PMID- 25781116 TI - Taxonomic review of the chironomid genus Cricotopus v.d. Wulp (Diptera: Chironomidae) from Australia: keys to males, females, pupae and larvae, description of ten new species and comments on Paratrichocladius Santos Abreu. AB - The Australian species of the Orthocladiinae genus Cricotopus Wulp (Diptera: Chironomidae) are revised for larval, pupal, adult male and female life stages. Eleven species, ten of which are new, are recognised and keyed, namely Cricotopus acornis Drayson & Cranston sp. nov., Cricotopus albitarsis Hergstrom sp. nov., Cricotopus annuliventris (Skuse), Cricotopus brevicornis Drayson & Cranston sp. nov., Cricotopus conicornis Drayson & Cranston sp. nov., Cricotopus hillmani Drayson & Cranston, sp. nov., Cricotopus howensis Cranston sp. nov., Cricotopus parbicinctus Hergstrom sp. nov., Cricotopus tasmania Drayson & Cranston sp. nov., Cricotopus varicornis Drayson & Cranston sp. nov. and Cricotopus wangi Cranston & Krosch sp. nov. Using data from this study, we consider the wider utility of morphological and molecular diagnostic tools in untangling species diversity in the Chironomidae. Morphological support for distinguishing Cricotopus from Paratrichocladius Santo-Abreu in larval and pupal stages appears lacking for Australian taxa and brief notes are provided concerning this matter. PMID- 25781117 TI - Review of the genus Abiskomyia Edwards (Diptera: Chironomidae: Orthocladiinae), with description of new taxa from the Russian Far East and bordering territories. AB - A systematic review of the genus Abiskomyia Edwards, 1937 is presented based on materials from the Russian Far East and bordering territories. Three new species: A. korbokhon sp. nov., A. levanidovi sp. nov., A. rivalis sp. nov. and one subspecies A. virgo orientalis subsp. nov. are described and figured. Emended generic diagnoses and keys to determination of adult males, pupae and fourth instar larvae of all known species and subspecies of the Abiskomyia of the Palaearctic region are provided. PMID- 25781118 TI - Taxonomic implications of morphological variation in three species of Trinomys (Rodentia: Echimyidae) from eastern Brazil. AB - Trinomys is a genus of terrestrial spiny rats from the Atlantic Forest, and three species occur in the state of Espirito Santo, eastern Brazil: T. gratiosus, T. paratus, and T. setosus. The levels of morphological variation within and among these species are virtually unknown, and their geographic ranges have not been properly assessed. These three species are externally very similar, hampering their identification in surveys and ecological studies that are not based on voucher specimens. We evaluated 162 specimens of Trinomys spp. from eastern Brazil, especially from the state of Espirito Santo, and used data from skulls, skins, and bacula to examine morphological variation and its taxonomic implications. We found extensive morphological variation in the skins and skulls even when diagnostic characters were examined, such as the number of dental lophs and bones contributing to the postorbital process. We also found variation in bacular shape among and within species, including polymorphism among individuals from the same population. The geographic range of each species in Espirito Santo was well defined: T. setosus occurred on the left (north) bank of the Doce River, and the other two species, T. gratiosus and T. paratus, occurred on the right (south) bank of this river; however, T. gratiosus was found at altitudes above 500 m, whereas T. paratus occurred below 580 m. Despite difficulties in species identification, the results of morphological and morphometric analyses are compatible with the current classification of these three species. In addition, the level of morphological variation found in specimens identified as T. g. panema--including types--falls within the range of T. g. gratiosus, confirming the taxonomic status of the former as a junior synonym of the latter. PMID- 25781119 TI - Two new stygobiotic species of Elaphoidella (Crustacea: Copepoda: Harpacticoida) with comments on geographical distribution and ecology of harpacticoids from caves in Thailand. AB - Elaphoidella thailandensis sp. nov. and E. jaesornensis sp. nov., collected during an investigation of cave-dwelling copepod fauna in the northern part of Thailand, are described and figured herein. The new species were collected from pools filled by percolating water from the unsaturated zone of a karstic aquifer in Phitsanulok and Lampang Provinces, respectively. Elaphoidella thailandensis, from Tham Khun cave, is distinguished from its congeners by the two-segmented endopod of pediger 1, the absence of endopod on pediger 4, and the setal formula 4, 5, 6 for the distal exopodal segment of pedigers 2-4. Elaphoidella jaesornensis, from Tham Phar Ngam cave, is distinguished from its most closely related species, E. namnaoensis Brancelj, Watiroyram & Sanoamuang, 2010, by the armature formula of the endopod of pedigers 2-5. The geographical distribution and ecology of Harpacticoida from Thai caves is also presented. PMID- 25781120 TI - Pseudopygmephorellus mazandaranicus sp. nov. (Acari: Heterostigmata: Pygmephoridae), phoretic on scarabaeid dung beetles (Coleoptera: Scarabaeidae) from Iran. AB - The mite species Pseudopygmephorellus mazandaranicus Katlav and Hajiqanbar sp. nov. (Acari: Prostigmata: Pygmephoridae) is described and illustrated from northern Iran. This new species was discovered phoretic on three different scarabaeid dung beetles: Onthophagus sp., Aphodius depressus (Kugelann, 1792), Aphodius varians Duftschmid, 1805. This finding presents the first record of the genus Pseudopygmephorellus Khaustov, 2008 from Asia. The host range/habitat and world-wide distribution of species of the genus Pseudopygmephorellus is reviewed and a key to world species of the genus is provided. PMID- 25781121 TI - Revision of the status of some genus-level water mite taxa in the families Pionidae Thor, 1900, Aturidae Thor, 1900, and Nudomideopsidae Smith, 1990 (Acari: Hydrachnidiae). AB - A number of changes to the status of genus group names in water mites are proposed to foster a more consistent and phylogenetically defensible approach to the ranking of taxa at this level of the classification. The water mite taxa Acercopsis Viets, 1926 (Pionidae: Tiphyinae), Madawaska Habeeb, 1954 (Pionidae: Foreliinae), Brachypodopsis Piersig, 1903, Cubanaxonopsis Orghidan & Gruia, 1981, Hexaxonopsis Viets, 1926, Paraxonopsis Motas & Tanasachi, 1947, Vicinaxonopsis Cook, 1974, Parabrachypoda Viets, 1929, and Ocybrachypoda Cook, 1974 (Aturidae: Axonopsinae), Ameribrachypoda Smith, 1991 (Aturidae: Aturinae), and Allomideopsis Smith, 1990 (Nudomideopsidae) are elevated in rank from subgenera to full genera to reflect current knowledge of their species diversity, morphological distinctness, relationships and apparent age. In light of the above changes in the subfamily Axonopsinae, the subgenera Kalobrachypoda Viets, 1929 and Navinaxonopsis Cook, 1967 are transferred from the genus Axonopsis to the genus Brachypodopsis, the subgenus Plesiobrachypoda Viets, 1942 is transferred from the genus Axonopsis to the genus Hexaxonopsis, and the species formerly placed in the subgenus Hemibrachypoda Viets, 1937 are transferred from the genus Brachypoda to the genus Parabrachypoda Viets, 1929, and Hemibrachypoda is placed in synonymy with Parabrachypoda. The family group taxa to which all of these genera belong are reviewed to provide context for the proposed changes. PMID- 25781122 TI - Redescription of Alitta succinea (Leuckart, 1847) and reinstatement of A. acutifolia (Ehlers, 1901) n. comb. based upon morphological and molecular data (Polychaeta: Nereididae). AB - The nereidid worm Alitta succinea (Leuckart, 1847), described from Western Germany, has been considered by some authors as a widespread and alien invasive species, or else as a group of morphologically indistinguishable species. Neither idea has yet been supported by critical taxonomic revisions of relevant material. Most characterizations of A. succinea were based upon a mixture of morphological features from specimens from the type locality and from other regions. Moreover, four species described from America are considered junior synonyms of A. succinea, including Nereis acutifolia Ehlers, 1901, described from the eastern tropical Pacific. The type material of the latter species has not been reviewed since its description. We re-examined type and topotype materials of A. succinea and N. acutifolia including atokous and epitokous specimens. In addition, newly collected specimens were used to evaluate genetic divergence between both species using the mitochondrial gene COI. Alitta succinea is redescribed from type material and specimens from Germany. We rejected the recent placement of the species in Neanthes and we transferred it to Alitta. Further, we refuse the synonymy of N. acutifolia with A. succinea due to morphological and molecular differences. Consequently, we regard Alitta acutifolia n. comb. as a valid species, and the supposed introduction and the alien status of A. succinea along the Mexican and Central American Pacific shores are rejected. PMID- 25781123 TI - Confocal microscopy refines generic concept of a problematic taxon: rediagnosis of the genus Neoprothrix and remarks on female anatomy of eriophyoids (Acari: Eriophyoidea). AB - Due to the higher resolution, confocal microscopy (CLSM) can be applied to refine the origin of tiny structures of the autofluorescent exoskeletons of microarthropods (mites in particular) which are hard to visualize using traditional differential interference contract light microscopy (DIC LM) and phase contrast light microscopy (PC LM). Three-dimensional (3D) reconstructions of the prodorsal shield topography of eriophyoid mites using Neoprothrix hibiscus Reis and Navia as a model, suggest that the structures originally treated as paired setae vi are two internal rod-like apodemes. Based on this, the genus Neoprothrix is excluded from the subfamily Prothricinae Amrine and transferred to the subfamily Sierraphytoptinae Keifer. Observations on partially cleared specimens of N. hibiscus showed that remnants of the central nervous system, paired glands and developing oocytes can be visualized using DIC LM and CLSM methods. New high quality microscope images are provided of recently described "flower-shaped" structures and two main components of yolk inclusions of the mature eggs inside the oviduct. PMID- 25781124 TI - A new species of Golinca Thomson (Coleoptera: Scarabaeidae: Cetoniinae): first record of the genus for Brazil. AB - Golinca trevisani Valois & Silva, new species (Coleoptera: Scarabaeidae: Cetoniinae: Trichiini: Incina) from Ouro Preto do Oeste, Rondonia, and Amazonas, Brazil is described, representing the first record of the genus Golinca for Brazil. Diagnosis, illustrations of key morphological characters, the first male genitalia description in the genus, and a key for identification of four species of Golinca are provided. PMID- 25781125 TI - On the occurrence of Varanus nebulosus (Gray, 1831) (Squamata: Varanidae) on Riau Archipelago, Indonesia. PMID- 25781126 TI - The genital area of Halacaridae (Acari), life stages and development of morphological characters and implication on the classification. AB - The genital region of juvenile and adult halacarid genera is described. Larvae are expected to be present in all, protonymphs at least in the majority of the genera. Two of the marine genera have three nymphal instars, in the others one or two nymphal instars are suppressed. Adults of marine species have one, two or three pairs of genital acetabula; intrageneric differences in the number of acetabula are present but rare. Derived from the number of perigenital setae and genital acetabula, in most genera it is the deutonymph which is suppressed, in a few others the tritonymph. Adults of species with two nymphal stages have either two or three pairs of acetabula, those with a single nymphal stage have either one or two pairs of acetabula. Two genera may lack the protonymphal stage, but more material is needed to prove the absence. The present-day classification is outlined and supplemented. Anomalohalacarus and Arenihalacarus are both assigned to the Anomalohalacarinae. The Halixodinae include Agaue, Bradyagaue and Halixodes, the knowledge of Australacarus and Colobocerasides is sparse, but they may have to be incorporated in the Halixodinae. The subfamily Halacarinae includes a single genus, namely Halacarus. PMID- 25781127 TI - A new genus and species of the leafhopper subtribe Paraboloponina from China (Hemiptera, Cicadellidae). AB - A new leafhopper genus and species Forficus maculatus Qu gen. nov., sp. nov. of the subtribe Paraboloponina (Deltocephalinae, Drabescini) are described from China. A checklist to the Paraboloponina from China is given and a key to genera is provided. PMID- 25781128 TI - An annotated checklist of the Recent non-marine ostracods (Ostracoda: Crustacea) from Italy. AB - We present an updated checklist of non-marine ostracods from Italy. Data were obtained from the published literature up to April 2013 and new collections carried out in 18 out of 20 Italian regions. Altogether, 1665 ostracod samples were collected from 1241 new sites visited between 1981 and 2013. Sites were selected to encompass the most widespread types of freshwater aquatic habitats (i.e., pools, ponds, peat bogs, springs and streams, etc.). This field study led to the identification of 89 ostracod species. Five additional taxa remained at the generic level because only few (juvenile) individuals were available or the material was damaged. Of particular interest is the occurrence of four species new to Italy: Candonocypris novaezelandiae, Eucypris elongata, Ilyocypris getica and I. hartmanni. In addition, three putative new species (Pseudolimnocythere sp., Candona sp.1 and Eucypris sp.1) are left in open nomenclature. After synonymising several species and removing invalid taxa reported in the literature, the updated checklist now includes 152 species and 5 taxa identified at supraspecific level, belonging to 57 genera and 12 families (Candonidae, Cyprididae, Cytherideidae, Darwinulidae, Ilyocyprididae, Notodromadidae, Limnocytheridae, Leptocytheridae, Loxochonchidae, Hemicytheridae, Xestoleberididae and Entocytheridae). For each species, its distribution in Italy and its bibliographic records (including synonyms) for Italy are provided. PMID- 25781129 TI - A new late Eocene Bicornucythere species (Ostracoda, Crustacea) from Myanmar, and its significance for the evolutionary history of the genus. AB - The ostracode genus Bicornucythere (Ostracoda, Crustacea) is abundant in modern day eutrophic marine bays, and is widely distributed in estuaries and inner bays throughout East Asia, including in China, Korea, Japan, and the Russian Far East. The evolutionary history of Bicornucythere is poorly understood. Here, we report on a new species of Bicornucythere (Bicornucythere concentrica sp. nov.) from the upper Eocene Yaw Formation in the Central Myanmar Basin. The oldest previously known Bicornucythere taxon, Bicornucythere secedens, was reported from lower Miocene strata in India, although a molecular phylogeny suggests that the genus first appeared in the Late Cretaceous. Bicornucythere concentrica sp. nov. is at least 10.9 million years older than the earliest known B. secedens. The new species occurs with Ammonia subgranulosa, a benthic foraminifer, an association that is representative of brackish water conditions in modern Asian bays. Our findings indicate that extant genera have inhabited Asian bays since the late Eocene. The paleobiogeography of Bicornucythere indicates that the taxon was dispersed onto Indian coasts during the collision between the Indian and Eurasian plates. PMID- 25781130 TI - A new alcyonacean octocoral (Cnidaria, Anthozoa, Octocorallia) from Chilean fjords. AB - A new species, Swiftia comauensis, is described from Chile. It occurs in shallow waters from 18 to 59 m in the Patagonian fjord region and seems to be endemic to the northern part of the region. The species is characterized by having straggly colonies with sparse branching and long drooping branches, prominent polyp mounds, and long, thin spindles; the colonies are bright orange with pale yellow polyp mounds. A sharp decline in colony abundance was observed between 2003 and 2013, and in January 2014 a proposal was submitted to the IUCN for the addition of this taxon to the Red List of Threatened Species. PMID- 25781131 TI - A new species of Acyrthosiphon (Hemiptera, Aphididae) from France and Spain. AB - A new species in one of the largest genera of Macrosiphini (Hemiptera, Aphididae), Acyrthosiphon pilosum sp. n., is described from apterous and alate viviparous females and oviparous females from French and Spanish Mediterranean localities, living on species of Ononis (Fabaceae), mainly O. natrix. The new species is characterized by the presence of many accessory setae on the ultimate rostral segment, and usually five setae on the first tarsal segments, a combination that is not present in any other known Acyrthosiphon species; in addition marginal tubercles are present on prothorax and several of abdominal segments 2-5. PMID- 25781132 TI - The number of zoeal stages in larval development of Nihonotrypaea petalura (Stimpson, 1860) (Decapoda: Axiidea: Callianassidae) from Russian waters of the Sea of Japan. AB - Zoeal stages of the mud shrimp Nihonotrypaea petalura (Stimpson, 1860) (Decapoda: Axiiidea: Callianassidae) inhabiting Peter the Great Bay (Sea of Japan) is described and illustrated from the larvae reared in the laboratory individually. The development included seven zoeal stages before molting to the megalopa. At 22 23 degrees C the first megalopa was attained 26 days after hatching. A range of the number of zoeal stages in the family Callianassidae is analyzed. The possibility of variation of the number of zoeal stages of burrowing shrimps in different populations of the same species and/or under different laboratory conditions is discussed. PMID- 25781133 TI - Taxonomic review of four western Atlantic dendrochirotids (Holothuroidea) with the description of a new Brazilian cucumariid species and designation of neotypes. AB - In this paper, we propose the reassignment of three western Atlantic species of the order Dendrochirotida to the family Sclerodactylidae (Euthyonidiella occidentalis comb. nov., Euthyonidiella arenicola comb. nov., and Thandarum manoelina comb. nov.) with a discussion on the classification of the dendrochirotids based on the morphology of the calcareous ring. We also propose the synonymization of Euthyonidiella dentata with Euthyonidiella occidentalis comb. nov., designate a neotype for this species and for Thandarum manoelina, and describe a new species of the genus Cucumaria from Brazil. PMID- 25781134 TI - Revalidation of Natrix clerki Wall, 1925, an overlooked species in the genus Amphiesma Dumeril, Bibron & Dumeril, 1854 (Squamata: Natricidae). AB - Natrix clerki Wall, 1925, previously known from its sole holotype and considered a synonym of Amphiesma parallelum (Boulenger, 1890), is resurrected in the genus Amphiesma on the basis of the analysis of morphological variation in 28 specimens of "Amphiesma parallelum" auctorum, plus six living, unvouchered specimens discovered in Arunachal Pradesh and Nagaland, India, and one vouchered specimen from Talle Valley in Arunachal Pradesh. Specimens from northeast India (Nagaland), northern Myanmar, and China (Yunnan), previously identified as Amphiesma parallelum either in the literature or in museum's catalogues, are also here referred to A. clerki. The holotype of Amphiesma clerki is redescribed. As a consequence, the definition of Amphiesma parallelum is modified. A. parallelum inhabits the Khasi Hills and Naga Hills in Northeast India, whereas A. clerki has a wider range in the Eastern Himalayas, northern Myanmar and Yunnan (China). Amphiesma clerki differs from A. parallelum by its longer tail, dorsal scales more strongly keeled, scales of the first dorsal scale row strongly keeled vs. smooth, a postocular streak not interrupted at the level of the neck, and a much more vivid pattern on a darker background colour. Characters of species of the Amphiesma parallelum group, i.e. A. clerki, A. parallelum, A. bitaeniatum, A. platyceps and A. sieboldii are compared. A key to this group is provided. PMID- 25781135 TI - New species of pollen wasps Paramasaris fernandae sp. nov. (Hymenoptera, Vespidae, Masarinae) from a rain forest locality in Brazilian Amazonia. AB - Paramasaris fernandae Silveira, sp. nov. is described from the Brazilian state of Para, and its affinities with other species in the genus are discussed. Record of this new species greatly expands geographical range of occurrences for Paramasaris Cameron as a whole, and in a kind of forest habitat unusual for the group. PMID- 25781136 TI - Water mites of the genus Unionicola Haldeman, 1842 (Acari, Hydrachnidia, Unionicolidae) in Russia. AB - This study presents a detailed taxonomic review of water mites of the genus Unionicola Haldeman, 1842 (Hygrobatoidea: Unionicolidae) found in the fauna of Russia during the long-term survey period of 1969-2013. The review includes (re)descriptions and illustrations of 21 Unionicola species found in this country: Unionicola intermedia (Koenike, 1882), U. crassipes (O.F. Muller, 1776), U. rossica sp.n., U. figuralis (Koch, 1836), U. gracilipalpis (Viets, 1908), U. markovensis Tuzovskij, 1990, U. minor (Soar, 1900), U. hankoi Szalay, 1927, U. aculeata (Koenike, 1890), U. aculeatella sp.n., U. bonzi (Claparede, 1869), U. inusitata Koenike, 1914, U. rezvoi Sokolow, 1931, U. samaraensis sp.n., U. setipella sp.n., U. setipes Sokolow, 1931, U. tricuspis (Koenike, 1895), U. japonensis Viets, 1933, U. primoryensis sp.n., U. ypsilophora (Bonz, 1783), U. arcuata (Wolcott, 1898). A key is presented for the Unionicola species of Russia based on males and females. PMID- 25781137 TI - Review of the genus Parerigone Brauer (Diptera: Tachinidae) with five new species from China. AB - The genus Parerigone (Diptera, Tachinidae) is reviewed. Five new species from China, P. atrisetosa sp. nov., P. flava sp. nov., P. flavisquama sp. nov., P. laxifrons sp. nov. and P. wangi sp. nov., are described and illustrated. Parerigone flavihirta (Chao & Sun) is proposed as a new synonym of P. takanoi Mesnil. Diagnosis of species examined and a key to the 15 species of Parerigone are provided. PMID- 25781138 TI - Three new species of Anatkina Young (Hemiptera: Cicadellidae: Cicadellini) from China, with a key and checklist of known Chinese species of the genus. AB - Three new species of the genus Anatkina Young, 1986 from China are described and illustrated: A. leishanensis sp. nov., A. alata sp. nov. and A. zhangi sp. nov. The type specimens of the new species are deposited in the Institute of Entomology, Guizhou University, Guiyang, China. In this paper, A. reticulosa Kuoh, 1993 and A. basimacula Kuoh, 1993 are placed as junior synonyms of A. infecta (Distant, 1908) and A. vespertinula (Breddin, 1903), respectively; A. inflammata (Distant, 1908) is recorded as new for China. A key and checklist of all Chinese species of the genus are provided. PMID- 25781139 TI - A new species of Japanagromyza Sasakawa (Diptera: Agromyzidae) from the Brazilian Amazon with notes on biology. AB - Japanagromyza sasakawai sp. n. is described from the Brazilian Amazon, based on the male, female, third instar larva and puparium. This species is a leaf-miner of Terminalia catappa L. (Combretaceae), which is an introduced plant from the Old World tropics used in Brazil as an ornamental. The male aedeagus of J. sasakawai sp. n. differs from other species mainly in having the mesophallus covered with many spine-like processes. This is the third record of Japanagromyza Sasakawa in Brazil and first in the Brazilian Amazon. The key to Neotropical species of Japanagromyza by Sousa & Couri (2014) is modified to include this new species. PMID- 25781140 TI - New species of Chaetozone and Tharyx (Polychaeta: Cirratulidae) from the Alaskan and Canadian Arctic and the Northeastern Pacific, including a description of the lectotype of Chaetozone setosa Malmgren from Spitsbergen in the Norwegian Arctic. AB - Eight new species of cirratulid polychaetes of the genus Chaetozone from the Alaskan (Beaufort Sea) and Canadian Arctic (Baffin Island, Baffin Bay, Labrador, Hudson Strait, and Hudson Bay) and the Northeastern Pacific are reported together with two new species of Tharyx from the Alaskan Beaufort Sea and the Strait of Juan de Fuca. The new species of Chaetozone and Tharyx are compared with related species; distinct species groups within these genera are discussed. A redescription of C. setosa Malmgren, 1867, the type species of the genus from Spitsbergen, based on a lectotype and associated paralectotypes designated by the late Dr. Mary E. Petersen is presented. A review of characters important in the taxonomy of the genera Chaetozone and Tharyx is presented. A key to species of Chaetozone from the Northeastern Pacific and North American Arctic is provided. PMID- 25781141 TI - A review of the genus Elephantomyia Osten Sacken from China, with descriptions of two new species (Diptera, Limoniidae). AB - The genus Elephantomyia from China is reviewed. Two species, E. laohegouensis sp. nov. and E. tianmushana sp. nov., are described as new to science. One species, E. inulta Alexander, 1938, is recorded for China for the first time. Seven known Chinese species/subspecies are redescribed and illustrated. A key to the species of the genus Elephantomyia from China is given. PMID- 25781142 TI - Contribution to the knowledge of Patagonia, Argentina: redescription of the genus Xenogenus Berg 1883 (Hemiptera: Heteroptera: Rhopalidae) and description of immature stages of Xenogenus gracilis Reed, 1899. AB - This is a review of Xenogenus Berg 1883 a Neotropical genus with two species: X. gracilis Reed (1899) and X. picturatum Berg 1883. Males of X. picturatum, males and females of X. gracilis are redescribed and illustrated; instars II-V of X. gracilis are described and illustrated. The host plant and new record data are also given for the latter. PMID- 25781143 TI - DNA barcoding and regional diversity of understudied Micropeplinae (Coleoptera: Staphylinidae) in Southwest China: phylogenetic implications and a new Micropeplus from Mount Emei. AB - Extensive litter sampling at eight forested localities in Yunnan and Sichuan detected 381 specimens of Micropeplinae rove beetles. DNA barcoding data from 85 representative specimens were analysed to delimit species and infer their relationships. Statistical methods were implemented to assess regional species diversity of understudied Micropeplinae. The total number of sampled Micropeplinae species varied between 14 and 17, depending on a splitting versus lumping approach for allopatric populations. A single Micropeplinae species was sampled in six of eight studied localities, three species were found on Mount Gongga, while ten species were discovered on hyperdiverse Mount Emei in Sichuan. All Micropeplinae specimens from our samples belong either to the genus Cerapeplus, or to three other inclusive groups temporarily retained inside Micropeplus sensu lato. Each of the three groups potentially represents a separate genus: tesserula group, sculptus group and Micropeplus sensu stricto. A new species Micropeplus jason sp. n. from Mount Emei in Sichuan is described. Numerous illustrations introduce regional fauna and clarify the discussed morphological characters. PMID- 25781144 TI - DAVID A. RIDER & HARRY BRAILOVSKY (2014) Pentamyrmexini, a new tribe for Pentamyrmex spinosus, a remarkable new genus and species of Pentatomidae (Hemiptera: Heteroptera) from Thailand . Zootaxa, 3895 (4): 595-600. PMID- 25781145 TI - Venous Thromboembolism in Cancer: Frequently Asked Questions When Guidelines are Inconclusive. AB - Management of Venous thromboembolism (VTE) in cancer patients is difficult when guidelines are inconclusive. To share a reasonable and homogeneous behavior in such circumstances, four issues, which are felt as problematic by oncologists and surgeons, have been selected; all were uncovered or only partially covered by current guidelines. Results from the literature and author's specific experience in the field were utilized to suggest reasonable solutions to the raised questions. The reported experience is the first to provide real-world management guidance for VTE in cancer patients. The effort of putting together literature review and author's experience brought to the adoption of a common behavior. PMID- 25781147 TI - Neutrophil-lymphocyte ratio as predictor of mortality and morbidity in cardiovascular surgery: a systematic review. AB - BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is an emerging biomarker of inflammation and predicts poorer outcome in cancer surgery. The prognostic value of NLR in cardiovascular surgery is unclear. METHODS: Systematic review and meta analysis of studies of in cardiovascular surgical patients were conducted to assess the role of perioperative NLR in predicting post-operative mortality and morbidity. Electronic searches were conducted on Ovid Medline, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systemic Reviews for all prospective clinical studies reporting on NLR and post-operative morbidity and mortality in cardiovascular surgical patient population. Our primary end point was all-cause post-operative mortality and the secondary end point was post-operative morbidity. Mortality outcome from prospective studies were pooled for a meta-analysis using a random-effect model. RESULTS: Of the 999 citations identified, five studies with 3487 patients met the inclusion criteria. In a pooled analysis of three prospective studies of 3108 patients, a preoperative increase in NLR (>3.3 in cardiac surgery, >5 in vascular surgery) was associated with increased mortality at a mean follow-up of 34.8 months (hazard ratio 1.85, 95% confidence interval 1.46-2.36; P < 0.00001). Raised NLR value was also associated with increased cardiac mortality, amputation in vascular operations and raised risk of post-operative re-intubation. CONCLUSIONS: Elevated NLR were associated with increased long-term mortality and morbidity after major cardiac and vascular surgery. NLR may guide perioperative management and risk-stratification of patients. PMID- 25781148 TI - Blood pressure and the natural diets: more to learn. PMID- 25781149 TI - Aqueous proton transfer across single-layer graphene. AB - Proton transfer across single-layer graphene proceeds with large computed energy barriers and is therefore thought to be unfavourable at room temperature unless nanoscale holes or dopants are introduced, or a potential bias is applied. Here we subject single-layer graphene supported on fused silica to cycles of high and low pH, and show that protons transfer reversibly from the aqueous phase through the graphene to the other side where they undergo acid-base chemistry with the silica hydroxyl groups. After ruling out diffusion through macroscopic pinholes, the protons are found to transfer through rare, naturally occurring atomic defects. Computer simulations reveal low energy barriers of 0.61-0.75 eV for aqueous proton transfer across hydroxyl-terminated atomic defects that participate in a Grotthuss-type relay, while pyrylium-like ether terminations shut down proton exchange. Unfavourable energy barriers to helium and hydrogen transfer indicate the process is selective for aqueous protons. PMID- 25781150 TI - The crystal structure of Z-Gly-Aib-Gly-Aib-OtBu. AB - The synthetic peptide Z-Gly-Aib-Gly-Aib-OtBu was dissolved in methanol and crystallized in a mixture of ethyl acetate and petroleum ether. The crystals belong to the centrosymmetric space group P4/n that is observed less than 0.3% in the Cambridge Structural Database. The first Gly residue assumes a semi-extended conformation (phi +/-62 degrees , psi ?131 degrees ). The right-handed peptide folds in two consecutive beta-turns of type II' and type I or an incipient 310 helix, and the left-handed counterpart folds accordingly in the opposite configuration. In the crystal lattice, one molecule is linked to four neighbors in the ab-plane via hydrogen bonds. These bonds form a continuous network of left and right-handed molecules. The successive ab-planes stack via apolar contacts in the c-direction. An ethyl acetate molecule is situated on and close to the fourfold axis. PMID- 25781151 TI - Pediatric drug development programs for type 2 diabetes: A review. AB - Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)-approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided. PMID- 25781152 TI - Development of a capillary electrophoresis method with direct UV detection for the analysis of thiodiglycol and its oxidation products. AB - A novel method based on CE with precolumn derivatization and direct UV detection for the determination of thiodiglycol (TDG), TDG sulfoxide, and TDG sulfone in water samples was developed. The lack of a UV chromophore of target analytes was overcome by derivatization with phthalic anhydride. The reactant concentrations, as well as the derivatization dependence on heating temperature and time, were carefully investigated. The baseline separation of three derivatives was achieved in less than 8 min by applying a simple BGE composed of a 30 mM borate buffer at pH 8.5. Several parameters affecting the separation efficiency (buffer pH and concentration, capillary temperature, and applied voltage) were evaluated. Calibration curves of all compounds showed good linear correlations (R(2) > 0.9994). The LODs of the TDG and its oxidation products were in the range of 98 154 ng/mL. The precision tests resulted in RSDs for migration times and peak areas of less than 1.2 and 3.6%, respectively. The developed method was successfully applied for the analysis of TDG and oxidation products in seawater, utilizing the carbon aerogel-based adsorbents for sample purification and concentration. Additionally, the method has the potential to be transformed into a portable CE format. PMID- 25781153 TI - The interactions between mitochondria and sarcoplasmic reticulum and the proteome characterization of mitochondrion-associated membrane from rabbit skeletal muscle. AB - To obtain a comprehensive understanding of proteins involved in mitochondrion sarcoplasmic reticulum (SR) linking, a catalog of proteins from mitochondrion associated membrane (MAM) of New Zealand white rabbit skeletal muscle were analyzed by an optimized shotgun proteomic method. The membrane fractions were prepared by differential centrifugation and separated by 1D electrophoresis followed by a highly reproducible, automated LC-MS/MS on the hybrid linear ion trap (LTQ)-Orbitrap mass spectrometer. By integrating as low as 1% false discovery rate as one of the features for quality control method, 459 proteins were identified from both of the two independent MAM preparations. Protein pI value, molecular weight range, and transmembrane region were calculated using bioinformatics softwares. One hundred one proteins were recognized as membrane proteins. This protein database suggested that the MAM preparations composed of proteins from mitochondrion, SR, and transverse-tubule. This result indicated mitochondria physically linked with SR in rabbit skeletal muscle, voltage dependent anion channel 1 (VDAC1), VDAC2, and VDAC3 might participate in formation of the tethers between SR and mitochondria. PMID- 25781154 TI - Decreases in mitochondrial reactive oxygen species initiate GABA(A) receptor mediated electrical suppression in anoxia-tolerant turtle neurons. AB - Anoxia induces hyper-excitability and cell death in mammalian brain but in the anoxia-tolerant western painted turtle (Chrysemys picta bellii) neuronal electrical activity is suppressed (i.e. spike arrest), adenosine triphosphate (ATP) consumption is reduced, and cell death does not occur. Electrical suppression is primarily the result of enhanced gamma-aminobutyric acid (GABA) transmission; however, the underlying mechanism responsible for initiating oxygen sensitive GABAergic spike arrest is unknown. In turtle cortical pyramidal neurons there are three types of GABA(A) receptor-mediated currents: spontaneous inhibitory postsynaptic currents (IPSCs), giant IPSCs and tonic currents. The aim of this study was to assess the effects of reactive oxygen species (ROS) scavenging on these three currents since ROS levels naturally decrease with anoxia and may serve as a redox signal to initiate spike arrest. We found that anoxia, pharmacological ROS scavenging, or inhibition of mitochondrial ROS generation enhanced all three types of GABA currents, with tonic currents comprising ~50% of the total current. Application of hydrogen peroxide inhibited all three GABA currents, demonstrating a reversible redox-sensitive signalling mechanism. We conclude that anoxia-mediated decreases in mitochondrial ROS production are sufficient to initiate a redox-sensitive inhibitory GABA signalling cascade that suppresses electrical activity when oxygen is limited. This unique strategy for reducing neuronal ATP consumption during anoxia represents a natural mechanism in which to explore therapies to protect mammalian brain from low-oxygen insults. PMID- 25781155 TI - Urodynamic catheter moisture sensor: A novel device to improve leak point pressure detection. AB - AIMS: High-quality urodynamic studies in patients with neurogenic lower urinary tract dysfunction are important, as UDS may be the only reliable gauge of potential risk for upper tract deterioration and the optimal tool to guide lower urinary tract management. Reliance on direct visualization of leakage during typical UDS remains a potential source of error. METHODS: Given the necessity of accurate leak point pressures, we developed a wireless leak detection sensor to eliminate the need for visual inspection during UDS. RESULTS: A mean decrease in detrusor leak point pressure of 3 cm/H2 0 and a mean 11% decrease in capacity at leakage was observed when employing the sensor compared to visual inspection in children undergoing two fillings during a single UDS session. CONCLUSION: Removing the visual inspection component of UDS may improve accuracy of pressure readings. Neurourol. Urodynam. 35:647-648, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25781156 TI - Noninvasive in vivo determination of residual strains and stresses. AB - Vascular growth and remodeling during embryonic development are associated with blood flow and pressure induced stress distribution, in which residual strains and stresses play a central role. Residual strains are typically measured by performing in vitro tests on the excised vascular tissue. In this paper, we investigated the possibility of estimating residual strains and stresses using physiological pressure-radius data obtained through in vivo noninvasive measurement techniques, such as optical coherence tomography or ultrasound modalities. This analytical approach first tested with in vitro results using experimental data sets for three different arteries such as rabbit carotid artery, rabbit thoracic artery, and human carotid artery based on Fung's pseudostrain energy function and Delfino's exponential strain energy function (SEF). We also examined residual strains and stresses in the human swine iliac artery using the in vivo experimental ultrasound data sets corresponding to the systolic-to-diastolic region only. This allowed computation of the in vivo residual stress information for loading and unloading states separately. Residual strain parameters as well as the material parameters were successfully computed with high accuracy, where the relative errors are introduced in the range of 0 7.5%. Corresponding residual stress distributions demonstrated global errors all in acceptable ranges. A slight discrepancy was observed in the computed reduced axial force. Results of computations performed based on in vivo experimental data obtained from loading and unloading states of the artery exhibited alterations in material properties and residual strain parameters as well. Emerging noninvasive measurement techniques combined with the present analytical approach can be used to estimate residual strains and stresses in vascular tissues as a precursor for growth estimates. This approach is also validated with a finite element model of a general two-layered artery, where the material remodeling states and residual strain generation are investigated. PMID- 25781157 TI - A novel laccase from fresh fruiting bodies of the wild medicinal mushroom Tricholoma matsutake. AB - The knowledge about biological activities of constituents from medicinal mushrooms belonging to the genus Tricholoma is limited. A 59-kDa laccase has now been purified from fresh fruiting bodies of the mushroom Tricholoma matsutake. The purification protocol entailed ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography on CM cellulose, affinity chromatography on ConA-Sepharose, and gel filtration by fast protein liquid chromatography on Superdex 75. Of the various affinity and ion exchange chromatographic media employed, the laccase bound only on Con A Sepharose. The activity of the laccase did not undergo major changes over the temperature range 20-80 degrees C. However, all activity vanished following exposure to 100 degrees C for 10 minutes. The enzyme activity varied only slightly over the pH range 3-5, with the optimal pH of 5, but exhibited a precipitous decline when the pH was increased to 6, and was undetectable at pH 8 and 9. The laccase showed activity in the decolorization of azo dyes without a mediator. Its N-terminal sequence demonstrated only slight resemblance to those of other mushroom laccases. The newly described laccase is distinctive from the previously isolated Tricholoma mushroom laccases in a number of aspects. PMID- 25781158 TI - Activity and kinetic properties of phosphotransacetylase from intestinal sulfate reducing bacteria. AB - Phosphotransacetylase activity and the kinetic properties of the enzyme from intestinal sulfate-reducing bacteria Desulfovibrio piger and Desulfomicrobium sp. has never been well-characterized and has not been studied yet. In this paper, the specific activity of phosphotransacetylase and the kinetic properties of the enzyme in cell-free extracts of both D. piger Vib-7 and Desulfomicrobium sp. Rod 9 intestinal bacterial strains were presented at the first time. The microbiological, biochemical, biophysical and statistical methods in this work were used. The optimal temperature and pH for enzyme reaction was determined. Analysis of the kinetic properties of the studied enzyme was carried out. Initial (instantaneous) reaction velocity (V0), maximum amount of the product of reaction (Pmax), the reaction time (half saturation period, tau) and maximum velocity of the phosphotransacetylase reaction (Vmax) were defined. Michaelis constants (Km) of the enzyme reaction (3.36 +/- 0.35 mM for D. piger Vib-7, 5.97 +/- 0.62 mM for Desulfomicrobium sp. Rod-9) were calculated. The studies of the phosphotransacetylase in the process of dissimilatory sulfate reduction and kinetic properties of this enzyme in intestinal sulfate-reducing bacteria, their production of acetate in detail can be perspective for clarification of their etiological role in the development of the humans and animals bowel diseases. These studies might help in predicting the development of diseases of the gastrointestinal tract, by providing further details on the etiology of bowel diseases which are very important for the clinical diagnosis of these disease types. PMID- 25781159 TI - Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment. AB - Several relations between cytokines and pathogenesis of diabetes are reviewed. In type 1 and type 2 diabetes an increased synthesis is observed and as well as the release of pro-inflammatory cytokines, which cause the damage of pancreatic islet cells and, in type 2 diabetes, the development of the insulin resistance. That process results in the disturbed balance between pro-inflammatory and protective cytokines. Pro-inflammatory cytokines such as interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), as well as recently discovered pancreatic derived factor PANDER are involved in the apoptosis of pancreatic beta-cells. Inside beta-cells, cytokines activate different metabolic pathways leading to the cell death. IL-1beta activates the mitogen-activated protein kinases (MAPK), affects the nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB) and activates the inducible nitric oxide synthase (iNOS). TNF-alpha and IFN-gamma in a synergic way activate calcium channels, what leads to the mitochondrial dysfunction and activation of caspases. Neutralization of pro-inflammatory cytokines, especially interleukin 1beta with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1beta antibodies might cause the extinction of the inflammatory process of pancreatic islets, and consequently normalize concentration of glucose in blood and decrease the insulin resistance. In type 1 diabetes interleukin-6 participates in regulation of balance between Th17 and regulatory T cells. In type 2 diabetes and obesity, the long-duration increase of IL-6 concentration in blood above 5 pg/ml leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in the insulin resistance in cells of the skeletal muscles, liver and adipose tissue. PMID- 25781160 TI - Disrupting protein expression with Peptide Nucleic Acids reduces infection by obligate intracellular Rickettsia. AB - Peptide Nucleic Acids (PNAs) are single-stranded synthetic nucleic acids with a pseudopeptide backbone in lieu of the phosphodiester linked sugar and phosphate found in traditional oligos. PNA designed complementary to the bacterial Shine Dalgarno or start codon regions of mRNA disrupts translation resulting in the transient reduction in protein expression. This study examines the use of PNA technology to interrupt protein expression in obligate intracellular Rickettsia sp. Their historically intractable genetic system limits characterization of protein function. We designed PNA targeting mRNA for rOmpB from Rickettsia typhi and rickA from Rickettsia montanensis, ubiquitous factors important for infection. Using an in vitro translation system and competitive binding assays, we determined that our PNAs bind target regions. Electroporation of R. typhi and R. montanensis with PNA specific to rOmpB and rickA, respectively, reduced the bacteria's ability to infect host cells. These studies open the possibility of using PNA to suppress protein synthesis in obligate intracellular bacteria. PMID- 25781161 TI - Comparative analysis of genomics and proteomics in Bacillus thuringiensis 4.0718. AB - Bacillus thuringiensis is a widely used biopesticide that produced various insecticidal active substances during its life cycle. Separation and purification of numerous insecticide active substances have been difficult because of the relatively short half-life of such substances. On the other hand, substances can be synthetized at different times during development, so samples at different stages have to be studied, further complicating the analysis. A dual genomic and proteomic approach would enhance our ability to identify such substances, and particularily using mass spectrometry-based proteomic methods. The comparative analysis for genomic and proteomic data have showed that not all of the products deduced from the annotated genome could be identified among the proteomic data. For instance, genome annotation results showed that 39 coding sequences in the whole genome were related to insect pathogenicity, including five cry genes. However, Cry2Ab, Cry1Ia, Cytotoxin K, Bacteriocin, Exoenzyme C3 and Alveolysin could not be detected in the proteomic data obtained. The sporulation-related proteins were also compared analysis, results showed that the great majority sporulation-related proteins can be detected by mass spectrometry. This analysis revealed Spo0A~P, SigF, SigE(+), SigK(+) and SigG(+), all known to play an important role in the process of spore formation regulatory network, also were displayed in the proteomic data. Through the comparison of the two data sets, it was possible to infer that some genes were silenced or were expressed at very low levels. For instance, found that cry2Ab seems to lack a functional promoter while cry1Ia may not be expressed due to the presence of transposons. With this comparative study a relatively complete database can be constructed and used to transform hereditary material, thereby prompting the high expression of toxic proteins. A theoretical basis is provided for constructing highly virulent engineered bacteria and for promoting the application of proteogenomics in the life sciences. PMID- 25781162 TI - Contribution of HIV-Tat protein to HIV-sequelae (part 1). PMID- 25781163 TI - Who benefits from government healthcare subsidies? An assessment of the equity of healthcare benefits distribution in China. AB - BACKGROUND: Improving the equitable distribution of government healthcare subsidies (GHS), particularly among low-income citizens, is a major goal of China's healthcare sector reform in China. OBJECTIVES: This study investigates the distribution of GHS in China between socioeconomic populations at two different points in time, examines the comparative distribution of healthcare benefits before and after healthcare reforms in Northwest China, compares the parity of distribution between urban and rural areas, and explores factors that influence equitable GHS distribution. METHODS: Benefit incidence analysis of GHS progressivity was performed, and concentration and Kakwani indices for outpatient, inpatient, and total healthcare were calculated. Two rounds of household surveys that used multistage stratified samples were conducted in 2003 (13,564 respondents) and 2008 (12,973 respondents). Data on socioeconomics, healthcare payments, and healthcare utilization were collected using household interviews. RESULTS: High-income individuals generally reap larger benefits from GHS, as reflected by positive concentration indices, which indicates a regressive system. Concentration indices for inpatient care were 0.2199 (95% confidence interval [CI], 0.0829 to 0.3568) and 0.4445 (95% CI, 0.3000 to 0.5890) in 2002 (urban vs. rural, respectively), and 0.3925 (95% CI, 0.2528 to 0.5322) and 0.4084 (95% CI, 0.2977 to 0.5190) in 2007. Outpatient healthcare subsidies showed different distribution patterns in urban and rural areas following the redesign of rural healthcare insurance programs (urban vs. rural: 0.1433 [95% CI, 0.0263 to 0.2603] and 0.3662 [95% CI, 0.2703 to 0.4622] in 2002, respectively; 0.3063 [95% CI, 0.1657 to 0.4469] and -0.0273 [95% CI, -0.1702 to 0.1156] in 2007). CONCLUSIONS: Our study demonstrates an inequitable distribution of GHS in China from 2002 to 2007; however, the inequity was reduced, especially in rural outpatient services. Future healthcare reforms in China should not only focus on expanding the coverage, but also on improving the equity of distribution of healthcare benefits. PMID- 25781164 TI - Ascites bacterial burden and immune cell profile are associated with poor clinical outcomes in the absence of overt infection. AB - Bacterial infections, most commonly spontaneous bacterial peritonitis in patients with ascites, occur in one third of admitted patients with cirrhosis, and account for a 4-fold increase in mortality. Bacteria are isolated from less than 40% of ascites infections by culture, necessitating empirical antibiotic treatment, but culture-independent studies suggest bacteria are commonly present, even in the absence of overt infection. Widespread detection of low levels of bacteria in ascites, in the absence of peritonitis, suggests immune impairment may contribute to higher susceptibility to infection in cirrhotic patients. However, little is known about the role of ascites leukocyte composition and function in this context. We determined ascites bacterial composition by quantitative PCR and 16S rRNA gene sequencing in 25 patients with culture-negative, non-neutrocytic ascites, and compared microbiological data with ascites and peripheral blood leukocyte composition and phenotype. Bacterial DNA was detected in ascitic fluid from 23 of 25 patients, with significant positive correlations between bacterial DNA levels and poor 6-month clinical outcomes (death, readmission). Ascites leukocyte composition was variable, but dominated by macrophages or T lymphocytes, with lower numbers of B lymphocytes and natural killer cells. Consistent with the hypothesis that impaired innate immunity contributes to susceptibility to infection, high bacterial DNA burden was associated with reduced major histocompatibility complex class II expression on ascites (but not peripheral blood) monocytes/macrophages. These data indicate an association between the presence of ascites bacterial DNA and early death and readmission in patients with decompensated cirrhosis. They further suggest that impairment of innate immunity contributes to increased bacterial translocation, risk of peritonitis, or both. PMID- 25781165 TI - Surgical management for thoracic spinal tuberculosis posterior only versus anterior video-assisted thoracoscopic surgery. AB - STUDY DESIGN: A comparable retrospective study. OBJECT: To compare the clinical outcomes of surgical treatment by posterior only and anterior video-assisted thoracoscopic surgery for thoracic spinal tuberculosis (TSTB). METHOD: 145 patients with TSTB treated by two different surgical procedures in our institution from June 2001 to June 2014 were studied. All cases were retrospectively analyzed and divided into two groups according to the given treatments: 75 cases (32F/43M) in group A performed single-stage posterior debridement, transforaminal thoracic interbody fusion and instrumentation, and 70 cases (30F/40M) in group B underwent anterior video-assisted thoracoscopic surgery (VATS). Clinical and radiographic results in the two groups were analyzed and compared. RESULTS: Patients in group A and B were followed up for an average of 4.6+/-1.8, 4.4+/-1.2 years, respectively. There was no statistically significant difference between groups in terms of the operation time, blood loss, bony fusion, neurological recovery and the correction angle of kyphotic deformity (P>0.05). Fewer pulmonary complications were observed in group A. Good clinical outcomes were achieved in both groups. CONCLUSIONS: Both the anterior VATS and posterior approaches can effectively treat thoracic tuberculosis. Nevertheless, the posterior approach procedure obtained less morbidity and complications than the other. PMID- 25781166 TI - Quantifying patterns of change in marine ecosystem response to multiple pressures. AB - The ability to understand and ultimately predict ecosystem response to multiple pressures is paramount to successfully implement ecosystem-based management. Thresholds shifts and nonlinear patterns in ecosystem responses can be used to determine reference points that identify levels of a pressure that may drastically alter ecosystem status, which can inform management action. However, quantifying ecosystem reference points has proven elusive due in large part to the multi-dimensional nature of both ecosystem pressures and ecosystem responses. We used ecological indicators, synthetic measures of ecosystem status and functioning, to enumerate important ecosystem attributes and to reduce the complexity of the Northeast Shelf Large Marine Ecosystem (NES LME). Random forests were used to quantify the importance of four environmental and four anthropogenic pressure variables to the value of ecological indicators, and to quantify shifts in aggregate ecological indicator response along pressure gradients. Anthropogenic pressure variables were critical defining features and were able to predict an average of 8-13% (up to 25-66% for individual ecological indicators) of the variation in ecological indicator values, whereas environmental pressures were able to predict an average of 1-5 % (up to 9-26% for individual ecological indicators) of ecological indicator variation. Each pressure variable predicted a different suite of ecological indicator's variation and the shapes of ecological indicator responses along pressure gradients were generally nonlinear. Threshold shifts in ecosystem response to exploitation, the most important pressure variable, occurred when commercial landings were 20 and 60% of total surveyed biomass. Although present, threshold shifts in ecosystem response to environmental pressures were much less important, which suggests that anthropogenic pressures have significantly altered the ecosystem structure and functioning of the NES LME. Gradient response curves provide ecologically informed transformations of pressure variables to explain patterns of ecosystem structure and functioning. By concurrently identifying thresholds for a suite of ecological indicator responses to multiple pressures, we demonstrate that ecosystem reference points can be evaluated and used to support ecosystem-based management. PMID- 25781167 TI - Estimation of signal-dependent noise level function in transform domain via a sparse recovery model. AB - This paper proposes a novel algorithm to estimate the noise level function (NLF) of signal-dependent noise (SDN) from a single image based on the sparse representation of NLFs. Noise level samples are estimated from the high-frequency discrete cosine transform (DCT) coefficients of nonlocal-grouped low-variation image patches. Then, an NLF recovery model based on the sparse representation of NLFs under a trained basis is constructed to recover NLF from the incomplete noise level samples. Confidence levels of the NLF samples are incorporated into the proposed model to promote reliable samples and weaken unreliable ones. We investigate the behavior of the estimation performance with respect to the block size, sampling rate, and confidence weighting. Simulation results on synthetic noisy images show that our method outperforms existing state-of-the-art schemes. The proposed method is evaluated on real noisy images captured by three types of commodity imaging devices, and shows consistently excellent SDN estimation performance. The estimated NLFs are incorporated into two well-known denoising schemes, nonlocal means and BM3D, and show significant improvements in denoising SDN-polluted images. PMID- 25781168 TI - Correction: Evaluation of the diagnostic accuracy of prototype rapid tests for human African trypanosomiasis. PMID- 25781169 TI - Overexpression of periostin in stroma positively associated with aggressive prostate cancer. AB - BACKGROUND: Periostin is an important extracellular matrix protein involved in cell development and adhesion. Previously, we identified periostin to be up regulated in aggressive prostate cancer (CaP) using quantitative glycoproteomics and mass spectrometry. The expression of periostin was further evaluated in primary radical prostatectomy (RP) prostate tumors and adjacent non-tumorous prostate tissues using immunohistochemistry (IHC). Our IHC results revealed a low background periostin levels in the adjacent non-tumorous prostate tissues, but overexpressed periostin levels in the peritumoral stroma of primary CaP tumors. METHODS: In this study, periostin expression in CaP was further examined on multiple tissue microarrays (TMAs), which were conducted in four laboratories. To achieve consistent staining, all TMAs were stained with same protocol and scored by same image computation tool to determine the total periostin staining intensities. The TMAs were further scored by pathologists to characterize the stromal staining and epithelial staining. RESULTS: The periostin staining was observed mainly in peritumoral stromal cells and in some cases in tumor epithelial cells though the stronger staining was found in peritumoral stromal cells. Both periostin stromal staining and epithelial staining can differentiate BPH from CaP including low grade CaP (Gleason score <=6), with significant p value of 2.2e-16 and 0.001, respectively. Periostin epithelial staining differentiated PIN from low grade CaP (Gleason score <=6) (p=0.001), while periostin stromal staining differentiated low grade Cap (Gleason score <=6) from high grade Cap (Gleason score <=6) (p=1.7e-05). In addition, a positive correlation between total periostin staining and Gleason score was observed (r=0.87, p=0.002). CONCLUSIONS: The results showed that periostin staining was positively correlated with increasing Gleason score and the aggressiveness of prostate disease. PMID- 25781170 TI - Different visual preference patterns in response to simple and complex dynamic social stimuli in preschool-aged children with autism spectrum disorders. AB - Eye-tracking studies in young children with autism spectrum disorder (ASD) have shown a visual attention preference for geometric patterns when viewing paired dynamic social images (DSIs) and dynamic geometric images (DGIs). In the present study, eye-tracking of two different paired presentations of DSIs and DGIs was monitored in a group of 13 children aged 4 to 6 years with ASD and 20 chronologically age-matched typically developing children (TDC). The results indicated that compared with the control group, children with ASD attended significantly less to DSIs showing two or more children playing than to similar DSIs showing a single child. Visual attention preference in 4- to 6-year-old children with ASDs, therefore, appears to be modulated by the type of visual stimuli. PMID- 25781171 TI - LRGUK-1 is required for basal body and manchette function during spermatogenesis and male fertility. AB - Male infertility affects at least 5% of reproductive age males. The most common pathology is a complex presentation of decreased sperm output and abnormal sperm shape and motility referred to as oligoasthenoteratospermia (OAT). For the majority of OAT men a precise diagnosis cannot be provided. Here we demonstrate that leucine-rich repeats and guanylate kinase-domain containing isoform 1 (LRGUK 1) is required for multiple aspects of sperm assembly, including acrosome attachment, sperm head shaping and the initiation of the axoneme growth to form the core of the sperm tail. Specifically, LRGUK-1 is required for basal body attachment to the plasma membrane, the appropriate formation of the sub-distal appendages, the extension of axoneme microtubules and for microtubule movement and organisation within the manchette. Manchette dysfunction leads to abnormal sperm head shaping. Several of these functions may be achieved in association with the LRGUK-1 binding partner HOOK2. Collectively, these data establish LRGUK 1 as a major determinant of microtubule structure within the male germ line. PMID- 25781172 TI - Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. AB - Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on genetic background. Here, in a genome wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ. PMID- 25781173 TI - Statistical determination of rainfall-runoff erosivity indices for single storms in the Chinese Loess Plateau. AB - Correlation analysis is popular in erosion- or earth-related studies, however, few studies compare correlations on a basis of statistical testing, which should be conducted to determine the statistical significance of the observed sample difference. This study aims to statistically determine the erosivity index of single storms, which requires comparison of a large number of dependent correlations between rainfall-runoff factors and soil loss, in the Chinese Loess Plateau. Data observed at four gauging stations and five runoff experimental plots were presented. Based on the Meng's tests, which is widely used for comparing correlations between a dependent variable and a set of independent variables, two methods were proposed. The first method removes factors that are poorly correlated with soil loss from consideration in a stepwise way, while the second method performs pairwise comparisons that are adjusted using the Bonferroni correction. Among 12 rainfall factors, I30 (the maximum 30-minute rainfall intensity) has been suggested for use as the rainfall erosivity index, although I30 is equally correlated with soil loss as factors of I20, EI10 (the product of the rainfall kinetic energy, E, and I10), EI20 and EI30 are. Runoff depth (total runoff volume normalized to drainage area) is more correlated with soil loss than all other examined rainfall-runoff factors, including I30, peak discharge and many combined factors. Moreover, sediment concentrations of major sediment-producing events are independent of all examined rainfall-runoff factors. As a result, introducing additional factors adds little to the prediction accuracy of the single factor of runoff depth. Hence, runoff depth should be the best erosivity index at scales from plots to watersheds. Our findings can facilitate predictions of soil erosion in the Loess Plateau. Our methods provide a valuable tool while determining the predictor among a number of variables in terms of correlations. PMID- 25781174 TI - Transcriptomic signatures in seeds of apple (Malus domestica L. Borkh) during fruitlet abscission. AB - Abscission is the regulated process of detachment of an organ from a plant. In apple the abscission of fruits occurs during their early development to control the fruit load depending on the nutritional state of the plant. In order to control production and obtain fruits with optimal market qualities, the horticultural procedure of thinning is performed to further reduce the number of fruitlets. In this study we have conducted a transcriptomic profiling of seeds from two different types of fruitlets, according to size and position in the fruit cluster. Transcriptomic profiles of central and lateral fruit seeds were obtained by RNAseq. Comparative analysis was performed by the functional categorization of differentially expressed genes by means of Gene Ontology (GO) annotation of the apple genome. Our results revealed the overexpression of genes involved in responses to stress, hormone biosynthesis and also the response and/or transport of auxin and ethylene. A smaller set of genes, mainly related to ion transport and homeostasis, were found to be down-regulated. The transcriptome characterization described in this manuscript contributes to unravelling the molecular mechanisms and pathways involved in the physiological abscission of apple fruits and suggests a role for seeds in this process. PMID- 25781175 TI - Product carbon footprints and their uncertainties in comparative decision contexts. AB - In response to growing awareness of climate change, requests to establish product carbon footprints have been increasing. Product carbon footprints are life cycle assessments restricted to just one impact category, global warming. Product carbon footprint studies generate life cycle inventory results, listing the environmental emissions of greenhouse gases from a product's lifecycle, and characterize these by their global warming potentials, producing product carbon footprints that are commonly communicated as point values. In the present research we show that the uncertainties surrounding these point values necessitate more sophisticated ways of communicating product carbon footprints, using different sizes of catfish (Pangasius spp.) farms in Vietnam as a case study. As most product carbon footprint studies only have a comparative meaning, we used dependent sampling to produce relative results in order to increase the power for identifying environmentally superior products. We therefore argue that product carbon footprints, supported by quantitative uncertainty estimates, should be used to test hypotheses, rather than to provide point value estimates or plain confidence intervals of products' environmental performance. PMID- 25781176 TI - Changes of phosphatidylcholine and fatty acids in germ cells during testicular maturation in three developmental male morphotypes of Macrobrachium rosenbergii revealed by imaging mass spectrometry. AB - Testis maturation, germ cell development and function of sperm, are related to lipid composition. Phosphatidylcholines (PCs) play a key role in the structure and function of testes. As well, increases of polyunsaturated fatty acids (PUFA) and highly unsaturated fatty acids (HUFA), especially arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are essential for male fertility. This study is the first report to show the composition and distribution of PCs and total fatty acids (FAs) in three groups of seminiferous tubules (STs) classified by cellular associations [i.e., A (STs with mostly early germ cells), B (STs with mostly spermatids), and C (STs with spermatozoa)], in three morphotypes of Macrobrachium rosenbergii, [i.e., small male (SM), orange claw male (OC), and blue claw male (BC)]. Thin layer chromatography exhibited levels of PCs reaching maxima in STs of group B. Imaging mass spectrometry showed remarkably high signals corresponding to PC (16:0/18:1), PC (18:0/18:2), PC (18:2/20:5), and PC (16:0/22:6) in STs of groups A and B. Moreover, most signals were detected in the early developing cells and the intertubular area, but not at the area containing spermatozoa. Finally, gas chromatography-mass spectrometry indicated that the major FAs present in the testes were composed of 14:0, 16:0, 17:0, 18:0, 16:1, 18:1, 18:2, 20:1, 20:2, 20:4, 20:5, and 22:6. The testes of OC contained the greatest amounts of these FAs while the testes of BC contained the least amounts of these FAs, and there was more EPA (20:5) in the testes of SM and OC than those in the BC. The increasing amounts of FAs in the SM and OC indicate that they are important for spermatogenesis and spermiogenesis. This knowledge will be useful in formulating diets containing PUFA and HUFA for prawn broodstocks in order to improve testis development, and lead to increased male fecundity. PMID- 25781177 TI - Synthesis and chemical reactivity of tetrahydro[60]fullerene epoxides with both amino and aryl addends. AB - Tetrahydro[60]fullerene epoxides C60(O)Ar(n)(NR2)(4-n), n = 1, 2, have been prepared by treating 1,4-adducts C60(OH)Ph and C60(Tol)2 with cyclic secondary amines. The epoxy moieties in these mixed tetrahydro[60]fullerene epoxides were hydrolyzed into the corresponding diol derivatives, which were further oxidized into diketone open-cage fullerenes with a 10-membered orifice. A few other reactions also showed that the present tetrahydro[60]fullerene epoxides with both amino and aryl addends exhibit improved chemical reactivity over the tetraamino[60]fullerene epoxide without any aryl group. PMID- 25781178 TI - Age, gender and normalization covariates for spinal cord gray matter and total cross-sectional areas at cervical and thoracic levels: A 2D phase sensitive inversion recovery imaging study. AB - The source of inter-subject variability and the influence of age and gender on morphometric characteristics of the spinal cord, such as the total cross sectional area (TCA), the gray matter (GM) and white matter (WM) areas, currently remain under investigation. Understanding the effect of covariates such as age, gender, brain volumes, and skull- and vertebra-derived metrics on cervical and thoracic spinal cord TCA and GM areas in healthy subjects would be fundamental for exploring compartment specific changes in neurological diseases affecting the spinal cord. Using Magnetic Resonance Imaging at 3T we investigated 32 healthy subjects using a 2D phase sensitive inversion recovery sequence and we measured TCA, GM and WM areas at 4 cervical and thoracic levels of the spinal cord. We assessed age and gender relationships of cord measures and explored associations between cord measures and a) brain volumes and b) skull- and vertebra-derived metrics. Age and gender had a significant effect on TCA, WM and GM areas (with women and elderly having smaller values than men and younger people respectively), but not on the GM area/TCA ratio. The total intracranial volume and C3 vertebra dimensions showed the highest correlations with cord measures. When used in multi-regression models, they reduced cord areas group variability by approximately a third. Age and gender influences on cord measures and normalization strategies here presented might be of use in the study of compartment specific changes in various neurological diseases affecting the spinal cord. PMID- 25781179 TI - Cigarette smoking causes hearing impairment among Bangladeshi population. AB - Lifestyle including smoking, noise exposure with MP3 player and drinking alcohol are considered as risk factors for affecting hearing synergistically. However, little is known about the association of cigarette smoking with hearing impairment among subjects who carry a lifestyle without using MP3 player and drinking alcohol. We showed here the influence of smoking on hearing among Bangladeshi subjects who maintain a lifestyle devoid of using MP3 player and drinking alcohol. A total of 184 subjects (smokers: 90; non-smokers: 94) were included considering their duration and frequency of smoking for conducting this study. The mean hearing thresholds of non-smoker subjects at 1, 4, 8 and 12 kHz frequencies were 5.63 +/- 2.10, 8.56+/-5.75, 21.06 +/- 11.06, 40.79 +/- 20.36 decibel (dB), respectively and that of the smokers were 7 +/- 3.8, 13.27 +/- 8.4, 30.66 +/- 12.50 and 56.88 +/- 21.58 dB, respectively. The hearing thresholds of the smokers at 4, 8 and 12 kHz frequencies were significantly (p<0.05) higher than those of the non-smokers, while no significant differences were observed at 1 kHz frequency. We also observed no significant difference in auditory thresholds among smoker subgroups based on smoking frequency. In contrast, subjects smoked for longer duration (>5 years) showed higher level of auditory threshold (62.16 +/- 19.87 dB) at 12 kHz frequency compared with that (41.52 +/- 19.21 dB) of the subjects smoked for 1-5 years and the difference in auditory thresholds was statistically significant (p<0.0002). In this study, the Brinkman Index (BI) of smokers was from 6 to 440 and the adjusted odds ratio showed a positive correlation between hearing loss and smoking when adjusted for age and body mass index (BMI). In addition, age, but not BMI, also played positive role on hearing impairment at all frequencies. Thus, these findings suggested that cigarette smoking affects hearing level at all the frequencies tested but most significantly at extra higher frequencies. PMID- 25781180 TI - Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits. AB - Mitochondrial inner membrane folds into cristae, which significantly increase its surface and are important for mitochondrial function. The stability of cristae depends on the mitochondrial contact site (MICOS) complex. In human mitochondria, the inner membrane MICOS complex interacts with the outer membrane sorting and assembly machinery (SAM) complex, to form the mitochondrial intermembrane space bridging complex (MIB). We have created knockdown cell lines of most of the MICOS and MIB components and have used them to study the importance of the individual subunits for the cristae formation and complex stability. We show that the most important subunits of the MIB complex in human mitochondria are Mic60/Mitofilin, Mic19/CHCHD3 and an outer membrane component Sam50. We provide additional proof that ApoO indeed is a subunit of the MICOS and MIB complexes and propose the name Mic23 for this protein. According to our results, Mic25/CHCHD6, Mic27/ApoOL and Mic23/ApoO appear to be periphery subunits of the MICOS complex, because their depletion does not affect cristae morphology or stability of other components. PMID- 25781181 TI - Fall risk awareness and safety precautions taken by older community-dwelling women and men--a qualitative study using focus group discussions. AB - INTRODUCTION: Daily life requires frequent estimations of the risk of falling and the ability to avoid a fall. The objective of this study was to explore older women's and men's understanding of fall risk and their experiences with safety precautions taken to prevent falls. METHODS: A qualitative study with focus group discussions was conducted. Eighteen community-dwelling people [10 women and 8 men] with and without a history of falls were purposively recruited. Participants were divided into two groups, and each group met four times. A participatory and appreciative action and reflection approach was used to guide the discussions. All discussions were audio recorded and transcribed verbatim. Data were analysed by qualitative content analysis, and categories were determined inductively. FINDINGS: Three categories describing the process of becoming aware of fall risks in everyday life were identified: 1] Facing various feelings, 2] Recognizing one's fall risk, and 3] Taking precautions. Each category comprised several subcategories. The comprehensive theme derived from the categories was "Safety precautions through fall risk awareness". Three strategies of ignoring [continuing a risky activity], gaining insight [realizing the danger in a certain situation], and anticipating [thinking ahead and acting in advance] were related to all choices of actions and could fluctuate in the same person in different contexts. CONCLUSIONS: The fall risk awareness process might be initiated for various reasons and can involve different feelings and precautions as well as different strategies. This finding highlights that there are many possible channels to reach older people with information about fall risk and fall prevention, including the media and their peers. The findings offer a deeper understanding of older peoples' conceptualizations about fall risk awareness and make an important contribution to the development and implementation of fall prevention programmes. PMID- 25781182 TI - Hydrogen crystallization in low-density aerogels. AB - Crystallization of liquids confined in disordered low-density nanoporous scaffolds is poorly understood. Here, we use relaxation calorimetry to study the liquid-solid phase transition of H2 in a series of silica and carbon (nanotube- and graphene-based) aerogels with porosities ?94%. Results show that freezing temperatures of H2 inside all the aerogels studied are depressed but do not follow predictions of the Gibbs-Thomson theory based on average pore diameters measured by conventional gas sorption techniques. Instead, we find that, for each material family investigated, the depression of average freezing temperatures scales linearly with the ratio of the internal surface area (measured by gas sorption) and the total pore volume derived from the density of aerogel monoliths. The slope of such linear dependences is, however, different for silica and carbon aerogels, which we attribute to microporosity of carbons and the presence of macropores in silica aerogels. Our results have important implications for the analysis of pore size distributions of low-density nanoporous materials and for controlling crystallization of fuel layers in targets for thermonuclear fusion energy applications. PMID- 25781183 TI - Dosimetric comparison of the simultaneous integrated boost in whole-breast irradiation after breast-conserving surgery: IMRT, IMRT plus an electron boost and VMAT. AB - OBJECTIVES: To compare the target volume coverage and doses to organs at risks (OARs) using three techniques that simultaneous integrated boost (SIB) in whole breast irradiation (WBI) after breast-conserving surgery, including intensity modulated radiation therapy (IMRT), IMRT plus an electron boost (IMRT-EB), and volumetric-modulated arc therapy (VMAT). METHODS: A total of 10 patients with early-stage left-sided breast cancer after breast-conserving surgery were included in this study. IMRT, IMRT-EB and VMAT plans were generated for each patient. RESULTS: The conformity index (CI) of the planning target volumes evaluation (PTV-Eval) of VMAT was significantly superior to those of IMRT and IMRT-EB (P < 0.05). The CI of the PTV Eval-boost of VMAT was better than that of IMRT (P = 0.018) and IMRT-EB (P < 0.001), while the CI of the PTV Eval-boost of IMRT was better than that of IMRT-EB (P = 0.002). The V5, V10 and Dmean in ipsilateral lung with VMAT were significantly higher than IMRT (P < 0.05) and IMRT-EB (P < 0.05). The Dmean, V5 and V10 in heart with VMAT were significantly greater than those of IMRT and IMRT-EB (P < 0.05). There was no significant difference in the OARs between IMRT and IMRT-EB (P > 0.05). CONCLUSIONS: Considered the target volume coverage and radiation dose delivered to the OARs (especially the heart and lung), IMRT may be more suitable for the SIB in WBI than IMRT-EB and VMAT. Additional clinical studies with a larger sample size will be needed to assess the long-term feasibility and efficacy of SIB using different radiotherapy techniques. PMID- 25781184 TI - The value of MRI in the diagnosis of primary biliary cirrhosis and assessment of liver fibrosis. AB - OBJECTIVES: To evaluate MRI findings in patients with primary biliary cirrhosis (PBC) and to determine the value of MRI in the diagnosis of PBC and assessment of liver fibrosis. MATERIALS AND METHODS: This study reviewed the prevalence of MRI abnormalities seen in 45 PBC patients in the past four years, including 33 patients who underwent liver biopsy. Correlation between the MRI findings and the pathological stage was determined. RESULTS: There were 33 patients who underwent liver biopsy. Twenty-five patients (75.8%) had non-homogeneous changes in the liver signal intensity, 25 (75.8%) had a periportal halo sign, and 29 (87.9%) had lymphadenopathy. The short axis of the enlarged lymph nodes was a mean of 1.2+/ 0.3 cm. A strong positive correlation was observed between histological stage and the inhomogeneity of liver signal intensity (P<0.001). There were significant differences among the four histological stages based on the periportal halo sign (P=0.034), and the grading of the periportal halo sign was found to be significantly correlated with the histological stage (P<0.001). Grading of the periportal halo sign was significantly different at stage II versus III, and stage III versus IV; no significant difference was found between stages I and II. There were also no significant differences among the four histological states in the occurrence and size of enlarged lymph nodes (P=0.674 and P=0.394). CONCLUSION: MRI is valuable in the diagnosis of PBC, and the periportal halo sign and liver signal intensity help to evaluate the degree of liver fibrosis. PMID- 25781185 TI - Risperidone long-acting injection and 1-year rehospitalization rate of schizophrenia patients: A retrospective cohort study. AB - AIMS: We wanted to present a picture of patients with schizophrenia receiving risperidone long-acting injection (RLAI) treatment in a real-world setting. METHODS: This was a retrospective cohort study; 379 patients with schizophrenia were enrolled and treated with different kinds of antipsychotic agents at E-Da Hospital, and received a 12-month follow up. The patients were distributed into three groups: the all-oral antipsychotic, oral risperidone and RLAI groups. The antipsychotic agents and dosages they used were recorded. The rate of rehospitalization, length of hospital stay, emergency room visits and medical expenditures were assessed. RESULTS: The RLAI group had a significantly higher rate of hospitalization before enrolment (the all-oral antipsychotic group was 32.1%, the oral risperidone group, 35.9%, and the RLAI group, 88.4%, P < 0.0001). After a 1-year follow up, all three groups were similar in rehospitalization rates (the all-oral antipsychotic group was 28.9%, the oral risperidone group, 30.1%, and the RLAI group, 30.2%, P > 0.999), length of hospital stay and number of emergency room visits during follow up. The most commonly used oral antipsychotics were risperidone (0.5-7 mg/day), quetiapine (65-1200 mg/day), and olanzapine (2-25 mg/day). CONCLUSIONS: Using RLAI reduces the severity of disease in more difficult patients. PMID- 25781186 TI - Indoor air pollution aggravates symptoms of atopic dermatitis in children. AB - Most of researches on the impact of indoor air pollutants on atopic dermatitis (AD) have been based upon animal models, in vitro experiments and case-control studies. However, human data to elucidate the role of indoor air pollution on worsening symptoms of pre-existing AD from a longitudinal study are scarce. The objective of this prospective study was to evaluate the effect of indoor air pollution on AD symptoms in children. We surveyed 30 children with AD in a day care centre, which moved to a new building during the study. These children stayed there for 8 hours a day Monday through Friday, and their daily symptom scores were recorded. Indoor and outdoor air pollutant levels were continuously measured 24 hours a day for 12 months (Period 1 to 4). Data were analyzed using a generalized linear mixed model. Compared to the period before moving (Period 1), concentrations of indoor air pollutants mostly increased after moving (Period 2) and decreased by natural ventilation and bake-out (Periods 3 and 4). The rate of positive AD symptom increased from 32.8% (Period 1) up to 43.8% (Period 2) and 50.5% (Period 3), then decreased to 35.4% in Period 4 (P < 0.0001). When the delayed effects of indoor air pollutants on AD symptoms 2 days later were evaluated, AD symptoms significantly increased by 12.7% (95% CI: -0.01 to 27.1) as toluene levels increased by 1 ppb (P = 0.05). In conclusion, indoor air pollutants increase the risk of AD aggravation in children and toluene in the indoor environment might act as an aggravating factor. PMID- 25781187 TI - Crystal and EM structures of human phosphoribosyl pyrophosphate synthase I (PRS1) provide novel insights into the disease-associated mutations. AB - Human PRS1, which is indispensable for the biosynthesis of nucleotides, deoxynucleotides and their derivatives, is associated directly with multiple human diseases because of single base mutation. However, a molecular understanding of the effect of these mutations is hampered by the lack of understanding of its catalytic mechanism. Here, we reconstruct the 3D EM structure of the PRS1 apo state. Together with the native stain EM structures of AMPNPP, AMPNPP and R5P, ADP and the apo states with distinct conformations, we suggest the hexamer is the enzymatically active form. Based on crystal structures, sequence analysis, mutagenesis, enzyme kinetics assays, and MD simulations, we reveal the conserved substrates binding motifs and make further analysis of all pathogenic mutants. PMID- 25781188 TI - MRSA clonal complex 22 strains harboring toxic shock syndrome toxin (TSST-1) are endemic in the primary hospital in Gaza, Palestine. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in both community and healthcare-related settings worldwide. Current knowledge regarding the epidemiology of S. aureus and MRSA in Gaza is based on a single community-based carriage study. Here we describe a cross-sectional analysis of 215 clinical isolates collected from Al-Shifa Hospital in Gaza during 2008 and 2012. METHODS: All isolates were characterized by spa typing, SCCmec typing, and detection of genes encoding Panton-Valentine leukocidin (PVL) and toxic shock syndrome toxin (TSST-1). Representative genotypes were also subjected to multilocus sequence typing (MLST). Antibiotic susceptibility testing was performed using VITEK2 and MicroScan. RESULTS: MRSA represented 56.3% of all S. aureus strains, and increased in frequency from 2008 (54.8%) to 2012 (58.4%). Aside from beta-lactams, resistance was observed to tetracycline, erythromycin, clindamycin, gentamicin, and fluoroquinolones. Molecular typing identified 35 spa types representing 17 MLST clonal complexes (CC), with spa 998 (Ridom t223, CC22) and spa 70 (Ridom t044, CC80) being the most prevalent. SCCmec types I, III, IV, V and VI were identified among MRSA isolates, while type II was not detected. PVL genes (lukF/S-PV) were detected in 40.0% of all isolates, while the TSST-1 gene (tst) was detected in 27.4% of all isolates, with surprisingly high frequency within CC22 (70.4%). Both PVL and TSST-1 genes were found in several isolates from 2012. CONCLUSIONS: Molecular typing of clinical isolates from Gaza hospitals revealed unusually high prevalence of TSST-1 genes among CC22 MRSA, which is noteworthy given a recent community study describing widespread carriage of a CC22 MRSA clone known as the 'Gaza strain'. While the latter did not address TSST 1, tst-positive spa 998 (Ridom t223) has been detected in several neighboring countries, and described as endemic in an Italian NICU, suggesting international spread of a 'Middle Eastern variant' of pandemic CC22 strain EMRSA-15. PMID- 25781189 TI - Design and mechanism of tetrahydrothiophene-based gamma-aminobutyric acid aminotransferase inactivators. AB - Low levels of gamma-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of gamma-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a pi-pi interaction with Phe-189, and a weak nonbonded S...O?C interaction with Glu-270, thereby inactivating the enzyme. PMID- 25781190 TI - miR-30c Mediates Upregulation of Cdc42 and Pak1 in Diabetic Cardiomyopathy. AB - AIM: Cardiac hypertrophy and myocardial fibrosis significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Altered expression of several genes and their regulation by microRNAs has been reported in hypertrophied failing hearts. This study aims to examine the role of Cdc42, Pak1, and miR-30c in the pathogenesis of cardiac hypertrophy in DCM. METHODS: DCM was induced in Wistar rats by low-dose streptozotocin-high-fat diet for 12 weeks. Cardiac expression of Cdc42, Pak1 and miR-30c, and hypertrophy markers (ANP and beta-MHC) was studied in DCM vs control rats and in high-glucose (HG)-treated H9c2 cardiomyocytes. RESULTS: Diabetic rats showed cardiomyocyte hypertrophy, increased heart-to-body weight ratio, and an increased expression of ANP and beta MHC. Cardiac expression of Cdc42 and Pak1 genes was increased in diabetic hearts and in HG-treated cardiomyocytes. miR-30c was identified to target Cdc42 and Pak1 genes, and cardiac miR-30c expression was found to be decreased in DCM rats, patients with DCM, and in HG-treated cardiomyocytes. miR-30c overexpression decreased Cdc42 and Pak1 genes and attenuated HG-induced cardiomyocyte hypertrophy, whereas miR-30c inhibition increased Cdc42 and Pak1 gene expression and myocyte hypertrophy in HG-treated cardiomyocytes. CONCLUSION: Downregulation of miR-30c mediates prohypertrophic effects of hyperglycemia in DCM by upregulation of Cdc42 and Pak1 genes. PMID- 25781191 TI - Basophil activation test: do not lose control. PMID- 25781192 TI - Longitudinal study of the expression of FcepsilonRI and IgE on basophils and dendritic cells in association with basophil function in two patients with severe allergic asthma treated with Omalizumab. AB - Severe asthma is a challenging disease, and omalizumab has been an important tool to help clinicians address more efficiently this problem. Besides reduction of free and total serum IgE levels, there are a number of other immunologic effects of omalizumab that may be of relevance in its therapeutic action. We report two mite-allergic severe asthmatic patients successfully treated with omalizumab for one year. Clinically, patients improved gradually, with no further need for systemic steroids or emergency department visits during that treatment period, and with Asthma Control Test (ACT) scores showing controlled disease, although pulmonary function didn't show any significant improvement. Immunologically, we observed marked down-regulation of surface IgE and FcepsilonRI on basophils, plasmacytoid and myeloid dendritic cells, as well as a reduction of basophil activation after specific allergen stimulation. These effects were clearly evident immediately after one month but were enhanced at 3, 6 and 12 months of omalizumab treatment, suggesting an advantage to continuing this therapy, and raising the hypothesis of some markers being useful to assess immunological responses to omalizumab, which could assist in the clinician's decision to stop or to restart this treatment. PMID- 25781193 TI - Serum Vitamin D levels and Vitamin D supplementation do not correlate with the severity of chronic eczema in children. AB - BACKGROUND: Eczema is one of the most common chronic inflammatory skin diseases, affecting about 20% of children. The pathogenic mechanisms of eczema are still not fully understood, and current treatment of moderate-severe eczema is often difficult. Recently, it has been suggested that Vitamin D plays a key role in this disease, even if mechanisms are only partially known. OBJECTIVE: The purpose of our study was to assess the 25-Hydroxyvitamin D serum levels in a pediatric population suffering from chronic eczema (IgE-mediated and non-IgE-mediated), and to correlate these phenotypes with the SCORAD severity and selected clinical and biological parameters. Moreover, we aimed to evaluate whether a supplementation of Vitamin D3 could affect the same clinical and laboratory parameters. METHODS: 89 children with chronic eczema were enrolled in the study. Severity of eczema was assessed with the SCORAD index. Past and present history was taken, and patients were divided into two groups according to the state of sensitization. According to a randomization schedule, the enrolled children were assigned to the following groups: supplementation group, which received a daily oral Vitamin D3 supplementation (2000 IUs) for 3 months; control group which received no supplementation. RESULTS: Vitamin D concentrations in patients with moderate and severe eczema were not statistically different from Vitamin D concentration detected in the serum of patients with mild eczema. Furthermore, we did not find any correlation between Vitamin D levels, total IgEs and SCORAD index, both in the Sensitized and in the Not-Sensitized group. The Vitamin D3 supplementation did not influence the SCORAD severity or the total IgEs concentration. CONCLUSION: To our knowledge, our study is the first one that shows no correlation between serum levels of Vitamin D, eczema severity and IgE sensitization in a pediatric population suffering from chronic eczema. PMID- 25781194 TI - Single NSAID hypersensitivity is associated with atopic status. AB - BACKGROUND: The relationship between hypersensitivity to NSAID and atopic status is still incompletely defined. Previous studies found a high prevalence of atopic diseases in multiple NSAID reactors. The present study aimed to investigate whether this is the case also in Italian adults hypersensitive to NSAIDs. METHODS: Skin tests with a large panel of seasonal and perennial airborne allergens were carried out in 252 patients with a clear-cut history of acute urticaria induced by nonsteroidal anti-inflammatory drugs. Patients were classified as single or multiple NSAID reactors based on clinical history, presence/absence of chronic urticaria, re-challenge with the reported offending drug in case of doubt history, and oral challenges with aspirin or propionic acid derivatives. RESULTS: Single NSAID reactors showed a much higher prevalence of atopic diseases than multiple NSAID reactors either with or without chronic urticaria (61% vs 19% and 19%, respectively; p < 0.001). CONCLUSION: As a difference from previous reports, in Italian patients hypersensitive to NSAID atopy is much more prevalent among single reactors, a finding that indirectly supports the possible IgE-mediated origin of this type of adverse drug reaction. PMID- 25781195 TI - High prevalence of gluten sensitivity in a cohort of patients with undifferentiated connective tissue disease. AB - OBJECTIVES: The aim of this study was to investigate if co-morbid conditions as hepatitis C virus infection and celiac disease may be associated to undifferentiated connective tissue disease. METHODS: We studied retrospectively and prospectively 52 patients with diagnosis of undifferentiated connective tissue disease, subdivided, according to Vaz criteria, in systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome-like subgroups. Serological markers of celiac disease as anti-gliadin, anti-endomysium and anti tissue transglutaminase antibodies were investigated. An esophagogastroduodenoscopy with duodenal biopsy and histological examination was proposed to patients with positive celiac disease serology. In addition antibodies directed to hepatitis C virus and total IgA-antibodies were investigated. RESULTS: Six patients (11,5%) were positive for celiac disease serological tests although two of them were asymptomatic. Four patients underwent an esophagogastroduodenoscopy, showing total or subtotal villous atrophy at duodenal biopsies. Hepatitis C virus serology was negative in all patients and none had IgA deficiency. 83% of celiac patients showed a scleroderma-like phenotype. We observed a statistically higher incidence of autoimmune symptoms in patients with gluten sensitivity. Fatigue and myalgia regressed early after the beginning of gluten-free diet. CONCLUSIONS: In our cohort of patients the prevalence of celiac disease was higher than that reported in the general population. We believe that all patients with diagnosis of undifferentiated connective tissue disease, especially those with a systemic sclerosis-like presentation, should be investigated for celiac disease, even in absence of gastrointestinal symptoms. Gluten-free diet should be early recommended to all patients having undifferentiated connective tissue disease and gluten sensitivity. PMID- 25781196 TI - Two cases of elevated tryptase in abdominal aortic aneurysm. AB - INTRODUCTION: From the literature, patients with a history of anaphylaxis to hymenoptera venom and positive specific IgE have shown a correlation between elevated tryptase levels and two clinical situations: systemic mastocytosis and an increased risk of reactions to venom immunotherapy or hymenoptera sting. Other clinical scenarios could explain elevated tryptase levels. MATERIAL AND METHODS: A 67 year old male (P1) and a 77 year old male (P2) were evaluated for previous severe anaphylaxis to hymenoptera sting. They underwent standard diagnostic work up for hymenoptera venom allergy. Having found elevated tryptase levels, these were followed by a bone marrow biopsy to rule out systemic mastocytosis. RESULTS: P1: specific IgE and skin tests were positive for Vespula species; tryptase 52.8 ng/ml; P2: specific IgE and skin tests were positive for Vespa cabro and tryptase 153 ng/ml. Bone marrow biopsy results were negative for mastocytosis. We carried out magnetic resonance imaging, in P1 to better characterize the severe osteoporosis and in P2 because during physical examination a pulsating mass had been identified in the mesogastrium, and an aneurysm of the abdominal aorta which required surgical intervention in both patients was detected. Eight months after surgery, tryptase levels had diminished significantly (P1: 11.6 ng/ml and P2: 14.5 ng/ml). DISCUSSION: The elevated tryptase levels were correlated to abdominal aneurysm in both patients. In fact, post-surgery tryptase levels dramatically decreased. These two cases demonstrate that high tryptase levels in subjects with a history of hymenoptera venom anaphylaxis can be associated to undiagnosed aneurysmatic disease. PMID- 25781197 TI - Clinical bystander effect exerted by allergen immunotherapy: a hypothesis. AB - Allergen Immunotherapy (AIT) is able to restore a physiological Th1 response and Tregs function. This effect is allergen-specific, even though it has been reported that it may also be non-specific, such as also extended to allergens not used in AIT. This immunological phenomenon may also be of clinical nature. This case report shows that a poly-allergic patient, successfully treated with Parietaria extract, also achieved a clinical tolerance towards other causal allergens, such as mites and cat. Of course, this was an anecdote, but it is reasonable to prospect the hypothesis that a bystander clinical effect may be observed during AIT in poly-allergic patients. PMID- 25781198 TI - Acute effects of an arginine-based supplement on neuromuscular, ventilatory, and metabolic fatigue thresholds during cycle ergometry. AB - The purpose of the present study was to examine the effects of an acute dose of an arginine-based supplement on the physical working capacity at the fatigue threshold (PWCFT), lactate threshold (LT), ventilatory threshold (VT), and peak oxygen uptake during incremental cycle ergometry. This study used a double blinded, placebo-controlled, within-subjects crossover design. Nineteen untrained men (mean age +/- SD = 22.0 +/- 1.7 years) were randomly assigned to ingest either the supplement (3.0 g of arginine, 300 mg of grape seed extract, and 300 mg of polyethylene glycol) or placebo (microcrystalline cellulose) and performed an incremental test on a cycle ergometer for determination of PWCFT, LT, VT, and peak oxygen uptake. Following a 1-week period, the subjects returned to the laboratory and ingested the opposite substance (either supplement or placebo) prior to completing another incremental test to be reassessed for PWCFT, LT, VT, and peak oxygen uptake. The paired-samples t tests indicated there were significant (P < 0.05) mean differences between the arginine and placebo conditions for the PWCFT (192 +/- 42 vs. 168 +/- 53 W, respectively) and VT (2546 +/- 313 vs. 2452 +/- 342 mL.min(-1)), but not the LT (135 +/- 26 vs. 138 +/- 22 W), absolute peak oxygen uptake (3663 +/- 445 vs. 3645 +/- 438 mL.min(-1)), or relative peak oxygen uptake (46.5 +/- 6.0 vs. 46.2 +/- 5.0 mL.kg(-1).min(-1)). These findings suggested that the arginine-based supplement may be used on an acute basis for delaying the onset of neuromuscular fatigue (i.e., PWCFT) and improving the VT in untrained individuals. PMID- 25781199 TI - Dietary restriction in moderately obese rats improves body size and glucose handling without the renal and hepatic alterations observed with a high-protein diet. AB - Obesity is increasing worldwide, and high-protein (HP) diets are widely used for weight loss. However, the overall safety of HP diets is not well established in obese individuals, who make up a significant proportion of the population. To evaluate the health effects of an HP diet in obesity, obesity-prone (OP) Sprague Dawley rats were given high-fat diets for 12 weeks to induce obesity. Following this, for 8 more weeks, these rats were given either a normal-protein (NP) (15% of energy) or an HP (35% of energy) diet ad libitum, or the NP diet at a restricted level to achieve body weights similar to those of the HP group (pair weighted (PW) group). Obesity-resistant (OR) control rats were also given the NP diet throughout the feeding period. The HP-OP group had higher food intake but lower body weight, improved glucose handling, and lowered serum haptoglobin compared with the NP-OP group. These benefits were also observed in PW-OP rats. In addition, PW-OP rats had less fat accumulation when compared with NP-OP rats, and an improved Lee index, lower liver size, and lower serum alanine aminotransferase when compared with HP-OP rats. On the other hand, kidney size, proteinuria, and serum homocysteine were increased in HP-OP rats compared with NP OP rats, whereas PW-OP rats did not experience these effects. These results indicate that in obese rats, more benefits are obtained via dietary restriction with an NP diet and without some of the potentially detrimental effects of an HP diet. PMID- 25781200 TI - Monosodium L-glutamate and dietary fat exert opposite effects on the proximal and distal intestinal health in growing pigs. AB - The Chinese population has undergone rapid transition to a high-fat diet. Furthermore, monosodium L-glutamate (MSG) is widely used as a flavour enhancer in China. Previous studies have reported that high-fat diet modifies intestinal metabolism and physiology. However, little information is available on the effects of oral MSG on intestine, and no study focus on the interaction of dietary fat and MSG for intestinal health. The aim of the present study was to evaluate the effects of MSG and dietary fat on intestinal health in growing pigs, and to try to identify possible interactions between these 2 nutrients for such effects. A total of 32 growing pigs were used and fed with 4 isonitrogenous and isocaloric diets (basal diet, high-fat diet, basal diet with 3% MSG and high fat diet with 3% MSG). Parameters related to reactive oxygen species metabolism, epithelial morphology, pro-inflammation factors and tight junction protein expression and several species of intestinal microbe were measured. Overall, dietary fat and MSG had detrimental effects on several of the physiological and inflammatory parameters measured in the proximal intestine, while exerting beneficial effects on the distal intestine in growing pigs, with generally antagonistic effects. These results may be of particular relevance for nutritional concerns in patients with intestinal diseases. PMID- 25781201 TI - Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells. AB - Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203 mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress responsive genes such as cytoglobin to confer its anticancer action. PMID- 25781203 TI - Effects of ripening temperature on starch structure and gelatinization, pasting, and cooking properties in rice (Oryza sativa). AB - The effect of ripening temperature on rice (Oryza sativa) grain quality was evaluated by assessing starch structure and gelatinization, pasting, and cooking properties. As the ripening temperature increased, the amylose content and number of short amylopectin chains decreased, whereas intermediate amylopectin chains increased, resulting in higher gelatinization temperatures and enthalpy in the starch. These results suggested that an increase in cooking temperature and time would be required for rice grown at higher temperatures. A high ripening temperature increased the peak, trough, and final viscosities and decreased the setback due to the reduction in amylose and the increase in long amylopectin chains. With regard to starch crystallinity and amylopectin molecular structure, the highest branches and compactness were observed at 28/20 degrees C. Rice that was grown at temperatures above 28/20 degrees C showed a deterioration of cooking quality and a tendency toward decreased palatability in sensory tests. PMID- 25781202 TI - Phase II trial of chemoradiotherapy with S-1 plus cisplatin for unresectable locally advanced head and neck cancer (JCOG0706). AB - We conducted a phase II study to evaluate the efficacy and safety of chemoradiotherapy concurrent with S-1 plus cisplatin in patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Chemotherapy consisted of S-1 twice daily on days 1-14 at 60 mg/m(2) /day and cisplatin at 20 mg/m(2) /day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. For patients achieving an objective response after chemoradiotherapy, two additional cycles of chemotherapy were administered. Of the 45 enrolled patients, the percentage of clinical complete remission, the primary endpoint, was 64.4% (8 complete response, 21 good partial response) on central review. After a median follow-up of 3.52 years, 3-year local progression-free survival was 62.2%, with 3-year progression-free survival of 60.0%, 3-year overall survival of 64.4%, and 3-year time to treatment failure of 48.9%. Grade 3 or 4 toxicity included pharyngeal mucositis (46.7%), oral mucositis (44.4%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%), and febrile neutropenia (4.4%). No treatment-related deaths were observed. This combination showed promising efficacy with acceptable toxicities. PMID- 25781204 TI - Active surveillance for clinically localized renal tumors: An updated review of current indications and clinical outcomes. AB - The widespread use of abdominal imaging has led to an increasing detection of small renal masses, and approximately 20-30% of those tumors will prove to be benign, with low metastatic potential if not immediately treated. In elderly or comorbid patients diagnosed with small renal masses, competing cause mortality seems to exceed cancer-specific mortality at short- and intermediate-term follow up. In these cases, surgery might represent an overtreatment, and an expectant management, such as active surveillance, might be proposed. According to the current available evidence, active surveillance is a safe and reasonable option for patients with renal tumors <=4 cm (cT1a) and short life expectancy. A few studies with short-term follow up reported the preliminary results of active surveillance even in cT1b-cT2 tumors, with acceptable risk of disease progression and mortality, even if this approach should be considered in this setting only for highly-selected and well-informed patients. Furthermore, surveillance protocols can be proposed in selected patients with uncomplicated benign tumors, such as angiomyolipomas, in which active surveillance should be considered the initial standard management. At present, reliable clinical predictors of a tumor's growth rate and aggressiveness are not available. Renal tumor biopsy is useful in the clinical work-up of patients who are candidates for active surveillance, in order to improve patient selection based on tumor histological characterization. Despite the proof of safety offered by expectant management for small renal masses in selected patients, further prospective studies with longer follow up are required in order to confirm the indications and long-term oncological outcomes of active surveillance protocols for renal tumors. PMID- 25781205 TI - Combined use of principal component analysis and random forests identify population-informative single nucleotide polymorphisms: application in cattle breeds. AB - The genetic identification of the population of origin of individuals, including animals, has several practical applications in forensics, evolution, conservation genetics, breeding and authentication of animal products. Commercial high-density single nucleotide polymorphism (SNP) genotyping tools that have been recently developed in many species provide information from a large number of polymorphic sites that can be used to identify population-/breed-informative markers. In this study, starting from Illumina BovineSNP50 v1 BeadChip array genotyping data available from 3711 cattle of four breeds (2091 Italian Holstein, 738 Italian Brown, 475 Italian Simmental and 407 Marchigiana), principal component analysis (PCA) and random forests (RFs) were combined to identify informative SNP panels useful for cattle breed identification. From a PCA preselected list of 580 SNPs, RFs were computed using ranking methods (Mean Decrease in the Gini Index and Mean Accuracy Decrease) to identify the most informative 48 and 96 SNPs for breed assignment. The out-of-bag (OOB) error rate for both ranking methods and SNP densities ranged from 0.0 to 0.1% in the reference population. Application of this approach in a test population (10% of individuals pre-extracted from the whole data set) achieved 100% of correct assignment with both classifiers. Linkage disequilibrium between selected SNPs was relevant (r(2) > 0.6) only in few pairs of markers indicating that most of the selected SNPs captured different fractions of variance. Several informative SNPs were in genes/QTL regions that affect or are associated with phenotypes or production traits that might differentiate the investigated breeds. The combination of PCA and RF to perform SNP selection and breed assignment can be easily implemented and is able to identify subsets of informative SNPs useful for population assignment starting from a large number of markers derived by high-throughput genotyping platforms. PMID- 25781206 TI - Distribution of Class 1 Integrons, sul1 and sul2 Genes Among Clinical Isolates of Stenotrophomonas maltophilia from a Tertiary Care Hospital in North India. AB - Stenotrophomonas maltophilia is an emerging nosocomial pathogen responsible for serious human infections. This study was carried out to determine antibiotic susceptibility, resistance mechanisms (integrons, sul1 and sul2), and genetic relatedness (Enterobacterial Repetitive Intergenic Consensus [ERIC]-PCR) among 106 clinical isolates of S. maltophilia from India. Twenty-four (22.6%) of S. maltophilia isolates exhibited resistance to mainstay antibiotic trimethoprim sulfamethoxazole (TMP-SMX). Except for 2 isolates which contained both TMP-SMX resistance determinants sul1 and sul2 genes, all other 22 TMP-SMX-resistant isolates carried either sul1 (10 isolates) or sul2 (12 isolates) genes. Class 1 integrons were present in 8.5% (9 out of 106) of S. maltophilia isolates, and only 5 out of these isolates were TMP-SMX resistant and positive for sul1 gene. The same isolates also carried resistance cassettes containing qac/smr gene. Minocycline and levofloxacin exhibited the maximum in vitro activity against S. maltophilia. ERIC-PCR revealed high diversity among S. maltophilia isolates. The present study demonstrated high (22.4%) TMP-SMX resistance in clinical isolates of S. maltophilia from India. TMP-SMX-resistant isolates carried relatively higher percentage of sul2 gene than sul1 gene as against the reported literature. Majority (58.3%) of sul1 gene positive were not associated with class 1 integrase gene. PMID- 25781207 TI - Basal cell carcinoma after treatment of childhood acute lymphoblastic leukemia and concise review of the literature. AB - Basal cell carcinoma (BCC) is a rare secondary malignancy which may occur more often in children with acute lymphoblastic leukemia (ALL) who have previously received radiation therapy compared to to those who received no radiation. PMID- 25781208 TI - Antioxidant icariside II combined with insulin restores erectile function in streptozotocin-induced type 1 diabetic rats. AB - Erectile dysfunction (ED) worsens in patients with diabetes mellitus (DM) despite good control of blood glucose level with insulin. Recent studies imply that diabetic vascular stresses (e.g. oxidative stress) persist in spite of glucose normalization, which is defined as metabolic memory. Studies suggest that the interaction between advanced glycation end products (AGEs) and their receptor (RAGE) mediates the development of metabolic memory. To investigate the effects of the antioxidant icariside II plus insulin on erectile function in streptozotocin (STZ)- induced type 1 diabetic rats. Fifty 8-week-old Sprague Dawley rats were randomly distributed into five groups: normal control, diabetic, insulin-treated diabetic, icariside II-treated diabetic, and insulin plus icariside II-treated diabetic. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, icariside II was administered by gastric lavage once a day (5 mg/kg) for 6 weeks; and 2-6 units of intermediate-acting insulin were given to maintain normal glycemia for 6 weeks. The main outcome measures were the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP); histology of penile endothelial cells and smooth muscle cells; neural nitric oxide synthase, AGEs and RAGE expression; malondialdehyde concentration; superoxide dismutase activity; and apoptosis index. Diabetic rats demonstrated a significantly lower ICP/MAP ratio, reduced penile endothelial cells, reduced smooth muscle cells, increased AGEs and RAGE, and increased apoptosis. Insulin and icariside II monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed significantly better erectile parameters, cytological components and biochemistry, similar to those in the normal control group. These results suggest that, although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus the antioxidant icariside II. The proposed combination therapy might have the potential to eliminate metabolic memory by down-regulating the AGEs-RAGE-oxidative stress axis. PMID- 25781209 TI - Near spectroscopically accurate ab initio potential energy surface for NH4(+) and variational calculations of low-lying vibrational levels. AB - A nine-dimensional potential energy surface (PES) for the ammonium cation has been constructed by fitting ~30 000 AE-CCSD(T)-F12a/cc-pCVTZ-F12 points up to 32 262 cm(-1) (4.0 eV) from the minimum. The fitting using the permutation invariant polynomial-neural network method has high fidelity, with a root-mean-square error of merely 2.34 cm(-1). The low-lying vibrational energy levels of NH4(+) have been determined quantum mechanically using both Jacobi and normal coordinates, and the fundamental frequencies are in excellent agreement with available experimental data. PMID- 25781210 TI - Association between depression and risk of atrial fibrillation and stroke in patients with psoriasis: a Danish nationwide cohort study. AB - BACKGROUND: Psoriasis and depression are associated with atrial fibrillation (AF) and stroke, but the influence of depression on the risk of stroke and AF in patients with psoriasis has not been examined. OBJECTIVES: We investigated the impact of depression on the risk of stroke and AF in patients with psoriasis in a nationwide cohort. METHODS: Data on all Danish citizens aged >= 18 years between 1 January 1997 and 31 December 2011 (n = 5 251 888) were linked at the individual level in nationwide registers. Incidence rates (IRs) per 1000 person-years were calculated, and hazard ratios (HRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by multivariate Cox regression models. RESULTS: There were 56,496 and 11,357 incident cases of mild and severe psoriasis, respectively. Incident depression occurred among 12,788 cases with mild and 3261 cases with severe psoriasis. IRs per 1000 patient-years of AF were 3.21, 5.02, 8.41, 5.39 and 7.41; and IRs of stroke were 2.62, 3.09, 6.71, 3.62 and 9.03 for the reference population, mild psoriasis without depression, mild psoriasis with depression, severe psoriasis without depression and severe psoriasis with depression, respectively. The respective HRs for new-onset AF were 1.14 [95% confidence interval (CI) 1.08-1.33], 1.19 (95% CI 1.06-1.33), 1.32 (95% CI 1.15 1.53) and 1.74 (95% CI 1.43-2.11), respectively. For stroke the HRs were 1.63 (95% CI 1.43-1.85) in patients with mild psoriasis and depression and 2.47 (95% CI 2.07-2.95) in patients with severe psoriasis and depression. CONCLUSIONS: In patients with psoriasis, depression is associated with an increased risk of incident AF and stroke. PMID- 25781212 TI - Rhombohedral polytypes of the layered honeycomb delafossites with optical brilliance in the visible. AB - We report the synthesis of the Delafossite honeycomb compounds Cu3Ni2SbO6 and Cu3Co2SbO6 via a copper topotactic reaction from the layered alpha-NaFeO2-like precursors Na3Ni2SbO6 and Na3Co2SbO6. The low-temperature exchange reaction exclusively produces the rhombahedral 3R polytype subcell, whereas only the hexagonal 2H polytype subcell has been made by conventional synthesis. The thus synthesized 3R variants are visually striking; they are bright lime-green (Ni variant) and terracotta-orange (Co variant), while both of the conventionally synthesized 2H variants have a burnt-red color. The new structures are characterized by powder X-ray diffraction and Rietveld analysis as well as magnetic susceptibility, X-ray photoelectron spectroscopy (XPS), and diffuse reflectance optical spectroscopy. Using thermogravimetric analysis, we identify a second order 3R -> 2H phase transition as well as a first-order structural transition associated with rearrangement of the honeycomb stacking layers. The optical absorbance spectra of the samples show discrete edges that correlate well to their visual colors. Exposing Cu3Ni2SbO6 to O2 and heat causes the sample to change color. XPS confirms the presence of Cu(2+) in these samples, which implies that the difference in color between the polytypes is due to oxygen intercalation resulting from their different synthetic routes. PMID- 25781211 TI - Optochemical dissection of T-box gene-dependent medial floor plate development. AB - In addition to their cell-autonomous roles in mesoderm development, the zebrafish T-box transcription factors no tail a (ntla) and spadetail (spt/tbx16) are required for medial floor plate (MFP) formation. Posterior MFP cells are completely absent in zebrafish embryos lacking both Ntla and Spt function, and genetic mosaic analyses have shown that the two T-box genes promote MFP development in a non-cell-autonomous manner. On the basis of these observations, it has been proposed that Ntla/Spt-dependent mesoderm-derived signals are required for the induction of posterior but not anterior MFP cells. To investigate the mechanisms by which Ntla and Spt regulate MFP development, we have used photoactivatable caged morpholinos (cMOs) to silence these T-box genes with spatiotemporal control. We find that posterior MFP formation requires Ntla or Spt activity during early gastrulation, specifically in lateral margin-derived cells that converge toward the midline during epiboly and somitogenesis. Nodal signaling-dependent MFP specification is maintained in the absence of Ntla and Spt function; however, midline cells in ntla;spt morphants exhibit aberrant morphogenetic movements, resulting in their anterior mislocalization. Our findings indicate that Ntla and Spt do not differentially regulate MFP induction along the anterior-posterior axis; rather, the T-box genes act redundantly within margin-derived cells to promote the posterior extension of MFP progenitors. PMID- 25781213 TI - Hierarchical effect behind the supramolecular chirality of silver(I)-cysteine coordination polymers. AB - Cysteine is a sulfur-containing amino acid that easily coordinates to soft metal ions and grafts to noble metal surfaces. Recently, chiroptical activity of Ag(+)/cysteine coordination polymers has been widely studied, while, on the other hand, the appearance of a plasmon-enhanced circular dichroic signal (PECD) at the plasmonic spectral region (lambda > 400 nm) has been observed for AgNPs capped with chiral sulfur-containing amino acids. These two events are both potentially exploited for sensing applications. However, the presence of Ag(+) ions in AgNP colloidal solution deals with the competition of cysteine grafting at the metal NP surface and/or metal ion coordination. Herein we demonstrate that the chiroptical activity observed by adding cysteine to AgNP colloids prepared by pulsed laser ablation in liquids (PLAL) is mainly related to the formation of CD active Ag(+)/cysteine supramolecular polymers. The strict correlation between supramolecular chirality and hierarchical effects, driven by different chemical environments experienced by cysteine when different titration modalities are used, is pivotal to validate cysteine as a fast and reliable probe to characterize the surface oxidation of AgNPs prepared by pulsed laser ablation in liquids by varying the laser wavelengths. PMID- 25781214 TI - The effects of creatine supplementation on thermoregulation and isokinetic muscular performance following acute (3-day) supplementation. AB - AIM: The purpose of this investigation was to determine the effects of 3 d of creatine supplementation on thermoregulation and isokinetic muscular performance. METHODS: Fourteen males performed two exercise bouts following 3 d of creatine supplementation and placebo. Subjects exercised for 60 min at 60-65% of VO2max in the heat followed by isokinetic muscular performance at 60, 180, and 300 degrees .s(-1). Dependent variables for pre- and postexercise included nude body weight, urine specific gravity, and serum creatinine levels. Total body water, extracellular water and intracellular water were measured pre-exercise. Core temperature was assessed every 5 min during exercise. Peak torque and Fatigue Index were used to assess isokinetic muscular performance. RESULTS: Core temperature increased during the run for both conditions. Total body water and extracellular water were significantly greater (P<0.05) following creatine supplementation. No significant difference (P>0.05) was found between conditions for intracellular water, nude body weight, urine specific gravity, and serum creatinine. Pre-exercise scores for urine specific gravity and serum creatinine were significantly less (P<0.05) versus post-exercise. No significant differences (P>0.05) were found in peak torque values or Fatigue Index between conditions for each velocity. A significant (P<0.05) overall velocity effect was found for both flexion and extension. As velocity increased, mean peak torque values decreased. CONCLUSION: Three d of creatine supplementation does not affect thermoregulation during submaximal exercise in the heat and is not enough to elicit an ergogenic effect for isokinetic muscle performance following endurance activity. PMID- 25781215 TI - Effect of foot type on knee valgus, ground reaction force, and hip muscle activation in female soccer players. AB - BACKGROUND: The purpose of this study was to determine the degree to which subtalar joint pronation resulting from a supple planus foot affects knee alignment, hip muscle activation and ground reaction force attenuation in female athletes during a broad jump-to-cut maneuver. METHODS: Twelve National Collegiate Athletic Association (NCAA) Division II female soccer players (age=19.4+/-1.4 years, height=1.64+/-0.05 m, mass=64.10+/-4.8 kg) were identified as having either supple planus (SP) or rigid feet (RF). Participants completed three broad jump-to-cut trials onto a force plate while EMG and motion data were collected. Muscle activation levels (percentage of maximal voluntary contraction [%MVC]) in the gluteus maximus, gluteus medius, biceps femoris, and rectus femoris were calculated, and peak vertical and medial shear force, rate of loading, and valgus angle were collected for each trial. RESULTS: Mann-Whitney U tests revealed no statistical significance between foot-type groups, however, effect size statistics revealed practical significance for between-group %MVC biceps femoris (d=1.107), %MVC gluteus maximus (d=1.069), and vertical ground reaction force (d=1.061). CONCLUSIONS: Athletes with a SP foot type may experience decreased hip muscle activation associated with increased vertical ground reaction force during a broad jump-to-cut maneuver. This might result in reduced dynamic stability and neuromuscular control during deceleration, potentially increasing the risk of non contact ACL injury in female soccer players. PMID- 25781216 TI - Highly enantioselective [3 + 2]-annulation of isatin-derived morita-baylis hillman adducts with cyclic sulfonimines. AB - An organocatalytic [3 + 2]-annulation between isatin-derived Morita-Baylis Hillman adducts and cyclic sulfonimines has been developed in high yields with excellent enantio- and diastereoselectivities via an allylic nitrogen-ylide intermediate. The reaction provides access to heavily substituted aza spirooxindole derivatives, which also contain ring fused cyclic sultams. PMID- 25781217 TI - Bisphenol A removal by a Pseudomonas aeruginosa immobilized on granular activated carbon and operating in a fluidized bed reactor. AB - Serratia rubidiae, Pseudomonas aeruginosa and Escherichia coli K12 have been studied for their ability of Bisphenol A removal from aqueous systems and biofilm formation on activated granule carbon. Mathematical equations for biodegradation process have been elaborated and discussed. P. aeruginosa was found the best strain to be employed in the process of Bisphenol A removal. The yield in BPA removal of a P. aeruginosa biofilm grown on GAC and operating in a fluidized bed reactor has been evaluated. The results confirm the usefulness in using biological activated carbon (BAC process) to remove phenol compounds from aqueous systems. PMID- 25781219 TI - Vitamin D status and acute respiratory infection: cross sectional results from the United States National Health and Nutrition Examination Survey, 2001-2006. AB - Vitamin D is a promising, though under-explored, potential modifiable risk factor for acute respiratory infections (ARIs). We sought to investigate the association of vitamin D status with ARI in a large, nationally-representative sample of non institutionalized individuals from the United States. We analyzed 14,108 individuals over 16 years of age in the National Health and Nutrition Survey (NHANES) 2001-2006 in this cross-sectional study. We used locally weighted scatterplot smoothing (LOWESS) to depict the relationship between increasing 25 hydroxyvitamin D (25OHD) levels and ARI. We then performed a multivariable regression analysis to investigate the association of 25OHD levels with ARI, while adjusting for known confounders. The median serum 25OHD level was 21 (IQR 15-27) ng/mL. Overall, 4.8% (95% CI: 4.5-5.2) of participants reported an ARI within 30 days before their participation in the national survey. LOWESS analysis revealed a near-linear relationship between vitamin D status and the cumulative frequency of ARI up to 25OHD levels around 30 ng/mL. After adjusting for season, demographic factors, and clinical data, 25OHD levels <30 ng/mL were associated with 58% higher odds of ARI (OR 1.58; 95% CI: 1.07-2.33) compared to levels >=30 ng/mL. Among the 14,108 participants in NHANES 2001-2006, 25OHD levels were inversely associated with ARI. Carefully designed, randomized, controlled trials are warranted to determine the effect of optimizing vitamin D status on the risk of ARI. PMID- 25781218 TI - Folate deficiency decreases apoptosis of endometrium decidual cells in pregnant mice via the mitochondrial pathway. AB - It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (DeltaPsim) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy. PMID- 25781220 TI - Gastroprotective efficacy and safety evaluation of scoparone derivatives on experimentally induced gastric lesions in rodents. AB - This study investigated the gastroprotective efficacy of synthesized scoparone derivatives on experimentally induced gastritis and their toxicological safety. Six scoparone derivatives were synthesized and screened for gastroprotective activities against HCl/ethanol- and indomethacin-induced gastric ulcers in rats. Among these compounds, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin were found to have gastroprotective activity greater than the standard drug rebamipide; 6-methoxy-7,8-methylenedioxycoumarin, 6-methoxy-7,8-(1-methoxy) methylenedioxycoumarin, 6,7-methylenedioxycoumarin, and 6,7-(1-methoxy) methylenedioxycoumarin were found to be equipotent or less potent that of rebamipide. Pharmacological studies suggest that the presence of a methoxy group at position C-5 or C-8 of the scoparone's phenyl ring significantly improves gastroprotective activity, whereas the presence of a dioxolane ring at C-6, C-7, or C-8 was found to have decreased activity. In order to assess toxicological safety, two of the potent gastroprotective scoparone derivatives-5,6,7 trimethoxycoumarin and 6,7,8-trimethoxycoumarin-were examined for their acute toxicity in mice as well as their effect on cytochrome P450 (CYP) enzyme activity. These two compounds showed low acute oral toxicity in adult male and female mice, and caused minimal changes to CYP3A4 and CYP2C9 enzyme activity. These results indicate that compared to other scoparone derivatives, 5,6,7 trimethoxycoumarin and 6,7,8-trimethoxycoumarin can improve gastroprotective effects, and they have low toxicity and minimal effects on drug-metabolizing enzymes. PMID- 25781221 TI - Could a change in diet revitalize children who suffer from unresolved fatigue? AB - Many children deal with fatigue for which no proper treatment can be given. A possible explanation for their fatigue is a micro deficiency of minerals and vitamins. In this non-randomized controlled trial, we clinically evaluated symptoms of fatigue in children for whom a nutrient-rich diet was advised. A group of 98 children (2-18 years old) with unexplained symptoms of fatigue was examined. The dietary modifications consisted of green vegetables, beef, whole milk and full-fat butter. Children in the intervention group were asked to follow the diet for three months, whereas the control-group followed their normal diet. The primary outcome was symptoms of fatigue, as determined by a PedsQL Multidimensional Fatigue Scale, and secondary outcomes were compliance with the diet and BMI. Children, who followed the diet showed a significant decrease in the need to sleep (CI 0.83; 14.86, p = 0.03). They slept better through the night and took fewer naps. When analyzing components of the advised diet separately, a significant larger decrease in cognitive fatigue symptoms was seen for eating green vegetables according to the diet guidelines (CI 2.27; 30.63, p = 0.024). Furthermore, a lower need to sleep was seen when whole milk was consumed almost daily (CI 0.02; 14.62, p = 0.049). Our study showed that nutritional advice is an elegant, and effective method for decreasing some symptoms of medically unresolved fatigue in children. PMID- 25781222 TI - Greater Step Widths Reduce Internal Knee Abduction Moments in Medial Compartment Knee Osteoarthritis Patients During Stair Ascent. AB - Increased step widths have been shown to reduce peak internal knee abduction moments in healthy individuals but not in knee osteoarthritis patients during stair descent. This study aimed to assess effects of increased step widths on peak knee abduction moments and associated variables in adults with medial knee osteoarthritis and healthy older adults during stair ascent. Thirteen healthy older adults and 13 medial knee osteoarthritis patients performed stair ascent using preferred, wide, and wider step widths. Three-dimensional kinematics and ground reaction forces (GRFs) using an instrumented staircase were collected. Increased step width reduced first and second peak knee abduction moments, and knee abduction moment impulse. In addition, frontal plane GRF at time of first and second peak knee abduction moment and lateral trunk lean at time of first peak knee abduction moment were reduced with increased step width during stair ascent in both groups. Knee abduction moment variables were not different between knee osteoarthritis patients and healthy controls. Our findings suggest that increasing step width may be an effective simple gait alteration to reduce knee abduction moment variables in both knee osteoarthritis and healthy adults during stair ascent. However, long term effects of increasing step width during stair ascent in knee osteoarthritis and healthy adults remain unknown. PMID- 25781224 TI - Theoretical analysis of ion conductance and gating transitions in the OpdK (OccK1) channel. AB - Electrophysiological measurements have shown that the channel protein OpdK, also known as OccK1, from Pseudomonas aeruginosa shows three conductance substates. Although several experimental studies have been performed, a description of the gating transitions at the molecular level remains elusive. In the present investigation, molecular dynamics simulations have been employed to elucidate the conductance and gating properties of the OpdK channel and loop deletion mutant thereof. Our results suggest that switching between different substates are coupled to conformational changes in the constriction loop L7 which is in accord with the experimental results. Unbiased simulations at different temperatures are analyzed and residues R284 and F291 on loop L7 have been identified to be key in the gating transitions. A plausible mechanism of gating for this channel is discussed. The obtained molecular level description might have important implications for understanding the functional properties of OpdK channel in vitro as well as within a cellular environment. PMID- 25781225 TI - The European Union Integrated Political Crisis Response Arrangements: Improving the European Union's Major Crisis Response Coordination Capacities. AB - In recent years, the European Union (EU) has progressively assumed more and more of a primary role in crisis response coordination. The EU Integrated Political Crisis Response arrangements (IPCR) were recently approved to facilitate this task. These new agreements, which substitute for the Crisis Coordination Agreements, will add more flexibility to crisis response mechanisms in the EU. They will also strengthen cooperation between the different relevant agents in a major crisis situation and create new useful tools, such as the Integrated Situational Awareness and Analysis. Their real performance still needs to be fully tested, but some weakness can already be foreseen. This article provides a deep analysis of this new legislation. PMID- 25781223 TI - Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors. AB - In recent years, the first generation of beta-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins. PMID- 25781227 TI - Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3beta pathway. AB - Pregnenolone sulfate, an endogenous neurosteroid in the central nervous system, is a positive allosteric modulator of the NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of pregnenolone sulfate using the dopamine transporter knockout (DAT-KO) mice, which exhibit endophenotypes that recapitulate certain symptoms of schizophrenia, including the psychomotor agitation, stereotypy, prepulse inhibition (PPI) deficits and cognitive impairments. We found that acute treatment with pregnenolone sulfate normalized the hyperlocomotion and stereotypic bouts, and rescued the PPI deficits of DAT-KO mice. In addition, long-term treatment with pregnenolone sulfate rescued the cognitive deficits of DAT-KO mice in the novel object recognition and social transmission of food preference tests. We also showed that pregnenolone sulfate normalized behavioral abnormalities in MK801-treated wild type mice, whereas pregnenolone, its precursor, only partially rescued MK801 induced behavioral abnormalities. This indicates that there are distinct mechanisms of action between pregnenolone sulfate and pregnenolone, and the involvement of NMDA receptor signaling in the action of pregnenolone sulfate. Moreover, we found that acute treatment with pregnenolone sulfate increased the phosphorylation levels of striatal AKT and GSK3beta in DAT-KO mice, and that long term treatment with pregnenolone sulfate increased expression levels of NR1 subunit of the NMDA receptor in hippocampus. Thus, pregnenolone sulfate was able to rescue the behavioral anomalies of DAT-KO mice through the NMDA receptor mediated, AKT/GSK3beta signaling pathway. PMID- 25781226 TI - Translational potential of olfactory mucosa for the study of neuropsychiatric illness. AB - The olfactory mucosa (OM) is a unique source of regenerative neural tissue that is readily obtainable from living human subjects and thus affords opportunities for the study of psychiatric illnesses. OM tissues can be used, either as ex vivo OM tissue or in vitro OM-derived neural cells, to explore parameters that have been difficult to assess in the brain of living individuals with psychiatric illness. As OM tissues are distinct from brain tissues, an understanding of the neurobiology of the OM is needed to relate findings in these tissues to those of the brain as well as to design and interpret ex vivo or in vitro OM studies. To that end, we discuss the molecular, cellular and functional characteristics of cell types within the olfactory mucosa, describe the organization of the OM and highlight its role in the olfactory neurocircuitry. In addition, we discuss various approaches to in vitro culture of OM-derived cells and their characterization, focusing on the extent to which they reflect the in vivo neurobiology of the OM. Finally, we review studies of ex vivo OM tissues and in vitro OM-derived cells from individuals with psychiatric, neurodegenerative and neurodevelopmental disorders. In particular, we discuss the concordance of this work with postmortem brain studies and highlight possible future approaches, which may offer distinct strengths in comparison to in vitro paradigms based on genomic reprogramming. PMID- 25781228 TI - Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence. AB - During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group's developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity-second diffusion eigenvalue-in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism. PMID- 25781229 TI - Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning. AB - Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual. PMID- 25781230 TI - Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence. AB - Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0-3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence. PMID- 25781234 TI - Update on inpatient diabetes management: call for action. PMID- 25781231 TI - Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression. AB - Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [(18)F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression. PMID- 25781235 TI - Differential therapeutic effects of nateglinide and acarbose on fasting and postprandial lipid profiles: a randomized trial. AB - BACKGROUND: Dyslipidemia is commonly seen in patients with type 2 diabetes mellitus (T2DM). The current study sought to compare the effects of nateglinide and acarbose, two antihyperglycemic agents, on both fasting and postprandial lipid profiles in Chinese subjects with T2DM. SUBJECTS AND METHODS: For this multicenter, open-label, randomized, active-controlled, parallel-group study, 103 antihyperglycemic agent-naive patients with T2DM were recruited from four hospitals in China. In total, 85 subjects (44 in the nateglinide group, 41 in the acarbose group) with a known complete lipid profile underwent the entire clinical trial and were included in the final analysis. Serum was collected in the fasting state and 30 and 120 min after a standardized meal (postprandial states) to measure the baseline lipid profiles; the same testing was performed upon completion of a 2-week course of nateglinide (120 mg three times a day) or acarbose (50 mg three times a day). RESULTS: Fasting triglyceride (TG) levels were significantly reduced by both nateglinide and acarbose (P<0.001), with acarbose providing a significantly more robust improvement (vs. nateglinide, P=0.005). Additionally, the TG levels at both postprandial times were significantly reduced by acarbose (P<0.001 at 30 min and P=0.002 at 120 min), whereas nateglinide treatment only significantly reduced the 30-min postprandial TG (P=0.029). Neither nateglinide nor acarbose treatment had significant impact on total cholesterol, high-density lipoprotein, low-density lipoprotein, or non high-density lipoprotein cholesterol. CONCLUSIONS: Compared with nateglinide, acarbose has superior therapeutic efficacy for reducing fasting and postprandial TG levels in patients with T2DM. PMID- 25781236 TI - Indispensability of chemotherapy in estrogen receptor-negative early breast cancer in elderly women with diabetes mellitus. AB - To evaluate whether chemotherapy is indispensable in elderly patients with early estrogen receptor (ER)-negative breast cancer and diabetes mellitus (DM), the data on 112 patients, >=70 years of age, with early, operable ER-negative breast cancer who were treated at the Cancer Hospital of Fudan University, Shanghai, China, between 2000 and 2010, were analyzed. The overall survival (OS), disease free survival (DFS), and breast cancer-specific survival (BCS) were compared. Survival analysis was performed using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of DM and chemotherapy for OS, DFS, and BCS. The univariate Cox regression analysis revealed that DM at diagnosis, the number of positive lymph nodes, and radiotherapy were associated with OS, the number of positive lymph nodes, human epidermal growth factor 2 (HER2/neu) status, and radiotherapy were associated with DFS, and the number of positive lymph nodes, tumor size, HER2/neu status, chemotherapy, and radiotherapy were associated with BCS. The subsequent multivariate analysis identified DM at diagnosis (hazard ratio [HR]=3.797; 95% confidence interval [CI], 1.515-9.520; P=0.004) as an independent prognostic factor for OS (with the addition of chemotherapy regimen). Chemotherapy was not an independent prognostic factor for either OS (HR=1.275; 95% CI, 0.614-2.646; P=0.515) or DFS (HR=0.849; 95% CI, 0.445-1.619; P=0.619) when other possible factors that may affect the results were adjusted. In conclusion, chemotherapy was not found to be indispensable for elderly (>=70 years of age) female patients with early ER-negative breast cancer with DM because, particularly in such patients, the treatment of DM may be more important compared with chemotherapy. PMID- 25781237 TI - Taxonomic review of Chinese species of ground beetles of the subgenus Pseudoophonus (genus Harpalus) (Coleoptera: Carabidae). AB - A taxonomic review of 23 species of the subgenus Pseudoophonus Motschulsky, 1844, the genus Harpalus Latreille, 1802, occurring in China is given, and a key to these species is provided. The species are divided in three species groups and five subgroups, the distinctive characters of which are listed. The following new synonyms are established: Harpalus calceatus Duftschmid, 1812 = Anisodactylus propinquus Ballion, 1870, syn. n.; H. davidi (Tschitscherine, 1897) = H. kailiensis Huang, 1992, syn. n.; = H. adenticulatus Huang, 1992, syn. n.; = H. cilihumerus Huang, Hu & Sun, 1994, syn. n.; H. fokienensis Schauberger, 1930 = H. muciulus Huang, 1992, syn. n.; H. griseus (Panzer, 1796) = H. xinjiangensis Huang, Hu & Sun, 1994, syn. n.; H. hauserianus Schauberger, 1929 = H. disaogashimensis Huang, 1995, syn. n.; H. pastor pastor Motschulsky, 1844 = H. penglainus Huang, Hu & Sun, 1994, syn. n.; = H. chiloschizontus Huang, 1995, syn. n.; H. rufipes (DeGeer, 1774) = H. scabripectus Huang, Hu & Sun, 1994, syn. n.; H. singularis Tschitscherine, 1906 = H. chengjiangensis Huang, 1993, syn. n.; H. sinicus Hope, 1845 = H. periglabellus Huang, 1992, syn. n.; = H. longihornus Lei & Huang, 1997, syn. n.; and H. tridens Morawitz, 1862 = H. hypogeomysis Huang, 1993, syn. n.; = H. pilosus Huang, 1995, syn. n. Statuses of H. yinchuanensis Huang, 1993 and H. disimuciulus Huang, Lei, Yan & Hu, 1996 are discussed. Lectotypes are designated for H. capito Morawitz, 1862, H. japonicus Morawitz, 1862 and H. eous Tschitscherine, 1901. New data on distribution of Pseudoophonus species in China are provided. Harpalus babai Habu, 1973 is reported from China (Jiangxi) for the first time. The following taxa are recorded from the following Chinese provinces for the first time: H. ussuriensis Chaudoir, 1863 from Hunan; H. aenigma (Tschitscherine, 1897) from Hubei, Jiangxi, and Guangxi; H. pastor Motschulsky, 1844 from Beijing and Xizang; H. fokienensis Schauberger, 1930 from Anhui and Jiangxi; H. simplicidens Schauberger, 1929 from Beijing, Shanghai, and Fujian; H. coreanus (Tschitscherine, 1895) from Anhui, Henan, Zhejiang, Shanghai, Hubei, and Guangdong; H. suensoni Kataev, 1997 from Yunnan; H. sinicus Hope, 1845 from Hainan; H. davidi (Tschitscherine, 1897) from Zhejiang, Hunan, and Guizhou; H. pseudohauserianus Kataev, 2001 from Sichuan; H. indicus orientalis Kataev, 2014 from Xizang, Guangxi, and Guangdong; H. hauserianus Schauberger, 1929 from Xizang and Guizhou; H. singularis Tschitscherine, 1906 from Taiwan; and H. calceatus Duftschmid, 1812 from Guangxi. In addition, H. sinicus and H. singularis are reported from Laos for the first time. PMID- 25781238 TI - Taxonomic review of Tapiena (Orthoptera: Phaneropteridae: Phaneropterinae), with key to species and new species from Thailand. AB - The genus Tapiena (Orthoptera: Phaneropteridae: Phaneropterinae), consisting of species from around Asia and Africa, is reviewed. Henningian species concept was applied and morphology was used to estimate species boundaries. From Sakaerat Environmental Research Station, Thailand, two new species are described: Tapiena sakaerat Tan, Liu, Artchawakom sp. n. and Tapiena denticulata Tan, Liu, Artchawakom sp. n. This represents the first record of the genus Tapiena in Thailand. A key to the species of Tapiena (for males only) is also provided. PMID- 25781239 TI - Revision of Campsurus violaceus species group (Ephemeroptera: Polymitarcyidae) with new synonymies and nomina dubia in Campsurus Eaton, 1868. AB - The violaceus species group (formerly notatus species group) of Campsurus Eaton is revised. All the species in the violaceus group are diagnosed. A new species, C. molinai sp. nov. is described based on male imagos from Bolivia, characterized by their large and sclerotized penes. The violaceus group is proposed to include the following species: C. assimilis Traver, C. truncatus Ulmer (=C. mahunkai Puthz = C. melanocephalus Pereira & da Silva, new synonyms), C. violaceus Needham & Murphy (= C. meyeri Navas = C. notatus Needham & Murphy = C. paranensis Navas, new synonyms), C. emersoni Traver, C. decoloratus (Hagen), and C. molinai sp.nov. Additionally we consider the following species as nomina dubia: C. longicauda Navas, C. pfeifferi Navas, C. zikani Navas, C. albicans (orig. Ephemera albicans Percheron in Guerin & Percheron), C. burmeisteri Ulmer, C. dallasi Navas, C. quadridentatus Eaton, C. claudus Needham & Murphy, C. corumbanus Needham & Murphy, C. dorsalis (Burmeister), C. mutilus Needham & Murphy, and C. striatus Needham & Murphy. Given the results presented herein (five species synonymized and 12 proposed as nomina dubia), only 28 valid species remain in the genus Campsurus. Additionally, the nymphal stages of C. violaceus and C. truncatus are described and illustrated. Female adult genitalia (sockets) and eggs of C. decoloratus are described for the first time. Diagnoses, new country records, and redescriptions of selected characters of the imagos for the species of the violaceus group are given. PMID- 25781240 TI - A new species of glassfrog, genus Hyalinobatrachium (Anura: Centrolenidae), from the Caribbean foothills of Costa Rica. AB - We describe a new glassfrog belonging to the genus Hyalinobatrachium from the tropical wet forests and premontane rainforests of the Caribbean foothills of Costa Rica, at elevations between 400-800 m. The type locality is approximately 4km west of Santa Clara, ca. 400 m a.s.l. (N 10.219, W 83.949). This new taxon is distinguished by its morphological characteristics, distinct advertisement call, and genetic distance (COI mRNA). The new species can be distinguished from other species of the genus Hyalinobatrachium by the combination of the following characters: (1) snout truncate in dorsal and lateral views; (2) granular dorsal skin; (3) parietal and cardial peritonea transparent; (4) hand webbing formula III 2(-)-2(+) IV; (5) in life having a uniform lime green dorsal surface that lacks any evident light or dark spots; (6) iris coloration silvery-white with fine dark spots or reticulation; (7) advertisement call consisting of a single tonal long metallic whistle-like note with a duration of 0.40-0.55 s (average 0.501 s) and a dominant frequency of 3.35-3.44 kHz (average 3.39 kHz); (8) highly divergent DNA sequences for the mitochondrial gene COI from other analysed members of the genus Hyalinobatrachium, with 12.4% divergence from its closest known species, Hyalinobatrachium chirripoi. PMID- 25781241 TI - Intra- and inter-population polymorphism in Coletinia maggii (Grassi, 1887) (Zygentoma: Nicoletiidae), an inhabitant of soil, mesovoid shallow substratum (MSS) and caves--A challenge for the strict classification of subterranean fauna? AB - New locations of Coletinia maggii (Grassi, 1887) have been discovered in the center of the Iberian Peninsula in different types of subterranean environments, such as a stony layer in the subsoil of an alluvial plain, an alluvial Mesovoid Shallow Substratum or Milieu Souterrain Superficiel (MSS) and a gypsum cave. This is the first record of both an alluvial MSS in the center of the Iberian Peninsula and of a subterranean species living in it. The high number of specimens captured allowed the first detailed study of the morphological intra- and inter-population variations of this species. The implications of its presence in these different environments, its wide distribution area across Europe, and the relevance of the morphological variation in the characters for the taxonomy of this species are discussed. Based on the results, Coletinia hernandoi Molero, Bach & Gaju, 2013 is proposed as a new synonym of C. maggii. PMID- 25781242 TI - Revision of the African pollen beetle genera Tarchonanthogethes and Xenostrongylogethes, with insect-host plant relationships, identification key, and cladistic analysis of the Anthystrix genus-complex (Coleoptera: Nitidulidae: Meligethinae). AB - The Afrotropical endemic pollen beetle genera Tarchonanthogethes Audisio & Cline and Xenostrongylogethes Audisio & Cline, of the Anthystrix genus-complex, are revised. Eleven new species of Tarchonanthogethes (T. autumnalis, sp. nov., T. bisignatus, sp. nov., T. fasciatus, sp. nov., T. gratiellae, sp. nov., T. hermani, sp. nov., T. hystrix, sp. nov., T. lilliputianus, sp. nov., T. maasai, sp. nov., T. manconiae, sp. nov., T. pectinipes, sp. nov., T. thalycriformis, sp. nov.) and one new Xenostrongylogethes (X. cychramoides, sp. nov.) are described, illustrated and compared with related taxa. Tarchonanthogethes hirtus Kirejtshuk & Easton, 1988 is synonymized with T. martini (syn. nov.). Meligethes assutus Easton, 1960 from Kenya is transferred from Afrogethes Audisio & Cline to Tarchonanthogethes (comb. nov.). Meligethes singularis Grouvelle, 1919 from southern Africa is transferred from Tarchonanthogethes to Meligethinus Grouvelle, 1906 (comb. nov.). Larval host-plants for Tarchonanthogethes and Xenostrongylogethes include dioecious bushes and trees of Tarchonantheae Asteraceae (genera Brachylaena R.Br. and Tarchonanthus L.). All species currently attributed to the genera Anthystrix Kirejtshuk, Sebastiangethes Audisio, Kirk Spriggs & Cline, Tarchonanthogethes and Xenostrongylogethes (Anthystrix genus complex) are included in a morphology-based cladistic analysis to provide a rigorous hypothesis of phylogenetic relationships. An identification key to all 25 known species in the Anthystrix genus-complex, including all available data on insect host plant relationships, is presented. PMID- 25781243 TI - Debroyerella gen. nov. and Ulladulla gen. nov., two new lysianassoid genera (Crustacea, Amphipoda, Lysianassoidea). AB - Two new genera and a new species of lysianassoid amphipods are described. Debroyerella gen. nov. is described for three Antarctic species previously assigned to the genus Cheirimedon. Ulladulla gen. nov. is described to accommodate the new species U. selje, from Australian waters. Diagnostic descriptions are given for the genera and all species are described in full. PMID- 25781244 TI - Discovery of a second species of Aesalini from Taiwan, with description of the new species of the genus Echinoaesalus Zelenka, 1993 (Coleoptera: Lucanidae). AB - Echinoaesalus chungi Huang & Chen, new species is described from Pingtung, Taiwan. It is the second species of the tribe Aesalini known from Taiwan. This new species is similar to the Bornean species Echinoaesalus arayai Huang & Imura, 2011, but can be distinguished mainly by the smaller size of the entire body, the laterally hooked sulcus on mentum of male, the separated sulci on mentum of female, the bristles inserted anteriorly in the wall of the punctures on dorsal surface of the body, the 9th abdominal segment of male with relatively larger paired pleurites, the medial lobe of parameres with weakly pigmented dorsal surface on distal half and with the pigmented distal sclerite interrupted on dorsal surface, and female genitalia with longer styli, thinner hemisternites and shorter bursa copulatrix. A key to the males of Echinoaesalus species is given. Female genitalia are described in detail for the new species and Echinoaesalus arayai. PMID- 25781245 TI - Pedunculate Molgula species (Ascidiidae, Molgulidae) from the French Antarctic sector. Redescription and taxonomic revision. AB - Following the Challenger Expedition in the southern Hemisphere, several international surveys have studied Antarctic ascidians. Several pedunculate Molgula were successively described under various names. From the French part of the Antarctic continent and the Kerguelen area, numerous Molgula were recently collected. They are described here in different species, but closely allied. Their taxonomy is revised with an historical review of the most detailed publications and a link to the ancient names. PMID- 25781246 TI - Corrections on the biology of Traumatomutilla Andre, 1901 (Hymenoptera: Mutillidae). PMID- 25781247 TI - A systematic study of Peliococcus Borchsenius (Hemiptera: Coccoidea: Pseudococcidae), with descriptions of a new Palaearctic genus and four new species from Turkey. AB - Within the Phenacoccinae (Hemiptera: Coccoidea: Pseudococcidae), there are four nominal genera that include species with clusters or groups of multilocular disc pores and/or oral collar tubular ducts of more than one size, namely Peliococcus Borchsenius (= Spinococcus Borchsenius and Eupeliococcus Savescu), Peliococcopsis Borchsenius, Erimococcus Ezzat, and Seyneria Goux. This study analysed molecular data (from the mitochondrial gene cytochrome oxidase I, COI, and a fragment of the D2 and D3 regions of the large subunit ribosomal DNA gene, 28S) from Palaearctic species of Peliococcus, Peliococcopsis and a new genus, Pelionella Kaydan to demonstrate: (i) that Peliococcus and several morphologically similar genera do not form a monophyletic group; (ii) Peliococcus, as currently understood, is not monophyletic, and (iii) the structure of the multilocular disc pores is important for recognising the systematic position of these genera. The morphological data were fitted to the molecular tree to allow reassessment of the generic classification and to produce morphological diagnoses of the genera. Five species have been moved to the genus Erimococcus Ezzat: Peliococcus kimmericus Kiritchenko, P. montanus Bazarov & Babaeva, P. multitubulatus (Danzig), P. salviae Hadzibejli and P. talhouki Matille-Ferrero, as E. kimmericus (Kiritchenko) comb. nov., E. montanus (Bazarov & Babaeva) comb. nov., E. multitubulatus (Danzig) comb. nov., E. salviae (Hadzibejli) comb.nov. and E. talhouki (Matille-Ferrero) comb. nov. In addition, a new species of Erimococcus is described, namely Erimococcus ozani Kaydan sp. nov. Also Peliococcus ilamicus Moghaddam syn. nov. is recognised as a junior synonym of Phenacoccus kimmericus Kiritchenko (previously in Peliococcus, now in Erimococcus). A new genus, Pelionella gen. nov. is introduced to take nine species, namely Peliococcus balteatus Green, P. cycliger Leonardi, P. manifectus Borchsenius, P. stellarocheae Goux, P. glandulifer Borchsenius, P. tritubulatus Kritchenko, P. sablius Goux, P. grassianus Goux, P. proeminens Goux, as Pelionella balteata (Green) comb. nov., Pelionella cycliger (Leonardi) comb. nov., Pelionella manifecta (Borchsenius) comb. nov., Pelionella stellarocheae (Goux) comb. nov., Pelionella glandulifer (Borchsenius) comb. nov., Pelionella tritubulata (Kritchenko) comb. nov., Pelionella sablia (Goux) comb. nov., Pelionella grassiana (Goux) comb. nov. and Pelionella proeminens (Goux) comb. nov. In addition, two species are described as new: Pelionella multipora Kaydan sp. nov. and Pelionella kansui Kaydan sp. nov. Three species, namely Peliococcus daganiae (Bodenheimer), P. orientalis Bazarov and Spinococcus giuliae Pellizzari, are transferred to Phenacoccus as: Phenacoccus daganiae (Bodenheimer), comb. nov., Phenacoccus orientalis (Bazarov), comb. nov. and Phenacoccus giuliae (Pellizzari), comb. nov. Three new species synonymies are recognised: Peliococcus deserticola Ben-Dov & Gerson syn. nov. of Peliococcus cycliger Leonardi (now Pelionella cycliger), Peliococcus albertaccius Goux syn. nov. of Peliococcus manifectus Borchsenius (now Pelionella manifecta) and Peliococcus lycicola Tang syn. nov. is recognised as a junior synonym of Peliococcus chersonensis Kiritshenko. In addition, a new Peliococcus species is described, namely Peliococcus agriensis Kaydan sp. nov. PMID- 25781248 TI - Redescription and phylogenetic placement of the Hispaniolan spider genus Lomaita Bryant, 1948 (Araneae, Linyphiidae). AB - The monotypic linyphiid genus Lomaita Bryant 1948 is redescribed. We present an updated description of the male of L. darlingtoni, the first description of the female and data on its natural history and distribution in the Dominican Republic. We provide a hypothesis on the phylogenetic placement of Lomaita based on cladistic analyses of morphological characters. PMID- 25781249 TI - A new cecidogenous species of Eugnosta Hubner (Lepidoptera: Tortricidae) associated with Baccharis salicifolia (Asteraceae) in the northern Chilean Atacama Desert: Life-history description and phylogenetic inferences. AB - Eugnosta Hubner, 1825 (Lepidoptera, Tortricidae, Tortricinae, Cochylini, Cochylina) is reported for the first time in Chile. Male and female adults, the pupa, the last-instar larva, and galls of Eugnosta azapaensis Vargas & Moreira, sp. n., are described and illustrated from the Azapa Valley in the northern Atacama Desert. The larvae induce fusiform galls on shoots of the shrub Baccharis salicifolia (Ruiz & Pav.) Pers. (Asteraceae). An assessment of phylogenetic relationships of E. azapaensis with two congeneric species based on mitochondrial DNA is provided. PMID- 25781250 TI - A new species of Deutonura (Collembola: Neanuridae: Neanurinae) from north eastern Algeria, and characterisation of two intraspecific lineages by their barcodes. AB - A new species of Deutonura, D. zana sp. nov., is described from north-eastern Algeria. It is morphologically similar in most characters to D. deficiens meridionalis and to D. luberonensis, both members of the D. phlegraea group, differing from the former by the absence of chaeta O on head, and from the later by the separation of tubercles Di and De on Th. I. The muscular insertion pattern of the new species is figured, and suggested as a potential new character for the taxonomy of Neanurinae. Deutonura zana sp. nov. is well characterised by its barcode sequence. Within the new species as morphologically defined, two groups of COI haplotypes, in individuals indistinguishable morphologically, are reported from two distinct mountain ranges. The need of a morphological assessment of demes diverging at significant infra-specific level in their barcodes is stressed. PMID- 25781251 TI - A review of the genus Chalcocopris Burmeister, 1846 (Coleoptera: Scarabaeidae: Scarabaeinae), with description of a new species. AB - Species included in the genus Chalcocopris Burmeister, 1846 are reviewed, including the description of a new species (Chalcocopris inexpectatus sp. nov.) from Central Brazil, and the designation of a neotype for Copris hesperus Olivier, 1789. Pictures, diagnostic characters and an identification key are provided. PMID- 25781252 TI - Molecular phylogeny and morphological revision of Myotis bats (Chiroptera: Vespertilionidae) from Taiwan and adjacent China. AB - In taxonomic accounts, three species of Myotis have been traditionally reported to occur on the island of Taiwan: Watase's bat (M. formosus watasei Kishida), the Formosan broad-muzzled bat (M. muricola latirostris Kishida) and the Formosan mouse-eared bat (M. adversus taiwanensis Linde). The discovery in 1997 of an unknown taxon not fitting to the description of any of these species encouraged us to re-examine more thoroughly the systematics and phylogeny of Myotis bats inhabiting Taiwan. We used a combination of morphologic and molecular methods to aid the identification of the different taxa from this island and reconstruct their phylogenetic relationships. Multivariate analyses based on 17 craniodental characters of 105 specimens caught across Taiwan and further external characters allowed us to discriminate eight taxa of Myotinae co-occurring on this island. A subset of 80 specimens were further sequenced for the cytochrome b gene (1140 bp) and subjected to phylogenetic reconstructions including representative species from adjacent China and from all main lineages of the worldwide Myotis radiation. These molecular reconstructions showed that the Myotinae from Taiwan are phylogenetically diverse and are issued from several independent clades. The genetic results were completely congruent with the phenetic groupings based on craniodental and external morphology, as each of the eight Taiwanese taxa proved to be reciprocally monophyletic. Two unnamed taxa that did not fit into any of the known species were described as species new to science. Furthermore the taxon latirostris usually associated to the Asian M. muricola, was phylogenetically and morphologically distant from any other known Myotis and was assigned here to the fossil (Miocene) genus Submyotodon. Submyotodon latirostris, M. secundus sp. n. and M. soror sp. n. are endemic species from Taiwan, whereas the other five Myotis are more widespread and also found in the mainland. An identification key is provided to ease the discrimination of these Myotinae species in Taiwan and adjacent China. PMID- 25781253 TI - Checklist and distribution of ciliates from the family Euplotidae Ehrenberg, 1838 (Protista: Ciliophora: Spirotrichea) in Slovakia, Central Europe. AB - A checklist of ciliates from the family Euplotidae recorded in the territory of Slovakia, Central Europe was assembled. Altogether, 11 species belonging to three genera of the family Euplotidae have been reported there: Euplotes alatus, Euplotes charon, Euplotes moebiusi, Euplotoides aediculatus, Euplotoides eurystomus, Euplotoides patella, Euplotoides woodruffi, Euplotopsis affinis, Euplotopsis finki, Euplotopsis muscicola, and Euplotopsis novemcarinata. However, records of the marine species E. alatus and E. charon are doubtful and very likely represent misidentifications of E. moebiusi. Since the euryhaline species E. woodruffi was found for the first time in Slovakia, its morphology is described. Based on the literature data and our own observations, the present checklist is also accompanied with distribution data on the 11 aforementioned species. As concerns ecology, Slovak euplotids typically occurred in freshwater bodies having higher trophic levels. Only two species, E. finki and E. muscicola, were isolated from terrestrial habitats, especially, from mosses, leaf-litter, and decaying wood mass. PMID- 25781254 TI - New records of sea lice (Copepoda: Caligidae) from marine fishes in Jaramijo, an area with potential for sea-cage aquaculture in Ecuador. AB - Farming of finfish in sea cages is gaining popularity worldwide. These systems are a suitable environment for the emergence, establishment and transmission of parasites or pathogens, such as sea lice (Copepoda: Caligidae), known to cause serious diseases and economic losses in finfish aquaculture worldwide. In coastal waters of Jaramijo, Ecuador, there are plans to culture spotted rose snapper (Lutjanus guttatus) and longfin yellowtail (Seriola rivoliana); however, the information about the occurrence of sea lice on fish from this country is scarce. To address this problem, a parasitological survey of economically important fish caught by artisanal fishermen was conducted between June 2013 and May 2014. A total of 608 fish belonging to 66 species were examined. Sea lice were found on 23 fish species. The diversity of these parasites consisted of 22 species of Caligus and 5 species of Lepeophtheirus. Most sea lice species (66%) occurred in a single fish species only, with low infection levels. The most frequently encountered species were Caligus asperimanus Pearse, 1951, Caligus mutabilis Wilson, 1905 and Caligus rufimaculatus Wilson, 1905. Taxonomic remarks are presented for some of the species recorded during this survey. All but two sea lice records are new to Ecuador, considerably expanding the geographical range of some species. PMID- 25781255 TI - New species and new records of Protaphorura species from northeast China (Collembola: Onychiuridae). AB - A new species, Protaphorura genheensis sp. nov., and two new records, Protaphorura taimyrica (Martynova, 1976) and Protaphorura kaszabi (Dunger, 1978) are reported from northeast China. New localities for P. bicampata are presented. P. genheensis sp. nov. belongs to the 'oligopseudocellar' group as having fewer pso on Th. II-III and can be distinguished by the dorsal pso formula, number of pso on the subcoxa 1 of legs, ventral psx formula and the number of chaetae on Th. I-III sterna. P. taimyrica is described basing on the Chinese specimens, and the individuals who have the dorsal pso formula as 33/012/33342 are found. PMID- 25781256 TI - First report on meiotic behavior of chromosomes in three species of subfamily Pentatominae (Pentatomidae: Heteroptera). AB - Regardless of rich biodiversity, cytogenetic reports on Pentatomidae refer to less than 400 species. This paper reports, for the first time, course of meiosis of three species of subfamily Pentatominae viz., Tolumnia antennata Distant, Cahara jugatoria (Lethierry) and Cahara confusa (Distant). Species-specific variations observed with respect to association pattern of X and Y during prophase, arrangement pattern of chromosomes at metaphase I and degree of association between X and Y in the pseudobivalent at metaphase II are explained in the present paper.Tolumnia antennata and Cahara jugatoria possess 2n=14=12A+XY while Cahara confusa possesses 2n=12=10A+XY. At least one ring bivalent is observed during diplotene in all the three species. X and Y dissociate to get well separated at diplotene in Cahara confusa, at diakinesis in Tolumnia antennata and at metaphase I in Cahara jugatoria. In Cahara jugatoria, at metaphase I, X and Y are peripheral forming a part of the ring. In Cahara confusa, at metaphase II, X is peripheral while Y lies in the centre and the two fail to associate to form a pseudobivalent, a phenomenon never recorded earlier in any pentatomid. PMID- 25781257 TI - A review of the genus Solariola Flach, 1908 (Coleoptera: Curculionidae: Entiminae, Peritelini). AB - The species of the Italian endemic weevil genus, Solariola Flach, 1908 (Coleoptera: Curculionidae: Entiminae), are revised, the genus is re-diagnosed, re-described and transferred from the tribe Otiorhynchini to Peritelini. Three new species are described: Solariola angelae n. sp. and Solariola pesarinii n. sp. from Sicily, and Solariola fraterna n. sp. from Calabria. Solariola hirtula (A. Solari & F. Solari, 1923) is considered a good species and not a subspecies of Solariola gestroi (A. Solari & F. Solari, 1904), bringing the total number of species considered valid to 9. All the previously described species are re described in detail. Distribution, ecology, maps and figures are provided for all the species of the genus, as well as a species-level identification key and a checklist of all known species. PMID- 25781258 TI - Unexpected occurrence of the genus Eratigena in Laos with description of a new species (Araneae: Agelenidae). AB - During fieldtrips to Laos in 2009 and 2012, two male agelenid specimens were collected from two different caves in the Bolikhamsay Province. Examination of morphological and molecular (CO1) characters revealed, that these specimens belong to a new species, Eratigena laksao sp. n. The cheliceral retromargin of the examined specimens have more than six teeth and the most proximal tooth is distinctly smaller, two character states that are regarded as synapomorphic for Eratigena. Nevertheless, due to the presence of ventral spines at tarsus IV, the completely reduced distal sclerite at the median apophysis, and the lack of females, the genus affiliation of this species remains tentative. E. laksao sp. n. can easily be identified by the unique presence of distinct bristles at the distal palpal tibia. PMID- 25781259 TI - A new species of Amerotyphlops from Northeastern Brazil, with comments on distribution of related species. AB - We describe a new species of Amerotyphlops from an upland forest enclave in the state of Paraiba, Northeastern Brazil. The new species is distinguished from the other seven South American species of Amerotyphlops by the combination of the following characters: nasal suture incomplete; rostral scale oval and yellowish cream with some dark brown spots; four supralabial scales; three infralabial scales; rows of scales around the body 18/18/18; middorsal scales from 204 to 225; dorsum with twelve to thirteen rows of scales dark brown and belly with four to five rows of scales immaculate yellowish cream; caudal spine dark brown; subcaudal scales 8-10 in female and 11-13 in males; maximum total length 233 mm. The new species is morphologically similar to A. amoipira and A. paucisquamus, sharing 18/18/18 rows of scales around the body and a small overlap of counts of middorsal scales. PMID- 25781260 TI - Nematocharax costai Braganca, Barbosa & Mattos a junior synonym of Nematocharax venustus Weitzman, Menezes & Britski (Teleostei: Characiformes: Characidae). AB - Analysis of morphometric and meristic data from specimens obtained from various river basins along the distribution of Nematocharax venustus revealed intraspecific variation among geographically isolated populations. A comparative analysis of these data with data from the original description of N. costai, in addition to data obtained from the holotype and topotypes of the species, showed broad overlap and absence of morphological features supporting the recognition of two species within Nematocharax. Characters previously used to distinguish N. costai from N. venustus, such as presence of hooks or spinules on dorsal and pelvic fins, number of hooks on anal-fin rays, occurrence of a pink horizontal mark on the caudal peduncle, number of supraneurals, and coloration of the pelvic fin filament, are not useful to distinguish the two putative species. Thus, N. costai is considered herein as a junior synonym of N. venustus. Presence of a complete lateral line and length of fin-filaments of N. venustus are briefly discussed and a current overview of the distribution of the species is given. In view of the proposed synonymy of a so recently described species and aiming to avoid problems of similar nature in the future, we also take the opportunity to reinforce herein the importance of the examination of large population samples and of intraspecific variation of secondary sexual features. PMID- 25781261 TI - The jumping plant-louse Diaphorina teucrii sp. nov. (Hemiptera, Liviidae) associated with Teucrium (Lamiaceae) and its parasitoid Tamarixia dorchinae sp. nov. (Hymenoptera, Eulophidae) from the Negev desert, Israel. AB - Adults and immatures of Diaphorina teucrii sp. nov. (Hemiptera, Liviidae, Euphyllurinae) and adults of Tamarixia dorchinae sp. nov. (Hymenoptera, Eulophidae, Tetrastichinae) from Israel are described, diagnosed and illustrated. D. teucrii sp. nov. develops on Teucrium capitatum (Lamiaceae), representing a family which was previously not recorded as a psyllid host from Israel, and is parasitised by Tamarixia dorchinae sp. nov. Identification keys are provided for the Diaphorina and Tamarixia species occurring in Israel. PMID- 25781262 TI - The first troglomorphic species of the genus Phrynus Lamarck, 1801 (Amblypygi: Phrynidae) from Mexico. AB - A new troglomorphic species, Phrynus perrii sp. nov., is described from two adult females from Cueva del Naranjo, Municipio Cintalapa, Chiapas, Mexico. This is the first continental record of a troglomorphic Phrynus species, and the second troglomorphic species of the genus. With the description of this species, in Mexico there are ten extant species, plus one fossil of the genus Phrynus, and it is the seventh species of troglobitic whip spiders from Mexico, making it the country with the highest richness of amblypygids species worldwide. PMID- 25781263 TI - Two new species and five new records of Nola Leach, [1815] (Lepidoptera, Nolidae, Nolinae) from China. PMID- 25781264 TI - Description of a new species of Anthrenus Geoffroy 1762, with a key to species from Nepal. AB - The genus Anthrenus, is in the subfamily Megatominae. It is relatively speciose within family Dermestidae and currently contains ca. 250 valid taxa which have been grouped within 10 subgenera. Most of the species are found in the Palearctic ecozone. Anthrenus (Helocerus) cechovskyi Hava & Kadej, sp. nov. is described from Nepal. The habitus, antenna, genitalia are illustrated and compared with related species. A key to the known species from the Nepal is presented. Only seven species of Dermestidae have been recorded from Nepal so far. Newly described species is the first species of subgenus Helocerus which have been found in Nepal. Further study of Dermestidae of Nepal and adjacent countries is required. PMID- 25781265 TI - Redescription of Trogoderma fasciolata Fairmaire, 1897, comb. rev. from Madagascar (Coleoptera: Dermestidae, Megatomini). AB - Trogoderma fasciolata Fairmaire, 1897, comb. rev. is redescribed, illustrated and restored to the genus Trogoderma Dejean, 1821 from Aethriostoma Motschulsky, 1858. A key to the known Trogoderma species from Madagascar is presented. PMID- 25781266 TI - On the Dermestidae (Insecta: Coleoptera) from Rey's collection. Part 2. Designation of neotype of Anthrenus pimpinellae var. incertus Mulsant et Rey, 1868 and recognition of a new synonymy within Palaearctic Anthrenus Geoffroy, 1762. AB - A neotype of Anthrenus pimpinellae var. incertus Mulsant et Rey, 1868 is designated, and a new synonym in Palearctic Anthrenus Geoffroy, 1762 is recognized. PMID- 25781267 TI - Division of surgeon workload in pancreaticoduodenectomy: striving to decrease post-operative pancreatic fistula. AB - BACKGROUND: Many studies have reported factors affecting pancreatic leakage after pancreaticoduodenectomy (PD), but there have been few reports on surgeon workload and post-operative pancreatic fistula (POPF). This study was conducted to explore whether a surgeon's workload during PD impacts the occurrence of POPF. METHODS: We retrospectively analysed 270 consecutive patients who underwent PD between January 2008 and June 2013 by a single experienced surgeon. These patients were divided into those who underwent PD entirely by a single operator (group 1) and those who received reconstructions by other operators (group 2). Duct-to-mucosa pancreaticojejunostomy was performed on all patients. The International Study Group on Pancreatic Fistula criteria were used to define POPF. RESULTS: There were 157 patients (58.1%) in group 1 and 113 patients (41.9%) in group 2. The post-operative morbidity rate was comparable between the two groups (55.4% versus 52.2%; P = 0.603), but the clinical pancreatic fistula (grade B/C) rate was significantly different (10.8% versus 2.7%; P = 0.011). The overall post operative mortality was one patient (0.4%). Significant associations were found between clinical pancreatic fistulas and soft pancreas texture (P = 0.021), preoperative serum albumin level <=3.5 g/dL (P = 0.012), other pathology besides pancreatic cancer (P = 0.027) and a single-operator procedure (P = 0.019). A multivariate logistic regression analysis revealed that a single operator (odds ratio: 4.2, P = 0.029) was a significant predictive risk factor for clinically relevant POPF. CONCLUSION: Dividing the surgeon's workload in PD is associated with lower rates of POPF. PMID- 25781269 TI - One short cysteine-rich sequence pattern - two different disulfide-bonded structures - a molecular dynamics simulation study. AB - The nematocyst walls of Hydra are formed by proteins containing small cysteine rich domains (CRDs) of ~25 amino acids. The first CRD of nematocyst outer all antigen (NW1) and the C-terminal CRD of minicollagen-1 (Mcol1C) contain six cysteines at identical sequence positions, however adopt different disulfide bonded structures. NW1 shows the disulfide connectivities C2-C14/C6-C19/C10-C18 and Mcol1C C2-C18/C6-C14/C10-C19. To analyze if both show structural preferences in the open, non-disulfide bonded form, which explain the formation of either disulfide connectivity pattern, molecular dynamics (MD) simulations at different temperatures were performed. NW1 maintained in the 100-ns MD simulations at 283 K a rather compact fold that is stabilized by specific hydrogen bonds. The Mcol1C structure fluctuated overall more, however stayed most of the time also rather compact. The analysis of the backbone Phi/psi angles indicated different turn propensities for NW1 and Mcol1C, which mostly can be explained based on published data about the influence of different amino acid side chains on the local backbone conformation. Whereas a folded precursor mechanism may be considered for NW1, Mcol1C may fold according to the quasi-stochastic folding model involving disulfide bond reshuffling and conformational changes, locking the native disulfide conformations. The study further demonstrates the power of MD simulations to detect local structural preferences in rather dynamic systems such as the open, non-disulfide bonded forms of NW1 and Mcol1C, which complement published information from NMR backbone residual dipolar couplings. Because the backbone structural preferences encoded by the amino acid sequence embedding the cysteines influence which disulfide connectivities are formed, the data are generally interesting for a better understanding of oxidative folding and the design of disulfide stabilized therapeutics. PMID- 25781268 TI - Neural Correlates of the Cortisol Awakening Response in Humans. AB - The cortisol rise after awakening (cortisol awakening response, CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation related to psychosocial stress and stress-related psychiatric disorders. However, the neural regulation of the CAR has not been examined in humans. Here, we studied neural regulation related to the CAR in a sample of 25 healthy human participants using an established psychosocial stress paradigm together with multimodal functional and structural (voxel-based morphometry) magnetic resonance imaging. Across subjects, a smaller CAR was associated with reduced grey matter volume and increased stress-related brain activity in the perigenual ACC, a region which inhibits HPA axis activity during stress that is implicated in risk mechanisms and pathophysiology of stress-related mental diseases. Moreover, functional connectivity between the perigenual ACC and the hypothalamus, the primary controller of HPA axis activity, was associated with the CAR. Our findings provide support for a role of the perigenual ACC in regulating the CAR in humans and may aid future research on the pathophysiology of stress-related illnesses, such as depression, and environmental risk for illnesses such as schizophrenia. PMID- 25781270 TI - Comparison of detection techniques for capillary electrophoresis analysis of gold nanoparticles. AB - As metallic nanoparticles are growing in importance as analytes in CE, increases an interest in appropriate detection methods for their quantification in various samples. For gold nanoparticles (AuNPs), the most common UV detection poses intricacy of inadequate sensitivity that hinders the applicability of CE. With the objective of resolving this challenge, UV detection was compared with C(4) D and ICP-MS as alternative modes of detection for AuNPs. A C(4) D detector, applied under pressure-driven conditions, exhibited better sensitivity than a UV detector. However, C(4) D turned to be unsatisfactory to differentiate the signal of AuNPs at common CE conditions despite varying the nature of BGE and detection conditions. Due to intrinsic sensitivity and low background levels typical to Au, ICP-MS greatly surpasses UV detection. After optimization trials, CE-ICP-MS gained the LOD of AuNPs as low as 2 * 10(-15) M, as well as an excellent performance in terms of signal stability and linearity. Also importantly, the optimized BGE appears to be well matched to explore the behavior of AuNPs in biologically relevant systems. This was demonstrated by probing the interaction between AuNPs and the main blood-transporting protein, HSA. PMID- 25781271 TI - Label-free detection of multidrug resistance in K562 cells through isolated 3D electrode dielectrophoresis. AB - Dielectrophoresis (DEP), a technique used to separate particles based on different sizes and/or dielectric properties under nonuniform electric field, is a promising method to be applied in label-free, rapid, and effective cell manipulation and separation. In this study, a microelectromechanical systems based, isolated 3D-electrode DEP device has been designed and implemented for the label-free detection of multidrug resistance in K562 leukemia cells, based on the differences in their cytoplasmic conductivities. Cells were hydrodynamically focused to the 3D-electrode arrays, placed on the side walls of the microchannel, through V-shaped parylene-C obstacles. 3D-electrodes extruded along the z direction provide uniformly distributed DEP force through channel depth. Cell suspension containing resistant and sensitive cancer cells with 1:100 ratio was continuously flown through the channel at a rate of 10 MUL/min. Detection was realized at 48.64 MHz, the cross-over frequency of sensitive K562 cells, at which sensitive cells flow with the fluid, while the resistant ones are trapped by positive DEP force. Device can be operated at considerably low voltages (<9 Vpp ). This is achieved by means of a very thin (0.5 MUm) parylene coating on electrodes, providing the advantages offered by the isolation of electrodes from the sample, while the working voltage can still be kept low. Results prove that the presented DEP device can provide an efficient platform for the detection of multidrug resistance in leukemia, in a label-free manner. PMID- 25781273 TI - Immune Thrombocytopenic Purpura Associated with Hepatitis A Infection in a Five year Old Boy: A Case Report. AB - Acute hepatitis A infection is usually a self-limiting disease and mostly asymptomatic in children younger than six years old. Extrahepatic autoimmune manifestations such as immune thrombocytopenic purpura (ITP) have been reported rarely in children with acute hepatitis A infection. We report herein a paediatric case with ITP which is due to hepatitis A virus infection. PMID- 25781272 TI - Proteomic screening and identification of microRNA-128 targets in glioma cells. AB - Brain-enriched miR-128 is repressed in glioma cells, and could inhibit the proliferation of gliomas by targeting genes such as E2F3a and BMI1. To identify more targets of miR-128 in glioblastoma multiforme, the pulse stable isotope labeling with amino acids in cell culture (pSILAC) technique was used to test its impact on whole protein synthesis in T98G glioma cells. We successfully identified 1897 proteins, of which 1459 proteins were quantified. Among them, 133 proteins were downregulated after the overexpression of miR-128. Through predictions using various bioinformatics tools, 13 candidate target genes were chosen. A luciferase assay validated that 11 of 13 selected genes were potential targets of miR-128, and a mutagenesis experiment confirmed CBFB, CORO1C, GLTP, HnRNPF, and TROVE2 as the target genes. Moreover, we observed that the expression of CORO1C, TROVE2, and HnRNPF were higher in glioma cell lines compared to normal brain tissues and presented a tendency toward downregulation after overexpression of miR-128 in T98G cells. Furthermore, we have validated that CORO1C, TROVE2, and HnRNPF could inhibit glioma cell proliferation. In sum, our data showed that the integration of pSILAC and bioinformatics analysis was an efficient method for seeking the targets of miRNAs, and plentiful targets of miR-128 were screened and laid the foundation for research into the miR-128 regulation network. PMID- 25781274 TI - Antihistamine Effect of a Pure Bioactive Compound Isolated from Slug (Diplosolenodes occidentalis) Material. AB - OBJECTIVE: Folklore claims of the therapeutic effect of garden slug (Diplosolenodes occidentalis) extract used to relieve bronchoconstriction in asthmatic individuals were never validated scientifically. The aim of this study was to isolate the pure bioactive compound from slug extract causing this effect. METHODS: The crude ground material was prepared in ethanol and after filtration, separation by flash column chromatography method was done. The structure was elucidated by data from hydrogen and carbon nuclear magnetic resonance (NMR) profiles. The bioactive compound was assessed for dose-dependent response effects on guinea pig tracheal smooth muscle pre-contracted with histamine. Receptor specificity studies were done by using HTMT dimaleate (H1 agonist). The type of antagonism was also identified. RESULTS: The pure component isolated from garden slug material was identified by spectral studies as glyceryl trilinolenate (GT). It caused dose-dependent relaxation in guinea pig tracheal smooth muscle strips pre-contracted with histamine, it acted via H1 type receptors and showed non competitive antagonism. CONCLUSION: Glyceryl trilinolenate produced dose dependent relaxation in tracheal smooth muscle strips in the presence of the agonist histamine. Glyceryl trilinolenate displayed non-competitive antagonism at H1 receptors in the trachea. This agent was able to alleviate bronchoconstriction in individuals presenting with atopic asthma in rural agricultural areas in Jamaica (verbal communications). It is possible that GT can be useful therapeutically to produce tracheal smooth muscle relaxation in individuals presenting with atopic asthma. PMID- 25781275 TI - A Comparative In Vitro Study on the Antioxidant and Anti-acetylcholinesterase Properties of Aerial Parts of Strophanthus preusii Engl & Pax. AB - OBJECTIVE: To evaluate and compare the antioxidant and acetylcholinestrase (AChE) inhibitory properties of aerial parts of Strophanthus preussii (leaves, stem and root named as SPL, SPS and SPR, respectively) while catechin served as standard. METHODS: The antioxidant and AchE-inhibitory properties of the methanol extracts of SP were evaluated by standard in vitro methods viz: DPPH (2,2-diphenyl-1 picrylhydrazine), nitric oxide (NO), hydroxyl radical (OH-) and hydrogen peroxide (H2O2) radical scavenging assays as well as reducing power, Fe2+/ascorbate induced lipid peroxidation (LPO) and AChE inhibition assays. The total phenolic and flavonoid contents of the extracts were also estimated. RESULTS: High phenolic and flavonoid contents were found in the aerial parts of Strophanthus preussii. The amount of phenolic and flavonoids contents followed the order SPL > SPR > SPS at 250?1000 ug/ml. The results revealed that all the extracts showed antioxidant activities in vitro. However, SPL had the highest DPPH, H2O2 and OH radical scavenging abilitie, while the reducing power of the extracts followed the order SPR > SPL > SPS at 1000 ug/ml. In addition, SPL, SPS and SPR significantly inhibited LPO in rat liver by 42%, 23%, 35% and in rat brain by 68%, 31% and 51%, respectively. The LPO inhibitory activities of SPL were statistically similar to the standard. Only SPS produced significant NO scavenging effects among the extracts. The percentage inhibition of AChE activity was significant for SPL and SPR at 750 and 1000 ug/ml. CONCLUSION: The leaves and root of Strophanthus preusii proved to be potent natural antioxidants and could justify their traditional use in the management of stress-related diseases. PMID- 25781276 TI - Hypertension and Diabetes Prevalence in Older Persons in Jamaica, 2012. AB - The Jamaican population is experiencing both a demographic and epidemiological transition. This 2012 study of 2943 community dwelling persons over sixty years of age sought to determine the prevalence of hypertension and diabetes and how it has increased since the earlier 1989 study. Hypertension was the most prevalent non-communicable disease with 61.4% and had increased from 41.4% since 1989. It increased with age and was more common in females than males. Diabetes, at 26.3%, was the third most prevalent; it had increased by 157.1% since 1989. While the majority of affected persons were on medication, control of both diseases was less than adequate. Obesity was associated with both diseases. The paper discusses the implications for healthcare systems. PMID- 25781277 TI - Ischaemic Heart Disease at the University Hospital of the West Indies: Trends in Hospital Admissions and Inpatient Mortality Rates 2005-2010. AB - OBJECTIVES: This study aimed to estimate hospital admission rates and inpatient mortality rates for ischaemic heart disease (IHD) and its subtypes at the University Hospital of the West Indies (UHWI) for the years 2005?2010, and to identify factors associated with inpatient mortality. METHODS: Data from electronic discharge summaries for patients diagnosed with acute myocardial infarction (A-MI), unstable angina (UA) or other IHD were obtained from the Patient Information Management Systems database of the Medical Records Department of the UHWI. Data were entered into an electronic database and analysed using Stata 10.1. Random effects logistic regression was used to identify factors associated with inpatient mortality. RESULTS: Analysis included 3794 admissions (2821 persons: 1415 males, 1406 females; mean age 63.9 +/- 13.5 years). Overall admission rates for IHD were 12.1% (95% CI 11.7, 12.5) for medical admissions and 4.02% (95% CI 3.89, 4.15) for non-paediatric admissions. Admission rates were higher among males compared to females. There was a statistically significant trend for an overall increase in the rates for IHD admissions over the study period. Inpatient mortality rate was 18.9% for A-MI, 1.6% for UA and 7.8% for other IHD. In multivariable models, adjusted for age and gender, A-MI was associated with higher mortality compared to other IHD (OR 3.38, p < 0.001). CONCLUSIONS: Ischaemic heart disease admission rate is increasing at the UHWI and accounts for approximately one of every eight medical admissions. Inpatient mortality for acute myocardial infarction is approximately 19%. Further studies are required to determine the factors associated with inpatient mortality and to inform strategies for improving outcomes. PMID- 25781278 TI - Sharp Force Injuries at the University Hospital of the West Indies, Kingston, Jamaica: A Seventeen-year Autopsy Review. AB - OBJECTIVES: This study aimed to ascertain the prevalence and patterns of fatal sharp force injuries, victims' demographics, cause of death and average survival time at the University Hospital of the West Indies (UHWI), Kingston, Jamaica. METHODS: The autopsy records for 1990-2010 were searched for fatal cases of sharp force injuries. The records for 1998-2001 were not located. A 17-year retrospective analysis was therefore performed and findings for the two periods, 1990-1997 and 2002-2010 were compared. All data were obtained from the provisional anatomical diagnoses (PAD) autopsy reports. RESULTS: During the 17 year period, 57/4264 autopsies were performed for sharp force injuries, yielding an overall autopsy prevalence rate of 1.34% (1.25%, 26/2086 (95% CI 0.77, 1.73) in Period 1 and 1.42%, 31/2178 (95% CI 0.92, 1.92) in Period 2). The majority were males (91.1%), in the age group 15-39 years (77%), mean age of 30.9 years (range = 17?65 years). Stab wounds predominated (91.3%) and the chest was the area most frequently stabbed (42.1%). In the 24 fatalities due to chest injuries only, eight (33.3%) had injuries to the heart alone. Forty-five patients (79.0%) died within 24 hours from exsanguination. Injury documentation at autopsy was deficient. CONCLUSION: Stabbing was the most common sharp force injury, mainly involving the chest and young men were at greatest risk. Most patients died from exsanguination within 24 hours of admission. Introduction of synoptic-type reports for both clinical and autopsy examination may improve documentation. PMID- 25781279 TI - Urinary Angiotensinogen as a Potential Biomarker of Intrarenal Renin-angiotensin System Activity in Chinese Patients with Chronic Kidney Disease. AB - Urinary angiotensinogen (AGT) mainly derives from the AGT produced in the proximal tubular cells. Evidence exists that supports the correlation between urinary AGT and circulating AGT. Previous studies measured urinary AGT by radioimmunoassay which is not convenient for clinical practice. In this study, we utilized an enzyme-linked immunosorbent assay (ELISA) based method to quantify urinary AGT. We analysed the relationship between urinary AGT and intrarenal angiotensin II (Ang II) activity in patients with chronic kidney disease (CKD). Urinary and plasma renin activity, AGT, Ang II and aldosterone were measured by radioimmunoassay or ELISA in 128 CKD patients. Furthermore, expression levels of intrarenal renin, AGT, Ang II and Ang II receptor were examined by immunohistochemistry staining (IHCS) in 72 CKD patients undergoing renal biopsy. Average urinary AGT was 2.02 +/- 0.55 ng/(mg Cr). Hypertension, urinary protein, urinary Ang II and urinary Type IV collagen (Col IV) positively correlated with urinary AGT. Estimated glomerular filtration rate (eGFR), urinary sodium and serum AGT negatively correlated with urinary AGT. Multiple regression analysis indicated that low serum AGT, high urinary protein, urinary Ang II and urinary Col IV correlated significantly with high urinary AGT. Moreover, we observed positive correlation between urinary AGT and positive IHCS area of AGT, Ang II and Ang II Type 1 receptor inrenal tissue. These data suggest that urinary AGT might be a potential biomarker of intrarenal angiotensin II activity in CKD patients. PMID- 25781280 TI - The Prevalence of Asthma in an Adult Population in Khorramabad, Iran. AB - OBJECTIVE: Asthma is one of the most common respiratory disorders. There have not been any studies assessing the prevalence rate for asthma based on spirometry in an adult population in the west of Iran. The aim of this study was to assess the prevalence of asthma in an adult population in Khorramabad, in the west of Iran. METHODS: This prospective cross-sectional study was done on adult residents in Khorramabad between 2009 and 2010. The samples were selected by cluster and systematic sampling methods. The interviewers went to the selected homes and evaluated the samples by the standard questionnaire of the European Community Respiratory Health Survey. The individuals who were susceptible to asthma were evaluated using a hand-held spirometer (ZAN 100, Obertulba, Germany). Also, in the patients whose first spirometry had been normal, a more than 10% reduction in forced expiratory volume in one second (FEV1) after the exercise and more than 12% rise in FEV1 after the salbutamol spray inhalation was considered as having asthma. Finally, the data were summarized using means and percentages. RESULTS: Eight hundred and fifty-seven adults were evaluated by the questionnaire and 450 were referred to the pulmonologist office. The frequency of spirometry-diagnosed asthma in the adult residents of Khorramabad was 9.45%. CONCLUSION: The prevalence of asthma in Khorramabad in our study was more than in similar studies in Iran and other countries. Doing analytical studies on the prevalence of asthma and its risk factors is recommended. PMID- 25781281 TI - Outcomes and Health-related Quality of Life following Intensive Care Unit Stay in Barbados. AB - OBJECTIVES: To evaluate the hospital outcome and health-related quality of life (HRQOL) in adult patients admitted to intensive care units (ICUs) in Barbados. METHODS: A prospective observational study was done in the medical and surgical intensive care units of the Queen Elizabeth Hospital, Barbados, to evaluate the outcomes and HRQOL in adult patients. The acute physiology and chronic health evaluation (APACHE) IV score was applied on admission to one hundred and fifty patients admitted to the ICUs. The HRQOL was evaluated by using Short Form 36 (SF 36) in 63 survivors, three months after ICU discharge. RESULTS: There was no significant difference between medical and surgical ICUs with respect to age, gender, APACHE IV scores, 90-day mortality, and length of stay. The mean (+/- SD) APACHE IV score was 42.6 (+/- 23.7). The observed mortality was 32.7% and the standardized mortality ratio (SMR) was 1.85. The APACHE IV scores were significantly higher in non-survivors compared to survivors (p < 0.001). Patients with APACHE IV of > 45, and who were ventilated in the first 24 hours had the highest mortality (66%). The mean ICU length of stay was 7.2 days. CONCLUSION: In this study, the SF-36 scores in all eight dimensions indicated that the HRQOL in the majority of the survivors was average or above average. There was a significant negative correlation between APACHE IV score and the SF-36 score. PMID- 25781282 TI - The Economic Burden of Femoral Neck Fractures in Jamaica. AB - Osteoporotic femoral neck fractures are increasing as the population ages. There is a significant cost to care for patients with such fractures. We prospectively analysed the in-hospital cost of managing 85 patients admitted to the University Hospital of the West Indies (UHWI) with such fractures. The majority of patients were females, 78.8%, and the mean age of the cohort was 83.7 years. There was a significant difference in the mean preoperative delay and length of stay between those patients treated publicly as compared to those treated privately, 9.6 vs 3.1 days and 18.9 vs 8.8 days, respectively. The mean acute cost of those treated publicly was 39% of the cost of those treated privately, J$110 878.80 vs J$284 287.61. The economic cost per year to the country for the acute management of femoral neck fractures was calculated at J$46 264 528.76 which is 0.30% of the 2005-2006 budgetary allocation for health. This cost was significantly associated with the length of hospital stay and the number of complications developed. PMID- 25781283 TI - Total Lymphocyte Count and Haemoglobin Concentration Combined as a Surrogate Marker for Initiating Highly Active Antiretroviral Therapy in a Resource-limited Setting as against CD4 Cell Count. AB - AIM: To find a sensitive and low-cost surrogate marker for CD4 count for initiating highly active antiretroviral therapy (HAART) [CD4 < 200 /mm3], in the form of total lymphocyte count (TLC) < 1200 /mm3 combined with haemoglobin (Hb) with multiple Hb cut-offs. METHOD: Two hundred and three consecutive treatment naive adult HIV positive outpatients attending the virology clinic in World Health Organization (WHO) clinical stage 1, 2 or 3 were enrolled in the study. Their complete blood counts and CD4 counts were done. Descriptive statistics was done by two methods correlating TLC alone with CD4 and the other using combined marker of TLC and Hb with CD4 count. RESULT: Total lymphocyte count alone did not correlate well with CD4 counts (r = 0.13; p = 0.065). Sensitivity of TLC < 1200 /mm3 to predict CD4 < 200 /mm3 was low (23.27%) and the sensitivity of the combined marker (TLC + Hb) increased with higher Hb cut-offs. CONCLUSION: Adding Hb to TLC markedly improved the sensitivity of the marker to predict CD4 count < 200/mm3. We also recommend a trade-off Hb cut-off of 10.5 g/dL for optimum sensitivity and specificity in this population subset. PMID- 25781284 TI - Normal Ranges for Acute Phase Reactants (Interleukin-6, Tumour Necrosis Factor alpha and C-reactive Protein) in Umbilical Cord Blood of Healthy Term Neonates at the Mount Hope Women's Hospital, Trinidad. AB - OBJECTIVE: To determine normal ranges for interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) in umbilical cord blood from healthy term neonates at the Mount Hope Women's Hospital (MHWH), Trinidad. METHODS: A prospective cohort study was conducted on healthy pregnant women admitted to the MHWH during the period October 1 to December 31, 2010. Women who were term with no signs of or risk factors for sepsis were recruited into the study after informed consent was obtained. Data were collected including maternal age, antenatal and perinatal history. Umbilical cord blood samples were collected and analysed for IL-6, TNF-alpha and CRP. Ethical approval was obtained from the Ethics Committee, Faculty of Medical Sciences, The University of the West Indies, Trinidad and Tobago. RESULTS: One hundred and sixty-two samples from healthy term neonates were analysed for IL-6 and TNF-alpha. One hundred and thirty-one samples were analysed for CRP due to one faulty kit. There were almost equal numbers of males (55%) and females (45%). Ninety per cent were > 2500 g at birth and 10% had low birthweight. Reference ranges of 0-16.4 pg/ml, 0-29.4 pg/ml and 0-12.4 mg/L were found for IL-6, TNF-alpha and CRP, respectively with 95% confidence intervals (11.6, 21.5 pg/ml; 24.0, 33.1 and 8.4, 15.1, respectively). CONCLUSION: The normal ranges for IL-6, TNF-alpha and CRP in umbilical cord blood for healthy term Trinidadian neonates were 0-16.4 pg/ml, 0-29.4 pg/ml and 0-12.4 mg/L, respectively. PMID- 25781286 TI - The Use of Analgesic Drugs in Patients with Sickle Cell Painful Crisis. AB - OBJECTIVE: To determine the drug options used for pain in patients with acute sickle cell painful crisis at the University Hospital of the West Indies (UHWI), Jamaica. METHOD: This retrospective study assessed all patients admitted to the UHWI between January 1, 2006 and December 31, 2010 with acute sickle cell anaemia painful crisis and the data obtained regarding site, severity, outcome and drug options selected for pain. RESULTS: There were 101 patients with a mean age (+/- SD) of 18.6 (+/- 14.3) years; there was no difference in gender (42 females, 59 males). Eight sites of pain were reported, with the most common site being the lower limbs (44.6%) and 60.3% experienced pain in more than one site. Most of the patients (75.2%) were diagnosed with severe pain. Drug options included opioid, non-opioid or a combination, with pethidine (76) and paracetamol (79) being the most common chosen opioid and non-opioid drugs selected for therapy. There was low correlation between pain severity and appropriate first-line treatment (Spearman's rho = 0.344; p < 0.000). All patients with "mild" and "mild to moderate" pain were initially treated and obtained resolution of pain with non opioid based therapy. However, most of the patients with severe pain (55.3%) required a second-line and some third-line (14.5%) of therapy for resolution at the time of discharge from the hospital. CONCLUSION: Painful crisis in patients with sickle cell anaemia is associated with severe pain in 75% and most will require second-line therapy for adequate resolution. Physicians need to provide adequate pain relief to decrease morbidity in these patients. PMID- 25781285 TI - The Evaluation of The Effects of Paternal And Maternal Silent Coeliac Disease on Birthweight and Gestational Age in Newborns. AB - OBJECTIVE: Coeliac disease is a chronic disease and is common all over the world. It has many other associated systemic side effects. This study investigated the effect of paternal and maternal silent coeliac disease on birthweight and gestational age in newborns. METHODS: The study group consisted of 81 newborns who were hospitalized for prematurity or term-intrauterine growth retardation. The parents of premature and/or small for gestational age babies born with coeliac disease-specific antigens were investigated. RESULTS: The differences were not statistically significant in fathers' tissue transglutaminase levels between premature appropriate gestational age, premature small gestational age and term small gestational age infants (p > 0.05), but statistically significant in mothers (p < 0.05). CONCLUSIONS: Silent coeliac disease may occur in parents, especially in mothers of preterm and small for gestational age infants, even in the absence of apparent clinical indications. PMID- 25781287 TI - About the Foreskin: Parents' Perceptions and Misconceptions. AB - OBJECTIVE: To determine parents' understanding of the foreskin, in an effort to improve parent education. METHODS: A questionnaire was administered to parents of patients attending outpatient clinics at the Wendy Fitzwilliam Paediatric Hospital (Eric Williams Medical Sciences Complex), the San Fernando General Hospital and the Scarborough General Hospital during an eight-month period. It comprised 15 questions, 10 of which asked about the role of the foreskin, retraction and views on circumcision. RESULTS: There were 520 completed questionnaires. The majority of participants were mothers. Twelve per cent of parents had a child who was circumcised. The reasons for circumcision were mostly because of phimosis (31%), religious reasons (26% Islamic), personal reference (21%) and infection (20%). Regarding the need for circumcision, 31% of parents believed all boys should be circumcised and 36% did not agree. The majority of parents felt that by one year, full retraction should occur and 66% of parents felt that circumcision should be performed if the foreskin is not retractable. With respect to hygiene, 75% felt that circumcision made cleaning the penis easier and 43% believed the foreskin causes infections. Concerning HIV/AIDS, 67% did not believe that circumcision helps to prevent its transmission. When considering penile cancer and sexual function, more than 50% of parents did not know the role of the foreskin. Approximately 25% of parents answered 'do not know' to most of the questions. CONCLUSIONS: Despite foreskin pathology being a common paediatric problem, it is clear that there is a lot of misunderstanding and ignorance of the facts relating to the function of the foreskin in children. There is an obvious need for better parent education. PMID- 25781288 TI - A Cross-sectional Study of Patients' Satisfaction with Dental Care Facilities: A Survey of Adult Treatment at The University of the West Indies, School of Dentistry. AB - OBJECTIVES: To determine the level of satisfaction with adult dental care at The University of the West Indies (UWI), School of Dentistry, using the Dental Satisfaction Questionnaire (DSQ) developed by Davies and Ware (1982) and to inferentially explore the factors associated with various patients' demographics. METHODS: A cross-sectional study was performed among adult dental patients attending UWI adult dental clinics. Data were collected using a self- administered, structured questionnaire which consisted of 19 questions on three subscales of pain management, quality and access (total). RESULTS: Sixty-nine per cent were female, 40% were between 45 and 64 years old, and 31.3% had excellent self-rated dental health status. A Dental Satisfaction Index (DSI overall) of 76.42% satisfaction was found, with the highest satisfaction subscale for quality (81.17%), while access (72%) was the lowest occurring subscale. The mean DSI was 3.57 for the UWI emergency dental clinic and 3.87 for the polyclinic. The difference between the DSI overall in the emergency clinic compared to the polyclinic was statistically significant (p < 0.05) CONCLUSIONS: There was a high level of overall satisfaction with dental care at the UWI dental school. Self rated oral health status may be important in patients' satisfaction. Policies and strategies promoting preventive dental advice are likely to improve patients' satisfaction with dental care and may lead to increased satisfaction with dental services. PMID- 25781289 TI - Dental Erosion and Medical Conditions: An Overview of Aetiology, Diagnosis and Management. AB - Tooth wear or tooth surface loss is a normal physiological process and occurs throughout life but is considered pathological when the degree of destruction is excessive or the rate of loss is rapid, causing functional, aesthetic or sensitivity problems. The importance of tooth wear as a dental problem has been increasingly recognized. The findings of a study in Trinidad indicate that the prevalence of tooth wear in a Trinidadian population is comparable to the United Kingdom (UK) and, indeed, that the level of moderate and severe wear is in fact nearly twice as high. The aetiology of tooth wear is attributed to four causes: erosion, attrition, abrasion and abfraction. Erosion is generally considered to be the most prevalent cause of tooth wear in the UK and Europe. Acids that cause dental erosion originate mainly from the diet or the stomach and to a lesser extent, the environment. Underlying medical problems can contribute to the progress of tooth wear due to erosion and the patient may not be aware of these conditions. Moderate to severe tooth wear poses a significant clinical challenge to dental practitioners and may result in treatment that is more complex and costly to the patient both in terms of finances and time spent in the dental chair. This paper provides an overview of aetiology and diagnosis of tooth wear, in particular tooth wear due to erosion, so that medical and dental practitioners may recognize tooth wear early, institute preventive measures and manage patients appropriately. PMID- 25781290 TI - Measurement of the Interantral Bone in Implant Dentistry Using Panoramic Radiography and Cone Beam Computed Tomography: A Human Radiographic Study. AB - OBJECTIVE: To analyse the dimensions of interantral bone available for dental implant placement in the fully edentulous maxilla. METHODS: Interantral bone height (IBH) was measured using panoramic radiography and computed tomography (CT). Interantral bone width (IBW) was measured by means of CT. RESULTS: The difference between both imaging methods in IBH assessment was highly statistically significant (p < 0.001) in the canine area, whereas in other areas it was found not to be significant. Measured in the CT scans, bone is significantly higher in the canine area compared to the area of central and lateral incisors (p < 0.001). Significant variations in IBW were found in all three locations: bone in the central incisor area is the widest, in the area of the lateral incisor, the narrowest (p < 0.001). CONCLUSIONS: Panoramic radiography is a sufficiently accurate method for IBH imaging in the incisor area, but not in the canine area. PMID- 25781291 TI - Issues with Consent in Stroke Patients. AB - BACKGROUND: Consent in stroke management may be required for either treatment, intervention or for research reasons. Consent capacity is an integral element of informed consent to treatment which requires that a patient's consent be voluntary, informed, and competent. Without proper informed consent, medical treatment provided to a patient is a legal and ethical minefield, even if the treatment is benign and intended to benefit the patient. RESULTS: Recent advances have enabled dramatic recovery in some stroke victims, transforming the previously generally negative outcomes of stroke care, whereas others face varying levels of disability. Explaining and sharing such details with patients and their families is essential. If this is not possible then there are other options such as emergency consent which may be justified in specific scenarios. Stroke may affect various areas of the brain and this may also include the prefrontal cortex which is involved in decision-making. There have been observations that individuals with damage to the ventro-medial prefrontal cortex may be prone to impulsive decision-making in real life and these patients are impaired on laboratory decision- making tasks that require balancing rewards, punishments and risk. This may therefore have an impact on consent decisions made by the patient. CONCLUSIONS: Ethical clinical research requires balancing several ethical requirements, including the requirement for scientific validity and the requirement to respect individuals by treating them as autonomous agents through the process of informed consent. Opportunities to improve on public awareness about stroke are essential to change the perception of this potentially devastating disorder. PMID- 25781292 TI - Metastatic Lung Cancer Presenting as Thoracic Empyema in an Old Patient. AB - An 83-year old male presented to the emergency department with productive cough and acute shortness of breath. Imaging, biochemical and microbiological studies of the pleural fluid indicated empyema. After antibiotic treatment and tube drainage, symptoms of the patient persisted and he received thoracoscopic decortication. His condition improved gradually, but histopathological examination showed metastatic adenocarcinoma of the lung. Clinicians are alerted to the possible association of malignant tumours and empyema in older patients. PMID- 25781293 TI - Percutaneous Antegrade Removal of Encrusted Broken Double J Ureteric Stent Using a Snare. AB - Percutaneous removal of partially encrusted broken double J ureteric stent from the renal pelvis using a snare is described. The patient is a 60-year old female, with a known case of hyperparathyroidism with double J ureteric stent placed one year earlier. Removal of the double J stent was attempted by cystoscopy but a loop of the stent was broken in the renal pelvis due to partial encrustation. Several unique aspects and technical challenges were encountered in this case including lack of pre-existing nephrostomy access in addition to a broken, partially encrusted stent which was near multiple renal stones and a newly-placed fully-functioning double J stent. The techniques to overcome those challenges are described. To the best of the author's knowledge, this is the first reported case of successful percutaneous removal of a broken encrusted double J stent by snare in the presence of such technical challenges. PMID- 25781294 TI - Clinical and Radiological Evaluation of Cleidocranial Dysplasia in Two Trinidadian Siblings. AB - Cleidocranial dysplasia is a rare developmental disorder of the skeleton and teeth that may be inherited as an autosomal dominant trait or occur spontaneously. This is a report of two Trinidadian, East Indian brothers aged 13 and 15 years referred from a private dental practice with the chief complaint of retained deciduous teeth. Subsequent clinical and radiographic investigations led to the diagnosis of cleidocranial dysplasia. The clinical and radiographic findings are discussed. PMID- 25781295 TI - Intra-articular Pulsed Mode Radiofrequency for Hip Pain: Inoperable Coxarthrosis Case. PMID- 25781296 TI - Budd-Chiari Syndrome in a Patient with JAK-2 V617F and Factor V G1691A Mutations. AB - Myeloproliferative neoplasms (MPN) are considered a risk factor for Budd-Chiari syndrome (BCS). The current classification of MPN by the World Health Organization is based on the presence of JAK-2 V617F somatic mutation, which is present in 40 to 60% of patients with BCS. Factor V Leiden mutation is found in around 53% of patients with BCS, representing the most common prothrombotic disease associated with the disorder. We describe a 48-year old woman with a past medical history of deep venous thrombosis in the left upper extremity and one episode in both lower extremities, one episode of transient ischaemic attack and essential thrombocythemia, who presented with jaundice, ascites and hepatomegaly. Budd-Chiari syndrome was diagnosed based on findings on Doppler ultrasound and liver biopsy. Doppler ultrasound showed narrowness of hepatic veins and inferior vena cava in its hepatic portion, diffuse echotexture and portal hypertension. Liver biopsy showed congestion of sinusoids and portal fibrosis. The patient was found to be a heterozygous carrier of Factor V and homozygous wild type G20210A prothrombin mutations. The JAK-2 V617F mutation was detected by allele-specific polymerase chain reaction (AS-PCR). The association of these mutations is rare, with only a few cases reported in the literature. The patient was treated with oral anticoagulation and antiplatelets with good results and proper follow-up. In conclusion, due to the possible coexistence of multiple prothrombotic factors in patients with Budd-Chiari syndrome, the approach to these patients must be focussed on searching for multiple factors and should include the JAK-2 V617F mutation. PMID- 25781297 TI - Spontaneous Early Recanalization after Acute Innominate Artery Thromboembolic Occlusion Secondary to Abrupt Aspirin and Statin Discontinuation: A Case Report. AB - Statin and antiplatelet drugs are widely used for prevention of ischaemic stroke and other cardiovascular diseases in high-risk patients. We report a rare case of a 49-year old man with a history of myocardial infarction and hyperlipidaemia who suffered an acute occlusion of his innominate artery (IA) accompanied by subclavian steal syndrome and cerebral infarction, on day seven after abrupt cessation of aspirin and statin, as confirmed by magnetic resonance and computed tomographic angiography of head and neck, and colour-coded Duplex ultrasonography (CCDU). Aspirin and atorvastatin were immediately re-started on admission. Spontaneous recanalization of IA was shown on repeat CCDU and digital subtraction angiography on day 10 after stroke onset. This case serves as a reminder that abrupt discontinuation of both aspirin and statin in patients with previous history of cardiovascular disease may increase the risk of ischaemic stroke. PMID- 25781298 TI - Small Bowel Obstruction and Enterocolic Fistula from a Gossypiboma after Caesarean Section. PMID- 25781299 TI - Penoplasty--Not Circumcision--for Buried Penis. PMID- 25781300 TI - Anaesthetic Management of Anaphylactic Shock Caused by Nonruptured Hydatid Cyst of the Liver. AB - Hepatic hydatid cyst (HC) caused by Echinococcus granulosus is still endemic in many parts of the world, and it is a common health problem, especially in developing countries. The rupture of the HC can cause anaphylactic shock or even death during surgical treatment. We present a case report regarding anaphylactic reaction due to surgery to the liver for HC which has an aberrant venous drainage incidentally detected during surgical operation in a 50-year old female patient. She was successfully treated with adrenaline, antihistamines, steroids, colloid or crystalloid fluids. After the surgery, she was transferred from the intensive care unit to the surgical ward on the first postoperative day. The possibility of anaphylaxis should be kept in mind; despite all the precautionary measures, nonrupture of the hydatic cyst and absence of spillage of the cyst to the circulation or into the surrounding tissues, anaphylaxis can still occur. Therefore, close monitoring for early diagnosis and appropriate management of anaphylaxis are essential to stabilize the patient and produce the best outcome. PMID- 25781301 TI - Cutaneous Metastases from Urothelial Carcinoma of the Bladder: A Rare Presentation and Literature Review. AB - With the advances in imaging, earlier detection of recurrence and metastatic disease is possible. However, there are limited data on the metastatic pattern of bladder cancer. In addition, cutaneous metastases from primary genitourinary malignancies are rare and, in spite of advances in imaging, which detect smaller lesions, the patterns of metastases from bladder cancer have not been well described. Very few cases of skin metastasis from urothelial carcinoma have been reported in the past. We present a case of primary bladder transitional cell carcinoma in which a cutaneous metastasis was the initial presentation. PMID- 25781302 TI - Keratosis Follicularis Spinulosa Decalvans Associated with Leukonychia. PMID- 25781303 TI - Safety Audit for Internal Emergencies and Theatre Disasters (SAFE-T): From Barbados. PMID- 25781304 TI - Fatal End-stage Renal Failure Aggravated by Recurrent Uterine Fibroids. PMID- 25781305 TI - Isotretinoin and Psychotic Mania. PMID- 25781306 TI - Dangerous Ulcerative Lesion in the Inguinal Area? PMID- 25781307 TI - Long-term functional outcomes in surgically treated patients with oropharyngeal cancer. AB - OBJECTIVES/HYPOTHESIS: As survival rates in oropharyngeal cancer improve, long term functional outcomes are increasingly important to understand. We report long term functional outcomes in a cohort of surviving patients with oropharyngeal squamous cell carcinoma treated with primary surgery +/- radiotherapy. STUDY DESIGN: Cross-sectional study. METHODS: Patients undergoing primary surgery for oropharyngeal cancer in Oxford, United Kingdom, between 2000 and 2010 were identified. The University of Washington Quality-of- Life and MD Anderson Dysphagia Inventory questionnaires were sent to all patients. Multivariate analysis was performed to determine the relationship between clinical factors and swallowing outcomes. RESULTS: Twenty percent of patients required gastrostomy tube placement (mean feed duration, 114 days). On multivariate analysis, increased age, advanced T stage, and an open surgical approach were associated with significantly reduced quality-of-life scores. CONCLUSIONS: Mean functional scores were comparable to previously published series of patients treated with primary surgery. Gastrostomy insertion rate was lower than in many previously published studies. Furthermore, specific variables have been identified that are associated with adverse functional outcome. PMID- 25781308 TI - Residue determination of plant activator benzo-1,2,3-thiadiazole-7-carboxylic acid 2-benzoyloxyethyl ester in water, soil, and vegetable by gas chromatography with tandem mass spectrometry. AB - This study aimed to develop a rapid, specific and sensitive method for the residue determination of benzo-1,2,3-thiadiazole-7-carboxylic acid 2 benzoyloxyethyl ester in soil, vegetable, and water by using gas chromatography with tandem mass spectrometry. During the extraction procedure, modified quick, easy, cheap, effective, rugged, and safe method using acetonitrile was compared with classical oscillating extraction using ethyl acetate and acetone, respectively. Before injection, a solid-phase extraction cartridge of Bond Elut Florisil was used for sample clean-up. The method was fully validated and showed satisfactory linearity (r(2) > 0.99) over the range to be assayed (10-1000 ng/mL), with the limits of detection ranging from 0.092-0.229 ng/mL and the limits of quantification ranging from 0.307-0.763 ng/mL. Recovery values at the spiked concentrations of 10, 100 and 1000 ng/g varied from 85.9-109.3%, 81.0 108.2%, 74.2-113.4% for water, soil and vegetable, respectively, with the maximum relative standard deviations of 12.2%. Results indicated that the established modified quick, easy, cheap, effective, rugged, and safe method coupled to gas chromatography with tandem mass spectrometry was promising for the residue monitoring of benzo-1,2,3-thiadiazole-7-carboxylic acid 2-benzoyloxyethyl ester in the environment and vegetable products. PMID- 25781309 TI - cDNA CLONING AND TRANSCRIPTIONAL REGULATION OF THE CECROPIN AND ATTACIN FROM THE ORIENTAL FRUIT FLY, Bactrocera dorsalis (DIPTERA: TEPHRITIDAE). AB - We described the cDNA cloning of two antimicrobial peptides (AMPs), cecropin (BdCec), and attacin C (BdAttC), from the oriental fruit fly, Bactrocera dorsalis (Hendel), a serious insect pest of fruit trees. Using rapid amplification of cDNA ends, fragments encompassing the entire open reading frames of BdCec and BdAttC were cloned and sequenced. The complete 425 bp cDNA of BdCec encodes a protein of 64 amino acids with a predicted molecular weight of 6.84 kDa. The 931 bp cDNA of BdAttC encodes a protein of 239 residues with a predicted molecular weight of 24.97 kDa. Real-time quantitative RT-PCR demonstrated that the developmental transcription profiles of BdCec and BdAttC were similar in each larvae, pupae, and adults. The constitutive expression levels of both AMPs were high in the first-instar and late third-instar larvae, suggesting that their antimicrobial activity is active in the newly hatched larvae and just before pupation. The basal expression levels were not significant different in adult fat bodies. The expression of BdCec and BdAttC was upregulated after bacterial challenge in adult fat bodies. The ratio of inducible expression to constitutive expression was lower in males compared to females. PMID- 25781310 TI - Monte Carlo modeling of light propagation in the human head for applications in sinus imaging. AB - Sinus blockages are a common reason for physician visits, affecting one out of seven people in the United States, and often require medical treatment. Diagnosis in the primary care setting is challenging because symptom criteria (via detailed clinical history) plus objective imaging [computed tomography (CT) or endoscopy] are recommended. Unfortunately, neither option is routinely available in primary care. We previously demonstrated that low-cost near-infrared (NIR) transillumination correlates with the bulk findings of sinus opacity measured by CT. We have upgraded the technology, but questions of source optimization, anatomical influence, and detection limits remain. In order to begin addressing these questions, we have modeled NIR light propagation inside a three-dimensional adult human head constructed via CT images using a mesh-based Monte Carlo algorithm (MMCLAB). In this application, the sinus itself, which when healthy is a void region (e.g., nonscattering), is the region of interest. We characterize the changes in detected intensity due to clear (i.e., healthy) versus blocked sinuses and the effect of illumination patterns. We ran simulations for two clinical cases and compared simulations with measurements. The simulations presented herein serve as a proof of concept that this approach could be used to understand contrast mechanisms and limitations of NIR sinus imaging. PMID- 25781311 TI - Rosalie Wolf Memorial Lecture: toward a more perfect union. PMID- 25781312 TI - beta-Cyclodextrin decorated nanocellulose: a smart approach towards the selective fluorimetric determination of danofloxacin in milk samples. AB - An innovative and versatile strategy of Solid Phase Microextraction (SPME) is shown by using a new type of beta-cyclodextrin-modified nanocellulose (CD-NC) as a sorbent material. beta-cyclodextrin (used as an inclusion-type selector) was covalently bonded to amine-modified nanocellulose by an amidation reaction. Such novel nanocavities were successfully applied to the selective recognition of danofloxacin (DAN), an antibiotic used to treat animal diseases, via supramolecular host-guest interactions. The SPME methodology, using a platform based on beta-cyclodextrin-"decorated" nanocellulose as a sorbent material, showed a wide linear fluorimetric response against DAN from 8 to 800 MUg L(-1) and a detection limit of 2.5 MUg L(-1). The specific recognition of DAN has been proven to be highly selective and efficient against this metabolite and other fluoroquinolones. The reusability and the high efficiency in the extraction and preconcentration of DAN in milk samples allow recoveries of 94%. PMID- 25781313 TI - Comparative distribution and in vitro activities of the urotensin II-related peptides URP1 and URP2 in zebrafish: evidence for their colocalization in spinal cerebrospinal fluid-contacting neurons. AB - Urotensin II (UII) is an evolutionarily conserved neuropeptide initially isolated from teleost fish on the basis of its smooth muscle-contracting activity. Subsequent studies have demonstrated the occurrence of several UII-related peptides (URPs), such that the UII family is now known to include four paralogue genes called UII, URP, URP1 and URP2. These genes probably arose through the two rounds of whole genome duplication that occurred during early vertebrate evolution. URP has been identified both in tetrapods and teleosts. In contrast, URP1 and URP2 have only been observed in ray-finned and cartilaginous fishes, suggesting that both genes were lost in the tetrapod lineage. In the present study, the distribution of urp1 mRNA compared to urp2 mRNA is reported in the central nervous system of zebrafish. In the spinal cord, urp1 and urp2 mRNAs were mainly colocalized in the same cells. These cells were also shown to be GABAergic and express the gene encoding the polycystic kidney disease 2-like 1 (pkd2l1) channel, indicating that they likely correspond to cerebrospinal fluid-contacting neurons. In the hindbrain, urp1-expressing cells were found in the intermediate reticular formation and the glossopharyngeal-vagal motor nerve nuclei. We also showed that synthetic URP1 and URP2 were able to induce intracellular calcium mobilization in human UII receptor (hUT)-transfected CHO cells with similar potencies (pEC50=7.99 and 7.52, respectively) albeit at slightly lower potencies than human UII and mammalian URP (pEC50=9.44 and 8.61, respectively). The functional redundancy of URP1 and URP2 as well as the colocalization of their mRNAs in the spinal cord suggest the robustness of this peptidic system and its physiological importance in zebrafish. PMID- 25781314 TI - Columnar architecture improves noise robustness in a model cortical network. AB - Cortical columnar architecture was discovered decades ago yet there is no agreed upon explanation for its function. Indeed, some have suggested that it has no function, it is simply an epiphenomenon of developmental processes. To investigate this problem we have constructed a computer model of one square millimeter of layer 2/3 of the primary visual cortex (V1) of the cat. Model cells are connected according to data from recent paired cell studies, in particular the connection probability between pyramidal cells is inversely proportional both to the distance separating the cells and to the distance between the preferred parameters (features) of the cells. We find that these constraints, together with a columnar architecture, produce more tightly clustered populations of cells when compared to the random architecture seen in, for example, rodents. This causes the columnar network to converge more quickly and accurately on the pattern representing a particular stimulus in the presence of noise, suggesting that columnar connectivity functions to improve pattern recognition in cortical circuits. The model also suggests that synaptic failure, a phenomenon exhibited by weak synapses, may conserve metabolic resources by reducing transmitter release at these connections that do not contribute to network function. PMID- 25781315 TI - Perceptions of intentionality for goal-related action: behavioral description matters. AB - Perceptions of intentionality critically guide everyday social interactions, though the literature provides diverging portraits of how such judgments are made. One view suggests that people have an "intentionality bias," predisposing them toward labeling behaviors as intentional. A second view focuses on a more complex pattern of reasoning whereby judgments of intentionality are shaped by information about social context and mental states. Drawing on the theory of action-identification, we attempt to integrate these two perspectives. We propose that people parse intentionality into two categories: judgments about concrete, low-level behaviors and judgments about relatively more abstract, high-level behaviors. Evidence from five studies supports this distinction. Low-level behaviors were perceived as intentional regardless of mental state information, supporting the "intentionality bias" view. In contrast, judgments about the intentionality of high-level behaviors varied depending on social context and mental states, supporting the systematic view of intentionality. PMID- 25781317 TI - Correction: Characterization of different substituted carboxymethyl starch microgels and their interactions with lysozyme. PMID- 25781316 TI - A deletion in FOXN1 is associated with a syndrome characterized by congenital hypotrichosis and short life expectancy in Birman cats. AB - An autosomal recessive syndrome characterized by congenital hypotrichosis and short life expectancy has been described in the Birman cat breed (Felis silvestris catus). We hypothesized that a FOXN1 (forkhead box N1) loss-of function allele, associated with the nude phenotype in humans, mice and rats, may account for the syndrome observed in Birman cats. To the best of our knowledge, spontaneous mutations in FOXN1 have never been described in non-human, non-rodent mammalian species. We identified a recessive c.1030_1033delCTGT deletion in FOXN1 in Birman cats. This 4-bp deletion was associated with the syndrome when present in two copies. Percentage of healthy carriers in our French panel of genotyped Birman cats was estimated to be 3.2%. The deletion led to a frameshift and a premature stop codon at position 547 in the protein. In silico, the truncated FOXN1 protein was predicted to lack the activation domain and critical parts of the forkhead DNA binding domain, both involved in the interaction between FOXN1 and its targets, a mandatory step to promote normal hair and thymic epithelial development. Our results enlarge the panel of recessive FOXN1 loss-of-function alleles described in mammals. A DNA test is available; it will help owners avoid matings at risk and should prevent the dissemination of this morbid mutation in domestic felines. PMID- 25781318 TI - Editorial: Neurological disorders. PMID- 25781319 TI - Graft rejection rate and graft failure rate of penetrating keratoplasty (PKP) vs lamellar procedures: a systematic review. AB - PURPOSE: The aim of our investigation was to conduct a quantitative meta-analysis of the present world literature comparing the major surgical outcomes of penetrating keratoplasty (PKP) to lamellar procedures. Our goal is that clinicians, eye bank administrators, and health policy makers will be able to utilize this study in implementing decisions in regards to corneal transplantation. METHODS: Pooled measures of association were with odds ratios and because of study heterogeneity, the pooled effects were assumed to follow a random effects model (DerSimonian-Laird). The comparisons were between 1) PKP's and all lamellar procedures (anterior AND posterior) and then 2) between PKP's and all anterior lamellar procedures and 3) PKP and all posterior lamellar procedures. RESULTS: For PKP vs anterior lamellar procedures, the pooled odds ratio for rejection of PKP over lamellar keratoplasty (LK) was 3.56 (95% CI: 1.76 7.20) and for outright failure, the pooled odds ratio of PKP failure vs LK was 2.85 (95% CI: 0.84-9.66). For posterior lamellar procedures, the pooled odds ratio for rejection of PKP over LK was 1.52 (95% CI: 1.00-2.32). The pooled odds ratio for outright failure of PKP over posterior lamellar procedures was 2.09 (95% CI: 0.57-7.59). The follow up time was significantly longer for full transplants than for lamellar procedures. CONCLUSIONS: For both anterior and posterior lamellar procedures, the odds ratios comparing rejection of full transplants to lamellar procedures (both anterior and posterior individually) were significantly higher in the PKP group. For outright failure, the PKP group also had a higher risk of failure than the lamellar groups but this was not statistically significant in either instance (anterior or posterior). Some of the clinical differences benefitting lamellar procedures may at least be partly explained by follow up time differences between groups and this needs to be accounted for more rigorously in future studies. PMID- 25781320 TI - Distribution of Lutzomyia longipalpis chemotype populations in Sao Paulo state, Brazil. AB - BACKGROUND: American visceral leishmaniasis (AVL) is an emerging disease in the state of Sao Paulo, Brazil. Its geographical expansion and the increase in the number of human cases has been linked to dispersion of Lutzomyia longipalpis into urban areas. To produce more accurate risk maps we investigated the geographic distribution and routes of expansion of the disease as well as chemotype populations of the vector. METHODOLOGY/PRINCIPAL FINDINGS: A database, containing the annual records of municipalities which had notified human and canine AVL cases as well as the presence of the vector, was compiled. The chemotypes of L. longipalpis populations from municipalities in different regions of Sao Paulo State were determined by Coupled Gas Chromatography - Mass Spectrometry. From 1997 to June 2014, L. longipalpis has been reported in 166 municipalities, 148 of them in the Western region. A total of 106 municipalities were identified with transmission and 99 were located in the Western region, where all 2,204 autochthonous human cases occurred. Both the vector and the occurrence of human cases have expanded in a South-easterly direction, from the Western to central region, and from there, a further expansion to the North and the South. The (S)-9 methylgermacrene-B population of L. longipalpis is widely distributed in the Western region and the cembrene-1 population is restricted to the Eastern region. CONCLUSION/SIGNIFICANCE: The maps in the present study show that there are two distinct epidemiological patterns of AVL in Sao Paulo State and that the expansion of human and canine AVL cases through the Western region has followed the same dispersion route of only one of the two species of the L. longipalpis complex, (S)-9-methylgermacrene-B. Entomological vigilance based on the routes of dispersion and identification of the chemotype population could be used to identify at-risk areas and consequently define the priorities for control measures. PMID- 25781321 TI - CT perfusion with acetazolamide challenge in C6 gliomas and angiogenesis. AB - BACKGROUND: This study was performed to investigate the correlation between CT perfusion with acetazolamide challenge and angiogenesis in C6 gliomas. METHODS: Thirty-two male Sprague-Dawley rats were evaluated. The rats were divided randomly to four groups: eight rats with orthotopically implanted C6 gliomas at 10-days old (Group A), eight rats with gliomas at 14-days old (Group B), eight rats with gliomas at 18-days old (Group C), eight rats with orthotopically injected normal saline served as controls. CT perfusion was performed before and after administration of acetazolamide. Changes in perfusion parameters due to acetazolamide administration were calculated and analyzed. RESULTS: Elevated carbon dioxide partial pressure and decreased pH were found in all 32 rats post acetazolamide challenge (P<0.01). Cerebral blood flow(pre-challenge) was increased in group C (95.0+/-2.5 ml/100 g/min), as compared to group B (80.1+/ 11.3 ml/100 g/min) and group A (63.1+/-2.1 ml/100 g/min). Cerebral blood flow percentage changes were detected with a reduction in group C (54.2+/-4.8%) as compared to controls (111.3+/-22.2%). Cerebral blood volume(pre-challenge) was increased in group C (50.8+/-1.7 ml/100 g), as compared to group B (45.7+/-1.9 ml/100 g) and group A (38.2+/-0.8 ml/100 g). Cerebral blood volume percentage changes were decreased in group C (23.5+/-4.6%) as compared to controls (113.5+/ 30.4%). Angiogenesis ratio = [(CD105-MVD) / (FVIII-MVD)] *100%. Positive correlations were observed between CD105-microvessel density, angiogenesis ratio, vascular endothelial growth factor, proliferation marker and cerebral blood flow(pre-challenge), cerebral blood volume(pre-challenge). Negative correlations were observed between CD105-microvessel density and cerebral blood flow percentage changes (P<0.01, correlation coefficient r=-0.788), cerebral blood volume percentage changes (P<0.01, r=-0.703). Negative correlations were observed between angiogenesis ratio, vascular endothelial growth factor, proliferation marker and cerebral blood flow percentage changes, cerebral blood volume percentage changes. CONCLUSION: Our findings suggest that CT perfusion with challenge can provide new insight into non-invasive assessment of rat C6 glioma angiogenesis. PMID- 25781322 TI - Deletion of PDK1 causes cardiac sodium current reduction in mice. AB - BACKGROUND: The AGC protein kinase family regulates multiple cellular functions. 3-phosphoinositide-dependent protein kinase-1 (PDK1) is involved in the pathogenesis of arrhythmia, and its downstream factor, Forkhead box O1 (Foxo1), negatively regulates the expression of the cardiac sodium channel, Nav1.5. Mice are known to die suddenly after PDK1 deletion within 11 weeks, but the underlying electrophysiological bases are unclear. Thus, the aim of this study was to investigate the potential mechanisms between PDK1 signaling pathway and cardiac sodium current. METHODS AND RESULTS: Using patch clamp and western blotting techniques, we investigated the role of the PDK1-Foxo1 pathway in PDK1 knockout mice and cultured cardiomyocytes. We found that PDK1 knockout mice undergo slower heart rate, prolonged QRS and QTc intervals and abnormal conduction within the first few weeks of birth. Furthermore, the peak sodium current is decreased by 33% in cells lacking PDK1. The phosphorylation of Akt (308T) and Foxo1 (24T) and the expression of Nav1.5 in the myocardium of PDK1-knockout mice are decreased, while the nuclear localization of Foxo1 is increased. The role of the PDK1-Foxo1 pathway in regulating Nav1.5 levels and sodium current density was verified using selective PDK1, Akt and Foxo1 inhibitors and isolated neonatal rat cardiomyocytes. CONCLUSION: These results indicate that PDK1 participates in the dysregulation of electrophysiological basis by regulating the PDK1-Foxo1 pathway, which in turn regulates the expression of Nav1.5 and cardiac sodium channel function. PMID- 25781323 TI - Reassessment of HIV-1 acute phase infectivity: accounting for heterogeneity and study design with simulated cohorts. AB - BACKGROUND: The infectivity of the HIV-1 acute phase has been directly measured only once, from a retrospectively identified cohort of serodiscordant heterosexual couples in Rakai, Uganda. Analyses of this cohort underlie the widespread view that the acute phase is highly infectious, even more so than would be predicted from its elevated viral load, and that transmission occurring shortly after infection may therefore compromise interventions that rely on diagnosis and treatment, such as antiretroviral treatment as prevention (TasP). Here, we re-estimate the duration and relative infectivity of the acute phase, while accounting for several possible sources of bias in published estimates, including the retrospective cohort exclusion criteria and unmeasured heterogeneity in risk. METHODS AND FINDINGS: We estimated acute phase infectivity using two approaches. First, we combined viral load trajectories and viral load infectivity relationships to estimate infectivity trajectories over the course of infection, under the assumption that elevated acute phase infectivity is caused by elevated viral load alone. Second, we estimated the relative hazard of transmission during the acute phase versus the chronic phase (RHacute) and the acute phase duration (dacute) by fitting a couples transmission model to the Rakai retrospective cohort using approximate Bayesian computation. Our model fit the data well and accounted for characteristics overlooked by previous analyses, including individual heterogeneity in infectiousness and susceptibility and the retrospective cohort's exclusion of couples that were recorded as serodiscordant only once before being censored by loss to follow-up, couple dissolution, or study termination. Finally, we replicated two highly cited analyses of the Rakai data on simulated data to identify biases underlying the discrepancies between previous estimates and our own. From the Rakai data, we estimated RHacute = 5.3 (95% credibility interval [95% CrI]: 0.79-57) and dacute = 1.7 mo (95% CrI: 0.55 6.8). The wide credibility intervals reflect an inability to distinguish a long, mildly infectious acute phase from a short, highly infectious acute phase, given the 10-mo Rakai observation intervals. The total additional risk, measured as excess hazard-months attributable to the acute phase (EHMacute) can be estimated more precisely: EHMacute = (RHacute - 1) * dacute, and should be interpreted with respect to the 120 hazard-months generated by a constant untreated chronic phase infectivity over 10 y of infection. From the Rakai data, we estimated that EHMacute = 8.4 (95% CrI: -0.27 to 64). This estimate is considerably lower than previously published estimates, and consistent with our independent estimate from viral load trajectories, 5.6 (95% confidence interval: 3.3-9.1). We found that previous overestimates likely stemmed from failure to account for risk heterogeneity and bias resulting from the retrospective cohort study design. Our results reflect the interaction between the retrospective cohort exclusion criteria and high (47%) rates of censorship amongst incident serodiscordant couples in the Rakai study due to loss to follow-up, couple dissolution, or study termination. We estimated excess physiological infectivity during the acute phase from couples data, but not the proportion of transmission attributable to the acute phase, which would require data on the broader population's sexual network structure. CONCLUSIONS: Previous EHMacute estimates relying on the Rakai retrospective cohort data range from 31 to 141. Our results indicate that these are substantial overestimates of HIV-1 acute phase infectivity, biased by unmodeled heterogeneity in transmission rates between couples and by inconsistent censoring. Elevated acute phase infectivity is therefore less likely to undermine TasP interventions than previously thought. Heterogeneity in infectiousness and susceptibility may still play an important role in intervention success and deserves attention in future analyses. PMID- 25781324 TI - Rapid identification by surface-enhanced Raman spectroscopy of cancer cells at low concentrations flowing in a microfluidic channel. AB - Reliable identification and collection of cells from bodily fluids is of growing interest for monitoring patient response to therapy and for early detection of disease or its recurrence. We describe a detection platform that combines microfluidics with surface-enhanced Raman spectroscopy (SERS) for the identification of individual mammalian cells continuously flowing in a microfluidics channel. A mixture of cancerous and noncancerous prostate cells was incubated with SERS biotags (SBTs) developed and synthesized by us, then injected into a flow-focused microfluidic channel, which forces the cells into a single file. The spectrally rich SBTs are based on a silver nanoparticle dimer core labeled with a Raman-active small reporter molecule paired with an affinity biomolecule, providing a unique barcode whose presence in a composite SERS spectrum can be deconvoluted. Individual cancer cells passing through the focused laser beam were correctly identified among a proportionally larger number of other cells by their Raman signatures. We examine two deconvolution strategies: principal component analysis and classical least-squares. The deconvolution strategies are used to unmix the overall spectrum to determine the relative contributions between two SBT barcodes, where one SBT barcode indicates neuropilin-1 overexpression, while a second SBT barcode is more universal and indicates unspecific binding to a cell's membrane. Highly reliable results were obtained for all of the cell mixture ratios tested, the lowest being 1 in 100 cells. PMID- 25781326 TI - Health-promoting lifestyles and depression in urban elderly Chinese. AB - OBJECTIVE: To explore health-promoting lifestyles, depression and provide further insight into the relationship between health-promoting lifestyles and depression in an urban community sample of elderly Chinese people. METHODS: A cross sectional descriptive and correlational study of 954 community-dwelling urban elderly Chinese (aged >= 60) was conducted from July to December 2010. Lifestyles and depression were assessed using the revised Chinese Version of the Health Promoting Lifestyle Profile (HPLP-C) and the Geriatric Depression Scale (GDS), respectively. RESULTS: In this cohort, 15.8% of elderly urban adults met the criteria for depression. Over half of the sample (62.1%) scored greater than 100 on the HPLP-C, with range of score sum from 55 to 160. There were significant correlations between self-actualization (OR = 1.167, 95%CI: 1.111-1.226), nutrition (OR = 1.118, 95%CI: 1.033-1.209), physical activity (OR = 1.111, 95%CI: 1.015-1.216) and depression among community-dwelling elderly Chinese. LIMITATIONS: This was a cross-sectional study. The significant associations found do not represent directional causation. Further longitudinal follow-up is recommended to investigate the specific causal relationship between lifestyles and depression. CONCLUSIONS: Depression was common with medium to high levels of health-promoting lifestyles among urban elderly Chinese people. Lifestyle behaviors such as self-actualization, good nutrition habits and frequent physical activity were correlated to fewer depressive symptoms. Healthy lifestyles should be further developed in this population and measures should be taken for improving their depression. PMID- 25781327 TI - Toward multifunctional "clickable" diamond nanoparticles. AB - Nanodiamonds (NDs) are among the most promising new carbon based materials for biomedical applications, and the simultaneous integration of various functions onto NDs is an urgent necessity. A multifunctional nanodiamond based formulation is proposed here. Our strategy relies on orthogonal surface modification using different dopamine anchors. NDs simultaneously functionalized with triethylene glycol (EG) and azide (-N3) functions were fabricated through a stoichiometrically controlled integration of the dopamine ligands onto the surface of hydroxylated NDs. The presence of EG functionalities rendered NDs soluble in water and biological media, while the -N3 group allowed postsynthetic modification of the NDs using "click" chemistry. As a proof of principle, alkynyl terminated di(amido amine) ligands were linked to these ND particles. PMID- 25781325 TI - Pelvic belt effects on pelvic morphometry, muscle activity and body balance in patients with sacroiliac joint dysfunction. AB - INTRODUCTION: The sacroiliac joint (SIJ) is frequently involved in low back and pelvic girdle pain. However, morphometrical and functional characteristics related to SIJ pain are poorly defined. Pelvic belts represent one treatment option, but evidence still lacks as to their pain-reducing effects and the mechanisms involved. Addressing these two issues, this case-controlled study compares morphometric, functional and clinical data in SIJ patients and healthy controls and evaluates the effects of short-term pelvic belt application. METHODS: Morphometric and functional data pertaining to pelvic belt effects were compared in 17 SIJ patients and 17 controls. Lumbar spine and pelvis morphometries were obtained from 3T magnetic resonance imaging. Functional electromyography data of pelvis and leg muscles and center of pressure excursions were measured in one-leg stance. The numerical rating scale was used to evaluate immediate pain-reducing effects. RESULTS: Pelvic morphometry was largely unaltered in SIJ patients and also by pelvic belt application. The angle of lumbar lateral flexion was significantly larger in SIJ patients without belt application. Muscle activity and center of pressure were unaffected by SIJ pain or by belt application in one-leg stance. Nine of 17 patients reported decreased pain intensities under moderate belt application, four reported no change and four reported increased pain intensity. For the entire population investigated here, this qualitative description was not confirmed on a statistical significant level. DISCUSSION: Minute changes were observed in the alignment of the lumbar spine in the frontal plane in SIJ patients. The potential pain-decreasing effects of pelvic belts could not be attributed to altered muscle activity, pelvic morphometry or body balance in a static short-term application. Long-term belt effects will therefore be of prospective interest. PMID- 25781328 TI - Altered microbiomes in bovine digital dermatitis lesions, and the gut as a pathogen reservoir. AB - Bovine digital dermatitis (DD) is the most important infectious disease associated with lameness in cattle worldwide. Since the disease was first described in 1974, a series of Treponema species concurrent with other microbes have been identified in DD lesions, suggesting a polymicrobial etiology. However, the pathogenesis of DD and the source of the causative microbes remain unclear. Here we characterized the microbiomes of healthy skin and skin lesions in dairy cows affected with different stages of DD and investigated the gut microbiome as a potential reservoir for microbes associated with this disease. Discriminant analysis revealed that the microbiomes of healthy skin, active DD lesions (ulcerative and chronic ulcerative) and inactive DD lesions (healing and chronic proliferative) are completely distinct. Treponema denticola, Treponema maltophilum, Treponema medium, Treponema putidum, Treponema phagedenis and Treponema paraluiscuniculi were all found to be present in greater relative abundance in active DD lesions when compared with healthy skin and inactive DD lesions, and these same Treponema species were nearly ubiquitously present in rumen and fecal microbiomes. The relative abundance of Candidatus Amoebophilus asiaticus, a bacterium not previously reported in DD lesions, was increased in both active and inactive lesions when compared with healthy skin. In conclusion, our data support the concept that DD is a polymicrobial disease, with active DD lesions having a markedly distinct microbiome dominated by T. denticola, T. maltophilum, T. medium, T. putidum, T. phagedenis and T. paraluiscuniculi. Furthermore, these Treponema species are nearly ubiquitously found in rumen and fecal microbiomes, suggesting that the gut is an important reservoir of microbes involved in DD pathogenesis. Additionally, the bacterium Candidatus Amoebophilus asiaticus was highly abundant in active and inactive DD lesions. PMID- 25781329 TI - Disease specific productivity of american cancer hospitals. AB - CONTEXT: Research-oriented cancer hospitals in the United States treat and study patients with a range of diseases. Measures of disease specific research productivity, and comparison to overall productivity, are currently lacking. HYPOTHESIS: Different institutions are specialized in research of particular diseases. OBJECTIVE: To report disease specific productivity of American cancer hospitals, and propose a summary measure. METHOD: We conducted a retrospective observational survey of the 50 highest ranked cancer hospitals in the 2013 US News and World Report rankings. We performed an automated search of PubMed and Clinicaltrials.gov for published reports and registrations of clinical trials (respectively) addressing specific cancers between 2008 and 2013. We calculated the summed impact factor for the publications. We generated a summary measure of productivity based on the number of Phase II clinical trials registered and the impact factor of Phase II clinical trials published for each institution and disease pair. We generated rankings based on this summary measure. RESULTS: We identified 6076 registered trials and 6516 published trials with a combined impact factor of 44280.4, involving 32 different diseases over the 50 institutions. Using a summary measure based on registered and published clinical trails, we ranked institutions in specific diseases. As expected, different institutions were highly ranked in disease-specific productivity for different diseases. 43 institutions appeared in the top 10 ranks for at least 1 disease (vs 10 in the overall list), while 6 different institutions were ranked number 1 in at least 1 disease (vs 1 in the overall list). CONCLUSION: Research productivity varies considerably among the sample. Overall cancer productivity conceals great variation between diseases. Disease specific rankings identify sites of high academic productivity, which may be of interest to physicians, patients and researchers. PMID- 25781330 TI - Spontaneous and divergent hexaploid triticales derived from common wheat * rye by complete elimination of D-genome chromosomes. AB - BACKGROUND: Hexaploid triticale could be either synthesized by crossing tetraploid wheat with rye, or developed by crossing hexaploid wheat with a hexaploid triticale or an octoploid triticale. METHODOLOGY/PRINCIPAL FINDINGS: Here two hexaploid triticales with great morphologic divergence derived from common wheat cultivar M8003 (Triticum aestivum L.) * Austrian rye (Secale cereale L.) were reported, exhibiting high resistance for powdery mildew and stripe rust and potential for wheat improvement. Sequential fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) karyotyping revealed that D-genome chromosomes were completely eliminated and the whole A genome, B-genome and R-genome chromosomes were retained in both lines. Furthermore, plentiful alterations of wheat chromosomes including 5A and 7B were detected in both triticales and additionally altered 5B, 7A chromosome and restructured chromosome 2A was assayed in N9116H and N9116M, respectively, even after selfing for several decades. Besides, meiotic asynchrony was displayed and a variety of storage protein variations were assayed, especially in the HMW/LMW GS region and secalins region in both triticales. CONCLUSION: This study confirms that whole D-genome chromosomes could be preferentially eliminated in the hybrid of common wheat * rye, "genome shock" was accompanying the allopolyploidization of nascent triticales, and great morphologic divergence might result from the genetic variations. Moreover, new hexaploid triticale lines contributing potential resistance resources for wheat improvement were produced. PMID- 25781332 TI - Functional neuroanatomy on the working memory under emotional distraction in patients with generalized anxiety disorder. AB - AIMS: Patients with generalized anxiety disorder (GAD) suffer the symptoms of psychological distress, including excessive and uncontrollable anxiety. Until now, the functional neuroanatomy for working memory (WM) in conjunction with the major anxiety symptoms in GAD patients has not yet been clearly identified. This study investigated the neural activation patterns associated with the effect of neutral and anxiety-inducing distractors during the delayed-response WM task in GAD patients. METHODS: Eighteen patients with GAD and 18 age-matched healthy controls participated in this study. The functional magnetic resonance images were obtained while the subjects performed a delayed-response WM task with neutral and anxiety-inducing distractors. RESULTS: During the neutral distractor, GAD patients compared to controls showed significantly lower activities in the fusiform gyrus, superior parietal gyrus, precuneus, superior occipital gyrus, lingual gyrus, cuneus, calcarine gyrus, parahippocampal gyrus and cerebellar cortex. During the anxiety-inducing distractor, GAD patients showed significantly higher activity in the hippocampus, whereas they showed lower activities in the dorsolateral prefrontal cortex, fusiform gyrus, superior parietal gyrus, precuneus, superior occipital gyrus and cerebellar cortex. The blood-oxygen-level dependent signal changes in the dorsolateral prefrontal cortex in GAD patients during the anxiety-inducing distractor were negatively correlated with Anxiety Sensitivity Index-Revised scores. CONCLUSIONS: This study identified the specific brain areas associated with the interaction between emotional regulation and cognitive function associated with neutral and anxiety-inducing distractors during WM maintenance in GAD patients. These findings will be helpful for understanding the neural mechanism on the WM-related cognitive deficits and emotional dysfunction with typical anxiety symptoms in GAD. PMID- 25781331 TI - Identification and expression analysis of MATE genes involved in flavonoid transport in blueberry plants. AB - Multidrug and toxic compound extrusion (MATE) proteins are the most recently identified family of multidrug transporters. In plants, this family is remarkably large compared to the human and bacteria counterpart, highlighting the importance of MATE proteins in this kingdom. Here 33 Unigenes annotated as MATE transporters were found in the blueberry fruit transcriptome, of which eight full-length cDNA sequences were identified and cloned. These proteins are composed of 477-517 residues, with molecular masses ~54 kDa, and theoretical isoelectric points from 5.35 to 8.41. Bioinformatics analysis predicted 10-12 putative transmembrane segments for VcMATEs, and localization to the plasma membrane without an N terminal signal peptide. All blueberry MATE proteins shared 32.1-84.4% identity, among which VcMATE2, VcMATE3, VcMATE5, VcMATE7, VcMATE8, and VcMATE9 were more similar to the MATE-type flavonoid transporters. Phylogenetic analysis showed VcMATE2, VcMATE3, VcMATE5, VcMATE7, VcMATE8 and VcMATE9 clustered with MATE-type flavonoid transporters, indicating that they might be involved in flavonoid transport. VcMATE1 and VcMATE4 may be involved in the transport of secondary metabolites, the detoxification of xenobiotics, or the export of toxic cations. Real-time quantitative PCR demonstrated that the expression profile of the eight VcMATE genes varied spatially and temporally. Analysis of expression and anthocyanin accumulation indicated that there were some correlation between the expression profile and the accumulation of anthocyanins. These results showed VcMATEs might be involved in diverse physiological functions, and anthocyanins across the membranes might be mutually maintained by MATE-type flavonoid transporters and other mechanisms. This study will enrich the MATE-based transport mechanisms of secondary metabolite, and provide a new biotechonology strategy to develop better nutritional blueberry cultivars. PMID- 25781333 TI - Temporal variations in soil moisture for three typical vegetation types in inner Mongolia, northern China. AB - Drought and shortages of soil water are becoming extremely severe due to global climate change. A better understanding of the relationship between vegetation type and soil-moisture conditions is crucial for conserving soil water in forests and for maintaining a favorable hydrological balance in semiarid areas, such as the Saihanwula National Nature Reserve in Inner Mongolia, China. We investigated the temporal dynamics of soil moisture in this reserve to a depth of 40 cm under three types of vegetation during a period of rainwater recharge. Rainwater from most rainfalls recharged the soil water poorly below 40 cm, and the rainfall threshold for increasing the moisture content of surface soil for the three vegetations was in the order: artificial Larix spp. (AL) > Quercus mongolica (QM) > unused grassland (UG). QM had the highest mean soil moisture content (21.13%) during the monitoring period, followed by UG (16.52%) and AL (14.55%); and the lowest coefficient of variation (CV 9.6-12.5%), followed by UG (CV 10.9-18.7%) and AL (CV 13.9-21.0%). QM soil had a higher nutrient content and higher soil porosities, which were likely responsible for the higher ability of this cover to retain soil water. The relatively smaller QM trees were able to maintain soil moisture better in the study area. PMID- 25781334 TI - Refined requirements for protein regions important for activity of the TALE AvrBs3. AB - AvrBs3, the archetype of the family of transcription activator-like (TAL) effectors from phytopathogenic Xanthomonas bacteria, is translocated by the type III secretion system into the plant cell. AvrBs3 localizes to the plant cell nucleus and activates the transcription of target genes. Crucial for this is the central AvrBs3 region of 17.5 34-amino acid repeats that functions as a DNA binding domain mediating recognition in a "one-repeat-to-one base pair" manner. Although AvrBs3 forms homodimers in the plant cell cytosol prior to nuclear import, it binds DNA as a monomer. Here, we show that complex formation of AvrBs3 proteins negatively affects their DNA-binding affinity in vitro. The conserved cysteine residues at position 30 of each repeat facilitate AvrBs3 complexes via disulfide bonds in vitro but are also required for the gene-inducing activity of the AvrBs3 monomer, i.e., activation of plant gene promoters. Our data suggest that the latter is due to a contribution to protein plasticity and that cysteine substitutions to alanine or serine result in a different DNA-binding mode. In addition, our studies revealed that extended parts of both the N-terminal and C terminal regions of AvrBs3 contribute to DNA binding and, hence, gene-inducing activity in planta. PMID- 25781335 TI - A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease. AB - One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer's disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been successfully applied to actual clinical trial data accrued from the Phase 3 clinical trials of solanezumab. PMID- 25781336 TI - Ocular signs correlate well with disease severity and genotype in Fabry disease. AB - Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the alpha-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; P<0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with null (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and alpha-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies are needed. PMID- 25781337 TI - Glycation of nail proteins: from basic biochemical findings to a representative marker for diabetic glycation-associated target organ damage. AB - BACKGROUND: Although assessment of glycated nail proteins may be a useful marker for monitoring of diabetes, their nature and formation are still poorly understood. Besides a detailed anatomical analysis of keratin glycation, the usefulness of glycated nail protein assessment for monitoring diabetic complications was investigated. METHODS: 216 patients (94 males, 122 females; mean age +/- standard deviation: 75.0 +/- 8.7 years) were enrolled. Glycation of nail and eye lens proteins was assessed using a photometric nitroblue tetrazolium based assay. Following chromatographic separation of extracted nail proteins, binding and nonbinding fractions were analyzed using one-dimensional gel electrophoresis. Using a hand piece containing a latch-type-bur, a meticulous cutting of the nail plate into superficial and deep layers was performed, followed by a differential analysis of fructosamine. RESULTS: Using SDS PAGE, four and two bands were identified among the nonglycated and glycated nail fraction respectively. Significantly lower fructosamine concentrations were found in the superficial nail layer (mean: 2.16 +/- 1.37 MUmol/g nails) in comparison with the deep layer (mean: 4.36 +/- 2.55 MUmol/g nails) (P<0.05). A significant higher amount of glycated eye lens proteins was found in diabetes mellitus patients (mean: 3.80 +/- 1.57 MUmol/g eye lens) in comparison with nondiabetics (mean: 3.35 +/- 1.34 MUmol/g eye lens) (P<0.05). A marked correlation was found between glycated nail and glycated eye lens proteins [y (glycated nail proteins) = 0.39 + 0.99 x (eye lens glycated proteins); r2 = 0.58, P<0.001]. The concentration of glycated eye lens proteins and the HbA1c level were found to be predictors of the concentration of glycated nail proteins. CONCLUSIONS: Glycation of nail proteins takes place in the deep layer of finger nails, which is in close contact with blood vessels and interstitial fluid. Glycation of nail proteins can be regarded as a representative marker for diabetic glycation-associated target organ damage. PMID- 25781338 TI - Biosynthetic versatility and coordinated action of 5'-deoxyadenosyl radicals in deazaflavin biosynthesis. AB - Coenzyme F420 is a redox cofactor found in methanogens and in various actinobacteria. Despite the major biological importance of this cofactor, the biosynthesis of its deazaflavin core (8-hydroxy-5-deazaflavin, F(o)) is still poorly understood. F(o) synthase, the enzyme involved, is an unusual multidomain radical SAM enzyme that uses two separate 5'-deoxyadenosyl radicals to catalyze F(o) formation. In this paper, we report a detailed mechanistic study on this complex enzyme that led us to identify (1) the hydrogen atoms abstracted from the substrate by the two radical SAM domains, (2) the second tyrosine-derived product, (3) the reaction product of the CofH-catalyzed reaction, (4) the demonstration that this product is a substrate for CofG, and (5) a stereochemical study that is consistent with the formation of a p-hydroxybenzyl radical at the CofH active site. These results enable us to propose a mechanism for F(o) synthase and uncover a new catalytic motif in radical SAM enzymology involving the use of two 5'-deoxyadenosyl radicals to mediate the formation of a complex heterocycle. PMID- 25781339 TI - Influence of Semiconductor Thickness and Molecular Weight on the Charge Transport of a Naphthalenediimide-Based Copolymer in Thin-Film Transistors. AB - The N-type semiconducting polymer, P(NDI2OD-T2), with different molecular weights (MW=23, 72, and 250 kg/mol) was used for the fabrication of field-effect transistors (FETs) with different semiconductor layer thicknesses. FETs with semiconductor layer thicknesses from ~15 to 50 nm exhibit similar electron mobilities (MU's) of 0.2-0.45 cm2 V(-1) s(-1). Reduction of the active film thickness led to decreased MU values; however, FETs with ~2 and ~5 nm thick P(NDI2OD-T2) films still exhibit substantial MU's of 0.01-0.02 and ~10(-4) cm2 V( 1) s(-1), respectively. Interestingly, the lowest molecular weight sample (P-23, MW~23 kg/mol, polydispersity index (PDI)=1.9) exhibited higher MU than the highest molecular weight sample (P-250, MW~250 kg/mol, PDI=2.3) measured for thicker devices (15-50 nm). This is rather unusual behavior because typically charge carrier mobility increases with MW where improved grain-to-grain connectivity usually enhances transport events. We attribute this result to the high crystallinity of the lowest MW sample, as confirmed by differential scanning calorimetry and X-ray diffraction studies, which may (over)compensate for other effects. PMID- 25781340 TI - Reduced Burden of Salmonella enterica in Bovine Subiliac Lymph Nodes Associated with Administration of a Direct-fed Microbial. AB - Despite effective food safety interventions within abattoirs, Salmonella enterica remains a common contaminant of raw ground beef. Research has recently implicated peripheral lymph nodes (PLNs) as a potential route by which Salmonella contaminates ground beef. This study examined the efficacy of using Lactobacillus animalis (formerly designated Lactobacillus acidophilus; NP51) and Propionibacterium freudenreichii (NP24), at 10(9) cfu/head/day, as a direct-fed microbial (DFM) in feedlot cattle diets to control Salmonella within PLNs. Two studies were conducted in which cattle were randomly allocated into either control or DFM treatment groups. Diets of treated cattle were supplemented with 10(9) cfu/head/day of the DFM, while control groups received no DFM supplementation. During slaughter at abattoirs, one subiliac lymph node (SLN) per carcass was collected from 627 carcasses from one study and 99 carcasses from the second study. Lymph nodes were cultured to estimate the presence and concentration of Salmonella. In the first study, effects of DFM supplementation varied across slaughter days. On the first and second slaughter days, prevalence was reduced by 50% (P = 0.0072) and 31% (P = 0.0093), respectively. No significant difference was observed on slaughter day three (P = 0.1766). In the second study, Salmonella was 82% less likely (P = 0.008) to be recovered from SLNs of treatment cattle. While a greater relative risk reduction was observed in the latter study, absolute risk reductions were similar across studies. A significant reduction in the concentration of Salmonella in SLNs (P < 0.0001) on a cfu/g and cfu/node basis was also observed in cattle administered NP51 and NP24 in the first study; in the second study, too few quantifiable SLNs were observed to facilitate meaningful comparisons. The results indicate that NP51 and NP24 supplementation may aid in reducing the prevalence and concentration of Salmonella in SLNs and, therefore, serve as an effective control measure to reduce Salmonella in ground beef products. PMID- 25781342 TI - Triaging Shakespeare. PMID- 25781341 TI - Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: impact on sorafenib cytotoxicity. AB - Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of these transporters. Genistein (GNT) is a phytoestrogen abundant in soybean that exerts its genomic effects through Estrogen-Receptors and Pregnane-X-Receptor (PXR), which are involved in the regulation of the above mentioned transporters. We evaluated the effect of GNT on the expression and activity of P-gp, MRP2, MRP3 and BCRP in HCC-derived HepG2 cells. GNT (at 1.0 and 10 MUM) increased P-gp and MRP2 protein expression and activity, correlating well with an increased resistance to sorafenib cytotoxicity as detected by the methylthiazole tetrazolium (MTT) assay. GNT induced P-gp and MRP2 mRNA expression at 10 but not at 1.0 MUM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 MUM GNT was prevented by cycloheximide, suggesting translational regulation. Downregulation of expression of the miR-379 by GNT could be associated with translational regulation of MRP2. Silencing of PXR abolished P-gp induction by GNT (at 1.0 and 10 MUM) and MRP2 induction by GNT (only at 10 MUM), suggesting partial mediation of GNT effects by PXR. Taken together, the data suggest the possibility of nutrient-drug interactions leading to enhanced chemoresistance in HCC when GNT is ingested with soy rich diets or dietary supplements. PMID- 25781343 TI - Registered report: Intestinal inflammation targets cancer-inducing activity of the microbiota. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered report describes the proposed replication plan of key experiments from 'Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota' by Arthur et al. (2012), published in Science in 2012. Arthur and colleagues identified a genotoxic island in Escherichia coli NC101 that appeared to be responsible for causing neoplastic lesions in inflammation-induced IL10-/- mice treated with azoxymethane. The experiments that will be replicated are those reported in Figure 4 (Arthur et al., 2012). Arthur and colleagues inoculated IL10 /- mice with a mutated strain of E. coli NC101 lacking the genotoxic island, and showed that those mice suffered from fewer neoplastic lesions than mice inoculated with the wild type form of E. coli NC101 (Figure 4). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. PMID- 25781344 TI - Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells. AB - Calcium-activated chloride channel regulator 1 (CLCA1) activates calcium dependent chloride currents; neither the target, nor mechanism, is known. We demonstrate that secreted CLCA1 activates calcium-dependent chloride currents in HEK293T cells in a paracrine fashion, and endogenous TMEM16A/Anoctamin1 conducts the currents. Exposure to exogenous CLCA1 increases cell surface levels of TMEM16A and cellular binding experiments indicate CLCA1 engages TMEM16A on the surface of these cells. Altogether, our data suggest that CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface expression, which results in increased calcium-dependent chloride currents. Our results identify the first Cl( ) channel target of the CLCA family of proteins and establish CLCA1 as the first secreted direct modifier of TMEM16A activity, delineating a unique mechanism to increase currents. These results suggest cooperative roles for CLCA and TMEM16 proteins in influencing the physiology of multiple tissues, and the pathology of multiple diseases, including asthma, COPD, cystic fibrosis, and certain cancers. PMID- 25781345 TI - Effect of heterogeneous investments on the evolution of cooperation in spatial public goods game. AB - Understanding the emergence of cooperation in spatial public goods game remains a grand challenge across disciplines. In most previous studies, it is assumed that the investments of all the cooperators are identical, and often equal to 1. However, it is worth mentioning that players are diverse and heterogeneous when choosing actions in the rapidly developing modern society and researchers have shown more interest to the heterogeneity of players recently. For modeling the heterogeneous players without loss of generality, it is assumed in this work that the investment of a cooperator is a random variable with uniform distribution, the mean value of which is equal to 1. The results of extensive numerical simulations convincingly indicate that heterogeneous investments can promote cooperation. Specifically, a large value of the variance of the random variable can decrease the two critical values for the result of behavioral evolution effectively. Moreover, the larger the variance is, the better the promotion effect will be. In addition, this article has discussed the impact of heterogeneous investments when the coevolution of both strategy and investment is taken into account. Comparing the promotion effect of coevolution of strategy and investment with that of strategy imitation only, we can conclude that the coevolution of strategy and investment decreases the asymptotic fraction of cooperators by weakening the heterogeneity of investments, which further demonstrates that heterogeneous investments can promote cooperation in spatial public goods game. PMID- 25781347 TI - Variability in performance on a work simulation test of physical fitness for firefighters. AB - The Canadian Forces Firefighter Physical Fitness Maintenance Evaluation (FF PFME) requires firefighters in full fire-protective ensemble, including self-contained breathing apparatus, to correctly complete 10 work-related tasks on a measured and calibrated course. Fitness for duty is inferred from completion time of the course. We hypothesized that completion time may be dependent on pacing strategy and day-to-day fluctuations in biological function. To examine variability in performance, 20 females and 31 males (mean +/- SD; age, 27.6 +/- 10.5 years; height, 176.7 +/- 8.3 cm; mass, 77.3 +/- 13.4 kg) were familiarized with the FF PFME and then completed the test on 6 separate days. Pre-test behaviours (e.g., sleep, diet) and test conditions (e.g., calibration, time of day) were consistent. Repeated-measures ANOVA revealed a significant decrease in completion time between tests 1 and 6 (18.7%) and between all sequential pairs (e.g., tests 1 and 2). There was also a small but significant increase in the fraction of total test time for task completion and a corresponding decrease in the time to transition between tasks. The performance improvements cannot be explained by differences in effort (heart rate and perceived exertion). Coefficient of variation for tests 1, 2, and 3 was 7% and for tests 4, 5, and 6 was 2.6%. The results indicate the importance of practice on performance and the potential for false-positive or false-negative decision errors if biological variability is not taken into account. PMID- 25781346 TI - Serotypes, antibiotic susceptibilities, and multi-locus sequence type profiles of Streptococcus agalactiae isolates circulating in Beijing, China. AB - BACKGROUND: To investigate the serotypes, antibiotic susceptibilities, and multi locus sequence type (MLST) profiles of Streptococcus agalactiae (S. agalactiae) in Beijing to provide references for the prevention and treatment of S. agalactiae infections. METHODS: All isolates were identified using the CAMP test and the latex-agglutination assay and serotyped using a Strep-B-Latex kit, after which they were assessed for antibiotic susceptibility, macrolide-resistance genes, and MLST profiles. RESULTS: In total, 56 S. agalactiae isolates were identified in 863 pregnant women (6.5%). Serotypes Ia, Ib, II, III, and V were identified, among which types III (32.1%), Ia (17.9%), Ib (16.1%), and V (14.3%) were the predominant serotypes. All isolates were susceptible to penicillin and ceftriaxone. The nonsusceptiblity rates measured for erythromycin, clarithromycin, azithromycin, telithromycin, clindamycin, tetracycline, and levofloxacin were 85.7%, 92.9%, 98.2%, 30.4%, 73.2%, 91%, and 39.3%, respectively. We identified 14 sequence types (STs) for the 56 isolates, among which ST19 (30.4%) was predominant. The rate of fluoroquinolone resistance was higher in serotype III than in the other serotypes. Among the 44 erythromycin resistant isolates, 32 (72.7%) carried ermB. CONCLUSION: S. agalactiae isolates of the serotypes Ia, Ib, III, and V are common in Beijing. Among the S. agalactiae isolates, the macrolide and clindamycin resistance rates are extremely high. Most of the erythromycin-resistant isolates carry ermB. PMID- 25781348 TI - Implementation of routine screening for chronic hepatitis B virus co-infection by HIV clinics in Lusaka, Zambia. PMID- 25781349 TI - A comparative analysis of robotic vs laparoscopic retroperitoneal lymph node dissection for testicular cancer. AB - OBJECTIVE: To compare the safety and perioperative outcomes of robotic retroperitoneal lymph node dissection (R-RPLND) vs laparoscopic RPLND (L-RPLND). PATIENTS AND METHODS: Our Institutional Review Board-approved retrospective testicular cancer registry was queried for patients who underwent a primary unilateral R-RPLND or L-RPLND by a single surgeon for a stage I testicular non seminomatous germ cell tumour. Groups were compared for differences in baseline and outcome variables. RESULTS: Between July 2006 and July 2014, 16 R-RPLND and 21 L-RPLND cases were performed by a single surgeon. Intra- and perioperative outcomes including operative time, estimated blood loss, lymph node yield, complicate rate, and ejaculatory status were similar between groups (all P > 0.1). CONCLUSIONS: As an early checkpoint, R-RPLND appears comparable to L-RPLND in terms of safety and perioperative outcomes. It remains unclear if R-RPLND offers any tangible benefits over standard laparoscopy. PMID- 25781350 TI - Novel image monitoring system using a head-mounted display for assistants in da Vinci surgery. PMID- 25781351 TI - Waist-to-Height Ratio and Triglycerides/High-Density Lipoprotein Cholesterol Were the Optimal Predictors of Metabolic Syndrome in Uighur Men and Women in Xinjiang, China. AB - OBJECTIVE: This study aimed to identify the best single predictor of metabolic syndrome by comparing the predictive ability of various anthropometric and atherogenic parameters among a Uighur population in Xinjiang, northwest China. METHODS: A total of 4767 Uighur participants were selected from the Cardiovascular Risk Survey (CRS), which was carried out from October, 2007, to March, 2010. Anthropometric data, blood pressure, serum concentration of serum total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting glucose were documented. Prevalence of metabolic syndrome and its individual components were confirmed according to International Diabetes Federation (IDF) criteria. Area under the receiver operating characteristic curve (AUC) of each variable for the presence of metabolic syndrome was compared. The sensitivity (Sen), specificity (Spe), distance in the receiver operating characteristic (ROC) curve, and cutoffs of each variable for the presence of metabolic syndrome were calculated. RESULTS: In all, 23.7% of men had the metabolic syndrome, whereas 40.1% of women had the metabolic syndrome in a Uighur population in Xinjiang; the prevalence of metabolic syndrome in women was significantly higher than that in men (P<0.001). In men, the waist-to-height ratio (WHtR) had the highest AUC value (AUC=0.838); it was followed by TGs/HDL-C (AUC=0.826), body mass index (BMI) (AUC=0.812), waist-to-hip ratio (WHR) (AUC=0.781), and body adiposity index (BAI) (AUC=0.709). In women, the TGs/HDL-C had the highest AUC value (AUC=0.815); it was followed by WHtR (AUC=0.780), WHR (AUC=0.730), BMI (AUC=0.719), and BAI (AUC=0.699). Similarly, among all five anthropometric and atherogenic parameters, the WHtR had the shortest ROC distance of 0.32 (Sen=85.40%, Spe=71.6%), and the optimal cutoff for WHtR was 0.55 in men. In women, TGs/HDL-C had the shortest ROC distance of 0.35 (Sen=75.29%, Spe=75.18%), and the optimal cutoff of TGs/HDL-C was 1.22. CONCLUSION: WHtR was the best predictor of metabolic syndrome in Uighur men, whereas TGs/HDL-C was the best predictor of metabolic syndrome in Uighur women in Xinjiang. PMID- 25781352 TI - Coxsackie eruption arising in areas of epidermolytic ichthyosis. AB - Coxsackie eruptions concentrated in areas of atopic dermatitis, a phenomenon termed "eczema coxsackium," has been well described in the literature but, to our knowledge, the concentration of coxsackie viral lesions to areas of ichthyosis has not been reported. This case describes a rare presentation of coxsackie viral lesions concentrated in areas of epidermolytic ichthyosis in a 3-year-old boy. PMID- 25781354 TI - Methyl substitution effect on the jet-cooled laser-induced fluorescence spectrum of cyclohexoxy radical. AB - Understanding the structure and properties of cyclohexoxy radical and its substitutes is important because of their presence in combustion processes, in atmospheric chemistry, and as intermediates in the hydrocarbon reactions. In this work, jet-cooled laser-induced fluorescence (LIF) spectra of five dimethyl substituted cyclohexoxy radicals are obtained for the first time. The correlation between the spectral variations and the radical structural changes is studied with the assistance of theoretical calculations at the B3LYP/6-31+G(d) and CASSCF/6-31+G(d) levels. The results show that the spectral characters of the dimethylcyclohexoxy radicals and their dissociation kinetics are predominantly affected by the methyl substitution position related to the C-O group. The spectral effect of the two methyl groups will add up if they locate on asymmetric carbons of the cyclohexoxy ring. Methyl substitution on beta carbon weakens the six-member ring of cyclohexoxy and results in unimolecular dissociation via beta C-C bond cleavage on the methyl group side and forms vinoxy variants. This study clearly shows that the LIF spectra can be used to identify cyclohexoxy and the isomers of its methyl substitutes. The results will help to understand the photochemistry of cyclic hydrocarbons in the atmospheric and combustion processes. PMID- 25781353 TI - Tat-antioxidant 1 protects against stress-induced hippocampal HT-22 cells death and attenuate ischaemic insult in animal model. AB - Oxidative stress-induced reactive oxygen species (ROS) are responsible for various neuronal diseases. Antioxidant 1 (Atox1) regulates copper homoeostasis and promotes cellular antioxidant defence against toxins generated by ROS. The roles of Atox1 protein in ischaemia, however, remain unclear. In this study, we generated a protein transduction domain fused Tat-Atox1 and examined the roles of Tat-Atox1 in oxidative stress-induced hippocampal HT-22 cell death and an ischaemic injury animal model. Tat-Atox1 effectively transduced into HT-22 cells and it protected cells against the effects of hydrogen peroxide (H2O2)-induced toxicity including increasing of ROS levels and DNA fragmentation. At the same time, Tat-Atox1 regulated cellular survival signalling such as p53, Bad/Bcl-2, Akt and mitogen-activate protein kinases (MAPKs). In the animal ischaemia model, transduced Tat-Atox1 protected against neuronal cell death in the hippocampal CA1 region. In addition, Tat-Atox1 significantly decreased the activation of astrocytes and microglia as well as lipid peroxidation in the CA1 region after ischaemic insult. Taken together, these results indicate that transduced Tat Atox1 protects against oxidative stress-induced HT-22 cell death and against neuronal damage in animal ischaemia model. Therefore, we suggest that Tat-Atox1 has potential as a therapeutic agent for the treatment of oxidative stress induced ischaemic damage. PMID- 25781355 TI - Incretin and glucagon levels in adult offspring exposed to maternal diabetes in pregnancy. AB - CONTEXT: Fetal exposure to maternal diabetes is associated with increased risk of type 2 diabetes mellitus (T2DM) later in life. The pathogenesis of T2DM involves dysfunction of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), as well as hyperglucagonemia. OBJECTIVE: Our aim was to investigate circulating plasma levels of GLP-1, GIP, and glucagon during the oral glucose tolerance test (OGTT) in adult offspring of women with diabetes in pregnancy. DESIGN AND PARTICIPANTS: We conducted a follow up study of 567 offspring, aged 18-27 years. We included two groups exposed to maternal diabetes in utero: offspring of women with diet-treated gestational diabetes mellitus (O-GDM; n = 163) or type 1 diabetes (O-T1DM; n = 146). Two reference groups were included: offspring of women with risk factors for GDM, but normoglycemia during pregnancy (O-NoGDM; n = 133) and offspring from the background population (O-BP; n = 125). The subjects underwent a 75-g OGTT with venous samples at 0, 30, and 120 minutes. RESULTS: Fasting plasma levels of GLP-1 were lower in the two diabetes-exposed groups compared to O-BP (O-GDM, P = .040; O-T1DM, P = .008). Increasing maternal blood glucose during OGTT in pregnancy was associated with reduced postprandial suppression of glucagon in the offspring. Lower levels of GLP-1 and higher levels of glucagon during the OGTT were present in offspring characterized by overweight or prediabetes/T2DM at follow-up, irrespective of exposure status. CONCLUSION: Lower levels of fasting GLP-1 and impaired glucagon suppression in adult offspring exposed to maternal diabetes during pregnancy are diabetogenic traits that may contribute to glucose intolerance in these persons, but further investigations are needed. PMID- 25781357 TI - Factors associated with islet yield and insulin independence after total pancreatectomy and islet cell autotransplantation in patients with chronic pancreatitis utilizing off-site islet isolation: Cleveland Clinic experience. AB - CONTEXT: Total pancreatectomy (TP) with islet cell autotransplantation (IAT) can reduce or prevent diabetes by preserving beta cell function and is normally performed with on-site isolation laboratory facilities. OBJECTIVE: We examined factors associated with islet yield and metabolic outcomes in patients with chronic pancreatitis undergoing TP-IAT. We report our experience of TP-IAT with an off-site islet isolation laboratory. PATIENTS AND METHODS: Data (August 2008 to February 2014) were obtained from a TP-IAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Each patient was assessed with pre- and postoperative 5-hour mixed-meal tolerance tests for metabolic measurements and with serial glycosylated hemoglobin (HbA1c) determinations. RESULTS: Thirty-six patients with a mean age of 38 years (range, 16-72 y) underwent TP-IAT for different etiologies. At a median follow-up time of 28 months (range, 3-66 mo), 12 patients were insulin independent and 24 patients were on at least one insulin injection a day. Postoperatively, C-peptide levels >=0.3 ng/mL were present in 23/33 (70%) of the patients, with a median fasting C-peptide value of 0.8 ng/mL (range, <0.2-1.5 ng/mL). Those who were insulin independent were more likely to be female (P = .012), have normal morphology on pre-operative pancreatic imaging (P = .011), and have significantly higher median islet yield (6845 islet equivalent numbers [IEQ]/kg, n = 12 vs 3333 IEQ/kg, n = 24; P < .001). CONCLUSIONS: IAT after TP performed in our facility with an off-site islet isolation laboratory shows islet yield and rates of insulin independence that are comparable to other large centers with on-site laboratories. PMID- 25781356 TI - Whole exome sequencing identifies RAI1 mutation in a morbidly obese child diagnosed with ROHHAD syndrome. AB - CONTEXT: The current obesity epidemic is attributed to complex interactions between genetic and environmental factors. However, a limited number of cases, especially those with early-onset severe obesity, are linked to single gene defects. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is one of the syndromes that presents with abrupt-onset extreme weight gain with an unknown genetic basis. OBJECTIVE: To identify the underlying genetic etiology in a child with morbid early-onset obesity, hypoventilation, and autonomic and behavioral disturbances who was clinically diagnosed with ROHHAD syndrome. Design/Setting/Intervention: The index patient was evaluated at an academic medical center. Whole-exome sequencing was performed on the proband and his parents. Genetic variants were validated by Sanger sequencing. RESULTS: We identified a novel de novo nonsense mutation, c.3265 C>T (p.R1089X), in the retinoic acid-induced 1 (RAI1) gene in the proband. Mutations in the RAI1 gene are known to cause Smith-Magenis syndrome (SMS). On further evaluation, his clinical features were not typical of either SMS or ROHHAD syndrome. CONCLUSIONS: This study identifies a de novo RAI1 mutation in a child with morbid obesity and a clinical diagnosis of ROHHAD syndrome. Although extreme early-onset obesity, autonomic disturbances, and hypoventilation are present in ROHHAD, several of the clinical findings are consistent with SMS. This case highlights the challenges in the diagnosis of ROHHAD syndrome and its potential overlap with SMS. We also propose RAI1 as a candidate gene for children with morbid obesity. PMID- 25781358 TI - Interchromosomal insertional translocation at Xq26.3 alters SOX3 expression in an individual with XX male sex reversal. AB - CONTEXT: 46,XX male sex reversal occurs in approximately 1: 20 000 live births and is most commonly caused by interchromosomal translocations of the Y-linked sex-determining gene, SRY. Rearrangements of the closely related SOX3 gene on the X chromosome are also associated with 46,XX male sex reversal. It has been hypothesized that sex reversal in the latter is caused by ectopic expression of SOX3 in the developing urogenital ridge where it triggers male development by acting as an analog of SRY. However, altered regulation of SOX3 in individuals with XX male sex reversal has not been demonstrated. PATIENTS AND METHODS: Here we report a boy with SRY-negative XX male sex reversal who was diagnosed at birth with a small phallus, mixed gonads, and borderline-normal T. Molecular characterization of the affected individual was performed using array comparative genomic hybridization, fluorescent in situ hybridization of metaphase chromosomes, whole-genome sequencing, and RT-PCR expression analysis of lymphoblast cell lines. RESULTS: The affected male carries ~774-kb insertion translocation from chromosome 1 into a human-specific palindromic sequence 82 kb distal to SOX3. Importantly, robust SOX3 expression was identified in cells derived from the affected individual but not from control XX or XY cells, indicating that the translocation has a direct effect on SOX3 regulation. CONCLUSION: This is the first demonstration of altered SOX3 expression in an individual with XX male sex reversal and suggests that SOX3 can substitute for SRY to initiate male development in humans. PMID- 25781359 TI - Association between serum thyroid-stimulating hormone levels and serum lipids in children and adolescents: a population-based study of german youth. AB - CONTEXT: No studies have examined the association between TSH and lipid profiles of healthy children and adolescents in the general population. OBJECTIVE: The objective was to investigate the association between TSH and lipid profiles. DESIGN: We used a population-based cross-sectional study design and analyzed our results using multivariable regression models. SETTING: The study was conducted in Germany. PARTICIPANTS: We analyzed data from 6622 children (ages 3-10 y) and 6134 adolescents (ages 11-17 y) drawn from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Blood samples were collected, and serum TSH levels were measured using the electrochemiluminescence method. High and low serum TSH levels were defined according to age-specific reference limits for the assay. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglyceride levels were determined with enzymatic color analyses. RESULTS: We found a significant positive association between TSH and all non-HDL parameters (total cholesterol, LDL-C, and triglycerides) in children (beta = 0.90, 95% confidence interval [CI], 0.53-1.27; beta = 0.78, 95% CI, 0.44-1.13; and beta = 0.90, 95% CI, 0.52-1.27, respectively) and in adolescents (beta = 0.90, 95% CI, 0.47-1.32; beta = 0.67, 95% CI, 0.29 1.05; and beta = 0.92, 95% CI, 0.49-1.35, respectively) (P < .05). Using stratified models, we found that this relationship was particularly present in overweight/obese children. Furthermore, high TSH levels in children were significantly associated with non-HDL parameters. CONCLUSIONS: Higher TSH levels are associated with less favorable lipid levels in children. Longitudinal studies are needed to clarify whether the association between TSH and lipid parameters in children and adolescents is a temporary phenomenon or is sustained into adulthood. PMID- 25781360 TI - Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia. AB - CONTEXT AND OBJECTIVE: A high level of retinol binding protein 4 (RBP4) is reported to be associated with insulin resistance in humans. However, evidence from large-scale populations about the relationship between serum RBP4 and metabolic phenotypes is scarce. In the present study, we aimed to evaluate serum RBP4 distribution and its association with metabolic phenotypes among middle-aged and elderly Chinese. DESIGN AND PARTICIPANTS: Serum concentrations of RBP4 in a cross-sectional sample of 2780 Chinese population aged 50-70 years old in Guangzhou were measured by ELISA. RESULTS: The mean of serum RBP4 concentration was 28.04 MUg/mL for male and 37.76 MUg/mL for female (P < .01), respectively. Circulating RBP4 was positively correlated with serum triglyceride and apolipoprotein B (apoB) concentrations. The odds ratio (OR) was substantially higher for hypertriglyceridemia (OR, 3.26; 95% confidence interval, 2.36-4.51) in the highest RBP4 quartile compared with those in the lowest quartile after multiple adjustment for confounders. Furthermore, serum RBP4 was significantly associated with fasting glucose, insulin levels, and homeostasis model assessment index-insulin resistance (HOMA-IR). Moreover, we showed that RBP4 enhanced microsomal triglyceride transfer protein (MTP) expression and activity via up regulation of protein disulfide isomerase (PDI), suppressed low-density lipoprotein receptor (LDLR) expression, and impaired insulin-signaling pathway, leading to inductions in apoB secretion both in vitro and in vivo. CONCLUSIONS: Elevated circulating RBP4 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride-rich apoB containing lipoproteins. PMID- 25781361 TI - Irisin and its relation to insulin resistance and puberty in obese children: a longitudinal analysis. AB - CONTEXT: Irisin is a recently identified myokine affecting metabolic and glucose homeostasis. However, the role of irisin in obesity and its metabolic consequences are controversial, and data in children are scarce. OBJECTIVE: To study the relationships between irisin, insulin resistance, and puberty before and after weight loss in obese children with and without impaired glucose tolerance. DESIGN: One-year follow-up study in obese children participating in a lifestyle intervention. SETTING: Primary care. PATIENTS: Forty obese children and 20 normal-weight children of similar age, gender, and pubertal stage. INTERVENTION: A 1-year outpatient intervention program based on exercise, behavior, and nutrition therapy. MAIN OUTCOMES MEASURES: Fasting serum irisin, weight status (body mass index [BMI] SD score), and the following parameters of the metabolic syndrome: insulin resistance index (homeostasis model of assessment), blood pressure, and lipids. RESULTS: The irisin levels were the highest in obese children with impaired glucose tolerance, followed by obese children with normal glucose tolerance, and levels were lowest in normal-weight children (P < .001). In a multiple linear regression analysis, baseline irisin was significantly associated with pubertal stage, high-density lipoprotein cholesterol, and homeostasis model of assessment, but not to age, gender, BMI, or any other parameter of the metabolic syndrome. The irisin concentrations were significantly (P = .010) lower in the prepubertal compared to the pubertal children. In longitudinal analyses, changes of irisin were significantly associated with entry into puberty, change of fasting glucose, and 2-hour glucose in an oral glucose tolerance test, but not with change of BMI or any other parameter. CONCLUSIONS: Irisin levels are related to pubertal stage and insulin resistance but not to weight status in childhood. PMID- 25781362 TI - A possible contribution of lipocalin-2 to the development of dermal fibrosis, pulmonary vascular involvement and renal dysfunction in systemic sclerosis. AB - BACKGROUND: Lipocalin-2 is an adipocytokine implicated in apoptosis, innate immunity, angiogenesis, and the development of chronic kidney disease. OBJECTIVES: To investigate the role of lipocalin-2 in systemic sclerosis (SSc). MATERIALS AND METHODS: Serum lipocalin-2 levels were determined by enzyme-linked immunosorbent assay in 50 patients with SSc and 19 healthy subjects. Lipocalin-2 expression was evaluated in the skin of patients with SSc and bleomycin (BLM) treated mice and in Fli1-deficient endothelial cells by reverse transcriptase real time polymerase chain reaction, immunoblotting and/or immunohistochemistry. RESULTS: Although serum lipocalin-2 levels were comparable between patients with SSc and healthy controls, the prevalence of scleroderma renal crisis was significantly higher in patients with SSc with elevated serum lipocalin-2 levels than in those with normal levels. Furthermore, serum lipocalin-2 levels inversely correlated with estimated glomerular filtration rate in patients with SSc with renal dysfunction. Among patients with SSc with normal renal function, serum lipocalin-2 levels positively correlated with skin score in patients with diffuse cutaneous SSc with disease duration of < 3 years and inversely correlated with estimated right ventricular systolic pressure in total patients with SSc. Importantly, in SSc lesional skin, lipocalin-2 expression was increased in dermal fibroblasts and endothelial cells. In BLM-treated mice, lipocalin-2 was highly expressed in dermal fibroblasts, but not in endothelial cells. On the other hand, the deficiency of transcription factor Fli1, which is implicated in SSc vasculopathy, induced lipocalin-2 expression in cultivated endothelial cells. CONCLUSIONS: Lipocalin-2 may be involved in renal dysfunction and dermal fibrosis of SSc. Dysregulated matrix metalloproteinase-9/lipocalin-2-dependent angiogenesis due to Fli1 deficiency may contribute to the development of pulmonary arterial hypertension associated with SSc. PMID- 25781363 TI - From thermodynamics to kinetics: enhanced sampling of rare events. AB - Despite great advances in molecular dynamics simulations, there remain large gaps between the simulations and experimental observations in terms of the time and length scales that can be approached. Developing fast and accurate algorithms and methods is of ultimate importance to bridge these gaps. In this Account, we briefly summarize recent efforts in such directions. In particular, we focus on integrated tempering sampling. The efficiency of this sampling method has been demonstrated by applications to a range of chemical and biological problems: protein folding, molecular cluster structure searches, and chemical reactions. The combination of integrated tempering sampling and a trajectory sampling method allows the calculation of rate constants and reaction pathways without predefined collective coordinates. PMID- 25781364 TI - Photoinduced PCET in ruthenium-phenol systems: thermodynamic equivalence of uni- and bidirectional reactions. AB - Six termolecular reaction systems comprised of Ru(4,4'-bis(trifluoromethyl)-2,2' bipyridine)32+, phenols with different para substituents, and pyridine in acetonitrile undergo proton-coupled electron transfer (PCET) upon photoexcitation of the metal complex. Five of these six phenols are found to release in concerted fashion an electron to the ruthenium photooxidant and a proton to the pyridine base. The kinetics for this concerted bidirectional PCET process and its relationship to the reaction free energy were compared to the driving-force dependence of reaction kinetics for unidirectional concerted proton-electron transfer (CPET) between the same phenols and Ru(2,2'-bipyrazine)32+, a combined electron/proton acceptor. The results strongly support the concept of thermodynamic equivalence between separated electron/proton acceptors and single reagent hydrogen-atom acceptors. A key feature of the explored systems is the similarity between molecules employed for bi- and unidirectional CPET. PMID- 25781365 TI - Computation and simulation of the structural characteristics of the kidney urea transporter and behaviors of urea transport. AB - Urea transporters are a family of membrane proteins that transport urea molecules across cell membranes and play important roles in a variety of physiological processes. Although the crystal structure of bacterial urea channel dvUT has been solved, there lacks an understanding of the dynamics of urea transport in dvUT. In this study, by using molecular dynamics simulations, Monte Carlo methods, and the adaptive biasing force approach, we built the equilibrium structure of dvUT, calculated the variation in the free energy of urea, determined the urea-binding sites of dvUT, gained insight into the microscopic process of urea transport, and studied the water permeability in dvUT including the analysis of a water chain in the pore. The strategy used in this work can be applied to studying transport behaviors of other membrane proteins. PMID- 25781366 TI - Levels of Fecal Calprotectin Are Associated With the Severity of Postoperative Endoscopic Recurrence in Asymptomatic Patients With Crohn's Disease. AB - OBJECTIVES: Fecal calprotectin (fCal) is widely used as marker of gut inflammation and is strongly associated with the severity of endoscopic lesions in Crohn's disease (CD). We analyzed the relationships between levels of fCal and high-sensitivity C-reactive protein (hsCRP) and the presence and severity of postoperative endoscopic recurrence in asymptomatic CD patients (Harvey-Bradshaw index<=3). METHODS: Blood and fecal samples were collected in consecutive asymptomatic CD patients (Harvey-Bradshaw index 0.85 +/- 0.19, mean +/- s.e.m.) who had undergone an ileocolonic resection. hsCRP and fCal were measured and a routine ileocolonoscopy was performed within 18 months (median 7 months) from resection, to detect endoscopic recurrence according to the Rutgeerts score. RESULTS: Eighty-six patients were included in this prospective multicenter observational cohort. fCal concentrations differed significantly in patients with endoscopic recurrence when compared with those in endoscopic remission (mean +/- s.e.m.: 473 +/- 78 MUg/g vs. 115 +/- 18 MUg/g; P<0.0001). The area under the receiver operating characteristic (ROC) curve to discriminate between patients in endoscopic remission and recurrence was 0.86 for fCal and lower for hsCRP (0.70). The best cutoff point for fCal to distinguish between endoscopic remission and recurrence was 100 MUg/g as determined by the ROC curve, and its sensitivity, specificity, positive and negative predictive values (NPVs), as well as overall accuracy were 95%, 54%, 69%, 93%, and 77%, respectively. CONCLUSION: Measurement of fCal concentrations is a promising and useful tool for monitoring asymptomatic CD patients after ileocolonic resection. Taking into account the high NPV of fCal, a threshold below 100 MUg/g could avoid systematic ileocolonoscopies in 30% of patients from this population. PMID- 25781368 TI - The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. AB - INTRODUCTION: The irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are associated with substantial symptom and disease burden. Although typically classified as distinct diseases, symptoms frequently overlap. AIM: The objective of this study was to characterize symptom and disease burden in IBS-C and CIC sufferers and examine a subset of CIC sufferers with abdominal symptoms. METHODS: In a US population-based survey, respondents meeting the Rome III criteria for IBS-C or CIC rated symptom frequency and bothersomeness, missed work and disrupted productivity, and degree of obtaining and satisfaction with physician care. CIC respondents were analyzed in two subgroups: those with abdominal symptoms >=once weekly (CIC-A) and those without (CIC-NA). RESULTS: Of the 10,030 respondents, 328 met the criteria for IBS-C and 552 for CIC (363 CIC-A; 189 CIC-NA). All symptoms were significantly more frequent in IBS-C vs. CIC respondents (P<0.0001). Constipation was extremely/very bothersome in 72% of IBS-C respondents, 62% of CIC-A, and 40% of CIC-NA (P<0.01 all pairs). All 11 other measured symptoms were significantly more bothersome in IBS-C and CIC-A vs. CIC-NA respondents. In IBS-C vs. CIC-A, abdominal discomfort, bloating, straining, and pellet-like stools were also significantly more bothersome, with other remaining symptoms similar. Gastrointestinal symptoms disrupted productivity a mean of 4.9 days per month in IBS-C respondents, 3.2 in CIC-A, and 1.2 in CIC-NA (P<0.001 all pairs); missed days were similar in IBS-C and CIC-A respondents. CONCLUSION: CIC respondents with abdominal symptoms experience greater disease burden compared with CIC respondents without frequent abdominal symptoms and have a disease burden profile that is similar to IBS-C respondents. PMID- 25781369 TI - Ligand-free Pd-catalyzed and copper-assisted C-H arylation of quinazolin-4-ones with aryl iodides under microwave heating. AB - A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4 ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones. PMID- 25781370 TI - Ultrasound-assisted activation of zero-valent magnesium for nitrate denitrification: identification of reaction by-products and pathways. AB - Zero-valent magnesium (Mg(0)) was activated by ultrasound (US) in an aim to promote its potential use in water treatment without pH control. In this context, nitrate reduction was studied at batch conditions using various doses of magnesium powder and ultrasound power. While neither ultrasound nor zero-valent magnesium alone was effective for reducing nitrate in water, their combination removed up to 90% of 50 mg/L NO3-N within 60 min. The rate of nitrate reduction by US/Mg(0) enhanced with increasing ultrasonic power and magnesium dose. Nitrogen gas (N2) and nitrite (NO2(-)) were detected as the major reduction by products, while magnesium hydroxide Mg(OH)2 and hydroxide ions (OH(-)) were identified as the main oxidation products. The results from SEM-EDS measurements revealed that the surface oxide level decreased significantly when the samples of Mg(0) particles were exposed to ultrasonic treatment. The surface passivation of magnesium particles was successfully minimized by mechanical forces of ultrasound, which in turn paved the way to sustain the catalyst activity toward nitrate reduction. PMID- 25781367 TI - Utility of a Noninvasive Serum Biomarker Panel for Diagnosis and Monitoring of Eosinophilic Esophagitis: A Prospective Study. AB - OBJECTIVES: Noninvasive biomarkers would be valuable for diagnosis and monitoring of eosinophilic esophagitis (EoE). The aim of this study was to determine the utility of a panel of serum biomarkers for the diagnosis and management of EoE. METHODS: We conducted a prospective cohort study of consecutive adults undergoing outpatient esophagogastroduodenoscopy. Incident cases of EoE were diagnosed per consensus guidelines; controls had gastroesophageal reflux disease (GERD) or dysphagia and did not meet the EoE criteria. EoE cases were treated with topical steroids and had repeat endoscopy. Pre- and post-treatment serum samples were analyzed in a blinded manner for interleukin (IL)-4, IL-5, IL-6, IL-9, IL-13, transforming growth factor (TGF)-alpha, TGF-beta, tumor necrosis factor-alpha, eotaxin-1, -2, and -3, thymic stromal lymphopoietin (TSLP), major basic protein, and eosinophil-derived neurotoxin. Cases and controls were compared at baseline, and pre- and post-treatment assays were compared in cases. RESULTS: A total of 61 incident EoE cases and 87 controls were enrolled; 51 EoE cases had post-treatment serum analyzed. There were no significant differences in any of the biomarkers between EoE cases and controls at baseline. IL-13 and eotaxin-3 for cases and controls were 85 +/- 160 vs. 43 +/- 161 pg/ml (P=0.12) and 41 +/- 159 vs. 21 +/- 73 (P=0.30). There were no significant differences in assay values among cases before and after treatment. There were also no differences after stratification by atopic status or treatment response. CONCLUSIONS: A panel of inflammatory factors known to be associated with EoE pathogenesis were not increased in the serum, nor were they responsive to therapy. None of these biomarkers are likely candidates for a serum test for EoE. Histologic analysis for diagnosis and management of EoE continues to be necessary, and novel, less invasive, biomarkers are needed. PMID- 25781371 TI - Synthesis and characterization of Ag3PO4 immobilized with graphene oxide (GO) for enhanced photocatalytic activity and stability over 2,4-dichlorophenol under visible light irradiation. AB - A series of visible-light responsive photocatalysts prepared using Ag3PO4 immobilized with graphene oxide (GO) with varying GO content were obtained by an electrostatically driven method, and 2,4-dichlorophenol (2,4-DCP) was used to evaluate the performance of the photocatalysts. The composites exhibited superior photocatalytic activity and stability compared with pure Ag3PO4. When the content of GO was 5%, the degradation efficiency of 2,4-DCP could reach 98.95%, and 55.91% of the total organic (TOC) content was removed within 60 min irradiation. Meanwhile, the efficiency of 91.77% was achieved for 2,4-DCP degradation even after four times of recycling in the photocatalysis/Ag3PO4-GO (5%) system. Reactive species of O2(-), OH and h(+) were considered as the main participants for oxidizing 2,4-DCP, as confirmed by the free radical capture experiments. And some organic intermediates including 4-chlorophenol (4-CP), hydroquinone (HQ), benzoquinone (BZQ), 2-chlorohydroquinone and hydroxyhydroquinone (HHQ) were detected by comparison with the standard retention times from the high performance liquid chromatography (HPLC). In short, the enhanced photocatalytic property of Ag3PO4-GO was closely related to the strong absorption ability of GO relative to 2,4-DCP, the effective separation of photogenerated electron-hole pairs, and the excellent electron capture capability of GO. PMID- 25781372 TI - Mechanism and kinetics of organic matter degradation based on particle structure variation during pig manure aerobic composting. AB - Characterization of the dynamic structure of composting particles may facilitate our understanding of the mechanisms of organic matter degradation during pig manure-wheat straw aerobic composting. In this study, changes in the size, shape, pores, chemical compositions, and crystal structures of pig manure particles during composting were investigated. The results showed that the median diameter (D50) decreased exponentially, while the particle aspect ratio and sphericity were unchanged, suggesting that particles were degraded uniformly along different radial directions. Pores had a mean diameter of 15-30 MUm and were elliptical. The particle porosity increased linearly mainly because of hemicellulose degradation. Furthermore, the influence of particle structure variation on the first order rate constant (k) of organic matter degradation was corrected, which may facilitate the optimization of operation conditions. The k value was proportional to the reciprocal of D50 according to the specific surface area of particles, and it decreased with increased porosity due to the stabilized chemical compositions and crystal structures of particles. However, the applicability of these data to other composting materials should be verified. PMID- 25781373 TI - Efficient remediation of pentachlorophenol contaminated soil with tetrapolyphosphate washing and subsequent ZVI/Air treatment. AB - In this study, we demonstrate that pentachlorophenol contaminated soil can be efficiently remediated with tetrapolyphosphate washing and subsequent zerovalent iron (ZVI)/Air treatment. 2 mmol L(-1) of tetrapolyphosphate could wash away 52.8% of pentachlorophenol (PCP) at pH 7.0 and 84.2% of pentachlorophenol at pH 11.0 from contaminated soil owing to the promotion effect of tetrapolyphosphate on the soil matrix dispersion and the subsequent solubilization of pentachlorophenol. More importantly, tetrapolyphosphate ions remained in the washing effluent could greatly enhance the molecular oxygen activation by ZVI to oxidize the desorbed PCP without any pH adjustment, and also avoid the competitive consumption of reactive oxygen species, as caused by the common organic surfactants in the washing effluent. Therefore, 85.1% of pentachlorophenol could be aerobically removed from the washing effluent by merely using 5 g L(-1) of ZVI. We also interestingly found that the dissolved iron ions released from the soil could enhance the oxidation of pentachlorophenol in the washing effluent, but the dissolved organic matter had the opposite effect. This study suggests the coupling tetrapolyphosphate washing and subsequent ZVI/Air treatment is an optional approach to remediate pentachlorophenol contaminated soil in view of its low cost and environmental benign. PMID- 25781374 TI - Soil geochemistry and digestive solubilization control mercury bioaccumulation in the earthworm Pheretima guillemi. AB - Mercury presents a potential risk to soil organisms, yet our understanding of mercury bioaccumulation in soil dwelling organisms is limited. The influence of soil geochemistry and digestive processes on both methylmercury (MeHg) and total mercury (THg) bioavailability to earthworms (Pheretima guillemi) was evaluated in this study. Earthworms were exposed to six mercury-contaminated soils with geochemically contrasting properties for 36 days, and digestive fluid was concurrently collected to solubilize soil-associated mercury. Bioaccumulation factors were 7.5-31.0 and 0.2-0.6 for MeHg and THg, respectively, and MeHg accounted for 17-58% of THg in earthworm. THg and MeHg measured in soils and earthworms were negatively associated with soil total organic carbon (TOC). Earthworm THg and MeHg also increased with increasing soil pH. The proportion of MeHg and THg released into the digestive fluid (digestive solubilizable mercury, DSM) was 8.3-18.1% and 0.4-1.3%, respectively. The greater solubilization of MeHg by digestive fluid than CaCl2, together with a biokinetic model-based estimate of dietary MeHg uptake, indicated the importance of soil ingestion for MeHg bioaccumulation in earthworms. PMID- 25781375 TI - Combined anaerobic-ozonation process for treatment of textile wastewater: removal of acute toxicity and mutagenicity. AB - A novel set up composed of an anaerobic biofilm reactor followed by ozonation was used for treatment of artificial and real textile effluents containing azo dyes. The biological treatment efficiently removed chemical oxygen demand and color. Ozonation further reduced the organic content of the effluents and was very important for the degradation of aromatic compounds, as shown by the reduction of UV absorbance. The acute toxicity toward Vibrio fischeri and the shrimp Artemia salina increased after the biological treatment. No toxicity was detected after ozonation with the exception of the synthetic effluent containing the highest concentration, 1 g/l, of the azo dye Remazol Red. Both untreated and biologically treated textile effluents were found to have mutagenic effects. The mutagenicity increased even further after 1 min of ozonation. No mutagenicity was however detected in the effluents subjected to longer exposure to ozone. The results of this study suggest that the use of ozonation as short post-treatment after a biological process can be beneficial for the degradation of recalcitrant compounds and the removal of toxicity of textile wastewater. However, monitoring of toxicity and especially mutagenicity is crucial and should always be used to assess the success of a treatment strategy. PMID- 25781376 TI - The Biomechanical Determinants of Concussion: Finite Element Simulations to Investigate Tissue-Level Predictors of Injury During Sporting Impacts to the Unprotected Head. AB - Biomechanical studies of concussions have progressed from qualitative observations of head impacts to physical and numerical reconstructions, direct impact measurements, and finite element analyses. Supplementary to a previous study, which investigated maximum principal strain, the current study used a detailed finite element head model to simulate unhelmeted concussion and no injury head impacts and evaluate the effectiveness of various tissue-level brain injury predictors: strain rate, product of strain and strain rate, cumulative strain damage measure, von Mises stress, and intracranial pressure. Von Mises stress was found to be the most effective predictor of concussion. It was also found that the thalamus and corpus callosum were brain regions with strong associations with concussion. Tentative tolerance limits for tissue-level predictors were proposed in an attempt to broaden the understanding of unhelmeted concussions. For the thalamus, tolerance limits were proposed for a 50% likelihood of concussion: 2.24 kPa, 24.0 s-1, and 2.49 s-1 for von Mises stress, strain rate, and the product of strain and strain rate, respectively. For the corpus callosum, tolerance limits were proposed for a 50% likelihood of concussion: 3.51 kPa, 25.1 s-1, and 2.76 s-1 for von Mises stress, strain rate, and the product of strain and strain rate, respectively. PMID- 25781377 TI - Synthesis and bioactivity of beta-substituted fosmidomycin analogues targeting 1 deoxy-D-xylulose-5-phosphate reductoisomerase. AB - Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. PMID- 25781378 TI - Developing emergency department physician shift schedules optimized to meet patient demand. AB - OBJECTIVES: 1) To assess temporal patterns in historical patient arrival rates in an emergency department (ED) to determine the appropriate number of shift schedules in an acute care area and a fast-track clinic and 2) to determine whether physician scheduling can be improved by aligning physician productivity with patient arrivals using an optimization planning model. METHODS: Historical data were statistically analyzed to determine whether the number of patients arriving at the ED varied by weekday, weekend, or holiday weekend. Poisson-based generalized additive models were used to develop models of patient arrival rate throughout the day. A mathematical programming model was used to produce an optimal ED shift schedule for the estimated patient arrival rates. We compared the current physician schedule to three other scheduling scenarios: 1) a revised schedule produced by the planning model, 2) the revised schedule with an additional acute care physician, and 3) the revised schedule with an additional fast-track clinic physician. RESULTS: Statistical modelling found that patient arrival rates were different for acute care versus fast-track clinics; the patterns in arrivals followed essentially the same daily pattern in the acute care area; and arrival patterns differed on weekdays versus weekends in the fast track clinic. The planning model reduced the unmet patient demand (i.e., the average number of patients arriving at the ED beyond the average physician productivity) by 19%, 39%, and 69% for the three scenarios examined. CONCLUSIONS: The planning model improved the shift schedules by aligning physician productivity with patient arrivals at the ED. PMID- 25781379 TI - Randomized controlled trial of a nursing intervention to reduce emergency department revisits. AB - OBJECTIVE: To determine whether a nursing intervention delivered at emergency department (ED) discharge would reduce ED revisits. METHOD: A randomized study was conducted in the ED of a tertiary cardiac hospital in Montreal, Quebec. Between November 2006 and March 2010, 3,795 patients were assessed for eligibility based on two risk factors for ED revisits (>=1 ED visit in the past year and >=6 medications); 132 were randomized to the experimental group (EG) and 133 to the control group (CG). The intervention included one nurse-patient meeting before leaving the ED, with two additional telephone contacts over the next 2 weeks. The primary outcome was time to ED revisits within 30 days after discharge. Secondary outcomes included time to ED revisits over 90, 180, and 365 days and hospitalizations over 30, 90, 180, and 365 days. RESULTS: A planned interim analysis that stopped the study with half of the planned sample showed that the time to ED revisits was similar in both groups at 30 days (p=0.81; revisits: 18.2% in EG, 19.6% in CG), 90 days (p=0.44), 180 days (p=0.98), and 365 days (p=0.75). The only difference identified was a lower hospitalization proportion at 180 days in the EG group (13.6% v. 24.1%; p=0.038). CONCLUSIONS: These findings are consistent with previous research showing that few ED-based interventions are successful in reducing ED returns. Factors other than those targeted by the intervention, including an improvement in usual care, may explain the findings. PMID- 25781380 TI - Impact of an in-house emergency radiologist on report turnaround time. AB - BACKGROUND: One of the many challenges facing emergency departments (EDs) across North America is timely access to emergency radiology services. Academic institutions, which are typically also regional referral centres, frequently require cross-sectional studies to be performed 24 hours a day with expedited final reports to accelerate patient care and ED flow. OBJECTIVE: The purpose of this study was to determine if the presence of an in-house radiologist, in addition to a radiology resident dedicated to the ED, had a significant impact on report turnaround time. METHODS: Preliminary and final report turnaround times, provided by the radiology resident and staff, respectively, for patients undergoing computed tomography or ultrasonography of their abdomen/pelvis in 2008 (before the implementation of emergency radiology in-house staff service) were compared to those performed during the same time frame in 2009 and 2010 (after staffing protocols were changed). RESULTS: A total of 1,624 reports were reviewed. Overall, there was no statistically significant decrease in the preliminary report turnaround times between 2008 and 2009 (p = 0.1102), 2009 and 2010 (p = 0.6232), or 2008 and 2010 (p = 0.0890), although times consistently decreased from a median of 2.40 hours to 2.08 hours to 2.05 hours (2008 to 2009 to 2010). There was a statistically significant decrease in final report turnaround times between 2008 and 2009 (p < 0.0001), 2009 and 2010 (p < 0.0011), and 2008 and 2010 (p < 0.0001). Median final report times decreased from 5.00 hours to 3.08 hours to 2.75 hours in 2008, 2009, and 2010, respectively. There was also a significant decrease in the time interval between preliminary and final reports between 2008 and 2009 (p < 0.0001) and 2008 and 2010 (p < 0.0001) but no significant change between 2009 and 2010 (p = 0.4144). CONCLUSION: Our results indicate that the presence of a dedicated ED radiologist significantly reduces final report turnaround time and thus may positively impact the time to ED patient disposition. Patient care is improved when attending radiologists are immediately available to read complex films, both in terms of health care outcomes and regarding the need for repeat testing. Providing emergency physicians with accurate imaging findings as rapidly as possible facilitates effective and timely management and thus optimizes patient care. PMID- 25781381 TI - Epidemiology and outcomes of bloodstream infections in patients discharged from the emergency department. AB - OBJECTIVE: To determine the outcomes of patients discharged from the emergency department (ED) with a bloodstream infection (BSI) and how these outcomes are influenced by antibiotic treatment. METHOD: We identified every BSI in adult patients discharged from our ED to the community between July 1, 2002, and March 31, 2011. The medical records of all cases were reviewed to determine antibiotic treatment in the ED and at discharge. Microorganism sensitivities were used to determine whether antibiotics were appropriate. These data were linked to population-based administrative data to determine specific patient outcomes within the subsequent 2-week period: death, urgent hospitalization, or an unplanned return to the ED. RESULTS: A total of 480 adults with BSI were identified (1.49 cases per 1,000 adults discharged from the department). Compared to controls (321,048 patients), BSI patients had a significantly higher risk of urgent hospitalization (adjusted OR 2.1 [95% CI 1.6-2.8]) and unplanned return to the ED (adjusted OR 4.1 [95% CI 3.3-4.9]). Outcome risk was significantly lowered in BSI patients who received appropriate antibiotics in the ED and at discharge. In elderly patients, the risk of urgent hospitalization increased significantly as the time to appropriate antibiotics was delayed. CONCLUSIONS: BSI patients discharged from the ED have a significantly increased risk of urgent hospitalization and unplanned return to the ED in the subsequent 2 weeks. These risks decrease significantly with the timely provision of appropriate antibiotics. Our results support the aggressive use of measures ensuring that such patients receive appropriate antibiotics as soon as possible. PMID- 25781382 TI - Normal renal sonogram identifies renal colic patients at low risk for urologic intervention: a prospective cohort study. AB - INTRODUCTION: Determining which patients with ureterolithiasis are likely to require urologic intervention is a common challenge in the emergency department (ED). The objective was to determine if normal renal sonogram could identify low risk renal colic patients, who were defined as not requiring urologic intervention within 90 days of their initial ED visit and can be managed conservatively. METHODS: This was a prospective cohort study involving adult patients presenting to the EDs of a tertiary care centre with suspected renal colic over a 20-month period. Renal ultrasonography (US) was performed in the diagnostic imaging department by trained ultrasonographers, and the results were categorized into four mutually exclusive groups: normal, suggestive of ureterolithiasis, visualized ureteric stone, or findings unrelated to urolithiasis. Electronic medical records were reviewed to determine if patients received urologic intervention within 90 days of their ED visit. RESULTS: Of 610 patients enrolled, 341 (55.9%) had US for suspected renal colic. Of those, 105 (30.8%) were classified as normal; none of these patients underwent urologic intervention within 90 days of their ED visit. Ninety (26.4%) US results were classified as suggestive, and nine (10%) patients received urologic intervention. A total of 139 (40.8%) US results were classified as visualized ureteric stone, and 34 (24.5%) patients had urologic intervention. Seven (2.1%) US results were classified as findings unrelated to urolithiasis, and none of these patients required urologic intervention. The rate of urologic intervention was significantly lower in those with normal US results (p<0.001) than in those with abnormal findings. CONCLUSION: A normal renal sonogram predicts a low likelihood for urologic intervention within 90 days for adult ED patients with suspected renal colic. PMID- 25781383 TI - Bronchodilator and steroid use for the management of bronchiolitis in Canadian pediatric emergency departments. AB - OBJECTIVE: Given the recent publication of several large trials and systematic reviews, we undertook a study of the current management of bronchiolitis in Canadian pediatric emergency departments (EDs) and explored physicians' rationale for their treatment decisions. The overarching purpose of this study was to assist in planning a future trial of combined epinephrine and dexamethasone for bronchiolitis. METHODS: Physicians in the Pediatric Emergency Research Canada (PERC) database received an 18-item electronic survey. A modified Dillman method was used. RESULTS: Of the 271 physicians surveyed, 191 (70.1%) responded. The majority (120 of 271; 66.5%) reported ''typically'' giving a bronchodilator trial in the ED, with respondents almost evenly divided between treatment with salbutamol (n=62) and treatment with epinephrine (n=61). Of those who use salbutamol, 77.4% indicated that they prefer it because it can be prescribed for home use. Of those who use epinephrine, 80.3% indicated that they believe the medical literature supports its benefit over salbutamol. Few participants (2.6%) reported ''always'' using steroids, whereas the majority (62.8%) reported ''sometimes'' using them. The most common factor reported to influence steroid use was illness severity (73.3%). The majority (60.5%) reported that if corticosteroids were beneficial in bronchiolitis, they prefered treatment with a single dose in the ED as opposed to a multiday course. CONCLUSIONS: Our results indicate that physicians practicing in Canadian pediatric EDs commonly use bronchodilators to manage bronchiolitis but use corticosteroids less commonly. They appear to be uncomfortable using corticosteroids, particularly longer courses, and have a stated preference for a single dose. Any future trial examining the role of corticosteroids in bronchiolitis should carefully consider the issue of steroid dosage. PMID- 25781384 TI - Effect of pain control in suspected acute appendicitis on the diagnostic accuracy of surgical residents. AB - OBJECTIVE: To determine the influence of early pain relief for patients with suspected appendicitis on the diagnostic performance of surgical residents. METHODS: A prospective randomized, double-blind, placebo-controlled trial was conducted for patients with suspected appendicitis. The patients were randomized to receive placebo (normal saline intravenous [IV]) infusions over 5 minutes or the study drug (morphine 5 mg IV). All of the clinical evaluations by surgical residents were performed 30 minutes after administration of the study drug or placebo. After obtaining the clinical probability of appendicitis, as determined by the surgical residents, abdominal computed tomography was performed. The primary objective was to compare the influence of IV morphine on the ability of surgical residents to diagnose appendicitis. RESULTS: A total of 213 patients with suspected appendicitis were enrolled. Of these patients, 107 patients received morphine, and 106 patients received placebo saline. The negative appendectomy percentages in each group were similar (3.8% in the placebo group and 3.2% in the pain control group, p=0.62). The perforation rates in each group were also similar (18.9% in the placebo group and 14.3% in the pain control group, p=0.75). Receiver operating characteristic analysis revealed that the overall diagnostic accuracy in each group was similar (the area under the curve of the placebo group and the pain control group was 0.63 v. 0.61, respectively, p=0.81). CONCLUSIONS: Early pain control in patients with suspected appendicitis does not affect the diagnostic performance of surgical residents. PMID- 25781385 TI - Presenting characteristics of patients undergoing cardiac troponin measurements in the emergency department. AB - INTRODUCTION: Not all patients with suspected acute coronary syndrome (ACS) receiving cardiac troponin (cTn) testing present to the emergency department (ED) with cardiac chest pain. Since elderly patients (age >=70) have increased morbidity and mortality associated with ACS, complaints other than cardiac chest pain may justify cTn testing. Our primary objective was to characterize the population of ED patients who receive cTn testing. The secondary objective was to determine if elderly patients underwent cTn testing for different presenting complaints than their younger counterparts. METHODS: We created an electronic database including Canadian Emergency Department Information Systems (CEDIS) presenting complaints, age, sex, disposition, and Canadian Triage Acuity Scale (CTAS) score, for patients who received cTn testing in three Canadian EDs during 2011. We analyzed the data for patient characteristics and sorted by age (<70 and >=70) for further analysis. RESULTS: In the 15,824 included patients, the average age was 66 (51%<70; 51% female). The most common presenting complaints were cardiac chest pain (n=3,267) and shortness of breath (n=2,266). The elderly underwent cTn testing for significantly (p<0.0001) different complaints than their younger counterparts. They more commonly presented with generalized weakness (n=898), whereas younger patients more frequently had abdominal pain (n=576). CONCLUSIONS: Cardiac chest pain and shortness of breath are presenting complaints in one-third of patients undergoing ED cTn testing. The majority of patients undergoing cTn testing did not have typical ACS symptoms. Half of all cTn testing in the ED is on the elderly, who present with different complaints than their younger counterparts. PMID- 25781386 TI - Prevalence of alternative diagnoses in patients with suspected uncomplicated renal colic undergoing computed tomography: a prospective study. AB - OBJECTIVES: Unenhanced computed tomography (CT) has become a standard imaging technique for uncomplicated renal colic in many countries. The appropriate timing of CT imaging has not been established, and guidelines recommend that this imaging be performed between 1 and 7 days of presentation. The primary objective of this study was to determine the prevalence of alternative diagnosis identified with low-dose unenhanced CT in the emergency department (ED) in patients with suspected uncomplicated renal colic. METHODS: This prospective single-centre study was carried out in a large university hospital ED. Over a 6-month period, all patients with clinically diagnosed renal colic and a plan to be discharged underwent low-dose unenhanced CT in the ED. Pregnant women, women of childbearing age not willing to have a pregnancy test, and patients who had already undergone diagnostic imaging were excluded. The primary outcome was the number and nature of the alternative diagnosis. Univariate analyses were performed to assess factors associated with the primary outcome. RESULTS: A total of 178 patients were screened, and 155 underwent CT in the ED. The mean age was 42.2 years; 69% were male. The diagnosis of uncomplicated renal colic was confirmed in 118 participants (76%); 27 (17%) had an inconclusive CT scan. Overall, 10 patients (6%; 95% confidence interval [CI] 3-10) had an alternative diagnosis, 5 of whom were subsequently hospitalized. CONCLUSION: Low-dose unenhanced CT in the ED detects alternative diagnoses in 6% (95% CI 3-10) of patients with suspected uncomplicated renal colic, half of whom are subsequently hospitalized. Our prospective findings, which were similar to those reported in retrospective studies, are a potential argument for a systematic approach to ED imaging in suspected renal colic. Future research involving intervention and control groups would be helpful. PMID- 25781387 TI - Airway management of an open penetrating neck injury. AB - Although penetrating neck injuries (PNIs) represent a small subset of patients presenting to the emergency department (ED), they can result in significant morbidity and mortality. The approach to airway management in PNI varies widely according to clinical presentation and local practice, such that global management statements are lacking. Although rapid sequence intubation (RSI) may be safe in most patients with PNI, the high-risk subset (10%) of patients with laryngotracheal injury require particularly judicious airway management. It is not known if RSI is safe in such patients, nor has there been reported use of videolaryngoscopy in patients with open PNI. Established principles of airway management in patients with an open airway injury include the avoidance of both positive pressure bag-mask ventilation and blind tube passage and the early consideration of a surgical airway. Because this high-risk subset may not be clinically apparent on initial presentation in the ED, such guiding principles apply to all patients with PNI until the nature of the injury is more accurately defined. In this report, we present the case of a patient who presented to the ED with a zone II open PNI, which occurred as a result of a stab wound. PMID- 25781388 TI - Inflating the endotracheal tube cuff with saline to confirm correct depth using bedside ultrasonography. AB - Although bedside ultrasonography can accurately distinguish esophageal from tracheal intubation, it is not used to establish the correct depth of endotracheal tube insertion. As indirect sonographic markers of endotracheal tube insertion depth have proven unreliable, a method for visual verification of correct tube depth would be ideal. We describe the use of saline to inflate the endotracheal cuff to confirm correct endotracheal tube depth (at the level of the suprasternal notch) by bedside ultrasonography during resuscitation. This rapid technique holds promise during emergency intubation. PMID- 25781389 TI - Selective turn-off phosphorescent and colorimetric detection of mercury(II) in water by half-lantern platinum(II) complexes. AB - The platinum(ii) half-lantern dinuclear complexes [{Pt(bzq)(MU-C7H4NS2 kappaN,S)}2] () and [{Pt(bzq)(MU-C7H4NOS-kappaN,S)}2] () [bzq = benzo[h]quinolinate, C7H4NS2 = 2-mercaptobenzothiazolate, C7H4NOS = 2 mercaptobenzoxazolate] in solution of DMSO-H2O undergo a dramatic color change from yellowish-orange to purple and turn-off phosphorescence in the presence of a small amount of Hg(2+), being discernible by the naked-eye and by spectroscopic methods. Other metal ions as Ag(+), Li(+), Na(+), K(+), Ca(2+), Mg(2+), Ba(2+), Pb(2+), Cd(2+), Zn(2+) and Tl(+) were tested and, even in a big excess, showed no interference in the selective detection of Hg(2+) in water. Job's plot analysis indicated a 1 : 1 stoichiometry in the complexation mode of Hg(2+) by /. The phosphorescence quenching attributed to the formation of [/ : Hg(2+)] complexes showed binding constants of K = 1.13 * 10(5) M(-1) () and K = 1.99 * 10(4) M(-1) (). The limit of detection has been also evaluated. In addition, dried paper test strips impregnated in DMSO solutions of and can detect concentration of Hg(2+) in water as low as 1 * 10(-5) M for and 5 * 10(-5) M for , making these complexes good candidates to be used as real-time Hg(2+) detectors. The nature of the interaction of the Pt2 half-lantern complex with the Hg(2+) cation, has been investigated by theoretical calculations. PMID- 25781390 TI - In vitro evaluation of the cellular effect of indium tin oxide nanoparticles using the human lung adenocarcinoma A549 cells. AB - Indium tin oxide (ITO) is widely used in liquid crystal displays (LCDs) or plasma and mobile phone displays. Elevated production and usage of ITO in such displays have led to increased concerns over the safety of industrial workers exposed to particulate aerosols produced during cutting, grinding and polishing of these materials. However, the cellular effects of ITO nanoparticles (NPs) are still unclear, although it has been reported that micro-scale ITO particles induce cytotoxicity. The aim of this study was to examine the potential of ITO NPs to induce cytotoxicity, oxidative stress, and DNA damage using human lung adenocarcinoma A549 cells. Here, stable dispersions of a medium containing ITO NPs were obtained using pre-adsorption and centrifugal fractionation methods, and the A549 cells were incubated in this medium. The ITO NPs showed low cytotoxic effects as shown by the WST-1 and LDH assays. Transmission electron microscopy observations showed the cellular uptake of ITO NPs. The ITO NPs increased the intracellular level of reactive oxygen species and the expression of the heme oxygenase 1 gene. Further, the results of alkaline comet assays showed that ITO NPs induced DNA damage. Thus, these results suggest that ITO NPs possess a genotoxic potential on human lung adenocarcinoma A549 cells. PMID- 25781391 TI - Viruses roll the dice: the stochastic behavior of viral genome molecules accelerates viral adaptation at the cell and tissue levels. AB - Recent studies on evolutionarily distant viral groups have shown that the number of viral genomes that establish cell infection after cell-to-cell transmission is unexpectedly small (1-20 genomes). This aspect of viral infection appears to be important for the adaptation and survival of viruses. To clarify how the number of viral genomes that establish cell infection is determined, we developed a simulation model of cell infection for tomato mosaic virus (ToMV), a positive strand RNA virus. The model showed that stochastic processes that govern the replication or degradation of individual genomes result in the infection by a small number of genomes, while a large number of infectious genomes are introduced in the cell. It also predicted two interesting characteristics regarding cell infection patterns: stochastic variation among cells in the number of viral genomes that establish infection and stochastic inequality in the accumulation of their progenies in each cell. Both characteristics were validated experimentally by inoculating tobacco cells with a library of nucleotide sequence tagged ToMV and analyzing the viral genomes that accumulated in each cell using a high-throughput sequencer. An additional simulation model revealed that these two characteristics enhance selection during tissue infection. The cell infection model also predicted a mechanism that enhances selection at the cellular level: a small difference in the replication abilities of coinfected variants results in a large difference in individual accumulation via the multiple-round formation of the replication complex (i.e., the replication machinery). Importantly, this predicted effect was observed in vivo. The cell infection model was robust to changes in the parameter values, suggesting that other viruses could adopt similar adaptation mechanisms. Taken together, these data reveal a comprehensive picture of viral infection processes including replication, cell-to-cell transmission, and evolution, which are based on the stochastic behavior of the viral genome molecules in each cell. PMID- 25781392 TI - A multi-platform metabolomics approach demonstrates changes in energy metabolism and the transsulfuration pathway in Chironomus tepperi following exposure to zinc. AB - Measuring biological responses in resident biota is a commonly used approach to monitoring polluted habitats. The challenge is to choose sensitive and, ideally, stressor-specific endpoints that reflect the responses of the ecosystem. Metabolomics is a potentially useful approach for identifying sensitive and consistent responses since it provides a holistic view to understanding the effects of exposure to chemicals upon the physiological functioning of organisms. In this study, we exposed the aquatic non-biting midge, Chironomus tepperi, to two concentrations of zinc chloride and measured global changes in polar metabolite levels using an untargeted gas chromatography-mass spectrometry (GC MS) analysis and a targeted liquid chromatography-mass spectrometry (LC-MS) analysis of amine-containing metabolites. These data were correlated with changes in the expression of a number of target genes. Zinc exposure resulted in a reduction in levels of intermediates in carbohydrate metabolism (i.e., glucose 6 phosphate, fructose 6-phosphate and disaccharides) and an increase in a number of TCA cycle intermediates. Zinc exposure also resulted in decreases in concentrations of the amine containing metabolites, lanthionine, methionine and cystathionine, and an increase in metallothionein gene expression. Methionine and cystathionine are intermediates in the transsulfuration pathway which is involved in the conversion of methionine to cysteine. These responses provide an understanding of the pathways affected by zinc toxicity, and how these effects are different to other heavy metals such as cadmium and copper. The use of complementary metabolomics analytical approaches was particularly useful for understanding the effects of zinc exposure and importantly, identified a suite of candidate biomarkers of zinc exposure useful for the development of biomonitoring programs. PMID- 25781393 TI - The effect of bifenthrin on the dopaminergic pathway in juvenile rainbow trout (Oncorhynchus mykiss). AB - Bifenthrin is a type I pyrethroid pesticide, which has been shown to increase plasma estrogen concentrations in several fish models. The mechanism of action by which bifenthrin alters 17beta-estradiol (E2) is unclear. E2 biosynthesis is regulated through pituitary follicle stimulating hormone, which is directly controlled by hypothalamic gonadotropin releasing hormone (GnRH2). Since dopaminergic signaling significantly influences GnRH2 release in fish, the goal of the study was to determine the effect of a 96 h and 2 weeks exposure to bifenthrin on dopaminergic signaling in juvenile rainbow trout (Oncorhynchus mykiss) (RT). Our results indicated that a decrease in dopamine receptor 2A (DR2A) expression was associated with a trend toward an increase in plasma E2 following exposure at 96 h and 2 weeks, and a significant increase in the relative expression of vitellogenin mRNA at 2 weeks. DR2A mRNA expression decreased 426-fold at 96 h and 269-fold at 2 weeks in the brains of 1.5 ppb (3.55 pM) bifenthrin treated RT. There was an increase in tyrosine hydroxylase transcript levels at 96 h, which is indicative of dopamine production in the brains of the 1.5 ppb (3.55 pM) bifenthrin treated RT. A significant increase in the relative expression of GnRH2 was observed at 96 h but a significant decrease was noted after 2 weeks exposure indicating potential feedback loop activation. These results indicate that the estrogenic-effects of bifenthrin may result in part from changes in signaling within the dopaminergic pathway, but that other feedback pathways may also be involved. PMID- 25781394 TI - Modeling the direct and indirect effects of copper on phytoplankton-zooplankton interactions. AB - Predicting the effects of pollution at the community level is difficult because of the complex impacts of ecosystem dynamics and properties. To predict the effects of copper on a plant-herbivore interaction in a freshwater ecosystem, we built a model that focuses on the interaction between an alga, Scenedesmus sp., and a herbivore, Daphnia sp. The model assumes logistic growth for Scenedesmus and a type II functional response for Daphnia. Internal copper concentrations in Scenedesmus and Daphnia are calculated using a biodynamic model. We include two types of direct effects of copper on Scenedesmus and Daphnia that results from hormesis: a deficiency effect at low concentration and a toxic effect at high concentration. We perform a numerical analysis to predict the combined effects of copper and nutrient enrichment on the Scenedesmus-Daphnia interaction. Results show three types of outcomes depending on copper concentration. First, low (4 MUg L(-1)) and high (50 MUg L(-1)) copper concentrations cause deficiency and toxicity, respectively, leading to the extinction of all populations; for less extreme concentrations (between 4 and 5 MUg L(-1) and between 16.5 and 50 MUg L( 1)), only the consumer population becomes extinct. The two populations survive with intermediate concentrations. Second, when population dynamics present oscillations, copper has a stabilizing effect and reduces or suppresses oscillations. Third, copper, on account of its stabilizing effect, opposes the destabilizing effect of nutrient enrichment. Our model shows that (1) Daphnia is affected by copper at lower concentrations when community interactions are taken into account than when analyzed alone, and (2) counterintuitive effects may arise from the interaction between copper pollution and nutrient enrichment. Our model also suggests that single-value parameters such as NOEC and LOEC, which do not take community interactions into account to characterize pollutants effects, are unable to determine pollutant effects in complex ecosystems. More generally, our model underscores the importance of ecosystem-scale studies to predict the effects of pollutants. PMID- 25781395 TI - The effects of zinc nanooxide on cellular stress responses of the freshwater mussels Unio tumidus are modulated by elevated temperature and organic pollutants. AB - Nanoparticle toxicity is a growing concern in freshwater habitats. However, understanding of the nanoparticle effects on aquatic organisms is impeded by the lack of the studies of the nanoparticles effects in the environmentally relevant context of multiple stress exposures. Zinc oxide nanoparticles (n-ZnO) are widely used metal-based nanoparticles in electronics and personal care products that accumulate in aquatic environments from multiple non-point sources. In this study, we evaluated the effects of n-ZnO in a model organism, a mussel Unio tumidus, and the potential modulation of these effects by common co-occurring environmental stressors. Male U. tumidus were exposed for 14 days to n-ZnO (3.1 MUM), Zn(2+) (3.1 MUM), Ca-channel blocker nifedipine (Nfd 10 MUM), combinations of n-ZnO and Nfd or n-ZnO and thiocarbamate fungicide Tattoo (Ta, 91 MUg L(-1)) at 18 degrees C, and n-ZnO at 25 degrees C (n-ZnO+t degrees ). Total and metallothionein-bound Zn levels as well as levels of metallothioneins (MT), cellular stress responses and cytotoxicity biomarkers were assessed in the mussels. The key biomarkers that showed differential responses to different single and combined stressors in this study were activities of caspase-3 and lysosomal cathepsin D, as well as protein carbonyl content. At 18 degrees C, exposures to n-ZnO, organic pollutants and their combinations led to a prominent up-regulation of MT levels (by ~30%) and oxidative stress response including up regulation of superoxide dismutase activity, an increase in oxyradical production, and a 2-3-fold decrease in the levels of protein carbonyls in all exposures except nZnO+Ta. Expos ure to n-ZnO in the absence of other stressors also led to a strong (~7-fold) elevation of cathepsin D activity. Cellular responses to Zn(2+) and n-ZnO were different indicating that n-ZnO was not due exclusively to Zn release. Ca-channel blocker Nfd affected intracellular Zn distribution (reflected in the prominent elevation of Zn-MT levels) and caused reductive stress indicated by elevated levels of reduced glutathione levels and an increase in lactate/pyruvate ratio (reflecting higher NADH/NAD ratio). Elevated temperature (25 degrees C) abolished most of the typical responses to n ZnO and induced oxidative injury, DNA fragmentation and caspase-3 mediated apoptosis in n-ZnO-exposed mussels. DNA fragmentation was also induced by exposure to organic toxins (alone and in combination with n-ZnO) but not by n-ZnO alone. These data indicate that n-ZnO toxicity to freshwater organisms is modulated by organic pollutants and enhanced by elevated temperatures. PMID- 25781398 TI - First species of Leptochelia Dana, 1849 (Crustacea: Tanaidacea) from the Eastern Pacific, with an annotated checklist and identification keys for the genus. AB - Forty three species of leptocheliids are known worldwide. In the American region only eight species have been described from the Western Atlantic, while for the Eastern Pacific none have been described, suggesting that the diversity of this family has been severely underestimated in this region. Here we describe the first species of Leptochelia from the Eastern Pacific, Leptochelia mexicana n. sp., which is characterized by the males having a spiniform seta on the second segment of uropodal endopod, a novel feature for the genus. In addition, the first annotated checklist and a taxonomic key with illustrations for Leptochelia species are included. The list includes the type locality, type depository, distribution, habitat and, in some cases, remarks. PMID- 25781399 TI - A review of the Strongylovelia Esaki, 1924 (Hemiptera: Heteroptera: Veliidae) from China, with descriptions of three new species. AB - Five species of genus Strongylovelia Esaki are now known from China. Of these, S. formosa Esaki, 1924 is the only member of the genus previously recorded from China and S. paitooni Chen, Nieser & Sangpradub, 2006 is newly recorded from China. In addition, three species, S. balteiformis sp. n., S. fasciaria sp. n. and S. hainanensis sp. n. are described as new to science. Photographs of the female and male dorsal habitus, male abdominal segment VIII, and male genitalic structures are provided, accompanied by line drawings of the female body in lateral view, views perpendicular to the distal part of the male paramere, and a distribution map for all Chinese Strongylovelia species. A key to the all five Chinese Strongylovelia species is also provided to assist in future identification. PMID- 25781400 TI - Taxonomic and distributional notes on two species groups of the genus Dasyrhicnoessa Hendel (Diptera: Canacidae: Tethininae). AB - Some taxonomic and distributional aspects of two species groups of the genus Dasyrhicnoessa Hendel, 1934, viz. D. tripunctata group and D. ciliata group, are discussed. Figures of the male terminalia and a key to species are also provided. PMID- 25781401 TI - Two new species in the endemic Chinese leafhopper genera Flexocerus and Idioceroides (Hemiptera: Cicadellidae: Idiocerinae). AB - Two new species of endemic Chinese leafhopper genera (Flexocerus Kuoh & Fang and Idioceroides Matsumura), F. sinuatus sp. nov. and I. petaliformis sp. nov. are described and illustrated. Keys to species for both genera are provided. PMID- 25781402 TI - A review of the genus Selasia (Elateridae: Agrypninae: Drilini) in the Palaearctic Region. AB - The six species of the soft-bodied elaterid genus Selasia Laporte (Agrypninae: Drilini) from the Palaearctic Region are reviewed: S. arabica Geisthardt, 2003 (Yemen, Oman, The Kingdom of Saudi Arabia), S. atriventris Pic, 1914 (India, Nepal), S. boruckae Kundrata, 2012 (Nepal), S. homhilia Geisthardt, 2003 (Yemen: Socotra), S. merkli Kundrata, 2012 (Pakistan), and S. socotrana Kundrata, 2012 (Yemen: Socotra). Selasia arabica and S. atriventris are recorded for the first time from Oman and Nepal, respectively. The variability in coloration of S. arabica is discussed. Selasia bleusei Olivier, 1913 from Rhodes is redescribed and transferred to Drilus Olivier, 1790 as D. bleusei (Olivier, 1913), comb. nov. A differential diagnosis is given and taxonomically important characters are figured. An identification key as well as data on the distributions, type depositories and bibliographic references of each Palaearctic Selasia species are provided. PMID- 25781403 TI - First Lanuginellinae (Porifera, Hexactinellida, Rossellidae) from the NE Pacific and first species of Doconesthes from the Pacific Ocean. AB - A new sac-shaped hexactinellid collected from western Canada bearing long lateral prostal spicules was first thought to be a typical Rossellinae. Subsequent examination of its spiculation proved it to have distinctive strobiloplumicomes, typical of the subfamily Lanuginellinae. Other spicules showed it to be a member of the monospecific genus Doconesthes, known previously only from the North Atlantic Ocean. The new species described here as Doconesthes dustinchiversi is only the second known species of the genus and the first to be found in the Pacific Ocean. PMID- 25781404 TI - A new species of Solitariopagurus from the Red Sea with notes on S. profundus (Crustacea: Decapoda: Paguridae). AB - A new species of Solitariopagurus, S. cauticolus, from the Red Sea is described. This is the second species of the genus associated with coral reefs, and the fifth known for the genus. New material of S. profundus from the central deep Red Sea is listed. The bivalve shell carrying is confirmed also for this deep sea species. PMID- 25781405 TI - A new species of the genus Pygophora Schiner from Laos (Diptera: Muscidae). AB - Two species of the genus Pygophora Schiner are recognized from Laos. This is the first time the genus is recorded to the country. A new species, Pygophora laoensis sp. nov., is described and P. immaculipennis Frey is newly recorded. Male and female terminalia of both species are illustrated. PMID- 25781406 TI - Description of the egg and immature stages of Martarega lofoides Padilla-Gil, 2010 (Hemiptera: Heteroptera: Notonectidae). AB - The egg and five nymphal stages, of the Neotropical species Martarega lofoides are described and illustrated for the first time. The immature stages are very similar, differing mainly in the body length, width of the body, head and pronotum, degree of wing pads development, synthlipsis width, and pattern of setae on the ventral abdomen. Adults and nymphs used in this study were collected from the Caunapi River in the Pacific region of southwestern Colombia. PMID- 25781407 TI - AKIHIKO SASAMOTO (2015) Anigosomphus yanagisawai sp. nov., a new gomphid dragonfly from northern Thailand (Odonata: Anisoptera: Gomphidae). Zootaxa, 3904 (3): 421-426. PMID- 25781408 TI - Autobiographical memory and well-being in aging: The central role of semantic self-images. AB - Higher levels of well-being are associated with longer life expectancies and better physical health. Previous studies suggest that processes involving the self and autobiographical memory are related to well-being, yet these relationships are poorly understood. The present study tested 32 older and 32 younger adults using scales measuring well-being and the affective valence of two types of autobiographical memory: episodic autobiographical memories and semantic self-images. Results showed that valence of semantic self-images, but not episodic autobiographical memories, was highly correlated with well-being, particularly in older adults. In contrast, well-being in older adults was unrelated to performance across a range of standardised memory tasks. These results highlight the role of semantic self-images in well-being, and have implications for the development of therapeutic interventions for well-being in aging. PMID- 25781409 TI - Enhanced Recovery After Surgery protocols for radical cystectomy surgery: review of current evidence and local protocols. AB - BACKGROUND: Radical cystectomy (RC) remains a morbid procedure. The use of Enhanced Recovery After Surgery (ERAS) pathways has proven to reduce care time and post-operative complications after colorectal surgery. There is a high potential for reducing morbidity associated with RC by utilizing ERAS in this setting. The purpose of this review is to examine the current evidence for ERAS in preoperative, intra-operative and post-operative setting of care for RC patients and to propose ERAS evidence-based protocol for patients undergoing RC in the Australian and New Zealand environment. PREOPERATIVE: Patient's medical optimization, avoidance of oral mechanical bowel preparation and emphasis on preoperative administration of high-energy carbohydrate drinks from colorectal literature has led to inclusion of these strategies in the preoperative considerations of ERAS in RC. INTRA-OPERATIVE: Epidural analgesia has an integral role in reducing surgical stress response, improving analgesia and expediting functional recovery and should be included in ERAS RC protocols. Of relevance is 72 h maximum length of its duration. With regard to minimally invasive approach to RC, despite encouraging results from high-volume centres, high-level evidence in this field are lacking (ongoing clinical trials). Standardized anaesthetic protocols with particular emphasis on perioperative fluid management are essential components of ERAS protocols. POST-OPERATIVE: Avoidance of routine nasogastric tube placement, early mobilization and multifaceted approach to optimization of gut function and elimination of post-operative ileus are the cornerstones of post-operative care in the setting of ERAS in RC patients. PMID- 25781410 TI - Luminescent copper(I) halide and pseudohalide phenanthroline complexes revisited: simple structures, complicated excited state behavior. AB - We have synthesized a series of luminescent trigonal [CuX(dtbphen)] (X = I (), Br (), Cl (), CN (), dtbphen = 2,9-di-tert-butylphenanthroline) and tetrahedral [Cu2(MU-I)2(L)2] (L = phenanthroline (), 2,9-dimethylphenanthroline ()) copper diimine complexes. Bearing in mind the chemical simplicity of this class of long known Cu(i) phenanthroline compounds, it is surprising that they exhibit non trivial photophysical properties, which have not been fully recognized. They display broad XMLCT absorption between ca. 450-600 nm, and the broad emission between ca. 550-850 nm in the solid state occurring with lifetimes on the MUs timescale indicates phosphorescence, although the energetic overlap between excitation and emission suggests thermally activated delayed fluorescence (TADF) from S1. In line with the latter assumption, low temperature measurements of in the solid state show an energetic separation of emission and excitation. However, a counter-intuitive decrease of emission intensity and simultaneous increase of the emission lifetime at low temperatures are observed for , which indicates two triplet states also being involved. Our DFT and TD-DFT calculations show that emission from the lowest excited triplet state T1 is of (3)LMXCT nature, separated by only ca. 0.16 eV from S1. Low temperature photophysical measurements at 77 K in a glassy matrix of in 2-Me-THF and of in the solid state are in agreement with the theoretical results, revealing in addition that pi interactions in the solid state also greatly influence the photophysical properties, making a clear conclusion towards TADF ambiguous. This study suggests that other related simple and long-known Cu(i) systems may exhibit a similar, more complex excited state behavior than previously appreciated, involving several emitting states and important intermolecular interactions. PMID- 25781411 TI - Registry-based randomized clinical trials--a new clinical trial paradigm. AB - Randomized clinical trials provide the foundation of clinical evidence to guide physicians in their selection of treatment options. Importantly, randomization is the only reliable method to control for confounding factors when comparing treatment groups. However, randomized trials have limitations, including the increasingly prohibitive costs of conducting adequately powered studies. Local and national regulatory requirements, delays in approval, and unnecessary trial processes have led to increased costs and decreased efficiency. Another limitation is that clinical trials involve selected patients who are treated according to protocols that might not represent real-world practice. A possible solution is registry-based randomized clinical trials. By including a randomization module in a large inclusive clinical registry with unselected consecutive enrolment, the advantages of a prospective randomized trial can be combined with the strengths of a large-scale all-comers clinical registry. We believe that prospective registry-based randomized clinical trials are a powerful tool for conducting studies efficiently and cost-effectively. PMID- 25781412 TI - Risk factors. Sauna bathing associated with reduced cardiovascular mortality. PMID- 25781413 TI - Management of atrial fibrillation in bradyarrhythmias. AB - Sinus node disease (SND), a common indication to implant a pacemaker, is frequently associated with atrial fibrillation (AF), either at implantation (paroxysmal AF) or during follow-up, which often evolves to persistent or permanent AF. Pacemakers with an atrial lead allow continuous monitoring of the atrial rhythm and enable detection of the burden of AF. Asymptomatic atrial tachyarrhythmias, being associated with increased risk of stroke, have important prognostic implications, and their detection could guide decision-making about antithrombotic prophylaxis. Pacing mode and pacing algorithms can influence the occurrence of AF and atrial tachyarrhythmias. In DDD/DDDR pacing mode, reduction of unnecessary right ventricular pacing positively affects the occurrence and evolution of AF, but patients with a history of atrial tachyarrhythmias maintain an increased risk of arrhythmic events. In the MINERVA study, the use of algorithms that act in the atrium for preventive pacing and atrial antitachycardia pacing while minimizing right ventricular pacing was beneficial in patients with SND and previous atrial tachyarrhythmias, and was associated with a significant reduction in evolution to permanent AF. New information available on therapies delivered at the atrial level by implanted devices suggests clinical advantages that could improve current guidelines for the management of AF and atrial tachyarrhythmias. PMID- 25781414 TI - Acute coronary syndromes. Risks linked to NSAID use after MI. PMID- 25781416 TI - Risk factors. Sleep apnoea, atrial fibrillation, and heart failure--quo vadis? AB - Strong associations exist between sleep disordered breathing (SDB) and both atrial fibrillation (AF) and heart failure (HF). Burgeoning epidemics of obesity, SDB, AF, and HF make these conditions priorities for health-care policymakers. Two observational studies now suggest outcome benefits from screening and treating for SDB in AF and HF. PMID- 25781417 TI - Revealing hidden evolutionary capacity to cope with global change. AB - The extent to which global change will impact the long-term persistence of species depends on their evolutionary potential to adapt to future conditions. While the number of studies that estimate the standing levels of adaptive genetic variation in populations under predicted global change scenarios is growing all the time, few studies have considered multiple environments simultaneously and even fewer have considered evolutionary potential in multivariate context. Because conditions will not be constant, adaptation to climate change is fundamentally a multivariate process so viewing genetic variances and covariances over multivariate space will always be more informative than relying on bivariate genetic correlations between traits. A multivariate approach to understanding the evolutionary capacity to cope with global change is necessary to avoid misestimating adaptive genetic variation in the dimensions in which selection will act. We assessed the evolutionary capacity of the larval stage of the marine polychaete Galeolaria caespitosa to adapt to warmer water temperatures. Galeolaria is an important habitat-forming species in Australia, and its earlier life-history stages tend to be more susceptible to stress. We used a powerful quantitative genetics design that assessed the impacts of three temperatures on subsequent survival across over 30 000 embryos across 204 unique families. We found adaptive genetic variation in the two cooler temperatures in our study, but none in the warmest temperature. Based on these results, we would have concluded that this species has very little capacity to evolve to the warmest temperature. However, when we explored genetic variation in multivariate space, we found evidence that larval survival has the potential to evolve even in the warmest temperatures via correlated responses to selection across thermal environments. Future studies should take a multivariate approach to estimating evolutionary capacity to cope with global change lest they misestimate a species' true adaptive potential. PMID- 25781415 TI - Causes, assessment, and treatment of stent thrombosis--intravascular imaging insights. AB - Stent thrombosis is a rare, but serious, complication of percutaneous coronary intervention and is associated with severe morbidity and mortality. In addition to clinical and pathological studies, intravascular imaging has advanced our understanding of the mechanisms underlying stent thrombosis. In particular, intravascular imaging has been used to study stent underexpansion, malapposition, uncovered struts, and neoatherosclerosis as risk factors for stent thrombosis. Intravascular ultrasonography and optical coherence tomography can be used to guide stent implantation and minimize the risk of stent thrombosis. Additionally, optical coherence tomography offers the unique potential to tailor treatment of stent thrombosis to address the specific mechanism underlying the thrombotic event. Bioresorbable stent technologies have been introduced with the goal of further reducing the incidence of stent thrombosis, and intravascular imaging has had an integral role in the development and assessment of these new devices. In this Review, we present insights gained through intravascular imaging into the causes of stent thrombosis, and the potential utility of intravascular imaging in the optimization of stent deployment and treatment of stent thrombosis events. PMID- 25781418 TI - Dielectrophoretic positioning of single nanoparticles on atomic force microscope tips for tip-enhanced Raman spectroscopy. AB - Tip-enhanced Raman spectroscopy, a combination of Raman spectroscopy and scanning probe microscopy, is a powerful technique to detect the vibrational fingerprint of molecules at the nanometer scale. A metal nanoparticle at the apex of an atomic force microscope tip leads to a large enhancement of the electromagnetic field when illuminated with an appropriate wavelength, resulting in an increased Raman signal. A controlled positioning of individual nanoparticles at the tip would improve the reproducibility of the probes and is quite demanding due to usually serial and labor-intensive approaches. In contrast to commonly used submicron manipulation techniques, dielectrophoresis allows a parallel and scalable production, and provides a novel approach toward reproducible and at the same time affordable tip-enhanced Raman spectroscopy tips. We demonstrate the successful positioning of an individual plasmonic nanoparticle on a commercial atomic force microscope tip by dielectrophoresis followed by experimental proof of the Raman signal enhancing capabilities of such tips. PMID- 25781419 TI - Improvement of reproducibility and sensitivity by reducing matrix effect in micellar electrokinetic chromatography for determination of amino acids in turtle jelly. AB - Matrix effect (ME) is commonly seen in electrophoretic separation, but this phenomenon lacks any systematic study. Our work aimed to find out the relationship between separation efficiency and current, and then figure out an effective, simple, and economic solution to overcome the negative impact of ME. This present study showed that small amount of NaCl (<=0.005 mg/mL) in the sample had no impact on the separation but enhanced the sensitivity. However, when concentration of NaCl increased above 0.005 mg/mL, it alleviated the separation efficiency, sensitivity, and migration time. Besides, increasing NaCl concentration resulted in increasing turning point. The study of relationship of current and NaCl concentration indicated that when the TP of a sample is higher than 62.36 MUA, desalination is necessary. Since the reported desalination methods are either expensive or complicated, we developed a simple and economic method by simply adding 12 times (volume) of chloroform/methanol (2:1, v/v) into the sample. When applied this method to turtle jelly, the number of theoretical plate (N) of 20 amino acids got up to threefold enhancement. PMID- 25781420 TI - The Role of Charge Density and Hydrophobicity on the Biocidal Properties of Self Protonable Polymeric Materials. AB - Intrinsic antimicrobial thermoplastic A(BC)n copolymers (n = 1, 2, 4), where A was poly(ethylene glycol) (PEG), BC was a random chain of methylmethacrylate (MMA), and alkyl-aminoethyl methacrylate (AAEMA), were synthesized and the antimicrobial activity and hemolyticity were evaluated on plaques obtained by casting as a function of the architecture, the N-substituent groups of the AAEMAs (methyl, ethyl, isopropyl, and tert-butyl groups) and the hydrophobic/charge density balance. Antimicrobial effectiveness and efficiency is controlled by the surface charge density and by the influence of N-alkyl groups on the surface morphology. Also interestingly, it is the absence of hemolitytic activity in all copolymers. In presence of Escherichia coli, the A(BC)2 copolymer with 40% of N methyl groups is the most efficient, killing 91% of the bacteria already after 1.5 h. PMID- 25781421 TI - Interventions for the treatment of Frey's syndrome. AB - BACKGROUND: Frey's syndrome is a rare disorder, the symptoms of which include sweating, flushing and warming over the preauricular and temporal areas following a gustatory stimulus. It often occurs in patients who have undergone parotidectomy, submandibular gland surgery, radical neck dissection, infection and traumatic injury in the parotid region, and is caused by the aberrant regrowth of facial autonomic nerve fibres. Currently there are several options used to treat patients with Frey's syndrome; for example, the topical application of anticholinergics and antiperspirants, and the intradermal injection of botulinum toxin. It is uncertain which treatment is most effective and safe. OBJECTIVES: To assess the efficacy and safety of different interventions for the treatment of Frey's syndrome. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials. The date of the search was 28 April 2014. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials (RCTs) in participants diagnosed with Frey's syndrome using a clinical standard such as Minor's starch-iodine test. We planned to include trials in which participants received any intervention versus no treatment (observation) or an alternative intervention, with or without a second active treatment. Our primary outcome measures were success rate (as assessed clinically by Minor's starch-iodine test, the iodine-sublimated paper histogram method, blotting paper technique or another method) and adverse events. Our secondary outcome measure was success rate as assessed by patients (disappearance or improvement of symptoms). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified no RCTs or quasi-RCTs that fulfilled the inclusion criteria. Our searches retrieved eight potentially relevant studies, but after assessment of the full-text reports we excluded all of them due to the absence of randomisation or because the patients did not have Frey's syndrome. We excluded one randomised controlled trial that compared two different doses of botulinum toxin in patients with Frey's syndrome because the comparator was not an alternative treatment. AUTHORS' CONCLUSIONS: We are unable to establish the efficacy and safety of the different methods used for the treatment of Frey's syndrome.RCTs are urgently needed to assess the effectiveness of interventions for the treatment of Frey's syndrome. Future RCTs should include patients with Frey's syndrome of different ranges of severity and report these patients separately. Studies should investigate all possibly effective treatments (such as anticholinergics, antiperspirants and botulinum toxin) compared to control groups using different treatments or placebo. Subjective assessment of Frey's syndrome should be considered as one of the outcome measures. PMID- 25781422 TI - Identification and quantification of 34 drugs and toxic compounds in blood, urine, and gastric content using liquid chromatography with tandem mass spectrometry. AB - A liquid chromatography with tandem mass spectrometry method was developed for the simultaneous screening of 34 drugs and poisons in forensic cases. Blood (0.5 mL, diluted 1:1 with water) or 1.0 mL of urine was purified by solid-phase extraction. Gastric contents (diluted 1:1 with water) were treated with acetonitrile, centrifuged, and supernatant injected. Detection was achieved using a Waters Alliance 2695/Quattro Premier XE liquid chromatography tandem mass spectrometry system equipped with electrospray ionization, operated in the multiple reaction monitoring modes. The method was validated for accuracy, precision, linearity, and recovery. The absolute recovery of drugs and toxic compounds in blood was greater than 51% with the limit of detection in the range of 0.02-20 ng/mL. The absolute recovery of drugs and toxic compounds in urine was greater than 61% with limit of detection in the range of 0.01-10 ng/mL. The matrix effect of drugs and toxic compounds in urine was 65-117% and 67-121% in blood. The limit of detection of drugs and toxic compounds in gastric content samples were in the range of 0.05-20 ng/mL. This method was applied to the routine analysis of drugs and toxic compounds in postmortem blood, urine, and gastric content samples. The method was applied to actual forensic cases with examples given. PMID- 25781423 TI - Emergency department presentation for uncomplicated acute rhinosinusitis is associated with poor access to healthcare. AB - OBJECTIVES/HYPOTHESIS: Uncomplicated acute rhinosinusitis (ARS) is most appropriately managed in an outpatient clinic setting. Some ARS patients present to emergency departments (EDs) for care. We investigates factors associated with ARS presentation to EDs versus outpatient settings. STUDY DESIGN: Cross-sectional study. METHODS: A total of 17,122,551 pediatric and adult patient visits from the 2009 and 2010 National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys for ARS were identified. Patients with ARS complications were excluded. Univariate and multivariate associations identified demographic and socioeconomic characteristics of ARS patients independently associated with ED presentation. Temperature >100 degrees F was used as a proxy for ARS severity. RESULTS: Patients with Medicaid (odds ratio [OR] = 10.82, P < .001) or no insurance (OR = 9.14, P < .001) more likely presented to EDs when compared to patients with private insurance or Medicare. Independently, black patients (OR = 6.01, P < .001) more likely presented to EDs when compared to white or Hispanic patients. No significant association was seen with metropolitan or socioeconomic status based upon the patients' home zip code. CONCLUSIONS: Presentation of ARS patients to EDs is associated with health insurance type and patient race independent of socioeconomic status. Healthcare access appears to be a primary determinant of whether patients present to an ED or outpatient setting for this common health problem. The association between race and ED presentation suggests cultural underpinnings requiring further characterization. Reducing barriers to care, for example through broader health insurance coverage, may enhance access to outpatient care providers and decrease costs associated with unnecessary ED presentation. LEVEL OF EVIDENCE: 4. PMID- 25781424 TI - DISTINCTIVE LOCALIZATION OF GROUP 3 LATE EMBRYOGENESIS ABUNDANT SYNTHESIZING CELLS DURING BRINE SHRIMP DEVELOPMENT. AB - Despite numerous studies on late embryogenesis abundant (LEA) proteins, their functions, roles, and localizations during developmental stages in arthropods remain unknown. LEA proteins protect crucial proteins against osmotic stress during the development and growth of various organisms. Thus, in this study, fluorescence in situ hybridization was used to determine the crucial regions protected against osmotic stress as well as the distinctive localization of group 3 (G3) LEA(+) cells during brine shrimp development. Several cell types were found to synthesize G3 LEA RNA, including neurons, muscular cells, APH-1(+) cells, and renal cells. The G3 LEA(+) neuronal cell bodies outside of the mushroom body projected their axonal bundles to the central body, but those inside the mushroom body projected their axonal bundles toward the deutocerebrum without innervating the central body. The cell bodies inside the mushroom body received axons of the G3 LEA(+) sensory cells at the medial ventral cup of the nauplius eye. Several glands were found to synthesize G3 LEA RNA during the nauplius stages of brine shrimp, including the sinus, antennal I and II, salt, and three ectodermal glands. This study provides the first demonstration of the formation of G3 LEA(+) sinus glands at the emergence stages of brine shrimp. These results suggest that G3 LEA protein is synthesized in several cell types. In particular, specific glands play crucial roles during the emergence and nauplius stages of brine shrimp. PMID- 25781427 TI - Do-si-do: Dan Christensen. PMID- 25781428 TI - Precision medicine: the future or simply politics? PMID- 25781429 TI - An observational study goes where randomized clinical trials have not. PMID- 25781435 TI - Reengineering advance care planning to create scalable, patient- and family centered interventions. PMID- 25781436 TI - The birth of public health education. PMID- 25781437 TI - A piece of my mind. Time will tell. PMID- 25781438 TI - Expertise vs evidence in assessment of breast biopsies: an atypical science. PMID- 25781439 TI - Aspirin and NSAID chemoprevention, gene-environment interactions, and risk of colorectal cancer. PMID- 25781441 TI - Diagnostic concordance among pathologists interpreting breast biopsy specimens. AB - IMPORTANCE: A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood. OBJECTIVES: To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics. DESIGN, SETTING, AND PARTICIPANTS: Study of pathologists who interpret breast biopsies in clinical practices in 8 US states. EXPOSURES: Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%. MAIN OUTCOMES AND MEASURES: The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed. RESULTS: Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N = 115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82% 86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n = 122) vs lower (n = 118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P < .001), and among pathologists who interpreted lower weekly case volumes (P < .001) or worked in smaller practices (P = .034) or nonacademic settings (P = .007). CONCLUSIONS AND RELEVANCE: In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management. PMID- 25781444 TI - Risk factors for suicides among army personnel. PMID- 25781443 TI - Association of early imaging for back pain with clinical outcomes in older adults. AB - IMPORTANCE: In contrast to the recommendations for younger adults, many guidelines allow for older adults with back pain to undergo imaging without waiting 4 to 6 weeks. However, early imaging may precipitate interventions that do not improve outcomes. OBJECTIVE: To compare function and pain at the 12-month follow-up visit among older adults who received early imaging with those who did not receive early imaging after a new primary care visit for back pain without radiculopathy. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of 5239 patients 65 years or older with a new primary care visit for back pain (2011 2013) in 3 US health care systems. We matched controls 1:1 using propensity score matching of demographic and clinical characteristics, including diagnosis, pain severity, pain duration, functional status, and prior resource use. EXPOSURES: Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) of the lumbar or thoracic spine within 6 weeks of the index visit. MAIN OUTCOME AND MEASURES: PRIMARY OUTCOME: back or leg pain-related disability measured by the modified Roland-Morris Disability Questionnaire (score range, 0 24; higher scores indicate greater disability) 12 months after enrollment. RESULTS: Among the 5239 patients, 1174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on the disability questionnaire. The mean score for patients who underwent early radiography was 8.54 vs 8.74 among the control group (difference, -0.10 [95% CI, -0.71 to 0.50]; mixed model, P = .36). The mean score for the early MRI/CT group was 9.81 vs 10.50 for the control group (difference,-0.51 [-1.62 to 0.60]; mixed model, P = .18). CONCLUSIONS AND RELEVANCE: Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain. PMID- 25781445 TI - Screening for abdominal aortic aneurysm. PMID- 25781446 TI - Diffuse vesicular rash with intractable pruritus. PMID- 25781442 TI - Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants. AB - IMPORTANCE: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. OBJECTIVE: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene * environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Case control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. EXPOSURES: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES: Colorectal cancer. RESULTS: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64 0.74]; P = 6.2 * 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 * 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 * 10( 33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 * 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 * 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). CONCLUSIONS AND RELEVANCE: In this genome-wide investigation of gene * environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies. PMID- 25781447 TI - Reporting of noninferiority trials in ClinicalTrials.gov and corresponding publications. PMID- 25781448 TI - BK virus prophylaxis with levofloxacin. PMID- 25781449 TI - BK virus prophylaxis with levofloxacin--reply. PMID- 25781450 TI - Perioperative treatment with aspirin or clonidine and risk of acute kidney injury. PMID- 25781451 TI - Perioperative treatment with aspirin or clonidine and risk of acute kidney injury -reply. PMID- 25781452 TI - Time-limited vs unlimited physician certification. PMID- 25781453 TI - Time-limited vs unlimited physician certification--reply. PMID- 25781455 TI - Courses and degrees in public health work. PMID- 25781456 TI - JAMA Patient Page. Infectious mononucleosis. PMID- 25781457 TI - Posttraumatic stress disorder symptoms, emotion dysregulation, and aggressive behavior among incarcerated methamphetamine users. AB - OBJECTIVE: Methamphetamine use remains a prevalent problem in the United States and is linked to numerous deleterious outcomes, including aggressive behavior, criminal activity, and incarceration. Given these associations, a greater understanding of factors that contribute to aggression among users of methamphetamine is needed, particularly within criminal justice settings, where users of this drug are overrepresented. METHODS: The present study examined the relationships between posttraumatic stress disorder (PTSD) symptoms and emotion dysregulation and in-prison physical aggression among incarcerated males who identified as methamphetamine users (N = 60). RESULTS: Participants' average age was 34.4 years (SD = 7.9), and they were predominantly European American (n = 48, 80%), had spent an average of 6.53 years incarcerated (SD = 4.64), and perpetrated about 1.54 acts of aggression (SD = 6.74) during the past three months. Bivariate correlations found that greater PTSD symptoms (p < .001), greater impulse control difficulties (p < .001), and limited access to emotion regulation strategies (p < .05) were associated with aggression perpetrated in prison. However, results from multiple regression analyses indicated that only PTSD symptoms (p <.001) and nonacceptance of emotional responses (p < .03) were predictive of aggression. Regression analyses also suggested that impulse control difficulties (p < .001), limited access to emotion regulation strategies (p < .04), and nonacceptance of emotional responses (p < .001) interacted with PTSD symptoms to predict increased aggressive behavior. The first interaction ran counter to study hypotheses: At greater levels of PTSD symptoms, those with greater acceptance of emotional responses reported greater aggression perpetration than those with lesser acceptance of emotional responses. The other two interactions were in line with hypotheses, showing that at greater levels of PTSD symptoms, those with greater impulse control difficulties (or lesser access to emotion regulation strategies) reported more aggressive behaviors. CONCLUSIONS: Consistent with theories of aggression, study findings suggest that PTSD symptoms bolster the risk of aggression via various forms emotion dysregulation. Results shed light on potential mechanisms that promote in-prison aggression and violent recidivism among this population. PMID- 25781440 TI - Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial. AB - IMPORTANCE: Despite antirestenotic efficacy of coronary drug-eluting stents (DES) compared with bare metal stents (BMS), the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Although dual antiplatelet therapy (DAPT) beyond 1 year provides ischemic event protection after DES, ischemic event risk is perceived to be less after BMS, and the appropriate duration of DAPT after BMS is unknown. OBJECTIVE: To compare (1) rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) after 30 vs 12 months of thienopyridine in patients treated with BMS taking aspirin and (2) treatment duration effect within the combined cohorts of randomized patients treated with DES or BMS as prespecified secondary analyses. DESIGN, SETTING, AND PARTICIPANTS: International, multicenter, randomized, double-blinded, placebo-controlled trial comparing extended (30-months) thienopyridine vs placebo in patients taking aspirin who completed 12 months of DAPT without bleeding or ischemic events after receiving stents. The study was initiated in August 2009 with the last follow-up visit in May 2014. INTERVENTIONS: Continued thienopyridine or placebo at months 12 through 30 after stent placement, in 11,648 randomized patients treated with aspirin, of whom 1687 received BMS and 9961 DES. MAIN OUTCOMES AND MEASURES: Stent thrombosis, MACCE, and moderate or severe bleeding. RESULTS: Among 1687 patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5% vs 1.11% (n = 4 vs 9; hazard ratio [HR], 0.49; 95% CI, 0.15-1.64; P = .24), rates of MACCE were 4.04% vs 4.69% (n = 33 vs 38; HR, 0.92; 95% CI, 0.57-1.47; P = .72), and rates of moderate/severe bleeding were 2.03% vs 0.90% (n = 16 vs 7; P = .07), respectively. Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41% vs 1.32% (n = 23 vs 74; HR, 0.31; 95% CI, 0.19-0.50; P < .001), rates of MACCE were 4.29% vs 5.74% (n = 244 vs 323; HR, 0.73; 95% CI, 0.62-0.87; P < .001), and rates of moderate/severe bleeding were 2.45% vs 1.47% (n = 135 vs 80; P < .001). CONCLUSIONS AND RELEVANCE: Among patients undergoing coronary stent placement with BMS and who tolerated 12 months of thienopyridine, continuing thienopyridine for an additional 18 months compared with placebo did not result in statistically significant differences in rates of stent thrombosis, MACCE, or moderate or severe bleeding. However, the BMS subset may have been underpowered to identify such differences, and further trials are suggested. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00977938. PMID- 25781458 TI - Three-dimensional spheroid cell model of in vitro adipocyte inflammation. AB - To improve treatment of obesity, a contributing factor to multiple systemic and metabolic diseases, a better understanding of metabolic state and environmental stress at the cellular level is essential. This work presents development of a three-dimensional (3D) in vitro model of adipose tissue displaying induced lipid accumulation as a function of fatty acid supplementation that, subsequently, investigates cellular responses to a pro-inflammatory stimulus, thereby recapitulating key stages of obesity progression. Three-dimensional spheroid organization of adipose cells was induced by culturing 3T3-L1 mouse preadipocytes on an elastin-like polypeptide-polyethyleneimine (ELP-PEI)-coated surface. Results indicate a more differentiated phenotype in 3D spheroid cultures relative to two-dimensional (2D) monolayer analogues based on triglyceride accumulation, CD36 and CD40 protein expression, and peroxisome proliferator-activated receptor gamma (PPAR-gamma) and adiponectin mRNA expression. The 3T3-L1 adipocyte spheroid model was then used to test the effects of a pro-inflammatory microenvironment, namely maturation in the presence of elevated fatty acid levels followed by acute exposure to tumor necrosis factor alpha (TNF-alpha). Under these conditions, we demonstrate that metabolic function was reduced across all cultures exposed to TNF-alpha, especially so when pre-exposed to linoleic acid. Further, in response to TNF-alpha, enhanced lipolysis, monitored as increased extracellular glycerol and fatty acids levels, was observed in adipocytes cultured in the presence of exogenous fatty acids. Taken together, our 3D spheroid model showed enhanced adipogenic differentiation and presents a platform for elucidating the key phenotypic responses that occur in pro-inflammatory microenvironments that characterize obesogenic states. PMID- 25781459 TI - "Once upon a time in the Mediterranean" long term trends of Mediterranean fisheries resources based on fishers' Traditional Ecological Knowledge. AB - We investigate long-term changes in the Mediterranean marine resources driving the trawl fisheries by analysing fishers' perceptions (Traditional Ecological Knowledge, TEK) throughout the Mediterranean Sea during the last 80 years. To this end, we conducted an extended set of interviews with experienced fishers that enabled us to classify species (or taxa) as 'decreasing' or 'increasing' both in terms of abundance, as well as average size in the catch. The aspect that most clearly emerged in all the investigated areas over time was the notable increase of fishing capacity indicators, such as engine power and fishing depth range. Atlantic mackerel, poor cod, scorpionfishes, striped seabream, and John Dory demonstrated a decreasing trend in the fishers' perceived abundance, while Mediterranean parrotfish, common pandora, cuttlefish, blue and red shrimp, and mullets gave indications of an increasing temporal trend. Although, as a rule, trawler captains did not report any cataclysmic changes (e.g. extinctions), when they were invited to estimate total catches, a clear decreasing pattern emerged; this being a notable finding taking into account the steep escalation of fishing efficiency during the past century. The overall deteriorating status of stocks in most Mediterranean regions calls for responsible management and design of rebuilding plans. This should include historical information accounting for past exploitation patterns that could help defining a baseline of fish abundance prior to heavy industrial fisheries exploitation. PMID- 25781460 TI - Inhibitor and substrate binding induced stability of HIV-1 protease against sequential dissociation and unfolding revealed by high pressure spectroscopy and kinetics. AB - High-pressure methods have become an interesting tool of investigation of structural stability of proteins. They are used to study protein unfolding, but dissociation of oligomeric proteins can be addressed this way, too. HIV-1 protease, although an interesting object of biophysical experiments, has not been studied at high pressure yet. In this study HIV-1 protease is investigated by high pressure (up to 600 MPa) fluorescence spectroscopy of either the inherent tryptophan residues or external 8-anilino-1-naphtalenesulfonic acid at 25 degrees C. A fast concentration-dependent structural transition is detected that corresponds to the dimer-monomer equilibrium. This transition is followed by a slow concentration independent transition that can be assigned to the monomer unfolding. In the presence of a tight-binding inhibitor none of these transitions are observed, which confirms the stabilizing effect of inhibitor. High-pressure enzyme kinetics (up to 350 MPa) also reveals the stabilizing effect of substrate. Unfolding of the protease can thus proceed only from the monomeric state after dimer dissociation and is unfavourable at atmospheric pressure. Dimer destabilizing effect of high pressure is caused by negative volume change of dimer dissociation of -32.5 mL/mol. It helps us to determine the atmospheric pressure dimerization constant of 0.92 MUM. High-pressure methods thus enable the investigation of structural phenomena that are difficult or impossible to measure at atmospheric pressure. PMID- 25781461 TI - Cardiac microvascular barrier function mediates the protection of Tongxinluo against myocardial ischemia/reperfusion injury. AB - OBJECTIVE: Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure function network. MATERIALS AND METHODS: To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed. RESULTS: Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R2=0.64, R2=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, beta-catenin, gamma-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, beta-catenin and gamma-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI. CONCLUSIONS: Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC. PMID- 25781462 TI - AGAPE (Automated Genome Analysis PipelinE) for pan-genome analysis of Saccharomyces cerevisiae. AB - The characterization and public release of genome sequences from thousands of organisms is expanding the scope for genetic variation studies. However, understanding the phenotypic consequences of genetic variation remains a challenge in eukaryotes due to the complexity of the genotype-phenotype map. One approach to this is the intensive study of model systems for which diverse sources of information can be accumulated and integrated. Saccharomyces cerevisiae is an extensively studied model organism, with well-known protein functions and thoroughly curated phenotype data. To develop and expand the available resources linking genomic variation with function in yeast, we aim to model the pan-genome of S. cerevisiae. To initiate the yeast pan-genome, we newly sequenced or re-sequenced the genomes of 25 strains that are commonly used in the yeast research community using advanced sequencing technology at high quality. We also developed a pipeline for automated pan-genome analysis, which integrates the steps of assembly, annotation, and variation calling. To assign strain-specific functional annotations, we identified genes that were not present in the reference genome. We classified these according to their presence or absence across strains and characterized each group of genes with known functional and phenotypic features. The functional roles of novel genes not found in the reference genome and associated with strains or groups of strains appear to be consistent with anticipated adaptations in specific lineages. As more S. cerevisiae strain genomes are released, our analysis can be used to collate genome data and relate it to lineage-specific patterns of genome evolution. Our new tool set will enhance our understanding of genomic and functional evolution in S. cerevisiae, and will be available to the yeast genetics and molecular biology community. PMID- 25781463 TI - 2H,3H-decafluoropentane-based nanodroplets: new perspectives for oxygen delivery to hypoxic cutaneous tissues. AB - Perfluoropentane (PFP)-based oxygen-loaded nanobubbles (OLNBs) were previously proposed as adjuvant therapeutic tools for pathologies of different etiology sharing hypoxia as a common feature, including cancer, infection, and autoimmunity. Here we introduce a new platform of oxygen nanocarriers, based on 2H,3H-decafluoropentane (DFP) as core fluorocarbon. These new nanocarriers have been named oxygen-loaded nanodroplets (OLNDs) since DFP is liquid at body temperature, unlike gaseous PFP. Dextran-shelled OLNDs, available either in liquid or gel formulations, display spherical morphology, ~600 nm diameters, anionic charge, good oxygen carrying capacity, and no toxic effects on human keratinocytes after cell internalization. In vitro OLNDs result more effective in releasing oxygen to hypoxic environments than former OLNBs, as demonstrated by analysis through oxymetry. In vivo, OLNDs effectively enhance oxy-hemoglobin levels, as emerged from investigation by photoacoustic imaging. Interestingly, ultrasound (US) treatment further improves transdermal oxygen release from OLNDs. Taken together, these data suggest that US-activated, DFP-based OLNDs might be innovative, suitable and cost-effective devices to topically treat hypoxia associated pathologies of the cutaneous tissues. PMID- 25781464 TI - Abbreviated half-lives and impaired fuel utilization in carnitine palmitoyltransferase II variant fibroblasts. AB - Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common causes of fatty acid oxidation metabolism disorders. However, the molecular mechanism between CPT2 gene polymorphisms and metabolic stress has not been fully clarified. We previously reported that a number of patients show a thermal instable phenotype of compound hetero/homozygous variants of CPT II. To understand the mechanism of the metabolic disorder resulting from CPT II deficiency, the present study investigated CPT II variants in patient fibroblasts, [c.1102 G>A (p.V368I)] (heterozygous), [c.1102 G>A (p.V368I)] (homozygous), and [c.1055 T>G (p.F352C)] (heterozygous) + [c.1102 G>A (p.V368I)] (homozygous) compared with fibroblasts from healthy controls. CPT II variants exerted an effect of dominant negative on the homotetrameric proteins that showed thermal instability, reduced residual enzyme activities and a short half-life. Moreover, CPT II variant fibroblasts showed a significant decrease in fatty acid beta-oxidation and adenosine triphosphate generation, combined with a reduced mitochondrial membrane potential, resulting in cellular apoptosis. Collectively, our data indicate that the CPT II deficiency induces an energy crisis of the fatty acid metabolic pathway. These findings may contribute to the elucidation of the genetic factors involved in metabolic disorder encephalopathy caused by the CPT II deficiency. PMID- 25781465 TI - Discovery of novel rhabdoviruses in the blood of healthy individuals from West Africa. AB - Next-generation sequencing (NGS) has the potential to transform the discovery of viruses causing unexplained acute febrile illness (UAFI) because it does not depend on culturing the pathogen or a priori knowledge of the pathogen's nucleic acid sequence. More generally, it has the potential to elucidate the complete human virome, including viruses that cause no overt symptoms of disease, but may have unrecognized immunological or developmental consequences. We have used NGS to identify RNA viruses in the blood of 195 patients with UAFI and compared them with those found in 328 apparently healthy (i.e., no overt signs of illness) control individuals, all from communities in southeastern Nigeria. Among UAFI patients, we identified the presence of nucleic acids from several well characterized pathogenic viruses, such as HIV-1, hepatitis, and Lassa virus. In our cohort of healthy individuals, however, we detected the nucleic acids of two novel rhabdoviruses. These viruses, which we call Ekpoma virus-1 (EKV-1) and Ekpoma virus-2 (EKV-2), are highly divergent, with little identity to each other or other known viruses. The most closely related rhabdoviruses are members of the genus Tibrovirus and Bas-Congo virus (BASV), which was recently identified in an individual with symptoms resembling hemorrhagic fever. Furthermore, by conducting a serosurvey of our study cohort, we find evidence for remarkably high exposure rates to the identified rhabdoviruses. The recent discoveries of novel rhabdoviruses by multiple research groups suggest that human infection with rhabdoviruses might be common. While the prevalence and clinical significance of these viruses are currently unknown, these viruses could have previously unrecognized impacts on human health; further research to understand the immunological and developmental impact of these viruses should be explored. More generally, the identification of similar novel viruses in individuals with and without overt symptoms of disease highlights the need for a broader understanding of the human virome as efforts for viral detection and discovery advance. PMID- 25781466 TI - Remote activation of the Wnt/beta-catenin signalling pathway using functionalised magnetic particles. AB - Wnt signalling pathways play crucial roles in developmental biology, stem cell fate and tissue patterning and have become an attractive therapeutic target in the fields of tissue engineering and regenerative medicine. Wnt signalling has also been shown to play a role in human Mesenchymal Stem Cell (hMSC) fate, which have shown potential as a cell therapy in bone and cartilage tissue engineering. Previous work has shown that biocompatible magnetic nanoparticles (MNP) can be used to stimulate specific mechanosensitive membrane receptors and ion channels in vitro and in vivo. Using this strategy, we determined the effects of mechano stimulation of the Wnt Frizzled receptor on Wnt pathway activation in hMSC. Frizzled receptors were tagged using anti-Frizzled functionalised MNP (Fz-MNP). A commercially available oscillating magnetic bioreactor (MICA Biosystems) was used to mechanically stimulate Frizzled receptors remotely. Our results demonstrate that Fz-MNP can activate Wnt/beta-catenin signalling at key checkpoints in the signalling pathway. Immunocytochemistry indicated nuclear localisation of the Wnt intracellular messenger beta-catenin after treatment with Fz-MNP. A Wnt signalling TCF/LEF responsive luciferase reporter transfected into hMSC was used to assess terminal signal activation at the nucleus. We observed an increase in reporter activity after treatment with Fz-MNP and this effect was enhanced after mechano-stimulation using the magnetic array. Western blot analysis was used to probe the mechanism of signalling activation and indicated that Fz-MNP signal through an LRP independent mechanism. Finally, the gene expression profiles of stress response genes were found to be similar when cells were treated with recombinant Wnt-3A or Fz-MNP. This study provides proof of principle that Wnt signalling and Frizzled receptors are mechanosensitive and can be remotely activated in vitro. Using magnetic nanoparticle technology it may be possible to modulate Wnt signalling pathways and thus control stem cell fate for therapeutic purposes. PMID- 25781467 TI - Yersinia pestis activates both IL-1beta and IL-1 receptor antagonist to modulate lung inflammation during pneumonic plague. AB - Pneumonic plague is the most rapid and lethal form of Yersinia pestis infection. Increasing evidence suggests that Y. pestis employs multiple levels of innate immune evasion and/or suppression to produce an early "pre-inflammatory" phase of pulmonary infection, after which the disease is highly inflammatory in the lung and 100% fatal. In this study, we show that IL-1beta/IL-18 cytokine activation occurs early after bacteria enter the lung, and this activation eventually contributes to pulmonary inflammation and pathology during the later stages of infection. However, the inflammatory effects of IL-1beta/IL-1-receptor ligation are not observed during this first stage of pneumonic plague. We show that Y. pestis also activates the induction of IL-1 receptor antagonist (IL-1RA), and this activation likely contributes to the ability of Y. pestis to establish the initial pre-inflammatory phase of disease. PMID- 25781468 TI - Paying physicians to prescribe generic drugs and follow-on biologics in the United States. AB - Aaron Kesselheim and colleagues examine potential strategies to promote greater prescribing of generic drugs and follow-on biologics. PMID- 25781469 TI - Broadband optical mammography: chromophore concentration and hemoglobin saturation contrast in breast cancer. AB - This study reports the optical characterization and quantitative oximetry of human breast cancer using spectrally-resolved images collected with a broadband, continuous-wave optical mammography instrument. On twenty-six cancer patients, we collected two-dimensional optical mammograms and created maps of the concentrations of hemoglobin, water, and lipids, as well as the oxygen saturation of hemoglobin. For each cancerous breast, we analyzed the difference between the tumor region (as identified by x-ray and optical mammography) and the remainder of breast tissue. With respect to the surrounding tissue, we found that cancer regions have significantly higher concentrations of total hemoglobin (+2.4 +/- 0.4 MUM) and water (+7 +/- 1% v/v), and significantly lower lipid concentration (8 +/- 2% v/v) and oxygen saturation of hemoglobin (5 +/- 1%). We also found a significant correlation between the tumor optical contrast and the grade of breast cancer as quantified by the Nottingham histologic score; this demonstrates how optical signatures may be representative of metabolic and morphological features, as well as the aggressive potential of the tumor. PMID- 25781470 TI - A psychophysical imaging method evidencing auditory cue extraction during speech perception: a group analysis of auditory classification images. AB - Although there is a large consensus regarding the involvement of specific acoustic cues in speech perception, the precise mechanisms underlying the transformation from continuous acoustical properties into discrete perceptual units remains undetermined. This gap in knowledge is partially due to the lack of a turnkey solution for isolating critical speech cues from natural stimuli. In this paper, we describe a psychoacoustic imaging method known as the Auditory Classification Image technique that allows experimenters to estimate the relative importance of time-frequency regions in categorizing natural speech utterances in noise. Importantly, this technique enables the testing of hypotheses on the listening strategies of participants at the group level. We exemplify this approach by identifying the acoustic cues involved in da/ga categorization with two phonetic contexts, Al- or Ar-. The application of Auditory Classification Images to our group of 16 participants revealed significant critical regions on the second and third formant onsets, as predicted by the literature, as well as an unexpected temporal cue on the first formant. Finally, through a cluster-based nonparametric test, we demonstrate that this method is sufficiently sensitive to detect fine modifications of the classification strategies between different utterances of the same phoneme. PMID- 25781471 TI - "Just get on with it": qualitative insights of coming to terms with a deteriorating body for older women with osteoarthritis. AB - OBJECTIVE: To qualify the psychosocial burden of osteoarthritis for older women and identify factors perceived to assist with psychological adjustment to the disease. METHODS: Women who indicated being diagnosed/treated for osteoarthritis in the previous three years in the fifth survey of the Australian Longitudinal Study on Women's Health provided the sampling frame. Participants were randomly sampled until saturation was reached using a systematic process. Thematic content analysis was applied to the 19 semi-structured telephone interviews using a realist framework. RESULTS: The findings indicate that the emotional burden of osteoarthritis is considerable, and the process of psychological adjustment complex. Older women with osteoarthritis have psychological difficulties associated with increasing pain and functional impairment. Psychological adjustment over time was attributed primarily to cognitive and attitudinal factors (e.g. stoicism, making downward comparisons and possessing specific notions about the cause of arthritis). This was a dynamic 'day to day' process involving a constant struggle between grieving physical losses and increasing dependence amidst symptom management. CONCLUSION: The findings of this study add to the current understanding of the complex processes involved in psychological adjustment over time. Targeted interventions focused on assisting women with arthritis redefine self-concepts outside the confines of caring responsibilities, coupled with public health education programs around understanding the destructive nature of arthritis are required. Understanding the destructive and (potentially) preventable nature of arthritis may facilitate early detection and increased uptake of appropriate treatment options for osteoarthritis that have the ability to modify disease trajectories. PMID- 25781472 TI - Influenza vaccine induces intracellular immune memory of human NK cells. AB - Influenza vaccines elicit antigen-specific antibodies and immune memory to protect humans from infection with drift variants. However, what supports or limits vaccine efficacy and duration is unclear. Here, we vaccinated healthy volunteers with annual vaccine formulations and investigated the dynamics of T cell, natural killer (NK) cell and antibody responses upon restimulation with heterologous or homologous influenza virus strains. Influenza vaccines induced potential memory NK cells with increased antigen-specific recall IFN-gamma responses during the first 6 months. In the absence of significant changes in other NK cell markers (CD45RO, NKp44, CXCR6, CD57, NKG2C, CCR7, CD62L and CD27), influenza vaccines induced memory NK cells with the distinct feature of intracellular NKp46 expression. Indeed, surface NKp46 was internalized, and the dynamic increase in NKp46(intracellular)+CD56dim NK cells positively correlated with increased IFN-gamma production to influenza virus restimulation after vaccination. In addition, anti-NKp46 antibodies blocked IFN-gamma responses. These findings provide insights into a novel mechanism underlying vaccine-induced immunity and NK-related diseases, which may help to design persisting and universal vaccines in the future. PMID- 25781474 TI - Executive dysfunction assessed by Clock-Drawing Test in older non-demented subjects with metabolic syndrome is not mediated by white matter lesions. AB - AIMS: Metabolic syndrome (MetS) has been associated with greater occurrence of white matter hyperintensities (WMH). It remains uncertain whether MetS as a construct is associated with poorer cognitive performances. This study explores whether MetS is associated with poorer performances in global and domain-specific cognitive tests in older non-demented subjects independently of its individual components, WMH severity and other variables. METHODS: MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III definition. Brain magnetic resonance studies (1.5T) were performed. Deep and periventricular WMH were graded using the Fazekas scale. Subjects underwent the Mini-Mental State Examination, the Babcock Short Story Recall test and the Clock Drawing Test (CDT). RESULTS: Eighty community-dwellers aged 67-91 years were studied. Subjects with MetS (n = 35) had more severe WMH, and poorer performances on the CDT (P = 0.003) and the Babcock Short Story Recall test (P = 0.027). After multiple adjustment, MetS was inversely associated with CDT scores (B = -1.285; 95% confidence interval = -1.996--0.575; P = 0.001) but not with episodic memory. Results were not affected by WMH severity. Interestingly, none of the individual components of MetS predicted poorer cognitive performances. CONCLUSIONS: Impairment in executive functions assessed by CDT may represent an early and specific sign of cognitive decline in older individuals with MetS. Future longitudinal studies are needed to better establish the predictive role of MetS on dementia and to demonstrate the possibility of dementia prevention by targeting MetS. PMID- 25781473 TI - Predicting object size from hand kinematics: a temporal perspective. AB - Research on reach-to-grasp movements generally concentrates on kinematics values that are expression of maxima, in particular the maximum aperture of the hand and the peak of wrist velocity. These parameters provide a snapshot description of movement kinematics at a specific time point during reach, i.e., the maximum within a set of value, but do not allow to investigate how hand kinematics gradually conform to target properties. The present study was designed to extend the characterization of object size effects to the temporal domain. Thus, we computed the wrist velocity and the grip aperture throughout reach-to-grasp movements aimed at large versus small objects. To provide a deeper understanding of how joint movements varied over time, we also considered the time course of finger motion relative to hand motion. Results revealed that movement parameters evolved in parallel but at different rates in relation to object size. Furthermore, a classification analysis performed using a Support Vector Machine (SVM) approach showed that kinematic features taken as a group predicted the correct target size well before contact with the object. Interestingly, some kinematics features exhibited a higher ability to discriminate the target size than others did. These findings reinforce our knowledge about the relationship between kinematics and object properties and shed new light on the quantity and quality of information available in the kinematics of a reach-to-grasp movement over time. This might have important implications for our understanding of the action-perception coupling mechanism. PMID- 25781475 TI - Isolation and identification of a natural reassortant mammalian orthoreovirus from least horseshoe bat in China. AB - BACKGROUND: Mammalian orthoreoviruses (MRVs) have a wide geographic distribution and can infect virtually all mammals. Infections in humans may be either symptomatic or asymptomatic. This study describes the isolation and identification of a natural reassortant MRV from least horseshoe bats (Rhinolophus pusillu) in China, referred to as RpMRV-YN2012. METHODS AND RESULTS: The RpMRV-YN2012 was obtained from urine samples of Rhinolophus pusillus by cell culture. Negative-staining electron microscopy revealed that RpMRV-YN2012 was a non-enveloped icosahedral virus with ~75 nm in diameter. Polyacrylamide gel electrophoresis (PAGE) migration patterns of the genome segments showed that RpMRV-YN2012 contained 10 segments in a 3:3:4 arrangement. The whole genome sequence of RpMRV2012 was determined. The consensus terminal sequences of all segments of 5'-GCUAh...yUCAUC-3' (h = A, U or C; y = C or U) were similar to the MRV species within the genus Orthoreovirus. Its evolution and evidence of genetic reassortment were analyzed by sequence comparison and phylogenetic analysis. The results showed that RpMRV-YN2012 is a novel serotype 2 MRV that may have originated from reassortment among bat, human, and/or pig MRV strains which associated with diarrhea, acute gastroenteritis and necrotizing encephalopathy in animals and humans. CONCLUSIONS: RpMRV-YN2012 is a novel bat reassortant MRV, which may have resulted from a reassortment involving MRVs known to infect humans and animals. It is necessary to identify whether RpMRV-YN2012 is associated with diarrhea, acute gastroenteritis and necrotizing encephalopathy in clinical patients. In addition, we should carefully monitor its evolution and virulence in real time. PMID- 25781477 TI - A Stochastic Algorithm for Generating Realistic Virtual Interstitial Cell of Cajal Networks. AB - Interstitial cells of Cajal (ICC) play a central role in coordinating normal gastrointestinal (GI) motility. Depletion of ICC numbers and network integrity contributes to major functional GI motility disorders. However, the mechanisms relating ICC structure to GI function and dysfunction remains unclear, partly because there is a lack of large-scale ICC network imaging data across a spectrum of depletion levels to guide models. Experimental imaging of these large-scale networks remains challenging because of technical constraints, and hence, we propose the generation of realistic virtual ICC networks in silico using the single normal equation simulation (SNESIM) algorithm. ICC network imaging data obtained from wild-type (normal) and 5-HT2B serotonin receptor knockout (depleted ICC) mice were used to inform the algorithm, and the virtual networks generated were assessed using ICC network structural metrics and biophysically-based computational modeling. When the virtual networks were compared to the original networks, there was less than 10% error for four out of five structural metrics and all four functional measures. The SNESIM algorithm was then modified to enable the generation of ICC networks across a spectrum of depletion levels, and as a proof-of-concept, virtual networks were successfully generated with a range of structural and functional properties. The SNESIM and modified SNESIM algorithms, therefore, offer an alternative strategy for obtaining the large scale ICC network imaging data across a spectrum of depletion levels. These models can be applied to accurately inform the physiological consequences of ICC depletion. PMID- 25781476 TI - In vivo localization of iris yellow spot tospovirus (Bunyaviridae)-encoded proteins and identification of interacting regions of nucleocapsid and movement proteins. AB - BACKGROUND: Localization and interaction studies of viral proteins provide important information about their replication in their host plants. Tospoviruses (Family Bunyaviridae) are economically important viruses affecting numerous field and horticultural crops. Iris yellow spot virus (IYSV), one of the tospoviruses, has recently emerged as an important viral pathogen of Allium spp. in many parts of the world. We studied the in vivo localization and interaction patterns of the IYSV proteins in uninfected and infected Nicotiana benthamiana and identified the interacting partners. PRINCIPAL FINDINGS: Bimolecular fluorescence complementation (BiFC) analysis demonstrated homotypic and heterotypic interactions between IYSV nucleocapsid (N) and movement (NSm) proteins. These interactions were further confirmed by pull-down assays. Additionally, interacting regions of IYSV N and NSm were identified by the yeast-2-hybrid system and beta-galactosidase assay. The N protein self-association was found to be mediated through the N- and C-terminal regions making head to tail interaction. Self-interaction of IYSV NSm was shown to occur through multiple interacting regions. In yeast-2-hybrid assay, the N- and C-terminal regions of IYSV N protein interacted with an N-terminal region of IYSV NSm protein. CONCLUSION/SIGNIFICANCE: Our studies provide new insights into localization and interactions of IYSV N and NSm proteins. Molecular basis of these interactions was studied and is discussed in the context of tospovirus assembly, replication, and infection processes. PMID- 25781478 TI - Separation of folinic acid diastereomers in capillary electrophoresis using a new cationic beta-cyclodextrin derivative. AB - A method for the separation of folinic acid diastereomers by capillary electrophoresis in chiral separation media was developed. Aiming to achieve a good separation of the anionic analytes, a newly synthesized cationic beta cyclodextrin derivative, mono-6-deoxy-6-piperdine-beta-cyclodextrin, was applied as the chiral selector. The effect of background electrolyte pH, the concentration of the cyclodextrin additive, and organic modifier on the separation was investigated. A good separation of folinic acid diastereomers was obtained with 30 mmol/L phosphate buffer at pH 6.50 containing 6.0 mmol/L of mono 6-deoxy-6-piperdine-beta-cyclodextrin in 10% acetonitrile. Based on the capillary electrophoresis data, the binding constants of each diastereomer with mono-6 deoxy-6-piperdine-beta-cyclodextrin were determined. Moreover, a computational modeling study, using the semi-empirical PM3 method, was used to discuss the possible mechanism of separation of folinic acid with mono-6-deoxy-6-piperdine beta-cyclodextrin. PMID- 25781479 TI - Imparting functionality to biocatalysts via embedding enzymes into nanoporous materials by a de novo approach: size-selective sheltering of catalase in metal organic framework microcrystals. AB - We develop a new concept to impart new functions to biocatalysts by combining enzymes and metal-organic frameworks (MOFs). The proof-of-concept design is demonstrated by embedding catalase molecules into uniformly sized ZIF-90 crystals via a de novo approach. We have carried out electron microscopy, X-ray diffraction, nitrogen sorption, electrophoresis, thermogravimetric analysis, and confocal microscopy to confirm that the ~10 nm catalase molecules are embedded in 2 MUm single-crystalline ZIF-90 crystals with ~5 wt % loading. Because catalase is immobilized and sheltered by the ZIF-90 crystals, the composites show activity in hydrogen peroxide degradation even in the presence of protease proteinase K. PMID- 25781480 TI - High-efficiency aqueous-solution-processed hybrid solar cells based on P3HT dots and CdTe nanocrystals. AB - Without using any environmentally hazardous organic solution, we fabricated hybrid solar cells (HSCs) based on the aqueous-solution-processed poly(3 hexylthiophene) (P3HT) dots and CdTe nanocrystals (NCs). As a novel aqueous donor material, the P3HT dots are prepared through a reprecipitation method and present an average diameter of 2.09 nm. When the P3HT dots are mixed with the aqueous CdTe NCs, the dependence of the device performance on the donor-acceptor ratio shows that the optimized ratio is 1:24. Specifically, the dependence of the device performance on the active-layer thermal annealing conditions is investigated. As a result, the optimized annealing temperature is 265 degrees C, and the incorporation of P3HT dots as donor materials successfully reduced the annealing time from 1 h to 10 min. In addition, the transmission electron microscopy and atomic force microscopy measurements demonstrate that the size of the CdTe NCs increased as the annealing time increased, and the annealing process facilitates the formation of a smoother interpenetrating network in the active layer. Therefore, charge separation and transport in the P3HT dots:CdTe NCs layer are more efficient. Eventually, the P3HT dots:CdTe NCs solar cells achieved 4.32% power conversion efficiency. The polymer dots and CdTe NCs based aqueous-solution processed HSCs provide an effective way to avoid a long-time thermal annealing process of the P3HT dots:CdTe NCs layer and largely broaden the donor materials for aqueous HSCs. PMID- 25781481 TI - An extensively hydrolysed casein-based formula for infants with cows' milk protein allergy: tolerance/hypo-allergenicity and growth catch-up. AB - Children with cows' milk protein allergy (CMPA) are at risk of insufficient length and weight gain, and the nutritional efficacy of hypo-allergenic formulas should be carefully assessed. In 2008, a trial assessed the impact of probiotic supplementation of an extensively hydrolysed casein-based formula (eHCF) on acquisition of tolerance in 119 infants with CMPA. First analysis of the study results showed that the studied formula allowed improvement of food-related symptoms. The scoring of atopic dermatitis (SCORAD) index was assessed at randomisation and after 6 months of feeding. A post hoc analysis was performed using WHO growth software's nutritional survey module (WHO Anthro version 3.2.2). All infants who were fed the study formula tolerated it well. The SCORAD index significantly improved from randomisation to 6 months of feeding with the study formula. Anthropometric data indicated a significant improvement in the weight for-age, length-for-age and weight-for-length z scores, as well as in the restoration of normal BMI. The probiotic supplementation did not show any impact on these parameters. The present data showed that this eHCF was clinically tolerated and significantly improved the SCORAD index and growth indices. PMID- 25781482 TI - Assessing the effects of multiple stressors on the recruitment of fruit harvested trees in a tropical dry forest, Western Ghats, India. AB - The harvest of non-timber forest products (NTFPs), together with other sources of anthropogenic disturbance, impact plant populations greatly. Despite this, conservation research on NTFPs typically focuses on harvest alone, ignoring possible confounding effects of other anthropogenic and ecological factors. Disentangling anthropogenic disturbances is critical in regions such as India's Western Ghats, a biodiversity hotspot with high human density. Identifying strategies that permit both use and conservation of resources is essential to preserving biodiversity while meeting local needs. We assessed the effects of NTFP harvesting (fruit harvest from canopy and lopping of branches for fruit) in combination with other common anthropogenic disturbances (cattle grazing, fire frequency and distance from village), in order to identify which stressors have greater effects on recruitment of three tropical dry forest fruit tree species. Specifically, we assessed the structure of 54 populations of Phyllanthus emblica, P. indofischeri and Terminalia chebula spread across the Nilgiri Biosphere Reserve, Western Ghats to ask: (1) How are populations recruiting? and (2) What anthropogenic disturbance and environmental factors, specifically forest type and elevation, are the most important predictors of recruitment status? We combined participatory research with an information-theoretic model-averaging approach to determine which factors most affect population structure and recruitment status. Our models illustrate that for T. chebula, high fire frequency and high fruit harvest intensity decreased the proportion of saplings, while lopping branches or stems to obtain fruit increased it. For Phyllanthus spp, recruitment was significantly lower in plots with more frequent fire. Indices of recruitment of both species were significantly higher for plots in more open-canopy environments of savanna woodlands than in dry forests. Our research illustrates an approach for identifying which factors are most important in limiting recruitment of NTFP populations and other plant species that may be in decline, in order to design effective management strategies. PMID- 25781483 TI - PYCNOIB: biodiversity and biogeography of Iberian pycnogonids. AB - Biodiversity and biogeographic studies comparing the distribution patterns of benthic marine organisms across the Iberian Atlantic and Mediterranean waters are scarce. The Pycnogonida (sea spiders) are a clear example of both endemicity and diversity, and are considered a key taxon to study and monitor biogeographic and biodiversity patterns. This is the first review that compiles data about abundance and diversity of Iberian pycnogonids and examines their biogeographic patterns and bathymetric constraints using GIS tools. A total of 17,762 pycnogonid records from 343 localities were analyzed and were found to contain 65 species, 21 genera and 12 families. Achelia echinata and Ammothella longipes (family Acheliidae) were the most abundant comprising ~80% of the total records. The Acheliidae is also the most speciose in Iberian waters with 15 species. In contrast, the family Nymphonidae has 7 species but is significantly less abundant (<1% of the total records) than Acheliidae. Species accumulation curves indicate that further sampling would increase the number of Iberian species records. Current sampling effort suggests that the pycnogonid fauna of the Mediterranean region may be richer than that of the Atlantic. The Strait of Gibraltar and the Alboran Sea are recognized as species-rich areas that act as buffer zones between the Atlantic and Mediterranean boundaries. The deep waters surrounding the Iberian Peninsula are poorly surveyed, with only 15% of the sampling sites located below 1000 m. Further deep-water sampling is needed mainly on the Iberian Mediterranean side. PMID- 25781484 TI - Informal child care and adolescent psychological well-being: Hong Kong's "Children of 1997" birth cohort. AB - BACKGROUND: Informal child care (child care by untrained family members, relatives or employees in the home) in Western populations is often associated with poorer psychological well-being, which may be confounded by socioeconomic position. We examined the association of informal child care, common in non Western settings, with adolescent psychological well-being, using Hong Kong's Chinese "Children of 1997" birth cohort. METHODS: Multivariable linear regression was used to examine the adjusted associations of informal child care (at 0.5, 3, 5 and 11 years) with parent-reported Rutter score for child behavior at 11 years, self-reported Culture-Free Self-Esteem Inventories score at 11 years and self reported Patient Health Questionnaire-9 depressive symptom score at 13 years. Model comparisons were used to identify the best representation of child care, in terms of a critical period of exposure to informal child care (independent variable) at a specific age, combination of exposures to informal child care at several ages or an accumulation of exposures to informal child care. RESULTS: Child care was not associated with behavioral problems. A model considering child care at 3 years best represented the association of child care with self-esteem while a model considering child care at 5 years best represented the association of child care with depressive symptoms. Informal child care at 3 years was associated with lower self-esteem (-0.70, 95% confidence interval (CI) -1.26 to 0.14). Informal child care at 5 years was associated with more depressive symptoms (0.45, 95% CI 0.17 to 0.73). CONCLUSION: In a developed non-Western setting, informal child care was associated with lower self-esteem and more depressive symptoms. PMID- 25781486 TI - The evolution of dental journals from 2003 to 2012: a bibliometric analysis. AB - Bibliometrics are a set of methods, which can be used to analyze academic literature quantitatively and its changes over time. The objectives of this study were 1) to evaluate trends related to academic performance of dental journals from 2003 to 2012 using bibliometric indices, and 2) monitor the changes of the five dental journals with the highest and lowest impact factor (IF) published in 2003. Data for the subject category "Dentistry, Oral Surgery & Medicine" was retrieved from the Journal Citation Reports (JCR) published from 2003 to 2012. Linear regressions analysis was used to determine statistical trends over the years with each bibliometric indicator as the dependent variable and the JCR year as the predictor variable. Statistically significant rise in the total number of dental journals, the number of all articles with the steepest rise observed for research articles, the number of citations and the aggregate IF was observed from 2003 to 2012. The analysis of the five top and five bottom-tire dental journals revealed a rise in IF however, with a wide variation in relation to the magnitude of this rise. Although the IF of the top five journals remained relatively constant, the percentile ranks of the four lowest ranking journals in 2003 increased significantly with the sharpest rise being noted for the British Journal of Oral & Maxillofacial Surgery. This study revealed significant growth of dental literature in absolute terms, as well as upward trends for most of the citation-based bibliometric indices from 2003 to 2012. PMID- 25781485 TI - Linking traits based on their shared molecular mechanisms. AB - There is growing recognition that co-morbidity and co-occurrence of disease traits are often determined by shared genetic and molecular mechanisms. In most cases, however, the specific mechanisms that lead to such trait-trait relationships are yet unknown. Here we present an analysis of a broad spectrum of behavioral and physiological traits together with gene-expression measurements across genetically diverse mouse strains. We develop an unbiased methodology that constructs potentially overlapping groups of traits and resolves their underlying combination of genetic loci and molecular mechanisms. For example, our method predicts that genetic variation in the Klf7 gene may influence gene transcripts in bone marrow-derived myeloid cells, which in turn affect 17 behavioral traits following morphine injection; this predicted effect of Klf7 is consistent with an in vitro perturbation of Klf7 in bone marrow cells. Our analysis demonstrates the utility of studying hidden causative mechanisms that lead to relationships between complex traits. PMID- 25781487 TI - Characteristics of an R-phycoerythrin with two gamma subunits prepared from red macroalga Polysiphonia urceolata. AB - An R-phycoerythrin (R-PE) was isolated by gel filtrations on Sepharose CL-4B and Sephadex G-150 from the phycobiliprotein extract of the marine red macroalga Polysiphonia urceolata Grev and further purified by ion exchange chromatography on DEAE-Sepharose Fast Flow. The purified R-PE showed three absorption peaks at 498 nm, 538 nm, 566 nm and one fluorescent emission maximum at 577 nm. Although the R-PE showed a single band on the examination by native PAGE, it exhibited two very close bands at pH about 4.7 in native isoelectric focusing (IEF). Polypeptide analysis of the R-PE demonstrated that it contained four chromophore carrying subunits, alpha18.2, beta20.6, gamma31.6 (gamma'), gamma34.6 (gamma), and no colorless polypeptide; its subunit composition was 6alpha18.2:6beta20.6:1 gamma31.6:2gamma34.6. The alpha and beta subunits were distributed within a acidic pH range from 5.0 to 6.0 in denaturing IEF and the gamma subunits were in a basic pH range from 7.6 to 8.1. These results reveal that the prepared R-PE may exist in two hexamers of gamma (alphabeta)3 gamma (alphabeta)3gamma' and gamma (alphabeta)3 gamma'(alphabeta)3 gamma and that the R-PE participate in the rod domain assembly of P. urceolata phycobilisomes by stacking each of its trimer (alphabeta)3 face-to-face with the aid of one gamma subunit (gamma or gamma'). PMID- 25781488 TI - Spiraeoside inhibits mast cells activation and IgE-mediated allergic responses by suppressing phospholipase C-gamma-mediated signaling. AB - Mast cells are responsible for IgE-mediated allergic responses through the secretion of various inflammatory cytokines and mediators. Therefore, the pharmacological regulation of mast cell activation is an important goal in the development of novel anti-allergic drugs. In this study, we found that spiraeoside (SP) inhibits mast cell activation and allergic responses in vivo. SP dose-dependently inhibited the degranulation induced by IgE-antigen (Ag) stimulation in RBL-2H3 mast cells without cytotoxic effects. At the molecular level, SP reduced the Ag-induced phosphorylation and subsequent activation of phospholipase C-gamma2 (PLC-gamma2). Moreover, SP inhibited the phosphorylation of spleen tyrosine kinase (Syk), linker for activation of T cells (LAT), and downstream MAPKs, such as ERK1/2, p38, and JNK, eventually attenuating expression of TNF-alpha and IL-4. Finally, we found that SP significantly inhibited IgE mediated passive cutaneous anaphylaxis (PCA) in mice. Taken together, our results strongly suggest that SP suppresses IgE-mediated mast cell activation and allergic responses by inhibiting Lyn-induced PLC-gamma2/MAPK signaling in mast cells. PMID- 25781489 TI - Bioactive bis-naphtho-gamma-pyrones from rice false Smut pathogen Ustilaginoidea virens. AB - Ustilaginoidins were bis-naphtho-gamma-pyrones mycotoxins possessing an aR configuration of the chiral axis previously reported from the false smut balls of rice infected by the fungal pathogen Ustilaginoidea virens. To investigate the chemical diversity of these metabolites and their bioactivities, we fermented this fungus on solid rice media, which afforded the isolation of 13 ustilaginoidins, including seven new compounds, namely ustilaginoidins K-P, 1-6, and E1, 7, together with the known ustilaginoidins A, 8, D, 9, E, 10, F, 11, and G, 12, and isochaetochromin B2, 13. The structures of the new compounds were elucidated by using (1D, 2D) NMR, high-resolution mass spectrometry, UV, and circular dichroism, as well as by comparison with the literature data. A plausible biosynthesis pathway was proposed for these dimeric polyketides. The isolated compounds were evaluated for their antibacterial, cytotoxic, and radicle elongation inhibitory activities. Ustilaginoidins K, 1 and L, 2 showed cytotoxic activities on the A2780 human ovarian cancer cell line with IC50 values of 4.18 and 7.26 MUM, respectively. Ustilaginoidins N, 4, D, 9, E, 10, and G, 12 were active against the tested pathogenic bacteria with MIC values in the range of 16 64 MUg/mL. Ustilaginoidins O, 5, E, 10, and F, 11, and isochaetochromin B2, 13 displayed moderate inhibitory activity on the radicle elongation of rice seeds. PMID- 25781490 TI - Multicentre prospective evaluation of the learning curve of holmium laser enucleation of the prostate (HoLEP). AB - OBJECTIVES: To describe the step-by-step learning curve of the holmium laser enucleation of the prostate (HoLEP) surgical technique. SUBJECTS/PATIENTS AND METHODS: A prospective, multicentre observational study was conducted, involving surgeons experienced in transurethral resection of the prostate and open prostatectomy but never having performed HoLEP. The main judgment criterion was the ability of the surgeon to perform four consecutive successful procedures, defined by the following: complete enucleation and morcellation within <90 min, without any conversion to standard transurethral resection of the prostate (TURP), with acceptable stress, and with acceptable difficulty (evaluated by Likert scales). Each surgeon included 20 consecutive cases. RESULTS: Of nine centres, three abandoned HoLEP before the end of the study due to complications, and one was excluded for treating patients off protocol. Only one centre achieved the main judgment criterion of four consecutive successful HoLEP procedures. Overall, the procedures were successfully performed in 43.6% of cases. Reasons for unsuccessful procedures were mainly operative time >90 min (n = 51), followed by conversion to TURP (n = 14), incomplete morcellation (n = 8), significant stress (n = 9), or difficulty (n = 14) during HoLEP. Ignoring operating time, 64% of procedures were successful and four out of five centres did four consecutive successful cases. Of the five centres that completed the study, four chose to continue HoLEP. CONCLUSION: Even in a prospective training structure, HoLEP has a steep learning curve exceeding 20 cases, with almost half of our centres choosing to abandon or not to continue with the technique. Operating time and difficulty of the enucleation seem the most important problems for a beginner. A more intensely mentored and structured mentorship programme might allow safer adoption of the procedure. PMID- 25781491 TI - Histone H2A/H2B chaperones: from molecules to chromatin-based functions in plant growth and development. AB - Nucleosomal core histones (H2A, H2B, H3 and H4) must be assembled, replaced or exchanged to preserve or modify chromatin organization and function according to cellular needs. Histone chaperones escort histones, and play key functions during nucleosome assembly/disassembly and in nucleosome structure configuration. Because of their location at the periphery of nucleosome, histone H2A-H2B dimers are remarkably dynamic. Here we focus on plant histone H2A/H2B chaperones, particularly members of the NUCLEOSOME ASSEMBLY PROTEIN-1 (NAP1) and FACILITATES CHROMATIN TRANSCRIPTION (FACT) families, discussing their molecular features, properties, regulation and function. Covalent histone modifications (e.g. ubiquitination, phosphorylation, methylation, acetylation) and H2A variants (H2A.Z, H2A.X and H2A.W) are also discussed in view of their crucial importance in modulating nucleosome organization and function. We further discuss roles of NAP1 and FACT in chromatin-based processes, such as transcription, DNA replication and repair. Specific functions of NAP1 and FACT are evident when their roles are considered with respect to regulation of plant growth and development and in plant responses to environmental stresses. Future major challenges remain in order to define in more detail the overlapping and specific roles of various members of the NAP1 family as well as differences and similarities between NAP1 and FACT family members, and to identify and characterize their partners as well as new families of chaperones to understand histone variant incorporation and chromatin target specificity. PMID- 25781492 TI - Editorial Comment to Venous tumor thrombus consistency is not predictive of survival in patients with renal cell carcinoma: A retrospective study of 147 patients. PMID- 25781493 TI - Associations Between Serum 25-Hydroxyvitamin D, Insulin Sensitivity, Insulin Secretion, and beta-Cell Function According to Glucose Tolerance Status. AB - BACKGROUND: The objective of this study was to determine whether glucose tolerance status influences the associations between serum 25-hydroxyvitamin D [25(OH)D], insulin sensitivity, insulin secretion, and beta-cell function. METHODS: This cross-sectional study included 112 French Canadian postmenopausal women with normal glucose tolerance (NGT; n = 65) or abnormal glucose tolerance (AGT; n = 47). Estimates of insulin sensitivity [homeostasis model assessment of insulin sensitivity (HOMA %S) and glucose disposal rate (GDR)], insulin secretion [area under the curve of C-peptide (AUC C-peptide)], and beta-cell function (GDR * AUC C-peptide) were derived from a 2-hr euglycemic-hyperinsulinemic clamp and a 75-gram 3-hr oral glucose tolerance test (OGTT). Measures of adiposity were taken (waist circumference, body mass index, fat mass by the hydrostatic weighting technique, and computed tomography (CT)-derived total and visceral adiposity), questionnaires on physical activity, dietary calcium, and vitamin D intake were administered, and blood was sampled for measurement of parathyroid hormone, interleukin-6, and adiponectin. RESULTS: AGT status was significantly associated with lower insulin sensitivity and beta-cell function (P <= 0.01 for all) but not with insulin secretion. Lower serum 25(OH)D concentrations were significantly associated with lower insulin sensitivity and secretion (P <= 0.01 for all) but not with beta-cell function. The interaction between glucose tolerance status and serum 25(OH)D concentration was not significant for either insulin sensitivity, insulin secretion, or beta-cell function, even after adjustment for potential confounders. CONCLUSION: Vitamin D and glucose tolerance status are both independently associated with measures of insulin sensitivity, insulin secretion, and beta-cell function. However, the association between serum 25(OH)D and these surrogate markers of type 2 diabetes mellitus risk is not influenced by glucose tolerance status. PMID- 25781494 TI - Enlargement of eccrine angiomatous hamartoma following trauma. AB - Eccrine angiomatous hamartoma (EAH) is a rare, benign hamartoma of eccrine and vascular components that predominantly affects children. Growth is typically commensurate with the child's growth. Herein we report an additional case of this rare entity that enlarged after trauma in a 7-year-old girl. PMID- 25781495 TI - Renalase contributes to the renal protection of delayed ischaemic preconditioning via the regulation of hypoxia-inducible factor-1alpha. AB - Ischaemic preconditioning (IPC) attenuates acute kidney injury (AKI) from renal ischaemia reperfusion. Renalase, an amine oxidase secreted by the proximal tubule, not only degrades circulating catecholamines but also protects against renal ischaemia reperfusion injury. Here, it has been suggested that the renoprotective effect of renal IPC is partly mediated by renalase. In a model of brief intermittent renal IPC, the increased cortex renalase expression was found to last for 48 hrs. IPC significantly reduced renal tubular inflammation, necrosis and oxidative stress following renal ischaemia reperfusion injury. Such effects were attenuated by blocking renalase with an anti-renalase monoclonal antibody. We further demonstrated that renalase expression was up-regulated by hypoxia in vitro via an hypoxia-inducible factor (HIF)-1alpha mechanism. The IPC induced up-regulation of renalase in vivo was also reduced by pre-treatment with an HIF-1alpha inhibitor, 3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole. In summary, the renoprotective effect of IPC is partly dependent on the renalase expression, which may be triggered by hypoxia via an HIF-1alpha mechanism. Endogenous renalase shows potential as a therapeutic agent for the prevention and treatment of AKI. PMID- 25781497 TI - Tracking the relaxation of 2,5-dimethylpyrrole by femtosecond time-resolved photoelectron and photoion detection. AB - The relaxation of 2,5-dimethylpyrrole after excitation in the 290-239 nm range, which covers the weak absorption of the S1 (1)A2 pisigma* state, dissociative along the N-H bond, and the stronger band mostly attributed to the (1)B2 pipi* state, has been investigated by time-resolved ion and photoelectron techniques. The measurements yield an invariant lifetime of ~55 fs for the (1)pisigma* state, after preparation in its Franck-Condon region with increasing vibrational content. This ultrafast rate indicates that, contrary to the observations made in pyrrole (Roberts et al. Faraday Discuss. 2013, 163, 95-116), the molecule reaches the dissociative part of the potential without any barrier effect, although calculations predict the latter to be higher than in the pyrrole case. The results are rationalized in terms of a barrier free multidimensional pathway that very likely involves out-of-plane vibrations. Additionally, a lifetime of ~100 fs is found after excitation along the higher (1)B2 pipi* <- S0 transition. The relaxation of this state by coupling to a very short living S1 (1)pisigma* state, or by alternative routes, is discussed in the light of the collected photoelectron measurements. PMID- 25781496 TI - A high excision potential of TALENs for integrated DNA of HIV-based lentiviral vector. AB - DNA-editing technology has made it possible to rewrite genetic information in living cells. Human immunodeficiency virus (HIV) provirus, an integrated form of viral complementary DNA in host chromosomes, could be a potential target for this technology. We recently reported that HIV proviral DNA could be excised from the chromosomal DNA of HIV-based lentiviral DNA-transduced T cells after multiple introductions of a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 endonuclease system targeting HIV long terminal repeats (LTR). Here, we generated a more efficient strategy that enables the excision of HIV proviral DNA using customized transcription activator-like effector nucleases (TALENs) targeting the same HIV LTR site. A single transfection of TALEN-encoding mRNA, prepared from in vitro transcription, resulted in more than 80% of lentiviral vector DNA being successfully removed from the T cell lines. Furthermore, we developed a lentiviral vector system that takes advantage of the efficient proviral excision with TALENs and permits the simple selection of gene transduced and excised cells in T cell lines. PMID- 25781498 TI - When is a post-mortem skeletal survey of the fetus indicated, and when not? AB - OBJECTIVE: Radiography after fetal or perinatal death has become a routine part of post-mortem diagnostics. However, only a selected subset of these babygrams or fetal post-mortem skeletal surveys (FPSSs) provides useful information. We investigated the indication for a FPSS. METHODS: Inclusion consisted of the routinely made FPSS (2002-2012) in our university hospital in cases of fetal or perinatal death up to 7 days after birth. We categorized the diagnostic value of the FPSS as no, minor, major or pathognomonic. Regression analysis was used to determine the selection criteria for a useful FPSS. RESULTS: Three hundred and thirty-seven FPSS were included. Three hundred and five (91%) FPSS showed no or minor skeletal malformations. Fourteen (4.2%) FPSS had major skeletal malformations. In 18 (5.3%) cases the diagnosis was based on the pathognomonic skeletal malformations on the FPSS. Two cases were false positive after major birth trauma. The presence of multiple skeletal malformations on prenatal ultrasound or at post-mortem external inspection was highly indicative of a diagnostic FPSS (p < 0.001). CONCLUSION: The majority of the babygrams/FPSS has no contribution to the diagnostic process. Multiple skeletal malformations on prenatal ultrasound or post-mortem external inspection are indicative for a diagnostic FPSS, and this should be the main selection criterion. PMID- 25781499 TI - Pathological examination of the placenta in small for gestational age (SGA) children with or without postnatal catch-up growth. AB - BACKGROUND/OBJECTIVE: Approximately 10% of small for gestational age (SGA) infants fail to catch up. The relationship between postnatal growth and placental pathology in SGA infants remains unclear. Our aim was to assess the involvement of placental pathology in postnatal growth of SGA infants. METHODS: We retrospectively evaluated placental pathology and postnatal growth in single pregnancy infants born after 37 gestational weeks in our institution, with both birth weight and length below -2 standard deviation scores (SDS) of the normal weight and length. "Catch-up" was defined as height reaching -2 SDS before the second birthday. Pathology of the placenta was classified into: abnormality due to maternal factors or fatal factors, villitis of unknown etiology (VUE), other abnormalities and no abnormality. RESULTS: Of the 33 084 infants, 142 met our criteria and 49 of them had analyzable data. The overall catch-up rate was 84%. Catch-up growth took place in all infants with no placental abnormality and only 57% of infants with abnormality due to fatal factors. There was no significant relationship between catch-up rate and other factors. CONCLUSION: Placental pathology is associated with postnatal growth in SGA children born at term. Placental abnormality due to fetal factors is related to poor catch-up rate. PMID- 25781501 TI - Postmodification of the electronic properties by addition of pi-stacking additives in N-heterocyclic carbene complexes with extended polyaromatic systems. AB - A series of iridium complexes containing phenanthro[4,5-abc]phenazino[11,12 d]imidazol-2-ylidene and acetonaphtho[1,2-b]quinoxaline[11,12-d]imidazol-2 ylidene ligands have been obtained and fully characterized. These complexes display highly extended polyaromatic systems attached to the backbone of the N heterocyclic carbene. The presence of this extended polyaromatic system makes the electron-donating character of these ligands sensitive to the presence of pi stacking additives, such as pyrene and hexafluorobenzene. The computational studies predict that the addition of pyrene affords an increase of the electron donating character of the polyaromatic ligand (Tolman electronic parameter (TEP) decreases), while the addition of hexafluorobenzene has the opposite effect (TEP increases). This prediction is experimentally corroborated by IR spectroscopy, by measuring the shift of the CO stretching bands of a series of IrCl(NHC)(CO)2 complexes, where NHC is the N-heterocyclic carbene ligand with the polyaromatic system. Finally, the energy of the pi-stacking interaction of one of the key Ir(I) complexes with pyrene and hexafluorobenzene has been estimated by using the Benesi-Hildebrand treatment, based on the delta-shifts observed by (1)H NMR spectroscopy. PMID- 25781500 TI - Ductal closure with intravenous paracetamol: a new approach to patent ductus arteriosus treatment. AB - OBJECTIVES: Indomethacin and ibuprofen are commonly used in the treatment of hemodynamically significant patent ductus arteriosus (hsPDA). These drugs are associated with serious adverse events, including gastrointestinal perforation, renal failure and bleeding. The role of paracetamol has been proposed for the treatment of PDA. METHODS: We report a series of 11 neonates (birth weight: 415 1580 g; gestational age: 23-30.3 weeks) who were treated with paracetamol for a hsPDA. Neonates with hsPDA were treated with paracetamol in the presence of contraindications to ibuprofen or indomethacin. The condition of significant PDA was defined by the presence of at least one of the following criteria: internal ductal diameter # 1.4 mm/kg body weight, left atrium (LA)-to-aortic (Ao) root ratio > 1.4, unrestrictive pulsatile transductal flow, reverse or absent diastolic flow in the descending aorta along with clinical findings. Intravenous (IV) paracetamol was given at doses 15 mg/kg every 6 h for three days. RESULTS: Successful ductal closure was achieved in 10 out of 11 babies (90.9%). No adverse or side effects were observed during the treatment. CONCLUSIONS: On the basis of these results, paracetamol could be considered as a promising and safe therapy for the treatment of PDA in preterm infants. PMID- 25781502 TI - Modulatory Role of Postsynaptic 5-Hydroxytryptamine Type 1A Receptors in (+/-)-8 Hydroxy-N,N-dipropyl-2-aminotetralin-Induced Hyperphagia in Mice. AB - Brain serotonin (5-HT) is involved in the control of food intake. The ingestive effects of 5-HT are mediated by various receptor subtypes, among others the 5 HT1A receptor. While the involvement of presynaptic 5-HT1A receptors is regarded as certain, the role of postsynaptic 5-HT1A receptors is rather vague. Here, we studied the role of the 5-HT1A receptor on feeding in non-food-deprived and food deprived (young adult and adult, both sexes) wild-type NMRI mice as well as transgenic NMRI mice, which are characterized by a distinct overexpression of postsynaptic 5-HT1A receptors. The known hyperphagic effect of the 5-HT1A receptor full agonist 8-OH-DPAT ((+/-)-8-hydroxy-N,N-dipropyl-2-aminotetralin) in non-food-deprived animals was demonstrated in male NMRI wild-type mice and could be antagonized by the selective 5-HT1A receptor antagonist WAY100635. In transgenic mice, this hyperphagic response was induced at lower doses, with an earlier onset and even in females. However, in adult male transgenic mice, the hyperphagic effect did not occur. In food-deprived NMRI wild-type as well as transgenic mice, 8-OH-DPAT first induced a hypophagic and subsequently a hyperphagic effect. Again, in transgenic animals most responses occurred at lower doses and with an earlier onset. The results indicate that postsynaptic 5-HT1A receptors exert a modulatory function in food intake in free-feeding and fasted mice, which for the first time shows an involvement of postsynaptic 5-HT1A receptors in feeding behavior. Understanding the function of pre- and postsynaptic 5-HT1A receptors may help to achieve new insights into the regulation of food intake and foster prospective treatment strategies for eating disorders. PMID- 25781503 TI - Correlation between glass-forming ability and fragility of pharmaceutical compounds. AB - Fragility is a measure of the departure from non-Arrhenius behavior for supercooled liquids and glasses, and various simple methods are available for its quantification. However, the obtained values usually do not agree with each other. One of the purposes of this study was to compare the fragility values obtained by different methodologies. Thermodynamic fragility (FT) is a simple concept that is evaluated from the heat capacity change at the glass transition temperature (Tg). Dynamic fragility is evaluated using three methodologies in this study: extrapolation of the configurational entropy (Sc) to the Kauzmann temperature (Tk) (FDC), ramp-rate dependence of Tg (FDTg), and that of the fictive temperature (Tf) (FDTf). FT and FDC of 19 pharmaceutical compounds were correlated, whereas FDTg and FDTf did not correlate with either of them. This result seems reasonable because both FT and FDC are calculated from thermodynamic parameters in the quasi-equilibrium state, but FDTg and FDTf are likely affected by kinetics as well. Another goal of this study was to find the correlation between the glass-forming ability (GFA) and fragility. FDTg was shown to correlate with GFA, presumably because both were determined on the balance of thermodynamic and kinetic factors. This correlation suggests that fragile glass has low GFA. Furthermore, the relevance of fragility to isothermal crystallization is discussed. Compounds with small FDTg and FDTf tended to exhibit pressure-controlled crystallization, for which better storage stability can be expected relative to temperature-controlled compounds. Fragility was shown to be a useful parameter practically as well as scientifically. PMID- 25781504 TI - Treatment of crusted scabies with acitretin. PMID- 25781505 TI - Highly enantioselective catalytic cross-dehydrogenative coupling of N-carbamoyl tetrahydroisoquinolines and terminal alkynes. AB - The first catalytic asymmetric cross-dehydrogenative coupling of cyclic carbamates and terminal alkynes has been established. The reaction features high enantiocontrol and excellent functional group tolerance and displays a wide range of structurally and electronically diverse carbamates as well as terminal alkynes. N-Acyl hemiaminals were identified as the reactive intermediates through preliminary control experiments. Employing readily removable carbamates as substrates rather than traditionally adopted N-aryl amines allows applications in complex molecule synthesis and therefore advances the C-H functionalization strategy to a synthetically useful level. PMID- 25781507 TI - Expected improvements in the quantitative remote sensing of optically complex waters with the use of an optically fast hyperspectral spectrometer-a modeling study. AB - Using simulated data, we investigated the effect of noise in a spaceborne hyperspectral sensor on the accuracy of the atmospheric correction of at-sensor radiances and the consequent uncertainties in retrieved water quality parameters. Specifically, we investigated the improvement expected as the F-number of the sensor is changed from 3.5, which is the smallest among existing operational spaceborne hyperspectral sensors, to 1.0, which is foreseeable in the near future. With the change in F-number, the uncertainties in the atmospherically corrected reflectance decreased by more than 90% across the visible-near-infrared spectrum, the number of pixels with negative reflectance (caused by over correction) decreased to almost one-third, and the uncertainties in the retrieved water quality parameters decreased by more than 50% and up to 92%. The analysis was based on the sensor model of the Hyperspectral Imager for the Coastal Ocean (HICO) but using a 30-m spatial resolution instead of HICO's 96 m. Atmospheric correction was performed using Tafkaa. Water quality parameters were retrieved using a numerical method and a semi-analytical algorithm. The results emphasize the effect of sensor noise on water quality parameter retrieval and the need for sensors with high Signal-to-Noise Ratio for quantitative remote sensing of optically complex waters. PMID- 25781506 TI - Validation of five minimally obstructive methods to estimate physical activity energy expenditure in young adults in semi-standardized settings. AB - We compared the accuracy of five objective methods, including two newly developed methods combining accelerometry and activity type recognition (Acti4), against indirect calorimetry, to estimate total energy expenditure (EE) of different activities in semi-standardized settings. Fourteen participants performed a standardized and semi-standardized protocol including seven daily life activity types, while having their EE measured by indirect calorimetry. Simultaneously, physical activity was quantified by an ActivPAL3, two ActiGraph GT3X+'s and an Actiheart. EE was estimated by the standard ActivPAL3 software (ActivPAL), ActiGraph GT3X+ (ActiGraph) and Actiheart (Actiheart), and by a combination of activity type recognition via Acti4 software and activity counts per minute (CPM) of either a hip- or thigh-worn ActiGraph GT3X+ (AGhip + Acti4 and AGthigh + Acti4). At group level, estimated physical activities EE by Actiheart (MSE = 2.05) and AGthigh + Acti4 (MSE = 0.25) were not significantly different from measured EE by indirect calorimetry, while significantly underestimated by ActiGraph, ActivPAL and AGhip + Acti4. AGthigh + Acti4 and Actiheart explained 77% and 45%, of the individual variations in measured physical activity EE by indirect calorimetry, respectively. This study concludes that combining accelerometer data from a thigh-worn ActiGraph GT3X+ with activity type recognition improved the accuracy of activity specific EE estimation against indirect calorimetry in semi-standardized settings compared to previously validated methods using CPM only. PMID- 25781508 TI - Digital control analysis and design of a field-sensed magnetic suspension system. AB - Magnetic suspension systems are mechatronic systems and crucial in several engineering applications, such as the levitation of high-speed trains, frictionless bearings, and wind tunnels. Magnetic suspension systems are nonlinear and unstable systems; therefore, they are suitable educational benchmarks for testing various modeling and control methods. This paper presents the digital modeling and control of magnetic suspension systems. First, the magnetic suspension system is stabilized using a digital proportional-derivative controller. Subsequently, the digital model is identified using recursive algorithms. Finally, a digital mixed linear quadratic regulator (LQR)/Hinfinity control is adopted to stabilize the magnetic suspension system robustly. Simulation examples and a real-world example are provided to demonstrate the practicality of the study results. In this study, a digital magnetic suspension system model was developed and reviewed. In addition, equivalent state and output feedback controls for magnetic suspension systems were developed. Using this method, the controller design for magnetic suspension systems was simplified, which is the novel contribution of this study. In addition, this paper proposes a complete digital controller design procedure for magnetic suspension systems. PMID- 25781509 TI - Evaluation and intercomparison of MODIS and GEOV1 global leaf area index products over four sites in North China. AB - This study investigated the performances of the Moderate Resolution Imaging Spectroradiometer (MODIS) and GEOLAND2 Version 1 (GEOV1) Leaf Area Index (LAI) products using ground measurements and LAI reference maps over four sites in North China for 2011-2013. The Terra + Aqua MODIS and Terra MODIS LAI retrieved by the main algorithm and GEOV1 LAI within the valid range were evaluated and intercompared using LAI reference maps to assess their uncertainty and seasonal variability The results showed that GEOV1 LAI is the most similar product with the LAI reference maps (R2 = 0.78 and RMSE = 0.59). The MODIS products performed well for biomes with low LAI values, but considerable uncertainty arose when the LAI was larger than 3. Terra + Aqua MODIS (R2 = 0.72 and RMSE = 0.68) was slightly more accurate than Terra MODIS (R2 = 0.57 and RMSE = 0.90) for producing slightly more successful observations. Both MODIS and GEOV1 products effectively followed the seasonal trajectory of the reference maps, and GEOV1 exhibited a smoother seasonal trajectory than MODIS. MODIS anomalies mainly occurred during summer and likely occurred because of surface reflectance uncertainty, shorter temporal resolutions and inconsistency between simulated and MODIS surface reflectances. This study suggests that further improvements of the MODIS LAI products should focus on finer algorithm inputs and improved seasonal variation modeling of MODIS observations. Future field work considering finer biome maps and better generation of LAI reference maps is still needed. PMID- 25781510 TI - Remarks on Peinado et al.'s Analysis of J3Gen. AB - Peinado et al. analyzed the security of the J3Gen pseudorandom number generator proposed by Melia-Segui et al., and claimed weaknesses regarding its security properties. They also presented a deterministic attack based on the decimation of the J3Gen output sequences. We show that the assumptions made by Peinado et al. are not correct and that the proposed deterministic attack against J3Gen does not hold in practice. PMID- 25781511 TI - Adjusting spectral indices for spectral response function differences of very high spatial resolution sensors simulated from field spectra. AB - The use of data from multiple sensors is often required to ensure data coverage and continuity, but differences in the spectral characteristics of sensors result in spectral index values being different. This study investigates spectral response function effects on 48 spectral indices for cultivated grasslands using simulated data of 10 very high spatial resolution sensors, convolved from field reflectance spectra of a grass covered dike (with varying vegetation condition). Index values for 48 indices were calculated for original narrow-band spectra and convolved data sets, and then compared. The indices Difference Vegetation Index (DVI), Global Environmental Monitoring Index (GEMI), Enhanced Vegetation Index (EVI), Modified Soil-Adjusted Vegetation Index (MSAVI2) and Soil-Adjusted Vegetation Index (SAVI), which include the difference between the near-infrared and red bands, have values most similar to those of the original spectra across all 10 sensors (1:1 line mean 1:1R2 > 0.960 and linear trend mean ccR2 > 0.997). Additionally, relationships between the indices' values and two quality indicators for grass covered dikes were compared to those of the original spectra. For the soil moisture indicator, indices that ratio bands performed better across sensors than those that difference bands, while for the dike cover quality indicator, both the choice of bands and their formulation are important. PMID- 25781512 TI - Study of the relationship between taste sensor response and the amount of epigallocatechin gallate adsorbed onto a lipid-polymer membrane. AB - A taste sensor using lipid-polymer membranes has been developed to evaluate the taste of foods, beverages and medicines. The response of the taste sensor, measured as a change in the membrane potential caused by adsorption (CPA), corresponds to the aftertaste felt by humans. The relationships between the CPA value and the amount of adsorbed taste substances, quinine and iso-alpha acid (bitterness), and tannic acid (astringency), have been studied so far. However, that of epigallocatechin gallate (EGCg) has not been clarified, although EGCg is abundantly present in green tea as one of its astringent substances. This study aimed at clarifying the response of the taste sensor to EGCg and its relationship with the amount of EGCg adsorbed onto lipid-polymer membranes. The lipid concentration dependence of the CPA value was similar to that of the amount of adsorbed EGCg, indicating a high correlation between the CPA value and the amount of adsorbed EGCg. The CPA value increased with increasing amount of adsorbed EGCg; however, the CPA value showed a tendency of leveling off when the amount of adsorbed EGCg further increased. PMID- 25781513 TI - The design and implementation of the leaf area index sensor. AB - The quick and accurate acquisition of crop growth parameters on a large scale is important for agricultural management and food security. The combination of photographic and wireless sensor network (WSN) techniques can be used to collect agricultural information, such as leaf area index (LAI), over long distances and in real time. Such acquisition not only provides farmers with photographs of crops and suggestions for farmland management, but also the collected quantitative parameters, such as LAI, can be used to support large scale research in ecology, hydrology, remote sensing, etc. The present research developed a Leaf Area Index Sensor (LAIS) to continuously monitor the growth of crops in several sampling points, and applied 3G/WIFI communication technology to remotely collect (and remotely setup and upgrade) crop photos in real-time. Then the crop photos are automatically processed and LAI is estimated based on the improved leaf area index of Lang and Xiang (LAILX) algorithm in LAIS. The research also constructed a database of images and other information relating to crop management. The leaf length and width method (LAILLW) can accurately measure LAI through direct field harvest. The LAIS has been tested in several exemplary applications, and validation with LAI from LAILLW. The LAI acquired by LAIS had been proved reliable. PMID- 25781514 TI - Effects of chronic exposure to lead, cadmium, and manganese mixtures on oxidative stress in rat liver and heart. AB - The aim of this study was to assess the effects of chronic combined exposure to low, environmental doses of Cd, Pb, and Mn on oxidative stress in the liver and heart of rats and on their liver function parameters. Male Wistar rats were divided randomly into eight groups. For nine months controls were receiving drinking water alone, whereas the exposed groups were receiving drinking water with Pb (0.2 mg L(-1)), Cd (1 mg L(-1)), and Mn (2 mg L(-1)) alone or in combinations. Malondialdehyde (MDA) significantly increased in both heart and liver of the animals after combined exposure to metals. Heart MDA correlated with blood Cd, Pb, and Mn and liver MDA with blood Cd. Aspartate aminotransferase (AST) activity and bilirubin concentration also increased significantly in the animal group exposed to all three metals and correlated positively with blood Cd, Pb, and Mn. Our study has confirmed the synergistic effect of the Cd, Mn, and Pb combination on the increase in heart MDA. A similar synergy was observed for Pb+Mn in the increase of serum alanine aminotransferase (ALT) activity as an indicator of liver function. PMID- 25781515 TI - Examiner's finger-mounted fetal tissue oximetry: a preliminary report on 30 cases. AB - OBJECTIVE: To describe preliminary experience with a finger-mounted fetal tissue oximetry probe during the 2nd stage of labor. MATERIALS AND METHODS: A total of 30 term pregnant women without pregnancy complications were recruited. We measured fetal tissue oxygen saturation (FtO2) by using a finger-mounted fetal tissue oximetry during cervical examinations in the 2nd stage of labor. The data capturing rate of FtO2 and the interclass correlation coefficient were also examined. The mean FtO2 was compared to the neonatal condition assessed by the levels of umbilical cord blood. RESULTS: FtO2 was obtained in all cases, regardless of wetness, hair color, the part of the fetal head that was exposed, rotation of the fetus, color of amniotic fluid, and caput succedaneum. The mean FtO2 was 65.5%+/-8.58% in normal neonates [Apgar score >7 (1 min), n=25]. The mean FtO2 was significantly correlated with umbilical cord arterial pH (r=0.52, P=0.0030, n=30), but not with umbilical cord arterial partial pressure of oxygen. The interclass correlation coefficient was 0.94. CONCLUSIONS: Tissue oxygen saturation of the fetal head was obtained easily by the examiner's finger-mounted fetal tissue oximetry. PMID- 25781516 TI - Age at menarche and diet among adolescents in slums of Nashik, India. AB - BACKGROUND AND AIM: The role of dietary patterns in determining age at menarche is insufficiently understood in low-income countries. The relationship between dietary patterns, particularly the consumption of oil, and age at menarche in a slum-dwelling adolescent population in India is examined. METHODS: Data were derived from a cross-sectional baseline survey and anthropometric measurements among 10- to 19-year-old adolescents (n=545, female respondents 272, of whom 160 were post-menarcheal) and a household survey in two slums in the city of Nashik, Western India. By using mixed effects linear regression models, the association between age at menarche and household-wise use of sources of animal protein and oil and fat is examined. RESULTS: Age at menarche (mean 13.7 years) in the slums studied was relatively high according to Indian standards. Age at menarche and the consumption of dairy products, meat, fish and eggs were not associated. The household per capita consumption of vegetable oil had an inverse association with a girl's age at menarche, and there was an indication of a positive association between use of ghee (clarified butter) and age at menarche. These associations did not disappear when controlling for anthropometric status and socio-economic characteristics. CONCLUSION: Intake of fats and foods that are important sources of protein among underprivileged households in India is low and reflected in the relatively late age at menarche. The potential differences in the association between various types of fatty acids, energy intake and age at menarche in conditions of undernutrition requires further prospective study. PMID- 25781517 TI - Urethral foreign body in an adolescent boy: report of two rare cases and review of literature. AB - The presence of a foreign body in the urethra is uncommon. A wide variety of foreign bodies have been described in urethras, but they are often missed in physical examinations as the patient tries to hide the fact. We report two unusual cases of foreign bodies in the urethra in two adolescent boys suffering from psychiatric disorders. In the first case, a 12-year-old boy presented with introduction of sewing needle into the urethra 3 days back. The patient in that case suffered from a delusional disorder. In the second case, a 19 year old man introduced a metallic screw into his urethra for sexual gratification several times in the preceding 4 years. That patient suffered from schizophrenia. Although psychiatric illness is associated with urethral foreign body, such underlying psychiatric disorders are very rare. PMID- 25781518 TI - Adolescent pesticide exposures reported to Texas poison centers. AB - BACKGROUND: Pesticides, particularly when misused, can cause serious morbidity and mortality. There is limited literature on pesticide exposures among adolescents. OBJECTIVE: The purpose of this study was to describe adolescent pesticide exposures reported to poison centers and compare them to adult exposures. SUBJECTS: Pesticide exposures reported to Texas poison centers during 2000-2013 where the patient was age 13 years or greater. METHODS: Cases were divided into adolescents (13-19 years) and adults (20 years or more). The distribution of the cases was determined for various factors, and comparisons were made between the two age groups. RESULTS: There were 2772 adolescent and 33,573 adult pesticide exposures. The most common types of pesticide among adolescent and adult cases, respectively, were insecticides (71% vs. 76%), herbicides (6% vs. 9%), repellents (11% vs. 8%), and rodenticides (10% vs. 5%). Adolescent patients were 56% male and 43% female; adult patients were 45% male and 55% female. The most common exposure routes among adolescent and adult cases, respectively, were dermal (29% vs. 38%), inhalation (22% vs. 33%), ingestion (47% vs. 29%), and ocular (14% vs. 13%). The exposure reason for adolescent and adult exposures, respectively, were unintentional (82% vs. 89%), intentional (13% vs. 7%), adverse reaction (2% vs. 3%), and other/unknown (3% vs. 1%). CONCLUSION: Compared to adult exposures, adolescent pesticide exposures were more likely to involve repellents and rodenticides, involve males, occur by ingestion, and be intentional. PMID- 25781519 TI - Iranian adolescents' insufficient physical activity: a mixed methods explanatory sequential study. AB - BACKGROUND: Adolescents' physical activity decreases from the stage of childhood to adulthood. This study was addressed to explain adolescents' insufficient physical activity (IPA) and its related factors. The subjects were 1201 adolescents in the quantitative phase and 25 adolescents in the quantitative phase. METHODS: An explanatory sequential mixed methods design with follow-up explanations variant was used, which involved collecting quantitative data (1201 adolescents) first and then explaining the quantitative results with in-depth interviews and written narrative (25 adolescents) during a qualitative study. RESULTS: The quantitative results showed that 98.8% of adolescents did not have the recommended physical activity. Five themes were extracted in the qualitative phase including the inhibitory effect of the school environment and peers, as well as the inhibitory effect of the family environment, lack of availability and cultural barriers for the presence of girls in the community, the effect of self feeling and self-understanding, and physical and mental exhaustion and permutation. According to the qualitative findings of the study, physical and mental exhaustion expressed the fact that, although adolescents had an unfavorable sense of IPA, they were under the effects of the intrinsic and extrinsic factors. CONCLUSION: The comparison of these themes indicates that this behavior is imposable but not optional. PMID- 25781520 TI - The understanding of risk factors for eating disorders in male adolescents. AB - OBJECTIVE: The study aimed to describe the medical, psychiatric, and cultural features of adolescent males with an eating disorder (ED). MATERIALS AND METHODS: This retrospective evaluation took place at Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey, and covered a 4-year period between 2010 and 2013. Sixty adolescents were diagnosed with an ED during this period, 47 (78.3%) were females and 13 were males (21.7%) male. All 13 male patients who met full criteria for an ED according to the DSM criteria were included. Medical and psychiatric records of male patients treated for an ED were re-evaluated. RESULTS: The most striking finding of the study was that the female to male ratio became 3.6:1, with the increasing number of male adolescents with an ED. In our study, medical findings and complications of males with ED were similar to those seen in females. However, the most predominant gender difference was the co occurrence of a comorbid physical or mental illness. CONCLUSION: It is imperative to raise awareness of EDs in males. Although the medical findings of the study suggest that male and female adolescents with EDs are clinically similar to each other, the understanding of certain gender-specific risk factors shown in our study, such as a medical illness and/or obesity and co-morbid psychiatric diagnosis, are essential in raising suspicion. Further studies that especially evaluate cultural and social factors that affect parenting styles for boys are important in addessing possible risk factors for the development of EDs in males within different societies. PMID- 25781521 TI - Risky health-related behaviours among school-aged adolescents: a rational 'consumer' choice? AB - Within the contemporary culture of consumption, school-aged adolescents, though neither waged nor salaried producers, are nevertheless treated by the media and the advertisers as if they are active consumers who are engaged in the project of the self. For those adolescents who lack the financial resources to 'buy into' this culture, anxiety may ensue. In order to ease this anxiety, and to acquire social status, some - not all - may make the 'rational' 'consumer' choice to engage in risky health-related behaviour. In situ ethnographic research is needed in order to complement and inform the existing survey-based evidence on the relationship between economic status and health-related behaviour among school aged adolescents as they deal with the pressures of consumerism. PMID- 25781522 TI - Neonatal thyroid storm accompanied with severe anaemia. AB - Neonatal thyroid storm is rare; the diagnostic criteria and management of neonatal thyroid storm have not been well established. In this paper, we report a preterm infant diagnosed with neonatal hyperthyroidism secondary to maternal Graves' disease who was discharged after therapy. Unfortunately, he was rehospitalised for neonatal thyroid storm. We will discuss the diagnosis and general therapy of neonatal thyroid storm. PMID- 25781523 TI - Growth hormone deficiency in a patient with mitochondrial disease. AB - INTRODUCTION: Mitochondrial respiratory chain (MRC) disorders, defined as primary diseases of the oxidative phosphorylation system, are a protean group of metabolic disorders, difficult to diagnose and classify. The diagnosis is complex and requires the integration of information obtained by clinical, laboratory testing, imaging and muscle biopsy. They may be associated with endocrine disorders, including hypothyroidism, diabetes mellitus, hyperinsulinemia and growth hormone (GH) deficiency. CASE REPORT: We describe a case of five years old male with polymalformative syndrome with a systemic involvement. At 6 months of age, he was sent to metabolic consultation because of facial dysmorphy and short stature. During the investigation it was diagnosed at the boy a growth hormone deficiency and because of his multisystemic involvement, muscle biopsy was carried out and showed reduced activity of complex II (38%) of the mitochondrial respiratory chain. Currently, the boy is under GH therapy with growth in the 5th percentile and coenzime Q10. DISCUSSION: Mitochondrial biology is one of the fastest growing areas in genetics and medicine. Disturbances in mitochondrial metabolism are now known to play a role not only in rare childhood diseases, but also in many common diseases of aging. In mitochondrial disorders, short stature is a common symptom, but its underlying lesion, growth hormone deficiency, is rarely investigated. PMID- 25781524 TI - Euprolactinemic galactorrhea secondary to domperidone treatment. AB - Milk leakage from the breast, which is known as galactorrhea, can be caused by a number of pharmacological, physical, and tumoral factors. Galactorrhea is a well known side effect of domperidone, and is usually associated with hyperprolactinemia. However, euprolactinemic galactorrhea secondary to domperidone is very rarely seen and has yet to be reported in children before. Here, we report an adolescent with euprolactinemic galactorrhea caused by domperidone. PMID- 25781525 TI - Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is characterized by irregular menses, elevated androgens, and insulin resistance. Little information is published about the treatment of adolescent PCOS. OBJECTIVES: The aim of this study was to evaluate metformin versus oral contraceptive pills (OCP) in treating adolescent PCOS. Twenty-two girls were randomized to either treatment for 6 months. The outcomes variables included body mass index (BMI) and free testosterone (FT). RESULTS: BMI decreased in all patients (metformin p=0.004, OCP p=0.045). FT decreased significantly only with OCP. Insulin resistance measures decreased in all patients but did not reach significance. The only significant difference in any of the variables between the two groups was number of menses. BMI and FT remained less than baseline for 3 months off treatment. CONCLUSIONS: Metformin and OCP have a positive effect on BMI, which persists after treatment is discontinued. FT decreased with both treatments, but only reached significance with OCP. PMID- 25781526 TI - Therapy monitoring in congenital adrenal hyperplasia by dried blood samples. AB - Careful monitoring of the therapy is crucial for patients with congenital adrenal hyperplasia (CAH) in order to prevent the effects of increased androgen production as well as life-threatening salt-wasting crisis. The key metabolite, 17alpha-hydroxyprogesterone (17-OHP) can be detected in serum, saliva or dried blood. In clinical practice there are challenges due to discomfort of venous blood sampling and complicated retrieval of saliva during infancy. Furthermore, the immunoassay method is limited in its specificity due to cross-reactions. In this observational study we prospectively examined over a period of 5 years, 20 patients with CAH due to 21-hydroxylase deficiency using standard immunoassays for serum samples (radioimmunoassay and enzyme immunoassay) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in dried blood spots. Bland Altman plots show goodness of agreement between both the methods for the desirable therapeutic concentration range of 17-OHP. LC-MS/MS is characterized by a high accuracy in the therapeutic concentration range of 17-OHP <100 nmol/L (r=0.91). Dried blood samples are convenient and reliable specimen for 17-OHP measured by LC-MS/MS. This method could be used for home monitoring of hydrocortisone replacement therapy both in salt-waster and simple virilizer CAH. PMID- 25781527 TI - Dietary intake, body composition, and physical activity among young patients with type 1 diabetes mellitus. AB - OBJECTIVE: The aim of this study was to assess dietary intake, nutritional status, body composition, and physical activity level in a group of Chilean children and adolescents with Type 1 diabetes mellitus (T1DM), compare these parameters with the recommendations of the International Society for Pediatric and Adolescent Diabetes (ISPAD), and determine the relationships between dietary intake, body composition, and diabetes control. METHODS: A total of 30 patients with T1DM (aged 15.2+/-4.0 years) were included. Dietary intake was assessed using a 92-item quantitative food frequency questionnaire. Body composition was determined using dual-energy X-ray densitometry. Physical activity was assessed by means of a survey. RESULTS: The energy intake of these patients was derived from 21.4% protein, 48% carbohydrates, and 31.2% fat. The glycosylated hemoglobin (HbA1c) was significantly correlated with fat as grams per day (r: 0.363, p<0.05) and calories per day (r: 0.364, p<0.05). The mean body fat percentage in females was 31.2% and 20.2% in males (p < 0.01) and the mean amount of physical activity was 4.5+/-2.7 h per week. CONCLUSIONS: The study patients had a higher protein intake than recommended by ISPAD. Dietary carbohydrate intake was rather low, and dietary fat intake was the same as the limits recommended by ISPAD. Diabetic control was significantly correlated with protein, carbohydrates, fat, and sodium intake. The girls in the study had a higher percentage of body fat than the standard recommendations for their age. The level of physical activity was adequate. PMID- 25781528 TI - Congenital adrenal hyperplasia in children--a survey on the current practice in the UK. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) in children varies in presentation and progression with several challenges in optimal management. Effective treatment is to achieve normal growth and development while avoiding adrenal crisis and hyperandrogenisation. AIM: Our aim was to ascertain the current practice in the UK on CAH management in children in comparison with the recommendations made by the Endocrine Society. METHODS: An online survey was emailed to the British Society of Paediatric Endocrinology (BSPED) members requesting a response from each centre regarding CAH management. RESULTS: The survey was completed by 35 out of 92 centres (38% response rate). Tertiary centres constituted 22/35, while 8/35 were district general hospitals providing tertiary services. Treatment varied among centres with 25/35 using 10-15 mg/m2/day of hydrocortisone and 21/35 of centres using 50-150 MUg/day of fludrocortisone. The frequency of clinical reviews was contentious and varied depending on the child's age and clinical status. Reviews were done 3-4 monthly in 68% and 6 monthly in 31% of centres. The frequency of investigations including 17-hydroxyprogesterone (66% 3-6 monthly; 34% yearly), testosterone/dehydroepiandrosterone sulphate (37% 6 monthly; 51% yearly), renin/aldosterone (31% 6 monthly; 69% yearly) and bone age (83% yearly, 6% 2 yearly) varied significantly among centres. Genetic counselling was provided at diagnosis in 69% of the centres while surgical (66%) and psychology (80%) input were provided on an as required basis. CONCLUSION: Our survey highlights the diversity in managing children with CAH in the UK as compared with the recommendations of the Endocrine Society. It also demonstrates inconsistent involvement of essential specialist services, which are essential for optimal management of this condition. PMID- 25781529 TI - Influence of the body weight on the onset and progression of puberty in boys. AB - BACKGROUND: Unlike in girls, the data on the relationship between pubertal development and body weight in boys are controversial. METHODS: We measured the height, body weight, body mass index (BMI), pubic hair stages, testicular volume, penis length and circumference of 4030 boys, aged between 7 and 19 years. According to their body weight, the investigated children and adolescents were divided in four groups at each age: underweight boys (BMI <12th percentile), boys with normal weight (12th-84.99th percentile), overweight boys (85th-94.99th percentile) and boys with obesity (BMI >=95th percentile), and their data were compared. RESULTS: The onset of puberty occurred when the boys' weight gained 40.33+/-9.03 kg (median 39.00) and BMI was 18.62+/-3.12 kg/m2 (median 17.80), whereas the late stage was reached at weight of 62.44+/-10.39 kg (median 61.00) and BMI 21.47+/-2.84 kg/m2 (median 21.20). Earlier maturing boys were heavier than their coevals, whereas underweight boys developed puberty later. CONCLUSIONS: The onset and progression of puberty in boys are in a significant positive relationship with weight and BMI. Moreover, in the overweight boys pubertal development begins and comes to the late stage earlier in comparison with normal weight children, whereas in those who are underweight a delay at every stage of the development is observed. PMID- 25781530 TI - Case report: long-term follow-up of a 45,X male with SHOX haploinsufficiency. AB - The 45,X disorder of sexual differentiation (DSD) is a rare disorder. We report long-term follow-up of a 5-year-old African-American male whose evaluation for short stature revealed a karyotype of 45,X der(X)t(X;Y)(p22.3;p11.2)(SRY+). Presence of the SRY (sex-determining region Y) gene resulted in his male development. His chromosome abnormality also resulted in a deletion of the SHOX (short stature homeobox-containing) gene, which partly contributed to his short stature and skeletal features. He underwent normal spontaneous pubertal development, but his final height remained compromised due to advanced bone age, non-optimal response to recombinant human growth hormone (rhGH) treatment during the period of compliance and ultimately non-compliance with rhGH therapy. To our knowledge, this is the first case report describing long-term follow-up of a 45,X male DSD which highlights the similarities and differences from Turner syndrome females. PMID- 25781531 TI - Triple A syndrome with a novel indel mutation in the AAAS gene and delayed puberty. AB - Triple A syndrome, formerly known as Allgrove syndrome, is an autosomal recessive disorder characterized clinically by adrenal insufficiency, alacrima, achalasia, and neurological abnormalities. We report a 17-year-old boy presented to the endocrine clinic with delayed puberty and a 4-year's history of fatigue and muscle weakness. He had achalasia, alacrima, and skin and mucosal hyperpigmentation. Hormonal assessment revealed isolated glucocorticoid deficiency. Clinical diagnosis of triple A syndrome was confirmed by sequencing the entire coding region including exon-intron boundaries of the AAAS gene. Analysis revealed a homozygous novel indel mutation encompassing intron 7 to intron 10 of the gene (g.16166_17813delinsTGAGGCCTGCTG; NG_016775). This is the first report of triple A syndrome in Jordan with a novel indel mutation and presenting with delayed puberty. PMID- 25781532 TI - Insulin resistance and cardiometabolic risk factors in obese children and adolescents: a hierarchical approach. AB - BACKGROUND: This study aims to globally assess the network of insulin resistance (IR)-related factors in a sample of overweight and obese Greek youths. METHODS: A total of 185 subjects were examined, and IR was quantified by homeostasis model assessment (HOMA-IR). Multivariate hierarchical approach was performed, and five distinct levels were recognized, namely, immutable demographic features and early life parameters, current anthropometric measures, IR, unfavorable clinical conditions, and social parameters. Two analyses were performed based on HOMA-IR cut-off values (3.16 and, as an alternative, 3.99). RESULTS: Obesity was associated with IR (adjusted OR=3.19, 95% CI: 1.12-9.09). IR steadily predicted low HDL (adjusted OR=5.75, 95% CI: 1.58-20.87), hypertriglyceridemia (adjusted OR=10.28, 95% CI: 1.18-89.55), and systolic hypertension. At the alternative analysis, IR was also associated with older age, older age at menarche, hyperuricemia, and low school grades. CONCLUSION: Emerging on the grounds of obesity, IR confers risks for dyslipidemia and hypertension at a relatively early age. Along with weight loss, interventions targeted at IR are required to prevent cardiometabolic risk in adolescence. PMID- 25781533 TI - Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene. AB - BACKGROUND: Hyperinsulinism-hyperammonemia syndrome (HI/HA) is a rare autosomal dominant disorder presenting with hypoglycemia and hyperammonemia. It is caused by activating mutations in the GLUD1 gene. CASE REPORTS: Three patients from two different centers, a 14-month-old female, a 28-year-old female (mother of the first patient) from Toronto and an unrelated 2.5-year-old male from Vienna, presented with multiple episodes of seizures associated with hypoglycemia. RESULTS: All patients had mild to moderate hypoglycemia, inappropriate insulin levels and mild hyperammonemia, thus suggesting a disorder of glutamate dehydrogenase (GDH). Molecular genetic testing of the GLUD1 gene identified heterozygous mutations in all patients (patient 1 and her mother a novel c.1526G>C mutation; patient 3 a known c.809C>G mutation). CONCLUSION: We present three new patients with GDH caused by heterozygous mutation in the GLUD1 gene. Mild hyperammonemia and inappropriately elevated insulin levels should suggest a GLUD1 mutation. Early onset hypoglycemia associated with seizures, and especially a good response to diazoxide treatment, should include this disorder in the differential diagnosis of hyperinsulinemic hypoglycemia. PMID- 25781534 TI - Successful use of continuous subcutaneous hydrocortisone infusion after bilateral adrenalectomy secondary to bilateral pheochromocytoma. AB - We report the use of continuous subcutaneous hydrocortisone infusion in an adolescent patient with primary adrenal insufficiency. This novel hydrocortisone delivery method proved to be a feasible, well-tolerated and safe option for selected patients with poor response to conventional therapy. PMID- 25781535 TI - Monitoring gonadotropin-releasing hormone analogue (GnRHa) treatment in girls with central precocious puberty: a comparison of four methods. AB - AIM: The objective of this study was to validate basal, post-gonadotropin releasing hormone analogue (post-GnRHa) and first-voided urinary LH (ULH) as alternatives to an LHRH stimulation test in monitoring treatment efficacy in central precocious puberty (CPP). METHODS: Seventeen girls with CPP were followed over 22.5+/-9.1 months during GnRHa (triptorelin) treatment. ULH and post-GnRHa LH levels were obtained every 4 months before and 24 h after GnRHa administration, respectively, along with clinical and bone age (BA) evaluation. LHRH stimulation tests were performed annually. RESULTS: A total of 36 LHRH stimulation tests demonstrated adequate suppression with a peak LH of 0.57+/-0.33 IU/L. The corresponding basal LH was 0.27+/-0.16 IU/L. Ninety post-GnRHa LH measurements were similar to LHRH-stimulated LH levels (0.56+/-0.31 IU/L), whereas 8% of ULH levels were above prepubertal threshold. Fourteen episodes of growth acceleration and ten episodes of BA advancement resolved without treatment modification. CONCLUSION: Suppressed basal and post-GnRHa LH levels indicate adequate suppression of puberty. Clinical breakthroughs during treatment are transient and resolved spontaneously. PMID- 25781536 TI - Diabetes mellitus in children and adolescents - a global epidemic which has become neglected. PMID- 25781537 TI - The effect of a home-based strength training program on type 2 diabetes risk in obese Latino boys. AB - OBJECTIVE: To determine the effects of a home-based strength training (HBST) intervention on insulin sensitivity (SI), compensatory acute insulin response and beta-cell function, body composition measures, and maximum strength in obese Latino boys. METHODS: A total of 26 obese Latino males aged between 14 and 18 years were randomized to either a twice-weekly (n=15) or a control group (C; n=15) for 16 weeks. HBST for 16 weeks, composed of two 1-h sessions per week. Outcome measures were assessed pre-and post-intervention/control condition and included SI, acute insulin response to glucose (AIR) and disposition index (DI), fasting glucose, 2-h glucose, body composition using waist-hip circumferences, body mass index (BMI), dual energy X-ray absorptiometry (DEXA) scan, blood pressure, and strength by 1-repetition maximum. A repeated measures GLM was used to assess differences in changes in outcome measures, between the C and the HBST groups. RESULTS: There were no significant overall intervention effects on any of the outcome variables (p<0.05). CONCLUSION: These results suggest that an HBST does not improve SI, maximal strength or decrease adiposity in obese Latino boys. PMID- 25781538 TI - Detection of inborn errors of metabolism using GC-MS: over 3 years of experience in southern China. AB - BACKGROUND: Inborn errors of metabolism (IEM) have been detected worldwide using gas chromatography mass spectrometry (GC-MS) since the 1980s, but few related reports exist on the incidence, spectrum, and clinical presentation features of IEM in southern China. METHOD: From January 2009 to March 2012, 16,075 urine samples were collected from patients who were highly suspected of having IEM in Guangzhou Women and Children's Medical Center. The specimens were evaluated using GC-MS. RESULTS: We diagnosed 303 cases of IEM by urine GC-MS analysis, including 197 cases with amino acid disorders, 86 cases with organic acidurias (OAs), 10 cases with fatty acid oxidative (FAO) disorders, and 10 cases with peroxisomal disorders. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) was the most common (153 cases), followed by methylmalonic aciduria (48 cases), urea cycle disorders (21 cases), phenylketonuria (20 cases), propionic aciduria (11 cases), X-linked adrenoleukodystrophy (10 cases), multiple carboxylase deficiency (8 cases), glutaric aciduria type I (7 cases), isovaleric aciduria (6 cases), glutaric aciduria type II (4 cases), short-chain acyl-CoA dehydrogenase deficiency (4 cases), 3-hydroxy-3-methylglutaric aciduria (3 cases), maple syrup urine disease (2 cases), very long-chain acyl-CoA dehydrogenase deficiency (1 case), malonic aciduria (1 case), mevalonic aciduria (1 case), Canavan disease (1 case), lysine protein intolerance (1 case), and medium-chain acyl-CoA dehydrogenase deficiency (1 case). The clinical and laboratory features of IEM are neurologic signs, jaundice, metabolic acidosis, ketotic hypoglycemia, and hyperammonemia. CONCLUSION: In our study, GC-MS provided a diagnostic clue to OAs, amino acid disorders, FAO, and peroxisomal disorders. Urease pretreatment is useful for the diagnosis of NICCD. In southern China, the majority of IEM were amino acid disorders and organic acid disorders. FAO disorders were relatively rare, which we need to investigate further. PMID- 25781539 TI - Evaluating the functional state of adult-born neurons in the adult dentate gyrus of the hippocampus: from birth to functional integration. AB - Hippocampal neurogenesis occurs in the adult brain in various species, including humans. A compelling question that arose when neurogenesis was accepted to occur in the adult dentate gyrus (DG) is whether new neurons become functionally relevant over time, which is key for interpreting their potential contributions to synaptic circuitry. The functional state of adult-born neurons has been evaluated using various methodological approaches, which have, in turn, yielded seemingly conflicting results regarding the timing of maturation and functional integration. Here, we review the contributions of different methodological approaches to addressing the maturation process of adult-born neurons and their functional state, discussing the contributions and limitations of each method. We aim to provide a framework for interpreting results based on the approaches currently used in neuroscience for evaluating functional integration. As shown by the experimental evidence, adult-born neurons are prone to respond from early stages, even when they are not yet fully integrated into circuits. The ongoing integration process for the newborn neurons is characterised by different features. However, they may contribute differently to the network depending on their maturation stage. When combined, the strategies used to date convey a comprehensive view of the functional development of newly born neurons while providing a framework for approaching the critical time at which new neurons become functionally integrated and influence brain function. PMID- 25781540 TI - Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation. AB - Host T cell activation, a key step in obtaining adaptive immunity against pathogens, is initiated by the binding of the T cell receptor to a foreign antigenic peptide presented by the major histocompatibility complex on the surface of an antigen-presenting cell and, consequently, formation of an immunological synapse. Within the immunological synapse, the engagement of the T cell receptor in cooperation with simultaneous ligation of co-stimulatory molecules induces a precisely organized cascade of signaling events and pathways that regulate clonal expansion and differentiation of naive T cells into effector T cells contributing to pathogen clearance. The biochemical changes that underlie T cell activation and differentiation, however, not only involve proteins but also lipids. In particular, catabolic cleavage of sphingomyelin generating ceramide can substantially influence functional responses in cells of the immune system. Changes in sphingomyelin and ceramide content have been reported to directly impact on membrane physiology, thus modifying signal transmission and interfering with diverse aspects of T cell activity. In this review we will focus on sphingomyelin breakdown/ceramide generation in T cells with regard to their function and development of T cell-mediated immunity. PMID- 25781541 TI - Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts. AB - Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors. PMID- 25781542 TI - Plant-specific CC-type glutaredoxins: functions in developmental processes and stress responses. AB - Glutaredoxins (GRXs) are small oxidoreductases of the thioredoxin family proteins that can either regulate the thiol redox state of proteins or are linked to iron metabolism because of their ability to incorporate iron-sulfur [2Fe-2S] clusters. Here we review recent research on a land plant-specific class of GRX-like proteins, which are characterized by the conserved CC motif in the active centre. Loss-of-function mutants of CC-type GRXs in Arabidopsis (also named ROXYs), maize, and rice have unraveled a role in floral development, including regulation of organ primordia initiation, control of organ identity gene expression, and progression into meiosis in the male germ line. Other CC-type GRXs play a role in stress responses, most likely through their capacity to regulate nuclear gene expression. Consistently, CC-type GRXs, physically and genetically interact with individual members of the TGA transcription factor family. One of the challenges in the future is to unravel whether ROXYs control the redox state of TGA factors or other yet unknown target proteins or whether they regulate gene expression through other processes. Other intriguing questions concern the original function of the first CC-type GRXs in basal land plants and their potential contribution to the extremely successful radiation of angiosperms. PMID- 25781544 TI - NT-proBNP levels and their relationship with systemic ventricular impairment in adult patients with transposition of the great arteries long after Mustard or Senning procedure. AB - BACKGROUND: The aim of the study was to investigate serum NT-proBNP levels in adult patients with transposition of the great arteries (d-TGA) corrected by atrial switch procedures (Mustard or Senning) operation and to assess the relationship with ventricular impairment and NYHA class. METHODS: Serum NT-proBNP levels were measured in a group of 81 consecutive adult patients (59 males, mean age 27 years and 22 females, mean age 28 years) with transposition of the great arteries (TGA) after surgical correction in childhood, and in a control group of 25 healthy individuals (16 males, mean age 32 years, and 9 females, mean age 29 years). Age-matched correlation of NT-proBNP concentrations in TGA patients after Mustard or Senning correction was performed, but this correlation was considered not significant (p=0.08). RESULTS: Concentrations of NT-proBNP in patients with TGA were significantly elevated compared to the control group of healthy individuals (203 ng/L vs. 41 ng/L, p<0.0001). Patients after the Mustard repair had significantly higher NT-proBNP values than patients after the Senning operation (234 ng/L vs. 148 ng/L, p=0.0023). NT-proBNP correlated negatively with the systemic right ventricular ejection fraction with the greatest significance in patients after Mustard correction (r=-0.32, p<0.0001). The concentration of NT proBNP was also associated with NYHA functional class (p=0.0035) with the greatest significance in patients with Mustard correction (p=0.028). CONCLUSIONS: Elevated levels of NT-proBNP appear to be a useful tool in assessing heart failure in patients with transposition of the great arteries after atrial switch correction. PMID- 25781545 TI - Validation of CFTR intronic variants identified during cystic fibrosis population screening by a minigene splicing assay. AB - BACKGROUND: Cystic fibrosis, caused by mutations of the CFTR gene, is the most common autosomal recessive condition in the European population and there are specific screening programs aimed at investigating healthy carriers. They are usually articulated in two steps: initially individuals are screened with a panel of the 20-50 most common CFTR mutations; the second step is offered to partners of carriers who were found negative at the first test and consists in the analysis of the entire CFTR gene. This strategy provides high sensitivity, however, it often identifies novel variants (especially in introns) of unknown significance. Establishing the pathogenicity of these variants of the CFTR gene is not a simple task. METHODS: We have examined five CFTR intronic variants of unclear significance (c.274-6T>C, c.744-6T>G, c.1117-64G>A, c.2620-26A>G, and c.3468+51C>A) using a functional splicing assay based on hybrid minigenes. RESULTS: Four out of five variants (including c.2620-26A>G which was previously reported as a possible splice-site mutation) did not alter the correct splicing of the minigene and are likely to be neutral polymorphisms, whereas c.744-6T>G caused complete skipping of CFTR exon 7 and should be therefore regarded as a pathogenic CFTR mutation. CONCLUSIONS: Hybrid minigenes assay are a simple and rapid tool to evaluate the effects of intronic variants without the need of analyzing patient's mRNA, and are particularly suited to analyze variants identified during population screenings. PMID- 25781546 TI - LC-MS/MS method for hepcidin-25 measurement in human and mouse serum: clinical and research implications in iron disorders. AB - BACKGROUND: The peptide hepcidin plays a central role in regulating dietary iron absorption and body iron distribution. This 25-amino acid hormone is produced and secreted predominantly by hepatocytes. Hepcidin has been suggested as a promising diagnostic marker for iron-related disorders. However, its accurate quantification for clinical use remains so far challenging. In this report we describe a highly specific and quantitative serum hepcidin method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). MATERIAL: The analytical validation included the determination of the limit of detection, of quantification, repeatability, reproducibility and linearity. This assay was developed for human and mouse hepcidin. The human assay was performed on serum patients with unexplained microcytic anemia. We applied our LC-MS/MS method for quantifying hepcidin-1 in mouse in various conditions: inflammation, hemolytic anemia, Hamp-1, Hjv and Hfe KO mice. RESULTS: We show that the LC-MS/MS is suitable for accurate determination of hepcidin-25 in clinical samples, thereby representing a useful tool for the clinical diagnosis and follow-up of iron related diseases. In mouse, a strong correlation between hepatic Hamp-1 mRNA expression and serum hepcidin-1 levels was found (r=0.88; p=0.0002) and the expected variations in mouse models of iron disorders were observed. CONCLUSIONS: Therefore, we propose this adaptive LC-MS/MS method as a suitable method for accurate determination of hepcidin-25 in clinical samples and as a major tool contributing to the clinical diagnosis, follow-up and management of iron-related disorders. It also opens new avenues to measure hepcidin in animal models without interspecies antigenic limitations. PMID- 25781547 TI - ABCB1 (MDR-1) pharmacogenetics of tacrolimus in renal transplanted patients: a Next Generation Sequencing approach. AB - BACKGROUND: A CYP3A5 gene polymorphism is the main determinant of Tacrolimus (Tac) dose requirements among renal transplanted patients. In spite of the utility of CYP3A5 genotyping to predict the Tac-dose, many patients exhibit an out of range blood Tac level and it is thus likely that other genes/polymorphisms contribute to define Tac bioavailability. To address this issue we searched for coding sequence variants in the ABCB1/MDR1 gene in renal transplanted patients treated with Tac and who had out of the range blood levels. METHODS: We studied 100 renal transplanted patients treated with Tac, 60 of whom had Tac blood levels below (n=39) and above (n=21) the target range (10-15 ng/mL) at 1 week post transplant. The DNA was subjected to multiplex amplification followed by massive parallel semiconductor sequencing in the Ion Torrent personal genome machine. RESULTS: We found four missense changes, all reported and present in cases above and below the blood Tac target. In addition, we did not find differences in the allele and genotype frequencies for the common rs1045642 polymorphism (p.I1145I) between the groups. CONCLUSIONS: Our results suggested that the ABCB1 variants had no effect on the risk of showing out of range Tac blood levels among renal transplanted patients. PMID- 25781548 TI - Impact of stopping vitamin K antagonist therapy on concentrations of dephospho uncarboxylated Matrix Gla protein. PMID- 25781549 TI - Adiposopathy in cancer and (cardio)metabolic diseases: an endocrine approach - part 2. PMID- 25781551 TI - Local adipocyte cancer cell paracrine loop: can "sick fat" be more detrimental? AB - This review article focuses on the emerging role of tumor resident adipocytes. It provides in vitro and in vivo evidence that they are essential for cancer development/progression. In addition to systemic effects, their tumor-promoting impact is dependent on local functions, notably via a complex adipocyte cancer cell paracrine loop (ACCPL). Indeed, this event leads to dramatic phenotypic and/or functional modifications of both cell types as well as of the extracellular matrix. Adipocytes undergo delipidation leading to adipocytes/cancer-associated adipocytes/cancer-associated fibroblasts de differentiation processes. In turn, cancer cell aggressiveness is exacerbated through increased proliferation, migration, and invasion properties. This is accompanied by intense tissue remodeling, conducting to the occurrence of the tumor stroma. The molecular pathways involved in ACCPL remain largely unknown. Nevertheless, several clues are starting to emerge. Moreover, obesity is currently a sign of increased risk and poor prognosis in human carcinomas. How adiposopathy might impact tumors and specifically the ACCPL is still under investigation. However, available experimental, epidemiological, and clinical data allow to draw some directions. Interestingly, there are numerous similarities between the ACCPL-induced and obesity-related molecular alterations. It might, therefore, be hypothesized that obesity provides a "constitutively active" local permissive environment for cancer cells. Improving our knowledge about ACCPL in both lean and obese patients remains a challenging task. Indeed, deciphering the cellular and molecular mechanisms behind ACCPL might provide new targets for improving diagnosis/prognosis and the design of innovative therapeutic strategies, and even, in case of obesity, for preventing cancer. PMID- 25781552 TI - Adipose tissue, obesity and adipokines: role in cancer promotion. AB - Adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term "adiposopathy" is used to describe this promotion of pathogenic adipocytes and associated adipose - elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of well-characterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence. PMID- 25781553 TI - Obesity-related proliferative diseases: the interaction between adipose tissue and estrogens in post-menopausal women. AB - Epidemiological studies have shown that overweight and cancer are closely related, even though obesity alone does not apparently heighten cancer risk by the same amount. Given the low overall risk of all cancers with obesity, it is unlikely that obesity alone causes cancer, but should instead be considered as a tumor promoter. There are three main hypotheses that could explain how obesity might contribute to cancer development and growth: the inflammatory cytokines from adipose tissue hypothesis, the insulin resistance and hyperinsulinemia hypothesis, and the unopposed estrogen cancer hypothesis. The link between obesity and cancer is that adipocytes constitute a major component of the tumor microenvironment for breast and abdominally metastasizing cancers, promoting tumor growth. This review will mainly focus attention on the relationship between adipose tissue, estrogens, and cancer risk. PMID- 25781550 TI - Adipose tissue dysfunction and its effects on tumor metabolism. AB - Growing by an alarming rate in the Western world, obesity has become a condition associated with a multitude of diseases such as diabetes, metabolic syndrome and various cancers. Generally viewed as an abnormal accumulation of hypertrophied adipocytes, obesity is also a poor prognostic factor for recurrence and chemoresistance in cancer patients. With more than two-thirds of the adult population in the United States considered clinically overweight or obese, it is critical that the relationship between obesity and cancer is further emphasized and elucidated. Adipocytes are highly metabolically active cells, which, through release of adipokines and cytokines and activation of endocrine and paracrine pathways, affect processes in neighboring and distant cells, altering their normal homeostasis. This work will examine specifically how adipocyte-derived factors regulate the cellular metabolism of malignant cells within the tumor niche. Briefly, tumor cells undergo metabolic pressure towards a more glycolytic and hypoxic state through a variety of metabolic regulators and signaling pathways, i.e., phosphoinositol-3 kinase (PI3K), hypoxia-inducible factor-1 alpha (HIF-1alpha), and c-MYC signaling. Enhanced glycolysis and high lactate production are hallmarks of tumor progression largely because of a process known as the Warburg effect. Herein, we review the latest literature pertaining to the body of work on the interactions between adipose and tumor cells, and underlining the changes in cancer cell metabolism that have been targeted by the currently available treatments. PMID- 25781555 TI - Adiposity and metabolic dysfunction in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among reproductive-age women and is associated with a high risk for metabolic disorders. Adiposity and insulin resistance are two prevalent conditions in PCOS and the likely culprits for the heightened metabolic risk. Up to 60% of women with PCOS are considered to be overweight or obese, and even among non-obese women with PCOS there is an increased accumulation of adipose tissue in abdominal depots. Insulin resistance in PCOS is unique and independent of obesity, as even non-obese women with this condition are frequently insulin resistant. However, obesity substantially aggravates the insulin resistance and the metabolic and reproductive abnormalities in women with PCOS. Recently, it has been shown that many aspects of adipose tissue function in PCOS are abnormal, and these abnormalities likely predispose to development of insulin resistance even in the absence of obesity. This review provides an overview of these abnormalities and their impact on development of metabolic disorders. At the end, an overview of the therapeutic options for management of adiposity and its complications in PCOS are discussed. PMID- 25781554 TI - Molecular cues on obesity signals, tumor markers and endometrial cancer. AB - Tumor markers are important tools for early diagnosis, prognosis, therapy response and endometrial cancer monitoring. A large number of molecular and pathologic markers have been described in types I and II endometrial cancers, which has served to define the main oncogenic, epidemiological, genetic, clinical and histopathological features. Ongoing attempts to stratify biological markers of endometrial cancer are presented. However, data on changes in tumor marker profiles in obesity-related endometrial cancer are scarce. Obesity is a pandemic in Western countries that has an important impact on endometrial cancers, albeit through not very well-defined mechanisms. Although endometrial cancer is more common in Caucasian women, higher mortality is found in African Americans who also show higher incidence of obesity. Here, we describe how obesity signals (estrogen, leptin, leptin induced-molecules, Notch; cytokines and growth factors) could affect endometrial cancer. Leptin signaling and its crosstalk may be associated to the more aggressive and poor prognosis type II endometrial cancer, which affects more postmenopausal and African-American women. In this regard, studies on expression of novel molecular markers (Notch, interleukin-1 and leptin crosstalk outcome) may provide essential clues for detection, prevention, treatment and prognosis. PMID- 25781556 TI - Heat shock proteins in obesity: links to cardiovascular disease. AB - Adipose tissue expansion is associated with adipocyte dysfunction and increased inflammatory processes. In the obese state, adipose tissue is characterized by an impaired intracellular stress defense system and dysbalanced heat shock response. Several members of the heat shock protein (HSP) family have been identified as novel adipokines released upon cellular stress, which might be a molecular link from adipose tissue inflammation to the cardiovascular system. Therefore, this review aims at summarizing and discussing our recent knowledge on HSPs in relation to obesity and their potential links to cardiovascular disease. Of particular importance/interest are two members of the HSP family, HSP60 and heme oxygenase 1 (HO-1), which have been well described as adipokines, and studied in the context of obesity and cardiovascular disease. HSP60 is regarded as a novel molecular link between adipose tissue inflammation and obesity-associated insulin resistance. The role of HO-1 induction in the obese state is well-documented, but a causal relationship between increased HO-1 levels and obesity-associated metabolic diseases is still controversial. Both HSP60 and HO-1 are also forthcoming targets for the treatment of cardiovascular disease, and the current knowledge will also be discussed in this review. PMID- 25781557 TI - Visceral adiposopathy: a vascular perspective. AB - Obesity has emerged as one of the most critical health care problems globally that is associated with the development of insulin resistance, type 2 diabetes mellitus, metabolic dysfunction and cardiovascular disease. Central adiposity with intra-abdominal deposition of visceral fat, in particular, has been closely linked to cardiometabolic consequences of obesity. Increasing epidemiological, clinical and experimental data suggest that both adipose tissue quantity and perturbations in its quality termed "adiposopathy" contribute to mechanisms of cardiometabolic disease. The current review discusses regional differences in adipose tissue characteristics and highlights profound abnormalities in vascular endothelial function and angiogenesis that are manifest within the visceral adipose tissue milieu of obese individuals. Clinical data demonstrate up regulation of pro-inflammatory and pro-atherosclerotic mediators in dysfunctional adipose tissue that may support pathological vascular changes not only locally in fat but also in multiple organ systems, including coronary and peripheral circulations, potentially contributing to mechanisms of obesity-related cardiovascular disease. PMID- 25781558 TI - Oxasqualenoids from Laurencia viridis: Combined Spectroscopic-Computational Analysis and Antifouling Potential. AB - The chemical study of the red alga Laurencia viridis has led to the isolation of four new polyether triterpenoids: 28-hydroxysaiyacenol B (2), saiyacenol C (3), 15,16-epoxythyrsiferol A (4), and 15,16-epoxythyrsiferol B (5). The structures of 2 and 3 were established mainly by NMR data analysis and comparison with the well known metabolite dehydrothyrsiferol (1). However, due to the existence of a nonprotonated carbon within the epoxide functionality, stereochemical assignments in 4 and 5 required an in-depth structural study that included NOESY data, J based configuration analysis, comparison with synthetic models, and DFT calculations. The biological activities of the new metabolites and other related oxasqualenoids were evaluated for the first time against a panel of relevant biofouling marine organisms, and structure-activity conclusions were obtained. PMID- 25781560 TI - Structural changes of block copolymers with bi-modal orientation under fast cyclical stretching as observed by synchrotron SAXS. AB - Load-bearing tissues are composite materials that depend strongly on anisotropic fibre arrangement to maximise performance. One such tissue is the heart valve, with orthogonally arranged fibrosa and ventricularis layers. Their function is to maintain mechanical stress while being resilient. It is postulated that while one layer bears the applied stress, the orthogonal layer helps to regenerate the microstructure when the load is released. The present paper describes changes in the microstructure of a block copolymer with cylindrical morphology, having a bio inspired microstructure of anisotropic orthogonally oriented layers, under uniaxial strain. To allow structural observations during fast deformation, equivalent to the real heart valve operation, we used a synchrotron X-ray source and recorded 2D SAXS patterns in only 1 ms per frame. The deformation behaviour of the composite microstructure has been reported for two arrangements of the cylinders in skin and core layers. The behaviour is very different to that observed either for uniaxially oriented or isotropic samples. Deformation is far from being affine. Cylinders aligned in the direction of stretch show fragmentation, but complete recovery of the spacing between cylinders on removal of the load. Those oriented perpendicular to the direction of stretch incline at an angle of approximately 25 degrees to their original direction during load. PMID- 25781561 TI - Nasal mucosa narrow band imaging in granulomatosis with polyangiitis (Wegener granulomatosis): A preliminary study. AB - BACKGROUND: Narrow band imaging (NBI) endoscopy is a technique that allows for real-time visualization of mucosal and submucosal vascular patterns. OBJECTIVE: Because granulomatosis with polyangiitis (GPA) (Wegener granulomatosis) is an autoimmune disease defined by vascular inflammation, we examined patients with GPA and with NBI to evaluate whether disease-specific mucosal vascular patterns were present. To the best of our knowledge, the use of NBI endoscopy for assessment of an immune system disease such as GPA has never been previously attempted. METHODS: We conducted a prospective observational study by performing an endoscopic evaluation of upper airways with NBI on patients diagnosed with GPA; on patients with symptoms and signs suggestive for GPA, who were scheduled to undergo nasal biopsy to confirm diagnosis; on patients affected by chronic rhinosinusitis with nasal polyps; and on healthy controls. RESULTS: We enrolled 69 patients. NBI vascular patterns in patients with GPA were consistently and recognizably different from healthy mucosal patterns in 53% of our cases. In patients with GPA, biopsy and NBI results were for the most part comparable, except for three cases. CONCLUSION: Nasal mucosa NBI endoscopy can be considered a promising rapid and noninvasive live imaging technique for nasal mucosa GPA that, based on further study, could become a supplementary diagnostic tool in the complex workup of GPA and vasculitis. PMID- 25781563 TI - Viral cell-to-cell transmission--why less is more. AB - During cell-to-cell transmission, only a minute fraction of viral genomes contribute to the progeny. A new study reveals the underlying stochastic processes and explains why these are advantageous for the virus. PMID- 25781564 TI - Murine Inhibin alpha-Subunit Haploinsufficiency Causes Transient Abnormalities in Prepubertal Testis Development Followed by Adult Testicular Decline. AB - Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-alpha gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-alpha concentrations in adult Inha+/- mice were approximately 33% lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11% larger than wild type and supported 44% greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27% reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-alpha subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function. PMID- 25781566 TI - Revision of the orb-weaving spider genus Verrucosa McCook, 1888 (Araneae, Araneidae). AB - The araneid spider genus Verrucosa McCook, 1888 is revised. Five of the seven previously known species, V. arenata (Walckenaer, 1841), V. lampra Soares & Camargo, 1948, V. meridionalis (Keyserling, 1892), V. undecimvariolata (O. Pickard-Cambridge, 1889) and V. zebra (Keyserling, 1892), are redescribed and illustrated. In addition, 37 new species of Verrucosa from the Neotropical region are described and illustrated: V. cachimbo n. sp., V. tarapoa n. sp., V. scapofracta n. sp., V. carara n. sp., V. latigastra n. sp., V. guatopo n. sp., V. cuyuni n. sp., V. benavidesae n. sp., V. rancho n. sp., V. excavata n. sp., V. meta n. sp., V. levii n. sp., V. chanchamayo n. sp., V. manauara n. sp., V. brachiscapa n. sp., V. macarena n. sp., V. pedrera n. sp., V. lata n. sp., V. galianoae n. sp., V. suaita n. sp., V. coroico n. sp., V. florezi n. sp., V. hoferi n. sp., V. caninde n. sp., V. opon n. sp., V. silvae n. sp., V. avilesae n. sp., V. tuberculata n. sp., V. alvarengai n. sp., V. apuela n. sp., V. bartica n. sp., V. cajamarca n. sp., V. canje n. sp., V. cuyabenoensis n. sp., V. sergipana n. sp., V. simla n. sp. and V. rhea n. sp. Mahadiva reticulata O. P. Cambridge, 1889 is removed from the synonymy of Verrucosa arenata (Walckenaer, 1841) and is recognized as a valid species, Verrucosa reticulata. Araneus cylicophorus Badcock, 1932 is transferred to Verrucosa by Mello-Leitao (1946) removed from the synonymy of Verrucosa meridionalis (Keyserling, 1892) and recognized as a valid species. The male of Verrucosa meridionalis (Keyserling, 1892) is described for the first time. Distributional maps are provided for all species. PMID- 25781567 TI - Systematic revision of the genus Calligrapha Chevrolat (Coleoptera: Chrysomelidae, Chrysomelinae) in Central America: The group of Calligrapha argus Stal. AB - Calligrapha Chevrolat is a large American leaf beetle genus of imprecise taxonomic boundaries. Most species occur in Central and South America where they have not been subject to modern systematic revisions. This work is the first attempt to clarify the systematics of the group by focusing on a relatively diverse species group well characterized from a morphological standpoint: the group of C. argus Stal. I provide a pragmatic identification key for major lineages in Calligrapha, highlighting a potentially useful character for supra specific rank systematics within this genus, namely the shape of the distal end of the flagellum in the penis. This key helps recognizing the C. argus species group as one with species having a single spot enclosed by humeral lunule and a complete arcuate band, laterally confluent with subsutural stripe (except in C. elegantula Jacoby), deep hypomeral furrow and with characteristic ventral carving at apex of flagellum, as major distinguishing features. The species group is subdivided into fourteen species, whereby one previously described taxon, C. famularis Stal, is subordinated as subspecies of C. geographica Stal stat. nov., and two new species from southern Mexico and Guatemala are described: C. anabelae sp. nov. and C. catarinae sp. nov. An identification key for all the species in the group is provided, as well as collection data for the approximately 2,100 specimens determined for this work and distribution maps based on these collection data. The group is centred in the Caribbean Mesoamerican biogeographic domain, with two species reaching the California-Rocky Mountain domain to the north (C. ancoralis Stal and C. diversa Stal), and three species reaching the Caribbean Northwest-South American domain to the south (C. argus Stal, C. diversa Stal and C. simillima Stal). PMID- 25781565 TI - Progesterone receptor transcriptome and cistrome in decidualized human endometrial stromal cells. AB - Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma that is required to establish and support pregnancy. Progesterone acting via its nuclear receptor, the progesterone receptor (PGR), is a critical regulator of decidualization and is known to interact with certain members of the activator protein-1 (AP-1) family in the regulation of transcription. In this study, we identified the cistrome and transcriptome of PGR and identified the AP-1 factors FOSL2 and JUN to be regulated by PGR and important in the decidualization process. Direct targets of PGR were identified by integrating gene expression data from RNA sequencing with the whole-genome binding profile of PGR determined by chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in primary human endometrial stromal cells exposed to 17beta-estradiol, medroxyprogesterone acetate, and cAMP to promote in vitro decidualization. Ablation of FOSL2 and JUN attenuates the induction of 2 decidual marker genes, IGFBP1 and PRL. ChIP-seq analysis of genomic binding revealed that FOSL2 is bound in proximity to 8586 distinct genes, including nearly 80% of genes bound by PGR. A comprehensive assessment of the PGR-dependent decidual transcriptome integrated with the genomic binding of PGR identified FOSL2 as a potentially important transcriptional coregulator of PGR via direct interaction with regulatory regions of genes actively regulated during decidualization. PMID- 25781568 TI - Annotated zoogeography of non-marine Tardigrada. Part II: South America. AB - This paper is the second monograph of nine that describes the global records of limno-terrestrial water bears (Tardigrada). Here, we provide a comprehensive list of non-marine tardigrades recorded from South America, providing an updated and revised taxonomy accompanied by geographic co-ordinates, habitat, and biogeographic comments. It is hoped this work will serve as a reference point and background for further zoogeographical and taxonomical studies. PMID- 25781569 TI - Genera of Pentatomidae (Hemiptera: Pentatomoidea) from south India--an illustrated key to genera and checklist of species. AB - Family Pentatomidae is represented by four subfamilies (Asopinae, Pentatominae, Phyllocephalinae and Podopinae) and 86 genera in south India. Pentatominae are the dominant group represented by 29 tribes and 72 genera. An illustrated key including the habitus of majority of genera as well as illustrations of important diagnostic features are given for the subfamilies, tribes and genera occurring in south India. In addition, a key to families of Pentatomoidea and a checklist of species of Pentatomidae occurring in south India are also included. PMID- 25781570 TI - Blood management in total hip replacement: an analysis of factors associated with allogenic blood transfusion. AB - BACKGROUND: The aim of this study was to audit the blood transfusion practice throughout the Epworth Healthcare Hospitals for patients undergoing primary total hip replacement (THR). We determined if blood-saving techniques were having an impact on the risk of allogenic blood transfusion and which patients were at risk of receiving allogenic blood transfusion. METHODS: This study uses a retrospective audit of 787 patients who had undergone primary THR surgery at three Melbourne hospitals: Epworth Richmond, Epworth Eastern and Epworth Freemasons in 2010. Patient demographics, transfusion requirements and blood conserving techniques were recorded. RESULTS: One hundred and eighty (23%) patients received allogenic blood transfusion and 18 (2.3%) patients received autologous blood transfusion. On multivariate analysis, preoperative anaemia (odds ratio (OR) 4.7, P < 0.0001), female gender (OR 3.1, P < 0.0001) and patient age (OR 1.07 per year of age increase, P < 0.0001) were shown to be significantly associated with higher risk of allogenic blood transfusion. Use of spinal anaesthetic was found to be associated with lower risk of transfusion (OR 0.6, P = 0.0180) compared with general anaesthetic alone. Cell saver, acute normovolaemic haemodilution and re-infusion drain tube usage did not have a significant impact on reducing the risk of allogenic blood transfusion. CONCLUSION: Identification of patients at risk of blood transfusion, correction of preoperative anaemia and a restrictive transfusion policy are important factors to consider in effective perioperative blood management. PMID- 25781571 TI - Genetics: Stromal signatures drive the oncogenic phenotype of colorectal cancer. PMID- 25781573 TI - Immunotherapy: The development of immunotherapy in urothelial bladder cancer. PMID- 25781574 TI - Lung cancer: Driver-mutation-dependent stratification: learning from STAT3. PMID- 25781575 TI - Genetics: CUP: discovering genetic opportunities. PMID- 25781572 TI - Genomics in acute lymphoblastic leukaemia: insights and treatment implications. AB - Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer and an important cause of morbidity from haematological malignancies in adults. In the past several years, we have witnessed major advances in the understanding of the genetic basis of ALL. Genome-wide profiling studies, including microarray analysis and genome sequencing, have helped identify multiple key cellular pathways that are frequently mutated in ALL such as lymphoid development, tumour suppression, cytokine receptors, kinase and Ras signalling, and chromatin remodeling. These studies have characterized new subtypes of ALL, notably Philadelphia chromosome-like ALL, which is a high-risk subtype characterized by a diverse range of alterations that activate cytokine receptors or tyrosine kinases amenable to inhibition with approved tyrosine kinase inhibitors. Genomic profiling has also enabled the identification of inherited genetic variants of ALL that influence the risk of leukaemia development, and characterization of the relationship between genetic variants, clonal heterogeneity and the risk of relapse. Many of these findings are of direct clinical relevance and ongoing studies implementing clinical sequencing in leukaemia diagnosis and management have great potential to improve the outcome of patients with high-risk ALL. PMID- 25781576 TI - Ki67--no evidence for its use in node-positive breast cancer. AB - The expression of Ki67 in breast cancer has been associated with the luminal B phenotype, a high risk of relapse, and likelihood of good response to neoadjuvant chemotherapy. Several guidelines propose assays to determine Ki67 expression levels to select which patients with early stage breast cancer and 1-3 positive axillary nodes should not receive adjuvant chemotherapy. We discuss why oncologists should not rely on the use of this biomarker for patients with early stage breast cancer and only 1-3 positive axillary nodes. First, Ki67 staining lacks analytical validity. Second, the performance of the biomarker for prognostic purposes is poor, with no compelling evidence to indicate that patients with oestrogen receptor (ER)-positive disease, low Ki67 expression and 1 3 positive axillary nodes have a very low risk of disease relapse. Finally, no robust evidence indicates that Ki67 staining predicts the efficacy of adjuvant chemotherapy. Overall, evidence does not support withholding adjuvant chemotherapy in patients with ER-positive, Ki67-low breast cancer and 1-3 positive nodes without risk in daily practice. PMID- 25781577 TI - Physiotherapy Research Priorities in Switzerland: Views of the Various Stakeholders. AB - BACKGROUND AND PURPOSE: Research priorities, defined by multiple stakeholders, can proximally facilitate the coordination of research projects and national and international cooperation and distally further improve the quality of physiotherapy practice. The aim of this study was therefore to establish physiotherapy research priorities in Switzerland considering multiple stakeholders' opinions. METHODS: A mixed methods design was chosen. For a qualitative identification of physiotherapy research topics, 18 focus group discussions and 23 semi-structured interviews/written commentaries were conducted. For the quantitative analysis, 420 participants prioritized research topics using a two-round Delphi questionnaire survey. The following stakeholder groups were surveyed in the German-speaking, French-speaking and Italian-speaking regions of Switzerland: physiotherapy researchers, practitioners and educators, representatives of patient organizations, public health organizations, health insurers, physicians, nurses, occupational therapists and other health professionals, as well as physical educators. RESULTS: The top five overall physiotherapy research priorities identified were as follows: physiotherapy treatment, physiotherapy assessment and diagnosis, prevention, physiotherapist patient interaction and physiotherapy professional education at the bachelor level. With regard to diagnostic groups, the highest priorities were placed on musculoskeletal disorders, neurology, orthopaedics, geriatrics and ergonomics/occupational health. Consensus was moderate to high, and only few differences between stakeholder groups were revealed. DISCUSSION: Research directly related to physiotherapy treatment is of highest priority. It should focus on diagnostic groups related to chronicity in anticipation of demographic changes. Multidisciplinary networks for research and practice, alongside sound coordination of research projects, should increase the impact of physiotherapy research. An accurate dissemination of research priorities, defined and supported by multiple stakeholder groups, might strengthen their impact on research and practice. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25781578 TI - Development of the resolution theory for gradient insulator-based dielectrophoresis. AB - New and important separations capabilities are being enabled by utilizing other electric field-induced forces besides electrophoresis, among these is dielectrophoresis. Recent works have used experimentally simple insulator-based systems that induce field gradients creating dielectrophoretic force in useful formats. Among these, juxtaposing forces can generate gradient-based steady-state separations schemes globally similar to isoelectric focusing. The system of interest is termed gradient insulator-based dielectrophoresis and can create extremely high resolution steady-state separations for particles four nanometers to ten micrometers in diameter, including nearly all important bioparticles (large proteins, protein aggregates, polynucleotides viruses, organelles, cells, bacteria, etc.). A theoretical underpinning is developed here to understand the relationship between experimental parameters and resolution and to identify the best expected resolution possible. According to the results, differences in particles (and bioparticles) as small as one part in 10(4) for diameter (subnanometer resolution for a one micrometer particle), one part in 10(8) for dielectrophoretic parameters (dielectrophoretic mobility, Clausius-Mossotti factor), and one part in 10(5) for electrophoretic mobility can be resolved. These figures of merit are generally better than any competing technique, in some cases by orders of magnitude. This performance is enabled by very strong focusing forces associated with localized gradients. PMID- 25781579 TI - On the use and misuse of scalar scores of confounders in design and analysis of observational studies. AB - We assess the asymptotic bias of estimates of exposure effects conditional on covariates when summary scores of confounders, instead of the confounders themselves, are used to analyze observational data. First, we study regression models for cohort data that are adjusted for summary scores. Second, we derive the asymptotic bias for case-control studies when cases and controls are matched on a summary score, and then analyzed either using conditional logistic regression or by unconditional logistic regression adjusted for the summary score. Two scores, the propensity score (PS) and the disease risk score (DRS) are studied in detail. For cohort analysis, when regression models are adjusted for the PS, the estimated conditional treatment effect is unbiased only for linear models, or at the null for non-linear models. Adjustment of cohort data for DRS yields unbiased estimates only for linear regression; all other estimates of exposure effects are biased. Matching cases and controls on DRS and analyzing them using conditional logistic regression yields unbiased estimates of exposure effect, whereas adjusting for the DRS in unconditional logistic regression yields biased estimates, even under the null hypothesis of no association. Matching cases and controls on the PS yield unbiased estimates only under the null for both conditional and unconditional logistic regression, adjusted for the PS. We study the bias for various confounding scenarios and compare our asymptotic results with those from simulations with limited sample sizes. To create realistic correlations among multiple confounders, we also based simulations on a real dataset. PMID- 25781580 TI - Continuous precipitation of IgG from CHO cell culture supernatant in a tubular reactor. AB - We successfully transferred a two-stage batch precipitation-based antibody capture step to continuous mode using continuous tubular reactors. The precipitation process solely employs a cheap mineral salt (CaCl2 ) and an organic solvent (ethanol) and could replace the costly protein A capture step in the purification of recombinant antibodies from cell culture supernatant. The time from startup untill attaining steady state conditions was reached in less than 15 minutes and both reactors were operated for several hours at steady state without manual intervention, delivering antibody at a constant yield and purity. An overall yield of > 90 percent, with a host cell protein reduction from 42 777 to 9000 ppm and a DNA reduction from 359 ppm to 7 ppm, could be achieved for the antibody investigated. The precipitated antibody can be dissolved at very high concentrations (> 40 g/L) in numerous buffer systems of various pH and high and low ionic strength, thereby rendering a subsequent concentration or buffer exchange step redundant. This system enables cell culture supernatants with low or high antibody titer to be processed with constant reactor size and without changing any parameters or increasing precipitant consumption. Aggregate levels were below 1% under all conditions tested. Purification by precipitation did not affect binding to CD16a or the isoform distribution of the antibody. PMID- 25781581 TI - Breast cancer risk after full-term pregnancies among African women from Nigeria, Cameroon, and Uganda. AB - BACKGROUND: The breast cancer (BC) risk profiles of African women differ significantly from those of women of European ancestry. African women are younger at the age of onset and tend to have high parity. The purpose of this study was to examine the relationship between full-term pregnancy (FTP) and the risk of BC. METHODS: A case-control study was conducted among 1995 women with invasive BC and 2631 controls in Nigeria, Cameroon, and Uganda. Odds ratios (ORs) for individual ages at FTP according to the time since delivery were calculated and adjusted for confounders. A fitted spline model was used to assess the impact of the number of pregnancies on BC risk. RESULTS: In comparison with a nulliparous woman, a parous woman with her first FTP at 20 years showed an OR of 0.76 (95% confidence interval [CI], 0.57-0.99) for developing BC in the following 5 years. Ten years later, this risk was 0.76 (95% CI, 0.58-0.99) and 0.76 (95% CI, 0.58-0.98) for women aged 25 and 30 years, respectively. Similarly, a parous woman with 1 pregnancy had an OR of 0.69 (95% CI, 0.49-0.96), whereas the OR was 0.66 (95% CI, 0.48-0.91) with 2 or 5 pregnancies and 0.67 (95% CI, 0.47-0.94) with 6 pregnancies in comparison with nulliparous women. CONCLUSIONS: In contrast to studies in women of European ancestry, this study showed no transient increase in the risk of developing BC after FTP among African women. Further studies are needed to examine the impact of reproductive factors on early-onset BC in African women. PMID- 25781583 TI - Nebulized isotonic saline improves voice production in Sjogren's syndrome. AB - OBJECTIVE: This study examined the effects of a topical vocal fold hydration treatment on voice production over time. STUDY DESIGN: Prospective, longitudinal, within-subjects A (baseline), B (treatment), A (withdrawal/reversal), B (treatment) experimental design. METHODS: Eight individuals with primary Sjogren's syndrome (SS), an autoimmune disease causing laryngeal dryness, completed an 8-week A-B-A-B experiment. Participants performed twice-daily audio recordings of connected speech and sustained vowels and then rated vocal effort, mouth dryness, and throat dryness. Two-week treatment phases introduced twice daily 9-mL doses of nebulized isotonic saline (0.9% Na(+)Cl(-)). Voice handicap and patient-based measures of SS disease severity were collected before and after each 2-week phase. Connected speech and sustained vowels were analyzed using the Cepstral Spectral Index of Dysphonia (CSID). Acoustic and patient-based ratings during each baseline and treatment phase were analyzed and compared. RESULTS: Baseline CSID and patient-based ratings were in the mild-to-moderate range. CSID measures of voice severity improved by approximately 20% with nebulized saline treatment and worsened during treatment withdrawal. Posttreatment CSID values fell within the normal-to-mild range. Similar patterns were observed in patient based ratings of vocal effort and dryness. CSID values and patient-based ratings correlated significantly (P < .05). CONCLUSION: Nebulized isotonic saline improves voice production based on acoustic and patient-based ratings of voice severity. Future work should optimize topical vocal fold hydration treatment formulations, dose, and delivery methodologies for various patient populations. This study lays the groundwork for future topical vocal fold hydration treatment development to manage and possibly prevent dehydration-related voice disorders. LEVEL OF EVIDENCE: 2b. PMID- 25781582 TI - Quality assessment of Fructus Ligustri Lucidi by the simultaneous determination of six compounds and chemometric analysis. AB - A comprehensive strategy was designed for the quality assessment of Fructus Ligustri Lucidi, a well-known and commonly used herbal medicine in clinical practice in China. First, a simple and stable method of high-performance liquid chromatography was developed for the simultaneous quantitative analysis of six compounds, namely, salidroside, nuzhenide, specnuezhenide, oleanic acid, ursolic acid, and acetyl oleanic acid in Fructus Ligustri Lucidi. The separation of analytes was conducted on a C18 column (200 mm * 4.6 mm, 5 MUm) at 30 degrees C, and the wavelength of UV detector was set at 210 nm. In quantitative analysis, all of the calibration curves showed good linear regression (R(2) > 0.9994) within the tested ranges, and the mean recoveries of three different concentrations ranged from 95.21-102.34%. The described method was applied to determine 11 batches of samples collected from different stores in China. Then multiple chemometrics analysis including hierarchical cluster analysis and principal component analysis were performed to classify samples and search significant compounds. Three notable compounds, specnuezhenide, oleanic acid, and acetyl oleanic acid, were discovered for better quality control compared with those stated in the China pharmacopeia. The results demonstrated that this strategy could be readily utilized for the comprehensive quality control of Fructus Ligustri Lucidi. PMID- 25781584 TI - The effects of cognitive reserve and lifestyle on cognition and dementia in Parkinson's disease--a longitudinal cohort study. AB - OBJECTIVE: Cognitive reserve theory seeks to explain the observed mismatch between the degree of brain pathology and clinical manifestations. Early-life education, midlife social and occupational activities and later-life cognitive and social interactions are associated with a more favourable cognitive trajectory in older people. Previous studies of Parkinson's disease (PD) have suggested a possible role for the effects of cognitive reserve, but further research into different proxies for cognitive reserve and longitudinal studies is required. This study examined the effects of cognitive lifestyle on cross sectional and longitudinal measures of cognition and dementia severity in people with PD. METHODS: Baseline assessments of cognition, and of clinical, social and demographic information, were completed by 525 participants with PD. Cognitive assessments were completed by 323 participants at 4-year follow-up. Cognition was assessed using the measures of global cognition dementia severity. Cross sectional and longitudinal serial analyses of covariance for cognition and binomial regression for dementia were performed. RESULTS: Higher educational level, socio-economic status and recent social engagement were associated with better cross-sectional global cognition. In those with normal cognition at baseline, higher educational level was associated with better global cognition after 4 years. Increasing age and low levels of a measure of recent social engagement were associated with an increased risk of dementia. CONCLUSIONS: Higher cognitive reserve has a beneficial effect on performance on cognitive tests and a limited effect on cognitive decline and dementia risk in PD. PMID- 25781585 TI - Molecular characterization of a novel hypovirus from the plant pathogenic fungus Fusarium graminearum. AB - A novel mycovirus, termed Fusarium graminearum Hypovirus 2 (FgHV2/JS16), isolated from a plant pathogenic fungus, Fusarium graminearum strain JS16, was molecularly and biologically characterized. The genome of FgHV2/JS16 is 12,800 nucleotides (nts) long, excluding the poly (A) tail. This genome has only one large putative open reading frame, which encodes a polyprotein containing three normal functional domains, papain-like protease, RNA-dependent RNA polymerase, RNA helicase, and a novel domain with homologous bacterial SMC (structural maintenance of chromosomes) chromosome segregation proteins. A defective RNA segment that is 4553-nts long, excluding the poly (A) tail, was also detected in strain JS16. The polyprotein shared significant aa identities with Cryphonectria hypovirus 1 (CHV1) (16.8%) and CHV2 (16.2%). Phylogenetic analyses based on multiple alignments of the polyprotein clearly divided the members of Hypoviridae into two major groups, suggesting that FgHV2/JS16 was a novel hypovirus of a newly proposed genus-Alphahypovirus-composed of the members of Group 1, including CHV1, CHV2, FgHV1 and Sclerotinia sclerotiorum hypovirus 2. FgHV2/JS16 was shown to be associated with hypovirulence phenotypes according to comparisons of the biological properties shared between FgHV2/JS16-infected and FgHV2/JS16-free isogenic strains. Furthermore, we demonstrated that FgHV2/JS16 infection activated the RNA interference pathway in Fusarium graminearum by relative quantitative real time RT-PCR. PMID- 25781586 TI - First-Person Perspectives on Dual Diagnosis Anonymous (DDA): A Qualitative Study. AB - OBJECTIVE: People with dually diagnosed substance abuse and mental illnesses often feel alienated at traditional 12-step meetings, yet they need the peer support provided by such groups. Dual Diagnosis Anonymous (DDA) is a peer-support program specifically for people with co-occurring disorders, which addresses many of the factors that members find alienating about traditional 12-step groups. This study aimed to elicit first-person perspectives on DDA. METHODS: Occupational therapy students conducted 13 focus groups with 106 DDA members in three settings: the community (6 groups, n = 36), correctional facilities (5 groups, n = 53), and the state psychiatric hospital (2 groups, n = 17). Researchers inductively analyzed focus group transcripts to identify prominent themes. RESULTS: The vast majority of participants were between the ages of 18 and 49 (n = 87, 82.1%) and were non-Hispanic/White (n = 82, 77.4%). Most participants had been using substances for more than 10 years and had a diagnosed mental illness for more than 10 years. The most common substance of choice among those in the community and corrections setting was multiple substances, while those in the state hospital identified alcohol most often. Bipolar disorder was the most common mental illness diagnosis among participants in the state hospital, but depression and anxiety were the two most common diagnoses in the community and corrections participants. Four primary themes emerged from the qualitative analysis: (1) feeling accepted by others in the group, (2) understanding the interactive nature of dual disorders, (3) the open discussions in DDA meetings, and (4) a focus on hope and recovery from both illnesses. CONCLUSIONS: DDA provides a helpful alternative for individuals who do not feel comfortable at traditional 12-step groups due to their mental illness. Members value the acceptance, understanding, discussion, and hope in DDA meetings. PMID- 25781587 TI - [Biomimetics--imitating nature to prevent disease]. PMID- 25781588 TI - [The ABCs of--Acute rupture of the Achilles tendon]. PMID- 25781589 TI - [ACG model can predict large consumers of health care. Health care resources can be used more wisely, individuals at risk can receive better care]. AB - We describe a method, which uses already existent administrative data to identify individuals with a high risk of a large need of healthcare in the coming year. The model is based on the ACG (Adjusted Clinical Groups) system to identify the high-risk patients. We have set up a model where we combine the ACG system stratification analysis tool RUB (Resource Utilization Band) and Probability High Total Cost >0.5. We tested the method with historical data, using 2 endpoints, either >19 physical visits anywhere in the healthcare system in the coming 12 months or more than 2 hospital admissions in the coming 12 months. In the region of Vastra Gotaland with 1.6 million inhabitants, 5.6% of the population had >19 physical visits during a 12 month period and 1.2% more than 2 hospital admissions. Our model identified approximately 24,000 individuals of whom 25.7% had >19 physical visits and 11.6% had more than 2 hospital admissions in the coming 12 months. We now plan a small test in ten primary care centers to evaluate if the model should be introduced in the entire Vastra Gotaland region. PMID- 25781591 TI - [Portrait of a portrait painter]. PMID- 25781590 TI - [Confusing diagnosis coding prevents historical and international comparisons. Diagnosing should be unambiguous and consistent]. PMID- 25781592 TI - ["Dialogical floor" can become a trap door]. PMID- 25781593 TI - [The therapist does the job, with the help of safe equipment]. PMID- 25781594 TI - [The medical students association protests against new lending rules: Should education abroad become a class issue?]. PMID- 25781595 TI - [The goal is for more people to be able to study abroad]. PMID- 25781597 TI - [A dark chapter in our history]. PMID- 25781596 TI - [Effective knowledge support called for]. PMID- 25781598 TI - [Saving lives and then land]. PMID- 25781599 TI - [Final reply from Hans Wingstrand and co-authors: Reintroduce confidentiality in IT systems]. PMID- 25781600 TI - [The Swedish National Board of Health and Welfare agrees with the need for reproducible diagnosis coding]. PMID- 25781601 TI - [Final reply from Magnus Westgren: My impression is that complaints against health professionals have increased]. PMID- 25781602 TI - [The Swedish National Board of Health and Welfare proposes reduced reference values for gestational diabetes]. PMID- 25781603 TI - [The need for a national coordinator of sickness absence issues. The unnecessary sickness absence]. PMID- 25781604 TI - Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells. AB - Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer. PMID- 25781605 TI - Postmastectomy radiotherapy improves disease-free survival of high risk of locoregional recurrence breast cancer patients with T1-2 and 1 to 3 positive nodes. AB - OBJECTIVES: The indications for post-mastectomy radiotherapy (PMRT) with T1-2 breast cancer and 1-3 positive axillary lymph nodes is still controversial. The purpose of this study was to investigate the role of PMRT in T1-2 breast cancer with 1-3 positive axillary lymph node. METHODS: We retrospectively reviewed the file records of 79 patients receiving PMRT and not receiving PMRT (618 patients). RESULTS: The median follow-up was 65 months. Multivariate analysis showed that PMRT was an independent prognostic factor of locoregional recurrence-free survival (LRFS) (P = 0.010). Subgroup analysis of patients who did not undergo PMRT showed that pT stage, number of positive axillary lymph nodes, and molecular subtype were independent prognostic factors of LRFS. PMRT improved LRFS in the entire group (P = 0.005), but did not affect distant metastasis-free survival (DMFS) (P = 0.494), disease-free survival (DFS) (P = 0.215), and overall survival (OS) (P = 0.645). For patients without PMRT, the 5-year LRFS of low-risk patients (0-1 risk factor for locoregional recurrence) of 94.5% was significantly higher than that of high-risk patients (2-3 risk factors for locoregional recurrence) (80.9%, P < 0.001). PMRT improved LRFS (P = 0.001) and DFS (P = 0.027) in high risk patients, but did not improve LRFS, DMFS, DFS, and OS in low-risk patients. CONCLUSIONS: PMRT is beneficial in patients with high risk of locoregional recurrence breast cancer patients with T1-2 and 1 to 3 positive nodes. PMID- 25781606 TI - Transcriptome analysis of maize leaf systemic symptom infected by Bipolaris zeicola. AB - Bipolaris zeicola is a fungal pathogen that causes Northern corn leaf spot (NCLS), which is a serious foliar disease in maize and one of the most significant pathogens affecting global food security. Here, we report a genome wide transcriptional profile analysis using next-generation sequencing (NGS) of maize leaf development after inoculation with B. zeicola. We performed High Throughput Digital Gene Expression analysis to identify differentially expressed genes (DEGs) in resistant inbred Mo17 lines after infection with B. zeicola at four successive disease development stages--CP (contact period), PP (penetration period), IP (incubation period), and DP (disease period); the expression of the genes was compared with those in a CK (mock-treatment) control. In addition, a sensitive maize line (Zheng58) was used for the comparisons with the Mo17. Among all tested genes, 466 differentially expressed genes were identified in all libraries, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these genes suggested that they are involved in many biological processes related to systemic symptom development, such as plant hormone signal transduction, starch and sucrose metabolism, phenylpropanoid biosynthesis and photosynthesis. Our systematic analysis provides comprehensive transcriptomic information regarding systemic symptom development in fungal-infected plants. This information will help in furthering our understanding of the detailed mechanisms of plant responses to fungal infection. PMID- 25781607 TI - Estrogens induce rapid cytoskeleton re-organization in human dermal fibroblasts via the non-classical receptor GPR30. AB - The post-menopausal decrease in estrogen circulating levels results in rapid skin deterioration pointing out to a protective effect exerted by these hormones. The identity of the skin cell type responding to estrogens is unclear as are the cellular and molecular processes they elicit. Here, we reported that lack of estrogens induces rapid re-organization of the human dermal fibroblast cytoskeleton resulting in striking cell shape change. This morphological change was accompanied by a spatial re-organization of focal adhesion and a substantial reduction of their number as evidenced by vinculin and actin co-staining. Cell morphology and cytoskeleton organization was fully restored upon 17beta-estradiol (E2) addition. Treatment with specific ER antagonists and cycloheximide respectively showed that the E2 acts independently of the classical Estrogen Receptors and that cell shape change is mediated by non-genomic mechanisms. E2 treatment resulted in a rapid and transient activation of ERK1/2 but not Src or PI3K. We show that human fibroblasts express the non-classical E2 receptor GPR30 and that its agonist G-1 phenocopies the effect of E2. Inhibiting GPR30 through treatment with the G-15 antagonist or specific shRNA impaired E2 effects. Altogether, our data reveal a novel mechanism by which estrogens act on skin fibroblast by regulating cell shape through the non-classical G protein-coupled receptor GPR30 and ERK1/2 activation. PMID- 25781608 TI - Phytase modulates ileal microbiota and enhances growth performance of the broiler chickens. AB - Phytase is well studied and explored, however, little is known about its effects on the microbial ecology of the gastrointestinal tract. In total, 400 one-day-old female Ross 308 chicks were randomly distributed to four experimental groups. The dietary treatments were arranged as a 2 * 2 complete factorial design, with the factors being adequate (PC) or insufficient calcium (Ca) and digestible phosphor (dP)(NC) and with or without 5000 phytase units (FTU)/kg of Escherichia coli 6 phytase. The gastrointestinal tract pH values, ileal microbial communities and short-chain fatty acid concentrations in the digesta were determined. The reduction in Ca and dP concentration significantly affected pH in the crop and caeca, and addition of phytase to the NC resulted in a pH increase in the ileum. The reduction in Ca and dP concentration significantly lowered, while phytase supplementation increased ileal total bacterial counts. Additionally, the deficient diet reduced butyrate- but increased lactate-producing bacteria. The addition of phytase increased Lactobacillus sp./Enterococcus sp. whereas in case of Clostridium leptum subgroup, Clostridium coccoides-Eubacterium rectale cluster, Bifidobacterium sp. and Streptococcus/Lactococcus counts, a significant Ca and dP level x phytase interaction was found. However, the recorded interactions indicated that the effects of phytase and Ca and dP levels were not consistent. Furthermore, the reduction of Ca and dP level lowered Clostridium perfringens and Enterobacteriaceae counts. The analysis of fermentation products showed that reducing the Ca and dP content in the diet reduced total SCFA, DL lactate, and acetic acid in the ileum whereas phytase increased concentrations of these acids in the NC group. This suggests that P is a factor which limits fermentation in the ileum. It may be concluded that phytase plays a role in modulating the gut microbiota of chicken, however, this is clearly linked with the levels of P and Ca in a diet. PMID- 25781609 TI - Olodaterol attenuates citric acid-induced cough in naive and ovalbumin-sensitized and challenged guinea pigs. AB - Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including beta2-adrenergic receptors (beta2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of beta2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting beta2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant beta2-AR agonists. In our study beta2-AR agonists were intratracheally administered, as dry powder, into the lungs of naive or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose dependently inhibited the number of cough events in naive and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naive and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naive and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of beta2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of beta2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the cough reflex, the mechanism underlying the pro-tussive property of indacaterol is not known. PMID- 25781610 TI - Bladder recovery by stem cell based cell therapy in the bladder dysfunction induced by spinal cord injury: systematic review and meta-analysis. AB - BACKGROUND: Bladder dysfunction induced by spinal cord injury (SCI) can become problematic and severely impair the quality of life. Preclinical studies of spinal cord injury have largely focused on the recovery of limb function while neglecting to investigate bladder recovery. OBJECTIVE: The present study was performed to investigate and review the effect of stem cell-based cell therapy on bladder recovery in SCI. METHODS: We conducted a meta-analysis of urodynamic findings of experimental trials that included studies of stem cell-based cell therapy in SCI. Relevant studies were searched using MEDLINE, EMBASE and Cochrane Library (January 1990 - December 2012). Final inclusion was determined by a urodynamic study involving detailed numerical values. Urodynamic parameters for analysis included voiding pressure, residual urine, bladder capacity and non voiding contraction (NVC). Meta-analysis of the data, including findings from urodynamic studies, was performed using the Mantel-Haenszel method. RESULTS: A total of eight studies were included with a sample size of 224 subjects. The studies were divided into different subgroups by different models of SCI. After a stem cell-based cell therapy, voiding pressure (-6.35, p <0.00001, I2 = 77%), NVC (-3.58, p <0.00001, I2 = 82%), residual urine (-024, p = 0.004, I2 = 95%) showed overall significant improvement. Bladder capacity showed improvement after treatment only in the transection type (-0.23, p = 0.0002, I2 = 0%). CONCLUSION: After stem cell-based cell therapy in SCI, partial bladder recovery including improvement of voiding pressure, NVC, and residual urine was demonstrated. Additional studies are needed to confirm the detailed mechanism and to obtain an ideal treatment strategy for bladder recovery. PMID- 25781613 TI - Medicinal chemistry in oncology: new approaches and future trends. PMID- 25781611 TI - CasEMBLR: Cas9-Facilitated Multiloci Genomic Integration of in Vivo Assembled DNA Parts in Saccharomyces cerevisiae. AB - Homologous recombination (HR) in Saccharomyces cerevisiae has been harnessed for both plasmid construction and chromosomal integration of foreign DNA. Still, native HR machinery is not efficient enough for complex and marker-free genome engineering required for modern metabolic engineering. Here, we present a method for marker-free multiloci integration of in vivo assembled DNA parts. By the use of CRISPR/Cas9-mediated one-step double-strand breaks at single, double and triple integration sites we report the successful in vivo assembly and chromosomal integration of DNA parts. We call our method CasEMBLR and validate its applicability for genome engineering and cell factory development in two ways: (i) introduction of the carotenoid pathway from 15 DNA parts into three targeted loci, and (ii) creation of a tyrosine production strain using ten parts into two loci, simultaneously knocking out two genes. This method complements and improves the current set of tools available for genome engineering in S. cerevisiae. PMID- 25781615 TI - Correction: Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PMID- 25781617 TI - Role of acute HIV infection in driving HIV transmission: implications for HIV treatment as prevention. PMID- 25781614 TI - Inflammatory cytokines in general and central obesity and modulating effects of physical activity. AB - CONTEXT: Chronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their relationship to physical activity and adipometrics has scarcely been reported to date. OBJECTIVE: To characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study comprising 117 obese patients (body mass index (BMI) >= 30) and 83 non-obese community-based volunteers. MAIN OUTCOMES MEASURES: Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha were measured. Physical activity and energy expenditure (MET) were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR), and waist-to-height-ratio (WHtR). RESULTS: General obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-gamma and TNF-alpha, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-gamma-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants. CONCLUSIONS: Results confirm up-regulation of certain pro- and anti inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes. PMID- 25781616 TI - The prevalence and patient characteristics of chronic obstructive pulmonary disease in non-smokers in Vietnam and Indonesia: An observational survey. AB - BACKGROUND AND OBJECTIVE: An estimated 25-40% of patients with chronic obstructive pulmonary disease (COPD) have never smoked. We investigated the prevalence and patient characteristics of COPD in non-smokers from Vietnam and Indonesia. METHODS: This population-based cross-sectional survey of participants from urban and rural Vietnam and Indonesia used a stratified multistage cluster sampling design, with sample and population weights applied to ensure representativeness. Participants were female or male (recruited in the ratio 2:1) non-smokers, 40 years or older and able to perform a spirometry test. Spirometry was performed at a single study visit. Other clinical information was collected via standardized questionnaires. RESULTS: The 1506 evaluable participants were approximately equally distributed between Vietnam and Indonesia, and rural and urban areas. Overall prevalence of COPD was found to be 6.9% (95% confidence interval (CI): 5.7-8.3), with almost three times higher prevalence in men than women (12.9% (95% CI: 9.1-18.0) vs 4.4% (95% CI: 3.0-6.5)). We found higher rates of COPD in Vietnam than Indonesia (8.1% (95% CI: 5.8-11.3) vs 6.3% (95% CI: 4.8 8.3)), with a particularly high prevalence in urban Vietnam (11.1% (95% CI: 8.1 15.1)). Very few participants (6%) diagnosed to have COPD during the study had been previously diagnosed with COPD. Respiratory symptoms and lower health related quality of life were more common in participants with COPD. CONCLUSIONS: The prevalence of COPD in non-smoking individuals from rural and urban Vietnam and Indonesia was 6.9%, of which a significant proportion (94%) were previously undiagnosed. PMID- 25781618 TI - Effect of paricalcitol vs calcitriol on hemoglobin levels in chronic kidney disease patients: a randomized trial. AB - BACKGROUND: Recent studies suggest that vitamin D deficiency represents an additional cofactor of renal anemia, with several mechanisms accounting for this relationship. In line with it, the administration of vitamin D or its analogues has been associated with an improvement of anemia. There are no data, however, about a direct effect of paricalcitol on hemoglobin (Hb) levels. Therefore, we conducted a study to determine whether paricalcitol, compared to calcitriol, improves anemia in patients with chronic kidney disease (CKD). METHODS: In this randomized trial 60 CKD patients stage 3b-5 and anemia (Hb levels: 10-12.5 g/dL) were assigned (1:1) to receive low doses of calcitriol (Group Calcitriol) or paricalcitol (Group Paricalcitol) for 6 months. All the patients had normal values of plasma calcium, phosphorus and PTH, a stable iron balance, and normal values of C-Reactive Protein. The primary endpoint was to evaluate the effects of the two treatments on Hb levels; the modifications in 24hr-proteinuria (UProt) were also evaluated. RESULTS: A significant Group x Time interaction effect was observed in the longitudinal analysis of Hb levels (F(1,172)=31.4, p<0.001). Subjects in Paricalcitol experienced a significant monthly increase of Hb levels equal to +0.16 g/dL [95% C.I. 0.10 to +0.22, p<0.001) while in Group Calcitriol, Hb decrease throughout the follow-up with an average monthly rate of -0.10 g/dL (95% C.I.: -0.17 to -0.04, p<0.001). In Group Paricalcitol, UProt was significantly reduced after 6 months [0.35 (0.1-1.2) vs 0.59 (0.2-1.6), p<0.01], whereas no significant difference emerged in Group Calcitriol. Plasma levels of calcium, phosphate, PTH and of inflammation markers remained in the normal range in both groups throughout the study. CONCLUSIONS: Short-term exposure to paricalcitol results in an independent increase in Hb levels, which occurred with no modification of iron balance, inflammatory markers, and PTH plasma concentrations, and was associated with a decrease in UProt. TRIAL REGISTRATION: ClinicalTrials.gov NCT01768351. PMID- 25781620 TI - Primitive fitting based on the efficient multiBaySAC algorithm. AB - Although RANSAC is proven to be robust, the original RANSAC algorithm selects hypothesis sets at random, generating numerous iterations and high computational costs because many hypothesis sets are contaminated with outliers. This paper presents a conditional sampling method, multiBaySAC (Bayes SAmple Consensus), that fuses the BaySAC algorithm with candidate model parameters statistical testing for unorganized 3D point clouds to fit multiple primitives. This paper first presents a statistical testing algorithm for a candidate model parameter histogram to detect potential primitives. As the detected initial primitives were optimized using a parallel strategy rather than a sequential one, every data point in the multiBaySAC algorithm was assigned to multiple prior inlier probabilities for initial multiple primitives. Each prior inlier probability determined the probability that a point belongs to the corresponding primitive. We then implemented in parallel a conditional sampling method: BaySAC. With each iteration of the hypothesis testing process, hypothesis sets with the highest inlier probabilities were selected and verified for the existence of multiple primitives, revealing the fitting for multiple primitives. Moreover, the updated version of the initial probability was implemented based on a memorable form of Bayes' Theorem, which describes the relationship between prior and posterior probabilities of a data point by determining whether the hypothesis set to which a data point belongs is correct. The proposed approach was tested using real and synthetic point clouds. The results show that the proposed multiBaySAC algorithm can achieve a high computational efficiency (averaging 34% higher than the efficiency of the sequential RANSAC method) and fitting accuracy (exhibiting good performance in the intersection of two primitives), whereas the sequential RANSAC framework clearly suffers from over- and under-segmentation problems. Future work will aim at further optimizing this strategy through its application to other problems such as multiple point cloud co-registration and multiple image matching. PMID- 25781619 TI - Inhibition of KIT-glycosylation by 2-deoxyglucose abrogates KIT-signaling and combination with ABT-263 synergistically induces apoptosis in gastrointestinal stromal tumor. AB - Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110 mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3 mimetics. Our data provide the first evidence that modulation of the glucose metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST. PMID- 25781621 TI - Chronic inflammatory disease and osteopathy: a systematic review. AB - BACKGROUND: Chronic inflammatory diseases (CID) are globally highly prevalent and characterized by severe pathological medical conditions. Several trials were conducted aiming at measuring the effects of manipulative therapies on patients affected by CID. The purpose of this review was to explore the extent to which osteopathic manipulative treatment (OMT) can be benefi-cial in medical conditions also classified as CID. METHODS: This review included any type of experimental study which enrolled sub-jects with CID comparing OMT with any type of control procedure. The search was conducted on eight databases in January 2014 using a pragmatic literature search approach. Two independent re-viewers conducted study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods. Heterogeneity was assessed and meta-analysis performed where possible. RESULTS: 10 studies met the inclusion criteria for this review enrolling 386 subjects. The search identified six RCTs, one laboratory study, one cross-over pilot studies, one observation-al study and one case control pilot study. Results suggest a potential effect of osteopathic medicine on patients with medical pathologies associated with CID (in particular Chronic Obstructive Pul-monary Disease (COPD), Irritable Bowel Syndrome, Asthma and Peripheral Arterial Disease) com-pared to no treatment or sham therapy although data remain elusive. Moreover one study showed possible effects on arthritis rat model. Meta-analysis was performed for COPD studies only show-ing no effect of any type of OMT applied versus control. No major side effects were reported by those receiving OMT. CONCLUSION: The present systematic review showed inconsistent data on the effect of OMT in the treatment of medical conditions potentially associated with CID, however the OMT appears to be a safe approach. Further more robust trials are needed to determine the direction and magnitude of the effect of OMT and to generalize favorable results. PMID- 25781623 TI - Multimodal Segmentation of Optic Disc and Cup From SD-OCT and Color Fundus Photographs Using a Machine-Learning Graph-Based Approach. AB - In this work, a multimodal approach is proposed to use the complementary information from fundus photographs and spectral domain optical coherence tomography (SD-OCT) volumes in order to segment the optic disc and cup boundaries. The problem is formulated as an optimization problem where the optimal solution is obtained using a machine-learning theoretical graph-based method. In particular, first the fundus photograph is registered to the 2D projection of the SD-OCT volume. Three in-region cost functions are designed using a random forest classifier corresponding to three regions of cup, rim, and background. Next, the volumes are resampled to create radial scans in which the Bruch's Membrane Opening (BMO) endpoints are easier to detect. Similar to in region cost function design, the disc-boundary cost function is designed using a random forest classifier for which the features are created by applying the Haar Stationary Wavelet Transform (SWT) to the radial projection image. A multisurface graph-based approach utilizes the in-region and disc-boundary cost images to segment the boundaries of optic disc and cup under feasibility constraints. The approach is evaluated on 25 multimodal image pairs from 25 subjects in a leave one-out fashion (by subject). The performances of the graph-theoretic approach using three sets of cost functions are compared: 1) using unimodal (OCT only) in region costs, 2) using multimodal in-region costs, and 3) using multimodal in region and disc-boundary costs. Results show that the multimodal approaches outperform the unimodal approach in segmenting the optic disc and cup. PMID- 25781622 TI - External validation of fatty liver index for identifying ultrasonographic fatty liver in a large-scale cross-sectional study in Taiwan. AB - BACKGROUND AND AIMS: The fatty liver index (FLI) is an algorithm involving the waist circumference, body mass index, and serum levels of triglyceride and gamma glutamyl transferase to identify fatty liver. Although some studies have attempted to validate the FLI, few studies have been conducted for external validation among Asians. We attempted to validate FLI to predict ultrasonographic fatty liver in Taiwanese subjects. METHODS: We enrolled consecutive subjects who received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was applied to diagnose fatty liver. The ability of the FLI to detect ultrasonographic fatty liver was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. RESULTS: Among the 29,797 subjects enrolled in this study, fatty liver was diagnosed in 44.5% of the population. Subjects with ultrasonographic fatty liver had a significantly higher FLI than those without fatty liver by multivariate analysis (odds ratio 1.045; 95% confidence interval, CI 1.044-1.047, p< 0.001). Moreover, FLI had the best discriminative ability to identify patients with ultrasonographic fatty liver (AUROC: 0.827, 95% confidence interval, 0.822-0.831). An FLI < 25 (negative likelihood ratio (LR-) 0.32) for males and <10 (LR- 0.26) for females rule out ultrasonographic fatty liver. Moreover, an FLI >= 35 (positive likelihood ratio (LR+) 3.12) for males and >= 20 (LR+ 4.43) for females rule in ultrasonographic fatty liver. CONCLUSIONS: FLI could accurately identify ultrasonographic fatty liver in a large-scale population in Taiwan but with lower cut-off value than the Western population. Meanwhile the cut-off value was lower in females than in males. PMID- 25781624 TI - Accuracy and Precision of Head Motion Information in Multi-Channel Free Induction Decay Navigators for Magnetic Resonance Imaging. AB - Free induction decay (FID) navigators were found to qualitatively detect rigid body head movements, yet it is unknown to what extent they can provide quantitative motion estimates. Here, we acquired FID navigators at different sampling rates and simultaneously measured head movements using a highly accurate optical motion tracking system. This strategy allowed us to estimate the accuracy and precision of FID navigators for quantification of rigid-body head movements. Five subjects were scanned with a 32-channel head coil array on a clinical 3T MR scanner during several resting and guided head movement periods. For each subject we trained a linear regression model based on FID navigator and optical motion tracking signals. FID-based motion model accuracy and precision was evaluated using cross-validation. FID-based prediction of rigid-body head motion was found to be with a mean translational and rotational error of 0.14+/-0.21 mm and 0.08+/ 0.13 degrees , respectively. Robust model training with sub-millimeter and sub degree accuracy could be achieved using 100 data points with motion magnitudes of +/-2 mm and +/-1 degrees for translation and rotation. The obtained linear models appeared to be subject-specific as inter-subject application of a "universal" FID-based motion model resulted in poor prediction accuracy. The results show that substantial rigid-body motion information is encoded in FID navigator signal time courses. Although, the applied method currently requires the simultaneous acquisition of FID signals and optical tracking data, the findings suggest that multi-channel FID navigators have a potential to complement existing tracking technologies for accurate rigid-body motion detection and correction in MRI. PMID- 25781625 TI - Costs and epidemiological changes of chronic diseases: implications and challenges for health systems. AB - BACKGROUND: The need to integrate economic and epidemiological aspects in the clinical perspective leads to a proposal for the analysis of health disparities and to an evaluation of the health services and of the new challenges which are now being faced by health system reforms in middle income countries. OBJECTIVE: To identify the epidemiological changes, the demand for health services and economic burden from chronic diseases (diabetes and hypertension) in a middle income county. METHODS: We conducted longitudinal analyses of costs and epidemiological changes for diabetes and hypertension in the Mexican health system. The study population included both the insured and uninsured populations. The cost-evaluation method was used, based on the instrumentation and consensus techniques. To estimate the epidemiological changes and financial consequences for 2014-2016, six models were constructed according to the Box-Jenkins technique, using confidence intervals of 95%, and the Box-Pierce test. RESULTS: Regarding epidemiological changes expected in both diseases for 2014 vs. 2016, an increase is expected, although results predict a greater increase for diabetes, 8 12% in all three studied institutions, (p < .05). Indeed, in the case of diabetes, the increase was 41469 cases for uninsured population (SSA) and 65737 for the insured population (IMSS and ISSSTE). On hypertension cases the increase was 38109 for uninsured vs 62895 for insured. Costs in US$ ranged from $699 to $748 for annual case management per patient in the case of diabetes, and from $485 to $622 in patients with hypertension. Comparing financial consequences of health services required by insured and uninsured populations, the greater increase (23%) will be for the insured population (p < .05). The financial requirements of both diseases will amount to 19.5% of the total budget for the uninsured and 12.5% for the insured population. CONCLUSIONS: If the risk factors and the different health care models remain as they currently are, the economic impact of expected epidemiological changes on the social security system will be particularly strong. Another relevant challenge is the appearance of internal competition in the use and allocation of financial resources with programs for other chronic and infectious diseases. PMID- 25781627 TI - Molecular motion, dielectric response, and phase transition of charge-transfer crystals: acquired dynamic and dielectric properties of polar molecules in crystals. AB - Molecules in crystals often suffer from severe limitations on their dynamic processes, especially on those involving large structural changes. Crystalline compounds, therefore, usually fail to realize their potential as dielectric materials even when they have large dipole moments. To enable polar molecules to undergo dynamic processes and to provide their crystals with dielectric properties, weakly bound charge-transfer (CT) complex crystals have been exploited as a molecular architecture where the constituent polar molecules have some freedom of dynamic processes, which contribute to the dielectric properties of the crystals. Several CT crystals of polar tetrabromophthalic anhydride (TBPA) molecules were prepared using TBPA as an electron acceptor and aromatic hydrocarbons, such as coronene and perylene, as electron donors. The crystal structures and dielectric properties of the CT crystals as well as the single component crystal of TBPA were investigated at various temperatures. Molecular reorientation of TBPA molecules did not occur in the single-component crystal, and the crystal did not show a dielectric response due to orientational polarization. We have found that the CT crystal formation provides a simple and versatile method to develop molecular dielectrics, revealing that the molecular dynamics of the TBPA molecules and the dielectric property of their crystals were greatly changed in CT crystals. The TBPA molecules underwent rapid in-plane reorientations in their CT crystals, which exhibited marked dielectric responses arising from the molecular motion. An order-disorder phase transition was observed for one of the CT crystals, which resulted in an abrupt change in the dielectric constant at the transition temperature. PMID- 25781626 TI - The receptor for advanced glycation end products (RAGE) contributes to the progression of emphysema in mice. AB - Several recent clinical studies have implied a role for the receptor for advanced glycation end products (RAGE) and its variants in chronic obstructive pulmonary disease (COPD). In this study we have defined a role for RAGE in the pathogenesis of emphysema in mice. RAGE deficient mice (RAGE-/-) exposed to chronic cigarette smoke were significantly protected from smoke induced emphysema as determined by airspace enlargement and had no significant reduction in lung tissue elastance when compared to their air exposed controls contrary to their wild type littermates. The progression of emphysema has been largely attributed to an increased inflammatory cell-mediated elastolysis. Acute cigarette smoke exposure in RAGE-/- mice revealed an impaired early recruitment of neutrophils, approximately a 6-fold decrease compared to wild type mice. Hence, impaired neutrophil recruitment with continued cigarette smoke exposure reduces elastolysis and consequent emphysema. PMID- 25781628 TI - Facile synthesis of nitrogen and sulfur codoped carbon from ionic liquid as metal free catalyst for oxygen reduction reaction. AB - Developing metal-free catalysts for oxygen reduction reaction (ORR) is a great challenge in the development of fuel cells. Nitrogen and sulfur codoped carbon with remarkably high nitrogen content up to 13.00 at % was successfully fabricated by pyrolysis of homogeneous mixture of exfoliated graphitic flakes and ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Bimi][Tf2N]). The exfoliated graphite flakes served as a structure-directing substance as well as additional carbon source in the fabrication. It was demonstrated that the use of graphite flakes increased the nitrogen doping level, optimized the composition of active nitrogen configurations, and enlarged the specific surface area of the catalysts. Electrochemical characterizations revealed that the N and S codoped carbon fabricated by this method exhibited superior catalytic activities toward ORR under both acidic and alkaline conditions. Particularly in alkaline solution, the current catalyst compared favorably to the conventional 20 wt % Pt/C catalyst via four-electron transfer pathway with better ORR selectivity. The excellent catalytic activity was mainly ascribed to high nitrogen doping content, appropriate constitution of active nitrogen configurations, large specific surface area, and synergistic effect of N and S codoping. PMID- 25781630 TI - Can the same species of Platynosomum (Trematoda: Dicrocoeliidae) infect both mammalian and avian hosts? AB - The importance of platynosomiasis has increased in feline veterinary practice, but aspects related to the specificity of Platynosomum spp. in definitive hosts requires further study. Although morphological traits suggest that the same species, P. illiciens, may infect both birds and mammals, the synonymies previously proposed have not been widely accepted, likely because host specificity is assumed. In addition, the name P. fastosum has frequently been used for parasites recovered from mammals. In the present study, metacercariae (n= 100/animal) of P. illiciens recovered from lizards (Hemidactylus mabouia) in Brazil were fed to Australian parakeets (Melopsittacus undulatus) and mice. Two parasites were recovered from the liver of one M. undulatus specimen during a necropsy that was performed 105 days after infection, and all mice were found to be infected with 37 +/- 12 (18-48) parasites. The morphology of the P. illiciens obtained from the parakeet was similar to that of parasites obtained from mice and those described previously from naturally infected birds and mammals. Non specificity of P. illiciens in hosts is discussed briefly, based on the parasitological and morphological results obtained during the avian experimental platynosomiasis and the epidemiology and geographical distribution of this parasite. PMID- 25781629 TI - The transcription factor c-Myc suppresses MiR-23b and MiR-27b transcription during fetal distress and increases the sensitivity of neurons to hypoxia-induced apoptosis. AB - Previous studies reported that the expression of miR-23b-27b cluster was downregulated in embryonic brain cortices during hypoxia-induced neuronal apoptosis. However, the mechanism underlying this downregulation is not completely understood. Here, we report that the transcription factor c-Myc plays an important role in regulating the expression of miR-23b-27b cluster during hypoxia. First, the c-Myc protein level was significantly elevated in embryonic brain cortices in a mouse model of fetal distress. Second, forced overexpression or knockdown of c-Myc could suppress or increase the expression of miR-23b-27b cluster polynucleotides. Third, we identified 2 conserved c-Myc binding sites (E boxes) in the enhancer and promoter regions of miR-23b-27b cluster in the mouse genome. Finally, we showed that elevated c-Myc expression led to an increase in the Apaf-1 level by suppressing miR-23b-27b cluster expression and that this enhanced neuronal sensitivity to apoptosis. In summary, our study demonstrates that c-Myc may suppress the expression of the miR-23b-27b cluster, resulting in additional neuronal apoptosis during hypoxia. PMID- 25781631 TI - Chalcogen bonding in solution: interactions of benzotelluradiazoles with anionic and uncharged Lewis bases. AB - Chalcogen bonding is the noncovalent interaction between an electron-deficient, covalently bonded chalcogen (Te, Se, S) and a Lewis base. Although substantial evidence supports the existence of chalcogen bonding in the solid state, quantitative data regarding the strengths of the interactions in the solution phase are lacking. Herein, determinations of the association constants of benzotelluradiazoles with a variety of Lewis bases (Cl(-), Br(-), I(-), NO3(-) and quinuclidine, in organic solvent) are described. The participation of the benzotelluradiazoles in chalcogen bonding interactions was probed by UV-vis, (1)H and (19)F NMR spectroscopy as well as nano-ESI mass spectrometry. Trends in the free energy of chalcogen bonds upon variation of the donor, acceptor and solvent are evident from these data, including a linear free energy relationship between chalcogen bond donor ability and calculated electrostatic potential at the tellurium center. Calculations using the dispersion-corrected B97-D3 functional were found to give good agreement with the experimental free energies of chalcogen bonding. PMID- 25781632 TI - Risk of cancer in patients with iron deficiency anemia: a nationwide population based study. AB - OBJECTIVE: This study evaluated the risk of cancer among patients with iron deficiency anemia (IDA) by using a nationwide population-based data set. METHOD: Patients newly diagnosed with IDA and without antecedent cancer between 2000 and 2010 were recruited from the Taiwan National Health Insurance Research Database. The standardized incidence ratios (SIRs) of cancer types among patients with IDA were calculated. RESULTS: Patients with IDA exhibited an increased overall cancer risk (SIR: 2.15). Subgroup analysis showed that patients of both sexes and in all age groups had an increased SIR. After we excluded patients diagnosed with cancer within the first and first 5 years of IDA diagnosis, the SIRs remained significantly elevated at 1.43 and 1.30, respectively. In addition, the risks of pancreatic (SIR: 2.31), kidney (SIR: 2.23), liver (SIR: 1.94), and bladder cancers (SIR: 1.74) remained significantly increased after exclusion of patients diagnosed with cancer within 5 years after IDA diagnosis. CONCLUSION: The overall cancer risk was significantly elevated among patients with IDA. After we excluded patients diagnosed with IDA and cancer within 1 and 5 years, the SIRs remained significantly elevated compared with those of the general population. The increased risk of cancer was not confined to gastrointestinal cancer when the SIRs of pancreatic, kidney, liver, and bladder cancers significantly increased after exclusion of patients diagnosed with IDA and cancer within the first 5 years. This finding may be caused by immune activities altered by IDA. Further study is necessary to determine the association between IDA and cancer risk. PMID- 25781634 TI - Enabling X-ray free electron laser crystallography for challenging biological systems from a limited number of crystals. AB - There is considerable potential for X-ray free electron lasers (XFELs) to enable determination of macromolecular crystal structures that are difficult to solve using current synchrotron sources. Prior XFEL studies often involved the collection of thousands to millions of diffraction images, in part due to limitations of data processing methods. We implemented a data processing system based on classical post-refinement techniques, adapted to specific properties of XFEL diffraction data. When applied to XFEL data from three different proteins collected using various sample delivery systems and XFEL beam parameters, our method improved the quality of the diffraction data as well as the resulting refined atomic models and electron density maps. Moreover, the number of observations for a reflection necessary to assemble an accurate data set could be reduced to a few observations. These developments will help expand the applicability of XFEL crystallography to challenging biological systems, including cases where sample is limited. PMID- 25781633 TI - Sensitization of neonatal rat lumbar motoneuron by the inflammatory pain mediator bradykinin. AB - Bradykinin (Bk) is a potent inflammatory mediator that causes hyperalgesia. The action of Bk on the sensory system is well documented but its effects on motoneurons, the final pathway of the motor system, are unknown. By a combination of patch-clamp recordings and two-photon calcium imaging, we found that Bk strongly sensitizes spinal motoneurons. Sensitization was characterized by an increased ability to generate self-sustained spiking in response to excitatory inputs. Our pharmacological study described a dual ionic mechanism to sensitize motoneurons, including inhibition of a barium-sensitive resting K(+) conductance and activation of a nonselective cationic conductance primarily mediated by Na(+). Examination of the upstream signaling pathways provided evidence for postsynaptic activation of B2 receptors, G protein activation of phospholipase C, InsP3 synthesis, and calmodulin activation. This study questions the influence of motoneurons in the assessment of hyperalgesia since the withdrawal motor reflex is commonly used as a surrogate pain model. PMID- 25781635 TI - Canolol inhibits gastric tumors initiation and progression through COX-2/PGE2 pathway in K19-C2mE transgenic mice. AB - 4-Vinyl-2, 6-dimethoxyphenol (canolol) is an antioxidant phenolic compound extracted from crude canola oil. In current research, K19-C2mE transgenic mice, developing hyperplastic tumors spontaneously in the glandular stomach, were used to study the mechanisms involved in the anti-inflammation and anti-tumor effects of canolol. Tg mice receiving canolol diet had a reduced tumor incidence, to 41.2%, compared with Non-treatment Tg mice, 77.8% of which had gastric tumor (P=0.002). Besides that, the mean tumor diameter was decreased from 6.5 mm to 4.5 mm (P<0.001) after canolol administration. COX-2/PGE2 pathway is known to play pivotal role in inflammation-induced gastric tumorigenesis. The neutrophils and lymphocytes infiltration was suppressed significantly, and the mRNA levels of the proinflammatory cytokines COX-2, IL-1beta and IL-12b were also downregulated in gastric mucosa. Additionally, immunohistochemical analysis showed that COX-2, EP2, Galphas and beta-catenin, key factors involving in PGE2 signal transduction, were positive staining with higher H scores in Non-treatment Tg mice, while the expressions were suppressed significantly by 0.1% canolol (P<0.001). In addition, tumor-suppressor miR-7 was reactivated after canolol administration, and COX-2 was showed to be a functional target of miR-7 to suppress the tumor progression. In conclusion, canolol could inhibit the gastritis-related tumor initiation and progression, and the suppression effect was correlated with the blocking up of canonical COX-2/PGE2 signaling pathway and might be regulated by miR-7. PMID- 25781636 TI - Brain-sparing methods for IMRT of head and neck cancer. AB - PURPOSE: Radical radiotherapy for head and neck cancer (HNC) may deliver significant doses to brain structures. There is evidence that this may cause a decline in neurocognitive function (NCF). Radiation dose to the medial temporal lobes, and particularly to the hippocampi, seems to be critical in determining NCF outcomes. We evaluated the feasibility of two alternative intensity-modulated radiotherapy (IMRT) techniques to generate hippocampus- and brain-sparing HNC treatment plans to preserve NCF. METHODS AND MATERIALS: A planning study was undertaken for ten patients with HNC whose planning target volume (PTV) included the nasopharynx. Patients had been previously treated using standard (chemo)-IMRT techniques. Bilateral hippocampi were delineated according to the RTOG atlas, on T1w MRI co-registered to the RT planning CT. Hippocampus-sparing plans (HSRT), and whole-brain/hippocampus-sparing fixed-field non-coplanar IMRT (BSRT) plans, were generated. DVHs and dose difference maps were used to compare plans. NTCP calculations for NCF impairment, based on hippocampal dosimetry, were performed for all plans. RESULTS: Significant reductions in hippocampal doses relative to standard plans were achieved in eight of ten cases for both HSRT and BSRT. EQD2 D40% to bilateral hippocampi was significantly reduced from a mean of 23.5 Gy (range 14.5-35.0) in the standard plans to a mean of 8.6 Gy (4.2-24.7) for HSRT (p = 0.001) and a mean of 9.0 Gy (4.3-17.3) for BSRT (p < 0.001). Both HSRT and BSRT resulted in a significant reduction in doses to the whole brain, brain stem, and cerebellum. CONCLUSION: We demonstrate that IMRT plans for HNC involving the nasopharynx can be successfully optimised to significantly reduce dose to the bilateral hippocampi and whole brain. The magnitude of the achievable dose reductions results in significant reductions in the probability of radiation induced NCF decline. These results could readily be translated into a future clinical trial. PMID- 25781637 TI - Differentiation of equine induced pluripotent stem cells into a keratinocyte lineage. AB - REASONS FOR PERFORMING STUDY: Skin trauma in horses often leads to the development of chronic nonhealing wounds that lack a keratinocyte cover, vital for healing. Reports in mouse and man confirm the possibility of generating functional keratinocytes from induced pluripotent stem cells (iPSC), thus presenting myriad potential applications for wound management or treatment of skin disease. Similarly, differentiation of equine iPSC (eiPSC) into a keratinocyte lineage should provide opportunities for the advancement of veterinary regenerative medicine. OBJECTIVES: The purpose of this study was to develop an efficient method for the differentiation of eiPSC into a keratinocyte lineage. It was hypothesised that eiPSC can form differentiated keratinocytes (eiPSC-KC) comparable with primary equine keratinocytes (PEK) in their morphological and functional characteristics. STUDY DESIGN: Experimental in vitro study. METHODS: Equine iPSC established using a nonviral system were treated for 30 days with retinoic acid and bone morphogenetic protein-4 to induce directed differentiation into iPSC-KC. Temporospatial gene and protein expression by eiPSC KC was measured at weekly intervals of differentiation and in response to calcium switch. Proliferative and migratory capacities of eiPSC-KC were compared with those of PEK. RESULTS: Equine iPSC, upon directed differentiation, showed loss of pluripotency genes and progressive increase in pancytokeratin expression indicating ectodermal specification into keratinocytes. High differentiation efficiency was achieved, with 82.5% of eiPSC expressing keratin 14, a marker of epidermal-specific basal stem cells, after 30 days of directed differentiation. Moreover, the proliferative capacity of eiPSC-KC was superior, while the migratory capacity (measured as the ability to epithelise in vitro wounds) was comparable with that of PEK. CONCLUSIONS: This proof of concept study suggests that eiPSC can successfully be differentiated into equine keratinocytes (eiPSC KC) with features that are promising to the development of a stem cell-based skin construct, with the potential to regenerate lost or damaged skin. PMID- 25781638 TI - Study of the cardiotoxicity of Venenum Bufonis in rats using an 1H NMR-based metabolomics approach. AB - Venenum Bufonis, a well-known traditional Chinese medicine, has been widely used in Asia and has gained popularity in Western countries over the last decade. Venenum Bufonis has obvious side effects that have been observed in clinical settings, but few studies have reported on its cardiotoxicity. In this work, the cardiotoxicity of Venenum Bufonis was investigated using a 11H NMR-based metabolomics approach. The 1H NMR profiles of the serum, myocardial extracts and liver extracts of specific-pathogen-free rats showed that Venenum Bufonis produced significant metabolic perturbations dose-dependently with a distinct time effect, peaking at 2 hr after dosing and attenuating gradually. Clinical chemistry, electrocardiographic recordings, and histopathological evaluation provided additional evidence of Venenum Bufonis-induced cardiac damage that complemented and supported the metabolomics findings. The combined results demonstrated that oxidative stress, mitochondrial dysfunction, and energy metabolism perturbations were associated with the cardiac damage that results from Venenum Bufonis. PMID- 25781639 TI - Potential Benefits of Edible Berries in the Management of Aerodigestive and Gastrointestinal Tract Cancers: Preclinical and Clinical Evidence. AB - Epidemiological reports as well as experimental studies have demonstrated the significant health benefits provided by regular berry consumption. Berries possess both prophylactic and therapeutic potential against several chronic illnesses, such as cardiovascular, neurodegenerative, and neoplastic diseases. Berries owe their health benefits to phytoconstituents, such as polyphenolic anthocyanins, ellagic acid, and a diverse array of phytochemicals bestowed with potent antioxidant and anti-inflammatory effects as well as the ability to engage a multitude of signaling pathways. This review highlights the principal chemical constituents present in berries and their primary molecular targets. The article presents and critically analyzes the chemopreventive and therapeutic potential of berry extracts, fractions, and bioactive components on various cancers of the gastrointestinal tract (GIT), including esophageal, stomach, intestinal, and colorectal cancers as well as cancers of the upper aerodigestive tract, such as oral cancer. The current status of clinical studies evaluating berry products in several aforementioned cancers is presented. Various emerging issues including dose-ranging and dosage forms, the role of synergy and the usage of combination therapy as well as other relevant areas essential for the development of berry phytoconstituents as mainstream chemopreventive and therapeutic agents against aerodigestive and GIT cancers are critically discussed. PMID- 25781640 TI - REV3L, a promising target in regulating the chemosensitivity of cervical cancer cells. AB - REV3L, the catalytic subunit of DNA Polymerase zeta (Polzeta), plays a significant role in the DNA damage tolerance mechanism of translesion synthesis (TLS). The role of REV3L in chemosensitivity of cervical cancer needs exploration. In the present study, we evaluated the expression of the Polzeta protein in paraffin-embedded tissues using immunohistochemistry and found that the expression of Polzeta in cervical cancer tissues was higher than that in normal tissues. We then established some cervical cancer cell lines with REV3L suppression or overexpression. Depletion of REV3L suppresses cell proliferation and colony formation of cervical cancer cells through G1 arrest, and REV3L promotes cell proliferation and colony formation of cervical cancer cells by promoting G1 phase to S phase transition. The suppression of REV3L expression enhanced the sensitivity of cervical cancer cells to cisplatin, and the overexpression of REV3L conferred resistance to cisplatin as evidenced by the alteration of apoptosis rates, and significantly expression level changes of anti apoptotic proteins B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2 associated x protein (Bax). Our data suggest that REV3L plays an important role in regulating cervical cancer cellular response to cisplatin, and thus targeting REV3L may be a promising way to alter chemosensitivity in cervical cancer patients. PMID- 25781641 TI - Increased ventral-striatal activity during monetary decision making is a marker of problem poker gambling severity. AB - The aim of this study was to examine the impact of different neural systems on monetary decision making in frequent poker gamblers, who vary in their degree of problem gambling. Fifteen frequent poker players, ranging from non-problem to high-problem gambling, and 15 non-gambler controls were scanned using functional magnetic resonance imaging (fMRI) while performing the Iowa Gambling Task (IGT). During IGT deck selection, between-group fMRI analyses showed that frequent poker gamblers exhibited higher ventral-striatal but lower dorsolateral prefrontal and orbitofrontal activations as compared with controls. Moreover, using functional connectivity analyses, we observed higher ventral-striatal connectivity in poker players, and in regions involved in attentional/motor control (posterior cingulate), visual (occipital gyrus) and auditory (temporal gyrus) processing. In poker gamblers, scores of problem gambling severity were positively associated with ventral-striatal activations and with the connectivity between the ventral striatum seed and the occipital fusiform gyrus and the middle temporal gyrus. Present results are consistent with findings from recent brain imaging studies showing that gambling disorder is associated with heightened motivational-reward processes during monetary decision making, which may hamper one's ability to moderate his level of monetary risk taking. PMID- 25781642 TI - The AreA transcription factor mediates the regulation of deoxynivalenol (DON) synthesis by ammonium and cyclic adenosine monophosphate (cAMP) signalling in Fusarium graminearum. AB - Deoxynivalenol (DON), a trichothecene mycotoxin produced by Fusarium graminearum, is harmful to humans and animals. Because different nitrogen sources are known to have opposite effects on DON production, in this study, we characterized the regulatory mechanisms of the AREA transcription factor in trichothecene biosynthesis. The DeltaareA mutant showed significantly reduced vegetative growth and DON production in cultures inoculated with hyphae. Suppression of TRI gene expression and DON production by ammonium were diminished in the DeltaareA mutant. The deletion of AREA also affected the stimulatory effects of arginine on DON biosynthesis. The AreA-green fluorescent protein (GFP) fusion complemented the DeltaareA mutant, and its localization to the nucleus was enhanced under nitrogen starvation conditions. Site-directed mutagenesis showed that the conserved predicted protein kinase A (PKA) phosphorylation site S874 was important for AreA function, indicating that AreA may be a downstream target of the cyclic adenosine monophosphate (cAMP)-PKA pathway, which is known to regulate DON production. We also showed that AreA interacted with Tri10 in co immunoprecipitation assays. The interaction of AreA with Tri10 is probably related to its role in the regulation of TRI gene expression. Interestingly, the DeltaareA mutant showed significantly reduced PKA activity and expression of all three predicted ammonium permease (MEP) genes, in particular MEP1, under low ammonium conditions. Taken together, our results show that AREA is involved in the regulation of DON production by ammonium suppression and the cAMP-PKA pathway. The AreA transcription factor may interact with Tri10 and control the expression and up-regulation of MEP genes. PMID- 25781643 TI - Editorial Comment to Maintenance monotherapy with gemcitabine after standard platinum-based chemotherapy in patients with advanced urothelial cancer. PMID- 25781644 TI - Healthcare utilization of people with type 2 diabetes in Germany: an analysis based on health insurance data. AB - AIMS: This population-based study assesses the healthcare utilization of people with Type 2 diabetes by analysing routine data from Allgemeine Orts-Krankenkasse (AOK), the largest statutory health insurance provider in Germany. METHODS: Anonymized billing data from all AOK-insured persons with at least one day of insurance during the evaluation year 2010 were analysed. Treatment and cost data from all areas of inpatient and outpatient care were available, as was information regarding patient age and sex. International Classification of Diseases (ICD-10) diagnosis and Anatomical Therapeutic Chemical (ATC) classification were used to identify 2.7 million insured persons with diabetes. RESULTS: The age- and sex-standardized prevalence of Type 2 diabetes was 9.8%. Of those patients identified, 33.9% had at least one diabetes-related complication and 83.0% had a diagnosis of hypertension. Almost two-thirds (63.1%) received antihyperglycaemic medication. Metformin and sulfonylurea were prescribed most often; medications without proof of benefit in endpoint studies were prescribed much less frequently. People without diabetes were admitted to hospital only half as often as those with Type 2 diabetes. The projected total expenditure in Germany for all people with Type 2 diabetes amounted to approximately ?33.3 billion in 2010. CONCLUSIONS: This study shows an increase in both the prevalence of diabetes and treatment costs. The majority of people with Type 2 diabetes were aged 70 years or older. One third of this group has diabetes-related complications. Antihyperglycaemic medications without proof of benefit in endpoint studies were prescribed much less frequently than drugs with proof of benefit. PMID- 25781646 TI - Rational synthesis and characterization of dimolybdenum(II) compounds bearing ferrocenyl-containing ligands toward modulation of electronic coupling. AB - Three novel cis-to-trans-converted dimolybdenum(II) complexes, trans-[Mo2(O2C Fc)2(DPPX)2][BF4]2 {2a-2c; DPPX = DPPA [N,N-bis(diphenylphosphino)amine], DPPM [1,1-bis(diphenylphosphino)methane], and DPPE [1,2-bis(diphenylphosphino)ethane], respectively}, were synthesized through the insertion of bulky diphosphine ligands, which force a permanent trans arrangement, as evidenced by X-ray crystallography and density functional theory calculations. All compounds were characterized by means of NMR, UV-vis, and IR spectroscopy as well as thermogravimetry-mass spectrometry measurements. Interestingly, uncommon UV-vis transitions and oxidation sequences were observed compared to previously reported ones. As verified by electrochemical measurements, all synthesized complexes show two separate one-electron-redox processes assigned to subsequent oxidations of the two redox-active ferrocenecarboxylate ligands, with a split of ca. 70 mV. This behavior reveals electronic interaction between the two equatorially trans positioned ferrocenyl units. The presented work provides new insights into the rational synthesis of electronically coupled trans-coordinated Mo2 systems, paving the way toward the design of linear multicenter redox-active oligomers. PMID- 25781645 TI - The activation of the atypical PKC zeta in light-induced retinal degeneration and its involvement in L-DNase II control. AB - Light-induced retinal degeneration is characterized by photoreceptor cell death. Many studies showed that photoreceptor demise is caspase-independent. In our laboratory we showed that leucocyte elastase inhibitor/LEI-derived DNase II (LEI/L-DNase II), a caspase-independent apoptotic pathway, is responsible for photoreceptor death. In this work, we investigated the activation of a pro survival kinase, the protein kinase C (PKC) zeta. We show that light exposure induced PKC zeta activation. PKC zeta interacts with LEI/L-DNase II and controls its DNase activity by impairing its nuclear translocation. These results highlight the role of PKC zeta in retinal physiology and show that this kinase can control caspase-independent pathways. PMID- 25781647 TI - Duchenne muscular dystrophy and the stomatognathic system. PMID- 25781648 TI - Surfactant aggregates templated by lateral confinement. AB - Self-assembly is widely seen as the method of choice for the bottom-up manufacture of supra-colloidal aggregates. Surfactants have been used extensively to appreciate qualitatively and quantify driving forces and methodologies for controlling self-assembling processes and the resultant self-assembled aggregates. However, not much is known regarding self-assembled surfactant aggregates formed on heterogeneous surfaces. If heterogeneous surface features affect the morphology of surfactant aggregates, it is possible that new templating methodologies could be designed by engineering surfaces. Here we report equilibrium dissipative particle dynamics simulation results for surfactants adsorbed on model heterogeneous surfaces. Our simulation results reveal that, depending on the morphological and chemical properties of the solid substrate, a number of not-before-reported structures can be obtained for the self-assembled aggregates. The results presented could be useful for the manufacture of new coatings and materials, e.g., via the admicellar polymerization procedure, as well as for interpreting experimental data for surfactant adsorption on heterogeneous surfaces. PMID- 25781649 TI - Potential treatments for genetic hearing loss in humans: current conundrums. AB - Genetic defects are a major cause of hearing loss in newborns. Consequently, hearing loss has a profound negative impact on human daily living. Numerous causative genes for genetic hearing loss have been identified. However, presently, there are no truly curative treatments for this condition. There have been several recent reports on successful treatments in mice using embryonic gene therapy, neonatal gene therapy and neonatal antisense oligonucleotide therapy. Herein, we describe state-of-the-art research on genetic hearing loss treatment through gene therapy and discuss the obstacles to overcome in curative treatments of genetic hearing loss in humans. PMID- 25781650 TI - Gene electrotransfer of plasmid AMEP, an integrin-targeted therapy, has antitumor and antiangiogenic action in murine B16 melanoma. AB - Gene therapy with Plasmid AMEP (antiangiogenic metargidin peptide) has recently been studied as a potential targeted therapy for melanoma. This plasmid is designed to downregulate alpha5beta1 and alphavbeta3 integrins. In our study, electroporation was used as a nonviral delivery system. We investigated the antiangiogenic and direct antitumor effectiveness of this gene therapy on low and highly metastatic B16 melanoma variants. In vitro, the antiangiogenic effectiveness as determined by tube formation assay on endothelial cells was predominantly dependent on AMEP expression levels. In vivo, antitumor effectiveness was mediated by the inhibition of proliferation, migration and invasion of melanoma cells and correlated with the expression of integrins on tumor cells after intratumor delivery. In addition, reduced metastatic potential was shown. Intramuscular gene electrotransfer of Plasmid AMEP, for AMEP systemic distribution, had no antitumor effect with this specific preventive treatment protocol, confirming that direct tumor delivery was more effective. This study confirms our previous in vitro data that the expression levels of integrins on melanoma cells could be used as a biomarker for antitumor effectiveness in integrin-targeted therapies, whereas the expression levels of AMEP peptide could be a predictive factor for antiangiogenic effectiveness of Plasmid AMEP in the treatment of melanoma. PMID- 25781652 TI - Synthesis and cavity size effect of Pd-containing macrocycle catalyst for efficient intramolecular hydroamination of allylurethane. AB - Palladium-containing macrocycle catalysts (PdMCs) with different ring sizes ranging from 24 to 30 members were synthesized. The intramolecular hydroamination of an allylurethane (AU) catalyzed by PdMCs proceeded efficiently to afford the corresponding oxazolidinone (OZ) in 95% isolated yield. The dependence of the hydroamination of AU to OZ on the cavity size indicated that the reaction rate was clearly controlled by both substrate uptake and product release steps. PMID- 25781651 TI - Gene delivery to the spinal cord using MRI-guided focused ultrasound. AB - Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 * 10(8), 2 * 10(9) and 7 * 10(9) vector genomes per gram (VG g(-1)). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 * 10(9) and 7 * 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 * 10(9) VG g(-1), GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner. PMID- 25781653 TI - The effects of bee venom acupuncture on the central nervous system and muscle in an animal hSOD1G93A mutant. AB - Amyotrophic lateral sclerosis (ALS) is caused by the degeneration of lower and upper motor neurons, leading to muscle paralysis and respiratory failure. However, there is no effective drug or therapy to treat ALS. Complementary and alternative medicine (CAM), including acupuncture, pharmacopuncture, herbal medicine, and massage is popular due to the significant limitations of conventional therapy. Bee venom acupuncture (BVA), also known as one of pharmacopunctures, has been used in Oriental medicine to treat inflammatory diseases. The purpose of this study is to investigate the effect of BVA on the central nervous system (CNS) and muscle in symptomatic hSOD1G93A transgenic mice, an animal model of ALS. Our findings show that BVA at ST36 enhanced motor function and decreased motor neuron death in the spinal cord compared to that observed in hSOD1G93A transgenic mice injected intraperitoneally (i.p.) with BV. Furthermore, BV treatment at ST36 eliminated signaling downstream of inflammatory proteins such as TLR4 in the spinal cords of symptomatic hSOD1G93A transgenic mice. However, i.p. treatment with BV reduced the levels of TNF-alpha and Bcl-2 expression in the muscle hSOD1G93A transgenic mice. Taken together, our findings suggest that BV pharmacopuncture into certain acupoints may act as a chemical stimulant to activate those acupoints and subsequently engage the endogenous immune modulatory system in the CNS in an animal model of ALS. PMID- 25781654 TI - Effects of acute exposure to increased plasma branched-chain amino acid concentrations on insulin-mediated plasma glucose turnover in healthy young subjects. AB - BACKGROUND: Plasma branched-chain amino acids (BCAA) are inversely related to insulin sensitivity of glucose metabolism in humans. However, currently, it is not known whether there is a cause-and-effect relationship between increased plasma BCAA concentrations and decreased insulin sensitivity. OBJECTIVE: To determine the effects of acute exposure to increased plasma BCAA concentrations on insulin-mediated plasma glucose turnover in humans. METHODS: Ten healthy subjects were randomly assigned to an experiment where insulin was infused at 40 mU/m2/min (40U) during the second half of a 6-hour intravenous infusion of a BCAA mixture (i.e., BCAA; N = 5) to stimulate plasma glucose turnover or under the same conditions without BCAA infusion (Control; N = 5). In a separate experiment, seven healthy subjects were randomly assigned to receive insulin infusion at 80 mU/m2/min (80U) in association with the above BCAA infusion (N = 4) or under the same conditions without BCAA infusion (N = 3). Plasma glucose turnover was measured prior to and during insulin infusion. RESULTS: Insulin infusion completely suppressed the endogenous glucose production (EGP) across all groups. The percent suppression of EGP was not different between Control and BCAA in either the 40U or 80U experiments (P > 0.05). Insulin infusion stimulated whole body glucose disposal rate (GDR) across all groups. However, the increase (%) in GDR was not different [median (1st quartile - 3rd quartile)] between Control and BCAA in either the 40U ([199 (167-278) vs. 186 (94-308)] or 80 U ([491 (414-548) vs. 478 (409-857)] experiments (P > 0.05). Likewise, insulin stimulated the glucose metabolic clearance in all experiments (P < 0.05) with no differences between Control and BCAA in either of the experiments (P > 0.05). CONCLUSION: Short-term exposure of young healthy subjects to increased plasma BCAA concentrations does not alter the insulin sensitivity of glucose metabolism. PMID- 25781656 TI - Healthy occupational culture for a worker-friendly workplace. AB - Work has numerous health and wellbeing benefits, but it also involves physical hazards and psychological exertion. Today the scale has tipped toward psychosocial factors. Workers' mental health affects their intellectual, emotional, and social growth, as well as work ability, productivity, and ultimately organisational productivity and competitiveness on the market. Even though companies may have an internal hierarchy that lowers stress at work, there are other formal and informal social processes that can affect (positively or negatively) the cohesion within the work unit. Safety culture of an organisation is a product of individual and group values, opinions, competences, and behavioural patterns that determine how occupational health and safety are implemented. Organisations that nurture positive safety culture understand the importance of health and safety and believe in prevention rather than dealing with consequences. Jobs that are stable, autonomous, and reasonably physically and psychologically demanding are far more likely to lower work-related stress and boost worker satisfaction. In fact, employee empowerment is one of the best ways to achieve good psychosocial health at the workplace. PMID- 25781655 TI - Limonoids and Triterpenoids from Dysoxylum mollissimum var. glaberrimum. AB - Seven new limonoids, dysomollides A-G (1-7), and two new cycloapotirucallane-type triterpenoids, dysomollins A and B (8 and 9), together with three known compounds, dysoxylumin A (10) and toonapubesins A (11) and B (12), were isolated from the twigs of Dysoxylum mollissimum var. glaberrimum. The structures of 1-9 were elucidated on the basis of spectroscopic methods. Compound 10 showed inhibitory activity against A549 cells with an IC50 value of 2.1 MUM, and compound 11 exhibited activity against P388 cells with an IC50 value of 6.7 MUM. PMID- 25781657 TI - Bionic approach for the prevention of exit-site infections of percutaneous devices. AB - Exit-site infections remain one of the main complications for percutaneous devices, such as catheters for peritoneal dialysis or drivelines for ventricular assist devices. Many efforts have been made to create a biological seal, yet without long-term success. This study investigates a new kind of percutaneous device which is coated with an extricable polymeric membrane. The bionic approach applies the naturally outwards directed growth of skin structures to technology: by pulling the protective membrane it slowly grows out of the body and a developing sulcus is exposed to dry air and an infection is avoided. In a feasibility study this kind of device was shown to reduce the rate of infection. To further investigate these devices, they were implanted in the skin of goats and observed for a period of more than 500 days. The membranes were pulled with a force of up to 2 N and the resulting movement was recorded. When being pulled, the membranes moved 0.4-0.9 mm per week, showing that the application of a continuously acting, defined force on the protective membrane causes the desired slow movement. PMID- 25781658 TI - Segmented independent component analysis for improved separation of fetal cardiac signals from nonstationary fetal magnetocardiograms. AB - Fetal magnetocardiograms (fMCGs) have been successfully processed with independent component analysis (ICA) to separate the fetal cardiac signals, but ICA effectiveness can be limited by signal nonstationarities due to fetal movements. We propose an ICA-based method to improve the quality of fetal signals separated from fMCG affected by fetal movements. This technique (SegICA) includes a procedure to detect signal nonstationarities, according to which the fMCG recordings are divided in stationary segments that are then processed with ICA. The first and second statistical moments and the signal polarity reversal were used at different threshold levels to detect signal transients. SegICA effectiveness was assessed in two fMCG datasets (with and without fetal movements) by comparing the signal-to-noise ratio (SNR) of the signals extracted with ICA and with SegICA. Results showed that the SNR of fetal signals affected by fetal movements improved with SegICA, whereas the SNR gain was negligible elsewhere. The best measure to detect signal nonstationarities of physiological origin was signal polarity reversal at threshold level 0.9. The first statistical moment also provided good results at threshold level 0.6. SegICA seems a promising method to separate fetal cardiac signals of improved quality from nonstationary fMCG recordings affected by fetal movements. PMID- 25781659 TI - Fuzzy decision tree to classify complex fractionated atrial electrograms. AB - Catheter ablation has emerged as an effective treatment strategy for atrial fibrillation (AF) in recent years. During AF, complex fractionated atrial electrograms (CFAE) can be recorded and are known to be a potential target for ablation. Automatic algorithms have been developed to simplify CFAE detection, but they are often based on a single descriptor or a set of descriptors in combination with sharp decision classifiers. However, these methods do not reflect the progressive transition between CFAE classes. The aim of this study was to develop an automatic classification algorithm, which combines the information of a complete set of descriptors and allows for progressive and transparent decisions. We designed a method to automatically analyze CFAE based on a set of descriptors representing various aspects, such as shape, amplitude and temporal characteristics. A fuzzy decision tree (FDT) was trained and evaluated on 429 predefined electrograms. CFAE were classified into four subgroups with a correct rate of 81+/-3%. Electrograms with continuous activity were detected with a correct rate of 100%. In addition, a percentage of certainty is given for each electrogram to enable a comprehensive and transparent decision. The proposed FDT is able to classify CFAE with respect to their progressive transition and may allow objective and reproducible CFAE interpretation for clinical use. PMID- 25781661 TI - A method for stereoscopic strain analysis of the right ventricle by digital image correlation during coronary bypass surgery: short communication. AB - Perioperative cardiosurgical management of volume therapy remains one of the challenging tasks in cases of patients with severe heart disease. Early detection of congestive cardiac failure prevents subsequent low output and worse outcome. An effective method for controlling extracorporeal circulation is created by developing a non-invasive intraoperative method for right ventricular strain analysis through digital image contrast correlation. PMID- 25781660 TI - Adhesive strength of total knee endoprostheses to bone cement - analysis of metallic and ceramic femoral components under worst-case conditions. AB - Evaluation of the adhesive strength of femoral components to the bone cement is a relevant parameter for predicting implant safety. In the present experimental study, three types of cemented femoral components (metallic, ceramic and silica/silane-layered ceramic) of the bicondylar Multigen Plus knee system, implanted on composite femora were analysed. A pull-off test with the femoral components was performed after different load and several cementing conditions (four groups and n=3 components of each metallic, ceramic and silica/silane layered ceramic in each group). Pull-off forces were comparable for the metallic and the silica/silane-layered ceramic femoral components (mean 4769 N and 4298 N) under standard test condition, whereas uncoated ceramic femoral components showed reduced pull-off forces (mean 2322 N). Loading under worst-case conditions led to decreased adhesive strength by loosening of the interface implant and bone cement using uncoated metallic and ceramic femoral components, respectively. Silica/silane-coated ceramic components were stably fixed even under worst-case conditions. Loading under high flexion angles can induce interfacial tensile stress, which could promote early implant loosening. In conclusion, a silica/silane-coating layer on the femoral component increased their adhesive strength to bone cement. Thicker cement mantles (>2 mm) reduce adhesive strength of the femoral component and can increase the risk of cement break-off. PMID- 25781662 TI - Differential osteogenicity of multiple donor-derived human mesenchymal stem cells and osteoblasts in monolayer, scaffold-based 3D culture and in vivo. AB - We set out to compare the osteogenicity of human mesenchymal stem (hMSCs) and osteoblasts (hOBs). Upon osteogenic induction in monolayer, hMSCs showed superior matrix mineralization expressing characteristic bone-related genes. For scaffold cultures, both cell types presented spindle-shaped, osteoblast-like morphologies forming a dense, interconnected network of high viability. On the scaffolds, hOBs proliferated faster. A general upregulation of parathyroid hormone-related protein (PTHrP), osteoprotegrin (OPG), receptor activator of NF-kappaB ligand (RANKL), sclerostin (SOST), and dentin matrix protein 1 (DMP1) was observed for both cell types. Simultaneously, PTHrP, RANKL and DMP-1 expression decreased under osteogenic stimulation, while OPG and SOST increased significantly. Following transplantation into NOD/SCID mice, MUCT and histology showed increased bone deposition with hOBs. The bone was vascularized, and amounts further increased for both cell types after recombinant human bone morphogenic protein 7 (rhBMP-7) addition also stimulating osteoclastogenesis. Complete bone organogenesis was evidenced by the presence of osteocytes and hematopoietic precursors. Our study results support the asking to develop 3D cellular models closely mimicking the functions of living tissues suitable for in vivo translation. PMID- 25781663 TI - Research on polyvinylidene fluoride (PVDF) hollow-fiber hemodialyzer. AB - In this study, polyvinylidene fluoride (PVDF) hollow-fiber hemodialysis membranes were prepared by non-solvent-induced phase separation. The PVDF hollow-fiber hemodialyzers were prepared by centrifugal casting. The results showed that the PVDF membrane had better mechanical and separation properties when the membrane wall thickness was 40 MUm and the N,N-dimethylacetamide in the core was 70 Vol%. Compared with commercial polysulfone hemodialysis membrane (Fresenius F60S membrane), the PVDF membrane had better mechanical property and ultrafiltration (UF) flux of pure water. The PVDF dialyzer's removal efficiency for middle molecules was proven to be much higher than that of the F60S dialyzer. The UF coefficient of a high-flux PVDF dialyzer is 62.6 ml/h/mm Hg, whereas F60S is 42.5 ml/h/mm Hg, which can promote clearance for middle molecules. PMID- 25781665 TI - Oral health habits, attitudes and behaviors of Portuguese adolescents. AB - PURPOSE: Oral health has a profound impact on the health of adolescents. The aim of the present study was to obtain information on habits, knowledge and oral hygiene attitudes of Portuguese teenagers and to study the gender differences concerning these issues. METHODS: A total of 1203 adolescents participated in the study (55.8% females; mean age, 14.9 years). To recruit participants, a national network of community dental hygienists, working in the health centers, was created, and adolescents were contacted at the schools. A questionnaire was applied in the classroom, during school hours, under supervision of one researcher and the classroom teacher, after collection of informed consent forms. RESULTS: Portuguese adolescents do not seem to have dental fear but have some anxiety when at the dental office; girls are more anxious than boys. Girls are also more concerned with esthetics and aware of dental problems and care about oral health of family and friends. Parental supervision is more relevant for boys in order to obtain better compliance with dental care; however, 97.2% of the adolescents do not consider maintaining teeth throughout the lifetime as relevant. CONCLUSION: Teenagers recognize dental professionals as educators and oral health as relevant in their lives. It is possible to assume that gender has an influence on adolescent's habits, behavior and attitudes regarding oral hygiene. There is a difference between boys and girls concerning their habits, knowledge and attitudes in dental hygiene; this difference may show the need to create different strategies for oral health promotion for these two groups of adolescents. PMID- 25781666 TI - Using UV photoaged photography to better understand Western Australian teenagers' attitudes towards adopting sun-protective behaviors. AB - BACKGROUND: This study aimed to determine whether the viewing of a personal photoaged photograph had the capacity to alter Western Australian teenagers' pro tanning attitudes. METHOD: Semi-structured interviews were conducted with fifteen teenagers. FINDINGS: The teenagers' pro-tanning attitudes prior to viewing their photoaged photograph are encapsulated in the study's central theme: 'You've got to look after your skin and use sunscreen, but I always forget!'. Post-viewing their photoaged facial image many teenagers reiterated their intentions to adopt (when they remembered) skin-protective measures. However, photoaged photography did not alter other teenagers' intention to tan. NEW KNOWLEDGE: Teenagers who choose to continue to tan were aware of the long-term health risks associated with ultra-violet over-exposure. However, their desire remained strong to emulate the media promoted image of bronzed youth being popular individuals. Indeed, the social benefits of being considered attractive to their peers became an attitudinal barrier to the teenagers' adoption of skin-protective behaviours. Those teenagers who changed their pro-tanning attitudes following their viewing of their ultra-violet photoaged photograph did so because of the shock they received when they saw their sun-damaged facial image. This suggests that photoageing photography can be effective with many adolescents because it reduces the cause-and-effect delay that exists between the occurrence of sun-damage and its visual presentation in later-life. CONCLUSION: Greater effort needs to be focused on increasing teenagers' understanding of how sun-damage occurs, when it is appropriate to apply sunscreen, as well as in changing the prevailing media image of an attractive body being a tanned body. PMID- 25781664 TI - Strain at the internal cervical os assessed with quasi-static elastography is associated with the risk of spontaneous preterm delivery at <=34 weeks of gestation. AB - AIM: To evaluate the association between cervical strain assessed with quasi static elastography and spontaneous preterm delivery. METHODS: Quasi-static elastography was used to estimate cervical strain in 545 pregnant women with singleton pregnancies from 11 weeks to 28 weeks of gestation. Cervical strain was evaluated in one sagittal plane and in the cross-sectional planes of the internal cervical os and external cervical os. The distribution of strain values was categorized into quartiles for each studied region and their association with spontaneous preterm delivery at <=34 weeks and at <37 weeks of gestation was evaluated using logistic regression. RESULTS: The prevalence of spontaneous preterm delivery at <37 weeks of gestation was 8.2% (n=45), and that at <=34 weeks of gestation was 3.8% (n=21). Strain in the internal cervical os was the only elastography value associated with spontaneous preterm delivery. Women with strain values in the 3rd and 4th quartiles had a significantly higher risk of spontaneous preterm delivery at <=34 weeks and at <37 weeks of gestation when compared to women with strain values in the lowest quartile. When adjusting for a short cervix (<25 mm) and gestational age at examination, women with strain values in the 3rd quartile maintained a significant association with spontaneous preterm delivery at <=34 weeks (OR 9.0; 95% CI, 1.1-74.0; P=0.02), whereas women with strain values in the highest quartile were marginally more likely than women with lowest quartile strain values to deliver spontaneously at <=37 weeks of gestation (OR 95% CI: 2.8; [0.9-9.0]; P=0.08). CONCLUSION: Increased strain in the internal cervical os is associated with higher risk of spontaneous preterm delivery both at <=34 and <37 weeks of gestation. PMID- 25781667 TI - Insights into Facebook Pages: an early adolescent health research study page targeted at parents. AB - Facebook has been used in health research, but there is a lack of literature regarding how Facebook may be used to recruit younger adolescents. A Facebook Page was created for an adolescent cohort study on the effects of puberty hormones on well-being and behaviour in early adolescence. Used as a communication tool with existing participants, it also aimed to alert potential participants to the study. The purpose of this paper is to provide a detailed description of the development of the study Facebook Page and present the fan response to the types of posts made on the Page using the Facebook-generated Insights data. Two types of posts were made on the study Facebook Page. The first type was study-related update posts and events. The second was relevant adolescent and family research and current news posts. Observations on the use of and response to the Page were made over 1 year across three phases (phase 1, very low Facebook use; phase 2, high Facebook use; phase 3, low Facebook use). Most Page fans were female (88.6%), with the largest group of fans aged between 35 and 44 years. Study-related update posts with photographs were the most popular. This paper provides a model on which other researchers could base Facebook communication and potential recruitment in the absence of established guidelines. PMID- 25781668 TI - Sensation seeking indirectly affects perceptions of risk for co-occurrent substance use. AB - High sensation seekers engage in more frequent substance use and perceive a host of potentially dangerous activities as less risky than do low sensation seekers. However, despite a plethora of research on these topics, no study has examined the extent to which personal substance use mediates the association between sensation seeking and perceived risk of substance use. To address this question, we recruited a sample of 79 young adults (mean age=19.1 years, standard deviation=1.4). Participants completed questionnaire measures of sensation seeking, substance use, and perceived risk of co-occurrent substance use. Results from path-analytic modeling indicated that both alcohol use and marijuana use mediated the influence of sensation seeking on perceptions of risk for moderately risky, but not highly risky, pairs of substances. Strengths and limitations of the present study were discussed and directions for future research were suggested. PMID- 25781669 TI - Cross-sectional data on alcohol and marijuana use and sexual behavior among male and female secondary school students in New Providence, The Bahamas. AB - BACKGROUND: While The Bahamas have significantly reduced poor reproductive health outcomes among adolescents and emerging adults, data indicate that youth are engaged in sexual risk behaviors. Substance use has been linked to increased risk for HIV and sexually transmitted infections in other contexts. There are limited data on Bahamian youth in relation to consumption of alcohol and marijuana use and engagement in sexual behaviors. OBJECTIVE: This study aimed to assess potential relationships between alcohol and marijuana use and engagement in sexual behavior among government secondary school students in New Providence, The Bahamas. MATERIALS AND METHODS: Total sample size was 2572, and about 56% of respondents were female. Mean age was 14.2 (SD 2.7 years). Cross-sectional data came from a baseline survey conducted as part of a longitudinal randomized controlled evaluation of a school-based HIV prevention and reproductive health program in New Providence. RESULTS: Overall, 46.5% (519) males and 44.8% (652) females reported alcohol consumption; 7.3% (82) males and 1.7% (25) females reported use of marijuana in the last 6 months. About 43% (477) male respondents and 16% (231) female respondents reported ever having vaginal sex. Logistic regression analysis indicates that increased likelihood of engaging in sex during the past 6 months is associated with being older, male, and consuming alcohol and marijuana. CONCLUSION: These data provide a 'global correlation' between substance use and engagement in sexual behaviors among Bahamian adolescents. Longitudinal research is needed to assess event specific risks and identify mediating and moderating factors. These findings indicate the importance of integrating reproductive health and substance use education. PMID- 25781671 TI - Association between cardiovascular risk factors and carotid intima-media thickness in prepubertal Brazilian children. AB - BACKGROUND: Early exposure to cardiovascular risk factors creates a chronic inflammatory state that could damage the endothelium followed by thickening of the carotid intima-media. OBJECTIVE: To investigate the association of cardiovascular risk factors and thickening of the carotid intima. SUBJECTS/METHODS: Media in prepubertal children. In this cross-sectional study, carotid intima-media thickness (cIMT) and cardiovascular risk factors were assessed in 129 prepubertal children aged from 5 to 10 year. Association was assessed by simple and multivariate logistic regression analyses. RESULTS: In simple logistic regression analyses, body mass index (BMI) z-score, waist circumference, and systolic blood pressure (SBP) were positively associated with increased left, right, and average cIMT, whereas diastolic blood pressure was positively associated only with increased left and average cIMT (p<0.05). In multivariate logistic regression analyses increased left cIMT was positively associated to BMI z-score and SBP, and increased average cIMT was only positively associated to SBP (p<0.05). CONCLUSIONS: BMI z-score and SBP were the strongest risk factors for increased cIMT. PMID- 25781670 TI - Endothelial dysfunction and negative emotions in adolescent girls. AB - BACKGROUND: Endothelial dysfunction predicts adult cardiovascular disorder and may be associated with negative emotions in adolescents. This study was conducted to determine if hopelessness, hostility, and depressive, anxiety, or conduct disorders were associated with compromised endothelial function and whether those associations were mediated by health risk behaviors. METHODS: Endothelial function, assessed through brachial artery reactive hyperemia, was measured in a psychopathology enriched sample of 60 15-18-year-old girls. The correlations between hopelessness, hostility, and depressive, anxiety, or conduct disorders and the percent change in forearm vascular resistance (PCFVR) were measured. Possible mediation effects of health risk behaviors were tested. RESULTS: Hopelessness was negatively associated with PCFVR, controlling for race and body mass index. Conduct disorder without any anxiety disorder was associated with better endothelial function. The other negative emotions were not associated with PCFVR. Risky health behaviors were associated with conduct disorder and hopelessness, but not with PCFVR, so there was no evidence of mediation. CONCLUSION: The main finding was that hopelessness in adolescent girls was associated with endothelial dysfunction. This may indicate that when present, hopelessness places a girl at risk for later cardiovascular disease, whether she has a psychiatric disorder or not. Possible mechanisms for this finding are examined and the surprising finding that conduct disorder is associated with better endothelial function is also discussed. Suggestions for future research are presented. PMID- 25781672 TI - Sulfonylurea in the treatment of neonatal diabetes mellitus children with heterogeneous genetic backgrounds. AB - OBJECTIVE: The pathogenic base of neonatal diabetes mellitus (NDM) is highly heterogeneous. Sulfonylurea (SU) has been successfully applied in majority of NDM patients with KATP channel mutations; however, its rationality and effectiveness among patients with NDM stemmed from other genetic mutations have not been established. The objective of the present study was to investigate the effectiveness of SU therapy in NDM patients with heterogeneous genetic backgrounds. METHODS: We identified 16 patients with NDM. These patients underwent SU titration and were followed after successful SU monotherapy. All patients were sequenced for all exons and adjacent intron-exon junctions of ABCC8, KCNJ11, and INS, and analyzed for 6q24 methylation defects. SU regimens were applied and glycemic status was evaluated in each patient. RESULTS: Of the 16 patients, 15 (94%) reached glycemic goal (7-10 mmol/L) after SU monotherapy except one patient with the INS mutation. No significant side effects or organ damage were found in any of the 16 patients. Among these patients, five were found to harbor ABCC8 mutations, another five had mutations in KCNJ11, two had INS gene mutations, one with 6q24 hypomethylation, and three were absent for defects in genes tested. CONCLUSION: Our study showed that SU monotherapy resulted in satisfactory glycemic control in most of the patients with NDM whose genetic defects are heterogeneous. The usage of SU may be considered as first line therapy for patients with NDM in developing countries where effective genetic screening is not established. PMID- 25781673 TI - Hypothalamic obesity in children: pathophysiology to clinical management. AB - Hypothalamic obesity (HyOb) is a complex neuroendocrine disorder caused by damage to the hypothalamus, which results in disruption of energy regulation. The key hypothalamic areas of energy regulation are the ARC (arcuate nucleus), the VMH (ventromedial hypothalamus), the PVN (paraventriculer nuclei) and the LHA (lateral hypothalamic area). These pathways can be disrupted mechanically by hypothalamic tumors, neurosurgery, inflammatory disorders, radiotherapy and trauma or functionally as such seen in genetic diseases. Rapid weight gain and severe obesity are the most striking features of HyOb and caused by hyperphagia, reduced basal metabolic rate (BMR) and decreased physical activity. HyOb is usually unresponsive to diet and exercise. Although, GLP-1 and its anologs seem to be a new agent, there is still no curative treatment. Thus, prevention is of prime importance and the clinicians should be alert and vigilant in patients at risk for development of HyOb. PMID- 25781674 TI - Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology. AB - Leukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic resonance imaging brain scans of elderly people with prevalence ranging from 50% to 100%. Although it remains asymptomatic, LA is not considered to be benign, and it is showed to be related to a host of poor clinical outcomes and increases the risk of disability, dementia, depression, stroke, and the overall morbidity and mortality. Pathologically, LA is characterized by loss of myelin and axons, patchy demyelination, and denudation of ependyma in regions of WMH. Age and hypertension are the most importantly established risk factors for LA. However, the precise pathogenic mechanisms remain unclear. Together with the previous findings, our recent genetic results strongly supported that LA is associated with immune response and neuroinflammation. Therefore, we confidently hypothesized that LA was not only a common neuroimaging phenomenon in the elderly but also an emerging neuroinflammatory disorder in the central nervous system. This article focusing on neuroimaging classification, genetics basis, and putative molecular mechanism introduced the basic knowledge and current status of LA and put forward some of our research ideas and results from our molecular genetics research, which may pave the way for deciphering the putative pathogenic mechanism, risk factor, epigenetic index, and its application in diagnostic agents or drug target for prevention and treatment. Thus, it could provide clinicians and researchers with a specific and modern overview of LA to enable the understanding of recent progress and future directions in this illness. PMID- 25781675 TI - Olfactory mucosa: a rich source of cell therapy for central nervous system repair. AB - Damage to the brain and spinal cord leads to permanent functional disability because of the very limited capacity of the central nervous system (CNS) for repair. Cell therapy is thought to be a promising strategy for CNS repair. The proper cell type of transplantation for CNS repair has not been identified until now, but autologous transplantation would be advantageous. The olfactory mucosa (OM), from the olfactory system, in which the neurosensory cells are replaced throughout adult life, is thought to be a rich source of cell therapy for CNS repair. The OM is a heterogeneous tissue composed of a variety of cells supporting both normal function and regenerative capacity, in which many studies focused on four major types of cells, including horizontal basal cells (HBCs), globose basal cells (GBC), mesenchymal stem cells (MSCs), and olfactory ensheathing cells (OECs). Here, we review the four major types of cells in the OM and shed light on the potential of the OM for CNS repair. PMID- 25781676 TI - Neurobehavioural evaluation of Lophira alata (Ochnaceae) stem bark extract in mice. AB - BACKGROUND: Stem bark and leaves of Lophira alata (Family: Ochnaceae) have been used traditionally for their anti-psychotic, anti-convulsant and anxiolytic properties. Since no existing data was found on the neurobehavioural properties, this study was carried out to evaluate some neurobehavioural properties of the aqueous extract of the stem bark of L. alata in animal models. METHODS: The oral mean lethal dose (LD50) of the extract was estimated, and preliminary phytochemical screening was conducted. Lophira alata extract (200, 400 and 800 mg/kg, p.o.) was investigated for antidepressant effect using the forced swim and tail suspension tests, and the anxiolytic potential was assessed using the stair case and hole board tests. Pentylenetetrazole-induced convulsion test was used to investigate the anticonvulsant potential of the extract. RESULTS: The LD50 was estimated to be >5000 mg/kg. Oral administration of L. alata extract produced a significant (p<0.05) non-dose-dependent decrease in the period of immobility in both the forced swim and tail suspension tests. While a significant decrease (p<0.05) in episodes of grooming was recorded in the staircase test, the number of head dips was not significantly reduced (p>0.05) in the hole board test. In the pentylenetetrazole-induced convulsion, a non-dose-dependent increase in onset of tonic-clonic seizures and protection from death was recorded. CONCLUSIONS: The results obtained suggest that the aqueous stem bark extract of L. alata possesses neurobehavioural properties which may account for its use in ethnomedicine. PMID- 25781677 TI - Redox regulation of T-cell receptor signaling. AB - T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling. PMID- 25781678 TI - The transporter associated with antigen processing: a key player in adaptive immunity. AB - The adaptive immune system co-evolved with sophisticated pathways of antigen processing for efficient clearance of viral infections and malignant transformation. Antigenic peptides are primarily generated by proteasomal degradation and translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). In the ER, peptides are loaded onto major histocompatibility complex I (MHC I) molecules orchestrated by a multisubunit peptide-loading complex (PLC). Peptide-MHC I complexes are targeted to the cell surface for antigen presentation to cytotoxic T cells, which eventually leads to the elimination of virally infected or malignantly transformed cells. Here, we review MHC I mediated antigen processing with a primary focus on the function and structural organization of the heterodimeric ATP-binding cassette (ABC) transporter TAP1/2. We discuss recent data on the molecular transport mechanism of the antigen translocation complex with respect to structural and biochemical information of other ABC exporters. We further summarize how TAP provides a scaffold for the assembly of the macromolecular PLC, thereby coupling peptide translocation with MHC I loading. TAP inhibition by distinct viral evasins highlights the important role of TAP in adaptive immunity. PMID- 25781679 TI - Functional properties of LptA and LptD in Anabaena sp. PCC 7120. AB - Lipopolysaccharides (LPS) are central components of the outer membrane and consist of Lipid A, the core polysaccharide, and the O-antigen. The synthesis of LPS is initiated at the cytosolic face of the cytoplasmic membrane. The subsequent transport to and across the outer membrane involves multiple lipopolysaccharide transport (Lpt) proteins. Among those proteins, the periplasmic-localized LptA and the outer membrane-embedded LptD participate in the last steps of transfer and insertion of LPS into the outer membrane. While the process is described for proteobacterial model systems, not much is known about the machinery in cyanobacteria. We demonstrate that anaLptD (alr1278) of Anabaena sp. PCC 7120 is important for cell wall function and its pore domain shows a Lipid A sensitive cation-selective gating behavior. The N-terminal domain of anaLptD recognizes anaLptA (alr4067), but not ecLptA. Furthermore, anaLptA specifically interacts with the Lipid A from Anabaena sp. PCC 7120 only, while anaLptD binds to Lipid A isolated from Escherichia coli as well. Based on the comparative analysis of proteins from E. coli and Anabaena sp. we discuss the properties of the cyanobacterial Lpt system. PMID- 25781680 TI - Rapid transfer of overexpressed integral membrane protein from the host membrane into soluble lipid nanodiscs without previous purification. AB - Structural and functional characterization of integral membrane proteins in a bilayer environment is strongly hampered by the requirement of detergents for solubilization and subsequent purification, as detergents commonly affect their structure and/or activity. Here, we describe a rapid procedure with minimal exposure to detergent to directly assemble an overexpressed integral membrane protein into soluble lipid nanodiscs prior to purification. This is exemplified with recombinant his-tagged rhodopsin, which is rapidly extracted from its host membrane and directly assembled into membrane scaffold protein (MSP) nanodiscs. We further demonstrate that, even when the MSP was his-tagged as well, partial purification of the rhodopsin-nanodiscs could be achieved exploiting immobilized metal chromatography. Recoveries of rhodopsin up to 80% were achieved in the purified nanodisc fraction. Over 95% of contaminating membrane protein and his tagged MSP could be removed from the rhodopsin-nanodiscs using a single Ni2+ affinity chromatography step. This level of purification is amply sufficient for functional studies. We provide evidence that the obtained rhodopsin-nanodisc preparations are fully functional both photochemically and in their ability to bind the cognate G-protein. PMID- 25781681 TI - Ras activation revisited: role of GEF and GAP systems. AB - Ras is a prototypical small G-protein and a central regulator of growth, proliferation and differentiation processes in virtually every nucleated cell. As such, Ras becomes engaged and activated by multiple growth factors, mitogens, cytokines or adhesion receptors. Ras activation comes about by changes in the steady-state equilibrium between the inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states of Ras, resulting in the mostly transient accumulation of Ras-GTP. Three decades of intense Ras research have disclosed various families of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) as the two principal regulatory elements of the Ras-GDP/GTP loading status. However, with the possible exception of the GEF Sos, we still have only a rudimentary knowledge of the precise role played by many GEF and GAP members in the signalling network upstream of Ras. As for GAPs, we even lack the fundamental understanding of whether they function as genuine signal transducers in the context of growth factor-elicited Ras activation or rather act as passive modulators of the Ras-GDP/GTP cycle. Here we sift through the large body of Ras literature and review the relevant data for understanding the participation and precise role played by GEFs and GAPs in the process of Ras activation. PMID- 25781682 TI - Sphingolipids in liver injury, repair and regeneration. AB - Sphingolipids are not only essential components of cellular membranes but also function as intracellular and extracellular mediators that regulate important physiological cellular processes including cell survival, proliferation, apoptosis, differentiation, migration and immune responses. The liver possesses the unique ability to regenerate after injury in a complex manner that involves numerous mediators, including sphingolipids such as ceramide and sphingosine 1 phosphate. Here we present the current understanding of the involvement of the sphingolipid pathway and the role this pathway plays in regulating liver injury, repair and regeneration. The regulation of sphingolipids and their enzymes may have a great impact in the development of novel therapeutic modalities for a variety of liver injuries and diseases. PMID- 25781683 TI - Overview of the roles of Sox2 in stem cell and development. AB - Sox2 is well known for its functions in embryonic stem (ES) cell pluripotency, maintenance, and self-renewal, and it is an essential factor in generating inducible pluripotent stem (iPS) cells. It also plays an important role in development and adult tissue homeostasis of different tissues, especially the central nervous system. Increasing evidence has shown that aging is a stemness related process in which Sox2 is also implicated as a key player, especially in the neural system. These distinct roles that Sox2 plays involve delicate regulatory networks consisting of other master transcription factors, microRNAs and signaling pathways. Additionally, the expression level of Sox2 can also be modulated transcriptionally, translationally or post-translationally. Here we will mainly review the roles of Sox2 in stem cell related development, homeostasis maintenance, aging processes, and the underlying molecular mechanisms involved. PMID- 25781684 TI - Fascin is a circulating tumor marker for head and neck cancer as determined by a proteomic analysis of interstitial fluid from the tumor microenvironment. AB - BACKGROUND: Head and neck cancer (HNC) is a prevalent cancer worldwide; however, clinically useful tumor markers for HNC have not been identified. Here, we aimed to identify secretory proteins from the tumor microenvironment as candidate circulating tumor markers. METHODS: Samples derived from seven pairs of tumor interstitial fluid (TIF) and normal interstitial fluid (NIF) samples from patients with HNC were analyzed. The proteomes were determined by gel-based-mass spectrometry proteomic methods. The most up-regulated protein, fascin was confirmed in the cancer tissues and cell culture supernatant by immunoblotting and immunohistochemistry assays. Serum fascin was determined in 40 HNC and 40 normal individuals by ELISA. RESULTS: After proteomics analysis, 189 peptides were identified, corresponding to 75 proteins. Of the 21 proteins which were identified more than twice, five up-regulated proteins identified most frequently including fascin. The most elevated fascin was over-expressed in cancer tissues and cell culture supernatant. Serum fascin was significantly up-regulated in the cancer patients (p<0.001) and correlated with pathological lymph node metastasis (p=0.022). To assess the diagnostic efficacy, serum levels of fascin and another potential biomarker SCCA were determined. Fascin showed a high predictable value with an area under the curve (AUC) of 0.808 (95% CI 0.723-0.901) in the receiver operator curve (ROC), compared to 0.501 (95% CI 0.378-0.634) for SCCA. CONCLUSIONS: We have identified 75 potential circulating tumor markers associated with HNC, including fascin. Serum fascin could discriminate cancer patients from healthy individuals; thus, it may serve as a circulating biomarker for HNC. PMID- 25781685 TI - Serum brain injury biomarkers as predictors of mortality after severe aneurysmal subarachnoid hemorrhage: preliminary results. PMID- 25781686 TI - Real-world costs of laboratory tests for non-small cell lung cancer. PMID- 25781687 TI - High-sensitivity assays for cardiac troponins. PMID- 25781688 TI - First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus. AB - BACKGROUND: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy. METHODS: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean+/-SD: TTR 3.96+/-0.89 MUmol/L vs. 4.68+/-1.21 MUmol/L, RBP4 1.13+/-0.25 MUmol/L vs. 1.33+/-0.38 MUmol/L and ROH 1.33+/-0.17 MUmol/L vs. 1.62+/-0.29 MUmol/L, p<0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p<0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95% CI 0.87-0.98, p<0.05). CONCLUSIONS: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM. PMID- 25781689 TI - Reply. Impact of assay design on test performance: lessons learned from 25 hydroxyvitamin D. Authors' response to the Letter to the Editor by Donnelly et al. PMID- 25781690 TI - Hemoglobin Valme HBB:c.124T>G: a new hemoglobin variant with diminished oxygen affinity causes interference in hemoglobin A1c measurement in an automated ion exchange HPLC method. PMID- 25781691 TI - Comparison of the bead-based simultaneous analysis of specific platelet antibodies assay (SASPA) and Pak Lx Luminex technology with the monoclonal antibody immobilization of platelet antigens assay (MAIPA) to detect platelet alloantibodies. AB - BACKGROUND: The identification of platelet alloantibodies is indispensible for the diagnoses of fetal/neonatal alloimmune thrombocytopenia and refractoriness to platelet transfusions. METHODS: We compared the results obtained with the gold standard assay for the detection and specification of platelet antibodies, the monoclonal antibody-specific immobilization of platelet antigen assay (MAIPA), with those from two bead-based assays, simultaneous analysis of specific platelet antibodies assay (SASPA), and the recently commercialized bead-based assay Pak Lx. RESULTS: For the detection of alloantibodies by SASPA, the sensitivity was 94.6%, the specificity was 99.5% The respective results for Pak Lx were 98% and 99.8%. Some antibody specificities were revealed by SASPA or Pak Lx but not by MAIPA. However, there were also antibodies detected by MAIPA that were not seen by SASPA or Pak Lx. Antibody dilution experiments suggest that SASPA or Pak Lx are more sensitive than MAIPA. CONCLUSIONS: All three assays have limitations, but Pak Lx is suited for screening. However, other assays are necessary if results are not conclusive or for evaluations beyond the commercial assay's design. PMID- 25781692 TI - Measurement of the inflammatory response in the early postoperative period after hip and knee arthroplasty. AB - BACKGROUND: The aim of this study was to identify an inflammatory marker with fast and predictable kinetics to enable future discrimination between normal postoperative inflammation and potential infection after total hip and knee arthroplasty cases. METHODS: Changes in serum levels of C-reactive protein (CRP), interleukins (IL) 1beta, 6 and 8 and NT-proCNP peptide were measured before and during first 5 postoperative days in 100 patients undergoing total hip or knee arthroplasty. We also compared two methods to describe the magnitude of inflammation--applying separate two sample tests at each time point, and summary measures--area under the curve (AUC). RESULTS: IL-6 showed a similar kinetics pattern to the CRP in response to surgical trauma. Significantly greater level changes in all markers but NT-proCNP were observed in knee patients. Persisting high levels of CRP, but not other markers, were observed in obese hip patients. IL-6 was found to be an adjunct to routine CRP use. CONCLUSIONS: IL-6 has faster kinetics and is less influenced by patient weight, therefore it seems to be more useful in clinical practice. Summary measures describe the inflammatory response well and are easier to analyze than multiple analyses of single time points. PMID- 25781693 TI - Identification of molecular species of oxidized triglyceride in plasma and its distribution in lipoproteins. AB - BACKGROUND: The role of triglycerides carried in the triglyceride-rich lipoproteins (TRL) in the progression of atherosclerosis is uncertain. Identification of oxidized triglycerides and its possible association with atherosclerosis were largely ignored. Here we applied mass spectrometric approach to detect and identify triglyceride hydroperoxides (TGOOH) in human plasma and lipoproteins. METHODS: EDTA plasma was collected from healthy human volunteers (n=9) after 14-16 h of fasting. Very low-density lipoprotein (VLDL) (d<1.006) and intermediate-density lipoprotein (IDL) (d=1.006-1.019) were isolated from the plasma (n=6) by sequential ultracentrifugation in KBr, followed by the isolation of LDL and high-density lipoprotein (HDL) using size-exclusion high-performance liquid chromatography (HPLC). Total lipids from the plasma and isolated lipoproteins were extracted, and analyzed for the detection and identification of TGOOH using liquid chromatography/LTQ ion trap Orbitrap mass spectrometry. All the processes, from specimen collection to the mass spectrometric analysis, were carried out at 4 degrees C in the presence of antioxidant to prevent oxidation of lipoproteins. RESULTS: We identified 11 molecular species of TGOOH in either plasma or VLDL and IDL, of which TGOOH-18:1/18:2/16:0, TGOOH-18:1/18:1/16:0, TGOOH-16:0/18:2/16:0, TGOOH-18:1/18:1/18:1, and TGOOH-16:0/20:4/16:0 were most dominant. These TGOOH molecules are carried by TRL but not by LDL and HDL. Mean concentration of TGOOH in plasma, VLDL and IDL were, respectively, 56.1 +/- 25.6, 349.8 +/- 253.6 and 512.5 +/- 173.2 MUmol/mol of triglycerides. CONCLUSIONS: This is the first report to identify several molecular species of oxidized triglycerides in TRL. Presence of oxidized triglyceride may contribute to the atherogenicity of TRL. Further work is needed to elucidate the association of the oxidized triglyceride in atherosclerosis. PMID- 25781694 TI - The relationship of fibroblast growth factors 21 and 23 and alpha-Klotho with platelet activity measured by platelet volume indices. AB - BACKGROUND: Subjects with high fibroblast growth factor 21(FGF21) and 23 (FGF23), endocrine hormones that regulate insulin sensitivity and phosphate metabolism, respectively, are reported to have a higher risk for adverse cardiovascular outcome. Therefore, the relationship of FGF21, FGF23, and alpha-Klotho (co receptor for FGF23 signaling) with mean platelet volume (MPV) and platelet distribution width (PDW), two platelet volume indices that reflect platelet activity, was investigated. METHODS: Data from 156 patients admitted to the cardiology department were analyzed. MPV and PDW were measured by an automatic blood counter, and serum FGF21, FGF23, and alpha-Klotho concentrations were measured by an enzyme-linked immunoassay. RESULTS: Log(FGF21) was significantly correlated with serum triglycerides but did not differ according to the use of non-use of antidiabetic or lipid-lowering drugs. MPV and PDW were significantly correlated (R=0.475, p<0.001). MPV was significantly correlated with log(FGF21) (R=-0.167, p<0.05) and log(FGF23) (R=0.351, p<0.001) but not with log(alpha Klotho). Linear regression analysis showed a negative and positive association of log(FGF21) and log(FGF23), respectively, with MPV that was independent of possible confounders including sex, age, renal function, and antithrombotic drug use. In addition, log(FGF23) was found to have a significant independent positive association with PDW. CONCLUSIONS: Among cardiac patients, FGF21 had a negative association with MPV, whereas FGF23 had a positive association. Future studies of serum FGF23/FGF21 concentrations and the incidence of thromboembolic disorders are warranted. PMID- 25781695 TI - Reference ranges of serum bile acids in children and adolescents. AB - BACKGROUND: Bile acids (BA) are found predominantly in bile but also in serum, where they can be used as markers for inborn and acquired hepatobiliary disorders. We measured serum BA levels by mass spectrometry to determine reference ranges for healthy children and adolescents in different age groups. METHODS: In 194 healthy children and adolescents (0-19 years) concentrations of serum BA and BA composition were determined using high-performance liquid chromatography high-resolution mass spectrometry. Individuals were classified by ages into five groups: 0-5 months, 6-24 months, 3-5 years, 6-11 years, and >11 years. RESULTS: The 95% confidence interval of serum total BA values in newborns was 3.85-6.32 MUmol/L. In the cohort aged 6-24 months total BA values were significantly higher (6.61-9.43 MUmol/L; p<0.001). During growth, values decreased (6-11 years; 3.61-5.41 MUmol/L), and after 11 years (3.09-4.12 MUmol/L) resembled those in adults (0.28-6.50 MUmol/L). With respect to conjugation patterns, in neonates BA were primarily conjugated with taurine; however, after 6 months glycine conjugates clearly predominated. CONCLUSIONS: Our data show that serum BA values vary substantially during the first years of life and that reference ranges for BA are age-dependent. The physiologic mechanisms underlying these variations remain to be determined. PMID- 25781696 TI - Practicability of fetal scalp blood sampling during labor using microtubes and a point-of-care (POC) lactate testing device: difficulty assessment, sampling time and failure rates. PMID- 25781697 TI - Serum calcitonin negative medullary thyroid carcinoma: a systematic review of the literature. AB - Generally, calcitonin (CT) values below the upper reference limit rule-out medullary thyroid carcinoma (MTC) with very high accuracy. However, sparse cases of serum-calcitonin-negative MTC (CT-NEG-MTC) have been reported. Here we reviewed CT-NEG-MTC reported in literature, discussed the potential causes and proposed a practical laboratory and clinical approach. A comprehensive literature search was conducted by using the terms "medullary thyroid carcinoma" AND "non secreting calcitonin" OR "undetectable calcitonin". The search was updated until December 2014. Original articles that described CT-NEG-MTC were eligible for inclusion. Only MTC cases with preoperative CT below the upper reference limit were included in the present review. Eleven papers with 18 CT-NEG-MTC cases (age 50 years, size 26 mm) were retrieved. Four patients with poorly differentiated MTC died within 3 years. Different CT assays were employed and different reference values were adopted. Preoperative serum CT values were below the institution cut-off levels in all cases, and undetectable in four patients. In some papers negative CT results were confirmed by additional tests. Further laboratory investigations were performed in some of the included studies. In patients with well founded suspicious of MTC and within the reference limits/undetectable CT other laboratory investigations [carcinoembryonic antigen (CEA), procalcitonin, CT stimulation, CT in washout of nodule's aspiration] have to be performed. Surgical approach to CT-NEG-MTC does not differ from those secreting CT. Postoperative follow-up of these rare cases should include periodical imaging and measurement of all potential markers. Patients with poorly differentiated MTC are at higher risk of disease-related death, and require more aggressive follow-up strategy. PMID- 25781698 TI - Troponin T measured with highly sensitive assay (hsTnT) on admission does not reflect infarct size in ST-elevation myocardial infarction patients receiving primary percutaneous coronary intervention. PMID- 25781699 TI - New endocrine biomarkers and cardiovascular disease: is it time for routinely screening? PMID- 25781700 TI - Formulation and characterization of solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsion of lornoxicam for transdermal delivery. AB - Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsion (NE) of lornoxicam (LRX) were prepared for the treatment of painful and inflammatory conditions of the skin. Compritol(r) 888 ATO, Lanette(r) O and oleic acid were used as solid and liquid lipids. SLN, NLC and NE were found physically stable at various temperatures for 6 months. Case I diffusional drug release was detected as the dominant mechanism indicating Fickian drug diffusion from nanoparticles and nanoemulsion. The highest rate of drug penetration through rat skin was obtained with NE followed by NLC, SLN and a gel formulation. Nanoformulations significantly increased drug penetration through rat skin compared to the gel (p<0.05). Thus, SLN, NLC and NE of LRX can be suggested for relieving painful and inflammatory conditions of the skin. PMID- 25781701 TI - Alginate microspheres obtained by the spray drying technique as mucoadhesive carriers of ranitidine. AB - The present study is aimed at formulation of alginate (ALG) microspheres with ranitidine (RNT) by the spray drying method. Obtained microspheres were characterized for particle size, surface morphology, entrapment efficiency, drug loading, in vitro drug release and zeta potential. Mucoadhesive properties were examined by a texture analyser and three types of adhesive layers--gelatine discs, mucin gel and porcine stomach mucosa. Microspheres showed a smooth surface with narrow particle size distribution and RNT loading of up to 70.9%. All formulations possessed mucoadhesive properties and exhibited prolonged drug release according to the first-order kinetics. DSC reports showed that there was no interaction between RNT and ALG. Designed microspheres can be considered potential carriers of ranitidine with prolonged residence time in the stomach. PMID- 25781702 TI - Dissolution improvement of solid self-emulsifying drug delivery systems of fenofibrate using an inorganic high surface adsorption material. AB - Solidification of lipid formulations using adsorbents is a recent technique attracting great interest due to its favourable properties including flexibility in dose division, reduction of intra-subject and inter-subject variability, improvement in efficacy/safety profile and enhancement of physical/ chemical stability. The current study aims to convert liquid self emulsifying/nanoemulsifying drug delivery systems (SEDDS/SNEDDS) into solid SEDDS/SNEDDS and to assess how adsorption of the drug onto an inorganic high surface area material, NeusilinR grade US2 (NUS2), affects its in vitro dissolution performance. Lipid formulation classification systems (LFCS) Type III formulations were designed for the model anti-cholesterol drug fenofibrate. NUS2 was used to solidify the SEDDS/SNEDDS. Particle size and SEM analyses of solid SEDDS/SNEDDS powder were carried out to investigate the adsorption efficiency. In vitro dissolution studies were conducted to compare the developed formulations with the marketed product. The results of characterization studies showed that the use of 50% (m/m) adsorbent resulted in superior flowability and kept the drug stable is amorphous state. Dissolution studies allow the conclusion that the formulation containing a surfactant of higher water solubility (particularly, Type IIIB SNEDDS) has comparably faster and higher release profiles than Type IIIA (SEDDS) and marketed product. PMID- 25781703 TI - Development and validation of a simple and sensitive size-exclusion chromatography method for quantitative determination of heparin in pharmaceuticals. AB - Heparin is widely used as an anticoagulant for the treatment and prevention of various thrombotic diseases. However, due to its high anionic charge, heterogeneity in size distribution and high polarity, its analysis is very challenging. In this paper, a novel method based on size-exclusion chromatography (SEC) for quantitative determination of intact heparin in pharmaceuticals is presented. Analyses were performed on a BioSep-SEC-S 2000 column with Larginine solution at pH 6.5 as mobile phase and UV detection at 210 nm. The proposed method was found to be selective, linear (R2>0.997) over the concentration range of 3.1 to 1222 MUg mL(-1), with a limit of detection of 1.0 MUg mL(-1). Intraday and inter-day precision were below 5.1% and inaccuracy expressed as bias did not exceed 6.5 %. The reported method is simple, selective, sensitive, and requires no laborious sample preparation, which makes it appropriate for routine quantitative analysis of heparin in pharmaceuticals. PMID- 25781704 TI - Potential antiproliferative effect of isoxazolo- and thiazolo coumarin derivatives on breast cancer mediated bone and lung metastases. AB - The study highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anticancer agents in metastatic breast cancer. Eight compounds, combining the coumarin core and five membered heterocycles (isoxazoles and thiazoles) in hydrazinyldiene- -chroman-2,4-diones, were characterized in terms of a potential antiproliferative effect on bone (SCP1833) and lung (SCP4175) metastatic breast cancer cell lines using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Cell viability was evaluated after 48 and 72 h of treatment and the 50 % inhibitory concentrations were determined. The results demonstrated dose- and time-dependent activity, with the most potent molecules having a thiazole moiety, without or with additional methyl group(s) attached to the carbon(s) at position(s) 5 and/or 4 in the thiazole ring. These molecules possessed significantly higher potency against both test cell lines compared to 4-hydroxycoumarin. PMID- 25781705 TI - Effect of oral administration of green tea extract in various dosage schemes on oxidative stress status of mice in vivo. AB - Green tea is a favorite beverage and its extracts are popular components of dietary supplements. The aim of the present in vivo study was to obtain detailed information about the effect of a standard green tea extract (Polyphenon, P), at different doses, on antioxidant enzymes and oxidative stress markers in murine blood, liver, small and large intestine. In all doses, P improved the oxidative stress status via an increased content of plasmatic SH-groups (by 21-67 %). Regarding antioxidant enzymes in tissues, the low dose of P had the best positive effect as it elevated the activity of NADPH quinone reductase in liver and small intestine, thioredoxin reductase in small intestine and hepatic superoxide dismutase. Based on these facts, consumption of green tea seems to be safe and beneficial, while consumption of dietary supplements containing high doses of catechins may disturb oxidative balance by lowering the activity of thioredoxin reductase, glutathione S-transferase, glutathione reductase and superoxide dismutase. PMID- 25781706 TI - Effect of 1-(phenyl)-N'-(4-methoxybenzylidene)-9H-pyrido[3,4-b] indole-3 carbohydrazide on in vitro poliovirus replication. AB - The effect of the alkaloid 1-(phenyl)-N'-(4-methoxybenzylidene)- 9H-pyrido[3,4 b]indole-3-carbohydrazide (PMC) on the poliovirus (PV) replication cycle in Vero cells was assayed by inhibition of the cytopathic effect (CPE) and inhibition of plaque forming units (PFU). Both methodologies suggested that the mode of action was avoidance of infection progression in the host cell. The compound was able to prevent CPE and PFU formation when the cells were pretreated with PMC for 24 h prior to PV infection. In addition, when the alkaloid was continuously maintained in the infected cultures, the spread of PV to adjacent cells was impaired. The pre-exposure and post-exposure prophylactic applications are possible situations in which an anti-PV drug might be used. Future studies are needed to elucidate the PMC mode of action and verify the feasibility of PMC use in vivo. No antipicornavirus agent is currently approved for clinical use. PMID- 25781707 TI - Development and optimization of the activated charcoal suspension composition based on a mixture design approach. AB - In this study, a new drug product containing activated charcoal was designed and developed. The excipient levels in the pharmaceutical formulation were optimized using a mixture design approach. The adsorption power of the activated charcoal suspension was selected as the critical quality attribute influencing the efficacy of medical treatment. Significant prognostic models (p<0.05) were obtained to describe in detail the interrelations between excipient levels and the adsorption power of the formulation. Liquid flavour had a critical impact on the adsorption power of the suspension. Formulations containing the largest amount of liquid flavour showed the lowest adsorption power. Sorbitol was not adsorbed onto activated charcoal so strongly as liquid flavour. A slight increase in the content of carboxymethylcellulose sodium led to a marked decrease in adsorption power. The obtained mathematical models and response surface allowed selection of the optimal composition of excipients in a final drug product. PMID- 25781708 TI - Compressibility of tableting materials and properties of tablets with glyceryl behenate. AB - The paper studies the compressibility of directly compressible tableting materials with dry binders, spray-dried lactose and microcrystalline cellulose, and glyceryl dibehenate at various concentrations. Compressibility was evaluated by means of the energy profile of compression and tensile strength of tablets. Release rate of the active ingredient, salicylic acid, from the tablets was also examined. In the case of microcrystalline cellulose, a higher concentration of glyceryl dibehenate increased the strength of tablets, while this did not occur in the case of spray-dried lactose. Increasing concentration of glyceryl dibehenate prolonged the release of salicylic acid; however, no statistically significant difference was found compared to the type of the dry binder used. PMID- 25781709 TI - Differences in antioxidant properties of ginkgo leaves collected from male and female trees. AB - Total phenolic content and antioxidant capacity (FRAP method) of Ginkgo biloba L. leaves collected from male and female trees were determined and compared. Different water and aqueous ethanolic (water/ethanol 80/20, V/V) extracts were prepared by varying the time of infusing, boiling and steeping in order to determine the effect of the extraction method on the above parameters. Antioxidant activity and phenolic content of ginkgo leaf extracts correlated well with significant correlation coefficients. Slopes of linear regression lines were not statistically different for either sex. PMID- 25781710 TI - Body fatness, related biomarkers and cancer risk: an epidemiological perspective. AB - Higher body fatness is not only associated with a higher risk of hypertension, type 2 diabetes, and coronary heart disease but also with certain types of cancer. The scope of this review is to summarize the epidemiological evidence for an association between body fatness and specific types of cancer and to outline the mediating role of obesity-related biomarkers in this context. Epidemiological studies have gathered convincing evidence that greater body fatness is associated with a higher risk of colorectal cancer, postmenopausal breast cancer, endometrial cancer, esophageal adenocarcinoma, renal cell carcinoma, and pancreatic cancer. Further, evidence for an association between higher body fatness and higher risk of ovarian cancer, advanced prostate cancer, and hepatocellular carcinoma is growing. Abdominal obesity is an independent risk factor for colorectal cancer beyond general obesity, whereas an independent role is less clear for other obesity-related cancer types. Epidemiological biomarker studies have shown that the positive association between body fatness and risk of cancer may be partly explained by hyperinsulinemia and altered concentrations in adipokines and sex-steroid hormones. In addition, obesity-associated low-grade inflammation plays a role in colorectal carcinogenesis. While epidemiology has contributed substantially to the understanding of the role of higher body fatness and related metabolic alterations in the development of cancer, further epidemiological biomarker studies are necessary to elucidate the complex interrelations between mediating pathways as well as to study novel pathways. Knowledge resulting from this research may help identify an obesity phenotype that is particularly strongly associated with cancer risk and thus pave the way for targeted prevention of cancer morbidity and mortality. PMID- 25781711 TI - Flexible regression models for rate differences, risk differences and relative risks. AB - Generalized additive models (GAMs) based on the binomial and Poisson distributions can be used to provide flexible semi-parametric modelling of binary and count outcomes. When used with the canonical link function, these GAMs provide semi-parametrically adjusted odds ratios and rate ratios. For adjustment of other effect measures, including rate differences, risk differences and relative risks, non-canonical link functions must be used together with a constrained parameter space. However, the algorithms used to fit these models typically rely on a form of the iteratively reweighted least squares algorithm, which can be numerically unstable when a constrained non-canonical model is used. We describe an application of a combinatorial EM algorithm to fit identity link Poisson, identity link binomial and log link binomial GAMs in order to estimate semi-parametrically adjusted rate differences, risk differences and relative risks. Using smooth regression functions based on B-splines, the method provides stable convergence to the maximum likelihood estimates, and it ensures that the estimates always remain within the parameter space. It is also straightforward to apply a monotonicity constraint to the smooth regression functions. We illustrate the method using data from a clinical trial in heart attack patients. PMID- 25781712 TI - Nearest-Neighbor Estimation for ROC Analysis under Verification Bias. AB - For a continuous-scale diagnostic test, the receiver operating characteristic (ROC) curve is a popular tool for displaying the ability of the test to discriminate between healthy and diseased subjects. In some studies, verification of the true disease status is performed only for a subset of subjects, possibly depending on the test result and other characteristics of the subjects. Estimators of the ROC curve based only on this subset of subjects are typically biased; this is known as verification bias. Methods have been proposed to correct verification bias, in particular under the assumption that the true disease status, if missing, is missing at random (MAR). MAR assumption means that the probability of missingness depends on the true disease status only through the test result and observed covariate information. However, the existing methods require parametric models for the (conditional) probability of disease and/or the (conditional) probability of verification, and hence are subject to model misspecification: a wrong specification of such parametric models can affect the behavior of the estimators, which can be inconsistent. To avoid misspecification problems, in this paper we propose a fully nonparametric method for the estimation of the ROC curve of a continuous test under verification bias. The method is based on nearest-neighbor imputation and adopts generic smooth regression models for both the probability that a subject is diseased and the probability that it is verified. Simulation experiments and an illustrative example show the usefulness of the new method. Variance estimation is also discussed. PMID- 25781713 TI - Making the most of simulated learning: understanding and managing perceptions. AB - Increased emphasis on the use of simulation by nursing education providers is evident world-wide. It is unclear what the implications of this initiative are for academic staff within nursing programs. Programs report a range of responses to simulation pedagogy amongst faculty ranging from enthusiasm to avoidance. This study identified a wide range of concerns encapsulating the staff themselves, their concern for students as well as organisational considerations that impact staff perceptions. METHODS: Nineteen in-depth, semi-structured interviews were conducted with faculty in a school of nursing and midwifery. Thematic analysis of data was carried out. RESULTS: This study reinforced other earlier research related to staff feelings about the introduction of a simulation program or uptake of existing equipment and facilities. This study reflects the knowledge and experience staff had of simulation and highlights the importance of ensuring all members have a collective frame of reference in order to create shared language and vision. CONCLUSION: This study adds to the research on staff attitudes to simulation by identifying the preconceived ideas that contribute to idea formation and relates this to the insight and self-efficacy of the faculty members. PMID- 25781715 TI - Corrigendum to: Simple estimators of false discovery rates given as few as one or two p-values without strong parametric assumptions. PMID- 25781714 TI - A novel method to prioritize RNAseq data for post-hoc analysis based on absolute changes in transcript abundance. AB - The use of fold-change (FC) to prioritize differentially expressed genes (DEGs) for post-hoc characterization is a common technique in the analysis of RNA sequencing datasets. However, the use of FC can overlook certain population of DEGs, such as high copy number transcripts which undergo metabolically expensive changes in expression yet fail to exceed the ratiometric FC cut-off, thereby missing potential important biological information. Here we evaluate an alternative approach to prioritizing RNAseq data based on absolute changes in normalized transcript counts (DeltaT) between control and treatment conditions. In five pairwise comparisons with a wide range of effect sizes, rank-ordering of DEGs based on the magnitude of DeltaT produced a power curve-like distribution, in which 4.7-5.0% of transcripts were responsible for 36-50% of the cumulative change. Thus, differential gene expression is characterized by the high production-cost expression of a small number of genes (large DeltaT genes), while the differential expression of the majority of genes involves a much smaller metabolic investment by the cell. To determine whether the large DeltaT datasets are representative of coordinated changes in the transcriptional program, we evaluated large DeltaT genes for enrichment of gene ontologies (GOs) and predicted protein interactions. In comparison to randomly selected DEGs, the large DeltaT transcripts were significantly enriched for both GOs and predicted protein interactions. Furthermore, enrichments were were consistent with the biological context of each comparison yet distinct from those produced using equal-sized populations of large FC genes, indicating that the large DeltaT genes represent an orthagonal transcriptional response. Finally, the composition of the large DeltaT gene sets were unique to each pairwise comparison, indicating that they represent coherent and context-specific responses to biological conditions rather than the non-specific upregulation of a family of genes. These findings suggest that the large DeltaT genes are not a product of random or stochastic phenomenon, but rather represent biologically meaningful changes in the transcriptional program. They furthermore imply that high abundance transcripts are associated with particularly cellular states, and as cells change in response to internal or external conditions, the relative distribution of the abundant transcripts changes accordingly. Thus, prioritization of DEGs based on the concept of metabolic cost is a simple yet powerful method to identify biologically important transcriptional changes and provide novel insights into cellular behaviors. PMID- 25781716 TI - Bovine colostrum: an emerging nutraceutical. AB - Nutraceutical, a term combining the words "nutrition" and "pharmaceuticals", is a food or food product that provides health benefits as an adjuvant or alternative therapy, including the treatment and prevention of infectious diseases in children and adults. There is emerging evidence that bovine colostrum (BC) may be one of the promising nutraceuticals which can prevent or mitigate various diseases in newborns and adults. Immunity-related disorders are one of the leading causes of mortality in the world. BC is rich in immunity, growth and antimicrobial factors, which promote tissue growth and the maturation of digestive tract and immune function in neonatal animals and humans. The immunoglobulins and lactoferrin present in colostrum are known to build natural immunity in newborns which helps to reduce the mortality rate in this population. Also, the side-effect profile of colostrum proteins and possible lactose intolerance is relatively less in comparison with milk. In general, BC is considered safe and well tolerated. Since colostrum has several important nutritional constituents, well-designed, double-blind, placebo-controlled studies with colostrum products should be conducted to widen its therapeutic use. The objectives of this review are to create awareness about the nutraceutical properties of colostrum and to discuss the various ongoing alternative treatments of colostrum and its active ingredients as well as to address colostrum's future nutraceutical and therapeutic implications in humans. PMID- 25781717 TI - Anti-inflammatory activity of Buchholzia coriacea Engl. (Capparaceae) leaf extract: evaluation of components of the inflammatory response involved. AB - BACKGROUND: Earlier studies in our laboratory demonstrated the anti-inflammatory activity of Buchholzia coriacea Engl. (Capparaceae) leaf extract, a herbal remedy used to treat disorders of inflammation. This study was undertaken to evaluate its anti-inflammatory mechanism(s). METHODS: The effects of methanol leaf extract of B. coriacea (200 and 400 mg/kg) on vascular permeability and leukocyte migration were studied in rodents, while activity on complement system and membrane stabilization were evaluated in vitro. RESULTS: The extract (200 and 400 mg/kg) inhibited acetic acid-induced increase in vascular permeability in a non dose-related manner and significantly (p < 0.05) reduced the total and differential leukocyte counts, respectively, in a dose-related manner. It also significantly (p < 0.05) inhibited complement-induced hemolysis of sheep red blood cells (40-72%) and moderately inhibited heat- (6%) and hypotonic solution (24%) induced hemolysis in vitro in a non-dose-related manner. CONCLUSIONS: Results demonstrated that the anti-inflammatory activity of B. coriacea leaf extract is mediated through inhibition of increase in vascular permeability, leukocyte migration and complement system, and enhanced membrane stabilization. PMID- 25781718 TI - Synthesis, characterisation, and dehydrocoupling ability of zirconium complexes bearing hindered bis(amido)silyl ligands. AB - Herein we detail the synthesis and characterisation of a series of zirconium compounds featuring the bis(amido)silyl ligand [(i)Pr2Si(NDipp)2](2-) (Dipp = 2,6 diisopropylphenyl). The functionalisation of bis(amido)silyl zirconium halide complexes with a variety of nucleophiles, such as LiNMe2, LiBH4 and MeLi, was explored and the resulting products showed a propensity to form anionic zirconate salts when the syntheses were carried out in THF. One of the zirconate products, [(i)Pr2Si(NDipp)2]Zr(NMe2)2.ClLi(THF)3, has the ability to catalyse the dehydrocoupling of primary and secondary amine-boranes at room temperature in aromatic solvents. PMID- 25781720 TI - Structure and growth behavior of centimeter-sized helical oleate assemblies formed with assistance of medium-length carboxylic acids. AB - The nonequilibrium organization of self-assemblies from small building-block molecules offers an attractive and essential means to develop advanced functional materials and to understand the intrinsic nature of life systems. Fatty acids are well-known amphiphiles that form self-assemblies of several shapes. Here, we found that the lengths of helical structures of oleic acid formed in a buffered aqueous solution are dramatically different by the presence or absence of certain amphiphilic carboxylic acids. For example, under the coexistence of a small amount of N-decanoyl-l-alanine, we observed the formation of over 1 centimeter long helical assemblies of oleate with a regular pitch and radius, whereas mainly less than 100 MUm-long helices formed without this additive. Such long helical assemblies are unique in terms of their highly dimensional helical structure and growth dynamics. Results from the real-time observation of self-assembly formation, site-selective small-angle X-ray scattering, high-performance liquid chromatography analysis, and pH titration experiments suggested that the coexisting carboxylates assist in elongation by supplying oleate molecules to a scaffold for oleate helical assembly. PMID- 25781722 TI - Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in coronary artery disease: A systematic review and meta-analysis. AB - BACKGROUND: The study performed a meta-analysis of the diagnostic performance of fractional flow reserve (FFR) derived from coronary computed tomography angiography (FFRCT) to assess the functional significance of coronary stenosis using FFR as the reference standard. METHODS: We searched the electronic databases of PubMed, EMBASE, The Chorance Library, Medion and Web of Science for relevant articles published until August 2014. Pooled estimates of sensitivity, specificity, positive (LR+) and negative likelihood ratios (LR-) with the corresponding 95% confidence intervals (CIs) and the summary receiver operating characteristic curve (SROC) were determined. RESULTS: Five studies, 706 patients and 1165 vessels or lesions were included in the meta-analysis. The pooled sensitivity and specificity for FFRCT at the per-patient level were 90% (95% CI, 85%-93%) and 72% (95% CI, 67%-76%), respectively. The corresponding pooled LR+ and LR- were 3.70 (95% CI, 2.11-6.49) and 0.15 (95% CI, 0.11-0.22), respectively. The pooled sensitivity and specificity for FFRCT on the per-vessel or per-lesion basis were 83% (95% CI, 79%-87%) and 78% (95% CI, 75%-81%), respectively. Corresponding pooled LR+ and LR- were 3.75 (95% CI, 2.09-6.74) and 0.22 (95% CI, 0.18-0.29), respectively. The area under the SROC (AUC) was 0.94 at the per patient level and 0. 91 at the per-vessel or per-lesion level. CONCLUSIONS: The existing evidence suggests that noninvasive FFRCT has high diagnostic performance compared with invasively measured FFR for the detection of ischemia-causing stenosis in stable patients with suspected or known coronary artery disease (CAD). PMID- 25781724 TI - Fast and Efficient Black Box Optimization Using the Parameter-less Population Pyramid. AB - The parameter-less population pyramid (P3) is a recently introduced method for performing evolutionary optimization without requiring any user-specified parameters. P3's primary innovation is to replace the generational model with a pyramid of multiple populations that are iteratively created and expanded. In combination with local search and advanced crossover, P3 scales to problem difficulty, exploiting previously learned information before adding more diversity. Across seven problems, each tested using on average 18 problem sizes, P3 outperformed all five advanced comparison algorithms. This improvement includes requiring fewer evaluations to find the global optimum and better fitness when using the same number of evaluations. Using both algorithm analysis and comparison, we find P3's effectiveness is due to its ability to properly maintain, add, and exploit diversity. Unlike the best comparison algorithms, P3 was able to achieve this quality without any problem-specific tuning. Thus, unlike previous parameter-less methods, P3 does not sacrifice quality for applicability. Therefore we conclude that P3 is an efficient, general, parameter less approach to black box optimization which is more effective than existing state-of-the-art techniques. PMID- 25781723 TI - Pulmonary hypertension and congenital heart disease: An insight from the REHAP National Registry. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is common in patients with congenital heart disease (CHD). Although Eisenmenger syndrome may be on decline, other types of PAH-CHD are increasing and little is known on long-term outcome of this population. We report the PAH-CHD population of Spain via a national registry with focus on long-term survival. METHODS AND RESULTS: A total of 240 consecutive patients (age 37.7 +/- 14.1 years, 67.9% females) with PAH-CHD included in the REHAP registry were analysed. Patients were classified into 3 groups: 1) Eisenmenger syndrome, 2) postoperative-PAH and 3) PAH associated with small defects. Over a median follow-up time of 4.5[1.6-7.1]years, 50 patients (20.8%) died or underwent lung/heart-lung transplantation. Patients with Eisenmenger syndrome had better survival than postoperative-PAH (HR 0.1 95% CI: 0.2-0.9, p=0.048) but no advantage compared to small defects (HR 4.4, 95% CI 0.6 31.4, p=0.15). In the overall PAH-CHD population, patients in NYHA functional class III-IV had a 3-fold increased risk of death (HR 3.0, 95% CI: 1.5-5.9, p=0.001). Amongst patients with Eisenmenger syndrome, a pre-tricuspid shunt had a 2.6-fold increase risk of death (HR 2.6, 95% CI: 1.2-5.6, p=0.03). There was no significant difference in survival between patients with postoperative-PAH and patients with iPAH (HR 0.99 95% CI: 0.6-1.7, p=0.97). CONCLUSION: PAH-CHD is associated with mid to long-term mortality. Outcome relates closely to functional class, type of PAH-CHD and within the Eisenmenger cohort, with location of the shunt. Adults with postoperative-PAH have the worse prognosis in the PAH-CHD cohort, reinforcing the need for lifelong close follow-up of such patients. PMID- 25781726 TI - Correction: The pharmacodynamics of the p53-Mdm2 targeting drug nutlin: the role of gene-switching noise. PMID- 25781725 TI - Histamine downregulates aquaporin 5 in human nasal epithelial cells. AB - BACKGROUND: Aquaporin 5 (AQP5) is a water-specific channel protein. It is thought to be a key participant in fluid secretion and a rate-limiting barrier to the secretion seen during allergic inflammation. We sought to determine the effect of histamine on AQP5 expression in human nasal epithelial cells (HNEpC). METHODS: HNEpC cells were cultured with four concentrations of histamine in vitro. The phosphorylation of cyclic adenosine monophosphate-responsive element binding protein (CREB) at serine 133 and the AQP5 protein were measured by using immunocytochemistry and Western blotting. Real-time polymerase chain reaction was used to detect AQP5 messenger ribonucleic acid (mRNA). RESULTS: Concentration dependent histamine induced-inhibition of CREB phosphorylation at serine 133 in HNEpC cells was observed, and AQP5 mRNA and protein were also downregulated in a concentration-dependent fashion. CONCLUSION: Histamine downregulates AQP5 production in HNEpC cells by inhibiting CREB phosphorylation at serine 133. PMID- 25781727 TI - Taxonomy of 'Euconnus complex'. Part III. Morphology of Euconnus subgenus Napochus and revision of the Australian species (Coleoptera, Staphylinidae, Scydmaeninae). AB - Morphological structures of the type species of Euconnus (Napochus) are described and illustrated, and compared with those of Euconnus s. str. Napochus is maintained as a subgenus of Euconnus, and its revised diagnosis is given. Australian species of Napochus are revised: E. palmwoodianus Franz and E. pisoniae Franz are redescribed, and E. setiphallus sp. n., E. yadhaigana sp. n., E. microlaminatus sp. n, E. feeneyi sp. n. (with a subspecies E. feeneyi parallelilaminatus ssp. n.) are described. An unusual variability in body size and proportions of body parts found in E. feeneyi is analyzed and discussed. PMID- 25781728 TI - Pictorial keys to the species of the subgenera Albuginosus and Aedimorphus (Grjebinei and Apicoannulatus groups) of the genus Aedes meigen in the afrotropical region (Diptera: Culicidae). AB - Nine species of the subgenus Albuginosus, one species of the subgenus Aedimorphus Grjebinei Group and two species of the subgenus Aedimorphus Apicoannulatus Group of the genus Aedes Meigen in the Afrotropical Region are treated in three pictorial keys based on diagnostic morphological features. PMID- 25781729 TI - Reinstatement of three species of the Marphysa sanguinea complex (Polychaeta: Eunicidae) from the Grand Caribbean Region. AB - As part of a study on Marphysa de Quatrefages, 1865 from the Grand Caribbean, three species regarded as junior synonyms of M. sanguinea (Montagu, 1913) were studied to clarify their taxonomic status. The examination of type and additional materials collected in the southern Gulf of Mexico and the Mexican Caribbean regions, allowed us to clarify that M. acicularum Webster, 1884, M. nobilis Treadwell, 1917 and M. viridis Treadwell, 1917 are distinct species. Therefore, the three species were redescribed and some important morphological features such as maxillary apparatus, shape of parapodial lobes, shape of ventral cirri and pectinate chaetae, among others, were described and evaluated. Furthermore, we consider that previous records of M. sanguinea for the Grand Caribbean are doubtful and it is necessary to reassess those specimens to clarify their taxonomic identity. PMID- 25781730 TI - A revision of the genus Conicofrontia Hampson (Lepidoptera, Noctuidae, Apameini, Sesamiina), with description of a new species: new insights from morphological, ecological and molecular data. AB - The aim of this study was to review the species of Conicofrontia Hampson, a small genus of noctuid stem borers (Noctuidae, Apameini) that is distributed in East and Southeastern Africa. We review the morphology of species in this group and provide new diagnoses and ecological data for five species. The following taxonomic changes are proposed: Hygrostola dallolmoi (Berio, 1973) (= Conicofrontia dallolmoi Berio, 1973) comb. n. and Conicofrontia bipartita (Hampson, 1910) (= Phragmatiphila bipartita Hampson, 1910) comb. n., stat. rev. One new species is also described: C. lilomwa, sp. n. from Tanzania. Wing patterns as well as male and female genitalia of the five species are described and illustrated. Finally we carried out molecular phylogenetic and molecular species delimitation analyses on a multi-marker dataset of 31 specimens and 15 species, including the five mentioned species. The results of molecular analyses provide a clear support for the proposed taxonomical changes. PMID- 25781731 TI - First Indochinese records of the plant bug genus Hypseloecus Reuter (Hemiptera: Heteroptera: Miridae: Phylinae: Pilophorini), with descriptions of eight new species from Thailand. AB - The phyline plant bug genus Hypseloecus Reuter is reported from Thailand as well as the Indochina region for the first time, diagnosed, and discussed on its phylogenetic position. Eight new species, Hypseloecus castaneus, H. katrinae, H. nigrobrevis, H. phuvasae, H. sakaerat, H. schuhianus, H. sericosagus and H. siamensis, are described, all with color photographic images of live individuals. Four species were confirmed to be associated with inflorescence and/or fruits of Loranthaceae mistletoe (Santalales), particularly Scurrula spp. in Thailand. A checklist of Asian and New Guinean congeners and a key to Asian species (from Japan, Indochina and Philippines) are provided. PMID- 25781732 TI - Description of the immature stages of nine species of Veturius (Coleoptera: Passalidae). AB - The third instar of Veturius aspina Kuwert, V. assimilis (Weber), V. simillimus Kuwert, V. sinuatocollis Kuwert, V. sinuatus (Eschscholtz), V. crassus (Smith), V. impressus Hincks (as well as pupal stage), V. negroensis Boucher, and the first instar of V. oberthuri (Hincks) (Coleoptera: Passalidae) are described for the first time based on specimens from Argentina, Brazil, and Colombia. The most distinctive characters for these species are the presence and distribution of primary setae and the position, number, and size of the teeth of the metathoracic legs. An evident difference in the number of micro-conical projections on the maxillary stipes and measurements of the pars stridens (mesocoxae) suggests that these characters are useful for species identification. We present an identification key to the species of known larval Veturius (13), representing the 17.6% of total species recognized into genus. Light micrographs and scanning electronic micrographs are included for detailed characters. PMID- 25781733 TI - New species of Omalodes and redefinition of the tribe Omalodini (Coleoptera: Histeridae: Histerinae). AB - A new species of Omalodini, Omalodes atacamanus sp. nov., is described from Chile. A redefinition of Omalodini is proposed and an identification key to the genera is provided. The new species can be distinguished from other species of Omalodes mainly by all tibiae having a row of setae on outer submarginal region. Omalodini sensu nov. is herein restricted to a lineage of Ebonius Lewis, 1885 and Omalodes Dejean, 1833. The tribe has known distribution across Latin America with some species reaching the southern USA. PMID- 25781734 TI - Beautiful bright belly: A distinctive new microhylid frog (Amphibia: Stumpffia) from eastern Madagascar. AB - We describe a new red-bellied species of the microhylid frog genus Stumpffia from the Andasibe region (18 degrees 56' S, 48 degrees 25' E, ca. 900 m elevation) in central-eastern Madagascar. Stumpffia kibomena sp. nov. differs from all other described Stumpffia species in coloration, morphology, and by genetic differentiation in the mitochondrial 16S rRNA gene (>=8.6% uncorrected p distance to all other nominal species of the genus). It is furthermore distinguished from most other Stumpffia species by its advertisement calls. The new species is reliably known only from a few specimens collected in the Andasibe region and based on the limited knowledge we suggest its IUCN Red List classification as "Data Deficient". PMID- 25781735 TI - A survey of Palaearctic Dictynidae (Araneae). 1. Taxonomic notes on Dictynomorpha Spassky, 1939, Brigittea Lehtinen, 1967 and Lathys Simon, 1884. AB - A new species, Dictynomorpha daemonis sp. n. (?) is described from South Kazakhstan and a new diagnosis is suggested for Dictynomorpha Spassky, 1939. The genus is redelimited and its type species D. strandi Spassky, 1939 redescribed. Three Dictynomorpha species are transferred to Ajmonia Caporiacco, 1934 and three new combinations are suggested: Ajmonia smaragdula (Simon, 1905) comb. n., Ajmonia bedeshai (Tikader, 1966) comb. n. and Ajmonia marakata (Sherriffs, 1927) comb. n. Brigittea Lehtinen, 1967 is removed from the synonymy with Dictyna Sundevall, 1833 and its composition is discussed. The type species of Brigittea, B. latens (Fabricius, 1775) is synonymized with B. latens mutabilis Spassky & Shnitnikov, 1937. Lathys spasskyi Andreeva & Tyshchenko, 1969 is removed from the synonymy with L. stigmatisata (Menge, 1869). New illustrations and distribution data are provided for Lathys truncata Danilov, 1994. Lathys mussooriensis Biswas & Roy, 2008 is transferred from Dictynidae to Amaurobiidae and tentatively placed in Himalmartensus Wang & Zhu, 2008, the new combination is suggested: Himalmartensus mussooriensis (Biswas & Roy, 2008) comb. n. PMID- 25781736 TI - The first African Anthracoptilidae (Insecta: Paoliida) near the Permian--Triassic boundary in Kenya. AB - The first findings of Antracoptilidae (Paoliida) from the Late Permian/ Early Triassic of Africa, i.e. the new genus Afrocladus comprising A. pumilio sp. nov. and A. kenyaensis sp. nov., are described from the Mombasa Basin of Maji ya Chumvi Formation in Kenya (Duruma sandstones). Both diagnoses are based on wing venation pattern. Their occurrences close to the P-T boundary possibly indicate the last appearence date of the group being known since early Pennsylvanian. Moreover, their significantly smaller wing sizes compared to known taxa suggest adaptations to different habitats and environmental conditions or different life strategy. PMID- 25781737 TI - The groundhopper fauna (Orthoptera: Tetrigidae) of Shiwanshan (Guangxi, China) with description of three new species. AB - This paper deals with 7 subfamilies, 30 genera and 82 species of Tetrigidae from Shiwanshan, Guangxi in China. Among them three new species of the subfamily Metrodorinae are described, namely Mazarredia convexaoides Deng & Zheng sp. nov., Mazarredia shiwanshanensis Deng & Zheng sp. nov. and Bolivaritettix shiwanshanensis Deng & Zheng sp. nov. Also, new synonyms are presented: Miriatroides quadrivertex Zheng & Jiang, 2002 syn.nov. is synonymized with Spadotettix hainanensis Gunther, 1939, thus genus Miriatroides Zheng & Jiang, 2002 with the genus Spadotettix Hancock, 1910. Finally, brief comments on faunistic characters of Tetrigidae from Shiwanshan are given. PMID- 25781738 TI - Revision of the Palaearctic and Oriental species of the genus Naarda Walker, 1866 (Lepidoptera: Erebidae, Hypeninae). Part 5. Description of 13 new species from Asia. AB - Descriptions of 13 new Naarda species, N. cingulata (Thailand), N. imitata (Cambodia), N. hallasana (Korea), N. calligrapha (India, Burma and Indonesia: Buru Island), N. felinopsis (Vietnam), N. furcipalpa (Brunei), N. uthanti (Burma), N. capreola (Cambodia), N. leptosigna (Sri Lanka), N. nigrissima (Cambodia, Thailand and Taiwan), N. bicolora (Cambodia), N. gigaloba (Sri Lanka) and N. numismata (India) spp. n. are given. With 50 figures. PMID- 25781739 TI - Chordodes combiareolatus, a new species of horsehair worms (Nematomorpha) from Nagaland, India, with further comments on Chordodes moutoni. AB - The currently known diversity of horsehair worms (Nematomorpha) from India is only 17 species. We report here two female specimens found on two occasions on a terrace paddy field in Tsupo, Viswema, Kohima, Nagaland, India. Although found at the same location, both species differ in their cuticular structures. One is determined as Chordodes moutoni, a species known from China, Malaysia and India. The other specimen shows a new type of cuticular structure, the areoles, which combines characters of both simple areoles and tubercle areoles. This specimen is described as a new species, C. combiareolatus. Both specimens show arrangements on the cuticle, in which a circle of areoles surrounds a region of "naked" cuticle. We interpret these regions as artifacts caused by the breaking off of the central crowned areoles, leaving only the circumcluster areoles behind. PMID- 25781740 TI - Description of a new genus and a new species of gaeticine crab (Crustacea: Brachyura: Varunidae) from the Ryukyu Islands, and a review of Acmaeopleura Stimpson, 1858, and Sestrostoma Davie & N.K. Ng, 2007. AB - Acmaeopleura parvula Stimpson, 1858, the type species of the varunid Acmaeopleura Stimpson, 1858, is redescribed, and a neotype is designated. Examination of all three species of the gaeticine Sestrostoma Davie & N.K. Ng, 2007, revealed that, although the diagnostic characters of Sestrostoma proposed by the previous study are variable and mostly overlap with those of Acmaeopleura, they can still be distinguished from each other by the characters of the carapace, the thoracic sternite 2, the third maxillipeds, and the ambulatory legs. The subfamilial position of Acmaeopleura was assessed by comparing it with all gaeticine genera. Gaetice Gistel, 1848, the type genus of the subfamily, has a very characteristic structure of the third maxilliped and the anterior sternal plate, which are partially shared with Gopkittisak Naruse & Clark, 2009, Brankocleistostoma Stevcic, 2011, Sestrostoma and Acmaeopleura in different combinations. The generic diagnostic characters of these four genera are unique among Varunidae and they are tentatively placed in Gaeticinae. A new genus and new species, which is allied to Sestrostoma but clearly distinguishable from all varunine genera, is described from Iriomote Island, Ryukyu Islands, Japan. PMID- 25781741 TI - Diversity of Piophilidae (Diptera) in northern Canada and description of a new Holarctic species of Parapiophila McAlpine. AB - Piophilidae (Diptera) were inventoried at 12 sites in boreal and arctic Canada as part of the 1947-1962 Northern Insect Survey and 2010-2011 Northern Biodiversity Program. Seventeen species were identified, including a new Holarctic species: Parapiophila kugluktuk sp. n. which is widespread in North America and northern Sweden. Allopiophila calceata Duda is considered a junior synonym of Parapiophila atrifrons (Melander & Spuler) syn. n. based on morphological and molecular evidence. Parapiophila baechlii Merz, previously known from Switzerland, is newly recorded in the Nearctic region, as well as Sweden and northeastern Russia (Cherskiy). Parapiophila pectiniventris (Duda), previously known from the Palaearctic region and Greenland, is newly recorded from North America. Species richness was highest in mainland subarctic sites (16 species, 246 specimens). Five species (13 specimens) were collected in boreal sites, and five species (701 specimens) were collected on the high arctic island sites. PMID- 25781742 TI - A new bathyal mysid of the family Petalophthalmidae (Crustacea: Mysida) from the Bismarck Sea (Western Tropical Pacific Ocean). AB - A new species of the genus Petalophthalmus (Crustacea: Mysida: Petalophthalmidae) is described, based on one specimen collected from the Bismarck Sea (Papua New Guinea, Western Pacific Ocean). This species can be distinguished from the other species of the genus Petalophthalmus by the globular cornea and the armature of the telson. This new species lives between 800 and 1065 m depth. A discussion on the geographic and bathymetric distribution and an identification key to world species of Petalophthalmus are provided. PMID- 25781743 TI - New Dicranoptycha Osten Sacken, 1859 Crane flies (Diptera: Limoniidae) of North and South Korea. AB - Two new species of Dicranoptycha Osten Sacken, 1859, crane flies (Diptera, Limoniidae) from the Korean peninsula are described, illustrated and compared with already known and related species. An identification key and check-list of all Korean Dicranoptycha is presented. PMID- 25781744 TI - The Maluti Mystery revisited: Taxonomy of African River Frogs (Pyxicephalidae, Amietia) on the Drakensberg Mountains in southern Africa. AB - The taxonomy of two similar frogs from the top of the Drakensberg escarpment, the Maluti River Frog and the Phofung River Frog is not settled. I examine the relevant types and type descriptions, and discover a number of errors in the literature. Some of the recent taxonomic changes were found to be unsupported. The Maluti River Frog is assigned to Amietia vertebralis (Hewitt, 1927), and the Phofung River Frog to Amietia hymenopus (Boulenger, 1920). PMID- 25781745 TI - The genus Folsomides Stach (Collembola, Isotomidae) in Kermanshah Province (W Iran) with the description of two new species. AB - The genus Folsomides Stach, 1922 is represented by four species in the Iranian fauna, two of which are new to the science. Folsomides halshinicus sp. nov. and Folsomides subvinosus sp. nov. are found in Kermanshah Province (Western Iran). The new species belong to the Folsomides angularis (Axelson, 1905) group and they are distinguishable from other congeneric species by the macrochaetotaxy (11/22233 macrochaetae on thoracic II to abdominal V tergites) and the number of chaetae on dens. A table with the diagnostic characters for the identification of Iranian species of Folsomides is given. Some figures of F.vinosus Fjellberg, 1993 from Canary Island was given after study of type specimens. PMID- 25781746 TI - New species from the genera Kansua and Anatlanticus (Orhtoptera: Tettigoniidae) in China. AB - The genus Kansua Uvarov was only known in East Asian, and is considered to approach Tettigonia Linnaeus or Glyphonotus Redtenbacher. After comparing male and female specimens of Kansua with other genera of the subfamily Tettigoniinae, we find that Kansua is very similar to Anatlanticus Bei-Bienko and Mongolodectes Bei-Bienko in pronotum, legs, and tegmen rather than Tettigonia and Glyphonotus. Description of one new species Kansua diebua Liu sp. n., of two new species of one newly recorded genus Anatlanticus from China, and first description of male of Mongolodectes alashanicus are presented. PMID- 25781747 TI - Opiliones are no longer the same--on suprafamilial groups in harvestmen (Arthropoda: Arachnida). AB - A review of the names used in the arachnid order Opiliones above superfamily level is presented. Many historical branching patterns of Opiliones (for five terminals), of Laniatores (for six terminals), and of Cyphophthalmi (for six terminals) are extrapolated, compared and graphically displayed. For the first time a historical review is made of the circumscriptions of those names and comparisons are drawn to current usage. Critical clades are used as terminals and represented by the oldest valid generic name of each. Comments are made on the variant usage for 25 suprafamilial names from the literature. Cladistic definitions are provided for these names under relevant hypotheses of phylogeny. It is noted that virtually all important suprafamilial names in Opiliones changed concept over time, and the purpose of this project is to clarify the original usage compared to current, and to add historical perspective. Two options are considered for higher-level nomenclature in Opiliones: (1) a circumscriptional option, sticking to the original inclusion of the names; (2) an inertial option, where no name has priority, and follows recent use in the literature. As there is no priority for names not regulated by ICZN, option 2 prevails, because it entails massive momentum. The following new names are introduced as unranked taxa to define clades under different hypotheses of phylogeny: Tricospilata (= Triaenonychidae + Grassatores), Lomaniatores (Laniatores in the restricted sense used by Loman/Pocock), and Eulaniatores (Laniatores excluding the bizarre Synthetonychiidae). Some of the hypotheses implied by these names are conflicting and mutually exclusive, but the state of knowledge of harvestman taxonomy is quickly changing, and no hypothesis that clearly supersedes the others can be detected. PMID- 25781748 TI - Redescription of Hemieuryale pustulata von Martens, 1867 (Echinodermata, Ophiuroidea) based on Brazilian specimens, with notes on systematics and habitat association. AB - We redescribe Hemieuryale pustulata on the basis of 325 specimens obtained from the continental shelf off northeastern and southeastern Brazil. This is the first record of the species for Brazil. We illustrate for the first time details of the dental plate, oral plate, and vertebrae. Few morphological variations were observed in our extensive material. All specimens were associated with the gorgonian Nicella guadalupensis, suggesting an obligatory association in the Brazilian littoral. H. pustulata did not reveal a particular pattern of distribution on its host gorgonian, but larger gorgonians tend to support a larger number of ophiuroids. In addition to expanding the knowledge on morphology and ecology, we extend the known bathymetric distribution of the species, which is now known from 18 to 330 m. PMID- 25781749 TI - Rugosothynnus gen. nov. (Hymenoptera: Tiphiidae: Thynninae: Rhagigasterini), a newly recognised Australian genus. AB - Rugosothynnus gen. nov. (type species Rhagigaster corrugatus Turner, 1910) is erected for 12 Rhagigaster-like species. Nine species are described and illustrated from Australia: R. brunneus sp. nov., R. clypeatus sp. nov., R. confusus sp. nov., R. depressus sp. nov., R. fulvescens sp. nov., R. houstoni sp. nov., R. monteithae sp. nov., R. neocorrugatus sp. nov. and R. schichai sp. nov. New combinations are proposed for R. burnsi (Given, 1959), comb. nov., R. corrugatus (Turner, 1910), comb. nov. and R. tristis (Smith, 1859), comb. nov. (all previously from genus Rhagigaster Guerin-Meneville, 1838). A key to both sexes of all species is provided except for the females of R. clypeatus sp. nov., R. depressus sp. nov., R. neocorrugatus sp. nov. and R. schichai sp. nov. which are unknown. PMID- 25781750 TI - Hydroids of the genus Sertularella (Cnidaria: Hydrozoa: Sertulariidae) from the Pacific coast of Canada in the collection of the Royal Ontario Museum, with descriptions of four new species. AB - Examination of the hydroid fauna of the Canadian Pacific coast in the collections of the Royal Ontario Museum collected between 1934 and 1985 indicates that the genus Sertularella Gray, 1848 from the infralittoral zone in the region remains poorly enumerated. The present study shows that several European or northeast Atlantic hydroid species, Sertularella conica Allman, 1877, Sertularella rugosa (Linnaeus, 1758), Sertularella tenella Alder, 1856, Sertularella polyzonias (Linnaeus, 1758), and Sertularella fusiformis (Hincks, 1861) have been incorrectly reported from the west coast of North America and suggests that assumptions of cosmopolitanism of some species require verification by continuing refinement of regional species-level taxonomy. Four new species, Sertularella cervicula, S. coronata, S. sacciformis, and S. pacifica are recognized and described in this paper. Sertularella gigantea Hincks, 1874 is recognized for the first time from the Pacific coast of North America. PMID- 25781751 TI - A review of the genus Lamellipalpodes Maulik (Coleoptera: Lampyridae). AB - The Ototretinae genus Lamellipalpodes Maulik, 1921 is reviewed. Four species are proposed as new to science, L. bajhangensis Bocakova sp. nov., L. holzschuhi Bocakova sp. nov. and L. godawarensis Bocakova sp. nov., all from Nepal, and L. yunnanensis Bocakova sp. nov. from China (Yunnan) and northern Laos. Six species are redescribed. Illustrations of diagnostic characters are included, with a checklist and a key to Lamellipalpodes species. The genus is newly recorded from China and Laos. PMID- 25781752 TI - A new species of Geholaspis Berlese (Acari: Mesostigmata: Macrochelidae) from Northern Iran. AB - Geholaspis (Geholaspis) pennulatus sp. nov. is described from females and males collected from forest leaf litter in Northern Iran. The new species can be easily recognised by its barbed setae j2 and z1, dorsal shield seta j5 located posterior to j6 and z6, a very wide ventri-anal shield, and the shape of the epistome. Geholaspis (G.) comelicensis Lombardini, 1962 is considered as a junior synonym of G. (G.) pauperior (Berlese, 1918). A new key for the separation of females of known species of Geholaspis (Geholaspis) is presented. PMID- 25781753 TI - A new species of decorator crabs, genus Menaethiops Alcock, 1895 (Crustacea: Decapoda: Brachyura: Majoidea: Epialthidae), from Abu-Musa Island, Persian Gulf, Iran. AB - Menaethiops abumusa n. sp. is closely similar to M. bicornis Alcock, 1985, and M. gadaniensis Kazmi & Tirmizi, 1999, regarding the relatively contiguous rostral spines. The new species is easily distinguishable from its two congeners by having distinctly round angles of orbital eaves and distally divergent rostral spines. Whereas in M. bicornis, and M. gadaniensis, the angles of orbital eaves are anteriorly produced and rostral spines are closely attached to each other along their entire length. Other morphological differences include the carapace spination/granulation, basal antennal segments, and morphology of the male's first gonopod. Menaethiops gadaniensis was described from Gadani, Pakistan and was only known from the type locality, but is here recorded for the first time from the Gulf of Oman. PMID- 25781754 TI - A new species of philichthyid copepod (Crustacea: Cyclopoida) parasitic on Stellifer spp. (Perciformes: Sciaenidae) from southeastern Brazil. AB - A new species of copepod, Colobomatus stelliferi n. sp., belonging to the cyclopoid family Philichthyidae Vogt, 1877 is proposed based on female specimens collected from the mandibular canals of three species of sciaenid teleosts: Stellifer brasiliensis (Schultz) (type-host), S. rastrifer (Jordan) and S. stellifer (Bloch), collected in Caraguatatuba Bay, State of Sao Paulo, Brazil. The new species can be distinguished from its closest congeners by the absence of lateral processes in the genital somite, the presence of one cephalic process in the cephalosome and one pair of dorso-lateral processes on the fused pedigerous somites. This is the first species of Colobomatus Hesse, 1873 described as parasites of species of the teleost genus Stellifer. PMID- 25781755 TI - A new freshwater snail (Caenogastropoda: Cochliopidae) from the Atacama Desert, northern Chile. AB - In the family Cochliopidae, Heleobia Stimpson, 1865 is the most speciose genus in South America, with about 90 species (Hershler & Thompson 1992; Cazzaniga 2011). A recent molecular and morphological analysis performed in northern Chile (Atacama Desert) showed that the previously undescribed springsnails from Aguada de Chorrillos belong to Heleobia (Collado et al. 2013). In this study I formally describe this new species. Although this paper does not treat morphology in detail, the anatomical characters, in combination with the previously published molecular data provides a strong basis for recognizing this population as a distinct species. PMID- 25781756 TI - Replacement name for Euwintonius insulanus Suzuki, 1982 (Opiliones: Laniatores: Assamiidae: Dampetrinae), primary junior homonym of E. insulanus Roewer, 1940. PMID- 25781757 TI - A revision of the Deltochilum subgenus Aganhyboma Kolbe, 1893 (Coleoptera: Scarabaeidae: Scarabaeinae). AB - The species of the Deltochilum subgenus Aganhyboma, endemic to Central and South America, are reviewed. The species have been divided into complexes, with a brief diagnosis presented for each. A key for identification of 26 currently recognized species is provided in English and Portuguese. Two major groups within the subgenus are recognized (trisignatum and valgum). The first is represented by species typically belonging to the subgenus Aganhyboma (Deltochilum (A.) trisignatum, D. (A.) kolbei, D. (A.) violaceum, D. (A.) cupreicolle and D. (A.) viridescens new status) and three new species described here (D. (A.) amandaarcanjoae, D. (A.) viridicatum and D. (A.) titovidaurrei). The second group (valgum) is represented by: D. (A.) valgum, D. (A.) longiceps new status, D. (A.) acropyge new status, D. (A.) acanthus, D. (A.) icaroides and D. (A.) icariforme), previously assigned to the subgenus Deltohyboma. Twelve new species are described for the valgum group (D. (A.) schefflerorum; D. (A.) streblopodum; D. (A.) feeri; D. (A.) larseni; D. (A.) arturoi; D. (A.) finestriatum; D. (A.) cangalha; D. (A.) alpercata; D. (A.) ritamourae; D. (A.) kolleri; D. (A.) paresi; D. (A.) subrubrum). A lectotype is designated for D. (A.) trisignatum and D. (A.) icariforme. A detailed literature review, synonymies, description, illustration of key morphological characters, data of the studied material and geographic distribution is provided for each species. PMID- 25781758 TI - Illustrated catalogue of Neotropical Ctenuchina, Euchromiina and Pericopina types (Lepidoptera, Erebidae, Arctiinae, Arctiini) described by Hans Zerny, with discussion on their taxonomic status. AB - The type material of 54 names of Ctenuchina, Euchromiina and Pericopina proposed by Hans Zerny are treated. Of these, the material belonging to 43 of the 54 names, represented by 118 specimens, are deposited at the Naturhistorisches Museum Wien (NHMW). The remaining are at the BMNH, NMNH, ZMHB or the ZSM, except for one of the species, which material was not traced. Comments on each name and its current taxonomic status, illustrations of holotypes and lectotypes, as well as information about their conservation status are provided. Lectotypes are designated for 23 of the taxa, and two new synonyms are proposed Eucyane variabilis flavofasciata and E. variabilis roseofasciata (=Hypocrita variabilis variabilis). Additionally, nine names have their taxonomic status changed: Correbia columbiana stat. nov., Autochloris jordani comb. nov., Chrostosoma exomelan comb. nov., C. flavothoracides comb. nov., C. pseudothia comb. nov., C. xanthomelan comb. nov., Ecdemus imbecillus comb. nov., Pseudomya clandestina comb. nov., and Uranophora felderi, comb. nov. Illustrations of the genitalia of some of the species are also provided. PMID- 25781759 TI - A new species of Haliclona (Demospongiae: Haplosclerida: Chalinidae) from southeastern Brazil and the first record of Haliclona vansoesti from the Brazilian coast. AB - In this paper we describe two species of the cosmopolitan sponge genus Haliclona from Rio de Janeiro State, SE Brazil, one of which is new to science and the other a new record to Brazil. Haliclona (Rhizoniera) fugidia sp. nov. is brownish pink, salmon or cream, thickly encrusting, without oscular tubes and tangential ectosomal reticulation. Choanosomal skeleton is a mostly unispicular ladder-like reticulation of oxeas, very organized near the sponge surface and denser and more disorganized in the interior of the sponge. Haliclona (Halichoclona) vansoesti de Weerdt et al., 1999 was originally described from the Caribbean. It has a very loose connection between ectosome and choanosome, a whitish translucent ectosome combined with a purplish choanosome, a cavernous structure and a friable or crispy consistency. The conspecificity of SE Brazilian and Caribbean populations of H. (Halich.) vansoesti was verified through phylogenetic analysis of small subunit 18S rRNA (18S) and mitochondrial cytochrome oxidase subunit I (COI) gene sequences. A maximum likelihood phylogenetic tree constructed with 18S sequences indicates that specimens of H. (Halich.) vansoesti from Rio de Janeiro were phylogenetically closer to the same species from the Caribbean than to other species of Haliclona. Although not available for H. (Halich.) vansoesti from the Caribbean, COI sequences of our specimens were also quite distinct from those of other Haliclona species. Molecular identification based on DNA sequences is a useful complement to traditional morphology-based taxonomy, especially in highly plastic sponges such as Haliclona spp. and other haplosclerids. PMID- 25781760 TI - Three new species of the genus Corymbitodes Buysson, 1904 from Nepal and India with a description of the male of Corymbitodes kambaitiana Fleutiaux, 1942 (Coleoptera: Elateridae). AB - In the present paper we introduce three new species of the genus Corymbitodes Buysson, 1904 from Nepal and from Northern India and provide the description of the male of C. kambaitiana Fleutiaux, 1942. No species of Corymbitodes was recorded from Nepal or India previously. The new species are C. bengalensis sp. nov. (India), C. chassaini sp. nov. (India), C. nepalensis sp. nov. (Nepal). C. kambaitiana Fleutiaux, 1942 was originally described based on female material from Myanmar. Here we describe the male based on material from Ganesh Himal in Nepal. PMID- 25781761 TI - Cicada genus Pomponia Stal, 1866 (Hemiptera: Cicadidae) from Vietnam and Cambodia, with a new species, a new record, and a key to the species. AB - The genus Pomponia Stal, 1866 from Vietnam and Cambodia is reviewed . Pomponia brevialata Lee & Pham, sp. nov. is described from Vietnam. Pomponia backanensis Pham & Yang, 2009 is added to the Cambodian cicada fauna. A key to the seven Vietnamese and Cambodian species of the genus Pomponia Stal, 1866 is provided: P. linearis (Walker, 1850), P. backanensis Pham & Yang, 2009, P. brevialata Lee & Pham, sp. nov., P. subtilita Lee, 2009, P. piceata Distant, 1905, P. daklakensis Sanborn, 2009, and P. orientalis (Distant, 1912). Synonymic lists, information on geographical distributions, and material examined for the Vietnamese and Cambodian species of Pomponia are provided. PMID- 25781762 TI - A new species of the enigmatic genus Osphyoplesius from Sicily (Coleoptera: Tenebrionoidea: Pythidae). AB - Osphyoplesius is an obscure Palearctic genus tentatively placed in Pythidae, comprising one species from Crimea and one from Greece, each of them collected only once. A third species is here described from Sicily, based on recently collected specimens. Despite the poor sample, statistic analysis of morphometrical data allowed to confirm the differentiation between the new species and its closest relative, and revealed the existence of sexual dimorphism in the genus. PMID- 25781763 TI - New species and new records of bryozoans from shallow waters of Madeira Island. AB - Two new species of bryozoans encrusting subtidal rocks are described from the shallow waters of Madeira Island. We describe one cyclostome, Favosipora purpurea sp. nov., which represents the first record of this genus in the Atlantic Ocean, and one cheilostome, Rhynchozoon papuliferum sp. nov. In addition, one species, Beania maxilladentata, is recorded for the first time outside of Rio de Janeiro, Brazil. Six other species previously recorded in Madeira are redescribed to provide new data and SEM images. PMID- 25781764 TI - A note on scale morphology in Collembola. PMID- 25781765 TI - A new species, Poecilocampa deqina (Lepidoptera: Lasiocampidae), from China. PMID- 25781766 TI - ANAIS GRAND, RENE ZARAGUETA BAGILS, LINA MARIA VELEZ & VISOTHEARY UNG (2014) A cladistic re-analysis of the Gadiformes (Teleostei, Paracanthopterygii) using three-item analysis. Zootaxa, 3889(4): 525-552. PMID- 25781767 TI - A review of the Carboniferous and Permian trilobites of Australia. AB - The first complete review of the Carboniferous and Permian trilobite species found within Australia is presented to assess the current standing of Australian taxa in a modern systematic context. The review consists of four families, 20 genera and 61 known species from the early Tournaisian to Moscovian (358.9 Ma to 304 Ma), throughout New South Wales, Tasmania, Western Australia and Queensland. The revision also includes a revised anatomical nomenclature for Australian Carboniferous trilobites. Emended diagnoses are provided for seven genera and 28 species. The genus Thalabaria is placed within the subfamily Archegoninae, and the genera Australokaskia and Planokaskia are placed within Cummingellinae. The subgenera Brachymetopus (Spinimetopus), Bollandia (Capricornia), Australokaskia (Longilobus) and Australokaskia (Planilobus) are suppressed within Brachymetopus, Bollandia, Australokaskia, respectively. All Brachymetopus (Brachymetopus) maccoyi subspecies are elevated to species. Species of Linguaphillipsia are considered sensu lato until there is adequate revision of the entire genus. New combinations include the following: Aprathia semicircularis is reassigned to Weania; Aprathia applanata is questionably reassigned to Carbonocoryphe; and Phillipsia squamata is tentatively reassigned to Palaeophillipsia. The following have been synonymised: Conophillipsia with Monodechenella; Megaproetus with Pudoproetus; Weberiphillipsia with Palaeophillipsia; Weania (Rosehillia) with Schizophillipsia; Conophillipsia breviceps dungogensis with Monodechenella breviceps; Linguaphillipsia raglanensis with Linguaphillipsia stanvellensis; and Weberiphillipsia girvanensis with Palaeophillipsia collinsi. Carbonocoryphe (Winterbergia) elegans, Carbonocoryphe (Winterbergia) keepitensis and Winterbergia? waterhousei are considered representatives of indeterminate genera. PMID- 25781768 TI - On the paraphyly of Homaloptera (Teleostei: Balitoridae) and description of a new genus of hillstream loaches from the Western Ghats of India. AB - Homaloptera van Hasselt 1823 as treated historically exhibits substantial morphological diversity and is paraphyletic based on both morphological and molecular data. The morphological diversity and phylogenetic relationships of Homaloptera, Homalopteroides Fowler 1905, Homalopterula Fowler 1940, and Balitoropsis Smith 1945, are elucidated. Pseudohomaloptera Silas 1953 is removed from the synonymy of Homaloptera. Homalopteroidini is created for the monophyly of Homalopteroides and Homalopterula; it is the sister group to balitorini Swainson 1839. Ghatsa n. gen. is created for species previously assigned to Homaloptera from the Western Ghats of India, and a redescription of Ghatsa montana (Herre 1945) is provided. PMID- 25781769 TI - New Hamacantha from Peru and resurrection of Zygherpe as subgenus (Demospongiae, Poecilosclerida, Hamacanthidae). AB - Two species of Hamacantha with tylostyles are reported here for the Peruvian coast, namely H. desmacelloides sp.nov. and H. hyaloderma. The former is the first species in the genus with apically microspined sigmas, similar to those known to occur in Neofibularia, and recently reported from genera Biemna, Desmacella, Rhabderemia and Sigmaxinella. Hamacantha hyaloderma was previously known from Mexico to Canada, and is here reported for the first time from the south east Pacific. The finding of a second species with tylostyles led us to reinstate subgenus Hamacantha (Zygherpe). The possible phylogenetic significance of apically microspined sigmas is discussed in view of recent findings on the basis of molecular data. PMID- 25781770 TI - Heth impalutiensis n. sp. (Nematoda: Ransomnematoidea: Hethidae) a millipede parasite from Central Mindanao, Philippines. AB - The nematode Heth impalutiensis n. sp. is described from an unidentified spirostreptid millipede (Harpagophoridae) from the Bukidnon Province of Mindanao, the Philippines. Based on morphological characters, H. impalutiensis n. sp. is closest to Asian-Pacific representatives of the genus. Females of H. impalutiensis n. sp. are close to H. dimorphum and H. vietnamensis in body size and form of the lateral lappets, but can be distinguished by the significantly longer tail. Males of H. impalutiensis n. sp. strongly resemble that of H. xaniophora by the presence of such a rare character combinations as mammiform papillae and a bursa-like cuticular fold, but can be easily differentiated by the numbers of genital papillae (7 vs 6 pairs, respectively). Heth impalutiensis n. sp. can be distinguished from all nominal species by hypertrophy of the anterior anal lip in females which overlaps the anal aperture. Phylogenetic analysis based on the newly obtained set of sequences did not provide an evidence of infraorder Rhigonematomorpha monophyly as two superfamilies Ransomnematoidea and Rhigonematoidea formed independent clades in the frames of ascaridid-spirurid oxyurid super clade (Clade III of Nadler et al., 2007). PMID- 25781771 TI - Two new species of Rykellus (Acari: Mesostigmata: Ologamasidae) from Brazil and a key to the world species of the genus. AB - Rykellus anibali n. sp. and Rykellus mineiroi n. sp. are described from adult females and males collected from litter and soil in the state of Sao Paulo, Brazil. A key for the identification of females of the eight recognisable world species of Rykellus is provided. PMID- 25781772 TI - Description of Sarasaeschna kaoi sp. nov. in Taiwan, with notes on the proposed differentiating characters of the pyanan-group (Odonata, Aeshnidae). AB - Sarasaeschna kaoi sp. nov. collected from Yuli, Hualien County in eastern Taiwan, is easily distinguished from all known congeners by its male having short and straight cerci. Judging from male penile structure, it is considered to belong to the pyanan-group of species and resembles in general appearance the Chinese S. zhuae described from Fujian. The only known habitat of S. kaoi is a muddy and grassy swamp in natural evergreen forest. The diagnostic characters of the pyanan group proposed by Karube & Yeh are also discussed. PMID- 25781773 TI - Three new species of the genus Exphora Signoret, 1860 (Hemiptera, Fulgoromorpha, Tropiduchidae) from Madagascar. AB - Three new species of the genus Exphora Signoret, 1860 (Hemiptera, Fulgoromorpha: Tropiduchidae) are described from Madagascar: E. constanti sp. n., E. stroinskii sp. n. and E. ambatolaonaensis sp. n. The male genitalia are described for the first time in this genus. The male genitalia, head and fore wing of the new species are illustrated with photos of habitus provided. Key to the known species of Exphora is given. PMID- 25781774 TI - Description of the final stadium larva of Heliocypha perforata perforata (Percheron), with discussion of the taxonomic characters of the larvae of the genus Heliocypha Fraser (Odonata: Zygoptera: Chlorocyphidae). AB - The final stadium larva of Heliocypha perforata perforata is described and illustrated for the first time. It is characterized by having a row of filiform setae present laterally on distal half of prementum, 6-7 setae on the outer side of palpal lobe, very long lateral gills and distinct abdominal color pattern. The taxonomic characters of the larvae of the genus Heliocypha Fraser are discussed and summarized. Heliocypha larvae share a high similarity with Rhinocypha in general appearance and cannot be clearly distinguished from the latter in structure. PMID- 25781775 TI - A new species of Lyria (Gastropoda: Volutidae) from Southern Japan. PMID- 25781776 TI - Discovery of the male Tiradelphe schneideri (Lepidoptera: Nymphalidae, Danainae)- missing piece in an insect evolution puzzle. AB - For 30 years the highly distinctive Schneider's Surprise butterfly, Tiradelphe schneideri Ackery & Vane-Wright, 1984, has been known only from the two original type specimens, both female. Here we describe and illustrate the previously unknown male of this Guadalcanal endemic member of the Danaina-the subtribe of Nymphalidae: Danainae to which Tiradelphe has always been assigned. Unexpectedly, male T. schneideri completely lack alar androconia, and are thus unlike all other species of Danaina and its sister group, the Amaurina. The new information will permit a reassessment of the phylogenetic relationships of Tiradelphe. This enigmatic genus may well be more isolated than previously supposed, with implications not only for our understanding of pheromone communication in these insects, but also the evolution and biogeography of the tribe Danaini in the Indo Pacific. PMID- 25781777 TI - Hermit crabs (Decapoda: Crustacea) from deep Mauritanian waters (NW Africa) with the description of a new species. AB - Thirteen hermit crab species of the families Diogenidae, Paguridae and Parapaguridae were captured in deep waters off Mauritania during Maurit surveys. A new species of the genus Paguristes, Paguristes candelae n. sp., is described. Areopaguristes mauritanicus n. comb. is proposed for Paguristes mauritanicus Bouvier, 1906 and Pseudopaguristes marocanus n. comb. for Paguristes marocanus A. Milne-Edwards & Bouvier, 1892; the females of the latter species are reported for the first time. Our data extends the geographical distribution of Pseudopaguristes marocanus southwards and that of Paragiopagurus macroceros northwards. Both species, together with Diogenes pugilator (Roux, 1829), are recorded for the first time in Mauritanian waters. New data about bathymetric ranges are also reported for Pseudopaguristes marocanus n. comb., Areopaguristes mauritanicus n. comb. and Paragiopagurus macroceros. PMID- 25781779 TI - New species, corallivory, in situ video observations and overview of the Goniasteridae (Valvatida, Asteroidea) in the Hawaiian Region. AB - Two new species of Goniasteridae, Astroceramus eldredgei n. sp. and Apollonaster kelleyi n. sp. are described from the Hawaiian Islands region. Prior to this occurrence, Apollonaster was known only from the North Atlantic. The Goniasteridae is the most diverse family of asteroids in the Hawaiian region. Additional in situ observations of several goniasterid species, including A. eldredgei n. sp. are reported. These observations extend documentation of deep sea corallivory among goniasterid asteroids. New species occurrences presented herein suggested further biogeographic affinities between tropical Pacific and Atlantic goniasterid faunas. PMID- 25781778 TI - Two new endangered species of Anomaloglossus (Anura: Aromobatidae) from Roraima State, northern Brazil. AB - We describe two new species of Anomaloglossus from Roraima State, Brazil, that are likely endemic to single mountains currently isolated among lowland forest and savanna ecosystems. The first species, Anomaloglossus tepequem sp. nov. was collected in 1986 and 1992 along a single stream at >500 m elevation on a tepui like mountain named Tepequem, but was not detected during recent investigations. It is mainly diagnosed from other Anomaloglossus species by its well developed foot webbing, immaculate cream abdomen colouration and small body size (males: 18.2-20.1 mm, females: 21.7-24.5). The second species, Anomaloglossus apiau sp. nov. was found along several streams between 500 and 1400 m elevation on Serra do Apiau, and is mainly diagnosed from congeners by its weakly webbed feet, males with swollen third finger and ventrolateral stripe formed by white dots, and its advertisement call; a long trill (up to almost 40 s) consisting of pairs of very short pulses. The discovery of these two apparently microendemic species suggests that additional Anomaloglossus species remain to be described in the Guiana Shield. Both species should be considered critically endangered given their seemingly reduced range size, association with highland habitat, and the anthropogenic pressure they currently face. PMID- 25781780 TI - Considerations on systematics of the Phytoseiidae (Acari: Mesostigmata), with definition of a new species group and description of a new species. AB - The authors debate some aspects of the classification of the Phytoseiidae, especially the subfamily Typhlodrominae. Within this taxon, the rhenanus group is the most numerous species group of Typhlodromus (Anthoseius), with 206 nominal species. Detailed observation of morphological characters of the species in this group showed a considerable variation, suggesting the presence of different natural lineages. The discovery of the new species here described, Typhlodromus (Anthoseius) sandrae Ragusa & Tsolakis n. sp., allowed the definition of the new porathi species group. Definition of the new species group, a dichotomous key as well as the description of the new species are given. PMID- 25781781 TI - Description of two new species of Neotanais Beddard, 1886 (Crustacea, Tanaidacea) from KODOS area. AB - Two new species of Neotanais Beddard, 1886 are described from the Korea Deep Ocean Study (KODOS) area in the Clarion-Clipperton Fracture Zone, based on the collections performed on board R/V Onnuri from a depth of 5180 m. Neotanais triqueturus n. sp. is similar to the 'pfaffi group' characterized by pereonites with a swollen distolateral margin, pleonites with mid-ventral spurs and tapered lateral margins but can be differentiated by a longer cephalothorax (length: width 1.6: 1), a cheliped with a large protrusion on the mid-dorsal margin of the fixed finger, and the presence of a ventral process on the cheliped carpus. Neotanais brevis n. sp. has the characteristics of the 'micromopher' group, with pleonites narrower than pereon, a cheliped carpus without a ventral process, and a uropod endopod with nine articles but can be differentiated by a combination of the pleonites without mid-ventral spurs, a relatively longer pleotelson (length: width 1: 1.5 vs. 1: 2), a uropod basis with one seta on each of the ventral and dorsal margins, and the cheliped fixed finger with proximal denticles. In this study, in order to prove N. triqueturus and N. brevis were new species, full descriptions and a comparison with the closely related species are given. In addition, comprehensive comparisons with the species of Neotanais from the east central Pacific are tabulated and discussed. PMID- 25781782 TI - Proszynellus--a new jumping spider genus from Australia (Araneae: Salticidae). AB - The new genus Proszynellus is described from Western Australia to include three new species: P. nasalis (??), P. wandae (??) and P. occidentalis (?), the first being designated the generic type. Diagnosis, descriptions, illustrations and distributional maps for all species are provided. Based on morphological characters, especially male palp and vulva, the genus is tentatively placed in Heliophaninae, being possibly close to Menemerus Simon. PMID- 25781783 TI - A new species of the nearctic gall-forming genus Tamalia Baker (Hemiptera: Aphididae: Tamaliinae). AB - The apterous viviparous female and alate oviparous female of a new aphid species, Tamalia milleri sp. nov., a representative of a nearctic relict genus Tamalia and associated with Arctostaphylos columbiana, is described and figured in detail from specimens collected in California and Oregon (USA) and deposited in the Natural History Museum, London (UK). The differences between T. milleri and a related species, T. dicksoni Remaudiere & Stroyan as well as other taxa of this genus are discussed. The distribution of Tamalia and a key to identification of the known species of the genus are provided. PMID- 25781784 TI - The misplaced genus Trischidocera Villeneuve (Diptera, Tachinidae). AB - Trischidocera Villeneuve, 1915 includes two species, T. sauteri Villeneuve, 1915 (Taiwan and Malaysia) and T. yunnanensis Chao & Zhou, 1987 (China). The systematic placement of Trischidocera has been controversial. It was originally placed within the "Thryptoceratidae" (= "Actiidae"), then moved to Germariini, then considered an unplaced Tachinidae, and more recently placed in Ormiini. Here, the genus is revised, the type-species is redescribed and illustrated, and its systematic placement is discussed. The genus is removed from Ormiini and considered incertae sedis. PMID- 25781785 TI - A new species of the water mite genus Hygrobates Koch, 1837 (Acari: Hydrachnidia: Hygrobatidae) from the ancient Lake Ohrid. AB - A new water mite species, Hygrobates zawali n. sp., is described from material collected in the ancient Lake Ohrid on the Balkan Peninsula. This species has been confused for a long time with the rhithrobiontic H. diversiporus Sokolow, 1927, known from the Caucasus (Russia) and Turkey. The new species closely resembles H. quanaticola Schwoerbel & Sepasgozarian, 1976, a little documented species described from Iran, which is here illustrated based on re-examination of the type material. Furthermore, a key for the identification of species of the subgenus Rivobates Thor, 1897, from the Western Palaearctic is given. PMID- 25781786 TI - A new extant species of Electribius Crowson from Honduras (Coleoptera: Elateroidea: Artematopodidae). AB - A new extant species of Electribius Crowson, E. llamae sp.n., is described from Cusuco National Park, Cortes Province, Honduras. This new species lacks one of the supposed autapomorphies of the genus; therefore the definition of the genus requires modification. A revised key to the known extant species is presented, and their known distributions are mapped. PMID- 25781787 TI - Coralliidae (Anthozoa: Octocorallia) from the INDEMARES 2010 expedition to north and northwest Spain (northeast Atlantic), with delimitation of a new species using both morphological and molecular approaches. AB - Three species of deep-water bathyal Coralliidae were collected during the INDEMARES 2010 expedition of the Spanish Institute of Oceanography to the Aviles Canyon System and the Galicia Bank (Spain, northeast Atlantic): Corallium occultum n. sp., Corallium cf. bayeri Simpson & Watling, 2011, and Corallium niobe Bayer, 1964. The new species is supported by both morphological and molecular evidence, and its phylogenetic relationship within the Coralliidae is inferred. Corallium cf. bayeri is first recorded from European waters. Corallium johnsoni Gray, 1860 from off Portugal and Madeira, and Corallium tricolor (Johnson, 1898) from Madeira are redescribed from museum material, and their sclerites first depicted by scanning electron microscopy. The sclerome of C. johnsoni is more complex than previously thought, with occurrence of double clubs, and 6-, 7- and 8-radiates. A key is proposed for the identification of all the Atlantic species of the genus Corallium. PMID- 25781788 TI - Redescription of Coronoquadroppia monstruosa (Hammer, 1979) (Acari, Oribatida, Quadroppiidae) from Java and variability of the species in Europe. AB - A main goal of this study was the comparison of type material of Coronoquadroppia monstruosa (Hammer, 1979) from Java with European populations which were supposed by authors to be conspecific. The species identity of most respective European findings with a type specimen can be confirmed. Yet within some populations from Germany, Austria and northern Italy, specimens with morphological variations are present, resembling partly C. gumista (Gordeeva et Tarba, 1990) from the Caucasus in regard of a transversal band in the rostral structure. This and other described modifications are supposed to be individual variability within the species C. monstruosa. A detailed morphological analysis is presented, resulting in the division of the Quadroppia complex into the genera Quadroppia and Coronoquadroppia as first proposed by Ohkubo (1995). PMID- 25781789 TI - Species of Platypalpus Macquart (Diptera: Hybotidae) from Uzbekistan, with descriptions of thirteen new species. AB - The genus Platypalpus Macquart is studied from Uzbekistan for the first time. Thirteen species are described as new for science: Platypalpus amankutanensis sp. nov., P. chimganensis sp. nov., P. commutatoides sp. nov., P. penesmirnovi sp. nov., P. sagma sp. nov., P. samarkandensis sp. nov., P. spatenkai sp. nov., P. subinfectus sp. nov., P. sublutescens sp. nov., P. tumidiarista sp. nov., P. uzbekistanicus sp. nov., P. virgatus sp. nov., and P. zeravshanensis sp. nov. Eight additional probable new species remain unnamed due to insufficient material. Platypalpus farabiensis Shamshev, 1998, P. kirtlingensis Grootaert, 1986, and P. longiseta (Zetterstedt, 1842) are recorded from Uzbekistan for the first time. A key to species of Platypalpus known from Middle Asia is compiled. PMID- 25781790 TI - The genus Hippomedon in Australian waters (Crustacea, Amphipoda, Lysianassidae, Tryphosinae). AB - Two new species of Hippomedon, H. hippolyte sp. nov. and H. tourville sp. nov. are described from Australian waters. The distribution of H. rodericki is extended from Tasmania northwards into New South Wales. The distribution of Hippomedon geelongi is also extended from Victoria northwards into New South Wales and southwards into Tasmania. PMID- 25781791 TI - Barilius ardens (Teleostei: Cyprinidae), a new species from the Western Ghats, India, with redescription of B. malabaricus and B. canarensis. AB - The identities of Barilius canarensis and B. malabaricus have hitherto been confused. An attempt to resolve their identities by examining fresh collections from their respective type localities, i.e., southern Karnataka and northern Kerala, yielded a new species, which is herein described as B. ardens. The new species differs from B. canarensis and B. malabaricus by the presence of a row of 7-9 large vertically elongate blotches on the flank, in large adults the first three blotches broken into a smaller row of intercalate spots (vs. two rows of spots: the first consisting of 9-11oval spots, the second with 3-4 smaller spots); and 5+4+3 (vs. 5+4+2) pharyngeal teeth. The new species is distinguished from B. bakeri by having 5+4+3 (vs. 5+4+2) pharyngeal teeth; and the dorsal and anal fins margined with bright orange (vs. white). Barilius malabaricus (hitherto in the synonymy of B. canarensis) is shown to be a valid species distinguished from the latter by having 111/2 (vs. 101/2) branched dorsal-fin rays and 141/2 151/2 (vs. 131/2) branched anal-fin rays; both species are redescribed. PMID- 25781792 TI - Two new species of the genus Pediculaster (Acari: Pygmephoridae) from Western Siberia, Russia. AB - Two new species of the genus Pediculaster Vitzthum, 1931 (Acari: Pygmephoroidea: Pygmephoridae), P. ermilovi sp. nov. and P. lignarius sp. nov. are described from rotten logs in Tyumen, Western Siberia, Russia. A key to phoretic females of Palaearctic species of the genus Pediculaster is provided. PMID- 25781793 TI - A new species of the genus Typton Costa (Crustacea: Decapoda: Palaemonidae: Pontoniinae) from the eastern tropical Pacific. AB - A new species of commensal shrimp of the genus Typton from holothurians is described and illustrated. The specimens were collected from a single specimen of Holothuria (Halodeima) inornata Semper, 1868 at a depth of 7 m. This is the first record of an association between a shrimp of the genus Typton and echinoderms. With this record, five species of Typton are now known from the eastern Pacific region and four of them are found in the Mexican Pacific. In Typton granulosus sp. nov., the distal part of the outer margin of the uropodal exopod is serrated, a feature shared with T. fapespae Almeida et al., 2014, T. holthuisi De Grave, 2010, T. prionurus Holthuis, 1951, T. serratus Holthuis, 1951, and T. spongicola Costa, 1844. However, the new species can be separated from the other five species of the genus by several morphological characters. PMID- 25781794 TI - New record of Anelytra (Anelytra) eunigrifrons Ingrisch, 1998 (Orthoptera, Tettigoniidae: Conocephalinae, Agraeciini) from India. AB - The record of Anelytra (Anelytra) eunigrifrons Ingrisch, 1998 (Conocephlinae: Agraeciini) collected from Umiam in the North-east province, Meghalaya (India) is reported for the first time. Previously, the species was reported from Indo China, Myanmar Burma, and Shan province, Carin Ghecu (Ingrisch, February 01, 1888 to March 31, 1888 and 1998). From India only one species, Anelytra (Anelytra) concolor Redtenbacher, 1891 has been recorded from Maharashtra, Mumbai. The paper includes the morphological characterization of the male of this species collected from North-east India. PMID- 25781795 TI - A taxonomic note on Erionota acroleuca (Wood-Mason & de Niceville, 1881) stat. rest. (Lepidoptera: Hesperiidae). AB - The purpose of this paper is to restore Erionota acroleuca (Wood-Mason & de Niceville, 1881) as a valid name, and to establish Erionota acroleuca apicalis de Jong & Treadaway, 1992 as a new subspecific combination, with its immature biology briefly introduced. PMID- 25781796 TI - First report of the Eucalyptus gall wasp, Ophelimus maskelli (Hymenoptera: Eulophidae), an invasive pest on Eucalyptus, from the Western Hemisphere. PMID- 25781797 TI - The rectal valve in Curculionoidea (Insecta: Coleoptera). AB - A rectal valve is known from Bostrichiformia (e.g. Dermestidae, Bostrichidae, Ptinidae), Cucujiformia (e.g. Chrysmeloidea, Cleridae, Curculionoidea, Endomychidae, Tenebrionidae) and Buprestidae, associated with the cryptonephridial system for water recovery from fecal matter. The valve is probably homologous in at least the Bostrichiformia and Cucujiformia although the form it takes may not be. It comprises a sclerotized band lying in the wall of the rectum where this meets the perinephric membrane. The valve is plesiomorphically a narrow crimped ring, probably acting as a sphincter to retain fecal matter for water extraction. Apomorphically it extends longitudinally along the rectum and supports the perinephric chamber; this state has probably arisen independently several times. Larval and adult morphology may be similar or different. Within the Curculionoidea different apomorphic forms suggest monophyly of groups within the Anthribidae and Dryophthoridae, and within the curculionid subfamilies Entiminae, Mesoptiliinae, Molytinae and Cossoninae + Scolytinae, although limited weight should be placed on a single character. No support is provided for a relationship between the Platypodinae and Scolytinae. The genera Cylindrotypetes Zimmerman 1942 and Edaphotrypetes Morimoto 1995 are transferred from Molytinae: Phoenicobatini to Cossoninae: Pentrarthini. PMID- 25781798 TI - A new genus and two new species of feather lice (Phthiraptera: Ischnocera: Philopteridae) from New Zealand endemic passerines (Aves: Passeriformes). AB - The first descriptions of New Zealand endemic feather lice belonging to the Brueelia-complex (Phthiraptera: Ischnocera: Philopteridae) are given. The new genus Melibrueelia and new species M. novaeseelandiae are described, illustrated and compared with morphologically close taxa within the complex. The type host of M. novaeseelandiae is the tui, Prosthemadera novaeseelandiae (Gmelin, 1788), and an additional host is the bellbird, Anthornis melanura (Sparrman, 1786) (Passeriformes: Meliphagidae), both endemic to New Zealand. Also, the new species Brueelia callaeincola is described and illustrated from four endemic bird species belonging to two endemic genera and an endemic family: Philesturnus carunculatus (Gmelin, 1789) (the type host), Ph. rufusater (Lesson, 1828), Callaeas cinerea (Gmelin, 1788) and C. wilsoni (Bonaparte, 1851) (Passeriformes: Callaeidae). Brief discussions on possible evolutionary histories of the new taxa are included. PMID- 25781799 TI - A review of Mimapsilopa Cresson (Diptera: Ephydridae) from Brazil. AB - Species of Mimapsilopa from Brazil are reviewed with an emphasis on the fauna from southern Brazil, where six new species were discovered and herein are diagnosed and described. To facilitate identification of species, we have included a diagnosis of the tribe Discomyzini and of Mimapsilopa and have also provided an annotated key to the New World genera of the tribe. We have also provided photos of representative specimens, illustrations of structures of the male terminalia and a distribution map for all included species. PMID- 25781800 TI - A new genus and species of xenodermatid snake (Squamata: Caenophidia: Xenodermatidae) from northern Lao People's Democratic Republic. AB - A male snake collected in Louangphabang Province and a second specimen observed in Houaphan Province, North Laos, share morphological characters with the Asian genus Fimbrios Smith, 1921, including erected edges on the first supra- and infralabial scales, but differ in the following morphological characters: fewer dorsal scale rows (25-27 vs. 30-33), fewer maxillary teeth (27 vs. 30-35), posterior teeth progressively slightly enlarged, and especially the correspondence of two dorsal scale rows per ventral plate throughout the body (i.e. the first dorsal scale row made of a small scale above the fore part of a ventral, followed by a much larger scale above its hind part), a condition known only in Xenodermus Reinhardt, 1836. As the Laotian specimens differ in morphological characters from other genera and species in the family Xenodermatidae, and on the basis of molecular analyses showing a large genetic divergence from the genus Fimbrios (p-distance >=14.7 %, mitochondrial COI gene), we place these specimens in a new genus, Parafimbrios gen. nov., and describe them as a new species, Parafimbrios lao sp. nov. Besides the characters mentioned above, the new species is diagnosed by a combination of the following ones: small, strongly keeled dorsal scales; rostral and first four supra- and infralabials with raised, erected edges; horizontal tissue ridges above the rostral; loreal single, large, elongate; ventral scales 177-189; subcaudals 55 56, undivided; dorsal colour purplish-grey, neck with a broad, very pale grey collar reaching downwards the pale grey colour of the venter. The morphological characters of the new genus are compared with those of the genera Fimbrios Smith, 1921, Xenodermus Reinhardt, 1836, Stoliczkaia Jerdon, 1870, Achalinus Peters, 1869, and Xylophis Beddome, 1878. A key to the genera Achalinus, Fimbrios and Parafimbrios gen. nov. is provided. Parafimbrios laos spec. nov. is the 111th snake species currently recorded from Laos. PMID- 25781801 TI - East African odontopygid millipedes 4: A restricted redefinition of the genus Rhamphidarpoides Kraus, 1960, a related new genus, five new species, and notes on solenomere function (Diplopoda; Spirostreptida; Odontopygidae). AB - Based mainly on morphology of the solenomere, a restricted redefinition of the millipede genus Rhamphidarpoides Kraus, 1960, is given. R. aberdarei (Brolemann, 1920), R. aloysiisabaudiae (Silvestri, 1907), R. alticolus (Brolemann, 1920), R. austrosudanicus n.sp., (South Sudan), R. collinus n.sp., (Kenya), R. cyclopyge (Attems, 1935), R. filigerus (Attems,1938), R. kenyanus (Brolemann, 1920), R. kilimanjaronus (Attems, 1909) n. comb. ex Odontopyge, R. lobiferus (Attems, 1938), R. milobontei Pierrard, 1970, R. pectinatus n.sp., (Kenya), R. regina (Carl, 1909), and R. ruandensis Kraus, 1960, are referred to Rhamphidarpoides in the restricted sense. Raduliverpa n.gen. is described to accommodate R. serpentispina n.sp. (TYPE SPECIES; Tanzania, Kenya), R. mitis n.sp. (Tanzania). R. serrata (Kraus, 1960), n.comb. ex Rhamphidarpoides, and R. sicaria (Attems, 1935) n. comb. ex Prionopetalum. Rhamphidarpe aculeata Attems, 1938, Rhamphidarpe armata Attems, 1938, Rhamphidarpoides bidens Kraus, 1960, Rhamphidarpoides bidenticulatus Pierrard, 1970, and Odontopyge winspearei Silvestri, 1907, are excluded from Rhamphidarpoides and placed incertae sedis. PMID- 25781802 TI - New species of mayflies (Ephemeroptera) from Cape Verde. AB - To date, no mayflies have been described from Cape Verde, an archipelago of volcanic islands in the Atlantic Ocean. Based on the material collected on two islands, Santo Antao and Santiago, two species of the genus Cloeon Leach, 1815 (Ephemeroptera: Baetidae) are described based on larvae and imagines. Cloeon morna sp. n., collected in Santo Antao, and C. sidadi sp. n., collected in Santiago, have 3-segmented maxillary palps and tapered labial palps of larvae. The new species can be distinguished from each other and from other West-African species of the genus mainly according to details of the lateral spines on larval abdominal segments and characteristic colourations of vitta and terga in female imagines and colours of male turbinate eyes. Affinities to the West African species of the genus are discussed. PMID- 25781803 TI - Description of the immature stages of Kuwanina betula Wu & Liu, with a discussion of its placement in the Acanthococcidae family group (Hemiptera: Coccoidea). AB - The immature stages of Kuwanina betula Wu & Liu are described and illustrated. Based on morphological and molecular data (18S and 28S rDNA), it is argued that K. betula is closer to Pseudochermes Nitsche than to Kuwanina Cockerell in Fernald and so this species is transferred to Pseudochermes as P. betula (Wu & Liu) comb. nov.. PMID- 25781804 TI - Additional descriptions of the plant bug genus Psallus from the Korean Peninsula (Hemiptera: Heteroptera: Miridae: Phylinae). AB - Three new species of the plant bug genus, Psallus are recognized from the Korean Peninsula: Psallus (Calopsallus) injensis Duwal sp. nov., P. (Hylopsallus) taehwana Duwal sp. nov. and P. (Phylidea) yongdaeri Duwal sp. nov. These species are described with illustrations of male and female genitalic structures. A revised key to known species from the Korean Peninsula, including new species and biological notes are provided. The species, Psallus sanguinarius is observed in the South Korea for the first time. PMID- 25781805 TI - A new species of the genus Oxyporus Fabricius (Coleoptera: Staphylinidae: Oxyporinae) in Yunnan, China. AB - Oxyporus (Oxyporus) kunmingius sp. nov. is described from Yunnan, China. Color images of the habitus and aedeagus of the new species are included. A key to the genus Oxyporus of Yunnan species is provided. PMID- 25781807 TI - Revision of the Bivalvia from the Upper Jurassic Reuchenette Formation, Northwest Switzerland--Ostreoidea. AB - The current work is the first part of a taxonomic revision of the highly diverse Kimmeridgian bivalve fauna of the Reuchenette Formation of northwestern Switzerland (Canton Jura). It provides a taxonomic, paleoecologic and bibliographic review of the eight oyster species characterizing the northern Helvetic shelf: Circunula n. gen. cotyledon (Contejean, 1859) (Gryphaeidae, ?Pycnodonteinae), Nanogyra (Nanogyra) nana (J. Sowerby, 1822), Nanogyra (Palaeogyra) reniformis (Goldfuss, 1833), Nanogyra (Palaeogyra) virgula (Deshayes, 1831) (Gryphaeidae, Exogyrinae), Helvetostrea n. gen. sequana (Thurmann & Etallon, 1862) (Flemingostreidae, Crassostreinae), Praeexogyra dubiensis (Contejean, 1859), Praeexogyra monsbeliardensis (Contejean, 1859) (Flemingostreidae, Liostreinae), and Actinostreon gregareum (J. Sowerby, 1815) (Arctostreidae, Palaeolophinae).The paper proposes two new genera: Circunula and Helvetostrea. Palaeogyra Mirkamalov, 1963, is considered a subgenus of Nanogyra Beurlen, 1958. Lectotypes are designated for six species: C. cotyledon, Praeexogyra acuminata, P. dubiensis, P. monsbeliardensis, H. caprina, H. sequana. The figured types of H. oxfordiana (Rollier, 1917) and N. auricularis (Munster in Goldfuss, 1833) are considered holotypes by monotypy. All types are refigured in drawings and/or photographs. Early phases of shell ontogeny in general and the generic characters of Praeexogyra are revisited. Larval shells or their internal moulds are shown for six species: N. nana, N. reniformis, N. virgula, N. cf. auricularis, Praeexogyra cf. sandalinoides (de Loriol, 1901), and Actinostreon marshii (J. Sowerby, 1814). All of them are "Crassostrea"-like suggesting a planktic-planktotrophic mode of development. Circunula n. gen. shows a relatively high incidence of prosogyry (up to ca. 20% of studied specimens) during very early postlarval development. To a lesser extent, prosogyry has also been observed in species of Catinula, Praeexogyra and Pernostrea. Chomata are typical of early ontogenetic stages of Circunula n. gen., but they disappear during later growth stages. Circunula n. gen. cotyledon is a typical early settler on hardgrounds but occurs also in subtidal soft-bottom environments attached to large shells. Nanogyra (N.) nana attached itself to all kinds of biogenous hard and soft substrates including algal stems and thalli. It is regularly found in calm to moderately energetic shallow marine paleoenvironments. Nanogyra (P.) reniformis frequently settled on the interior of empty bivalve shells. Nanogyra (P.) virgula was esentially a secondary soft-bottom dweller of shallow marine marls and lime muds. The species is often found concentrated in widely distributed (par)autochthonous lumachelles ("virgula marls" of authors) in the Upper Oxfordian, Upper Kimmeridgian and Tithonian. Praeexogyra dubiensis and P. monsbeliardensis occur in marly, shallow marine paleoenvironments. Praeexogyra dubiensis appears to have preferred attachment to small objects in a moderately energetic facies. In the study area it is also associated with algal meadows. Praeexogyra monsbeliardensis was preferentially gregarious in somewhat deeper and calmer paleoenvironments. The strongly chambered and probably fast growing Helvetostrea n. gen. sequana was adapted to moderate to high energetic shallow marine, marly habitats. It is frequently associated with corals and forms ostreoliths or small oyster buildups. Actinostreon gregareum usually lived gregariously but was also able to attach itself to algae on soft substrates. The species is known from calm marly to higher energetic coralline paleoenvironments. PMID- 25781808 TI - A revision of the Nearctic species of Brachygluta Thomson, 1859 (Coleoptera: Staphylinidae: Pselaphinae). AB - The North American species of Brachygluta Thomson, 1859 are revised, treating a total of 29 species. Six names are placed as junior synonyms: Bryaxis perpunctata Brendel, 1890 (=B. luniger LeConte, 1849), B. labyrinthea Casey, 1894 (=B. intermedia Brendel, 1866), B. loripes Casey, 1894 and B. jacobina Casey, 1908 (=B. foveata LeConte, 1851), B. arizonae Casey, 1887 (=B. texana Casey, 1886), and B. intricata Casey, 1894 (=B. terebrata Casey, 1894). Twelve new Brachygluta species are described: B. chisos Sabella (USA), B. cochimi Buckle (Mexico), B. eldredgei Chandler (USA), B. kiowa Sabella (USA), B. klamath Buckle (USA), B. lareaui Chandler (USA), B. mayo Sabella (Mexico), B. miccosukee Buckle (USA), B. seri Chandler (Mexico), B. shawnee Chandler (USA), B. tamaulipec Sabella (Mexico and USA), and B. wickhami Buckle (USA). Problems with the identities of the following three species based on missing types are discussed: Bryaxis abdominalis Aube, 1833; Bryaxis curvicera Motschulsky, 1854; and Pselaphus dentatus Say, 1824, with a Neotype being designated for P. dentatus. Nisa Casey, 1886 is removed from synonymy of Brachygluta and reinstituted as a subgenus. A key to the males is provided, nine species-groups are formed and defined, all species are characterized, distributions are detailed, and habitat/collecting data are summarized. Lectotypes are designated for Bryaxis arguta Casey, Bryaxis belfragei LeConte, Bryaxis foveata LeConte, Bryaxis infinita Casey, Brachygluta jacobina Casey, and Brachygluta mormon Bowman. PMID- 25781809 TI - Catalog of Hymenoptera described by Giovanni Gribodo (1846-1924) (Insecta). AB - Giovanni Gribodo (1846-1924) was an Italian civil engineer who described 377 new taxa of Hymenoptera, 199 of which are still valid and in use today, and proposed 6 replacement names. The present catalog provides a brief biography of Gribodo, a bibliography of his 42 publications and a complete list of the taxa proposed by Gribodo. The catalog lists, for all published names, details on the type series, type locality and collector, present status based on literature, all data labels, relevant references and remarks. A gazetteer of type-localities, a systematical list of Genus- and Species-group names, a chronological list of new names proposed by Giovanni Gribodo, with name-bearing types, and a list of Algerian species and varieties are also given. Furthermore, an unpublished manuscript by Gribodo on hymenopterological fauna of Tunisia, still kept at the Civic Museum of Natural History "Giacomo Doria" (Genoa, Italy), is described, and data on the 57 "new" taxa therein listed are reported, discussing their relevance in order to ascertain the original type series of 27 taxa validly published later. Finally, the problem posed by the enigmatic "disappearance" of a large number of Algerian types, already faced by several entomologists in the past, is analyzed, in order to prevent future mistaken designations of lectotypes and neotypes. The following six nomenclatural acts are proposed here by R. Wahis: Hemipepsis sycophanta Gribodo, 1884 = Hemipepsis bellicosa (Smith, 1873) new synonym; Anospilus sulcithorax (Gribodo, 1924) new combination; Auplopus validus (Gribodo, 1884) new combination; Dichragenia quartinae (Gribodo, 1884) new combination; Diplonyx caesar (Gribobo, 1894) new combination; Paracyphononyx melanicrus Gribodo, 1884 status revalidated (resurrected from synonymy with Pompilus ruficrus Klug, 1834). The following four nomenclatural acts are proposed by F. Penati: Parachrysis Gribodo, 1879 [subgenus of Chrysis Linnaeus] = Chrysis Linnaeus, 1760 new synonym; Psammotherma (Mutilla) quartinae Gribodo, 1884 = Psammotherma flabellata (Fabricius, 1804) new synonym; Megascolia (Regiscolia) alecto (Smith, 1858) subspecies vespillo (Gribodo, 1893) new combination; Megachile (Megachile) moutoni Gribodo, 1894 emendated name. PMID- 25781810 TI - A revision of Megagraphydrus Hansen (Coleoptera, Hydrophilidae): synonymization with Agraphydrus Regimbart and description of seven new species. AB - The genus Megagraphydrus Hansen, 1999 is revised. Eleven of the twelve previously described species are recognized as valid, with Megagraphydrus wangi Hebauer, 2000 syn. nov. found to be a junior synonym of M. politus Hansen, 1999. Most significantly, Megagraphydrus itself is found to be a junior synonym of Agraphydrus Regimbart, 1903. The species are assigned to the subgenus Agraphydrus. This nomenclatural act results in the following new combinations: Agraphydrus (Agraphydrus) anhuianus (Hebauer, 2000) comb. nov., A. (A.) attenuatus (Hansen, 1999) comb. nov., A. (A.) jaechi (Hansen, 1999) comb. nov., A. (A.) luteilateralis (Minoshima & Fujiwara, 2009) comb. nov., A. (A.) malayanus (Hebauer, 2000) comb. nov., A. (A.) politus (Hansen, 1999) comb. nov., A. (A.) puzhelongi (Jia, 2010) comb. nov., A. (A.) regularis (Hansen, 1999) comb. nov., A. (A.) siamensis (Hansen, 1999) comb. nov., A. (A.) superans (Hebauer, 2000) comb. nov., and A. (A.) uvaensis (Hebauer, 2000) comb. nov. All species are redescribed with the exclusion of A. superans, A. luteilateralis, and A. puzhelongi. Seven new species are described: Agraphydrus (Agraphydrus) biprojectus sp. nov., A. (A.) coronarius sp. nov., A. (A.) decipiens sp. nov., A. (A.) insidiator sp. nov., A. (A.) masatakai sp. nov., A. (A.) montanus sp. nov., A. (A.) thaiensis sp. nov. Digital and SEM photographs are provided, and the male and female genital segments are illustrated and described. PMID- 25781811 TI - Systematic revision of the ormiine genera Aulacephala Macquart and Phasioormia Townsend (Diptera, Tachinidae). AB - The tribe Ormiini comprises 64 species in six genera. In the present paper, the ormiine genera Aulacephala Macquart and Phasioormia Townsend are revised, with two valid species recognized in the former and three valid species recognized in the latter. All available nominal species in Aulacephala and Phasioormia were examined and are revised herein, so that previous synonymies could be confirmed. Furthermore, Phasioormia papuana sp. nov. is described from Papua New Guinea and Indonesia, and Therobia punctigera (Paramonov, 1955) is proposed as a new synonym of Aulacephala hervei Bequaert, 1922, syn. nov. Keys to species and illustrations of male and female terminalia are provided for both genera. PMID- 25781812 TI - Anatomical deviation of male organs of land planarians from Rio de Janeiro, Brazil, with description of two new species of Cratera (Platyhelminthes, Tricladida). AB - Two new land planarian species, collected in the State of Rio de Janeiro, Brazil, are described. Their external aspect is similar to that of Imbira marcusi Carbayo et al., 2013 and Pseudogeoplana theresopolitana (Schirch, 1929), respectively. The analysis of the internal organs, however, revealed they belong to the genus Cratera. The male copulatory organs of one species is very different from any other geoplaninid, for the penis papilla holds a large, distal cavity receiving the ejaculatory duct and, furthermore, the papilla projects vertically downwards from the roof of the male atrium. Thus we consider it as a new species, Cratera cuarassu sp. nov. The second species differs from its congeners in that the dorsal insertion of the penis papilla is anterior to the ventral one, and in that the female atrium is narrowed in the anterior portion. The species was found in the type locality of Pseudogeoplana theresopolitana (Schirch, 1929) and compares well with it in the external features. However, since its internal organs are unknown and the type material of the species is seemingly lost, we describe it as Cratera anamariae Carbayo, sp. nov. PMID- 25781813 TI - Six new species of the genus Opopaea Simon, 1891 from Xishuangbanna Rainforest, southwestern China (Araneae: Oonopidae). AB - Seven species of the genus Opopaea Simon, 1891 from Xishuangbanna Rainforest, Yunnan, China are recognized, including six new species: Opopaea auriforma sp. nov. (male, female), Opopaea cornuta Yin & Wang, 1984, Opopaea flabellata sp. nov. (female), Opopaea macula sp. nov. (male, female), Opopaea rigidula sp. nov. (male, female), Opopaea semilunata sp. nov. (female), and Opopaea zhengi sp. nov. (male, female). Morphological descriptions and illustrations of all the six new species are given. All the types are deposited in the Institute of Zoology, Chinese Academy of Sciences in Beijing (IZCAS). PMID- 25781814 TI - The Rediscovery of Sphenomorphus malayanus Doria, 1888 (Squamata: Scincidae) from the Titiwangsa Mountain Range of Peninsular Malaysia and its re-description as S. senja sp. nov. AB - The discovery of an additional specimen of Sphenomorphus malayanus Doria, 1888 from Gunung Brinchang, Cameron Highlands, Pahang in Peninsular Malaysia reveals that it is not conspecific with the type specimen from Gunung Singgalan, West Sumatra, 600 km to the south. The new specimen and an additional specimen previously collected from Gunung Gerah, Perak, Peninsular Malaysia, 56 km to the north, are described here as the new species S. senja sp. nov. and differ from S. malayanus by having a larger SVL (60.0-65 mm versus 53 mm); a deeply recessed as opposed to a shallow tympanum; 72 or 73 versus 76 paravertebral scales; eight or nine superciliary scales as opposed to 10; and the posteriormost superciliary scale being large as opposed to small. Cameron Highlands is unique among other upland areas in Peninsular Malaysia in that it harbors an unprecedented number of closely related ecological equivalents living in close sympatry or syntopy. PMID- 25781815 TI - First record of the African-Indian centipede genus Digitipes Attems, 1930 (Scolopendromorpha: Otostigminae) from Myanmar, and the systematic position of a new species based on molecular phylogenetics. AB - The first Southeast Asian record of the scolopendrid centipede Digitipes Attems, 1930, has been collected and analyzed based on a new species from Myanmar, males possessing a distomedial process on the ultimate leg femur that is diagnostic of the genus. Digitipes kalewaensis n. sp., described herein, is distinguished from other members of Digitipes by its 2.5 to 2.7 dorsally glabrous antennal articles, an unusually long basal suture on the tooth-plates, absence of a lateral spine on the coxopleural process, and a lack of median and dorso-median spines on the ultimate leg prefemur. Maximum likelihood and Bayesian analyses of two molecular markers (mitochondrial COI and 16S rRNA) supported the proposal of a new species from Myanmar. The phylogenetic tree identifies Digitipes barnabasi from the Western Ghats, India, in a polytomy with members of other genera of Otostigminae (Otostigmus, Ethmostigmus and Rhysida) and a robust Indian-Burmese Digitipes clade in which D. kalewaensis n. sp. is resolved as sister group to a clade composed of most Indian species. Available molecular dates for the diversification of Indian Digitipes are consistent with introduction of the genus into SE Asia when the Indian subcontinent made contact with Myanmar in the early Palaeogene. PMID- 25781816 TI - Rotylenchus castilloi n. sp. (Nematoda: Hoplolaimidae), a new species with long stylet from northern Iran. AB - Rotylenchus castilloi n. sp., a new bisexual species is described and illustrated based on morphological, morphometric and molecular data. The new species is characterised by having a hemispherical, continuous lip region with an irregular corncob-like appearance under SEM, very long stylet (62-68 um), vulva located at 49.7-62.2% of body length from anterior end, with a protruding double epiptygma, a rounded to convex-conoid (rarely bi-lobed) tail with 8-12 annuli and specific sequences of D2-D3 segments of 28S and ITS1-rRNA genes. Differences between the new species and four other species of the genus (R. mesorobustus, R. cazorlaensis, R. magnus and R. jaeni) are discussed. Morphologically, the new species can be separated from these species mostly by its body length, lip region characters, stylet length and location of phasmid. Phylogenetic analyses using 721 bp partial sequences of D2-D3 expansion segments of the 28S and 590 bp ITS1 rRNA genes revealed the new species forming a clade with two isolates of R. eximius and two isolates of R. unisexus, two morphologically unrelated species. PMID- 25781817 TI - The assassin bug subfamily Harpactorinae (Hemiptera: Reduviidae) from Vietnam: an annotated checklist of species. AB - A checklist of all known Vietnamese species of the assassin bug subfamily Harpactorinae (Hemiptera: Heteroptera: Reduviidae) is presented with distributional and taxonomic notes. Sixty-five species in 35 genera of the subfamily are recognized in Vietnam. Eleven genera and 32 species are reported herein for the first time from this country. Newly recorded genera are Henricohahnia Breddin, 1900, Kalonotocoris Miller, 1941, Lingnania China, 1940, Lopodytes Stal, 1853, Macracanthopsis Reuter, 1881, Sclomina Stal, 1861, Serendiba Distant, 1906, Serendus Hsiao, 1979, Vesbius Stal, 1866, Villanovanus Distant, 1904, and Yolinus Amyot & Serville, 1843. New record species are Biasticus confusus Hsiao, 1979, B. flavinotus (Matsumura, 1913), Cosmolestes annulipes Distant, 1879, C. pulcher Hsiao, 1979, Cydnocoris fasciatus Reuter, 1881, C. gilvus (Burmeister, 1838), Endochus nigricornis Stal, 1859, Henricohahnia vittata Miller, 1954, Isyndus heros (Fabricius, 1803), I. pilosipes Reuter, 1881, Kalonotocoris curvipes Miller, 1941, Lingnania braconiformis China, 1940, Lopodytes spectabilis Miller, 1941, Macracanthopsis nodipes Reuter, 1881, Sclomina erinacea Stal, 1861, Serendiba nigrospina Hsiao, 1979, S. staliana (Horvath, 1879), Serendus geniculatus Hsiao, 1979, Sphedanolestes annulipes Distant, 1903, S. gularis Hsiao, 1979, S. impressicollis (Stal, 1861), S. pubinotus Reuter, 1881, S. trichrous Stal, 1874, S. xiongi Cai & Cai, 2004, Sycanus croceus Hsiao, 1979, Velinus annulatus Distant, 1879, V. malayus (Stal, 1863), V. rufiventris Hsiao, 1979, Vesbius purpureus (Thunberg, 1784), V. sanguinosus Stal, 1874, Villanovanus nigrorufus Hsiao, 1979, and Yolinus albopustulatus China, 1940. All the species are examined with Vietnamese materials except for Agriosphodrus dohrni (Signoret, 1862), Cydnocoris russatus Stal, 1867, and Sycanus atrocoeruleus Signoret, 1862. PMID- 25781818 TI - A new species of Oromia (Coleoptera: Curculionidae) from the Canary Islands. AB - The weevil Oromia thoracica n. sp. from Gran Canaria (Canary Islands) is described and compared to its closest allies. It can easily be distinguished by less sculptured elytra, its differently shaped antennal scrobe, and by the pronotum not constricted anteriorly and expanded over the head. Some ecological data are also provided, and considerations on the fauna occurring in the mesovoid shallow substratum (MSS) from the locality of this new species are made. Additional records and comments on other Oromia species as well as an identification key to the species of the genus are given. PMID- 25781819 TI - First fossil Lamprosomatinae leaf beetles (Coleoptera: Chrysomelidae) with descriptions of new genera and species from Baltic amber. AB - In the current paper the first fossil representatives of leaf-beetles from the subfamily Lamprosomatinae (Coleoptera: Chrysomelidae) are described and illustrated from Upper Eocene Baltic amber: Succinoomorphus warchalowskii gen. et sp. nov., Archelamprosomius balticus gen. et sp. nov., and Archelamprosomius kirejtshuki sp. nov. A key to fossil Lamprosomatinae is provided. PMID- 25781820 TI - Coreoleuciscus aeruginos (Teleostei: Cypriniformes: Cyprinidae), a new species from the Seomjin and Nakdong rivers, Korea. AB - Coreoleuciscus splendidus was first reported as a monotypic species. Recent morphological and genetic studies have revealed that the species is represented by two disjunct and distinct lineages. The two lineages of C. splendidus include populations inhabiting the Han and Geum rivers in the East Korea Subdistrict and populations inhabiting the Seomjin and Nakdong rivers in the South Korea Subdistrict. In this study, significant differences were found between these two independent lineages through a high degree of genetic divergence in the mitochondrial cytochrome c oxidase subunit I gene as well as conspicuous morphological differences in body coloration and shapes of black stripes on dorsal, anal and caudal fin rays. These morphological and genetic differences provide supporting evidence that the populations in the South Korea Subdistrict represent a new species, Coreoleuciscus aeruginos. PMID- 25781821 TI - Revision of the Recent Mediterranean species of Mitromorpha Carpenter, 1865 (Gastropoda, Conoidea, Mitromorphidae) with the description of seven new species. AB - The Mediterranean species of the genus Mitromorpha Carpenter, 1865 as currently conceived, are herein reviewed. The genus is represented in the Mediterranean Sea by eleven species, of which seven are here described as new, all included conservatively in the subgenus Mitrolumna Bucquoy, Dautzenberg & Dollfus, 1883: Mitromorpha (Mitrolumna) columbellaria (Scacchi, 1836), Mitromorpha (Mitrolumna) olivoidea (Cantraine, 1835), Mitromorpha (Mitrolumna) karpathoensis (Nordsieck, 1969), Mitromorpha (Mitrolumna) wilhelminae (van Aartsen, Menkhorst & Gittenberger, 1984), Mitromorpha (Mitrolumna) alyssae n. sp., Mitromorpha (Mitrolumna) bogii n. sp., Mitromorpha (Mitrolumna) cossyrae n. sp., Mitromorpha (Mitrolumna) nofronii n. sp., Mitromorpha (Mitrolumna) mariottinii n. sp., Mitromorpha (Mitrolumna) mifsudi n. sp., and Mitromorpha (Mitrolumna) tricolorata n. sp. Neotypes are designated for: Mitra columbellaria Scacchi, 1836, [currently Mitromorpha columbellaria (Scacchi, 1836) comb. nov.], and Mitrolumna algeriana Pallary, 1900 ex Monterosato ms. [currently Mitromorpha algeriana (Pallary, 1900) comb. nov.] considered as a synonym of Mitromorpha columbellaria (Scacchi, 1836). The latter is the oldest available name for the most common and widespread Mediterranean species of Mitromorpha. A lectotype is selected for Mitra leontocroma Brusina, 1866 [currently Mitromorpha leontocroma (Brusina, 1866) comb. nov.], previously considered as a junior synonym of Mitromorpha olivoidea (Cantraine, 1835) but here considered as a junior synonym of Mitromorpha columbellaria (Scacchi, 1836). Mitromorpha melitensis (Mifsud, 1993) is a synonym of Mitromorpha olivoidea (Cantraine, 1835). Mitromorpha mediterranea Mifsud, 2001 is a synonym of Mitromorpha columbellaria (Scacchi, 1836). PMID- 25781822 TI - The Neotropical genus Ginungagapus gen. nov. (Hesperiidae, Hesperiinae, Moncini): phylogenetic position and taxonomic review. AB - A taxonomic and phylogenetic study based on morphological characters revealed the type species of the genus Lucida Evans, 1955, Lucida lucia (Capronnier, 1874) to be paraphyletic to other species of the genus. As a result, a new genus, Ginungagapus gen. nov., is erected including four species previously placed in Lucida: Ginungagapus schmithi (Bell, 1930) comb. nov., Ginungagapus bocus (Bell, 1947) comb. nov., Ginungagapus ranesus (Schaus, 1902) comb. nov., and Ginungagapus rogan (Evans, 1955) comb. nov.; and four new species are added: Ginungagapus awarreni, sp. nov., Ginungagapus tangerinii, sp. nov., Ginungagapus fiedleri, sp. nov. and Ginungagapus brasilia, sp. nov. The new genus is taxonomically revised, genitalia are illustrated, except of the female of G. rogan (Evans, 1955) and of the male of G. brasilia, sp. nov., which are still unknown. An identification key is provided. PMID- 25781823 TI - A new species of Leptolalax (Anura: Megophryidae) from the western Langbian Plateau, southern Vietnam. AB - We describe a new species of megophryid frog from Loc Bac forest in the western part of the Langbian Plateau in the southern Annamite Mountains, Vietnam. Leptolalax pyrrhops sp. nov. is distinguished from its congeners by a combination of the following morphological attributes: (1) presence of distinct dark brown/black dorsolateral markings, including blackish spots on flanks and dark canthal and/or temporal streaks; (2) rudimentary webbing on toes; (3) tympanum externally distinct; (4) dorsal skin finely shagreened with numerous small tubercles and pustules; (5) medium size for the genus (30.3-33.9 mm in 2 adult males, 30.8-34.3 mm in 7 females); (6) grey-pinkish to dark brownish-violet chest and belly with numerous whitish speckles, also covering the lateral sides of body; (7) ventrolateral glands small, indistinct, do not form a distinct line; (8) pectoral glands comparatively small, comprising 1-3% of adult SVL; (10) iris bicolored, typically bright orange-red in upper two-thirds, fading to silvery green in lower third. The male advertisement call of the new species is also unique among those Leptolalax species for which calls are known, with a single long 'introductory' note, consisting of 5-12 pulses, followed by of 4-5 predominantly single-pulsed notes, and an average dominant frequency of 1.91-2.23 kHz. From the morphologically similar L. applebyi, L. melicus and L. bidoupensis, Leptolalax pyrrhops sp. nov. can be further distinguished by 13.5%, 13.7% and 10.3% sequence divergence at the 16S rRNA mtDNA gene. At present, the new species is known from montane evergreen forest between 800-1100 m elevation. We suggest the species should be considered as Data Deficient following IUCN's Red List categories. To date our finding represents the southernmost known record of the genus Leptolalax from Vietnam. PMID- 25781825 TI - New Chinese species of the genus Thalassaphorura Bagnall, 1949 (Collembola: Onychiuridae). AB - Thalassaphorura is the most diverse genus in China so far. Three new species (T. guangdongensis sp. nov., T. xihuensis sp. nov. and T. linzhiensis sp. nov.) are reported from China. T. guangdongensis sp. nov. is characterized by its pso formulae (32/122/33343 dorsally and 11/000/01010 ventrally), 4+4 medial p-chaetae between posterior pso on head, 2+2 chaetae on Abd. I-III terga along axial line and axial chaeta m0 present on Abd. VI tergum. T. xihuensis sp. nov. belongs to the group of species characterized by the presence of only 4 papillae in AIIIO. T. linzhiensis sp. nov. is most similar to T. hainanica Sun, Gao & Potapov, 2014, and differs from the latter by undifferentiated S-chaetae, more vesicles in PAO, two axial chaetae on Abd. VI tergum, the presence of chaetae on Th. I sternum and longer anal spines. PMID- 25781824 TI - Description of two new species and a new combination for the leafhopper genus Reticuluma (Hemiptera: Cicadellidae: Deltocephalinae: Penthimiini) from China. AB - Two new species of Reticuluma from China, R. dactyla Fu & Zhang sp. nov. and R. eurya sp. nov., are described and illustrated. A new combination, R. testacea (Kuoh) n. comb. is transferred from the genus Penthimia. PMID- 25781826 TI - New species and additional records of Amaurodera Fauvel in southern China (Coleoptera, Staphylinidae, Aleocharinae). AB - Material of the lomechusine genus Amaurodera Fauvel from southern China is studied. In total, four species are recognized, among which one is described here as new: Amaurodera darenae sp. nov., and new records for three previously described are provided. All of these species are illustrated. PMID- 25781827 TI - A new species of Pactola Pascoe, 1876 (Coleoptera: Curculionidae: Eugnomini) from New Caledonia. AB - Pactola corporosa sp. n. is described from New Caledonia. Illustrations of body parts, terminalia of both sexes and distributional data of the new species are provided. The genus Pactola Pascoe, 1876 now contains thirteen species distributed in New Zealand, New Caledonia and Taevuni Island (Fiji Archipelago). PMID- 25781828 TI - Two new species in the genus Geritola Libert, 1999 (Lepidoptera: Lycaenidae, Epitolini). AB - Two Geritola (Lepidoptera: Lycaenidae) species, closely related to the Central African G. nitidica, have been recognised as new to science. G. wardi sp. n. was captured in small series in Mabira, an eastern outlier forest in Uganda, while G. pacifica sp. n. was discovered in Liberia, in classic Upper-Guinean hyper-wet rainforests. Both of them are described in comparison to their allopatric relative G. nitidica, including male genitalia. PMID- 25781829 TI - A new littoral interstitial species of the genus Isotomodes (Collembola, Isotomidae) from Italy. PMID- 25781830 TI - Addendum to: Joseph Vachal (1838-1911): French entomologist and politician (Zootaxa, 3442, 1-52). PMID- 25781831 TI - Systematics and biology of mites associated with neotropical hispine beetles in unfurled leaves of Heliconia, with descriptions of two new genera of the family Melicharidae (Acari: Mesostigmata: Gamasina: Ascoidea). AB - Two new genera Makarovaia and Hispiniphis are described from adults and immatures of newly described species associated with hispine beetles of the genera Chelobasis and Cephaloleia, respectively, occupying unfurled leaves of Heliconia in lowland rainforest of Costa Rica. The new genera share a suite of unique morphological attributes, but are tentatively assigned to the family Melicharidae. While all instars of the mites can be found under the elytra of their adult beetle hosts, adult mites also move freely on and off the beetles. A new form of laboulbeniaceous fungus of the genus Rickia is frequently associated with adult mites of Makarovaia as well as their beetle hosts, yet evidently rarely with mites of a species of Hispiniphis or its beetle hosts which may co occupy the same host leaves. Limited data suggest considerable host specificity between mites and their beetle hosts. Whether the association of these mites with hispine beetles may be ancient, prior to the beetles' adaptation to living in unfurled leaves of host plants, or is a more recent invasion and partitioning of the rolled leaf beetle fauna, is discussed. PMID- 25781832 TI - A checklist of the amphibians and reptiles of Honduras, with additions, comments on taxonomy, some recent taxonomic decisions, and areas of further studies needed. AB - An updated checklist of the amphibians and reptiles of Honduras is provided. The list includes three amphibian species (Ptychohyla euthysanota, Bolitoglossa odonnelli, Oedipina chortiorum) and two reptile species (Laemanctus waltersi [elevated from subspecies status], Epictia phenops) not included in the most recent checklist of the amphibians and reptiles of the country. Also, one amphibian genus and species (Triprion petasatus) is removed from the country list and one Honduran lizard (Ctenosaura praeocularis) is synonymized with an older name. Comments where more study is needed are also included where pertinent. Authors, dates, and original spellings of the higher-level taxonomy of all taxa covered herein are also given. A total of 401 species (137 amphibians and 264 reptiles) are now known from the country with 111 species (27.7%) being Honduran endemics (52 amphibians and 59 reptiles). PMID- 25781833 TI - Revision of emmenomma simon (amaurobiidae, macrobuninae). AB - The genus Emmenomma is revised and now includes three species from Southern Chile, Argentina and Falkland Islands (Islas Malvinas). The type species Emmenomma oculatum is redescribed and considered a senior synonym of E. beauchenicum. Emmenomma oculatum obscurum is removed from synonymy with E. oculatum, raised to the species level and redescribed; the male of this species remains unknown. A new species, Emmenomma joshuabelli sp. nov. is described. The presence of a grate shaped tapetum outside the Lycosoidea clade is described. Detailed images are provided for all known species. PMID- 25781834 TI - A review of the genus Carchesiopygus Schedl (Coleoptera: Curculionidae: Platypodinae), with keys to species. AB - The ten species included by Schedl (1972) in the Oriental platypodine genus Carchesiopygus Schedl are reviewed. The genus is rediagnosed and restricted to the following species: Carchesiopygus wollastoni (Chapuis) (type species), C. alternantes Schedl, C. assamensis (Beeson), C. impariporus (Beeson), C. multidentatus (Strohmeyer) and C. oculatus (Beeson), and distinguished from Crossotarsus Chapuis and related genera. The following species are transferred to Platypus Herbst: Carchesiopygus dentipennis Schedl, Carchesiopygus lobacanthus Schedl, Crossotarsus acanthurus Beeson, Crossotarsus psilacanthurus Beeson. Keys are provided to males and females of Carchesiopygus. The taxonomy, distribution and biology of the species are briefly reviewed, and some new records included. PMID- 25781835 TI - Description of five new species of Cnemomis, with a key to the known species (Hemiptera: Heteroptera: Coreidae: Discogastrini). AB - Five new species of the genus Cnemomis Stal, 1859 are described: C. kondratieffi from Brazil and French Guyana, C. lepida from French Guyana, C. nigroscutellata from Brazil, C. primigena from Peru, and C. refulgens from Venezuela. New distributional records for some previously known species are added. Dorsal view photographs and a key for the 13 known species are included. The male genital capsule of C. kondratieffi and C. lepida are illustrated. PMID- 25781836 TI - Synopsis of the hymenopteran fauna of Lord Howe Island with a preliminary checklist of species. AB - Lord Howe Island is an eroded remnant of a shield volcano approximately 600 km northeast of Sydney, New South Wales, Australia. It has fascinated biologists for more than a century because of its unique and iconic fauna and flora, and was declared a World Heritage Site in 1982. Although the terrestrial invertebrate fauna is reasonably well known for many groups, most Hymenoptera, apart from ants, have received scant attention. Here we use material collected from a recent intensive invertebrate survey, in conjunction with the published literature, to provide an overview of the Hymenoptera known from the island that can act as a basis for future taxonomic and biodiversity research. In doing so, we record 318 species from 31 hymenopteran families from the Island, and assess the proportion that are flightless and likely to be endemic to the island. PMID- 25781837 TI - A new subspecies of Phascolion Theel, 1875 (Sipuncula: Golfingiidae) from Indian waters. AB - A new subspecies of Phascolion pacificum Murina, 1957 is described from shallow waters (15-20 m deep) off Malvan and Ratnagiri in India. Phascolion pacificum denticulatum ssp. nov. is characterized by the presence of a prominent tooth-like projection in the median part of the free border of the holdfast papillae. This finding represents the first record of any Phascolion species for all the Indian coasts. PMID- 25781838 TI - Species checklist for the tribe Vartini Zahniser & Dietrich, 2013 (Hemiptera: Cicadellidae: Deltocephalinae) from China, with description of a new species. AB - An annotated checklist and generic key to the leafhopper tribe Vartini from China is provided. A new species Xenovarta falcata sp. nov. is described and illustrated, and a key is given to separate species of this genus from China. A map showing the geographic distribution of the new species is also provided. The type specimen of the new species is deposited in the Institute of Entomology, Guizhou University, Guiyang, China (GUGC). PMID- 25781839 TI - A new species of Zeanichnus Jaloszynski in New Zealand (Coleoptera, Staphylinidae, Scydmaeninae). AB - A new species of the cyrtoscydmine genus Zeanichnus Jaloszynski, Z. aupourianus sp. n. is described. This third representative of Zeanichnus is known to occur in the northernmost tip of North Island, New Zealand. Comparative notes on diagnostic characters are given, and the male copulatory organ of the new species is illustrated. PMID- 25781840 TI - Advertisement call of Rhinella inopina Vaz-Silva, Valdujo & Pombal, 2012 (Anura: Bufonidae) from the type-locality, northeastern Goias State, Central Brazil. PMID- 25781841 TI - Molecular phylogenetics, systematics and host-plant associations of the Bruchidius albosparsus (Fahraeus) species group (Coleoptera, Chrysomelidae, Bruchinae) with the description of four new species. AB - Bruchidius Schilsky is a large paraphyletic genus of seed beetles (Coleoptera: Chrysomelidae: Bruchinae) which consists of multiple lineages that are usually associated with narrow sets of host-plants. In this study we focus on a group that mostly develops on wattle trees (acacias) belonging to the genus Vachellia Wight & Arn. This group originally included nine species and was designated as the Bruchidius centromaculatus (Allard) species group, but recent phylogenetic analyses revealed that these species belong to a much wider group of species with similar morphologies. For reasons of anteriority we call this enlarged group Bruchidius albosparsus (Fahraeus). Here we review the morphology of species in this group and provide new diagnoses and ecological data for 10 species. The following combinations and synonymies are proposed: Bruchidius tanaensis (Pic, 1921) (= Bruchus tanaensis Pic, 1921) comb. nov. and Bruchidius albosparsus (Fahraeus, 1839) (= Bruchus spadiceus Fahraeus, 1839) syn. nov. Four new species are also described: B. eminingensis sp. nov., B. gerrardiicola sp. nov., B. glomeratus sp. nov. and B. haladai sp. nov. Finally we carried out molecular phylogenetic analyses on a multi-marker dataset of 59 specimens and 35 species, including 14 species from the group. The resulting trees allow us to confirm the monophyly of the group of interest and provide a more detailed picture of their evolutionary relationships. PMID- 25781842 TI - Two new species of dragon millipedes, genus Desmoxytes Chamnerlin, 1923, from Laos (Diplopoda: Polydesmida: Paradoxosomatidae), with redescriptions of all four species of Attems from Vietnam. AB - Two new species of Desmoxytes are described and abundantly illustrated: D. rhinoceros sp. n. and D. rhinoparva sp. n., from southern and northern Laos, respectively. Illustrated redescriptions of all four Vietnamese Desmoxytes species proposed by Carl Attems are also provided, based on type material. PMID- 25781843 TI - Status changes, new synonymies, key and descriptions of seven new species in the subgenus Scarabaeus (Scarabaeolus) Balthasar 1965 (Coleoptera: Scarabaeidae: Scarabaeinae). AB - Distribution of the subgenus Scarabaeus (Scarabaeolus) Balthasar 1965 (tribe Scarabaeini) is centred on southern and south central Africa with only three out of 27 species recorded from West and northeast Africa. After taxonomic corrections and descriptions of seven new southern African species this somewhat controversial subgenus now comprises 33 valid species of which one is flightless. In this paper, Scarabaeus (Scarabaeolus) vansoni Ferreira 1958 syn. nov. is synonymized with Scarabaeus (Scarabaeolus) lucidulus (Boheman 1860) and Scarabaeus (Scarabaeolus) xavieri Ferreira 1968 syn. nov. is synonymized with Scarabaeus (Scarabaeolus) andreaei zur Strassen 1963. Scarabaeus (Scarabaeolus) reichei Waterhouse 1890 stat. rev. is removed from synonymy with Scarabaeus (Scarabaeolus) canaliculatus Fairmaire, 1888 and reinstated as a valid species. Distribution maps for S. (S.) reichei, S. (S.) canaliculatus and a third close relative, Scarabaeus (Scarabaeolus) fritschi Harold 1868 are provided. The seven new species comprise: Scarabaeus (Scarabaeolus) soutpansbergensis Deschodt and Davis spec. nov., Scarabaeus (Scarabaeolus) megaparvulus Davis and Deschodt spec. nov., Scarabaeus (Scarabaeolus) niemandi Deschodt and Davis spec. nov., Scarabaeus (Scarabaeolus) carniphilus Davis and Deschodt spec. nov., Scarabaeus (Scarabaeolus) ermienae Deschodt and Davis spec. nov., Scarabaeus (Scarabaeolus) planipennis Davis and Deschodt spec. nov. and Scarabaeus (Scarabaeolus) nitidus Davis and Deschodt spec. nov. A key is provided for all the known winged species together with notes on some of the previously described species. PMID- 25781844 TI - A new genus and species of false vampire (Chiroptera: Megadermatidae) from peninsular Thailand. AB - A new genus and associated species of false vampire, family Megadermatidae, are described based on three specimens from Bala Forest, Narathiwat Province, peninsular Thailand. The new taxon is characterised by a unique combination of distinctive dental, cranial, and external characters, some of which are shared with exclusively African genera and some with Asian genera. These characters are comparable to, or exceed in number, those differentiating currently recognised genera in the family Megadermatidae. They include the absence of a first upper premolar; greatly enlarged upper canine without an anterolingual cingular cusp but with a robust posterolingual cusp; unmodified upper first molar with the preparacrista subequal in length to the postmetacrista, the metastyle not reduced and situated labially; robust lower canine without an anterolingual cusp; the first lower premolar enlarged, equal to or larger than the second lower premolar. In the skull, there is a pronounced rostral depression but no well developed frontal shield with preorbital and/or postorbital processes; the coronoid process is greatly enlarged in each half mandible. Externally, the body size is relatively large and the posterior noseleaf is rounded. The baculum has a robust shaft and two short prongs-the bacula of all five other species of megadermatid are illustrated for the first time; extraordinarily, those of Macroderma gigas and Megaderma lyra comprise two separate bones. DNA barcoding indicate a genetic divergence of about 20 percent (sequence divergence in the mitochondrial gene CO1) between the new genus and species of Megaderma and Cardioderma. Currently, despite numerous bat surveys in peninsular Thailand, the new genus is only known from Bala Forest. The small area of this forest and the very low capture rate suggest that the new species may be extremely rare. Its natural history is little known, although its robust dental and cranial features when coupled with chance observations of its feeding behaviour, suggest it may specialise in eating large beetles. Its conservation status is considered to be at risk owing to the rapid loss of forest habitat in much of the Thai-Malay peninsula. PMID- 25781845 TI - Nanocladius (Plecopteracoluthus) shigaensis sp. nov. (Chironomidae: Orthocladiinae) whose larvae are phoretic on nymphs of stoneflies (Plecoptera) from Japan. AB - We identified a new species, Nanocladius (Plecopteracoluthus) shigaensis, from Shiga and Gifu Prefectures, Japan, whose larvae are phoretic on nymphs of Plecoptera. Although this new species is morphologically similar to Nanocladius (Plecopteracoluthus) asiaticus Hayashi (1998), which is phoretic on Megaloptera larvae, it differs from N. (P.) asiaticus: the color of the larval head capsule is light brown in N. (P.) shigaensis and dark brown in N. (P.) asiaticus and the larval capsule index of the former is significantly larger than that of the latter. Moreover, analyses based on DNA sequence of cytochrome c oxidase subunit I (COI) supported the hypothesis that N. (P.) shigaensis and N. (P.) asiaticus are two distinct species. This is the first record of a phoretic chironomid on a plecopteran nymph in the Palaearctic region. PMID- 25781846 TI - Redescription of Astyanax guianensis Eigenmann 1909 (Characiformes: Characidae), a poorly known and widespread fish from the Amazon, Orinoco and Guiana Shield drainages. AB - Astyanax guianensis is redescribed based on the holotype, paratypes, and additional specimens from the rio Essequibo in Guyana, rio Orinoco in Venezuela and from several localities in the Amazon river basin in Brazil, Colombia and Bolivia. Astyanax guianensis is diagnosed by having five to 10 maxillary teeth, 31 to 35 pored lateral-line scales, 21 to 25 branched anal-fin rays, and a dark vertical humeral blotch followed by a clear area and then by a dark longitudinal stripe, ending before the caudal-fin rays. In addition, comments on the importance of revisionary studies on the species of the Characidae are provided. PMID- 25781847 TI - A new species in the newly recorded genus Trachyusa (Hymenoptera: Braconidae: Alysiinae) from China. AB - Trachyusa whartoni Yao sp. nov. from Dalian, Liaoning, China is described and illustrated. Trachyusa is a newly recorded genus in China. A key to the species of Trachyusa is provided based on the keys of Belokobylskij (1998), Papp (1967), and van Achterberg and O'Connor (1990). Type specimens of the new species are deposited in the Beneficial Insects Institute, Fujian Agriculture and Forestry University, Fuzhou, China. PMID- 25781848 TI - A new species of Fizesereneia Takeda & Tamura, 1980 (Crustacea: Brachyura: Cryptochiridae) from the Red Sea and Oman. AB - A new species of cryptochirid crab, Fizesereneia panda van der Meij, is described and illustrated based on specimens collected from the scleractinian corals Lobophyllia cf. hemprichii and L. cf. corymbosa from the Farasan Banks, Farasan Islands, and the reefs off Thuwal in the Saudi Arabian Red Sea, and from Symphyllia recta from reefs in the Gulf of Oman. This is the second cryptochirid species with the Red Sea as type locality. It can be separated from its congeners by the subrectangular carapace, raised midline and the complete division of the carapace depressions, and reddish black colour pattern of these concavities in live specimens. This new species is the seventh assigned to Fizesereneia. A DNA barcode for the new species has been deposited in GenBank. PMID- 25781849 TI - A new species of Alterosa Blahnik (Trichoptera: Philopotamidae: Philopotaminae) from Espirito Santo State, southeastern Brazil. PMID- 25781850 TI - EVY ARIDA & SRI CATUR SETYAWATININGSIH (2015) On the occurrence of Varanus nebulosus (Gray, 1831) (Squamata: Varanidae) on Riau Archipelago, Indonesia. Zootaxa, 3919 (1): 197-200. PMID- 25781851 TI - Taxonomic revision of the American spider genus Arachosia (Araneae: Anyphaenidae). AB - We review the American spider genus Arachosia O.P.-Cambridge, and present a descriptive taxonomic study with a comparative dichotomous key including 21 species, of which seven are newly described (A. avalosi sp. nov., A. carancho sp. nov., A. kapiipeoi sp. nov., A. magna sp. nov., A. monserrate sp. nov., A. pinhalito sp. nov. and A. tungurahua sp. nov.). Four species names are considered nomina dubia: Oxysoma dubium Berland, Gayenna duplovittata Mello-Leitao, Oxysoma polytrichium Mello-Leitao, and Arachosia sulfurea Mello-Leitao. Arachosia bonneti (Mello-Leitao) is newly synonymized with A. albiventris Mello-Leitao, and A. mezenioides Mello-Leitao with A. freiburgensis Keyserling. Previous problems with the identification of species in a species complex including A. cubana (Banks) are resolved. A disjunct distributional pattern is reported for A. kapiipeoi sp. nov.; a preliminary phylogenetic analysis based on mitochondrial COI sequences shows that these may correspond with two cryptic species. In this contribution, grassland and forests are discussed as the two main habitats inhabited by species of Arachosia. Finally, we propose a hypothesis of matching sexes based on functionality of some genital structures, involving sclerites of the male copulatory organ with structures of the epigyne: the prolateral projection on the primary conductor of the male would have a direct interaction with the lateral projections of the anterior pouch on the median epigynal field of females. PMID- 25781852 TI - The Sarcophaginae (Diptera: Sarcophagidae) of Southern South America. I. The species of Microcerella Macquart from the Patagonian Region. AB - A revision is given of the species placed in the genus Microcerella Macquart, known from the southern extreme of South America, the so-called Patagonian Region. A new diagnosis of the genus is given on the basis of the revision of a large number of Neotropical species. A total of 25 valid species are recognized in the region. Most of these (21 species) are divided into four species-groups on the basis of general groundplan of genitalia and external characters. Four new species are described, M. deliae sp. nov., M. holmbergi sp. nov., M. nataliae sp. nov. and M. paetoi sp. nov. One new synonymy is established: Austrohartigia shannoni Lopes as a new junior synonym of Microcerella spinosa (Hall), syn. nov. A lectotype is designated for Doringia subandina Blanchard [a junior synonym of Microcerella spinigena (Rondani)]. Two species are recorded from Argentina for the first time: M. chicoensis (Lopes) and M. engeli (Hall). Three nominal species were not examined and are treated as nomina dubia within Microcerella: M. apicalis (Townsend), M. rufomaculata Macquart and M. sarcophagina Thomson. An illustrated key is provided to the males of Patagonian species of Microcerella allowing for separation of 25 species. Additionally, a series of images of male genitalia based on color photography and illustrations is provided to aid in the identification of these species of Microcerella. Biological information is given for the species, where known. PMID- 25781853 TI - A revision of the Australian species of Trimma (Actinopterygii, Gobiidae), with descriptions of six new species and redescriptions of twenty-three valid species. AB - The gobiid genus Trimma currently contains 75 valid species, with another 20-30 known but undescribed species. There are 29 species in Australian waters (six undescribed). This paper describes the six new species, and provides redescriptions of most of the 23 previously described species known from the region, as well as a key for all the species. The six new species are: T. insularum (endemic to Cocos (Keeling) Islands), T. kitrinum (Fiji to Great Barrier Reef), T. meristum (Cape York to the Bismark Archipelago and Fiji), T. pentherum (Great Barrier Reef to Fiji and the South-West Islands of Palau), T. readerae (Australia to Japan), and T. xanthum (Palau to Fiji, Great Barrier Reef to Christmas Island). The following 23 species have been recorded from Australian waters, and most are redescribed here: T. anaima (Comores to Fiji), T. annosum (Maldives to the Phoenix Islands, Taiwan to the southern Great Barrier Reef), T. benjamini (southern Vietnam to the Marshall Islands, Samoa and southern Barrier Reef), T. caesiura (Ryukyus through the Marshall Islands to Samoa and Elizabeth Reef on the Lord Howe Rise), T. capostriatum (New Caledonia to eastern Australia and Papua New Guinea), T. maiandros (Java to the Ryukyus, Marshalls to Great Barrier Reef), T. emeryi (Comores to Ryukyus and Samoa), T. fangi (western South China Sea through to the Solomons), T. flavatrum (Ryukyu Islands to Western Australia and Samoa), T. hoesei (Chagos Archipelago, central Indian Ocean to Palau and Solomons), T. lantana (Australia, Solomons, northern New Guinea, South West Islands of Palau), T. macrophthalmus (Ryukyu Islands to Cocos (Keeling) Islands and Samoa), T. milta (Taiwan to Western Australia, Society Islands and Hawaii), T. nasa (Sumbawa, Indonesia to Fiji), T. necopinum (northern tip of Cape York to Sydney), T. nomurai (Japan to northern Australia and New Caledonia), T. okinawae (western Thailand to Japan and the Phoenix Islands, north-west Australia to the Great Barrier Reef), T. preclarum (Palau to Fiji, Great Barrier Reef), T. stobbsi (Maldives to New Caledonia), T. striatum (Maldives to Palau, to northern Australia), T. taylori (Red Sea to Hawaii and Society Islands), T. tevegae (Red Sea to Ryukyu Islands, Marshall Islands to Samoa), and T. unisquame (Comores to Hawaii and Easter Island). PMID- 25781854 TI - The tropical talitrid genus Floresorchestia (Crustacea, Amphipoda, Talitridae). AB - Floresorchestia floresiana (Weber, 1892) from Flores, F. anomala (Chevreux, 1901) from the Seychelles, F. malayensis (Tattersall, 1922) from Singapore and F. thienemanni (Schellenberg, 1931) from Java are redescribed based on original type material or newly collected material from near the type locality. Nine new species are described, in the widespread Indo-West Pacific and Caribbean talitrid genus Floresorchestia: F. andrevo sp. nov. and F. itampolo sp. nov. from Madagascar; F. kalili sp. nov. from the Bismarck Archipelago, Papua New Guinea; F. laurenae sp. nov. from Timor-Leste; F. oluanpi sp. nov. from southern Taiwan; F. papeari sp. nov. from Tahiti; F. serejoae sp. nov. from far north Queensland, Australia; F. seringat sp. nov. from Singapore; and F. yap sp. nov. from Micronesia; plus Floresorchestia sp. 1 from Hainan Island, South China Sea, Floresorchestia sp. 2 from Kilakarai and other sites in south-eastern India and Floresorchestia sp. 3 from Phuket Island, Thailand. Floresorchestia contains 28 species. In this paper all are catalogued and diagnosed. PMID- 25781855 TI - Endoscopic sphincterotomy with sphincteroplasty for the management of choledocholithiasis: a single-centre experience. AB - BACKGROUND: Balloon dilatation of the ampulla at endoscopic retrograde cholangiopancreatography (ERCP) is increasingly utilized in the management of large bile duct stones. The aim of this study was to review and compare the outcomes of using endoscopic sphincterotomy with endoscopic balloon dilatation (sphincteroplasty) in a combined approach as a single-stage (immediate) or a two stage procedure (delayed). METHODS: A retrospective review of medical records for all patients undergoing ERCP and balloon dilatation for choledocholithiasis between January 2010 and December 2012 was undertaken. Outcomes measured included patient demographics, stone size, degree of dilatation performed, success of stone extraction, number of procedures required for duct clearance and procedure related complications. RESULTS: One hundred and thirty-six ERCPs were performed with balloon sphincteroplasty. One hundred and four had a previous sphincterotomy with a delayed balloon dilatation and 32 had sphincterotomy with immediate dilatation. The overall clearance rate of the common bile duct for immediate and delayed groups was 93% (28/30) and 93% (81/87), respectively. Bile duct clearance after the first procedure was achieved in 70% (21/30) of patients in the immediate group and 74% (64/87) in the delayed group. There were six complications in the delayed group and four in the immediate group. The most frequently used balloon size was 10 mm for both groups with mean sizes of 10.34 (2.93) and 11.73 (2.87) in the immediate and delayed groups, respectively. CONCLUSION: Our study suggests that use of a combined approach is safe and effective and may provide benefits over using endoscopic balloon dilatation or endoscopic sphincterotomy alone in the treatment of choledocholithiasis. PMID- 25781856 TI - Gut microbiota: Firmicutes and Bacteroidetes involved in insulin resistance by mediating levels of glucagon-like peptide 1. PMID- 25781858 TI - Diabetic nephropathy: How does exercise affect kidney disease in T1DM? PMID- 25781859 TI - Improvements in Functional Exercise Capacity after a Residential Behavioural Change, Diet and Fitness Program for Obese Adults. AB - BACKGROUND AND PURPOSE: Obese adults are at an increased risk for mobility related problems. National guidelines recommend calorie restrictions and exercise for obese adults as a means to improve functional fitness capacity and to increase mobility. Yet, lifestyle weight loss interventions often fail to measure fitness changes. The aim of this study was to assess whether a 1-month, intensive behavioural change, diet and fitness intervention for overweight and obese adults would result in statistically significant and clinically meaningful changes in functional exercise. METHODS: A pre-post test design was used in this study. Seventy-two participants (40 women, 32 men; mean baseline body mass index (BMI) = 42.6 + 9.0; mean age = 45.8 + 16.8) completed a modified 6-minute walk test (6MWT), performed on a treadmill, at baseline and at end of treatment. RESULTS: Significant improvements included decreased BMI (2.7 + 1.7 kg m(-2) , p < 0.001) and increased 6MWT distance (66.4 + 73.0 m, p < 0.001). The 6MWT improved by 66 m on average, a reported clinically meaningful difference. Greater improvements in the 6MWT were significantly correlated with greater weight loss and BMI reduction. DISCUSSION: Our findings suggest that rehabilitation beyond weight loss may be derived from participation in a brief, intensive behavioural change, diet and fitness programme. Physiotherapists are in a prime position to address the physical and motivational challenges participants face while living with severe obesity: targeting functional exercise capacity is one key strategy for addressing immobility associated with obesity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25781860 TI - Methods for proper handling of overrunning and underrunning in phase II designs for oncology trials. AB - Phase II studies in oncology are frequently conducted as two-stage single-arm trials with a binary endpoint indicating tumor response. As a common feature of these designs, the sample sizes of the two stages and the decision rules for the interim and the final analysis have to be pre-specified and adhered to strictly during the course of the trial in order to assure control of the type I error rate. In practice, however, the attained sample sizes often deviate from the planned ones leading to the situation of overrunning or underrunning. The currently available approaches to deal with this problem are either based on assumptions that are rarely met in practice or do not guarantee that the significance level is kept. However, strict control of the type I error rate plays an important role also for single-arm cancer trials, as they are frequently a fundamental part of the registration information. We propose a general methodology that allows handling both unintentional and intentional overrunning and underrunning while strictly controlling the type I error rate. Application of the proposed procedure and some of its characteristics are illustrated with a real phase II oncology trial. PMID- 25781857 TI - New insights in prolactin: pathological implications. AB - Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR. PMID- 25781861 TI - A new use for existing technology - continuous precipitation for purification of recombination proteins. PMID- 25781863 TI - Simultaneous determination of antiviral drugs in chicken tissues by ultra high performance liquid chromatography with tandem mass spectrometry. AB - An ultra high performance liquid chromatography with tandem mass spectrometry method was established for the rapid and simultaneous analysis of seven antiviral drugs, amantadine, rimantadine, memantine, moroxydine, imiquimod, oseltamivir, and acyclovir, in chicken liver, muscle, and egg. Homogenized samples were extracted with trichloroacetic acid and acetonitrile solutions and then purified by cation-exchange solid-phase extraction. The target drugs were analyzed by liquid chromatography with a UPLC BEH Amide column (2.1 mm * 100 mm, 1.7 MUm) coupled with a tandem mass spectrometer operating in the positive multiple reaction mode. A perfectly linear relationship was obtained within the concentration ranges of 0.5-20 MUg/L for acyclovir and 0.1-10 MUg/L for the other six antiviral drugs. The average recoveries of the seven antiviral drugs using four addition levels in chicken liver, muscle, and eggs were 82.67-90.10, 82.30 92.27, and 81.98-93.77%, respectively, and the acceptable coefficients of variation were 5.18-9.88, 4.84-11.2, and 42.8-9.95%, respectively. The detection limits and detection capabilities of the analysis method for the seven antiviral drugs were in the ranges of 0.04-0.64 and 0.11-0.78 MUg/kg, respectively. Additionally, an inter-laboratory study among five laboratories further validated the method. PMID- 25781862 TI - Differences in the survival of patients with recurrent versus de novo metastatic KRAS-mutant and EGFR-mutant lung adenocarcinomas. AB - BACKGROUND: Prognostic variables are independently associated with survival and are fundamental to clinical trial design. In the current study, the authors evaluated the impact of stage of disease at the time of the initial diagnosis on overall survival (OS) in 2 independent, oncogene-defined cohorts. METHODS: All patients with epidermal growth factor receptor (EGFR)-mutant and KRAS-mutant metastatic lung adenocarcinomas were identified through routine molecular testing from January 2005 through January 2011. Clinical characteristics were obtained. OS from the date of diagnosis of recurrent or de novo metastatic disease was estimated using the Kaplan-Meier method. RESULTS: A total of 635 patients with KRAS-mutant and 496 patients with EGFR-mutant metastatic lung adenocarcinomas were identified. Among patients with KRAS-mutant lung adenocarcinomas, those with de novo metastatic disease were found to have a shorter median OS compared with those with recurrent metastatic disease (13 months vs 18 months; P = .003). In a multivariable analysis of patients with KRAS-mutant lung adenocarcinomas, de novo metastatic disease at the time of diagnosis (TNM stage IV vs stage I-III: hazard ratio, 1.5 [95% confidence interval, 1.2-1.8]; P<.001) was independently associated with shorter OS. In patients with EGFR-mutant lung adenocarcinomas, after controlling for age and Karnofsky performance status, de novo metastatic disease at the time of diagnosis (stage IV vs stage I-III: hazard ratio, 1.3 [95% confidence interval, 1.0-1.7]; P = .03) was found to be independently associated with shorter OS. CONCLUSIONS: Among patients with KRAS-mutant lung adenocarcinomas, stage of disease at diagnosis was associated with OS from the time of diagnosis of recurrent/metastatic disease. In multivariable analyses, in both patients with EGFR-mutant and KRAS-mutant lung adenocarcinomas, advanced stage at the time of diagnosis was found to be independently associated with shorter survival. Stage at diagnosis is a prognostic variable that should be accounted for in prospective studies in patients with metastatic lung adenocarcinomas. PMID- 25781866 TI - Effects of the buffering capacity of the soil on the mobilization of heavy metals. Equilibrium and kinetics. AB - Understanding the possible pH-buffering processes is of maximum importance for risk assessment and remediation feasibility studies of heavy-metal contaminated soils. This paper presents the results about the effect of the buffering capacity of a polluted soil, rich in carbonates, on the pH and on the leaching evolution of its main contaminant (lead) when a weak acid (acetic acid) or a strong one (nitric acid) are slowly added. In both cases, the behavior of lead dissolution could be predicted using available (scientifically verified freeware) models assuming equilibrium between the solid and the aqueous phase. However, the experimental results indicate that the dissolution of calcium and magnesium carbonates is kinetically controlled. These kinetic limitations affect the overall behavior, and should be considered to understand also the response of the metals under local equilibrium. The well-known BCR sequential extraction procedure was used before- and after-treatment, to fractionate the lead concentration in the soil according to its mobility. The BCR results were also in agreement with the predictions of the equilibrium model. This agreement allows new insights about the information that could be derived from the BCR fractionation analysis. PMID- 25781864 TI - Impact of educational intervention on the interrater agreement of nasal endoscopy interpretation. AB - OBJECTIVE: Nasal endoscopy is integral to the evaluation of sinonasal disorders. However, prior studies have shown significant variability in the interrater agreement of nasal endoscopy interpretation among practicing rhinologists. The objective of the current study is to evaluate the interrater agreement of nasal endoscopy among otolaryngology residents from a single training program at baseline and following an educational intervention. METHODS: Eleven otolaryngology residents completed nasal endoscopy grading forms for eight digitally recorded nasal endoscopic examinations. An instructional lecture reviewing nasal endoscopy interpretation was subsequently provided. The residents then completed grading forms for eight different nasal endoscopic examinations. Interrater agreement among residents for the pre- and postlecture videos was calculated using the unweighted Fleiss' kappa (Kf) statistic and intraclass correlation agreement (ICC). RESULTS: Interrater agreement improved from a baseline level of fair (Kf range 0.268-0.383) to a posteducational level of moderate (Kf range 0.401-0.547) for nasal endoscopy findings of middle meatus mucosa, middle turbinate mucosa, middle meatus discharge, sphenoethmoid recess mucosa, sphenoethmoid recess discharge, and atypical lesions (ICC, P < 0.001). The baseline level of agreement for evaluation of nasal septum deviation was poor/fair and did not improve following educational intervention. CONCLUSIONS: This study demonstrates a limited baseline level of interrater agreement of nasal endoscopy interpretation among otolaryngology residents. The interrater agreement for the majority of the characteristics that were evaluated improved after educational intervention. Further study is needed to improve nasal endoscopy interpretation. LEVEL OF EVIDENCE: N/A. PMID- 25781867 TI - Psychiatric services and prescription fills among veterans with serious mental illness in methadone maintenance treatment. AB - OBJECTIVE: Comorbidity and co-prescription patterns of people with serious mental illness in methadone maintenance may complicate their treatment and have not been studied. The goal of this study was to examine the care and characteristics of people with serious mental illness in methadone maintenance treatment nationally in the Veterans Health Administration (VHA). METHODS: Using national VHA data from FY2012, bivariate and multiple logistic regression analyses were used to compare veterans in methadone maintenance treatment wo had a serious mental illness (schizophrenia, bipolar disorder, or major affective disorder) to patients in methadone maintenance treatment without serious mental illness and patients with serious mental illness who were not in methadone maintenance treatment. RESULTS: Only a small fraction of patients with serious mental illness were receiving methadone maintenance treatment (0.65%), but a relatively large proportion in methadone maintenance treatment had a serious mental illness (33.2%). Compared to patients without serious mental illness, patients with serious mental illness in methadone maintenance treatment were more likely to have been homeless, to have had a recent psychiatric hospitalization, to be over 50% disabled, and to have had more fills for more classes of psychotropic drugs. Compared to other patients with serious mental illness, patients with serious mental illness in methadone maintenance treatment were more likely to have a drug abuse diagnosis and to reside in large urban areas. CONCLUSIONS: One-third of patients in methadone maintenance treatment have serious mental illness and more frequent psychiatric comorbidity, and they are more likely to use psychiatric and general health services and fill more types of psychiatric prescriptions. Further study and clinical awareness of potential drug-drug interactions in this high medication and service using population are needed. PMID- 25781868 TI - Three-Dimensional Histological Structures of the Human Dermis. AB - Spatial information has been shown to be critical for cell differentiation and function. Therefore, a better understanding of skin microstructures is very important for biomimetic and bioengineered scaffolds of engineering skin. The purpose of the study was to generate collagen/elastin-based three-dimensional (3D) images of human dermis to further understand the microstructures of the skin, which is believed to be helpful in the fabrication of bionic engineered skin. Skin samples were fixed, embedded, serially sectioned, stained with aldehyde-fuchsin, and photographed as serial panoramas. Dermal subregions were divided according to dermal depth and distance to hair follicle. The porosity, pore diameters, and wall thickness of human acellular dermal matrix (ADM) were measured by microcomputed tomography (micro-CT). Three-dimensional reconstructed images of collagen and elastic fibers were generated. Our results showed that there were fewer elastic fibers in the subregions close to hair follicles than in the subregions far away from hair follicles (p<0.001), but the collagen fibers were evenly distributed. Both collagen and elastic fibers were found in fewer numbers in the layers either close to the epidermis or close to the hypodermis. The mean proportions of collagen fibers and elastic fibers in the whole dermis were 28.96%+/-14.63% and 8.06%+/-3.75%, respectively. The porosity of ADM calculated by micro-CT was 68.3%+/-5.8%. The mean pore diameter of ADM was 131.2+/-96.8 MUm, and the wall thickness of pores was 207.2+/-251.7 MUm. This study represents for the first time that 3D histological cutaneous structures have been presented, which may be helpful for the next generation of skin engineering. PMID- 25781869 TI - Effect of Treadmill Running on Apelin and APJ Expression in Adipose Tissue and Skeletal Muscle in Rats Fed a High-fat Diet. AB - Apelin, an adipokine and also a myokine, is involved in glucose homeostasis. In this study we investigated the effect of insulin resistance and exercise on the regulation of apelin and APJ in adipose tissue and skeletal muscle. After 20 weeks of a high-fat diet (HFD), rats showed severe insulin resistance, with increased fasting blood sugar and plasma insulin and impaired glucose tolerance. Plasma apelin immunoreactivity as well as apelin and APJ expression in adipose tissue and gastrocnemius muscle were significantly increased, with no difference in soleus muscle. Treadmill running completely ameliorated the HFD-induced insulin resistance, decreased plasma apelin level, and downregulated apelin and APJ expression in adipose tissue. However, apelin and APJ expression was upregulated in soleus and gastrocnemius muscle with treadmill training and a HFD. Exercise had a tissue-dependent effect on apelin and APJ expression in rats fed a HFD. PMID- 25781870 TI - Body Composition Evolution in Elite Football Referees; an Eleven-years Retrospective Study. AB - Fitness, and specifically body composition of football referees requires attention in order to achieve the highest possible standards. The aim of the present study was to describe body composition of elite Spanish football referees over 11 years. Data from 2001 to 2012 pre-seasons were analyzed from a total of 470 referees of 1(st) and 2(nd) categories in Spanish male football (1C and 2C respectively). Body mass index (BMI), sum of 6 skinfolds (6SS) and percentage of body fat (%BF) were assessed. 2-independent samples Student's t-test between categories, and ANOVA tests with Bonferroni post-hoc analyses among seasons were applied. Overall, 1C referees were older than 2C in every season, and both 1C and 2C showed a decrease in 6SS, BMI and %BF throughout seasons (all p<0.05; from 82.5 to 62.9 mm, from 23.7 to 22.4 kg/m(2) and from 13.7 to 11.7%). No differences were observed between categories in any season. Since football referees at the highest levels need to have a low %BF for the intense matches nowadays, an improvement in their body composition profile has been observed in a highly competitive league as 'La Liga' in Spain over the last decade. PMID- 25781871 TI - Effect of "Touch Rugby" Training on the Cardiovascular Autonomic Control In Sedentary Subjects. AB - This study aimed to explore the effects of "touch-rugby" training on the cardiovascular autonomic control in sedentary subjects. 22 adults (30-64 years old) were included in this study. Before (pre-test) and after (post-test) the period of training, cardio-respiratory recordings were achieved at rest and during a graded maximal exercise on a treadmill. The Smoothed-Pseudo-Wigner-Ville Distribution provided instantaneous time frequency components of RR intervals and systolic blood pressure variability in low- and high-frequency bands. The baroreflex sensitivity was assessed in low-frequency and high-frequency bands. Between pre-test and post-test, resting heart rate (74+/-10 vs. 69+/-12 beats.min(-1), p<0.05) and systolic blood pressure (118+/-19 vs. 103+/-22 mm Hg, p<0.01) decreased. Root mean square of successive differences (34.6+/-30.1 vs. 47.6+/-34.8 ms, p<0.001), high-frequency RR variability (590+/-288 vs. 1262+/-767 ms2, p<0.001) increased whereas low-frequency/high-frequency ratio decreased (3.5+/-3.4 vs. 1.5+/-0.9, p<0.05). The high-frequency baroreflex sensitivity increased (13.4+/-10.1 vs. 26.0+/-20.9 ms.mmHg(-1), p<0.05). Playing touch rugby with one session weekly over 3 months modified the cardiovascular autonomic control of sedentary subjects. A decrease in the sympathetic tone combined with both an increase in the vagal tone and a decrease in systolic blood pressure at rest were observed. Therefore, such training appears to be beneficial to cardiac health. PMID- 25781872 TI - Effects of Rest Interval on Strength Recovery in Breast Cancer Survivors. AB - The purpose of this study was to compare the acute effect of 2 different resting intervals (RI) between sets of isokinetic knee extension exercise on peak torque (PT) and total work (TW) in breast cancer survivors (BCS) and control group (CNT). 16 BCS (52+/-4 years) and 14 CNT (53+/-6 years) performed 3 sets of 10 unilateral isokinetic knee extension repetitions at 60 degrees .s(- 1) on 2 separate days with 2 different RI between sets (1 and 2 min). There was a significant interaction between groups vs. exercise sets (p=0.03) and RI vs. exercise sets (p<0.001) for PT. PT was greater in CNT at 1(st) and 2(nd) sets compared to BCS group (CNT, 133.4+/-20.8 and BCS 107.6+/-19.9 Nm, p=0.012 and CNT, 118.9+/-19.6 and BCS, 97.1+/-15.9 Nm, p=0.045, respectively). The TW of the knee extensor was significant greater in CNT than BCS group for all 3 knee extension exercise sets. In conclusion, the present study suggests that Breast Cancer Survivors women may need a longer rest interval (longer than 2 min) to be able to fully recover during a 3 sets of isokinetic knee extension exercise training session. PMID- 25781873 TI - Advancing novel molecular imaging agents from preclinical studies to first-in humans phase I clinical trials in academia--a roadmap for overcoming perceived barriers. AB - There is a critical need to advance promising novel molecular imaging (MI) agents for cancer from preclinical studies to first-in-humans Phase I clinical trials in order to realize their full potential for cancer detection and for predicting or monitoring response to targeted ("personalized") cancer therapies. Steps to clinical translation include radiopharmaceutical formulation, preclinical pharmacology and toxicology studies, clinical trial design and human ethics approval, and regulatory agency submission. In this Topical Review, we provide a "roadmap" to advancing one class of novel MI agents to Phase I trials in academia and illustrate the processes that we have successfully applied for (111)In labeled pertuzumab, a MI probe for monitoring response of HER2-positive breast cancer to treatment with trastuzumab (Herceptin). We hope that our experience will encourage other academic radiopharmaceutical scientists to embrace this challenge. PMID- 25781874 TI - Randomized spatial context for object search. AB - Searching visual objects in large image or video data sets is a challenging problem, because it requires efficient matching and accurate localization of query objects that often occupy a small part of an image. Although spatial context has been shown to help produce more reliable detection than methods that match local features individually, how to extract appropriate spatial context remains an open problem. Instead of using fixed-scale spatial context, we propose a randomized approach to deriving spatial context, in the form of spatial random partition. The effect of spatial context is achieved by averaging the matching scores over multiple random patches. Our approach offers three benefits: 1) the aggregation of the matching scores over multiple random patches provides robust local matching; 2) the matched objects can be directly identified on the pixelwise confidence map, which results in efficient object localization; and 3) our algorithm lends itself to easy parallelization and also allows a flexible tradeoff between accuracy and speed through adjusting the number of partition times. Both theoretical studies and experimental comparisons with the state-of the-art methods validate the advantages of our approach. PMID- 25781875 TI - Image denoising by exploring external and internal correlations. AB - Single image denoising suffers from limited data collection within a noisy image. In this paper, we propose a novel image denoising scheme, which explores both internal and external correlations with the help of web images. For each noisy patch, we build internal and external data cubes by finding similar patches from the noisy and web images, respectively. We then propose reducing noise by a two stage strategy using different filtering approaches. In the first stage, since the noisy patch may lead to inaccurate patch selection, we propose a graph based optimization method to improve patch matching accuracy in external denoising. The internal denoising is frequency truncation on internal cubes. By combining the internal and external denoising patches, we obtain a preliminary denoising result. In the second stage, we propose reducing noise by filtering of external and internal cubes, respectively, on transform domain. In this stage, the preliminary denoising result not only enhances the patch matching accuracy but also provides reliable estimates of filtering parameters. The final denoising image is obtained by fusing the external and internal filtering results. Experimental results show that our method constantly outperforms state-of-the-art denoising schemes in both subjective and objective quality measurements, e.g., it achieves >2 dB gain compared with BM3D at a wide range of noise levels. PMID- 25781876 TI - High-resolution face verification using pore-scale facial features. AB - Face recognition methods, which usually represent face images using holistic or local facial features, rely heavily on alignment. Their performances also suffer a severe degradation under variations in expressions or poses, especially when there is one gallery per subject only. With the easy access to high-resolution (HR) face images nowadays, some HR face databases have recently been developed. However, few studies have tackled the use of HR information for face recognition or verification. In this paper, we propose a pose-invariant face-verification method, which is robust to alignment errors, using the HR information based on pore-scale facial features. A new keypoint descriptor, namely, pore-Principal Component Analysis (PCA)-Scale Invariant Feature Transform (PPCASIFT)-adapted from PCA-SIFT-is devised for the extraction of a compact set of distinctive pore scale facial features. Having matched the pore-scale features of two-face regions, an effective robust-fitting scheme is proposed for the face-verification task. Experiments show that, with one frontal-view gallery only per subject, our proposed method outperforms a number of standard verification methods, and can achieve excellent accuracy even the faces are under large variations in expression and pose. PMID- 25781877 TI - Combining facial dynamics with appearance for age estimation. AB - Estimating the age of a human from the captured images of his/her face is a challenging problem. In general, the existing approaches to this problem use appearance features only. In this paper, we show that in addition to appearance information, facial dynamics can be leveraged in age estimation. We propose a method to extract and use dynamic features for age estimation, using a person's smile. Our approach is tested on a large, gender-balanced database with 400 subjects, with an age range between 8 and 76. In addition, we introduce a new database on posed disgust expressions with 324 subjects in the same age range, and evaluate the reliability of the proposed approach when used with another expression. State-of-the-art appearance-based age estimation methods from the literature are implemented as baseline. We demonstrate that for each of these methods, the addition of the proposed dynamic features results in statistically significant improvement. We further propose a novel hierarchical age estimation architecture based on adaptive age grouping. We test our approach extensively, including an exploration of spontaneous versus posed smile dynamics, and gender specific age estimation. We show that using spontaneity information reduces the mean absolute error by up to 21%, advancing the state of the art for facial age estimation. PMID- 25781879 TI - Implementation and preliminary validation of a new score that predicts post operative complications. AB - BACKGROUND: An accurate pre-operative risk assessment could reduce morbidity and mortality for high-risk surgical patients. The aim of the study was to implement and preliminary validate a new score that could predict the occurrence of post operative complications (PoCs): the Anesthesiological and Surgical Postoperative Risk Assessment (ASPRA) score. METHODS: The ASPRA score was created through a literature's review; a score of 1-3 was given to each identified risk factor, according to its statistical correlation with PoC. ASPRA was retrospectively applied to a derivation set of 176 surgical patients. A receiver operating characteristic (ROC) analysis evaluated the discriminating ability of the score and cutoff value in predicting the occurrence of PoCs, according to the Clavien Dindo classification of surgical complications. The statistical validation of the score and related cutoff values was prospectively ran within a validation set of 1928 surgical patients. RESULTS: Through ROC analysis, an ASPRA score of 7 was chosen as the cutoff value in the derivation set. In the validation set, 65.3% of patients presented a PoC (Clavien >= 1). In this group, ROC analysis showed an area under the curve (AUC) of 0.72, and although potentially related to the high rate of complications a high positive predictive value of 87.0% has been observed. No significant differences were found in ROC-AUC, sensitivity, specificity, or positive or negative predictive value between the derivation and validation sets (P > 0.05). CONCLUSION: The new ASPRA score has a high positive predictive value to predict the occurrence of PoCs. Further prospective studies are required to confirm these results. PMID- 25781878 TI - Construction of an interspecific genetic map based on InDel and SSR for mapping the QTLs affecting the initiation of flower primordia in pepper (Capsicum spp.). AB - Re-sequencing permits the mining of genome-wide variations on a large scale and provides excellent resources for the research community. To accelerate the development and application of molecular markers and identify the QTLs affecting the flowering time-related trait in pepper, a total of 1,038 pairs of InDel and 674 SSR primers from different sources were used for genetic mapping using the F2 population (n = 154) derived from a cross between BA3 (C. annuum) and YNXML (C. frutescens). Of these, a total of 224 simple PCR-based markers, including 129 InDels and 95 SSRs, were validated and integrated into a map, which was designated as the BY map. The BY map consisted of 13 linkage groups (LGs) and spanned a total genetic distance of 1,249.77 cM with an average marker distance of 5.60 cM. Comparative analysis of the genetic and physical map based on the anchored markers showed that the BY map covered nearly the whole pepper genome. Based on the BY map, one major and five minor QTLs affecting the number of leaves on the primary axis (Nle) were detected on chromosomes P2, P7, P10 and P11 in 2012. The major QTL on P2 was confirmed based on another subset of the same F2 population (n = 147) in 2014 with selective genotyping of markers from the BY map. With the accomplishment of pepper whole genome sequencing and annotations (release 2.0), 153 candidate genes were predicted to embed in the Nle2.2 region, of which 12 important flowering related genes were obtained. The InDel/SSR-based interspecific genetic map, QTLs and candidate genes obtained by the present study will be useful for the downstream isolation of flowering time-related gene and other genetic applications for pepper. PMID- 25781880 TI - Platelet count and early outcome in patients with spontaneous cerebellar hemorrhage: a retrospective study. AB - INTRODUCTION: The importance of coagulation, hematology, and biochemical variables have been investigated in the stroke population but have not been systemically surveyed in cerebellar hemorrhage (CH) population. The aim of the study was to explore the predictive value of these factors for early outcome in this population. MATERIALS AND METHODS: Eighty patients with acute spontaneous CH were retrospectively analyzed. Clinical and laboratory data were collected on admission for analysis. The patients were divided by Glasgow outcome scale (GOS) score at discharge into the good outcome group (GOS score 4 or 5) and the poor outcome group (GOS score 1, 2, or 3). The association between early outcome and clinical or laboratory variables were investigated by binary logistic regression. RESULTS: There were 46 (57.5%) patients in the poor outcome group and 34 (42.5%) in the good outcome group. The platelet count (PC) was significantly lower in the poor outcome group (187.3 +/- 53.0 * 10(9)/l) compared with good outcome group (244.9 +/- 63.9 * 10(9)/l) (p < 0.001). Moreover, PC (OR 0.97; p = 0.004) was the strong predictor with poor early outcome. CONCLUSIONS: We firstly show that lower PC is the independent predictor for poor early outcome in patients with spontaneous CH. PMID- 25781881 TI - Microbial population, chemical composition and silage fermentation of cassava residues. AB - In order to effectively use the cassava (Manihot esculenta Crantz) residues, including cassava leaves, peel and pulp for livestock diets, the chemical and microbiological composition, silage preparation and the effects of lactic acid bacteria (LAB) inoculants on silage fermentation of cassava residues were studied. These residues contained 10(4) to 10(5) LAB and yeasts, 10(3) to 10(4) coliform bacteria and 10(4) aerobic bacteria in colony forming units (cfu) on a fresh matter (FM) basis. The molds were consistently at or below the detectable level (10(2) cfu of FM) in three kinds of cassava residues. Dry matter (DM), crude protein (CP) and neutral detergent fiber (NDF) content of cassava residues were 17.50-30.95%, 1.30-16.41% and 25.40-52.90% on a DM basis, respectively. The silage treatments were designed as control silage without additive (CO) or with LAB inoculants Chikuso-1 (CH, Lactobacillus plantarum) and Snow Lacto (SN, Lactobacillus rhamnosus) at a rate of 5 mg/kg of FM basis. All silages were well preserved with a low pH (below 4.0) value and when cassava residues silage treated with inoculants CH and SN improved fermentation quality with a lower pH, butyric acid and higher lactic acid than control silage. PMID- 25781882 TI - JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL. AB - Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations. PMID- 25781883 TI - Differential dependence on N-glycosylation of anthrax toxin receptors CMG2 and TEM8. AB - ANTXR 1 and 2, also known as TEM8 and CMG2, are two type I membrane proteins, which have been extensively studied for their role as anthrax toxin receptors, but with a still elusive physiological function. Here we have analyzed the importance of N-glycosylation on folding, trafficking and ligand binding of these closely related proteins. We find that TEM8 has a stringent dependence on N glycosylation. The presence of at least one glycan on each of its two extracellular domains, the vWA and Ig-like domains, is indeed necessary for efficient trafficking to the cell surface. In the absence of any N-linked glycans, TEM8 fails to fold correctly and is recognized by the ER quality control machinery. Expression of N-glycosylation mutants reveals that CMG2 is less vulnerable to sugar loss. The absence of N-linked glycans in one of the extracellular domains indeed has little impact on folding, trafficking or receptor function of the wild type protein expressed in tissue culture cells. N glycans do, however, seem required in primary fibroblasts from human patients. Here, the presence of N-linked sugars increases the tolerance to mutations in cmg2 causing the rare genetic disease Hyaline Fibromatosis Syndrome. It thus appears that CMG2 glycosylation provides a buffer towards genetic variation by promoting folding of the protein in the ER lumen. PMID- 25781884 TI - Small toxic protein encoded on chromosome VII of Saccharomyces cerevisiae. AB - In a previous study, we found an unknown element that caused growth inhibition after its copy number increased in the 3' region of DIE2 in Saccharomyces cerevisiae. In this study, we further identified this element and observed that overexpression of a small protein (sORF2) of 57 amino acids encoded in this region caused growth inhibition. The transcriptional response and multicopy suppression of the growth inhibition caused by sORF2 overexpression suggest that sORF2 overexpression inhibits the ergosterol biosynthetic pathway. sORF2 was not required in the normal growth of S. cerevisiae, and not conserved in related yeast species including S. paradoxus. Thus, sORF2 (designated as OTO1) is an orphan ORF that determines the specificity of this species. PMID- 25781885 TI - Different associations of CD45 isoforms with STAT3, PKC and ERK regulate IL-6 induced proliferation in myeloma. AB - In response to interleukin 6 (IL-6) stimulation, both CD45RO and CD45RB, but not CD45RA, translocate to lipid rafts. However, the significance of this distinct translocation and the downstream signals in CD45 isoforms-participated IL-6 signal are not well understood. Using sucrose fractionation, we found that phosphorylated signal transducer and activator of transcription (STAT)3 and STAT1 were mainly localized in lipid rafts in response to IL-6 stimulation, despite both STAT3 and STAT1 localizing in raft and non-raft fractions in the presence or absence of IL-6. On the other hand, extracellular signal-regulated kinase (ERK), and phosphorylated ERK were localized in non-raft fractions regardless of the existence of IL-6. The rafts inhibitor significantly impeded the phosphorylation of STAT3 and STAT1 and nuclear translocation, but had little effect on (and only postponing) the phosphorylation of ERK. This data suggests that lipid raft dependent STAT3 and STAT1 pathways are dominant pathways of IL-6 signal in myeloma cells. Interestingly, the phosphorylation level of STAT3 but not STAT1 in CD45+ cells was significantly higher compared to that of CD45- cells, while the phosphorylation level of ERK in CD45+ myeloma cells was relatively low. Furthermore, exogenously expressed CD45RO/RB significantly enhanced STAT3, protein kinase C (PKC) and downstream NF-kappaB activation; however, CD45RA/RB inhibited IL-6-induced ERK phosphorylation. CD45 also enhanced the nuclear localization of STAT3 but not that of STAT1. In response to IL-6 stimulation, CD45RO moved into raft compartments and formed a complex with STAT3 and PKC in raft fraction, while CD45RA remained outside of lipid rafts and formed a complex with ERK in non-raft fraction. This data suggests a different role of CD45 isoforms in IL-6-induced signaling, indicating that while CD45RA/RB seems inhibit the rafts-unrelated ERK pathway, CD45RO/RB may actually work to enhance the rafts related STAT3 and PKC/NF-kappaB pathways. PMID- 25781886 TI - Polymorphisms of chicken TLR3 and 7 in different breeds. AB - Toll-like receptors (TLRs) mediate immune responses via the recognition of pathogen-associated molecular patterns (PAMPs), thus playing important roles in host defense. Among the chicken (Ch) TLR family, ChTLR3 and 7 have been shown to recognize viral RNA. In our earlier studies, we have reported polymorphisms of TLR1, 2, 4, 5, 15 and 21. In the present study, we amplified TLR3 and 7 genes from different chicken breeds and analyzed their sequences. We identified 7 amino acid polymorphism sites in ChTLR3 with 6 outer part sites and 1 inner part site, and 4 amino acid polymorphism sites in ChTLR7 with 3 outer part sites and 1 inner part site. These results demonstrate that ChTLR genes are polymorphic among different chicken breeds, suggesting a varied resistance across numerous chicken breeds. This information might help improve chicken health by breeding and vaccination. PMID- 25781887 TI - Does positivity mediate the relation of extraversion and neuroticism with subjective happiness? AB - Recent theories suggest an important role of neuroticism, extraversion, attitudes, and global positive orientations as predictors of subjective happiness. We examined whether positivity mediates the hypothesized relations in a community sample of 504 adults between the ages of 20 and 60 years old (females = 50%). A model with significant paths from neuroticism to subjective happiness, from extraversion and neuroticism to positivity, and from positivity to subjective happiness fitted the data (Satorra-Bentler scaled chi-square (38) = 105.91; Comparative Fit Index = .96; Non-Normed Fit Index = .95; Root Mean Square Error of Approximation = .060; 90% confidence interval = .046, .073). The percentage of subjective happiness variance accounted for by personality traits was only about 48%, whereas adding positivity as a mediating factor increased the explained amount of subjective happiness to 78%. The mediation model was invariant by age and gender. The results show that the effect of extraversion on happiness was fully mediated by positivity, whereas the effect of neuroticism was only partially mediated. Implications for happiness studies are also discussed. PMID- 25781888 TI - A new approach to improving healthcare personnel influenza immunization programs: a randomized controlled trial. AB - BACKGROUND: Healthcare personnel influenza immunization rates remain sub-optimal. Following multiple studies and expert consultations, the "Successful Influenza Immunization Programs for Healthcare Personnel: A Guide for Program Planners" was produced. This trial assessed the impact of the Guide with facilitation in improving healthcare personnel influenza immunization rates in Canadian healthcare organizations. METHODS: A sample of 26 healthcare organizations across six Canadian provinces (ON, MB, NS, BC, SK, NL) was randomized to Intervention (n=13) or Control groups (n=13). Baseline influenza immunization rates were obtained for 2008-2009; the study groups were followed over two subsequent influenza seasons. The Intervention group received the Guide, facilitation support through workshops for managers and ongoing support. The Control groups conducted programs as usual. The Groups were compared using their reported influenza healthcare personnel influenza immunization rates and scores from a program assessment questionnaire. FINDINGS: Twenty-six organizations agreed to participate. 35% (9/26) of sites were acute care hospitals, 19% (5/26) continuing care, long-term care organizations or nursing homes, and 46% (12/26) were mixed acute care hospitals and long-term care or regional health authorities. The median rate of influenza immunization among healthcare personnel for the Intervention group was 43%, 44%, and 51% at three points in time respectively, and in the CONTROL GROUP: 62%, 57%, and 55% respectively. No significant differences were observed between the groups at the three points in time. However, there was a 7% increase in the median rates between the Baseline Year and Year Two in the Intervention group, and a 6% decrease in the CONTROL GROUP over the same time period, which was statistically significant (0.071 versus 0.058, p < 0.001). INTERPRETATION: This pragmatic randomized trial of the Guide with facilitation of its implementation improved healthcare personnel immunization rates, but these rates continued to be sub-optimal and below rates achievable in programs requiring personnel to be immunized. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207518. PMID- 25781889 TI - Synthesis and characterization of green Zn-Ag-In-S and red Zn-Cu-In-S quantum dots for ultrahigh color quality of down-converted white LEDs. AB - Eco-friendly green Zn-Ag-In-S (ZAIS) and red Zn-Cu-In-S (ZCIS) core/shell-like alloyed quantum dots (QDs) have been synthesized by a facile hot-injection method with a multiple injection approach. Broad full-width at half-maximum (fwhm) of the photoluminescence (PL) emission and tunability of the green ZAIS and red ZCIS QDs were obtained by adopting a low-temperature core growth and high-temperature multiple alloyed reaction. The alloyed green ZAIS and red ZCIS QDs reached PL quantum yields as high as 0.61 and 0.53; fwhm of the PL peaks were as wide as 81 and 106 nm, respectively. This demonstrates the practical realization of white down-converted light-emitting diodes (DC-LEDs), fully covering the whole visible wavelength range and the cyan gap, using two broad fwhm green ZAIS and red ZCIS QDs. We also characterized the vision and color performance using luminous efficacy (LE), color rendering index (CRI), special CRI for strong red (R9), and color quality scale (CQS) of white DC-LEDs incorporated with green ZAIS and red ZCIS QDs at the correlated color temperature (CCT) range of 2700-10 000 K. The tricolor white DC-LED using broad fwhm green-emitting ZAIS and red-emitting ZCIS core/shell-like alloyed QDs exhibits a moderate LE (31.2 lm/W) and ultrahigh color qualities (CRI = 97, R9 = 97, and CQS = 94) with warm white at a CCT of 3500 K. PMID- 25781890 TI - Development of a single nucleotide polymorphism barcode to genotype Plasmodium vivax infections. AB - Plasmodium vivax, one of the five species of Plasmodium parasites that cause human malaria, is responsible for 25-40% of malaria cases worldwide. Malaria global elimination efforts will benefit from accurate and effective genotyping tools that will provide insight into the population genetics and diversity of this parasite. The recent sequencing of P. vivax isolates from South America, Africa, and Asia presents a new opportunity by uncovering thousands of novel single nucleotide polymorphisms (SNPs). Genotyping a selection of these SNPs provides a robust, low-cost method of identifying parasite infections through their unique genetic signature or barcode. Based on our experience in generating a SNP barcode for P. falciparum using High Resolution Melting (HRM), we have developed a similar tool for P. vivax. We selected globally polymorphic SNPs from available P. vivax genome sequence data that were located in putatively selectively neutral sites (i.e., intergenic, intronic, or 4-fold degenerate coding). From these candidate SNPs we defined a barcode consisting of 42 SNPs. We analyzed the performance of the 42-SNP barcode on 87 P. vivax clinical samples from parasite populations in South America (Brazil, French Guiana), Africa (Ethiopia) and Asia (Sri Lanka). We found that the P. vivax barcode is robust, as it requires only a small quantity of DNA (limit of detection 0.3 ng/MUl) to yield reproducible genotype calls, and detects polymorphic genotypes with high sensitivity. The markers are informative across all clinical samples evaluated (average minor allele frequency > 0.1). Population genetic and statistical analyses show the barcode captures high degrees of population diversity and differentiates geographically distinct populations. Our 42-SNP barcode provides a robust, informative, and standardized genetic marker set that accurately identifies a genomic signature for P. vivax infections. PMID- 25781891 TI - Timing matters: the impact of label synchrony on infant categorisation. AB - The impact of labelling on infant visual categorisation has yielded contradictory outcomes. Some findings indicate a beneficial role while others point to interference effects in the presence of labels. The locus of these divergent outcomes is largely unclear. We explore the hypothesis that the timing of the label is of crucial importance, proposing that synchronous presentation of words and objects induces a higher processing load than asynchronous presentation (image onset before labelling). A novelty preference experiment with 12-month olds reveals that synchronous presentation leads to a diminished preference for a novel object on test in comparison to asynchronous labelling, suggesting a detrimental impact on category learning. However, analyses of infants' gaze patterns to object parts reveal that even synchronous labels do not hinder learning completely. We conclude that synchronous labels interfere with the familiarisation process, but this process involves shifts in familiarity vs. novelty preference rather than overshadowing of visual learning. Besides offering detailed insight into the effects of labelling on infants' visual attention, these findings offer the potential to reconcile previous contradictory results. PMID- 25781892 TI - Isotretinoin and vitiligo: can chronic cheilitis cause koebnerization? AB - Vitiligo after trauma through koebnerization is a widely reported phenomenon. Herein we present a case of vitiligo in an area of chronic cheilitis after isotretinoin treatment. PMID- 25781893 TI - STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms influence the risk of developing juvenile idiopathic arthritis in Han Chinese patients. AB - Juvenile idiopathic arthritis (JIA) is a common autoimmune disease characterized by environmental influences along with several predisposing genes in the pathogenesis. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) and signal transducer and activator of transcription factor 4 (STAT4) have been recognized as susceptibility genes for numerous autoimmune diseases. Associations of STAT4 rs7574865 G/T and PTPN22 (rs2488457 G/C and rs2476601 C/T) polymorphisms with JIA have repeatedly been replicated in several Caucasian populations. The aim of this study was to investigate the influence of three polymorphisms mentioned above on the risk of developing JIA in Han Chinese patients. Genotyping was performed on a total of 137 Chinese patients with JIA (JIA group) and 150 sex and age frequency matched healthy volunteers (Control group). The single-nucleotide polymorphisms (SNP) were determined by using direct sequencing of PCR-amplified products. There were significant differences of PTPN22 rs2488457 G/C and STAT4 rs7574865 G/T polymorphisms between both groups. However, no significant difference was observed in distribution frequencies of PTPN22 rs2476601 polymorphism. The association with the PTPN22 rs2488457 G/C polymorphism remained significant in the stratifications by age at onset, ANA status, splenomegaly, lymphadenectasis and involvement joints. As with the STAT4 rs7574865 G/T polymorphisms, the enthesitis-related arthritis and presence of hepatomegaly had strong effect on the association. Our data strengthen STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms as susceptibility factors for JIA. PMID- 25781894 TI - Silvicolous on a small scale: possibilities and limitations of habitat suitability models for small, elusive mammals in conservation management and landscape planning. AB - Species distribution and endangerment can be assessed by habitat-suitability modelling. This study addresses methodical aspects of habitat suitability modelling and includes an application example in actual species conservation and landscape planning. Models using species presence-absence data are preferable to presence-only models. In contrast to species presence data, absences are rarely recorded. Therefore, many studies generate pseudo-absence data for modelling. However, in this study model quality was higher with null samples collected in the field. Next to species data the choice of landscape data is crucial for suitability modelling. Landscape data with high resolution and ecological relevance for the study species improve model reliability and quality for small elusive mammals like Muscardinus avellanarius. For large scale assessment of species distribution, models with low-detailed data are sufficient. For regional site-specific conservation issues like a conflict-free site for new wind turbines, high-detailed regional models are needed. Even though the overlap with optimally suitable habitat for M. avellanarius was low, the installation of wind plants can pose a threat due to habitat loss and fragmentation. To conclude, modellers should clearly state the purpose of their models and choose the according level of detail for species and environmental data. PMID- 25781895 TI - Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape. AB - Dendritic cells (DCs) and macrophages (Mos) internalize and process exogenous HIV derived antigens for cross-presentation by MHC-I to cytotoxic CD8+ T cells (CTL). However, how degradation patterns of HIV antigens in the cross-presentation pathways affect immunodominance and immune escape is poorly defined. Here, we studied the processing and cross-presentation of dominant and subdominant HIV-1 Gag-derived epitopes and HLA-restricted mutants by monocyte-derived DCs and Mos. The cross-presentation of HIV proteins by both DCs and Mos led to higher CTL responses specific for immunodominant epitopes. The low CTL responses to subdominant epitopes were increased by pretreatment of target cells with peptidase inhibitors, suggestive of higher intracellular degradation of the corresponding peptides. Using DC and Mo cell extracts as a source of cytosolic, endosomal or lysosomal proteases to degrade long HIV peptides, we identified by mass spectrometry cell-specific and compartment-specific degradation patterns, which favored the production of peptides containing immunodominant epitopes in all compartments. The intracellular stability of optimal HIV-1 epitopes prior to loading onto MHC was highly variable and sequence-dependent in all compartments, and followed CTL hierarchy with immunodominant epitopes presenting higher stability rates. Common HLA-associated mutations in a dominant epitope appearing during acute HIV infection modified the degradation patterns of long HIV peptides, reduced intracellular stability and epitope production in cross presentation-competent cell compartments, showing that impaired epitope production in the cross-presentation pathway contributes to immune escape. These findings highlight the contribution of degradation patterns in the cross presentation pathway to HIV immunodominance and provide the first demonstration of immune escape affecting epitope cross-presentation. PMID- 25781896 TI - Molecular epidemiology and in-vitro antifungal susceptibility of Aspergillus terreus species complex isolates in Delhi, India: evidence of genetic diversity by amplified fragment length polymorphism and microsatellite typing. AB - Aspergillus terreus is emerging as an etiologic agent of invasive aspergillosis in immunocompromised individuals in several medical centers in the world. Infections due to A. terreus are of concern due to its resistance to amphotericin B, in vivo and in vitro, resulting in poor response to antifungal therapy and high mortality. Herein we examined a large collection of molecularly characterized, geographically diverse A. terreus isolates (n = 140) from clinical and environmental sources in India for the occurrence of cryptic A. terreus species. The population structure of the Indian A. terreus isolates and their association with those outside India was determined using microsatellite based typing (STR) technique and Amplified Fragment Length Polymorphism analysis (AFLP). Additionally, in vitro antifungal susceptibility of A. terreus isolates was determined against 7 antifungals. Sequence analyses of the calmodulin locus identified the recently described cryptic species A. hortai, comprising 1.4% of Aspergillus section Terrei isolates cultured from cases of aspergilloma and probable invasive aspergillosis not reported previously. All the nine markers used for STR typing of A. terreus species complex proved to be highly polymorphic. The presence of high genetic diversity revealing 75 distinct genotypes among 101 Indian A. terreus isolates was similar to the marked heterogeneity noticed in the 47 global A. terreus population exhibiting 38 unique genotypes mainly among isolates from North America and Europe. Also, AFLP analysis showed distinct banding patterns for genotypically diverse A. terreus isolates. Furthermore, no correlation between a particular genotype and amphotericin B susceptibility was observed. Overall, 8% of the A. terreus isolates exhibited low MICs of amphotericin B. All the echinocandins and azoles (voriconazole, posaconazole and isavuconazole) demonstrated high potency against all the isolates. The study emphasizes the need of molecular characterization of A. terreus species complex isolates to better understand the ecology, acquisition and transmission of this species. PMID- 25781897 TI - High-level expression of endo-beta-N-acetylglucosaminidase H from Streptomyces plicatus in Pichia pastoris and its application for the deglycosylation of glycoproteins. AB - Endo-beta-N-acetylglucosaminidase H (Endo H, EC3.2.1.96) is a glycohydrolase that is widely used in the study of glycoproteins. The present study aimed to assess the effect of high-level endo-beta-N-acetylglucosaminidase H expression in Pichia pastoris. The DNA coding sequence of this enzyme was optimized based on the codon usage bias of Pichia pastoris and synthesized through overlapping PCR. This novel gene was cloned into a pHBM905A vector and introduced into Pichia pastoris GS115 for secretary expression. The yield of the target protein reached approximately 397 mg/l after a 6-d induction with 1% (v/v) methanol in shake flasks, which is much higher than that observed upon heterologous expression in Escherichia coli and silkworm. This recombinant enzyme was purified and its enzymatic features were studied. Its specific activity was 461573 U/mg. Its optimum pH and temperature were pH 5.5 and 37 degrees C, respectively. Moreover, our study showed that the N-linked glycan side-chains of several recombinant proteins expressed in Pichia pastoris can be efficiently removed through either the co fermentation of this recombinant strain with strains expressing substrates or by mixing the cell culture supernatants of the endo-beta-N-acetylglucosaminidase H expressing strain with strains expressing substrates after fermentation. This is the first report of high-level endo-beta-N-acetylglucosaminidase H expression in Pichia pastoris and the application of this enzyme in the deglycosylation of raw glycoproteins heterologously expressed in Pichia pastoris using simplified methods. PMID- 25781898 TI - Co-infection with Mycobacterium tuberculosis impairs HIV-Specific CD8+ and CD4+ T cell functionality. AB - The ability of antigen-specific T cells to simultaneously produce multiple cytokines is thought to correlate with the functional capacity and efficacy of T cells. These 'polyfunctional' T cells have been associated with control of HIV. We aimed to assess the impact of co-infection with Mycobacterium tuberculosis (MTB) on HIV-specific CD8+ and CD4+ T cell function. We assessed T cell functionality in 34 South African adults by investigating the IFN-y, IL-2, TNF alpha, IL-21 and IL-17 cytokine secretion capacity, using polychromatic flow cytometry, following HIV Gag-specific stimulation of peripheral blood mononuclear cells. We show that MTB is associated with lower HIV-specific T cell function in co-infected as compared to HIV mono-infected individuals. This decline in function was greatest in co-infection with active Tuberculosis (TB) compared to co-infection with latent MTB (LTBI), suggesting that mycobacterial load may contribute to this loss of function. The described impact of MTB on HIV-specific T cell function may be a mechanism for increased HIV disease progression in co infected subjects as functionally impaired T cells may be less able to control HIV. PMID- 25781899 TI - Mitofusin 2-deficiency suppresses cell proliferation through disturbance of autophagy. AB - Mitofusin2 (Mfn2), a mitochondrial outer membrane protein serving primarily as a mitochondrial fusion protein, has multiple functions in regulating cell biological processes. Defects of Mfn2 were found in diabetes, obesity, and neurodegenerative diseases. In the present study, we found that knockdown of Mfn2 by shRNA led to impaired autophagic degradation, inhibited mitochondrial oxygen consumption rate and cell glycolysis, reduced ATP production, and suppressed cell proliferation. Inhibition of autophagic degradation mimicked Mfn2-deficiency mediated cell proliferation suppression, while enhancement of autophagosome maturation restored the suppressed cell proliferation by Mfn2-deficiency. Thus, our findings revealed the role of Mfn2 in regulating cell proliferation and mitochondrial metabolism, and shed new light on understanding the mechanisms of Mfn2 deficiency related diseases. PMID- 25781900 TI - Immediate Loaded Implants in Split-Crest Procedure. AB - BACKGROUND: The aim of this study was to assess survival rate of immediate loading implants placed after split-crest technique. METHODS: Thirty-six patients were enrolled in the study. They underwent placement of 93 dental implants in edentulous region after split-crest ridge expansion procedure. Implants followed an immediate loading procedure. Crestal bone levels were measured at baseline, at temporary prosthesis placement, at 1 year, and at 2 years from implant placement. RESULTS: For dental implants, a survival rate of 98.92% was reported at 2-year follow-up, with a mean value bone loss of -1.02 +/- 0.48. CONCLUSION: This study assessed immediate loading implant placement after split-crest procedure at 2 year follow-up. PMID- 25781901 TI - Combination of adrenomedullin with its binding protein accelerates cutaneous wound healing. AB - Cutaneous wound continues to cause significant morbidity and mortality in the setting of diseases such as diabetes and cardiovascular diseases. Despite advances in wound care management, there is still an unmet medical need exists for efficient therapy for cutaneous wound. Combined treatment of adrenomedullin (AM) and its binding protein-1 (AMBP-1) is protective in various disease conditions. To examine the effect of the combination treatment of AM and AMBP-1 on cutaneous wound healing, full-thickness 2.0-cm diameter circular excision wounds were surgically created on the dorsum of rats, saline (vehicle) or AM/AMBP 1 (96/320 MUg kg BW) was topically applied to the wound daily and wound size measured. At days 3, 7, and 14, skin samples were collected from the wound sites. AM/AMBP-1 treated group had significantly smaller wound surface area than the vehicle group over the 14-day time course. At day 3, AM/AMBP-1 promoted neutrophil infiltration (MPO), increased cytokine levels (IL-6 and TNF-alpha), angiogenesis (CD31, VEGF and TGFbeta-1) and cell proliferation (Ki67). By day 7 and 14, AM/AMBP-1 treatment decreased MPO, followed by a rapid resolution of inflammation characterized by a decrease in cytokines. At the matured stage, AM/AMBP-1 treatment increased the alpha smooth muscle actin expression (mature blood vessels) and Masson-Trichrome staining (collagen deposition) along the granulation area, and increased MMP-9 and decreased MMP-2 mRNA expressions. TGFbeta-1 mRNA levels in AM/AMBP-1 group were 5.3 times lower than those in the vehicle group. AM/AMBP-1 accelerated wound healing by promoting angiogenesis, collagen deposition and remodeling. Treatment also shortened the days to reach plateau for wound closure. Thus, AM/AMBP-1 may be further developed as a therapeutic for cutaneous wound healing. PMID- 25781902 TI - Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer. AB - OBJECTIVES: To examine the effects of combined treatment with sulfoquinovosylacylpropanediol and X-ray irradiation on the remodeling of the prostate cancer microenvironment, including angiogenic and hypoxic characteristics. METHODS: Human prostate cancer cells (DU145 and PC3) were implanted subcutaneously into the right hind legs of athymic nude mice. After the tumor volume reached 100-300mm(3) , 2mg/kg/day sulfoquinovosylacylpropanediol was given intravenously from day0 to day4, and cells were exposed to 4Gy X-ray irradiation on days0 and 3 (for a total of 8Gy). Tumors were fixed and stained for pathological analyses and immunohistochemical evaluations. To analyze vascular normalization, 60mg/kg pimonidazole dissolved in saline was injected intraperitoneally. RESULTS: Combined treatment with sulfoquinovosylacylpropanediol plus X-ray irradiation enhanced growth inhibition in DU145 xenografts. The tumor vessel density in DU145 cells significantly decreased after the combined treatment. Staining for alphasmooth muscle actin in vessels was significantly increased. Pimonidazole staining, showing hypoxic lesions, was negative from 72h, but positive at 6 and 24h after the first combined treatment. In contrast, no enhancement of the microenvironment in PC3 xenografts was observed with sulfoquinovosylacylpropanediol plus X-ray irradiation. CONCLUSION: Sulfoquinovosylacylpropanediol could be a novel potent radiosensitizing agent targeting angiogenesis in prostate cancer. PMID- 25781904 TI - Abstracts of the 19th Annual Meeting of French Society of Pharmacology and Therapeutics, 36th Pharmacovigilance Meeting, 16th APNET Seminar, 13th CHU CIC Meeting, 21-23 April, 2015, Caen, France. PMID- 25781903 TI - Antiretroviral Non-Adherence is Associated With a Retrieval Profile of Deficits in Verbal Episodic Memory. AB - HIV-associated deficits in verbal episodic memory are commonly associated with antiretroviral non-adherence; however, the specific aspects of memory functioning (e.g., encoding, consolidation, or retrieval) that underlie this established relationship are not well understood. This study evaluated verbal memory profiles of 202 HIV+ participants who underwent a 30-day electronic monitoring of antiretroviral adherence. At the group level, non-adherence was significantly associated with lower scores on immediate and delayed passage recall and word list learning. Retention and recognition of passages and word lists were not related to adherence. Participants were then classified as having either a normal verbal memory profile, a "subcortical" retrieval profile (i.e., impaired free recall with relatively spared recognition), or a "cortical" encoding profile (e.g., cued recall intrusions) based on the Massman et al. ( 1990 ) algorithm for the California Verbal Learning Test. HIV+ participants with a classic retrieval deficit had significantly greater odds of being non-adherent than participants with a normal or encoding profile. These findings suggest that adherence to prescribed antiretroviral regimens may be particularly vulnerable to disruption in HIV+ individuals due to deficits in the complex process of efficiently accessing verbal episodic information with minimal cues. A stronger relationship between non-adherence and passage (vs. word list) recall was also found and may reflect the importance of contextual features in remembering to take medications. Targeted interventions for enhancing and supporting episodic memory retrieval processes may improve antiretroviral adherence and overall health outcomes among persons living with HIV. PMID- 25781905 TI - Stoichiometric reactions and catalytic hydrogenation with a reactive intramolecular Zr(+)/amine frustrated Lewis pair. AB - Methyl anion abstraction from Cp*2Zr(CH3)OCH2CH2N(i)Pr2 (13) with trityl cation generates [Cp*2Zr(OCH2CH2N(i)Pr2)](+) (14). Complex 14 behaves as a reactive Zr(+)/amine frustrated Lewis pair (FLP). It reacts with dichloromethane to give the [Zr]Cl[OCH2CH2N(CH2Cl)(i)Pr2](+) cation (15), it slowly loses H2 upon standing at 60 degrees C to give a metallacyclic iminium cation product 18, and it reacts with terminal alkynes to give the [Zr]-alkynyl/ammonium systems 19. The organometallic FLP 14 cleaves dihydrogen heterolytically at near to ambient conditions to give the [Zr]H[OCH2CH2NH(i)Pr2](+) complex 20, which reduces benzaldehyde to the respective [Zr]OCH2Ph product 21 and is able to transfer the H(+)/H(-) pair to styrene to give ethylbenzene. Consequently, the Zr(+)/amine FLP 14 was used as an active hydrogenation catalyst for a series of alkenes and internal alkynes. The catalytic hydrogenation reactions were carried out under mild conditions (r.t., 1.5 bar of H2) using between 1 and 4 mol % FLP catalyst 14. PMID- 25781906 TI - "It's my secret": fear of disclosure among sub-Saharan African migrant women living with HIV/AIDS in Belgium. AB - Patients with HIV not only have to deal with the challenges of living with an incurable disease but also with the dilemma of whether or not to disclose their status to their partners, families and friends. This study explores the extent to which sub-Saharan African (SSA) migrant women in Belgium disclose their HIV positive status, reasons for disclosure/non-disclosure and how they deal with HIV disclosure. A qualitative study consisting of interviews with twenty-eight SSA women with HIV/AIDS was conducted. Thematic content analysis was employed to identify themes as they emerged. Our study reveals that these women usually only disclose their status to healthcare professionals because of the treatment and care they need. This selective disclosure is mainly due to the taboo of HIV disease in SSA culture. Stigma, notably self-stigma, greatly impedes HIV disclosure. Techniques to systematically incorporate HIV disclosure into post test counseling and primary care services are highly recommended. PMID- 25781907 TI - A new technology for applanation free corneal trephination: the picosecond infrared laser (PIRL). AB - The impact of using a Femtosecond laser on final functional results of penetrating keratoplasty is low. The corneal incisions presented here result from laser ablations with ultrafast desorption by impulsive vibrational excitation (DIVE). The results of the current study are based on the first proof-of principle experiments using a mobile, newly introduced picosecond infrared laser system, and indicate that wavelengths in the mid-infrared range centered at 3 MUm are efficient for obtaining applanation-free deep cuts on porcine corneas. PMID- 25781908 TI - Transesterification of PHA to oligomers covalently bonded with (bio)active compounds containing either carboxyl or hydroxyl functionalities. AB - This manuscript presents the synthesis and structural characterisation of novel biodegradable polymeric controlled-release systems of pesticides with potentially higher resistance to weather conditions in comparison to conventional forms of pesticides. Two methods for the preparation of pesticide-oligomer conjugates using the transesterification reaction were developed. The first method of obtaining conjugates, which consist of bioactive compounds with the carboxyl group and polyhydroxyalkanoates (PHAs) oligomers, is "one-pot" transesterification. In the second method, conjugates of bioactive compounds with hydroxyl group and polyhydroxyalkanoates oligomers were obtained in two-step method, through cyclic poly(3-hydroxybutyrate) oligomers. The obtained pesticide PHA conjugates were comprehensively characterised using GPC, 1H NMR and mass spectrometry techniques. The structural characterisation of the obtained products at the molecular level with the aid of mass spectrometry confirmed that both of the synthetic strategies employed led to the formation of conjugates in which selected pesticides were covalently bonded to PHA oligomers via a hydrolysable ester bond. PMID- 25781909 TI - Induction of p53-independent growth inhibition in lung carcinoma cell A549 by gypenosides. AB - The objectives of this study are to investigate antiproliferative effect and mechanisms of bioactive compounds from Gynostemma pentaphyllum (G. pentaphyllum) on lung carcinoma cell A549. Saponins, carotenoids and chlorophylls were extracted and fractionated by column chromatography, and were subjected to high performance liquid chromatography-mass spectrometry analyses. The saponin fraction, which consisted mainly of gypenoside (Gyp) XXII and XXIII, rather than the carotenoid and chlorophyll ones, was effective in inhibiting A549 cell growth in a concentration- and a time-dependent manner as evaluated using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The estimated half maximal inhibitory concentration (IC50 ) of Gyp on A549 cells was 30.6 MUg/ml. Gyp was further demonstrated to induce an apparent arrest of the A549 cell cycle at both the S phase and the G2/M phase, accompanied by a concentration and a time-dependent increase in the proportions of both the early and late apoptotic cells. Furthermore, Gyp down-regulated cellular expression of cyclin A and B as well as BCL-2, while up-regulated the expression of BAX, DNA degradation factor 35 KD, poly [ADP-ribose] polymerase 1, p53, p21 and caspase-3. Nevertheless, both the treatment of a p53 inhibitor, pifithrin-alpha, and the small hairpin RNA-mediated p53 knockdown in the A549 cells did not alter the growth inhibition effect induced by Gyp. As a result, the cell cycle arrest and apoptosis of A549 cells induced by Gyp would most likely proceed through p53 independent pathway(s). PMID- 25781911 TI - The Serotonin 2C Receptor Agonist Lorcaserin Attenuates Intracranial Self Stimulation and Blocks the Reward-Enhancing Effects of Nicotine. AB - Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5 HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphe nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3-1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to nicotine prevented the reward-enhancing effect of nicotine across multiple test sessions. These results demonstrated that lorcaserin reduces the rewarding value of BSR and also prevents nicotine from facilitating ICSS. Hence, lorcaserin may be effective in treating psychiatric disorders, including obesity and nicotine addiction, by reducing the value of food or drug rewards. PMID- 25781912 TI - A neutral cluster cage with a tetrahedral [Pd12(II)L6] framework: crystal structures and host-guest studies. AB - A charge-neutral tetrahedral [(Pd3X)4L6] cage assembly built from a trinuclear polyhedral building unit (PBU), [Pd3X](3+), cis-blocked with an imido P(V) ligand, [(N(i)Pr)3PO](3-) (X(3-)), and oxalate dianions (L(2-)) is reported. Use of benzoate or ferrocene dicarboxylate anions, which do not offer wide-angle chelation as that of oxalate dianions, leads to smaller prismatic clusters instead of polyhedral cage assemblies. The porosity of the tetrahedral cage assembly was determined by gas adsorption studies, which show a higher uptake capacity for CO2 over N2 and H2. The tetrahedral cage was shown to encapsulate a wide range of neutral guest solvents from polar to nonpolar such as dimethyl sulfoxide, benzene, dichloromethane, chloroform, carbon tetrachloride, and cyclopentane as observed by mass spectral and single-crystal X-ray diffraction studies. The (1)H two-dimensional diffusion ordered spectroscopy NMR analysis shows that the host and guest molecules exhibit similar diffusion coefficients in all the studied host-guest systems. Further, the tetrahedral cage shows selective binding of benzene, CCl4, and cyclopentane among other solvents from their categories as evidenced from mass spectral analysis. A preliminary density functional theory analysis gave a highest binding energy for benzene among the other solvents that were structurally shown to be encapsulated at the intrinsic cavity of the tetrahedral cage. PMID- 25781910 TI - Hes1: a key role in stemness, metastasis and multidrug resistance. AB - Hes1 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability. Recent studies have shown that Hes1 functions in the maintenance of cancer stem cells (CSCs), metastasis and antagonizing drug-induced apoptosis. Pathways that are involved in the up-regulation of Hes1 level canonically or non-canonically, such as the Hedgehog, Wnt and hypoxia pathways are frequently aberrant in cancer cells. Here, we summarize the recent data supporting the idea that Hes1 may have an important function in the maintenance of cancer stem cells self-renewal, cancer metastasis, and epithelial-mesenchymal transition (EMT) process induction, as well as chemotherapy resistance, and conclude with the possible mechanisms by which Hes1 functions have their effect, as well as their crosstalk with other carcinogenic signaling pathways. PMID- 25781913 TI - Effects of dietary pantothenic acid on growth, intestinal function, anti oxidative status and fatty acids synthesis of juvenile blunt snout bream Megalobrama amblycephala. AB - Four groups of juvenile Megalobrama amblycephala were fed three times daily with six semi-purified diets containing 3.39 (PA unsupplied diet), 10.54, 19.28, 31.04, 48.38 and 59.72 mg kg(-1) calcium D-pantothenate. The results showed that survival rate, final weight, specific growth rate, protein efficiency ratio and nitrogen retention efficiency all increased significantly (P<0.01) as dietary PA levels increased from 3.39 to 19.28 mg kg(-1), whereas the opposite was true for feed conversion ratio. Whole-body crude protein increased as dietary PA levels increased, while the opposite pattern was found for the crude lipid content. Intestinal alpha-amylase, lipase, protease, Na+-K+-ATPase, alkaline phosphatase and gamma-glutamyl transferase activities were all elevated in fish fed PA supplemented diets. Hepatic catalase activities improved with increases in dietary PA, while the opposite was true for malondialdehyde contents. The liver PA concentration and coenzyme A content rose significantly (P<0.01), up to 31.04 mg kg(-1), with increasing dietary PA levels and then plateaued. The percentage of hepatic saturated fatty acids increased significantly (P<0.01) as dietary PA levels increased, while the percentages of monounsaturated fatty acids and polyunsaturated fatty acid (PUFA) decreased as dietary PA increased. Fish fed diets containing 19.28 and 31.04 mg kg(-1) PA exhibited higher (P<0.01) docosahexaenoic acid and PUFA percentages in muscle than those fed with other diets. The expression of the gene encoding pantothenate kinase was significantly up-regulated (P<0.01) in fish fed PA-supplemented diets. Hepatic Acetyl-CoA carboxylase alpha, fatty acid synthetase, stearoyl regulatory element-binding protein 1 and X receptor alpha genes all increased significantly (P<0.01) as dietary PA levels increased from 3.39 to 31.04 mg kg(-1). Based on broken-line regression analyses of weight gain, liver CoA concentrations and PA contents against dietary PA levels, the optimal dietary PA requirements of juvenile blunt snout bream were estimated to be 24.08 mg kg(-1). PMID- 25781914 TI - A retrospective study of the use of active suction wound drains in dogs and cats. AB - OBJECTIVES: To report indications for use and complications associated with commonly used closed active suction wound drains in a large number of clinical cases. METHODS: Retrospective review of medical case records (from 2004 to 2010) for dogs and cats that had a closed active suction drain placed into a wound. Only the four most common drain types were included: Mini Redovac(r), Redovac(r), Jackson Pratt(r) and Wound Evac(r). RESULTS: Two hundred and fifty-three drains were placed in 33 cats and 195 dogs. Mini Redovac drains were used most frequently in cats (76 . 5%) and Redovac drains in dogs (54 . 3%). The infection rate for clean surgeries in dogs was 15 . 6% (unattainable in cats). Major complications occurred in four dogs; minor complications occurred in 12 drains in cats (35 . 3%), and in 74 drains in dogs (33 . 8%). There was no statistically significant association between the type of drain and complication rate for either species. CLINICAL SIGNIFICANCE: Although closed active suction drains can be used with low risk of major complications, they lead to a high rate of infection in clean surgeries in dogs. It is recommended that such drains are kept in place for the shortest time possible and that strict asepsis is adhered to both during placement and management. PMID- 25781915 TI - Time and frequency-domain measurement of ground-state recovery times in red fluorescent proteins. AB - The field of bioimaging and biosensors has been revolutionized by the discovery of fluorescent proteins (FPs) and their use in live cells. FPs are characterized with rich photodynamics due to the presence of nonfluorescent or dark states which are responsible for fluorescence intermittency or "blinking", which has been exploited in several localization-based super-resolution techniques that surpass the diffraction-limited resolution of conventional microscopy. Molecules that convert to these dark states recover to the ground states either spontaneously or upon absorption of another photon, depending on the particular FP and the structural transition that is involved. In this work, we demonstrate time- and frequency-domain methods for the measurement of the ground-state recovery (GSR) times of FPs both in live cells and in solutions. In the time domain method, we excited the sample with millisecond pulses at varying dark times to obtain percent-recovery. In the frequency-domain method, dark-state hysteresis was employed to obtain the positive phase shift or "phase advance". We extracted the GSR time constants from our measurements using calculations and simulations based on a three-state model system. The GSR time constants of the red FPs studied in these experiments fall in the range from MUs to msec time scales. We find that the time- and frequency-domain techniques are complementary to each other. While accurate GSR times can be extracted from the time-domain technique, frequency-domain measurements are primarily sensitive to the rates of dark-state conversion (DSC) processes. A correlation between GSR times, DSC, and photobleaching rates for the red FPs mCherry, TagRFP-T, and Kriek were observed. These time- and frequency-domain methods can be used in high-throughput screening and sorting of FPs clones based on GSR time constant and photostability and will therefore be valuable for the development of new photoswitchable or photoactivatable FPs. PMID- 25781916 TI - MicroRNAs are part of the regulatory network that controls EGF induced apoptosis, including elements of the JAK/STAT pathway, in A431 cells. AB - MiRNAs are known to regulate gene expression and in the context of cancer have been shown to regulate metastasis, cell proliferation and cell death. In this report we describe potential miRNA regulatory roles with respect to induction of cell death by pharmacologic dose of Epidermal Growth Factor (EGF). Our previous work suggested that multiple pathways are involved in the induction of apoptosis, including interferon induced genes, cytokines, cytoskeleton and cell adhesion and TP53 regulated genes. Using miRNA time course expression profiling of EGF treated A431 cells and coupling this to our previous gene expression and proteomic data, we have been able to implicate a number of additional miRNAs in the regulation of apoptosis. Specifically we have linked miR-134, miR-145, miR-146b-5p, miR-432 and miR-494 to the regulation of both apoptotic and anti-apoptotic genes expressed as a function of EGF treatment. Whilst additional miRNAs were differentially expressed, these had the largest number of apoptotic and anti-apoptotic targets. We found 5 miRNAs previously implicated in the regulation of apoptosis and our results indicate that an additional 20 miRNAs are likely to be involved based on their correlated expression with targets. Certain targets were linked to multiple miRNAs, including PEG10, BTG1, ID1, IL32 and NCF2. Some miRNAs that target the interferon pathway were found to be down regulated, consistent with a novel layer of regulation of interferon pathway components downstream of JAK/STAT. We have significantly expanded the repertoire of miRNAs that may regulate apoptosis in cancer cells as a result of this work. PMID- 25781917 TI - The similarity of the structure of DSM-IV criteria for major depression in depressed women from China, the United States and Europe. AB - BACKGROUND: Do DSM-IV diagnostic criteria for major depression (MD) in Chinese and Western women perform in a similar manner? METHOD: The CONVERGE study included interview-based assessments of women of Han Chinese descent with treated recurrent MD. Using Mplus software, we investigated the overall degree of between sample measurement invariance (MI) for DSM-IV diagnostic criteria for MD in the CONVERGE sample and samples selected from four major Western studies from the USA and Europe matched to the inclusion criteria of CONVERGE. These analyses were performed one pair at a time. We then compared the results from CONVERGE paired with Western samples to those obtained when examining levels of MI between pairs of the Western samples. RESULTS: Assuming a single factor model for the nine diagnostic criteria for MD, the level of MI based on global fit indexes observed between the CONVERGE and the four Western samples was very similar to that seen between the Western samples. Comparable results were obtained when using a two factor structure for MI testing when applied to the 14 diagnostic criteria for MD disaggregated for weight, appetite, sleep, and psychomotor changes. CONCLUSIONS: Despite differences in language, ethnicity and culture, DSM criteria for MD perform similarly in Chinese women with recurrent MD and comparable subjects from the USA and Europe. The DSM criteria for MD may assess depressive symptoms that are relatively insensitive to cultural and ethnic differences. These results support efforts to compare findings from depressed patients in China and Western countries. PMID- 25781920 TI - Temporal resolution of idiopathic granulomatous mastitis with resumption of bromocriptine therapy for prolactinoma. AB - INTRODUCTION: Idiopathic granulomatous mastitis (IGM) is becoming more commonly recognized and reported more often. Currently, many recommend corticosteroids in its management. PRESENTATION OF CASE: A 34-year-old G3P2 Hispanic female, 28 weeks pregnant, presented with a 19cm right breast mass. She had a known prolactinoma treated with bromocriptine which was discontinued during her pregnancy. Ultrasound guided core biopsy procedure revealed granulomatous mastitis. The patient was told that the mass would resolve with observation. The patient seen at another institution by an infectious disease specialist who started treatment with amphotericin for presumptive disseminated coccidioidomycosis. Repeated titers were negative for coccidioides antibody. Repeat cultures were negative as well. Due to the persistence of the infectious disease specialist, tissue cultures were performed on fresh tissue specimens, which did not grow bacterial, fungal, nor acid fast organisms. The amphotericin regimen resulted in no improvement of her breast mass after 10 weeks. Within two weeks of stopping the antifungal therapy, however, the mass diminished to 6cm. The patient delivered at 39 weeks. Bromocriptine was restarted, and within 4 weeks, the lesion was no longer palpable. She had not shown signs of recurrence for 32 months. DISCUSSION: Treatment recommendations for IGM vary widely but antibiotics and antifungal medications are not recommended. Corticosteroid treatment is most commonly recommended, however, outcomes may not be different from management with observation. Prolactin may be involved in the pathophysiology of the process. CONCLUSION: IGM is becoming recognized more frequently. Observation and patience with natural history can be an effective management. PMID- 25781919 TI - Simple mathematical models do not accurately predict early SIV dynamics. AB - Upon infection of a new host, human immunodeficiency virus (HIV) replicates in the mucosal tissues and is generally undetectable in circulation for 1-2 weeks post-infection. Several interventions against HIV including vaccines and antiretroviral prophylaxis target virus replication at this earliest stage of infection. Mathematical models have been used to understand how HIV spreads from mucosal tissues systemically and what impact vaccination and/or antiretroviral prophylaxis has on viral eradication. Because predictions of such models have been rarely compared to experimental data, it remains unclear which processes included in these models are critical for predicting early HIV dynamics. Here we modified the "standard" mathematical model of HIV infection to include two populations of infected cells: cells that are actively producing the virus and cells that are transitioning into virus production mode. We evaluated the effects of several poorly known parameters on infection outcomes in this model and compared model predictions to experimental data on infection of non-human primates with variable doses of simian immunodifficiency virus (SIV). First, we found that the mode of virus production by infected cells (budding vs. bursting) has a minimal impact on the early virus dynamics for a wide range of model parameters, as long as the parameters are constrained to provide the observed rate of SIV load increase in the blood of infected animals. Interestingly and in contrast with previous results, we found that the bursting mode of virus production generally results in a higher probability of viral extinction than the budding mode of virus production. Second, this mathematical model was not able to accurately describe the change in experimentally determined probability of host infection with increasing viral doses. Third and finally, the model was also unable to accurately explain the decline in the time to virus detection with increasing viral dose. These results suggest that, in order to appropriately model early HIV/SIV dynamics, additional factors must be considered in the model development. These may include variability in monkey susceptibility to infection, within-host competition between different viruses for target cells at the initial site of virus replication in the mucosa, innate immune response, and possibly the inclusion of several different tissue compartments. The sobering news is that while an increase in model complexity is needed to explain the available experimental data, testing and rejection of more complex models may require more quantitative data than is currently available. PMID- 25781921 TI - A case of adenoid cystic carcinoma associated with IgG4-related disease. AB - INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is an inflammatory condition associated with elevated serum IgG4 levels and tissue infiltration by IgG4-expressing plasma cells. We present a case of adenoid cystic carcinoma (ACC) of the submandibular gland with possible involvement of IgG4-RD. PRESENTATION OF CASE: The patient was a 59-year-old man presenting with a swollen right submandibular gland. Laboratory tests revealed IgG4 levels of 176mg/dl (reference range: 4.8-105). An initial open biopsy for histological diagnosis showed chronic sialadenitis. The region was monitored on an outpatient basis, and finally the right submandibular was totally resected because malignant tumor could not be excluded. Histological examination of the submandibular gland showed an ACC with lymphocytic infiltration containing many IgG4-positive plasma cells in the tumor stroma. DISCUSSION: We have described a case that indicated a possible involvement of ACC with IgG4-RD. This allows us to speculate that longstanding IgG4-RD may progress to malignancy or infiltration of IgG4-positive plasma cells through the signals of tumor stimuli. Further investigations are required to determine the potential pathogenic mechanism underlying this unique tumor. CONCLUSION: This case underscores that caution is needed in the diagnosis of masses with high serum IgG4 levels, as the differential diagnosis includes malignancy. PMID- 25781918 TI - Advanced molecular surveillance of hepatitis C virus. AB - Hepatitis C virus (HCV) infection is an important public health problem worldwide. HCV exploits complex molecular mechanisms, which result in a high degree of intrahost genetic heterogeneity. This high degree of variability represents a challenge for the accurate establishment of genetic relatedness between cases and complicates the identification of sources of infection. Tracking HCV infections is crucial for the elucidation of routes of transmission in a variety of settings. Therefore, implementation of HCV advanced molecular surveillance (AMS) is essential for disease control. Accounting for virulence is also important for HCV AMS and both viral and host factors contribute to the disease outcome. Therefore, HCV AMS requires the incorporation of host factors as an integral component of the algorithms used to monitor disease occurrence. Importantly, implementation of comprehensive global databases and data mining are also needed for the proper study of the mechanisms responsible for HCV transmission. Here, we review molecular aspects associated with HCV transmission, as well as the most recent technological advances used for virus and host characterization. Additionally, the cornerstone discoveries that have defined the pathway for viral characterization are presented and the importance of implementing advanced HCV molecular surveillance is highlighted. PMID- 25781922 TI - Effect of dual treatment with SDF-1 and BMP-2 on ectopic and orthotopic bone formation. AB - PURPOSES: The potent stem cell homing factor stromal cell-derived factor-1 (SDF 1) actively recruits mesenchymal stem cells from circulation and from local bone marrow. It is well established that bone morphogenetic protein-2 (BMP-2) induces ectopic and orthotopic bone formation. However, the exact synergistic effects of BMP-2 and SDF-1 in ectopic and orthotopic bone regeneration models have not been fully investigated. The purpose of this study was to evaluate the potential effects of simultaneous SDF-1 and BMP-2 treatment on bone formation. MATERIALS AND METHODS: Various doses of SDF-1 were loaded onto collagen sponges with or without BMP-2.These sponges were implanted into subcutaneous pockets and critical size calvarial defects in C57BL/6 mice. The specimens were harvested 4 weeks post surgery and the degree of bone formation in specimens was evaluated by histomorphometric and radiographic density analyses. Osteogenic potential and migration capacity of mesenchymal cells and capillary tube formation of endothelial cells following dual treatment with SDF-1 and BMP-2 were evaluated with in vitro assays. RESULTS: SDF-1-only-treated implants did not yield significant in vivo bone formation and SDF-1 treatment did not enhance BMP-2 induced ectopic and orthotopic bone regeneration. In vitro experiments showed that concomitant use of BMP-2 and SDF-1 had no additive effect on osteoblastic differentiation, cell migration or angiogenesis compared to BMP-2 or SDF-1 treatment alone. CONCLUSIONS: These findings imply that sequence-controlled application of SDF-1 and BMP-2 must be further investigated for the enhancement of robust osteogenesis in bone defects. PMID- 25781923 TI - Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment. AB - Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 * 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model. PMID- 25781924 TI - Association of functional polymorphisms from brain-derived neurotrophic factor and serotonin-related genes with depressive symptoms after a medical stressor in older adults. AB - Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S' 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. PMID- 25781925 TI - Correction: Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden. PMID- 25781926 TI - Beriberi (thiamine deficiency) and high infant mortality in northern Laos. AB - BACKGROUND: Infantile beriberi (thiamine deficiency) occurs mainly in infants breastfed by mothers with inadequate intake of thiamine, typically among vulnerable populations. We describe possible and probable cases of infantile thiamine deficiency in northern Laos. METHODOLOGY/PRINCIPAL FINDINGS: Three surveys were conducted in Luang Namtha Province. First, we performed a retrospective survey of all infants with a diagnosis of thiamine deficiency admitted to the 5 hospitals in the province (2007-2009). Second, we prospectively recorded all infants with cardiac failure at Luang Namtha Hospital. Third, we further investigated all mothers with infants (1-6 months) living in 22 villages of the thiamine deficiency patients' origin. We performed a cross-sectional survey of all mothers and infants using a pre-tested questionnaire, physical examination and squat test. Infant mortality was estimated by verbal autopsy. From March to June 2010, four suspected infants with thiamine deficiency were admitted to Luang Namtha Provincial hospital. All recovered after parenteral thiamine injection. Between 2007 and 2009, 54 infants with possible/probable thiamine deficiency were diagnosed with acute severe cardiac failure, 49 (90.2%) were cured after parenteral thiamine; three died (5.6%). In the 22 villages, of 468 live born infants, 50 (10.6%, 95% CI: 8.0-13.8) died during the first year. A peak of mortality (36 deaths) was reported between 1 and 3 months. Verbal autopsy suggested that 17 deaths (3.6%) were due to suspected infantile thiamine deficiency. Of 127 mothers, 60 (47.2%) reported edema and paresthesia as well as a positive squat test during pregnancy; 125 (98.4%) respected post-partum food avoidance and all ate polished rice. Of 127 infants, 2 (1.6%) had probable thiamine deficiency, and 8 (6.8%) possible thiamine deficiency. CONCLUSION: Thiamine deficiency may be a major cause of infant mortality among ethnic groups in northern Laos. Mothers' and children's symptoms are compatible with thiamine deficiency. The severity of this nutritional situation requires urgent attention in Laos. PMID- 25781927 TI - Evaluation of the contribution of the EYA4 and GRHL2 genes in Korean patients with autosomal dominant non-syndromic hearing loss. AB - EYA4 and GRHL2 encode transcription factors that play an important role in regulating many developmental stages. Since EYA4 and GRHL2 were identified as the transcription factors for the DFNA10 and DFNA28, 8 EYA4 mutations and 2 GRHL2 mutations have been reported worldwide. However, these genes have been reported in few studies of the Korean population. In this study, we performed a genetic analysis of EYA4 and GRHL2 in 87 unrelated Korean patients with autosomal dominant non-syndromic hearing loss (NSHL). A total of 4 genetic variants in the EYA4 gene were identified, including the 2 nonsense mutations p.S288X and p.Q393X. The novel mutation p.Q393X (c.1177C>T) resulted in a change in the codon at amino acid position 393 from a glutamine to a stop codon. The p.Q393X allele was predicted to encode a truncated protein lacking the entire C-terminal Eya homolog region (Eya HR), which is essential for the interaction with the transcription factor SIX3. The p.S288X (c.863C>A) mutation was found in a Korean family from a previous study. We analyzed p.S288X-linked microsatellite markers and determined that p.S288X might be a founder mutation and a hotspot mutation in Koreans. In GRHL2, a total of 4 genetic variants were identified, but none were associated with hearing loss in Korean patients. This suggests that GRHL2 may not be a main causal gene for autosomal dominant NSHL in Korean patients. In conclusion, our data provide fundamental information to predict the genotypes of Korean patients diagnosed with autosomal dominant NSHL. PMID- 25781928 TI - Claudin-2 knockout by TALEN-mediated gene targeting in MDCK cells: claudin-2 independently determines the leaky property of tight junctions in MDCK cells. AB - Tight junctions (TJs) regulate the movements of substances through the paracellular pathway, and claudins are major determinants of TJ permeability. Claudin-2 forms high conductive cation pores in TJs. The suppression of claudin-2 expression by RNA interference in Madin-Darby canine kidney (MDCK) II cells (a low-resistance strain of MDCK cells) was shown to induce a three-fold increase in transepithelial electrical resistance (TER), which, however, was still lower than in high-resistance strains of MDCK cells. Because RNA interference-mediated knockdown is not complete and only reduces gene function, we considered the possibility that the remaining claudin-2 expression in the knockdown study caused the lower TER in claudin-2 knockdown cells. Therefore, we investigated the effects of claudin-2 knockout in MDCK II cells by establishing claudin-2 knockout clones using transcription activator-like effector nucleases (TALENs), a recently developed genome editing method for gene knockout. Surprisingly, claudin-2 knockout increased TER by more than 50-fold in MDCK II cells, and TER values in these cells (3000-4000 Omega.cm2) were comparable to those in the high-resistance strains of MDCK cells. Claudin-2 re-expression restored the TER of claudin-2 knockout cells dependent upon claudin-2 protein levels. In addition, we investigated the localization of claudin-1, -2, -3, -4, and -7 at TJs between control MDCK cells and their respective knockout cells using their TALENs. Claudin-2 and -7 were less efficiently localized at TJs between control and their knockout cells. Our results indicate that claudin-2 independently determines the 'leaky' property of TJs in MDCK II cells and suggest the importance of knockout analysis in cultured cells. PMID- 25781929 TI - Angling-induced barotrauma in snapper Chrysophrys auratus: are there consequences for reproduction? AB - In response to concerns regarding the potential for sub-lethal impacts of barotrauma on reproductively active Chrysophrys auratus during catch and release, 90 males and 90 females representing five reproductive stages (immature or resting--28%, developing--8%, developed--7%, ripe or spawning--23% and spent- 34%) were angled from 8-70 m and macroscopically assessed (on-board and then in a laboratory). Irrespective of sex, all fish exhibited various clinical signs of barotrauma, including a prolapsed cloaca (60% of fish); gastric herniation (46%); ruptured swim bladder (73%); organ displacement (48%); and kidney (3%), liver (73%) and coloemic-cavity haemorrhaging (33%); with the frequency of nearly all positively associated with capture depth. Reproductive stage was also an important barotrauma predictor (reflecting related morphological changes) with a general trend towards spent fish least likely to incur the various clinical signs -especially for a prolapsed cloaca (also common among immature or resting fish and significantly affected by food in the digestive tract) and a ruptured swim bladder (common among ripe or spawning fish). The only macroscopically visible gonad damage was haemorrhaging, which was least common among immature or resting and spent fish and, irrespective of reproductive stage, temporally reduced in frequency, and more quickly among males than females. While further research is required to accurately describe the effects of angling at each stage of the reproductive cycle and the physiological consequences of barotrauma on the gonads of C. auratus, given the observed influences of reproductive stage and depth on barotrauma found in this study, any adverse effects might be partially managed by regulating either temporal or spatial fishing effort. PMID- 25781930 TI - Tissue distribution of the Ehrlichia muris-like agent in a tick vector. AB - Human pathogens transmitted by ticks undergo complex life cycles alternating between the arthropod vector and a mammalian host. While the latter has been investigated to a greater extent, examination of the biological interactions between microbes and the ticks that carry them presents an equally important opportunity for disruption of the disease cycle. In this study, we used in situ hybridization to demonstrate infection by the Ehrlichia muris-like organism, a newly recognized human pathogen, of Ixodes scapularis ticks, a primary vector for several important human disease agents. This allowed us to assess whole sectioned ticks for the patterns of tissue invasion, and demonstrate generalized dissemination of ehrlichiae in a variety of cell types and organs within ticks infected naturally via blood feeding. Electron microscopy was used to confirm these results. Here we describe a strong ehrlichial affinity for epithelial cells, neuronal cells of the synganglion, salivary glands, and male accessory glands. PMID- 25781931 TI - Adaptive resistance in bacteria requires epigenetic inheritance, genetic noise, and cost of efflux pumps. AB - Adaptive resistance emerges when populations of bacteria are subjected to gradual increases of antibiotics. It is characterized by a rapid emergence of resistance and fast reversibility to the non-resistant phenotype when the antibiotic is removed from the medium. Recent work shows that adaptive resistance requires epigenetic inheritance and heterogeneity of gene expression patterns that are, in particular, associated with the production of porins and efflux pumps. However, the precise mechanisms by which inheritance and variability govern adaptive resistance, and what processes cause its reversibility remain unclear. Here, using an efflux pump regulatory network (EPRN) model, we show that the following three mechanisms are essential to obtain adaptive resistance in a bacterial population: 1) intrinsic variability in the expression of the EPRN transcription factors; 2) epigenetic inheritance of the transcription rate of EPRN associated genes; and 3) energetic cost of the efflux pumps activity that slows down cell growth. While the first two mechanisms acting together are responsible for the emergence and gradual increase of the resistance, the third one accounts for its reversibility. In contrast with the standard assumption, our model predicts that adaptive resistance cannot be explained by increased mutation rates. Our results identify the molecular mechanism of epigenetic inheritance as the main target for therapeutic treatments against the emergence of adaptive resistance. Finally, our theoretical framework unifies known and newly identified determinants such as the burden of efflux pumps that underlie bacterial adaptive resistance to antibiotics. PMID- 25781932 TI - The network of antigen-antibody reactions in adult women with breast cancer or benign breast pathology or without breast pathology. AB - The Immunoglobulin G (IgG) antibody response to different protein antigens of the mammary ductal carcinoma by adult women affected by Breast Cancer (BC) distinguishes at least 103 proteins that differ in their molecular weights (MW). The IgG producing cell clones (nodes) coexist with each other in each individual organism and share energy resources among themselves, as well as factors that control the level of expression and Specificity of their IgG antibodies. So, it can be proposed that among them there is a Network of interconnections (links) unveiled by the antigens, which specifically react with the IgG antibodies produced by the clones. This Network possibly regulates IgG antibodies' activity and effectiveness. We describe the Network of nodes and links that exists between the different antigens and their respective IgG producing cell clones against the extracted protein antigens from the cells of the T47D Cell-Line, in 50 women with BC, 50 women with Benign Breast Pathology (BBP) and 50 women without breast pathology (H). We have found that women with BBP have the highest number of Links, followed by the H group and, lastly, the women with BC, a finding which suggests that cancer interferes with the Connectivity between the IgG producing cell clones and blocks the expression of 322 links in women with BBP and 32 links in women with H. It is also plausible that the largest number of links in the women with BBP indicates the Network's state of arousal that provides protection against BC. On the other hand, there were many missing links in the BC group of women; the clone which lost more links in the BC group was the hub 24, which point to some of the antigens of T47D as potentially useful as vaccines, as the immune system of women with BBP is well aware of them. PMID- 25781933 TI - A single pair of neurons modulates egg-laying decisions in Drosophila. AB - Animals have to judge environmental cues and choose the most suitable option for them from many different options. Female fruit flies selecting an optimum site to deposit their eggs is a biologically important reproductive behavior. When given the direct choice between ovipositing their eggs in a sucrose-containing medium or a caffeine-containing medium, female flies prefer the latter. However, the neural circuits and molecules that regulate this decision-making processes during egg-laying site selection remain poorly understood. In the present study, we found that amnesiac (amn) mutant flies show significant defects in egg-laying decisions, and such defects can be reversed by expressing the wild-type amn transgene in two dorsal paired medial (DPM) neurons in the brain. Silencing neuronal activity with an inward rectifier potassium channel (Kir2.1) in DPM neurons also impairs egg-laying decisions. Finally, the activity in mushroom body alphabeta neurons is required for the egg-laying behavior, suggesting a possible "DPM-alphabeta neurons" brain circuit modulating egg-laying decisions. Our results highlight the brain circuits and molecular mechanisms of egg-laying decisions in Drosophila. PMID- 25781934 TI - Tinnitus: a large VBM-EEG correlational study. AB - A surprising fact in voxel-based morphometry (VBM) studies performed in tinnitus is that not one single region is replicated in studies of different centers. The question then rises whether this is related to the low sample size of these studies, the selection of non-representative patient subgroups, or the absence of stratification according to clinical characteristics. Another possibility is that VBM is not a good tool to study functional pathologies such as tinnitus, in contrast to pathologies like Alzheimer's disease where it is known the pathology is related to cell loss. In a large sample of 154 tinnitus patients VBM and QEEG (Quantitative Electroencephalography) was performed and evaluated by a regression analysis. Correlation analyses are performed between VBM and QEEG data. Uncorrected data demonstrated structural differences in grey matter in hippocampal and cerebellar areas related to tinnitus related distress and tinnitus duration. After control for multiple comparisons, only cerebellar VBM changes remain significantly altered. Electrophysiological differences are related to distress, tinnitus intensity, and tinnitus duration in the subgenual anterior cingulate cortex, dorsal anterior cingulate cortex, hippocampus, and parahippocampus, which confirms previous results. The absence of QEEG-VBM correlations suggest functional changes are not reflected by co-occurring structural changes in tinnitus, and the absence of VBM changes (except for the cerebellum) that survive correct statistical analysis in a large study population suggests that VBM might not be very sensitive for studying tinnitus. PMID- 25781935 TI - A genome-wide association study in large white and landrace pig populations for number piglets born alive. AB - The number of piglets born alive (NBA) per litter is one of the most important traits in pig breeding due to its influence on production efficiency. It is difficult to improve NBA because the heritability of the trait is low and it is governed by a high number of loci with low to moderate effects. To clarify the biological and genetic background of NBA, genome-wide association studies (GWAS) were performed using 4,012 Large White and Landrace pigs from herdbook and commercial breeding companies in Germany (3), Austria (1) and Switzerland (1). The animals were genotyped with the Illumina PorcineSNP60 BeadChip. Because of population stratifications within and between breeds, clusters were formed using the genetic distances between the populations. Five clusters for each breed were formed and analysed by GWAS approaches. In total, 17 different significant markers affecting NBA were found in regions with known effects on female reproduction. No overlapping significant chromosome areas or QTL between Large White and Landrace breed were detected. PMID- 25781936 TI - A purification method for a molecular complex in which a scaffold molecule is fully loaded with heterogeneous molecules. AB - An affinity resin-based pull-down method is convenient for the purification of biochemical materials. However, its use is difficult for the isolation of a molecular complex fully loaded with multiple components from a reaction mixture containing the starting materials and intermediate products. To overcome this problem, we have developed a new purification procedure that depends on sequential elimination of the residues. In practice, two affinity resins were used for purifying a triangular-shaped RNP (RNA-protein complex) consisting of three ribosomal proteins (L7Ae) bound to an RNA scaffold. First, a resin with immobilized L7Ae protein captured the incomplete RNP complexes and the free RNA scaffold. Next, another resin with an immobilized chemically modified RNA of a derivative of Box C/D motif, the binding partner of L7Ae, was used to capture free protein. The complete triangular RNP was successfully purified from the mixture by these two steps. Obviously, the purified triangular RNP displaying three protein-binding peptides exhibited an improved performance when compared with the unrefined product. Conceptually, this purification procedure should be applicable for the purification of a variety of complexes consisting of multiple components other than RNP. PMID- 25781938 TI - Contrasting effects of intraspecific trait variation on trait-based niches and performance of legumes in plant mixtures. AB - Niche differentiation, assumed to be a key mechanism of species coexistence, requires that species differ in their functional traits. So far it remains unclear to which extent trait plasticity leads to niche shifts of species at higher plant diversity, thereby increasing or decreasing niche overlap between species. To analyse this question it is convenient to measure niches indirectly via the variation in resource-uptake traits rather than directly via the resources used. We provisionally call these indirectly measured niches trait based niches. We studied shoot- and leaf-morphological characteristics in seven legume species in monoculture and multi-species mixture in experimental grassland. Legume species varied in the extent of trait variation in response to plant diversity. Trait plasticity led to significant shifts in species niches in multiple dimensions. Single-species niches in several traits associated with height growth and filling of canopy space were expanded, while other niche dimensions were compressed or did not change with plant diversity. Niche separation among legumes decreased in dimensions related to height growth and space filling, but increased in dimensions related to leaf size and morphology. The total extent of occupied niche space was larger in mixture than in the combined monocultures for dimensions related to leaf morphology and smaller for dimensions related to whole-plant architecture. Taller growth, greater space filling and greater plasticity in shoot height were positively, while larger values and greater plasticity in specific leaf area were negatively related with increased performance of species in mixture. Our study shows that trait variation in response to plant diversity shifts species niches along trait axes. Plastically increased niche differentiation is restricted to niche dimensions that are apparently not related to size-dependent differences between species, but functional equivalence (convergence in height growth) rather than complementarity (divergence in traits associated with light acquisition) explains increased performance of legumes in mixture. PMID- 25781937 TI - Escherichia coli alpha-hemolysin counteracts the anti-virulence innate immune response triggered by the Rho GTPase activating toxin CNF1 during bacteremia. AB - The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1beta signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1beta antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1beta and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the alpha-hemolysin toxin inhibits IL-1beta secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia. PMID- 25781939 TI - Mycoplasma gallisepticum inactivated by targeting the hydrophobic domain of the membrane preserves surface lipoproteins and induces a strong immune response. AB - An innovative approach for inactivation of Mycoplasma gallisepticum using the hydrophobic photoinduced alkylating probe 1, 5-iodonaphthylazide (INA) is described. Treatment of washed M. gallisepticum mid-exponential culture (0.2 mg cell protein /mL) with INA followed by irradiation with far-ultraviolet light (310-380 nm) completely abolished viability. Transmission electron microscopy showed that the majority of the inactivated M. gallisepticum were comparable in size to intact cells, but that part of the INA-treated M. gallisepticum preparation also contained low density cells and membrane vesicles. Confocal microscopy revealed that untreated M. gallisepticum cells were internalized by chicken red blood cells (c-RBCs), whereas the INA-inactivated cells remained attached to the outer surface of the c-RBCs. INA treatment of M. gallisepticum resulted in a complete inactivation of F0F1 -ATPase and of the L-arginine uptake system, but the cytoplasmatic soluble NADH2 dehydrogenase was only partially affected. Western blot analysis of the lipoprotein fraction showed that the INA treated M. gallisepticum retained their lipoproteins. Following subcutaneous injection of M. gallisepticum INA-bacterin, 100% and 68.8% of chickens were positive by the rapid serum agglutination test and enzyme-linked immunosorbent assay respectively, 2 weeks post-injection. These data suggest that the photoinducible alkylating agent INA inactivates M. gallisepticum but preserves its surface lipoproteins and thus has the potential to be used as a general approach for the inactivation of mycoplasmas for vaccine development. PMID- 25781940 TI - Prevalence and factors associated with road traffic crash among taxi drivers in Mekelle town, northern Ethiopia, 2014: a cross sectional study. AB - OBJECTIVES: The 2013 World Health Organization Status Report on Road Safety estimated that approximately 1.24 million deaths occur annually due to road traffic crashes with most of the burden falling on low- and middle-income countries. The objective of this research is to study the prevalence of road traffic crashes in Mekelle, Tigray, Northern Ethiopia and to identify risk factors with the ultimate goal of informing prevention activities and policies. METHODS: This study used a cross-sectional design to measure the prevalence and factors associated with road traffic crashes among 4-wheeled minibus (n = 130) and 3-wheeled Bajaj (n = 582) taxi drivers in Mekelle, Ethiopia. Bivariate and multivariate logistic regression were used to evaluate the association between risk factors and drivers' involvement in a road traffic crash within the 3 years prior to the survey. FINDINGS: Among the 712 taxi drivers, 26.4% (n = 188) of them reported involvement in a road traffic crash within the past 3 years. Drivers who listened to mass media had decreased likelihood of road traffic crash involvement (AOR = 0.51, 0.33-0.78), while speedy driving (AOR = 4.57, 3.05 7.44), receipt of a prior traffic punishment (AOR = 4.57, 2.67-7.85), and driving a mechanically faulty taxi (AOR = 4.91, 2.81-8.61) were strongly associated with road traffic crash involvement. Receiving mobile phone calls while driving (AOR = 1.91, 1.24-2.92) and history of alcohol use (AOR = 1.51, 1.00-2.28) were also associated with higher odds of road traffic crash involvement. CONCLUSION: The results of this study show that taxi drivers in Mekelle habitually place themselves at increased risk of road traffic crashes by violating traffic laws, especially related to speedy driving, mobile phone use, and taxi maintenance. This research can be used to support re-evaluation of the type, severity, and enforcement of traffic violation penalties. PMID- 25781941 TI - Transgenic petunia with the iron(III)-phytosiderophore transporter gene acquires tolerance to iron deficiency in alkaline environments. AB - Iron is an essential nutrient for all plants. However, terrestrial plants often suffer from iron deficiency in alkaline soil due to its extremely low solubility. Alkaline soil accounts for about 30% of all cultivated ground in the world. Plants have evolved two distinct strategies, I and II, for iron uptake from the soil. Dicots and non-graminaceous monocots use Strategy I, which is primarily based on the reduction of iron(III) to iron(II) and the uptake of iron(II) by the iron-regulated transporter, IRT1. In contrast, graminaceous plants use Strategy II to efficiently acquire insoluble iron(III). Strategy II comprises the synthesis and secretion of iron-chelating phytosiderophores, such as mugineic acids and the Yellow Stripe 1 transporter proteins of the iron(III) phytosiderophore complex. Barley, which exhibits the highest tolerance to iron deficiency in alkaline soil among graminaceous plants, utilizes mugineic acids and the specific iron(III)-mugineic acids transporter, HvYS1. In this study, we established the transgenic plant Petunia hybrida, which originally had only Strategy I, by introducing the HvYS1 transporter gene derived from barley. When the transgenic plants were grown hydroponically in media containing the iron(III) 2'-deoxymugineic acid complex, free 2'-deoxymugineic acid and its iron(III) complex were detected in the root extract of the transgenic plant by electrospray ionization-Fourier transform-ion cyclotron resonance mass spectrometry. The growth of the transgenic petunia was significantly better than that of the control host in alkaline conditions. Consequently, the transgenic plant acquired a significantly enhanced tolerance to alkaline hydroponic media in the presence of the iron(III)-2'-deoxymugineic acid complex. Furthermore, the flower color of the transgenic plant deepened. The results showed that iron-phytosiderophore complexes and their transporters can potentially be utilized to overcome the worldwide iron uptake problems to diverse plant species that are found in areas with alkaline conditions. PMID- 25781942 TI - Country, cover or protection: what shapes the distribution of red deer and roe deer in the Bohemian Forest Ecosystem? AB - The Bohemian Forest Ecosystem encompasses various wildlife management systems. Two large, contiguous national parks (one in Germany and one in the Czech Republic) form the centre of the area, are surrounded by private hunting grounds, and hunting regulations in each country differ. Here we aimed at unravelling the influence of management-related and environmental factors on the distribution of red deer (Cervus elaphus) and roe deer (Capreolus capreolus) in this ecosystem. We used the standing crop method based on counts of pellet groups, with point counts every 100 m along 218 randomly distributed transects. Our analysis, which accounted for overdispersion as well as zero inflation and spatial autocorrelation, corroborated the view that both human management and the physical and biological environment drive ungulate distribution in mountainous areas in Central Europe. In contrast to our expectations, protection by national parks was the least important variable for red deer and the third important out of four variables for roe deer; protection negatively influenced roe deer distribution in both parks and positively influenced red deer distribution in Germany. Country was the most influential variable for both red and roe deer, with higher counts of pellet groups in the Czech Republic than in Germany. Elevation, which indicates increasing environmental harshness, was the second most important variable for both species. Forest cover was the least important variable for roe deer and the third important variable for red deer; the relationship for roe deer was positive and linear, and optimal forest cover for red deer was about 70% within a 500 m radius. Our results have direct implications for the future conservation management of deer in protected areas in Central Europe and show in particular that large non-intervention zones may not cause agglomerations of deer that could lead to conflicts along the border of protected, mountainous areas. PMID- 25781944 TI - Reduced hornbill abundance associated with low seed arrival and altered recruitment in a hunted and logged tropical forest. AB - Logging and hunting are two key direct threats to the survival of wildlife in the tropics, and also disrupt important ecosystem processes. We investigated the impacts of these two factors on the different stages of the seed dispersal cycle, including abundance of plants and their dispersers and dispersal of seeds and recruitment, in a tropical forest in north-east India. We focused on hornbills, which are important seed dispersers in these forests, and their food tree species. We compared abundances of hornbill food tree species in a site with high logging and hunting pressures (heavily disturbed) with a site that had no logging and relatively low levels of hunting (less disturbed) to understand logging impacts on hornbill food tree abundance. We compared hornbill abundances across these two sites. We, then, compared the scatter-dispersed seed arrival of five large-seeded tree species and the recruitment of four of those species. Abundances of hornbill food trees that are preferentially targeted by logging were two times higher in the less disturbed site as compared to the heavily disturbed site while that of hornbills was 22 times higher. The arrival of scatter-dispersed seeds was seven times higher in the less disturbed site. Abundances of recruits of two tree species were significantly higher in the less disturbed site. For another species, abundances of younger recruits were significantly lower while that of older recruits were higher in the heavily disturbed site. Our findings suggest that logging reduces food plant abundance for an important frugivore-seed disperser group, while hunting diminishes disperser abundances, with an associated reduction in seed arrival and altered recruitment of animal-dispersed tree species in the disturbed site. Based on our results, we present a conceptual model depicting the relationships and pathways between vertebrate-dispersed trees, their dispersers, and the impacts of hunting and logging on these pathways. PMID- 25781943 TI - Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury. AB - BACKGROUND: New evidence shows that high density lipoproteins (HDL) have protective effects beyond their role in reverse cholesterol transport. Reconstituted HDL (rHDL) offer an attractive means of clinically exploiting these novel effects including cardioprotection against ischemia reperfusion injury (IRI). However, basic rHDL composition is limited to apolipoprotein AI (apoAI) and phospholipids; addition of bioactive compound may enhance its beneficial effects. OBJECTIVE: The aim of this study was to investigate the role of rHDL in post-ischemic model, and to analyze the potential impact of sphingosine-1 phosphate (S1P) in rHDL formulations. METHODS AND RESULTS: The impact of HDL on IRI was investigated using complementary in vivo, ex vivo and in vitro IRI models. Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01). Treatment with rHDL of basic formulation (apoAI + phospholipids) had a non-significant impact on cell death in vitro and on the infarct size ex vivo and in vivo. In contrast, rHDL containing S1P had a highly significant, protective influence ex vivo, and in vivo (-50%, p<0.01). This impact was comparable with the effects observed with native HDL. Pro survival signaling proteins, Akt, STAT3 and ERK1/2 were similarly activated by HDL and rHDL containing S1P both in vitro (isolated cardiomyocytes) and in vivo. CONCLUSION: HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P. The protective impact of HDL appears to target directly the cardiomyocyte. PMID- 25781945 TI - A highly efficient recombinant laccase from the yeast Yarrowia lipolytica and its application in the hydrolysis of biomass. AB - A modified thermal asymmetric interlaced polymerase chain reaction was performed to obtain the first yeast laccase gene (YlLac) from the isolated yeast Yarrowia lipolytica. The 1557-bp full-length cDNA of YlLac encoded a mature laccase protein containing 519 amino acids preceded by a signal peptide of 19 amino acids, and the YlLac gene was expressed in the yeast Pichia pastoris. YlLac is a monomeric glycoprotein with a molecular mass of ~55 kDa as determined by polyacrylamide-gel electrophoresis. It showed a higher catalytic efficiency towards 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (kcat/Km = 17.5 s(-1) MUM(-1)) and 2,6-dimethoxyphenol (kcat/Km = 16.1 s(-1) MUM(-1)) than other reported laccases. The standard redox potential of the T1 site of the enzyme was found to be 772 mV. The highest catalytic efficiency of the yeast recombinant laccase, YlLac, makes it a good candidate for industrial applications: it removes phenolic compounds in acid-pretreated woody biomass (Populus balsamifera) and enhanced saccharification. PMID- 25781946 TI - Possible dual role of decorin in abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is characterized by chronic inflammation, which leads to pathological remodeling of the extracellular matrix. Decorin, a small leucine-rich repeat proteoglycan, has been suggested to regulate inflammation and stabilize the extracellular matrix. Therefore, the present study investigated the role of decorin in the pathogenesis of AAA. Decorin was localized in the aortic adventitia under normal conditions in both mice and humans. AAA was induced in mice using CaCl2 treatment. Initially, decorin protein levels decreased, but as AAA progressed decorin levels increased in all layers. Local administration of exogenous decorin prevented the development of CaCl2-induced AAA. However, decorin was highly expressed in the degenerative lesions of human AAA walls, and this expression positively correlated with matrix metalloproteinase (MMP)-9 expression. In cell culture experiments, the addition of decorin inhibited secretion of MMP-9 in vascular smooth muscle cells, but had the opposite effect in macrophages. The results suggest that decorin plays a dual role in AAA. Adventitial decorin in normal aorta may protect against the development of AAA, but macrophages expressing decorin in AAA walls may facilitate the progression of AAA by up-regulating MMP-9 secretion. PMID- 25781947 TI - Association between arterial stiffness and serum L-octanoylcarnitine and lactosylceramide in overweight middle-aged subjects: 3-year follow-up study. AB - Existing data on the association between being overweight and cardiovascular morbidity and mortality risk in adults are inconsistent. We prospectively and longitudinally investigated the effects of weight on arterial stiffness and plasma metabolites in middle-aged subjects (aged 40-55 years). A group of 59 individuals who remained within the range of overweight during repeated measurements over a 3-year period was compared with a control group of 59 normal weight subjects who were matched for age and gender. Changes in metabolites by UPLC-LTQ-Orbitrap mass spectrometry and changes in brachial-ankle pulse wave velocity (ba-PWV) were examined. At baseline, the overweight group showed higher BMI, waist circumference, triglyceride, free fatty acid (FFA), glucose, insulin, and hs-CRP, and lower HDL-cholesterol than controls. After 3 years, the changes in waist circumference, diastolic and systolic blood pressure (DBP and SBP), triglyceride, FFA, glucose, insulin, hs-CRP, and ba-PWV observed in the overweight group were significantly different from those in the control group after adjusting for baseline levels. Furthermore, the overweight group showed greater increases in L-octanoylcarnitine (q=0.006) and decanoylcarnitine (q=0.007), and higher peak intensities of L-leucine, L-octanoylcarnitine, and decanoylcarnitine. Multiple linear regression analysis showed that the change in ba-PWV was independently and positively associated with changes in L octanoylcarnitine, lactosylceramide, and SBP, and with baseline BMI. Our results indicate that the duration of overweight is an important aggravating factor for arterial stiffness, especially during middle age. Additionally, an age-related increase in plasma L-octanoylcarnitine, lactosylceramide, SBP, and baseline BMI are independent predictors of increased arterial stiffness in middle-aged individuals. PMID- 25781948 TI - Tumor progression locus 2 differentially regulates IFNgamma and IL-17 production by effector CD4+ T cells in a T cell transfer model of colitis. AB - Autoimmune diseases are approaching epidemic levels, estimated to affect 5-8% of the population. A number of autoimmune diseases are believed to be driven by autoreactive T cells, specifically by T helper 1 (Th1) cells and T helper 17 (Th17) cells. One molecule gaining interest as a therapeutic target is the serine threonine kinase, Tpl2, which promotes expression of proinflammatory mediators. We previously demonstrated that Tpl2 regulates Th1 differentiation, secretion of the inflammatory cytokine IFNgamma, and host defense against the intracellular parasite Toxoplasma gondii. The goal of this study was to determine whether Tpl2 also regulates Th1 or Th17 differentiation in vivo in a model of colitis associated with mixed Th1/Th17 pathology. In vitro, Tpl2-/- naive CD4 T cells were significantly impaired in IL-17A secretion under traditional Th17 inducing conditions. Reduced IL-17A secretion correlated with increased expression of FoxP3, a transcription factor known to antagonize RORgammat function. In a murine T cell transfer model of colitis, transfer of Tpl2-/- T cells resulted in reduced proportions of CD4 T cells expressing IFNgamma, but not IL-17A, compared to that induced by wild type T cells. Further studies revealed that IL-17A differentiation induced by IL-6 and IL-23, cytokines implicated in driving Th17 differentiation in vivo, was unaffected by Tpl2 deficiency. Collectively, these results implicate Tpl2 in TGF-beta-induced FoxP3 expression. Additionally, they underscore the contribution of Tpl2 to Th1 immunopathology specifically, which suggests that Tpl2 inhibitors may selectively target Th1-based inflammation. PMID- 25781949 TI - Framingham ten-year general cardiovascular disease risk: agreement between BMI based and cholesterol-based estimates in a South Asian convenience sample. AB - The goal of this analysis was to determine the agreement between body mass index based and cholesterol-based ten-year Framingham general cardiovascular disease risk scores among a convenience sample of 773 South Asian Canadian adults attending community-based screening clinics. Scores were calculated using age, systolic blood pressure, antihypertensive use, current smoking, diabetes, and total cholesterol and high density lipoprotein (for cholesterol-based risk) or height and weight (for body mass index-based risk). Mean risk score differences (body mass index-based risk minus cholesterol-based risk) were estimated using paired t-tests. Bland-Altman plots were used to assess agreement between scores. Finally, agreement across risk categories (low [<10%], moderate [10% to <20%], high [> = 20%]) was examined using the kappa statistic. Average agreement between the two risk scores was quite good overall (mean differences of 0.6% for men and 0.5% for women), but increased to about 3% among participants 60-74 years of age. However, Bland-Altman plots revealed that the differences between the two scores and the variability of the differences increased with increasing average 10-year risk. In terms of clinical importance, the limits of agreement were reasonable for women < 60 years (95% confidence interval: -3.2% to 3.1%), but of concern for women 60-74 years (95% confidence interval: -6.0% to 12.3%), men < 60 years (95% confidence interval: -7.1% to 7.3%) and men 6-074 years (95% confidence interval: -13.8% to 18.8%). Agreement across categories was moderate for most sex and age groups examined (kappa values: 0.51 for women < 60 years, 0.50 for women 60-74 years, 0.65 for men < 60 years), except for men 60-74 years, where agreement was only fair (kappa = 0.26). In light of these disagreements, evaluation of a participant's change in cardiovascular disease risk over time will necessitate use of the same risk score (i.e., either body mass index-based or cholesterol based) at all screening sessions. PMID- 25781950 TI - Irisin in blood increases transiently after single sessions of intense endurance exercise and heavy strength training. AB - PURPOSE: Irisin is a recently identified exercise-induced hormone that increases energy expenditure, at least in rodents. The main purpose of this study was to test the hypothesis that Irisin increases acutely in blood after singular sessions of intense endurance exercise (END) and heavy strength training (STR). Secondary, we wanted to explore the relationship between body composition and exercise-induced effects on irisin, and the effect of END and STR on muscular expression of the irisin gene FNDC5. METHODS: Nine moderately trained healthy subjects performed three test days using a randomized and standardized crossover design: one day with 60 minutes of END, one day with 60 minutes of STR, and one day without exercise (CON). Venous blood was sampled over a period of 24h on the exercise days. RESULTS: Both END and STR led to transient increases in irisin concentrations in blood, peaking immediately after END and one hour after STR, before gradually returning to baseline. Irisin responses to STR, but not END, showed a consistently strong negative correlation with proportions of lean body mass. Neither END nor STR affected expression of FNDC5, measured 4h after training sessions, though both protocols led to pronounced increases in PGC 1alpha expression, which is involved in transcriptional control of FNDC5. CONCLUSION: The results strongly suggest that single sessions of intense endurance exercise and heavy strength training lead to transient increases in irisin concentrations in blood. This was not accompanied by increased FNDC5 expression, measured 4h post-exercise. The results suggest that irisin responses to resistance exercise are higher in individuals with lower proportions of lean body mass. PMID- 25781951 TI - Analysis of the role of interleukin 6 receptor haplotypes in the regulation of circulating levels of inflammatory biomarkers and risk of coronary heart disease. AB - Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T--block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C- block 2) were identified in the IL6R gene. IL6R haplotype associations with C reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF alpha in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation. PMID- 25781953 TI - Vibrotactile Guidance for Wayfinding of Blind Walkers. AB - We propose a vibrotactile interface in the form of a belt for guiding blind walkers. This interface enables blind walkers to receive haptic directional instructions along complex paths without negatively impacting users' ability to listen and/or perceive the environment the way some auditory directional instructions do. The belt interface was evaluated in a controlled study with 10 blind individuals and compared to the audio guidance. The experiments were videotaped and the participants' behaviors and comments were content analyzed. Completion times and deviations from ideal paths were also collected and statistically analyzed. By triangulating the quantitative and qualitative data, we found that the belt resulted in closer path following to the expense of speed. In general, the participants were positive about the use of vibrotactile belt to provide directional guidance. PMID- 25781952 TI - Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression. AB - Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression. PMID- 25781954 TI - Surface-Roughness-Based Virtual Textiles: Evaluation Using a Multi-Contactor Display. AB - Virtual textiles, generated in response to exploratory movements, are presented to the fingertip via a 24-contactor vibrotactile array. Software models are based on surface-roughness profiles from real textiles. Results suggest that distinguishable "textile-like" surfaces are produced, but these lack the necessary accuracy for reliable matching to real textiles. PMID- 25781955 TI - Activation of the low molecular weight protein tyrosine phosphatase in keratinocytes exposed to hyperosmotic stress. AB - Herein, we provide new contribution to the mechanisms involved in keratinocytes response to hyperosmotic shock showing, for the first time, the participation of Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) activity in this event. We reported that sorbitol-induced osmotic stress mediates alterations in the phosphorylation of pivotal cytoskeletal proteins, particularly Src and cofilin. Furthermore, an increase in the expression of the phosphorylated form of LMWPTP, which was followed by an augment in its catalytic activity, was observed. Of particular importance, these responses occurred in an intracellular milieu characterized by elevated levels of reduced glutathione (GSH) and increased expression of the antioxidant enzymes glutathione peroxidase and glutathione reductase. Altogether, our results suggest that hyperosmostic stress provides a favorable cellular environment to the activation of LMWPTP, which is associated with increased expression of antioxidant enzymes, high levels of GSH and inhibition of Src kinase. Finally, the real contribution of LMWPTP in the hyperosmotic stress response of keratinocytes was demonstrated through analysis of the effects of ACP1 gene knockdown in stressed and non-stressed cells. LMWPTP knockdown attenuates the effects of sorbitol induced-stress in HaCaT cells, mainly in the status of Src kinase, Rac and STAT5 phosphorylation and activity. These results describe for the first time the participation of LMWPTP in the dynamics of cytoskeleton rearrangement during exposure of human keratinocytes to hyperosmotic shock, which may contribute to cell death. PMID- 25781957 TI - The investigation of posttraumatic pseudoaneurysms in patients treated with nonoperative management for blunt abdominal solid organ injuries. AB - BACKGROUND: Posttraumatic pseudoaneurysms (PAs) have been recognized as the cause of delayed hemorrhage complicated with nonoperative management (NOM), although the need for intervention in patients with small-sized PAs and the relationship between the occurrence of PAs and bed-rest has been also unclear. OBJECTIVES: The purpose of this study was to investigate the clinical history of small-sized PAs (less than 10 mm in diameter) which occurred in abdominal solid organs, and to analyze the relationship between the occurrence of PAs and early mobilization from bed. METHODS: Sixty-two patients who were successfully managed with NOM were investigated. Mobilization within three days post-injury was defined as "early mobilization" and bed-rest lasting over three days was defined as "late mobilization." A comparison of the clinical factors, including the duration of bed-rest between patients with and without PAs detected by follow-up CT was performed. Furthermore, a multiple logistic regression model analysis on the occurrence of PAs was performed. RESULTS: PAs were detected in 7 of the 62 patients. The One patient with PAs measuring larger than 10 mm received trans arterial embolization, and the remaining six patients with PAs smaller than 10 mm were managed conservatively. Consequently, no delayed hemorrhage occurred, and the PAs spontaneously disappeared in all of the six patients managed without intervention. The multiple regression model analysis revealed that early mobilization was not a significant factor predicting new-onset PAs. CONCLUSIONS: Small PAs can be expected to disappear spontaneously. Moreover, early mobilization is not a significant risk factor for the occurrence of PAs. PMID- 25781956 TI - Utilizing targeted mass spectrometry to demonstrate Asf1-dependent increases in residue specificity for Rtt109-Vps75 mediated histone acetylation. AB - In Saccharomyces cerevisiae, Rtt109, a lysine acetyltransferase (KAT), associates with a histone chaperone, either Vps75 or Asf1. It has been proposed that these chaperones alter the selectivity of Rtt109 or which residues it preferentially acetylates. In the present study, we utilized a label-free quantitative mass spectrometry-based method to determine the steady-state kinetic parameters of acetylation catalyzed by Rtt109-Vps75 on H3 monomer, H3/H4 tetramer, and H3/H4 Asf1 complex. These results show that among these histone conformations, only H3K9 and H3K23 are significantly acetylated under steady-state conditions and that Asf1 promotes H3/H4 acetylation by Rtt109-Vps75. Asf1 equally increases the Rtt109-Vps75 specificity for both of these residues with a maximum stoichiometry of 1:1 (Asf1 to H3/H4), but does not alter the selectivity between these two residues. These data suggest that the H3/H4-Asf1 complex is a substrate for Rtt109-Vps75 without altering selectivity between residues. The deletion of either Rtt109 or Asf1 in vivo results in the same reduction of H3K9 acetylation, suggesting that Asf1 is required for efficient H3K9 acetylation both in vitro and in vivo. Furthermore, we found that the acetylation preference of Rtt109-Vps75 could be directed to H3K56 when those histones already possess modifications, such as those found on histones purified from chicken erythrocytes. Taken together, Vps75 and Asf1 both enhance Rtt109 acetylation for H3/H4, although via different mechanisms, but have little impact on the residue selectivity. Importantly, these results provide evidence that histone chaperones can work together via interactions with either the enzyme or the substrate to more efficiently acetylate histones. PMID- 25781959 TI - Manifold Learning for Multivariate Variable-Length Sequences With an Application to Similarity Search. AB - Multivariate variable-length sequence data are becoming ubiquitous with the technological advancement in mobile devices and sensor networks. Such data are difficult to compare, visualize, and analyze due to the nonmetric nature of data sequence similarity measures. In this paper, we propose a general manifold learning framework for arbitrary-length multivariate data sequences driven by similarity/distance (parameter) learning in both the original data sequence space and the learned manifold. Our proposed algorithm transforms the data sequences in a nonmetric data sequence space into feature vectors in a manifold that preserves the data sequence space structure. In particular, the feature vectors in the manifold representing similar data sequences remain close to one another and far from the feature points corresponding to dissimilar data sequences. To achieve this objective, we assume a semisupervised setting where we have knowledge about whether some of data sequences are similar or dissimilar, called the instance level constraints. Using this information, one learns the similarity measure for the data sequence space and the distance measures for the manifold. Moreover, we describe an approach to handle the similarity search problem given user-defined instance level constraints in the learned manifold using a consensus voting scheme. Experimental results on both synthetic data and real tropical cyclone sequence data are presented to demonstrate the feasibility of our manifold learning framework and the robustness of performing similarity search in the learned manifold. PMID- 25781958 TI - Doing no harm? Adverse events in a nation-wide cohort of patients with multidrug resistant tuberculosis in Nigeria. AB - BACKGROUND: Adverse events (AEs) of second line anti-tuberculosis drugs (SLDs) are relatively well documented. However, the actual burden has rarely been described in detail in programmatic settings. We investigated the occurrence of these events in the national cohort of multidrug-resistant tuberculosis (MDR-TB) patients in Nigeria. METHOD: This was a retrospective, observational cohort study, using pharmacovigilance data systematically collected at all MDR-TB treatment centers in Nigeria. Characteristics of AEs during the intensive phase treatment were documented, and risk factors for development of AEs were assessed. RESULTS: Four hundred and sixty patients were included in the analysis: 62% were male; median age was 33 years [Interquartile Range (IQR):28-42] and median weight was 51 kg (IQR: 45-59). Two hundred and three (44%) patients experienced AEs; four died of conditions associated with SLD AEs. Gastro-intestinal (n = 100), neurological (n = 75), ototoxic (n = 72) and psychiatric (n = 60) AEs were the most commonly reported, whereas ototoxic and psychiatric AEs were the most debilitating. Majority of AEs developed after 1-2 months of therapy, and resolved in less than a month after treatment. Some treatment centers were twice as likely to report AEs compared with others, highlighting significant inconsistencies in reporting at different treatment centers. Patients with a higher body weight had an increased risk of experiencing AEs. No differences were observed in risk of AEs between HIV-infected and uninfected patients. Similarly, age was not significantly associated with AEs. CONCLUSION: Patients in the Nigerian MDR-TB cohort experienced a wide range of AEs, some of which were disabling and fatal. Early identification and prompt management as well as standardized reporting of AEs at all levels of healthcare, including the community is urgently needed. Safer regimens for drug-resistant TB with the shortest duration are advocated. PMID- 25781960 TI - Dynamic Uncertain Causality Graph for Knowledge Representation and Probabilistic Reasoning: Directed Cyclic Graph and Joint Probability Distribution. AB - Probabilistic graphical models (PGMs) such as Bayesian network (BN) have been widely applied in uncertain causality representation and probabilistic reasoning. Dynamic uncertain causality graph (DUCG) is a newly presented model of PGMs, which can be applied to fault diagnosis of large and complex industrial systems, disease diagnosis, and so on. The basic methodology of DUCG has been previously presented, in which only the directed acyclic graph (DAG) was addressed. However, the mathematical meaning of DUCG was not discussed. In this paper, the DUCG with directed cyclic graphs (DCGs) is addressed. In contrast, BN does not allow DCGs, as otherwise the conditional independence will not be satisfied. The inference algorithm for the DUCG with DCGs is presented, which not only extends the capabilities of DUCG from DAGs to DCGs but also enables users to decompose a large and complex DUCG into a set of small, simple sub-DUCGs, so that a large and complex knowledge base can be easily constructed, understood, and maintained. The basic mathematical definition of a complete DUCG with or without DCGs is proved to be a joint probability distribution (JPD) over a set of random variables. The incomplete DUCG as a part of a complete DUCG may represent a part of JPD. Examples are provided to illustrate the methodology. PMID- 25781961 TI - Distance Metric Learning Using Privileged Information for Face Verification and Person Re-Identification. AB - In this paper, we propose a new approach to improve face verification and person re-identification in the RGB images by leveraging a set of RGB-D data, in which we have additional depth images in the training data captured using depth cameras such as Kinect. In particular, we extract visual features and depth features from the RGB images and depth images, respectively. As the depth features are available only in the training data, we treat the depth features as privileged information, and we formulate this task as a distance metric learning with privileged information problem. Unlike the traditional face verification and person re-identification tasks that only use visual features, we further employ the extra depth features in the training data to improve the learning of distance metric in the training process. Based on the information-theoretic metric learning (ITML) method, we propose a new formulation called ITML with privileged information (ITML+) for this task. We also present an efficient algorithm based on the cyclic projection method for solving the proposed ITML+ formulation. Extensive experiments on the challenging faces data sets EUROCOM and CurtinFaces for face verification as well as the BIWI RGBD-ID data set for person re identification demonstrate the effectiveness of our proposed approach. PMID- 25781962 TI - Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders. AB - Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i) this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii) that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects. PMID- 25781963 TI - Classification of Implantable Rotary Blood Pump States With Class Noise. AB - A medical case study related to implantable rotary blood pumps is examined. Five classifiers and two ensemble classifiers are applied to process the signals collected from the pumps for the identification of the aortic valve nonopening pump state. In addition to the noise-free datasets, up to 40% class noise has been added to the signals to evaluate the classification performance when mislabeling is present in the classifier training set. In order to ensure a reliable diagnostic model for the identification of the pump states, classifications performed with and without class noise are evaluated. The multilayer perceptron emerged as the best performing classifier for pump state detection due to its high accuracy as well as robustness against class noise. PMID- 25781964 TI - Optimal drug prediction from personal genomics profiles. AB - Cancer patients often show heterogeneous drug responses such that only a small subset of patients is sensitive to a given anticancer drug. With the availability of large-scale genomic profiling via next-generation sequencing, it is now economically feasible to profile the whole transcriptome and genome of individual patients in order to identify their unique genetic mutations and differentially expressed genes, which are believed to be responsible for heterogeneous drug responses. Although subtyping analysis has identified patient subgroups sharing common biomarkers, there is no effective method to predict the drug response of individual patients precisely and reliably. Herein, we propose a novel computational algorithm to predict the drug response of individual patients based on personal genomic profiles, as well as pharmacogenomic and drug sensitivity data. Specifically, more than 600 cancer cell lines (viewed as individual patients) across over 50 types of cancers and their responses to 75 drugs were obtained from the genomics of drug sensitivity in cancer database. The drug specific sensitivity signatures were determined from the changes in genomic profiles of individual cell lines in response to a specific drug. The optimal drugs for individual cell lines were predicted by integrating the votes from other cell lines. The experimental results show that the proposed drug prediction algorithm can be used to improve greatly the reliability of finding optimal drugs for individual patients and will, thus, form a key component in the precision medicine infrastructure for oncology care. PMID- 25781965 TI - Classification of voluntary cough airflow patterns for prediction of abnormal spirometry. AB - Measurement of partial expiratory flow-volume curves has become an important technique in diagnosing lung disease, particularly in children and in the elderly. The objective of this study was to investigate the feasibility of predicting abnormal spirometry using the partial flow-volume curve generated during a voluntary cough. Here, abnormal spirometry is defined as less than the lower limit of normal (LLN) predicted by standard reference equations [1]. Cough airflow signals of 107 subjects (56 male, 51 female) were previously collected [2] from patients performing spirometry in a pulmonary function clinic. A variety of features were extracted from the airflow signal. A support vector machine (SVM) classifier was developed to predict abnormal spirometry. Airflow signal features and SVM parameters were selected using a genetic algorithm. The ability of the classifier to distinguish between normal and abnormal spirometry based on cough flow was evaluated by comparing the classifiers decisions with the LLN for the given subject's spirometry, including forced expiratory volume in one second (FEV1), forced vital capacity (FV C), and their ratio (FEV1=FV C%). Findings indicated that it was possible to classify patients whose spirometry results were less than the LLN with an overall accuracy of 76% for FEV1, 65% for FV C, and 76% for the ratio FEV1=FV C%. Accuracies were determined by repeated double cross validation [3]. This study demonstrates the potential of using airflow measured during voluntary coughing to identify test subjects with abnormal spirometry. PMID- 25781966 TI - Crystal structure of Helicobacter pylori pseudaminic acid biosynthesis N acetyltransferase PseH: implications for substrate specificity and catalysis. AB - Helicobacter pylori infection is the common cause of gastroduodenal diseases linked to a higher risk of the development of gastric cancer. Persistent infection requires functional flagella that are heavily glycosylated with 5,7 diacetamido-3,5,7,9-tetradeoxy-L-glycero-L-manno-nonulosonic acid (pseudaminic acid). Pseudaminic acid biosynthesis protein H (PseH) catalyzes the third step in its biosynthetic pathway, producing UDP-2,4-diacetamido-2,4,6-trideoxy-beta-L altropyranose. It belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily. The crystal structure of the PseH complex with cofactor acetyl-CoA has been determined at 2.3 A resolution. This is the first crystal structure of the GNAT superfamily member with specificity to UDP-4-amino-4,6-dideoxy-beta-L AltNAc. PseH is a homodimer in the crystal, each subunit of which has a central twisted beta-sheet flanked by five alpha-helices and is structurally homologous to those of other GNAT superfamily enzymes. Interestingly, PseH is more similar to the GNAT enzymes that utilize amino acid sulfamoyl adenosine or protein as a substrate than a different GNAT-superfamily bacterial nucleotide-sugar N acetyltransferase of the known structure, WecD. Analysis of the complex of PseH with acetyl-CoA revealed the location of the cofactor-binding site between the splayed strands beta4 and beta5. The structure of PseH, together with the conservation of the active-site general acid among GNAT superfamily transferases, are consistent with a common catalytic mechanism for this enzyme that involves direct acetyl transfer from AcCoA without an acetylated enzyme intermediate. Based on structural homology with microcin C7 acetyltransferase MccE and WecD, the Michaelis complex can be modeled. The model suggests that the nucleotide- and 4-amino-4,6-dideoxy-beta-L-AltNAc-binding pockets form extensive interactions with the substrate and are thus the most significant determinants of substrate specificity. A hydrophobic pocket accommodating the 6'-methyl group of the altrose dictates preference to the methyl over the hydroxyl group and thus to contributes to substrate specificity of PseH. PMID- 25781968 TI - Correction: Association of GWAS-identified lung cancer susceptibility loci with survival length in patients with small-cell lung cancer treated with platinum based chemotherapy. PMID- 25781967 TI - Uncovering genes and ploidy involved in the high diversity in root hair density, length and response to local scarce phosphate in Arabidopsis thaliana. AB - Plant root hairs increase the root surface to enhance the uptake of sparingly soluble and immobile nutrients, such as the essential nutrient phosphorus, from the soil. Here, root hair traits and the response to scarce local phosphorus concentration were studied in 166 accessions of Arabidopsis thaliana using split plates. Root hair density and length were correlated, but highly variable among accessions. Surprisingly, the well-known increase in root hair density under low phosphorus was mostly restricted to genotypes that had less and shorter root hairs under P sufficient conditions. By contrast, several accessions with dense and long root hairs even had lower hair density or shorter hairs in local scarce phosphorus. Furthermore, accessions with whole-genome duplications developed more dense but phosphorus-insensitive root hairs. The impact of genome duplication on root hair density was confirmed by comparing tetraploid accessions with their diploid ancestors. Genome-wide association mapping identified candidate genes potentially involved in root hair responses tp scarce local phosphate. Knock-out mutants in identified candidate genes (CYR1, At1g32360 and RLP48) were isolated and differences in root hair traits in the mutants were confirmed. The large diversity in root hair traits among accessions and the diverse response when local phosphorus is scarce is a rich resource for further functional analyses. PMID- 25781969 TI - Structural and enzymatic characterization of the choline kinase LicA from Streptococcus pneumoniae. AB - LicA plays a key role in the cell-wall phosphorylcholine biosynthesis of Streptococcus pneumonia. Here we determined the crystal structures of apo-form LicA at 1.94 A and two complex forms LicA-choline and LicA-AMP-MES, at 2.01 and 1.45 A resolution, respectively. The overall structure adopts a canonical protein kinase-like fold, with the active site located in the crevice of the N- and C terminal domains. The three structures present distinct poses of the active site, which undergoes an open-closed-open conformational change upon substrate binding and product release. The structure analyses combined with mutageneses and enzymatic assays enabled us to figure out the key residues for the choline kinase activity of LicA. In addition, structural comparison revealed the loop between helices alpha7 and alpha8 might modulate the substrate specificity and catalytic activity. These findings shed light on the structure and mechanism of the prokaryotic choline kinase LicA, and might direct the rational design of novel anti-pneumococcal drugs. PMID- 25781971 TI - Ensemble and Arithmetic Recombination-Based Speciation Differential Evolution for Multimodal Optimization. AB - Multimodal optimization problems consists of multiple equal or comparable spatially distributed solutions. Niching and clustering differential evolution (DE) techniques have been demonstrated to be highly effective for solving such problems. The key challenge in the speciation niching technique is to balance between local solution exploitation and global exploration. Our proposal enhances exploration by applying arithmetic recombination with speciation and improves exploitation of individual peaks by applying neighborhood mutation with ensemble strategies. Our novel algorithm, called ensemble and arithmetic recombination based speciation DE, is shown to either outperform or perform comparably to the state-of-the-art algorithms on 29 common multimodal benchmark problems. Comparable performance is observed only when some problems are solved perfectly by the algorithms in the literature. PMID- 25781972 TI - An Improved Multiobjective Optimization Evolutionary Algorithm Based on Decomposition for Complex Pareto Fronts. AB - The multiobjective evolutionary algorithm based on decomposition (MOEA/D) has been shown to be very efficient in solving multiobjective optimization problems (MOPs). In practice, the Pareto-optimal front (POF) of many MOPs has complex characteristics. For example, the POF may have a long tail and sharp peak and disconnected regions, which significantly degrades the performance of MOEA/D. This paper proposes an improved MOEA/D for handling such kind of complex problems. In the proposed algorithm, a two-phase strategy (TP) is employed to divide the whole optimization procedure into two phases. Based on the crowdedness of solutions found in the first phase, the algorithm decides whether or not to delicate computational resources to handle unsolved subproblems in the second phase. Besides, a new niche scheme is introduced into the improved MOEA/D to guide the selection of mating parents to avoid producing duplicate solutions, which is very helpful for maintaining the population diversity when the POF of the MOP being optimized is discontinuous. The performance of the proposed algorithm is investigated on some existing benchmark and newly designed MOPs with complex POF shapes in comparison with several MOEA/D variants and other approaches. The experimental results show that the proposed algorithm produces promising performance on these complex problems. PMID- 25781970 TI - Optomotor-blind negatively regulates Drosophila eye development by blocking Jak/STAT signaling. AB - Organ formation requires a delicate balance of positive and negative regulators. In Drosophila eye development, wingless (wg) is expressed at the lateral margins of the eye disc and serves to block retinal development. The T-box gene optomotor blind (omb) is expressed in a similar pattern and is regulated by Wg. Omb mediates part of Wg activity in blocking eye development. Omb exerts its function primarily by blocking cell proliferation. These effects occur predominantly in the ventral margin. Our results suggest that the primary effect of Omb is the blocking of Jak/STAT signaling by repressing transcription of upd which encodes the Jak receptor ligand Unpaired. PMID- 25781973 TI - A Level Set Approach to Image Segmentation With Intensity Inhomogeneity. AB - It is often a difficult task to accurately segment images with intensity inhomogeneity, because most of representative algorithms are region-based that depend on intensity homogeneity of the interested object. In this paper, we present a novel level set method for image segmentation in the presence of intensity inhomogeneity. The inhomogeneous objects are modeled as Gaussian distributions of different means and variances in which a sliding window is used to map the original image into another domain, where the intensity distribution of each object is still Gaussian but better separated. The means of the Gaussian distributions in the transformed domain can be adaptively estimated by multiplying a bias field with the original signal within the window. A maximum likelihood energy functional is then defined on the whole image region, which combines the bias field, the level set function, and the piecewise constant function approximating the true image signal. The proposed level set method can be directly applied to simultaneous segmentation and bias correction for 3 and 7T magnetic resonance images. Extensive evaluation on synthetic and real-images demonstrate the superiority of the proposed method over other representative algorithms. PMID- 25781974 TI - A CRE/AP-1-like motif is essential for induced syncytin-2 expression and fusion in human trophoblast-like model. AB - Syncytin-2 is encoded by the envelope gene of Endogenous Retrovirus-FRD (ERVFRD 1) and plays a critical role in fusion of placental trophoblasts leading to the formation of the multinucleated syncytiotrophoblast. Its expression is consequently regulated in a strict manner. In the present study, we have identified a forskolin-responsive region located between positions -300 to -150 in the Syncytin-2 promoter region. This 150 bp region in the context of a minimal promoter mediated an 80-fold induction of promoter activity following forskolin stimulation. EMSA analyses with competition experiments with nuclear extracts from forskolin-stimulated BeWo cells demonstrated that the -211 to -177 region specifically bound two forskolin-induced complexes, one of them containing a CRE/AP-1-like motif. Site-directed mutagenesis of the CRE/AP-1 binding site in the context of the Syncytin-2 promoter or a heterologous promoter showed that this motif was mostly essential for forskolin-induced promoter activity. Transfection experiments with dominant negative mutants and constitutively activated CREB expression vectors in addition to Chromatin Immunoprecipitation suggested that a CREB family member, CREB2 was binding and acting through the CRE/AP-1 motif. We further demonstrated the binding of JunD to this same motif. Similar to forskolin and soluble cAMP, CREB2 and JunD overexpression induced Syncytin-2 promoter activity in a CRE/AP-1-dependent manner and Syncytin-2 expression. In addition, BeWo cell fusion was induced by both CREB2 and JunD overexpression, while being repressed following silencing of either gene. These results thereby demonstrate that induced expression of Syncytin-2 is highly dependent on the interaction of bZIP-containing transcription factors to a CRE/AP 1 motif and that this element is important for the regulation of Syncytin-2 expression, which results in the formation of the peripheral syncytiotrophoblast layer. PMID- 25781975 TI - Eugenol: a phyto-compound effective against methicillin-resistant and methicillin sensitive Staphylococcus aureus clinical strain biofilms. AB - BACKGROUND: Inhibition and eradication of Staphylococcus aureus biofilms with conventional antibiotic is difficult, and the treatment is further complicated by the rise of antibiotic resistance among staphylococci. Consequently, there is a need for novel antimicrobials that can treat biofilm-related infections and decrease antibiotics burden. Natural compounds such as eugenol with anti microbial properties are attractive agents that could reduce the use of conventional antibiotics. In this study we evaluated the effect of eugenol on MRSA and MSSA biofilms in vitro and bacterial colonization in vivo. METHODS AND RESULTS: Effect of eugenol on in vitro biofilm and in vivo colonization were studied using microtiter plate assay and otitis media-rat model respectively. The architecture of in vitro biofilms and in vivo colonization of bacteria was viewed with SEM. Real-time RT-PCR was used to study gene expression. Check board method was used to study the synergistic effects of eugenol and carvacrol on established biofilms. Eugenol significantly inhibited biofilms growth of MRSA and MSSA in vitro in a concentration-dependent manner. Eugenol at MIC or 2*MIC effectively eradicated the pre-established biofilms of MRSA and MSSA clinical strains. In vivo, sub-MIC of eugenol significantly decreased 88% S. aureus colonization in rat middle ear. Eugenol was observed to damage the cell-membrane and cause a leakage of the cell contents. At sub-inhibitory concentration, it decreases the expression of biofilm-and enterotoxin-related genes. Eugenol showed a synergistic effect with carvacrol on the eradication of pre-established biofilms. CONCLUSION/MAJOR FINDING: This study demonstrated that eugenol exhibits notable activity against MRSA and MSSA clinical strains biofilms. Eugenol inhibited biofilm formation, disrupted the cell-to-cell connections, detached the existing biofilms, and killed the bacteria in biofilms of both MRSA and MSSA with equal effectiveness. Therefore, eugenol may be used to control or eradicate S. aureus biofilm-related infections. PMID- 25781976 TI - Direct detection of fungal siderophores on bats with white-nose syndrome via fluorescence microscopy-guided ambient ionization mass spectrometry. AB - White-nose syndrome (WNS) caused by the pathogenic fungus Pseudogymnoascus destructans is decimating the populations of several hibernating North American bat species. Little is known about the molecular interplay between pathogen and host in this disease. Fluorescence microscopy ambient ionization mass spectrometry was used to generate metabolic profiles from the wings of both healthy and diseased bats of the genus Myotis. Fungal siderophores, molecules that scavenge iron from the environment, were detected on the wings of bats with WNS, but not on healthy bats. This work is among the first examples in which microbial molecules are directly detected from an infected host and highlights the ability of atmospheric ionization methodologies to provide direct molecular insight into infection. PMID- 25781977 TI - A randomized controlled trial of increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti microfilaremics in Odisha, India. AB - Although current programmes to eliminate lymphatic filariasis have made significant progress it may be necessary to use different approaches to achieve the global goal, especially where compliance has been poor and 'hot spots' of continued infection exist. In the absence of alternative drugs, the use of higher or more frequent dosing with the existing drugs needs to be explored. We examined the effect of higher and/or more frequent dosing with albendazole with a fixed 300 mg dose of diethylcarbamazine in a Wuchereria bancrofti endemic area in Odisha, India. Following screening, 104 consenting adults were randomly assigned to treatment with the standard regimen annually for 24 months (S1), or annually with increased dose (800 mg albendazole)(H1) or with increased frequency (6 monthly) with either standard (S2) or increased (H2) dose. Pre-treatment microfilaria counts (GM) ranged from 348 to 459 mf/ml. Subjects were followed using microfilaria counts, OG4C3 antigen levels and ultrasound scanning for adult worm nests. Microfilarial counts tended to decrease more rapidly with higher or more frequent dosing at all time points. At 12 months, Mf clearance was marginally greater with the high dose regimens, while by 24 months, there was a trend to higher Mf clearance in the arm with increased frequency and 800 mg of albendazole (76.9%) compared to other arms, (S1:64%, S2:69.2% & H1:73.1%). Although higher and/or more frequent dosing showed a trend towards a greater decline in antigenemia and clearance of "nests", all regimens demonstrated the potential macrofilaricidal effect of the combination. The higher doses of albendazole did not result in a greater number or more severe side effects. The alternative regimens could be useful in the later stages of existing elimination programmes or achieving elimination more rapidly in areas where programmes have yet to start. PMID- 25781980 TI - HIV-associated neurocognitive disorders and central nervous system drug penetration: what next? AB - The current prevalence of cognitive impairment in HIV-infected individuals is surprisingly high, even in those with undetectable plasma HIV RNA. The aetiology is unknown but one possibility is inadequate control of persistent central nervous system (CNS) HIV infection. The CNS Penetration Effectiveness (CPE) rank has been proposed to predict how well an antiretroviral regimen treats CNS infection. Fabbiani et al. report that 'correcting' the CPE rank of each drug in an individual's regimen for the results of genotypic susceptibility (the CPE-GSS score) results in better ability to predict whether the regimen will improve cognition. The CPE-GSS score may help us better understand the aetiology of HIV associated cognitive impairment. Whether it will be useful in the management of individual patients requires further study. PMID- 25781978 TI - Molecular dynamics simulation and experimental verification of the interaction between cyclin T1 and HIV-1 Tat proteins. AB - The viral encoded Tat protein is essential for the transcriptional activation of HIV proviral DNA. Interaction of Tat with a cellular transcription elongation factor P-TEFb containing CycT1 is critically required for its action. In this study, we performed MD simulation using the 3D data for wild-type and 4CycT1mutants3D data. We found that the dynamic structural change of CycT1 H2' helix is indispensable for its activity for the Tat action. Moreover, we detected flexible structural changes of the Tat-recognition cavity in the WT CycT1 comprising of ten AAs that are in contact with Tat. These structural fluctuations in WT were lost in the CycT1 mutants. We also found the critical importance of the hydrogen bond network involving H1, H1' and H2 helices of CycT1. Since similar AA substitutions of the Tat-CycT1 chimera retained the Tat-supporting activity, these interactions are considered primarily involved in interaction with Tat. These findings described in this paper should provide vital information for the development of effective anti-Tat compound. PMID- 25781979 TI - Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice. AB - We previously reported that the ability of continuously elevated PTH to stimulate osteoblastic differentiation in bone marrow stromal cell cultures was abrogated by an osteoclastic factor secreted in response to cyclooxygenase-2 (Cox2) produced prostaglandin E2. We now examine the impact of Cox2 (Ptgs2) knockout (KO) on the anabolic response to continuously elevated PTH in vivo. PTH (40 MUg/kg/d) or vehicle was infused for 12 or 21 days in 3-mo-old male wild type (WT) and KO mice in the outbred CD-1 background. Changes in bone phenotype were assessed by bone mineral density (BMD), MUCT and histomorphometry. PTH infusion for both 12 and 21 days increased femoral BMD in Cox2 KO mice and decreased BMD in WT mice. Femoral and vertebral trabecular bone volume fractions were increased in KO mice, but not in WT mice, by PTH infusion. In the femoral diaphysis, PTH infusion increased cortical area in Cox2 KO, but not WT, femurs. PTH infusion markedly increased trabecular bone formation rate in the femur, serum markers of bone formation, and expression of bone formation-related genes, growth factors, and Wnt target genes in KO mice relative to WT mice, and decreased gene expression of Wnt antagonists only in KO mice. In contrast to the differential effects of PTH on anabolic factors in WT and KO mice, PTH infusion increased serum markers of resorption, expression of resorption-related genes, and the percent bone surface covered by osteoclasts similarly in both WT and KO mice. We conclude that Cox2 inhibits the anabolic, but not the catabolic, effects of continuous PTH. These data suggest that the bone loss with continuously infused PTH in mice is due largely to suppression of bone formation and that this suppression is mediated by Cox2. PMID- 25781981 TI - Glycine-containing flaxseed orbitides. AB - Five new orbitides, cyclolinopeptides 21-25, were identified in flaxseed oil (Linum usitatissimum) extracts. Their HPLC-ESIMS quasimolecular ion peaks at m/z 1097.7 (21), 1115.6 (22), 1131.6 (23), 1018.6 (24), and 1034.6 (25) [M + H](+) corresponded to the molecular formulae C59H89N10O10, C58H87N10O10S, C58H87N10O11S, C53H80N9O9S, and C53H80N9O10S, respectively. Their structures were elucidated by extensive HPLC-ESIMS/MS analyses, and their presence was confirmed by precursor proteins identified in flax genomic DNA sequence data. The amino acid sequences of these orbitides were confirmed as [1-10-NalphaC]-GILVPPFFLI, [1 10-NalphaC]-GMLIPPFFVI, [1-10-NalphaC]-GOLIPPFFVI, [1-9-NalphaC]-GMLVFPLFI, and [1-9-NalphaC]-GOLVFPLFI for cyclolinopeptides 21-25, respectively. Previously reported orbitides, [1-9-NalphaC]-ILVPPFFLI (1), [1-9-NalphaC]-MLIPPFFVI (2), [1 9-NalphaC]-OLIPPFFVI (3), [1-8-NalphaC]-MLVFPLFI (7), and [1-8-NalphaC]-OLVFPLFI (8), were also present in flaxseed oil. The precursors of orbitides 21, 22, and 24 also produced orbitides 1, 2, and 7 by alternative cyclization. Cyclolinopeptides 3, 8, 23, and 25 contain MetO (O) and are not directly encoded, but are products of post-translational modification of the Met present in 2, 7, 22, and 24, respectively. Sufficient cyclolinopeptide 23 was isolated for characterization via 1D ((1)H and (13)C) and 2D (NOESY and HMBC) NMR spectroscopy. These compounds have been named as cyclolinopeptides U, V, W, X, and Y for 21, 22, 23, 24, and 25, respectively. PMID- 25781982 TI - Differential regulation of proton-sensitive ion channels by phospholipids: a comparative study between ASICs and TRPV1. AB - Protons are released in pain-generating pathological conditions such as inflammation, ischemic stroke, infection, and cancer. During normal synaptic activities, protons are thought to play a role in neurotransmission processes. Acid-sensing ion channels (ASICs) are typical proton sensors in the central nervous system (CNS) and the peripheral nervous system (PNS). In addition to ASICs, capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channels can also mediate proton-mediated pain signaling. In spite of their importance in perception of pH fluctuations, the regulatory mechanisms of these proton-sensitive ion channels still need to be further investigated. Here, we compared regulation of ASICs and TRPV1 by membrane phosphoinositides, which are general cofactors of many receptors and ion channels. We observed that ASICs do not require membrane phosphatidylinositol 4-phosphate (PI(4)P) or phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for their function. However, TRPV1 currents were inhibited by simultaneous breakdown of PI(4)P and PI(4,5)P2. By using a novel chimeric protein, CF-PTEN, that can specifically dephosphorylate at the D3 position of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), we also observed that neither ASICs nor TRPV1 activities were altered by depletion of PI(3,4,5)P3 in intact cells. Finally, we compared the effects of arachidonic acid (AA) on two proton-sensitive ion channels. We observed that AA potentiates the currents of both ASICs and TRPV1, but that they have different recovery aspects. In conclusion, ASICs and TRPV1 have different sensitivities toward membrane phospholipids, such as PI(4)P, PI(4,5)P2, and AA, although they have common roles as proton sensors. Further investigation about the complementary roles and respective contributions of ASICs and TRPV1 in proton-mediated signaling is necessary. PMID- 25781983 TI - Head-to-head comparison of two popular cortical thickness extraction algorithms: a cross-sectional and longitudinal study. AB - BACKGROUND AND PURPOSE: The measurement of cortical shrinkage is a candidate marker of disease progression in Alzheimer's. This study evaluated the performance of two pipelines: Civet-CLASP (v1.1.9) and Freesurfer (v5.3.0). METHODS: Images from 185 ADNI1 cases (69 elderly controls (CTR), 37 stable MCI (sMCI), 27 progressive MCI (pMCI), and 52 Alzheimer (AD) patients) scanned at baseline, month 12, and month 24 were processed using the two pipelines and two interconnected e-infrastructures: neuGRID (https://neugrid4you.eu) and VIP (http://vip.creatis.insa-lyon.fr). The vertex-by-vertex cross-algorithm comparison was made possible applying the 3D gradient vector flow (GVF) and closest point search (CPS) techniques. RESULTS: The cortical thickness measured with Freesurfer was systematically lower by one third if compared to Civet's. Cross-sectionally, Freesurfer's effect size was significantly different in the posterior division of the temporal fusiform cortex. Both pipelines were weakly or mildly correlated with the Mini Mental State Examination score (MMSE) and the hippocampal volumetry. Civet differed significantly from Freesurfer in large frontal, parietal, temporal and occipital regions (p<0.05). In a discriminant analysis with cortical ROIs having effect size larger than 0.8, both pipelines gave no significant differences in area under the curve (AUC). Longitudinally, effect sizes were not significantly different in any of the 28 ROIs tested. Both pipelines weakly correlated with MMSE decay, showing no significant differences. Freesurfer mildly correlated with hippocampal thinning rate and differed in the supramarginal gyrus, temporal gyrus, and in the lateral occipital cortex compared to Civet (p<0.05). In a discriminant analysis with ROIs having effect size larger than 0.6, both pipelines yielded no significant differences in the AUC. CONCLUSIONS: Civet appears slightly more sensitive to the typical AD atrophic pattern at the MCI stage, but both pipelines can accurately characterize the topography of cortical thinning at the dementia stage. PMID- 25781984 TI - Dermal neutrophil, macrophage and dendritic cell responses to Yersinia pestis transmitted by fleas. AB - Yersinia pestis, the causative agent of plague, is typically transmitted by the bite of an infected flea. Many aspects of mammalian innate immune response early after Y. pestis infection remain poorly understood. A previous study by our lab showed that neutrophils are the most prominent cell type recruited to the injection site after intradermal needle inoculation of Y. pestis, suggesting that neutrophil interactions with Y. pestis may be important in bubonic plague pathogenesis. In the present study, we developed new tools allowing for intravital microscopy of Y. pestis in the dermis of an infected mouse after transmission by its natural route of infection, the bite of an infected flea. We found that uninfected flea bites typically induced minimal neutrophil recruitment. The magnitude of neutrophil response to flea-transmitted Y. pestis varied considerably and appeared to correspond to the number of bacteria deposited at the bite site. Macrophages migrated towards flea bite sites and interacted with small numbers of flea-transmitted bacteria. Consistent with a previous study, we observed minimal interaction between Y. pestis and dendritic cells; however, dendritic cells did consistently migrate towards flea bite sites containing Y. pestis. Interestingly, we often recovered viable Y. pestis from the draining lymph node (dLN) 1 h after flea feeding, indicating that the migration of bacteria from the dermis to the dLN may be more rapid than previously reported. Overall, the innate cellular host responses to flea-transmitted Y. pestis differed from and were more variable than responses to needle-inoculated bacteria. This work highlights the importance of studying the interactions between fleas, Y. pestis and the mammalian host to gain a better understanding of the early events in plague pathogenesis. PMID- 25781985 TI - High expression level of Tra2-beta1 is responsible for increased SMN2 exon 7 inclusion in the testis of SMA mice. AB - Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by deletion or mutation of SMN1 gene. All SMA patients carry a nearly identical SMN2 gene, which produces low level of SMN protein due to mRNA exon 7 exclusion. Previously, we found that the testis of SMA mice (smn-/- SMN2) expresses high level of SMN2 full-length mRNA, indicating a testis-specific mechanism for SMN2 exon 7 inclusion. To elucidate the underlying mechanism, we established primary cultures of testis cells from SMA mice and analyzed them for SMN2 exon 7 splicing. We found that primary testis cells after a 2-hour culture still expressed high level of SMN2 full-length mRNA, but the level decreased after longer cultures. We then compared the protein levels of relevant splicing factors, and found that the level of Tra2-beta1 also decreased during testis cell culture, correlated with SMN2 full-length mRNA downregulation. In addition, the testis of SMA mice expressed the highest level of Tra2-beta1 among the many tissues examined. Furthermore, overexpression of Tra2-beta1, but not ASF/SF2, increased SMN2 minigene exon 7 inclusion in primary testis cells and spinal cord neurons, whereas knockdown of Tra2-beta1 decreased SMN2 exon 7 inclusion in primary testis cells of SMA mice. Therefore, our results indicate that high expression level of Tra2-beta1 is responsible for increased SMN2 exon 7 inclusion in the testis of SMA mice. This study also suggests that the expression level of Tra2-beta1 may be a modifying factor of SMA disease and a potential target for SMA treatment. PMID- 25781987 TI - An iTRAQ-based proteomics approach to clarify the molecular physiology of somatic embryo development in Prince Rupprecht's larch (Larix principis-rupprechtii Mayr). AB - Prince Rupprecht's larch (Larix principis-rupprechtii Mayr) is a native high value forest tree species in North China whose clonal propagation through somatic embryogenesis (SE) has the potential to rapidly capture the benefits of breeding or genetic engineering programs and to improve raw material uniformity and quality. To date, research has focused on clarifying the molecular mechanism of SE, but proteomic studies are still in the early stages. In this study, isobaric tags for relative and absolute quantitation (iTRAQ) analysis was performed on three developmental stages of SE in L. principis-rupprechtii in an attempt to identify a wide range of proteins that are regulated differentially during this process. Proteins were extracted and analyzed from the pro-embryogenic mass (PEM), globular embryo (GE), and cotyledon embryo (CE) stages of embryo development. We detected 503 proteins in total and identified 96 proteins expressed differentially during different developmental stages. The identified proteins were analyzed further to provide information about their expression patterns and functions during SE. Four clusters of proteins based on shared expression profiles were generated. Functional analysis showed that proteins involved in primary metabolism, phosphorylation, and oxidation reduction were upregulated during somatic embryo development. This work provides novel insights into the process of larch embryo development in vitro and a basis for further study of the biological process and opportunities for practical application of this knowledge. PMID- 25781988 TI - Comparative study of antimicrobial activity of AgBr and Ag nanoparticles (NPs). AB - The diverse mechanism of antimicrobial activity of Ag and AgBr nanoparticles against gram-positive and gram-negative bacteria and also against several strains of candida was explored in this study. The AgBr nanoparticles (NPs) were prepared by simple precipitation of silver nitrate by potassium bromide in the presence of stabilizing polymers. The used polymers (PEG, PVP, PVA, and HEC) influence significantly the size of the prepared AgBr NPs dependently on the mode of interaction of polymer with Ag+ ions. Small NPs (diameter of about 60-70 nm) were formed in the presence of the polymer with low interaction as are PEG and HEC, the polymers which interact with Ag+ strongly produce nearly two times bigger NPs (120-130 nm). The prepared AgBr NPs were transformed to Ag NPs by the reduction using NaBH4. The sizes of the produced Ag NPs followed the same trends--the smallest NPs were produced in the presence of PEG and HEC polymers. Prepared AgBr and Ag NPs dispersions were tested for their biological activity. The obtained results of antimicrobial activity of AgBr and Ag NPs are discussed in terms of possible mechanism of the action of these NPs against tested microbial strains. The AgBr NPs are more effective against gram-negative bacteria and tested yeast strains while Ag NPs show the best antibacterial action against gram-positive bacteria strains. PMID- 25781989 TI - Development of indicators for patient care and monitoring standards for secondary health care services of Mumbai. AB - BACKGROUND: The Qualitative aspect of health care delivery is one of the major factors in reducing morbidity and mortality in a health care setup. The expanding suburban secondary health care delivery facilities of the Municipal Corporation of Greater Mumbai are an important part of the healthcare backbone of Mumbai and therefore the quality of care delivered here needed standardization. MATERIAL AND METHODS: The project was completed over a period of one year from Jan to Dec, 2013 and implemented in three phases. The framework with components and sub components were developed and formats for data collection were standardized. The benchmarks were based on past performance in the same hospital and probability was used for development of normal range. An Excel spreadsheet was developed to facilitate data analysis. RESULTS: The indicators comprise of 3 components- Statutory Requirements, Patient care & Cure and Administrative efficiency. The measurements made, pointed to the broad areas needing attention. CONCLUSION: The Indicators for patient care and monitoring standards can be used as a self assessment tool for health care setups for standardization and improvement of delivery of health care services. PMID- 25781990 TI - Prediction and analysis of quorum sensing peptides based on sequence features. AB - Quorum sensing peptides (QSPs) are the signaling molecules used by the Gram positive bacteria in orchestrating cell-to-cell communication. In spite of their enormous importance in signaling process, their detailed bioinformatics analysis is lacking. In this study, QSPs and non-QSPs were examined according to their amino acid composition, residues position, motifs and physicochemical properties. Compositional analysis concludes that QSPs are enriched with aromatic residues like Trp, Tyr and Phe. At the N-terminal, Ser was a dominant residue at maximum positions, namely, first, second, third and fifth while Phe was a preferred residue at first, third and fifth positions from the C-terminal. A few motifs from QSPs were also extracted. Physicochemical properties like aromaticity, molecular weight and secondary structure were found to be distinguishing features of QSPs. Exploiting above properties, we have developed a Support Vector Machine (SVM) based predictive model. During 10-fold cross-validation, SVM achieves maximum accuracy of 93.00%, Mathew's correlation coefficient (MCC) of 0.86 and Receiver operating characteristic (ROC) of 0.98 on the training/testing dataset (T200p+200n). Developed models performed equally well on the validation dataset (V20p+20n). The server also integrates several useful analysis tools like "QSMotifScan", "ProtFrag", "MutGen" and "PhysicoProp". Our analysis reveals important characteristics of QSPs and on the basis of these unique features, we have developed a prediction algorithm "QSPpred" (freely available at: http://crdd.osdd.net/servers/qsppred). PMID- 25781986 TI - High frequency of transmitted HIV-1 Gag HLA class I-driven immune escape variants but minimal immune selection over the first year of clade C infection. AB - In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses. PMID- 25781991 TI - Tfap2a promotes specification and maturation of neurons in the inner ear through modulation of Bmp, Fgf and notch signaling. AB - Neurons of the statoacoustic ganglion (SAG) transmit auditory and vestibular information from the inner ear to the hindbrain. SAG neuroblasts originate in the floor of the otic vesicle. New neuroblasts soon delaminate and migrate towards the hindbrain while continuing to proliferate, a phase known as transit amplification. SAG cells eventually come to rest between the ear and hindbrain before terminally differentiating. Regulation of these events is only partially understood. Fgf initiates neuroblast specification within the ear. Subsequently, Fgf secreted by mature SAG neurons exceeds a maximum threshold, serving to terminate specification and delay maturation of transit-amplifying cells. Notch signaling also limits SAG development, but how it is coordinated with Fgf is unknown. Here we show that transcription factor Tfap2a coordinates multiple signaling pathways to promote neurogenesis in the zebrafish inner ear. In both zebrafish and chick, Tfap2a is expressed in a ventrolateral domain of the otic vesicle that includes neurogenic precursors. Functional studies were conducted in zebrafish. Loss of Tfap2a elevated Fgf and Notch signaling, thereby inhibiting SAG specification and slowing maturation of transit-amplifying cells. Conversely, overexpression of Tfap2a inhibited Fgf and Notch signaling, leading to excess and accelerated SAG production. However, most SAG neurons produced by Tfap2a overexpression died soon after maturation. Directly blocking either Fgf or Notch caused less dramatic acceleration of SAG development without neuronal death, whereas blocking both pathways mimicked all observed effects of Tfap2a overexpression, including apoptosis of mature neurons. Analysis of genetic mosaics showed that Tfap2a acts non-autonomously to inhibit Fgf. This led to the discovery that Tfap2a activates expression of Bmp7a, which in turn inhibits both Fgf and Notch signaling. Blocking Bmp signaling reversed the effects of overexpressing Tfap2a. Together, these data support a model in which Tfap2a, acting through Bmp7a, modulates Fgf and Notch signaling to control the duration, amount and speed of SAG neural development. PMID- 25781992 TI - Adenovirus and herpesvirus diversity in free-ranging great apes in the Sangha region of the Republic Of Congo. AB - Infectious diseases have caused die-offs in both free-ranging gorillas and chimpanzees. Understanding pathogen diversity and disease ecology is therefore critical for conserving these endangered animals. To determine viral diversity in free-ranging, non-habituated gorillas and chimpanzees in the Republic of Congo, genetic testing was performed on great-ape fecal samples collected near Odzala Kokoua National Park. Samples were analyzed to determine ape species, identify individuals in the population, and to test for the presence of herpesviruses, adenoviruses, poxviruses, bocaviruses, flaviviruses, paramyxoviruses, coronaviruses, filoviruses, and simian immunodeficiency virus (SIV). We identified 19 DNA viruses representing two viral families, Herpesviridae and Adenoviridae, of which three herpesviruses had not been previously described. Co detections of multiple herpesviruses and/or adenoviruses were present in both gorillas and chimpanzees. Cytomegalovirus (CMV) and lymphocryptovirus (LCV) were found primarily in the context of co-association with each other and adenoviruses. Using viral discovery curves for herpesviruses and adenoviruses, the total viral richness in the sample population of gorillas and chimpanzees was estimated to be a minimum of 23 viruses, corresponding to a detection rate of 83%. These findings represent the first description of DNA viral diversity in feces from free-ranging gorillas and chimpanzees in or near the Odzala-Kokoua National Park and form a basis for understanding the types of viruses circulating among great apes in this region. PMID- 25781993 TI - A molecular analysis provides novel insights into androgen receptor signalling in breast cancer. AB - BACKGROUND: Androgen Receptor (AR) is an essential transcription factor for the development of secondary sex characteristics, spermatogenesis and carcinogenesis. Recently AR has been implicated in the development and progression of breast and prostate cancers. Although some of the functions of the AR are known but the mechanistic details of these divergent processes are still not clear. Therefore understanding the regulatory mechanisms of the functioning of the AR in ER-/AR+ breast cancer will provide many novel targets for the purpose of therapeutic intervention. METHODS/RESULTS: Using bioinformatics tools, we have identified 75 AR targets having prominent roles in cell cycle, apoptosis and metabolism. Herein, we validated 10 genes as AR targets by studying the regulation of these genes in MDA-MB-453 cell line on stimulation by androgens like 5alpha dihydrotestosterone (DHT), using RT-qPCR and ChIP assay. It was observed that all the identified genes involved in cell cycle except MAD1L1 were found to be up regulated whereas expression of apoptosis related genes was decreased in response to DHT treatment. We performed an exhaustive, rigid-body docking between individual ARE and DNA binding domain (DBD) of the AR protein and it was found that novel residues K567, K588, K591 and R592 are involved in the process of DNA binding. To verify these specific DNA-protein interactions electrostatic energy term calculations for each residue was determined using the linearized Poisson Boltzmann equation. Our experimental data showed that treatment of breast cancer cells with DHT promotes cell proliferation and decreases apoptosis. It was observed that bicalutamide treatment was able to reverse the effect of DHT. CONCLUSION: Taken together, our results provide new insights into the mechanism by which AR promotes breast cancer progression. Moreover our work proposes to use bicalutamide along with taxanes as novel therapy for the treatment of TNBCs, which are positive for downstream AR signalling. PMID- 25781994 TI - The influence of body mass index on outcomes in patients undergoing cardiac surgery: does the obesity paradox really exist? AB - PURPOSE: Obesity influences risk stratification in cardiac surgery in everyday practice. However, some studies have reported better outcomes in patients with a high body mass index (BMI): this is known as the obesity paradox. The aim of this study was to quantify the effect of diverse degrees of high BMI on clinical outcomes after cardiac surgery, and to assess the existence of an obesity paradox in our patients. METHODS: A total of 2,499 consecutive patients requiring all types of cardiac surgery with cardiopulmonary bypass between January 2004 and February 2009 were prospectively studied at our institution. Patients were divided into four groups based on BMI: normal weight (18.5-24.9 kg?m-2; n = 523; 21.4%), overweight (25-29.9 kg?m-2; n = 1150; 47%), obese (>= 30-<= 34.9 kg?m-2; n = 624; 25.5%) and morbidly obese (>= 35kg?m-2; n = 152; 6.2%). Follow-up was performed in 2,379 patients during the first year. RESULTS: After adjusting for confounding factors, patients with higher BMI presented worse oxygenation and better nutritional status, reflected by lower PaO2/FiO2 at 24h and higher albumin levels 48 h after admission respectively. Obese patients showed a higher risk for Perioperative Myocardial Infarction (OR: 1.768; 95% CI: 1.035-3.022; p = 0.037) and septicaemia (OR: 1.489; 95% CI: 1.282-1.997; p = 0.005). In-hospital mortality was 4.8% (n = 118) and 1-year mortality was 10.1% (n = 252). No differences were found regarding in-hospital mortality between BMI groups. The overweight group showed better 1-year survival than normal weight patients (91.2% vs. 87.6%; Log Rank: p = 0.029. HR: 1.496; 95% CI: 1.062-2.108; p = 0.021). CONCLUSIONS: In our population, obesity increases Perioperative Myocardial Infarction and septicaemia after cardiac surgery, but does not influence in hospital mortality. Although we found better 1-year survival in overweight patients, our results do not support any protective effect of obesity in patients undergoing cardiac surgery. PMID- 25781995 TI - Structure of the DNA duplex d(ATTAAT)2 with Hoogsteen hydrogen bonds. AB - The traditional Watson-Crick base pairs in DNA may occasionally adopt a Hoogsteen conformation, with a different organization of hydrogen bonds. Previous crystal structures have shown that the Hoogsteen conformation is favored in alternating AT sequences of DNA. Here we present new data for a different sequence, d(ATTAAT)2, which is also found in the Hoogsteen conformation. Thus we demonstrate that other all-AT sequences of DNA with a different sequence may be found in the Hoogsteen conformation. We conclude that any all-AT sequence might acquire this conformation under appropriate conditions. We also compare the detailed features of DNA in either the Hoogsteen or Watson-Crick conformations. PMID- 25781996 TI - Correction: Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery. PMID- 25781997 TI - Mass transport properties of the rabbit aortic wall. AB - Uptake of circulating macromolecules by the arterial wall may be a critical step in atherogenesis. Here we investigate the age-related changes in patterns of uptake that occur in the rabbit. In immature aortas, uptake was elevated in a triangle downstream of branch ostia, a region prone to disease in immature rabbits and children. By 16-22 months, uptake was high lateral to ostia, as is lesion prevalence in mature rabbits and young adults. In older rabbits there was a more upstream pattern, similar to the disease distribution in older people. These variations were predominantly caused by the branches themselves, rather than reflecting larger patterns within which the branches happened to be situated (as may occur with patterns of haemodynamic wall shear stress). The narrow streaks of high uptake reported in some previous studies were shown to be post mortem artefacts. Finally, heparin (which interferes with the NO pathway) had no effect on the difference in uptake between regions upstream and downstream of branches in immature rabbits but reversed the difference in older rabbits, as does inhibiting NO synthesis directly. Nevertheless, examination of uptake all around the branch showed that changes occurred at both ages and that they were quite subtle, potentially explaining why inhibiting NO has only minor effects on lesion patterns in mature rabbits and contradicting the earlier conclusion that mechanotransduction pathways change with age. We suggest that recently established changes in the patterns of haemodynamic forces themselves are more likely to account for the age-dependence of uptake patterns. PMID- 25781998 TI - Comparative transcriptome analysis of Anthurium "Albama" and its anthocyanin-loss mutant. AB - Anthurium is one of the most important tropical ornamental plants in the world. The traded value of anthurium is second only to that of tropical orchids among the tropical flowers. The spathe is the main ornamental organ and its color variation mainly arises from anthocyanin contents. Understanding the molecular regulation of spathe color will accelerate new variety creation of anthurium. To announce gene expression differences between Anthurium andraeanum 'Albama' and its one unique anthocyanin-loss mutant, we collected spathes of the wild-type and the mutant from two stages in spathe development (the flower separates protrude from the sheath and the spathe is fully expanded) and extracted total RNAs for transcriptome profiling. Using short read sequencing technology (Illumina), 51,955,564, 53,822,224, 54,221,990 and 52,276,418 sequencing raw reads, respectively, for wild-type and mutant in the two stages were assembled de novo into 111,268 unique sequences (unigenes) with a mean length of 652 bp. 47,563 unigenes had significant hits to the sequences in the Nr database, and 32,768 unigenes showed significant similarity to known proteins in the Swiss-Prot database. 28,350 and 19,293 unigenes had significant similarity to existing sequences in the KEGG and COG databases, respectively. Further, analysis of differentially expressed genes in the comparison between wild-type and mutant and between the two different developmental stages was carried out, indicating that the expression of an extensive set of genes changed as the result of mutation. Taken together, these data demonstrated that the Illumina sequencing allowed de novo transcriptome assembly and could obtain differentially expressed genes between A. andraeanum wild-type and the anthocyanin-loss mutant. The expression differences of AN2 and UFGT might cause the anthocyanin-loss mutation. PMID- 25781999 TI - The cost-effectiveness of biologics for the treatment of rheumatoid arthritis: a systematic review. AB - BACKGROUND AND OBJECTIVES: Economic evaluations provide information to aid the optimal utilization of limited healthcare resources. Costs of biologics for Rheumatoid arthritis (RA) are remarkably high, which makes these agents an important target for economic evaluations. This systematic review aims to identify existing studies examining the cost-effectiveness of biologics for RA, assess their quality and report their results systematically. METHODS: A literature search covering Medline, Scopus, Cochrane library, ACP Journal club and Web of Science was performed in March 2013. The cost-utility analyses (CUAs) of one or more available biological drugs for the treatment of RA in adults were included. Two independent investigators systematically collected information and assessed the quality of the studies. To enable the comparison of the results, all costs were converted to 2013 euro. RESULTS: Of the 4890 references found in the literature search, 41 CUAs were included in the current systematic review. While considering only direct costs, the incremental cost-effectiveness ratio (ICER) of the tumor necrosis factor inhibitors (TNFi) ranged from 39,000 to 1,273,000 ?/quality adjusted life year (QALY) gained in comparison to conventional disease modifying antirheumatic drugs (cDMARDs) in cDMARD naive patients. Among patients with an insufficient response to cDMARDs, biologics were associated with ICERs ranging from 12,000 to 708,000 ?/QALY. Rituximab was found to be the most cost effective alternative compared to other biologics among the patients with an insufficient response to TNFi. CONCLUSIONS: When 35,000 ?/QALY is considered as a threshold for the ICER, TNFis do not seem to be cost-effective among cDMARD naive patients and patients with an insufficient response to cDMARDs. With thresholds of 50,000 to 100,000 ?/QALY biologics might be cost-effective among patients with an inadequate response to cDMARDs. Standardization of multiattribute utility instruments and a validated standard conversion method for missing utility measures would enable better comparison between CUAs. PMID- 25782000 TI - Molecular identification of sibling species of Sclerodermus (Hymenoptera: Bethylidae) that parasitize buprestid and cerambycid beetles by using partial sequences of mitochondrial DNA cytochrome oxidase subunit 1 and 28S ribosomal RNA gene. AB - The species belonging to Sclerodermus (Hymenoptera: Bethylidae) are currently the most important insect natural enemies of wood borer pests, mainly buprestid and cerambycid beetles, in China. However, some sibling species of this genus are very difficult to distinguish because of their similar morphological features. To address this issue, we conducted phylogenetic and genetic analyses of cytochrome oxidase subunit I (COI) and 28S RNA gene sequences from eight species of Sclerodermus reared from different wood borer pests. The eight sibling species were as follows: S. guani Xiao et Wu, S. sichuanensis Xiao, S. pupariae Yang et Yao, and Sclerodermus spp. (Nos. 1-5). A 594-bp fragment of COI and 750-bp fragment of 28S were subsequently sequenced. For COI, the G-C content was found to be low in all the species, averaging to about 30.0%. Sequence divergences (Kimura-2-parameter distances) between congeneric species averaged to 4.5%, and intraspecific divergences averaged to about 0.09%. Further, the maximum sequence divergences between congeneric species and Sclerodermus sp. (No. 5) averaged to about 16.5%. All 136 samples analyzed were included in six reciprocally monophyletic clades in the COI neighbor-joining (NJ) tree. The NJ tree inferred from the 28S rRNA sequence yielded almost identical results, but the samples from S. guani, S. sichuanensis, S. pupariae, and Sclerodermus spp. (Nos. 1-4) clustered together and only Sclerodermus sp. (No. 5) clustered separately. Our findings indicate that the standard barcode region of COI can be efficiently used to distinguish morphologically similar Sclerodermus species. Further, we speculate that Sclerodermus sp. (No. 5) might be a new species of Sclerodermus. PMID- 25782001 TI - Effect of oral glucose administration on rebound growth hormone release in normal and obese women: the role of adiposity, insulin sensitivity and ghrelin. AB - CONTEXT: Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue. OBJECTIVE: The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity. PARTICIPANTS AND METHODS: We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed. RESULTS: The AUC of GH (MUg/L*min) was lower in obese (249.8+/-41.8) than in healthy women (490.4+/-74.6), P=0.001. The AUC of total ghrelin (pg/mL*min) was lower in obese (240995.5+/-11094.2) than in healthy women (340797.5+/-37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH. PMID- 25782002 TI - Apelin-13 enhances arcuate POMC neuron activity via inhibiting M-current. AB - The hypothalamus is a key element of the neural circuits that control energy homeostasis. Specific neuronal populations within the hypothalamus are sensitive to a variety of homeostatic indicators such as circulating nutrient levels and hormones that signal circulating glucose and body fat content. Central injection of apelin secreted by adipose tissues regulates feeding and glucose homeostasis. However, the precise neuronal populations and cellular mechanisms involved in these physiological processes remain unclear. Here we examine the electrophysiological impact of apelin-13 on proopiomelanocortin (POMC) neuron activity. Approximately half of POMC neurons examined respond to apelin-13. Apelin-13 causes a dose-dependent depolarization. This effect is abolished by the apelin (APJ) receptor antagonist. POMC neurons from animals pre-treated with pertussis toxin still respond to apelin, whereas the Gbetagamma signaling inhibitor gallein blocks apelin-mediated depolarization. In addition, the effect of apelin is inhibited by the phospholipase C and protein kinase inhibitors. Furthermore, single-cell qPCR analysis shows that POMC neurons express the APJ receptor, PLC-beta isoforms, and KCNQ subunits (2, 3 and 5) which contribute to M type current. Apelin-13 inhibits M-current that is blocked by the KCNQ channel inhibitor. Therefore, our present data indicate that apelin activates APJ receptors, and the resultant dissociation of the Galphaq heterotrimer triggers a Gbetagamma-dependent activation of PLC-beta signaling that inhibits M-current. PMID- 25782003 TI - Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme. AB - The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA) in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme. PMID- 25782004 TI - Age-Related Decline in Brain and Hepatic Clearance of Amyloid-Beta is Rectified by the Cholinesterase Inhibitors Donepezil and Rivastigmine in Rats. AB - In Alzheimer's disease (AD), accumulation of brain amyloid-beta (Abeta) depends on imbalance between production and clearance of Abeta. Several pathways for Abeta clearance have been reported including transport across the blood-brain barrier (BBB) and hepatic clearance. The incidence of AD increases with age and failure of Abeta clearance correlates with AD. The cholinesterase inhibitors (ChEIs) donepezil and rivastigmine are used to ease the symptoms of dementia associated with AD. Besides, both drugs have been reported to provide neuroprotective and disease-modifying effects. Here, we investigated the effect of ChEIs on age-related reduced Abeta clearance. Findings from in vitro and in vivo studies demonstrated donepezil and rivastigmine to enhance (125)I-Abeta40 clearance. Also, the increase in brain and hepatic clearance of (125)I-Abeta40 was more pronounced in aged compared to young rats, and was associated with significant reduction in brain Abeta endogenous levels determined by ELISA. Furthermore, the enhanced clearance was concomitant with up-regulation in the expression of Abeta major transport proteins P-glycoprotein and LRP1. Collectively, our findings that donepezil and rivastigmine enhance Abeta clearance across the BBB and liver are novel and introduce an additional mechanism by which both drugs could affect AD pathology. Thus, optimizing their clinical use could help future drug development by providing new drug targets and possible mechanisms involved in AD pathology. PMID- 25782005 TI - Sleep duration and quality among different occupations--China national study. AB - OBJECTIVE: To examine the associations between occupation, sleep duration and sleep quality. METHODS: The data for this study was extracted from data collected from the 2008 Chinese Sub-optimal Health Study. Our study sample consisted of 18,316 Chinese subjects aged 18-65. Occupation and other relevant characteristics to sleep were collected. We used the Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality and multiple logistic regression models to examine the association of occupation with shortened sleep duration and poor sleep quality. RESULTS: Farmers had the longest sleep duration (mean=8.22 hours) while the civil servants had the shortest sleep duration (mean=7.85 hours). Farmers also had the best sleep quality (mean score=3.74) while professional workers had the worst sleep quality (mean score=4.87). Compared to civil servants, the OR of shortened sleep duration and poor sleep quality for blue collar workers is 1.39 (95%CI: 1.11-1.73) and 1.28 (95%-CI: 1.15-1.42), respectively, after adjusting for age, sex, marital status, education, area, smoking, drinking, pain, and health status. CONCLUSION: sleep duration and quality varied among different Chinese occupation populations. The blue collar workers are more likely to have shortened sleep duration and poor sleep quality. PMID- 25782007 TI - The place of targeted agents in the treatment of elderly patients with metastatic colorectal cancer. AB - Despite the high prevalence of colorectal cancer in a continuously aging population and the substantial advances in the treatment of metastatic disease during the past decade, the treatment of elderly patients with advanced, unresectable or metastatic colorectal cancer is a clearly unmet need. Since older patients are under-represented or even excluded from randomized trials, the evidence that oncologists use as guidance is weak. However, small prospective studies, pooled analyses and observational studies show that combination approaches are safe, efficacious and feasible in the geriatric population with metastatic colorectal cancer. The use of biologic agents targeting angiogenesis and the epidermal growth factor receptor, which have been shown to clearly improve outcomes in multiple prospective trials in patients with advanced colorectal cancer, is a vital component of the aforementioned combination approaches. Herein, we review all available data concerning the management of elderly patients with these agents and underscore the differences between this age subgroup and younger patients. PMID- 25782008 TI - Variability assessment of (15)N metabolic labeling-based proteomics workflow in mouse plasma and brain. AB - (15)N metabolic labeling-based quantitative proteomics is used for the identification of disease- and phenotype-related alterations in live organisms. The variability of (15)N metabolic labeling proteomics workflows has been assessed in plants and bacteria. However, no study has addressed this topic in mice. We have investigated the repeatability of a quantitative in vivo(15)N metabolic labeling proteomics workflow in mice by assessing LC variability, peptide and protein profiling characteristics and overall (15)N/(14)N protein quantification accuracy in technical replicates of plasma and brain specimens. We furthermore examined how sample preparation affects these parameters in plasma and brain. We found that specimen type (i.e. plasma or brain) influences the variability of the (15)N metabolic labeling workflow in an LC-independent manner. PMID- 25782009 TI - Characterization and biological activity of Taishan Pinus massoniana pollen polysaccharide in vitro. AB - Taishan Pinus massoniana pollen polysaccharide (TPPPS) improves cellular and humoral immune responses of animals and is a novel potential immunomodulator. However, the components of TPPPS have not been recognized. To investigate the composition of TPPPS, crude polysaccharide was obtained from Taishan P. massoniana pollen through water extraction and ethanol precipitation. Three homogeneous polysaccharide fractions (TPPPS1, TPPPS2, and TPPPS3) were purified from TPPPS by DEAE-cellulose column chromatography. The average molecular weights of the three polysaccharides were 56, 25, and 128 kDa, respectively. Results of high-performance liquid chromatography (HPLC) showed that TPPPS comprised mannose, ribose, xylose, glucuronic acid, galacturonic acid, glucose, galactose, and arabinose. The biological activity assays showed that TPPPS2 and TPPPS3 significantly promoted spleen lymphocyte proliferation, and that TPPPS3 showed better effect than TPPPS2. TPPPS3 enhanced the secretion of cytokine IL-2 and TNF, whereas TPPPS2 mainly elevated IL-2 secretion. By contrast, TPPPS1 exhibited other effects, and it induced the highest amount of NO production, thereby indicating that TPPPS1 had the best antioxidant activity. TPPPS3 at 50 MUg/mL significantly inhibited the proliferation of subgroup B Avian Leukosis virus (ALV B) through virus adsorption interference in vitro. Results indicated that TPPPS comprised three main components, among which, TPPPS1 mainly showed antioxidant effects, whereas TPPPS2 and TPPPS3 played key roles in immunomodulation, especially TPPPS3. Further studies on the use of a reasonable proportion of TPPPS1-3 may facilitate the development of an effective immunomodulator. PMID- 25782006 TI - Evidence for ubiquitin-regulated nuclear and subnuclear trafficking among Paramyxovirinae matrix proteins. AB - The paramyxovirus matrix (M) protein is a molecular scaffold required for viral morphogenesis and budding at the plasma membrane. Transient nuclear residence of some M proteins hints at non-structural roles. However, little is known regarding the mechanisms that regulate the nuclear sojourn. Previously, we found that the nuclear-cytoplasmic trafficking of Nipah virus M (NiV-M) is a prerequisite for budding, and is regulated by a bipartite nuclear localization signal (NLSbp), a leucine-rich nuclear export signal (NES), and monoubiquitination of the K258 residue within the NLSbp itself (NLSbp-lysine). To define whether the sequence determinants of nuclear trafficking identified in NiV-M are common among other Paramyxovirinae M proteins, we generated the homologous NES and NLSbp-lysine mutations in M proteins from the five major Paramyxovirinae genera. Using quantitative 3D confocal microscopy, we determined that the NES and NLSbp-lysine are required for the efficient nuclear export of the M proteins of Nipah virus, Hendra virus, Sendai virus, and Mumps virus. Pharmacological depletion of free ubiquitin or mutation of the conserved NLSbp-lysine to an arginine, which inhibits M ubiquitination, also results in nuclear and nucleolar retention of these M proteins. Recombinant Sendai virus (rSeV-eGFP) bearing the NES or NLSbp lysine M mutants rescued at similar efficiencies to wild type. However, foci of cells expressing the M mutants displayed marked fusogenicity in contrast to wild type, and infection did not spread. Recombinant Mumps virus (rMuV-eGFP) bearing the homologous mutations showed similar defects in viral morphogenesis. Finally, shotgun proteomics experiments indicated that the interactomes of Paramyxovirinae M proteins are significantly enriched for components of the nuclear pore complex, nuclear transport receptors, and nucleolar proteins. We then synthesize our functional and proteomics data to propose a working model for the ubiquitin regulated nuclear-cytoplasmic trafficking of cognate paramyxovirus M proteins that show a consistent nuclear trafficking phenotype. PMID- 25782010 TI - A novel mouse model for stable engraftment of a human immune system and human hepatocytes. AB - Hepatic infections by hepatitis B virus (HBV), hepatitis C virus (HCV) and Plasmodium parasites leading to acute or chronic diseases constitute a global health challenge. The species tropism of these hepatotropic pathogens is restricted to chimpanzees and humans, thus model systems to study their pathological mechanisms are severely limited. Although these pathogens infect hepatocytes, disease pathology is intimately related to the degree and quality of the immune response. As a first step to decipher the immune response to infected hepatocytes, we developed an animal model harboring both a human immune system (HIS) and human hepatocytes (HUHEP) in BALB/c Rag2-/- IL-2Rgammac-/- NOD.sirpa uPAtg/tg mice. The extent and kinetics of human hepatocyte engraftment were similar between HUHEP and HIS-HUHEP mice. Transplanted human hepatocytes were polarized and mature in vivo, resulting in 20-50% liver chimerism in these models. Human myeloid and lymphoid cell lineages developed at similar frequencies in HIS and HIS-HUHEP mice, and splenic and hepatic compartments were humanized with mature B cells, NK cells and naive T cells, as well as monocytes and dendritic cells. Taken together, these results demonstrate that HIS-HUHEP mice can be stably (> 5 months) and robustly engrafted with a humanized immune system and chimeric human liver. This novel HIS-HUHEP model provides a platform to investigate human immune responses against hepatotropic pathogens and to test novel drug strategies or vaccine candidates. PMID- 25782011 TI - A response regulator from a soil metagenome enhances resistance to the beta lactam antibiotic carbenicillin in Escherichia coli. AB - Functional metagenomic analysis of soil metagenomes is a method for uncovering as yet unidentified mechanisms for antibiotic resistance. Here we report an unconventional mode by which a response regulator derived from a soil metagenome confers resistance to the beta-lactam antibiotic carbenicillin in Escherichia coli. A recombinant clone (betalr16) harboring a 5,169 bp DNA insert was selected from a metagenomic library previously constructed from a remote Alaskan soil. The betalr16 clone conferred specific resistance to carbenicillin, with limited increases in resistance to other tested antibiotics, including other beta-lactams (penicillins and cephalosporins), rifampin, ciprofloxacin, erythromycin, chloramphenicol, nalidixic acid, fusidic acid, and gentamicin. Resistance was more pronounced at 24 degrees C than at 37 degrees C. Zone-of-inhibition assays suggested that the mechanism of carbenicillin resistance was not due to antibiotic inactivation. The DNA insert did not encode any genes known to confer antibiotic resistance, but did have two putative open reading frames (ORFs) that were annotated as a metallopeptidase and a two-component response regulator. Transposon mutagenesis and subcloning of the two ORFs followed by phenotypic assays showed that the response regulator gene was necessary and sufficient to confer the resistance phenotype. Quantitative reverse transcriptase PCR showed that the response regulator suppressed expression of the ompF porin gene, independently of the small RNA regulator micF, and enhanced expression of the acrD, mdtA, and mdtB efflux pump genes. This work demonstrates that antibiotic resistance can be achieved by the modulation of gene regulation by heterologous DNA. Functional analyses such as these can be important for making discoveries in antibiotic resistance gene biology and ecology. PMID- 25782012 TI - Intermittent Pringle maneuver is unlikely to induce bacterial translocation to the portal vein: a study using bacterium-specific ribosomal RNA-targeted reverse transcription-polymerase chain reaction. AB - BACKGROUND: The occurrence of bacterial translocation (BT) to the mesenteric lymph nodes following the Pringle maneuver is well established; however, the incidence of BT to the portal circulation remains unclear. METHODS: Portal blood of patients with suspected hilar malignancy who underwent major hepatobiliary resection with cholangiojejunostomy was sampled three times during surgery: immediately after laparotomy (PV-1); before liver transection and after skeletonization of the hepatoduodenal ligament (PV-2); and after completion of the liver transection (PV-3). The samples were analyzed for microbes with a bacterium-specific ribosomal RNA-targeted reverse transcription-polymerase chain reaction method. RESULTS: Fifty patients were enrolled in the study, with a mean total Pringle time of 86 min. Microbes in the portal blood were detected in 11 (22%) of the 50 patients. The occurrence of microbes was not different among the PV-1 samples (8% = 4/50), PV-2 samples (14% = 7/50), and PV-3 samples (14% = 7/50) (P = 0.567). Obligate anaerobes were predominantly detected. The positivity of the PV-3 samples showed no correlation with the total Pringle time or with the occurrence of postoperative infectious complications. The total Pringle time did not affect the surgical outcomes, including infectious complications, liver failure, or mortality. The concentrations of aspartate aminotransferase and alanine aminotransferase on postoperative day 1 significantly correlated with the total Pringle time. CONCLUSIONS: The intermittent Pringle maneuver is unlikely to induce BT to the portal circulation and is safe, even in difficult, complicated hepatobiliary resections requiring long clamping times. PMID- 25782013 TI - Correction: An electric-field induced dynamical state in dispersions of charged colloidal rods. PMID- 25782015 TI - A 10-year retrospective study of interhospital patient transport using inhaled nitric oxide in Norway. AB - BACKGROUND: Anaesthesiologists from Oslo University Hospital have transported patients with severe oxygenation failure with inhaled nitric oxide (usually 20 ppm) from other hospitals to a tertiary care centre since 2002 in an effort to reduce the number of patients that otherwise would require transport with ongoing extracorporeal membrane oxygenation. The aim of this study was to evaluate the patient safety during transport with inhaled nitric oxide. METHODS: All patient transports with ongoing nitric oxide treatment undertaken from 2003 to 2012 were identified in the transport database. The frequency of adverse events and their impact on patient safety were studied in addition to response to inhaled nitric oxide and adjusted intensive care treatment and time aspects of the transports. Information about in-hospital treatment and survival were extracted from the hospital patient records. RESULTS: Adverse events were recorded in 12 of the 104 transports. Seven of the adverse events were due to malfunctioning technical equipment, three were related to medication other than the inhaled nitric oxide and two were related to ventilation. No adverse events resulted in permanent negative patient consequences or in discontinuation of the transport. Out of 104 patients, 79 responded to treatment with inhaled nitric oxide and other treatment changes by an increase in oxygen saturation of more than 5%. The 30-day mortality was 27% in the group transported with inhaled nitric oxide. CONCLUSION: Transporting patients on inhaled nitric oxide is an alternative in selected patients who would otherwise require extracorporeal membrane oxygenation during transport. PMID- 25782017 TI - Effects of local testicular heat treatment on Leydig cell hyperplasia and testosterone biosynthesis in rat testes. AB - Cryptorchidism or local testicular heat treatment induces reversible oligospermia or azoospermia in rodents and humans via increased germ cell apoptosis. Research in this field has concentrated on the impact of heat on spermatogenesis, with rather little attention paid to the molecular effects of heat treatment on Leydig cell function. In the present study, we investigated the effects of exposure to heat stress on the proliferative activity and testosterone biosynthesis of Leydig cells. We subjected adult rats to a single local testicular heat treatment of water at 43 degrees C for 30min. The expression of Leydig cell-specific markers, such as cholesterol side-chain cleavage (P450SCC) and 3?-hydroxysteroid dehydrogenase, was evaluated by immunohistochemistry and western blot analysis. The proliferative activity of Leydig cells was detected by immunostaining with proliferation-associated markers, including Ki67, bromodeoxyuridine and phosphohistone-H3 (pHH3). The mRNA and protein levels of cell cycle proteins and testosterone synthesis-related enzymes were measured by real-time polymerase chain reaction and western blot analysis, respectively. The testes of heat treated rats contained 50% more Leydig cells than those of control rats, indicating induction of Leydig cell hyperplasia by testicular heat treatment. Increased proliferative activity in Leydig cells, evidenced by enhanced expression of cell cycle proteins, was the main cause of Leydig cell hyperplasia. In addition, heat treatment reduced serum and testicular testosterone concentrations. Consistent with this finding, heat stress downregulated two enzymes required for testosterone biosynthesis, namely cytochrome P450, family 17 (CYP17) and steroidogenic acute regulatory protein, in Leydig cells. Together, the results suggest that testicular heat leads to Leydig cell hyperplasia and a reduction in testosterone biosynthesis in adult rat testes. PMID- 25782016 TI - Controlled aggregation of primary human pancreatic islet cells leads to glucose responsive pseudoislets comparable to native islets. AB - Clinical islet transplantation is a promising treatment for patients with type 1 diabetes. However, pancreatic islets vary in size and shape affecting their survival and function after transplantation because of mass transport limitations. To reduce diffusion restrictions and improve islet cell survival, the generation of islets with optimal dimensions by dispersion followed by reassembly of islet cells, can help limit the length of diffusion pathways. This study describes a microwell platform that supports the controlled and reproducible production of three-dimensional pancreatic cell clusters of human donor islets. We observed that primary human islet cell aggregates with a diameter of 100-150 MUm consisting of about 1000 cells best resembled intact pancreatic islets as they showed low apoptotic cell death (<2%), comparable glucose-responsiveness and increasing PDX1, MAFA and INSULIN gene expression with increasing aggregate size. The re-associated human islet cells showed an a typical core shell configuration with beta cells predominantly on the outside unlike human islets, which became more randomized after implantation similar to native human islets. After transplantation of these islet cell aggregates under the kidney capsule of immunodeficient mice, human C-peptide was detected in the serum indicating that beta cells retained their endocrine function similar to human islets. The agarose microwell platform was shown to be an easy and very reproducible method to aggregate pancreatic islet cells with high accuracy providing a reliable tool to study cell-cell interactions between insuloma and/or primary islet cells. PMID- 25782018 TI - Optimising the application of multiple-capture traps for invasive species management using spatial simulation. AB - Internationally, invasive vertebrate species pose a significant threat to biodiversity, agricultural production and human health. To manage these species a wide range of tools, including traps, are used. In New Zealand, brushtail possums (Trichosurus vulpecula), stoats (Mustela ermine), and ship rats (Rattus rattus) are invasive and there is an ongoing demand for cost-effective non-toxic methods for controlling these pests. Recently, traps with multiple-capture capability have been developed which, because they do not require regular operator-checking, are purported to be more cost-effective than traditional single-capture traps. However, when pest populations are being maintained at low densities (as is typical of orchestrated pest management programmes) it remains uncertain if it is more cost-effective to use fewer multiple-capture traps or more single-capture traps. To address this uncertainty, we used an individual-based spatially explicit modelling approach to determine the likely maximum animal-captures per trap, given stated pest densities and defined times traps are left between checks. In the simulation, single- or multiple-capture traps were spaced according to best practice pest-control guidelines. For possums with maintenance densities set at the lowest level (i.e. 0.5/ha), 98% of all simulated possums were captured with only a single capacity trap set at each site. When possum density was increased to moderate levels of 3/ha, having a capacity of three captures per trap caught 97% of all simulated possums. Results were similar for stoats, although only two potential captures per site were sufficient to capture 99% of simulated stoats. For rats, which were simulated at their typically higher densities, even a six-capture capacity per trap site only resulted in 80% kill. Depending on target species, prevailing density and extent of immigration, the most cost-effective strategy for pest control in New Zealand might be to deploy several single-capture traps rather than investing in fewer, but more expense, multiple-capture traps. PMID- 25782019 TI - Uptake of rabies control measures by dog owners in Flores Island, Indonesia. AB - BACKGROUND: Rabies has been a serious public health threat in Flores Island, Indonesia since it was introduced in 1997. To control the disease, annual dog vaccination campaigns have been implemented to vaccinate all dogs free of charge. Nevertheless, the uptake rate of the vaccination campaigns has been low. The objective of this paper is to identify risk factors associated with the uptake of rabies control measures by individual dog owners in Flores Island. METHODOLOGY/PRINCIPAL FINDINGS: A total of 450 dog owners from 44 randomly selected villages in the Sikka and Manggarai regencies were interviewed regarding their socio-demographic factors, knowledge of rabies, and their uptake of rabies control measures. The majority of dog owners surveyed (>90%) knew that rabies is a fatal disease and that it can be prevented. Moreover, 68% of the dog owners had a high level of knowledge about available rabies control measures. Fifty-two percent of the dog owners had had at least one of their dogs vaccinated during the 2012 vaccination campaign. Vaccination uptake was significantly higher for dog owners who resided in Sikka, kept female dogs for breeding, had an income of more than one million Rupiah, and had easy access to their village. The most important reasons not to join the vaccination campaign were lack of information about the vaccination campaign schedule (40%) and difficulty to catch the dog during the vaccination campaign (37%). CONCLUSIONS/SIGNIFICANCE: Dog owners in Flores Island had a high level of knowledge of rabies and its control, but this was not associated with uptake of the 2012 vaccination campaign. Geographical accessibility was one of the important factors influencing the vaccination uptake among dog owners. Targeted distribution of information on vaccination schedules and methods to catch and restrain dogs in those villages with poor accessibility may increase vaccination uptake in the future. PMID- 25782020 TI - Pulse steroid therapy in idiopathic sudden sensorineural hearing loss: A randomized controlled clinical trial. AB - OBJECTIVES/HYPOTHESIS: To evaluate in patients with idiopathic sensorineural hearing loss whether pulse therapy with methylprednisolone leads to better recovery of hearing than traditional oral prednisolone therapy. STUDY DESIGN: Randomized controlled trial. METHODS: Sixty-seven patients diagnosed with idiopathic sensorineural hearing loss were randomly divided into two groups based on therapy. The study group received 500-mg daily intravenous methylprednisolone for 3 consecutive days, followed by 1 mg/kg (maximum 60 mg) oral prednisolone for 11 days (total treatment: 14 days). The control group received 1 mg/kg (maximum 60 mg) oral prednisolone for 14 days. Hearing change was evaluated by comparing initial hearing tests and the third-month hearing tests in three ways: 1) pure tone improvement in each individual tone (0.5, 1, 2, 3, and 4 kHz); 2) word recognition score improvement; and 3) complete, partial, and no recovery of hearing calculated (as defined by American Academy of Otolaryngology-Head and Neck Surgery Clinical Practice Guidelines). RESULTS: Sixty of 67 patients, 29 of 34 patients in the study group and 31 of 33 patients in the control group, completed the study. Frequency-specific hearing improvement did not differ significantly among the groups. Word-recognition score improvement was 20.34% +/- 27.35% for the study group and 13.41% +/- 23.48% for the control group, which had no statistically significant difference. There was also no significant difference in hearing recovery rates for the two groups. CONCLUSION: Pulse therapy with methylprednisolone and traditional oral prednisolone therapy resulted in similar hearing improvement. PMID- 25782021 TI - Development of a Bronchial Wall Model: Triple Culture on a Decellularized Porcine Trachea. AB - In vitro coculture models mimicking the bronchial barrier are a significant step forward in investigating the behavior and function of the upper respiratory tract mucosa. To date, mostly synthetic materials have been used as substrates to culture the cells. However, decellularized tissues provide a more in vivo-like environment based on the native extracellular matrix. In this study, an in vitro, bronchial wall coculture model has been established using a decellularized, porcine luminal trachea membrane and employing three relevant human cell types. The tissue was decellularized and placed in plastic transwell supports. The human bronchial epithelial cell line, 16HBE14o-, was seeded on the apical side of the membrane with the human lung fibroblast cell line, Wi-38, and/or the microvascular endothelial cell line, ISO-HAS-1, seeded on the basolateral side. Transepithelial electrical resistance (TER) was measured over 10 days and tight/adherens junctions (ZO-1, occludin/beta-catenin) were studied through immunofluorescence. Scanning electron microscopy (SEM) was performed to evaluate microvilli and cilia formation. All cultures grew successfully on the membrane. TER values of 555 Omega.cm(2) (+/-21, SEM) were achieved in the monoculture. Cocultures with fibroblasts reached 565 Omega.cm(2) (+/-41, SEM), with endothelial cells at 638 Omega.cm(2) (+/-37, SEM), and the triple culture achieved 552 Omega.cm(2) (+/-38, SEM). ZO-1, occludin, and beta-catenin were expressed in 16HBE14o- under all culture conditions. Using SEM, a dense microvilli population was found. Prominent cell-cell contacts and clusters of emerging cilia could be identified. Fibroblasts and endothelial cells strengthened the formation of a tight barrier by the 16HBE14o-. Thus, the coculture of three relevant cell types in combination with native decellularized scaffolds as a substrate approaches more closely the in vivo situation and could be used to study mechanisms of upper respiratory damage and regeneration. PMID- 25782022 TI - Fish community reassembly after a coral mass mortality: higher trophic groups are subject to increased rates of extinction. AB - Since Gleason and Clements, our understanding of community dynamics has been influenced by theories emphasising either dispersal or niche assembly as central to community structuring. Determining the relative importance of these processes in structuring real-world communities remains a challenge. We tracked reef fish community reassembly after a catastrophic coral mortality in a relatively unfished archipelago. We revisited the stochastic model underlying MacArthur and Wilson's Island Biogeography Theory, with a simple extension to account for trophic identity. Colonisation and extinction rates calculated from decadal presence-absence data based on (1) species neutrality, (2) trophic identity and (3) site-specificity were used to model post-disturbance reassembly, and compared with empirical observations. Results indicate that species neutrality holds within trophic guilds, and trophic identity significantly increases overall model performance. Strikingly, extinction rates increased clearly with trophic position, indicating that fish communities may be inherently susceptible to trophic downgrading even without targeted fishing of top predators. PMID- 25782023 TI - Walking Distance as a Predictor of Falls in People With Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: People with multiple sclerosis (PwMS) experience falls, usually when walking and transferring. The aim was to investigate if walking distance and patient overestimate of walking distance are predictors of falls in PwMS. METHODS: A prospective study was conducted, with a single test occasion followed by prospective registration of falls for 3 months. All PwMS in Region Orebro County with a previously registered Expanded Disability Status Scale score between 3.0 and 7.0 in the Swedish MS Registry were invited to participate (n = 149). Altogether, data from 49 PwMS being relapse free for at least 3 months and with a confirmed Expanded Disability Status Scale between 1.5 and 7.0 upon study entry were analysed. RESULTS: Twenty-two PwMS (45%) fell during the study period, providing information of 66 falls. Walking distance or overestimate of one's walking distance, as compared with test results, did not predict falls in this MS sample. DISCUSSION: Walking and standing activities are associated with numerous falls in PwMS. Our data do not clearly support routine measurements of walking distance in assessing individual fall risk. (c) 2015 The Authors. Physiotherapy Research International published by John Wiley & Sons, Ltd. PMID- 25782024 TI - Screening of French groundwater for regulated and emerging contaminants. AB - Nationwide screening of 411 emerging contaminants and other regulated compounds, including parent molecules and transformation products (TPs) having various uses and origins, was done at 494 groundwater sites throughout France during two sampling campaigns in the Spring and the Fall of 2011. One hundred and eighty substances (44% of the targeted compounds) were quantified in at least one sampling point. These included pharmaceuticals, industrial products, pesticides, their transformation products and other emerging compounds. Fifty-five compounds were quantified in more than 1% of the samples. Both regulated and emerging compounds were found. Among the unregulated compounds, acetaminophen, carbamazepine, perfluorinated compounds, dioxins/furans, tolyltriazole, bisphenol A, triazine transformation products, and caffeine were quantified in more than 10% of the samples analyzed. Concentrations exceeding the threshold of toxicological concern of 0.1 MUg/L were found for tolyltriazole, bisphenol A and some of the triazine transformation products (DEDIA). These new results should help the water resource managers and environmental regulators develop sound policies regarding the occurrence and distribution of regulated and emerging contaminants in groundwater. PMID- 25782025 TI - Nephrotoxic contaminants in drinking water and urine, and chronic kidney disease in rural Sri Lanka. AB - Chronic kidney disease of unknown ("u") cause (CKDu) is a growing public health concern in Sri Lanka. Prior research has hypothesized a link with drinking water quality, but rigorous studies are lacking. This study assesses the relationship between nephrotoxic elements (namely arsenic (As), cadmium (Cd), lead (Pb), and uranium (U)) in drinking water, and urine samples collected from individuals with and/or without CKDu in endemic areas, and from individuals without CKDu in nonendemic areas. All water samples - from a variety of source types (i.e. shallow and deep wells, springs, piped and surface water) - contained extremely low concentrations of nephrotoxic elements, and all were well below drinking water guideline values. Concentrations in individual urine samples were higher than, and uncorrelated with, those measured in drinking water, suggesting potential exposure from other sources. Mean urinary concentrations of these elements for individuals with clinically diagnosed CKDu were consistently lower than individuals without CKDu both in endemic and nonendemic areas. This likely stems from the inability of the kidney to excrete these toxic elements via urine in CKDu patients. Urinary concentrations of individuals were also found to be within the range of reference values measured in urine of healthy unexposed individuals from international biomonitoring studies, though these reference levels may not be safe for the Sri Lankan population. The results suggest that CKDu cannot be clearly linked with the presence of these contaminants in drinking water. There remains a need to investigate potential interactions of low doses of these elements (particularly Cd and As) with other risk factors that appear linked to CKDu, prior to developing public health strategies to address this illness. PMID- 25782026 TI - Evaluation of diffusion coefficient of thiocholine in enzyme-loaded polypyrrole composite film through different methods and electrode polarization. AB - In this work, the diffusion of thiocholine ion into an enzyme-loaded polypyrrole film was evaluated by different methods, and the results were compared to identify the most suitable method. The enzyme-loaded polypyrrole film was coated with a thin layer of gelatin and gluteraldehyde so as to prevent enzyme leaching. Diffusion coefficients under normal and prepolarized conditions were calculated by five different methods, namely, the Cottrell method, the method of Peerce and Bard, the theoretical impedance model, the electrochemically stimulated conformational relaxation (ESCR) method, and the direct impedance measurement method. The theoretical model of Vortynstev was used to calculate the parameters from the impedance spectra using simplex technique in MATLAB. The results indicate that under normal unpolarized condition the ESCR method gives a diffusion coefficient close to that given by Vortynstev method, but under polarized conditions the Cottrell method can provide a better value of diffusion coefficient than ESCR. The diffusion coefficient of thiocholine in PPy composite film from an electrolytic background of phosphate buffer of pH 7.4 was found to be 1.00 * 10(-8) cm(2) s(-1) based on Vortynstev method. The mechanism of thiocholine diffusion into the positively charged/polarized matrix is attributed to be through the formation of a dinegative ion between thiocholine and phosphate anion via electrostatic attraction. PMID- 25782028 TI - Simple approach to superhydrophobic nanostructured Al for practical antifrosting application based on enhanced self-propelled jumping droplets. AB - Frost formation can cause operational difficulty and efficiency loss for many facilities such as aircraft, wind turbines, and outdoor heat exchangers. Self propelled jumping by condensate droplets on superhydrophobic surfaces delays frost formation, so many attempts have been made to exploit this phenomenon. However, practical application of this phenomenon is currently unfeasible because many processes to fabricate the superhydrophobic surfaces are inefficient and because self-propelled jumping is difficult to be achieved in a humid and low temperature environment because superhydrophobicity is degraded in these conditions. Here, we achieved significantly effective anti-icing superhydrophobic aluminum. Its extremely low adhesive properties allow self-propelled jumping under highly supersaturated conditions of high humidity or low surface temperature. As a result, this surface helps retard frost formation at that condition. The aluminum was made superhydrophobic by a simple and cost-effective process that is adaptable to any shape. Therefore, it has promise for use in practical and industrial applications. PMID- 25782030 TI - Viral pathogen production in a wild grass host driven by host growth and soil nitrogen. AB - Nutrient limitation is a basic ecological constraint that has received little attention in studies on virus production and disease dynamics. Nutrient availability could directly limit the production of viral nucleic acids and proteins, or alternatively limit host growth and thus indirectly limit metabolic pathways necessary for viral replication. In order to compare direct and indirect effects of nutrient limitation on virus production within hosts, we manipulated soil nitrogen (N) and phosphorus (P) availability in a glasshouse for the wild grass host Bromus hordeaceus and the viral pathogen Barley yellow dwarf virus PAV. We found that soil N additions increased viral concentrations within host tissues, and the effect was mediated by host growth. Specifically, in statistical models evaluating the roles of host biomass production, leaf N and leaf P, viral production depended most strongly on host biomass, rather than the concentration of either nutrient. Furthermore, at low soil N, larger plants supported greater viral concentrations than smaller ones, whereas at high N, smaller plants supported greater viral concentrations. Our results suggest that enhanced viral productivity under N enrichment is an indirect consequence of nutrient stimulation to host growth rate. Heightened pathogen production in plants has important implications for a world facing increasing rates of nutrient deposition. PMID- 25782027 TI - Surgical salvage improves overall survival for patients with HPV-positive and HPV negative recurrent locoregional and distant metastatic oropharyngeal cancer. AB - BACKGROUND: Human papillomavirus (HPV) tumor status and surgical salvage are associated with improved prognosis for patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC). Current data regarding types of surgery and the impact of surgery for patients with distant metastatic disease are limited. METHODS: A retrospective analysis of patients with recurrent OPSCC from 2 institutions between 2000 and 2012 was performed. p16 immunohistochemistry and/or in situ hybridization, as clinically available, were used to determine HPV tumor status. Clinical characteristics, distribution of recurrence site, and treatment modalities were compared by HPV tumor status. Overall survival (OS) was examined using Kaplan-Meier and Cox proportional hazards methods. RESULTS: The current study included 108 patients with 65 locoregional and 43 distant metastatic first recurrences. The majority of patients were HPV-positive (80 patients). HPV positive tumor status was associated with longer time to disease recurrence (P<.01). Anatomic site distribution of disease recurrences did not differ by HPV tumor status. HPV-positive tumor status (adjusted HR [aHR], 0.23; 95% confidence interval [95% CI], 0.09-0.58 [P = .002]), longer time to disease recurrence (>= 1 year; aHR, 0.36; 95% CI, 0.18-0.74 [P = .006]), and surgical salvage (aHR, 0.26; 95% CI, 0.12-0.61 [P = .002]) were found to be independently associated with OS after disease recurrence. Surgical salvage was independently associated with improved OS compared with nonsurgical treatment among patients with both locoregional (aHR, 0.15; 95% CI, 0.04-0.56 [P = .005]) and distant (aHR, 0.19; 95% CI, 0.05-0.75 [P = .018]) metastatic disease recurrences. CONCLUSIONS: Surgical salvage was found to be associated with improved OS for patients with recurrent locoregional and distant metastatic OPSCC, independent of HPV tumor status. Further prospective data are needed to confirm the role of surgical salvage for distant metastases. PMID- 25782031 TI - Past climate change drives current genetic structure of an endangered freshwater mussel species. AB - Historical-to-recent climate change and anthropogenic disturbance affect species distributions and genetic structure. The Rio Grande watershed of the United States and Mexico encompasses ecosystems that are intensively exploited, resulting in substantial degradation of aquatic habitats. While significant anthropogenic disturbances in the Rio Grande are recent, inhospitable conditions for freshwater organisms likely existed prior to such disturbances. A combination of anthropogenic and past climate factors may contribute to current distributions of aquatic fauna in the Rio Grande basin. We used mitochondrial DNA and 18 microsatellite loci to infer evolutionary history and genetic structure of an endangered freshwater mussel, Popenaias popeii, throughout the Rio Grande drainage. We estimated spatial connectivity and gene flow across extant populations of P. popeii and used ecological niche models (ENMs) and approximate Bayesian computation (ABC) to infer its evolutionary history during the Pleistocene. structure results recovered regional and local population clusters in the Rio Grande. ENMs predicted drastic reductions in suitable habitat during the last glacial maximum. ABC analyses suggested that regional population structure likely arose in this species during the mid-to-late Pleistocene and was followed by a late Pleistocene population bottleneck in New Mexico populations. The local population structure arose relatively recently, perhaps due to anthropogenic factors. Popenaias popeii, one of the few freshwater mussel species native to the Rio Grande basin, is a case study for understanding how both geological and anthropogenic factors shape current population genetic structure. Conservation strategies for this species should account for the fragmented nature of contemporary populations. PMID- 25782032 TI - Once-daily oxybutynin patch improves nocturia and sleep quality in Japanese patients with overactive bladder: Post-hoc analysis of a phase III randomized clinical trial. AB - OBJECTIVES: To investigate the efficacy of a once-daily oxybutynin patch for nocturia, and its influence on sleep quality in patients with overactive bladder. METHODS: We carried out post-hoc analysis of a phase III, randomized, double blind, comparative study in which an oxybutynin patch was administered once daily for 12 weeks to Japanese patients with overactive bladder. Patients with a baseline mean of one or more episodes of nocturia per night (data from voiding diaries) were analyzed. The mean number of micturitions, mean voided volume per micturition, mean first voided volume at night, mean sleep duration, and hours of undisturbed sleep were compared between the once-daily oxybutynin patch group and the placebo group. All parameters were expressed as the least squares mean values. RESULTS: The analysis included 576 patients. The number of nocturia episodes decreased by 0.66 in the oxybutynin patch group versus 0.51 in the placebo group (P = 0.0249). Also, the voided volume per nocturnal micturition and the first voided volume at night showed a significant increase in the oxybutynin patch group compared with the placebo group (P = 0.0073 and P = 0.0005, respectively). The hours of undisturbed sleep showed significant prolongation by 76.14 min in the oxybutynin patch group versus 56.07 min in the placebo group (P = 0.0257). CONCLUSIONS: Oxybutynin patch treatment reduces the number of nocturia episodes and prolongs the hours of undisturbed sleep, thus improving sleep quality and sleep-related quality of life in patients with overactive bladder. PMID- 25782033 TI - Antichlamydial sterol from the Red Sea sponge Callyspongia aff. implexa. AB - Marine sponges are rich sources of natural products exhibiting diverse biological activities. Bioactivity-guided fractionation of the Red Sea sponge Callyspongia aff. implexa led to the isolation of two new compounds, 26,27-bisnorcholest-5,16 dien-23-yn-3beta,7alpha-diol, gelliusterol E (1) and C27-polyacetylene, callimplexen A (2), in addition to the known compound beta-sitosterol (3). The structures of the isolated compounds were determined by 1D- and 2D-NMR techniques as well as high-resolution tandem mass spectrometry and by comparison to the literature. The three compounds (1-3) were tested against Chlamydia trachomatis, an obligate intracellular gram-negative bacterium, which is the leading cause of ocular and genital infections worldwide. Only gelliusterol E (1) inhibited the formation and growth of chlamydial inclusions in a dose-dependent manner with an IC50 value of 2.3 uM. PMID- 25782034 TI - Pharmacokinetic evaluation of avicularin using a model-based development approach. AB - The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5 mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans. PMID- 25782035 TI - Ameliorative effects of Trichosanthes dioica Extract in suppressing inflammatory mediators and attenuating oxidative stress. AB - The present study aimed to investigate the anti-inflammatory activity of the ethanolic extract of the aerial parts of Trichosanthes dioica and its successive fractions. The effect on oxidative stress involved in the pathogenesis of inflammation was evaluated. The ethanolic extract and its successive fractions were administered at a dose of 150 and 300 mg/kg b. w. for testing their anti inflammatory activity by a carrageenan-induced edema model. The results showed that the ethyl acetate fraction exhibited significant potency against inflammation. Pertaining to mechanistic insight, the anti-inflammatory effect might be attributed to the attenuation in tumor necrosis factor-alpha level (ELISA assay) and reduced expression of cyclooxygenase-2 and nuclear transcription factor-kappaB (immunohistochemistry). The alleviation in oxidative stress has been pertinent to the elevation in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) by active fractions. Furthermore, the ulcerogenic effect was insignificant even at a three times higher dose. Finally, it was concluded that the ethyl acetate fraction which showed significant biological potential against inflammation and oxidative stress could be viewed as a source of effective treatment. PMID- 25782036 TI - Extracts of Glycyrrhiza uralensis and isoliquiritigenin counteract amyloid-beta toxicity in Caenorhabditis elegans. AB - Alzheimer's disease is a rising threat for modern societies as more and more people reach old age. To date, there is no effective treatment for this condition. In this study, we investigated the potential of Glycyrrhiza uralensis to counteract amyloid-beta toxicity, one of the key features of Alzheimer's disease. An LC-MS/MS analysis revealed glycyrrhizic acid and glycosylated forms of isoliquiritigenin and liquiritigenin as major constituents of water and methanol extracts of G. uralensis. These extracts and the pure compounds were tested for their activity in two Caenorhabditis elegans models of amyloid-beta aggregation and amyloid-beta toxicity, respectively. The number of amyloid-beta aggregates decreased by 30% after treatment with isoliquiritigenin, the methanol extract could reduce the number by 14%, liquiritigenin and glycyrrhizic acid by 15%, and the aglycon of glycyrrhizic acid, glycyrrhetinic acid, by 20%. Both extracts and isoliquiritigenin also showed significant activity against acute amyloid-beta toxicity in transgenic C. elegans that express human amyloid-beta peptides, delaying the paralysis in this model by 1.8 h and 1.1 h, respectively. We conclude that secondary compounds of G. uralensis may become interesting drug candidates for the treatment of Alzheimer's disease, which, however, need further analysis in other model systems. PMID- 25782037 TI - Pistacia lentiscus Oleoresin: Virtual Screening and Identification of Masticadienonic and Isomasticadienonic Acids as Inhibitors of 11beta Hydroxysteroid Dehydrogenase 1. AB - In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor gamma agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11beta-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11beta hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11beta-hydroxysteroid dehydrogenase 1 over 11beta hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11beta-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum. PMID- 25782038 TI - Cutaneous epithelioid hemangioendothelioma on the sole of a child. AB - Epithelioid hemangioendothelioma (EHE) has been considered to be a low-grade malignant vascular neoplasm, although follow-up of recent series has demonstrated that EHE involving the skin and soft tissues should be better regarded as a fully malignant vascular tumor since it has more metastatic potential than previously thought. We report a case of an EHE involving the left sole of 6-year-old boy, the youngest patient with cutaneous EHE described to date. Immunohistochemical studies demonstrated a lymphatic endothelial line of differentiation for neoplastic cells. Cutaneous EHE is rare in childhood, with only five previously described cases. PMID- 25782039 TI - Cold-air atmospheric pressure plasma against Clostridium difficile spores: a potential alternative for the decontamination of hospital inanimate surfaces. AB - Clostridium difficile spores survive for months on environmental surfaces and are highly resistant to decontamination. We evaluated the effect of cold-air plasma against C. difficile spores. The single-jet had no effect while the multi-jet achieved 2-3 log10 reductions in spore counts and may augment traditional decontamination. PMID- 25782040 TI - Immunoreactive pattern of Staphylococcus epidermidis biofilm against human whole saliva. AB - Saliva is essential to interact with microorganisms in the oral cavity. Therefore, the interest in saliva antimicrobial properties is on the rise. Here, we used an immunoproteomic approach, based on protein separation of Staphylococcus epidermidis biofilms by 2DE, followed by Western-blotting, to compare human serum and saliva reactivity profile. A total of 17 proteins were identified by MALDI-TOF/TOF. Serum and saliva presented a distinct pattern of immunoreactive proteins. Our results suggest that saliva seems to have higher propensity to react against S. epidermidis proteins with oxidoreductase activity and proteins involved with L-serine metabolic processes. We show that saliva was a powerful tool for the identification of potential S. epidermidis biofilms proteins. PMID- 25782041 TI - A spatiotemporal quantile regression model for emergency department expenditures. AB - Motivated by a recent study of geographic and temporal trends in emergency department care, we develop a spatiotemporal quantile regression model for the analysis of emergency department-related medical expenditures. The model yields distinct spatial patterns across time for each quantile of the response distribution, which is important in the spatial analysis of expenditures, as there is often little spatiotemporal variation in mean expenditures but more pronounced variation in the extremes. The model has a hierarchical structure incorporating patient-level and region-level predictors as well as spatiotemporal random effects. We model the random effects via intrinsic conditionally autoregressive priors, improving small-area estimation through maximum spatiotemporal smoothing. We adopt a Bayesian modeling approach based on an asymmetric Laplace distribution and develop an efficient posterior sampling scheme that relies solely on conjugate full conditionals. We apply our model to data from the Duke support repository, a large georeferenced database containing health and financial data for Duke Health System patients residing in Durham County, North Carolina. PMID- 25782043 TI - Determination of trantinterol enantiomers in human plasma by high-performance liquid chromatography - tandem mass spectrometry using vancomycin chiral stationary phase and solid phase extraction and stereoselective pharmacokinetic application. AB - A sensitive and enantioselective vancomycin chiral stationary phase high performance liquid chromatography-tandem mass spectrometry method was developed for the determination of trantinterol enantiomers in human plasma. Baseline resolution was achieved using the vancomycin chiral stationary phase known as Chirobiotic V with polar ionic mobile phase consisting of acetonitrile-methanol (60:40, v/v) containing 0.01% ammonia and 0.02% acetic acid at a flow rate of 1.0 mL/min. Waters Oasis HLB C18 solid phase extraction cartridges were used in the sample preparation of trantinterol samples from plasma. The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization. The calibration curve was linear in a concentration range from 0.0606 to 30.3 ng/mL in plasma, with the lower limit of quantification of 0.0606 ng/mL. The intra- and interday precision (relative standard deviation) values were within 9.7% and the accuracy (relative error) was from -6.6 to 7.2% at all quality control levels. The method was successfully applied to a study of stereoselective pharmacokinetics in human. PMID- 25782042 TI - Increased risk of revision for infection in rheumatoid arthritis patients with total hip replacements. AB - BACKGROUND AND PURPOSE: Medical treatment of rheumatoid arthritis (RA) has changed dramatically over the last 15 years, including immune modulation. We investigated the risk of revision for infection after primary total hip replacement (THR) in patients with rheumatoid arthritis over a 16-year period, and compared it with that in THR patients with osteoarthritis (OA). PATIENTS AND METHODS: We identified 13,384 THRs in RA patients and 377,287 THRs in OA patients from 1995 through 2010 in a dataset from the Nordic Arthroplasty Register Association (NARA). Kaplan-Meier survival curves, with revision for infection as the endpoint, were constructed. Cox regression analyses were performed to calculate the relative risk (RR) of revision for infection adjusted for age, sex, fixation technique, and year of primary surgery. RESULTS: RA patients had a 1.3 times (95% CI 1.0-1.6) higher risk of revision for infection. After 2001, this risk increased more for RA patients than for OA patients. During the first 3 months and from 8 years postoperatively, the risk of revision for infection was higher in RA patients with THRs fixated with antibiotic-loaded cement than in corresponding OA patients. INTERPRETATION: We found a slightly higher overall risk of revision for infection in RA patients than in OA patients, but this difference was only present after 2001. In THRs with antibiotic-loaded cement, the risk of very early and late infections leading to revision was higher in RA patients than in OA patients. PMID- 25782044 TI - Do caregiving burden and satisfaction predict loneliness in older care recipients? AB - OBJECTIVES: The goal of this study was to assess the extent to which caregiving burden and satisfaction of primary family caregivers in Israel predict loneliness among their older care recipients. METHOD: The study included a convenience sample of 325 dyads of respondents. The short version of Zarit Caregiving Burden Interview and Lawton Caregiving Appraisal measures were used to assess caregiving burden and satisfaction; the de Jong Gierveld Loneliness Scale was used to assess care recipient's loneliness. RESULTS: The results showed that greater caregiving burden was significantly correlated with increased loneliness, whereas greater caregiving satisfaction was significantly correlated with lower levels of loneliness. CONCLUSION: The literature has broadly addressed the association between caregiving burden and satisfaction and the caregivers' well-being, whereas this association with regard to care recipients' well-being has been barely examined. The multivariate analyses showed that caregiving burden was insignificant in explaining loneliness, whereas greater caregiving satisfaction was found significant in explaining lower levels of loneliness. The results and implications for further research and practice are discussed. PMID- 25782045 TI - In Vitro Implant Impression Accuracy Using a New Photopolymerizing SDR Splinting Material. AB - PURPOSE: The study aims to evaluate three-dimensionally (3D) the accuracy of implant impressions using a new resin splinting material, "Smart Dentin Replacement" (SDR). MATERIALS AND METHODS: A titanium model of an edentulous mandible with six implant analogues was used as a master model and its dimensions measured with a coordinate measuring machine. Before the total 60 impressions were taken (open tray, screw-retained abutments, vinyl polysiloxane), they were divided in four groups: A (test): copings pick-up splinted with dental floss and fotopolymerizing SDR; B (test): see A, additionally sectioned and splinted again with SDR; C (control): copings pick-up splinted with dental floss and autopolymerizing Duralay(r) (Reliance Dental Mfg. Co., Alsip, IL, USA) acrylic resin; and D (control): see C, additionally sectioned and splinted again with Duralay. The impressions were measured directly with an optomechanical coordinate measuring machine and analyzed with a computer-aided design (CAD) geometric modeling software. The Wilcoxon matched-pair signed-rank test was used to compare groups. RESULTS: While there was no difference (p = .430) between the mean 3D deviations of the test groups A (17.5 MUm) and B (17.4 MUm), they both showed statistically significant differences (p < .003) compared with both control groups (C 25.0 MUm, D 19.1 MUm). CONCLUSIONS: Conventional impression techniques for edentulous jaws with multiple implants are highly accurate using the new fotopolymerizing splinting material SDR. Sectioning and rejoining of the SDR splinting had no impact on the impression accuracy. PMID- 25782046 TI - Guideliner use for the percutaneous treatment of right coronary artery arising from the left circumflex (L-type single coronary artery). PMID- 25782047 TI - Using PTFE covered stent-artery anastomosis in a new hybrid operation for giant juxta-skull internal carotid aneurysm with tortuous internal carotid artery. PMID- 25782048 TI - Characteristics and outcome of congenital left ventricular aneurysm and diverticulum: Analysis of 809 cases published since 1816. AB - BACKGROUND: Congenital left ventricular aneurysm (LVA) or diverticulum (LVD) is rare cardiac anomalies. We aimed to analyse the clinical characteristics and outcome in all ever published patients. METHODS: MEDLINE, Web of science, Google and EMBASE, and reference lists of relevant articles were searched for publications reporting on LVA or LVD patients. RESULTS: We identified 809 patients published since 1816 [354 (49.1%) LVA, 453 (50.6%) LVD, 2 (0.3%) both]. Mean age at diagnosis was 34.1+/-27 (LVA) and 29.7+/-27.6years (LVD; p=0.05). 48.9% were male. LVA was larger (38.7+/-22.5mm versus 31.4+/-21.2mm; p=0.002) and frequently found in submitral location (33% versus 4.9%; p<0.001), LVD was frequently located at the LV-apex (61.2% versus 28.7%; p<0.001). LVD was often associated with cardiac (34.2% versus 11%; p<0.001) or extracardiac anomalies (32.7% versus 3%; p<0.001). LVA patients presented more frequently with ventricular tachycardia/fibrillation (18.1% versus 13.1%; p=0.01), the incidences of rupture (4% versus 4.5%; p=0.9), syncope (8.3% versus 5.1%; p=0.1), and embolic events (4.9% versus 3.6%; p=0.4) at presentation were not different between LVA and LVD. Mean follow-up was 56.3+/-43months. Cardiac death occurred more frequently in the LVA group (11.5% versus 5.0%; p=0.05) at a median age of 0.8 [LVA] and 2.5 [LVD] years. The leading cause of cardiac death was congestive heart failure in the LVA-group (50.0% versus 0.0%; p=0.01), and rupture in the LVD-group (75.0% versus 27.3%; p=0.04). CONCLUSIONS: LVA and LVD are distinct congenital anomalies with different clinical and morphological characteristics. The prognosis of LVA is significantly worse during long-term follow-up. PMID- 25782049 TI - Habitual snoring and risk of stroke: A meta-analysis of prospective studies. PMID- 25782050 TI - Ischemic colitis as a complication of acute myocardial infarction. PMID- 25782051 TI - Effects of slow breathing rate on blood pressure and heart rate variabilities in essential hypertension. PMID- 25782052 TI - Localized metal solubilization in the rhizosphere of Salix smithiana upon sulfur application. AB - A metal-accumulating willow was grown under greenhouse conditions on a Zn/Cd polluted soil to investigate the effects of sulfur (S(0)) application on metal solubility and plant uptake. Soil porewater samples were analyzed 8 times during 61 days of growth, while DGT-measured metal flux and O2 were chemically mapped at selected times. Sulfur oxidation resulted in soil acidification and related mobilization of Mn, Zn, and Cd, more pronounced in the rooted compared to bulk soil. Chemical imaging revealed increased DGT-measured Zn and Cd flux at the root soil interface. Our findings indicated sustained microbial S(0) oxidation and associated metal mobilization close to root surfaces. The localized depletion of O2 along single roots upon S(0) addition indicated the contribution of reductive Mn (oxy)hydoxide dissolution with Mn eventually becoming a terminal electron acceptor after depletion of O2 and NO3(-). The S(0) treatments increased the foliar metal concentrations (mg kg(-1) dwt) up to 10-fold for Mn, (5810 +/- 593), 3.3-fold for Zn (3850 +/- 87.0), and 1.7-fold for Cd (36.9 +/- 3.35), but had no significant influence on biomass production. Lower metal solubilization in the bulk soils should translate into reduced leaching, offering opportunities for using S(0) as environmentally favorable amendment for phytoextraction of metal polluted soils. PMID- 25782053 TI - Nonchromophoric halide ligand variation in polyazine-bridged Ru(II),Rh(III) bimetallic supramolecules offering new insight into photocatalytic hydrogen production from water. AB - The new bimetallic complex [(Ph2phen)2Ru(dpp)RhBr2(Ph2phen)](PF6)3 (1) (Ph2phen = 4,7-diphenyl-1,10-phenanthroline; dpp = 2,3-bis(2-pyridyl)pyrazine) was synthesized and characterized to compare with the Cl(-) analogue [(Ph2phen)2Ru(dpp)RhCl2(Ph2phen)](PF6)3 (2) in an effort to better understand the role of halide coordination at the Rh metal center in solar H2 production schemes. Electrochemical properties of complex 1 display a reversible Ru(II/III) oxidation, and cathodic scans indicate multiple electrochemical mechanisms exist to reduce Rh(III) by two electrons to Rh(I) followed by a quasi-reversible dpp(0/ ) ligand reduction. The weaker sigma-donating ability of Br(-) vs Cl(-) impacts the cathodic electrochemistry and provides insight into photocatalytic function by these bimetallic supramolecules. Complexes 1 and 2 exhibit identical light absorbing properties with UV absorption dominated by intraligand (IL) pi -> pi* transitions and visible absorption by metal-to-ligand charge transfer (MLCT) transitions to include a lowest energy Ru(dpi) -> dpp(pi*) (1)MLCT transition (lambda(abs) = 514 nm; epsilon = 16 000 M(-1) cm(-1)). The relatively short lived, weakly emissive Ru(dpi) -> dpp(pi*) (3)MLCT excited state (tau = 46 ns) for both bimetallic complexes is attributed to intramolecular electron transfer from the (3)MLCT excited state to populate a low-energy Ru(dpi) -> Rh(dsigma*) triplet metal-to-metal charge transfer ((3)MMCT) excited state that allows photoinitiated electron collection. Complex 1 outperforms the related Cl(-) bimetallic analogue 2 as a H2 photocatalyst despite identical light-absorbing and excited-state properties. Additional H2 experiments with added halide suggest ion pairing plays a role in catalyst deactivation and provides new insight into observed differences in H2 production upon halide variation in Ru(II),Rh(III) supramolecular architectures. PMID- 25782054 TI - Echocardiographic correlates of persistent pulmonary hypertension of the newborn. AB - AIMS: To compare echocardiographic (ECHO) measures of ventricular function and hemodynamics of infants with persistent pulmonary hypertension of the newborn (PPHN) and normal controls; and to examine their association with clinical outcomes in PPHN. DESIGN/SUBJECTS: We performed a retrospective review of ECHOs of mechanically ventilated infants (>= 34 weeks gestational age) with PPHN. Infants with congenital heart disease were excluded. Controls had normal ECHOs within 1 week of age. OUTCOMES: ECHOs measures included a) right (RVO) and left ventricular output (LVO) b) RV and LV myocardial performance index (MPI) c) right ventricular systolic to diastolic duration (S/D) ratio and d) eccentricity index in systole (EIs) and diastole (EId). RESULTS: Infants with PPHN (n = 117), 63% of whom were males, had mean (SD) GA and birth weights of 38.6 (1.9) weeks and 3.3 (0.65) kg respectively. LVO, RVO and EIs were significantly lower and heart rate, MPI and RV S/D ratio were significantly higher in infants with PPHN, compared to controls (n = 35). The mean RV S/D ratios were significantly higher in infants with PPHN who died or required ECMO (n = 61), compared to survivors without ECMO (n = 56). Increasing RV S/D ratio was independently associated with a reduction in survival without ECMO [0.21; 95% C.I. 0.06-0.74, p = 0.015]. RV S/D ratio >1.3 had a sensitivity of 93 (95% C.I. 85-99) % for death or ECMO. CONCLUSIONS: Elevated RV S/D ratio, a marker of global RV dysfunction, was associated with adverse outcomes in PPHN. Its routine measurement in this population may aid risk identification and targeted interventions. PMID- 25782055 TI - Discovery of a Cyclic Boronic Acid beta-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases. AB - The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the beta-lactam class of antimicrobials. A program was initiated to discover a new series of serine beta-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine beta lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria. PMID- 25782056 TI - A Case-Only Study of Vulnerability to Heat Wave-Related Mortality in New York City (2000-2011). AB - BACKGROUND: As a result of climate change, the frequency of extreme temperature events is expected to increase, and such events are associated with increased morbidity and mortality. Vulnerability patterns, and corresponding adaptation strategies, are most usefully conceptualized at a local level. METHODS: We used a case-only analysis to examine subject and neighborhood characteristics that modified the association between heat waves and mortality. All deaths of New York City residents from 2000 through 2011 were included in this analysis. Meteorological data were obtained from the National Climatic Data Center. Modifying characteristics were obtained from the death record and geographic data sets. RESULTS: A total of 234,042 adult deaths occurred during the warm season of our study period. Compared with other warm-season days, deaths during heat waves were more likely to occur in black (non-Hispanic) individuals than other race/ethnicities [odds ratio (OR) = 1.08; 95% CI: 1.03, 1.12], more likely to occur at home than in institutions and hospital settings (OR = 1.11; 95% CI: 1.06, 1.16), and more likely among those living in census tracts that received greater public assistance (OR = 1.05; 95% CI: 1.01, 1.09). Finally, deaths during heat waves were more likely among residents in areas of the city with higher relative daytime summer surface temperature and less likely among residents living in areas with more green space. CONCLUSION: Mortality during heat waves varies widely within a city. Understanding which individuals and neighborhoods are most vulnerable can help guide local preparedness efforts. PMID- 25782057 TI - Coupled molecular switching processes in ordered mono- and multilayers of stimulus-responsive rotaxanes on gold surfaces. AB - Interfaces provide the structural basis for function as, for example, encountered in nature in the membrane-embedded photosystem or in technology in solar cells. Synthetic functional multilayers of molecules cooperating in a coupled manner can be fabricated on surfaces through layer-by-layer self-assembly. Ordered arrays of stimulus-responsive rotaxanes undergoing well-controlled axle shuttling are excellent candidates for coupled mechanical motion. Such stimulus-responsive surfaces may help integrate synthetic molecular machines in larger systems exhibiting even macroscopic effects or generating mechanical work from chemical energy through cooperative action. The present work demonstrates the successful deposition of ordered mono- and multilayers of chemically switchable rotaxanes on gold surfaces. Rotaxane mono- and multilayers are shown to reversibly switch in a coupled manner between two ordered states as revealed by linear dichroism effects in angle-resolved NEXAFS spectra. Such a concerted switching process is observed only when the surfaces are well packed, while less densely packed surfaces lacking lateral order do not exhibit such effects. PMID- 25782058 TI - Effect of monensin withdrawal on rumen fermentation, methanogenesis and microbial populations in cattle. AB - This study was designed to obtain information on the residual influence of dietary monensin on ruminant fermentation, methanogenesis and bacterial population. Three ruminally cannulated crossbreed heifers (14 months old, 363 +/- 11 kg) were fed Italian ryegrass straw and concentrate supplemented with monensin for 21 days before sampling. Rumen fluid samples were collected for analysis of short chain fatty acid (SCFA) profiles, monensin concentration, methanogens and rumen bacterial density. Post-feeding rumen fluid was also collected to determine in vitro gas production. Monensin was eliminated from the rumen fluid within 3 days. The composition of SCFA varied after elimination of monensin, while total production of SCFA was 1.78 times higher than on the first day. Methane production increased 7 days after monensin administration ceased, whereas hydrogen production decreased. The methanogens and rumen bacterial copy numbers were unaffected by the withdrawal of monensin. PMID- 25782059 TI - Towards an assistive peripheral visual prosthesis for long-term treatment of retinitis pigmentosa: evaluating mobility performance in immersive simulations. AB - OBJECTIVE: The prospective efficacy of a future peripheral retinal prosthesis complementing residual vision to raise mobility performance in non-end stage retinitis pigmentosa (RP) was evaluated using simulated prosthetic vision (SPV). APPROACH: Normally sighted volunteers were fitted with a wide-angle head-mounted display and carried out mobility tasks in photorealistic virtual pedestrian scenarios. Circumvention of low-lying obstacles, path following, and navigating around static and moving pedestrians were performed either with central simulated residual vision of 10 degrees alone or enhanced by assistive SPV in the lower and lateral peripheral visual field (VF). Three layouts of assistive vision corresponding to hypothetical electrode array layouts were compared, emphasizing higher visual acuity, a wider visual angle, or eccentricity-dependent acuity across an intermediate angle. Movement speed, task time, distance walked and collisions with the environment were analysed as performance measures. MAIN RESULTS: Circumvention of low-lying obstacles was improved with all tested configurations of assistive SPV. Higher-acuity assistive vision allowed for greatest improvement in walking speeds-14% above that of plain residual vision, while only wide-angle and eccentricity-dependent vision significantly reduced the number of collisions-both by 21%. Navigating around pedestrians, there were significant reductions in collisions with static pedestrians by 33% and task time by 7.7% with the higher-acuity layout. Following a path, higher-acuity assistive vision increased walking speed by 9%, and decreased collisions with stationary cars by 18%. SIGNIFICANCE: The ability of assistive peripheral prosthetic vision to improve mobility performance in persons with constricted VFs has been demonstrated. In a prospective peripheral visual prosthesis, electrode array designs need to be carefully tailored to the scope of tasks in which a device aims to assist. We posit that maximum benefit might come from application alongside existing visual aids, to further raise life quality of persons living through the prolonged early stages of RP. PMID- 25782060 TI - Primary asymptomatic desmoid tumor of the mesentery. AB - BACKGROUND: Desmoid-type fibromatosis (DF) is a rare entity that predominantly involves the extremities, the trunk, and the abdominal cavity. It is a non metastasizing, sporadic mesenchymal tumor with high tendency to recurrence and often is categorized as low-grade sarcoma. CASE REPORT: We present here an extremely rare case of a mesenteric desmoid tumor (DT). A 40-year-old man presented to our clinic with a mass in the right-lower quadrant of the abdomen, which he incidentally palpated. A computerized tomography (CT) scan of the abdomen showed a mass between the loops of small intestine. The patient was treated successfully with wide excision of involved mesentery and adjacent small intestine. Histopathology of the mass revealed DT of the mesentery. No adjuvant treatment was applied and the patient was free of disease after a 6-month follow up. CONCLUSIONS: Intra-abdominal DF is a rare pathology which should be differentiated while exploring abdominal tumors. Surgery, when dealing with operable masses, is the appropriate treatment. PMID- 25782061 TI - Community engagement research and dual diagnosis anonymous. AB - Community engagement research is widely discussed but rarely implemented. This article describes the implementation of a community engagement research project on Dual Diagnosis Anonymous, a rapidly spreading peer support program in Oregon for people with co-occurring mental illness and substance use disorders. After three years of discussions, overcoming barriers, and involving several institutions, this grassroots research project has been implemented and is expanding. Active participants in Dual Diagnosis Anonymous inspired and instructed policy makers, professionals, and students. Community engagement research requires frontline participants, community members, and professional collaborators to overcome multiple barriers with persistence and steadfastness. Building trust, collaboration, and structures for community engagement research takes time and a community effort. PMID- 25782062 TI - Gel-free proteomic methodologies to study reversible cysteine oxidation and irreversible protein carbonyl formation. AB - Oxidative modifications in proteins have been traditionally considered as hallmarks of damage by oxidative stress and aging. However, oxidants can generate a huge variety of reversible and irreversible modifications in amino acid side chains as well as in the protein backbones, and these post-translational modifications can contribute to the activation of signal transduction pathways, and also mediate the toxicity of oxidants. Among the reversible modifications, the most relevant ones are those arising from cysteine oxidation. Thus, formation of sulfenic acid or disulfide bonds is known to occur in many enzymes as part of their catalytic cycles, and it also participates in the activation of signaling cascades. Furthermore, these reversible modifications have been usually attributed with a protective role, since they may prevent the formation of irreversible damage by scavenging reactive oxygen species. Among irreversible modifications, protein carbonyl formation has been linked to damage and death, since it cannot be repaired and can lead to protein loss-of-function and to the formation of protein aggregates. This review is aimed at researchers interested on the biological consequences of oxidative stress, both at the level of signaling and toxicity. Here we are providing a concise overview on current mass spectrometry-based methodologies to detect reversible cysteine oxidation and irreversible protein carbonyl formation in proteomes. We do not pretend to impose any of the different methodologies, but rather to provide an objective catwalk on published gel-free approaches to detect those two types of modifications, from a biologist's point of view. PMID- 25782063 TI - 17-Norpimaranes and (9betaH)-17-Norpimaranes from the Tuber of Icacina trichantha. AB - Seven new 17-norpimarane and (9betaH)-17-norpimarane diterpenoids, icacinlactones A-G (1-7), were isolated from the tuber of Icacina trichantha. The structures were elucidated by spectroscopic and HRMS techniques, and the absolute configuration of 2 was determined by means of X-ray crystallographic analysis. Compounds 1-7, as well as four known related structures, were evaluated for cytotoxic activity against MDA-MB-435 (human melanoma cancer), MDA-MB-231 (human breast cancer), and OVCAR3 (human ovarian cancer) cell lines. Several of these natural products displayed significant cytotoxic activity, with humirianthenolide C being the most active. PMID- 25782064 TI - MicroRNA-423-5p Promotes Autophagy in Cancer Cells and Is Increased in Serum From Hepatocarcinoma Patients Treated With Sorafenib. AB - Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths worldwide. Sorafenib is the only approved drug for patients with advanced HCC but has shown limited activity. microRNAs (miRs) have been involved in several neoplasms including HCC suggesting their use or targeting as good tools for HCC treatment. The purpose of this study was to identify novel approaches to sensitize HCC cells to sorafenib through miRs. miR-423-5p was validated as positive regulator of autophagy in HCC cell lines by transient transfection of miR and anti-miR molecules. miR-423-5p expression level was evaluated by real time polymerase chain reaction (PCR) in sera collected from 39 HCC patients before and after treatment with sorafenib. HCC cells were cotreated with sorafenib and miR-423-5p and the effects on cell cycle, apoptosis, and autophagy were evaluated. Secretory miR-423-5p was upregulated both in vitro and in vivo by sorafenib treatment and its increase was correlated with response to therapy since 75% of patients in which an increase of secretory miR423-5p was found were in partial remission or stable disease after 6 moths from the beginning of therapy. HCC cells transfected with miR-423-5p showed an increase of cell percentage in S-phase of cell cycle paralleled by a similar increase of autophagic cells evaluated at both fluorescence activated cell sorter (FACS) and transmission electron microscopy. Our results suggest the miR423-5p can be used as a useful tool to predict response to sorafenib in HCC patients and is involved in autophagy regulation in HCC cells. PMID- 25782065 TI - Attentional distraction during exercise in overweight and normal-weight boys. AB - The purpose of this study was to investigate the effect of attentional distraction on field running distance and activity intensity during an exercise session in normal-weight and overweight youngsters and to investigate potential mediators. Fifty-three 12-14 yr-old boys participated twice in a 12-min running test and a 20-min exercise session, once with attentional distraction (by listerning to music) and once without distraction (counterbalanced randomised controlled design). At the end of the endurance test running distance was recorded. During the exercise session activity intensity was assessed by accelerometers. After each experiment, rate of perceived exertion (RPE) was estimated and seven questions were asked about how participants experienced the experiment. Both overweight and normal-weight boys ran further during the running test with music (p<0.05) and this effect was mediated by a decrease in feelings of annoyance. During the exercise session with music, both overweight and normal weight boys exercised less at low and high intensity and more at moderate and very high intensity (p<0.01) and this effect was mediated by a decrease in RPE. We can conclude that attentional distraction has a positive effect on running distance on a field endurance test and on activity intensity during an exercise session through different mechanisms in both overweight and normal-weight boys. PMID- 25782067 TI - Transforming a presentation to a publication: Tips for nurse practitioners. AB - PURPOSE: Nurse practitioners (NPs) routinely make presentations at regional, national, and international conferences. However, compared to other health professionals, fewer of the presentations are followed by manuscripts in peer reviewed journals. For more than 20 years, the Abstract to Publication rate has been a marker of conference quality and a trail of new knowledge development and dissemination. The purpose of this manuscript is to provide NPs with an approach for converting a presentation to a full manuscript. DATA SOURCES: Editorials, journal articles, style guides. CONCLUSIONS: The overlap between a podium or poster presentation and a fully developed manuscript is quite significant; the difference is in the style of presentation. IMPLICATIONS FOR PRACTICE: While scholarly writing may be somewhat daunting at first, resources are available to help any NP publish following a presentation. With sufficient planning, NPs can increase their Abstract to Publication rate. PMID- 25782066 TI - 4th international conference on tumor progression and therapeutic resistance: meeting report. AB - The fourth international conference on tumor progression and therapeutic resistance organized in association with GTCbio was held in Boston, MA from March 9 to 11, 2014. The meeting attracted a diverse group of experts in the field of cancer biology, therapeutics and medical oncology from academia and industry. The meeting addressed the current challenges in the treatment of cancer including tumor heterogeneity, therapy resistance and metastasis along with the need for improved biomarkers of tumor progression and clinical trial design. Keynote speakers included Clifton Leaf, Editor at Fortune Magazine, Dr. Mina Bissell from the Lawrence Berkeley National Laboratory and Dr. Levi Garraway from the Dana Farber Cancer Institute. The meeting featured cutting edge tools, preclinical models and the latest basic, translational and clinical research findings in the field. PMID- 25782068 TI - Gender differences in upper extremity motor performance of older persons. AB - BACKGROUND: Motor performance declines with age. Although gender differences in motor strength and speed have been widely reported, the extent to which these differences are maintained in old age has not been well established. METHODS: Upper extremity motor performance was assessed in 234 men and 530 women Catholic clergy members aged 65 years or older with no clinical evidence of dementia who were participants in the Religious Orders Study. As part of a uniform clinical evaluation, upper extremity motor performance including strength (grip and pinch dynamometry), movement speed including finger tapping and Purdue pegboard and muscle bulk of the arm were collected. RESULTS: Men were stronger than women at all ages but this difference became less prominent at older ages. Women scored higher on the Purdue Pegboard than men whereas men had faster maximal finger tapping rates than women. Gender differences in speed were not modified by age. Men had greater muscle bulk than women at all ages and these differences were not modified by age. These relationships were not modified by participants with a clinical diagnosis of Parkinson's disease or stroke or by hormone replacement therapy in women. CONCLUSIONS: Gender differences in upper extremity speed and muscle bulk appear to be relatively stable with increasing age, whereas gender differences in strength were reduced in the oldest old. Longitudinal studies are needed to determine if men and women differ in the rate of decline of strength in old age. PMID- 25782069 TI - Ionic conductivity enhancement of polymer electrolytes with ceramic nanowire fillers. AB - Solid-state electrolytes provide substantial improvements to safety and electrochemical stability in lithium-ion batteries when compared with conventional liquid electrolytes, which makes them a promising alternative technology for next-generation high-energy batteries. Currently, the low mobility of lithium ions in solid electrolytes limits their practical application. The ongoing research over the past few decades on dispersing of ceramic nanoparticles into polymer matrix has been proved effective to enhance ionic conductivity although it is challenging to form the efficiency networks of ionic conduction with nanoparticles. In this work, we first report that ceramic nanowire fillers can facilitate formation of such ionic conduction networks in polymer-based solid electrolyte to enhance its ionic conductivity by three orders of magnitude. Polyacrylonitrile-LiClO4 incorporated with 15 wt % Li0.33La0.557TiO3 nanowire composite electrolyte exhibits an unprecedented ionic conductivity of 2.4 * 10( 4) S cm(-1) at room temperature, which is attributed to the fast ion transport on the surfaces of ceramic nanowires acting as conductive network in the polymer matrix. In addition, the ceramic-nanowire filled composite polymer electrolyte shows an enlarged electrochemical stability window in comparison to the one without fillers. The discovery in the present work paves the way for the design of solid ion electrolytes with superior performance. PMID- 25782071 TI - Renal haemodynamic response to amino acids infusion in an experimental porcine model of septic shock. AB - BACKGROUND: Acute kidney injury (AKI) is common in sepsis. Treatments allowing maintenance of renal blood flow (RBF) could help to prevent AKI associated with renal hypoperfusion. Amino acids (AA) have been associated with an increase of RBF and glomerular filtration rate (GFR) in several species. The aim of this study was to evaluate the effects of an AA infusion on RBF and GFR in a porcine model of septic shock. METHODS: A total of 17 piglets were randomly assigned into three groups: Sham (Sham, n = 5), sepsis without AA (S-NAA, n = 6), sepsis treated with AA (S-AA, n = 6). Piglets preparation included the placement of ultrasonic transit time flow probes around left renal artery for continuous RBF measurement; ureteral catheters for GFR and urine output evaluation; pulmonary artery catheter for cardiac output (CO) and pulmonary arterial pressure measurements. Mean arterial pressure (MAP) and renal vascular resistance (RVR) were also determined. Septic shock was induced with a live Pseudomonas aeruginosa infusion. Crystalloids, colloids and epinephrine infusion were used to maintain and restore MAP > 60 mmHg and CO > 80% from baseline. RESULTS: Renal haemodynamic did not change significantly in the Sham group, whereas RBF increased slightly in the S-NAA group. Conversely, a significant increase in RVR and a decrease in RBF and GFR were observed in the S-AA group. AA infusion was associated with a higher requirement of epinephrine [340.0 (141.2; 542.5) mg vs. 32.5 (3.8; 65.0) mg in the S-NAA group P = 0.044]. CONCLUSION: An infusion of amino acids impaired renal haemodynamics in this experimental model of septic shock. PMID- 25782072 TI - High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss. AB - Mitochondrial dysfunction plays an important role in obesity-induced cardiac impairment. SIRT3 is a mitochondrial protein associated with increased human life span and metabolism. This study investigated the functional role of SIRT3 in obesity-induced cardiac dysfunction. Wild-type (WT) and SIRT3 knockout (KO) mice were fed a normal diet (ND) or high-fat diet (HFD) for 16 weeks. Body weight, fasting glucose levels, reactive oxygen species (ROS) levels, myocardial capillary density, cardiac function and expression of hypoxia-inducible factor (HIF)-1alpha/-2alpha were assessed. HFD resulted in a significant reduction in SIRT3 expression in the heart. Both HFD and SIRT3 KO mice showed increased ROS formation, impaired HIF signalling and reduced capillary density in the heart. HFD induced cardiac hypertrophy and impaired cardiac function. SIRT3 KO mice fed HFD showed greater ROS production and a further reduction in cardiac function compared to SIRT3 KO mice on ND. Thus, the adverse effects of HFD on cardiac function were not attributable to SIRT3 loss alone. However, HFD did not further reduce capillary density in SIRT3 KO hearts, implicating SIRT3 loss in HFD induced capillary rarefaction. Our study demonstrates the importance of SIRT3 in preserving heart function and capillary density in the setting of obesity. Thus, SIRT3 may be a potential therapeutic target for obesity-induced heart failure. PMID- 25782073 TI - Activation of P2X7 receptors decreases the proliferation of murine luteal cells. AB - Extracellular ATP regulates cellular function in an autocrine or paracrine manner through activating purinergic signalling. Studies have shown that purinergic receptors were expressed in mammalian ovaries and they have been proposed as an intra-ovarian regulatory mechanism. P2X7 was expressed in porcine ovarian theca cells and murine and human ovarian surface epithelium and is involved in ATP induced apoptotic cell death. However, the role of P2X7 in corpus luteum is still unclear. The aim of this study was to investigate the role of ATP signalling in murine luteal cells and the possible mechanism(s) involved. We found that P2X7 was highly expressed in murine small luteal cells. The agonists of P2X7, ATP and BzATP, inhibited the proliferation of luteal cells. P2X7 antagonist BBG reversed the inhibition induced by ATP and BzATP. Further studies showed that ATP and BzATP inhibited the expression of cell cycle regulators cyclinD2 and cyclinE2. ATP and BzATP also inhibited the p38-mitogen-activated protein kinase (MAPK) signalling pathway. These results reveal that P2X7 receptor activation is involved in corpus luteum formation and function. PMID- 25782074 TI - Controlling flow behavior of water in microfluidics with a chemically patterned anisotropic wetting surface. AB - We report the flow behavior of water in microfluidic systems based on a chemically patterned anisotropic wetting surface. When water flows inside a microchannel on top of a micropatterned surface with alternating hydrophilic/hydrophobic stripes, it exhibits an anisotropic flowing characteristic owing to the anisotropic wettability; thus, the patterned surface acts as a microvalve for the microfluidic system. The anisotropic flow of water is influenced by the microscale features of the patterns and the dimensions of the microchannels. Furthermore, by reasonably combining the patterned surface and microchannel together, we realize the transportation of water in a microchannel along a "virtual" wall, which is the boundary of the hydrophilic and hydrophobic area. We believe that the chemically patterned surfaces could be an alternative strategy to control the flow behavior of water in microfluidic channels. PMID- 25782075 TI - Diagnostic accuracy of history and physical examination in bacterial acute rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: To evaluate the diagnostic accuracy of symptoms, the symptom progression pattern, and clinical signs in identifying bacterial acute rhinosinusitis (ARS). STUDY DESIGN: We conducted an inception cohort study among 50 military recruits with ARS. METHODS: We collected symptoms daily from the onset of symptoms to approximately 10 days. At 9 to 10 days, standardized data on symptoms and physical findings were gathered. A positive culture of maxillary sinus aspirate was considered to be the reference standard for bacterial ARS. RESULTS: At 9 to 10 days, the presence or deterioration after 5 days of any of the symptoms could not be used to diagnose bacterial ARS. Toothache had an adequate positive likelihood ratio (positive likelihood ratio [LR+] 4.4) but was too rare to be used for screening. In contrast, several physical findings at 9 to 10 days were of more diagnostic use and frequent enough for screening. Moderate or profuse (vs. none/minimal) amount of secretion in nasal passage seen in anterior rhinoscopy satisfactorily either ruled in, if present (LR+ 3.2), or ruled out, if absent (negative likelihood ratio 0.2), bacterial ARS. If any secretion was seen in the posterior pharynx or middle meatus, the probability of bacterial ARS increased markedly (LR+ 5.3 and LR+ 11.0, respectively). CONCLUSION: We found symptoms or their change to be of little use in identifying bacterial ARS. In contrast, we observed several clinical findings after 9 to 10 days of symptoms to predict bacterial ARS quite accurately. PMID- 25782076 TI - Lower extremity kinematics that correlate with success in lateral load transfers over a low friction surface. AB - We previously studied balance during lateral load transfers, but were left without explanation of why some individuals were successful in novel low friction conditions and others were not. Here, we retrospectively examined lower extremity kinematics between successful (SL) and unsuccessful (UL) groups to determine what characteristics may improve low friction performance. Success versus failure over a novel slippery surface was used to dichotomise 35 healthy working-age individuals into the two groups (SL and UL). Participants performed lateral load transfers over three sequential surface conditions: high friction, novel low friction, and practiced low friction. The UL group used a wide stance with rotation mostly at the hips during the high and novel low friction conditions. To successfully complete the practiced low friction task, they narrowed their stance and pivoted both feet and torso towards the direction of the load, similar to the SL group in all conditions. This successful kinematic method potentially results in reduced muscle demand throughout the task. Practitioner Summary: The reason for this paper is to retrospectively examine the different load transfer strategies that are used in a low friction lateral load transfer. We found stance width to be the major source of success, while sagittal plane motion was altered to potentially maintain balance. PMID- 25782077 TI - Clinical application of a vascular interventional robot in cerebral angiography. AB - BACKGROUND: Cardiovascular and cerebrovascular diseases have become the leading cause of death for people, and endovascular surgery has become the main therapeutic method. Robot technology would overcome some limitations of conventional surgery, and has good prospects. METHODS: A total of 15 patients received cerebral angiography assisted by a vascular interventional robot following preoperative examination, with approval from the hospital ethics committee and informed consent by the patients' families. RESULTS: Robot-assisted angiography was performed quickly and smoothly without surgical complications. The remote positioning accuracy was 1.05 +/- 0.28 mm. The time staff were exposed to the digital subtraction angiography (DSA) machine was 0 min. The entire experimental process was mechanized and automated. CONCLUSION: This system achieved the preliminary purposes, including a reduction in radiation for the surgeons, facilitation of the application of interventional procedures, a decrease in operation time, and an improvement in operation quality. PMID- 25782078 TI - Re: Major postoperative complications following elective resection for colorectal cancer decrease long-term survival but not the time to recurrence. PMID- 25782079 TI - Human and biophysical drivers of fires in Semiarid Chaco mountains of Central Argentina. AB - Fires are a recurrent disturbance in Semiarid Chaco mountains of central Argentina. The interaction of multiple factors generates variable patterns of fire occurrence in space and time. Understanding the dominant fire drivers at different spatial scales is a fundamental goal to minimize the negative impacts of fires. Our aim was to identify the biophysical and human drivers of fires in the Semiarid Chaco mountains of Central Argentina and their individual effects on fire activity, in order to determine the thresholds and/or ranges of the drivers at which fire occurrence is favored or disfavored. We used fire frequency as the response variable and a set of 28 potential predictor variables, which included climatic, human, topographic, biological and hydrological factors. Data were analyzed using Boosted Regression Trees, using data from near 10,500 sampling points. Our model identified the fire drivers accurately (75.6% of deviance explained). Although humans are responsible for most ignitions, climatic variables, such as annual precipitation, annual potential evapotranspiration and temperature seasonality were the most important determiners of fire frequency, followed by human (population density and distance to waste disposals) and biological (NDVI) predictors. In general, fire activity was higher at intermediate levels of precipitation and primary productivity and in the proximity of urban solid waste disposals. Fires were also more prone to occur in areas with greater variability in temperature and productivity. Boosted Regression Trees proved to be a useful and accurate tool to determine fire controls and the ranges at which drivers favor fire activity. Our approach provides a valuable insight into the ecology of fires in our study area and in other landscapes with similar characteristics, and the results will be helpful to develop management policies and predict changes in fire activity in response to different climate changes and development scenarios. PMID- 25782080 TI - Temporal evolution of organic carbon concentrations in Swiss lakes: trends of allochthonous and autochthonous organic carbon. AB - Evaluation of time series of organic carbon (OC) concentrations in lakes is useful for monitoring some of the effects of global change on lakes and their catchments. Isolating the evolution of autochthonous and allochthonous lake OC might be a useful way to differentiate between drivers of soil and photosynthetic OC related changes. However, there are no temporal series for autochthonous and allochthonous lake OC. In this study, a new approach has been developed to construct time series of these two categories of OC from existing dissolved organic carbon (DOC) data. First, temporal series (longer than ten years) of OC have been compiled for seven big Swiss lakes and another 27 smaller ones and evaluated by using appropriate non-parametric statistical methods. Subsequently, the new approach has been applied to construct time series of autochthonous and allochthonous lake OC in the seven big lakes. Doing this was possible because long term series of DOC concentrations at different depths are available for these lakes. Organic carbon concentrations generally increase in big lakes and decrease in smaller ones, although only in some cases are these trends statistically significant. The magnitude of the observed changes is generally small in big lakes (<1% annual change) and larger in smaller lakes. Autochthonous DOC concentrations in big lakes increase or decrease depending on the lake and the station but allochthonous DOC concentrations generally increase. This pattern is consistent with an increase in the OC input from the lakes' catchments and/or an increase in the refractoriness of the OC in question, and with a temporal evolution of autochthonous DOC depending on the degree of recovery from past eutrophication of each particular lake. In small lakes, OC dynamics are mainly driven by decreasing biological productivity, which in many, but not all cases, outweighs the probable increase of allochthonous OC. PMID- 25782081 TI - Color and texture morphing with colloids on multilayered surfaces. AB - Dynamic morphing of marine species to match with environment changes in color and texture is an advanced means for surviving, self-defense, and reproduction. Here we use colloids that are placed inside a multilayered structure to demonstrate color and texture morphing. The multilayer is composed of a thermal insulating base layer, a light absorbing mid layer, and a liquid top layer. When external light of moderate intensity (~0.2 W cm(-2)) strikes the structure, colloids inside the liquid layer will be assembled to locations with an optimal absorption. When this system is exposed to continuous laser pulses, more than 18,000 times of reversible responses are recorded, where the system requests 20 ms to start the response and another 160 ms to complete. The flexibility of our concept further allows the system to be built on a variety of light-absorbing substrates, including dyed paper, gold thin film, and amorphous silicon, with the top layer even a solid. PMID- 25782084 TI - Implementation of a novel real-time platelet inventory management system at a multi-site transfusion service. AB - BACKGROUND: Blood platelets (PLTs) are a valuable commodity. Management of their inventory has implications both for patient care and for the cost of health care delivery. There are a variety of different methods of managing PLT inventory currently in practice and multiple theoretical models aimed at improving PLT inventory metrics. In this study we evaluate the ability of a novel electronic dashboard system that monitors and displays both PLT inventory and patient data to improve transfusion metrics at a quaternary health care center. STUDY DESIGN AND METHODS: The Capital District Health Authority is a quaternary health care center that transfuses approximately 2500 PLT units annually. To improve PLT discard rates a novel, low-overhead system that interfaces with the laboratory information system and displays real-time data between transfusion sites on PLT inventory and orders was implemented in November 2011. This study examines the transfusion quality metrics data from the 24 months before and after implementation. RESULTS: A significant reduction in mean monthly PLT outdate rate was observed after the implementation of the PLT dashboard suite from 24.5% (n = 24, SD +/- 6.4%) to 15.1% (n = 24, SD +/- 6.4%; p < 0.001). PLT age at time of transfusion was also reduced from 3.60 days (n = 4796, SD +/- 0.97 days) to 3.46 days (n = 4881, SD +/- 1.00 days; p < 0.001). CONCLUSIONS: This study describes the implementation of a novel PLT dashboard suite. This suite significantly reduced PLT outdate rates at our institution over the 48-month study period. PMID- 25782082 TI - Patient characteristics associated with the level of patient-reported care coordination among male patients with colorectal cancer in the Veterans Affairs health care system. AB - BACKGROUND: The current study was performed to determine whether patient characteristics, including race/ethnicity, were associated with patient-reported care coordination for patients with colorectal cancer (CRC) who were treated in the Veterans Affairs (VA) health care system, with the goal of better understanding potential goals of quality improvement efforts aimed at improving coordination. METHODS: The nationwide Cancer Care Assessment and Responsive Evaluation Studies survey involved VA patients with CRC who were diagnosed in 2008 (response rate, 67%). The survey included a 4-item scale of patient-reported frequency ("never," "sometimes," "usually," and "always") of care coordination activities (scale score range, 1-4). Among 913 patients with CRC who provided information regarding care coordination, demographics, and symptoms, multivariable logistic regression was used to examine odds of patients reporting optimal care coordination. RESULTS: VA patients with CRC were found to report high levels of care coordination (mean scale score, 3.50 [standard deviation, 0.61]). Approximately 85% of patients reported a high level of coordination, including the 43% reporting optimal/highest-level coordination. There was no difference observed in the odds of reporting optimal coordination by race/ethnicity. Patients with early-stage disease (odds ratio [OR], 0.60; 95% confidence interval [95% CI], 0.45-0.81), greater pain (OR, 0.97 for a 1-point increase in pain scale; 95% CI, 0.96-0.99), and greater levels of depression (OR, 0.97 for a 1-point increase in depression scale; 95% CI, 0.96-0.99) were less likely to report optimal coordination. CONCLUSIONS: Patients with CRC in the VA reported high levels of care coordination. Unlike what has been reported in settings outside the VA, there appears to be no racial/ethnic disparity in reported coordination. However, challenges remain in ensuring coordination of care for patients with less advanced disease and a high symptom burden. Cancer 2015;121:2207-2213. (c) 2015 American Cancer Society. PMID- 25782085 TI - Genetically distinct populations of northern shrimp, Pandalus borealis, in the North Atlantic: adaptation to different temperatures as an isolation factor. AB - The large-scale population genetic structure of northern shrimp, Pandalus borealis, was investigated over the species' range in the North Atlantic, identifying multiple genetically distinct groups. Genetic divergence among sample localities varied among 10 microsatellite loci (range: FST = -0.0002 to 0.0475) with a highly significant average (FST = 0.0149; P < 0.0001). In contrast, little or no genetic differences were observed among temporal replicates from the same localities (FST = 0.0004; P = 0.33). Spatial genetic patterns were compared to geographic distances, patterns of larval drift obtained through oceanographic modelling, and temperature differences, within a multiple linear regression framework. The best-fit model included all three factors and explained approximately 29% of all spatial genetic divergence. However, geographic distance and larval drift alone had only minor effects (2.5-4.7%) on large-scale genetic differentiation patterns, whereas bottom temperature differences explained most (26%). Larval drift was found to promote genetic homogeneity in parts of the study area with strong currents, but appeared ineffective across large temperature gradients. These findings highlight the breakdown of gene flow in a species with a long pelagic larval phase (up to 3 months) and indicate a role for local adaptation to temperature conditions in promoting evolutionary diversification and speciation in the marine environment. PMID- 25782086 TI - A 57-bp deletion in the ovine KAP6-1 gene affects wool fibre diameter. AB - High glycine-tyrosine keratin-associated proteins (HGT-KAPs) are predominantly present in the orthocortex of wool fibres. They vary in abundance in different wools and have been implicated in regulating wool fibre properties, but little is known about the functional roles of these proteins in the fibre matrix. In this study, we used polymerase chain reaction--single-strand conformational polymorphism (PCR-SSCP) analysis to screen for variation in a gene encoding the ovine HGT-KAP6-1 protein. We identified three gene variants (A, B and C). Variants A and B were similar to each other, with only three nucleotide differences occurring downstream of the coding sequence. However, variant C had a 57-bp deletion that would notionally result in a loss of 19 amino acids in the protein. The presence of C was found to be associated with an increase in mean fibre diameter (MFD), fibre diameter standard deviation (FDSD), coefficient of variation of fibre diameter (CVFD) and prickle factor (percentage of fibres over 30 microns; PF). Sheep of genotype BC produced wool of greater MFD, FDSD and PF than sheep of genotypes AA, AB and BB. The CVFD was greater in the BC sheep than the AB sheep. The results suggest that variation in ovine KRTAP6-1 affects wool fibre diameter-associated traits and that the 57-bp deletion in this gene would lead to coarser wool with greater FDSD, CVFD and PF. PMID- 25782087 TI - The in vitro impact of toothpaste extracts on cell viability. AB - Toothpastes contain three main components: detergents, abrasives, and fluoride. Detergents, particularly sodium lauryl sulfate, have been proposed as components that enable toothpastes to produce cytotoxic effects in vitro. However, not all toothpastes contain sodium lauryl sulfate, and almost no studies have found an association between detergents and the in vitro cytotoxicity of toothpastes. The present study examined the in vitro cytotoxicity of nine commercially available toothpastes containing four different detergents. Toothpastes were diluted in serum-free medium, centrifuged, and filter sterilized. The half-lethal concentration of the toothpaste-conditioned medium (TCM) was calculated based on the formation of formazan by gingival fibroblasts, oral squamous cell carcinoma HSC-2 cells, and L929 cells. Cell proliferation was analyzed, and live-dead staining was performed, after exposure of cells to conditioned medium prepared with 1% toothpaste (1% TCM). It was found that toothpastes containing sodium lauryl sulfate and amine fluoride strongly inhibited cell viability with the half lethal concentration being obtained with conditioned medium prepared with approximately 1% toothpaste (1% TCM). Toothpastes containing cocamidopropyl betaine and Steareth-20 showed higher half-lethal concentration values, with the half-lethal concentration being obtained with conditioned medium prepared with 10% (10% TCM) and 70% (70% TCM) toothpaste, respectively. Proliferation and live dead data were consistent with the cell-viability analyses. These results demonstrate that the type of detergent in toothpastes can be associated with changes in in vitro cell toxicity. PMID- 25782088 TI - [Mothers with cystic fibrosis: psychosocial data about an almost unknown group]. AB - AIMS: To explore pregnancy and motherhood in cystic fibrosis patients from the women's perspective. METHODS: Data were assessed with a purpose designed questionnaire and the paper focuses on the following sections: "pregnancy and birth" (feedback of significant others, women's knowledge, concerns, and overall judgement), and the "first year as a mother" (overall judgement). SAMPLE: 38/73 mothers filled in the questionnaire; mean age was 33.8 y +/- 7.1 y and mean age of firstborn child was 6.9 y +/- 5.7 years. Nine women had more than one biological child. 18 mothers (47 %) were currently employed, 12 of whom with 19 to 30 hours per week and none full-time. Mean FEV1 in perc. Pred. was 66 +/- 19 %. RESULTS: Pregnancy in CF should be planned and prepared, and this was achieved in 28 women, while 10 pregnancies were unplanned. The feedback of significant others towards wish for child/pregnancy was more positive in those who planned. Mothers' own parents reacted least enthusiastic, irrespective of whether or not pregnancy had been planned. The feedback of CF-teams differed according to women's lung function. The women's knowledge about "pregnancy and CF" was rather poor. Their concerns predominantly referred to detrimental effects of CF medication to the unborn child. CONCLUSIONS: Motherhood is increasingly becoming an option for young women with CF. Therefore, CF-teams are well-advised to proactively engage them in a dialogue about wish for child and impact of CF on motherhood. Knowledge about pregnancy/motherhood and CF should be increased. PMID- 25782089 TI - Palmoplantar hyperkeratosis: a rare cutaneous manifestation of juvenile dermatomyositis. AB - We report the case of a 12-year-old girl with juvenile dermatomyositis (JDM). She had a 12-month history of palmoplantar hyperkeratosis that was initially treated as eczema. We wish to alert clinicians to this rare cutaneous manifestation of JDM. PMID- 25782090 TI - Fast reversible single-step method for enhanced band contrast of polyacrylamide gels for automated detection. AB - Staining SDS-PAGE is commonly used in protein analysis for many downstream characterization processes. Although staining and destaining protocols can be adjusted, they can be laborious, and faint bands often become false negatives. Similarly, these faint bands hinder automated software band detections that are necessary for quantitative analyses. To overcome these problems, we describe a single-step rapid and reversible method to increase (up to 500%) band contrast in stained gels. Through the use of alcohols, we improved band detection and facilitated gel storage by drying the gels into compact white sheets. This method is suitable for all stained SDS-PAGE gels, including gradient gels and is shown to improve automated band detection by enhanced band contrast. PMID- 25782091 TI - Mixed HCV infection and reinfection in people who inject drugs--impact on therapy. AB - The majority of new and existing cases of HCV infection in high-income countries occur among people who inject drugs (PWID). Ongoing high-risk behaviours can lead to HCV re-exposure, resulting in mixed HCV infection and reinfection. Assays used to screen for mixed infection vary widely in sensitivity, particularly with respect to their capacity for detecting minor variants (<20% of the viral population). The prevalence of mixed infection among PWID ranges from 14% to 39% when sensitive assays are used. Mixed infection compromises HCV treatment outcomes with interferon-based regimens. HCV reinfection can also occur after successful interferon-based treatment among PWID, but the rate of reinfection is low (0-5 cases per 100 person-years). A revolution in HCV therapeutic development has occurred in the past few years, with the advent of interferon-free, but still genotype-specific regiments based on direct acting antiviral agents. However, little is known about whether mixed infection and reinfection has an effect on HCV treatment outcomes in the setting of new direct-acting antiviral agents. This Review characterizes the epidemiology and natural history of mixed infection and reinfection among PWID, methodologies for detection, the potential implications for HCV treatment and considerations for the design of future studies. PMID- 25782092 TI - Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. AB - Congenital diarrhoeal disorders (CDDs) represent an evolving web of rare chronic enteropathies, with a typical onset early in life. In many of these conditions, severe chronic diarrhoea represents the primary clinical manifestation, whereas in others diarrhoea is only a component of a more complex multi-organ or systemic disorder. Typically, within the first days of life, diarrhoea leads to a life threatening condition highlighted by severe dehydration and serum electrolyte abnormalities. Thus, in the vast majority of cases appropriate therapy must be started immediately to prevent dehydration and long-term, sometimes severe, complications. The number of well-characterized disorders attributed to CDDs has gradually increased over the past several years, and many new genes have been identified and functionally related to CDDs, opening new diagnostic and therapeutic perspectives. Molecular analysis has changed the diagnostic scenario in CDDs, and led to a reduction in invasive and expensive procedures. Major advances have been made in terms of pathogenesis, enabling a better understanding not only of these rare conditions but also of more common diseases mechanisms. PMID- 25782094 TI - Microbiota: Sewage comes up smelling like roses for microbiota research. PMID- 25782095 TI - Enhancing luminescence properties of lanthanide(III)/pyrimidine-4,6-dicarboxylato system by solvent-free approach. AB - The solvent-free melt reactions between lanthanide(iii) nitrates and pyrimidine 4,6-dicarboxylic acid (H2pmdc) led to three-dimensional (3D) coordination polymers with formula [Ln(MU4-pmdc)(NO3)(H2O)]n () [Ln(iii) = La, Ce, Pr, Nd, Sm, and Eu] and {[Ln(MU4-pmdc)(NO3)(H2O)].H2O}n () [Ln(iii) = Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu]. The crystal structure of compounds is built up from the junction of centrosymmetric Ln(iii)-pmdc dimers, where pmdc ligand adopts an unusual MU4 kappa(2)N,O:kappa(2)N',O':kappa(2)O,O'':kappaO''' coordination mode, rendering a metal coordination number of 10. The smaller ionic radii of the second half of the series prevents the latter coordination mode in , giving rise to a framework based on triangular shaped motifs. A common structural feature is the coordination of the nitrate anion as terminal chelating ligand which limits the presence of a unique coordination water molecule. Magnetic properties have been analysed for all compounds, through the variable temperature susceptibility and field dependent magnetization. Photoluminescence measurements were performed at different temperatures and excitation wavelengths upon Sm(3+), Eu(3+), Tb(3+), and Dy(3+) containing compounds which exhibit strong characteristic emissions in the visible region. Decay lifetime measurements indicate long-lived excitation states in the compounds by achieving values in the range of millisecond for the terbium compound. The absolute quantum yields of the polycrystalline samples result in 20% and 18% for and , respectively, and in almost negligible response for and . Illumination of single crystals of these compounds revealed waveguiding behaviour along the edges of the main axis of the crystals. PMID- 25782096 TI - The formation of novel social category conjunctions in working memory: A possible role for the episodic buffer? AB - Recent research (e.g., Hutter, Crisp, Humphreys, Waters, & Moffit; Siebler) has confirmed that combining novel social categories involves two stages (e.g., Hampton; Hastie, Schroeder, & Weber). Furthermore, it is also evident that following stage 1 (constituent additivity), the second stage in these models involves cognitively effortful complex reasoning. However, while current theory and research has addressed how category conjunctions are initially represented to some degree, it is not clear precisely where we first combine or bind existing social constituent categories. For example, how and where do we compose and temporarily store a coherent representation of an individual who shares membership of "female" and "blacksmith" categories? In this article, we consider how the revised multi-component model of working memory (Baddeley) can assist in resolving the representational limitations in the extant two-stage theoretical models. This is a new approach to understanding how novel conjunctions form new bound "composite" representations. PMID- 25782097 TI - New approaches to the assessment and treatment of suicidal adolescents. PMID- 25782093 TI - Alcoholic liver disease: mechanisms of injury and targeted treatment. AB - Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways. PMID- 25782099 TI - Risk factors for weight gain and metabolic syndrome in adolescents with psychiatric disorders: a historical prospective study. AB - OBJECTIVE: Adolescents with mental disorders are at increased risk for being overweight or obese, and subsequently developing metabolic syndrome. However, data regarding risk factors for weight gain during psychiatric hospitalization of adolescents are limited and inconsistent. The aim of this study was to investigate the sociodemographic, clinical, and pharmacological risk factors for weight gain during psychiatric treatment, in order to improve prevention of subsequent metabolic syndrome. METHODS: We conducted a historical prospective study of 146 adolescent patients (mean age 15.2+/-1.9 years, 52.7% males), consecutively admitted for day treatment in an adolescent day unit (length of stay 141+/-76 days). Anthropometric measurements and laboratory analyses of fasting glucose and lipid levels were conducted as part of the routine medical care at admission and discharge. Psychiatric diagnoses, medication histories, and sociodemographic data were obtained from the electronic medical records system. RESULTS: A significant increase in age- and gender adjusted body mass index (BMI) (i.e., z score) was observed (0.5+/-1.2 vs. 0.7+/-1.1 at admission and discharge, respectively, p<0.001). Male subjects were more prone to weight gain than females (odds ratio [OR]=3.5, 95% CI=1.2-10.3) and BMI z score at admission was inversely associated with weight gain (R (2)=0.2, p<0.0001). Surprisingly, age at admission, psychiatric diagnoses, length of stay, and number of medications were not associated with weight gain. Despite weight gain, fasting blood glucose and lipid profile did not change significantly during the study period. CONCLUSIONS: Hospitalization of adolescents in a psychiatric day unit may be associated with a significant weight gain, especially in male subjects and those with normal weight at admission. Efforts should be aimed to reduce weight gain among youth with psychiatric disorders during treatment, to avoid a subsequent metabolic syndrome. PMID- 25782098 TI - Loxapine add-on for adolescents and adults with autism spectrum disorders and irritability. AB - OBJECTIVES: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation. METHODS: We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped. RESULTS: Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype. CONCLUSIONS: Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study. PMID- 25782100 TI - Pharmacotherapeutic challenges in treatment of a child with "the triad" of obsessive compulsive disorder, attention-deficit/hyperactivity disorder and Tourette's disorder. PMID- 25782101 TI - Quetiapine and clozapine combination treatment for tourette's syndrome in an adolescent boy: potential role of dopamine supersensitivity in loss of treatment response. PMID- 25782103 TI - Sm@C2v(19138)-C76: A Non-IPR Cage Stabilized by a Divalent Metal Ion. AB - Although a non-IPR fullerene cage is common for endohedral cluster fullerenes, it is very rare for conventional endofullerenes M@C2n, probably because of the minimum geometry fit effect of the endohedral single metal ion. In this work, we report on a new non-IPR endofullerene Sm@C2v(19138)-C76, including its structural and electrochemical features. A combined study of single-crystal X-ray diffraction and DFT calculations not only elucidates the non-IPR cage structure of C2v(19138)-C76 but also suggests that the endohedral Sm(2+) ion prefers to reside along the C2 cage axis and close to the fused pentagon unit in the cage framework, indicative of a significant metal-cage interaction, which alone can stabilize the non-IPR cage. Furthermore, electrochemical studies reveal the fully reversible redox behaviors and small electrochemical gap of Sm@C2v(19138)-C76, which are comparable to those of IPR species Sm@D3h-C74. PMID- 25782102 TI - Unconjugated bilirubin inhibits proteolytic cleavage of von Willebrand factor by ADAMTS13 protease. AB - BACKGROUND: Bilirubin is a yellow breakdown product of heme catabolism. Increased serum levels of unconjugated bilirubin are conditions commonly seen in premature neonates and adults with acute hemolysis including thrombotic microangiopathy. Previous studies have shown that unconjugated bilirubin lowers plasma ADAMTS13 activity, but the mechanism is not fully understood. OBJECTIVES: The study is to determine whether unconjugated bilirubin directly inhibits the cleavage of von Willebrand factor (VWF) and its analogs by ADAMTS13. METHODS: Fluorogenic, surface-enhanced laser desorption/ionization time-of-flight mass spectrometric assay, and Western blotting analyses were used to address this question. RESULTS: Unconjugated bilirubin inhibits the cleavage of F485-rVWF73-H, D633-rVWF73-H, and GST-rVWF71-11K by ADAMTS13 in a concentration-dependent manner with a half maximal inhibitory concentration of ~13, ~70, and ~17 MUmol L(-1) , respectively. Unconjugated bilirubin also dose-dependently inhibits the cleavage of multimeric VWF by ADAMTS13 under denaturing conditions. The inhibitory activity of bilirubin on the cleavage of D633-rVWF73-H and multimeric VWF, but not F485-rVWF73-H, was eliminated after incubation with bilirubin oxidase that converts bilirubin to biliverdin. Furthermore, plasma ADAMTS13 activity in patients with hyperbilirubinemia increased after treatment with bilirubin oxidase. CONCLUSIONS: Unconjugated bilirubin directly inhibits ADAMTS13's ability to cleave both peptidyl and native VWF substrates in addition to its interference with certain fluorogenic assays. Our findings may help proper interpretation of ADAMTS13 results under pathological conditions. Whether elevated serum unconjugated bilirubin has prothrombotic effect in vivo remains to be determined in our future study. PMID- 25782104 TI - Mercury isotope fractionation during precipitation of metacinnabar (beta-HgS) and montroydite (HgO). AB - To utilize stable Hg isotopes as a tracer for Hg cycling and pollution sources in the environment, it is imperative that fractionation factors for important biogeochemical processes involving Hg are determined. Here, we report experimental results on Hg isotope fractionation during precipitation of metacinnabar (beta-HgS) and montroydite (HgO). In both systems, we observed mass dependent enrichments of light Hg isotopes in the precipitates relative to the dissolved Hg. Precipitation of beta-HgS appeared to follow equilibrium isotope fractionation with an enrichment factor epsilon(202)Hg(precipitate-supernatant) of -0.630/00. Precipitation of HgO resulted in kinetic isotope fractionation, which was described by a Rayleigh model with an enrichment factor of -0.320/00. Small mass-independent fractionation was observed in the HgS system, presumably related to nuclear volume fractionation. We propose that Hg isotope fractionation in the HgS system occurred in solution during the transition of O- to S coordination of Hg(II), consistent with theoretical predictions. In the HgO system, fractionation was presumably caused by the faster precipitation of light Hg isotopes, and no isotopic exchange between solid and solution was observed on the timescale investigated. The results of this work emphasize the importance of Hg solution speciation and suggest that bonding partners of Hg in solution complexes may control the overall isotope fractionation. The determined fractionation factor and mechanistic insights will have implications for the interpretation of Hg isotope signatures and their use as an environmental tracer. PMID- 25782105 TI - Design of a potent antibiotic peptide based on the active region of human defensin 5. AB - Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel beta strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design. PMID- 25782106 TI - The neurotechnological revolution: unlocking the brain's secrets to develop innovative technologies as well as treatments for neurological diseases. AB - The brain contains all that makes us human, but its complexity is the source of both inspiration and frailty. Aging population is increasingly in need of effective care and therapies for brain diseases, including stroke, Parkinson's disease and Alzheimer's disease. The world's scientific community working hard to unravel the secrets of the brain's computing power and to devise technologies that can heal it when it fails and restore critical functions to patients with neurological conditions. Neurotechnology is the emerging field that brings together the development of technologies to study the brain and devices that improve and repair brain function. What is certain is the momentum behind neurotechnological research is building, and whether through implants, BCIs, or innovative computational systems inspired by the human brain, more light will be shed on our most complex and most precious organ, which will no doubt lead to effective treatment for many neurological conditions. PMID- 25782107 TI - Unlocking pain: deep brain stimulation might be the key to easing depression and chronic pain. AB - Depression and chronic pain know no geographical boundaries. About 350 million people around the world experience long-lasting sadness and an unshakeable sense of hopelessness, and one person out of ten tries to live each day to its fullest despite continuous physical pain. These two difficult conditions frequently coexist, becoming more common with age. Looking ahead, we can expect the incidence of depression and chronic illness to grow, since more people over age 65 will populate the world by 2020 than children younger than five. PMID- 25782108 TI - Outside access: advances in tDCS could provide a mainstream clinical tool for noninvasive neuromodulation. AB - A treatment for depression, chronic pain, cravings, and more--this is the emerging field of transcranial direct current stimulation (tDCS). In tDCS, transcranial means through the skull, and direct current is a weak stimulation current delivered to the brain using noninvasive electrodes placed on the scalp [Figure 1(a)]. PMID- 25782109 TI - Inside tract: can deep brain stimulation survive its reputation for success? AB - When she was 37, Clare developed a tremor down her left side. At 39, she was diagnosed with Parkinson's disease and put on a series of medications. These helped for a time, but the effect didn't last. Within a few years, her tremors had grown so severe that Clare was dropping food at her waitressing job. She couldn't seat guests, and she burned herself when she tried to help out in the kitchen. Increasingly unable to support herself and at a loss for other options, Clare began to look into something called deep brain stimulation (DBS). PMID- 25782110 TI - Sending out an SOS...and more: next-generation textiles and EEG headsets transport vital biomed information. AB - It seems as if many of us are getting used to the idea of wearing sensors, whether they are counting the number of steps we take each day with an iPhone connected pedometer or keeping track of heart rate while we are doing an exercise routine or out riding a bicycle. That's probably good preparation, because a new generation of wearable sensors and smart textiles are coming to the fore to provide extended biomedical monitoring of heart, brain, muscle, and other physiological activity. PMID- 25782111 TI - Learning how we learn: in an unlikely confluence, bioengineers are finding fertile ground in research and teaching about learning. AB - "You know too much; it's time to kill you." In Russian, the phrase rhymes. The captain raised his glass, steering an inebriated wink my way. PMID- 25782112 TI - The great divide: some worry of a gap between what is being taught in American university undergraduate BME programs and the job market. AB - For decades, BME has been touted worldwide as the rising star in engineering disciplines. The number of technological advancements that can be credited to the field since the 1950s is staggering, ranging from new biomedical diagnostics and therapeutics to sensors, imaging technology, and orthopedics. In the United States, job numbers are on a steady rise and expected to grow by 27% within the next ten years, according to the U.S. Bureau of Labor Statistics. In those terms, "there has never been a better, more exciting time to enter the field," says Bruce Wheeler (Figure 1), former president of the IEEE Engineering in Medicine and Biology Society and a BME professor at the University of Florida in Gainesville. PMID- 25782113 TI - The real world: BME graduates reflect on whether universities are providing adequate preparation for a career in industry. AB - Let's face it: In the United States, a college degree isn't what it used to be. These days, 46% of recent college graduates consider themselves underemployed and in jobs that do not require their college degrees--degrees that have already cost many of these grads and their families hundreds of thousands of dollars in student loans, with no promise of a job and salary to pay those loans back. But engineering majors are said to be outliers. Engineering as a field is widely considered one of, if not the most, lucrative academic paths for students seeking well-paid employment immediately following college. The U.S. Bureau of Labor Statistics indicates that nearly 40% of the 45 most highly paid professions that require only a bachelor's degree are in engineering. Salaries for all biomedical engineers, entry level or not, are among the highest, with a median pay of US$86,960. And engineering departments at colleges are not shy to advertise these numbers: the Biomedical Engineering Department at the University of Texas, Austin, declares on its Web page that, "electing to graduate with a major in biomedical engineering opens the door to an ever-growing amount of job opportunities," citing a 72%, ten-year job growth forecast. Boston University's program cites U.S. News and World Report's claim that BME is the country's fastest-growing occupation. PMID- 25782114 TI - Allele-specific polymerase chain reaction typing and sequencing of mitochondrial D-loop region in broiler chickens in Japan. AB - This study aimed to comprehend a feature of single nucleotide polymorphism (SNP) in mitochondrial DNA (mtDNA) mainly of general broiler chickens in Japan. We typed two SNP sites (199C/T and 792A/G) of the D-loop region in mtDNA by allele specific PCR (AS-PCR) in 359 broiler (182 chunky and 177 cobb) and 506 layer (233 White Leghorn, 140 Barred Plymouth Rock and 133 Rhode Island Red) chickens. The SNP of 199C or 792A by AS-PCR was observed in the chunky and cobb chickens, and not in the layers. The haplotype 199T/792G was observed in a part of cobb and all layers. By the result of AS-PCR haplotyping and the broiler brands, the D-loop region was sequenced in 44 broiler chickens (20 chunky and 24 cobb) and compared with the layers' sequence data. Among the broiler and layer chickens, 21 SNP sites (including one insertion) and 11 sequence haplotypes were observed. Haplotype variation or correspondence was observed in and between the broiler brands. This study provides important information to establish a chicken meat traceability system by SNP haplotyping of mtDNA in Japan. PMID- 25782116 TI - Increased level of red cell distribution width is associated with poor coronary collateral circulation in patients with stable coronary artery disease. AB - OBJECTIVES: Previous studies have shown the association between various hematological parameters and cardiovascular diseases, and their prognostic value. In this study, we compared red cell distribution width (RDW), neutrophil lymphocyte ratio (NLR) and mean platelet volume (MPV) measurements among patients with poor coronary collateral circulation (CCC) and well-developed CCC. STUDY DESIGN: 326 patients with stable coronary artery disease (CAD) were evaluated retrospectively. CCC was graded by using the Rentrop classification. The poor CCC group included patients with Rentrop 0-1 CCC, and the good CCC group included Rentrop 2-3 CCC. RESULTS: There were 171 subjects (84% male; mean age 56.6+/-10.4 years) in the poor CCC group, and 155 subjects (89% male; mean age 57.6+/-9.7 years) in the good CCC group. The total number of vessels with >95% stenosis (1.1+/-0.5 vs. 1.0+/-0.4; p=0.64) and Gensini scores (84.4+/-38.8 vs. 83.3+/ 37.4; p=0.83) was not higher in the poor CCC group compared to the good CCC group. RDW was significantly higher in the poor CCC group compared to the good CCC group (14.19+/-1.36% vs. 13.89+/-1.19%; p=0.04). In multivariate logistic regression analysis, elevated levels of RDW and LDL were found to be independent predictors of poor CCC (OR 1.73, 95% CI: 1.30-2.29, p=0.01 and OR 1.01 95% CI 1.002-1.02; p=0.02, respectively). CONCLUSION: In the present study, poor CCC was found to be independently correlated with RDW, but not with any other hematological parameters in patients with stable CAD. PMID- 25782115 TI - Measurement of Total and Free Urinary Phenol and Paraben Concentrations over the Course of Pregnancy: Assessing Reliability and Contamination of Specimens in the Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Exposures to environmental phenols and parabens may be harmful, especially in utero. Prior studies have demonstrated high within-person variability of urinary concentrations across pregnancy. OBJECTIVES: We sought to measure phenol and paraben biomarker concentrations for the Norwegian Mother and Child Cohort (MoBa) study, assess within-person variability, and investigate any possible external phenol or paraben contamination of specimens. METHODS: We collected three spot urine samples at approximately 17, 23, and 29 weeks gestation in a hospital setting and added a preservative containing ethyl paraben. We measured urinary concentrations and within-person variability for phenols and parabens in a MoBa sample (n = 45), including a subgroup of 15 participants previously randomly selected for a bisphenol A (BPA) exposure study who had unusually high total BPA concentrations. Additionally, we compared reliability results for total, conjugated, and free concentrations of phenolic compounds. RESULTS: We detected total and free BPA, butyl paraben, propyl paraben, and methyl paraben in 100% of samples, total benzophenone-3 in 95% of samples, and infrequently detected free benzophenone-3 and total and free 2,4 dichlorophenol and 2,5-dichlorophenol. Intraclass correlation coefficients (ICCs) for total, conjugated, and free concentrations ranged from relatively low for BPA to moderate for propyl paraben. ICCs were generally similar overall and by subgroup. CONCLUSIONS: Using conjugated concentrations improved reliability estimates only for BPA. Measuring total and free concentrations, an approach that may be useful for future studies, allowed us to identify likely BPA and butyl paraben contamination of archived MoBa urine specimens. PMID- 25782117 TI - Evaluation of malnutrition with blood ghrelin and fecal elastase levels in acute decompensated heart failure patients. AB - OBJECTIVES: Exocrine pancreatic dysfunction may contribute to malnutrition and lack of appetite in the advanced stages of heart failure. Nutritional assessment was carried out on patients diagnosed with mild or moderate/severe heart failure. Fecal elastase levels are an indicator of pancreatic exocrine function and ghrelin is an appetite hormone which is also investigated for its contribution to malnutrition. STUDY DESIGN: This is an observational study. 52 patients (32 males, 20 females) aged over eighteen years and hospitalized for acute decompensated heart failure (ADHF) were included in the study. They were compared with 31 people (16 male, 15 female) of the same age as Control Group (C). Patients in New York Heart Association (NYHA) stages 1 and 2 were grouped as mild (miADHF), while those in NYHA stages 3 and 4 were grouped as moderate/severe ADHF (seADHF). Fecal and blood samples were taken at admission. In ADHF patients, exocrine pancreatic functions and their relationship with malnutrition were evaluated. Statistical analyses were performed using Tukey's test, the independent-sample t-test, the Kruskal-Wallis test, the Mann-Whitney U-test, the chi-square test and Pearson's bivariate correlation analysis. RESULTS: Significantly decreased fecal elastase levels were found when moderate/severe ADHF patients and the control group were compared. (C 278.9+/-144.8, miADHF 336.6+/-181.7, seADHF 168.7+/-153.6, p=0.002). 10 seADHF patients (50%) had severe, 4 (20%) moderate, and 6 (30%) mild pancreatic insufficiency. Ghrelin levels were higher in seADHF patients compared to C and miADHF patients (C 69.7+/ 34.6, miCHF 82.5+/-48.2, SeADHF 105.0+/-78.1 p=0.361). CONCLUSION: Fecal elastase and ghrelin hormone levels can contribute to the determination of malnutrition in ADHF patients. PMID- 25782119 TI - Association of fragmented QRS complexes on ECG with left ventricular diastolic function in hypertensive patients. AB - OBJECTIVES: Diastolic dysfunction occurs as a result of interstitial fibrosis in hypertensive patients. Fragmented QRS (fQRS) on ECG signifies myocardial fibrosis in various clinical situations. We investigated whether fQRS on ECG is related to diastolic dysfunction in patients with hypertension. STUDY DESIGN: The study population included 72 hypertensive patients with normal coronary angiogram. Fragmented QRS was defined as the presence of an additional R wave (R'), notching of the R or S wave or fragmentation in two contiguous leads corresponding to a major coronary artery. Echocardiography was performed to all patients to detect diastolic dysfunction. Diastolic dysfunction was regarded as non-severe if patients had normal diastolic function or grade 1 diastolic dysfunction or severe if they had grade >=2 diastolic dysfunction. RESULTS: Thirty-two patients had fQRS on ECGs (fQRS [+] group) and there were 40 patients who did not have fQRS on their ECGs (fQRS [-] group). The two groups were similar in terms of baseline characteristics. In patients with fQRS on the ECG, severe diastolic dysfunction was more prevalent (59.4% vs. 7.5%, p<0.001). The duration of hypertension was longer in patients with fQRS on the ECG (p<0.001). The presence of fQRS on the ECG was an indicator for severe diastolic dysfunction (B=1.954; odds ratio=7; 95% confidence interval=1.4-35.4; p=0.018). CONCLUSION: The presence of fQRS complexes on ECG predicts more severe diastolic dysfunction in patients with hypertension. PMID- 25782118 TI - Chronic inhibition of tumor necrosis factor-alpha with infliximab improves myocardial deformation in parallel with aortic elasticity in rheumatoid arthritis. AB - OBJECTIVES: This study investigated the effects of infliximab, a monoclonal antibody against TNFalpha, on myocardial deformation and aortic elasticity in patients with rheumatoid arthritis (RA), and the association of aortic elasticity with myocardial deformation. STUDY DESIGN: 38 female rheumatoid arthritis (RA) patients and 30 healthy controls were included in the study. Twenty patients received infliximab and 18 patients received prednisolone. Left ventricular (LV) longitudinal, circumferential and radial strain, systolic strain rate and early diastolic strain rate using speckle-tracking echocardiography, and aortic elasticity using M-mode echocardiography were assessed at baseline and post treatment. RESULTS: LV systolic longitudinal basal-, mid-, and apical strain, systolic mid- and apical strain rate, basal-, mid- and apical early strain rate, circumferential systolic apical strain and systolic strain rate were reduced in RA patients compared to controls. Compared to baseline, infliximab treatment increased aortic strain, aortic distensibility and decreased aortic beta index. No significant aortic elastic changes were observed with prednisolone treatment. Longitudinal basal- and apical strain, basal-, mid- and apical systolic and diastolic strain rates, circumferential basal systolic strain, radial mid- and apical strain and apical strain rate were increased following infliximab treatment. Infliximab treatment improves aortic elasticity in parallel to myocardial deformation, but no significant association was observed following prednisolone treatment. CONCLUSION: Myocardial deformation is impaired in RA patients and is related to aortic stiffness. Chronic inhibition of TNFalpha improves LV deformation in association with aortic elasticity. PMID- 25782121 TI - Predictors of survival in heart failure. PMID- 25782120 TI - The importance of hematologic indices in the risk stratification of patients with acute decompensated systolic heart failure. AB - OBJECTIVES: In patients with heart failure, a variety of hemogram parameters are known to be of prognostic significance. This study aimed to investigate which of these parameters is/are useful in predicting one-year all-cause mortality in patients with acute decompensated heart failure (ADHF). STUDY DESIGN: Patients who were hospitalized between September 2012-March 2013 in our hospital with systolic-ADHF with ejection fraction <=40%, symptoms, and findings of congestion were enrolled retrospectively in the study. The study population was divided into two groups based on one-year-mortality. RESULTS: 119 patients with ADHF (mean-age 67+/-14 years; 55% male) were enrolled in the study. One-year-mortality occurred in 29% of patients. Hemoglobin levels, platelet, basophil and lymphocyte counts were significantly lower, while red-cell distribution width (RDW) was found to be significantly higher in the one-year-mortality group. Neutrophil, monocyte, and eosinophil counts were similar in the two groups. Furthermore, lower estimated glomerular-filtration-rate (eGFR) and unused angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) were associated with mortality. Age, presence of hypertension, right-ventricular diameter, eGFR, ACE/ARB treatment, hemoglobin levels, RDW and platelet, leukocyte, lymphocyte, basophil, neutrophil, monocyte, and eosinophil-counts were found to have prognostic significance in univariate analysis. In multivariate analysis, decreased platelet, lymphocyte-counts and hemoglobin level on admission and unused ACE/ARB treatment at discharge (p<0.05) were found to be independent factors predicting one-year-mortality. CONCLUSION: Among hematological indices; hemoglobin level, platelet and lymphocyte counts are readily available, useful and inexpensive markers for the prediction of one-year all-cause mortality in ADHF patients. PMID- 25782123 TI - Acute inferior myocardial infarction after electrical weapon exposure: case report and review of the literature. AB - The use of conducted electrical weapons (CEWs) by legal security forces and in civil society is rapidly increasing. While they are generally considered safe devices, and fatal complications are rare, it is possible to see a small number of complications. In the present case, we describe the detection of acute inferior myocardial infarction in a patient who experienced chest pain after being exposed to a CEW. In such cases, multiple factors should be considered, and the choice of treatment and follow-up should be decided accordingly. PMID- 25782124 TI - Transjugular approach for radiofrequency ablation of permanent junctional reciprocal tachycardia in a newborn with bilateral femoral vein thrombosis. AB - Although radiofrequency ablation is the first line therapy in some children with supraventricular tachycardia, its application in small children is still limited. Herein, we presented a premature newborn diagnosed as multidrug-resistant permanent junctional reciprocal tachycardia, and treated by radiofrequency ablation via the jugular vein approach because of bilateral femoral vein thrombosis. We think that when there is limited vascular access, the transjugular route for radiofrequency ablation might be considered as an alternative treatment in newborns with multidrug-resistant supraventricular tachycardia. PMID- 25782122 TI - An epidemiological study to evaluate the use of vitamin K antagonists and new oral anticoagulants among non-valvular atrial fibrillation patients in Turkey- AFTER-2 study design. AB - OBJECTIVES: Atrial fibrillation (AF) is one of the most common causes of preventable ischemic stroke and is related to increased cardiovascular morbidity and mortality. There is a lack of data in Turkey on the use of new oral anticoagulants (NOACs), and time in therapeutic INR range (TTR) in vitamin K antagonist users and AF management modality. In this multi-center trial, we aimed to analyze, follow and evaluate the epidemiological data in non-valvular AF patients. STUDY DESIGN: Four thousand one hundred consecutive adult patients from 42 centers with at least one AF attack identified on electrocardiography will be included in the study. Patients with rheumatic mitral valve stenosis and prosthetic valve disease will be excluded from the study. At the end of one year, the patients will be evaluated in terms of major cardiac end points (death, transient ischemic attack, stroke, systemic thromboembolism, major bleeding and hospitalization). RESULTS: First results are expected in June 2015. Data about major cardiovascular end-points will be available in January 2016. CONCLUSION: The rates and kind of oral anticoagulant use, TTR in vitamin K antagonist users and main management modality applied in non-valvular AF patients will be determined by AFTER-2 study. In addition, the rate of major adverse events (MACEs) and the independent predictors of these MACEs will be detected (AFTER-2 Study ClinicalTrials.gov number, NCT02354456.). PMID- 25782125 TI - Delayed right-ventricular perforation by pacemaker lead; a rare complication in a 12-year-old girl. AB - Developments in the diagnosis and treatment of congenital heart diseases have led to an increase in the need for intracardiac pacemaker and implantable cardioverter defibrillator (ICD) implantation. Various complications related to these interventions can be seen in the short term (pneumothorax, pericardial effusion, cardiac perforation, etc...) and in the long term (infection, subclavian vein thrombosis, sensing and pacing problems, battery erosion and cardiac perforation). In this report, we present a rare case of cardiac perforation occurring 2 years after pacemaker implantation. PMID- 25782126 TI - [Ventriculer fibrillation due to Prinzmetal angina in a pregnant patient]. AB - Variant angina, which is also referred to as prinzmetal or coronary vasospastic angina, is a clinical entity characterized by episodes of angina pectoris, usually at rest and often between midnight and early morning, in association with ST-segment elevation on the electrocardiogram. Angina is usually caused by focal spasm of a major coronary artery resulting in a high-grade obstruction, and myocardial infarction may develop in some cases. We report a prinzmetal angina which caused ventricular fibrillation and cardiac arrest in an 18-week pregnant woman. PMID- 25782127 TI - Simultaneous transcatheter closure of intralobar pulmonary sequestration and patent ductus arteriosus in a patient with infantile Scimitar syndrome. AB - Scimitar syndrome is a rare disease associated with a right lung sequestration vascularised by arteries arising from the abdominal aorta and abnormal venous drainage into the inferior vena cava. The infantile form is generally presented with severe heart failure, pulmonary hypertension and respiratory distress. It may be associated with various intracardiac defects, including atrial septal defects, ventricular septal defects, patent ductus arteriosus or more complicated structural congenital heart defects. Here, we present a 2-month-old girl with Scimitar syndrome whose pulmonary arterial pressure decreased after transcatheter patent ductus arteriosus closure and embolization of the anomalous systemic arterial supply. PMID- 25782128 TI - Hypoglycemia detected during cardiac arrest of a non-diabetic patient with heart failure. AB - Hypoglycemia in non-diabetic patients with heart failure is a rare finding. It is thought to be caused by hepatic dysfunction secondary to chronic passive congestion, and reduced gluconeogenesis. In this report we present a 23-year-old man with a history of Duchenne muscular dystrophy hospitalized for decompensated heart failure and implantable cardioverter defibrillator shock. Laboratory examination on admission showed slightly elevated levels of hepatic enzymes. Despite the therapy for heart failure the patient's clinical status deteriorated, and sinus bradycardia and then cardiac arrest occured. After successful 5-minute cardiopulmonary resuscitation, an arterial blood sample revealed metabolic acidosis with a level of pH 7.04, bicarbonate 9.3, and glucose of 22 mg/dl. Acute treatment of metabolic acidosis with hypoglycemia was successfully performed. Based on this case, possible causes of unexplained hypoglycemia in non-diabetic patients with heart failure were described in a short literature review. PMID- 25782129 TI - The mysterious light of dark chocolate. AB - A healthy diet plays a key role in the prevention and management of cardiovascular diseases. Dark chocolate in particular has been shown to improve endothelial functions and lipid profile and to have cardiovascular protective effects via an inhibitory action on platelet functions. Recently, several studies have demonstrated the beneficial effects of chocolate, primarily on hypertension and other conditions such as coronary artery disease and hyperlipidemia. The present review provides a summary of the ingredients, bioavailability and cardiovascular protective effects of chocolate / cocoa and the published effects of chocolate on a number of cardiovascular diseases. PMID- 25782130 TI - Case images: a rare cause of severe aortic valve regurgitation: isolated aortic valve prolapse. PMID- 25782131 TI - Case images: a ring-shaped image in the right atrium. PMID- 25782132 TI - Case images: multimodality diagnostic imaging of a giant coronary artery aneurysm. PMID- 25782133 TI - Case images: quantification of a left atrial myxoma by three-dimensional speckle tracking echocardiography (From the MAGYAR-Path Study). PMID- 25782134 TI - Case images: Juxtarenal Leriche syndrome. PMID- 25782135 TI - Letter to the Editor: Persistent Stage-1 changes imply sustained perimyocardial irritation. PMID- 25782136 TI - Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery: a randomized controlled trial. AB - BACKGROUND: Preoperative conditions may play a significant role in postoperative cognitive dysfunction (POCD) development in elderly patients. We aimed to investigate whether preoperative cognitive training could lower the incidence of POCD one week after surgery. MATERIAL AND METHODS: A total of 141 ASA I-III elderly patients who underwent gastrointestinal surgery were enrolled into the study. Patients were randomized into either the Intervention group (69 analyzed) or the Control group (72 analyzed). Patients in the intervention group were instructed and trained in a cognition mnemonic skill for a total of three 1-hour sessions with the method of loci (MoL). Controls did not receive any cognitive training during hospitalization. All patients were tested using neuropsychological battery tests (NPTs) on admission and one week after surgery. RESULTS: The incidence of POCD in the intervention group (15.9%) was significantly lower than in the controls (36.1%) (P<0.05). Patients' performance in Brief Visuospatial Memory Test-Revised and Symbol-Digit Modalities Test were improved by the cognitive training. Increasing age, longer length of anesthesia and surgery, and lack of cognitive training were associated with a significantly higher risk of POCD (P<0.05). CONCLUSIONS: Cognitive training with MoL can reduce the decline of early postoperative cognitive function in elderly patients undergoing major gastrointestinal surgery. PMID- 25782137 TI - Peripheral substitution as a tool for tuning electron-accepting properties of phthalocyanine analogs in intramolecular charge transfer. AB - The intramolecular charge transfer (ICT), which is a pathway for excited state relaxation, was studied on the newly synthesized zinc(ii) complexes of tetrapyrazinoporphyrazines bearing one fixed donor (i.e., a dialkylamino substituent). The rest of the peripheral substituents on the core was designed with respect to their different electronic effects (OBu, neopentyl, StBu, COOBu). The photophysical (singlet oxygen and fluorescence quantum yields) and electrochemical (reduction potentials) properties were determined and compared within the series and with compounds that did not contain a donor moiety. The ICT efficiency correlated well with both the electron-deficient character of the core and the Hammett substituent constants sigmap. The most efficient ICT was observed for the core with the most electron-accepting substituent (COOBu), and the lowest ICT efficiency was detected for the least electron-deficient core (substituted by OBu). Titration of DMSO solutions of target compounds with H2SO4 indicated that basicity of the azomethine bridges was largely influenced by the character of the peripheral substituents while the dialkylamino donor center remained nearly unaffected. Furthermore, protonation of the donor nitrogen caused partial restoration of the fluorescence quantum yield (increase up to 90 times) due to blocking of ICT. The results implied that the ICT efficiency was strongly dependent on the electron-accepting properties of the core whose properties can be readily affected by suitable selection of peripheral substituents. PMID- 25782138 TI - A call for creativity in dual diagnosis research. PMID- 25782139 TI - Impact of Dietary Habits and Physical Activity on Bone Health among 40 to 60 Year Old Females at Risk of Osteoporosis in India. AB - Osteoporosis is a disorder of bones with increasing risk among women. However, a number of modifiable factors can help in combating this disorder. Present study examined the relationship of diet and physical activity and risk of osteoporosis through biochemical tests, bone mass density (BMD) scores, and standard questionnaires. Genetic risk for osteoporosis, presence of osteoarthritis, and thyroid problems were found among 8%, 7%, and 3% of participants, respectively; and 78% had onset of menopause between 47 to 55 years of age. Results revealed that less intake of proteins, minerals, and diverse fruit and vegetable consumption was significantly (p<=0.05; 0.01) correlated with decreased BMD score and serum calcium. It was concluded that adequate intake of varied fruits and vegetables, good protein, habit of daily physical activity, adequate sun exposure, and dietary calcium, may play a promising role in decreasing the risk of osteoporosis among women of this age group. PMID- 25782140 TI - Iron-catalyzed C-H borylation of arenes. AB - Well-defined iron bis(diphosphine) complexes are active catalysts for the dehydrogenative C-H borylation of aromatic and heteroaromatic derivatives with pinacolborane. The corresponding borylated compounds were isolated in moderate to good yields (25-73%) with a 5 mol% catalyst loading under UV irradiation (350 nm) at room temperature. Stoichiometric reactivity studies and isolation of an original trans-hydrido(boryl)iron complex, Fe(H)(Bpin)(dmpe)2, allowed us to propose a mechanism showing the role of some key catalytic species. PMID- 25782154 TI - Microarray analysis on gene regulation by estrogen, progesterone and tamoxifen in human endometrial stromal cells. AB - Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone responsive genes may be involved in normal uterine function and the development of endometrial malignancies. PMID- 25782155 TI - Accurate splicing of HDAC6 pre-mRNA requires SON. AB - Pre-mRNA splicing requires proper splice site selection mediated by many factors including snRNPs and serine-arginine rich (SR) splicing factors. Our lab previously reported that the SR-like protein SON maintains organization of pre mRNA splicing factors in nuclear speckles as well as splicing of many human transcripts including mRNAs coding for the chromatin-modifying enzymes HDAC6, ADA and SETD8. However, the mechanism by which SON maintains accurate splicing is unknown. To build tools for understanding SON-dependent pre-mRNA splicing, we constructed a minigene reporter plasmid driving expression of the genomic sequence spanning exons 26 through 29 of HDAC6. Following SON depletion, we observed altered splicing of HDAC6 reporter transcripts that showed exclusion of exons 27 and 28, reflecting the splicing patterns of endogenous HDAC6 mRNA. Importantly, loss of HDAC6 biological function was also observed, as indicated by truncated HDAC6 protein and corresponding absence of aggresome assembly activities of HDAC6 binding-of-ubiquitin zinc finger (BUZ) domain. We therefore propose that SON-mediated splicing regulation of HDAC6 is essential for supporting protein degradation pathways that prevent human disease. PMID- 25782156 TI - Positive selection and functional divergence of R2R3-MYB paralogous genes expressed in inflorescence buds of Scutellaria species (Labiatae). AB - Anthocyanin is the main pigment forming floral diversity. Several transcription factors that regulate the expression of anthocyanin biosynthetic genes belong to the R2R3-MYB family. Here we examined the transcriptomes of inflorescence buds of Scutellaria species (skullcaps), identified the expression R2R3-MYBs, and detected the genetic signatures of positive selection for adaptive divergence across the rapidly evolving skullcaps. In the inflorescence buds, seven R2R3-MYBs were identified. MYB11 and MYB16 were detected to be positively selected. The signature of positive selection on MYB genes indicated that species diversification could be affected by transcriptional regulation, rather than at the translational level. When comparing among the background lineages of Arabidopsis, tomato, rice, and Amborella, heterogeneous evolutionary rates were detected among MYB paralogs, especially between MYB13 and MYB19. Significantly different evolutionary rates were also evidenced by type-I functional divergence between MYB13 and MYB19, and the accelerated evolutionary rates in MYB19, implied the acquisition of novel functions. Another paralogous pair, MYB2/7 and MYB11, revealed significant radical amino acid changes, indicating divergence in the regulation of different anthocyanin-biosynthetic enzymes. Our findings not only showed that Scutellaria R2R3-MYBs are functionally divergent and positively selected, but also indicated the adaptive relevance of regulatory genes in floral diversification. PMID- 25782157 TI - Ameliorative effects of PACAP against cartilage degeneration. Morphological, immunohistochemical and biochemical evidence from in vivo and in vitro models of rat osteoarthritis. AB - Osteoarthritis (OA); the most common form of degenerative joint disease, is associated with variations in pro-inflammatory growth factor levels, inflammation and hypocellularity resulting from chondrocyte apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide endowed with a range of trophic effects in several cell types; including chondrocytes. However; its role in OA has not been studied. To address this issue, we investigated whether PACAP expression is affected in OA cartilage obtained from experimentally-induced OA rat models, and then studied the effects of PACAP in isolated chondrocytes exposed to IL-1beta in vitro to mimic the inflammatory milieu of OA cartilage. OA induction was established by histomorphometric and histochemical analyses. Changes in PACAP distribution in cartilage, or its concentration in synovial fluid (SF), were assessed by immunohistochemistry and ELISA. Results showed that PACAP abundance in cartilage tissue and SF was high in healthy controls. OA induction decreased PACAP levels both in affected cartilage and SF. In vitro, PACAP prevented IL-1beta-induced chondrocyte apoptosis, as determined by MTT assay; Hoechst staining and western blots of apoptotic-related proteins. These changes were also accompanied by decreased i-NOS and COX-2 levels, suggesting an anti-inflammatory effect. Altogether, these findings support a potential role for PACAP as a chondroprotective agent for the treatment of OA. PMID- 25782158 TI - Molecular mechanisms of taste recognition: considerations about the role of saliva. AB - The gustatory system plays a critical role in determining food preferences and food intake, in addition to nutritive, energy and electrolyte balance. Fine tuning of the gustatory system is also crucial in this respect. The exact mechanisms that fine tune taste sensitivity are as of yet poorly defined, but it is clear that various effects of saliva on taste recognition are also involved. Specifically those metabolic polypeptides present in the saliva that were classically considered to be gut and appetite hormones (i.e., leptin, ghrelin, insulin, neuropeptide Y, peptide YY) were considered to play a pivotal role. Besides these, data clearly indicate the major role of several other salivary proteins, such as salivary carbonic anhydrase (gustin), proline-rich proteins, cystatins, alpha-amylases, histatins, salivary albumin and mucins. Other proteins like glucagon-like peptide-1, salivary immunoglobulin-A, zinc-alpha-2 glycoprotein, salivary lactoperoxidase, salivary prolactin-inducible protein and salivary molecular chaperone HSP70/HSPAs were also expected to play an important role. Furthermore, factors including salivary flow rate, buffer capacity and ionic composition of saliva should also be considered. In this paper, the current state of research related to the above and the overall emerging field of taste related salivary research alongside basic principles of taste perception is reviewed. PMID- 25782159 TI - RNA-Seq transcriptome analysis of maize inbred carrying nicosulfuron-tolerant and nicosulfuron-susceptible alleles. AB - Postemergence applications of nicosulfuron can cause great damage to certain maize inbred lines and hybrids. Variation among different responses to nicosulfuron may be attributed to differential rates of herbicide metabolism. We employed RNA-Seq analysis to compare transcriptome responses between nicosulfuron treated and untreated in both tolerant and susceptible maize plants. A total of 71.8 million paired end Illumina RNA-Seq reads were generated, representing the transcription of around 40,441 unique reads. About 345,171 gene ontology (GO) term assignments were conducted for the annotation in terms of biological process, cellular component and molecular function categories, and 6413 sequences with 108 enzyme commission numbers were assigned to 134 predicted Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways. Digital gene expression profile (DGE) analysis using Solexa sequencing was performed within the susceptible and tolerant maize between the nicosulfuron-treated and untreated conditions, 13 genes were selected as the candidates most likely involved in herbicide metabolism, and quantitative RT-PCR validated the RNA-Seq results for eight genes. This transcriptome data may provide opportunities for the study of sulfonylurea herbicides susceptibility emergence of Zea mays. PMID- 25782160 TI - Isolation of a pluripotent neural stem cell from the embryonic bovine brain. AB - We recently isolated stem cells derived from the brain of a bovine fetus, utilizing a particular mechanical separation method. After improving our experimental conditions, we obtained neural stem cells using an optimized culture medium system. The cells were expanded, established in continuous cell culture and used for immunofluorescence cytochemistry. RT-PCR showed that embryonic neural stem cells (NSCs) not only expresses the protein Sox2, Nestin but also Pax6, Musashi proteins and were differentiated into the three classical neuronal phenotypes (neurons, astrocytes, and oligodendrocytes). PMID- 25782161 TI - Locus number estimation of MHC class II B in stone flounder and Japanese flounder. AB - Members of major histocompatibility complex (MHC) family are important in immune systems. Great efforts have been made to reveal their complicated gene structures. But many existing studies focus on partial sequences of MHC genes. In this study, by gene cloning and sequencing, we identified cDNA sequences and DNA sequences of the MHC class II B in two flatfishes, stone flounder (Kareius bicoloratus) and homozygous diploid Japanese flounder (Paralichthys olivaceus). Eleven cDNA sequences were acquired from eight stone flounder individuals, and most of the polymorphic sites distributed in exons 2 and 3. Twenty-eight alleles were identified from the DNA fragments in these eight individuals. It could be deduced from their Bayesian inference phylogenetic tree that at least four loci of MHC class II B exist in stone flounder. The detailed whole-length DNA sequences in one individual were analyzed, revealing that the intron length varied among different loci. Four different cDNA sequences were identified from one homozygous diploid Japanese flounder individual, implying the existence of at least four loci. Comparison of the cDNA sequences to the DNA sequence confirmed that six exons existed in this gene of Japanese flounder, which was a common feature shared by Pleuronectiformes fishes. Our results proved the multi-locus feature of MHC class II B. The sequences we obtained would provide detailed and systematic data for further research. PMID- 25782163 TI - A primary care intervention to improve weight in obese children: A feasibility study. AB - PURPOSE: Examine the effects of a primary care weight management program, which used a parent-child-provider collaborative negotiation intervention, among rural dwelling families with obese children. DATA SOURCES: Health histories, physical examinations, fasting blood samples, interviews, and questionnaires. CONCLUSIONS: Feasibility of implementing a family weight management intervention in a rural primary care setting was demonstrated. Few differences between the treatment and comparison groups were found; however, more favorable trends and outcomes occurred in those who received the intervention. IMPLICATIONS FOR PRACTICE: Positive provider-patient communication in helping families with obese children make difficult lifestyle changes should be encouraged in primary care clinics as small changes in behavior can result in reducing risk and improving health outcomes. PMID- 25782162 TI - Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells. AB - Recent studies indicate that post-translational protein neddylation is required for the maintenance of cell viability in several lymphoma cell lines, while inhibition of the neddylation pathway with an NEDD8-activating enzyme (NAE) inhibitor MLN4924 induces apoptosis in lymphoma cells. However, the mechanism by which neddylation inhibition induces apoptosis in lymphoma cells has not been fully elucidated. Moreover, it is unknown whether neddylation inhibition triggers non-apoptotic cell-killing responses, such as cell senescence, in lymphoma cells. Here, we report that MLN4924 specifically inhibited protein neddylation, inactivated cullin-RING E3 ligase (CRL), the best-known neddylation substrate, and induced the accumulation of tumor-suppressive CRL substrates in lymphoma cells. Moreover, MLN4924 potently suppressed the growth of lymphoma cells by inducing G2 cell-cycle arrest, followed by apoptosis or senescence in a cell line dependent manner. MLN4924-induced apoptosis was mediated by intrinsic apoptotic signaling with substantial up-regulation of pro-apoptotic Bik and Noxa as well as down-regulation of anti-apoptotic XIAP, c-IAP1 and c-IAP2, while senescence induction upon neddylation inhibition seemed dependent on the expression of tumor suppressor p21/p27. Together, these findings expand our understanding on how lymphoma cells respond to neddylation inhibition and support the development of neddylation inhibitors (e.g. MLN4924) for the treatment of lymphoma. PMID- 25782164 TI - Moderate cyclic tensile strain alters the assembly of cartilage extracellular matrix proteins in vitro. AB - Mechanical loading influences the structural and mechanical properties of articular cartilage. The cartilage matrix protein collagen II essentially determines the tensile properties of the tissue and is adapted in response to loading. The collagen II network is stabilized by the collagen II-binding cartilage oligomeric matrix protein (COMP), collagen IX, and matrilin-3. However, the effect of mechanical loading on these extracellular matrix proteins is not yet understood. Therefore, the aim of this study was to investigate if and how chondrocytes assemble the extracellular matrix proteins collagen II, COMP, collagen IX, and matrilin-3 in response to mechanical loading. Primary murine chondrocytes were applied to cyclic tensile strain (6%, 0.5 Hz, 30 min per day at three consecutive days). The localization of collagen II, COMP, collagen IX, and matrilin-3 in loaded and unloaded cells was determined by immunofluorescence staining. The messenger ribo nucleic acid (mRNA) expression levels and synthesis of the proteins were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and western blots. Immunofluorescence staining demonstrated that the pattern of collagen II distribution was altered by loading. In loaded chondrocytes, collagen II containing fibrils appeared thicker and strongly co stained for COMP and collagen IX, whereas the collagen network from unloaded cells was more diffuse and showed minor costaining. Further, the applied load led to a higher amount of COMP in the matrix, determined by western blot analysis. Our results show that moderate cyclic tensile strain altered the assembly of the extracellular collagen network. However, changes in protein amount were only observed for COMP, but not for collagen II, collagen IX, or matrilin-3. The data suggest that the adaptation to mechanical loading is not always the result of changes in RNA and/or protein expression but might also be the result of changes in matrix assembly and structure. PMID- 25782165 TI - Neurohistological abnormalities during early porcine endotoxemia. AB - BACKGROUND: Brain dysfunction is common in sepsis. We aimed to assess whether cerebral perfusion, oxygenation, and/or metabolism are abnormal during early endotoxemia, and how they may relate to potential neurohistological changes. METHODS: In this prospective animal study, we included 12 pigs (weight: 42 +/- 4 kg; mean +/- SD) that were exposed to Escherichia coli lipopolysaccharide (E. coli LPS B0111 : B4, 0.4 MUg/kg/h) or saline infusion (n = 6, each) for 10 h. Systemic hemodynamics, cerebral blood flow, intracranial pressure, and brain tissue oxygen tension were continuously measured. At the end of the experiment, formalin-fixed brains were cut in coronal sections and embedded in paraffin. Afterwards, the sections were cut at 5 microns and stained with hematoxylin and eosin. RESULTS: Stable systemic hemodynamics in both groups were associated with higher carotid arterial blood flow after 10 h of endotoxemia (9.0 +/- 2.2 ml/kg/min) compared to controls (6.6 +/- 1.2 ml/kg/min; time-group interaction: P = 0.014). Intracranial pressure, cerebral perfusion pressure, brain oxygen consumption, and brain tissue oxygen tension were similar in both groups. In four of the six endotoxemic animals but in none of the controls, cerebral tissue lesions were found (encephalomalacia with spongy degeneration of white matter, axonal swelling, and ischemic neuronal thalamic necrosis), including significant venous vascular alterations, predominantly in the brainstem, in three of the four animals. CONCLUSIONS: Early endotoxemia seems to be associated with histological signs of brain damage unrelated to systemic or cerebral hemodynamics or oxygenation. PMID- 25782166 TI - Impact of initial 24-h urine output on short-term outcomes in patients with ST segment elevation myocardial infarction admitted without cardiogenic shock and renal dysfunction. AB - OBJECTIVES: Our study aims to evaluate the prognostic value of initial 24-h urine output (UO) in patients with ST-segment elevation myocardial infarction (STEMI) admitted without cardiogenic shock and renal dysfunction, and to determine the additional risk stratification offered by adding initial 24-h UO to TIMI risk score (TRS). METHODS: Data from 7078 consecutive STEMI patients in a multi-center registry were retrospectively analyzed. Patients were divided into 4 groups according to initial 24-h UO quartiles. The primary endpoints were 7- and 30-day all-cause mortality. RESULTS: Patients in the lowest UO quartile (<=1020 mL) had significantly higher 7- and 30-day all-cause mortality rates, cardiogenic shock, and major adverse cardiovascular events (MACE) than those in other groups (all P<0.05). After multivariate adjustment, initial 24-h UO<=1020 mL was independently associated with an increased risk in 7-day all-cause mortality (HR=4.649, 95%CI 3.348-6.455) and 30-day all-cause mortality (HR=3.775, 95%CI 2.891-4.931) as well as 7-day MACE (HR=1.845, 95%CI 1.563-2.179) and 30-day MACE (HR=1.818, 95%CI 1.553-2.127). Initial 24-h UO provided additional risk stratification across all TRS groups and improved the discriminatory ability of TRS with respect to 7-day all-cause mortality (c-statistic from 0.704 to 0.764) and 30-day all-cause mortality (c-statistic from 0.706 to 0.743). CONCLUSION: Reduced initial 24-h UO (<=1020 mL) was associated with an increased risk in 7- and 30-day all-cause mortality and MACE in STEMI patients admitted without cardiogenic shock and renal dysfunction. The combination of initial 24-h UO and TRS improved short-term outcome prediction when compared to TRS alone, particularly in patients with initial 24-h UO<=1020 mL. PMID- 25782167 TI - The effects of alterations in the osseous external auditory canal on perceived sound quality. AB - OBJECTIVES/HYPOTHESIS: To evaluate the perceptual effect of the altered shape of the osseous external auditory canal (OEAC) on sound quality. STUDY DESIGN: Prospective study. METHODS: Twenty subjects with normal hearing were presented with six simulated sound conditions representing the acoustic properties of six different ear canals (three normal ears and three cavities). The six different real ear unaided responses of these ear canals were used to filter Dutch sentences, resulting in six simulated sound conditions. A seventh unfiltered reference condition was used for comparison. Sound quality was evaluated using paired comparison ratings and a visual analog scale (VAS). RESULTS: Significant differences in sound quality were found between the normal and cavity conditions (all P < .001) using both the seven-point paired comparison rating and the VAS. No significant differences were found between the reference and normal conditions. Sound quality deteriorates when the OEAC is altered into a cavity. CONCLUSIONS: This proof of concept study shows that the altered acoustic quality of the OEAC after radical cavity surgery may lead to a clearly perceived deterioration in sound quality. Nevertheless, some questions remain about the extent to which these changes are affected by habituation and by other changes in middle ear anatomy and functionality. LEVEL OF EVIDENCE: 4 PMID- 25782168 TI - Technical considerations in laparoscopic near-infrared sentinel lymph node mapping in early colonic neoplasia--a video vignette. PMID- 25782169 TI - T lymphocytes need less than 3 min to discriminate between peptide MHCs with similar TCR-binding parameters. AB - T lymphocytes need to detect rare cognate foreign peptides among numerous foreign and self-peptides. This discrimination seems to be based on the kinetics of TCRs binding to their peptide-MHC (pMHC) ligands, but there is little direct information on the minimum time required for processing elementary signaling events and deciding to initiate activation. Here, we used interference reflection microscopy to study the early interaction between transfected human Jurkat T cells expressing the 1G4 TCR and surfaces coated with five different pMHC ligands of 1G4. The pMHC concentration required for inducing 50% maximal IFN-gamma production by T cells, and 1G4-pMHC dissociation rates measured in soluble phase or on surface-bound molecules, displayed six- to sevenfold variation among pMHCs. When T cells were dropped onto pMHC-coated surfaces, rapid spreading occurred after a 2-min lag. The initial spreading rate measured during the first 45 s, and the contact area, were strongly dependent on the encountered TCR ligand. However, the lag duration did not significantly depend on encountered ligand. In addition, spreading appeared to be an all-or-none process, and the fraction of spreading cells was tightly correlated to the spreading rate and spreading area. Thus, T cells can discriminate between fairly similar TCR ligands within 2 min. PMID- 25782170 TI - Efficacy and Safety of an Oral Ambroxol Spray in the Treatment of Acute Uncomplicated Sore Throat. AB - OBJECTIVE: Compare the efficacy and tolerability of oral spray formulations delivering 2.5, 5, and 10 mg ambroxol (AXS) per application (4 actuations/application) in relieving acute sore throat vs. spraying a matched placebo solution. DESIGN: Multi-centre, placebo-controlled, randomised, double blind trial with up to 6 daily applications of the assigned medication for up to 3 days. PATIENTS: 511 outpatients with acute sore throat were enrolled, 494 were treated. TREATMENTS: Up to 6 spray applications per day as needed for up to 3 days. RESULTS: All treatments led to a reduction in pain intensity (PI); the mean cumulative PI-reductions over the first 2 h after the 1(st) dose (SPIDnorm(0-2)) were 24.7, 26.6, 26.0, and 32.2% (SEM: 0.023) of the predose PI for treatment with placebo, and the 2.5, 5, and 10 mg AXS, respectively. These mean reductions were 2 (CI: -3.6; 7.5), 1.3 (CI: -4.3; 6.8), and 7.5 (CI: 2.0;13.1) percent points larger than for placebo. The 2.5 and 5 mg AXS were not distinguishable from placebo, but the 10 mg AXS was evidently superior. The numbers needed to treat (NNT) when comparing 10 mg AXS with placebo, were 9.5 and 8.8 for an average pain relief of 33 and 50% of the maximum achievable effect over the first 2 h. CONCLUSIONS: 10 mg AXS showed a statistically significantly superior pain reduction relative to the placebo spray. Treatment with 10 mg AXS reaches an extent of pain relief that can be accepted to be clinically meaningful and was well tolerated. PMID- 25782171 TI - Sexual dysfunction: Beyond the curve-CCH shows promise for Peyronie's. PMID- 25782172 TI - Kidney cancer: SETD2 affects DNA replication. PMID- 25782173 TI - Bladder cancer: Urinary EGFR and EpCAM predict cancer-specific survival. PMID- 25782174 TI - Prostate cancer: Multifocal disease--independent clonal lineages in malignant nodules and even in normal tissue. PMID- 25782175 TI - Tetramethylammonium-lactobionate: A novel ionic liquid chiral selector based on saccharides in capillary electrophoresis. AB - Chiral ionic liquids (ILs) have aroused widespread interest in separation science; however, only a few papers have reported the application of chiral ILs in CE for enantioseparation, and the use of chiral ILs as the sole chiral selector in an electrophoretic or a chromatographic system was reported in only three papers. In this study, we designed a lactobionic acid LA-based IL, tetramethylammonium-lactobionate (TMA-LA), and it is very interesting to find that the chiral separation capability can be remarkably improved when a conventional saccharide chiral selector evolved into an IL chiral selector. A comparative study of the enantiorecognition capability of three separation systems (single LA system, LA + TMA-chloride (TMA-Cl) system, and TMA-LA IL system) was also conducted, and the results showed that the use of TMA-LA IL as the sole chiral selector exhibited a remarkable superiority. A series of parameters affecting the enantioseparation, such as the type and proportion of organic modifier, buffer composition and pH, chiral selector concentration, as well as applied voltage were systematically investigated. The best enantioseparation was obtained at pH 7.6 using a 40 mM borax buffer with 40% v/v methanol, 200 mM TMA-LA, and 20 kV applied voltage. It is the first time that a saccharide-based IL is evaluated as a sole chiral selector in CE, and we hope this study would provide a new direction for the development of novel ILs chiral selectors based on conventional chiral selectors. PMID- 25782176 TI - New benzo[d]thiazol-2-yl-aminoacetamides as potential anticonvulsants: synthesis, activity and prediction of molecular properties. AB - A series of N-(substituted-2-oxo-4-phenylazetidin-1-yl)-2-((6 substitutedbenzo[d]thiazol-2-yl)amino)acetamide derivatives were synthesized using pharmacophoric features with aromatic hydrophobic aryl ring (A), NH-C=O as hydrogen bonding domain, the nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). The synthesized molecules were initially screened for anticonvulsant activity using the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole test in albino mice. An acute neurotoxicity study on the synthesized molecules was also carried out using the rotarod test. The results of these tests revealed that two compounds, 5b and 5q, showed promising activity with ED50 values of 15.4 and 18.6 mg/kg and protective indices of 20.7 and 34.9 in the MES test, respectively, which are found to be approximately fourfold higher than those of the standard drugs phenytoin (6.9) and carbamazepine (8.1). These molecules may act as lead of the designed scheme. The pharmacokinetic profiles of all the synthesized compounds were estimated using Molinspiration software. None of the compounds violated Lipinski's "rule of five". The possible structure-activity relationship was discussed. In conclusion, this manuscript shows that the developed model has a highly prognostic power for the further investigation of better benzothiazole derivatives for future discovery and development. PMID- 25782177 TI - An exploratory analysis of the relationship between ambient ozone and particulate matter concentrations during early pregnancy and selected birth defects in Texas. AB - We performed an exploratory analysis of ozone (O3) and fine particulate matter (PM2.5) concentrations during early pregnancy and multiple types of birth defects. Data on births were obtained from the Texas Birth Defects Registry (TBDR) and the National Birth Defects Prevention Study (NBDPS) in Texas. Air pollution concentrations were previously determined by combining modeled air pollution concentrations with air monitoring data. The analysis generated hypotheses for future, confirmatory studies; although many of the observed associations were null. The hypotheses are provided by an observed association between O3 and craniosynostosis and inverse associations between PM2.5 and septal and obstructive heart defects in the TBDR. Associations with PM2.5 for septal heart defects and ventricular outflow tract obstructions were null using the NBDPS. Both the TBDR and the NBPDS had inverse associations between O3 and septal heart defects. Further research to confirm the observed associations is warranted. PMID- 25782178 TI - Simultaneous ultrasound-assisted ternary adsorption of dyes onto copper-doped zinc sulfide nanoparticles loaded on activated carbon: optimization by response surface methodology. AB - The simultaneous and competitive ultrasound-assisted removal of Auramine-O (AO), Erythrosine (Er) and Methylene Blue (MB) from aqueous solutions were rapidly performed onto copper-doped zinc sulfide nanoparticles loaded on activated carbon (ZnS:Cu-NP-AC). ZnS:Cu nanoparticles were studied by FESEM, XRD and TEM. First, the effect of pH was optimized in a one-at-a-time procedure. Then the dependency of dyes removal percentage in their ternary solution on the level and magnitude of variables such as sonication time, initial dyes concentrations and adsorbent dosage was fully investigated and optimized by central composite design (CCD) under response surface methodology (RSM) as well as by regarding desirability function (DF) as a good and general criterion. The good agreement found between experimental and predicted values supports and confirms the suitability of the present model to predict adsorption state. The applied ultrasound strongly enhanced mass transfer process and subsequently performance. Hence, a small amount of the adsorbent (0.04 g) was capable to remove high percentage of dyes, i.e. 100%, 99.6% and 100% for MB, AO and Er, respectively, in very short time (2.5 min). The experimental equilibrium data fitting to Langmuir, Freundlich, Temkin and Dubinin-Radushkevich models showed that the Langmuir model applies well for the evaluation and description of the actual behavior of adsorption. The small amount of proposed adsorbent (0.015 g) was applicable for successful removal of dyes (RE>99.0%) in short time (2.5 min) with high adsorption capacity in single component system (123.5 mg g(-1) for MB, 123 mg g(-1) for AO and 84.5 mg g(-1) for Er). Kinetics evaluation of experiments at various time intervals reveals that adsorption processes can be well predicated and fitted by pseudo second-order and Elovich models. PMID- 25782179 TI - Synthesis, characterization, and biological evaluation of Schiff base platinum(II) complexes. AB - The platinum complexes of Schiff base ligands derived from 4-aminoantipyrine and a few substituted aldehydes were synthesized and characterized by elemental analysis, mass, (1)H NMR, IR, electronic spectra, molar conductance, and powder XRD. The structure of one of the ligands L5 was confirmed by a single crystal XRD analysis. The Schiff base ligand crystallized in the triclinic, space group P-1 with a=7.032(2)A, b=9.479(3)A, c=12.425(4)A, alpha=101.636(3) degrees , beta=99.633(3) degrees , gamma=94.040(3) degrees , V=795.0(4)A(3), Z=2, F(000)=352, Dc=1.405 mg/m(3), MU=0.099 mm(-1), R=0.0378, and wR=0.0967. The spectral results show that the Schiff base ligand acts as a bidentate donor coordinating through the azomethine nitrogen and the carbonyl oxygen atoms. The geometrical structures of these complexes are found to be square planar. Antimicrobial studies indicate that these complexes exhibit better activity than the ligand. The anticancer activities of the complexes have also been studied towards human cervical cancer cell line (HeLa), Colon Cancer Cells (HCT116) and Epidermoid Carcinoma Cells (A431) and it was found that the [Pt(L3)Cl2] complex is more active. PMID- 25782180 TI - Using Raman spectroscopy to understand the origin of the phase transitions observed in [(C3H7)4N]2Zn2Cl6 compound. AB - Phase transitions of the centrosymmetric compound, [(C3H7)4N]2Zn2Cl6, were studied by differential scanning calorimetry (DSC), X-ray diffraction, Raman spectroscopy and dielectric measurements. Two reversible order-disorder and displacive phase transitions are observed at T1=327K and T2=347K with 3K and 4K hysteresis respectively, indicating a first order character. The evolution of Raman line shifts, "nu", and the half-width, "Deltanu", versus temperature show some singularities associated with the transitions, suggesting that they are governed by the reorientational and the displacement of the organic part. Besides the results of the dielectric permittivity study confirms the conclusion drawn from the calorimetric and Raman measurements that the phase transition located in the vicinity of the temperature of the dielectric proprieties is characterized by change of dynamical state of cation. PMID- 25782181 TI - A Standard of Knowledge for the Professional Practice of Toxicology. AB - BACKGROUND: Employers, courts, and the general public judge the credibility of professionals based on credentials such as academic degrees, publications, memberships in professional organizations, board certifications, and professional registrations. However, the relevance and merit of these credentials can be difficult to determine objectively. Board certification can be a reliable indicator of proficiency if the certifying organization demonstrates, through regularly scheduled independent review, that its processes meet established standards and when a certificate holder is required to periodically demonstrate command of a body of knowledge that is essential to current professional practice. OBJECTIVE: We report herein a current Standard of Knowledge in general toxicology compiled from the experience and opinions of 889 certified practicing professional toxicologists. DISCUSSION: An examination is the most commonly used instrument for testing a certification candidate's command of the body of knowledge. However, an examination-based certification is only creditable when the body of knowledge, to which a certification examination tests, is representative of the current knowledge, skills, and capabilities needed to effectively practice at the professional level. Thus, that body of knowledge must be the current "Standard of Knowledge" for the profession, compiled in a transparent fashion from current practitioners of the profession. CONCLUSION: This work was conducted toward ensuring the scientific integrity of the products produced by professional toxicologists. PMID- 25782182 TI - Cognitive Interviews of Vietnamese Americans on Healthy Eating and Physical Activity Health Educational Materials. AB - The purpose of this study was to better understand if a health educational presentation using culturally adapted materials was understandable and culturally appropriate, and that the content was retained, in an older Vietnamese American population. This study used cognitive interviewing. A convenient sampling was used to recruit eight participants by staff of a community-based organization from its client base. This is the first study to document that family eating style poses a challenge for estimating food intake among Vietnamese Americans. Participants who ate in a family eating style were not able to recall or estimate the number of servings of protein and vegetables. Some older Vietnamese Americans used food for healing and self-adjusted portion sizes from dietary recommendations. Cognitive interviewing is a useful method to improve comprehension, retention, and cultural appropriateness of health educational materials. Further nutrition research concerning intake measurement in ethnic groups that practice a family eating style is warranted. PMID- 25782183 TI - Interventional retrieval by catheter of a migrated atrial appendage occluder located in the arcus aortae. PMID- 25782184 TI - Real-world experience with a novel biodegradable polymer sirolimus-eluting stent: twelve-month results of the BIOFLOW-III registry. AB - AIMS: We aimed to assess the safety and performance of a novel sirolimus-eluting stent with biodegradable polymer under real-world conditions. METHODS AND RESULTS: This prospective, multicentre, observational, all-comers registry enrolled 1,356 patients. The primary endpoint was target lesion failure at 12 months: it occurred in 5.1% (95% CI: 4.0-6.4) of patients in the overall population and in 7.7% (95% CI: 5.5-10.9), 5.8% (95% CI: 4.2-8.1), 1.8% (95% CI: 0.2-11.8) and 7.2% (95% CI: 5.1-10.0) of patients with diabetes mellitus, small vessels, chronic total occlusion and acute myocardial infarction, respectively. CONCLUSIONS: This novel stent platform demonstrated good clinical outcomes in an all-comers population, even in predefined high-risk groups. ClinialTrials.gov identifier: NCT01553526 PMID- 25782185 TI - The effects of being in a "new relationship" on levels of testosterone in men. AB - In light of previous research showing that different types of relationships affect levels of testosterone in men, this study examined whether categorizing relationship types according to relationship length can shed further light on variations in levels of testosterone. Salivary testosterone samples were obtained from a sample of men and details about their relationship status, sociosexual orientation, extra-pair sexual interest, and their perceptions of their relationships were recorded. Using a median split analysis, participants who indicated that they had been in their relationship for less than 12 months were categorized as being in "new relationships" and those in longer relationships being categorized as in long-term relationships. Results showed that levels of testosterone of single men and men in new relationships did not differ, but both had significantly greater levels of testosterone than men in long-term relationships. Differences in levels of testosterone were unrelated to sociosexual orientation and extra-pair sexual interest. These findings support the evolutionary explanation of levels of testosterone in men varying in accordance with their internal motivation to seek new potential mates. PMID- 25782186 TI - Information presentation features and comprehensibility of hospital report cards: design analysis and online survey among users. AB - BACKGROUND: Improving the transparency of information about the quality of health care providers is one way to improve health care quality. It is assumed that Internet information steers patients toward better-performing health care providers and will motivate providers to improve quality. However, the effect of public reporting on hospital quality is still small. One of the reasons is that users find it difficult to understand the formats in which information is presented. OBJECTIVE: We analyzed the presentation of risk-adjusted mortality rate (RAMR) for coronary angiography in the 10 most commonly used German public report cards to analyze the impact of information presentation features on their comprehensibility. We wanted to determine which information presentation features were utilized, were preferred by users, led to better comprehension, and had similar effects to those reported in evidence-based recommendations described in the literature. METHODS: The study consisted of 5 steps: (1) identification of best-practice evidence about the presentation of information on hospital report cards; (2) selection of a single risk-adjusted quality indicator; (3) selection of a sample of designs adopted by German public report cards; (4) identification of the information presentation elements used in public reporting initiatives in Germany; and (5) an online panel completed an online questionnaire that was conducted to determine if respondents were able to identify the hospital with the lowest RAMR and if respondents' hospital choices were associated with particular information design elements. RESULTS: Evidence-based recommendations were made relating to the following information presentation features relevant to report cards: evaluative table with symbols, tables without symbols, bar charts, bar charts without symbols, bar charts with symbols, symbols, evaluative word labels, highlighting, order of providers, high values to indicate good performance, explicit statements of whether high or low values indicate good performance, and incomplete data ("N/A" as a value). When investigating the RAMR in a sample of 10 hospitals' report cards, 7 of these information presentation features were identified. Of these, 5 information presentation features improved comprehensibility in a manner reported previously in literature. CONCLUSIONS: To our knowledge, this is the first study to systematically analyze the most commonly used public reporting card designs used in Germany. Best-practice evidence identified in international literature was in agreement with 5 findings about German report card designs: (1) avoid tables without symbols, (2) include bar charts with symbols, (3) state explicitly whether high or low values indicate good performance or provide a "good quality" range, (4) avoid incomplete data (N/A given as a value), and (5) rank hospitals by performance. However, these findings are preliminary and should be subject of further evaluation. The implementation of 4 of these recommendations should not present insurmountable obstacles. However, ranking hospitals by performance may present substantial difficulties. PMID- 25782187 TI - Technology advances in hospital practices: robotics in treatment of patients. AB - Laparoscopic cholecystectomy is widely considered as the treatment of choice for acute cholecystitis. The safety of the procedure and its minimal invasiveness made it a valid treatment option for a patient not responding to antibiotic therapy. Our research shows that patients positively assess this treatment method, but the world's tendency is to turn to a more sophisticated method utilizing robot-assisted surgery as a gold standard. Providing patient with minimally invasive surgical procedures that utilize the state-of-the-art equipment like the da Vinci Robotic Surgical System underscores the commitment to high-quality patient care while enhancing patient safety. The advantages include minimal invasive scarring, less pain and bleeding, faster recovery time, and shorter hospital stay. The move toward less invasive and less morbid procedures and a need to re-create the true open surgical experience have paved the way for the development and application of robotic and computer-assisted systems in surgery in Poland as well as the rest of the world. PMID- 25782188 TI - Impact of Node Negative Target Volume Delineation on Contralateral Parotid Gland Dose Sparing Using IMRT in Head and Neck Cancer. AB - There is considerable practice variation in treatment of the node negative (N0) contralateral neck in patients with head and neck cancer. In this study, we examined the impact of N0 neck target delineation volume on radiation dose to the contralateral parotid gland. Following institutional review board approval, 12 patients with head and neck cancer were studied. All had indications for treatment of the N0 neck, such as midline base of tongue or soft palate extension or advanced ipsilateral nodal disease. The N0 neck volumes were created using the Radiation Therapy Oncology Group head and neck contouring atlas. The physician drawn N0 neck clinical target volume (CTV) was expanded by 25% to 200% to generate volume variation, followed by a 3-mm planning target volume (PTV) expansion. Surrounding organs at risk were contoured and complete intensity modulated radiation therapy plans were generated for each N0 volume expansion. The median N0 target volume drawn by the radiation oncologist measured 93 cm(3) (range 71-145). Volumetric expansion of the N0 CTV by 25% to 200% increased the resultant mean dose to the contralateral parotid gland by 1.4 to 8.5 Gray (Gy). For example, a 4.1-mm increase in the N0 neck CTV translated to a 2.0-Gy dose increase to the parotid, 7.4 mm to a 4.5 Gy dose increase, and 12.5 mm to an 8.5 Gy dose increase, respectively. The treatment volume designated for the N0 neck has profound impact on resultant dose to the contralateral parotid gland. Variations of up to 15 mm are routine across physicians in target contouring, reflecting individual preference and training expertise. Depending on the availability of immobilization and image guidance techniques, experts commonly recommend 3 to 10 mm margin expansions to generate the PTV. Careful attention to the original volume of the N0 neck CTV, as well as expansion margins, is important in achieving effective contralateral gland sparing to reduce the resultant xerostomia and dysguesia that may ensue after radiotherapy. PMID- 25782189 TI - Evaluation of mathematical algorithms for automatic patient alignment in radiosurgery. AB - Image registration techniques based on anatomical features can serve to automate patient alignment for intracranial radiosurgery procedures in an effort to improve the accuracy and efficiency of the alignment process as well as potentially eliminate the need for implanted fiducial markers. To explore this option, four two-dimensional (2D) image registration algorithms were analyzed: the phase correlation technique, mutual information (MI) maximization, enhanced correlation coefficient (ECC) maximization, and the iterative closest point (ICP) algorithm. Digitally reconstructed radiographs from the treatment planning computed tomography scan of a human skull were used as the reference images, while orthogonal digital x-ray images taken in the treatment room were used as the captured images to be aligned. The accuracy of aligning the skull with each algorithm was compared to the alignment of the currently practiced procedure, which is based on a manual process of selecting common landmarks, including implanted fiducials and anatomical skull features. Of the four algorithms, three (phase correlation, MI maximization, and ECC maximization) demonstrated clinically adequate (ie, comparable to the standard alignment technique) translational accuracy and improvements in speed compared to the interactive, user-guided technique; however, the ICP algorithm failed to give clinically acceptable results. The results of this work suggest that a combination of different algorithms may provide the best registration results. This research serves as the initial groundwork for the translation of automated, anatomy-based 2D algorithms into a real-world system for 2D-to-2D image registration and alignment for intracranial radiosurgery. This may obviate the need for invasive implantation of fiducial markers into the skull and may improve treatment room efficiency and accuracy. PMID- 25782190 TI - Grief intensity, psychological well-being, and the intimate partner relationship in the subsequent pregnancy after a perinatal loss. AB - OBJECTIVE: To examine the construct validity of the Perinatal Grief Intensity Scale (PGIS) and the associations of grief intensity with psychological well being and the quality of intimate partner relationships of women in the subsequent pregnancy after perinatal loss. The consequences of intense grief due to perinatal loss may include significant couple relationship issues, depression, anxiety, and post-traumatic stress that may extend into the subsequent healthy pregnancy. DESIGN AND SETTING: A correlational, descriptive research design was used to collect survey data in this cross-sectional, web-based study. PARTICIPANTS: Participants were 227 currently pregnant women who experienced perinatal loss in their immediate past pregnancies. METHODS: Instruments included the Pregnancy Outcome Questionnaire (pregnancy-specific anxiety), Impact of Event Scale (post-traumatic stress), Center for Epidemiologic Studies-Depression Scale (depression symptoms), the Autonomy and Relatedness Inventory (quality of the intimate partner relationship), and the Perinatal Grief Intensity Scale (perinatal grief intensity). RESULTS: As hypothesized, greater grief intensity was associated with higher pregnancy-specific anxiety, depression symptoms, and post-traumatic stress as well as poorer quality of the intimate partner relationship. CONCLUSIONS: Support for the construct validity of the PGIS was demonstrated by its significant associations in the expected directions with pregnancy-specific anxiety, depression symptoms, post-traumatic stress, and the quality of the intimate partner relationship. The scale may be useful to health care providers in identifying mothers in need of follow-up for intense grief and other clinically relevant symptoms after perinatal loss. PMID- 25782191 TI - A case report on the anxiolytic properties of nitrous oxide during labor. AB - Widely used in Europe as a labor analgesic, nitrous oxide (N2O) is making a dramatic return in the United States. Valued for its analgesic properties, N2O also has anxiolytic characteristics. Fear and anxiety in childbirth have been associated with various negative effects, and N2O may have the potential to lessen these effects for some women. Women in the United States should have the option of using N2O during labor. PMID- 25782192 TI - Evidence-based practice to improve outcomes for late preterm infants. AB - Infants born between 34 weeks 0 days to 36 weeks 6 days gestation have been identified as late preterm infants (LPIs) and account for 70% of preterm births and 9% of all births. The rise in elective deliveries in the past decade is believed to have contributed to the number of late preterm births. An interprofessional team including labor and delivery, neonatal intensive care, and postpartum care providers collaborated to address this issue at an urban academic medical center. PMID- 25782193 TI - Effects of home visiting and maternal mental health on use of the emergency department among late preterm infants. AB - OBJECTIVE: To describe use of the emergency department (ED) among late preterm versus term infants enrolled in a home visiting program and to determine whether home visiting frequency was associated with outcome differences. DESIGN: Retrospective, cohort study. SETTING: Regional home visiting program in southwest Ohio from 2007-2010. PARTICIPANTS: Late preterm and term infants born to mothers enrolled in home visiting. Program eligibility requires >= one of four characteristics: unmarried, low income, < 18 years, or suboptimal prenatal care. METHODS: Data were derived from vital statistics, hospital discharges, and home visiting records. Negative binomial regression was used to determine association of ED visits in the first year with late preterm birth and home visit frequency, adjusting for maternal and infant characteristics. RESULTS: Of 1,804 infants, 9.2% were born during the late preterm period. Thirty-eight percent of all infants had at least one ED visit, 15.6% had three or more. No significant difference was found between the number of ED visits for late preterm and term infants (39.4% vs. 37.8% with at least one ED visit, p = .69). In multivariable analysis, late preterm birth combined with a maternal mental health diagnosis was associated with an ED incident rate ratio (IRR) of 1.26, p = .03; high frequency of home visits was not significant (IRR = .92, p = .42). CONCLUSIONS: Frequency of home visiting service over the first year of life is not significantly associated with reduced ED visits for infants with at-risk attributes and born during the late preterm period. Research on how home visiting can address ED use, particularly for those with prematurity and maternal mental health conditions, may strengthen program impact and cost benefits. PMID- 25782194 TI - Response to Dr Katz's letter to the editor. PMID- 25782195 TI - [Classification, epidemiology and etiology of chronic kidney disease]. AB - Chronic kidney disease (CKD) poses an important health problem. It is a progressive disease with a high risk of cardiovascular complications. In this paper the new classification and diagnostic criteria established in 2012 by Kidney Disease Improving Global Outcomes (KDIGO) are shortly overviewed. PMID- 25782196 TI - [General approach to treatment of chronic kidney disease]. AB - In this paper the main therapeutic goals in chronic kidney disease (CKD) are summarized, together with the methods of its early detection, the main rules of nephro- and cardioprotection, as well as the prevention of the other complications. PMID- 25782197 TI - [Pathophysiology of hypertension in chronic kidney disease]. AB - Hypertension is both an important cause and consequence of chronic kidney disease (CKD). It is present in 80-85% of the patients. The article summarizes the main pathogenetic factors of hypertension in CKD such as: sodium retention, increased activity the renin-angiotensin-aldosterone system and sympathetic nervous system, impaired nitric oxide synthesis and endothelium-mediated vasodilatation, oxidative stress, disorders of calcium metabolism and parathyroid hormone secretion, vascular calcification and increased arterial stiffness. PMID- 25782198 TI - [Treatment of hypertension in chronic kidney disease]. AB - Adequate treatment of hypertension in patients with chronic kidney disease reduces the risk of cardiovascular complications, slows down the progression of renal failure, and is an important element in nephroprotection, delaying the onset of renal replacement therapy. Non-pharmacological methods, especially salt restriction, and most of the available antihypertensive medicines are in use. It is often necessary to combine drugs from different groups, among which inhibitors of renin-angiotensin-aldosterone (RAA) system and diuretics are the most important. The choice of an appropriate combination depends on the degree of renal failure, concomitant diseases, extent of proteinuria, and the presence or absence of edema and hypervolemia. Recommended blood pressure is below 140/90 mmHg in patients with proteinuria less than 0.5 g/24 h, and below 130/80 mmHg if daily proteinuria exceeds 0.5 g/24 h. PMID- 25782199 TI - [Safe and effective diuretic use in chronic kidney disease]. AB - Recent epidemiological studies show significant prevalence of chronic kidney disease (CKD) in the general population. Diuretics are critical in therapy ofvolume overload and hypertension commonly encountered in these patients. However, they frequently demonstrate relevant diuretic resistance, and from the other hand diuretic overdose may lead to dehydratation and worsening of kidney function. In this paper the main principles of diuretic treatment in CKD are described, including the diuretic agent and its dose selection, as well as adverse effects of the therapy. PMID- 25782200 TI - [Anemia in chronic kidney disease--reasons and treatment]. AB - Anemia in chronic kidney disease (CKD) may affect up to 90% of the patients. It is one of the non typical risk factors of cardiovascular disease, specific for this population. The main reasons of the anemia in CKD are iron and erythropoietin deficiency. It is recognized in women with hemoglobin concentration < 11 g/dl and in men and postmenopausal women with hemoglobin concentration < 12 g/dl. Other potentially reversible reasons of anemia should be excluded in differential diagnosis. Iron and erythropoiesis stimulating agents (ESA) constitute the main treatment of anemia of CKD. PMID- 25782201 TI - [Erythropoiesis stimulating agents in clinical practice]. AB - Anemia is one of the most common problems of patients with advanced chronic kidney disease (CKD). Its main causes in this population are: iron deficiency and a decreased renal synthesis of erythropoietin. Up to the 80's of the twentieth century, treatment of anemia in CKD was limited to blood and red blood cells transfusions. However during last three decades there has been a huge progress in the field, starting with introduction into clinical practice of human recombinant erythropoietin (rHuEPO), followed by an appearance of agents with a longer duration of action, darbepoetin alfa and methoxy polyethylene glycol-epoetin beta, all of which are shortly reviewed in this paper. PMID- 25782202 TI - [Treatment of metabolic acidosis in chronic kidney disease]. AB - Metabolic acidosis is defined as a decrease of bicarbonates in the blood, below normal range, with a reduction of blood pH. It is a common disorder in chronic kidney disease (CKD). Clinically apparent fairly late (GFR < 30 ml/min/m2), although usually mild, it can have adverse effects on important functions of the human body. In the article the pathomechanism of metabolic acidosis in CKD, its influence on human body and treatment is shortly reviewed. PMID- 25782203 TI - [Mineral and bone disorder in chronic kidney disease]. AB - Chronic kidney disease-mineral bone disorder (CKD-MBD) is characterized by at least one ofthefollowing: 1. biochemical abnormalities in calcium, phosphate, parathormone (PTH) and vitamin D metabolism; 2. renal osteodystrophy; and 3. cardiovascular or other soft tissue calcifications. All these abnormalities are interrelated and significantly contribute to the increased morbidity and mortality in patients with CKD. PMID- 25782204 TI - [Recommendations for mineral and bone disorder in chronic kidney disease]. AB - The current recommendations for the diagnostics and therapy in mineral and bone disorders (MBD) in chronic kidney disease (CKD) developed by an international group of experts KDIGO and the Board of the Polish Nephrology Consultant's Working Group are presented in the paper. MBD--begin already in the early stages of CKD, and are an important cause of increased morbidity and mortality in this population. The main goals of the therapy are to maintain calcium and phosphate homeostasis and to keep serum parathyroid hormone concentrations in the optimal range. PMID- 25782205 TI - [Current guidelines for treatment of dyslipidemia in kidney diseases]. AB - Dyslipidemia is a risk factor of cardiovascular diseases and progression of chronic renal failure. Hypertriglyceridemia is the most common lipid abnormality among patients with chronic kidney disease, cholesterol levels may be high, normal or low. High triglycerides and cholesterol are observed in nephrotic syndrome, whereas cholesterol levels may be low in inflammation and malnutrition. Treatment of dyslipidemia includes modification of lifestyle, treatment of diabetes, hypertension, nephrotic syndrome, and therapy with statins in majority of patients over 50 years of age, with GFR < 60 ml/min, regardless of other risk factors of atherosclerosis. Statins decrease mortality and risk of cardio vascular events, but have not been proven to slow down the progression of renal failure. Non- pharmacological treatment is suggested in hypertriglyceridemia > 500 mg/dl, and fibrates are not recommended, especially in combination with statins. PMID- 25782206 TI - [The integrated renal replacement therapy]. AB - The integrated renal replacement therapy (RRT) concept assumes that all its methods: kidney transplantation (Tx), hemodialysis (HD) and peritoneal dialysis (PD) can be applied in a complementary manner, according to the clinical situation of the particular patient and his preferences. Besides the integration of treatments this concept also emphasizes timely patient referral, predialysis education and timely start of RRT. PMID- 25782207 TI - [Predialysis education]. AB - There is a substantial evidence that late referral for renal replacement therapy leads to poor outcomes for patients with advanced chronic kidney disease, with many complications, prolonged hospital stays and rehabilitation, and increased mortality. However, in many services worldwide, a lot of patients still do not begin dialysis treatment electively despite prior nephrology care. The predialysis education in addition to standard nephrology follow-up enhances the probability of planned dialysis start and may improve dialysis patient outcomes. PMID- 25782208 TI - [Living kidney donation in Poland and all over the world]. AB - Living kidney transplantation is considered as preferred, and sometimes the only possible, treatment option for improving survival and quality of life of patients with end-stage kidney disease. The main obstacle in the development of transplantation is shortage of organs, but in certain regions of the world also organizational, legislative and economic limitations. The paper some data on the kidney transplantation from living donors in Poland, Europe and the world are presented. PMID- 25782209 TI - [The assessment of C4d urinary excretion in early and late post kidney transplant periods]. AB - INTRODUCTION: Recent data describes the involvement of compliment elements in humoral kidney graft rejection. The C4d deposits in peritubular capilars are the marker of compliment activity and the element of humoral acute graft rejection. The aim of the study was the assessment of C4d urinary excretion in early and late post-kidney transplant periods. MATERIAL AND METHODS: The study comprised 185 patients who underwent kidney allograft transplantation (KTx). The urinary specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion. The study population was grouped according the post-transplant time i.e. <1 and >1 year after KTx. RESULTS: In the study the C4d urinary excretion in patients <1 year and >1 year post kidney transplantation were 4.6 +/- 7.5 and 5.3 +/- 7.9 ng/mgCr, respectively. The mean C4d excretion was 4.8 +/- 7.6 ng/mgCr. The values did not differ significantly. The direct assessment of C4d excretion (not divided per creatinuria) were also comparable in the study groups (207.2 +/- 261.8 ng/ml and 212.9 +/- 249.3 ng/ml, respectively). CONCLUSIONS: C4d urinary excretion did not depend on post transplant time. PMID- 25782210 TI - [The influence of pre-transplantation dialysis modality on late C4d urinary excretion in kidney graft recipients]. AB - INTRODUCTION: The C4d deposits as well as its urinary excretion are markers of the humoral acute kidney graft rejection. The pre-transplant dialysis modality influences on the post-transplant outcomes and it is possible that it may modify C4d urinary excretion. AIM: The aim of the study was the assessment of the pre transplant dialysis modality on late C4d urinary excretion. MATERIAL AND METHODS: The study comprised 185 patients who underwent kidney allograft transplantation (KTx). The urinary specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion. The study population was grouped according the pre-transplant dialysis modality i.e. hemo- and peritoneal dialysis RESULTS: In the study the C4d urinary excretion in patients treated with hemodialysis was higher than in peritoneal dialysis, irrespectively whether in direct measurements 221.1 +/- 239.9 ng/ml vs 156.4 +/- 188.7 ng/ml (p < 0.05) or when calculated per urinary creatinine 5.2 +/- 7.1 ng/mgCr i 3.4 +/- 7.9 ng/mgr (p < 0.05). CONCLUSIONS: Pre-transplant dialysis modality influences late C4d urinary excretion. PMID- 25782211 TI - [The nephrological knowledge of patricipants of World Kidney Day 2012 in Gdansk center]. AB - INTRODUCTION: In many countries on different continents, at least 10-12% of people are suffering from chronic kidney disease (CKD). These data indicate that CKD is a big problem, much more than previously expected. Therefore, programs should be promoted for early detection of kidney diseases and carry out public education and also the medical community. MATERIAL AND METHODS: The aim of this article was the assessment of the nephrology knowledge of participants of the World Kidney Day in Gdansk in 2012. Analysis of the survey conducted for the entire cohort and the separate subgroups of people who were more than 60 years old and less than 60. RESULTS: Among the total sample and in the subgroups, complications of hypertension knowledge was declared by more than 75% of the participants, diabetes more than 70%. However the symptoms of CKD have been known only for about 60%, the concept of creatinine 40%, while the concept of dialysis/transplant for about 80% of respondents. The main source of medical information were non-medical journals for more than 50% of study participants. However the doctor as a source of medical knowledge, identified 47% of respondents. CONCLUSIONS: Participants of questionnaires have showed in described analysis mediocre acquaintance of signs of kidney disease, the notion of creatinine in comparison for acquaintance of complication of hypertension and diabetes. However, for all participants of research and for older subgroup, main source of medical knowledge was a physician and unmedical magazines. But internet or television was the main source of knowledge for younger subgroup. PMID- 25782212 TI - [Are sleep disorders an underestimated symptom? Preliminary report from the screening study]. AB - introduction: Sleep disorders are burdensome health problem coexisting with mental disorders and somatic diseases. The study aim was to assess prevalence of sleep disorders and analyses of comorbidity. MATERIAL AND METHODS: Study included 76 participants (50 women and 26 men; mean age: 48.5) who attended prophylactic examinations. We used Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) created for preliminary diagnosis of mental disorders. Among items assessing depression there is a question concerning sleep disorders. Data from medical review were used. RESULTS: Sleep disorders were declared by 50% of participants, 54% of them were women. In age group between 60 76 disorders were declared by 68.2%, from group 16-39 years--45% and 41.2% aged 40-59 years. Among those with sleep disorders 42.1% had preliminary diagnosis of mental disorders. In this group significantly higher was the percentage of patients with diagnosed somatic disease as well as the number of somatic complaints and stress factors. CONCLUSIONS: 1. Sleep disorders are common symptoms, especially in older adults and women. 2. Mental disorders, somatic diseases and complaints as well as stress factors are significantly more common among patients with sleep disorders. 3. Sleep disorders consist important premise for diagnosing mental disorders. 4. Screening for sleep disorders may be vital element of diagnostic and therapeutic process in primary care. PMID- 25782213 TI - [The impact of demographic factors on the course and outcome of stroke]. AB - INTRODUCTION: The aim of the study was to answer the question, whether living in urban or suburban areas has an impact on disease course and outcome of stroke patients. MATERIAL AND METHODS: The study included patients with a diagnosed cerebrovascular disease treated in the Department of Neurology, Provincial Hospital in Czestochowa in 2004-2005. Data were obtained on the basis of a retrospective analysis of medical records. The assessment of the functional status of patients was based on the scale of Activities of Daily Living (ADL) and the modified Rankin scale. RESULTS: The study included 294 patients (152 women, 142 men) hospitalized for a stroke. The mean age was 70.2 +/- 13.2 years. Patients were divided into two groups, Group 1 living in suburban environment (n = 153, 52.0%), and Group 2--living in urban environment (n = 141, 48.0%). There were no statistically significant differences in age, sex, and type of stroke between the two groups. In Group 1, hospitalization time was longer (17.7 +/- 13.5 days) compared with patients in Group 2--12.0 +/- 10.2 days (p = 0.05). There were no statistically significant differences in the ADL scale between the two groups, both on admission and discharge. However, in the Rankin scale status of patients from urban areas was better on the day of admission (p = 0.005) and at discharge. Seizure onset of the disease, the presence of coronary artery disease and dyslipidemia had a strongest influence on the functional status of patients. Patients from both groups were discharged home with a similar frequency. CoNCLUSIONS: The study showns that there are slight differences in the course of the disease in patients from different backgrounds. PMID- 25782214 TI - [Attempt to objectify of coronary vessels course variability on the standard arteriograms by using original image processing algorithm]. AB - The aim of paper: the analysis of standard angiograms of the left coronary artery was done in this paper in purpose of performing the uniform mathematical description of the coronary branches (both proximal and distal) course. The changes the coronary branches underwent depending the phase of cardiac cycle (diastole, isovolumic systole and tonic systole) were examined as well. The examined material consists of sequences of standard angiograms of the left coronary artery (LCA) obtained from 10 patients (5 male and 5 female) undergoing the standard diagnostic procedure in course of suspected unstable cardiac ischemia. The coronarograms were applied with digital angiography system INNOVA 2000 GE. The average age of the patients was 51 years. The method was based on using the original algorithm of image processing allowing automatic, in real time, vessel edges detection and mathematical description of the vessels course. The software ImageJ, deriving from public domain of National Institutes of Health of USA was used for image analysis and for statistical analysis Statistica for Windows 5.5 version. The obtained results of examined dependences and describing them mathematically polynomial equations were presented on the diagrams. Among examined parameters the ferret diameter, area and perimeter of vessel outlines (both proximal and distal branches) were the most reliable. Their changes in relation to the phase of cardiac cycle were very close to the level of statistical significance. In conclusion the performed analysis allows to objectify description of coronary vessels course and variability. It also makes possible to identify the abnormal manners of vessels outlines that could be suspected of structural disorders even despite the absence of significant coronary stenosis. PMID- 25782215 TI - [Vitamins and microelements in patients with chronic kidney disease]. AB - The supply of vitamins and microelements in patients with chronic kidney disease (CKD) is very important and requires special attention. CKD patients presented deficiency of these substances in the diet and in organism, but also excess of fat-soluble vitamins or trace elements is observed. Studies indicate that deficiency of vitamins and antioxidants in diet and also enhanced oxidative stress are cause of many complications for example: accelerated process of arteriosclerosis in patients with chronic kidney disease. PMID- 25782216 TI - [The beneficial effects of protein and calcium from dairy products of the symptoms of metabolic syndrome]. AB - Metabolic syndrome is the name for a group of risk factors that occur together and increase the risk for atherogenic dyslipidemia, impaired glucose tolerance, central obesity and hypertension. It is the most important cause of the development of cardiovascular diseases and diabetes type II. In the last few years studies have focused on the influence of the nutrient components of the disease, especially calcium and protein intake from dairy products. Studies have shown that varying degrees, and the mechanism may favourably affect the risk factors, but most of them do not take into consideration people with the full symptoms of the metabolic syndrome. Dairy products may play an important role in the prevention and mitigation components of the metabolic syndrome. It is not clear which ingredients of the food groups may be responsible for the positive health effects, and the possible mechanism for their actions. PMID- 25782217 TI - [Review of diagnostic scoring systems in acute appendicitis]. AB - Acute appendicitis (AA) is the leading of emergency surgeries performed at general surgery departments. Prevalence of acute appendicitis is estimated at 6 8% of population. Clinical presentation is very diverse and despite common occurence it remains a diagnostic challenge. Acute appendicitis diagnostics consist of clinical examination, laboratory tests, diagnostic scoring systems (DSS), computer programs as physician aids and imaging examination. About 30-45% patients suspected of acute appendicitis have atypical clinical presentation. Even nowadays incorrect preoperative diagnoses are quite common and result in performing negative appendectomies (NA) in average 10-30% patients while in childbearing women even to 45%. In order to improve diagnostics accuracy of AA diagnostic scoring system can be used. Scoring systems link clinical examination and labarotory tests by certain quantification of symptoms, signs and laboratory parameters. This article is a review of a few diagnostic scoring systems. Scoring systems were compared with special attention payed to their similarity and differences. Scoring systems have many advantages, they are non-invasive, cheap and don't require any special equipment to be employed. Scoring systems are very helpful surgical tool to make a diagnosis of AA or exclude it. PMID- 25782218 TI - Urinary tract injury associated with pelvic fractures. AB - INTRODUCTION: Pelvic trauma associated with urinary tract injury is a severe trauma, mostly caused by traffic accidents and falls from heights. These injuries require urgent treatment and close teamwork between urologic and orthopaedic surgeons. MATERIAL AND METHODS: In this retrospective study there were analyzed patients with pelvic trauma and extraperitoneal injury of urinary tract, treated surgically at Clinic for Ortopaedic Surgery and Traumatology and Urology Clinic in Clinical Center Nis. Surgical intervention in these patients had been realized as the synchronized work of both orthopaedic and urologic surgeons. The pelvis was treated by external and internal fixation. Mitkovic type external fixator was used for pelvic external fixation. Plating was used for pelvic internal fixation. Pelvic fractures were classified using Tile's classification system. The final functional results had been scored using Majeed score system. RESULTS: There were 42 patients with the injury of pelvic ring, treated at Clinic for Ortopaedic Surgery and Traumatology and at Urology Clinic, Clinical Center Nis, in the period of 01.01.2011. to 31.12.2013, 30 males and 12 females, with average age of 53.69 (19-84) years old. In 80% of cases pelvic fractures were caused by high energy trauma in traffic accidents. According to Tile's classification, 9 patients (21,42%) had pelvic fracture type A, 23 patients (54,46%) had pelvic fracture type B and 10 patients (23,80%) had pelvic fracture type C. Urinary tract injury was diagnosed in 9 patients (21,42%): 5 patients (11,9%) with bladder injury, 3 patients (7,14%) with posterior urethra injury and 1 patient (2,38%) with both bladder and posterior urethra injury. CONCLUSION: Urgent repair of extraperitoneal urinary tract injury by urologic surgeons and synchronized pelvic reduction and fixation using external or internal fixation by ortopaedic surgeon, in the same surgical procedure, is the standard method for treatment of this severe injury. PMID- 25782219 TI - Retrospective evaluation of male slings for patients with urinary incontinence after radical prostatectomy--one surgeon's experience. AB - INTRODUCTION: Stress urinary incontinence is one of the main complications after radical prostatectomy (RP) with a significant percentage of patients reporting bothersome incontinence > 1 year after surgery. OBJECTIVE: Assessment of one surgeon's results in surgical treatment of urinary stress incontinence of patients with radical prostatectomy applying transobturator and suprapubic slings. PATIENTS AND METODS: From February 2010-February 2014, 20 patients, age 57-76, with moderate and severe stress urinary incontinence (SUI) were treated surgically. All patients previously had radical prostatectomy due to prostate cancer. RESULTS: All 20 patients with stress urinary incontinence (PRPUI) had Argus slings placement after radical prostatectomy. Patients were followed for a longer period of time, 6 months minimum, 48 months maximum.18 patients (90%) had negative, dry PAD test after surgery, one patient (5%) had positive PAD test, and one patient (5%) who previously had Advance transobturator sling placement with no positive results, had sling removed due to an infection. 6 patients (30%) needed additional sling adjustment, performed between 9-21st day after the surgery. CONCLUSION: We concluded that Argus sligs, suprapubic or transobturatory are an effective and safe treatment for PRPUI. This procedure is minimal invasive and our results clearly demonstrate that both heavy and moderate incontinence responds well. PMID- 25782220 TI - Diode laser vaporization of prostate as treatment for benign prostatic enlargement: initial results of 73 patients with 1 year follow-up. AB - OBJECTIVE: Our objective is to evaluate the efficacy, safety and 12 month outcome of a 980 nm diode laser with Twister fiber in the treatment of benign prostatic enlargement. MATERIALS AND METHODS: Between February 2011 and January 2013, 73 patients with benign pros- tatic enlargement had undergone diode laser vaporization of prostate at our institution. The fol- lowing parameters were assessed at baseline, and after a follow-up period of 3 and 12 months: International Prostate Symptom Score, peak urinary flow rate, post-void residual urine volume, and quality of life score. RESULTS: The procedure was completed successfully in all patients with no intraoperative complications. At 12 months postoperatively the percentage improvements in IPSS was -69.09%, Qmax +197%, PVR 88.54%, and QoL -68.29%. CONCLUSION: Diode laser vaporization of prostate is safe and effective method for treatment of benign prostatic enlargement. PMID- 25782221 TI - Surgical care vesicovaginal fistulas in women with malignant gynecological disease. AB - Vesicovaginal fistulae (VVF)represents one of the most frequent complications of various gynecological and obstetric procedures. In presence of a gynecological malignant tumor, fistula could be the outcome of surgical complications, radiotherapy or consequence of the tumor process. Reparation of these fistulae is a very complex problem. Our aim was to analyze the results of surgical care VVF-s occurred in women with malignant gynecological disease which was treated surgically or with radiotherapy. Out of the 48 surgically treated patients with primary VVF, in 28 of them fistula occurred after hysterectomy, and in 20 patients after radiotherapy. In 15 patients (31.25%) transvaginal approach was applied, and in 33 patients (68.75%) abdominal approach was applied, with the interposition of a well vascularized lobe being used in 25 patients. All the VVFs that occurred after radiotherapy were repaired by using the abdominal approach. The efficiency of surgical treatment of VVFs after hysterectomy due to a malignant disease was 78.5%, and after radiotherapy 65%. In patients that have not been subjected to radiotherapy, depending on the characteristics of the fistula, transvaginal or abdominal approach is applicable in VVF reparation, while the abdominal approach remains a golden standard in post-radiation fistula treatment, despite the fact that it has not solved the problem after the first medical treatment in as far as 35% of patients. PMID- 25782222 TI - Sigma-rectum pouch (Mainz pouch II). AB - The Mainz pouch II is a well tolerated form of continent urinary diversion in terms of morbidity, protection of the upper urinary tract and continence rate, even in patients aged > 65 years. Mainz pouch II was described by Fisch and Hohenfellner in 1991. They viewed the simplicity and reproducibility of the operation as one of its major advantages. A good continence rates between 93% 100% after this procedure has been shown in previous studies. The longer follow up will show whether these high rates of continence can be maintained with increasing age. The Mainz Pouch II serves as a satisfying continent urinary diversion for both sexes in selected patients in terms of quality of life. Evaluation of overall quality of life in patients with Mainz pouch II urinary derivation has given encouraging results. Compliance and cooperation of the patients, together with preoperative tests for anal competence, are mandatory to avoid complications. The Mainz group reported that the overall complication rate was low and comparable with other techniques of continent urinary diversion. During the past years modifications of the original technique have been described. These represent an increasing interest in the procedure. Today, the techniques of low-pressure and reservoirs have completely replaced classical ureterosigmoidostomy. In this review article the main focus is aimed at history, complications, continence and quality of life of patients with Mainz pouch II. PMID- 25782223 TI - Laparoscopic transperitoneal renal cyst decortication. AB - The aim of this study was to report our experience with the llaparoscopic transperitoneal treatment of simple renal cysts, to analyze the immediate and long-term clinical outcomes, and to evaluate the efficacy and safety of this miniinvasive surgical technique. Between 2009 and 2014 we diagnosed and treated a total of 48 patients with symptomatic simple renal cysts. The diagnosis was set up by ultrasound (US) and/or computed tomography (CT) examination. All cases were managed by transperitoneal laparoscopic cyst decortication. Demographic data, perioperative blood loss, duration of operative procedure, length of hospital stay and peri- and postoperative complications were analyzed. Follow-up included clinical examination and renal US, performed at 3-monthly intervals during the first year and yearly thereafter. Patient age ranged from 32 to 68 years (mean age 52.4 years). 27 (56.2%) of the patients were males and 21 (43.8%)--females. 42 (87.5%) of the cysts were peripheral, and 6 (12.5%)-peripelvic; 28 (58.3%) were localized to the left and 20 (41.7%)--to the right; and they ranged by size from 5 to 30 cm (mean 9.8 cm). 45 (93.8%) of the cysts were identified as category I, and only 3 (6.2%)--as category II, according to the Bosniak classification. None of the cases required conversion to open surgery. There were no peri- and postoperative complications. The average duration of the laparoscopic procedure was 55 min, and the average perioperative blood loss--50 mL. All patients had negative cytological and histological findings indicative for malignancy. The follow-up period ranged from 5 to 52ain months (average--25.4 months). In 47 cases (97.9%) exellent therapeutic results were reported: complete relief of clinical symptoms, fast recovery of physical activity and patient quality of life. There were three recurrences (6.2%) met in patients with multiple cysts, but only one of them required repeated surgery. Laparoscopic transperitoneal decortication is a miniinvasive, highly effective and safe method of treatment of symptomatic renal cysts. The immediate relief of clinical symptoms, the short period of reconvalescence, the excellent quality of life after surgery, and the low relapse rate confidently define it as the surgical method of choice. PMID- 25782224 TI - Reconstruction of the long urethral strictures with the buccal mucosal free graft. AB - INTRODUCTION: Reconstruction of the long urethral strictures is a difficult task in urology. The most frequently usedmethod is augmentation with the free buccal mucosal graft. MATERIAL AND METHODS: Restrospective analysis of 57 patients with the long urethral stricture was performed. All patients were evaluated endosco- pically and radiologically before the surgery. Buccal mucosal graft harvested from the inner side of the cheek (unilateral or bilateral) was used for the urethral reconstruction in all patients. Follow-up was one year. RESULTS: Complete follow up is achieved in 44/57 (77.2%) patients. The most important etiology of the strictures was previous iatrogenic trauma (instrumentation). The strictures were the most frequently located in the bulbar urethra. Preoperative exact evaluation of the stricture length was possible in only 35/57 patients (61.4%). Overall success rate of the surgery was 38/44 (86.3%). Complications occurred in 6/44 (13.7%) of patients--primary graft failure and urinary fistula. Mean preoperative IPSS was 19.2 +/- 5.2, and postoperative 10.3 +/- 3.2 (p < 0.0001). IPSSQOL was 4.9 +/- 3.7 before the surgery, 2.9 +/- 1.1 after the surgery (p < 0.001). Persistent urinary infection was present in 12/44 (27.2%) patients. CONCLUSION: Buccal mucosal free graft could be successfully used in the reconstruction of long urethral strictures. However, complications are not uncommon, and residual symptoms still exist after the surgery, and could not be neglected. PMID- 25782225 TI - Preservation surgery in patients with localized renal cell cancer--nephron sparing surgery. AB - INTRODUCTION: Renal Cell Cancer ( RCC) is third most frequent urological cancer behind Prostate cancer and Bladder cancer. It represents 2-3 % of all cancers with annual increase in incidence of 2% in Europe (except Denmark and Sweden) and worldwide. Surgery is the only curative procedure, performed as radical nephrectomy (RN) or partial nephrectomy (nephron sparing surgery-NSS). Radical nephrectomy consists of nephrectomy with ipsilateral adrenalectomy and lymphadenetomy, but partial nephrectomy means resection of the tumor only with 1 3 mm of healthy surrounding tissue and preservation of the rest of the kidney as well as ipsilateral adrenal gland and lymph nodes. NSS is a method of conservation of attacked kidney and preservation of kidney's function with previous radical resection of localized RCC, respecting of all oncological principles. The aim of this study is to describe NSS procedure in details and present results of its 13 year use at Clinic of Urology in Novi Sad. MATERIAL AND METHODS: In the last 13 years there were 868 patients (pts) with RCC. NSS has been performed in 242 pts (27.88%). Bilateral tumors: synchronous 8 pts, asynchronous 3 pts. Better kidney has been operated, first. Indications for NSS were: absolute--34 pts (15.0%), relative--58 pts (23.1%) and elective--150 pts (61.9%).Surgery was performed according to esta- blished protocol for this procedure based on recommendation of Prof. A. Novick, Cleveland, USA. RESULTS: All patients underwent surgery under general anesthesia through lumbothomy, mostly.Tumor size was between 2.5-4.5 cm: over 4.5 cm (4-7 cm): 4 pts. Average age of pts--63.5 years (37-84), male: 148 (61.1%), female: 94 (38.9%). From 2001 2005, 2006-2010 i 2011-2013, 39,111 i 92 NSS has been done, respectively. It represented 13.5%, 36.6% , 50.54% of all pts with RCC underwent surgery in that period, respectively. There was an increase of NSS in that period compared to RN for localized RCC. There were no death outcomes inpts underwent NSS, local recurrence was seen in 1 patient (0.6%), urine leakage > 2 weeks 5 pts (5/242 = 2.06%),severe hemorrhage: 3 pts (1.23%), nephrectomy has been done. We do not have patients with von Hippel Landau (VHL) disease. CONCLUSION: Nephron sparing surgery Is the first choice of surgery for patients with low grade kidney tumors (up to 4.5 cm, even 7 cm), has excellent onco- logical results-comparable with radical nephrectomy, but with preservation of renal function and should be done by an experienced urological team in specialized urological centers with good anesteziological support. PMID- 25782226 TI - Complications associated with percutaneous nephrolitholapaxy (PCNL)--our experience and literature review. AB - BACKGROUND: PCNL is safe procedure which is well tolerated, but as with any other surgical procedure, it is associated with a specific set of complications. There is a marked heterogeneity in reporting complication rates in literature, and this problem was highlighted in Ad Hoc EAU guidelines panel who recommended urgent creation of uniform and reproducible quality system. Modified Dindo-Clavien grading system today is the most utilized classification for complications in urology, and standard in reporting complications for PCNL. AIM(S): To analyze the complication rate for PCNL using the modified Dindo-Clavien grading system in our patients and literature review. METHODS: In our institution, with few breaks, PCNL was performed since mid 2010. Complication rate in 63 patients was analyzed retrospectively. Modified Dindo-Clavien grading system that is validated for PCNL has been accepted for classification of complication for PCNL, and literature review was performed. We have summarized the most significant factors which may affect the complication rate during and after PCNL. RESULTS: Overall complication rate was 30% in our study population. The most common complications observed were: postoperative fever Grade 1-2 (9.52%) and bleeding Grade l (7.9%), Grade 2 (3.17%), Grade 3a (4.76%) and Grade 3b (1.58%). Nephrostomy tube leakage was not found in our sample, mostly due to specific postoperative utilizing of auxiliary procedures. CONCLUSION: Reporting of complication for PCNL should be uniform, and modified Dindo-Clavien grading system that is validated for PCNL should be accepted to be a standard in urology. Surgeons training and experience are the most important to ensure the efficacy of procedure, therefore we suggest that learning of percutaneous renal access should be mandatory in residents trainee program. PMID- 25782227 TI - Usage of GreenLight HPS 180-W laser vaporisation for treatment of benign prostatic hyperplasia. AB - INTRODUCTION: Laser therapy has gained increasing acceptance as a relatively less invasive treatment for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). From the early procedure of interstitial laser coagulation through to the use of holmium laser enucleation of the prostate, there has been an expanding body of evidence on the efficacy of such procedures. One of the newer lasers is the Green Light HPS 180 W laser. Studies with this GreenLight laser (GLL) (American Medical Systems, Inc, Minnetonka, MN, USA) showing results as good as those of transurethral resection of the prostate (TURP). In this paper, the efficacy of the new GLL 180-W versus the gold standard TURP in patients with LUTS due to BPH was tested in a prospective clinical trial. OBJECTIVE: To compare results of Green light laser (GLL) evaporisation of the prostatae and transurethral resection of the prostate (TURP) for treatment of BPH. MATERIJALS AND METHODS: A total of 62 patients with BPH were randomly assigned to two equal groups: TURP or GLL. RESULTS: Both groups were compared regarding all relevant preoperative, operative, and postoperative parameters. Functional results in terms of improvement of International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), and postvoid residual (PVR) urine were assessed at 1, 3, 6 and 12 mo. A total of 62 patients completed 12 mo of follow up in the TURP and GLL groups, respectively. Baseline characteristics were comparable. Mean operative time was significantly shorter for TURP. Compared to preoperative values, there was significant reduction in hemoglobin levels at the end of TURP only. A significant difference in favor of GLL was achieved regarding the duration of catheterization and hospital stay. In the GLL, no major intraoperative complications were recorded and none of the patients required blood transfusion. Among TURP patients, 6 required transfusion, 1 developed TUR syndrome, and capsule perforation was observed in 5 patients. There was dramatic improvement in Qmax, IPSS, and GLL compared with preoperative values and the degree of improvement was comparable in both groups at all time points of follow up. Four TURP patients and one GLL patients developed bladder neck contracture treated by bladder neck incision; none in either group experienced urethral stricture or urinary incontinence. CONCLUSIONS: Compared to transurethral resection of the prostate, GreenLight HPS 180-W laser photoselective vaporization of the prostate is safe and effective in the treatment of patients suffering from lower urinary tract symptoms due to benign prostatic hyperplasia. PMID- 25782228 TI - Orthotopic urinary diversion after radical cystectomy in treatment of muscle invasive bladder cancer. AB - Surgical treatment of invasive carcinoma of the bladder in males includes total cystectomy removal of the prostate, seminal vesicles, and the distal parts of the urethers and the pelvic lymph node dissection as well. At this moment it is not possible to recommend a particular type of urinary diversion, but today in clinical practice commonly used derivative are ileal orthotopic neobladder as the continent one and ileal conduit as non-continent urinary diversion. Continent urinary diversion after radical cystectomy are the result of the application of technological innovation in surgery, but also knowledge, imagination and skill of well trained urologist. This type of operation significantly improves the quality of life in patients who underwent radical cystectomy, and the proposal is to operate whenever there is a possibility for this type of procedure. Also it is very important, during surgery to respect oncological principles, of complete removal of tumorous tissue and that the functional principle of ensur- ing that the patients have daytime and also nighttime continence later on after the surgery. PMID- 25782229 TI - Trans-Obturator-Tape (T.O.T.) "outside-in" approach in surgical treatment of female stress urinary incontinence. AB - OBJECTIVE: The aim of the study was to analyzed the efficacy and safety of a minimally invasive surgical procedure using the Trans- Obturator-Tape with "outside-in" approach for treatment female stress urinary incontinence. PATIENTS AND METHODS: 171 women with stress urinary incontinence (SUI) associated with urethral hypermobility, underwent the T.O.T. procedure (March 2010 to January 2014). 27 patients were previously operated for incontinence. Mean age was 59 years (37-80). 6 patients were having mixed incontinence, and 51 had SUI with urgencies. A non-elastic, polypropylene tape was placed under the mid-urethra. The surgical placement technique utilises a trans-obturator percutaneous approach. All patients underwent post-operative clinical examination, cough stress test (full bladder), uroflowmetry, and post-voiding residual assessment. RESULTS: Mean follow-up was 22 months (4-45). At 12 months follow-up 91,2% of the patients were completely cured. The overall peri-operative complication rate was 6.4% with no vascular, nerve or bowel injury. 5 patients (2.9%) had post operative urinary retention. CONCLUSION: The present study confirms the results obtained by the instigator of the technique, E. Delorme, and allows us to consider T.O.T. as an effective and safe technique for the treatment of female stress urinary incontinence. PMID- 25782230 TI - Management of JJ stent-related symptoms. AB - Ureteric JJ stents are inserted in numerous pa- tients as a routine procedure. Nevertheless, the ideal JJ stent that does not cause any lower urinary tract symptoms has not been developed yet. Even special validated ques- tionnaires have been used for the assessment of JJ stent-related symtoms. For the management of such symtoms usually alpha-blockers are admin- istered. Also, studies have examined the efficacy and safety of anticholinergics and calcium channel blo- ckers. In this article we review the literature upon the management of JJ stent related symptoms. PMID- 25782231 TI - New and experimental techniques in the treatment of benign prostatic diseases. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) and chronic prostatitis (CP) are disorders with high prevalence and have a great impact on overall morbidity in men. The patients that do not respond to medical therapy for lower urinary tract symptoms (LUTS) related to BPH are candidates for surgery. However, the number of men with BPH/LUTS seeking for non-surgical, or for less invasive treatment is growing. AIM: To present the basic information about minimally invasive treatment modalities for BPH and CP: intraprostatic injections, urethral lift procedures, modifications of transurethral microwave thermotherapy (TUMT), prostatic artery embolization etc. CONCLUSION: The majority of these techniques is still in experimental phase and not widely accepted. However, it is very likely that new, safe and minimally invasive techniques will appear in the near future. PMID- 25782232 TI - Tension free vaginal tape (TVT) vs Transobturator tape (TOT) complications and outcomes. AB - BACKGROUND: Stress urinary incontinence (SUI) is managed with both TVT and TOT. The TVT route of placement could result in a higher com-plication rate. The aim of this study is to analyze and compare outcomes and complications of TVT and TOT in SUI treatment. METHODS: Prospective study in 64 women with isolated SUI was validated through Urogenital Distress Inventory (UDI-6), Incontinence Impact questionnaire (IIQ-7) and International Continence Impact Questionnaire (ICIQ5 SF). Intraoperative and postoperative complications were noted. Patients were considered cured when negative on stress test and with no need for additional surgery during follow up, after one and three months. RESULTS: The cure rates for both TVT 26/30 (86,6%) and TOT 30/34 (88,2) were comparable. Higher rates of bleeding, bladder perforations, pain and dyspareunia are recorded in TVT group. Quality of life graded on the questionnaire basis proved significant improvement in both procedures. CONCLUSION: Both TVT and TOT have comparable cure results in the treatment of SUI. The TOT is equally effective in the SUI treatment with significantly lower complication incidence. PMID- 25782233 TI - Etiopathogenesis, diagnostics and history of surgical treatment of stress urinary incontinence. AB - Urinary incontinence represents involuntary urine leakage into the urethra. This pathological condition represents a major medical, social and hygienic problem. The paper presents risk factors for development of the disorder, as well as diagnostic methods applied in evaluation of the female patients. Chronological review of diverse surgical techniques used in treatment of stress urinary incontinence reported in the published scientific papers is also presented. Review of the literature data was also performed. Sling procedures with application of suburethral loops have been used since the beginning of the last century in treatment of this disorder. Surgical treatment of stress urinary incontinence is applied when conservative treatment fails to give any effects according to strictly defined indications. During the last 100 years, surgical techniques have undergone different improvements and the results have also been significantly improved. PMID- 25782234 TI - Men with LUTS and diabetes mellitus. AB - INTRODUCTION: Diabetic urinary bladder disfunction is a common problem. Disfunction will occur in about 80% of diabetic patients. Comon symptoms include retention, overactive bladder, sfincted dissinergy and urinary tract infections. MATERIAL AND METHODS: In nine months period from 08.2013. to 05.2014. fourteen patients with lower urinary tract symptoms (LUTS) and diabetes were evaluated by uroflowmetry, cistotonometry with electromyography and pressure flow study. Including criteria consisted of IPSS more than 8, PSA lower than 4, RT carcinoma excluded and prostate size more than 25 cm3. REZULTS: Patient age was 50 to 77 years. In two patients due to acute retention urinary catheter was inserted. Only they were treated with alfa blockers while other patients received no therapy. Four patient had insulin dependant diabetes while ten of them had diabetes regulated with oral antidiabetics. Cistotonometry presented detrusor overactivity in two patients, treated with M cholinergics. In one patient overactive detrusor activity was in the same time presented with urge incontinence and treated in the same way. Normal detrusor activity was recorded in 14 patients on pressure flow evaluation. In 8 patients with Q max more than 15 ml/s treatment was watchfull waiting. In 4 patients with Q max more than 12 ml/s alfa blockers were introduced. In 2 patients with Q max less than 10 ml/s bipolar TURP was the treatment. CONCLUSION: Diabetes and diabetic bladder disfunction will have a great impact on quality of life due to an aging population. All specialities should be informed for diabetic bladder disfunction and necesssity for recognition and treatment. Further investigation is needed in terms of understanding the risk factors, mechanisms and the most adequate therapy. PMID- 25782235 TI - Complications of Camey-Le Duck ureteral reimplantation technique in modified ureterosigmoidostomy (Mainz pouch II) urinary diversion. AB - OBJECTIVE: to analyze complications and clinical outcome of Camey-Le Duck ureteral reimplantation technique in modified Mainz pouch II urinary diversion. PATIENTS AND METHODS: this retrospective study included a total of 110 patients (101 male and 9 female, mean age 59.2 years, SD = 10.2), who had underwent a modified Mainz pouch II urinary diversion with Camey-Le Duck ureteral reimplantation technique, following total cystectomy, during the period 1995 2014. The mean follow-up, available for 90 (82%) patients period was 19 (1-74) months. Early and late postoperative complications were analyzed. RESULTS: early complications developed in 22 (20%) patients as follow: unilateral ureterohydronephrosis in 8 (7%) patients, bilateral ureterohydronephrosis in one (1%)-two RU (renoureteral units), urinary leakage in 8 (7%), and pyelonephritis in 5 (5%) patients. Late complications developed in 28 (25%) patients: pyelonephritis in 17 (15%), and ureteral reimplantation site stenosis in 11 (10%) patients with 12 RU. Balloon dilatation procedure was applied in all 12 RU, with additional metallic Strecker stent insertion in 5 RU. At 24-month follow-up, all patients with metallic Strecker stent had normal results of serum biochemistry, blood gas analysis and renal ultrasound. In the rest of six patients with 7RU, balloon dilatation has failed and restenosis of ureteral reimplantation site with consequent ipsilateral hydronephrosis was verified. In these patients, permanent percutaneous nephrostomy catheter was applied. CONCLUSION: Camey-Le Duck ureteral reimplantation technique following Mainz pouch II urinary diversion is simple, reliable and durable. It enables well upper urinary tract protection and is associated with relatively low major complication rates. PMID- 25782236 TI - Management of penile trauma caused by a dog bite. AB - BACKGROUND: Dog bites to the external genitalia are extremely rare. The literature shows only sporadic cases of penile injuries due to dog bites, presenting mostly as children and adolescents. CASE PRESENTATION: We report the case of a 45-year old patient with avulsion and traumatic de-gloving of the penile skin, with exposure of the tunica albuginea, which surrounds the cavernous bodies. CONCLUSION: Dog bite wounds pose a serious medical threat. An effective initial treatment of the wound, as well as adequate supportive treatments are essential for the efficient healing of the resulting infection. PMID- 25782237 TI - A case report of the first laparoscopic radical nephrectomy done at the Clinic of Urology, Clinical Centre of Serbia. AB - Laparoscopic interventions are at the very beginning of its evolution in the Clinic of Urology. The first steps have been made primarily to cope with problem of varicocele. We continued to gain laparoscopic experience by switching to solving some demanding intervention, primarily kidney cyst. The only logical next step lead to laparoscopic renal surgery. So, after a few successful primary simple nephrectomy, the next step was to perform a laparoscopic radical nephrectomy. Today, at the Clinic of Urology, Clinical Center of Serbia we successfully perform much more demanding interventions, such as extraperitoneal laparoscopic radical prostatectomy. In this paper we present our experience with the first laparoscopic radical nephrectomy, which was done at the Clinic of Urology, Clinical Center of Serbia. PMID- 25782238 TI - Diagnostic and therapeutic protocol in the treatment of hypo functional kidney. AB - Laparoscopic nephrectomy is indicated in the treatment of many benign conditions of the kidneys. Hydronephrosis caused by obstruction of the ureter, either internal, or external, is one of the main indications for laparoscopic reconstruction. If an obstruction is prolonged, consequently, it leads to chronic inflammatory process accompanied by persistent and recurrent pain with fever, which eventually become resistant to therapy. If not operated sufficiently fast to resolve the causes, as a consequence it leads to hypofunction and ultimately afunction of affected kidney. In such a situation, the only therapeutic option is surgical treatment. By analyzing the case, we will try to illustrate the diagnostic algorithm and therapeutic treatment modality. PMID- 25782239 TI - [The evidences for formulation of schistosomiasis control and elimination criteria: results from a large scale of retrospective investigations]. AB - In this study, we summarized the results from the retrospective investigation on endemic situation of schistosomiasis that was implemented in nine provinces (autonomous region), China in 2009, demonstrated the role of these retrospective investigations in accelerating the progress of schistosomiasis control in China, and clarified the great significance of the investigation for summarizing the experiences for the control of schistosomiasis, and analyzing the changing patterns and affecting factors of endemic status of schistosomiasis in China. In addition, these retrospective investigations provide reliable evidence for revising the Criteria of Schistosomiasis Control and Elimination, and for the more accurate and scientific assessment of the effectiveness of schistosomiasis control in China. PMID- 25782240 TI - [Survey of endemic situations in schistosomiasis transmission controlled or interrupted regions in Anhui Province]. AB - OBJECTIVE: To understand the variation rules of schistosomiasis endemic situation before and after schistosomiasis transmission controlled or interrupted, so as to provide the evidence for the consolidation of control achievements. METHODS: In Anhui Province, 3 counties reaching the criteria of schistosomiasis transmission controlled or interrupted were selected and their historical endemic data were collected and analyzed statistically from 10 years before the schistosomiasis transmission controlled to 2008. RESULTS: In Tianchang City, the Oncomelania hupensis snail area was 3.54 hm2 in a part of the lake marshland in the year reaching the criteria of transmission controlled (1998), and no snails were found in the year of transmission interrupted (2008). No stool-test-positive resident was detected except there were 58 acute schistosomiasis cases in 1993, and the sero-test-positive rate of local residents remained at low levels (0-1.55%). In Taihu County, the snail area was 0.84 hm2 accounting for 0.06% of its historical accumulative snail areas in the year of transmission controlled (1971) , and no snails were found three years before the transmission interrupted (1983). However, the schistosomiasis endemic rebounded 12 years later (1995), there was an outbreak of acute schistosome infections (73 cases), and the snail area increased again to 133.7 hm2 accounting for 2.91% of historical accumulative snail areas. After that, the snail area kept on rising and the infection rates of residents and bovine remained higher than 1%. In Guangde County, the snail area was 32.4 hm2 accounting for 1.90% of its historical accumulative snail areas in the year of transmission controlled (1995). After that, the snail area increased progressively, and the schistosomiasis endemic rebounded and there were acute schistosome infections 5 years later. The Spearman tests showed that the sero test-positive rate (Tianchang City) and the stool-test-positive rates of residents and bovine (Taihu County) had positive correlations with the snail areas (r = 0.582, 0.401, 0.596, all P < 0.05). CONCLUSION: The snail status is a key for the consolidation of schistosomiasis transmission controlled and interrupted. Therefore, a valid surveillance system of snail situation should be established as quickly as possible. PMID- 25782241 TI - [Retrospective investigation on endemic situation of schistosomiasis in Hubei Province]. AB - OBJECTIVE: To explore the changing rules of schistosomiasis infection and Oncomelania hupensis snail situation in areas where schistosomiasis transmission was controlled or interrupted or transmission rebounded after the interruption. METHODS: Daye City, Wuxue City and Jingshan County were selected and investigated retrospectively to collect the schistosomiasis epidemiological information 10 years before they reached the criteria of transmission controlled and the subsequent years until 2008. The database of retrospective investigation was established for analyzing the trends and rules of the changes of snail status and human infection status. RESULTS: In Daye City, there was no snail areas and schistosomiasis patients and cattle after reaching the criteria of transmission interrupted in 1987. The infection rate of residents were positively correlative with the infection rate of cattle and snail areas (r = 0.865, 0.843, P < 0.01). In Wuxue City, the proportion of snail areas occupying the historic snail areas kept a steady from the transmission controlled to transmission interrupted, but it began to rebound to the highest level in the history (8.93%) after the transmission interrupted for 3 years. In Jingshan County, the infection rates of residents and cattle were all stable from 1% to 2% after the transmission controlled. The proportion of snail areas occupying the historic snail areas was rebounded from 1.63% in 1985 to 21.50% in 2008, and the densities of living snails rebounded from 2005. CONCLUSIONS: The infected snails could be the sensitive indicator of the rebound of snail situation and human infection. The elimination of schistosomiasis still depends on the control of snail areas, including strengthening the infected snail control. PMID- 25782242 TI - [Retrospective investigation of schistosomiasis endemic situation in Hunan Province]. AB - OBJECTIVE: To understand the dynamic rules of schistosomiasis endemic situation before and after reaching the criteria of schistosomiasis transmission controlled or transmission interrupted, so as to provide the evidence for improving schistosomiasis control. METHODS: Wuling District, Xihu District and Linli County were selected and investigated retrospectively to collect the schistosomiasis epidemiological information 10 years before they reached the criteria of transmission controlled and the subsequent years until 2008. A database of retrospective investigation was established for analyzing the trends and rules of changes of the Oncomelania hupensis snail status and infection status of cattle and human. RESULTS: In Wuling District, the endemic situation was declining, and no schistosome infection persons, animals and snails were found after 1974. There was no rebound until 2008. In Xihu District, the endemic situation reached the criteria of transmission controlled in 1997, and the endemic situation was stable. The human infection rate was positively correlated with the area of infection snails (r = 0.584, P < 0.05). In Linli County, there were no snails, no infected persons and cattle twice, but 2 endemic rebounds, and there were positive correlations between the densities of living snails and the infection rates of human and animal during the endemic rebound period. CONCLUSION: The snail status is an important indicator of schistosomiasis endemic rebound. Therefore, the snail control is one of the most important schistosomiasis control measures. PMID- 25782243 TI - [Changes of schistosomiasis endemic situation in Sichuan Province and impact on schistosomiasis transmission in Three Gorges Reservoir area after construction of Three Gorges Reservoir]. AB - OBJECTIVE: To understand the changes of schistosomiasis endemic situation in Sichuan Province, the upstream of Yangtze River basin, and the impact on schistosomiasis transmission in Three Gorges Reservoir area after the construction of Three Gorges Reservoir. METHODS: The annual reports of the schistosomiasis endemic situation in Sichuan Province from 2000-2012, the data of the schistosomiasis surveillance sites in Sichuan Province from 2001-2012, the data of the schistosomiasis sampling survey in Sichuan Province in 2001, and the relevant reference of Three Gorges Reservoir were collected. The schistosomiasis prevalence in human and cattle, and Oncomelania hupensis snail status were investigated. The snail survey was implemented in Qianjin Village, Jianyang City, Sichuan Province, the nearest village to Three Gorges Reservoir Area. RESULTS: The schistosomiasis endemic situation presented a continuous declining state in Sichuan Province from 2000-2012, and reached the criteria of schistosomiasis transmission controlled in 2008. From 2012, 65.07% of endemic counties reached the criteria of schistosomiasis transmission interrupted. From 2006, no schistosome infected snails were found. In Qianjin Village, 1714 m2 environments were surveyed and no snails were found. CONCLUSIONS: The schistosomiasis endemic area and snail area are significantly reduced in Sichuan Province, the upstream of Yangtze River basin, after the construction of Three Gorges Reservoir. Therefore, the possibility of schistosomiasis endemic diffusing to Three Gorges Reservoir area is minimum. PMID- 25782244 TI - [Impact of implementation of Three Gorges Project on schistosomiasis endemic situation in Hubei Province]. AB - OBJECTIVE: To understand the change of hydrological regime in the Yangtze River and schistosomiasis endemic situation after the implementation of Three Gorges Project in Hubei Province. METHODS: The data of hydrological regime of the Yangtze River, schistosomiasis epidemic situation, and Oncomelania hupensis snail status were collected and analyzed in Hubei Province from 2002 to 2012. RESULTS: After the implementation of the Three Gorges Project in 2003, the water level of the Yangtze River slightly rose from January to March, the average water level in May and August both reduced compared with that in 2002, and the time of water withdrawal was moved up. The endemic situation of schistosomiasis showed a decline tendency in areas along the Yangtze River in Hubei Province. The positive rate of serological tests in the residents and the Schistosoma ja- ponicum infection rate in bovine decreased by 2.97% and 92.64% respectively. The numbers of human and bovine infected with S. japonicum decreased by 48.35% and 94.48%, respectively. CONCLUSION: After the implementation of the Three Gorges Project, the schistosomiasis endemic situation shows a decline tendency in the areas along the Yangtze River in Hubei Province, but the long-term monitoring still need to be carried out. PMID- 25782245 TI - [Surveillance and risk assessment system of schistosomiasis in Jiangsu Province. I. Distribution of surveillance site and effectiveness of the system]. AB - OBJECTIVE: To establish the surveillance and risk assessment system of schistosomiasis in Jiangsu Province, so as to provide technical support for timely understanding of the risk of schistosomiasis transmission and implementation of targeted control measures. METHODS: The surveillance sites of schistosomiasis were assigned according to the epidemic status and endemic type of schistosomiasis as well as the characteristics of the water system, and the prevalence of Schistosoma japonicum in humans and domestic animals, and snail status were investigated. In addition, the quality control of serum detection of S. japonicum infections was performed. The prevalence of human and animal S. japonicum infections, snail status and missing diagnosis of serum detection were analyzed and compared among regions. RESULTS: A total of 27 surveillance sites of schistosomiasis were set up in 26 counties of 10 cities, Jiangsu Province, including 14 sites in transmission-interrupted villages and 13 sites in transmission-controlled villages, and 15 sites in marshland and lake regions, 9 sites in plain regions with water network and 3 sites in mountainous region. In the 27 surveillance sites, a total of 16 617 residents were screened for S. japonicum infection by using dipstick dye immunoassay (DDIA), and 326 were sero positive, with a sero-prevalence of 1.96% (2.17% for men and 1.8% for women). Of the 326 individuals undergoing parasitological examination, 2 positive cases were detected in the marshland and lake region, with a S. japonicum human prevalence of 0.01%. Of the 762 floating population detected, 10 were positive for blood test, with a sero-prevalence of 1.31%, and no egg-positive individuals were detected. No infection was found in the 476 domestic animals. Of the 746 settings surveyed, a total of 240.7 hm2 snail area was detected, with a mean snail density of 0.06 snails/0.1 m2, and no infected snails were found. There were 780 quality control sera detected in 26 surveillance sites of schistosomiasis, and the gross coincidence rate was 95.13%, with misdiagnosis rate of 1.28% and missing diagnosis rate of 19.23%. CONCLUSION: The surveillance sites of schistosomiasis show reasonable distribution in Jiangsu Province, and the endemic situation of schistosomiasis appears a low level in the whole province. PMID- 25782246 TI - [Surveillance and forecast system of schistosomiasis in Jiangsu Province. VI. Detection technology of water infectivity based on enrichment of Schistosoma japonicum cercariae on water surface]. AB - OBJECTIVE: To explore the enrichment technique of Schistosoma japonicum cercariae on the water surface, so as to establish a new method combined with the existing technology to detect the cercarial infested water body quickly and sensitively. METHODS: Soybean oil, gasoline, kerosene and isophorone were screened as expanding agents. The cercariae were enriched by the thrust of the expanding agents when diffusing on the water surface, and PE adsorption film and C-6 film were applied to seize them so as to determine the infectivity of the water quickly. The relationship between the dose of expanding agents and diffusion radius were explored. RESULTS: Gasoline, kerosene and isophorone were suitable expanding agents, and the diffusion effect of isophorone was the best. After the enrichment by the expanding agents, the detection rate of cercariae of the method seizing cercariae with the film significantly improved in the water. CONCLUSION: This new method could effectively improve the detection rate of the cercarial infested water and is suitable for the low-degree infested water. PMID- 25782247 TI - [Epidemiological analysis of malaria prevalence in Jiangsu Province in 2013]. AB - OBJECTIVE: To understand the malaria epidemic situation and characteristics in Jiangsu Province in 2013, so as to provide the evidence for formulating and adjusting effective malaria elimination strategies and measures. METHODS: The reported malaria cases from the Internet Reporting System and the epidemiological data of malaria in Jiangsu Province were collected and analyzed. RESULTS: A total of 341 malaria cases were reported in Jiangsu Province in 2013 with the incidence of 0.050/10 000, which increased by 72.22% compared with that in 2012 (198 cases). All the cases were imported from other countries including one infected by blood transfusion resulted from imported infection. The cases were mainly distributed in Lianyungang City (15.84%, 54 cases), Nantong City (14.08%, 48 cases), Yangzhou City (14.08%, 48 cases), Huaian City (11.44%, 39 cases) and Yancheng City (8.50%, 29 cases). All the cases were confirmed in Jiangsu Provincial Reference Laboratory and there were 286 cases of Plasmodium falciparum, 8 cases of P. vivax, 9 cases of P. malariae, 30 cases of P. ovale and 8 cases of mixed infections. CONCLUSIONS: There were no local malaria cases reported from Jiangsu Province in the last two years which reflected effective achievements of malaria elimination. However, the situation of imported malaria is more serious and the species of infected plasmodium are more diverse. Imported malaria from other countries remains the key of malaria control in Jiangsu Province. PMID- 25782248 TI - [Application of health education of house-to-house visit in malaria prevention and control]. AB - OBJECTIVE: To evaluate the effects of health education of house-to-house visit in malaria prevention and control in the border and minority areas. METHODS: A health education of house-to-house visit in malaria prevention and control was carried out, and baseline and follow up surveys were conducted by qualitative and quantitative methods to document the changes of local villagers' knowledge, attitudes and behaviors (KAP) of malaria prevention and control in 2 counties of Yunnan Province, and the results before and after the interventions were analyzed and compared. RESULTS: After the intervention, the cognition rates about malaria symptoms and signs, transmission mode, preventive measures and health-seeking behaviors were 99.3%, 98.9%, 79.9% and 99.3% respectively in the local residents, and those were 39.2%, 8.2%, 47.0% and 49.9% respectively before the intervention, and all the differences were statistically significant (P all < 0.01). CONCLUSIONS: KAP related to malaria among the targeting population has improved after the interventions and the house-to-house visit is an effective community based health education approach. PMID- 25782249 TI - [Detection of Plasmodium falciparum by using magnetic nanoparticles separation based quantitative real-time PCR assay]. AB - OBJECTIVE: To establish a magnetic nanoparticles separation-based quantitative real-time PCR (RT-PCR) assay for fast and accurate detection of Plasmodium falciparum and providing a technical support for improving the control and prevention of imported malaria. METHODS: According to the conserved sequences of the P. falciparum genome 18SrRNA, the species-specific primers and probe were designed and synthetized. The RT-PCR was established by constructing the plasmid standard, fitting the standard curve and using magnetic nanoparticles separation. The sensitivity and specificity of the assay were evaluated. RESULTS: The relationship between the threshold cycle (Ct) and logarithm of initial templates copies was linear over a range of 2.5 x 10(1) to 2.5 x 10(8) copies/MUl (R2 = 0.999). Among 13 subjects of entry frontier, a P. falciparum carrier with low load was detected by using the assay and none was detected with the conventional examinations (microscopic examinations and rapid tests). CONCLUSION: This assay shows a high sensitivity in detection of P. falciparum, with rapid and accurate characteristics, and is especially useful in diagnosis of P. falciparum infectors with low parasitaemia at entry-exit frontier ports. PMID- 25782250 TI - [Sequence analysis of ribosomal DNA internal transcribed spacer 2 of sympatric populations of Anopheles sinensis of different feeding preferences]. AB - OBJECTIVE: To investigate the existence of genetic divergence of sympatric populations of Anopheles sinensis of different feeding preferences based on the rDNA-ITS2 sequence differences. METHODS: A large number of wild anopheles populations were trapped all night by man-baited net and calf-baited net that had been set up between high-density natural villages of An. sinensis populations and vector-breeding sites, from which two groups of An. sinensis were separated by morphological identification and brought back to the lab for conventional breeding. A large closed greenhouse which temperature and humidity was appropriate was selected as research settings of mark-release-recapture methods by female mosquitoes, in the center of which above An. sinensis populations baited by man and calf and respectively correspondingly marked by red and yellow phosphors were released in together, in each side of which An. sinensis were recaptured simultaneously by man-baited net and calf-baited net. An. sinensis populations trapped by man twice were brought back to the lab and bred with man blood, correspondingly ones trapped by calf with calf-blood. Man-preferring and calf-preferring strains were screened respectively from An. sinensis which had been baited by man and calf by the mark-release-recapture methods after parent and F1 mosquitoes, and sequencing and aligning of both rDNA-ITS2 were conducted via PCR amplification. RESULTS: The recapture ratios of wild parental mosquitoes An. sinensis of man-preferring group by man-baited net and calf-baited net were 54.07% (339/627) and 45.93% (288/627) respectively, and ones of calf-preferring group by man-baited net and calf-baited net were 58.01% (409/705) and 41.99% (296/ 705) respectively. Two groups of parental mosquitoes trended towards selecting the original blood hosts in host-seeking preference (Chi2 = 19.42, P < 0.01). The recapture ratios of F1 mosquitoes An. sinensis of man-preferring group by man-baited net and calf-baited net were 63.43% (765/1 206) and 36.57% (441/1 206), and ones of calf-preferring group by man-baited net and calf-baited net were 68.22% (1 039/1 523) and 31.78% (484/1 523). Two groups of F1 mosquitoes had more significant characteristics of selecting the original blood hosts in host seeking preference (Chi2 = 271.69, P < 0.01) and showed the genetic differentiation phenomenon, but the results of sequencing and aligning of the rDNA-ITS2 via PCR amplification showed no difference in base sequence between the two strains and both were 469 bp. CONCLUSIONS: The genetic divergence based on the rDNA-ITS2 sequence does not happen in An. sinensis sympatric populations of different feeding preferences. PMID- 25782251 TI - [Experimental study on cross-resistance of Culex pipiens pallens to 3 kinds of chemical pesticides]. AB - OBJECTIVE: To understand the cross-resistance of Culex pipiens pallens to common pesticides, so as to provide the evidence for improving the application of chemical pesticides. METHODS: The IV instar larvae of DDVP-resistant, propoxur resistant and cypermethrin-resistant strains as well as the sensitive strain of Culex pipiens pallens were collected to detect the resistance to DDVP, propoxur and cypermethrin based on the WHO bioassay method. RESULTS: The resistance coefficients of DDVP-resistant strain to DDVP, propoxur and cypermethrin were 14.47, 8.96 and 207.27 respectively. The resistance coefficients of propoxur resistant strain to DDVP, propoxur and cypermethrin were 3.27, 6.93 and 8.65 respectively. The resistance coefficients of cypermethrin-resistant strain to DDVP, propoxur and cypermethrin were 2.93, 1.61 and 501.11 respectively. CONCLUSION: The resistance and cross-resistance could be generated during the long-term application of a single kind of chemical pesticide, and we should pay more attention to the varieties and dosages of them. PMID- 25782252 TI - [Survey of infections of intestinal parasites and related factors in north-west Shandong Province]. AB - OBJECTIVE: To understand the infection status of intestinal parasites and related knowledge and behavior factors of the residents in north-west Shandong Province, so as to provide the evidence for taking targeted preventive measures. METHODS: Eighteen villages were randomly selected as survey spots by the stratified multi stage sample method. The Kato-Katz technique was used to detect intestinal parasite eggs among the residents and the cellophane tape anus test was used to detect Enterobius vermicularis eggs among 3-12 years old children. Questionnaires were applied to investigate related knowledge and behavior factors about the intestinal parasite infections in the residents. RESULTS: Totally 6 366 residents were detected for intestinal parasites and the infection rate was 0.28% (18 cases). Totally 895 children were detected for E. vermicularis and the infection rate was 5.70% (51 cases). Totally 2 915 residents were investigated by questionnaires and the awareness rate of knowledge about preventing parasitic diseases was 26.72%. The formation rates of washing hands before meal and after WC, washing fruit and vegetable before eating, never drinking unboiled water were 55.42%, 42.87%, 43.54% and 83.04% respectively. The awareness rate of knowledge about preventing parasitic diseases of 3-12 years old children was 12.24%; and the formation rates of washing hands before meal and after WC were 47.04% and 30.44% respectively. CONCLUSIONS: The total infection rate of intestinal parasites is low but the E. vermicularis infection rate is high among children in north-west Shandong Province. The awareness rate of knowledge about preventing parasitic diseases and the formation rates of healthy behaviors are all low. Therefore, the targeted health education should be taken to increase the awareness rate and guide the residents to develop their healthy behaviors. PMID- 25782253 TI - [Retrospective investigation for endemic situation of schistosomiasis in Zhejiang Province]. AB - OBJECTIVE: To analyze the changing rules of schistosomiasis endemic situation before and after reaching the criteria of schistosomiasis transmission controlled or transmission interrupted in Zhejiang Province, so as to provide scientific evidence for schistosomiasis control. METHODS: Xiuzhou District and Zhuji City were selected and investigated retrospectively to collect schistosomiasis epidemiological information 10 years before they reached the criteria of transmission controlled and the subsequent years until 2008. The database of retrospective investigation was established for analyzing the trends and rules of changes of Oncomelania hupensis snail status and schistosome infection status of cattle and human. RESULTS: The snail status and schistosome infection kept a steady declining before reaching the criteria of transmission controlled, and there were positive correlations between the area of living snails and the infection rates of human and animal in two places (r(human) = 0.764, P < 0.01, r(catlle) = 0.709, P < 0.01; r(huma) = 0.775, P < 0.01, r(catlle) = 0.676, P < 0.01); No local infection person and animal except residual snails, and found 7 cases of imported infection source were found after reaching the transmission interruption. CONCLUSION: The epidemic status of schistosomiasis in zhejiang is stable after reaching the criteria of transmission interruption, and residual snail are easy to re-found and spread under some certain conditions, and some imported cases were found sometimes, which may increase the risks for re emergence of schistosomiasis. The integrated solidification strategy with emphasis on control of residual snails and imported cases should be taken in the areas of transmission interruption in the future. PMID- 25782254 TI - [Retrospective survey of schistosomiasis epidemic situation in Jianchuan County, Yunnan Province]. AB - OBJECTIVE: To understand the dynamic status of schistosomiasis epidemic situation and Oncomelania hupensis snail status before and after the schistosomiasis transmission interrupted in the mountainous areas of Yunnan Province. METHODS: The data of schistosomiasis epidemic situation and snail status were collected and analyzed statistically in Jianchuan County from 10 years before the schistosomiasis transmission interrupted to 2008. RESULTS: The schistosomiasis control began in Jianchuan County from 1954. In 1976, the criteria of schistosomiasis endemic controlled were reached, and the infection rate of population was 0.65% and the infection rate of snails was 0.40%. In 1981, the criteria of schistosomiasis transmission controlled were reached, and the infection rate of population was 0.34% and the infection rate of snails was 1.41%. In 1993, the criteria of schistosomiasis transmission interrupted were reached, and the infection rate of population was 0 and the infection rate of snails was 0. There was a fluctuation in the schistosomiasis epidemic situation and snail status during the whole control duration, but the trend was decreasing. CONCLUSION: The time from schistosomiasis endemic controlled to transmission controlled is relatively short, but the time from transmission controlled to transmission interrupted is relatively long. In the original schistosomiasis endemic areas, there might be some areas where there is no the disease bud there still are snails. PMID- 25782255 TI - [Seasonal changes of glucose levels in Oncomelania hupensis]. AB - OBJECTIVE: To study the seasonal changes of glucose levels per unit soft tissue of Oncomelania hupensis. METHODS: O. hupensis snails were collected from the beach of the Qingyi River in Wuhu City, Anhui Province from August 2012 to July 2013. They were kept in minus 80 degrees C refrigerator immediately. The male snails were distinguished from female, and their soft tissues were collected separately after crushing their shells. The hexokinase method was used to measure the glucose concentrations, and the results were analyzed statistically. RESULTS: The contents of glucose decreased from March to July. The lowest glucose content in the female was 1.87 MUg/mg in March, and that in male was 3.70 MUg/mg in July. Both of them increased from August and reached peak levels in September (Female = 57.38 MUg/mg, male = 44.39 MUg/mg), and then gradually decreased from October to next January and increased in February. CONCLUSION: The contents of glucose have seasonal changes regularly in O. hupensis. PMID- 25782256 TI - [Distribution of historical Oncomelania hupensis snail environments and wetland environments in Wuxi City]. AB - OBJECTIVE: To understand the distribution and characteristics of historical Oncomelania hupensis snail environments and wetland environments in Wuxi City since 1952, so as to provide the evidence for formulating the monitoring strategy after the schistosomiasis transmission was interrupted. METHODS: A cross sectional survey was conducted to collect the information of historical O. hupensis snail environments and wetland environments. Google Earth was used to present and analyze the distribution and characteristics of them. RESULTS: There were 2 124 historical O. hupensis snail environments in Wuxi City and the accumulative area was 2 995.7 hm2. In 2013, there were 61 surveillance sites of wetland with the area of 32.8 hm2; totally 1 695 snails were caught and no O. hupensis snails were found. CONCLUSION: The historical O. hupensis snail environments were distributed widely and covered a large area in Wuxi City. The surveillance should be focused on the key environments and wetland. PMID- 25782257 TI - [Endemic situation of malaria in Dongtai City, 1999-2013]. AB - OBJECTIVE: To understand the characteristics of malaria endemic situation in Dongtai City, from 1999 to 2013. METHODS: The data of diagnosed malaria cases and related information of prevention and treatment were collected and analyzed with the epidemiological method. RESULTS: From 1999 to 2013, there were 27 malaria cases in total, and among which 2 cases were local-infected with Plasmodium vivax, 10 cases were imported P. vivax infections, 13 cases were imported P. falciparum infections, and 1 case was a mixed infections (P. falciparum, P. vivax and P. ovale). The imported cases accounted for 92.59% and local-infected cases accounted for 7.41%. There were no local-infected cases after 2003, and all the cases were overseas-imported. The main first-diagnosis points were town hospitals and village health stations, accounting for 33.33% and 33.33% respectively. Totally 62.96% of cases visited the clinic in 1 day after the attacking, the median of time-interval from the attacking to visiting the clinic was 1 day, the median of time-interval from the attacking to confirmed diagnosis was 3 days, and the max time from the attacking to confirmed diagnosis was 33 days. CONCLUSION: The malaria cases are mainly imported cases in Dongtai City from 1999 to 2013, and therefore, the key of eliminating malaria should be the monitoring of the retuned exporting labors. PMID- 25782258 TI - [Investigation of Capillaria hepatica infection in rodents from Wuhan section of Yangtze River marshland]. AB - OBJECTIVE: To understand the prevalence of Capillaria hepatica in rodents from Wuhan section of the Yangtze River marshland. METHODS: Rodents were trapped in Jiang'an section of Wuhan marshland of the Yangtze River. The livers of the rodents were examined for pathological changes by unaided eyes and the liver tissues were examined for the eggs of C. hepatica by a microscope. RESULTS: According to the natural conditions, the investigation was carried out in 6 survey areas. Each survey area was placed with 60 mousetraps, and all 360 mousetraps were recovered. A total of 31 rodents (rodent density 8.61%) were captured and examined, including 24 Apodemus agrarius, 3 Rattus norvegicus, 4 Sorex caecutiens, and C. hepatica eggs were found in 1 R. norvegicus (1/3) and not found in A. agrarius, and S. caecutiens. CONCLUSION: This study has documented a prevalence of C. hepatica in rodents from Wuhan section of the Yangtze River marshland where is a natural epidemic focus of capillariasis hepatica. PMID- 25782259 TI - [Construction and operation of network laboratory for schistosomiasis diagnosis in Jianglin County]. AB - OBJECTIVE: To build a high quality diagnosis system for schistosomiasis surveillance in the situation of low infection in Jianglin County. METHODS: The network laboratory for schistosomiasis diagnosis was built according to the national criteria in Jianglin County in 2012. RESULTS: The network laboratory for schistosomiasis diagnosis was established successfully and the operation was quiet well. CONCLUSION: The establishment and operation of the laboratory play an important role in the realization of schistosomiasis elimination. PMID- 25782260 TI - [Strategy and effect of schistosomiasis emergency control after earthquake in Lushan County]. AB - OBJECTIVE: To evaluate the effects of measures on the schistosomiasis control after the earth quake in Lushan County, so as to provide the experiences for post disaster schistosomiasis control. METHODS: The measures taken in schistosomiasis control after the earth quake were reviewed in Lushan County in 2013, and the epidemic situation of schistosomiasis was investigated and the results were analyzed. RESULTS: The schistosomiasis control in floating population and the control of Oncomelania hupensis snails were enhanced, and no schistosome infections were found in both human and livestock. No infected snails and infested water were found. CONCLUSION: The measures of schistosomiasis control after the disaster are effective in Lushan County, and the goal to prevent major plague after the earth quake is achieved. PMID- 25782261 TI - [Advanced schistosomiasis prevalence in Jingmen City from 2004 to 2013]. AB - OBJECTIVE: To understand the advanced schistosomiasis prevalence trend in Jingmen City, so as to provide the evidence for improving the disease prevention and control. METHODS: The changes of advanced schistosomiasis prevalence were investigated and the distribution characteristics of the patients were analyzed in Jingmen City from 2004 to 2013. RESULTS: In recent 10 years, the incidence of advanced schistosomiasis dropped from 0.014/thousand to 0.009/thousand, and the regional distribution of the patients did not change. The number of male patients was still more than that of female patients, but more old aging patients were found. The ascetic type and splenomegaly type of advanced schistosomiasis patients were the most. CONCLUSION: In the next few years, the advanced schistosomiasis patients Jingmen City will reduce quickly, and concentrate on the aging group and ascetic type. PMID- 25782262 TI - [Natural environment and schistosomiasis transmission in Poyang Lake region]. AB - Schistosomiasis is closely related to natural environmental factors. The changes of environmental factors, such as temperature, hydrology, vegetation, soil etc., all impact the scope and extent of schistosomiasis transmission. Poyang Lake is the largest freshwater lake and one of the major endemic areas with schistosomiasis in China. With global warming, the implementation of the Three Gorges Dam operation, and the Poyang Lake Ecological Economic Planning, the natural environment in Poyang Lake area has been and will continue to change, especially, the water environment and climate environment, which are more closely related to the schistosomiasis transmission. These changes, to some extent, have affected and will continue to affect the prevalence and transmission of schistosomiasis. This article reviews the relationship between the natural environment and its changes and schistosomiasis transmission in the Poyang Lake region. PMID- 25782263 TI - [Selection of epidemic indicators for schistosomiasis GIS platform in Dongting Lake area]. AB - Dongting Lake area is one of the major marshland schistosomiasis endemic areas in China. In recent years, spatial epidemiology is widely used in the research of schistosomiasis, which is a new opportunity to break through the current wandering situation of schistosomiasis control. In this article, both the generalized and Dongting-Lake-specific epidemic indicators of schistosomiasis are reviewed to provide the basis to construct the schistosomiasis Geographic Information System (GIS) database of Hunan Province. PMID- 25782264 TI - [Research progress of immunoregulation of B cells to schistosome infection]. AB - Recent studies found that B cell subsets and their factors have double effects on anti- and aiding schistosome infection. This article summarizes the research progress of positive and negative immunoregulation of schistosome infection involving B lymphocytes, antibody and regulatory B cells (Bregs) relating cytokines (IL-10, IL-7 and TGF-beta). PMID- 25782265 TI - [Molluscicidal effect of 5% niclosamide ethanolamine granules against Oncomelania hupensis in a marshland field]. AB - OBJECTIVE: To investigate the molluscicidal effect of 5% niclosamide ethanolamine granules against Oncomelania hupensis in a marshland field. METHODS: The 5% niclosamide ethanolamine granules were sprayed at a dose of 40 g/m2 on 3 snail breeding marshlands in Yangzhong City of Jiangsu Province to assess its field molluscicidal actions, while 26% suspension concentrate of metaldehyde and niclosamide (MNSC); at a dose of 4 g/m2) and fresh water served as controls. RESULTS: After seven days spraying, 5% niclosamide ethanolamine granules resulted in a of snail mortal85.42%ity, while the mortality rates of snails were 82.35% and 2.86% in the MNSC and water control groups, respectively. CONCLUSION: 5% niclosamide ethanolamine granules exhibit a high molluscicidal activity, which is suitable to be used in the mashland. PMID- 25782266 TI - [Effects of comprehensive schistosomiasis control in marshlands of Pukou District, Nanjing City]. AB - OBJECTIVE: To evaluate the effects of comprehensive schistosomiasis control in marshlands of Pukou District, Nanjing City so as to provide the evidence for developing the strategy of the disease control. METHODS: The information of the prevention and control of schistosomiasis was collected in Pukou District from 2004 to 2013. The variations of the infection rates of human, livestock and Oncomelania hupensis snails were analyzed. RESULTS: In 2013, the area with snails in the entire district was 384.09 hm2, which was 66.24% decrease compared to 1 137.61 hm2 in 2004. Moreover, after 2008, no infected-snails and schistosomiasis patients were found, and both the density of live snails and serum positive rate of schistosomiasis declined with years. CONCLUSIONS: After the comprehensive prevention and control is conducted, the schistosomiasis situation in Pukou District is stable. However, in order to consolidate the results, it is still essential to continue monitoring the previous infected snail environments and implementing the comprehensive prevention and control measures. PMID- 25782267 TI - [Clinical analysis of early esophageal varices bleeding after endoscopic varices ligation in advanced schistosomiasis patients]. AB - OBJECTIVE: To study the clinical characteristics of early esophageal varices bleeding after endoscopic varices ligation (EVL) in advanced schistosomiasis patients. METHODS: The data of 206 advanced schistosomiasis patients who received VEL were collected and studied retrospectively. RESULTS: There were 17 cases of early esophageal varices bleeding after EVL including 1 died case, the early hemorrhage rate was 8.25%, and the mortality rate was 0.5%. The early bleeding occurred from the 4th to 12th day, and 76% occurred from the 7th to 9th day postoperatively. The direct cause of hemorrhagic was ligation ring falling off, and the inducements were the improper diet (10 cases, 58.8%) and increased abdominal pressure (6 cases, 35%). All the cases of early esophageal varices bleeding occurred in the patients whose liver function being Child-Pugh C. CONCLUSIONS: The incidence and mortality of EVL early postoperative hemorrhage are both low, and mostly occur from the 7th to 9th day postoperatively. We should pay attention to the diet and nursing, and the patients with Child-Pugh C liver function are the high risk group. PMID- 25782268 TI - [Surveillance of schistosomiasis in Hubei Province in 2013]. AB - OBJECTIVE: To understand the dynamic schistosomiasis situation in Hubei Province so as to provide the evidence for formulating the effective control strategy. METHODS: According to the Scheme of Schistosomiasis Surveillance in Hubei Province (the 2009 edition) , 207 endemic villages were selected and investigated for the schistosome infections of residents and livestock, and the distribution of Oncomelania hupensis snails. RESULTS: The average infection rates of residents and cattle were 0.35% and 0.15% respectively, and the endemic situation of fishermen and farmers were relatively serious (0.44% and 0.42%, respectively). The density of living snails was 0.30 snail/0.1m2, but no infected snails were found. CONCLUSION: The endemic situation of schistosomiasis in Hubei Province was stable in 2013, but the efforts for the infectious source control still should be strengthened. PMID- 25782269 TI - [Effect of integrated control of schistosomiasis in Shashi District from 2009 to 2013]. AB - OBJECTIVE: To evaluate the effect of integrated schistosomiasis control in Shashi District from 2009 to 2013, so as to provide the evidence for the development and adjustment of schistosomiasis control strategies. METHODS: The data of integrated schistosomiasis control from 2009 to 2013 were collected and analyzed for the epidemic situations of human, livestock and Oncomelania hupensis snails. RESULTS: From 2009 to 2013, the infection rates of human and cattle decreased from 2.24% and 1.92% to 0.63% and 0, with decrease rates of 71.88% and 100%, respectively; the area with snails decreased from 760.40 hm2 to 715.08 hm2, with a decrease rate of 5.69%; the occurrence rate of frames with living snails and the average density of living snails decreased from 26.32% and 0.67 snail/0.1 m2 to 18.30% and 0.53 snail/0.1 mi2, with decrease rates of 30.47% and 20.90%, respectively. No infected living snails were found from 2012 to 2013. CONCLUSION: The integrated schistosomiasis prevention and control strategies with emphasis on infectious source control could effectively reduce the infection rates of human and cattle as well as the snail situation. PMID- 25782270 TI - [Serological survey of Toxoplasma gondii infection in some areas of Pu' er City]. AB - OBJECTIVE: To understand the status of Toxoplasma gondii infection in the population of Pu'er City, so as to provide the evidence for formulating the strategy of toxoplasmosis control. METHODS: The population from Jingdong, Jinggu, and Menglian counties in Pu' er City was surveyed; IgG of T. gondii in serum was detected by ELISA. RESULTS: Totally 906 resident serum samples were detected and the IgG positive rate was 24.2%. The positive rates were higher in the aged groups of 30-39 years and 60-69 years, and the difference among different aged groups was significant (Chi2 = 17.77, P < 0.01). There were no significant differences between different sexualities, and among different educational levels and living habits (P > 0.05). The positive rates were 26.6% (194/730), 15.5% (22/142), and 8.8% (3/34) in farmers, students and other occupations, respectively, and there was a significant difference among them (Chi2 = 12.51, P < 0.01). The positive rates were 23.3% (198/849)and 36.8% (21/57) in the farmers who had the habit of rearing pigs in pens and the farmers who had the habit of free ranging pigs, respectively, and there was a significant difference between them (Chi2 = 5.33, P < 0.05). CONCLUSION: The IgG positive rate of T. gondii is very high in Pu'er City, and therefore, the health education for toxoplasmosis control should be strengthened. PMID- 25782271 TI - [Malaria endemic situation in Xuzhou City from 2010 to 2013]. AB - OBJECTIVE: To understand the incidence and trend of malaria in Xuzhou City, so as to provide the evidence for formulating the malaria control measures. METHODS: The information of network reported malaria cases and epidemiological data were collected and analyzed statistically in Xuzhou City from 2010-2013. RESULTS: A total of 109 malaria cases were reported by the special report systems and the network report system in Xuzhou City from 2010 to 2013, in which there were 44 cases (40.37%) of vivax malaria, 62 cases (56.88%) of falciparum malaria, 2 cases (1.83%) of quartan malaria, 1 case (0.92%) of ovale malaria. The latter three were all imported from other countries. Totally 93 cases (85.32%) were confirmed by laboratory, and other 16 cases (14.68%) were diagnosed clinically. There was the incidence throughout the year and there were no obvious seasonal characteristics. The positive rate of blood test in the floating population was significantly higher than that of the local residents (Chi2 = 868.23, P < 0.01). CONCLUSION: The malaria endemic situation is in the steady decline period in Xuzhou City. The local infections decrease significantly but the imported falciparum malaria cases increase year by year. Therefore, the management for floating population and fever patients should be strengthened. PMID- 25782272 TI - [Schistosomiasis endemic situation at a national surveillance site in Gong'an County, Hubei Province from 2004 to 2013]. AB - OBJECTIVE: To understand the schistosomiasis endemic situation at a national surveillance site in Gong'an County, Hubei Province. METHODS: According to The Scheme of Schistosomiasis Surveillance in China, the schistosome infection rates of residents and cattle, and the Oncomelania hupensis snail status were investigated yearly in Zhangjiahu Village, a national surveillance site, in Gong' an County from 2004 to 2013. RESULTS: From 2004 to 2013, the human schistosome infection rates decreased from 10.66% to 0.58%, and the cattle schistosome infection rates from 12.75% to 0. Meanwhile, the snail areas and densities reduced, and the schistosome infected snails were eliminated. CONCLUSION: The schistosomiasis endemic situation declined dramatically at the surveillance site, and schistosomiasis is well-controlled. PMID- 25782273 TI - [Origination and evolution of plastids]. AB - Plastids are photosynthetic DNA-containing organelles of plants and algae. In the review, the history of their origination and evolution within different taxa is considered. All of the plastids appear to be descendants of cyanobacteria that colonized eukaryotic cells. The first plastids arose through symbiosis of cyanobacteria with algal ancestors from Archaeplastida kingdom. Later, there occurred repeated secondary symbioses of other eukariotes with photosynthetic protists: in this way plastids emerged in organisms of other taxa. Co-evolution of cyanobacteria and ancestral algae led to extensive transformation of both: reduction of endosymbiont, mass transfer of cyanobacteria genes into karyogenome, formation of complex system of proteins transportation to plastids and their functioning regulation. PMID- 25782274 TI - [A study of the distribution ranges of small mammals from South-Eastern Transbaikalia with ecological niche modeling methods]. AB - Distribution models were constructed for 36 species of small mammals from South Eastern Transbaikalia. Distribution of environmental factors (climatic data and remote sensing of the earth surface) in the set of localities where each of the species was caught was taken as initial data for modeling. Species distribution ranges can be explained by distribution of environmental factors only in 30 cases out of 36. Seventeen of them can be explained by one or two environmental factors only. In 6 cases notable influence of historical factors or interspecific competition on present species distribution was found out. For these 6 species, modeling results make it possible to suggest hypotheses about reasons behind present distribution, which could not be advanced without modeling approach. PMID- 25782275 TI - [Immunocompetence and reproductive characteristics of male Campbell dwarf hamsters selected for low and high humoral immune response to SRBC: testing the immunocompetence handicap hypothesis]. AB - We selected Campbell dwarf hamsters (Phodopus campbelli Thomas, 1905) for low and high humoral immune response to the sheep red blood cells (SRBC) challenge in three generations (P, F1, F2). Non-specific innate immunity and acquired T-cell immunity, resting metabolic rate, testosterone, and cortisole hormone levels, reproductive characteristics, including maturation related morphological traits, and aggressive behavior were studied within sets of males:with low (LI) and high (HI) immune response to SRBC. We found no difference between LI and HI males in cutaneous response to injection of phytohemagglutinin, (DTH test for T-cell immunity), in activity of Peroxidase - Endogenous Hydrogen Peroxide System of Neutrophils , in the white blood count, in resting metabolic rate, in body mass and ano-genital distance at the age of two months, in the blood level of testosterone before and after recurrent immunization by SRBC and in the blood level of cortisole in response to the social stressor (10 min encounter in the neutral arena). At that, LI males had significantly higher basal level of blood cortisole, were less aggressive in response to stranger male and had smaller testosterone-dependent mid-ventral specific skin gland at the age of two months. Males of two groups did not differ in the initial mating success with intact young females (time since pair formation until first litter born), although females of LI males born fewer number of pups. In fact, our results do not support the Handicap Immunocompetence Hypothesis (Folstad, Karter, 1999) which is based on the assumption of trade-off between immunocompetence and reproductive effort. PMID- 25782276 TI - [A modular approach to studying of fluctuating asymmetry of complex morphological structures in rodents with the mandible of the bank vole (Clethrionomys glareolus, Arvicolinae, Rodentia) as an example]. AB - The expediency of a modular approach to estimating fluctuating asymmetry (FA) of complex morphological structures was shown using the mandible of the bank vole (Clethrionomys glareolus Schreber, 1780) as an example. FA of the shape of two mandibular regions (modules) defined developmentally and functionally, was assessed by means of geometric morphometrics. The differences between mandibular regions in the FA levels were found for both individual landmarks and integral indices of asymmetry. Regardless of age, gender or sampling year, FA estimates obtained for posterior region including part of the ramus and processes were higher than those for anterior region including the diastemal area. The results suggest that modularity of complex morphological structures should be taken into account when analyzing FA. PMID- 25782277 TI - [Upward and regeneration fluxes of inorganic nitrogen and phosphorus in the deep water areas of the Black-Sea]. AB - Upward and regeneration fluxes of inorganic nitrogen and phosphorusin the euphotic zone of the Black Sea deep waters were estimated using data from long term observations of nitrate and phosphate vertical distribution and modeling of plankton month- and area-averaged nutrients excretion. The upward fluxes were calculated using monthly average nitrate and phosphate concentrations and their gradients beneath the euphotic layer assuming that the vertical transport rates are controlled by the density gradient at the upper layer of the main pycnocline throughout the year. According to the calculations, the nutrient input into the euphotic layer due to physical processes changes gradually throughout the year from minimum values in July-August (0.1-0.3 mg-atN x m(-2) x day(-1) and 0.02 0.04 mg-atP x m(-2) x day(-1)) up to maximum ones in February-March (1.2-1.8 mg atN x m(-2) x day(-1) and 0.2-0.3 mg-atP x m(-2) x day(-1)), contrary to the seasonal dynamics of the regeneration flux rates. In summer, plankton regeneration rates increase nearly five-fold as compared to the winter months. The contribution of the upward flux to the total nutrient euphotic zone input was calculated and designated as F(N)(F(P))-ratio along the lines with the f-ratio and e-ratio that reflect the ratio of "new" production and particle export to primary production, respectively. The monthly means vary for F(N) from 5 to 50% and for F(P) from 10 to 70% throughout the year in the same manner as the upward flux. Relationships between the monthly mean values of F(N,P) and vertically integrated nitrate and phosphate concentrations, chlorophyll "a", phytoplankton biomass, and primary production in the euphotic zone were established. The obtained relationships correspond to the general relationships between primary production, "new" production and the sinking flux of particles known for the Ocean. Potential values of "new", regenerated, and total production of phytoplankton in the deep-water areas of the Black Sea are identified. Average monthly and annual primary production estimates, calculated on the base of nutrient flows, are consistent with estimates of primary production according to the averaged data of in situ measures. PMID- 25782278 TI - [Early history of the Metazoa--a palaeontologist's viewpoint]. AB - The molecular biology success, which became influential for a revision of principal views on the relationships and evolutionary pathways of major groups ("phyla") of multicellular animals, were much more appreciated by palaeontologists rather than by neontologists. This is not surprising because this is the fossil record that serves as a firm test for molecular biological hypotheses. The fossil record indicates that the different "phyla" united nowadays into the Ecdysozoa, namely, arthropods, onychophorans, tardigrades, priapulids, nematomorphs, comprise a number of transitional forms having become extinct already in the early Palaeozoic. The very appearance of those organisms fits entirely to hypothetical ancestral forms which have to exist in accordance with some data on ontogeny. There are no even tentative intermediates between arthropods and annelids in the fossil record. The oldest Deuterostomia, which is the only branch of the Bilateria being agreed upon by all the biological disciplines, allow us, although in less details, to present their early history and point to agile bilaterally-symmetrical forms at the dawn of chordates, hemichordates, and echinoderms. The interpretation of the early history of the Lophotrochozoa is even more difficult because in comparison to other bilaterians, their oldest fossils are preserved as mineralized skeletons only. However, a unity of microstructures of molluscs, brachiopods, and bryozoans, absent in other metazoans, is indicative of the presence of close relatives among different earliest lophotrochozoans some of which are sedentary filterers while others are motile epibenthic detritophages. In the aggregate, modern data of molecular biology, palaeontology, and comparative embryology/morphology, having got a second wind with an introduction of new microscopy techniques, imply that the suggestion of a planktotrophic gastraea-like common ancestor is the least possible among diverse suggestions on the Metazoa origins. The common ancestor of the Bilateria had to be a motile epibenthic animal and the explosive metazoan diversification embracing the late Ediacaran--early Cambrian interval (c. 40 Ma) was probably a real event, which was predated by a long (c. a billion years) assembly of the metazoan genome within unicellular and colonial common ancestors of the Opisthokonta and even the Unikonta as a whole. PMID- 25782279 TI - [The double DNA content is detected in hemocytes of snail Lymnaea stagnalis from a population with high radiation load]. AB - The research of hemocytes of laboratory cultivated pond snails Lymnaea stagnalis originating from two areas near Chernobyl with different radiation load has been carried out by means of comet assay. Significant interpopulation distinctions in parameters of DNA-comets have been revealed by means of the software analysis of hemocyte DNA-comet images: hemocytes of mollusks from radiationally unfavourable "Perstok" population have contained a twice DNA quantity in comparison with "Pripyat" population, and also have been statistically more resistant to the influence of strontium. Strontium reduces the amount of DNA in hemocytes, at that strontium dose of 0.5 MPC is already substantial (i.e., causes a negative impact).for snail Lymnaea stagnalis. According to a RAPD-analysis previously conducted, the snails of two populations are characterized by high genetic similarity, on the basis of which a hypothesis is suggested that the observed differences in the DNA content of hemocytes and resistance to strontium are inherited as prolonged adaptive modification (epigenetic change) in response to the intensive damaging impact of environment. Comet assay can be its indicator while carrying out the environmental monitoring. PMID- 25782280 TI - [Syntaxonomic analysis of restorative successions after cutting down light coniferous forests of South Ural Region]. AB - Discussed are the possibilities of using syntaxa from floristic classification for the analysis of secondary restorative successions after forest cutting in South Ural Region. Peculiarities of secondary forest communities classification that may be viewed as subjects of indigenous vegetation syntaxa forming, sub associations or could be systematized according to 'deductive' classification introduced by K. Kopecky and S. Heiny are considered. An example is presented of an analysis of communities succession system formed after cutting down hemiboreal pine and birch-pine herbaceous forests of Bupleuro-Pinetum association. Within this system the processes of divergence and convergence of succession series take place. Divergence occur as a result of lifting of the influence caused by dominants edificating role and manifestation of differences in soil humidification, also as a consequence of soil enrichment by mineral elements after burning down the felling debris. The reason behind convergence is grading influence of renewed forest stand. Trends in species richness changes during restorative successions may differ depending on ecotope features. In course of a succession, models of tolerance and inhibition become apparent. PMID- 25782281 TI - [Motion aftereffect as a universal phenomenon for sensory systems involved in orientation in space. I. Visual aftereffects]. AB - At present there are serious grounds to believe that motion aftereffect is characteristic for all sensory systems involved in spatial orientation, and that adaptation to movement in one sensory system causes changes in another one and that such adjustment is of critical adaptive significance. In this part of the review there are briefly presented developments and the current state of studies on this issue in visual modality. The visual motion aftereffect has been studied considerably more completely as compared with other modalities. The main concepts about mechanisms of this phenomenon and employment of adaptation to motion in studies of visual analysis of movement at its different levels are actively used in the current scientific literature to understand mechanisms of this phenomenon in other sensory systems. The leading role of vision for orientation in space is manifested in the multimodal interaction where visual adaptation to movement produces significant changes of perception in other modalities. PMID- 25782282 TI - [Evolution of mechanisms of Ca(2+)-signaling. Role of Ca2+ in regulation of specialized functions of cardiomyocytes in chronic heart diseases]. AB - The review considers role of Ca2+ ions in regulation of specialized functions of cardiomyocytes (CM) in disturbances of heart activity. Problems of Ca(2+) dependent signaling mechanisms leading to pathological hypertrophy, arrythmogenesis, and heart failure are elucidated. A particular attention is paid to analysis of Ca(2+)-dependent molecular mechanisms leading to remodeling of contractile proteins, apoptosis, or pathological growth of CM. PMID- 25782283 TI - [Role of adenosine A(2A) receptors of preoptical area in realization of somnogenic effect of protein 70 kDa in pigeons]. AB - In representatives of class of birds (pigeons Columba livia) using electrophysiological methods for the first time there was performed analysis of effects of microinjections into the hypothalamic ventrolateral preoptical area (VLPA) of antagonists of the adenosine A(2A) type receptors on the sleep-wale cycle under natural conditions and on realization of somnogenic effect of Heat shock protein 70 kDa (Hsp70). The following has been established: 1) microinjections of adenosine A(2A) receptors antagonist (8-(3-Chlorostyryl) caffeine (ChC)) into VLPA at the beginning of inactive phase of the 24-h period dose-dependently increase wakefulness and suppress sleep; 2) microinjections of Hsp70 into VLPA produce somnogenic effect manifested as an increase of the total time of slow sleep (SS) and enhancement of mechanisms of initiation and maintenance of SS; 3) block of adenosine A(2A) receptors by ChC suppresses the Hsp70-induced SS. The obtained data indicate participation of adenosine A(2A) receptors located in VLPA in modulation of the sleep-wake cycle under natural conditions and in realization of somnogenic effect of Hsp70 in pigeons. A hypothesis is put forward that the somnogenic action of Hsp70 is mediated by modulating effect of this chaperone on function of adenosine proteins-receptors. PMID- 25782284 TI - [Effects of neurohypophysial nonapeptides and their analogues on magnesium excretion by rat kidney]. AB - Effects of neurohypophysial nonapeptides of vertebrates (vasopressin, vasotocin, and their synthetized analogues) on urinary magnesium excretion were studied in rats. Neurohypophysial hormones and their analogues at doses stimulating V2 receptors (0.0001-0.001 nmol/100 g BW) produced antidiuretic effect and reduced urinary magnesium excretion. At the higher doses activating V2- and V1a-receptors (0.025-0.1 nmol/100g BW), vasotocin and its analogues (deamino-vasotocin (dAVT), deamino-Thr4-vasotocin, deamino-hArg8-vasotocin, deaminomonocarbo-vasotocin) enhanced excretion of magnesium and sodium ions. Direct relation between increase in renal excretion of sodium and magnesium ions was found under these conditions. dAVT induced 10 times lesser increase in magnesium excretion after administration of a V1a-receptor antagonist. An antagonist of V2-receptors did not affect the dAVT-induced magniuresis. The obtained data suggest that V-receptors take part in regulation of magnesium transport in rat kidney. PMID- 25782285 TI - [Properties of spontaneous and miniature excitatory postsynaptic currents of rat prefrontal cortex neurons]. AB - Quantum analysis of postsynaptic currents is important for fundamental and applied studies of synaptic transmission. In the present work, we investigated the possibility of using the characteristics of spontaneous excitatory postsynaptic currents (EPSCs) for estimation of quantum parameters of excitatory synaptic transmission in different types of neurons from rat prefrontal cortex slices. By blocking spontaneous spiking activity in slices by tetrodotoxin, we showed that spontaneous and miniature EPSCs in prefrontal cortex neurons did not differ by their properties. Thereby, both spontaneous and miniature responses can be used for estimation of quantum parameters of excitatory synaptic transmission in this preparation. We also revealed that excitatory spontaneous responses of pyramidal cells were 2 times lower by amplitude, had twice lower the coefficient of variation and exhibited much slower kinetics than responses of the fast spiking and regular-spiking interneurons. Possible mechanisms of these differences are considered. PMID- 25782286 TI - [Repeated action of hyperbaria on rat blood system]. AB - There are considered reactions of male Wistar rat blood system to repeated action of nitrogen-oxygen hyperbaria (pressure 0.5 MPa, density of gas medium 6 g/l, pO2 = 0.02-0.03 MPa). Rats were placed into a barochamber for 5 h 24, 72, and 120 h after the first exposition (control in air without the increased pressure). Parameters of red blood were studied and the general state of the animals was estimated. It has been established that after the first hyperbaria seance the stress-reaction develops in rats with all objective stress parameters (level of corticosteroids and content of ascorbic acid in adrenals). At repeated exposure after 24 h the almost complete normalization of all stress parameters was observed, except for the increased hemoglobin content in plasma as a result of impair of permeability of erythrocytic membranes. After repeated actions 72 and 120 h later, the stress parameters manifested again. After exposure 120 h later, the general state of animals was sharply deteriorated they did not move in the "open" field, could not be hold on a horizontal bar, and mainly were lying. The performed control with the immobilization stress showed that after the initial stress-reaction the rats were recovered completely and at repeated exposures no changes were observed in the blood system and in the general state of the animals. We belive that the hyperbaria-produced stress is connected with difficult breathing under pressure. Thereby, the repeated action of hyperbaria is a harmful factor and habituation to it does not occur. PMID- 25782287 TI - [Reabsorption of yellow fluorescent protein in the Rana temporaria kidney by receptor-mediated endocytosis]. AB - The absorption of yellow fluorescent protein (YFP) and the expression of the endocytic receptors, megalin and cubilin, were investigated in the renal proximal tubules (PT) in frogs Rana temporaria after parenteral YFP injections. The methods of confocal microscopy and immunohistochemistry were used. The dynamics of YFP absorption was analyzed 2 h after injection. The logarithmic time dependence of the accumulation of YFP-containing endocytic vesicles in PT cells and the completion of absorption process 90-120 min after injection were shown. Unlike substantial megalin and cubilin expression 15-30 min after YFP introduction, immunolabeled endocytic receptors were not detected in PT cells after 2 h. The re-injection of YFP led to the appearance of apical endocytic vesicles containing megalin or cubilin colocalized with YFP. At the same time, the decrease of YFP uptake associated with reduction in the number of receptor containing vesicles was demonstrated, suggesting a failure of megalin and cubilin expression. The decrease of absorption capacity of PT cells after YFP re injection was similar to that found previously under conditions of the competitive absorption of green fluorescent protein (GFP) and YFP injected in different sequences. The data are the further demonstration of the proposed mechanism limiting the tubular protein absorption in the frog kidney and suggest the involvement of megalin and cubilin in uptake and vesicular transport of YFP. PMID- 25782288 TI - [Morphofunctional changes in field CA1 of the rat hippocampus after pentylenetetrazole and lithium-pilocarpine induced seizures]. AB - Animal models of epilepsy are very diverse and are used to elucidate the mechanisms underlying epileptogenesis and seizures. A single administration of pentylenetetrazole (PTZ) induces seizures, however it does not increase risk of further development of epilepsy. Pilocarpine immediately after injection evokes status epilepticus and after a latent period spontaneous convulsions develop in animals, i. e., the drug initiates the process of epileptogenesis. Assuming that in the PTZ model morphofunctional changes are mainly transient whereas changes in the lithium-pilocarpine (PC) model can indicate development of the brain epileptizationm, we compared morphological and functional characteristics in field CA1 of the hippocampus in a control and two groups of experimental animals 24 h after administration of convulsants. We revealed changes specific to the PC model and indicating the process of neurodegeneration: a decrease of the cell density, an altered NeuN expression, and an increase of the proapoptotic protease caspase-3 activity. A characteristic feature of the PTZ model was appearance of hyperchromic neurons with normal viability. In both models expression of the excitatory amino acids carrier EAAT1 increased by about 40% as compared to control. These morphofunctional correlates of reversible changes in the nervous tissue, caused by the convulsive state, and the early disturbances leading to the long-term brain epileptization can be used as indicators for evaluating therapeutic potential of novel anticonvulsive drugs. PMID- 25782289 TI - [Probable structural functional evolution of sensory surface of osphradia of aquatic prosobranchian molluscs]. AB - At present, in ecotoxicological studies, as biomarkers there are used physiological reactions of invertebrates, based on diverse reflex. The primary chain of the reflex is chemo-, mechano-, and osmoreceptors. The structures are exposed on the surface of body and mantle cavity. Earlier, a hypothesis was put forward, which suggested that the polymodal osphradial organ of the pond snail might participate in adaptive reactions of aquatic molluscs to toxicants. The known homology of osphradial structures allows spreading this suggestion on marine representatives of various subclasses of Mollusca, although diversity of structure, of ways of nutrition, and multiplicity of aquatic molluscs can impede interpretation of future ecotoxicological studies. To elucidate this issue, we carried out the comparative electron microscopy study of osphradial organs in representatives of various families of Prosobranchia (Mollusca, Gastropoda). By ultrastructural parameters in the osphradial organs, five sensory cellular complexes (SCC) have been revealed. A probable connection is demonstrated of these cellular complexes with the known chemo-, mechano-, and osmoreceptor modalities. Structure of the complexes become more complicated in the process of evolution of gastropods and depends on the way of nutrition of molluscs. Thus, the primitively built osphradium of the herbivorous mollusc Viviparus sp. is a polymodal receptor and initial prototype for further morphophysiological constructions. Osphradium of littorine is the next chain of evolitionary transformations and combines in itself the osmo- and chemosensory SCC. In osphradia of the new, ctenidial type the total receptor surface increases and the ultrastructural specialization of cellular complexes occurs, which promotes the appearance in them of the sarcophagous way of nutrition. For predator marine molluscs actively searching for their preys by odor, there is identified an additional superficial sensory cellular complex. It is located on lateral surfaces and on ventral edge of petals of osphradia, near zones of cilium supportive cells. These seem to be mechanoreceptor structures tracing direction and rate of flow of liquid along osphradium. A connection of SCC with the certain modality of outer nutrition and with the way of nutrition is suggested. PMID- 25782290 TI - [On inheritance of the calling song features in the cricket Gryllus bimacultus]. PMID- 25782291 TI - [The role of disturbances in the hormonal signaling systems in etiology and pathogenesis of diabetes mellitus]. AB - The role of disturbances in the hormonal signaling systems of brain and peripheral tissues in etiology and pathogenesis of diabetes mellitus (DM) of the types 1 and 2 is discussed. Available data confirming the hypothesis of central genesis of some forms of DM caused by disturbances in the brain neurotransmitter systems are presented. It is concluded that the study of disturbances in the hormonal signaling systems is a promising approach for development of new strategies of DM treatment, based on correction of these disturbances in the CNS and the periphery. PMID- 25782292 TI - [Role of magnetic resonance imaging in the early diagnosis of cognitive impairments in patients with type 1 diabetes mellitus]. AB - OBJECTIVE: To assess the role of brain magnetic resonance imaging (MRI) in patients with type 1 diabetes mellitus (DMI) in relation to clinical, metabolic, and psychoneurological disorders. MATERIAL AND METHODS: Fifty-eight patients aged 16 to 30 years with DM1 were examined; a control group consisted of 29 healthy young people matched by gender and age. Their examination involved clinical, metabolic, and psychological testing. The quality of life was assessed using the general Medical Outcomes Study Short Form (MOS SF-36) and the specific Audit Dependent Quality of Life (AdDQoL). The Montreal Cognitive Assessment (MoCa test) was employed to screen for cognitive impairments. All the patients were advised by a neurologist. Brain MRI using a 1.0 T Siemens Magnetom scanner was carried out to evaluate structural changes in the central nervous system. RESULTS: The examination of the patients with DM1 revealed the signs of grey matter atrophy, enlarged Virchow-Robin spaces, white matter injury, which correlated with the presence of chronic hyperglycemia, cognitive impairments, and microvascular complications. CONCLUSIONS: Routine brain MRI is best carried out in patients with DMI and poor disease control to timely implement therapeutic-and prophylactic measures for preventing cognitive impairments and improving the quality of life. PMID- 25782293 TI - [Comparative analysis of the informative value of 18F-fluorodeoxyglucose and 11C methionine positron emission tomography in the differential diagnosis of solitary lung masses]. AB - OBJECTIVE: To study the possibilities of enhancing the efficiency of differential diagnosis of solitary lung masses by optimizing the quantitative analysis of positron emission tomography (PET) data when two radiopharmaceuticals (RP) (18F fluorodeoxyglucose (18F-FDG) and 11C-methionine) are used alone and in combination. MATERIAL AND METHODS: A comprehensive examination involving 18F-FDG and 11C-methionine PET was made in 116 patients with solitary lung masses of various genesis. A final diagnosis in the examinees was established from the results of postoperative material morphological analysis and/or laboratory tests and those of X-ray follow-up. RESULTS: No 18F-FDG and 11C-methionine hyperfixation was found in patients with benign tumors and in the majority of patients with focal pneumofibrosis. At 18F-FDG and 11C-methionine PET, RP accumulation was recorded in all patients with lung cancer (LC) and in patients with inflammatory diseases. Three patients with 18F-FDG PET-negative typical carcinoid tumors were noted to have increased 11C-methionine uptake. At 11C methionine PET, RP accumulation was recorded in the projection of formation in all the patients with LC and in 38 of the 42 patients with inflammatory diseases. Regardless of the used RP, the Standardized Uptake Value (SUV) was significantly lower in the patients with inflammatory diseases than in those with LC (p <= 0.05). CONCLUSIONS: When RP is used alone, the diagnostic efficiency of C methionine PET in the differential diagnosis of lung tumors and inflammations is higher than that of 18F-FDG PET. At the same time, the highest PET is seen when 18F-FDG and 11C-methionine are used in combination. PMID- 25782294 TI - [Coronary angioplasty and stenting in patients with ischemic cardiomyopathy]. AB - Multiple coronary artery atherosclerotic lesions are a major cause of ischemic cardiomyopathy. Myocardial revascularization in patients with ischemic cardiomyopathy in the presence of the viable myocardium and/or ischemic areas leads to improved central hemodynamic parameters and as a consequence to better quality of life and prognosis as a whole. The paper describes a clinical case of successful coronary artery angioplasty and stenting in a patient with ischemic cardiomyopathy. Following 8 months, there was a considerable improvement in the patient's general condition, an increase in left ventricular ejection fraction, and a reduction in cardiac cavity sizes. PMID- 25782295 TI - [Capabilities of magnetic resonance imaging to diagnose infiltrating pelvic endometriosis]. AB - Deep infiltrating endometriosis is a disease in reproductive-aged women, resulting in varying chronic pelvic pains and infertility, which requires surgical treatment. Objective--to determine the capabilities of magnetic resonance imaging (MRI) to diagnose pelvic endometriosis and to elaborate an optimal scanning protocol if this disease is suspected. Small pelvic MRI has a high accuracy in the diagnosis of endometriosis and can visualize most endometrioid implants, including those that are located under adhesions and in the subperitoneal regions. Just the same, a radiodiagnostician should not forget that MRI is of low informative value in identifying bowel endometriosis. Hence, when diagnosing deep infiltrating endometriosis, MRI should be complemented with transvaginal ultrasonography to detect endometrioid implants on the bowel walls as the informative value in this aspect is above. PMID- 25782296 TI - [Radiology report: past, present and future]. AB - The analysis of literature data showed that the creation and implementation of a new form of radiology reports into clinical practice is an actual problem of modern medicine. Although imaging modalities have undergone dramatic evolution over the past century, radiology reporting has remained largely static, in both content and structure. In recent years the necessity to create a structured reporting is widely discussed in the literature. A universal format of radiology report hasn't been found yet. The standard of reporting system is absent, a wide variety of styles in radiology reporting currently exists. The challenging goal is improvement of existing protocols and creation of a new form of radiology reports--the protocols of the future. PMID- 25782297 TI - [Computed tomography in studying the surgical anatomy of the posterior cranial fossa]. AB - OBJECTIVE: To determine the individual roentgenometric parameters of the posterior cranial fossa and the specific features of the location of brain structures on computed tomography scans in terms of their possible use on planning surgical approaches. MATERIAL AND METHODS: The computed tomography scans of the bony base of the posterior cranial fossa and the projection variants of the location of brain structures relative to the osseous landmarks were roentgenometrically studied in 116 patients without pathology of the cranial bones and brain. RESULTS: The main linear (length, width, depth) and angular (a pyramidal convergence angle, a pyramidal occipital angle, a slope angle, and occipital squama inclination) roentgenometric parameters determining the shape of the posterior cranial fossa were determined. The most commonly encountered (long narrow deep, long wide fine, long narrow fine, long wide deep, and short narrow fine) shapes were identified according to the combination of the extrema of these parameters. The variants of the location of brain structures were determined within the projection planes. CONCLUSION: There were the roentgenometric parameters and craniocerebral ratios, which are of value in the individual planning of surgical approaches to the structures of the posterior cranial fossa. PMID- 25782298 TI - [Anatomic rationale and radiological experience in using an individual anatomical landmark during linear imaging of the human temporomandibular joint]. AB - OBJECTIVE: To provide a rationale for determining the midsagittal plane of temporomandibular joint (TMJ) elements by the anatomical landmark for estimation of the individual depth of a tomographic section at targeted linear TMJ imaging. MATERIAL AND METHODS: Cephalometry of 20 human skulls. Targeted linear TMJ imaging in the lateral projection in 176 patients. RESULTS: The anatomical landmarks of the midsagittal plane of a tomographic section were determined and the latter's anatomical landmark (a reference searching point) was found to estimate the individual depth of the tomographic section at targeted linear TMJ imaging. There was an agreement between the midsagittal plane of the TMJ and that of the frontal process of the zygomatic bone (the lateral orbital wall). The latter was ascertained to be rightly used as a cephalometric point and taken as an individual anatomical landmark indicating the level of a tomographic section at targeted linear TMJ imaging. The individual anatomical landmark was used to examine 176 patients at targeted linear TMJ imaging. Six hundred and four tomography scans were studied. Excellent- and good-quality pictures were obtained in 94.2% of cases. The section depth was 2.0 to 3.0 cm in 86.7% of cases (2.5, 2.0, and 3.0 cm in 42.2, 21.6, and 22.9%, respectively). CONCLUSION: The proposed procedure could exclude search samples and minimize the dose of radiation and the time of survey depth determination. PMID- 25782299 TI - [Problems of X-ray mammology manpower training and management]. AB - The paper considers the issues of manpower training in X-ray mammology. It mentions staff shortage and no special training, which reduces the efficient activities of X-ray mammographic rooms, as well as shortage of training facilities and no unified educational programs within interdisciplinary integration, inadequate technical equipment in the training facilities, the lack of an accounting system for training higher- and mid-level health workers, as well as engineers. Emphasis is placed on that the educational programs must comply with the organizational forms of testing the specialists to be employed. The introduction of a continuous education system should be accelerated to rule out the decay period of specialists' competence. PMID- 25782300 TI - [Chronic renal disease--a global problem in the XXI century]. AB - In 2002, it was proposed to consider functional renal disorders 3 and more months in duration under the general name chronic renal disease (CRD) bearing in mind the common mechanism behind progressive nephropathy and high cardiovascular mortality of such patients. The prevalence of CRD in Russia is unknown; it is supposed that every tenth adult in the world has CRD. Diagnostics of CRD requires at least measurement of serum creatinine, calculation of the glomerular filtration rate by CKD-EPI formula, and determination of albuminuria. A main cause of CRD is cardiovascular disorders. Complicated relationships between cardiac insufficiency and CRD account for 5 types of cardiorenal syndrome. CRD patients are at risk of terminal renal insufficiency requiring replacement therapy; moreover, CRD enhances cardiovascular morbidity and predisposes to acute renal lesion that in turn accelerates progress of CRD. Taken together these events account for the global character of the CRD problem. PMID- 25782301 TI - [Microalbuminurea as an early indicator of renal lesion in arterial hypertension]. AB - Arterial hypertension (AH) is undoubtedly associated with progressive renal dysfunction. Microalbminuria (MAU) is a reliable indicator of the early stage of renal disease and predictor of AH progress as well as an independent risk factor of cardiovascular mortality and death. The main pathophysiological mechanisms of MAU in AH are enhanced glomerular hydrostatic pressure, structural changes and endothelial dysfunction in glomerular capillaries. Also, an important role is played by AH-related progressive chronic preclinical inflammation as appears from positive correlation between MAU and CRP, fibrinogen, and cytokines. It is concluded that evaluation of MAU as an indicator of cardiovascular risk needs to be widely used in clinical practice for the improvement of AH treatment and the reduction of probability of complications. PMID- 25782302 TI - [Hypoglycemic activity of hypolipidemic preparations]. AB - The system of glucose metabolism regulation is millions of years older than the insilin system and locomotor function. For this reason, the hypoglycemic activity of the hormone is mediated through fatty acid (FA) metabolism. Insulin blocks the ability of mitochondria to oxidize ketone bodies, short-, medium- and long-chain FA and makes them oxidize glucose, i.e. a physiologically unoptimal substrate. The relationship between FA and glucose in the Rnadle cycle is apparent only on the autocrine level (in the cell); they determine alternation of nutritive function (trophology) and biological exo/endo-reactions (after and without feeding respectively). Most antidiabetic medicines exhibit hypoglycemic activity, like insulin; they reduce the level of lipid substrates of oxidation in cytosol and mitochondria have to oxidize glucose. In these conditions, insulin increases glucose uptake by the cells mediated through GLUT4 transporters. Sulfonylurea derivatives enhance secretion of insulin by beta-cell. Biguanides covalently and irreversibly bind ketone bodies thereby preventing their oxidation by mitochondria. Fibrates, glitazones, flavonides, flavones, lipoic thio-FA, endogenous eicosanoids, derivatives of Omega-3 and Omega-6 essential polyenic FA, and conjugated unsaturated FA are agonists of peroxisome proliferator-activated receptors. They stimulate alpha-, beta-, and Omega-oxidation of all exogenous a physiological FA and excessive palmitic saturated FA in peroxisomes which leads to cytosol hypolipidemia. Hypoglycemic preparations with the activity of oxidation beta-blockers arrest FA uptake by mitochondria. Hypoglycemic Omega-3 essential polyenoic FA activate GLUT4 function. Type 2 diabetes in middle-aged patients is a symptom of atherosclerosis, i.e. deficit of essential polyenoic FA caused by disturbed phospholipid synthesis and GLUT4 function. Diabetes should be in the first place considered as pathological FA metabolism and only in the second place as glucose pathology. This inference needs to be taken into account in the treatment of diabetes and in strategic programs of its prophylaxis. PMID- 25782303 TI - [Syndrome of diabetic foot: modern diagnostic methods]. AB - We summarize the literature data on diagnostics of diabetic foot syndrome including clinical examination and special invasive and non-invasive studies of the vascular system. The main methods are ultrasound dopplerography, X-ray contrast angiography, and ultrasound duplex scanning. Special attention is given to instrumental diagnostics of diabetic neuropathies. The golden standard for the evaluation of the function of the peripheral nervous system is electroneuromyography. Methods for the study of diabetic foot complications, such as osteoarthropathy and trophic ulcers, are discussed. PMID- 25782304 TI - [Helicobacter pylori infection: what else besides gastric problems?]. AB - The role of Helicobacter pylori infection (HPI) in the development of chronic gastritis, ulcer disease, MALT-lymphoma, stomach cancer, and other diseases is considered. HPI is directly or indirectluy associated with colon adenoma and colorectal cancer, hepatic disorders, coronary heart disease, idiopathic iron deficiency anemia and thrombocytopenia. The role of HPI in the development of gastroesophageal reflux disease remains to be elucidated. HPI is negatively related to bronchial asthma and chronic inflammatory intestinal diseases. Pathophysiological and clinical aspects of HPI and the aforementioned pathologies await further investigations. PMID- 25782305 TI - [The influence of structural and functional disorders in cardiovascular and renal systems and metabolic disturbances on perinatal outcomes in pregnant women with chronic arterial hypertension]. AB - We studied the influence of structural and functional disorders in cardiovascular and renal system and metabolic disturbances on perinatal outcomes in pregnant women with chronic arterial hypertension. The study included 100 women with these pathologies and 30 patients with physiological pregnancy. Comprehensive evaluation of the cardiovascular system, metabolic status, and perinatal outcomes was undertaken. The results indicate that atherogenic dyslipidemia is significantly associated with the reduction of body mass while glomerular filtration rate, concentric and eccentric left ventricular hypertrophy with the decrease of both weight and height of the newborns. PMID- 25782306 TI - [The use of piribedil for the prevention of falls in elderly patients with metabolic syndrome]. AB - Effects of pirebedil used to prevent falls in elderly patients with metabolic syndrome are discussed. A prospective controlled study showed that therapy with pirebedil significantly decreases the frequency of falls, reduces severity of pro inflammatory and pro-oxidative activities, improves cognitive abilities. Prevention of falls by virtue of improved cognitive abilities is a new clinical effect of pirebedil and gives reason to recommend it for the treatment of geriatric patients with metabolic syndrome. PMID- 25782307 TI - [Activation of neurohormonal system as an independent mechanism of heart remodeling in patients with chronic obstructive pulmonary disease]. AB - AIM: To evaluate the contribution of activation of cytokines and renin angiotensin-aldosterone system to heart remodeling in patients with chronic obstructive pulmonary disease in the course of a 2 year study and to estimate its relation to severe pulmonary hypertension. MATERIALS AND METHODS: 117 patients with COPD underwent measurement of TNFalpha, IL-6 levels and renin levels, spirometry and echocardiography (mean pressure in pulmonary artery, MPPA)). The data obtainedwere compared with the degree of remodeling of right and left ventricles. After 2 years 30 and 33 of the 63 patients were referred to groups with aggressive and moderate remodeling of the right ventricle respectively. Regressive analysis was used to detect predictors of aggressive remodeling. RESULTS: Initial remodeling severity and rate showed stronger correlation with TNFalpha, IL-6 levels and renin levels than with MPPA. Multifactor analysis demonstrated that renin activity and creatinine level were the most reliable predictors of remodeling (p = 0.041 and 0.049 respectively). CONCLUSION: Neurohormonal and imunno-inflammatory changes stimulate remodeling of right and left heart chambers. They independently affect myocardium and their influence is only partly mediated through exacerbation of pulmonary hypertension. PMID- 25782308 TI - [Respiratory disorders during sleep in patients with cardiovascular diseases at the stage of rehabilitation]. AB - High prevalence of cardiovascular and cerebrovascular diseases dictates the necessity of enhancing the efficacy of preventive and rehabilitative programs, elaboration and implementation of innovative medical technologies. Sleep disturbances and especially associated respiratory disorders are important risk factors of arterial hypertension, cardiac insufficiency, abnormal heart rhythms, cerebrovascular pathology, insulin resistance, and type 2 diabetes mellitus. Introduction of the methods for diagnostics and correction of sleep disturbances into rehabilitative programs improves immediate and long-term results of the treatment. PMID- 25782309 TI - [Ambulatory treatment of gouty arthritis]. AB - AIM: To estimate effectiveness of ambulatory treatment of gouty arthritis (GA) using non-steroidal anti-inflammatory agents (NAIA) and detect factors associated with the impairment of the functional state of kidneys during short-term therapy. MATERIALS AND METHODS: The functional state of kidneys in 100 patients with GA was estimated from creatinine clearance (CC) calculated by the Cockroft-Gault formula on day 2 after their examination in a polyclinic and prescription of NAIA to stop the gout attack or during the first days after hospitalization. Mean duration of NAIA therapy was 10.8 +/- 4. 77 days. RESULTS: 18% of the outpatients with CC < 60 ml/min were given high doses of NAIA, 47% patients received them during the entire period of treatment, 36% were prescribed combined therapy with two or more NAIA. A short course of NAIA therapy resulted in the enhancement of CC in 46% of the patients and its fall in 54%. In 1 patient CC decreased by more than 50% compared with initial level; in 12 patients the decrease exceeded 25%. The risk of CC reduction under effect of NAIA increased in case of high NAIA doses (OR = 1.52, 95% CI 1.05 = 2.20, p = 0.024), combination of several NAIA (OR = 2.74, 95% CI 1:95-3.87, p = 0.02), concomitant infection and antibiotic therapy (OR = 11.51, 95% CI 8.76-15.13, p = 0.005), II-III NYHA FC chronic cardiac insufficiency (CCI) (OR =4.88, 95% CI 9.83-1681, p = 0.019). CONCLUSION: Physicians of outpatient facilities do not always take account of the functional state of kidneys when prescribing NAIA for the treatment of GA. Kidney conditions in such patients deteriorate in case of high NAIA doses or combination of two and more NAIA during the entire period of therapy, in the presence of infection requiring antibiotic therapy or CCI. PMID- 25782310 TI - [Urogenic reactive arthritis morbidity in Kazakhstan]. AB - Statistical data on osteo-muscular morbidity in Kazakhstan are presented. Their comparative analysis revealed a 5% rise in general morbidity and a 1% rise in the frequency of urogenic Chlamydial infection. The frequency of inflammatory joint diseases including urogenic reactive arthritis among the patients of a military hospital amounted to 51%. PMID- 25782311 TI - [Comparative evaluation of the health status of descendants of people residing in environmentally unfriendly regions by means of mathematical modeling]. AB - The aim of the study was to evaluate reproductive health of descendants of people who experienced effects of adverse environmental factors, such as radiation and chemical contamination (the descendants themselves were unaffected by these factors). Reproductive health of women was assessed by mathematical modeling. Factors of greatest importance for the health status of the descendants were distinguished among the 76 ones studied. It was shown that reproductive health of the subjects descending from the people exposed to radiation deteriorated more significantly than of those whose ancestors were affected by chemical factors. PMID- 25782312 TI - [Successful correction of arterial fistula between coronary arteries and pulmonary trunk]. AB - A case of congenital heart disease (fistula between left coronary artery and right pulmonary artery, right coronary artery and pulmonary trunk) diagnosed accidentally during planned medical examination is reported. Corrective surgery included disconnection of left coronary and right pulmonay arteries, right coronary artery and pulmonary trunk under artificial circulation and warm blood cardioplegia. PMID- 25782314 TI - [Yu.V. Tel'nykh (on the occasion of his 75th birthday)]. PMID- 25782313 TI - [On the article "Clinical significance of Helicobacter pylori infection" by prof. Maev I.V. et al]. PMID- 25782315 TI - [Evolution of pathogenesis of atherosclerosis in phylogenesis]. AB - The first atherosclerosis pandemics developed in phylogenesis when animals went out of the ocean, the second coincided with mutations of proteins that transferred zero-cholesterol esters, the third (present-day pandemics) results from disturbed biological function of trophology, abnormally high content of saturated fatty acids and their trans-forms in food, and blockade of bioavailability of polyenic FA (PNFA) for cells. The blood pool of ligand-free lipoproteins, phylogenetically early macrophages are only partly utilized in intima giving rise to atheromatosis. When active absorption of w-3 and w-6 PNFA is blocked, the cells synthesize by way of compensation non-physiological w-9 eicosanoids which creates the basis of pathogenesis of atherosclerosis, pathology ofautocrine regulation, and paracrine humoral regulation of cell communities and the body. A rise in the frequency of non-infectious diseases above 5-7% is regarded as pathology of biological functions and reactions. Non-physiological environmental effects should be neutralized by normalization of tropholgy function, exotrophic biological reaction. Metabolic pandemics may have two outcomes. First: (a) effective reduction to a minimum of infavourable environmental effects, i.e. normalization of the nutritive function, (b) matching it with possibilities of lipoproteins, (c) reduction of morbidity and mortality from atherosclerosis. Second: man continues to develop as in phylogenesis and adapts himself to nonphysiological nutrition. Mortality from infarction and stroke will remain high during the next 40-50 thousand years. Increased content of w-3 PNFA in food without reduction of NAF with blockade of bioavailability will further facilitate atheromatosis. Man should rely on physiological nutrition, there is no reason to rely on hypolipidemic agents. Otherwise, the second outcome awaits the mankind. Tertium non datum. PMID- 25782316 TI - [Radiological and anatomical approaches to the evaluation of blood circulation and functional state of a cardiopatient]. AB - Cardiovascular diseases are ranked worldwide as the key factor of morbidity and mortality; they impair the quality of life and cause great losses to state economy. Coronary heart disease is of special significance due to the high prevalence, high risk and frequency of complications. Radiodiagnostics used to examine cardiologic patients makes possible visualization of coronary arteries and evaluation of their morphometric parameters, but it fails to provide information on the changes in hemomicrocirculation and to estimate myocardial perfusion or changes in the structural and functional changes in myocardial tissue and cardiac afferent system. It does not allow to determine severity of cardiac insuffciency resulting in hemodynamic changes at the tissue, organ, and body levels. We are unaware of publications showing correlation between morphofunctional organization ofhemocilculatory system and the functional state of cardiomyocytes. None of the anatomical or clinical-diagnostic criteria of modern radiological methods gives an answer to the question of correlation between myocardial vessel structure and structural-functional state of cardiomyocytes in subjects of different sex and age. To recall, the functional potential of the heart as a whole organ is determined by that of contractile (working, typical) and atypical (conducting) cardiomyocytes responsible for impulse conduction from the pacemaker which implies differential approach to the elucidation of correlations between angioarchitectonics of vessels in different heart regions and functional potential of typical and atypical cardiomyocytes. PMID- 25782317 TI - [Evaluation of myocardial perfusion by single-photon emission CT in the treatment with beta-adrenoblockers and calcium channel blockers]. AB - Single-photon emission CT of the heart was used to observe coronary blood flow and reveal the maximum perfusion region in patients with coronary heart disease (CHD) treated with beta-adrenoblockers and calcium channel blockers. Dynamic observation showed changes and redistribution of myocardial perfusion. Specific features of coronary blood flow were demonstrated depending on the therapeutic modality (beta-blocker metoprolol, calcium channel blocker amlodipine). Parameters of prognostic value were identified depending on the effectiveness of the agents used. This approach together with the traditional nosological one to the choice of CHD therapy permits to individualize the therapeutic influence depending on myocardial micriocirculatory features, such as the spread and depth of perfusion disturbances. PMID- 25782318 TI - [Orthostatic reactions in prognosis of the risks of arterial hypertension as a component of metabolic syndrome]. AB - It was shown that parameters of metabolic syndrome as predictors of lethal vascular outcomes of arterial hypertension (AH) in Belarus are significantly different fiom those proposed in WHO recommendations (1999). The glucose level of informative value in WHO recommendations is 6.1 mmol/l versus 5.6 mmol/l in Belarus, total cholesterol 5.0 and 5.9 mmol/l respectively. A more detailed verification of the value of both parameters is needed for the patients in Belarus and Russia depending on age and sex using non-linear models. We used a comprehensive approach to prognosis of the risk of vascular lethal outcomes of AH as a component of metabolic syndrome with the evaluation of results of clinical and laboratory examination as well as orthostatic reactions in patients of different age groups. Construction of the prognostic algorithm "Classification tree" taking account of orthostatic reactions enhances the correctness of lethal outcome prognosis up to 81.8%. The study revealed the prognostic value of systolic and diastolic arterial pressure in the supine position (15 min of active aortostatic sample) for prognostication of vascular lethal outcomes. Further studies are needed on the role of orthostatic reactions in AH patients of old age together with clinical and laboratory parameters in the prognostication of outcomes of various cardiovascular diseases. PMID- 25782319 TI - [The influence of combined therapy with calcium antagonist and angiotensin converting enzyme inhibitor on the circadian profile of arterial pressure in patients with arterial hypertension in the Far North]. AB - AIM: To study effect of combined therapy with amlodipine with ramipril on the circadian profile of arterial pressure in patients with arterial hypertension in the Far North depending on the shiftwork regime. MATERIALS AND METHODS: 130 patients with grade 2-3 AH were divided into 2 groups depending on the work-time schedule. Group 1 included 67 daywork patients group 2 consisted of 63 patients working in the alternating daywork and nightwork regime. 24 hr AH monitoring was performed before, 4 weeks and 6 months after the onset of the study. RESULTS: Six months after the onset of therapy practically all patients reached the target AD level (94.4% in group 1 and 94.7% in group). The patients fairly well tolerated therapy AD circadian profile was normalized 1.9 times in group 1 and 3.2 times in group 2. Recovered AP variability in group 1 resulted in a decreased frequency of target organ affection. In group 2, the initially higher variability accounted for the normalization of only diastolic AP variability after 6 month therapy. It suggests the necessity of prescription of a third anti-AH preparation to these patients. Morning AP dynamics improved in both groups. PMID- 25782320 TI - [Remodeling of heart and neutrophil intracellular metabolism in obese men]. AB - AIM: To study remodeling of heart and its influence on intracellular metabolism of neutrophils in obese men. MATERIALS AND METHODS: 85 men aged 30-63 years free from coronary heart disease underwent ECG examination with the evaluation of diastolic properties and diagnostics of left ventricle remodeling with special reference to oxygen-dependent metabolism and antioxidant protection of neutrophils. RESULTS AND DISCUSSION: Increased degree of obesity in men leads to enhanced frequency of diastolic dysfunction and left ventricular myocardium remodeling accompanied by a rise in myeloperoxidase activity in neutrophils. The latter was especially high in patients with concentric hypertrophy of left ventricular myocardium. CONCLUSION: Increased degree of heart remodeling with enhanced severity of obesity in men is accompanied by activation of oxygen dependent metabolism in neutrophils. PMID- 25782321 TI - [Oxidative stress in pathogenesis of bronchial asthma: a method of correction by inhalation of phospholipid nanoparticles]. AB - The authors present the results of a prospective simple blind randomized placebo controlled study for the evaluation of dynamics of biomarkers of oxidative stress (total concentration of nitrate- and nitrite-anions in condensed exhaled breath and plasma, pH of exhaled breath, total antioxidative activity of plasma in patients with bronchial asthma inhaling phospholipid nanoparticles. The results suggest significant positive effect of proposed therapy on dynamics of the main parameters of oxidative stress including reduced concentration of nitric oxide metabolites and increased total antioxidative activity of plasma. No clinically significant reactions were documented. PMID- 25782322 TI - [Quality of life and hypoglycemia burden in patients with type 2 diabetes mellitus on basal-bolus insulin therapy]. AB - This paper presents the results of the observational program "Parameters of life quality, symptoms of hypoglycemia and treatment satisfaction in patients with type 2 diabetes mellitus on basal-bolus insulin therapy" (2012-2014). The analysis included 1000 patients. It showed that their quality of life was below that of the general population due to compromised physical, role physical, and role emotional functioning (p < 0.001). Hypoglycemia is a serious challenge to the treatment of patients with type 2 diabetes mellitus on basal-bolus insulin therapy. They are characterized by impaired physical, psychological, and social functioning compared with the patients without hypoglycemic episodes (p < 0.01). Patients experiencing mild hypoglycemic episodes were not significantly different from those without them. In patients experiencing severe hypoglycemic episodes the quality of life was much worse (ES = 0.22-0.51). The profile of hypoglycemic episodes differed in different forms of hypoglycemia. The spectrum of symptoms and problems related to hypoglycemia was broader in patients with severe and/or nocturnal hypoglycemia. Patients free from hypoglycemia were less afraid of it than those used to have hypoglycemic episodes (p < 0.001). The stronger the fear, the more pronounced disturbances in social functioning, vitality, psychic and general health (p = 0.0001). It is concluded that evaluation of quality of life and hypoglycemia-related symptoms in patients with type 2 diabetes mellitus on basal-bolus insulin therapy allows for comprehensive estimation of the effectiveness of therapy on an individual basis. PMID- 25782323 TI - [Compliance to treatment and effectiveness of therapy in different regimes of monitoring activity of patients with axial spondyloarthritis]. AB - AIM: To study compliance to treatment and effectiveness of therapy in patients with axial spondyloarthritis (ax-SpA) in different observational regimes. METHODS: 168 patients without TNF-alpha therapy and BASDAI >= 4 were randomized into 3 groups. 96 of them were observed in a traditional manner, 26 visited a rheumatologist every 12 weeks, and 46 were counseled by phone once in 4 weeks. In all these cases, rheumatologists collected data on the activity of the disease (BASDAI, ASDAS, PASS, etc.) and the effectiveness of therapy. RESULTS: BASDAI in group 1 was 5.32 +/- 3.2 initially and 5.17 +/- 2.16 one year after onset of the study, ASDAS 3.45 +/- 2.1 and 3.1 +/- 1.1 respectively (p > 0.05). In group 2, BASDAI values were 5.21 +/- 3.0 and 4.77 +/- 2.2; ASDAS 3.42 +/- 2.9 and 2.79 +/- 2.6 respectively. In group 3, BASDAI values were 5.32 +/- 3.2 and 3.17 +/- 2.12; ASDAS 3.44 +/- 3.1 and 2.6 +/- 1.8; p < 0.05 for the differences between initial and subsequent values in groups 2 and 3 and final values for all groups. Positive PASS was reached in 15 patients (57.69%, n = 26) of group 3, in 4 ones (20%, n = 20) of group 2, and in 0 (0%) patients of group 1. Five (19.23%), 15 (75%) and 93 (96.87%) patients in groups 1, 2 and 3 respectively wilfully ceased to take NSAID. 96 (100%), 19 (95%) and 3 (11.5%) patients of these groups stated that they needed hospitalization. CONCLUSION: Telephone monitoring of ax-SpA activity once in every 4 weeks revealed a better compliance with the treatment and results of therapy than active observation every 12 weeks or arbitrary monitoring. PMID- 25782324 TI - [Infectious-inflammatory complications of cerebral insulitis]. AB - Pneumonia and urinary tract infections develop in roughly 1/3 of the survivors of cerebral stroke. Post-stroke pneumonia results from aspiration and uroinfection from neurogenic disturbances of urination and bladder catheterization. Post stroke immune deficiency increases the risk of infectious and inflammatory complications. These conditions are treated in accordance with the general principles of management of these diseases. Prophylaxis of pneumonia is reduced to the principle of "nothing orally" before the swallowing capacity is tested, early mobilization, and oral cavity hygiene. Studies on the role of prophylactic antibiotic therapy and ACE inhibitors in the prevention of post-stroke pneumonia are currently underway. Bladder catheterization under strict indications and the use ofcatheters coated with antibacterial agents or condom urine bags in men are likely to reduce the risk of uroinfection. Infectious and inflammatory complications impair the outcome of stroke. Their prophylaxis and adequate treatment are prerequisites of successful recovery after stroke. PMID- 25782325 TI - [Clinical evaluation of the influence of certain initial status parameters on the development of type 2 diabetes mellitus in patients with metabolic syndrome]. AB - Type 2 diabetes mellitus (DM2) is one of the clinical outcomes of metabolic syndrome (MS). We observed 201 patients with MS during 10 years. At the study end point 144 (71.9%) of them developed DM2. The study aimed at evaluating effect of initial parameter of MS on the rate of DM2 development. Results of correlation analysis show that the rate of DM2 development depends in the first place on the patients' age, severity of abdominal obesity, vicious habits and their combination with disturbed lipid metabolism, sympatho-adrenal disbalance , and arterial hypertension rather than on disordered carbohydrate metabolism at the onset of the disease. PMID- 25782326 TI - [Intestinal diseases, problems of terminology and classification]. PMID- 25782327 TI - DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan. AB - AIMS: Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. METHODS: Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir 27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs. RESULTS: None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C. CONCLUSIONS: Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization. PMID- 25782329 TI - Design optimization study of a shape memory alloy active needle for biomedical applications. AB - Majority of cancer interventions today are performed percutaneously using needle based procedures, i.e. through the skin and soft tissue. The difficulty in most of these procedures is to attain a precise navigation through tissue reaching target locations. To overcome this challenge, active needles have been proposed recently where actuation forces from shape memory alloys (SMAs) are utilized to assist the maneuverability and accuracy of surgical needles. In the first part of this study, actuation capability of SMA wires was studied. The complex response of SMAs was investigated via a MATLAB implementation of the Brinson model and verified via experimental tests. The isothermal stress-strain curves of SMAs were simulated and defined as a material model in finite element analysis (FEA). The FEA was validated experimentally with developed prototypes. In the second part of this study, the active needle design was optimized using genetic algorithm aiming its maximum flexibility. Design parameters influencing the steerability include the needle's diameter, wire diameter, pre-strain and its offset from the needle. A simplified model was presented to decrease the computation time in iterative analyses. Integration of the SMA characteristics with the automated optimization schemes described in this study led to an improved design of the active needle. PMID- 25782330 TI - Comparing passive angle-torque curves recorded simultaneously with a load cell versus an isokinetic dynamometer during dorsiflexion stretch tolerance assessments. AB - The purpose of the present study was to compare the passive angle-torque curves and the passive stiffness (PS, N m degrees (-)(1)) values recorded simultaneously from a load cell versus an isokinetic dynamometer during dorsiflexion stretch tolerance assessments in vivo. Nine healthy men (mean +/- SD age = 21.4 +/- 1.6 years) completed stretch tolerance assessments on a custom built apparatus where passive torque was measured simultaneously from an isokinetic dynamometer and a load cell. Passive torque values that corresponded with the last 10 degrees of dorsiflexion, verified by surface electromyographic amplitude, were analyzed for each device (theta1, theta2, theta3, ..., theta10). Passive torque values measured with the load cell were greater (p <= 0.05) than the dynamometer torque values for theta4 through theta10. There were more statistical differentiations among joint angles for passive torque measured by the load cell, and the load cell measured a greater (p <= 0.01) increase in passive torque and PS than the isokinetic dynamometer. These findings suggested that when examining the angle-torque curves from passive dorsiflexion stretch tolerance tests, a load cell placed under the distal end of the foot may be more sensitive than the torque recorded from an isokinetic dynamometer. PMID- 25782328 TI - Improving external beam radiotherapy by combination with internal irradiation. AB - The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed. PMID- 25782331 TI - Ability of self-reported estimates of dietary sodium, potassium and protein to detect an association with general and abdominal obesity: comparison with the estimates derived from 24 h urinary excretion. AB - As under-reporting of dietary intake, particularly by overweight and obese subjects, is common in dietary surveys, biases inherent in the use of self reported dietary information may distort true diet-obesity relationships or even create spurious ones. However, empirical evidence of this possibility is limited. The present cross-sectional study compared the relationships of 24 h urine derived and self-reported intakes of Na, K and protein with obesity. A total of 1043 Japanese women aged 18-22 years completed a 24 h urine collection and a self administered diet history questionnaire. After adjustment for potential confounders, 24 h urine-derived Na intake was associated with a higher risk of general obesity (BMI>=25 kg/m2) and abdominal obesity (waist circumference>=80 cm; both P for trend=0.04). For 24 h urine-derived protein intake, positive associations with general and abdominal obesity were observed (P for trend=0.02 and 0.053, respectively). For 24 h urine-derived K intake, there was an inverse association with abdominal obesity (P for trend=0.01). Conversely, when self reported dietary information was used, only inverse associations between K intake and general and abdominal obesity were observed (P for trend=0.04 and 0.02, respectively), with no associations of Na or protein intake. In conclusion, we found positive associations of Na and protein intakes and inverse associations of K intake with obesity when using 24 h urinary excretion for estimating dietary intakes. However, no association was observed based on using self-reported dietary intakes, except for inverse association of K intake, suggesting that the ability of self-reported dietary information using the diet history questionnaire for investigating diet-obesity relationships is limited. PMID- 25782332 TI - Is zidovudine first-line therapy virologically comparable to tenofovir in resource-limited settings? AB - OBJECTIVE: To compare virologic success between adult patients on tenofovir (TDF) and zidovudine (AZT)-containing first-line antiretroviral (ART) regimens in 10 rural clinics in Lesotho, Southern Africa. METHODS: Multicentre cross-sectional study, patients >=16 years, on first-line ART >=6 months, receiving AZT/lamivudine (3TC) or TDF/3TC combined with efavirenz (EFV) or nevirapine (NVP). Patient characteristics and clinical/therapeutic history were collected on the day of blood draw for viral load (VL). Analysis was stratified for non nucleoside reverse transcriptase inhibitor (EFV or NVP). A logistic regression model weighted for patients' baseline characteristics was used to assess the likelihood of virologic success (<80 copies/ml) in patients with TDF- as compared to AZT-backbones. RESULTS: In total 1539 patients were included in the analysis. Most were clinically and immunologically stable (clinical failure: 2.7% (AZT) and 2.8% (TDF); immunological failure: 4.6% (AZT) and 4.8% (TDF)). In EFV-based regimens (n = 1162), TDF was significantly associated with higher rates of virologic suppression than AZT (93.8% vs. 88.1%; weighted odds ratio: 2.15 (95% CI: 1.29-3.58; P = 0.003)). In NVP-based regimens, a similar trend was observed, but not significant (89.4% vs. 86.7%; 1.99 (0.83-4.75, P = 0.121)). CONCLUSION: These findings support the WHO recommendation to use TDF/3TC/EFV as first-line regimen. They do, however, not support the recommendation that patients who are clinically stable on AZT should continue on this first-line regimen. PMID- 25782333 TI - The relationship between baseline exhaled nitric oxide levels and acute mountain sickness. AB - BACKGROUND: Acute mountain sickness (AMS) is a common disabling condition observed in people ascending to high altitudes. However, a simple predictive test for AMS is not known. The aim of this study was to assess the relationship between baseline exhaled nitric oxide (FENO) and AMS occurrence. METHODS: Eighty healthy lowland Chinese adults were recruited for this study. FENO was measured at baseline, as well as 6 and 24 hours after arrival in Tibet. The standard Lake Louise Score (LLS) consensus symptoms questionnaire was used to assess the incidence and severity of AMS. RESULTS: Individuals with a high LLS (> 3) had higher FENO levels at baseline and after arrival in Tibet than people with a low LLS (<= 3) (baseline: 22.9 +/- 11.9 versus 16.7 +/- 6.4; 6 hours: 26.2 +/- 16.7 versus 17.9 +/- 5.7; 24 hours: 24.9 +/- 13.1 versus 16.3 +/- 1.7; all P < 0.01). Evaluation of risk factors revealed that female gender, diabetes and not smoking were associated with a high AMS score (all P < 0.05), but that hypertension showed no association (P > 0.05). CONCLUSIONS: This prospective observational study suggests that baseline FENO levels may be positively correlated with AMS in healthy Chinese lowlanders. PMID- 25782335 TI - Renal Dysfunction and hsCRP Predict Long-term Outcomes of Percutaneous Coronary Intervention in Acute Myocardial Infarction. AB - BACKGROUND: This study assessed the combined utility of estimated glomerular filtration rate (eGFR) and serum high-sensitivity C-reactive protein (hsCRP) levels to predict long-term mortality and cardiovascular outcomes of patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Elevated CRP levels and renal dysfunction have both been shown to independently and jointly predict mortality and cardiovascular outcomes after PCI in the short term. However, long-term results in patients with acute STEMI undergoing PCI have not been reported. METHODS: A total of 262 patients with acute STEMI undergoing primary PCI were classified at admission into quartiles according to eGFR (<60, 60-70, 70-80 and >=80 mL.min.1.73 m) and hsCRP (<3 and >=3 mg/L). Mortality, nonfatal myocardial infarction (MI) and major adverse cardiac events (MACEs) were compared among the groups. RESULTS: During a median follow-up of 48.3 months, the composite of all cause mortality and nonfatal MI (mortality + MI) was significantly higher (35.09%) in the group with the lowest eGFR compared with that of the other 3 eGFR groups (14.29%, 3.77% and 9.43%, respectively, P < 0.0001) and the group with elevated hsCRP (34.29%) versus that with hsCRP <3 mg/L (4.41%, P < 0.0001). A combined analysis showed an exaggerated hazard in patients with the lowest eGFR and highest hsCRP (hazard ratio: 44.658; 95% confidence interval: 5.955-111.890). CONCLUSIONS: Renal dysfunction and elevated hsCRP predict a high long-term incidence of MACE in patients with acute STEMI undergoing primary PCI, with the combination being of prognostic significance for long-term mortality and MI in these patients. PMID- 25782334 TI - Alteration of type I collagen in the radial artery of patients with end-stage renal disease. AB - BACKGROUND: Cardiovascular disease is the leading cause of death in chronic kidney disease. Extracellular matrix remodeling is implicated in atherosclerosis development. This study investigated the effects and possible mechanism of type I collagen expression on radial artery elasticity in patients with end-stage renal disease (ESRD). METHODS: Sixty-five patients receiving forearm arteriovenous fistula in the Fourth Hospital of Hebei Medical University from January 2010 to December 2012 were enrolled in the study. The echo-tracking technique was used to measure radial artery 1-point pulse wave velocity (PWVbeta), and immunohistochemical staining was used to detect the expression of type I collagen and transcription factor CBFA1, a marker for calcification, in the radial artery. Uremic serum and serum from healthy volunteers of different concentrations were then used to treat the rat aortic vascular smooth muscle cells (VSMCs), reverse transcription polymerase chain reaction (PCR) was used to measure COL1A1 and CBFA1 transcription and a Western blot was performed to detect type I collagen expression in the rat aortic VSMCs. RESULTS: In patients with ESRD, increased COL1A1 expression was an independent risk factor for radial artery PWVbeta (P < 0.05) and was positively associated with that of CBFA1 (r = 0.573, P < 0.001). In the rat aortic VSMCs, serum from patients with ESRD upregulated COL1A1 and CBFA1 transcription as well as type I collagen expression in a concentration-dependent manner (P < 0.05). CONCLUSIONS: Type I collagen expression is an essential factor for radial artery elasticity dysfunction in patients with ESRD. Uremic toxins apparently induced a phenotypic transition of the rat aortic VSMCs, leading to increased type I collagen secretion and subsequent extracellular matrix remodeling. PMID- 25782336 TI - Disruption of th17/treg balance in the sputum of patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Amplified inflammation persists in the airways of patients with chronic obstructive pulmonary disease (COPD); however, the underlying mechanism is still unclear. Th17/T regulatory cells (Treg) imbalance may exist in the airways and contribute to this abnormal inflammation. METHODS: This study involved 21 patients with COPD, 21 healthy smokers (HS), and 21 healthy nonsmokers (HNS). We investigated receptor-related orphan receptor (RORC2) and forkhead box P3 (FOXP3) mRNA expression in induced sputum by real-time polymerase chain reaction and assayed IL-17, IL-10, TGF-beta and IL-6 by enzyme-linked immunosorbent assay. Th17 and Treg cells in peripheral blood were analyzed by flow cytometry. RESULTS: The level of sputum FOXP3 mRNA in both COPD and HNS was lower than that in HS (PCOPD = 0.017; PHNS = 0.009). In contrast, the level of RORC2 mRNA was markedly higher in COPD than in either HS or HNS (PHS = 0.005; PHNS < 0.001). There was a correspondingly elevated ratio of sputum RORC2 to FOXP3 mRNA in COPD. Concentrations of IL-17, TGF-beta and IL-6 were elevated in COPD sputum. In peripheral blood, both Th17 and Treg cells were elevated in COPD. CONCLUSIONS: A compartmental imbalance of Th17 over Treg exists in the airways of patients with COPD, suggesting a defect in anti-inflammatory homeostasis in COPD. PMID- 25782337 TI - Utility of the shock index in patients with sepsis. AB - The shock index (SI) equals the heart rate/systolic blood pressure and has been used to predict clinical outcomes, especially in trauma and surgery patients. The authors reviewed the literature to determine its utility in the management of patients with sepsis and in the prediction of adverse outcomes in these patients. The medical literature was searched using PubMed, Scopus, Web of Science and Google Scholar databases to identify articles in English on the SI in humans. These studies demonstrated that the SI could help evaluate the adequacy of fluid resuscitation and the potential response to additional fluid. It can predict the presence of lactic acidosis. The SI also helps predict the development of organ failure and mortality. Consequently, this easily available bedside measurement has utility in the identification, management and prediction of prognosis in patients with sepsis. PMID- 25782338 TI - Dieulafoy lesion: CT diagnosis of this lesser-known cause of gastrointestinal bleeding. AB - A Dieulafoy lesion describes a tortuous, submucosal artery in the gastrointestinal tract--most commonly the posterior stomach--that penetrates through the mucosa over time, eventually perforating to cause severe gastrointestinal bleeding. Due to its insidious onset, tendency to cause intermittent but severe bleeding, and difficulty of endoscopic diagnosis, Dieulafoy lesion has a very high mortality rate. Although originally thought not to be a radiologically diagnosable entity, Dieulafoy lesions can be seen at enhanced CT of the abdomen. The purpose of this review is to summarize the pathophysiology, epidemiology, diagnosis, and management of Dieulafoy lesions with a focus on diagnostic findings at enhanced CT imaging. PMID- 25782339 TI - Characterising benign fibrous soft-tissue tumours in adults: why is it so difficult and what do we need to know? AB - Fibrous, myofibroblastic, and fibrohistiocytic soft-tissue tumours are amongst the most common benign soft-tissue lesions encountered in clinical practice. They demonstrate varied biological behaviour and imaging characteristics. Benign fibroblastic lesions, such as nodular fasciitis, are small, have a self-limited course, and rarely recur after excision, whereas deep fibromatosis and plexiform fibrohistiocytic tumours tend to exhibit more aggressive features and often have high recurrence rates. MRI with its superior tissue contrast, multiplanar imaging capability, and lack of ionising radiation is regarded as the preferred method of tumour evaluation, tissue characterisation, and assessment of treatment response. Histopathological features are depicted at MRI, reflecting the amount and distribution of the cellular and fibrous matrix. Cellular tumours tend to show higher T2 signal intensity and post-contrast enhancement as compared to tumours with greater collagenous content, which appear dark and show less enhancement. Awareness of MR characteristics, pathological behaviour, and common sites of occurrence of fibrous soft-tissue tumours will help radiologists to determine the appropriate differential diagnosis and guide patient management. PMID- 25782340 TI - Phenolic Profiling of Olives and Olive Oil Process-Derived Matrices Using UPLC DAD-ESI-QTOF-HRMS Analysis. AB - All of the matrices entailed in olive oil processing were screened for the presence of known and new phenol constituents in a single study, combining an ultra high pressure liquid chromatography system with diode array and electrospray ionization quadrupole time-of-flight high resolution mass spectrometry (ESI-QTOF-HRMS) detection. Their trail was followed from the fruit (peel/pulp and stone) to the paste and final products, i.e. pomace, wastewater, and oil, providing important insight into the origin, disappearance, and evolution of each during the operational steps. Eighty different phenols, composed of fruit native representatives and their technologically formed and/or released derivatives, were detected in six olive matrices and fully characterized on the basis of HRMS and UV-vis spectroscopic data. In addition to phenols already known in olive matrices, four new molecular formulas were proposed and three new tentative identities assigned to newly discovered phenols, i.e., beta methyl-OH-verbascoside, methoxynuzhenide, and methoxynuzhenide 11-methyl oleoside. PMID- 25782341 TI - Augmenting the decision making process in acute appendicitis: A retrospective cohort study. AB - INTRODUCTION: Acute appendicitis is a common surgical diagnosis. We investigated the use of blood markers (WCC, CRP and serum bilirubin) and diagnostic imaging (USS and CT scan) to arrive at this diagnosis, as well as the surgical approach used for appendicectomy. METHODS: This was a retrospective analysis of consecutive patients undergoing appendicectomy in seven hospitals within GG&C Health Board during a 6 month study period. Data were collected from electronic patient records. Sensitivity and specificity of each investigation for diagnosing acute appendicitis was calculated. RESULTS: 363 patients were included. Appendicectomy was performed open in 53%, laparoscopically in 43% and converted in 4%. Diagnostic imaging was used in 38%. The overall negative appendicectomy rate was 15% (18% when no imaging was used, 23% when USS was used and 1% when CT scanning was used). Elevated bilirubin had a sensitivity of 0.44 and a specificity of 0.84 for detecting acute appendicitis. Sensitivity and specificity for elevated WCC were 0.78 and 0.55, and for elevated CRP were 0.81 and 0.59, respectively. The specificity of bilirubin for diagnosing perforated appendicitis was 0.63. DISCUSSION: WCC and CRP were sensitive blood markers in acute appendicitis, whereas serum bilirubin was more specific. Diagnostic imaging with a CT scan was very effective at reducing the rate of negative appendicectomy, but USS was not. CONCLUSION: Serum bilirubin has utility in diagnosing acute appendicitis, irrespective of whether perforation has occurred. CT scanning should be considered the first line imaging modality for investigation of acute appendicitis if diagnosis is in doubt. PMID- 25782342 TI - Clinical Implantation with the novel D-13 prosthesis for inguinal hernioplasty: A retrospective cohort study. AB - INTRODUCTION: Using a mesh to repair inguinal hernias is now a standard procedure that is widely accepted as superior to primary suture repair. Although a variety of meshes are available, individual meshes may have their own unattractive features. This retrospective study examines the efficacy of our originally designed D-13 prosthesis, which is used in patients with inguinal hernias. METHODS: A total of 305 patients who underwent a herniorrhaphy between January 2009 and March 2011 were included in this study. The recurrent rate, chronic pain and feeling of a foreign body were examined at a 3-year follow-up. The D-13 prosthesis, made from clear polypropylene monofilament mesh, was originally designed by the first author of this study and constructed with the upper and lower pieces of polypropylene mesh having different shapes and sizes. Both pieces are linked together by a connector. RESULTS: The mesh is well tolerated. At a 3 year follow-up, only two patients had a foreign body sensation at the operative site, and three patients had recurrent hernias. CONCLUSION: The unique design of the D-13 prosthesis with two pieces of mesh provided encouraging long-term outcome for hernia recurrence, chronic pain and the feeling of a foreign body. PMID- 25782343 TI - Experts for Validation Studies in Nursing: New Proposal and Selection Criteria. AB - OBJECTIVE: To propose new criteria for expert selection for validation studies in nursing in Brazil. METHODS: (a) Literature review on terms related to expertise and criteria for expert selection; and (b) development of new consensus criteria for expert selection and consensus building. RESULTS: Definitions for the terms novice, advanced beginner, competent, proficient, and expert were found. In the second phase, criteria to rank the experts (junior, senior, and master) were developed and validated according to a score of 5-20. CONCLUSION AND IMPLICATIONS FOR NURSING PRACTICE: The new criteria valued clinical experience over academic experience. The use of these criteria by researchers in the country should reduce uncertainties, difficulties, and limitations imposed by the modification/current adaptation of already existing criteria. PMID- 25782344 TI - Conformationally switchable water-soluble fluorescent bischolate foldamers as membrane-curvature sensors. AB - Membrane curvature is an important parameter in biological processes such as cellular movement, division, and vesicle fusion and budding. Traditionally, only proteins and protein-derived peptides have been used as sensors for membrane curvature. Three water-soluble bischolate foldamers were synthesized, all labeled with an environmentally sensitive fluorophore to report their binding with lipid membranes. The orientation and ionic nature of the fluorescent label were found to be particularly important in their performance as membrane-curvature sensors. The bischolate with an NBD group in the hydrophilic alpha-face of the cholate outperformed the other two analogues as a membrane-curvature sensor and responded additionally to the lipid composition including the amounts of cholesterol and anionic lipids in the membranes. PMID- 25782345 TI - Erratum to: Malignant melanoma: factors affecting the surgical interval from excision biopsy to definitive surgical management. PMID- 25782346 TI - An Accelerated Analytical Process for the Development of STR Profiles for Casework Samples. AB - Significant efforts are being devoted to the development of methods enabling rapid generation of short tandem repeat (STR) profiles in order to reduce turnaround times for the delivery of human identification results from biological evidence. Some of the proposed solutions are still costly and low throughput. This study describes the optimization of an analytical process enabling the generation of complete STR profiles (single-source or mixed profiles) for human identification in approximately 5 h. This accelerated process uses currently available reagents and standard laboratory equipment. It includes a 30-min lysis step, a 27-min DNA extraction using the Promega Maxwell((r)) 16 System, DNA quantification in <1 h using the Qiagen Investigator((r)) Quantiplex HYres kit, fast amplification (<26 min) of the loci included in AmpFlSTR((r)) Identifiler((r)), and analysis of the profiles on the 3500-series Genetic Analyzer. This combination of fast individual steps produces high-quality profiling results and offers a cost-effective alternative approach to rapid DNA analysis. PMID- 25782347 TI - Reduced Corneal Endothelial Cell Density in Patients With Dry Eye Disease. AB - PURPOSE: To evaluate corneal endothelial cell density (ECD) in patients with dry eye disease (DED) compared to an age-matched control group. DESIGN: Cross sectional, controlled study. METHODS: This study included 90 eyes of 45 patients with moderate to severe DED (aged 53.7 +/- 9.8 years) and 30 eyes of 15 normal controls (aged 50.7 +/- 9.8 years). All subjects had a complete ophthalmic evaluation including symptom assessment using the Ocular Surface Disease Index (OSDI) and corneal fluorescein staining. In addition, laser scanning in vivo confocal microscopy was performed to measure the density of the following parameters in the central cornea: endothelial cells, subbasal nerves, and subbasal immune dendritic cells. RESULTS: Corneal ECD was significantly lower in the DED group (2595.8 +/- 356.1 cells/mm(2)) than in the control group (2812.7 +/ 395.2 cells/mm(2), P = .046). The DED group showed significantly lower corneal subbasal nerve density (17.1 +/- 6.9 mm/mm(2)) compared to the control group (24.7 +/- 4.4 mm/mm(2), P < .001). Dendritic cell density was significantly higher in the DED group than in the controls (111.7 +/- 137.3 vs 32.0 +/- 24.4 cells/mm(2), respectively, P = .002). There were statistically significant correlations between corneal ECD and dry eye severity parameters including the OSDI score (rs = -0.26, P = .03), and corneal fluorescein staining (rs = -0.28, P = .008). CONCLUSIONS: There is a significant reduction in corneal ECD in DED that correlates with clinical severity of the disease. PMID- 25782348 TI - u-XRF Analysis of Trace Elements in Lapis Lazuli-Forming Minerals for a Provenance Study. AB - This paper presents new developments on the provenance study of lapis lazuli started by our group in 2008: during the years a multi-technique approach has been exploited to obtain minero-petrographic characterization and creation of a database considering only rock samples of known provenance. Since the final aim of the study is to develop a method to analyze archeological findings and artworks made with lapis lazuli in a completely non-invasive way, ion beam analysis techniques were employed to trace the provenance of the raw material used for the production of artifacts. Continuing this goal and focusing the analysis on determination of more significant minero-chemical markers for the provenance study of trace elements in different minerals, the method was extended with the use of micro X-ray fluorescence (u-XRF), to test the potential of the technique for this application. The analyzes were focused on diopside and pyrite in lapis lazuli samples of known provenance (Afghanistan, Tajikistan, and Siberia). In addition, u-XRF data were compared with micro proton-induced X-ray emission (u-PIXE) results to verify the agreement between the two databases and to compare the analytical performance of both techniques for this application. PMID- 25782350 TI - Influences of age and sex on leukocytes of healthy horses and their ex vivo cytokine release. AB - Leukocytes and their functional capacities are used extensively as biomarkers in immunological research. Commonly employed indicators concerning leukocytes are as follows: number, composition in blood, response to discrete stimuli, cytokine release, and morphometric characteristics. In order to employ leukocytes as biomarkers for disease and therapeutic monitoring, physiological variations and influencing factors on the parameters measured have to be considered. The aim of this report was to describe the ranges of selected leukocyte parameters in a sample of healthy horses and to analyse whether age, sex, breed, and sampling time point (time of day) influence peripheral blood leukocyte composition, cell morphology and release of cytokines ex vivo. Flow cytometric comparative characterisation of cell size and complexity in 24 healthy horses revealed significant variance. Similarly, basal release of selected cytokines by blood mononuclear cells also showed high variability [TNFalpha (65-16,624pg/ml), IFNgamma (4-80U/ml), IL-4 (0-5069pg/ml), IL-10 (49-1862pg/ml), and IL-17 (4 1244U/ml)]. Each animal's age influenced leukocyte composition, cell morphology and cytokine release (TNFalpha, IL-4, IL-10) ex vivo. Geldings showed smaller monocytes and higher spontaneous production of IL-10 when compared to the mares included. The stimulation to spontaneous release ratios of TNFalpha, IL-4 and IL 17 differed in Warmblood and Thoroughbred types. Sampling time influenced leukocyte composition and cell morphology. In summary, many animal factors - age being the dominant one - should be considered for studies involving the analysis of equine leukocytes. In addition, high inter-individual variances argue for individual baseline measurements. PMID- 25782349 TI - Engineered chloroplast dsRNA silences cytochrome p450 monooxygenase, V-ATPase and chitin synthase genes in the insect gut and disrupts Helicoverpa zea larval development and pupation. AB - In the past two decades, chloroplast genetic engineering has been advanced to achieve high-level protein accumulation but not for down-regulation of targeted genes. Therefore, in this report, lepidopteran chitin synthase (Chi), cytochrome P450 monooxygenase (P450) and V-ATPase dsRNAs were expressed via the chloroplast genome to study RNA interference (RNAi) of target genes in intended hosts. PCR and Southern blot analysis confirmed homoplasmy and site-specific integration of transgene cassettes into the chloroplast genomes. Northern blots and real-time qRT-PCR confirmed abundant processed and unprocessed dsRNA transcripts (up to 3.45 million copies of P450 dsRNAs/MUg total RNA); the abundance of cleaved dsRNA was greater than the endogenous psbA transcript. Feeding of leaves expressing P450, Chi and V-ATPase dsRNA decreased transcription of the targeted gene to almost undetectable levels in the insect midgut, likely after further processing of dsRNA in their gut. Consequently, the net weight of larvae, growth and pupation rates were significantly reduced by chloroplast-derived dsRNAs. Taken together, successful expression of dsRNAs via the chloroplast genome for the first time opens the door to study RNA interference/processing within plastids. Most importantly, dsRNA expressed in chloroplasts can be utilized for gene inactivation to confer desired agronomic traits or for various biomedical applications, including down-regulation of dysfunctional genes in cancer or autoimmune disorders, after oral delivery of dsRNA bioencapsulated within plant cells. PMID- 25782351 TI - Vaccination of cattle with a methanogen protein produces specific antibodies in the saliva which are stable in the rumen. AB - Methane is produced in the rumen of cattle by a group of archaea (single-celled organisms forming a domain distinct from bacteria and eucarya) called methanogens. Vaccination against methanogens has the potential to reduce methane emissions by inducing antibodies in saliva which are transferred to the rumen and diminish the ability of methanogens to produce methane. Since it is likely that an effective vaccination strategy will need to produce high levels of methanogen specific antibody in the saliva; the choice of adjuvant, route of vaccination and stability of saliva-derived antibody in the rumen all need to be considered. In this study, stability of IgA and IgG in rumen fluid was determined using an in vitro assay. IgA levels in cattle saliva were reduced by only 40% after 8h exposure to rumen contents while IgG levels were reduced by 80%. These results indicated that antibody is relatively stable in the bovine rumen. A trial was conducted in cattle to investigate induction of immune responses to a methanogen protein, recombinant glycosyl transferase protein (rGT2) from Methanobrevibacter ruminantium M1. Groups of cattle (n=6) were vaccinated subcutaneously with rGT2, formulated with Montanide ISA61 with or without the TLR4 agonist, monophosphoryl lipid A (MPL). A control group (n=6) was not vaccinated. Strong antigen-specific IgG and moderate IgA responses were measured in the serum and saliva of the vaccinated animals and antibody was also detected in the rumen. PMID- 25782361 TI - Primary and secondary battery consumption trends in Sweden 1996-2013: method development and detailed accounting by battery type. AB - In this article, a new method based on Material Flow Accounting is proposed to study detailed material flows in battery consumption that can be replicated for other countries. The method uses regularly available statistics on import, industrial production and export of batteries and battery-containing electric and electronic equipment (EEE). To promote method use by other scholars with no access to such data, several empirically results and their trends over time, for different types of batteries occurrence among the EEE types are provided. The information provided by the method can be used to: identify drivers of battery consumption; study the dynamic behavior of battery flows - due to technology development, policies, consumers behavior and infrastructures. The method is exemplified by the study of battery flows in Sweden for years 1996-2013. The batteries were accounted, both in units and weight, as primary and secondary batteries; loose and integrated; by electrochemical composition and share of battery use between different types of EEE. Results show that, despite a fivefold increase in the consumption of rechargeable batteries, they account for only about 14% of total use of portable batteries. Recent increase in digital convergence has resulted in a sharp decline in the consumption of primary batteries, which has now stabilized at a fairly low level. Conversely, the consumption of integrated batteries has increased sharply. In 2013, 61% of the total weight of batteries sold in Sweden was collected, and for the particular case of alkaline manganese dioxide batteries, the value achieved 74%. PMID- 25782362 TI - Hepatitis B immunoprophylaxis failure and the presence of hepatitis B surface gene mutants in the affected children. AB - Hepatitis B virus (HBV) infection is usually vertically transmitted from the mother to child during birth in Asian countries. Despite immunization, immunoprophylaxis failure is well-documented. The aim of the study was to study immunoprophylaxis failure rate in the cohort of infants delivered by chronic HBV infected mothers and to determine risk factors for failure. This was an observational study involving chronic hepatitis B infected mothers seen at a tertiary care center in Singapore between June 2009 and December 2013. Infants born to these mothers were recruited after they had completed the recommended vaccination schedule. Serological testing for the children was performed 3 months after completion of the last dose of vaccine. HBV surface gene sequencing was carried out if HBV DNA was detectable in the children. Among the 161 mothers enrolled, most were HBeAg negative. HBeAg positive mothers were younger and had a significantly higher viral load (6.5 log) as compared to HBeAg negative mothers (1.35 log) (P < 0.001). Four children (2.6%) were found to have immunoprophylaxis failure. Two occurred in children delivered by mothers with extremely high viral load of more than 5 * 10(7) IU/ml. HBV surface gene mutations were detected in most children (3 out of 4) with immunoprophylaxis failure. The overall effectiveness of the hepatitis B vaccination program was high. High maternal viral load and presence of surface gene mutants may be potential contributors. PMID- 25782363 TI - Detection and recognition of angular frequency patterns. AB - Previous research has extensively explored visual encoding of smoothly curved, closed contours described by sinusoidal variation of pattern radius as a function of polar angle (RF patterns). Although the contours of many biologically significant objects are curved, we also confront shapes with a more jagged and angular appearance. To study these, we introduce here a novel class of visual stimuli that deform smoothly from a circle to an equilateral polygon with N sides (AF patterns). Threshold measurements reveal that both AF and RF patterns can be discriminated from circles at the same deformation amplitude, approximately 18.0arcsec, which is in the hyperacuity range. Thresholds were slightly higher for patterns with 3.0 cycles than for those with 5.0 cycles. Discrimination between AF and RF patterns was 75% correct at an amplitude that was approximately 3.0 times the threshold amplitude, which implies that AF and RF patterns activate different neural populations. Experiments with jittered patterns in which the contour was broken into several pieces and shifted inward or outward had much less effect on AF patterns than on RF patterns. Similarly, thresholds for single angles of AF patterns showed no significant difference from thresholds for the entire AF pattern. Taken together, these results imply that the visual system incorporates angles explicitly in the representation of closed object contours, but it suggests that angular contours are represented more locally than are curved contours. PMID- 25782364 TI - Motion-induced position shifts are influenced by global motion, but dominated by component motion. AB - Object motion and position have long been thought to involve largely independent visual computations. However, the motion-induced position shift (Eagleman & Sejnowski, 2007) shows that the perceived position of a briefly presented static object can be influenced by nearby moving contours. Here we combine a particularly strong example of this illusion with a bistable global motion stimulus to compare the relative effects of global and component motion on the shift in perceived position. We used a horizontally oscillating diamond (Lorenceau & Shiffrar, 1992) that produces two possible global directions (left and right when fully visible versus up and down when vertices are occluded by vertical bars) as well as the oblique component motion orthogonal to each contour. To measure the motion-induced shift we flashed a test dot on the contour as the diamond reversed direction (Cavanagh & Anstis, 2013). Although the global motion had a highly significant influence on the direction and size of the motion induced position shift, the perceived displacement of the probe was closer to the direction of the component motion. These findings show that while global motion can clearly influence position shifts, it is the component motion that dominates in setting the position shift. This is true even though the perceived motion is in the global direction and the component motion is not consciously experienced. This suggests that perceived position is influenced by motion signals that arise earlier in time or earlier in processing compared to the stage at which the conscious experience of motion is determined. PMID- 25782365 TI - Altered thermal grill response and paradoxical heat sensations after topical capsaicin application. AB - The thermal grill illusion, where interlaced warm and cold bars cause an unusual burning sensation, and paradoxical heat sensations (PHS), where cold is perceived as warm when alternating warm and cold, are examples of a complex integration of thermal sensations. Here, we investigated the effect of sensitization of heat sensitive neurons on cold and warm integration. We examined thermal thresholds, PHS, and warm, cold, and pain sensations to alternating cold (10 degrees C) and warm (40 degrees C) bars (the thermal grill [TG]) in the primary area (application site) after topical application with capsaicin and vehicle control (ethanol) on the volar forearms in randomized order in 80 healthy participants. As expected, capsaicin induced heat allodynia and hyperalgesia and decreased cold and cold pain sensation. In addition, we found that after capsaicin application, the TG caused less pain and burning than the 40 degrees C bars alone in contrast to the control side where the TG caused more pain and burning, consistent with the thermal grill illusion. In both situations, the pain intensity during the TG correlated inversely with both cold and warm pain thresholds but not with detection thresholds. Paradoxical heat sensation was only seen in 3 participants after control application but in 19 participants after capsaicin. Those with PHS after capsaicin application had higher detection thresholds to both cold and warm than those without PHS, but there was no difference in thermal pain threshold. These results suggest that a complex cross talk among several cold and warm sensitive pathways shapes thermal perception. PMID- 25782366 TI - Reversal of insular and microstructural nerve abnormalities following effective surgical treatment for trigeminal neuralgia. AB - Classical trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder commonly associated with neurovascular compression at the trigeminal nerve root entry zone (REZ). Neurosurgical interventions can relieve TN pain, but the mechanisms underlying these effects are unknown. We determined whether the abnormalities we previously reported at the REZ of TN patients using diffusion tensor imaging (DTI) and brain gray matter (GM) analyses resolve after effective neurosurgical treatment. Twenty-five patients who underwent either microvascular decompression surgery or Gamma Knife radiosurgery for right-sided TN had magnetic resonance imaging scans before and after treatment and were compared with age matched controls. Cortical thickness and voxel-based morphometry examined specific brain GM we previously reported as abnormal in TN. White matter metrics of fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, and AD, respectively) were extracted bilaterally from each trigeminal REZ. Before treatment, patients had widespread GM abnormalities including thinner ventral anterior insula (vAI) cortex, and REZ microstructural abnormalities (lower FA, and higher MD, RD, and AD) compared with controls. We considered a 75% reduction in pain as effective treatment. The right vAI was the only GM region that normalized toward the level of healthy controls after effective treatment. At the REZ, effective treatment reversed FA, MD, RD, and AD abnormalities and was correlated with pain relief after treatment. These results demonstrate that treatment can effectively resolve pain by normalizing REZ abnormalities, which may influence vAI abnormalities. Future studies should consider DTI as an adjunct to assess the patient outcome and subtle microstructural changes after treatment. PMID- 25782367 TI - Self-reports of medication side effects and pain-related activity interference in patients with chronic pain: a longitudinal cohort study. AB - The primary purpose of this study was to examine the association between self reports of medication side effects and pain-related activity interference in patients with chronic pain. The potential moderators of the association between reports of side effects and pain-related activity interference were also examined. A total of 111 patients with chronic musculoskeletal pain were asked to provide, once a month for a period of 6 months, self-reports of medication use and the presence of any perceived side effects (eg, nausea, dizziness, headaches) associated with their medications. At each of these time points, patients were also asked to provide self-reports of pain intensity, negative affect, and pain related activity interference. Multilevel modeling analyses revealed that month to-month increases in perceived medication side effects were associated with heightened pain-related activity interference (P < 0.05). Importantly, multilevel models revealed that perceived medication side effects were associated with heightened pain-related activity interference even after controlling for the influence of patient demographics, pain intensity, and negative affect. This study provides preliminary evidence that reports of medication side effects are associated with heightened pain-related activity interference in patients with chronic pain beyond the influence of other pain-relevant variables. The implications of our findings for clinical practice and the management of patients with chronic pain conditions are discussed. PMID- 25782370 TI - Large-area synthesis of monolayer WS2 and its ambient-sensitive photo-detecting performance. AB - We demonstrate the synthesis of large-area monolayer WS2 films by chemical vapor deposition (CVD) and investigate their photoresponse properties by fabricating n type field effect transistors (FETs) with Al as the ohmic contact. Our CVD-grown monolayer WS2 shows an electron mobility of 0.91 cm(2) V(-1) s(-1) and an ON/OFF ratio of 10(6), indicating its comparable electronic properties to the mechanically exfoliated flake sample. In a vacuum, by applying a gate bias (60 V), the responsivity of the monolayer WS2 phototransistor can increase up to 22.1 A W(-1) and a decent sub-second level response time can be maintained. In contrast, in air, it shows a very fast response time of less than 4.5 ms, but at the cost of responsivity reduction to 0.24 mA W(-1). Such a distinctive ambient sensitive photo-detecting performance can be well-explained by the pronounced effect of charge-acceptor-like O2/H2O molecule adsorption/desorption on the photocarrier transport. Our CVD-grown high quality monolayer WS2 may pave the way for developing industrial-scale optoelectronic devices for photo-detecting and chemical sensing applications. [Corrected] PMID- 25782369 TI - Allogeneic stem cell transplantation using lymphoablative rather than myeloablative conditioning regimen for relapsed or refractory lymphomas. AB - In relapsed or refractory non-Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides graft-versus-lymphoma activity resulting in fewer incidences of relapse. However, therapy-related mortality (TRM) remains an important challenge. We attempted to introduce our reduced intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo-HSCT. All were pre-conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B-cell lymphomas, seven peripheral T-cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto-HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo-HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow-up of 24.8 months, 3-year overall survival and disease-free survival were 62.4 and 59.2% and the 3-year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft-versus-host diseases (GVHDs) were identified in 17 (>=Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC-allo-HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25782368 TI - A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. AB - Targeting proteins within the N-type voltage-gated calcium channel (CaV2.2) complex has proven to be an effective strategy for developing novel pain therapeutics. We describe a novel peptide aptamer derived from the collapsin response mediator protein 2 (CRMP2), a CaV2.2-regulatory protein. Addition of a 14-carbon myristate group to the peptide (myr-tat-CBD3) tethered it to the membrane of primary sensory neurons near surface CaV2.2. Pull-down studies demonstrated that myr-tat-CBD3 peptide interfered with the CRMP2-CaV2.2 interaction. Quantitative confocal immunofluorescence revealed a pronounced reduction of CaV2.2 trafficking after myr-tat-CBD3 treatment and increased efficiency in disrupting CRMP2-CaV2.2 colocalization compared with peptide tat CBD3. Consequently, myr-tat-CBD3 inhibited depolarization-induced calcium influx in sensory neurons. Voltage clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after myr-tat-CBD3 exposure. Current clamp electrophysiology experiments demonstrated a reduction in excitability of small-diameter dorsal root ganglion neurons after exposure to myr tat-CBD3. Myr-tat-CBD3 was effective in significantly attenuating carrageenan induced thermal hypersensitivity and reversing thermal hypersensitivity induced by a surgical incision of the plantar surface of the rat hind paw, a model of postoperative pain. These effects are compared with those of tat-CBD3-the nonmyristoylated tat-conjugated CRMP2 peptide as well as scrambled versions of CBD3 and CBD3-lacking control peptides. Our results demonstrate that the myristoyl tag enhances intracellular delivery and local concentration of the CRMP2 peptide aptamer near membrane-delimited calcium channels resulting in pronounced interference with the calcium channel complex, superior suppression of calcium influx, and better antinociceptive potential. PMID- 25782371 TI - Genetic variations in sites of affinity between FVIII and LRP1 are not associated with high FVIII levels in venous thromboembolism. AB - Increased factor VIII (FVIII) levels are a prevalent and independent risk factor for venous thromboembolism (VTE). The low density lipoprotein receptor-related protein 1 (LRP1) has been associated with FVIII catabolism. After a median of 10 years of the first thrombotic episode, we evaluated FVIII activity levels in 75 patients with VTE and high FVIII levels and in 74 healthy controls. Subsequently, we evaluated the regions of F8 and LRP1 genes coding sites of affinity between these proteins, with the objective of determining genetic alterations associated with plasma FVIII levels. After a median time of 10 years after the VTE episode, FVIII levels were significantly higher in patients when compared to controls (158.6 IU/dL vs. 125.8 IU/dL; P <= 0.001]. Despite the fact that we found 14 genetic variations in F8 and LRP1 genes, no relationship was found between FVIII levels with these variations. We demonstrated a persistent increase of FVIII levels in patients with VTE, but in a much lower magnitude after 10 years when compared to 3-years after the episode. Moreover, we observed no relationship of genetic variations in the gene regions coding affinity sites between LRP1 and FVIII with FVIII levels. PMID- 25782372 TI - Role of primary surgery in the treatment of advanced oropharyngeal cancer. AB - BACKGROUND: The purpose of this study was to compare survival outcomes of patients with advanced stage oropharyngeal squamous cell carcinoma (SCC) according to surgical and nonsurgical treatments, when stratified by smoking and p16 status. METHODS: We conducted a prospective longitudinal population-based study of 279 patients diagnosed with advanced oropharyngeal SCC. Patients were stratified by smoking and p16 status. RESULTS: There was no significant disease specific survival (DSS) difference in combined modality treatment groups in nonsmokers that had p16-positive cancers, however, in smokers with p16-positive cancers, the DSS surgery + postoperative chemoradiotherapy (S+CRT) was significantly higher than chemoradiotherapy (CRT) alone. Patients who had p16 negative cancers had the highest DSS when treated with surgery + adjuvant therapy (S+RT)/CRT. Multivariate Cox regression analysis showed that increasing Eastern Cooperative Oncology Group (ECOG) score, smoking, p16 status, higher stage, and treatment with surgery protocols were significant determinants of survival. CONCLUSION: Primary surgical approaches offer the best survival outcomes in smokers with p16-positive cancers and in patients with p16-negative cancers. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E-E, 2016. PMID- 25782373 TI - Effect on the H19 gene methylation of sperm and organs of offspring after chlorpyrifos-methyl exposure during organogenesis period. AB - To elucidate the effect on the H19 gene methylation of sperm and organs in offspring by chlorpyrifos-methyl (CPM) exposure during organogenesis period, CPM was administered at doses of 4 (CPM4), 20 (CPM20), and 100 (CPM100) mg/kg bw/day from 7 days post coitum (d.p.c.) to 17 d.p.c. after mating CAST/Ei (?) and B6 (?). Anogenital distance (AGD) was measured at postnatal day (PND) 21. Clinical signs, body weights, feed and water consumption, organs weights, serum hormone values, and H19 methylation level of organ and sperm were measured at PND63. Body weights were significantly lower than control until PND6. AGD was significantly decreased in the CPM100 group in males and increased in the CPM20 group in females. The absolute weights of the thymus and epididymis were significantly increased for males in all of CPM treatment groups. In the CPM20 group, absolute weights of liver, kidney, heart, lung, spleen, prostate gland, and testes were significantly increased. Testosterone concentrations in serum were significantly increased by CPM treatment in males. H19 methylation level of liver and thymus showed decreased pattern in a dose-dependent manner in males. The levels of H19 methylation in sperm were 73.76 +/- 7.16% (Control), 57.84 +/- 12.94% (CPM4), 64.24 +/- 3.79% (CPM20), and 64.24 +/- 3.79% (CPM100). Conclusively, CPM exposure during organogenesis period can disrupt H19 methylation in sperm, liver, and thymus and disturb the early development of offspring. PMID- 25782397 TI - Distribution and heritability of diurnal preference (chronotype) in a rural Brazilian family-based cohort, the Baependi study. AB - Diurnal preference (chronotype) is a useful instrument for studying circadian biology in humans. It harbours trait-like dimensions relating to circadian period and sleep homeostasis, but also has ontogenetic components (morningness increases with age). We used the Morningness-Eveningness questionnaire (MEQ) in the Baependi study, a family-based cohort study based in a small town in Minas Gerais, Brazil. The population is highly admixed and has a cohesive and conservative lifestyle. 825 individuals (497 female) aged 18-89 years (average +/ SD = 46.4 +/- 16.3) and belonging to 112 different families participated in this study. The average MEQ score was 63.5 +/- 11.2 with a significant (P < 0.0001) linear increase with age. Morningness was significantly (P < 0.0001) higher in the rural (70.2 +/- 9.8) than in the municipal zone (62.6 +/- 11.1), and was also significantly (P = 0.025) higher in male (64.6 +/- 10.9) than in female (62.8 +/- 11.2) participants. Thus, in spite of universal access to electricity, the Baependi population was strongly shifted towards morningness, particularly in the rural zone. Heritability of MEQ score was 0.48 when adjusted for sex and age, or 0.38 when adjusted for sex, age, and residential zone. The reported MEQ score heritability is more akin to those of previous twin studies than previous family studies. PMID- 25782398 TI - Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways. AB - Second generation antipsychotic drugs (SGAs) such as risperidone are increasingly prescribed (mostly for off-label use) to children and adolescents for treating various mental disorders. SGAs cause serious weight gain/obesity and other metabolic side-effects. This study aimed to establish an animal model of risperidone-induced weight gain in female juvenile rats, and to investigate the effects of risperidone on the expression of hypothalamic histaminergic H1 receptors (H1R) and neuropeptides, and their association with weight gain. Female Sprague Dawley rats were treated orally with risperidone (0.3mg/kg, 3 times/day) or vehicle (control) starting from postnatal day (PD) 23 (+/-1 day) for 3 weeks (a period corresponding to the childhood-adolescent period in humans). In the female juvenile rats, risperidone treatment increased food intake and body weight gain, which started to appear after 12 days' treatment. Risperidone also significantly decreased the locomotor activity of the female rats. Consistently, risperidone significantly elevated mRNA expression of hypothalamic H1R, neuropeptide Y (NPY), and agouti-related peptide (AgRP) compared to controls, and H1R and NPY levels were correlated with risperidone enhanced weight gain and food intake in the female juvenile rats. However, risperidone did not affect hypothalamic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA expression. Therefore, these results suggested that risperidone elevated appetite and body weight gain in juveniles via regulation of the hypothalamic H1R, NPY and AgRP pathways, as well as by reducing activity. PMID- 25782400 TI - Pachymetry-guided intrastromal air injection ("pachy-bubble") for deep anterior lamellar keratoplasty: results of the first 110 cases. AB - PURPOSE: To report intraoperative and 1-year postoperative results of the pachy bubble technique for deep anterior lamellar keratoplasty (DALK). METHODS: This prospective interventional case series included 110 eyes of 107 patients with anterior corneal pathology who underwent DALK, including 78 with keratoconus. Outcome measures included the rate of bubble formation, rate of completing DALK, bubble types, complications, and visual and keratometric parameters. RESULTS: Intrastromal air injection was attempted in 109 eyes, and the air bubble was achieved in 93 eyes (85.3%). Intrastromal 2% methylcellulose injection was attempted in 9 eyes, after unsuccessful air bubble formation, and the viscobubble was achieved in 7 eyes (77.8%). Manual layer-by-layer dissection was performed in 8 eyes. Bubble formation was reached in 100 eyes (90.9%). Overall, 105 eyes (95.5%) achieved DALK. Air bubble occurred as type 1 (white margin) in 96.6% of the cases and as type 2 (clear margin) in 3.4%. There was a statistically significant improvement in all visual and keratometric parameters analyzed. Macroperforations converted to penetrating keratoplasty occurred in 5 eyes (4.5%) and microperforations in 12 (10.9%). There were significantly higher rates of perforation when a bubble was not achieved (P = 0.018) and when it was achieved as type 2 (P = 0.033). Interface haze occurred in 5 eyes (4.5%) and stromal rejection in 11 (10.0%). A short learning curve was observed for air bubble formation. CONCLUSIONS: Bubble formation, especially type 1, is the key to decrease the risk of perforation in DALK. The pachy-bubble was safe, effective, and reproducible in promoting DALK with air bubble and viscobubble formation with a short learning curve. PMID- 25782399 TI - Human growth hormone promotes corneal epithelial cell migration in vitro. AB - PURPOSE: Corneal wound healing is a highly regulated process that requires the proliferation and migration of epithelial cells and interactions between epithelial cells and stromal fibroblasts. Compounds that can be applied topically to the ocular surface and that have the capability of activating corneal epithelial cells to proliferate and/or migrate would be useful to promote corneal wound healing. We hypothesize that human growth hormone (HGH) will activate signal transducers and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial cell and fibroblast proliferation and/or migration in vitro. The purpose of this study was to test these hypotheses. METHODS: We studied cell signaling, proliferation, and migration using an immortalized human corneal epithelial cell line and primary human corneal fibroblasts in vitro. We also examined whether insulin-like growth factor-1 (IGF-1), a hormone known to mediate many of HGH's growth promoting actions, may play a role in this effect. RESULTS: We show that HGH activates STAT5 signaling and promotes corneal epithelial cell migration in vitro. The migratory effect requires an intact communication between corneal epithelia and fibroblasts and is not mediated by IGF-1. CONCLUSIONS: HGH may represent a topical therapeutic to promote corneal epithelial wound healing. This warrants further investigation. PMID- 25782401 TI - Concordance between patient and clinician assessment of dry eye severity and treatment response in Taiwan. AB - PURPOSE: Accurate diagnosis and early recognition of dry eye symptoms are important in the management of dry eye disease (DED). This study aimed to evaluate concordance between patient and clinician assessment of DED severity and treatment response. METHODS: This cross-sectional study was conducted in 2 ophthalmology clinics in Taiwan. Clinicians assessed severity based on the Dry Eye Workshop severity grading (levels 1-4; where 4 = most severe), whereas patients completed the Ocular Surface Disease Index questionnaire. To evaluate the treatment response, patients completed the Subject Global Assessment scale, and clinicians independently assessed patients using the Clinical Global Impression scale. RESULTS: A total of 466 patients were included. Clinicians graded 88.3% of patients as level 1/2, 9.0% as level 3, and 2.7% as level 4 Dry Eye Workshop severity, whereas 44.9% of patients reported normal/mild symptoms, 17.1% with moderate severity, and 38.0% with severe DED. Patients were primarily treated with artificial tears. The clinician assessed 10.3% of patients as unchanged on disease severity after treatment and 88.0% as improved, whereas 49.2% of patients reported dry eye symptoms being almost the same after treatment and 34.6% reported improved symptoms. There was low agreement between clinician and patient assessments in terms of disease severity (rho = 0.17, P < 0.001) and treatment response (rho = 0.22, P < 0.001). CONCLUSIONS: There were marked differences in the degree of DED severity and treatment response between patient and clinician assessment. Clinicians may underestimate DED severity and persistence of dry eye symptoms after treatment with artificial tears.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01942226. PMID- 25782402 TI - Screening of refractive surgery candidates for LASIK and PRK. PMID- 25782403 TI - Schiotz tonometry accurately measures intraocular pressure in Boston type 1 keratoprosthesis eyes. AB - PURPOSE: To evaluate the location of the eye and tonometry device that provides the most accurate intraocular pressure (IOP) measurements in eyes with Boston type 1 keratoprosthesis. METHODS: A single surgeon sutured a Boston keratoprosthesis into the central cornea in the usual manner in 5 eyes of deceased donors. Another investigator used a 27-gauge needle, digital manometry, and gravity infusion to set the IOP at levels of 10, 20, 30, and 40 mm Hg in random order. A second investigator masked to the level of IOP used a Schiotz tonometer (Sklar) with a 7.5-g plunger load and a Tono-pen XL tonometer (Medtronic) to determine IOP at the temporal corneoscleral limbus and temporal sclera (3 mm temporal to the corneoscleral limbus). We used generalized estimation equation models to determine an average absolute difference between the tonometer measurements compared with the "gold standard" digital manometric IOP. RESULTS: The Schiotz tonometer had a lower median absolute error compared with the Tono-pen at both temporal sclera (5.4 mm Hg vs. 39.0 mm Hg, P < 0.001) and corneoscleral limbus (4.9 vs. 15.0 mm Hg, P = 0.03). The median absolute error for Schiotz was similar at the temporal sclera and corneoscleral limbus (P = 0.44). CONCLUSIONS: The Schiotz tonometer has the highest accuracy of IOP compared with the Tono-pen and gold standard digital manometry. Clinicians could consider Schiotz tonometry when measuring IOP in patients with keratoprosthesis. PMID- 25782404 TI - Keratoconus and allergic diseases among Israeli adolescents between 2005 and 2013. AB - PURPOSE: The aim of this study was to evaluate the association between keratoconus (KC) and common allergic conditions, such as asthma, atopic dermatitis, and allergic rhinitis in a large-scale database-based epidemiological study. METHODS: We conducted a cross-sectional study to estimate the epidemiologic relationship between KC and allergic diseases. The study population included all Israeli adolescents who underwent medical evaluation by the Israeli Defense Force, between the years 2005 and 2013. The presence of KC was determined by corneal topography read by an ophthalmologist. RESULTS: A statistically significantly increased odds ratio (OR) for the presence of KC was found for asthma [OR: 2.0; 95% confidence interval (CI): 1.6-2.5; P < 0.001], allergic rhinitis (OR: 1.6; 95% CI: 1.3-2.0; P < 0.001), and the combination of allergic conjunctivitis, chronic blepharitis, and vernal keratoconjunctivitis (AC/CB/VKC), for which a particularly strong association was found (OR: 6.0; 95% CI: 4.0-9.2; P < 0.001). No significant association was found between angioedema, urticaria, history of anaphylaxis, allergy to hymenoptera sting or atopic dermatitis, and KC. After stratifying the patients according to the severity of the allergic disease, the association between severe (AC/CB/VKC) and KC was very high (OR: 36.5; 95% CI: 20.4-65.4; P < 0.001). CONCLUSIONS: In this study, we demonstrated a substantial association between (AC/CB/VKC), asthma, allergic rhinitis, and KC, with no significant association between other allergic diseases and KC. The severity of the allergic status is without doubt associated with a greater risk of having KC. The mechanism causing this association is still unclear. PMID- 25782405 TI - Reply: To PMID 25811730. PMID- 25782406 TI - The association between heart rate reactivity and fluid intelligence in children. AB - This study aimed to examine (a) whether findings of increased cardiovascular reactivity in relation to cognitive ability seen in infants, young adults and the elderly can be extended to middle childhood and (b) which specific aspect(s) of intelligence is related to cardiovascular reactivity. We examined cardiovascular activity in 340 8- and 9-year-old children during a number judgment task and measured fluid and crystallized IQ using the WISC-IV (Wechsler, 2003). Regression analyses revealed that heart rate (HR) reactivity was positively associated with fluid intelligence and perceptual reasoning in particular, after controlling for the effects of sex, age, task performance, social adversity, and resting HR. Intelligence scores were not associated with respiratory sinus arrhythmia (RSA) reactivity. Findings are consistent with prior literature in infants and older populations and for the first time suggest that the association between HR reactivity and cognitive ability is specific for fluid reasoning. PMID- 25782407 TI - The temporal dynamics of emotional acceptance: Experience, expression, and physiology. AB - Emotional acceptance has begun to attract considerable attention from researchers and clinicians alike. It is not yet clear, however, what effects emotional acceptance has on early emotion response dynamics. To address this question, participants (N = 37) were shown emotional pictures and cued either to simply attend to them, or to accept or suppress their emotional responses. Continuous measures of emotion experience, expressive behavior, and autonomic responses were obtained. Results indicated that, compared to no regulation, acceptance led to more positive emotions, transiently enhanced expressivity, and lowered respiratory rate. Compared to suppression, acceptance led to more positive emotions, stronger expressivity, and smaller changes in heart rate, blood pressure, and pulse amplitude, as well as greater oxygenation. Acceptance and suppression thus have opposite effects on emotional response dynamics. Because acceptance enhances positive emotion experience and expression, this strategy may be particularly useful in facilitating social interactions. PMID- 25782408 TI - Generic Clopidogrel Besylate in the Secondary Prevention of Atherothrombotic Events: A 6-month Follow-up of a Randomised Clinical Trial. AB - BACKGROUND: The aim of the present interim analysis was to compare the clinical efficacy and safety of the generic clopidogrel besylate (CB) with the innovator clopidogrel hydrogen sulphate (CHS) salt in patient groups eligible to receive clopidogrel. METHODS: A 2-arm, multicenter, open-label, phase 4 clinical trial. Consecutive patients (n=1,864) were screened and 1,800 were enrolled in the trial and randomized to CHS (n=759) or CB (n=798). Primary efficacy end point was the composite of myocardial infarction, stroke or death from vascular causes, and primary safety end point was rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. RESULTS: At 6-months follow-up no differences were observed between CB and CHS in primary efficacy end point (OR, 0.80; 95% CI, 0.37 to 1.71; p=0.57). Rates of BARC-1,-2,-3a and -5b bleeding were similar between the two study groups whereas no bleeding events according to BARC 3b, -3c, -4 and -5a were observed in either CHS or CB group. CONCLUSION: The clinical efficacy and safety of the generic CB is similar to that of the innovator CHS salt, thus, it can be routinely used in the secondary prevention of atherothrombotic events for a period of at least 6 months. (Salts of Clopidogrel: Investigation to ENsure Clinical Equivalence, SCIENCE study Clinical Trials.gov Identifier: NCT02126982). PMID- 25782409 TI - Erratum to: Dual-reporter surrogate systems for efficient enrichment of genetically modified cells. PMID- 25782412 TI - Labour promises to abolish competition in NHS and promote "true integration". PMID- 25782410 TI - Food odors trigger an endocrine response that affects food ingestion and metabolism. AB - Food odors stimulate appetite and innate food-seeking behavior in hungry animals. The smell of food also induces salivation and release of gastric acid and insulin. Conversely, sustained odor exposure may induce satiation. We demonstrate novel effects of food odors on food ingestion, metabolism and endocrine signaling in Drosophila melanogaster. Acute exposure to attractive vinegar odor triggers a rapid and transient increase in circulating glucose, and a rapid upregulation of genes encoding the glucagon-like hormone adipokinetic hormone (AKH), four insulin like peptides (DILPs) and some target genes in peripheral tissues. Sustained exposure to food odors, however, decreases food intake. Hunger-induced strengthening of synaptic signaling from olfactory sensory neurons (OSNs) to brain neurons increases food-seeking behavior, and conversely fed flies display reduced food odor sensitivity and feeding. We show that increasing the strength of OSN signaling chronically by genetic manipulation of local peptide neuromodulation reduces feeding, elevates carbohydrates and diminishes lipids. Furthermore, constitutively strengthened odor sensitivity altered gene transcripts for AKH, DILPs and some of their targets. Thus, we show that food odor can induce a transient anticipatory endocrine response, and that boosted sensitivity to this odor affects food intake, as well as metabolism and hormonal signaling. PMID- 25782413 TI - Adam's heart failure-lessons in communication. PMID- 25782411 TI - The novel role of miRNAs for tamoxifen resistance in human breast cancer. AB - The selective estrogen receptor modulator tamoxifen is the most commonly used treatment for patients with ER-positive breast cancer. However, tumor cells often develop resistance to tamoxifen therapy, which is a major obstacle limiting the success of breast cancer treatment. miRNAs, as oncogenic or tumor suppressor genes, regulate the expression and function of their related target genes to affect the biological behaviors of cancer cells, including cancer initiation, progression, metastasis, and therapeutic resistance. In detail, many miRNAs associated with breast cancer tamoxifen resistance have been identified, which offer new targets for breast cancer therapy. Here, we review the miRNAs involved in regulation of tamoxifen resistance in human breast cancer and the mechanism of how the modulation of miRNAs may regulate the sensitivity of breast cancer cells to tamoxifen. We also discuss the future prospects of studies about miRNAs in regulation of tamoxifen resistance and miRNA-based therapeutics for tamoxifen resistance breast cancer patients. PMID- 25782414 TI - Implant-Based Breast Reconstruction in Patients with Connective Tissue Disease: A Case Report Demonstrating Safety and Efficacy in Marfan Syndrome. PMID- 25782415 TI - The genetic truth of surrogate parentage. AB - Old family laws presume that the husband is the father of any child born to a married couple; a socio-legal fiction. A social and biological father is presumed to be one and the same. The cocoon of legitimacy protects marriage but the child born outside valid marriage is recognised as 'illegitimate'. Assisted reproduction technologies strengthened reproductive rights but confuse purity of lineage and genetically divorce socio-legal parentage from biological parentage. The lesbian, gay, bisexual, and transgender reproductive rights, surrogacy, gamete donation, delayed pregnancies using cryopreserved embryos, single parentage, virgin mothers (virgin birth), live-in relationship are increasingly recognised under the cover of human dignity but obscure parentage. In contrast to parental rights of reproductive autonomy, equity demands the child's right to know its biological parentage, recognised under Article 7 of the UN Convention on the Rights of the Child, 1989. DNA profiling may clarify the genetic parentage with virtual certainty but with multiple limitations. DNA forensics ascertains the genetic makeup of a child linking putative parents irrespective of any social relationship between them. The right to know biological linkages gained paramount significance in cases like displacement, adoption, child trafficking and variants of cross-genetic in vitro fertilization including complete surrogacy. The 'reproductive tourism' promotes crossing borders and bodies, enabling conception in the countries with extreme religious and legal barriers. PMID- 25782416 TI - Importance of pharmacokinetic studies in the management of acquired factor X deficiency. AB - Up to 14% of individuals with systemic AL amyloidosis develop acquired factor X deficiency, which occurs due to adsorption of factor X onto amyloid fibrils. Although baseline factor X levels are not predictive of bleeding risk in these patients, serious hemorrhagic complications can occur, particularly during invasive procedures. Optimal management strategies to attenuate bleeding risk in these patients are unknown. We describe our experience in the management of acquired factor X deficiency, secondary to systemic AL amyloidosis, in a case series of three patients who received prothrombin complex concentrates (PCCs) for treatment and prevention of bleeding events. We performed a retrospective review extracting information on baseline demographics, laboratory data, pharmacokinetic (PK) studies, and clinically documented bleeding events. Our case series demonstrates that individuals with acquired factor X deficiency secondary to amyloidosis have variable laboratory and clinical responses to PCCs. This is likely due to distinct amyloid loads and fibril sequences, leading to different binding avidities for factor X. Our data emphasize the importance of performing PK testing prior to any invasive procedures to determine the dose and frequency interval to achieve adequate factor X levels for hemostasis, given the variable response between individuals. PMID- 25782417 TI - Security of quantum digital signatures for classical messages. AB - Quantum digital signatures can be used to authenticate classical messages in an information-theoretically secure way. Previously, a novel quantum digital signature for classical messages has been proposed and gave an experimental demonstration of distributing quantum digital signatures from one sender to two receivers. Some improvement versions were subsequently presented, which made it more feasible with present technology. These proposals for quantum digital signatures are basic building blocks which only deal with the problem of sending single bit messages while no-forging and non-repudiation are guaranteed. For a multi-bit message, it is only mentioned that the basic building blocks must be iterated, but the iteration of the basic building block still does not suffice to define the entire protocol. In this paper, we show that it is necessary to define the entire protocol because some attacks will arise if these building blocks are used in a naive way of iteration. Therefore, we give a way of defining an entire protocol to deal with the problem of sending multi-bit messages based on the basic building blocks and analyse its security. PMID- 25782418 TI - Erratum to: platelet apoptosis in patients with acute coronary syndromes. PMID- 25782419 TI - Controlling radical formation in the photoactive yellow protein chromophore. AB - To understand how photoactive proteins function, it is necessary to understand the photoresponse of the chromophore. Photoactive yellow protein (PYP) is a prototypical signaling protein. Blue light triggers trans-cis isomerization of the chromophore covalently bound within PYP as the first step in a photocycle that results in the host bacterium moving away from potentially harmful light. At higher energies, photoabsorption has the potential to create radicals and free electrons; however, this process is largely unexplored. Here, we use photoelectron spectroscopy and quantum chemistry calculations to show that the molecular structure and conformation of the isolated PYP chromophore can be exploited to control the competition between trans-cis isomerization and radical formation. We also find evidence to suggest that one of the roles of the protein is to impede radical formation in PYP by preventing torsional motion in the electronic ground state of the chromophore. PMID- 25782420 TI - Optimal waist-to-height ratio cutoff values for predicting cardio-metabolic risk in Han and Uygur adults in northwest part of China. AB - BACKGROUND/OBJECTIVES: Optimal obesity indices in predicting cardio-metabolic risk are less studied in Asian. We evaluated optimal waist-to-height ratio (WHtR) for predicting hypertension, dyslipidemia and diabetes in Han and Uygur populations in Xinjiang, a northwest part of China. SUBJECTS/METHODS: This study involved 5603 Han and 4657 Uyghur participants. Anthropometric data, blood pressure, serum total cholesterol (TC), triglyceride, low-density lipoprotein, high-density lipoprotein and fasting glucose were determined. The cutoff values of WHtR were calculated; the relation between WHtR and prevalence of cardio metabolic risks was evaluated. RESULTS: There was a positive correlation between WHtR and blood pressure, TC, triglycerides and fasting glucose in both Han and Uygur participants (all P<0.001). The prevalence of hypertension, dyslipidemia and diabetes was higher with increased WHtR for both ethnic groups after adjusted by age. Calculated cutoff values of WHtR for predicting hypertension, dyslipidemia, diabetes or ? 2 of these risk factors were 0.54 for both men and women in Han and 0.55 in male and 0.57 in female Uygur participants. A significant difference in blood pressure, triglycerides and fasting glucose between subgroups with WHtR either above or below the cutoff values was observed in both men and women of the two ethnicities. CONCLUSIONS: The optimal cutoff value of WHtR is a useful screen tool for predicting cardio-metabolic risks in Han and Uygur population in Xinjiang, northwest part of China. PMID- 25782421 TI - Vitamin D status during pregnancy: time for a more unified approach beyond borders? AB - Maternal hypovitaminosis D during pregnancy has been associated with a plethora of adverse health effects on the offspring. Maternal vitamin D status during pregnancy is affected by local climatic conditions. The aim of this article was to report on difficulties related to the heterogeneity of studies available in current literature on vitamin D status during pregnancy and discuss the incorporation of geophysical data in future studies, in an attempt to optimize their design and facilitate their interpretation. We focused on current vitamin D trials during pregnancy and their association with local regional climatic condition in geographical regions such as the Mediterranean basin based on our perspective on the field. Conduction of studies from areas with similar geophysical conditions is necessary, in order to extend our knowledge with respect to the question of which populations and under which circumstances would benefit most from vitamin D supplementation. Future vitamin D studies could benefit from the adoption of a unified concept minimizing these variations by selecting populations residing in areas with similar geophysical conditions adjusting also for their social and dietary habits. PMID- 25782423 TI - Refeeding encephalopathy revisited: Reply to Tasci et al. PMID- 25782422 TI - Vitamin D3 seems more appropriate than D2 to sustain adequate levels of 25OHD: a pharmacokinetic approach. AB - BACKGROUND/OBJECTIVES: The superiority of cholecalciferol (D3) over ergocalciferol (D2) in sustaining serum 25-hydroxy vitamin D (25OHD) levels is controversial. To compare D2 with D3 we performed a single-blind, placebo controlled randomized trial spanning 11 weeks. SUBJECTS/METHODS: Healthy volunteers (n=33, aged 33.4+/-6 years) were divided into three groups (n=11, each): D2, D3 and placebo. Treatment started with a loading dose (100,000 IU) followed by 4800 IU/day (d) between d7 and d20 and follow-up until d77. Serum samples were obtained at baseline and at days 3, 7, 14, 21, 35, 49, 63 and 77. RESULTS: Baseline 25OHD values in the D2 group were lower than those in the D3 and placebo groups (P<0.01). Placebo 25OHD levels never changed. As after the loading dose both D2 and D3 groups had reached similar 25OHD levels, we tested equivalence of the area under the concentration * time curve (AUC) between d7 and d77. The AUC was 28.6% higher for D3 compared with D2, and both were higher with respect to placebo. At d77, D2 25OHD levels were higher than those at baseline, but similar to placebo; both were lower than D3 (P<0.04). According to raw data, the elimination half-life of 25OHD was 84 and 111 days under D2 and D3 supplementation, respectively; after subtracting the placebo values, the corresponding figures were 33 and 82 days. CONCLUSIONS: D2 and D3 were equally effective in elevating 25OHD levels after a loading dose. In the long term, D3 seems more appropriate for sustaining 25OHD, which could be relevant for classic and non-classic effects of vitamin D. PMID- 25782424 TI - The role of computed tomography in evaluating body composition and the influence of reduced muscle mass on clinical outcome in abdominal malignancy: a systematic review. AB - It is estimated that there were 3.45 million new cases and 1.75 million deaths from cancer in Europe in 2012. Colorectal cancer was one of the most common cancers, accounting for 13% of new cases and 12.2% of all deaths. Conditions causing reduced muscle mass, such as sarcopenia, can increase the morbidity and mortality of people with cancer. Computed tomography (CT) scans can provide accurate, high-quality information on body composition, including muscle mass. To date, there has been no systematic review on the role of CT scans in identifying sarcopenia in abdominal cancer. This review aimed to examine the role of CT scans in determining the influence of reduced muscle mass on clinical outcome in abdominal cancer. A systematic review of English-language articles published in 2000 or later was conducted. Articles included cohort, randomised controlled trials and validation studies. Participants were people diagnosed with abdominal cancer who had undergone a CT scan. Data extraction and critical appraisal were undertaken. Ten cohort studies met the inclusion criteria. Seven studies demonstrated that low muscle mass was significantly associated with poor clinical outcome, with six specifically demonstrating reduced survival rates. Eight studies demonstrated that a greater number of patients (27.3-66.7%) were identified as sarcopenic using CT scans compared with numbers identified as malnourished using body mass index. CT scans can identify reduced muscle mass and predict negative cancer outcomes in people with abdominal malignancies, where traditional methods of assessment are less effective. PMID- 25782425 TI - Muscle function-dependent sarcopenia and cut-off values of possible predictors in community-dwelling Turkish elderly: calf circumference, midarm muscle circumference and walking speed. AB - BACKGROUND/OBJECTIVES: The aim of this study was to determine the prevalence of muscle strength-based sarcopenia and to determine possible predictors. SUBJECTS/METHODS: This is a cross-sectional population-based study in the community-dwelling Turkish elderly. Anthropometric measurements, namely body height, weight, triceps skin fold (TSF), mid upper arm circumference (MUAC), waist circumference (WC) and calf circumference (CC), were noted. The midarm muscle circumference (MAMC) was calculated by using MUAC and TSF measurement. Sarcopenia was assessed, adjusted for body mass index (BMI) and gender, according to muscle strength. Physical performance was determined by 4 m walking speed (WS; m/s). The receiver operating curve analysis was performed to determine cut-offs of CC, MAMC and 4 m WS. RESULTS: A total of 879 elderly subjects, 50.1% of whom were female, were recruited. The mean handgrip strength (HGS) and s.d. was 24.2 (8.8) kg [17.9 (4.8) female, 30.6 (7.1) male]. The muscle function-dependent sarcopenia was 63.4% (female 73.5%, male 53.2%). The muscle mass-dependent sarcopenia for CC (<31 cm) and MAMC(<21.1 cm in males, <19.9 cm in females) was 6.7% and 7.3%, respectively. The prevalence of low 4 m WS (<= 0.8 m/s) was 81.8% (91.3% in females and 72.3% in males, respectively). We compared MAMC, CC and 4 m WS and found that AUC for 4 m WS was the best predictor of sarcopenia. CONCLUSIONS: An adequate muscle mass may not mean a reliable muscle function. Muscle function may describe sarcopenia better compared with muscle mass. The CC, MAMC and 4 m WS cut-offs may be used to assess sarcopenia in certain age groups. PMID- 25782426 TI - Nutritional impact of sodium reduction strategies on sodium intake from processed foods. AB - BACKGROUND/OBJECTIVES: Sodium intake in the Netherlands is substantially above the recommended intake of 2400 mg/day. This study aimed to estimate the effect of two sodium reduction strategies, that is, modification of the composition of industrially processed foods toward the technologically feasible minimum level or alteration of consumers' behavior on sodium intake in the Netherlands. SUBJECTS/METHODS: Data from the Dutch National Food Consumption Survey (2007 2010) and the Food Composition Table (2011) were used to estimate the current sodium intake. In the first scenario, levels in processed foods were reduced toward their technologically feasible minimum level (sodium reduction in processed foods scenario). The minimum feasible levels were based on literature searches or expert judgment. In the second scenario, foods consumed were divided into similar food (sub)groups. Subsequently, foods were replaced by low-sodium alternatives (substitution of processed foods scenario). Sodium intake from foods was calculated based on the mean of two observation days for the current food consumption pattern and the scenarios. RESULTS: Sodium levels of processed foods could be reduced in most food groups by 50%, and this may reduce median sodium intake from foods by 38% (from 3042 to 1886 mg/day in adult men). Substitution of foods may reduce sodium intake by 47% (from 3042 to 1627 mg/day in adult men), owing to many low-sodium alternatives within food groups. CONCLUSIONS: In the Netherlands, reduction of sodium intake by modification of food composition or by alteration of behavior may substantially reduce the median sodium intake from foods below the recommended sodium intake. PMID- 25782427 TI - The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a double-blind randomized controlled clinical trial. AB - BACKGROUND/OBJECTIVES: A relationship between osteocalcin (OC) levels and factors associated with energy metabolism and insulin resistance has been reported recently. The aim of this study was to investigate whether modulation of ostecalcin isoforms via vitamin K1 supplementation would affect glucose metabolism or insulin sensitivity in prediabetic and premenopause women. SUBJECTS/METHODS: Eighty-two prediabetic women were randomized to consume vitamin K1 supplement (n = 39) or placebo (n = 43) for 4 weeks. Participants in the vitamin K1 supplement group received one pearl softgel capsule containing 1000 MUm of phylloquinone, and the placebo group received one placebo capsule daily for 4 weeks. Blood samples were collected at baseline and after the 4-week intervention period to quantify carboxylated OC (cOC), undercarboxylated OC (ucOC) and relevant variables. RESULTS: Phylloquinone supplementation increased the serum levels of cOC and decreased ucOC, compared with placebo (12.53 +/- 5.95 compared with 7.43 +/- 4.85 ng/ml and 2.47 +/- 1.91 compared with 4.79 +/- 2.43 ng/ml, respectively; P < 0.001). Furthermore, intake of phylloquinone supplement led to significant decreases in %ucOC (17.97 +/- 12.24 compared with 43.80 +/- 19.86) and 2-h post-oral glucose tolerance test (OGTT) glucose (7.32 +/- 1.50 compared with 8.62 +/- 1.45 mmol/l), and 2-h post-OGTT insulin level (80.34 +/- 42.24 compared with 112.43 +/- 53.19 MUIU/ml) and increased insulin sensitivity index (2.46 +/- 0.71 compared with 1.75 +/- 0.61) compared with placebo. Overall, a significant association was found between changes in %ucOC and changes in 2-h post-OGTT glucose (r = 0.308, P = 0.028). CONCLUSIONS: The results of this study demonstrated that vitamin K1 supplementation for 4 weeks did not affect insulin resistance in premenopausal and prediabetic women but had beneficial effects on glycemic status and insulin sensitivity. PMID- 25782428 TI - Effect of whole soy and purified daidzein on ambulatory blood pressure and endothelial function--a 6-month double-blind, randomized controlled trial among Chinese postmenopausal women with prehypertension. AB - BACKGROUND/OBJECTIVES: Although observational studies suggest that soy foods or isoflavones are cardio-protective, clinical trials on whole soy or isoflavone daidzein (one major isoflavone and the precursor of equol) on blood pressure (BP) and endothelial function (EF) are few and have not been specifically conducted among equol producers, a population most likely to benefit from soy treatment. SUBJECTS/METHODS: We performed a 6-month double-blind, randomized, placebo controlled trial to examine the effect of whole soy (soy flour) or purified daidzein on BP and EF in prehypertensive or untreated hypertensive postmenopausal women verified to be equol producers. A total of 270 eligible women were recruited and randomized to either one of the three treatment groups, 40 g soy flour (whole soy group), 40 g low-fat milk powder+63 mg daidzein (daidzein group) or 40 g low-fat milk powder (active control group) daily, each given as a solid beverage powder for 6 months. The primary outcome measures were 24 h ambulatory BP (ABP) and EF assessed by flow-mediated dilation using brachial artery ultrasound. RESULTS: A total of 253 subjects completed the study according to protocol. Urinary isoflavones indicated good compliance with the interventions. Intention to treat and per-protocol analysis indicated that there was no significant difference in the 6-month changes or % changes in parameters of ABP and brachial flow-mediated dilation among the three treatment groups. A further subgroup analysis among hypertensive women (n=138) did not alter the conclusions. CONCLUSIONS: Whole soy and purified daidzein had no significant effect on BP and vascular function among equol-producing postmenopausal women with prehypertension or untreated hypertension. PMID- 25782429 TI - Influence of fruit consumption and fluoride application on the prevalence of caries and erosion in vegetarians--a controlled clinical trial. AB - BACKGROUND/OBJECTIVES: Caries and erosion are common diseases of the dental hard tissues. The influence of vegetarianism on the development of caries and erosion has scarcely been investigated in the past. The aim of the present study was to evaluate the influence of fruit consumption and topical fluoride application on the prevalence of caries and erosion in vegetarians. SUBJECTS/METHODS: In 100 vegetarians and 100 nonvegetarians, a dental examination was performed. The indices for decayed, missing, filled teeth (DMFT) and surfaces (DMFS) were determined. DMFT and DMFS were subdivided into decayed teeth (DT), filled teeth (FT), decayed surfaces (DS) and filled surfaces (FS). In addition, the hygiene index and the number of teeth with dental erosion (DE), root caries (RC) and overhanging restoration margins (ORM) were recorded. A questionnaire assessed patients' eating habits, frequency of oral hygiene, dentist visits and topical fluoride application. For statistical analysis, unpaired t-test, Mann-Whitney test and Pearson's chi-square test were applied. RESULTS: Vegetarians had significantly more DT (P<0.001), DS (P<0.001), more teeth with DE (P=0.026), RC (P=0.002) and ORM (P<0.001) than nonvegetarians. Daily consumption of fruits was significantly more prevalent (P<0.001), and topical fluoride application was less prevalent (P<0.001) in vegetarians compared with nonvegetarians. In particular, fluoride-containing toothpaste (P<0.001) and table salt (P=0.039) were less frequently used in vegetarians. CONCLUSION: The presented data suggest that vegetarians have an increased risk for caries and erosion. Topical fluoride application was shown to be effective in preventing caries, but not in preventing erosion. PMID- 25782431 TI - Lending to Parents and Insuring Children: Is There a Role for Microcredit in Complementing Health Insurance in Rural China? AB - This paper assesses the causal impact on child health of borrowing formal microcredit for Chinese rural households by exploiting a panel dataset (2000 and 2004) in a poor northwest province. Endogenous borrowing is controlled for in a dynamic regression-discontinuity design creating a quasi-experimental environment for causal inferences. There is causal relationship running from formal microcredit to improved child health in the short term, while past borrowing behaviour has no protracted impact on subsequent child health outcomes. Moreover, formal microcredit appears to be a complement to health insurance in improving child health through two mechanisms-it enhances affordability for out-of-pocket health care expenditure and helps buffer consumption against adverse health shocks and financial risk incurred by current health insurance arrangements. Government efforts in expanding health insurance for rural households would be more likely to achieve its optimal goals of improving child health outcomes if combined with sufficient access to formal microcredit. PMID- 25782430 TI - Slow early growers have more muscle in relation to adult activity: evidence from Cebu, Philippines. AB - BACKGROUND/OBJECTIVES: Adult skeletal muscle mass (SMM) protects against type 2 diabetes, but little is known about its developmental antecedents. We examined whether pace of early weight gain predicted adult SMM in a birth cohort from Cebu City, Philippines. In addition, we examined whether increases in SMM associated with adult muscle-building exercise varied according to the early growth. SUBJECTS/METHODS: Data came from 1472 participants of the Cebu Longitudinal Health and Nutrition Survey. Weight was measured at birth and at 6-month intervals through the age of 24 months. Adult SMM was estimated from anthropometric measurements when participants were 20-22-years old. Interviews provided the information on adult exercise/lifestyle habits. RESULTS: SMM (mean +/- s.d.) was 20.8 +/- 3.9 kg (men) and 13.6 +/- 3.4 kg (women). Faster early weight gain predicted a higher adult SMM. After adjustment for height and lifestyle factors, strongest associations with SMM were found for 6-12 months growth in men (beta=0.17, P=0.001) and for birth weight in women (beta=0.14, P=0.001). Individuals who had grown slowly displayed greater SMM in association with adult weightlifting, basketball playing and physically demanding forms of employment (men) or household chores (women). CONCLUSIONS: These results suggest heightened sensitivity of activity-induced muscle hypertrophy among the adults who were born light or who gained weight slowly as infants. Future research should test this finding by comparing responses of muscle mass to an intervention in slow vs fast early growers. Findings suggest that adults who display a reduced SMM following suboptimal early growth may be good candidates for new anti diabetes interventions that promote muscle-building activities. PMID- 25782432 TI - Laser all-ceramic crown removal and pulpal temperature--a laboratory proof-of principle study. AB - The objective of this proof-of-principle laboratory pilot study was to evaluate the temperature increase in the pulp chamber in a worst case scenario during Er:YAG laser debonding of all-ceramic crowns. Twenty extracted molars were prepared to receive all-ceramic IPS E.max CAD full contour crowns. The crowns were bonded to the teeth with Ivoclar Multilink Automix. Times for laser debonding and temperature rise in the pulp chamber using micro-thermocouples were measured. The Er:YAG was used with 560 mJ/pulse. The irradiation was applied at a distance of 5 mm from the crown surface. Additional air-water spray for cooling was utilized. Each all-ceramic crown was successfully laser debonded with an average debonding time of 135 +/- 35 s. No crown fractured, and no damage to the underlying dentin was detected. The bonding cement deteriorated, but no carbonization at the dentin/cement interface occurred. The temperature rise in the pulp chamber averaged 5.4 degrees +/- 2.2 degrees C. During 8 out of the 20 crown removals, the temperature rise exceeded 5.5 degrees C, lasting 5 to 43 s (average 18.8 +/- 11.6 s). A temperature rise of 11.5 degrees C occurred only once, while seven times the temperature rise was limited to 6.8 +/- 0.5 degrees C. Temperature rises above 5.5 degrees C occurred only when the laser was applied from one side and additional cooling from the side opposite the irradiation. Er:YAG laser energy can successfully be used to efficiently debond all-ceramic crowns from natural teeth. Temperature rises exceeding 5.5 degrees C only occur when an additional air/water cooling from a dental syringe is inaccurately directed. To avoid possible thermal damage and to allow further heat diffusion, clinically temperature-reduced water might be applied. PMID- 25782433 TI - Canonical Wnt signaling in the oligodendroglial lineage--puzzles remain. AB - The straightforward concept that accentuated Wnt signaling via the Wnt-receptor beta-catenin-TCF/LEF cascade (also termed canonical Wnt signaling or Wnt/beta catenin signaling) delays or blocks oligodendrocyte differentiation is very appealing. According to this concept, canonical Wnt signaling is responsible for remyelination failure in multiple sclerosis and for persistent hypomyelination in periventricular leukomalacia. This has given rise to the hope that pharmacologically inhibiting this signaling will be of therapeutic potential in these disabling neurological disorders. But current studies suggest that Wnt/beta catenin signaling plays distinct roles in oligodendrogenesis, oligodendrocyte differentiation, and myelination in a context-dependent manner (central nervous system regions, developmental stages), and that Wnt/beta-catenin signaling interplays with, and is subjected to regulation by, other central nervous system factors and signaling pathways. On this basis, we propose the more nuanced concept that endogenous Wnt/beta-catenin activity is delicately and temporally regulated to ensure the seamless development of oligodendroglial lineage cells in different contexts. In this review, we discuss the role Wnt/beta-catenin signaling in oligodendrocyte development, focusing on the interpretation of disparate results, and highlighting areas where important questions remain to be answered about oligodendroglial lineage Wnt/beta-catenin signaling. PMID- 25782434 TI - Subcomponents and connectivity of the superior longitudinal fasciculus in the human brain. AB - The subcomponents of the human superior longitudinal fasciculus (SLF) are disputed. The objective of this study was to investigate the segments, connectivity and asymmetry of the SLF. We performed high angular diffusion spectrum imaging (DSI) analysis on ten healthy adults. We also conducted fiber tracking on a 30-subject DSI template (CMU-30) and 488-subject template from the Human Connectome Project (HCP-488). In addition, five normal brains obtained at autopsy were microdissected. Based on tractography and microdissection results, we show that the human SLF differs significantly from that of monkey. The fibers corresponding to SLF-I found in 6 out of 20 hemispheres proved to be part of the cingulum fiber system in all cases and confirmed on both DSI and HCP-488 template. The most common patterns of connectivity bilaterally were as follows: from angular gyrus to caudal middle frontal gyrus and dorsal precentral gyrus representing SLF-II (or dorsal SLF), and from supramarginal gyrus to ventral precentral gyrus and pars opercularis to form SLF-III (or ventral SLF). Some connectivity features were, however, clearly asymmetric. Thus, we identified a strong asymmetry of the dorsal SLF (SLF-II), where the connectivity between the supramarginal gyrus with the dorsal precentral gyrus and the caudal middle frontal gyrus was only present in the left hemisphere. Contrarily, the ventral SLF (SLF-III) showed fairly constant connectivity with pars triangularis only in the right hemisphere. The results provide a novel neuroanatomy of the SLF that may help to better understand its functional role in the human brain. PMID- 25782435 TI - Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor. AB - Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2 MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit. PMID- 25782436 TI - Monitoring sialylation levels of Fc-fusion protein using size-exclusion chromatography as a process analytical technology tool. AB - OBJECTIVE: To develop a rapid process analytical technology (PAT) tool that can measure sialic acid content of an Fc-fusion protein from cell culture samples. RESULTS: A statistical significant correlation between the sialic acid content and size-exclusion chromatography (SEC)-HPLC retention time of an Fc-fusion protein was observed when analyzing the titer of the samples. Using linear fitting analysis, the data fit the model well with R (2) = 0.985. Based on the SDS-PAGE and oligosaccharide analysis, we speculate that the amounts of the glycans could expand the structure of the Fc-fusion protein. This was manifested by the SEC-HPLC method in which proteins were separated based on its molecular size. In order to development a robust PAT method, an internal standard was used to improve the precision of the method by reducing systematic errors. We found the change of SEC retention time (delta t) and sialic acid content were highly correlated (R (2) = 0.992). This method was further validated by a 1500 l production process. CONCLUSION: SEC-HPLC is a promising PAT tool to monitor the sialic acid content of Fc-fusion protein during biomanufacturing or medium optimization processes. PMID- 25782437 TI - Bivalirudin Versus Heparin Plus Glycoprotein IIb/IIIa Inhibitors in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials. AB - Diabetes mellitus (DM) is a pro-thrombotic state with enhanced thrombin generation and platelet reactivity. For most patients undergoing percutaneous coronary intervention (PCI), bivalirudin demonstrates efficacy comparable with that of heparin and glycoprotein IIb/IIIa inhibitors (GPIs). Yet, because of their pro-thrombotic condition, we hypothesized that patients with DM may benefit from more aggressive dual antithrombin and antiplatelet therapy. The aim of this paper was to provide a systematic review comparing outcomes of PCI with bivalirudin versus heparin plus GPI in patients with DM using meta-analytical techniques. Eligible studies needed to have reported a subgroup analysis of outcomes among diabetic patients. Six trials comprising 5924 diabetic patients were eligible. At 30 days, bivalirudin was associated with a reduction in net adverse cardiac events [relative risk (RR) 0.81, 95 % confidence interval (CI) 0.70-0.93, p = 0.002] and major bleeds (RR 0.68, 95 % CI 0.49-0.95; p = 0.02), with no difference in composite ischemia (RR 0.92, 95 % CI 0.74-1.14; p = 0.43) or mortality (RR 0.71, 95 % CI 0.45-1.13; p = 0.15). At 1 year, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.73, 95 % CI 0.54-1.00, p = 0.05) despite similar composite ischemia (RR 1.02, 95 % CI 0.56 1.21, p = 0.811). In conclusion, thrombin inhibition with bivalirudin alone was associated with reduced 30-day major bleeding and 1-year all-cause mortality compared with heparin plus GPI in diabetic patients undergoing PCI. PMID- 25782438 TI - Neurophysiological modeling of bladder afferent activity in the rat overactive bladder model. AB - The overactive bladder (OAB) is a syndrome-based urinary dysfunction characterized by "urgency, with or without urge incontinence, usually with frequency and nocturia". Earlier we developed a mathematical model of bladder nerve activity during voiding in anesthetized rats and found that the nerve activity in the relaxation phase of voiding contractions was all afferent. In the present study, we applied this mathematical model to an acetic acid (AA) rat model of bladder overactivity to study the sensitivity of afferent fibers in intact nerves to bladder pressure and volume changes. The afferent activity in the filling phase and the slope, i.e., the sensitivity of the afferent fibers to pressure changes in the post-void relaxation phase, were found to be significantly higher in AA than in saline measurements, while the offset (nerve activity at pressure ~0) and maximum pressure were comparable. We have thus shown, for the first time, that the sensitivity of afferent fibers in the OAB can be studied without cutting nerves or preparation of single fibers. We conclude that bladder overactivity induced by AA in rats is neurogenic in origin and is caused by increased sensitivity of afferent sensors in the bladder wall. PMID- 25782441 TI - Development of multiple nevi and lentigines in a child with Netherton's syndrome treated with narrowband ultraviolet B phototherapy. PMID- 25782440 TI - Bioinspired hierarchical nanotubular titania immobilized with platinum nanoparticles for photocatalytic hydrogen production. AB - A bioinspired nanocomposite composed of platinum nanoparticles and nanotubular titania was fabricated in which the titania matter was templated by natural cellulose substance. The composite possesses three- dimensional hierarchical structures, and ultrafine metallic platinum particles with sizes of ca. 2 nm were immobilized uniformly on the surfaces of the titania nanotubes. Such a nanocomposite with 1.06 wt % of platinum content shows the optimal photocatalytic hydrogen production activity from water splitting of 16.44 mmol h(-1) g(-1) , and excessive loading of platinum results in poorer photocatalytic performance. The structural integrity of the nanocomposite upon cyclic water-splitting processes results in its sufficient photocatalytic stability. PMID- 25782439 TI - Zebrafish mutants of the neuromuscular junction: swimming in the gene pool. AB - This review provides an overview of zebrafish mutants with dysfunctional acetylcholine receptors or related proteins at the neuromuscular junction (NMJ). The NMJ, which has served as the classical model of the chemical synapse, uses acetylcholine as the neurotransmitter, and mutations of proteins involved in the signaling cascade lead to a variety of behavioral phenotypes. Mutants isolated after random chemical mutagenesis screening are summarized, and advances in the field resulting from these mutants are discussed. PMID- 25782442 TI - Expanding the scope of strained-alkyne chemistry: a protection-deprotection strategy via the formation of a dicobalt-hexacarbonyl complex. AB - A protection-deprotection strategy for strained alkynes used for bioorthogonal chemistry is reported. A strained alkyne can be protected with dicobalt octacarbonyl and we demonstrate for the first time that a strained alkyne can be re-formed and isolated under mild reaction conditions for further bioorthogonal reactivity. The protection-deprotection strategy herein reported will expand the versatility of strained alkynes for the preparation of substrates in chemical biology and materials applications. PMID- 25782443 TI - Influence of cryopreservation and mechanical stimulation on equine Autologous Conditioned Plasma (ACP(r)). AB - OBJECTIVE: To determine the influence of cryopreservation at two different temperatures on platelet concentration, growth factor (GF) levels and platelet activation parameters in equine ACP(r); moreover, to determine if adding mechanical ACP(r) stimulation to freeze-thaw activation amplifies GF release from platelets. MATERIAL AND METHODS: Firstly, blood from five horses was used to prepare ACP(r). Platelet, platelet derived growth factor BB (PDGF-BB) and transforming growth factor beta1 (TGF-beta1) concentrations as well as mean platelet volume (MPV) and mean platelet component (MPC) were determined in fresh and corresponding ACP(r) samples after 2 months cryopreservation at -20 degrees C and -80 degrees C, respectively. Secondly, ACP(r) was prepared from blood of nine horses. Half of ACP(r) was activated using one freeze-thaw-cycle at -20 degrees C, whereas the rest was first vortexed. Their PDGF-BB and TGF-beta1 concentrations were subsequently determined. RESULTS: Platelet concentration significantly decreased after -80 degrees C cryopreservation. PDGF-BB level augmented significantly after both storage methods, whereas TGF-beta1 concentration was not significantly altered. MPV significantly increased after 20 degrees C cryopreservation. Both storage regimens induced a significant MPC decrease. No significant differences in GF concentrations between the vortexed and non-vortexed samples were detected. DISCUSSION: Both cryopreservation methods induced platelet activation, but storage at -80 degrees C apparently harmed the platelets without generating higher GF release than -20 degrees C. The mechanical stimulation process could not enhance GF release in subsequently frozen-thawed ACP(r). CONCLUSION AND CLINICAL RELEVANCE: Storage of ACP(r) at -20 degrees C could be useful in equine practice, but, before this procedure can be recommended, further qualitative tests are needed. The mechanical stimulation technique should be adjusted in order to increase platelet activation. PMID- 25782444 TI - Development of reporter gene imaging techniques for long-term assessment of human circulating angiogenic cells. AB - The use of biomaterials and tracking the long-term fate of the transplanted cells is expected to help improve the clinical translation of cell therapies for cardiac regeneration. To this end, reporter gene strategies are promising for monitoring the fate of cells transplanted with or without a delivery biomaterial; however, their application with primary adult progenitor cells (such as human circulating angiogenic cells (CACs)) has not been extensively evaluated. In this study, human CACs were transduced with reporter genes via one of two lentiviral (LV) vectors: LV-GFP-iresTK or LV-Fluc-RFP-tTK. The mean transduction efficiency was 15% (LV-GFP-iresTK) and 13% (LV-Fluc-RFP-tTK) at multiplicities of infection (MOI) of 10 and 50, respectively. Western blot analysis confirmed HSV1-tk protein expression in transduced CACs. There was no significant difference in viability between the transduced CACs and the untreated controls at a MOI of 50 or below. However, a reduction was observed in cell viability of CACs transduced with LV Fluc-RFP-tTK at an MOI of 100. Cell migration and angiogenic potential were not affected by transduction protocol. After 4 weeks, 80.3 +/- 8.4% of the labeled cells continued to express the reporters and could be visualized when embedded within a collagen matrix scaffold. Therefore, quiescent human CACs can be stably transduced to express reporter genes without affecting their function. This reporter gene technique is a promising approach to be further tested for tracking transplanted CACs (+/-delivery matrix) non-invasively and longitudinally. PMID- 25782445 TI - Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome. AB - Lynch syndrome (LS) is an inherited form of colorectal cancer (CRC) caused by germline mutations in the mismatch repair (MMR) genes. It accounts for approximately 5% of all CRCs. The prevalence of LS among US Hispanics is unknown. The objective of this study was to describe the germline mutations of LS in Caribbean Hispanics from Puerto Rico and Dominican Republic. A total of 89 subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. A total of 35 individuals with deficient MMR system were identified: 22 had MMR mutations and 13 had tumors with absent MMR protein expression. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7%) mutations, followed by MLH1 (25.0%). One mutation was identified in MSH6 (8.3%). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutation positive individuals were found to be more likely to have a prominent family history of CRC and tumors located at the proximal colon. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC and LS associated cancers. Furthermore, insurance coverage for genetic testing was found to be limited in the study population with 65.1% of the individuals recruited were denied coverage. This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients. PMID- 25782446 TI - Soft network composite materials with deterministic and bio-inspired designs. AB - Hard and soft structural composites found in biology provide inspiration for the design of advanced synthetic materials. Many examples of bio-inspired hard materials can be found in the literature; far less attention has been devoted to soft systems. Here we introduce deterministic routes to low-modulus thin film materials with stress/strain responses that can be tailored precisely to match the non-linear properties of biological tissues, with application opportunities that range from soft biomedical devices to constructs for tissue engineering. The approach combines a low-modulus matrix with an open, stretchable network as a structural reinforcement that can yield classes of composites with a wide range of desired mechanical responses, including anisotropic, spatially heterogeneous, hierarchical and self-similar designs. Demonstrative application examples in thin, skin-mounted electrophysiological sensors with mechanics precisely matched to the human epidermis and in soft, hydrogel-based vehicles for triggered drug release suggest their broad potential uses in biomedical devices. PMID- 25782447 TI - Dynamic Autoregulatory Response After Aneurysmal Subarachnoid Hemorrhage and Its Relation to Angiographic Vasospasm and Clinical Outcome. AB - BACKGROUND: Impaired cerebral autoregulation (CA) is increasingly recognized to contribute to sequelae after aneurysmal subarachnoid hemorrhage (SAH). The current study characterizes the course of the dynamic autoregulation index (ARI) during the first 8 days after SAH and its coherence with angiographic vasospasm (VS) and clinical outcome. METHODS: Fifty-one patients with SAH were prospectively included within 48 h after the ictus. The ARI was determined daily for each hemisphere with the thigh cuff test. The degree of cerebral VS was evaluated based on a baseline digital subtraction angiography (DSA) after the ictus and a follow-up DSA on day 8. The clinical outcome was determined by the Modified Rankin Scale (mRS), the Glasgow Outcome Scale Extended (GOSE), and the National Institute of Health Stroke Scale (NIHSS) at discharge from the intensive care unit. RESULTS: Impaired CA significantly correlated with unfavorable clinical outcome scores (mRS, p = 0.0021; GOSE, p = 0.0027; NIHSS, p = 0.0091). ARI-values of patients with a favorable clinical outcome (mRS 0-3) showed a significant improvement during the first 8 days (+0.1964/day; p = 0.0148) compared to a significant decrease of ARI-values in patients with an unfavorable clinical outcome (-0.2976/day; p = 0.0182). The degree of CA impairment significantly correlated with the severity of VS in the middle cerebral artery (p = 0.0184). CONCLUSIONS: Early deterioration of CA significantly correlates with unfavorable clinical outcome and severity of angiographic vasospasm. Dynamic CA measurements might represent an important tool in stratifying therapy guidelines in patients after SAH. PMID- 25782449 TI - Organellar genome copy number variation and integrity during moderate maturation of roots and leaves of maize seedlings. AB - Little information is available about organellar genome copy numbers and integrity in plant roots, although it was reported recently that the plastid and mitochondrial genomes were damaged under light, resulting in non-functional fragments in green seedling leaves in a maize line. In the present study, we investigated organellar genome copy numbers and integrity, after assessing the cellular ploidy, in seedling leaves and roots of two elite maize (Zea mays) cultivars using both long-fragment polymerase chain reaction (long-PCR) and real time quantitative polymerase chain reaction (qPCR, a type of short-PCR). Since maize leaf and root cells are mainly diploid according to chromosome number counting and the literature, the DNA amount ratio between the organellar genomes and the nuclear genome could be used to estimate average organellar genome copy numbers per cell. In the present study, both long-PCR and qPCR analyses found that green leaves had dramatically more plastid DNA and less mitochondrial DNA than roots had in both cultivars. The similarity in results from long-PCR and qPCR suggests that green leaves and roots during moderate maturation have largely intact plastid and mitochondrial genomes. The high resolution of qPCR led to the detection of an increase in copies in the plastid genome and a decrease in copies in the analyzed mitochondrial sub-genomes during the moderate maturation of seedling leaves and roots. These results suggest that green seedling leaves and roots of these two maize cultivars during moderate maturation had essentially intact organellar genomes, an increased copy number of the plastid genome, and decreased copy numbers of certain mitochondrial sub-genomes. PMID- 25782448 TI - Gene targeting in the oil-producing fungus Mortierella alpina 1S-4 and construction of a strain producing a valuable polyunsaturated fatty acid. AB - To develop an efficient gene-targeting system in Mortierella alpina 1S-4, we identified the ku80 gene encoding the Ku80 protein, which is involved in the nonhomologous end-joining pathway in genomic double-strand break (DSB) repair, and constructed ku80 gene-disrupted strains via single-crossover homologous recombination. The Deltaku80 strain from M. alpina 1S-4 showed no negative effects on vegetative growth, formation of spores, and fatty acid productivity, and exhibited high sensitivity to methyl methanesulfonate, which causes DSBs. Dihomo-gamma-linolenic acid (DGLA)-producing strains were constructed by disruption of the Delta5-desaturase gene, encoding a key enzyme of bioconversion of DGLA to ARA, using the Deltaku80 strain as a host strain. The significant improvement of gene-targeting efficiency was not observed by disruption of the ku80 gene, but the construction of DGLA-producing strain by disruption of the Delta5-desaturase gene was succeeded using the Deltaku80 strain as a host strain. This report describes the first study on the identification and disruption of the ku80 gene in zygomycetes and construction of a DGLA-producing transformant using a gene-targeting system in M. alpina 1S-4. PMID- 25782450 TI - Promoting positive human development and social justice: Integrating theory, research and application in contemporary developmental science. AB - The bold claim that developmental science can contribute to both enhancing positive development among diverse individuals across the life span and promoting social justice in their communities, nations and regions is supported by decades of theoretical, methodological and research contributions. To explain the basis of this claim, I describe the relational developmental systems (RDS) metamodel that frames contemporary developmental science, and I present an example of a programme of research within the adolescent portion of the life span that is associated with this metamodel and is pertinent to promoting positive human development. I then discuss methodological issues associated with using RDS-based models as frames for research and application. Finally, I explain how the theoretical and methodological ideas associated with RDS thinking may provide the scholarly tools needed by developmental scientists seeking to contribute to human thriving and to advance social justice in the Global South. PMID- 25782451 TI - Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients. AB - AIMS: Despite numerous studies identifying specific microRNA (miRNA) expression profiles associated with atrial fibrillation (AF), changes in plasma miRNA expression in pre- and post-operative AF patients who have received catheter ablation, remain poorly characterized. This study aimed to reveal disease-related biomarkers by detecting plasma miRNA expression in AF patients, and examining the levels of AF-specific miRNAs in patients after catheter ablation, in order to help gauge therapeutic effects and assess prognosis. METHODS AND RESULTS: A total of 100 Han Chinese patients with AF who had received catheter ablation, and 100 healthy individuals, were sequentially recruited to the study. Atrial fibrillation-specific plasma miRNAs were detected by Solexa sequencing and quantitative reverse transcription polymerase chain reaction. The expression levels of AF-specific miRNAs were also investigated in 40 post-operative patients (24-48 h) and 20 patients followed up (58.52 +/- 36.00 days) after catheter ablation, to explore changes in miRNA expression. The expressions of miR-409-3p and miR-432 in the plasma of AF patients were lower than healthy individuals. In binary logistic regression analyses, reduced miR-409-3p and miR-432 levels were independently associated with AF (95% confidence interval: 1.02-2.22 and 1.09 2.43, P = 0.040 and 0.018, respectively). The levels of miR-409-3p and miR-432 showed no significant difference between post-operative patients and healthy individuals (P = 0.411 and 0.681, respectively), or between followed-up patients and healthy individuals (P = 0.720 and 0.073, respectively). CONCLUSION: We suggest that plasma miR-409-3p and miR-432 are potential markers of AF, and catheter ablation restores their decreased levels in AF patients. PMID- 25782452 TI - Pulmonary vein exit block despite recovery of entry conduction during redo ablation for atrial fibrillation. PMID- 25782453 TI - Isolated transient aphasia at emergency presentation is associated with a high rate of cardioembolic embolism. AB - OBJECTIVE: A cardiac source is often implicated in strokes where the deficit includes aphasia. However, less is known about the etiology of isolated aphasia during transient ischemic attack (TIA). Our objective was to determine whether patients with isolated aphasia are likely to have a cardioembolic etiology for their TIA. METHODS: We prospectively studied a cohort of TIA patients in eight tertiary-care emergency departments. Patients with isolated aphasia were identified by the treating physician at the time of emergency department presentation. Patients with dysarthria (i.e., a phonation disturbance) were not included. Potential cardiac sources for embolism were defined as atrial fibrillation on history, electrocardiogram, Holter monitor, atrial fibrillation on echocardiography, or thrombus on echocardiography. RESULTS: Of the 2,360 TIA patients identified, 1,155 had neurological deficits at the time of the emergency physician assessment and were included in this analysis, and 41 had isolated aphasia as their only neurological deficit. Patients with isolated aphasia were older (73.9+/-10.0 v. 67.2+/-14.5 years; p=0.003), more likely to have a history of heart failure (9.8% v. 2.6%; p=0.027), and were twice as likely to have any cardiac source of embolism (22.0% v. 10.6%; p=0.037). CONCLUSIONS: Isolated aphasia is associated with a high rate of cardioembolic sources of embolism after TIA. Emergency patients with isolated aphasia diagnosed with a TIA warrant a rapid and thorough assessment for a cardioembolic source. PMID- 25782454 TI - Implication of corticotropic hormone axis in eating behaviour pattern in obese and type 2 diabetic participants. AB - In Algeria, eating behaviour has been increasingly deviated from its traditional Mediterranean diet to modern fast food style. The present study examines the interactions between eating behaviour pattern (EBP), corticotropic hormone axis and the metabolic syndrome. Our Algerian population cohort comprised of 410 participants (130 obese, 170 type 2 diabetics and 110 healthy participants). The EBP was evaluated by the Three-Factor Eating Questionnaire test. The anthropometric and metabolic parameters (glucose, TAG, HDL, LDL and cholesterol) and the concentrations of hormones (insulin, adrenocorticotropin hormone (ACTH), cortisol and growth hormone) were determined by biometrics, spectrophotometry and RIA, respectively. Multivariate analyses showed a high correlation between the EBP and the metabolic syndrome, particularly between insulin-resistant state and hypertrophy of visceral adipose tissue. Compared with healthy participants, obese ones showed the hyperphagic type of EBP, i.e. disinhibition and hunger disorders. Conversely, the diabetics showed both the hypophagic and hyperphagic type of EBP. In diabetic and obese participants, cortisol and ACTH secretions were significantly altered, leading to metabolic disorders. The present study confirms the role of EBP in obesity and diabetes. PMID- 25782455 TI - The Anabaena sp. PCC 7120 Exoproteome: Taking a Peek outside the Box. AB - The interest in examining the subset of proteins present in the extracellular milieu, the exoproteome, has been growing due to novel insights highlighting their role on extracellular matrix organization and biofilm formation, but also on homeostasis and development. The cyanobacterial exoproteome is poorly studied, and the role of cyanobacterial exoproteins on cell wall biogenesis, morphology and even physiology is largely unknown. Here, we present a comprehensive examination of the Anabaena sp. PCC 7120 exoproteome under various growth conditions. Altogether, 139 proteins belonging to 16 different functional categories have been identified. A large fraction (48%) of the identified proteins is classified as "hypothetical", falls into the "other categories" set or presents no similarity to other proteins. The evidence presented here shows that Anabaena sp. PCC 7120 is capable of outer membrane vesicle formation and that these vesicles are likely to contribute to the exoproteome profile. Furthermore, the activity of selected exoproteins associated with oxidative stress has been assessed, suggesting their involvement in redox homeostasis mechanisms in the extracellular space. Finally, we discuss our results in light of other cyanobacterial exoproteome studies and focus on the potential of exploring cyanobacteria as cell factories to produce and secrete selected proteins. PMID- 25782456 TI - Acute Effects of "Hyping" a Black&Mild Cigarillo. AB - INTRODUCTION: Cigars remain a widely used tobacco product among adolescent and adult populations. The appeal of a certain type of cigar, the cigarillo, may be enhanced by users' beliefs that their harm potential can be reduced by removing the inner tobacco liner before use (a.k.a. "hyping"). The purpose of this within subject study was to compare the acute effects of smoking an original cigarillo, a modified ("hyped") cigarillo, and an unlit cigarillo. METHODS: Twenty smokers (19 males, 1 female; 19 non-Hispanic blacks, 1 Hispanic "other") of at least 7 Black&Mild (B&M) cigarillos/week and at most 5 cigarettes/day completed the study. All participants reported hyping their cigarillos at least occasionally. Primary outcomes, assessed over two, 30-minute smoking bouts, included plasma nicotine, expired air carbon monoxide (CO) concentration, subjective ratings (product effects, nicotine abstinence symptoms), and puff topography. RESULTS: Mean plasma nicotine concentration increased significantly within (pre- to post bouts), but not between, original and modified B&M conditions. Mean CO concentration was significantly lower for modified, relative to original, B&M smoking at all post-administration timepoints. Both smoked conditions significantly increased ratings of positive product effects (satisfaction, pleasant) and decreased abstinence symptom magnitude; however, ratings generally did not differ between these conditions. Overall, topography outcomes did not differ between modified and original B&M smoking. CONCLUSIONS: Results are consistent with a previous report in that "hyping" may decrease users' CO, but not nicotine, exposure. While these data collectively suggest reduced exposure to CO acutely with engagement in "hyping," longer-term assessments are needed to determine the impact on individual and public health. PMID- 25782457 TI - Higher Adherence During Reimbursement of Pharmacological Smoking Cessation Treatments. AB - INTRODUCTION: In the Netherlands, pharmacologic Smoking Cessation Treatments (pSCTs) were reimbursed in 2011. In 2012 the reimbursement was discontinued. As of 2013, pSCTs were again reimbursed, provided they are accompanied by behavioral counseling. The aim of this article is to assess the impact of changes in reimbursement policy on use of-and adherence to-pSCTs. METHODS: A retrospective dispensing database analysis was performed on real-world observational data (2010 2013) from the Netherlands. Data on use and adherence was collected, in patients who were dispensed bupropion or varenicline in community pharmacies for the first time. Using the InterActionDataBase (iadb.nl), adherence per patient that initiated varenicline or bupropion was calculated by adding up all dispenses between initiation of the therapy and the 120 days thereafter. Good adherence was defined as using minimal 80% of the recommended duration and intensity of use. RESULTS: The prevalence of patients initiating pSCTs was stable at 0.4 per 1000 inhabitants per quarter during 2010. In 2011, the prevalence was on average 0.7, with peaks in the first (0.8 per 1000) and fourth (1.0 per 1000) quarters of 2011. In 2012, the prevalence was stable again at 0.3. In 2013, prevalence was on average 0.4, with a small peak in the first quarter. Adherence was 15.4% in 2010 versus 20.1% in 2011 (P = .002). In 2012, adherence was 13.9%, compared with 18.9% in 2013 (P = .008). CONCLUSIONS: Not only the likelihood of initiating pSCTs, but also the extent of adherence to these treatments, although generally low, seems higher during reimbursement. PMID- 25782459 TI - SRNT Trainee Network Spotlight. PMID- 25782458 TI - Minority Stress, Smoking Patterns, and Cessation Attempts: Findings From a Community-Sample of Transgender Women in the San Francisco Bay Area. AB - INTRODUCTION: Research has demonstrated associations between reports of minority stressors and smoking behaviors among lesbian, gay, and bisexual populations; however, little is known about how minority stressors are related to smoking behaviors and cessation attempts among transgender women. The purpose of this study was twofold: (1) to examine the associations between transgender-based discrimination and smoking patterns among a sample of transgender women; and (2) to identify barriers to smoking cessation in a sample of transgender women with a history of smoking. METHODS: A community sample of 241 transgender women completed a one-time survey. Binary and multinomial logistic regression models examined associations between minority stressors and (1) smoking behaviors and (2) cessation attempts. Both models adjusted for income, education, race/ethnicity, recent sex work, HIV status, depression, alcohol use, and current hormone use. RESULTS: Overall, 83% of participants indicated that they had smoked a cigarette in the last month. Of these women, 62.3% reported daily smoking and 51.7% reported an unsuccessful quit attempt. Discrimination was positively associated with currently smoking (adjusted odds ratio [AOR] = 1.04, 95% confidence interval [CI]: 1.01, 1.08). Discrimination was positively associated with unsuccessful cessation (AOR = 1.03, 95% CI: 1.01, 1.18) and never attempting (AOR = 1.04, 95% CI: 1.01, 1.11) compared to successful cessation. Discrimination was also positively associated with never attempting compared to unsuccessful cessation (AOR = 1.01, 95% CI: 1.00, 1.03). CONCLUSIONS: Smoking cessation may be driven by unique transgender-related minority stressors, such as discrimination. Future research is warranted to address unique stigmatizing contexts when understanding and providing tailored intervention addressing smoking among transgender women. PMID- 25782460 TI - An attachment-based intervention for parents of adolescents at risk: mechanisms of change. AB - Mechanisms that account for treatment effects are poorly understood. The current study examined processes that may underlie treatment outcomes of an attachment based intervention (Connect) for parents of pre-teens and teens with serious behavior problems. Parents (N = 540) in a non-randomized trial reported on their teen's functioning prior to and following treatment. Results confirmed significant decreases in parents' reports of teens' externalizing and internalizing symptoms, replicating prior evaluations of this program. Reductions in parents' reports of teen attachment avoidance were associated with decreases in externalizing symptoms, while reductions in parents' reports of teen attachment anxiety were associated with decreases in internalizing symptoms. Parents' reports of improved teen affect regulation were also associated with decreases in both internalizing and externalizing symptoms. Results were comparable across gender and for parents of teens with pre-treatment externalizing symptoms in the clinical versus sub-clinical range. A model of therapeutic change in attachment-based parenting programs is discussed. PMID- 25782461 TI - Bioactive triterpenoids from Atriplex lasiantha. AB - Chromatographic purification of the ethyl acetate soluble fraction from the methanolic extract of Atriplex lasiantha yielded a new triterpenoid, 7beta,15alpha,16beta-trihydroxyolean-12-ene-28,30-dioic acid-3-O-beta-D xylopyranoside (1), along with two known triterpenoids, rotundifolioside I (2) and corchorusin B (3). Structures of the compounds 1-3 were elucidated through sophisticated NMR studies and high resolution mass spectrometry. The three isolates (1-3) were evaluated for antibacterial, antioxidant, and antiurease activities. Compound 2 exhibited the best antibacterial activity against Escherichiacoli with IC50 value of 66.25 MUg/ml, whereas, all the tested compounds exhibited antioxidant (IC50 values of 68.7-75.4 MUg/ml) and antiurease (IC50 values of 25.5-49.3 MUg/ml) activities, respectively. PMID- 25782463 TI - Obstetrician and gynecologists' population-based screening practices. AB - BACKGROUND: The ability to obtain genetic information can now be accomplished in far greater detail, and more quickly than in the past. It is important to understand obstetrician-gynecologists' (ob-gyns) screening practices as these changes occur. METHODS: Cross-sectional survey was performed by mailing paper surveys to Fellows of the American College of Obstetricians and Gynecologists and a subset of Fellows who belong to the Collaborative Ambulatory Research Network (CARN). RESULTS: Response rates were 57% for the CARN network. Almost all responders (92%) offer population-based genetic screening in the prenatal period and almost all (93%) conduct counseling prior to the provision of genetic testing. Almost all (92%) counsel patients when the result is positive, with 46% being the primary counselor and 55% calling the patient themselves. When results are negative, 73% counsel with 58% indicating they are the primary counselor and 17% call patients themselves. A total of 72% have received continuing medical education (CME) on genetics within 5 years, with 79% receiving CME at conferences and 21% receiving CME online. CONCLUSION: Ob-gyns have a large role in providing patients new genetic screening technologies. This role requires a significant knowledge base, some of which can be obtained by online modules; however, our study suggests online education is underutilized as a means for CME on genetic screening among ob-gyns. PMID- 25782462 TI - Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries. AB - OBJECTIVE: To assess the diagnostic value of cardiac MRI (CMR) in patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. METHODS: This study included a total of 125 patients treated in the chest pain unit during a 39-month period. Each included patient underwent MRI within a median of 3 days after cardiac catheterization. The MRI protocol comprised cine, oedema-sensitive and late gadolinium-enhancement imaging. The standard of reference was a consensus diagnosis based on clinical follow-up and the synopsis of all clinical, laboratory and imaging data. RESULTS: MRI revealed a multitude of diagnoses, including ischaemic cardiomyopathy (CM), dilated CM, myocarditis, Takotsubo CM, hypertensive heart disease, hypertrophic CM, cardiac amyloidosis and non-compaction CM. MRI-based diagnoses were the same as the final reference diagnoses in 113/125 patients (90%), with the two diagnoses differing in only 12/125 patients. In two patients, no final diagnosis could be established. CONCLUSION: CMR performed early after the onset of symptoms revealed a broad spectrum of diseases. CMR delivered a correct final diagnosis in 90% of patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. ADVANCES IN KNOWLEDGE: Diagnosing patients with acute coronary syndrome but unobstructed coronary arteries remains a challenge for cardiologists. CMR performed early after catheterization reveals a broad spectrum of diseases with only a simple and quick examination protocol, and there is a high concordance between MRI-based diagnoses and final reference diagnoses. PMID- 25782464 TI - Establishing the first mobile stroke unit in the United States. AB - BACKGROUND AND PURPOSE: Recently, the Mobile Stroke Unit (MSU) concept was introduced in Germany demonstrating prehospital treatment of more patients within the first hour of symptom onset. However, the details and complexities of establishing such a program in the United States are unknown. We describe the steps involved in setting up the first MSU in the United States. METHODS: Implementation included establishing leadership, fund-raising, purchase and build out, knitting a collaborative consortium of community stakeholders, writing protocols to ensure accountability, radiation safety, purchasing supplies, licensing, insurance, establishing a base station, developing a communication plan with city Emergency Medical Services, Emergency Medical Service training, staffing, and designing a research protocol. RESULTS: The MSU was introduced after ~1 year of preparation. Major obstacles to establishing the MSU were primarily obtaining funding, licensure, documenting radiation safety protocols, and establishing a smooth communication system with Emergency Medical Services. During an 8 week run-in phase, ~2 patients were treated with recombinant tissue type plasminogen activator per week, one-third within 60 minutes of symptom onset, with no complications. A randomized study to determine clinical outcomes, telemedicine reliability and accuracy, and cost effectiveness was formulated and has begun. CONCLUSION: The first MSU in the United States has been introduced in Houston, TX. The steps needed to accomplish this are described. PMID- 25782465 TI - Response to letter regarding article, "fibroblast growth factor 23 and risk of incident stroke in community-living adults". PMID- 25782466 TI - Fixed-dose combination treatment after stroke for secondary prevention in China: a national community-based study. AB - BACKGROUND AND PURPOSE: There is evidence and international consensus on the advantages and potential of a polypill for established cardiovascular disease patients to improve adherence in the secondary prevention of cardiovascular disease. This study aimed to estimate the numbers of stroke patients who would be eligible for the polypill strategy in China, and the suitable composition of a polypill, based on data of the China National Stroke Prevention Project. METHODS: A total of 717 620 residents aged >=40 years from 6 Chinese representative provinces were screened for prevalent stroke from 2011 to 2012 with an 84.4% response rate. Participants with a history of stroke received further investigation of risk factors and treatments. The potential need for treatment was classified according to the guidelines. Rates were standardized using the population composition of the Sixth National Population Census of China. RESULTS: The standardized prevalence rate of stroke was 1.9%. Up to 93.1% of stroke patients were eligible for a polypill containing at least 2 types of medications, with 75.3% eligible for a statin and antiplatelet agent and 70.6% for antihypertensive and antiplatelet medications. Considering 3 therapies, 54% were eligible for antihypertensive, statin, and antiplatelet medications. The current treatment rate with all required combinations of separate pills was only 6.9%. CONCLUSIONS: A huge number of stroke patients in China require preventive therapy and would be eligible for a polypill. This study indicates that it would be reasonable to consider and assess the value of a polypill strategy to improve secondary prevention of stroke in China. PMID- 25782467 TI - Letter by Zou and Zheng regarding article, "fibroblast growth factor 23 and risk of incident stroke in community-living adults". PMID- 25782468 TI - Receptor for advanced glycation end-product antagonist reduces blood-brain barrier damage after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1). METHODS: Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood-brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection. RESULTS: Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood-brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-kappaB p65 upregulation were also observed when FeCl2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood-brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor kappaB p65, proinflammatory mediators interleukin 1beta, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl2-induced RAGE and nuclear factor-kappaB p65 upregulation. CONCLUSIONS: RAGE signaling is involved in blood-brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH. PMID- 25782470 TI - Affective matching of odors and facial expressions in infants: shifting patterns between 3 and 7 months. AB - Recognition of emotional facial expressions is a crucial skill for adaptive behavior. Past research suggests that at 5 to 7 months of age, infants look longer to an unfamiliar dynamic angry/happy face which emotionally matches a vocal expression. This suggests that they can match stimulations of distinct modalities on their emotional content. In the present study, olfaction-vision matching abilities were assessed across different age groups (3, 5 and 7 months) using dynamic expressive faces (happy vs. disgusted) and distinct hedonic odor contexts (pleasant, unpleasant and control) in a visual-preference paradigm. At all ages the infants were biased toward the disgust faces. This visual bias reversed into a bias for smiling faces in the context of the pleasant odor context in the 3-month-old infants. In infants aged 5 and 7 months, no effect of the odor context appeared in the present conditions. This study highlights the role of the olfactory context in the modulation of visual behavior toward expressive faces in infants. The influence of olfaction took the form of a contingency effect in 3-month-old infants, but later evolved to vanish or to take another form that could not be evidenced in the present study. PMID- 25782471 TI - Quantitative Phase Analysis by the Rietveld Method for Forensic Science. AB - Quantitative phase analysis (QPA) is helpful to determine the type attribute of the object because it could present the content of the constituents. QPA by Rietveld method requires neither measurement of calibration data nor the use of an internal standard; however, the approximate crystal structure of each phase in a mixture is necessary. In this study, 8 synthetic mixtures composed of potassium nitrate and sulfur were analyzed by Rietveld QPA method. The Rietveld refinement was accomplished with a material analysis using diffraction program and evaluated by three agreement indices. Results showed that Rietveld QPA yielded precise results, with errors generally less than 2.0% absolute. In addition, a criminal case which was broken successfully with the help of Rietveld QPA method was also introduced. This method will allow forensic investigators to acquire detailed information of the material evidence, which could point out the direction for case detection and court proceedings. PMID- 25782469 TI - Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers. AB - AIM: The pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg(-1) alcohol using 40% vodka). METHODS: In a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. RESULTS: Alcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. CONCLUSION: SMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed. PMID- 25782472 TI - Value of fetuin-A as a predictor of liver fibrosis in patients with nonalcoholic fatty liver disease. PMID- 25782473 TI - Benign lymphangioendothelioma on a vascular birthmark following examination of a cardiac catheter. PMID- 25782474 TI - [Behavior of antioxidant parameters in young cattle during the course of the year]. AB - OBJECTIVE: To analyze the behavior of antioxidant parameters in young cattle over 1 year and to detect possible health-related deficits during certain periods. MATERIALS AND METHODS: Every 2 months over the course of 1 year, six healthy 12 month-old Holstein Friesian/German black and white heifers underwent a clinical examination and blood samples were obtained. The 36 animals were kept in tie stalls during September, November, January, March and July, and solely at pasture in May. The antioxidant parameters superoxide dismutase (SOD), glutathione peroxidase (GPX) and the Trolox equivalent antioxidant capacity (TEAC), hematocrit and the metabolic parameters beta-hydroxybutyrate, bilirubin, cholesterol, protein, albumin, urea, haptoglobin, calcium, inorganic phosphate, iron, alkaline phosphatase, aspartate transaminase, glutamate dehydrogenase and creatine kinase were determined. RESULTS: The GPX activities in September and January were significantly lower than those from March till July. The TEAC concentrations were in particular lower in January and significantly lower in March than in September and November. Differing SOD activities were not statistically significant. The correlation between SOD and GPX during the entire period was significant as well as between SOD and TEAC throughout the year except in January, whereas GPX and the TEAC only significantly correlated in November and from March till July. Albumin significantly correlated with the TEAC. The metabolic parameters were within the physiological range at all times, except urea in November and July and phosphate in May. CONCLUSION: The young cattle showed significantly reduced GPX activities from September to January, and reduced TEAC concentrations particularly in January and March. Decreased GPX activity is indicative of a low selenium supply. Among other disadvantages, this is unfavorable for the development of heifers. A reduced provision with antioxidant agents, particularly vitamin E and beta-carotene, is indicated by the TEAC and has negative effects that are comparable to those caused by a lack of selenium. In terms of health prophylaxis, particularly during winter, specific attention should be given to the supply of sufficient trace elements and good quality silage. PMID- 25782475 TI - Single dopants in semiconductors. PMID- 25782476 TI - Diagnostic challenges of oral and cutaneous Kaposi's sarcoma in resource constrained settings. AB - OBJECTIVES: Kaposi's sarcoma (KS), caused by HHV-8, is the most frequent HIV associated malignancy worldwide and remains a major scourge in Sub-Saharan Africa. KS is also endemic in much of Africa. There is a risk of misdiagnosis based solely on clinical appearance and haematoxylin and eosin (H&E) staining, especially with other reactive and neoplastic vascular proliferations which occur in the mouth. This study examined oral and cutaneous biopsies from clinically diagnosed lesions of KS in Kenya, using histopathology supplemented with immunohistochemistry (IHC) and polymerase chain reaction (PCR) for HHV-8 as confirmation of diagnosis. METHODS: Biopsies of 49 lesions (28 oral, 21 cutaneous) previously diagnosed as 'KS' were re-examined by H&E staining and IHC targeting HHV-8 LANA-1. Positive controls were sections from embedded BCBL-1 cell lines. Negative controls were from three different HHV-8-negative biopsies. Confirmation of HHV-8 immunohistochemistry was sought by PCR and by determining the HHV-8 ORFK1 subtype. RESULTS: Whilst most cases were confirmed, 12 oral and 4 cutaneous lesions displayed clinical and histological features of KS but were negative to HHV-8 IHC. These oral lesions were re-diagnosed as pyogenic granulomata (n = 6), deep mycosis (n = 1), inflamed mucosa (n = 2) or 'uncertain but not KS' (n = 3). Whilst PCR is usually helpful in differentiating HHV-8 disease, all samples were HHV-8 PCR positive, with identical sequences, suggesting cross-contamination of samples in the original pathology laboratories. CONCLUSION: HHV-8 IHC is essential for the correct diagnosis of KS, but due to the high level of contamination in resource-poor settings, PCR is inadvisable. PMID- 25782525 TI - On-demand one-step synthesis of monodisperse functional polymeric microspheres with droplet microfluidics. AB - A simple and robust method for one-step synthesis of monodisperse functional polymeric microspheres was established by generation of reversed microemulsion droplets in aqueous phase inside microfluidic chips and controlled evaporation of the organic solvent. Using this method, water-soluble nanomaterials can be easily encapsulated into biodegradable Poly(D,L-lactic-co-glycolic acid) (PLGA) to form functional microspheres. By controlling the flow rate of microemulsion phase, PLGA polymeric microspheres with narrow size distribution and diameters in the range of ~50-100 MUm were obtained. As a demonstration of the versatility of the approach, high-quality fluorescent CdTe:Zn(2+) quantum dots (QDs) of various emission spectra, superparamagnetic Fe3O4 nanoparticles, and water-soluble carbon nanotubes (CNTs) were used to synthesize fluorescent PLGA@QDs, magnetic PLGA@Fe3O4, and PLGA@CNTs polymeric microspheres, respectively. In order to show specific applications, the PLGA@Fe3O4 were modified with polydopamine (PDA), and then the silver nanoparticles grew on the surfaces of the PLGA@Fe3O4@PDA polymeric microspheres by reducting the Ag(+) to Ag(0). The as-prepared PLGA@Fe3O4@PDA-Ag microspheres showed a highly efficient catalytic reduction of the 4-nitrophenol, a highly toxic substance. The monodisperse uniform functional PLGA polymeric microspheres can potentially be critically important for multiple biomedical applications. PMID- 25782527 TI - Need for Reinforced Strategies to Support Delivery of HIV Clinical Services During the Ebola Outbreak in Guinea, Liberia, and Sierra Leone. AB - The Ebola Virus Disease (EVD) outbreak in West Africa has been declared a public health emergency of international concern by the World Health Organization. The Ebola outbreak has led to the disruption of already fragile but essential health services and drug distribution systems; HIV clinical services in Liberia, Sierra Leone, and Guinea were particularly affected. Targeted approaches are necessary to protect the continuity of HIV treatment for people living with HIV and should be integrated within the broader Ebola response; this will save lives, prevent drug resistance, and decrease the likelihood of HIV transmission. PMID- 25782526 TI - Cortisol Response to Stress in Adults with Attention Deficit Hyperactivity Disorder. AB - BACKGROUND: Differences in the cortisol response have been reported between children exhibiting the inattentive and hyperactive/impulsive subtypes of attention deficit hyperactivity disorder. However, there is no such information about adults. The aim of the present study was to determine the possible differences between the combined and inattentive subtypes in the cortisol response to stress. METHODS: Ninety-six adults with attention deficit hyperactivity disorder, 38 inattentive and 58 combined, without any medical or psychiatric comorbidities and 25 healthy controls were included. The Trier Social Stress Test was used to assess physiological stress responses. Clinical data and subjective stress levels, including the Perceived Stress Scale, were also recorded. RESULTS: No significant differences in the cortisol response to the Trier Social Stress Test were found between patients and controls. However, albeit there were no basal differences, lower cortisol levels at 15 (P=.015), 30 (P=.015), and 45 minutes (P=.045) were observed in the combined compared with the inattentive subtype after the stress induction; these differences disappeared 60 minutes after the stress. In contrast, the subjective stress responses showed significant differences between attention deficit hyperactivity disorder patients and controls (P<.001), but no differences were seen between attention deficit hyperactivity disorder subtypes. In turn, subjective stress measures, such as the Perceived Stress Scale, positively correlated with the whole cortisol stress response (P<.027). CONCLUSIONS: Both the combined and inattentive attention deficit hyperactivity disorder adults exhibited a normal cortisol response to stress when challenged. Nevertheless, the inattentive patients displayed a higher level of cortisol after stress compared with the combined patients. Despite the differences in the cortisol response, adults with attention deficit hyperactivity disorder reported high levels of subjective stress in their every-day life. PMID- 25782528 TI - Viral gene therapy for head and neck cancer. AB - BACKGROUND: Viral gene therapy is a promising new treatment modality for head and neck cancer. This paper provides the reader with a review of the relevant literature in this field. RESULTS: There are government licensed viral gene therapy products currently in use for head and neck cancer, utilised in conjunction with established treatment modalities. The viruses target tumour associated genes, with the first licensed virus replacing p53 gene function, which is frequently lost in tumourigenesis. Oncolytic viruses selectively destroy cancer cells through viral replication and can be armed with therapeutic transgenes. CONCLUSION: Despite considerable advances in this field over the last 40 years, further research is needed to improve the overall efficacy of the viruses and allow their widespread utilisation in the management of head and neck cancer. PMID- 25782529 TI - Applying attachment theory to effective practice with hard-to-reach youth: the AMBIT approach. AB - Adolescent Mentalization-Based Integrative Treatment (AMBIT) is a developing approach to working with "hard-to-reach" youth burdened with multiple co occurring morbidities. This article reviews the core features of AMBIT, exploring applications of attachment theory to understand what makes young people "hard to reach," and provide routes toward increased security in their attachment to a worker. Using the theory of the pedagogical stance and epistemic ("pertaining to knowledge") trust, we show how it is the therapeutic worker's accurate mentalizing of the adolescent that creates conditions for new learning, including the establishment of alternative (more secure) internal working models of helping relationships. This justifies an individual keyworker model focused on maintaining a mentalizing stance toward the adolescent, but simultaneously emphasizing the critical need for such keyworkers to remain well connected to their wider team, avoiding activation of their own attachment behaviors. We consider the role of AMBIT in developing a shared team culture (shared experiences, shared language, shared meanings), toward creating systemic contexts supportive of such relationships. We describe how team training may enhance the team's ability to serve as a secure base for keyworkers, and describe an innovative approach to treatment manualization, using a wiki format as one way of supporting this process. PMID- 25782530 TI - Antioxidative and anticarcinogenic activities of methylpheophorbide a, isolated from wheat grass (Triticum aestivum Linn.). AB - Methylphophorbide a (MPa) has been isolated from the ethanol extract of the wheat grass plant. Its antioxidative efficacy is evaluated by hydroxyl radical scavenging activities and reducing capacity which are significantly up regulated in comparison with aqueous extract of the plant. The compound shows iron-binding capacity where the Fe(2+) binds with MPa by two types of binding patterns with dissociation constants 157.17 and 27.89. It has antioxidative and cytotoxic effects on HeLa and Hep G2 cells. The cancerous cell survivability decreases with increasing concentration of MPa. These findings have provided evidence for the traditional use of the wheat grass plant in the treatment of cancers, oxidative stress and iron overloaded disorders. PMID- 25782531 TI - Eight-year preservation of knee function with radiographic healing phenomena after anti-tumor necrosis factor-alpha therapy for a severely erosive knee in a young patient with rheumatoid arthritis. AB - A 23-year-old woman developed rheumatoid arthritis (RA). The pain in her right knee was aggravated and anti-tumor necrosis factor (TNF)-alpha therapy was selected at the age of 35. The range of motion and Larsen grade were 5o to 120o and 4, respectively. Infliximab and etanercept therapies were quite effective and the pain of the right knee improved. An X-ray at 1 year showed radiographic healing phenomena that included reappearance of a clear visible cortical plane, partial filling-in of erosions and cysts, and sclerosis of the subchondral bone. An X-ray at the age of 43 showed that the radiographic healing phenomena were still preserved after 7 years. The right knee remained pain-free although the Larsen grade was still 4, and the knee function was preserved for 8 years. In conclusion, anti-TNF-alpha therapy may preserve knee function with radiographic healing phenomena and prevent total arthroplasty of severely erosive knees in young RA patients. PMID- 25782532 TI - Utilization of microbial community potential for removal of chlorpyrifos: a review. AB - Chlorpyrifos (CP) is the most commonly used pesticide in agricultural fields worldwide. Exposure to CP and its metabolites creates severe neuron-disorders in human beings. Improper handling and uncontrolled application of CP by farmers have lead to the contamination of surface and ground water bodies. Biodegradation offers an efficient and cost effective method for the removal of CP and other toxic organophosphorus pesticides from the contaminated environment. The degradation of CP by various microorganisms has been investigated by several researchers over the past few years. This review presents a critical summary of the recent published results on the biodegradation of CP. A diverse range of bacterial species such as Agrobacterium sp., Alcaligenes faecalis, Enterobacter sp. Arthrobacter sp. Bacillus pumilus, Pseudomonas sp. etc., fungal species like Trichoderma viridae, Aspergillus niger, Verticillium sp., Acremonium sp. Cladosporium cladosporiodes, etc. and certain algal species viz. Chlorella vulgaris, Spirulina platensis, Synechocystis sp., etc., have been shown to degrade CP. The efficacy of these communities for CP degradation in batch and continuous modes has also been discussed but more studies are required on continuous reactors. Also, the available published information on kinetics of biodegradation of CP along with the available results on molecular biological approaches are discussed in this work. PMID- 25782533 TI - Molecular dynamics simulations of nanoscale and sub-nanoscale friction behavior between graphene and a silicon tip: analysis of tip apex motion. AB - A sliding object on a crystal surface with a nanoscale contact will always experience stick-slip movement. However, investigation of the slip motion itself is rarely performed due to the short slip duration. In this study, we performed molecular dynamics simulation and frictional force microscopy experiments for the precise observation of slip motion between a graphene layer and a crystalline silicon tip. The simulation results revealed a hierarchical structure of stick and slip motion. Nanoscale stick and slip motion is composed of sub-nanoscale stick and slip motion. Sub-nanoscale stick and slip motion occurred on a timescale of a few ps and a force scale of 10(-1) nN. The relationship between the trajectories of the silicon tip and stick-slip peak revealed that in-plane and vertical motions of the tip provide information about stick and slip motion in the sub-nanoscale and nanoscale ranges, respectively. Parametric studies including tip size, scan angle, layer thickness, and flexibility of the substrate were also carried out to compare the simulation results with findings on lateral force microscopy. PMID- 25782534 TI - High chemiluminescence activity of an Fe(III)-TAML activator in aqueous-organic media and its use in the determination of organic peroxides. AB - High activity of Fe(III)-TAML, peroxidase mimic, upon the catalytic oxidation of luminol in aqueous-organic media (ethanol, isopropanol and acetonitrile) was determined. Using Fe(III)-TAML the sensitive chemiluminescence assays for the determination of benzoyl peroxide and tert-butyl hydroperoxide in the presence of organic solvents were performed. PMID- 25782536 TI - The molecular motion of bovine serum albumin under physiological conditions is ion specific. AB - Specific ion effects on the Brownian molecular motion of BSA protein under physiological conditions are investigated. New useful insights into Hofmeister phenomena related to electrolyte-protein interactions are presented. PMID- 25782535 TI - Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, tolerability and cardiac repolarization in healthy subjects. AB - AIMS: Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects. METHODS: Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated. RESULTS: AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration-effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience. CONCLUSION: Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen. PMID- 25782557 TI - A curious ulcer on the pinna: rhinosporidiosis at an unusual place. PMID- 25782537 TI - Electrophysiological measures of resting state functional connectivity and their relationship with working memory capacity in childhood. AB - Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher-order control regions to lower-order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter-subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto-parietal network and lower-level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability. PMID- 25782558 TI - Assay Development and Validation of an 8-SNP Multiplex Test to Predict Eye and Skin Coloration. AB - Identifying human remains is one of the many responsibilities of forensic scientists. An eye- and skin-color predictor translates genotypic information into phenotypic description. Eight single nucleotide polymorphisms (SNPs) are utilized for this predictor, five for eye, and six for skin coloration. Here, we describe the development and validation of an 8-SNP multiplex assay that consists of a multiplex PCR, followed by a multiplexed single-base primer extension reaction generating fluorescently labeled oligonucleotides of distinct length that are detected by multicolor capillary electrophoresis. Validation of this assay included tests for reproducibility, reliability, sensitivity, species specificity, its performance on degraded DNA, and on forensic samples. It can be concluded that the 8-SNP multiplex assay is robust and can be used on challenging samples, including bones, to reliably determine the genotypes to predict eye and skin color of individuals. This information can assist in the identification of human remains and missing persons. PMID- 25782560 TI - Seamless Transitions: Achieving Patient Safety Through Communication and Collaboration. AB - BACKGROUND: Although more than a decade has passed since the imperative to reduce fragmentation of care, high rehospitalization rates among Medicare patients with chronic diseases persist; at least 25% of these are considered preventable. Transitional care models that emphasize coordination among providers have demonstrated significant reductions in hospitalization rates. However, achieving effective collaboration among providers across disciplines and/or facilities through implementation of transitional care models can be challenging. OBJECTIVES: The aims of this article are to (1) describe a collaborative transitional care program implemented by a 7-hospital health care system and a postacute senior care service provider organization to pilot a transitional care program (Transitions Across Care Settings [TRACS]) for improving coordination of care for their mutual patients and (2) share results and lessons learned from this quality initiative. METHODS: The goal of the TRACS program, which used the Coleman Care Transitions Intervention model, was to reduce 30-day readmissions to lower than the national averages for an initial target population of inpatients with pneumonia, congestive heart failure, and acute myocardial infarction diagnoses. RESULTS: The overall readmission rate for 104 patients in the pilot TRACS program was 4.8%. Readmission rates were 0% for acute myocardial infarction, 7.1% for congestive heart failure, and 4.4% for pneumonia. CONCLUSIONS: A culture of patient safety was facilitated by a registered nurse transitions coach through consistent communication and flow of patient information during patient hand offs across the care continuum. More than 1000 patients are already admitted to the next iteration of the TRACS program, resulting in a sustainable enterprise. PMID- 25782559 TI - Medications and Patient Characteristics Associated With Falling in the Hospital. AB - OBJECTIVES: The aim of this study was to evaluate specific medications and patient characteristics as risk factors of falling in the hospital. METHODS: This is a case-control study comparing demographic, health, mobility, and medication data for 228 patients who fell between June 29, 2007, and November 14, 2007, at a large tertiary care hospital and 690 randomly selected control patients. Logistic regression was used to identify fall risk factors. RESULTS: Independent risk factors of falling included history of falls (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.8-4.2); needing an assistive device (OR, 3.2; 95% CI, 1.5-6.8) or person assistance (OR, 2.1; 95% CI, 1.3-3.3) to ambulate; being underweight (OR, 2.4; 95% CI, 1.2-4.7) or obese (OR, 1.6; 95% CI, 1.0-2.5); confusion (OR, 2.4; 95% CI, 1.5-4.0); dizziness (OR, 2.1; 95% CI, 1.1-4.3); incontinence (OR, 1.5; 95% CI, 1.0-2.3); and an order for a hydantoin (OR, 3.3; 95% CI, 1.3-8.0) or benzodiazepine anticonvulsant (OR, 2.2; 95% CI, 1.5-3.3), haloperidol (OR, 2.8; 95% CI, 1.2-6.8), tricyclic antidepressant (OR, 2.4; 95% CI, 1.2-4.9), or insulin (OR, 1.5; 95% CI, 1.0-2.1). Female sex (OR, 0.8; 95% CI, 0.6-1.0), proton pump inhibitors (OR, 0.6; 95% CI, 0.4-0.9), and muscle relaxants (OR, 0.4; 95% CI, 0.3-0.7) were associated with lower risk for falling. CONCLUSIONS: This study identified medications and patient characteristics associated with increased risk for falling in the hospital. High-risk medications identified in this study may serve as targets for medication review or adjustment, which have been recommended as a component of multifaceted fall prevention programs. PMID- 25782561 TI - A Comprehensive Program to Reduce Rates of Hospital-Acquired Pressure Ulcers in a System of Community Hospitals. AB - OBJECTIVES: The prevention of hospital-acquired pressure ulcers (PrUs) has significant consequences for patient outcomes and the cost of care. Providers are challenged with evaluating available evidence and best practices, then implementing programs and motivating change in various facility environments. METHODS: In a large system of community hospitals, the Reducing Hospital Acquired PrUs Program was developed to provide a toolkit of best practices, timely and appropriate data for focusing efforts, and continuous implementation support. Baseline data on PrU rates helped focus efforts on the most vulnerable patients and care situations. Facilities were empowered to use and adapt available resources to meet local needs and to share best practices for implementation across the system. Outcomes were measured by the rate of hospital-acquired PrUs, as gathered from patient discharge records. RESULTS: The rate of hospital acquired stage III and IV PrUs decreased 66.3% between 2011 and 2013. Of the 149 participating facilities, 40 (27%) had zero hospital-acquired stage III and IV PrUs and 77 (52%) had a reduction in their PrU rate. Rates of all PrUs documented as present on admission did not change during this period. A comparison of different strategies used by the most successful facilities illustrated the necessity of facility-level flexibility and recognition of local workflows and patient demographics. CONCLUSIONS: Driven by the combination of a repository of evidence-based tools and best practices, readily available data on PrU rates, and local flexibility with processes, the Reducing Hospital Acquired-PrUs Program represents the successful operationalization of improvement in a wide variety of facilities. PMID- 25782562 TI - Examining Wrong Eye Implant Adverse Events in the Veterans Health Administration With a Focus on Prevention: A Preliminary Report. AB - OBJECTIVE: The study goals were to examine wrong intraocular lens (IOL) implant adverse events in the Veterans Health Administration (VHA), identify root causes and contributing factors, and describe system changes that have been implemented to address this challenge. DESIGN: This study represents collaboration between the VHA's National Center for Patient Safety (NCPS) and the National Surgery Office (NSO). PARTICIPANTS: This report includes 45 wrong IOL implant surgery adverse events reported to established VHA NCPS and NSO databases between July 1, 2006, and June 31, 2014. There are approximately 50,000 eye implant procedures performed each year in the VHA. METHODS: Wrong IOL implant surgery adverse events are reported by VHA facilities to the NCPS and the NSO. Two authors (A.C. and J.N.) coded the reports for event type (wrong lens or expired lens) and identified the primary contributing factor (coefficient kappa = 0.837). A descriptive analysis was conducted, which included the reported yearly event rate. MAIN OUTCOME MEASURE: The main outcome measure was the reported wrong IOL implant surgery adverse events. RESULTS: There were 45 reported wrong IOL implant surgery adverse events. Between 2011 and June 30, 2014, there was a significant downward trend (P = 0.02, R = 99.7%) at a pace of -0.08 (per 10,000 cases) every year. The most frequently coded primary contributing factor was incomplete preprocedure time-out (n = 12) followed by failure to perform double check of preprocedural calculations based upon original data and implant read-back at the time the surgical eye implant was performed (n = 10). CONCLUSIONS: Preventing wrong IOL implant adverse events requires diligence beyond performance of the preprocedural time-out. In 2013, the VHA has modified policy to ensure double check of preprocedural calculations and implant read-back with positive impact. Continued analysis of contributing human factors and improved surgical team communication are warranted. PMID- 25782563 TI - Cupping (Hijama) Treatment: Benign or Sinister? AB - Cupping treatment is on the rise in the Western world as an alternative medicine modality.We present a hitherto unreported complication of bilateral subdural hemorrhage associated with this therapy, highlighting the need for vigilance in patients presenting with headache because they may get misdiagnosed unless history for such therapies is explored. PMID- 25782564 TI - Environmental factors and ram influence litter size, birth, and weaning weight in Saint Croix hair sheep under semi-arid conditions in Mexico. AB - This study was conducted to evaluate the effects of season, year of lambing, parity, and the effect of ram on litter size, birth, and weaning weight through 8 years. Data of 4078 lambs sired by 21 rams and 1072 ewes were analyzed by a lineal model. There was a significant effect (P < 0.05) of lambing number on litter size and birth weight, but not on weaning weight (P > 0.05). For litter size, the lowest numbers were obtained on the first lambing ewes (1.21 +/- 0.03) and the highest ones inewes starting from the fourth lambing (1.69 +/- 0.04). Lowest body weights were found in lambs born from first lambing ewes (3.01 +/- 0.1 kg) and the highest ones in lambs born from the second (3.14 +/- 0.1) to the fifth (3.15 +/- 0.2) lambing ewes. The lambing breeding season had a significant effect on weaning weight: the highest weaning weights were recorded in lambs born in spring (12.70 +/- 0.20 kg) and the lowest ones in those born in summer (11.93 +/- 0.20 kg). Lambing year had a significant effect (P < 0.05) on litter size and weaning weight, since the values of both traits improved through the years. Effect of ram was significant (P < 0.05) for each of the traits considered: there were differences up to one lamb per litter, also differences up to 1.5 kg for birth weight and up to 6.5 kg for weaning weight among rams. In conclusion, these results indicate that environmental conditions are important source of variation in litter size, birth, and weaning weight in hair sheep under semi-arid climate. PMID- 25782565 TI - Prevalence of porcine circovirus-2 DNA-positive ovarian and uterine tissues in gilts culled due to reproductive disturbance in Thailand. AB - The present study aimed to determine the prevalence of porcine circovirus-2 (PCV 2) DNA-positive ovarian and uterine tissues in gilts culled due to reproductive disturbance in Thailand. Tissues (70 ovaries and 102 uteri) and serum (n = 102) samples from 102 gilts were included. PCV-2 DNA was detected by using polymerase chain reactions. The localisation of PCV-2 antigen was determined by immunohistochemistry, and PCV-2 antibody was evaluated by ELISA. PCV-2 DNA was detected in 30.0 % (21/70) of the ovaries and in 45.1 % (46/102) of the uteri. Age did not influence the frequency of PCV-2 DNA detection in these reproductive organs of gilts (P > 0.05). The prevalence of PCV-2 DNA-positive uterine tissue in gilts culled due to non-reproductive problems (20.0 %) was lower than gilts culled due to abortion (85.0 %), abnormal vaginal discharge (47.5 %) and anoestrus (53.5 %) (P < 0.05). The prevalence of PCV-2 DNA-positive uterine tissue in the gilts with high antibody titres (23.0 %) was lower than in gilts with low antibody titres (57.6 %) and seronegative gilts (64.5 %) (P < 0.05). PCV 2 immunostaining was detected in the endometrial cells, lymphocytes and macrophages of the uteri and in oocytes and granulosa cells of the ovaries. In conclusion, the detection of PCV-2 in the reproductive organs reveals an important potential impact of this virus on the reproductive apparatus in gilts. PMID- 25782567 TI - Methadone for Fun Sake... Kidneys Are at Stake!!! AB - Acute renal failure from rhabdomyolysis is a well-established clinical entity; however, rhabdomyolysis exclusively caused by the ingestion of methadone requiring hemodialysis is very uncommon. With a similar mechanism to opiates, methadone can cause rhabdomyolysis and further consequences. Given the increasing use of methadone as a therapy for opiate dependence, clinicians prescribing this medication should be aware of this life-threatening complication. PMID- 25782568 TI - Electroporation Parameters for Successful Transdermal Delivery of Insulin. AB - This work investigates the effects of electroporation parameters on the transdermal delivery of insulin. Electroporation (EP) is known to induce temporal pores in the membrane, which are expected to enhance the diffusion of insulin through rabbits' skin. For such purpose, 5 different formulations of insulin and enhancers are applied to rabbit groups (5 rabbits each) with induced hyperglycemia in the presence of electroporative pulses. The blood sugar level (BSL) is followed up to 5-hour duration starting from the administration of the hyperglycemia-inducing factor. The effect of different electroporation parameters on BSL of rabbits is examined and compared with control groups. Results show that the increase in the number of pulses (from 15 up to 60 successive pulses) at an insulin concentration of 50 IU/mL, the increase in insulin concentration (from 50 to 70 IU/mL), and the decrease in applied field strength (from 200 to 100 V/cm) result in a significant decrease in BSL compared with control. Among all of the investigated formulations, the best performance is recorded for the insulin solution + EP (without enhancers) in almost all of the studied experimental conditions. PMID- 25782569 TI - A Descriptive Analysis of Changes in Selected Drug Groups Available to Primary Care Physicians in Israel From 2000 to 2013. AB - Several medical and economic factors affect the process of development and introduction of new drugs and the disappearance of various medical agents from the drug market. There are no data in the existing literature on quantitative and qualitative changes in the drug market. We assessed changes in the drug market in Israel over 14 years, focusing on drug groups that, in our subjective opinion, are mainly used in primary care medicine: pain medications, lipid lowering agents, drugs for diabetes, and antihypertensives. We assessed volume of drugs and changes and trends in terms of therapeutic efficacy and safety in selected drugs in each of the groups over the study time period. We used the Medic Compendium for the analyses. Medic contains a listing of drugs that are approved and available for use in Israel. It is updated every 2 months. In 2000, there were 253 available drugs in the study groups that contained 124 active agents. In contrast, in 2013, there were 278 available drugs that contained 130 active agents. Over the study years, there was an increase in the number of drugs that are effective, "user friendly," and have a high safety profile. Our study provides the first data on quantitative and qualitative changes that have taken place in selected groups of drugs. Although the availability of the drugs in different countries is determined by multiple factors, we assumed that there are other countries with a similar situation in terms of their drug markets. PMID- 25782566 TI - Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. AB - Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms among women and the third largest number among men. Many new methods of treatment have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2014 for treatment of colorectal cancer (JSCCR Guidelines 2014) have been prepared as standard treatment strategies for colorectal cancer, to eliminate treatment disparities among institutions, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding among health-care professionals and patients by making these guidelines available to the general public. These guidelines have been prepared as a result of consensuses reached by the JSCCR Guideline Committee on the basis of careful review of evidence retrieved by literature searches and taking into consideration the medical health insurance system and actual clinical practice in Japan. They can, therefore, be used as a guide for treating colorectal cancer in clinical practice. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions of the Guideline Committee, controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories, on the basis of consensus reached by Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2014. PMID- 25782570 TI - Clopidogrel-Associated Neutropenia: Case Report and Review of the Literature. AB - Clopidogrel is a second generation of thienopyridine, which has antiplatelet effect by inhibiting P2Y12 receptor. Hematologic adverse effect is very uncommon during clopidogrel use, but some cases of clopidogrel-associated neutropenia were reported in the past decade. Until now, there was no summary data to delineate the clinical course and safe alternatives of this event. We report 2 cases of clopidogrel-associated neutropenia and review other 10 case reports from 2000 to 2014. The median onset of neutropenia was 22 days, and the recovery time was 4 days after receiving granulocyte-colony-stimulating factor. Bone marrow studies in 6 cases all showed hypocellular or toxic damage. Six cases used cilostazol, prasugrel, or ticagrelor as safe alternatives. Closely monitoring blood cell counts is highly suggested in the first month after using clopidogrel. Newer P2Y12 inhibitors, especially ticagrelor, could be effective and safe alternatives if patients had a history of clopidogrel-associated neutropenia. PMID- 25782571 TI - Histopathologic lesions in conventional pigs experimentally infected with Haemophilus parasuis serovar 5. AB - OBJECTIVE: In the present study various tissues of pigs were investigated for the presence of histopathologic lesions after an experimental infection with Haemophilus (H.) parasuis serovar 5. MATERIAL AND METHODS: Conventional pigs (n = 36) were divided into a control group B (n = 9) and a challenge group A (n = 27), which was infected intratracheally. Pigs that did not die prior to study termination were euthanized on day 14 post inoculation. Postmortem samples of the lung, heart, liver, kidney, spleen, left tarsal joint capsule and brain were collected. RESULTS: All but one pig with detectable histopathologic lesions (n = 11) showed typical macroscopic changes. Histopathologic examination of all tissue samples identified pyelitis (n = 10), synovitis (n = 7) and meningitis (n = 7) and all those animals were euthanized prior to study termination. No histopathologic lesions were found in pigs of the control group. The correlations between pyelitis and meningitis, pyelitis and synovitis and synovitis and meningitis were significant (p < 0.001). No significant correlation could be observed between the histopathologic and the clinical examination of the joints. The investigation of samples from the joints by PCR was not significantly correlated with the observed synovitis. The clinical observation of neurologic signs was significantly correlated with meningitis (p = 0.03). A significant correlation (p < 0.001) could be detected between meningitis and the detection of H. parasuis by PCR in brain samples. CONCLUSIONS: H. parasuis constantly causes clinical signs and pathologic lesions as soon as it infects the brain while it can infect the joints without causing histopathologic lesions. Pigs with histopathologic lesions do not always show typical clinical signs. Only few studies described the finding of kidney lesions in pigs with Glasser's disease and this is the first study to describe a pyelitis in pigs experimentally infected with H. parasuis. The observed pyelitis mainly occurred in acute cases. PMID- 25782572 TI - Gelatin sponge to decrease pedicle bleeding after paramedian forehead flap. PMID- 25782573 TI - Outcome of microscopic excision of a subungual glomus tumor: a 12-year evaluation. AB - BACKGROUND: Glomus tumors are rare benign neurovascular tumors, up to 75% of which occur in the hand, mainly the subungual area. Local recurrence and nail deformity are commonly seen if tumor excision is not performed completely or properly. OBJECTIVE: This study was designed to assess the long-term efficacy of microscopic excision of subungual glomus tumors. MATERIALS AND METHODS: This retrospective analysis reviewed a total of 22 patients diagnosed with glomus tumors who underwent microscopic surgical excision at a single medical center over a 12-year period (2002-2014). Outcomes were analyzed based on symptom relief, recurrence rate, finger function, nail esthetics, and patient satisfaction. RESULTS: With a mean follow-up period of 48.4 months, neither recurrence nor postexcision nail deformity developed in any patient. Patient satisfaction was rated as "good" in 86.3% of patients (19/22). CONCLUSION: Microscopic surgical excision enables the surgeon to completely remove a glomus tumor while minimizing damage to the nail unit, thereby resulting in significantly decreased recurrence and nail deformity. In this study, an incision made according to the anatomic location provided an easy approach and the best visualization. Patients' finger function was successfully restored, nail esthetic outcome was good, and patient satisfaction was high. PMID- 25782577 TI - Iron loading site on the Fe-S cluster assembly scaffold protein is distinct from the active site. AB - Iron-sulfur (Fe-S) cluster containing proteins are utilized in almost every biochemical pathway. The unique redox and coordination chemistry associated with the cofactor allows these proteins to participate in a diverse set of reactions, including electron transfer, enzyme catalysis, DNA synthesis and signaling within several pathways. Due to the high reactivity of the metal, it is not surprising that biological Fe-S cluster assembly is tightly regulated within cells. In yeast, the major assembly pathway for Fe-S clusters is the mitochondrial ISC pathway. Yeast Fe-S cluster assembly is accomplished using the scaffold protein (Isu1) as the molecular foundation, with assistance from the cysteine desulfurase (Nfs1) to provide sulfur, the accessory protein (Isd11) to regulate Nfs1 activity, the yeast frataxin homologue (Yfh1) to regulate Nfs1 activity and participate in Isu1 Fe loading possibly as a chaperone, and the ferredoxin (Yah1) to provide reducing equivalents for assembly. In this report, we utilize calorimetric and spectroscopic methods to provide molecular insight into how wt Isu1 from S. cerevisiae becomes loaded with iron. Isothermal titration calorimetry and an iron competition binding assay were developed to characterize the energetics of protein Fe(II) binding. Differential scanning calorimetry was used to identify thermodynamic characteristics of the protein in the apo state or under iron loaded conditions. Finally, X-ray absorption spectroscopy was used to characterize the electronic and structural properties of Fe(II) bound to Isu1. Current data are compared to our previous characterization of the D37A Isu1 mutant, and these suggest that when Isu1 binds Fe(II) in a manner not perturbed by the D37A substitution, and that metal binding occurs at a site distinct from the cysteine rich active site in the protein. PMID- 25782576 TI - Principles for studying in vivo attenuation of virus mutants: defining the role of the cytomegalovirus gH/gL/gO complex as a paradigm. AB - Initial virus entry into cells of host organs and subsequent spread of viral progeny between tissue cells are events fundamental to viral pathogenesis. Glycoprotein complexes inserted in the virion envelope are critically involved in the cell entry process. Here we review and discuss recent work that has shed light on the in vivo role of the trimeric glycoprotein complex gH/gL/gO of murine cytomegalovirus (mCMV) as a model to propose the role of the corresponding complex of human CMV, for which experimental studies in vivo are not feasible due to the host species specificity of CMVs and evident ethical constraints. A novel approach combining gO transcomplementation of a genetically gO-deficient virus and a mathematical log-linear regression analysis of the viral multiplication kinetics in host tissues revealed a critical role of mCMV gH/gL/gO only in first target cell entry of virions arriving with the circulation, whereas intra-tissue spread proceeded unaffected also in the absence of gH/gL/gO. These findings predict that targeting gO for an antiviral intervention may be of prophylactic value in preventing the seeding of virus to organs, but will likely fail to interfere with an established primary organ infection or with recurrent infection after virus reactivation from latency within tissue cells. The demonstration in the murine model of alternative gH/gL complexes gH/gL/gO and gH/gL/MCK-2, substituting one another in a redundant fashion for securing viral spread in tissues, has the medically interesting bearing that targeting the gH/gL core complex directly may be a promising approach to preventing primary, established, and recurrent CMV infections. PMID- 25782578 TI - Effect of dietary oxidized konjac glucomannan on Schizothorax prenanti growth performance, body composition, intestinal morphology and intestinal microflora. AB - The aim of the present study was to examine the effect of oxidized konjac glucomannan (OKGM) on Schizothorax prenanti growth performance, body composition, intestinal morphology and intestinal microflora. Fish were fed a basal diet or basal diet plus 4.0, 8.0, 16.0 and 32.0 g kg(-1) OKGM for 60 days. The results indicated that WGR and SGR were significantly higher in fish fed 8.0 and 16.0 g kg(-1) OKGM diets (P < 0.05) than those in fish fed basal diet, and PER was significantly higher and FCR was significantly lower in fish fed 16.0 g kg(-1) OKGM diet (P < 0.05). The content of body protein, lipid and moisture was affected by the OKGM diets. The light and electron microscopy demonstrated that intestinal morphology of fish fed 8.0 and 16.0 g kg(-1) OKGM diet was better (P < 0.05) than the control group, including mucosa fold height, mucosal epithelial height, submucosa height, longitudinal muscularis thickness and circular muscularis thickness. Compared with the control group, fish fed 32.0 g kg(-1) OKGM diet showed significantly lower goblet cell number in anterior intestine (P < 0.05). Furthermore, intestinal microflora was analyzed by PCR-DGGE, and the results showed that OKGM diets also significantly modulated the intestinal microflora of fish (P < 0.05). The study clearly demonstrates that OKGM could enhance the growth performance, improve intestinal morphology and modulate intestinal microflora of S. prenanti, and the optimal dietary OKGM levels was suggested to be 16.0 g kg(-1). PMID- 25782579 TI - Impairment of Rat Spatial Learning and Memory in a New Model of Cold Water Induced Chronic Hypothermia: Implication for Alzheimer's Disease. AB - Alzheimer's disease (AD) is a primary neurodegenerative disorder associated with progressive memory impairment. Recent studies suggest that hypothermia may contribute to the development and exacerbation of AD. The aim of this study was to investigate the role of chronic hypothermia on spatial learning and memory performance as well as brain immunohistochemical (IHC) and molecular changes. Four groups of male rats were placed in cold water (3.5 +/- 0.5 degrees C) once a day for 1, 3, 6, and 14 days, four other groups were placed in warm water (32 degrees C) as the control groups to eliminate the effect of swimming stress, and one more group which comprised intact animals that were kept in a normothermic situation and had no swimming stress. Twenty-four hours after the last intervention, spatial learning and memory were assessed, using the modified Morris water maze. After the behavioral test, the rats' brains were removed for IHC and Western blotting. The results showed that memory retrieval is impaired after 14 days of cold water-induced hypothermia (CWH) (P < 0.05). IHC showed the formation of beta-amyloid plaques after a 14-day CWH. The molecular changes demonstrated that a 14-day CWH induces tau hyperphosphorylation, apoptosis, and reduces COX-II expression. Therefore, chronic CWH, independent of forced swimming stress, impairs learning and memory through molecular mechanisms similar to those of AD. In conclusion, CWH may serve as an important model to assess the role of hypothermia in AD pathogenesis. PMID- 25782581 TI - Bistable Si dopants in the GaAs (1 1 0) surface. AB - In this review, recent work is discussed on bistable Si dopants in the GaAs (1 1 0) surface, studied by scanning tunneling microscopy (STM). The bistability arises because the dopant atom can switch between a positive and a negative charge state, which are associated with two different lattice configurations. Manipulation of the Si atom charge configuration is achieved by tuning the local band bending with the STM tip. Furthermore, illuminating the sample with a laser also influences the charge state, allowing the operation of the dopant atom as an optical switch. The switching dynamics without illumination is investigated in detail as a function of temperature, lateral tip position, and applied tunneling conditions. A physical model is presented that independently describes the thermal and quantum tunneling contributions to the switching frequency and charge state occupation of a single Si atom. The basic functionality of a memory cell is demonstrated employing a single bistable Si dopant as the active element, using the STM tip as a gate to write and read the information. PMID- 25782580 TI - SRC family kinase inhibitors antagonize the toxicity of multiple serotypes of botulinum neurotoxin in human embryonic stem cell-derived motor neurons. AB - Botulinum neurotoxins (BoNTs), the causative agents of botulism, are potent inhibitors of neurotransmitter release from motor neurons. There are currently no drugs to treat BoNT intoxication after the onset of the disease symptoms. In this study, we explored how modulation of key host pathways affects the process of BoNT intoxication in human motor neurons, focusing on Src family kinase (SFK) signaling. Motor neurons derived from human embryonic stem (hES) cells were treated with a panel of SFK inhibitors and intoxicated with BoNT serotypes A, B, or E (which are responsible for >95 % of human botulism cases). Subsequently, it was found that bosutinib, dasatinib, KX2-391, PP1, PP2, Src inhibitor-1, and SU6656 significantly antagonized all three of the serotypes. Furthermore, the data indicated that the treatment of hES-derived motor neurons with multiple SFK inhibitors increased the antagonistic effect synergistically. Mechanistically, the small molecules appear to inhibit BoNTs by targeting host pathways necessary for intoxication and not by directly inhibiting the toxins' proteolytic activity. Importantly, the identified inhibitors are all well-studied with some in clinical trials while others are FDA-approved drugs. Overall, this study emphasizes the importance of targeting host neuronal pathways, rather than the toxin's enzymatic components, to antagonize multiple BoNT serotypes in motor neurons. PMID- 25782582 TI - Alterations of the thioredoxin system during subarachnoid hemorrhage-induced cerebral vasospasm. AB - BACKGROUND: The exact underlying pathogenic mechanisms and effective preventive or therapeutic interventions for cerebral vasospasm remain obscure. The thioredoxin (Trx) system performs important functions in the central nervous system including neurotrophic and neuroprotective actions. There is no study directly investigating the effects of subarachnoid hemorrhage (SAH) induced cerebral vasospasm on the Trx system in the literature. METHODS: Sixteen male New Zealand rabbits were randomly divided into two groups of eight rabbits each: a control group and a SAH group. The control group, (n = 8) was a sham surgery group in which SAH was not induced. In the SAH group, (n = 8), the SAH protocol was used to induce cerebral vasospasm. The brain and brainstem were removed and each brainstem was cut coronally into two pieces: an anterior part that contains basilar artery and a dorsal part that contains brainstem tissue. The brainstem tissue thioredoxin-1(Trx1), thioredoxin-2 (Trx2), thioredoxin reductase (TrxR), thioredoxin reductase-1 (TrxR1), thioredoxin-interacting protein (TXNIP) levels were investigated. Total oxidant status (TOS), total antioxidant status (TAS), malondialdehyde levels (MDA) and tumor necrosis factor alpha (TNF-alpha) levels were investigated for determining the oxidative-antioxidative status of the related brain tissues. Basilar artery segments were investigated for cross sectional area and wall thickness measurements. RESULTS: SAH statistically significantly reduced the tissue levels of Trx1 (p < 0.01) and TrxR (p < 0.01). Trx2 levels were not significantly altered after SAH (p > 0.05). SAH significantly reduced the expression of TrxR1 (p < 0.01) and significantly increased the expression of TXNIP (p < 0.01) when compared with controls. TOS levels and MDA levels significantly increased after SAH (p < 0.01) and TAS levels significantly reduced after SAH (p < 0.01). TNF-alpha levels significantly increased after SAH (p < 0.01). SAH-induced cerebral vasospasm significantly (p < 0.05) increased the wall thickness and reduced the mean cross-sectional area of the basilar artery (p < 0.05). CONCLUSIONS: The Trx system seems to be negatively affected by the simultaneously interrelated enzymatic alterations during cerebral vasospasm. PMID- 25782583 TI - The suboccipital midline approach to foramen magnum meningiomas; feasible, but is it optimal? PMID- 25782584 TI - Serum levels of C-peptide are associated with coronary artery calcification in patients with rheumatoid arthritis. AB - C-peptide has pro-atherogenic effects in animal models, and elevated C-peptide levels are associated with cardiovascular and all-cause mortality in patients undergoing coronary angiography. This cross-sectional study investigated the association between C-peptide serum levels and coronary artery calcification (CAC) in patients with rheumatoid arthritis (RA), a high-risk group for cardiovascular events. Fifty-four patients with RA were recruited from an arthritis outpatient department at the University Hospital in Aachen, Germany. CAC was measured by multi-slice CT scan, and blood samples were drawn from all patients for the analysis of C-peptide and other cardiovascular biomarkers. Mean serum levels of C-peptide (1.187 +/- 0.771 vs 0.745 +/- 0.481 nmol/L, p = 0.02), YKL-40, LDL cholesterol, and triglycerides were significantly higher in patients with CAC (n = 32, 59 %) compared to those without CAC (n = 22, 41 %). Univariate analysis revealed a significant association of C-peptide [OR 4.7, 95 % CI (1.1, 20.2)], YKL-40, triglycerides, hypertension, smoking, age, and male sex with the presence of CAC. After adjustment for body mass index, cholesterol, diabetes, adiponectin, calcium, and phosphate, C-peptide was still significantly associated with CAC in a multivariate logistic regression model. In conclusion, C-peptide serum levels are independently associated with the presence of CAC in patients with RA. These data suggest a potential role of C-peptide in cardiovascular disease in patients with RA. PMID- 25782585 TI - The addition of upper cervical manipulative therapy in the treatment of patients with fibromyalgia: a randomized controlled trial. AB - The aim of this study was to investigate the immediate and long-term effects of a one-year multimodal program, with the addition of upper cervical manipulative therapy, on fibromyalgia management outcomes in addition to three-dimensional (3D) postural measures. This randomized clinical trial with one-year follow-up was completed at the research laboratory of our university. A total of 120 (52 female) patients with fibromyalgia syndrome (FMS) and definite C1-2 joint dysfunction were randomly assigned to the control or an experimental group. Both groups received a multimodal program; additionally, the experimental group received upper cervical manipulative therapy. Primary outcomes were the Fibromyalgia Impact Questionnaire (FIQ), whereas secondary outcomes included Pain Catastrophizing Scale (PCS), algometric score, Pittsburgh Sleep Quality Index (PSQI), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and 3D postural measures. Measures were assessed at three time intervals: baseline, 12 weeks, and 1 year after the 12-week follow-up. The general linear model with repeated measures indicated a significant group * time effect in favor of the experimental group on the measures of 3D postural parameters (P < .0005), FIQ (P < .0005), PCS (P < .0005), algometric score (F = P < .0005), PSQI (P < .0005), BAI (P < .0005), and BDI (P < .0005). The addition of the upper cervical manipulative therapy to a multimodal program is beneficial in treating patients with FMS. PMID- 25782586 TI - Infrapatellar fat pad volume is greater in individuals with patellofemoral joint osteoarthritis and associated with pain. AB - There is relatively little research specifically investigating patellofemoral joint osteoarthritis (PFJ OA). In particular, the source of pain in PFJ OA has not been established. One structure that may be an important contributor is the infrapatellar fat pad (IPFP). This cross-sectional study aimed to: (1) compare IPFP volume in individuals with and without PFJ OA and (2) assess the relationship between IPFP volume and pain in individuals with PFJ OA. Thirty-five participants with symptomatic and radiographic PFJ OA and 11 asymptomatic controls with no radiographic signs of OA were recruited. IPFP volume was measured in both groups from magnetic resonance images, and pain in the PFJ OA group was determined using the pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS-pain). The PFJ OA group had 23.6 % greater IPFP volume than the control group (p = 0.04). After the inclusion of covariates, IPFP volume remained 19.6 % greater in the PFJ OA group (p = 0.03). IPFP volume explained 20.1 % of the variance in KOOS-pain in the PFJ OA group, with a larger IPFP being associated with worse pain (p < 0.01). Individuals with PFJ OA had a larger IPFP than controls, and IPFP volume was directly related to PFJ OA pain. These data suggest a role for the IPFP in PFJ OA and highlight a need for further investigation into the casual relationship between IPFP and PFJ changes. PMID- 25782587 TI - LATS2 induced by TNF-alpha and inhibited cell proliferation and invasion by phosphorylating YAP in oral squamous cell carcinoma. AB - OBJECTIVE: Many reports indicated LATS2 was a component of the Hippo pathway, could phosphorylate and inactivate YAP, acted as a tumor suppressor in human cancers. But few studies investigated the role of LATS2 in oral squamous cell carcinoma (OSCC) and clarified the mechanisms of regulation of LATS2 expression. DESIGN: The expressions of LATS2 and phosphorylated YAP were detected by Western blotting in HN6 cells treated with TNF-alpha in different time and different dose. Luciferase reporter assays were performed to detect whether YAP can be phosphorylated by LATS2 in HN6 cells. Cell proliferation, anchorage independent growth in soft agar, transwell cell invasion assay, and nu mice in vivo xenografts growth were performed to study the effects of overexpression of LATS2 on OSCC cells. RESULTS: In this study, we confirmed that YAP can be phosphorylated by LATS2. LATS2 can be dose- and time-dependently induced by TNF alpha in HN6 cells. Overexpression of LATS2 inhibited cell proliferation, colony formation, cell invasion, and in vivo xenografts growth in OSCC cells. CONCLUSION: LATS2 could be induced by TNF-alpha and inhibited cell proliferation and invasion by phosphorylating YAP in OSCC cells. LATS2 might play a role in the tumorigenesis of OSCC and might be a potential therapeutic target in OSCC treatment. PMID- 25782588 TI - Small-for-Size Liver Syndrome: a Case Series with a Proposal for Management Based on Portal Flow Modulation. PMID- 25782589 TI - Patterns of Failure for Lymph Node-Positive Resected Pancreatic Adenocarcinoma After Adjuvant Radiotherapy or Gemcitabine-based Chemotherapy Alone. AB - PURPOSE: The purpose of this study was to investigate the effect of radiotherapy on local control and mordibity for patients with resected lymph node-positive pancreatic cancer as compared to gemcitabine-based chemotherapy alone. MATERIALS AND METHODS: Sixty-nine patients received adjuvant therapy for pancreatic adenocarcinoma with lymph node involvement after surgical resection and met the inclusion criteria for this analysis. Forty (58 %) patients received postoperative radiotherapy (PORT) to a median dose of 50.4 Gy with capecitabine or 5-fluorouracil concurrently in all but one case; 15 patients also received gemcitabine prior to PORT. Twenty-nine (42 %) patients received gemcitabine-based chemotherapy without PORT for a median of 6 cycles. RESULTS: The median overall survival for patients receiving PORT was 24.4 months compared to 25.6 months for patients not receiving PORT (p = 0.943). At 2 years, the rate of local control was 57 % for patients receiving PORT compared to 37 % for those who did not (p = 0.034). At 2 years, the rate of palliative local interventions was 16 % for patients receiving PORT compared to 18 % for patients who did not (p = 0.821). CONCLUSION: The use of PORT was associated with improved local control in the gemcitabine era for patients with resected, node-positive, pancreatic adenocarcinoma. The rates of overall survival and palliative interventions did not differ between the two groups. PMID- 25782590 TI - Potential of plant growth promoting traits by bacteria isolated from heavy metal contaminated soils. AB - Rhizobacteria can enhance biomass production and heavy metal tolerance of plants under the stress environment. The aim of this study was to collect soil samples from different industrial sites followed by their heavy metal analysis. After performing the ICP-AES analysis of soil samples from seven different sites, bacterial strains were isolated from the soil samples of most polluted (heavy metal) site. Phylogenetic analysis of isolates based on 16S rDNA sequences showed that the isolates belonged to four species: Bacillus thuringiensis, Azotobacter chroococcum, Paenibacillus ehimensis and Pseudomonas pseudoalcaligenes. Plant growth promoting activities; siderophore production, indole acetic acid production, HCN production, and phosphate solubilisation were assayed in vitro, and statistically analysis done by using ANOVA analysis and Tukey's Honestly Significant Difference test (p <= 0.05). Plant growth-promoting characteristics of isolated strains were higher compared to the control Pseudomonas fluorescens (NICM 5096). In vitro study was performed to check resistance against two heavy metals of isolates. It was observed that isolated bacterial strains have higher heavy metal resistance as compared to control E. coli (NICM 2563). These isolates may cause pathogenic effects, so to avoid this risk, their antibacterial susceptibility was checked against eight antibiotics. Among the eight antibiotics, Ciprofloxacin-1 has shown higher inhibition against all the isolated bacterial strains. PMID- 25782591 TI - Virtual Reality Simulation Training for Ebola Deployment. AB - Both virtual and hybrid simulation training offer a realistic and effective educational framework and opportunity to provide virtual exposure to operational public health skills that are essential for infection control and Ebola treatment management. This training is designed to increase staff safety and create a safe and realistic environment where trainees can gain essential basic and advanced skills. PMID- 25782592 TI - Outcome of facial physiotherapy in patients with prolonged idiopathic facial palsy. AB - OBJECTIVE: This study investigated whether patients who remain symptomatic more than a year following idiopathic facial paralysis gain benefit from tailored facial physiotherapy. METHODS: A two-year retrospective review was conducted of all symptomatic patients. Data collected included: age, gender, duration of symptoms, Sunnybrook facial grading system scores pre-treatment and at last visit, and duration of treatment. RESULTS: The study comprised 22 patients (with a mean age of 50.5 years (range, 22-75 years)) who had been symptomatic for more than a year following idiopathic facial paralysis. The mean duration of symptoms was 45 months (range, 12-240 months). The mean duration of follow up was 10.4 months (range, 2-36 months). Prior to treatment, the mean Sunnybrook facial grading system score was 59 (standard deviation = 3.5); this had increased to 83 (standard deviation = 2.7) at the last visit, with an average improvement in score of 23 (standard deviation = 2.9). This increase was significant (p < 0.001). CONCLUSION: Tailored facial therapy can improve facial grading scores in patients who remain symptomatic for prolonged periods. PMID- 25782593 TI - Perceptions of practice guidelines for people with spinal cord injury. AB - PURPOSE: The Consortium for Spinal Cord Medicine published clinical practice guidelines (CPG) related to upper limb (UL) preservation in people with spinal cord injury (SCI) in 2005. The purpose of this qualitative research was to identify stakeholder agreement with recommendations, performance gaps, and barriers and facilitators to CPG implementation. DESIGN: This 6-month study focused on the perspectives of healthcare providers, veterans, and key informants. The Promoting Action on Research Implementation in Health Services (PARiHS) was used to frame the interview questions, analyze data from focus groups and interviews, and develop conclusions and recommendations. METHOD: SCI Centers at the Tampa, Seattle, and Hines Veterans' hospitals participated. The purposeful sample for the focus groups included 32 healthcare providers, 21 veterans with SCI, and 3 key informants. Analysis of qualitative data netted the percent of agreement with recommendations, performance gaps, and strategies for CPG implementation. FINDINGS: Content analysis of focus group data revealed that healthcare providers agreed or partially agreed with 20 (57%) of the 35 CSCM CPG on UL preservation of function. Agreement ranged from 100% for assessment to 28% for equipment use. Barriers for implementation related to administrative and system issues. CONCLUSION: Consideration of gaps, barriers, and facilitators to implementation will assist clinicians to target interventions to preserve UL function. PMID- 25782594 TI - Quantitative microleakage analysis of root canal filling materials in single rooted canals. AB - The purpose of this study was to analyze the sealing ability of different root canal filling materials over a 6-week period using a glucose penetration model. Forty-six recently extracted human premolars were used in this study. The root canals were enlarged to 40/0.06. Prepared canals were randomly assigned into four groups (n = 10) as follows: Group 1, Gutta-Percha (GP)/AH Plus with cold lateral compaction; Group 2, GP/AH Plus with continuous wave compaction; Group 3, RealSeal SE obturation system; and Group 4, OrthoMTA. The remaining specimens were used as positive and negative controls, and all specimens underwent thermocycling (10,000; 5-55 degrees C). The sealing ability of all samples was evaluated at 24 h, 1, 2, 4, and 6 weeks using a quantitative glucose leakage model, and scanning electron microscope (SEM) images were taken. A mixed effect analysis using R statistical language was performed. Groups 1, 2, and 4 showed low leakage levels during experimental periods. Group 3 showed low leakage levels for the first 2 weeks; however, the leakage level was significantly increased after 2 weeks compared to negative control group (p < 0.05). In the SEM results, Group 3 showed imperfect dentin bonding, whereas Group 4 showed calcium silicate hydrate short tags, which are formed at the access of the dentin tubules. GP/AH Plus and OrthoMTA showed less microleakage than RealSeal SE obturation system when used as root canal filling materials. Traditional GP/AH Plus sealer and the newly developed OrthoMTA are more appropriate for ideal sealing of the root canals. PMID- 25782596 TI - Atypical Localized Rheumatoid Nodule: Case Report. AB - Rheumatoid nodules can be seen in about 30% of patiens with rheumatoid arthritis. They are occasionally localized subcutaneous, but they can rarely seen in visceral organs. Their appearance can be confused with many clinical conditions when they have atypical localizations. To exclude the presence of a malignancy, these lesions should always be investigated. We aimed to discuss a patient with rheumatoid nodule localized in close neighborhood of hyoid bone, presumed as malignancy. PMID- 25782595 TI - An aptamer-targeting photoresponsive drug delivery system using "off-on" graphene oxide wrapped mesoporous silica nanoparticles. AB - We have developed a novel aptamer-targeting photoresponsive drug delivery system by non-covalent assembly of a Cy5.5-AS1411 aptamer conjugate on the surface of graphene oxide wrapped doxorubicin (Dox)-loaded mesoporous silica nanoparticles (MSN-Dox@GO-Apt) for light-mediated drug release and aptamer-targeted cancer therapy. The two "off-on" switches of the MSN-Dox@GO-Apt were controlled by aptamer targeting and light triggering, respectively. The Cy5.5-AS1411 ligand provides MSN-Dox@GO-Apt with nucleolin specific targeting and real-time indicator abilities by "off-on" Cy5.5 fluorescence recovery. The GO acts as a gatekeeper to prevent the loaded Dox from leaking in the absence of laser irradiation, and to control the Dox release in response to laser irradiation. When the GO wrapping falls off upon laser irradiation, the "off-on" photoresponsive drug delivery system is activated, thus inducing chemotherapy. Interestingly, with an increase in laser power, the synergism of chemotherapy and photothermal therapy in a single MSN-Dox@GO-Apt platform led to much more effective cancer cell killing than monotherapies, providing a new approach for treatment against cancer. PMID- 25782597 TI - Chemical composition and antibacterial activity of the essential oil from Agathis dammara (Lamb.) Rich fresh leaves. AB - The essential oil of fresh leaves from Agathis dammara (Lamb.) Rich was extracted using hydro-distillation, and GC-FID and GC-MS were used to analyse the essential oil. Nineteen compounds were identified, among which the major components were limonene (36.81%), beta-bisabolene (33.43%) and beta-myrcene (25.48%). In the antibacterial test, disc diffusion method and micro-well dilution assay proved that the essential oil had significant antibacterial activities. The inhibition zones against Staphylococcus aureus and Pseudomonas aeruginosa were 23.7 and 23 mm, respectively, which demonstrated that the inhibition effects were greater than positive control (10 MUg/disc streptomycin). And the lowest MIC value of the essential oil was found against S. aureus (1.25 mg/mL) and Bacillus subtilis (1.25 mg/mL). This is the first report on the antibacterial activities of A. dammara essential oil. PMID- 25782598 TI - Maxillary carcinosarcoma: Identification of a novel MET mutation in both carcinomatous and sarcomatous components through next generation sequencing. AB - BACKGROUND: Carcinosarcoma is a rare tumor with biphasic growth of the carcinomatous and sarcomatous components. Prognosis is generally poor and characterization of the molecular mechanisms may provide information for the development of novel antitumor agents and biomarkers. METHODS AND RESULTS: We present the case of 66-year-old man with a complaint of nasal obstruction. He was diagnosed with maxillary carcinosarcoma and coexisting papilloma. He underwent multimodal treatment but died of uncontrolled local disease 10 months after the initial presentation. Genetic testing using next-generation sequencing (NGS) revealed that both the carcinomatous and sarcomatous components carried a somatic mutation in the conserved domain of the mesenchymal-epithelial transition factor (MET) proto-oncogene. CONCLUSION: Our observation highlighted the importance of the MET gene in the oncogenesis of maxillary carcinosarcoma and is indicative of the common clonal origin of both malignant components. This suggested a possibility of treating MET mutation-positive carcinosarcomas with c-MET inhibitors. PMID- 25782599 TI - Evaluating technology-enhanced learning: A comprehensive framework. AB - BACKGROUND: The absence of a standard, comprehensive approach to evaluating technology-enhanced learning (TEL) limits the utility of individual evaluations, and impedes the integration and synthesis of results across studies. PURPOSE: To outline a comprehensive framework for approaching TEL evaluation in medical education, and to develop instruments for measuring the perceptions of TEL learners and instructors. METHODS AND RESULTS: Using both theoretical constructs of inquiry in education and a synthesis of existing models and instruments, we outlined a general model for evaluation that links utility, principles, and practices. From this we derived a framework for TEL evaluation that identifies seven data collection activities: needs analysis; documentation of processes, decisions, and final product; usability testing; observation of implementation; assessment of participant experience; assessment of learning outcomes; and evaluation of cost, reusability, and sustainability. We then used existing quality standards and approaches to develop instruments for assessing the experiences of learners and instructors using TEL. CONCLUSIONS: No single evaluation is likely to collect all of this information, nor would any single audience likely find all information elements equally useful. However, consistent use of a common evaluation framework across different courses and institutions would avoid duplication of effort and allow cross-course comparisons. PMID- 25782600 TI - Improving assessment practice through cross-institutional collaboration: An exercise on the use of OSCEs. AB - BACKGROUND: This study was undertaken to improve assessment practice on OSCEs through collaboration across geographically dispersed medical schools in Australia. METHODS: A total of eleven OSCE stations were co-developed by four medical schools and used in summative 2011 and 2012 examinations for the assessment of clinical performance in the early clinical and exit OSCEs in each school's medical course. Partial Credit Rasch Model was used to evaluate the psychometric properties of the shared OSCE data. Evaluation of the quality assurance reports was used to determine the beneficial impact of the collaborative benchmarking exercise on learning and teaching outcomes. RESULTS: The data for each examination demonstrated sufficient fit to the Rasch model with infit mean square values ranging from 0.88 to 0.99. Person separation (1.25-1.63) indices indicated good reliability. Evaluation of perceived benefits showed that the benchmarking process was successful as it highlighted common curriculum areas requiring specific focus and provided comparable data on the quality of teaching at the participating medical schools. CONCLUSION: This research demonstrates the validity of the psychometric data and benefits of evaluating clinical competence across medical schools without the enforcement of a prescriptive national curriculum or assessment. PMID- 25782601 TI - An online app platform enhances collaborative medical student group learning and classroom management. AB - PURPOSE: The authors presented their results in effectively using a free and widely-accessible online app platform to manage and teach a first-year pathology course at Mayo Medical School. METHODS USED: The authors utilized the Google "Blogger", "Forms", "Flubaroo", "Sheets", "Docs", and "Slides" apps to effectively build a collaborative classroom teaching and management system. Students were surveyed on the use of the app platform in the classroom, and 44 (94%) students responded. RESULTS: Thirty-two (73%) of the students reported that "Blogger" was an effective place for online discussion of pathology topics and questions. 43 (98%) of the students reported that the "Forms/Flubaroo" grade reporting system was helpful. 40 (91%) of the students used the remote, collaborative features of "Slides" to create team-based learning presentations, and 39 (89%) of the students found those collaborative features helpful. "Docs" helped teaching assistants to collaboratively create study guides or grading rubrics. Overall, 41 (93%) of the students found that the app platform was helpful in establishing a collaborative, online classroom environment. CONCLUSIONS: The online app platform allowed faculty to build an efficient and effective classroom teaching and management system. The ease of accessibility and opportunity for collaboration allowed for collaborative learning, grading, and teaching. PMID- 25782602 TI - Alternative accounting in maternal and infant global health. AB - Efforts to augment accountability through the use of metrics, and especially randomised controlled trial or other statistical methods place an increased burden on small nongovernmental organisations (NGOs) doing global health. In this paper, we explore how one small NGO works to generate forms of accountability and evidence that may not conform to new metrics trends but nevertheless deserve attention and scrutiny for being effective, practical and reliable in the area of maternal and infant health. Through an analysis of one NGO and, in particular, its organisational and ethical principles for creating a network of safety for maternal and child health, we argue that alternative forms of (ac)counting like these might provide useful evidence of another kind of successful global health work. PMID- 25782603 TI - Health-related quality of life of HIV-infected adults receiving combination antiretroviral therapy in Addis Ababa. AB - Health-related quality of life (HRQoL) is an important outcome measure among HIV infected patients receiving combination antiretroviral therapy (cART), but has not been studied extensively in resource-limited settings. Insight in the predictors or correlates of poor HRQoL may be helpful to identify patients most in need of additional support and to design appropriate interventions. A cross sectional study was conducted between September 2012 and April 2013 in 10 healthcare facilities in Addis Ababa, Ethiopia. Patients who were at least 6 months on cART were randomly selected and individual patient data were retrieved from medical records. HRQoL was measured by the WHOQoL-HIVBREF, depressive symptoms by the Kessler-6 scale, and stigma by the Kalichman internalized AIDS related stigma scale. Multivariate linear regression analysis was carried-out to examine associations between HRQoL and the other variables. A total of 664 patients (response-rate 95%) participated in the study. A higher level of depressive-symptoms was most strongly and consistently associated with a lower HRQoL, both in terms of the magnitude of the relationship and in the number of HRQoL domains associated with it. Also, a higher level of HIV-stigma was associated with a lower HRQoL except for the physical domain, while obtaining sufficient nutritious food and job opportunity were associated with a better HRQoL except for the spiritual and social domains, respectively. Demographics, clinical, and treatment characteristics yielded few significant associations with HRQoL. Our study findings suggest that interventions to improve HRQoL should focus on reducing depressive-symptoms and HIV-stigma, and on enhancing food security and job opportunity. PMID- 25782604 TI - Synthesis of cyclopropyl-substituted furans by bronsted Acid promoted cascade reactions. AB - Chloroacetic acid promotes an efficient and diastereoselective intramolecular cascade reaction of electron-deficient ynenones to deliver products featuring a 2,3,5-trisubstituted furan bearing a fused cyclopropyl substituent at the 5 position. Synthetically relevant polycyclic building blocks featuring rings of various sizes and heteroatoms have been synthesized in high yield using this mild acid-catalyzed reaction. PMID- 25782605 TI - Synthesis of elusive chloropnictenium ions. AB - This work describes the synthesis and full characterization of elusive chloropnictenium ion salts of the type [(R)Ar*N(SiMe)ECl][A] ((R)Ar* = 2,6 (CHPh2)-4-R-C6H2, R = Me, tBu; E = Sb, Bi; A(-) = GaCl4, Al(OCH(CF3)2)4). In these species the cation is significantly stabilized by weak arene interactions to flanking phenyl groups of the (R)Ar* moiety. In this context the bonding situation has been studied by computational means and the reactivity towards the Lewis base 4-dimethylaminopyridine (dmap) was investigated. PMID- 25782606 TI - Implantable nonenzymatic glucose/O2 micro film fuel cells assembled with hierarchical AuZn electrodes. AB - Hierarchical AuZn dendrites revealed electrocatalytic properties towards the glucose oxidation and the four-electron O2 reduction. The micro fuel cell using AuZn electrodes generated a power density of 2.07 and 0.29 mW cm(-2) for glucose and human whole blood. The micro film fuel cell implanted into the rat brain produced ~0.52 V continuously operating for more than 18 days. PMID- 25782607 TI - Failure to Obtain Reinstatement of an Olfactory Representation. AB - It has long been suspected that attentional processes differ between olfaction and the other senses. Here, we test whether voluntary dishabituation, seen, for example, when we re-attend to the ticking of a clock, can occur in olfaction. Participants were seated in an odorized room, where at various intervals they had to evaluate what they could smell. An experimental group had one nostril open and the other closed, except during the evaluations, so that the closed side was subject to centrally driven habituation, but not peripheral adaptation. A control group had both nostrils closed except during evaluations. Following exposure, the experimental group could not report the room's odor in either the centrally habituated nostril (i.e., that remained closed) or the nostril that remained open, while the control group could. This effect could result from a number of causes, including olfaction's unique neuroanatomy, functional constraints imposed by detecting volatile chemicals, and as a consequence of limited cortical resources, with implications for the functional value of consciousness. PMID- 25782608 TI - Optimism and depression: a new look at social support as a mediator among women at risk for breast cancer. AB - OBJECTIVE: Breast cancer risk is a chronic stressor associated with depression. Optimism is associated with lower levels of depression among breast cancer survivors. However, to our knowledge, no studies have explored the relationship between optimism and depression among women at risk for breast cancer. We hypothesized that women at risk for breast cancer who have higher levels of optimism would report lower levels of depression and that social support would mediate this relationship. METHOD: Participants (N = 199) with elevated distress were recruited from the community and completed self-report measures of depression, optimism, and social support. Participants were grouped based on their family history of breast cancer. Path analysis was used to examine the cross-sectional relationship between optimism, social support, and depressive symptoms in each group. RESULTS: Results indicated that the variance in depressive symptoms was partially explained through direct paths from optimism and social support among women with a family history of breast cancer. The indirect path from optimism to depressive symptoms via social support was significant (beta = -.053; 90% CI = -.099 to -.011, p = .037) in this group. However, among individuals without a family history of breast cancer, the indirect path from optimism to depressive symptoms via social support was not significant. CONCLUSIONS: These results suggest that social support partially mediates the relationship between optimism and depression among women at risk for breast cancer. Social support may be an important intervention target to reduce depression among women at risk for breast cancer. PMID- 25782609 TI - Development of a cognitive testing apparatus for socially housed mother-peer reared infant rhesus monkeys. AB - Though cognitive testing of infant monkeys has been practiced for the past 40 years, these assessments have been limited primarily to nursery-reared infants due to the confounds of separating mother-reared infants for assessments. Here, we describe a pilot study in which we developed a cognitive testing apparatus for socially housed, mother-peer-reared rhesus macaques under 1 year of age (Macaca mulatta) that allowed the infants to freely return to their mothers for contact comfort. Infants aged 151.2 +/- 18.3 days (mean +/- SEM; n = 5) were trained and tested on an object detour reach task. Infants completed training in 5.0 +/- 0.2 days, and completed testing in 6.2 +/- 0.9 days. Across 4 days of testing, infants improved to nearly errorless performance (Friedman test: chi(2) = 13.27, df = 3, p = 0.004) and learned to do the task more quickly (Friedman test: chi(2) = 11.69, df = 3, p = 0.009). These are the first cognitive data in group-housed, mother-peer-reared rhesus monkeys under 1 year of age, and they underscore the utility of this apparatus for studying cognitive development in a normative population of infant monkeys. PMID- 25782610 TI - Direct C(sp(2) )-C(sp(3) ) Cross-Coupling of Diaryl Zinc Reagents with Benzylic, Primary, Secondary, and Tertiary Alkyl Halides. AB - The direct C(sp(2) )-C(sp(3) ) cross-coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp(2) )-C(sp(3) ) cross-coupling showed excellent functional group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp(2) ) C(sp(3) ) bonds. PMID- 25782612 TI - Hydrogen sulfide signaling: interactions with nitric oxide and reactive oxygen species. AB - Signaling in cells involving reactive compounds is well established. Reactive oxygen species (ROS) and nitric oxide (NO) are known to be extremely influential in the control of a range of physiological responses in many organisms, from animals to plants. Often, their generation is triggered in reaction to stress, and it is common for ROS and NO metabolism to interact to give a coordinated response. Recently, hydrogen sulfide (H2 S) has also been found to be an important signaling molecule, being shown to be involved in vascular tone in animals. Of relevance to respiration, in plants, H2 S has been shown to affect stomatal apertures and the transpiration stream, while, in animals, H2 S has been shown to be a source of electrons for ATP synthesis in mitochondria. However, in signaling, H2 S does not work in isolation, and it is likely that it will interact with both ROS and NO. This may occur at a variety of levels, from influencing the generation of such molecules, interacting directly, or competing for control of downstream signaling events. A full understanding of the impact of this toxic molecule in the control of cells requires all these factors to be taken into account. PMID- 25782613 TI - Resilience, job satisfaction and anticipated turnover in nurse leaders. AB - AIMS: The aim was to identify relationships between resilience, job satisfaction and anticipated turnover among nurse leaders. BACKGROUND: Despite the reported value of resilience, there is a lack of research on resilience in nurse leaders. This study examined how nurse leaders describe their resilience and the relationship it has with job satisfaction and anticipated turnover. METHODS: This quantitative study used a sample of 89 nurse leaders (bedside, department, division and organisational) from a multi-hospital health-care system in southwestern Virginia. RESULTS: There are significant relationships between resilience, job satisfaction and anticipated turnover. Additionally, it was found that the variables of job satisfaction and anticipated turnover significantly overlapped in their meaning and created a new construct of intent to remain (ITR) that has a statistically significant relationship with resilience. IMPLICATIONS FOR NURSING MANAGEMENT: A stable nursing team has a positive impact on improving patient outcomes. To mitigate the impact of a nursing shortage, nurse leaders can enhance their own resilience and then recruit, hire and retain resilient staff nurses in an effort to improve nurses' ITR. CONCLUSION: With higher resilience, nurse leaders are more likely to intend to remain in their leadership positions. PMID- 25782614 TI - Solving the mystery: the true prevalence of gestational diabetes in indigenous women. AB - This commentary briefly reviews what is currently known about estimating the prevalence of gestational diabetes in indigenous women. It offers insights into numerous factors likely playing a role in its observed variability. It also highlights important key concepts to consider in the overall evaluation and management of gestational diabetes in this particular population. PMID- 25782616 TI - Solitary circumscribed neuroma: a clinical and dermoscopic mimicker of basal cell carcinoma. PMID- 25782611 TI - Morphological plasticity of astroglia: Understanding synaptic microenvironment. AB - Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use-dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. PMID- 25782617 TI - Inactivation of Shiga toxin-producing Escherichia coli O104:H4 using cold atmospheric pressure plasma. AB - From cultivation to the end of the post-harvest chain, heat-sensitive fresh produce is exposed to a variety of sources of pathogenic microorganisms. If contaminated, effective gentle means of sanitation are necessary to reduce bacterial pathogen load below their infective dose. The occurrence of rare or new serotypes raises the question of their tenacity to inactivation processes. In this study the antibacterial efficiency of cold plasma by an atmospheric pressure plasma-jet was examined against the Shiga toxin-producing outbreak strain Escherichia coli O104:H4. Argon was transformed into non-thermal plasma at a power input of 8 W and a gas flow of 5 L min(-1). Basic tests were performed on polysaccharide gel discs, including the more common E. coli O157:H7 and non pathogenic E. coli DSM 1116. At 5 mm treatment distance and 10(5) cfu cm(-2) initial bacterial count, plasma reduced E. coli O104:H4 after 60 s by 4.6 +/- 0.6 log, E. coli O157:H7 after 45 s by 4.5 +/- 0.6 log, and E. coli DSM 1116 after 30 s by 4.4 +/- 1.1 log. On the surface of corn salad leaves, gentle plasma application at 17 mm reduced 10(4) cfu cm(-2) of E. coli O104:H4 by 3.3 +/- 1.1 log after 2 min, whereas E. coli O157:H7 was inactivated by 3.2 +/- 1.1 log after 60 s. In conclusion, plasma treatment has the potential to reduce pathogens such as E. coli O104:H4 on the surface of fresh produce. However, a serotype-specific adaptation of the process parameters is required. PMID- 25782618 TI - Pyrolytic characteristics of biodiesel prepared from lipids accumulated in diatom cells with growth regulation. AB - Dynamic compositions of lipids accumulated in two diatoms Chaetoceros gracilis and Nitzschia closterium cultured with nitrogen and silicon deprivation were studied. It was found that short-chain fatty acids (C14-C16) content was much higher than long-chain fatty acids (C18-C20) content in lipids of two diatoms. The pyrolytic characteristics of biodiesel made from two diatoms and two plant seeds were compared by thermogravimetric analysis. The highest activation energy of 46.68 kJ mol(-1) and the minimum solid residue of 25.18% were obtained in the pyrolysis of biodiesel made from C. gracilis cells, which were cultured with 0.5 mmol L(-1) of nitrogen (no silicon) and accumulated the minimum polyunsaturated fatty acid (C20:5). The pyrolysis residue percentage of C. gracilis biodiesel was lower than that of N. closterium biodiesel and higher than those of plant (Cormus wilsoniana and Pistacia chinensis) biodiesels. PMID- 25782620 TI - What to do when the numbers don't add up. PMID- 25782619 TI - Characterization of lipid and fatty acids composition of Chlorella zofingiensis in response to nitrogen starvation. AB - Cellular biochemical composition of the microalga Chlorella zofingiensis was studied under favorable and nitrogen starvation conditions, with special emphasis on lipid classes and fatty acids distribution. When algal cells were grown in nitrogen-free medium (N stress), the increase in the contents of lipid and carbohydrate while a decrease in protein content was detected. Glycolipids were the major lipid fraction (50.7% of total lipids) under control condition, while neutral lipids increased to be predominant (86.7% of total lipids) under N stress condition. Triacylglycerol (TAG) content in N stressed cells was 27.3% dw, which was over three times higher than that obtained under control condition. Within neutral lipids fraction, monounsaturated fatty acids (MUFA) were the main group (40.6%) upon N stress, in which oleic acid was the most representative fatty acids (34.5%). Contrarily, glycolipids and phospholipids showed a higher percentage of polyunsaturated fatty acids (PUFA). Lipid quality assessment indicated the potential of this alga as a biodiesel feedstock when its neutral lipids were a principal lipid fraction. The results demonstrate that the neutral lipids content is key to determine the suitability of the microalga for biodiesel, and the stress cultivation is essential for lipid quality. PMID- 25782621 TI - Contribution of Antemortem Computed Tomography Findings to Cause of Death Determination: An Unusual Fatal Stroke. AB - In the case reported here, the antemortem computed tomography scan (CT scan) was essential in the forensic investigation. A 32-year-old man was found fully awake with a facial abrasion, after what seemed to be a car accident. He lost consciousness suddenly one hour after initial management. Successive CT scan showed a facial fracture and a metallic foreign body in the carotid canal associated with an occlusion/dissection of the left internal carotid, a pseudoaneurysm, and a carotid-cavernous fistula. The victim died from a stroke. Autopsy confirmed that the facial abrasion was a gunshot entrance wound, the metallic foreign body being a projectile. Intracranial vascular injuries linked with gunshot wounds are most of the time isolated and due to pelet embolism. The observed vascular injury association has never been described in the existing literature. The CT scan provided a better understanding of the chronology of events that led to death. PMID- 25782622 TI - Usefulness of citric cough test for screening of silent aspiration in subacute stroke patients: a prospective study. AB - OBJECTIVE: To detect silent aspiration in a homogeneous sample of stroke patients using the citric acid cough test. DESIGN: Prospective study. SETTING: Public university tertiary hospital. PARTICIPANTS: Consecutive subacute stroke patients (N=134; 74 men, 60 women; mean age +/- SD, 62.2+/-11.9y; 11.7+/-9.9d after stroke) who had complained of dysphagic symptoms, referred for rehabilitation from December 2010 to October 2012. INTERVENTION: All patients were administered a citric acid cough test and underwent a videofluoroscopic swallowing study (VFSS). A reduced or an absent response on the citric acid cough test was considered when cough peaks were <=4. A control group of healthy volunteers was also screened. MAIN OUTCOME MEASURES: The citric acid cough test results were compared with the VFSS results, which were used as a criterion standard. RESULTS: There were 36 patients with a positive citric acid cough test, of which the VFSS revealed penetration in 14 cases (38.9%), aspiration in 5 (13.9%), silent aspiration in 5 (13.9%), and normality in 12 patients (33.3%). The sensitivity and specificity indexes for the reliability of citric acid cough test as a screening method for silent aspiration in comparison with the VFSS were .19 and .71, respectively. Other comparisons were made between silent aspirators (Penetration Aspiration Scale=8) and different subgroups of patients, but values remained poor. CONCLUSIONS: The citric acid cough test using 1.0 (weight by volume)% for 1 minute does not seem to be a useful standalone tool to screen for silent aspiration in subacute stroke patients with suspected dysphagia. PMID- 25782624 TI - New double-stapled anastomotic technique to avoid crossing staple lines. PMID- 25782623 TI - The application of PADUA scoring system for predicting complications of laparoscopic renal cryoablation. AB - PURPOSE: To evaluate the clinical application of preoperative aspects and dimensions used for anatomical (PADUA) scoring system in predicting perioperative surgical outcomes in patients undergoing laparoscopic cryoablation (LCA). METHODS: A total of 95 consecutive renal tumors treated with LCA between January 2007 and April 2013 were collected. Renal tumors were categorized into low- (6 7), moderate- (8-9), and high-complexity (10-13) groups according to PADUA indices. Demographics, perioperative variables, and complication rates were compared among three groups. Surgical conversion, blood loss >100 mL, tumor fracture, and incomplete ablation were regarded as intraoperative complications (IOCs). All postoperative complications (POCs) were graded using the Clavien Dindo system. The risk for complications was assessed by univariate and multivariate logistic regression analyses. RESULTS: The estimated blood loss during LCA was associated with PADUA score. There were 17 (17.9%) IOCs and 20 (21.1%) POCs. Blood loss (>100 mL) was the most common IOC, which occurred in 10 (10.5%) patients. For POC, there were 15 (15.8%) minor complications (Clavien 1 2) and 5 (5.3%) major complications (Clavien 3a). Higher grade of PADUA scores was significantly correlated with the increase incidence of IOC and POC. The PADUA score was an independent predictive factor for POC, and the patients with moderate and high PADUA scores had an over sixfold and 17-fold higher risk compared to the patients with low scores, respectively. CONCLUSION: Our findings demonstrated, for the first time, the PADUA scoring system is an efficient assessment tool for predicting the perioperative complications in patients undergoing laparoscopic renal cryoablation. PMID- 25782625 TI - Aniosotropically organized LDH on PVDF: a geometrically templated electrospun substrate for advanced anion conducting membranes. AB - A bioinspired geometric templating of an electrospun PVDF substrate with hexagonal platelets of Mg-Al layered double hydroxide (LDH), an intrinsic anion conductor, is presented. The distinctive morphology restructures the internal pore geometry and modulates the dynamic wetting profile of PVDF, transforming it into a highly functional substrate for SAFC anion conducting membranes. The membrane fabricated with PVDF-LDH substrate exhibited exceptionally high durability (>140 degrees C), high anionic conductivity, ion exchange capacity (IEC), restricted swelling, and improved tensile strength, overcoming critical challenges associated with PVDF electrospun substrates and validating its immense potential as a high-temperature-stable and durable substrate for advanced fuel cell membrane applications. PMID- 25782626 TI - Adaptation and penetration of resin-based root canal sealers in root canals irradiated with high-intensity lasers. AB - This research analyzed the quality of resin-based sealer adaptation after intracanal laser irradiation. Extracted teeth (n = 168) were root canal treated and divided into four groups, according to dentin surface treatment: no laser; Nd:YAG laser (1.5 W, 100 mJ, 15 Hz); diode laser (2.5 W in CW), and Er:YAG laser (1 W, 100 mJ, 10 Hz). The teeth were divided into four subgroups according to the sealer used: AH Plus, EndoREZ, Epiphany, and EpiphanySE. For testing the sealing after root canal obturation, the penetration of silver nitrate solution was measured, whereas to evaluate the adaptation and penetration of the sealer into the dentin, environmental scanning electron microscopy (ESEM) was used. The ESEM images were analyzed using a four-grade criteria score by three evaluators. The inter-examiner agreement was confirmed by Kappa test and the scores statistically compared by the Kruskal-Wallis' test (p < 0.05). Both adaptation and sealer penetration in root canals were not affected by the laser irradiation. Nd:YAG and diode laser decreased the tracer penetration for AH Plus, whereas EndoREZ and EpiphanySE performances were affected by Nd:YAG irradiation (p < 0.05). It can be concluded that intracanal laser irradiation can be used as an adjunct in endodontic treatment; however, the use of hydrophilic resin sealers should be avoided when root canals were irradiated with Nd:YAG laser. PMID- 25782627 TI - Serum albumin and health in older people: Review and meta analysis. AB - Albumin is the most abundant plasmatic protein. It is only produced by the liver and the full extent of its metabolic functions is not known in detail. One of the main roles assigned to albumin is as an indicator of malnutrition. There are many factors, in addition to nutrition, that influence levels of albumin in plasma. The main aim of this review is to assess the clinical significance of albumin in elderly people in the community, in hospital and in care homes. Following the review, it can be stated that age is not a cause of hypoalbuminemia. Albumin is a good marker of nutritional status in clinically stable people. Significant loss of muscle mass has been observed in elderly people with low albumin levels. Hypoalbuminemia is a mortality prognostic factor in elderly people, whether they live in the community or they are in hospital or institutionalized. Low levels of albumin are associated to worse recovery following acute pathologies. Inflammatory state and, particularly, high concentrations of IL-6 and TNF-alpha, are two of the main influencing factors of hypoalbuminemia. In elderly patients with a hip fracture, albumin levels below 38 g/L are associated to a higher risk of post-surgery complications, especially infections. Further research is needed on the impact of nutritional intervention upon albumin levels and on the outcomes in elderly people in the community, in hospital and in care. PMID- 25782628 TI - Mass spectrometric methods to analyze the structural organization of macromolecular complexes. AB - With the development of soft ionization techniques such as electrospray ionization (ESI), mass spectrometry (MS) has found widespread application in structural biology. The ability to transfer large biomolecular complexes intact into the gas-phase, combined with the low sample consumption and high sensitivity of MS, has made ESI-MS a method of choice for the characterization of macromolecules. This paper describes the application of MS to study large non covalent complexes. We categorize the available techniques in two groups. First, solution-based techniques in which the biomolecules are labeled in solution and subsequently characterized by MS. Three MS-based techniques are discussed, namely hydroxyl radical footprinting, cross-linking and hydrogen/deuterium exchange (HDX) MS. In the second group, MS-based techniques to probe intact biomolecules in the gas-phase, e.g. side-chain microsolvation, HDX and ion mobility spectrometry are discussed. Together, the approaches place MS as a powerful methodology for an ever growing plethora of structural applications. PMID- 25782630 TI - Evidence that the expression of transferrin receptor 1 on erythroid marrow cells mediates hepcidin suppression in the liver. AB - Hepcidin is the key regulator of iron absorption and recycling, and its expression is suppressed by red blood cell production. When erythropoiesis is expanded, hepcidin expression decreases. To gain insight into the stage of erythroid differentiation at which the regulation might originate, we measured serum hepcidin levels in archived pure red cell aplasia samples from patients whose block in erythroid differentiation was well defined by hematopoietic colony assays and marrow morphologic review. Hepcidin values are high or high normal in pure red cell aplasia patients in whom erythropoiesis is inhibited prior to the proerythroblast stage, but are suppressed in patients with excess proerythroblasts and few later erythroid cells. These data suggest that the suppressive effect of erythropoietic activity on hepcidin expression can arise from proerythroblasts, the stage at which transferrin receptor 1 expression peaks, prompting the hypothesis that transferrin receptor 1 expression on erythroid precursors is a proximal mediator of the erythroid regulator of hepcidin expression. Our characterization of erythropoiesis, iron status, and hepcidin expression in mice with global or hematopoietic cell-specific haploinsufficiency of transferrin receptor 1 provides initial supporting data for this model. The regulation appears independent of erythroferrone and growth differentiation factor 15, supporting the concept that several mechanisms signal iron need in response to an expanded erythron. PMID- 25782629 TI - Evaluating kinase ATP uptake and tyrosine phosphorylation using multiplexed quantification of chemically labeled and post-translationally modified peptides. AB - Cancer biologists and other healthcare researchers face an increasing challenge in addressing the molecular complexity of disease. Biomarker measurement tools and techniques now contribute to both basic science and translational research. In particular, liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) for multiplexed measurements of protein biomarkers has emerged as a versatile tool for systems biology. Assays can be developed for specific peptides that report on protein expression, mutation, or post translational modification; discovery proteomics data rapidly translated into multiplexed quantitative approaches. Complementary advances in affinity purification enrich classes of enzymes or peptides representing post translationally modified or chemically labeled substrates. Here, we illustrate the process for the relative quantification of hundreds of peptides in a single LC-MRM experiment. Desthiobiotinylated peptides produced by activity-based protein profiling (ABPP) using ATP probes and tyrosine-phosphorylated peptides are used as examples. These targeted quantification panels can be applied to further understand the biology of human disease. PMID- 25782631 TI - Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice. AB - Arginine vasopressin (AVP) plays a regulatory role in nociception. Intrathecal administration of AVP displays an antinociceptive effect. However, little is understood about the mechanism underlying spinal AVP analgesia. Here, we have found that spinal AVP dose dependently reduced the second, but not first, phase of formalin-induced spontaneous nociception in mice. The AVP analgesia was completely blocked by intrathecal injected SR 49059, a vasopressin-1A (V1A) receptor antagonist. However, spinal AVP failed to exert its antinociceptive effect on the second phase formalin-induced spontaneous nociception in V1A receptor knock-out (V1A-/-) mice. The AVP analgesia was also reversed by bicuculline, a GABAA receptor antagonist. Moreover, AVP potentiated GABA activated currents in dorsal root ganglion neurons from wild-type littermates, but not from V1A-/- mice. Our results may reveal a novel spinal mechanism of AVP analgesia by enhancing the GABAA receptor function in the spinal cord through V1A receptors. PMID- 25782632 TI - Carbon filtration cathode in microbial fuel cell to enhance wastewater treatment. AB - A homogeneous carbon membrane with multi-functions of microfiltration, electron conduction, and oxygen reduction catalysis was fabricated without using noble metals. The produced carbon membrane has a pore size of 553nm, a resistance of 6.0+/-0.4Omegacm(2)/cm, and a specific surface area of 32.2m(2)/g. After it was assembled in microbial fuel cell (MFC) as filtration air cathode, a power density of 581.5mW/m(2) and a current density of 1671.4mA/m(2) were achieved, comparable with previous Pt air cathode MFCs. The filtration MFC was continuously operated for 20days and excellent wastewater treatment performance was also achieved with removal efficiencies of TOC (93.6%), NH4(+)-N (97.2%), and total nitrogen (91.6%). In addition, the carbon membrane was much cheaper than traditional microfiltration membrane, suggesting a promising multi-functional material in wastewater treatment field. PMID- 25782633 TI - Simultaneous utilization of glucose and mannose from woody hydrolysate for free fatty acid production by metabolically engineered Escherichia coli. AB - In this study, the Escherichia coli strain MG1655 with fadD mutant (named as ML103), and MG1655 with fadD and ptsG double mutant (named as ML190) carrying the plasmid with the acyl-ACP thioesterase (TE) from Ricinus communis (pXZ18) or the plasmid with the combination of the TE and the native (3R)-hydroxyacyl-ACP dehydrase (fabZ) (pXZ18Z), produced free fatty acids (FFAs) efficiently using mannose as the sole carbon source. Due to the carbon catabolite repression (CCR) regulation, ML103(pXZ18) utilized glucose and mannose sequentially in the mixed sugar culture, while ML190(pXZ18) and ML190(pXZ18Z), with ptsG mutation, used glucose and mannose simultaneously. The highest total FFA concentration from the mixed sugar culture reached 2.96g/L by ML190(pXZ18Z). Furthermore, the strain ML190(pXZ18Z) can produce 2.86g/L FFAs with a high yield of 0.23g/g using hydrolysate mainly contained glucose and mannose from a commercial plant. PMID- 25782634 TI - Arsenic biotransformation and release by bacteria indigenous to arsenic contaminated groundwater. AB - Arsenic (As) biotransformation and release by indigenous bacteria from As rich groundwater was investigated. Metabolic landscape of 173 bacterial isolates indicated broad catabolic repertoire including abundance of As(5+) reductase activity and abilities in utilizing wide ranges of organic and inorganic respiratory substrates. Abundance of As homeostasis genes and utilization of hydrocarbon as carbon/electron donor and As(5+) as electron acceptor were noted within the isolates. Sediment microcosm study (for 300 days) showed a pivotal role of metal reducing facultative anaerobic bacteria in toxic As(3+) release in aqueous phase. Inhabitant bacteria catalyze As transformation and facilitate its release through a cascade of reactions including mineral bioweathering and As(5+) and/or Fe(3+) reduction activities. Compared to anaerobic incubation with As(5+) reducing strains, oxic state and/or incubation with As(3+) oxidizing bacteria resulted in reduced As release, thus indicating a strong role of such condition or biocatalytic mechanism in controlling in situ As contamination. PMID- 25782635 TI - Global health perspective on gynecologic oncology. AB - OBJECTIVE: To describe challenges faced by low-middle income countries (LMICs) across the cancer spectrum, with specific focus on gynecologic cancers. METHODS: MEDLINE was searched for research articles published in English between January 1, 2000 and February 1, 2015 which reported on global health efforts in LMICs. RESULTS: An estimated 80% of global cancer burden and only 5% of global cancer spending affect LMICs. The overwhelming majority of cervical cancer cases and related deaths occur in LMICs. The charge to close this cancer divide is at the center of global health efforts. CONCLUSIONS: Prevention is central to global health efforts to close the cancer divide. The gynecologic oncology community is well positioned to lead efforts in global health by partnering with institutions, professional societies and advocacy groups. PMID- 25782636 TI - Mirror-image gastroschisis in monochorionic female twins. AB - We report a case of "mirror-image" gastroschisis in female monochorionic twins. One of the twins presents a right-sided gastroschisis, the other a left-sided gastroschisis. Both twins have anteriorly placed anus and sacral dimple. To the best of our knowledge, this represents the first case of mirror image or discordant left and right gastroschisis in monochorionic twins reported in the literature. This observation may shed further light on the pathogenesis of gastroschisis. PMID- 25782637 TI - Proteus syndrome: Report of a case with AKT1 mutation in a dental cyst. AB - Proteus syndrome (PS) is a sporadic and rare congenital disorder characterized by a patchy or mosaic postnatal overgrowth, sometimes involving the face. The onset of overgrowth typically occurs in infancy and can commonly involve skin, connective tissue, central nervous system, eyes and viscera. The progressive overgrowth causes severe complications, such as skeletal deformities, cystic lung disease, invasive lipomas, connective tissue hyperplasia, benign and malignant tumours and deep venous thrombosis with pulmonary embolism, which can cause premature death. This disorder is caused by somatic mosaicism for a specific activating AKT1 mutation that would be lethal in a non-mosaic state. In this report, current knowledge of the aetiology, the diagnosis and the craniofacial manifestations of the disorder are reviewed. The short-term management of a 7 year-old patient with unusual oral manifestations is described. For the first time mutation of AKT1 (c.49G > A) gene was detected both in cranial exostosis and in central odontogenic fibroma of the lower jaw. PMID- 25782638 TI - Phenotype-genotype correlations for clinical variants caused by CYLD mutations. AB - Brooke-Spiegler syndrome (BSS; OMIM 605041) is an autosomal dominant condition characterized by skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. In 1996, the gene locus for BSS was mapped to 16q12-13, and, in 2000, mutations in the cylindromatosis (CYLD) gene were determined to cause BSS, familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606). The CYLD gene encodes an enzyme with deubiquitinase activity. To date, a total of 95 different diseases-causing mutations have been published for the CYLD gene. A summary of mutations identified in Hungarian patients and a review of previously published mutations are presented in this update. The majority of the sequence changes are frameshift (48%), nonsense (27%), missense (12%) and splice-site (11%) mutations; however, two in-frame deletions have also been reported. Most mutations are located in exons 9-20. Analysis of the identified CYLD gene mutations and the observed BSS, FC and MFT1 clinical phenotypes of the patients revealed significant genotype-phenotype correlations. Elucidation of these genotype phenotype correlations is critical for the diagnosis of these rare monogenic skin diseases. In addition, characterizing these correlations may promote the understanding of their mechanisms and may hopefully contribute to the development of future therapeutic modalities. PMID- 25782639 TI - Salt's Portable Ether Inhaler. PMID- 25782640 TI - Flipping the Paradigm: From Surgery-specific to Patient-driven Perioperative Analgesic Algorithms. PMID- 25782641 TI - Lizzie's Laughing Gas Request on a Dam Family Postcard. PMID- 25782642 TI - Sailor advertising card for "compound oxygen". PMID- 25782643 TI - How chloroforming rice launched a university and a moonshot. PMID- 25782644 TI - Analgesic effect of perioperative escitalopram in high pain catastrophizing patients after total knee arthroplasty: a randomized, double-blind, placebo controlled trial. AB - BACKGROUND: Sufficient pain treatment remains a challenge after total knee arthroplasty (TKA), especially in high pain catastrophizing patients. Serotonergic signaling may be involved in pain processing, but the effect of selective serotonin reuptake inhibitors on well-defined postoperative pain has not previously been investigated. The authors hypothesized that perioperative escitalopram would reduce pain after TKA in high pain catastrophizing patients. METHODS: A total of 120 pain catastrophizing patients (selected using the pain catastrophizing scale as preoperative screening tool) scheduled for TKA were randomized in a double-blind manner to either 10 mg escitalopram or placebo daily from preanesthesia to postoperative day 6 in addition to a standardized analgesic regime. The primary outcome was pain upon ambulation 24 h after surgery. Secondary outcomes were overall pain during well-defined mobilizations and at rest from 2 to 48 h and from days 2 to 6, morphine equivalents, anxiety, depression, and side effects. RESULTS: Pain upon ambulation (mean [95% CI]) 24 h after surgery in the escitalopram versus placebo group was 58 (53 to 64) versus 64 (58 to 69), the mean difference being -5 (-13 to 3), P = 0.20. Overall pain upon ambulation and at rest from days 2 to 6 was lower in the escitalopram versus placebo group, as was depression score at day 6 (all P <= 0.01 in analyses uncorrected for multiple tests). Side effects were nonsignificant except for reduced tendency to sweat and prolonged sleep in the escitalopram group. No other between-group differences were observed. CONCLUSIONS: Escitalopram did not reduce pain upon ambulation 24 h after TKA in high pain catastrophizing patients. Future studies on optimal timing, dose, and duration of selective serotonin reuptake inhibitor treatment might be warranted. PMID- 25782645 TI - When the statistics steal the show. PMID- 25782646 TI - Cost effectiveness of continuous femoral blocks for total knee replacement. PMID- 25782647 TI - In reply. PMID- 25782648 TI - Another role of limb remote ischemic preconditioning in patients with lung cancer. PMID- 25782649 TI - In reply. PMID- 25782656 TI - The effect of exercise training on the pulmonary arterial system in patients with pulmonary hypertension. AB - Given the unique and clinically ominous pathology associated with pulmonary arterial (PA) hypertension (PH) and its implications for the eventual deterioration of right ventricular function, exercise training (ET) was historically not recommended. More recently, a body of literature demonstrating the safety and efficacy of ET in PH has emerged. The primary focus of this review is to provide a synopsis of current evidence assessing the effects of ET on the PA system in patients with PH. The current body of evidence is relatively small and it is not clear if ET improves PA function or vessel characteristics. Nevertheless, studies have consistently found ET leads to numerous clinically relevant benefits including increased: 1) aerobic capacity, 2) muscle strength, 3) exercise tolerance, and 4) quality of life. Thus, ET, given its clinical benefits, is likely to enjoy increased utilization in patients with PH. PMID- 25782657 TI - Does Maternal Perinatal Probiotic Supplementation Alter the Intestinal Microbiota of Mother and Child? AB - OBJECTIVES: Maternal probiotic supplementation has been shown to prevent the development of atopic dermatitis in the offspring. We aimed to investigate whether probiotics in pregnant and breast-feeding mothers altered the colonization pattern and the diversity of the mothers' and children's intestinal microbiota. METHODS: In a randomized, double-blind trial, women received probiotic milk or placebo from 36 weeks of gestation up to 3 months postnatally while breast-feeding. The probiotic milk contained Lactobacillus rhamnosus GG, L acidophilus La-5, and Bifidobacterium animalis subsp. lactis Bb-12. Stool samples were collected from the mothers at 30 to 36 weeks of gestation and 3 months after birth, and from the child at age 10 days, 3 months, 1 year, and 2 years, and bacteria were analyzed by quantitative polymerase chain reaction. Additionally, stool samples from 3-month-old and 2-year-old children were characterized using 16S ribosomal RNA gene deep sequencing to estimate the bacterial classes and genera, and the alpha- and beta-diversity. RESULTS: Three months after birth, both the prevalence and the relative abundance of the administered probiotic bacteria were significantly increased among the mothers in the probiotic group compared with among those in the placebo group. Only the Lactobacillus rhamnosus GG bacteria colonized the children at 10 days and at 3 months of age. There were no significant differences in the abundance of the administered probiotic bacteria between the groups at 1 and 2 years of age. For the bacterial classes and genera, and alpha- and beta-diversity, there were no significant differences between the groups. CONCLUSIONS: Different probiotic bacteria seem to have different ability to transfer from the mother to the child. We found no evidence that the probiotics altered the microbial composition or alpha- and beta diversity of the children. PMID- 25782658 TI - Pancreatic Enzyme Replacement Therapy and Coefficient of Fat Absorption in Children and Adolescents With Cystic Fibrosis. AB - OBJECTIVES: Pancreatic enzyme replacement therapy (PERT) is the proven therapy to substantially reduce fat malabsorption in patients with cystic fibrosis (CF). Few details of the daily practice regarding PERT and the resulting coefficient of fat absorption (CFA) are known. We therefore recorded the PERT and CFA in a large cohort of pancreatic insufficient pediatric patients with CF. METHODS: We retrospectively studied 1719 completed 3-day dietary food records, including the pancreatic enzyme intake registrations, and 1373 CFA assessments of 224 patients with CF, ages 0-17 years. The clinical characteristics, PERT, expressed as an intake of lipase unit (LU) per gram of fat per day and LU per kilogram per day, and the CFA were described for the group as a whole and separately for those on enteral tube feeding. Cross-sectional relationship between the CFA and the LU per gram of fat per day and LU per kilogram per day were determined for each year of age. We also addressed the effect of the interventions done in patients with CFA outcomes <85%. RESULTS: The LU per gram of fat per day was relatively stable throughout the age groups, whereas the LU per kilogram per day fell markedly with age. The median CFA in the age group 17 varied between 86% and 91%, however, with a CFA below 85% in 325 of 1373 (24%) of the measurements. No relationship was found between PERT and CFA. The patients with persistent CFA less than 85% had significant lower z scores weight for age and weight for height (P = 0.01) than those with CFA at least 85%. CONCLUSIONS: In this study population, no correlation between an enzyme dosage and the degree of fat malabsorption was found; however, a CFA below 85% was found in 24% of the measurements. PMID- 25782659 TI - Gluten-Free Diet and Lipid Profile in Children With Celiac Disease: Comparison With General Population Standards. AB - OBJECTIVES: A gluten-free diet (GFD) may carry high energy and fat load. We verified lipid profile and dietary indicators cross-sectionally and prospectively in patients with celiac disease (CD). METHODS: In any consecutive child receiving a GFD (group 1) or newly diagnosed as having CD (group 2), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), anthropometric data, physical activity, and a 24-hour food diary were collected during follow-up visits (yearly in group 1 and during the first year of GFD in group 2). RESULTS: In group 1 (132 girls, 73 boys, 10.7 +/- 4.2 years), TC (P = 0.006), TG (P = 0.014), and HDL (P = 0.019) were significantly higher in girls than in boys. Compared with the general pediatric population, group 1 girls had higher TC, TG, HDL, and low-density lipoprotein; group 1 boys had lower TC, TG, and low-density lipoprotein and higher HDL. TC was significantly and positively affected by age, sex, and time receiving GFD, whereas HDL was significantly and positively affected by body mass index, diastolic BP, and sex; TG was negatively affected by diastolic BP. Compared with recommendations, group 1 children introduced less calories, iron, and calcium; one-third more sodium; similar amounts of fiber; and twice as many proteins. In group 2 (20 girls, 10 boys, 8.6 +/- 3.55 years), TC did not change over time and TG diminished, whereas HDL, blood glucose, and body mass index increased; saturated fats and caloric intake were below recommendations, whereas proteins were excessively introduced. Fibers were optimal. HDL was inversely correlated to calories and saturated fat (R2 = 80, P = 0.011). CONCLUSIONS: Lipid profiles of children with CD differ across sexes and from reference population. GFD, being unexpectedly appropriate in fibers and fat proportion, may be a contributor. PMID- 25782660 TI - Dietary Effects on Plasma Glycerophospholipids. AB - OBJECTIVE: Human milk provides a complex mixture of animal lipids, whereas the fat supply of most modern infant formula is based on vegetable oils. We studied the effects of breast-feeding and of feeding infant formula either without or with dairy goat lipids on the composition of infant plasma glycerophospholipids. METHODS: Healthy-term infants were randomized double blind to feeding with infant formula based on whole goats' milk (GIF, approximately 60% milk fat and 40% vegetable oils) or a control cows' milk infant formula based on vegetable oils (VIF) from 2 weeks after birth. A reference group of fully breast-fed infants was also followed. At the age 4 months, blood samples were collected and plasma glycerophospholipids were analyzed with liquid chromatography coupled to triple quadrupole mass spectrometry. RESULTS: The group of breast-fed infants showed significantly higher contents of glycerophospholipid species containing sn-2 palmitic acid [PC(16:0/16:0) and PC(18:0/16:0)] and significantly higher contents of glycerophospholipid species containing long-chain polyunsaturated fatty acids than infants in both formula groups. The GIF group demonstrated significantly higher glycerophospholipid species containing myristic acid [LPC(14:0), PC(14:0/18:1), PC(16:0/14:0)] and palmitoleic acid [LPC(16:1), PC(16:0/16:1), and PC(16:1/18:1)] than the VIF group. CONCLUSIONS: We conclude that breast-feeding induces marked differences in infant plasma glycerophospholipid profiles compared with formula feeding, whereas the studied different sources of formula fat resulted in limited effects on plasma glycerophospholipids. PMID- 25782661 TI - Wireless capsule endoscopy of the small intestine in children. AB - Wireless capsule endoscopy (CE) for the diagnosis of small-bowel disease has been in clinical use for more than a decade, and is no longer an emerging technology, but rather one that has reached fruition. This noninvasive technology has been readily embraced by both physicians and patients. Used in the diagnosis of inflammatory bowel disease, for locating sources of obscure gastrointestinal bleeding, and for assessing small-bowel polyp burden in polyposis syndromes as well as for less common indications, CE has transformed the diagnostic algorithms of small-bowel investigations. Although already in widespread use, the technology incorporated into the various CE platforms continues to improve and expand. Here, we briefly review the indications, limitations, and advances in video capsule technology, with an emphasis on its use in pediatrics. PMID- 25782662 TI - Ropivacaine 0.375% vs. 0.75% with prilocaine for intermediate cervical plexus block for carotid endarterectomy: A randomised trial. AB - BACKGROUND: Carotid endarterectomy is widely performed under regional anaesthesia. Ultrasound guidance is increasingly used in many regional anaesthetic procedures to improve safety and efficacy, and because it can reduce the amount of local anaesthetic required. Despite this, an ideal approach and dosing regimen for cervical plexus block remain elusive. OBJECTIVE: The aim of this study was to compare two different concentrations of ropivacaine in terms of analgesic adequacy, haemodynamic effects and plasma concentration using an ultrasound-guided triple approach for intermediate cervical plexus blockade. DESIGN: A randomised, placebo-controlled, blinded study. SETTING: University Clinic Salzburg, Department of Anaesthesiology, Perioperative Medicine and Intensive Care, Paracelsus Medical University, Salzburg, Austria, from 16 November 2012 to 17 September 2013. PATIENTS: Forty-six patients prospectively randomised to receive ultrasound-guided intermediate cervical block with either 20 ml ropivacaine 0.75% or 20 ml ropivacaine 0.375% each with 20 ml prilocaine 1%. INTERVENTION: After subcutaneous infiltration, blocks were performed using ultrasound-guided infiltration below the sternocleidomastoid muscle, and ultrasound-guided infiltration of the carotid sheath. Ropivacaine and prilocaine plasma concentrations were measured at intervals. MAIN OUTCOME: The primary study endpoint was the volume of supplementary lidocaine 1% required to achieve adequate surgical anaesthesia. Perioperative haemodynamic variables and pain scores were recorded. RESULTS: There was no statistical difference in the volume of supplementary lidocaine given: 5.0 (+/-3.63) ml in the ropivacaine 0.375% group and 5.17 (+/-2.76) ml in the ropivacaine 0.75% group (P = 0.846). Pain scores were similarly low across both groups. Measured concentrations of ropivacaine and prilocaine did not reach toxic levels in either group. Levels of ropivacaine were approximately two-fold higher in the 0.75% group [mean area under the curve (AUC) 10 531.11 (+/-2912.84) vs. 5264.34 ng (+/-1594.69), P < 0.0001]. Perioperative cardiovascular stability was excellent in both groups. There were no serious block-related complications. CONCLUSION: An ultrasound guided intermediate block provides adequate anaesthesia for carotid thrombendarterectomy with a little need for supplementary local anaesthetic. Use of 0.375% ropivacaine provided similarly effective analgesia as 0.75%, but resulted in significantly lower plasma concentrations. TRIAL REGISTRATION: The study was registered at the European Clinical Trial Database (Eudra CT No.: 2012 002769) as well as at ClinicalTrials.gov (NCT01759940). PMID- 25782663 TI - Reply to: Statistical analysis methods for meta-analysis of times to emergence. PMID- 25782664 TI - Overexpression of DHX32 contributes to the growth and metastasis of colorectal cancer. AB - Our previous work demonstrates that DHX32 is upregulated in colorectal cancer (CRC) compared to its adjacent normal tissues. However, how overexpressed DHX32 contributes to CRC remains largely unknown. In this study, we reported that DHX32 was overexpressed in human colon cancer cells. Overexpressed DHX32 promoted SW480 cancer cells proliferation, migration, and invasion, as well as decreased the susceptibility to chemotherapy agent 5-Fluorouracil. Furthermore, PCR array analyses revealed that depleting DHX32 in SW480 colon cancer cells suppressed expression of WISP1, MMP7 and VEGFA in the Wnt pathway, and anti-apoptotic gene BCL2 and CA9, however, elevated expression of pro-apoptotic gene ACSL5. The findings suggested that overexpressed DHX32 played an important role in CRC progression and metastasis and that DHX32 has the potential to serve as a biomarker and a novel therapeutic target for CRC. PMID- 25782665 TI - Differentiation of human induced pluripotent stem cells to mature functional Purkinje neurons. AB - It remains a challenge to differentiate human induced pluripotent stem cells (iPSCs) or embryonic stem (ES) cells to Purkinje cells. In this study, we derived iPSCs from human fibroblasts and directed the specification of iPSCs first to Purkinje progenitors, by adding Fgf2 and insulin to the embryoid bodies (EBs) in a time-sensitive manner, which activates the endogenous production of Wnt1 and Fgf8 from EBs that further patterned the cells towards a midbrain-hindbrain boundary tissue identity. Neph3-positive human Purkinje progenitors were sorted out by using flow cytometry and cultured either alone or with granule cell precursors, in a 2-dimensional or 3-dimensional environment. However, Purkinje progenitors failed to mature further under above conditions. By co-culturing human Purkinje progenitors with rat cerebellar slices, we observed mature Purkinje-like cells with right morphology and marker expression patterns, which yet showed no appropriate membrane properties. Co-culture with human fetal cerebellar slices drove the progenitors to not only morphologically correct but also electrophysiologically functional Purkinje neurons. Neph3-posotive human cells could also survive transplantation into the cerebellum of newborn immunodeficient mice and differentiate to L7- and Calbindin-positive neurons. Obtaining mature human Purkinje cells in vitro has significant implications in studying the mechanisms of spinocerebellar ataxias and other cerebellar diseases. PMID- 25782666 TI - Isotopic resonance hypothesis: experimental verification by Escherichia coli growth measurements. AB - Isotopic composition of reactants affects the rates of chemical and biochemical reactions. As a rule, enrichment of heavy stable isotopes leads to progressively slower reactions. But the recent isotopic resonance hypothesis suggests that the dependence of the reaction rate upon the enrichment degree is not monotonous. Instead, at some "resonance" isotopic compositions, the kinetics increases, while at "off-resonance" compositions the same reactions progress slower. To test the predictions of this hypothesis for the elements C, H, N and O, we designed a precise (standard error +/-0.05%) experiment that measures the parameters of bacterial growth in minimal media with varying isotopic composition. A number of predicted resonance conditions were tested, with significant enhancements in kinetics discovered at these conditions. The combined statistics extremely strongly supports the validity of the isotopic resonance phenomenon (p ? 10( 15)). This phenomenon has numerous implications for the origin of life studies and astrobiology, and possible applications in agriculture, biotechnology, medicine, chemistry and other areas. PMID- 25782667 TI - Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability. AB - Recent findings revealed rare copy number variants and missense changes in the X linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P=6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P=0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P=7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P=0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P=0.003, permP=0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder. PMID- 25782668 TI - Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2. AB - Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 function-affecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance. PMID- 25782669 TI - Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. AB - This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access. PMID- 25782670 TI - Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. AB - Tuberous sclerosis complex is an autosomal dominant disorder that occurs owing to inactivating mutations in either TSC1 or TSC2. Tuberous sclerosis complex-related tumors in the brain, such as subependymal giant cell astrocytoma, and in the kidney, such as angiomyolipoma, can cause significant morbidity and mortality. Recently, randomized clinical trials (EXIST-1 and EXIST-2) of everolimus for each of these tuberous sclerosis complex-associated tumors demonstrated the benefit of this drug, which blocks activated mammalian target of rapamycin complex 1. Here we report on the spectrum of mutations seen in patients treated during these trials and the association between mutation and response. TSC2 mutations were predominant among patients in both trials and were present in nearly all subjects with angiomyolipoma in whom a mutation was identified (97%), whereas TSC1 mutations were rare in those subjects (3%). The spectrum of mutations seen in each gene was similar to those previously reported. In both trials, there was no apparent association between mutation type or location within each gene and response to everolimus. Everolimus responses were also seen at a similar frequency for the 16-18% of patients in each trial in whom no mutation in either gene was identified. These observations confirm the strong association between TSC2 mutation and angiomyolipoma burden seen in previous studies, and they indicate that everolimus response occurs regardless of mutation type or location or when no mutation in TSC1 or TSC2 has been identified. PMID- 25782671 TI - The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis. AB - The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of function of the Zone of Polarizing Activity Regulatory Sequence, the only limb specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype. PMID- 25782672 TI - Intra-individual plasticity of the TAZ gene leading to different heritable mutations in siblings with Barth syndrome. AB - Infantile-onset skeletal myopathy Barth syndrome (OMIM #302060) is caused by mutations in the X-linked TAZ gene and hence usually manifests itself only in hemizygous males. Confirmatory testing is provided by mutational analysis of the TAZ gene and/or by biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin ratio. Heterozygous females do not usually display a clinical phenotype but may undergo molecular genetic prenatal diagnosis during pregnancy. We characterized two novel and non-identical TAZ gene rearrangements in the offspring of a single female carrier of Barth syndrome. The hg19chrX:g.153634427_153644361delinsKP_123427.1 TAZ gene rearrangement was identified in her affected son, whereas the NM_000116.3(TAZ)c.-72_109+51del TAZ gene deletion was identified in a male foetus during a subsequent pregnancy. The unaffected mother was surprisingly found to harbour both variants in addition to a wild-type TAZ allele. A combination of breakpoint junction sequencing, linkage analysis and assessment of allelic dosage revealed that the two variants had originated independently from an apparently unstable/mutable TAZ maternal allele albeit via different mutational mechanisms. We conclude that molecular prenatal diagnosis in Barth syndrome families with probands carrying TAZ gene rearrangements should include investigation of the entire coding region of the TAZ gene. The identification of the breakpoint junctions of such gross gene rearrangements is important to ensure accurate ascertainment of carriership with a view to providing appropriate genetic counselling. PMID- 25782673 TI - Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations. AB - Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC - the gene encoding SP-C - SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation. PMID- 25782674 TI - A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy. AB - IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In ~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN. PMID- 25782676 TI - Sebaceus and Becker's Nevus: Overview of Their Presentation, Pathogenesis, Associations, and Treatment. AB - Nevus sebaceus (NS) and Becker's nevus (BN) are two variants of epidermal nevi. NS clinically presents as a yellowish-orange, hairless plaque on the scalp, face, or neck, while BN presents as a tan-to-brown hyperpigmented, sometimes hypertrichotic, plaque typically on the chest and shoulder. Histologically, NS displays mature or nearly mature sebaceus glands as well as acanthosis and fibroplasia of the papillary dermis. BN shows variable papillomatosis, acanthosis, and hyperkeratosis, with hyperpigmentation of the basal/suprabasal layer. While the genetic basis of NS is thought to be due to post-zygotic mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS)/Kristen rat sarcoma viral oncogene homolog (KRAS) genes, the genetic basis of BN is relatively unknown and is implicated with paradominant inheritance. In some patients, NS and BN can each be associated with additional cutaneous and extra cutaneous anomalies, ranging from benign or malignant tumors to multiple organ irregularities. Due to the wide range of possible associations, treatment for NS and BN is devised on a case-by-case basis. In this article, we review the features, etiology, and diagnosis/management of NS and BN, with a focus on associations. We also report a patient who concomitantly presents with both lesions. PMID- 25782675 TI - Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution. AB - Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin gamma-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants. PMID- 25782677 TI - Together in the fight against neglected public health problems: worldwide network cooperation on waterborne diseases and emerging parasitic diseases. AB - A symposium held in Guangzhou, China, aimed to become starting point of an international cooperation in the fight against waterborne diseases, which obtain more and more importance in times of global warming and globalization. PMID- 25782678 TI - Molecular cloning and characterization of Fasciola gigantica thioredoxin glutathione reductase. AB - The Fasciola gigantica thioredoxin-glutathione reductase (FgTGR) gene is a fusion between thioredoxin reductase (TR) and a glutaredoxin (Grx) gene. FgTGR was cloned by polymerase chain reaction (PCR) from adult complementary DNA (cDNA), and its sequences showed two isoforms, i.e., the cytosolic and mitochondrial FgTGR. Cytosolic FgTGR (cytFgTGR) was composed of 2370 bp, and its peptide had no signal sequence and hence was not a secreted protein. Mitochondrial FgTGR (mitFgTGR) was composed of 2506 bp with a signal peptide of 43 amino acids; therefore, it was a secreted protein. The putative cytFgTGR and mitFgTGR peptides comprised of 598 and 641 amino acids, respectively, with a molecular weight of 65.8 kDa for cytFgTGR and mitFgTGR, with a conserved sequence (CPYC) of TR, and ACUG and CVNVGC of Grx domains. The recombinant FgTGR (rFgTGR) was expressed in Escherichia coli BL21 (DE3) and used for production for a polyclonal antibody in rabbits (anti-rFgTGR). The FgTGR protein expression, estimated by indirect ELISA using the rabbit anti-rFgTGR as probe, showed high levels of expression in eggs, and 2- and 4-week-old juveniles and adults. The rFgTGR exhibited specific activities in the 5,5'-dithiobis (2-nitro-benzoic acid) (DTNB) reductase assay for TR activity and in beta-hydroxyethul disulfide (HED) for Grx activity. When analyzed by immunoblotting and immunohistochemistry, rabbit anti-rFgTGR reacted with natural FgTGR at a molecular weight of 66 kDa from eggs, whole body fraction (WB) of metacercariae, NEJ, 2- and 4-week-old juveniles and adults, and the tegumental antigen (TA) of adult. The FgTGR protein was expressed at high levels in the tegument of 2- and 4-week-old juveniles. The FgTGR may be one of the major factors acting against oxidative stresses that can damage the parasite; hence, it could be considered as a novel vaccine or a drug target. PMID- 25782679 TI - Absence of detectable benzimidazole-resistance associated alleles in Haemonchus placei in cattle in Nigeria revealed by pyrosequencing of beta-tubulin isotype 1. AB - Trichostrongyles are gastrointestinal parasites that occur globally and can cause subclinical to severe, sometimes life-threatening, infections in ruminants, particularly young animals. Benzimidazoles (BZ) are commonly used for the treatment of gastrointestinal parasites in ruminants. Increasing spread of worm populations with anthelmintics resistance has been reported and is considered a consequence of highly frequent and longstanding use of anthelmintics. To obtain initial information regarding the occurrence of putatively BZ-resistant Nigerian Haemonchus populations, screening based on the molecular analysis of BZ resistance-associated beta-tubulin isotype 1 gene sequence polymorphisms was undertaken. Genomic DNA was isolated from pooled adult Haemonchus sp. from 35 animals from each of the six states of southwestern Nigeria. Sequencing of internal transcribed spacer 2 (ITS-2) and external transcribed spacer (ETS) regions was used to determine the Haemonchus species. Pyrosequencing assays were used for detection of single-nucleotide polymorphisms (SNPs) in the beta-tubulin isotype 1 genes of the worms at codons 200 and 167 (TTC/TAC) or 198 (GAA/GCA). Exclusively, Haemonchus placei was detected and allele frequencies obtained at all three positions showed no evidence for the presence of resistance-related alleles. For Lagos State, pools of 10 worms from 30 different animals were analyzed separately for the codon 200 SNP, successfully excluding the presence of resistance-associated SNPs in very low frequencies. These positive findings, showing absence of elevated frequencies of BZ-resistance-associated beta-tubulin alleles, have considerable significance since it suggests that farmers can still rely on the efficacy of this important drug class when used for controlling trichostrongyle infections in cattle in Nigeria. PMID- 25782680 TI - Toxicity of seaweed-synthesized silver nanoparticles against the filariasis vector Culex quinquefasciatus and its impact on predation efficiency of the cyclopoid crustacean Mesocyclops longisetus. AB - Nearly 1.4 billion people in 73 countries worldwide are threatened by lymphatic filariasis, a parasitic infection that leads to a disease commonly known as elephantiasis. Filariasis is vectored by mosquitoes, with special reference to the genus Culex. The main control tool against mosquito larvae is represented by treatments with organophosphates and insect growth regulators, with negative effects on human health and the environment. Recently, green-synthesized nanoparticles have been proposed as highly effective larvicidals against mosquito vectors. In this research, we attempted a reply to the following question: do green-synthesized nanoparticles affect predation rates of copepods against mosquito larvae? We proposed a novel method of seaweed-mediated synthesis of silver nanoparticles using the frond extract of Caulerpa scalpelliformis. The toxicity of the seaweed extract and silver nanoparticles was assessed against the filarial vector Culex quinquefasciatus. Then, we evaluated the predatory efficiency of the cyclopoid crustacean Mesocyclops longisetus against larval instars of C. quinquefasciatus in a nanoparticle-contaminated water environment. Green-synthesized silver nanoparticles were characterized by UV-vis spectrum, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). In mosquitocidal assays, the LC50 values of the C. scalpelliformis extract against C. quinquefasciatus were 31.38 ppm (I), 46.49 ppm (II), 75.79 ppm (III), 102.26 ppm (IV), and 138.89 ppm (pupa), while LC50 of silver nanoparticles were 3.08 ppm, (I), 3.49 ppm (II), 4.64 ppm (III), 5.86 ppm (IV), and 7.33 ppm (pupa). The predatory efficiency of the copepod M. longisetus in the control treatment was 78 and 59% against I and II instar larvae of C. quinquefasciatus. In a nanoparticle-contaminated environment, predation efficiency was 84 and 63%, respectively. Predation was higher against first instar larvae over other instars. Overall, our study showed that seaweed synthesized silver nanoparticles can be proposed in synergy with biological control agents against Culex larvae, since their use leads to little detrimental effects against aquatic predators, such as copepods. PMID- 25782681 TI - Evaluation of conjunctival swab as a mass-screening tool for molecular diagnosis of canine visceral leishmaniasis. AB - The canine visceral leishmaniasis (CVL) diagnosis is an important step of visceral leishmaniasis control program in Brazil once the dog is the main reservoir host of the disease. The aim of this study was to evaluate the conjunctival swab (CS) as a mass-screening tool for CVL molecular diagnosis in an endemic area classified as priority for the Brazilian Ministry of Healthy for surveillance action. A total of 1350 domiciled dogs were screened. The animals were evaluated by serological tests (enzyme-linked immunosorbent assay (ELISA) as screening and immunofluorescence antibody test (IFAT) for confirmation) and by CS associated to real-time PCR, using primers addressed to kinetoplast DNA (kDNA) minicircles and SYBR Green. Canine beta-globin gene amplification was used to evaluate the sample DNA integrity. A subgroup of 484 animals was also submitted to clinical evaluation. Among the 1350 dogs screened, 369 (27.3%) were positive by CS real-time PCR and 126 (9.3%) tested positive by ELISA. Thirty-one percent (39/126) of the ELISA-positive dogs were confirmed by IFAT. CS real-time PCR was able to detect infection in dogs independently of the symptomatology degree (p > 0.05), while ELISA was more sensitive in the group of dogs that present three or more clinical signs related to CVL. The results demonstrated that CS real-time PCR was able to detect a higher number of infected dogs than ELISA and that the prevalence of canine infections has been underestimated by the serological assays. The use of sensitive molecular diagnostic methods like CS real-time PCR, mainly in endemic areas, could greatly contribute to disease control. PMID- 25782682 TI - Genome-wide characterization of microsatellites and marker development in the carcinogenic liver fluke Clonorchis sinensis. AB - Clonorchis sinensis is an important carcinogenic human liver fluke endemic in East and Southeast Asia. There are several conventional molecular markers that have been used for identification and genetic diversity; however, no information about microsatellites of this liver fluke is published so far. We here report microsatellite characterization and marker development for a genetic diversity study in C. sinensis, using a genome-wide bioinformatics approach. Based on our search criteria, a total of 256,990 microsatellites (>=12 base pairs) were identified from a genome database of C. sinensis, with hexanucleotide motif being the most abundant (51%) followed by pentanucleotide (18.3%) and trinucleotide (12.7%). The tetranucleotide, dinucleotide, and mononucleotide motifs accounted for 9.75, 7.63, and 0.14%, respectively. The total length of all microsatellites accounts for 0. 72% of 547 Mb of the whole genome size, and the frequency of microsatellites was found to be one microsatellite in every 2.13 kb of DNA. For the di-, tri-, and tetranucleotide, the repeat numbers redundant are six (28%), four (45%), and three (76%), respectively. The ATC repeat is the most abundant microsatellites followed by AT, AAT, and AC, respectively. Within 40 microsatellite loci developed, 24 microsatellite markers showed potential to differentiate between C. sinensis and Opisthorchis viverrini. Seven out of 24 loci showed to be heterozygous with observed heterozygosity that ranged from 0.467 to 1. Four primer sets could amplify both C. sinensis and O. viverrini DNA with different sizes. This study provides basic information of C. sinensis microsatellites, and the genome-wide markers developed may be a useful tool for the genetic study of C. sinensis. PMID- 25782684 TI - Effects of juvenoid Pyriproxyfen on reproduction and F1 progeny in myiasis causing flesh fly Sarcophaga ruficornis L. (Sarcophagidae: Diptera). AB - Freshly emerged virgin female Sarcophaga ruficornis were topically treated with different doses of pyriproxyfen to test the efficacy on reproduction and subsequent F1 progeny. The results included mortality of the treated adults, significant reduction in fecundity, more than 90% inhibition in larvae production, mortality in F1 generation during larval instars, reduction in pupariation, and adult emergence and production of deformed adults. There was a dose-dependent response showing high degree of correlation in the doses administered and deformities observed. The effects in F1 generation show that an intraovarial transfer of pyriproxyfen was responsible for the various deformations observed, showing the potency of juvenoid pyriproxyfen for longer durations across generations. This is the first study that clearly demonstrates the efficacy of pyriproxyfen against reproduction in S. ruficornis and its potential for the management of this notorious pest of medico-veterinary importance. PMID- 25782683 TI - Understanding drug resistance in human intestinal protozoa. AB - Infections with intestinal protozoa continue to be a major health problem in many areas of the world. The widespread use of a limited number of therapeutic agents for their management and control raises concerns about development of drug resistance. Generally, the use of any antimicrobial agent should be accompanied by meticulous monitoring of its efficacy and measures to minimize resistance formation. Evidence for the occurrence of drug resistance in different intestinal protozoa comes from case studies and clinical trials, sometimes with a limited number of patients. Large-scale field-based assessment of drug resistance and drug sensitivity testing of clinical isolates are needed. Furthermore, the association of drug resistance with certain geographic isolates or genotypes deserves consideration. Drug resistance has been triggered in vitro and has been linked to modification of pyruvate:ferredoxin oxidoreductase, nitroreductases, antioxidant defense, or cytoskeletal system. Further mechanistic studies will have important implications in the development of second generation therapeutic agents. PMID- 25782685 TI - Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III-IV unresectable head and neck cancer: Results of a randomized phase II study. AB - PURPOSE: Concurrent chemoradiotherapy (CRT) is the standard treatment for advanced head and neck squamous cell carcinoma. In this phase II randomized study, the efficacy and toxicity of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy (ICT) followed by concurrent CRT was compared with those after standard CRT alone in patients with locally advanced, unresectable head and neck cancer. PATIENTS AND METHODS: Between January 2007 and June 2009, 66 patients with advanced (stage III or IV) unresectable squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx, and larynx) were randomly assigned to two groups: one receiving two cycles of docetaxel, cisplatin, and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone. Response rate, local tumor control (LTC), locoregional tumor control (LRTC), overall survival (OS), progression-free survival (PFS), and toxicity results were assessed. RESULTS: Three patients from the ICT + CRT group did not appear at the first treatment, so a total of 63 patients were evaluated in the study (30 ICT + CRT group and 33 CRT group). Three patients died of febrile neutropenia after ICT. The median follow-up time for surviving patients was 63 months (range 53-82 months). The rate of radiologic complete response was 63% following ICT + CRT, whereas 70% after CRT alone. There were no significant differences in the 3-year rates of LTC (56 vs. 57%), LRTC (42 vs. 50%), OS (43 vs. 55%), and PFS (41 vs. 50%) in the ICT + CRT group and in the CRT group, respectively. The rate of grade 3-4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group (37 and 12%; p = 0.024). Late toxicity (grade 2 or 3 xerostomia) developed in 59 and 42% in the ICT + CRT and CRT groups, respectively. CONCLUSION: The addition of ICT to CRT did not show any advantage in our phase II trial, while the incidence of adverse events increased. The three deaths as a consequence of ICT call attention to the importance of adequate patient selection if ICT is considered. PMID- 25782686 TI - Acute effects of submaximal endurance training on arterial stiffness in healthy middle- and long-distance runners. AB - Measures of arterial stiffness are indicators for cardiovascular health and predictors of cardiovascular events. Arterial stiffness is responsive to acute physiologic stressors such as exercise. However, the acute effects of intensive exercise and recovery on arterial stiffness are controversial. Thirty-seven healthy middle- and long-distance runners (33 men, mean age 26.5+/-6.6 years) underwent evaluation of their cardiovascular stiffness at rest, after a 15-minute warm-up, immediately after vigorous running 3 km at the pace of their 10-km personal best, and finally 30 minutes after terminating their workout. Peripheral and central systolic blood pressure, as well as augmentation index and pulse wave velocity (PWV), increased during exercise in comparison to baseline (P<.001, general linear model). Thirty minutes after terminating the workout, a drop in peripheral blood pressure (P<.001), central blood pressure (P<.001), and PWV (P=.001) below baseline was observed. Therefore, the authors found that exercise of either moderate or vigorous intensity causes a temporary increase in arterial stiffness in middle- and long-distance runners. PMID- 25782688 TI - Influence of the local environment on Mn acceptors in GaAs. AB - As transistors continue to shrink toward nanoscale dimensions, their characteristics are increasingly dependent on the statistical variations of impurities in the semiconductor material. The scanning tunneling microscope (STM) can be used to not only study prototype devices with atomically precise placement of impurity atoms, but can also probe how the properties of these impurities depend on the local environment. Tunneling spectroscopy of Mn acceptors in GaAs indicates that surface-layer Mn act as a deep acceptor, with a hole binding energy that can be tuned by positioning charged defects nearby. Band bending induced by the tip or by these defects can also tune the ionization state of the acceptor complex, evident as a ring-like contrast in STM images. The interplay of these effects is explored over a wide range of defect distances, and understood using iterative simulations of tip-induced band bending. PMID- 25782687 TI - New challenges in kidney cancer management: integration of surgery and novel therapies. AB - Despite early renal carcinoma diagnosis is more frequent nowadays, ~25-30 % of patients have metastatic disease at presentation and another ~30 % develop recurrent or metastatic disease after radical treatment for localized disease. In recent years, treatment of renal carcinoma is increasing in complexity due to the inclusion of a number of effective systemic treatments prolonging survival and increasing the therapeutic strategies for tumor debulking, or even achieving surgical complete responses and prolonged disease-free intervals. Initial multimodal approaches with immunotherapeutic agents are now being validated in patients treated with the new-targeted agents. Patients are now able to receive an optimal therapeutic strategy seeking a longer survival with an acceptable life quality and avoiding unnecessary comorbidities. In this context and as an initial therapeutic approach, it is imperative to promote patients' selection with established prognostic models within a multidisciplinary team to assess the recommendation of a cytoreductive nephrectomy (CN), metastasectomy, and/or systemic treatment. In the context of mRCC, when feasible and in patients with favorable prognostic factors, the strategy should be to consider a CN or metastasectomy for tumor debulking in order to achieve free intervals of prolonged disease. By contrast, it is recommended to evaluate whether to perform a biopsy for histological diagnosis without nephrectomy in the following situations: high surgical risk, bulky metastatic disease or in specific sites (brain or liver) or ECOG PS 3/4. The following review covers from initial to recent studies on the integration of systemic treatment and surgery in the context of metastatic disease for an optimal multimodal management in renal carcinoma. PMID- 25782689 TI - Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. AB - Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice. PMID- 25782690 TI - Neuronal serine racemase regulates extracellular D-serine levels in the adult mouse hippocampus. AB - In the hippocampus of mice lacking the gene for serine racemase (SR), a D-serine synthesizing enzyme, in the CaMKIIalpha-expressing neurons, we observed a significant decrease in the extracellular concentration of D-serine, a coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR), and NMDAR hypofunction as revealed by diminished extracellular taurine concentrations after an intra-hippocampal NMDA infusion when compared to the wild type controls. Therefore, the neuronal SR could regulate the extracellular D-serine signaling responsible for NMDAR activation in the hippocampus. PMID- 25782692 TI - Thyroid function testing in primary care: overused and under-evidenced? A study examining which clinical features correspond to an abnormal thyroid function result. AB - BACKGROUND AND AIM: Diagnostic testing is increasing in primary care, including for thyroid disease. This study examined which clinical features were associated with an abnormal thyroid stimulating hormone (TSH) result. DESIGN AND SETTING: This was a cross-sectional study in one general practice of 16,487 patients in Exeter, Devon, UK. METHODS: We examined the primary care records relating to every TSH test taken in the year from August 2012, and extracted symptoms and/or the indication for testing. Associations with an abnormal result were tested using multivariable logistic regression. A cohort study was then performed of 100 patients newly recorded with each of the six features associated with an abnormal test result in the cross-sectional study, and the proportions tested for TSH and the results of that testing identified. RESULTS: Two thousand thirty-five patients (12% of the practice population) had TSH testing in the year. Of these 35 (1.7%) had a TSH >4.5 mIU/l, suggesting hypothyroidism, and 7 (0.3%) had TSH <0.01 mIu/l suggesting hyperthyroidism. Features associated with an abnormal TSH were: pregnancy, odds ratio 41 (95% confidence interval 9.3-180), constipation 9.7 (2.1-45), palpitations 23 (3.4-150), hair loss, 21 (2.0-230), weight gain, 18 (1.6-190) and diarrhoea, 13 (1.2-130); in separate analyses only pregnancy and constipation were associated with a raised TSH, and the remaining four features with a low TSH. CONCLUSION: The diagnostic yield of thyroid disease in this study was 2.1% suggests testing could be better targeted without missing diagnoses. The symptoms associated with thyroid disease differ from those generally reported. This may represent fewer patients presenting with advanced disease. PMID- 25782691 TI - Characterisation of the dark green islands of cucumber mosaic virus infected Nicotiana tabacum. AB - KEY MESSAGE: There are significant differences between the DGIs and LGTs. Additionally, most of the characteristics indicate that the DGIs are more similar to recovered tissue and can resist viral attacks. Dark green islands (DGIs) surrounded by light green tissues (LGTs) are common leaf symptoms of plants that are systemically infected by various mosaic viruses. We performed cytological, physiological and molecular biological analyses of the DGIs and LGTs in cucumber mosaic virus-infected Nicotiana tabacum leaves. Our results indicated that the DGIs contained less virus than did the LGTs. Compared to the LGTs, the DGIs contained higher levels of the metabolites involved in plant defence. The contents of reduced glutathione and ascorbic acid were increased in the DGIs to reach levels that were even higher than those of control plants. Moreover, hormone measurements and quantitative real-time PCR analysis revealed that the endogenous salicylic acid, ethylene and defence genes mediated these elevations by playing positive roles in the regulation of the DGIs responses to viral infection. The accumulation of cytokinin was also much greater in the DGIs than in the LGTs. Finally, northern blotting analysis indicated that the accumulation of viral small interfering RNAs was decreased in the DGIs compared to the LGTs. Taken together, these results suggest that DGIs might represent leaf areas that have recovered from viral infection due to locally enhanced defence responses. PMID- 25782694 TI - PCSK9 inhibitors reduce cardiovascular events, preliminary data show. PMID- 25782695 TI - Baastrup's Disease: a poorly recognised cause of back pain. AB - A 56-year-old male complained about progressive mechanical back pain for more than 10 years, which worsened with prolonged orthostatism and spine extension and improved in fetal position. His lumbar spine radiography revealed enlargement and sclerosis of the spinous processes which was confirmed by computed tomography, suggesting Baastrup's disease. This condition is characterized by enlargement, close approximation and impingement of one spinous process on another ("kissing spines"). There are few studies on Baastrup's disease epidemiology and their results are inconsistent. Patients often complain of back pain, typically increased with extension and relieved by flexion. Radiographically, spinous process impingement leads to reactive sclerosis, enlargement, flattening, and remodeling of the involved vertebral spines. Physicians frequently miss it on radiographs due to lack of knowledge and overexposure of spinous processes in most X rays. Both conservative and surgical options are available for treatment. Baastrup's disease should be considered in differential diagnosis of back pain, although one must be aware the typical radiographic changes appear to be common with aging and may not be the cause of patient's symptoms. PMID- 25782693 TI - The HAAPI (Home Arm Assistance Progression Initiative) Trial: A Novel Robotics Delivery Approach in Stroke Rehabilitation. AB - BACKGROUND: Geographical location, socioeconomic status, and logistics surrounding transportation impede access of poststroke individuals to comprehensive rehabilitative services. Robotic therapy may enhance telerehabilitation by delivering consistent and state-of-the art therapy while allowing remote monitoring and adjusting therapy for underserved populations. The Hand Mentor Pro (HMP) was incorporated within a home exercise program (HEP) to improve upper-extremity (UE) functional capabilities poststroke. OBJECTIVE: To determine the efficacy of a home-based telemonitored robotic-assisted therapy as part of a HEP compared with a dose-matched HEP-only intervention among individuals less than 6 months poststroke and characterized as underserved. METHODS: In this prospective, single-blinded, multisite, randomized controlled trial, 99 hemiparetic participants with limited access to UE rehabilitation were randomized to either (1) the experimental group, which received combined HEP and HMP for 3 h/d *5 days *8 weeks, or (2) the control group, which received HEP only at an identical dosage. Weekly communication between the supervising therapist and participant promoted compliance and progression of the HEP and HMP prescription. The Action Research Arm Test and Wolf Motor Function Test along with the Fugl-Meyer Assessment (UE) were primary and secondary outcome measures, respectively, undertaken before and after the interventions. RESULTS: Both groups demonstrated improvement across all UE outcomes. CONCLUSIONS: Robotic + HEP and HEP only were both effectively delivered remotely. There was no difference between groups in change in motor function over time. Additional research is necessary to determine the appropriate dosage of HMP and HEP. PMID- 25782696 TI - Astrocyte-neuronal interactions in epileptogenesis. AB - Pentylenetetrazol, kainic acid, or pilocarpine can be used to induce seizures in animal models of epilepsy. The present Review describes disturbances in astrocyte neuron interactions in the acute, latent, and chronic phases analyzed by magnetic resonance spectroscopy of brain tissue extracts from rats injected with [1 (13)C]glucose and [1,2-(13)C]acetate. The most consistent change after onset of seizures was the decrease in (13)C labeling of glutamate (GLU) from [1-(13) C]glucose regardless of brain area, severity, or duration of the period with seizures and toxin used. In most cases this decrease was accompanied by a reduction in glutamine (GLN) labeling from [1-(13)C]glucose, presumably as a direct consequence of the reduction in labeling of GLU and the GLU-GLN cycle. Amounts of GLN were never changed. Reduction in the content of N-acetyl aspartate (NAA) was first detectable some time after status epilepticus but before the occurrence of spontaneous seizures. This decrease can be an indication of neuronal death and/or mitochondrial impairment and might indicate beginning gliosis. It is known that gliosis occurs in the chronic phase of temporal lobe epilepsy in hippocampus, but astrocyte metabolism appears normal in this phase, indicating that the gliotic astrocytes have a somewhat reduced metabolism per volume. A decrease in (13)C labeling of GLU from [1-(13)C]glucose is a very sensitive measure for the onset of epileptogenesis, whereas reduction of NAA is first detectable later. In the chronic phases of the hippocampal formation, astrocyte metabolism is upregulated given that the number of neurons is reduced. PMID- 25782697 TI - Label free sensing of creatinine using a 6 GHz CMOS near-field dielectric immunosensor. AB - In this work we present a CMOS high frequency direct immunosensor operating at 6 GHz (C-band) for label free determination of creatinine. The sensor is fabricated in standard 0.13 MUm SiGe:C BiCMOS process. The report also demonstrates the ability to immobilize creatinine molecules on a Si3N4 passivation layer of the standard BiCMOS/CMOS process, therefore, evading any further need of cumbersome post processing of the fabricated sensor chip. The sensor is based on capacitive detection of the amount of non-creatinine bound antibodies binding to an immobilized creatinine layer on the passivated sensor. The chip bound antibody amount in turn corresponds indirectly to the creatinine concentration used in the incubation phase. The determination of creatinine in the concentration range of 0.88-880 MUM is successfully demonstrated in this work. A sensitivity of 35 MHz/10 fold increase in creatinine concentration (during incubation) at the centre frequency of 6 GHz is gained by the immunosensor. The results are compared with a standard optical measurement technique and the dynamic range and sensitivity is of the order of the established optical indication technique. The C-band immunosensor chip comprising an area of 0.3 mm(2) reduces the sensing area considerably, therefore, requiring a sample volume as low as 2 MUl. The small analyte sample volume and label free approach also reduce the experimental costs in addition to the low fabrication costs offered by the batch fabrication technique of CMOS/BiCMOS process. PMID- 25782699 TI - Harvesting canthinones: identification of the optimal seasonal point of harvest of Zanthoxylum chiloperone leaves as a source of 5-methoxycanthin-6-one. AB - This article is focused on the seasonal variation in the contents of 5 methoxycanthin-6-one from the leaves of Zanthoxylum chiloperone (Rutaceae). Based on the pharmacological interest presented by 5-methoxycanthin-6-one, its seasonal variation in Z. chiloperone leaves was analysed in order to determine the best time for harvesting, optimising the 5-methoxycanthin-6-one content. The seasonal dynamics of canthinone alkaloids can be the key to improve the isolation from natural sustainable sources, such as leaves. Complementarily, this study describes the phytochemistry of leaf from this Ruraceae species. PMID- 25782700 TI - Orbital carcinomas treated with adjuvant intensity-modulated radiation therapy. AB - BACKGROUND: The purpose of this study was to assess outcomes of patients with orbital carcinomas treated with orbital exenteration and intensity-modulated radiation therapy (IMRT). METHODS: Twenty-nine patients were treated with orbital exenteration and postoperative IMRT between 2002 through 2011; their medical records were retrospectively reviewed. RESULTS: Adenoid cystic carcinoma represented the most common histology (41%) followed by squamous cell carcinoma (21%). Perineural invasion (PNI) was identified in 22 patients (76%). The median radiation dose was 60 Gy (range, 60-70). Seven patients (24%) received neck radiation. The median follow-up was 43 months (range, 5-102 months). Five-year local control, overall survival (OS), and disease-free survival rates were 83%, 60%, and 55%, respectively. PNI (p = .01) and especially involvement of a named nerve (p = .001) significantly correlated with worse OS. CONCLUSION: Favorable disease control rates for orbital carcinomas are achievable with IMRT after orbital exenteration even for patients with advanced disease. Toxicity for the contralateral eye was minimal. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E580-E587, 2016. PMID- 25782702 TI - Footballers' movement behaviour during 2-, 3-, 4- and 5-a-side small-sided games. AB - The aim of this study was to compare footballers' movement behaviour during 2-, 3 , 4- and 5-a-side small-sided games. Ten young professional players (age = 18.0 +/- 0.67 years) participated in 3 bouts of each small-sided games for 6 min with 1 min of active rest between bouts. Positional data were collected using GPS system units and used to calculate the following variables: team centroid, distance between each player and own and opponent team centroids and distance between centroids. Approximate entropy was used to identify the time series regularity for each variable. The distance to own team centroid increased with the number of players (effect sizes from moderate to perfect). The results from the distance to the opponent's centroid exhibited a similar trend. The distance between centroids decreased from 2- to the 4-a-side, but then increased in 5-a side. A higher number of players were associated with lower approximate entropy values, suggesting higher positional organisation in small-sided games with more players. The highest movement regularity found in 4- and 5-a-side identified these formats as more adequate to promote team-related emergent and self organised behaviours. PMID- 25782703 TI - Solvent-enabled nonenyzmatic sugar production from biomass for chemical and biological upgrading. AB - We recently reported a nonenzymatic biomass deconstruction process for producing carbohydrates using homogeneous mixtures of gamma-valerolactone (GVL) and water as a solvent. A key step in this process is the separation of the GVL from the aqueous phase, enabling GVL recycling and the production of a concentrated aqueous carbohydrate solution. In this study, we demonstrate that phenolic solvents-sec-butylphenol, nonylphenol, and lignin-derived propyl guaiacol-are effective at separating GVL from the aqueous phase using only small amounts of solvent (0.5 g per g of the original water, GVL, and sugar hydrolysate). Furthermore, using nonylphenol, we produced a hydrolysate that supported robust growth and high yields of ethanol (0.49 g EtOH per g glucose) at an industrially relevant concentration (50.8 g L(-1) EtOH). These results suggest that using phenolic solvents could be an interesting solution for separating and/or detoxifying aqueous carbohydrate solutions produced using GVL-based biomass deconstruction processes. PMID- 25782704 TI - Prevalence and risk factors of early onset of sexual intercourse in a random sample of a multiethnic adolescent population in French Guiana. AB - French Guiana, a French overseas department in South America, has been classified epidemic for HIV. This territory is consisting of a very young population with almost 45% of them being younger than 20 years of age. Delaying the onset of first sexual intercourse (SI) is one of the major objectives to fight HIV infection in adolescents. The objective of this study is to identify the age of first SI and the risk factors of early onset. A behavioural surveillance survey among students living on the coastline and alongside the Maroni River was conducted in 2011/2012. A total of 1603 students filled out the survey. While 60% had already SI, the mean age of first intercourse was 12.1 years for boys and 13.9 years for girls. Accordingly, over 90% had a premature onset of SI. Risk factors are age, male gender, living alongside the Maroni River, another language than the French being mother tongue, not being religious, alcohol and cannabis consumption and a bad attitude towards condom use. Risk factors for girls are an older first sexual partner, having more than three lifetime sexual partners and condom rupture. Evidence-based implementation with respect of local and socio demographic aspects is necessary to improve youths' appreciation of SI and related risk of sexual transmitted diseases. PMID- 25782705 TI - Allergic Contact Dermatitis to Benzoyl Peroxide Resembling Impetigo. AB - A 17-year-old boy presented with recurring severe dermatitis of the face of 5 months duration that resembled impetigo. He had been treated with several courses of antibiotics without improvement. Biopsy showed changes consistent with allergic contact dermatitis and patch testing later revealed sensitization to benzoyl peroxide, which the patient had been using for the treatment of acne vulgaris. PMID- 25782707 TI - Progress on all ends for carbon-carbon bond formation through photoredox catalysis. AB - Dual role for catalysts: Novel routes for the generation of asymmetric stereocenters using photoredox catalysis were recently developed. Different chiral catalytic systems allowed new C?C bonds to form in good yields and enantioselectivities using a mild methodology in which light is used as the energy source. PMID- 25782706 TI - Gonadectomy before puberty increases the number of neurons and glia in the medial prefrontal cortex of female, but not male, rats. AB - The human prefrontal cortex, important for executive functions, loses gray matter throughout the adolescent period. In rats, our laboratory demonstrated that a loss of neurons between adolescence and adulthood partially underlies the loss of volume, and this loss is greater in females than males. Here, we examine whether being deprived of gonadal hormones before puberty through adulthood influences the number of neurons in the medial prefrontal cortex (mPFC). Prior to puberty, the testes or ovaries were removed in male and female rats. In adulthood, the number of neurons and glia in the mPFC were quantified using unbiased stereology, and the volume of the frontal white matter was measured. Prepubertal ovariectomy resulted in a higher number of neurons and glia and a larger volume of white matter compared to sham control littermates. Castrated males were not different from sham males on any measure. Thus ovarian hormones secreted after puberty influence the cellular composition of the medial prefrontal cortex. PMID- 25782708 TI - Carcinogenic HPV infection in the cervical squamo-columnar junction. AB - Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to (1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and (2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analysed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16(ink4), Ki67, and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from eight of ten with visible SCJ cells, six of which were HPV16/18 DNA positive. In five of these latter cases, the SCJ cells were positive for p16(ink4) and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in microdissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16(ink4) immunoreactivity, elevated proliferative index, and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16(ink4) expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high-grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ. PMID- 25782709 TI - Equine-assisted therapy for anxiety and posttraumatic stress symptoms. AB - We tested the efficacy of the Equine Partnering Naturally((c)) approach to equine assisted therapy for treating anxiety and posttraumatic stress disorder (PTSD) symptoms. Participants were 16 volunteers who had experienced a Criterion A traumatic event, such as a rape or serious accident, and had current PTSD symptoms above 31 on the PTSD Checklist (PCL-S; Weathers, Litz, Herman, Huska, & Keane, ). Participants engaged in tasks with horses for 6 weekly 2-hour sessions. Immediately following the final session, participants reported significantly reduced posttraumatic stress symptoms, d = 1.21, less severe emotional responses to trauma, d = 0.60, less generalized anxiety, d = 1.01, and fewer symptoms of depression, d = 0.54. As well, participants significantly increased mindfulness strategies, d = 1.28, and decreased alcohol use, d = 0.58. There was no significant effect of the treatment on physical health, proactive coping, self efficacy, social support, or life satisfaction. Thus, we found evidence that the Equine Partnering Naturally((c)) approach to equine-assisted therapy may be an effective treatment for anxiety and posttraumatic stress symptoms. Future research should include larger groups, random assignment, and longer term follow up. PMID- 25782710 TI - Guest Editorial: Reflections on a crisis for an older lay person. PMID- 25782713 TI - Leopoldo de Meis (1938-2014). PMID- 25782712 TI - Overlapping genetic and environmental influences among men's alcohol consumption and problems, romantic quality and social support. AB - BACKGROUND: Alcohol consumption and problems are associated with interpersonal difficulties. We used a twin design to assess in men the degree to which genetic or environmental influences contributed to the covariance between alcohol consumption and problems, romantic quality and social support. METHOD: The sample included adult male-male twin pairs (697 monozygotic and 487 dizygotic) for whom there were interview-based data on: alcohol consumption (average monthly alcohol consumption in the past year); alcohol problems (lifetime alcohol dependence symptoms); romantic conflict and warmth; friend problems and support; and relative problems and support. RESULTS: Key findings were that genetic and unique environmental factors contributed to the covariance between alcohol consumption and romantic conflict; genetic factors contributed to the covariance between alcohol problems and romantic conflict; and common and unique environmental factors contributed to the covariance between alcohol problems and friend problems. CONCLUSIONS: Recognizing and addressing the overlapping genetic and environmental influences that alcohol consumption and problems share with romantic quality and other indicators of social support may have implications for substance use prevention and intervention efforts. PMID- 25782711 TI - RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling. AB - Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention and accumulation of macrophages in the vascular wall remain unclear. Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation. Here we show that Rgs1 is upregulated in atherosclerotic plaque and aortic aneurysms. Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling. In early atherosclerotic lesions, Rgs1 regulates macrophage accumulation and is required for the formation and rupture of Angiotensin II induced aortic aneurysms, through effects on leukocyte retention. Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease. PMID- 25782715 TI - Scanning electron microscopic examination of the hair shaft abnormalities in Netherton's syndrome. PMID- 25782716 TI - Nanoantennas as biomarkers for bacterial detection. AB - Understanding the biology of bacteria is critical for exploiting their beneficial properties and for preventing and treating bacterial diseases. Nanobioscience is an area that has recently seen major scientific progress. Here, we demonstrate that a raspberry-shaped nanostructure with a high density of gold nanoparticles acts like an excellent antenna due to its optical properties, which permit sensitive detection and analysis of bacterial cells. By using antibodies, these nanoantennas can be engineered to recognize only specific bacterial species. This system provides a new technique that will allow for more sensitive detection of specific bacteria. PMID- 25782717 TI - A rest-activity biomarker to predict response to SSRIs in major depressive disorder. AB - Most adults with Major Depressive Disorder (MDD) will not experience a remission with the first antidepressant trial. No practical biomarkers presently exist to predict responsiveness to antidepressants. Herein we report pilot data for a rest activity biomarker of antidepressant response. Fifty-eight medication-free adults with MDD underwent a week-long collection of actigraphic data before beginning a 9 week open label trial of fluoxetine, coupled with blinded randomized assignment to eszopiclone/placebo. Depression severity was repeatedly measured with the Hamilton Rating Scale for Depression (HRSD). Baseline actigraphic data was analyzed with functional data analysis to create smoothed 24-h curves of activity. The time of the lowest point of activity (the bathyphase) was calculated for each patient, as well the mean difference between bedtime and the bathyphase (BBD). At the end of treatment, patients were characterized as treatment responders (50% reduction in HRSD) or non-responders, and receiver operating curves were calculated to find the optimal cut point of the BBD for prediction of treatment response. The best cut point for BBD was at 260.2 min, resulting in an effect size of 1.45, and with a positive predictive value of 0.75 and a negative predictive value of 0.88. We conclude that actigraphically determined measures of rest-activity patterns show promise as potential biomarker predictors of antidepressant response. However, this conclusion is based upon a small number of patients who received only one choice of antidepressant, for a single trial. Replication with a larger sample is needed. PMID- 25782718 TI - Social support buffers the effect of self-esteem on quality of life of early stage cervical cancer survivors in Taiwan. AB - PURPOSE: The purpose of this study was to examine the effects of self-esteem and social support on quality of life (QoL) in stage I and II cervical cancer survivors. METHOD: The sample consisted of 110 participants who had been diagnosed with stage I-II cervical cancer and had completed their treatment 5 years or more before data collection. Each participant completed four structured questionnaires: a demographic-disease survey, the Rosenberg Self-Esteem Scale, Medical Outcomes Study Social Support Survey, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30. Data were analyzed using descriptive statistics, independent sample t-test, one-way ANOVA, and hierarchical multiple linear regression analyses. RESULTS: The participants' mean age was 60.74 +/- 10.69 years. Better QoL was significantly associated with younger age, higher self-esteem, and stronger social support; in addition, social support buffered the effect of self-esteem on global QoL. Together, five variables (age, time since treatment, self-esteem, social support, and the interaction term of self-esteem and social support) explained 36% of the variance in global QoL, with self-esteem being the strongest predictor. CONCLUSIONS: The results of this study advance current knowledge of QoL in cervical cancer survivors by demonstrating that survivors with low self-esteem and social support tend to have lower QoL than those with low self-esteem but high social support. Health professionals should help survivors seek support and provide appropriate strategies to expand their social networks and enhance their self-esteem to improve their global QoL after cervical cancer. PMID- 25782719 TI - Oncology nurses' experience of collaboration: A case study. AB - PURPOSE: Changes in the health system have created new models of healthcare delivery such as nurse-led teams. This has resulted in the increased opportunity for enhanced collaboration among nurses. Oncology nurses have a long history of working together, yet little is known about their perceptions about collaboration in the practice setting. This paper aimed to explore and describe the experiences of collaboration among oncology nurses, and to understand the factors that influenced collaboration. METHOD: Qualitative, case study design was used to study fourteen oncology nurses from one cancer center in Canada. Participants were registered nurses or nurse practitioners, employed full-time or permanent part-time in an oncology nurse role, and working on an in-patient or out-patient unit. Data were collected in 2013 using individual telephone interviews and document reviews. RESULTS: Thematic analysis revealed two themes: Art of dancing together, and the stumbling point. The first theme related to the facilitators of collaboration including having: regular face-to-face interaction, an existing and/or previous relationship, oncology nursing experience, and good interpersonal skills. The second theme related to the barriers to collaboration such as: role ambiguity, organizational leadership, and multi-generational differences. CONCLUSIONS: Collaboration is a complex process that does not occur spontaneously. To improve collaboration nursing leadership needs to support and promote opportunities for nurses to build the relationships required to effectively collaborate. It is equally important that individual nurses be willing to collaborate and possess the interpersonal skills required to build and maintain the collaborative relationship despite differences in age, generation, and clinical experience. PMID- 25782720 TI - The prevalence and correlates of symptom distress and quality of life in Chinese oesophageal cancer patients undergoing chemotherapy after radical oesophagectomy. AB - PURPOSE: The current study was designed to describe the symptom distress and quality of life (QoL) in Chinese oesophageal cancer patients undergoing chemotherapy after radical oesophagectomy and to identify the factors that influenced symptom distress and the relationship between symptom distress and QoL. METHODS: The sample consisted of 102 oesophageal cancer patients undergoing chemotherapy after radical oesophagectomy. The patients completed the Chinese versions of the M.D. Anderson Symptom Inventory (MDASI, an instrument that measures symptom distress), the Hospital Anxiety and Depression Scale (HADS), the Medical Coping Modes Questionnaire (MCMQ) and the Functional Assessment of Cancer Treatment-General (FACT-G, an instrument that measures QoL). RESULTS: The symptoms and symptom interference scores of the patients in the current research were 3.62 (SD 1.66) and 2.94 (SD 1.76), respectively. Occupation after illness, anxiety, types of surgery, whether chemotherapy was on schedule and confrontation coping strategies were factors that influenced symptom distress. There was a negative relationship between symptom distress and QoL scores. CONCLUSION: Oesophageal cancer patients receiving chemotherapy suffer many limitations due to symptom distress and disruptions in their QoL. Oesophageal cancer patients should be assessed regularly and should be supported on an ongoing basis. PMID- 25782721 TI - Assessment of sleep disturbances in patients with cancer: Cross-sectional study in a radiotherapy department. AB - PURPOSE: To explore sleep-related problems reported by patients with cancer prior to undergoing radiotherapy, and to analyse the effect of cancer severity, history of treatment and psychosomatic symptomatology on these problems. METHOD: A descriptive cross-sectional study was conducted. One hundred and five patients with cancer were evaluated prior to radiotherapy. The primary endpoint was the sleep problem score measured by a self-rated version of the Oviedo Sleep Questionnaire. Secondary variables were impact of pain on sleep, anxiety and asthenia. RESULTS: Patients reported important levels of insomnia and hypersomnia. Insomnia-related problems were significantly higher in patients with more-severe disease (P < 0.05), and led to higher levels of hypnotic drug intake. Prior chemotherapy was significantly associated with hypersomnia-related problems (P < 0.05). Anxiety was significantly associated with both sleep-related problems. CONCLUSIONS: Sleep problems are significant among patients with cancer prior to undergoing radiotherapy, and were found to be associated with progression of cancer, prior treatments and other psychosomatic symptoms (e.g. anxiety). Sleep problems within this context must be explored to provide adequate guidelines to palliate their effects on quality of life. PMID- 25782722 TI - Improving communication with palliative care cancer patients at home - A pilot study of SAGE & THYME communication skills model. AB - PURPOSE: To pilot an evidence-based communication skills model (SAGE & THYME) with UK District Nurses (DNs) who visit patients with advanced cancer early in the dying trajectory. Evidence suggests that DNs lack confidence in communication skills and in assessing cancer patients' psycho-social needs; also that they lack time. SAGE & THYME is a highly structured model for teaching patient centred interactions. It addresses concerns about confidence and time. METHOD: Mixed methods. 33 DNs were trained in SAGE & THYME in a three hour workshop and interviewed in focus groups on three occasions: pre-training, immediately post training and two months post-training. Questionnaires measuring perceived outcomes of communication, confidence in communication and motivation to use SAGE & THYME were administered at the focus groups. RESULTS: SAGE & THYME provided a structure for conversations and facilitated opening and closing of interactions. The main principle of patient centeredness was reportedly used by all. Knowledge about communication behaviours helpful to patients improved and was sustained two months after training. Increased confidence in communication skills was also sustained. Motivation to use SAGE & THYME was high and remained so at two months, and some said the model saved them time. Challenges with using the model included controlling the home environment and a change in style of communication which was so marked some DNs preferred to use it with new patients. CONCLUSION: Training DNs in SAGE & THYME in a three hour workshop appears to be a promising model for improving communication skills when working with cancer patients. PMID- 25782723 TI - Ontogeny of Size and Shape Sexual Dimorphism in the Pubis: A Multislice Computed Tomography Study by Geometric Morphometry. AB - Few studies have been conducted to determine sex differences in the immature coxal bone and the results were often contradictory. The authors studied sexual dimorphic differences of the pubis using geometric morphometric analysis of five osteometric landmarks recorded by multislice computed tomography (MSCT), based on three-dimensional reconstructions of 188 children (95 boys, 93 girls) living in the region of Toulouse, southwestern France, ranging in age from 1 to 18 years old. They used geometric morphometric methodology first to test sexual dimorphism in size (centroid size) and shape (Procrustes residuals) and second to examine patterns of shape change with age (development) and size change with age (growth). Based on statistical significance test results, the pubic shape became sexually dimorphic at 13 years old, although visible shape differences were observed as early as 9 years old. This work showed that the trajectories of pubis shape (development) and size (growth) differed throughout ontogeny and between sexes. PMID- 25782724 TI - Carcinoma ex-pleomorphic adenoma of the parotid gland consisting of high-grade salivary duct carcinoma and keratinizing squamous cell carcinoma. AB - Carcinoma ex-pleomorphic adenoma (CXPA) is a rare salivary gland malignancy that presents diagnostic difficulties partly because of its wide range of histologic presentations. We report a case of a 77-year-old man, who presented with a 6-year history of a parotid mass that had undergone rapid growth within weeks. Magnetic resonance imaging revealed an infiltrative mass in the parotid gland, and the fine-needle aspiration (FNA) biopsy result was highly suspicious for carcinoma. Subsequent excision of the tumor demonstrated a poorly differentiated epithelial neoplasm consisting of keratinizing squamous cell carcinoma (SCC) and adenocarcinoma with regions of both ductal carcinoma in situ and invasive salivary duct carcinoma (SDC). Only focal areas exhibited a benign pleomorphic adenoma component. To our knowledge, this is the first case of a CXPA that consists of both a high-grade SDC and a keratinizing SCC in the parotid gland. PMID- 25782725 TI - Management of fractures of the atrophic mandible: a case series. AB - OBJECTIVE: This study aims to report the outcome of patients with atrophic mandible fractures. STUDY DESIGN: Atrophic mandible fractures in 11 patients (7 females and 4 males) were approached with a transcervical incision, and bone segments were stabilized with 2.7-mm reconstruction titanium plates and locking screws placed at the lateral border of the mandible. In 6 of the 11 cases, autogenous cancellous bone was used to repair a continuity defect or to augment the vertical height of the bone in the region of the fracture(s). RESULTS: No major intraoperative or postoperative complications were encountered in any patient. Two patients presented with postoperative infections that resolved with incision-drainage and antibiotics, and removal or replacement of the reconstruction plates or the bone grafts was not required. CONCLUSIONS: Treatment of atrophic mandible fractures can be performed safely and effectively with reconstruction plates, with or without bone grafting. The most conservative and predictable treatment in the long term is the definitive reconstructive surgical procedure to restore form and immediate function. PMID- 25782726 TI - The binding of Abeta1-42 to lipid rafts of RBC is enhanced by dietary docosahexaenoic acid in rats: Implicates to Alzheimer's disease. AB - Once amyloid beta peptides (Abetas) of the Alzheimer's disease build up in blood circulation, they are capable of binding to red blood cell (RBC) and inducing hemolysis of RBC. The mechanisms of the interactions between RBC and Abeta are largely unknown; however, it is very important for the therapeutic target of Abeta-induced hemolysis. In the present study, we investigated whether Abeta1-42 interacts with caveolin-1-containing detergent-resistant membranes (DRMs) of RBC and whether the interaction could be modulated by dietary pre-administration of docosahexaenoic acid (DHA). DHA pre-administration to rats inhibited hemolysis by Abeta1-42. This activity was accompanied by increased DHA levels and membrane fluidity and decreased cholesterol level, lipid peroxidation, and reactive oxygen species in the RBCs of the DHA-pretreated rats, suggesting that the antioxidative property of DHA may rescue RBCs from oxidative damage by Abeta1-42. The level of caveolin-1 was augmented in the DRMs of DHA-pretreated rats. Binding between Abeta1-42 and DRMs of RBC significantly increased in DHA-rats. When fluorescently labeled Abeta1-42 (TAMRA-Abeta1-42) was directly infused into the bloodstream, it again occupied the caveolin-1-containing DRMs of the RBCs from the DHA-rats to a greater extent, indicating that circulating Abetas interact with the caveolin-1 rich lipid rafts of DRMs and the interaction is stronger in the DHA-enriched RBCs. The levels of TAMRA-Abeta1-42 also increased in liver DRMs, whereas it decreased in plasma of DHA-pretreated rats. DHA might help clearance of circulating Abetas by increased lipid raft-dependent degradation pathways and implicate to therapies in Alzheimer's disease. PMID- 25782727 TI - Increased membrane surface positive charge and altered membrane fluidity leads to cationic antimicrobial peptide resistance in Enterococcus faecalis. AB - To understand the role of cell membrane phospholipids during resistance development to cationic antimicrobial peptides (CAMPs) in Enterococcus faecalis, gradual dose-dependent single exposure pediocin-resistant (Pedr) mutants of E. faecalis (Efv2.1, Efv3.1, Efv3.2, Efv4.1, Efv4.2, Efv5.1, Efv5.2 and Efv5.3), conferring simultaneous resistance to other CAMPs, selected in previous study were characterized for cell membrane phospholipid head-groups and fatty acid composition. The involvement of phospholipids in resistance acquisition was confirmed by in vitro colorimetric assay using PDA (polydiacetylene)-biomimetic membranes. Estimation of ratio of amino-containing phospholipids to amino-lacking phospholipids suggests that phospholipids in cell membrane of Pedr mutants loose anionic character. At moderate level of resistance, the cell-membrane becomes neutralized while at further higher level of resistance, the cell-surface acquired positive charge. Increased expression of mprF gene (responsible for lysinylation of phospholipids) was also observed on acquiring resistance to pediocin in PedrE. faecalis. Decreased level of branched chain fatty acids in Pedr mutants might have contributed in enhancing rigidification of cell membrane and contributing towards resistance. The interaction of pediocin with PDA biomimetic membranes prepared from wild-type and Pedr mutants was monitored by measuring percent colorimetric response (%CR). Increased %CR of pediocin against PDA-biomimetic membranes prepared from Pedr mutants confirmed that cell membrane phospholipids are involved in the interactions of pore formation by CAMPs. There was a direct linear relationship between percent colorimetric response and IC50 of CAMPs for wild-type and Pedr mutants. This relationship further reveals that in vitro colorimetric assay can be used effectively for quantification of resistance to CAMPs. PMID- 25782728 TI - Isolation and full genome characterization of avian influenza subtype H9N2 from poultry respiratory disease outbreak in Egypt. AB - Low pathogenic avian influenza virus of subtype H9N2 is panzootic in multiple avian species causing respiratory manifestations and severe economic losses. H9N2 co-circulate simultaneously with high pathogenic avian influenza virus subtype H5N1 in Egyptian chicken farms suggesting the possibility of reassortment. The aim of the present study was to isolate and characterize H9N2 from the recent outbreaks in chicken farms. Also the diversity of amantadine-resistant mutants among these isolates was tested by in situ ELISA and sequence analysis. Three influenza H9N2 viruses, designated A/chicken/Egypt/SCU8/2014, A/chicken/Egypt/SCU9/2014 and A/chicken/Egypt/SCU20/2014 were isolated from commercial broiler and broiler breeder chickens in specific pathogen free embryonated chicken eggs. The eight gene segments were amplified by RT-PCR, cloned, and subjected to full length sequencing. Phylogenetic analysis of these viruses revealed a close relationship between Egyptian, Middle Eastern and Israel isolates with an average of 96-99 % nucleotide homology and identified an ancestor relationship to low pathogenic H9N2 Quail/HK/G1/1997 prototype. The internal segments of the currently isolated viruses were derived from the same sub-lineage with no new evidence of reassortment. The three isolates were sensitive to amantadine as suggested by absence of mutations of M2 and confirmed by a phenotypic assay. In conclusion, avian influenza H9N2 virus is circulating in Egyptian chicken farms causing respiratory manifestations. Continuous monitoring of the molecular epidemiology and its impact on the virulence as well as emergence of new strains are necessary. PMID- 25782729 TI - Effect of cinacalcet cessation on hyperparathyroidism in kidney transcaplant patients after long-term dialysis therapy. AB - BACKGROUND: Cinacalcet is a promising therapy widely used in dialysis patients with hyperparathyroidism resistant to conventional therapy. However, reports regarding the influence of cinacalcet cessation after long-term use on kidney transplantation patients are few. METHODS: This retrospective observational study included 40 dialysis patients who underwent kidney transplantation. Creatinine, corrected calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone levels were assessed before and after kidney transplantation according to pretransplant treatment of chronic kidney disease-mineral and bone disorder. RESULTS: Ultrasonography revealed enlargement of the parathyroid in all patients treated with cinacalcet. Although the data at the time of kidney transplantation were comparable, the serum levels of calcium, alkaline phosphatase, and intact parathyroid hormone after kidney transplantation were higher in patients treated with cinacalcet than in those treated without. However, serum phosphate levels in the cinacalcet group were slightly higher at the time of kidney transplantation and significantly lower 3 months later. CONCLUSIONS: Mineral abnormalities persisted in kidney transplant patients with enlarged parathyroid glands after discontinuation of cinacalcet treatment. Parathyroidectomy should be considered in kidney transplant candidates with the risk of developing refractory hyperparathyroidism after transplantation. PMID- 25782730 TI - Functionalization of DNA-dendron supramolecular fibers and application in regulation of Escherichia coli association. AB - Specific carbohydrate recognition in biology is a dynamic process. Thus, supramolecular multivalent scaffolds with dynamic features have been applied to mimic this process. Herein, we prepared DNA-dendron supramolecular fibers and synthesized carbohydrate-oligonucleotide conjugates (C18-mannose). Via DNA hybridization, the C18-mannose could be guided onto the fiber platform and form multiple mannose-functionalized fibers, which can be utilized to agglutinate E. coli because of high affinity among multivalent mannose ligands and receptors on E. coli. In addition, via chain exchange reaction of DNAs, the E. coli could be dissociated by replacing multivalent mannose ligands with competitive unmodified DNA sequences. The association and dissociation processes of E. coli are confirmed by fluorescent microscope and transmission electron microscope (TEM). These results not only demonstrate the ability of DNA-dendron fibers in reversibly associating E. coli but also illustrate their potential to be an easily modified multivalent supramolecular platform. PMID- 25782731 TI - Thymic Mucoepidermoid Carcinoma: Report of a Case With CTRC1/3-MALM2 Molecular Studies. AB - Thymic mucoepidermoid carcinoma (TMEC) is a vanishingly rare entity that usually presents as low to intermediate grade MEC and carries a better prognosis when compared with other poorly differentiated thymic carcinomas. The recently described fusions, t(11;19)(q21;p13) CREB (cAMP response element-binding protein) regulated transcription coactivator 1 and MAML2, mastermind-like gene 2 (CRTC1 MAML2) and t(11:15)(q21;q26) CRTC3-MAML2 characterize a considerable proportion of MEC examples arising from a variety of anatomical sites. Recent data point out that the aberrant proteins produced by this fusion drive oncogenesis by disrupting the cAMP/CREB and NOTCH1 pathways. To date, only 2 TMEC cases have been reported to have MAML2 rearrangements, a feature that was found to be absent in TMEC mimics. These findings led the authors to recommend this test as a diagnostic tool in the differential diagnosis for thymic carcinoma. Herein, we present a case of TMEC arising in a 58-year-old woman, which was predominantly cystic with intracystic papillary formations composed of a mixture of mucinous cells and intermediate/epidermoid eosinophilic cells. This case was negative for CTCR1-MAML2 and CTCR3-MAML2 fusion transcripts by reverse transcriptase polymerase chain reaction and lacked a MAML2 rearrangement by fluorescence in situ hybridization. We report a CTCR1/3-MAML2 fusion and MAML2 rearrangement negative TMEC, indicating that a different molecular pathway must be involved in the generation of these tumors. The possibility of fusion-negative TMEC should be taken into consideration in the differential diagnosis of a thymic carcinoma. PMID- 25782732 TI - Pancreatobiliary intraductal papillary neoplasms: what is in a name? PMID- 25782733 TI - Benign monsters. PMID- 25782734 TI - Breast implant-associated anaplastic large cell lymphoma. PMID- 25782735 TI - Compensatory "eryhtrocytosis" in cyanotic heart disease. PMID- 25782736 TI - The pregnant heart: cardiac emergencies during pregnancy. AB - BACKGROUND: Cardiovascular emergencies in pregnant patients are often considered a rare event; however, heart disease as a cause of maternal mortality is steadily increasing. DISCUSSION: In this article, we review 3 common cardiovascular emergencies and the important subtle differences in their treatment in the pregnant patient: peripartum/postpartum cardiomyopathy, acute myocardial infarction, and cardiac resuscitation. CONCLUSION: Managing these conditions in the emergency department setting requires a high index of suspicion, knowledge of anatomical and physiologic changes associated with pregnancy, and updated management strategies related to optimizing maternal and fetal health. PMID- 25782737 TI - Angiographic embolization in chest wall hematoma due to handlebar injury-a rare case report. PMID- 25782738 TI - Effect of re-irradiation for painful bone metastases on urinary markers of osteoclast activity (NCIC CTG SC.20U). AB - PURPOSE: The NCIC CTG Symptom Control.20 randomized trial (SC.20) confirmed the effectiveness of re-irradiation to painful bone metastases. This companion study correlates urinary markers of osteoclast activity with response to re irradiation, survival and skeletal related events (SREs). METHODS: Pain response was assessed using the International Consensus Endpoints. Urinary markers of bone turnover-pyridinoline (PYD), deoxypyridinoline (DPD), N-telopeptide (NTX), Alpha and Beta cross-laps of C-telopeptide (CTX)-before and 1month after re-irradiation were correlated to response to re-irradiation and then to both, either or none of the initial and re-irradiation: frequent responders (response to both); eventual responders (response to re-irradiation only); eventual non-responders (response to initial radiation only), and absolute non-responders (no response to both). RESULTS: Significant differences between 40 responders and 69 non-responders to re-irradiation existed for PYD (p=0.03) and DPD (p=0.04) at baseline. When patients were categorized as frequent responders (N=34), eventual responders (6), eventual non-responders (59) and absolute non-responders (10), the mean values of all markers in the absolute non-responders at baseline and the follow-up were about double those for the other three groups with statistically significant difference for DPD (p=0.03) at baseline. Absolute non-responders had the worst survival. The few occurrences of the SREs did not allow meaningful comparisons among the groups. CONCLUSION: There were significant differences between responders and non-responders to re-irradiation for PYD and DPD at baseline. The urinary markers in the absolute non-responders were markedly elevated at both baseline and follow-up with a statistically significant difference for DPD at baseline. PMID- 25782739 TI - Functional analysis of TPM domain containing Rv2345 of Mycobacterium tuberculosis identifies its phosphatase activity. AB - Mycobacterium tuberculosis (Mtb) is the causal agent of tuberculosis, the second largest infectious disease. With the rise of multi-drug resistant strains of M. tuberculosis, serious challenge lies ahead of us in treating the disease. The availability of complete genome sequence of Mtb has improved the scope for identifying new proteins that would not only further our understanding of biology of the organism but could also serve to discover new drug targets. In this study, Rv2345, a hypothetical membrane protein of M. tuberculosis H37Rv, which is reported to be a putative ortholog of ZipA cell division protein has been assigned function through functional annotation using bioinformatics tools followed by experimental validation. Sequence analysis showed Rv2345 to have a TPM domain at its N-terminal region and predicted it to have phosphatase activity. The TPM domain containing region of Rv2345 was cloned and expressed using pET28a vector in Escherichia coli and purified by Nickel affinity chromatography. The purified TPM domain was tested in vitro and our results confirmed it to have phosphatase activity. The enzyme activity was first checked and optimized with pNPP as substrate, followed by using ATP, which was also found to be used as substrate by the purified protein. Hence sequence analysis followed by in vitro studies characterizes TPM domain of Rv2345 to contain phosphatase activity. PMID- 25782740 TI - Improving storage stability of recombinant organophosphorus hydrolase. AB - Organophosphorus hydrolase (OPH) is a ~38kDa enzyme encoded by opd gene of Flavobacterium sp. The enzyme can hydrolyze and inactivate variety of organophosphate (OP)-compounds, including chemical warfare nerve agents. Thus, OPH is a strong candidate for the development of therapeutic intervention against OP-poisoning in humans and other animals. It is also a promising bio decontaminating agent for clean-up of OP-contaminated objects and areas. For successful commercial application, long-term storage stability of purified OPH enzyme is important. In this study we have cloned and expressed recombinant OPH (r-OPH) in Escherichia coli and the effect of different excipients on the long term storage stability of purified enzyme was analyzed. The enzyme was stored in either aqueous solution or in lyophilized form at 25 degrees C for 60days in the presence or absence of different excipients and the stability of the enzyme was determined by monitoring the paraoxon-hydrolyzing activity. Our results suggest that, (a) maltose, trehalose, arginine and proline were most effective in stabilizing the enzyme when stored in aqueous buffer at 25 degrees C, and (b) maltose, trehalose, and mannose exerted maximum stabilization effect when the enzyme was stored in lyophilized form at 25 degrees C for 60days. The study shows that common excipients can be used to stabilize purified OPH enzyme in order to store it for long period of time under different storage conditions. The results of this study can be used to develop formulation(s) of OPH enzyme for commercial use. PMID- 25782741 TI - Positional effects of fusion partners on the yield and solubility of MBP fusion proteins. AB - Escherichia coli maltose-binding protein (MBP) is exceptionally effective at promoting the solubility of its fusion partners. However, there are conflicting reports in the literature claiming that (1) MBP is an effective solubility enhancer only when it is joined to the N-terminus of an aggregation-prone passenger protein, and (2) MBP is equally effective when fused to either end of the passenger. Here, we endeavor to resolve this controversy by comparing the solubility of a diverse set of MBP fusion proteins that, unlike those analyzed in previous studies, are identical in every way except for the order of the two domains. The results indicate that fusion proteins with an N-terminal MBP provide an excellent solubility advantage along with more robust expression when compared to analogous fusions in which MBP is the C-terminal fusion partner. We find that only intrinsically soluble passenger proteins (i.e., those not requiring a solubility enhancer) are produced as soluble fusions when they precede MBP. We also report that even subtle differences in inter-domain linker sequences can influence the solubility of fusion proteins. PMID- 25782742 TI - trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: prime site exploration using an amino linker. AB - Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2. PMID- 25782743 TI - AIMing towards improved antitumor efficacy. AB - Using the structure-activity relationship emerging from previous Letter, and guided by pharmacokinetic properties, new AIMs have been prepared with both improved efficacy against human glioblastoma cells and cell permeability as determined by fluorescent confocal microscopy. We present our first unambiguous evidence for telomeric G4-forming oligonucleotide anisotropy by NMR resulting from direct interaction with AIMs, which is consistent with both our G4 melting studies by CD, and our working hypothesis. Finally, we show that AIMs induce apoptosis in SNB-19 cells. PMID- 25782744 TI - Azachalcones: a new class of potent polyphenol oxidase inhibitors. AB - A library of potent inhibitors of polyphenol oxidase and their structure activity relationships are described. Azachalcone derivatives were synthesized and tested for their tyrosinase inhibitory activity. Their inhibitory activities on mushroom tyrosinase using l-DOPA as a substrate were investigated. Two compounds that are the reduction congeners of the pyridinyl azachalcones strongly inhibited the enzyme activity and were more potent than the positive control kojic acid. PMID- 25782745 TI - Design strategies to address kinetics of drug binding and residence time. AB - The kinetics of drug binding and drug residence time are recognized to be important in the clinical effectiveness of drug candidates. In most cases a long residence time of the drug-target complex results in an extended duration of pharmacodynamic activity, even when systemic concentrations of drug have been notably reduced through elimination routes. Hence, if selective for target, long residence times can increase the duration of drug efficacy in vivo and can significantly diminish the potential for off-target-mediated toxicities. Furthermore, a compound with a slower dissociation rate may allow a reduced dosing schedule relative to a compound with a rapid dissociation rate. Factors contributing to long residence time that could be useful to medicinal chemists in the prospective design of compounds with long residence times will be discussed in this perspective. Particular emphasis will be on case studies highlighting how kinetics can be measured, modulated based on supporting structure kinetic relationships and whether these effects are translatable into man. PMID- 25782747 TI - Agmatine attenuates hyperactivity and weight loss associated with activity-based anorexia in female rats. AB - Anorexia nervosa is a debilitating eating disorder characterized by hypophagia, body weight loss, amenorrhea and intense fear of weight gain. In present study, the effect of subchronic agmatine treatment on development of activity based anorexia (ABA) in female rats has been investigated. Animals were injected with saline or agmatine (10-40 mg/kg, ip) just before the onset of dark phase and shifted to experimental cage with wheel for ABA test for 10days. A pre-weighed quantity of food pellets (10g) was placed daily for a restricted period of only 2h (1700-1900h) and food intake was monitored (g) manually by weighing the leftover food. Rats restricted to ABA paradigm, showed greater wheel running, suppressed food consumption, disrupted estrous cycle and weight loss. On the other hand, subchronic agmatine (10-40mg/kg, ip, for 10days) treatment decreased wheel running activity, pronounced increased in food intake and restored body weights as compared to saline treated animals. Further, agmatine treatment decreased corticosterone levels in ABA rats, thereby stabilizing HPA axis in ABA rats. Subchronic agmatine treatment also prevented the disruptions of estrous cycle. Considering the common resistance of anorexia nervosa to current pharmacotherapy, the preliminary data on reduction of physical activity by agmatine, may have potential therapeutic importance. Thus, the role of agmatine in feeding behavior is likely to provide insight into the circumstances that facilitate treatment in eating disorders like anorexia nervosa. PMID- 25782746 TI - Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats. AB - The present study explored the effects of supplementing male rats with either choline, omega-3 fatty acids, or phytoestrogens, from weaning into early adulthood, on emotionality and hippocampal plasticity. Because of the neuroprotective properties of these nutrients, we hypothesized that they would positively affect both behavior and hippocampal function when compared to non supplemented control rats. To test this hypothesis, male Sprague Dawley rats were assigned to one of four nutrient conditions after weaning: 1) control (normal rat chow); 2) choline (supplemented in drinking water); 3) omega 3 fatty acids (daily oral supplements); or 4) phytoestrogens (supplemented in chow). After 4weeks on their respective diets, a subset of rats began 3weeks of behavioral testing, while the remaining behaviorally naive rats were sacrificed after 6weeks on the diets to assess numbers of adult-born hippocampal neurons using the immature neuron marker, doublecortin. The results revealed that choline supplementation affected emotional functioning; compared to rats in other diet conditions, rats in this group were less anxious in an open field and after exposure to predator odor and showed less behavioral despair after forced swimming. Similar behavioral findings were evident following supplementation with omega-3 fatty acids and phytoestrogen supplementation, though not on all tests and not to the same magnitude. Histological findings followed a pattern consistent with the behavioral findings: choline supplementation, followed by omega-3 fatty acid supplementation, but not phytoestrogen supplementation, significantly increased the numbers of new-born hippocampal neurons. Choline and omega-3 fatty acids have similar biological functions-affecting cell membranes, growth factor levels, and epigenetically altering gene transcription. Thus, the present findings suggest that targeting nutrients with these effects may be a viable strategy to combat adult psychopathologies. PMID- 25782748 TI - High throughput proteomic analysis and a comparative review identify the nuclear chaperone, Nucleophosmin among the common set of proteins modulated in Chikungunya virus infection. AB - Global re-emergence of Chikungunya virus (CHIKV) has renewed the interest in its cellular pathogenesis. We subjected CHIKV-infected Human Embryo Kidney cells (HEK293), a widely used cell-based system for CHIKV infection studies, to a high throughput expression proteomics analysis by Liquid Chromatography-tandem mass spectrometry. A total of 1047 differentially expressed proteins were identified in infected cells, consistently in three biological replicates. Proteins involved in transcription, translation, apoptosis and stress response were the major ones among the 209 proteins that had significant up-regulation. In the set of 45 down regulated proteins, those involved in carbohydrate and lipid metabolism predominated. A STRING network analysis revealed tight interaction of proteins within the apoptosis, stress response and protein synthesis pathways. We short listed a common set of 30 proteins that can be implicated in cellular pathology of CHIKV infection by comparing our results and results of earlier CHIKV proteomics studies. Modulation of eight proteins selected from this set was re confirmed at transcript level. One among them, Nucleophosmin, a nuclear chaperone, showed temporal modulation and cytoplasmic aggregation upon CHIKV infection in double immunofluorescence staining and confocal microscopy. The short-listed cellular proteins will be potential candidates for targeted study of the molecular interactions of CHIKV with host cells. BIOLOGICAL SIGNIFICANCE: Chikungunya remained as a neglected tropical disease till its re-emergence in 2005 in the La ReUnion islands and subsequently, in India and many parts of South East Asia. These and the epidemics that followed in subsequent years ran an explosive course leading to extreme morbidity and attributed mortality to this originally benign virus infection. Apart from classical symptoms of acute fever and debilitating polyarthralgia lasting for several weeks, a number of complications were documented. These included aphthous-like ulcers and vesiculo bullous eruptions on the skin, hepatic involvement, central nervous system complications such as encephalopathy and encephalitis, and transplacental transmission. The disease has recently spread to the Americas with its initial documentation in the Caribbean islands. The Asian genotype of this positive stranded RNA virus of the Alphavirus genus has been attributed in these outbreaks. However, the disease ran a similar course as the one caused by the East, Central and South African (ECSA) genotype in the other parts of the world. Studies have documented a number of mutations in the re-emerging strains of the virus that enhances mosquito adaptability and modulates virus infectivity. This might support the occurrence of fiery outbreaks in the absence of herd immunity in affected population. Several research groups work to understand the pathogenesis of chikungunya and the mechanisms of complications using cellular and animal models. A few proteomics approaches have been employed earlier to understand the protein level changes in the infected cells. Our present study, which couples a high throughput proteomic analysis and a comparative review of these earlier studies, identifies a few critical molecules as hypothetical candidates that might be important in this infection and for future study. PMID- 25782749 TI - Extracting high confidence protein interactions from affinity purification data: at the crossroads. AB - Deriving protein-protein interactions from data generated by affinity purification and mass spectrometry (AP-MS) techniques requires application of scoring methods to measure the reliability of detected putative interactions. Choosing the appropriate scoring method has become a major challenge. Here we apply six popular scoring methods to the same AP-MS dataset and compare their performance. The comparison was carried out for six distinct datasets from human, fly and yeast, which focus on different biological processes and differ in their coverage of the proteome. Results show that the performance of a given scoring method may vary substantially depending on the dataset. Disturbingly, we find that the high confidence (HC) PPI networks built by applying the six scoring methods to the same raw AP-MS dataset display very poor overlap, with only 1.7 4.1% of the HC interactions present in all the networks built, respectively, from the proteome-wide human, fly or yeast datasets. Various properties of the shared versus unique interactions in each network, including biases in protein abundance, suggest that current scoring methods are able to eliminate only the most obvious contaminants, but still fail to reliably single out specific interactions from the large body of spurious associations detected in the AP-MS experiments. BIOLOGICAL SIGNIFICANCE: The fast progress in AP-MS techniques has prompted the development of a multitude of scoring methods, which are relied upon to remove contaminants and non-specific binders. Choosing the appropriate scoring scheme for a given AP-MS dataset has become a major challenge. The comparative analysis of 6 of the most popular scoring methods, presented here, reveals that overall these methods do not perform as expected. Evidence is provided that this is due to 3 closely related issues: the high 'noise' levels of the raw AP-MS data, the limited capacity of current scoring methods to deal with such high noise levels, and the biases introduced using Gold Standard datasets to benchmark the scoring functions and threshold the networks. For the field to move forward, all three issues will have to be addressed. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras. PMID- 25782750 TI - Hsp90 inhibition induces both protein-specific and global changes in the ubiquitinome. AB - Inhibition of the essential chaperone Hsp90 with drugs causes a global perturbation of protein folding and the depletion of direct substrates of Hsp90, also called clients. Ubiquitination and proteasomal degradation play a key role in cellular stress responses, but the impact of Hsp90 inhibition on the ubiquitinome has not been characterized on a global scale. We used stable isotope labeling and antibody-based peptide enrichment to quantify more than 1500 protein sites modified with a Gly-Gly motif, the remnant of ubiquitination, in human T cells treated with an Hsp90 inhibitor. We observed rapid changes in GlyGly modification sites, with strong increases for some Hsp90 clients but also decreases for a majority of cellular proteins. A comparison with changes in total protein levels and protein synthesis and decay rates from a previous study revealed a complex picture with different regulatory patterns observed for different protein families. Overall the data support the notion that for Hsp90 clients GlyGly-modification correlates with targeting by the ubiquitin-proteasome system and decay, while for other proteins levels of GlyGly-modification appear to be mainly influenced by their synthesis rates. Therefore a correct interpretation of changes in ubiquitination requires knowledge of multiple parameters. Data are available via ProteomeXchange with identifier PXD001549. BIOLOGICAL SIGNIFICANCE: Proteostasis, i.e. the capacity of the cell to maintain proper synthesis and maturation of proteins, is a fundamental biological process and its perturbations have far-reaching medical implications e.g. in cancer or neurodegenerative diseases. Hsp90 is an essential chaperone responsible for the correct maturation and stability of a number of key proteins. Inhibition of Hsp90 triggers a global stress response caused by accumulation of misfolded chains, which have to be either refolded or eliminated by protein degradation pathways such as the Ubiquitin-Proteasome System (UPS). We present the first global assessment of the changes in the ubiquitinome, the subset of ubiquitin-modified proteins, following Hsp90 inhibition in human T-cells. The results provide clues on how cells respond to a specific proteostasis challenge. Furthermore, our data also suggest that basal ubiquitination levels for most proteins are influenced by synthesis rates. This has broad significance as it implies that a proper interpretation of data on ubiquitination levels necessitates simultaneous knowledge of other parameters. PMID- 25782751 TI - Synaptic mitochondria: a brain mitochondria cluster with a specific proteome. AB - The synapse is a particularly important compartment of neurons. To reveal its molecular characteristics we isolated whole brain synaptic (sMito) and non synaptic mitochondria (nsMito) from the mouse brain with purity validated by electron microscopy and fluorescence activated cell analysis and sorting. Two dimensional differential gel electrophoresis and mass spectrometry based proteomics revealed 22 proteins with significantly higher and 34 proteins with significantly lower levels in sMito compared to nsMito. Expression differences in some oxidative stress related proteins, such as superoxide dismutase [Mn] (Sod2) and complement component 1Q subcomponent-binding protein (C1qbp), as well as some tricarboxylic acid cycle proteins, including isocitrate dehydrogenase subunit alpha (Idh3a) and ATP-forming beta subunit of succinyl-CoA ligase (SuclA2), were verified by Western blot, the latter two also by immunohistochemistry. The data suggest altered tricarboxylic acid metabolism in energy supply of synapse while the marked differences in Sod2 and C1qbp support high sensitivity of synapses to oxidative stress. Further functional clustering demonstrated that proteins with higher synaptic levels are involved in synaptic transmission, lactate and glutathione metabolism. In contrast, mitochondrial proteins associated with glucose, lipid, ketone metabolism, signal transduction, morphogenesis, protein synthesis and transcription were enriched in nsMito. Altogether, the results suggest a specifically tuned composition of synaptic mitochondria. BIOLOGICAL SIGNIFICANCE: Neurons communicate with each other through synapse, a compartment metabolically isolated from the cell body. Mitochondria are concentrated in presynaptic terminals by active transport to provide energy supply for information transfer. Mitochondrial composition in the synapse may be different than in the cell body as some examples have demonstrated altered mitochondrial composition with cell type and cellular function in the muscle, heart and liver. Therefore, we posed the question whether protein composition of synaptic mitochondria reflects its specific functions. The determined protein difference pattern was in accordance with known functional specialties of high demand synaptic mitochondria. The data also suggest specifically tuned metabolic fluxes for energy production by means of interaction with glial cells surrounding the synapse. These findings provide possible mechanisms for dynamically adapting synaptic mitochondrial output to actual demand. In turn, an increased vulnerability of synaptic mitochondria to oxidative stress is implied by the data. This is important from theoretical but potentially also from therapeutic aspects. Mitochondria are known to be affected in some neurodegenerative and psychiatric disorders, and proteins with elevated level in synaptic mitochondria, e.g. C1qbp represent targets for future drug development, by which synaptic and non-synaptic mitochondria can be differentially affected. PMID- 25782752 TI - Metabolomic and proteomic responses of Staphylococcus aureus to prolonged cold stress. AB - The high pathogenicity of Staphylococcus aureus is thought to be due to its extraordinary capacity to rapidly adapt to changes in environmental conditions. This study was carried out to investigate whether the cytoplasmic profiles of metabolites and proteins of S. aureus were altered in response to prolonged exposure to cold stress. Metabolic profiling and proteomics were used to characterise alterations in cytoplasmic proteins and metabolites in cells from the mid-exponential phase of growth under ideal conditions at 37 degrees C and compared with equivalent cells exposed to prolonged cold stress for 2 weeks at 4 degrees C. Principle component analysis (PCA) of the metabolomic and proteomic data indicated that, at the mid-exponential phase of growth, prolonged cold stress conditions generated cells with different metabolite and protein profiles compared with those grown at 37 degrees C. Nine ribosomal proteins and citric acid were substantially elevated in the cytoplasmic fractions from the cells adapted to cold-stress but most amino acids showed a reduction in their concentration in cold-stressed samples. The data provided strong evidence supporting the hypothesis that specific changes in metabolic homeostasis and protein composition were critical to the adaptive processes required for survival under cold stress. BIOLOGICAL SIGNIFICANCE: Work in our laboratory has shown that prolonged exposure of S. aureus to cold stress can result in the formation of small colony variants (SCVs) associated with significant alterations in the cell wall composition. Further studies revealed that S. aureus altered cell size and cell wall thickness in response to exposure to cold temperatures, alterations in pH and exposure to antibiotics. The current study has utilised the prolonged exposure to cold stress as a model system to explore changes in the proteome and associated metabolic homeostasis following environmental challenges. The study provides an improved understanding of how S. aureus adapts to the changing environment whilst in transition between human hosts. The results indicated an unexpected production of 9 ribosomal proteins and citric acid in response to cold stress suggesting specific survival roles for these proteins and citric acid as an adaptation mechanism for empowering survival under these conditions. PMID- 25782753 TI - Norepinephrine Decreases Fluid Requirements and Blood Loss While Preserving Intestinal Villi Microcirculation during Fluid Resuscitation of Uncontrolled Hemorrhagic Shock in Mice. AB - BACKGROUND: Norepinephrine administration is controversial during hemorrhagic shock resuscitation to stabilize mean arterial pressure (MAP) level because it could have deleterious effects on local circulations. The authors investigated the effect of norepinephrine on intestinal microcirculation during fluid resuscitation in uncontrolled hemorrhagic shock. METHODS: Mice (n = 6 per group) submitted to an uncontrolled hemorrhagic shock by tail section were randomly assigned to a resuscitation with fluid but without norepinephrine to target a MAP level of 50 mmHg (FR50) or 60 mmHg (FR60) or a resuscitation with fluid and norepinephrine to target a MAP level of 50 mmHg (FRNE50) or 60 mmHg (FRNE60). Intestinal microcirculation was observed by intravital microscopy. RESULTS: Fluid requirements were lower in groups resuscitated with fluid and norepinephrine than in groups resuscitated with fluid without norepinephrine (74.6 +/- 45.1 in FR50 vs. 28.1 +/- 10.0 ul/g in FRNE50; P = 0.004 and 161.9 +/- 90.4 in FR60 vs. 44.5 +/- 24.0 ul/g in FRNE60; P = 0.041). Blood loss was not statistically different between FR50 and FRNE50 (14.8 +/- 8.3 vs. 8.5 +/- 2.9 ul/g; P = 0.180) but was significantly lower in FRNE60 than in FR60 (10.1 +/- 4.2 vs. 22.6 +/- 9.6 ul/g; P = 0.015). This beneficial effect was associated with the restoration of intestinal microcirculation to the same extent in fluid resuscitated groups without norepinephrine (FR50 and FR60) and fluid resuscitated groups with norepinephrine (FRNE50 and FRNE60). CONCLUSIONS: During MAP-directed resuscitation of uncontrolled hemorrhagic shock, the administration of norepinephrine decreased blood loss and fluid requirements while preserving intestinal villi microcirculation. PMID- 25782754 TI - Impact of Hyperpolarization-activated, Cyclic Nucleotide-gated Cation Channel Type 2 for the Xenon-mediated Anesthetic Effect: Evidence from In Vitro and In Vivo Experiments. AB - BACKGROUND: The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined. METHODS: The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels. RESULTS: Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel mediated Ih current amplitude by 33.4 +/- 12.2% (at -133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from 98.8 +/- 1.6 to -108.0 +/- 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo. CONCLUSIONS: Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon. PMID- 25782755 TI - Definition and evaluation of the monotonicity condition for preference-based instruments. AB - BACKGROUND: Preference-based instrumental variable methods are often used in comparative effectiveness research. Many instrumental variable studies estimate the local average treatment effect (ie, the effect in the "compliers") under the assumption of monotonicity, ie, no "defiers," and well-defined compliance types. However, the monotonicity assumption has not been empirically tested and the meaning of monotonicity itself is unclear. METHODS: Here, we clarify the definition of local and global monotonicity and propose a novel study design to assess the monotonicity assumption empirically. Our design requires surveying physicians about their treatment plans and prescribing preferences for the same set of patients. We also discuss measures of monotonicity that can be calculated from this survey data. As an illustration, we conducted a pilot study in a survey of 53 physicians who reported treatment plans and prescribing preferences for hypothetical patients who were candidates for antipsychotic treatment. RESULTS: In our study, nearly all patients exhibited some degree of monotonicity violations. In addition, patients could not be cleanly classified as compliers, defiers, always-takers, or never-takers. CONCLUSIONS: We conclude that preference based instrumental variable estimates should be interpreted cautiously because bias due to monotonicity violations is likely and because the subpopulation to which the estimate applies may not be well defined. Investigators using preference-based instruments may consider supplementing their study with a survey to empirically assess the magnitude and direction of bias due to violations of monotonicity. PMID- 25782756 TI - Fractionation of oil sands-process affected water using pH-dependent extractions: a study of dissociation constants for naphthenic acids species. AB - The fractionation of oil sands process-affected water (OSPW) via pH-dependent extractions was performed to quantitatively investigate naphthenic acids (NAs, CnH2n+ZO2) and oxidized NAs (Ox-NAs) species (CnH2n+ZO3 and CnH2n+ZO4) using ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC TOFMS). A mathematical model was also developed to estimate the dissociation constant pKa for NAs species, considering the liquid-liquid extraction process and the aqueous layer acid-base equilibrium. This model provides estimated dissociation constants for compounds in water samples based on fractionation extraction and relative quantification. Overall, the sum of O2-, O3-, and O4-NAs species accounted for 33.6% of total extracted organic matter. Accumulative extracted masses at different pHs revealed that every oxygen atom added to NAs increases the pKa (i.e., O2-NAs= 0.70) for 7 of 12 dimensions. Most pair-wise correlations were significant and <0.5, implying good construct validity. CONCLUSION: The Dutch and French translations of the HSPSC were found tobe valid and reliable for measuring patient safety culture in psychiatric hospitals. Our results also suggest the use of combinations of specific dimensions as recommended in previous research. PMID- 25782765 TI - Advancing the accessibility of psychotherapy: learning from our international colleagues. AB - Although the Affordable Care Act has theoretically made access to mental health care possible for all patients, the United States continues to lag behind other countries with respect to the provision of psychotherapeutic treatments. In the United Kingdom, for example, substantial resources have been committed to increase the availability of effective psychotherapies, particularly for depression and anxiety disorders. This development required a significant deployment of resources, with more than one billion dollars committed over the course of 7 years (2008-2015). Over 6,000 therapists have been trained and are currently being deployed in specialized local services to treat patients with depression and anxiety. A second phase of the initiative aims to bring psychotherapeutic treatment to patients with schizophrenia, bipolar disorder, and borderline personality disorder. Psychotherapy advocates in the United States may be more successful in advocating for such treatments by using similar methods to influence legislators and insurers. PMID- 25782764 TI - Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. AB - BACKGROUND: Approximately 45% of patients with major depressive disorder (MDD) do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents with different mechanisms of action. Early proof of concept (POC) studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate (NMDA) receptor blockers (eg, ketamine) can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist. METHOD: In this double-blind, randomized, placebo controlled study, a single intravenous (IV) dose of GLYX-13 (1, 5, 10, or 30 mg/kg) or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 (Ham-D17), which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration. RESULTS: GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects. CONCLUSION: In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned. PMID- 25782766 TI - A case with reversible neurotoxicity after 2 years of dementia secondary to maintenance lithium treatment. AB - Chronic neurotoxicity caused by lithium salts can be reversible or irreversible and may appear after years of treatment, even at serum levels considered within the usual therapeutic range. The authors present the case of a patient with bipolar disorder who developed dementia at the age of 54 after being treated with lithium carbonate at therapeutic levels for 4 years. Nevertheless, lithium treatment was continued. At age 56, the patient presented with an acute encephalopathy caused by toxic lithium levels, which resolved only after lithium carbonate was discontinued. Full recovery from the dementia, which had started 2 years earlier, occurred only after cessation of lithium. The authors conclude that when patients treated with lithium develop subacute cognitive impairment, the possibility of lithium toxicity should be considered, even if the serum levels are considered within the therapeutic range. A long duration of neurotoxicity associated with lithium treatment does not necessarily indicate an irreversible prognosis. PMID- 25782767 TI - Challenges of the capacity evaluation for the consultation-liaison psychiatrist. AB - Assessing medical decision-making capacity is a clinical skill required of all medical professionals, but it is particularly essential for consultation- liaison psychiatrists. Medical decision-making capacity, often confused with competency, is evaluated by assessing 4 standards, which include whether a patient (1) can understand his or her medical situation, (2) can manipulate the information, (3) can evidence a choice about the proposed treatment, and (4) can appreciate the situation and its consequences. Multiple myths and pitfalls may be encountered during capacity evaluations; many of these can be avoided by proper education and training. We discuss the case of a 71-year-old man who presented to the emergency department by ambulance and was refusing non-emergent neurosurgery after a self inflicted gunshot wound to the head. He was evaluated for medical decision-making capacity, specifically on whether he had the capacity to refuse neurosurgery and accept intravenous antibiotic treatment. In discussing this case, which illustrates the elements, challenges, and ethical dilemmas of the capacity evaluation, we review several mental illnesses that may prevent individuals from having medical decision-making capacity. Myths and pitfalls of capacity evaluations and possible methods for avoiding them are proposed. Specifically, we emphasize the importance of communication between the primary team and the consultationliaison psychiatry service and describe possible solutions to common communication problems that may arise between services. It is hoped that this case presentation and review will help educate psychiatry residents and other physicians so that they are well prepared to perform a medical decision-making capacity evaluation. PMID- 25782769 TI - The correct name of the type species of the genus Methanocorpusculum. Request for an Opinion. AB - We propose that Methanocorpusculum parvum with type strain XII must remain the nomenclatural type of the genus Methanocorpusculum, in spite of the fact that the description of Methanogenium aggregans with type strain MSt, later transferred to the genus Methanocorpusculum as comb. nov. and then proposed as a heterotypic synonym of Methanocorpusculum parvum, was published before Methanocorpusculum parvum strain XII. PMID- 25782768 TI - Phenotypic characterization of Sodalis praecaptivus sp. nov., a close non-insect associated member of the Sodalis-allied lineage of insect endosymbionts. AB - A Gram-stain-negative bacterium, isolated from a human wound was previously found to share an unprecedentedly close relationship with Sodalis glossinidius and other members of the Sodalis-allied clade of insect symbionts. This relationship was inferred from sequence analysis of the 16S rRNA gene and genomic comparisons and suggested the strain belonged to a novel species. Biochemical and genetic analyses supported this suggestion and demonstrated that the organism has a wide repertoire of metabolic properties, which is consistent with the presence of a relatively large gene inventory. Among members of the Sodalis-allied clade, this is the first representative that has sufficient metabolic capabilities to sustain growth in minimal media. On the basis of the results of this study, we propose that this organism be classified as a representative of a novel species, Sodalis praecaptivus sp. nov. (type strain HS(T) = DSM 27494(T) = ATCC BAA-2554(T)). PMID- 25782770 TI - Effects of Endurance Training Combined With Cognitive Remediation on Everyday Functioning, Symptoms, and Cognition in Multiepisode Schizophrenia Patients. AB - Aerobic exercise has been shown to improve symptoms in multiepisode schizophrenia, including cognitive impairments, but results are inconsistent. Therefore, we evaluated the effects of an enriched environment paradigm consisting of bicycle ergometer training and add-on computer-assisted cognitive remediation (CACR) training. To our knowledge, this is the first study to evaluate such an enriched environment paradigm in multiepisode schizophrenia. Twenty-two multiepisode schizophrenia patients and 22 age- and gender-matched healthy controls underwent 3 months of endurance training (30min, 3 times/wk); CACR training (30min, 2 times/wk) was added from week 6. Twenty-one additionally recruited schizophrenia patients played table soccer (known as "foosball" in the United States) over the same period and also received the same CACR training. At baseline and after 6 weeks and 3 months, we measured the Global Assessment of Functioning (GAF), Social Adjustment Scale-II (SAS-II), schizophrenia symptoms (Positive and Negative Syndrome Scale), and cognitive domains (Verbal Learning Memory Test [VLMT], Wisconsin Card Sorting Test [WCST], and Trail Making Test). After 3 months, we observed a significant improvement in GAF and in SAS-II social/leisure activities and household functioning adaptation in the endurance training augmented with cognitive remediation, but not in the table soccer augmented with cognitive remediation group. The severity of negative symptoms and performance in the VLMT and WCST improved significantly in the schizophrenia endurance training augmented with cognitive remediation group from week 6 to the end of the 3-month training period. Future studies should investigate longer intervention periods to show whether endurance training induces stable improvements in everyday functioning. PMID- 25782771 TI - Exploring the potential of phyllosilicate minerals as potassium fertilizers using sodium tetraphenylboron and intensive cropping with perennial ryegrass. AB - In response to addressing potassium (K) deficiency in soil and decreasing agricultural production costs, the potential of K-bearing phyllosilicate minerals that can be directly used as an alternative K source has been investigated using sodium tetraphenylboron (NaTPB) extraction and an intensive cropping experiment. The results showed that the critical value of K-release rate and leaf K concentration was 3.30 g kg(-1) h(-1) and 30.64 g (kg dry matter)(-1), respectively under the experimental conditions. According to this critical value, the maximum amount of released K that could be utilized by a plant with no K deficiency symptoms was from biotite (27.80 g kg(-1)) and vermiculite (5.58 g kg( 1)), followed by illite, smectite and muscovite with 2.76, 0.88 and 0.49 g kg( 1), respectively. Ryegrass grown on phlogopite showed K deficiency symptoms during the overall growth period. It is concluded that biotite and vermiculite can be directly applied as a promising and sustainable alternative to the use of classical K fertilizers, illite can be utilized in combination with soluble K fertilizers, whereas muscovite, phlogopite and smectite may not be suitable for plant growth. Further field experiments are needed to assess the use of these phyllosilicate minerals as sources of K fertilizer. PMID- 25782772 TI - Fat mass- and obesity-associated gene Fto affects the dietary response in mouse white adipose tissue. AB - Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism. PMID- 25782773 TI - Sensitization of Gram-negative bacteria to rifampin and OAK combinations. AB - While individually inefficient against Gram-negative bacteria, in-vitro combinations of rifampin and OAK were mutually synergistic since sub-minimal inhibitory concentrations of one compound have potentiated the other by 2-4 orders of magnitude. Synergy persisted in-vivo as single-dose systemic treatment of Klebsiella infected mice resulted in 10-20% versus 60% survival, respectively accomplished by individual and combined compounds. This outcome was achieved without drug formulation, rather, pharmacokinetic considerations have inspired the therapeutic regimen. PMID- 25782774 TI - Altered drug disposition following bariatric surgery: a research challenge. AB - Bariatric surgery constitutes an approach to the management of obesity in which the anatomy of the gastrointestinal tract is altered to reduce access of nutrients to absorptive surfaces, to restrict the absolute volume of material that can be ingested at once, or a combination of the two. Roux-en-Y gastric bypass (RYGB), currently the most common bariatric surgical procedure worldwide, has both malabsorptive and restrictive features. RYGB can be associated with alterations in absorption and disposition of medications. However documenting and predicting the specific pharmacokinetic changes associated with RYGB is a difficult research challenge. Because obesity and weight loss themselves can alter drug disposition, it may be difficult or impossible to resolve whether pharmacokinetic alterations in post-RYGB patients are due to the surgery itself as opposed to the subsequent weight loss. Changes in disposition of medications may be drug-specific as opposed to generalized. Further, statistically significant modifications in drug disposition are not necessarily of clinical importance. Clinical decisions on medication use in post-bariatric surgical patients should be based on a review of the original literature dealing with the particular drug in question. PMID- 25782775 TI - Status of cardiovascular health in US children up to 11 years of age: the National Health and Nutrition Examination Surveys 2003-2010. AB - BACKGROUND: The American Heart Association recently defined cardiovascular health (CVH) to monitor it over time for all Americans. Nationally representative prevalence estimates for children under 12 years according to sex and race/ethnicity have not been reported. METHODS AND RESULTS: The study sample comprised 8961 children aged 2 to 11 years from 2003 to 2010 National Health and Nutrition Examination Surveys. National prevalence of ideal, intermediate, and poor CVH as defined by American Heart Association was estimated for each of 4 available metrics (body mass index [BMI], healthy diet score, total cholesterol, and blood pressure). No children had ideal levels for either zero or all 4 metrics. Ideal healthy diet score was least prevalent, ranging from 0 to 0.1%, whereas ideal blood pressure was most prevalent ranging from 88% to 93% across sex, race/ethnicity groups. Ideal BMI was less frequent at ages 6 to 11 years than at ages 2 to 5 years (67% versus 77%). Approximately 40% of children had intermediate or poor total cholesterol levels. The dietary intake of diet score components was associated with BMI, which was associated with blood pressure and total cholesterol. CONCLUSIONS: Ideal CVH status for BMI, total cholesterol, and blood pressure was prevalent in young children, whereas ideal diet was rare. Diet and BMI were important components to achieve ideal CVH metrics in children. Limited availability of data for all CVH metrics is a major obstacle for CVH assessment in the youngest age groups and represents an important missed opportunity for surveillance and secular trends analyses with aging. PMID- 25782776 TI - SIRT1 overexpression in skeletal muscle in vivo induces increased insulin sensitivity and enhanced complex I but not complex II-V functions in individual subsarcolemmal and intermyofibrillar mitochondria. AB - SIRT1 is known to improve insulin resistance (IR), but whether this effect is direct or not is still unclear, and this question has not been addressed in vivo in the skeletal muscle. Therefore, we sought to test if acute overexpression of SIRT1 in skeletal muscle of high-fat diet (HFD) rats in vivo would affect subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial complexes I-V activities and antioxidant enzymes thereby improving insulin action. In vivo electrotransfer was used to overexpress SIRT1 in the skeletal muscle of rats fed HFD for 12 weeks. Skeletal muscle insulin sensitivity and downstream effects of SIRT1 on AMPK, SIRT3, and mitochondrial biogenesis were studied. Citrate synthase (CS), complexes I-V, oxidative stress, and antioxidant levels were assessed in SS and IMF mitochondria. HFD rats showed skeletal muscle IR as well as decreased SIRT1 and SIRT3 expressions, mitochondrial DNA (mtDNA), and mitochondrial biogenesis (p < 0.05). SS and IMF mitochondria displayed lower CS, complexes I-V, and antioxidant enzyme activities (p < 0.05). By contrast, moderate (~2.5 folds) SIRT1 overexpression attenuated HFD-induced skeletal muscle IR. This improvement was associated with increased AMPK, PGC-1alpha, SIRT3, and mtDNA expressions as well as SS and IMF mitochondrial CS and complexes I-V activities. Importantly, SIRT1 overexpression largely restored antioxidant enzyme activities and enhanced complex I but not complexes II-V functions in individual SS and IMF mitochondria. This study suggests that SIRT1 overexpression improved IR at least partly by targeting complex I functions of SS and IMF mitochondria through the activation of SIRT1 and SIRT3. PMID- 25782777 TI - Nutri(meta)genetics and cardiovascular disease: novel concepts in the interaction of diet and genomic variation. AB - In addition to the interaction of nutrition and genetic variation on the genesis and natural history of cardiovascular disease, recent studies have revealed an entire new genome that resides in the trillions of microbes that exist in various human habitats, predominantly in the gut, that may also contribute to the pathogenesis of cardiovascular disease. This microbial genome and the proteins for which it codes have important functions in homeostatic adaptations to the past and present changes in diet and environment accompanying human civilization. Both preclinical and clinical investigations suggest the role of commensal microbiota in promoting adverse cardiovascular risk. Specifically, microbial metabolism of methylated amines leads to direct pro-atherogenic effects in humans. Further investigations are needed to understand the complex relationships among nutritional status, genetic variation, and the microbial genome, which may explain the recent negative results of clinical trials of nutritional interventions such as B vitamin therapy to lower plasma homocysteine levels. The results of such contemporary genomic investigations would allow us to utilize personalized nutritional interventions to reduce cardiovascular risk. PMID- 25782779 TI - [Implementation of a new emergency room protocol at a University Medical Center in Germany: basis for improved flow of information, adequate quality management and scientific assessment]. AB - BACKGROUND: After analyzing the existing documentation protocol for the emergency room (ER), the department of anesthesiology of the Medical University of Gottingen (UMG) developed a new department-specific ER protocol. AIM: The objective was to improve the flow of patient information from the preclinical situation through the emergency room to the early inpatient period. With this in mind a new emergency protocol was developed that encompasses the very heterogeneic patient collective in the ER as well as forming a basis for quality management and scientific investigation, taking user friendliness and efficiency into consideration. MATERIAL AND METHODS: A strategical development of a new emergency room protocol is represented, which was realized using a self-developed 8-step approach. Technical support and realization was carried out using the Scribus 1.4.2 open source desktop and GIMP 2.8.4 GNU image manipulation graphic programs. RESULTS: The new emergency room protocol was developed based on scientific knowledge and defined targets. The following 13 sections represent the contents of the new protocol: general characteristics, emergency event, initial findings and interventions, vital parameters, injury pattern, vascular access, hemodynamics, hemogram/blood gas analysis (BGA), coagulopathy, diagnostics, emergency interventions, termination of ER treatment and final evaluation. CONCLUSION: The structured and elaborated documentation was limited to the target of two sides and succeeds in incorporating trauma patients as well as non-trauma patients in the ER. PMID- 25782778 TI - The promise of proprotein convertase subtilisin/kexin 9 inhibitors for the treatment of familial hypercholesterolemia. AB - Familial hypercholesterolemia comprises a constellation of genetic disorders resulting in very high cholesterol levels since childhood. If untreated, it is associated with accelerated atherosclerosis and premature cardiovascular disease. It has been shown that if aggressive cholesterol lowering is achieved in familial hypercholesterolemia, the incidence of cardiovascular disease can be lowered. However, currently approved pharmacological therapies are not able to lower cholesterol to optimal levels in a large number of these patients. Proprotein convertase subtilisin/kexin 9 inhibitors are a new class of cholesterol-lowering medications that can significantly reduce cholesterol levels in these patients especially those with at least some functioning low-density lipoprotein receptors. In this article, we will briefly review familial hypercholesterolemia and the role of proprotein convertase subtilisin/kexin 9 inhibitors in this condition. PMID- 25782780 TI - [Management for the operating room]. AB - Business companies, which in the current times also includes hospitals, must create customer benefits and as a prerequisite for this must sustainably generate profits. Management in the world of business means the formation and directing of a company or parts of a company on a permanent basis, whereby management in this context is not exercising power but function. This concept of management is exemplary developed in this article for the important services sector of the operating room (OR) and individual functions, such as resource control, capacity planning and materials administration are presented in detail. Some OR-specific management challenges are worked out. From this it becomes clear that the economic logic of the most efficient implementation possible is not a contradiction of medical ethics, enabling the most effective treatment possible for patients while safeguarding the highest possible levels of safety and quality. The article aims to build a bridge for medical specialists to the language and world of commerce, emphasizing the profession-based competence and hopefully to arouse interest to go into more detail. PMID- 25782842 TI - Pre-discharge home assessment visits in assisting patients' return to community living: A systematic review and meta-analysis. AB - OBJECTIVE: To determine the effectiveness of pre-discharge home assessment visits by occupational therapists in assisting hospitalized patients from a range of settings to return to community living. DATA SOURCES: Electronic databases MEDLINE, CINAHL, Embase, PsychINFO, Cochrane Central Register of Controlled Trials and OTseeker were searched until February 2014. STUDY SELECTION: Quantitative and qualitative studies were included if they evaluated pre discharge home assessment visits by an occupational therapist. Of 1,778 potentially relevant articles, 14 studies met the inclusion criteria. DATA EXTRACTION: After data extraction, study quality was assessed using check-lists. DATA SYNTHESIS: Pre-discharge home assessment visits reduced the risk of falling (risk ratio 0.68, 95% confidence interval (95% CI) 0.49-0.94) and increased participation levels (standardized mean difference 0.49; 95% CI 0.01-0.98) in geriatric and mixed rehabilitation settings. The risk of readmission to hospital was also reduced (risk ratio 0.47, 95% CI 0.33-0.66), but not for patients following stroke. There was no effect on activity or quality of life. Patients and carers perceived that home assessment visits were beneficial and were satisfied with the process. CONCLUSION: There is low-to-moderate quality evidence that pre-discharge home assessment visits reduce patients' risk of falling and increase participation. The risk of readmission to hospital is also reduced, but not for patients following stroke. PMID- 25782841 TI - Transcriptomic analysis to elucidate the molecular mechanisms that underlie feed efficiency in meat-type chickens. AB - Feed efficiency phenotypes defined by genotypes or gene markers are unknown. To date, there are only limited studies on global gene expression profiling on feed efficiency. The objective of this study was to identify genes and pathways associated with residual feed intake (RFI) through transcriptional profiling of duodenum at two different ages in a chicken population divergently selected for low (LRFI) or high (HRFI) RFI. The global gene expression differences in LRFI and HRFI were assessed by the Affymetrix GeneChip((r)) Chicken Genome Array and RT PCR using duodenal tissue on days 35 and 42. The Ingenuity Pathway Analysis program was used to identify canonical and gene network pathways associated with RFI. A global view of gene expression differences between LRFI and HRFI suggest that RFI can be explained by differences in cell division, growth, proliferation and apoptosis, protein synthesis, lipid metabolism, and molecular transport of cellular molecules. Chickens selected for improved RFI achieve efficiency by reducing feed intake with a nominal or no change in weight gain by either up regulating CD36, PPARalpha, HMGCS2, GCG or down-regulating PCSK2, CALB1, SAT1, and SGK1 genes within the lipid metabolism, small molecule biochemistry, molecular transport, cell death, and protein synthesis molecular and cellular functions. Chickens selected for reduced RFI via reduced feed intake with no change in weight gain achieve feed efficiency for growth by the up-regulation of genes that reduce appetite with increased cellular oxidative stress, prolonged cell cycle, DNA damage, and apoptosis in addition to increased oxidation of dietary fat and efficient fatty acids transported from the intestines. PMID- 25782843 TI - Interprofessional collaboration: changing the future. PMID- 25782844 TI - Midwife and obstetrician collaborative care: the whole is better than the parts. PMID- 25782845 TI - Collaboration between midwives and nurses: past, present, and future. PMID- 25782846 TI - The United States midwifery education, regulation, and association work group: what is it and what does it hope to accomplish? PMID- 25782847 TI - The development of a consensus statement on normal physiologic birth: a modified Delphi study. AB - INTRODUCTION: This article describes the process of developing consensus on a definition of, and best practices for, normal physiologic birth in the United States. Evidence supports the use of physiologic birth practices, yet a working definition of this term has been elusive. METHODS: We began by convening a task force of 21 individuals from 3 midwifery organizations and various childbirth advocacy and consumer groups. A modified Delphi approach was utilized to achieve consensus around 2 research questions: 1) What is normal physiologic birth? and 2) What practices most effectively support its achievement? Answers to these questions were collected anonymously from task force members during multiple phases that included a preliminary briefing, an initial face-to-face roundtable, 9 iterative Delphi rounds, and reciprocal feedback from a wider audience of stakeholders at national and international conferences. Content analysis identified specific statements and concepts in the first Delphi round, which were subsequently ranked in following rounds. An initial draft was constructed based on the priorities that emerged and presented for feedback to peers and childbirth advocates whose comments were incorporated into the final document. RESULTS: Four key themes were identified from our initial questions; these provided the framework for the document: 1) definitions of normal physiologic birth, 2) mechanisms and outcomes of normal physiologic birth, 3) factors that influence normal physiologic birth, and 4) recommendations for increasing normal physiologic birth. These areas comprised the final sections in the multi organizational consensus statement. DISCUSSION: The modified Delphi approach we employed allowed for the development of a consensus statement that will serve as a template for education, practice, and future research in maternity care. The completion of this statement marks the beginning of a project to promote systemic changes that support normal physiologic birth, and thus, have the potential to improve outcomes for mothers and infants. PMID- 25782848 TI - Primary care of women aging with HIV. AB - Women are living longer with HIV infection, but their life expectancy remains shorter than for women in the general population. How best to manage the multiple comorbidities and polypharmacy that are common in individuals wtih HIV has not been studied. This article explores areas where the primary care of women with HIV may differ from that of aging women in the general population. We also discuss aspects of care that may not commonly be considered in those under the age of 65, specifically multimorbidity and polypharmacy. Incorporating a gerontologic approach in the care of these women may optimize outcomes until research provides more definitive answers for how best to collaborate with women with HIV in order to provide them with optimal care. PMID- 25782850 TI - Why female college students risk pregnancy: i just wasn't thinking. AB - INTRODUCTION: To explore the meaning or meanings of "I just wasn't thinking" as a reason for contraceptive risk-taking among women and to illuminate what this phrase actually means when used by women as an explanation for contraceptive risk taking. METHODS: Forty-five in-depth semistructured interviews were conducted with sexually active women on a college campus. Interviews were transcribed and coded thematically using NVivo 10. RESULTS: "I just wasn't thinking" has multiple meanings. Major themes in women's explanations of the meaning were: 1) They pushed it to the back of their minds, that they did not think they would get pregnant; 2) they did not think about it due to impairment resulting from alcohol use; 3) they would deal with the possibility of pregnancy later; and 4) they did not think about contraception or pregnancy at all. Most of these responses were based on erroneous risk calculations that led the women to believe they were not likely to experience a pregnancy. DISCUSSION: Reasons women give for noncontraceptive use may have deeper meanings. It is important for both clinicians and researchers to think about possible underlying meanings and to acknowledge that they may be different than the face value of the statement. In the future, clinical questioning of women about noncontraceptive use and research into reasons for noncontraceptive use should take into account the variability of just not thinking and include appropriate follow-up questions to clarify its meaning. PMID- 25782849 TI - Factors associated with young adults' pregnancy likelihood. AB - INTRODUCTION: Although progress has been made to reduce adolescent pregnancies in the United States, rates of unplanned pregnancy among young adults aged (aged 18 29 years) remain high. In this study, we assessed factors associated with perceived likelihood of pregnancy (likelihood of getting pregnant/getting partner pregnant in the next year) among sexually experienced young adults who were not trying to get pregnant and had previously used contraceptives. METHODS: We conducted a secondary analysis of 660 young adults, aged 18 to 29 years in the United States, from the cross-sectional National Survey of Reproductive and Contraceptive Knowledge. Logistic regression and classification tree analyses were conducted to generate profiles of young adults most likely to report anticipating a pregnancy in the next year. RESULTS: Nearly one-third (32%) of young adults indicated that they believed they had at least some likelihood of becoming pregnant in the next year. Young adults who believed that avoiding pregnancy was not very important were most likely to report pregnancy likelihood (odds ratio [OR], 5.21; 95% confidence interval [CI], 2.80-9.69), as were young adults who considered avoiding a pregnancy to be important but who were not satisfied with their current contraceptive method (OR, 3.93; 95% CI, 1.67-9.24) and who attended religious services frequently (OR, 3.0; 95% CI, 1.52-5.94), were uninsured (OR, 2.63; 95% CI, 1.31-5.26), and were likely to have unprotected sex in the next 3 months (OR, 1.77; 95% CI, 1.04-3.01). DISCUSSION: These results may help guide future research and the development of pregnancy-prevention interventions targeting sexually experienced young adults. PMID- 25782851 TI - Evaluation of a midwife- and nurse-delivered 5 A's prenatal smoking cessation program. AB - INTRODUCTION: West Virginia has the highest rate of prenatal smoking in the United States. The aim of this pilot study was to evaluate the implementation of the American College of Obstetricians and Gynecologists' 5 A's smoking cessation intervention among pregnant women being cared for by 5 A's-trained midwives working with a team of nurse researchers in an effort to reduce prenatal smoking exposure. The evidence-based 5 A's smoking cessation program has been recommended for use in prenatal care by health care providers. METHODS: A pilot study was conducted evaluating the implementation of the 5 A's prenatal smoking cessation program for 35 women who smoked during pregnancy. The women received consistent messages to quit or reduce smoking from the midwives and were followed by the nurse research team via telephone with continued support, guidance, and strategic planning for tobacco exposure reduction. RESULTS: Among the 35 women who enrolled in the study, 32 (91.4%) decreased smoking and 3 (8.6%) quit smoking by one month after the intervention. For those who continued to smoke, the average number of cigarettes smoked was reduced from 10 cigarettes per day at baseline to 8 cigarettes per day at one month, 7 cigarettes per day at 2 months, and 6 cigarettes per day by the end of pregnancy. The women further reduced their tobacco exposure by delaying the timing of initiating smoking in the morning and by increasing indoor smoking restrictions. DISCUSSION: Midwives and nurses can be trained in the implementation of the evidence-based 5 A's smoking cessation program for incorporation into regular prenatal care of pregnant women who smoke. By guiding women in techniques aimed at reducing the amount and frequency of cigarette smoking, nurses and midwives facilitate a decrease in prenatal smoking exposure. PMID- 25782852 TI - Influence of acupuncture on the third stage of labor: a randomized controlled trial. AB - INTRODUCTION: A prolonged third stage of labor is considered to be a risk factor for postpartum hemorrhage. The objective of this study was to determine the ability of acupuncture to reduce the length of the third stage of labor. METHODS: Seventy-six puerperal women who had a normal spontaneous birth at the Hospital Universitario Principe de Asturias, Alcala de Henares, Spain, were included in a single-blind randomized trial and evaluated by a third party. Women were randomly assigned to receive true acupuncture or placebo acupuncture (also known as sham acupuncture). In the first group, a sterilized steel needle was inserted at the Ren Mai 6 point, which is located on the anterior midline between the umbilicus and the upper part of the pubic symphysis. In the second group, the insertion site was located at the same horizontal level as the Ren Mai 6 point but shifted slightly to the left of the anterior midline. The management of the third stage of labor was the same in both groups. RESULTS: Statistically significant differences were found, with an average time to placental expulsion of 15.2 minutes in the placebo group and 5.2 minutes in the acupuncture group. No major complications occurred in either group. DISCUSSION: These results confirm that acupuncture at the Ren Mai 6 point can decrease the time to placental expulsion. This treatment represents a simple, safe, and inexpensive way of decreasing the duration of the third stage of labor. PMID- 25782853 TI - Critical congenital heart disease screening practices among licensed midwives in washington state. AB - INTRODUCTION: Since 2011, pulse oximetry screening for critical congenital heart disease (CCHD) has been recommended for newborns. Initial implementation guidelines focused on in-hospital births. Recent publications affirm the importance of universal screening, including for out-of-hospital births. No published data describe CCHD screening rates for out-of-hospital births. METHODS: Licensed midwives in Washington state were surveyed regarding their current CCHD screening practices, volume of births attended annually, and typical newborn follow-up practices. For those who indicated they were screening, additional information was obtained about equipment used, timing of screening, and rationale for voluntarily initiating screening. For those who indicated that they were not screening, information regarding barriers to implementation was solicited. RESULTS: Of the 61 midwives in our sample, 98% indicated they were aware of published guidelines recommending universal newborn screening for CCHD utilizing pulse oximetry. Furthermore, 52% indicated that they were screening for CCHD currently. Ten percent stated they do not intend to screen, whereas the remaining respondents indicated that they plan to screen in the future. The primary barriers to screening were the cost of pulse oximetry equipment and inadequate training in screening technique and interpretation. CONCLUSION: Although voluntary implementation of CCHD screening by licensed midwives in Washington is increasing, it lags behind the implementation rates reported for in-hospital births. PMID- 25782854 TI - Part II: the centering pregnancy model of group prenatal care. PMID- 25782855 TI - Current resources for evidence-based practice, March/April 2015. PMID- 25782856 TI - US Preventive Services Task Force guideline supports low-dose aspirin for prevention of preeclampsia. PMID- 25782857 TI - American College of Obstetricians and Gynecologists releases committee opinion on estimation of due date. PMID- 25782858 TI - Electronic access now available for updated adult immunization schedules. PMID- 25782859 TI - Data from 6 health plans in the United States show elective inductions on the decline. PMID- 25782860 TI - Rethinking old practices: evidence supports wiping, not suctioning, newborn secretions at birth. PMID- 25782861 TI - A systematic approach to caring for women with persistent and recurrent vaginitis. PMID- 25782863 TI - Cervical cancer screening. PMID- 25782864 TI - Effect of friction on vibrotactile sensation of normal and dehydrated skin. AB - BACKGROUND: Vibrotactile sensation mediated is highly dependent on surface mechanical and frictional properties. Dehydration of skin could change these properties. OBJECTIVES: To investigate the relationship between friction and vibrotactile sensation of normal and dehydrated skin. METHODS: Vibrations were firstly measured during surface exploration using a biomimetic sensor. Piglet skin was used as human skin model to study frictional properties for both normal and dehydrated skin using an atomic force microscope on nanoscale and a pin-on disk tribometer on macroscale. Effect of vibrational frequency on friction and vibrotactile perception was also observed on nano and macro scale for normal and dehydrated skin. RESULTS: The result indicated that dehydrated skin was less sensitive than normal skin. The coefficient of friction of dehydrated skin is smaller than that of normal skin on both nano and macro scale. The coefficient of friction increases as increasing scanning frequencies. CONCLUSION: There is a positive correlation between coefficient of friction and vibrotactile sensation on nanoscale and macroscale. PMID- 25782865 TI - Rapid emergence of a PB2-E627K substitution confers a virulent phenotype to an H9N2 avian influenza virus during adoption in mice. AB - The worldwide circulation of H9N2 avian influenza virus in poultry, the greater than 2.3 % positive rate for anti-H9 antibodies in poultry-exposed workers, and several reports of human infection indicate that H9N2 virus is a potential threat to human health. Here, we found three mutations that conferred high virulence to H9N2 virus in mice after four passages. The PB2-E627K substitution rapidly appeared at the second passage and played a decisive role in virulence. Polymerase complexes possessing PB2-E627K displayed 16.1-fold higher viral polymerase activity when compared to the wild-type virus, which may account for enhanced virulence of this virus. The other two substitutions (HA-N313D and HA N496S) enhanced binding to both alpha2,3-linked and alpha2,6-linked sialic acid receptors; however, the HA-N313D and N496S substitutions alone decreased the virulence of mouse-adapted virus. Furthermore, this mouse-adapted virus was still not transmissible among guinea pigs by direct contact (0/3 pairs). Our findings show that adaption in mice enhanced the viral polymerase activity and receptor binding ability, which resulted in a virulent phenotype in mice but not a transmissible phenotype in guinea pigs, indicating that host factors play an important role in adaptive evolution of influenza in new hosts. PMID- 25782866 TI - Spatially resolved resonant tunneling on single atoms in silicon. AB - The ability to control single dopants in solid-state devices has opened the way towards reliable quantum computation schemes. In this perspective it is essential to understand the impact of interfaces and electric fields, inherent to address coherent electronic manipulation, on the dopants atomic scale properties. This requires both fine energetic and spatial resolution of the energy spectrum and wave-function, respectively. Here we present an experiment fulfilling both conditions: we perform transport on single donors in silicon close to a vacuum interface using a scanning tunneling microscope (STM) in the single electron tunneling regime. The spatial degrees of freedom of the STM tip provide a versatility allowing a unique understanding of electrostatics. We obtain the absolute energy scale from the thermal broadening of the resonant peaks, allowing us to deduce the charging energies of the donors. Finally we use a rate equations model to derive the current in presence of an excited state, highlighting the benefits of the highly tunable vacuum tunnel rates which should be exploited in further experiments. This work provides a general framework to investigate dopant based systems at the atomic scale. PMID- 25782867 TI - The impact of the AB0 and the Rhesus blood group system on outcomes in bladder cancer patients treated with radical cystectomy. AB - PURPOSE: To investigate the impact of the AB0 and the Rhesus blood group system on outcomes of urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). METHODS: We included 511 UCB patients treated with RC without neoadjuvant chemotherapy from 1996 to 2011 at our institution. Cox and logistic regression models assessed the association of the AB0 blood group antigen and Rhesus factor expression with tumor biologic features and outcomes, respectively. RESULTS: In total, 216 patients (42.3 %) had the blood group antigen A0, 73 patients (14.3 %) the antigen B0, 33 patients (6.4 %) the antigen AB and 189 patients (37.0 %) the antigen 00. In addition, 414 patients (81.0 %) were Rhesus factor positive. The AB0 blood group antigen expression was associated with a higher tumor grade (p = 0.003). In contrast, the Rhesus factor was not associated with any clinicopathologic characteristics. Neither the AB0 blood group antigens nor the Rhesus factor was associated with survival. In a sensitivity analysis of patients receiving adjuvant chemotherapy, however, the blood group antigen AB expression was associated with reduced cancer-specific and overall survival. CONCLUSION: The AB0 blood group antigens and the Rhesus factor are not associated with survival. Although the AB0 blood groups and the Rhesus factor are analyzed in every patient treated with RC, they do not represent appropriate biomarkers for UCB outcome prognostication. The association of the AB0 blood group antigens with response to adjuvant chemotherapy requires further validation. PMID- 25782868 TI - Silencing of TGIF1 in bone mesenchymal stem cells applied to the post-operative rotator cuff improves both functional and histologic outcomes. AB - Stem cells have long been hypothesized to improve outcomes following rotator cuff repair. However, these cells must be signaled in order to do so. TGIF1 is a transcription factor that has been found to be down-regulated in cells involved in chondrogenesis. We therefore wished to examine whether stem cells expressing lower levels of TGIF1 could better improve outcomes following rotator cuff repair than stem cells expressing normal levels of TGIF1. Bone mesenchymal stem cells (BMSCs) were transduced with TGIF1 siRNA to suppress native TGIF1. Nontransduced BMSCs were also obtained for the control group. Following suprapinatus tendon repair, rats were either treated with transduced BMSCs or nontransduced BMSCs. Histologic and functional testing were performed on both groups. Rats treated with transduced TGIF1 siRNA BMSCs following suprapinatus repair expressed significantly higher levels of chondrogenic proteins at 4 weeks than rats treated with nontransduced BMSCs. Further, rats treated with BMSCs transduced with TGIF1 siRNA had both a significantly greater maximum load at failure and stiffness. Rats treated with transduced TGIF1 siRNA BMSCs following supraspinatus repair perform better both histologically and functionally at 4 weeks. PMID- 25782869 TI - Erratum to: single-agent bevacizumab is an effective treatment in recurrent glioblastoma. PMID- 25782870 TI - TAT-OSBP-1-MKK6(E), a novel TAT-fusion protein with high selectivity for human ovarian cancer, exhibits anti-tumor activity. AB - To improve the selectivity of TAT-fusion proteins for targeted cancer therapy, we developed a novel TAT-based target-specific fusion protein, TAT-OSBP-1-MKK6(E), and evaluated its selectivity and anti-tumor activity in vitro and in vivo. The fusion protein containing TAT-OSBP-1-MKK6(E) has three functional domains: (1) the protein transduction domain of TAT, (2) the human ovarian cancer HO8910 cell specific binding peptide (OSBP-1) and (3) the potential anti-tumor effector domain of MKK6(E). The transduction efficiency, selectivity, cytotoxicity and apoptotic effect of TAT-OSBP-1-MKK6(E) were examined using immunofluorescence, CCK8 assay and flow cytometry. The in vivo anti-tumor efficacy and target specificity of the fusion protein were evaluated using a nude mouse model with subcutaneous xenografts of human ovarian cancer HO8910 cells. Tumor-bearing mice were divided into three treatment groups that received tail vein injections of TAT-OSBP-1-MKK6(E), TAT-OSBP-1 or normal saline. Tumor growth inhibition was determined by tumor volume, weight and morphology. The distribution and apoptotic effect of TAT-OSBP-1-MKK6(E) were assessed by immunohistochemical staining and TUNEL assays. TAT-OSBP-1-MKK6(E) can be selectively internalized into human ovarian cancer HO8910 cells, rather than normal ovarian OSE cells. In vivo, the fusion protein was mainly expressed in the tumor xenograft, but not in ovary or liver tissues. As a result, TAT-OSBP-1-MKK6(E) significantly induced growth inhibition and apoptosis of tumor cells in vitro and in vivo, with limited effects in normal cells and tissues. TAT-OSBP-1-MKK6(E) treatment can selectively target HO8910 cells in vitro and in vivo, leading to growth inhibition and apoptosis of tumor cells. As such, TAT-OSBP-1-MKK6(E) may be a potential approach for ovarian cancer target therapy. PMID- 25782871 TI - Relationship between LINE-1 hypomethylation and Helicobacter pylori infection in gastric mucosae. AB - The DNA methylation alterations occurring in human cancers have two types: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Recently, to assess global DNA methylation, long interspersed nucleotide element 1 (LINE-1) retrotransposons, constituting a substantial portion of the human genome, attracts much attention. The aim of the current study was to clarify the significance of LINE-1 methylation level for epigenetic field defects and the relationships among LINE-1 methylation level in gastric mucosae, clinical and pathological features, including infection by Helicobacter pylori (H. pylori), a bacterium implicated in gastric cancer. By bisulfite-PCR pyrosequencing, we quantified the LINE-1 methylation levels in noncancerous gastric mucosae and cancer tissues from 87 gastric cancer patients, in gastric mucosae from 17 autopsied individuals without gastric cancers and in 20 gastric fresh frozen samples from non-gastric cancer patients. LINE-1 methylation in the noncancerous gastric mucosae of gastric cancer patients was significantly higher than in cancer tissues (P = 0.0006), but significantly lower than in the gastric mucosae of the autopsied individuals (P = 0.026), suggesting the formation of epigenetic field defect in noncancerous gastric mucosae. Moreover, LINE-1 hypomethylation of noncancerous gastric mucosae in gastric cancer patients significantly correlated with H. pylori infection (P = 0.037). We prospectively confirmed the similar result in 20 non-gastric cancer patients (P = 0.010). LINE-1 hypomethylation of gastric mucosae significantly correlated with H. pylori infection, supporting the potential of LINE-1 methylation level as a surrogate marker of epigenetic field defects for gastric cancer cancerization, particularly induced by H. pylori. PMID- 25782872 TI - Quantitative profiling of endocannabinoids in lipoproteins by LC-MS/MS. AB - Endocannabinoids belong to a diverse family of endogenous lipid bioregulators acting as physiological ligands of cannabinoid receptor type 1 and cannabinoid receptor type 2 in the central and peripheral nervous system. They are also present in nmol L(-1) concentrations in human blood plasma; however, their association with possible molecular carriers remains poorly characterized. Here we report on the quantification of 46 endogenous molecular species from five major classes of endocannabinoids and endocannabinoid-related compounds in three lipoprotein fractions of human blood plasma: VLDL, LDL, HDL, and in the plasma lipoprotein-free fraction. Although sizable quantities of endocannabinoid-related molecules are associated with lipoproteins, we identified the lipoprotein-free fraction as a major carrier of endocannabinoids in blood circulation with the exception of 2-acylglycerols, which are markedly abundant in VLDL. PMID- 25782873 TI - Angularly resolved ellipsometric optical biosensing by means of Bloch surface waves. AB - In label-free biosensing, a continuous improvement of the limit of detection is necessary to resolve the small change of the surface refractive index produced by interacting biomolecules at a very small concentration. In the present work, optical sensors based on one-dimensional photonic crystals supporting Bloch surface waves are proposed and adopted for label-free optical biosensing. We describe the implementation of an angularly resolved ellipsometric optical sensing scheme based on Bloch surface waves sustained by tantala/silica multilayers. The angular operation is obtained using a focused beam at fixed wavelength and detection of the angular reflectance spectrum by means of an array detector. The results show that the experimental limit of detection for a particular photonic crystal design is 6.5 * 10(-7) refractive index units (RIU)/Hz(1/2) and further decrease could be obtained. For the first time, we report on the practical application of this technique to a cancer biomarker protocol that aims at the detection of a specific glycoprotein (angiopoietin 2) involved in angiogenesis and inflammation processes. PMID- 25782890 TI - Warming Up Your Tick-Tock: Temperature-Dependent Regulation of Circadian Clocks. AB - Circadian clocks are endogenous time-keeping mechanisms to adaptively coordinate animal behaviors and physiology with daily environmental changes. So far many circadian studies in model organisms have identified evolutionarily conserved molecular frames of circadian clock genes in the context of transcription translation feedback loops. The molecular clockwork drives cell-autonomously cycling gene expression with ~24-hour periodicity, which is fundamental to circadian rhythms. Light and temperature are two of the most potent external time cues to reset the circadian phase of the internal clocks, yet relatively little is known about temperature-relevant clock regulation. In this review, we describe recent findings on temperature-dependent clock mechanisms in homeothermic mammals as compared with poikilothermic Drosophila at molecular, neural, and organismal levels. We propose thermodynamic transitions in RNA secondary structures might have been potent substrates for the molecular evolution of temperature-relevant post-transcriptional mechanisms. Future works should thus validate the potential involvement of specific post-transcriptional steps in temperature-dependent plasticity of circadian clocks. PMID- 25782891 TI - Regional infection control assessment of antibiotic resistance knowledge and practice. AB - OBJECTIVE: Multidrug-resistant organisms (MDROs) are an increasing burden among healthcare facilities. We assessed facility-level perceived importance of and responses to various MDROs. DESIGN: A pilot survey to assess staffing, knowledge, and the perceived importance of and response to various multidrug resistant organisms (MDROs) SETTING: Acute care and long-term healthcare facilities METHODS: In 2012, a survey was distributed to infection preventionists at ~300 healthcare facilities. Pathogens assessed were Clostridium difficile, carbapenem resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, multidrug-resistant (defined as bacterial resistance to >=3 antibiotic classes) Pseudomonas, and extended-spectrum beta-lactamase-producing Escherichia coli. RESULTS: A total of 74 unique facilities responded, including 44 skilled nursing facilities (SNFs) and 30 acute care facilities (ACFs). While ACFs consistently isolated patients with active infections or colonization due to these MDROs, SNFs had more variable responses. SNFs had more multi-occupancy rooms and reported less specialized training in infection control and prevention than did ACFs. Of all facilities with multi-occupancy rooms, 86% employed a cohorting practice for patients, compared with 50% of those without multi occupancy rooms; 20% of ACFs and 7% of SNFs cohorted staff while caring for patients with the same MDRO. MRSA and C. difficile were identified as important pathogens in ACFs and SNFs, while CRE importance was unknown or was considered important in <50% of SNFs. CONCLUSION: We identified stark differences in human resources, knowledge, policy, and practice between ACFs and SNFs. For regional control of emerging MDROs like CRE, there is an opportunity for public health officials to provide targeted education and interventions. Education campaigns must account for differences in audience resources and baseline knowledge. PMID- 25782892 TI - Risk factors for gyrA and parC mutations in Pseudomonas aeruginosa. AB - OBJECTIVE: The major mechanism of fluoroquinolone (FQ) resistance in Pseudomonas aeruginosa (PSA) is modification of target proteins in DNA gyrase and topoisomerase IV, most commonly the gyrA and parC subunits. The objective of this study was to determine risk factors for PSA with and without gyrA or parC mutations. DESIGN: Case-case-control study SETTING: Two adult academic acute-care hospitals PATIENTS: Case 1 study participants had a PSA isolate on hospital day 3 or later with any gyrA or parC mutation; case 2 study participants had a PSA isolate on hospital day 3 or later without these mutations. Controls were a random sample of all inpatients with a stay of 3 days or more. METHODS: Each case group was compared to the control group in separate multivariate models on the basis of demographics and inpatient antibiotic exposure, and risk factors were qualitatively compared. RESULTS: Of 298 PSA isolates, 172 (57.7%) had at least 1 mutation. Exposure to vancomycin and other agents with extended Gram-positive activity was a risk factor for both cases (case 1 odds ratio [OR], 1.09; 95% confidence interval [CI], 1.04-1.13; OR, 1.14; 95% CI, 1.03-1.26; case 2 OR, 1.09; 95% CI, 1.03-1.14; OR, 1.13; 95% CI, 1.01-1.25, respectively). CONCLUSIONS: Exposure to agents with extended Gram-positive activity is a risk factor for isolation of PSA overall but not for gyrA/parC mutations. FQ exposure is not associated with isolation of PSA with mutations. PMID- 25782893 TI - Extensive dissemination of extended spectrum beta-lactamase-producing Enterobacteriaceae in a Dutch nursing home. AB - OBJECTIVE: Risk factors for rectal carriage of ESBL-E and transmission were investigated in an outbreak of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E). DESIGN: Rectal carriage of ESBL-E was determined in a cross-sectional survey by culture of perianal swabs or fecal samples. Both phenotypical and genotypical methods were used to detect the production of ESBL. Nosocomial transmission was defined as the presence of genotypically related strains in >=2 residents within the NH. Patient characteristics and variables in infection control practices were registered to investigate risk factors for transmission. SETTING: A nursing home (NH) in the southern Netherlands. PARTICIPANTS: Of 189 residents, 160 residents (84.7%) were screened for ESBL-E carriage. Of these 160 residents, 33 (20.6%) were ESBL-E positive. ESBL carriage rates varied substantially between wards (range, 0-47%). Four different ESBL-E clusters were observed. A bla CTX-M1-15 positive E. coli ST131 constituted the largest cluster (n=21) and was found in multiple wards (n=7). RESULTS: Our investigation revealed extensive clonal dissemination of bla CTX-M1-15-positive E. coli ST131 in a nursing home. Unexplained differences in ESBL prevalence were detected among the wards. CONCLUSIONS: As NHs constitute potential sources of multidrug-resistant bacteria, it is important to gain a better understanding of the risks factors and routes of transmission of ESBL-E. PMID- 25782894 TI - Universal screening and decolonization for control of MRSA in nursing homes: a cluster randomized controlled study. AB - OBJECTIVE: The risk of carrying methicillin-resistant Staphylococcus aureus (MRSA) is higher among nursing home (NH) residents than in the general population. However, control strategies are not clearly defined in this setting. In this study, we compared the impact of standard precautions either alone (control) or combined with screening of residents and decolonization of carriers (intervention) to control MRSA in NHs. DESIGN: Cluster randomized controlled trial. SETTING: NHs of the state of Vaud, Switzerland. PARTICIPANTS: Of 157 total NHs in Vaud, 104 (67%) participated in the study. INTERVENTION: Standard precautions were enforced in all participating NHs, and residents underwent MRSA screening at baseline and 12 months thereafter. All carriers identified in intervention NHs, either at study entry or among newly admitted residents, underwent topical decolonization combined with environmental disinfection, except in cases of MRSA infection, MRSA bacteriuria, or deep skin ulcers. RESULTS: NHs were randomly allocated to a control group (51 NHs, 2,412 residents) or an intervention group (53 NHs, 2,338 residents). Characteristics of NHs and residents were similar in both groups. The mean screening rates were 86% (range, 27%-100%) in control NHs and 87% (20%-100%) in intervention NHs. Prevalence of MRSA carriage averaged 8.9% in both control NHs (range, 0%-43%) and intervention NHs (range, 0%-38%) at baseline, and this rate significantly declined to 6.6% in control NHs and to 5.8% in intervention NHs after 12 months. However, the decline did not differ between groups (P=.66). CONCLUSION: Universal screening followed by decolonization of carriers did not significantly reduce the prevalence of the MRSA carriage rate at 1 year compared with standard precautions. PMID- 25782895 TI - Diminishing surgical site infections in Australia: time trends in infection rates, pathogens and antimicrobial resistance using a comprehensive Victorian surveillance program, 2002-2013. AB - OBJECTIVE: To evaluate time trends in surgical site infection (SSI) rates and SSI pathogens in Australia. DESIGN: Prospective multicenter observational cohort study. SETTING: A group of 81 Australian healthcare facilities participating in the Victorian Healthcare Associated Infection Surveillance System (VICNISS). PATIENTS: All patients underwent surgeries performed between October 1, 2002, and June 30, 2013. National Healthcare Safety Network SSI surveillance methods were employed by the infection prevention staff at the participating hospitals. INTERVENTION: Procedure-specific risk-adjusted SSI rates were calculated. Pathogen-specific and antimicrobial-resistant (AMR) infections were modeled using multilevel mixed-effects Poisson regression. RESULTS: A total of 183,625 procedures were monitored, and 5,123 SSIs were reported. Each year of observation was associated with 11% risk reduction for superficial SSI (risk ratio [RR], 0.89; 95% confidence interval [CI], 0.88-0.90), 9% risk reduction for deep SSI (RR, 0.91; 95% CI, 0.90-0.93), and 5% risk reduction for organ/space SSI (RR, 0.95; 95% CI, 0.93-0.97). Overall, 3,318 microbiologically confirmed SSIs were reported. Of these SSIs, 1,174 (35.4%) were associated with orthopedic surgery, 827 (24.9%) with coronary artery bypass surgery, 490 (14.8%) with Caesarean sections, and 414 (12.5%) with colorectal procedures. Staphylococcus aureus was the most frequently identified pathogen, and a statistically significant increase in infections due to ceftriaxone-resistant Escherichia coli was observed (RR, 1.37; 95% CI, 1.10-1.70). CONCLUSIONS: Standardized SSI surveillance methods have been implemented in Victoria, Australia. Over an 11-year period, diminishing rates of SSIs have been observed, although AMR infections increased significantly. Our findings facilitate the refinement of recommended surgical antibiotic prophylaxis regimens and highlight the need for a more expansive national surveillance strategy to identify changes in epidemiology. PMID- 25782897 TI - Central line-associated bloodstream infections in non-ICU inpatient wards: a 2 year analysis. AB - OBJECTIVE: Little is known about patient-specific factors contributing to central line-associated bloodstream infection (CLABSI) outside of the intensive care unit (ICU). We sought to describe these factors and hypothesized that dialysis patients would comprise a significant proportion of this cohort. DESIGN: Retrospective observational study from January 2010 to December 2011. SETTING: An 880-bed tertiary teaching hospital. PATIENTS: Patients with CLABSI in non-ICU wards. METHODS: CLABSI patients were identified from existing infection-control databases and primary chart review was conducted. National Health and Safety Network (NHSN) definitions were utilized for CLABSI and pathogen classification. CLABSI rates were calculated per patient day. Total mortality rates were inclusive of hospice patients. RESULTS: Over a 2-year period, 104 patients incurred 113 CLABSIs for an infection rate of 0.35 per 1,000 patient days. The mean length of hospital stay prior to CLABSI was 16+/-13.3 days, which was nearly 3 times that of hospital-wide non-ICU length of stay. Only 11 patients (10.6%) received dialysis within 48 hours of CLABSI. However, 67% of patients had a hematologic malignancy, and 91.8% of those admitted with a malignant hematologic diagnosis were neutropenic at the time of CLABSI. Enterococcus spp. was the most common organism recovered, and half of all central venous catheters (CVCs) present were peripherally inserted central catheters (PICC lines). Mortality rates were 18.3% overall and 27.3% among dialysis patients. CONCLUSIONS: In patients with CLABSIs outside of the ICU, only 10.6% received dialysis prior to infection. However, underlying hematologic malignancy, neutropenia, and PICC lines were highly prevalent in this population. PMID- 25782896 TI - Surgical site infection after renal transplantation. AB - OBJECTIVE: To identify factors associated with the development of surgical site infection (SSI) among adult patients undergoing renal transplantation DESIGN: A retrospective cohort study. SETTING: An urban tertiary care center in Baltimore, Maryland, with a well-established renal transplantation program that performs ~200-250 renal transplant procedures annually. RESULTS: At total of 441 adult patients underwent renal transplantation between January 1, 2010, and December 31, 2011. Of these 441 patients, 66 (15%) developed an SSI; of these 66, 31 (47%) were superficial incisional infections and 35 (53%) were deep-incisional or organ space infections. The average body mass index (BMI) among this patient cohort was 29.7; 84 (42%) were obese (BMI >30). Patients who developed an SSI had a greater mean BMI (31.7 vs 29.4; P=.004) and were more likely to have a history of peripheral vascular disease, rheumatologic disease, and narcotic abuse. History of cerebral vascular disease was protective. Multivariate analysis showed BMI (odds ratio [OR] 1.06; 95% confidence interval [CI], 1.02-1.11) and past history of narcotic use/abuse (OR, 4.86; 95% CI, 1.24-19.12) to be significantly associated with development of SSI after controlling for National Healthcare Surveillance Network (NHSN) score and presence of cerebrovascular, peripheral vascular, and rheumatologic disease. CONCLUSIONS: We identified higher BMI as a risk factor for the development of SSI following renal transplantation. Notably, neither aggregate comorbidity scores nor NHSN risk index were associated with SSI in this population. Additional risk adjustment measures and research in this area are needed to compare SSIs across transplant centers. PMID- 25782898 TI - Impact of universal gowning and gloving on health care worker clothing contamination. AB - OBJECTIVE: To determine whether gowning and gloving for all patient care reduces contamination of healthcare worker (HCW) clothing, compared to usual practice. DESIGN: Cross-sectional surveys. SETTING: Five study sites were recruited from intensive care units (ICUs) randomized to the intervention arm of the Benefits of Universal Gown and Glove (BUGG) study. PARTICIPANTS: All HCWs performing direct patient care in the study ICUs were eligible to participate. METHODS: Surveys were performed first during the BUGG intervention study period (July-September 2012) with universal gowning/gloving and again after BUGG study conclusion (October-December 2012), with resumption of usual care. During each phase, HCW clothing was sampled at the beginning and near the end of each shift. Cultures were performed using broth enrichment followed by selective media. Acquisition was defined as having a negative clothing culture for samples taken at the beginning of a shift and positive clothing culture at for samples taken at the end of the shift. RESULTS: A total of 348 HCWs participated (21-92 per site), including 179 (51%) during the universal gowning/gloving phase. Overall, 51 (15%) HCWs acquired commonly pathogenic bacteria on their clothing: 13 (7.1%) HCWs acquired bacteria during universal gowning/gloving, and 38 (23%) HCWs acquired bacteria during usual care (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.2-0.6). Pathogens identified included S. aureus (25 species, including 7 methicillin-resistant S. aureus [MRSA]), Enterococcus spp. (25, including 1 vancomycin-resistant Enterococcus [VRE]), Pseudomonas spp. (4), Acinetobacter spp. (4), and Klebsiella (2). CONCLUSION: Nearly 25% of HCWs practicing usual care (gowning and gloving only for patients with known resistant bacteria) contaminate their clothing during their shift. This contamination was reduced by 70% by gowning and gloving for all patient interactions. PMID- 25782899 TI - Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection. AB - OBJECTIVE: Clostridium difficile infection (CDI) places a high burden on the US healthcare system. Recurrent CDI (RCDI) occurs frequently. Recently proposed guidelines from the American College of Gastroenterology (ACG) and the American Gastroenterology Association (AGA) include fecal microbiota transplantation (FMT) as a therapeutic option for RCDI. The purpose of this study was to estimate the cost-effectiveness of FMT compared with vancomycin for the treatment of RCDI in adults, specifically following guidelines proposed by the ACG and AGA. DESIGN: We constructed a decision-analytic computer simulation using inputs from the published literature to compare the standard approach using tapered vancomycin to FMT for RCDI from the third-party payer perspective. Our effectiveness measure was quality-adjusted life years (QALYs). Because simulated patients were followed for 90 days, discounting was not necessary. One-way and probabilistic sensitivity analyses were performed. RESULTS: Base-case analysis showed that FMT was less costly ($1,669 vs $3,788) and more effective (0.242 QALYs vs 0.235 QALYs) than vancomycin for RCDI. One-way sensitivity analyses showed that FMT was the dominant strategy (both less expensive and more effective) if cure rates for FMT and vancomycin were >=70% and <91%, respectively, and if the cost of FMT was <$3,206. Probabilistic sensitivity analysis, varying all parameters simultaneously, showed that FMT was the dominant strategy over 10, 000 second order Monte Carlo simulations. CONCLUSIONS: Our results suggest that FMT may be a cost-saving intervention in managing RCDI. Implementation of FMT for RCDI may help decrease the economic burden to the healthcare system. PMID- 25782900 TI - Molecular epidemiology of Clostridium difficile infections in children: a retrospective cohort study. AB - OBJECTIVE: The molecular epidemiology of pediatric Clostridium difficile infection (CDI) is poorly understood. We aimed to identify the restriction endonuclease analysis (REA) groups causing CDI and to determine risk factors and outcomes associated with CDI caused by epidemic strains in children. DESIGN: Retrospective cohort study. PATIENTS: Inpatients and outpatients >1 year old receiving care between December 2012 and December 2013. SETTING: An academic children's hospital in Chicago, Illinois. METHODS: C. difficile PCR-positive stools were cultured, and C. difficile isolates were typed by REA. REA of isolates from patients with multiple CDIs was performed to differentiate relapse (infection with same strain) from reinfection (different strains) irrespective of time between CDIs. RESULTS: A total of 189 CDIs occurred among 145 patients. REA groups were widely distributed. The BI/NAP1/027 strain caused CDI in only 1 patient. DH/NAP11/106, the predominant epidemic strain identified, was associated with the use of third- or fourth-generation cephalosporins (risk ratio [RR], 3.2; 95% confidence interval [CI], 1.1-9.9; P=.04). CDI relapse commonly occurred up to 20 weeks later. Compared with CDI caused by non-DH/NAP11/106 strains, CDI caused by DH/NAP11/106 was more likely to result in multiple CDI relapses (40% vs 8%; P=.05) among children with multiple CDIs. CONCLUSIONS: REA identified the exceedingly low prevalence of BI/NAP1/027 and the high prevalence of DH/NAP11/106, a common epidemic strain in the United Kingdom that is less often reported in the United States. CDI relapse commonly occurred up to 20 weeks from the previous CDI. Defining recurrent CDI as that occurring only within 8 weeks of the original infection may lead to misclassification of some recurrent CDIs as new CDIs in children. PMID- 25782901 TI - Examining hospital patients' knowledge and attitudes toward hospital-acquired infections and their participation in infection control. AB - It is crucial to assess patients' understanding of and readiness to participate in infection control programs. While 80% of hospital patients reported that they were willing to help hospital staff with infection prevention, many felt that they would not feel comfortable asking a healthcare worker to sanitize his or her hands. PMID- 25782902 TI - Substantial variation in hospital rankings after adjusting for hospital-level predictors of publicly-reported hospital-associated Clostridium difficile infection rates. AB - Across 366 California hospitals, we identified hospital-level characteristics predicting increased hospital-associated Clostridium difficile infection (HA-CDI) rates including more licensed beds, teaching and long-term acute care (LTAC) hospitals, and polymerase chain reaction testing. Adjustment for these characteristics impacted rankings in 24% of teaching hospitals, 13% of community hospitals, and 11% of LTAC hospitals. PMID- 25782903 TI - The potential impact of excluding funguria from the surveillance definition of catheter-associated urinary tract infection. AB - Funguria rarely represents true infection in the urinary tract. Excluding yeast from the catheter-associated urinary tract infection (CAUTI) surveillance definition reduced CAUTI rates by nearly 25% in community hospitals and at an academic, tertiary-care medical center. PMID- 25782904 TI - Overtreatment of asymptomatic bacteriuria: identifying targets for improvement. AB - Treatment of asymptomatic bacteriuria contributes to antimicrobial overuse in hospitalized patients. Indications for urine culture, treatment, and targets for improvement were evaluated in 153 patients. Drivers of antimicrobial overuse included fever with an alternative source, altered mental status, and leukocytosis, which led 435 excess days of antimicrobial therapy. PMID- 25782905 TI - Antibiotic prescribing at the transition from hospitalization to discharge: a target for antibiotic stewardship. AB - Of 300 patients prescribed oral antibiotics at the time of hospital discharge, urinary tract infection, community-acquired pneumonia, and skin infections accounted for 181 of the treatment indications (60%). Half of the prescriptions were antibiotics with broad Gram-negative activity. Discharge prescriptions were inappropriate in 79 of 150 cases reviewed (53%). PMID- 25782906 TI - Risk factors for central-line-associated bloodstream infections: a focus on comorbid conditions. AB - Centers for Disease Control and Prevention (CDC) risk adjustment methods for central-line-associated bloodstream infections (CLABSI) only adjust for type of intensive care unit (ICU). This cohort study explored risk factors for CLABSI using 2 comorbidity classification schemes, the Charlson Comorbidity Index (CCI) and the Chronic Disease Score (CDS). Our study supports the need for additional research into risk factors for CLABSI, including electronically available comorbid conditions. PMID- 25782907 TI - Compliance with the World Health Organization hand hygiene technique: a prospective observational study. PMID- 25782908 TI - Sterilization indicators in central sterile supply department: quality assurance and cost implications. PMID- 25782909 TI - Making the case for textiles with a dual mechanism of action. PMID- 25782910 TI - Mobile phone microbial contamination among neonatal unit healthcare workers. PMID- 25782911 TI - Potential risk of aerosol-borne Francisella tularensis transmission in the operating room. PMID- 25782912 TI - Port-related nontyphoidal Salmonella bacteremia. PMID- 25782913 TI - Fibroblast growth factor 7 is a nociceptive modulator secreted via large dense core vesicles. AB - Fibroblast growth factor (FGF) 7, a member of FGF family, is initially found to be secreted from mesenchymal cells to repair epithelial tissues. However, its functions in the nervous system are largely unknown. The present study showed that FGF7 was a neuromodulator localized in the large dense-core vesicles (LDCVs) in nociceptive neurons. FGF7 was mainly expressed in small-diameter neurons of the dorsal root ganglion and could be transported to the dorsal spinal cord. Interestingly, FGF7 was mostly stored in LDCVs that did not contain neuropeptide substance P. Electrophysiological recordings in the spinal cord slice showed that buffer-applied FGF7 increased the amplitude of excitatory post-synaptic current evoked by stimulating the sensory afferent fibers. Behavior tests showed that intrathecally applied FGF7 potentiated the formalin-induced acute nociceptive response. Moreover, both acute and inflammatory nociceptive responses were significantly reduced in Fgf7-deficient mice. These results suggest that FGF7 exerts an excitatory modulation of nociceptive afferent transmission. PMID- 25782914 TI - Catastrophic antiphospholipid syndrome associated with systemic lupus erythematosus treated with rituximab: case report and a review of the literature. AB - Catastrophic antiphospholipid syndrome (CAPS) is a rare, acute, life-threatening form of antiphospholipid syndrome. In the last several decades there has been a significant improvement in the treatment of patients with CAPS, but the overall mortality is still very significant. The use of rituximab has been reported in the treatment of refractory cases of CAPS but the data are still scarce and inconclusive. We report a case of 47-year old male patient with long standing SLE and secondary APS who presented with acute thromboembolic incident (partial thrombosis of superior mesenteric artery). During the first week of his hospitalization he met the criteria for probable CAPS. He was treated with anticoagulants, glucocorticoids, intravenous immunoglobulins and systemic antibiotics. Finally he was treated with rituximab. There was no response to the implemented treatment and he eventually died. Autopsy showed evidence of small vessel thrombosis in the lung microvasculature. With this the criteria for definitive CAPS were fulfilled. To our knowledge, at present time, this is the first ever reported case of definitive CAPS associated with SLE treated with rituximab. There is a great need for further investigation to evaluate the effectiveness of rituximab in treatment of CAPS. PMID- 25782915 TI - Effects of oxaliplatin and oleic acid Gc-protein-derived macrophage-activating factor on murine and human microglia. AB - The biological properties and characteristics of microglia in rodents have been widely described, but little is known about these features in human microglia. Several murine microglial cell lines are used to investigate neurodegenerative and neuroinflammatory conditions; however, the extrapolation of the results to human conditions is frequently met with criticism because of the possibility of species-specific differences. This study compares the effects of oxaliplatin and of oleic acid Gc-protein-derived macrophage-activating factor (OA-GcMAF) on two microglial cell lines, murine BV-2 cells and human C13NJ cells. Cell viability, cAMP levels, microglial activation, and vascular endothelial growth factor (VEGF) expression were evaluated. Our data demonstrate that oxaliplatin induced a significant decrease in cell viability in BV-2 and in C13NJ cells and that this effect was not reversed with OA-GcMAF treatment. The signal transduction pathway involving cAMP/VEGF was activated after treatment with oxaliplatin and/or OA GcMAF in both cell lines. OA-GcMAF induced a significant increase in microglia activation, as evidenced by the expression of the B7-2 protein, in BV-2 as well as in C13NJ cells that was not associated with a concomitant increase in cell number. Furthermore, the effects of oxaliplatin and OA-GcMAF on coculture morphology and apoptosis were evaluated. Oxaliplatin-induced cell damage and apoptosis were nearly completely reversed by OA-GcMAF treatment in both BV-2/SH SY5Y and C13NJ/SH-SY5Y cocultures. Our data show that murine and human microglia share common signal transduction pathways and activation mechanisms, suggesting that the murine BV-2 cell line may represent an excellent model for studying human microglia. PMID- 25782916 TI - HDAC Inhibitors as Novel Anti-Cancer Therapeutics. AB - Malignant growth of cells is a condition characterized by unchecked cellular proliferation, genetic instability and epigenetic dysregulation. Up-regulated HDAC (Histone Deacetylase) enzyme activity is associated with a closed chromatin assembly and subsequent gene repression, forming a characteristic feature of malignantly transformed cells. Novel therapeutics are now targeting the zinc containing HDAC enzymes for treating various types of cancers. Recently, a spate of drugs acting via HDAC inhibition have been undergoing clinical trials and several patents present exciting molecules like PCI-24781 (Abexinostat), ITF- 2357 (Givinostat); MS-275 (Entinostat), MGCD 0103 (Mocetinostat), LBH-589 (Panobinostat), FK228 (Romidepsin), PXD-101 (Belinostat) and Valproic Acid to be used as alternatives or adjuvants to traditional chemotherapeutics. However, only three HDAC inhibitors have acquired FDA approval till date. Recently, PXD-101 obtained FDA approval for the treatment of Refractory or Relapsed Peripheral T cell lymphoma. The current article reviews patents that have introduced novel molecules that are HDAC isoform specific, superior to first generation HDAC inhibitors like SAHA (Suberoylanilide Hydroxamic Acid) and TSA (Trichostatin A) and can be modified structurally to reduce toxic side effects and increase specificity. These molecules can combine the best characteristics of an ideal HDAC inhibiting drug either as monotherapy or in combinatorial therapy for cancer treatment thus, indicating promise to be included in the next generation of target specific HDAC inhibiting drugs. PMID- 25782917 TI - Quantitative evaluation of micronuclei in oral squamous cell carcinoma and oral submucous fibrosis patients: a comparative study. AB - BACKGROUND: The forte of research today aims at determining genotoxic changes in human cells as rapidly as possible. Micronuclei estimation in exfoliated cells is an easy, noninvasive and a reliable method to monitor genotoxic changes due to various reasons in oral mucosal cells. AIMS AND OBJECTIVES: To identify, quantify and compare micronuclei in exfoliated buccal mucosal cells of healthy, oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC) participants. PATIENTS AND METHODS: In the present study, buccal smears from the 60 participants (30 each of OSMF and OSCC) and 30 age and sex matched controls were obtained and stained using Papanicolaou (PAP) staining method and observed under 100X magnification to identify and quantify micronuclei in the exfoliated cells of oral mucosa. RESULTS: There was a significant increase in micronuclei count from control to OSMF to OSCC. Also, a significant increase in the micronuclei frequency is observed with the different clinical stages and histological grades of OSMF and different histological grades of OSCC. CONCLUSION: Micronucleus assay can be used as an easy and consistent marker for genotoxic evaluation in higher risk groups and can be used for better treatment evaluation and prognosis in cases of OSMF and OSCC. Some relevant patents are also outlined in this article. PMID- 25782919 TI - Prospective, randomized controlled trial on use of ropivacaine after robotic thyroid surgery: Effects on postoperative pain. AB - BACKGROUND: We evaluated the effects of ropivacaine for pain relief after robotic thyroid surgery. METHODS: One hundred eight patients scheduled for robotic thyroid surgery were randomized into ropivacaine (n = 54) or control (n = 54) groups. After surgery, 40 mL of 0.25% ropivacaine or 0.9% saline (control) was instilled into the skin flap. Postoperative pain intensity (visual analog scale [VAS]), analgesic requirements (fentanyl), and adverse events were assessed at 1, 2, 4, 8, 16, and 24 hours postoperatively. RESULTS: One hundred three patients completed the study protocol. VAS scores were lower in the ropivacaine group than the control group (p = .010); however, VAS scores were not significantly different after 8 hours postoperatively. Total analgesic consumption was higher in controls than ropivacaine-treated patients (p = .01). Adverse events did not differ between the 2 groups. CONCLUSION: Ropivacaine instillation after robotic thyroid surgery reduces acute postoperative pain and analgesic requirements without adverse events. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E-E, 2016. PMID- 25782918 TI - Detection and characterization of nonspecific, sparsely populated binding modes in the early stages of complexation. AB - A method is proposed to study protein-ligand binding in a system governed by specific and nonspecific interactions. Strong associations lead to narrow distributions in the proteins configuration space; weak and ultraweak associations lead instead to broader distributions, a manifestation of nonspecific, sparsely populated binding modes with multiple interfaces. The method is based on the notion that a discrete set of preferential first-encounter modes are metastable states from which stable (prerelaxation) complexes at equilibrium evolve. The method can be used to explore alternative pathways of complexation with statistical significance and can be integrated into a general algorithm to study protein interaction networks. The method is applied to a peptide-protein complex. The peptide adopts several low-population conformers and binds in a variety of modes with a broad range of affinities. The system is thus well suited to analyze general features of binding, including conformational selection, multiplicity of binding modes, and nonspecific interactions, and to illustrate how the method can be applied to study these problems systematically. The equilibrium distributions can be used to generate biasing functions for simulations of multiprotein systems from which bulk thermodynamic quantities can be calculated. PMID- 25782920 TI - Antibacterial activity of essential oils mixture against PSA. AB - Pseudomonas syringae pv. actinidiae (PSA) is the causal agent of bacterial canker of kiwifruit. It is very difficult to treat pandemic disease. The prolonged treatment with antibiotics, has resulted in failure and resistance and alternatives to conventional antimicrobial therapy are needed. The aim of our study was to analyse the phenotypic characteristics of PSA, identify new substances from natural source i.e. essential oils (EOs) able to contain the kiwifruit canker and investigate their potential use when utilised in combination. Specially, we investigated the morphological differences of PSA isolates by scanning electron microscope, and the synergic action of different EOs by time-kill and checkerboard methods. Our results demonstrated that PSA was able to produce extracellular polysaccharides when it was isolated from trunk, and, for the first time, that it was possible to kill PSA with a mixture of EOs after 1 h of exposition. We hypothesise on its potential use in agriculture. PMID- 25782921 TI - Sleep quality and its correlates in patients with chronic kidney disease: a cross sectional design. AB - PURPOSE: Since sympathovagal imbalance influences clinical phenomena, such as hypertension, diabetes mellitus, chronic kidney disease (CKD) and sleeping problems, there should be correlations between these conditions. We hypothesized that sleep quality would be correlated with estimated glomerular filtration rate (eGFR), blood pressure and the presence of diabetes. METHODS: We included 303 CKD patients in this study. We employed the Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI) and Short Form 36 Quality of Life Health Survey Questions (SF-36) to screen sleeping disturbances, depression and quality of life, respectively. A chart review was performed for the patients' demographics, diagnoses and certain laboratory parameters--including blood glucose, hemoglobin, albumin, calcium, phosphate, parathyroid hormone and eGFR. Multivariate logistic regression models were employed to estimate odds ratios with 95% confidence intervals. RESULTS: We included 303 patients in this cross-sectional study. A total of 101 patients were on dialysis. In the univariate models, gender, calcium and mental component summary scores (MCS) reached a significant level of 0.1, and those covariates were included in the multivariate analysis. The reduced models included gender and MCS categories. Female gender increases the risk for poor sleep quality. In our report, evidence suggests MCS domain scores are inversely related to the risk for impaired sleep. CONCLUSION: Our results indicated a high burden of sleep disturbances in kidney patients. In addition, female gender and having low MCS scores may influence sleep quality in kidney patients. PMID- 25782922 TI - The role of renin-angiotensin system in the chronic allograft nephropathy: an immunohistochemical study. AB - BACKGROUND: Evidences suggest a role of renin-angiotensin system (RAS) in the development of chronic allograft injury. METHODS: We correlated intrarenal angiotensin-converting enzyme, angiotensin II (Angio II) and transforming growth factor beta1 (TGFbeta1) expression in 58 biopsies-proven chronic allograft nephropathy (CAN) with tissue injury and allograft survival. RESULTS: The biopsies with CAN were graded according to Banff classification as I (22 cases), II (17) and III (19); 27 biopsies also showed a mononuclear inflammatory infiltrate in scarred areas. There were increased expression of angiotensin converting-enzyme (ACE), Angio II and TGFbeta1 mainly in tubulointerstitial compartment in the group with CAN; there was no association of Angio II and TGFbeta1 expression with interstitial fibrosis. There were no significant differences of ACE, Angio II and TGFbeta1 expression between the patients treated and untreated with RAS blockade, and with the graft outcome. Interstitial inflammatory infiltrate had positive correlation with interstitial fibrosis and significant impact on graft survival at 8 years. CONCLUSIONS: Our study showed in a group of cases with CAN a high percentage of inflammatory infiltrate that correlated with interstitial fibrosis and graft outcome. The chronic inflammatory changes in these cases did not show significant association with local RAS expression. PMID- 25782923 TI - Dream anxiety in renal transplant recipients. AB - OBJECTIVE: Although low quality of sleep has been reported in kidney transplant patients with functioning allografts, there are no previous studies investigating the dreams of these patients. We aimed to investigate the differences in dream anxiety level between renal transplant patients and healthy control subjects. We also planned to compare depression and anxiety symptoms, sleep quality and sleepiness level between these two groups. METHODS: Twenty-two living-donor renal transplant recipients followed at an outpatient nephrology clinic and 22 healthy controls were enrolled in this observational cross-sectional study. Sociodemographic Data Collection Form, and the Van Dream Anxiety Scale (VDAS), the Pittsburg Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), Beck Depression and Anxiety Inventories were used for the assessment of the necessary features. Hemoglobin (Hb), blood urea nitrogen (BUN), creatinine (Cr) and glucose levels were measured. RESULTS: There were no significant differences between the groups in terms of dream anxiety (p = 0.45), depression (p = 0.76), sleep quality (p = 0.8), insomnia severity (p = 0.08) and Hb (p = 0.11) and glucose levels (p = 0.14). Although, BUN (p = 0.00) and creatinine (p = 0.00) levels differed significantly between the two groups, both parameters were found to be within their normal range. CONCLUSIONS: In our study, chronic renal failure patients with a successful kidney transplant were found to be able to completely return to normal in terms of metabolic parameters, sleep quality and mood. Similar levels of dream anxiety are also consistent with these findings. PMID- 25782971 TI - Boundary Engineering for the Thermoelectric Performance of Bulk Alloys Based on Bismuth Telluride. AB - Thermoelectrics, which transports heat for refrigeration or converts heat into electricity directly, is a key technology for renewable energy harvesting and solid-state refrigeration. Despite its importance, the widespread use of thermoelectric devices is constrained because of the low efficiency of thermoelectric bulk alloys. However, boundary engineering has been demonstrated as one of the most effective ways to enhance the thermoelectric performance of conventional thermoelectric materials such as Bi2 Te3 , PbTe, and SiGe alloys because their thermal and electronic transport properties can be manipulated separately by this approach. We review our recent progress on the enhancement of the thermoelectric figure of merit through boundary engineering together with the processing technologies for boundary engineering developed most recently using Bi2 Te3 -based bulk alloys. A brief discussion of the principles and current status of boundary-engineered bulk alloys for the enhancement of the thermoelectric figure of merit is presented. We focus mainly on (1) the reduction of the thermal conductivity by grain boundary engineering and (2) the reduction of thermal conductivity without deterioration of the electrical conductivity by phase boundary engineering. We also discuss the next potential approach using two boundary engineering strategies for a breakthrough in the area of bulk thermoelectric alloys. PMID- 25782972 TI - A novel symptom cluster analysis among ambulatory HIV/AIDS patients in Uganda. AB - Symptom clusters are gaining importance given HIV/AIDS patients experience multiple, concurrent symptoms. This study aimed to: determine clusters of patients with similar symptom combinations; describe symptom combinations distinguishing the clusters; and evaluate the clusters regarding patient socio demographic, disease and treatment characteristics, quality of life (QOL) and functional performance. This was a cross-sectional study of 302 adult HIV/AIDS outpatients consecutively recruited at two teaching and referral hospitals in Uganda. Socio-demographic and seven-day period symptom prevalence and distress data were self-reported using the Memorial Symptom Assessment Schedule. QOL was assessed using the Medical Outcome Scale and functional performance using the Karnofsky Performance Scale. Symptom clusters were established using hierarchical cluster analysis with squared Euclidean distances using Ward's clustering methods based on symptom occurrence. Analysis of variance compared clusters on mean QOL and functional performance scores. Patient subgroups were categorised based on symptom occurrence rates. Five symptom occurrence clusters were identified: Cluster 1 (n=107), high-low for sensory discomfort and eating difficulties symptoms; Cluster 2 (n=47), high-low for psycho-gastrointestinal symptoms; Cluster 3 (n=71), high for pain and sensory disturbance symptoms; Cluster 4 (n=35), all high for general HIV/AIDS symptoms; and Cluster 5 (n=48), all low for mood-cognitive symptoms. The all high occurrence cluster was associated with worst functional status, poorest QOL scores and highest symptom-associated distress. Use of antiretroviral therapy was associated with all high symptom occurrence rate (Fisher's exact=4, P<0.001). CD4 count group below 200 was associated with the all high occurrence rate symptom cluster (Fisher's exact=41, P<0.001). Symptom clusters have a differential, affect HIV/AIDS patients' self reported outcomes, with the subgroup experiencing high-symptom occurrence rates having a higher risk of poorer outcomes. Identification of symptom clusters could provide insights into commonly co-occurring symptoms that should be jointly targeted for management in patients with multiple complaints. PMID- 25782970 TI - Neuronal and vascular interactions. AB - The brain, which represents 2% of body mass but consumes 20% of body energy at rest, has a limited capacity to store energy and is therefore highly dependent on oxygen and glucose supply from the blood stream. Normal functioning of neural circuits thus relies on adequate matching between metabolic needs and blood supply. Moreover, not only does the brain need to be densely vascularized, it also requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for synaptic transmission and neuronal function. In this review, we focus on three major factors that ensure optimal brain perfusion and function: the patterning of vascular networks to efficiently deliver blood and nutrients, the function of the blood-brain barrier to maintain brain homeostasis, and the regulation of cerebral blood flow to adequately couple energy supply to neural function. PMID- 25782973 TI - Chloroplastic and cytoplasmic overexpression of sheep serotonin N acetyltransferase in transgenic rice plants is associated with low melatonin production despite high enzyme activity. AB - Serotonin N-acetyltransferase (SNAT), the penultimate enzyme in melatonin biosynthesis, catalyzes the conversion of serotonin into N-acetylserotonin. Plant SNAT is localized in chloroplasts. To test SNAT localization effects on melatonin synthesis, we generated transgenic rice plants overexpressing a sheep (Ovis aries) SNAT (OaSNAT) in their chloroplasts and compared melatonin biosynthesis with that of transgenic rice plants overexpressing OaSNAT in their cytoplasm. To localize the OaSNAT in chloroplasts, we used a chloroplast targeting sequence (CTS) from tobacco protoporphyrinogen IX oxidase (PPO), which expresses in chloroplasts. The purified recombinant CTS:OaSNAT fusion protein was enzymatically functional and localized in chloroplasts as confirmed by confocal microscopic analysis. The chloroplast-targeted CTS:OaSNAT lines and cytoplasm expressed OaSNAT lines had similarly high SNAT enzyme activities. However, after cadmium and butafenacil treatments, melatonin production in rice leaves was severalfold lower in the CTS:OaSNAT lines than in the OaSNAT lines. Notably, enhanced SNAT enzyme activity was not directly proportional to the production of N-acetylserotonin, melatonin, or 2-hydroxymelatonin, suggesting that plant SNAT has a role in the homeostatic regulation of melatonin rather than in accelerating melatonin synthesis. PMID- 25782974 TI - Regioselective chromatic orthogonality with light-activated metathesis catalysts. AB - The ability to selectively guide consecutive chemical processes towards a preferred pathway by using light of different frequencies is an appealing concept. Herein we describe the coupling of two photochemical reactions, one the photoisomerization and consequent activation of a sulfur-chelated latent olefin metathesis catalyst at 350 nm, and the other the photocleavage of a silyl protecting group at 254 nm. Depending on the steric stress exerted by a photoremovable neighboring chemical substituent, we demonstrate the selective formation of either five- or six-membered-ring frameworks by light-triggered ring closing metathesis. The orthogonality of these light-induced reactions allows the initiation of these processes independently and in interchangeable order, according to the wavelength of light used to promote them. PMID- 25782975 TI - Early gait development in human infants: Plasticity and clinical applications. AB - In this paper we focus on how a developmental perspective on plasticity in the control of human movement can promote early therapy and improve gait acquisition in infants with developmental disabilities. Current knowledge about stepping development in healthy infants across the first year of life highlights strong plasticity, both in behavioral outcome and in underlying neuro-muscular activation. These data show that stepping, like other motor skills, emerges from the interaction between infant's maturation and the environment. This view is reinforced by showing that infants with different internal resources (like genetic disorder or neural tube defect) show unique developmental trajectories when supported on a treadmill, yet do respond. Moreover, we will show that their behavior can be improved by context manipulations (mostly sensory stimulation) or practice. Overall, plasticity in the neural, skeletal, and muscle tissues create new opportunities for optimizing early intervention by creatively tapping into the same developmental processes experienced by healthy infants. PMID- 25782977 TI - Single-step deposition of high-mobility graphene at reduced temperatures. AB - Current methods of chemical vapour deposition (CVD) of graphene on copper are complicated by multiple processing steps and by high temperatures required in both preparing the copper and inducing subsequent film growth. Here we demonstrate a plasma-enhanced CVD chemistry that enables the entire process to take place in a single step, at reduced temperatures (<420 degrees C), and in a matter of minutes. Growth on copper foils is found to nucleate from arrays of well-aligned domains, and the ensuing films possess sub-nanometre smoothness, excellent crystalline quality, low strain, few defects and room-temperature electrical mobility up to (6.0+/-1.0) * 10(4) cm(2) V(-1) s(-1), better than that of large, single-crystalline graphene derived from thermal CVD growth. These results indicate that elevated temperatures and crystalline substrates are not necessary for synthesizing high-quality graphene. PMID- 25782978 TI - The importance of being isomeric. AB - In the normal individual, the parietal components of the body are mirror-imaged and appropriately described as isomeric. The thoraco-abdominal organs, in contrast, are lateralized. However, in "visceral heterotaxy," the thoraco abdominal organs also show some degree of isomerism, best seen in the arrangement of the bronchial tree. Whether isomerism can be found within the heart remains controversial. One of two recent publications in this journal emphasized the crucial features of bronchial isomerism; the other, in contrast, confused the situation of isomerism within the heart. In this review, we show how the topic of cardiac isomerism is clarified by concentrating on the anatomical features of the cardiac components and determining how best they can be described. Appropriate manipulation of developing mice produces unequivocal evidence of isomerism of the atrial appendages, but with no evidence of ventricular isomerism. In hearts from patients with so-called "heterotaxy," only the atrial appendages, distinguished on the basis of the pectinate muscles lining their walls, are uniformly isomeric, permitting the syndrome to be differentiated into the subsets of left as opposed to right atrial appendage isomerism. Thus, controversies are defused by simply describing the isomerism of the atrial appendages rather than "atrial isomerism," recognizing the frequency of abnormal venoatrial connections in these settings. Any suggestion of ambiguity is removed by the equally simple expedient of describing all the variable cardiac features, describing the arrangements of the thoracic and abdominal organs separately should there be discordances. PMID- 25782980 TI - Real-Time MEG Source Localization Using Regional Clustering. AB - With its millisecond temporal resolution, Magnetoencephalography (MEG) is well suited for real-time monitoring of brain activity. Real-time feedback allows the adaption of the experiment to the subject's reaction and increases time efficiency by shortening acquisition and off-line analysis. Two formidable challenges exist in real-time analysis: the low signal-to-noise ratio (SNR) and the limited time available for computations. Since the low SNR reduces the number of distinguishable sources, we propose an approach which downsizes the source space based on a cortical atlas and allows to discern the sources in the presence of noise. Each cortical region is represented by a small set of dipoles, which is obtained by a clustering algorithm. Using this approach, we adapted dynamic statistical parametric mapping for real-time source localization. In terms of point spread and crosstalk between regions the proposed clustering technique performs better than selecting spatially evenly distributed dipoles. We conducted real-time source localization on MEG data from an auditory experiment. The results demonstrate that the proposed real-time method localizes sources reliably in the superior temporal gyrus. We conclude that real-time source estimation based on MEG is a feasible, useful addition to the standard on-line processing methods, and enables feedback based on neural activity during the measurements. PMID- 25782981 TI - Laboratory development and field testing of sentinel toys to assess environmental faecal exposure of young children in rural India. AB - BACKGROUND: Sentinel toys are increasingly used as a method of assessing young children's exposure to faecal pathogens in households in low-income settings. However, there is no consensus on the suitability of different approaches. METHODS: We evaluated three types of toy balls with different surfaces (plastic, rubber, urethane) in the laboratory to compare the uptake of faecal indicator bacteria (Escherichia coli) on their surface. We performed bacteria survival analysis under different environmental conditions and tested laboratory methods for bacteria removal and recovery. In a field study we distributed sterile urethane balls to children <5 from 360 households in rural India. After 24 hours, we collected and rinsed the toys in sterile water, assayed for thermotolerant coliforms (TTC) and explored associations between the level of contamination and household characteristics. RESULTS: In the laboratory, urethane foam balls took up more indicator bacteria than the other balls. Bacteria recovery did not differ based on mechanic vs no agitation. Higher temperatures and moisture levels increased bacterial yield. In the field, the only factor associated with a decreased recovery of TTC from the balls was having a soil (unpaved) floor. CONCLUSIONS: Sentinel toys may be an effective tool for assessing young children's exposure to faecal pathogens. However, even using methods designed to increase bacterial recovery, limited sensitivity may require larger sample sizes. PMID- 25782982 TI - Unintentional ingestion of cleaners and other substances in an immigrant Mexican population: a qualitative study. AB - Paediatric poisoning is a salient issue worldwide and also affects the USA. In past years, ingestion of household cleaners was the second leading cause of unintentional poisonings in children. All children are at risk for ingestions, although immigrant children may be at greater risk. The purpose of this study was to document child ingestion experiences from toxic household substances via semistructured interviews with immigrant Mexican mothers. Participants were recruited from a paediatric primary care practice in Dallas/Fort Worth, Texas (N=35). Eighteen of 35 respondents (51%) reported that their child, nephew/niece or a friend's child had accidentally ingested a cleaning solution, gasoline or herbal remedy. Of those ingestions, 12 were reportedly from an alternative container, such as a juice box or soda bottle. Improper storage was the primary reason for ingestion. Culturally appropriate home visits and interventions are needed to better prevent ingestion in young children. PMID- 25782983 TI - Radiographic evaluation of complete and incomplete discoid lateral meniscus. AB - OBJECTIVES: The aim of this retrospective study was (1) to evaluate the radiographic features to differentiate arthroscopically confirmed complete and incomplete discoid lateral meniscus (DLM) (2) to determine the cutoff values for any parameter that was found to differentiate complete from incomplete DLM. MATERIALS AND METHODS: We retrospectively analyzed plain knee radiographs of 130 arthroscopically proven DLM. Seventy-nine patients had complete DLM and 51 patients incomplete DLM. Knee radiographs from 52 patients with arthroscopically proven normal lateral meniscus acted as control group. Radiographic parameters measured included fibular height, lateral joint space, condylar cutoff sign, height of lateral tibial spine, obliquity of lateral tibial spine, squaring of the lateral femoral condyle, and cupping of the lateral tibial plateau. RESULTS: Among radiographic parameters, high fibular head, widening of the lateral joint space and femoral condylar cutoff sign showed statistically significant (p<0.0001) differences between complete and incomplete DLM. At specific threshold points of fibular height<11 mm, lateral joint space>6 mm and condylar cutoff sign<0.80, the diagnosis of complete DLM revealed 87.3% sensitivity, 81.6% specificity and 78.4% positive predictive value (PPV) for the fibular height, 81.0% sensitivity, 86.6% specificity and 83.1% PPV for the lateral joint space, and 86.1% sensitivity, 83.5% specificity and 80% PPV for the condylar cutoff sign. CONCLUSIONS: Radiographic features of fibular height, lateral joint space and condylar cut off sign can be used for screening of a complete type of DLM. However, radiographs are not a reliable screening tool for an incomplete DLM. LEVEL OF EVIDENCE: IV, Case Series. PMID- 25782984 TI - Outcomes and Resource Utilization of Endoscopic Mass-Closure Technique for Laryngeal Clefts. AB - OBJECTIVE: To compare resource utilization and clinical outcomes between endoscopic mass-closure and open techniques for laryngeal cleft repair. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic children's hospital. SUBJECTS AND METHODS: Pediatric patients undergoing repair for Benjamin Inglis type 1-3 laryngeal clefts over a 15-year period. All 20 patients undergoing endoscopic repair were included. Eight control patients undergoing open repair were selected using matching by age and cleft type. Demographic, clinical, and resource utilization data were collected. RESULTS: Twenty-eight patients were included (20 endoscopic, 8 open). Mean age, rates of tracheostomy and vocal fold immobility, and distribution of cleft types were not different between the 2 groups (all P > .2). Mean operative time (P = .004) and duration of hospital stay (P < .001) were significantly shorter in the endoscopic group. All repairs were intact in both groups at final postoperative endoscopy. Rates of persistent laryngeal penetration or aspiration on swallow study were not different between groups (P = 1.000), although results were available for only 11 patients. CONCLUSION: Endoscopic laryngeal cleft repair using a mass-closure technique provides a durable result while requiring significantly shorter operative times and hospital stays than open repair and avoiding the potential morbidity of laryngofissure. However, open repair may allow the simultaneous performance of other airway reconstructive procedures and may be a useful salvage technique when endoscopic repair fails. Postoperative swallowing results require further study. PMID- 25782986 TI - Denominator doesn't matter: standardizing healthcare-associated infection rates by bed days or device days. AB - OBJECTIVE: To examine the impact on infection rates and hospital rank for catheter-associated urinary tract infection (CAUTI), central line-associated bloodstream infection (CLABSI), and ventilator-associated pneumonia (VAP) using device days and bed days as the denominator DESIGN: Retrospective survey from October 2010 to July 2013 SETTING: Veterans Health Administration medical centers providing acute medical and surgical care PATIENTS: Patients admitted to 120 Veterans Health Administration medical centers reporting healthcare-associated infections METHODS: We examined the importance of using device days and bed days as the denominator between infection rates and hospital rank for CAUTI, CLABSI, and VAP for each medical center. The relationship between device days and bed days as the denominator was assessed using a Pearson correlation, and changes in infection rates and device utilization were evaluated by an analysis of variance. RESULTS: A total of 7.9 million bed days were included. From 2011 to 2013, CAUTI decreased whether measured by device days (2.32 to 1.64, P=.001) or bed days (4.21 to 3.02, P=.006). CLABSI decreased when measured by bed days (1.67 to 1.19, P=.04). VAP rates and device utilization ratios for CAUTI, CLABSI, and VAP were not statistically different across time. Infection rates calculated with device days were strongly correlated with infection rates calculated with bed days (r=0.79-0.94, P<.001). Hospital relative performance measured by ordered rank was also strongly correlated for both denominators (r=0.82-0.96, P<.001). CONCLUSIONS: These findings suggest that device days and bed days are equally effective adjustment metrics for comparing healthcare-associated infection rates between hospitals in the setting of stable device utilization. PMID- 25782987 TI - The rheology of aqueous solutions of ethyl hydroxy-ethyl cellulose (EHEC) and its hydrophobically modified analogue (hmEHEC): extensional flow response in capillary break-up, jetting (ROJER) and in a cross-slot extensional rheometer. AB - Cellulose derivatives containing associating hydrophobic groups along their hydrophilic backbone are used as rheology modifiers in the formulation of water based spray paints, medicinal sprays, cosmetics and printable inks. Jetting and spraying applications of these materials involve progressive thinning and break up of a fluid column or sheet into drops. Strong extensional kinematics develop in the thinning fluid neck. In viscous Newtonian fluids, inertial and viscous stresses oppose the surface tension-driven instability. In aqueous solutions of polymers such as Ethyl Hydroxy-Ethyl Cellulose (EHEC), chain elongation provides additional elastic stresses that can delay the capillary-driven pinch-off, influencing the sprayability or jettability of the complex fluid. In this study, we quantify the transient response of thinning filaments of cellulose ether solutions to extensional flows in a Capillary Break-up Extensional Rheometer (CaBER) and in a forced jet undergoing break-up using Rayleigh Ohnesorge Jetting Extensional Rheometry (ROJER). We also characterize the steady state molecular deformations using measurements of the flow-induced birefringence and excess pressure drop in an extensional stagnation point flow using a Cross-Slot Extensional Rheometer (CSER). We show that under the high extension rates encountered in jetting and spraying, the semi-dilute solutions of hydrophobically modified ethyl hydroxy-ethyl cellulose (hmEHEC) exhibit extensional thinning, while the unmodified bare chains of EHEC display an increase in extensional viscosity, up to a plateau value. For both EHEC and hmEHEC dispersions, the low extensibility of the cellulose derivatives limits the Trouton ratio observed at the highest extension rates attained (close to 10(5) s(-1)) to around 10-20. The reduction in extensional viscosity with increasing extension rate for the hydrophobically modified cellulose ether is primarily caused by the disruption of a transient elastic network that is initially formed by intermolecular association of hydrophobic stickers. This extensional thinning behavior, in conjunction with the low extensibility of the hydrophobically modified cellulose ether additives, makes these rheology modifiers ideal for controlling the extensional rheology in formulations that require jetting or spraying, with minimal residual stringiness or stranding. PMID- 25782985 TI - Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction. AB - BACKGROUND: Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. METHODS AND RESULTS: A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29+/-0.28 mm Hg/mL versus +0.02+/-0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30+/ 0.45 versus -0.17+/-0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (DeltaPWR/EDV 52+/-70 versus +0+/-40 mm Hg/s, P=0.006; DeltaSW/EDV +0.3+/-5.8 versus -6.0+/-5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure. CONCLUSIONS: In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302. PMID- 25782988 TI - Ferroportin deficiency impairs manganese metabolism in flatiron mice. AB - We examined the physiologic role of ferroportin (Fpn) in manganese (Mn) export using flatiron (ffe/+) mice, a genetic model of Fpn deficiency. Blood (0.0123 vs. 0.0107 mg/kg; P = 0.0003), hepatic (1.06 vs. 0.96 mg/kg; P = 0.0125), and bile Mn levels (79 vs. 38 mg/kg; P = 0.0204) were reduced in ffe/+ mice compared to +/+ controls. Erythrocyte Mn-superoxide dismutase was also reduced at 6 (0.154 vs. 0.096, P = 0.0101), 9 (0.131 vs. 0.089, P = 0.0162), and 16 weeks of age (0.170 vs. 0.090 units/mg protein/min; P < 0.0001). (54)Mn uptake after intragastric gavage was markedly reduced in ffe/+ mice (0.0187 vs. 0.0066% dose; P = 0.0243), while clearance of injected isotope was similar in ffe/+ and +/+ mice. These values were compared to intestinal absorption of (59)Fe, which was significantly reduced in ffe/+ mice (8.751 vs. 3.978% dose; P = 0.0458). The influence of the ffe mutation was examined in dopaminergic SH-SY5Y cells and human embryonic HEK293T cells. While expression of wild-type Fpn reversed Mn-induced cytotoxicity, ffe mutant H32R failed to confer protection. These combined results demonstrate that Fpn plays a central role in Mn transport and that flatiron mice provide an excellent genetic model to explore the role of this exporter in Mn homeostasis. - PMID- 25782989 TI - TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways. AB - Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO-TPN mice and prevents mucosal atrophy. C57Bl/6 and strain-matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF-alpha decreased in TLR4KO-TPN versus wild-type (WT)-TPN mice. Apoptotic positive crypt cells were 15-fold higher in WT-TPN versus TLR4KO-TPN mice. Bcl-2 was significantly increased in TLR4KO-TPN mice, while Bax decreased 10-fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO-sTPN mice. TLR4 blockade significantly prevented TPN-associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF alpha abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN-associated atrophy. PMID- 25782990 TI - Intracellular plasma membrane guidance of Photorhabdus asymbiotica toxin is crucial for cell toxicity. AB - The bacterial toxin Photorhabdus asymbiotica toxin (PaTox) modifies Rho proteins by tyrosine GlcNAcylation and heterotrimeric Galpha proteins by deamidation. Inactivation of Rho proteins results in F-actin disassembly in host cells. Here, we analyzed the subcellular distribution of PaTox and show that the glycosyltransferase domain of PaTox associates with the negatively charged inner surface of the plasma membrane. Localization studies with site-directed mutants, liposome precipitation analysis, lipid overlay assays, and confocal time-lapse microscopy revealed that a patch of positively charged lysine and arginine residues located on helix alpha1 of the glycosyltransferase is essential for membrane attachment. Using a helix1 deletion mutant, we show that plasma membrane localization of PaTox is essential for cytotoxicity and proved this by substitution of helix1 by an N-terminal myristoylation signal peptide, which restored plasma membrane localization and cytotoxicity. Furthermore, we also show that the intracellular deamidase activity of PaTox depends on the presence of the membrane localization domain. Comparison of PaTox membrane-binding domain with the 4-helix-bundle membrane-binding domain of Pasteurella multocida toxin, Vibrio cholerae multifunctional autoprocessing repeats-in-toxin, and clostridial glucosylating toxins revealed similar spatial geometry and charge distribution but different structural topology, indicating convergent evolution of toxin domains for optimized host target interaction. PMID- 25782992 TI - Dissociation of beta2-microglobulin determines the surface quality control of major histocompatibility complex class I molecules. AB - Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2K(b) class I proteins from the cell surface. We find that the binding of their light chain, beta2-microglobulin (beta2m), protects them from endocytic destruction. Thus, the extended survival of suboptimally loaded K(b) molecules at 25 degrees C is attributed to decreased dissociation of beta2m. Because all forms of K(b) are constantly internalized but little beta2m-receptive heavy chain is present at the cell surface, it is likely that beta2m dissociation and recognition of the heavy chain for lysosomal degradation take place in an endocytic compartment. PMID- 25782991 TI - RNA binding protein Musashi-1 directly targets Msi2 and Erh during early testis germ cell development and interacts with IPO5 upon translocation to the nucleus. AB - Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the process of gamete development, male germ cells experience extended periods of inactive transcription despite requirements for continued growth and differentiation. Spermatogenesis therefore provides an ideal model to study the effects of posttranscriptional control on gene regulation. During spermatogenesis posttranscriptional regulation is orchestrated by abundantly expressed RNA-binding proteins. One such group of RNA-binding proteins is the Musashi family, previously identified as a critical regulator of testis germ cell development and meiosis in Drosophila and also shown to be vital to sperm development and reproductive potential in the mouse. We focus in depth on the role and function of the vertebrate Musashi ortholog Musashi-1 (MSI1). Through detailed expression studies and utilizing our novel transgenic Msi1 testis-specific overexpression model, we have identified 2 unique RNA-binding targets of MSI1 in spermatogonia, Msi2 and Erh, and have demonstrated a role for MSI1 in translational regulation. We have also provided evidence to suggest that nuclear import protein, IPO5, facilitates the nuclear translocation of MSI1 to the transcriptionally silenced XY chromatin domain in meiotic pachytene spermatocytes, resulting in the release of MSI1 RNA-binding targets. This firmly establishes MSI1 as a master regulator of posttranscriptional control during early spermatogenesis and highlights the significance of the subcellular localization of RNA binding proteins in relation to their function. PMID- 25782993 TI - Monitoring phases and phase transitions in phosphatidylethanolamine monolayers using active interfacial microrheology. AB - Active interfacial microrheology is a sensitive tool to detect phase transitions and headgroup order in phospholipid monolayers. The re-orientation of a magnetic nickel nanorod is used to explore changes in the surface rheology of 1,2 dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE) and 1,2-dimyristoyl-sn-glycero 3-phosphoethanolamine (DMPE), which differ by two CH2 groups in their alkyl chains. Phosphatidylethanolamines such as DLPE and DMPE are a major component of cell membranes in bacteria and in the nervous system. At room temperature, DLPE has a liquid expanded (LE) phase for surface pressure, Pi < ~38 mN m(-1); DMPE has an LE phase for Pi < ~7 mN m(-1). In their respective LE phases, DLPE and DMPE show no measurable change in surface viscosity with Pi, consistent with a surface viscosity <10(-9) N s m(-1), the resolution of our technique. However, there is a measurable, discontinuous change in the surface viscosity at the LE to liquid condensed (LC) transition for both DLPE and DMPE. This discontinuous change is correlated with a significant increase in the surface compressibility modulus (or isothermal two-dimensional bulk modulus). In the LC phase of DMPE there is an exponential increase in surface viscosity with Pi consistent with a two-dimensional free area model. The second-order LC to solid (S) transition in DMPE is marked by an abrupt onset of surface elasticity; there is no measurable elasticity in the LC phase. A measurable surface elasticity in the S phase suggests a change in the molecular ordering or interactions of the DMPE headgroups that is not reflected in isotherms or in grazing incidence X-ray diffraction. This onset of measurable elasticity is also seen in DLPE, even though no indication of a LC-S transition is visible in the isotherms. PMID- 25782994 TI - Analysis of Hypodermic Needles and Syringes for the Presence of Blood and Polydimethylsiloxane (Silicone) Utilizing Microchemical Tests and Infrared Spectroscopy. AB - Suspect hypodermic needles and syringes were seized from an unlicensed individual who was allegedly injecting patients with silicone (polydimethylsiloxane [PDMS]) for cosmetic enhancement. Since control syringe barrels and needles often contain an interfering PDMS lubricant, a risk for false positives of foreign PDMS exists. The focus of this report was to minimize this risk and determine a quick and reliable test for the presence of blood in PDMS matrices. Using ATR-FT-IR spectroscopy, the risk for false-positive identification of foreign PDMS was reduced by (i) overfilling the sampling aperture to prevent spectral distortions and (ii) sampling a region of the suspect syringe/needle assembly where manufacturer-applied PDMS is not typically located. Analysis for blood indicated that the Teichman microchemical test was effective for detecting blood in the presence of PDMS. Overall, detecting PDMS established intent and detecting blood established that the needle containing the PDMS had been used for injection. PMID- 25782995 TI - Neurosyphilis and brain magnetic resonance imaging. PMID- 25782996 TI - The effects of epidural anesthesia on growth of Escherichia coli at pseudosurgical site: the roles of the lipocalin-2 pathway. AB - BACKGROUND: Neutrophil-derived lipocalin-2 exerts bacteriostatic effects through retardation of iron uptake by the Gram-negative organisms like Escherichia coli. We tested the hypothesis that the expression of lipocalin-2, a bacteriostatic protein, was upregulated by induction of surgical site infection (SSI) with E coli in healthy and diseased rats and that epidural anesthesia modulated its expression. METHODS: Male Wistar rats were randomized into a healthy or disease group, the latter of which was administered lipopolysaccharide. Both groups were further divided into 3 subgroups, the control, saline, and lidocaine groups: group healthy control (n = 10), healthy saline (n = 10), and healthy lidocaine (n = 10) versus group disease control (n = 15), disease saline (n = 18), and disease lidocaine (n = 19), respectively. While saline was epidurally administered to the control and saline groups, lidocaine was administered to the lidocaine groups. Except for the control groups, E coli was injected to the pseudosurgical site to mimic SSI after abdominal surgery. Plasma concentrations of inflammatory cytokine and lipocalin-2 were measured. At 72 hours, the surgical site tissues were obtained to evaluate mRNA expression of lipocalin-2 and E coli DNA expression. RESULTS: All disease subgroups showed markedly increased plasma inflammatory cytokines versus the healthy subgroups. Among the disease subgroups, plasma concentrations of lipocalin-2 and tissue mRNA expression of lipocalin-2 were significantly increased in group disease lidocaine versus the others. Concurrently, E coli DNA expression in the tissue specimens was also significantly lower in group disease lidocaine as compared with group disease saline. CONCLUSIONS: Epidural anesthesia was associated with an increase in the expression lipocalin-2 and a decrease in the expression of E coli DNA at pseudosurgical sites in sick but not healthy rats. These observations suggest a potential mechanism by which epidural anesthesia could reduce the risk of SSI. PMID- 25782997 TI - INTRAARTERIAL INJECTION OF IODINATED CONTRAST MEDIUM FOR CONTRAST ENHANCED COMPUTED TOMOGRAPHY OF THE EQUINE HEAD. AB - Minimizing the volume of contrast administered for contrast-enhanced computed tomography (CT) of the equine head is desirable for reducing costs and risks of adverse reactions, however evidence-based studies on the effects of varying volumes on image quality are currently lacking. The objective of the current study was to determine whether low-volume intraarterial administration of contrast medium would result in an equivalent image quality and tissue attenuation vs. high-volume intravenous bolus administration. A prospective cross over experimental design was used in a sample of six horses. After anesthetic induction, the right carotid artery was exposed surgically and catheterized. Four CT scans of the cranium were performed for each horse: baseline, immediately following intraarterial contrast injection, five-min postinjection (return to baseline) and a final scan after intravenous contrast administration. Soft tissue attenuation in predetermined regions of interest (ROI); and length, width, and height measurements of the pituitary gland were recorded at each time point. Horses were euthanized and measurements of the pituitary gland were repeated postmortem. No adverse reactions to contrast administration were observed. Intraarterial and intravenous administration of contrast medium resulted in significantly greater soft tissue enhancement of some brain ROI's and the pituitary gland vs. baseline values. Pituitary gland measurements made on postcontrast CT images did not differ from those obtained during postmortem examination. Findings indicated that low-dose intraarterial administration of contrast material in the equine head resulted in comparable soft tissue enhancement vs. high volume intravenous administration. PMID- 25782998 TI - Nematode signaling molecules derived from multimodular assembly of primary metabolic building blocks. AB - In the nematode model organisms Caenorhabditis elegans and Pristionchus pacificus, a new class of natural products based on modular assembly of primary metabolism-derived building blocks control organismal development and behavior. We report identification and biological activities of the first pentamodular metabolite, pasa#9, and the 8-oxoadenine-containing npar#3 from P. pacificus. These structures suggest co-option of nucleoside and tryptophan metabolic pathways for the biosynthesis of endogenous metabolite libraries that transcend the dichotomy between "primary" and "secondary" metabolism. PMID- 25782999 TI - Stress-induced release of GUT peptides in young women classified as restrained or unrestrained eaters. AB - Basal release of GUT peptides has been found to be altered in restrained eaters. Stress-induced secretion, however, has not yet been described, but could be a biological basis of overeating that exposes restrained eaters to a higher risk of becoming obese. The aim of the present study was to compare restrained and unrestrained eaters with respect to stress-induced release of the GUT peptides ghrelin and PYY. 46 young women were studied. Blood sampling for peptides was done before and after the Trier Social Stress Test. Ghrelin secretion after stress was significantly elevated in the restrained eaters, whereas no significant differences were detected for PYY. Stress-induced release of GUT peptides can be interpreted as a cause as well as a consequence of restrained eating. PMID- 25783000 TI - Proteomic analysis of cellular protein expression profiles in response to grass carp reovirus infection. AB - Grass carp (Ctenopharyngodon idella) hemorrhagic disease, caused by grass carp reovirus (GCRV), is emerging as a serious problem in grass carp aquaculture. To better understand the molecular responses to GCRV infection, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization tandem mass spectroscopy were performed to investigate altered proteins in C. idella kidney (CIK) cells. Differentially expressed proteins in mock infected CIK cells and GCRV-infected CIK cells were compared. Twenty-three differentially expressed spots were identified (22 upregulated spots and 1 downregulated spot), which included cytoskeleton proteins, macromolecular biosynthesis-associated proteins, stress response proteins, signal transduction proteins, energy metabolism associated proteins and ubiquitin proteasome pathway-associated proteins. Moreover, 10 of the corresponding genes of the differentially expressed proteins were quantified by real-time reverse transcription polymerase chain reaction to examine their transcriptional profiles. The T cell internal antigen 1 (TIA1) and Ras-GTPase-activating SH3-domain-binding protein1 (G3BP1) of the cellular stress granule pathway from grass carp C. idella (designated as CiTIA1 and CiG3BP1) were upregulated and downregulated during GCRV infection, respectively. The full length cDNA of CiTIA1 was 2753 bp, with an open reading frame (ORF) of 1155bp, which encodes a putative 385-amino acid protein. The 2271 bp full-length cDNA of CiG3BP1 comprised an ORF of 1455 bp that encodes a putative 485-amino acid protein. Phylogenetic analysis revealed that the complete ORFs of CiTIA1 and CiG3BP1 were very similar to zebrafish and well-characterized mammalian homologs. The expressions of the cellular proteins CiTIA1 and CiG3BP1 in response to GCRV were validated by western blotting, which indicated that the GCRV should unlink TIA1 aggregation and stress granule formation. This study provides useful information on the proteomic and cellular stress granule pathway's responses to GCRV infection, which adds to our understanding of viral pathogenesis. PMID- 25783001 TI - Comparative evaluation of infection methods and environmental factors on challenge success: Aeromonas salmonicida infection in vaccinated rainbow trout. AB - When testing vaccine-induced protection an effective and reliable challenge method is a basic requirement and we here present a comparative study on different challenge methods used for infection of rainbow trout Oncorhynchus mykiss with Aeromonas salmonicida, a bacterial pathogen eliciting furunculosis. Fish were vaccinated with three different adjuvanted trivalent vaccines containing formalin killed A. salmonicida, Vibrio anguillarum O1 and O2a. These were 1) the commercial vaccine Alpha Ject 3000, 2) an experimental vaccine with water in paraffin oil adjuvant, 3) an experimental vaccine with water in paraffin oil in water adjuvant. Fish were then exposed to A. salmonicida challenge using i.p. injection, cohabitation in freshwater, cohabitation in saltwater (15 ppt) or combined fresh/saltwater cohabitation. Cohabitation reflects a more natural infection mode and was shown to give better differentiation of vaccine types compared to i.p. injection of live bacteria. The latter infection mode is less successful probably due to the intra-abdominal inflammatory reactions (characterized in this study according to the Speilberg scale) induced by i.p. vaccination whereby injected live bacteria more effectively become inactivated at the site of injection. Compared to cohabitation in freshwater, cohabitation in saltwater was less efficient probably due to reduced survivability of A. salmonicida in saltwater, which was also experimentally verified in vitro. PMID- 25783002 TI - Improvement of immunity and disease resistance in the Nile tilapia, Oreochromis niloticus, by dietary supplementation with Bacillus amyloliquefaciens. AB - Probiotics can be used as immunostimulants in aquaculture. The aim of this study was to evaluate the immune responses of Nile tilapia Oreochromis niloticus following feeding with Bacillus amyloliquefaciens spores at concentrations of 1 * 10(6) (G3) and 1 * 10(4) (G2) colony-forming units per gram (CFU/g) of feed compared with a basal diet with no probiotics (G1). A total of 180 fingerlings (27.7 +/- 0.22 g) were divided into three groups (G1-G3 of 20 fish per group) in triplicate. Innate immunities were measured every two weeks based on serum bactericidal activity, lysozyme activity, a nitric oxide assay (mmo/l) and phagocytic activity, and the expressions of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) were examined after one month. Moreover, the survival of tilapia upon challenge with Yersinia ruckeri or Clostridium perfringens type D was determined at the end of feeding trial. After 15 d, the serum killing percentages and phagocytic activities were significantly higher in G3 than in G1 and G2, whereas the same parameters had significantly higher values in G3 and G2 than in G1 after 30 d. After both 15 d and 30 d, the lysozyme activities and nitric oxide assay results (mmo/l) were significantly higher in G3 than G2, and the lowest values were observed in G1. The percentage of serum killing, serum nitric oxide and serum lysozyme activity were significantly increased by the time of B. amyloliquefaciens administration independently of the probiotic dose, and the phagocytic activity percentage was significantly decreased at the end of the experiment. Dietary B. amyloliquefaciens caused significant increases in IL-1 and TNF alpha mRNA levels in the kidneys in the following pattern: G3 > G2 > G1. Fish that were fed B. amyloliquefaciens exhibited better relative survival percentages than the controls when challenged by Y. ruckeri or C. perfringens type D. Dietary supplementation with B. amyloliquefaciens improves immune status and disease resistance in Nile tilapia. PMID- 25783004 TI - Hospital Community Benefit in the Context of the Larger Public Health System: A State-Level Analysis of Hospital and Governmental Public Health Spending Across the United States. AB - CONTEXT: Achieving meaningful population health improvements has become a priority for communities across the United States, yet funding to sustain multisector initiatives is frequently not available. One potential source of funding for population health initiatives is the community benefit expenditures that are required of nonprofit hospitals to maintain their tax-exempt status. OBJECTIVE: In this article, we explore the importance of nonprofit hospitals' community benefit dollars as a funding source for population health. DESIGN: Hospitals' community benefit expenditures were obtained from their 2009 IRS (Internal Revenue Service) Form 990 Schedule H and complemented with data on state and local public health spending from the Association of State and Territorial Health Officials and the National Association of County & City Health Officials. Key measures included indicators of hospitals' community health spending and governmental public health spending, all aggregated to the state level. Univariate and bivariate statistics were used to describe how much hospitals spent on programs and activities for the community at large and to understand the relationship between hospitals' spending and the expenditures of state and local health departments. RESULTS: Tax-exempt hospitals spent a median of $130 per capita on community benefit activities, of which almost $11 went toward community health improvement and community-building activities. In comparison, median state and local health department spending amounted to $82 and $48 per capita, respectively. Hospitals' spending thus contributed an additional 9% to the resources available for population health to state and local health departments. Spending, however, varied widely by state and was unrelated to governmental public health spending. Moreover, adding hospitals' spending to the financial resources available to governmental public health agencies did not reduce existing inequalities in population health funding across states. CONCLUSIONS: Hospitals' community health investments represent an important source for public health activities, yet inequalities in the availability of funding across communities remain. PMID- 25783003 TI - Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1. AB - BACKGROUND: The Activity-regulated cytoskeleton-associated protein, Arc, is an immediate-early gene product implicated in various forms of synaptic plasticity. Arc promotes endocytosis of AMPA type glutamate receptors and regulates cytoskeletal assembly in neuronal dendrites. Its role in endocytosis may be mediated by its reported interaction with dynamin 2, a 100 kDa GTPase that polymerizes around the necks of budding vesicles and catalyzes membrane scission. METHODS: Enzymatic and turbidity assays are used in this study to monitor effects of Arc on dynamin activity and polymerization. Arc oligomerization is measured using a combination of approaches, including size exclusion chromatography, sedimentation analysis, dynamic light scattering, fluorescence correlation spectroscopy, and electron microscopy. RESULTS: We present evidence that bacterially-expressed His6-Arc facilitates the polymerization of dynamin 2 and stimulates its GTPase activity under physiologic conditions (37 degrees C and 100mM NaCl). At lower ionic strength Arc also stabilizes pre-formed dynamin 2 polymers against GTP-dependent disassembly, thereby prolonging assembly-dependent GTP hydrolysis catalyzed by dynamin 2. Arc also increases the GTPase activity of dynamin 3, an isoform of implicated in dendrite remodeling, but does not affect the activity of dynamin 1, a neuron-specific isoform involved in synaptic vesicle recycling. We further show in this study that Arc (either His6-tagged or untagged) has a tendency to form large soluble oligomers, which may function as a scaffold for dynamin assembly and activation. CONCLUSIONS AND GENERAL SIGNIFICANCE: The ability of Arc to enhance dynamin polymerization and GTPase activation may provide a mechanism to explain Arc-mediated endocytosis of AMPA receptors and the accompanying effects on synaptic plasticity. PMID- 25783005 TI - Erratum to: Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia. PMID- 25783007 TI - The metabolic syndrome is an important concept in therapeutic decision-making. AB - Traditional risk factors can underestimate the true risk of developing atherosclerotic cardiovascular disease. Abdominal obesity is associated with a cluster of risk factors that include dyslipidemia, dysglycemia, and hypertension, termed metabolic syndrome (MS). The presence of MS increases cardiovascular risk 50%-100% beyond that defined according to traditional risk factors, and increases the risk of developing type 2 diabetes. Recognition of patients with MS is important to: (1) identify patients at increased risk beyond that conveyed by traditional risk factors; and (2) understand that the metabolic abnormalities associated with MS are largely reversed by measures that reduce abdominal obesity. PMID- 25783006 TI - An actin filament population defined by the tropomyosin Tpm3.1 regulates glucose uptake. AB - Actin has an ill-defined role in the trafficking of GLUT4 glucose transporter vesicles to the plasma membrane (PM). We have identified novel actin filaments defined by the tropomyosin Tpm3.1 at glucose uptake sites in white adipose tissue (WAT) and skeletal muscle. In Tpm 3.1-overexpressing mice, insulin-stimulated glucose uptake was increased; while Tpm3.1-null mice they were more sensitive to the impact of high-fat diet on glucose uptake. Inhibition of Tpm3.1 function in 3T3-L1 adipocytes abrogates insulin-stimulated GLUT4 translocation and glucose uptake. In WAT, the amount of filamentous actin is determined by Tpm3.1 levels and is paralleled by changes in exocyst component (sec8) and Myo1c levels. In adipocytes, Tpm3.1 localizes with MyoIIA, but not Myo1c, and it inhibits Myo1c binding to actin. We propose that Tpm3.1 determines the amount of cortical actin that can engage MyoIIA and generate contractile force, and in parallel limits the interaction of Myo1c with actin filaments. The balance between these actin filament populations may determine the efficiency of movement and/or fusion of GLUT4 vesicles with the PM. PMID- 25783008 TI - Ischemic preconditioning inhibits expression of Na(+)/H(+) exchanger 1 (NHE1) in the gerbil hippocampal CA1 region after transient forebrain ischemia. AB - The participation of Na(+)/H(+) exchanger (NHE) in neuronal damage/death in the hippocampal CA1 region (CA1) induced by transient forebrain ischemia has not been well established, although acidosis may be involved in neuronal damage/death. In the present study, we examined the effect of ischemic preconditioning (IPC) on NHE1 immunoreactivity following a 5min of transient forebrain ischemia in gerbils. The animals used in the study were randomly assigned to four groups (sham-operated-group, ischemia-operated-group, IPC plus (+) sham-operated-group and IPC+ischemia-operated-group). IPC was induced by subjecting animals to 2min of ischemia followed by 1day of recovery. A significant neuronal loss was found in the stratum pyramidale (SP) of the CA1, not the CA2/3, of the ischemia operated-group at 5days post-ischemia. However, in the IPC+ischemia-operated group, neurons in the SP of the CA1 were well protected. NHE1 immunoreactivity was not detected in any regions of the CA1-3 of the sham- and IPC+sham-operated groups. However, the immunoreactivity was apparently expressed in the SP of the CA1-3 after ischemia, and the NHE1immunoreactivity was very weak 5days after ischemia; however, at this point in time, strong NHE1immunoreactivity was found in astrocytes in the CA1. In the CA2/3, NHE1immunoreactivity was slightly changed, although NHE1immunoreactivity was expressed in the SP. In the IPC+ischemia-operated-groups, NHE1 immunoreactivity was also expressed in the SP of the CA1-3; however, the immunoreactivity was more slightly changed than that in the ischemia-operated-groups. In brief, our findings show that IPC dramatically protected CA1 pyramidal neurons and strongly inhibited NHE1 expression in the SP of the CA1 after ischemia-reperfusion. These findings suggest that the inhibition of NHE1 expression may be necessary for neuronal survival from transient ischemic damage. PMID- 25783009 TI - Early fibrinogen degradation coagulopathy: a predictive factor of parenchymal hematomas in cerebral rt-PA thrombolysis. AB - BACKGROUND AND PURPOSE: The purpose of this study was to systematically determine the correlations between the post-thrombolytic changes of hemostasis parameters and the occurrence of early intracerebral hemorrhage (ICH). METHODS: In 72 consecutive patients with cerebral infarcts treated with rt-PA, plasma levels of fibrinogen, plasminogen, alpha2-antiplasmin, factor XIII, fibrin(ogen) degradation products (FDPs) and d-Dimers were measured at baseline, 2 and 24h after thrombolysis. Correlations were studied between the hemostasis events and early (less than 24h) hemorrhagic infarcts (HIs) or parenchymatous hematomas (PH). RESULTS: Of 72 patients, 6 patients (8.3%) had early PHs, 11 (15.3%) had early HIs, and 55 (76.4%) had no bleeding. Early HIs were not linked to any hemostasis parameter at any time. Univariate comparison of patients having early PHs with non-bleeding patients showed hemostasis abnormalities at 2h: high FDP (p=0.01), high Log FDP (p=0.01), low fibrinogen (p=0.01), and low Log fibrinogen (p=0.01). Logistic regression adjusted for age, NIHSS and diabetes confirmed these 2hour predictors: Log FDP (OR: 7.50; CI: 1.26 to 44.61, p=0.03), and Log fibrinogen (OR: 19.32; CI: 1.81 to 205.98, p=0.01). The decrease in fibrinogen less than 2g/L multiplies the odds of early PH by a factor 12.82. CONCLUSION: An early fibrinogen degradation coagulopathy involving an increase of FDP and a massive consumption of circulating fibrinogen is predictive of early parenchymal hematomas, indicating the occurrence of a particularly intense lysis of circulating fibrinogen. These results, if confirmed by future studies, suggest that early assays of fibrinogen and FDP may be useful in predicting the risk of post-thrombolytic intracerebral hematoma. PMID- 25783010 TI - Increased interhemispheric resting-state functional connectivity in paroxysmal kinesigenic dyskinesia: a resting-state fMRI study. AB - PURPOSE: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder. The underlying neural mechanisms have not been fully understood. This study aimed to examine the alteration of resting-state functional connectivity (RSFC) between interhemispheric homotopic regions in PKD using a technique called "voxel mirrored homotopic connectivity" (VMHC). METHODS: The VMHC analysis was performed on resting-state functional MRI data from 11 PKD patients and 17 age and gender matched healthy subjects. Comparison between the two groups was conducted. The correlation relationship between VMHC and illness duration was analyzed. RESULTS: Compared with healthy subjects, PKD patients showed increased interhemispheric RSFC in bilateral putamen, primary motor cortex, supplementary motor area, dorsal lateral prefrontal cortex, primary somatosensory cortex, superior and middle occipital gyri, as well as cerebellar tonsil. Besides, negative correlation was detected between illness duration and VMHC in bilateral putamen and the insular cortex. CONCLUSION: The present study provided preliminary evidence of increased interhemispheric RSFC in PKD mainly in the basal ganglia-thalamo-cortical circuitry and cerebellum. A negative correlation between VMHC and illness duration was also detected. These findings could further enhance our understandings of the pathophysiology of PKD. PMID- 25783012 TI - Idiopathic Juvenile Osteoporosis: Clinical Experience from a Single Centre and Screening of LRP5 and LRP6 Genes. AB - We report clinical findings, bone mineral density (BMD) and bone biopsy data in ten children with features of classic idiopathic juvenile osteoporosis (IJO). We also screened the patients for mutations in LRP5 and LRP6. We found low BMD in the lumbar spine, the hip and distal radius. In the spine and distal radius, the reduction in BMD was more marked in the trabecular compartment. Biopsy confirmed that the trabecular compartment is more severely involved with reduction in bone formation and increase in bone resorption. No mutations in LRP5 and LRP6 could be identified. IJO is likely to be a heterogeneous bone disorder, and next generation genomic sequencing studies may help reveal causative genes. PMID- 25783013 TI - Validated spectrofluorimetric method for the determination of carbamazepine in pharmaceutical dosage forms after reaction with 4-chloro-7--nitrobenzo-2-oxa-1,3 diazole (NBD-Cl). AB - A sensitive and simple spectrofluorimetric method has been developed and validated for the determination of the anti-epileptic drug carbamazepine (CBZ) in its dosage forms. The method was based on a nucleophilic substitution reaction of CBZ with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) in borate buffer (pH 9) to form a highly fluorescent derivative that was measured at 530 nm after excitation at 460 nm. Factors affecting the formation of the reaction product were studied and optimized, and the reaction mechanism was postulated. The fluorescence-concentration plot is rectilinear over the range of 0.6-8 ug/mL with limit of detection of 0.06 ug/mL and limit of quantitation of 0.19 ug/mL. The method was applied to the analysis of commercial tablets and the results were in good agreement with those obtained using the reference method. Validation of the analytical procedures was evaluated according to ICH guidelines. PMID- 25783011 TI - The Role of Water Compartments in the Material Properties of Cortical Bone. AB - Comprising ~20% of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in two general compartments: within pores and bound to the matrix. The amount of pore water-residing in the vascular-lacunar-canalicular space-primarily reflects intracortical porosity (i.e., open spaces within the matrix largely due to Haversian canals and resorption sites) and as such is inversely proportional to most mechanical properties of bone. Movement of water according to pressure gradients generated during dynamic loading likely confers hydraulic stiffening to the bone as well. Nonetheless, bound water is a primary contributor to the mechanical behavior of bone in that it is responsible for giving collagen the ability to confer ductility or plasticity to bone (i.e., allows deformation to continue once permanent damage begins to form in the matrix) and decreases with age along with fracture resistance. Thus, dehydration by air-drying or by solvents with less hydrogen bonding capacity causes bone to become brittle, but interestingly, it also increases stiffness and strength across the hierarchical levels of organization. Despite the importance of matrix hydration to fracture resistance, little is known about why bound water decreases with age in hydrated human bone. Using (1)H nuclear magnetic resonance (NMR), both bound and pore water concentrations in bone can be measured ex vivo because the proton relaxation times differ between the two water compartments, giving rise to two distinct signals. There are also emerging techniques to measure bound and pore water in vivo with magnetic resonance imaging (MRI). The NMR/MRI-derived bound water concentration is positively correlated with both the strength and toughness of hydrated bone and may become a useful clinical marker of fracture risk. PMID- 25783014 TI - Influence of molecular structure on physicochemical properties and digestibility of normal rice starches. AB - Normal rice starches were isolated from six different rice varieties grown in Korea and their molecular structure, crystalline structure, and in vitro digestibility were investigated. Apparent amylose content was the highest in starch from Junam cultivar (25.5%) and lowest in Hopum (22.4%). Starch from Hiami cultivar had the lowest molecular weights of amylose and amylopectin, average amylopectin chain length, proportion of short chains (DP 6-12), and proportion of long chains (DP>=37) among the tested rice starches. The relative crystallinity and ratio of 1047/1022 ranged from 30.2 to 36.7% and from 0.638 to 0.652, respectively. Hiami had the lowest gelatinization temperatures and the highest gelatinization enthalpy. Hiami had the highest pasting temperature (92.1 degrees C), the lowest setback (515cP) and final viscosity (876cP), whereas Hanareum had the lowest pasting temperature (82.7 degrees C), the highest setback (1002cP), and final viscosity (1580cP). The rapidly digestible starch (RDS), slowly digestible starch (SDS), and resistant starch (RS) content ranged from 43.9 53.5%, 35.5-52.6%, and 0.5-15.6%, respectively. The Junam cultivar had the lowest RDS content, whereas Hiami had the highest RDS content. The RS content of Hanareum (16.2%) and Boramchan (14.5%) was significantly higher than that of other normal rice cultivars (3.0-6.5%). PMID- 25783015 TI - Protection of turmeric plants from rhizome rot disease under field conditions by beta-D-glucan nanoparticle. AB - The rhizome rot caused by Pythium aphanidermatum is one of the most devastating diseases of the turmeric crop. Fungicides are unable to control the rapidly evolving P. aphanidermatum and new control strategies are urgently needed. This study examined the effect of beta-d-glucan nanoparticles (GNP) in turmeric plants under field condition by the foliar spray method. Enhanced plant growth, rhizome yield, and curcumin content demonstrate the positive effect of the GNP on turmeric plants. Rapid activation of various defense enzymes was also observed in leaves and rhizomes of treated plants. GNP-treated plants showed a decreased rot incidence. It may be possible that increased defense enzymes might have played a role in reducing the colonization of pathogen. PMID- 25783016 TI - Preparation and characterization of N-benzoyl-O-acetyl-chitosan. AB - A novel amphipathic chitosan derivative, N-benzoyl-O-acetyl-chitosan (BACS), was prepared by using the selective partial acylation of chitosan (CS), benzoyl chloride, and acetic acid under high-intensity ultrasound. The chemical structure and physical properties of BACS were characterized by FTIR, (1)H NMR, TGA, and XRD techniques. The degrees of substitution of benzoyl and acetyl for the chitosan derivatives were 0.26 and 1.15, respectively, which were calculated from the peak areas in NMR spectra by using the combined integral methods. The foaming properties of CS and BACS were determined and the results suggested BACS had better foam capacity and stability than those of chitosan. In addition, the antimicrobial activities of CS and BACS were also investigated against two species of bacteria (Escherichia coli and Staphylococcus aureus) and a fungus (Aspergillus niger), the results indicated that the antibacterial and antifungal activities of BACS were much stronger than those of the parent chitosan. These findings suggested that BACS was preferable for use as a food additive with a dual role of both foaming agent and food preservative. PMID- 25783017 TI - Extraction, characterization and antioxidant activities of Se-enriched tea polysaccharides. AB - Se-polysaccharides from Se-enriched tea leaves were purified by DEAE-sepharose fast flow gel column (2.5*60cm) and three polysaccharide fractions (Se-TPS1, Se TPS2, and Se-TPS3) were isolated and purified with yields of 6.5, 37.14, and 8.57%, respectively. The average sizes of Se-TPS1 and Se-TPS2 were determined by HPGPC system, with molecular weights of 1.1*10(5) and 2.4*10(5)Da, respectively. Se-TPS3 was a polysaccharide polymer with two peaks with molecular weights of 9.2*10(5) and 2.5*10(5)Da. Monosaccharide components analysis by ion chromatography revealed Se-polysaccharides were acidic polysaccharoses and different from each other in monosaccharide kinds and molar ratio. Elements of Se, C, H, N, S, and 14 kinds of mineral elements were analyzed by AFS, EA, and ICP-AES, respectively. Spectral analysis (IR and UV) indicated Se-polysaccharides were typical glycoproteins. Morphological analyses of the samples were determined by SEM and AFM. In addition, the DPPH and superoxide radicals scavenging activities were also discussed to assess antioxidant activities of the samples, and Se-polysaccharides showed higher antioxidant activities compared to the ordinary polysaccharides. PMID- 25783018 TI - Marine-derived biological macromolecule-based biomaterials for wound healing and skin tissue regeneration. AB - Wound healing is a complex biological process that depends on the wound condition, the patient's health, and the physicochemical support given through external materials. The development of bioactive molecules and engineered tissue substitutes to provide physiochemical support to enhance the wound healing process plays a key role in advancing wound-care management. Thus, identification of ideal molecules in wound treatment is still in progress. The discovery of natural products that contain ideal molecules for skin tissue regeneration has been greatly advanced by exploration of the marine bioenvironment. Consequently, tremendously diverse marine organisms have become a great source of numerous biological macromolecules that can be used to develop tissue-engineered substitutes with wound healing properties. This review summarizes the wound healing process, the properties of macromolecules from marine organisms, and the involvement of these molecules in skin tissue regeneration applications. PMID- 25783019 TI - Structural characterization and immunostimulating activity of a levan-type fructan from Curcuma kwangsiensis. AB - A fructan designated as CKNP with apparent molecular weight of 5.3kD was isolated from the hot water extract of Curcuma kwangsiensis through a combination of ion exchange chromatography on DEAE 650M and gel filtration on Superdex G-200. CKNP was characterized by chemical derivatization as well as HPLC, GC, and GC-MS technologies. Structural studies revealed that CKNP is composed predominately of fructose (96.8%) and a small amount of glucose (3.2%) with a degree of polymerization (DP) of 30-31. It was deduced to be a levan-type fructan containing a backbone composed of (2->6)-linked beta-d-Fruf residues and single beta-d-Fruf residues as side chains branched at the O-1 position along the backbone. Preliminary in vitro bioactive tests on RAW 264.7 murine macrophage cells revealed that the levan-type fructan from C. kwangsiensis shows significant immunostimulating activity based on its ability to stimulate macrophage proliferation and enhance phagocytosis. PMID- 25783020 TI - Role of 13-(di)phenylalkyl berberine derivatives in the modulation of the activity of human topoisomerase IB. AB - Topoisomerases IB are anticancer and antimicrobial targets whose inhibition by several natural and non-natural compounds has been documented. The inhibition effect by berberine and some 13-(di)phenylalkyl berberine derivatives has been tested towards human topoisomerase IB. Derivatives belonging to the 13 diphenylalkyl series display an efficient inhibition of the DNA relaxation and cleavage step, that increases upon pre-incubation with the enzyme. The religation step of the enzyme catalytic cycle is not affected by compounds and only slightly upon pre-incubation. The binding of the protein to the DNA substrate occurs also in the presence of the compounds, as monitored by a DNA shift assay, indicating that the compounds are not able to inhibit the formation of the enzyme-DNA complex but that they act as catalytic inhibitors. PMID- 25783021 TI - Knee osteoarthritis: Clinical connections to articular cartilage structure and function. AB - Articular cartilage is a unique biphasic material that supports a lifetime of compressive and shear forces across joints. When articular cartilage deteriorates, whether due to injury, wear and tear or normal aging, osteoarthritis and resultant pain can ensue. Understanding the basic science of the structure and biomechanics of articular cartilage can help clinicians guide their patients to appropriate activity and loading choices. The purpose of this article is to examine how articular cartilage structure and mechanics, may interact with risk factors to contribute to OA and how this interaction provides guidelines for intervention choices This paper will review the microstructure of articular cartilage, its mechanical properties and link this information to clinical decision making. PMID- 25783023 TI - Exciton binding energy of monolayer WS2. AB - The optical properties of monolayer transition metal dichalcogenides (TMDC) feature prominent excitonic natures. Here we report an experimental approach to measuring the exciton binding energy of monolayer WS2 with linear differential transmission spectroscopy and two-photon photoluminescence excitation spectroscopy (TP-PLE). TP-PLE measurements show the exciton binding energy of 0.71 +/- 0.01 eV around K valley in the Brillouin zone. PMID- 25783022 TI - A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD. AB - Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a short-term mouse model that reproduced the hallmark features of RV-induced exacerbation of COPD. Evaluation of complex protocols involving multiple dose elastase and lipopolysaccharide (LPS) administration combined with RV1B infection showed suppression rather than enhancement of inflammatory parameters compared with control mice infected with RV1B alone. Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects. In contrast, a single elastase treatment followed by RV infection led to heightened airway neutrophilic and lymphocytic inflammation, increased expression of tumour necrosis factor (TNF) alpha, C-X-C motif chemokine 10 (CXCL10)/IP-10 (interferon gamma-induced protein 10) and CCL5 [chemokine (C-C motif) ligand 5]/RANTES (regulated on activation, normal T-cell expressed and secreted), mucus hypersecretion and preliminary evidence for increased airway hyper-responsiveness compared with mice treated with elastase or RV infection alone. In summary, we have developed a new mouse model of RV-induced COPD exacerbation that mimics many of the inflammatory features of human disease. This model, in conjunction with human models of disease, will provide an essential tool for studying disease mechanisms and allow testing of novel therapies with potential to be translated into clinical practice. PMID- 25783024 TI - Impact of resection margin status on outcome after salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to present the postoperative local tumor control and survival with regard to the different resection margin statuses during salvage nasopharyngectomy. METHODS: We conducted a whole-organ study of nasopharyngectomy specimens. RESULTS: Between 2005 and 2010, 126 patients underwent maxillary swing nasopharyngectomy. The T classification of the recurrent tumor was: T1, 23.8%; T2, 41.3%; T3, 28.6%; and T4, 6.3%. The chance of clear, close, and involved resection margins at nasopharyngectomy was 44.4%, 31.0%, and 24.6%, respectively. At follow-up, the corresponding risk of local tumor recurrence after surgery was 10.7%, 38.5%, and 67.7%, respectively. The local tumor control was significantly worse in patients with involved margins compared with those with close margins (p = .01), which was, in turn, significantly worse than those with clear margins (p = .04). CONCLUSION: The primary objective of salvage nasopharyngectomy is to achieve clear resection margins. Close and involved margins result in significantly inferior local tumor control and overall survival. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E594 E599, 2016. PMID- 25783025 TI - Renal cell carcinoma in patients with end-stage renal disease is associated with more favourable histological features and prognosis. AB - OBJECTIVE: End-stage renal disease (ESRD) patients with acquired cystic kidney disease are at higher risk of developing renal cell carcinoma (RCC) than the general population. The aim of this study was to investigate the clinical and histopathological differences between ESRD patients and the general population with RCC. MATERIALS AND METHODS: Data were retrospectively collected from all nephrectomies performed for localized RCC from 2000 to 2010. Age at nephrectomy, gender, race, symptoms, baseline Eastern Cooperative Oncology Group (ECOG) performance status, Charlson Comorbidity Index score and histological data were extracted. Independent-samples t test and Mann-Whitney test were used for quantitative data, while chi-squared (two-sided) and Fisher's exact tests were used for qualitative data. RESULTS: This study included 627 patients: 73 with and 554 without ESRD. The majority of patients were Chinese. The male to female ratio of 2:1 was identical in both groups. Baseline ECOG performance status and Charlson Comorbidity score were higher in the ESRD group. RCC in ESRD patients was more frequently asymptomatic (56.2% vs 44.9%, p = 0.071), diagnosed earlier (53.6 +/- 11.8 years vs 57.9 +/- 12.2 years, p = 0.004) and of lower stage (p < 0.001). The ESRD cohort had a higher proportion of the papillary histological subtype (21.9% vs 9.7%, p < 0.001). Importantly, there was a trend towards more favourable outcomes in ESRD patients in terms of cancer-specific (p = 0.203) and relapse-free survival (p = 0.096). CONCLUSION: This study suggests that RCC in ESRD patients is associated with more favourable clinical and histological features and oncological outcome compared with that in patients with normal renal function. PMID- 25783027 TI - The Potential of Cosmetic Applicators as a Source of DNA for Forensic Analysis. AB - Personal products, such as toothbrushes, have been used as both known reference and evidentiary samples for forensic DNA analysis. This study examined the viability of a broad selection of cosmetic applicators for use as targets for human DNA extraction and short tandem repeat (STR) analysis using standard polymerase chain reaction (PCR) conditions. Applicator types included eyeliner smudgers, pencils and crayons, eye shadow sponges, mascara wands, concealer wands, face makeup sponges, pads and brushes, lipsticks and balms, and lip gloss wands. The quantity and quality of DNA extracted from each type of applicator were examined by assessing the number of loci successfully amplified and the peak balance of the heterozygous alleles in each full STR profile. While degraded DNA, stochastic amplification, and PCR inhibition were observed for some items, full STR profiles were developed for 14 of 76 applicators. The face makeup sponge applicators yielded the highest proportional number of full STR profiles (4/7). PMID- 25783026 TI - Establishment of Salvia castanea Diels f. tomentosa Stib. hairy root cultures and the promotion of tanshinone accumulation and gene expression with Ag+, methyl jasmonate, and yeast extract elicitation. AB - Salvia castanea Diels f. tomentosa Stib. is an endemic medicinal plant distributed in China, and the notably high content of tanshinone IIA in the root is proven effective for the therapy of heart diseases. Hairy root induction of this Salvia species was inoculated with Agrobacterium rhizogenes strain ATCC 15834. Transformed hairy root was cultured in 6,7-V liquid medium for growth kinetics assessment and elicitation. An S curve was present in the hairy root cultures based on the fresh and dry weights with an interval of 3 days. An optimum concentration of the applied elicitors (15 MUM Ag(+), 200 MUM methyl jasmonate, and 200 mg l(-1) yeast extract elicitor) benefitted both the growth status and tanshinone accumulation in the hairy root cultures. Tanshinone IIA contents were mostly stimulated 1.8-fold and 1.99-fold compared with the control by Ag(+) and methyl jasmonate elicitation, respectively. Yeast extract dramatically enhanced dry mass accumulation, while it promoted cryptotanshinone content of 2.84 +/- 0.33 mg g(-1) dry weight at most in the hairy root cultures. Selected elicitors diversely influenced tanshinone accumulation in the time courses of hairy root cultures within 7 days. Furthermore, transcripts of selected genes in the tanshinone biosynthetic pathway were remarkably upregulated with elicitation. Yeast extract elicitor heightened 13.9-fold of isopentenyl diphosphate isomerase expression level at 12 h, while it increased 16.7-fold of geranylgeranyl diphosphate synthase transcript at 24 h compared with that of the control, which was more effective than Ag(+) and methyl jasmonate. This study provided a convenient hairy root culture system of S. castanea Diels f. tomentosa Stib. for tanshinone production for the first time. PMID- 25783028 TI - DENEDDYLASE1 deconjugates NEDD8 from non-cullin protein substrates in Arabidopsis thaliana. AB - The evolutionarily conserved 8-kD protein NEDD8 (NEURAL PRECURSOR CELL EXPRESSED, DEVELOPMENTALLY DOWN-REGULATED8) belongs to the family of ubiquitin-like modifiers. Like ubiquitin, NEDD8 is conjugated to and deconjugated from target proteins. Many targets and functions of ubiquitylation have been described; by contrast, few targets of NEDD8 have been identified. In plants as well as in non plant organisms, the cullin subunits of cullin-RING E3 ligases are NEDD8 conjugates with a demonstrated functional role for the NEDD8 modification. The existence of other non-cullin NEDD8 targets has generally been questioned. NEDD8 is translated as a precursor protein and proteolytic processing exposes a C terminal glycine required for NEDD8 conjugation. In animals and yeast, DENEDDYLASE1 (DEN1) processes NEDD8. Here, we show that mutants of a DEN1 homolog from Arabidopsis thaliana have no detectable defects in NEDD8 processing but do accumulate a broad range of NEDD8 conjugates; this provides direct evidence for the existence of non-cullin NEDD8 conjugates. We further identify AUXIN RESISTANT1 (AXR1), a subunit of the heterodimeric NEDD8 E1 activating enzyme, as a NEDD8-modified protein in den1 mutants and wild type and provide evidence that AXR1 function may be compromised in the absence of DEN1 activity. Thus, in plants, neddylation may serve as a regulatory mechanism for cullin and non-cullin proteins. PMID- 25783030 TI - Correction. Auxin depletion from the leaf axil conditions competence for axillary meristem formation in Arabidopsis and tomato. PMID- 25783029 TI - Transcription factors SOD7/NGAL2 and DPA4/NGAL3 act redundantly to regulate seed size by directly repressing KLU expression in Arabidopsis thaliana. AB - Although seed size is one of the most important agronomic traits in plants, the genetic and molecular mechanisms that set the final size of seeds are largely unknown. We previously identified the ubiquitin receptor DA1 as a negative regulator of seed size, and the Arabidopsis thaliana da1-1 mutant produces larger seeds than the wild type. Here, we describe a B3 domain transcriptional repressor NGATHA-like protein (NGAL2), encoded by the suppressor of da1-1 (SOD7), which acts maternally to regulate seed size by restricting cell proliferation in the integuments of ovules and developing seeds. Overexpression of SOD7 significantly decreases seed size of wild-type plants, while the simultaneous disruption of SOD7 and its closest homolog DEVELOPMENT-RELATED PcG TARGET IN THE APEX4 (DPA4/NGAL3) increases seed size. Genetic analyses indicate that SOD7 and DPA4 act in a common pathway with the seed size regulator KLU to regulate seed growth, but do so independently of DA1. Further results show that SOD7 directly binds to the promoter of KLUH (KLU) in vitro and in vivo and represses the expression of KLU. Therefore, our findings reveal the genetic and molecular mechanisms of SOD7, DPA4, and KLU in seed size regulation and suggest that they are promising targets for seed size improvement in crops. PMID- 25783032 TI - Correction. Arabidopsis RNA-dependent RNA polymerases and dicer-like proteins in antiviral defense and small interfering RNA biogenesis during Turnip mosaic virus infection. PMID- 25783031 TI - RNA sequencing of laser-capture microdissected compartments of the maize kernel identifies regulatory modules associated with endosperm cell differentiation. AB - Endosperm is an absorptive structure that supports embryo development or seedling germination in angiosperms. The endosperm of cereals is a main source of food, feed, and industrial raw materials worldwide. However, the genetic networks that regulate endosperm cell differentiation remain largely unclear. As a first step toward characterizing these networks, we profiled the mRNAs in five major cell types of the differentiating endosperm and in the embryo and four maternal compartments of the maize (Zea mays) kernel. Comparisons of these mRNA populations revealed the diverged gene expression programs between filial and maternal compartments and an unexpected close correlation between embryo and the aleurone layer of endosperm. Gene coexpression network analysis identified coexpression modules associated with single or multiple kernel compartments including modules for the endosperm cell types, some of which showed enrichment of previously identified temporally activated and/or imprinted genes. Detailed analyses of a coexpression module highly correlated with the basal endosperm transfer layer (BETL) identified a regulatory module activated by MRP-1, a regulator of BETL differentiation and function. These results provide a high resolution atlas of gene activity in the compartments of the maize kernel and help to uncover the regulatory modules associated with the differentiation of the major endosperm cell types. PMID- 25783033 TI - Exploration-exploitation strategy is dependent on early experience. AB - Traditional conceptualizations of early adversity characterize behavioral outcomes as maladaptive. However, conditional adaptation theory proposes that differing behavioral phenotypes following early experience are appropriate for the expected environment (e.g., behaviors likely to result in the best outcome based on environmental expectations). In the present study, youth with (n = 46) and without (n = 91) a history of previous institutionalization completed a laboratory-based experimental paradigm in which exploration-exploitation strategy was examined, a phenotype relevant to environmental expectations. Previous institutionalization was associated with decreased exploration and increased exploitation. A strategy favoring exploration resulted in greater success in the generous task condition whereas a strategy favoring exploitation produced greater success in the restricted task condition. These results suggest that exploration exploitation strategy may be influenced by early experience, and the resulting success of strategy choice is context dependent and in line with expectations of the future environment based on early experience. PMID- 25783034 TI - Secondary-ion mass spectrometry of genetically encoded targets. AB - Secondary ion mass spectrometry (SIMS) is generally used in imaging the isotopic composition of various materials. It is becoming increasingly popular in biology, especially for investigations of cellular metabolism. However, individual proteins are difficult to identify in SIMS, which limits the ability of this technology to study individual compartments or protein complexes. We present a method for specific protein isotopic and fluorescence labeling (SPILL), based on a novel click reaction with isotopic probes. Using this method, we added (19) F enriched labels to different proteins, and visualized them by NanoSIMS and fluorescence microscopy. The (19) F signal allowed the precise visualization of the protein of interest, with minimal background, and enabled correlative studies of protein distribution and cellular metabolism or composition. SPILL can be applied to biological systems suitable for click chemistry, which include most cell-culture systems, as well as small model organisms. PMID- 25783035 TI - pH-responsive lyotropic liquid crystals and their potential therapeutic role in cancer treatment. AB - A weak amphiphilic base, pyridinylmethyl linoleate, is blended with monolinolein, yielding mesophases with a pH-induced hexagonal-to-cubic transition at pH <= 5.5. We show the potential therapeutic role of this mesophase in treating cancerous tissues exploiting their more acidic pH compared to healthy tissues. In vitro release studies with doxorubicin on HT29 human colon cancer cells show a 10-fold faster release and 3-fold increased efficiency for killing cancer cells at pH 5.5 versus pH 7.4, demonstrating the potential of this strategy in cancer treatment. PMID- 25783036 TI - eHealth literacy and Web 2.0 health information seeking behaviors among baby boomers and older adults. AB - BACKGROUND: Baby boomers and older adults, a subset of the population at high risk for chronic disease, social isolation, and poor health outcomes, are increasingly utilizing the Internet and social media (Web 2.0) to locate and evaluate health information. However, among these older populations, little is known about what factors influence their eHealth literacy and use of Web 2.0 for health information. OBJECTIVE: The intent of the study was to explore the extent to which sociodemographic, social determinants, and electronic device use influences eHealth literacy and use of Web 2.0 for health information among baby boomers and older adults. METHODS: A random sample of baby boomers and older adults (n=283, mean 67.46 years, SD 9.98) participated in a cross-sectional, telephone survey that included the eHealth literacy scale (eHEALS) and items from the Health Information National Trends Survey (HINTS) assessing electronic device use and use of Web 2.0 for health information. An independent samples t test compared eHealth literacy among users and non-users of Web 2.0 for health information. Multiple linear and logistic regression analyses were conducted to determine associations between sociodemographic, social determinants, and electronic device use on self-reported eHealth literacy and use of Web 2.0 for seeking and sharing health information. RESULTS: Almost 90% of older Web 2.0 users (90/101, 89.1%) reported using popular Web 2.0 websites, such as Facebook and Twitter, to find and share health information. Respondents reporting use of Web 2.0 reported greater eHealth literacy (mean 30.38, SD 5.45, n=101) than those who did not use Web 2.0 (mean 28.31, SD 5.79, n=182), t217.60=-2.98, P=.003. Younger age (b=-0.10), more education (b=0.48), and use of more electronic devices (b=1.26) were significantly associated with greater eHealth literacy (R(2) =.17, R(2)adj =.14, F9,229=5.277, P<.001). Women were nearly three times more likely than men to use Web 2.0 for health information (OR 2.63, Wald= 8.09, df=1, P=.004). Finally, more education predicted greater use of Web 2.0 for health information, with college graduates (OR 2.57, Wald= 3.86, df =1, P=.049) and post graduates (OR 7.105, Wald= 4.278, df=1, P=.04) nearly 2 to 7 times more likely than non-high school graduates to use Web 2.0 for health information. CONCLUSIONS: Being younger and possessing more education was associated with greater eHealth literacy among baby boomers and older adults. Females and those highly educated, particularly at the post graduate level, reported greater use of Web 2.0 for health information. More in-depth surveys and interviews among more diverse groups of baby boomers and older adult populations will likely yield a better understanding regarding how current Web-based health information seeking and sharing behaviors influence health-related decision making. PMID- 25783037 TI - The fat cell epigenetic signature in post-obese women is characterized by global hypomethylation and differential DNA methylation of adipogenesis genes. AB - BACKGROUND/OBJECTIVES: Obese subjects have increased number of enlarged fat cells that are reduced in size but not in number in post-obesity. We performed DNA methylation profiling in fat cells with the aim of identifying differentially methylated DNA sites (DMS) linked to adipose hyperplasia (many small fat cells) in post-obesity. SUBJECTS/METHODS: Genome-wide DNA methylation was analyzed in abdominal subcutaneous fat cells from 16 women examined 2 years after gastric bypass surgery at a post-obese state (body mass index (BMI) 26+/-2 kg m(-2), mean+/-s.d.) and from 14 never-obese women (BMI 25+/-2 kg m(-2)). Gene expression was analyzed in subcutaneous adipose tissue from nine women in each group. In a secondary analysis, we examined DNA methylation and expression of adipogenesis genes in 15 and 11 obese women, respectively. RESULTS: The average degree of DNA methylation of all analyzed CpG sites was lower in fat cells from post-obese as compared with never-obese women (P=0.014). A total of 8504 CpG sites were differentially methylated in fat cells from post-obese versus never-obese women (false discovery rate 1%). DMS were under-represented in CpG islands and surrounding shores. The 8504 DMS mapped to 3717 unique genes; these genes were over-represented in cell differentiation pathways. Notably, 27% of the genes linked to adipogenesis (that is, 35 of 130) displayed DMS (adjusted P=10(-8)) in post-obese versus never-obese women. Next, we explored DNA methylation and expression of genes linked to adipogenesis in more detail in adipose tissue samples. DMS annotated to adipogenesis genes were not accompanied by differential gene expression in post-obese compared with never-obese women. In contrast, adipogenesis genes displayed differential DNA methylation accompanied by altered expression in obese women. CONCLUSIONS: Global CpG hypomethylation and over representation of DMS in adipogenesis genes in fat cells may contribute to adipose hyperplasia in post-obese women. PMID- 25783039 TI - Quantifying nanosheet graphene oxide using electrospray-differential mobility analysis. AB - We report a high-resolution, traceable method to quantify number concentrations and dimensional properties of nanosheet graphene oxide (N-GO) colloids using electrospray-differential mobility analysis (ES-DMA). Transmission electron microscopy (TEM) was employed orthogonally to provide complementary data and imagery of N-GOs. Results show that the equivalent mobility sizes, size distributions, and number concentrations of N-GOs were able to be successfully measured by ES-DMA. Colloidal stability and filtration efficiency of N-GOs were shown to be effectively characterized based on the change of size distributions and number concentrations. Through the use of an analytical model, the DMA data were able to be converted into lateral size distributions, showing the average lateral size of N-GOs was ~32 nm with an estimated thickness ~0.8 nm. This prototype study demonstrates the proof of concept of using ES-DMA to quantitatively characterize N-GOs and provides traceability for applications involving the formulation of N-GOs. PMID- 25783038 TI - Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery. AB - BACKGROUND/OBJECTIVES: Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear. SUBJECTS/METHODS: We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. RESULTS: The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. CONCLUSIONS: The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting. PMID- 25783040 TI - Heart rate complexity and attentional orienting: a new look at the role of vagal tone. AB - This study is aimed at elucidating (a) whether heart rate (HR) complexity measures are associated with the attentional orienting function, and (b) which of these measures better predicts orienting efficiency indexes. Vagal tone, sample entropy, scaling exponents ?1 and ?2, and fractal dimension (FD) were calculated in HR time series (n=109). Vagal tone, entropy, and FD were positively associated with orienting, while this association was negative for ?2. These results show that HR scaling properties, which underlie the role of vagal tone and reflect allometric control mechanisms, are associated with orienting deficits. FD was the best predictor of attentional orienting. PMID- 25783041 TI - On the Interplay between Order Parameter Dynamics and System Parameter Dynamics in Human Perceptual-Cognitive-Behavioral Systems. AB - Previous research has demonstrated that perceiving, thinking, and acting are human activities that correspond to self-organized patterns. The emergence of such patterns can be completely described in terms of the dynamics of the pattern amplitudes, which are referred to as order parameters. The patterns emerge at bifurcations points when certain system parameters internal and external to a human agent exceed critical values. At issue is how one might study the order parameter dynamics for sequences of consecutive, emergent perceptual, cognitive, or behavioral activities. In particular, these activities may in turn impact the system parameters that have led to the emergence of the activities in the first place. This interplay between order parameter dynamics and system parameter dynamics is discussed in general and formulated in mathematical terms. Previous work that has made use of this two-tiered framework of order parameter and system parameter dynamics are briefly addressed. As an application, a model for perception under functional fixedness is presented. Finally, it is argued that the phenomena that emerge in this framework and can be observed when human agents perceive, think, and act are just as likely to occur in pattern formation systems of the inanimate world. Consequently, these phenomena do not necessarily have a neurophysiological basis but should instead be understood from the perspective of the theory of self-organization. PMID- 25783042 TI - Fractal coordination in adults' attention to hierarchical visual patterns. AB - A display that contains hierarchically nested levels of order requires the perceiver to selectively attend to one of the levels. We investigate the degree to which such selective attention is sustained by a soft-assembled emergent coordinative process, one that does not require designated executive control. In the case of emergent soft-assembly, performance from one trial to the next should show characteristic interdependence, visible in the fractal structure of reaction time. To test this hypothesis, we asked participants across three experiments to decide whether two displays matched in a certain way (e.g., in a local element). In order to gauge this coordinative process, task constraints were experimentally manipulated (e.g., familiarity, predictability, and task instruction). Obtained reaction-time data were subjected to a spectral analysis to measure the degree of interdependence among trials. As predicted, results show correlated structure across trials, significantly different from what would be predicted by an independent-process view of selective attention. Results also show that the obtained spectral scaling exponents track the degree of coupling in the task as a function of the degree of task constraints. Findings are discussed in terms of the relative organism-environment coupling to sustain an adaptive behavior. PMID- 25783043 TI - Catastrophe models for cognitive workload and fatigue in N-back tasks. AB - N-back tasks place a heavy load on working memory, and thus make good candidates for studying cognitive workload and fatigue (CWLF). This study extended previous work on CWLF which separated the two phenomena with two cusp catastrophe models. Participants were 113 undergraduates who completed 2-back and 3-back tasks with both auditory and visual stimuli simultaneously. Task data were complemented by several measures hypothesized to be related to cognitive elasticity and compensatory abilities and the NASA TLX ratings of subjective workload. The adjusted R2 was .980 for the workload model, which indicated a highly accurate prediction with six bifurcation (elasticity versus rigidity) effects: algebra flexibility, TLX performance, effort, and frustration; and psychosocial measures of inflexibility and monitoring. There were also two cognitive load effects (asymmetry): 2 vs. 3-back and TLX temporal demands. The adjusted R2 was .454 for the fatigue model, which contained two bifurcation variables indicating the amount of work done, and algebra flexibility as the compensatory ability variable. Both cusp models were stronger than the next best linear alternative model. The study makes an important step forward by uncovering an apparently complete model for workload, finding the role of subjective workload in the context of performance dynamics, and finding CWLF dynamics in yet another type of memory-intensive task. The results were also consistent with the developing notion that performance deficits induced by workload and deficits induced by fatigue result from the impact of the task on the workspace and executive functions of working memory respectively. PMID- 25783044 TI - Complexity and behavioral economics. AB - This paper will consider the relationship between complexity economics and behavioral economics. A crucial key to this is to understand that Herbert Simon was both the founder of explicitly modern behavioral economics as well as one of the early developers of complexity theory. Bounded rationality was essentially derived from Simon's view of the impossibility of full rationality on the part of economic agents. Modern complexity theory through such approaches as agent-based modeling offers an approach to understanding behavioral economics by allowing for specific behavioral responses to be assigned to agents who interact within this context, even without full rationality. Other parts of modern complexity theory are considered in terms of their relationships with behavioral economics. Fundamentally, complexity provides an ultimate foundation for bounded rationality and hence the need to use behavioral economics in a broader array of contexts than most economists have thought appropriate. PMID- 25783045 TI - 3D polyaniline porous layer anchored pillared graphene sheets: enhanced interface joined with high conductivity for better charge storage applications. AB - Here, we report synthesis of a 3-dimensional (3D) porous polyaniline (PANI) anchored on pillared graphene (G-PANI-PA) as an efficient charge storage material for supercapacitor applications. Benzoic acid (BA) anchored graphene, having spatially separated graphene layers (G-Bz-COOH), was used as a structure controlling support whereas 3D PANI growth has been achieved by a simple chemical oxidation of aniline in the presence of phytic acid (PA). The BA groups on G-Bz COOH play a critical role in preventing the restacking of graphene to achieve a high surface area of 472 m(2)/g compared to reduced graphene oxide (RGO, 290 m(2)/g). The carboxylic acid (-COOH) group controls the rate of polymerization to achieve a compact polymer structure with micropores whereas the chelating nature of PA plays a crucial role to achieve the 3D growth pattern of PANI. This type of controlled interplay helps G-PANI-PA to achieve a high conductivity of 3.74 S/cm all the while maintaining a high surface area of 330 m(2)/g compared to PANI-PA (0.4 S/cm and 60 m(2)/g). G-PANI-PA thus conceives the characteristics required for facile charge mobility during fast charge-discharge cycles, which results in a high specific capacitance of 652 F/g for the composite. Owing to the high surface area along with high conductivity, G-PANI-PA displays a stable specific capacitance of 547 F/g even with a high mass loading of 3 mg/cm(2), an enhanced areal capacitance of 1.52 F/cm(2), and a volumetric capacitance of 122 F/cm(3). The reduced charge-transfer resistance (RCT) of 0.67 Omega displayed by G-PANI-PA compared to pure PANI (0.79 Omega) stands out as valid evidence of the improved charge mobility achieved by the system by growing the 3D PANI layer along the spatially separated layers of the graphene sheets. The low RCT helps the system to display capacitance retention as high as 65% even under a high current dragging condition of 10 A/g. High charge/discharge rates and good cycling stability are the other highlights of the supercapacitor system derived from this composite material. PMID- 25783046 TI - Multi-bio and multi-scale systems biology. PMID- 25783047 TI - Mutations in KISS1 are not responsible for idiopathic hypogonadotropic hypogonadism in Chinese patients. AB - PURPOSE: To investigate whether mutations in the KISS1 gene are present in 170 Chinese patients with idiopathic hypogonadotropic hypogonadism (IHH). METHODS: Mutational screening of the KISS1 gene was performed in 170 Chinese patients with IHH (133 male cases and 37 female cases) and 187 matched controls (94 males and 93 females). RESULTS: Two known single-nucleotide polymorphisms (SNP), c. 58G > A in exon 1 and c. 242C > G in exon 2, were identified. However, no difference of genotype and allelic frequencies between cases and controls was observed. CONCLUSIONS: The results suggest that mutations in the coding sequence of KISS1 are not common in patients with IHH in this Chinese population. PMID- 25783048 TI - Prescription of perioperative analgesics by UK small animal veterinary surgeons in 2013. AB - Data from a survey conducted in 1996-1997 suggested a low level of perioperative analgesic administration to cats and dogs in the UK. In order to evaluate current practice and attitudes with regards to perioperative analgesic prescription, a cross-sectional survey of UK practising small animal veterinary surgeons was undertaken in spring 2013. Four thousand one hundred paper questionnaires were distributed and the survey was made available online. Seven hundred and twenty valid responses were received and analysed. All respondents had access to at least one non-steroidal anti-inflammatory drug (NSAID) and one opioid within their practice. Respondents considered analgesic efficacy, and degree of intraoperative pain, the most important factors governing their selection of NSAID and opioid analgesics. Perioperative NSAIDs were administered by approximately 98 per cent of respondents to dogs and cats undergoing neutering. Multimodal (opioid+NSAID) analgesia was prescribed by the majority of respondents. Neutering was considered more painful in dogs than in cats, and lower rates of opioid and postdischarge NSAID prescription were reported for cats. Orthopaedic, abdominal and dental surgeries were considered equally painful in dogs and cats. Local analgesic techniques were not commonly used. Analgesic prescription has increased since previous surveys, which should translate to improved animal welfare. PMID- 25783049 TI - Using size-selected gold clusters on graphene oxide films to aid cryo transmission electron tomography alignment. AB - A three-dimensional reconstruction of a nano-scale aqueous object can be achieved by taking a series of transmission electron micrographs tilted at different angles in vitreous ice: cryo-Transmission Electron Tomography. Presented here is a novel method of fine alignment for the tilt series. Size-selected gold clusters of ~2.7 nm (Au561+/-14 ), ~3.2 nm (Au923+/- 22 ), and ~4.3 nm (Au2057+/-45) in diameter were deposited onto separate graphene oxide films overlaying holes on amorphous carbon grids. After plunge freezing and subsequent transfer to cryo Transmission Electron Tomography, the resulting tomograms have excellent (de )focus and alignment properties during automatic acquisition. Fine alignment is accurate when the evenly distributed 3.2 nm gold particles are used as fiducial markers, demonstrated with a reconstruction of a tobacco mosaic virus. Using a graphene oxide film means the fiducial markers are not interfering with the ice bound sample and that automated collection is consistent. The use of pre deposited size-selected clusters means there is no aggregation and a user defined concentration. The size-selected clusters are mono-dispersed and can be produced in a wide size range including 2-5 nm in diameter. The use of size-selected clusters on a graphene oxide films represents a significant technical advance for 3D cryo-electron microscopy. PMID- 25783050 TI - Accuracy of interchangeable implant impression systems: an in vitro pilot study. AB - PURPOSE: To evaluate the accuracy of impressions on changing the implant component (coping and abutment replica) between Branemark and BIOMET 3i and between Straumann and Allfit. MATERIALS AND METHODS: Two master casts were constructed, one containing pair of Branemark self-tap Mk II fixtures (Nobel Biocare) labeled Master cast I and the other containing pair of Straumann Standard plus implant, SLA fixtures (Straumann) labeled Master cast II. Ten impressions of each master cast were made by open tray technique using polyether impression material. Five out of 10 impressions made from master cast I contained Branemark pair of coping and replica and the other 5 contained 3i (Implant Innovations). Five out of 10 impressions made from master cast II contained Straumann pair of copings and replica and the remaining 5 contained Allfit implants (Ihde Dental). Duplicated casts were prepared, and distances between copings were measured using traveling microscope and compared the distance in master casts. RESULT: No significant difference was observed in mean value between 2 master casts and their duplicates. CONCLUSION: The interchangeability of coping and abutment replica between Branemark and BIOMET 3i and between Straumann and Allfit was found to be possible without compromising the quality of impressions. PMID- 25783051 TI - MicroRNA-224 targets ERG2 and contributes to malignant progressions of meningioma. AB - MicroRNA-224 is overexpressed in various malignant tumors with poor prognosis, which plays a critical role in biological processes including cell proliferation, apoptosis and several developmental and physiological progressions. However, the potential association between miR-224 and clinical outcome in patients with meningiomas remains unknown. Here, we investigate miR-224 expression and biological functions in meningiomas. MiR-224 expression was measured by Northern blot analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in meningioma and normal brain tissues. Kaplan-Meier analysis and Cox regression analysis were used to exam its correlation with clinicopathological features and prognostic value. The biological effects of miR-224 on the cell proliferation and apoptosis in meningioma cells were examined by MTT assay and apoptosis assay. We found the expression levels of miR-224 were significantly higher in meningioma tissues than that in normal brain, positively correlated with advanced pathological grade. Kaplan-Meier analysis indicated that meningioma patients with low miR-224 expression exhibited significantly prolonged overall and recurrence-free survival. Furthermore, we demonstrated that ERG2 was an identical candidate target gene of MiR-224 in vitro. Our results indicated that downregulation of miR-224 suppressed cell growth and resulted in the enhancement of cell apoptosis through activation of the ERG2-BAK-induced apoptosis pathway. Our findings imply the miR-224 expression could predict the overall survival and recurrence-free survival of patients with meningioma and it might be a promising therapeutic target for treating malignant meningiomas. PMID- 25783052 TI - Hepatoprotective effect of phosphatidylcholine against carbon tetrachloride liver damage in mice. AB - It has been shown that phosphatidylcholine (PC) extracted from egg yolk possesses a variety of biological activities, such as anti-inflammatory and anti-oxidant effects, and prevents oxidative stress. The aim of this study was to evaluate the hepatoprotective effects of PC against carbon tetrachloride (CCl4), which is a well-known hepatotoxicant that causes extensive oxidative liver damage, and to investigate the mechanisms involved in this protective effect. Mice were treated with PC (0.1 ml, 10 or 100 mg/kg, orally) once daily for 5 consecutive days prior to CCl4 administration (0.1 ml, 20 mg/kg, intraperitoneally). The experimental data show that pretreatment with PC significantly prevented increases of serum aspartate transaminase, alanine transaminase, and alkaline phosphatase, and reduced reactive oxygen species levels. Histopathological evaluation of the liver also revealed that PC effectively ameliorated CCl4-induced hepatic injury and fibrosis. In addition, PC significantly counteracted the increase in glutathione levels and glutathione-S-transferase activity induced by CCl4. Concordantly, PC significantly decreased CCl4-induced upregulation of apoptotic proteins in the liver. These results suggest that PC exerts its protective effects against CCl4 induced hepatotoxicity via its activities as an anti-oxidant and free radical scavenger. PMID- 25783053 TI - Ang-(1-7) promotes the migration and invasion of human renal cell carcinoma cells via Mas-mediated AKT signaling pathway. AB - Ang-(1-7) is an active peptide component of renin-angiotensin system and endogenous ligand for Mas receptor. In the current study, we showed that Ang-(1 7) enhanced migratory and invasive abilities of renal cell carcinoma cells 786-O and Caki-1 by wound-healing, transwell migration and transwell invasion assays. Mas antagonist A779 pretreatment or shRNA-mediated Mas knockdown abolished the stimulatory effect of Ang-(1-7). Furthermore, Ang-(1-7)-stimulated AKT activation was inhibited by either A779 pretreatment or Mas knockdown. Blockage of AKT signaling by AKT inhibitor VIII inhibited Ang-(1-7)-induced migration and invasion in 786-O cells. Taken together, our results provided the first evidence for the pro-metastatic role of Ang-(1-7) in RCC, which may help to better understand the molecular mechanism underlying the progression of this tumor. PMID- 25783054 TI - A mechanistic study into the epoxidation of carboxylic acid and alkene in a mono, di-acylglycerol lipase. AB - More and more industrial chemistry reactions rely on green technologies. Enzymes are finding increasing use in diverse chemical processes. Epoxidized vegetable oils have recently found applications as plasticizers and additives for PVC production. We report here an unusual activity of the Malassezia globosa lipase (SMG1) that is able to catalyze epoxidation of alkenes. SMG1 catalyzes formation of peroxides from long chain carboxylic acids that subsequently react with double bonds of alkenes to produce epoxides. The SMG1 is selective towards carboxylic acids and active also as a mutant lacking hydrolase activity. Moreover we present previously unobserved mechanism of catalysis that does not rely on acyl-substrate complex nor tetrahedral intermediate. Since SMG1 lipase is activated by allosteric change upon binding to the lipophilic-hydrophilic phase interface we reason that it can be used to drive the epoxidation in the lipophilic phase exclusively. PMID- 25783055 TI - RCAN 1 and 3 proteins regulate thymic positive selection. AB - Cooperation between calcineurin (CN)-NFATc and RAF-MEK-ERK signaling pathways is essential in thymocyte positive selection. It is known that the Regulators of Calcineurin (RCAN) proteins can act either facilitating or suppressing CN dependent signaling events. Here, we show that RCAN genes are expressed in lymphoid tissues, and address the role of RCAN proteins in T cell development. Overexpression of human RCAN3 and RCAN1 can modulate T cell development by increasing positive selection-related surface markers, as well as the "Erk(hi) competence state" in double positive thymocytes, a characteristic molecular signature of positive selection, without affecting CN activity. We also found that RCAN1/3 interact with RAF kinases and CN in a non-exclusive manner. Our data suggests that the balance of RCAN interactions with CN and/or RAF kinases may influence T cell positive selection. PMID- 25783056 TI - Transcription outcome of promoters enriched in histone variant H3.3 defined by positioning of H3.3 and local chromatin marks. AB - Replication-independent histone variant H3.3 is incorporated into distinct genomic regions including promoters. However topology of promoter-associated H3.3 in relation to chromatin modifications and transcriptional outcome is not known, providing no insight on any distinction between H3.3-containing active and inactive promoters. Here, we report algorithms providing information on gene expression status as a function of density and position of multiple chromatin marks on promoters. We identify a relationship between promoter enrichment in epitope-tagged H3.3 or its canonical isoform H3.2 and corresponding transcriptional outcomes, as a function of sub-promoter positioning of DNA methylation and H3K4me3, H3K9me3 and H3K27me3. We identify a low-frequency configuration of H3.3 and H3K9me3 co-occupancy associated with transcriptional activity, while H3.3 and H3K27me3 promoters are invariably inactive. We unveil H3.3 and DNA methylated promoters whose transcription outcome depends on H3.3 sub promoter positioning. Our results indicate how spatially restricted positioning of H3.3 may add another layer of transcription regulation. PMID- 25783057 TI - Tactile friction of topical formulations. AB - BACKGROUND: The tactile perception is essential for all types of topical formulations (cosmetic, pharmaceutical, medical device) and the possibility to predict the sensorial response by using instrumental methods instead of sensory testing would save time and cost at an early stage product development. Here, we report on an instrumental evaluation method using tactile friction measurements to estimate perceptual attributes of topical formulations. METHODS: Friction was measured between an index finger and an artificial skin substrate after application of formulations using a force sensor. Both model formulations of liquid crystalline phase structures with significantly different tactile properties, as well as commercial pharmaceutical moisturizing creams being more tactile-similar, were investigated. Friction coefficients were calculated as the ratio of the friction force to the applied load. The structures of the model formulations and phase transitions as a result of water evaporation were identified using optical microscopy. RESULTS: The friction device could distinguish friction coefficients between the phase structures, as well as the commercial creams after spreading and absorption into the substrate. In addition, phase transitions resulting in alterations in the feel of the formulations could be detected. A correlation was established between skin hydration and friction coefficient, where hydrated skin gave rise to higher friction. Also a link between skin smoothening and finger friction was established for the commercial moisturizing creams, although further investigations are needed to analyse this and correlations with other sensorial attributes in more detail. CONCLUSION: The present investigation shows that tactile friction measurements have potential as an alternative or complement in the evaluation of perception of topical formulations. PMID- 25783142 TI - Development and preliminary evaluation of the caregiver assistive technology outcome measure. AB - INTRODUCTION: Assistive technology is often recommended with the aim of increasing user independence and reducing the burden on informal caregivers. However, until now, there has been no tool to measure the outcomes of this process for caregivers. OBJECTIVES: To describe the development of the Caregiver Assistive Technology Outcome Measure (CATOM), a tool developed to measure the impact of assistive technology interventions on the burden experienced by informal caregivers, and to undertake preliminary evaluation of its psychometric properties. METHODS: Based on an existing conceptual framework, existing measures were reviewed to identify potential items in a preliminary version of the measure. Cognitive interviewing was used to identify items needing clarification. A revised CATOM and manual were then reviewed by clinicians. After revising some items based on the interview findings, the measure was piloted as part of an intervention study examining the impact of assistive technology on the users' informal caregivers (n = 44). RESULTS: Based on a review of 12 existing measures, a 3-part measure was developed and questions were refined based on cognitive interviews with informal caregivers and feedback experienced assistive technology practitioners. For the activity-specific and overall portions of the measure, the 6-week, test-retest intraclass correlations coefficients were 0.88 (95% CI 0.64 0.96) and 0.86 (95% CI 0.60-0.95), respectively. The CATOM data correlated as hypothesized with other measures. CONCLUSION: The CATOM is a promising measure with good content validity and encouraging psychometric properties. PMID- 25783143 TI - An in-house prevocational training program for newly discharged psychiatric inpatients: exploring its employment outcomes and the predictive factors. AB - Individuals with severe mental disorders continue to experience low employment rates. Occupational therapists play an important role in helping these individuals develop the skills and obtain the supports necessary for productive living. This retrospective cohort study aimed to explore employment outcomes and identify factors predictive of the outcomes of an in-house prevocational training program designed for newly discharged psychiatric inpatients. Data retrieved from the files of 58 participants including demographics, diagnostic history, physical fitness, functional assessment results, the use of vocational counselling service and employment status were analyzed. The overall employment rates among the participants were high (67.2-79.3%) within the 6 months following the prevocational training program. No significant differences were found in the employment rates across the 1, 3 and 6-month time periods post-training. Vocational counselling service post-training and hand function were two factors predictive of participants' employment outcomes. Occupational therapists should attend to the clients' need for continuous vocational support and carefully identify the personal, functional and environmental factors contributing to successful employment. Caution in interpreting the results is warranted because of the lack of control and randomization in this retrospective study. Additional longitudinal cohort or experimental studies would add further certainty to the current findings. PMID- 25783144 TI - Tell the story of what you did. AB - Writing for publication can be a daunting experience for the novice and experienced researcher. Writing is an acquired skill that only develops through regular practice and persistence in working to improve each piece. Yet telling the story of what you did, what you found or what worked is so important for all researchers. PMID- 25783145 TI - Interviews in qualitative research. AB - Interviews are a common method of data collection in nursing research. They are frequently used alone in a qualitative study or combined with other data collection methods in mixed or multi-method research. Semi-structured interviews, where the researcher has some predefined questions or topics but then probes further as the participant responds, can produce powerful data that provide insights into the participants' experiences, perceptions or opinions. PMID- 25783146 TI - Bracketing as a skill in conducting unstructured qualitative interviews. AB - AIM: To provide an overview of bracketing as a skill in unstructured qualitative research interviews. BACKGROUND: Researchers affect the qualitative research process. Bracketing in descriptive phenomenology entails researchers setting aside their pre-understanding and acting non-judgementally. In interpretative phenomenology, previous knowledge is used intentionally to create new understanding. DATA SOURCES: A literature search of bracketing in phenomenology and qualitative research. REVIEW METHODS: This is a methodology paper examining the researchers' impact in creating data in creating data in qualitative research. DISCUSSION: Self-knowledge, sensitivity and reflexivity of the researcher enable bracketing. CONCLUSION: Skilled and experienced researchers are needed to use bracketing in unstructured qualitative research interviews. IMPLICATIONS FOR RESEARCH/PRACTICE: Bracketing adds scientific rigour and validity to any qualitative study. PMID- 25783147 TI - Use of Skype in interviews: the impact of the medium in a study of mental health nurses. AB - AIM: To discuss the use of Skype as a medium for undertaking semi-structured interviews. BACKGROUND: Internet-based research is becoming increasingly popular, as communication using the internet takes a bigger role in our working and personal lives. Technology such as Skype allows research encounters with people across geographical divides. The semi-structured interview is a social encounter with a set of norms and expectations for both parties ( Doody and Noonan 2012 ). Proceedings must take account of the social context of both semi-structured interviews per se, and that of internet mediated communication. DATA SOURCES: The findings of the qualitative phase of a mixed-methods study are compared with other reports comparing the use of Skype with face-to-face and telephone interviews. REVIEW METHODS: This paper is a methodological discussion of the use of Skype as an online research methodology. DISCUSSION: Choosing Skype as a means of interviewing may affect the characteristics of participants and decisions about consent. Rapport, sensitivity and collaboration may be addressed differently in Skype interviews compared with face-to-face interviews. CONCLUSION: Skype offers researchers the opportunity to reach a geographical spread of participants more safely, cheaply and quickly than face-to-face meetings. Rapport, sensitivity and degrees of collaboration can be achieved using this medium. IMPLICATIONS FOR RESEARCH/PRACTICE: The use of Skype as a medium for semi-structured interview research is better understood. This paper contributes to the growing body of literature on the use of the internet as a medium for research by nurses. PMID- 25783148 TI - Using extant literature in a grounded theory study: a personal account. AB - AIM: To provide a personal account of the factors in a doctoral study that led to the adoption of classic grounded theory principles relating to the use of literature. BACKGROUND: Novice researchers considering grounded theory methodology will become aware of the contentious issue of how and when extant literature should be incorporated into a study. The three main grounded theory approaches are classic, Straussian and constructivist, and the seminal texts provide conflicting beliefs surrounding the use of literature. A classic approach avoids a pre-study literature review to minimise preconceptions and emphasises the constant comparison method, while the Straussian and constructivist approaches focus more on the beneficial aspects of an initial literature review and researcher reflexivity. The debate also extends into the wider academic community, where no consensus exists. REVIEW METHODS: This is a methodological paper detailing the authors' engagement in the debate surrounding the role of the literature in a grounded theory study. DISCUSSION: In the authors' experience, researchers can best understand the use of literature in grounded theory through immersion in the seminal texts, engaging with wider academic literature, and examining their preconceptions of the substantive area. The authors concluded that classic grounded theory principles were appropriate in the context of their doctoral study. CONCLUSION: Novice researchers will have their own sets of circumstances when preparing their studies and should become aware of the different perspectives to make decisions that they can ultimately justify. IMPLICATIONS FOR RESEARCH/PRACTICE: This paper can be used by other novice researchers as an example of the decision-making process that led to delaying a pre-study literature review and identifies the resources used to write a research proposal when using a classic grounded theory approach. PMID- 25783149 TI - Ethical issues when involving people newly diagnosed with dementia in research. AB - AIM: To discuss the methodological and ethical review challenges encountered by researchers who want to enable people with dementia to be involved in research. BACKGROUND: There has been increasing recognition of the importance of involving people with dementia in research. However, an argument has centred on the protection of these vulnerable clients versus their freedom to be involved as participants in research. People with dementia do have the right to have their experiences explored. Involving this client group in research is essential to gain a true understanding of their needs. DATA SOURCES: The lead author's experience of conducting a study in which people newly diagnosed with dementia were recruited as research participants. REVIEW METHODS: An interpretive phenomenological approach was adopted during this qualitative study, with data collected by means of one to one interviews with people newly diagnosed with dementia. DISCUSSION: This study was completed within the set timeframe, but a large part of the work was spent gaining ethical approval. This meant that the timeframe of the study period was reduced and as a result, it was only possible to recruit three participants. However, people with dementia are perhaps one of the most vulnerable client groups and it is only right that they should not be subjected to harm. CONCLUSION: Ethical review is an important part of research. Meeting the ethical requirements of research involving people with dementia requires time and careful preparation to ensure that researchers safeguard the interests of this vulnerable client group, while also allowing the participants the opportunity to exercise their autonomy to their fullest potential. IMPLICATIONS FOR RESEARCH/PRACTICE: Conducting research that involves people with dementia may be time consuming, but it is only fair that this client group are afforded the freedom to be involved in research. This small time-limited study points to the need for larger pilot studies to hear from individuals what needs they have following a diagnosis of dementia. PMID- 25783150 TI - Choosing phenomenology as a guiding philosophy for nursing research. AB - AIM: To provide an overview of important methodological considerations that nurse researchers need to adhere to when choosing phenomenology as a guiding philosophy and research method. BACKGROUND: Phenomenology is a major philosophy and research method in the humanities, human sciences and arts disciplines with a central goal of describing people's experiences. However, many nurse researchers continue to grapple with methodological issues related to their choice of phenomenological method. DATA SOURCES: The author conducted online and manual searches of relevant research books and electronic databases. REVIEW METHODS: Using an integrative method, peer-reviewed research and discussion papers published between January 1990 and December 2011 and listed in the CINAHL, Science Direct, PubMed and Google Scholar databases were reviewed. In addition, textbooks that addressed research methodologies such as phenomenology were used. DISCUSSION: Although phenomenology is widely used today to broaden understanding of human phenomena relevant to nursing practice, nurse researchers often fail to adhere to acceptable scientific and phenomenological standards. Cognisant of these challenges, researchers are expected to indicate in their work the focus of their investigations, designs, and approaches to collecting and analysing data. They are also expected to present their findings in an evocative and expressive manner. CONCLUSIONS: Choosing phenomenology requires researchers to understand it as a philosophy, including basic assumptions and tenets of phenomenology as a research method. This awareness enables researchers, especially novices, to make important methodological decisions, particularly those necessary to indicate the study's scientific rigour and phenomenological validity. IMPLICATIONS FOR RESEARCH/PRACTICE: This paper adds to the discussion of phenomenology as a guiding philosophy for nursing research. It aims to guide new researchers on important methodological decisions they need to make to safeguard their study's scientific rigour and phenomenological validity. PMID- 25783151 TI - van Manen's method and reduction in a phenomenological hermeneutic study. AB - AIM: To describe van Manen's method and concept of reduction in a study that used a phenomenological hermeneutic approach. BACKGROUND: Nurse researchers have used van Manen's method in different ways. Participants' lifeworlds are described in depth, but descriptions of reduction have been brief. DATA SOURCES: The literature and knowledge review and manual search of research articles. REVIEW METHODS: Databases Web Science, PubMed, CINAHL and PsycINFO, without applying a time period, to identify uses of van Manen's method. DISCUSSION: This paper shows how van Manen's method has been used in nursing research and gives some examples of van Manen's reduction. CONCLUSION: Reduction enables us to conduct in-depth phenomenological hermeneutic research and understand people's lifeworlds. IMPLICATIONS FOR RESEARCH/PRACTICE: As there are many variations in adapting reduction, it is complex and confusing. This paper contributes to the discussion of phenomenology, hermeneutic study and reduction. It opens up reduction as a method for researchers to exploit. PMID- 25783154 TI - Effect of Nasal Continuous Positive Airway Pressure (NCPAP) Cycling and Continuous NCPAP on Successful Weaning: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the effectiveness of nasal continuous positive airway pressure (NCPAP) cycling with continuous NCPAP in the successful weaning of preterm infants of 25(0)-28(6) wk gestation to nasal prongs. METHODS: A total of 30 infants with a gestational age (GA) of 25(0)-28(6) wk, ventilated for respiratory distress syndrome (RDS) and extubated to NCPAP were eligible for the study. They were randomized to NCPAP cycling [Group A: cycling between NCPAP of 4 cm and 1 liter per minute (LPM) of nasal prongs] or to continuous NCPAP at 4 cm of H2O (Group B). Primary outcome was successful weaning off NCPAP to nasal prongs at the end of 72 h of the intervention and remaining off NCPAP for the next 72 h. RESULTS: The demographic characteristics were similar in both the groups. Infants were randomized to Group A (n = 13) and Group B (n = 17). The primary outcome was not significantly different between the groups (successful weaning to nasal prongs: 31 vs. 41 %; p 0.71). CONCLUSIONS: In this pilot, feasibility study there were no differences in the rates of successful weaning of NCPAP to nasal prongs using either cycling NCPAP or continuous NCPAP in preterm infants. A need exists for a large randomized controlled trial (RCT) to determine the role of cycling NCPAP on neonatal outcomes. PMID- 25783156 TI - Focus issue: noncoding RNAs in cancer. AB - Through various means, noncoding RNAs regulate the expression of genes, many of which are associated with cellular homeostasis. Noncoding RNAs--especially microRNAs--are critical regulators of the mechanisms underlying numerous processes in cell biology, particularly those involved in the development and progression of cancer. This special issue of Science Signaling sheds light on the physiological and pathophysiological functions of this distinct class of molecules. PMID- 25783155 TI - Sleep Habits and Sleep Problems in Healthy Preschoolers. AB - OBJECTIVES: To describe the sleep patterns and problems in children aged between 12 and 36 mo of age. METHODS: This cross sectional survey was collected over a span of 1 y in Advanced Pediatric Centre, PGIMER, Chandigarh and creches of Chandigarh. Children in the age group of 12 to 36 mo were included in study. Children with chronic illness, developmental delay, seizure disorder and lack of consent were excluded. A total of 368 children were enrolled. Main outcome measures were sleep duration over 1 to 3 y of life; sleep behavior at onset, during and waking of sleep and parent reported sleep problems and their predictors. RESULTS: The average duration of sleep was 12.5 h (S.D = 1.9). The mean total sleep duration and mean day time sleep duration decreased, while mean night time sleep increased as the age advanced from 12 to 36 mo. Following were the frequency of sleep habits seen in the index study; bed time routine was seen only in 68(18.5 %), a regular bed time ritual was seen in 281(76.4 %), 329(89.4 %) children frequently required 0-20 min time to fall asleep, 11(3 %) parents used sleep inducing drugs. Night waking (1 to 3 times a night) was seen in 297(80.7 %) and its frequency declined with age. Parent reported sleep problems were seen in 12.8 % (47/368). Lack of co-sleeping and night waking were considered as strongest predictors of parent reported sleep problems. CONCLUSIONS: Toddlers' sleep duration, night waking behavior, and day time naps decrease as the age progress while night time sleep duration increases with age. Lack of co-sleeping and night waking are considered as strongest predictors of parent reported sleep problems. PMID- 25783157 TI - Interleukin-10-producing CD5+ B cells inhibit mast cells during immunoglobulin E mediated allergic responses. AB - Subsets of B cells inhibit various immune responses through their production of the cytokine interleukin-10 (IL-10). We found that IL-10-producing CD5(+) B cells suppressed the immunoglobulin E (IgE)- and antigen-mediated activation of mast cells in vitro as well as allergic responses in mice in an IL-10-dependent manner. Furthermore, the suppressive effect of these B cells on mast cells in vitro and in vivo depended on direct cell-to-cell contact through the costimulatory receptor CD40 on CD5(+) B cells and the CD40 ligand on mast cells. This contact enhanced the production of IL-10 by the CD5(+) B cells. Through activation of the Janus-activated kinase-signal transducer and activator of transcription 3 pathway, IL-10 decreased the abundance of the kinases Fyn and Fgr and inhibited the activation of the downstream kinase Syk in mast cells. Together, these findings suggest that an important function of IL-10-producing CD5(+) B cells is inhibiting mast cells and IgE-mediated allergic responses. PMID- 25783158 TI - EGF induces microRNAs that target suppressors of cell migration: miR-15b targets MTSS1 in breast cancer. AB - Growth factors promote tumor growth and metastasis. We found that epidermal growth factor (EGF) induced a set of 22 microRNAs (miRNAs) before promoting the migration of mammary cells. These miRNAs were more abundant in human breast tumors relative to the surrounding tissue, and their abundance varied among breast cancer subtypes. One of these miRNAs, miR-15b, targeted the 3' untranslated region of MTSS1 (metastasis suppressor protein 1). Although xenografts in which MTSS1 was knocked down grew more slowly in mice initially, longer-term growth was unaffected. Knocking down MTSS1 increased migration and Matrigel invasion of nontransformed mammary epithelial cells. Overexpressing MTSS1 in an invasive cell line decreased cell migration and invasiveness, decreased the formation of invadopodia and actin stress fibers, and increased the formation of cellular junctions. In tissues from breast cancer patients with the aggressive basal subtype, an inverse correlation occurred with the high expression of miRNA-15b and the low expression of MTSS1. Furthermore, low abundance of MTSS1 correlated with poor patient prognosis. Thus, growth factor inducible miRNAs mediate mechanisms underlying the progression of cancer. PMID- 25783160 TI - Dysregulation of microRNA biogenesis and gene silencing in cancer. AB - MicroRNAs (miRNAs) are small noncoding RNAs that suppress the abundance of partially complementary mRNAs and inhibit their translation. Each miRNA can regulate hundreds of mRNAs, sometimes strongly but often weakly, to mediate a diverse array of biological functions, including proliferation, cell signaling, differentiation, stress responses and DNA repair, cell adhesion and motility, inflammation, cell survival, senescence, and apoptosis, all intimately related to cancer initiation, treatment response, and metastasis. The expression and activity of miRNAs are spatially and temporally controlled. Global miRNA expression is reduced in many cancers. In addition, the expression and processing of cancer-related miRNAs that act as oncogenes ("oncomiRs") or tumor suppressors are often dysregulated in cancer. In this review, we summarize emerging knowledge about how miRNA biogenesis and gene silencing are altered to promote cancer. PMID- 25783159 TI - Outside the coding genome, mammalian microRNAs confer structural and functional complexity. AB - MicroRNAs (miRNAs) comprise a class of small, regulatory noncoding RNAs (ncRNAs) with pivotal roles in posttranscriptional gene regulation. Since their initial discovery in 1993, numerous miRNAs have been identified in mammalian genomes, many of which play important roles in diverse cellular processes in development and disease. These small ncRNAs regulate the expression of many protein-coding genes posttranscriptionally, thus adding a substantial complexity to the molecular networks underlying physiological development and disease. In part, this complexity arises from the distinct gene structures, the extensive genomic redundancy, and the complex regulation of the expression and biogenesis of miRNAs. These characteristics contribute to the functional robustness and versatility of miRNAs and provide important clues to the functional significance of these small ncRNAs. The unique structure and function of miRNAs will continue to inspire many to explore the vast noncoding genome and to elucidate the molecular basis for the functional complexity of mammalian genomes. PMID- 25783162 TI - Probable delayed-type hypersensitivity to nickel-containing cerebral aneurysm clip associated with neurologic deficits. PMID- 25783161 TI - Markers of Differential Response to Inhaled Corticosteroid Treatment Among Children with Mild Persistent Asthma. AB - BACKGROUND: Inhaled corticosteroids are recommended as first-line therapy for children with mild persistent asthma; however, specific patient characteristics may modify the treatment response. OBJECTIVE: Identify demographic, clinical, and atopic characteristics that may modify the inhaled corticosteroid treatment response among children enrolled in the Treating Children to Prevent Exacerbations of Asthma trial. METHODS: Children aged 6 to 18 years with mild persistent asthma were randomized to 44 weeks of combined, daily, rescue, or placebo treatment. Daily treatment consisted of 40 MUg of beclomethasone twice daily. Rescue treatment consisted of 40 MUg of beclomethasone accompanying each symptom-driven albuterol actuation. Combined treatment consisted of both. Outcomes included time to first exacerbation and proportion of asthma control days. Fourteen baseline characteristics were selected for interaction testing on the basis of their clinical relevance. RESULTS: Two hundred eighty-eight children were randomized. Seventy-five percent were white, and 55% were male. As measured by time to first exacerbation, 4 characteristics identified children who received greater benefit from treatment: non-Hispanic ethnicity, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/MUL or more, and history of oral corticosteroid use in the year before enrollment. As measured by asthma control days, 4 characteristics identified children who received greater benefit from treatment: male sex, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/MUL or more, and incomplete run-in asthma control. CONCLUSIONS: Children with mild persistent asthma who have markers of atopic asthma or who have greater asthma burden may obtain greater benefit from beclomethasone therapy. Additional study is needed to confirm whether these markers can guide individualized therapy. PMID- 25783163 TI - Managing produced water from coal seam gas projects: implications for an emerging industry in Australia. AB - This paper reviews the environmental problems, impacts and risks associated with the generation and disposal of produced water by the emerging coal seam gas (CSG) industry and how it may be relevant to Australia and similar physical settings. With only limited independent research on the potential environmental impacts of produced water, is it necessary for industry and government policy makers and regulators to draw upon the experiences of related endeavours such as mining and groundwater extraction accepting that the conclusions may not always be directly transferrable. CSG is widely touted in Australia as having the potential to provide significant economic and energy security benefits, yet the environmental and health policies and the planning and regulatory setting are yet to mature and are continuing to evolve amidst ongoing social and environmental concerns and political indecision. In this review, produced water has been defined as water that is brought to the land surface during the process of recovering methane gas from coal seams and includes water sourced from CSG wells as well as flowback water associated with drilling, hydraulic fracturing and gas extraction. A brief overview of produced water generation, its characteristics and environmental issues is provided. A review of past lessons and identification of potential risks, including disposal options, is included to assist in planning and management of this industry. PMID- 25783164 TI - Updated clinical practice guidelines for the management of biliary tract cancers: revision concepts and major revised points. AB - BACKGROUND: In 2008, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) launched the clinical practice guideline for the management of biliary tract cancers. JSHBPS decided to revise these guidelines for distribution of updated points concerning the treatment of biliary tract cancers. METHODS: To make clearer recommendations, we introduced the concepts of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, in which the strength of recommendations are decided considering not only quality of evidence, but also balance of benefits and harms/burdens, patients' preferences, and cost benefits. RESULTS: We emphasize the importance of the dynamic contrast enhanced multiple row detector CT (MDCT) in the diagnosis of biliary tract and gallbladder carcinomas. For biliary drainage, we suggest to perform endoscopic approaches instead of percutaneous approach to avoid complications. Regarding the surgical treatments, we included new clinical questions about the importance of combined vascular resection, intraoperative histological examination of the bile duct resection margin, and the combined extrahepatic bile duct resection for the gallbladder carcinoma. We also discussed details about premalignant lesions and non-neoplastic lesions in pathology section. CONCLUSION: With this major revision, we expect that the Japanese standards of treatments of these diseases are recorded and reported in the universal language. PMID- 25783165 TI - [Deep sclerectomy. An alternative to trabeculectomy]. AB - BACKGROUND: Deep sclerectomy was developed to avoid the intraoperative and postoperative complications seen with trabeculectomy. METHODS: Compared to trabeculectomy, the anterior chamber is not opened in deep sclerectomy. In addition to a superficial scleral flap as performed in trabeculectomy, a second deep scleral flap is created directly beneath the first flap so that the external part of Schlemm's canal is opened and corneal tissue removed leaving only Descemet's membrane separating the anterior chamber. Various implants serve to delay or avoid formation of scar tissue. In cases of insufficient reduction of intraocular pressure (IOP) Descemet's membrane can be finely perforated by an additional goniopuncture leading to better drainage of the aqueous humor. CONCLUSIONS: There is a controversial discussion about the pressure lowering effect of deep sclerectomy in comparison to trabeculectomy. Some studies have shown a similar long-term efficacy for both procedures but others showed an advantage for trabeculectomy. As expected, the complication rate could be clearly reduced with deep sclerectomy. Deep sclerectomy therefore represents a safe alternative to trabeculectomy. PMID- 25783166 TI - Odd-mode surface plasmon polaritons supported by complementary plasmonic metamaterial. AB - Surface plasmon polaritons (SPPs), either on metal-dielectric interfaces in optical frequencies or on structured metal surfaces in the lower frequencies, are dominantly even modes. Here we discover dominant odd-mode SPPs on a complementary plasmonic metamaterial, which is constructed by complementary symmetric grooves. We show that the fundamental SPP mode on such a plasmonic metamaterial is a tightly confined odd mode, whose dispersion curve can be tuned by the shape of groove. According to the electric field distributions of odd-mode SPPs, we propose a high-efficiency transducer using asymmetric coplanar waveguide and slot line to excite the odd-mode SPPs. Numerical simulations and experimental results validate the high-efficiency excitation and excellent propagation performance of odd-mode SPPs on the complementary plasmonic waveguides in the microwave frequencies. PMID- 25783167 TI - Coordinated regulation of melatonin synthesis and degradation genes in rice leaves in response to cadmium treatment. AB - We investigated the expression patterns of genes involved in melatonin synthesis and degradation in rice leaves upon cadmium (Cd) treatment and the subcellular localization sites of melatonin 2-hydroxylase (M2H) proteins. The Cd-induced synthesis of melatonin coincided with the increased expression of melatonin biosynthetic genes including tryptophan decarboxylase (TDC), tryptamine 5 hydroxylase (T5H), and N-acetylserotonin methyltransferase (ASMT). However, the expression of serotonin N-acetyltransferase (SNAT), the penultimate gene in melatonin biosynthesis, was downregulated, suggesting that melatonin synthesis was counter-regulated by SNAT. Notably, the induction of melatonin biosynthetic gene expression was coupled with the induction of four M2H genes involved in melatonin degradation, which suggests that genes for melatonin synthesis and degradation are coordinately regulated. The induced M2H gene expression was correlated with enhanced M2H enzyme activity. Three of the M2H proteins were localized to the cytoplasm and one M2H protein was localized to chloroplasts, indicating that melatonin degradation occurs both in the cytoplasm and in chloroplasts. The biological activity of 2-hydroxymelatonin in the induction of the plant defense gene expression was 50% less than that of melatonin, which indicates that 2-hydroxymelatonin may be a metabolite of melatonin. Overall, our data demonstrate that melatonin synthesis occurs in parallel with melatonin degradation in both chloroplasts and cytoplasm, and the resulting melatonin metabolite 2-hydroxymelatonin also acts as a signaling molecule for defense gene induction. PMID- 25783168 TI - An overactive bladder symptom and health-related quality of life short-form: validation of the OAB-q SF. AB - AIMS: The Overactive Bladder Questionnaire (OAB-q) has demonstrated robust psychometric properties in continent and incontinent OAB patients. However, there is a need for a short-form of this instrument for settings where completing the full OAB-q may be too burdensome. The purpose of this manuscript is to describe the validation of the OAB-q short-form. METHODS: Three studies were used to derive and validate the OAB-q SF: a 12-week, multicenter, open-label clinical trial of tolterodine ER (N = 865 incontinent OAB [I-OAB]; the "Noble Nested Case Control" [NCC] study; N = 523 healthy controls; N = 396 OAB); and a test-retest validation study (N = 47). Rasch analysis and confirmatory factor analysis (CFA) were performed to assess the subscale structure, and the psychometric performance of the resulting scales was evaluated. RESULTS: Based on the Rasch analysis, 6 items were retained in the OAB-q SF Symptom Bother Scale and 13-items were retained in the HRQL scale. CFAs showed excellent model fit and internal consistency in the study populations. Both scales demonstrated good convergent validity, discriminant validity, internal reliability, reproducibility, and responsiveness to change. The OAB-q SF scales clearly differentiated among I-OAB, C-OAB, and healthy controls. CONCLUSION: The OAB-q SF captures the full spectrum of OAB Symptom Bother and HRQL impact with good reliability, validity, and responsiveness, while being less time-consuming for patients to complete. PMID- 25783169 TI - Single atom devices by ion implantation. AB - To expand the capabilities of semiconductor devices for new functions exploiting the quantum states of single donors or other impurity atoms requires a deterministic fabrication method. Ion implantation is a standard tool of the semiconductor industry and we have developed pathways to deterministic ion implantation to address this challenge. Although ion straggling limits the precision with which atoms can be positioned, for single atom devices it is possible to use post-implantation techniques to locate favourably placed atoms in devices for control and readout. However, large-scale devices will require improved precision. We examine here how the method of ion beam induced charge, already demonstrated for the deterministic ion implantation of 14 keV P donor atoms in silicon, can be used to implant a non-Poisson distribution of ions in silicon. Further, we demonstrate the method can be developed to higher precision by the incorporation of new deterministic ion implantation strategies that employ on-chip detectors with internal charge gain. In a silicon device we show a pulse height spectrum for 14 keV P ion impact that shows an internal gain of 3 that has the potential of allowing deterministic implantation of sub-14 keV P ions with reduced straggling. PMID- 25783170 TI - Pride and physical activity: behavioural regulations as a motivational mechanism? AB - OBJECTIVES: The purpose of this study was to examine the association between fitness-related pride and moderate-to-vigorous physical activity (MVPA). A secondary aim was to examine behavioural regulations consistent with organismic integration theory (OIT) as potential mechanisms of the pride-MVPA relationship. DESIGN: This study used a cross-sectional design. METHODS: Young adults (N = 465; Mage = 20.55; SDage = 1.75 years) completed self-report instruments of fitness related pride, motivation and MVPA. RESULTS: Both authentic and hubristic fitness related pride demonstrated a moderate positive relationship with MVPA, as well as positive associations to more autonomous regulations. Behavioural regulations mediated the relationship between both facets of pride and MVPA with specific indirect effects noted for identified regulation and intrinsic motivation. CONCLUSION: Overall, these findings demonstrate the association between experiencing fitness-related pride and increased engagement in MVPA. The tenability of OIT was also demonstrated for offering insight into explaining the association between pride and physical activity engagement. PMID- 25783171 TI - Choosing wisely for health. PMID- 25783172 TI - Diastereoselective synthesis of gamma-lactones through reaction of enediolates with alpha,beta-unsaturated sulfoxonium salts. AB - Studies of the reaction of lithium enediolates with alpha,beta-unsaturated sulfoxonium salts are described. gamma-Lactones were formed in very good to excellent yields (82% -> 99% for 11 examples) and with very good to excellent diastereoselectivity (dr >90:10 for 10 examples), favoring the trans diastereomer. PMID- 25783173 TI - Aging does not affect the ability of human monocyte-derived dendritic cells to phagocytose Candida albicans. AB - BACKGROUND: Dendritic cells (DCs) are the most potent antigen-presenting cells, playing a key role in induction of both innate and adaptive immunity. Immunosenescence refers to age-associated changes in the immune system, which may be associated with susceptibility to infections and their clinical complications. The precise effects of aging on DCs in immunity to infections are not well understood. Among the common pathogenic microorganisms, the fungus Candida albicans is an important pathogen for the development of invasive infections, especially in immunocompromised individuals, as well as during aging. AIMS: To make a comparative in vitro evaluation of the immunomodulatory function of DCs challenged with C. albicans, by phagocytosis of the fungal cells, and determine the involvement of TLR2 and TLR4 receptors. For this purpose, DCs were generated with the use of peripheral blood monocytes from healthy young and aged subjects. RESULTS: The phagocytosis of C. albicans is developed by DCs in TLR2- and TLR4 dependent way. This mechanism is not affected by aging. CONCLUSION: Given the important role of the DCs in responses against the fungus, it is evident that if changes in phagocytosis occurred with aging, impairment in the elderly could develop. However, the evidence that phagocytosis of this fungus by DCs is not impaired with aging, brings us to the question of which are the mechanisms truly associated with the prevalence of certain diseases in the elderly. PMID- 25783175 TI - Ten-year pruritic eruption in a Japanese man. PMID- 25783180 TI - Impacts of degraded DNA on restriction enzyme associated DNA sequencing (RADSeq). AB - Degraded DNA from suboptimal field sampling is common in molecular ecology. However, its impact on techniques that use restriction site associated next generation DNA sequencing (RADSeq, GBS) is unknown. We experimentally examined the effects of in situDNA degradation on data generation for a modified double digest RADSeq approach (3RAD). We generated libraries using genomic DNA serially extracted from the muscle tissue of 8 individual lake whitefish (Coregonus clupeaformis) following 0-, 12-, 48- and 96-h incubation at room temperature posteuthanasia. This treatment of the tissue resulted in input DNA that ranged in quality from nearly intact to highly sheared. All samples were sequenced as a multiplexed pool on an Illumina MiSeq. Libraries created from low to moderately degraded DNA (12-48 h) performed well. In contrast, the number of RADtags per individual, number of variable sites, and percentage of identical RADtags retained were all dramatically reduced when libraries were made using highly degraded DNA (96-h group). This reduction in performance was largely due to a significant and unexpected loss of raw reads as a result of poor quality scores. Our findings remained consistent after changes in restriction enzymes, modified fold coverage values (2- to 16-fold), and additional read-length trimming. We conclude that starting DNA quality is an important consideration for RADSeq; however, the approach remains robust until genomic DNA is extensively degraded. PMID- 25783181 TI - Efficient access to titanaaziridines by C-H activation of N-methylanilines at ambient temperature. AB - Titanaaziridines or eta(2)-imine titanium complexes are considered key intermediates of the titanium-catalyzed hydroaminoalkylation of alkenes. Herein, we present an efficient synthetic route to this class of compounds, starting from N-methylanilines and a bis(eta(5):eta(1)-pentafulvene)titanium complex. Consecutive reactions on the eta(2)-methyleneaniline complexes, characterized for the first time, prove a high chemical versatility. In particular, hydroaminoalkylation products were found in reactions of the three-membered titanacycles with alkenes. For the first time, all the intermediates of the hydroaminoalkylation of alkenes were isolated and characterized. PMID- 25783182 TI - Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer. AB - The tumor microenvironment plays a critical role in regulating breast tumor progression. Signaling between preadipocytes and breast cancer cells has been found to promote breast tumor formation and metastasis. Exosomes secreted from preadipocytes are important components of the cancer stem cell niche. Mouse preadipocytes (3T3L1) are treated with the natural antitumor compound shikonin (SK) and exosomes derived from mouse preadipocytes are co-cultured with MCF10DCIS cells. We examine how preadipocyte-derived exosomes can regulate early-stage breast cancer via regulating stem cell renewal, cell migration, and tumor formation. We identify a critical miR-140/SOX2/SOX9 axis that regulates differentiation, stemness, and migration in the tumor microenvironment. Next, we find that the natural antitumor compound SK can inhibit preadipocyte signaling inhibiting nearby ductal carcinoma in situ (DCIS) cells. Through co-culture experiments, we find that SK-treated preadipocytes secrete exosomes with high levels of miR-140, which can impact nearby DCIS cells through targeting SOX9 signaling. Finally, we find that preadipocyte-derived exosomes promote tumorigenesis in vivo, providing strong support for the importance of exosomal signaling in the tumor microenvironment. Our data also show that targeting the tumor microenvironment may assist in blocking tumor progression. PMID- 25783183 TI - Hypermethylation of BRCA1 gene: implication for prognostic biomarker and therapeutic target in sporadic primary triple-negative breast cancer. AB - Paraffin sections from 239 cases of surgical resected mammary gland carcinomas were assessed to determine the role of BRCA1 gene methylation in sporadic triple negative breast cancer and to evaluate the relationship between BRCA1 gene methylation and clinicopathologic features of triple-negative breast cancer in the National Cancer Center, China. Diagnostic tissues collected from patients received mastectomy in the National Cancer Center from January 1, 1999 to December 31, 2008 were reviewed. Tissue microarrays were constructed using 239 triple-negative breast cancer cases and stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor. Methylation status of the BRCA1 promoter was measured by methylation-specific PCR and analyzed against clinicopathologic characteristics, subtypes, and prognosis using standard statistical methods. Among the 239 triple-negative breast cancer cases, 137 (57.3 %) showed methylation of the BRCA1. According to the immunohistochemistry results, triple negative breast cancer cases were classified into basal-like breast cancer (60.7 %) and non-basal-like breast cancer (39.3 %). The frequency of BRCA1 methylation was significantly higher in basal-like breast cancer subtype (71.7 %) than the non-basal subtype (35.1 %). Thus, BRCA1 methylation is statistically significantly correlated with basal-like breast cancer subtype (p < 0.001). Multivariate analyses further showed that BRCA1 promoter methylation is an independently predictor of overall survival (p = 0.023; HR 2.32; 95 % CI 1.12 4.81) and disease-free survival (p = 0.022; HR 2.36; 95 % CI 1.13-4.90) in triple negative breast cancer. Here we demonstrated that epigenetic alteration of key tumor suppressor gene can be a promising biomarker for the prognosis of triple negative breast cancer/basal-like breast cancer. Specifically our finding revealed that BRCA1 methylation is closely associated with a significant decrease in overall survival and disease-free survival, highlighting BRCA1 promoter methylation as promising and powerful biomarkers for effect and better prognosis of DNA damaging agents for triple-negative breast cancer/basal-like breast cancer. PMID- 25783184 TI - Impact of breast cancer subtypes and patterns of metastasis on outcome. AB - Clinical outcome of patients with stage IV breast cancer is dependent on tumor biology, extent, and localization of metastases. Routine imaging diagnostics for distant metastasis is not recommended by the national guidelines for breast cancer follow-up. In this study, we evaluated different patterns of metastases of cancer subtypes in order to generate hypotheses on individualization of follow-up after breast cancer in the adjuvant setting. Patients of the Regional Breast Cancer Center Dresden diagnosed within the years 2006-2011 were classified into the five intrinsic subtypes luminal A (ER+, Her2-, G1/2), luminal B/Her2 negative (ER+, Her2-, G3), triple positive (ER+, PR+, Her2+), Her2-enriched (ER-, Her2+), and triple negative (ER-, PR-, Her2-) and with a median follow-up of 45 months. Tumor stage at time of first diagnosis of breast cancer as well as time and site of metastasis at first diagnosis of distant metastatic disease was analyzed. Tumor specimen of 2284 female patients with primary breast cancer was classified into five subtypes. Distant recurrence-free survival at 3 years was most unfavorable in Her2-enriched (66.8 %), triple negative (75.9 %), and triple positive breast cancer (81.7 %). The same subtypes most frequently presented with visceral metastases only at first presentation: Her2-enriched 46.9 %, triple negative 45.5 %, and triple-positive breast cancer 37.5 %. Longest median survival of 2.3 years was seen in luminal A and in Her2-enriched metastatic disease, respectively. Median survival was significantly better in the luminal A, Her2-enriched, and triple-positive subtype compared to triple-negative breast cancer (p < 0.005). Differences in time to metastatic disease, first localization of metastases, and overall survival after diagnosis of metastatic disease were shown. Considering new targeted therapies and the option of surgery of oligometastases, screening for visceral metastases might be reasonable after diagnosis of Her2-positive subtypes. PMID- 25783185 TI - Overall survival (OS) endpoint: an incomplete evaluation of metastatic breast cancer (MBC) treatment outcome. AB - Overall survival (OS) has been debated as the most important clinical endpoint in metastatic breast cancer (MBC) trials mainly because survival could be influenced by treatment after progression in an era of effective subsequent-line agents. We conducted a search strategy using PubMed for all the phase 3 trials in the last two decades evaluating survival outcome in MBC. We investigated the frequency of trials reporting survival outcome and response/resistance to treatment beyond progression. One hundred fifteen trials met our eligibility criteria: 69 (60 %) evaluated chemotherapy regimens (group A), 32 (28 %) evaluated targeted therapies (group B), and 14 (12 %) focused on endocrine treatment (group C). An OS benefit was demonstrated in approximately 22 % of the trials in each group. Less than 10 % of the trials in group A and B reported response data after progression on trial therapy. Post-progression treatment resistance was only reported in group A in 3 % (2/69) of the trials. In addition, the number of lines of treatment used post-progression was reported in 14 % (10/69), 9.4 % (3/32), and 14 % (2/14) of the trials in group A, B, and C, respectively. Post-progression survival and its effect on OS was reported in only 1 % (1/69), 3 % (1/32), and 7 % (1/14) of the trials for group A, B, and C respectively. A clear paucity of post-progression treatment information is noted in the majority of the phase 3 trials for MBC. We do know that OS can be affected partially or directly by treatments used after progression. In order to assess the true clinical benefit of a new drug and to have a complete evaluation of OS outcome, a detailed collection of post progression treatment information is required and should be mandated in MBC trials. PMID- 25783186 TI - Note of clarification of data in the paper entitled association between BRIP1 (BACH1) polymorphisms and breast cancer risk. AB - With great interest, we read the recent article entitled "Association between BRIP1 (BACH1) polymorphisms and breast cancer risk: a meta-analysis" published online in Pabalan et al. (Breast Cancer Res Treat 137:553-558, 2013). This article suggests that overall summary estimates imply no associations but suggest susceptibility among carriers of the C47G polymorphism and Pro-Ser genotype in premenopausal women. The result is encouraging. Nevertheless, several key issues in this meta-analysis are worth noticing. PMID- 25783188 TI - New era for chimpanzee research: broad implications of chimpanzee research decisions. AB - The unprecedented recent decision-making about chimpanzees supported for biomedical science by the US National Institutes of Health attracted international attention and significantly changed many dimensions of chimpanzee research. Many public and media portrayals incorrectly generalized the NIH findings to conclude that chimpanzee research itself was no longer necessary. In fact, the broader question of the necessity and value of the full range of chimpanzee research was never asked, evaluated, or within the NIH's primary charge. The Institute of Medicine evaluative panel found that research with chimpanzees was necessary for some, but not all, purposes. The panel's findings also led the NIH to introduce new standards for the care and management of NIH supported chimpanzees and a new mechanism for ethical review of grant proposals involving chimpanzees. The NIH evaluation and decisions could not address all captive chimpanzees and all types of research. However, the process did underscore the need for a more expansive framework for continued ethical review and decision-making to responsibly address the future of captive chimpanzee management and research. Among the broader considerations are extension of evidence-informed standards to ensure equitable care and treatment of all chimpanzees; determining the global impact of limited captive populations; and balancing benefit and harm at individual, species, societal, and environmental levels. The breadth and longevity of impact from the current US decisions suggest the need for many voices, disciplines, and stakeholders to address the complex interplay between science, animal welfare, and global health. PMID- 25783189 TI - Acute Poisoning During Pregnancy: Observations from the Toxicology Investigators Consortium. AB - Acute poisonings during pregnancy pose a particular challenge to health care providers because of the potential for an immediate life threat or possible life long implications for both the mother and fetus, including teratogenicity of the poison or its antidote. We describe recent consequential exposures among pregnant women in the USA. We identified all poisoning cases involving pregnant women that were catalogued by the medical toxicology services across the 37 sites of the Toxicology Investigators Consortium (ToxIC) Registry of the American College of Medical Toxicology between January 2010 and December 2012. Of 17,529 exposure cases reported in the ToxIC Registry, 103 (0.6 %) involved pregnant women, 80 % of whom were symptomatic and about a quarter displayed a specific toxidrome. The majority of cases (n = 53; 51.5 %) involved intentional exposures, most commonly to pharmaceutical agents, followed by unintentional pharmaceutical exposures (10 %) and withdrawal syndromes (9 %). Non-opioid analgesics were the most common class of agents encountered (31 %), followed by sedative-hypnotics/muscle relaxants (18 %), opioids (17 %), anti-convulsants (10 %), and anti-depressants (10 %). Over a third of cases involved exposure to multiple substances, and 32 % involved exposure to more than one drug class. The most commonly administered antidotes were N-acetylcysteine (23 %), sodium bicarbonate (10 %), flumazenil (4 %), and physostigmine (4 %). About half of acute poisoning cases among pregnant women presenting for emergency care involved intentional exposures, mostly with over-the-counter analgesics and psychoactive medications. Clinicians should be cognizant of the unique circumstances, maternal and fetal risks, and management principles of the acutely poisoned pregnant woman. PMID- 25783190 TI - Synthesis of hydrolysis-resistant pyridoxal 5'-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin. AB - A set of phosphonic acid derivatives (1-4) of pyridoxal 5'-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79MUM, which was in the range of the Km of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75A resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents. PMID- 25783192 TI - Neonatal purpura fulminans due to protein C deficiency. PMID- 25783191 TI - Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl 3,14beta-dihydroxy-4,5alpha-epoxy-6alpha-(isoquinoline-3'-carboxamido)morphinan analogues as opioid receptor ligands. AB - A series of 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6alpha (isoquinoline-3'-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1'- and/or 4'-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6'- and/or 7'-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca(2+) increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6'-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. PMID- 25783193 TI - Perinatal factors associated with long-term respiratory sequelae in extremely low birthweight infants. AB - OBJECTIVE: To assess lung function at 8 years old in extremely low birthweight (ELBW) survivors and to identify perinatal determinants associated with impaired lung function. DESIGN: Retrospective cohort study. SETTING: Level III neonatal intensive care unit. PATIENTS: ELBW survivors born in 1990-2004 with available spirometry at 8 years old were studied. Children were excluded if they had a Wechsler Intelligence Scale for Children Third Edition full IQ <70. MAIN OUTCOME MEASURES: Multivariate logistic regression analysis was used to identify perinatal determinants associated with airway obstruction (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <80%) at school age and the predictive power of potential determinants. Potential risk factors and predictors assessed in this study were gestational age, birth weight, small for gestational age, sex, chorioamnionitis, premature rupture of membranes, antenatal steroids, surfactant administration, respiratory distress syndrome, postnatal steroids, severe bronchopulmonary dysplasia and bubbly/cystic appearances of the lungs by X-ray during the neonatal period. RESULTS: Of 656 ELBW survivors, 301 (45.9%) had attended a school-age follow-up at 8 years old. A total of 201 eligible children completed the lung function test. Bubbly/cystic appearance of the lungs (OR 4.84, 95% CI 1.26 to 18.70) was associated with a low FEV1/FVC ratio. Children with bubbly/cystic appearance had characteristics of immaturity and intrauterine inflammation. CONCLUSIONS: Within a cohort of ELBW infants, a bubbly/cystic appearance of the lungs in the neonatal period was the strongest determinant of a low FEV1/FVC ratio at school age. PMID- 25783194 TI - Synthesis of grafted phosphorylcholine polymer layers as specific recognition ligands for C-reactive protein focused on grafting density and thickness to achieve highly sensitive detection. AB - We studied the effects of layer thickness and grafting density of poly(2 methacryloyloxyethyl phosphorylcholine) (PMPC) thin layers as specific ligands for the highly sensitive binding of C-reactive protein (CRP). PMPC layer thickness was controlled by surface-initiated activators generated by electron transfer for atom transfer radical polymerization (AGET ATRP). PMPC grafting density was controlled by utilizing mixed self-assembled monolayers with different incorporation ratios of the bis[2-(2-bromoisobutyryloxy)undecyl] disulfide ATRP initiator, as modulated by altering the feed molar ratio with (11 mercaptoundecyl)tetra(ethylene glycol). X-ray photoelectron spectroscopy and ellipsometry measurements were used to characterize the modified surfaces. PMPC grafting densities were estimated from polymer thickness and the molecular weight obtained from sacrificial initiator during surface-initiated AGET ATRP. The effects of thickness and grafting density of the obtained PMPC layers on CRP binding performance were investigated using surface plasmon resonance employing a 10 mM Tris-HCl running buffer containing 140 mM NaCl and 2 mM CaCl2 (pH 7.4). Furthermore, the non-specific binding properties of the obtained layers were investigated using human serum albumin (HSA) as a reference protein. The PMPC layer which has 4.6 nm of thickness and 1.27 chains per nm(2) of grafting density showed highly sensitive CRP detection (limit of detection: 4.4 ng mL(-1)) with low non-specific HSA adsorption, which was improved 10 times than our previous report of 50 ng mL(-1). PMID- 25783195 TI - Methylphenidate and environmental enrichment ameliorate the deleterious effects of prenatal stress on attention functioning. AB - Either pre- or post-natal environmental factors seem to play a key role in brain and behavioral development and to exert long-term effects. Increasing evidence suggests that exposure to prenatal stress (PS) leads to motor and learning deficits and elevated anxiety, while enriched environment (EE) shows protective effects. The dopaminergic system is also sensitive to environmental life circumstances and affects attention functioning, which serves as the preliminary gate to cognitive processes. However, the effects of methylphenidate (MPH) on the dopaminergic system and attentional functioning, in the context of these life experiences, remain unclear. Therefore, we aimed to examine the effects of EE or PS on distinct types of attention, along with possible effects of MPH exposure. We found that PS impaired selective attention as well as partial sustained attention, while EE had beneficial effects. Both EE and MPH ameliorated the deleterious effects of PS on attention functioning. Considering the possible psychostimulant effect of MPH, we examined both anxiety-like behavior as well as motor learning. We found that PS had a clear anxiogenic effect, whereas EE had an anxiolytic effect. Nevertheless, the treatment with both MPH and/or EE recovered the deleterious effects of PS. In the motor-learning task, the PS group showed superior performance while MPH led to impaired motor learning. Performance decrements were prevented in both the PS + MPH and EE + MPH groups. This study provides evidence that peripubertal exposure to EE (by providing enhanced sensory, motor, and social opportunities) or MPH treatments might be an optional therapeutic intervention in preventing the PS long-term adverse consequences. PMID- 25783196 TI - Adverse childhood experiences and chronic hypothalamic-pituitary-adrenal activity. AB - Inconsistencies exist in the current literature regarding hypothalamic-pituitary adrenal (HPA) regulation following exposure to repeated stressful events. These inconsistencies stem, in part, from the limitations imposed by measuring cortisol in saliva or plasma (i.e. "point measures" of HPA activity). The present study used a cross-sectional, correlational design to examine the relationship between childhood stress (assessed using the adverse childhood experiences [ACEs] questionnaire) and hair cortisol (a biomarker of chronic HPA activity) in 55 healthy 18-24-year-old college students. Dichotomous ACE score for two models using different cut-points was significantly, inversely related to hair cortisol level (B = 1.03, p = 0.046 and B = 1.09, p = 0.031). These results are consistent with theoretical models where exposure to repeated stressful events results in chronic HPA dysregulation, which may include down-regulation under certain conditions. PMID- 25783197 TI - Response to stress in Drosophila is mediated by gender, age and stress paradigm. AB - All living organisms must maintain equilibrium in response to internal and external challenges within their environment. Changes in neural plasticity (alterations in neuronal populations, dendritic remodeling, and synaptic turnover) are critical components of the homeostatic response to stress, which has been strongly implicated in the onset of affective disorders. However, stress is differentially perceived depending on the type of stress and its context, as well as genetic background, age and sex; therefore, an individual's maintenance of neuronal homeostasis must differ depending upon these variables. We established Drosophila as a model to analyze homeostatic responses to stress. Sexually immature and mature females and males from an isogenic wild-type strain raised under controlled environmental conditions were exposed to four reproducible and high-throughput translatable stressors to facilitate the analysis of a large number of animals for direct comparisons. These animals were assessed in an open-field arena, in a light-dark box, and in a forced swim test, as well as for sensitivity to the sedative effects of ethanol. These studies establish that immature and mature females and males represent behaviorally distinct populations under control conditions as well as after exposure to different stressors. Therefore, the neural substrates mediating the stress response must be differentially expressed depending upon the hormonal status of the brain. In addition, an adaptive response to a given stressor in one paradigm was not predictive for outcomes in other paradigms. PMID- 25783198 TI - Randomized Study on Early Detection of Lung Cancer with MSCT in Germany: Results of the First 3 Years of Follow-up After Randomization. AB - INTRODUCTION: The German Lung Cancer Screening Intervention Trial (LUSI) is one of the European randomized trials investigating the efficacy of low-dose multislice computed tomography (MSCT) as a screening tool for lung cancer. In the evaluation of the first (prevalence) screening round, we observed exceptionally high early recall rates, which made the routine application of MSCT screening questionable. Because screening may behave differently in subsequent (incidence) screening rounds, we analyzed (a) basic characteristics for the annual rounds 2 to 4, which have now also been completed, and (b) the first 3 years with complete follow-up since time of randomization. METHODS: Data material was the data record of LUSI after the fourth screening round and the 3-year follow-up had been completed. Basic characteristics of screening, e.g., early recall rate, detection rate, and interval cancers as well of proportion of advanced cancers, were descriptively evaluated and, if informative, group differences were tested for statistical significance. RESULTS: Early recall rates were significantly lower in the subsequent screening rounds than in the first one if the MSCT information from the previous screening rounds was available. Detection and biopsy rates were approximately 1% or lower, ratio of benign:malignant biopsies: 1:1.6 to 1:3. CONCLUSION: Our recent data may not only settle one concern regarding high recall rates in routine MSCT screening but also indicate that screening must be strictly organized to be effective. Performance indicators are similar to those in mammography screening. Nevertheless, possible consequences for the participants (diagnostic workup of suspicious findings, biopsies) are more invasive than in mammography screening. PMID- 25783199 TI - Reduced MCMV Deltam157 viral clearance in the absence of TSAd. AB - The T cell specific adapter protein (TSAd) is expressed in activated T cells and NK cells. While TSAd is beginning to emerge as a critical regulator of Lck and Itk activity in T cells, its role in NK cells has not yet been explored. Here we have examined susceptibility to virus infections in a murine model using various viral infection models. We report that TSAd-deficient mice display reduced clearance of murine cytomegalovirus (MCMV) that lack the viral MHC class I homologue m157, which is critical for Ly49H-mediated NK cell recognition of infected cells. In this infection model, NK cells contribute in the early stages of the disease, whereas CD8+ T cells are critical for viral clearance. We found that mice infected with MCMV Deltam157 displayed reduced viral clearance in the spleen as well as reduced proliferation in spleen NK cells and CD8+ T cells in the absence of TSAd. Though no other immunophenotype was detected in the infection models tested, these data suggests that in the absence of the Ly49H ligand activation, NK cell and CD8+ T cell responses may be compromised in TSAd deficient mice. PMID- 25783200 TI - SRY gene transferred by extracellular vesicles accelerates atherosclerosis by promotion of leucocyte adherence to endothelial cells. AB - We set out to investigate whether and how SRY (sex-determining region, Y) DNAs in plasma EVs (extracellular vesicles) is involved in the pathogenesis of atherosclerosis. PCR and gene sequencing found the SRY gene fragment in plasma EVs from male, but not female, patients; EVs from male patients with CAD (coronary artery disease) had a higher SRY GCN (gene copy number) than healthy subjects. Additional studies found that leucocytes, the major source of plasma EVs, had higher SRY GCN and mRNA and protein expression in male CAD patients than controls. After incubation with EVs from SRY-transfected HEK (human embryonic kidney)-293 cells, monocytes (THP-1) and HUVECs (human umbilical vein endothelial cells), which do not endogenously express SRY protein, were found to express newly synthesized SRY protein. This resulted in an increase in the adherence factors CD11-a in THP-1 cells and ICAM-1 (intercellular adhesion molecule 1) in HUVECs. EMSA showed that SRY protein increased the promoter activity of CD11-a in THP-1 cells and ICAM-1 in HUVECs. There was an increase in THP-1 cells adherent to HUVECs after incubation with SRY-EVs. SRY DNAs transferred from EVs have pathophysiological significance in vivo; injection of SRY EVs into ApoE-/- (apolipoprotein-knockout) mice accelerated atherosclerosis. The SRY gene in plasma EVs transferred to vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis; this mechanism provides a new approach to the understanding of inheritable CAD in men. PMID- 25783202 TI - Commentary to "Robot-assisted laparoscopic pyeloplasty: Multi-institutional experience in infants". PMID- 25783201 TI - Prioritizing therapeutic targets using patient-derived xenograft models. AB - Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDXs) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximize insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design. PMID- 25783204 TI - The cost-benefit of federal investment in preventing Clostridium difficile infections through the use of a multifaceted infection control and antimicrobial stewardship program. AB - OBJECTIVE: To determine the potential epidemiologic and economic value of the implementation of a multifaceted Clostridium difficile infection (CDI) control program at US acute care hospitals DESIGN: Markov model with a 5-year time horizon PARTICIPANTS: Patients whose data were used in our simulations were limited to hospitalized Medicare beneficiaries >=65 years old. BACKGROUND: CDI is an important public health problem with substantial associated morbidity, mortality, and cost. Multifaceted national prevention efforts in the United Kingdom, including antimicrobial stewardship, patient isolation, hand hygiene, environmental cleaning and disinfection, and audit, resulted in a 59% reduction in CDI cases reported from 2008 to 2012. METHODS: Our analysis was conducted from the federal perspective. The intervention we modeled included the following components: antimicrobial stewardship utilizing the Antimicrobial Use and Resistance module of the National Healthcare Safety Network (NHSN), use of contact precautions, and enhanced environmental cleaning. We parameterized our model using data from CDC surveillance systems, the AHRQ Healthcare Cost and Utilization Project, and literature reviews. To address uncertainty in our parameter estimates, we conducted sensitivity analyses for intervention effectiveness and cost, expenditures by other federal partners, and discount rate. Each simulation represented a cohort of 1,000 hospitalized patients over 1,000 trials. RESULTS In our base case scenario with 50% intervention effectiveness, we estimated that 509,000 CDI cases and 82,000 CDI-attributable deaths would be prevented over a 5-year time horizon. Nationally, the cost savings across all hospitalizations would be $2.5 billion (95% credible interval: $1.2 billion to $4.0 billion). CONCLUSIONS: The potential benefits of a multifaceted national CDI prevention program are sizeable from the federal perspective. PMID- 25783203 TI - Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes. AB - The mammalian homotypic fusion and vacuole protein sorting (HOPS) complex is comprised of six subunits: VPS11, VPS16, VPS18, VPS39, VPS41 and the Sec1/Munc18 (SM) family member VPS33A. Human HOPS has been predicted to be a tethering complex required for fusion of intracellular compartments with lysosomes, but it remains unclear whether all HOPS subunits are required. We showed that the whole HOPS complex is required for fusion of endosomes with lysosomes by monitoring the delivery of endocytosed fluorescent dextran to lysosomes in cells depleted of individual HOPS proteins. We used the crystal structure of the VPS16/VPS33A complex to design VPS16 and VPS33A mutants that no longer bind each other and showed that, unlike the wild-type proteins, these mutants no longer rescue lysosome fusion with endosomes or autophagosomes in cells depleted of the endogenous proteins. There was no effect of depleting either VIPAR or VPS33B, paralogs of VPS16 and VPS33A, on fusion of lysosomes with either endosomes or autophagosomes and immunoprecipitation showed that they form a complex distinct from HOPS. Our data demonstrate the necessity of recruiting the SM protein VPS33A to HOPS via its interaction with VPS16 and that HOPS proteins, but not VIPAR or VPS33B, are essential for fusion of endosomes or autophagosomes with lysosomes. PMID- 25783205 TI - Prospective motion correction of 3D echo-planar imaging data for functional MRI using optical tracking. AB - We evaluated the performance of an optical camera based prospective motion correction (PMC) system in improving the quality of 3D echo-planar imaging functional MRI data. An optical camera and external marker were used to dynamically track the head movement of subjects during fMRI scanning. PMC was performed by using the motion information to dynamically update the sequence's RF excitation and gradient waveforms such that the field-of-view was realigned to match the subject's head movement. Task-free fMRI experiments on five healthy volunteers followed a 2 * 2 * 3 factorial design with the following factors: PMC on or off; 3.0mm or 1.5mm isotropic resolution; and no, slow, or fast head movements. Visual and motor fMRI experiments were additionally performed on one of the volunteers at 1.5mm resolution comparing PMC on vs PMC off for no and slow head movements. Metrics were developed to quantify the amount of motion as it occurred relative to k-space data acquisition. The motion quantification metric collapsed the very rich camera tracking data into one scalar value for each image volume that was strongly predictive of motion-induced artifacts. The PMC system did not introduce extraneous artifacts for the no motion conditions and improved the time series temporal signal-to-noise by 30% to 40% for all combinations of low/high resolution and slow/fast head movement relative to the standard acquisition with no prospective correction. The numbers of activated voxels (p<0.001, uncorrected) in both task-based experiments were comparable for the no motion cases and increased by 78% and 330%, respectively, for PMC on versus PMC off in the slow motion cases. The PMC system is a robust solution to decrease the motion sensitivity of multi-shot 3D EPI sequences and thereby overcome one of the main roadblocks to their widespread use in fMRI studies. PMID- 25783206 TI - Upper bounds on noise and model misspecification for robust estimation of real time brain activity from functional near infrared spectroscopy. AB - The robust characterization of real-time brain activity carries potential for many applications. However, the contamination of measured signals by various instrumental, environmental, and physiological sources of noise introduces a substantial amount of signal variance and, consequently, challenges real-time estimation of contributions from underlying neuronal sources. Functional near infrared spectroscopy (fNIRS) is an emerging imaging modality whose real-time potential is yet to be fully explored. The objectives of the current study are to (i) validate a time-dependent linear model of hemodynamic responses in fNIRS, and (ii) test the robustness of this approach against measurement noise (instrumental and physiological) and mis-specification of the hemodynamic response basis functions (amplitude, latency, and duration). We propose a linear hemodynamic model with time-varying parameters, which are estimated (adapted and tracked) using a dynamic recursive least square algorithm. Owing to the linear nature of the activation model, the problem of achieving robust convergence to an accurate estimation of the model parameters is recast as a problem of parameter error stability around the origin. We show that robust convergence of the proposed method is guaranteed in the presence of an acceptable degree of model misspecification and we derive an upper bound on noise under which reliable parameters can still be inferred. While here applied to fNIRS, the proposed methodology is applicable to other hemodynamic-based imaging technologies such as functional magnetic resonance imaging. PMID- 25783207 TI - Investigating the field-dependence of the Davis model: Calibrated fMRI at 1.5, 3 and 7T. AB - Gas calibrated fMRI in its most common form uses hypercapnia in conjunction with the Davis model to quantify relative changes in the cerebral rate of oxygen consumption (CMRO2) in response to a functional stimulus. It is most commonly carried out at 3T but, as 7T research scanners are becoming more widespread and the majority of clinical scanners are still 1.5T systems, it is important to investigate whether the model used remains accurate across this range of field strengths. Ten subjects were scanned at 1.5, 3 and 7T whilst performing a bilateral finger-tapping task as part of a calibrated fMRI protocol, and the results were compared to a detailed signal model. Simulations predicted an increase in value and variation in the calibration parameter M with field strength. Two methods of defining experimental regions of interest (ROIs) were investigated, based on (a) BOLD signal and (b) BOLD responses within grey matter only. M values from the latter ROI were in closer agreement with theoretical predictions; however, reassuringly, ROI choice had less impact on CMRO2 than on M estimates. Relative changes in CMRO2 during motor tasks at 3 and 7T were in good agreement but were over-estimated at 1.5T as a result of the lower signal to noise ratio. This result is encouraging for future studies at 7T, but also highlights the impact of imaging and analysis choices (such as ASL sequence and ROI definition) on the calibration parameter M and on the calculation of CMRO2. PMID- 25783208 TI - Heterogeneously catalyzed direct C-H thiolation of heteroarenes. AB - The first general methodology for the direct thiolation of electron-rich heteroarenes was developed by employing Pd/Al2 O3 , a recoverable and commercially available heterogeneous catalyst, and CuCl2 . This method represents an operationally simple approach for the synthesis of these valuable compounds. Preliminary mechanistic studies indicate a heterogeneous catalytic system, in which both metals play a complementary role in the formation of the thiolated products. PMID- 25783209 TI - Beyond EUV lithography: a comparative study of efficient photoresists' performance. AB - Extreme ultraviolet (EUV) lithography at 13.5 nm is the main candidate for patterning integrated circuits and reaching sub-10-nm resolution within the next decade. Should photon-based lithography still be used for patterning smaller feature sizes, beyond EUV (BEUV) lithography at 6.x nm wavelength is an option that could potentially meet the rigid demands of the semiconductor industry. We demonstrate simultaneous characterization of the resolution, line-edge roughness, and sensitivity of distinct photoresists at BEUV and compare their properties when exposed to EUV under the same conditions. By using interference lithography at these wavelengths, we show the possibility for patterning beyond 22 nm resolution and characterize the impact of using higher energy photons on the line edge roughness and exposure latitude. We observe high sensitivity of the photoresist performance on its chemical content and compare their overall performance using the Z-parameter criterion. Interestingly, inorganic photoresists have much better performance at BEUV, while organic chemically amplified photoresists would need serious adaptations for being used at such wavelength. Our results have immediate implications for deeper understanding of the radiation chemistry of novel photoresists at the EUV and soft X-ray spectra. PMID- 25783210 TI - Immediate Reconstruction with Autologous fat Transfer Following Breast-Conserving Surgery. AB - This study explores the technical viability of autologous fat grafting for immediate partial breast reconstruction following the primary conservative surgery for breast cancer; restoring volume, shape, and symmetry to the treated breast. We analyze the impact in relation to mammographic follow-up and the subjective degree of satisfaction with esthetic results and although we didn't have any local failure during the observation period; we understand that is too early for any kind of conclusion. From June of 2010 to July of 2011, 20 patients were selected for breast-conserving surgery (BCS) with partial breast reconstruction with autologous fat grafting performed during the same operation by the same medical team. The fat graft was injected in the subcutaneous and intraglandular breast tissue around the resected area. We performed an overcorrection, predicting a resorbing of about 30-50% of the volume grafted. All patients received the literature-based recommendations for breast cancer treatment with complementary radiotherapy. The follow-up period after the completion of radiotherapy ranged from 13 to 29 months. The average volume grafted was 121 cc and it was 2.1 times larger than the resected volume. The esthetic scores were considered very good or good in the majority of cases. Mammograms were taken every 6 months after radiotherapy and only one patient had a mammogram classified as BI-RADS 3, suggesting fat necrosis. The remaining patients were classified as BI-RADS 2. Immediate autologous fat grafting is a promising technique for partial breast reconstruction after BCS. It is associated with high patient and physician satisfaction. It is an alternative for reconstruction of small- and medium-sized breasts. This technique has the advantage that enables the reconstruction of defects in areas difficult to repair, particularly in the upper inner quadrants. It also may reduce the need for major glandular or myocutaneous flaps mobilization. PMID- 25783211 TI - When do performance-based risk-sharing arrangements make sense? PMID- 25783212 TI - [Selected bacterial infections of the skin in childhood]. AB - Bacterial infections of the skin are often seen by dermatologists. The majority of infections are caused by the gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. These induce blistering/erosive (impetigo, ecthymata) and abceeding (folliculitis) infections of the skin, respectively. Owing to their differences in virulence factors and host immunity, these strains can lead to varying presentations and courses of the infections. This review focuses on impetigo, folliculitis, perianal streptococcal dermatitis, and ecthymata. PMID- 25783213 TI - [Molecular diagnostics in melanoma]. AB - The molecular landscape of melanoma is changing more rapidly than ever since new molecular technology approaches have made it possible to examine human melanoma for genetic alterations underlying the disease. In recent years, these approaches have identified new familial melanoma susceptibility genes, most of them also conferring risk to other cancers. This has implications for clinical testing and surveillance. Furthermore, molecular testing of melanoma to determine therapeutic eligibility for targeted therapies is now standard of care and should be familiar to the dermatologist. PMID- 25783214 TI - Biological role of mannose binding lectin: From newborns to centenarians. AB - Mannose binding lectin (MBL) is a protein of innate immunity that activates the complement and promotes opsonophagocytosis. The deficiency of MBL due to several common gene polymorphisms significantly enhances the risk of severe infections, particularly in the neonatal age and in childhood. On the contrary, the role of the protein in carcinogenesis and atherogenesis is still debated: MBL has a relevant role against neoplastic cells, but some studies described a protective effect of low levels of MBL toward breast cancer and a longer survival of lung cancer patients with a reduced MBL activity. Similarly, some studies concluded on the protective role of low levels of MBL toward cardiovascular diseases while other focused on a higher risk of myocardial infarction in subjects with a deficient activity of the protein. More recently, a role of MBL in the clearance of senescent cells emerged, and a study in two large cohorts of centenarians demonstrated that a high biological activity of the protein enhances the risk of autoimmune diseases. This body of data strongly suggests that the optimal levels of MBL activity depend on the age and on the environmental context of each subject. PMID- 25783215 TI - Outside rules inside: the role of electron-active substituents in thiophene-based heterophenoquinones. AB - The biradicaloid vs. quinoidal character of the ground state of thiophene-based heterophenoquinones bearing donor or acceptor groups is investigated. Keeping the conjugation length fixed, namely, the 5,5'-bis(3,5-di-tert-butyl-4-oxo-2,5 cyclohexadiene-1-ylidene)-2,2'-dihydroxy bithiophene backbone, an opposite effect occurs depending on the donating or withdrawing nature of the substituents. The character of the ground state depends not only on the electronic nature of the substituents but also on their position on the molecular skeleton: donor groups on the 3,3'-positions of the bithiophene central core stabilize a quinoidal ground state, whereas a biradicaloid electronic structure results from the introduction of the same donor groups onto the lateral phenones. Withdrawing groups behave similar to donors, but in the opposite direction. PMID- 25783216 TI - Effect of Dy(3+) or Eu(2+) co-activator on a BaCa(SO4)2:Ce(3+) mixed alkaline earth sulfate phosphor. AB - The individual emission and energy transfer between Ce(3+) and Eu(2+) or Dy(3+) in BaCa(SO4)2 mixed alkaline earth sulfate phosphor prepared using a co precipitation method is described. The phosphor was characterized by X-ray diffraction (XRD) and photoluminescence (PL) studies and doped by Ce;Eu and Dy rare earths. All phosphors showed excellent blue-orange emission on excitation with UV light. PL measurements reveal that the emission intensity of Eu(2+) or Dy(3+) dopants is greater than when they are co-doped with Ce(3+). An efficient Ce(3+) -> Eu(2+) [(2) T2g(4f(6)5d) -> (8)S7/2(4f7)] and Ce(3+) -> Dy(3+) ((4)F9/2 -> (6)H15/2 and (4)F9/2 -> (6)H13/2) energy transfer takes place in the BaCa(SO4)2 host. A strong blue emission peak was observed at 462 nm for Eu(2+) ions and an orange emission peak at 574 nm for Dy(3+) ions. Hence, this phosphor may be used as a lamp phosphor. PMID- 25783217 TI - Chemical two-photon fluorescence. AB - We describe a method based on a caged fluorescent molecule that can act as a chemical two-photon probe. It is composed of an organic fluorophore and a ruthenium-bipyridine complex that acts as a photoremovable quencher. For the fluorophore to be emissive, two independent photons must act on the molecule: the first photon frees the fluorescent ligand from the Ru complex and the second photon excites the fluorescence. In this two-photon regime, the emission is not proportional to the excitation intensity but rather to its second power, as in traditional two-photon systems based on ultrashort pulsed high-power lasers. This quadratic relationship implies a much higher spatial precision on the z-axis when the probe is used in a microscopy technique. The chemical nature of the two photon excitation mechanism allows the use of inexpensive low-power lasers. PMID- 25783218 TI - Enrichment and Characterization of a Psychrotolerant Consortium Degrading Crude Oil Alkanes Under Methanogenic Conditions. AB - Anaerobic alkane degradation via methanogenesis has been intensively studied under mesophilic and thermophilic conditions. While there is a paucity of information on the ability and composition of anaerobic alkane-degrading microbial communities under low temperature conditions. In this study, we investigated the ability of consortium Y15, enriched from Shengli oilfield, to degrade hydrocarbons under different temperature conditions (5-35 degrees C). The consortium could use hexadecane over a low temperature range (15-30 degrees C). No growth was detected below 10 degrees C and above 35 degrees C, indicating the presence of cold-tolerant species capable of alkane degradation. The preferential degradation of short chain n-alkanes from crude oil was observed by this consortium. The structure and dynamics of the microbial communities were examined using terminal restriction fragment length polymorphism (T-RFLP) fingerprinting and Sanger sequencing of 16S rRNA genes. The core archaeal communities were mainly composed of aceticlastic Methanosaeta spp. Syntrophaceae related microorganisms were always detected during consecutive transfers and dominated the bacterial communities, sharing 94-96 % sequence similarity with Smithella propionica strain LYP(T). Phylogenetic analysis of Syntrophaceae related clones in diverse methanogenic alkane-degrading cultures revealed that most of them were clustered into three sublineages. Syntrophaceae clones retrieved from this study were mainly clustered into sublineage I, which may represent psychrotolerant, syntrophic alkane degraders. These results indicate the wide geographic distribution and ecological function of syntrophic alkane degraders. PMID- 25783219 TI - Long-term outcomes of remote magnetic navigation for ablation of supraventricular tachycardias. AB - BACKGROUND: Little is known about the long-term outcomes of catheter ablation of supraventricular tachycardia (SVT) using remote magnetic navigation system (RMN). METHODS: One hundred twenty patients underwent catheter ablation of SVTs with RMN (Niobe, Stereotaxis, USA): atrioventricular nodal re-entrant tachycardia (AVNRT; n = 59), atrioventricular re-entrant tachycardia (AVRT; n = 45), and focal atrial tachycardia (AT, n = 16). The outcome of AVRT with right free wall accessory pathway was compared with those of a group of 26 consecutive patients undergoing manual ablation. RESULTS: Mean follow-up period was 2.2 +/- 1.4 years. Overall arrhythmia-free survival was 86%; AVRT (77%), AVNRT (96%), and focal AT (71%). After the learning period (initial 50 cases), procedural outcomes had improved for AVRT and AVNRT (91% in overall group, 90% in AVRT group, 100% in AVNRT group, and 68% in focal AT group). The recurrence-free rate was higher for the free wall accessory pathways than those of the other sites (92 vs. 73%, log-rank P = 0.06). Furthermore, when it is confined for the right free wall accessory pathway, RMN showed excellent long-term outcome (7/7, 100 %) compared to the results of manual approach (18/26, 69.2%, log-rank P = 0.07). CONCLUSIONS: RMN showed favorable long-term outcomes for the ablation of SVT. In our experience, RMN-guided ablation may be associated with a higher success rate as compared to manual ablation when treating right-sided free wall pathways. PMID- 25783220 TI - The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity? AB - Depression is a major psychiatric disorder affecting more than 120 million people worldwide every year. Changes in monoaminergic transmitter release are suggested to take part in the pathophysiology of depression. However, more recent experimental evidence suggests that glutamatergic mechanisms might play a more central role in the development of this disorder. The importance of the glutamatergic system in depression was particularly highlighted by the discovery that N-methyl-D-aspartate (NMDA) receptor antagonists (particularly ketamine) exert relatively long-lasting antidepressant like effects with rapid onset. Importantly, the antidepressant-like effects of NMDA receptor antagonists, but also other antidepressants (both classical and novel), require activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Additionally, expression of AMPA receptors is altered in patients with depression. Moreover, preclinical evidence supports an important involvement of AMPA receptor-dependent signaling and plasticity in the pathophysiology and treatment of depression. Here we summarize work published on the involvement of AMPA receptors in depression and discuss a possible central role for AMPA receptors in the pathophysiology, course and treatment of depression. PMID- 25783221 TI - Sensing the body in chronic pain: a review of psychophysical studies implicating altered body representation. AB - There is growing evidence that chronic pain conditions can have an associated central pathology, involving both cortical reorganisation and an incongruence between expected and actual sensory-motor feedback. While such findings are primarily driven by the recent proliferation of neuroimaging studies, the psychophysical tasks that complement those investigations have received little attention. In this review, we discuss the literature that involves the subjective appraisal of body representation in patients with chronic pain. We do so by examining three broad sensory systems that form the foundations of the sense of physical self in patients with common chronic pain disorders: (i) reweighting of proprioceptive information; (ii) altered sensitivity to exteroceptive stimuli; and, (iii) disturbed interoceptive awareness of the state of the body. Such findings present compelling evidence for a multisensory and multimodal approach to therapies for chronic pain disorders. PMID- 25783222 TI - Effects of individual health topic familiarity on activity patterns during health information searches. AB - BACKGROUND: Non-medical professionals (consumers) are increasingly using the Internet to support their health information needs. However, the cognitive effort required to perform health information searches is affected by the consumer's familiarity with health topics. Consumers may have different levels of familiarity with individual health topics. This variation in familiarity may cause misunderstandings because the information presented by search engines may not be understood correctly by the consumers. OBJECTIVE: As a first step toward the improvement of the health information search process, we aimed to examine the effects of health topic familiarity on health information search behaviors by identifying the common search activity patterns exhibited by groups of consumers with different levels of familiarity. METHODS: Each participant completed a health terminology familiarity questionnaire and health information search tasks. The responses to the familiarity questionnaire were used to grade the familiarity of participants with predefined health topics. The search task data were transcribed into a sequence of search activities using a coding scheme. A computational model was constructed from the sequence data using a Markov chain model to identify the common search patterns in each familiarity group. RESULTS: Forty participants were classified into L1 (not familiar), L2 (somewhat familiar), and L3 (familiar) groups based on their questionnaire responses. They had different levels of familiarity with four health topics. The video data obtained from all of the participants were transcribed into 4595 search activities (mean 28.7, SD 23.27 per session). The most frequent search activities and transitions in all the familiarity groups were related to evaluations of the relevancy of selected web pages in the retrieval results. However, the next most frequent transitions differed in each group and a chi-squared test confirmed this finding (P<.001). Next, according to the results of a perplexity evaluation, the health information search patterns were best represented as a 5-gram sequence pattern. The most common patterns in group L1 were frequent query modifications, with relatively low search efficiency, and accessing and evaluating selected results from a health website. Group L2 performed frequent query modifications, but with better search efficiency, and accessed and evaluated selected results from a health website. Finally, the members of group L3 successfully discovered relevant results from the first query submission, performed verification by accessing several health websites after they discovered relevant results, and directly accessed consumer health information websites. CONCLUSIONS: Familiarity with health topics affects health information search behaviors. Our analysis of state transitions in search activities detected unique behaviors and common search activity patterns in each familiarity group during health information searches. PMID- 25783223 TI - Testing reliability and validity of the eHealth Literacy Scale (eHEALS) for older adults recruited online. AB - Currently, vast amounts of health information and health management tools are available to the public online. To maximize the benefits of these e-health technologies, it is important to assess the e-health literacy of individuals. The eHealth Literacy Scale has been used widely in the past several years, but mainly in younger populations. The purpose of this study was to test the psychometric aspects of the eHealth Literacy Scale for older adults using a secondary data analysis (N=866; mean age, 62.8+/-8.5 years). Reliability of the eHealth Literacy Scale was examined by calculating alpha coefficients and conducting test-retest procedures. Its validity was assessed using exploratory factor analysis and the hypothesis testing procedure. Findings demonstrated that eHealth Literacy Scale was internally consistent (alpha=.94) and stable (t244=-1.48, P=.140). The exploratory factor analysis yielded a single factor structure explaining 67.3% of the variance. The hypothesis testing also supported the validity of eHealth Literacy Scale. In recent years, there have been great efforts to use e-health interventions to engage patients in healthcare and to help them manage their own health. Our study suggests that the eHealth Literacy Scale, a short screening tool for e-health literacy, can be successfully used for older adults. PMID- 25783224 TI - Examination of the effect of Stratum Corneum isolation process on the integrity of the barrier function: a confocal Raman spectroscopy study. AB - BACKGROUND: Stratum Corneum (SC) is the most superficial layer of the epidermis. It plays the main barrier role against water loss and the aggression of external chemical and biological substances. Thermal treatment in warm purified water followed by trypsin incubation of excised human skin is a well-established in vitro method for SC removal. Different protocols can be found in literature, but little is described about the effect of temperature and trypsin during isolation process on its barrier function. METHODS: In this study, we have examined the epidermis and SC matrix structural change upon isolation by means of confocal Raman spectroscopy. RESULTS: Several spectral features, i.e. in-depth and planar lateral packing, conformational order and secondary structure have been investigated to reveal modifications in the structural properties of the lipids and proteins in the SC. Thermal treatment at 60 degrees C leads to a losing in compactness and a steeper concentration of the lipid and protein descriptors while the trypsinization step modifies the organization of the proteins and of the lipid barrier, leading to a domain organization. CONCLUSIONS: The present study improves the knowledge of the effects on the barrier function of SC removal protocol. PMID- 25783225 TI - Bioconversion of FR901459, a novel derivative of cyclosporin A, by Lentzea sp. 7887. AB - FR901459, a product of the fungus Stachybotrys chartarum No. 19392, is a derivative of cyclosporin A (CsA) and a powerful immunosuppressant that binds cyclophilin. Recently, it was reported that CsA was effective against hepatitis C virus (HCV). However, FR901459 lacks active moieties, which are essential for synthesizing more potent and safer derivatives of this anti-HCV agent. Here we identified an actinomycete strain (designated 7887) that was capable of efficient bioconversion of FR901459. Structural elucidation of the isolated bioconversion products (1-7) revealed that compounds 1-4 were mono-hydroxylated at the position of 1-MeBmt or 9-MeLeu, whereas compounds 5-7 were bis-hydroxylated at both positions. The results of morphological and chemical characterization, as well as phylogenetic analysis of 16S ribosomal DNA (rDNA), suggested that strain 7887 belonged to the genus Lentzea. Comparison of the FR901459 conversion activity of strain 7887 with several other Lentzea strains revealed that although all examined strains metabolized FR901459, strain 7887 had a characteristic profile with respect to bioconversion products. Taken together, these findings suggest that strain 7887 can be used to derivative FR901459 to produce a chemical template for further chemical modifications that may provide more effective and safer anti-HCV drugs. PMID- 25783227 TI - Real-Time In Vivo Characterization of Primary Liver Tumors With Diffuse Optical Spectroscopy During Percutaneous Needle Interventions: Feasibility Study in Woodchucks. AB - OBJECTIVE: This study presents the first in vivo real-time optical tissue characterization during image-guided percutaneous intervention using near infrared diffuse optical spectroscopy sensing at the tip of a needle. The goal of this study was to indicate transition boundaries from healthy tissue to tumors, namely, hepatic carcinoma, based on the real-time feedback derived from the optical measurements. MATERIALS AND METHODS: Five woodchucks with hepatic carcinoma were used for this study. The woodchucks were imaged with contrast enhanced cone beam computed tomography with a flat panel detector C-arm system to visualize the carcinoma in the liver. In each animal, 3 insertions were performed, starting from the skin surface toward the hepatic carcinoma under image guidance. In 2 woodchucks, each end point of the insertion was confirmed with pathologic examination of a biopsy sample. While advancing the needle in the animals under image guidance such as fluoroscopy overlaid with cone beam computed tomography slice and ultrasound, optical spectra were acquired at the distal end of the needles. Optical tissue characterization was determined by translating the acquired optical spectra into clinical parameters such as blood, water, lipid, and bile fractions; tissue oxygenation levels; and scattering amplitude related to tissue density. The Kruskal-Wallis test was used to study the difference in the derived clinical parameters from the measurements performed within the healthy tissue and the hepatic carcinoma. Kurtoses were calculated to assess the dispersion of these parameters within the healthy and carcinoma tissues. RESULTS: Blood and lipid volume fractions as well as tissue oxygenation and reduced scattering amplitude showed to be significantly different between the healthy part of the liver and the hepatic carcinoma (P < 0.05) being higher in normal liver tissue. A decrease in blood and lipid volume fractions and tissue oxygenation as well as an increase in scattering amplitude were observed when the tip of the needle crossed the margin from the healthy liver tissue to the carcinoma. The kurtosis for each derived clinical parameter was high in the hepatic tumor as compared with that in the healthy liver indicating intracarcinoma variability. CONCLUSIONS: Tissue blood content, oxygenation level, lipid content, and tissue density all showed significant differences when the needle tip was guided from the healthy tissue to the carcinoma and can therefore be used to identify tissue boundaries during percutaneous image-guided interventions. PMID- 25783226 TI - Nonomuraea indica sp. nov., novel actinomycetes isolated from lime-stone open pit mine, India. AB - A Gram-positive, aerobic, nonmotile actinomycete strain designated DRQ-2(T) was isolated from the soil sample collected from lime-stone open pit mine from the Gulbarga region, Karnataka province, India. Strain DRQ-2(T) was identified as a member of the genus Nonomuraea by a polyphasic approach. Strain DRQ-2(T) could be differentiated from other members of the genus Nonomuraea on the basis of physiology and 16S rRNA gene sequence analysis. The 16S rRNA gene sequence similarity of strain DRQ-2(T) showed highest sequence similarity to Nonomuraea muscovyensis DSM 45913(T) (99.1%), N. salmonea DSM 43678(T) (98.2%) and N. maheshkhaliensis JCM 13929(T) with 98.0%, respectively. Chemotaxonomic properties showing predominant menaquinones of MK-9 (H4), MK-9(H2) and MK-9(H6), major polar lipids comprised diphosphatidylglycerol, phosphatidylmono methyl ethanolamine (PME), phosphatidylethanolamine (PE), hydroxy-PME (OH-PME), hydroxy PE (OH-PEE), phosphatidylglycerol (PG), ninhydrin-positive phosphoglycolipid and unknown phospholipid, fatty acids with major amounts of i-C16:0, ai-C15:0 and ai-C17:0 supported allocation of the strain to the genus Nonomuraea. Results of DNA-DNA hybridization and physiological tests allowed genotypic and phenotypic differentiation of strain DRQ-2(T) from closely related species. The genomic DNA G+C content of the organism was 72.5 mol%. On the basis of phenotypic, chemotypic and molecular characteristics, strain DRQ-2(T) represents a novel species of the genus Nonomuraea, for which the name N. indica sp. nov. is proposed, with type strain DRQ-2(T) (=NCIM 5480(T)= CCTCC AA 209050(T)). PMID- 25783228 TI - Three-dimensional black-blood T1-weighted turbo spin-echo techniques for the diagnosis of deep vein thrombosis in comparison with contrast-enhanced magnetic resonance imaging: a pilot study. AB - OBJECTIVES: The objective of this study was to evaluate the feasibility of a novel 3-dimensional turbo spin-echo technique with isotropic resolution for the diagnosis of deep vein thrombosis (DVT) in comparison with contrast-enhanced magnetic resonance imaging (CE-MRI) and sonography. MATERIALS AND METHODS: Thirteen patients (8 males, 17-93 years) with proven DVT in duplex ultrasound (n = 11) or with pulmonary embolism and suspected to have DVT (n = 2) were consecutively imaged at 3.0 T with 1.2-mm isotropic-resolution volumetric isotropic turbo spin-echo acquisition (VISTA). Sensitivity (SE), specificity (SP), positive and negative predictive values (PPV and NPV, respectively), Cohen kappa, as well as accuracy of VISTA-MRI were calculated and compared with CE-MRI and sonography as a standard of reference. Image quality and diagnostic confidence were assessed on a 4-point scale. RESULTS: Image quality and diagnostic confidence level of VISTA-MRI and CE-MRI were comparable (3.54 vs 3.55 and 3.80 vs 3.77; both P values are nonsignificant). Using CE-MRI as the criterion standard, there was a high agreement between the CE-MRI and the 3 dimensional VISTA examinations for the detection of DVT, with kappa of 0.89 for reader 1 and kappa of 0.88 for reader 2 (both P < 0.001). The SE, SP, PPV, NPV, as well as accuracy of VISTA-MRI were 92.5%, 97.9%, 89.3%, 98.6%, and 97.1% for reader 1 as well as 90.7%, 97.9%, 89.1%, 98.3%, and 96.8% for reader 2. For both readers, combined comparison of VISTA-MRI and sonography resulted in an SE, SP, PPV, and NPV of 77.8%, 94.8%, 85.4%, and 91.6%, respectively. CONCLUSIONS: Volumetric isotropic turbo spin-echo acquisition magnetic resonance imaging can be used to diagnose DVT with good to excellent agreement compared with CE-MRI and sonography. It might be useful when contrast media is prohibited and in patients with suspected thrombosis of the iliac veins, which can be hard to detect with sonography. PMID- 25783229 TI - The core competencies for mental, neurological, and substance use disorder care in sub-Saharan Africa. AB - The 2010 Global Burden of Disease Study points to a changing landscape in which non-communicable diseases, such as mental, neurological, and substance use (MNS) disorders, account for an increasing proportion of premature mortality and disability globally. Despite evidence of the need for care, a remarkable deficit of providers for MNS disorder service delivery persists in sub-Saharan Africa. This critical workforce can be developed from a range of non-specialist and specialist health workers who have access to evidence-based interventions, whose roles, and the associated tasks, are articulated and clearly delineated, and who are equipped to master and maintain the competencies associated with providing MNS disorder care. In 2012, the Neuroscience Forum of the Institute of Medicine convened a meeting of key stakeholders in Kampala, Uganda, to discuss a set of candidate core competencies for the delivery of mental health and neurological care, focusing specifically on depression, psychosis, epilepsy, and alcohol use disorders. This article discusses the candidate core competencies for non specialist health workers and the complexities of implementing core competencies in low- and middle-income country settings. Sub-Saharan Africa, however, has the potential to implement novel training initiatives through university networks and through structured processes that engage ministries of health. Finally, we outline challenges associated with implementing competencies in order to sustain a workforce capable of delivering quality services for people with MNS disorders. PMID- 25783230 TI - Treatment of heavy oil wastewater by UASB-BAFs using the combination of yeast and bacteria. AB - A novel system integrating an upflow anaerobic sludge blanket (UASB) reactor and a two-stage biological aerated filter (BAF) system was investigated as advanced treatment of heavy oil wastewater with large amounts of dissolved recalcitrant organic substances and low levels of nitrogen and phosphorus nutrients. #1 BAF, inoculated with two yeast strains (Candida tropicalis and Rhodotorula dairenensis), was installed in the upper reaches of #2 BAF inoculated with activated sludge. During the 180-day study period, the chemical oxygen demand (COD), ammonia nitrogen (NH3-N), oil and polyaromatic hydrocarbons (PAHs) in the wastewater were removed by 90.2%, 90.8%, 86.5% and 89.4%, respectively. Although the wastewater qualities fluctuated and the hydraulic retention time continuously decreased, the effluent quality index met the national discharge standard steadily. The UASB process greatly improved the biodegradability of the wastewater, while #1 BAF played an important role not only in degrading COD but also in removing oil and high molecular weight PAHs. This work demonstrates that the hybrid UASB-BAFs system containing yeast-bacteria consortium has the potential to be used in bioremediation of high-strength oily wastewater. PMID- 25783231 TI - Rasch validation of the Prosthetic Mobility Questionnaire: A new outcome measure for assessing mobility in people with lower limb amputation. AB - OBJECTIVE: To create a new outcome measure of mobility in people with lower limb amputation, based on a pool of 14 items assessing prosthetic mobility, comprising the 12-item Prosthesis Evaluation Questionnaire (Mobility Section) plus 2 new items. DESIGN: Cross-sectional study. SUBJECTS: A total of 100 subjects (median age 58 years; 46 males; median body mass index 23.8) who had recently undergone lower limb amputation. METHODS: Each patient completed the 14-item questionnaire twice: (i) at admission to the rehabilitation unit for prosthetic rehabilitation training; (ii) at 6-month follow-up after discharge. RESULTS: After Rasch analysis, 2 items were deleted (one due to misfit, the other because showing large (> 0.30) positive correlation of residuals with two other items (local dependence). The remaining items fitted the Rasch model (internal construct validity), giving a new 12-item scale with a 5-level response format, the Prosthetic Mobility Questionnaire (PMQ), which demonstrated unidimensionality, lack of differential item functioning, and good reliability indices (person separation reliability = 0.87; Cronbach's alpha 0.88). CONCLUSION: Although further studies are needed to increase confidence in clinical use of the PMQ, this new questionnaire appears to be a promising, psychometrically-sound patient reported outcome measure for assessment of mobility in subjects with lower limb amputation who use a prosthesis. PMID- 25783234 TI - Let's see action on Willis' framework for education. AB - I don't suppose many of you will have ploughed through the 72 pages that make up the Shape of Caring review, which sets out a framework for the future of nursing education. It is not the first such report, and won't be the last. This one contains many noble sentiments and sensible ideas on how nurses and care assistants should be trained and developed throughout their careers, but it fails to deliver a coherent strategy that everyone can get behind. PMID- 25783235 TI - Cancer task force chair yields to pressure over 'glaring omission'. PMID- 25783236 TI - Shape of Caring recommends new training model to reinforce skills. PMID- 25783237 TI - Intensive intervention for teenage mothers widened. PMID- 25783232 TI - The ureteric bud epithelium: morphogenesis and roles in metanephric kidney patterning. AB - The mammalian metanephric kidney is composed of two epithelial components, the collecting duct system and the nephron epithelium, that differentiate from two different tissues -the ureteric bud epithelium and the nephron progenitors, respectively-of intermediate mesoderm origin. The collecting duct system is generated through reiterative ureteric bud branching morphogenesis, whereas the nephron epithelium is formed in a process termed nephrogenesis, which is initiated with the mesenchymal-epithelial transition of the nephron progenitors. Ureteric bud branching morphogenesis is regulated by nephron progenitors, and in return, the ureteric bud epithelium regulates nephrogenesis. The metanephric kidney is physiologically divided along the corticomedullary axis into subcompartments that are enriched with specific segments of these two epithelial structures. Here, we provide an overview of the major molecular and cellular processes underlying the morphogenesis and patterning of the ureteric bud epithelium and its roles in the cortico-medullary patterning of the metanephric kidney. PMID- 25783239 TI - 'Good care guide' invites feedback from relatives. PMID- 25783238 TI - Pay increase for Scotland's NHS staff puts them ahead of others in UK. PMID- 25783240 TI - Team with a mountain to climb. PMID- 25783241 TI - Australian safe staffing ratios lack flexibility, says top nurse after visit. PMID- 25783243 TI - Cancer specialist staff crisis looms. PMID- 25783244 TI - Joint diabetes prevention initiative unveiled for England. PMID- 25783246 TI - NHS staff to be given help to lose weight and live healthier lifestyles. PMID- 25783247 TI - 'The standards of a degree-based nurse are absolutely unchangeable'. PMID- 25783253 TI - Chronic pain. AB - Essential facts Chronic pain is pain that persists or recurs for more than three months. It may be related to a condition, or may be pain from an injury or operation that continues after healing would usually take place. According to guidance from the Scottish Intercollegiate Guidelines Network (SIGN), around 18 per cent of Europe's population are currently affected by moderate to severe chronic pain. It has a considerable effect on quality of life, and can cause significant suffering and disability. PMID- 25783254 TI - Incentives that draw staff to a trust. AB - Many trusts are struggling to fill nursing vacancies. In an attempt to stand out from the crowd, some are offering loyalty packages and promoting their positive working environments, as well as the opportunities for training and career progression. Those that present a 'rose-tinted' picture risk alienating new recruits. PMID- 25783255 TI - Working towards a new standard of care. AB - The Care Certificate is aimed at all healthcare assistants and support workers to ensure they deliver 15 standards of effective care. It is not a legal requirement, so there are concerns that in a sector such as social care, it may be more costly to implement than existing training programmes. PMID- 25783256 TI - Give cancer patients a choice about fertility. AB - Surveys by Breast Cancer Care suggest that younger women with breast cancer can be denied the chance to preserve their fertility. Treatments, including chemotherapy, can cause infertility, so healthcare professionals should discuss options such as egg freezing beforehand. PMID- 25783257 TI - Real concern. PMID- 25783258 TI - Voices - Like nurses, education must adapt to changes in care, says Janet Finch. AB - Nurses and midwives will play a vital role in meeting the health challenges of the future. While it is impossible to foresee all the ways in which practice will change over the next decade, we do know that nurses and midwives will be working with an ageing population, with more community-based services and growing public expectations. PMID- 25783259 TI - Why it's good to talk. PMID- 25783260 TI - Wasted time. PMID- 25783261 TI - Ethical dilemmas. PMID- 25783262 TI - Readers panel - Is pay deal too little, too late? PMID- 25783263 TI - Starting out - My efforts to promote nursing's 6Cs in practice inspired me and others. PMID- 25783266 TI - NHS choices: check your heart age. PMID- 25783267 TI - Anatomy Quiz Pro app. PMID- 25783269 TI - Shifting the financial burden of health care has a heavy price. PMID- 25783270 TI - Professionals who feel valued by their managers deliver better care. PMID- 25783271 TI - I am puzzled that staffing ratios continue to be controversial. PMID- 25783272 TI - Good nursing requires caring practitioners with knowledge. PMID- 25783273 TI - I wish RCNi had been around to help me with my master's degree. PMID- 25783275 TI - Website opens up a vast universe of knowledge for every nurse. PMID- 25783276 TI - To cut benefits because someone is obese would be inhumane. PMID- 25783277 TI - Ian Jacobs 1958-2014. PMID- 25783278 TI - Deborah Bone 1963-2014. PMID- 25783280 TI - Infection prevention and control. AB - All newly registered graduate nurses are required to have the appropriate knowledge and understanding to perform the skills required for patient care, specifically the competencies identified in the Nursing and Midwifery Council's essential skills clusters. This article focuses on the third essential skills cluster - infection prevention and control. It provides an overview and discussion of the key skills and behaviours that must be demonstrated to meet the standards set by the Nursing and Midwifery Council. In doing so, it considers the key principles of infection prevention and control, including local and national policies, standard infection control precautions, risk assessment, standard isolation measures and asepsis. PMID- 25783281 TI - Synthesising the literature as part of a literature review. AB - This article examines how to synthesise and critique research literature. To place the process of synthesising the research literature into context, the article explores the critiquing process by breaking it down into seven sequential steps. The article explains how and why these steps need to be kept in mind if a robust comprehensive literature search and analysis are to be achieved. The article outlines how to engage in the critiquing process and explains how the literature review needs to be assembled to generate a logical and reasoned debate to examine a topic of interest or research in more detail. PMID- 25783282 TI - Child maltreatment: every nurse's business. AB - Every nurse has a responsibility for protecting children, even nurses who do not work directly with children. However, nurses may be reluctant to deal with child maltreatment issues because they do not want to get things wrong or make a situation worse. The aim of this article is to assist nurses in their child protection role. It describes the different types of child maltreatment, the risk factors and potential consequences. The nurse's role in recognising and responding to suspected child maltreatment is discussed. PMID- 25783283 TI - Chronic pain in adults. PMID- 25783284 TI - Challenging the system. PMID- 25783286 TI - Suited, booted and ready to help. AB - UK-Med recruits and co-ordinates healthcare professionals from the NHS to respond to international humanitarian crises. PMID- 25783287 TI - A massive opportunity. PMID- 25783288 TI - Student life - Helping hands in the placement process. PMID- 25783289 TI - Prognostic factors for prediction of survival of hepatocellular cancer patients after selective internal radiation therapy. AB - AIM: In this study, it was aimed to explore the prognostic factors in patients who received selective internal radiation therapy for hepatocellular cancer. MATERIALS AND METHODS: A retrospective evaluation was made of 28 (24 male, 4 female, mean age 65.4 +/- 6.8 years) hepatocellular cancer patients who received selective internal radiation therapy with Y-90 resin microspheres. Using Cox proportional hazards regression analysis, the relationship between age, gender, MELD score, serum albumin and AFP levels, number of liver lesions, size of the largest lesion, absence of (18)F-FDG uptake, maximum standardized uptake value and overall survival times was analyzed. RESULTS: Treatment was applied to the right lobe in 22 and both in 6 patients. Mean treatment dose was 1.5 +/- 0.2 GBq. Number of liver lesions were 1, <5 and multiple in 16, 5 and 7 patients, respectively, and the mean size of the largest lesion was 41.5 mm (min-max 15-160 mm). While (18)F-FDG uptake was seen in 24 patients, liver lesions were hypometabolic in 4 patients. Mean SUVmax of liver lesions was calculated as 5.3 +/- 0.3. During the mean 17.8 (min-max 2-39) months follow-up period, 19 patients died. Median survival time was computed as 18 +/- 5 months (95% CI 8.1-27.8). Age (p = 0.04), serum AFP level (p = 0.03) and size of the largest lesion (p = 0.02) had a significant negative effect on survival according to the Cox proportional hazards regression analysis. CONCLUSION: Age, serum AFP level and the size of the largest liver lesion have a negative significant effect on survival of hepatocellular cancer patients who received selective internal radiation therapy. PMID- 25783290 TI - Letter to the Editor. PMID- 25783291 TI - An implemented MRI program to eliminate radiation from the evaluation of pediatric appendicitis. AB - BACKGROUND: Recent efforts have been directed at reducing ionizing radiation delivered by CT scans to children in the evaluation of appendicitis. MRI has emerged as an alternative diagnostic modality. The clinical outcomes associated with MRI in this setting are not well-described. METHODS: Review of a 30-month institutional experience with MRI as the primary diagnostic evaluation for suspected appendicitis (n=510). No intravenous contrast, oral contrast, or sedation was administered. Radiologic and clinical outcomes were abstracted. RESULTS: MRI diagnostic characteristics were: sensitivity 96.8% (95% CI: 92.1% 99.1%), specificity 97.4% (95% CI: 95.3-98.7), positive predictive value 92.4% (95% CI: 86.5-96.3), and negative predictive value 98.9% (95% CI: 97.3%-99.7%). Radiologic time parameters included: median time from request to scan, 71 minutes (IQR: 51-102), imaging duration, 11 minutes (IQR: 8-17), and request to interpretation, 2.0 hours (IQR: 1.6-2.6). Clinical time parameters included: median time from initial assessment to admit order, 4.1 hours (IQR: 3.1-5.1), assessment to antibiotic administration 4.7 hours (IQR: 3.9-6.7), and assessment to operating room 9.1 hours (IQR: 5.8-12.7). Median length of stay was 1.2 days (range: 0.2-19.5). CONCLUSION: Given the diagnostic accuracy and favorable clinical outcomes, without the potential risks of ionizing radiation, MRI may supplant the role of CT scans in pediatric appendicitis imaging. PMID- 25783292 TI - Management of periorbital microcystic lymphatic malformation with blepharoptosis: Surgical treatment combined with intralesional bleomycin injection. AB - OBJECTIVES: Periorbital microcystic lymphatic malformations (LM) can cause severe symptoms, such as blepharoptosis, amblyopia, chemosis, strabismus, diminished vision, and blindness. The purpose of this study was to evaluate the clinical outcome in periorbital microcystic LM patients with blepharoptosis who underwent surgical treatment combined with intralesional bleomycin injection. PATIENTS AND METHODS: A retrospective study including nine patients diagnosed as periorbital microcystic LM with blepharoptosis was conducted. All of the patients underwent surgical treatment and bleomycin injection from January 2010 to January 2014. The lesion was resected through the lower eyebrow and/or a coronal incision at the first stage, and levator resection was performed at the second stage. Any persistent lesion or its recurrence was managed by intralesional bleomycin injection. RESULTS: Blepharoptosis and visual obstruction were corrected in all patients. Mean follow-up was 24.6 months. Six patients had recurrence during the follow-up, and two patients who had partial eyelid closure after the second stage surgery recovered in three months. Amblyopia, astigmatism, and strabismus were not improved after treatment. All of the patients had excellent aesthetic improvement and corrected blepharoptosis. CONCLUSIONS: Resection through a lower eyebrow and coronal incision and levator resection performed in two stages can quickly correct the visual impairment caused by periorbital microcystic lymphatic malformation with blepharoptosis. Intralesional bleomycin injection is a promising adjunctive therapy for residual or recurrent lesions after surgery. PMID- 25783293 TI - Trends in incidence of childhood malignant solid tumors in Japan: Estimation based on hospital-based registration. AB - BACKGROUND/PURPOSE: In Japan, an increase in hepatoblastoma with low birth weight has become evident since the 1990 s, and there is concern about a possible increase in unfavorable neuroblastomas after the cessation of mass screening in 2004. METHODS: The trends in incidence of malignant solid tumors in children younger than 15 years of age were inferred by evaluating registration incidence in the registry of the Japanese Society of Pediatric Surgeons. RESULTS: A significant trend toward an increase in the registration incidence for hepatoblastoma was observed (p<0.001). Hepatoblastomas with low birth weight (<1500 g) represented as many as 16% of hepatoblastomas. In hepatocellular carcinoma, there was a significant trend toward a decrease (p=0.042). The registration incidence of nonmass screening-detected neuroblastoma remained unchanged until 2003, but the registration incidence in the period from 2004 to 2012 was significantly higher than that in the period from 1996 to 2003 (p=0.021). There was an increase in the relative incidence of favorable stages after the cessation of mass screening. CONCLUSIONS: The notable increase in hepatoblastoma during the last three decades is partly attributed to an increase in hepatoblastoma in children of low birth weight, but this alone is not sufficient to explain the increase in hepatoblastoma. The increase in neuroblastoma after the halt of mass screening is so minimal that it is not recommended to consider reimplementation of mass screening. PMID- 25783294 TI - Environmental pesticides increase the risk of developing hypertrophic pyloric stenosis. AB - BACKGROUND: Hypertrophic pyloric stenosis (HPS) is a condition noted within the first several weeks of life that results in hypertrophy of the pyloric muscle between the stomach and duodenum. The etiology has not been elucidated but genetic and environmental influences are suspected. We hypothesized that agricultural pesticides would be associated with an increased incidence of pyloric stenosis. STUDY DESIGN: Data from infants with HPS were obtained from the Indiana Birth Defects Registry (IBDR) for all counties in Indiana from 2005 to 2009. Data from all live births were obtained from the Indiana State Health Department (ISHD). Maternal demographics and clinical characteristics of infants were abstracted. The US Geological Survey (USGS) provided estimated use of agricultural pesticides (EPEST), and these values were correlated with HPS incidence. Univariate and multivariate logistical regression models were used to assess the association between HPS risk and pesticide use. RESULTS: A total of 442,329 newborns were studied with 1313 HPS cases recorded. The incidence of HPS was 30/10,000 live births. HPS incidence was correlated with total county pesticide use, as well as subcategories of pesticides (fungicides, fumigants, insecticides, herbicides). Indiana counties were then divided into low, moderate and high pesticide use (mean+/-standard deviation: 127,722+/-73,374, 308,401+/ 36,915, and 482,008+/-97,260pounds of pesticides). Incidence of HPS was 26, 29, and 36 cases per 10,000 in low, moderate and high pesticide-use counties respectively. Subset analysis showed that the positive association between HPS and county pesticide use was more likely for male infants from mothers who were white, aged 20-35 years, had education at high school or lower, and smoked (p<0.05). CONCLUSION: Pesticide use correlated significantly with incidence of HPS. Positive correlations between HPS risk and pesticide use were found for most risk factors. Further studies will be needed to verify our findings and further delineate the nature of this correlation. PMID- 25783295 TI - Impact of central surgical review in a study of malignant germ cell tumors. AB - BACKGROUND: Verification of surgical staging has received little attention in clinical oncology trials. Central surgical review was undertaken during a study of malignant pediatric germ cell tumors. METHODS: Children's Oncology Group study AGCT0132 included central surgical review during the study. Completeness of submitted data and confirmation of assigned stage were assessed. Review responses were: assigned status confirmed, assignment withheld pending review of additional information requested, or institutional assignment of stage disputed with explanation given. Changes in stage assignment were at the discretion of the enrolling institution. RESULTS: A total of 206 patients underwent central review. Failure to submit required data elements or need for clarification was noted in 40%. Disagreement with stage assignment occurred in 10% with 17/21 discordant patients reassigned to stage recommended by central review. Four ovarian tumor patients not meeting review criteria for Stage I remained in that stratum by institutional decision. Two-year event free survival in Stage I ovarian patients was 25% for discordant patients compared to 57% for those meeting Stage I criteria by central review. CONCLUSIONS: Central review of stage assignment improved complete data collection and assignment of correct tumor stage at study entry, and allowed for prompt initiation of chemotherapy in patients determined not to have Stage I disease. PMID- 25783296 TI - Protective effect of early placement of nasogastric tube with solid dilator on tissue damage and stricture formation after caustic esophageal burns in rabbits. AB - BACKGROUND: The ingestion of caustic substances remains an important public health issue worldwide. Children represent 80% of the ingestion injury population globally. Accidental alkaline material accounts for most caustic ingestions. There is no conclusive evidence of tissue damage and stricture protection of a nasogastric-tube with a solid dilator in the literature, therefore it was hypothesized that early intraesophageal tube placement does not cause additional histopathologic damage and prevents strictures. METHODS: An exploratory study on experimental caustic esophageal burns in a rabbit model was designed. In the treated group a silicone tube was placed immediately after causing the burns, while the untreated group followed the natural course of the burn. On the twenty secondday, an esophagectomy was performed on all animals for microscopic (Histopathologic Damage Score and Stenosis Index) and macroscopic analysis. RESULTS: Forty animals were randomly divided into two groups. The Histopathologic Damage Score was 3.7+/-1.1 in the treated group versus 3.9+/-1.2 in the untreated group (p=.9690). The Stenosis Index was 0.6+/-0.1 in treated rabbits versus 2.3+/ 0.2 in untreated (p<.0001). CONCLUSION: The early placement of an intraesophageal tube with solid dilator prevents stenosis formation and does not produce greater tissue damage. PMID- 25783297 TI - Intestinal fatty acid-binding protein levels in Necrotizing Enterocolitis correlate with extent of necrotic bowel: results from a multicenter study. AB - BACKGROUND: Intestinal fatty acid-binding protein (I-FABP) is considered as a specific marker for enterocyte damage in necrotizing enterocolitis (NEC). OBJECTIVE: The purpose of this study was to evaluate the association of plasma and urinary I-FABP levels with the extent of macroscopic intestinal necrosis in surgical NEC. METHODS: We combined data from prospective trials from two large academic pediatric surgical centers. Nine and 10 infants with surgical NEC were included, respectively. Plasma and urinary of I-FABP at disease onset were correlated with the length of intestinal resection during laparotomy. RESULTS: Median length of bowel resection was 10cm (range 2.5-50) and 17cm (range 0-51), respectively. Median I-FABP levels were 53ng/mL (range 6.3-370) and 4.2ng/mL (range 1.1-15.4) in plasma in cohort 1 respectively cohort 2 and 611ng/mL (range 3-23,336) in urine. The length of bowel resection significantly correlated with I FABP levels in plasma (Rho 0.68; p=0.04 and Rho 0.66;p=0.04) and in urine (Rho 0.92; p=0.001). CONCLUSION: This 'proof of concept' study demonstrates that plasma and urine I-FABP levels at disease onset was strongly associated with the length of intestinal resection in surgical NEC. This offers further evidence that I-FABP levels are a promising biomarker for assessing intestinal necrosis in infants with advanced NEC. PMID- 25783298 TI - Apocynin attenuates testicular ischemia-reperfusion injury in rats. AB - OBJECTIVE: This study was designed to examine the possible protective effect of apocynin, a NADPH oxidase inhibitor, against torsion/detorsion (T/D) induced ischemia/reperfusion (I/R) injury in testis. METHODS: Male Wistar albino rats were divided into sham-operated control, and either vehicle, apocynin 20mg/kg- or apocynin 50mg/kg-treated T/D groups. In order to induce I/R injury, left testis was rotated 720 degrees clockwise for 4 hours (torsion) and then allowed reperfusion (detorsion) for 4 hours. Left orchiectomy was done for the measurement of tissue malondialdehyde (MDA), glutathione (GSH) levels, myeloperoxidase (MPO) activity, and luminol, lucigenin, nitric oxide (NO) and peroxynitrite chemiluminescences (CL). Testicular morphology was examined by light microscopy. RESULTS: I/R caused significant increases in tissue luminol, lucigenin, nitric oxide and peroxynitrite CL demonstrating increased reactive oxygen and nitrogen metabolites. As a result of increased oxidative stress tissue MPO activity, MDA levels were increased and antioxidant GSH was decreased. On the other hand, apocynin treatment reversed all these biochemical indices, as well as histopathological alterations that were induced by I/R. According to data, although lower dose of apocynin tended to reverse the biochemical parameters, high dose of apocynin provides better protection since values were closer to the control levels. CONCLUSION: Findings of the present study suggest that NADPH oxidase inhibitor apocynin by inhibiting free radical generation and increasing antioxidant defense exerts protective effects on testicular tissues against I/R. The protection with apocynin was more pronounced with high dose. PMID- 25783299 TI - Global comparison of pediatric surgery workforce and training. AB - INTRODUCTION: The number of pediatric surgeons and their distribution vary greatly throughout the world. The purpose of this study is to examine potential influential factors including the length of education and training, pediatric population, birth rate, and gross domestic product (GDP) per capita. METHODS: An internet search was conducted to determine the duration of education from grade school to pediatric surgery fellowship, number of pediatric surgeons, birth rate, GDP, and population under 15 years of age in 15 countries. The number of pediatric surgeons per million children was correlated with these factors. RESULTS: The number of pediatric surgeons per million children varied from 0.51 to 29.3. The total length of education from grade school to completion of pediatric surgery training ranged from 23 to 29 years. There was no correlation between pediatric surgeons per million children with the duration of training. The number of pediatric surgeon per million children was inversely correlated with the birth rate. There was a positive correlation between the GDP per capita and pediatric surgeons per million children. CONCLUSION: There is a tremendous variability in pediatric surgeons around the world. There appears to be a significant shortage of pediatric surgeons in countries with a high birth rate and low GDP per capita. PMID- 25783300 TI - Subcutaneous entomophthoromycosis mimicking soft-tissue sarcoma in children. AB - AIM: Subcutaneous entomophthoromycosis (EM) is an uncommon fungal infection of childhood. This article is intended to draw the attention of pediatric surgeons to the fact that EM can mimic soft-tissue tumor. METHODS: It is a retrospective review of 16 children treated for subcutaneous EM between 2000 and 2013. RESULTS: The median age of patients was 3.5 years. The typical lesion was a discoid subcutaneous mass that can be easily lifted from deeper tissues (the doughnut lifting sign). Lesions were mostly distributed in the lower half of body. All the patients were immunocompetent. Correct clinical diagnosis was made only in 4 cases while others were mistaken for a tumor. All the 8 children who underwent wide excision of the pseudotumor had local recurrence. Supersaturated solution of potassium iodide was curative in 11 cases while addition of itraconazole was needed in one case. One child died of multi-drug resistant infection. The mean treatment duration was 4.7 months (range 2-8 months). CONCLUSION: Subcutaneous EM can mimic soft-tissue tumor. High index of suspicion is essential to avoid misdiagnosis and inappropriate treatment. A newly described "doughnut-lifting sign' may be helpful in clinical diagnosis. Emergence of multi-drug resistant infection is a source of concern. PMID- 25783301 TI - Impact of experience on quality outcomes in single-incision laparoscopy for simple and complex appendicitis in children. AB - BACKGROUND: Single-incision laparoscopic appendectomy (SILA) is an effective treatment for appendicitis in children. We report our experience with SILA, focusing on how surgeon experience may impact quality outcomes. METHODS: A retrospective review of patients who underwent SILA from August 2009 to November 2013 was performed. Patients were grouped by early experience, late experience without surgical trainees, and late experience with trainees and further stratified into simple and complex appendicitis. RESULTS: SILA was performed on 703 patients with a mean age of 11.8+/-3.9years. Four hundred eleven (58.5%) patients were diagnosed with simple and 292 (41.5%) with complex appendicitis. There was a significant decrease in operative time between early and late groups for both simple and complex appendicitis. Following the introduction of surgical trainees, there was a significant increase in operative time compared to the late group for simple appendicitis. There were no significant differences in complication rates between any of the groups. CONCLUSION: The adoption of SILA requires a significant learning curve even for the experienced laparoscopist with the potential for decreased operative times with experience. While there may be an increase in operative time with the introduction of trainees, this does not impact quality outcomes. PMID- 25783302 TI - Assessing medical care availability for student athletes of a large urban high school district. AB - BACKGROUND: The need for medical care for student athletes is mounting, as participation in high school athletics is continuing to rise. This study assessed medical care available to high school student athletes in a large, urban school district in California that has not been studied since 2002. By surveying athletic directors and coaches, we expected to find inadequate availability of medical care in the studied district and predicted that care would be more widely available for student athletes at larger high schools. METHODS: We developed and validated a questionnaire assessing practice and game coverage, emergency preparedness, treatment, and injury prevention measures. The survey was administered to athletic directors and coaches at a school district athletic directors' meeting. RESULTS: Forty-three (57%) of 75 distributed surveys were completed. We found that 70% of schools did not staff a healthcare provider for practices, 28% did not staff home games, and 30% did not staff away games, for any sports. We found no significant differences between school sizes with respect to physician referrals after a student was injured, provision of health education, or implementation of emergency action plans. CONCLUSIONS: Although these data do not support our hypothesis of larger schools providing better medical care, it suggests that there are multiple areas of inadequate healthcare regardless of school size. We identified numerous gaps; thus, future work will examine the impact of these gaps. PMID- 25783303 TI - Selective inhibition of nitric oxide synthase causes increased muscle thickness in rat esophagus. AB - AIM: Achalasia is a primary motor dysfunction of esophagus which can be created experimentally by nitric oxide synthase (NOS) inhibition. Although several theories have been suggested, mechanism of increased esophageal muscle thickness in achalasia is still unclear. An experimental study was performed to evaluate the esophageal muscle thickness after selective inhibition of NOS in rats. MATERIALS AND METHODS: Wistar albino rats (n=18) weighing 150-200g of both sexes were included in the study. After anesthetization with ketamine hydrochloride, esophageal body and distal esophagus were sampled in control group (CG, n=6). In sham group (SG, n=6), intraperitoneal saline (1ml) injection was performed for 21days. l-NAME (l-nitroarginin metyl ester, selective inhibitor of NOS) group (LNAMEG, n=6) received 100mg/kg/d l-NAME intraperitoneally for 21days. The esophageal body and distal esophagus were removed for histopathological analysis in each group. All samples were evaluated for total and circular muscle thickness with hemotoxylene-eosine (HE) staining. RESULTS: None of the samples showed pathologic finding in esophageal mucosa. There was no difference between CG and SG for total and circular muscle thickness in esophageal body and distal esophagus. LNAMEG had higher median levels of both total and circular muscle thickness than CG and SG in esophageal body (P<0.05). However, in distal esophageal segments, only total muscle thickness was statistically higher in LNAMEG than CG and SG (P<0.05). CONCLUSION: Selective inhibition of NOS causes increased total smooth muscle thickness in esophageal body and distal esophagus. However, this effect could not detected in circular muscle in the distal esophagus. We suggest that NOS inhbition not only increases esophageal peristalsis but also causes muscle hypertrophy in esophagus. PMID- 25783304 TI - Pediatric thyroidectomy in a high volume thyroid surgery center: Risk factors for postoperative hypocalcemia. AB - INTRODUCTION: Hypocalcemia is a common complication following thyroid surgery. We seek to report on our experience in pediatric thyroidectomy in a high volume thyroid surgery center and accurately assess the incidence of postoperative hypocalcemia. MATERIALS AND METHODS: A retrospective review of patients aged 18 and younger who underwent thyroid surgery between 1992 and 2013. The primary endpoints were the occurrence of postoperative hypocalcemia as by defined as a nadir calcium <8.0mg/dL and being discharged on oral calcium supplementation, need for intravenous calcium and the occurrence of permanent hypoparathyroidism. RESULTS: 171 patients who underwent 186 thyroid operations were analyzed. The average age was 15.4years with 82.3% female. The most common indications for surgery were nodular disease (74.7%) and hyperthyroidism (12.4%). 24 patients (12.9%) experienced postoperative hypocalcemia with 13 (7.0%) requiring intravenous calcium infusion. One patient (0.9%) experienced permanent hypoparathyroidism. Risk factors for postoperative hypocalcemia included total thyroidectomy (OR 7.39, p<0.01), central and bilateral lateral neck dissection (OR 22.26, p=0.01), Graves' disease (OR 3.99, p=0.02), and malignancy (OR 2.96, p=0.03). CONCLUSIONS: Pediatric patients who undergo total thyroidectomy for underlying malignancy or Graves' disease and those who have more extensive nodal dissections are at increased risk of developing this postoperative hypocalcemia. These patients may benefit from more vigilant preoperative preparation and postoperative calcium and vitamin D supplementation. PMID- 25783305 TI - Protective effects of dexpanthenol in an experimental model of necrotizing enterocolitis. AB - BACKGROUND/PURPOSE: In pathogenesis of necrotizing enterocolitis (NEC), both oxidative stress and inflammation are considerable risk factors. The study was designed to evaluate whether administration of dexpanthenol (Dxp) is able to attenuate intestinal injury through the antioxidant and antiinflammatory mechanisms in a neonatal rat model of NEC. METHODS: Forty newborn pups divided into four groups were included in the study: control, control+Dxp, NEC, and NEC+Dxp. NEC was induced by hyperosmolar formula and additionally the pups were exposed to hypoxia/hyperoxia and cold stress. They were sacrificed on postnatal day four, and their intestinal tissues were analyzed biochemically and histopathologically. RESULTS: Dxp caused a significant decrease in intestinal damage as determined by the histological score, villus height and number of goblet cells in NEC groups (p<0.0001). Tissue malondialdehyde, total oxidant status, and oxidative stress indexes levels were higher in the NEC group than in the control and control+Dxp groups (p<0.001). These values were reduced in the pups treated with Dxp (p<=0.004). Superoxide dismutase, glutathione peroxidase, and reduced glutathione activities were significantly reduced in the NEC group compared to the others (p<0.005). Treatment with Dxp significantly reduced elevations in tissue homogenate levels of tumor necrosis factor-alpha and interleukin-1beta in the NEC+Dxp group (p=0.002 and p=0.01, respectively). CONCLUSIONS: Dexpanthenol seems to have antiinflammatory and antioxidant properties. Prophylaxis with Dxp has a potential to reduce the severity of intestinal damage in NEC in the animals. PMID- 25783306 TI - Clinical management of infantile cholelithiasis. AB - PURPOSE: Infantile cholelithiasis is a rare disease process, and management strategies are poorly defined. We therefore examined the risk factors, complications, and management of this disease at our institution. METHODS: We retrospectively reviewed infants with cholelithiasis diagnosed on ultrasound between 1997 and 2013. Details of the patient's medical history, presentation, imaging findings, laboratory values, and treatment were reviewed and analyzed. RESULTS: Over the 16-year period, 50 infants were evaluated for cholelithiasis. Thirty-seven (74%) had at least one risk factor for gallstone development which included total parenteral nutrition, diuretic therapy, cephalosporin antibiotic treatment, sepsis, congenital heart disease (CHD), prematurity, or a malabsorptive gastrointestinal condition. Thirteen (26%) infants were symptomatic, most commonly presenting with emesis and jaundice. Complications from gallstones included choledocholithiasis (9), cholecystitis (3), and pancreatitis (1). Nearly half (6/13) of patients with complicated cholelithiasis had CHD. Of infants presenting with complications, 9 had a cholecystectomy, most commonly via a laparoscopic approach, 2 had an ERCP for choledocholithiasis, and 2 were medically managed. In patients managed conservatively, resolution of gallstones occurred in 25%. CONCLUSIONS: Infantile cholelithiasis has variable outcomes ranging from spontaneous resolution to choledocholithiasis or cholecystitis. While patients with complicated cholelithiasis often undergo an operation, infants <1year of age have higher anesthetic and surgical risks. Conservative management with ERCP or medical treatment can also be successful, which offers an alternative to operative intervention in properly selected patients. PMID- 25783307 TI - Passing the baton: The pediatric surgical perspective on transition. AB - BACKGROUND/PURPOSE: Transition of care from pediatric to adult providers is garnering intense national interest in pediatrics but is largely driven by nonsurgeons. We sought to describe the preferences of pediatric surgeons and their current transition practice patterns for various populations and wondered whether gender, experience, or practice setting affected surgeons' perspectives. METHODS: All American Pediatric Surgical Association (APSA) members were surveyed electronically. Responses were voluntary and confidential. RESULTS: Survey response rate was 22%. Most surgeons (95%) treated patients up to 22 years of age, and many cared for older patients (23-26 years, 49%; 27-30 years, 25%; 31-40 years, 18%; >40 years, 13%). Developmentally delayed adults comprised a significant portion of this population (54%). Congenital conditions such as Hirschsprung disease (25%), anorectal malformations (22%) and cystic fibrosis (22%) were most commonly reported. About half (52%) of respondents reported institutional limits for age. Lack of qualified adult surgeons was felt to be the greatest barrier to transition (p<0.001). Experience, gender and practice type did not significantly affect opinions of transition. CONCLUSIONS: Pediatric surgeons care for adult patients with a variety of surgical conditions, particularly those with developmental delay and congenital anomalies. The perception of a deficit of qualified adult providers warrants further exploration. Understanding the barriers to surgical transition represents a critical step in improving the quality and appropriateness of care transitions. PMID- 25783308 TI - Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center. AB - BACKGROUND: First generation cephalosporins are commonly used as antibiotic prophylaxis prior to surgery. Patients labeled as penicillin-allergic are often precluded from receiving cephalosporins because of an allergic cross-reactivity. The aims of this study were to evaluate the clinical practice for surgical prophylaxis at Nationwide Children's Hospital and to determine the incidence of adverse effects and allergic reactions when using cephalosporins in patients labeled as penicillin-allergic. METHODS: A retrospective chart review was performed to identify patients who were allergic to penicillin, penicillin antibiotic family, who required surgical treatment for an existing medical condition, and received an antibiotic to prevent surgical site infection. RESULTS: Five hundred thirteen penicillin-allergic patients were identified, encompassing 624 surgical cases. Cephalosporins were administered in 153 cases (24.5%) with cefazolin used 83% of the time. Only one documented case of nonanaphylactic reaction was reported. Clindamycin was the most common cephalosporin substitute (n=387), and the reported adverse reaction rate was 1.5%. No cases of anaphylaxis were documented. CONCLUSIONS: Our data suggest that the administration of cephalosporins for surgical prophylaxis following induction of anesthesia in a patient with a known or reported penicillin-allergy appears appropriate and results in a lower adverse event rate that when clindamycin is administered. PMID- 25783309 TI - A comparison of injuries sustained from recreational compared to organized motorized vehicle use in children. AB - PURPOSE: To examine the injury severity and patterns of injury for pediatric motorized recreational vehicle (MRV) drivers injured during organized events (OE) compared to recreational use (RU). METHODS: All pediatric MRV injuries between 2006 and 2012 in our institutional trauma registry were studied for mechanism of injury, initial evaluation, and treatment. Injuries with an Abbreviated Injury Scale >=2 were categorized by body region and diagnosis. RESULTS: Out of 589 collisions, 92 (16%) occurred during an OE. Compared to RU drivers, OE drivers were more likely to wear helmets (92% vs. 40%, p<0.001) and other protective equipment (79% vs. 6%, p<0.001). There was no difference in rates of hospital admission, rates of surgical intervention, injury severity scores, rates of intensive care unit admission, or lengths of stay. There were no differences in injuries by body region or injury type, except that dislocations were more common in OE drivers (2% vs. 0%, p=0.038). CONCLUSION: Despite higher rates of helmet and protective gear use, pediatric MRV drivers participating in OEs sustain similarly severe injuries as drivers using MRVs recreationally. No differences were observed in body regions involved or outcomes. Public perception that OE use of MRV for children is safe should be addressed. PMID- 25783310 TI - Risk of malignancy for each Bethesda class in pediatric thyroid nodules. AB - PURPOSE: The Bethesda classification for cytology is used to classify thyroid nodules into one of six categories, and for each category there is an implied cancer risk and also recommendation for management. Despite lack of data in children, the American thyroid association promotes the use of the same management guidelines as in adults. Our aim was to study the risk of malignancy for each Bethesda class in children with thyroid nodules. METHODOLOGY: We included all patients <=18years of age that had underwent a thyroid fine needle aspiration (FNA) at one of two centers between January 1998 and July 2013. FNA results were reclassified according to the Bethesda criteria. Histological, repeat cytological, radiological and clinical follow-up were recorded. RESULTS: Fifty-six patients (66 nodules) underwent FNB. Mean age was 13.6 years. Numbers of nodules reported as BI-BVI were 7, 38, 11, 4, 3 and 3, respectively. Follow-up was achieved for 55 (83%) nodules. Twelve (18%) nodules were malignant by histology and revealed papillary (n=7), follicular (n=3) or insular thyroid cancer (n=2), The proportion of nodules with malignancy for BI-BVI was: 0%, 0%, 18%, 100%, 100% and 100%. CONCLUSION: The rate of malignancy in thyroid nodules in children seems to be higher than reported in adults. The Bethesda criteria seem to accurately identify benign nodules, but other categories have a very high rate of malignancy and BIII nodules pose a particular challenge. PMID- 25783311 TI - Innate healing in the fetal sheep model of myelomeningocele: A standardized defect grading system. AB - BACKGROUND/PURPOSE: The fetal sheep model of myelomeningocele (MMC) is well established. While the variability of innate fetal healing of the defect at the time of the repair operation has been acknowledged, it remains poorly described. We characterized the healing within the fetal sheep MMC model and present a standardized defect grading system. METHODS: Forty-three fetuses underwent surgical MMC creation at a gestational age of 75 days and repair at 100 days. Defects were graded based on percentage of exposed spinal cord and degree of scarring. A scale was developed and validated by interrater reliability testing. RESULTS: The phenotypic appearance of the defect at the time of the repair operation was highly variable. The defect length ranged from 3.0 to 5.5cm. Three spinal cords remained fully exposed across their length; 18 were completely covered in fibrinous exudate. Twenty-two fetuses demonstrated varying degrees of open spinal cord. Interrater reliability revealed consistent grades 91% of the time. CONCLUSION: Despite consistent defect creation, the fetal MMC defect has a wide spectrum of appearance at the time of the second surgery. This study describes the innate fetal healing within the model and presents a feasible and valid grading scale to ensure scientific rigor within the model. PMID- 25783312 TI - Irreducible inguinal hernia in children: how serious is it? AB - BACKGROUND/PURPOSE: We evaluated the experience with irreducible inguinal hernias at our institution. METHODS: We reviewed patients with an inguinal hernia operation at our institution between 1st January 2004 and 31st December 2013. Individuals with a failed manual reduction of an incarcerated hernia under sedation by the attending surgeon were included into the study group as irreducible hernia. RESULTS: Overall 2184 individuals (426 females) had an inguinal herniotomy with the following distribution: right 1116 (51.1%), left 795 (36.4%) and bilateral 273 (12.5%) cases. A laparoscopic herniotomy was done in 1882 (86.4%). 34 patients (3 females) - just 1.6% of the total - presented at a median age (corrected for gestation) of 12 months (range 2 weeks to 16 years) with an irreducible hernia, of which 24 individuals (70%) were right sided. A laparoscopic approach was attempted in 21 (62%), two required a conversion. The open technique was chosen in 13 (38%) individuals. The content of the hernia sac was distal small bowel in 21 (62%), omentum in four (12%) and an ovary in three (9%) cases. Four patients (12%) required laparoscopic assisted bowel resection and two partial omentectomy (6%). Two gonads (6%) were lost: one intraoperative necrotic ovary and one testis atrophied over time. There was no recurrent hernia. CONCLUSION: Irreducible inguinal hernias constitute 1.6% of the workload on inguinal hernia repair. The hernia sac contains in males most frequently small bowel and in females exclusively a prolapsed ovary. Significant comorbidity is present in 18%. Laparoscopic and open techniques complement each other in addressing the issue. PMID- 25783313 TI - Pulmonary support on day of life 30 is a strong predictor of increased 1 and 5 year morbidity in survivors of congenital diaphragmatic hernia. AB - PURPOSE: Pulmonary support (PS) on day-of-life-30 (DOL-30) has been shown to be the strongest predictor of subsequent morbidity and in-patient mortality in congenital diaphragmatic hernia (CDH). We hypothesized that PS on DOL-30 can also predict long-term outcomes in CDH survivors. METHODS: We analyzed records of 201 CDH survivors followed by a single multidisciplinary clinic (1995-2010). Follow up was 83 and 70% at 1 and 5years respectively. PS was defined as: (1) invasive support (n=44), (2) noninvasive support (n=54), or (3) room air (n=103). Logistic regression was used to estimate the adjusted association of PS on DOL-30 with outcomes at 1 and 5-years. RESULTS: Use of PS on DOL-30 was significantly associated with pulmonary and developmental morbidities at 1 and 5-years. Even after adjusting for defect-size and presence of ventilation/perfusion mismatch, greater PS on DOL-30 was associated with a significantly increased odds of requiring supplemental oxygen and developmental referral at 1-year, and asthma and developmental referral at 5-years. CONCLUSION: CDH survivors continue to have significant long-term pulmonary and developmental morbidities. PS on DOL-30 is a strong independent predictor of morbidity at 1 and 5-years and may be used as a simple prognostic tool to identify high-risk infants. PMID- 25783315 TI - Ventilation causes pulmonary vascular dilation and modulates the NOS and VEGF pathway on newborn rats with CDH. AB - BACKGROUND/PURPOSE: Congenital diaphragmatic hernia (CDH) is a defect that presents high mortality because of pulmonary hypoplasia and hypertension. Mechanical ventilation changes signaling pathways, such as nitric oxide and VEGF in the pulmonary arterioles. We investigated the production of NOS2 and NOS3 and expression of VEGF and its receptors after ventilation in rat fetuses with CDH. METHODS: CDH was induced by Nitrofen. The fetuses were divided into 6 groups: 1) control (C); 2) control ventilated (CV); 3) exposed to nitrofen (N-); 4) exposed to nitrofen ventilated (N-V), 5) CDH and 6) CDH ventilated (CDHV). Fetuses were harvested and ventilated. We assessed body weight (BW), total lung weight (TLW), TLW/BW ratio, the median pulmonary arteriolar wall thickness (MWT). We analyzed the expression of NOS2, NOS3, VEGF and its receptors by immunohistochemistry and Western blotting. RESULTS: BW, TLW, and TLW/BW ratio were greater on C than on N- and CDH (p<0.05). The MWT was higher in CDH than in CDHV (p<0.001). CDHV showed increased expression of NOS3 (p<0.05) and VEGFR1 (p<0.05), but decreased expression of NOS2 (p<0.05) and VEGFR2 (p<0.001) compared to CDH. CONCLUSION: Ventilation caused pulmonary vasodilation and changed the expression of NOS and VEGF receptors. PMID- 25783314 TI - Correlation between selected angiogenic markers and prognosis in pediatric adrenocortical tumors: Angiogenic markers and prognosis in pediatric ACTs. AB - BACKGROUND/PURPOSE: Pediatric adrenocortical tumor (ACT) remains a challenging disease. Tumor weight and disease stage are still the most used indicators to prognosis and guidance of clinical decisions. Histology has not added meaningful data for risk stratification and management. ACT is metabolically active, highly vascularized, locally invasive and has the propensity to produce distant metastasis. Our objective was to correlate the expression of vascular endothelial growth factor (VEGF) and intratumoral microvessel density (MVD) with clinical and prognostic aspects in pediatric ACT. PROCEDURE: In 27 tumors, immunohistochemical expression of VEGF, CD105 (endoglin) and CD34 was analyzed. MVD was determined by CD34 and CD105 antibodies. MVD and VEGF expression was correlated with clinical characteristics and outcome. Normal pediatric glands were used as controls. RESULTS: Endoglin MVD was significantly higher and CD34 MVD was significantly lower in ACT than control. The VEGF expression did not differ between groups. Cytoplasmic staining for endoglin was correlated with hypertension in ACT. Endoglin MVD greater than 1 mv/field, CD34 MVD less than 32 mv/field and VEGF expression levels above 4.8% were associated with clinical and biological indicators of poor prognosis. CONCLUSIONS: Endoglin and CD34 MVD values are potential histological markers to refine the histologic classification of pediatric ACT. PMID- 25783316 TI - Can a simplified algorithm prevent incomplete laparoscopic pyloromyotomy? AB - PURPOSE: The purpose of this study is to analyze an algorithm intended to prevent incomplete pyloromyotomy in 3-port laparoscopic (3TP) and laparoendoscopic single site (LESS-P) procedures in a teaching hospital. METHODS: We defined the pyloroduodenal and pyloroantral junctions as anatomical margins prior pyloromyotomy by palpating and coagulating the serosa with the hook cautery instrument. Incomplete pyloromyotomies, mucosa perforations, serosa lacerations, and wound infections were recorded for pediatric surgical trainees (PST) and board-certified pediatric surgeons (BC). RESULTS: We reviewed the medical files of 233 infants, who underwent LESS-P (n=21), 3TP (n=71), and open pyloromyotomy (OP, n=141). No incomplete pyloromyotomies occurred. In contrast to OP, mucosa perforations did not occur in the laparoscopic procedures during the study period (6.38% vs. 0%, P=.013). OP had insignificantly more serosal lacerations (3.5% vs. 1.4%, P=.407). There was no difference in the rate of wound infections between OP and laparoscopic procedures (2.8% vs. 4.3%, P=.715). In the latter, all wound infections were associated with the use of skin adhesive. CONCLUSIONS: This algorithm helps avoiding incomplete laparoscopic pyloromyotomy during the learning curve and in a teaching setting. It is not risky to assist 3TP and LESS P to PST as this led to a decreased rate of mucosa perforations without experiencing incomplete pyloromyotomies. PMID- 25783317 TI - Surgical correction of pectus carinatum improves perceived body image, mental health and self-esteem. AB - PURPOSE: The purpose of this study was to assess the effects of surgical correction of pectus carinatum on health-related quality of life and self-esteem. METHODS: Between May 2012 and May 2013, a prospective observational single-center cohort study was conducted on consecutive patients undergoing surgical correction of pectus carinatum at our institution. Patients filled in questionnaires on health-related quality of life and self-esteem before and six months after surgery. RESULTS: Disease-specific health-related quality of life was improved by 33% (95% CI: 23; 44%) according to responses to the Nuss Questionnaire modified for Adults. The improvement for generic mental health-related quality of life was 7% (95% CI: 3; 12%) in responses to the Short Form-36 Questionnaire. The improvement in self-esteem was 9% (95% CI: 2; 17%) as assessed with the Rosenberg Self-Esteem Scale. A Single Step Questionnaire supported the improvements in health-related quality of life and self-esteem six months postsurgery. CONCLUSION: This study confirms positive effects of surgical correction of pectus carinatum on health-related quality of life and self-esteem. Patients were to a greater extent self-satisfied about chest appearance following surgery, indicating this to be a step in the right direction toward improved body image, mental health and self-esteem. PMID- 25783318 TI - The bridge technique for pectus bar fixation: a method to make the bar un rotatable. AB - PURPOSE: Pectus bar rotation is a major challenge in pectus repair. However, to date, no satisfactory technique to completely eliminate bar displacement has been introduced. Here, we propose a bar fixation technique using a bridge that makes the bar unmovable. The purpose of this study was to determine the efficacy of this bridge technique. METHODS: A total of 80 patients underwent pectus bar repair of pectus excavatum with the bridge technique from July 2013 to July 2014. The technique involved connecting 2 parallel bars using plate-screws at the ends of the bars. To determine bar position change, the angles between the sternum and pectus bars were measured on postoperative day 5 (POD5) and 4 months (POM4) and compared. RESULTS: The mean patient age was 17.5 years (range, 6-38 years). The mean difference between POD5 and POM4 were 0.23 degrees (P=.602) and 0.35 degrees (P=.338) for the upper and lower bars, respectively. Bar position was virtually unchanged during the follow-up, and there was no bar dislocation or reoperation. CONCLUSIONS: A "bridge technique" designed to connect 2 parallel bars using plates and screws was demonstrated as a method to avoid pectus bar displacement. This approach was easy to implement without using sutures or invasive devices. PMID- 25783319 TI - APRi predicts native liver survival by reflecting portal fibrogenesis and hepatic neovascularization at the time of portoenterostomy in biliary atresia. AB - BACKGROUND: Aspartate aminotransferase-to-platelet ratio index (APRi) may be useful noninvasive prognostic tool in biliary atresia (BA). We studied whether APRi predicts native liver survival and parallels biochemical and immunohistological signs of liver injury and fibrogenesis at the time of Kasai portoenterostomy (PE). METHODS: Serum and liver specimens were obtained at PE from 29 BA patients for liver biochemistry including APRi, histology and immunohistochemical analysis of collagen 1, alpha-SMA and CD34. APRi values were related to native liver survival and other clinical data as well as serum liver biochemistry, liver histology and immunohistochemistry at PE. RESULTS: Median age at PE was 63 (range 7-141) days and median APRi was 0.92 (0.13-6.39). APRi had strong positive correlations with patient age (r=0.684, p<0.001) and biochemical signs of hepatocyte injury and cholestasis. APRi showed no significant correlations with Metavir (r=0.336, p=0.223) or Ishak (r=0.289, p=0.262) global fibrosis scores nor with liver collagen 1 expression (r=0.260, p=0.222). In contrast, portal fibrosis score (r=0.515, p=0.013), predominantly portal alpha SMA expression (r=0.519, p=0.015) and amount CD34-positive microvessels in the centrizonal region (r=0.604, p=0.004) correlated positively with APRi. Patients (n=10) who underwent liver transplantation had significantly higher APRi at presentation (1.34 vs. 0.77, p=0.017) compared to those who survived with native liver (n=19). CONCLUSIONS: APRi correlates with portal fibrosis, expression of alpha-SMA and the amount of CD34-positive microvessels, suggesting that APRi predicts native liver survival by reflecting portal myofibroblastic cell activation, fibrogenesis and associated neovascularization. PMID- 25783320 TI - What is the best option for 10-20mm renal pelvic stones undergoing ESWL in the pediatric population: stenting, alpha blockers or conservative follow-up? AB - OBJECTIVE: In this study we aimed to identify the effect of three different modalities (stenting, doxazosin and conservative follow-up) on stone free rates and complication rates for 10-20mm renal pelvic stones in pediatric patients who underwent shock wave lithotripsy. PATIENTS AND METHODS: In this study data from 241 renal units (RUs) of 195 consecutive patients with 10-20mm renal pelvis stones were analyzed retrospectively. There were 3 groups in the study; 56 (23.2%) RUs with ureteral stenting were categorized as group 1, and 39 (16.2%) RUs that received doxazosin were categorized as group 2. The remaining 146 (60.6%) RUs without history of ureteral stenting or alpha-blockers usage were categorized as group 3. Patient demographics, stone characteristics, stone free rates (SFRs), time to stone expulsion and complications were documented and compared in each group. RESULTS: Mean age of the population was 6.6 years and mean stone size was 13.8 +/- 2.9 mm. Demographic characteristics of the 3 groups were not significantly different. SFRs of the three groups were 89.2%, 87.1% and 82.1% (p = 0.275). Mean time to stone expulsion for groups 1 and 2 were 17.4 and 21.8 days respectively and significantly lower than that in group 3 (31.3 days). CONCLUSIONS: Ureteral stenting or doxazosin for shockwave lithotripsy (SWL) is not superior to watchful waiting in terms of SFR and complications however both modalities shorten the stone expulsion time for 10-20mm renal pelvis stones in the pediatric population. PMID- 25783321 TI - The Depression Index: an objective measure of the severity of pectus excavatum based on vertebral diameter, a morphometric correlate to patient size. AB - BACKGROUND/PURPOSE: In patients with Pectus Excavatum (PEX), the proposed Depression Index (DI) is derived from the absolute measurement of sternal depression using the transverse vertebral body diameter as a surrogate for height. The previously described objective and useful Pectus Index (PI) and Correction Index (CI), utilize thoracic diameters and do not always reflect the severity of the deformity as observed by clinicians. METHODS: Data for age, weight, height and vertebral diameter of T9, 10 and 11 were collected on 60 patients, with normal skeletons, undergoing CT scanning. The DI, PI and CI were calculated from CT scans on 76 patients with PEX. Indices were also compared to subjective rankings of the deformity from visual inspection of photographs by 5 clinicians. RESULTS: All parameters of age, weight and height correlated with the vertebral diameter. The DI correlated with the severity of the PEX deformity as also measured by the PI and the CI. There was a better correlation of the observed deformity severity to the DI than the PI or CI. CONCLUSION: There is a strong correlation between transverse vertebral size and patient height. The DI is an objective measurement of the severity of a PEX deformity that is independent of the thoracic diameters. PMID- 25783322 TI - A single center retrospective review of hair tourniquet syndrome and a proposed treatment algorithm. AB - INTRODUCTION: Hair tourniquet syndrome (HTS) is a rare disorder characterized by a hair becoming tightly wound around an appendage. There is little known about the epidemiology, optimal treatment, or indications for surgical intervention in HTS. We hypothesized that HTS could be readily diagnosed and treated in the pediatric emergency department and we sought out factors predictive of surgical intervention. METHODS: We performed a single center retrospective review of all patients who presented with a hair tourniquet from May 2004 till March 2014. RESULTS: Eighty-one patients were diagnosed with HTS, ranging in age from 2 weeks to 22 years. Of these patients, 69 were located on the toes, 5 on fingers, and 7 on genitalia. The average ages for each location were statistically different (p<0.0001). Ninety-four percent of patients were successfully treated by nonoperative means. Cellulitis was found in two patients. Tissue necrosis occurred in one patient. CONCLUSION: HTS is an uncommon disorder and location differs with age. Chemical depilatory agents should be a first line treatment for this condition in most patients. If chemical tourniquet release fails, then the patient should undergo mechanical tourniquet release. If edema, erythema and pain fail to resolve after tourniquet release, then persistent hair tourniquet should be investigated. PMID- 25783323 TI - Placental drug delivery for treatment of congenital hematopoietic disorders. AB - OBJECTIVE: The success of in utero hematopoietic cell transplantation (IUHCTx) hinges on successful conditioning strategies of the host to overcome barriers to engraftment. The "space" barrier is a reflection of a finite number of hematopoietic stem cell (HSC) niches within the host. Independent of the number of donor HSCs transplanted, engraftment is frequently low. By conditioning fetal mice using a monoclonal antibody against the c-kit receptor (ACK2) found on HSCs, we can effectively increase space for donor HSC engraftment. We questioned whether simple placental injection of ACK2 early in gestation could effectively deplete host HSCs within the fetal liver and neonatal bone marrow. METHODS: In this set of experiments, we injected mice with ACK2 (5 MUg/fetus) or PBS at E11.5 12.5 and harvested the fetal liver at 2 and 4 days and the neonatal bone marrow at 7 days following injection. Survival and total number of HSCs within the fetal liver or bone marrow were quantified and compared. RESULTS: Survival between the treated and control group was similar (73% and 71%, respectively). The total number of HSCs within the fetal liver was not significantly lower following ACK2 treatment compared to PBS injected fetuses at 2 days but was by 4 days. Additionally, ACK2 resulted in a significant reduction in the number of HSCs within neonatal mice 7 days after treatment. CONCLUSION: Survival following placental ACK2 injection is comparable to control animals and provides a simple non-invasive strategy to deliver ACK2 into the fetal circulation which successfully depletes the host HSCs. PMID- 25783324 TI - The effects of language concordant care on patient satisfaction and clinical understanding for Hispanic pediatric surgery patients. AB - BACKGROUND: Hispanics account for over 60% of the U.S. population growth and 25% speak little-to-no English. This language barrier adversely affects both access to and quality of care. Surgical specialties trail other medical fields in assessing the effects of language barriers to surgical clinical care and patient satisfaction. This study was designed to assess the effects of patient-provider language concordance on a pediatric surgery practice. METHODS: A surgery specific, 7-point Likert scale questionnaire was designed with 14 questions modeled after validated patient satisfaction surveys from the literature. Questions concerning provider-patient language concordance, quality of understanding, and general satisfaction were included. Surveys were administered to families of patients in the General Pediatric Surgery Clinic at our institution. Families were categorized into three groups: English-speaking, regardless of race/ethnicity; Spanish-speaking using interpreter services with an English-speaking medical team; and Spanish-speaking communicating directly with a Spanish-speaking medical team (Hispanic Center for Pediatric Surgery, HCPS). One way analysis of variance was used to test for group differences. RESULTS: We administered 226 surveys; 49 were removed due to lack literacy proficiency. Families in the HCPS group reported a higher level of satisfaction than the interpreter and English groups (p<0.01). The HCPS group also indicated improved understanding of the information from the visit (p<0.001). Spanish-speaking only families felt that communicating directly with their health care team in their primary language was more important than their English-speaking counterparts (p<0.001). CONCLUSIONS: In a pediatric surgery clinic, language concordant care improves patient satisfaction and understanding for Hispanic families in comparison to language discordant care. Other clinics in other surgery sub specialties may consider using this model to eliminate language barriers and improve patient satisfaction and understanding of surgical care. PMID- 25783325 TI - Postoperative Regimentation Of Treatment Optimizes Care and Optimizes Length of Stay (PROTOCOL) after pyloromyotomy. AB - BACKGROUND/PURPOSE: A non-standardized approach to caring for infants after pyloromyotomy for pyloric stenosis was associated with prolonged postoperative length of stay (pLOS) at our institution. We studied the impact of a standardized postoperative care protocol on pLOS, patients' clinical course, and nursing care. METHODS: A retrospective chart review identified that 27% of infants who underwent uncomplicated pyloromyotomy had prolonged pLOS, defined as more than one postoperative midnight. A comprehensive postoperative care protocol was developed for infants undergoing pyloromyotomy. Patients were recruited prospectively and those with complications were excluded. A sample size of 70 in each cohort (historic and prospective) allowed 80% power to detect a 50% reduction in the proportion of patients with prolonged pLOS (alpha=0.05). The prospective group and historic cohort were compared using nonparametric statistics. RESULTS: The historic cohort had 70 patients and the prospective cohort had 66. Protocol implementation resulted in fewer patients with prolonged pLOS, shorter time to feeds, fewer feeds to discharge, less emesis, and improved nursing documentation. CONCLUSION: Implementation of a postoperative care protocol improved various aspects of patient care and nursing care studied. Protocols outline a patient's course and serve as a common platform for communication among care providers; they can facilitate, expedite, and enhance patient care. PMID- 25783326 TI - Factors affecting short-term neurodevelopmental outcome in children operated on for major congenital anomalies. AB - PURPOSE: Identify clinical and socio-demographic risk-factors affecting short term neurodevelopmental outcome (NDO) in children operated on for abdominal and thoracic congenital anomalies (CA). METHODS: Prospective cohort observational study on newborns operated on for non-cardiac major CA. Evaluations were conducted at 6 and 12 months of age. Univariate linear regression and multivariate regression were conducted to analyze the impact on NDO of clinical and sociodemographic variables. Infants were evaluated with the Bayley Scales of Infant and Toddler Development-3rd Edition. RESULTS: One-hundred-fifty-five children were enrolled. They were affected by the following anomalies: Esophageal Atresia (N=41), Congenital Diaphragmatic Hernia (N=42), Midgut Malformations (N=34), Abdominal Wall Defects (N=18), Colorectal Malformations (N=20). There were no statistically significant differences among the five groups of CA as to NDO. Variables which reached statistical significance at multivariate regression (p<=0.001) at 6 and 12 months as to cognitive and motor development were: ventilatory time, associated malformations, medical appliances for feeding, number of surgery and length of hospital stay. CONCLUSIONS: On the average, children born with CA show a NDO within normal range. The identified risk-factors could prompt health care professionals to conduct a close surveillance on most vulnerable children giving them the best chance to reach their full potential. PMID- 25783327 TI - Surviving Sengstaken. AB - AIM OF THE STUDY: To report the outcomes of children who underwent Sengstaken Blakemore tube (SBT) insertion for life-threatening haemetemesis. METHODS: Single institution retrospective review (1997-2012) of children managed with SBT insertion. Patient demographics, diagnosis and outcomes were noted. Data are expressed as median (range). MAIN RESULTS: 19 children [10 male, age 1 (0.4-16) yr] were identified; 18 had gastro-oesophageal varices and 1 aorto-oesophageal fistula. Varices were secondary to: biliary atresia (n=8), portal vein thrombosis (n=5), alpha-1-anti-trypsin deficiency (n=1), cystic fibrosis (n=1), intrahepatic cholestasis (n=1), sclerosing cholangitis (n=1) and nodular hyperplasia with arterio-portal shunt (n=1). Three children deteriorated rapidly and did not survive to have post-SBT endoscopy. The child with an aortooesophageal fistula underwent aortic stent insertion and subsequently oesophageal replacement. Complications included gastric mucosal ulceration (n=3, 16%), pressure necrosis at lips and cheeks (n=6, 31%) and SBT dislodgment (n=1, 6%). Six (31%) children died. The remaining 13 have been followed up for 62 (2-165) months; five required liver transplantation, two underwent a mesocaval shunt procedure and 6 have completed endoscopic variceal obliteration and are under surveillance. CONCLUSIONS: SBT can be an effective, albeit temporary, life-saving manoeuvre in children with catastrophic haematemesis. PMID- 25783328 TI - Bowel function and lower urinary tract symptoms in females with anterior anus treated conservatively: Controlled outcomes into adulthood. AB - PURPOSE: Anterior anus (AA) is a low type of anorectal malformation that is seen exclusively in females, characterized by an essentially normal appearing anus in an abnormally anterior position. In AA, the anal canal is located mostly within the voluntary sphincter complex, differentiating it from a perineal fistula in females, and allowing for a nonoperative approach to management. This study aimed to characterize the controlled, long-term bowel functional outcomes and lower urinary tract symptoms (LUTS) in females with conservatively treated anterior anus. METHODS: A single-institution, cross-sectional study. All females treated conservatively for AA between 1983 and 2006 were invited to answer a postal questionnaire on bowel function and lower urinary tract symptoms. Each patient was matched by age and gender to 3 controls that had answered the same questionnaire. Ethical approval was obtained. RESULTS: Among 45 respondents (67%; median age 10.2 (4-20) years), fecal continence was comparable to controls overall (p=NS). Constipation affected a significantly higher proportion patients (36%) than controls (13%; p=0.002) and tended to decline with age. Outcomes by bowel function score were good/normal in 93%, satisfactory in 7% and poor in none. Lower urinary tract symptoms and age at toilet training were comparable to controls (p=NS). CONCLUSIONS: Up to adulthood, long-term bowel functional outcomes comparable to matched peers can be achieved in nearly all of females with AA with conservative management alone, provided that effective control of constipation is achieved. The prevalence of LUTS is comparable to controls, and toilet training can be expected to occur at the normal age. PMID- 25783329 TI - Quality of reporting of the literature on gastrointestinal reflux after repair of esophageal atresia-tracheoesophageal fistula. AB - OBJECTIVES: There is variation in the management of postoperative gastroesophageal reflux (GER) in esophageal atresia-tracheoesophageal fistula (EA TEF). Well-reported literature is important for clinical decision-making. We assessed the quality of reporting (QOR) of postoperative GER management in EA TEF. METHODS: A comprehensive search of MEDLINE, EMBASE, CINHAL, CENTRAL databases and gray literature was conducted. Included articles reported a primary diagnosis of EA-TEF, a secondary diagnosis of postoperative GER, and primary treatment of GER with antireflux medications. The QOR was assessed using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. RESULTS: Retrieval of 2910 articles resulted in 48 relevant articles (N=2592 patients) with an overall quality percentage score of 48%-95% (median=65%). The best reported items were "participants" and "outcome data" (93.8% each), "generalisability" (91.7%) and "background/rationale" (89.6%). Less than 20% of studies provided detailed "main results"; less than 5% of studies reported adequately on "bias" or "funding." Sample size calculation and study limitations were included in 17 (35.4%) and 16 (33.3%) studies respectively. Follow-up time was inconsistently reported. CONCLUSIONS: Although the overall QOR is moderate using STROBE, important areas are underreported. Inadequate methodological reporting may lead to inappropriate clinical decisions. Awareness of STROBE, emphasizing proper reporting is needed. PMID- 25783330 TI - Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up. AB - PURPOSE: To present the long-term outcomes of appendicovesicostomy using the Mitrofanoff principle for end-stage Wolfram bladder dysfunction as an alternative to clean intermittent self-catheterization (CIC) per urethra mainly following blindness. METHODS: Twelve Wolfram patients presenting with bilateral hydroureteronephrosis and advanced bladder dysfunction were included in this study. All patients were managed initially by CIC per urethra. All of these patients became blind during follow-up and were unable to perform urethral CIC independently. Out of these patients, six patients agreed to proceed to appendicovesicostomy. Appendicovesicostomy urinary diversion using the Mitrofanoff principle was performed in these six blind patients. The rest of the patients stopped CIC or performed CIC irregularly. RESULTS: Severe hydroureteronephrosis and large bladders were found in all patients prior to intervention. All patients were able to conduct CIC independently through the stoma and maintained overnight bladder free drainage. In all patients with urinary diversion and CIC, the hydroureteronephrosis was reduced and renal function returned to normal. However, the non-intervention group ended with different degrees of progressive renal failure with three mortalities during the follow-up. CONCLUSIONS: We suggest appendicovesicostomy as a safe and lifesaving procedure for long-term management of bladder dysfunction in Wolfram syndrome particularly after progression to blindness. PMID- 25783331 TI - Risk factors for mortality in patients with multifocal and diffuse hepatic hemangiomas. AB - PURPOSE: Multifocal and diffuse hepatic hemangiomas are true infantile hemangiomas, which likely exist in a continuum. We reviewed our hepatic hemangioma registry to identify prognostic indicators for mortality. METHODS: Registry records entered between 1995 and 2012 were reviewed. Clinical characteristics were evaluated for prognostic significance using the multivariable Cox proportional hazards model. Survival data were analyzed using the Kaplan-Meier product-limit method. RESULTS: We identified 123 patients with multifocal (n=91) and diffuse (n=32) hepatic hemangiomas. Mortality was 16% (n=20); 40% (n=8) had multifocal and 60% (n=12) had diffuse lesions. A diagnosis of diffuse disease (hazard ratio: 9.9, 95% CI: 2.0-50.8, P=.002) and congestive heart failure (CHF) (hazard ratio: 3.9, 95% CI: 1.3-14.2, P=.031) were significant risk factors for mortality across the continuum; age at presentation, cardiomegaly, presence of shunts, and hypothyroidism were not statistically significant independent risk factors. Among patients with diffuse lesions, eight (67%) who died had abdominal compartment syndrome, which was also associated with mortality (P=.002). CONCLUSIONS: Hepatic hemangioma patients with CHF or diffuse disease are at higher risk for mortality. Patients with multifocal lesions without CHF may go undetected until lesions become diffuse. Aggressive treatment of symptomatic patients and close follow-up of asymptomatic patients may improve mortality. PMID- 25783332 TI - A multidisciplinary approach to the management of anterior mediastinal masses in children. AB - PURPOSE: Anterior mediastinal masses (AMM) pose a diagnostic challenge to surgeons, oncologists, anesthesiologists, intensivists, and interventional radiologists as induction of general anesthesia can cause airway obstruction and cardiovascular collapse. We hypothesized that in the majority of patients, diagnosis can be obtained through biopsy of extrathoracic tissue. METHODS: We performed a retrospective review of all patients in the solid tumor oncology clinic with a diagnosis of AMM between 2002 and 2012 including preoperative evaluation and management prior to obtaining a tissue diagnosis, clinical course and complications. RESULTS: We identified 69 patients with AMM (mean age 12.2+/ 4.4years, 64% male) secondary to Hodgkin lymphoma (34), Non-Hodgkin lymphoma (26), and other diagnoses (9). The majority of patients (56, 81.2%) underwent biopsy of tissue outside of the mediastinal mass. Local anesthesia with sedation was used for successful biopsy in 21 (30%) patients. Four (5.8%) required repeat biopsy due to inadequate sample obtained at initial procedure. Three (4.4%) suffered respiratory complications with no fatalities or severe complications. CONCLUSIONS: Our data demonstrate that in the majority of children with AMM, tissue biopsy can be successfully obtained from tissue outside of the mass itself with minimal complications and highlight the importance of multidisciplinary preoperative planning to minimize anesthetic risks. PMID- 25783333 TI - Predictors of gastrostomy placement in children with inherited metabolic diseases treated by umbilical cord blood transplantation. AB - BACKGROUND/PURPOSE: Children with inherited metabolic diseases (IMDs) undergoing umbilical cord blood transplantation (UCBT) who are at risk for post-transplant failure to thrive may benefit from pretransplant gastrostomy tube (GT) placement. Here we sought to determine predictors of posttransplant failure to thrive. METHODS: A retrospective analysis was performed for IMD patients who underwent UCBT at a single center from 2001 to 2011. Patients who received GTs were compared with controls. Multivariable logistic regression was used to determine significant predictors for GT placement. Recursive partitioning was performed to determine appropriate cut-offs for significant continuous variables. RESULTS: Two hundred and seventeen patients met inclusion criteria of which twenty-three were excluded due to death within one hundred days of transplant. Forty (20.6%) of the remaining patients underwent a surgical GT placement. Multivariable logistic regression demonstrated that weight percentile at time of transplant was significantly associated with GT placement (Adjusted odds ratio (AOR): 0.87 per 10th percentile, p=0.022). Recursive partitioning demonstrated that the 40th weight percentile at time of transplant was an optimal cut-off for predicting GT placement. CONCLUSIONS: Patients preparing for umbilical cord transplantation who are below the 40th percentile for weight may benefit from pre-emptive GT placement prior to transplant. PMID- 25783334 TI - Is B-Flow USG superior to Color Doppler USG for evaluating blood flow patterns in ovarian torsion? AB - OBJECTIVE: Ovarian torsion is an uncommon gynecological emergency that most often affects women of reproductive age. Its signs and symptoms are similar to those of other abdominal conditions, which make its differential diagnosis challenging. Color Doppler (Doppler USG) and B-flow ultrasonography (B-flow USG) are used for the differential diagnosis of ovarian torsion, and in this study, we aimed to evaluate these two techniques, validate B-flow USG as the gold standard non invasive diagnostic tool in the early phase of an ovarian torsion, and show that the B-flow USG is superior to the color Doppler USG. MATERIALS AND METHODS: Sixteen rabbits of the same age and weight were separated into 2 subgroups of 8. In Group I (sham group), right ovaries were fixated, and in Group II (torsion group), right ovaries underwent 720 degrees torsion in a counterclockwise direction. At 1h and 2h of ischemia, both ovaries were measured by the two techniques, and an additional measurement was taken at 24h to determine any changes in the left ovary due to the right ovary ischemia. Volume flow, peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI) and pulsatility index (PI) measurements were taken both with color Doppler USG (using a 12MHz linear probe, General Electric Medical Systems Logic 7, Milwaukee, USA) and with B-flow USG. RESULTS: The right Doppler RI and PI values at 1h were significantly higher than the right B-flow values (p<0.05). The difference between the left B-flow RI and PI values and the left Doppler values at 1h was not significant (p>0.05), nor was the difference between the right B-flow RI value at 2h and the right Doppler RI value at 2h (p>0.05). The right B-flow PI value at 2h was statistically different from the right Doppler PI value at 2h (p<0.05), although the differences between the left B-flow RI and PI values at 1h and 2h and the left Doppler RI and PI values were not (p>0.05). However, there was a significant difference between the RI values at 24h (p<0.05). CONCLUSIONS: In this study, the decrease in blood reperfusion at 1h measured by B-flow USG was apparently higher than that measured by Doppler USG. However, by the end of 2h, the measurements were equal (see Fig. 3 and 4). In conclusion, B-flow USG reveals the decrease in the blood flow more distinctly in the early phase. Moreover, B flow Doppler USG is more reliable and advantageous than color Doppler USG because it provides a more accurate preoperative evaluation of the unilateral and contralateral preoperative adnexial structures, and allows for a better assessment of blood flow in the ovarian torsion. PMID- 25783335 TI - Twenty-years of splenic preservation at a level 1 pediatric trauma center. AB - BACKGROUND: Splenic preservation is the standard of care for hemodynamically stable children with splenic injuries. We report a 20-year single-institutional series of children with splenic injuries managed without a splenectomy. METHODS: Children evaluated and treated for blunt splenic injury at Boston Children's Hospital from 1994 to 2014 were extracted from the trauma registry. Demographics, clinical characteristics, complications, and outcomes were reviewed. Three time periods were evaluated based upon the development and modification of splenic injury clinical pathway guidelines (CPGs). Survival was defined as being discharged from the hospital alive. RESULTS: 502 suffered isolated splenic injuries. The median AAST grade of splenic injury increased across the three CPG time periods (p<0.001). No splenic-injury related mortalities occurred. Hospital length of stay decreased significantly secondary to splenic injury CPGs (p<0.001). 99% of the patients were discharged home. CONCLUSION: In children managed over the last 20years for isolated splenic injury, no patient died or underwent splenectomy. Hospital length of stay decreased across time, despite an increase in the severity of splenic injuries encountered. Splenectomy has become so unusual in the management of hemodynamically stable children with a splenic injury that it may no longer be a legitimate outcome marker. PMID- 25783336 TI - Threat perception, anxiety and noncompliance with preoperative fasting instructions among mothers of children attending elective same day surgery. AB - PURPOSE: The current study examined possible links between threat perception, anxiety, conscientiousness and parental noncompliance with preoperative fasting instructions for their children. METHODS: 100 mothers of children about to undergo an ambulatory elective surgery were divided to two equal groups based on compliance/noncompliance with pre surgery fasting requirements. Logistic regression analysis was preformed to predict compliance/noncompliance. In addition a logistic model estimating the effect of anxiety and conscientiousness levels, and their interaction, on the probability of fasting was performed. RESULTS: Mothers who did not comply with fasting requirements perceived the procedure as more threatening, were more anxious and had lower conscientiousness levels. Additionally, mother's anxiety prior to surgery mediated the association between mothers' threat perception and compliance. Finally, conscientiousness moderated the anxiety and compliance association so that high conscientiousness levels reduced the effect of anxiety, elevating the likelihood of anxious mothers to comply with fasting guidelines. CONCLUSIONS: Based on these findings we recommend medical staff to make significant efforts to identify highly anxious parents as early as possible during the preoperative process. Innovative assessment and intervention tools should be developed in order to conduct a smooth medical operation and reduce the chance of unnecessary and costly surgery cancelation. PMID- 25783337 TI - Concomitant fundoplication increases morbidity of gastrostomy tube placement. AB - BACKGROUND: Fundoplication is often performed in conjunction with gastrostomy tube (GT) placement in children, but there is a great deal of variation in rates of and indications for this procedure. Little is known about the impact of fundoplication on peri-operative outcomes. This study examines a national cohort of pediatric patients to compare risk-adjusted surgical outcomes in patients undergoing GT placement with or without concomitant fundoplication. METHODS: We identified all patients undergoing GT placement in the 2012 National Surgical Quality Improvement Program - Pediatric. We evaluated demographics, comorbidities, complications, and length of stay for GT with fundoplication versus GT alone. We defined composite morbidity as a dichotomous variable for the presence of any complication. Logistic regression was performed to identify predictors of morbidity after adjusting for covariates. RESULTS: 1289 GT patients were identified, and 148 (11.5%) underwent concurrent fundoplication. The fundoplication patients were more likely to be younger, have cardiac risk factors, and be on respiratory support. They also had higher rates of surgical site infection (7.4% vs 3.7%, p=0.03) and composite morbidity (16.9% vs 8.7%, p=0.001), and longer LOS (median 5 vs 3 days, p=<0.0001) compared to GT only. After adjusting for covariates, fundoplication was a predictor of composite morbidity and increased LOS. CONCLUSION: Concomitant fundoplication is an independent risk factor for 30-day post-operative morbidity in patients undergoing GT placement. These findings do not negate the value of fundoplication but underscore the importance of careful patient selection, and should be taken into consideration when discussing risks and benefits with families. PMID- 25783338 TI - Spontaneous biliary perforation in infancy: Management strategies and outcomes. AB - PURPOSE: Infantile spontaneous biliary perforation is rare with variable management strategies ranging from nonoperative treatment to complex operations such as biliary-enteric reconstruction. Biliary fistula and portal vein thrombosis are known complications, though outcomes are poorly defined. METHODS: We assessed the incidence of spontaneous biliary perforation in infants <1 year old using a population database. Next, we describe 4 patients treated at our institution and review all reported cases within the past 25 years. RESULTS: The incidence of spontaneous biliary perforation is 1.5 in 1,000,000 live births. Over the past 25 years, 90 cases were reported, over half of which were initially managed with a surgical drainage procedure. The most common reason for failure of this strategy was CBD obstruction. Our 4 patients were successfully managed without biliary reconstruction despite 2 presenting with CBD obstruction. Reported complications occurred in 22% of patients, most frequently biliary fistula requiring delayed biliary reconstruction. CONCLUSIONS: Surgical drainage is an effective method for treatment of infantile spontaneous biliary perforation; however a persistent biliary fistula should prompt evaluation for distal CBD obstruction. Though biliary-enteric anastomosis is the historic procedure of choice for persistent fistula, with improvements in endoscopic and percutaneous treatment, extensive biliary reconstruction may be avoided in the future. PMID- 25783339 TI - Methylene blue attenuates renal ischemia-reperfusion injury in rats. AB - BACKGROUND AND PURPOSE: In our study, we investigated the effects of methylene blue (MB) on histopathological changes in renal ischemia/reperfusion (I/R) injury rat model. MATERIAL AND METHODS: Twenty-one Sprague-Dawley male rats were divided equally into three groups. Group 1 (control) was administered intraperitoneal saline solution. In Groups 2 (untreated group) and 3 (MB treatment), the renal arteries were clamped, and ischemia (for 1 hour) and then reperfusion (for 4 hours) were applied. Thirty minutes before ischemia, the untreated group received physiological saline, whereas the treatment group was administered 30 mg/kg MB through an intraperitoneal route. Blood samples were drawn, and renal specimens were harvested 5.5 hours after physiologic saline injection in the control and immediately after the reperfusion period in the other groups. The levels of tissue superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total oxidant status (TOS), total antioxidant status (TAS), plasma urea, creatinine and ischemia modified albumin (IMA) were measured. Moreover, the histopathological damage score of the renal tissue was determined. RESULTS: MB significantly alleviated the severity of histopathological damage by increasing the levels of tissue SOD and TAS and decreasing TOS concentrations in the renal I/R model (p<0.05). CONCLUSION: Administration of MB in renal I/R damage may play a protective role. PMID- 25783341 TI - Association of Hirschsprung's disease with anorectal malformations: the early alarming signs for diagnosis and comorbidity related to this association. AB - BACKGROUND AND AIM: The association of Hirschsprung's disease (HD) and anorectal malformation (ARM) is rare. The aim of this study is to highlight the frequency of this rare association and comorbidity that may be related to this association. PATIENTS AND METHODS: Eleven cases out of four hundred forty six cases (2.5%) with ARM found to have HD association presented to Assiut University Children Hospital. All cases were diagnosed by complete clinical, radiological assessment and histopathological examination before correction. The evaluating parameters for those patients were the early warning signs for diagnosis, any unnecessary procedures done and any associated morbidity related to misdiagnosis of this association. RESULTS: Age at presentation of these eleven cases ranged from 2 days to 10 years. The diagnosis started early during neonatal period only in four cases either by change of bowel caliber or nonfunctioning stoma. In the remaining seven cases the diagnosis was delayed because of unsuspected association. Fecal fistula after closure of stoma and wound dehiscence followed by incisional hernia is evident associated comorbidity. CONCLUSIONS: The incidence of HD in ARM population seems to be more common than its incidence in the general pediatric population. Caliber change of the bowel during the first operation or nonfunctioning stoma is early alarming sign for diagnoses of such association and should direct the attention for stomal biopsy. PMID- 25783340 TI - Tracheoplasty with cartilage-engineered esophagus environments. AB - PURPOSE: Our objective was to investigate the feasibility of engineering cartilage on the esophagus layer and outside the esophagus. Moreover, we investigated the feasibility of tracheoplasty with cartilage engineered on the esophagus in rabbits. METHODS: Chondrocytes were isolated from auricular cartilages. 1. Engineered cartilage formation by histological findings on/into the esophageal layer was compared with that of injectable scaffold and preformed scaffold with chondrocytes. 2. Chondrocytes adhered to gelatin+vicryl meshTM and b-FGF, were implanted on the outer esophageal surface. Four weeks after seeding, we found that cartilage was implanted in the midposterior portion of the cervical trachea (n=5), and it was retrieved 8weeks after seeding. RESULTS: 1. A gelatin sponge incorporating beta-TCP with vicryl meshTM showed the best performance for fabricating engineered cartilage on the outer side of the esophagus. 2. Two of 5 rabbits died due to obstructed esophagus. Cartilage engineered outside the esophagus by a composite scaffold as the main material in the gelatin sponge, maintained the airway structure for up to 1month after implantation. Tracheal epithelial regeneration occurred in the internal lumen of this engineered cartilage. CONCLUSION: Tracheoplasty with cartilage engineered outside the esophagus may be useful for reconstructing airways. PMID- 25783342 TI - Incidence and prognosis of intraabdominal hypertension and abdominal compartment syndrome in children. AB - PURPOSE: Intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are associated with high mortality rates in children (40-60%). However, literature lacks comprehensive series in childhood. In this study, we aimed to determine the incidences of IAH and ACS, to identify high risk disorders for the development of IAH/ACS and to decrease ACS-associated mortality by early diagnosis and timely intervention. METHODS: A prospective study was performed between December 2009 and October 2010 in our institution. IAH was defined by a sustained or repeated pathological elevation in IAP>=12mmHg without a new organ failure. ACS was identified as a sustained IAP>15mmHg with a new organ dysfunction/failure. After recognition of IAH or ACS, patients underwent prompt decompressive interventions as medical or surgical procedures. RESULTS: 150 patients were enrolled to the study (86 M, 64 F). The incidences of IAH and ACS were 9% and 4%, respectively. High risk disorders were trauma, ileus, necrotizing enterocolitis, abdominal wall defects, diaphragmatic hernia and septic shock with massive fluid resuscitation. 14 patients with IAH were treated and mean IAP was decreased from 13.9+/-1.9mmHg to 9.2+/-2.1mmHg (p<0.001). None of them progressed to ACS. Six patients with ACS underwent decompressive laparotomy. Mean IAP decreased significantly from 20+/-3mmHg to 9+/-1.4mmHg (p=0.001). Vital signs like mean urine output, abdominal perfusion pressure (APP) and respiratory rate were significantly improved after surgery (p<0.05). ACS-associated mortality rate was determined as 16%. CONCLUSIONS: IAH or ACS was occurred in nearly one tenth of patients admitted to neonatal and pediatric intensive care units. High clinical suspect must be drawn on to recognize and treat these clinical complications more efficiently. Regular and frequent IAP measurement in high risk disorders is essential for early diagnosis. Lower mortality rates can be achieved by early recognition and timely intervention in children. PMID- 25783343 TI - Small left colon syndrome in 3 sisters. AB - Neonatal small left colon syndrome is a rare cause of bowel obstruction. Its etiology remains unknown, but a significant association has been noted between maternal diabetes and small left colon. No reported cases within the same family could be found in the literature, excepting 2 sets of twins. We report 3 cases of small left colon syndrome in 3 consecutive sisters born of a nondiabetic mother. This raises the question of a genetic factor in its etiology. PMID- 25783344 TI - Dose dependent protective effects of vardenafil on ischemia-reperfusion injury with biochemical and histopathologic evaluation in rat ovary. AB - PURPOSE: The purpose of the study is to evaluate the effect of vardenafil on the histopathology and biochemical parameters in reducing damage in experimental ovarian ischemia and ischemia/reperfusion injury in a rat model and to compare the effect of two different doses of vardenafil. METHODS: Forty-two rats with experimental ovarian torsion. Group-I: sham; Group-II: ovarian ischemia; Group III: 2 hours of ischemia followed by a 2-hour reperfusion. Group-IV: two hours before the sham operation, rats received 1mg/kg vardenafil; Group V and VI: A 2 hour period of ovarian ischemia was applied, in which rats were treated with intraperitoneal vardenafil 1 and 2mg/kg dose, after 1.5 hours of ovarian ischemia. After 2 hours of reperfusion, the ovaries on the right side were removed for examination. The ovarian ischemia/reperfusion injury was evaluated by calculating total antioxidant status, total oxidant status and oxidative stress index; and histopathologic examination of all ovarian rat tissue. RESULTS: The histologic findings in vardenafil treatment groups were statistically significant decreased edema and follicle degeneration, with vascular congestion, hemorrhage and follicle degeneration being dose-dependent. There were no statistically significant changes in the biochemical parameters. CONCLUSIONS: According to histopathological examination, low and high dose vardenafil is effective in attenuating ischemia-reperfusion induced ovary injury. PMID- 25783345 TI - Associating liver partition with portal vein ligation and staged hepatectomy (ALPPS) for the treatment of liver tumors in children. AB - Resection is the only curative treatment option for primary and secondary malignant tumors of the liver. Although curative resection is associated with long-term survival rates, it can only be performed in 10% of patients with primary tumors and 25% of patients with liver metastases. Liver insufficiency is one of the most serious postoperative complications of patients undergoing extensive liver resections. When total liver resection is necessary liver transplant is mandatory, with the burden of long-term immunosuppression and its complications. Among several different strategies to increase the resectability of liver tumors, portal vein occlusion (embolization or ligature), bilateral tumor resection in two stages, and resection combined with loco regional therapy are the most popular. A new strategy for patients with marginally resectable liver tumors previously considered to be unresectable was formally reported by Baumgart et al. in 2011, originally developed by Hans Schlitt in 2007. This technique consists of a two-staged hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma, and it is known as ALPPS (associating liver partition with portal vein ligation for staged hepatectomy). The aim of this study is to present the first series of pediatric patients with marginally resectable liver tumors previously considered to be unresectable treated with two-stage hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma. Two patients were diagnosed with hepatoblastoma, and one each with rhabdomyosarcoma, hepatocellular carcinoma, and nodular focal hyperplasia. ALPPS technique was considered whenever the future liver remnant (FLR) was 40% or less of the total liver volume (TLV) determined by CT or MRI scans. The ratio of FLR to TLV before the first procedure ranged from 0.15 to 0.38, with a mean+/-sd of 0.253+/-0.07. In all patients, a rapid growth of the FLR was observed. Estimates of the FRL volume prior to surgical treatment ranged from 110cc to 750cc, with a mean+/-sd of 361.6+/-213.75cc. Just before the second procedure, the volume of the remnant liver ranged from 225cc to 910cc, with a mean+/-sd of 563.6cc+/-221.7cc. The FRL volume increase had a mean+/-sd of 72.56%+/-29.05%, with a median of 83.8%. The second procedure was performed after 7 to 12days with a median of 11days. The only postoperative complication observed in one patient was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications. ALPPS was shown to be effective and a safe procedure to treat large tumors in children. PMID- 25783346 TI - Use of real-time ultrasound during central venous catheter placement: Results of an APSA survey. AB - PURPOSE: The purpose of this study was to document the attitudes and practice patterns of pediatric surgeons regarding use of RTUS with CVC placement. METHODS: An analytic survey composed of 20 questions was sent via APSA headquarters to all practicing members. Answers were summarized as frequency and percentage. Distributions of answers were compared using the chi-square tests. P-values <=0.05 were considered statistically significant. RESULTS: 361 of 1072 members chose to participate for a response rate of 34%. Most placed CVCs into the subclavian veins (SCV) of patients without coagulopathy, with the left SCV chosen approximately four times more often than the right. Conversely, RTUS use at the internal jugular vein (IJV) was significantly greater than that for the SCV (p<0.001). Coagulopathy, multiple previous catheters, and morbid obesity were identified as patient characteristics that would encourage RTUS use. The most commonly cited potential barriers to RTUS use were lack of formal ultrasound training and the belief that ultrasound is not necessary. CONCLUSIONS: Variability exists among pediatric surgeons regarding use of RTUS during CVC placement. Additional studies are needed to document actual frequency of use, how RTUS is implemented, and its efficacy of preventing adverse events in children. PMID- 25783347 TI - Intraperitoneal microdialysis in the postoperative surveillance of infants undergoing surgery for congenital abdominal wall defect: A pilot study. AB - PURPOSE: This study aims to investigate the safety and clinical implication of intraperitoneal microdialysis (MD) in newborns operated on for congenital abdominal wall defect. PATIENTS AND METHODS: 13 infants underwent intraperitoneal microdialysis (9 with gastroschisis and 4 with omphalocele). MD samples were collected every four hours and the concentrations of lactate, glycerol, glucose and pyruvate were measured. The results of MD were compared between the group of infants with gastroschisis and the group with omphalocele. The duration of parenteral nutrition and tube feeding were compared for high and low levels of intraperitoneal lactate, glycerol, and glucose and lactate/pyruvate ratio respectively. High and low levels were defined as above or below the median value on day one. RESULTS: Results from intraperitoneal MD showed a significantly higher mean lactate concentration in the group of infants with gastroschisis compared with the group of infants with omphalocele. The median values were 6.19 mmol/l and 2.19 mmol/l, respectively (P=0.006). The results from MD in the six infants in the gastroschisis group who underwent secondary closure after Silo treatment were similar to those who underwent primary closure. None of the infants with omphalocele received parenteral nutrition whereas all of the infants with gastroschisis did. There was no significant difference in duration of parenteral nutrition or tube feeding, respectively, when comparing the gastroschisis children with high versus low intraperitoneal lactate values. Placement of the MD catheter in the intraperitoneal cavity was feasible and without any major complications. CONCLUSION: Intraperitoneal MD is a safe procedure and an applicable method in surveillance of inflammatory changes in the peritoneal cavity in infants after operation for congenital abdominal wall defect. The true clinical value in infants with congenital wall defect remains unknown. PMID- 25783348 TI - Heterotaxy syndrome and intestinal rotational anomalies: Impact of the Ladd procedure. AB - BACKGROUND: Children with heterotaxy syndrome and intestinal rotational anomalies (IRA) are at risk for midgut volvulus and ischemia. Controversy exists regarding risks and benefits of prophylactic Ladd procedures. The purpose of this study is to assess the impact of Ladd procedures on adverse events for children with heterotaxy and IRA. METHODS: A retrospective cohort study using the Pediatric Health Information System (PHIS) database was performed. All children with heterotaxy and IRA admitted at age <= 30 days and discharged between 1/1/2004 and 1/1/2011 were included with a minimum 2-year follow-up period. The primary outcome was major morbidity, defined as a composite variable for intestinal obstruction/volvulus, ischemia, or resection, or inhospital mortality. Univariable and multivariable analyses were performed. RESULTS: There were 325 patients who met the inclusion criteria, including 92 (28%) patients with single ventricles. Mean gestational age was 38.0 +/- 2.1 weeks and birth weight was 3.1 +/- 0.6 kg. Ladd procedure was performed during initial hospitalization on 188 (58%) children. In multivariable analyses, Ladd procedure on initial hospitalization was associated with a 2.2 times increased odds of adverse events on subsequent admissions (95% CI 1.3-4.0, p = 0.007). CONCLUSIONS: Ladd procedure is associated with increased odds of adverse events for children with heterotaxy and IRA. PMID- 25783349 TI - Operative Findings Are a Better Predictor of Resource Utilization in Pediatric Appendicitis. AB - PURPOSE: Post-operative management following appendectomy is dependent upon intraoperative assessment. We determined concordance between surgical and histopathologic diagnosis to better predict resource utilization in pediatric patients undergoing appendectomy. METHODS: A retrospective analysis of 326 patients with operative appendicitis from July 2012 to July 2013 was performed. Based on operative findings, patients were classified as simple appendicitis (SA) or complex appendicitis (CA). RESULTS: The SA group included 194 (59.5%) patients while the CA group included 132 (40.5%) patients. There were significant differences in WBC, CRP, operative time, length of stay, and 30-day complications. Seventy percent of patients with intra-operative findings of SA were found to have complex pathology while 10.6% with intra-operative findings of CA were found to have simple pathology. There is poor agreement between intra operative findings and histopathologic findings (kappa=0.173). Although 70% of patients with intra-operative findings of SA were labeled as complex pathology, 86% followed a fast track protocol (same day discharge) with a low complication rate (1.7%). CONCLUSIONS: Pathology findings that overestimate the severity of disease correlate poorly with the post-operative outcomes for appendicitis. We conclude that operative findings are more predictive of clinical course than histopathologic results. This can have an impact on resource utilization planning. PMID- 25783350 TI - Increased pulmonary RhoA expression in the nitrofen-induced congenital diaphragmatic hernia rat model. AB - PURPOSE: Persistent pulmonary hypertension remains a major cause of mortality and morbidity in cases of congenital diaphragmatic hernia (CDH). Recently, RhoA/Rho kinase-mediated vasoconstriction has been reported to be important in the pathogenesis of pulmonary hypertension (PH). Several recent reports have described that fasudil, a potent Rho-kinase inhibitor and vasodilator, could represent a potential therapeutic option for PH. We designed this study to investigate the hypothesis that the expression level of RhoA is increased in the nitrofen-induced CDH rat model. The expression level of Wnt11, an activator of RhoA, was also evaluated. METHODS: Pregnant rats were treated with or without nitrofen on gestational day 9 (D9). Fetuses were sacrificed on D17, D19 and D21 and were divided into control and CDH groups. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression levels of both Wnt11 and RhoA. An immunofluorescence study was also performed to evaluate the expression and localization of RhoA. RESULTS: The relative mRNA expression levels of pulmonary Wnt11 and RhoA on D21 were significantly increased in the CDH group compared with the control group (p=0.016 and p=0.008, respectively). The immunofluorescence study confirmed the overexpression of RhoA in the pulmonary vessels of CDH rats on D21. CONCLUSIONS: Our results provide evidence that the RhoA/Rho-kinase-mediated pathway is involved in the pathogenesis of PH in the nitrofen-induced CDH rat model. Our data also suggest that the fasudil, a Rho kinase inhibitor, could represent a therapeutic option for the treatment of PH in CDH. PMID- 25783351 TI - Breast Imaging-Reporting and Data System (BI-RADS) classification in 51 excised palpable pediatric breast masses. AB - INTRODUCTION: The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classification was developed to risk stratify breast lesions and guide surgical management based on imaging. Previous studies validating BI-RADS for US do not include pediatric patients. Most pediatric breast masses present as palpable lesions and frequently undergo ultrasound, which is often accompanied with a BI-RADS classification. Our study aimed to correlate BI-RADS with pathology findings to assess applicability of the classification system to pediatric patients. METHODS: We performed a retrospective review of all patients who underwent excision of a breast mass at a single center from July 2010 to November 2013. We identified all patients who underwent preoperative ultrasound with BI-RADS classification. Demographic data, imaging results, and surgical pathology were analyzed and correlated. RESULTS: A total of 119 palpable masses were excised from 105 pediatric patients during the study period. Of 119 masses, 81 had preoperative ultrasound, and BI-RADS categories were given to 51 masses. Of these 51, all patients were female and the average age was 15.9 years. BI-RADS 4 was given to 25 of 51 masses (49%), and 100% of these lesions had benign pathology, the most common being fibroadenoma. CONCLUSIONS: Treatment algorithm based on BI-RADS classification may not be valid in pediatric patients. In this study, all patients with a BI-RADS 4 lesion had benign pathology. BI-RADS classification may overstate the risk of malignancy or need for biopsy in this population. Further validation of BI-RADS classification with large scale studies is needed in pediatric and adolescent patients. PMID- 25783352 TI - Reply to letter to the editor. PMID- 25783353 TI - Letter to the editor. PMID- 25783354 TI - Letter to the editor. PMID- 25783355 TI - Systemic hypertension in giant omphalocele: An underappreciated association. AB - PURPOSE: To evaluate the incidence, severity and duration of systemic hypertension in infants born with giant omphalocele (GO). METHODS: A retrospective review of patients born from 2003 through 2013 with a GO or intestinal atresia (control population) and managed at a single institution was performed. The hospital course was reviewed including all blood pressures, method of omphalocele repair, requirement for antihypertensive medications and renal function. RESULTS: Forty-five GO and 20 control patients met criteria for the study. Thirty-three GO patients underwent Schuster repair and 12 GO patients underwent delayed repair after epithelialization. Overall, 78% of GO patients had episodes of hypertension (82% Schuster and 67% delayed repair) compared to 15% of control patients (P<0.001). The majority of episodes were transient and occurred in the postoperative period (97%). Hypertension was persistent in 4 GO patients. These patients required antihypertensive medication at discharge, which was discontinued as an outpatient. No patient demonstrated significant evidence of renal abnormalities as indicated by renal ultrasound, urinalysis and/or serum creatinine level at the time of hypertension. CONCLUSION: Episodes of systemic hypertension are frequent in patients with GO. Episodes are often post-operative, transient and can be present in patients undergoing either a delayed or Schuster repair. A small subset of patients will have persistent hypertension requiring antihypertensive medication that can be weaned off in an outpatient setting. PMID- 25783356 TI - Appendicitis in preschool aged children: Regression analysis of factors associated with perforation outcome. AB - OBJECTIVES: Apply multivariate regression analysis to determine the significance of clinical variables for perforation outcome of a large series of preschool aged children with appendicitis. METHODS: Retrospective case review of 180 consecutive children<5 years of age diagnosed with appendicitis during an 8-year period. RESULTS: This age group accounted for only 9% of all cases of pediatric appendicitis at our institution during the study period. Perforation rate was inversely proportional to patient age, occurring in 100% aged<1 year, 91% ages 1 2 years, 76% ages 2-3 years, 73% ages 3-4 years, and 57% ages 4-5 years. Risk for perforation increased proportionately with duration of symptoms, ranging from 48% when<1 day vs 84% when>1 day; and 93% when>2 days. One-quarter with perforation had a prior recent medical evaluation with an alternative diagnosis rendered preappendicitis diagnosis. The mean duration of hospitalization was four times longer in those with perforation [8 days] vs no perforation [2 days]. Univariate analysis showed each of the following factors was significantly associated with perforation outcome: younger patient age, female gender, prior medical visit<48 hours of appendicitis diagnosis, symptom duration, presence of fever, and presence of appendicolith. Multivariate logistic regression combining all significant univariate predictors showed only duration of symptoms and presence of appendicolith were significantly associated with perforation outcome; receiver operating characteristic curves are generated to evaluate the predictive accuracy of these two factors, both individually and when combined. CONCLUSIONS: Although relatively uncommon in this age group, appendicitis is frequently associated with delayed diagnosis and perforation outcome. Risk for perforation is directly proportional to increasing duration of symptoms. Clinicians must maintain a high index of suspicion for this condition in these younger children, as early diagnosis is essential to maximizing outcome. PMID- 25783357 TI - Spleen-preserving proximal splenic-left intrahepatic portal shunt for the treatment of extrahepatic portal hypertension in children. AB - PURPOSE: The Rex shunt has been employed successfully to treat patients with extrahepatic portal hypertension. In the conventional Rex shunt, the internal jugular vein is used as a venous graft. Inevitably, such a procedure requires neck exploration and sacrifice of the internal jugular vein. The authors describe a novel adaptation of spleen-preserving spleno-Rex bypass, successfully carried out in children with extrahepatic portal hypertension. METHODS: The mean age of the four patients (1 boy, 3 girls) was 46 months at the time of operation. All children had a history of upper gastrointestinal bleeding, and suffered from splenomegaly and hypersplenism. Spleen-preserving proximal splenic-left intrahepatic portal shunt was performed in all patients. The splenic artery and vein were ligated at the splenic hilum, and the splenic vein was completely separated from the bed of the pancreas to its junction with the inferior mesenteric vein. The freed splenic vein was anastomosed to left portal vein. The short gastric and left gastroepiploic vessels were kept intact to supply and drain the spleen. All patients were followed-up for 7-33 months (median: 21.5 months). RESULTS: The spleen-preserving spleno-Rex bypass was successfully performed in all 4 patients. The median operative time was 225 min (range: 215 260 min). One patient received blood transfusion, and the postoperative length of hospital stay varied from 4 to 6 days (median: 4.5 days). Intraoperative portal venous angiography demonstrated the patency of the shunt in all patients. Postoperatively, the complete blood count normalized and the biochemistry tests were within normal range. Postoperative ultrasound confirmed shunt patency and satisfactory flow in the proximal splenic-portal shunt in each patient. The size of the spleen decreased and there was no recurrence of variceal bleeding. CONCLUSIONS: The spleen-preserving spleno-Rex bypass is a viable option to treat EHPVO in children. PMID- 25783358 TI - Treatment of esophageal achalasia in children: Today and tomorrow. AB - BACKGROUND: Esophageal achalasia (EA) is a rare esophageal motility disorder in children. Laparoscopic Heller myotomy (LHM) represents the treatment of choice in young patients. Peroral endoscopic myotomy (POEM) is becoming an alternative to LHM. The aim of this study is to evaluate the effectiveness, safety, and outcomes of POEM vs LHM in treatment of children with EA. METHODS: Data of pediatric patients with EA, who underwent LHM and POEM from February 2009 to December 2013 in two centers, were collected. RESULTS: Eighteen patients (9 male, mean age: 11.6 years; range: 2-17 years) were included. Nine patients (6 male, mean age: 10.7 years; range: 2-16 years) underwent LHM, and the other 9 (3 males, mean age: 12.2 years; range: 6-17 years) underwent POEM procedure. Mean operation time was shorter in POEM group compared with LHM group (62/149 minutes). Myotomy was longer in POEM group than in LHM group (11/7 cm). One major complication occurred after LHM (esophageal perforation). No clinical and manometric differences were observed between LHM and POEM in follow-up. The incidence of iatrogenic gastroesophageal reflux disease was low (1 patient in both groups). CONCLUSIONS: Results of a midterm follow-up show that LHM and POEM are safe and effective treatments also in children. Besides, POEM is a mini-invasive technique with an inferior execution timing compared to LHM. A skilled endoscopic team is mandatory to perform this procedure. PMID- 25783359 TI - The 46th annual meeting of the canadian association of pediatric surgeons. PMID- 25783360 TI - The level of evidence keeps improving: An updated analysis of the scientific program at the Canadian Association of Paediatric Surgeons Annual Meeting. AB - INTRODUCTION: The purpose of this study is to examine the scientific program of the Canadian Association of Pediatric Surgeons (CAPS) to determine if the quality of research has improved. METHODS: CAPS abstracts from 2010 to 2013 were reviewed by two independent researchers. Presentation type, study design, and level of evidence (LOE) were recorded. All differences were adjudicated by an epidemiologist. Fisher's exact test compared results to a previous study that assessed LOE in CAPS abstracts from 2005 to 2009. RESULTS: 291 abstracts were reviewed with 53 excluded and 238 included in final analysis. Reviewers demonstrated high agreement for study design (ICC=0.767 95%CI 0.715-0.810) and LOE (ICC=0.914 95%CI 0.892-0.931). Out of 238 studies, 117 (49%) were podium and 122 (51%) posters. Number of high-quality studies increased in 2010-2013 versus 2005-2009 (n=253), specifically systematic reviews (n=15 (6%) vs. n=3 (1%) p<0.01), randomized controlled trials (n=4 (2%) vs. n=0 (0%), p=0.05), and prospective cohort studies (n=41 (17%) vs. n=26 (10%), p<0.001). Retrospective cohort is still the most common. However, the number of studies has significantly decreased (n=121 (51%) vs. n=171 (68%), p<0.001). The proportion of high-level studies (LOE 2 or better) also improved (48 (20%) vs. 24 (10%) p<0.001). CONCLUSION: The quality of research presented at CAPS has greatly improved, especially in the past five years. PMID- 25783361 TI - Targeted needs assessment for a transitional "boot camp" curriculum for pediatric surgery residents. AB - INTRODUCTION: Transition periods in medical education are associated with increased risk for learners and patients. For pediatric surgery residents, the transition to training is especially difficult as learners must adjust to new patient populations. In this study we perform a targeted needs assessment to determine the ideal content and format of a pediatric surgery boot camp to facilitate the transition to residency. METHODS: A needs assessment survey was developed and distributed to pediatric surgery residents and staff across North America. The survey asked participants to rank 30 pediatric surgical diagnoses, 20 skills, and 11 physiological topics on "frequency" and "importance". Items were then ranked using empirical methods. The survey also evaluated the preferred boot camp format. RESULTS: In total, 12 residents and 23 staff completed the survey. No significant differences were identified between staff and residents in survey responses. The top 5 topics identified for inclusion in a boot camp were: (1) fluid and electrolyte management, (2) appendicitis, (3) pediatric hernias, (4) nutrition and (5) pain management. The preferred format for a boot camp was 3 4days in duration applying a blend of educational methods. CONCLUSIONS: Based on the results of the needs assessment survey, a novel pediatric surgery boot camp curriculum can be developed. PMID- 25783362 TI - Major thrombotic complications with lower limb PICCs in surgical neonates. AB - BACKGROUND: PICC lines are now used routinely to provide central access for neonatal intensive care unit (NICU) patients. Neonates are known to be at risk for venous thromboembolism (VTE) related to central catheters. No literature exists about VTE PICC-related morbidity in the NICU abdominal surgery subgroup. METHODS: With REB approval, a retrospective review of a NICU database of PICC insertions performed at a tertiary children's hospital was conducted (January 2010-June 2013). Information about PICCs and complications was recorded. For patients with a major thrombotic complication, charts were reviewed. A major thrombotic complication was defined as a thrombosis which required medical and/or surgical intervention. RESULTS: 692 PICCs were inserted (485 in the upper extremity, 142 in the lower extremity, and 65 in the scalp). Seventy-four patients had significant intraabdominal pathology, and 5 had a major thrombotic complication. All patients with a major thrombotic complication had a lower extremity PICC which was at or below L1 (L1-S1) running parenteral nutrition. CONCLUSIONS: In the current study, only neonates with abdominal pathology and a lower extremity insertion site suffered major thrombotic complications from PICC lines. Given all patients' PICC tips were below the recommended location, more rigorous surveillance (with repositioning if required) may avoid these complications for future patients. PMID- 25783363 TI - Determinants of survival and resource utilization for pediatric extracorporeal membrane oxygenation in the United States 1997-2009. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) remains a vital therapy for children requiring cardiopulmonary support. METHODS: The Kids' Inpatient Database (KID) was analyzed for ECMO (ICD-9-CM 39.65) patients between 1997 and 2009. RESULTS: Overall, 8005 cases were identified, consisting of neonatal (ECMO <30days of life; 33%), infant (30days to 1year; 46%), young child (1year to 5years; 9.7%), and older child (>5years; 11%) groups. Patients were most commonly male (56%), Caucasian (49%), and insured by Medicaid (46%). ECMO was indicated for respiratory distress syndrome (RDS; 33%), cardiac and circulatory congenital anomalies (CCCA; 22%), congenital diaphragmatic hernia (CDH; 13%), and persistent pulmonary hypertension of the newborn (PPHN; 10%). On multivariate analysis, length of stay (LOS) decreased over the study period, while total charges (TC) increased over time, p<0.001. Survival was higher for boys and those treated in large or urban teaching hospitals, p<0.05. ECMO for CDH, CCCA, and RDS had the highest associated mortality, p<0.001. Neonatal and infant ECMO had no difference in mortality vs. older children. CONCLUSIONS: While LOS for ECMO has decreased over time, TC has increased steadily. Improved survival is found in boys and patients at large or urban teaching hospitals. CDH, CCCA, and RDS portend poor survival outcomes as indicators for ECMO. PMID- 25783364 TI - Mucous fistula refeeding in neonates with enterostomies. AB - BACKGROUND/PURPOSE: Neonates with intestinal pathology may require staged surgery with creation of an enterostomy and mucous fistula (MF). Refeeding (MFR) of ostomy output may minimize fluid and electrolyte losses and reduce dependence on parenteral nutrition (PN), though a paucity of evidence exists to support this practice. The purpose of this study was to assess the outcomes of infants undergoing MFR and document associated complications. METHODS: With REB approval, infants with intestinal failure undergoing MFR between January 2000 and December 2012 were identified. A chart review was conducted and relevant data were collected. Descriptive statistics were used. RESULTS: Twenty-three neonates underwent MFR. Mean gestational age and birth weight were 35weeks and 2416grams. Pathologies included intestinal atresia (n=12), necrotizing enterocolitis (n=5), meconium ileus (n=4), and other (n=6). Seven patients were able to wean from PN. Four patients had complications: 3 had perforation of the MF, 1 had bleeding. Four patients died, with one death directly attributable to MFR. CONCLUSIONS: In this cohort MF refeeding was associated with significant complications and ongoing PN dependence. With advances in intestinal rehabilitation and PN, the benefit of MF refeeding must be weighed against the potential complications. PMID- 25783365 TI - Compliance with published recommendations for postoperative antibiotic management of children with appendicitis: A chart audit. AB - BACKGROUND: Recommendations for postoperative antibiotics for appendicitis were published by the American Pediatric Surgical Association (APSA) in 2010. However, implementation of practice recommendations often takes years. We measured compliance of pediatric surgeons (who receive reminders every 6months from the Division Chief) with the APSA recommendations. METHODS: With Research Ethics Board approval, we completed a retrospective review of children who underwent appendectomy since 2010. Compliance with APSA recommendations was analyzed descriptively. Agreement between pediatric surgeons and pathologists was analyzed by kappa. RESULTS: We reviewed 242 charts. Patients were excluded for missing data (n=5) and diagnosis other than appendicitis (n=27), resulting in 210 patients with appendicitis (119 acute, 91 perforated). Agreement of perforation status between surgeons and pathologists was good (kappa=0.75; 95% CI: 0.66 0.83). Many patients with nonperforated appendicitis received antibiotics in excess of the APSA recommendations (62/119 (52%)), as did those with uncomplicated perforated appendicitis (52/84 (62%)). CONCLUSIONS: Despite the availability of published recommendations, surgeons continue to prescribe postoperative antibiotics for appendicitis in excess of the recommendations. Overtreatment leads to potential medication errors and increased length-of stay/medication costs. An intensive implementation program with ongoing education/monitoring may improve compliance with established recommendations to decrease the use of excess postoperative antibiotics and their associated costs/risks. PMID- 25783366 TI - Neck and spine injuries in Canadian cheerleaders: An increasing trend. AB - BACKGROUND/PURPOSE: Cheerleading, now increasingly practiced in Canada, has a high propensity to cause traumatic neck and spine injuries. We aimed to evaluate the importance of neck and spine injuries in the practice of cheerleading and their occurrence mechanisms in order to propose preventive measures. METHODS: A retrospective cohort study of cheerleading injuries extracted from the Canadian Hospitals Injury Reporting and Prevention Program database between 1990 and 2010 was performed. RESULTS: Overall, there were 1496 cases of injuries documented secondary to cheerleading (median age 15, 4 (IQR=2, 2) years; 1410 women (94%)). Of those, 125 cases (8%) were neck and spine injuries. The most frequent injury was a sprain/strain (47%). More severe injuries included fractures (4%), muscle or tendon injury (3%), dislocation (1%), and nerve injury (1%). Over half of these injuries were caused by either falling from (26%) or basing/spotting a stunt from height (26%). Other mechanisms include being thrown/falling from a high toss (10%) and falling from a pyramid (8%). Of the 125 cases, 3 (2, 4%) were admitted to hospital. CONCLUSIONS: Most neck and spine injuries were related to stunts. Although the proportion of serious injury is low, the increasing trend for the practice of cheerleading calls for preventive measures. PMID- 25783367 TI - Post-ECMO chest tube placement: A propensity score-matched survival analysis. AB - BACKGROUND: Severe morbidity and mortality has been reported from chest tube (CT) placement during pediatric extracorporeal membrane oxygenation (ECMO). METHODS: Kids' Inpatient Database (KID) was analyzed for ECMO with CT placed <8days postcannulation (1997-2009). RESULTS: Overall, 5884 patients were identified (213 CT) (56% male, 49% white), with a median (IQR) age at ECMO cannulation 7 (117)days, length of stay (LOS) 26 (35)days, and total charges (TC) 342,116 (409,573) USD. Diagnoses included congenital diaphragmatic hernia (CDH) 16%, meconium aspiration (MA) 2%, pulmonary hypertension (PH) 13%, respiratory distress syndrome (RDS) 41%, and cardiac (C) 29%. Survival was overall 57%, CDH 47%, MA 88%, PH 75%, RDS 57%, and C 52%. There were no differences in survival between CT and non-CT patients compared overall, or by diagnosis, or by age <30days, or by diagnosis and age <30days. Multivariate analysis and propensity score matching for all ages, or <30days of age by diagnosis showed no difference in survival between CT and non-CT patients. CONCLUSION: Analysis of KID with correlative propensity score matching demonstrates no increased mortality in pediatric ECMO patients requiring CT placement. PMID- 25783368 TI - Evaluating the introduction of extracorporeal life support technology to a tertiary-care pediatric institution: Smoothing the learning curve through interprofessional simulation training. AB - BACKGROUND: Extracorporeal life support (ECLS) is a life-saving technology for the critically ill child. Our objective was to evaluate the outcomes of an educational curriculum designed to introduce an ECLS program to a noncardiac pediatric surgical center. METHODS: An interdisciplinary curriculum was developed consisting of didactic courses, animal labs, simulations, and debrief sessions. We reviewed all patients requiring ECLS between October 2011 and December 2013. All health care practitioners involved in the ECLS training curriculum were surveyed to evaluate their perception of the educational program. Primary outcomes include successful cannulation and 30-day survival. RESULTS: The knowledge and confidence improved with statistical significance (p<0.0001-0.0003) for all of the components of the training curriculum. The highest score was given to the simulations. Twenty-one patients underwent cannulation. All patients were successfully cannulated to bypass, including six (28.6%) ECPR. Median time from activation to cutting was 52min (IQR 40-72), and from cutting to bypass 40min (IQR 30-45). Sixteen patients (76.2%) were decannulated to a sustainable cardiac rhythm and survived 30-days. CONCLUSION: An ECLS curriculum incorporating simulation and dedicated practice seems to have eliminated the potential learning curve associated with the introduction of a complex technology to a novice environment. PMID- 25783369 TI - A comparison of surgical outcomes between in-hours and after-hours tracheoesophageal fistula repairs. AB - BACKGROUND: Emerging literature has found increased complications for some patients undergoing nonemergent surgeries performed after-hours. For infants born with esophageal atresia and tracheoesophageal fistula (EA/TEF), no literature exists addressing the impact of the timing of surgery on outcomes. METHODS: With IRB approval, EA/TEF repairs (2005-2010) performed at a tertiary children's hospital were reviewed retrospectively. All patients had an esophageal anastomosis. After-hours surgeries were defined as 1530-0800 Monday to Friday, weekends/holidays. Demographics, EA/TEF type, operative details, anastomotic tension, and complications were compared. Outcomes measured included intraoperative desaturations, esophageal complications (leak, stricture, recurrence), pneumothorax, and mortality. RESULTS: There were 28 patients, of which 21 underwent the procedure in-hours and 7 after-hours. Patient age, gestational age, weight, EA/TEF type, cardiac anomalies, and preoperative, intraoperative, and postoperative variables were not different between the groups. Operative time, intraoperative desaturations, anastomotic tension, blood loss, total ventilation days, or length of hospitalization were not significantly different. There was a significant increase in esophageal leaks in the after hours group (n=3) vs. the in-hours (n=0) group (p=0.014). CONCLUSIONS: In this study, infants with an EA/TEF repaired after-hours had a significant increase in anastomotic leaks. The observed increase in leaks requires further evaluation to ensure more optimal outcomes for this fragile group of patients. PMID- 25783370 TI - Predictors of poor prognosis in prenatally diagnosed sacrococcygeal teratoma: A multiinstitutional review. AB - INTRODUCTION: Attempts at defining predictors of poor outcome in fetal sacrococcygeal teratoma (SCT) have been hampered by small patient numbers. We sought to validate the utility of tumor volume to fetal weight ratio (TFR) as a predictor of poor prognosis and to identify other morphological outcome predictors in a multicenter series. METHODS: Records of prenatally diagnosed SCT at three fetal centers from 1986 to 2011 were reviewed. Prenatal imaging characteristics including TFR, morphology, hydrops, and placentomegaly were assessed. Poor prognosis was defined as fetal demise, need for fetal intervention, or perinatal death. Receiver operating characteristic (ROC) analysis was used to select a TFR cutoff value. RESULTS: Seventy-nine fetuses with SCT were evaluated. Eleven pregnancies ending in elective termination were excluded. ROC analysis revealed that TFR >0.12 prior to 24 weeks gestation was predictive of poor prognosis (AUC=0.913; Sensitivity=91.7%, Specificity=76.2%, PPV=86.8%; NPV=84.2%). Solid tumor morphology and presence of hydrops were found to be predictors of poor prognosis. None of the factors associated with poor prognosis were independent predictors on multivariate analysis. CONCLUSION: This study validates TFR >0.12 prior to 24 weeks gestation as an objective predictor of outcomes in fetuses with SCT that can be easily applied in most clinical settings. PMID- 25783371 TI - The burden of waiting: DALYs accrued from delayed access to pediatric surgery in Kenya and Canada. AB - BACKGROUND: Disability-adjusted life years (DALYs) have become the standard metric for estimating burden of disease (BoD), but have not yet been applied to delayed access to surgical procedures. This study estimates the DALYs accrued from delayed access to surgical care in two pediatric surgical units in Kenya and Canada. METHODS: Records of operations for 13 congenital health states in a Kenyan and a Canadian hospital were prospectively collected for 2012. DALYs caused by delayed presentation were estimated using disability weights and ideal and actual age at surgery. RESULTS: 1208 first-time procedures in general surgery, neurosurgery, plastic surgery, and urology were included. Delays were longest in general surgery and longer in Kenya than in Canada in all specialties. The longest delays in Kenya were for orchidopexy (72 months) and anorectoplasty (PSARP) (74 months), and in Canada for orchidopexy (40 months). Corresponding total delayed BoD was highest in general surgery and neurosurgery and higher again in Kenya than in Canada (484 cf. 84 DALYs). CONCLUSIONS: Estimating BoD resulting from delayed surgery is feasible and reflects both late presentation and limited access to care. Further exploration of these factors can make delayed DALYs a useful measure of health care coverage and waitlist prioritization. PMID- 25783372 TI - Granular cell tumors and congenital granular cell epulis in children: Similar entities. AB - BACKGROUND/PURPOSE: Granular cell tumor (GCT) is an unusual lesion thought to originate from Schwann cells. Congenital granular cell epulis (CGCE) is a rare fibroma-like lesion arising from the alveolar ridge in newborns. These entities have been described as distinct entities. METHODS: A retrospective review was performed of children with a histopathologic diagnosis of GCT or CGCE from 1991 2014. Data were recorded and analyzed. All values reported as the mean+/-standard deviation. RESULTS: GCT or CGCE was identified in 41 patients with a mean age of 7.8+/-6.1years. Thirty-one patients had GCT, and 10 had CGCE. All patients underwent excisional biopsy, except 1 who underwent incisional biopsy only. Fifteen patients had positive margins after excision (12 GCT and 3 CGCE). Only 1 had a local recurrence, and this same patient had multifocal GCT. Only 1 patient had an invasive lesion without recurrence after wide local excision. All patients survived, with a median follow-up of 42.5months (0.2-204.2months). CONCLUSION: In children, both GCT and CGCE exhibit benign behavior, and complete excision does not appear to be mandatory, as recurrence or invasive disease is rare. When invasive features are present, wide local excision should be undertaken. PMID- 25783373 TI - Mortality of pediatric surgical conditions in low and middle income countries in Africa. AB - BACKGROUND: There are ongoing efforts to improve the quality of surgical care for children in low and middle-income countries (LMICs) in Africa. The purpose of this study was to review the recent literature and estimate the mortality associated with pediatric surgical conditions in this setting. METHODS: We completed a comprehensive search for studies that: (1) reported outcomes associated with pediatric surgical conditions; (2) were conducted in LMICs in Africa; and (3) were published between 2007 and 2012. Abstract screening, full text review, and data abstraction were completed in duplicate. Mortality rates were pooled using a random effects model. RESULTS: Out of 2085 abstracts, 292 were selected for textual review, and 107 underwent complete data abstraction. Only 74 (68%) of these reported mortality explicitly. The highest pooled mortality rates were seen with esophageal atresia (72%), midgut volvulus (36%), and jejunoileal atresia (35%). Pooled mortality was 17% for congenital conditions and 9% for acquired disease. The overall mortality rate for all conditions was 12%. CONCLUSIONS: Mortality following pediatric surgical conditions in LMICs in Africa remains high, especially for congenital conditions in neonates. Future studies should report mortality explicitly and provide accurate follow-up data whenever possible. PMID- 25783374 TI - The correlation between the time spent in utero and the severity of bowel matting in newborns with gastroschisis. AB - BACKGROUND: Optimal timing of delivery in fetuses with gastroschisis (GS) is unknown. Some favor early induced delivery to prevent bowel injury. This study evaluates the correlation between bowel injury and the gestational age at birth using the Gastroschisis Prognostic Score (GPS). METHODS: A national database was analyzed from 2005 to 2013. Patients were pooled based on their gestational age at birth. The mean GPS and % of patients with severe bowel matting were tabulated for each week in utero. Regression modeling was used to evaluate the relationship between the dependent (severe matting and GPS) and independent (gestational age) variables and the R(2) coefficient of determination was derived to evaluate model strength. Additional factors influencing the timing of delivery were evaluated. RESULTS: Of 780 cases, 88 were excluded because of missing data. A linear relationship is seen between increasing gestational age and decreasing bowel matting (R(2)=0.66) and GPS (R(2)=0.72). For every week in utero, the % of patients with severe matting decreases by 3.6%. CONCLUSION: Early induced delivery simply to protect the bowel from ongoing in utero damage appears unfounded and should be reserved for evidence of closing gastroschisis or traditional obstetrical/fetal indications. PMID- 25783375 TI - Interstitial cells of Cajal are decreased in patients with gastroschisis associated intestinal dysmotility. AB - BACKGROUND: Gastroschisis associated intestinal dysmotility (GAID) is poorly understood. Animal experiments suggest that interstitial cells of Cajal (ICC), play an important role. METHODS: Infants with gastroschisis (GS) and GAID (time to full feed >42days) were selected. Age matched GS and control (NEC, ileal atresia, malrotation, and volvulus) samples from primary (T1) and secondary (T2) time points underwent standard histopathology and immunohistochemistry for identification of ICC, followed by evaluation of ICC numbers, distribution, morphology, relation to ganglion cells, and myenteric plexus architecture. Groups were compared using parametric and nonparametric tests. MAIN RESULTS: Twelve patients had samples available for histopathological evaluation. GAID patients had a significantly lower total number of ICCs than controls (3 vs. 8, P<0.0029). ICC number at T1 was 2.5 vs. 6 (P=0.0629) and significantly lower at T2. (3.5 vs. 11, P=0.0124). GAID patients did not show a significant increase of ICC from T1 to T2. Controls showed a significant increase of ICC over time (6 vs. 11, P=0.0408). CONCLUSION: Intestinal samples from infants with GAID who underwent stoma formation demonstrated fewer ICC than controls. There was no improvement or cell recovery during the study period. The ability to modulate ICC may have significant implications for the management of GAID. PMID- 25783376 TI - Persistent hypercarbia after resuscitation is associated with increased mortality in congenital diaphragmatic hernia patients. AB - BACKGROUND: Within congenital diaphragmatic hernia (CDH) care, there have been attempts to identify clinical parameters associated with patient survival, including markers of postnatal pulmonary gas exchange. This study aimed to identify whether postnatal pulmonary gas exchange parameters correlated with CDH patient survival. METHODS: A retrospective review was performed of isolated CDH neonates treated at a single institution from 1/2007 to 12/2013. Patient demographics, prenatal imaging, and postnatal clinical parameters, including arterial blood gas values within the first 24hours of life, were collected. RESULTS: Seventy-four patients with isolated CDH were identified. Fifty-seven had fetal MRI. Overall, 30-day patient survival was 85%. Sixteen infants (22%) required ECMO within 24hours. Mean initial PaCO2 in nonsurvivors was higher, and infants who remained hypercarbic postresuscitation (72+/-19mmHg) had a worse prognosis than those who resuscitated to a normal PaCO2 (39+/-1.6mmHg) (p<0.001). Prenatal fetal lung volumes measured by MRI were not strongly correlated with PaCO2 levels. CONCLUSION: CDH nonsurvivors are unable to maintain sufficient pulmonary gas exchange during the first 24hours of resuscitation. Furthermore, prenatal fetal lung volumes are weakly correlated with actual pulmonary gas exchange. These data may be useful for patient counseling during the resuscitative phase of CDH care. PMID- 25783377 TI - Clinical characteristics and outcomes of patients with right congenital diaphragmatic hernia: A population-based study. AB - PURPOSE: The purpose of this study was to compare RCDH to LCDH from the perspective of prenatal diagnosis, illness severity, treatment, and outcome. METHODS: A retrospective study of all cases of CDH registered in the Canadian Pediatric Surgery Network (CAPSNet) database from 2005 to 2013 was conducted. Side of defect comparisons were made by prenatal diagnostic features, birth demographic data, intensity of medical treatment, timing and type of surgery, and outcomes. Outcomes prediction with logistic regression modeling using side of defect as an exploratory covariate was performed. RESULTS: The study cohort included 498 patients, of which 84 (17%) cases had RCDH. Prenatal diagnosis was more commonly made for LCDH. No difference existed in perinatal risk factors (GA, illness severity (SNAP-II) score, associated anomalies), preoperative treatment intensity (use of vasodilators, inotropes), timing of surgery, ventilation days, need for ECMO, LOS, and overall survival. Significant differences between RCDH and LCDH were detected for patch repair rate (48.2% vs. 30.6%; p=0.036) and recurrence (4.1% vs. 0.6%; p=0.038). Stepwise regression modeling identified side of hernia as independently predictive of need for patch. CONCLUSIONS: Overall, little difference exists between RCDH and LCDH in terms of prognostic factors and outcomes. PMID- 25783378 TI - Long-term nutritional morbidity for congenital diaphragmatic hernia survivors: Failure to thrive extends well into childhood and adolescence. AB - BACKGROUND: Failure to thrive (FTT) is well documented among congenital diaphragmatic hernia (CDH) survivors <=3years of age, but its etiology, severity, and persistence beyond this age require further elucidation. METHODS: We conducted a single-center, retrospective study assessing anthropometrics, measured energy expenditure, and feeding tube (FT) use of 5-17 year olds in our multidisciplinary CDH clinic since January 2001. We stratified clinic visits based on age A: 5.0-6.9, B: 7.0-9.9, C: 10.0-14.9, and D: 15-17.9years. RESULTS: One hundred sixteen patients with 376 outpatient visits were reviewed. Anthropometric z-scores were below zero and did not vary across age cohorts. FTT and growth stunting each occurred in 14% of clinic visits. FTs inserted during infancy occurred in 25% of patients, and 60% remained by age 7years. In cohort A, those with FTs were lighter and shorter than those without (p<0.05) but had similar BMIs. FTT incidence was higher in the FT group (p=0.020), but FTs were present in only 30% of those with FTT. Indirect calorimetry revealed increased energy expenditure in 58% of patients. CONCLUSIONS: Failure to thrive continues in long-term CDH survivors, FTs may not improve incidence of FTT. Increased energy expenditure may play a role. PMID- 25783379 TI - The association between congenital diaphragmatic hernia and undescended testes. AB - BACKGROUND: Undescended testes (UDT) is a common abnormality treated by pediatric surgeons. Embryological development of the genitourinary ridge is in close proximity with the pleuroperitoneal fold. The purpose of this paper is to describe the association between congenital diaphragmatic hernia (CDH) and UDT. MATERIALS/METHODS: As part of the DHREAMS (Diaphragmatic Hernia Research and Exploration: Advancing Molecular Science) study (www.cdhgenetics.com), all living children had tissue banked and analyzed for common genetic mutations and had a health assessment performed by telephone consultation with the parents at two years of age. The incidence of UDT was then compared to clinical and genetic findings previously identified. RESULTS: Sixty-five males had complete information from their 2year health assessment. Of these, twelve (18%) had a UDT repaired by the time of the 2year assessment. Of the twelve who had a repair, no child had a unilateral UDT which was contralateral to the side of the CDH. There were no differences in rate or number of mutations of any of the genes we checked as part of our study. CONCLUSION: It appears that a deficiency of diaphragm tissue may affect the first or transabdominal phase of the testicular descent, leading to an increased incidence of UDT. PMID- 25783380 TI - Increased pulmonary vascular expression of receptor for advanced glycation end products (RAGE) in experimental congenital diaphragmatic hernia. AB - AIM OF THE STUDY: Persistent pulmonary hypertension (PH) continues to be a major cause of high mortality in congenital diaphragmatic hernia (CDH). The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin protein family. Recently, RAGE has been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodeling in experimental PH. RAGE has been reported to be highly upregulated in lung tissue of patients with severe PH. We designed this study to investigate the hypothesis that RAGE expression is increased in nitrofen-induced CDH. METHODS: Pregnant rats were exposed to nitrofen or vehicle on D9. Fetuses were sacrificed on D21 and divided into nitrofen (n=16) and control group (n=16). Quantitative real-time polymerase chain reaction, Western blotting, and confocal immunofluorescence were performed. MAIN RESULTS: Pulmonary RAGE gene expression levels were significantly increased in nitrofen-induced CDH compared to controls (p<0.003). Western blotting and confocal microscopy revealed increased pulmonary RAGE protein expression in CDH compared to controls. CONCLUSION: This study provides striking evidence of increased gene and protein expression of RAGE in the pulmonary vasculature of nitrofen-induced CDH, suggesting that increased expression of RAGE may play a role in the pathogenesis of PH in nitrofen-induced CDH. PMID- 25783381 TI - Post-Operative Impact of Nasogastric Tubes on length of stay in infants with pyloric Stenosis (POINTS): A prospective randomized controlled pilot trial. AB - INTRODUCTION: Postoperative emesis commonly affects infants after pyloromyotomy for pyloric stenosis. This randomized controlled trial investigates the impact of preoperative nasogastric tubes (NGTs) on postoperative emesis rate and length of stay (LOS). METHODS: Patients from January 2010 to June 2012 were screened and randomized to have an 8 French NGT or no NGT inserted prior to surgery. Patients contraindicated for NGT or pyloromyotomy, those < 6 months of age, born prematurely, or with cardiac malformations were excluded. Patient demographics, blood work, postoperative feeding, postoperative emesis rate, and postoperative LOS were collected. Student's t test and Fisher's exact test were used to compare postoperative emesis rate and LOS. RESULTS: Of 125 patients screened, 65 (52%) were eligible, and 50 (77%) were recruited. The NGT (n = 25) and no NGT (n = 25) groups had no significant difference in baseline characteristics. Postoperative emesis occurred in 17 (68%) patients with NGT compared to 12 (48%) in patients with no NGT (p = 0.25). Postoperative emesis events (52 [23%] vs. 47 [20%], p = 0.50), emesis per patient (2.08 +/- 2.23 vs. 1.88 +/- 2.70, p = 0.76 95% CI: 1.21 to 1.61), and LOS (34.77 +/- 13.74 vs. 36.33 +/- 19.36, p = 0.74 95% CI: 11.11 to 7.98) were similar between NGT and no NGT groups. CONCLUSION: Preoperative NGT insertion had no demonstrable effect on LOS or postoperative emesis rate after pyloromyotomy. PMID- 25783382 TI - Routine gastrostomy tube placement in children: Does preoperative screening upper gastrointestinal contrast study alter the operative plan? AB - BACKGROUND: Upper GI (UGI) studies are routinely ordered to screen for malrotation before routine placement of gastrostomy (G) tubes. However, the usefulness of this study is unknown. METHODS: A retrospective review of children with surgically placed G-tubes over a 2 year period (2011-2013) was performed. Patients with concomitant fundoplications were excluded. RESULTS: Three hundred ninety-three patients underwent G-tube placement. Of these, 299 patients (76%) had preoperative UGI, and 11 patients (3.7%) were identified with malrotation on UGI. Five (1.7%) patients underwent a Ladd's procedure. The remaining 6 either had malrotation associated with gastroschisis (n=5) or were lost to follow-up (n=1). Children <1 year did not have different rates of malrotation compared to older children (4.3% vs. 3.2%, p=0.617). Likewise, children with neurologic impairment (NI) had similar rates of malrotation compared to neurologically normal (NN) children (2.6% vs. 3.8%, p=0.692). The only significant difference in malrotation rate was between those with congenital gastrointestinal anomalies (24%) and those without (1.5%) (p<0.001). CONCLUSION: Preoperative screening UGI before routine G-tube placement led to an unexpected diagnosis of malrotation in only 1.7%. Given the added radiation risk associated with an UGI, our data suggest that an UGI is unnecessary prior to routine G-tube placement. A larger prospective study is warranted to validate these results. PMID- 25783383 TI - A systematic review and meta-analysis of gastrostomy insertion techniques in children. AB - BACKGROUND: Gastrostomy tubes are inserted via multiple techniques to provide a route for enteral feeding in the pediatric population. This review compares the rate of major complications and resource utilization associated with the various insertion techniques. METHODS: Major electronic databases were queried for comparative studies of two or more insertion techniques, including open, laparoscopic, percutaneous endoscopic, or fluoroscopic guided. Major complications were defined as reoperation within 1 year or death. Screening of eligible studies, data extraction, and assessment of methodological quality were conducted independently by two reviewers. Forest and funnel plots were generated for outcomes using Revman 5.1, with p<0.05 considered significant. RESULTS: Twenty-two studies with a total of 5438 patients met inclusion criteria. No differences in major complications were noted in studies comparing open versus laparoscopic approaches or open versus PEG. Studies comparing laparoscopic gastrostomy and PEG revealed a significantly increased risk in major complications with PEG (n=10 studies, OR 0.29, 95% CI: 0.17-0.51, p<0.0001). The number needed to treat to reduce one major complication by abandoning PEG is 45. CONCLUSIONS: PEG is associated with an increased risk of major complications when compared to the laparoscopic approach. Advantages in operative time appear outweighed by the increased safety profile of laparoscopic gastrostomy insertion. PMID- 25783384 TI - Fundoplication and gastrostomy versus percutaneous gastrojejunostomy for gastroesophageal reflux in children with neurologic impairment: A systematic review and meta-analysis. AB - BACKGROUND: Children with neurologic impairment often fail medical management of gastroesophageal reflux and proceed to fundoplication and gastrostomy (FG) or percutaneous gastrojejunostomy (GJ). Current guidelines do not recommend one treatment over the other, and there is ongoing uncertainty regarding clinical management. METHODS: We conducted a structured search of Medline, Embase, trial registries, and the gray literature. We included studies that compared outcomes for FG and GJ in children with neurologic impairment. RESULTS: We identified 556 children from three retrospective studies who underwent FG (n=431) or GJ (n=125). There were no differences in rates of pneumonia (17% vs 19%, p=0.74) or mortality (13% vs 14%, p=0.76). Few deaths were due to procedural complications (1%) or reflux (2%). There was a trend towards more major complications with FG (29%) compared to GJ (12%) (risk ratio=1.70, 0.85-3.41, p=0.14). Minor complications were more common with GJ (70%) than FG (45%), but this difference was also not statistically significant (risk ratio=0.38, 0.05-3.07, p=0.36). No studies reported quality of life using validated measures. CONCLUSIONS: The quality of the evidence for outcomes of FG versus GJ is very low. Large comparative studies are needed to determine which approach is associated with the best quality-of life outcomes. PMID- 25783385 TI - Obituary: Sigmund Ein, MD, 1936-2015. PMID- 25783386 TI - Prediction of esophageal varices in biliary atresia: Derivation of the "varices prediction rule", a novel noninvasive predictor. AB - BACKGROUND AND AIMS: Liver fibrosis and cirrhosis are nearly inevitable following Kasai portoenterostomy (KPE) for biliary atresia (BA), though the formation of varices is not. We sought to assess the value of noninvasive indices of portal hypertension (PHT), in predicting significant esophageal varices, and to develop a novel prediction model through regression modeling. METHODS: This is a retrospective, observational study with analysis of routine biochemical and ultrasound data. Five indices were examined: AST-to-platelet ratio index (APRi); hepatic artery resistance index (HARI); spleen size z score (SSAZ); platelet count-to-SSAZ ratio (P/SSAZ); and clinical prediction rule (CPR) [(0.75 * platelets)/(SSAZ+5)]+(2.5 * albumin), each at specific time points following KPE (6 months, 1 year and 2 years). Significant varices were defined as grade >= 2 at endoscopy (screening or following a gastrointestinal bleed). AUROC was calculated for all indices. Univariate analysis was used to assess variables' suitability for inclusion in a subsequent multivariate logistic regression model to generate a predictive index. Data are quoted as median (range). P values <= 0.05 were regarded as significant. RESULTS: 195 infants (median age at KPE of 55 days [11 216]) were analyzed. 42 (22%) had significant varices (median time to first presentation of varices of 1.20 [0.20-6.40] years). CPR and APRi (AUROCs ranging from 0.73-0.80 and 0.69-0.83 respectively) performed best overall. Multiple logistic regression modeling yielded a novel predictor at 6 months post-KPE: the Varices Prediction Rule (albumin * platelets/1000) (AUROC 0.75, sensitivity 86%, sensitivity 71%). CONCLUSIONS: Noninvasive indices such as CPR, APRi and now VPR can provide a tool for stratifying BA patients for elective endoscopy and possible preemptive intervention. PMID- 25783387 TI - A population-based, complete follow-up of 146 consecutive patients after transanal mucosectomy for Hirschsprung disease. AB - OBJECTIVE: The objective of the study is to define the population-based bowel functional outcomes and enterocolitis following transanal endorectal pull-through (TEPT) in patients with Hirschsprung disease (HD) treated at our institution between 1986 and 2011. METHODS: 146 consecutive patients who had undergone primary surgical treatment for HD were included. The median follow-up time was 15 (3-33) years. The clinical details and prevalence of enterocolitis were evaluated in all patients, and bowel function in patients >3 years of age with functional intestino-anal continuity. RESULTS: No patients were lost to follow-up. Overall survival was 98%. The level of disease was rectosigmoid in 83%, long segment in 7%, total colonic in 4%, and extending up to the small bowel in 6%. 29% had an associated syndrome. 22% had a preoperative stoma. Operations included TEPT (89%), proctocolectomy with ileoanal anastomosis in 9%, and 3% had a permanent endostomy owing to small intestinal aganglionosis. One patient underwent intestinal transplantation. At the latest follow-up, 42% had occasional soiling, 12% had frequent soiling and 46% had no soiling. Constipation occurred in 9%. An associated syndrome was the only predictor for soiling or constipation (OR 4.3, 95% CI 1.5-12). 44% developed recurrent postoperative enterocolitis, which was predicted by extended aganglionosis (OR 6.9, 95% CI 2.4-20) and syndromatic disease (OR 2.4, 95% CI 1.2-5.0). CONCLUSION: The major functional sequelae following TEPT were recurrent enterocolitis and fecal soiling, which was mostly occasional. An associated syndrome was a predictor of a reduced bowel functional outcome, and alongside extended aganglionosis were significant risk factors for recurrent postoperative enterocolitis. PMID- 25783388 TI - Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome. AB - BACKGROUND: Biliary atresia (BA), a cholangiopathy of unknown etiology is associated with intrahepatic mononuclear cell infiltrate. An abnormal reaction to viral exposure has been hypothesized in some cases. We aimed to investigate the nature of the CD4+ hepatic infiltrate in defined clinical variants of BA by quantification of inflammatory cell components. METHODS: Liver biopsies of infants obtained at Kasai portoenterostomy (KPE) were stained immunohistochemically using monoclonal antibodies to Tbet, GATA-3, FOXP3 and interleukin (IL) 17, identifying Th-1, Th-2, Tregs and Th-17 cells respectively. T cells were counted with the aid of a graticule. Data are reported as median (range) of cells per high-power-field (*400) and compared using nonparametric statistical tests with P<=0.05 regarded as significant. RESULTS: Liver biopsies from BA (n=37) and age-matched cholestatic controls (e.g. alpha-1-anti trypsin deficiency, Alagilles syndrome, n=12) were investigated. BA infants were divided into three groups: cytomegalovirus IgM +ve (CMV; n=9); BA splenic malformation (BASM; n=9) and isolated BA (IBA; n=19). All T-cell subsets were present in the portal tracts, with an overrepresentation of Th-1 (P<0.001) and Th-17 (P<0.03), but not Th-2 (P=0.94) or Tregs (P=0.15), compared to controls. Th-1 cells predominated in the CMV group; (18 [7-37] vs. 3 [0-14] [BASM] and vs. 5 [3-23] [IBA]; P<0.01 both), while no subgroup differences were seen for Th-17 cells. The degree of Th-1 cell infiltrate inversely correlated with platelet count (rS= 0.49; P<0.01). Th-17 cells were fewer (6 [2-11] vs. 11 [8-20]; P=0.02) in infants who cleared their jaundice (n=15, <20MUmol/L) although this did not translate to improved native liver survival (P=0.17). CONCLUSIONS: Th-17 cells infiltrate the liver in BA and are associated with a worse surgical outcome; a Th-1 profile predominates in CMV-associated BA. PMID- 25783389 TI - Posterior sagittal anorectoplasty results in better bowel function and quality of life in adulthood than pull-through procedures. AB - BACKGROUND/PURPOSE: The short-term outcome of posterior sagittal anorectoplasty (PSARP) procedure has been reported to be better than after abdominoperineal or abdominosacroperineal (AP) procedures. This study aimed to investigate the long term functional outcome and quality of life after PSARP in adulthood and compare with the outcome after AP procedures. METHODS: Twenty-four patients operated with PSARP at the Department of Pediatric Surgery, Uppsala, Sweden, from 1984 to 1993 were identified. They were compared with 20 patients that underwent AP pull through procedures from 1974 to 1983. The patients were sent validated bowel function and quality of life (SF-36) questionnaires. Sixteen PSARP (median age 21, five females) patients and fourteen AP patients (seven abdominosacroperineal and seven abdominoperineal pull-throughs, median age 32, seven females) responded and were included in the study. RESULTS: The median Miller incontinence score was 1 (range 0-13) in the PSARP group and 10 (range 3-16) in the pull-through group (P=0.0042). The use of underwear protection and oral loperamide was significantly less frequent in the PSARP group (P=0.0096 and 0.0021 respectively). The SF-36 scores of Vitality, Mental health and Mental Cluster Scale were higher in the PSARP group (P=0.0291, 0.0500, 0.0421 respectively). CONCLUSIONS: PSARP results in superior bowel function and better quality of life in adulthood compared with AP procedures for the repair of anorectal malformations. PMID- 25783390 TI - Heterotopic gastric mucosa mimicking a Meckel's diverticulum in a young girl. AB - Heterotopic gastric mucosa (HGM) is a rare, but acknowledged source of gastrointestinal pathology in pediatric patients. Sometimes clinically confused with a Meckel's diverticulum, HGM diagnosis is often made postoperatively by pathology. We present a case of jejunal HGM with a positive technetium pertechnetate scan in the right lower quadrant that resembled a Meckel's diverticulum. PMID- 25783391 TI - Establishing pediatric surgical services in emerging countries: What the first world can learn from Vanuatu. AB - INTRODUCTION: Conventional surgical aid to emerging countries often does little to build capacity or infrastructure. An evolving model in the South Pacific has been designed to promote local expertise by training local surgeons to a high standard and helping establish sustainable pediatric surgical services in those regions. This review identifies the key elements required to improve and expand local specialist pediatric surgical capacity in Vanuatu. It highlights some of the challenges that face external agencies in helping to create sufficient local infrastructure to achieve these goals and describes how the impediments can be overcome. METHODOLOGY: We conducted a review of the program that provides a sustainable pediatric surgical service to the small and poor Pacific nation of Vanuatu through the involvement and support of the Pacific Island Project administered by the Royal Australasian College of Surgeons. RESULTS: A needs assessment must be done from the recipient's perspective and can be achieved by collaboration between an external agency and existing local surgeons. The key to a sustainable service is identifying and training high quality young indigenous doctors early and providing mentorship and support, including after their return. A sustainable and viable service requires an adequately resourced position for the new surgeons(s) within a framework of a long term strategic plan for the specialty and adequate infrastructure in place on their return. Development of rapport with government and influencing strategic health priorities is a prerequisite of a new national specialty service. CONCLUSIONS: (1) Establishing long term viable pediatric surgical capability can only be achieved through the local health system with local leadership and ownership. (2) Internal capability includes governance, alignment with ministry of health priorities and policies, and effective clinical leadership. (3) Selection of person(s) to be trained is best done early, and he/she must be supported throughout training and afterwards. (4) Long term dependence on a single person makes the service vulnerable. (5) Ultimately, a service configuration that ensures children have timely access to quality specialist advice and which reflects the needs of the population is the main determinant of clinical outcomes. PMID- 25783392 TI - Esophageal perforations due to foreign body impaction in children. AB - AIMS: The treatment of perforating esophageal foreign body impaction (FBI) is complex and unclear. We present the outcome of surgical treatment of esophageal perforations due to FBI in children along with a management algorithm. METHODS: During a period of 7 years, 7 cases of esophageal perforations due to foreign body (FB) ingestion were referred to our unit. We analyzed the FB types, lodging duration and location, complications, and the surgical approaches. RESULTS: There were 4 male and 3 female patients. Mean age was 28 months (5 months-6 years). Six patients had metal FBs of variable shapes and 1 had glass marble. Three patients had witnessed history of FB ingestion. Duration of ingestion was variable and unknown in half of the patients. The site of impaction was cervical (1) and thoracic (5) esophagus. One patient had a marble as FB in the superior mediastinum. One patient manifested with features of perforation after removal of the impacted FB and 5 patients presented with perforations. Two patients presented with subcutaneous emphysema. One patient had trachea-esophageal fistula (TEF) after disc battery ingestion. Rigid esophagoscopy failed in 4 out of 6 patients. Five patients underwent thoracotomy, and repair with a pleural patch reinforcement. One patient had lateral esophagotomy in the cervical esophagus for removal of the impacted FB. Mediastinal FB was removed without opening the esophagus. All the patients were discharged uneventfully. CONCLUSIONS: Esophageal perforation following FBI is rare and requires prompt treatment. Surgical treatment tailored to the needs of individual patients is associated with a successful outcome and decreased morbidity. PMID- 25783393 TI - Single-incision laparoscopic excision of pancreatic tumor in children. AB - PURPOSE: Single-incision laparoscopic surgery (SILS) as a surgical approach in treatment of pancreatic disease has recently been reported in adults. However, its application in pancreatic surgery in children is limited. In this article, we report our preliminary experience of SILS in children with pancreatic disease. METHODS: Three children with pancreatic tumor underwent single-incision laparoscopic partial pancreatectomy between July 2011 and August 2013. Two of three children were girls, and one was a boy. The ages ranged from 2 to 10 months, with an average age of 6.7 months. RESULTS: All operations were successfully performed. There was no conversion to the conventional multi incision surgery. The mean operation time of the 3 cases was 153.3 minutes (range 120-200 minutes). The postoperative hospital stay was 7 days. The drainage tubes were kept for 3 to 4 days after surgery. There was no pancreatic juice leak in this case series. All patients were followed up and there was no recurrence. CONCLUSIONS: Single-incision laparoscopic partial pancreatectomy for children with pancreatic tumor is feasible. PMID- 25783394 TI - Improving central line infection rates in the neonatal intensive care unit: Effect of hospital location, site of insertion, and implementation of catheter associated bloodstream infection protocols. AB - INTRODUCTION: Catheter associated blood stream infections (CABSIs) are morbid and expensive for all ages, including neonates. Thus far, the impact of CABSI prevention protocols, such as insertion and maintenance bundles, in the neonatal intensive care unit (NICU) is largely unknown. We hypothesized that lines placed in the operating room (OR) would have a lower infection rate due to established insertion protocols and a more sterile environment. METHODS: A retrospective chart review of NICU patients who received a percutaneous or tunneled central venous catheter between 2005 and 2012 was performed. ECMO cannulas, PICC and umbilical catheters were excluded. Variables of interest included demographics, anatomical site, hospital location, line days, and line infection. Line infection was defined as a positive blood culture drawn through the catheter. RESULTS: A total of 368 catheters were placed in 285 NICU patients. Majority of catheters (65.5%) were placed in OR. Saphenous and femoral veins were most common anatomical sites (50.8%). Twenty-eight catheters were infected (7.6%). After adjusting for preoperative antibiotics, anatomical site, and SNAPPE-II scores, lines placed in OR were three times less likely to become infected (Odds Ratio=0.32, p=0.038). Although implementation of CABSI prevention protocols resulted in statistically significant reductions in infection (Odds Ratio=0.4, p=0.043), lines placed in the OR remained less likely to become infected. CONCLUSIONS: NICU line infection rates decreased with implementation of CABSI prevention protocols. Despite this implementation, catheters placed in the NICU continued to have higher infection rates. As a result, when patient status allows it, we recommend that central lines in newborns be placed in the operating room. PMID- 25783395 TI - Clinical application of indocyanine green (ICG) fluorescent imaging of hepatoblastoma. AB - BACKGROUND/PURPOSE: Although the usefulness of intraoperative indocyanine green (ICG) fluorescent imaging for the resection of hepatocellular carcinoma has been reported, its usefulness for the resection of hepatoblastoma remains unclear. This study clarifies the feasibility of intraoperative ICG fluorescent imaging for the resection of hepatoblastoma. METHODS: In three hepatoblastoma patients, a primary tumor, recurrent tumor, and lung metastatic lesions were intraoperatively examined using a near-infrared fluorescence imaging system after the preoperative administration of ICG. RESULTS: ICG fluorescent imaging was useful for the surgical navigation in hepatoblastoma patients. In the first case, the primary hepatoblastoma exhibited intense fluorescence during right hepatectomy, but no fluorescence was detected in the residual liver. In the second case, a recurrent tumor exhibited fluorescence between the residual liver and diaphragm. A complete resection of the residual liver, with a partial resection of the diaphragm, followed by liver transplantation was performed. In the third case with multiple lung metastases, each metastatic lesion showed positive fluorescence, and all were completely resected. These fluorescence-positive lesions were pathologically proven to be viable hepatoblastoma cells. CONCLUSION: Intraoperative ICG fluorescence imaging for patients with hepatoblastoma was feasible and useful for identifying small viable lesions and confirming that no remnant tumor remained after resection. PMID- 25783396 TI - Altered distribution of small-conductance calcium-activated potassium channel SK3 in Hirschsprung's disease. AB - PURPOSE: SK3 channels are voltage-independent Ca(2+)-dependent K(+) channels that play a key role in regulating smooth muscle membrane potential during purinergic inhibitory neurotransmission in the colon. Dysmotility problems are common after a properly performed pull-through operation for Hirschsprung's disease (HSCR). We hypothesised that ganglionic bowel just proximal to the transition zone is abnormal and designed this study to investigate SK3 channel expression in HSCR. METHODS: Entire resected bowel specimens were collected at the time of pull through surgery for HSCR (n=6). Control colonic specimens were obtained at the time of colostomy closure in patients following anorectoplasty (n=6). SK3 protein expression was assessed qualitatively using immunofluorescence with confocal microscopy and quantitatively using western blot (WB) analysis. RESULTS: Positive SK3 immunofluorescence was seen in the mucosa and in all three smooth muscle layers and the myenteric plexus in control specimens. SK3 immunofluorescence co localised with PDGFRalpha. A band was detected at ~70kDa on WB. SK3 protein expression was barely detectable in aganglionic tissue and markedly reduced in the ganglionic bowel of 3 patients with HSCR compared to controls. CONCLUSION: Decreased SK3 expression in ganglionic bowel may explain the basis of persistent bowel symptoms in some patients following a properly performed pull-through operation for HSCR. PMID- 25783397 TI - The effect of hypothermia on adnexal torsion/detorsion injury in a rat ovary model. AB - PURPOSE: Much attention has been given to hypothermia as it is effective in inhibiting inflammatory responses and also ischemia/reperfusion injury. Therefore, the aim of this study was to evaluate the effect of hypothermia on torsion/detorsion injury in rats. METHODS: Twenty-eight rats were randomly divided into four groups of sham-operated (SG), adnexal torsion/detorsion group (TG), adnexal torsion/detorsion+hypothermia group (THG) and hypothermia group (HG). In the SG group, right ovaries were excised after 3-h fixation to abdominal wall. In the TG, right adnexal underwent 720 degrees torsion in a counterclockwise direction for 3h and then excised after 3-h detorsion period. In the THG, after 3-h torsion period, ovaries were immediately subjected to hypothermia (4 degrees C) for 30-min and they were excised after 3-h detorsioned period. In the HG, the right ovaries were subjected to hypothermia for 30-min and excised after 3-h fixation period. One half of each ovary was immediately stored for antioxidant enzyme activity and tissue lipid peroxidation. The remainder was fixed for histopathological examination. RESULTS: Adnexal torsion and detorsion significantly increased the tissue level of Malondialdehyde, Superoxide dismutase and Reduced glutathione. On the other hand, hypothermia significantly reduced these oxidative stress parameters. The histopathological changes were less in the THG group; these changes were not statistically different from the other groups. CONCLUSION: The results of this study suggested that hypothermia inhibited the production of oxidative stress in the ovaries subjected to torsion/detorsion injury. PMID- 25783398 TI - Treatment of spontaneous rupture of lung hydatid cysts into a bronchus in children. AB - PURPOSE: While several publications have reported the treatment of ruptured lung hydatid cysts (HC) in adults, there is limited information on the treatment of children. This study summarizes the treatment approach and outcomes of 11 children with spontaneous rupture of lung HCs into a bronchus. METHODS: The complete medical records of 11 patients with spontaneous lung HC bronchus rupture between March 1993 and April 2012 were examined retrospectively. Gender, age at the time of diagnosis, patient symptoms, lung localization, dimensions of the cyst, medical treatment duration, and associated morbidities were evaluated. Routine chest x-rays, ultrasonography, computed tomography and serological tests were used. RESULT: The study included 11 patients [4 males, 7 females; average age 7.45 (range 5-11) years] presenting to the Emergency Department. The symptoms at the time of presentation were coughing in 81.8% (n=9), hemoptysis in 54.5% (n=6), and chest pain in 54.5% (n=6). The average cyst diameter was 8.71(35-15) cm. The rupture involved the left lung in 7 (63.6%) patients and the right in 4 (36.4%). Serological tests were positive in seven patients and all patients had eosinophilia. The treatment of one patient was discontinued, while all of the other patients were treated medically. Pneumonia developed in four patients and lung abscesses in two. Both patients who developed lung abscesses had cysts with diameters greater than 10 cm. The average follow-up period was 48.4 (range 15-85) months; no mortality occurred. CONCLUSION: In our experience, medical treatment is adequate for patients with lung HCs progressing to spontaneous bronchus rupture. There was a high rate of abscess development within the thoracic cavity in patients with cysts over 10 cm in diameter; these patients can be treated effectively with a medical approach. PMID- 25783399 TI - The effects of acute tension increase on rat esophageal muscle contractions: An in vitro study. AB - In long-gap esophageal atresia surgeries, anastomoses can be tensioned by several traction methods in order to establish esophageal continuity. It is unclear whether the etiology of esophageal dysmotility after traction is related with esophageal atresia itself or tensioned esophagus. Therefore, we evaluated the effects of acute in vitro esophageal tension application on esophageal muscle contractility in rats. 26 Wistar rats weighing 250-300 g were included to the study. After diethyl ether anesthesia, proximal segment (PS) and distal segment (DS) of esophagus were removed and suspended in an isolated organ bath kept at 37 degrees C, Krebs-Henseleit solution. Rats were enrolled into four groups including control group (CG, n=14) without tension, 5 g (5G, n=4), 15 g (15G, n=4) and 25 g (25G, n=4) tension groups. In all groups, contractile responses to electrical field stimulation (EFS), carbachol and KCl, and relaxation responses to serotonin were obtained. In CG, higher contractile responses were obtained in PS than DS after EFS. Both PS and DS showed higher contractile amplitudes in 5G with respect to that of CG, 15G and 25G (p<0.05). In 5G, contractile responses to carbachol were significantly increased in both PS and DS with respect to CG (p<0.05). However, contractile amplitudes in response to carbachol were decreased in PS when tension was increased to 15 g and 25 g. In DS, contractile responses in 15G and 25G were lower than 5G, and still higher than CG. Serotonin relaxation responses in PS were decreased when compared to CG at tension levels of 5 g, 15 g and 25 g (p<0.05). In DS, responses to serotonin were also decreased in tension groups. PS had higher contraction amplitudes than DS when contractile responses were obtained by high K(+) (p<0.05). Tension groups of both PS and DS showed increased contractions to high K(+) compared to CG (p<0.05). Increased esophageal tension led to increase in cholinergic responses of smooth muscles as well as in EFS-induced skeletal muscle responses. On the other hand, relaxation responses induced by serotonin decreased. These data indicate that esophageal tension increase impairs esophageal motility in both segments. PMID- 25783400 TI - Congenital paraesophageal hernia: The Montreal experience. AB - INTRODUCTION: Congenital paraesophageal hernia (CPEH) is the least common congenital diaphragmatic hernia. We performed an extensive review to further define this entity. METHODS: A retrospective study of children with CPEH (types II-IV hiatal hernias) treated at two children's hospitals over a 25-year period (1988-2013) was performed. RESULTS: Fourteen patients were diagnosed at a median age of 35 days (range 0-500), with one prenatal diagnosis. The most common symptoms were emesis in type II hernias (50%), and respiratory distress in types III and IV hernias (75% and 50%, respectively). Gastroesophageal reflux was concomitantly diagnosed in 50%, while concurrent congenital anomalies existed in 36%. A correct initial diagnosis was made in only 29% of cases. The diagnosis was most often established by UGI study (64%). The method of repair was laparoscopy in 21%, and laparotomy in 71%. An antireflux procedure was done in 13 (93%) patients. Long-term follow up data was available for 86% of patient. During follow-up, one patient recurred and one required sequential pneumatic esophageal dilations. There were no mortalities. CONCLUSIONS: CPEH is a rare entity often associated with gastroesophageal reflux disease and other congenital anomalies. Prognosis is excellent, but awareness of this anomaly may lead to earlier diagnosis. PMID- 25783401 TI - Anterior Cutaneous Nerve Entrapment Syndrome in Children. AB - PURPOSE: The purpose of this manuscript is to report on an entity known as Anterior Cutaneous Nerve Entrapment Syndrome (ACNES) and its relevance to chronic abdominal pain encountered in children. METHODS: Following institutional review board approval, we retrospectively reviewed patients who underwent operation for presumed ACNES from 2011-2014. Variables reviewed included age, gender, age at surgery, time from onset of pain to surgery, additional medical treatments, and surgery performed. The main outcome measure was amelioration of pain. RESULTS: Nine patients met the study criteria whereby 7 were female and 2 were male patients. Median age at time of surgery was 14 years (range: 10-19 years) and time from onset of symptoms to surgery was 10 months (range: 0.5-60 months). Eight reported complete resolution of the original symptoms in follow-up appointments. One patient reported new, yet similar symptoms on her opposite trunk. CONCLUSION: ACNES is a reported cause of chronic abdominal pain that can be managed surgically in the pediatric patient once medical management has been optimized. Close collaboration between surgeons and pain specialists helps identify patients who will benefit from surgical interventions and consideration of this condition could result in more timely pain relief in children. Further studies on a larger scale are needed to determine the long-term outcomes of this procedure. PMID- 25783402 TI - Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors. AB - PURPOSE: Antiangiogenic agents show significant antitumor activity against various tumor types. In a study evaluating the combination of sorafenib, bevacizumab, and low-dose cyclophosphamide in children with solid tumors, an unexpectedly high incidence of pneumothorax was observed. We evaluated patient characteristics and risk factors for the development of pneumothorax in patients receiving this therapy. PATIENTS AND METHODS: Demographics, clinical course, and radiographic data of 44 patients treated with sorafenib, bevacizumab and cyclophosphamide were reviewed. Risk factors associated with the development of pneumothorax were analyzed. RESULTS: Pneumothorax likely related to study therapy developed in 11 of 44 (25%) patients of whom 33 had pulmonary abnormalities. Median age of patients was 14.7 years (range, 1.08-24.5). Histologies associated with pneumothorax included rhabdoid tumor, synovial sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, and renal cell carcinoma. Cavitation of pulmonary nodules in response to therapy was associated with pneumothorax development (P<0.001). Median time from start of therapy to development of pneumothorax was 5.7 weeks (range, 2.4-31). CONCLUSION: The development of cavitary pulmonary nodules in response to therapy is a risk factor for pneumothorax. As pneumothorax is a potentially life-threatening complication of antiangiogenic therapy in children with solid tumors, its risk needs to be evaluated when considering this therapy. PMID- 25783404 TI - Liver fibrosis during the development of biliary atresia: Proof of principle in the murine model. AB - BACKGROUND: The murine model of biliary atresia (BA) is used for examining the pathogenesis of BA. The aim of the study was description of the morphological features and illustrating the detailed development of fibrosis using the Biliary Atresia Research Consortium (BARC) system. METHODS: Neonatal mice were injected intraperitoneally with rhesus rotavirus (RRV) strain (N=17). Healthy mice were the control group (N=29). All mice were sacrificed at 7 or 14days after birth. Two pathologists examined the morphological features using the BARC system; CK19, alphaSMA and collagen type I were assessed by immunohistochemistry. RESULTS: In RRV mice, portal fibrous expansion with focal bile duct proliferation and strong portal cellular infiltrate was found in contrast to healthy mice. In RRV mice, CK19 bile duct staining was significantly less or absent (p<0.01), with stronger portal staining of collagen type I (p=0.02). Expansion of staining for alphaSMA was more in RRV mice (p<0.01), but alphaSMA portal staining was stronger in healthy mice (p=0.02). CONCLUSIONS: The morphological features observed in the murine model of BA correspond with the BA characteristics according to the BARC criteria. Fibrosis is an important feature of the model. Therefore, this murine model is useful for investigating the pathogenesis of BA. PMID- 25783403 TI - A cross-sectional nationwide survey on esophageal atresia and tracheoesophageal fistula. AB - BACKGROUND: Our study aims at disclosing epidemiology and most relevant clinical features of esophageal atresia (EA) pointing to a model of multicentre collaboration. METHODS: A detailed questionnaire was sent to all Italian Units of pediatric surgery in order to collect data of patients born with EA between January and December 2012. The results were crosschecked by matching date and place of birth of the patients with those of diagnosis-related group provided by the Italian Ministry of Health (MOH). RESULTS: A total of 146 questionnaires were returned plus a further 32 patients reported in the MOH database. Basing on a total of 178 patients with EA born in Italy in 2012, the incidence of EA was calculated in 3.33 per 10,000 live births. Antenatal diagnosis was suspected in 29.5% patients. 55.5% showed associated anomalies. The most common type of EA was Gross type C (89%). Postoperative complications occurred in 37% of type C EA and 100% of type A EA. A 9.5% mortality rate was reported. CONCLUSIONS: This is the first Italian cross-sectional nationwide survey on EA. We can now develop shared guidelines and provide more reliable prognostic expectations for our patients. PMID- 25783405 TI - Learning curve evaluation using cumulative summation analysis-a clinical example of pediatric robot-assisted laparoscopic pyeloplasty. AB - BACKGROUND: The cumulative summation (CUSUM) method for learning curve analysis remains under-utilized in the surgical literature in general, and is described in only a small number of publications within the field of pediatric surgery. This study introduces the CUSUM analysis technique and applies it to evaluate the learning curve for pediatric robot-assisted laparoscopic pyeloplasty (RP). METHODS: Clinical data were prospectively recorded for consecutive pediatric RP cases performed by a single-surgeon. CUSUM charts and tests were generated for set-up time, docking time, console time, operating time, total operating room time, and postoperative complications. Conversions and avoidable operating room delay were separately evaluated with respect to case experience. Comparisons between case experience and time-based outcomes were assessed using the Student's t-test and ANOVA for bi-phasic and multi-phasic learning curves respectively. Comparison between case experience and complication frequency was assessed using the Kruskal-Wallis test. RESULTS: A total of 90 RP cases were evaluated. The learning curve transitioned beyond the learning phase at cases 10, 15, 42, 57, and 58 for set-up time, docking time, console time, operating time, and total operating room time respectively. All comparisons of mean operating times between the learning phase and subsequent phases were statistically significant (P=<0.001 0.01). No significant difference was observed between case experience and frequency of post-operative complications (P=0.125), although the CUSUM chart demonstrated a directional change in slope for the last 12 cases in which there were high proportions of re-do cases and patients <6 months of age. CONCLUSIONS: The CUSUM method has a valuable role for learning curve evaluation and outcome quality monitoring. In applying this statistical technique to the largest reported single surgeon series of pediatric RP, we demonstrate numerous distinctly shaped learning curves and well-defined learning phase transition points. PMID- 25783406 TI - Anal endosonography and bowel function in patients undergoing different types of endorectal pull-through procedures for Hirschsprung disease. AB - BACKGROUND: The reasons for fecal incontinence after surgery for Hirschsprung disease (HD) remain unclear. The aim of this study was to examine the anal sphincters by anal endosonography and manometry after transanal endorectal pull through, with or without laparotomy or laparoscopy, in HD patients. Furthermore, we aimed to correlate these findings to bowel function. PATIENTS AND METHODS: Fifty-two HD patients were followed after endorectal pull-through. Anal endosonography and manometry were performed without sedation at the age of 3 to 16 years. RESULTS: Endosonographic internal anal sphincter (IAS) defects were found in 24/50 patients, more frequently after transanal than transabdominal procedures (69 vs. 19%, p=0.001). In a multiple variable logistic regression model, operative approach was the only significant predictor for IAS defects. Anal resting pressure (median 40mm Hg, range 15-120) was not correlated to presence of IAS defects. Daily fecal incontinence occurred more often in patients with IAS defects (54 vs. 25%, p=0.03). CONCLUSIONS: Postoperative IAS defects were frequently detected and were associated with daily fecal incontinence. IAS defects occurred more often after solely transanal procedures. We propose that these surgical approaches are compared in a randomized controlled trial before solely transanal endorectal pull-through is performed as a routine procedure. PMID- 25783407 TI - Assessment of the role of LASER-Doppler in the treatment of port-wine stains in infants. AB - BACKGROUND: Port-wine stains (PWS) are malformations of capillaries in 0.3% of newborn children. The treatment of choice is by pulsed dye LASER (PDL), and requires several sessions. The efficacy of this treatment is at present evaluated on the basis of clinical inspection and of digital photographs taken throughout the treatment. LASER-Doppler imaging (LDI) is a noninvasive method of imaging the perfusion of the tissues by the microcirculatory system (capillaries). The aim of this paper is to demonstrate that LDI allows a quantitative, numerical evaluation of the efficacy of the PDL treatment of PWS. METHOD: The PDL sessions were organized according to the usual scheme, every other month, from September 1, 2012, to September 30, 2013. LDI imaging was performed at the start and at the conclusion of the PDL treatment, and simultaneously on healthy skin in order to obtain reference values. The results evidenced by LDI were analyzed according to the "Wilcoxon signed-rank" test before and after each session, and in the intervals between the three PDL treatment sessions. RESULTS: Our prospective study is based on 20 new children. On average, the vascularization of the PWS was reduced by 56% after three laser sessions. Compared with healthy skin, initial vascularization of PWS was 62% higher than that of healthy skin at the start of treatment, and 6% higher after three sessions. During the 2 months between two sessions, vascularization of the capillary network increased by 27%. CONCLUSION: This study shows that LDI can demonstrate and measure the efficacy of PDL treatment of PWS in children. The figures obtained when measuring the results by LDI corroborate the clinical assessments and may allow us to refine, and perhaps even modify, our present use of PDL and thus improve the efficacy of the treatment. PMID- 25783408 TI - Congenital diaphragmatic eventration in children: 12 years' experience with 177 cases in a single institution. AB - OBJECTIVE: This study sought to summarize the diagnostic and treatment aspects of congenital diaphragmatic eventration (CDE) in children by retrospectively analyzing their medical records to identify and understand the complications of CDE, its treatment, and to evaluate the long-term outcomes of diaphragmatic plication. METHODS: The medical records of children who received treatment for CDE from January 2000 to December 2011 at the Children's Hospital of Chongqing Medical University, China were analyzed. Data analyzed included the following: age, sex, symptom, location of eventration, associated anomalies, surgical procedures, complications, and survival and follow up details after diaphragmatic plication. RESULTS: The medical records of 177 children (boys: 128, girls: 49, mean age: 10.28+/-2.35 months) with CDE were included in this study. Specific symptoms of eventration of the diaphragm were reported for 86 cases; and the typical symptoms included rapid breathing, vomiting, and recurrent respiratory infections. Except for a bilateral case, all the other patients had unilateral CDE. Associated malformations were observed in 31 cases (17.5%), hypoplastic lung (10 cases) was the most common followed by congenital heart disease (9 cases), and cryptorchidism (3 cases). Interestingly, 91 patients were asymptomatic. Diaphragmatic plication was performed in all symptomatic patients (86 cases, 48.5%) and none had recurrence. CONCLUSIONS: Clinical symptoms of CDE varied in severity, ranging from asymptomatic conditions to life-threatening respiratory distress. Timely accurate diagnosis and treatment of symptomatic CDE could effectively resolve respiratory morbidity and reduce complications. The diaphragm plication surgery provided good results among the study population with no recurrence. PMID- 25783409 TI - Novel approach to vaginal calculus in a girl with urogenital sinus anomaly. AB - Isolated urogenital sinus can cause distended bladder and/or vagina and may present with an abdominal mass and sepsis during infancy. Older children may present with recurrent urinary tract infections and hematocolpos. We describe a 3 year-old girl with recurrent urinary tract infections thought to be secondary to vesicoureteric reflux. On further investigation, an isolated urogenital sinus anomaly with a calculus inside one of the hemivaginae was noted. She was managed expectantly with a plan to intervene at puberty. At puberty, during removal of the stone, the hemivaginal introitus was found to be stenotic. Gradually increasing sizes of Amplatz type graduated renal dilators were introduced from the introitus of the urogenital sinus into the hemivaginal stone until a size 22F Amplatz sheath could be passed easily. Size 10F cystoscope was passed through this channel, and the stone was fragmented using electrohydraulic lithotripsy. At a later date, she underwent staged anterior sagittal transvulval mobilization of the urogenital sinus. PMID- 25783410 TI - Effects of shakuyakukanzoto and its absorbed components on twitch contractions induced by physiological Ca2+ release in rat skeletal muscle. AB - Shakuyakukanzoto (SKT) is a kampo medicine composed of equal proportions of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix). A double-blind study reported that SKT significantly ameliorated painful muscle cramp in cirrhosis patients without the typical severe side effects of muscle weakness and central nervous system (CNS) depression. Previous basic studies reported that SKT and its active components induced relaxation by a direct action on skeletal muscle and that SKT did not depress CNS functions; however, why SKT has a lower incidence of muscle weakness remains unknown. In the present study, we investigated which components are absorbed into the blood of rats after a single oral administration of SKT to identify the active components of SKT. We also investigated the effects of SKT and its components on the twitch contraction induced by physiological Ca(2+) release. Our study demonstrated that SKT and five G. radix isolates, which are responsible for the antispasmodic effect of SKT, did not inhibit the twitch contraction in contrast to dantrolene sodium, a direct-acting peripheral muscle relaxant, indicating that the mechanisms of muscle contraction of SKT and dantrolene in skeletal muscle differ. These findings suggest that SKT does not reduce the contractile force in skeletal muscle under physiological conditions, i.e., SKT may have a low risk of causing muscle weakness in clinical use. Considering that most muscle relaxants and anticonvulsants cause various harmful side effects such as weakness and CNS depression, SKT appears to have a benign safety profile. PMID- 25783411 TI - Kaempferol-3-O-rutinoside from Afgekia mahidoliae promotes keratinocyte migration through FAK and Rac1 activation. AB - The restoration of the epidermal epithelium through re-epithelialization is a critical process in wound healing. Directed keratinocyte migration to the wound is required, and the retardation of this process may result in a chronic, non healing wound. The present study contributes to research aiming to identify promising compounds that promote wound healing using a human keratinocyte model. The effects of three kaempferol glycosides from an Afgekia mahidoliae leaf extract, kaempferol-3-O-arabinoside, kaempferol-3-O-glucoside, and kaempferol-3-O rutinoside, on keratinocyte migration were determined. Interestingly, kaempferol 3-O-rutinoside exhibited a pronounced effect on wound closure in comparison to the parental kaempferol and other glycosides. The mechanism by which kaempferol-3 O-rutinoside enhances cell migration involves the induction of filopodia and lamellipodia formation, increased cellular levels of phosphorylated FAK (Tyr 397) and phosphorylated Akt (Ser 473), and up-regulation of active Rac1-GTP. The data obtained in this study may support the development of this compound for use in wound healing therapies. PMID- 25783412 TI - In vivo chemical and structural analysis of plant cuticular waxes using stimulated Raman scattering microscopy. AB - The cuticle is a ubiquitous, predominantly waxy layer on the aerial parts of higher plants that fulfils a number of essential physiological roles, including regulating evapotranspiration, light reflection, and heat tolerance, control of development, and providing an essential barrier between the organism and environmental agents such as chemicals or some pathogens. The structure and composition of the cuticle are closely associated but are typically investigated separately using a combination of structural imaging and biochemical analysis of extracted waxes. Recently, techniques that combine stain-free imaging and biochemical analysis, including Fourier transform infrared spectroscopy microscopy and coherent anti-Stokes Raman spectroscopy microscopy, have been used to investigate the cuticle, but the detection sensitivity is severely limited by the background signals from plant pigments. We present a new method for label free, in vivo structural and biochemical analysis of plant cuticles based on stimulated Raman scattering (SRS) microscopy. As a proof of principle, we used SRS microscopy to analyze the cuticles from a variety of plants at different times in development. We demonstrate that the SRS virtually eliminates the background interference compared with coherent anti-Stokes Raman spectroscopy imaging and results in label-free, chemically specific confocal images of cuticle architecture with simultaneous characterization of cuticle composition. This innovative use of the SRS spectroscopy may find applications in agrochemical research and development or in studies of wax deposition during leaf development and, as such, represents an important step in the study of higher plant cuticles. PMID- 25783413 TI - The Arabidopsis RNA-binding protein AtRGGA regulates tolerance to salt and drought stress. AB - Salt and drought stress severely reduce plant growth and crop productivity worldwide. The identification of genes underlying stress response and tolerance is the subject of intense research in plant biology. Through microarray analyses, we previously identified in potato (Solanum tuberosum) StRGGA, coding for an Arginine Glycine Glycine (RGG) box-containing RNA-binding protein, whose expression was specifically induced in potato cell cultures gradually exposed to osmotic stress. Here, we show that the Arabidopsis (Arabidopsis thaliana) ortholog, AtRGGA, is a functional RNA-binding protein required for a proper response to osmotic stress. AtRGGA gene expression was up-regulated in seedlings after long-term exposure to abscisic acid (ABA) and polyethylene glycol, while treatments with NaCl resulted in AtRGGA down-regulation. AtRGGA promoter analysis showed activity in several tissues, including stomata, the organs controlling transpiration. Fusion of AtRGGA with yellow fluorescent protein indicated that AtRGGA is localized in the cytoplasm and the cytoplasmic perinuclear region. In addition, the rgga knockout mutant was hypersensitive to ABA in root growth and survival tests and to salt stress during germination and at the vegetative stage. AtRGGA-overexpressing plants showed higher tolerance to ABA and salt stress on plates and in soil, accumulating lower levels of proline when exposed to drought stress. Finally, a global analysis of gene expression revealed extensive alterations in the transcriptome under salt stress, including several genes such as ASCORBATE PEROXIDASE2, GLUTATHIONE S-TRANSFERASE TAU9, and several SMALL AUXIN UPREGULATED RNA-like genes showing opposite expression behavior in transgenic and knockout plants. Taken together, our results reveal an important role of AtRGGA in the mechanisms of plant response and adaptation to stress. PMID- 25783414 TI - Different bacterial models for in vitro induction of non-cavitated enamel caries like lesions: Microhardness and polarized light miscroscopy analyses. AB - The aim of this study was to compare different bacterial models for in vitro induction of non-cavitated enamel caries-like lesions by microhardness and polarized light microscopy analyses. One hundred blocks of bovine enamel were randomly divided into four groups (n = 25) according to the bacterial model for caries induction: (A) Streptococcus mutans, (B) S. mutans and Lactobacillus acidophilus, (C) S. mutans and L. casei, and (D) S. mutans, L. acidophilus, and L. casei. Within each group, the blocks were randomly divided into five subgroups according to the duration of the period of caries induction (4-20 days). The enamel blocks were immersed in cariogenic solution containing the microorganisms, which was changed every 48 h. Groups C and D presented lower surface hardness values (SMH) and higher area of hardness loss (DeltaS) after the cariogenic challenge than groups A and B (P < 0.05). As regards lesion depth, under polarized light microscopy, group A presented significantly lower values, and groups C and D the highest values. Group B showed a higher value than group A (P < 0.05). Groups A and B exhibited subsurface caries lesions after all treatment durations, while groups C and D presented erosion-type lesions with surface softening. The model using S. mutans, whether or not it was associated with L. acidophilus, was less aggressive and may be used for the induction of non cavitated enamel caries-like lesions. The optimal period for inducing caries-like lesions was 8 days. PMID- 25783415 TI - Cryopreserved arterial grafts as a conduit in outflow reconstruction in living donor liver transplantation. AB - BACKGROUND: Few reports have addressed the use of cryopreserved arterial grafts (CAG) for anterior section drainage in right lobe living donor liver transplantation (RL LDLT), and the impact of atherosclerosis on patency rate (PR) is not well studied. Also, those reports have limited case numbers. The aim of the present study is to report the largest experience with CAG in outflow reconstruction in RL LDLT and the impact of atherosclerosis on its patency. METHODS: During 2010 and 2011, 62 of 243 patients who underwent LDLT received outflow reconstruction with CAG for RL grafts. Atherosclerosis in CAG was classified into early, intermediate and advanced lesions according to the classification adopted by the American Heart Association: group 1 with grafts having no atherosclerosis or early lesions; and group 2 with grafts having intermediate and advanced lesions. Patency rates of CAG correlated with atherosclerotic change of CAG were retrospectively analyzed. RESULTS: The study group comprised 65 CAGs with 1, 3 and 6 months PR of 86.2%, 84.6% and 75.2% respectively. Histopathological examination was successful in 53 CAGs. The 1, 3 and 6 months PR of group with no/early atherosclerosis were 86%, 83.7% and 76.7%, respectively, while for groups with intermediate/advanced lesions they were 90%. However, there was no significant difference between the two groups (P = 0.384). CONCLUSIONS: Cryopreserved arterial grafts can be used for outflow reconstruction in RL LDLT with a good patency rate. Atherosclerosis appears to have minimal effect on CAG patency, yet further studies with larger cohorts are needed to support our results. PMID- 25783416 TI - Identification and characterization of a novel citrate synthase from Streptomyces diastaticus No. 7 strain M1033. AB - Citrate synthase (CS) is a key enzyme of the tricarboxylic acid cycle and is widely distributed among prokaryotes and eukaryotes. Here, we report for the first time, the cloning, expression, and characterization of a novel CS from Streptomyces diastaticus No. 7 strain M1033 (SdCS). Gel filtration chromatography and matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) analyses indicate that SdCS forms homodimers with a molecular mass of approximately 100.0 kDa. The predicted amino acid sequence of SdCS is highly similar to those of bacterial homodimeric type I CSs. The pH and temperature optima for SdCS activity were 8.0 and 35 degrees C, respectively. The half-life (t1/2 ) of SdCS was 10 Min at 50 degrees C and was increased to 210 Min in the presence of oxaloacetate. The kinetic parameters of SdCS (kcat = 262.8 and 230.7 s(-1); Km = 58.4 and 11.2 uM for acetyl-CoA and oxaloacetate, respectively) were comparable to those of dimeric CSs isolated from Gram-positive bacteria and eukaryotes. Moreover, SdCS activity was inhibited by ATP and ADP and stimulated by AMP. These findings provide a foundation for further investigations on the three-dimensional structure and mechanism of catalysis of SdCS. PMID- 25783417 TI - Possible superconductivity in Sr2IrO4 probed by quasiparticle interference. AB - Based on the possible superconducting (SC) pairing symmetries recently proposed, the quasiparticle interference (QPI) patterns in electron- and hole-doped Sr2IrO4 are theoretically investigated. In the electron-doped case, the QPI spectra can be explained based on a model similar to the octet model of the cuprates while in the hole-doped case, both the Fermi surface topology and the sign of the SC order parameter resemble those of the iron pnictides and there exists a QPI vector resulting from the interpocket scattering between the electron and hole pockets. In both cases, the evolution of the QPI vectors with energy and their behaviors in the nonmagnetic and magnetic impurity scattering cases can well be explained based on the evolution of the constant-energy contours and the sign structure of the SC order parameter. The QPI spectra presented in this paper can be compared with future scanning tunneling microscopy experiments to test whether there are SC phases in electron- and hole-doped Sr2IrO4 and what the pairing symmetry is. PMID- 25783418 TI - Estimation of perinatal mortality rate for institutional births in Rajasthan state, India, using capture-recapture technique. AB - OBJECTIVE: The objective of our investigation was to estimate the perinatal mortality rate among institutional births and to compare the sensitivities of different data collection methods. SETTING: A hospital-based prospective cohort study was undertaken during late-2012 in 21 public sector health facilities of 10 districts of the northern state of Rajasthan, India. PARTICIPANTS: A total of 6872 births were included in this epidemiological study. PRIMARY AND SECONDARY OUTCOME MEASURES: Perinatal mortality rate of institutional births was the primary outcome. Sensitivities of 'active' and passive' data collection methods were the secondary outcome measures. METHODS: All stillbirth data were from routine government records ('passive system'); early neonatal outcome data from government records ('passive') were compared against the method of 'phone tracking' of outcomes through the community health worker ('active system'). The Lincoln-Petersen formula for capture-recapture method was used to calculate the probable missing number of early neonatal deaths and thereby estimate the institutional perinatal mortality rate. RESULTS: Ratio of births in district:subdistrict facilities was 55:45. The estimated perinatal mortality rate (95% CI) by capture-recapture method was 35.8 (34 to 37) per 1000 births. The sensitivity of the passive system was 87-89% while the sensitivity of the active system was 91%. Three-fourths of perinatal deaths were documented as stillbirths. However, for these reported intrauterine deaths or stillbirths, clinical classification by typologies (term vs preterm; intrapartum vs antepartum; macerated vs fresh; with or without congenital anomalies) was absent in the recording system. CONCLUSIONS: Capture-recapture technique can be used to estimate the institutional perinatal mortality rate and also to assess the level of under-reporting by the 'passive' government reporting system. This can subsequently be used for monitoring of trends and studying the impact of health interventions. Accurate clinical categorisation of perinatal deaths is also recommended for improving quality of care. PMID- 25783419 TI - Multimorbidity and weight loss in obese primary care patients: longitudinal study based on electronic healthcare records. AB - OBJECTIVE: To analyse the association between cardiovascular and mental comorbidities of obesity and weight loss registered in the electronic primary healthcare records. DESIGN AND SETTING: Longitudinal study of a cohort of adult patients assigned to any of the public primary care centres in Aragon, Spain, during 2010 and 2011. PARTICIPANTS: Adult obese patients for whom data on their weight were available for 2010 (n=62,901), and for both 2010 and 2011 (n=42,428). OUTCOMES: Weight loss (yes/no) was calculated based on the weight difference between the first value registered in 2010 and the last value registered in 2011. Multivariate logistic regression models were adjusted for individuals' age, sex, total number of chronic comorbidities, type of obesity and length of time between both weight measurements. RESULTS: According to the recorded clinical information, 9 of 10 obese patients showed at least one chronic comorbidity. After adjusting for covariates, weight loss seemed to be more likely among obese patients with a diagnosis of diabetes and/or dementia and less likely among those with hypertension, anxiety and/or substance use problems (p<0.05). The probability of weight loss was also significantly higher in male patients with more severe obesity and older age. CONCLUSIONS: An increased probability of weight loss over 1 year was observed in older obese male patients, especially among those already manifesting high levels of obesity and severe comorbidities such as diabetes and/or dementia. Yet patients with certain psychological problems showed lower rates of weight reduction. Future research should clarify if these differences persist beyond potential selective weight documentation in primary care, to better understand the trends in weight reduction among obese patients and the underlying role of general practitioners regarding such trends. PMID- 25783420 TI - Doctors' approaches to PSA testing and overdiagnosis in primary healthcare: a qualitative study. AB - OBJECTIVES: (1) To explain general practitioners' (GPs') approaches to prostate specific antigen (PSA) testing and overdiagnosis; (2) to explain how GPs reason about their PSA testing routines and (3) to explain how these routines influence GPs' personal experience as clinicians. SETTING: Primary care practices in Australia including men's health clinics and rural practices with variable access to urology services. PARTICIPANTS: 32 urban and rural GPs within Australia. We included GPs of varying ages, gender (11 female), clinical experience and patient populations. All GPs interested in participating in the study were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were analysed using grounded theory methods to determine how and why GPs provide (or do not provide) PSA testing to their asymptomatic male patients. RESULTS: We observed patterned variation in GP practice, and identified four heuristics to describe GP preference for, and approaches to, PSA testing and overdiagnosis: (1) GPs who prioritised avoiding underdiagnosis, (2) GPs who weighed underdiagnosis and overdiagnosis case by case, (3) GPs who prioritised avoiding overdiagnosis and (4) GPs who did not engage with overdiagnosis at all. The heuristics guided GPs' Routine Practice (usual testing, communication and responses to patient request). The heuristics also reflected GPs' different Practice Rationales (drawing on experience, medicolegal obligations, guidelines and evidence) and produced different Practice Outcomes (GPs' experiences of the consequences of their PSA testing decisions). Some of these heuristics were more responsive to patient preferences than others. CONCLUSIONS: Variation in GPs' PSA testing practices is strongly related to their approach to overdiagnosis and underdiagnosis of prostate cancer. Men receive very different care depending on their GP's reasoning and practice preferences. Future policy to address overdiagnosis will be more likely to succeed if it responds to these patterned variations. PMID- 25783422 TI - The pathway to diagnosis of type 1 diabetes in children: a questionnaire study. AB - OBJECTIVE: To explore the pathway to diagnosis of type 1 diabetes (T1D) in children. DESIGN: Questionnaire completed by parents. PARTICIPANTS: Parents of children aged 1 month to 16 years diagnosed with T1D within the previous 3 months. SETTING: Children and parents from 11 hospitals within the East of England. RESULTS: 88/164 (54%) invited families returned the questionnaire. Children had mean+/-SD age of 9.41+/-4.5 years. 35 (39.8%) presented with diabetic ketoacidosis at diagnosis. The most common symptoms were polydipsia (97.7%), polyuria (83.9%), tiredness (75.9%), nocturia (73.6%) and weight loss (64.4%) and all children presented with at least one of those symptoms. The time from symptom onset to diagnosis ranged from 2 to 315 days (median 25 days). Most of this was the appraisal interval from symptom onset until perceiving the need to seek medical advice. Access to healthcare was good but one in five children presenting to primary care were not diagnosed at first encounter, most commonly due to waiting for fasting blood tests or alternative diagnoses. Children diagnosed at first consultation had a shorter duration of symptoms (p=0.022) and children whose parents suspected the diagnosis were 1.3 times more likely (relative risk (RR) 1.3, 95% CI 1.02 to 1.67) to be diagnosed at first consultation. CONCLUSIONS: Children present with the known symptoms of T1D but there is considerable scope to improve the diagnostic pathway. Future interventions targeted at parents need to address the tendency of parents to find alternative explanations for symptoms and the perceived barriers to access, in addition to symptom awareness. PMID- 25783421 TI - Socioeconomic status in relation to cardiovascular disease and cause-specific mortality: a comparison of Asian and Australasian populations in a pooled analysis. AB - OBJECTIVES: In Western countries, lower socioeconomic status is associated with a higher risk of cardiovascular disease (CVD) and premature mortality. These associations may plausibly differ in Asian populations, but data are scarce and direct comparisons between the two regions are lacking. We, thus, aimed to compare such associations between Asian and Western populations in a large collaborative study, using the highest level of education attained as our measure of social status. SETTING: Cohort studies in general populations conducted in Asia or Australasia. PARTICIPANTS: 303,036 people (71% from Asia) from 24 studies in the Asia Pacific Cohort Studies Collaboration. Studies had to have a prospective cohort study design, have accumulated at least 5000 person-years of follow-up, recorded date of birth (or age), sex and blood pressure at baseline and date of, or age at, death during follow-up. OUTCOME MEASURES: We used Cox regression models to estimate relationships between educational attainment and CVD (fatal or non-fatal), as well as all-cause, cardiovascular and cancer mortality. RESULTS: During more than two million person-years of follow-up, 11,065 deaths (3655 from CVD and 4313 from cancer) and 1809 CVD non-fatal events were recorded. Adjusting for classical CVD risk factors and alcohol drinking, hazard ratios (95% CIs) for primary relative to tertiary education in Asia (Australasia) were 1.81 (1.38, 2.36) (1.10 (0.99, 1.22)) for all-cause mortality, 2.47(1.47, 4.17) (1.24 (1.02, 1.51)) for CVD mortality, 1.66 (1.00, 2.78) (1.01 (0.87, 1.17)) for cancer mortality and 2.09 (1.34, 3.26) (1.23 (1.04, 1.46)) for all CVD. CONCLUSIONS: Lower educational attainment is associated with a higher risk of CVD or premature mortality in Asia, to a degree exceeding that in the Western populations of Australasia. PMID- 25783423 TI - Lifelong bound feet in China: a quantitative ultrasound and lifestyle questionnaire study in postmenopausal women. AB - OBJECTIVE: The phenomenon of foot binding, also known as 'lotus feet', has an enduring and influential history in China. To achieve a man-made smaller foot size, lifelong foot binding may have had adverse effects on the skeleton. We investigated bone properties in postmenopausal women with bound feet, which may provide new information for developing countermeasures for prevention of fragility fractures. DESIGN: Population-based cohort study. PARTICIPANTS: This study involved 254 postmenopausal women aged 65-80, including 172 with bound feet and 82 age- and gender-matched control subjects, living in a remote region of China. OUTCOMES: Anthropometric, SF-36 Lifestyle Questionnaire and heel quantitative ultrasound (QUS) data were collected for the whole study population. A small subset of two cases was also invited for assessment of bone mineral density and microarchitecture at the distal tibia using high-resolution peripheral quantitative CT (HR-pQCT) and gait and balance tests. RESULTS: Women with bound feet had significantly lower QUS values than age-matched women with normal feet; this was supported by HR-pQCT data. However, SF-36 Questionnaire results did not reveal any statistically significant differences in any categorical responses, including physical functioning, general health vitality and physical component summary score, and number of previous fractures. No impairment of body balance was found in the small subset. CONCLUSIONS: The man made changes caused by foot binding led to reduced physical activity, making the subjects prone to osteoporosis. Women with bound feet and osteoporosis did not have a higher incidence of fragility fractures than controls. This might be explained by compensation in physical activity to improve body balance, implying the importance of improving or maintaining body balance in overall prevention strategies against fragility fractures. PMID- 25783424 TI - Small-for-gestational age and large-for-gestational age thresholds to predict infants at risk of adverse delivery and neonatal outcomes: are current charts adequate? An observational study from the Born in Bradford cohort. AB - OBJECTIVES: Construct an ethnic-specific chart and compare the prediction of adverse outcomes using this chart with the clinically recommended UK-WHO and customised birth weight charts using cut-offs for small-for-gestational age (SGA: birth weight <10th centile) and large-for-gestational age (LGA: birth weight >90th centile). DESIGN: Prospective cohort study. SETTING: Born in Bradford (BiB) study, UK. PARTICIPANTS: 3980 White British and 4448 Pakistani infants with complete data for gestational age, birth weight, ethnicity, maternal height, weight and parity. MAIN OUTCOME MEASURES: Prevalence of SGA and LGA, using the three charts and indicators of diagnostic utility (sensitivity, specificity and area under the receiver operating characteristic (AUROC)) of these chart-specific cut-offs to predict delivery and neonatal outcomes and a composite outcome. RESULTS: In White British and Pakistani infants, the prevalence of SGA and LGA differed depending on the chart used. Increased risk of SGA was observed when using the UK-WHO and customised charts as opposed to the ethnic-specific chart, while the opposite was apparent when classifying LGA infants. However, the predictive utility of all three charts to identify adverse clinical outcomes was poor, with only the prediction of shoulder dystocia achieving an AUROC>0.62 on all three charts. CONCLUSIONS: Despite being recommended in national clinical guidelines, the UK-WHO and customised birth weight charts perform poorly at identifying infants at risk of adverse neonatal outcomes. Being small or large may increase the risk of an adverse outcome; however, size alone is not sensitive or specific enough with current detection to be useful. However, a significant amount of missing data for some of the outcomes may have limited the power needed to determine true associations. PMID- 25783425 TI - The efficacy of sodium bicarbonate in preventing contrast-induced nephropathy in patients with pre-existing renal insufficiency: a meta-analysis. AB - OBJECTIVE: The aim of this meta-analysis was to explore the efficacy of sodium bicarbonate in preventing contrast-induced nephropathy (CIN). METHODS: We searched PubMed, Medline and the Cochrane Library from 1 January 2004 to 1 August 2014. The effect estimate was expressed as a pooled OR with 95% CI, using the fixed-effects or random-effects model. RESULTS: 20 randomised controlled trials (n=4280) were identified. Hydration with sodium bicarbonate was associated with a significant decrease in CIN among patients with pre-existing renal insufficiency (OR 0.67, 95% CI 0.47 to 0.96; p=0.027). However, moderate heterogeneity was noted across trials (I(2)=48%; p=0.008). Subgroup analyses indicated a better effect of sodium bicarbonate in studies using low-osmolar (OR 0.59, 95% CI 0.37 to 0.93; p=0.024) compared with iso-osmolar contrast agents (OR 0.76, 95% CI 0.43 to 1.34; p=0.351). The odds of CIN with sodium bicarbonate were lower in studies including only patients undergoing emergency (OR 0.16, 95% CI 0.05 to 0.51; p=0.002) compared with elective procedures (OR 0.76, 95% CI 0.54 to 1.06; p=0.105). Sodium bicarbonate was more beneficial in patients given a bolus injection before procedures (OR 0.15, 95% CI 0.04 to 0.54; p=0.004) compared with continuous infusion (OR 0.75, 95% CI 0.53 to 1.05; p=0.091). Sodium bicarbonate plus N-acetylcysteine (OR 0.17, 95% CI 0.04 to 0.79; p=0.024) was better than sodium bicarbonate alone (OR 0.71, 95% CI 0.48 to 1.03; p=0.071). The effect of sodium bicarbonate was considered greater in papers published before (OR 0.19, 95% CI 0.09 to 0.41; p=0.000) compared with after 2008 (OR 0.85, 95% CI 0.62 to 1.16; p=0.302). However, no significant differences were found in mortality (OR 0.69, 95% CI 0.36 to 1.32; p=0.263) or requirement for dialysis (OR 1.08, 95% CI 0.52 to 2.25; p=0.841). CONCLUSIONS: Sodium bicarbonate is effective in preventing CIN among patients with pre-existing renal insufficiency. However, it fails to lower the risks of dialysis and mortality and therefore cannot improve the clinical prognosis of patients with CIN. PMID- 25783426 TI - Lung cancer in South Africa: a forecast to 2025 based on smoking prevalence data. AB - OBJECTIVE: This study aims to forecast lung cancer mortality with respect to recent changes in smoking prevalence and compares the results to estimates from GLOBOCAN and the Global Burden of Disease study. SETTING: An established epidemiological model is applied to detailed smoking prevalence data from South Africa to estimate lung cancer mortality from 2010 to 2025. PARTICIPANTS: Data from the South Africa Demographic and Health Survey conducted in 2003 was analysed by sex and ethnic group, and combined with longitudinal estimates on smoking prevalence from 1980 to 2010. PRIMARY AND SECONDARY OUTCOME MEASURES: Results provide detailed data on tobacco smoking behaviour by age, sex and ethnic group as well as modelled age-adjusted lung cancer mortality and number of yearly lung cancer deaths. RESULTS: From 2010 to 2025, a decrease in age-adjusted lung cancer mortality is shown from 17.1 to 14.1 among men; whereas rates were stable around 7.2 among women. As a consequence, the estimated number of yearly lung cancer deaths is expected to increase slightly for men and more for women. With respect to ethnic groups, male mortality is expected to be highest for Asians and lowest for blacks. Female rates were lowest for Asians and highest for whites and for coloured. CONCLUSIONS: Mortality estimates of this study are close to the WHO mortality database and to Global Burden of Disease estimates for 2010, but significantly lower compared with GLOBOCAN estimates. In conclusion, our study demonstrates the impact of demographic changes and the positive effects of antismoking policy on lung cancer mortality in South Africa. Results may help decision makers to further improve smoking control. PMID- 25783427 TI - Prevalence and incidence of dyslipidaemia among adults in Africa: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death globally and disproportionately affects low-income and middle-income countries. Dyslipidaemia is an important modifiable risk factor for CVD. There are important knowledge gaps regarding the population levels of lipid variables and frequency of non-optimal levels in populations within Africa. We propose to conduct a systematic review to determine the prevalence and occurrence of dyslipidaemia in adult populations within countries in Africa. METHODS AND ANALYSIS: We will perform a comprehensive search to identify all possible published and unpublished studies on the prevalence or incidence of dyslipidaemia in Africa reported from 1 January 1980, without language restriction. The scientific databases PubMed MEDLINE, EMBASE and ISI Web of Science will be searched, as well as Grey literature. Following study selection, full-text papers acquisition, and data extraction and synthesis, we will appraise the quality of studies and risk of bias, and assess heterogeneity. Prevalence/incidence data will be summarised by country and geographic regions and a meta-analysis will be conducted for variables defined identically across studies. Variance stabilising transformations will be applied as appropriate to the row data before meta analysis. This systematic review will be reported according to the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies. ETHICS AND DISSEMINATION: The current study is based on published data and as such ethics consideration is not a requirement. This review is expected to provide relevant data to help in quantifying the magnitude of dyslipidaemia in African populations, to emphasise the need for appropriate prevention and control strategies, and to identify research gaps and remaining challenges. The final report of the systematic review in the form of a scientific paper will be published in peer-reviewed journals. Findings will further be presented at conferences and submitted to relevant health authorities. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014015376. PMID- 25783429 TI - Drugs' stories and itineraries. On the making of Asian industrial medicines. PMID- 25783428 TI - Development and validation of risk prediction algorithms to estimate future risk of common cancers in men and women: prospective cohort study. AB - OBJECTIVE: To derive and validate a set of clinical risk prediction algorithm to estimate the 10-year risk of 11 common cancers. DESIGN: Prospective open cohort study using routinely collected data from 753 QResearch general practices in England. We used 565 practices to develop the scores and 188 for validation. SUBJECTS: 4.96 million patients aged 25-84 years in the derivation cohort; 1.64 million in the validation cohort. Patients were free of the relevant cancer at baseline. METHODS: Cox proportional hazards models in the derivation cohort to derive 10-year risk algorithms. Risk factors considered included age, ethnicity, deprivation, body mass index, smoking, alcohol, previous cancer diagnoses, family history of cancer, relevant comorbidities and medication. Measures of calibration and discrimination in the validation cohort. OUTCOMES: Incident cases of blood, breast, bowel, gastro-oesophageal, lung, oral, ovarian, pancreas, prostate, renal tract and uterine cancers. Cancers were recorded on any one of four linked data sources (general practitioner (GP), mortality, hospital or cancer records). RESULTS: We identified 228,241 incident cases during follow-up of the 11 types of cancer. Of these 25,444 were blood; 41,315 breast; 32,626 bowel, 12,808 gastro oesophageal; 32,187 lung; 4811 oral; 6635 ovarian; 7119 pancreatic; 35,256 prostate; 23,091 renal tract; 6949 uterine cancers. The lung cancer algorithm had the best performance with an R(2) of 64.2%; D statistic of 2.74; receiver operating characteristic curve statistic of 0.91 in women. The sensitivity for the top 10% of women at highest risk of lung cancer was 67%. Performance of the algorithms in men was very similar to that for women. CONCLUSIONS: We have developed and validated a prediction models to quantify absolute risk of 11 common cancers. They can be used to identify patients at high risk of cancers for prevention or further assessment. The algorithms could be integrated into clinical computer systems and used to identify high-risk patients. WEB CALCULATOR: There is a simple web calculator to implement the Qcancer 10 year risk algorithm together with the open source software for download (available at http://qcancer.org/10yr/). PMID- 25783430 TI - Malignant cell-derived extracellular vesicles express different chromogranin epitopes compared to prostasomes. AB - BACKGROUND: Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS: We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS: A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION: Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers. PMID- 25783433 TI - Usefulness of Serum Albumin Concentration to Predict High Coronary SYNTAX Score and In-Hospital Mortality in Patients With Acute Coronary Syndrome. AB - High SYNTAX score is a predictor of adverse cardiovascular events, including mortality, in acute coronary syndromes (ACSs). Decreased serum albumin (SA) concentration is associated with an increased risk of cardiovascular events. We aimed to investigate whether SA levels at admission are associated with high SYNTAX score and in-hospital mortality in patients with ACS. The study included 1303 patients with ACS who underwent coronary angiography (CA). The patients were divided into 2 groups as high SYNTAX score (>=33) and lower SYNTAX score (<=32). Baseline SA levels were significantly lower in patients with high SYNTAX score than with lower SYNTAX score (3.46 +/- 0.42 mg/dL vs 3.97+/-0.37 mg/dL, respectively; P < .001). On multivariate logistic regression, SA (<3.65 mg/dL) was an independent predictor of high SYNTAX score (odds ratio 4.329, 95% confidence interval 2.028-8.264; P < .001) together with admission glucose, estimated glomerular filtration rate, and left ventricular ejection fraction. In Cox regression analyses, systolic blood pressure, high SYNTAX score, and SA (<3.65 mg/dL) were found as independent predictors of in-hospital all-cause mortality. In conclusion, SA concentration on admission is inversely associated with high SYNTAX score and in-hospital mortality in ACS. PMID- 25783434 TI - Predicting intention and behaviour following participation in a theory-based intervention to improve gluten free diet adherence in coeliac disease. AB - OBJECTIVE: To determine whether changes in theory of planned behaviour (TPB) constructs could predict intention and gluten-free diet (GFD) adherence following participation in an online theory-based intervention designed to improve adherence in coeliac disease. DESIGN: Theory-based process evaluation of the mechanisms of change over the course of a six-week online intervention. Measures of GFD adherence and TPB variables were administered at baseline and follow-up (immediate post-intervention: n = 74; three-month: n = 68; six-month: n = 65). Hierarchical regression analyses using residualised change scores were conducted at each time point (dependent variables: intention and adherence). RESULTS: Baseline intention and GFD adherence were the strongest predictors of follow-up intention and adherence, respectively. Change in attitude accounted for significant variance in intention. Change in intention accounted for significant variance in GFD adherence immediately post-intervention; by the six-month follow up change in perceived behavioural control was the stronger predictor. CONCLUSIONS: Partial support for the hypotheses suggests that, for certain behaviours, the TPB may be relevant in explaining the mechanism of action responsible for changes in intention and behaviour following participation in a behaviour change intervention. Additional predictive pathways are also likely to exist and, in the area of GFD adherence, may include habit strength and actual behavioural control. PMID- 25783435 TI - Quantifying the quantum gate fidelity of single-atom spin qubits in silicon by randomized benchmarking. AB - Building upon the demonstration of coherent control and single-shot readout of the electron and nuclear spins of individual (31)P atoms in silicon, we present here a systematic experimental estimate of quantum gate fidelities using randomized benchmarking of 1-qubit gates in the Clifford group. We apply this analysis to the electron and the ionized (31)P nucleus of a single P donor in isotopically purified (28)Si. We find average gate fidelities of 99.95% for the electron and 99.99% for the nuclear spin. These values are above certain error correction thresholds and demonstrate the potential of donor-based quantum computing in silicon. By studying the influence of the shape and power of the control pulses, we find evidence that the present limitation to the gate fidelity is mostly related to the external hardware and not the intrinsic behaviour of the qubit. PMID- 25783436 TI - Improving molecular diagnosis of distal myopathies by targeted next-generation sequencing. PMID- 25783437 TI - The identification of cognitive subtypes in Alzheimer's disease dementia using latent class analysis. AB - OBJECTIVE: Alzheimer's disease (AD) is a heterogeneous disorder with complex underlying neuropathology that is still not completely understood. For better understanding of this heterogeneity, we aimed to identify cognitive subtypes using latent class analysis (LCA) in a large sample of patients with AD dementia. In addition, we explored the relationship between the identified cognitive subtypes, and their demographical and neurobiological characteristics. METHODS: We performed LCA based on neuropsychological test results of 938 consecutive probable patients with AD dementia using Mini-Mental State Examination as the covariate. Subsequently, we performed multinomial logistic regression analysis with cluster membership as dependent variable and dichotomised demographics, APOE genotype, cerebrospinal fluid biomarkers and MRI characteristics as independent variables. RESULTS: LCA revealed eight clusters characterised by distinct cognitive profile and disease severity. Memory-impaired clusters-mild-memory (MILD-MEM) and moderate-memory (MOD-MEM)-included 43% of patients. Memory-spared clusters mild-visuospatial-language (MILD-VILA), mild-executive (MILD-EXE) and moderate-visuospatial (MOD-VISP) -included 29% of patients. Memory-indifferent clusters mild-diffuse (MILD-DIFF), moderate-language (MOD-LAN) and severe-diffuse (SEV-DIFF) -included 28% of patients. Cognitive clusters were associated with distinct demographical and neurobiological characteristics. In particular, the memory-spared MOD-VISP cluster was associated with younger age, APOE e4 negative genotype and prominent atrophy of the posterior cortex. CONCLUSIONS: Using LCA, we identified eight distinct cognitive subtypes in a large sample of patients with AD dementia. Cognitive clusters were associated with distinct demographical and neurobiological characteristics. PMID- 25783439 TI - The role of teleconferences in global public health education. AB - This paper presents a global health education program using a 'Teleconference' approach. It provides examples of how technology can be used to deliver health education at the international level. Two international teleconferences about public health issues were conducted in 2013 and 2014 involving universities and public health institutions in Colombia, Dominican Republic, Costa Rica, Uganda, and the United States. More than 400 students, faculty, and community members attended these educational events. These teleconferences served as the medium to unite countries despite the geographical distances and to facilitate collaborations and networking across nations. Teleconferences are an example of effective technology-based health education and health promotion programs. PMID- 25783440 TI - Subcutaneous nodules with sporotrichoid spread in the forearm of a patient with rheumatoid arthritis. PMID- 25783438 TI - LOPED study: looking for an early diagnosis in a late-onset Pompe disease high risk population. AB - OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age >=5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid alpha-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14 month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression. PMID- 25783441 TI - Catalytic trifluoromethylation of aryl- and vinylboronic acids by 2-cyclopropyl-1 (trifluoromethyl)benzo[b]thiophenium triflate. AB - Catalytic trifluoromethylation of aryl- and vinylboronic acids by 2-cyclopropyl-1 (trifluoromethyl)benzo[b]thiophenium triflate is described. In the presence of a catalytic amount of CuOAc and 2,4,6-collidine in ethyl acetate, the reaction proceeded in good to high yields for various substrates under mild reaction conditions at room temperature. PMID- 25783442 TI - Water, Sanitation, and Hygiene at the World's Largest Mass Gathering. AB - The 2013 Kumbh Mela, a Hindu religious festival and the largest human gathering on earth, drew an estimated 120 million pilgrims to bathe at the holy confluence of the Ganga (Ganges) and Yamuna rivers. To accommodate the massive numbers, the Indian government constructed a temporary city on the flood plains of the two rivers and provided it with roads, electricity, water and sanitation facilities, police stations, and a tiered healthcare system. This phenomenal operation and its impacts have gone largely undocumented. To address this gap, the authors undertook an evaluation and systematic monitoring initiative to study preparedness and response to public health emergencies at the event. This paper describes the water, sanitation, and hygiene components, with particular emphasis on preventive and mitigation strategies; the capacity for surveillance and response to diarrheal disease outbreaks; and the implications of lessons learned for other mass gatherings. PMID- 25783443 TI - Necessity for lifelong follow-up of patients with familial paraganglioma syndrome: A case report. AB - BACKGROUND: Patients with established familial paraganglioma (PGL) syndrome may have multiple metachronous lesions. This article illustrates, via imaging and findings, the need for lifetime follow-up of patients with familial PGL syndromes. METHODS: Patients' medical charts and radiological images were reviewed in a retrospective analysis. RESULTS: Over the course of 18 years, this patient developed 2 simultaneous carotid PGLs, a cardiac PGL, and a biochemically active interaortocaval PGL. CONCLUSION: PGLs do not necessarily occur simultaneously in patients with familial PGL syndrome. Lifelong observation is needed to detect these lesions before they become large and symptomatic. Lack of biochemical activity is not a predictor of future lesions being inactive. Cardiac PGLs are rare and require resection. PMID- 25783444 TI - Important Differences Exist in Posterior Condylar Offsets in an Osteological Collection of 1,058 Femurs. AB - Posterior condylar offset (PCO) has important implications in total knee arthroplasty (TKA) function and design. In an osteological study of 1,058 femurs, we measured PCO using two separate techniques with a 3D digitizer. Measurements were standardized for the size of the femur. The medial PCO was greater than lateral PCO (32.6mm vs. 31.2mm, P<0.0001). In 53% of individuals, the medial PCO differed between sides by more than 2mm. Age did not affect standardized medial or lateral PCO. Compared with African-Americans, Caucasians had a larger standardized medial (1.3mm vs. 1.2mm, P=0.006) and lateral (1.1mm vs. 1.0mm, P=0.004) PCOs. The standardized medial (1.2mm vs. 1.3mm, P=0.073), and lateral (1.1mm vs. 1.1mm, P=0.098), PCO did not differ between men and women, respectively. PMID- 25783445 TI - Levels of angiogenesis-related vascular endothelial growth factor family in neovascular glaucoma eyes. AB - PURPOSE: This study aimed to evaluate the angiogenesis-related factors of the vascular endothelial growth factor (VEGF) family in the aqueous humour of patients with neovascular glaucoma (NVG). METHODS: This study involved 22 eyes of 22 patients with advanced NVG requiring antiglaucomatous surgery and 20 control subjects with cataracts. The NVG eyes received an intravitreal injection of ranibizumab (IVR) treatment before antiglaucomatous surgery. Aqueous humour and blood were collected at the time of IVR and cataract surgery. Protein concentration of VEGF-A, VEGF-B and placenta growth factor (PlGF) in aqueous humour and plasma was determined by ELISA tests. RESULTS: The mean concentration (standard deviation) of VEGF-A and PlGF in the aqueous humour of patients with NVG were 3037 (2387) pg/ml and 1078 (712) pg/ml, respectively; both were significantly higher than the control group (both p < 0.001). However, levels of VEGF-A and PlGF in the serum of NVG and control subjects remained low. High concentrations of VEGF-A were closely correlated with high levels of PlGF in patients with NVG (r = 0.593, p = 0.004). Concentrations of VEGF-B in aqueous humour and serum remained unchanged (p > 0.05). CONCLUSION: There were high concentrations of angiogenesis factors of the VEGF family, with the exception of VEGF-B, in the aqueous humour of patients with NVG, and there was a positive correlation between VEGF-A and PlGF. High PlGF levels in patients with NVG may provide another potential target for treatment of NVG. PMID- 25783446 TI - Tumorigenesis: Order matters. PMID- 25783447 TI - Cancer genetics: CRISPR screens go in vivo. PMID- 25783449 TI - Coordination chemistry of N-heterocyclic nitrenium-based ligands. AB - Comprehensive studies on the coordination properties of tridentate nitrenium based ligands are presented. N-heterocyclic nitrenium ions demonstrate general and versatile binding abilities to various transition metals, as exemplified by the synthesis and characterization of Rh(I) , Rh(III) , Mo(0) , Ru(0) , Ru(II) , Pd(II) , Pt(II) , Pt(IV) , and Ag(I) complexes based on these unusual ligands. Formation of nitrenium-metal bonds is unambiguously confirmed both in solution by selective (15) N-labeling experiments and in the solid state by X-ray crystallography. The generality of N-heterocyclic nitrenium as a ligand is also validated by a systematic DFT study of its affinity towards all second-row transition and post-transition metals (Y-Cd) in terms of the corresponding bond dissociation energies. PMID- 25783450 TI - Active touch in late-preterm and early-term neonates. AB - An infant-controlled tactile habituation without visual control procedure was used to evaluate the ability of 32 late-preterm neonates (mean gestational age: 34 weeks) and 32 early-term neonates (mean gestational age: 38 weeks) to actively explore with hands objects varying in texture (smooth, granular). Holding time and Hand Pressure Frequency (HPF) were recorded. Holding time decreased as habituation progressed in both group of neonates. Holding time increased from habituation trials to test trials only in early-term neonates. A reaction to novelty was only observed in early-term neonates. During habituation, HPF remained unchanged in late-preterm infants whereas HPF decreased in early-term infants. HPF increased from habituation trials to test trials in early-term neonates and in late-preterm infants. However, reaction to novelty was only observed for early-term infants. The significance of these results is discussed in reference to brain maturation in preterm infants. PMID- 25783448 TI - Evolutionary insights into host-pathogen interactions from mammalian sequence data. AB - Infections are one of the major selective pressures acting on humans, and host pathogen interactions contribute to shaping the genetic diversity of both organisms. Evolutionary genomic studies take advantage of experiments that natural selection has been performing over millennia. In particular, inter species comparative genomic analyses can highlight the genetic determinants of infection susceptibility or severity. Recent examples show how evolution-guided approaches can provide new insights into host-pathogen interactions, ultimately clarifying the basis of host range and explaining the emergence of different diseases. We describe the latest developments in comparative immunology and evolutionary genetics, showing their relevance for understanding the molecular determinants of infection susceptibility in mammals. PMID- 25783451 TI - Response of microbial communities to bioturbation by artificially introducing macrobenthos to mudflat sediments for in situ bioremediation in a typical semi enclosed bay, southeast China. AB - Although microbes play important roles during the bioremediation process using macrobenthos in degraded environments, their response to macrobenthos bioturbation remains poorly understood. This study used 16S rRNA gene-Illumina Miseq sequencing to investigate the microbial communities and their response to bioturbation by artificially introducing macrobenthos to the mudflat of Sansha Bay, southeast China. A total of 56 phyla were identified, dominated by delta- and gamma-Proteobacteria, with a total percentage of over 50%. Others, such as Acidobacteria, Chloroflexi, Bacteroidetes, Planctomycetes and Alphaproteobacteria occupied 4-7% respectively. Eighteen genera indicating the microbial communities response to bioturbation and seasonal change were identified. Bioturbated samples contained more ecologically important genera, and untreated samples contained more genera ubiquitous in marine environments. The physicochemical characteristics did not change significantly probably due to the short time of bioremediation and low survival rate of macrobenthos, confirming that microbial communities are more sensitive and can serve as sentinels for environmental changes. PMID- 25783453 TI - Synthesis of ultrathin face-centered-cubic au@pt and au@pd core-shell nanoplates from hexagonal-close-packed au square sheets. AB - The synthesis of ultrathin face-centered-cubic (fcc) Au@Pt rhombic nanoplates is reported through the epitaxial growth of Pt on hexagonal-close-packed (hcp) Au square sheets (AuSSs). The Pt-layer growth results in a hcp-to-fcc phase transformation of the AuSSs under ambient conditions. Interestingly, the obtained fcc Au@Pt rhombic nanoplates demonstrate a unique (101)f orientation with the same atomic arrangement extending from the Au core to the Pt shell. Importantly, this method can be extended to the epitaxial growth of Pd on hcp AuSSs, resulting in the unprecedented formation of fcc Au@Pd rhombic nanoplates with (101)f orientation. Additionally, a small amount of fcc (100)f -oriented Au@Pt and Au@Pd square nanoplates are obtained with the Au@Pt and Au@Pd rhombic nanoplates, respectively. We believe that these findings will shed new light on the synthesis of novel noble bimetallic nanostructures. PMID- 25783454 TI - The French bioethics public consultation and the anonymity doctrine: empirical ethics and normative assumptions. AB - The French bioethics laws of 1994 contain the principles of the anonymity and non commodification of all donations of body parts and products including gametes in medically assisted reproduction. The two revisions of the law, in 2004 and 2011 have upheld the rule. In view of the latest revision process, the French government organized a large public consultation in 2009 ("Etats generaux de la bioethique"). Within the event a "consensus conference" was held in Rennes about different aspects of assisted reproduction (access, anonymity, gratuity and surrogacy). In what follows we shall first describe the anonymity clause for gamete donations in the French law and the debates surrounding it. We shall then analyse the procedure used for the 2009 public consultation and the related consensus conference, as well as its upshot concerning the anonymity doctrine. In this respect we shall compare the citizens' own recommendations on the gamete anonymity issue and its translation in the consultation's final report drafted by a philosopher mandated by the organizing committee. Whereas the final report cited some fundamental ethical arguments as reason for upholding the provisions of the law-most notably the refusal of the 'all biological' approach to reproductive issues-citizens were more careful and tentative in their position although they also concluded that for pragmatic reasons the anonymity rule should continue to hold. We shall argue that the conservative upshot of the public consultation is due to some main underlying presuppositions concerning the citizens' role and expertise as well as to the specific design of the consensus conference. Our conclusion will be that public consultations and consensus conferences can only serve as an empirical support for devising suitable bioethics norms by using second-order normative assumptions. PMID- 25783455 TI - Cervical cancer screening of underserved women in the United States: results from the National Breast and Cervical Cancer Early Detection Program, 1997-2012. AB - OBJECTIVE: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides breast and cervical cancer screens to low-income, uninsured, and underinsured women. We describe the number and proportion of women eligible for cervical cancer screening services and the proportion of eligible women screened over the period 1997-2012. METHODS: Low-income, uninsured, and underinsured women aged 18-64 years who have not had a hysterectomy are eligible for cervical cancer screening through the NBCCEDP. We estimated the number of low income, uninsured women using data from the US Census Bureau. We adjusted our estimates for hysterectomy status using the National Health Interview Survey and the Behavioral Risk Factor Surveillance System. We used data from the NBCCEDP to describe the number of women receiving NBCCEDP-funded screening and calculated the proportion of eligible women who received screening through the NBCCEDP at the national level (by age group, race/ethnicity) and at the state level by age group. We used the Medical Expenditure Panel Survey to estimate the proportion of NBCCEDP-eligible women who were screened outside the NBCCEDP and the proportion that are not screened. RESULTS: We estimate that in 2010-2012, 705,970 women aged 18-64 years, 6.5 % (705,970 of 9.8 million) of the eligible population, received NBCCEDP-funded Pap tests. We estimate that 60.2 % of eligible women aged 18-64 years were screened outside the NBCCEDP and 33.3 % were not screened. The NBCCEDP provided 623,603 screens to women aged 40-64 years, an estimated 16.5 % of the eligible population, and 83,660 screens to women aged 18-39 years, representing an estimated 1.2 % of the eligible population. The estimated proportions of eligible women screened in each state ranged from 1.5 to 32.7 % and 5 % to 73.2 % among the 18-64 and 40-64 years age groups, respectively. Changes in the proportion of eligible women screened over the study period were nonsignificant. CONCLUSIONS: Although the program provided cervical screening to over 700,000 women between 2010 and 2012, it served a small percent of those eligible. The proportion of women screened varied substantially across age groups, racial/ethnic groups, and states. Many low-income, uninsured women are not being screened. PMID- 25783456 TI - Preventing premature deaths from breast and cervical cancer among underserved women in the United States: insights gained from a national cancer screening program. AB - This commentary highlights some of the valuable insights gained from a special collection of papers that utilized data from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) and appear in this special issue. The data and experiences of the NBCCEDP can inform the identification of new opportunities and directions for meeting the cancer screening needs of underserved women in a complex and changing health care environment. PMID- 25783457 TI - Hookah use prevalence, predictors, and perceptions among Canadian youth: findings from the 2012/2013 Youth Smoking Survey. AB - PURPOSE: Few national surveys currently assess hookah smoking among youth. This study describes the prevalence, patterns of use, and perceptions about hookah in a nationally representative survey of Canadian grades 9-12 students. METHODS: The Youth Smoking Survey 2012/2013 was administered to 27,404 Canadian grades 9-12 students attending schools in nine Canadian provinces representing 96 % of Canadian population. Relevant dichotomous outcomes included ever use, use in the last 30 days, and the belief that hookah use is less harmful than cigarette smoking. Covariates included smoking status, sex, grade, province of residence, race/ethnicity, and amount of weekly spending money. Logistic regression models were used to examine: covariates related to the odds of ever and last-30-day hookah use; covariates related to perceptions about the harms of hookah smoking; the extent to which perceptions were associated with odds of hookah use; and whether survey year (2010/2011 or 2012/2013) was associated with hookah use, and marginal effects were calculated. RESULTS: In Canada, 5.4 % of students in grades 9-12 currently use hookah and 14.3 % report ever using hookah. In 2012/2013, students had significantly higher odds of using hookah compared to students in 2010/2011 (OR 1.5, 95 % CI 1.2, 2.1). About half of hookah users (51 %) used flavored hookah. Students who believed that hookah use was less harmful than cigarette smoking had significantly higher odds of current hookah use (OR 2.6, 95 % CI 1.9, 3.5), as did students who reported higher amounts of weekly spending money. Current smokers had an 18 % higher predicted probability of currently using hookah compared to non-smokers. CONCLUSIONS: Hookah use among youth is of growing concern in Canada. Findings can be used to inform policy development related to youth hookah smoking. PMID- 25783459 TI - Adherence to a healthy Nordic food index and breast cancer risk: results from a Swedish cohort study. AB - BACKGROUND: A healthy Nordic dietary pattern has shown beneficial effects in relation to several chronic diseases. However, no study has evaluated the association between a healthy Nordic food index (HNFI) and risk of breast cancer. METHODS: We conducted a prospective cohort study including 44,296 women, aged 29 49 at baseline in 1991-1992, who completed a food frequency questionnaire at baseline, and have been followed up ever since, through the Swedish Cancer Registry and Cause of Death Registry. Each woman was assigned a HNFI score ranging from 0 to 6. We calculated multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Poisson regression models with attained age as the underlying timescale. The association between the HNFI and risk of breast cancer was assessed both overall, by menopausal status and by hormone receptor status. RESULTS: A total of 1,464 breast cancer cases were diagnosed during a median follow-up time of 20 years. A higher adherence to the HNFI was not associated with a lower risk of breast cancer overall, nor of varied hormone receptor status, or when we examining premenopausal and postmenopausal women separately. The multivariable RRs (95% CI) for breast cancer per 1-point increment in the HNFI were 1.02 (95% CI 0.98-1.06) for all women, 1.01 (95% CI 0.95-1.08) for premenopausal women, and 1.02 (95% CI 0.97-1.07) for postmenopausal women. CONCLUSION: Adherence to a HNFI was not associated with breast cancer incidence in this cohort of relatively young women, regardless of menopausal status or hormone receptor status. PMID- 25783458 TI - Incremental benefits of screening colonoscopy over sigmoidoscopy in average-risk populations: a model-driven analysis. AB - PURPOSE: Screening colonoscopy and flexible sigmoidoscopy (FSG) reduce the risk of colorectal cancer (CRC), but the magnitude and duration of protection, particularly against right-sided cancer, remain uncertain. We computed the incremental benefit of colonoscopy over FSG using a validated mathematical model, which reflects colorectal neoplasia growth characteristics while allowing uncertainty in endoscopic detection and removal of adenomas. METHODS: We calibrated models of CRC incidence within a multistage clonal expansion framework to data from: (1) San Francisco-Oakland SEER registry (reference population) and (2) FSG long-term follow-up data from 50,757 individuals after a negative FSG in the Kaiser Permanente system. We compared the residual CRC risks after FSG with full-length colonoscopy. RESULTS: Our model mirrors trial data with 10-year CRC risk reductions after FSG screening at age 50 years of approximately one-third; the optimal age for a 'once-only' FSG exam was between ages 50 and 60 years; and the greater benefit was for men compared with women. There were considerable incremental gains in reduction in CRC risk by colonoscopy compared with FSG with the greatest benefit for screening colonoscopy at age 50 years. These results held up against lowering the right-sided adenoma detection sensitivity by 30%, as well as reducing the curative efficacy of polypectomy throughout the colon. CONCLUSIONS: Mathematical modeling of CRC screening, which takes account of important aspects of tumor biology, demonstrates superior risk reductions by colonoscopy over FSG. Our predictions provide further rationale for recommending screening colonoscopy in average-risk populations before the age of 60. PMID- 25783464 TI - Synthesis and hydrolysis of gas-phase lanthanide and actinide oxide nitrate complexes: a correspondence to trivalent metal ion redox potentials and ionization energies. AB - Several lanthanide and actinide tetranitrate ions, M(III)(NO3)4(-), were produced by electrospray ionization and subjected to collision induced dissociation in quadrupole ion trap mass spectrometers. The nature of the MO(NO3)3(-) products that result from NO2 elimination was evaluated by measuring the relative hydrolysis rates under thermalized conditions. Based on the experimental results it is inferred that the hydrolysis rates relate to the intrinsic stability of the M(IV) oxidation states, which correlate with both the solution IV/III reduction potentials and the fourth ionization energies. Density functional theory computations of the energetics of hydrolysis and atoms-in-molecules bonding analysis of representative oxide and hydroxide nitrates substantiate the interpretations. The results allow differentiation between those MO(NO3)3(-) that comprise an O(2-) ligand with oxidation to M(IV) and those that comprise a radical O(-) ligand with retention of the M(III) oxidation state. In the particular cases of MO(NO3)3(-) for M = Pr, Nd and Tb it is proposed that the oxidation states are intermediate between M(III) and M(IV). PMID- 25783465 TI - Palladium-catalyzed dicarbonylative synthesis of tetracycle quinazolinones. AB - An interesting procedure for the synthesis of isoindolo[1,2-b]quinazolin-10(12H) ones has been developed. Starting from commercially available 2-bromoanilines and 2-bromobenzyl amines, with the assistance of a palladium catalyst, the desired products were isolated in good yields. Notably, this procedure proceeded in a highly selective manner; two molecules of CO were incorporated into the substrates selectively. PMID- 25783466 TI - Effective saccharification of kraft pulp by using a cellulase cocktail prepared from genetically engineered Aspergillus oryzae. AB - Kraft pulp is a promising feedstock for bioproduction. The efficiency of kraft pulp saccharification was improved by using a cellulase cocktail prepared from genetically engineered Aspergillus oryzae. Application of the cellulase cocktail was demonstrated by simultaneous saccharification and fermentation, using kraft pulp and non-cellulolytic yeast. Such application would make possible to do an efficient production of other chemicals from kraft pulp. PMID- 25783467 TI - Prognostic impact of chemotherapy-induced amenorrhea on premenopausal breast cancer: a meta-analysis of the literature. AB - OBJECTIVE: We conducted this meta-analysis of published data to assess the exact prognostic value of adjuvant chemotherapy-induced amenorrhea (CIA) as a prognostic factor for premenopausal breast cancer. METHODS: We searched for all relevant studies published before May 2014 in the PubMed, OVID, and EMBASE databases. Relative risks (RRs) were used to estimate the association between CIA and various survival outcomes, including disease-free survival (DFS) and overall survival (OS). RESULTS: This meta-analysis identified 13 eligible studies including 5,513 cases and 2,008 controls for DFS and 5 eligible studies including 2,331 cases and 776 controls for OS. Results demonstrated that CIA is associated with improved DFS (RR, 0.67; 95% CI, 0.61-0.74; P < 0.001) and OS (RR, 0.60; 95% CI, 0.50-0.72; P < 0.001). In subgroup analyses, CIA was found to affect DFS (RR, 0.73; 95% CI, 0.61-0.88; P = 0.001) in estrogen receptor (ER)-positive patients; however, similar results were not observed in ER-negative patients (for DFS: RR, 0.97; 95% CI, 0.66-1.41; P = 0.858). Participants with CIA achieved a significantly better prognosis than participants without CIA, irrespective of nodal status, chemotherapy regimen, endocrine therapy, or publication year. CONCLUSIONS: This meta-analysis clarifies that CIA contributes to improved prognosis in premenopausal women with ER-positive breast cancer and is at least partially responsible for the benefits of adjuvant chemotherapy in these women, which induce chemical castration. PMID- 25783468 TI - Body composition and bone mineral density after ovarian hormone suppression with or without estradiol treatment. AB - OBJECTIVE: Suppression of ovarian hormones in premenopausal women on gonadotropin releasing hormone agonist (GnRH(AG)) therapy can cause fat mass (FM) gain and fat free mass (FFM) loss. Whether this is specifically caused by a decline in serum estradiol (E2) is unknown. This study aims to evaluate the effects of GnRH(AG) with placebo (PL) or E2 add-back therapy on FM, FFM, and bone mineral density (BMD). Our exploratory aim was to evaluate the effects of resistance exercise training on body composition during the drug intervention. METHODS: Seventy healthy premenopausal women underwent 5 months of GnRH(AG) therapy and were randomized to receive transdermal E2 (GnRH(AG) + E2, n = 35) or PL (GnRH(AG) + PL, n = 35) add-back therapy. As part of our exploratory aim to evaluate whether exercise can minimize the effects of hormone suppression, some women within each drug arm were randomized to undergo a resistance exercise program (GnRH(AG) + E2 + Ex, n = 12; GnRH(AG) + PL + Ex, n = 12). RESULTS: The groups did not differ in mean (SD) age (36 [8] and 35 [9] y) or mean (SD) body mass index (both 28 [6] kg/m). FFM declined in response to GnRH(AG) + PL (mean, -0.6 kg; 95% CI, -1.0 to 0.3) but not in response to GnRH(AG) + E2 (mean, 0.3 kg; 95% CI, -0.2 to 0.8) or GnRH(AG) + PL + Ex (mean, 0.1 kg; 95% CI, -0.6 to 0.7). Although FM did not change in either group, visceral fat area increased in response to GnRH(AG) + PL but not in response to GnRH(AG) + E2. GnRH(AG) + PL induced a decrease in BMD at the lumbar spine and proximal femur that was prevented by E2. Preliminary data suggest that exercise may have favorable effects on FM, FFM, and hip BMD. CONCLUSIONS: Suppression of ovarian E2 results in loss of bone and FFM and expansion of abdominal adipose depots. Failure of hormone suppression to increase total FM conflicts with previous studies of the effects of GnRH(AG). Further research is necessary to understand the role of estrogen in energy balance regulation and fat distribution. PMID- 25783469 TI - Prevalence and severity of menopause symptoms and associated factors across menopause status in Korean women. AB - OBJECTIVE: The present study investigated the prevalence and severity of menopause symptoms experienced by Korean women aged 44 to 56 years and their associated factors. METHODS: A cross-sectional study was performed on 2,201 women aged 44 to 56 years in health checkup centers between November 2012 and March 2013. The 29-item Menopause-Specific Quality of Life Questionnaire was used to assess vasomotor, psychosocial, physical, and sexual symptoms related to menopause. The guidelines for the classification of reproductive aging stages proposed at the Stages of Reproductive Aging Workshop were used. Multivariable linear regression analyses were performed to identify factors associated with severity of menopause symptoms. RESULTS: Among participants, 42.6% were premenopausal, 36.7% were perimenopausal, and 20.7% were postmenopausal. Although physical symptoms were the most severe menopause symptoms experienced by premenopausal and perimenopausal women, postmenopausal women reported sexual symptoms as the most bothersome. The mean scores for each domain increased from the premenopausal period through the postmenopausal period (P for trend < 0.001). The regression model revealed that age (for vasomotor and sexual symptoms) and obesity (for vasomotor and physical symptoms) were significantly associated with severity of menopause symptoms (P < 0.05). Physically active women had fewer severe physical symptoms related to menopause than inactive women. CONCLUSIONS: Postmenopausal women experience the most severe symptoms. Obesity and physical activity are the main modifiable factors associated with symptom severity. Further studies are needed to examine the effects of physical activity promotion and weight control interventions on preventing menopause symptoms in Korean women. PMID- 25783470 TI - Vasomotor and depression symptoms may be associated with different sleep disturbance patterns in postmenopausal women. AB - OBJECTIVE: This study aims to explore the association of vasomotor symptoms (VMS) and depression symptoms with different symptoms of subjective sleep disturbance in postmenopausal women. METHODS: This is a cross-sectional study of 163 postmenopausal women (not taking hormone therapy) attending a university menopause clinic. Measures included the Athens Insomnia Scale, Greene Climacteric Scale, and Symptom Checklist-90-Revised depression subscale. Covariate-adjusted ordinal logistic regression was used to investigate the association of VMS and depression with each item of the Athens Insomnia Scale. RESULTS: Controlling for confounding factors, we found VMS to be significantly associated with awakenings during the night (odds ratio [OR], 1.85; P < 0.001), overall quality of sleep (OR, 2.00; P < 0.001), well-being during the day (OR, 1.63; P = 0.008), functioning capacity during the day (OR, 1.72; P = 0.01), and sleepiness during the day (OR, 1.66; P = 0.03); whereas we found Symptom Checklist-90-Revised depression subscale scores to be associated with sleep induction (OR, 2.09; P < 0.001), final awakening earlier than desired (OR, 2.21; P < 0.001), total sleep duration (OR, 1.62; P = 0.01), overall quality of sleep (OR, 1.64; P = 0.009), well-being during the day (OR, 1.67; P = 0.006), functioning capacity during the day (OR, 1.68; P = 0.01), and sleepiness during the day (OR, 1.57; P = 0.04). CONCLUSIONS: VMS and depression symptoms are associated with different patterns of sleep disturbance. Although both symptoms are related to sleep quality, daytime functioning, and daytime well-being, depression is uniquely associated with difficulty falling asleep and waking up earlier than desired, whereas VMS are related to frequent awakenings during sleep. The findings are limited by the cross-sectional design and relatively small sample size of the study. Recommendations for future research are discussed to guide this line of inquiry and to gain a better understanding of the complex relationship between climacteric and mood symptoms and their contribution to the development of sleep disturbances during menopause. PMID- 25783471 TI - Association between accelerometer-measured physical activity and muscle capacity in middle-aged postmenopausal women. AB - OBJECTIVE: Greater muscle strength and power are associated with better physical function in middle-aged and older women. The aim of the present study was to determine whether accelerometer-measured physical activity was associated with muscle strength and power in middle-aged postmenopausal women. METHODS: Postmenopausal women (N = 60; mean [SD] age, 58.9 [3.9] y) were assessed for physical activity (step count and moderate to vigorous physical activity [MVPA]) via accelerometer, for body composition via dual-energy x-ray absorptiometry, for concentric isokinetic knee torque at 60 degrees /s and 180 degrees /s using isokinetic dynamometry, and for leg extensor power with the Nottingham power rig. RESULTS: In linear regression analysis, daily step count was independently associated with isokinetic knee torque at 60 degrees /s (standardized beta = 0.32, P = 0.01), isokinetic knee torque at 180 degrees /s (standardized beta = 0.32, P = 0.01), and total leg extensor power (beta = 0.36, P = 0.01) after adjustment for covariates. Daily MVPA had similar associations with isokinetic knee torque at 60 degrees /s (beta = 0.38, P < 0.01), isokinetic knee torque at 180 degrees /s (beta = 0.41, P < 0.01), and leg power (beta = 0.31, P = 0.02). Analysis of covariance indicated that women who engaged in MVPA for 30 minutes or more per day produced significantly greater isokinetic knee torque (60 degrees /s and 180 degrees /s) and leg extensor power compared with women not meeting this guideline (all P < 0.05). CONCLUSIONS: These findings suggest that daily step count and MVPA are independently associated with muscle strength and power in middle-aged postmenopausal women. Future studies should determine whether interventions that increase habitual physical activity in middle-aged women are associated with concomitant improvements in muscle capacity. PMID- 25783472 TI - Risk factors for hot flashes among women undergoing the menopausal transition: baseline results from the Midlife Women's Health Study. AB - OBJECTIVE: The aim of this study was to examine the associations of demographic characteristics, health behaviors, and hormone concentrations with the experience of any, current, more severe, and more frequent midlife hot flashes. METHODS: Baseline data from 732 women aged 45 to 54 years who were enrolled in the Midlife Women's Health Study were analyzed. A clinic visit was conducted to collect blood samples for hormone assays and to measure ovarian volume using transvaginal ultrasound. A self-administered questionnaire ascertained information on demographic factors, health habits, and hot flash history. Multivariable logistic regression was conducted to examine associations between potential risk factors and hot flash outcomes. RESULTS: Approximately 45% of participants reported experiencing midlife hot flashes. In covariate-adjusted models, older age, perimenopause status, current and past cigarette smoking, and depressive symptoms were significantly associated with increased odds of all of the hot flash outcomes. In addition, history of oral contraceptive use was associated with increased odds of any hot flashes. In contrast, higher current alcohol intake was significantly associated with decreased odds of any, current, and more severe hot flashes. Higher estradiol and progesterone concentrations were significantly associated with decreased odds of all hot flash outcomes. CONCLUSIONS: Although the temporality of such associations is not known because of the cross-sectional nature of the data, these observed relationships can help to identify women at risk for hot flashes. PMID- 25783473 TI - Genomic characterization and molecular investigation of VP7 epitopes of uncommon G10P[8] group A rotavirus strains detected in Italy in 2009. AB - Rotavirus strains with the uncommon genotype G10 have been detected sporadically in cases of acute gastroenteritis in humans and are thought to be transmitted zoonotically. During 2009, 10 G10P[8] rotavirus strains were detected in the stools of children hospitalized with acute diarrhoea in several paediatric hospitals in Italy. The phylogenetic analysis of the VP7 gene of the Italian G10P[8] strains analysed revealed nucleotide identities ranging from 94 to 99 %. Molecular characterization of the 11 genomic segments was performed for one of the G10 strains, which displayed a complete genomic constellation 1 for the non-G genes. The analysis of the deduced amino acid sequences of the G10 VP7 epitopes revealed low amino acid identity with common human strains of different G genotype and with the VP7 proteins included in both anti-rotavirus commercial vaccines (Rotarix and RotaTeq). Amongst the common G genotypes, the VP7 amino acid sequence of the G10 strains showed a high similarity with sequences from G9 strains. A hydrophobic cluster analysis (HCA) of the VP7 protein including aa 20 298 was performed for the G10 Italian sequences in comparison with the major human group A rotavirus G genotypes. The HCA analysis confirmed the findings obtained previously by amino acid analysis of the VP7 epitopes, detecting a genotype-specific pattern of hydrophobicity in the hypervariable regions of the major outer capsid protein. PMID- 25783474 TI - Activation and degradation of open reading frame 45 by the replication and transcription activator of Kaposi's sarcoma-associated herpesvirus. AB - The open reading frame 45 (ORF45) of the Kaposi's sarcoma-associated herpesvirus (KSHV) is an immediate-early phosphorylated tegument protein critical for viral escape from host immune surveillance. Its expression is upregulated by the viral replication and transcription activator (RTA), a key protein that controls the switch from latency to lytic replication. We report here that ORF45 expression was not only upregulated by RTA, but ORF45 could also be degraded by RTA in a proteasome-dependent manner. The ORF45 was activated by RTA via activation of the ORF45 promoter, and the promoter region from nt 69 271 to nt 69 026 was involved. In chronic KSHV infected TRE-BCBL-1 RTA cells, the endogenous ORF45 protein increased dramatically after the induction of RTA expression, but then decreased rapidly after 8 h post-induction. Our study suggests that RTA might control the kinetics of viral replication through fine-tuning of the level of ORF45 and other viral/host proteins. PMID- 25783475 TI - Virus uncoating is required for apoptosis induction in cultured mammalian cells infected with African horse sickness virus. AB - Infection of cultured mammalian cells with African horse sickness virus (AHSV) is known to induce cell death. To date, the trigger(s) of this response, the apoptotic pathways activated during AHSV infection and the functional consequences of apoptosis on the virus replication cycle have yet to be characterized. This study demonstrated that extracellular treatment of BHK-21 cells with both of the AHSV4 outer capsid proteins, VP2 and VP5, was sufficient to trigger apoptosis. Whether steps in AHSV4 replication subsequent to viral attachment were required for AHSV4-induced apoptosis was also investigated. Apoptosis was induced in BHK-21 cells infected with UV-inactivated AHSV4 and in ribavirin-treated cells infected with AHSV4. However, both AHSV4- and VP2/VP5 stimulated apoptotic responses were inhibited in the presence of the endosomal acidification inhibitors ammonium chloride and chloroquine. These results indicated that uncoating of AHSV4 virions, but not viral transcription or subsequent steps in viral replication, was required for AHSV4 to induce apoptosis in BHK-21 cells. Furthermore, this study showed that both the extrinsic (caspase 8) and intrinsic (caspase-9) apoptotic pathways were induced following AHSV4 infection. The inhibition of caspase activity in AHSV4-infected cells did not diminish AHSV4 replication, but reduced the release and dissemination of progeny viral particles. Taken together, the data indicated that uncoating of AHSV virions was required for apoptosis induction, and that apoptosis enhanced virus spread and release. PMID- 25783476 TI - Macaques exhibit a naturally-occurring depression similar to humans. AB - Rodent models have dominated preclinical investigations into the mechanisms of depression. However, these models-which rely on subjecting individual rodents to physical stressors - do not realistically resemble the etiopathological development of depression, which occurs naturally in a social context. A non human primate model that better reflects the social ethological aspects of depression would be more advantageous to investigating pathophysiological mechanisms and developing antidepressant therapeutics. Here, we describe and model a naturally-occurring depressive state in a non-human primate species, the cynomolgus monkey (Macaca fascicularis), in a realistic social ethological context and associate the depressed behavioral phenotype with significant serum metabolic perturbations. One to two subjects per stable social colony (17-22 subjects) manifested a depressive phenotype that may be attributed to psychosocial stress. In accordance with rodent and human studies, the serum metabolic phenotype of depressed and healthy subjects significantly differed, supporting the model's face validity. However, application of the fast-acting antidepressant ketamine failed to demonstrate predictive validity. This study proposes a non-human primate depression model in a realistic social ethological context that can better approximate the psychosocial stressors underlying depression. PMID- 25783478 TI - Fastigial nucleus stimulation regulates neuroprotection via induction of a novel microRNA, rno-miR-676-1, in middle cerebral artery occlusion rats. AB - Previous studies have shown that fastigial nucleus stimulation (FNS) reduces tissue damage resulting from focal cerebral ischemia. Although the mechanisms of neuroprotection induced by FNS are not entirely understood, important data have been presented in the past two decades. MicroRNAs (miRNAs) are a newly discovered group of non-coding small RNA molecules that negatively regulate target gene expression and are involved in the regulation of cell proliferation and cell apoptosis. To date, no studies have demonstrated whether miRNAs can serve as mediators of the brain's response to FNS, which leads to endogenous neuroprotection. Therefore, this study investigated the profiles of FNS-mediated miRNAs. Using a combination of deep sequencing and microarray with computational analysis, we identified a novel miRNA in the rat ischemic cortex after 1 h of FNS. This novel miRNA (PC-3p-3469_406), herein referred to as rno-miR-676-1, was upregulated in rats with cerebral ischemia after FNS. In vivo observations indicate that this novel miRNA may have antiapoptotic effects and contribute to neuroprotection induced by FNS. Our study provides a better understanding of neuroprotection induced by FNS. MicroRNA (miRNA) is defined as a small non-coding RNA that fulfills both the expression and biogenesis criteria. Here, we describe a novel miRNA in the rat ischemic cortex expressed after 1 h of fastigial nucleus stimulation (FNS). The miRNA was functionally characterized by secondary structure, quantitative expression, the conservation analysis, target gene analysis, and biological functions. We consider rno-miR-676-1 to be a true microRNA and present evidence for its neuroprotective effects exerted after induction by FNS. PMID- 25783477 TI - Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Despite intense investigations, little is known about its pathological mediators. Here, we report the marked upregulation of RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in the serum of hemiparkinsonian monkeys. Interestingly, 1-methyl-4-phenylpyridinium (MPP(+)), a Parkinsonian toxin, increased the expression of RANTES and eotaxin in mouse microglial cells. The presence of NF-kappaB binding sites in promoters of RANTES and eotaxin and down regulation of these genes by NEMO-binding domain (NBD) peptide, selective inhibitor of induced NF-kappaB activation, in MPP(+)-stimulated microglial cells suggest that the activation of NF-kappaB plays an important role in the upregulation of these two chemokines. Consistently, serum enzyme-linked immuno assay (ELISA) and nigral immunohistochemistry further confirmed that these chemokines were strongly upregulated in MPTP-induced hemiparkinsonian monkeys and that treatment with NBD peptides effectively inhibited the level of these chemokines. Furthermore, the microglial upregulation of RANTES in the nigra of hemiparkinsonian monkeys could be involved in the altered adaptive immune response in the brain as we observed greater infiltration of CD8(+) T cells around the perivascular niche and deep brain parenchyma of hemiparkinsonian monkeys as compared to control. The treatment of hemiparkinsonian monkeys with NBD peptides decreased the microglial expression of RANTES and attenuated the infiltration of CD8(+) T cells in nigra. These results indicate the possible involvement of chemokine-dependent adaptive immune response in Parkinsonism. PMID- 25783479 TI - Liver Transplantation-Associated Lung Cancer: Comparison of Clinical Parameters and Outcomes. AB - BACKGROUND: The incidence of lung cancer (LC) is increased in patients with a history of liver transplantation (LT). The purpose of our study was to compare the clinical characteristics and outcomes of patients with postliver transplantation LC (PLTLC) with cohorts of patients with "transplant-naive" LC, and LT patients without LC. PATIENTS AND METHODS: All the patients who had undergone LT or had been diagnosed with LC from 1987 to 2012 were included in the present analysis. The PLTLC cohort was compared with a LT cohort (n = 725) and the local LC registry (n = 2803). The standardized incidence ratios (SIRs) were computed in the classic manner after adjustment for sex, age, and year of follow up. RESULTS: Within the LT cohort, 22 patients (5 women) developed PLTLC (2.3%). The SIR for LC in LT recipients was 4.4 in the women and 2.6 in the men. The PLTLC cohort was older at LT (58.4 vs. 53.3 years; P = .028). Also, 90.5% of the PLTLC group had a history of smoking; 8 patients (42.1%) had had LC detected by annual routine lung cancer screening. The median post-LT survival was significantly inferior in the PLTLC cohort (117.1 vs. 182.6 months; P = .041). The median overall survival (OS), starting from the diagnosis of LC, was similar in the PLTLC and LC cohort (14.7 vs. 15.1 months; P = .519). CONCLUSION: The incidence of LC is significantly increased in the LT population. Therefore, LC screening might be an option for LT patients with a history of smoking. The prognosis of LC does not seem to be impaired by LT, suggesting a minor effect of LT on OS in patients with lung cancer. PMID- 25783480 TI - Q fever infection in dairy cattle herds: increased risk with high wind speed and low precipitation. AB - Ruminants are considered the main reservoir for transmission of Coxiella burnetii (Cb) to humans. The implementation of effective control measures against Cb in ruminants requires knowledge about potential risk factors. The objectives of this study were (i) to describe the spatial distribution of Q fever-infected dairy cattle herds in Sweden, (ii) to quantify the respective contributions of wind and animal movements on the risk of infection, while accounting for other sources of variation, and (iii) to investigate the possible protective effect of precipitation. A total of 1537 bulk milk samples were collected and tested for presence of Cb antibodies. The prevalence of test-positive herds was higher in the south of Sweden. For herds located in areas with high wind speed, open landscape, high animal densities and high temperature, the risk of being infected reached very high values. Because these factors are difficult to control, vaccination could be an appropriate control measure in these areas. Finally, the cumulated precipitation over 1 year was identified as a protective factor. PMID- 25783481 TI - Characterization of a palladium dihydrogen complex. AB - The preparation and isolation of the first palladium dihydrogen complex is described. NMR spectroscopy reveals a very short H-H bond length, but the hydrogen molecule is activated toward heterolytic cleavage. An X-ray crystal structure suggests that proton transfer to the (tBu) PCP (kappa(3)-2,6 ((t)Bu2PCH2)2C6H3) pincer ligand is possible. The basicity of the ipso-carbon atom of the pincer ligand was investigated in a related complex. PMID- 25783482 TI - Modeling longitudinal osteoarthritis data to identify homogeneous subgroups: opportunities and challenges in a burgeoning literature. PMID- 25783483 TI - Whole-exome sequencing identifies OR2W3 mutation as a cause of autosomal dominant retinitis pigmentosa. AB - Retinitis pigmentosa (RP), a heterogeneous group of inherited ocular diseases, is a genetic condition that causes retinal degeneration and eventual vision loss. Though some genes have been identified to be associated with RP, still a large part of the clinical cases could not be explained. Here we reported a four generation Chinese family with RP, during which 6 from 9 members of the second generation affected the disease. To identify the genetic defect in this family, whole-exome sequencing together with validation analysis by Sanger sequencing were performed to find possible pathogenic mutations. After a pipeline of database filtering, including public databases and in-house databases, a novel missense mutation, c. 424 C > T transition (p.R142W) in OR2W3 gene, was identified as a potentially causative mutation for autosomal dominant RP. The mutation co-segregated with the disease phenotype over four generations. This mutation was validated in another independent three-generation family. RT-PCR analysis also identified that OR2W3 gene was expressed in HESC-RPE cell line. The results will not only enhance our current understanding of the genetic basis of RP, but also provide helpful clues for designing future studies to further investigate genetic factors for familial RP. PMID- 25783484 TI - Circulating tumour necrosis factor receptors 1 and 2 predict contrast-induced nephropathy and progressive renal dysfunction: a prospective cohort study. AB - AIM: Contrast-induced nephropathy (CIN) is an important cause of hospital acquired acute kidney injury. An accurate understanding of the pathogenesis of CIN is crucial. The aim of this study was to evaluate the clinical role of circulating tumour necrosis factor receptors (cTNFRs) in CIN. METHODS: From May 2013 to February 2014, 262 patients who underwent coronary angiography and/or percutaneous coronary intervention at Seoul National University Boramae Medical Center were enrolled. CIN was defined as either an increase in serum creatinine >= 22.1 MUmol/L or >= 25% within 48 h after the procedure. RESULTS: Diabetes and chronic kidney disease accounted for 27.5% and 17.6% of the patients, respectively, and the mean age was 65 years. All patients received fluid therapy, and 36.3% underwent percutaneous coronary intervention. A total of 4.2% of the patients developed CIN; younger age, underlying diseases (e.g., stroke and chronic kidney disease), the use of N-acetylcysteine, and elevated concentrations of ln(cTNFRs) were associated with development of CIN. Increased values of ln(cTNFR1) (OR 6.32, 95% CI 2.46-16.28, P < 0.001) and ln(cTNFR2) (OR 3.24, 95% CI 1.26-8.31, P = 0.015) were significantly associated with CIN after adjusting for other risk factors, including baseline renal function. Moreover, an increase of cTNFRs levels was independently correlated with the deterioration of renal function. CONCLUSION: Markedly elevated concentrations of circulating TNFRs were correlated with the occurrence of CIN and significantly associated with prolonged renal dysfunction regardless of the development of CIN. PMID- 25783485 TI - Performance of case-control rare copy number variation annotation in classification of autism. AB - BACKGROUND: A substantial proportion of Autism Spectrum Disorder (ASD) risk resides in de novo germline and rare inherited genetic variation. In particular, rare copy number variation (CNV) contributes to ASD risk in up to 10% of ASD subjects. Despite the striking degree of genetic heterogeneity, case-control studies have detected specific burden of rare disruptive CNV for neuronal and neurodevelopmental pathways. Here, we used machine learning methods to classify ASD subjects and controls, based on rare CNV data and comprehensive gene annotations. We investigated performance of different methods and estimated the percentage of ASD subjects that could be reliably classified based on presumed etiologic CNV they carry. RESULTS: We analyzed 1,892 Caucasian ASD subjects and 2,342 matched controls. Rare CNVs (frequency 1% or less) were detected using Illumina 1M and 1M-Duo BeadChips. Conditional Inference Forest (CF) typically performed as well as or better than other classification methods. We found a maximum AUC (area under the ROC curve) of 0.533 when considering all ASD subjects with rare genic CNVs, corresponding to 7.9% correctly classified ASD subjects and less than 3% incorrectly classified controls; performance was significantly higher when considering only subjects harboring de novo or pathogenic CNVs. We also found rare losses to be more predictive than gains and that curated neurally relevant annotations (brain expression, synaptic components and neurodevelopmental phenotypes) outperform Gene Ontology and pathway-based annotations. CONCLUSIONS: CF is an optimal classification approach for case control rare CNV data and it can be used to prioritize subjects with variants potentially contributing to ASD risk not yet recognized. The neurally-relevant annotations used in this study could be successfully applied to rare CNV case control data-sets for other neuropsychiatric disorders. PMID- 25783486 TI - Sex- and habitat-specific movement of an omnivorous semi-terrestrial crab controls habitat connectivity and subsidies: a multi-parameter approach. AB - Distinct habitats are often linked through fluxes of matter and migration of organisms. In particular, intertidal ecotones are prone to being influenced from both the marine and the terrestrial realms, but whether or not small-scale migration for feeding, sheltering or reproducing is detectable may depend on the parameter studied. Within the ecotone of an upper saltmarsh in the United States, we investigated the sex-specific movement of the semi-terrestrial crab Armases cinereum using an approach of determining multiple measures of across-ecotone migration. To this end, we determined food preference, digestive abilities (enzyme activities), bacterial hindgut communities (genetic fingerprint), and the trophic position of Armases and potential food sources (stable isotopes) of males versus females of different sub-habitats, namely high saltmarsh and coastal forest. Daily observations showed that Armases moved frequently between high intertidal (saltmarsh) and terrestrial (forest) habitats. Males were encountered more often in the forest habitat, whilst gravid females tended to be more abundant in the marsh habitat but moved more frequently. Food preference was driven by both sex and habitat. The needlerush Juncus was preferred over three other high-marsh detrital food sources, and the periwinkle Littoraria was the preferred prey of male (but not female) crabs from the forest habitats; both male and female crabs from marsh habitat preferred the fiddler crab Uca over three other prey items. In the field, the major food sources were clearly vegetal, but males have a higher trophic position than females. In contrast to food preference, isotope data excluded Uca and Littoraria as major food sources, except for males from the forest, and suggested that Armases consumes a mix of C4 and C3 plants along with animal prey. Digestive enzyme activities differed significantly between sexes and habitats and were higher in females and in marsh crabs. The bacterial hindgut community differed significantly between sexes, but habitat effects were greater than sex effects. By combining multiple measures of feeding ecology, we demonstrate that Armases exhibits sex-specific habitat choice and food preference. By using both coastal forest and saltmarsh habitats, but feeding predominantly in the latter, they possibly act as a key biotic vector of spatial subsidies across habitat borders. The degree of contributing to fluxes of matter, nutrients and energy, however, depends on their sex, indicating that changes in population structure would likely have profound effects on ecosystem connectivity and functioning. PMID- 25783487 TI - Rhizobacterial colonization of roots modulates plant volatile emission and enhances the attraction of a parasitoid wasp to host-infested plants. AB - Beneficial root-associated microbes modify the physiological status of their host plants and affect direct and indirect plant defense against insect herbivores. While the effects of these microbes on direct plant defense against insect herbivores are well described, knowledge of the effect of the microbes on indirect plant defense against insect herbivores is still limited. In this study, we evaluate the role of the rhizobacterium Pseudomonas fluorescens WCS417r in indirect plant defense against the generalist leaf-chewing insect Mamestra brassicae through a combination of behavioral, chemical, and gene-transcriptional approaches. We show that rhizobacterial colonization of Arabidopsis thaliana roots results in an increased attraction of the parasitoid Microplitis mediator to caterpillar-infested plants. Volatile analysis revealed that rhizobacterial colonization suppressed the emission of the terpene (E)-alpha-bergamotene and the aromatics methyl salicylate and lilial in response to caterpillar feeding. Rhizobacterial colonization decreased the caterpillar-induced transcription of the terpene synthase genes TPS03 and TPS04. Rhizobacteria enhanced both the growth and the indirect defense of plants under caterpillar attack. This study shows that rhizobacteria have a high potential to enhance the biocontrol of leaf chewing herbivores based on enhanced attraction of parasitoids. PMID- 25783488 TI - Decoupling of female host plant preference and offspring performance in relative specialist and generalist butterflies. AB - The preference-performance hypothesis posits that the host plant range of plant feeding insects is ultimately limited by larval costs associated with feeding on multiple resources, and that female egg-laying preferences evolve in response to these costs. The trade-off of either using few host plant species and being a strong competitor on them due to effective utilization or using a wide host plant range but being a poor competitor is further predicted to result in host plant specialization. This follows under the hypothesis that both females and offspring are ultimately favoured by utilizing only the most suitable host(s). We develop an experimental approach to identify such trade-offs, i.e. larval costs associated with being a host generalist, and apply a suite of experiments to two sympatric and syntopic populations of the closely related butterflies Pieris napi and Pieris rapae. These butterflies show variation in their level of host specialization, which allowed comparisons between more and less specialized species and between families within species. Our results show that, first, the link between female host preference and offspring performance was not significantly stronger in the specialist compared to the generalist species. Second, the offspring of the host plant specialist did not outperform the offspring of the generalist on the former's most preferred host plant species. Finally, the more generalized species, or families within species, did not show higher survival or consistently higher growth rates than the specialists on the less preferred plants. Thus, the preference and performance traits appear to evolve as largely separated units. PMID- 25783489 TI - The role of dew in Negev Desert plants. AB - We investigated the possible use of dew as a water source for three desert plant species native to the Negev Desert: an annual Salsola inermis, and two perennials Artemisia sieberi and Haloxylon scoparium, with different rooting depths of 15, 30 and 90 cm, respectively. We quantified dew-water inputs and used stable isotope analyses to determine the proportion of dew as compared to the proportion of soil water each species utilized. Dew was isotopically enriched (deltaD values ranged from -25 to 5 0/00), relative to rainfall with deltaD values that ranged from -40 to -20 0/00 and relative to soil water with deltaD values that ranged from -65 to -35 0/00. Using a two-source isotope mixing model, we found that S. inermis, A. sieberi and H. scoparium used, on average, 56, 63 and 46 % of their water from dewfall, respectively. Our results suggest that dew-water utilization by Negev Desert plants is highly significant ecologically and thus may be more common than previously thought. In light of future predicted climate change, it may be increasingly important for plants of the Negev Desert to make use of dew as a water resource as it may play an important role in their ability to cope with the associated hydrological constraints predicted for the Negev region. PMID- 25783490 TI - Plant community responses to precipitation and spatial pattern of nitrogen supply in an experimental grassland ecosystem. AB - Recent work suggests that soil nutrient heterogeneity may modulate plant responses to drivers of global change, but interactions between N heterogeneity and changes in rainfall regime remain poorly understood. We used a model grassland system to investigate the interactive effects of N application pattern (homogeneous, heterogeneous) and precipitation-magnitude manipulation during the growing season (control, +50 % rainfall, -50 % rainfall) on aboveground biomass and plant community dominance patterns. Our study resulted in four major findings: patchy N addition increased within-plot variability in plant size structure at the species level, but did not alter total aboveground biomass; patchy N addition increased community dominance and caused a shift in the ranking of subordinate plant species; unlike community-level biomass, plant species differed in their biomass response to the rainfall treatments; and neither aboveground biomass nor community dominance showed significant interactions between N pattern and rainfall manipulation, suggesting that grassland responses to patchy N inputs are insensitive to water addition or rainfall reduction in our temperate study system. Overall, our results indicate that the spatial pattern of N inputs has greater effects on species biomass variability and community dominance than on aboveground production. These short-term changes in plant community structure may have significant implications for longer-term patterns of vegetation dynamics and plant-soil feedbacks. Moreover our results suggest that the magnitude of precipitation during the growing season plays a limited role in grassland responses to heterogeneous organic N inputs, emphasizing the need to consider other components of precipitation change in future heterogeneity studies. PMID- 25783491 TI - Seventy years after the end of World War II. PMID- 25783492 TI - Prevention of posterior capsular opacification. AB - Posterior capsular opacification (PCO) is a common complication of cataract surgery. The development of PCO is due to a combination of the processes of proliferation, migration, and transdifferentiation of residual lens epithelial cells (LECs) on the lens capsule. In the past decades, various forms of PCO prevention have been examined, including adjustments of techniques and intraocular lens materials, pharmacological treatments, and prevention by interfering with biological processes in LECs. The only method so far that seems effective is the implantation of an intraocular lens with sharp edged optics to mechanically prevent PCO formation. In this review, current knowledge of the prevention of PCO will be described. We illustrate the biological pathways underlying PCO formation and the various approaches to interfere with the biological processes to prevent PCO. In this type of prevention, the use of nanotechnological advances can play a role. PMID- 25783493 TI - Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. AB - Photooxidative damage and chronic innate immune activation have been implicated in retinal pigment epithelium (RPE) dysfunction, a process that underlies blinding diseases such as age-related macular degeneration (AMD). To identify a potential molecular link between these mechanisms, we investigated whether lipofuscin-mediated phototoxicity activates the NLRP3 inflammasome in RPE cells in vitro. We found that blue light irradiation (dominant wavelength 448 nm, irradiance 0.8 mW/cm(2), duration 6 h) of lipofuscin-loaded primary human RPE cells and ARPE-19 cells induced photooxidative damage, lysosomal membrane permeabilization (79.5 % of cells vs. 3.8 % in nonirradiated controls), and cytosolic leakage of lysosomal enzymes. This resulted in activation of the inflammasome with activation of caspase-1 and secretion of interleukin-1beta (14.6 vs. 0.9 pg/ml in nonirradiated controls) and interleukin-18 (87.7 vs. 0.2 pg/ml in nonirradiated controls). Interleukin secretion was dependent on the activity of NLRP3, caspase-1, and lysosomal proteases cathepsin B and L. These results demonstrate that accumulation of lipofuscin-like material in vitro renders RPE cells susceptible to phototoxic destabilization of lysosomes, resulting in NLRP3 inflammasome activation and secretion of inflammatory cytokines. This new mechanism of inflammasome activation links photooxidative damage and innate immune activation in RPE pathology and may provide novel targets for therapeutic intervention in retinal diseases such as AMD. KEY MESSAGE: * Visible light irradiation of lipofuscin-loaded RPE cells activates inflammasome. * Inflammasome activation results from lysosomal permeabilization and enzyme leakage. * Inflammasome activation induces secretion of inflammatory cytokines by RPE cells. * Photooxidative damage by visible light as new mechanism of inflammasome activation. * Novel link between hallmark pathogenetic features of retinal degenerative diseases. PMID- 25783494 TI - Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes. AB - 4-Alkyl-substituted 1,4-dihydropyridines (DHP) exhibit inhibitory activity toward certain cytochrome P450 enzymes (P450) during their biotransformation by these enzymes, which is called mechanism-based inactivation. Though much experimental evidence had proved the essentiality of alkyl radical for P450 inactivation, the underlying mechanism of such radical formation remains elusive. In the present study, density functional calculations were employed to investigate the dealkylation mechanism of 4-alkyl-substituted DHPs mediated by P450. Interestingly, our results indicate that the initial N-H activation proceeds via a proton-coupled electron transfer process, not via the long presumed hydrogen atom transfer mechanism or the stepwise electron transfer/proton transfer one, to form the amino radical and Cpd II complex. Subsequently, homolytic C-C bond cleavage at the 4-position occurs to afford the product complex involving an alkyl radical, an aromatic pyridine derivative. This C-C cleavage step is rate determining for the whole metabolic reaction, with an energy barrier of 7.9/7.9 kcal/mol on the quartet/doublet state, to which aromatization contributes as an essential intrinsic driving force. The 4-substituent groups induce differences in activation energy barriers and in the transition state structures of hydrogen abstraction process. The substrate reactivity correlates well with the stability of the generated alkyl radical as well as the C-C bond dissociation energy. Understanding the metabolic mechanism of DHP analogs is indeed essential for the related design of safer and more efficient drugs. Furthermore, our findings also enrich the mechanistic picture of amine oxidation catalyzed by P450. PMID- 25783495 TI - Thiol-mediated multiple mechanisms centered on selenodiglutathione determine selenium cytotoxicity against MCF-7 cancer cells. AB - Selenium (Se) is an essential antioxidative micronutrient but can exert cancer selective cytotoxicity if the nutritional levels are too high. Selenodiglutathione (GSSeSG) is a primary Se metabolite conjugated with two glutathione (GSH) moieties. GSSeSG has been suggested to be an important molecule for cytotoxicity. Here, we propose the underlying mechanisms for the potent cytotoxicity of GSSeSG: cellular intake; reductive metabolism; production of reactive oxygen species; oxidative damage to DNA; apoptosis induction. GSSeSG rather than selenite decreased cell viability and induced apoptosis accompanied by increases in intracellular Se contents. Therefore, GSSeSG-specific cytotoxicity may be ascribed to its preferable incorporation. Base oxidation and strand fragmentation in genomic DNA preceded cell death, suggesting that oxidative stress (including DNA damage) is crucial for GSSeSG cytotoxicity. Strand breaks of purified DNA were caused by the coexistence of GSSeSG and thiols (GSH, cysteine, homocysteine), but not the oxidized form or non-thiol reductants. This implies the important role of intracellular thiols in the mechanism of Se toxicity. GSH-assisted DNA strand breaks were inhibited by specific scavengers for hydrogen peroxide or hydroxyl radicals. The GSSeSG metabolite selenide induced some DNA strand breaks without GSH, whereas elemental Se did so only with GSH. These observations suggest involvement of Fenton-type reaction in the absence of transition metals and reactivation of inert elemental Se. Overall, our results suggest that chemical interactions between Se and the sulfur of thiols are crucial for the toxicity mechanisms of Se. PMID- 25783496 TI - Diffusion-limited attachment of large spherical particles to flexible membrane immobilized receptors. AB - Relatively large (~100 nm) spherical particles, e.g., virions, vesicles, or metal nanoparticles, often interact with short (<10 nm) flexible receptors immobilized in a lipid membrane or on other biologically relevant surfaces. The attachment kinetics of such particles may be limited globally by their diffusion toward a membrane or locally by diffusion around receptors. The detachment kinetics, also, can be limited by diffusion. Focusing on local diffusion limitations and using suitable approximations, we present expressions for the corresponding rate constants and identify their dependence on particle size and receptor length. We also illustrate features likely to be observed in such kinetics for particles (e.g., vesicles) with a substantial size distribution. The results obtained are generic and can be used to interpret a variety of situations. For example, we estimate upper values of virion attachment rate constants and clarify the likely effect of vesicle size distribution on previously observed non-exponential kinetics of vesicle detachment. PMID- 25783497 TI - Multi-spectroscopic methods investigation on the interaction of tenoxicam with DNA. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) show chemopreventive and chemosuppressive effects on various cancer cell lines. They exert anticancer activities by inhibiting both at the protein level and/or at the transcription level. Thus, in this paper, the interaction between tenoxicam (TXM) and calf thymus DNA (ct-DNA) was investigated by UV-visible light, fluorescence, viscosity experiments and DNA melting studies. The results showed that TXM could bind to ct DNA in the groove binding mode. The binding constants were 7.67 * 10(3) and 5.48 * 10(3) M(-1) at 293 and 300 K, respectively. Furthermore, the calculated thermodynamic parameters suggested that hydrogen bonds or van der Waals force might play an important role in the binding of TXM to ct-DNA. The obtained results should give new insight into the pharmacological activity of TXM. PMID- 25783498 TI - 2013 trends and statistics for prescription medications in the United States: CNS highest ranked and record number of prescriptions dispensed. PMID- 25783500 TI - Method for determination of polyethylene glycol molecular weight. AB - A method utilizing competitive adsorption between polyethylene glycols (PEGs) and labeled protein to nanoparticles was developed for the determination of PEG molecular weight (MW) in a microtiter plate format. Two mix-and-measure systems, time-resolved luminescence resonance energy transfer (TR-LRET) with donor europium(III) polystyrene nanoparticles and acceptor-labeled protein and quenching with quencher gold nanoparticles and fluorescently labeled protein were compared for their performance. MW is estimated from the PEG MW dependent changes in the competitive adsorption properties, which are presented as the luminescence signal vs PEG mass concentration. The curves obtained with the TR-LRET system overlapped for PEGs larger than 400 g/mol providing no information on MW. Distinctly different curves were obtained with the quenching system enabling the assessment of PEG MW within a broad dynamic range. The data was processed with and without prior knowledge of the PEG concentration to measure PEGs over a MW range from 62 to 35,000 g/mol. The demonstration of the measurement independent of the PEG concentration suggests that the estimation of MW is possible with quenching nanoparticle system for neutrally charged and relatively hydrophilic polymeric molecules widening the applicability of the simple and cost-effective nanoparticle-based methods. PMID- 25783501 TI - Upregulation of cell proliferation via Shc and ERK1/2 MAPK signaling in SaOS-2 osteoblasts grown on magnesium alloy surface coating with tricalcium phosphate. AB - Magnesium (Mg) alloys have been demonstrated to be viable orthopedic implants because of mechanical and biocompatible properties similar to natural bone. In order to improve its osteogenic properties, a porous beta-tricalcium phosphate (beta-TCP) was coated on the Mg-3AI-1Zn alloy by alkali-heat treatment technique. The human bone-derived cells (SaOS-2) were cultured on (beta-TCP)-Mg-3AI-1Zn in vitro, and the osteoblast response, the morphology and the elements on this alloy surface were investigated. Also, the regulation of key intracellular signalling proteins was investigated in the SaOS-2 cells cultured on alloy surface. The results from scanning electron microscope and immunofluorescence staining demonstrated that (beta-TCP)-Mg-3AI-1Zn induced significant osteogenesis. SaOS-2 cell proliferation was improved by beta-TCP coating. Moreover, the (beta-TCP)-Mg 3AI-1Zn surface induced activation of key intracellular signalling proteins in SaOS-2 cells. We observed an enhanced activation of Src homology and collagen (Shc), a common point of integration between bone morphogenetic protein 2, and the Ras/mitogen-activated protein kinase (MAPK) pathway. ERK1/2 MAP kinase activation was also upregulated, suggesting a role in mediating osteoblastic cell interactions with biomaterials. The signalling pathway involving c-fos (member of the activated protein-1) was also shown to be upregulated in osteoblasts cultured on the (beta-TCP)-Mg-3AI-1Zn. These results suggest that beta-TCP coating may contribute to successful osteoblast function on Mg alloy surface. (beta-TCP)-Mg 3AI-1Zn may upregulate cell proliferation via Shc and ERK1/2 MAPK signaling in SaOS-2 osteoblasts grown on Mg alloy surface. PMID- 25783502 TI - In vitro study of partially hydrolyzed poly(2-ethyl-2-oxazolines) as materials for biomedical applications. AB - Polymers based on 2-oxazoline, such as poly(2-ethyl-2-oxazolines) (PETOx), are considered to be a type of 'pseudopeptide' with the ability to form novel biomaterials. The hydrolysis of PETOx was carried out to evaluate its use in biomedical applications. In the present work, PETOx samples with a range of molar masses were prepared by living cationic polymerization. Hydrolysis was carried out at time intervals ranging from 15 to 180 min to prepare copolymers with different amounts of ethylene imine units. (1)H NMR spectroscopy was used to identify the structure of the hydrolyzed polymers. The dependence of in vitro cell viability on the degree of hydrolysis was determined using three different model cell lines, namely, mouse embryonic 3T3 fibroblasts, pancreatic betaTC3 cells, and mouse lymphoid macrophages P388.D1. It was demonstrated that increasing the degree of hydrolysis decreased cell viability for all cell types. Fibroblast cells displayed the highest tolerance; additionally, the effect of polymer size showed no observable significance. Macrophage cells, immune system representatives, displayed the highest sensitivity to contact with hydrolyzed PETOx. The effect of polymer hydrolysis, polymer concentration and the incubation time on cell viability was experimentally observed. Confocal laser-scanning microscopy provided evidence of cellular uptake of pyrene-labeled (co)polymers. PMID- 25783503 TI - Comparative cellular toxicity of titanium dioxide nanoparticles on human astrocyte and neuronal cells after acute and prolonged exposure. AB - Although in the last few decades, titanium dioxide nanoparticles (TiO2NPs) have attracted extensive interest due to their use in wide range of applications, their influences on human health are still quite uncertain and less known. Evidence exists indicating TiO2NPs ability to enter the brain, thus representing a realistic risk factor for both chronic and accidental exposure with the consequent needs for more detailed investigation on CNS. A rapid and effective in vitro test strategy has been applied to determine the effects of TiO2NPs anatase isoform, on human glial (D384) and neuronal (SH-SY5Y) cell lines. Toxicity was assessed at different levels: mitochondrial function (by MTT), membrane integrity and cell morphology (by calcein AM/PI staining) after acute exposure (4-24-48 h) at doses from 1.5 to 250 MUg/ml as well as growth and cell proliferation (by clonogenic test) after prolonged exposure (7-10 days) at sub-toxic concentrations (from 0.05 to 31 MUg/ml). The cytotoxic effects of TiO2NPs were compared with those caused by TiO2 bulk counterpart treatment. Acute TiO2NP exposure produced (i) dose- and time-dependent alterations of the mitochondrial function on D384 and SH-SY5Y cells starting at 31 and 15 MUg/ml doses, respectively, after 24h exposure. SH-SY5Y were slightly more sensitive than D384 cells; and (ii) cell membrane damage occurring at 125 MUg/ml after 24h exposure in both cerebral cells. Comparatively, the effects of TiO2 bulk were less pronounced than those induced by nanoparticles in both cerebral cell lines. Prolonged exposure indicated that the proliferative capacity (colony size) was compromised at the extremely low TiO2NP doses namely 1.5 MUg/ml and 0.1 MUg/ml for D384 and SH-SY5Y, respectively; cell sensitivity was still higher for SH-SY5Y compared to D384. Colony number decrease (15%) was also evidenced at >=0.2 MUg/ml TiO2NP dose. Whereas, TiO2 bulk treatment affected cell morphology only. TiO2 internalization in SH-SY5Y and D384 cells was appreciated using light microscopy. These findings indicated, that (i) human cerebral SH-SY5Y and D384 cell lines exposed to TiO2NPs were affected not only after acute but even after prolonged exposure at particularly low doses (>= 0.1 MUg/ml), (ii) these in vitro critical doses were comparable to literature brain Ti levels detected in lab animal intranasally administered with TiO2NP and associated to neurotoxic effects. In summary, the applied cell-based screening platform seems to provide effective means to initial evaluation of TiO2NP toxicity on CNS. PMID- 25783505 TI - Thymoma treated with 177Lu DOTATATE induction and maintenance PRRT. AB - A 47-year-old man presented with a recurrent thymoma World Health Organization type A of the anterior chest wall with pleural metastases after failing chemotherapy. The tumor was positive on In-octreotide, and he was referred for peptide receptor radionuclide therapy (PRRT) with Lu DOTATATE. He received 4 induction and 2 maintenance Lu DOTATATE treatments (total dose, 1000 mCi) and reported significant improvement in symptoms. Before the seventh treatment, mild progression was diagnosed on CT, and PRRT was terminated. The use of induction and maintenance Lu DOTATATE PRRT therapy in the management of thymoma warrants further research. PMID- 25783504 TI - Combined diazepam and MK-801 therapy provides synergistic protection from tetramethylenedisulfotetramine-induced tonic-clonic seizures and lethality in mice. AB - The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl(-) channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK 801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 h lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or simultaneous administration of, these two agents in treating TMDT poisoning. PMID- 25783506 TI - Unusual soft tissue infiltrates with 18F-FDG uptake in a patient with hairy cell leukemia. AB - Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder, representing approximately 2% of leukemias. Diagnostic features include pancytopenia, splenomegaly, bone marrow reticulin fibrosis, and circulating hairy cells. Less commonly, there may be involvement of the liver and lymph nodes. We present a case of a 53-year-old man with HCL who was found to have soft tissue masses within the mediastinum and neck during pretreatment workup. An F-FDG PET/CT scan was requested to assess these lesions before treatment. These extensive infiltrates were FDG avid, and core biopsy of the mediastinal tissue was undertaken. Results were consistent with HCL. PMID- 25783507 TI - Peritoneal carcinomatosis in primary ovarian cancer staging: comparison between MDCT, MRI, and 18F-FDG PET/CT. AB - PURPOSE: The aim of this study was to compare multidetector CT (MDCT), MRI, and FDG PET/CT imaging for the detection of peritoneal carcinomatosis (PC) in ovarian cancer. PATIENTS AND METHODS: Fifteen women with ovarian cancer and suspected PC underwent MDCT, MRI, and FDG PET/CT, shortly before surgery. Nine abdominopelvic regions were defined according to the peritoneal cancer index. We applied lesion size scores on MDCT and MR and measured FDG PET/CT standard uptake. We blindly read MDCT, MR, and PET/CT before joint review and comparison with histopathology. Receiver operating characteristics analysis was performed. RESULTS: Ten women had PC (67%). Altogether, 135 abdominopelvic sites were compared. Multidetector CT, MRI, and FDG PET/CT had a sensitivity of 96%, 98%, and 95%, and specificity was 92%, 84%, and 96%, respectively. Corresponding receiver operating characteristics area was 0.94, 0.90, and 0.96, respectively, without any significant differences between them (P = 0.12). FDG PET/CT detected supradiaphragmatic disease in 3 women (20%) not seen by MDCT or MRI. CONCLUSIONS: Although MRI had the highest sensitivity and FDG PET/CT had the highest specificity, no significant differences were found between the 3 techniques. Thus, MDCT, as the fastest, most economical, and most widely available modality, is the examination of choice, if a stand-alone technique is required. If inconclusive, PET/CT or MRI may offer additional insights. Whole-body FDG PET/CT may be more accurate for supradiaphragmatic metastatic extension. PMID- 25783508 TI - (18)F-FDG dynamic PET/CT in patients with multiple myeloma: patterns of tracer uptake and correlation with bone marrow plasma cell infiltration rate. AB - PURPOSE: The value of F-FDG PET in the diagnostic approach of multiple myeloma (MM) remains incompletely elicited. Little is known about the kinetics of F-FDG in the bone marrow and extramedullary sites in MM. This study aimed to evaluate quantitative data on kinetics and distribution patterns of F-FDG in MM patients with regard to pelvic bone marrow plasma cell infiltration. PROCEDURES: The study included 40 patients with primary MM. Dynamic PET/CT scanning of the lower lumbar spine and pelvis was performed after the administration of F-FDG. Whole-body PET/CT studies were performed. Sites of focal increased tracer uptake were considered as highly suggestive of myelomatous involvement after taking into account the patient history and CT findings. Bone marrow of the os ilium without pathologic tracer accumulation served as reference. The evaluation of dynamic PET/CT studies was based in addition to the conventional visual (qualitative) assessment, on semiquantitative (SUV) calculations, as well as on absolute quantitative estimations after application of a 2-tissue compartment model and a noncompartmental approach. F-FDG quantitative information and corresponding distribution patterns were correlated with pelvic bone marrow plasma cell infiltration. RESULTS: Fifty-two myelomatous lesions were detected in the pelvis. All parameters in suspected MM lesions ranged in significantly higher levels than in reference tissue (P < 0.01). Correlative analyses revealed that bone marrow plasma cell infiltration rate correlated significantly with SUVaverage, SUVmax, and the parameters K1, influx, and fractal dimension of F-FDG in reference bone marrow (P < 0.01). In addition, whole-body static PET/CT imaging demonstrated 4 patterns of tracer uptake; these are as follows: negative, focal, diffuse, and mixed (focal/diffuse) tracer uptake. Patients with a mixed pattern of radiotracer uptake had the highest mean plasma cell infiltration rate in their bone marrow, whereas those with negative PET/CT scans demonstrated the lowest bone marrow plasma cell infiltration. In total, 265 focal myeloma-indicative F-FDG-avid lesions were detected, 129 of which correlated with low-dose CT osteolytic findings. No significant correlation between the number of focal lesions detected in PET/CT and bone marrow infiltration was detected. CONCLUSIONS: The F-FDG kinetic parameters K1, influx, and fractal dimension as well as SUVaverage from reference tissue correlated significantly with bone marrow malignant plasma cell infiltration rate. Patients with negative PET/CT demonstrated the lowest bone marrow infiltration by malignant plasma cells, whereas those with a mixed pattern of tracer uptake had the highest infiltration. PMID- 25783509 TI - Accuracy of 68Ga DOTANOC PET/CT Imaging in Patients With Multiple Endocrine Neoplasia Syndromes. AB - OBJECTIVE: The aim of this study was to evaluate the role of 68Ga DOTANOC PET/CT imaging in patients with multiple endocrine neoplasia (MEN) syndromes. PATIENTS AND METHODS: Data of 33 patients (age, 33.5 [13.8] years; male 14/female 19) with MEN syndromes (MEN 1, 9; MEN 2A, 19; MEN 2B, 5) who underwent 41 68Ga DOTANOC PET/CT studies were retrospectively analyzed. Twenty PET/CTs were done for staging and 21 for restating. PET/CT images were evaluated in consensus by 2 nuclear medicine physicians, qualitatively and semiquantitatively (SUV(max)). A combination of histopathology, clinical, and biomarker follow-up was taken as reference standard. RESULTS: Of the total 41 68Ga DOTANOC PET/CTs, 34 were interpreted as positive for neuroendocrine tumors (NETs) and 7 as negative. The patientwise sensitivity of PET/CT was 94% (95% confidence interval [CI], 80-99), specificity was 71% (95% CI, 29-96), positive predictive value was 94% (95% CI, 80-99), negative predictive value was 71% (95% CI, 29-96), and accuracy was 90%. A total of 74 disease sites were demonstrated on PET/CT, including 41 primary NETs (pancreas, 10; stomach, 2; pheochromocytoma, 10; medullary thyroid carcinoma, 19), 31 metastatic sites (lymph node, 15; liver, 10; bone, 4; lung, 1; breast, 1), and 2 parathyroid adenomas. Lesionwise sensitivity, positive predictive value, and accuracy of PET/CT were 93%, 96%, and 90% overall, 89%, 95%, and 85% for primary tumors, and 100%, 97%, and 97% for metastasis, respectively. Among primary tumors, the SUV(max) of medullary thyroid carcinoma was significantly lower than gastro pancreatic NETs (P = 0.003) and pheochromocytomas (P = 0.003). No site-specific difference was seen in SUV(max) of metastatic lesions. CONCLUSIONS: 68Ga DOTANOC PET/CT shows high diagnostic accuracy in MEN syndrome and can demonstrate both primary and metastatic NETs in these patients. PMID- 25783510 TI - Somatostatin imaging of neuroendocrine-differentiated prostate cancer. AB - After prolonged androgen deprivation therapy, a subset of castrate-resistant prostate cancer patients will develop neuroendocrine prostate cancer (NEPC) associated with resistance to further hormonal therapy and frequent visceral metastases. Imaging the presence of somatostatin receptors on the cancer cell surface may provide a readily available, noninvasive means to distinguish adenocarcinoma from NEPC. This distinction is important for therapeutic decision making and may open the door for developing novel radionuclide targets for the treatment of this aggressive subtype of prostate cancer. We describe a case of NEPC successfully imaged using In-labeled octreotide. PMID- 25783511 TI - The impact of DaTscan in the diagnosis of Parkinson disease. AB - PURPOSE: The aim of this study was to evaluate the impact of DaTscan in a heterogeneous group of patients with movement disorders as well as the degree of confidence in scan findings between different readers. PROCEDURES: A retrospective evaluation of consecutive patients who underwent DaTscan during 1 year was performed. The patients' demographics, symptoms, duration, clinical diagnosis, and medications were collected. The scan findings were categorized by 2 blinded observers on a semiquantitative scale as follows: 0, normal; 1, mild; 2, moderate; 3, marked; and 4, absent uptake for each of the caudate heads and putamina separately. A correlation of the scan findings with the clinical symptoms and diagnosis as well as interobserver agreement was performed. Disagreement was considered when a difference greater than 2 in more than 1 area of the basal ganglia was recorded. Descriptive statistics and kappa test for interobserver agreement were used for data analysis. RESULTS: Fifty-seven patients were included (mean age, 63.4 years; 29 men, 28 women). Clinical diagnosis of Parkinson disease (PD) was certain in 26 and uncertain in 31 patients. DaTscan was markedly abnormal in 24 (92%) of 26 patients with certain clinical diagnosis of PD and normal in the remaining 2 (8%). In 31 patients with uncertain diagnosis, 15 (48%) had markedly abnormal scans, 5 (16%) had mild abnormalities, and 11 (36%) had normal scans. Each of the sensitivity and positive predictive value of DaTscan in patients who had certain clinical diagnosis of PD (26 patients) is 92%. Interobserver agreement occurred in 52 (91%) of 57 scans and disagreement in 5 (9%) of 57 (kappa = 0.82). There was also a good correlation with laterality of symptoms in 32 (82%) of 39 positive studies. CONCLUSIONS: Markedly abnormal DaTscan is confirmed as the diagnostic pattern for PD. This pattern helps confirm the diagnosis in patients with unclear clinical diagnosis. Good interobserver agreement is easily obtained in reading DaTscans. PMID- 25783512 TI - (111)In WBC SPECT/CT detection of a radiographically occult solitary infected renal cyst in polycystic kidney disease. AB - Renal cyst infection-pyocystis-is a potentially life-threatening complication of autosomal-dominant polycystic kidney disease. Differentiation of pyocystis from pyelonephritis is important for antibiotic management. A 56-year-old woman with autosomal-dominant polycystic kidney disease and recurrent urinary tract infections was admitted to the hospital with suspicion of pyelonephritis. CT and static planar In-labeled WBC examinations failed to show a specific focus of infection. Abdominal imaging with In-labeled WBC SPECT/CT revealed abnormal leukocyte accumulation within a solitary right renal cyst. Precise SPECT/CT localization of the infected renal cyst is illustrated along with comparative CT images. PMID- 25783513 TI - Untreated Hodgkin Lymphoma With Skin Infiltration and Satellite Skin Nodule in a 15-Year-Old Female Adolescent. AB - A 15-year-old female adolescent presented with progressive neck swelling of 1 year duration and received 6 months of antituberculosis therapy in a local hospital with no benefit. After excision biopsy, she came to our institution. Examination showed 3 fungating, ulcerating neck masses and a chest wall skin nodule. Pathology confirmed Hodgkin lymphoma, stage IV BXE. FDG PET/CT showed a large neck tumor, a satellite skin nodule with local skin infiltration of tumor. She received 6 cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and radiation therapy 2100 cGy. After chemotherapy, FDG PET/CT was negative. She is 2 years disease free. PMID- 25783514 TI - Comparison of Coregistration Accuracy of Pelvic Structures Between Sequential and Simultaneous Imaging During Hybrid PET/MRI in Patients with Bladder Cancer. AB - PURPOSE: The aim of this study was to compare coregistration of the bladder wall, bladder masses, and pelvic lymph nodes between sequential and simultaneous PET and MRI acquisitions obtained during hybrid (18)F-FDG PET/MRI performed using a diuresis protocol in bladder cancer patients. METHODS: Six bladder cancer patients underwent (18)F-FDG hybrid PET/MRI, including IV Lasix administration and oral hydration, before imaging to achieve bladder clearance. Axial T2 weighted imaging (T2WI) was obtained approximately 40 minutes before PET ("sequential") and concurrently with PET ("simultaneous"). Three-dimensional spatial coordinates of the bladder wall, bladder masses, and pelvic lymph nodes were recorded for PET and T2WI. Distances between these locations on PET and T2WI sequences were computed and used to compare in-plane (x-y plane) and through plane (z-axis) misregistration relative to PET between T2WI acquisitions. RESULTS: The bladder increased in volume between T2WI acquisitions (sequential, 176 [139] mL; simultaneous, 255 [146] mL). Four patients exhibited a bladder mass, all with increased activity (SUV, 9.5-38.4). Seven pelvic lymph nodes in 4 patients showed increased activity (SUV, 2.2-9.9). The bladder wall exhibited substantially less misregistration relative to PET for simultaneous, compared with sequential, acquisitions in in-plane (2.8 [3.1] mm vs 7.4 [9.1] mm) and through-plane (1.7 [2.2] mm vs 5.7 [9.6] mm) dimensions. Bladder masses exhibited slightly decreased misregistration for simultaneous, compared with sequential, acquisitions in in-plane (2.2 [1.4] mm vs 2.6 [1.9] mm) and through-plane (0.0 [0.0] mm vs 0.3 [0.8] mm) dimensions. FDG-avid lymph nodes exhibited slightly decreased in-plane misregistration (1.1 [0.8] mm vs 2.5 [0.6] mm), although identical through-plane misregistration (4.0 [1.9] mm vs 4.0 [2.8] mm). CONCLUSIONS: Using hybrid PET/MRI, simultaneous imaging substantially improved bladder wall coregistration and slightly improved coregistration of bladder masses and pelvic lymph nodes. PMID- 25783515 TI - Total lesion glycolysis determined per RECIST 1.1 criteria predicts survival in EGFR mutation-negative patients with advanced lung adenocarcinoma. AB - OBJECTIVE: The aim of this retrospective study was to investigate the clinical impact of F-FDG PET in patients with advanced lung adenocarcinoma stratified according to the epidermal growth factor receptor (EGFR) mutation status. PATIENTS AND METHODS: A total of 56 patients with advanced lung adenocarcinoma were included in the study. Thirty-one patients (55%) were EGFR mutation positive, whereas the remaining 25 (45%) participants tested negative for EGFR mutations. All of the patients underwent F-FDG PET/CT for pretreatment planning. The main outcome measure was overall survival (OS) at 24 months. The following F FDG PET/CT-derived variables were tested for their associations with OS: main tumor SUVmax, main tumor total lesion glycolysis, and target lesions TLG determined per RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria (TLGRECIST). We also investigated the clinical characteristics in relation to OS and EGFR mutation status. RESULTS: In EGFR mutation-positive patients, neither the clinical characteristics nor F-FDG PET/CT-derived parameters were significantly associated with OS. In contrast, univariate analysis identified male sex, a positive history of smoking, and TLGRECIST greater than or equal to 412 g as adverse prognostic factors for OS in EGFR mutation-negative patients. After adjustment for potential confounders in multivariate analysis, TLGRECIST was the sole independent predictor of OS in this subgroup. CONCLUSIONS: TLG determined per RECIST 1.1 criteria is an independent predictor of OS in EGFR mutation-negative patients with advanced lung adenocarcinoma. Further studies are needed to investigate whether this parameter may be a promising tool for stratifying such patients for risk-adapted therapies. PMID- 25783516 TI - Direct comparison of neck pinhole dual-tracer and dual-phase MIBI accuracies with and without SPECT/CT for parathyroid adenoma detection and localization. AB - INTRODUCTION: There is uncertainty about accuracies of dual-phase (DP) and dual tracer (DT) parathyroid scintigraphy with the newly added SPECT/CT. Although SPECT/CT was shown to be helpful in parathyroid adenoma (PA) localization, it may not have optimal resolution as pinhole. This study directly compared diagnostic accuracies and confidences of various imaging protocols on same patients. PATIENTS AND METHODS: One hundred fifty-five patients with pathologically confirmed diagnosis were included. Pinhole DP, pinhole DT, pinhole DP SPECT/CT, pinhole DT SPECT/CT, and SPECT/CT with only pinhole-delayed MIBI (D) were reviewed for accuracies and certainties of PA diagnosis/localization. Parathyroid adenomas were classified as clearly or unclearly distinguishable from thyroid. Furthermore, the contribution of pinhole DP to pinhole DT SPECT/CT was assessed. RESULTS: Of 153 PAs, the correct diagnosis/localization was significantly higher by pinhole DT SPECT/CT than pinhole DP SPECT/CT, SPECT/CT D, pinhole DT alone, and DP alone. Parathyroid adenomas were clearly more distinguished from thyroid in pinhole DT than DP with/without SPECT/CT. Consequently, PA diagnosis certainty was higher in pinhole DT than DP, whereas PA localization certainty was higher in both with SPECT/CT. In pinhole DT SPECT/CT, the pinhole DP addition confirmed diagnosis/localization of only 24 uncertain PAs. CONCLUSIONS: In this large patient group, the accuracy and certainty of PA diagnosis/localization were higher in pinhole DT SPECT/CT than all other parathyroid scintigraphy protocols. Pinhole DT better identified PA than pinhole DP, whereas SPECT/CT improved PA localization in both protocols. Pinhole DP showed limited contribution and thus should be only considered when PA diagnosis/localization is uncertain by pinhole DT SPECT/CT. PMID- 25783517 TI - Adolescent With 68Ga DOTATATE-Avid Vertebral Hemangioma Mimicking Metastasis in PET Imaging. AB - 68Ga DOTATATE PET/CT is a well-established method in the diagnostic workup of neuroendocrine tumors. We report the case of a 15-year-old adolescent boy with histologically proven appendiceal carcinoid tumor referred for 68Ga DOTATATE PET/CT to identify residual or metastatic disease. PET images showed increased tracer uptake in the body of T4 vertebra. This uptake could be misdiagnosed for bone metastasis, but CT characteristic appearance was in keeping with vertebral hemangioma. Both bone metastasis in carcinoid tumor and bone hemangiomas in adolescents are rare conditions, but the combined metabolic and morphological information on PET/CT can lead to the correct diagnosis. PMID- 25783518 TI - Use of SPECT/CT to confirm inconclusive gastric emptying scintigraphy results. AB - A 70-year-old man with cramping, abdominal pain, and diarrhea for 5 months after revision of a Nissen fundoplication underwent further evaluation with solid gastric emptying scintigraphy. On sequential planar images, we were uncertain if activity was present within the stomach or within loops of small bowel. SPECT/CT performed at 4 hours was used to localize the tracer, confirming its presence within the stomach. PMID- 25783519 TI - 11C-choline PET/CT identifies osteoblastic and osteolytic lesions in patients with metastatic prostate cancer. AB - AIM: The aim of this study was to compare C-choline PET/CT, prostate-specific antigen (PSA), PSA kinetics, and C-choline uptake in recurrent metastatic prostate cancer patients with osteoblastic and osteolytic bone metastases. PATIENTS AND METHODS: We retrospectively analyzed 140 patients with the following criteria: (a) positive bone lesions identified with C-choline PET/CT and validated as true positive by histology (14.2%), correlative imaging (33.4%), or clinical follow-up (52.4%); (b) after radical prostatectomy (67.9%) or primary radiotherapy (22.1%); (c) proven biochemical relapse with rising PSA levels; (d) no chemotherapy, zoledronic acid, or palliative bone external beam radiation therapy previously administrated during biochemical relapse; and (f) asymptomatic for bone pain. Lesions were categorized as osteoblastic, osteolytic, or bone marrow lesions. Patients were divided into osteoblastic and osteolytic patient groups. RESULTS: C-Choline PET/CT detected oligometastatic bone disease (1-3 lesions) in 98 (70%) of the 140 patients and multiple bone lesions in 42 (30%) of the 140 patients. By per-lesion analysis of 304 lesions, there were 184 osteoblastic, 99 osteolytic, and 21 bone marrow lesions.By per-patient analysis, 97 (69.3%) of the 140 patients were in the osteoblastic group, whereas 43 (30.7%) of the 140 patients were in the osteolytic group. Statistically significant differences in SUVmax (P < 0.001), fast PSA doubling time (P = 0.01), and PSA velocity (P = 0.01) were observed between osteoblastic (lower values) and osteolytic (higher values) groups. By multivariate analysis, fast PSA doubling time was a significant predictor for osteolytic lesions. CONCLUSIONS: We demonstrated differences in PSA kinetics and SUVmax between osteolytic and osteoblastic lesions. C-Choline PET/CT may identify patients that could benefit from early targeted therapies, depending on the type of bone lesions expressed. PMID- 25783520 TI - Economic choices of national planners who may be dealing with large numbers of orthopaedic procedures and the potential benefits to the system of those choices. PMID- 25783521 TI - Hippocampal sclerosis in the parkinsonism-dementia complex of Guam: quantitative examination of neurons, neurofibrillary tangles, and TDP-43 immunoreactivity in CA1. AB - The cornu ammonis 1 (CA1) area in the hippocampus of the parkinsonism-dementia complex (PDC) of Guam was examined quantitatively with special references to the number of neurons, intraneuronal (i) and extracellular (e) neurofibirillary tangles (NFTs), and TDP-43 (43-kDa trans-activation-responsive region DNA-binding protein)-immunopositive structures, in 24 Chamorro patients with PDC of Guam and seven control Chamorro Guamanians (both groups having no ischemic or anoxic complications). The results were that: (i) in the patients with mildly involved PDC, total numbers of neurons, iNFTs and eNFTs were almost the same as those of neurons of controls; (ii) in patients severely involved, total numbers of neurons, iNFTs and eNFTs decreased markedly; (iii) the decrease of the number of pyramidal neurons in CA1 with positive nuclear TDP-43 was intimately correlated with the decrease in total neuron numbers; (iv) whereas the numbers of neurons and TDP-43-immunopositive intracytoplasmic aggregation in the CA1 area were inversely correlated; and (v) depression of nuclear TDP-43 immuonostainability was not affected by the presence or absence of NFTs. In conclusion, hippocampal sclerosis exists in PDC; there is a possibility of elimination of eNFTs which appeared in the CA1 in patients with PDC and loss of the neurons correlates with disappearance of nuclear TDP-43, but not with appearance of intraneurocytoplasmic TDP-43 aggregation or iNFTs. PMID- 25783522 TI - The effects of smoked nicotine on measures of subjective states and hypothalamic pituitary-adrenal axis hormones in women during the follicular and luteal phases of the menstrual cycle. AB - OBJECTIVES: To determine the acute effects of cigarette smoking on hypothalamic pituitary-adrenal (HPA) axis hormones and subjective states as a function of the menstrual cycle in nicotine-dependent women. METHODS: Seventeen healthy nicotine dependent women were studied during the follicular and/or luteal phase of the menstrual cycle. Because of observation of a possible bimodal distribution of progesterone levels within the luteal phase group, we performed a set of a posteriori analyses. Therefore, we divided the luteal group into a low progesterone and a high progesterone groups. RESULTS: Smoked nicotine activated HPA, measured by adrenocorticotropin hormone (ACTH), cortisol, and dehydroepiandrosterone (DHEA) response and affected subjective states in both follicular and luteal phases, with increased "High," "Rush," and decreased "Craving." The HPA stimulation revealed a blunting of ACTH response. There was only modest evidence for a blunting of subjective state responses in the luteal phase. However, upon post hoc analyses, the high progesterone luteal group showed a marked blunting of measures of subjective states and a blunted ACTH response. Examining the association between hormone and measures of subjective states revealed tentative associations of ACTH stimulation with increased "Rush" and "Craving," and DHEA stimulation with increased "Craving." CONCLUSIONS: This pilot study suggests that menstrual cycle phase differences in progesterone levels may attenuate nicotine's addictive effects via diminution of its reinforcing properties and augmentation of its aversive effects interfering with the pleasure associated with cigarette smoking. PMID- 25783523 TI - A comparison of four embedded validity indices for the RBANS in a memory disorders clinic. AB - This examination of four embedded validity indices for the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) explores the potential utility of integrating cognitive and self-reported depressive measures. Examined indices include the proposed RBANS Performance Validity Index (RBANS PVI) and the Charleston Revised Index of Effort for the RBANS (CRIER). The CRIER represented the novel integration of cognitive test performance and depression self-report information. The sample included 234 patients without dementia who could be identified as having demonstrated either valid or invalid responding, based on standardized criteria. Sensitivity and specificity for invalid responding varied widely, with the CRIER emerging as the best all-around index (sensitivity = 0.84, specificity = 0.90, AUC = 0.94). Findings support the use of embedded response validity indices, and suggest that the integration of cognitive and self-report depression data may optimize detection of invalid responding among older Veterans. PMID- 25783524 TI - Molecular targeting in combination with platinum-based chemoradiotherapy in head and neck cancer treatment. AB - BACKGROUND: Significant evidence exists supporting the use of platinum-based chemoradiotherapy (CRT) as a primary curative approach in locoregionally advanced head and neck cancer (HNSCC). Despite these aggressive protocols, 70% of patients die within 5 years because of locoregional recurrence or distant metastasis. To increase the response and survival of patients with HNSCC, CRT has been combined with molecular agents targeting distinct kinases. METHODS: This study was performed using a systematic literature review. RESULTS: The effect of targeted therapy on patient survival in the context of CRT remains controversial, with toxicities tending to be more severe but still acceptable. CONCLUSION: Supplementing CRT with target therapeutics might only improve survival in some patients with locally advanced HNSCC. Therefore, future studies must address the underlying biological mechanisms that can have an impact on treatment response. Such knowledge is essential in order to facilitate the effective and personalized treatment of patients with locally advanced HNSCC by combining CRT and targeted therapy. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2173-E2181, 2016. PMID- 25783525 TI - Competitive exclusion and coexistence in an n-species Ricker model. AB - We analyse a discrete-time Ricker competition model with n competing species and give sufficient conditions, which depend on the competition coefficients only, for one species to survive (not necessarily at an equilibrium) and to drive all the other species to extinction. Our results complement and extend similar existing results from the literature. For the model reduced to three species ([Formula: see text]), we also investigate various scenarios under which all species coexist, in the sense that each species is robustly uniformly persistent. We provide a few numerical simulations to illustrate that coexistence does not necessarily mean convergence to the interior equilibrium, and that the interior dynamics can be quite complex. PMID- 25783526 TI - Computer simulation of improvements in hospital length of stay for rehabilitation patients. AB - OBJECTIVE: To estimate the potential improvement in acute and rehabilitation hospital length of stay for rehabilitation patients from hypothetical scenarios that address barriers to patient flow. DESIGN: Data about the duration of key processes for patients (n = 360) admitted to acute hospitals and subsequently transferred to inpatient rehabilitation in 2 wards in Melbourne, Australia were used to develop a computer simulation model. SUBJECTS: Simulated patients. METHODS: A computer model of length of stay was developed, validation checks performed and alternate care pathways simulated. RESULTS: Almost all scenarios resulted in significant changes in the length of stay compared with baseline. The effect size for the changes was typically small to medium. The duration of the rehabilitation discharge barriers showed significant changes in all hypothetical scenarios. The effect size was smaller when changes were made to a single barrier, but larger when multiple barriers were changed simultaneously. CONCLUSION: Health system modelling can provide information regarding potential improvements in length of stay from addressing barriers to patient flow affecting rehabilitation patients. This can inform reforms to models of care and assist with cost benefit analyses. PMID- 25783527 TI - Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC. AB - Hepatocellular carcinoma (HCC) has very poor prognosis. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including the Eag1 (ether a-go-go-1) potassium channel that is overexpressed in human HCC. Eag1 channels are regulated by cancer etiological factors and have been proposed as early tumor markers. Here, we found that HepG2 and HuH-7 HCC cells displayed Eag1 messenger RNA (mRNA) and protein expression, determined by real-time RT-PCR and immunochemistry, respectively. Astemizole inhibited human HCC cell proliferation (assessed by metabolic activity assay) and induced apoptosis (studied with flow cytometry) in both cell lines. The subcellular Eag1 protein localization was modified by astemizole in the HepG2 cells. The treatment with astemizole prevented diethylnitrosamine (DEN)-induced rat HCC development in vivo (followed by studying gamma-glutamyl transpeptidase (GGT) activity). The Eag1 mRNA and protein levels were increased in most DEN treated groups but decreased after astemizole treatment. GGT activity was decreased by astemizole. The Eag1 protein was detected in cirrhotic and dysplastic rat livers. Astemizole might have clinical utility for HCC prevention and treatment, and Eag1 channels may be potential early HCC biomarkers. These data provide significant basis to include astemizole in HCC clinical trials. PMID- 25783528 TI - Antagomir-1290 suppresses CD133+ cells in non-small cell lung cancer by targeting fyn-related Src family tyrosine kinase. AB - Cancer stem-like cells (CSLCs) are involved in cancer initiation, development, and metastasis, and microRNAs (miRNAs) play pivotal roles in regulating CSLCs. miRNA-based therapeutic strategy associated with CSLCs might promise potential new therapeutic approaches. In the present study, we found that miR-1290 was increased in CD133(+) cells. Antagomir-1290 significantly suppressed tumor volume and weight initiated by CD133(+) cells in vivo. Furthermore, antagomir-1290 significantly inhibited the proliferation, clonogenicity, invasion, and migration of CD133(+) cells by targeting fyn-related Src family tyrosine kinase. These findings provide insights into the clinical prospect of miR-1290-based therapies for non-small cell lung cancer. PMID- 25783529 TI - Stanniocalcin-1, a new biomarker of glioma progression, is associated with prognosis of patients. AB - Stanniocalcin-1 (STC1) is a secreted glycoprotein hormone and highly expressed in various types of human malignancies. Although evidence points to the role of STC1 in human cancers, the clinical significance of STC1 expression in glioma has not been established. Here, we investigated the relationship between STC1 expression and clinicopathological significance in glioma. In our study, we selected 60 cases of different grades glioma tissues to detect the expression of STC1. Data showed that the mRNA and protein levels of STC1 in high-grade glioma tissues were significantly higher than that in low-grade tissues. The results of double immunofluorescent staining disclosed STC1 distribution in vascular endothelial cells and the cytoplasm in high-grade glioma, but almost distributed only in vascular endothelial cells in low-grade glioma. By immunohistochemistry, we got the same results and the expression of STC1 has significant difference in high grade gliomas and low-grade gliomas. Furthermore, the results of Kaplan-Meier analysis indicated that cases with high STC1expression had significantly worse overall survival than those with low level of STC1. These results suggested that STC1 may be a valuable biomarker in diagnosing malignant degree of glioma and evaluating prognostic following surgery. Next, we would study the pathophysiological mechanism of STC1 in glioma. PMID- 25783557 TI - A novel susceptibility locus for Takayasu arteritis in the IL12B region can be a genetic marker of disease severity. AB - Takayasu arteritis (TAK) is an acute and chronic vasculitis of unknown etiology. Recently, our group reported that SNP rs6871626 in the IL12B region had significant association with disease susceptibility to TAK. However, association of the SNP with clinical characteristics of TAK has yet to be determined. Therefore, we assessed whether this SNP was associated with TAK disease severity as represented by early onset and/or refractoriness to medical therapy. A total of 90 patients were genotyped for rs6871626 and their clinical charts were reviewed retrospectively. By examining the relationship between genotype and clinical profiles of patients, we found a strong association between the number of risk alleles and the frequency of severe cases as defined by (1) age at onset <20 years old, (2) steroid resistance, and/or (3) a relapse of disease [p = 0.03; odds ratio 3.75 (95 % confidence interval 1.13-13.5)]. Thus, our study points to potential diagnostic use of SNP rs6871626 for predicting disease severity of TAK, with the goal of genotyping-oriented therapy in the near future. PMID- 25783558 TI - Controlled release of vascular endothelial growth factor from spray-dried alginate microparticles in collagen-hydroxyapatite scaffolds for promoting vascularization and bone repair. AB - A major limitation with current tissue-engineering approaches is creating functionally vascularized constructs that can successfully integrate with the host; this often leads to implant failure, due to avascular necrosis. In order to overcome this, the objective of the present work was to develop a method to incorporate growth factor-eluting alginate microparticles (MPs) into freeze dried, collagen-based scaffolds. A collagen-hydroxyapatite (CHA) scaffold, previously optimized for bone regeneration, was functionalized for the sustained delivery of an angiogenic growth factor, vascular endothelial growth factor (VEGF), with the aim of facilitating angiogenesis and enhancing bone regeneration. VEGF was initially encapsulated in alginate MPs by spray-drying, producing particles of < 10 um in diameter. This process was found to effectively encapsulate and control VEGF release while maintaining its stability and bioactivity post-processing. These VEGF-MPs were then incorporated into CHA scaffolds, leading to homogeneous distribution throughout the interconnected scaffold pore structure. The scaffolds were capable of sustained release of bioactive VEGF for up to 35 days, which was proficient at increasing tubule formation by endothelial cells in vitro. When implanted in vivo in a rat calvarial defect model, this scaffold enhanced vessel formation, resulting in increased bone regeneration compared to empty-defect and VEGF-free scaffolds. This biologically functionalized scaffold, composed entirely of natural-based materials, may offer an ideal platform to promote angiogenesis and tissue regeneration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25783560 TI - Quantum interference induced photon blockade in a coupled single quantum dot cavity system. AB - We propose an experimental scheme to implement a strong photon blockade with a single quantum dot coupled to a nanocavity. The photon blockade effect can be tremendously enhanced by driving the cavity and the quantum dot simultaneously with two classical laser fields. This enhancement of photon blockade is ascribed to the quantum interference effect to avoid two-photon excitation of the cavity field. Comparing with Jaynes-Cummings model, the second-order correlation function at zero time delay g((2))(0) in our scheme can be reduced by two orders of magnitude and the system sustains a large intracavity photon number. A red (blue) cavity-light detuning asymmetry for photon quantum statistics with bunching or antibunching characteristics is also observed. The photon blockade effect has a controllable flexibility by tuning the relative phase between the two pumping laser fields and the Rabi coupling strength between the quantum dot and the pumping field. Moreover, the photon blockade scheme based on quantum interference mechanism does not require a strong coupling strength between the cavity and the quantum dot, even with the pure dephasing of the system. This simple proposal provides an effective way for potential applications in solid state quantum computation and quantum information processing. PMID- 25783561 TI - Variations in albumin use in patients with cirrhosis: An AASLD members survey. PMID- 25783559 TI - White matter integrity of the cerebellar peduncles as a mediator of effects of prenatal alcohol exposure on eyeblink conditioning. AB - Fetal alcohol spectrum disorders (FASD) are characterized by a range of neurodevelopmental deficits that result from prenatal exposure to alcohol. These can include cognitive, behavioural, and neurological impairment, as well as structural and functional brain damage. Eyeblink conditioning (EBC) is among the most sensitive endpoints affected in FASD. The cerebellar peduncles, large bundles of myelinated nerve fibers that connect the cerebellum to the brainstem, constitute the principal white matter element of the EBC circuit. Diffusion tensor imaging (DTI) is used to assess white matter integrity in fibre pathways linking brain regions. DTI scans of 54 children with FASD and 23 healthy controls, mean age 10.1 +/- 1.0 years, from the Cape Town Longitudinal Cohort were processed using voxelwise group comparisons. Prenatal alcohol exposure was related to lower fractional anisotropy (FA) bilaterally in the superior cerebellar peduncles and higher mean diffusivity (MD) in the left middle peduncle, effects that remained significant after controlling for potential confounding variables. Lower FA and higher MD in these regions were associated with poorer EBC performance. Moreover, effects of alcohol exposure on EBC decreased significantly after inclusion of these DTI measures in regression models, suggesting that these white matter deficits partially mediate the relation of prenatal alcohol exposure to EBC. The associations of greater alcohol consumption with these DTI measures are largely attributable to greater radial diffusivity, possibly indicating poorer myelination. Thus, these data suggest that fetal alcohol-related deficits in EBC are attributable, in part, to poorer myelination in key regions of the cerebellar peduncles. PMID- 25783562 TI - Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis. AB - Neutrophil is a key cell in pathophysiology of granulomatosis with polyangiitis. Recently, neutrophil extracellular traps were described in this disease. Mitochondrial DNA is also released during traps formation. We measured circulating cell-free mitochondrial and genomic DNA in serum of patients with granulomatosis with polyangiitis. Subjects with the disease (14 active and 11 in remission stage) and 10 healthy controls were enrolled. Quantitative real-time polymerase chain reaction (PCR) was used to measure 79 base pairs (bp) and 230 bp mtDNA fragments. Alu repeats were quantified to evaluate abundance of nuclear DNA in serum at the presence of plasmid control. Both fragments of mtDNA (79 bp and 230 bp) and genomic DNA were elevated significantly in granulomatosis with polyangiitis compared to controls. Only the shorter 79 bp mtDNA correlated with active stage of granulomatosis with polyangiitis and clinical symptoms. A mechanism of extracellular release of mitochondrial DNA accompanies the active stage of the disease. Circulating mtDNA is extremely high in untreated patients. This suggests that biomarker properties of mtDNA are useful for monitoring of treatment. PMID- 25783563 TI - Purulent pericardial effusion and mycotic pseudoaneurysm following insertion of a bare metal stent. AB - A 65-year-old male was diagnosed with purulent pericarditis, caused by Staphylococcus aureus five weeks after bare metal stenting for a 90% stenosis of the right coronary artery ostium. Subsequently, he developed a pseudoaneurysm in the right coronary sinus of Valsalva (CSV) requiring surgical intervention during the treatment of the pericarditis. Bacteremia after percutaneous coronary intervention (PCI) occurs in < 1% of patients and usually has insignificant clinical sequelae. We present an infected coronary bare metal stent of the proximal right coronary artery after PCI that resulted in a purulent pericardial effusion and mycotic pseudoaneurysm of the right coronary sinus of Valsalva (CSV). The patient successfully underwent surgical treatment. PMID- 25783565 TI - Achieving a tissue diagnosis in PS3 patients with advanced lung cancer: what are the safety and diagnostic outcomes with EBUS? PMID- 25783564 TI - Stem cells from human amniotic fluid exert immunoregulatory function via secreted indoleamine 2,3-dioxygenase1. AB - Although human amniotic fluid does contain different populations of foetal derived stem cells, scanty information is available on the stemness and the potential immunomodulatory activity of in vitro expanded, amniotic fluid stem cells. By means of a methodology unrequiring immune selection, we isolated and characterized different stem cell types from second-trimester human amniotic fluid samples (human amniotic fluid stem cells, HASCs). Of those populations, one was characterized by a fast doubling time, and cells were thus designated as fHASCs. Cells maintained their original phenotype under prolonged in vitro passaging, and they were able to originate embryoid bodies. Moreover, fHASCs exhibited regulatory properties when treated with interferon (IFN)-gamma, including induction of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). On coculture with human peripheral blood mononuclear cells, IFN-gamma treated fHASCs caused significantly decreased T-cell proliferation and increased frequency in CD4(+) CD25(+) FOXP3(+) regulatory T cells. Both effects required an intact IDO1 function and were cell contact-independent. An unprecedented finding in our study was that purified vesicles from IFN-gamma-treated fHASCs abundantly expressed the functional IDO1 protein, and those vesicles were endowed with an fHASC-like regulatory function. In vivo, fHASCs were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. This was concurrent with the expansion of CD4(+) CD25(+) Foxp3(+) T cells in graft-draining lymph nodes from recipient mice. Thus fHASCs, or vesicles thereof, may represent a novel opportunity for immunoregulatory maneuvers both in vitro and in vivo. PMID- 25783566 TI - The coupled atom transistor. AB - We describe the first implementation of a coupled atom transistor where two shallow donors (P or As) are implanted in a nanoscale silicon nanowire and their electronic levels are controlled with three gate voltages. Transport spectroscopy through these donors placed in series is performed both at zero and microwave frequencies. The coherence of the charge transfer between the two donors is probed by Landau-Zener-Stuckelberg interferometry. Single-charge transfer at zero bias (electron pumping) has been performed and the crossover between the adiabatic and non-adiabatic regimes is studied. PMID- 25783567 TI - Structure and dynamics of room temperature ionic liquids with bromide anion: results from 81Br NMR spectroscopy. AB - We report the results of a comprehensive (81)Br NMR spectroscopic study of the structure and dynamics of two room temperature ionic liquids (RTILs), 1-butyl-3 methylimidazolium bromide ([C(4)mim]Br) and 1-butyl-2,3-dimethylimidazolium bromide ([C(4)C(1)mim]Br), in both liquid and crystalline states. NMR parameters in the gas phase are also simulated for stable ion pairs using quantum chemical calculations. The combination of (81)Br spin-lattice and spin-spin relaxation measurements in the motionally narrowed region of the stable liquid state provides information on the correlation time of the translational motion of the cation. (81) Br quadrupolar coupling constants (C(Q)) of the two RTILs were estimated to be 6.22 and 6.52 MHz in the crystalline state which were reduced by nearly 50% in the liquid state, although in the gas phase, the values are higher and span the range of 7-53 MHz depending on ion pair structure. The C(Q) can be correlated with the distance between the cation-anion pairs in all the three states. The (81)Br C(Q) values of the bromide anion in the liquid state indicate the presence of some structural order in these RTILs, the degree of which decreases with increasing temperature. On the other hand, the ionicity of these RTILs is estimated from the combined knowledge of the isotropic chemical shift and the appropriate mean energy of the excited state. [C(4)C(1)mim]Br has higher ionicity than [C(4)mim]Br in the gas phase, while the situation is reverse for the liquid and the crystalline states. PMID- 25783568 TI - From raw material to dish: pasta quality step by step. AB - Pasta is a traditional Italian cereal-based food that is popular worldwide because of its convenience, versatility, sensory and nutritional value. The aim of this review is to present a step-by-step guide to facilitate the understanding of the most important events that can affect pasta characteristics, directing the reader to the appropriate production steps. Owing to its unique flavor, color, composition and rheological properties, durum wheat semolina is the best raw material for pasta production. Although pasta is traditionally made from only two ingredients, sensory quality and chemical/physical characteristics of the final product may vary greatly. Starting from the same ingredients, there are a lot of different events in each step of pasta production that can result in the development of varieties of pasta with different characteristics. In particular, numerous studies have demonstrated the importance of temperature and humidity conditions of the pasta drying operation as well as the significance of the choice of raw material and operating conditions on pasta quality. PMID- 25783595 TI - Kohler disease: an infrequent or underdiagnosed cause of child's limping? AB - Kohler disease (KD) is the osteochondrosis of the tarsal navicular bone of the young children, which is a self-limited condition. Typically the child reports pain with mechanical characteristics in the medial region of the foot, however, intermittent or continuous limping may be the only clinical manifestation, which delays the diagnosis and consequently exposes to unnecessary tests and treatments. We describe a bilateral KD whose clinical manifestation was unilateral limping with 4 months evolution. The radiologic evaluation showed flattening, sclerosis and irregular rarefaction of both navicular bones. Claudication persisted for four weeks, after which, the child remains asymptomatic. PMID- 25783596 TI - Synchronous reconstruction of bilateral osteoradionecrosis of the mandible using a single fibular osteocutaneous flap in patients with nasopharyngeal carcinoma. AB - BACKGROUND: The reconstruction of bilateral osteoradionecrosis (ORN) of mandibular defects using a single free bone flap is rarely performed because extensively radiated neck tissue with severe fibrosis is usually unsuitable for vascularized reconstruction. METHODS: Thirty-one patients with nasopharyngeal carcinoma (NPC) underwent bilateral reconstruction of advanced ORN in the mandible using a single fibular osteocutaneous flap. Clinical factors associated with the operation were assessed, including classification of mandible defects, types of recipient vessels, perioperative complications, and postoperative outcomes. RESULTS: All of the fibular osteocutaneous flaps survived completely, with the exception of 1 inner skin paddle that presented partial necrosis in a reconstruction of through-and-through defects. All patients experienced an improvement in cosmetic results 6 months after the reconstruction, whereas 23 patients experienced improved mouth opening compared to the preoperative condition. CONCLUSION: Advanced bilateral ORN in patients with NPC could be synchronously reconstructed with a single fibular osteocutaneous flap. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E-E, 2016. PMID- 25783594 TI - CHD2 variants are a risk factor for photosensitivity in epilepsy. AB - Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 * 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 * 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability. PMID- 25783597 TI - Infantile-onset saccade initiation delay (congenital ocular motor apraxia). AB - Infantile-onset saccade initiation delay, also known as congenital ocular motor apraxia, typically presents in early infancy with horizontal head thrusts once head control is achieved. Defective initiation of horizontal saccades and saccade hypometria with normal saccadic velocity are characteristic findings. Isolated impairment of vertical saccades is rare. Impaired smooth ocular pursuit may be seen. Other relatively common features include developmental delay, hypotonia, ataxia, or clumsiness. Brain MRI may be normal or show a diverse range of abnormalities, most commonly involving the cerebellum. Defective slow phases of the optokinetic response are commonly associated with brain MRI abnormalities. Isolated defect of vertical saccade initiation may indicate supratentorial brain abnormalities on MRI. Joubert syndrome, a developmental midbrain-hindbrain malformation, and ataxia telangiectasia are both commonly associated with defective volitional and reflexive saccade initiation, saccade hypometria, and head thrusts. Both horizontal and vertical saccades are impaired in these two disorders. PMID- 25783599 TI - Biointerphases in focus on bio surface analysis. PMID- 25783598 TI - Community-based palliative care is associated with reduced emergency department use by people with dementia in their last year of life: A retrospective cohort study. AB - OBJECTIVE: To describe patterns in the use of hospital emergency departments in the last year of life by people who died with dementia and whether this was modified by use of community-based palliative care. DESIGN: Retrospective population-based cohort study of people in their last year of life. Time-to-event analyses were performed using cumulative hazard functions and flexible parametric proportional hazards regression models. SETTING/PARTICIPANTS: All people living in Western Australia who died with dementia in the 2-year period 1 January 2009 to 31 December 2010 (dementia cohort; N = 5261). A comparative cohort of decedents without dementia who died from other conditions amenable to palliative care (N = 2685). RESULTS: More than 70% of both the dementia and comparative cohorts attended hospital emergency departments in the last year of life. Only 6% of the dementia cohort used community-based palliative care compared to 26% of the comparative cohort. Decedents with dementia who were not receiving community based palliative care attended hospital emergency departments more frequently than people receiving community-based palliative care. The magnitude of the increased rate of emergency department visits varied over the last year of life from 1.4 (95% confidence interval: 1.1-1.9) times more often in the first 3 months of follow-up to 6.7 (95% confidence interval: 4.7-9.6) times more frequently in the weeks immediately preceding death. CONCLUSIONS: Community-based palliative care of people who die with or of dementia is relatively infrequent but associated with significant reductions in hospital emergency department use in the last year of life. PMID- 25783601 TI - Merlin Regulates Epithelial-to-Mesenchymal Transition of ARPE-19 Cells via TAK1 p38MAPK-Mediated Activation. AB - PURPOSE: The purpose of this study was to investigate the function of merlin, which is a binding partner of the hyaluronan receptor CD44, during the epithelial to-mesenchymal transition (EMT) of human retinal pigment epithelium (ARPE-19) cells. METHODS: Human retinal pigment epithelium cells were stimulated with TNF alpha and treated using epithelial-to-mesenchymal-transition inhibitors (a dynamin inhibitor or transforming growth factor-beta-activated kinase 1 [TAK1] inhibitor). Levels of protein expression were assessed by immunoblot analysis, and localization of the relevant proteins was determined by immunofluorescence microscopy. Cell proliferation was evaluated by bromodeoxyuridine (BrdU) incorporation assays. All experiments were performed in serum-free medium. RESULTS: Tumor necrosis factor-alpha treatments downregulated the expression of merlin and led to the dissociation of CD44 and merlin. The ezrin-radixin-moesin (ERM) proteins were phosphorylated, and hyaluronan endocytosis was accelerated in merlin small interfering RNA (siMerlin)-transfected cells. Treatment with the endocytosis inhibitor dynasore blocked hyaluronan endocytosis, whereas treatment with TNF-alpha induced mesenchymal phenotypes and downregulation of merlin. Additionally, siMerlin transfection promoted p38MAPK phosphorylation, which was inhibited not only by TAK1 inhibitor treatment but also by TAK1 small interfering RNA (siRNA, siTAK1) transfection. The increased level of BrdU incorporation in siMerlin cells was reduced by additional siTAK1 transfection. Furthermore, TNF alpha-induced mesenchymal differentiation and high motility were also inhibited by TAK1 inhibitor treatment and by siTAK1 transfection. CONCLUSIONS: Our findings demonstrated that merlin exerts inhibitory effects on TNF-alpha-induced EMT by regulating hyaluronan endocytosis and the TAK1-p38MAPK signaling pathway. The proliferative and mesenchymal characteristics of RPE cells play important roles in the development of intraocular fibrotic disorders, such as proliferative vitreoretinopathy (PVR), and our findings provide new therapeutic strategies to prevent the development of PVR. PMID- 25783602 TI - Relationship Between Optic Nerve Protrusion Measured by OCT and MRI and Papilledema Severity. AB - PURPOSE: To develop measures of optic nerve protrusion length (NPL) from optical coherence tomography (OCT) and magnetic resonance imagining (MRI) and compare these measures with papilledema severity in idiopathic intracranial hypertension (IIH). METHODS: Optical coherence tomography and MRI scans were obtained from 11 newly diagnosed untreated IIH patients (30 +/- 10 years; body mass index [BMI] 36 +/- 4 kg/m2). Optic nerve protrusion length was measured for each eye using OCT and MRI independently. The relationship between the NPL measures and their association with the Frisen scale for papilledema severity were assessed. Two different OCT-based measures of NPL were derived to assess the influence of the retinal thickness on the association with papilledema severity. Additional OCT scans from 11 healthy subjects (38 +/- 7 years) were analyzed to establish reliability of the NPL measurement. RESULTS: Optical coherence tomography and MRI measurements of NPL were significantly linearly correlated (R = 0.79, P < 0.0001). Measurements of NPL from OCT and MRI were significantly associated with Frisen papilledema grade (P < 0.0001). Mean OCT measurement of NPL in the papilledema cohort was significantly larger than in the healthy cohort (0.62 +/- 0.24 vs. 0.09 +/- 0.03 mm, P < 0.0001). CONCLUSIONS: Significant linear correlation between OCT and MRI measurements of NPL supports the reliability of the OCT-based measurements of NPL in papilledema. Significant association between the papilledema grade and OCT- and MRI-based measurements of NPL highlights the potential of NPL as an objective and more sensitive marker of papilledema severity than the Frisen scale. PMID- 25783603 TI - Role of neuronal nitric oxide synthase in regulating retinal blood flow during flicker-induced hyperemia in cats. AB - PURPOSE: To investigate how neuronal nitric oxide synthase (nNOS) contributes to regulation of the retinal circulation during rest and flicker stimulation in cats. METHODS: Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. After intravitreal injections of Nomega Nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, and Nomega propyl-L-arginine (L-NPA), a selective nNOS inhibitor, we continuously monitored the retinal circulation without any perturbations for 2 hours. We then examined the changes in the RBF in response to 16-Hz flicker stimuli for 3 minutes at 2 hours after intravitreal injection of phosphate-buffered saline (PBS) as a control, L-NAME, L-NPA, and thromboxane A2 (TXA2) analogue U46619 as a basal tone adjusted control. RESULTS: After intravitreal injection of L-NAME and L-NPA, the baseline RBF decreased gradually in a dose-dependent manner. In the PBS group, the RBF increased gradually and reached a maximal level after 2 to 3 minutes of flicker stimuli. After 3 minutes of 16-Hz flicker stimuli, the RBF increased by 53.5% +/- 3.4% compared with baseline. In the L-NAME and L-NPA groups, the increases in RBF during flicker stimulation were attenuated significantly compared with the PBS group. In the TXA2 group, the reduction in the flicker induced increase in RBF was comparable to that in the PBS group. CONCLUSIONS: The current results suggested that increased RBF in response to flicker stimulation may be mediated by nitric oxide (NO) production via nNOS activation. PMID- 25783605 TI - Scleral Thickness in Chinese Eyes. AB - PURPOSE: We measured scleral thickness in eyes of Chinese, and assessed interregional differences and associations with age and axial length. METHODS: Using light microscopy, we histomorphometrically measured scleral thickness at various locations in eyeballs from Chinese patients that had been enucleated due to retinoblastoma, uveal melanoma, or absolute painful glaucoma. RESULTS: The study included 281 globes from patients with a mean age of 24.8 +/- 23.1 years (range, 1-83 years) and mean axial length of 24.3 +/- 3.9 mm (range, 17.0-35.7 mm). In multivariate analysis in children aged <=2 years, thicker posterior scleral thickness was marginally significantly associated with older age (P = 0.07; standardized correlation coefficient beta, 0.21; correlation coefficient B, 62.2; 95% confidence interval [CI], -4.3,128.8) after adjusting for shorter axial length (P = 0.01). In participants aged >=5 years, larger posterior scleral thickness was significantly associated only with shorter axial length (P < 0.001; beta, -0.49; B, -24.1; 95% CI, -30.6,-17.6), but not with age (P = 0.93). The ratio of posterior scleral thickness to scleral thickness in the pars plana region decreased significantly with increasing axial length. The correlation coefficients were higher for the ratio of scleral thickness posterior pole/pars plana region than for posterior pole/ora serrata, posterior pole/equator, or posterior pole/midpoint posterior pole to equator. Scleral thickness measurements were not significantly (all P > 0.10) associated with adult glaucoma. CONCLUSIONS: Scleral thickness increased up to an age of 2 years, while afterwards scleral thickness was independent of age and decreased with longer axial length. Differences in the associations between the regional scleral thickness ratios and axial length suggested a scleral thinning taking place in axially elongated eyes predominantly in the posterior globe segment. PMID- 25783604 TI - Ornithine-delta-Aminotransferase Inhibits Neurogenesis During Xenopus Embryonic Development. AB - PURPOSE: In humans, deficiency of ornithine-delta-aminotransferase (OAT) results in progressive degeneration of the neural retina (gyrate atrophy) with blindness in the fourth decade. In this study, we used the Xenopus embryonic developmental model to study functions of the OAT gene on embryonic development. METHODS: We cloned and sequenced full-length OAT cDNA from Xenopus oocytes (X-OAT) and determined X-OAT expression in various developmental stages of Xenopus embryos and in a variety of adult tissues. The phenotype, gene expression of neural developmental markers, and enzymatic activity were detected by gain-of-function and loss-of-function manipulations. RESULTS: We showed that X-OAT is essential for Xenopus embryonic development, and overexpression of X-OAT produces a ventralized phenotype characterized by a small head, lack of axial structure, and defective expression of neural developmental markers. Using X-OAT mutants based on mutations identified in humans, we found that substitution of both Arg 180 and Leu 402 abrogated both X-OAT enzymatic activity and ability to modulate the developmental phenotype. Neurogenesis is inhibited by X-OAT during Xenopus embryonic development. CONCLUSIONS: Neurogenesis is inhibited by X-OAT during Xenopus embryonic development, but it is essential for Xenopus embryonic development. The Arg 180 and Leu 402 are crucial for these effects of the OAT molecule in development. PMID- 25783606 TI - Viral Vector Effects on Exoenzyme C3 Transferase-Mediated Actin Disruption and on Outflow Facility. AB - PURPOSE: Purified Clostridium botulinum exoenzyme C3 transferase (C3) effects on the actin cytoskeleton in human trabecular meshwork cells (HTM) and on the outflow facility response in monkey organ-cultured anterior segments (MOCAS) were determined in the presence or absence of viral vectors. METHODS: Human adenovirus type 5 (AdV) and feline immunodeficiency virus (FIV) vectors were produced using kits. Cell soluble purified C3 (C3cs) was purchased commercially. Recombinant C3 (C3rec) cDNA was overexpressed in Escherichia coli and purified. The HTM cells were incubated with up to 10 MUg/mL C3cs or with 5 MUg of C3rec and/or viral vector (multiplicity of infection [MOI] = 25). Cells then were fixed and stained for actin. Outflow facility in MOCAS was measured at baseline, 4 hours, 24 hours, and 3 to 4 days following bolus injection of AdV (1.6 * 107 transducing units) and/or 2.5 MUg C3rec. RESULTS: The HTM cells treated for 4 hours with C3cs (all doses) or for 24 hours with C3rec developed a rounded morphology and lost stress fibers. Cells transduced with vectors alone showed no changes at any time point. Cells exposed to C3rec and cotransduced with either viral vector showed significant disruption of the actin cytoskeleton within 4 hours after exposure, which persisted at 24 hours. In MOCAS, the AdV vector alone had no effect on outflow facility, but enhanced the response to C3rec at 4 hours. CONCLUSIONS: Coadministration of viral vectors enhances the ability of C3 transferase to disrupt actin stress fiber formation in HTM cells and increase outflow facility in MOCAS. Viral vectors potentially could be used to increase the bioavailability of proteins for cells that are difficult to transfect. PMID- 25783608 TI - Macular Pigment and Visual Performance in Low-Light Conditions. AB - PURPOSE: By reducing rod intrusion and improving efficiency of neural signaling throughout the visual system, macular pigment (MP) could improve many aspects of visual performance in low-light level conditions. Our study examined this possibility for a variety of visual performance parameters, including spatial resolution, dark adaptation kinetics, and color detection. METHODS: Twenty-seven subjects participated in the study. Spatial profiles of MP optical density (MPOD) were determined by using heterochromatic flicker photometry. Mesopic- and scotopic-adaptation level experiments were conducted in Maxwellian view. RESULTS: Subjects with higher MPOD required significantly lower contrast to detect the mesopic-level resolution targets; this effect became stronger with increasing spatial frequency. Dark adaptation recovery times were significantly faster as a function of MPOD (by nearly 2 minutes for the lowest mesopic-level task [high versus low MPOD]; P < 0.001). Absolute scotopic thresholds were also significantly associated with MPOD (P < 0.001). Macular pigment optical density was inversely associated with detection of yellow (P < 0.001), and, paradoxically, approached a significant positive correlation with the detection of blue (P = 0.06). CONCLUSIONS: Macular pigment appears to enhance visual function in low-light conditions. Based on the results of this study, it can be said that MP extends the range of foveal vision into lower light. Additionally, MP appears to enhance dark adaptation kinetics, which suggests that increased MPOD leads to more efficient photopigment regeneration. The findings of the color detection portion of the study are suggestive of an active compensatory mechanism that offsets absorption by MP in order to maintain normal color perception. PMID- 25783607 TI - A High-Throughput Drug Screening Strategy for Detecting Rhodopsin P23H Mutant Rescue and Degradation. AB - PURPOSE: Inherent instability of the P23H mutant opsin accounts for approximately 10% of autosomal dominant retinitis pigmentosa cases. Our purpose was to develop an overall set of reliable screening strategies to assess if either stabilization or enhanced degradation of mutant rhodopsin could rescue rod photoreceptors expressing this mutant protein. These strategies promise to reveal active compounds and clarify molecular mechanisms of biologically important processes, such as inhibition of target degradation or enhanced target folding. METHODS: Cell-based bioluminescence reporter assays were developed and validated for high throughput screening (HTS) of compounds that promote either stabilization or degradation of P23H mutant opsin. Such assays were further complemented by immunoblotting and image-based analyses. RESULTS: Two stabilization assays of P23H mutant opsin were developed and validated, one based on beta-galactosidase complementarity and a second assay involving bioluminescence resonance energy transfer (BRET) technology. Moreover, two additional assays evaluating mutant protein degradation also were employed, one based on the disappearance of luminescence and another employing the ALPHA immunoassay. Imaging of cells revealed the cellular localization of mutant rhodopsin, whereas immunoblots identified changes in the aggregation and glycosylation of P23H mutant opsin. CONCLUSIONS: Our findings indicate that these initial HTS and following assays can identify active therapeutic compounds, even for difficult targets such as mutant rhodopsin. The assays are readily scalable and their function has been proven with model compounds. High-throughput screening, supported by automated imaging and classic immunoassays, can further characterize multiple steps and pathways in the biosynthesis and degradation of this essential visual system protein. PMID- 25783610 TI - A robust and efficient cobalt molecular catalyst for CO2 reduction. AB - Visible-light driven CO2 reduction is considered to be a sustainable energy source. However, earth-abundant molecular catalysts with high efficiency and robustness towards solar-driven CO2 reduction are limited. Herein, we report a cobalt complex supported by a tetradentate tripodal ligand, which demonstrates catalytic solar-driven CO2 reduction with TON(CO) > 900 over 70 h in the presence of a photosensitizer. PMID- 25783609 TI - The Inferior Whorl For Detecting Diabetic Peripheral Neuropathy Using Corneal Confocal Microscopy. AB - PURPOSE: In vivo corneal confocal microscopy (CCM) is increasingly used as a surrogate endpoint in studies of diabetic polyneuropathy (DPN). However, it is not clear whether imaging the central cornea provides optimal diagnostic utility for DPN. Therefore, we compared nerve morphology in the central cornea and the inferior whorl, a more distal and densely innervated area located inferior and nasal to the central cornea. METHODS: A total of 53 subjects with type 1/type 2 diabetes and 15 age-matched control subjects underwent detailed assessment of neuropathic symptoms (NPS), deficits (neuropathy disability score [NDS]), quantitative sensory testing (vibration perception threshold [VPT], cold and warm threshold [CT/WT], and cold- and heat-induced pain [CIP/HIP]), and electrophysiology (sural and peroneal nerve conduction velocity [SSNCV/PMNCV], and sural and peroneal nerve amplitude [SSNA/PMNA]) to diagnose patients with (DPN+) and without (DPN-) neuropathy. Corneal nerve fiber density (CNFD) and length (CNFL) in the central cornea, and inferior whorl length (IWL) were quantified. RESULTS: Comparing control subjects to DPN- and DPN+ patients, there was a significant increase in NDS (0 vs. 2.6 +/- 2.3 vs. 3.3 +/- 2.7, P < 0.01), VPT (V; 5.4 +/- 3.0 vs. 10.6 +/- 10.3 vs. 17.7 +/- 11.8, P < 0.01), WT ( degrees C; 37.7 +/- 3.5 vs. 39.1 +/- 5.1 vs. 41.7 +/- 4.7, P < 0.05), and a significant decrease in SSNCV (m/s; 50.2 +/- 5.4 vs. 48.4 +/- 5.0 vs. 39.5 +/- 10.6, P < 0.05), CNFD (fibers/mm2; 37.8 +/- 4.9 vs. 29.7 +/- 7.7 vs. 27.1 +/- 9.9, P < 0.01), CNFL (mm/mm2; 27.5 +/- 3.6 vs. 24.4 +/- 7.8 vs. 20.7 +/- 7.1, P < 0.01), and IWL (mm/mm2; 35.1 +/- 6.5 vs. 26.2 +/- 10.5 vs. 23.6 +/- 11.4, P < 0.05). For the diagnosis of DPN, CNFD, CNFL, and IWL achieved an area under the curve (AUC) of 0.75, 0.74, and 0.70, respectively, and a combination of IWL-CNFD achieved an AUC of 0.76. CONCLUSIONS: The parameters of CNFD, CNFL, and IWL have a comparable ability to diagnose patients with DPN. However, IWL detects an abnormality even in patients without DPN. Combining IWL with CNFD may improve the diagnostic performance of CCM. PMID- 25783611 TI - Illiterate to literate: behavioural and cerebral changes induced by reading acquisition. AB - The acquisition of literacy transforms the human brain. By reviewing studies of illiterate subjects, we propose specific hypotheses on how the functions of core brain systems are partially reoriented or 'recycled' when learning to read. Literacy acquisition improves early visual processing and reorganizes the ventral occipito-temporal pathway: responses to written characters are increased in the left occipito-temporal sulcus, whereas responses to faces shift towards the right hemisphere. Literacy also modifies phonological coding and strengthens the functional and anatomical link between phonemic and graphemic representations. Literacy acquisition therefore provides a remarkable example of how the brain reorganizes to accommodate a novel cultural skill. PMID- 25783612 TI - The neuroscience of mindfulness meditation. AB - Research over the past two decades broadly supports the claim that mindfulness meditation - practiced widely for the reduction of stress and promotion of health - exerts beneficial effects on physical and mental health, and cognitive performance. Recent neuroimaging studies have begun to uncover the brain areas and networks that mediate these positive effects. However, the underlying neural mechanisms remain unclear, and it is apparent that more methodologically rigorous studies are required if we are to gain a full understanding of the neuronal and molecular bases of the changes in the brain that accompany mindfulness meditation. PMID- 25783613 TI - Tunable photochromism in the robust dithienylethene-containing phospholes: design, synthesis, characterization, electrochemistry, photophysics, and photochromic studies. AB - A series of dithienylethene-containing phosphole derivatives has been designed, synthesized and characterized. One of the compounds has been characterized by X ray crystallography. Upon photoexcitation, the compounds exhibit drastic color changes, ascribed to the reversible photochromic behavior. Their photochromic, photophysical and electrochemical properties have been studied. They show photochromic reactivities with high photocyclization quantum yields. Their photophysical and photochromic properties are found to be facilely tuned in this system by substitution at the phosphole backbone, as well as variation on the extent of pi-conjugation of the phosphole backbone. Some selected compounds have been demonstrated to exhibit photochromic properties in polymethylmethacrylate (PMMA) films. PMID- 25783615 TI - Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. PMID- 25783616 TI - Tandem Catalytic C(sp(3) )-H Amination/Sila-Sonogashira-Hagihara Coupling Reactions with Iodine Reagents. AB - A new tandem C-N and C-C bond-forming reaction has been achieved through Rh(II) /Pd(0) catalysis. The sequence first involves an iodine(III) oxidant, then the in situ generated iodine(I) by-product is used as a coupling partner. The overall process demonstrates the synthetic value of iodoarenes produced in trivalent iodine reagent mediated oxidations. PMID- 25783617 TI - Longitudinal examination of infant baseline and reactivity cortisol from ages 7 to 16 months. AB - This study characterized the longitudinal evolution of HPA axis functioning from 7 to 16 months of age and identified individual and environmental factors that shape changes in HPA axis functioning over time. Participants were 167 mother infant dyads drawn from a larger longitudinal study, recruited based on maternal history of being maltreated during childhood. Salivary cortisol levels were assessed before and after age-appropriate psychosocial stressors when infants were 7 and 16 months old. Maternal observed parenting and maternal reports of infant and environmental characteristics were obtained at 7 months and evaluated as predictors of changes in infant baseline cortisol and reactivity from 7 to 16 months. Results revealed that infants did not show a cortisol response at 7 months, but reactivity to psychosocial stress emerged by 16 months. Individual differences in cortisol baseline and reactivity levels over time were related to infant sex and maternal overcontrolling behaviors, underscoring the malleable and socially informed nature of early HPA axis functioning. Findings can inform prevention and intervention efforts to promote healthy stress regulation during infancy. PMID- 25783619 TI - Relational diagnosis--an idea whose time has come. PMID- 25783618 TI - Cost-effectiveness analysis of two therapeutic schemes in the treatment of acromegaly: a retrospective study of 168 cases. AB - PURPOSE: This study aimed to estimate the cost effectiveness of two therapeutic schemes, including preoperative medical therapy and surgery as primary therapy. METHODS: A total of 168 acromegaly cases were retrospectively investigated for a comparative evaluation of surgery and preoperative medical therapy. A Markov model was developed to simulate treatment cost-effectiveness and progression of acromegaly. RESULTS: Overall effectiveness of preoperative medical therapy was significantly higher than surgery in acromegalic patients with macroadenoma. In addition, life expectancy, and cost per life-year gained were slightly higher in the preoperative medical therapy group than in the initial surgery group when patients received surgery as a secondary treatment. Interestingly, preoperative medical therapy achieved a significant increase in life expectancy and reduced cost for patients who received long-term medical therapy as secondary treatment. CONCLUSIONS: In acromegalic patients with macroadenoma, the cost-effectiveness analysis revealed more satisfactory outcomes in preoperative therapy, compared with primary surgery. PMID- 25783621 TI - An OHD-RIKES and simulation study comparing a benzylmethylimidazolium ionic liquid with an equimolar mixture of dimethylimidazolium and benzene. AB - The principal difference between 1-benzyl-3-methyl-imidazolium triflimide [BzC1im][NTf2] and an equimolar mixture of benzene and dimethylimidazolium triflimide [C1C1im][NTf2] is that in the former the benzene moieties are tied to the imidazolium ring, while in the latter they move independently. We use femtosecond optical heterodyne-detected Raman-induced Kerr effect spectroscopy (OHD-RIKES) and molecular simulations to explore some properties of these two systems. The Kerr spectra show small differences in the spectral densities; the simulations also show very similar environments for both the imidazolium rings and the phenyl or benzene parts of the molecules. The low frequency vibrational densities of states are also similar in the model systems. In order to perform the simulations we developed a model for the [BzC1im](+) cation and found that the barriers to rotation of the two parts of the molecule are low. PMID- 25783620 TI - Advances in anti-angiogenic agents for ovarian cancer treatment: The role of trebananib (AMG 386). AB - Ovarian cancer is a multifaceted and genomically complex disease and has emerged as leading cause of death among gynecological malignancies. Gold-standard treatment consisted of cytoreductive surgery and paclitaxel-carboplatin chemotherapy. Recently, promising results of randomized trials have definitively confirmed the importance of angiogenesis in oncogenesis and ovarian cancer behavior, by showing a significant prolongation of progression-free survival with the addiction of an angiogenesis inhibitor to standard treatment in the first and second line setting. Research over the years has sequentially provided a rapidly broadening signaling landscape and many drugs targeting different signaling pathways of angiogenesis have been developed and investigated. Recently accumulating scientific evidence has started to shed light on the efficacy of AMG 386, a new peptibody reported to neutralize the interaction between angiopoietins (Ang1/2) and their Tie2 receptors, thus representing a promising alternative, both in terms of efficacy and toxicity profile and is considerably under investigation. The aim of this review is to summarize the recent researches and clinical progresses of AMG 386 as a novel target agent in ovarian cancer. PMID- 25783622 TI - Do Arterial Hemodynamic Parameters Predict Cognitive Decline Over a Period of 2 Years in Individuals Older Than 80 Years Living in Nursing Homes? The PARTAGE Study. AB - OBJECTIVES: Several studies have highlighted a link between vascular alterations and cognitive decline. The PARTAGE study showed that arterial stiffness as evaluated by carotid-femoral pulse wave velocity (cfPWV) was associated with a more pronounced cognitive decline over a 1-year period in very old frail institutionalized individuals. The aim of the present analysis was to assess the role of hemodynamic parameters, such as blood pressure (BP), heart rate (HR), cfPWV, and central/peripheral pulse pressure amplification (PPA) on cognitive decline over 2 years in very old frail individuals. METHODS: A total of 682 individuals from the PARTAGE study cohort, aged older than 80 years (mean age at inclusion: 87.5 +/- 5.0 years) and living in French and Italian nursing homes, were analyzed. Mini-Mental State Examination (MMSE) score was assessed at baseline (BL) and at the end of the first and second year of follow-up (2y-FU). Those with a decrease in MMSE of 3 or more points between BL and 2y-FU were considered as "decliners." The cfPWV and PPA at baseline were assessed with an arterial tonometer. RESULTS: After adjustment for baseline MMSE, HR, body mass index, age, education level, and activities of daily living (ADLs), cfPWV was higher and PPA lower in "decliners" compared with "nondecliners," whereas BP did not differ between the 2 groups. Logistic multivariate analysis also revealed that high cfPWV, low PPA, high HR, and low ADLs were all determinants of MMSE decline. CONCLUSION: This 2-year longitudinal study in very old institutionalized individuals shows that arterial stiffness and high HR enabled us to identify subjects at higher risk of cognitive decline, whereas BP alone did not appear to have a significant predictive value. These findings highlight the contribution of vascular determinants in cognitive decline even in this very old population. PMID- 25783623 TI - How many older people are frail? Using multiple imputation to investigate frailty in the population. AB - OBJECTIVES: The objective of this study was to establish the extent to which frailty was associated with attrition and then compare estimates of frailty prevalence and progression estimated from the observed data to those estimated after imputation. DESIGN: Population-based cohort study. SETTING: The Health in Men Study (HIMS) with frailty estimated at Wave 2 (2001/2004) and Wave 3 (2008) and mortality follow-up to 2010. PARTICIPANTS: Participants were 10,305 community dwelling men aged 70 and older, followed for up to 10 years. MEASUREMENTS: Participants completed an extensive questionnaire covering functional activities and illnesses. Frailty was assessed using the FRAIL Scale and a 32-item Frailty Index. RESULTS: Nonresponders at Wave 3 were more likely to have been frail at Wave 2. Imputed estimates of frailty prevalence were 8% to 10% higher than those derived from the observed data. CONCLUSION: Epidemiological surveys may substantially underestimate the levels of frailty among older people in the general population. This selective nonresponse results in an overoptimistic view of aging populations, particularly for the very old. PMID- 25783624 TI - Global Prevalence of Physical Frailty by Fried's Criteria in Community-Dwelling Elderly With National Population-Based Surveys. AB - This study presents a brief review of 6 articles published between 2001 and 2014 that examined the prevalence of frailty as defined by the Fried scale in community-dwelling adults representative of the national population, age 65 years and older. PMID- 25783626 TI - The secretion process of liquid silk with nanopillar structures from Stenopsyche marmorata (Trichoptera: Stenopsychidae). AB - Stenopsyche marmorata larvae spin underwater adhesive silk for constructing nests and capture nets. The silk can be divided into fiber and adhesive regions, according to their function. The silk fiber region has a two-layer structure: a core layer situated at the center of the fiber and S. marmorata fibroin, the major component of the silk. In the anterior part of the anterior silk gland, the morphological characteristics suggest that the silk insolubilization leading to fibrillation occurs by luminal pH neutralization. The adhesive region is composed of three layers: the outermost (OM), B, and C layers. On the B layer, coated with the OM layer, numerous nano-order pillar structures (nanopillar structures) are located at regular intervals. A nanopillar structure is approximately 40 nm in diameter and 125 nm in length. The precursor materials of the nanopillar structure are electron-dense globules of approximately 25 nm in diameter that are located in the A layer of the lumen of the middle silk gland. The precursor globules autonomously connect to one another on the B layer when the liquid silk is transported to the lumen of the bulbous region. The nanopillar structures probably contribute to the strong underwater adhesion of S. marmorata silk. PMID- 25783627 TI - Simultaneous saccharification and fermentation of cellulose in ionic liquid for efficient production of alpha-ketoglutaric acid by Yarrowia lipolytica. AB - Ionic liquids (ILs) are benign solvents that are highly effective for biomass pretreatment. However, their applications for scale-up biorefinery are limited due to multiple expensive IL recovery and separation steps that are required. To overcome this limitation, it is very critical to develop a compatible enzymatic and microbial biocatalyst system to carry the simultaneous saccharification and fermentation in IL environments (SSF-IL). While enzymatic biocatalysts have been demonstrated to be compatible with various IL environments, it is challenging to develop microbial biocatalysts that can thrive and perform efficient biotransformation under the same conditions (pH and temperature). In this study, we harnessed the robust metabolism of Yarrowia lipolytica as a microbial platform highly compatible with the IL environments such as 1-ethyl-3-methylimidazolium acetate ([EMIM][OAc]). We optimized the enzymatic and microbial biocatalyst system using commercial cellulases and demonstrated the capability of Y. lipolytica to convert cellulose into high-value organics such as alpha ketoglutaric acid (KGA) in the SSF-IL process at relatively low temperature 28 degrees C and high pH 6.3. We showed that SSF-IL not only enhanced the enzymatic saccharification but also produced KGA up to 92% of the maximum theoretical yield. PMID- 25783628 TI - Thermoadaptation-directed evolution of chloramphenicol acetyltransferase in an error-prone thermophile using improved procedures. AB - Enhancing the thermostability of thermolabile enzymes extends their practical utility. We previously demonstrated that an error-prone thermophile derived from Geobacillus kaustophilus HTA426 can generate mutant genes encoding enzyme variants that are more thermostable than the parent enzyme. Here, we used this approach, termed as thermoadaptation-directed enzyme evolution, to increase the thermostability of the chloramphenicol acetyltransferase (CAT) of Staphylococcus aureus and successfully generated a CAT variant with an A138T replacement (CAT(A138T)). This variant was heterologously produced, and its enzymatic properties were compared with those of the wild type. We found that CAT(A138T) had substantially higher thermostability than CAT but had comparable activities, showing that the A138T replacement enhanced protein thermostability without affecting the catalytic activity. Because variants CAT(A138S) and CAT(A138V), which were generated via in vitro site-directed mutagenesis, were more thermostable than CAT, the thermostability enhancement resulting from the A138T replacement can be attributed to both the presence of a hydroxyl group and the bulk of the threonine side chain. CAT(A138T) conferred chloramphenicol resistance to G. kaustophilus cells at high temperature more efficiently than CAT. Therefore, the gene encoding CAT(A138T) may be useful as a genetic marker in Geobacillus spp. Notably, CAT(A138T) generation was achieved only by implementing improved procedures (plasmid-based mutations on solid media); previous procedures (chromosome-based mutations in liquid media) were unsuccessful. This result suggests that this improved procedure is crucial for successful thermoadaptation directed evolution in certain cases and increases the opportunities for generating thermostable enzymes. PMID- 25783629 TI - Extracellular esterases of phylloplane yeast Pseudozyma antarctica induce defect on cuticle layer structure and water-holding ability of plant leaves. AB - Aerial plant surface (phylloplane) is a primary key habitat for many microorganisms but is generally recognized as limited in nutrient resources. Pseudozyma antarctica, a nonpathogenic yeast, is commonly isolated from plant surfaces and characterized as an esterase producer with fatty acid assimilation ability. In order to elucidate the biological functions of these esterases, culture filtrate with high esterase activity (crude enzyme) of P. antarctica was applied onto leaves of tomato and Arabidopsis. These leaves showed a wilty phenotype, which is typically associated with water deficiency. Furthermore, we confirmed that crude enzyme-treated detached leaves clearly lost their water holding ability. In treated leaves of both plants, genes associated to abscisic acid (ABA; a plant stress hormone responding osmotic stress) were activated and accumulation of ABA was confirmed in tomato plants. Microscopic observation of treated leaf surfaces revealed that cuticle layer covering the aerial epidermis of leaves became thinner. A gas chromatography-mass spectrometry (GC-MS) analysis exhibited that fatty acids with 16 and 18 carbon chains were released in larger amounts from treated leaf surfaces, indicating that the crude enzyme has ability to degrade lipid components of cuticle layer. Among the three esterases detected in the crude enzyme, lipase A, lipase B, and P. antarctica esterase (PaE), an in vitro enzyme assay using para-nitrophenyl palmitate as substrate demonstrated that PaE was the most responsible for the degradation. These results suggest that PaE has a potential role in the extraction of fatty acids from plant surfaces, making them available for the growth of phylloplane yeasts. PMID- 25783630 TI - Extracellular Matrix Glycoprotein-Derived Synthetic Peptides Differentially Modulate Glioma and Sarcoma Cell Migration. AB - Glycoproteins of the extracellular matrix (ECM) regulate proliferation, migration, and differentiation in numerous cell lineages. ECM functions are initiated by small peptide sequences embedded in large constituents that are recognized by specific cellular receptors. In this study, we have investigated the biological effects of peptides derived from collagen type IV and tenascin-C compared to the well-known RGD peptide originally discovered in fibronectin. The influence of glycoproteins and corresponding peptides on the migration of the glioma cell lines U-251-MG and U-373-MG and the sarcoma line S-117 was studied. When the cell lines were tested in a modified Boyden chamber assay on filters coated with the ECM glycoproteins, glioma cells showed a strong migration response on tenascin-C and the basal lamina constituent collagen IV, in contrast to S-117 cells. In order to identify relevant stimulatory motifs, peptides derived from fibronectin (6NHX-GRGDSF), tenascin-C (TN-C, VSWRAPTA), and collagen type IV (MNYYSNS) were compared, either applied in solution in combination with ECM glycoprotein substrates, in solution in the presence of untreated membranes, or coated on the filters of the Boyden chambers. Using this strategy, we could identify the novel tenascin-C-derived peptide motif VSWRAPTA as a migration stimulus for glioma cells. Furthermore, while kin peptides generally blocked the effects of the respective homologous ECM proteins, unexpected effects were observed in heterologous situations. There, in several cases, addition of soluble peptides strongly boosted the response to the coated ECM proteins. We propose that peptides may synergize or antagonize each other by stimulating different signaling pathways. PMID- 25783631 TI - Altered Expression of Intersectin1-L in Patients with Refractory Epilepsy and in Experimental Epileptic Rats. AB - Epilepsy is a common neurological disorder. Because its underlying mechanisms remain incompletely understood, current treatments are not adequate for all epilepsy patients, and some patients progress to refractory epilepsy. Under physiological conditions, excitatory and inhibitory neurons function in a dynamic balance. Epilepsy develops when this balance is disrupted. Intersectin1-L is a major scaffold protein in the central nervous system that contains multiple functional domains, and it is the long form of intersectin1. Recent studies have shown that intersectin1-L plays an important role in the process of neurotransmitter release. In this study, we investigated the expression pattern and distribution of intersectin1-L in patients with refractory epilepsy, in a rat model of pilocarpine-induced epilepsy, and in a rat model of amygdala-kindled epilepsy by immunohistochemistry, immunofluorescence, and Western blotting. The purpose of this study was to explore the relationship between epilepsy and intersectin1-L. The results showed that the intersectin1-L protein was primarily expressed in neurons in brain tissue. Its expression was remarkably increased in patients with refractory epilepsy and in epilepsy model rats. These results suggest that the abnormal expression of the intersectin1-L protein in epileptic brain tissue may play an important role in epilepsy, especially refractory epilepsy. PMID- 25783632 TI - Improving the electrochemical performance of the li4 ti5 o12 electrode in a rechargeable magnesium battery by lithium-magnesium co-intercalation. AB - Rechargeable magnesium batteries have attracted recent research attention because of abundant raw materials and their relatively low-price and high-safety characteristics. However, the sluggish kinetics of the intercalated Mg(2+) ions in the electrode materials originates from the high polarizing ability of the Mg(2+) ion and hinders its electrochemical properties. Here we report a facile approach to improve the electrochemical energy storage capability of the Li4 Ti5 O12 electrode in a Mg battery system by the synergy between Mg(2+) and Li(+) ions. By tuning the hybrid electrolyte of Mg(2+) and Li(+) ions, both the reversible capacity and the kinetic properties of large Li4 Ti5 O12 nanoparticles attain remarkable improvement. PMID- 25783633 TI - Hematopoietic stem cell transplantation in nodal T cell non-hodgkin lymphomas: revisiting the issues. PMID- 25783634 TI - Assessing Costs, Benefits, and Risks in Chronic Disease: Taking the Long View. PMID- 25783635 TI - Autologous hematopoietic stem cell transplantation for plasmablastic lymphoma: the European Society for Blood and Marrow Transplantation experience. PMID- 25783636 TI - miR-210 mediates vagus nerve stimulation-induced antioxidant stress and anti apoptosis reactions following cerebral ischemia/reperfusion injury in rats. AB - Vagus nerve stimulation (VNS) exerts neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury and modulates redox status, potentially through the activity of miR-210, an important microRNA that is regulated by hypoxia inducible factor and Akt-dependent pathways. The aim of this study was to determine the mechanisms of VNS- and miR-210-mediated hypoxic tolerance. Male Sprague-Dawley rats were preconditioned with a miR-210 antagomir (A) or with an antagomir control (AC), followed by middle cerebral artery occlusion and VNS treatment. The animals were divided into eight groups: sham I/R, I/R, I/R+AC, I/R+A, sham I/R+VNS, I/R+VNS, I/R+VNS+AC, and I/R+VNS+A. Activation of the endogenous cholinergic a7 nicotinic acetylcholine receptor (a7nAchR) pathway was identified using double immunofluorescence staining. miR-210 expression was measured by PCR. Behavioral outcomes, infarct volume, and neuronal apoptosis were observed at 24 h following reperfusion. Markers of oxidative stress were detected using ELISA. Rats treated with VNS showed increased miR-210 expression as well as decreased apoptosis and antioxidant stress responses compared with the I/R group; these rats also showed increased p-Akt protein expression and significantly decreased levels of cleaved caspase 3 in the ischemic penumbra, as measured by western blot and immunofluorescence analyses, respectively. Strikingly, the beneficial effects of VNS were attenuated following miR-210 knockdown. In conclusion, our results indicate that miR-210 is a potential mediator of VNS induced neuroprotection against I/R injury. Our study highlights the neuroprotective potential of VNS, which, to date, has been largely unexplored. Since approved by the FDA in 1997, vagus nerve stimulation (VNS) has proven to be a safe and effective treatment for refractory epilepsy and resistant depression. Recent studies have found that VNS also provided neuroprotective effects against ischemic injury in a rat stroke model. We showed that miR-210 played an important role in the antioxidant stress and anti-apoptosis responses induced by VNS. This is the first report showing the effects of VNS at the mRNA level. Therefore, VNS represents a promising candidate treatment for ischemic stroke patients. Schematic view of the role of miR210 mediated in the protective effects of the VNS on the acute cerebral ischemia. VNS acts to activate neuronal and astrocytes a7nAchR , inhibits the apoptosis and oxidant stress responses possibly associated with increased Akt phosphorylation and miR210 expression. PMID- 25783637 TI - A case with life-threatening uterine bleeding due to postmenopausal uterine arteriovenous malformation. AB - BACKGROUND: Uterine arteriovenous malformation is a rare but life-threatening condition that accounts for 1-2% of massive vaginal bleeding. Uterine arteriovenous malformations are less common after menopause. The condition can be diagnosed using Doppler ultrasound, magnetic resonance imaging, computed tomography, and pelvic angiography. CASE PRESENTATION: We report a postmenopausal patient with a uterine arteriovenous malformation who underwent emergency hysterectomy for sudden onset of life-threatening uterine bleeding following an initially successful but ultimately failed uterine artery embolization. Interestingly, it was not difficult to ligate and cut the dilated vessels and we were able to safely perform the hysterectomy with little bleeding in the operative field. The hysterectomy was successful, with most of the intraoperative vaginal blood loss due to the ruptured arteriovenous malformation. One year after surgery, the patient has had no vaginal bleeding. CONCLUSION: We consider hysterectomy to be a comparatively safe and effective therapeutic option for postmenopausal women who suffered from uterine arteriovenous malformations with life-threatening uterine bleeding. PMID- 25783638 TI - Sexual experiences of married HIV positive women in Osogbo, southwest Nigeria: role of inappropriate status disclosure. AB - BACKGROUND: Worldwide heterosexual sex is the most common mode of HIV transmission, with the marital heterosexual route becoming a major contributor in sub-Sahara Africa. This study examined the role of inappropriate HIV status disclosure, after diagnosis, on marital sexual experiences of HIV positive women. METHODS: The study employed a descriptive cross-sectional design. An interviewer administered questionnaire that elicited information about HIV status disclosure to partners, sexual experiences, condom use and parity was administered to 122 married women living with HIV/AIDS. Participants were referred from peripheral health centres to receive comprehensive HIV care at the State Specialist Hospital, Osogbo, Nigeria. RESULTS: Mean age (SD) of respondents was 33.8 (8.9) years. Only 23.8% of partners had HIV screening, with 3.3% being HIV positive. A majority (62%) of respondents reported experiencing marital sex deprivation since their partners became aware of their HIV status. There was a reported rejection (74.3%) of condom use by partners during sexual intercourse. Fear of becoming infected (85.7%) and blaming the women for their positive status (85.7%) were the main reasons the respondents gave for being sexually deprived by their partners. CONCLUSION: Inappropriate status disclosure due to poor HIV counseling and testing (HCT) practices resulted in sexual deprivation of married HIV positive women. Adequate training and retraining of health care workers on HCT and HIV status disclosure will reduce experience of sexual deprivation among married HIV positive women. PMID- 25783639 TI - The prevalence and nature of the use of preconception services by women with chronic health conditions: an integrative review. AB - BACKGROUND: There is growing evidence that preconception care may have an important role in preventing short and long term adverse health consequences for women and their offspring. This is particularly the case for women with chronic health conditions due to the rising prevalence of chronic disease in global populations. With this in mind, this paper presents an integrative systematic review of contemporary research outlining the use of preconception services and practices by women with chronic health conditions. METHODS: A search was conducted through PubMed, CINAHL, AMED, and Maternity and Infant Care databases which identified 672 papers examining preconception care and preconception services for women with chronic health conditions. Fourteen papers which were written in English, presented original research, and reported on the prevalence or nature of use of preconception care by women with chronic health conditions were included in the review. Critical appraisal of study quality and thematic categorical grouping of identified papers was undertaken. RESULTS: Current research evidence, as identified through this review, examines three major topic areas: the prevalence of preconception care practices, use of services and characteristics of users; knowledge of the value and impact of preconception care and availability of preconception services for women with chronic health conditions; and women's attitudes, approaches and experiences of preconception care and preconception services. Prevalence estimates of engagement with preconception care range between 18.1% and 45%, with most studies focusing on women with type 1 or 2 diabetes. Significant gaps in women's knowledge of preconception care for women with chronic health conditions were also identified. Women with chronic health conditions reported experiencing emotional distress as a result of their engagement with preconception care services. They also commonly described feeling a need to employ discipline to comply with preconception care programs, and experiencing a fear of pregnancy complications. CONCLUSION: Future research requires a broad and sophisticated approach to research design and analysis, improved consideration of temporal changes to women's health behaviour, representative samples to more effectively inform health policy, and a deeper understanding of women's motivations, attitudes and perceptions of preconception care to assist in the development of tailored preconception health services. PMID- 25783640 TI - Multiplicative disadvantage of being an unmarried and inadequately insured woman living in poverty with colon cancer: historical cohort exploration in California. AB - BACKGROUND: Many Americans diagnosed with colon cancer do not receive indicated chemotherapy. Certain unmarried women may be particularly disadvantaged. A 3-way interaction of the multiplicative disadvantages of being an unmarried and inadequately insured woman living in poverty was explored. METHODS: California registry data were analyzed for 2,319 women diagnosed with stage II to IV colon cancer between 1996 and 2000 and followed until 2014. Socioeconomic data from the 2000 census classified neighborhoods as high poverty (>=30% of households poor), middle (5-29%) or low poverty (<5% poor). Primary health insurance was private, Medicare, Medicaid or none. Comparisons of chemotherapy rates used standardized rate ratios (RR). We respectively used logistic and Cox regression models to assess chemotherapy and survival. RESULTS: A statistically significant 3-way marital status by health insurance by poverty interaction effect on chemotherapy receipt was observed. Chemotherapy rates did not differ between unmarried (39.0%) and married (39.7%) women who lived in lower poverty neighborhoods and were privately insured. But unmarried women (27.3%) were 26% less likely to receive chemotherapy than were married women (37.1%, RR = 0.74, 95% CI 0.58, 0.95) who lived in high poverty neighborhoods and were publicly insured or uninsured. When this interaction and the main effects of health insurance, poverty and chemotherapy were accounted for, survival did not differ by marital status. CONCLUSIONS: The multiplicative barrier to colon cancer care that results from being inadequately insured and living in poverty is worse for unmarried than married women. Poverty is more prevalent among unmarried women and they have fewer assets so they are probably less able to absorb the indirect and direct, but uncovered, costs of colon cancer care. There seem to be structural inequities related to the institutions of marriage, work and health care that particularly disadvantage unmarried women that policy makers ought to be cognizant of as future reforms of the American health care system are considered. PMID- 25783641 TI - Symptomatic presentation with cervical cancer in Uganda: a qualitative study assessing the pathways to diagnosis in a low-income country. AB - BACKGROUND: Symptomatic cervical cancer patients in low- and middle-income countries usually present with late stage disease and have poor survival. We explored the views of cervical cancer patients on their symptom appraisal and interpretations, and their help-seeking including lay consultations. METHODS: We conducted an in-depth interview study in two northern Ugandan hospitals. Theoretical models underpinned the study guide for data collection and analysis. We used thematic analysis techniques, informed by the theoretical concepts in the Model of Pathways to Treatment. Sub-themes and themes were identified through consensus among investigators. RESULTS: Eighteen women aged 35-56 years, recently diagnosed with cervical cancer were interviewed. Their first symptoms included abnormal vaginal bleeding, offensive vaginal discharge and lower abdominal pain. Most participants did not perceive themselves to be at risk for cervical cancer and they usually attributed the initial symptoms to normal bodily changes or common illnesses such as sexually transmitted diseases. Lay consultations with husbands, relatives and friends were common and often influenced decisions and timing for seeking care. Prompt help-seeking was frequently triggered by perceived life threatening symptoms such as heavy vaginal bleeding or lower abdominal pain; symptom burden sufficient to interfere with patients' work routines; and persistence of symptoms in spite of home-based treatments. Participants did not promptly seek care when they perceived symptoms as mild; interpreted symptoms as due to normal bodily changes e.g. menopause; and attributed symptoms to common illnesses they could self-manage. Their cancer diagnosis was often further delayed by long help-seeking processes including repeated consultations. Some healthcare professionals at private clinics and lower level health facilities failed to recognize symptoms of cervical cancer promptly therefore delayed referring women to the tertiary hospitals for diagnosis and treatment. CONCLUSION: Ugandan patients with symptomatic cervical cancer often misattribute their gynaecological symptoms, and experience long appraisal and help-seeking intervals. These findings can inform targeted interventions including community awareness campaigns about cervical cancer symptoms, and promote prompt help-seeking in Uganda and other low- and middle income countries with high incidence and mortality from cervical cancer. PMID- 25783642 TI - Prevalence of Trichomonas vaginalis infection among Egyptian women using culture and Latex agglutination: cross-sectional study. AB - BACKGROUND: This is a cross-sectional study carried out in the Obstetrics and Gynecology Department at Kasr Al- Ainy Cairo University Hospitals. METHODS: One thousand female patients in the child bearing period (age 18-45 yrs) were included in this study. These females were non-pregnant and non-menstruating with no douching or intercourse for at least 2-3 days, no use of antibiotics, anti protozoal or steroids for the past 15 days complaining of vaginal discharge with or without itching, burning sensation or both. Vaginal swabs were obtained from all patients for examination by direct wet mount examination, Giemsa staining, Modified Diamond culture and latex agglutination test Kalon) to detect the presence of Trichomonas vaginalis infection. RESULTS: The prevalence of trichomonas infection was 50 cases, latex agglutination test detected 50 positive cases, 30 of which were also positive by culture, and only 10 were detected both by Giemsa staining and by wet mount. The wet mount, Giemsa staining and Kalon latex test had sensitivities of 33.3, 33.3% and 100% respectively while their specificities were 100%, 100% and 97.9% respectively. CONCLUSION: Screening tests should be done routinely to depict cases of T. vaginalis infection and should be included in the control programs of sexually transmitted infections. Although wet mount is not a sensitive method for diagnosis of T. vaginalis yet, it is a good positive one. Staining is only useful when there is heavy T. vaginalis infection. Latex agglutination is a highly sensitive, simple, rapid and cost effective test. It provides results within 2-3 minutes and it has the potential for use in screening and diagnosis of T. vaginalis infection. PMID- 25783643 TI - Endometriosis node in gynaecologic scars: a study of 17 patients and the diagnostic considerations in clinical experience in tertiary care center. AB - BACKGROUND: Endometriosis nodes are observed in extra pelvic locations, particularly in gynaecological scars, with the abdominal wall being one of the most frequent locations. The main objective of the study is to review patient characteristics of cases of endometriosis nodes in gynaecological scars. METHODS: A retrospective, observational and descriptive study with a cohort of patients from Hospital 12 de Octubre was conducted from January 2000 to January 2012. We analysed all of the patients who presented with an endometriosis node in a gynaecological scar presentation who had undergone surgery in that period. Descriptive data were collected and analysed. RESULTS: A total of 17 patients with an anatomopathological diagnosis of an endometriosis node in a gynaecological scar were found. The following variables were studied: the age at diagnosis (32.5 years +/- 5.5 years), personal and obstetric history, time from surgery to diagnosis (4.2 years +/- 3.4 years), symptoms (a painful mass that grows during menstruation is the most frequent symptom in our patients), technical analyses by computed tomography (CT), magnetic resonance (MR) or fine needle aspiration (FNA) (77% of the patients), node size (2.5 cm +/- 1.1 cm) and location (caesarean scar, 82%; episiotomy scar, 11.7%; and laparoscopic surgery port, 5.8%), involvement of adjacent structures (29% of the patients), treatment (exeresis with a security margin in all the patients) and other endometriosis locations (14% of the patients). CONCLUSIONS: A high level of suspicion is required to diagnose gynaecological scar endometriosis, which should be suspected in the differential diagnosis of scar masses in reproductive-aged women. Several theories have been proposed to explain the formation of endometriosis nodes in extrauterine localizations. The two of them that seem to be more plausible are the metaplasia and transport theories. Imaging with ultrasound, CT and MR facilitate the diagnosis. FNA could be used for preoperative diagnosis. Treatment must be by node resection with a security margin. In some cases, surgery could be combined with hormonal treatment. PMID- 25783644 TI - Breast cancer risk and genetic ancestry: a case-control study in Uruguay. AB - BACKGROUND: Uruguay exhibits one of the highest rates of breast cancer in Latin America, similar to those of developed nations, the reasons for which are not completely understood. In this study we investigated the effect that ancestral background has on breast cancer susceptibility among Uruguayan women. METHODS: We carried out a case-control study of 328 (164 cases, 164 controls) women enrolled in public hospitals and private clinics across the country. We estimated ancestral proportions using a panel of nuclear and mitochondrial ancestry informative markers (AIMs) and tested their association with breast cancer risk. RESULTS: Nuclear individual ancestry in cases was (mean +/- SD) 9.8 +/- 7.6% African, 13.2 +/- 10.2% Native American and 77.1 +/- 13.1% European, and in controls 9.1 +/- 7.5% African, 14.7 +/- 11.2% Native American and 76.2 +/- 14.2% European. There was no evidence of a difference in nuclear or mitochondrial ancestry between cases and controls. However, European mitochondrial haplogroup H was associated with breast cancer (OR = 2.0; 95% CI 1.1, 3.5). CONCLUSIONS: We have not found evidence that overall genetic ancestry differs between breast cancer patients and controls in Uruguay but we detected an association of the disease with a European mitochondrial lineage, which warrants further investigation. PMID- 25783645 TI - Risk factors for high-risk and multi-type Human Papillomavirus infections among women in Ho Chi Minh City, Vietnam: a cross-sectional study. AB - BACKGROUND: Concurrent infection with multiple types of Human Papillomavirus (HPV) is associated with an increased risk of cervical cancer; yet, little is known about risk factors for concurrent HPV infection in Vietnam. This study investigated the prevalence of and risk factors for high-risk-type HPV and multi type HPV infections among women in Ho Chi Minh City, Vietnam. METHODS: Data were collected from a population-based survey of 1,550 women (mean age = 42.4; SD = 9.5), using a multi-stage sampling process. Socio-demographic and behavioral variables were obtained by self-report. HPV genotypes in cervical specimens were identified using PCR protocols. RESULTS: The prevalence of any high-risk HPV infection was 9.0%, and of multi-type HPV infection was 1.9%. In the HPV+ subsample, the percentage of high-risk HPV was 84% and of multi-type HPV was 20%. All multi-type HPV infections were high-risk-type. Lifetime smoking and older age of first sex were significantly associated with any high-risk and multi-type HPV infections. Regular condom use was inversely associated with high-risk and multi type HPV infection. CONCLUSIONS: Risk factors for high-risk and multi-type HPV infections were similar. Further research and intervention are needed to reduce HPV infections in order to prevent HPV-related cancers. PMID- 25783646 TI - Uptake and predictors of contraceptive use in Afghan women. AB - BACKGROUND: Afghanistan has one of the world's highest fertility rates and, related to this, an infant mortality rate far higher than its South Asian neighbors. Contraception enhances family spacing, improves women's safety in child birth and, as a result, reduces infant and child mortality. Until recently, there has been a paucity of information on the comparative rates of contraceptive practices in the country and socioeconomic correlates of uptake. We aimed to elucidate the factors influencing the use of contraception in Afghanistan using recent, robust national data. METHODS: Using Afghanistan Mortality Survey (AMS) 2010 data, the distribution of Contraceptive Prevalence Rate (CPR) and correlates of contraceptive use among currently married women aged 15-49 years were explored. We initially summarised descriptive data on 25,743 married women and then derived predictors of the use of any form of contraception using a multiple logistic regression model. RESULTS: The prevalence of self-reported current use of any contraceptive method was 21.8% (95% CI: 20.4-23.4) at the national level though there was a wide variation in practice between provinces. Herat province in the West region had a highest contraceptive prevalence rate of 49.4% while Paktika in the Southeast region had the lowest CPR of 2%. Multiple logistic regression analysis showed that a family size of greater than 6 living children strongly predicted contraceptive use (AOR 7.4 (95% CI:6.1-9.0)). Other independent predictors included: secondary or high level of education (AOR 2.1 (95% CI: 1.8-2.5)) and being in the wealthiest stratum (OR 2.1 (95% CI 1.5-3.0)). Rural residence predicted a lower use of contraception (AOR, 0.72; 95% CI: 0.56 0.92). CONCLUSION: Contraceptive uptake rate was low overall with wide inter provincial variation. Strengthening female education, targeting married women in rural area and women with no education may enhance the effectiveness of National Family planning program in Afghanistan. PMID- 25783647 TI - A comparison between type 3 excision of the transformation zone by straight wire excision of the transformation zone (SWETZ) and large loop excision of the transformation zone (LLETZ): a randomized study. AB - BACKGROUND: The management of preinvasive cervical lesions has the objective to ensure the absence of invasive lesions and to prevent progression to cancer. Excisional procedures have been preferred to treat these lesions as they report the presence of unsuspected invasive lesions and the status of surgical margins, allowing inferring full excision when such are free of disease. The purpose of this study is to determine whether Straight Wire Excision of the Transformation Zone (SWETZ) is a better alternative than Large Loop Excision of the Transformation Zone (LLETZ-cone) as a type 3 excision of the Transformation Zone (TZ) to reduce incomplete excision and concerning other outcomes of surgical interest. METHOD: Randomized controlled trial including women who needed type 3 excision of the TZ referred to a colposcopy clinic after cytological screening between January 2008 thru December 2011. The interventions were performed using local anesthesia and sedation in an inpatient basis by different experienced surgeons. The study enrolled and randomized 164 women, of which 82 were allocated to each group. After exclusions, 78 remained in SWETZ and 76 in LLETZ-cone groups for the analysis of outcomes of surgical interest and 52 and 54, respectively, for the margins analysis. RESULTS: There was an even distribution between the groups after randomization and exclusions, concerning mean age, parity, current smoking, prior cytological diagnosis and histopathological diagnosis obtained in cone specimen even after exclusions. We observed significantly higher risk of compromised or damaged endocervical margin in specimens resulting from the LLETZ cone in relation to SWETZ (RR 1.72, 95% CI: 1.14 to 2.6), with an absolute risk reduction (ARR) of 26.4% (95% CI: 8.1 to 44.8) for patients operated by SWETZ. The specimens obtained by SWETZ showed less fragmentation (ARR = 19.8%, 95% CI: 10.3 - 29.3%), but the procedure took longer. There were complications in 5.6% of the procedures, with no significant differences between the groups. CONCLUSION: This study showed a lower proportion of compromised or damaged endocervical surgical margin in specimens resulting from SWETZ in relation to LLETZ-cone. SWETZ demonstrated to be more efficient than LLETZ-cone concerning less fragmentation of the specimen obtained. However, it accounted for longer surgical time. Both techniques showed morbidity TRIAL REGISTRATION: Number at ClinicalTrials.gov: NCT01929993 (June 10, 2012). PMID- 25783648 TI - Marital status and abortion among young women in Rupandehi, Nepal. AB - BACKGROUND: Despite liberalization of the Nepal abortion law, young women continue to experience barriers to safe abortion services. We hypothesize that marital status may differentially impact such barriers, given the societal context of Nepal. METHODS: We evaluated differences in reproductive knowledge and attitudes by marital status with a probability-based, cross-sectional survey of young women in Rupandehi district, Nepal. Participants (N = 600) were surveyed in 2012 on demographics, romantic experiences, media habits, reproductive information, and abortion knowledge and attitudes. We used logistic regression to assess differences by marital status, controlling for age. RESULTS: Participants, who comprised never-married (54%) and ever-married women (45%), reported good access to basic reproductive health and abortion information. Social desirability bias might have prevented reporting of premarital romantic and sexual activity given that participants reported more premarital activities for their friends than for themselves. Only 45% knew that abortion was legal, and fewer ever married women were aware of abortion legality. Never-married women expected more negative responses from having an abortion than ever-married women. CONCLUSIONS: Findings highlight the need for providing sexual and reproductive health care information and services to young women regardless of marital status. PMID- 25783649 TI - Relationship between Type-D personality, physical activity behaviour and climacteric symptoms. AB - BACKGROUND: A number of factors have been identified which might influence the variation observed in climacteric symptoms in peri- and post-menopausal women. We examined the role of the distressed or Type-D personality and mode of physical activity or exercise on the climacteric symptoms experienced by peri- or post menopausal women. METHODS: 213 Women (M age 52.2 years, SD = 5.9), 58% classified as peri- and 42% as post-menopausal completed a questionnaire pack consisting of demographic questions, the DS14 (Type-D personality), Kaiser Physical Activity Survey (assessing household care giving, occupational, active living and sport and exercise index) and the Greene Climacteric Scale (Psychological, somatic/physical, vasomotor and sexual symptoms). RESULTS: Type-D personality and increased levels of household care-giving physical activity were both associated with increased bothersomness for all four climacteric factors. Increased levels of sport and exercise participation on the other hand resulted in less psychological, somatic/physical and sexual functioning problems whereas the active living index was inversely related to somatic/physical climacteric symptoms. Finally, lower income was associated with more psychological and somatic/physical symptoms and being peri-menopausal resulted in more vasomotor symptoms. CONCLUSIONS: The results suggest that mode of physical activity is an important moderator in alleviating climacteric symptoms. In addition, our results support previous findings in that Type-D personality is associated with negative health outcomes. In particular menopausal women with Type-D personality would benefit from interventions (coping, mindfulness training) and regular sport and exercise participation to reduce climacteric symptomology. PMID- 25783651 TI - Postpartum contraceptive use in Gondar town, Northwest Ethiopia: a community based cross-sectional study. AB - BACKGROUND: Addressing family planning in the postpartum period is crucial for better maternal, neonatal and child survival because it enables women to achieve healthy interval between births. The contraceptive behavior of women in the postpartum period is usually different from other times in a woman's life cycle due to the additional roles and presence of emotional changes. Therefore, this study is conducted with the aim of assessing the contraceptive behavior of women in the postpartum period. METHODS: A community-based cross-sectional study was conducted in August 2013 among women who gave birth one year before the study period in Gondar town, Northwest Ethiopia. Multistage cluster sampling technique was employed to recruit a total of 703 study participants. For data collection, a structured and pretested questionnaire was used. Descriptive statistics were done to characterize the study population using different variables. Bivariate and multiple logistic regression models were fitted. Odds ratios with 95% confidence intervals were computed to identify factors associated with contraceptive use. RESULTS: Nearly half (48.4%) of the postpartum women were using different types of contraceptives. The most commonly used method was injectable (68.5%). Resumption of mensus [Adjusted Odds Ratio (AOR) = 8.32 95% Confidence Interval (CI): (5.27, 13.14)], age <=24 years [AOR = 2.36, 95% CI: (1.19, 4.69), duration of 7-9 months after delivery [AOR = 2.26 95% CI: (1.12, 4.54)], and having antenatal care [AOR = 5.76, 95% CI: (2.18, 15.2)] were the factors positively associated with contraceptive use in the extended postpartum period. CONCLUSION: Postpartum contraceptive practice was lower as compared to the Ethiopian demographic and health survey 2011 report for urban areas. Strengthening family planning counseling during antenatal care visit and postnatal care would improve contraceptive use in the postpartum period. PMID- 25783650 TI - Ultrasound guided aspiration of hydrosalpinx fluid versus salpingectomy in the management of patients with ultrasound visible hydrosalpinx undergoing IVF-ET: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to compare the efficacy of ultrasound guided aspiration of hydrosalpinx fluid at the time of oocyte retrieval with salpingectomy in the management of patients with ultrasound visible hydrosalpinx undergoing IVF-ET. METHODS: One hundred and sixty patients with ultrasound visible hydrosalpinx were randomized into salpingectomy group and aspiration group using computer generated randomization list and sequentially numbered sealed envelopes containing allocation information written on a card. RESULTS: The clinical pregnancy rate per started cycle and the implantation rate were non- significantly higher in the salpingectomy group compared with the aspiration group [40% vs. 27.5% (p value = 0.132) and 18.95% vs. 12.82% (p value =0.124), respectively]. In the aspiration group, 34.21% of patients had rapid re accumulation of the hydrosalpinx fluid (i.e. within first two weeks after embryo transfer). Whereas, the clinical pregnancy rate per transfer cycle and the implantation rate were significantly higher in salpingectomy group compared with the subgroup of patients with rapid re-accumulation of hydrosalpinx fluid [42.67% vs. 19.23% (p value = 0.036) and 18.95% vs. 7.58% (p value = 0.032), respectively], no significant differences were detected between the salpingectomy group and the subgroup of patients with no re-accumulation of hydrosalpinx fluid (42.67% vs. 34% (p value = 0.356) and 18.95% vs. 15.5% (p value = 0.457), respectively). CONCLUSION: The small sample size could be the cause of failure of detecting significant increase in implantation and pregnancy rates in salpingectomy group compared with aspiration group. Further larger randomized controlled trials are needed to determine whether salpingectomy is more effective than aspiration of hydrosalpinx fluid or not. Moreover, the data presented in this study suggested that rapid re-accumulation of hydrosalpinx fluid is an obstacle against successful implantation and the cause of lower success rate with ultrasound guided aspiration of hydrosalpinx fluid compared with salpingectomy. TRIAL REGISTRATION: Clinical trials.gov ( NCT02008240 ), registered 8 December 2013. PMID- 25783652 TI - Effectiveness of transcervical hysteroscopic endometrial resection based on the prevention of the recurrence of endometrial polyps in post-menopausal women. AB - BACKGROUND: The objectives of this study were to determine the effectiveness the effectiveness of post-polypectomy hysteroscopic endometrial resection in preventing the recurrence of endometrial polyps in post-menopausal patients and analyse the complications and necessity of additional surgery in patients, in addition to their degree of satisfaction. METHODS: A prospective longitudinal study of post-menopausal patients diagnosed with endometrial polyps was conducted including polypectomy and hysteroscopic endometrial resection following the therapeutic purposes (endometrial polyp removal) and prevention of recurrence of endometrial polyps. We evaluated the general condition and characteristics of the patients, including age, BMI, smoking habits, medical, surgical, and obstetrics history and menstrual status. The results were analysed at several time points, 6, 18, 42 and 60 months by hysteroscopy, including the presence of vaginal bleeding and/or possible intracavitary pathology. RESULTS: A total of 89.5% (n = 355) of our patients had profile factors associated with the increased incidence of endometrial polyps and hyperestrogenism (diabetes mellitus, hypertension and overweight); 89.5% (n = 355) of patients were overweight; 34% had grade I obesity. The surgical procedure was safe, with a 90% (n = 357) success rate without complications, which was higher than the 95-99.5% at the beginning and end time points of the study. Patient acceptance and satisfaction was 90 and 84%, respectively. CONCLUSIONS: Endometrial resection proved effective in preventing the recurrence of endometrial polyps. It is a safe and effective method. Post menopausal bleeding reduces the presence of endometrial polyps. Patients reported satisfaction and acceptance of the procedure. PMID- 25783653 TI - Histories of forced sex and health outcomes among Southern African lesbian and bisexual women: a cross-sectional study. AB - BACKGROUND: Experiences of forced sex have been shown to be prevalent in Southern Africa. Negative outcomes of forced sex have been documented in general populations of women and men and include alcohol abuse, drug use, mental health problems, mental distress, sexual health problems and poor overall health. This study is the first to examine experiences of forced sex and associated health problems among lesbian and bisexual women in Southern Africa. METHODS: This study is based on data collected as part of a collaborative endeavor involving various Southern African community-based organizations. Lesbian and bisexual women in four Southern African countries participated in a cross-sectional survey, for a total study sample of 591. RESULTS: Nearly one-third of participants had been forced to have sex at some time in their lives. Thirty-one percent of all women reported to have experienced forced sex at least once in their life: 14.9% reported forced sex by men only; 6.6% reported forced sex by women only; 9.6% had had forced sexual experiences with both men and women. Participants experienced forced sex by men as more serious than forced sex by women; forced sex by women was more likely to involve intimate partners compared to forced sex by men. Participants who experienced forced sex by men were more likely to report drug problems, mental distress and lower sense of belonging. Forced sex by women was associated with drinking problems and mental distress. Having experienced forced sex by both men and women was associated with lower sense of belonging to the LGBT community, drug use problem and mental distress. CONCLUSIONS: The findings indicate that forced sex among Southern African women is a serious issue that needs further exploration. Clinicians should be made aware of the prevalence and possible consequences of forced sex among lesbian and bisexual women. Policies and community interventions should be designed to address this problem. PMID- 25783654 TI - Efficacy of laparoscopic adenomyomectomy using double-flap method for diffuse uterine adenomyosis. AB - BACKGROUND: Adenomyomectomy has recently been considered the priority option for the treatment of adenomyosis, however, the surgical efficacy and modes are still debated. We aimed to evaluate the efficacy of laparoscopic adenomyomectomy using a double-flap method for the treatment of uterine diffuse adenomyosis when compared with conventional laparoscopic adenomyomectomy. METHODS: Laparoscopic adenomyomectomy using the conventional method (group A, n = 48) and the double flap method (group B, n = 46) to treat diffuse uterine adenomyosis, respectively. Visual analog scale (VAS), menstrual amount, serum CA125 levels, and uterine volume were comparatively analyzed in both groups. RESULTS: The VAS scores, menstrual amount, serum CA125 levels, and uterine volume at 12 or 24 months after surgery significantly reduced in group B than in group A (P < 0.05); these parameters were statistically decreased in both groups after surgery compared with those obtained before surgery (P < 0.001). Moreover, serum CA125 levels and uterine volume at six months of follow up were significantly lower in group B than in group A (P < 0.01). In addition, blood loss during surgery was similar in groups A and B (P > 0.05), although the operative time was significantly longer in group B than that in group A (P < 0.05). CONCLUSIONS: Laparoscopic adenomyomectomy using the double-flap method may be an effective technique to treat uterine diffuse adenomyosis. PMID- 25783655 TI - Integration of HIV and cervical cancer screening perceptions and preferences of communities in Uganda. AB - BACKGROUND: Despite the fact that HIV-positive women carry an increased risk of developing cervical cancer (CC) in comparison with HIV-negative women, HIV and CC screening programs in many developing countries have remained unintegrated. The objective of this study is to explore perceptions and preferences of community members in Uganda, including women, men, and village health teams, regarding the integration of HIV and CC screening services in a single-visit approach. METHODS: This qualitative study was conducted in three districts in Uganda. Data were collected through focus group discussions with women and village health teams, and individual interviews with men. Respondents were purposely selected from among those linked to three CC clinics in the three districts. The content analysis method was used to analyze the data. RESULTS: Three themes emerged from the data, namely appreciating the benefits of integration, worrying about the challenges of integration, and preferences for integration. The women endorsed the benefits. However, there were worries that integration would prolong the waiting time at the health facility and induce tiredness in both the healthcare providers and the women. There were also fears of being found positive for both HIV and CC and the consequences such as stress, self-isolation, and social conflicts. Participants, particularly the women, considered the challenges of screening integration to be manageable by, for example, taking a day off work to visit the hospital, delegating house chores to other family members, or taking a packed lunch on visiting the hospital. CONCLUSIONS: The community members in Uganda perceive the benefits of HIV and CC screening integration to outweigh the challenges, and expect that the challenges can be minimized or managed by the women. Therefore, when considering HIV and CC screening integration, it is important to not only recognize the benefits but also take into consideration the perceived challenges and preferences of community members. PMID- 25783656 TI - Contribution of Arab countries to breast cancer research: comparison with non Arab Middle Eastern countries. AB - BACKGROUND: Breast cancer is one of the most common types of cancers affecting women worldwide. The main objective of this study was to assess and compare research activity in breast cancer in Arab countries with non-Arab Middle Eastern countries. METHODS: Publications about "breast cancer" as a research topic were retrieved using the ISI Web of Science database. Analysis was confined to original research and review articles. Research productivity was assessed by assessing number of publications and time trend of these publications, names of journals, citation analysis, top 10 active institutions as well as country contribution to breast cancer research. The quantity and quality of publications from Arab countries in addition to 3 other Middle East countries (Turkey, Iran and Israel) were assessed and compared using the h-index tool. RESULTS: A total of 1658 original research and review articles about "breast cancer" were published from Arab countries. Annual research productivity from Arab countries in the field of "breast cancer" was negligible but showed a significant increase in the last decade. Retrieved documents had relatively high citation parameters as measured by h-index of 61 and average citations of 17.46 per document. The highest research productivity was from Egypt with a total publication of 582 (35.10%). Cairo University with a total of 149 (8.99%) publications had the highest research productivity among institutions in Arab world. Forty four documents (2.65%) of breast cancer documents were published in Saudi Medical Journal. Arab researchers collaborated mostly with researchers from the United States of America (305; 18.40%) in breast cancer research. Compared with other non-Arab Middle Eastern countries, Arab countries had higher research productivity than some countries and lower than others, particularly Israel. CONCLUSIONS: The present data reveals a good contribution of some Arab countries to the field of "breast cancer" research. There is a gap between Arab countries and Israel in the quality of breast cancer research. PMID- 25783657 TI - Pain-preventing strategies in mammography: an observational study of simultaneously recorded pain and breast mechanics throughout the entire breast compression cycle. AB - BACKGROUND: Many women consider mammography painful. Existing studies on pain preventing strategies only mention pain scores reported before and after breast compression. Studying the pain dynamics during the entire compression cycle may provide new insights for effective pain-preventing strategies. METHODS: This observational study included 117 women who consented to use a custom turning knob to indicate their pain experience during standard mammographic breast compressions in the Academic Medical Center in Amsterdam, The Netherlands. The breast thickness, compression force, contact area, contact pressure and pain experience were recorded continuously. Breast volume was calculated retrospectively from the mammograms. We visualized the progression of pain in relation to breast mechanics for five groups of breast volumes and we performed multivariable regressions to identify factors that significantly predict pain experience. RESULTS: Breast compressions consisted of a deformation phase for flattening, and a clamping phase for immobilization. The clamping phase lasted 12.8 +/- 3.6 seconds (average +/- standard deviation), 1.7 times longer than the 7.5 +/- 2.6 seconds deformation phase. During the clamping phase, the average pain score increased from 4.75 to 5.88 (+24 %) on a 0 - 10 Numerical Rating Scale (NRS), and the proportion of women who reached severe pain (NRS >= 7) increased from 23 % to 50 % (more than doubled). Moderate pain (NRS >= 4) was reported up to four days after the mammogram. Multivariable analysis showed that pain recollection of the previous mammogram and breast pain before the compression, are significant predictors for pain. Women with smallest breasts experienced most pain: They received highest contact pressures (force divided by contact area) and the pressure increased at the highest rate. CONCLUSION: We suggest further research on two pain-preventing strategies: 1) using a personalized compression protocol by applying to all breasts the same target pressure at the same, slow rate, and 2) shortening the phase during which the breast is clamped. PMID- 25783659 TI - Moderate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats. AB - Painful neuropathy is a long-term and difficult to treat complication of diabetes that affects 25% of diabetic patients and interferes with their quality of life. Unfortunately, available medical treatments are relatively ineffective due to dependency and addiction. Emerging research indicates that moderate-to-vigorous physical activity provides health-related benefits. However, adequate data is not available to determine whether regular exercise would prevent or delay the development of painful neuropathy in subjects with Type 1 diabetes. This study demonstrates the significance of moderate exercise in the amelioration of pain in animals with Type 1 diabetes after 6weeks of exercise paradigm. After initial acclimatization, streptozotocin-diabetic animals were placed in motorized running wheels for 60minperday, for five days a week for 6weeks starting at one week after diabetes. A growing body of evidence suggests that the release of proinflammatory cytokines plays an important role in the development and persistence of pain. This study demonstrates that moderate exercise increases the expression of inhibitory neurotransmitter enkephalin and also reduces the presence of a number of proinflammatory cytokines in the dorsal root ganglia (DRG), subsequently impeding the development of neuropathy along with a decrease in the voltage gated ion channels in the DRG. Overall, the study suggests that exercise may provide an alternate route of treatment of painful neuropathy in Type 1 diabetic subjects by decreasing the use of pain medications, thereby providing a more useful and efficient way for pain management. PMID- 25783658 TI - Venous system in acute brain injury: Mechanisms of pathophysiological change and function. AB - Cerebral vascular injury is a major component of acute brain injury. Currently, neuroprotective strategies primarily focus on the recanalization of cerebral arteries and capillaries, and the protection of insulted neurons. Hitherto, the role of vein drainage in the pathophysiology of acute brain injury has been overlooked, due to an under appreciation of the magnitude of the impact of veins in circulation. In this review, we summarize the changes in the vein morphology and functions that are known, or likely to occur related to acute brain injury, and aim to advance the therapeutic management of acute brain injury by shifting the focus from reperfusion to another term: recirculation. Recent progress in the neurobiological understanding of the vascular neural network has demonstrated that cerebral venous systems are able to respond to acute brain injury by regulating the blood flow disharmony following brain edema, blood brain barrier disruption, ischemia, and hemorrhage. With the evidence presented in this review, future clinical management of acutely brain injured patients will expand to include the recirculation concept, establishing a harmony between arterial and venous systems, in addition to the established recanalization and reperfusion strategies. PMID- 25783660 TI - Use of cell-based assays in myasthenia gravis and other antibody-mediated diseases. AB - The increasing demand on diagnostic assays that are sensitive and specific for pathogenic antibodies, and the interest in identifying new antigens, prompted the development of cell-based assays for the detection of autoantibodies in myasthenia gravis and other autoimmune disorders. Cell-based assays were initially used to show that clustering the AChR improved the positivity in myasthenia gravis, and similar assays have now been applied to detection of antibodies to neuromuscular junction candidate proteins such as LRP4 and agrin. In addition cell-based assays have been used in the routine detection of antibodies to proteins expressed on the surface of neurons (NMDAR, LGI1, CASPR2, AMPAR, GABA-A/B, GlyR, and DPPX) and glia (AQP4, MOG). Here, we summarize the findings in myasthenia and discuss the advantages, disadvantages and controversial issues of using cell-based assays in the detection of these antibodies, and their relevance to the testing of preclinical models of disease. PMID- 25783661 TI - Recall accuracy of mobile phone calls among Japanese young people. AB - This study aimed to elucidate the recall accuracy of mobile phone calls among young people using new software-modified phone (SMP) technology. A total of 198 Japanese students aged between 10 and 24 years were instructed to use a SMP for 1 month to record their actual call statuses. Ten to 12 months after this period, face-to-face interviews were conducted to obtain the self-reported call statuses during the monitoring period. Using the SMP record as the gold standard of validation, the recall accuracy of phone calls was evaluated. A total of 19% of the participants (34/177) misclassified their laterality (i.e., the dominant side of ear used while making calls), with the level of agreement being moderate (kappa-statistics, 0.449). The level of agreement between the self-reports and SMP records was relatively good for the duration of calls (Pearson's r, 0.620), as compared with the number of calls (Pearson's r, 0.561). The recall was prone to small systematic and large random errors for both the number and duration of calls. Such a large random recall error for the amount of calls and misclassification of laterality suggest that the results of epidemiological studies of mobile phone use based on self-assessment should be interpreted cautiously. PMID- 25783662 TI - Microbial abundance and community structure in a melting alpine snowpack. AB - Snowmelt is a crucial period for alpine soil ecosystems, as it is related to inputs of nutrients, particulate matter and microorganisms to the underlying soil. Although snow-inhabiting microbial communities represent an important inoculum for soils, they have thus far received little attention. The distribution and structure of these microorganisms in the snowpack may be linked to the physical properties of the snowpack at snowmelt. Snow samples were taken from snow profiles at four sites (1930-2519 m a.s.l.) in the catchment of the Tiefengletscher, Canton Uri, Switzerland. Microbial (Archaea, Bacteria and Fungi) communities were investigated through T-RFLP profiling of the 16S and 18S rRNA genes, respectively. In parallel, we assessed physical and chemical parameters relevant to the understanding of melting processes. Along the snow profiles, density increased with depth due to compaction, while other physico-chemical parameters, such as temperature and concentrations of DOC and soluble ions, remained in the same range (e.g. <2 mg DOC L(-1), 5-30 MUg NH4 (+)-N L(-1)) in all samples at all sites. Along the snow profiles, no major change was observed either in cell abundance or in bacterial and fungal diversity. No Archaea could be detected in the snow. Microbial communities, however, differed significantly between sites. Our results show that meltwater rearranges soluble ions and microbial communities in the snowpack. PMID- 25783663 TI - Evacuate or Shelter-in-place? The Role of Corporate Memory and Political Environment in Hospital-evacuation Decision Making. AB - PROBLEM: Hospital-evacuation decisions are rarely straightforward in protracted advance-warning events. Previous work provides little insight into the decision making process around evacuation. This study was conducted to identify factors that most heavily influenced the decisions to evacuate the US Department of Veterans Affairs (VA) New York Harbor Healthcare System's (NYHHS; New York USA) Manhattan Campus before Hurricane Irene in 2011 and before Superstorm Sandy in 2012. METHODS: Semi-structured interviews with 11 senior leaders were conducted on the processes and factors that influenced the evacuation decisions prior to each event. RESULTS: The most influential factor in the decision to evacuate the Manhattan Campus before Hurricane Irene was New York City's (NYC's) hospital evacuation mandate. As a federal facility, the Manhattan VA medical center (VAMC) was exempt from the city's order, but decision makers felt compelled to comply. In the case of Superstorm Sandy, corporate memory of a similar 1992 storm that crippled the Manhattan facility drove the decision to evacuate before the storm hit. CONCLUSIONS: Results suggest that hospital-evacuation decisions are confounded by political considerations and are influenced by past disaster experience. Greater shared situational awareness among at-risk hospitals, along with a more coordinated approach to evacuation decision making, could reduce pressure on hospitals to make these high-stakes decisions. Systematic mechanisms for collecting, documenting, and sharing lessons learned from past disasters are sorely needed at the institutional, local, and national levels. PMID- 25783664 TI - Giant negative magnetoresistance in Manganese-substituted Zinc Oxide. AB - We report a large negative magnetoresistance in Manganese-substituted Zinc Oxide thin films. This anomalous effect was found to appear in oxygen-deficient films and to increase with the concentration of Manganese. By combining magnetoresistive measurements with magneto-photoluminescence, we demonstrate that the effect can be explained as the result of a magnetically induced transition from hopping to band conduction where the activation energy is caused by the sp-d exchange interaction. PMID- 25783665 TI - Magnitude-based inference: progressive approach or flawed statistic? PMID- 25783666 TI - The case for magnitude-based inference. PMID- 25783667 TI - Response. PMID- 25783668 TI - Psychiatrists' awareness of partial- and non-adherence to antipsychotic medication in schizophrenia: results from the Australian ADHES survey. AB - OBJECTIVES: The Adherence in Schizophrenia (ADHES) initiative aimed to assess physicians' perspectives about treatment adherence in people with schizophrenia, and assess strategies to improve adherence. METHODS: Between March and April 2012, a 20-question survey was delivered to Australian psychiatrists (n = 3400). These anonymous surveys were returned by mail. The survey asked about the demographics of participating psychiatrists and the respondents' perceptions of different factors that affect the adherence of people with schizophrenia to their treatment with antipsychotic medications. Adherence was defined by the proportion of prescribed doses taken: non-adherence, if < 30%; partial-adherence, 30%-90%; and adherent, > 90%. Data were reported descriptively and were not weighted. RESULTS: Respondent psychiatrists (n = 406; response rate 12%) reported that one half (51%) of people with schizophrenia were either non-adherent (20%) or only partially adherent (31%). This was despite most (72%) psychiatrists' reporting that they assessed adherence to medication at every visit. The main reported reasons for medication discontinuation were: lack of insight (45%), drug or alcohol abuse (3%), or side effects (29%). The preferred strategies for improving adherence were switching to or adding a long-acting antipsychotic (40%), or simplifying the medication regimen (30%). CONCLUSIONS: Lack of adherence to antipsychotic medication remains a problem. More proactive management is required, to improve adherence and long-term outcomes. PMID- 25783669 TI - A qualitative evaluation of leadership development workshops for mental health workers from four Pacific Island Countries. AB - OBJECTIVE: This paper provides a qualitative evaluation of a series of leadership development workshops held at the New South Wales Institute of Psychiatry (NSWIOP) for mental health workers from Papua New Guinea, Federated States of Micronesia, Republic of Marshall Islands, and Palau. METHOD: Fourteen mental health workers attended the week-long training focused on project management and partnership development skills. In-depth interviews were conducted with participants at the commencement and conclusion of the training, and questionnaires were completed. A focus group was conducted with the NSWIOP organisers. The data was analysed using qualitative techniques to identify emergent themes for both participants and NSWIOP project team. FINDINGS: All Pacific Island participants responded positively to the training. All reported greater confidence in taking on formal or informal leadership roles in the workplace, developing project planning skills and interpersonal skills such as networking and partnerships. The NSWIOP organisers identified strengths and weaknesses in the delivery of this training. CONCLUSIONS: The strong partnerships developed between NSWIOP and the Ministry of Health in all four countries contributed to the success of the training. Leadership Development Programs are an important aspect of building capacity in the mental health services of Pacific Island Countries. PMID- 25783670 TI - Stopping the run-around? A study of services for people with comorbid mental health and substance use disorders in northern Adelaide. AB - OBJECTIVE: Comorbidity between mental health and alcohol and other drug (AOD) disorders is common. This study aimed to identify and describe all of the local government and non-government (NGO) mental health and AOD services in a socially disadvantaged urban region in Adelaide, South Australia. METHOD: Services were identified using telephone directories and the internet, and via information from workers employed by a wide range of mental health and AOD services. RESULTS: Local mental health and AOD services were difficult to locate, but eventually we identified a total of 70 services. Soon after this, reorganisation of the mental health services and a new NGO funding round changed the service configuration, with a decrease in the number of services. The available services were fragmented, and rarely addressed comorbidity specifically. CONCLUSION: Our real world study demonstrates the lack of a clear pathway for people to access existing services. Further, changes occur frequently as government funded services generally reorganise every couple of years, and NGO services come and go according to funding. There is a need for a central, widely available database for mental health and AOD services. More services addressing comorbid mental health and AOD disorders are required. PMID- 25783671 TI - A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease. AB - BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2 2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7 0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls. PMID- 25783672 TI - Lowered national cesarean section rates after a concerted action. AB - OBJECTIVE: To evaluate national cesarean section (CS) rates and other obstetric indicators after a concerted action to reduce CS rates was undertaken in Portugal from 2010 onwards. This action was based on the transmission of information and training of healthcare professionals, together with the inclusion of CS rates as a criterion for hospital funding. DESIGN: Retrospective observational population based study. SETTING: Portugal. POPULATION: Births occurring in Portugal between 2000 and 2014. METHODS: Governmental sources were used to obtain data on national CS, perinatal and maternal mortality rates. Rates of instrumental vaginal delivery, vaginal birth after cesarean (VBAC), hypoxia-related complications and perineal lacerations were retrieved for state-owned hospitals. MAIN OUTCOME MEASURES: CS, perinatal and maternal mortality, instrumental vaginal delivery, VBAC, hypoxia-related complications and perineal lacerations. RESULTS: After a continuous rise between 2000 and 2009, national CS rates declined significantly over the following 5 years (36.6% vs. 33.1%, time trend p <= 0.001). Perinatal mortality maintained a downward trend during this period, while maternal mortality remained unchanged. Rates of instrumental vaginal delivery, VBAC and perineal lacerations increased, while the incidence of hypoxia-related complications decreased. CONCLUSIONS: A concerted action based on the transmission of information and training of healthcare professionals, together with the inclusion of CS rates as a criterion for hospital funding, was followed by a significant reduction in national CS rates, as well as an improvement in most related obstetric indicators. There may be an association between the reported intervention and the observed changes. PMID- 25783673 TI - Coupling of ascorbate and nitric oxide dynamics in vivo in the rat hippocampus upon glutamatergic neuronal stimulation: a novel functional interplay. AB - BACKGROUND: Ascorbate and neuronal-derived nitric oxide (NO) play regulatory roles in the brain that tare dependent on their compartmentalization and diffusion. Glutamatergic activation triggers both ascorbate fluxes toward extracellular medium and NO production. The information on the profiles of change in time and space upon glutamatergic activation is scarce and yet this knowledge is important for the understanding of ascorbate and NO functions in vivo, in particular in the case of a coupled interaction between both dynamics. HYPOTHESIS: NO produced upon NMDA receptor activation is a modulator of ascorbate release to the extracellular space. METHODS: In this work, carbon fiber microelectrodes for simultaneous measurements of these substances in the hippocampus were used to collect information about ascorbate and NO dynamic profiles in real time. RESULTS: Glutamate stimulation evoked transient ascorbate and NO signals with high degree of spatial and temporal correlation between them. Combined experiments encompassing direct stimulus with NO and inhibitors of glutamate uptake and nNOS provided additional evidence supporting the modulator role of NO in the release of ascorbate to the extracellular space. CONCLUSIONS: The coupling between NO and ascorbate upon glutamatergic activation points to a functional impact on the activities of both compounds and, although the precise molecular mechanism needs to be clarified, such a coupling lays the foundations for new regulatory mechanisms in the brain. PMID- 25783674 TI - Sprouty2 mediated tuning of signalling is essential for somite myogenesis. AB - BACKGROUND: Negative regulators of signal transduction cascades play critical roles in controlling different aspects of normal embryonic development. Sprouty2 (Spry2) negatively regulates receptor tyrosine kinases (RTK) and FGF signalling and is important in differentiation, cell migration and proliferation. In vertebrate embryos, Spry2 is expressed in paraxial mesoderm and in forming somites. Expression is maintained in the myotome until late stages of somite differentiation. However, its role and mode of action during somite myogenesis is still unclear. RESULTS: Here, we analysed chick Spry2 expression and showed that it overlaps with that of myogenic regulatory factors MyoD and Mgn. Targeted mis expression of Spry2 led to inhibition of myogenesis, whilst its C-terminal domain led to an increased number of myogenic cells by stimulating cell proliferation. CONCLUSIONS: Spry2 is expressed in somite myotomes and its expression overlaps with myogenic regulatory factors. Overexpression and dominant-negative interference showed that Spry2 plays a crucial role in regulating chick myogenesis by fine tuning of FGF signaling through a negative feedback loop. We also propose that mir-23, mir-27 and mir-128 could be part of the negative feedback loop mechanism. Our analysis is the first to shed some light on in vivo Spry2 function during chick somite myogenesis. PMID- 25783675 TI - Effects of genetic and environmental risk assessment feedback on colorectal cancer screening adherence. AB - Little is known about the impact of genetic and environmental risk assessment (GERA) feedback on colorectal cancer (CRC) screening. In a recently completed randomized trial, primary care patients received GERA feedback based on a blood test for genetic polymorphisms and serum folate level (GERA Group) versus usual care (Control Group). Subsequently, participants were offered CRC screening. Among participants who received GERA feedback, being at elevated risk was negatively associated with prospective CRC screening adherence. Secondary analyses of data from this study were performed to identify independent predictors of adherence among participants who received GERA feedback. We obtained baseline survey, follow-up survey, and endpoint medical records data on sociodemographic background, knowledge, psychosocial characteristics, risk status, and adherence for 285 GERA Group participants. Univariate and multivariable analyses were performed to identify predictors of CRC screening adherence. Following a 6-month outcomes observation period, we also conducted two focus groups with GERA Group participants to assess their perceptions of GERA risk feedback and screening. Content analyses of focus group data were evaluated to gain insights into participant response to risk feedback. Overall, half of GERA Group participants adhered to screening within 6 months after randomization. Multivariable analyses showed a statistically significant interaction between race and GERA feedback status relative to screening adherence (p = 0.043). Among participants who received average risk feedback, adherence was comparable among whites (49.7 %) and nonwhites (54.1 %); however, among those at elevated risk, adherence was substantially higher among whites (66.7 %) compared to nonwhites (33.3 %). Focus group findings suggest that whites were more likely than nonwhites to view elevated risk feedback as a prompt to screen. In response to receiving elevated risk feedback, nonwhites were more likely than whites to report feeling anxiety about the likelihood of being diagnosed with CRC. Further research is needed to explore race-related CRC screening differences in response to GERA feedback. PMID- 25783676 TI - Recurrence Risk-Scoring Model for Stage I Adenocarcinoma of the Lung. AB - PURPOSE: The aim of this retrospective, multicenter study was to develop a recurrence risk-scoring model in patients with curatively resected stage I lung adenocarcinoma (ADC). METHODS: Clinicopathologic and outcome data for a development cohort of 1,700 patients with pathologic stage I ADC from four institutions resected between January 2000 and December 2009 were evaluated. A phantom study was performed for correction of inter-institutional differences in positron emission tomography-standardized uptake value (PET-SUV). A nomogram for recurrence prediction was developed using Cox proportional hazards regression. This model was validated in a cohort of 460 patients in two other hospitals. The recurrence rate was 21.0 % for the development cohort and 22.1 % for the validation cohort. RESULTS: In multivariable analysis, three independent predictors for recurrence were identified: pathologic tumor size (hazard ratio [HR] 1.03, 95 % CI 1.017-1.048; p < 0.001), corrected PET-SUV (HR 1.08, 95 % CI 1.051-1.105; p < 0.001), and lymphovascular invasion (HR 1.65, 95 % CI 1.17-2.33; p = 0.004). The nomogram was made based on these factors and a calculated risk score was accorded to each patient. Kaplan-Meier analysis of the development cohort showed a 5-year recurrence-free survival (RFS) of 83 % (95 % CI 0.80-0.86) in low-risk patients and 59 % (95 % CI 0.54-0.66) in high-risk patients with the highest 30 percentile scores. The concordance index was 0.632 by external validation. CONCLUSIONS: This recurrence risk-scoring model can be used to predict the RFS for pathologic stage I ADC patients using the above three easily measurable factors. High-risk patients need close follow-up and can be candidates for adjuvant chemotherapy. PMID- 25783677 TI - Moving fast and moving slow. PMID- 25783678 TI - Management of Premenopausal Women with Neoadjuvant Endocrine Therapy: A Single Institution Experience. AB - BACKGROUND: In postmenopausal women with hormone receptor (HR)-positive breast cancer, neoadjuvant endocrine therapy (ET) provides effective downstaging of tumor for improved surgical outcome and offers an important advantage of assessing tumor endocrine responsiveness for individualized therapy in the adjuvant setting. Although approximately 60 % of breast cancers in premenopausal women are HR positive, the role of neoadjuvant ET in this population is not well defined. METHODS: We identified 162 patients with stage I-III estrogen receptor positive breast cancer treated with neoadjuvant ET between 2003 and 2012. Of this group, 17 patients were premenopausal. Data included patient/tumor characteristics, surgical, systemic, and radiation treatment received, and outcomes. Descriptive statistics were used for data summary. RESULTS: The cohort included 17 patients with a mean age of 46.2 years (range 39-53 years). Patients were treated with a combination of gonadotrophic-releasing hormone agonist with either an aromatase inhibitor (n = 14) or tamoxifen (n = 3) for 4-6 months. Among the premenopausal patients, six underwent breast-conserving therapy, with 3 of 6 (50.0 %) having positive margins. Adjuvant chemotherapy was recommended for 13 (76.5 %), and adjuvant radiotherapy was recommended for 13 (76.5 %). Of the 17 premenopausal women, 11 had a clinical response based on response evaluation criteria in solid tumors (RECIST) of a decrease in tumor size of 30 % (64.7 %); this is similar to that of postmenopausal women, where 85 of 145 (58.6 %) patients showed a clinical response. CONCLUSION: As with all neoadjuvant systemic interventions, we identified those with disease that did and did not respond to ET, emphasizing the heterogeneity of HR-positive breast cancers. The response rate of premenopausal women to neoadjuvant ET is similar to that of postmenopausal women. PMID- 25783679 TI - Quality of life, functional outcomes, and wound complications in patients with soft tissue sarcomas treated with preoperative chemoradiation: a prospective study. AB - BACKGROUND: Preoperative irradiation reduces local recurrence of soft tissue sarcomas (STSs), but major wound complication rates approach 25-35 %. Using a novel neoadjuvant chemoradiation protocol, we prospectively documented functional outcomes and quality of life (QOL) and hypothesized a lower major wound complication rate. METHODS: Patients with STS deep to muscular fascia were treated with 3 days of doxorubicin (30 mg/day) and 10 days of irradiation (300 cGy/day) followed by limb-sparing surgery. Wound complications were assessed, and functional assessment and QOL were followed prospectively using the Toronto Extremity Salvage Score (TESS), Musculoskeletal Tumor Society (MSTS), and Short Form (SF)-36 questionnaires preoperatively and 6 and 12 months postoperatively. RESULTS: Altogether, 52 consecutive patients were accrued during 2006-2011. Overall, 80.8 % of STSs were >5 cm, and 67.3 % involved the lower extremity. Seven (13.5 %) major wound complications occurred, all requiring reoperation. Preoperative scores for TESS, MSTS, and SF-36 physical (PCS) and mental (MCS) health components were 83.3, 86.7, 40.6, and 49.4, respectively. There were no differences seen 6 months postoperatively. By 12 months, however, patients showed improved functional scores (TESS 93.0, p = 0.02; MSTS 93.3, p < 0.01) and QOL scores (PCS 45.1, p = 0.02; MCS = 52.9, p = 0.05). No differences in scores were seen between patients with or without wound complications. CONCLUSIONS: Patients treated with our neoadjuvant chemoradiation protocol had stable QOL and functional scores 6 months postoperatively and showed improvement by 12 months. Importantly, the major wound complication rate was low. PMID- 25783681 TI - Quilting Suture of Mastectomy Dead Space Compared with Conventional Closure with Drain. AB - PURPOSE: This study was designed to compare conventional closure with a drain and quilting suture of mastectomy dead space for preventing wound seroma. METHODS: Consecutive patients undergoing mastectomy for breast cancer were included in this retrospective observational study. Patients received conventional closure with drainage or quilting suture for wound closure. Propensity score (PS) matching was performed based on potential confounders to minimize selection bias. The primary outcome was the rate of type 2 or 3 wound seroma according to the common terminology criteria for adverse events (CTCAE) definition. RESULTS: A total of 119 patients were included (quilting suture n = 59; conventional closure n = 60). Type 2 or 3 seroma was observed in 6.8 % of the quilting suture group and 21.7 % of the conventional closure group (crude odds ratio 0.26; 95 % confidence interval 0.08-0.86; p = 0.03). The overall seroma rate was 15.2 % in the quilting suture group and 51.7 % in the conventional closure group (p < 0.001). Persistent pain at days 15-21 was significantly less frequent in the quilting suture group than in the conventional suture group. PS matched analysis confirmed these findings, in particular the lower rate of type 2 or 3 seroma in the quilting suture group than in the conventional closure group (PS-matched odds ratio 0.16; 95 % confidence interval 0.04-0.72; p = 0.02). CONCLUSIONS: Quilting suture of the mastectomy dead space is associated with significantly less frequent seroma than conventional closure with drain. PMID- 25783680 TI - Substaging Nodal Status in Ampullary Carcinomas has Significant Prognostic Value: Proposed Revised Staging Based on an Analysis of 313 Well-Characterized Cases. AB - BACKGROUND: Current nodal staging (N-staging) of ampullary carcinoma in the TNM staging system distinguishes between node-negative (N0) and node-positive (N1) disease but does not consider the metastatic lymph node (LN) number. METHODS: Overall, 313 patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma were categorized as N0, N1 (1-2 metastatic LNs), or N2 (>=3 metastatic LNs), as proposed by Kang et al. Clinicopathological features and overall survival (OS) of the three groups were compared. RESULTS: The median number of LNs examined was 11, and LN metastasis was present in 142 cases (45 %). When LN-positive cases were re-classified according to the proposed staging system, 82 were N1 (26 %) and 60 were N2 (19 %). There was a significant correlation between proposed N-stage and lymphovascular invasion, perineural invasion, increased tumor size (each p < 0.001), and surgical margin positivity (p = 0.001). The median OS in LN-negative cases was significantly longer than that in LN-positive cases (107.5 vs. 32 months; p < 0.001). Patients with N1 and N2 disease had median survivals of 40 and 24.5 months, respectively (p < 0.0001). In addition, 1-, 3-, and 5-year survivals were 88, 76, 62 %, respectively, for N0; 90, 55, 31.5 %, respectively, for N1; and 68, 34, 30 %, respectively for N2 (p < 0.001). Even with multivariate modeling, the association between higher proposed N stage and shorter survival persisted (hazard ratio 1.6 for N1 and 1.9 for N2; p = 0.018). CONCLUSIONS: Classification of nodal status in ampullary carcinomas based on the number of metastatic LNs has a significant prognostic value. A revised N-staging classification system should be incorporated into the TNM staging of ampullary cancers. PMID- 25783682 TI - Analysis of protein expression changes of the Vero E6 cells infected with classic PEDV strain CV777 by using quantitative proteomic technique. AB - Recent outbreaks of porcine epidemic diarrhea virus (PEDV) have caused widespread concern. The identification of proteins associated with PEDV infection might provide insight into PEDV pathogenesis and facilitate the development of novel antiviral strategies. We analyzed the differential protein profile of PEDV infected Vero E6 cells using mass spectrometry and an isobaric tag for relative and absolute quantification. A total of 126 proteins were identified that were differentially expressed between the PEDV-infected and mock-infected groups (P<0.05, quantitative ratio >=1.2), among which the expression of 58 proteins was up-regulated and that of 68 proteins was down-regulated in the PEDV-infected Vero E6 cells, involving in integrin beta2/beta3, cystatin-C. The Gene Ontology analysis indicated that the molecular function of the differentially expressed proteins (DEPs) was primarily related to binding and catalytic activity, and that the biological functions in which the DEPs are involved included metabolism, organismal systems, cellular processes, genetic information processing, environmental information processing, and diseases. Among the disease-related functions, certain anti-viral pathways and proteins, such as the RIG-I-like receptor, Rap1, autophagy, mitogen-activated protein kinase, PI3K-Akt and Jak STAT signaling pathways, and integrin beta2/beta3 and cystatin-C proteins, represented potential factors in PEDV infection. Our findings provide valuable insight into PEDV-Vero E6 cell interactions. PMID- 25783683 TI - An ex vivo avian leukocyte culture model for West Nile virus infection. AB - West Nile virus (WNV) replicates in a wide variety of avian species, which act as amplification hosts. In particular, WNV generates high titers and elicits severe pathology in American crows (AMCRs; Corvus brachyrhynchos), a species that has been used as a sentinel for WNV transmission. Although the specific cellular targets of WNV replication in AMCRs are not well defined, preliminary evidence suggests that leukocytes may be an important target of early replication. Therefore, development of a protocol for ex vivo culture of AMCR leukocytes as a model for assessing differential avian host susceptibility is described herein. WNV growth in these cultures mirrored in vivo viremia profiles. These data indicate that ex vivo leukocyte cultures can be used for preliminary pathological assessment of novel WNV strains and potentially of other flaviviruses that use avian reservoir hosts. PMID- 25783684 TI - Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. AB - INTRODUCTION: Pregestational and gestational diabetes mellitus (PGDM; GDM) are significant health concerns because they are associated with an increased rate of malformations and maternal health complications. METHODS: We reviewed the data that help us to understand the effects of diabetes in pregnancy. RESULTS: Diabetic embryopathy can affect any developing organ system, but cardiovascular and neural tube defects are among the most frequent anomalies. Other complications include preeclampsia, preterm delivery, fetal growth abnormalities, and perinatal mortality. Neurodevelopmental studies on offspring of mothers with diabetes demonstrated increased rate of Gross and Fine motor abnormalities, of Attention Deficit Hyperactivity Disorder, learning difficulties, and possibly also Autism Spectrum Disorder. The mechanisms underlying the effects of maternal hyperglycemia on the developing fetus may involve increased oxidative stress, hypoxia, apoptosis, and epigenetic changes. Evidence for epigenetic changes are the following: not all progeny are affected and not to the same extent; maternal diet may influence pregnancy outcomes; and maternal diabetes alters embryonic transcriptional profiles and increases the variation between transcriptomic profiles as a result of altered gene regulation. Research in animal models has revealed that maternal hyperglycemia is a teratogen, and has helped uncover potential therapeutic targets which, when blocked, can mitigate or ameliorate the negative effects of diabetes on the developing fetus. CONCLUSIONS: Tight metabolic control, surveillance, and labor management remain the cornerstone of care for pregnant women with diabetes, but advances in the field indicate that new treatments to protect the mother and baby are not far from becoming clinical realities. PMID- 25783685 TI - Adeno-associated virus-mediated gene therapy in cardiovascular disease. AB - PURPOSE OF REVIEW: The use of adeno-associated virus (AAV) as an efficient, cardiotropic, and safe vector, coupled with the identification of key molecular targets, has placed gene-based therapies within reach of cardiovascular diseases. The purpose of this review is to provide a focused update on the current advances related to AAV-mediated gene therapy in cardiovascular diseases, and particularly in heart failure (HF), wherein gene therapy has recently made important progress. RECENT FINDINGS: Multiple successful preclinical studies suggest a potential utility of AAV gene therapy for arrhythmias and biological heart pacing, as well as RNA overexpression. Moreover, AAV-mediated overexpression of several molecular targets involved in HF has demonstrated promising results in clinically relevant large animal models. In humans, a safe and successful completion of a phase 2 clinical trial targeting the sarcoplasmic reticulum calcium ATPase pump with AAV has been reported. Serial studies are ongoing to further prove the efficacy of AAV-mediated sarcoplasmic reticulum calcium ATPase pump gene transfer in human HF. SUMMARY: Significant progress in clinical translation of AAV-mediated cardiac gene therapy has been achieved in recent years. This will prompt further clinical trials, and positive results could open a new era for cardiac gene therapy. PMID- 25783686 TI - Atypical sporadic CJD-MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease. AB - We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain. PMID- 25783687 TI - [Bone marrow edema in trauma surgery]. PMID- 25783688 TI - [Pathophysiology of traumatic bone marrow edema]. AB - BACKGROUND: Morphologically, bone marrow edema (BME) is an accumulation of fluid in the bone marrow. The BME is per se non-specific but can be identified at an early stage with magnetic resonance imaging (MRI). The underlying pathomechanism remains unclear. The BME can occur as an individual entity and as an accompanying condition of many diseases. The BME can be divided into three groups, ischemic, reactive and mechanical BME. Mechanical BME occurs after trauma or repetitive strain. Typical histological changes are present and there is no clear boundary between edema and microfracture. Some forms of trauma show BME in typical localizations. Both the trauma and the possible accompanying injuries can be indirectly indicated in this way in cases with an unknown trauma mechanism. CONCLUSION: The BME can be present as an isolated entity or as a comorbidity. For initiation of therapy, a comprehensive medical history and targeted diagnostics are indispensable. In some cases BME is indicative of the trauma mechanism and possible further accompanying injuries. PMID- 25783689 TI - [Occult fractures of extremities in adults and children. Exemplified by foot and ankle injuries]. AB - BACKGROUND: Occult fractures in children and adults cannot by definition be diagnosed by conventional radiographs. These injuries are usually recognized as bone marrow edema by magnetic resonance imaging (MRI). There are no randomized controlled trials or prospective cohort studies concerning the correct management of occult fractures and, therefore, no evidence-based treatment guidelines can be drafted. OBJECTIVES: This article summarizes the current diagnostic and treatment concepts for occult fractures under special consideration of foot and ankle injuries. METHODS: A selective search of the current literature was performed and also taking own experience into consideration. RESULTS AND CONCLUSION: The clinical prognosis of occult fractures is generally good and there is no evidence that these lesions need specific treatment. Besides forensic applications and problems pursuant to insurance law, MRI examination is only indicated when conventional radiographs are unremarkable, pain persists for an unusually long period of time and when a relevant therapeutic consequence can be expected from the MRI results. Classical pitfalls are combinations of occult fractures with potentially unstable ligamentous injuries and patients with disordered pain perception as in cases of diabetic polyneuropathy, as the common therapeutic concept of weight bearing according to pain is not suitable for these patients and can lead to severe complications. PMID- 25783690 TI - [Differentiation between acute osteoporotic and metastatic vertebral body fractures by imaging]. AB - OBJECTIVES: This article discusses the morphological criteria for the differentiation between acute osteoporotic and metastatic vertebral body fractures and new imaging methods, such as diffusion-weighted and chemical shift magnetic resonance imaging (MRI) are presented. BACKGROUND: The differential diagnostics of osteoporotic and metastatic vertebral body fractures can be difficult in some cases. Both entities normally occur without adequate trauma and predominantly in elderly patients. IMAGING: Conventional X-ray examination is the initial imaging method of choice but is not able to reliably differentiate between the osteoporotic or metastatic etiology of a fracture. Computed tomography (CT) clearly depicts osseous destruction in metastatic fractures but lacks specificity. Magnetic resonance imaging (MRI) shows a higher sensitivity and specificity in differentiating osteoporotic and metastatic fractures. DIFFERENTIAL DIAGNOSTICS: The combination CT and MRI allows an accurate diagnosis with respect to an osteoprorotic or metastatic etiology in most of cases but bone marrow edema in acute fractures sometimes leads to ambiguous results and differential diagnostic problems. PMID- 25783691 TI - [Therapy of bone marrow edema syndrome in the knee with denosumab. Case report]. AB - BACKGROUND: The bone marrow edema syndrome (BMES) is a painful joint disease which usually affects healthy middle aged persons. It is usually treated conservatively. AIM: This case report describes the clinical history of a patient with BMES and a therapy attempt with denosumab. RESULTS AND DISCUSSION: Complete restitution of the bone marrow edema in the knee and the disappearance of clinical complaints were observed 8 weeks after a single therapy with 60 mg denosumab (Prolia(r)) as a subcutaneous injection. No side-effects of the therapy were noted. PMID- 25783692 TI - [Deployment and efficacy of ground versus helicopter emergency service for severely injured patients. Analysis of a nationwide Swiss trauma center]. AB - The influence of the transport mode, i.e. Helicopter Emergency Medical Service (HEMS) versus ground-based Emergency Medical Service (EMS) on the mortality of multiple trauma patients is still controversially discussed in the literature. In this study a total of 333 multiple trauma patients treated over a 1-year period in a level I trauma center in Switzerland were analyzed. Using the newly established revised injury severity classification (RISC) score there was a tendency towards a better outcome for patients transported by HEMS (standardized mortality ratio 1.06 for HEMS versus 1.29 for EMS). Overall a short preclinical time and the presence of an emergency physician (EP) were associated with a better outcome. PMID- 25783693 TI - [Stabilization of the pelvic ring with photodynamic bone stabilization (IlluminOssTM)]. AB - We describe the case of an 88-year-old woman who presented with painful symptoms of the pelvis after low-energy trauma. Conservative treatment with pain therapy and pain-adapted mobilization was unsuccessful. Diagnostics showed a fragility fracture of the pelvic ring; therefore, we performed photodynamic bone stabilization (IlluminOssTM) of the pubic bone and percutaneous cement-augmented fixation of the iliosacral joint assisted by computed tomography (CT) fluoroscopy. Imaging showed a stable healed fracture 4 months after surgery. PMID- 25783694 TI - Accessible protocol for asymmetric hydroformylation of vinylarenes using formaldehyde. AB - We report herein on an accessible protocol for the asymmetric hydroformylation of vinylarenes using formaldehyde as a substitute for syngas. The regioselectivity (branched/linear = up to 96/4) and enantioselectivity (up to 95% ee) can be attributed to the use of chiral Ph-bpe as a ligand. PMID- 25783696 TI - Co-registered Topographical, Band Excitation Nanomechanical, and Mass Spectral Imaging Using a Combined Atomic Force Microscopy/Mass Spectrometry Platform. AB - The advancement of a hybrid atomic force microscopy/mass spectrometry imaging platform demonstrating the co-registered topographical, band excitation nanomechanical, and mass spectral imaging of a surface using a single instrument is reported. The mass spectrometry-based chemical imaging component of the system utilized nanothermal analysis probes for pyrolytic surface sampling followed by atmospheric pressure chemical ionization of the gas-phase species produced with subsequent mass analysis. The basic instrumental setup and operation are discussed, and the multimodal imaging capability and utility are demonstrated using a phase-separated polystyrene/poly(2-vinylpyridine) polymer blend thin film. The topography and band excitation images showed that the valley and plateau regions of the thin film surface were comprised primarily of one of the two polymers in the blend with the mass spectral chemical image used to definitively identify the polymers at the different locations. Data point pixel size for the topography (390 nm * 390 nm), band excitation (781 nm * 781 nm), and mass spectrometry (690 nm * 500 nm) images was comparable and submicrometer in all three cases, but the data voxel size for each of the three images was dramatically different. The topography image was uniquely a surface measurement, whereas the band excitation image included information from an estimated 20 nm deep into the sample and the mass spectral image from 110 to 140 nm in depth. Because of this dramatic sampling depth variance, some differences in the band excitation and mass spectrometry chemical images were observed and were interpreted to indicate the presence of a buried interface in the sample. The spatial resolution of the chemical image was estimated to be between 1.5 and 2.6 MUm, based on the ability to distinguish surface features in that image that were also observed in the other images. PMID- 25783697 TI - Videofluoroscopic Validation of a Translational Murine Model of Presbyphagia. AB - Presbyphagia affects approximately 40% of otherwise healthy people over 60 years of age. Hence, it is a condition of primary aging rather than a consequence of primary disease. This distinction warrants systematic investigations to understand the causal mechanisms of aging versus disease specifically on the structure and function of the swallowing mechanism. Toward this goal, we have been studying healthy aging C57BL/6 mice (also called B6), the most popular laboratory rodent for biomedical research. The goal of this study was to validate this strain as a model of presbyphagia for translational research purposes. We tested two age groups of B6 mice: young (4-7 months; n = 16) and old (18-21 months; n = 11). Mice underwent a freely behaving videofluoroscopic swallow study (VFSS) protocol developed in our lab. VFSS videos (recorded at 30 frames per second) were analyzed frame-by-frame to quantify 15 swallow metrics. Six of the 15 swallow metrics were significantly different between young and old mice. Compared to young mice, old mice had significantly longer pharyngeal and esophageal transit times (p = 0.038 and p = 0.022, respectively), swallowed larger boluses (p = 0.032), and had a significantly higher percentage of ineffective primary esophageal swallows (p = 0.0405). In addition, lick rate was significantly slower for old mice, measured using tongue cycle rate (p = 0.0034) and jaw cycle rate (p = 0.0020). This study provides novel evidence that otherwise healthy aging B6 mice indeed develop age-related changes in swallow function resembling presbyphagia in humans. Specifically, aging B6 mice have a generally slow swallow that spans all stages of swallowing: oral, pharyngeal, and esophageal. The next step is to build upon this foundational work by exploring the responsible mechanisms of presbyphagia in B6 mice. PMID- 25783698 TI - 'Food Sticking in My Throat': Videofluoroscopic Evaluation of a Common Symptom. AB - Prevalence of the symptom of food 'sticking' during swallowing has been reported to range from 5 to 50%, depending on the assessment setting. However, limited objective evidence has emerged to clarify factors that contribute to this symptom. Three hundred and fifteen patient records from an outpatient dysphagia clinic were reviewed to identify patients with symptoms of 'food sticking in the throat.' Corresponding videofluoroscopic swallowing studies for patients with this complaint were reviewed for the following variables: accuracy of symptom localization, identification and characteristics (anatomic, physiologic) of an explanatory cause for the symptom, and the specific swallowed material that identified the explanatory cause. One hundred and forty one patients (45%) were identified with a complaint of food 'sticking' in their throat during swallowing. Prevalence of explanatory findings on fluoroscopy was 76% (107/141). Eighty five percent (91/107) of explanatory causes were physiologic in nature, while 15% (16/107) were anatomic. The majority of explanatory causes were identified in the esophagus (71%). Symptom localization was more accurate when the explanatory cause was anatomic versus physiologic (75 vs. 18%). A non-masticated marshmallow presented with the highest diagnostic yield in identification of explanatory causes (71%). Patients complaining of 'food sticking in the throat' are likely to present with esophageal irregularities. Thus, imaging studies of swallowing function should include the esophagus. A range of materials, including a non masticated marshmallow, is helpful in determining the location and characteristics of swallowing deficits contributing to this symptom. PMID- 25783699 TI - Genetic architecture and functional characterization of genes underlying the rapid diversification of male external genitalia between Drosophila simulans and Drosophila mauritiana. AB - Male sexual characters are often among the first traits to diverge between closely related species and identifying the genetic basis of such changes can contribute to our understanding of their evolutionary history. However, little is known about the genetic architecture or the specific genes underlying the evolution of male genitalia. The morphology of the claspers, posterior lobes, and anal plates exhibit striking differences between Drosophila mauritiana and D. simulans. Using QTL and introgression-based high-resolution mapping, we identified several small regions on chromosome arms 3L and 3R that contribute to differences in these traits. However, we found that the loci underlying the evolution of clasper differences between these two species are independent from those that contribute to posterior lobe and anal plate divergence. Furthermore, while most of the loci affect each trait in the same direction and act additively, we also found evidence for epistasis between loci for clasper bristle number. In addition, we conducted an RNAi screen in D. melanogaster to investigate if positional and expression candidate genes located on chromosome 3L, are also involved in genital development. We found that six of these genes, including components of Wnt signaling and male-specific lethal 3 (msl3), regulate the development of genital traits consistent with the effects of the introgressed regions where they are located and that thus represent promising candidate genes for the evolution these traits. PMID- 25783700 TI - Dominance genetic variance for traits under directional selection in Drosophila serrata. AB - In contrast to our growing understanding of patterns of additive genetic variance in single- and multi-trait combinations, the relative contribution of nonadditive genetic variance, particularly dominance variance, to multivariate phenotypes is largely unknown. While mechanisms for the evolution of dominance genetic variance have been, and to some degree remain, subject to debate, the pervasiveness of dominance is widely recognized and may play a key role in several evolutionary processes. Theoretical and empirical evidence suggests that the contribution of dominance variance to phenotypic variance may increase with the correlation between a trait and fitness; however, direct tests of this hypothesis are few. Using a multigenerational breeding design in an unmanipulated population of Drosophila serrata, we estimated additive and dominance genetic covariance matrices for multivariate wing-shape phenotypes, together with a comprehensive measure of fitness, to determine whether there is an association between directional selection and dominance variance. Fitness, a trait unequivocally under directional selection, had no detectable additive genetic variance, but significant dominance genetic variance contributing 32% of the phenotypic variance. For single and multivariate morphological traits, however, no relationship was observed between trait-fitness correlations and dominance variance. A similar proportion of additive and dominance variance was found to contribute to phenotypic variance for single traits, and double the amount of additive compared to dominance variance was found for the multivariate trait combination under directional selection. These data suggest that for many fitness components a positive association between directional selection and dominance genetic variance may not be expected. PMID- 25783740 TI - Nocturnal Blood Pressure in Young Adults and Cognitive Function in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: Nocturnal blood pressure (BP) is associated with risk for cardiovascular events. However, the relationship between nocturnal BP in young adults and cognitive function in midlife remains unclear. METHODS: We used data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults Study, including 224 participants (mean age 30 years, 45% men, 63% African Americans). At the 20-year follow-up, the Stroop test (executive function), Digit Symbol Substitution Test (psychomotor speed), and Rey Auditory Verbal Learning Test (verbal memory) were assessed. RESULTS: Baseline mean office, daytime, and nocturnal BP were 109/73, 120/74, and 107/59 mm Hg, respectively. Nocturnal BP dipping, calculated as (nocturnal systolic BP [SBP]- daytime SBP) * 100/daytime SBP, was divided into quartiles (Q1: -39.3% to -16.9%; Q2: -16.8% to -13.2%, Q3 [reference]: -13.1% to -7.8%, and Q4: -7.7% to +56.4%). In multiple regression analyses, the least nocturnal SBP dipping (Q4 vs. reference) and higher nocturnal diastolic BP level were associated with worse Stroop scores, with adjustments for demographic and clinical characteristics, and cumulative exposure to office BP during follow-up (beta [standard error]: 0.37 [0.18] and 0.19 [0.07], respectively; all P < 0.05). Digit Symbol Substitution Test and Rey Auditory Verbal Learning Test were not significantly associated with nocturnal SBP dipping or nocturnal SBP/diastolic BP levels. CONCLUSIONS: Among healthy young adults, less nocturnal SBP dipping and higher nocturnal diastolic BP levels were associated with lower executive function in midlife, independent of multiple measures of office BP during long-term follow-up. PMID- 25783742 TI - Safety culture and the 5 steps to safer surgery: an intervention study. AB - BACKGROUND: Improvements in safety culture have been postulated as one of the mechanisms underlying the association between the introduction of the World Health Organisation (WHO) Surgical Safety Checklist with perioperative briefings and debriefings, and enhanced patient outcomes. The 5 Steps to Safer Surgery (5SSS) incorporates pre-list briefings, the three steps of the WHO Surgical Safety Checklist (SSC) and post-list debriefings in one framework. We aimed to identify any changes in safety culture associated with the introduction of the 5SSS in orthopaedic operating theatres. METHODS: We assessed the safety culture in the elective orthopaedic theatres of a large UK teaching hospital before and after introduction of the 5SSS using a modified version of the Safety Attitude Questionnaire - Operating Room (SAQ-OR). Primary outcome measures were pre-post intervention changes in the six safety culture domains of the SAQ-OR. We also analysed changes in responses to two items regarding perioperative briefings. RESULTS: The SAQ-OR survey response rate was 80% (60/75) at baseline and 74% (53/72) one yr later. There were significant improvements in both the reported frequency (P<0.001) and perceived importance (P=0.018) of briefings, and in five of the six safety culture domain scores (Working Conditions, Perceptions of Management, Job Satisfaction, Safety Climate and Teamwork Climate) of the SAQ-OR (P<0.001 in all cases). Scores in the sixth domain (Stress Recognition) decreased significantly (P=0.028). CONCLUSIONS: Implementation of the 5SSS was associated with a significant improvement in the safety culture of elective orthopaedic operating theatres. PMID- 25783741 TI - N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) and Risk of Hypertension in the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Brain natriuretic peptide (BNP) is released by the heart in response to ventricular and auricular wall stress. Release of BNP is traditionally considered part of the body's protective mechanism against pressure overload by inducing vasodilatation and diuresis. More recent evidence demonstrates that BNP also promotes vessel wall stress and preliminary studies suggest that chronic increased levels may increase risk of hypertension. This study aimed to evaluate the prospective association of N-terminal BNP (NT-proBNP), a cleavage product of BNP, with risk of hypertension in the Atherosclerosis Risk in Communities cohort study. METHODS: We conducted a prospective analysis of 3,798 middle-aged participants in the ARIC study without hypertension at baseline (1996-1998). Using Cox proportional hazards models, we characterized the association between NT-proBNP at baseline and newly diagnosed hypertension for a maximum of 14 years of follow-up (median = 9 years). RESULTS: We observed 2,113 new hypertension cases over the follow-up period. Higher baseline NT-proBNP was independently associated with an increased risk of hypertension. Adjusted hazard ratios for incident hypertension in the highest quartile compared to the lowest quartile of NT-proBNP at baseline was 1.24 (95% CI: 1.08-1.42). Each log-unit increase in NT proBNP was associated with an 8% increased risk of hypertension (95% CI: 1.03 1.13). CONCLUSIONS: Persons with elevated NT-proBNP, even with normal blood pressure at baseline, were at increased risk of developing hypertension. Our results suggest that elevated circulating BNP might contribute to the development of hypertension in previously normotensive individuals. PMID- 25783743 TI - Detection of subclinical recurrence or second primary cancer using (18) F-FDG PET/CT in patients treated curatively for head and neck squamous cell carcinoma. AB - BACKGROUND: The efficacy of posttreatment surveillance (18) F-fluorodeoxyglucose positron emission tomography ((18) F-FDG PET)/CT was evaluated in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The subjects were 158 patients with HNSCC who underwent PET/CT after definitive treatment. PET/CT detection of subclinical recurrence or a second primary cancer and the effect of timing of PET/CT scans on survival were analyzed. RESULTS: Recurrence or a second primary cancer occurred in 70 patients, and 67% of these cases were detected by PET/CT. Detection rates were 17%, 9%, 5%, and 5% in the first, second, third, and fourth scans at 4, 9, 15, and 21 months, respectively. In multivariate analysis, patients who underwent early first scans had significantly better disease specific (hazard ratio [HR] = 0.37; p = .031) and overall (HR = 0.45; p = .040) survival compared with those who underwent late first scans. CONCLUSION: Earlier detection of subclinical lesions by surveillance PET/CT within 4 months after treatment may improve survival in patients with HNSCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E511-E518, 2016. PMID- 25783744 TI - Mandibular bone exposure and osteonecrosis as a complication of general anaesthesia. PMID- 25783745 TI - Arctic marine mammal population status, sea ice habitat loss, and conservation recommendations for the 21st century. AB - Arctic marine mammals (AMMs) are icons of climate change, largely because of their close association with sea ice. However, neither a circumpolar assessment of AMM status nor a standardized metric of sea ice habitat change is available. We summarized available data on abundance and trend for each AMM species and recognized subpopulation. We also examined species diversity, the extent of human use, and temporal trends in sea ice habitat for 12 regions of the Arctic by calculating the dates of spring sea ice retreat and fall sea ice advance from satellite data (1979-2013). Estimates of AMM abundance varied greatly in quality, and few studies were long enough for trend analysis. Of the AMM subpopulations, 78% (61 of 78) are legally harvested for subsistence purposes. Changes in sea ice phenology have been profound. In all regions except the Bering Sea, the duration of the summer (i.e., reduced ice) period increased by 5-10 weeks and by >20 weeks in the Barents Sea between 1979 and 2013. In light of generally poor data, the importance of human use, and forecasted environmental changes in the 21st century, we recommend the following for effective AMM conservation: maintain and improve comanagement by local, federal, and international partners; recognize spatial and temporal variability in AMM subpopulation response to climate change; implement monitoring programs with clear goals; mitigate cumulative impacts of increased human activity; and recognize the limits of current protected species legislation. PMID- 25783746 TI - Drug eruption following high-calorie infusion: a possible systemic type IV allergic reaction to sulphites. PMID- 25783747 TI - Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. AB - Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status. PMID- 25783749 TI - Adjuvant chemotherapy for patients with rectal cancer - will the controversy be resolved? PMID- 25783748 TI - BMP-2-transduced human bone marrow stem cells enhance neo-bone formation in a rat critical-sized femur defect. AB - Synthetic graft materials are considered as possible substitutes for cancellous bone, but lack osteogenic and osteoinductive properties. In this study, we investigated how composite scaffolds of betaTCP containing osteogenic human bone marrow mesenchymal stem cells (hBMSCs) and osteoinductive bone morphogenetic protein-2 (BMP-2) influenced the process of fracture healing. hBMSCs were loaded into betaTCP scaffolds 24 h before implantation in a rat critical-sized bone defect. hBMSCs were either stimulated with rhBMP-2 or transduced with BMP-2 by gene transfer. The effect of both protein stimulation and gene transfer was compared for osteogenic outcome. X-rays were conducted at weeks 0, 1, 3, 6, 9 and 12 post-operatively. In addition, bone-labelling fluorochromes were applied at 0, 3, 6 and 9 weeks. Histological analysis was performed for the amount of callus tissue and cartilage formation. At 6 weeks, the critical-sized defect in 33% of the rats treated with the Ad-BMP-2-transduced hBMSCs/betaTCP scaffolds was radiographically bridged. In contrast, in only 10% of the rats treated with rhBMP2/hBMSCs, 12 weeks post-treatment, the bone defect was closed in all treated rats of the Ad-BMP-2 group except for one. Histology showed significantly higher amounts of callus formation in both Ad-BMP-2- and rhBMP-2-treated rats. The amount of neocartilage was less pronounced in both BMP-2-related groups. In summary, scaffolds with BMP-2-transduced hBMSCs performed better than those with the rhBMP2/hBMSCs protein. These results suggest that combinations of osteoconductive biomaterials with genetically modified MSCs capable of secreting osteoinductive proteins may represent a promising alternative for bone regeneration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25783750 TI - Temporal characteristics of hyolaryngeal structural movements in normal swallowing. AB - OBJECTIVES/HYPOTHESIS: To evaluate the relationship between movements of hyolaryngeal structures and fluid bolus transition in normal swallowing using automatized kinematic analysis of the videofluoroscopic swallowing study (VFSS). STUDY DESIGN: A prospective, descriptive study. METHODS: Seventy-five healthy volunteers underwent VFSS with 2 mL of diluted barium. The timing and sequence of structural movements were measured for laryngeal elevation (LE), hyoid excursion (HE), epiglottic rotation (ER), and fluid bolus transition. RESULTS: The rapid movement of LE (reference time point) was initiated simultaneously with the fluid bolus head passing the mandibular angle (-0.05 s, P = .07), followed by rapid onset of HE with significant temporal difference (P < .001). After the hyoid onset, onset of ER (0.17 s, P < .001), entrance of the bolus through upper esophageal sphincter (0.33 s, P < .001), maximal point of LE (0.52 s, P < .001), HE (0.53 s, P = .344), and maximal point of ER (0.64 s, P < .001) followed sequentially. For subgroup analysis, we classified 50 subjects without premature bolus loss (PBL) or pharyngeal triggering delay (PTD) into the "early group," and 24 subjects with PBL or PTD for <1 s into the "late group." In both groups, the sequence of the structural movements did not change. The early group showed significant correlation between the fluid transition and structural movements; both LE and HE were initiated when the bolus passed the mandibular angle, and the ER was initiated when the bolus reached the vallecula. CONCLUSIONS: We demonstrated a characteristic pattern of hyolaryngeal structural movements in normal swallowing. The results may serve as a basis for classifying and analyzing aspiration patterns in patients with dysphagia. LEVEL OF EVIDENCE: NA. PMID- 25783751 TI - Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcgamma receptors. AB - Dengue virus (DENV) is the most significant human arboviral pathogen and causes ~400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels of MC activation are correlated with disease severity in human DENV patients (St John et al., 2013b). A major risk factor for developing severe dengue is secondary infection with a heterologous serotype. The dominant theory explaining increased severity during secondary DENV infection is that cross reactive but non-neutralizing antibodies promote uptake of virus and allow enhanced replication. Here, we define another mechanism, dependent on FcgammaR mediated enhanced degranulation responses by MCs. Antibody-dependent mast cell activation constitutes a novel mechanism to explain enhanced vascular leakage during secondary DENV infection. PMID- 25783752 TI - Negative affect, negative urgency, thought suppression, and bulimic symptoms: a moderated mediation analysis in a sample at-risk for bulimic symptoms. AB - Research suggests that negative affect, negative urgency, and thought suppression are related to bulimic symptoms, either directly or indirectly. This study examined associations between these constructs in a sample at-risk for bulimic symptoms. Participants (N = 80) recruited from a residential substance abuse treatment facility completed self-report questionnaires. A regression-based bootstrapping approach was used to examine the indirect effect of negative affect on bulimic symptoms through negative urgency and the moderating role of thought suppression in the association between negative affect and negative urgency. Results revealed a significant indirect effect, significant moderation, and a significant moderated mediation effect, with an indirect effect of negative affect on bulimic symptoms through negative urgency, conditional upon low to moderate (but not high) levels of thought suppression. These findings suggest that negative affect may promote rash actions, particularly in the context of low to moderate thought suppression, leading to increased risk of bulimic symptoms. PMID- 25783754 TI - Is There Evidence of Any Safety Differences Among DPP-4 Inhibitors in the Treatment of People with Type 2 Diabetes Mellitus and Reduced GFR Due to Chronic Kidney Disease? PMID- 25783753 TI - A phase II study of bendamustine plus rituximab in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma previously treated with rituximab: BRB study. AB - To evaluate the efficacy and safety of a combined regimen of bendamustine (B) and rituximab (R) in Japanese patients with relapsed/refractory (r/r) indolent B-cell non-Hodgkin lymphomas (B-NHLs) and mantle cell lymphoma (MCL). Patients aged 20 79 years with pathologically confirmed B-NHLs or MCL, which were r/r after 1-2 R containing regimens, were included in this study. The BR regimen consisted of B (90 mg/m(2)) for two consecutive days and R (375 mg/m(2)) on day 1, 2, or 3. The course was repeated every 4 weeks for up to four cycles. Fifty-three patients were enrolled in this study and analyzed. The diagnosis included follicular lymphoma (FL) (77 %), mucosa-associated lymphoid tissue lymphoma (13 %) and others (10 %). Forty-seven (90 %) patients completed four cycles of treatment as per schedule. Best overall response rate (ORR) and complete response rate (CRR) was 94 and 71 %, respectively (for FL, ORR 95 % and CRR 80 %). The treatment was well tolerated and the primary toxicity was myelosuppression; the incidence of grade 3/4 leukopenia and neutropenia were 42 and 40 %, respectively. There were no grade 5 toxicities. The BR regimen is safe in Japanese patients with r/r indolent B-NHLs and MCL, and is effective for those with r/r indolent B-NHLs. For the evaluation of late toxicity, especially infection, longer follow-up of this cohort is needed. PMID- 25783755 TI - Effects of magnetic nanoparticles and external magnetostatic field on the bulk heterojunction polymer solar cells. AB - The price of energy to separate tightly bound electron-hole pair (or charge transfer state) and extract freely movable charges from low-mobility materials represents fundamental losses for many low-cost photovoltaic devices. In bulk heterojunction (BHJ) polymer solar cells (PSCs), approximately 50% of the total efficiency lost among all energy loss pathways is due to the photogenerated charge carrier recombination within PSCs and low charge carrier mobility of disordered organic materials. To address these issues, we introduce magnetic nanoparticles (MNPs) and orientate these MNPS within BHJ composite by an external magnetostatic field. Over 50% enhanced efficiency was observed from BHJ PSCs incorporated with MNPs and an external magnetostatic field alignment when compared to the control BHJ PSCs. The optimization of BHJ thin film morphology, suppression of charge carrier recombination, and enhancement in charge carrier collection result in a greatly increased short-circuit current density and fill factor, as a result, enhanced power conversion efficiency. PMID- 25783756 TI - Overactive Performance Monitoring as an Endophenotype for Obsessive-Compulsive Disorder: Evidence From a Treatment Study. AB - OBJECTIVE: Overactive performance monitoring, as measured by the error-related negativity in the event-related brain potential, represents one of the most robust psychophysiological alterations in obsessive-compulsive disorder (OCD). It has been proposed as an endophenotype for OCD because it is heritable and more prevalent in families of OCD patients. Consistent with this notion, it is also independent of symptom profile and symptom severity in cross-sectional studies. Longitudinally, it has been shown to be state independent in pediatric patients with OCD. The purpose of the present study was to investigate the state dependency of error monitoring by examining adult OCD patients before and after symptom reduction through cognitive-behavioral therapy (CBT). METHOD: Error related and correct-related negativity as electrophysiological indicators of performance monitoring were recorded from 45 OCD patients and 39 healthy comparison subjects while performing a flanker task. Patients were assessed before starting and after completing a standard 30-session CBT, including exposure and response prevention, and healthy comparison subjects were tested after a comparable time interval. RESULTS: Pretreatment, patients with OCD were characterized by enhanced error-related and correct-related negativity compared with healthy comparison subjects. This difference persisted after treatment when symptoms were substantially reduced. There was no significant correlation between symptom improvement and changes in performance monitoring and no difference in performance monitoring between treatment responders and nonresponders. CONCLUSIONS: This is the first longitudinal study in adult OCD patients showing stability of enhanced error monitoring following successful symptom reduction through CBT. It supports the hypothesis that overactive performance monitoring is an endophenotype that indicates vulnerability for OCD. PMID- 25783758 TI - Donor hyperfine Stark shift and the role of central-cell corrections in tight binding theory. AB - Atomistic tight-binding (TB) simulations are performed to calculate the Stark shift of the hyperfine coupling for a single arsenic (As) donor in silicon (Si). The role of the central-cell correction is studied by implementing both the static and the non-static dielectric screenings of the donor potential, and by including the effect of the lattice strain close to the donor site. The dielectric screening of the donor potential tunes the value of the quadratic Stark shift parameter (eta2) from -1.3 * 10(-3) um(2) V(-2) for the static dielectric screening to -1.72 * 10(-3) um(2) V(-2) for the non-static dielectric screening. The effect of lattice strain, implemented by a 3.2% change in the As Si nearest-neighbour bond length, further shifts the value of eta2 to -1.87 * 10( 3) um(2) V(-2), resulting in an excellent agreement of theory with the experimentally measured value of -1.9 +/- 0.2 * 10(-3) um(2) V(-2). Based on our direct comparison of the calculations with the experiment, we conclude that the previously ignored non-static dielectric screening of the donor potential and the lattice strain significantly influence the donor wave function charge density and thereby leads to a better agreement with the available experimental data sets. PMID- 25783757 TI - Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment. AB - OBJECTIVE: The authors tested whether clonidine blocks stress-induced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients' stress to test hypotheses about clonidine's behavioral mechanism of action. METHOD: The authors conducted a randomized double-blind placebo controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5-6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo (N=57) for 14 weeks. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine test, and relapse as two or more consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test, and ecological momentary assessment data were examined with generalized linear mixed models. RESULTS: In an intent-to-treat analysis, clonidine produced the longest duration (in consecutive days) of abstinence from opioids during the intervention phase (34.8 days [SD=3.7] compared with 25.5 days [SD=2.7]; Cohen's d=0.38). There was no group difference in time to relapse, but the clonidine group took longer to lapse (hazard ratio=0.67, 95% CI=0.45-1.00). Ecological momentary assessment showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting the authors' hypothesized mechanism for clonidine's benefits. CONCLUSIONS: Clonidine, a readily available medication, is useful in opioid dependence not just for reduction of withdrawal signs, but also as an adjunctive maintenance treatment that increases duration of abstinence. Even in the absence of physical withdrawal, it decouples stress from craving in everyday life. PMID- 25783759 TI - Sequential monitoring and stability of ex vivo-expanded autologous and nonautologous regulatory T cells following infusion in nonhuman primates. AB - Ex vivo-expanded cynomolgus monkey CD4(+)CD25(+)CD127(-) regulatory T cells (Treg) maintained Foxp3 demethylation status at the Treg-specific demethylation region, and potently suppressed T cell proliferation through three rounds of expansion. When carboxyfluorescein succinimidyl ester- or violet proliferation dye 450-labeled autologous (auto) and nonautologous (non-auto)-expanded Treg were infused into monkeys, the number of labeled auto-Treg in peripheral blood declined rapidly during the first week, but persisted at low levels in both normal and anti-thymocyte globulin plus rapamycin-treated (immunosuppressed; IS) animals for at least 3 weeks. By contrast, MHC-mismatched non-auto-Treg could not be detected in normal monkey blood or in blood of two out of the three IS monkeys by day 6 postinfusion. They were also more difficult to detect than auto-Treg in peripheral lymphoid tissue. Both auto- and non-auto-Treg maintained Ki67 expression early after infusion. Sequential monitoring revealed that adoptively transferred auto-Treg maintained similarly high levels of Foxp3 and CD25 and low CD127 compared with endogenous Treg, although Foxp3 staining diminished over time in these nontransplanted recipients. Thus, infused ex vivo-expanded auto-Treg persist longer than MHC-mismatched non-auto-Treg in blood of nonhuman primates and can be detected in secondary lymphoid tissue. Host lymphodepletion and rapamycin administration did not consistently prolong the persistence of non-auto Treg in these sites. PMID- 25783760 TI - Protective role of insulin-like growth factor-1 receptor in endothelial cells against unilateral ureteral obstruction-induced renal fibrosis. AB - Insulin-like growth factor-1 receptor (IGF-1R) can regulate vascular homeostasis and endothelial function. We studied the role of IGF-1R in oxidative stress induced endothelial dysfunction. Unilateral ureteral obstruction (UUO) was performed in wild-type (WT) mice and mice with endothelial cell (EC)-specific IGF 1R knockout (KO). After UUO in endothelial IGF-1R KO mice, endothelial barrier dysfunction was more severe than in WT mice, as seen by increased inflammatory cell infiltration and vascular endothelial (VE)-cadherin phosphorylation. UUO in endothelial IGF-1R KO mice increased interstitial fibroblast accumulation and enhanced extracellular protein deposition as compared with the WT mice. Endothelial barrier function measured by transendothelial migration in response to hydrogen peroxide (H2O2) was impaired in ECs. Silencing IGF-1R enhanced the influence of H2O2 in disrupting the VE-protein tyrosine phosphatase/VE-cadherin interaction. Overexpression of IGF-1R suppressed H2O2-induced endothelial barrier dysfunction. Furthermore, by using the piggyBac transposon system, we expressed IGF-1R in VE cells in mice. The expression of IGF-1R in ECs also suppressed the inflammatory cell infiltration and renal fibrosis induced by UUO. IGF-1R KO in the VE-cadherin lineage of bone marrow cells had no significant effect on the UUO induced fibrosis, as compared with control mice. Our results indicate that IGF-1R in the endothelium maintains the endothelial barrier function by stabilization of the VE-protein tyrosine phosphatase/VE-cadherin complex. Decreased expression of IGF-1R impairs endothelial function and increases the fibrosis of kidney disease. PMID- 25783761 TI - Influence of first proximal phalanx geometry on hallux valgus deformity: a finite element analysis. AB - Hallux abducto valgus (HAV), one of the most common forefoot deformities, occurs primarily in elderly women. HAV is a complex disease without a clearly identifiable cause for its higher prevalence in women compared with men. Several studies have reported various skeletal parameters related to HAV. This study examined the geometry of the proximal phalanx of the hallux (PPH) as a potential etiologic factor in this deformity. A total of 43 cadaver feet (22 males and 21 females) were examined by means of cadaveric dissection. From these data, ten representative PPHs for both genders were selected, corresponding to five percentiles for males (0, 25, 50, 75, and 100%) and five for females. These ten different PPHs were modeled and inserted in ten foot models. Stress distribution patterns within these ten PPH models were qualitatively compared using finite element analysis. In the ten cases analyzed, tensile stresses were larger on the lateral side, whereas compressive stresses were larger on the medial side. The bones of males were larger than female bones for each of the parameters examined; however, the mean difference between lateral and medial sides of the PPH (mean +/ SD) was larger in women. Also the shallower the concavity at the base of the PPH, the larger the compressive stresses predicted. Internal forces on the PPH, due to differences in length between its medial and lateral sides, may force the PPH into a less-stressful position. The geometry of the PPH is a significant factor in HAV development influencing the other reported skeletal parameters and, thus, should be considered during preoperative evaluation. Clinical assessment should evaluate the first ray as a whole and not as isolated factors. PMID- 25783762 TI - Global sensitivity analysis of the joint kinematics during gait to the parameters of a lower limb multi-body model. AB - Sensitivity analysis is a typical part of biomechanical models evaluation. For lower limb multi-body models, sensitivity analyses have been mainly performed on musculoskeletal parameters, more rarely on the parameters of the joint models. This study deals with a global sensitivity analysis achieved on a lower limb multi-body model that introduces anatomical constraints at the ankle, tibiofemoral, and patellofemoral joints. The aim of the study was to take into account the uncertainty of parameters (e.g. 2.5 cm on the positions of the skin markers embedded in the segments, 5 degrees on the orientation of hinge axis, 2.5 mm on the origin and insertion of ligaments) using statistical distributions and propagate it through a multi-body optimisation method used for the computation of joint kinematics from skin markers during gait. This will allow us to identify the most influential parameters on the minimum of the objective function of the multi-body optimisation (i.e. the sum of the squared distances between measured and model-determined skin marker positions) and on the joint angles and displacements. To quantify this influence, a Fourier-based algorithm of global sensitivity analysis coupled with a Latin hypercube sampling is used. This sensitivity analysis shows that some parameters of the motor constraints, that is to say the distances between measured and model-determined skin marker positions, and the kinematic constraints are highly influencing the joint kinematics obtained from the lower limb multi-body model, for example, positions of the skin markers embedded in the shank and pelvis, parameters of the patellofemoral hinge axis, and parameters of the ankle and tibiofemoral ligaments. The resulting standard deviations on the joint angles and displacements reach 36 degrees and 12 mm. Therefore, personalisation, customisation or identification of these most sensitive parameters of the lower limb multi-body models may be considered as essential. PMID- 25783763 TI - Interactions between natural organic matter and organic pollutants as revealed by NMR spectroscopy. AB - Natural organic matter (NOM) plays a critical role in regulating the transport and the fate of organic contaminants in the environment. NMR spectroscopy is a powerful technique for the investigation of the sorption and binding mechanisms between NOM and pollutants, as well as their mutual chemical transformations. Despite NMR relatively low sensibility but due to its wide versatility to investigating samples in the liquid, gel, and solid phases, NMR application to environmental NOM-pollutants relations enables the achievement of specific and complementary molecular information. This report is a brief outline of the potentialities of the different NMR techniques and pulse sequences to elucidate the interactions between NOM and organic pollutants, with and without their labeling with nuclei that enhance NMR sensitivity. PMID- 25783764 TI - Nrf2, but not beta-catenin, mutation represents an early event in rat hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether Nrf2/Keap1 mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2-acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). CONCLUSION: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development. PMID- 25783765 TI - Supervised exercise training reduces oxidative stress and cardiometabolic risk in adults with type 2 diabetes: a randomized controlled trial. AB - To evaluate the effects of supervised exercise training (SET) on cardiometabolic risk, cardiorespiratory fitness and oxidative stress status in 2 diabetes mellitus (T2DM), twenty male subjects with T2DM were randomly assigned to an intervention group, which performed SET in a hospital-based setting, and to a control group. SET consisted of a 12-month supervised aerobic, resistance and flexibility training. A reference group of ten healthy male subjects was also recruited for baseline evaluation only. Participants underwent medical examination, biochemical analyses and cardiopulmonary exercise testing. Oxidative stress markers (1-palmitoyl-2-[5-oxovaleroyl]-sn-glycero-3-phosphorylcholine [POVPC]; 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine [PGPC]) were measured in plasma and in peripheral blood mononuclear cells. All investigations were carried out at baseline and after 12 months. SET yielded a significant modification (p < 0.05) in the following parameters: V'O2max (+14.4%), gas exchange threshold (+23.4%), waist circumference (-1.4%), total cholesterol ( 14.6%), LDL cholesterol (-20.2%), fasting insulinemia (-48.5%), HOMA-IR (-52.5%), plasma POVPC (-27.9%) and PGPC (-31.6%). After 12 months, the control group presented a V'O2max and a gas exchange threshold significantly lower than the intervention group. Plasma POVC and PGPC were significantly different from healthy subjects before the intervention, but not after. In conclusion, SET was effective in improving cardiorespiratory fitness, cardiometabolic risk and oxidative stress status in T2DM. PMID- 25783766 TI - Potential use of acupuncture in the treatment of first bite syndrome. AB - OBJECTIVES: First bite syndrome (FBS) is an early postoperative pain syndrome characterized by the sudden onset of pain in the parotid region at the first bite of each meal. The etiology is not certain, hence a standardized therapy does not exist. METHODS: A 50-year old woman referred to us complaining of a swelling in the right parotid region. Fine-needle aspiration biopsy (FNAB) was diagnostic for pleomorphus adenoma of the deep lobe of the parotid gland. A 50-year old man presented with a mass in the right side of the neck, FNAB was diagnostic for parapharyngeal space neurinoma. The first patient was submitted to total parotidectomy with facial nerve preservation, the second to extracapsular dissection of the tumor. A week after surgery both patients developed FBS. A qualitative/quantitative description of pain was obtained by means of a self coded questionnaire. The score ranges from 8 to 44, corresponding to the lowest and the highest discomfort possible, respectively. Acupuncture was used to treat these 2 patients. The treatment protocol comprised 6 sessions, one per week, lasting 30 minutes each. RESULTS: Our questionnaire was administered before and after treatment and the score dropped from 33 to 25 in the female, from 30 to 15 in the male patient. CONCLUSION: FBS is a complication of upper cervical surgery with a high morbidity rate. We describe the first two cases of FBS that were successfully treated with acupuncture in our ENT department. We believe that this procedure may represent a valid therapeutic alternative in the future. PMID- 25783768 TI - Different effect of handle region peptide on beta-cell function in different sexes of rats neonatally treated with sodium L-glutamate. AB - BACKGROUND The (pro)renin receptor ((P)RR) was reported to be expressed in various tissues including the pancreas, and handle region peptide (HRP) is believed to block the function of (P)RR. This study aimed to investigate the effect of HRP on the glucose tolerance status and beta-cell function of female rats, neonatally treated with sodium L-glutamate (MSG) and to compare with the previously reported HRP effect on male rats. MATERIAL AND METHODS Female MSG rats aged 8 weeks were divided into MSG control group and HRP treated group and the normal SD rats served as control. The MSG rats were treated with HRP by osmotic minipumps with dose of 1 mg/kg per day for total 28 days. Glucose tolerance status was evaluated at the end of the study. Islets alpha-cell and beta-cell were marked with insulin antibody and glucagon antibody respectively. The proliferation of islet cells and expression of subunit of NADPH oxidase P22phox were marked by PCNA and P22phox antibody. Picrosirius red staining was performed for evaluating fibrosis of islets. RESULTS HRP improved the glucose status tolerance with decreasing alpha-cell mass, islets PCNA-positive cells, expression of P22phox and picrosirius red stained areas, and increasing beta-cell mass in female MSG rats. The indexes with obviously interacted effect of sexes and HRP for the MSG rats were the AUC of blood glucose concentration (P<0.01), alpha-cell mass (P<0.05), proliferation of islet cells (P<0.01) and area of picrosirius red staining (P<0.01). CONCLUSIONS HRP improved the glucose tolerance status in the females although it was previously reported to worsen the glucose tolerance in male MSG rats. Different levels of sex hormones may partly account for the disparate effects observed for HRP in different sexes. PMID- 25783769 TI - In Vitro Differentiation of Pluripotent Stem Cells into Functional beta Islets Under 2D and 3D Culture Conditions and In Vivo Preclinical Validation of 3D Islets. AB - Since the advent of pluripotent stem cells, (embryonic and induced pluripotent stem cells), applications of such pluripotent stem cells are of prime importance. Indeed, scientists are involved in studying the basic biology of pluripotent stem cells, but equal impetus is there to direct the pluripotent stem cells into multiple lineages for cell therapy applications. Scientists across the globe have been successful, to a certain extent, in obtaining cells of definitive endoderm and also pancreatic beta islets by differentiating human pluripotent stem cells. Pluripotent stem cell differentiation protocols aim at mimicking in vivo embryonic development. As in vivo embryonic development is a complex process and involves interplay of multiple cytokines, the differentiation protocols also involve a stepwise use of multiple cytokines. Indeed the novel markers for pancreas organogenesis serve as the roadmaps to develop new protocols for pancreatic differentiation from pluripotent stem cells. Earliest developed protocols for pancreas differentiation involved "Nestin selection pathway," a pathway common for both neuronal and pancreatic differentiation lead to the generation of cells that were a combination of cells from neuronal lineage. Eventually with the discovery of hierarchy of beta cell transcription factors like Pdx1, Pax4, and Nkx2.2, forced expression of such transcription factors proved successful in converting a pluripotent stem cell into a beta cell. Protocols developed almost half a decade ago to the recent ones rather involve stepwise differentiations involving various cytokines and could generate as high as 25 % functional insulin-positive cells in vitro. Most advanced protocols for beta islet differentiations from human pluripotent stem cells focused on 3D culture conditions, which reportedly produced 60-65 % functional beta islet cells. Here, we describe the protocol for differentiation of human pluripotent stem cells into functional beta cells under both 2D and 3D culture conditions. PMID- 25783770 TI - Early oral cancer diagnosis: The Aarhus statement perspective. A systematic review and meta-analysis. AB - BACKGROUND: Mortality is linked to diagnostic intervals in certain cancers. As symptom perception is conditioned by tumor site, a specific study on oral cancer is needed. METHODS: This study's inclusion criteria were original data, symptomatic primary oral squamous cell carcinoma, and exposure of interest, diagnostic interval, or diagnostic delay. The outcome of interest was survival and disease stage. A meta-analysis was undertaken to investigate the relationship between intervals to diagnosis, TNM classification, and survival in oral cancer. RESULTS: Regarding referral delay, the results present no heterogeneity and showed a risk increase in mortality of 2.48 (range = 1.39-4.42). The larger the diagnostic delay, the more advanced the stage at diagnosis. High quality studies reveal a higher risk increase than low quality studies (odds ratio [OR] = 2.44; 95% confidence interval [CI] = 1.36-4.36 vs OR = 1.53; 95% CI = 1.26-1.86). CONCLUSION: A longer time interval from first symptom to referral for diagnosis is a risk factor for advanced stage and mortality of oral cancer. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2182-E2189, 2016. PMID- 25783771 TI - Dual role of dopamine D(2)-like receptors in the mediation of conditioned and unconditioned fear. AB - A reduction of dopamine release or D2 receptor blockade in the terminal fields of the mesolimbic system, particularly the amygdala, clearly reduces conditioned fear. Similar D2 receptor antagonism in the neural substrates of fear in the midbrain tectum attenuates the processing of unconditioned aversive information. However, the implications of the interplay between opposing actions of dopamine in the rostral and caudal segments of the dopaminergic system are still unclear. Previous studies from this laboratory have reported the effects of dopaminergic drugs on behavior in rats in the elevated plus maze, auditory-evoked potentials (AEPs) recorded from the midbrain tectum, fear-potentiated startle, and conditioned freezing. These findings led to an interesting framework on the functional roles of dopamine in both anxiety and fear states. Dopamine D2 receptor inhibition in the terminal fields of the mesolimbic dopamine system generally causes anxiolytic-like effects, whereas the activity of midbrain substrates of unconditioned fear are enhanced by D2 receptor antagonists, suggesting that D2 receptor-mediated mechanisms play opposing roles in fear/anxiety processes, depending on the brain region under study. Dopamine appears to mediate conditioned fear by acting at rostral levels of the brain and regulate unconditioned fear at the midbrain level, likely by reducing the sensorimotor gating of aversive events. PMID- 25783772 TI - Tuning coordination in s-block carbazol-9-yl complexes. AB - 1,3,6,8-Tetra-tert-butylcarbazol-9-yl and 1,8-diaryl-3,6-di(tert-butyl)carbazol-9 yl ligands have been utilized in the synthesis of potassium and magnesium complexes. The potassium complexes (1,3,6,8-tBu4carb)K(THF)4 (1; carb = C12H4N), [(1,8-Xyl2-3,6-tBu2carb)K(THF)]2 (2; Xyl = 3,5-Me2C6H3) and (1,8-Mes2-3,6 tBu2carb)K(THF)2 (3; Mes = 2,4,6-Me3C6H2) were reacted with MgI2 to give the Hauser bases 1,3,6,8-tBu4carbMgI(THF)2 (4) and 1,8-Ar2-3,6-tBu2carbMgI(THF) (Ar = Xyl 5, Ar = Mes 6). Structural investigations of the potassium and magnesium derivatives highlight significant differences in the coordination motifs, which depend on the nature of the 1- and 8-substituents: 1,8-di(tert-butyl)-substituted ligands gave pi-type compounds (1 and 4), in which the carbazolyl ligand acts as a multi-hapto donor, with the metal cations positioned below the coordination plane in a half-sandwich conformation, whereas the use of 1,8-diaryl substituted ligands gave sigma-type complexes (2 and 6). Space-filling diagrams and percent buried volume calculations indicated that aryl-substituted carbazolyl ligands offer a steric cleft better suited to stabilization of low-coordinate magnesium complexes. PMID- 25783773 TI - Survey of bullous pemphigoid disease in northern Iran. AB - BACKGROUND: Bullous pemphigoid is an autoimmune subepidermal blistering skin and mucous membrane disease that usually occurs in elderly people. This study was done to determine clinical features, paraclinical findings, incidence of mucosal lesions, prognosis, course of the disease, and mortality rate of patients with bullous pemphigoid. METHOD: Retrospective descriptive study that reviews the existing files of 122 patients with bullous pemphigoid referred to dermatology clinics of Ghaem and Imam Reza hospitals in Mashhad, Iran, from 1995 to 2010. RESULT: The majority of patients were aged between 60 and 79 years, and 53% of them were women. The major prodromal lesions were erythematous and urticarial (36.8%) and eczematous lesions (32.7%); 84.3% of patients complained of pruritus, and mucosal lesions were observed in 31.1% of patients (all in the oral mucosa). The most frequent concurrent diseases with pemphigoid were hypertension and diabetes mellitus. CONCLUSION: Clinical features, paraclinical findings, incidence of mucosal lesions, prognosis, course of the disease, and mortality rate of bullous pemphigoid in the Khorasan region were approximately similar to results from other regions. PMID- 25783774 TI - Mixing biomimetic heterodimers of nucleopeptides to generate biocompatible and biostable supramolecular hydrogels. AB - As a new class of biomaterials, most supramolecular hydrogels formed by small peptides require the attachment of long alkyl chains, multiple aromatic groups, or strong electrostatic interactions. Based on the fact that the most abundant protein assemblies in nature are dimeric, we select short peptide sequences from the interface of a heterodimer of proteins with known crystal structure to conjugate with nucleobases to form nucleopeptides. Being driven mainly by hydrogen bonds, the nucleopeptides self-assemble to form nanofibers, which results in supramolecular hydrogels upon simple mixing of two distinct nucleopeptides in water. Moreover, besides being biocompatible to mammalian cells, the heterodimer of the nucleopeptides exhibit excellent proteolytic resistance against proteinase K. This work illustrates a new and rational approach to create soft biomaterials by a supramolecular hydrogelation triggered by mixing heterodimeric nucleopeptides. PMID- 25783775 TI - On the Hospital Volume and Outcome Relationship: Does Specialization Matter More Than Volume? AB - OBJECTIVE: To evaluate the relationship between hospital volume and outcome by focusing on alternative measures of volume that capture specialization and overall throughput of hospitals. DATA SOURCES/STUDY SETTING: Hospital administrative data from the state of Victoria, Australia; data contain 1,798,474 admitted episodes reported by 135 public and private acute-care hospitals. STUDY DESIGN: This study contrasts the volume-outcome relationship using regression models with different measures of volume; two-step and single-step risk adjustment methods are used. DATA COLLECTION/EXTRACTION METHODS: The sample is restricted to ischemic heart disease (IHD) patients (ICD-10 codes: I20-I25) admitted during 2001/02 to 2004/05. PRINCIPAL FINDINGS: Overall hospital throughput and degree of specialization display more substantive implications for the volume-outcome relationship than conventional caseload volume measure. Two step estimation when corrected for heteroscedasticity produces comparable results to single-step methods. CONCLUSIONS: Different measures of volume could lead to vastly different conclusions about the volume-outcome relationship. Hospital specialization and throughput should both be included as measures of volume to capture the notion of size, focus, and possible congestion effects. PMID- 25783778 TI - Multiple active zones in hybrid QM/MM molecular dynamics simulations for large biomolecular systems. AB - A new QM/MM molecular dynamics approach that can deal with the dynamics of large real systems involving several simultaneous active zones is presented. Multiple, unconnected but interacting quantum regions are treated independently in an ordinary QM/MM approach but in a manner which converges to a unique simulation. The multiple active zones in the hybrid QM/MM molecular dynamics methodology (maz QM/MM MD) involve molecular dynamics that is driving the whole simulation with several parallel executions of energy gradients within the QM/MM approach that merge into each MD step. The Ewald-summation method is used to incorporate long range electrostatic interactions among the active zones in conjunction with periodic boundary conditions. To illustrate and ascertain capabilities and limitations, we present several benchmark calculations using this approach. Our results show that the maz-QM/MM MD method is able to provide simultaneous treatment of several active zones of very large proteins such as the Cu-4His DeltaC* cage, a self-assembly of a 24-mer cage-like protein ferritin. PMID- 25783779 TI - A model of blind zone for in situ monitoring the solid/liquid interface using ultrasonic wave. AB - To in situ monitor a solid/liquid interface to control metal qualities, the paper analysis blind models of the ultrasonic propagation in the solidifying molten metal with a solid/liquid interface in the Bridgman type furnace, and a mathematical calculation model of blind zone with different source locations and surface concavities is built. The study points out that the blind zone I is caused by ray bending in the interface edge, and the blind zone II is caused by totally reflection which is related with initial ray angle, critical refraction angle of solid/liquid media. A serial of simulation experiments are operated on the base of the model, and numerical computation results coincide with model calculated results very well. Therefore, receiver should locate beyond these blind zones in the right boundary to obtain time of flight data which is used to reconstruct the solid/liquid interface. PMID- 25783780 TI - Dynamic interrogator for elastic wave sensing using Fabry Perot filters based on fiber Bragg gratings. AB - Use of in-fiber Fabry-Perot (FP) filters based on fiber Bragg gratings as both sensor as well as an interrogator for enhancing the detection limit of elastic wave sensing is investigated in this paper. The sensitivity of such a demodulation scheme depends on the spectral discrimination of the sensor and interrogator gratings. Simulations have shown that the use of in-fiber FP filters with high finesse provide better performance in terms of sensitivity compared to the demodulation using fiber Bragg gratings. Based on these results, a dynamic interrogator capable of sensing acoustic waves with amplitude of less than 1 micro-strain over frequencies of 10 kHz to several 100 kHz has been implemented. Frequency response of the fiber Bragg gratings in the given experimental setup has been compared to that of the conventional piezo sensors demonstrating that fiber Bragg gratings can be used over a relatively broad frequency range. Dynamic interrogator has been packaged in a compact box without any degradation in its performance. PMID- 25783781 TI - Integrated plant phenotypic responses to contrasting above- and below-ground resources: key roles of specific leaf area and root mass fraction. AB - Plants adapt phenotypically to different conditions of light and nutrient supply, supposedly in order to achieve colimitation of these resources. Their key variable of adjustment is the ratio of leaf area to root length, which relies on plant biomass allocation and organ morphology. We recorded phenotypic differences in leaf and root mass fractions (LMF, RMF), specific leaf area (SLA) and specific root length (SRL) of 12 herbaceous species grown in factorial combinations of high/low irradiance and fertilization treatments. Leaf area and root length ratios, and their components, were influenced by nonadditive effects between light and nutrient supply, and differences in the strength of plant responses were partly explained by Ellenberg's species values representing ecological optima. Changes in allocation were critical in plant responses to nutrient availability, as the RMF contribution to changes in root length was 2.5* that of the SRL. Contrastingly, morphological adjustments (SLA rather than LMF) made up the bulk of plant response to light availability. Our results suggest largely predictable differences in responses of species and groups of species to environmental change. Nevertheless, they stress the critical need to account for adjustments in below-ground mass allocation to understand the assembly and responses of communities in changing environments. PMID- 25783782 TI - Decreased Bdnf expression and reduced social behavior in periadolescent rats following prenatal stress. AB - Prenatal stress (PNS) is a risk factor for the development of neuropsychiatric disorders. This study was aimed at assessing, in a rodent model, changes in gene expression profiles and behavioral output as a result of PNS, during periadolescence, a critical developmental period for the onset of psychopathology. Social behavior was studied in a standardized social interaction paradigm and the expression of Brain-Derived Neurotrophic Factor (Bdnf), a marker of neuronal plasticity, and of inhibitory and excitatory mechanisms (Na(+)-K(+) 2Cl(-) and K(+)-Cl(-) cotransporters ratio, NKCC1/KCC2) was analyzed. Results indicate that PNS reduced Bdnf transcripts while increasing the NKCC1/KCC2 ratio, primarily in the hippocampus. In the prefrontal cortex, changes in Bdnf were found to be gender-dependent. These effects were accompanied by reduced levels of affiliative and investigative social behaviors. Interestingly, interaction with non-stressed subjects was able to improve sociality in PNS rats suggesting that the social environment could be exploited for therapeutic intervention. PMID- 25783783 TI - Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model. AB - Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated. PMID- 25783784 TI - Sleep and physical activity measured by accelerometry in Crohn's disease. AB - BACKGROUND: Sleep and physical activity are inherent to human living, yet appear affected by Crohn's disease (CD), resulting in fatigue and disability. AIM: To objectively assess sleep quality and physical activity and their associations using accelerometers, comparing CD vs. matched healthy control (HC) subjects. METHODS: Exactly 49 CD and 30 HC subjects completed surveys encompassing self reported fatigue and sleep quality, pathology testing and wore an accelerometer for 7 days, measuring physical activity and sleep. In this cross-sectional observational study, per-group comparisons were performed and in CD, factors associated with reduced activity and/or sleep quality were assessed via multivariate analyses. RESULTS: Regarding physical activity, CD subjects overall performed less total accelerometer counts (median 1.3 * 10(6) vs. 2.0 * 10(6) ), were more sedentary (97.7% vs. 96.2%) and completed fewer bouts of moderate vigorous intensity exercise (1.0 vs. 5.0, each P < 0.01 (Mann-Whitney) than HC over 7 days. Factors associated with poor physical activity in CD included elevated serum CRP (OR = 22.6), lower vitamin D3 (OR = 13.1) and longer disease duration (OR = 1.2 per year, each P < 0.05). Regarding sleep, the CD group had similar total sleep time (median 458 vs. 447 min, P = 0.56), but more awakenings post-sleep onset (22 vs. 11, P = 0.01). Factors associated with severe sleep dysfunction in CD included lower haemoglobin (OR = 6.7) concurrent anti-TNF (OR = 6.5, each P < 0.05) and opioid therapy (OR = 6.6, P = 0.09). CONCLUSION: Utilising objective measurement in a habitual context over 7 days, patients with Crohn's disease exhibited poorer sleep quality and less physical activity than well-matched healthy controls. PMID- 25783786 TI - Canine urothelial carcinoma: genomically aberrant and comparatively relevant. AB - Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications. PMID- 25783787 TI - Development of gas exchange and ion regulation in two species of air-breathing fish, Betta splendens and Macropodus opercularis. AB - Aquatic air-breathing anabantoids, a group of fish species characterized by the presence of a labyrinth organ and some gills, exhibit morphological variations. This study aimed to examine whether unequal gill growth begins during the early stages and described the sequence of the early gill developmental events in Betta splendens and Macropodus opercularis. To determine when the ion regulatory and gas exchange abilities first appear in the gills, mitochondria-rich cells (MRCs) and neuroepithelial cells (NECs) were examined in young B. splendens. To evaluate the relative importance of the gills and the labyrinth organ under different levels of oxygen uptake stress, the levels of carbonic anhydrase II (CAII) and Na(+)/K(+)-ATPase (NKA) protein expressions in 2 gills and the labyrinth organ were examined in M. opercularis. We found that the first 3 gills developed earlier than the 4th gill in both species, an indication that the morphological variation begins early in life. In B. splendens, the MRCs and NECs clearly appeared in the first 3 gills at 4 dph and were first found in the 4th gill until 11 dph. The oxygen-sensing ability of the gills was concordant with the ionoregulatory function. In M. opercularis, the hypoxic group had a significantly higher air-breathing frequency. CAII protein expression was higher in the labyrinth organ in the hypoxic group. The gills exhibited increased NKA protein expression in the hypoxic and restricted groups, respectively. Functional plasticity in CAII and NKA protein expressions was found between the gills and the labyrinth organ in adult M. opercularis. PMID- 25783788 TI - Endoscopic ultrasound-guided biliary drainage: a review. AB - OPINION STATEMENT: Endoscopic retrograde cholangiography (ERCP) has become the standard tool for diagnosis and treatment of patients with biliary obstruction. However, despite the reported success rate of >90 % in expert centers, the common bile duct may still be occasionally inaccessible due to anatomical or technical issues. Over the past decade, endoscopic ultrasound-guided biliary drainage (EUS BD) has emerged as an effective alternative over percutaneous transhepatic biliary drainage (PTBD) or surgical bypass for biliary drainage after unsuccessful ERCP. EUS-BD includes rendezvous techniques (EUS-RV), EUS-guided choledochoduodenostomy (EUS-CDS), and EUS-guided hepatogastrostomy (EUS-HGS). Published data demonstrated high success rates especially for EUS-CDS and EUS HGS. Complication rates, however, are also higher in these two techniques. The indications and anatomical requirements for the three techniques differ and should be considered complementary to each other. Most reported studies only included a small number of patients, and larger-scaled randomized trials are required to establish the efficacy among various EUS techniques and to compare to traditional means of radiological or surgical drainage. PMID- 25783789 TI - Endoscopic imaging. AB - OPINION STATEMENT: The most important tools are the eye and the brain. A detailed white-light high-resolution examination and ability to recognize subtle lesions provide the foundation of the ability to detect lesions in the gastrointestinal tract. Novel technologies are now available to provide additional information with the goals of detection, delineation, or classification often with a focus on neoplasia in the gastrointestinal tract. The observer using these new tools must still recognize, interpret, and then make a clinically relevant conclusion. Therefore, the assessment of these tools may focus on both the technical feasibility to use the respective equipment to obtain an image and then also the associated cognitive-based criteria for image interpretation. PMID- 25783790 TI - MicroRNA-34a suppresses the breast cancer stem cell-like characteristics by downregulating Notch1 pathway. AB - MicroRNAs play pivotal roles in cancer stem cell regulation. Previous studies have shown that microRNA-34a (miR-34a) is downregulated in human breast cancer. However, it is unknown whether and how miR-34a regulates breast cancer stem cells. Notch signaling is one of the most important pathways in stem cell maintenance and function. In this study, we verified that miR-34a directly and functionally targeted Notch1 in MCF-7 cells. We reported that miR-34a negatively regulated cell proliferation, migration, and invasion and breast cancer stem cell propagation by downregulating Notch1. The expression of miR-34a was negatively correlated with tumor stages, metastasis, and Notch1 expression in breast cancer tissues. Furthermore, overexpression of miR-34a increased chemosensitivity of breast cancer cells to paclitaxel (PTX) by downregulating the Notch1 pathway. Mammosphere formation and expression of the stemness factor ALDH1 were also reduced in the cells treated with miR-34a and PTX compared to those treated with PTX alone. Taken together, our results indicate that miR-34a inhibited breast cancer stemness and increased the chemosensitivity to PTX partially by downregulating the Notch1 pathway, suggesting that miR-34a/Notch1 play an important role in regulating breast cancer stem cells. Thus miR-34a is a potential target for prevention and therapy of breast cancer. PMID- 25783791 TI - Prediction of mid-term outcome after cryo-balloon ablation of atrial fibrillation using post-procedure high-sensitivity troponin level. AB - OBJECTIVE: High-sensitivity troponin I (hsTnI) assays lead to, among other things, improvement in the detection of myocardial injury and improved risk stratification of patients with atrial fibrillation (AF). The aim of this study was to investigate the association between post-procedure cardiac biomarkers and clinical outcome in patients undergoing cryo-balloon ablation (CA) for AF. METHODS: A total of 57 patients (mean age 55.1 +/- 12.2 years, 50.9% female) with symptomatic paroxysmal AF underwent the CA procedure. Two hundred and twenty eight pulmonary veins (PVs) were attempted for pulmonary vein isolation (PVI) with a second-generation cryo-balloon. hsTnI, CK-MB mass and myoglobin samples were prospectively obtained before and 24 hours after ablation. RESULTS: At a mean follow up of 214.6 +/- 24.3 days, the probability of being arrhythmia free after a single procedure was 86%. Post-ablation hsTnI (p = 0.001), left atrial (LA) diameter (p = 0.002), duration of AF (p = 0.002), mean minimal temperature of the left superior pulmonary vein (p = 0.005), and age (p = 0.021) were associated with increased AF recurrence rate. On multivariate analysis, lower hsTnI level was the only independent predictor for AF recurrence (p = 0.012). Post-ablation hsTnI levels lower than 4.40 ng/ml predicted AF recurrence during follow up, with a sensitivity of 86% and a specificity of 96%. CONCLUSION: It is well recognised that the PV antrum contributes to initiation and/or perpetuation of AF. A lower postablation hsTnI level may predict an increased AF recurrence rate, suggesting inadequate ablation of the PV antrum. This may be used as a non invasive marker to predict the outcome of AF. PMID- 25783792 TI - Psychometric testing of the Revised Humane Caring Scale for adult patients in Singapore. AB - In this study, we examined the validity and reliability of the Revised Humane Caring Scale as used by adult patients in a tertiary hospital in Singapore. A three-phase descriptive quantitative study was conducted. In phase I, an expert panel of nurses and inpatients examined the content validity of the scale; phase II comprised a pilot study on 20 patients; and in phase III, a large-scale study on 235 patients was implemented to test the internal consistency of the scale. The results revealed that the content validity index of the scale ranged from 0.856 to 1, and the scale had a high inter-rater agreement kappa value of 0.940. Cronbach's alpha ranged from 0.798 to 0.877 in phase II, and from 0.579 to 0.760 in phase III, respectively. The Revised Humane Caring Scale revealed good content validity and an acceptable level of internal consistency. The scale is an acceptable measurement tool for evaluating adult patients' satisfaction during hospitalization. PMID- 25783794 TI - Mitochondrial plasticity in cancer-related muscle wasting: potential approaches for its management. AB - PURPOSE OF REVIEW: Cancer cachexia represents a critical problem in clinical oncology due to its negative impact on patients' quality of life, therapeutic tolerance and survival. This paraneoplasic condition is characterized by significant weight loss mainly from skeletal muscle wasting. Understanding the molecular mechanisms underlying cancer cachexia is urgent in order to develop and apply efficient therapeutic strategies. RECENT FINDINGS: Mitochondrial dysfunction is an early event in cancer-induced muscle wasting. Decreased ability for ATP synthesis, impaired mitochondrial biogenesis, increased oxidative stress, impairment of protein quality control systems, increased susceptibility to mitophagy and to apoptosis were all shown to mediate contractile dysfunction and wasting in cancer cachexia. Anti-inflammatory therapies as well as exercise training seem to counteract muscle mass loss in part by improving mitochondrial functionality. SUMMARY: Given its central role in muscle wasting, mitochondrial plasticity should be viewed as a key therapeutic target for the preservation of muscle mass in cancer cachexia. Few studies have addressed the mitochondrial events modulated by cancer cachexia and contradictory data were reported. Scarcer studies have focused on the mitochondrial adaptation to anticancer cachexia strategies. PMID- 25783796 TI - Well-defined copper(i) fluoroalkoxide complexes for trifluoroethoxylation of aryl and heteroaryl bromides. AB - Copper(I) fluoroalkoxide complexes bearing dinitrogen ligands were synthesized and the structure and reactivity of the complexes toward trifluoroethoxylation, pentafluoropropoxylation, and tetrafluoropropoxylation of aryl and heteroaryl bromides were investigated. PMID- 25783797 TI - Differential Diagnosis of Benign and Malignant Breast Tumors Using Apparent Diffusion Coefficient Value Measured Through Diffusion-Weighted Magnetic Resonance Imaging. AB - OBJECTIVE: Apparent diffusion coefficient (ADC) value measurement of nodes in diffusion-weighted imaging was widely used in differentiating different types of human tumors. The aim of this meta-analysis was to evaluate the clinical value of ADC measurement through diffusion-weighted magnetic resonance imaging (DW-MRI) in the differential diagnosis of benign and malignant breast tumors. METHODS: Relevant studies were identified through computer-based search of databases, which were supplemented through manual search strategies. Case-control studies were selected in adherence with our strict inclusion and exclusion criteria. Statistical analysis was conducted using Stata 12.0 statistical software (StataCorp, College Station, Tex). RESULTS: Our database searches initially retrieved 602 studies (320 studies in Chinese and 282 studies in English), and 31 studies (18 studies in English and 13 studies in Chinese) were eventually selected for meta-analysis. These 31 case-control studies included a total of 926 normal breast tissues and 2323 breast tumors (911 benign tumors and 1412 malignant tumors). Our meta-analysis showed that ADC values measured through DW MRI were higher in benign breast tumors compared with malignant breast tumors, and this difference was statistically significant. In addition, the ADC values in the normal breast tissues were markedly higher than the benign breast tumors, which were also at a statistically significant level. Consistent with these observations, the ADC values in the normal breast tissues were significantly higher when compared with the values found in the malignant breast tumors. CONCLUSIONS: Our data strongly support the conclusion that the ADC value measured through DW-MRI is an important radiographic index for differential diagnosis of benign and malignant breast tumors and is critical to our assessment of the internal structure of tumors. PMID- 25783795 TI - The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. AB - This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370. PMID- 25783798 TI - Characterization of multiple sclerosis plaques using susceptibility-weighted imaging at 1.5 T: can perivenular localization improve specificity of imaging criteria? AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine if magnetic resonance (MR) susceptibility-weighted imaging (SWI) can increase the conspicuity of corticomedullary veins within the white matter lesions of multiple sclerosis (MS) and, thus, aid in distinguishing plaques from leukoaraiosis. METHODS: We retrospectively reviewed MR examinations in 21 patients with a clinical diagnosis of MS and 18 patients with a clinical diagnosis of dementia. Examinations included fluid-attenuated inversion recovery (FLAIR) and SWI sequences obtained in the axial plane. Lesions greater than 5 mm in diameter on the axial FLAIR sequence were identified as periventricular or subcortical. Three neuroradiologists evaluated SWI images, compared with FLAIR, for a centrally located signal void in each lesion that was scored as present, absent, or indeterminate. RESULTS: In patients with MS, central veins were present in both periventricular lesions (75%, P < 0.001) and subcortical lesions (52%, P < 0.005). In patients with dementia, central veins were seen much less frequently in subcortical lesions (14%, P < 0.001); their association with periventricular lesions was not significant. CONCLUSIONS: Central veins were detected in MS lesions with a significantly greater frequency than that in patients with dementia. Susceptibility-weighted imaging increases the conspicuity of corticomedullary veins and may improve the specificity of MR findings in MS. PMID- 25783799 TI - Computed Tomographic Diagnosis of Myocardial Fat Deposits in Sarcoidosis. AB - OBJECTIVE: Fat deposits in the left ventricle (LV) myocardium are uncommon and usually indicate scar due to chronic myocardial infarction. The purpose of this study was to determine the incidence of fatty lesions in the LV of patients with sarcoidosis. MATERIALS AND METHODS: Review of noncontrast computed tomographic images (2-mm thickness) in 133 patients with documented extracardiac sarcoidosis (age, 35-82 years, 55 +/- 10 years, 67% female) with no history of significant coronary artery disease (clinical and coronary calcium) was performed. A control group included noncontrast computed tomographies with no coronary calcium in 133 patients with age/sex (59 +/- 6 years, 73% female) similar to the sarcoid target group. Locations and morphology (linear vs bulky) of fat deposits (-30 to -180 Hounsfield units) and relevant intrathoracic findings were recorded. RESULTS: We found 35 fat deposits in 19 (14.3%) of sarcoid patients (target group: age, 59 +/ 7 years, 78% female). Lesions were mainly at the LV apical level (n = 14). In the control group, 15 lesions in 13 (9.7%) patients were found. Numbers of fatty lesions in sarcoid targets were significantly higher than those in the control group (P = 0.015). The number of bulky lesions was significantly higher in sarcoid (n = 9) than in control (n = 1; P < 0.05). No significant difference was found for the rate of linear lesions. Interstitial lung disease was seen in 9 and enlarged lymph nodes in 9 of the sarcoid target group. There was no significant correlation between the severity of interstitial lung disease and the number of fatty lesions. CONCLUSIONS: Sarcoid patients demonstrate a higher chance of having LV fat deposits with a characteristic bulky morphology. PMID- 25783800 TI - Comparison of Dynamic Phase Enhancement of Hepatocellular Carcinoma Using Gadoxetate Disodium vs Gadobenate Dimeglumine. AB - OBJECTIVE: To determine the differences in enhancement of hepatocellular carcinoma during the first 5 minutes of postcontrast phases with gadoxetic acid (Gd-EOB-DTPA) vs gadobenate dimeglumine. METHODS: Ninety-five cirrhotic patients with hepatocellular carcinoma were examined on a 1.5-T scanner: 74 patients with Gd-BOPTA and 21 patients with Gd-EOB-DTPA. Same magnetic resonance imaging parameters were used for both groups. Gadoxetate isodium was administered at a dose of 0.025 mmol/kg; and Gd-BOPTA, at a dose of 0.1 mmol/kg. RESULTS: Mean contrast-to-noise ratios (CNR) were similar in arterial (P = 0.3), portal venous (P = 0.1), and 5-minute delayed phases (P = 0.73). The CNRs of lesions in the Gd EOB-DTPA group were lower in arterial phase, although this did not reach statistical significance. The CNRs of Gd-EOB-DTPA during the equilibrium phase was higher (P = 0.006). CONCLUSIONS: Gadoxetate isodium resulted in lower CNR during the arterial phase and higher CNR during the portal venous, equilibrium, and 5-minute delayed phases compared with gadobenate dimeglumine using the Food and Drug Administration-approved doses; however, overall, there was no statistical significance (P = 0.077). PMID- 25783801 TI - Rational linkage of magnetic molecules using click chemistry. AB - CuAAC click reactions were used for the first time to assemble click functionalized magnetic molecules into extended molecular arrangements in a deliberate manner. PMID- 25783802 TI - What is the password? Female bark beetles (Scolytinae) grant males access to their galleries based on courtship song. AB - Acoustic signals are commonly used by insects in the context of mating, and signals can vary depending on the stage of interaction between a male and female. While calling songs have been studied extensively, particularly in the Orthoptera, much less is known about courtship songs. One outstanding question is how potential mates are differentiated by their courtship signal characteristics. We examined acoustic courtship signals in a new system, bark beetles (Scolytinae). In the red turpentine beetle (Dendroctonus valens) males produce chirp trains upon approaching the entrance of a female's gallery. We tested the hypotheses that acoustic signals are honest indicators of male condition and that females choose males based on signal characteristics. Males generated two distinct chirp types (simple and interrupted), and variability in their prevalence correlated with an indicator of male quality, body size, with larger males producing significantly more interrupted chirps. Females showed a significant preference for males who produced interrupted chirps, suggesting that females distinguish between males on the basis of their chirp performances. We suggest that interrupted chirps during courtship advertise a male's size and/or motor skills, and function as the proverbial 'passwords' that allow him entry to a female's gallery. PMID- 25783803 TI - Six playback experimental designs fail to demonstrate acoustic preferences in common waxbills (Estrildidae: Estrilda astrild). AB - Playback experiments in controlled laboratory settings have been instrumental in studies of animal communication and signal evolution. Nonetheless, applying common methods to wild or non-model species can be challenging. We tested male and female common waxbills (Estrilda astrild) for behavioural preferences of conspecific vs. heterospecific songs, and of conspecific song vs. calls. Although common waxbills are related to model species used in this type of experiments, we could not demonstrate the predicted preference for conspecific over heterospecific song, or differential behavioural responses for conspecific song vs. calls. We confirm these results with experimental designs that either monitor movements, vocal responses, or active eliciting of playbacks, and that test birds in isolation or not, with or without visual stimuli accompanying playbacks. We discuss difficulties that may commonly apply to playback experiments with wild and social animals, and stress the importance of using simple discrimination tasks to validate common methods in novel species. PMID- 25783804 TI - The copyist model and the shaping view of reinforcement. AB - The strengthening view of reinforcement attributes behavior change to changes in the response strength or the value of the reinforcer. In contrast, the shaping view explains behavior change as shaping different response units through differential reinforcement. In this paper, we evaluate how well these two views explain: (1) the response-rate difference between variable-ratio and variable interval schedules that provide the same reinforcement rate; and (2) the phenomenon of matching in choice. The copyist model (Tanno and Silberberg, 2012) a shaping-view account - can provided accurate predictions of these phenomena without a strengthening mechanism; however, the model has limitations. It cannot explain the relation between behavior change and stimulus control, reinforcer amount, and reinforcer quality. These relations seem easily explained by a strengthening view. Future work should be directed at a model which combine the strengths of these two types of accounts. PMID- 25783805 TI - Designed angiopoietin-1 variant, COMP-angiopoietin-1, rescues erectile function through healthy cavernous angiogenesis in a hypercholesterolemic mouse. AB - Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, the link between ED and cardiovascular disease was unveiled and the main etiology of ED was found to be vasculogenic. Therefore, neovascularization is a promising strategy for curing ED. Angiopoietin-1 (Ang1) is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Here, we demonstrate that local delivery of the soluble, stable, and potent Ang1 variant, COMP-Ang1 gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in Nos3(-/-) mice and in the presence of the NOS inhibitor, L-NAME. COMP-Ang1 also restored the integrity of endothelial cell-cell junction by down-regulating the expression of histone deacetylase 2 in the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells. These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED. PMID- 25783806 TI - Declaration of a state of emergency in Trinidad and Tobago: effect on the trauma admissions at the National Referral Trauma Centre. AB - OBJECTIVE: To determine the effect of a State of Emergency (SOE) on penetrating injuries at the main trauma center in Trinidad and Tobago. METHODS: Emergency room registers were accessed in order to identify all patients treated for penetrating injuries from July 1, 2010 through December 30, 2012. This study period was chosen to include injuries one year before and one year after the SOE that spanned from August 21, 2011 to December 5, 2011. Data were analyzed using SPSS version 19 and a P value<.05 was considered statistically significant. RESULTS: There were 1,067 patients treated for penetrating injuries. There were significantly more injuries from gunshots compared to stab wounds (64.7% vs 35.3%; P<.001), and this pattern was maintained during the SOE (54.7% vs 45.3%; P=.37). There was a significant fall in mean monthly admissions for penetrating trauma during the SOE when compared to the 12-month period before its imposition (17.7, SD=4.0 vs 38.9, SD=12.3; CI, 5.6-36.8; P=.0108). One year later, mean monthly admissions for penetrating trauma were similar to those during the SOE (22.7, SD=2.1 vs 17.6, SD=4.0; CI, -2.3-12.3; P=.1295). The incidence of gunshot wounds remained low and stab wounds increased. CONCLUSION: This study has demonstrated that there was a reduction in the incidence of penetrating trauma at the national trauma center after the SOE, with a shift from gunshot to stab wounds. PMID- 25783808 TI - The role of catecholamine innervation in the medial prefrontal cortex on the regulation of body weight and food intake. AB - Effects of 6-hydroxydopamine (6-OHDA) lesions in the medial prefrontal cortex with or without protection of norepinephrine (NE) fibers were examined on basic regulatory processes of feeding. Daily body weight, food and water intake were measured. Locomotor activity, ingestion after food or water deprivation, and preference for 5% and 10% glucose solution were examined. Dopamine (DA) and NE content, as well as, tyrosine hydroxylase immunoreactivity were assessed to confirm the neurotoxic effect of treatments. 6-OHDA lesions of the medial prefrontal cortex with or without NE fiber protection resulted in body weight loss. Diminished habituation in open field tests, i.e. a persistently high motor activity, was also observed. Application of 6-OHDA with NE fiber protection led to increased food consumption following food-deprivation and to enhanced glucose preference. Enhanced intake of 10% over 5% glucose solution was also detected. 6 OHDA lesion resulted in a decrease to 20% of NE tissue concentration and only to 75% of DA concentration. In case of lesion with NE protection the NE content decreased to 69% and DA level to 51% with significant loss of tyrosine hydroxylase positive fibers in the deeper layers of the medial prefrontal cortex. DA depletion in the medial prefrontal cortex resulted in increased behavioral responsiveness to hunger and glucose, as well as, to open field environment. Pronounced lesion of NE terminals caused increased reaction to the environment in open field but not to hunger or glucose solution. PMID- 25783809 TI - Evolution of a complex behavior: the origin and initial diversification of foliar galling by Permian insects. AB - A central notion of the early evolution of insect galling is that this unique behavior was uncommon to rare before the diversification of angiosperms 135 to 125 m.yr. ago. However, evidence accumulated during recent years shows that foliar galls were diverse and locally abundant as early as the Permian Period, 299 to 252 m.yr. ago. In particular, a diversity of leaf galling during the Early Permian has recently been documented by the plant-damage record of foliar galls and, now, our interpretation of the body-fossil record of culprit insect gallers. Small size is a prerequisite for gallers. Wing-length measurements of Permian insects indicate that several small-bodied hemipteroid lineages originated early during the Permian, some descendant lineages of which gall the leaves of seed plants to the present day. The earliest foliar gallers likely were Protopsyllidiidae (Hemiptera) and Lophioneuridae (Thripida). Much of the Early Permian was a xeric interval, and modern galls are most common in dry, extra tropical habitats such as scrubland and deserts. Plant-damage, insect body fossils, and the paleoclimate record collectively support the ecological expansion of foliar galling during the Early Permian and its continued expansion through the Late Permian. PMID- 25783810 TI - Strengthening Clinical Skills Using Peer-Student Validation. AB - This study compared nursing students' satisfaction with the peer-student validation (PSV) method for learning basic skills and the traditional method. Students in the PSV group (n = 41) were compared with students in the traditional method group (n = 46) using a posttest survey. The PSV group reported significantly greater improvements in communication with their patients (P < .04) and time to practice skills (P < .01) and were more satisfied with the organization of the skills laboratory content (P < .04) than the traditional group. PMID- 25783811 TI - Transforming a Curriculum to Progress the Associate Degree Nurse to Advanced Practice. AB - The educational preparation of associate degree nurses to the master's level requires attainment of baccalaureate-level content. This preparation involves specialized curriculum and varied teaching techniques. Using adult learning theory and aspects of competency-based learning, students and faculty may participate in a gratifying and successful educational experience. The revision of an ongoing associate degree to baccalaureate-level curriculum is presented in this article. PMID- 25783812 TI - Faculty Experiences Developing and Implementing Policies for Exit Exam Testing. AB - Nursing schools use standardized exit examinations to determine student readiness for the NCLEX-RN. Yet little is known about how nursing programs develop policies for using the examinations, set benchmarks scores, and implement remediation strategies with their students. In a phenomenological study, faculty identified a testing policy process that fell into the major themes of triggers for change, policy modification, and reactions to change. PMID- 25783813 TI - Professional Values of RN-to-BSN Students in an Online Program. AB - Professional values are an important component of nursing education. This cross sectional study assessed the professional values of 222 students in an online RN to-BSN program. Higher scores were related to items reflecting direct patient care and accountability for nursing practice. Items focusing on nursing theory, cost of care, and professional nursing organization revealed lower scores. PMID- 25783814 TI - Operationalizing the Student Electronic Portfolio for Doctoral Nursing Education. AB - There is an increasing trend toward use of the electronic portfolio (e-portfolio) in Doctor of Nursing Practice programs. E-portfolios can provide documentation of competencies and achievement of program outcomes while showcasing a holistic view of the student achievement. Implementation of the e-portfolio requires careful decision making concerning software selection, set-up, portfolio components, and evaluation. The purpose of this article is to describe the implementation of an e portfolio in a Doctor of Nursing Practice program and provide lessons learned during the implementation stage. PMID- 25783815 TI - Patient Deception: Nursing Students' Beliefs and Attitudes. AB - This study examined nursing students' beliefs about indicators of deception and their attitudes toward patient deception. Fifty-eight participants from various nursing programs at a southwestern university completed a Detection of Deception Questionnaire and Attitudes Toward Patient Deception Scale. Findings indicated that nursing students have a number of inaccurate beliefs about deception and possess a number of negative attitudes toward patients who lie. Implications for nursing education are discussed. PMID- 25783816 TI - Flexibility in Graduate Clinical Assignments: Self-assigned Deadlines. PMID- 25783817 TI - Feasibility and accuracy of computational robot-assisted partial nephrectomy planning by virtual partial nephrectomy analysis. AB - OBJECTIVES: To evaluate the feasibility and accuracy of virtual partial nephrectomy analysis, including a color-coded three-dimensional virtual surgical planning and a quantitative functional analysis, in predicting the surgical outcomes of robot-assisted partial nephrectomy. METHODS: Between 2012 and 2014, 20 patients underwent virtual partial nephrectomy analysis before undergoing robot-assisted partial nephrectomy. Virtual partial nephrectomy analysis was carried out with the following steps: (i) evaluation of the arterial branch for selective clamping by showing the vascular-supplied area; (ii) simulation of the optimal surgical margin in precise segmented three-dimensional model for prediction of collecting system opening; and (iii) detailed volumetric analyses and estimates of postoperative renal function based on volumetric change. At operation, the surgeon identified the targeted artery and determined the surgical margin according to the virtual partial nephrectomy analysis. The surgical outcomes between the virtual partial nephrectomy analysis and the actual robot assisted partial nephrectomy were compared. RESULTS: All 20 patients had negative cancer surgical margins and no urological complications. The tumor-specific renal arterial supply areas were shown in color-coded three-dimensional model visualization in all cases. The prediction value of collecting system opening was 85.7% for sensitivity and 100% for specificity. The predicted renal resection volume was significantly correlated with actual resected specimen volume (r(2) = 0.745, P < 0.001). The predicted estimated glomerular filtration rate was significantly correlated with actual postoperative estimated glomerular filtration rate (r(2) = 0.736, P < 0.001). CONCLUSIONS: Virtual partial nephrectomy analysis is able to provide the identification of tumor-specific renal arterial supply, prediction of collecting system opening and prediction of postoperative renal function. This technique might allow urologists to compare various arterial clamping methods and resection margins with surgical outcomes in a non-invasive manner. PMID- 25783818 TI - A general method of fabricating flexible spinel-type oxide/reduced graphene oxide nanocomposite aerogels as advanced anodes for lithium-ion batteries. AB - High-capacity anode materials for lithium ion batteries (LIBs), such as spinel type metal oxides, generally suffer from poor Li(+) and e(-) conductivities. Their drastic crystal structure and volume changes, as a result of the conversion reaction mechanism with Li, severely impede the high-rate and cyclability performance toward their practical application. In this article, we present a general and facile approach to fabricate flexible spinel-type oxide/reduced graphene oxide (rGO) composite aerogels as binder-free anodes where the spinel nanoparticles (NPs) are integrated in an interconnected rGO network. Benefiting from the hierarchical porosity, conductive network and mechanical stability constructed by interpenetrated rGO layers, and from the pillar effect of NPs in between rGO sheets, the hybrid system synergistically enhances the intrinsic properties of each component, yet is robust and flexible. Consequently, the spinel/rGO composite aerogels demonstrate greatly enhanced rate capability and long-term stability without obvious capacity fading for 1000 cycles at high rates of up to 4.5 A g(-1) in the case of CoFe2O4. This electrode design can successfully be applied to several other spinel ferrites such as MnFe2O4, Fe3O4, NiFe2O4 or Co3O4, all of which lead to excellent electrochemical performances. PMID- 25783819 TI - Practical neuroimaging of central nervous system tumors for surgical pathologists. AB - Imaging has established itself as an irreplaceable component of neuro-oncology, and provided much insight in all aspects of central nervous system (CNS) tumors. Today, similar to some other medical specialties, such as bone and joint disorders, it is an integral part of the diagnosis of CNS tumors. This brief review highlights the critical elements of neuroimaging, especially of MRI, in the study and diagnosis of brain tumors, and considers some of the common entities for the diagnosis, of which a good understanding of imaging characteristics is extremely helpful. PMID- 25783820 TI - The basics of intraoperative diagnosis in neuropathology. AB - Intraoperative pathologic consultation continues to be an essential tool during neurosurgical procedures, helping to ensure adequacy of material for achieving a pathologic diagnosis and to guide surgeons. For pathologists, successful consultation with central nervous system lesions involves not only a basic familiarity with the pathologic features of such lesions but also an understanding of their clinical and radiologic context. This review discusses a basic approach to intraoperative diagnosis for practicing pathologists, including preparation for, performance of, and interpretation of an intraoperative neuropathologic evaluation. The cytologic and frozen section features of select examples of common pathologic entities are described. PMID- 25783821 TI - Practical molecular pathologic diagnosis of infiltrating gliomas. AB - Recent advances in molecular diagnostics have led to better understanding of glioma tumorigenesis and biology. Numerous glioma biomarkers with diagnostic, prognostic, and predictive value have been identified. Although some of these markers are already part of the routine clinical management of glioma patients, data regarding others are limited and difficult to apply routinely. In addition, multiple methods for molecular subclassification have been proposed either together with or as an alternative to the current morphologic classification and grading scheme. This article reviews the literature regarding glioma biomarkers and offers a few practical suggestions. PMID- 25783822 TI - Practical molecular pathologic diagnosis of pilocytic astrocytomas. AB - The pilocytic astrocytoma is predominantly a tumor of childhood and the most common type of circumscribed astrocytoma. The indolent nature of this tumor allows for prolonged survival for most patients, rendering the disease a rather "chronic" one, with potential long-term sequelae that are occasionally related to treatment. Two critical features of this tumor are its tendency to remain dormant, or involute even after subtotal resection, and the exceptional anaplastic transformation, sometimes following adjuvant therapy. The biological behavior of pilocytic astrocytoma can often be related to molecular alterations in the MAPK pathway. PMID- 25783823 TI - Practical molecular pathology and histopathology of embryonal tumors. AB - There have been significant improvements in understanding of embryonal tumors of the central nervous system (CNS) in recent years. These advances are most likely to influence the diagnostic algorithms and methodology currently proposed by the World Health Organization (WHO) classification scheme. Molecular evidence suggests that the tumors presumed to be specific entities within the CNS/primitive neuroectodermal tumors spectrum are likely to be reclassified. All these developments compel reassessing current status and expectations from the upcoming WHO classification efforts. This review provides a synopsis of current developments and a practical algorithm for the work-up of these tumors in practice. PMID- 25783824 TI - Recent developments in paraneoplastic disorders of the nervous system. AB - Paraneoplastic disorders of the nervous system (PNDs) are rare and unique disorders, where a specific pattern of neural damage occurs as a side effect of the interaction between the neoplasm and the host immune response. Clinical recognition of PNDs may be challenging but can lead to early detection of an occult neoplasm. Their study may lead to a better understanding of nervous system autoimmunity and even to devising novel immunotherapies against certain tumor types. Familiarity with the clinical syndromes, neuroradiological findings, autoantibodies, and tissue responses associated with PND may help arrive at a correct diagnosis in most cases. PMID- 25783828 TI - Practical issues in diagnostic neuropathology: it is not even the end of the beginning! PMID- 25783831 TI - Anastomotic leakage after laparoscopic single-port sigmoid resection: combined transanal and transabdominal minimal invasive management. AB - BACKGROUND: Laparoscopic colorectal surgery has become the gold standard in the therapy of benignant and malignant colorectal pathologies. Anastomotic leakage is still a reason for laparotomy; applying a diverting stoma or performing a Hartman's procedure is common [1, 2]. Laparoscopic treatment of an early-detected anastomotic leakage is suggested from other authors [3, 4]. In our video we demonstrate a combined minimal invasive transabdominal and transanal treatment concept in patients with early-detected anastomotic leakage. METHODS: Two consecutive patients developing an anastomotic leakage after single-port laparoscopic sigmoid resection for stage II/III diverticulitis (Hanson & Stock) were treated with a combined minimal invasive approach. Anastomotic leakage was diagnosed by triple contrast computed tomography on postoperative day 4 in patient one and on postoperative day 7 in patient two. Operative treatment was performed immediately on the same day without delay. RESULTS: In both patients a combined transanal and transabdominal approach was performed. First step was a diagnostic laparoscopy in order to exclude fecal peritonitis. Using a single-port device (SILS Port Covidien), transanal inspection of the anastomosis was also performed: In both patients anastomotic tissue margins were vital, and the leakage affected only a quarter of the anastomotic circumference. Transanal stitches were placed to close the anastomotic leakage. Laparoscopic transabdominal irrigation was performed, and two suction drainages were placed in the pelvis. Postoperative antibiotic treatment and a gradual return to slid food were carried out. Functional result at follow-up of 102 and 112 days (with rectoscopy) showed no residual leak and no stricture of the anastomosis, and both of patients had a normal rectal function. PMID- 25783832 TI - Safety and feasibility of simultaneous endoscopic submucosal dissection for multiple gastric neoplasias. AB - BACKGROUND: Synchronous gastric neoplasms are not infrequently detected, thus endoscopic submucosal dissection (ESD) for multiple early gastric neoplasia is occasionally considered. However, there have been few investigations of the safety and feasibility of simultaneous ESD for multiple gastric lesions. This study aims to evaluate the safety and feasibility of simultaneous ESD for multiple gastric neoplasia. METHODS: A total of 1823 patients who underwent ESD for 1929 gastric adenomas or early gastric cancers were retrospectively reviewed in this study. Two hundred gastric adenomas or early gastric cancers among 94 patients were treated by ESD simultaneously (multiple group), and 1729 patients were treated with ESD for a single lesion (single group). RESULTS: En bloc resection (P = 0.060), complete resection (P = 0.362) and curative resection (P = 0.108) rates did not differ between the two groups. Rates of adverse events including bleeding (P = 0.317), perforation (P = 0.316) and aspiration pneumonia (P = 0.563) were not higher in the multiple group. Long-term follow-up showed more frequent local recurrence (P < 0.001), synchronous neoplasia (P = 0.041) and metachronous neoplasia (P < 0.001) per patient in the multiple group; however, local recurrence per lesion did not differ between the two groups (P = 0.103). CONCLUSIONS: Simultaneous ESD for multiple synchronous gastric neoplasms is safe and feasible compared to single ESD. However, thorough examination for local recurrence and synchronous and metachronous neoplasia is required. PMID- 25783833 TI - Trans-oral anterior fundoplication: 5-year follow-up of pilot study. AB - BACKGROUND: This is a report of an IRB-approved pilot study of 13 patients who received a trans-oral anterior partial fundoplication for the treatment of GERD using an ultrasound-guided, flexible surgical stapler. All patients had a history of PPI use, objective evidence of GERD, and no significant comorbidity. Under general anesthesia, a flexible stapler was passed trans-orally into the stomach and placed two or three quintuplets of titanium staples approximately 3 cm above the gastroesophageal junction. The stapler contains an ultrasonic range finder, video camera, and illuminator. METHODS: Primary follow-up at 6 weeks included pH metrics, GERD-HRQL scores, and PPI use. The protocol allowed annual telephone interviews for the following 5 years to collect GERD-HRQL scores, PPI use, satisfaction with the procedure, and willingness to have the procedure again. RESULTS: At 6 weeks, mean total acid exposure was significantly reduced, and 12/13 patients reduced GERD-HRQL scores by >=50%. Twelve of 13 patients had stopped daily GERD medications, and nine of 13 had stopped all GERD medications. Each year, 11 of the 13 patients could be reached with all 13 patients having at least 4-year follow-up. Throughout the follow-up period, GERD-HRQL scores were normal (<10) in all but one patient. All patients would agree to do the procedure again. The median satisfaction score is 8 (range 6-10) on a scale of 1-10. None reported dysphagia. At 1 year, 54% of respondents (6/11) had eliminated PPI use, with another 27% (3/11) taking a reduced dose. Combining respondents at 4 and 5 years to account for all patients, 54% (7/13) had eliminated and another 23% (3/13) reduced PPI use >=50 %. CONCLUSION: At 5 years, the procedure remained effective as demonstrated by the improved quality of life and changes in PPI use. The results remained stable after the second year. PMID- 25783834 TI - Pain during sexual activity before and after laparoscopic inguinal hernia repair. AB - BACKGROUND: Sexual life may be impaired by pain during sexual activity in patients with inguinal hernia. On the other hand, inguinal hernia repair has also been reported to cause sexual dysfunction in terms of pain during sexual activity and ejaculation. The primary aim of this study was to estimate the prevalence of pain during sexual activity before and after laparoscopic inguinal hernia repair, and the secondary, to describe pain location, frequency of pain during sexual activity, and to which degree sexual life was affected by the pain. Furthermore, to examine whether preoperative pain during sexual activity was a risk factor for postoperative pain during sexual activity. METHODS: A prospective questionnaire study before and 6 months after hernia repair was conducted. Men (age 18-85 years) undergoing laparoscopic inguinal hernia repair were included. RESULTS: In total, 160 men were included. Overall, 23% of patients complained preoperatively of pain during sexual activity. Sexual life was affected in moderate-to-severe degree in 17%. Ten percent had pain during sexual activity 6 months after hernia repair. The prevalence of men with pain during sexual activity was not increased after hernia repair (p = 0.080). Instead, there was a trend toward a reduction. Both before and after hernia repair sexually related pain was primarily located in the groin area and in the scrotum. Patients with preoperative pain during sexual activity had a higher risk of postoperative pain during sexual activity compared with patients without pain preoperatively (p = 0.0007). CONCLUSION: Having an inguinal hernia may be related to pain during sexual activity before operation. We did not find an increase in sexually related pain after operation. On the contrary, there was a trend toward decreased pain related to sexual activity after laparoscopic inguinal hernia repair. Preoperative pain during sexual activity predisposed to postoperative pain during sexual activity. PMID- 25783835 TI - Comparison of two laparoscopic splenectomy plus pericardial devascularization techniques for management of portal hypertension and hypersplenism. AB - OBJECTIVE: Our research was conducted to analyze the outcomes of two laparoscopic splenectomy plus pericardial devascularization (LSPD) techniques in the management of portal hypertension (PTH) and hypersplenism. METHODS: Between May 2012 and May 2013, 41 patients with PTH and hypersplenism undergoing LSPD were retrospectively analyzed. Of them, 29 patients received LSPD by LigaSure Vessel Sealing System (LVSS) and Endo-GIA universal endoscopic vascular linear staplers (Endo-GIA) (EG Group) and 12 patients received LSPD by LVSS and Hem-o-Lock (HL Group). Operating time, intraoperative blood loss, postoperative course, and hospitalization costs were compared between the two LSPD combination techniques. RESULTS: There were no significant differences in preoperative patient characteristics of the two groups. Significantly less operating time, intraoperative blood loss, and postoperative complications were observed in EG Group. The incidence of portal vein thrombosis was lower in the EG Group (3.4 vs. 8.3%), as well as the incidence of pancreatic fistula (0 vs. 8.3%). Upper gastrointestinal hemorrhage was not observed in either group. Uncontrolled bleeding warranted conversion to open surgery in one case in EG Group (conversion rate 3.4%) and in two cases in HL Group (conversion rate 16.7%). Two patients (16.7%) in HL Group underwent successful emergency exploratory laparotomy due to uncontrolled intraabdominal bleeding postoperatively. No re-operation was needed in EG Group. Two patients experienced liver failure after surgery in each group. Of those, three patients were managed successfully and one patient refused further therapy. While the overall complication rate was significantly lower in EG Group (17.2 vs. 58.3%, P < 0.05), overall hospitalization costs remained significantly higher for EG Group. CONCLUSION: The results suggest that the modified Endo-GIA and LVSS technique is a safe and effective combination approach to LSPD with shorter operative time, less intraoperative blood loss, lower conversion rate to laparotomy, shorter hospital stay, better recovery, and lower postoperative complication rate compared with the Hem-o-Lock and LVSS approach. Higher hospitalization expenses associated with the Endo-GIA and LVSS approach. PMID- 25783836 TI - Adverse events associated with endoscopic dilation for gastric stenosis after endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND: Gastric stenosis is a major problem after endoscopic submucosal dissection (ESD) for large early gastric cancer, but little is known about the incidence of adverse events associated with endoscopic dilation (ED) for stenosis caused by gastric ESD. The aims of this study were to determine the incidence and risk of bleeding and perforation associated with ED for gastric stenosis after ESD. METHODS: This was a single-center, retrospective cohort study conducted at a specialized center for treating cancer. A total of 342 procedures of wire-guided balloon ED were performed for stenosis after gastric ESD in 64 patients. The incidence of adverse events and related clinical characteristics was analyzed. RESULTS: The incidence of bleeding was 3.1% (2/64) per patient and 0.6% (2/342) per procedure. One bleeding case with incomplete cessation of antithrombotics before ED required blood transfusion. The incidence of perforation was 7.8% (5/64) per patient and 1.5% (5/342) per procedure. All perforations occurred in the lower part of the stomach. Two of the five perforation cases were inappropriate for nonoperative therapy, and thus, emergency surgery was performed. Among the other three perforation cases, one case required surgery for refractory stenosis and ED was continued in one case after nonoperative therapy. CONCLUSIONS: The incidence of bleeding caused by ED for gastric stenosis after ESD was small. Although not significant, ED in the lower stomach presents a substantial risk of perforation. PMID- 25783838 TI - Erratum to: 3-Dimensional (3D) laparoscopy improves operating time in small spaces without impact on hemodynamics and psychomental stress parameters of the surgeon. PMID- 25783837 TI - Laparoscopic pancreaticoduodenectomy: single-surgeon experience. AB - BACKGROUND: Innovations in surgical strategies and technologies have facilitated laparoscopic pancreaticoduodenectomy (LPD). However, data regarding the short term and long-term results of LPD are sparse, and this procedure is the primary focus of the current study. METHODS: Between October 2010 and October 2013, a total of 31 consecutive patients received LPD, including hand-assisted laparoscopic pancreaticoduodenectomy, total laparoscopic pancreaticoduodenectomy, and laparoscopic pylorus-preserving pancreaticoduodenectomy. Data regarding short term surgical outcomes and long-term oncological results were collected prospectively. RESULTS: The median operative time was 515.0 min (interquartile range 465.0-585.0 min). The median intraoperative estimated blood loss was 260.0 mL (interquartile range 150.0-430.0 mL). Conversion to open pancreaticoduodenectomy was required in three patients (9.7%) due to intraoperative pneumoperitoneum intolerance (n = 1, 3.2%) and tumor adherence to the superior mesenteric vein (n = 2, 6.5%). No significant differences between the surgical approaches were observed in regard to intraoperative and postoperative data. Postoperative severe complications (Clavien >= III) were detected in three (9.7%) patients, including one grade C pancreatic fistula, one grade B postoperative bleeding event, and one afferent loop obstruction. There were no deaths within 30 days following LPD. The final pathological results revealed duodenal adenocarcinoma in 14 (45.2%) patients, ampullary adenocarcinoma in four (12.9%) patients, distal common bile duct cancer in six (19.4%) patients, pancreatic ductal adenocarcinoma in five (16.1%) patients, gastrointestinal stroma tumor in one (3.2%) patient, and chronic pancreatitis in one (3.2%) patient. All patients suffering from tumors underwent R0 resection (n = 30, 100.0%), with the optimal number of collected lymph nodes (median: 13, interquartile range 11-19). At the most recent follow-up, 20 patients were still alive, and the 1-, and 3-year overall survival for patients with duodenal adenocarcinoma were 100.0 and 71.4%, respectively. CONCLUSIONS: According to this study, LPD is feasible and technically safe for highly selected patients and can offer acceptable oncological outcomes and long-term survival. PMID- 25783839 TI - Attenuation of LPS-induced cyclooxygenase-2 and inducible NO synthase expression by lysophosphatidic acid in macrophages. AB - LPS can activate the inflammatory cascades by inducing various inflammatory mediators, such as prostaglandin E(2) (PGE(2)) resulting from cyclooxygenase-2 (COX-2), and NO produced by inducible NO synthase (iNOS). Lysophosphatidic acid (LPA) has been demonstrated to participate in inflammation. This study aimed to clarify the impact and the involving mechanisms of LPA on LPS-incurred inflammation in macrophages. First, LPA appeared to attenuate LPS-induced protein and mRNA expression of COX-2 and iNOS genes, as well as production of PGE(2) and NO. By using selective inhibitors targeting various signaling players, the inhibitory G protein alpha subunit (Galpha(i)) seemed to be involved in the effect of LPA; p38, ERK and NF-kappaB were involved in the LPS-mediated COX 2/PGE(2) pathway; and p38, JNK, phosphoinositide-3-kinase and NF-kappaB were involved in the LPS-mediated iNOS/NO pathway. LPA was able to diminish LPS induced phosphorylation of p38 and Akt, as well as NF-kappaB p65 nuclear translocation. By utilization of inhibitors of COX-2 and iNOS, there appeared to be no modulation between the COX-2/PGE(2) and the iNOS/NO signaling pathways. Our findings demonstrate a clear anti-inflammatory role of LPA acting via Galpha(i) in LPS-mediated inflammatory response in macrophages, owing, at least in part, to its suppressive effect on LPS-induced activation of p38, Akt and NF-kappaB. PMID- 25783840 TI - Regulation of CCN1 (Cyr61) in a porcine model of intestinal ischemia/reperfusion. AB - Intestinal ischemia is a serious condition that may lead to both local and systemic inflammatory responses. Restoration of blood supply (reperfusion) to ischemic tissues often increases the extent of the tissue injury. Cysteine-rich angiogenic inducer 61 (Cyr61)/CCN1 is an extracellular matrix-associated signaling protein that has diverse functions. CCN1 is highly expressed at sites of inflammation and wound repair, and may modify cell responses. This study aimed to investigate regulation and cellular distribution of CCN1 in intestinal ischemia/reperfusion (I/R) injury in pigs. After intestinal I/R, increased expression of CCN1 was detected by quantitative RT-PCR, Western blot analysis and immunohistochemistry compared with non-ischemic intestine. Immunoflorescence staining revealed that CCN1 was mainly up-regulated in intestinal mucosa after intestinal I/R. Microvillus epithelial cells and vascular endothelial cells were strongly positive for CCN1 in intestinal I/R, while natural killer cells and/or subsets of neutrophils were only modestly positive for CCN1. Furthermore, blood samples taken from the portal and caval veins during ischemia and after reperfusion showed no change of the CCN1 levels, indicating that CCN1 was locally regulated. In conclusion, these observations show, for the first time, that the CCN1 molecule is up-regulated in response to intestinal I/R in a local manner. PMID- 25783841 TI - Lars Grimelius and his silver impregnation method--Commentaries on the paper in Upsala Journal of Medical Sciences with the highest number of citations. PMID- 25783843 TI - Safety and efficacy of concurrent neck dissection and transoral robotic surgery. AB - BACKGROUND: The literature is scarce regarding transoral robotic surgery (TORS) with simultaneous neck dissection. This study evaluates the safety and efficacy of concurrent neck dissection in oropharyngeal squamous cell carcinoma (SCC) treated with TORS. METHODS: Analysis of 113 patients with oropharyngeal SCC treated with TORS and concurrent neck dissection. RESULTS: Six intraoperative communications between the pharynx and neck region were recognized. After pharyngeal mucosal flap advancement, 1 defect was closed primarily and another one was reinforced with acellular dermal matrix. In 1 case, submandibular gland was transposed posteriorly over the sutured defect as a support. One omohyoid and 2 digastric muscular pedicle rotation flaps were used in the remaining 3 patients for the reconstruction of pharyngeal communications. None of the patients developed postoperative pharyngocutaneous fistula. CONCLUSION: The advantage of TORS oropharyngectomy, when compared with open approaches, is the avoidance of pharyngocutaneous fistula even in the presence of concurrent neck dissection (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E519-E523, 2016. PMID- 25783842 TI - ACVIM consensus statement on therapeutic antimicrobial use in animals and antimicrobial resistance. AB - The epidemic of antimicrobial resistant infections continues to challenge, compromising animal care, complicating food animal production and posing zoonotic disease risks. While the overall role of therapeutic antimicrobial use in animals in the development AMR in animal and human pathogens is poorly defined, veterinarians must consider the impacts of antimicrobial use in animal and take steps to optimize antimicrobial use, so as to maximize the health benefits to animals while minimizing the likelihood of antimicrobial resistance and other adverse effects. This consensus statement aims to provide guidance on the therapeutic use of antimicrobials in animals, balancing the need for effective therapy with minimizing development of antimicrobial resistance in bacteria from animals and humans. PMID- 25783844 TI - Posteroinferior shoulder instability: clinical outcome of arthroscopic stabilization in 32 shoulders and categorization based on labral mapping. AB - INTRODUCTION: Posterior shoulder instability is rare, appears in varying clinical patterns and can be the main symptom in patients with instability in more than one direction. The purpose was to analyze and categorize our patients and to report on the results of operative treatment by arthroscopy. MATERIALS AND METHODS: A consecutive series of 32 shoulders in 31 patients from a 7-year period was chosen for retrospective clinical evaluation with VAS for pain, Rowe Score, Constant Score and Simple Shoulder Test. Follow-up rate was 100 %, the mean FU period was 28 months (range 13-58). Allocation based on clinical and intraoperative criteria resulted in the 4 groups A to D characterized by an increasing traumatic impact. Patients received a posterior Bankart repair with bone anchors in 21 or capsular plication to the intact labrum in 11 cases. RESULTS: The clinical outcome scores were generally good and all showed a trend towards better results from A to D, but without significance. Pain on VAS pre- and postoperatively showed a significant (p < 0.0001) overall decline from 7.4 to 1.8. The Rowe Score increased significantly (p < 0.0001) from a mean value of 41.4 to 89.5 points. Three patients were reoperated and satisfied, four patients (12.5 %) not satisfied at follow-up. The drive-through sign was significantly (p = 0.003) more distinct in the less traumatic groups A and B than groups C and D. Subgroup allocation resulted in the following distribution: 7 patients qualified for group A (PPM = predominantly posterior multidirectional), 13 for B (RPS = recurrent posterior subluxation), 7 for C (unidirectional) and 5 patients for group D (bi-directional). Graphic display of labral lesions, called "labral mapping", revealed typical patterns for the groups. CONCLUSION: In patients with posteroinferior shoulder instability, good results can be obtained with the arthroscopic treatment of all identified pathologies. Categorization into one of four subgroups might be a valuable tool regarding the choice of the operative treatment options. PMID- 25783845 TI - Frontal plane stability following UKA in a biomechanical study. AB - INTRODUCTION: Function and kinematics following unicondylar knee arthroplasty (UKA) have been reported to be close to the native knee. Gait, stair climbing and activities of daily living expose the knee joint to a combination of varus and valgus moments. Replacement of the medial compartment via UKA is likely to change the physiologic knee stability and its ability to respond to varus and valgus moments. It was hypothesized that UKA implantation would stiffen the knee and decrease range of motion in the frontal plane. MATERIALS AND METHODS: Six fresh frozen cadaver knees were prepared and mounted in a six-degrees-of-freedom robot. An axial load of 200 N was applied with the knee in 15 degrees , 45 degrees and 90 degrees of flexion. Varus and valgus moments were added, respectively, before and after implantation of medial UKA. Tests were than redone with a thicker polyethylene inlay to simulate overstuffing of the medial compartment. Range of motion in the frontal plane and the tibial response to moments were recorded via the industrial robot. RESULTS: The range of motion in the frontal plane was decreased with both, balanced and overstuffed UKA and shifted towards valgus. When exposed to valgus moments, knees following UKA were stiffer in comparison with the native knee. The effect was even more pronounced with medial overstuffing. CONCLUSION: In UKA, the compressive anatomy is replaced by much stiffer components. This lack of medial compression and relative overstuffing leads to a tighter medial collateral ligament. This drives the trend towards a stiffer joint as documented by a decrease in frontal plane range of motion. Overstuffing should strictly be avoided when performing UKA. PMID- 25783846 TI - Absence of full-length neurokinin-1 receptor protein expression by cutaneous T cells: implications for substance P-mediated signaling in mycosis fungoides. PMID- 25783847 TI - Intratympanic steroid injection as a first-line therapy in uremia patients with sudden sensorineural hearing loss. AB - CONCLUSIONS: ITSI as a first-line therapy in uremia patients with SSNHL offers a valid and safe treatment compared with intravenous systemic steroid treatment. A specific pathophysiology caused by possible sodium pump paralysis may be explained for uremia patients with SSNHL. OBJECTIVE: To compare the efficacy of intratympanic steroid injection (ITSI) with that of systemic intravenous steroids as a first-line therapy in uremia patients with sudden sensorineural hearing loss (SSNHL). MATERIALS AND METHODS: A total of 23 consecutive uremia patients with SSNHL were enrolled in this study. Patients were divided into two groups: the ITSI group (n = 15) and the non-ITSI group (n = 8), in which patients received intravenous systemic steroid treatment. The two groups were homogeneous in all respects. RESULTS: The hearing improvement and relative gain were statistically significant between the two groups. The value of hearing gain (DeltaPTA = PTA pre - PTA post) in the ITSI group and the non-ITSI group was 24.6 +/- 16.4dB and 8.4 +/- 19.3dB. The value of relative gain (DeltaPTA/PTApre) in the ITIS group and the non-ITSI group was 31.1 +/- 22% and 9.4 +/- 20.5%. In the ITSI group, 11 patients (73.3%) exhibited hearing recovery (DeltaPTA > 10 dB). PMID- 25783848 TI - Enhancement of periosteal bone formation by basic fibroblast-derived growth factor containing polycystic kidney disease and collagen-binding domains from Clostridium histolyticum collagenase. AB - Recombinant basic fibroblast growth factor (bFGF) is a potent mitogen for mesenchymal cells that accelerates bone union and repair when applied locally at defect sites. However, because bFGF diffuses rapidly from bone defect sites, repeated dosing is required for sustained therapeutic effect. We previously fused the collagen-binding domain (CBD) and polycystic kidney disease (PKD) domain of Clostridium histolyticum class II collagenase (ColH) to bFGF and demonstrated that the fusion protein markedly enhances bone formation when loaded onto collagen materials used for grafting. However, systemic injection of a fusion protein consisting of parathyroid hormone (PTH) and a CBD was shown to accelerate bone formation in an osteoporosis model more rapidly than treatment with a PTH PKD-CBD fusion protein. Here, we compared the biological properties of two collagen-binding forms of bFGF, bFGF-CBD and bFGF-PKD-CBD. Both fusion proteins promoted the in vitro proliferation of periosteal mesenchymal cells, indicating that they had biological activity similar to that of native bFGF. In vivo periosteal bone formation assays in rat femurs showed that both bFGF-CBD and bFGF PKD-CBD induced periosteal bone formation at higher rates than collagen sheet alone and bFGF. However, bFGF-PKD-CBD markedly enhanced bone formation and had higher collagen-binding ability than bFGF-CBD in in vitro protein release assays. Taken together, these results suggest that the PKD domain increases the retention of bFGF at graft sites by enhancing collagen-binding affinity. Therefore, bFGF PKD-CBD-collagen composite appears to be a promising material for bone repair in the clinical setting. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25783849 TI - Short-term intensive family therapy for adolescent eating disorders: 30-month outcome. AB - Family therapy approaches have generated impressive empirical evidence in the treatment of adolescent eating disorders (EDs). However, the paucity of specialist treatment providers limits treatment uptake; therefore, our group developed the intensive family therapy (IFT)-a 5-day treatment based on the principles of family-based therapy for EDs. We retrospectively examined the long term efficacy of IFT in both single-family (S-IFT) and multi-family (M-IFT) settings evaluating 74 eating disordered adolescents who underwent IFT at the University of California, San Diego, between 2006 and 2013. Full remission was defined as normal weight (>= 95% of expected for sex, age, and height), Eating Disorder Examination Questionnaire (EDE-Q) global score within 1 SD of norms, and absence of binge-purging behaviours. Partial remission was defined as weight >= 85% of expected or >= 95% but with elevated EDE-Q global score and presence of binge-purging symptoms (<1/week). Over a mean follow-up period of 30 months, 87.8% of participants achieved either full (60.8%) or partial remission (27%), while 12.2% reported a poor outcome, with both S-IFT and M-IFT showing comparable outcomes. Short-term, intensive treatments may be cost-effective and clinically useful where access to regular specialist treatment is limited. PMID- 25783850 TI - Coping styles in adults with cystic fibrosis: implications for emotional and social quality of life. AB - As life expectancy increases, interest has grown surrounding the factors that may influence quality of life (QOL) for people with cystic fibrosis (CF). The aim of the current study was to examine which specific coping styles were positively or negatively associated with social and emotional QOL in a CF sample. One hundred and twenty-two respondents aged 18 and over were recruited through an online support group. Respondents completed the 'CF Questionnaire-Revised (CFQ-R)' and the 'Brief COPE'. The CFQ-R is a disease-specific instrument designed to measure the impact of CF on nine QOL domains and the Brief COPE is a 28 item questionnaire which assesses 14 coping scales. A multivariate regression model revealed that higher substance abuse and disengagement was associated with lower emotional QOL whereas greater use of religion, instrumental coping and acceptance was positively associated with emotional QOL. Active coping was linked to better social QOL and a negative association was reported between distraction coping with both emotional and social domains. Given the burden of CF, ascertaining which factors enhance or diminish emotion and social well-being is now an integral component of QOL research. The current findings may therefore have value in informing clinical interventions which aim to cater for the psychological needs of individuals with CF. PMID- 25783851 TI - Single nucleotide polymorphisms in candidate genes and their relation with somatic cell scores in Argentinean dairy cattle. AB - The prevention and control of bovine mastitis by enhancing natural defenses in animals is important to improve the quality of dairy products. Mastitis resistance is a complex trait which depends on genetic components, as well as environmental and physiological factors. The limitations of classical control measures have led to the search for alternative approaches to minimize the use of antibiotics by selecting naturally resistant animals. Polymorphisms in genes associated with the innate immune system are strong candidates to be evaluated as genetic markers. In this work, we evaluated a set of single nucleotide polymorphisms (SNPs) in candidate genes for health and production traits, and determined their association with the somatic cell score (SCS) as an indicator of mastitis in Argentinean dairy cattle. We evaluated 941 cows: Holstein (n = 677) and Holstein * Jersey (n = 264) crossbred, daughters from 22 bulls from 14 dairy farms located in the central dairy area of Argentina. Two of the 21 successfully genotyped markers were found to be significantly associated (p < 0.05) with the SCS: GHR_140 and OPN_8514C-T. The heterozygote genotype for GHR_140 showed a favorable effect in reducing the SCS. On the other hand, heterozygote genotypes for OPN8514C-T caused an increase in the SCS; moreover, combined genotypes for OPN SNPs showed an even larger effect. These findings can contribute to the design of effective marker-assisted selection programs. PMID- 25783852 TI - Breeding scheme and maternal small RNAs affect the efficiency of transgenerational inheritance of a paramutation in mice. AB - Paramutations result from interactions between two alleles at a single locus, whereby one induces a heritable change in the other. Although common in plants, paramutations are rarely studied in animals. Here, we report a new paramutation mouse model, in which the paramutant allele was induced by an insertional mutation and displayed the "white-tail-tip" (WTT) phenotype. The paramutation phenotype could be transmitted across multiple generations, and the breeding scheme (intercrossing vs. outcrossing) drastically affected the transmission efficiency. Paternal (i.e., sperm-borne) RNAs isolated from paramutant mice could induce the paramutation phenotype, which, however, failed to be transmitted to subsequent generations. Maternal miRNAs and piRNAs appeared to have an inhibitory effect on the efficiency of germline transmission of the paramutation. This paramutation mouse model represents an important tool for dissecting the underlying mechanism, which should be applicable to the phenomenon of epigenetic transgenerational inheritance (ETI) in general. Mechanistic insights of ETI will help us understand how organisms establish new heritable epigenetic states during development, or in times of environmental or nutritional stress. PMID- 25783855 TI - Enhancing the bioavailability of mebendazole by integrating the principles solid dispersion and nanocrystal techniques, for safe and effective management of human echinococcosis. AB - The method based on integrating the principles of solid dispersion and nanocrystal techniques was developed to prepare polymer crystals (PCs) of mebendazole (MBZ) and polyethylene glycol (PEG). Powder X-Ray diffraction (PXRD) of the PC crystals shows the required integrated crystalline and amorphous regions. The in vitro solubility studies showed a 32-fold increase in the solubility of the drug. Tests of dissolution of the PCs showed that the crystals have an enhanced dissolution rate in comparison to those in the MF. The results of the pharmacokinetic study showed a 2.12-fold increase in the bioavailability of the drug. Thus, the present study has proved the potential in enhancing solubility, dissolution, and bioavailability of the drug. PMID- 25783854 TI - Full-genome evolutionary histories of selfing, splitting, and selection in Caenorhabditis. AB - The nematode Caenorhabditis briggsae is a model for comparative developmental evolution with C. elegans. Worldwide collections of C. briggsae have implicated an intriguing history of divergence among genetic groups separated by latitude, or by restricted geography, that is being exploited to dissect the genetic basis to adaptive evolution and reproductive incompatibility; yet, the genomic scope and timing of population divergence is unclear. We performed high-coverage whole genome sequencing of 37 wild isolates of the nematode C. briggsae and applied a pairwise sequentially Markovian coalescent (PSMC) model to 703 combinations of genomic haplotypes to draw inferences about population history, the genomic scope of natural selection, and to compare with 40 wild isolates of C. elegans. We estimate that a diaspora of at least six distinct C. briggsae lineages separated from one another approximately 200,000 generations ago, including the "Temperate" and "Tropical" phylogeographic groups that dominate most samples worldwide. Moreover, an ancient population split in its history approximately 2 million generations ago, coupled with only rare gene flow among lineage groups, validates this system as a model for incipient speciation. Low versus high recombination regions of the genome give distinct signatures of population size change through time, indicative of widespread effects of selection on highly linked portions of the genome owing to extreme inbreeding by self-fertilization. Analysis of functional mutations indicates that genomic context, owing to selection that acts on long linkage blocks, is a more important driver of population variation than are the functional attributes of the individually encoded genes. PMID- 25783856 TI - Synthesis and evaluation of single-wall carbon nanotube-paclitaxel-folic acid conjugate as an anti-cancer targeting agent. AB - Single-wall carbon nanotubes (SWCNT) represent a novel nanomaterial applied in various nanotechnology fields because of their surface chemistry properties and high drug cargo capacity. In this study, SWCNT are pre-functionalized covalently with paclitaxel (PTX) - an anticancer drug, and folic acid (FA), as a targeting agent for many tumors. The samples are investigated and evaluated by different analyses such as Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), absorption spectroscopic measurements (UV-Visible), elemental analysis, and cell analyses with cancer cell line cultures. The results show good conjugation of the targeting molecule and the anticancer drug on the surface of the carbon nanotubes (CNT). This work demonstrates that the SWCNT-PTX-FA system is a potentially useful system for the targeted delivery of anticancer drugs. PMID- 25783857 TI - Theory of one and two donors in silicon. AB - We provide here a roadmap for modeling silicon nano-devices with one or two group V donors (D). We discuss systems containing one or two electrons, that is, D(0), D(-), D(+)(2) and D(0)(2) centers. The impact of different levels of approximation is discussed. The most accurate instances--for which we provide quantitative results--are within multivalley effective mass including the central cell correction and a configuration interaction account of the electron-electron correlations. We also derive insightful, yet less accurate, analytical approximations and discuss their validity and limitations--in particular, for a donor pair, we discuss the single orbital LCAO method, the Huckel approximation and the Hubbard model. Finally, we connect these results with recent experiments on devices with few dopants. PMID- 25783858 TI - Association of left ventricular strain with 30-day mortality and readmission in patients with heart failure. AB - BACKGROUND: Heart failure (HF) readmissions are a common and serious problem of heterogeneous etiology. Left ventricular (LV) ejection fraction has not been found to be a consistent risk marker. However, LV strain has been shown to predict outcomes in other settings, so the aim of this study was to determine the association of LV strain with 30-day HF readmission, independent of and incremental to clinical and basic echocardiographic parameters. METHODS: A total of 468 patients who underwent echocardiography at the time of the first admission for HF from July 2009 to June 2012 were retrospectively studied. Clinical parameters were comprehensively assessed, and standard echocardiographic parameters and two strain parameters (global longitudinal strain [GLS] and global circumferential strain) were measured using speckle-tracking. Patients were followed for all-cause 30-day hospital readmission or death after discharge, and the associations of parameters with outcome were assessed using Cox proportional hazards models. RESULTS: Readmission within 30 days (n = 92 patients [20%]) was associated with greater impairment of LV GLS (-8.6% [interquartile range, -10.9% to -5.9%] vs -11.1% [interquartile range, -14.6% to -7.7%], P < .01). The association of GLS with readmission (hazard ratio, 1.13; 95% confidence interval, 1.07-1.19; P < .01) was independent of age, male gender, systolic blood pressure, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and comorbidity, as well as renal function, sodium, hematocrit, LV mass, left atrial size, and mitral regurgitation. Global circumferential strain was associated with outcome but not was independent after adjustment with echocardiographic parameters. In sequential models for 30-day outcome, GLS added incremental information to clinical parameters and LV ejection fraction and significantly improved reclassification (categorical net reclassification improvement, 0.34; P = .04) when LV ejection fraction was >50%. CONCLUSIONS: GLS is associated with HF readmission, independent of and incremental to clinical and basic echocardiographic parameters. PMID- 25783859 TI - Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade. AB - The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance. PMID- 25783860 TI - Functional analysis of the stomatognathic system in individuals infected with human immunodeficiency virus. AB - PURPOSE: To understand the effects of HIV type 1 on the function of the masticatory muscles. METHODS: Sixty individuals were selected from both genders, aged between 22 and 57years (mean 36.77+/-9.33years), and divided into two groups: Group HIVG, 30 individuals with HIV subtype 1, and Group CG, 30 healthy individuals (control group). The individuals were submitted to assessments of their masticatory muscle activity, biting strength and thickness of the masticatory muscles by means of electromyography, maximal molar bite force and ultrasound imaging, respectively. The resultant data were statistically analyzed by t-tests (p<0.05). RESULTS: The HIVG normalized EMG data from a mandibular rest position, protrusion, right and left laterality movement of the jaw showed that HIVG presented a relative increase in EMG activity compared to the CG. The HIVG had a lower masticatory cycle ability while chewing Parafilm M(r), Raisins and Peanuts when compared to CG. During rest conditions, the ultrasound images showed a greater average muscular thickness in the right and left temporal region compared to CG. Upon maximal voluntary contraction, an increased average thickness was seen in the temporalis muscles and left sternocleidomastoid muscle when compared to the CG. CONCLUSION: Based on the results of this research, it can be concluded that individuals with acquired immunodeficiency syndrome showed muscular changes related to the stomatognathic system, especially concerning EMG activity and muscle thickness. PMID- 25783861 TI - T-cell therapy targets glioblastoma. PMID- 25783862 TI - Health sector operational planning and budgeting processes in Kenya-"never the twain shall meet". AB - Operational planning is considered an important tool for translating government policies and strategic objectives into day-to-day management activities. However, developing countries suffer from persistent misalignment between policy, planning and budgeting. The Medium Term Expenditure Framework (MTEF) was introduced to address this misalignment. Kenya adopted the MTEF in the early 2000s, and in 2005, the Ministry of Health adopted the Annual Operational Plan process to adapt the MTEF to the health sector. This study assessed the degree to which the health sector Annual Operational Plan process in Kenya has achieved alignment between planning and budgeting at the national level, using document reviews, participant observation and key informant interviews. We found that the Kenyan health sector was far from achieving planning and budgeting alignment. Several factors contributed to this problem including weak Ministry of Health stewardship and institutionalized separation between planning and budgeting processes; a rapidly changing planning and budgeting environment; lack of reliable data to inform target setting and poor participation by key stakeholders in the process including a top-down approach to target setting. We conclude that alignment is unlikely to be achieved without consideration of the specific institutional contexts and the power relationships between stakeholders. In particular, there is a need for institutional integration of the planning and budgeting processes into a common cycle and framework with common reporting lines and for improved data and local-level input to inform appropriate and realistic target setting. (c) 2015 The Authors. International Journal of Health Planning and Management published by John Wiley & Sons, Ltd. PMID- 25783863 TI - Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria. AB - Commensal bacteria have been proposed to play a role in liver repair after partial (67%) hepatectomy. However, the underlying immune mechanisms remain elusive. Here, we show that liver regeneration was impaired in antibiotic (Atb) water-treated mice and this impairment strongly correlated with commensal bacterial load. Among the various Atbs used in our cocktail, ampicillin-sensitive commensal bacterial was associated with normal liver regeneration. The number of CD1d-dependent natural killer T (NKT) cells in Atb-treated hepatectomized mice was markedly increased, and these NKT cells were functionally overactivated to produce higher interferon-gamma. Deficiency of NKT cells or antibody blockade of the CD1d-NKT interaction increased hepatocyte proliferation, which improved liver regeneration. Importantly, an increased number of Kupffer cells were observed in Atb-treated mice, and these Kupffer cells produced higher interleukin-12, which then functioned to activate hepatic NKT cells. Interleukin-12p40 deficiency or treatment with an anti-interleukin-12 antibody significantly inhibited NKT cell overactivation and recovered liver regeneration in Atb-treated mice. CONCLUSION: Commensal bacteria play a critical role in maintaining Kupffer cells in a tolerant state, preventing subsequent NKT cell overactivation during liver regeneration. Moreover, our data suggest that long-term Atb use, which can impair the gut microbiota, may influence liver function by retarding liver regeneration. PMID- 25783865 TI - Shifting trends in the incidence of Pseudomonas aeruginosa septicemia in hospitalized adults in the United States from 1996-2010. AB - BACKGROUND: Pseudomonas aeruginosa septicemia (PAS) is associated with high mortality rates and substantial resource utilization; however, the burden of PAS in the United States in recent years is unknown. METHODS: This was a retrospective analysis of the U.S. National Hospital Discharge Surveys from 1996 2010. Adult patients with an ICD-9-CM code for PAS (038.43) were included. Incidence, in-hospital mortality, and hospital length of stay (LOS) for PAS discharges were reported. Incidence was calculated as PAS discharges per 10,000 total adult discharges. RESULTS: Overall, 213,553 patients had a PAS discharge diagnosis during the study period. Patients had a median (interquartile range [IQR]) age of 69 (55-78) years and were predominately men (61%) and white (75%). PAS incidence declined from 6.5 per 10,000 in 1996 to 3.1 per 10,000 in 2001 and then increased to 6.5 per 10,000 in 2010. PAS incidence was highest in the Northeast (7.6 per 10,000) and lowest in the South (6.2 per 10,000). The overall mortality rate was 16%, but this ranged from 10%-26% over the study period. Median LOS was 10 (IQR, 6-19) days, and this varied over the study period (8-13 days). CONCLUSIONS: The incidence of PAS has increased among hospitalized adults in the United States since 2001, with little evidence of improvement in mortality or LOS. PMID- 25783864 TI - Insights into the role of humic acid on Pd-catalytic electro-Fenton transformation of toluene in groundwater. AB - A recently developed Pd-based electro-Fenton (E-Fenton) process enables efficient in situ remediation of organic contaminants in groundwater. In the process, H2O2, Fe(II), and acidic conditions (~pH 3) are produced in situ to facilitate the decontamination, but the role of ubiquitous natural organic matters (NOM) remain unclear. This study investigated the effect of Aldrich humic acid (HA) on the transformation of toluene by the Pd-based E-Fenton process. At pH 3 with 50 mA current, the presence of HA promoted the efficiency of toluene transformation, with pseudo-first-order rate constants increase from 0.01 to 0.016 as the HA concentration increases from 0 to 20 mg/L. The HA-enhanced toluene transformation was attributed to the accelerated thermal reduction of Fe(III) to Fe(II), which led to production of more hydroxyl radicals. The correlation of the rate constants of toluene transformation and HA decomposition validated hydroxyl radical (.OH) as the predominant reactive species for HA decomposition. The finding of this study highlighted that application of the novel Pd-based E-Fenton process in groundwater remediation may not be concerned by the fouling from humic substances. PMID- 25783866 TI - Cerebral Venous Sinus Thrombosis: Clinical Characteristics and Factors Influencing Clinical Outcome. AB - The frequency of patients diagnosed with cerebral venous sinus thrombosis (CVST) has increased due to the expanded use of noninvasive brain imaging methods. The aim of this study was to assess the correlations between the location and extent of venous sinus impairment, clinical presentation during the acute phase, recanalization, the presence of parenchymal lesions, and clinical outcome after 3 to 4 months in patients with CVST. In a retrospective study, clinical and magnetic resonance imaging data from a cohort of 51 consecutive patients with CVST (mean age 33.1 +/- 15.4 years) were collected and analyzed. Good clinical outcome after 3 to 4 months, which was assessed using the modified Rankin scale, significantly negatively correlated with a thrombosis location in the left transverse, left sigmoid, or superior sagittal sinus (P = .022, P = .045, and P = .046, respectively) and positively correlated with recanalization (P = .048). The clinical outcome was significantly more favorable in the females with gender specific risk factors than in the males (P = .029). In conclusion, successful recanalization substantially helps to achieve good clinical outcome in patients with CVST. PMID- 25783867 TI - Plasma Concentrations of Protein Z and Protein Z-Dependent Protease Inhibitor in Patients With Essential Thrombocythemia. AB - The pathological consequences of decreased protein Z (PZ) and/or Z-dependent protease inhibitor (ZPI) levels remain as yet unclear, despite a growing body of evidence which supports their involvement in an increased thrombotic risk. The purpose of the present study was 2-fold: to evaluate plasma concentrations of protein Z and ZPI in patients with essential thrombocythemia (ET) and to determine their significance in thrombotic complications. The median (range) plasma concentrations of PZ in our patients with ET were lower, but not significantly, than in healthy individuals: PZ (1.42 ug/mL, 0.36-3.14 ug/mL vs 1.6 ug/mL, 0.75-2.56 ug/mL, P = .08). On the other hand, the median (range) plasma concentrations of ZPI in the said patients with ET were meaningfully lower than in the reference group: ZPI (3.22 ug/mL, 0.85-6.97 ug/mL vs 4.41 ug/mL, 1.63 7.83 ug/mL, P = .0004). More importantly, the study revealed a statistically significant lower concentration of PZ and ZPI in patients with the presence of the JAK2V617F mutation relative to patients without the mutation, for PZ: 1.38 ug/mL, 0.36-2.6 ug/mL versus 1.63 ug/mL, 0.88-3.14 ug/mL, P = .03, and ZPI 2.89 ug/mL, 0.85-5.91 ug/mL versus 3.61 ug/mL, 1.53-6.97 ug/mL, P = .002. Additionally, significant differences between the concentrations of PZ and ZPI were found in patients with venous thrombotic episodes compared to healthy individuals, for PZ: 1.23 ug/mL, 0.82-1.99 ug/mL versus 1.6 ug/mL, 0.75-2.56 ug/mL, P = .043, and ZPI: 2.42 ug/mL, 0.85-4.21 ug/mL versus 4.41 ug/mL, 1.63 7.83 ug/mL, P < .0001. To recapitulate, our results suggest that the deficiency of PZ may increase tendency to thrombosis in patients with ET. PMID- 25783869 TI - The application of machine learning to the modelling of percutaneous absorption: an overview and guide. AB - Machine learning (ML) methods have been applied to the analysis of a range of biological systems. This paper reviews the application of these methods to the problem domain of skin permeability and addresses critically some of the key issues. Specifically, ML methods offer great potential in both predictive ability and their ability to provide mechanistic insight to, in this case, the phenomena of skin permeation. However, they are beset by perceptions of a lack of transparency and, often, once a ML or related method has been published there is little impetus from other researchers to adopt such methods. This is usually due to the lack of transparency in some methods and the lack of availability of specific coding for running advanced ML methods. This paper reviews critically the application of ML methods to percutaneous absorption and addresses the key issue of transparency by describing in detail - and providing the detailed coding for - the process of running a ML method (in this case, a Gaussian process regression method). Although this method is applied here to the field of percutaneous absorption, it may be applied more broadly to any biological system. PMID- 25783870 TI - Comparison of global and mode of action-based models for aquatic toxicity. AB - The ability to estimate aquatic toxicity is a critical need for ecological risk assessment and chemical regulation. The consensus in the literature is that mode of action (MOA) based toxicity models yield the most toxicologically meaningful and, theoretically, the most accurate results. In this study, a two-step prediction methodology was developed to estimate acute aquatic toxicity from molecular structure. In the first step, one-against-the-rest linear discriminant analysis (LDA) models were used to predict the MOA. The LDA models were able to predict the MOA with 85.8-88.8% accuracy for broad and specific MOAs, respectively. In the second step, a multiple linear regression (MLR) model corresponding to the predicted MOA was used to predict the acute aquatic toxicity value. The MOA-based approach was found to yield similar external prediction accuracy (r(2) = 0.529-0.632) to a single global MLR model (r(2) = 0.551-0.562) fit to the entire training set. Overall, the global hierarchical clustering approach yielded a higher combination of accuracy and prediction coverage (r(2) = 0.572, coverage = 99.3%) than the other approaches. Utilizing multiple two dimensional chemical descriptors in MLR models yielded comparable results to using only the octanol-water partition coefficient (log K(ow)). PMID- 25783871 TI - A cystic growth on the lower eyelid: a presentation of two cases. PMID- 25783872 TI - Correlation of human papillomavirus status with apparent diffusion coefficient of diffusion-weighted MRI in head and neck squamous cell carcinomas. AB - BACKGROUND: Identification of prognostic patient characteristics in head and neck squamous cell carcinoma (HNSCC) is of great importance. Human papillomavirus (HPV)-positive HNSCCs have favorable response to (chemo)radiotherapy. Apparent diffusion coefficient, derived from diffusion-weighted MRI, has also shown to predict treatment response. The purpose of this study was to evaluate the correlation between HPV status and apparent diffusion coefficient. METHODS: Seventy-three patients with histologically proven HNSCC were retrospectively analyzed. Mean pretreatment apparent diffusion coefficient was calculated by delineation of total tumor volume on diffusion-weighted MRI. HPV status was analyzed and correlated to apparent diffusion coefficient. RESULTS: Six HNSCCs were HPV-positive. HPV-positive HNSCC showed significantly lower apparent diffusion coefficient compared to HPV-negative. This correlation was independent of other patient characteristics. CONCLUSION: In HNSCC, positive HPV status correlates with low mean apparent diffusion coefficient. The favorable prognostic value of low pretreatment apparent diffusion coefficient might be partially attributed to patients with a positive HPV status. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E613-E618, 2016. PMID- 25783873 TI - Simultaneous assessment of cAMP signaling events in different cellular compartments using FRET-based reporters. AB - Several aspects of the cAMP signaling cascade, including the levels of the messenger itself and the activity of its main effector protein kinase A (PKA), can be measured in living cells, thanks to genetically encoded probes based on fluorescence resonance energy transfer (FRET). While these biosensors enable the assessment of cAMP or PKA activity with great spatial and temporal resolution, concomitant events triggered by the same stimuli at the same or other cellular compartments are not easily assessed. In this chapter we present a simple approach that allows the simultaneous measurement of cAMP and its actions in subcellular compartments of neighboring cells. As proof of principle, we compare cAMP signals and PKA activity in the cytosol of neighboring HEK cells. We propose that this flexible and powerful method can significantly improve the direct comparison of cAMP signals and their action in specific cellular domains. PMID- 25783874 TI - Recording intracellular cAMP levels with EPAC-based FRET sensors by fluorescence lifetime imaging. AB - Eukaryotic cells use second messengers such as Ca(2+), IP3, cGMP, and cAMP to transduce extracellular signals like hormones, via membrane receptors to downstream cellular effectors. FRET-based sensors are ideal to visualize and measure these rapid changes of second messenger concentrations in time and place. Here, we describe the use of EPAC-based FRET sensors to measure cAMP with spatiotemporal resolution in cells by fluorescence lifetime imaging (FLIM). PMID- 25783875 TI - A novel approach combining real-time imaging and the patch-clamp technique to calibrate FRET-based reporters for cAMP in their cellular microenvironment. AB - Fluorescence resonance energy transfer (FRET)-based reporters are invaluable tools to study spatiotemporal aspects of cyclic adenosine monophosphate (cAMP) signaling and compartmentalization in living cells. These sensors allow estimation of relative changes of cAMP levels in real-time and intact cells. However, one of their major shortcomings is that they do not easily allow direct measurement of cAMP concentrations. This is mainly due to the fact that the methods to calibrate these sensors in their physiological microenvironment are not generally available. All published approaches to calibrate FRET-based reporters rely at least in part on data derived under nonphysiological conditions. Here, we present a protocol to calibrate FRET reporters completely "in cell." We introduce a combination of FRET imaging of cAMP and the whole-cell patch-clamp techniques to microinfuse or dilute intracellular cAMP to known concentrations. This method represents a general tool to accurately estimate intracellular cAMP concentrations by allocating concentration values to FRET ratio changes. PMID- 25783876 TI - Structure-based, in silico approaches for the development of novel cAMP FRET reporters. AB - A significant contribution to the research in cAMP signaling has been made by the development of genetically encoded FRET sensors that allow detection of local concentrations of second messengers in living cells. Nowadays, the availability of a number of 3D structures of cyclic nucleotide-binding domains (CNBD) undergoing conformational transitions upon cAMP binding, along with computational tools, can be exploited for the design of novel or improved sensors. In this chapter we will overview some coarse-grained geometrical considerations on fluorescent proteins, CNBD, and linker peptides to draw simple qualitative rules that may aid the design of novel sensors. Finally, we will illustrate how the application of these simple rules can be used to describe the mechanistic basis of cAMP sensors reported in the literature. PMID- 25783877 TI - Automated image analysis of FRET signals for subcellular cAMP quantification. AB - A variety of FRET probes have been developed to examine cAMP localization and dynamics in single cells. These probes offer a readily accessible approach to measure localized cAMP signals. However, given the low signal-to-noise ratio of most FRET probes and the dynamic nature of the intracellular environment, there have been marked limitations in the ability to use FRET probes to study localized signaling events within the same cell. Here, we outline a methodology to dissect kinetics of cAMP-mediated FRET signals in single cells using automated image analysis approaches. We additionally extend these approaches to the analysis of subcellular regions. These approaches offer an unique opportunity to assess localized cAMP kinetics in an unbiased, quantitative fashion. PMID- 25783878 TI - Channel-based reporters for cAMP detection. AB - In the last 15 years, tremendous progress has been made in the development of single-cell cAMP sensors. Sensors are based upon cAMP-binding proteins that have been modified to transduce cAMP concentrations into electrical or fluorescent readouts that can be readily detected using patch clamp amplifiers, photomultiplier tubes, or cameras. Here we describe two complementary approaches for the detection and measurement of cAMP signals near the plasma membrane of cells. These probes take advantage of the ability of cyclic nucleotide-gated (CNG) channels to transduce small changes in cAMP concentrations into ionic flux through channel pores that can be readily detected by measuring Ca(2+) and/or Mn(2+) influx or by measuring ionic currents. PMID- 25783879 TI - Imaging sub-plasma membrane cAMP dynamics with fluorescent translocation reporters. AB - Imaging cAMP dynamics in single cells and tissues can provide important insights into the regulation of a variety of cellular processes. In recent years, a large number of tools for cAMP measurements have been developed. While most cAMP reporters are designed to undergo changes in fluorescence resonance energy transfer (FRET), there are alternative techniques with advantages for certain applications. Here, we describe protocols for cAMP measurements in the sub-plasma membrane space based on the detection of the cAMP-induced translocation of engineered fluorescent protein-tagged subunits of protein kinase A between the cytoplasm and the plasma membrane. Total internal reflection fluorescence (TIRF) imaging of the changes in reporter localization yields robust signal changes and has contributed to the discovery of cAMP oscillations in the sub-plasma membrane space of insulin-secreting beta-cells stimulated with glucose and gluco-incretin hormones. We also demonstrate how the technique can be combined with measurements of the cytosolic Ca(2+) concentration or with recordings of the subcellular localization of the cAMP effector protein Epac2. The translocation reporter approach provides a valuable complement to other methods for imaging sub-membrane cAMP dynamics in various types of cells. PMID- 25783880 TI - Adenoviral transduction of FRET-based biosensors for cAMP in primary adult mouse cardiomyocytes. AB - Genetically encoded biosensors that make use of fluorescence resonance energy transfer (FRET) are important tools for the study of compartmentalized cyclic nucleotide signaling in living cells. With the advent of germ line and tissue specific transgenic technologies, the adult mouse represents a useful tool for the study of cardiovascular pathophysiology. The use of FRET-based genetically encoded biosensors coupled with this animal model represents a powerful combination for the study of cAMP signaling in live primary cardiomyocytes. In this chapter, we describe the steps required during the isolation, viral transduction, and culture of cardiomyocytes from an adult mouse to obtain reliable expression of genetically encoded FRET biosensors for the study of cAMP signaling in living cells. PMID- 25783881 TI - Generation of transgenic mice expressing FRET biosensors. AB - Transgenic mice play a significant role in modern biomedical research. They allow not only mechanistic insights into the functions of specific genes and proteins. Recent strategies have also established the use of transgenic mice as an exciting tool for the expression and in vivo or in situ analysis of fluorescent biosensors, which are capable of directly reporting second messenger levels and biochemical processes in real time and in living cells. In this chapter, we present a detailed protocol for the generation of plasmid vectors and transgenic mice expressing a Forster resonance energy transfer (FRET)-based biosensor for the second messenger 3',5'-cyclic adenosine monophosphate. These tools and techniques should provide great potential for the analysis of second messenger dynamics in a more physiologically relevant context. PMID- 25783882 TI - Photoactivatable adenylyl cyclases (PACs) as a tool to study cAMP signaling in vivo: an overview. AB - Photoactivatable adenylyl cyclases (PACs) are proteins that combine the capacity of a photoreceptor with that of an adenylyl cyclase. When ectopically expressed under the control of specific promoters, these naturally occurring proteins become potent transgenic tools that facilitate the increase of cellular cAMP levels by the use of light. Currently, three different PAC transgenes-the euglenoid euPACalpha and euPACbeta, as well as the b eggiatoan bPac-are available. These transgenic tools provide cyclase activity capable of increasing cellular cAMP levels up to a hundredfold with either phasic- or tonic-like kinetic characteristics. Here, we consider the functional features of different cyclases and provide operating guidelines to optimize the use of PACs in vivo. PMID- 25783883 TI - Selective disruption of the AKAP signaling complexes. AB - Synthesis of the second messenger cAMP activates a variety of signaling pathways critical for all facets of intracellular regulation. Protein kinase A (PKA) is the major cAMP-responsive effector. Where and when this enzyme is activated has profound implications on the cellular role of PKA. A-Kinase Anchoring Proteins (AKAPs) play a critical role in this process by orchestrating spatial and temporal aspects of PKA action. A popular means of evaluating the impact of these anchored signaling events is to biochemically interfere with the PKA-AKAP interface. Hence, peptide disruptors of PKA anchoring are valuable tools in the investigation of local PKA action. This article outlines the development of PKA isoform-selective disruptor peptides, documents the optimization of cell-soluble peptide derivatives, and introduces alternative cell-based approaches that interrogate other aspects of the PKA-AKAP interface. PMID- 25783884 TI - Screening for small molecule disruptors of AKAP-PKA interactions. AB - Protein-protein interactions (PPIs) are highly specific and diverse. Their selective inhibition with peptides, peptidomimetics, or small molecules allows determination of functions of individual PPIs. Moreover, inhibition of disease associated PPIs may lead to new concepts for the treatment of diseases with an unmet medical need. Protein kinase A (PKA) is an ubiquitously expressed protein kinase that controls a plethora of cellular functions. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that directly interact with PKA. AKAPs spatially and temporally restrict PKA activity to defined cellular compartments and thereby contribute to the specificity of PKA signaling. However, it is largely unknown which of the plethora of PKA-dependent signaling events involve interactions of PKA with AKAPs. Moreover, AKAP-PKA interactions appear to play a role in a variety of cardiovascular, neuronal, and inflammatory diseases, but it is unclear whether these interactions are suitable drug targets. Here we describe an enzyme-linked immunosorbent assay (ELISA) for the screening of small molecule libraries for inhibitors of AKAP-PKA interactions. In addition, we describe a homogenous time-resolved fluorescence (HTRF) assay for use in secondary validation screens. Small molecule inhibitors are invaluable molecular tools for elucidating the functions of AKAP-PKA interactions and may eventually lead to new concepts for the treatment of diseases where AKAP-PKA interactions represent potential drug targets. PMID- 25783885 TI - Structure-based bacteriophage screening for AKAP-selective PKA regulatory subunit variants. AB - cAMP-dependent protein kinase (PKA) is tethered at different subcellular locations by A-kinase anchoring proteins (AKAPs). AKAPs present amphipathic helices that bind to the docking and dimerization (D/D) domain of PKA regulatory subunits. Peptide disruptors derived from AKAP anchoring helices are powerful tools for determining whether PKA anchoring is important in different biological processes. Focusing on the reciprocal side of the AKAP-PKA interface can enable development of tools for determining the roles of individual AKAPs. Accordingly, here we describe a bacteriophage screening procedure for identifying variants of PKA regulatory subunit D/D domains that bind selectively to individual AKAPs. This procedure can be adapted for engineering specificity into other shared protein interfaces. PMID- 25783886 TI - A yeast-based high-throughput screen for modulators of phosphodiesterase activity. AB - Cell-based high-throughput screens (HTSs) targeting heterologously expressed proteins in yeast identify compounds that often display relevant biological activity when tested in cell culture. We developed a fission yeast-based HTS to detect small-molecule inhibitors of mammalian cyclic nucleotide phosphodiesterases (PDEs). These screens are carried out in Schizosaccharomyces pombe using a PKA-repressed fbp1-ura4 reporter whose expression due to low PKA activity prevents cells from growing in medium containing the pyrimidine analog 5 fluoro orotic acid (5FOA). We describe here the steps required to construct strains for screening and to optimize conditions for successful screens. PMID- 25783887 TI - Separation of PKA and PKG signaling nodes by chemical proteomics. AB - The chemically quite similar cyclic nucleotides cAMP and cGMP are two second messengers that activate the homologous cAMP- and cGMP-dependent protein kinases (PKA and PKG, respectively). To gain specificity in space and time in vivo, PKA is compartmentalized by the interaction of its regulatory subunits with A-kinase anchoring proteins (AKAPs), which often form the core of larger signaling protein machineries. In a similar manner, PKG is also found to be compartmentalized close to specific, local pools of cGMP through interaction with G-kinase-anchoring proteins (GKAPs), although the extent and mechanisms mediating these interactions are only marginally understood. In affinity-based chemical proteomics strategies, small molecules are immobilized on solid supports in order to enrich for specific target proteins. We have shown the utility of immobilized cAMP and cGMP to enrich for PKA and PKG and their associated proteins. Unfortunately, both PKA and PKG are enriched in the pull downs with both immobilized compounds. Although this proved sufficient to identify novel AKAPs, the lower abundance of PKG has seriously hampered the enrichment and identification of novel GKAPs. Here we present an improved chemical proteomics method involving in-solution competition with low doses of different free cyclic nucleotides to segregate the cAMP/PKA- and cGMP/PKG-based signaling nodes, allowing the purification and subsequent identification of new scaffold proteins for PKG. PMID- 25783888 TI - Development of computational models of cAMP signaling. AB - Despite the growing evidence defining the cAMP signaling network as a master regulator of cellular function in a number of tissues, regulatory feedback loops, signal compartmentalization, as well as cross-talk with other signaling pathways make understanding the emergent properties of cAMP cellular action a daunting task. Dynamical models of signaling that combine quantitative rigor with molecular details can contribute valuable mechanistic insight into the complexity of intracellular cAMP signaling by complementing and guiding experimental efforts. In this chapter, we review the development of cAMP computational models. We describe how features of the cAMP network can be represented and review the types of experimental data useful in modeling cAMP signaling. We also compile a list of published cAMP models that can aid in the development of novel dynamical models of cAMP signaling. PMID- 25783889 TI - Efficiency and safety of pulmonary rehabilitation in acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Pulmonary rehabilitation (PR) is able to improve dyspnea, endurance capacity, and health-related quality of life in chronic obstructive pulmonary disease (COPD) patients, but it is rarely used in China. This study aimed to assess the effectiveness and safety of PR after exacerbation of COPD. MATERIAL AND METHODS: Patients admitted to hospital due to an exacerbation of COPD were randomized to receive either PR or routine care (control group). The PR program was performed from the second day of admission until discharge. The pre-post changes in 6-minute walk distance (6MWD), self-reported quality of life (QOL) assessed by CAT score and CRQ-SAS score, and activity of daily life assessed by ADL-D score were determined. The perceived end-effort dyspnea (Borg scale) was measured throughout the study. RESULTS: A total of 101 patients were enrolled, of whom 7 withdrew after randomization, and 94 completed this study. There were 66 patients in the PR group and 28 in the control group. The 6MWD, resting SpO2, and exercise Borg dyspnea score were significantly improved in the PR group. In addition, the PR group had greater improvement in the total CRQ-SAS score and had a lower CAT score. Significant improvements were also found in the ADL-D and BODE index in the PR group. No adverse events were recorded during exercise. CONCLUSIONS: Our study provides evidence that it is safe and feasible to apply an early PR in patients with acute exacerbation of COPD. PMID- 25783890 TI - Fabrication of b-Oriented MFI Zeolite Films under Neutral Conditions without the Use of Hydrogen Fluoride. AB - The fabrication of MFI zeolite films with particular b-axis orientation is especially fascinating. Unlike the conventional alkaline or hydrofluoric acid (HF) assisted neutral synthesis route, here we develop a novel neutral synthesis solution system of TPABr/fumed silica/H2 O without the use of HF and successfully synthesize highly b-oriented MFI zeolite films on glass-plate substrates by secondary growth. The localized weak alkaline environment created by the dissolved Na2 O species from the substrate is identified as the key factor for the depolymerization of fumed silica and subsequently the in-plane growth of zeolite seed layers. Continuous b-oriented MFI films can also be synthesized on other substrates in the presence of a glass plate or a trace amount of NaOH, which making our neutral synthesis route promising for the direct synthesis of MFI zeolite films and membranes on various substrates. PMID- 25783891 TI - Formal total synthesis of aliskiren. AB - The efficient and selective formal total synthesis of aliskiren is described. Aliskiren, a renin inhibitor drug, has received considerable attention, primarily because it is the first of the renin inhibitor drugs to be approved by the FDA. Herein, the formal synthesis of aliskiren by iridium-catalyzed asymmetric hydrogenation of two allylic alcohol fragments is reported. Screening a number of N,P-ligated iridium catalysts yielded two catalysts that gave the highest enantioselectivity in the hydrogenation, which gave the saturated alcohols in 97 and 93 % ee. In only four steps after hydrogenation, the fragments were combined by using the Julia-Kocienski reaction to produce late-stage intermediate in an overall yield of 18 %. PMID- 25783892 TI - Chronic overeating impairs hepatic glucose uptake and disposition. AB - Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of ~25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n = 6) or excessive (Hkcal; n = 7) amounts for 4 wk (cumulative weight gain 0.0 +/- 0.3 and 1.5 +/- 0.5 kg, respectively, P < 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4* basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg.kg(-1).min(-1) plus Pe glucose for the final 90 min (P2). NHGU was blunted (P < 0.05) in Hkcal during both periods (mg.kg(-1).min(-1); P1: 1.7 +/- 0.2 vs. 0.3 +/- 0.4; P2: 3.6 +/- 0.3 vs. 2.3 +/- 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P < 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P < 0.05), with a 91% increase in glycogen phosphorylase activity (P < 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism. PMID- 25783893 TI - The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice. AB - Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor involved in the control of numerous functions in various organs (organogenesis, differentiation, metabolic homeostasis, etc.). The aim of the present work was to characterize the regulation and contribution of COUP-TFII in the control of hepatic fatty acid and glucose metabolisms in newborn mice. Our data show that postnatal increase in COUP-TFII mRNA levels is enhanced by glucagon (via cAMP) and PPARalpha. To characterize COUP-TFII function in the liver of suckling mice, we used a functional (dominant negative form; COUP-TFII DN) and a genetic (shRNA) approach. Adenoviral COUP-TFII-DN injection induces a profound hypoglycemia due to the inhibition of gluconeogenesis and fatty acid oxidation secondarily to reduced PEPCK, Gl-6-Pase, CPT I, and mHMG-CoA synthase gene expression. Using the crossover plot technique, we show that gluconeogenesis is inhibited at two different levels: 1) pyruvate carboxylation and 2) trioses phosphate synthesis. This could result from a decreased availability in fatty acid oxidation arising cofactors such as acetyl-CoA and reduced equivalents. Similar results are observed using the shRNA approach. Indeed, when fatty acid oxidation is rescued in response to Wy-14643-induced PPARalpha target genes (CPT I and mHMG-CoA synthase), blood glucose is normalized in COUP-TFII-DN mice. In conclusion, this work demonstrates that postnatal increase in hepatic COUP-TFII gene expression is involved in the regulation of liver fatty acid oxidation, which in turn sustains an active hepatic gluconeogenesis that is essential to maintain an appropriate blood glucose level required for newborn mice survival. PMID- 25783894 TI - C1q-TNF-related protein-9, a novel cardioprotetcive cardiokine, requires proteolytic cleavage to generate a biologically active globular domain isoform. AB - Prevalence and severity of postmyocardial infarction heart failure continually escalate in type 2 diabetes via incompletely understood mechanisms. The discovery of the cardiac secretomes, collectively known as "cardiokines", has significantly enhanced appreciation of the local microenvironment's influence on disease development. Recent studies demonstrated that C1q-TNF-related protein-9 (CTRP9), a newly discovered adiponectin (APN) paralog, is highly expressed in the heart. However, its relationship with APN (concerning diabetic cardiovascular injury in particular) remains unknown. Plasma CTRP9 levels are elevated in APN knockout and reduced in diabetic mice. In contrast to APN, which circulates as full-length multimers, CTRP9 circulates in the plasma primarily in the globular domain isoform (gCTRP9). Recombinant full-length CTRP9 (fCTRP9) was cleaved when incubated with cardiac tissue extracts, generating gCTRP9, a process inhibited by protease inhibitor cocktail. gCTRP9 rapidly activates cardiac survival kinases, including AMPK, Akt, and endothelial NOS. However, fCTRP9-mediated kinase activation is much less potent and significantly delayed. Kinase activation by fCTRP9, but not gCTRP9, is inhibited by protease inhibitor cocktail. These results demonstrate for the first time that the novel cardiokine CTRP9 undergoes proteolytic cleavage to generate gCTRP9, the dominant circulatory and actively cardioprotective isoform. Enhancing cardiac CTRP9 production and/or its proteolytic posttranslational modification are of therapeutic potential, attenuating diabetic cardiac injury. PMID- 25783943 TI - Assessment of groundwater pollution from ash ponds using stable and unstable isotopes around the Koradi and Khaperkheda thermal power plants (Maharashtra, India). AB - The impact on local water resources due to fly ash produced in the Koradi and Khaperkheda thermal power plants (district of Nagpur, Maharashtra - India) and disposed in large ponds at the surface was assessed through the study of environmental variation of ratios of stable and unstable isotopes. Analyses of oxygen and hydrogen isotopes suggest scarce interaction between the water temporarily stored in the ponds and the groundwater in the study area. Data also highlight that the high salinity of groundwater measured in the polluted wells is not due to evaporation, but to subsequent infiltration of stream waters draining from the ponds to the local aquifer. (87)Sr/(86)Sr values, when associated with Sr/Ca ratios, demonstrate the dominant role of waste waters coming from tens of brick kilns surrounding the pond sulfate pollution. Uranium isotopic analyses clearly show evidence of the interaction between groundwater and aquifer rocks, and confirm again the low influence of ash ponds. A new conceptual model based on the study of the isotopes of radium is also proposed and used to estimate residence times of groundwater in the area. This model highlights that high salinity cannot be in any case attributed to a prolonged water-rock interaction, but is due to the influence of untreated waste water of domestic or brick kiln origin on the shallow and vulnerable aquifers. PMID- 25783895 TI - Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice. AB - Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in mice and humans, and yet the tissue-specific contributions to these phenotypes remain unknown. The goal of this study was to determine the relative contribution of ATGL-mediated triacylglycerol hydrolysis in adipocytes vs. skeletal myocytes to acute exercise performance. To achieve this goal, we generated murine models with adipocyte- and skeletal myocyte-specific targeted deletion of ATGL. We then subjected untrained mice to acute peak and submaximal exercise interventions and assessed exercise performance and energy substrate metabolism. Impaired ATGL mediated lipolysis within adipocytes reduced peak and submaximal exercise performance, reduced peripheral energy substrate availability, shifted energy substrate preference toward carbohydrate oxidation, and decreased HSL Ser(660) phosphorylation and mitochondrial respiration within skeletal muscle. In contrast, impaired ATGL-mediated lipolysis within skeletal myocytes was not sufficient to reduce peak and submaximal exercise performance or peripheral energy substrate availability and instead tended to enhance metabolic flexibility during peak exercise. Furthermore, the expanded intramyocellular triacylglycerol pool in these mice was reduced following exercise in association with preserved HSL phosphorylation, suggesting that HSL may compensate for impaired ATGL action in skeletal muscle during exercise. These data suggest that adipocyte rather than skeletal myocyte ATGL-mediated lipolysis plays a greater role during acute exercise in part because of compensatory mechanisms that maintain lipolysis in muscle, but not adipose tissue, when ATGL is absent. PMID- 25783944 TI - Identification of microRNAs and their mRNA targets during soybean nodule development: functional analysis of the role of miR393j-3p in soybean nodulation. AB - Plant microRNAs (miRNAs) play important regulatory roles in a number of developmental processes. The present work investigated the roles of miRNAs during nodule development in the crop legume soybean (Glycine max). Fifteen soybean small RNA libraries were sequenced from different stages of nodule development, including young nodules, mature nodules and senescent nodules. In order to identify the regulatory targets of the miRNAs, five parallel analysis of RNA ends (PARE) libraries were also sequenced from the same stages of nodule development. Sequencing identified 284 miRNAs, including 178 novel soybean miRNAs. Analysis of miRNA abundance identified 139 miRNAs whose expression was significantly regulated during nodule development, including 12 miRNAs whose expression changed > 10-fold. Analysis of the PARE libraries identified 533 miRNA targets, including three nodulation-related genes and eight nodule-specific genes. miR393j-3p was selected for detailed analysis as its expression was significantly regulated during nodule formation, and it targeted a nodulin gene, Early Nodulin 93 (ENOD93). Strong, ectopic expression of miR393j-3p, as well as RNAi silencing of ENOD93 expression, significantly reduced nodule formation. The data indicate that miR393j-3p regulation of ENOD93 mRNA abundance is a key control point for soybean nodule formation. PMID- 25783945 TI - In vitro biocompatibility evaluation of bioresorbable copolymers prepared from L lactide, 1, 3-trimethylene carbonate, and glycolide for cardiovascular applications. AB - PLLA-TMC-GA terpolymer was prepared by ring-opening polymerization of L-lactide, 1, 3-trimethylene carbonate (TMC), and glycolide (GA). The biocompatibility of terpolymer was evaluated in comparison with PLLA and PLLA-TMC with the aim of assessing their potential in the development of bioresorbable cardiovascular stents. Various aspects of in vitro biocompatibility were considered, including MTT assay, hemolytic test, dynamic clotting time, platelet adhesion, platelet activation, protein adsorption, plasma recalcification time and release of cytokines. The results revealed that the terpolymer presents good cytocompatibility and hemocompatibility. Moreover, no significant increase in the release of cytokines was detected. It is thus concluded that these polymers, in particular PLLA-TMC-GA terpolymer present good biocompatibility for cardiovascular applications. PMID- 25783946 TI - Exercise intolerance in heart failure with preserved ejection fraction: what does the heart have to do with it? PMID- 25783947 TI - Natriuretic peptides for risk stratification of patients with valvular aortic stenosis. PMID- 25783948 TI - Use of extracorporeal membrane oxygenation for mechanical circulatory support in a patient with 5-fluorouracil induced acute heart failure. PMID- 25783949 TI - Letter by Guazzi regarding article, "differential hemodynamic effects of exercise and volume expansion in people with and without heart failure". PMID- 25783950 TI - The Children's Sleep Comic: Psychometrics of a Self-rating Instrument for Childhood Insomnia. AB - The Children's Sleep Comic is a standardized self-report questionnaire for assessing insomnia in children ages 5-11 years. The goal of the present study is to introduce a revised version of this measure and to present psychometrics and a cut-off score. Therefore, the revised Children's Sleep Comic, the Sleep Self Report, the Children's Sleep Habits Questionnaire, and the Child Behavior Checklist were applied to a sample of 393 children and their parents. Of the parents who participated voluntarily, a subsample (n = 176) was interviewed on the phone to diagnose their children with sleep disorders according to the International Classification of Sleep Disorders, if applicable. The results indicated that the Children's Sleep Comic is a reliable self-rating instrument for diagnosing childhood insomnia. Internal consistency was alpha = 0.83; and convergent and divergent validity were adequate. The child-friendly format can foster a good therapeutic relationship, and thus establish the basis for successful intervention. PMID- 25783951 TI - An enhanced home cage modulates hypothalamic CRH-ir labeling in juvenile rats, with and without sub-threshold febrile convulsions. AB - Pre and postnatal environments can have a profound impact on offspring development. This is especially true when considering the origin of neurological diseases, including epilepsy, a relatively common and chronic neurological condition, affecting 1-2% of the population. Previously, we have used maternal stress and an enhanced home cage (EHC) in an effort to identify potential factors in the early environment that may increase the risk for experiencing seizures. First, pregnant Long-Evans rats were exposed to a predator stress (PS). Then, at birth, litters were divided into standard cage (SC) and EHC groups until postnatal Day 14 (PD14) when a model of febrile convulsions was used to determine convulsion susceptibility of the various groups. Twenty-four hours later, pup brains were processed for immunohistochemical detection of corticotrophic releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus. Analysis of CRH immunoreactive (-ir) patterns revealed a buffering of CRH-ir in EHC reared offspring. Further, experiencing convulsions led to decreased CRH-ir. Our results support the concept that postnatal environmental influences affect neonatal programming and neurodevelopment of processes that could underlie seizure susceptibility, and that these effects can be modulated by EHC conditions. PMID- 25783952 TI - Prevalence of visual impairment and refractive errors among different ethnic groups in schoolchildren in Turpan, China. AB - BACKGROUND: There is currently limited information about ethnic differences in myopia prevalence within mainland China, especially in rural or semi-rural areas. We examined the prevalence of refractive errors, visual impairment and spectacle coverage in school children of varying ethnicity in Turpan, Xinjiang province. METHODS: A community eye care service was provided for five schools. Presenting monocular distance and near visual acuity (VA), and ocular alignment were assessed. Retinoscopy and cycloplegic subjective refraction were performed for participants with presenting visual impairment (distance VA worse than 0.3 logMAR; Snellen 6/12 or 20/40) or abnormal binocular vision. Questionnaires administered prior to the eye examinations were used to collect information regarding personal lifestyle and parental myopia. RESULTS: A total of 646 out of 690 (94%) subjects aged four to 19 years (11.9 +/- 2.6; mean +/- S.D.) completed the eye examination. Three hundred and eighty-two (59%) of participants were of Uyghur ethnicity, followed by Han, 176 (27%) and Hui, 74 (12%). The mean age of Uyghur, Han and Hui students was 12.3 +/- 2.7, 11.4 +/- 2.6 and 11.4 +/- 2.3 years respectively, in which the Uyghur students were significantly older than the Han and Hui students (F(3,631) = 5.58 p < 0.001). In total, 170 (27%) and 85 (13%) subjects failed the screening examination for one eye or both eyes, respectively. The prevalence of presenting visual impairment was not significantly different among the ethnic groups (p = 0.26). After cycloplegic refraction, most subjects' VA (98%) improved to better than 0.3 logMAR (Snellen 6/12 or 20/40). The prevalence of "clinically-significant myopia" (<=-0.50 dioptres) was 27%, 18% and 13% in Han, Hui and Uyghur children, respectively (p < 0.001). In contrast, Uyghur students had the highest prevalence of astigmatism (Uyghur 12%, Han 5%, Hui 4%). The overall spectacle coverage was 36%, while spectacle coverage among ethnic groups were similar (Han, 41%; Uyghur, 32%; Hui, 41%; chi(2) = 2.23, df = 2, p = 0.33). CONCLUSION: The prevalence of clinically significant myopia varied markedly with ethnicity in school children sampled from a semi-rural region of mainland China (Han > Hui > Uyghur). As reported previously, uncorrected/under-corrected refractive error was the main cause of presenting visual impairment. PMID- 25783953 TI - A novel cytochrome P450 CYP6AB14 gene in Spodoptera litura (Lepidoptera: Noctuidae) and its potential role in plant allelochemical detoxification. AB - Cytochrome P450 monooxygenases (P450s) play a prominent role in the adaptation of insects to host plant chemical defenses. To investigate the potential role of P450s in adaptation of the lepidopteran pest Spodoptera litura to host plant allelochemicals, an expressed sequence data set derived from 6th instar midgut tissues was first mined. One sequence identified from the S. litura 6th instar midgut EST database was determined by phylogenetic analysis to belong to the CYP6AB P450 subfamily, and named CYP6AB14. Dietary supplementation of S. litura larvae with either xanthotoxin (XAN), coumarin (COU) and flavone (FLA) led to elevated CYP6AB14 transcript levels in both midgut and fat body tissues. Injection of CYP6AB14-derived double-stranded RNA (dsRNA) into S. litura individuals significantly reduced CYP6AB14 transcript levels, and resulted in increased developmental abnormalities and higher mortality rates among XAN, COU and FLA-fed larvae. Our results strongly suggest a key role for CYP6AB14 in plant allelochemical detoxification in S. litura. PMID- 25783954 TI - The multifaceted activity of insect caspases. AB - Caspases are frequently considered synonymous with apoptotic cell death. Increasing evidence demonstrates that these proteases may exert their activities in non-apoptotic functions. The non-apoptotic roles of caspases may include developmentally regulated autophagy during insect metamorphosis, as well as neuroblast self-renewal and the immune response. Here, we summarize the established knowledge and the recent advances in the multiple roles of insect caspases to highlight their relevance for physiological processes and survival. PMID- 25783955 TI - Sex peptide receptor is required for the release of stored sperm by mated Drosophila melanogaster females. AB - The storage of sperm in mated females is important for efficient reproduction. After sperm are transferred to females during mating, they need to reach and enter into the site(s) of storage, be maintained viably within storage, and ultimately be released from storage to fertilize eggs. Perturbation of these events can have drastic consequences on fertility. In Drosophila melanogaster, females store sperm for up to 2 weeks after a single mating. For sperm to be released normally from storage, Drosophila females need to receive the seminal fluid protein (SFP) sex peptide (SP) during mating. SP, which binds to sperm in storage, signals through the sex peptide receptor (SPR) to elicit two other effects on mated females: the persistence of egg laying and a reduction in sexual receptivity. However, it is not known whether SPR is also needed to mediate SP's effect on sperm release. By phenotypic analysis of flies deleted for SPR, and of flies knocked down for SPR, ubiquitously or in specific tissues, we show that SPR is required to mediate SP's effects on sperm release from storage. We show that SPR expression in ppk(+) neurons is needed for proper sperm release; these neurons include those that mediate SP's effect on receptivity and egg laying. However, we find that SPR is also needed in the spermathecal secretory cells of the female reproductive tract for efficient sperm release. Thus, SPR expression is necessary in both the nervous system and in female reproductive tract cells to mediate the release of stored sperm. PMID- 25783956 TI - Biological and physiological characterization of in vitro blood feeding in nymph and adult stages of Ornithodoros turicata (Acari: Argasidae). AB - Biological and physiological aspects of blood feeding in nymph and adult Ornithodoros turicata were investigated using an in vitro technique combined with electrophysiological recordings and respirometry. The duration of blood feeding through a Parafilm(r) membrane was similar (19.2-22.6 min) in both developmental stages. The mean (+/-SD) size of blood meal ingested by nymphs, females, and males was 44.2+/-17.9, 150.6+/-48.7, and 74.2+/-36.9 mg, respectively, representing a 2.5-, 2.8- and 3.0-fold increase from their respective unfed weights. Electrophysiological recordings of the pharyngeal pump during blood feeding revealed that ticks ingested blood at a rate of 6.1-6.4 suctions per second. Mean blood volume ingested per suction was 0.013 MUl in females and 0.007 MUl in both males and nymphs. Blood meal size (mg) correlated with unfed body weight (mg) (r(2)=0.50, p<0.05) and with blood volume ingested per suction (r(2)=0.71, p<0.05). Unfed ticks exhibited a circadian ventilation rhythm with discontinuous gas exchange pattern during the daytime and continuous pattern during nighttime. Mean standard metabolic rates (SMR, V(CO2)) in unfed nymphs, females and males of 1.4, 3.0 and 0.9 MUl h(-1) increased to 2.0, 5.7 and 2.4 MUl h(-1), respectively, after a blood meal. SMR correlated positively with blood meal size (r(2)=0.89, p<0.05). Mean coxal fluid weight excreted after a blood meal in nymphs, females, and males was 8.7, 20.0, and 7.7 mg, respectively, which represents 27.0%, 23.4% and 26.7% of their blood meal size. This study revealed biological and physiological characteristics of soft tick blood feeding and metabolism important to tick survival. PMID- 25783957 TI - PO-CALC: a novel tool to correct common inconsistencies in the measurement of phenoloxidase activity. AB - A broad range of physiological and evolutionarily studies requires standard and robust methods to assess the strength and activity of an individual's immune defense. In insects, this goal is generally reached by spectrophotometrically measuring (pro-) phenoloxidase activity, an enzymatic and non-specific process activated after wounding and parasite infections. However, the literature surprisingly lacks a standard method to calculate these values from spectrophotometer data and thus to be able to compare results across studies. In this study, we demonstrated that nine methods commonly used to extract phenoloxidase activities (1) provide inconsistent results when tested on the same data sets, at least partly due to their specific sensitivity to the noise regularly present in enzymatic reaction curves. To circumvent this issue, we then (2) developed a novel, free and simple R-based program called PO-CALC and (3) demonstrated the robustness of its calculations for the different types of noises. Overall, we show that PO-CALC corrects overlooked though important inconsistencies in the measurement of phenoloxidase activities, and claim that its broad use would increase the significance and general validity of studies on invertebrate immunity. PMID- 25783958 TI - Effect of radiologists' experience with an adaptive statistical iterative reconstruction algorithm on detection of hypervascular liver lesions and perception of image quality. AB - PURPOSE: To prospectively evaluate whether clinical experience with an adaptive statistical iterative reconstruction algorithm (ASiR) has an effect on radiologists' diagnostic performance and confidence for the diagnosis of hypervascular liver tumors, as well as on their subjective perception of image quality. MATERIALS AND METHODS: Forty patients, having 65 hypervascular liver tumors, underwent contrast-enhanced MDCT during the hepatic arterial phase. Image datasets were reconstructed with filtered backprojection algorithm and ASiR (20%, 40%, 60%, and 80% blending). During two reading sessions, performed before and after a three-year period of clinical experience with ASiR, three readers assessed datasets for lesion detection, likelihood of malignancy, and image quality. RESULTS: For all reconstruction algorithms, there was no significant change in readers' diagnostic accuracy and sensitivity for the detection of liver lesions, between the two reading sessions. However, a 60% ASiR dataset yielded a significant improvement in specificity, lesion conspicuity, and confidence for lesion likelihood of malignancy during the second reading session (P < 0.0001). The 60% ASiR dataset resulted in significant improvement in readers' perception of image quality during the second reading session (P < 0.0001). CONCLUSIONS: Clinical experience using an ASiR algorithm may improve radiologists' diagnostic performance for the diagnosis of hypervascular liver tumors, as well as their perception of image quality. PMID- 25783959 TI - The "dot-dash" sign. PMID- 25783961 TI - Self-harm and ethnicity: A systematic review. AB - AIMS: This review will focus on the rates, clinical characteristics, risk factors and methods of self-harm and suicide in different ethnic groups in the United Kingdom, providing an update synthesis of recent literature. METHODS: Studies that met the inclusion criteria between 2003 and 2013 were reviewed using the following databases: MEDLINE, PsycINFO, EMBASE and CINAHL. The methodological quality of each study was then assessed using a structured scoring system. RESULTS: A total of 2,362 articles were retrieved, 10 of which matched the inclusion criteria were reviewed. Significant differences were found in the rates of self-harm between ethnic groups with Asian males being least likely to self harm and Black females being most likely to self-harm. Also, Black and South Asian people were less likely to repeat self-harm. Factors that may help protect or predispose individuals to self-harm or attempt suicide (such as religion, mental health and coping styles) also differ between ethnic groups. CONCLUSIONS: There are clear ethnic differences in self-harm and suicide, which may be affected by factors such as cultural pressures and prevalence of mental illness. An awareness of these differences is vital to help prevent further attempts of self-harm and suicide. Further research into differences between ethnic and cultural groups and self-harm continues to be important. PMID- 25783962 TI - A Role for the Inflammatory Mediators Cox-2 and Metalloproteinases in Cancer Stemness. AB - In solid tumors, neoplastic cells are surrounded by a specific microenvironment that integrates the extracellular matrix, lymphatic and blood vessels, and mesenchymal and immune cells, which together are known as the tumor microenvironment (TME). The TME governs many of the aggressive features of tumors, such as local invasion and metastasis. Additionally, new evidence indicates that the TME can trigger stem cell-like programs in cancer cells, forming cancer stem cells (CSC). Experimental and clinical studies suggest that CSCs are resistant to current common cancer therapies and are responsible for tumor recurrence. In this review, we will describe the TME by focusing on how matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2) induce stemness and sustain stem cell maintenance. This reprogramming toward a CSC phenotype may be critical in tumor cell responses to chemotherapy and relapse with more aggressive tumor clones. Therefore, therapeutic agents targeting MMPs and COX-2 in the tumor microenvironment may become important drugs to control the establishment of CSCs and in the overall prognosis of the disease. PMID- 25783963 TI - Effects of Plants and Isolates of Celastraceae Family on Cancer Pathways. AB - The evaluation of crude drugs of natural origin as sources of new effective anticancer agents continues to be important due to the lack of effective anticancer drugs currently used in practice which are generally accompanied with adverse effects at different levels of severity. The aim of this concise review is to gather existing literature on anticancer potential of extracts and compounds isolated from Celastraceae species. This review covers six genera (Maytenus, Tripterygium, Hippocratea, Gymnosporia, Celastrus and Austroplenckia) belonging to this family and their 33 isolates. Studies carried out by using different cell lines have shown remarkable indication of anticancer activity, however, only a restricted number of studies have been reported using in vivo tumor models. Some of the compounds, such as triptolide, celastrol and demethylzeylasteral from T. wilfordii, have been extensively studied on their mechanisms of action due to their potent activity on various cancer cell lines. Such promising lead compounds should generate considerable interest among scientists to improve their therapeutic potential with fewer side effects by molecular modification. PMID- 25783964 TI - 4,6-diaryl Pyrimidones as Constrained Chalcone Analogues: Design, Synthesis and Evaluation as Antiproliferative Agents. AB - 4,6-diarylpyrimidones as constrained chalcone analogues have been synthesised in the present study. The synthesised compounds were evaluated against a panel of human cancer cell lines. Striking selectivity was displayed by the compounds against MiaPaCa (Pancreatic) cell lines while PC-3 (prostate) and A-549 (lung) cell lines were almost resistant to the exposure of the test compounds. Compound SK - 25 exhibited remarkable cytotoxicity against MiaPaca-2 cell line with an IC50 value of 1.95 uM and was found to induce apoptosis evidenced through phase contrast microscopy, DAPI staining and mitochondrial membrane potential loss. The cell phase distribution studies indicated that the apoptotic population increased from 1.79% in control sample to 30.33 % in sample treated with 20 uM compound SK 25. PMID- 25783965 TI - The Applications of Targeting Anti-Cancer Agents in Cancer Therapeutics. AB - Anti-cancer targeting drugs appear to be a new and powerful "weapon" for cancer therapies. These targeting drugs are directed against specific molecules that are over-expressed or where certain unique factors are aberrantly expressed either in cancer cells or in diseased cell sites. Compared with traditional chemotherapeutic drugs, these targeting drugs have the advantages of high specificity, efficacy and less side effects. Target therapy is a breakthrough and revolutionary advance in the field of cancer therapy. Tumor angiogenesis plays a key role in tumor growth and metastasis and the mutation of tyrosine kinases is also strongly associated with cancer progression. Thus, in this review, we will discuss the advances in the development of targeting anti-cancer drugs by narrowing it down to small molecule tyrosine kinase inhibitors, monoclonal antibodies against epidermal growth factor receptors belonging to the ErbB family of receptor tyrosine kinases and angiogenic inhibitors. It will also address concerns for drug resistance and adverse events. PMID- 25783966 TI - Humanitarian assistance and accountability: what are we really talking about? AB - BACKGROUND: In the past two decades, there has been a worldwide increase in the number of disasters, as well as the number of people affected, along with the number of foreign medical teams (FMTs) deployed to provide assistance. However, in the wake of the 2010 Haiti earthquake, multiple reports and anecdotes questioned the actual, positive contribution of such FMTs and even the intentions behind these aid efforts. This brought on a renewed interest in the humanitarian community towards accountability. Between 2000 and 2012, the number of "Quality and Accountability" initiatives and instruments more than tripled from 42 to 147. Yet, to date, there is no single accepted definition of accountability in the humanitarian context. AIM: The aim of this report was to explore and assess how accountability in the humanitarian context is used and/or defined in the literature. METHODS: The electronic database PubMed and a predefined list of grey literature comprising 46 organizations were searched for articles that discussed or provided a definition of accountability in the humanitarian context. The definitions found in these articles were analyzed qualitatively using a framework analysis method based on principles of grounded theory as well as using a summative content analysis method. RESULTS: A total of 85 articles were reviewed in-depth. Fifteen organizations had formal definitions of accountability or explained what it meant to them. Accountability was generally seen in two paradigms: as a "process" or as a "goal." A total of 16 different concepts were identified amongst the definitions. Accountability to aid recipients had four main themes: empowering aid recipients, being in an optimal position to do the greatest good, meeting expectations, and being liable. The concepts of "enforcement/enforceability" under the last theme of "being liable" received the least mention. CONCLUSION: The concept of accountability is defined poorly in many humanitarian organizations. Humanitarian providers often refer to different concepts when talking about accountability in general. The lack of a common understanding is contributed by the semantic and practical complexities of the term. The lack of emphasis on "enforcement/enforceability" is noteworthy. Other aspects of accountability, such as its "measurability" and by whom, similarly lack a common understanding and community-wide consensus. To what extent these vague definitions of accountability affect agencies' work in the field remains to be documented. PMID- 25783968 TI - TGF-beta-mediated airway tolerance to allergens induced by peptide-based immunomodulatory mucosal vaccination. AB - We sought to modulate mucosal immune responses using neonatal vaccination to avert the development of allergic airways disease (AAD). Pulmonary pathology in AAD is driven by T helper (TH)2 cytokines, in particular interleukin (IL)4 and IL13, the expression and actions of which are regulated by the transcription factor STAT6. We developed a peptide homolog of STAT6, STAT6-IP. Neonatal mice given, intranasally, STAT6-IP, in an effort to modulate de novo airways immune responses, developed tolerance following subsequent allergen sensitization, with either ovalbumin or ragweed allergens, as demonstrated by reduced TH2 cytokines and specific immunoglobulin (Ig)E and the significant increases in the latency associated peptide (LAP)(+) T-regulatory (Treg) cell subset and expression of transforming growth factor (TGF)-beta. This regulatory phenotype was transferrable by CD4(+) T cells or CD11c(+) dendritic cells (DCs) derived from STAT6-IP-vaccinated mice. Anti-TGF-beta treatment during allergen sensitization, however, re-established the pro-inflammatory TH2 response. Thus, neonatal STAT6 IP vaccination induces prospective TGF-beta-dependent tolerance to allergen and constitutes a novel highly effective immunomodulatory allergy prevention strategy. PMID- 25783967 TI - In situ hematopoiesis: a regulator of TH2 cytokine-mediated immunity and inflammation at mucosal surfaces. AB - Hematopoiesis refers to the development of blood cells in the body through the differentiation of pluripotent stem cells. Although hematopoiesis is a multifocal process during embryonic development, under homeostatic conditions it occurs exclusively within the bone marrow. There, a limited number of hematopoietic stem cells differentiate into a rapidly proliferating population of lineage-restricted progenitors that serve to replenish circulating blood cells. However, emerging reports now suggest that under inflammatory conditions, alterations in hematopoiesis that occur outside of the bone marrow appear to constitute a conserved mechanism of innate immunity. Moreover, recent reports have identified previously unappreciated pathways that regulate the egress of hematopoietic progenitor cells from the bone marrow, alter their activation status, and skew their developmental potential. These studies suggest that progenitor cells contribute to inflammatory response by undergoing in situ hematopoiesis (ISH). In this review, we highlight the differences between homeostatic hematopoiesis, which occurs in the bone marrow, and ISH, which occurs at mucosal surfaces. Further, we highlight factors produced at local sites of inflammation that regulate hematopoietic progenitor cell responses and the development of TH2 cytokine-mediated inflammation. Finally, we discuss the therapeutic potential of targeting ISH in preventing the development of inflammation at mucosal sites. PMID- 25783969 TI - Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of allergic airway inflammation. AB - The epithelial lining of the airway tract and allergen-specific IgE are considered essential controllers of inflammatory responses to allergens. The human low affinity IgE receptor, CD23 (FcERII), is capable of transporting IgE or IgE-allergen complexes across the polarized human airway epithelial cell (AEC) monolayer in vitro. However, it remains unknown whether the CD23-dependent IgE transfer pathway in AECs initiates and facilitates allergic inflammation in vivo, and whether inhibition of this pathway attenuates allergic inflammation. To this end, we show that in wild-type (WT) mice, epithelial CD23 transcytosed both IgE and ovalbumin (OVA)-IgE complexes across the airway epithelial barrier, whereas neither type of transcytosis was observed in CD23 knockout (KO) mice. In chimeric mice, OVA sensitization and aerosol challenge of WT/WT (bone-marrow transfer from the WT to WT) or CD23KO/WT (CD23KO to WT) chimeric mice, which express CD23 on radioresistant airway structural cells (mainly epithelial cells) resulted in airway eosinophilia, including collagen deposition and a significant increase in goblet cells, and increased airway hyperreactivity. In contrast, the absence of CD23 expression on airway structural or epithelial cells, but not on hematopoietic cells, in WT/CD23KO (the WT to CD23KO) chimeric mice significantly reduced OVA-driven allergic airway inflammation. In addition, inhalation of the CD23-blocking B3B4 antibody in sensitized WT mice before or during airway challenge suppressed the salient features of asthma, including bronchial hyperreactivity. Taken together, these results identify a previously unproven mechanism in which epithelial CD23 plays a central role in the development of allergic inflammation. Further, our study suggests that functional inhibition of CD23 in the airway is a potential therapeutic approach to inhibit the development of asthma. PMID- 25783971 TI - Evidence of a role for GTP cyclohydrolase-1 in visceral pain. AB - BACKGROUND: The enzyme guanosine triphosphate-cyclohydrolase-1 (GCH-1) is a rate limiting step in the de novo synthesis of tetrahydrobiopterin (BH4) a co-factor in monoamine synthesis and nitric oxide production. GCH-1 is strongly implicated in chronic pain based on data generated using the selective GCH-1 inhibitor 2,4 diamino-6-hydroxypyrimidine (DAHP), and studies which have identified a pain protective GCH-1 haplotype associated with lower BH4 production and reduced pain. METHODS: To investigate the role for GCH-1 in visceral pain we examined the effects of DAHP on pain behaviors elicited by colorectal injection of mustard oil in rats, and the pain protective GCH-1 haplotype in healthy volunteers characterized by esophageal pain sensitivity before and after acid injury, and assessed using depression and anxiety questionnaires. KEY RESULTS: In rodents pretreatment with DAHP produced a substantial dose related inhibition of pain behaviors from 10 to 180 mg/kg i.p. (p < 0.01 to 0.001). In healthy volunteers, no association was seen between the pain protective GCH-1 haplotype and the development of hypersensitivity following injury. However, a substantial increase in baseline pain thresholds was seen between first and second visits (26.6 +/- 6.2 mA) in subjects who sensitized to esophageal injury and possessed the pain protective GCH-1 haplotype compared with all other groups (p < 0.05). Furthermore the same subjects who sensitized to acid and possessed the haplotype, also had significantly lower depression scores (p < 0.05). CONCLUSIONS & INFERENCES: The data generated indicate that GCH-1 plays a role in visceral pain processing that requires more detailed investigation. PMID- 25783972 TI - [Chemotherapy of brain tumors in aduts]. AB - The treatment of patients with brain tumors has long been the domain of neurosurgery and radiotherapy but chemotherapy is now well established as an additional treatment option for many tumor entities in neuro-oncology. This is particularly true for patients with newly diagnosed and relapsing glioblastoma and anaplastic glioma as well as the treatment of medulloblastoma and primary lymphoma of the central nervous system (CNS). In addition to purely histopathological features, treatment decisions including those for chemotherapy are now based increasingly more on molecular tumor profiling. Within the group of gliomas these markers include the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the 1p/19q status, which reflects the loss of genetic material on chromosome arms 1p and 19q. The presence of a 1p/19q codeletion is associated with a better prognosis and increased sensitivity to alkylating chemotherapy in patients with anaplastic gliomas. PMID- 25783973 TI - What Drives National Differences in Intensive Grandparental Childcare in Europe? AB - OBJECTIVES: Grandparents play an important role in looking after grandchildren, although intensive grandparental childcare varies considerably across Europe. Few studies have explicitly investigated the extent to which such cross-national variations are associated with national level differences in individual demographic and socio-economic distributions along with contextual-structural and cultural factors (e.g., variations in female labor force participation, childcare provision, and cultural attitudes). METHODS: We used multilevel models to examine associations between intensive grandparental childcare and contextual-structural and cultural factors, after controlling for grandparent, parent, and child characteristics using nationally representative data from the Survey of Health, Ageing and Retirement in Europe. RESULTS: Even controlling for cross-national differences in demographic and socio-economic distributions, contextual structural factors play an important role in explaining grandparental childcare variations in Europe. In particular, higher levels of intensive grandparental childcare are found in countries with low labor force participation among younger and older women, and low formal childcare provision, where mothers in paid work largely rely on grandparental support on an almost daily basis. DISCUSSION: Encouraging older women to remain in paid work is likely to have an impact on grandchild care which in turn may affect mothers' employment, particularly in Southern European countries where there is little formal childcare. PMID- 25783975 TI - IP-10 measured by Dry Plasma Spots as biomarker for therapy responses in Mycobacterium Tuberculosis infection. AB - Tuberculosis (TB) has huge impact on human morbidity and mortality and biomarkers to support rapid TB diagnosis and ensure treatment initiation and cure are needed, especially in regions with high prevalence of multi-drug resistant TB. Soluble interferon gamma inducible protein 10 (IP-10) analyzed from dry plasma spots (DPS) has potential as an immunodiagnostic marker in TB infection. We analyzed IP-10 levels in plasma directly and extracted from DPS in parallel by ELISA from 34 clinically well characterized patients with TB disease before and throughout 24 weeks of effective anti-TB chemotherapy. We detected a significant decline of IP-10 levels in both plasma and DPS already after two weeks of therapy with good correlation between the tests. This was observed both in pulmonary and extrapulmonary TB. In conclusion, plasma IP-10 may serve as an early biomarker for anti-TB chemotherapy responses and the IP-10 DPS method has potential to be developed into a point-of care test for use in resource-limited settings. Further studies must be performed to validate the use of IP-10 DPS in TB high endemic countries. PMID- 25783974 TI - The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial. AB - Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (+/- SD) recipient age was 49.9 +/- 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (DeltaMaximal Intimal Thickness 0.03 +/- 0.06 and 0.08 +/- 0.12 mm, DeltaPercent Atheroma Volume 1.3 +/- 2.3 and 4.2 +/- 5.0%, DeltaTotal Atheroma Volume 1.1 +/- 19.2 mm(3) and 13.8 +/- 28.0 mm(3) [all p-values <= 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients. PMID- 25783976 TI - Novel lactic acid bacteria isolated from the bumble bee gut: Convivina intestini gen. nov., sp. nov., Lactobacillus bombicola sp. nov., and Weissella bombi sp. nov. AB - Twelve isolates of lactic acid bacteria (LAB) were obtained in the course of a bumble bee gut microbiota study and grouped into four matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry clusters. Comparative 16S rRNA gene sequence analysis revealed that cluster 1 isolates, represented by strain LMG 28288(T), are most closely related to Lactobacillus apis (97.0% sequence similarity to that of L. apis LMG 26964(T)). Cluster 2 isolates represented by strain LMG 28290(T) are most closely related to Weissella hellenica (99.6% sequence similarity to that of W. hellenica LMG 15125(T)). The single cluster 3 and 4 isolates had identical 16S rRNA gene sequences which were 94.8% similar to that of Leuconostoc mesenteroides subsp. mesenteroides LMG 6893(T), their nearest phylogenetic neighbour. A polyphasic taxonomic study additionally including comparative pheS sequence analysis, DNA-DNA hybridization experiments, DNA G+C content analysis, (GTG)5-PCR fingerprinting and a biochemical characterization, demonstrated that cluster 1 isolates represent a novel Lactobacillus species for which we propose the name Lactobacillus bombicola sp. nov. with LMG 28288(T) (= DSM 28793(T)) as the type strain; and that cluster 2 isolates represent a novel Weissella species for which we propose the name Weissella bombi sp. nov. with LMG 28290(T) (= DSM 28794(T)) as the type strain. Cluster 3 and 4 isolates, in contrast, represented a very distinct, novel taxon that could be distinguished from members of the genera Leuconostoc and Fructobacillus, its nearest phylogenetic neighbours, by its cellular morphology, non-fructophilic metabolism and DNA G+C content. We therefore classify both isolates into a novel species representing a novel LAB genus for which the name Convivina intestini gen. nov., sp. nov. is proposed with LMG 28291(T) (= DSM 28795(T)) as the type strain. PMID- 25783977 TI - Costs and effectiveness of genomic testing in the management of colorectal cancer. AB - Numerous genomic tests are available for use in colorectal cancer, with a widely variable evidence base for their effectiveness and cost-effectiveness. In this review, we highlight many of these tests, with a focus on their proposed role, the evidence base to support that role, and the associated costs and risks. The tests with the strongest evidence base are KRAS genetic testing in the metastatic setting and microsatellite instability testing in selected patients and in stage II disease. There also may be a role for delineating recurrence-risk signatures for selected patients with stage II disease. The evidence to support broad utilization of uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and dihydropyrimidine dehydrogenase (DPD) testing to guide irinotecan and fluorouracil dosing remains limited. There is much anticipation that next generation sequencing will herald a new era of targeted therapy for patients with colorectal cancer; however, currently there are no data to support the introduction of widespread testing. PMID- 25783978 TI - Cost-effectiveness of genomic testing for colorectal cancer: are we there yet? PMID- 25783979 TI - Genomic testing in colorectal cancer: how much is enough? PMID- 25783980 TI - Acute Effects of Online Mind-Body Skills Training on Resilience, Mindfulness, and Empathy. AB - BACKGROUND: Some studies have begun to show benefits of brief in-person mind-body skills training. We evaluated the effects of 1-hour online elective mind-body skills training for health professionals on mindfulness, resilience, and empathy. METHODS: Between May and November, 2014, we described enrollees for the most popular 1-hour modules in a new online mind-body skills training program; compared enrollees' baseline stress and burnout to normative samples; and assessed acute changes in mindfulness, resilience, and empathy. RESULTS: The 513 enrollees included dietitians, nurses, physicians, social workers, clinical trainees, and health researchers; about 1/4 were trainees. The most popular modules were the following: Introduction to Stress, Resilience, and the Relaxation Response (n = 261); Autogenic Training (n = 250); Guided Imagery and Hypnosis for Pain, Insomnia, and Changing Habits (n = 112); Introduction to Mindfulness (n = 112); and Mindfulness in Daily Life (n = 102). Initially, most enrollees met threshold criteria for burnout and reported moderate to high stress levels. Completing 1-hour modules was associated with significant acute improvements in stress (P < .001), mindfulness (P < .001), empathy (P = .01), and resilience (P < .01). CONCLUSION: Online mind-body skills training reaches diverse, stressed health professionals and is associated with acute improvements in stress, mindfulness, empathy, and resilience. Additional research is warranted to compare the long-term cost-effectiveness of different doses of online and in person mind-body skills training for health professionals. PMID- 25783981 TI - Methoxy and Methyl Group Rotation: Solid-State NMR (1) H Spin-Lattice Relaxation, Electronic Structure Calculations, X-ray Diffractometry, and Scanning Electron Microscopy. AB - We report solid-state (1) H nuclear magnetic resonance (NMR) spin-lattice relaxation experiments, X-ray diffractometry, field-emission scanning electron microscopy, and both single-molecule and cluster ab initio electronic structure calculations on 1-methoxyphenanthrene (1) and 3-methoxyphenanthrene (2) to investigate the rotation of the methoxy groups and their constituent methyl groups. The electronic structure calculations and the (1) H NMR relaxation measurements can be used together to determine barriers for the rotation of a methoxy group and its constituent methyl group and to develop models for the two coupled motions. PMID- 25783982 TI - Reinvention of chemotherapy: drug conjugates and nanoparticles. AB - PURPOSE OF REVIEW: Recent advances in nanotechnology have addressed some of the issues related to lack of selectivity and nonspecific toxicities associated with conventional chemotherapy. Nanoparticles are therapeutic carriers that can be fine tuned for specific application and for passive or active tumor targeting. RECENT FINDINGS: Although the nanoparticle field is rapidly expanding, there are to date only six nanoparticle-based drug delivery platforms and two antibody-drug conjugates that are clinically approved for cancer therapy. Here, we review the clinical data of liposomal anthracyclines, nanoparticle formulations of paclitaxel and trastuzumab emtansine. We then briefly comment on efficacy and safety issues of nanoparticles, as well as on the next-generation nanoparticles for cancer therapy. SUMMARY: The emerging development of cancer nanotechnology offers the opportunity of reinvestigating the potential of cytotoxic agents, improving tumor targeting and drug delivery, leading to better safety profile and antitumor activity. Adding specificity to nanoparticles may allow personalization of cancer therapy using chemotherapy. PMID- 25783983 TI - Two Different Emission-Wavelength Fluorescent Probes for Aluminum Ion based on Tunable Fluorophores in Aqueous Media. AB - Two simply and highly selective aluminium ion fluorescent probes based on 4 aminoantipyrine derivate have been successfully synthesized and systemically characterized, The investigation of absorption and emission spectra revealed that the compounds exhibited highly selective fluorescence behaviours toward Al(3+) in aqueous media and showed differential fluorescent emission peaks corresponding to blue and green. which resulted from different fluorophores, and the fluorescence process is attributed to the Photoinduced Electron Transfer (PET) mechanism, In addition, the association constants between sensors L1 and L2 with aluminum ion are 1.58 * 10(6) M(-1) and 8.72 * 10(6) M(-1), respectively, which were obtained by fluorescent titration experiments. Moreover, the binding site of sensors with Al(3+) were determined by (1)HNMR titration experiments. PMID- 25783985 TI - Hierarchical Bi2MoO6 nanosheet-built frameworks with excellent photocatalytic properties. AB - Herein, we demonstrate for the first time the fabrication of one-dimensional (1D) Bi2MoO6 inter-crossed nanosheet-built frameworks by using MoO3 nanobelts as the growth templates and molybdate source. Especially, this novel Bi2MoO6 framework structure exhibits remarkably enhanced photocatalytic activity toward the degradation of organic dyes under visible-light irradiation, far exceeding that of conventional Bi2MoO6 nanoplates and nanoparticles. The photoelectrochemical study suggests that the hierarchical framework structure could facilitate the photoinduced charge separation and transfer from the inter-crossed Bi2MoO6 nanosheets, which may make a significant contribution to the enhanced photocatalytic activity. PMID- 25783984 TI - Fluorogenic recognition of Zn(2+), Al(3+) and F(-) ions by a new multi-analyte chemosensor based bisphenol A-quinoline. AB - A new available multi-analyte fluorescent sensor based on a bisphenol A-quinoline conjugate (BFQ) was synthesized in two facile steps and was characterized systematically. BFQ exhibited an effectively selective and sensitive recognition toward Zn(2+)and Al(3+) cations in EtOH-H2O (v/v = 9/1) over other cations and F( ) anion in CH3CN over other anions with remarkably enhanced fluorescent intensities. According to the quantum yield (Phi) measurements, BFQ-Zn(2+), BFQ Al(3+) and BFQ-F(-) complexes showed 16, 22 and 30 times higher Phi values than BFQ, respectively. The complexation properties of BFQ with Zn(2+), Al(3+) and F( ) ions were also examined by (1)H NMR titration experiments. PMID- 25783986 TI - The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas. AB - Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3 expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM 3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC. PMID- 25783987 TI - Amyloid-beta mediates the receptor of advanced glycation end product-induced pro inflammatory response via toll-like receptor 4 signaling pathway in retinal ganglion cell line RGC-5. AB - Patients with diabetes mellitus have an increased risk of developing Alzheimer's disease. Amyloid-beta, a product of amyloid precursor protein, is associated with neuro-inflammation in patients with Alzheimer's diseases. The correlation between amyloid-beta and advanced glycation end products, which accumulate in tissue of diabetic patients, is not clear. The aims of this study were to determine the effect of advanced glycation end product on the expression of amyloid precursor protein/amyloid-beta and associated pro-inflammatory responses in retinal ganglion cell line RGC-5. Treatment with advanced glycation end product produced upregulation of amyloid precursor protein and increased secretion of amyloid beta(1-40). Additionally, amyloid-beta(1-40) induced toll-like receptor 4 dependent phosphorylation of tyrosine in myeloid differentiation primary response gene (88). We found that N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, a gamma-secretase inhibitor, reduced the secretion of amyloid beta(1-40) and inhibited the advanced glycation end product-induced activation of myeloid differentiation primary response gene (88). Amyloid-beta(1-40) induced the activation of NF-kappaB and the expression of TNFalpha mRNA. Knockdown of toll-like receptor 4 inhibited the amyloid-beta(1-40)-induced phosphorylation of p65 in NF-kappaB. Additionally, the nuclear translocation of p65 and transcriptions of TNFalpha were inhibited by siRNA knockdown of receptor of advanced glycation end product or toll-like receptor 4. The advanced glycation end product-induced secretion of VEGF-A was also reduced by knockdown of toll like receptor 4. Taken together, our data suggested that amyloid-beta(1-40) mediates the interaction between receptor of advanced glycation end product and toll-like receptor 4. Inhibition of the toll-like receptor 4 is an effective method for suppressing the amyloid-beta(1-40)-induced pro-inflammatory responses in RGC-5 cells. PMID- 25783989 TI - Amino acid mutations in Ebola virus glycoprotein of the 2014 epidemic. AB - Zaire Ebola virus (EBOV) is an enveloped non-segmented negative strand RNA virus of 19 kb in length belonging to the family Filoviridae. The virus was isolated and identified in 1976 during the epidemic of hemorrhagic fever in Zaire. The most recent outbreak of EBOV among humans, was that occurred in the forested areas of south eastern Guinea, that began in February 2014 and is still ongoing. The recent Ebola outbreak, is affecting other countries in West Africa, in addiction to Guinea: Liberia, Nigeria, and Sierra Leone. In this article, a selective pressure analysis and homology modeling based on the G Glycoprotein (GP) sequences retrieved from public databases were used to investigate the genetic diversity and modification of antibody response in the recent outbreak of Ebola Virus. Structural and the evolutionary analysis underline the 2014 epidemic virus being under negative selective pressure does not change with respect to the old epidemic in terms of genome adaptation. PMID- 25783990 TI - The interstate medical licensure compact. PMID- 25783988 TI - Aminoglycoside ototoxicity and hair cell ablation in the adult gerbil: A simple model to study hair cell loss and regeneration. AB - The Mongolian gerbil, Meriones unguiculatus, has been widely employed as a model for studies of the inner ear. In spite of its established use for auditory research, no robust protocols to induce ototoxic hair cell damage have been developed for this species. In this paper, we demonstrate the development of an aminoglycoside-induced model of hair cell loss, using kanamycin potentiated by the loop diuretic furosemide. Interestingly, we show that the gerbil is relatively insensitive to gentamicin compared to kanamycin, and that bumetanide is ineffective in potentiating the ototoxicity of the drug. We also examine the pathology of the spiral ganglion after chronic, long-term hair cell damage. Remarkably, there is little or no neuronal loss following the ototoxic insult, even at 8 months post-damage. This is similar to the situation often seen in the human, where functioning neurons can persist even decades after hair cell loss, contrasting with the rapid, secondary degeneration found in rats, mice and other small mammals. We propose that the combination of these factors makes the gerbil a good model for ototoxic damage by induced hair cell loss. PMID- 25783991 TI - The presidential CT: the exam heard 'round the world. PMID- 25783992 TI - Adding value in radiology: establishing a designated quality control radiologist in daily workflow. PMID- 25783993 TI - Theoretical study of formamide decomposition pathways over (6,0) silicon-carbide nanotube. AB - In this study, we systematically identified possible reaction pathways for the catalytic decomposition of formamide (FM) on a (6,0) silicon-carbide nanotube surface by means of density functional theory. To gain insight into the catalytic activity of the surface, the interaction between the FM and SiCNT is analyzed by detailed electronic analysis such as adsorption energy, charge density difference and activation barrier. The energy barriers for the dehydrogenation, decarbonylation, and dehydration processes are found to be in the range of 0.2-49 kcal. Our results indicate that dehydrogenation and decarbonylation pathways are possible routes to get gaseous HNCO, H2, NH3, and CO molecules. In contrast, the reaction of HCONH -> CONH + H presents a large activation energy (about 49 kcal mol(-1)) which makes the FM dehydration an unfavorable reaction. Moreover, the dehydrogenation appears to be particularly favorable at low temperatures. The theoretical insights gained in this study could be useful for designing and developing metal-free catalysts based on SiC nanostructures. PMID- 25783994 TI - Mechanistic insights from molecular dynamic simulation of Rv0045c esterase in Mycobacterium tuberculosis. AB - Rv0045c is an esterase involved in lipid metabolism of Mycobacterium tuberculosis. It belongs to the alpha/beta hydrolase family. In the current study, we performed sequence- and structure-based analysis of Rv0045c followed by molecular dynamics (MD) simulation for 100 ns to investigate conformational changes in the enzyme. Sequence analysis revealed that this enzyme is possibly a hormone-sensitive lipase. Further, through structural analysis, a putative catalytic tetrad containing "Ser-Asp-Ser-His" and residues involved in the formation of an oxyanion hole were identified. MD simulation of Rv0045c revealed a conformational transition from an open to a closed state. The active site pocket was found to be gated by four loops. The potential role of the cap domain and the mobile histidine is discussed. From the simulation, we see that the conformational changes mimic the different stages in the reaction mechanism of Rv0045c. These results support the hypothesis that free enzyme simulation encompasses all the conformations necessary for the different stages of catalysis. Our findings add to the growing knowledge of an important family of esterases in Mycobacterium tuberculosis. PMID- 25783995 TI - Establishment of the straightforward electro-transformation system for Phytophthora infestans and its comparison with the improved PEG/CaCl2 transformation. AB - Phytophthora infestans is the most devastating pathogen of potato. For the biology study of P. infestans at the molecular level, one of the difficulties is the technique for the genetic transformation. In this study, the straightforward electro-transformation system was established for P. infestans with a green fluorescent protein expression vector and compared with the improved PEG/CaCl2 mediated protoplast transformation system. The results showed that the straightforward electro-transformation could work in P. infestans and 32 positive transformants were obtained per about 1.10*10(6) zoospores. The transformants per MUg of vector DNA were 1.08. The transformation efficiency of the straightforward electro-transformation was approximately 2 times higher than that of the improved PEG/CaCl2 mediated protoplast transformation (17 positive transformants per about 1.05*10(6) protoplasts, 0.58 transformants per MUg of vector DNA) according to the reported procedures. Furthermore, compared with the improved PEG/CaCl2 transformation, the straightforward electroporation is simpler and requires less starting materials and operating time from collecting material to obtaining the resistant transformants. Our work will lay a foundation for the biology study of P. infestans in the future. PMID- 25783996 TI - Father role: A comparison between teenage and adult first-time fathers in Thailand. AB - In this study, we compared perceived father roles among teenage and adult first time fathers in Thailand. The design was cross-sectional and comparative, and the sample involved 70 teenage and 70 adult fathers, whose children were 2-6 months old. The fathers were recruited from 32 primary healthcare centers in the western region of Thailand. Three validated, self-reported questionnaires with multiple choice questions were used for data collection. Differences between the two groups were analyzed using chi(2)-test and the Mann-Whitney U-test. The results revealed differences between teenage and adult fathers concerning income, educational level, and intention to have a baby. The teenage father group had a lower sense of competence, and scored lower on childrearing behavior and father child relationship than the adult father group. These findings provide healthcare professionals with increased knowledge and understanding of teenage fathers' needs in preparing for parenthood. Given that we now know the importance of positive father roles in children's lives, health authorities should be expected to provide resources to help support these fathers. PMID- 25783997 TI - Population divergence of aggregation pheromone responses in Ips subelongatus in northeastern China. AB - The Asian larch bark beetle, Ips subelongatus, is considered to be the major pest of larch within its natural range. We investigated the electrophysiological and behavioral characteristics as well as mitochondrial DNA cytochrome oxidase subunit I sequences of I. subelongatus from 13 geographic populations throughout northeastern China in order to explore population divergence of aggregation pheromone responses and the extent of potential genetic divergence. Electrophysiological analyses showed that antennae of I. subelongatus from all the six tested populations responded strongly to (S)-(-)-ipsenol (100% detection; 0.35-0.73 mV) in gas chromatography (GC)-electroantennographic detection (EAD) analyses, while its antipode, (R)-(+)-ipsenol was antennally inactive. I. subelongatus populations varied in their responses to (R)-(-)- and (S)-(+) ipsdienol in GC-EAD analyses. Behavioral bioassays demonstrated that (S)-(-) ipsenol alone was significantly attractive at all the tested sites, supporting its status as a key pheromone component of I. subelongatus, whereas (S)-(+) ipsdienol was inactive alone. Adding (S)-(+)-ipsdienol to (S)-(-)-ipsenol did not have any effect on the trap catches from some populations in Inner Mongolia. However, (S)-(+)-ipsdienol showed a strong synergistic effect on (S)-(-)-ipsenol from several populations in Jilin and Liaoning Provinces, and a weak synergistic effect from some transition populations in Heilongjiang Province. Furthermore, 27 mitochondrial haplotypes were found among the 13 populations (intraspecific nucleotide divergence, 0.1%-1.1%). Analyses of molecular variance and haplotype networks indicated that different geographic populations have developed some genetic variation but did not form completely independent groups. From an applied point of view, a universal synthetic binary blend of racemic ipsenol and (S)-(+) ipsdienol might have a potential for monitoring or even mass-trapping of I. subelongatus across northeastern China, even though some populations only use (S) (-)-ipsenol alone as their active pheromone component. PMID- 25783998 TI - Importance of prostate volume in the stratification of patients with intermediate risk prostate cancer. AB - OBJECTIVES: To evaluate the role of prostate volume assessed at final pathology in the risk of biochemical recurrence in patients with clinically localized prostate cancer treated with radical prostatectomy. METHODS: Overall, 5637 patients treated with radical prostatectomy between January 1993 and August 2013 were identified. Multivariable Cox regression analyses tested the association between prostate volume and biochemical recurrence in the overall population and after stratifying patients according to the D'Amico risk groups. RESULTS: Mean (median) prostate volume was 50.61 mL (46 mL). When patients were stratified according to D'Amico risk groups, mean (median) prostate volume was 51.7 mL (48 mL), 49.8 mL (45 mL) and 50.6 mL (46 mL) in low-, intermediate-, and high-risk prostate cancer, respectively (P = 0.04). Overall, the 5-year biochemical recurrence-free survival rate was 87.9%. In multivariable Cox regression analyses, prostate volume was associated with a lower risk of biochemical recurrence (hazard ratio 0.99, 95% confidence interval 0.99-1.00), after accounting for disease characteristics. However, when patients were stratified according to D'Amico risk groups, prostate volume represented an independent predictor of biochemical recurrence only in individuals with intermediate-risk disease (hazard ratio 0.99, 95% confidence interval 0.99-1.00). Conversely, prostate volume was not associated with the risk of experiencing biochemical recurrence in patients with low- and high-risk disease. CONCLUSIONS: Smaller prostates are associated with increased risk of biochemical recurrence after surgery only in men with intermediate-risk disease. In this category, the preoperative assessment of prostate volume might be helpful in order to identify patients at higher risk of biochemical recurrence after surgery. Additionally, prostate volume might be used to individualize follow-up schedules after radical prostatectomy. PMID- 25783999 TI - The interdependent roles of Ca(2+) and cAMP in axon guidance. AB - Axon guidance is a fundamental process in the developing and regenerating nervous system that is necessary for accurate neuronal wiring and proper brain function. Two of the most important second messengers in axon guidance are Ca(2+) and cAMP. Recently experimental and theoretical studies have uncovered a Ca(2+) - and cAMP dependent mechanism for switching between attraction and repulsion. Here, we review this process and related Ca(2+) and cAMP interactions, the mechanisms by which necessary intracellular calcium elevations are created, and the pathways, which effect attractive and repulsive responses to the switch. PMID- 25784000 TI - Tunneled Hemodialysis Catheter Removals by Non-Interventional Nephrologists: The University of Mississippi Experience. AB - Bedside removal of tunneled hemodialysis catheters (TDC) by noninterventional Nephrologists has not been frequently performed or studied. We performed a retrospective review of bedside TDC removal at the University of Mississippi Medical Center between January, 2010 and June, 2013. We collected data on multiple patients and procedure-related variables, success, and complications rates. Of the 138 subjects, mean age was 50 (+/-15.9) years, 49.3% were female, 88.2% African American and 41% diabetics. Site of removal was the right internal jugular (IJ) in 76.8%, the left IJ in 15.2%, and the femoral vein in 8% of patients. Exactly 44.9% of removals took place in the outpatient setting. Main indications for the removal were proven bacteremia in 30.4%, sepsis or clinical concerns for infection in 15.2% of the cases, while TDC was no longer necessary in 52.2% of patients. All removals were technically successful and well tolerated, but we observed Dacron "cuff" separation and subcutaneous retention in 6.5% of the cases. There was a significant association between outpatient removal and cuff retention (p = 0.007), but not with the site of removal or operator experience. In this relatively large mixed cohort of inpatients and outpatients, bedside TDC removal was well tolerated with a minimal complication rate. PMID- 25784001 TI - Input-Output Characteristics of Late Corticospinal Silent Period Induced by Transcranial Magnetic Stimulation. AB - PURPOSE: Corticospinal silent period (SP) may be interrupted by a burst of muscle activity followed by a second (late) SP, generally assumed to be a continuation from the primary SP. Our objective was to characterize the input-output behavior of the late SP. METHODS: Transcranial magnetic stimulation was applied on the cortical representation area of the right-hand muscles of 12 healthy subjects. Single-pulse transcranial magnetic stimulation was given with varying stimulation intensities normalized to the individual resting motor threshold (60% to 130% of the resting motor threshold) during voluntary muscle contraction. Electromyogram was recorded from first dorsal interosseous and abductor pollicis brevis muscles. Primary and late SPs were analyzed as absolute SPs, and input-output characteristics were assessed. RESULTS: The late SP exhibited fundamentally different input-output characteristics from that of the primary SP. The late SP most likely presented itself at stimulation intensities of 90% to 100% of the resting motor threshold. CONCLUSIONS: Different input-output characteristics of the late SP compared with the primary SP indicate that the late SP possess mechanisms different from the primary SP. The exact origin of the late SP remains unclear. Understanding the origins of the late SP could provide valuable insight on corticospinal inhibitory processes. PMID- 25784002 TI - Actinic keratoses, actinic field change and associations with squamous cell carcinoma in renal transplant recipients in Manchester, UK. AB - While actinic keratoses (AKs) have a known association with cutaneous squamous cell carcinoma (SCC), the relation of actinic field change to SCC has not been quantified. This study investigated the presence of field change and AKs in renal transplant recipients (RTRs) and estimated SCC risk. In May 2010 to October 2011, a dermatologist examined 452 white RTRs (mean age 53 years) at two hospitals in Manchester, UK, counting AKs and recording field change presence by body site and SCCs arising during the study period. Of the participants 130 (29%) had AKs at examination. In 60 (13%) RTR patients with AKs but no field change, 4 (7%) developed SCCs, compared with 15 (21%) of the 70 (15%) with AKs and field change. SCCs developed directly within field change areas in 11/15 (73%) RTRs. This study confirms that RTRs with widespread confluent actinic skin damage are at very high risk of SCC and should be monitored closely. PMID- 25784003 TI - WEED: marijuana, medicine and neuroscience: history of the Alfred I. duPont Columbia University Award. PMID- 25784005 TI - Concussion related to white matter abnormalities and cognitive dysfunction in aging athletes. PMID- 25784006 TI - Inherent limitations of tractography for accurate connectivity maps. PMID- 25784007 TI - Progesterone is not effective in the treatment of traumatic brain injury. PMID- 25784008 TI - Closed-loop deep brain stimulation successfully modulates hippocampal activity in an animal model. PMID- 25784009 TI - Combined direct and indirect revascularization is associated with low rates of recurrent ischemic and hemorrhagic stroke in adult moyamoya disease. PMID- 25784010 TI - Toxin-secreting implantable therapeutic stem cells. PMID- 25784011 TI - Timing is everything in corticospinal tract recovery after stroke. PMID- 25784012 TI - A multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke caused by proximal arterial occlusion in the anterior circulation. PMID- 25784013 TI - The use of nanotechnology to improve the neuroprotective effects of adenosine in stroke and spinal cord injury. PMID- 25784014 TI - Focused ultrasound with microbubbles increases temozolomide delivery in U87 transfected mice. PMID- 25784017 TI - The impact of disease duration on quality of life in children with nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study. AB - BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS) II is a prospective study that evaluates patient reported outcomes in pediatric chronic diseases as a measure of health-related quality of life (HRQOL). We have evaluated the influence of disease duration on HRQOL and, for the first time, compared the findings of the PROMIS measures to those of the PedsQLTM 4.0 Generic Scales (PedsQL) from the PROMIS II nephrotic syndrome (NS) longitudinal cohort. METHODS: This was a prospective study in which 127 children (age range 8-17 years) with active NS from 14 centers were enrolled. Children with active NS defined as the presence of nephrotic range proteinuria (>2+ urinalysis and edema or urine protein/creatinine ratio >2 g/g) were eligible. Comparisons were made between children with prevalent (N = 67) and incident (N = 60) disease at the study enrollment visit. RESULTS: The PROMIS scores were worse in prevalent patients in the domains of peer relationship (p = 0.01) and pain interference (p < 0.01). The PedsQL showed worse scores in prevalent patients for social functioning (p < 0.01) and school functioning (p = 0.03). Multivariable analyses showed that prevalent patients had worse scores in PROMIS pain interference (p = 0.02) and PedsQL social functioning (p < 0.01). CONCLUSION: The PROMIS measures detected a significant impact of disease duration on HRQOL in children, such that peer relationships were worse and pain interfered with daily life to a greater degree among those with longer disease duration. These findings were in agreement with those for similar domains in the PedsQL legacy instrument. PMID- 25784019 TI - Influence of depression and anxiety on circulating endothelial progenitor cells in patients with acute coronary syndromes. AB - OBJECTIVES: Circulating endothelial progenitor cells (EPCs) are related to endothelial function and progression of coronary artery disease. There is evidence of decreased numbers of circulating EPCs in patients with a current episode of major depression. We investigated the relationships between the level of circulating EPCs and depression and anxiety in patients with acute coronary syndrome (ACS). METHODS: Patients with ACS admitted to three Cardiology Intensive Care Units were evaluated by the SCID-I to determine the presence of lifetime and/or current mood and anxiety disorders according to DSM-IV criteria. The EPCs were defined as CD133(+) CD34(+) KDR(+) and evaluated by flow cytometry. All patients underwent standardized cardiological and psychopathological evaluations. Parametric and nonparametric statistical tests were performed where appropriate. RESULTS: Out of 111 ACS patients, 57 were found to have a DSM-IV lifetime or current mood or anxiety disorder at the time of the inclusion in the study. The ACS group with mood or anxiety disorders showed a significant decrease in circulating EPC number compared with ACS patients without affective disorders. In addition, EPC levels correlated negatively with severity of depression and anxiety at index ACS episode. CONCLUSIONS: The current study indicates that EPCs circulate in decreased numbers in ACS patients with depression or anxiety and, therefore, contribute to explore new perspectives in the pathophysiology of the association between cardiovascular disorders and affective disorders. PMID- 25784018 TI - Perioperative fluid management and postoperative hyponatremia in children. AB - Intravenous (IV) fluids are used ubiquitously when children undergo surgical procedures. Until recently, Holliday and Segar's guidelines for calculating maintenance fluids dictated fluid management strategies in postoperative pediatric patients. An increased recognition of hospital-acquired hyponatremia and its associated morbidity has led to a critical re-examination of IV fluid management in this population. Postsurgical patients are at high risk of developing hyponatremia due to the presence of non-osmotic stimuli for antidiuretic hormone release. Recent studies have established that, as they are administered in current practice, hypotonic maintenance fluids are associated with increased rates of hyponatremia. The best available data demonstrate that administration of isotonic fluid reduces hyponatremic risk. In this review, we discuss the collective data available on the subject and offer guidelines for fluid management and therapeutic monitoring. PMID- 25784020 TI - Introduction to noninvasive cardiac mapping. AB - From the dawn of the twentieth century, the electrocardiogram (ECG) has revolutionized the way clinical cardiology has been practiced, and it has become the cornerstone of modern medicine today. Driven by clinical and research needs for a more precise understanding of cardiac electrophysiology beyond traditional ECG, inverse solution electrocardiography has been developed, tested, and validated. This article outlines the important progress from ECG development, through more extensive measurement of body surface potentials, and the fundamental leap to solving the inverse problem of electrocardiography, with a focus on mathematical methods and experimental validation. PMID- 25784021 TI - Computation and projection of spiral wave trajectories during atrial fibrillation: a computational study. AB - To show how atrial fibrillation rotor activity on the heart surface manifests as phase on the torso, fibrillation was induced on a geometrically accurate computer model of the human atria. The Hilbert transform, time embedding, and filament detection were compared. Electrical activity on the epicardium was used to compute potentials on different surfaces from the atria to the torso. The Hilbert transform produces erroneous phase when pacing for longer than the action potential duration. The number of phase singularities, frequency content, and the dominant frequency decreased with distance from the heart, except for the convex hull. PMID- 25784022 TI - Analysis of cardiac fibrillation using phase mapping. AB - The sequence of myocardial electrical activation during fibrillation is complex and changes with each cycle. Phase analysis represents the electrical activation recovery process as an angle. Lines of equal phase converge at a phase singularity at the center of rotation of a reentrant wave, and the identification of reentry and tracking of reentrant wavefronts can be automated. We examine the basic ideas behind phase analysis. With the exciting prospect of using phase analysis of atrial electrograms to guide ablation in the human heart, we highlight several recent developments in preprocessing electrograms so that phase can be estimated reliably. PMID- 25784023 TI - Comparative analysis of diagnostic 12-lead electrocardiography and 3-dimensional noninvasive mapping. AB - The clinical utility of noninvasive electrocardiographic imaging has been demonstrated in a variety of conditions. It has recently been shown to have superior predictive accuracy and higher clinical value than validated 12-lead electrogram algorithms in the localization of arrhythmias arising from the ventricular outflow tract, and displays similar potential in other conditions. PMID- 25784024 TI - Noninvasive diagnostic mapping of supraventricular arrhythmias (Wolf-Parkinson White syndrome and atrial arrhythmias). AB - The 12-lead electrocardiogram has limited value in precisely identifying the origin of focal or critical component of reentrant arrhythmias during supraventricular arrhythmias, as well as precisely locating accessory atrioventricular conduction pathways. Because of these limitations, efforts have been made to reconstruct epicardial activation sequences from body surface measurements obtained noninvasively. The last decade has registered significant progress in obtaining clinically useful data from the attempts to noninvasively map the epicardial electrical activity. This article summarizes the recent advances made in this area, specifically addressing the clinical outcomes of such efforts relating to atrial arrhythmias and Wolf-Parkinson-White syndrome. PMID- 25784025 TI - Noninvasive mapping to guide atrial fibrillation ablation. AB - Atrial fibrillation (AF) is a dynamic rhythm. Noninvasive mapping overcomes many previous barriers to mapping such a dynamic rhythm, by providing a beat-to-beat, biatrial, panoramic view of the AF process. Catheter ablation of AF drivers guided by noninvasive mapping has yielded promising clinical results and has advanced understanding of the underlying pathophysiologic processes of this common heart rhythm disorder. PMID- 25784026 TI - Noninvasive mapping of ventricular arrhythmias. AB - Several decades of research has led to the development of a 252-lead electrocardiogram-based three-dimensional imaging modality to refine noninvasive diagnosis and improve the management of heart rhythm disorders. This article reviews the clinical potential of this noninvasive mapping technique in identifying the sources of electrical disorders and guiding the catheter ablation of ventricular arrhythmias (premature ventricular beats and ventricular tachycardia). The article also briefly refers to the noninvasive electrical imaging of the arrhythmogenic ventricular substrate based on the electrophysiologic characteristics of postinfarction ventricular myocardium. PMID- 25784027 TI - Ablation of premature ventricular complexes exclusively guided by three dimensional noninvasive mapping. AB - Preprocedural detailed characterization of premature ventricular complexes before ablation, currently limited to the 12-lead electrocardiogram, may aid in planning and improve procedural outcomes. This article summarizes current published data on feasibility, accuracy, and impact on clinical outcomes of a novel, three dimensional, noninvasive, single-beat mapping system (ECVUE, CardioInsight). ECVUE technology offers premature ventricular complex characterization and localization with clinically relevant accuracy and performance superior to the surface electrocardiogram. With its noninvasive and single beat advantages, ECVUE has the potential to simplify mapping, and reduce ablation and procedural time. PMID- 25784028 TI - Utility of noninvasive arrhythmia mapping in patients with adult congenital heart disease. AB - Arrhythmia management in patients with adult congenital heart disease (ACHD) is a challenge on many levels, as tachycardic episodes may lead to hemodynamic impairment in otherwise compensated patients even if episodes are only transient. Recently several technical advances, including 3-dimensional (3D) image integration, 3D mapping, and remote magnetic navigation, have been introduced to facilitate curatively intended ablation procedures in patients with ACHD. This review attempts to outline the role of a novel technology of simultaneous, noninvasive mapping in this patient cohort, and gives details of the authors' single-center experience. PMID- 25784029 TI - Noninvasive mapping of electrical dyssynchrony in heart failure and cardiac resynchronization therapy. AB - Causes for diverse effects of cardiac resynchronization therapy (CRT) are poorly understood. Because CRT is an electrical therapy, it may be best understood by detailed characterization of electrical substrate and its interaction with pacing. Electrocardiogram (ECG) features affect CRT outcomes. However, the surface ECG reports rudimentary electrical data. In contrast, noninvasive electrocardiographic imaging provides high-resolution single-beat ventricular mapping. Several complex characteristics of electrical substrate, not decipherable from the 12-lead ECG, are linked to CRT effect. CRT response may be improved by candidate selection and left ventricular lead placement directed by more precise electrical evaluation, on an individual patient basis. PMID- 25784030 TI - Distinct localized reentrant drivers in persistent atrial fibrillation identified by noninvasive mapping: relation to f-wave morphology. AB - Noninvasive mapping overcomes previous barriers to provide panoramic beat-to-beat mapping during atrial fibrillation (AF). This article demonstrates the utility of noninvasive mapping in identifying localized driving sources in persistent AF. Reentrant driver activity detected by noninvasive mapping from specific regions correlated with distinct f-wave morphologies. Ablation targeting these drivers resulted in progressive AF cycle length prolongation and termination of the arrhythmia. PMID- 25784031 TI - Rotors in patients with persistent atrial fibrillation: case report of a left atrial appendage rotor identified by a novel computational mapping algorithm integrated into 3-dimensional mapping and termination of atrial fibrillation with ablation. AB - Recent clinical trials using panoramic mapping techniques have shown success in targeting rotors and focal impulses in atrial fibrillation (AF). Ablations directed toward these organized sources improve outcomes in AF. The left atrial appendage (LAA) has been suspected as a possible extrapulmonary source of AF, and ablation within the LAA or electrical isolation of the LAA improves outcomes in certain cases. This case highlights a unique example of panoramic imaging created with a computational mapping algorithm integrated in 3-dimensional mapping, which identified rotors within the LAA. Furthermore, ablations performed near an identified rotor core within the LAA terminated AF. PMID- 25784032 TI - Noninvasive cardiac mapping: a new era in electrophysiology. PMID- 25784033 TI - Deciphering the role of a coleopteran steering muscle via free flight stimulation. AB - Testing hypotheses of neuromuscular function during locomotion ideally requires the ability to record cellular responses and to stimulate the cells being investigated to observe downstream behaviors [1]. The inability to stimulate in free flight has been a long-standing hurdle for insect flight studies. The miniaturization of computation and communication technologies has delivered ultra small, radio-enabled neuromuscular recorders and stimulators for untethered insects [2-8]. Published stimulation targets include the areas in brain potentially responsible for pattern generation in locomotion [5], the nerve chord for abdominal flexion [9], antennal muscles [2, 10], and the flight muscles (or their excitatory junctions) [7, 11-13]. However, neither fine nor graded control of turning has been demonstrated in free flight, and responses to the stimulation vary widely [2, 5, 7, 9]. Technological limitations have precluded hypotheses of function validation requiring exogenous stimulation during flight. We investigated the role of a muscle involved in wing articulation during flight in a coleopteran. We set out to identify muscles whose stimulation produced a graded turning in free flight, a feat that would enable fine steering control not previously demonstrated. We anticipated that gradation might arise either as a function of the phase of muscle firing relative to the wing stroke (as in the classic fly b1 muscle [14, 15] or the dorsal longitudinal and ventral muscles of moth [16]), or due to regulated tonic control, in which phase-independent summation of twitch responses produces varying amounts of force delivered to the wing linkages [15, 17, 18]. PMID- 25784034 TI - Elementary motion detectors. AB - A quick guide to the elementary motion detector- a model of how a simple neural circuit can detect visual motion, developed from work on insect vision but which seems also to be relevant to vertebrate visual systems. PMID- 25784035 TI - White-Nose Syndrome fungus introduced from Europe to North America. AB - The investigation of factors underlying the emergence of fungal diseases in wildlife has gained significance as a consequence of drastic declines in amphibians, where the fungus Batrachochytrium dendrobatidis has caused the greatest disease-driven loss of biodiversity ever documented [1]. Identification of the causative agent and its origin (native versus introduced) is a crucial step in understanding and controlling a disease [2]. Whereas genetic studies on the origin of B. dendrobatidis have illuminated the mechanisms behind the global emergence of amphibian chytridiomycosis [3], the origin of another recently emerged fungal disease, White-Nose Syndrome (WNS) and its causative agent, Pseudogymnoascus destructans, remains unresolved [2,4]. WNS is decimating multiple North American bat species with an estimated death toll reaching 5-6 million. Here, we present the first informative molecular comparison between isolates from North America and Europe and provide strong evidence for the long term presence of the fungus in Europe and a recent introduction into North America. Our results further demonstrate great genetic similarity between the North American and some European fungal populations, indicating the likely source population for this introduction from Europe. PMID- 25784036 TI - Opportunities and costs for preventing vertebrate extinctions. AB - Despite an increase in policy and management responses to the global biodiversity crisis, implementation of the 20 Aichi Biodiversity Targets still shows insufficient progress [1]. These targets, strategic goals defined by the United Nations Convention on Biological Diversity (CBD), address major causes of biodiversity loss in part by establishing protected areas (Target 11) and preventing species extinctions (Target 12). To achieve this, increased interventions will be required for a large number of sites and species. The Alliance for Zero Extinction (AZE) [2], a consortium of conservation-oriented organisations that aims to protect Critically Endangered and Endangered species restricted to single sites, has identified 920 species of mammals, birds, amphibians, reptiles, conifers and reef-building corals in 588 'trigger' sites [3]. These are arguably the most irreplaceable category of important biodiversity conservation sites. Protected area coverage of AZE sites is a key indicator of progress towards Target 11 [1]. Moreover, effective conservation of AZE sites is essential to achieve Target 12, as the loss of any of these sites would certainly result in the global extinction of at least one species [2]. However, averting human-induced species extinctions within AZE sites requires enhanced planning tools to increase the chances of success [3]. Here, we assess the potential for ensuring the long-term conservation of AZE vertebrate species (157 mammals, 165 birds, 17 reptiles and 502 amphibians) by calculating a conservation opportunity index (COI) for each species. The COI encompasses a set of measurable indicators that quantify the possibility of achieving successful conservation of a species in its natural habitat (COIh) and by establishing insurance populations in zoos (COIc). PMID- 25784037 TI - Coupled computations of three-dimensional shape and material. AB - Retinal image structure arises from the interaction between a surface's three dimensional shape, its reflectance and transmittance properties, and the surrounding light field. Any local image structure can be generated by an infinite number of different combinations of surface properties, which suggests that the visual system must somehow constrain the possible scene interpretations. The research on this has searched for such constraints in statistical regularities of two-dimensional image structure [1,2]. Here, we present a new class of displays in which the perception of material properties cannot be explained with two-dimensional image properties. The displays manipulate the perceived three-dimensional shape of identical luminance gratings, and demonstrate that perceived three-dimensional shape can alter perceived surface reflectance. PMID- 25784038 TI - Cell biology: scaling and the emergence of evolutionary cell biology. AB - A new study investigating the origins of diversity in the structure of the mitotic spindle in nematode embryos, at timescales spanning a few generations to hundreds of millions of years, finds that most features of the spindle evolve via a scaling relationship generated by natural selection acting directly upon embryo size. PMID- 25784039 TI - Life history evolution: what does a menopausal killer whale do? AB - Menopause evolved in humans and whales, presumably because older females can help their kin. But how do they help? New research shows that post-menopausal female killer whales lead foraging groups. This leadership is most significant when food is scarce. PMID- 25784040 TI - Microbial diversity: a bonanza of phyla. AB - Metagenomics and single-cell genomics are now the gold standard for exploring microbial diversity. A new study focusing on enigmatic ultra-small archaea greatly expands known genetic diversity within Archaea, and reports the first complete archaeal genomes reconstructed from metagenomic data only. PMID- 25784041 TI - Growth control: re-examining Zyxin's role in the hippo pathway. AB - The Hippo pathway is a conserved regulator of organ growth that computes information from the cellular microenvironment. A new study examines the role of the Hippo pathway protein Zyxin and finds that it antagonises Expanded to modulate F-actin and organ size. PMID- 25784042 TI - Motor control: how dragonflies catch their prey. AB - Detailed measurements of head and body motion have revealed previously unknown complexity in the predatory behavior of dragonflies. The new evidence suggests that the brains of these agile predators compute internal models of their own actions and those of their prey. PMID- 25784043 TI - Neurodegeneration: paying it off with sleep. AB - A new study in fruit flies suggests modulation of neural activity links sleep and Alzheimer's disease. Both sleep loss and amyloid beta increase neural excitability, which reinforces the accumulation of amyloid beta and shortens lifespan. PMID- 25784044 TI - Animal cognition: bumble bees suffer 'false memories'. AB - The existence of 'false memories', where individuals remember events that they have never actually experienced, is well established in humans. Now a new study reports that insects similarly form illusory memories through merging of memory traces. PMID- 25784045 TI - Autophagy: starvation relieves transcriptional repression of ATG genes. AB - Autophagy is a highly regulated process about which relatively little is known, particularly concerning the transcriptional control of autophagy regulation. A new study identifies a key regulator of the expression of autophagy-related genes, thereby providing insights into the signalling pathways modulating autophagy. PMID- 25784046 TI - Insect navigation: do honeybees learn to follow highways? AB - Radar studies of a honeybee's flights when it first leaves its nest suggest the features of the surrounding landscape that it learns guide future foraging trips. PMID- 25784048 TI - Outstanding blue delayed fluorescence and significant processing stability of cuprous complexes with functional pyridine-pyrazolate diimine ligands. AB - Thermally activated delayed fluorescence (TADF) of five novel cuprous complexes, with quantum yields near 1 in the solid state, has been realized. Meanwhile, these complexes are significantly stable upon processing with small emission spectral variations from the solid to the thin film to the solvent state. PMID- 25784047 TI - Bacterial actin and tubulin homologs in cell growth and division. AB - In contrast to the elaborate cytoskeletal machines harbored by eukaryotic cells, such as mitotic spindles, cytoskeletal structures detectable by typical negative stain electron microscopy are generally absent from bacterial cells. As a result, for decades it was thought that bacteria lacked cytoskeletal machines. Revolutions in genomics and fluorescence microscopy have confirmed the existence not only of smaller-scale cytoskeletal structures in bacteria, but also of widespread functional homologs of eukaryotic cytoskeletal proteins. The presence of actin, tubulin, and intermediate filament homologs in these relatively simple cells suggests that primitive cytoskeletons first arose in bacteria. In bacteria such as Escherichia coli, homologs of tubulin and actin directly interact with each other and are crucial for coordinating cell growth and division. The function and direct interactions between these proteins will be the focus of this review. PMID- 25784049 TI - Suppressive function of low-dose deguelin on the invasion of oral cancer cells by downregulating tumor necrosis factor alpha-induced nuclear factor-kappa B signaling. AB - BACKGROUND: Deguelin has both antiproliferation and antimetastasis activities. However, high-dose deguelin elicits many undesired side effects. The purpose of this study was to investigate whether the low-dose deguelin can prevent the metastasis of oral cancer. METHODS: The dose effects of deguelin on metastasis of oral cancer cells were analyzed by in vitro invasion assay and an orthotropic xenograft mouse model. The involvement of tumor necrosis factor alpha (TNF-alpha) induced nuclear factor-kappa B (NF-kappaB) signaling was examined by Western blot and reporter assay. RESULTS: Low-dose deguelin, which has minimal cytotoxicity, significantly inhibited the invasion and migration of oral cancer cells. These inhibitory effects of low-dose deguelin were mediated by suppressing TNF-alpha induced activation of IkappaB kinase leading to the inhibition of IkappaB phosphorylation, NF-kappaB transcriptional activity, and matrix metalloproteinase 2 (MMP2) expression. The low-dose deguelin treatment significantly inhibited tumor growth and invasion without systemic toxicity. CONCLUSION: The low-dose deguelin suppressed the invasion and migration of oral cancer by downregulating TNF-alpha-induced NF-kappaB signaling. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E524-E534, 2016. PMID- 25784051 TI - Cellulose degradation by polysaccharide monooxygenases. AB - Polysaccharide monooxygenases (PMOs), also known as lytic PMOs (LPMOs), enhance the depolymerization of recalcitrant polysaccharides by hydrolytic enzymes and are found in the majority of cellulolytic fungi and actinomycete bacteria. For more than a decade, PMOs were incorrectly annotated as family 61 glycoside hydrolases (GH61s) or family 33 carbohydrate-binding modules (CBM33s). PMOs have an unusual surface-exposed active site with a tightly bound Cu(II) ion that catalyzes the regioselective hydroxylation of crystalline cellulose, leading to glycosidic bond cleavage. The genomes of some cellulolytic fungi contain more than 20 genes encoding cellulose-active PMOs, suggesting a diversity of biological activities. PMOs show great promise in reducing the cost of conversion of lignocellulosic biomass to fermentable sugars; however, many questions remain about their reaction mechanism and biological function. This review addresses, in depth, the structural and mechanistic aspects of oxidative depolymerization of cellulose by PMOs and considers their biological function and phylogenetic diversity. PMID- 25784050 TI - Application of the protein semisynthesis strategy to the generation of modified chromatin. AB - Histone proteins are subject to a host of posttranslational modifications (PTMs) that modulate chromatin structure and function. Such control is achieved by the direct alteration of the intrinsic physical properties of the chromatin fiber or by regulating the recruitment and activity of a host of trans-acting nuclear factors. The sheer number of histone PTMs presents a formidable barrier to understanding the molecular mechanisms at the heart of epigenetic regulation of eukaryotic genomes. One aspect of this multifarious problem, namely how to access homogeneously modified chromatin for biochemical studies, is well suited to the sensibilities of the organic chemist. Indeed, recent years have witnessed a critical role for synthetic protein chemistry methods in generating the raw materials needed for studying how histone PTMs regulate chromatin biochemistry. This review focuses on what is arguably the most powerful, and widely employed, of these chemical strategies, namely histone semisynthesis via the chemical ligation of peptide fragments. PMID- 25784055 TI - Indocyanine green fluorescence mapping of sentinel lymph node in patients with recurrent nasopharyngeal carcinoma after previous radiotherapy. AB - BACKGROUND: The purpose of this study was to present the feasibility of indocyanine green (ICG) mapping of sentinel lymph node in recurrent nasopharyngeal carcinoma (NPC). M1ETHODS: Peritumoral injection of 5-mg ICG solution and real-time mapping of the sentinel lymph nodes in the neck was performed during surgery. The sentinel lymph node identified was excised and sent separately for laboratory analysis. Selective neck dissection was then performed. The number and level of the sentinel lymph nodes, their signal-to-background ratio, and the histopathology of the sentinel lymph nodes and the neck dissection specimens were studied. RESULTS: A total of 5 patients were recruited into this study, of which 9 sentinel lymph nodes were identified. The majority of them were located in level II. The mean detection time after ICG injection was 288 seconds. The sentinel lymph nodes in 3 patients tested positive for malignancy. None of the selective neck dissection specimens harbored microscopic tumor deposits. CONCLUSION: ICG mapping of sentinel lymph nodes in locally recurrent NPC is potentially feasible. It offers a better nodal staging in patients with clinically N0 disease status. PMID- 25784052 TI - Mechanisms and Regulation of Alternative Pre-mRNA Splicing. AB - Precursor messenger RNA (pre-mRNA) splicing is a critical step in the posttranscriptional regulation of gene expression, providing significant expansion of the functional proteome of eukaryotic organisms with limited gene numbers. Split eukaryotic genes contain intervening sequences or introns disrupting protein-coding exons, and intron removal occurs by repeated assembly of a large and highly dynamic ribonucleoprotein complex termed the spliceosome, which is composed of five small nuclear ribonucleoprotein particles, U1, U2, U4/U6, and U5. Biochemical studies over the past 10 years have allowed the isolation as well as compositional, functional, and structural analysis of splicing complexes at distinct stages along the spliceosome cycle. The average human gene contains eight exons and seven introns, producing an average of three or more alternatively spliced mRNA isoforms. Recent high-throughput sequencing studies indicate that 100% of human genes produce at least two alternative mRNA isoforms. Mechanisms of alternative splicing include RNA-protein interactions of splicing factors with regulatory sites termed silencers or enhancers, RNA-RNA base-pairing interactions, or chromatin-based effects that can change or determine splicing patterns. Disease-causing mutations can often occur in splice sites near intron borders or in exonic or intronic RNA regulatory silencer or enhancer elements, as well as in genes that encode splicing factors. Together, these studies provide mechanistic insights into how spliceosome assembly, dynamics, and catalysis occur; how alternative splicing is regulated and evolves; and how splicing can be disrupted by cis- and trans-acting mutations leading to disease states. These findings make the spliceosome an attractive new target for small-molecule, antisense, and genome-editing therapeutic interventions. PMID- 25784053 TI - The biology of proteostasis in aging and disease. AB - Loss of protein homeostasis (proteostasis) is a common feature of aging and disease that is characterized by the appearance of nonnative protein aggregates in various tissues. Protein aggregation is routinely suppressed by the proteostasis network (PN), a collection of macromolecular machines that operate in diverse ways to maintain proteome integrity across subcellular compartments and between tissues to ensure a healthy life span. Here, we review the composition, function, and organizational properties of the PN in the context of individual cells and entire organisms and discuss the mechanisms by which disruption of the PN, and related stress response pathways, contributes to the initiation and progression of disease. We explore emerging evidence that disease susceptibility arises from early changes in the composition and activity of the PN and propose that a more complete understanding of the temporal and spatial properties of the PN will enhance our ability to develop effective treatments for protein conformational diseases. PMID- 25784054 TI - The Clothes Make the mRNA: Past and Present Trends in mRNP Fashion. AB - Throughout their lifetimes, messenger RNAs (mRNAs) associate with proteins to form ribonucleoproteins (mRNPs). Since the discovery of the first mRNP component more than 40 years ago, what is known as the mRNA interactome now comprises >1,000 proteins. These proteins bind mRNAs in myriad ways with varying affinities and stoichiometries, with many assembling onto nascent RNAs in a highly ordered process during transcription and precursor mRNA (pre-mRNA) processing. The nonrandom distribution of major mRNP proteins observed in transcriptome-wide studies leads us to propose that mRNPs are organized into three major domains loosely corresponding to 5' untranslated regions (UTRs), open reading frames, and 3' UTRs. Moving from the nucleus to the cytoplasm, mRNPs undergo extensive remodeling as they are first acted upon by the nuclear pore complex and then by the ribosome. When not being actively translated, cytoplasmic mRNPs can assemble into large multi-mRNP assemblies or be permanently disassembled and degraded. In this review, we aim to give the reader a thorough understanding of past and current eukaryotic mRNP research. PMID- 25784056 TI - CASP7 variants modify susceptibility to cervical cancer in Chinese women. AB - Polymorphisms in Caspase-7 (CASP7) may modulate the programmed cell death and thus contribute to cervical cancer risk. In this case-control study of 1,486 cervical cancer cases and 1,301 controls, we investigated associations between four potentially functional polymorphisms in CASP7 and cervical cancer risk and evaluated their locus-locus interaction effects on the risk. The genotype phenotype correlation was performed by a generalized linear regression model. We found that the rs4353229 polymorphism was associated with cervical cancer risk (under a recessive model: crude OR = 1.20, 95% CI = 1.02-1.40). Compared with the TT genotype, the rs10787498GT genotype was associated with an increased cervical cancer risk (adjusted OR = 1.19, 95% CI = 1.00-1.41). Combination analysis showed that subjects with four putative risk genotypes had a 1.54-fold increased cancer risk, compared with those who carried three or less putative risk genotypes. We also observed significant locus-locus joint effects on the risk, which may be mediated by the polymorphisms regulating CASP7 mRNA expression. Subsequent multifactor dimensionality reduction and classification and regression tree analyses indicated that the CASP7 genotypes might have a locus-locus interaction effect that modulated cervical cancer risk. Out data suggest that CASP7 polymorphisms may interact to modify cervical cancer risk by a possible mechanism of regulating CASP7 mRNA expression. PMID- 25784058 TI - The value of Bayes' theorem for interpreting abnormal test scores in cognitively healthy and clinical samples. AB - The base rates of abnormal test scores in cognitively normal samples have been a focus of recent research. The goal of the current study is to illustrate how Bayes' theorem uses these base rates--along with the same base rates in cognitively impaired samples and prevalence rates of cognitive impairment--to yield probability values that are more useful for making judgments about the absence or presence of cognitive impairment. Correlation matrices, means, and standard deviations were obtained from the Wechsler Memory Scale--4th Edition (WMS-IV) Technical and Interpretive Manual and used in Monte Carlo simulations to estimate the base rates of abnormal test scores in the standardization and special groups (mixed clinical) samples. Bayes' theorem was applied to these estimates to identify probabilities of normal cognition based on the number of abnormal test scores observed. Abnormal scores were common in the standardization sample (65.4% scoring below a scaled score of 7 on at least one subtest) and more common in the mixed clinical sample (85.6% scoring below a scaled score of 7 on at least one subtest). Probabilities varied according to the number of abnormal test scores, base rates of normal cognition, and cutoff scores. The results suggest that interpretation of base rates obtained from cognitively healthy samples must also account for data from cognitively impaired samples. Bayes' theorem can help neuropsychologists answer questions about the probability that an individual examinee is cognitively healthy based on the number of abnormal test scores observed. PMID- 25784057 TI - Extract of Rhus verniciflua stokes protects the diet-induced hyperlipidemia in mice. AB - Rhus verniciflua stokes (RVS) is a popular medicinal plant in oriental medicines which is commonly used to resolve extravasated blood. To elucidate the molecular mechanism of the role of RVS extracts on the regulation of lipid and cholesterol biosynthesis, we investigated whether RVS extract protect the hyperlipidemia in western diet-induced C57BL6/J mice. Mice fed a western diet and additionally RVS extracts was administered orally at a dose of 0.1 or 1 g/kg/day for 2 weeks respectively. Group with higher dose of RVS extract showed a significantly decreased body weight compared with western diet fed mice groups. And total cholesterol, LDL-cholesterol levels and fatty liver formation were also improved especially in group of mice fed western diet supplemented high dose RVS extracts. Next, synthesis of hepatic bile acids were significantly increased in RVS extract fed groups. Furthermore, RVS extracts significantly increase promoter activity of Cyp7a1 via up-regulate the transcriptional expression level of LXRalpha. Our data suggest that RVS extracts could be a potent therapeutic ingredient for prevent a hyperlipidemia via increase of bile acids biosynthesis. PMID- 25784059 TI - [Dengue and chikungunya acquired during travel in the tropics]. AB - The global incidence of dengue and chikungunya has greatly increased over recent decades, partly due to the increase of geographic distribution of both vectors. These infections are endemic to the tropics and subtropics, however autochthonous transmission and outbreaks have been described in non-endemic areas. Currently, there is a large chikungunya outbreak in the western hemisphere which started in the Caribbean. Chikungunya had not previously been endemic to this region. Both arboviral infections are important causes of fever in Dutch travellers returning from tropical destinations. The clinical presentations of dengue and chikungunya overlap; both are characterised by high fever and arthralgia. Bleeding and plasma leakage are potentially life-threatening complications of dengue, while persistent arthralgia typifies chikungunya. The prevention of mosquito bites, by using protective clothing and insect repellents, is the only way to prevent infection. No vaccine is yet available. PMID- 25784060 TI - [Rare metastatic infection sites in S. aureus bacteraemia]. AB - BACKGROUND: Bacteraemia caused by Staphylococcus aureus may result in metastatic infection sites. The most common types of metastatic infection are endocarditis and spondylodiscitis. Less common sites of infection can cause atypical symptoms and be a challenge to diagnose. CASE DESCRIPTION: A 23-year-old male presented at the Emergency Room with acute abdominal pain radiating to his groin area, abnormal gait and fever. Blood cultures showed S. aureus. Endocarditis was ruled out by transthoracic echocardiography. CT and FDG-PET scans showed infarction of the spleen and symphysitis pubica with abscesses in the surrounding muscles as a cause of the symptoms. CONCLUSION: A FDG-PET/CT scan can be helpful in diagnosing metastatic infections and their sites caused by S. aureus bacteraemia, especially if presentation is atypical. This way proper treatment can be started sooner. PMID- 25784061 TI - [Scapula alata following a gunshot injury]. AB - BACKGROUND: The clinical condition "winged scapula" (scapula alata) is frequently not recognized as such. The accompanying symptoms are often attributed to more frequently occurring shoulder disorders, which can lead to unnecessary surgical procedures. CASE DESCRIPTION: A 41-year-old man was shot during a robbery 3 years ago, resulting in a complete paraplegia from the fourth thoracic vertebra downwards. Within a year of the attack, during rehabilitation towards wheelchair use, he developed pain around his right shoulder. He also had diminished strength when extending his right arm and problems with trunk balance. These symptoms were long thought to be caused by shoulder overuse during wheelchair use, but turned out to be a consequence of injury to the long thoracic nerve. CONCLUSION: Shoulder symptoms due to scapula alata can be caused be a penetrating wound leading to nerve injury. The treatment of patients with a scapula alata calls for a multidisciplinary approach. PMID- 25784062 TI - [Susac's syndrome: psychosis as a presenting symptom of rare angiopathy]. AB - BACKGROUND: Susac's syndrome is a rare angiopathy characterised by the triad of encephalopathy, hearing loss and retinal artery occlusions. The diagnosis relies on the clinical picture, brain MRI scan, audiometry, fundoscopy and fluorescein angiography. Swift, intensive and prolonged treatment with immunosuppressants, immunoglobulins, plasmapheresis and anticoagulants can result in full or partial remission. CASE DESCRIPTION: A 31-year-old woman became increasingly confused while on holiday in Aruba. On returning to Holland she was admitted for a psychotic episode. Because of the atypical nature of the psychiatric symptoms and subtle neurological deficits, extensive somatic investigations were conducted. Typical lesions in the corpus callosum were found on brain MRI. After treatment with immunosuppressants the psychotic symptoms disappeared. CONCLUSION: In Susac's syndrome psychiatric symptoms can initially dominate the clinical picture. To diagnose this condition correctly, extensive multidisciplinary collaboration is essential. PMID- 25784063 TI - [Cognitive aid for emergencies in the OR--AMC bundle helps ensure that no steps are left out]. AB - Crucial management steps in unexpected perioperative emergencies are frequently omitted by OR teams because of the suboptimal performance of the brain under stress.A cognitive aid is a tool that will help care providers to perform and speed up all the necessary management steps of a critical event. We have created a Dutch adaption of the Stanford Emergency Manual, a bundle of cognitive aids to manage a number of life threatening emergencies in the operating theatre. The effectiveness of these cognitive aids has been demonstrated in simulated emergencies. Their use has furthermore, been standard practice in other high-risk industries for many years. Further research should therefore mainly focus on the implementation and optimisation of these tools. PMID- 25784065 TI - [FDG-PET/CT: a valuable technique in Staphylococcus aureus bacteraemia]. AB - Staphylococcus aureus bacteraemia is often complicated by metastatic infectious foci. Some of these metastatic foci do not cause any localizing symptoms, which complicates early detection and adequate treatment. Where localizing symptoms are absent FDG-PET/CT is highly useful as a screening method for the identification of metastatic foci as it provides whole-body coverage. Furthermore, it detects early metabolic activity rather than the late anatomical changes needed for detection with CT or MRI. FDG-PET/CT has proven its clinical value and cost effectiveness in diagnosing metastatic infections in patients with Gram positive bacteraemia, including S. aureus. Therefore, we firmly believe that all patients with a community-acquired S. aureus bacteraemia infection, with a time span longer than 48 h between the first symptoms and initiation of antibiotic therapy, fever that still persists after 72 h, or positive follow-up blood cultures at 48 h after the start of treatment would benefit from an FDG-PET/CT scan for timely detection of metastatic infection and optimal treatment. PMID- 25784066 TI - [Guild medals from the Surgeons' Guild of Amsterdam]. AB - Between around 1620 and the end of the eighteenth century, every surgeon working in Amsterdam was presented with a guild medal on passing their surgeon's exams. These medals actually represented membership of the Surgeon's Guild of Amsterdam and could be used as proof of attendance at meetings of the Guild. From 1864 onwards surgeons also received the Hortus medal, which allowed them entry to the Hortus Medicus. Less common medals include medals for ensuring the surgeon's apprentices attended lectures, funeral medals for ensuring correct procedures regarding casket bearing duties were followed at a funeral, and medals of honour recognising services to the Guild. The collection of 17th and 18th century Amsterdam Surgeon's Guild medals numbers some 230 examples, and is the largest and most varied collection of its kind in the world. A few of the medals that have been preserved actually belonged to surgeons depicted in the famous series of group portraits. We examined who these surgeons were and what the purpose of these medals was. PMID- 25784067 TI - [A woman with a red nipple with purulent discharge]. AB - We describe a 49-year-old woman who presented to the surgeon with recurring complaints of her right nipple, such as redness, pain, swelling and purulent discharge from the areolar margin. The diagnosis 'Zuska's disease' should be distinguished from breast cancer, Paget's and Mondor's disease. Treatment is surgical with a microdochectomy. PMID- 25784068 TI - [A new protocol, is the spine still safe?]. AB - The latest version of the Dutch National Protocol Ambulance Care (Landelijk Protocol Ambulancezorg LPA8), introduced on 1 January 2015, contains too few guarantees of the safety of trauma patients in whom spinal immobilisation has to be performed. A number of strict indications have been removed and too much freedom is also permitted with respect to implementation. Although the previous standard method using a spinal board, collar and blocks did have disadvantages, the new operating method has been insufficiently substantiated and, in addition, is not well matched to the protocols of Accident and Emergency departments. It is vital that the agencies involved collaborate to reach a joint solution. PMID- 25784069 TI - Deficiency of Sustained Attention in ADHD and Its Potential Genetic Contributor MAOA. AB - OBJECTIVE: To investigate the genetic contributors to ADHD sustained attention deficit among noradrenergic genes responsible for the synthesis (dopamine-beta hydroxylase gene, DBH), transport (norepinephrine transporter gene, NET1), reception (alpha-2A adrenergic receptor gene, ADRA2A), and metabolism (monoamine oxidase A gene, MAOA) of noradrenalin (NE). METHOD: A total of 456 children with ADHD and 108 normal controls were included in a digit cancellation test (DCT). DNA was collected from 242 participants and genotyped for 14 single nucleotide polymorphisms (SNPs) of noradrenergic genes. RESULTS: Compared with normal controls, children with ADHD showed a lower total score and higher mean error rate in the DCT, indicating poorer sustained attention function. Analysis of covariance showed an association between MAOA genotypes and ADHD performance in DCT, with poorer performance in risk allele carriers. No association was found for other noradrenergic genes. CONCLUSION: Children with ADHD presented with a sustained attention deficit compared with normal controls. The sustained attention deficit of children with ADHD may be associated with genetic variant of MAOA. PMID- 25784070 TI - Identification of intestinal bacterial flora in Rhipicephalus microplus ticks by conventional methods and PCR-DGGE analysis. AB - In this study, we have analyzed the intestinal microbial flora associated with Rhipicephalus microplus ticks using both culture-dependent and independent methods based on PCR and denaturing gradient gel electrophoresis (PCR-DGGE). The R. microplus ticks were collected from cattle and goats in Jiangxi, Hunan and Guizhou Provinces of China. Three distinct strains of bacteria were isolated using culture-dependent methods: Staphylococcus simulans, Bacillus subtilis and Bacillus flexus strain. Nineteen distinct DGGE bands were found using PCR-DGGE analysis, and their search for identity shows that they belonged to Rickettsiaceae, Xanthomonadaceae, Coxiella sp., Ehrlichia sp., Pseudomonas sp., Ehrlichia sp., Orphnebius sp., Rickettsia peacockii, Bacillus flexus. Rickettsia peacockii and Coxiella genus were the dominant strain of the R. microplus ticks from cattle, Pseudomonas sp. and B. flexus strain were the most common species in all tick samples from goats. Ehrlichia canis were detected only in R. microplus ticks from Yongshun area in Hunan Province. The results indicate that the intestinal microbial diversity of R. microplus ticks was influenced by tick hosts and local differences in the sampling location and these two aspects may affect transmission of pathogen to humans and animals. PMID- 25784071 TI - A survey of ticks (Acari: Ixodida) infesting some wild animals from Sivas, Turkey. AB - In order to determine the species composition of infesting ticks, between 2011 and 2012 a total of 1118 wild animals were captured from various regions of Zara, Sivas province, Turkey. A total of 138 ticks were obtained from the 58 host animals. Ticks were identified as Dermacentor marginatus (Sulzer), Haemaphysalis erinacei taurica Pospelova-Shtrom, Haemaphysalis parva (Neumann), Haemaphysalis punctata Canestrini and Fanzago, Haemaphysalis sulcata Canestrini and Fanzago, Hyalomma marginatum Koch, Ixodes laguri Olenev, Ixodes ricinus (L.), Ixodes vespertilionis Koch and Rhipicephalus turanicus Pomerantzev. To the best of our knowledge, there are several new host records for D. marginatus, H. e. taurica and I. laguri. In addition, I. vespertilionis was recorded for the first time in the Central Anatolian Region in Turkey, whereas I. laguri and H. e. taurica are firstly reported in Sivas. PMID- 25784072 TI - Molecular detection of Rickettsia, Borrelia, and Babesia species in Ixodes ricinus sampled in northeastern, central, and insular areas of Italy. AB - The aim of the present study was to provide insight into the diversity of tick borne pathogens circulating in Italy, carried/transmitted by Ixodes ricinus, one of the most abundant tick species in the country. A total of 447 specimens sampled in five areas of northeastern, central and insular Italy were analysed by polymerase chain reaction and sequencing for the presence of rickettsiae, borreliae and babesiae. Several rickettsial species of the spotted fever group of zoonotic concern and other zoonotic pathogens were found, such as Borrelia burgdorferi s.s., Borrelia afzelii, Borrelia garinii, and Babesia venatorum. These findings confirm a wide distribution of tick-borne bacterial and protozoan species in Italy, and highlight the sanitary importance of I. ricinus, often recorded as feeding on humans. PMID- 25784073 TI - Preparation and evaluation of Baicalin-loaded cationic solid lipid nanoparticles conjugated with OX26 for improved delivery across the BBB. AB - PURPOSE: A novel brain targeting drug delivery system based on OX26 antibody conjugation on PEGylated cationic solid lipid nanoparticles (OX26-PEG-CSLN) was prepared. METHODS: The Baicalin-loaded PEGylated cationic solid lipid nanoparticles modified by OX26 antibody (OX26-PEG-CSLN) were prepared by emulsion evaporation-solidification at low temperature method. The immune-gold labeled OX26-PEG-CSLN was visualized by transmission electron microscopy. The mean diameter and zeta potential of OX26-PEG-CSLN, PEG-CSLN and CSLN were determined using a Zetasizer. The entrapment efficiency of OX26-PEG-CSLN, PEG-CSLN and CSLN was determined by ultrafiltration centrifugation method. And the solid-state characterization of OX26-PEG-CSLN and CSLN were analyzed by X-ray. Pharmacokinetics studies were conducted by in vivo microdialysis in rat cerebrospinal fluid. RESULTS: The results showed that the OX26-PEG-CSLN, PEG-CSLN and CSLN had average diameters of 47.68 +/- 1.65, 27.20 +/- 1.70 and 33.89 +/- 5.74 nm, Zeta potentials of -0.533 +/- 0.115 mV, 11.200 +/- 0.500 mV and 11.080 +/- 1.170 mV and entrapment efficiencies of 83.03 +/- 0.01%, 92.90 +/- 3.50% and 97.83 +/- 0.19%, respectively. In the pharmacokinetics studies, the AUC value of OX26-PEG-CSLN was11.08-fold higher than that of the Baicalin solution (SOL) (p<0.01), and 1.12-fold higher than that of the CSLN (p>0.05); the Cmax value of OX26-PEG-CSLN was 7.88-fold higher than that of SOL (p<0.01) and 1.12-fold (p<0.01) higher than that of the CSLN, respectively. CONCLUSION: These results demonstrated OX26-PEG-CSLN could be a promising carrier to deliver drugs across the BBB for the treatment of brain diseases. PMID- 25784074 TI - Fecal Microbiota in Patients with Irritable Bowel Syndrome Compared with Healthy Controls Using Real-Time Polymerase Chain Reaction: An Evidence of Dysbiosis. AB - BACKGROUND: Dysbiosis may play a role in irritable bowel syndrome (IBS), hitherto an enigmatic disorder. We evaluated selected fecal microbes in IBS patients and healthy controls (HC). METHODS: Fecal 16S rRNA copy number of selected bacteria was studied using qPCR in 47 patients with IBS (Rome III) and 30 HC. RESULTS: Of 47 patients, 20 had constipation (IBS-C), 20 diarrhea (IBS-D), and seven unclassified IBS (IBS-U). Relative difference in 16S rRNA copy number of Bifidobacterium (P = 0.042) was lower, while those of Ruminococcus productus Clostridium coccoides (P = 0.016), Veillonella (P = 0.008), Bacteroides thetaiotamicron (P < 0.001), Pseudomonas aeruginosa (P < 0.001), and Gram negative bacteria (GNB, P = 0.001) were higher among IBS patients than HC. Number of Lactobacillus (P = 0.002) was lower, while that of Bacteroides thetaiotamicron (P < 0.001) and segmented filamentous bacteria (SFB, P < 0.001) was higher among IBS-D than IBS-C. Numbers of Bacteroides thetaiotamicron (P < 0.001), P. aeruginosa (P < 0.001), and GNB (P < 0.01) were higher among IBS-C and IBS-D than HC. Quantity of SFB was higher among IBS-D (P = 0.011) and lower among IBS-C (P = 0.002) than HC. Number of Veillonella species was higher among IBS-C than HC (P = 0.002). P. aeruginosa was frequently detected among IBS than HC (46/47 [97.9 %] vs. 10/30 [33.3 %], P < 0.001). Abdominal distension (n = 34/47) was associated with higher number of Bacteroides thetaiotamicron, Clostridium coccoides, P. aeruginosa, SFB, and GNB; bloating (n = 22/47) was associated with Clostridium coccoides and GNB. Microbial flora was different among IBS than HC on principal component analysis. CONCLUSION: Fecal microbiota was different among IBS than HC, and different sub-types were associated with different microbiota. P. aeruginosa was more frequent and higher in number among IBS patients. PMID- 25784076 TI - 5-year mortality in cardiac surgery patients with low cardiac output syndrome treated with levosimendan: prognostic evaluation of nt-probnp and c-reactive protein. AB - AIM: To determine the clinical risk factors predictive of the 5--year mortality in patients with low cardiac output syndrome (LCOS) after cardiac surgery. In addition, to assess the influence of inflammation and myocardial dysfunction severity, as measured by C--reactive protein (CRP) and N--terminal pro--brain natriuretic peptide (NT--proBNP) concentrations, on outcome. METHODS: We studied 30 patients who underwent cardiac surgery and developed postoperative LCOS requiring inotropic support for longer than 48 hours after intensive care unit (ICU) admission. All patients received a 24--hour infusion of levosimendan after study enrolment. We measured the following at baseline, 24 h, 48 h and 7 days: clinical data, serum NT--proBNP and serum CRP levels. Patients were followed--up at 5 years for death by any cause. A risk--adjusted Cox proportional hazards regression model was used for statistical analysis. Hazard ratios and their 95% confidence intervals (CI) are presented. RESULTS: The 5--year mortality was 36.6% (n = 11). The predictors of 5--year mortality were the presence of dilated cardiomyopathy (HR = 36.909; 95% CI: 1.901-716.747; P = 0.017), a higher central venous pressure (CVP) at 48 hours (HR = 2.686; 95% CI: 1.383-5.214; P = 0.004), and lower CRP levels on day 7 (HR = 0.963; 95% CI: 0.933-0.994; P = 0.021). NT- proBNP levels showed a trend to higher initial levels in survivors without statistical significance, but were not associated with 5--year mortality. CONCLUSIONS: The presence of dilated cardiomyopathy, elevated CVP at 48 h and reduced CRP levels on day 7 predicted 5--year mortality in patients who developed postoperative LCOS after cardiac surgery. NT--proBNP levels in the first postoperative week were not predictors of long--term outcomes. PMID- 25784077 TI - Energy landscape exploration of sub-nanometre copper-silver clusters. AB - The energy landscapes of sub-nanometre bimetallic coinage metal clusters are explored with the Threshold Algorithm coupled with the Birmingham Cluster Genetic Algorithm. Global and energetically low-lying minima along with their permutational isomers are located for the Cu(4)Ag(4) cluster with the Gupta potential and density functional theory (DFT). Statistical tools are employed to map the connectivity of the energy landscape and the growth of structural basins, while the thermodynamics of interconversion are probed, based on probability flows between minima. Asymmetric statistical weights are found for pathways across dividing states between stable geometries, while basin volumes are observed to grow independently of the depth of the minimum. The DFT landscape is found to exhibit significantly more frustration than that of the Gupta potential, including several open, pseudo-planar geometries which are energetically competitive with the global minimum. The differences in local minima and their transition barriers between the two levels of theory indicate the importance of explicit electronic structure for even simple, closed shell clusters. PMID- 25784075 TI - Nonalcoholic Steatohepatitis (NASH) Is Associated with a Decline in Pancreatic Beta Cell (beta-Cell) Function. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) represents a histological spectrum ranging from benign hepatic steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD is closely associated with insulin resistance (IR), and although the role of IR in NAFLD has been an area of intense investigation, there are limited data on pancreatic beta-cell function. AIM: To evaluate the pancreatic beta-cell function in NAFLD using the homeostatic model assessment beta (HOMA-beta) and beta-cell index (BI). METHODS: HOMA-beta was measured in ninety-nine non-diabetic subjects with histologically confirmed NAFLD and compared to lean (age- and gender-matched) and obese (age-, gender-, and BMI matched) controls. Using the values from an oral glucose tolerance test, BI was compared in 31 non-diabetic, non-cirrhotic subjects with NASH and gender- and BMI matched controls. RESULTS: The subjects with NAFLD had higher HOMA-beta compared to both lean and obese controls (43.1 vs. 9 vs. 22.1 %, respectively, P < 0.05). HOMA-beta was directly related to serum alkaline phosphate, total bilirubin, and weight and inversely related to age. There was no difference in HOMA-beta between subjects with NAFL and NASH. Subjects with NASH had lower beta-cell function as measured by a lower BI (2.09 +/- 1.64 vs. 7.74 +/- 25.12; P = 0.04). In patients with NASH, BI was inversely associated with fibrosis independent of age, BMI, and serum ALT levels. In contrast, HOMA-beta was directly associated with fibrosis stage. CONCLUSION: NASH is associated with strained pancreatic beta-cell function in non-diabetic subjects. Future studies are necessary to evaluate the temporal relationship between beta-cell function and hepatic histology. PMID- 25784078 TI - The development of the MIBBO: A measure of resident preferences for physical activity in long term care settings. AB - Offering physical activities matching with the preferences of residents in long term care facilities could increase compliance and contribute to client-centered care. A measure to investigate meaningful activities by using a photo-interview has been developed ("MIBBO"). In two pilot studies including 133 residents living on different wards in long-term care facilities, feasibility, most chosen activities, and consistency of preferences were investigated. It was possible to conduct the MIBBO on average in 30 min with the majority (86.4%) of residents. The most frequently chosen activities were: gymnastics and orchestra (each 28%), preparing a meal (31%), walking (outside, 33%), watering plants (38%), and feeding pets (40%). In a retest one week after the initial interview 69.4% agreement of chosen activities was seen. The MIBBO seems a promising measure to help health care professionals in identifying residents' preferred activities. Future research should focus on the implementation of the tailored activity plan, incorporating it into the daily routine. PMID- 25784080 TI - Caregiver person-centeredness and behavioral symptoms during mealtime interactions: development and feasibility of a coding scheme. AB - Mealtime behavioral symptoms are distressing and frequently interrupt eating for the individual experiencing them and others in the environment. A computer assisted coding scheme was developed to measure caregiver person-centeredness and behavioral symptoms for nursing home residents with dementia during mealtime interactions. The purpose of this pilot study was to determine the feasibility, ease of use, and inter-observer reliability of the coding scheme, and to explore the clinical utility of the coding scheme. Trained observers coded 22 observations. Data collection procedures were acceptable to participants. Overall, the coding scheme proved to be feasible, easy to execute and yielded good to very good inter-observer agreement following observer re-training. The coding scheme captured clinically relevant, modifiable antecedents to mealtime behavioral symptoms, but would be enhanced by the inclusion of measures for resident engagement and consolidation of items for measuring caregiver person centeredness that co-occurred and were difficult for observers to distinguish. PMID- 25784079 TI - Mindfulness meditation in older adults with postherpetic neuralgia: a randomized controlled pilot study. AB - This parallel-group, randomized controlled pilot study examined daily meditation in a diverse sample of older adults with postherpetic neuralgia. Block randomization was used to allocate participants to a treatment group (n = 13) or control group (n = 14). In addition to usual care, the treatment group practiced daily meditation for six weeks. All participants completed questionnaires at enrollment in the study, two weeks later, and six weeks after that, at the study's end. Participants recorded daily pain and fatigue levels in a diary, and treatment participants also noted meditation practice. Results at the 0.10 level indicated improvement in neuropathic, affective, and total pain scores for the treatment group, whereas affective pain worsened for the control group. Participants were able to adhere to the daily diary and meditation requirements in this feasibility pilot study. PMID- 25784081 TI - Health screening assistance--a patient centered approach. PMID- 25784082 TI - Factors that influence physical function and emotional well-being among Medicare Medicaid enrollees. AB - Dually enrolled Medicare-Medicaid older adults are a vulnerable population. We tested House's Conceptual Framework for Understanding Social Inequalities in Health and Aging in Medicare-Medicaid enrollees by examining the extent to which disparities indicators, which included race, age, gender, neighborhood poverty, education, income, exercise (e.g., walking), and physical activity (e.g., housework) influence physical function and emotional well-being. This secondary analysis included 337 Black (31%) and White (69%) older Medicare-Medicaid enrollees. Using path analysis, we determined that race, neighborhood poverty, education, and income did not influence physical function or emotional well being. However, physical activity (e.g., housework) was associated with an increased self-report of physical function and emotional well-being of beta = .23, p < .001; beta = .17, p < .01, respectively. Future studies of factors that influence physical function and emotional well-being in this population should take into account health status indicators such as allostatic load, comorbidity, and perceived racism/discrimination. PMID- 25784083 TI - Financial strain is associated with increased oxidative stress levels: the Women's Health and Aging Studies. AB - Elevated oxidative stress levels may be one mechanism contributing to poor health outcomes. Financial strain and oxidative stress are each predictors of morbidity and mortality, but little research has investigated their relationship. Community dwelling older adults (n = 728) from the Women's Health and Aging Studies I and II were included in this cross-sectional analysis. Financial strain was ascertained as an ordinal response to: "At the end of the month, do you have more than enough money left over, just enough, or not enough?" Oxidative stress was measured using serum protein carbonyl concentrations. Linear regression was used to quantify the relationship between financial strain and oxidative stress. Participants who reported high financial strain exhibited 13.4% higher protein carbonyl concentrations compared to individuals who reported low financial strain (p = 0.002). High financial strain may be associated with increased oxidative stress, suggesting that oxidative stress could mediate associations between financial strain and poor health. PMID- 25784084 TI - Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B. AB - Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and myocardial thinning without a preceding hypertrophic response. This was accompanied by widespread myocardial interstitial fibrosis and myo-sarcomeric disarray. By targeted candidate gene quantitative RT PCR, we discovered an over-activity of cryptic splice sites in the sarcomeric gene Myh7, resulting in a transcript with 8 exons missing. Moreover, a region of differential methylation overlies the splice site locus in the hearts of the cardiac-specific conditional knockout (CKO) mice. Although abundant and complex forms of alternative splice variants have been reported in diseased hearts and the contribution of each remains to be understood in further detail, our results demonstrate for the first time that a link may exist between alternative splicing and the cardiac epigenome. In particular, this gives the novel evidence whereby the loss of an epigenome modifier promotes the development and progression of heart disease. PMID- 25784085 TI - Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy. AB - Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24-48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection. PMID- 25784086 TI - Increasing body mass index identifies Chinese patients with type 2 diabetes mellitus at risk of poor outcomes. AB - AIMS: Association between body mass index (BMI) and glycemic control, comorbidities/complications, and health-related quality of life (HRQoL) was assessed in Chinese patients with type 2 diabetes mellitus (T2DM) enrolled in the Diabetes Disease Specific Programme. METHODS: Surveys of 200 physicians and 2052 patients with T2DM captured demographic, clinical, and HRQoL information. Adjusted and unadjusted analyses were conducted across 3 BMI groups; normal (18.5 <24.0, n=998), overweight (24.0-<28.0, n=822), and obese (>=28.0, n=212). RESULTS: There were no between group differences in the achievement of glycated hemoglobin (HbA1c) <7.0% (48mmol/mol); however, compared with the normal BMI group, more obese patients had an HbA1c >9.0% (75mmol/mol; 4.3% vs 10.2%, P=0.002). More obese patients compared with normal BMI patients had hypertension (48.6% vs 35.3%, P<0.001), dyslipidemia (35.4% vs 18.8%, P<0.001), or both hypertension and dyslipidemia (24.1% vs 13.9%, P<0.001). Patients in the obese group reported worse HRQoL and greater effects of diabetes on their daily living. CONCLUSIONS: Obesity in Chinese patients with T2DM results in poor glycemic control, more comorbidities, and worse HRQoL. Management of these patients should include efforts to reduce weight. Selection of weight-neutral or weight-reducing anti-diabetic medications maybe useful in these patients. PMID- 25784089 TI - Self-reported gagging in dentistry: prevalence, psycho-social correlates and oral health. AB - Although gagging has a profound effect on the delivery of dental care, it is a relatively under-investigated phenomenon. This study aimed to derive a prevalence estimate of gagging during dental treatment based on patient-reported information, to determine some socio-demographic and psychological correlates and to assess the relationship of gagging with self-reported oral health and avoidance of dental care. Data were collected with a survey among Dutch twin families (n = 11 771). Estimated overall prevalence of gagging during dental treatment was 8.2% (95% CI 7.7-8.7). Patients' self-report of gagging was found to be significantly associated with female sex, a lower level of education and higher levels of dental trait anxiety, gagging-related fears (e.g. fear of objects in the mouth), anxious depression and neuroticism. Gagging also appeared to be significantly associated with untreated cavities, gingival bleeding and wearing full dentures, but not with avoidance of dental care. It can be concluded that individuals who report to gag during dental treatment are moderately dentally anxious, fear-specific situations that can trigger a gagging response and, albeit visiting the dentist equally frequently, report to have a poorer oral health compared to those who do not gag. PMID- 25784087 TI - Association of parental history of diabetes with cardiovascular disease risk factors in children with type 2 diabetes. AB - AIMS: Determine if parental diabetes (DM) is associated with unhealthier cardiovascular disease (CVD) risk profiles in youth with type 2 diabetes (T2D), and whether associations differed by race/ethnicity. METHODS: Family history was available for 382 youth with T2D from 2001 prevalent and 2002-2005 incident SEARCH for Diabetes in Youth cohorts. Parental DM was evaluated in two ways: two category-any parent vs. no parent DM (evaluated overall and stratified by race/ethnicity); and four-category-both parents, mother only, father only, or no parent DM (evaluated overall only). Associations with hemoglobin A1c (HbA1c), fasting lipids, blood pressure (BP), and urine albumin:creatinine ratio (ACR) were examined using regression models. RESULTS: Overall, sample characteristics included: 35.9% male, 19.1% non-Hispanic white (NHW), mean T2D duration 26.6+/ 22.2months, mean HbA1c 7.9%+/-2.5% (62.6+/-27.8mmol/mol). Unadjusted two-category comparisons showed that youth with parental DM had higher HbA1c, higher DBP, and higher frequency of elevated ACR. Adjusted two-category comparisons showed associations remaining in non-stratified analysis for ACR [OR (95% CI)=2.3 (1.1, 5.0)] and in NHW youth for HbA1c [6.8%+/-0.4 vs. 8.0+/-0.4 (51.1+/-4.8 vs. 63.9+/ 4.2mmol/mol), p=.015], DBP (67.7%+/-4.5 vs. 76.9+/-4.4mm Hg, p=.014) and lnTG (4.7+/-0.3 vs. 5.3+/-0.3, p=.008). There were no significant findings in the adjusted four-category evaluation. CONCLUSIONS: Parental history of diabetes may be associated with unhealthier CVD risk factors in youth with T2D. PMID- 25784088 TI - Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: a case control study. AB - AIMS: There is inconclusive evidence regarding the potential link between diabetes mellitus (DM) and colorectal cancer (CRC). Associations between type 2 DM and colorectal neoplasia (CRN; colorectal cancer and/or adenomas) have not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM. This study aims to assess the association between type 2 DM and CRN in Hispanics. METHODS: Hispanics with incident CRN and colonoscopy-negative controls from 2005 to 2009 were evaluated. Diagnosis of type 2 DM was established by previous medical diagnosis and/or use of DM treatments. Unconditional logistic regression was performed to estimate odds ratios for the association between type 2 DM and CRN. RESULTS: A total of 451 participants (mean age 61.1+/-11.9years, 59.6 % men) were evaluated (218 with incident CRC, 77 with colorectal adenomas, and 156 colonoscopy-negative controls). The prevalence of type 2 DM in this study was 25.1%. After adjusting for potential confounding variables, women with type 2 DM were 2.74 (95% CI: 0.94-7.99) times more likely to have CRN and 4.83 times more likely to present with proximal colonic CRN (95% CI: 1.25-18.58) than women without type 2 DM. No statistically significant associations were found between type 2 DM and CRN among men. CONCLUSIONS: An increased odds for CRN and proximal location of CRN was observed among Hispanic women with type 2 DM. Since DM is a highly prevalent disease in this population, adherence to routine CRC screening is of outmost importance. PMID- 25784090 TI - Inflammatory Factor Alterations in the Gastrointestinal Tract of Cocks Overexposed to Arsenic Trioxide. AB - Exposure of people and animals to arsenic (As) is a global public health concern because As is widely distributed and associated with numerous adverse effects. As is a poisonous metalloid and arsenic trioxide (As2O3) is a form of As. Thus far, there have been very few reports on the inflammatory factor alterations of the gastrointestinal tract in birds exposed to As2O3. To investigate the possible correlation of As2O3 with inflammatory injury induced by an arsenic-supplemented diet in birds, 72 1-day-old male Hy-line cocks were selected and randomly divided into four groups. They were fed with either a commercial diet or an arsenic supplemented diet containing 7.5, 15, and 30 mg/kg As2O3. The experiment lasted for 90 days, and samples of gizzard, glandular stomach, duodenum, jejunum, ileum, cecum, and rectum were collected at days 30, 60, and 90 of the experiment period. The inflammation-related genes were determined, including NF-kappaB, iNOS, COX-2, PTGEs, and TNF-alpha. The connection between arsenic dosage and inflammation related genes was assessed. The content of inducible NO synthase (iNOS) was measured by Western blot of the samples. The results showed that arsenic supplementation increased the mRNA expression levels of inflammation-related genes in the gastrointestinal tract of cocks at different time points (p < 0.05). Moreover, the expression of the tissue and organ injury-related gene iNOS was upregulated (p < 0.05). These data suggest that As induces the inflammatory response and may trigger digestive function regression of the gastrointestinal tract by affecting inflammation-related genes and iNOS in cocks. This study offers some information on the mechanism of gastrointestinal tract inflammatory injury and iNOS expression level alterations induced by arseniasis. PMID- 25784091 TI - Controlled formation of fluorescent metalloporphyrin-containing coordination polymer particles from seed structures by designed shape-transformation reactions. AB - Herein, nanorod structures and four-leaf clover structures of fluorescent zinc 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine (ZnTPyP)-containing coordination polymer particles (CPPs) were first synthesized by a bottom-up strategy assisted by surfactants and then employed as seed structures for further shape transformation reactions. We have successfully designed the morphological transformation for different dimensions, achieving the controlled formation of octahedron structures at both the nanometer scale and micrometer scale from the seed structures. Our approach illustrates a new method to design and synthesize metalloporphyrin-containing CPPs in a systematic and controllable manner. PMID- 25784092 TI - Acute generalized exanthematous pustulosis by azithromycin. PMID- 25784093 TI - Induction of T regulatory subsets from naive CD4+ T cells after exposure to breast cancer adipose derived stem cells. AB - BACKGROUND: Adipose derived stem cells (ASCs) provoke the accumulation and expansion of regulatory T cells, leading to the modulation of immune responses in tumor microenvironment. OBJECTIVE: To assess the effect of tumoral ASCs on the trend of regulatory T cells differentiation. METHODS: Peripheral blood naive CD4+ T cells were co-cultured with ASCs derived from breast cancer or normal breast tissues. In separate cultures peripheral blood naive CD4+ T cells were exposed to the culture supernatants of ASCs. RESULTS: Generation of CD4+CD25+Foxp3+ and CD4+CD25-Foxp3+ Treg subsets was observed after coculture of naive CD4+ T cell with either ASCs or the related supernatant. The percentage of CD4+CD25+Foxp3+ cells increased after exposing naive CD4+ T cells to both ASCs and their supernatants while augmentation of CD4+CD25-Foxp3+ subset mostly depended on the presence of ASCs. Similarly, upregulation of FoxP3 molecule was more significant in condition of cell to cell contact. IL-4 and IL-10 were up-regulated in the cocultured naive CD4+ T cells after exposure to ASCs/supernatant while IFN-gamma was down-regulated in the presence of ASCs. CONCLUSION: ASC may act as one of the major players in tumor site with immunomodulatory effects, which may mostly be carried out through direct cell-cell interaction. PMID- 25784094 TI - CD26+ Cord Blood Mononuclear Cells Significantly Produce B, T, and NK Cells. AB - BACKGROUND: Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cell transplantation (HSCT), used in Leukemia treatment. CD26+ cells, a fraction of CD34+cells, are a major population of UCB cells which negatively regulate the in vivo homing and engraftment of HSCs. CD26 is highly expressed in various cells such as HSCs, immune cells, fibroblasts, and epithelial cells. It has been shown that the inhibition of the CD26 on CD34+ cells improves the efficiency of Hematopoietic Stem and Progenitor Cell (HPC) transplantation. OBJECTIVE: To evaluate the relationship between the production of B, T, and NK cells from the CD26+ fraction of cord blood mononuclear cells. METHODS: Cord blood mononuclear cells were cultured for 21 days using different combinations of stem cell factors (SCF), Flt3 ligand (FL), IL-2, IL-7, and IL-15. The harvested cells were then analyzed by flowcytometry every week for 21 days. RESULTS: T cell differentiation from CD26 subset of cord blood mononuclear cells increased by using IL-2 and IL-7. Our data showed that IL-2 and IL-7 significantly affected the generation of B cells from CD26 positive cord blood mononuclear cells. On the other hand, NK (NKp46+) derived CD26+ cells increased by IL-15 and IL-2. CONCLUSION: Taking all into account, we conclude that B, T, and NK cells can differentiate from the CD26+ subset of mononuclear cord blood cells by using key regulatory cytokines. PMID- 25784095 TI - Symptomatic Reactivation of HSV Infection Correlates with Decreased Serum Levels of TNF-alpha. AB - BACKGROUND: Herpes simplex viruses (HSV) are human pathogens that establish lytic and latent infections. Reactivation from latency occurs intermittently, which represents a life-long source for recurrent infection. The role of immune factors in the control of recurrent symptomatic HSV lesions is complex and the exact role of cytokines remains unclear. OBJECTIVE: To assess the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) along with anti-herpetic IgG and IgM, in the symptomatic reactivation of HSV infection. METHODS: Thirty-six patients with recurrent symptomatic herpes infection were selected as the study group and thirty-two healthy individuals with no history of symptomatic labial herpes infection enrolled as the control group. Skin swabs were obtained from lip and skin lesions for viral culture. Confirmation of HSV cytopathic effect was carried out using PCR assay. The levels of TNF-alpha, IL-10, IgG and IgM were measured using ELISA. RESULTS: The level of TNF-alpha was significantly lower in individuals with recurrent symptomatic herpes infection in comparison with the controls (p=0.04). Also a significant elevation was observed in the levels of specific IgG in patients compared to controls (p<0.05). CONCLUSION: The decreased level of TNF-alpha and increased levels of IgG in individuals with a history of symptomatic reactivation of HSV infection is suggestive of a probable shift in favor of the Th2 immune response. PMID- 25784096 TI - Vitamin D Modulates the Expression of IL-27 and IL-33 in the Central Nervous System in Experimental Autoimmune Encephalomyelitis (EAE). AB - BACKGROUND: It has been reported that vitamin D has broad anti-inflammatory and immunomodulatory effects. OBJECTIVE: To evaluate the effects of vitamin D on the expression of IL-27 and IL-33 in a model of experimental autoimmune encephalomyelitis (EAE). METHODS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein mixed with complete Freund's adjuvant. The mice were administered with PBS or olive oil, intraperitoneally, in the control groups and vitamin D (200 ng every two days) in the treatment group, from day +3 to +30. At day 31, the mice were scarified and their spinal cords and brains were harvested. The expression of the IL-27 and IL-33 mRNA in the spinal cord was measured using real time-PCR. RESULTS: In PBS- or olive oil-treated EAE mice the expression of IL-27 P28 mRNA was significantly lower than that in the healthy control group (p<0.002). In both PBS- and olive oil-treated EAE groups, the expression of IL-27 EBI3 mRNA was also lower than that observed in the healthy group, but the differences were not significant. In vitamin D-treated EAE group, the expression of IL-27 P28 and IL-27 EBI3 were significantly higher compared with the olive oil-treated EAE groups (p<0.002 and p<0.04, respectively). The expression of IL-33 was significantly higher in PBS-or olive oil-treated EAE groups compared with healthy mice (p<0.05 and p<0.02, respectively). Vitamin D significantly decreased the expression of IL-33 compared with PBS- or olive oil-treated EAE mice (p<0.04, p<0.02, respectively). The PBS- or olive oil -treated EAE mice showed the clinical symptoms of EAE at days 9 and 10, respectively. The vitamin D-treated EAE group exhibited the symptoms at day 12 post immunization. The maximum mean clinical score and mean pathological scores were also significantly lower in vitamin D-treated EAE group, in comparison with PBS- or olive oil treated EAE mice (p<0.001). CONCLUSION: Vitamin D may modulate the expression of IL-27 and IL-33 in the spinal cord of EAE mice and also ameliorate the clinical symptoms of the disease. PMID- 25784097 TI - Antigenic profile of muscularis mucosae and muscularis propria of the urinary bladder. AB - BACKGROUND: Differentiation between the muscularis mucosae (MM) and muscularis propria (MP) of the bladder remains challenging. OBJECTIVE: To identify MM- and MP-specific antigens that could be of potential value for staging of urothelial carcinoma in a pilot study. METHOD: The expression of 12 protein antigens in 11 human bladder specimens was examined. There were 5 post radical cystectomy specimens and 6 normal bladder autopsy specimens. Antibodies against actin, caldesmon, type IV collagen, cytokeratin, desmin, elastin, fibronectin, filamin, laminin, miotilin, smoothelin, and vimentin were used. Slides were stained with immunohistochemical reagents and assessed using light microscopy. The intensity of the immune reaction within MM and MP was evaluated in a four-level scale as negative and weakly, moderately or strongly positive. RESULTS: The presence of MM was noticed in 63.6% of specimens. The expression of desmin, filamin, and smoothelin was stronger within MP compared to MM in all cases. Stronger reaction with anti-type IV collagen antibodies was noticed within MP in 80% of the cases. In the whole study group, the expression of vimentin was stronger within MM than MP. CONCLUSIONS: MM and MP cells are of different antigenic characteristics. This can be used in the microscopic diagnostics of selected cases. The results need to be validated in a series of specimens from transurethral resection. PMID- 25784098 TI - Adverse Effect of T-2 Toxin and the Protective Role of Selenium and Vitamin E on Peripheral Blood B lymphocytes. AB - BACKGROUND: T-2 mycotoxin belongs to the Trichothecene family and has damaging effects on the immune system. OBJECTIVE: To investigate the toxic effect of T-2 toxin on the percentage of peripheral blood B lymphocytes and the potential protective role of selenium and vitamin E. METHOD: Frequencies of B lymphocytes (CD19+) were analyzed after injection of sublethal doses of T-2 toxin into Balb/c mice at different time points, using flowcytometry. Additionally, the effects of selenium and vitamin E on B lymphocyte, as either prophylaxis or simultaneously administered with T-2 toxin, were investigated. RESULTS: After injection of a sublethal dose of T-2 toxin, the number of B cells (CD19+) significantly decreased at 12 h and became normal at 72 h. When selenium was injected both 24 h before and simultaneously with T-2 toxin, it was able to inhibit B lymphocyte (CD19+) reduction. In contrast, injecting vitamin E, 24 h before or simultaneously with T-2 toxin did not regulate B lymphocyte alteration. CONCLUSION: Selenium plays pivotal role on altered B lymphocyte subset induced by T-2 toxin comparing to vitamin E. PMID- 25784099 TI - Disseminated Bacillus Calmette-Guerin Disease after BCG Vaccination: A Case Report from China. PMID- 25784100 TI - Simultaneous Detection of IgA/IgG Anti-Tissue Transglutaminase/Deamidated Gliadin Peptides in Serodiagnosis of Celiac Disease. PMID- 25784102 TI - Minimally invasive procedure for axillary osmidrosis. PMID- 25784101 TI - The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. AB - Beyond the well-defined role of the Eph (erythropoietin-producing hepatocellular) receptor tyrosine kinases in developmental processes, cell motility, cell trafficking/adhesion, and cancer, nothing is known about their involvement in liver pathologies. During blood-stage rodent malaria infection we have found that EphB2 transcripts and proteins were up-regulated in the liver, a result likely driven by elevated surface expression on immune cells including macrophages. This was significant for malaria pathogenesis because EphB2(-/-) mice were protected from malaria-induced liver fibrosis despite having a similar liver parasite burden compared with littermate control mice. This protection was correlated with a defect in the inflammatory potential of hepatocytes from EphB2(-/-) mice resulting in a reduction in adhesion molecules, chemokine/chemokine receptor RNA levels, and infiltration of leukocytes including macrophages/Kupffer cells, which mediate liver fibrosis during rodent malaria infections. These observations are recapitulated in the well-established carbon tetrachloride model of liver fibrosis in which EphB2(-/-) carbon tetrachloride-treated mice showed a significant reduction of liver fibrosis compared to carbon tetrachloride-treated littermate mice. Depletion of macrophages by clodronate-liposomes abrogates liver EphB2 messenger RNA and protein up-regulation and fibrosis in malaria-infected mice. CONCLUSION: During rodent malaria, EphB2 expression promotes malaria associated liver fibrosis; to our knowledge, our data are the first to implicate the EphB family of receptor tyrosine kinases in liver fibrosis or in the pathogenesis of malaria infection. PMID- 25784103 TI - Long-term changes in nipple-areolar complex position and inferior pole length in superomedial pedicle inverted 't' scar reduction mammaplasty. AB - BACKGROUND: Proper nipple-areolar complex position in reduction mammoplasty patients is a challenging problem regardless of the preferred technique. Postoperatively, the nipple-areolar complex is often not located at the most projected area of the breast. This retrospective observational study aimed to find the long-term measurements of the nipple-areolar complex position and inferior pole length after inverted T scar-superomedial pedicle reduction mammoplasty. METHODS: Forty-eight female patients (96 breasts) were included in this study. The inclusion criteria were that no previous operation should have been done on any of the breasts and both NAC complexes should be at least 30 cm from the midclavicular point. Preoperatively, the distance from the midclavicular point to the new nipple was recorded. All patients were operated on with the inverted T pattern and superomedial pedicle technique. The resection weights, the distance from the midclavicular point to the nipple distance, and the distance from the NAC lower border to the inframammary fold were evaluated postoperatively with an average of 15-month follow-up. RESULTS: The mean preoperative distance from the midclavicular point to the nipple was 34.21 cm for the right breast and 34.26 cm for the left breast. The mean resection weight per breast was 1035 g for the right breast and 1081 g for the left breast. The descent of the NAC was 1.61 cm for the right breast and 1.79 cm for left breast (mean: 1.7 cm) at the end of the follow-up. Additionally, the inframammary length increased 3.31 cm for the right breast and 3.59 cm for the left breast (mean: 3.45 cm). CONCLUSION: In this study, we found that the new nipple-areolar complex does not go upward but goes downward. However, it was not located at the most projected area of the breast as it was set intra-operatively. This was because the lower pole of the breast sagged more than the nipple: clinically, we observed a nipple superior displacement of 1.75 cm (3.45 - 1.7 = 1.75). According to this calculation, we believe that the new nipple position should be marked at 1.5-1.75 cm below the most projected area of the breast after final shaping so that in the long term, the nipple-areolar complex would be at the proper position. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25784105 TI - Anthocyanin-rich extract from Hibiscus sabdariffa calyx counteracts UVC-caused impairments in rats. AB - CONTEXT: Ultraviolet radiation (UV) was reported to cause oxidative stress. Hibiscus sabdariffa L. (Malvaceae) calyx is commonly used in traditional Asian and African medicines and possesses strong antioxidant capacity due to its anthocyanin (ANTH) content. OBJECTIVE: This study researched the possible protective role of Hibiscus sabdariffa calyx extract (HSCE) in UVC exposure of rats. MATERIAL AND METHODS: Levels of serum enzymes, renal function tests, and some oxidant/antioxidant biomarkers of skin, lens, and retina tissues were monitored. Rats were exposed to UVC 4 h daily for 40 d and simultaneously received HSCE containing 2.5, 5, and 10 mg doses of ANTH in drinking water. RESULTS: Significant (p < 0.05) increases in the levels of serum aminotransferases, lactate dehydrogenase, urea, creatinine, and uric acid were noted after UVC exposure. In skin, lens, and retina tissues, total oxidant status, oxidative stress index, lipid peroxidation, and protein oxidation escalated markedly (p < 0.05) whereas total antioxidant status, reduced glutathione, and superoxide dismutase decreased dramatically (p < 0.05) related to UVC. Co-administration of HSCE with each ANTH dose significantly (p < 0.05) reversed aforementioned parameters (except total oxidant status) almost in all tissues. The LD50 of HSCE in rats was determined to be above 5000 mg/kg. DISCUSSION AND CONCLUSION: Our data revealed that HSCE has a remarkable potential to counteract UVC-caused impairments, probably through its antioxidant and free radical-defusing effects. Therefore, HSCE could be useful against some cutaneous and ocular diseases in which UV and oxidative stress have a role in the etiopathogenesis. PMID- 25784106 TI - Update on pneumatic retinopexy. AB - PURPOSE OF REVIEW: Pneumatic retinopexy is an effective, cost-efficient procedure for retinal detachment repair. We review the history, indications, procedure, outcomes, economics, and trends regarding this in-office procedure. RECENT FINDINGS: Pneumatic retinopexy is classically performed in patients with small, superior retinal breaks, but these indications are expanding, with good results. Retinal reattachment rates with pneumatic retinopexy vary from 60% to 91% depending upon patient selection. Pneumatic retinopexy is less costly to perform than scleral buckling and pars plana vitrectomy and avoids many of the complications associated with these procedures. Despite these good results, recent data suggest that the use of pneumatic retinopexy is on the decline. SUMMARY: Recent review of the literature and our own personal experience using pneumatic retinopexy in selected cases of retinal detachment indicate that it is an effective and inexpensive procedure that avoids many of the complications that are associated with other retinal reattachment procedures. PMID- 25784107 TI - Vitrectomy for vitreous floaters: analysis of the benefits and risks. AB - PURPOSE OF REVIEW: To review the pros and cons of small-gauge vitrectomy for symptomatic floaters. RECENT FINDINGS: Current treatment options for floaters include Nd:YAG vitreolysis and pars plana vitrectomy. There are risks and benefits associated with vitrectomy for floaters. However, small-gauge vitrectomy is a minimally invasive way of removing the floaters. The current literature demonstrates vitrectomy has some risk, but is highly effective at improving vision, symptoms, contrast sensitivity, and quality of life. SUMMARY: Small-gauge vitrectomy for floaters is a well tolerated and effective procedure to remove the symptomatic floaters. Symptomatic patients are willing to take some risk to have their troublesome vitreous floaters removed, often resulting in an improvement in their vision and quality of life. PMID- 25784108 TI - Clinical management of vitreomacular traction. AB - PURPOSE OF REVIEW: To describe recent evidence regarding the clinical management of vitreomacular traction (VMT). RECENT FINDINGS: Recent studies have reported favorable outcomes in patients with VMT managed with observation, pharmacologic vitreolysis with ocriplasmin, and intravitreal perfluoropropane gas. Subgroup analysis has identified features associated with spontaneous release of VMT as well as features associated with successful pharmacologic release of VMT with ocriplasmin. SUMMARY: Observation may be an appropriate initial recommendation for patients with mild VMT. When treatment is necessary, pharmacologic vitreolysis with ocriplasmin is an effective nonsurgical therapeutic option. Careful patient selection improves success rates with ocriplasmin. Further study is necessary to establish the efficacy of intravitreal perfluoropropane gas for VMT as well as the efficacy of ocriplasmin in patients with VMT and concurrent retinal disease. As these treatments are more widely used, prospective data will continue to clarify their risk/benefit profile. PMID- 25784109 TI - Ambulatory 24-h intraocular pressure monitoring in the management of glaucoma. AB - PURPOSE OF REVIEW: To review current status and future of ambulatory 24-h intraocular pressure monitoring. Despite important advances in the diagnosis and management of glaucoma during the last decade, the fundamental understanding of intraocular pressure, its only modifiable risk factor, remains elusive. The current practice of single intraocular pressure measurements during a clinic visit does not adequately reflect the variability of intraocular pressure throughout the 24-h day. RECENT FINDINGS: There has been considerable progress recently with the prototype and commercial introduction of continuous 24-h intraocular pressure monitoring devices. Implantable intraocular pressure sensors have the advantage to directly measure intraocular pressure over many months and years, whereas temporary (contact lens based) approaches provide a noninvasive alternative for repeated 24-h periods. This review provides an overview of implantable devices as well as a critical assessment of a 24-h contact lens sensor. SUMMARY: Recent advances in microelectromechanical systems and nanoelectromechanical systems have enabled the development of 24-h intraocular pressure monitoring devices. Once these technologies have shown their safety and efficacy, larger questions as to the data interpretation and handling will arise. It is likely that the use of 24-h intraocular pressure monitoring will herald fundamental changes in our understanding and management of glaucoma. PMID- 25784110 TI - Current and future applications of corneal cross-linking. AB - PURPOSE OF REVIEW: To review current concepts and future directions of corneal cross-linking (CXL) as a treatment for keratoconus, ectasia after refractive surgery and infectious keratitis. RECENT FINDINGS: Several important laboratory and clinical studies have established the safety and success of corneal cross linking for the treatment of keratoconus and other corneal ectasias. Recently, additional studies have analyzed new directions and controversies in corneal cross-linking, exploring new indications, comparing new techniques and analyzing results of new protocols. SUMMARY: The results of bench and clinical research are providing the foundation to allow for protocol modifications of the standard cross-linking protocols and expansion of cross-linking concepts for techniques such as accelerated cross-linking, epithelium-sparing protocols and measurement of progression and success. PMID- 25784111 TI - What have we learnt about the management of diabetic macular edema in the antivascular endothelial growth factor and corticosteroid era? AB - PURPOSE OF REVIEW: To summarize the outcomes of the use of antivascular endothelial growth factor (anti-VEGF) agents and corticosteroids on the treatment paradigm for diabetic macular edema (DME). RECENT FINDINGS: Favorable efficacy data along with acceptable long-term safety results of anti-VEGF agents have made them the standard first-line therapy in the management of DME. Level I evidence from large, multicenter clinical trials has established the beneficial role of anti-VEGF agents and intravitreal steroids. In addition, the role of anti-VEGF agents in the treatment of diabetic retinopathy has also been recently recognized. However, concerns such as suboptimal response, VEGF resistance, and long-term effects on retinal layers and vasculature have also been highlighted recently. SUMMARY: The use of anti-VEGF agents and corticosteroids has revolutionized the management of DME. Despite the advantages including ease of administration, low incidence of adverse events, and concomitant improvement in retinopathy status, limitations of this therapeutic approach have been recognized. The current review will focus on the lessons learnt in the management of DME in the anti-VEGF and steroid era. PMID- 25784112 TI - Introduction to microperimetry and its use in analysis of geographic atrophy in age-related macular degeneration. AB - PURPOSE OF REVIEW: This article discusses recent advances in the fundus-guided perimetry (microperimetry) and its utilization in evaluation and monitoring of patients with geographic atrophy. RECENT FINDINGS: Although best-corrected visual acuity has been gold standard in clinical practice for decades, it does not provide an entire assessment of visual function that determines daily activity and quality of life of a patient. Furthermore, psychophysical tests, including low-luminance visual acuity, reading speed, and contrast sensitivity, cannot be used to quantify retinal sensitivity or detect pattern of retinal dysfunction. Microperimetry provides a true evaluation of visual function by offering fundus controlled testing through eye-tracking technology that allows for structural and functional correlation and test-retest reliability for the same test point. Furthermore, it enables precise assessment of location and stability of fixation. Recent research has shown microperimetry to be more representative of the macular function in macular diseases. SUMMARY: Microperimetry is currently the clinical investigation of choice to assess residual visual functions and functional vision in macular degenerative diseases, especially geographic atrophy. There is an increasing popularity to employ microperimetry in clinical trials investigating new treatments for geographic atrophy, as well as other macular degenerative diseases, as a reliable functional outcome measure. PMID- 25784128 TI - Aberrant T-cell antigen expression in Jordanian children with B lymphoblastic leukemia. PMID- 25784113 TI - Clinically significant association between the maximum standardized uptake value on 18F-FDG PET and expression of phosphorylated Akt and S6 kinase for prediction of the biological characteristics of renal cell cancer. AB - BACKGROUND: The relationship between the clinicopathological features and molecular changes associated with standardized uptake value (SUV) determined by Positron emission tomography (PET) with [18F] fluorodeoxyglucose (18F-FDG PET) in human renal cell carcinoma (RCC) has not been elucidated. On the other hand, overactivation of the phosphatidylinositol 3'kinase (PI3K), serine/threonine kinase Akt, and mammalian target of rapamycin (mTOR) pathway has been detected in a variety of human cancers, including RCC. So far, little is known about the relationship between the SUV and these proteins in human RCC. Thus, it is important to study the relevance of SUV with clinicopathological features in human RCCs from a molecular point of view. METHODS: Seventy-seven consecutive patients with RCC who underwent nephrectomy and pretreatment determination of the maximum SUV (SUVmax) by 18F-FDG PET were analyzed. We investigated the relationship between the SUVmax, phosphorylated-Akt (Ser-473) (pAkt(Ser-473)), phosphorylated-Akt (Thr-308) (pAkt(Thr-308), and phosphorylated-S6 ribosomal protein (Ser-235/236) (pS6) protein levels in the primary tumor and various clinicopathological features. RESULTS: The average SUVmax of the primary tumor was 6.9 (1.5 to 40.3). A higher SUVmax was correlated with higher expression of pAkt(Ser-473), pAkt (Thr-308), and pS6 protein in the primary tumor. A higher SUVmax and increased expression of pAkt (Ser-473), pAkt (Thr-308), and pS6 of the primary tumor was associated with less tumor differentiation, a higher pT stage, regional lymph node involvement, microscopic vascular invasion, and distant metastasis, as well as with early relapse following radical nephrectomy in patients who had localized or locally advanced RCC without distant metastasis (cTanyNanyM0) and with shorter overall survival in all patients. CONCLUSIONS: A higher SUVmax on 18F-FDG PET is associated with elevated tumor levels of pAkt and pS6 protein and with aggressive behavior and metastatic potential of RCC, as well as with early relapse following radical nephrectomy and shorter overall survival. These findings suggest that SUVmax may be useful for predicting the biological characteristics of RCC. PMID- 25784129 TI - Ocular metastasis of colorectal cancer: An uncommon presentation of a common malignancy. AB - Approximately 20% of patients with colorectal cancer have metastatic disease at time of diagnosis, and another 25-35% develop metastases during the course of their disease. Liver, peritoneum, and lungs are the most common sites of metastases. We report the case of a 60-year-old female who presented with ocular metastasis 4 years after her initial curative-intent treatment for T3N1M0 rectal adenocarcinoma. After local eye radiation therapy, she received palliative systemic chemotherapy and enjoyed a good quality of life for 32 months before succumbing to progressive disease. Ocular metastasis of colorectal cancer is rare. When present, it usually occurs in the setting of diffuse hematogenous spread. In addition to local therapy, systemic chemotherapy should also be considered. PMID- 25784130 TI - Discovery and validation of plasma biomarkers for major depressive disorder classification based on liquid chromatography-mass spectrometry. AB - Major depressive disorder (MDD) is a debilitating mental disease with a pronounced impact on the quality of life of many people; however, it is still difficult to diagnose MDD accurately. In this study, a nontargeted metabolomics approach based on ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to find the differential metabolites in plasma samples from patients with MDD and healthy controls. Furthermore, a validation analysis focusing on the differential metabolites was performed in another batch of samples using a targeted approach based on the dynamic multiple reactions monitoring method. Levels of acyl carnitines, ether lipids, and tryptophan pronouncedly decreased, whereas LPCs, LPEs, and PEs markedly increased in MDD subjects as compared with the healthy controls. Disturbed pathways, mainly located in acyl carnitine metabolism, lipid metabolism, and tryptophan metabolism, were clearly brought to light in MDD subjects. The binary logistic regression result showed that carnitine C10:1, PE-O 36:5, LPE 18:1 sn-2, and tryptophan can be used as a combinational biomarker to distinguish not only moderate but also severe MDD from healthy control with good sensitivity and specificity. Our findings, on one hand, provide critical insight into the pathological mechanism of MDD and, on the other hand, supply a combinational biomarker to aid the diagnosis of MDD in clinical usage. PMID- 25784131 TI - [Liver volume, intrahepatic fat and body weight in the course of a lifestyle interventional study: Analysis with quantitative MR-based methods]. AB - OBJECTIVES: The aim of this study was to investigate potential associations between changes in liver volume, the amount of intrahepatic lipids (IHL) and body weight during lifestyle interventions. MATERIAL AND METHODS: In a prospective study 150 patients with an increased risk for developing type 2 diabetes mellitus were included who followed a caloric restriction diet for 6 months. In the retrospective analysis 18 women and 9 men (age range 22-71 years) with an average body mass index (BMI) of 32 kg/m(2) were enrolled. The liver volume was determined at the beginning and after 6 months by three-dimensional magnetic resonance imaging (3D-MRI, echo gradient, opposed-phase) and IHLs were quantified by volume-selective MR spectroscopy in single voxel stimulated echo acquisition mode (STEAM). Univariable and multivariable correlation analyses between changes of liver volume (Deltaliver volume), intrahepatic lipids (DeltaIHL) and body weight (DeltaBW) were performed. RESULTS: Univariable correlation analysis in the whole study cohort showed associations between DeltaIHL and DeltaBW (r = 0.69; p < 0.0001), DeltaIHL and Deltaliver volume (r = 0.66; p = 0.0002) as well as DeltaBW and Deltaliver volume (r = 0.5; p = 0.0073). Multivariable correlation analysis revealed that changes of liver volume are primarily determined by changes in IHL independent of changes in body weight (beta = 0.0272; 95% CI: 0.0155-0.034; p < 0.0001). CONCLUSION: Changes of liver volume during lifestyle interventions are independent of changes of body weight primarily determined by changes of IHL. These results show the reversibility of augmented liver volume in steatosis if it is possible to reduce IHLs during lifestyle interventions. PMID- 25784132 TI - [Inflammatory spinal disease: Spondyloarthritis: Importance of imaging]. AB - Conventional radiography of the pelvis and lumbar spine is the method of choice for the initial evaluation of spondyloarthritis (SpA). Sacroiliitis is classified according to the modified New York grading criteria; however, to improve the early diagnosis of SpA, magnetic resonance imaging (MRI) should be performed as MRI enables the detection of early inflammation, such as subchondral bone marrow edema of the sacroiliac joints (SIJ), which defines sacroiliitis. Sacroiliitis and HLA-B27 are considered to be equivalent criteria for the diagnosis of SpA. In equivocal findings in the SIJ, an evaluation of the whole spine might be helpful because involvement of the thoracic and lumbar spine, shiny corner sign (Romanus lesions) and spondylodiscitis (Andersson lesions), as well as inflammation of the pedicles, zygoapophyseal joints and longitudinal ligaments, are typical findings in SpA. The prevalence of seronegative SpA is higher than has been previously assumed. Imaging in SpA plays an important role in selecting patients with inflammatory back pain and thus, helping to prevent irreversible changes through adequate early treatment. PMID- 25784134 TI - Isoprenoids and phenylpropanoids are part of the antioxidant defense orchestrated daily by drought-stressed Platanus * acerifolia plants during Mediterranean summers. AB - The hypothesis was tested that isoprenoids and phenylpropanoids play a prominent role in countering photooxidative stress, following the depletion of antioxidant enzyme activity in plants exposed to severe drought stress under high solar irradiance and high temperatures. Platanus * acerifolia, a high isoprene-emitting species, was drought-stressed during summer (WS) and compared with unstressed controls (WW). Water relations and photosynthetic parameters were measured under mild, moderate, and severe drought stress conditions. Volatile and nonvolatile isoprenoids, antioxidant enzymes, and phenylpropanoids were measured with the same time course, but in four different periods of the day. Drought severely inhibited photosynthesis, whereas it did not markedly affect the photochemical machinery. Isoprene emission and zeaxanthin concentration were higher in WS than in WW leaves, particularly at mild and moderate stresses, and during the hottest hours of the day. The activities of catalase and ascorbate peroxidase steeply declined during the day, while the activity of guaiacol peroxidase and the concentration of quercetin increased during the day, peaking in the hottest hours in both WW and WS plants. Our experiment reveals a sequence of antioxidants that were used daily by plants to orchestrate defense against oxidative stress induced by drought and associated high light and high temperature. Secondary metabolites seem valuable complements of antioxidant enzymes to counter oxidative stress during the hottest daily hours. PMID- 25784135 TI - Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta analysis of observational studies. AB - INTRODUCTION: Natural anticoagulants deficiency (antithrombin [AT], protein C [PC], protein S [PS]) is a rare, but potent risk factor for venous thromboembolism (VTE). We performed a meta-analysis of observational studies evaluating the impact of inherited natural anticoagulants deficiency on VTE risk. MATERIALS AND METHODS: Case-control and cohort studies evaluating the association of these abnormalities with VTE were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS: Twenty-one studies were included in the analysis. Thirteen studies (3,452 cases and 11,562 controls) showed an increased risk of first VTE in AT deficient subjects compared to controls (OR: 16.26, 95%CI:9.90-26.70; P<0.00001). An increased risk of first VTE was also found in PC (11 studies, 2,554 cases and 9,355 controls; OR: 7.51, 95%CI:3.21-17.52; P<0.00001) and PS deficient patients (14 studies, 4,955 cases and 9,267 controls; OR: 5.37; 95%CI:2.70-10.67; P<0.00001) compared to controls. Evaluating the risk of VTE recurrence, we found a significant association with AT (4 studies, 142 cases and 1,927 controls; OR: 3.61; 95%CI:1.46-8.95; P=0.006) and with PC (2 studies, 80 cases and 546 controls; OR: 2.94; 95%CI:1.43-6.04; P=0.03), but not with PS deficiency (2 studies, 57 cases and 589 controls; OR: 2.52; 95%CI:0.89-7.16; P=0.08). Sensitivity and subgroup analyses confirmed these results. The association among natural anticoagulants deficiency and VTE was maximal for patients with unprovoked events. CONCLUSION: The VTE risk is increased in patients with natural anticoagulants deficiency, but additional studies are warranted to better assess the risk of VTE recurrence. PMID- 25784136 TI - The usefulness of antithrombin activity monitoring during antithrombin supplementation in patients with sepsis-associated disseminated intravascular coagulation. AB - INTRODUCTION: Recent studies have repeatedly reported the effectiveness of antithrombin (AT) supplementation for sepsis-associated disseminated intravascular coagulation (DIC). In this study, we intended to elucidate the usefulness of monitoring antithrombin activity during antithrombin supplementation. METHODS: Data of 926 patients with sepsis-associated DIC who had been undergone AT substitution were retrospectively analyzed. All the patients had received 1500IU/day of AT concentrate for three consecutive days. The patients' demographic characteristics, including the age, body weight, baseline DIC score and baseline AT activity, and treatment-related markers such as the change in DIC score and the change in the AT activity with treatment were analyzed in relation to the 28-day mortality. RESULTS: Logistic regression analysis revealed a significant association of the patients' age, baseline AT activity, Delta AT activity, baseline DIC score and Delta DIC score to the patients' outcomes. The cutoff values of the AT activities for death calculated by the ROC curve analysis were 41.3% for the baseline AT activity, 72.9% for the post-treatment AT activity and 37.0% for Delta AT activity. The area under the ROC curve (AUC) showed discriminative powers for the baseline AT activity, post treatment AT activity and Delta AT activity of 0.58, 0.69 and 0.66, respectively. CONCLUSIONS: Monitoring of the AT activity is useful to predict the patients' outcome. Furthermore, the measurement of baseline AT activity may help in determining the appropriate dose for AT supplementation. PMID- 25784137 TI - Multimodality Imaging in Cardiac Sarcoidosis: Is There a Winner? AB - Sarcoidosis is a multisystem granulomatous disease of unknown cause that can affect the heart. Cardiac sarcoidosis may be present in as many as 25% of patients with systemic sarcoidosis, and it is frequently underdiagnosed. The early and accurate diagnosis of myocardial involvement is challenging. Advanced imaging techniques play important roles in the diagnosis and management of patients with cardiac sarcoidosis. PMID- 25784138 TI - Development and Impact of De Novo Anti-HLA Antibodies in Pediatric Heart Transplant Recipients. AB - There is increasing evidence that de novo anti-HLA antibodies, more specifically de novo donor-specific antibodies (DSA) following solid organ transplantation may be associated with negative outcomes including rejection in the first year and graft loss. Limited data are available in pediatric heart transplant recipients. We sought to prospectively determine the incidence, class and early impact of de novo anti-HLA antibodies in a cohort of pediatric heart transplant recipients. Serial panel reactive antibody testing posttransplant was performed in 25 patients (14 males) transplanted between January 2008 and June 2010. Five patients were sensitized pretransplant; all patients had negative direct crossmatch. Seventy-two percent developed de novo anti-HLA antibodies at a median of 2.6 weeks (IQR 1.2 weeks to 6.2 months) posttransplant; 67% of these were DSA. The majority of recipients in our cohort developed de novo anti-HLA antibodies within the first year posttransplant, with two-thirds being donor-specific. Acute cellular rejection, though frequent, was not different in patients with antibody development regardless of class or specificity, and there was no antibody mediated rejection, graft loss or early cardiac allograft vasculopathy. PMID- 25784139 TI - Prayer Marks in Immigrants from Bangladesh with Diabetes Who Live in Greece. AB - Prayer marks (PMs) are commonly occurring dermatologic changes in muslims who pray and develop over a long period of time as a consequence of repeated and extended pressure. PMs need careful examination especially for patients with diabetes, who are more vulnerable due to predisposing factors such as venous insufficiency and peripheral neuropathy. A total of 166 patients with diabetes (150 males, 16 females) and 65 normal subjects from Bangladesh were examined for the appearance of PMs. Twenty-eight patients (16.9 %) and one normal subject (1.5 %) had PMs. The marks were not itchy or painful and they were observed on the dorsal aspect of the left foot, which was attributed to a more typical prayer position that placed pressure on the left foot. PMs are not a rare clinical entity among muslim patients with diabetes and most clinicians should be aware of it as it can be the predominant cause of an ulcer. PMID- 25784140 TI - Impact of Routine Quantiferon Testing on Latent Tuberculosis Diagnosis and Treatment in Refugees in Multnomah County, Oregon, November 2009-October 2012. AB - Interferon-gamma release assays have potentially been transformative to screening programs focused on latent tuberculosis infection (LTBI) in foreign-born persons. We sought to add to this assessment by presenting the impact of a well established refugee screening and treatment program switching from skin testing to Quantiferon((r))-TB Gold (QFT). We completed a retrospective cohort of refugees screened for tuberculosis between November 1, 2009-April 30, 2011 (pre QFT) and May 1, 2011-October 31, 2012 (post-QFT). Among 2244 refugees screened that met the inclusion criteria, there was a significant difference in the proportion of refugees diagnosed with LTBI between the two time periods (p = <0.0001). In multivariate analysis, refugees tested with QFT had a greater odds of treatment initiation (adjusted odds ratio 1.53; 95% CI 1.02-2.29, p = 0.040). However, test type had no impact on treatment completion (odds ratio 0.88; 95% CI 0.57-1.36, p = 0.560). Although we demonstrated increased efficiency in LTBI diagnosis in this group, treatment completion rates indicate other barriers to treatment that must be addressed. PMID- 25784141 TI - Mortality by Cause of Death Among Immigrants and Natives in a South European Country: The Case of Greece, 2011. AB - The aim of the paper is to examine for the first time in Greece mortality by cause of death among immigrants. The analysis makes use of vital registration statistics for 2010-2012 and census data for 2011; standardised mortality ratios are estimated for four distinct groups: natives, migrants from EU-27 (excluding Greece), other Europeans (mainly Albanians) and those from all other countries (mainly Asia/Africa). All immigrants seem to experience favourable mortality from neoplasms but higher mortality from external causes in comparison to Greeks. The results regarding cardiovascular diseases are mixed. Persons originating in Asian/African regions exhibit higher mortality from infectious diseases and TB. The findings highlight the specificities of immigrant mortality which stem from pre-existing conditions in the country of origin as well as from the adverse socio-economic environment in the country of destination. As immigrants experience some excessive 'avoidable' mortality implementation of appropriate measures should be a social policy priority. PMID- 25784142 TI - Needs, Risks, and Context in Sexual Health Among Temporary Foreign Migrant Farmworkers in Canada: A Pilot Study with Mexican and Caribbean Workers. AB - Every year Canada hosts approximately 40,000 temporary foreign migrant farmworkers (MFWs). They are predominantly Mexican and Caribbean married men or single mothers who leave their families for months at a time over a span of many years. This pilot study investigated their knowledge about HIV/AIDS, attitudes towards condoms and their use, and perceived barriers to accessing sexual health services. A survey (n = 103) and four focus groups (n = 21) were conducted in Ontario's Niagara Region. The results suggest that MFWs commonly face vulnerabilities to HIV/AIDS, STIs and other sexual health issues due to personal, social-cultural, environmental and structural factors. The findings highlight the need for increasing culturally and gender sensitive sexual health education and harm reduction outreach and providing information about local health care systems and resources for MFWs. The study also calls for further community-based research and actions to reduce MFWs' perceived access barriers to health care services. PMID- 25784143 TI - Frequency and Perceptions of Herbal Medicine use Among Hmong Americans: a Cross Sectional Survey. AB - To determine the frequency and perceptions of herbal medicine use among Hmong Americans. Cross-sectional telephone survey. Sacramento, California Hmong community. Out of 118 subjects reached, 77 (65.3 %) reported lifetime use of herbal medicines. A majority of respondents agreed that herbal medicines were able to treat the body as a whole. Respondents felt that a leaflet of information indicating uses/side effects would be important to include for herbal medicines. Herbal medicine use was commonly reported among Hmong Americans. Thus, health care providers should be encouraged to discuss these alternative medicines with their Hmong American patients. PMID- 25784144 TI - A Systematic Review of the Physical, Mental, Social, and Economic Problems of Immigrant Women in the Perinatal Period in Japan. AB - The perinatal mortality of immigrants in Japan is higher than that of Japanese women. However, details of the problems of immigrant perinatal women that contribute to worsening of their health are still unknown. This review describes the physical, psychological, social, and economic problems of immigrant women during the perinatal period in Japan. Medline, CINAHL, PsycINFO, and Igaku-Chuo Zasshi were searched and 36 relevant articles were reviewed. The related descriptions were collected and analyzed by using content analysis. The results showed that immigrant perinatal women in Japan experienced the following problems: language barriers, a problematic relationship with a partner, illegal residency, emotional distress, physical distress, adjustment difficulties, lack of utilization of services, social isolation, lack of support, lack of information, low economic status, unsatisfactory health care, and discrimination. These results indicated that multilingual services, strengthening of social and support networks, and political action are necessary to resolve their problems. PMID- 25784147 TI - Biotechnological aspects of cytoskeletal regulation in plants. AB - The cytoskeleton is a protein-based intracellular superstructure that evolved early after the appearance of bacterial prokaryotes. Eventually cytoskeletal proteins and their macromolecular assemblies were established in eukaryotes and assumed critical roles in cell movements, intracellular organization, cell division and cell differentiation. In biomedicine the small-molecules targeting cytoskeletal elements are in the frontline of anticancer research with plant derived cytoskeletal drugs such as Vinca alkaloids and toxoids, being routinely used in the clinical practice. Moreover, plants are also major material, food and energy resources for human activities ranging from agriculture, textile industry, carpentry, energy production and new material development to name some few. Most of these inheritable traits are associated with cell wall synthesis and chemical modification during primary and secondary plant growth and inevitably are associated with the dynamics, organization and interactions of the plant cytoskeleton. Taking into account the vast intracellular spread of microtubules and actin microfilaments the cytoskeleton collectively assumed central roles in plant growth and development, in determining the physical stance of plants against the forces of nature and becoming a battleground between pathogenic invaders and the defense mechanisms of plant cells. This review aims to address the role of the plant cytoskeleton in manageable features of plants including cellulose biosynthesis with implications in wood and fiber properties, in biofuel production and the contribution of plant cytoskeletal elements in plant defense responses against pathogens or detrimental environmental conditions. Ultimately the present work surveys the potential of cytoskeletal proteins as platforms of plant genetic engineering, nominating certain cytoskeletal proteins as vectors of favorable traits in crops and other economically important plants. PMID- 25784145 TI - Protein design: Past, present, and future. AB - Building on the pioneering work of Ho and DeGrado (J Am Chem Soc 1987, 109, 6751 6758) in the late 1980s, protein design approaches have revealed many fundamental features of protein structure and stability. We are now in the era that the early work presaged - the design of new proteins with practical applications and uses. Here we briefly survey some past milestones in protein design, in addition to highlighting recent progress and future aspirations. PMID- 25784146 TI - Increased CD1c+ mDC1 with mature phenotype regulated by TNFalpha-p38 MAPK in autoimmune ocular inflammatory disease. AB - In this study we investigated the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1), a key mDC subtype, in patients with autoimmune uveitis. We observed a significant increase of blood CD1c(+) mDC1 in uveitis patients. The increased CD1c(+) mDC1 exhibited high HLADR expression and less antigen uptake. CD1c(+) mDC1 were divided into two subpopulations. CD1c(hi) mDC1 subpopulation showed less antigen uptake and higher HLADR expression compared to CD1c(lo) mDC1 subpopulation. Importantly, the CD1c(hi) mDC1 subpopulation was increased in uveitis patients. In vitro, mature monocyte-derived dendritic cells (MoDCs), characterized by lower levels of antigen uptake, induced more CD4(+)CD62L(-) T helper cell proliferation. The mature phenotype and function of CD1c(+) mDC1 were regulated by TNFalpha via a p38 MAPK-dependent pathway. These data show that alterations in the systemic immune response are involved in the pathogenesis of autoimmune uveitis and invite the therapeutic possibility of attenuating uveitis by manipulating blood CD1c(+) mDC1. PMID- 25784148 TI - Antimicrobial peptide production and plant-based expression systems for medical and agricultural biotechnology. AB - Antimicrobial peptides (AMPs) are vital components of the innate immune system of nearly all living organisms. They generally act in the first line of defense against various pathogenic bacteria, parasites, enveloped viruses and fungi. These low molecular mass peptides are considered prospective therapeutic agents due to their broad-spectrum rapid activity, low cytotoxicity to mammalian cells and unique mode of action which hinders emergence of pathogen resistance. In addition to medical use, AMPs can also be employed for development of innovative approaches for plant protection in agriculture. Conferred disease resistance by AMPs might help us surmount losses in yield, quality and safety of agricultural products due to plant pathogens. Heterologous expression in plant-based systems, also called plant molecular farming, offers cost-effective large-scale production which is regarded as one of the most important factors for clinical or agricultural use of AMPs. This review presents various types of AMPs as well as plant-based platforms ranging from cell suspensions to whole plants employed for peptide production. Although AMP production in plants holds great promises for medicine and agriculture, specific technical limitations regarding product yield, function and stability still remain. Additionally, establishment of particular stable expression systems employing plants or plant tissues generally requires extended time scale for platform development compared to certain other heterologous systems. Therefore, fast and promising tools for evaluation of plant based expression strategies and assessment of function and stability of the heterologously produced AMPs are critical for molecular farming and plant protection. PMID- 25784149 TI - Blood Aspiration During IM Injection. AB - The World Health Organization and Centers for Disease Control and Prevention no longer recommend aspiration during intramuscular (IM) injections. The purpose of this study was to investigate the technique registered nurses (RNs) use during IM injections and incidence of blood aspiration. This descriptive study surveyed 164 RNs. Results noted that 74% of the sample continue to aspirate at least 90% of the time. Of the participants who continue to aspirate, only 3% aspirate for the recommended 5 to 10 s. Forty percent reported having aspirated blood at least once, whereas 6 RNs (4%) noted blood aspiration >=13 times. Blood aspiration occurred most frequently in the dorsal gluteal (15%) and deltoid (12%). Based on the findings, it is recommended that RNs use a decision-making process to select the safest technique for IM injections. If a parental medication has different administration rates, dose, viscosity, or other concerns when given IM versus intravenously (IV), aspiration during IM administration should be implemented. PMID- 25784150 TI - Controllable synthesis of CeO2/g-C3N4 composites and their applications in the environment. AB - This research has developed a photocatalytic reactor that includes circulating water, light, and a temperature control system. CeO2/g-C3N4 composites with high photocatalytic activity and stability were synthesized by a simple and facile hydrothermal method. The obtained photocatalysts were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). It was found that in the CeO2/g-C3N4 composites, the CeO2 nanoparticles were homogeneously cubic in shape (from 3 to 10 nm) and were evenly dispersed on the surface of the g-C3N4. At constant temperature (30 degrees C), 5% CeO2/g-C3N4 photocatalyst showed the best photocatalytic activity for degrading organic dye methylene blue (MB) under visible light irradiation. The photocatalytic reaction for degrading MB followed first-order kinetics and 5% CeO2/g-C3N4 exhibited a higher apparent rate of 1.2686 min(-1), 7.8 times higher than that of the pure g-C3N4 (0.1621 min(-1)). In addition, it was found that 5% CeO2/g-C3N4 had a new property that it could be used as a sensor for the determination of trace amounts of Cu(2+). Such unique design and one-step synthesis, with an exposed high-activity surface, are important for both technical applications and theoretical investigations. PMID- 25784151 TI - Bioorthogonal deprotection on the dendritic cell surface for chemical control of antigen cross-presentation. AB - The activation of CD8(+) T-cells requires the uptake of exogenous polypeptide antigens and proteolytic processing of these antigens to octamer or nonamer peptides, which are loaded on MHC-I complexes and presented to the T-cell. By using an azide as a bioorthogonal protecting group rather than as a ligation handle, masked antigens were generated-antigens that are not recognized by their cognate T-cell unless they are deprotected on the cell using a Staudinger reduction. PMID- 25784152 TI - Brain thromboxane A2 via arachidonic acid cascade induces the hypothalamic pituitary-gonadal axis activation in rats. AB - The current study was designed to determine the effect of centrally administrated arachidonic acid (AA) on plasma gonadotropin hormone-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone level, and sperm parameters, and to show the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway in AA-induced hormonal and sperm parameter effects. Studies were performed in male Sprague Dawley rats. A total of 150 or 300 MUl/5 MUl doses of AA were injected intracerebroventricularly (icv). AA significantly caused dose- and time-dependent increases in plasma FSH, LH and testosterone levels of animals, but not plasma GnRH level. AA also significantly increased sperm motility of the rats without change sperm number. Pretreated with ibuprofen, a nonselective COX inhibitor (250 MUg/5 MUl; icv), and furegrelate, a TXA2 synthesis inhibitor (250 MUg/5 MUl; icv), prevented AA-evoked increase in plasma FSH, LH and testosterone levels, and sperm motility. In conclusion, our findings show that centrally administered AA increases plasma FSH, LH and testosterone levels and sperm motility of conscious male rats. Moreover, according to our findings, central COX-TXA2 signaling pathway mediates these AA-induced effects. PMID- 25784153 TI - Severe maxillofacial renal osteodystrophy in two patients with chronic kidney disease. AB - Renal osteodystrophy (ROD) is the bone pathology that occurs as an uncommon complication related to the several alterations in mineral metabolism present in patients with chronic kidney disease (CKD). This paper describes two cases of severe ROD affecting the maxilla and mandible and causing facial disfigurement of a young and a middle-aged female patient with CKD. Both patients had a history of secondary hyperparathyroidism, previously treated by surgery. The pathogenesis of the disease, as well as its clinical, imaging, and histopathological features, and management of the patient are discussed. PMID- 25784154 TI - Evaluation of the rigidity of sagittal split ramus osteotomy fixation using four designs of biodegradable and titanium plates--a numerical study. AB - PURPOSE: This study was conducted to determine the best design of biodegradable plates for providing rigidity when used for fixation of sagittal split ramus osteotomy. METHODS: A computerized tomography image of a patient was used to generate a 3D model of a hemi-mandible. Four plate designs were merged with the hemi-mandible. They were (1) straight plate, (2) double straight plate, (3) T shaped plate, and (4) double Y-shaped plate. Four finite element models were analyzed using the properties of biodegradable materials for the plates, and four additional models were analyzed using titanium alloy properties. RESULTS: The models predicted that rigidity of fixation would be noticeably less among biodegradable plates than titanium plates. They also predicted that the most rigid design among the titanium plates would be the straight plate, but among the biodegradable plates, it would be the double Y-shaped plate. CONCLUSION: The double Y-shaped design is recommended when using biodegradable plates in fixation of sagittal split ramus osteotomy. PMID- 25784155 TI - Norovirus genotype diversity in community-based sporadic gastroenteritis incidents: a five-year study. AB - Although norovirus is a known cause of sporadic gastroenteritis, the incidence and genotypes of norovirus associated with sporadic community-based gastroenteritis are poorly understood. The current study examined this issue by using material from alleged food poisoning incidents in the state of Victoria, Australia, for the period 2008-2012. Norovirus was identified, by either ORF (open reading frame) 1 or ORF 2 RT-PCR methodology, in 159 of 379 (42.0%) sporadic gastroenteritis incidents, thereby showing that norovirus was an important cause of sporadic gastroenteritis. The number of sporadic norovirus incidents did not vary significantly from year to year, indicating that the pool of circulating norovirus remained constant. Norovirus ORF 1 genotypes identified included GI.1, GI.2, GI.3, GI.4, GI.b, GI.d, GII.2, GII.4 (including variants 2006a, 2006b, 2007, and 2009), GII.16, GII.22, GII.b, GII.e, and GII.g. Norovirus ORF 2 genotypes identified included GI.1, GI.2, GI.3, GI.4, GI.6, GII.2, GII.3, GII.4 (variants 2006b, 2009, 2009-like, 2012, and "unknown"), GII.6, GII.7, GII.9, GII.12, and GII.13. Five ORF 1/ORF 2 norovirus recombinant forms were confirmed: GII.b/GII.3, GII.e/GII.4 (2012), GII.e/GII.4 (unknown), GII.g/GII.12 and GII.16/GII.2. Although the incidence of ORF 2 GI.3 was significantly higher in children than in adults, this was not the case for other major ORF 2 genotypes (GII.2, GII.4, and GII.6) which occurred equally in all age groups. The findings demonstrate the importance and diverse nature of norovirus in sporadic community based gastroenteritis incidents and indicate that the development of successful vaccine strategies may be difficult. PMID- 25784156 TI - Nanofiber adsorbents for high productivity continuous downstream processing. AB - An ever increasing focus is being placed on the manufacturing costs of biotherapeutics. The drive towards continuous processing offers one opportunity to address these costs through the advantages it offers. Continuous operation presents opportunities for real-time process monitoring and automated control with potential benefits including predictable product specification, reduced labour costs, and integration with other continuous processes. Specifically to chromatographic operations continuous processing presents an opportunity to use expensive media more efficiently while reducing their size and therefore cost. Here for the first time we show how a new adsorbent material (cellulosic nanofibers) having advantageous convective mass transfer properties can be combined with a high frequency simulated moving bed (SMB) design to provide superior productivity in a simple bioseparation. Electrospun polymeric nanofiber adsorbents offer an alternative ligand support surface for bioseparations. Their non-woven fiber structure with diameters in the sub-micron range creates a remarkably high surface area material that allows for rapid convective flow operations. A proof of concept study demonstrated the performance of an anion exchange nanofiber adsorbent based on criteria including flow and mass transfer properties, binding capacity, reproducibility and life-cycle performance. Binding capacities of the DEAE adsorbents were demonstrated to be 10mg/mL, this is indeed only a fraction of what is achievable from porous bead resins but in combination with a very high flowrate, the productivity of the nanofiber system is shown to be significant. Suitable packing into a flow distribution device has allowed for reproducible bind-elute operations at flowrates of 2,400 cm/h, many times greater than those used in typical beaded systems. These characteristics make them ideal candidates for operation in continuous chromatography systems. A SMB system was developed and optimised to demonstrate the productivity of nanofiber adsorbents through rapid bind-elute cycle times of 7s which resulted in a 15-fold increase in productivity compared with packed bed resins. Reproducible performance of BSA purification was demonstrated using a 2-component protein solution of BSA and cytochrome c. The SMB system exploits the advantageous convective mass transfer properties of nanofiber adsorbents to provide productivities much greater than those achievable with conventional chromatography media. PMID- 25784157 TI - A chimeric vacuolar Na(+)/H(+) antiporter gene evolved by DNA family shuffling confers increased salt tolerance in yeast. AB - The vacuolar Na(+)/H(+) antiporter plays an important role in maintaining ionic homeostasis and the osmotic balance of the cell with the environment by sequestering excessive cytoplasmic Na(+) into the vacuole. However, the relatively low Na(+)/H(+) exchange efficiency of the identified Na(+)/H(+) antiporter could limit its application in the molecular breeding of salt tolerant crops. In this study, DNA family shuffling was used to create chimeric Na(+)/H(+) antiporters with improved transport activity. Two homologous Na(+)/H(+) antiporters from halophytes Salicornia europaea (SeNHX1) and Suaeda salsa (SsNHX1) were shuffled to generate a diverse gene library. Using a high throughput screening system of yeast complementation, a novel chimeric protein SseNHX1 carrying 12 crossover positions and 2 point mutations at amino acid level was selected. Expression of SseNHX1 in yeast mutant exhibited approximately 46% and 22% higher salt tolerance ability in yeast growth test than that of SsNHX1and SeNHX1, respectively. Measurements of the ion contents demonstrated that SseNHX1 protein in yeast cells accumulated more Na(+) and slightly more K(+) than the parental proteins did. Furthermore, this chimera also conferred increased tolerance to LiCl and a similar tolerance to hygromycin B compared with the parental proteins in yeast. PMID- 25784158 TI - Clinicopathological and virological characteristics of superficially invasive squamous-cell carcinoma of the anus. AB - AIM: The clinicopathological and virological characteristics of anal superficially invasive squamous-cell carcinoma (SISCCA) were determined. METHOD: Seventeen patients with a completely excised stage T1N0M0 anal squamous-cell carcinoma (SCC) were included in the study. The tumours were divided into superficially invasive and invasive. Patients with anal high-grade squamous intraepithelial dysplasia, which corresponded to anal intraepithelial neoplasia (AIN) Grades 2 or 3, were used as a control group. Clinicopathological and virological characteristics were investigated. Overall survival and cancer recurrence-free survival were also assessed. RESULTS: Of the 17 patients, 12 (70.5%) were men. Ten (58.8%) were human immunodeficiency virus positive. Seven (41%) patients met the same diagnostic criteria as those recently proposed for anal SISCCA. According to the results obtained using the polymerase chain reaction, human papillomavirus (HPV) 16 was the most commonly detected (94%) type of HPV. Twelve (70.6%) patients with an inadequate surgical margin around the tumour received adjuvant radiotherapy, including the two (11.7%) tumours that locally recurred, one of which was an anal SISCCA. Superficially invasive anal cancers differed from the other T1N0M0 anal carcinomas according to the clinical presentation and the absence of lymph-vascular invasion (LVI). There were no differences in cancer recurrence-free and overall survival rates between the superficially invasive and invasive groups. CONCLUSION: Anal SISCCAs have a low index of clinical suspicion, are associated with an absence of LVI and are linked to high-risk HPV. Prospective studies are needed to define the clinical behaviour of these anal tumours and to determine their best therapeutic strategy. PMID- 25784159 TI - "It takes two": the interaction between parenting and child temperament on parents' stress physiology. AB - The biological basis of parenting has received recent attention given the profound effects of parenting on both child and parent health outcomes. This study examined the moderating role of child temperamental effortful control on the association between observed parental hostility and parents' cortisol awakening response (CAR), a critical index of stress system functioning. Participants included 149 parents and their preschool-aged children. Parents obtained salivary cortisol samples at waking, and 30 and 45 min post-waking across two consecutive days. Parental hostility was assessed during an observational parent-child interaction task, and child effortful control was assessed using parent report. Parental hostility was associated with parents' lower cortisol levels at 30 and 45 min post-waking and lower CAR. Moreover, results demonstrated an interaction between parenting and child temperament on parent CAR. The findings highlight the need to examine the interplay between parenting and child temperament on parents' stress physiology. PMID- 25784160 TI - A novel composite conductive microfiltration membrane and its anti-fouling performance with an external electric field in membrane bioreactors. AB - Membrane fouling remains an obstacle to wide-spread applications of membrane bioreactors (MBRs) for wastewater treatment and reclamation. Herein, we report a simple method to prepare a composite conductive microfiltration (MF) membrane by introducing a stainless steel mesh into a polymeric MF membrane and to effectively control its fouling by applying an external electric field. Linear sweep voltammetry and electrochemical impedance spectroscopy analyses showed that this conductive membrane had very good electrochemical properties. Batch tests demonstrated its anti-fouling ability in filtration of bovine serum albumin, sodium alginate, humic acid and silicon dioxide particles as model foulants. The fouling rate in continuous-flow MBRs treating wastewater was also decreased by about 50% for this conductive membrane with 2 V/cm electric field compared to the control test during long-term operation. The enhanced electrostatic repulsive force between foulants and membrane, in-situ cleaning by H2O2 generated from oxygen reduction, and decreased production of soluble microbial products and extracellular polymeric substances contributed to fouling mitigation in this MBR. The results of this study shed light on the control strategy of membrane fouling for achieving a sustainable operation of MBRs. PMID- 25784161 TI - Effect of electric field gradient on sub-nanometer spatial resolution of tip enhanced Raman spectroscopy. AB - Tip-enhanced Raman spectroscopy (TERS) with sub-nanometer spatial resolution has been recently demonstrated experimentally. However, the physical mechanism underlying is still under discussion. Here we theoretically investigate the electric field gradient of a coupled tip-substrate system. Our calculations suggest that the ultra-high spatial resolution of TERS can be partially attributed to the electric field gradient effect owning to its tighter spatial confinement and sensitivity to the infrared (IR)-active of molecules. Particularly, in the case of TERS of flat-lying H2TBPP molecules,we find the electric field gradient enhancement is the dominating factor for the high spatial resolution, which qualitatively coincides with previous experimental report. Our theoretical study offers a new paradigm for understanding the mechanisms of the ultra-high spatial resolution demonstrated in tip-enhanced spectroscopy which is of importance but neglected. PMID- 25784162 TI - An expanded regulatory network temporally controls Candida albicans biofilm formation. AB - Candida albicans biofilms are composed of highly adherent and densely arranged cells with properties distinct from those of free-floating (planktonic) cells. These biofilms are a significant medical problem because they commonly form on implanted medical devices, are drug resistant and are difficult to remove. C. albicans biofilms are not static structures; rather they are dynamic and develop over time. Here we characterize gene expression in biofilms during their development, and by comparing them to multiple planktonic reference states, we identify patterns of gene expression relevant to biofilm formation. In particular, we document time-dependent changes in genes involved in adhesion and metabolism, both of which are at the core of biofilm development. Additionally, we identify three new regulators of biofilm formation, Flo8, Gal4, and Rfx2, which play distinct roles during biofilm development over time. Flo8 is required for biofilm formation at all time points, and Gal4 and Rfx2 are needed for proper biofilm formation at intermediate time points. PMID- 25784163 TI - Charged/Polar-residue scanning of the hydrophobic face of transmembrane domain 9 of the yeast glutathione transporter, hgt1p, reveals a conformationally critical region for substrate transport. AB - Unraveling the mechanistic workings of membrane transporters has remained a challenging task. We describe a novel strategy that involves subjecting the residues of the hydrophobic face of a transmembrane helix to a charged/polar scanning mutagenesis. TMD9 of the yeast glutathione transporter, Hgt1p, has been identified as being important in substrate binding, and two residues, F523 and Q526, are expected to line the substrate translocation channel while the other face is hydrophobic. The hydrophobic face of TMD9 helix consists of residues A509, V513, L517, L520, I524, and I528, and these were mutated to lysine, glutamine, and glutamic acid. Among the 16 charged mutants created, six were nonfunctional, revealing a surprising tolerance of charged residues in the hydrophobic part of TM helices. Furthermore, the only position that did not tolerate any charged residue was I524, proximal to the substrate binding residues. However, P525, also proximal to the substrate binding residues, did tolerate charged/polar residues, suggesting that mere proximity to the substrate binding residues was not the only factor. The I524K/E/Q mutants expressed well and localized correctly despite lacking any glutathione uptake capability. Isolation of suppressors for all nonfunctional mutants yielded second-site suppressors only for I524K and I524Q, and suppressors for these mutations appeared at G202K/I and G202K/Q, respectively. G202 is in the hydrophilic loop between TMD3 and TMD4. The results suggest that I524 in the hydrophobic face interacts with this region and is also in a conformationally critical region for substrate translocation. PMID- 25784165 TI - Double Whammy: best or worst of two worlds. PMID- 25784166 TI - The effects of cardiopulmonary bypass on pulmonary function during robotic cardiac surgery. AB - BACKGROUND: We aimed to investigate the effects of cardiopulmonary bypass (CPB) on pulmonary function under the conditions of one-lung ventilation (OLV) and carbon dioxide pneumothorax in robotic cardiac surgery. METHODS: Ninety-eight patients underwent robotic cardiac surgery using the da Vinci Surgical System, including 58 on-pump surgeries and 40 off-pump surgeries. Respiratory parameters and arterial blood gases were assessed at the following time points: 25 min after the induction of anesthesia under two-lung ventilation (T1), 25 min after OLV (T2), 25 min after the termination of CPB under OLV in the on-pump group or 25 min after the main surgery intervention in the off-pump group (T3) and 20 min before the end of surgery (T4). Dynamic lung compliance (Cdyn), alveolar-arterial PO2 difference (PA-aDO2), oxygenation index (OI) and artery-alveolar O2 pressure ratio (a/A) were calculated. RESULTS: No significant differences in pulmonary function parameters between T2 and T3 were observed in the off-pump group. However, in the on-pump group, compared with those at T2, PETCO2, Ppeak, PaCO2 and PA-aDO2 at T3 were higher, whereas SpO2, Cdyn, PaO2, OI and a/A were lower (p<0.05). Comparisons between the two groups at T3 indicated that SpO2, Cdyn, PaO2, OI and a/A were higher, while Ppeak, PaCO2 and PA-aDO2 were lower in the off-pump group (p<0.01). CONCLUSIONS: In robotic cardiac surgery under the conditions of OLV and carbon dioxide pneumothorax, CPB worsened pulmonary function and tolerance to OLV and carbon dioxide pneumothorax. PMID- 25784164 TI - Quantitative genetics of migration-related traits in rainbow and steelhead trout. AB - Rainbow trout (Oncorhynchus mykiss) exhibit remarkable life history diversity throughout their native range, and among the most evident is variation in migratory propensity. Although some populations and ecotypes will remain resident in freshwater habitats throughout their life history, others have the ability to undertake tremendous marine migrations. Those that migrate undergo a suite of behavioral, morphological, and physiological adaptations in a process called smoltification. We describe a quantitative genetic analysis of 22 growth, size, and morphological traits in addition to overall life history classification (resident or migrant) over the temporal process of smoltification in a large multi-generation experimental pedigree (n = 16,139) of migratory and resident rainbow trout derived from a wild population, which naturally segregates for migratory propensity. We identify significant additive genetic variance and covariance among the suite of traits that make up a component of the migratory syndrome in this species. Additionally, we identify high heritability estimates for the life history classifications and observe a strong negative genetic correlation between the migratory and resident life history trajectories. Given the large heritability estimates of all of the traits that segregate between migratory and resident rainbow trout, we conclude that these traits can respond to selection. However, given the high degree of genetic correlation between these traits, they do not evolve in isolation, but rather as a suite of coordinated characters in a predictable manner. PMID- 25784168 TI - Neuropsychological test performance among healthy persons in northern India: development of normative data. AB - Accurate identification of neurocognitive impairment associated with HIV infection (and other CNS-involved conditions) is dependent upon utilization of appropriate normative neuropsychological test performance data from healthy individuals with a similar background, culture, and characteristics of the target individual or group to be tested. In India, regional differences in language, culture, and availability of resources can significantly affect performance on neuropsychological testing. This study developed age- and education-adjusted normative data for commonly used neuropsychological test scores for use in northern India. PMID- 25784169 TI - The association between follicular size at the time of spontaneous rupture and pregnancy rates in clomiphene citrate treated PCOS patients in coit cycles. AB - OBJECTIVE: To investigate the follicular size at spontaneous rupture on pregnancy rate in patients with polycystic ovary syndrome (PCOS) undergoing clomiphene citrate (CC) ovulation. DESIGN: Cross-sectional study. PATIENTS AND METHODS: One hundred and four women with ovulatory cycles after use of CC followed by ultrasound to determine the follicle size at the time of rupture, which was subsequently correlated with the occurrence of pregnancy or not in coit cycles. RESULTS: In the group of follicular rupture at a mean diameter <=25 mm (n = 54), pregnancy rate was 35.1% and when follicular rupture occurred at a mean diameter >25 mm (n = 50), it was 34% (p > 0.05). When different diameters at follicular rupture were randomly correlated with the pregnancy rate, there was no significant difference. CONCLUSION: Our data suggest that the occurrence of pregnancy after ovulation induction with CC in women with PCOS is not associated with follicle size at the time of rupture. PMID- 25784171 TI - Impact of an exercise program on the physiologic, biologic and psychologic profiles in patients with schizophrenia. PMID- 25784170 TI - Neuronal plasticity in the mushroom body calyx during adult maturation in the honeybee and possible pheromonal influences. AB - Honeybee workers express a pronounced age-dependent polyethism switching from various indoor duties to foraging outside the hive. This transition is accompanied by tremendous changes in the sensory environment that sensory systems and higher brain centers have to cope with. Foraging and age have earlier been shown to be associated with volume changes in the mushroom bodies (MBs). Using age- and task-controlled bees this study provides a detailed framework of neuronal maturation processes in the MB calyx during the course of natural behavioral maturation. We show that the MB calyx volume already increases during the first week of adult life. This process is mainly driven by broadening of the Kenyon cell dendritic branching pattern and then followed by pruning of projection neuron axonal boutons during the actual transition from indoor to outdoor duties. To further investigate the flexible regulation of division of labor and its neuronal correlates in a honeybee colony, we studied the modulation of the nurse-forager transition via a chemical communication system, the primer pheromone ethyl oleate (EO). EO is found at high concentrations on foragers in contrast to nurse bees and was shown to delay the onset of foraging. In this study, EO effects on colony behavior were not as robust as expected, and we found no direct correlation between EO treatment and synaptic maturation in the MB calyx. In general, we assume that the primer pheromone EO rather acts in concert with other factors influencing the onset of foraging with its effect being highly adaptive. PMID- 25784172 TI - Involvement of interleukin-21 in the pathophysiology of aplastic anemia. AB - OBJECTIVE: Recently enhanced T-helper type 17 (Th17) immune responses and deficient CD4(+) CD25(hi) FoxP3(+) regulatory T cells (Tregs) have been reported in acquired aplastic anemia (AA). Interleukin-21 (IL-21), a CD4(+) T-cell-derived proinflammatory cytokine, modulates the balance between Th17 cells and Tregs. However, its role in AA remains unclear. METHODS: IL-21 gene expression was examined by quantitative real-time PCR. Cytokines in plasma and cell culture supernatants were detected by ELISA. Cytokines-producing T cells and Tregs were evaluated by flow cytometry. RESULTS: IL-21 mRNA levels in circulating CD4(+) T cells and IL-21 levels in blood plasma were markedly increased in patients with newly diagnosed AA. Moreover, elevated IL-21-producing CD4(+) T cells were accompanied by Th17 cells accumulation and Tregs decrease, and correlated with AA activity. In vitro, IL-21 not only inhibited the expression of FoxP3, but also induced the expression of IL-17 in CD4(+) T cells of AA patients. More importantly, we found that T cells within the bone marrow (BM) of AA patients were in a heightened activation state, which may be related to IL-21. CONCLUSION: Our data suggested a critical role of IL-21 in breaking immune homeostasis in AA by promoting Th17 cells, activating BM T cells and suppressing Tregs. PMID- 25784173 TI - Reducing arterial stiffness in CKD: revising the paradigms. PMID- 25784174 TI - Effect of lisinopril and atenolol on aortic stiffness in patients on hemodialysis. AB - BACKGROUND AND OBJECTIVES: Whether improvements in arterial compliance with BP lowering are because of BP reduction alone or if pleiotropic effects of antihypertensive agents contribute remains unclear. It was hypothesized that, among patients on hemodialysis, compared with a beta-blocker (atenolol), a lisinopril-based therapy will better reduce arterial stiffness. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 200 participants of the Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril Trial, 179 patients with valid assessment of aortic pulse wave velocity at baseline (89 patients randomly assigned to open-label lisinopril and 90 patients randomly assigned to atenolol three times a week after dialysis) were included in the secondary analysis. Among them, 109 patients had a valid pulse wave velocity measurement at 6 months. Monthly measured home BP was targeted to <140/90 mmHg by addition of antihypertensive drugs and dry weight adjustment. The difference between drugs in percentage change of aortic pulse wave velocity from baseline to 6 months was analyzed. RESULTS: Contrary to the hypothesis, atenolol-based treatment induced greater reduction in aortic pulse wave velocity relative to lisinopril (between drug difference, 14.8%; 95% confidence interval, 1.5% to 28.5%; P=0.03). Reduction in 44-hour ambulatory systolic and diastolic BP was no different between groups (median [25th, 75th percentile]; atenolol: -21.5 [-37.7, -7.6] versus lisinopril: -15.8 [-28.8, -1.5] mmHg; P=0.27 for systolic BP; -14.1 [ 22.6, -5.3] versus -10.9 [-18.4, -0.9] mmHg, respectively; P=0.30 for diastolic BP). Between-drug difference in change of aortic pulse wave velocity persisted after adjustments for age, sex, race, other cardiovascular risk factors, and baseline ambulatory systolic BP but disappeared after adjustment for change in ambulatory systolic BP (11.8%; 95% confidence interval, -2.3% to 25.9%; P=0.10). CONCLUSIONS: Among patients on dialysis, atenolol was superior in improving arterial stiffness. However, differences between atenolol and lisinopril in improving aortic stiffness among patients on hemodialysis may be explained by BP lowering effects of drugs. PMID- 25784176 TI - 3,6-Dihydroxyflavone Suppresses Breast Carcinogenesis by Epigenetically Regulating miR-34a and miR-21. AB - Our previous study selected a promising chemopreventive agent 3,6 dihydroxyflavone (3,6-DHF) and found that 3,6-DHF significantly upregulates miR 34a and downregulates miR-21 in breast carcinogenesis, yet the upstream and downstream events of the anticancer mechanism remain unclear. The present study showed that 3,6-DHF cotreatment effectively inhibits carcinogens-induced breast carcinogenic transformation in human breast epithelial MCF10A cells. The data revealed the significant downregulation of miR-34a and upregulation of miR-21 in breast carcinogenesis, which could be mitigated by 3,6-DHF treatment. Methylation specific PCR detections showed that 3,6-DHF inhibits the hypermethylation of the miR-34a promoter. Further studies indicated that 3,6-DHF is an effective methyltransferase (DNMT)1 inhibitor, docking to the putative cytosine pocket of the protein, and thus decreases the DNMT activity in a dose-dependent manner. Moreover, the ChIP-qPCR analysis for histone modifications showed that 3,6-DHF treatment significantly lowers the H3K9-14ac on the miR-21 promoter. In addition, our study revealed that 3,6-DHF represses the PI3K/Akt/mTOR signaling pathway in breast carcinogenesis in vitro and in vivo. Inhibition of miR-34a or overexpression of miR-21 significantly reduced the effects of 3,6-DHF on Notch-1 and PTEN, and consequently weakened the suppression of 3,6-DHF on PI3K/Akt/mTOR. We concluded that 3,6-DHF upregulates miR-34a via inhibiting DNMT1 and hypermethylation, whereas downregulates miR-21 by modulating histone modification, and consequently suppresses the PI3K/Akt/mTOR signaling pathway in breast carcinogenesis. PMID- 25784177 TI - UCP2 knockout suppresses mouse skin carcinogenesis. AB - Mitochondrial uncoupling (uncouples electron transport from ATP production) has recently been proposed as a novel survival mechanism for cancer cells, and reduction in free radical generation is the accepted mechanism of action. However, there is no direct evidence supporting that uncoupling proteins promote carcinogenesis. Herein, we examined whether mitochondrial uncoupling affects mouse skin carcinogenesis using uncoupling protein 2 (UCP2) homozygous knockout and wild-type mice. The results indicate that knockout of Ucp2 significantly reduced the formation of both benign (papilloma) and malignant (squamous cell carcinoma) tumors. UCP2 knockout did not cause increases in apoptosis during skin carcinogenesis. The rates of oxygen consumption were decreased only in the carcinogen-treated UCP2 knockout mice, whereas glycolysis was increased only in the carcinogen-treated wild-type mice. Finally, the levels of metabolites pyruvate, malate, and succinate showed different trends after carcinogen treatments between the wild-type and UCP2 knockout mice. Our study is the first to demonstrate that Ucp2 knockout suppresses carcinogenesis in vivo. Together with early studies showing that UCP2 is overexpressed in a number of human cancers, UCP2 could be a potential target for cancer prevention and/or therapy. Cancer Prev Res; 8(6); 487-91. (c)2015 AACR. PMID- 25784178 TI - Sentinel node status and immunosuppression: recurrence factors in localized Merkel cell carcinoma. AB - The prognostic value of the sentinel lymph node in Merkel cell carcinoma (MCC) has been examined previously in heterogeneous retrospective studies. The current retrospective study included a homogeneous population of patients with a localized MCC, all staged with sentinel lymph node biopsy. Factors associated with 3-year progression-free survival were analysed using logistic regression. The sentinel lymph node was positive in 32% of patients. The recurrence rate was 26.9%. In first analyses (n = 108), gender (p = 0.0115) and the presence of immunosuppression (p = 0.0494) were the only significant independent factors. In further analyses (n = 80), excluding patients treated with regional radiotherapy, sentinel lymph node status was the only significant prognostic factor (p = 0.0281). Immunosuppression and positive sentinel lymph node are associated with a worse prognosis in patients with MCC. Nodal irradiation impacts on the prognostic value of the sentinel lymph node status. PMID- 25784179 TI - Erratum to: One-year follow-up of mud-bath therapy in patients with bilateral knee osteoarthritis: a randomized, single-blind controlled trial. PMID- 25784180 TI - 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4'-DMAR, 4,4' dimethylaminorex): availability, prevalence of use, desired effects and acute toxicity. AB - OBJECTIVE: 4-Methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4' dimethylaminorex (4,4'-DMAR)) is a derivative of the controlled substances aminorex and 4-methylaminorex marketed as a potential novel psychoactive substance. This paper brings together the published scientific and 'grey' literature to understand 4,4'-DMAR as a novel psychoactive substance. METHODS: Searches of the published scientific and 'grey' literature, using the keywords '4 methyl-euphoria', '4-methyl-U4Euh', '4-M-4-MAR', '4,4-dimethylaminorex', '4,4' DMAR', 'para-methyl-4-aminorex' and 'Serotoni', were undertaken to identify information on the availability, prevalence of use and desired/unwanted effects of 4,4'-DMAR. RESULTS: No studies have reported the prevalence of use of 4,4' DMAR. Internet snapshot studies in April and May 2014 showed availability of 4,4' DMAR from one and two Internet suppliers respectively. Price decreased with increasing purchase amounts from ?12/g for a 1-g purchase to ?2.20/g for a 100-g purchase in April 2014. Internet discussion fora suggest that the desired and unwanted effects of 4,4'-DMAR are similar to those seen with other sympathomimetic drugs such as 3,4-methylenedioxy-methamphetamine and mephedrone, although the duration of unwanted effects and 'comedown' appear to be longer. Unwanted effects were reported at doses of 5-200 mg, which overlaps with the reported doses (10-200 mg) associated with desired effects. 4,4'-DMAR has been detected, along with other drugs, in 27 deaths in Europe; the contribution of the 4,4'-DMAR in these deaths has not been established. CONCLUSIONS: Currently, there appears to limited availability of 4,4'-DMAR; therefore, use is likely to be low. Its desired and unwanted effects appear similar to other sympathomimetic recreational drugs such as methylenedioxy-methamphetamine or mephedrone. PMID- 25784181 TI - Effect of FK506 on apoptosis of facial motor neurons in rats and its possible mechanism. AB - To investigate the effect of FK506 on apoptosis of facial motor neurons in rats and its possible mechanism. A total of 48 Wistar rats were randomly divided into experimental group and control group. Facial nerve injury model was established by transection of facial nerve at stylomastoid foramen. Rats in experimental group and control group were provided with FK506 and normal saline by intraperitoneal injection, respectively. The morphology of facial neurons was observed under light microscope at different time points after injury. Apoptotic facial motor neurons were detected by TdT-mediated dUTP-biotin nick and labeling (TUNEL) staining, and expression of bcl-2 and bax was evaluated by immunohistochemistry. After facial nerve transection, the apoptotic cells in experimental group significantly decreased compared to control group (P < 0.05), with higher expression of bcl-2 and lower expression of bax in experimental group. FK506 could inhibit apoptosis of facial motor neurons after facial nerve transection, possibly via up-regulation of bcl-2 expression and down-regulation of bax expression. PMID- 25784182 TI - Value of systematic analysis of the olfactory cleft in case of cerebrospinal rhinorrhea: incidence of olfactory arachnoid dilatation. AB - To report on the presence of olfactory arachnoid dilatations (OAD), a previously undescribed radiologic feature of spontaneous cerebrospinal fluid (CSF) rhinorrhea originating from the cribriform plate of the ethmoid bone. The medical records of all patients treated between 2001 and 2011 at a tertiary care center for a spontaneous CSF rhinorrhea originating from the cribriform plate were retrospectively reviewed. The radiological work-up included high-resolution computed tomography and magnetic resonance imaging with at least the following sequences: T1, T2, and T2 with fast imaging employing steady state acquisition (FIESTA). Thirty cases were identified. The mean age at diagnosis was 49. Fourteen patients (47 %) had a body mass index (BMI) of 30 or more and 3 patients (10 %) had a BMI between 25 and 29.9. Five patients had a history of meningitis. The imaging work-up revealed a bone defect of the cribriform plate in 6 cases (20 %), associated to a typical meningocele in 14 cases (47 %). In ten patients (33 %), there was no defect of the cribriform plate, but ultrathin coronal T2-FIESTA sequences revealed an OAD, i.e. a dilatation of the arachnoid sheath of the olfactory fibers, in nine cases (30 %), or a "pseudo-polyp" outlined by a thin layer of arachnoid (1 patient, 3 %). Preoperative imaging should be carefully analyzed for the presence of OAD or "pseudo-polyp" in patients presenting with a CSF rhinorrhea without bony defect of the cribriform plate. PMID- 25784183 TI - The impact of surgical technique on neck dissection nodal yield: making a difference. AB - The nodal yield of neck dissections is an independent prognostic factor in several types of head and neck cancer. The authors aimed to determine whether the applied dissection technique has a significant impact on nodal yield. This is a single-institution, prospective study with internal control group (level of evidence: 2A). Data of 150 patients undergoing 223 neck dissections between February 2011 and March 2013 have been collected in a comprehensive cancer centre. Eighty-two patients underwent neck dissection with unwrapping the cervical fascia from lateral to medial, while 68 patients were operated without specifically unwrapping the fascia, in a caudal to cranial fashion. The standardised, horizontal neck dissection technique along the fascial planes resulted in a significantly higher nodal count in Levels I, II, III and IV, as well as in terms of overall nodal yield (mean: n = 22.53) than that of the vertical dissection applied in the control group (mean: n = 15.00). This is the first publication showing a direct correlation between neck dissection nodal yield and surgical technique. Therefore, it is paramount to optimise the applied surgical concept to maximise the oncological benefit. PMID- 25784184 TI - The establishment of preliminary safety threshold values for cyanobacteria based on periodic variations in different microcystin congeners in Lake Chaohu, China. AB - As harmful cyanobacterial proliferation threatens the safety of drinking water supplies worldwide, it is essential to establish a safety threshold (ST) for cyanobacteria to control cyanobacterial density effectively in water sources. For this purpose, cyanobacterial abundance, microcystin (MC) production, and environmental parameters were monitored monthly from September 2011 to August 2012 in one drinking water source of Lake Chaohu. The cyanobacterial density ranged from 1400 to 220 000 cells per mL with the succession of two dominant species Microcystis and Dolichospermum, which was determined by water temperature and nutrient loading. The MC concentrations were correlated significantly with the cyanobacterial density and they varied between 0.28 and 8.86 MUg L(-1). Therefore, the characteristics of MC cell quotas were classified according to four stages of the development of cyanobacteria, namely: recruitment, multiplication, decline and dormancy. The ST for cyanobacteria was established for different periods based on the MC cell quota and its guideline wherein three commonly monitored MC congeners (MC-LR, -RR and -YR) were considered in the present study. Its reliability was verified in the water source using the data collected between June 2013 and May 2014. The results highlighted the necessity to classify the ST-values in different periods referring to the main MC congeners rather than MC-LR, which will facilitate the management and control of toxic cyanobacterial proliferation in drinking water sources. PMID- 25784185 TI - Low kV settings CT angiography (CTA) with low dose contrast medium volume protocol in the assessment of thoracic and abdominal aorta disease: a feasibility study. AB - OBJECTIVE: To assess the diagnostic quality of low dose (100 kV) CT angiography (CTA), by using ultra-low contrast medium volume (30 ml), for thoracic and abdominal aorta evaluation. METHODS: 67 patients with thoracic or abdominal vascular disease underwent multidetector CT study using a 256 slice scanner, with low dose radiation protocol (automated tube current modulation, 100 kV) and low contrast medium volume (30 ml; 4 ml s(-1)). Density measurements were performed on ascending, arch, descending thoracic aorta, anonymous branch, abdominal aorta, and renal and common iliac arteries. Radiation dose exposure [dose-length product (DLP)] was calculated. A control group of 35 patients with thoracic or abdominal vascular disease were evaluated with standard CTA protocol (automated tube current modulation, 120 kV; contrast medium, 80 ml). RESULTS: In all patients, we correctly visualized and evaluated main branches of the thoracic and abdominal aorta. No difference in density measurements was achieved between low tube voltage protocol (mean attenuation value of thoracic aorta, 304 HU; abdominal, 343 HU; renal arteries, 331 HU) and control group (mean attenuation value of thoracic aorta, 320 HU; abdominal, 339; renal arteries, 303 HU). Radiation dose exposure in low tube voltage protocol was significantly different between thoracic and abdominal low tube voltage studies (490 and 324 DLP, respectively) and the control group (thoracic DLP, 1032; abdomen, DLP 1078). CONCLUSION: Low tube-voltage protocol may provide a diagnostic performance comparable with that of the standard protocol, decreasing radiation dose exposure and contrast material volume amount. ADVANCES IN KNOWLEDGE: Low-tube-voltage-setting protocol combined with ultra-low contrast agent volume (30 ml), by using new multidetector row CT scanners, represents a feasible diagnostic tool to significantly reduce the radiation dose delivered to patients and to preserve renal function, while also maintaining adequate diagnostic quality images in assessment of aorta. PMID- 25784186 TI - Case of mucoepidermoid carcinoma of the sublingual gland accompanied with extensive dystrophic calcification and intratumoral bone formation. AB - BACKGROUND: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Although the histopathological findings are diverse, no case of salivary MEC accompanied with bone formation has been reported. Herein, we present the first case of MEC with intratumoral bone formation. METHODS AND RESULTS: A case of a 75-year-old female patient with an asymptomatic mass of the oral floor is presented. Enhanced CT revealed a tumorous mass with radiopaque materials in the oral floor. A pathological diagnosis of MEC was obtained by biopsy. Radical surgery was performed with the patient under general anesthesia. The resected specimen was finally diagnosed as MEC. Histopathologically, hyalinization, and dystrophic calcification were conspicuous within the stromal components of the tumor. Interestingly, ectopic bone formation was also found in the tumor tissues. Bony materials with osteocyte-like cells were also observed in a series of dystrophic calcification. CONCLUSION: These findings suggest that bony materials are associated with dystrophic calcification. PMID- 25784187 TI - Recommendations for implant-retained nasal prostheses after ablative tumor surgery: Minimal surgical aftercare, high implant survival, and satisfied patients. AB - BACKGROUND: Nasal defects resulting from tumor resection are preferably rehabilitated with implant-retained nasal prostheses. Aftercare, clinical outcome of the implants, and patients' satisfaction with implant-retained nasal prostheses were assessed. METHODS: Twenty-eight consecutive patients needing total rhinectomy because of tumor resection between 1998 and 2013 were treated according to a standardized protocol with 2 implants in the nasal floor. Surgical and prosthetic aftercare was scored using patient records. Finally in 2014, skin reaction, peri-implant bone loss, and patients' satisfaction were assessed in all 13 still living patients. RESULTS: In total, 56 implants were inserted (median follow-up, 35.1 months; interquartile range [IQR], 8.9-63.3). Implant survival was 96.4%. Implant survival was independent of radiotherapy. Peri-implant skin was healthy and patients' satisfaction high. Longevity of the prostheses was limited. CONCLUSION: Rehabilitation of nasal defects resulting from total rhinectomy with implant-retained nasal prostheses, according to our protocol, resulted in high patient satisfaction and favorable treatment outcome. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E-E, 2016. PMID- 25784188 TI - Hydrogen-bonding-supported self-healing antifogging thin films. AB - Inspired by the repair of DNA through efficient reformation of hydrogen bonds (H bonds), herein we report a facile one-step approach to construction of self healing antifogging thin films on the basis of partly cross-linked poly(vinyl alcohol)(PVA) and poly(acrylic acid)(PAA). By designing the molar ratio of hydroxyl groups to carboxyl groups, the cross-linked polymer thin films maintain abundant free hydroxyl groups to present excellent antifogging property, which is derived from the hydrophilicity and hygroscopicity of the thin films. The thin films showed smart intrinsic self-healing characteristics towards wounds caused by external forces, which is attributed to sufficient free hydroxyl groups at the scratched interfaces to reform H-bonds across the interfaces and a sufficient chain mobility that is indispensable for chain diffusion across the interfaces and hydroxyl groups association to form H-bonds. No synthetic surfaces reported so far possess all the unique characteristics of the polymer thin films: intrinsic self-healing, long-term antifogging, excellent mechanical property, high transmittance and large-scale feasibility. PMID- 25784189 TI - Breast density: the trend in breast cancer screening. AB - The primary modality for breast cancer screening is mammography. Recent investigations, however, have indicated that an insufficient number of life threatening cases have been detected by mammography while mammography can often results in a large number of overdiagnoses. To make breast cancer screening more effective, potential factors that influence screening efficacy need to be elucidated. Breast density is one of limiting factors for breast cancer detection using mammography. In this article, influence of breast density on breast screening is explained. Current topics related to breast density, objective assessment of breast density using applications, revision of breast composition classification in Breast Imaging-Reporting and Data System Mammography fifth edition, and legislative movement regarding breast density in the United States, are also mentioned in this review article. PMID- 25784191 TI - Determinants of trends in breast-feeding indicators in Nigeria, 1999-2013. AB - OBJECTIVE: The present study aimed to examine the trends and differentials in key breast-feeding indicators in Nigeria for the period 1999-2013. DESIGN: Longitudinal study of trends (1999-2013) in optimal feeding practices using a series of population-based Nigerian Demographic and Health Surveys. Trends in socio-economic, health service and individual characteristics associated with key breast-feeding indicators were examined using multilevel regression analyses. SETTING: Nigeria. SUBJECTS: Children (n 88 152) aged under 24 months (n 8199 in 1999; n 7620 in 2003; n 33 385 in 2008; n 38 948 in 2013). RESULTS: Among educated mothers, there was an increase in prevalence of exclusive breast-feeding (26% in 1999 to 30% in 2013) and predominant breast-feeding (27% in 1999 to 39% in 2013) compared with mothers with no schooling. A similar increasing trend was evident for mothers from wealthier households and mothers who had a higher frequency of health service access compared with mothers from poorer households and women who reported no health service access, respectively. Mothers with no schooling predominantly breast-fed, but the odds for bottle-feeding were higher among educated mothers and women from wealthier households. The odds for early initiation of breast-feeding were lower for mothers who reported no health service contacts and mothers of lower socio-economic status. CONCLUSIONS: Significant increasing trends in key breast-feeding indicators were evident among mothers with higher socio-economic status and mothers who had more health service access in Nigeria. Broader national and sub-national policies that underpin nursing mothers in work environments and a comprehensive community-based approach are proposed to improve feeding practices in Nigeria. PMID- 25784190 TI - Network-based proteomic approaches reveal the neurodegenerative, neuroprotective and pain-related mechanisms involved after retrograde axonal damage. AB - Neurodegenerative processes are preceded by neuronal dysfunction and synaptic disconnection. Disconnection between spinal motoneuron (MN) soma and synaptic target leads either to a retrograde degenerative process or to a regenerative reaction, depending injury proximity among other factors. Distinguished key events associated with one or other processes may give some clues towards new therapeutical approaches based on boosting endogenous neuroprotective mechanisms. Root mechanical traction leads to retrograde MN degeneration, but share common initial molecular mechanisms with a regenerative process triggered by distal axotomy and suture. By 7 days post-injury, key molecular events starts to diverge and sign apart each destiny. We used comparative unbiased proteomics to define these signatures, coupled to a novel network-based analysis to get biological meaning. The procedure implicated the previous generation of combined topological information from manual curated 19 associated biological processes to be contrasted with the proteomic list using gene enrichment analysis tools. The novel and unexpected results suggested that motoneurodegeneration is better explained mainly by the concomitant triggering of anoikis, anti-apoptotic and neuropathic-pain related programs. In contrast, the endogenous neuroprotective mechanisms engaged after distal axotomy included specifically rather anti-anoikis and selective autophagy. Validated protein-nodes and processes are highlighted across discussion. PMID- 25784199 TI - Understanding socio-economic inequalities in food choice behaviour: can Maslow's pyramid help? AB - Socio-economic groups differ in their material, living, working and social circumstances, which may result in different priorities about their daily-life needs, including the priority to make healthy food choices. Following Maslow's hierarchy of human needs, we hypothesised that socio-economic inequalities in healthy food choices can be explained by differences in the levels of need fulfilment. Postal survey data collected in 2011 (67.2 % response) from 2903 participants aged 20-75 years in the Dutch GLOBE (Gezondheid en Levens Omstandigheden Bevolking Eindhoven en omstreken) study were analysed. Maslow's hierarchy of human needs (measured with the Basic Need Satisfaction Inventory) was added to age- and sex-adjusted linear regression models that linked education and net household income levels to healthy food choices (measured by a FFQ). Most participants (38.6 %) were in the self-actualisation layer of the pyramid. This proportion was highest among the highest education group (47.6 %). Being in a higher level of the hierarchy was associated with a higher consumption of fruits and vegetables as well as more healthy than unhealthy bread, snack and dairy consumption. Educational inequalities in fruit and vegetable intake (B= -1.79, 95 % CI -2.31, -1.28 in the lowest education group) were most reduced after the hierarchy of needs score was included (B= -1.57, 95 % CI - .09, -1.05). Inequalities in other healthy food choices hardly changed after the hierarchy of needs score was included. People who are satisfied with higher-level needs make healthier food choices. Studies aimed at understanding socio-economic inequalities in food choice behaviour need to take differences in the priority given to daily-life needs by different socio-economic groups into account, but Maslow's pyramid offers little help. PMID- 25784200 TI - Evidence-Informed, Individual Treatment of a Child with Sexual Behavior Problems: A Case Study. AB - Children with sexual behavior problems pose a significant challenge for community based mental health clinicians. Very few clinical trials are available to guide intervention and those interventions that are available are based in a group format. The current case study demonstrates the application of evidence-informed treatment techniques during the individual treatment of a 10-year-old boy displaying interpersonal sexual behavior problems. Specifically, the clinician adapts and implements a group-based model developed and tested by Bonner et al. (1999) for use with an individual child and his caregivers. Key points of the case study are discussed within the context of implementing evidence-informed treatments for children with sexual behavior problems. PMID- 25784202 TI - Recognition of familiar people with a mobile cloud architecture for Alzheimer patients. AB - PURPOSE: This article aims to the evaluation of a prototypal assistive technology for Alzheimer's disease (AD) patients that helps them to remember personal details of familiar people they meet in their daily lives. METHOD: An architecture is proposed for a personal information system powered by face recognition, where the main AD patient's interaction is performed in a smart watch device and the face recognition is carried out on the Cloud. A prototype was developed to perform some tests in a real-life scenario. RESULTS: The prototype showed correct results as a personal information system based on face recognition. However, usability flaws were identified in the interaction with the smart watch. CONCLUSIONS: Our architecture showed correct performance and we realized that it could be introduced in other fields, apart from assistive technology. However, when being targeted to patients with dementia some usability problems appeared, such as difficulties to read information in a small screen or take a proper photo. These problems should be addressed in further research. Implications for Rehabilitation This article presents a prototypal assistive technology for Alzheimer's disease (AD) patients. It targets AD patients to recognize their familiars, especially in medium-advanced stages of the disease. Analysing pictures taken by a smart watch, which the patient carries, the person in front is recognized and information about him is sent to the watch. This technology enables patients to have all the information of any close person, as a remainder, easing their daily lives, improving their self-esteem and stimulating the patient with novel technology. PMID- 25784201 TI - Determinants of handbike use in persons with spinal cord injury: results of a community survey in Switzerland. AB - PURPOSE: To examine the prevalence and determinants of handbike use in persons living with spinal cord injury in Switzerland. METHOD: A population-based cross sectional survey in Switzerland. RESULTS: The crude prevalence of handbike use among the 1549 participants was 22.6%, varying between 25.3% in men and 17.7% in women. Prevalence was higher in complete than in incomplete spinal cord injury (SCI) (41.5% versus 11.9% in paraplegia, 25.6% versus 11.1% in tetraplegia). Multivariable analysis of handbike use confirmed differences with lesion characteristics and gender and showed a decline with age, lowest rates in the low income group, variation with language, but no association with level of education or cause of spinal cord injury. In total, 45.8% of users reported to engage in handcycling at least once a week. Frequent contextual reasons for refraining from handcycling were: no interest (26%); inability due to disability (20%); unfamiliarity with the handbike (19%) and financial constraints (14%). CONCLUSIONS: Conditional on the major determinants that include demographic factors and lesion characteristics, main barriers involve contextual factors that can principally be overcome. Our findings thus suggest scope for promoting handcycling as a means towards a healthy and more physically active lifestyle in persons living with SCI. IMPLICATIONS FOR REHABILITATION: Handcycling is an effective means of improving health and quality of life of persons with a spinal cord injury. Persons with the following traits are most likely to use the handbike: persons younger than 62 years, with a complete paraplegia, who are German-speaking (vs. French/Italian) and having a middle or high net income. Indicated reasons for not using a handbike varied by SCI characteristics and included disinterest, inability related to the level of impairment, unfamiliarity and financial costs. Barriers that involve the above mentioned contextual factors can principally be overcome by targeted policy or information campaigns. PMID- 25784203 TI - The Geriatric ICF Core Set reflecting health-related problems in community-living older adults aged 75 years and older without dementia: development and validation. AB - PURPOSE: The aim of the present study was to develop a valid Geriatric ICF Core Set reflecting relevant health-related problems of community-living older adults without dementia. METHODS: A Delphi study was performed in order to reach consensus (>=70% agreement) on second-level categories from the International Classification of Functioning, Disability and Health (ICF). The Delphi panel comprised 41 older adults, medical and non-medical experts. Content validity of the set was tested in a cross-sectional study including 267 older adults identified as frail or having complex care needs. RESULTS: Consensus was reached for 30 ICF categories in the Delphi study (fourteen Body functions, ten Activities and Participation and six Environmental Factors categories). Content validity of the set was high: the prevalence of all the problems was >10%, except for d530 Toileting. The most frequently reported problems were b710 Mobility of joint functions (70%), b152 Emotional functions (65%) and b455 Exercise tolerance functions (62%). No categories had missing values. CONCLUSION: The final Geriatric ICF Core Set is a comprehensive and valid set of 29 ICF categories, reflecting the most relevant health-related problems among community-living older adults without dementia. This Core Set may contribute to optimal care provision and support of the older population. Implications for Rehabilitation The Geriatric ICF Core Set may provide a practical tool for gaining an understanding of the relevant health-related problems of community-living older adults without dementia. The Geriatric ICF Core Set may be used in primary care practice as an assessment tool in order to tailor care and support to the needs of older adults. The Geriatric ICF Core Set may be suitable for use in multidisciplinary teams in integrated care settings, since it is based on a broad range of problems in functioning. Professionals should pay special attention to health problems related to mobility and emotional functioning since these are the most prevalent problems in community-living older adults. PMID- 25784205 TI - Oxygen sorption and desorption properties of selected lanthanum manganites and lanthanum ferrite manganites. AB - Temperature-programmed desorption (TPD) with a carrier gas was used to study the oxygen sorption and desorption properties of oxidation catalysts and solid-oxide fuel cell (SOFC) cathode materials (La(0.85) Sr(0.15)0.95 MnO(3+delta) (LSM) and La(0.60) Sr(0.40) Fe(0.80) Mn(0.20) O(3-delta) (LSFM). The powders were characterized by X-ray diffractometry, atomic force microscopy (AFM), and BET surface adsorption. Sorbed oxygen could be distinguished from oxygen originating from stoichiometry changes. The results indicated that there is one main site for oxygen sorption/desorption. The amount of sorbed oxygen was monitored over time at different temperatures. Furthermore, through data analysis it was shown that the desorption peak associated with oxygen sorption is described well by second order desorption kinetics. This indicates that oxygen molecules dissociate upon adsorption and that the rate-determining step for the desorption reaction is a recombination of monatomic oxygen. Typical problems with re-adsorption in this kind of TPD setup were revealed to be insignificant by using simulations. Finally, different key parameters of sorption and desorption were determined, such as desorption activation energies, density of sorption sites, and adsorption and desorption reaction order. PMID- 25784204 TI - Convection-enhancement delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model. AB - The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum-based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin(TM) - liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with gamma radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra venous (i.v.) administration, and by 9- to 34-fold, when compared to intra arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later. PMID- 25784206 TI - Parenting after preterm birth: link between infant medical risk and premature parenthood. A pilot study. AB - BACKGROUND: The aim of the present study was to examine the relationship between parental emotion regulation, infant medical risks and representation of child's behavior at 3 months corrected age. METHODS: The sample includes 28 couples (parents) and 32 preterm infants (4 set of twins) (AG average: 29 weeks), low birth weight (average weight: 1180.62 g), hospitalized for about two months. At the 3rd month of corrected age of the child all couples were interviewed using the "Clinical Interview for Parents of High Risk Infants" (CLIP), which explores the emotional aspects associated with preterm birth. The interviews were recorded, transcribed and analysed using ATLAS.TI. After the interview, only 14 mothers and 14 fathers completed the Behavior Rating Scale (SVC-80; Laicardi, 1998), which explores the observational-representative styles of each parent with respect to the child's behavior in the context of everyday life. We identified three Couples Groups indicating qualitative differences in the emotional functioning of the subjects mainly in the temporal dimension: 1) 12 "future oriented"; 2) 12 "suspended in the present"; 3) 4 "oriented to the past". RESULTS: The results show that the infant's medical status has a impact on ability of parents to process the experience of preterm birth: increasing the infant's medical risks increases the difficulty of parents ability to process the experience. CONCLUSIONS: The CLIP can be a useful screening tool to identify difficulties of parents, to structure interventions focused on the elaboration of the traumatic experience of birth and on improving the quality of parent-infant relationship. PMID- 25784207 TI - Central venous catheter placement in children with thrombocytopenia. AB - BACKGROUND: The use of central venous catheter (CVC) is essential in the management of chronically ill children. Thrombocytopenia is a common hematological finding in these patients, with an increased risk of bleeding during the insertion of CVC. No clear guidelines are reported regarding the CVC positioning in patients with disorders of hemostasis, and prophylactic platelet (PLT) transfusions are still controversial. Aim of this study was to report the bleeding risk in pediatric patients with thrombocytopenia who underwent positioning of CVC. METHODS: A retrospective single-center study of all CVCs surgically inserted over a 2-year period (April 2011 - April 2013) at our institution was performed. Age, gender, diagnosis, type of CVC, hematological values (hemoglobin and PLT count, prothrombin international normalized ratio, active partial thromboplastin time) and post-operative bleeding complications were compared between patients with PLT count below (group A) and above 50*109/L (group B). RESULTS: Seventy-two CVC procedures were performed in 67 patients, with a median age of 45 months. Of these, 25 (35%) catheters were positioned in 25 patients included in group A and the remaining 47 (65%) in 42 patients in group B. All twenty-five cases in group A received a prophylactic PLT transfusion prior to the procedure. Bleeding complications were reported in only two cases in group A (8%). CONCLUSIONS: CVC placement in pediatric patients with thrombocytopenia can be safely performed. We believe a randomized multicenter study could be necessary to determine the benefit of PLT transfusions in children with a PLT count below the recommended level of 50*109/L. PMID- 25784208 TI - Percutaneous internal jugular venous cannulation for extracorporeal circulation during minimally invasive technique in children with congenital heart disease: operative technique and results. AB - BACKGROUND: The aim of this study was to evaluate the safety and efficacy of the percutaneous cannulation of the internal jugular venous (PCIJV) for extracorporeal circulation during minimally invasive cardiac surgery (MICS) in children with simple congenital heart disease. METHODS: From September 2007, 83 children (<16 years) underwent PCIJV for extracorporeal circulation. Primary outcome of the study was to evaluate the safety and advantages of PCIJV technique. Technical steps and pitfalls of PCIJV technique are described. RESULTS: Median age at surgery was 9 years (range 3.5-16 years) and median body weight was 31 kilograms (range 13-72 kilograms); 32 patients (40%) had a body weight less than 30 kilograms. The PCIJV was achieved with a 14 French cannula in 61 pts (73%), with a 17 Fr cannula in 22 (23%). The PIJVC was judged difficult in 2 patients (2.4%); in both of them cannulation was achieved at a different venous site There were no procedure-related complications and no flow disturbances during the extracorporeal circulation. CONCLUSIONS: The PCIJV during MICS is an effective and reproducible technique for achieving peripheral CPB in children with simple CHDs. We progressively expanded the use of this technique in smaller children and this allows us to further minimize surgical trauma without experiencing venous drainage's problems. PMID- 25784209 TI - Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice. AB - Apolipoprotein D (apoD) is expressed in the brain and levels are increased in affected brain regions in Alzheimer's disease (AD). The role that apoD may play in regulating AD pathology has not been addressed. Here, we crossed both apoD null mice and Thy-1 human apoD transgenic mice with APP-PS1 amyloidogenic AD mice. Loss of apoD resulted in a nearly 2-fold increase in hippocampal amyloid plaque load, as assessed by immunohistochemical staining. Conversely, transgenic expression of neuronal apoD reduced hippocampal plaque load by approximately 35%. This latter finding was associated with a 60% decrease in amyloid beta 1-40 peptide levels, and a 34% decrease in insoluble amyloid beta 1-42 peptide. Assessment of beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) levels and proteolytic products of amyloid precursor protein and neuregulin-1 point toward a possible association of altered BACE1 activity in association with altered apoD levels. In conclusion, the current studies provide clear evidence that apoD regulates amyloid plaque pathology in a mouse model of AD. PMID- 25784211 TI - Mitochondrial Genome Maintenance 1 (Mgm1) Protein Alters Membrane Topology and Promotes Local Membrane Bending. AB - Large GTPases of the dynamin superfamily promote membrane fusion and division, processes that are crucial for intracellular trafficking and organellar dynamics. To promote membrane scission, dynamin proteins polymerize, wrap around, and constrict the membrane; however, the mechanism underlying their role in membrane fusion remains unclear. We previously reported that the mitochondrial dynamin related protein mitochondrial genome maintenance 1 (Mgm1) mediates fusion by first tethering opposing membranes and then undergoing a nucleotide-dependent structural transition. However, it is still unclear how Mgm1 directly affects the membrane to drive fusion of tethered membranes. Here, we show that Mgm1 association with the membrane alters the topography of the membrane, promoting local membrane bending. We also demonstrate that Mgm1 creates membrane ruffles resulting in the formation of tubular structures on both supported lipid bilayers and liposomes. These data suggest that Mgm1 membrane interactions impose a mechanical force on the membrane to overcome the hydrophilic repulsion of the phospholipid head groups and initiate the fusion reaction. The work reported here provides new insights into a possible mechanism of Mgm1-driven mitochondrial membrane fusion and sheds light into how members of the dynamin superfamily function as fusion molecules. PMID- 25784210 TI - Age-related changes in regulator of G-protein signaling (RGS)-10 expression in peripheral and central immune cells may influence the risk for age-related degeneration. AB - Inflammation in the aging brain increases risk for neurodegenerative disease. In humans, the regulator of G-protein signaling-10 (RGS10) locus has been associated with age-related maculopathy. Chronic peripheral administration of lipopolysaccharide in the RGS10-null mice induces nigral dopaminergic (DA) degeneration, suggesting that RGS10 modulates neuroimmune interactions and may influence susceptibility to neurodegeneration. Because age is the strongest risk factor for neurodegenerative disease, we assessed whether RGS10 expression changes with age and whether aged RGS10-null mice have altered immune cell profiles. Loss of RGS10 in aged mice does not alter the regulation of nigral DA neurons but does alter B-cell, monocyte, microglial, and CD4+ T-cell populations and inflammatory cytokine levels in the cerebrospinal fluid. These results suggest that loss of RGS10 is associated with an age-dependent dysregulation of peripheral and central immune cells rather than dysregulation of DA neuron function. PMID- 25784212 TI - Salivary microRNAs in oral cancer. AB - OBJECTIVE: This study investigated the use of three salivary microRNAs (miRNA-21, miRNA-184, and miRNA-145) as possible markers for malignant transformation in oral mucosal lesions. MATERIALS AND METHODS: Salivary whole unstimulated samples were collected from a study group of 100 subjects, consisting of 20 clinically healthy controls, 40 patients with oral potentially malignant disorders (PMDs) [20 with dysplastic lesions and 20 without dysplasia], 20 with biopsy-confirmed oral squamous cell carcinoma (OSCC), and 20 with recurrent aphthous stomatitis (RAS) as disease controls. Total RNA was isolated and purified from saliva samples using the microRNA Isolation Kit (Qiagen, UL). miRNA expression analysis was performed using qRT-PCR (Applied Biosystems). RESULTS: There was a highly significant increase in salivary miRNA-21 and miRNA-184 in OSCC and PMD (with and without dysplasia) when compared to healthy and disease controls (P < 0.001). Conversely, miRNA-145 levels showed a highly significant decrease in OSCC and PMD overall (P < 0.001). RAS cases showed no significant difference from normal controls in any measured miRNA (P > 0.05). The only microRNA to discriminate between OSCC and PMD with dysplasia was miRNA-184. When receiver operating characteristic curves were designed for the three miRNAs, cutoff points delineating the occurrence of malignant change were a fourfold increase in miRNA 21 with specificity 65% and sensitivity 65%, a 0.6 decrease in miRNA-145, with specificity 70% and sensitivity 60%, and a threefold increase of miRNA-184, with specificity 75% and sensitivity 80%. Calculating the area under the curve revealed that miRNA-184 was the only one among the studied miRNAs that provided good diagnostic value. CONCLUSION: Salivary determination of the miRNAs tested might furnish a noninvasive, rapid adjunctive aid for revealing malignant transformation in oral mucosal lesions, particularly miRNA-184. PMID- 25784213 TI - Technique for identifying Schlemm's canal in paediatric glaucoma surgery. PMID- 25784214 TI - The relationship between structure and function as measured by OCT and Octopus perimetry. AB - BACKGROUND/AIMS: To determine the structure-function relationship between equivalent visual field areas obtained with the Octopus perimeter (OP), and the peripapillary retinal nerve fibre layer (RNFL) thickness measured with spectral domain optical coherence tomography (OCT) in healthy individuals and patients with glaucomatous optic neuropathy. METHODS: Eighty-eight normal subjects and 150 patients with open-angle glaucoma were prospectively recruited. Eligible participants for the glaucoma group were required to have elevated intraocular pressure and glaucomatous optic nerve head morphology. All participants underwent reliable automated perimetry with OP, and optic nerve head imaging with the Cirrus OCT. Principal component analysis of the mean threshold values for the visual field test points were performed independently for each hemifield. Pearson correlations were calculated between visual field regions and RNFL thickness sectors. RESULTS: Mild to moderate correlations were observed between the visual field regions and the peripapillary RNFL thicknesses. Each visual field region was significantly correlated with more than one RNFL sector, and vice versa. The strongest correlation was observed between the RNFL thickness at 5 and 7 clock hour positions and the superonasal region of OP (r=0.63). CONCLUSIONS: Retinal sensitivity evaluated with OP correlated moderately well with the RNFL thickness measured by OCT. There was an overlap of the visual field regions within the optic disc. PMID- 25784215 TI - The treatment of carcinoma in situ and squamous cell carcinoma of the conjunctiva with fractionated strontium-90 radiation in a population with a high prevalence of HIV. AB - BACKGROUND: This study explores the safety and efficacy of strontium 90 (Sr-90) brachytherapy as the sole adjuvant therapy for carcinoma in situ (CIS) and squamous cell carcinoma (SCC) of the conjunctiva in a high HIV prevalent area. METHODS: This is a retrospective case review of patients treated with 60 Gray Sr 90 brachytherapy in four divided doses after resection with a 2 mm margin and histological confirmation. Cryotherapy or alcohol debridement was not performed at the time of excision due to limited resources. Two plaque sizes, 8.5 mm and 18 mm, were used. RESULTS: Sixty-nine patients were treated and had a median follow up of 27 months (range 6-127). Thirty-three (47.8%) were HIV-positive. CIS was present in 40.6% and SCC in 59.4%. The surgical margins were positive in 39 (56.5%). Twenty patients (29.0%) were treated with the 18 mm plaque and 49 (71.0%) with the 8.5 mm plaque. Eight (11.6%) patients developed a recurrence at a median of 5 months (range 2-40). Recurrences only occurred in patients treated with the 8.5 mm plaque (p=0.094). There was no significant effect of HIV status, positive margins or staging on the number of recurrences. Treatment side effects were a dry eye in five patients which was successfully managed with topical lubricants, and induced astigmatism of 1 dioptre of cylinder in one patient. CONCLUSIONS: Sr-90 brachytherapy is safe and effective in preventing recurrences in ocular surface squamous neoplasia in a high HIV prevalent setting. The 18 mm plaque size is superior to the 8.5 mm plaque size. PMID- 25784217 TI - Photocurrent generation through charge-transfer processes in noncovalent perylenediimide/DNA complexes. AB - The charge-transfer process in noncovalent perylenediimide (PDI)/DNA complexes has been investigated by using nanosecond laser flash photolysis (LFP) and photocurrent measurements. The PDI/DNA complexes were prepared by inclusion of cationic PDI molecules into the artificial cavities created inside DNA. The LFP experiments showed that placement of the PDI chromophore at a specific site and included within the base stack of DNA led to the efficient generation of a charge separated state with a long lifetime by photoexcitation. When two PDI chromophores were separately placed at different positions in DNA, the yield of the charge-separated state with a long lifetime was dependent upon the number of A-T base pairs between the PDIs, which was explained by electron hopping from one PDI to another. Photocurrent generation of the DNA-modified electrodes with the complex was also dependent upon the arrangement of the PDI chromophores. A good correlation was obtained between observed charge separation and photocurrent generation on the PDI/DNA-modified electrodes, which demonstrated the importance of the defined arrangement and assembly of organic chromophores in DNA for efficient charge separation and transfer in multichromophore arrays. PMID- 25784216 TI - Effects of food on pharmacokinetics of immediate release oral formulations of aspirin, dipyrone, paracetamol and NSAIDs - a systematic review. AB - AIMS: It is common to advise that analgesics, and especially non-steroidal anti inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states. METHODS: A systematic review of comparisons of oral analgesics in fed and fasting states published to October 2014 reporting kinetic parameters of bioavailability, time to maximum plasma concentration (tmax ), and its extent (Cmax ) was conducted. Delayed-release formulations were not included. RESULTS: Bioavailability was not different between fasted and fed states. Food typically delayed absorption for all drugs where the fasting tmax was less than 4 h. For the common analgesics (aspirin, diclofenac, ibuprofen, paracetamol) fed tmax was 1.30 to 2.80 times longer than fasted tmax . Cmax was typically reduced, with greater reduction seen with more rapid absorption (fed Cmax only 44-85% of the fasted Cmax for aspirin, diclofenac, ibuprofen and paracetamol). CONCLUSION: There is evidence that high, early plasma concentrations produces better early pain relief, better overall pain relief, longer lasting pain relief and lower rates of remedication. Taking analgesics with food may make them less effective, resulting in greater population exposure. It may be time to rethink research priorities and advice to professionals, patients and the public. PMID- 25784218 TI - Acid citrate dextrose extracorporeal photopheresis is an alternative treatment option for patients with heparin allergy. PMID- 25784219 TI - A flexible mixed-effect negative binomial regression model for detecting unusual increases in MRI lesion counts in individual multiple sclerosis patients. AB - We develop a new modeling approach to enhance a recently proposed method to detect increases of contrast-enhancing lesions (CELs) on repeated magnetic resonance imaging, which have been used as an indicator for potential adverse events in multiple sclerosis clinical trials. The method signals patients with unusual increases in CEL activity by estimating the probability of observing CEL counts as large as those observed on a patient's recent scans conditional on the patient's CEL counts on previous scans. This conditional probability index (CPI), computed based on a mixed-effect negative binomial regression model, can vary substantially depending on the choice of distribution for the patient-specific random effects. Therefore, we relax this parametric assumption to model the random effects with an infinite mixture of beta distributions, using the Dirichlet process, which effectively allows any form of distribution. To our knowledge, no previous literature considers a mixed-effect regression for longitudinal count variables where the random effect is modeled with a Dirichlet process mixture. As our inference is in the Bayesian framework, we adopt a meta analytic approach to develop an informative prior based on previous clinical trials. This is particularly helpful at the early stages of trials when less data are available. Our enhanced method is illustrated with CEL data from 10 previous multiple sclerosis clinical trials. Our simulation study shows that our procedure estimates the CPI more accurately than parametric alternatives when the patient specific random effect distribution is misspecified and that an informative prior improves the accuracy of the CPI estimates. PMID- 25784221 TI - The role of paroxysmal nocturnal hemoglobinuria clones in response to immunosuppressive therapy of patients with severe aplastic anemia. AB - Whether paroxysmal nocturnal hemoglobinuria (PNH) clone in aplastic anemia (AA) is a prognostic factor to immunosuppressive therapy is a subject of debate. We evaluated hematological responses to immunosuppressive therapy (IST) in severe AA (SAA) patients with or without the presence of a PNH clone. In 97 SAA patients who received first-line IST between January and December 2011, 24 (24.7 %) had a PNH clone prior to treatment, with a median clone size of 7.82 % (range 1.19 45.46 %). The response rates to IST for patients with or without a PNH clone were 66.7 and 50.7 % (P < 0.172), 79.2 and 57.5 % (P < 0.057), and 79.2 and 67.1 % (P < 0.264) at 3, 6, and 12 months, respectively. Combined rate of complete and good partial responses differed between patients with or without a PNH clone: insignificantly at 3 months (41.7 vs. 21.9 %, P < 0.058), but significantly at 6 (66.7 vs. 31.5 %, P < 0.002) and 12 (75.0 vs. 46.6 %, P < 0.015) months. Multivariate analysis revealed that a pretreatment neutrophil count of >0.2 * 10(9)/L is indicative of a better response, while the presence of a PNH clone is predictive to a higher combined rate of complete and good partial responses. This study demonstrated that the presence of a PNH clone could predict a better hematological response instead of a higher response rate in patients with SAA. PMID- 25784222 TI - Allogeneic transplantation with myeloablative FluBu4 conditioning improves survival compared to reduced intensity FluBu2 conditioning for acute myeloid leukemia in remission. AB - The optimal intensity of conditioning for allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) remains undefined. Traditionally, myeloablative conditioning regimens improve disease control, but at the risk of greater nonrelapse mortality. Because fludarabine with myeloablative doses of intravenous busulfan using pharmacokinetic monitoring has excellent tolerability, we reasoned that this regimen would limit relapse without substantially elevating toxicity when compared to reduced intensity conditioning. We retrospectively analyzed 148 consecutive AML patients in remission receiving T cell replete HCT conditioned with fludarabine and intravenous busulfan at doses defined as reduced (6.4 mg/kg; FluBu2, n = 63) or myeloablative (12.8 mg/kg; FluBu4, n = 85). Early and late nonrelapse mortality (NRM) was similar among FluBu4 and FluBu2 recipients, respectively (day + 100: 4 vs 0 %; 5 years: 19 vs 22 %; p = 0.54). NRM did not differ between FluBu4 and FluBu2 in patients >50 years of age (24 vs 22 %, p = 0.75). Relapse was lower in recipients of FluBu4 (5 years: 30 vs 49 %; p = 0.04), especially in patients with poor risk cytogenetics (22 vs 59 %; p = 0.02) and those >50 years of age (28 vs 51 %; p = 0.02). Overall survival favored FluBu4 recipients at 5 years (53 vs 34 %, p = 0.02), a finding confirmed in multivariate analysis (HR: 0.57; 95 % CI: 0.34-0.95; p = 0.03). These data suggest that myeloablative FluBu4 may provide equivalent NRM, reduced relapse, and improved survival compared to FluBu2, emphasizing the importance of busulfan dose in conditioning for AML. PMID- 25784223 TI - Cutaneous mucormycosis of scalp and eyelids in a child with type I diabetes mellitus. AB - Scalp mucormycosis in children is extremely rare. We present a case of pediatric scalp mucormycosis caused by Rhizopus oryzae in a 9-year-old diabetic girl who was successfully diagnosed and treated with amphotericin B deoxycholate and wound debridement. At 3 months follow up, the patient was stable although she had lost her vision. PMID- 25784224 TI - Prepubertal onset of hidradenitis suppurativa in a girl: A case report and literature review. PMID- 25784220 TI - A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. AB - Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 * 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 * 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells. PMID- 25784225 TI - Peripheral T-cell lymphoma, not otherwise specified presenting with multiple tender cutaneous nodules and plaques. PMID- 25784226 TI - Histiocytoid sweet syndrome related to bortezomib: A mimicker of cutaneous infiltration by myeloma. PMID- 25784227 TI - Oculocutaneous tyrosinemia: A case report with delayed diagnosis and excellent response to dietary modification. PMID- 25784228 TI - Scar examination in sporotrichosis: An additional tool for clinical diagnosis. PMID- 25784229 TI - Sclerodermoid plaques: A riddle of 'H'. PMID- 25784245 TI - Antibiotic therapy for ventilator-associated tracheobronchitis: a standard of care to reduce pneumonia, morbidity and costs? AB - PURPOSE OF REVIEW: The present review draws our attention to ventilator associated tracheobronchitis (VAT) as a distinct clinical entity that has been associated with progression to ventilator-associated pneumonia (VAP) and worse patient outcomes. In contrast to VAP, which has been extensively investigated for over the past 30 years, most VAT studies have been conducted in the past decade. There are ample data which demonstrate that VAT may progress to VAP, have more ventilator days, and have longer ICU stay that may translate into higher healthcare costs. RECENT FINDINGS: The article focuses on the diagnostic criteria for VAT, causative agents, and studies analyzing associations between VAT and patient outcomes in relation to early, appropriate intravenous, and/or aerosolized antibiotic therapy. Aerosolized antibiotic treatment delivered by improved device technology is a novel approach that has proved to be effective for the treatment and eradication of multidrug-resistant bacterial pathogens. Aerosolized antibiotics are effective in decreasing the use of systemic antibiotics, reducing bacterial resistance, and may also facilitate clinical resolution of infection. SUMMARY: Evidence presented in this review supports treatment of VAT with early and appropriate antibiotic therapy as a standard of care to reduce VAP, ventilator days, and duration of ICU stay in high-risk patient population. PMID- 25784247 TI - Ventilator-associated infection: the role for inhaled antibiotics. AB - PURPOSE OF REVIEW: Despite multiple protocols for the prevention of ventilator associated pneumonia (VAP), respiratory infections have not been eliminated in the ICU. The profound disruption in both airway integrity and mucociliary clearance caused by the endotracheal tube makes it unlikely there will ever be a zero rate of respiratory infection in critically ill ventilated patients or a 100% cure rate when infection is present. In fact, options for treatment are diminishing as bacteria resistant to most, or in some hospitals all, systemic antibiotics increase in prevalence from our liberal use of systemic antibiotics. Inhaled therapy with proper delivery will result in the high concentrations of antibiotics needed in the treatment of increasingly resistant organisms. RECENT FINDINGS: Data from many recent investigations have focused on inhaled antibiotics as: adjunctive therapy to systemic antibiotic for VAP, monotherapy for VAP, and as monotherapy for ventilator-associated tracheobronchitis. The clinical outcomes of these studies will be reviewed as well as their effect on multidrug-resistant organisms. SUMMARY: The present review will focus on the rationale for inhaled therapy, the current studies examining the delivery and clinical efficacy of inhaled antibiotics, and the potential role for this mode of delivery actually decreasing antibiotic resistance in the respiratory tract. PMID- 25784248 TI - Targeting antimicrobial-resistant bacterial respiratory tract pathogens: it is time to 'get smart'. AB - PURPOSE OF REVIEW: Pathogen-directed therapy targeting multidrug-resistant bacteria in pneumonia can be a challenge. We reviewed the recent literature on bacterial resistance, diagnostic methods, and treatment strategies to guide pathogen-directed therapy of respiratory infections. RECENT FINDINGS: Antibiotic resistance is a growing problem in both community and nosocomial settings. Macrolide resistance in Streptococcus pneumoniae varies geographically, ranging from 45 to 88%, and has been associated with prior antibiotic use. Methicillin resistant Staphylococcus aureus and multidrug-resistant Gram-negative bacilli remain the main targets for pathogen-directed therapy in patients with hospital acquired and ventilator-associated pneumonia. Rapid molecular tests show promise to facilitate pathogen-directed therapy. Improved antibiotic use with the right drug and optimal dose is a key strategy in tackling antimicrobial resistance. Evidence supporting de-escalation for hospital-acquired and ventilator-associated pneumonia has been increasing. To date, no convincing evidence exists to support combination therapy for severe infections due to carbapenem-resistant Gram negative bacilli. Aerosolized therapy might provide additive benefits to parenteral therapy, but requires further study. SUMMARY: Pathogen-directed therapy guided by in-vitro microbiological data is a safe approach for the treatment of respiratory infections due to antibacterial-resistant bacteria. Further research should focus on the role of rapid diagnostic tools, new antibiotics, and novel immunotherapy for respiratory infection. PMID- 25784246 TI - Pneumonia in the neutropenic cancer patient. AB - PURPOSE OF REVIEW: Pneumonia is the leading cause of death among neutropenic cancer patients, particularly those with acute leukaemia. Even with empiric therapy, case fatality rates of neutropenic pneumonias remain unacceptably high. However, recent advances in the management of neutropenic pneumonia offer hope for improved outcomes in the cancer setting. This review summarizes recent literature regarding the clinical presentation, microbiologic trends, diagnostic advances and therapeutic recommendations for cancer-related neutropenic pneumonia. RECENT FINDINGS: Although neutropenic patients acquire pathogens both in community and nosocomial settings, patients' obligate healthcare exposures result in the frequent identification of multidrug-resistant bacterial organisms on conventional culture-based assessment of respiratory secretions. Modern molecular techniques, including expanded use of galactomannan testing, have further facilitated identification of fungal pathogens, allowing for aggressive interventions that appear to improve patient outcomes. Multiple interested societies have issued updated guidelines for antibiotic therapy of suspected neutropenic pneumonia. The benefit of antibiotic medications may be further enhanced by agents that promote host responses to infection. SUMMARY: Neutropenic cancer patients have numerous potential causes for pulmonary infiltrates and clinical deterioration, with lower respiratory tract infections among the most deadly. Early clinical suspicion, diagnosis and intervention for neutropenic pneumonia provide cancer patients' best hope for survival. PMID- 25784249 TI - Respiratory tract infections in community and healthcare settings: epidemiological, diagnostic and management challenges. PMID- 25784250 TI - Lactoferrin: A Roadmap to the Borderland between Caries and Periodontal Disease. AB - Lactoferrin is one of a number of multifunctional proteins that are present in or on all mucosal surfaces throughout the body. Levels of lactoferrin are consistently elevated in inflammatory diseases such as arthritis, inflammatory bowel diseases, corneal disease, and periodontitis. Single-nucleotide polymorphisms (SNPs) in lactoferrin have been shown to be present in individuals susceptible to Escherichia coli-induced travelers' diarrhea and in tear fluid derived from virally associated corneal disease. Here, we review data showing a lactoferrin SNP in amino acid position 29 in the antimicrobial region of lactoferrin that acts against caries associated bacteria. This SNP was initially discovered in African American subjects with localized aggressive periodontitis (LAP) who had proximal bone loss but minimal proximal caries. Results were confirmed in a genetic association study of children from Brazil with this same SNP who showed a reduced level of caries. In vitro data indicate that lactoferrin from whole saliva derived from subjects with this SNP, recombinant human lactoferrin containing this SNP, or an 11-mer peptide designed for this SNP kills mutans streptococci associated with caries by >1 log. In contrast, the SNP has minimal effect on Gram-negative species associated with periodontitis. Moreover, periodontally healthy subjects homozygous for this lysine (K) SNP have lactoferrin in their saliva that kills mutans streptococci and have reduced proximal decay. The review summarizes data supporting the ecologic plaque hypothesis and suggests that a genetic variant in lactoferrin with K in position 29 when found in saliva and crevice fluid can influence community biofilm composition. We propose that, for caries, this SNP is ethnicity independent and protective by directly killing caries-provoking bacteria (reducing proximal decay). However, the clinical effect of this SNP in LAP is ethnicity dependent, destructive (increases LAP incidence), and complex with mechanisms still to be determined. PMID- 25784251 TI - Effect of Antimuscarinic Autoantibodies in Primary Sjogren's Syndrome. AB - The presence of functional autoantibodies against the muscarinic type 3 receptor (M3R) has been reported in primary Sjogren's syndrome (pSS). However, the pathogenic role of these autoantibodies in pSS development remains to be elucidated. In this experiment, we investigated a pathologic role of pSS autoantibodies (pSS IgG) associated with downregulation of the major histocompatibility complex I (MHC I) molecule with M3R through internalization. Anti-M3R autoantibodies in purified control and pSS IgG were detected using 4 synthesized cyclic M3R peptides by enzyme-linked immunosorbent assay. The binding reactivity of pSS IgG to M3R in situ was analyzed by a dual immunostaining method. Surface expression, interaction, and internalization of M3R with MHC I were analyzed by immunofluorescence confocal microscopy and biochemical assays. Synthetic cyclic peptides M3RP(205-221) and M3RP(520-527) showed significantly high reactivity with pSS IgG compared to the control IgG or the other 3 peptides (P < 0.05). Significantly high reactivity of pSS IgG to M3R in situ was observed. PSS IgG increased the interaction of membrane M3R with MHC I and induced their internalization in primary human submandibular gland cells. The pSS IgG-induced internalization of M3R with MHC I was significantly inhibited by the cholesterol sequestering drug filipin. Our novel finding-namely, strong downregulation of the membrane MHC I with M3R through internalization of the cholesterol-rich microdomain associating with anti-M3R autoantibodies-could be an important mechanism contributing to the impaired salivation seen in pSS and linking secretory hypofunction to autoimmune pathogenesis. PMID- 25784252 TI - MicroRNA-200a Regulates the Development of Mandibular Condylar Cartilage. AB - Mandibular condylar cartilage (MCC) is classified as secondary cartilage, the histologic structure of which is unique from that of primary cartilage. MicroRNA (miRNA) is a small noncoding RNA that binds to the messenger RNA (mRNA) target to repress its translation and plays an important role in cell differentiation, proliferation, and death. Microarray analysis revealed that miR-200a was characteristically expressed during embryonic development. We hypothesized that miR-200a may be involved in regulating the formation of cartilage during MCC growth. We investigated the function of miR-200a by transfecting an inhibitor or mimic into MCC organ and cell cultures. A histologic examination revealed the localized inhibitory effects of the miR-200a mimic and widespread enhancing effects of the inhibitor on chondrocytic differentiation in the MCC organ culture system. An immunohistochemical examination and gene expression analysis demonstrated that the miR-200a inhibitor enhanced chondrogenesis, while the mimic had the opposite effect by enhancing cell proliferation. Quantitative reverse transcription polymerase chain reaction analysis revealed that miR-200a downregulated the gene expression of chondrocyte markers. Moreover, transfection of the miR-200a mimic into ATDC5 cells repressed the formation of the cartilaginous matrix. These results indicate that miR-200a contributed to chondrogenesis in developing MCC by controlling proliferation and differentiation in MCC cells. PMID- 25784268 TI - Professionalism in Iranian Nursing: Concept Analysis. AB - PURPOSE: The present study was conducted with the aim of clarifying and reducing the semantic ambiguities around the concept of professionalism. METHODS: The concept analysis method of Walker and Avant was used. FINDINGS: The analysis demonstrated that professionalism in nursing consists of three main pillars: principles of care, communication, and ethics. CONCLUSIONS: Given that the process of professionalism in nursing may have positive outcomes for the nurse, the nursing profession, and the health system of the community, these items have been attended to. IMPLICATIONS FOR NURSING PRACTICE: The present concept analysis can open the way to conducting more extensive research and devising tools to identify the barriers, facilitators, and administrative arrangements by clarifying the concept. PMID- 25784267 TI - Metabonomic Changes Associated with Atherosclerosis Progression for LDLR(-/-) Mice. AB - Atherosclerosis resulting from hyperlipidemia causes many serious cardiovascular diseases. To understand the systems changes associated with pathogenesis and progression of atherosclerosis, we comprehensively analyzed the dynamic metabonomic changes in multiple biological matrices of LDLR(-/-) mice using NMR and GC-FID/MS with gene expression, clinical chemistry, and histopathological data as well. We found that 12 week "Western-type" diet (WD) treatment caused obvious aortic lesions, macrophage infiltration, and collagen level elevation in LDLR(-/-) mice accompanied by up-regulation of inflammatory factors including aortic ICAM-1, MCP-1, iNOS, MMP2, and hepatic TNFalpha and IL-1beta. The WD induced atherosclerosis progression was accompanied by metabonomic changes in multiple matrices including biofluids (plasma, urine) and (liver, kidney, myocardial) tissues involving multiple metabolic pathways. These included disruption of cholesterol homeostasis, disturbance of biosynthesis of amino acids and proteins, altered gut microbiota functions together with metabolisms of vitamin-B3, choline, purines, and pyrimidines. WD treatment caused down regulation of SCD1 and promoted oxidative stress reflected by urinary allantoin elevation and decreases in hepatic PUFA-to-MUFA ratio. When switching to normal diet, atherosclerotic LDLR(-/-) mice reprogrammed their metabolisms and reversed the atherosclerosis-associated metabonomic changes to a large extent, although aortic lesions, inflammation parameters, macrophage infiltration, and collagen content were only partially alleviated. We concluded that metabolisms of fatty acids and vitamin-B3 together with gut microbiota played crucially important roles in atherosclerosis development. These findings offered essential biochemistry details of the diet-induced atherosclerosis and demonstrated effectiveness of the integrated metabonomic analysis of multiple biological matrices for understanding the molecular aspects of cardiovascular diseases. PMID- 25784269 TI - [Epigenetics in urothelial cancer: Pathogenesis, improving diagnostics and developing novel treatment options]. AB - Urothelial carcinoma of the bladder is a common tumor for which improvements in diagnostic markers and new therapy approaches, in addition to or combined with standard chemotherapy, are urgently required. Epigenetic alterations could provide both novel diagnostic markers and therapeutic targets as they are emerging as crucial factors in the development and progression of this tumor type, likely contributing to altered differentiation and metastatic potential. These alterations affect DNA methylation, histone modifications, chromatin remodeling, long noncoding RNAs, and microRNAs. Factors involved in histone modifications and chromatin remodeling appear to be particularly frequently inactivated by mutations. Thus, histone-modifying enzymes may represent good targets for rational new therapeutic approaches, although thorough investigation of their complex functions is a prerequisite. DNA methylation changes and altered miRNA expression provide promising biomarkers for diagnosis and prognosis that need further validation in comprehensive and well-standardized studies. PMID- 25784270 TI - [Diagnostics of nonmuscle-invasive urothelial cell carcinoma of the bladder]. AB - Cystoscopy and transurethral resection in combination with urinary cytology are integral parts of the diagnosis and therapy of urothelial cell carcinoma of the bladder. Given the fact that low grade bladder cancer has high recurrence and extremely low progression rates, the benefit for additional diagnostics needs to be further evaluated. In high grade tumors, early and accurate diagnosis is of high importance. Fluorescence cystoscopy and narrow band imaging are procedures to increase the detection rate. This article provides an overview of the current value of these two procedures. PMID- 25784272 TI - [Regional for residents: GeSRU programs at regional urology meetings in 2015]. PMID- 25784271 TI - [Therapy of low-grade nonmuscle-invasive bladder cancer]. AB - Nonmuscle-invasive bladder cancer (NMIBC) comprises a very heterogeneous group of malignancies; the biological behavior of these tumors depends primarily on their grading. Low-grade NMIBC are characterized by a high propensity for recurrence but a very low risk for progression to muscle invasion or metastatic disease. Thus, the first line goal of diagnostic procedures and therapy is reliable visualization and complete resection of all foci. Cytology and other urine-based markers fail due to insufficient sensitivity. A second resection might be necessary only in selected intermediate risk cases; the positive effect of maintenance instillation protocols beyond a single postoperative instillation is questionable for the majority of patients. Risk stratification, e.g., according to the EORTC or EAU proposals, also makes sense in low grade NMIBC. PMID- 25784273 TI - The novel inhaled glucocorticoid receptor agonist GW870086X protects against adenosine-induced bronchoconstriction in asthma. PMID- 25784274 TI - IL-13 mediates IL-33-dependent mast cell and type 2 innate lymphoid cell effects on bronchial epithelial cells. PMID- 25784275 TI - Severity of virus-induced asthma symptoms is inversely related to resolution IFN lambda expression. PMID- 25784276 TI - Efficient synthesis of highly substituted tetrahydroindazolone derivatives. AB - A straightforward and efficient method for the synthesis of novel highly substituted and diversely functionalized indazolone derivatives has been developed. The transformation consists of a cyclocondensation of selected 1,3,3' tricarbonyls with monosubstituted hydrazines. The starting beta-triketones were prepared by an efficient chemo- and regioselective method under MW irradiation, exploiting the oxazolone chemistry. The reaction is easily accomplished under mild conditions and appears versatile, providing a synthetic diversification method with potential for drug-like compounds preparation. PMID- 25784277 TI - Straightforward strategy to substitute amide bonds by 1,2,3-triazoles in peptaibols analogs using Aibpsi[Tz]-Xaa dipeptides. AB - Structured peptides gained more attention over a decade because of their biological properties, biocompatibility and ability to act as modulators of protein/protein interactions, antibiotics, analgesics, immunosuppressants or as imaging agents to cite a few relevant applications. However, their poor bioavalability due in part to the susceptibility of the peptide bond to proteolytic cleavages often impaired their development and considerably limited their therapeutic use. To circumvent these problems, many efforts are undertaken to discover stable amide bond mimics resistant to proteolytic degradation. Among them the 1,2,3-triazole emerged as a highly stable analogue of the trans-peptide bond to generate bioactive peptides. Here we report a convenient approach to readily substitute amide bonds by triazole rings in Aib-containing peptides using Aibpsi[Tz]-Xaa dipeptide-like units. We defined their application in solid phase synthesis and generated short model peptide sequences to study the impact of the triazole incorporation on their conformations in solution by circular dichroism and nuclear magnetic resonance spectroscopies. PMID- 25784278 TI - Bisphenol A disrupts gene expression in human placental trophoblast cells. AB - This study examined the effect of bisphenol A (BPA) on human placental gene expression using primary trophoblast cells as an in vitro model system. Trophoblast cells were isolated from human placentas at term, cultured and then exposed to environmentally relevant concentrations of BPA (0.1-2 MUg/ml) for up to 24h, after which levels of 11beta-HSD2 mRNA, protein and activity were determined by standard radiometric conversion assay, western blotting, and qRT PCR, respectively. The mRNA levels of several other prominent placental hormones/factors were also assessed by qRT-PCR. BPA dramatically increased levels of 11beta-HSD2 activity, protein and mRNA in a time- and concentration-dependent manner (> 4-fold). BPA also augmented aromatase, glucose transporter-1, CRH, and hCG mRNA levels while reducing the level of leptin mRNA. These findings demonstrate that BPA severely disrupts human placental gene expression in vitro, which suggests that exposure to BPA may contribute to altered placental function and consequent pregnancy complications. PMID- 25784279 TI - Spectroscopic determination of relative Bronsted acidity as a predictor of reactivity in aprotic ionic liquids. AB - A simple titration technique utilizing pyridine as a FTIR spectroscopy probe is demonstrated to successfully predict relative Bronsted acid-limited reaction rates in different ionic liquid (IL) environments. Relative acidity is shown to vary across three aprotic ILs in a manner that is specific to the particular acid IL pairing. PMID- 25784280 TI - Pinaverium in Irritable Bowel Syndrome: Old Drug, New Tricks? PMID- 25784281 TI - A Rare Case of Pancreas Pseudodivisum. PMID- 25784282 TI - Optimization of Time Controlled 6-mercaptopurine Delivery for Site- Specific Targeting to Colon Diseases. AB - BACKGROUND: 6-MP has short elimination time (<2 h) and low bioavailability (~ 50%). Present study was aimed to develop time controlled and site targeted delivery of 6-Mercaptopurine (6-MP) for treatment of colon diseases. METHODS: Compression coating technique was used. 32 full factorial design was designed for optimization of the outer coat for the core tablet. For outer coat amount of Eudragit RS 100 and hydroxypropyl methylcellulose (HPMC K100) were employed as independent variables each at three levels while responses evaluated were swelling index and bursting time. Direct compression method was used for tablets formulation. RESULTS: 80% w/w of microcrystalline cellulose and 20% w/w of croscarmellose sodium were found to be optimum concentration for the core tablet. The outer coat of optimized batch (ED) contains 21.05% w/w Eudragit RS 100 and 78.95% w/w HPMC K100 of total polymer weight. In-vitro dissolution study indicated that combination of polymer retards the drug release in gastric region and releases >=95% of drug in colonic region after >=7 h. Whereas in case of in vivo placebo x-ray imaging study had shown that the tablet reaches colonic part after 5+/-0.5 h providing the proof of arrival in the colon. Stability study indicated that the optimized formulation were physically and chemically stable. CONCLUSION: Present research work concluded that compression coating by Eudragit RS 100 and HPMC K100 to 6-MP core provides potential colon targeted system with advantages of reduced gastric exposure and enhanced bioavailability. Formulation can be considered as potential and promising candidate for the treatment of colon diseases. PMID- 25784283 TI - The impact on long term health outcomes for STEMI patients during a period of process change to reduce door to balloon time. AB - BACKGROUND: Guidelines for the management of ST-segment elevation myocardial infarction (STEMI) recommend a 'door to balloon time' (DTBT) within 90 minutes. It is unclear whether strategies to reduce DTBT translate to improved longer-term health outcomes for STEMI patients. AIMS: This study sought to determine whether implemented strategies to improve timely management of STEMI reduced DTBT and impacted upon health outcomes such as length of stay, unplanned readmission and 12-month mortality. Predictors of timely management for STEMI were also examined. METHODS: A five-year review was undertaken on primary percutaneous coronary intervention for STEMI in one tertiary hospital. Comparisons were made between process change groups and DTBT. Logistic regression identified predictors of timely management. RESULTS: 470 STEMI patients underwent immediate primary percutaneous coronary intervention. Process change improved the median DTBT (109 min vs. 72 min, p<0.001) with no significant effect on length of stay (p=0.83), unplanned cardiac readmissions (p=0.68) or 12-month mortality (9.0% vs. 8.6%, p=0.64). Those receiving timely treatment (i.e. DTBT< 90 min) were younger (p<0.05), male (p<0.03), presented via ambulance (p<0.004), during business hours (p<0.0001) and had a lower Thrombolysis In Myocardial Infarction score (p<0.006). Timely treatment was associated with lower 12-month mortality (3.7% vs. 15.7%, p<0.0001) and increased uptake of inpatient cardiac rehabilitation (p<0.005), with length of stay and unplanned readmission similar between groups (p=NS). CONCLUSIONS: Process changes improved DTBT but had no effect on length of stay, readmission rate or 12-month mortality. Yet, timely management was critical to 12 month outcomes. Further studies are required to explore the barriers to timely treatment. PMID- 25784284 TI - Highly Regio- and Stereoselective Hydrosilylation of Internal Thioalkynes under Mild Conditions. AB - A general and mild hydrosilylation of thioalkynes is described. With the cationic catalyst [Cp*Ru(MeCN)3 ](+) and the bulky silane (TMSO)3 SiH, a range of thioalkynes underwent smooth hydrosilylation at room temperature with excellent alpha regioselectivity and syn stereoselectivity. DFT calculations provided important insight into the mechanism, particularly the unusual syn selectivity with the [Cp*Ru(MeCN)3 ](+) catalyst. The sulfenyl group in the substrates was found to provide important chelation stabilization to direct the reaction through a new mechanistic pathway. PMID- 25784285 TI - Incidence of respiratory viruses in Peruvian children with acute respiratory infections. AB - Acute respiratory infections are responsible for high morbi-mortality in Peruvian children. However, the etiological agents are poorly identified. This study, conducted during the pandemic outbreak of H1N1 influenza in 2009, aims to determine the main etiological agents responsible for acute respiratory infections in children from Lima, Peru. Nasopharyngeal swabs collected from 717 children with acute respiratory infections between January 2009 and December 2010 were analyzed by multiplex RT-PCR for 13 respiratory viruses: influenza A, B, and C virus; parainfluenza virus (PIV) 1, 2, 3, and 4; and human respiratory syncytial virus (RSV) A and B, among others. Samples were also tested with direct fluorescent-antibodies (DFA) for six respiratory viruses. RT-PCR and DFA detected respiratory viruses in 240 (33.5%) and 85 (11.9%) cases, respectively. The most common etiological agents were RSV-A (15.3%), followed by influenza A (4.6%), PIV 1 (3.6%), and PIV-2 (1.8%). The viruses identified by DFA corresponded to RSV (5.9%) and influenza A (1.8%). Therefore, respiratory syncytial viruses (RSV) were found to be the most common etiology of acute respiratory infections. The authors suggest that active surveillance be conducted to identify the causative agents and improve clinical management, especially in the context of possible circulation of pandemic viruses. PMID- 25784286 TI - Effect of body mass index on maternal morbidity following peripartum hysterectomy. AB - The objective of this study was to estimate the impact of maternal body mass index (BMI) on maternal morbidity following unscheduled peripartum hysterectomy. A retrospective cohort study of consecutive peripartum hysterectomies at our institution from 1988 through 2012; scheduled hysterectomies were excluded. Medical records were reviewed and maternal, foetal and surgical data collected for each subject. Maternal BMI was categorized by the National Institute of Health classifications for overweight and obese. Statistical analyses included evaluation for trend. A total of 360,774 women delivered at Parkland Hospital during the study period with 665 (1.8 per 1000 deliveries) unscheduled peripartum hysterectomies performed. BMI was available for 635 women. Gestational diabetes, chronic hypertension and pregnancy-related hypertension were significantly higher in all three obesity categories, P = < 0.01. Post-partum complications, such as venous thrombosis and composite surgical morbidity did not differ among BMI groups. Estimated blood loss and units transfused did not differ across the BMI categories, P = 0.42 and P = 0.38, respectively. Increasing BMI was associated with longer surgical times and more wound infections, P = 0.01. These complications should be considered when approaching a peripartum hysterectomy in patients with obesity. PMID- 25784287 TI - Structure and antimicrobial activity relationship of royalisin, an antimicrobial peptide from royal jelly of Apis mellifera. AB - Royalisin is a 5.5-kDa antibacterial peptide isolated from the royal jelly of the honeybee (Apis mellifera). The antimicrobial activity of royalisin against fungi, Gram-positive and Gram-negative bacteria has been revealed. Compared with another insect antibacterial peptide, there is an extra stretch of 11 amino acid residues at the C-terminus of royalisin. In this study, a recombinant shortened form of royalisin named as royalisin-D, was constructed without the 11 amino acid residues at the C-terminal of royalisin and linked to the C-terminal of oleosin by an inteinS fragment. The recombinant protein was overexpressed in Escherichia coli, purified by artificial oil body system and subsequently released through self-splicing of inteinS induced by the changes of temperature. The antibacterial activity of royalisin-D was compared with royalisin via minimal inhibitory concentration (MIC) assay, minimal bactericidal concentration (MBC) assay, microbial adhesion to solvents (MATS) methods, and cell membrane permeability. Furthermore, the recombinant royalisin and royalisin-D have also been treated with the reducing agent of disulfide bonds, dithiothreitol (DTT), to investigate the importance of the intra-disulfide bond in royalisin. In our results, royalisin-D exhibited similar antimicrobial activity to royalisin. Royalisin and royalisin D lost their antimicrobial activities when the intra-disulfide bonds were reduced by DDT. The intra-disulfide bond plays a more important role than the extra stretch of 11 amino acid residues at the C-terminus of royalisin in terms of the antimicrobial properties of the native royalisin. PMID- 25784288 TI - Effect of enalapril maleate on ghrelin levels in metabolic syndrome in rats. AB - We have explored how enalapril affects ghrelin levels in serum and renal tissues of rats with fructose-induced MetS, using 5-week-old Wistar albino male rats weighing 220 +/- 20 g. They divided into 5 groups: (i) control (CT), no fructose supplement fed on standard rat pellet and tap water for 60 days, (ii) metabolic syndrome (MetS) fed with 10% fructose for 60 days, (iii) rats after metabolic syndrome developed treated with enalapril over 30 days (MetS+E30), (iv) rats in which only enalapril was administered for 60 days (E60), and (v) MetS-treated with enalapril for 60 days (MetS+E60). Enalapril maleate was given at 20mg/kg per day by gavage. Fasting serum insulin, uric acid, triglyceride, low-density lipoprotein cholesterol and total cholesterol levels were significantly higher, and the amount of high density lipoprotein cholesterol, and acylated and desacyl ghrelin levels was significantly lower in the MetS groups. Ghrelins were significantly lower in all 3 groups, which were administered enalapril than that of MetS and the control group. Immunohistochemical staining showed that the density of ghrelin was parallel to the serum levels of the peptide. Ghrelin immunoreactivity in the kidneys was of moderate density in the distal and collecting tubules, mild density in the proximal tubule and glomeruli, whereas the density decreased in the MetS group and other enalapril-treated groups. In conclusion, ghrelin levels in MetS groups were significantly lower than control group, and thus Enalapril treatment improves components of MetS and has direct effects on serum ghrelin levels that are independent of MetS. PMID- 25784289 TI - Sports hernias: experience in a sports medicine center. AB - PURPOSE: Chronic pain of the inguino-crural region or "pubalgia" explains the 0.5 6.2% of the consultations by athletes. Recently, areas of weakness in the posterior wall called "sports hernias," have been identified in some of these patients, capable of producing long-standing pain. Several authors use different image methods (CT, MRI, ultrasound) to identify the lesion and various techniques of repair, by open or laparoscopic approaches, have been proposed but there is no evidence about the superiority of one over others due to the difficulty for randomizing these patients. In our experience, diagnosis was based on clinical and ultrasound findings followed by laparoscopic exploration to confirm and repair the injury. The present study aims to assess the performance of our diagnostic and therapeutic management in a series of athletes affected by "pubalgia". METHODS: 1450 athletes coming from the orthopedic office of a sport medicine center were evaluated. In 590 of them (414 amateur and 176 professionals) sports hernias were diagnosed through physical examination and ultrasound. We performed laparoscopic "TAPP" repair and, thirty days after, an assessment was performed to determine the evolution of pain and the degree of physical activity as a sign of the functional outcome. We used the U Mann-Whitney test for continuous scale variables and the chi-square test for dichotomous variables with p < 0.05 as a level of significance. RESULTS: In 573 patients ultrasound examination detected some protrusion of the posterior wall with normal or minimally dilated inguinal rings, which in 498 of them coincided with areas affected by pain. These findings were confirmed by laparoscopic exploration that also diagnosed associated contralateral (30.1%) and ipsilateral defects, resulting in a total of 1006 hernias. We found 84 "sport hernias" in 769 patients with previous diagnosis of adductor muscle strain (10.92%); on the other hand, in 127 (21.52%) of our patients with "sport hernias" US detected concomitant injuries of the adductor longus tendon, 7 of which merited additional surgical maneuvers (partial tenotomy). Compared with the findings of laparoscopy, ultrasound had a sensitivity of 95.42% and a specificity of 100%; the positive and negative predictive values were 100 and 99.4% respectively. No postoperative complications were reported. Only seven patients suffered recurrence of pain (successful rate: 98.81%); the ultrasound ruled out hernia recurrence, but in three cases it diagnosed tendinitis of the rectus abdominis muscle. CONCLUSIONS: Our series reflects the multidisciplinary approach performed in a sports medicine center in which patients are initially evaluated by orthopedic surgeons in order to discard the most common causes of "pubalgia". "Sports hernias" are often associated with adductor muscle strains and other injuries of the groin allowing speculate that these respond to a common mechanism of production. We believe that, considering the difficulty to design randomized trials, only a high coincidence among the diagnostic and therapeutic instances can ensure a rational health care. PMID- 25784291 TI - The safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a comprehensive review. AB - OBJECTIVE: The present study provides a comprehensive review of the existing literature on the safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and lactation. METHODS: Studies published in English, reporting the use of SNRIs in pregnant and/or breastfeeding women, were identified by searching MEDLINE/Pubmed, PsycINFO, and EMBASE. RESULTS: Twenty-nine studies were included in the review. Altogether, the initial evidence coming from the reviewed studies suggests a lack of association between SNRIs and an increased risk of major congenital malformations. Conversely, exposure to SNRIs seems to be significantly associated with an increased risk of some perinatal complications. No neonatal adverse events emerged, so far, in the few studies concerning the safety of SNRIs during breastfeeding. CONCLUSIONS: Available data suggest that venlafaxine is relatively safe during pregnancy, in particular as far as major malformations are concerned, whereas considering the small number of studies published, no definitive conclusions can be drawn on its safety during breastfeeding. Because of the few studies so far published, the safety of duloxetine during pregnancy and breastfeeding remains to be well established. PMID- 25784290 TI - Cross-species identification of a plasma microRNA signature for detection, therapeutic monitoring, and prognosis in osteosarcoma. AB - Osteosarcoma (OS) is the primary bone tumor in children and young adults. Currently, there are no reliable, noninvasive biologic markers to detect the presence or progression of disease, assess therapy response, or provide upfront prognostic insights. MicroRNAs (miRNAs) are evolutionarily conserved, stable, small noncoding RNA molecules that are key posttranscriptional regulators and are ideal candidates for circulating biomarker development due to their stability in plasma, ease of isolation, and the unique expressions associated with specific disease states. Using a qPCR-based platform that analyzes more than 750 miRNAs, we analyzed control and diseased-associated plasma from a genetically engineered mouse model of OS to identify a profile of four plasma miRNAs. Subsequent analysis of 40 human patient samples corroborated these results. We also identified disease-specific endogenous reference plasma miRNAs for mouse and human studies. Specifically, we observed plasma miR-205-5p was decreased 2.68 fold in mice with OS compared to control mice, whereas, miR-214, and miR-335-5p were increased 2.37- and 2.69-fold, respectively. In human samples, the same profile was seen with miR-205-5p decreased 1.75-fold in patients with OS, whereas miR-574-3p, miR-214, and miR-335-5p were increased 3.16-, 8.31- and 2.52-fold, respectively, compared to healthy controls. Furthermore, low plasma levels of miR 214 in metastatic patients at time of diagnosis conveyed a significantly better overall survival. This is the first study to identify plasma miRNAs that could be used to prospectively identify disease, potentially monitor therapeutic efficacy and have prognostic implications for OS patients. PMID- 25784292 TI - Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development. PMID- 25784294 TI - Endoscopic retrograde cholangiopancreatography in Ayrshire, Scotland: a comparison of two age cohorts. AB - BACKGROUND AND AIMS: There is an increased trend in prevalence of pancreato biliary disease in the elderly population. Consequently there is an increasing demand for endoscopic retrograde cholangiopancreatography (ERCP). The aims of this study were to compare ERCP outcomes in patients over 80 with those aged between 60 and 79 years and with the published literature. METHODS AND RESULTS: Data were collected from a prospectively maintained database. All patients over the age of 60 years who underwent ERCP from May 2010 to May 2012 were identified. Two cohorts were formed, group A: 60-79 years (n = 66) and group B: > 80 years old (n = 49). Data on indications for ERCP, outcome, complications and repeat procedures were collected. One hundred and fifteen patients between the age of 60 and 92 years were identified. Group A had a total of 89 ERCPs and group B 69. Cannulation, overall procedure success, complication and mortality rates were comparable between both groups. Group B contained two cases of perforation with one associated mortality (1.4%) which did not reach statistical significance. CONCLUSIONS: ERCP in octogenarians is safe and effective when compared to patients aged 60-79. PMID- 25784295 TI - A treacherous case of primary non-Hodgkin lymphoma of the bone: appearances can be deceptive. AB - INTRODUCTION: Primary lymphoma of the bone constitutes an extremely rare but distinctive clinical entity, accounting for approximately 3% of all primary bone malignancies and less than 1% of all non-Hodgkin lymphomas. CASE PRESENTATION: We report a rare case of a male patient with an atypical clinical presentation of non-Hodgkin primary lymphoma of the bone, initially misdiagnosed as ankylosing spondylitis. To our knowledge, this is the first case in the literature in which magnetic resonance imaging was contra-indicated. The atypical radiological imaging of the tumor, despite its aggressiveness, rendered the diagnostic approach a challenging but strenuous process. CONCLUSION: Plain radiographs and even computerized tomography images of primary lymphoma of the bone may appear as normal, but other imaging modalities should be used including radionuclide scans, especially when imaging techniques of greater accuracy such as magnetic resonance imaging are contraindicated. A patient-centred approach with emphasis on the main symptoms is the key to the diagnostic challenge of revealing the extremely unusual cases of primary lymphoma of the bone. PMID- 25784296 TI - Rhododendron album Blume inhibits iNOS and COX-2 expression in LPS-stimulated RAW264.7 cells through the downregulation of NF-kappaB signaling. AB - Rhododendron album Blume (RA) has traditionally been used as an herbal medicine and is considered to have anti-inflammatory properties. In the present study, we screened RA extracts with anti-inflammatory properties. The biological effects of an RA methanol extract (RAME) on inflammation were investigated in lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cells. We investigated the effects of RAME on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated RAW264.7 cells. To explore the anti-inflammatory mechanisms of RAME, we measured the mRNA and protein expression of pro inflammatory mediators induced by RAME in the LPS-stimulated RAW264.7 cells by RT PCR and western blot analysis, respectively. RAME significantly inhibited the production of NO, PGE2, interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha in the LPS-stimulated RAW264.7 cells. It also suppressed the mRNA and protein expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and mitogen-activated protein kinases (MAPKs) with a concomitant decrease in the nuclear translocation of nuclear factor-kappaB (NF-kappaB) in the LPS-stimulated RAW264.7 cells. These results indicate that RAME inhibits LPS-induced inflammatory responses. These effects were considered to be strongly associated with the suppression of NF-kappaB activation. We therefore suggest that RAME may be prove to be an effective therapeutic agent for the treatment of inflammatory diseases. PMID- 25784293 TI - Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory. AB - Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in nonhuman animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume, and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status, nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. PMID- 25784297 TI - Sex differences and effects of prenatal exposure to excess testosterone on ventral tegmental area dopamine neurons in adult sheep. AB - Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesised to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep, with higher numbers of tyrosine hydroxylase (TH)-immunoreactive (-ir) cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30-90 or 60-90 resulted in increased numbers of VTA TH-ir cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T-treated ewes, which was primarily accounted for by greater numbers of TH-ir cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T-treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels within dopamine cells. Sex differences were also noted in numbers of TH-ir cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH-ir cells in the substantia nigra, suggesting that this sex difference is organised independently of prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T. PMID- 25784298 TI - Quantitative analysis of retinal layers' optical intensities on 3D optical coherence tomography for central retinal artery occlusion. AB - Optical coherence tomography (OCT) provides not only morphological information but also information about layer-specific optical intensities, which may represent the underlying tissue properties. The purpose of this study is to quantitatively investigate the optical intensity of each retinal layers in central retinal artery occlusion (CRAO). Twenty-nine CRAO cases at acute phase and 33 normal controls were included. Macula-centered 3D OCT images were segmented with a fully-automated Iowa Reference Algorithm into 10 layers. Layer specific mean intensities were determined and compared between the patient and control groups using multiple regression analysis while adjusting for age and optical intensity of the entire region. The optical intensities were higher in CRAO than in controls in layers spanning from the retinal ganglion cell layer to outer plexiform layer (standardized beta = 0.657 to 0.777, all p < 0.001), possibly due to ischemia. Optical intensities were lower at the photoreceptor, retinal pigment epithelium (RPE), and choroid layers (standardized beta = -0.412 to -0.611, all p < 0.01), possibly due to shadowing effects. Among the intraretinal layers, the inner nuclear layer was identified as the best indicator of CRAO. Our study provides in vivo information of the optical intensity changes in each retinal layer in CRAO patients. PMID- 25784300 TI - Collagen/chitosan film containing biotinylated glycol chitosan nanoparticles for localized drug delivery. AB - The objective of this study was to design a drug delivery system consisting of biotinylated cholesterol-modified glycol chitosan (Bio-CHGC) nanoparticles and fish collagen/chitosan (Col/Ch) film for localized chemotherapy. Bio-CHGC was synthesized, and then its self-assembled nanoparticles were prepared by probe sonication. Doxorubicin (DOX)-loaded Bio-CHGC (DBC) nanoparticles prepared by dialysis had spherical shape, and their sizes were in the range of 330-397 nm. Col/Ch/DBC nanoparticle films were fabricated by freeze-drying. SEM showed that the DBC nanoparticles were uniformly distributed into the films, and the films retained their structural integrity. A higher degradation and swelling rate of the drug films led to a higher diffusion rate of the nanoparticles from the films, resulting in an increase in the drug release from nanoparticles. The release of DOX from the films or Bio-CHGC nanoparticles was sensitive to the pH value of the release medium. In addition, the DOX release ratio of the drug films was lower than that of the nanoparticles alone, suggesting that the drug films had a double-sustained effect on the drug release. MTT assay implied that the DBC nanoparticle film showed a higher inhibitory ratio than the film containing nanoparticles without biotin, indicating that biotin moieties in the nanoparticles played an important role in exerting a cytotoxic effect. These data demonstrate that Col/Ch/DBC nanoparticle film has the potential to be used as a localized delivery system for hydrophobic antitumor drugs. PMID- 25784299 TI - Synergetic action of domain II and IV underlies persistent current generation in Nav1.3 as revealed by a tarantula toxin. AB - The persistent current (INaP) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Nav1.3 intrinsically generates a small INaP, although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Nav1.3 in INaP generation was investigated using the tarantula toxin alpha hexatoxin-MrVII (RTX-VII). RTX-VII activated Nav1.3 and induced a large INaP. A pre-activated state binding model was proposed to explain the kinetics of toxin channel interaction. Of the four domains of Nav1.3, both domain II and IV might play important roles in the toxin-induced INaP. Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of INaP in Nav1.3. PMID- 25784301 TI - Bioremediation of wastewaters with decabromodiphenyl ether by anaerobic granular sludge. AB - Facilities adopting anaerobic granular sludge are widely used for the treatment of high strength wastewater, and hence collect many polybrominated diphenyl ethers (PBDEs), especially decabromodiphenyl ether (BDE-209). We initiated a detailed investigation to gain insight into the bioremoval of BDE-209 by anaerobic granules. Influenced by solution pH, ionic strength and temperature, the equilibrium time was ~6 h and the biosorption amount increased from 0.099 to 1.25 mg/g suspended sludge with the increase of BDE-209 concentrations. Kinetic studies indicate that BDE-209 biosorption on anaerobic granules follows the pseudo second-order kinetic model. Isotherm analysis exhibits that the Langmuir model fits the data at low temperature, while the Freundlich model is appropriate at room temperature. Thermodynamic analysis shows that biosorption followed an endothermic path and was nonspontaneous with negative value of DeltaG0. XPS and FTIR spectra confirmed that oxygen and nitrogen atoms notably contributed to BDE 209 binding. PMID- 25784302 TI - Preparation of core-shell magnetic polydopamine/alginate biocomposite for Candida rugosa lipase immobilization. AB - A flexible, biocompatible and bioadhesive enzyme immobilizing material, which was synthesized based on the covalent assembly of biomimetic polymer and oxidized polysaccharide on magnetic nanoparticles (NPs), has been developed in this feasibility study. In this work, the bio-inspired polymer, polydopamine (PDA), was used to modify the well-monodispersed Fe3O4 NPs (mPDA NPs) with a controllable thickness via a dip-coating process, then the alginate di-aldehyde (ADA) was covalently assembled on the mPDA NPs and employed as a naturally occurring linking agent for Candida rugosa lipase (CRL) immobilization. The resulting support material was characterized by means of the transmission electron microscope (TEM), Fourier transform infrared spectra (FT-IR), X-ray diffraction (XRD), thermogravimetry (TG) analyser, and vibrating sample magnetometer (VSM). It was verified that the prepared mPDA NPs possessed distinct core-shell structure with uniform size and high saturation magnetization. For further application, the mPDA NPs was utilized in CRL immobilizing procedures and demonstrated can facilitate improving the enzyme activities. The optimum amount of lipase was 200 mg g(-1) support, the optimal pH and temperature for the catalyse condition of the immobilized CRL was 7.0 and 40 degrees C, respectively. Moreover, the immobilized CRL kept the high activity at 77% after 12 times of recycling for batch hydrolysis of olive oil emulsion. This magnetic bioadhesive composite with functionalized properties and adhesion strength presents a general strategy for the immobilization of macromolecules. PMID- 25784303 TI - Promoting aging well: evaluation of Vital-Aging-Multimedia Program in Madrid, Spain. AB - This article attests to the effectiveness of Vital Aging-Multimedia (VA-M, 'Vivir con Vitalidad-M'), a psycho-educational multimedia program designed to promote successful aging. The program was implemented over 3 months through 35 h of video lessons grouped into 15 thematic units addressing four domains of experience commonly associated with aging well: health and healthy habits, cognitive functioning, aging self-efficacy and well-being and social participation. In accordance with a quasi-experimental design, a total of 115 senior citizens (aged 54-82) participated: 73 subjects attended the VA-M, while 42 subjects with similar characteristics served as controls. All subjects were assessed before and after the program on target variables related to the above domains of functioning. Significant changes in most of the examined variables documented the positive effects of the program. PMID- 25784304 TI - Singing for respiratory health: theory, evidence and challenges. AB - The premise that singing is a health promoting activity for people with respiratory conditions of chronic obstructive pulmonary disease (COPD) and asthma is a growing area of interest being investigated by researchers from various disciplines. The preliminary evidence, a theoretical framework and identification of methodological challenges are discussed in this perspective article with an eye to recommendations for further research to advance knowledge. After a brief summary of main research findings on singing in healthy people to provide background context, research is reviewed on singing in people with COPD and asthma. Studies include published research and as yet unpublished work by the authors. Methodological challenges arising from the reviewed studies are identified such as attrition from singing or control groups based on weak and strong, respectively, beliefs about singing's effectiveness. Potential solutions for these problems are considered with further recommendations made for other singing research. PMID- 25784305 TI - Researching health-related quality of life at a community level: results from a population survey conducted in Burgas, Bulgaria. AB - Researching health-related quality of life (HrQoL) at a community health promotion level is an approach to understand the health inequalities. The objective of this study is to measure the health of a representative sample by conducting a population survey in Burgas by using the EuroQoL EQ-5D-3L questionnaire, and further to assess the influence of socio-economic, demographic and behavioural factors on HrQoL. The relationship between HrQoL and social capital is analysed through a network-based approach. The achieved ambition was to build the public health capacity of the key stakeholders in order to support decision making. A cross-sectional study was conducted in 2011 using a representative sample of the citizens of Burgas (n = 1050, >18 years old). Respondents were selected through the method of two-stage random selection. HrQoL was assessed by the standardized EQ-5D-3L questionnaire. People without any problem in all five dimensions represent only 26.5% (n = 278) of the respondents, whereas 52.2% (n = 548) reported a moderate problem in at least one dimension; any extreme problem reported 11.6% (n = 122) of the respondents. The mean state of health recorded on the Visual Analogue Scale was 70 (SD +/-23). There were differences in self-reported health based on the respondent's age, occupation, education, income, smoking behaviour and membership in community groups. People who have hobby and practice sports assessed their health status higher. The results were communicated in a following Delphi-study; a consensus has been reached that the combination of routine measures of health with measurement of self-rated health could provide better understandings of the community health needs. PMID- 25784306 TI - Correlates of cognitive flexibility in veterans seeking treatment for posttraumatic stress disorder. AB - This study examined the association between cognitive flexibility and variables that may be associated with treatment outcome for 579 veterans seeking Veterans Health Administration treatment for posttraumatic stress disorder (PTSD) secondary to combat or sexual trauma. Factors associated with severity of PTSD (level of PTSD symptoms and guilt cognitions) and with PTSD prognosis (posttraumatic growth and optimistic expectations for the future) were examined. Regression analyses revealed that cognitive flexibility was associated with lower levels of PTSD symptoms and fewer guilt cognitions. Cognitive flexibility was positively associated with posttraumatic growth and optimistic expectations for the future, even when controlling for PTSD severity. These results suggest that interventions designed to increase cognitive flexibility in veterans may be a worthwhile adjunct to treatment for PTSD as we continue efforts to improve treatment outcomes. PMID- 25784307 TI - Suicidal ideation and sex differences in relation to 18 major psychiatric disorders in college and university students: anonymous web-based assessment. AB - College/university students are at high risk for psychiatric disorder and suicide secondary to age, campus stressors, and social pressures. We therefore report frequencies of 18 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision disorders and suicidal ideation (SI) acquired anonymously from a Web site receiving 113,181 visits from more than 1,500 predominantly US colleges/universities. Depression was foremost, followed by social phobia and eating disorders. Substance-related disorders were less frequent than expected. SI occurred in 47.1% of students, with women evidencing somewhat stronger findings than men. SI was more associated with substance, bipolar, and panic disorders than depression. Self-reported emotional volatility exceeded thoughts of self-harm for all disorders. The results support two subtypes of suicide risk: dysphoric premeditators and those primarily angry and/or impulsive. Clinicians and researchers should therefore consider suicide as an independent psychopathological phenomenon that includes emotional volatility as a risk factor and thoroughly evaluate psychiatric disorders potentially conferring greater suicidal propensity than depression. PMID- 25784308 TI - A study on the effect of dianionic tridentate ligands on the radiative and nonradiative processes for gold(III) alkynyl systems by a computational approach. AB - Gold(III) alkynyl complexes with dianionic tridentate pincer ligands have received growing attention recently because of their rich luminescence behavior and their potential applications in areas such as optoelectronics and sensors. In this study, density functional theory (DFT) and time-dependent DFT (TDDFT) calculations have been performed to investigate the radiative and nonradiative processes for the gold(III) alkynyl complexes with different dianionic tridentate ligands, [Au(C^N^C)(C=CC6H5)] (1; C^N^C = 2,6-diphenylpyridine), [Au(C(Np)^N^C(Np))(C=CC6H5)] [2; C(Np)^N^C(Np) = 2,6-di(2-naphthyl)pyridine], [Au(N^N^N)(C=CC6H5)] [3; N^N^N = 2,6-bis(benzimidazol-2'-yl)pyridine], and [Au(C^C^N)(C=CC6H5)] [4; C^C^N = 3-(2-pyridyl)biphenyl]. It has been found that the electronic properties of the tridentate ligand could have a significant impact on the radiative and nonradiative processes. This study provides an in depth understanding on the effect of the dianionic pincer ligands on the different photophysical behaviors among the gold(III) alkynyl complexes and crucial information for the future design of gold(III) complexes in various applications. PMID- 25784309 TI - Quantitative reverse transcription polymerase chain reaction-based detection of thyroid-specific gene expression in fine-needle aspirate for thyroid cancer recurrence evaluation: a case report and review of the literature. AB - BACKGROUND: Despite improved surveillance for patients after total thyroidectomy for cancer, there has yet to be a diagnostic method that detects recurrence with 100% accuracy. METHODS: A 60-year-old woman with a family history of papillary thyroid cancer (PTC) underwent total thyroidectomy and radioactive iodine ablation. On postoperative surveillance, ultrasound examination of the neck demonstrated a focus concerning for recurrence and a fine-needle aspirate (FNA) was performed. The cytology report was nondiagnostic and, hence, RNA was extracted from the specimen followed by reverse transcription (cDNA), and quantitative real-time polymerase chain reaction (qRT-PCR) to detect thyroid specific gene expression (thyroglobulin =Tg; sodium-iodide symporter = NIS; thyroperoxidase = TPO). RESULTS: Expression of select thyroid-specific genes was demonstrated, and given the patient's remarkable cancer and family history, surgical resection was elected. Final pathology demonstrated follicular adenoma. CONCLUSION: This case demonstrates a novel approach used in the evaluation for recurrent thyroid cancer as an adjunct to FNA cytology. PMID- 25784310 TI - Tree branch-shaped cupric oxide for highly effective photoelectrochemical water reduction. AB - Highly efficient tree branch-shaped CuO photocathodes are fabricated using the hybrid microwave annealing process with a silicon susceptor within 10 minutes. The unique hierarchical, one-dimensional structure provides more facile charge transport, larger surface areas, and increased crystallinity and crystal ordering with less defects compared to irregular-shaped CuO prepared by conventional thermal annealing. As a result, the photocathode fabricated with the tree branch shaped CuO produces an unprecedently high photocurrent density of -4.4 mA cm(-2) at 0 VRHE under AM 1.5 G simulated sunlight compared to -1.44 mA cm(-2) observed for a photocathode fabricated by thermal annealing. It is also confirmed that stoichiometric hydrogen and oxygen are produced from photoelectrochemical water splitting on the tree branch-shaped CuO photocathode and a platinum anode. PMID- 25784311 TI - From the editor's desk. PMID- 25784312 TI - Is the relationship of body mass index to severity of coronary artery disease different from that of waist-to-hip ratio and severity of coronary artery disease? Paradoxical findings. AB - BACKGROUND: Although for decades there has been controversy regarding the relationship between obesity and coronary artery disease (CAD), it has been assumed that high body mass index (BMI) is a risk factor for CAD. However, the findings of some recent studies were paradoxical. OBJECTIVES: The aim of this study was to find a relationship between high BMI and waist-to-hip ratio (WHR) with severity of CAD. METHODS: This study was a cross-sectional, prospective study where 414 patients with suspected coronary artery disease, in whom coronary angiography was performed, were enrolled. The mean +/- SD of their ages was 61.2 +/- 27.4 years (range 25-84), and 250 (60.4%) were male. Regarding cardiovascular risk factors, 113 (27.3%) patients had a history of diabetes mellitus (DM), 162 (39.1%) had hypercholesterolaemia, 238 (57.4%) had hypertension, 109 (26.3%) were current smokers and 24 (5.8%) had a family history of CAD. The mean +/- SD of the patients' BMI was 26.04 +/- 4.08 kg/m(2) (range 16-39) and means +/- SD of their WHR ranged from 0.951 +/- 0.07 to 0.987 +/- 0.05. The mean +/- SD of the severity of CAD according to the SYNTAX and Duke scores were 17.7 +/- 9.6 (range 0-64) and 3.2 +/- 1.7 (range 0-12), respectively. RESULTS: In this study, findings showed a negative correlation between the severity of CAD and BMI, according to both SYNTAX and Duke scores (p <= 0.001 and p = 0.001, respectively). However, there was a positive correlation between WHR and severity of CAD, according to the Duke score (p = 0.03). CONCLUSION: BMI had a negative correlation with the severity of CAD, but waist-to-hip ratio had a positive correlation with severity of CAD. PMID- 25784313 TI - Circulating adhesion molecules and arterial stiffness. AB - AIM: VCAM-1 and ICAM-1 are two important members of the immunoglobulin gene superfamily of adhesion molecules, and their potential role as biomarkers of diagnosis, severity and prognosis of cardiovascular disease has been investigated in a number of clinical studies. The aim of the present study was to determine the relationship between circulating ICAM-1 and VCAM-1 levels and aortic stiffness in patients referred for echocardiographic examination. METHODS: Aortic distensibility was determined by echocardiography using systolic and diastolic aortic diameters in 63 consecutive patients referred for echocardiography. Venous samples were collected in the morning after a 12-hour overnight fast, and serum concentrations of ICAM-1 and VCAM-1 were measured using commercial enzyme immunoassay kits. RESULTS: Data of a total of 63 participants (mean age 55.6 +/- 10.5 years, 31 male) were included in the study. Circulating levels of adhesion molecules were VCAM-1: 12.604 +/- 3.904 ng/ml and ICAM-1: 45.417 +/- 31.429 ng/ml. We were unable to demonstrate any correlation between indices of aortic stiffness and VCAM-1 and ICAM-1 levels. CONCLUSION: The role of soluble adhesion molecules in cardiovascular disease has not been fully established and clinical studies show inconsistent results. Our results indicate that levels of circulating adhesion molecules cannot be used as markers of aortic stiffness in patients. PMID- 25784314 TI - Social support and management of hypertension in South-west Nigeria. AB - INTRODUCTION: Social support can facilitate compliance or adherence to recommended treatment regimens, especially for chronic disease management. There is little data from Africa on the role of social support in the management of chronic disease. OBJECTIVE: The current study investigated the relationship between social support for treatment compliance among hypertensive subjects in a poor urban community in southwest Nigeria. A second objective was identifying the correlates of social support in the study sample. METHODS: The study was a community-based, cross-sectional and descriptive study of 440 community residents (mean age 60 years, 65.2% women) from Idikan community, Ibadan, Nigeria who had hypertension. RESULTS: Most subjects (~ 93%) reported receiving some social support from family members and approximately 55% reported receiving social support from friends. Social support from friends (p < 0.0001) but not from family (p = 0.162) was significantly associated with good compliance with treatment for hypertension. Factors associated with receiving significant support from both family and friends included marital status and religion, while age and educational level were associated with receiving significant support from family members only. Gender was not significantly associated with receiving social support. CONCLUSION: We concluded that social support is strongly associated with hypertension treatment compliance in this community in south-west Nigeria. These findings suggest a need for exploring the promotion of social support as a useful tool in chronic disease treatment programmes. PMID- 25784315 TI - Comparison between superficial femoral artery stenting and bypass surgery in severe lower-limb ischaemia: a retrospective study. AB - BACKGROUND: Symptomatic femoro-popliteal disease is treated by bypass surgery or angioplasty with or without stenting. The aim of this study was to compare the results of stenting and bypass surgery with regard to limb salvage in patients with severe leg ischaemia. METHODS: A total of 213 patients with femoro-popliteal disease presenting with severe claudication or critical limb ischaemia between January 2009 and December 2013 were evaluated; 118 patients (139 limbs) had stents placed and 95 patients (104 limbs) had bypass surgery. Most (60%) presented with critical limb ischaemia (rest pain 40%, tissue necrosis 20%), and the remainder with severe claudication. The treatment groups had matching risk factors. RESULTS: The average age was 66 years and 73% were male. Tissue necrosis was found in 26% of the stent group and 12% of the bypass group (p = 0.009). In the stent group 26% had adjunctive procedures, compared to 16% in the bypass group (p = 0.138). During the one-year follow up, there were 30 stent occlusions (22%) and 18 graft occlusions (17%) (p = 0.42). There were 14 major amputations (10%) in the stent group, and 13 (13%) in the bypass group (p = 0.68). Limb salvage rate was 90% in the stent group, and 88% in the bypass group (p = 0.68). There were no peri-operative deaths in the stent group, but one in the bypass group (1%). One-year mortality rate was equal (8%) in both groups (p = 1.00). CONCLUSION: One-year outcome was comparable in both groups with regard to mortality, stent or graft patency and limb salvage rates. PMID- 25784316 TI - Study of the effect of altitude on the measurement of glycated haemoglobin using point-of-care instruments. AB - We measured the glycated haemoglobin (HbA1c) levels of a total of 24 non-diabetic volunteers and diabetic patients using a point-of-care (POC) analyser in three Cameroonian cities at different altitudes. Although 12 to 25% of duplicates had more than 0.5% (8 mmol/mol) difference across the sites, HbA1c values correlated significantly (r = 0.89-0.96). Further calibration studies against gold-standard measures are warranted. PMID- 25784317 TI - U-vein compressor improves early haemodynamic outcomes in radiocephalic arterio venous fistulae in under 2-mm superficial veins. AB - AIM: In this study, we sought to determine the early postoperative results of arterio-venous fistulae (AVF) created by U-vein compressors with veins between 1.5 and 2 mm in size. METHODS: Pre-operative venous mapping was done. The fistula tract was marked at 0-, 4-, 8- and 12-cm points; 0 cm was the estimated point where the anastomosis would be done. With Doppler ultrasonography, transverse diameters in the estimated fistula tract were measured at the 0-, 4-, 8- and 12 cm points. A superficial vein that would be used as the fistula tract was dilated using U-vein compressors. In the first postoperative hour, the flow in the anastomosis, and the transverse diameter of the fistula tract at the 0-, 4-, 8- and 12-cm points were measured by Doppler ultrasonography. RESULTS: Forty patients were included in the study. U-vein compressors were used for 20 patients. Postoperative expansion of vein diameters and postoperative flow velocities were found to be statistically significantly different in patients where a U-vein compressor had been used (p < 0.001). CONCLUSION: We present a technique to dilate veins that are between 1.5 and 2 mm in diameter, which are generally accepted as poor vessels to create radiocephalic arteriovenous fistulae. PMID- 25784318 TI - An alternative method of transperitoneal graft introduction in aortobifemoral bypass surgery. AB - INTRODUCTION: Intestinal injury and bleeding, which usually occurs while taking the graft through the transperitoneal tunnel, is one of the most important complications of aortobifemoral bypass surgery. In this study, case reports were examined where, for some reason, the tunneller instrument could not be used to create the transperitoneal tunnel and the tunnelling forceps was used. In some of these cases, the grafts were taken through conventionally and in others an alternative method was used. METHODS: Between 2002 and 2013, the records of 81 patients treated surgically by aortobifemoral bypass for peripheral arterial disease, were investigated retrospectively. In the conventional method, after creating a tunnel with tunnelling forceps, the forceps was re-introduced into the tunnel and the graft was clasped and brought through the tunnel. In the alternative method, a nylon tape was left as a guide in the tunnel while creating the tunnel, and the forceps was not introduced again. The graft was taken through the tunnel with the help of the nylon tape. Patients treated with the conventional method were included in group 1 (n = 49) and patients in which the graft was guided with nylon tape were included in group 2 (n = 32). The groups were compared peri-operatively. RESULTS: There were no significant differences between the groups in terms of co-morbidity factors. Extubation time, intensive care length of stay, revision for bleeding, other postoperative complications, and infection and late-term infection rates were similar in the two groups (p > 0.05). Hospital length of stay and blood usage were significantly higher in group 1 (p < 0.05). Drainage amounts were higher in group 1 but not statistically significant. CONCLUSION: Using nylon tape to introduce the graft into the femoral area during aortobifemoral bypass operations was found to be more effective than using the tunnelling forceps. PMID- 25784319 TI - Outcome of acute myeloid leukemia patients with pulmonary nodules of uncertain etiology receiving allogeneic hematopoietic progenitor cell transplant. AB - Pulmonary nodules (PNs) develop frequently in patients with acute myeloid leukemia (AML). They are of infectious or inflammatory origin. They pose potential challenges to successful hematopoietic progenitor cell (HPC) transplant as they may be niches for infection reactivation or sites susceptible to subsequent infections. We retrospectively analyzed the outcome of 20 AML patients with multiple PNs who underwent allogeneic HPC transplants (12 related, 8 unrelated). There were 13 males and seven females (median age 52 yrs). Nine patients were in CR1, seven in CR2, and four with residual disease. The median times from appearance of PNs and from last positive CT scans to transplant were three and two months, respectively. The median time from pretransplant CT scans to transplant was one month. Multiple PNs were still reported in 5/20 of the pretransplant scans. The PNs in all five patients did not worsen after transplant. Four patients (one with positive pretransplant CT scan) died within the first 100 d after transplant, but none from primary pulmonary pathology. The median survival of this group of patients was 350 d. Our results, therefore, suggest that multiple PNs of uncertain etiology in patients with AML do not impact adversely on the outcome of allogeneic HPC transplant. PMID- 25784320 TI - Coronary artery fistula in adults: evaluation with dual-source CT coronary angiography. AB - OBJECTIVE: To evaluate the clinical value of dual-source CT (DSCT) coronary angiography in the diagnosis of coronary artery fistula (CAF) in adults. METHODS: A large cohort of 17,548 patients, who underwent DSCT coronary angiography in our hospital between January 2008 and October 2013, were retrospectively reviewed for CAF. The origin, course and drainage site of CAF and coexisting abnormalities were analysed. The conventional angiography results, treatments and follow-up DSCT images were also evaluated. RESULTS: A total of 33 CAFs from 17,548 patients were detected. The incidence of CAF was 0.19% by DSCT. CAF originating from the left coronary artery (LCA) was found in 14 (42.4%) patients, from right coronary artery (RCA) in 4 (12.1%) cases and from both LCA and RCA in 15 (45.5%) patients. The pulmonary artery was the most common site of drainage (28/33, 84.8%). 8 of the 33 (24.2%) cases were associated with aneurysms. Six cases were associated with coronary artery atherosclerosis. Four patients underwent conventional angiography. CONCLUSION: Coronary-pulmonary artery fistula in adults was found more often than in previous studies. CAF commonly originates from LCA or both LCA and RCA in adults. DSCT is a robust tool for investigating the origin, course and drainage site of CAF and coexistent abnormalities. ADVANCES IN KNOWLEDGE: A large adult patient cohort who underwent DSCT angiography was reviewed to assess CAFs. Coronary-pulmonary artery fistula in adults was found more often than in previous studies. CAF was observed to originate from the LCA or both coronary arteries in adults. DSCT could clearly depict the fistula origin, course, drainage site and coexisting abnormalities. Conventional angiography results, treatments and follow up DSCT images were analysed. PMID- 25784321 TI - Reproduction and vegetative growth in the dioecious shrub Acer barbinerve in temperate forests of Northeast China. AB - KEY MESSAGE: Trade-off in dioecious plant. The trade-off between reproduction, vegetative growth and maintenance is a major issue in the life history of an organism and a record of the process which is producing the largest possible number of living offspring by natural selection. Dioecious species afford an excellent opportunity for detecting such possible trade-offs in resource allocation. In this study, we selected the dioecious shrub Acer barbinerve to examine possible trade-offs between reproduction and vegetative growth in both genders at different modular levels during three successive years. Reproductive and vegetative biomass values were assessed during successive years to evaluate their intra-annual and inter-annual trade-offs. These trade-offs were examined at shoot, branch and shrub modular levels in Acer barbinerve shrubs. An intra-annual trade-off was detected at the shoot level for both genders in 2011 and 2012. Both males and females showed a negative correlation between reproduction and vegetative growth, but this was more prominent in males. For the females of the species, inter-annual trade-offs were only found at branch and shrub levels. Slightly negative correlations in females were detected between the reproduction in 2012 and the reproduction in the two previous years. The gender ratio was significantly male biased during the three successive years of our investigation. Females had higher mortality rates in the larger diameter classes, both in 2011 and 2012. This study revealed a clear trade-off between reproduction and vegetative growth in Acer barbinerve, but results varied between males and females. The degree of autonomy of the different modular levels may affect the ability to detect such trade-offs. PMID- 25784322 TI - Overdiagnosis in the era of neuropsychiatric imaging. AB - New guidelines proposed by the National Institute of Mental Health are intended to transform the management of patients with psychiatric disorders. It is anticipated that neuroimaging and other biomarkers will play a more prominent role in diagnosis and prognosis, especially in the prodromal phase of illness. Earlier treatment of psychiatric disorders has the potential to improve outcomes significantly. However, diagnosis in the absence of symptoms can lead to overdiagnosis. Overdiagnosis is a problem in many fields of medicine but could pose additional problems in psychiatry because of the stigmatization that often accompanies a diagnosis of mental illness. This review discusses the magnetic resonance imaging methods that hold the most promise for evaluating neuropsychiatric disorders, the likelihood that they could lead to overdiagnosis, and opportunities to minimize the impact of overdiagnosis in psychiatric disorders. PMID- 25784323 TI - Is "prepectoral edema" a morphologic sign for malignant breast tumors? AB - RATIONALE AND OBJECTIVES: A variety of morphologic and kinetic signs of benign or malignant breast lesions contribute to a final diagnosis and differential diagnosis in magnetic resonance (MR) mammography (MRM). As a new sign, prepectoral edema (PE) in patients without any history of previous biopsy, operation, radiation, or chemotherapy was detected during routine breast MR examinations. The purpose of this study was to retrospectively evaluate the role of this morphologic sign in the differential diagnosis of breast lesions. MATERIALS AND METHODS: Between January 2005 and October 2006, a total of 1109 consecutive MRM examinations have been performed in our institution. In this study, only patients who would later be biopsied or operated in our own hospital were included. They had no previous operation, biopsy, intervention, chemotherapy, hormone replacement therapy, or previous mastitis. In total, 162 patients with 180 lesions were included, histologically correlated later-on by open biopsy (124 patients and 136 lesions) or core biopsy (38 patients and 44 lesions). The evaluations were performed by four experienced radiologists in consensus. RESULTS: One hundred eighty evaluated lesions included 104 malignant lesions (93 invasive and 11 noninvasive cancers) and 76 benign lesions. PE was detected in 2.6% of benign lesions (2 of 76), in none of the Ductal cacinoma in situ (DCIS) cases (0 of 11), and in 25.8% of malignant lesions (24 of 93; P < .000). PE was found significantly more frequently in presence of malignant tumors >2 cm in diameter (48.5%, 17 of 35 vs. 13.8%, 8 of 58; P < .001). PE was not statistically associated to malignant tumor type, presence or absence of additional DCIS, and number of lesions. This resulted in the following diagnostic parameters for PE as an indicator for malignancy: sensitivity of 19.3%, specificity of 97.3%, positive predictive value (PPV) of 92.3%, negative predictive value of 48%, and accuracy of 57.7%. CONCLUSIONS: In case of occurrence, the "PE sign" seems to be a specific indicator for malignant tumors with a high PPV, independent from its entity. PMID- 25784324 TI - Intracranial aneurysms: a game of millimeters. AB - RATIONALE AND OBJECTIVES: In this review we will discuss the historic development of intracranial aneurysms as a pathologic entity and the potential for overdiagnosis. MATERIALS AND METHODS: We conducted a literature search to assess the prevalence, rupture rate, and treatment of intracranial aneurysms. RESULTS: Intracranial aneurysms represent a necessary example of overdiagnosis. CONCLUSIONS: A change in the nomenclature of small aneurysms is a possible solution to mitigate patient anxiety from a diagnosis of intracranial aneurysm. PMID- 25784326 TI - What will it take to create a tobacco-free world? PMID- 25784325 TI - Graphics Processing Unit-Accelerated Nonrigid Registration of MR Images to CT Images During CT-Guided Percutaneous Liver Tumor Ablations. AB - RATIONALE AND OBJECTIVES: Accuracy and speed are essential for the intraprocedural nonrigid magnetic resonance (MR) to computed tomography (CT) image registration in the assessment of tumor margins during CT-guided liver tumor ablations. Although both accuracy and speed can be improved by limiting the registration to a region of interest (ROI), manual contouring of the ROI prolongs the registration process substantially. To achieve accurate and fast registration without the use of an ROI, we combined a nonrigid registration technique on the basis of volume subdivision with hardware acceleration using a graphics processing unit (GPU). We compared the registration accuracy and processing time of GPU-accelerated volume subdivision-based nonrigid registration technique to the conventional nonrigid B-spline registration technique. MATERIALS AND METHODS: Fourteen image data sets of preprocedural MR and intraprocedural CT images for percutaneous CT-guided liver tumor ablations were obtained. Each set of images was registered using the GPU-accelerated volume subdivision technique and the B spline technique. Manual contouring of ROI was used only for the B-spline technique. Registration accuracies (Dice similarity coefficient [DSC] and 95% Hausdorff distance [HD]) and total processing time including contouring of ROIs and computation were compared using a paired Student t test. RESULTS: Accuracies of the GPU-accelerated registrations and B-spline registrations, respectively, were 88.3 +/- 3.7% versus 89.3 +/- 4.9% (P = .41) for DSC and 13.1 +/- 5.2 versus 11.4 +/- 6.3 mm (P = .15) for HD. Total processing time of the GPU-accelerated registration and B-spline registration techniques was 88 +/- 14 versus 557 +/- 116 seconds (P < .000000002), respectively; there was no significant difference in computation time despite the difference in the complexity of the algorithms (P = .71). CONCLUSIONS: The GPU-accelerated volume subdivision technique was as accurate as the B-spline technique and required significantly less processing time. The GPU-accelerated volume subdivision technique may enable the implementation of nonrigid registration into routine clinical practice. PMID- 25784327 TI - Mental health and the UK general election. PMID- 25784328 TI - The future of health in Nigeria. PMID- 25784329 TI - The National Health Service: value for money, value for many. PMID- 25784330 TI - Deaths and taxes: stronger global tobacco control by 2025. PMID- 25784331 TI - Progress with the global tobacco epidemic. PMID- 25784332 TI - Trade and investment agreements: a call for evidence. PMID- 25784334 TI - Syrian crisis: health experts say more can be done. PMID- 25784335 TI - David Nott: providing surgical care at the frontline of conflicts. PMID- 25784337 TI - Tariana Turia: looking ahead to a tobacco-free New Zealand. PMID- 25784338 TI - The cigarette catastrophe continues. PMID- 25784340 TI - Smoking ban in Austria: a long overdue step but still a lot to be done. PMID- 25784341 TI - Health in Cuba: the other side of the story. PMID- 25784342 TI - Cuba-US collaboration and the role of bioethics. PMID- 25784345 TI - Humanism and medicine in China. PMID- 25784347 TI - Global trends and projections for tobacco use, 1990-2025: an analysis of smoking indicators from the WHO Comprehensive Information Systems for Tobacco Control. AB - BACKGROUND: Countries have agreed on reduction targets for tobacco smoking stipulated in the WHO global monitoring framework, for achievement by 2025. In an analysis of data for tobacco smoking prevalence from nationally representative survey data, we aimed to provide comprehensive estimates of recent trends in tobacco smoking, projections for future tobacco smoking, and country-level estimates of probabilities of achieving tobacco smoking targets. METHODS: We used a Bayesian hierarchical meta-regression modelling approach using data from the WHO Comprehensive Information Systems for Tobacco Control to assess trends from 1990 to 2010 and made projections up to 2025 for current tobacco smoking, daily tobacco smoking, current cigarette smoking, and daily cigarette smoking for 173 countries for men and 178 countries for women. Modelling was implemented in Python with DisMod-MR and PyMC. We estimated trends in country-specific prevalence of tobacco use, projections for future tobacco use, and probabilities for decreased tobacco use, increased tobacco use, and achievement of targets for tobacco control from posterior distributions. FINDINGS: During the most recent decade (2000-10), the prevalence of tobacco smoking in men fell in 125 (72%) countries, and in women fell in 156 (88%) countries. If these trends continue, only 37 (21%) countries are on track to achieve their targets for men and 88 (49%) are on track for women, and there would be an estimated 1.1 billion current tobacco smokers (95% credible interval 700 million to 1.6 billion) in 2025. Rapid increases are predicted in Africa for men and in the eastern Mediterranean for both men and women, suggesting the need for enhanced measures for tobacco control in these regions. INTERPRETATION: Our findings show that striking between-country disparities in tobacco use would persist in 2025, with many countries not on track to achieve tobacco control targets and several low-income and middle-income countries at risk of worsening tobacco epidemics if these trends remain unchanged. Immediate, effective, and sustained action is necessary to attain and maintain desirable trajectories for tobacco control and achieve global convergence towards elimination of tobacco use. FUNDING: Ministry of Health, Labour and Welfare, Japan; Ministry of Education, Culture, Sports and Technology, Japan; Department of Health, Australia; Bloomberg Philanthropies. PMID- 25784348 TI - A tobacco-free world: a call to action to phase out the sale of tobacco products by 2040. AB - The time has come for the world to acknowledge the unacceptability of the damage being done by the tobacco industry and work towards a world essentially free from the sale (legal and illegal) of tobacco products. A tobacco-free world by 2040, where less than 5% of the world's adult population use tobacco, is socially desirable, technically feasible, and could become politically practical. Three possible ways forward exist: so-called business-as-usual, with most countries steadily implementing the WHO Framework Convention on Tobacco Control (FCTC) provisions; accelerated implementation of the FCTC by all countries; and a so called turbo-charged approach that complements FCTC actions with strengthened UN leadership, full engagement of all sectors, and increased investment in tobacco control. Only the turbo-charged approach will achieve a tobacco-free world by 2040 where tobacco is out of sight, out of mind, and out of fashion--yet not prohibited. The first and most urgent priority is the inclusion of an ambitious tobacco target in the post-2015 sustainable development health goal. The second priority is accelerated implementation of the FCTC policies in all countries, with full engagement from all sectors including the private sector--from workplaces to pharmacies--and with increased national and global investment. The third priority is an amendment of the FCTC to include an ambitious global tobacco reduction goal. The fourth priority is a UN high-level meeting on tobacco use to galvanise global action towards the 2040 tobacco-free world goal on the basis of new strategies, new resources, and new players. Decisive and strategic action on this bold vision will prevent hundreds of millions of unnecessary deaths during the remainder of this century and safeguard future generations from the ravages of tobacco use. PMID- 25784349 TI - The road to effective tobacco control in China. AB - The non-communicable disease burden in China is enormous, with tobacco use a leading risk factor for the major non-communicable diseases. The prevalence of tobacco use in men is one of the highest in the world, with more than 300 million smokers and 740 million non-smokers exposed to second-hand smoke. In the past decade public awareness of the health hazards of tobacco use and exposure to second-hand smoke has grown, social customs and habits have changed, aggressive tactics used by the tobacco industry have been revealed, and serious tobacco control policies have been actively promoted. In 2014, national legislators in China began actively considering national bans on smoking in public and work places and tobacco advertising. However, tobacco control in China has remained particularly difficult because of interference by the tobacco industry. Changes to the interministerial coordinating mechanism for implementation of the WHO Framework Convention on Tobacco Control are now crucial. Progress towards a tobacco-free world will be dependent on more rapid action in China. PMID- 25784351 TI - Abiotrophia defectivus infectious endocarditis: think beyond the heart. PMID- 25784350 TI - Exposing and addressing tobacco industry conduct in low-income and middle-income countries. AB - The tobacco industry's future depends on increasing tobacco use in low-income and middle-income countries (LMICs), which face a growing burden of tobacco-related disease, yet have potential to prevent full-scale escalation of this epidemic. To drive up sales the industry markets its products heavily, deliberately targeting non-smokers and keeps prices low until smoking and local economies are sufficiently established to drive prices and profits up. The industry systematically flaunts existing tobacco control legislation and works aggressively to prevent future policies using its resource advantage to present highly misleading economic arguments, rebrand political activities as corporate social responsibility, and establish and use third parties to make its arguments more palatable. Increasingly it is using domestic litigation and international arbitration to bully LMICs from implementing effective policies and hijacking the problem of tobacco smuggling for policy gain, attempting to put itself in control of an illegal trade in which there is overwhelming historical evidence of its complicity. Progress will not be realised until tobacco industry interference is actively addressed as outlined in Article 5.3 of the Framework Convention on Tobacco Control. Exemplar LMICs show this action can be achieved and indicate that exposing tobacco industry misconduct is an essential first step. PMID- 25784353 TI - Structure based aggregation studies reveal the presence of helix-rich intermediate during alpha-Synuclein aggregation. AB - Mechanistic understanding of nucleation dependent polymerization by alpha synuclein (alpha-Syn) into toxic oligomers and amyloids is important for the drug development against Parkinson's disease. However the structural and morphological characterization during nucleation and subsequent fibrillation process of alpha Syn is not clearly understood. Using a variety of complementary biophysical techniques monitoring entire pathway of nine different synucleins, we found that transition of unstructured conformation into beta-sheet rich fibril formation involves helix-rich intermediates. These intermediates are common for all aggregating synucleins, contain high solvent-exposed hydrophobic surfaces, are cytotoxic to SHSY-5Y cells and accelerate alpha-Syn aggregation efficiently. A multidimensional NMR study characterizing the intermediate accompanied with site specific fluorescence study suggests that the N-terminal and central portions mainly participate in the helix-rich intermediate formation while the C-terminus remained in an extended conformation. However, significant conformational transitions occur at the middle and at the C-terminus during helix to beta-sheet transition as evident from Trp fluorescence study. Since partial helix-rich intermediates were also observed for other amyloidogenic proteins such as Abeta and IAPP, we hypothesize that this class of intermediates may be one of the important intermediates for amyloid formation pathway by many natively unstructured protein/peptides and represent a potential target for drug development against amyloid diseases. PMID- 25784355 TI - ERRATUM: Line-patterning of polyaniline coated MWCNT on stepped substrates using DC electric field. PMID- 25784354 TI - Inability to Process Negative Emotions in Cerebellar Damage: a Functional Transcranial Doppler Sonographic Study. AB - Recent studies have implicated the cerebellum as part of a circuitry that is necessary to modulate higher order and behaviorally relevant information in emotional domains. However, little is known about the relationship between the cerebellum and emotional processing. This study examined cerebellar function specifically in the processing of negative emotions. Transcranial Doppler ultrasonography was performed to detect selective changes in middle cerebral artery flow velocity during emotional stimulation in patients affected by focal or degenerative cerebellar lesions and in matched healthy subjects. Changes in flow velocity during non-emotional (motor and cognitive tasks) and emotional (relaxing and negative stimuli) conditions were recorded. In the present study, we found that during negative emotional task, the hemodynamic pattern of the cerebellar patients was significantly different to that of controls. Indeed, whereas relaxing stimuli did not elicit an increase in mean flow velocity in any group, negative stimuli increased the mean flow velocity in the right compared with left middle cerebral artery only in the control group. The patterns by which mean flow velocity increased during the motor and cognitive tasks were similar within patients and controls. These findings support that the cerebellum is part of a network that gives meaning to external stimuli, and this particular involvement in processing negative emotional stimuli corroborates earlier phylogenetic hypotheses, for which the cerebellum is part of an older circuit in which negative emotions are crucial for survival and prepare the organism for rapid defense. PMID- 25784357 TI - Cooperative dehydrogenation of N-heterocycles using a carbon nanotube-rhodium nanohybrid. AB - Rhodium nanoparticles were anchored on carbon nanotubes and the resulting nanohybrid was studied as co-catalyst, along with tert-butylcatechol, for the dehydrogenation of various N-heterocycles. The co-catalytic system operates in high yields, under the mildest conditions reported so far, and can be applied to a wide variety of secondary amine-containing scaffolds. PMID- 25784356 TI - Antiplatelet therapy as a modulator of stroke aetiology: a meta-analysis. AB - AIMS: Antiplatelet therapy reduces the incidence of ischaemic stroke. Platelet mediated thrombosis contributes variably to the major subtypes of stroke as defined by the TOAST criteria: large artery atherosclerosis (LAA), cardioembolic (CE) and small vessel occlusion (SVO). The effect of antiplatelet therapy on the incidence of each subtype is unknown and is the subject of this meta-analysis. METHODS: Electronic databases were searched for articles comparing the effect of antiplatelet therapy on the incidence of stroke according to aetiological subtype. Studies containing subjects prescribed anticoagulant therapy or solely investigating subjects with atrial fibrillation were excluded. Pooled odds ratios (ORs) were calculated using a fixed effects model. RESULTS: Nine studies were included (n = 5739). In patients who had an ischaemic stroke, pre-event antiplatelet therapy was associated with significantly decreased incidence of LAA (OR 0.88, 95% CI 0.79, 0.99; P = 0.026), increased incidence of CE (OR 1.23, 95% CI 1.08, 1.41; P = 0.002) and no effect on SVO (OR 0.99, 95% CI 0.88, 1.11; P = 0.806). Concordant non-significant trends were observed in primary prevention populations (n = 751): LAA (OR 0.81, 95% CI 0.57, 1.15; P = 0.240), CE (OR 1.29, 95% CI 0.89, 1.87; P = 0.179) and SVO (OR 0.99, 95% CI 0.73, 1.36; P = 0.970). Subgroup analysis of aspirin monotherapy (n = 3786) demonstrated a significant reduction in LAA (OR 0.87, 95% CI 0.76, 1.00; P = 0.046), but non-significant effects on the incidence of CE (OR 1.17, 95% CI 0.99, 1.39; P = 0.068) and SVO (OR 1.04, 95% CI 0.91, 1.20; P = 0.570). Probability of publication bias was low (P > 0.05). CONCLUSIONS: Antiplatelet therapy preferentially reduces the incidence of LAA stroke compared with CE and SVO subtypes. PMID- 25784358 TI - TREATMENT OF EXUDATIVE AGE-RELATED MACULAR DEGENERATION WITH RANIBIZUMAB COMBINED WITH KETOROLAC EYEDROPS OR PHOTODYNAMIC THERAPY. AB - PURPOSE: To evaluate whether ketorolac eyedrops plus intravitreal ranibizumab (IVR) or verteporfin photodynamic therapy plus IVR provides additional benefit over IVR monotherapy for treatment of choroidal neovascularization in age-related macular degeneration. METHODS: This was a prospective, randomized, pilot study in 75 patients with naive choroidal neovascularization. Patients were randomized 1:1:1 into 3 groups: ranibizumab monotherapy (RM), ranibizumab plus ketorolac, or ranibizumab plus loading-phase reduced-fluence verteporfin photodynamic therapy (RV) groups. RESULTS: At 12 months, all groups showed significant improvement in both best-corrected visual acuity and central retinal thickness. The mean best corrected visual acuity change from baseline to 12 months was -0.14 +/- 0.52 logMAR (20/73 +/- 20/29), -0.25 +/- 0.60 logMAR (20/46 +/- 20/27), and -0.10 +/- 0.30 (20/97 +/- 20/40) logMAR in RM, ranibizumab plus ketorolac, and RV groups, respectively. The mean central retinal thickness change from baseline to 12 months was -125 +/- 15 MUm, -141 +/- 21 MUm, and -130 +/- 15 MUm in RM, ranibizumab plus ketorolac, and RV groups, respectively. Both ranibizumab plus ketorolac and RV groups required fewer IVR treatments than RM. CONCLUSION: Compared with RM and ranibizumab plus verteporfin photodynamic therapy, the combination of 0.45% ketorolac eyedrops 3 times a day and ranibizumab in patients with choroidal neovascularization provided superior best-corrected visual acuity and central retinal thickness outcomes. Both combination regimens required fewer IVR injections than RM during the 12-month follow-up period. PMID- 25784359 TI - Correspondence. PMID- 25784360 TI - Reply: To PMID 25462436. PMID- 25784361 TI - Reply: To PMID 24999724. PMID- 25784363 TI - Prevalence of refractive error in Europe: the European Eye Epidemiology (E(3)) Consortium. AB - To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E(3)) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia <= 0.75 diopters (D), high myopia <=-6D, hyperopia >=1D and astigmatism >=1D. Meta analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those >=25 and <90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4-30.9], high myopia 2.7 % (95 % CI 2.69-2.73), hyperopia 25.2 % (95 % CI 25.0-25.4) and astigmatism 23.9 % (95 % CI 23.7-24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8-52.5) in 25-29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe. PMID- 25784364 TI - Effects of obesity and hormone therapy on surgically-confirmed fibroids in postmenopausal women. AB - To examine the association between body mass index (BMI), use of menopausal hormone therapy (HT), and incidence of uterine fibroids in postmenopausal women, 610,604 postmenopausal women without prior hysterectomy or diagnosis of fibroids were followed as part of a large United Kingdom prospective cohort study. We used Cox regression models to calculate adjusted relative risks (RRs) of surgically confirmed fibroids (defined as a hospital admission with uterine fibroids as a primary diagnosis with a related surgical procedure), in relation to BMI and use of HT. During an average of 11.4 years of follow-up, 3561 women were admitted to hospital with surgically-confirmed fibroids. Five-year incidence rates decreased with age, from 0.50% (1 in 200 women) at age 50-54, to 0.11% (1 in 1000 women) at age 75-79. The 5-year rate in postmenopausal women aged 50-54 was about a quarter that seen in premenopausal women of the same age (1 in 200 vs. 1 in 50). Compared with normal weight women, obese women had a RR of surgically-detected fibroids of 1.46 (95% CI 1.33-1.59; p < 0.0001). HT use was associated with a RR of 2.33 (95% CI 2.18-2.49; p < 0.0001) in ever versus never users. When we analysed HT use and BMI together, obese vs. normal weight never users had a RR of 2.00 (95% CI 1.77 2.26): the highest risks were seen in women who were obese and had ever used HT, RR = 3.30 (95% CI 2.88-3.79). Uterine fibroids continue to occur in postmenopausal women; obesity and hormone therapy use are important modifiable risk factors. PMID- 25784366 TI - Incidence and prediction of falls in Parkinson's disease: a prospective cohort study. PMID- 25784365 TI - Preeclampsia in pregnancy and later use of antihypertensive drugs. AB - We explored the association between preeclampsia and later use of antihypertensive drugs in a population-based study with data from the Medical Birth Registry of Norway and the Norwegian Prescription Database. The study cohort consisted of 980,000 women having 2.1 million pregnancies during 1967 2012. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were estimated in multivariate time-dependent Cox proportional hazards regression models. Overall, the HR of later use of antihypertensive drugs was 2.0 (95% CI 2.0-2.0) in women with one preeclamptic pregnancy compared to women without preeclamptic pregnancies. The HR increased by increasing number of preeclamptic pregnancies, both term and preterm pregnancies. In women with two or more preeclamptic pregnancies, the HR was 2.8 (2.7-3.0). The overall HR after 40 years of follow-up for women with one preeclamptic pregnancy was 1.3 (1.2-1.4) and for two or more preeclamptic pregnancies the HR was 1.6 (1.1-2.1). The first 5 years after the first birth, the HR of being dispensed antihypertensive drugs was higher in preterm [8.4 (7.7-9.1)] than term preeclamptic pregnancies [4.3(4.0-4.6)]. However, after 10 years, this difference was no longer present. The HR of later use of antihypertensive drugs increased with the number of preeclamptic pregnancies, and in the first 10 years the HR was higher after a preterm than a term preeclamptic pregnancy. Although the HR decreased with time since first birth, the risk was still elevated after 40 years. PMID- 25784367 TI - A patient with a 12-year history characterized by four non-AIDS-related malignancies, occurring before and after the disclosure of HIV infection. PMID- 25784369 TI - PROMIS for Laparoscopy. AB - INTRODUCTION: We tested the responsiveness of the National Institutes of Health sponsored Patient-Reported Outcomes Measures Information System (PROMIS) global health short form and a linear analog self-assessment for laparoscopy. METHODS: From May 2011 through December 2013, patients undergoing laparoscopy responded to patient reported outcome questionnaires perioperatively. Composite and single item scores were compared. RESULTS: One hundred fifteen patients, mean age 55 years, 58 % female, were enrolled. Visual analog pain scores differed significantly from baseline (mean 1.7 +/- 2.3) to postoperative day 1 (mean 4.8 +/- 2.6) and 7 (mean 2.5 +/- 2.1) (p<0.0001). PROMIS physical subscale and total physical component subscore differed significantly from baseline (14.4 +/- 3.0/47.4 +/- 8.3) to postoperative day 1 (12.7 +/- 3.2/42.1 +/- 8.8) (p=0.0007/0.0003), due to everyday physical activities (p=0.0001). Linear analog self-assessment scores differed from baseline for pain frequency (p<0.0001), pain severity (p<0.0001), and social activity (p=0.0052); 40 % of subjects reported worsening in PROMIS physical T-score to postoperative day 1 and 25 % to postoperative day 7. Linear analog self-assessment mental well-being scores were worse in 32 % of patients at postoperative day 7, emotional well-being in 28 %, social activity in 24 %, and fatigue in 20 % of patients. CONCLUSION: Single items and change from baseline are responsive perioperative quality of life assessments for laparoscopy. PMID- 25784371 TI - Abstracts of the Urological Society of Australia and New Zealand 68th Annual Scientific Meeting, 11-14 April, 2015, Adelaide, Australia. PMID- 25784368 TI - Adherence to the healthy Nordic food index and total and cause-specific mortality among Swedish women. AB - Several healthy dietary patterns have been linked to longevity. Recently, a Nordic dietary pattern was associated with a lower overall mortality. No study has, however, investigated this dietary pattern in relation to cause-specific mortality. The aim of the present study was to examine the association between adherence to a healthy Nordic food index (consisting of wholegrain bread, oatmeal, apples/pears, root vegetables, cabbages and fish/shellfish) and overall mortality, and death by cardiovascular disease, cancer, injuries/suicide and other causes. We conducted a prospective analysis in the Swedish Women's Lifestyle and Health cohort, including 44,961 women, aged 29-49 years, who completed a food frequency questionnaire between 1991-1992, and have been followed up for mortality ever since, through Swedish registries. The median follow-up time is 21.3 years, and mortality rate ratios (MRR) were calculated using Cox Proportional Hazards Models. Compared to women with the lowest index score (0-1 points), those with the highest score (4-6 points) had an 18% lower overall mortality (MRR 0.82; 0.71-0.93, p < 0.0004). A 1-point increment in the healthy Nordic food index was associated with a significantly lower risk of all cause mortality: 6% (3-9%), cancer mortality: 5% (1-9%) and mortality from other causes: 16% (8-22%). When examining the diet components individually, only wholegrain bread and apples/pears were significantly inversely associated with all-cause mortality. We observed no effect-modification by smoking status, BMI or age at baseline. The present study encourages adherence to a healthy Nordic food index, and warrants further investigation of the strong association with non cancer, non-cardiovascular and non-injury/suicide deaths. PMID- 25784370 TI - Distilled Water Lavage During Surgery Improves Long-Term Outcomes of Patients with Ruptured Hepatocellular Carcinoma. AB - BACKGROUND: Rupture of hepatocellular carcinoma (HCC) releases tumor cells and furthers peritoneal metastasis. The present study investigated the killing effects of distilled water (DW) on HCC cells and the clinical outcomes of patients undergoing liver resection with DW lavage for spontaneously ruptured HCC. MATERIALS AND METHODS: Human HCC cells (BEL-7402, SMMC7721) were treated with DW, the morphological changes observed, and cell viability measured. DW treated HCC cells were also injected intraperitoneally into nude mice, and the formation of tumor nodules and overall survival (OS) measured. The clinicopathological data of 141 consecutive patients undergoing liver resection for spontaneously ruptured HCC during 1998-2011 were retrospectively reviewed. RESULTS: Fifteen minutes of DW exposure caused complete cell lysis of HCC cells in vitro and completely prevented tumor formation and prolonged survival time in nude mice. Among the 141 patients, the 1-, 3-, and 5-year disease-free survival (DFS) and OS rates in patients administered DW lavage during surgery were 68.9, 24.6, and 6.6%, respectively, and 95.1, 65.1, and 40%, respectively, which were significantly higher than those in patients who did not (P < 0.05). DW lavage was an independent predictor of recurrence (odds ratio (OR), 0.34; 95% confidence interval (CI), 0.23-0.51; P < 0.001) and OS (OR, 0.35; 95% CI, 0.23-0.53; P < 0.001). CONCLUSIONS: Fifteen minutes of DW lavage can effectively kill HCC cells in vitro and prevent tumor formation in vivo. DW lavage significantly improves long-term outcomes in patients undergoing liver resection for spontaneously ruptured HCC and could be administered intra-operatively when tumor cell liberation is suspected. PMID- 25784372 TI - Attenuated acute salivary alpha-amylase responses to gustatory stimulation with citric acid in thin children. AB - Salivary alpha-amylase (sAA) is responsible for the 'pre-digestion' of starch in the oral cavity and accounts for up to 50 % of salivary protein in human saliva. An accumulating body of literature suggests that sAA is of nutritional importance; however, it is still not clear how sAA is related to individual's nutritional status. Although copy number variations (CNV) of the salivary amylase gene (AMY1) are associated with variation in sAA levels, a significant amount of sAA variation is not explained by AMY1 CNV. To measure sAA responses to gustatory stimulation with citric acid, we used sAA ratio (the ratio of stimulated sAA levels to those of resting sAA) and investigated acute sAA responses to citric acid in children with normal (Normal-BMI, n 22) and low (Low-BMI, n 21) BMI. The AMY1 gene copy number was determined by quantitative PCR. We, for the first time, demonstrated attenuated acute sAA responses (decreased sAA ratio) to gustatory stimulation in Low-BMI (thinness grade 3) children compared with the Normal-BMI children, which suggest that sAA responses to gustatory stimulation may be of nutritional importance. However, child's nutritional status was not directly related to their resting or stimulated sAA levels, and it was not associated with AMY1 gene copy number. Finally, AMY1 CNV might influence, but did not eventually determine, sAA levels in children. PMID- 25784373 TI - Establishment of a novel human papillomavirus-negative and radiosensitive head and neck squamous cell carcinoma cell line. AB - BACKGROUND: The purpose of this study was to develop a CMCSCC-1 cell line for head and neck cancer research into new therapies for head and neck squamous cell carcinoma (HNSCC). METHODS: The CMCSCC-1 cell line was isolated from a primary oral tongue tumor specimen of a female patient. Tumor cells were evaluated for biomarkers expression by Western blots, reverse transcriptase-polymerase chain reaction (RT-PCR), fluorescence activated cell sorter, and immunostaining. Cell proliferation in response to radiation was measured by the WST-8 assay. RESULTS: The characterization analyses revealed a typical epithelial morphology; a doubling time of approximately 24 hours, high tumorigenicity in immunodeficient mice, and upregulated biomarkers. CMCSCC-1 cells were negative for human papillomavirus (HPV) infection, but more sensitive to radiation compared with those FaDu cell lines. CONCLUSION: CMCSCC-1, a novel oral tongue SCC cell line, was established. It will help in the elucidation of the molecular pathogenesis of HPV-negative radiosensitive tumors. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E542-E551, 2015. PMID- 25784374 TI - Accuracy of Magnetic Resonance Imaging/Ultrasound Fusion Targeted Biopsies to Diagnose Clinically Significant Prostate Cancer in Enlarged Compared to Smaller Prostates. AB - PURPOSE: We assessed the accuracy of magnetic resonance imaging/transrectal ultrasound fusion biopsies to diagnose prostate cancer according to gland size. MATERIALS AND METHODS: A prospective study was performed in 232 men with a first round biopsy, multiparametric magnetic resonance imaging with a lesion, a Likert score of 2 or greater and prostate specific antigen less than 10 ng/ml. All men underwent a standard 12-core protocol plus a protocol of 2 or 3 targeted cores. Significant prostate cancer was defined as at least 1 core with a Gleason score of 7 (3 + 4) or 6 with a greater than 4 mm maximal cancer core length. RESULTS: Mean +/- SD patient age was 64 +/- 6.4 years, mean prostate specific antigen was 6.65 +/- 1.8 ng/ml and mean prostate volume was 40 +/- 24.3 ml. The overall detection rate of clinically significant prostate cancer was 44%. The detection rate of clinically significant prostate cancer by magnetic resonance imaging transrectal ultrasound fusion guided biopsy was 77% for prostate glands less than 30 cm(3), and 61%, 47% and 34% for glands 30 to less than 38.5, 38.5 to less than 55 and 55 to 160 cm(3), respectively (p = 0.001). Differences in prostate cancer detection rates between the standard and targeted protocols were not significant for patients with a prostate volume of 40 cm(3) or less (p = 0.8). Conversely 12 patients with a prostate volume greater than 40 cm(3) had clinically significant prostate cancer using the targeted but not the standard protocol and in 3 prostate cancer was detected by the standard but not the targeted protocol (p = 0.04). CONCLUSIONS: Magnetic resonance imaging-transrectal ultrasound fusion biopsies increased the yield of first round prostate biopsies in patients with a prostate volume greater than 40 cm(3). PMID- 25784376 TI - Helicobacter pylori-induced epithelial-mesenchymal transition, a potential role of gastric cancer initiation and an emergence of stem cells. AB - We know little concerning the expression of transforming growth factor-beta1 (TGF beta1) and TGF-beta1-induced epithelial-mesenchymal transition (EMT) markers in gastric mucosa and their changes after eradication of Helicobacter pylori infection have not yet been clarified. In the present study, we compared the time course of messenger RNA (mRNA) expression of TGF-beta1 and five EMT markers (Twist, Snail, Slug, vimentin and E-cadherin) in 111 controls, 55 patients with gastric dysplasia and 71 patients with early gastric cancer, following eradication of H.pylori. mRNA levels in non-cancerous gastric mucosa were measured using quantitative real time-polymerase chain reaction and the histologic findings of gastric mucosa were compared before and after eradication. The average duration of follow-up was 46.7 months (6.0-112.4). The levels of TGF beta1, Twist, Snail, Slug and vimentin mRNA, in addition to levels of CD44 detected by immunohistochemistry, showed all up-regulation in patients with dysplasia or early gastric cancer compared with controls (P < 0.05); moreover, the mRNA levels of E-cadherin, an epithelial marker, were decreased in these patients compared with the control group (P < 0.001). Eradication of H.pylori reduced the expression of TGF-beta1, Twist, Snail, Slug and vimentin mRNA (P value for slope <0.001), as well as the immunohistochemical expression of CD44 (P = 0.014), whereas it enhanced the expression of E-cadherin (P-value for slope < 0.05). Thus, H.pylori infection may trigger the TGF-beta1-induced EMT pathway and the emergence of gastric cancer stem cells (CSCs). Its eradication may prevent the carcinogenesis of gastric cancer by inhibiting these two pathways. PMID- 25784377 TI - Dynamic changes in microRNA expression profiles reflect progression of Barrett's esophagus to esophageal adenocarcinoma. AB - Esophageal adenocarcinoma (EAC) is highly aggressive malignancy that frequently develops from Barrett's esophagus (BE), a premalignant pathologic change occurring in the lower end of the esophagus. MicroRNAs (miRNAs) are small, non coding RNAs that function as posttranscriptional regulators of gene expression and were repeatedly proved to play key roles in pathogenesis of BE as well as EAC. In our study, we used Affymetrix GeneChip miRNA arrays to obtain miRNA expression profiles in total of 119 tissue samples [24 normal esophageal mucosa (EM), 60 BE and 35 EAC]. We identified a number of miRNAs, that showed altered expression progressively in sequence EM, BE and EAC, including for instance miR 21, miR-25, miR-194 and miR-196a with increasing levels (P < 0.0015) and miR-203, miR-205, miR-210 and miR-378 with decreasing levels (P < 0.0001). The subsequent analysis revealed four diagnostic miRNA signatures enabling to distinguish EM and BE [12 miRNAs, area under curve (AUC) = 0.971], EM and EAC (13 miRNAs, AUC = 1.0), BE without and BE with dysplasia (21 miRNAs, AUC = 0.856) and BE without dysplastic changes and BE with dysplasia together with EAC (2 miRNAs, AUC = 0.886). We suggest that miRNA expression profiling expands current knowledge in molecular pathology of Barrett's-based carcinogenesis and enables identification of molecular biomarkers for early detection of BE dysplasia and progression to EAC. PMID- 25784378 TI - A case of pyoderma gangrenosum associated with anterior necrotizing scleritis in a patient with ulcerative colitis. PMID- 25784375 TI - Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors. AB - Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression. PMID- 25784379 TI - Triple-helical nanowires by tomographic rotatory growth for chiral photonics. AB - Three dimensional helical chiral metamaterials resulted in effective manipulation of circularly polarized light in the visible infrared for advanced nanophotonics. Their potentialities are severely limited by the lack of full rotational symmetry preventing broadband operation, high signal-to-noise ratio and inducing high optical activity sensitivity to structure orientation. Complex intertwined three dimensional structures such as multiple-helical nanowires could overcome these limitations, allowing the achievement of several chiro-optical effects combining chirality and isotropy. Here we report three dimensional triple-helical nanowires, engineered by the innovative tomographic rotatory growth, on the basis of focused ion beam-induced deposition. These three dimensional nanostructures show up to 37% of circular dichroism in a broad range (500-1,000 nm), with a high signal-to-noise ratio (up to 24 dB). Optical activity of up to 8 degrees only due to the circular birefringence is also shown, tracing the way towards chiral photonic devices that can be integrated in optical nanocircuits to modulate the visible light polarization. PMID- 25784381 TI - The impact of gout guidelines. AB - PURPOSE OF REVIEW: This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. RECENT FINDINGS: Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. SUMMARY: Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care. PMID- 25784380 TI - Biologic basis of osteoarthritis: state of the evidence. AB - PURPOSE OF REVIEW: Evidence accumulated since 2010 indicates that human osteoarthritis should now be reclassified as a systemic musculoskeletal disease rather than a focal disorder of synovial joints. RECENT FINDINGS: Inflammation was seen as the key component promoting synovitis as well as progression of cartilage and bone destruction in osteoarthritis. Thus, metabolic-triggered inflammation involving cytokines, adipokines, abnormal metabolites, acute phase reactants and even complement, all appear to play major roles in osteoarthritis pathophysiology. Immune-mediated inflammation involving T cells and B cells as well as macrophages is now considered a common finding in osteoarthritis synovial tissue. Many experimental and clinical analyses showed that the proinflammatory cytokines, which stimulate matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motif gene transcription in normal and osteoarthritis human chondrocyte cultures, are also present at significantly elevated levels in the synovial fluid of osteoarthritis patients compared with nonarthritic synovial fluids. SUMMARY: Human osteoarthritis is a systemic musculoskeletal disorder involving activation of innate and adaptive immune systems accompanied by inflammation exemplified by the elevated production of proinflammatory cytokines, which play a significant role in the progression of the disease. The future of novel therapies for osteoarthritis should consider developing drug development strategies designed to inhibit proinflammatory cytokine-induced signal transduction. These strategies have been successful in the development of drugs for the treatment of rheumatoid arthritis. PMID- 25784382 TI - New insights into the measurement of disease activity in rheumatoid arthritis. AB - PURPOSE OF REVIEW: Disease activity assessment in rheumatoid arthritis (RA) is a rapidly evolving field. Not only are new measures suggested or introduced in the field, but also we continuously learn about the better use of existing ones in the context of managing disease. On that background, we reviewed the literature on disease activity in RA of 2014 and selected interesting or relevant studies for further discussion. RECENT FINDINGS: EULAR Management Criteria suggest that stringent disease activity targets should be used to guide treatment adaptation. Several studies support this, some even claim to change cutpoints for existing composite indices to match this stringency requirement, while others suggest seeking additional guidance by musculoskeletal ultrasound. One study suggests substantial modifications of existing composite measures in order to make them more objective, although the evident patient contribution to treatment decisions from another study would claim the opposite, namely to give more emphasis on the patient's perspective. New measures of disease activity include modification of core set parameters or existing MRI scores, but range up to currently less feasible whole-body MRI scans or sophisticated nuclear medicine methods. SUMMARY: Here, we review several new studies on disease activity assessment in the management of RA. On the basis of the studies in 2014, we expect that this specific field will continue to attract scientific attention. PMID- 25784383 TI - Conventional medical therapy for osteoarthritis: current state of the evidence. AB - PURPOSE OF REVIEW: The incidence and prevalence of osteoarthritis at the knee, hip, and hand joints are rising. Knowledge about recent developments in the treatment of osteoarthritis is highly relevant to current medical and rheumatology practice. This review will highlight key findings from the published literature in the past 18 months, identified via a PubMed search, including the context for these studies, their key findings, and implications. RECENT FINDINGS: Main themes from the literature covered by this article include a continued focus on acetaminophen and glucosamine-chondroitin as therapeutic agents in the medical management of osteoarthritis. In addition, there is a relatively novel focus on use of adalimumab, a tumor necrosis factor inhibitor, and on strontium ranelate, in relation to outcomes of pain and structural progression in osteoarthritic joints. SUMMARY: Recent studies convey a continued focus on potential therapeutic benefit derived from a combination of glucosamine-chondroitin, and intrigue the reader with a focus on biologic therapy (i.e. tumor necrosis factor antagonist) for osteoarthritis, and with use of strontium ranelate as a newer agent with potential therapeutic benefit. PMID- 25784384 TI - Should very low doses of hydroxychloroquine and quinacrine be employed in combination for long-term maintenance of remission in systemic lupus to reduce the risk of ocular toxicity? PMID- 25784385 TI - Acceleration of Long-Range Photoinduced Electron Transfer through DNA by Hydroxyquinolines as Artificial Base Pairs. AB - The C-nucleoside based on the hydroxyquinoline ligand (Hq) is complementary to itself and forms stable Hq-Hq pairs in double-stranded DNA. These artificial Hq Hq pairs may serve as artificial electron carriers for long-range photoinduced electron transfer in DNA, as elucidated by a combination of gel electrophoretic analysis of irradiated samples and time-resolved transient absorption spectroscopy. For this study, the Hq-Hq pair was combined with a DNA-based donor acceptor system consisting of 6-N,N-dimethylaminopyrene conjugated to 2' deoxyuridine as photoinducible electron donor, and methyl viologen attached to the 2'-position of uridine as electron acceptor. The Hq radical anion was identified in the time-resolved measurements and strand cleavage products support its role as an intermediate charge carrier. Hence, the Hq-Hq pair significantly enhances the electron hopping capability of DNA compared to natural DNA bases over long distances while keeping the self-assembly properties as the most attractive feature of DNA as a supramolecular architecture. PMID- 25784386 TI - Detangling complex relationships in forensic data: principles and use of causal networks and their application to clinical forensic science. AB - The search for complex, nonlinear relationships and causality in data is hindered by the availability of techniques in many domains, including forensic science. Linear multivariable techniques are useful but present some shortcomings. In the past decade, Bayesian approaches have been introduced in forensic science. To date, authors have mainly focused on providing an alternative to classical techniques for quantifying effects and dealing with uncertainty. Causal networks, including Bayesian networks, can help detangle complex relationships in data. A Bayesian network estimates the joint probability distribution of data and graphically displays dependencies between variables and the circulation of information between these variables. In this study, we illustrate the interest in utilizing Bayesian networks for dealing with complex data through an application in clinical forensic science. Evaluating the functional impairment of assault survivors is a complex task for which few determinants are known. As routinely estimated in France, the duration of this impairment can be quantified by days of 'Total Incapacity to Work' ('Incapacite totale de travail,' ITT). In this study, we used a Bayesian network approach to identify the injury type, victim category and time to evaluation as the main determinants of the 'Total Incapacity to Work' (TIW). We computed the conditional probabilities associated with the TIW node and its parents. We compared this approach with a multivariable analysis, and the results of both techniques were converging. Thus, Bayesian networks should be considered a reliable means to detangle complex relationships in data. PMID- 25784387 TI - Assessing the effects of tooth loss in adult crania using geometric morphometrics. AB - With high numbers of unidentified skeletonised remains recovered annually in South Africa and an increased number of edentate individuals being reported, the question arises as to whether tooth loss would result in craniofacial changes which might alter the accuracy of osteological analyses. Forty-five fixed landmarks together with sliding semilandmarks were collected from 229 white South African crania and were used to capture curve data pertaining to the basicranium, alveoli, zygomatic arches, nasal aperture and orbits. Geometric morphometric methods were employed to assess the effects of tooth loss on these structures. Although a number of effects were seen when the skull was analysed in its entirety, only the alveoli proved to be significantly affected when regions were analysed individually. Both upper facial height and palate shape were affected by tooth loss, which may influence various osteometric measurements and qualitative traits that are used during the assessment of ancestry and sex. PMID- 25784388 TI - Dose selection of siltuximab for multicentric Castleman's disease. AB - PURPOSE: Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD). METHODS: PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin's lymphoma (n = 17), multiple myeloma (n = 13), or CD (n = 17). Siltuximab was administered as 2.8, 5.5, or 11 mg/kg q2wks, 11 mg/kg q3wks, or 5.5 mg/kg weekly. Simulations of studied or hypothetical siltuximab dosage regimens (15 mg/kg q4wks) were also performed to evaluate maintenance of CRP suppression below the cutoff value of 1 mg/L. RESULTS: A two-compartment PK model and an inhibitory indirect response PD model adequately described the serum siltuximab and CRP concentration-time profiles simultaneously. PD parameter estimates were physiologically plausible. For all disease types, simulations showed that 11 mg/kg q3wks or 15 mg/kg q4wks would reduce serum CRP to below 1 mg/L after the second dose and throughout the treatment period. CONCLUSIONS: PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions. PMID- 25784389 TI - Determination of UCP1 expression in subcutaneous and perirenal adipose tissues of patients with hypertension. AB - The objective of this study is to determine the property of human perirenal adipose tissue (PAT) and assess the adipose property of PAT in hypertension. Ninety-four patients, including 64 normotensive patients (T-NP) and 30 hypertensive patients (HP), who underwent renal surgery were included. Expression analysis was performed using quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry in PAT and back subcutaneous adipose tissue (bSAT) depots. Compared with bSAT, PAT adipocytes were smaller, and the expressions of uncoupling protein-1 (UCP1) mRNA and protein were markedly higher, while the mRNA expressions of markers for classic beige and white adipocytes were lower in PAT. Immunohistochemistry analysis showed more multilocular UCP1 positive adipocytes in PAT than in bSAT. UCP1 expressions were lower in PAT in HP than in the T-NP or age- and body mass index-matched NP groups. Bigger unilocular adipocytes with less UCP1 staining in PAT were detected in HP than in NP group, although no such difference was observed in bSAT. PAT acts as a brown-like fat. UCP1 expression of PAT was lower in HP than in normotensive patients. UCP1 expression of PAT may serve as a protective indicator for hypertension. PMID- 25784390 TI - Biomarkers of acromegaly. PMID- 25784394 TI - How do mood states change in a multi-stage cycling competition? Comparing high and low performers. AB - BACKGROUND: Our purpose was to investigate: (1) differences in mood states between high and low performers at the beginning and end of the Girobio 2012 cycling race, and in respect to both actual and perceived performance; (2) whether the participants' mood states predicted the actual and perceived performance. METHODS: Profile of Mood States (POMS) of 72 elite cyclists were assessed the day prior to the first (T0) and last stage (T1). At the end of the race, we created two rankings, one based on the total time spent to complete the race (actual ranking) and one based on the average of self-evaluations provided at the end of each stage (perceived ranking). We compared high and low performers, considering both rankings, using a general measure of mood; i.e. the total mood disturbance. RESULTS: Total mood disturbance differed among high and low performers. In particular, high performers mood disturbance did not differ between T0 and T1, whereas low performing cyclists showed higher levels of mood disturbance at the end of the race. Furthermore, we found that mood disturbance at T0 did not predict either actual or perceived performance. CONCLUSIONS: The cyclists' mood states at the beginning of the race were not reliable predictors of performance throughout the race. High-performing cyclists maintained a more positive mood profile than their low-performing counterparts at the beginning and end of a multi-stage race. PMID- 25784395 TI - Injuries to young professional baseball pitchers cannot be prevented solely by restricting number of innings pitched. AB - BACKGROUND: The Major League Baseball schedule is longer and more intensive than minor and amateur leagues. As a result, major league pitchers endure a considerably higher cumulative workload throughout the season. Ligament, tendon, muscle, and bone tissues in young pitchers need time to adapt to the workload a major league pitcher must endure. To mitigate the risk of overuse injury, and allow time for tissue adaptation to occur, most teams limit the number of innings a young pitcher may throw. This study examined the relationship between innings pitched and future injury in young professional baseball pitchers. METHODS: All pitchers under 25 years of age that pitched at least one third of an inning in Major League Baseball during the 2002-2007 seasons were included in this study. Total innings pitched were accumulated for each season across three levels of professional baseball (Major League Baseball, and two levels of Minor Leagues). Regression analyses were preformed comparing innings pitched during a single season and difference in innings pitched over consecutive seasons to future injury, as measured by time spent on the disabled list. RESULTS: No significant correlation was found between innings pitched and future injury or consecutive season innings pitched difference and future injury. No significant differences were found when pitchers were split into groups based upon consecutive season innings pitched difference cutoffs. CONCLUSIONS: Based upon the evidence presented, strength and conditioning coaches, sports medicine specialists, and team trainers cannot rely solely on inning counts to accurately measure the tissue demands of professional baseball pitching. Therefore, inning limits alone cannot be used to protect young professional pitchers against the threat of injury. PMID- 25784396 TI - Stress related changes during TeamGym competition. AB - AIM: The aim of the present study was to investigate the stress--related changes of a TeamGym competition considering both physiological [i.e. salivary cortisol (sC) and alpha--amylase (sAA)] and psychological (i.e. state anxiety) responses in relation to exercise intensity and competition outcomes. METHODS: Eleven (5 males and 6 females) elite TeamGym athletes (age: 21--28 yrs) were administered the State--Trait Anxiety Inventory before an official international TeamGym competition. sAA and sC samples were collected 15 minutes prior to competition, after each apparatus, 10--min and 30--min after competition. Exercise intensity was estimated by heart rate (HR) recording and performance was evaluated by three international judges. All these parameters were correlated with competition outcomes. RESULTS: TeamGym competition posed a low exercise load (most of exercise was performed below 85% of the individual HR max ). Significant increases (P<0.004) in sAA (3.53 fold induction) and state anxiety (P=0.045) were observed, with respect to baseline values. Conversely, sC remained stable throughout the competition. Significant (P=0.029) correlation between sAA, state anxiety and competition outcomes emerged. CONCLUSIONS: Present findings provide the first evidence that the psycho--physiological stress response prior to and during competition can affect performance outcome, especially in a technical sport such as TeamGym. PMID- 25784397 TI - Effects of early or late-evening fatiguing physical activity on sleep quality in non-professional sportsmen. AB - AIMS: This study aims to understand whether night sleep--quality is distorted by fatiguing physical activity (PA) when conducted early or late in the evening. METHODS: Participants and Intervention: 9 males (18--38yrs) performed sessions of fatiguing--PA over 3 consecutive days (Mon--Wed), for 2 weeks. One week the PA was performed at 17h, and in the other week at 21h. A Control--week included no PA (PA ABSENT ). The fatiguing--PA sessions comprised several sets of the 20m Shuttle--Run--Test (20mSRT). Sleep was assessed by actigraphic recordings acquired over 3 nights each week. It included the nights following the PA- sessions and the same days in the week of PA ABSENT . Sleep--quality perception was evaluated by mean of the National Sleep Foundation--Sleep Diary. The heart- rate (HR) and body--temperature (BT) at bed--time and waking--up were also registered. RESULTS: Neither the 20mSTR--estimated VO 2max nor the number of maximal 20mSRT sets were different in the PA 17h and PA 21h sessions. Compared to the PA ABSENT , the PA 17h and PA 21h sessions increased the HR at bedtime, which recovered to baseline level after the night of sleep. BT was also reduced when waking--up compared to bed--time, but this was also observed in PA ABSENT . Sleep parameters measured by means of actigraphy were not modified by fatiguing activity when compared to PA ABSENT. Nevertheless, the subjective perception of sleep--quality was negatively altered by fatiguing PA. CONCLUSIONS: Fatiguing PA performed early or late at the evening has no impact on objective sleep--quality but, subjectively, a deterioration of sleep--quality is perceived by the subjects. PMID- 25784398 TI - Impaired cardiorespiratory responses when wearing an upper body compression garment during recovery in a hot environment (40 oC). AB - BACKGROUND: Previous studies have not investigated the effects of a heat dissipating upper body compression garment (UBCG) during cycling in a hot environment. The present study examined the effects of a heat dissipating UBCG on thermoregulatory, cardiorespiratory and perceptual responses (thermal sensation and exertion scales), during cycling at a fixed workload (~50% VO2peak) and during active recovery (~25% VO2peak). METHODS: Thirteen untrained males (mean+/ SD; age 21+/-6 years, VO2peak 53.7+/-5.0 ml.kg-1.min-1) completed two randomized cycling trials consisting of a 5 min rest on a cycling ergometer, followed by 4 bouts of 14 min at a fixed load + 1 min active recovery. Followed further by 10 min of active recovery. Testing occurred in a hot environment (~40+/-0.4 oC, 35+/ 2 % relative humidity, ~2.5 m.s-1 air velocity) and volunteers wore either a UBCG or non-UBCG (CON). RESULTS: Wearing UBCG resulted in significantly smaller reduction in heart rate (31+/-11 bpm vs. 46+/-15 bpm) and higher VO2 and VCO2 values (P<0.05) during 10 min recovery period. No differences in rectal, skin and body temperature were observed during the trial between garment conditions. Clothing wetness sensation remained significantly higher wearing CON (P<0.05) during exercise although no significant differences in weight loss or in sweat rate were observed. CONCLUSIONS: These results suggest that wearing heat dissipating UBCG had no thermoregulatory benefits during exercise and it had impaired cardiorespiratory responses during active recovery when exercising in a hot environment. PMID- 25784399 TI - Perspective of pharmacists in Qatar regarding doping and anti-doping in sports. AB - BACKGROUND: The aim of this study was to evaluate the current knowledge and perceptions of pharmacists in Qatar with regard to the use of drugs in sport and to explore their views on the introduction of education and training in the area of sports pharmacy. METHODS: A cross-sectional survey was conducted targeting both hospital and community pharmacists in Qatar. A questionnaire consisting of three domains pertaining to participants' knowledge, perceived role of healthcare professionals, and attitudes towards educational needs on the use of drugs in sports was developed and validated. The online survey link and paper-based questionnaires were distributed to the target population. Data analyses were performed using IBM SPSS Statistics. Descriptive and inferential statistics were utilized for the analyses, where P<0.05 indicates statistical significance. RESULTS: A total of 300 pharmacists responded to the survey. Respondents had a limited awareness of doping and anti-doping and achieved an average knowledge score of 53.2% regarding the prohibited status of drugs that may be used by athletes, particularly with respect to over-the-counter medicines and supplements. The majority (81.7%) of the pharmacists expressed an interest in receiving education and training on sports pharmacy. CONCLUSIONS: Specialized training programs are warranted to ensure that pharmacists have the knowledge and skills required to provide athletes with accurate information about anti-doping issues and the safe and effective use of medicines in sport. The development of these programs should be supported by national pharmacy policy makers and designed in collaboration with anti-doping agencies and sports pharmacy experts and educators. PMID- 25784400 TI - Reduction of fertility in male mice immunised with pSG.SS.C3d3.YL.Bin1b recombinant vaccine. AB - OBJECTIVES: To study the anti-fertility effect of a DNA vaccine using Bin1b as the target antigen in male mice. METHODS: A novel recombinant eukaryotic vector containing a fusion gene sequence of mouse Bin1b in tandem with three copies of C3d fragment (C3d3) was used to construct pSG.SS.C3d3.YL.Bin1b. The correct expression of the Bin1b-C3d3 protein was confirmed in transfected HEK293 cells by indirect immunofluorescence and western blot analysis. The fertility of immunised mice was determined by a mating experiment and sperm motility test. Anti-Bin1b antibody titres in sera were examined by ELISA assays. Binding activity of C3d3 fragment of the fusion protein was verified in C3d receptor-expressing Raji cells and flow cytometric analysis. RESULTS: Immunisation of pSG.SS.C3d3.YL.Bin1b recombinant DNA vaccine significantly decreased sperm motility and compromised fertility in male mice. ELISA results showed that the titres of anti-Bin1b IgG in sera of immunised mice increased markedly with the immunisation process. Further, the anti-fertility effect of pSG.SS.C3d3.YL.Bin1b was significantly better than that of pSG.SS.YL.Bin1b DNA vaccine and generated higher titres of anti-Bin1b antibody. CONCLUSIONS: Our results show that recombinant DNA vaccine targeting Bin1b can markedly reduce fertility in male mice, providing an alternative approach for birth control. PMID- 25784401 TI - Modelling both dominance and species distribution provides a more complete picture of changes to mangrove ecosystems under climate change. AB - Dominant species influence the composition and abundance of other species present in ecosystems. However, forecasts of distributional change under future climates have predominantly focused on changes in species distribution and ignored possible changes in spatial and temporal patterns of dominance. We develop forecasts of spatial changes for the distribution of species dominance, defined in terms of basal area, and for species occurrence, in response to sea level rise for three tree taxa within an extensive mangrove ecosystem in northern Australia. Three new metrics are provided, indicating the area expected to be suitable under future conditions (Eoccupied ), the instability of suitable area (Einstability ) and the overlap between the current and future spatial distribution (Eoverlap ). The current dominance and occurrence were modelled in relation to a set of environmental variables using boosted regression tree (BRT) models, under two scenarios of seedling establishment: unrestricted and highly restricted. While forecasts of spatial change were qualitatively similar for species occurrence and dominance, the models of species dominance exhibited higher metrics of model fit and predictive performance, and the spatial pattern of future dominance was less similar to the current pattern than was the case for the distributions of species occurrence. This highlights the possibility of greater changes in the spatial patterning of mangrove tree species dominance under future sea level rise. Under the restricted seedling establishment scenario, the area occupied by or dominated by a species declined between 42.1% and 93.8%, while for unrestricted seedling establishment, the area suitable for dominance or occurrence of each species varied from a decline of 68.4% to an expansion of 99.5%. As changes in the spatial patterning of dominance are likely to cause a cascade of effects throughout the ecosystem, forecasting spatial changes in dominance provides new and complementary information in addition to that provided by forecasts of species occurrence. PMID- 25784402 TI - Extemporaneous benznidazole oral suspension prepared from commercially available tablets for treatment of Chagas disease in paediatric patients. AB - OBJECTIVE: To develop an extemporaneous 1% benznidazole (BNZ) suspension, with masked taste and adequate stability starting from available commercial tablets. The quality of compounding was evaluated through content uniformity measurement and physical and microbiological stability evaluation, under different storage conditions during 90 days. METHODS: Six batches of 1% BNZ suspension were prepared using safe excipients currently available in a galenic area of Hospital Pharmacy and then stored at 5 and 25 degrees C for 90 days. The BNZ content was determined by UV spectrophotometry. Physical stability was defined as the absence of colour, odour and/or flavour changes and the re-suspension of solid phase by a reasonable amount of simple 15-s shaking. The compliance with microbiological attributes of non-sterile pharmaceutical products was also evaluated. RESULTS: An oral liquid suspension, containing 1% of BNZ, was developed from commercially available BNZ tablets. The formulations stored for 90 days were easily re dispersed after a simple 15-s shaking, ensuring the pouring of a liquid volume containing the desired dose of BNZ. All samples were within the acceptable range of BNZ concentration with minimal standard deviations. There were no detectable changes in colour, odour, viscosity, pH and microbial growth, complying with official quality requirements. The quality attributes were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multidose containers. CONCLUSION: Paediatric oral liquid suspension containing 1.0% of BNZ was easily prepared starting from commercial tablets, being an interesting alternative for optimising the paediatric treatment of Chagas disease. PMID- 25784403 TI - Under way to academic primary health care. PMID- 25784437 TI - Adaptation of the Sexual Adjustment and Body Image Scale in Turkish Breast Cancer Women. AB - PURPOSE: To investigate the validity and reliability of the Sexual Adjustment and Body Image Scale in Turkish breast cancer women. METHODS: This is a methodological and cross-sectional study, and included 161 breast cancer women. RESULTS: The factor loadings in the exploratory factor analysis ranged from 0.83 to 0.90 for the sexual adjustment scales and ranged from 0.52 to 0.86 for the body image scale. The Cronbach's alpha values were 0.86, 0.83, and 0.89 for the subscales of sexual adjustment and 0.77 and 0.81 for the subscales of body image. CONCLUSION: The scale is a valid and reliable tool to evaluate sexual adjustment and body image in Turkish breast cancer women. PMID- 25784438 TI - Telaprevir decreases estimated glomerular filtration rate in HIV-hepatitis C virus coinfected patients. AB - We investigated kidney function outcome in 24 chronic hepatitis C genotype 1 patients coinfected with HIV receiving telaprevir in a single tertiary care hospital in Spain. A statistically significant median (interquartile range) decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 m) relative to baseline [93.6 (73.0-109.0)] was seen at weeks 4 [86.5 (34.0-112.0), P = 0.014], 8 [90.0 (49.0-111.0), P = 0.026] and 12 [89.5 (54.0-113.0), P = 0.017]. These changes reversed after telaprevir discontinuation. Patients presenting an eGFR decrease had a higher risk of haematological toxicity. PMID- 25784440 TI - Nonalbumin proteinuria predominates in biopsy-proven tenofovir nephrotoxicity. AB - OBJECTIVE: Tenofovir disoproxil fumarate (TDF) nephrotoxicity is characterized by proximal renal tubular injury and dysmorphic mitochondria resulting in proteinuria, orthoglycemic glycosuria, and other markers of proximal tubular dysfunction. The objective of this study was to determine the pattern of proteinuria in patients with biopsy-proven TDF nephrotoxicity. DESIGN: Retrospective chart review. METHODS: Patients with biopsy-proven TDF nephrotoxicity were identified and their medical charts and biopsy reports were reviewed. Comparison was made with HIV-infected patients not on TDF who underwent kidney biopsy. RESULTS: We identified 43 biopsy-proven cases of TDF nephrotoxicity; mean age 54.7 +/- 0.4 years, 53% men, 42% whites. Thirty-seven cases reported proteinuria by dipstick of which only 60% had at least 2+ proteinuria. Twenty-seven patients had urine protein quantified by either 24-h collection or spot urine protein-to-creatinine ratio; median proteinuria was 1742 mg/day [interquartile range (IQR) 1200-2000 mg] and 1667 mg/g creatinine (IQR 851 1967 mg/g), respectively. Ten patients had concurrent urinary albumin measured, with a median 236 mg/g creatinine (IQR 137-343 mg/g). The mean urine albumin-to urine protein ratio (uAPR) was 0.17 (IQR 0.14-0.19), confirming that TDF nephrotoxicity is primarily associated with nonalbumin proteinuria. Control cases had a uAPR of 0.65 (IQR 0.55-0.79) P < 0.001. Histopathology showed the predominance of proximal tubular injury with characteristic mitochondrial abnormalities. CONCLUSION: In the largest published cohort of patients with biopsy-proven TDF nephrotoxicity, we show that low uAPR is a reliable feature of this disease. Because of the predominance of nonalbumin proteinuria, dipstick urinalysis may be unreliable in TDF nephrotoxicity. PMID- 25784439 TI - Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy. AB - OBJECTIVE: To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in gut-associated lymphoid tissue. DESIGN: Profibrotic changes within the secondary lymphoid organs and mucosa have been implicated in failed immune reconstitution following effective combination antiretroviral therapy (cART). Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are nonprofessional antigen presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen. METHODS: Duodenal biopsies, obtained from patients naive to cART, underwent trichrome staining and were examined for tissue growth factor-beta (TGF-beta) expression. Combined immunostaining and second harmonic generation analysis were used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine IMF activation and Toll-like receptor (TLR)4 expression. Finally, primary IMF cultures were stimulated with lipopolysaccharide to demonstrate the expression of the inflammatory biomarkers. RESULTS: The expression of the fibrosis-promoting molecule, TGF-beta1, is significantly increased in duodenal biopsies from HIV patients naive to cART, and negatively correlated with subsequent peripheral CD4(+) recovery. The increase in TGF-beta1 coincided with an increase in collagen deposition in the duodenal mucosa in the tissue area adjacent to the IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-beta1, and interleukin-6. CONCLUSION: Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes, and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients. PMID- 25784441 TI - Interferon-induced transmembrane protein-3 rs12252-C is associated with rapid progression of acute HIV-1 infection in Chinese MSM cohort. AB - BACKGROUND: The interferon-inducible transmembrane protein-3 (IFITM3) is a protein that restricts multiple pathogenic viruses such as influenza virus. The single-nucleotide polymorphism rs12252-C, which is rare in Caucasian populations, but much more common in the Han Chinese population, has been found in much higher homozygous frequency in patients with severe acute influenza. Until now, there has been no study on the effect of this genetic variant on the clinical control of other viral infections. OBJECTIVES: To investigate the impact of IFITM3 rs12252 genotypes on primary HIV-1 infection progression in an acute HIV-1 infected cohort in Beijing (PRIMO), China. DESIGN AND METHODS: We identified IFITM3-rs12252 genotypes of 178 acute HIV-1-infected patients and 196 HIV negative candidates from the PRIMO cohort. HIV-1 viral load and CD4(+) T-cell counts were monitored at multiple time points during the first year of infection, and the association between IFITM3-rs12252 genotype and disease progression was evaluated. RESULTS: The current study shows that the IFITM3-rs12252 genetic variant affects the progression of HIV-1 infection, but not the acquisition. A significantly higher frequency of the CC/CT genotypes was found in rapid progressors compared to nonprogressors. Patients with CC/CT genotypes showed an elevated peak viremia level and significantly lower CD4(+) T-cell count at multiple time points during the first year of primary infection, and a significantly higher risk of rapid decline of the CD4(+) T-cell count to below 350 cells/MUl. CONCLUSION: A novel association between IFITM3 gene polymorphism and rapid disease progression is reported in an acute HIV-1-infected MSM cohort in China. PMID- 25784442 TI - Limited reporting of major harms in studies of initial combination antiretroviral therapy: a systematic review. AB - OBJECTIVES: Risk-benefit assessment of combination antiretroviral therapy (cART) requires consideration of all potential serious harms. Studies of initial cART may permit identification of associations between particular regimens and uncommon harms, but only if comprehensively reported in the public domain. DESIGN: Study-based, systematic review of published initial cART studies (in adult patients) for completeness of serious harms reporting. METHODS: Electronic databases, abstracts, and regulatory/sponsor reports were searched (1 January 1996 - 31 December 2012). Reporting of pre-specified harms - deaths, new/recurrent AIDS events, serious non-AIDS events (2010 INSIGHT classification) and serious adverse events (SAEs) - were assessed as the proportion of studies providing data (reporting frequency). Pharmaceutical sponsors were approached for unreported data. RESULTS: 103 studies (86% randomized, 54% industry-sponsored) were included. Deaths, AIDS events, serious non-AIDS events and SAEs were reported for 85 (83%), 55 (53%), 26 (25%) and 43 (42%) studies, respectively. Deaths were better reported for academic than industry-sponsored studies (91 vs. 75%; P = 0.03); the converse applied for SAEs (26 vs. 55%; P = 0.002). SAEs were better reported for randomized than cohort studies (46 vs. 14%; P = 0.03), and for phase 3 than phase 2 or 4 studies (58 vs. 32 and 29%, respectively; P = 0.02). SAE reporting increased over time [rho = 0.704, P = 0.002 (Spearman)]. Unreported data acquired for 34 (61%) of 56 industry-sponsored studies improved ascertainment in these studies to between 82 and 100% (P < 0.001). CONCLUSION: Public domain reporting of serious harms for initial cART studies is limited. Insufficient data exist to determine if particular ART drugs/regimens are associated with most serious harms. PMID- 25784444 TI - [Urogynecology]. PMID- 25784443 TI - Activated microglia contribute to convergent nociceptive inputs to spinal dorsal horn neurons and the development of neuropathic pain. AB - The activation of microglia in the spinal dorsal horn following peripheral nerve injury has been reported previously, and this change has been proposed to contribute to the development of a neuropathic pain state. We recently demonstrated that peripheral nerve injury activated convergent nociceptive inputs to spinal dorsal horn neurons. The present study was designed to further examine the role of microglia in the activation of convergent nociceptive inputs as well as development of a neuropathic pain state after peripheral nerve injury. Tibial nerve injury initially induced hyposensitivity at 3 days post-injury, and this was followed by hypersensitivity to tactile and thermal stimuli at 14 days. The intraperitoneal administration of minocycline (30 mg/kg), an inhibitor of microglial activation, for 8 days starting on the day of surgery prevented increases in OX-42 immunofluorescence labeling in the spinal dorsal horn and the development of tactile and thermal hypersensitivity at 14 days post-injury. The same minocycline treatment (day 0-7) also reduced the nerve injury-induced convergence of nociceptive inputs to spinal dorsal horn neurons, as revealed by double immunofluorescence labeling for c-Fos induced by noxious heat stimulation of the hindpaw and phosphorylated extracellular signal-regulated kinase induced by electrical stimulation of the injured tibial nerve. However, the administration of minocycline for 8 days starting 7 days after surgery did not prevent nerve injury-induced microglial activation, convergent nociceptive inputs, or tactile and thermal hypersensitivity. These results suggest that microglial activation in the early stage following peripheral nerve injury plays an important role in the anomalous convergence of nociceptive signals to spinal dorsal horn neurons and the development of neuropathic pain. PMID- 25784445 TI - [Vesicovaginal fistula. Incidence, etiology and phenomenology in Germany]. AB - BACKGROUND: Vesicovaginal fistulae are much more common in developing countries along the equatorial fistula belt than in industrialized countries. However, although the classical obstetric fistula caused by lack of medical support through pregnancy and delivery in adolescent primiparae has almost vanished in Germany, we are now facing new and predominantly iatrogenic variants. Increasing frequency of gynecological surgery as well as pelvic radiation, forgotten vaginal foreign bodies, or uninhibited cancer growth are the modern causes for vesicovaginal fistula in elderly patients. Comorbidities and genital atrophy impair surgical therapy in view of a limited success rate of conservative transient transurethral catheterization. METHODS: Diagnostics should start early and should be initially limited to vaginal inspection, cystourethroscopy, and the blue dye test. Radiological investigations including CT and MRI are only indicated in patients suspicious for ureterovaginal fistula or with inconclusive findings or malignant fistula. The surgical armamentarium comprises vaginal, abdominal, and combined approaches, which all underlie basic principles of fistula repair: protection of the ureteral orifices, complete excision of the fistula canal, accurate separation of the organs connected to the fistula, sufficient tissue mobilization for tension-free suturing, interposition of padding material for prevention of recurrency. CONCLUSION: Depending on the degree of sphincter damage, stress urinary incontinence might persist despite successful fistula repair, requiring further incontinence surgery or ultimate urinary diversion in recurrent cases that are hopeless. PMID- 25784446 TI - [Neuromodulation - new techniques]. AB - Neuromodulative procedures have become an inherent component in the therapy of functional urinary bladder and pelvic floor function disorders. Sacral neuromodulation has been used in Germany for more than 20 years and reresents the standard neuromodulative therapy. Technical improvements in the field of test stimulation and the phasing out of the large pulse generator models represent current changes with the resulting advantages and disadvantages. Pudendal neuromodulation (PNM) has been known for many years as a procedure for treatment of chronic diseases of the urinary bladder and the lesser pelvis and is predominantly used as second-line neuromodulative therapy; however, for pelvic pain syndromes and in particular for pudendal neuralgia, it represents a promising minimally invasive first-line therapy. Due to the technically demanding puncture procedure, PNM has so far only been used in Germany in specialized centers. Through the development of new operation techniques, the prerequisites for a wider multicentric use, with the future aim of approval of the procedure, have been achieved. External transdermal pudendal neuromodulation is a promising therapeutic approach and after further testing in randomized studies could find an application as a conservative step before minimally invasive pudendal neuromodulation. Although the technique of laparoscopic electrode placement on neural structures of the lesser pelvis is technically attractive, it predominantly finds a monocentric use and must in due course be critically compared with established minimally invasive procedures. PMID- 25784447 TI - [S2k guidelines of the German Society of Urology. Management and implementation of intermittent catheterization in neurogenic bladder dysfunction]. AB - BACKGROUND: As a considerable heterogeneity in the procedure of intermittent catheterization (IC) was identified by a questionnaire survey conducted in hospitals and institutions for the treatment of patients with spinal cord injury in 2010, it became necessary to standardize the IC procedure (i.e. self catheterization and assisted catheterization). METHOD: These guidelines were developed within a structured consensus process (e.g. several consensus conferences and nominal group process) by members of the working group on neurourology (Arbeitskreis Neuro-Urologie) and the working group on nursing (Arbeitskreis Pflege) of the German-speaking Medical Society of Paraplegia (DMGP), a section of the German Society for Orthopedics and Traumatology (DGOU) and were published as S2k guidelines of the German Society of Urology (DGU). The guidelines developer group consisted of representatives from the following professional groups: neurourology, surgery, health and nursing, nursing science, urotherapy and hygiene. RESULTS: Firstly, the indications for IC are presented and concepts such as sterile, aseptic and hygienic catheterization are defined. The materials necessary for the IC (e.g. quality of the customized single-use catheter and approved disinfectants for disinfection of the meatus) are presented in detail. The disinfection and catheterization techniques are described and a detailed explanation of the potential complications and their management is given. Finally, the legal aspects and issues of eligibility of catheter material and disinfectants are discussed. CONCLUSIONS: The purpose of this consensus is to contribute to the standardization of IC. It should remove uncertainty and offer assistance to users (i.e. patients, staff and care providers). A particular focus is placed on practical instructions for carrying out the IC. The intention is to support the realization of IC in various settings (e.g. hospital, rehabilitation, long-term care institutions and home-based care). A wide implementation of the guidelines should lead to a reduction of the risks and complications of IC, which in most cases is a procedure that will be necessary throughout life. PMID- 25784448 TI - [Study on the treatment of nonmuscle invasive bladder cancer: A phase III efficacy study for intravesical instillation of mistletoe extract in superficial bladder cancer (TIM) AB 40/11 of the AUO]. PMID- 25784449 TI - [From Nobody to Nobel laureate? The case of Werner Forbetamann]. AB - The surgeon and urologist Werner Forbetamann (1904-1979) was awarded the Nobel Prize for Physiology or Medicine in 1956. At the time of the prize ceremony, several newspapers portrayed Forssmann as an unknown rural physician who suddenly had become an international star. Drawing on nominations and reports in the Nobel Prize Archive for Physiology or Medicine in Stockholm as well as correspondence from the private archive of the Forbetamann family, this paper reconstructs why the Nobel Committee chose to award Forbetamann. We show that Forssmann's work was appreciated in medical textbooks and that he enjoyed a relatively sound reputation in the international scientific community even before he became a Nobel Prize laureate. At a more general level, we use his example to explore some mechanisms of scientific recognition. PMID- 25784450 TI - Regulation of embryonic development and apoptotic-related gene expression by brain-derived neurotrophic factor in two different culture conditions in ovine. AB - In the present study, we aimed to evaluate effects of brain-derived neurotrophic factor (BDNF) which is a member of neurotrophic factor family on developmental competence of oocytes in sheep. In vitro maturation was performed in presence of various concentrations (0, 10, and 100 ng/mL) of BDNF. Meiotic maturation, levels of intracellular glutathione, embryonic developmental potential after parthenogenetic activation, number of total and apoptotic cells in blastocysts, and expression of Bax and Bcl-2 genes in blastocyst cells were determined. Under unstressed condition, while at 100 ng/mL concentration, BDNF increased the IVM rate; an increase of glutathione level was observed at 10 ng/mL concentration. Moreover, when BDNF-treated oocytes were used for parthenogenetic activation, more blastocyst at both 10 and 100 ng/mL levels was obtained in comparison with the untreated group. Under heat stress (HS), the blastocyst rate was dramatically reduced in untreated oocytes compared to that obtained from 10 ng/mL BDNF groups. Total cell number in blastocysts was not affected by the treatment groups. The mean of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei in blastocysts was not influenced by addition of BDNF in medium and that presence or absence of thermal stress during IVM than the control group. Moreover, our data revealed that the expression of Bax and Bcl-2 genes in blastocysts was affected by both BDNF concentration and HS. Conclusively, supplementation of IVM medium with 10 ng/mL BDNF had a beneficial effect on sheep oocyte competence by increasing the rate of blastocyst especially when HS exists. PMID- 25784451 TI - Prevalence of bovine sperm-bound antisperm antibodies and their association with semen quality. AB - The objectives of this study were to determine reference intervals (RIs) for sperm-bound immunoglobulins G and A (IgG and IgA), prevalence of antisperm antibodies (ASAs) in satisfactory and nonsatisfactory breeders, and association between ASAs and semen quality in beef bulls. It was hypothesized that ASA binding differed with breeding soundness classification and semen quality. The percentage of IgG- (IgGperc) and IgA-bound (IgAperc) spermatozoa was evaluated in satisfactory (n = 134) and nonsatisfactory (n = 71) breeder beef bulls using flow cytometry. The RI for IgGperc was 0% to 13.5%. The RIs for IgAperc were 0% to 25.8% in yearling Aberdeen Angus bulls and 0% to 12% in all other bulls. The prevalence of IgA-positive samples was higher in nonsatisfactory (14.1%) than that in satisfactory (1.5%) breeders (P = 0.0003). However, the prevalence of IgG positive samples did not differ. Similarly, IgA binding was higher in nonsatisfactory (median; interquartile range; 2.18; 0.77%-8.57%) than that in satisfactory breeders (median; interquartile range; 1.11; 0.32%-3.16%; P = 0.0035), but IgG binding did not differ. Among ASA-positive bulls, median IgA and IgG binding was 39.7% (range, 18.8%-96.2%) and 24.8% (range, 14.2%-33.1%), respectively. Immunoglobulin A binding correlated with the percentage of total (P < 0.0001; r(2) = -0.345) and progressively motile spermatozoa (P < 0.0001; r(2) = -0.329), morphologically normal spermatozoa (P = 0.0004; r(2) = -0.256), sperm head abnormalities (P = 0.0416; r(2) = 0.149), proximal droplets (P = 0.0227; r(2) = 0.167), and coiled tails (P = 0.0338; r(2) = 0.156). Immunoglobulin G binding correlated with the percentage of total (P < 0.0001; r(2) = -0.373) and progressively motile spermatozoa (P < 0.0001; r(2) = -0.455) and sperm concentration (P = 0.0332; r(2) = -0.195). Reference intervals were established for determination of cutoffs for clinically significant sperm-bound IgA and IgG with flow cytometry. Immunoglobulin A binding was both higher and more prevalent in nonsatisfactory breeder bulls. Although IgG binding did not differ with breeding soundness classification, detection of surface-bound IgG and IgA was associated with changes in semen quality. PMID- 25784452 TI - Age-associated potency decline in bovine oocytes is delayed by blocking extracellular Ca(2+) influx. AB - Oocyte aging due to delayed fertilization is associated with declining quality and developmental potential. Intracellular calcium (Ca(2+)) concentration ([Ca(2+)]i) regulates oocyte growth, maturation, and fertilization and has also been implicated in aging. Using bovine oocytes, we tested the hypothesis that oocyte aging could be delayed by reducing [Ca(2+)]ivia blocking the influx of extracellular Ca(2+) or chelating ooplasmic free Ca(2+). After IVM, cumulus oocyte complexes or denuded oocytes were cultured in medium supplemented with 1 octanol, phorbol 12-myristate 13-acetate, or 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid tetrakis-acetoxymethyl ester (BAPTA-AM) to manipulate [Ca(2+)]i. Addition of 1-mM 1-octanol increased blastocyst development rates in the cumulus-oocyte complexes aged for 6 hours by IVF and for 6, 12, and 24 hours by parthenoactivation, and this effect was independent of the presence of cumulus cells. The intracellular levels of ATP, Glutathione, and Glutathione disulfide were not affected by 1-octanol, but [Ca(2+)]i was significantly decreased. When oocytes were cultured in Ca(2+)-free medium for 12 hours, the blastocyst development rate was greater and the beneficial effects of 1-octanol on oocyte aging were abolished. However, when the medium was supplemented with phorbol 12 myristate 13-acetate, [Ca(2+)]i increased and the blastocyst development rate decreased. Moreover, BAPTA-AM reduced [Ca(2+)]i and increased blastocyst development rates after IVF or parthenoactivation. We conclude that the age associated developmental potency decline was delayed by blocking the influx of extracellular Ca(2+) or reducing ooplasmic free Ca(2+). 1-Octanol, BAPTA-AM, or Ca(2+)-free medium could be used to lengthen the fertilization windows of aged bovine oocytes. PMID- 25784453 TI - Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue. AB - Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. FROM THE CLINICAL EDITOR: Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations. PMID- 25784454 TI - Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions. AB - IRF6 and RIPK4 are critical regulators of keratinocyte differentiation and their mutation cause the developmental syndromes Van der Woude syndrome (VWS) and Bartsocas-Papas syndrome (BPS), respectively. RIPK4 promotes keratinocyte differentiation, in part, by inducing IRF6 transactivator function through the phosphorylation of its C-terminal domain at Ser413 and Ser424. Although more than 200 IRF6 mutations have been identified in VWS, a p.Arg412X nonsense mutation is particularly prevalent. A RIPK4 p.Ser376X nonsense mutation in BPS was also recently identified. Here, we demonstrated for the first time that the truncation of IRF6 at Arg412 causes its rapid proteasome-dependent degradation. The truncation of IRF6 also prevented the induction of its transactivator function by RIPK4. Similarly, the p.Ser376X mutation in RIPK4 impaired its induction of IRF6 transactivator function. The mutation also inhibited the stabilisation of beta catenin by RIPK4, and thus may additionally impair Wnt signalling. Collectively, our findings provide important mechanistic insight into how the p.Arg412X and p.Ser376X mutations may cause VWS and BPS, respectively. PMID- 25784455 TI - Design and production of a multiepitope construct derived from hepatitis E virus capsid protein. AB - The aim of this study was to design a high density multiepitope protein, which can be a promising multiepitope vaccine candidate against Hepatitis E virus (HEV). Initially, conserved and antigenic helper T-lymphocyte (HTL) epitopes in the HEV capsid protein were predicted by in silico analysis. Subsequently, a multiepitope comprising four HTL epitopes with high-affinity binding to the HLA molecules was designed, and repeated four times as high density multiepitope construct. This construct was synthesized and cloned into pET-30a (+) vector. Then, it was transformed and expressed in Escherichia coli BL21 cells. The high density multiepitope protein was purified by Ni-NTA agarose and concentrated using Amicon filters. Finally, the immunological properties of this high density multiepitope protein were evaluated in vitro. The results showed that the high density multiepitope construct was successfully expressed and purified. SDS-PAGE and Western blot analyses showed the presence of a high density multiepitope protein band of approximately 33 kDa. Approximately 1 mg of the purified protein was obtained from each liter of the culture media. Moreover, the purified multiepitope protein was capable of induction of proliferation responses, IFN gamma ELISPOT responses and IFN-gamma and IL-12 cytokines production in a significant level in peripheral blood mononuclear cells (PBMCs) isolated from HEV recovered individuals compared to the control group. In conclusion, the newly produced multiepitope protein can induce significant T helper type 1 responses in vitro, and can be considered as a novel strategy for the development of HEV vaccines in the future. PMID- 25784457 TI - Control of the interface between heterotypic cell populations reveals the mechanism of intercellular transfer of signaling proteins. AB - Direct intercellular transfer of cellular components is a recently described general mechanism of cell-cell communication. It is a more non-specific mode of intercellular communication that is not actively controlled by the participating cells. Though membrane bound proteins and small non-protein cytosolic components have been shown to be transferred between cells, the possibility of transfer of cytosolic proteins has not been clearly established, and its mechanism remains unexplained. Using a cell-cell pair of metastatic melanoma and endothelial cells, known to interact at various stages during cancer progression, we show that cytosolic proteins can indeed be transferred between heterotypic cells. Using precise relative cell patterning we provide evidence that this transfer depends on extent of the interface between heterotypic cell populations. This result is further supported by a mathematical model capturing various experimental conditions. We further demonstrate that cytosolic protein transfer can have important functional consequences for the tumor-stroma interactions, e.g., in heterotypic transfer of constitutively activated BRAF, a common melanoma associated mutation, leading to an enhanced activation of the downstream MAPK pathway. Our results suggest that cytosolic protein transfer can have important consequences for regulation of processes involving physical co-location of heterotypic cell types, particularly in invasive cancer growth. PMID- 25784456 TI - Empirical estimation of local dielectric constants: Toward atomistic design of collagen mimetic peptides. AB - One of the key challenges in modeling protein energetics is the treatment of solvent interactions. This is particularly important in the case of peptides, where much of the molecule is highly exposed to solvent due to its small size. In this study, we develop an empirical method for estimating the local dielectric constant based on an additive model of atomic polarizabilities. Calculated values match reported apparent dielectric constants for a series of Staphylococcus aureus nuclease mutants. Calculated constants are used to determine screening effects on Coulombic interactions and to determine solvation contributions based on a modified Generalized Born model. These terms are incorporated into the protein modeling platform protCAD, and benchmarked on a data set of collagen mimetic peptides for which experimentally determined stabilities are available. Computing local dielectric constants using atomistic protein models and the assumption of additive atomic polarizabilities is a rapid and potentially useful method for improving electrostatics and solvation calculations that can be applied in the computational design of peptides. PMID- 25784459 TI - Standards of care for feline urethral catheters in the UK. AB - OBJECTIVES: This study aimed to determine the standards of care for urethral catheters (UCs) placed in male cats for treatment of urethral obstruction (UO). It also assessed whether these standards were influenced by year of graduation of the veterinary surgeon (VS). METHODS: One hundred veterinary practices were randomly selected, and a telephone survey was conducted with a VS in the practice. Regarding the last urethral catheterisation performed for a male cat with UO, the VS was asked about the use of antibiotics while the catheter was in situ, whether a closed urinary collection system was used, whether aseptic skin preparation of the patient was performed and whether aseptic hand preparation was performed. A chi(2) test was used to determine whether there were significant differences in these percentages when considering year of graduation. RESULTS: Twenty-seven percent of VSs did not use antibiotics while the urethral catheter was in place, 44% used closed urinary collection systems, 41% performed aseptic skin preparation of the patient and 60% aseptically prepared their hands and wore sterile gloves. There was a statistically significant (P <0.01) difference in antibiotic usage, closed collection system usage and aseptic hand preparation across graduation year groups. CONCLUSIONS AND RELEVANCE: Non-sterile urethral catheter placement with open urinary drainage and antibiotic prophylaxis is still a widespread practice among VSs; however, more recent graduates are more likely to perform the procedure aseptically with a closed urinary collection system and withholding of antibiotics. There is a need for further education for postgraduate veterinarians in the prevention of catheter-associated urinary tract infections in cats and further research to provide evidence-based guidelines for feline urethral catheter care. PMID- 25784458 TI - Symptomatic Bipartite Medial Cuneiform: Report of Five Cases and Review of the Literature. AB - Bipartition of the medial cuneiform is a well-described but rarely seen anatomic variant. The majority of literature focuses on anatomic description and incidents based on studies of archeological collections. Symptomatic cases can be overlooked or misdiagnosed initially given the vague complaint of pain either chronic in nature or following an acute injury that could result in a myriad of foot conditions. Treatment ranges from orthotics, immobilization, injection therapy, and surgery. Presented here is a series of 5 cases treated successfully with conservative and surgical measures. LEVELS OF EVIDENCE: Therapeutic, Level IV. PMID- 25784460 TI - Assessment of intravenous adipose-derived allogeneic mesenchymal stem cells for the treatment of feline chronic kidney disease: a randomized, placebo-controlled clinical trial in eight cats. AB - OBJECTIVES: Feline chronic kidney disease (CKD) is characterized by chronic tubulointerstitial nephritis, and inflammation contributes to the progression of renal fibrosis. Mesenchymal stem cells (MSCs) have demonstrated anti-inflammatory and antifibrotic effects in rodent CKD models. However, few randomized trials evaluating the effectiveness of MSC therapy for diseases in companion animals have been reported. The purpose of this study was to evaluate the effectiveness of allogeneic MSCs for the treatment of feline CKD using a randomized, placebo controlled trial. METHODS: MSCs were isolated from the cryopreserved adipose tissues of specific pathogen-free research cats and culture expanded. CKD cats were enrolled in a randomized, placebo-controlled, blinded one-way crossover clinical study. Four CKD cats were randomized to receive 2 * 10(6) MSCs/kg intravenously at 2, 4 and 6 weeks. Four CKD cats were randomized to receive placebo, with two cats crossing over to the MSC treatment group and one cat failing to complete the trial. Complete blood counts, chemistry and urinalysis were performed at weeks 0, 2, 4, 6 and 8. Glomerular filtration rate (GFR) via nuclear scintigraphy and urine protein:creatinine ratio (UPC) were determined at weeks 0 and 8. RESULTS: Six cats received three doses of allogeneic MSC culture expanded from cryopreserved adipose without adverse effects. No significant change in serum creatinine, blood urea nitrogen, potassium, phosphorus, GFR by nuclear scintigraphy, UPC or packed cell volume was seen in cats treated with MSCs. Individual changes in GFR were 12%, 8%, 8%, 2%, -13% and -67% in treated cats compared with 16%, 36% and 0% in placebo-treated cats. CONCLUSIONS AND RELEVANCE: While administration of MSC culture expanded from cryopreserved adipose was not associated with adverse effects, significant improvement in renal function was not observed immediately after administration. Long-term follow-up is necessary to determine whether MSC administration affects disease progression in cats with CKD. PMID- 25784461 TI - An elderly lady with significant weight loss. AB - We present a rare case of collagenous sprue in an elderly woman with significant weight loss and malnutrition. Collagenous sprue is a rare, female-predominant and immune-mediated gastrointestinal disease that can affect any part of the gut, and shares a strong association with Coeliac disease. The diagnosis is confirmed by gut histopathology demonstrating a subepithelial collagenous band and inflammatory infiltrate in the lamina propria. The pathogenesis and natural history is poorly elucidated, and treatment involves a gluten-free diet and/or immunomodulatory therapy. PMID- 25784462 TI - Narcissistic self-sorting in self-assembled cages of rare Earth metals and rigid ligands. AB - Highly selective, narcissistic self-sorting can be achieved in the formation of self-assembled cages of rare earth metals with multianionic salicylhydrazone ligands. The assembly process is highly sensitive to the length of the ligand and the coordination geometry. Most surprisingly, high-fidelity sorting is possible between ligands of identical coordination angle and geometry, differing only in a single functional group on the ligand core, which is not involved in the coordination. Supramolecular effects allow discrimination between pendant functions as similar as carbonyl or methylene groups in a complex assembly process. PMID- 25784463 TI - Hydrodynamic characteristics of the helical flow pump. AB - The helical flow pump (HFP) was invented to be an ideal pump for developing the TAH and the helical flow TAH (HFTAH) using two HFPs has been developed. However, since the HFP is quite a new pump, hydrodynamic characteristics inside the pump are not clarified. To analyze hydrodynamic characteristics of the HFP, flow visualization study using the particle image velocimetry and computational fluid dynamics analysis were performed. The experimental and computational models were developed to simulate the left HFP of the HFTAH and distributions of flow velocity vectors, shear stress and pressure inside the pump were examined. In distribution of flow velocity vectors, the vortexes in the vane were observed, which indicated that the HFP has a novel and quite unique working principle in which centrifugal force rotates the fluid in the helical volutes and the fluid is transferred from the inlet to the outlet helical volutes according to the helical structure. In distribution of shear stress, the highest shear stress that was considered to be occurred by the shunt flow across the impeller was found around the entrance of the inlet helical volute. However, it was not so high to cause hemolysis. This shunt flow is thought to be improved by redesigning the inlet and outlet helical volutes. In distribution of pressure, negative pressure was found near the entrance of the inlet helical volute. However, it was not high. Negative pressure is thought to be reduced with an improvement in the design of the impeller or the vane shape. PMID- 25784465 TI - Parasitism disruption a likely consequence of belowground war waged by exotic plant invader. PMID- 25784466 TI - Novel insights on the structure and composition of pseudostomata of Sphagnum. AB - PREMISE OF THE STUDY: The occurrence of stomata on sporophytes of mosses and hornworts is congruent with a single origin in land plants. Although true stomata are absent in early-divergent mosses, Sphagnum has specialized epidermal cells, pseudostomata, that partially separate but do not open to the inside. This research examined two competing hypotheses that explain the origin of pseudostomata: (1) they are modified stomata, or (2) they evolved from epidermal cells independently from stomata.* METHODS: Capsule anatomy and ultrastructure of pseudostomata were studied using light and electron microscopy, including immunolocalization of pectins.* KEY RESULTS: Cell walls in pseudostomata are thin, two-layered, and rich in pectins, similar to young moss stomata, including the presence of cuticle on exterior walls. Outer and ventral walls have a thick cuticle that suggests that initial separation of ventral walls involves cuticle deposition as in true stomata. Further mechanical separation between ventral walls does not form a pore and occurs as the capsule dries.* CONCLUSIONS: As in moss stomata, pseudostomata wall architecture and behavior facilitate capsule dehydration, shape change, and dehiscence, supporting a common function. The divergent structure and fate of pseudostomata may be explained by the retention of Sphagnum sporophytes within protective leaves until nearly mature. Ultrastructural and immunocytological data suggest that pseudostomata are related to stomata but do not conclusively support either hypothesis. Solving the relationship of early land plants is critical to understanding stomatal evolution. Pseudostomata are structurally and anatomically unique, but their relationship to true stomata remains to be determined. PMID- 25784467 TI - Floral development of Sabia (Sabiaceae): evidence for the derivation of pentamery from a trimerous ancestry. AB - * PREMISE OF THE STUDY: Flowers of Sabiaceae diverge from basal eudicots in combining pentamery with superposed whorls of sepals, petals, and stamens and are therefore crucial in understanding origins of core eudicot flowers. Different hypotheses are tested using floral developmental evidence, whether the pentamerous flower is derived from a spiral, trimerous, or dimerous progenitor.* METHODS: The floral development of two species of Sabia was investigated with the scanning electron microscope to understand their unusual floral morphology and the origin of pentamery.* KEY RESULTS: The species show major developmental differences in their inflorescence morphology and organ initiation sequence. In S. limoniacea, flowers are subtended by a pherophyll preceding two prophylls, one of which encloses a younger flower; floral organs arise in a continuous spiral sequence without interruption between different organs. The ovary is oriented in an oblique-median position. In S. japonica, one prophyll replaces one of the sepals, and there is a disruption in the spiral sequence. As a result, the ovary is inserted more or less transversally.* CONCLUSIONS: The flower of Sabiaceae is structurally best interpreted as derived from a trimerous progenitor, and a derivation from a dimerous or spiral progenitor is less likely. One organ of each median adaxial whorl is interpreted as lost (from K3+3 C3+3 A3+3 G3 to K3+2 C3+2 A3+2 G2). The number of sepals is variable as pherophylls, prophylls, and sepals cannot be distinguished by shape and intergrade with each other. The floral organization of Sabia is reminiscent of trimerous Ranunculales and supports an earlier divergence of Sabiaceae relative to Proteales. PMID- 25784468 TI - Large size and high light do not lower the cost of reproduction for the Neotropical herb Goeppertia marantifolia. AB - * PREMISE OF THE STUDY: Sexual reproduction is often associated with a cost in terms of reduced survival, growth, or future reproduction. It has been proposed that plant size and the environment (availability of key resources) can sometimes lower or even nullify the cost of reproduction.* METHODS: We address this issue experimentally with the Neotropical herb Goeppertia marantifolia, by manipulating sexual reproductive effort and measuring the demographic performance of plants and of their clonal offspring, in the context of natural variation in light availability.* KEY RESULTS: Plants in the high-reproductive-effort treatment grew less between seasons but did not differ in their probability of flowering the second season or in inflorescence size compared with plants in the low-effort treatment. Reproductive effort of parent plants influenced the leaf area of their clonal offspring. Plants that invested less in sexual reproduction produced clonal offspring that were initially larger than those produced by plants that invested more in reproduction. The magnitude of this effect was greater in parent plants that received two seasons of the manipulated reproductive effort than in those that received a single season. The trade-off between reproductive modes dampened with time, leading to smaller differences in clonal offspring leaf area between treatments over time.* CONCLUSIONS: We found evidence of a cost of reproduction and trade-offs between reproductive modes, although the magnitude of these costs was small. However, we found no evidence of lower costs of reproduction for larger plants or for plants in higher-light environments over our 2-yr study period. PMID- 25784469 TI - Effects of arbuscular mycorrhizal fungi and maternal plant sex on seed germination and early plant establishment. AB - * PREMISE OF THE STUDY: Arbuscular mycorrhizal fungi usually enhance overall plant performance, yet their effects on seed germination and early plant establishment, crucial steps in plant cycles, are generally overlooked. In gynodioecious species, sexual dimorphism in these traits has been reported, with females producing seeds that germinate at a faster rate than seeds from hermaphrodites.* METHODS: Using the gynodioecious plant Geranium sylvaticum, I investigated in a greenhouse experiment whether the presence of arbuscular mycorrhizal spores affects seed germination and early plant establishment, examining at the same time whether the sex of the mother producing the seeds also influences these parameters and whether sex-specific interactions between these two factors exist.* KEY RESULTS: The presence of arbuscular mycorrhizal spores in the soil decreased seed germination, did not affect plant survival, but did increase plant growth. Moreover, no significant differences in seed traits were detected between the sexes of the plants producing the seeds.* CONCLUSIONS: This study demonstrates that arbuscular mycorrhizal fungi may have contrasting effects for plants during early life stages and that mycorrhizal effects can take place even at the precolonization stage. PMID- 25784470 TI - Evolutionary divergence of leaf width and its correlates. AB - * PREMISE OF THE STUDY: The question why leaf dimensions vary so much between species has long puzzled ecologists. Presumably, variation arises from selective forces acting on leaf function but which selective forces and which leaf functions? This investigation assesses the consistency of divergence in plant traits and habitat variables in association with leaf width divergence in the flora of NSW, Australia.* METHODS: More than 80 traits and habitat variables were measured for 25 independent evolutionary divergence events (PICs). Each PIC was represented by two related plant species that had diverged substantially in leaf width. Outgroup species provided indications of the direction of divergence. Most PICs were within genus, so divergences represent relatively recent evolutionary events.* KEY RESULTS: No plant traits or habitat variables were 100% consistently associated with a divergence in leaf width, and surprisingly few diverged in a consistent direction significantly more than what might be expected by chance. This surprising lack of consistent divergence with leaf width contrasted with the result that many of these traits and habitat variables were correlated with leaf width across all species in our data set and in line with correlations reported from other studies. Subcategorizing PICs according to the probable direction of leaf width divergence did not improve consistency.* CONCLUSIONS: These results indicate that evolutionarily recent leaf width divergence events are not tightly tied to divergences in other leaf traits or in environmental situations, despite the broad correlations that have been observed across many species. Rather, cross species correlations are underpinned by earlier divergence events in the phylogeny. PMID- 25784471 TI - Effects of floral metal accumulation on floral visitor communities: introducing the elemental filter hypothesis. AB - * PREMISE OF THE STUDY: For plant species that occur in heavy-metal-rich soil, floral metal accumulation may produce an "elemental filter" that reduces pollinator visitation rate and species richness and changes pollinator species composition relative to closely related species growing on normal soils. Consequently, metal hyperaccumulation may contribute to pollinator-mediated reproductive isolation between closely related plant species that differ in metal accumulation.* METHODS: To test these ideas, we characterized plant-pollinator interactions in a sympatric pair of species that differ in metal accumulation (Streptanthus polygaloides, a nickel (Ni) hyperaccumulator, and S. tortuosus, a nonaccumulator). To test the elemental filter hypothesis, we presented arrays of S. polygaloides that were grown in either Ni-treated or control soils to insects at both S. polygaloides and S. tortuosus sites and recorded visitation.* KEY RESULTS: Naturally occurring S. polygaloides hyperaccumulated Ni in anthers and accumulated Ni in nectar, while S. tortuosus did not. Floral visitation rates in natural populations were higher to S. tortuosus than S. polygaloides. In addition, while floral visitor richness was similar, few pollinator taxa were shared between the two plant species. Nickel-treatment of S. polygaloides reduced visits by bees, but only for arrays presented at S. tortuosus sites.* CONCLUSIONS: We show that the Ni hyperaccumulator S. polygaloides hosts a distinct floral visitor community, indicating that metal accumulation creates a filter for pollinators, similar to that documented for herbivores. Our study highlights a novel mechanism by which the abiotic environment can alter plant pollinator interactions, and consequently plant reproduction and speciation. PMID- 25784472 TI - Ex situ germination as a method for seed viability assessment in a peatland orchid, Platanthera blephariglottis. AB - * PREMISE OF THE STUDY: Assessing seed quality in orchids has been hindered by stringent germination requirements. Seed quality has traditionally been assessed in orchids using in vitro or in situ germination protocols or viability staining. However, these methods are not always well suited for rapid assessment of viability in the context of ecological studies.* METHODS: The potential of an ex situ protocol for seed viability assessment of orchids in ecological studies was investigated by sowing seeds of Platanthera blephariglottis on Sphagnum moss collected in the orchid's natural habitat. Ex situ germination results were compared with those obtained by viability staining using triphenyltetrazolium chloride (TTC), and the effect of seed testa color on staining and germination results was investigated.* KEY RESULTS: The ex situ protocol yielded high germination rates, with 66% of the seeds germinating after 9 wk. Depending on the seed testa color class, ex situ germination rates were about 1.4 to 2.5 times higher than viability rates determined using TTC, indicating that the TTC technique underestimated viability compared with the method using ex situ germination. The TTC estimates of viability rates were higher for seeds with dark colored testae than for pale ones, whereas seed testa color had no effect on germination.* CONCLUSIONS: Our study showed promising results for the use of ex situ germination as an alternative to previously developed protocols for seed viability assessment of orchids in ecological studies. Staining using TTC might not be well suited for this purpose, since it introduced a bias with respect to seed testa color. PMID- 25784473 TI - An ultraviolet floral polymorphism associated with life history drives pollinator discrimination in Mimulus guttatus. AB - * PREMISE OF THE STUDY: Ultraviolet (UV) floral patterns are common in angiosperms and mediate pollinator attraction, efficiency, and constancy. UV patterns may vary within species, yet are cryptic to human observers. Thus, few studies have explicitly described the distribution or ecological significance of intraspecific variation in UV floral patterning. Here, we describe the geographic distribution and pattern of inheritance of a UV polymorphism in the model plant species Mimulus guttatus (Phrymaceae). We then test whether naturally occurring UV phenotypes influence pollinator interactions within M. guttatus.* METHODS: We document UV patterns in 18 annual and 19 perennial populations and test whether UV pattern is associated with life history. To examine the pattern of inheritance, we conducted crosses within and between UV phenotypes. Finally, we tested whether bee pollinators discriminate among naturally occurring UV phenotypes in two settings: wild bee communities and captive Bombus impatiens.* KEY RESULTS: Within M. guttatus, perennial populations exhibit a small bulls-eye pattern, whereas a bilaterally symmetric runway pattern occurs mainly in annual populations. Inheritance of UV patterning is consistent with a single-locus Mendelian model in which the runway phenotype is dominant. Bee pollinators discriminate against unfamiliar UV patterns in both natural and controlled settings.* CONCLUSIONS: We describe a widespread UV polymorphism associated with life history divergence within Mimulus guttatus. UV pattern influences pollinator visitation and should be considered when estimating reproductive barriers between life history ecotypes. This work develops a new system to investigate the ecology and evolution of UV floral patterning in a species with extensive genomic resources. PMID- 25784474 TI - Relation between flower head traits and florivory in Asteraceae: a phylogenetically controlled approach. AB - * PREMISE OF THE STUDY: While much research has examined the relation between leaf traits and herbivory, very little is known about the interaction between floral traits, particularly biochemical traits, and florivory. We investigated patterns between floral traits and florivory across multiple species using phylogenetic comparative approaches to enhance our understanding of the evolution of plant-florivore interactions.* METHODS: The relation between the intensity of florivory and five biochemical traits (concentrations of carbon, nitrogen, phosphorus, water, and total phenolics) and two morphological traits (diameter and number of flower heads) were investigated in wild individuals of 18 native species of Asteraceae. The phylogenetic signals in the morphological traits and intensity of florivory were also tested.* KEY RESULTS: We found that species with higher nitrogen, water, and total phenolics and lower phosphorus concentrations in the flower heads and species with a large number and diameter of flower heads tended to be attacked by florivores. In addition, we found significant phylogenetic signals in florivory and morphological traits.* CONCLUSIONS: Our results clearly show that biochemical traits also play important roles in plant florivore interactions, as previously shown in plant-leaf herbivore interactions. The positive relationship between florivory and total phenolics implies that phenolic compounds in flower heads may not act as a defense in the species. In addition, the observed pattern of signals in florivory might not be solely explained by the signals of the measured traits and other plant traits may also play significant roles in plant-florivore interaction in these species. PMID- 25784475 TI - Coleochaete and the origin of sporophytes. AB - * PREMISE OF THE STUDY: Zygotes of Coleochaete are provisioned by the maternal thallus before undergoing 3-5 rounds of division to produce 8-32 zoospores. An understanding of the selective forces favoring postzygotic divisions would be relevant not only to the interpretation of Coleochaete life history but also to the origin of a multicellular diploid phase in embryophytes.* METHODS: Simple optimization models are developed of the number of zygotes per maternal thallus and number of zoospores per zygote.* KEY RESULTS: Zygotic mitosis is favored once zygotic size exceeds a threshold, but natural selection usually promotes investment in additional zygotes before zygotes reach this threshold. Factors that favor production of fewer, larger zygotes include multiple paternity, low fecundity, and accessory costs of zygote production. Such factors can result in zygotes exceeding the size at which zygotic mitosis becomes profitable.* CONCLUSIONS: Coleochaete may possess large zygotes that undergo multiple fission because of accessory costs associated with matrotrophy, including costs of cortical cells and unfertilized oogonia. The unpredictability of fertilization on land is proposed to have increased accessory costs from unfertilized ova and, as a consequence, to have favored the production of larger zygotes that underwent postzygotic division to produce diploid sporophytes. PMID- 25784476 TI - Smilax (Smilacaceae) from the Miocene of western Eurasia with Caribbean biogeographic affinities. AB - * PREMISE OF THE STUDY: Recent molecular studies provide a phylogenetic framework and some dated nodes for the monocot genus Smilax. The Caribbean Havanensis group of Smilax is part of a well-supported "New World clade" with a few disjunct taxa in the Old World. Although the fossil record of the genus is rich, it has been difficult to assign fossil taxa to extant groups based on their preserved morphological characters.* METHODS: Leaf fossils from Europe and Asia Minor were studied comparatively and put into a phylogenetic and biogeographic context using a molecular phylogeny of the genus.* KEY RESULTS: Fossils from the early Miocene of Anatolia represent a new species of Smilax with systematic affinities with the Havanensis group. The leaf type encountered in the fossil species is exclusively found in species of the Havanensis group among all modern Smilax. Scattered fossils of this type from the Miocene of Greece and Austria, previously referred to Quercus (Fagaceae), Ilex (Aquifoliaceae), and Mahonia (Berberidaceae) also belong to the new species.* CONCLUSIONS: The new Smilax provides first fossil evidence of the Havanensis group and proves that this group had a western Eurasian distribution during the Miocene. The age of the fossils is in good agreement with the (molecular-based) purported split between the Havanensis and Hispida groups within Smilax. The Miocene Smilax provides evidence that all four subclades within the "New World clade" had a disjunct intercontinental distribution during parts of the Neogene involving trans-Atlantic crossings (via floating islands or the North Atlantic land bridge) and the Beringia land bridge. PMID- 25784477 TI - Cold tolerance in Arabidopsis kamchatica. AB - * PREMISE OF THE STUDY: Cold tolerance is a critically important factor determining how plants will be influenced by climate change, including changes in snowcover and extreme weather events. Although a great deal is known about cold tolerance in Arabidopsis thaliana, it is not highly cold tolerant. This study examined cold tolerance and its genetic diversity in an herbaceous subarctic relative, Arabidopsis kamchatica, which generally occurs in much colder climates.* METHODS: Thermal analysis and electrolyte leakage were used to estimate supercooling points and lethal temperatures (LT50) in cold-acclimated and nonacclimated families from three populations of A. kamchatica.* KEY RESULTS: Arabidopsis kamchatica was highly cold tolerant, with a mean LT50 of -10.8 degrees C when actively growing, and -21.8 degrees C when cold acclimated. It also was able to supercool to very low temperatures. Surprisingly, actively growing plants supercooled more than acclimated plants (-14.7 vs. -12.7 degrees C). There was significant genetic variation for cold tolerance both within and among populations. However, both cold tolerance and genetic diversity were highest in the midlatitude population rather than in the far north, indicating that adaptations to climate change are most likely to arise in the center of the species range rather than at the edges.* CONCLUSIONS: Arabidopsis kamchatica is highly cold tolerant throughout its range. It is far more freeze tolerant than A. thaliana, and supercooled to lower temperatures, suggesting that A. kamchatica provides a valuable complement to A. thaliana for cold tolerance research. PMID- 25784478 TI - Range-wide population genetics and variation in morph ratio in style-dimorphic Narcissus papyraceus. AB - * PREMISE OF THE STUDY: Theoretical models state that natural selection and mating patterns account for floral morph ratio in style-polymorphic plants. However, the demographic history of populations can also influence variation in morph ratios. If so, we hypothesize an association between the morph ratios and the genetic structure across populations.* METHODS: We used nuclear microsatellites to assess genetic variation and structure in populations of Narcissus papyraceus, a style-dimorphic plant whose floral morph ratios (L-morph to S-morph) gradually vary throughout its distribution range in the southwestern Mediterranean Basin. We implemented analyses to relate the genetic features of populations with their morph ratios.* KEY RESULTS: We found greater frequencies of the S-morph in central populations and declining frequencies toward the periphery. This geographic pattern was not associated with the genetic structure of populations. Instead, we found two distinct genetic groups, mainly separated by the Strait of Gibraltar, with a mixture of morph ratios within each one. Overall, there was a weak genetic structure. Genetic diversity was greater in central and southern dimorphic populations than in northern L-monomorphic populations.* CONCLUSIONS: Altogether, our results do not support the hypothesis that the demographic history of populations can account for the observed geographical pattern of morph ratios in N. papyraceus. We suggest that adaptive processes shown in previous studies in the species are the main determinant of the existing variation in the morph composition of populations. PMID- 25784479 TI - Aerodynamics and pollen ultrastructure in Ephedra. AB - * PREMISE OF THE STUDY: Pollen dispersal is affected by the terminal settling velocity (Ut) of the grains, which is determined by their size, bulk density, and by atmospheric conditions. The likelihood that wind-dispersed pollen is captured by ovulate organs is influenced by the aerodynamic environment created around and by ovulate organs. We investigated pollen ultrastructure and Ut of Ephedra foeminea (purported to be entomophilous), and simulated the capture efficiency of its ovules. Results were compared with those from previously studied anemophilous Ephedra species.* METHODS: Ut was determined using stroboscopic photography of pollen in free fall. The acceleration field around an "average" ovule was calculated, and inflight behavior of pollen grains was predicted using computer simulations. Pollen morphology and ultrastructure were investigated using SEM and STEM.* KEY RESULTS: Pollen wall ultrastructure was correlated with Ut in Ephedra. The relative proportion and amount of granules in the infratectum determine pollen bulk densities, and (together with overall size) determine Ut and thus dispersal capability. Computer simulations failed to reveal any functional traits favoring anemophilous pollen capture in E. foeminea.* CONCLUSION: The fast Ut and dense ultrastructure of E. foeminea pollen are consistent with functional traits that distinguish entomophilous species from anemophilous species. In anemophilous Ephedra species, ovulate organs create an aerodynamic microenvironment that directs airborne pollen to the pollination drops. In E. foeminea, no such microenvironment is created. Ephedroid palynomorphs from the Cretaceous share the ultrastructural characteristics of E. foeminea, and at least some may, therefore, have been produced by insect-pollinated plants. PMID- 25784480 TI - The ecology, evolution, and biogeography of dioecy in the genus Solanum: with paradigms from the strong dioecy in Solanum polygamum, to the unsuspected and cryptic dioecy in Solanum conocarpum. AB - * PREMISE OF THE STUDY: Island plants are over-exploited and "under-explored." Understanding the reproductive biology of plants, especially rare species, is fundamental to clarifying their evolution, estimating potential for change, and for creating effective conservation plans. Clarification of sexual systems like dioecy, and unusual manifestations of it in specific studies within Solanum, helps elucidate evolutionary patterns and genetic and ecological control of sex expression.* METHODS: Studies of reproductive systems of two Caribbean endemics, S. polygamum and S. conocarpum, combined multifaceted analyses of field populations and of multiple generations of greenhouse plants.* KEY RESULTS: The dioecy in both species is, like that in other solanums, largely cryptic, although the gender of S. polygamum flowers is obvious. The rare S. conocarpum is recognized as dioecious; floral gender is not obvious. Variation in sex expression facilitated experiments and promoted hypotheses on control and significance of morphological features and sex expression.* CONCLUSIONS: Confirmed dioecy in at least 15 solanums is distributed across the genus, with perhaps 6 independent origins, and with crypticity in the form of morphologically hermaphroditic, but functionally unisexual, flowers characterizing all species. Dioecy is not more strongly associated with islands. Inaperturate pollen in pistillate flowers characterizes almost all, but not the two dioecious species studied herein. Dioecy in both species indicates leakiness (rare hermaphroditic flowers on male plants) that helps explain island colonization and radiation. Leakiness allowed confirmation-usually impossible for dioecious species-of self compatibility for S. polygamum, and thus support for the hypothesis that dioecy evolved to promote outcrossing. PMID- 25784481 TI - An investigation of self-incompatibility within the genus Restrepia. AB - * PREMISE OF THE STUDY: The genus Restrepia (Orchidaceae) is indigenous to montane rain forests of Central and South America. Recently, as habitat has fragmented and wild populations dwindled, the chances for successful cross pollination within the genus have been reduced. Since cultivated species of Restrepia have been vegetatively propagated, they remain genetically close to those in the wild, making ex situ collections of the genus useful model populations for investigating breeding systems. Restrepia are found in clade B of the Pleurothallidinae, the only clade in which self-incompatibility (SI) has not yet been confirmed. In the current study, private collections of Restrepia were used to study the operation of SI within the genus to assist future ex situ conservation of this and related genera.* METHODS: A variety of self-pollination, intraspecific, and interspecific crosses were performed across the genus, and pollen tube growth was studied.* KEY RESULTS: Individual species exhibited varying degrees of SI. Self-pollinations performed across 26 species in the genus produced few viable seeds, with the exception of R. aberrans. Viable "filled" seeds with embryos were shown to require an intraspecific cross. Primary hybrids between species produced >90% seeds with embryos that germinated well.* CONCLUSIONS: The type of SI operating within the genus was considered to be best explained by gametophytic self-incompatibility (GSI) with interspecific variation in its phenotypic expression. The implications of these findings are discussed in relation to SI in the Pleurothallidinae and conservation strategies for Restrepia and related genera. PMID- 25784482 TI - Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance? AB - Apoptosis, cell death executed by caspases, is essential to normal breast development and homeostasis. Pro-apoptotic and anti-apoptotic signals are tightly regulated in normal breast epithelial cells. Dysregulation of this balance is required for breast tumorigenesis and increases acquired resistance to treatments, including molecularly targeted therapies, radiation and chemotherapies. The pro-apoptotic or anti-apoptotic Bcl-2 family members interact with each other to maintain mitochondrial integrity and regulate cellular commitment to apoptosis. Among the anti-apoptotic Bcl-2 family members, Mcl-1 is uniquely regulated by numerous oncogenic signaling pathways. This review will focus on the role of Bcl-2 family proteins in normal breast development, breast tumorigenesis and acquired resistance to breast cancer treatment strategies, while highlighting Mcl-1 as a promising target to improve breast cancer tumor cell killing. PMID- 25784484 TI - High preoperative levels of serum glypican-3 containing N-terminal subunit are associated with poor prognosis in patients with hepatocellular carcinoma after partial hepatectomy. AB - Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface glycoprotein overexpressed in hepatocellular carcinoma (HCC) cells and may serve as a potential molecular target for therapeutic intervention. This study evaluated the prognostic significance of serum GPC3 in HCC patients receiving curative surgery. A novel sandwich enzyme-linked immunosorbent assay for the quantitative and sensitive determination of serum GPC3 N-terminal subunit antigen (sGPC3N) was developed and used to measure sGPC3N levels in 25 healthy volunteers and 115 HCC patients who underwent curative partial hepatectomy. The relationships between sGPC3N and clinicopathologic features were analyzed and the prognostic impact on overall survival (OS) or disease-free survival (DFS) was also investigated. Mean and median levels of sGPC3N in healthy controls were 110.12 and 115.95 pg mL(-1) , respectively, with 185.52 pg mL(-1) (mean + 2 SD) being set as the upper limit of the normal range. In HCC patients, sGPC3N levels were significantly increased (mean/median, 405.16/236.19 pg mL(-1) ) compared to healthy controls (p < 0.0001), and 60% of HCC cases (69/115) showed sGPC3N levels that were higher than the upper normal limit. High sGPC3N levels were significantly associated with serum AFP level, high Child-Pugh score and positive HCV. Kaplan-Meier analysis indicated that elevated pre-operative sGPC3N was associated with shorter OS and DFS after hepatectomy (p <= 0.01). Multivariate analysis revealed elevated sGPC3N as an independent poor prognostic marker for OS (p < 0.05) and DFS (p < 0.01). The pre-operative sGPC3N level serves as an independent prognostic biomarker in HCC patients. PMID- 25784483 TI - Potential crosstalk between cofilin-1 and EGFR pathways in cisplatin resistance of non-small-cell lung cancer. AB - Current challenge in oncology is to establish the concept of personalized medicine in clinical practice. In this context, non-small-cell lung cancer (NSCLC) presents clinical, histological and molecular heterogeneity, being one of the most genomically diverse of all cancers. Recent advances added Epidermal Growth Factor Receptor (EGFR) as a predictive biomarker for patients with advanced NSCLC. In tumors with activating EGFR mutations, tyrosine kinase inhibitors (TKI) are indicated as first-line treatment, although restricted to a very small target population. In this context, cofilin-1 (a cytosolic protein involved with actin dynamics) has been widely studied as a biomarker of an aggressive phenotype in tumors, and overexpression of cofilin-1 is associated with cisplatin resistance and poor prognosis in NSCLC. Here, we gather information about the predictive potential of cofilin-1 and reviewed the crosstalk between cofilin-1/EGFR pathways. We aimed to highlight new perspectives of how these interactions might affect cisplatin resistance in NSCLC. We propose that cofilin-1 quantification in clinical samples in combination with presence/absence of EGFR mutation could be used to select patients that would benefit from TKI's treatment. This information is of paramount importance and could result in a possibility of guiding more effective treatments to NSCLC patients. PMID- 25784485 TI - A delay-specific differential outcomes effect in delayed matching to sample. AB - In delay-specific remembering, accuracy in delayed matching-to-sample tasks is enhanced after single delays or retention intervals relative to performance at other delays. In the differential-outcomes effect (DOE), accuracy is enhanced at all delays when the outcomes of correct choices are quantitatively or qualitatively different, compared to when outcomes are the same. In the present experiments, we aimed to demonstrate a delay-specific DOE by arranging differential outcomes for correct responses at some delays and same outcomes at other delays. In each of two experiments, four pigeons worked in delayed matching to-sample tasks with delays of 0.5, 5, and 15 s, or 0 s, 3 s, and 12 s mixed within session. Correct choices produced different reward durations (differential outcomes) at one or two delays, or the same reward durations (same outcomes) at the other delays, on a within-session basis. There was evidence of improved accuracy at delays at which differential outcomes were arranged, compared to accuracy at delays at which same outcomes were arranged, that is, a delay specific DOE. The more usual DOE was confirmed in a third experiment with same outcomes at all delays in one condition and differential outcomes at all delays in another. We discuss implications of a delay-specific DOE for theories of the DOE which attribute the effect to enhanced stimulus control by expectancies of reward outcomes generated at the time of sample presentation. PMID- 25784486 TI - Sperm retrieval outcomes with microdissection testicular sperm extraction (micro TESE) in men with cryptozoospermia. AB - Several studies support of the use of testicular rather than ejaculated spermatozoa for intracytoplasmic sperm injection (ICSI) in couples with virtual azoospermia or cryptozoospermia, although this approach remains controversial. We sought to evaluate sperm retrieval outcomes with microdissection testicular sperm extraction (micro-TESE) in men with cryptozoospermia. We conducted a retrospective study of 24 consecutive micro-TESEs in men with cryptozoospermia. We also evaluated the outcomes of seven consecutive TESAs (testicular sperm aspiration) in cryptozoospermic men during the same time period (January 2007 and September 2014). Micro-TESE and TESA were performed on the day prior to ICSI. Final assessment of sperm recovery (reported on the day of ICSI) was recorded as (i) successful (available spermatozoa for ICSI) or (ii) unsuccessful (no spermatozoa for ICSI). The decision to perform a unilateral or bilateral micro TESE was guided by the intra-operative evaluation of sperm recovery from the first testicle. A unilateral procedure was performed in 87.5% (21/24) and 57% (4/7) of the micro-TESE and TESA cohorts, respectively. Sperm recovery was successful in 96% (23/24) of the men who underwent micro-TESE and 43% (3/7) of the men who underwent TESA (p < 0.01). The ICSI pregnancy rates (per embryo transfer) in the micro-TESE and TESA groups were comparable [33% (6/18) and 50% (1/2), respectively]. The data indicate that micro-TESE is a highly successful sperm retrieval technique for men with cryptozoospermia and few of these men will require a bilateral procedure. Moreover, sperm retrieval rates are higher with micro-TESE than TESA in this group of men. PMID- 25784487 TI - MRL calculations based on both intra- and inter-trial residue variability. AB - Methods for calculating maximum residue levels or, at least, high percentile values (e.g. 95th percentile) to support the estimation have been developed in recent years. A mathematical equation is proposed that, for a set of supervised pesticide residue trials on a crop, expresses the incidence of residues as a function of residue concentration in the food commodity. Each residue concentration is expressed as a population reflecting its intra-trial variability. The equation is then the sum of these sub-populations to represent the set of trials, a population of sub-populations (POSP). The equation is formulated so that the area under the curve precisely equals the number of trials. Calculation of a residue concentration corresponding to a percentage of the area under the curve produces the required percentile. Results are generally consistent with the current OECD method calculation. The POSP calculation will be a useful tool in estimating maximum residue levels, where the first choice, other matters being acceptable, would be a value between the 95th and 99th percentiles. Replicate data are directly accommodated in the calculation. The POSP calculator can answer such questions as: what percentile corresponds to the highest residue (HR) in the residue data set? PMID- 25784489 TI - Auditory stimulation enhances thalamic somatosensory high-frequency oscillations in healthy humans: a neurophysiological marker of cross-sensory sensitization? AB - Electrical stimulation of upper limb nerves evokes a train of high-frequency wavelets (high-frequency oscillations, HFOs) on the human scalp. These HFOs are related to the influence of arousal-promoting structures on somatosensory input processing, and are generated in the primary somatosensory cortex (post-synaptic HFOs) and the terminal tracts of thalamocortical radiations (pre-synaptic HFOs). We previously reported that HFOs do not undergo habituation to repeated stimulations; here, we verified whether HFOs could be modulated by external sensitizing stimuli. We recorded somatosensory evoked potentials (SSEPs) in 15 healthy volunteers before and after sensitization training with an auditory stimulus. Pre-synaptic HFO amplitudes, reflecting somatosensory thalamic/thalamocortical activity, significantly increased after the sensitizing acoustic stimulation, whereas both the low-frequency N20 SSEP component and post synaptic HFOs were unaffected. Cross-talk between subcortical arousal-related structures is a probable mechanism for the pre-synaptic HFO effect observed in this study. We propose that part of the ascending somatosensory input encoded in HFOs is specifically able to convey sensitized inputs. This preferential involvement in sensitization mechanisms suggests that HFOs play a critical role in the detection of potentially relevant stimuli, and act at very early stages of somatosensory input processing. PMID- 25784490 TI - Analysis of the metabolome of Anopheles gambiae mosquito after exposure to Mycobacterium ulcerans. AB - Infection with Mycobacterium ulcerans causes Buruli Ulcer, a neglected tropical disease. Mosquito vectors are suspected to participate in the transmission and environmental maintenance of the bacterium. However, mechanisms and consequences of mosquito contamination by M. ulcerans are not well understood. We evaluated the metabolome of the Anopheles gambiae mosquito to profile the metabolic changes associated with bacterial colonization. Contamination of mosquitoes with live M. ulcerans bacilli results in disruptions to lipid metabolic pathways of the mosquito, specifically the utilization of glycerolipid molecules, an affect that was not observed in mosquitoes exposed to dead M. ulcerans. These results are consistent with aberrations of lipid metabolism described in other mycobacterial infections, implying global host-pathogen interactions shared across diverse saprophytic and pathogenic mycobacterial species. This study implicates features of the bacterium, such as the putative M. ulcerans encoded phospholipase enzyme, which promote virulence, survival, and active adaptation in concert with mosquito development, and provides significant groundwork for enhanced studies of the vector-pathogen interactions using metabolomics profiling. Lastly, metabolic and survival data suggest an interaction which is unlikely to contribute to transmission of M. ulcerans by A. gambiae and more likely to contribute to persistence of M. ulcerans in waters cohabitated by both organisms. PMID- 25784491 TI - Evaluating preceptors: a methodological study. AB - The purpose of this study was to develop and test the Baptist Health Lexington Performance and Proficiency Assessment for validity and reliability. Twelve expert nurse educators evaluated the instrument for content validity. The sample for test-retest included nurse administrators (5), preceptors (9), and new graduates (10). To evaluate internal consistency, administrators (12), preceptors (66), and new graduates (43) responded. Strong validity and reliability were found for all subscales on the preceptor and new graduate versions. PMID- 25784492 TI - Ametoctradin is a potent Qo site inhibitor of the mitochondrial respiration complex III. AB - Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc1 complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Q(o) site inhibitor of bc1 complex. Subsequently, a series of new 1,2,4 triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5 a]pyrimidine. The calculated binding free energies (DeltaG(cal)) of newly synthesized analogues as Qo site inhibitors correlated very well (R(2) = 0.96) with their experimental binding free energies (DeltaG(exp)). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc1 inhibitor. PMID- 25784493 TI - Pharyngocutaneous fistula and delay in free oral feeding after pharyngolaryngectomy for hypopharyngeal cancer. AB - BACKGROUND: Risk factors for pharyngocutaneous fistula and associated delay in free oral feeding after pharyngolaryngectomy for patients with hypopharyngeal cancer remain uncertain. METHODS: We used a Japanese national inpatient database to perform a retrospective cohort study between 2007 and 2013. We performed multivariable logistic regression analysis to identify patient characteristics associated with pharyngocutaneous fistula formation, and Cox regression analysis to evaluate factors affecting the interval from pharyngolaryngectomy to free oral feeding. RESULTS: Among 549 eligible patients, 33 had developed pharyngocutaneous fistula, 19 of whom required surgical closure. Preoperative radiotherapy significantly increased risk of pharyngocutaneous fistula (odds ratio [OR] = 3.17; 95% confidence interval [CI] = 1.10-9.12; p = .033). Pharyngocutaneous fistula significantly prolonged the interval to oral feeding (median days, 67 vs 20 in those with and without pharyngocutaneous fistula, respectively; hazard ratio [HR], = 0.26; 95% CI = 0.15-0.44; p < .001). CONCLUSION: Preoperative radiotherapy was associated with increased occurrence of pharyngocutaneous fistula and subsequent delay in free oral feeding. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E-E, 2016. PMID- 25784494 TI - Tuning thermal contact conductance at graphene-copper interface via surface nanoengineering. AB - Due to rapidly increasing power densities in nanoelectronics, efficient heat removal has become one of the most critical issues in thermal management and nanocircuit design. In this study, we report a surface nanoengineering design that can reduce the interfacial thermal resistance between graphene and copper substrate by 17%. Contrary to the conventional view that a rough surface tends to give higher thermal contact resistances, we find that by engraving the copper substrate with nanopillared patterns, an optimized hybrid structure can effectively facilitate the thermal transport across the graphene-copper interface. This counterintuitive behavior is due to the enhanced phonon interactions with the optimal nanopillared pattern. For pliable 2D materials like graphene, the structures can be easily bent to fit the surface formations of the substrate. The suspended areas of graphene are pulled towards the substrate via an attractive interatomic force, causing high local pressures (~2.9 MPa) on the top region of nanopillars. The high local pressures can greatly enhance the thermal energy coupling between graphene and copper, thereby lowering the thermal contact resistances. Our study provides a practical way to manipulate the thermal contact resistance between graphene and copper for the improvement of nano-device performance through engineering optimal nanoscale contact. PMID- 25784495 TI - Five-year follow up of Konno aortoventriculoplasty for repeat aortic valve replacement in an adult patient. AB - Konno aortoventriculoplasty (AVP) is performed for various types of left ventricular outflow tract obstruction. We report on a 32-year-old woman who had undergone double valve replacement five years earlier. She presented with increased interventricular septum thickness, small aortic root and gradient across the aortic mechanical valve. We performed Konno AVP with repeat aortic valve replacement (AVR). The control echocardiography showed no significant residual gradient. Konno AVP with repeat AVR may be safely performed with satisfactory results. PMID- 25784496 TI - An unusual cause of generalised seizure following cardiac surgery: with bolus cefazolin administration. AB - Although some of the aetiological factors of seizure, such as cerebral microemboli, cerebral oedema, hypoperfusion, cerebral hypoxia and metabolic encephalopathy cannot be completely controlled during cardiac surgery, cautious management of all steps in the procedure may prevent the administrative causes of seizure. Cefazolin, which is known to be a proconvulsant agent, may be a suspected agent of seizure complications in patients with renal insufficiency. Surprisingly, intravenous bolus administration of cefazolin may also trigger seizure in patients with normal renal function. In this case report, a complication of generalised seizure after cardiac surgery with intravenous bolus administration of cefazolin is described, along with a brief review of the literature. PMID- 25784497 TI - Late coronary stent dislodgement following coronary artery stenting. AB - Recently, coronary artery stenting has been successful when used as an intervention for percutaneous coronary artery disease. However, the procedure may frequently produce complications. Although rare, stent dislodgement is one such complication, which may result in serious problems including coronary artery dissection, myocardial infarction, peripheral embolisation and death. Stent dislodgement is known to be an early complication of the coronary artery stenting procedure. In this case report, we present a 53-year-old male with late coronary stent dislodgement. To the best of our knowledge, no such case has been addressed in the literature to date. PMID- 25784498 TI - The relationship of TIMI risk index with SYNTAX and Gensini risk scores in predicting the extent and severity of coronary artery disease in patients with STEMI undergoing primary percutaneous coronary intervention. AB - OBJECTIVE: The prognostic value of the Global Registry of Acute Coronary Events (GRACE) risk score (GRS) and the Thrombolysis in Myocardial Infarction (TIMI) risk index (TRI) have been reported in patients with coronary artery disease (CAD). In this study, we sought to evaluate the association between TRI and the extent and severity of CAD evaluated by SYNTAX score (SS) and Gensini score in patients with ST elevation myocardial infarction (STEMI). METHODS: A total of 290 patients with STEMI were included in the study. GRS and TRI were calculated on admission using specified variables. The extent and severity of CAD were evaluated using the SS and Gensini scores. The patients were divided into low (TRI ?19), intermediate (TRI 19-30), and high (TRI ?30) risk groups. A Pearson correlation analysis was used for the relationship between TRI, GRS, Gensini score and SS. RESULTS: There were significant differences in the mean age (p < 0.001), admission heart rate (p < 0.001), admission systolic blood pressure (p = 0.009), SS (p < 0.001), GRS (p < 0.001) and in-hospital major adverse cardiac events (MACE) in all patients between the low, intermediate and high TRI risk groups. There was a positive significant correlation between TRI and SS (r = 0.24, p < 0.001), Gensini score (r = 0.18, p = 0.002), GRS (r = 0.74, p = 0.001) and in-hospital MACE (r = 0.29, p < 0.001). CONCLUSION: TRI is significantly related to SS and Gensini score in predicting the extent and severity of CAD in patients with STEMI. PMID- 25784499 TI - A balloon-expandable sheath facilitates transfemoral TAVR in patients with peripheral vascular disease and tortuosity. AB - OBJECTIVES: We sought to perform transcatheter aortic valve replacement (TAVR) via the transfemoral approach in patients with peripheral arterial disease (PAD), small caliber ileofemoral vessels and vascular tortuosity. BACKGROUND: For patients with increased surgical risk, TAVR is associated with a higher 1-year survival rate than surgical aortic valve replacement (SAVR). Transfemoral vascular access for TAVR results in superior outcomes versus procedures performed via other routes in terms of mortality, morbidity and healthcare economics. In many patients, the ability to safely perform the procedure via the transfemoral approach is limited by narrow, diseased and tortuous ileofemoral vasculature. METHODS: We employed the SoloPath Balloon Expandable TransFemoral Access System (Terumo Med. Corp., Tokyo, Japan) to perform transfemoral TAVR in five patients with PAD, small caliber ileofemoral vessels and vascular tortuosity. RESULTS: We report our experience using this balloon-expandable sheath during 5 cases of transfemoral TAVR in patients with inhospitable ileofemoral vasculature of mean diameter ? 5.8 mm. The unexpanded sheath's malleable structure and hydrophilic coating permitted deployment despite severe stenoses and tortuosity. Subsequent inflation to 18 Fr facilitated successful TAVR. Postprocedural angiography demonstrated no significant vascular access complications. In one case, the entire procedure was performed percutaneously, without common femoral artery surgical cutdown. CONCLUSIONS: The SoloPath sheath system permits transfemoral TAVR in patients with PAD small caliber ileofemoral vessels and vascular tortuosity. The transfemoral balloon-expandable sheath allowed these patients to avoid the increased morbidity and mortality risks associated with direct aortic or transapical access. PMID- 25784500 TI - An investigation of nursing students' knowledge of dementia: A questionnaire study. AB - BACKGROUND: Globally, rising rates of dementia indicate the need for more nurses skilled in caring for people with this condition. However nursing students may not acquire the requisite knowledge from existing undergraduate curricula. OBJECTIVES: To investigate the dementia knowledge of second-year nursing students before and after a supported placement in a residential aged care facility. Assessment of the level of knowledge of dementia is important to provide evidence of the need to enhance dementia learning in the nursing curriculum. DESIGN: A pre post control-intervention questionnaire study. SETTINGS: 16 Tasmanian residential aged care facilities (RACFs). PARTICIPANTS: 99 Tasmanian second-year nursing undergraduate students (52 intervention, 47 control). METHODS: Second year nursing students were engaged in a three week RACF clinical placement at one of the 14 control facilities or one of the 2 involved in the development of teaching aged care facilities. Pre/post data were collected using the 21-item 'Dementia Knowledge Assessment Tool 2.0' and demographic survey questions, and analysed using descriptive analyses and nonparametric significance tests. RESULTS: The data showed that these nursing students had a poor knowledge of dementia, with limited understanding of key items relevant to their clinical practice. Knowledge of dementia was significantly improved after students' participation in supported clinical placements at an intervention residential aged care facility. This knowledge improvement was significantly higher than that of students who attended clinical placements at control facilities. CONCLUSIONS: A well-supported clinical placement at a residential aged care facility can improve nursing students' knowledge of dementia, in particular in relation to aspects directly relevant to their clinical practice. PMID- 25784501 TI - Assessing students' English language proficiency during clinical placement: A qualitative evaluation of a language framework. AB - The increase in nursing students for whom English is an additional language requires clinical facilitators to assess students' performance regarding clinical skills, nursing communication and English language. However, assessing language proficiency is a complex process that is often conflated with cultural norms and clinical skills, and facilitators may lack confidence in assessing English language. This paper discusses an evaluation of a set of guidelines developed in a large metropolitan Australian university to help clinical facilitators make decisions about students' English language proficiency. The study found that the guidelines were useful in helping facilitators assess English language. However, strategies to address identified language problems needed to be incorporated to enable the guidelines to also be used as a teaching tool. The study concludes that to be effective, such guidelines need embedding within a systematic approach that identifies and responds to students who may be underperforming due to a low level of English language proficiency. PMID- 25784502 TI - Massive subcutaneous emphysema, bilateral pneumothorax, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum, and pneumoscrotum after multiple direct laryngoscopies: an autopsy case report. AB - Multiple endotracheal intubation (ETI) attempts increase the risk of airway related adverse events. However, little is known about autopsy findings after severe ETI-related complications. We present the detailed pathological findings in a patient with severe ETI-related complications. A 77-year-old obese male suffered cardiopulmonary arrest after choking at a rehabilitation facility. Spontaneous circulation returned after chest compressions and foreign-body removal. After multiple failed direct laryngoscopies, the patient was transferred to our hospital. He had massive subcutaneous emphysema, bilateral pneumothorax, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum, and pneumoscrotum on admission, and died from hypoxic brain injury 15 h later. Autopsy revealed severe oropharyngeal, laryngeal, and left lung lower lobe injury. The likely mechanisms of diffuse emphysema were (1) oropharyngeal injury associated with multiple ETI attempts and excessive ventilation pressures and (2) left lung lower lobe injury associated with chest compressions and other resuscitative procedures. Multiple laryngoscopies can cause severe upper-airway injury, worsen respiratory status, and make ETI more difficult-a vicious circle that can be prevented by limiting ETI attempts. This is particularly important in unfavorable environments, in which backup devices and personnel are not easily obtained. The pathological findings in our patient caution against repeated attempts at ETI during resuscitation. PMID- 25784504 TI - Neuronal identity genes regulated by super-enhancers are preferentially down regulated in the striatum of Huntington's disease mice. AB - Huntington's disease (HD) is a neurodegenerative disease associated with extensive down-regulation of genes controlling neuronal function, particularly in the striatum. Whether altered epigenetic regulation underlies transcriptional defects in HD is unclear. Integrating RNA-sequencing (RNA-seq) and chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), we show that down-regulated genes in HD mouse striatum associate with selective decrease in H3K27ac, a mark of active enhancers, and RNA Polymerase II (RNAPII). In addition, we reveal that decreased genes in HD mouse striatum display a specific epigenetic signature, characterized by high levels and broad patterns of H3K27ac and RNAPII. Our results indicate that this signature is that of super-enhancers, a category of broad enhancers regulating genes defining tissue identity and function. Specifically, we reveal that striatal super-enhancers display extensive H3K27 acetylation within gene bodies, drive transcription characterized by low levels of paused RNAPII, regulate neuronal function genes and are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Together, our results provide evidence for preferential down regulation of genes controlled by super-enhancers in HD striatum and indicate that enhancer topography is a major parameter determining the propensity of a gene to be deregulated in a neurodegenerative disease. PMID- 25784505 TI - Re: 'response to letter to the editor on "Galectin-3, carotid plaque vulnerability, and potential effects of statin therapy"'. PMID- 25784506 TI - Endovascular revascularization for carotid artery occlusion in patients with Takayasu arteritis. AB - OBJECTIVES: Type I Takayasu arteritis is a progressive inflammatory disease involving the aortic arch and its main branches. If untreated, patients may develop a variety of serious conditions ranging from hemiplegia to death. Whilst there is a relatively strong evidence base for the outcome of surgical techniques, few reports have focused on revascularization using an endovascular technique in patients with Takayasu arteritis. METHODS: From May 2007 to March 2013, 11 consecutive patients with Takayasu arteritis presenting with severe cerebral ischemia symptoms caused by occlusive lesion in carotid artery underwent elective revascularization, 10 on the left carotid artery and 1 on the right. All patients received immunosuppressive treatment pre-and post-operation. Contraindications to open surgery included: ESR >40 mm/h; ipsilateral cerebral infarction of <2 weeks duration and sufficient poor health whereby the patient cannot tolerate general anesthesia. Quality of life was analyzed using the EQ-5D questionnaire before and after surgery. RESULTS: Patients were followed for a mean of 31.6+/-27.4 months. Seven cases of total occlusion and 2 cases of severe stenosis were recanalized successfully and experienced clinical remission. Recanalization failed in 2 patients, both of whom had occlusion of a long segment of the artery. Initial endovascularization comprised small diameter, low pressure dilatation only to allow time for the reopened arteries to respond. If clinically indicated, repeat angioplasty with a larger diameter balloon was performed 1-3 months later. Major complications occurred in 2 patients. Eight of the recanalized carotid arteries were patent at the end of follow-up and patients had satisfactory quality of life CONCLUSIONS: In patients with Takayasu arteritis, carotid artery recanalization via endovascular surgery combined with immunosuppressive therapy is effective and can be performed safely and repeatedly. The improvement in carotid artery blood flow supplying the central nervous system relieves symptoms of cerebral ischemia and is associated with an improved quality of life. PMID- 25784503 TI - Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals. AB - Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) >= 40 kg/m(2)], but their contribution to common obesity (BMI >= 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 * 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 * 10( 7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (beta = 0.02, 95% CI 0.00-0.03; P = 5.57 * 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta analysis published to date in genetic epidemiology. PMID- 25784507 TI - Surgical treatment of central venous catheter related septic deep venous thrombosis. AB - OBJECTIVE/BACKGROUND: The aim of this study was to evaluate the clinical features and outcomes of catheter related central venous thrombosis and whether a surgical approach can be an effective treatment modality in selected cases that are refractory to conservative management. METHODS: This was a retrospective review of the 46 consecutive patients who were suspected of having central venous catheter related infected deep venous thrombosis and who met the eligibility criteria. RESULTS: Conservative management achieved clinical improvement in 26 (56.5%) patients and failed in 20 (43.5%), of whom surgical thrombectomy was performed in 13. The remaining seven patients died before surgery could be performed or their clinical condition was too poor. Apart from one case of wound hematoma (7.7%), post-operative complications that related to the surgical procedure were not observed. Patency of the involved vein was re-established in 12 of the 13 (92.3%) surgically treated patients, and clinical improvement was achieved in 11 (84.6%). In particular, the five patients whose blood cultures revealed Candida species exhibited prompt defervescence after surgical thrombectomy. CONCLUSION: Although conservative management is the first therapy of choice in patients with central venous catheter related infected thrombosis, surgical treatment that removes the septic material can be regarded as a last resort in critically ill patients with septic thrombophlebitis that is refractory to conservative management. PMID- 25784508 TI - The 30th Anniversary of the First Clinical Application of Endovascular Stent grafting. PMID- 25784509 TI - Effect of rivaroxaban versus warfarin on health care costs among nonvalvular atrial fibrillation patients: observations from rivaroxaban users and matched warfarin users. AB - INTRODUCTION: New target-specific oral anticoagulants may have benefits, such as shorter hospital length of stay, compared to warfarin in patients with nonvalvular atrial fibrillation (NVAF). This study aimed to assess, among patients with NVAF, the effect of rivaroxaban versus warfarin on health care costs in a cohort of rivaroxaban users and matched warfarin users. METHODS: Health care claims from the Humana database from 5/2011 to 12/2012 were analyzed. Adult patients newly initiated on rivaroxaban or warfarin with >=2 atrial fibrillation (AF) diagnoses (The International Classification of Diseases, Ninth Revision, Clinical Modification: 427.31) and without valvular AF were identified. Based on propensity score methods, warfarin patients were matched 1:1 to rivaroxaban patients. Patients were observed up to end of data, end of insurance coverage, death, a switch to another anticoagulant, or treatment nonpersistence. Health care costs [hospitalization, emergency room (ER), outpatient, and pharmacy costs] were evaluated using Lin's method. RESULTS: Matches were found for all rivaroxaban patients, and characteristics of the matched groups (n = 2253 per group) were well balanced. Estimated mean all-cause and AF-related hospitalization costs were significantly lower for rivaroxaban versus warfarin patients (all-cause: $5411 vs. $7427, P = 0.047; AF-related: $2872 vs. $4147, P = 0.020). Corresponding estimated mean all-cause outpatient visit costs were also significantly lower, but estimated mean pharmacy costs were significantly higher for rivaroxaban patients ($5316 vs. $2620, P < 0.001). Although estimated mean costs of ER visits were higher for rivaroxaban users compared to those of warfarin users, differences were not statistically significant. Including anticoagulant costs, mean overall total all-cause costs were comparable for rivaroxaban versus warfarin users due to cost offset from a reduction in the number and length of hospitalizations and number of outpatient visits ($17,590 vs. $18,676, P = 0.542). CONCLUSION: Despite higher anticoagulant cost, mean overall total all-cause and AF-related cost remains comparable for patients with NVAF treated with rivaroxaban versus warfarin due to the cost offset from reduced health care resource utilization. PMID- 25784510 TI - Echinacea reduces the risk of recurrent respiratory tract infections and complications: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Respiratory tract infections are common, and these infections occur frequently in children, susceptible adults, and older persons. The risk for recurrences and complications relates not only to the presence of viruses but also to immune function. Therefore, modulation of the immune system and antiviral interventions such as echinacea might reduce the risk of recurrences and possibly the development of complications. METHODS: MEDLINE, EMBASE, CAplus, BIOSIS, CABA, AGRICOLA, TOXCENTER, SCISEARCH, NAHL, and NAPRALERT were searched for clinical trials that studied recurrent respiratory infections and complications on treatment with echinacea extracts in a generally healthy population. Two independent reviewers selected randomized, placebo-controlled studies of high methodological quality and a Jadad score of >=4. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated according to a fixed effect model. RESULTS: Six clinical studies with a total of 2458 participants were included in the meta-analysis. Use of echinacea extracts was associated with reduced risk of recurrent respiratory infections (RR 0.649, 95% CI 0.545-0.774; P < 0.0001). Ethanolic extracts from echinacea appeared to provide superior effects over pressed juices, and increased dosing during acute episodes further enhanced these effects. Three independent studies found that in individuals with higher susceptibility, stress or a state of immunological weakness, echinacea halved the risk of recurrent respiratory infections (RR 0.501, 95% CI 0.380-0.661; P < 0.0001). Similar preventive effects were observed with virologically confirmed recurrent infections (RR 0.420, 95% CI 0.222-0.796; P = 0.005). Complications including pneumonia, otitis media/externa, and tonsillitis/pharyngitis were also less frequent with echinacea treatment (RR 0.503, 95% CI 0.384-0.658; P < 0.0001). CONCLUSION: Evidence indicates that echinacea potently lowers the risk of recurrent respiratory infections and complications thereof. Immune modulatory, antiviral, and anti-inflammatory effects might contribute to the observed clinical benefits, which appear strongest in susceptible individuals. PMID- 25784511 TI - Anatomy of vertical heteroepitaxial interfaces reveals the memristive mechanism in Nb2O5-NaNbO3 thin films. AB - Dynamic oxygen vacancies play a significant role in memristive switching materials and memristors can be realized via well controlled doping. Based on this idea we deposite Nb2O5-NaNbO3 nanocomposite thin films on SrRuO3-buffered LaAlO3 substrates. Through the spontaneous phase separation and self-assembly growth, two phases form clear vertical heteroepitaxial nanostructures. The interfaces between niobium oxide and sodium niobate full of ion vacancies form the conductive channels. Alternative I-V behavior attributed to dynamic ion migration reveals the memristive switching mechanism under the external bias. We believe that this phenomenon has a great potential in future device applications. PMID- 25784512 TI - Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. AB - Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels>=80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to <=25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n=100] or bococizumab [n=251]). The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days. Compared with placebo, bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl; this was despite dose reductions in 32.5% and 34.2% of subjects at week 10 or 8, respectively. Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl, respectively. Adverse events were similar across placebo and bococizumab groups. Few subjects (n=7; 2%) discontinued treatment because of treatment-related adverse events. In conclusion, bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects. Model based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction. The Q14 days regimen is being evaluated in phase 3 clinical trials. PMID- 25784513 TI - Costs and in-hospital outcomes of transcatheter aortic valve implantation versus surgical aortic valve replacement in commercial cases using a propensity score matched model. AB - The aim of this study was to compare in-hospital cost and outcomes between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). TAVI is an effective treatment option in patients with symptomatic aortic stenosis who are at high risk for traditional SAVR. Several studies using trial data or outside United States registry data have addressed TAVI cost issues, although there is a paucity of cost data involving commercial cases in the United States. Using Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Nationwide Inpatient Sample files, a propensity score-matched analysis of all commercial TAVI and SAVR cases performed in 2011 was conducted. Overall hospital cost and length of stay, as well as procedural complications, were compared between the 2 matched cohorts: 595 TAVI patients were matched to 1,785 SAVR patients in a 1:3 ratio. There was no difference in mean ($181,912 vs $196,298) or median ($152,993 vs $155,974) hospital cost between TAVI and SAVR (p = 0.60). The TAVI group had significantly shorter lengths of hospital stay than the SAVR group (mean 9.76 vs 12.01 days, p <0.001). There was no difference in postprocedural in-hospital death or stroke, but TAVI patients were more likely to have bleeding complications, to have vascular complications, and to require pacemakers. In conclusion, when analyzing in-hospital cost of commercial TAVI and SAVR cases using the Nationwide Inpatient Sample data set, TAVI is an economically satisfactory alternative to SAVR and results in an approximately 2-day shorter length of stay during the index hospitalization. PMID- 25784514 TI - Outcomes after nonemergent electrical cardioversion for atrial arrhythmias. AB - Electrical cardioversion (ECV) is recommended for rhythm control in patients with atrial arrhythmia; yet, ECV use and outcomes in contemporary practice are unknown. We reviewed all nonemergent ECVs for atrial arrhythmias at a tertiary care center (2010 to 2013), stratifying patients by transesophageal echocardiography (TEE) use before ECV and comparing demographics, history, vitals, and laboratory studies. Outcomes included postprocedural success and complications and repeat cardioversion, rehospitalization, and death within 30 days. Overall, 1,017 patients underwent ECV, 760 (75%) for atrial fibrillation and 240 (24%) for atrial flutter; 633 underwent TEE before ECV and 384 did not. TEE recipients were more likely to be inpatients (74% vs 44%, p <0.001), have higher mean CHADS2 scores (2.6 vs 2.4, p = 0.03), and lower mean international normalized ratios (1.2 vs 2.1, p <0.001). Overall, 89 patients (8.8%) did not achieve sinus rhythm and 14 experienced procedural complications (1.4%). Within 30 days, 80 patients (7.9%) underwent repeat ECV, 113 (11%) were rehospitalized, and 14 (1.4%) died. Although ECV success was more common in patients who underwent TEE before ECV (77% vs 68%, p = 0.01), there were no differences in 30 day death or rehospitalization rates (11.1% vs 13.0%, p = 0.37). In multivariate analyses, higher pre-ECV heart rate was associated with increased rehospitalization or death (adjusted hazard ratio 1.15/10 beats/min, 95% confidence interval 1.07 to 1.24, p <0.001), whereas TEE use was associated with lower rates (adjusted hazard ratio 0.58, 95% confidence interval 0.39 to 0.86, p = 0.007). In conclusion, failures, complications, and rehospitalization after nonemergent ECV are common and associated more with patient condition than procedural characteristics. TEE use was associated with better clinical outcomes. PMID- 25784515 TI - Meta-analysis of clinical outcomes of patients who underwent percutaneous coronary interventions for chronic total occlusions. AB - Successful percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) has been associated with clinical benefit. There are no randomized controlled trials on long-term clinical outcomes after CTO PCI, limiting the available evidence to observational cohort studies. We sought to perform a weighted meta-analysis of the long-term outcomes of successful versus failed CTO PCI. A total of 25 studies, published from 1990 to 2014, with 28,486 patients (29,315 CTO PCI procedures) were included. We analyzed data on mortality, subsequent coronary artery bypass grafting (CABG), myocardial infarction, major adverse cardiac events, angina pectoris, stroke, and target vessel revascularization using random-effects models. Procedural success was 71% (range 51% to 87%). During a weighted mean follow-up of 3.11 years, compared with unsuccessful, successful CTO PCI was associated with lower mortality (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.43 to 0.63), less residual angina (OR 0.38, 95% CI 0.24 to 0.60), lower risk for stroke (OR 0.72, 95% CI 0.60 to 0.88), less need for subsequent coronary artery bypass grafting (OR 0.18, 95% CI 0.14 to 0.22), and lower risk for major adverse cardiac events (0.59, 95% CI 0.44 to 0.79). There was no difference in the incidence of target vessel revascularization (OR 0.66, 95% CI 0.36 to 1.23) or myocardial infarction (OR 0.73, 95% CI 0.52 to 1.03). Outcomes were similar in patients who underwent balloon angioplasty only or stenting with bare metal or drug-eluting stents. Compared with failed procedures, successful CTO PCIs are associated with a lower risk of death, stroke, and coronary artery bypass grafting and less recurrent angina pectoris. PMID- 25784516 TI - Clinical significance of exercise pulmonary hypertension in secondary mitral regurgitation. AB - In patients with heart failure, exercise echocardiography can help in risk stratification and decision making. The prognostic significance of exercise pulmonary hypertension (PH) in patients with secondary mitral regurgitation (MR) remains unknown. The aim of the present study was to assess the prognostic value of exercise PH in patients with secondary MR and narrow QRS intervals. From 2005 to 2012, 159 consecutive patients with secondary MR, narrow QRS intervals, left ventricular dysfunction (mean ejection fraction 36 +/- 7%), and measurable systolic pulmonary arterial pressure (SPAP) during exercise echocardiography were included. Resting and exercise PH were defined as SPAP >50 and >60 mm Hg, respectively. Exercise PH was more frequent than resting PH (40% vs 13%, p <0.0001). On multivariate logistic regression, the independent determinants of exercise PH were resting SPAP (p <0.0001), exercise MR severity (p <0.0001), and e'-wave velocity (p = 0.004). The incidence of cardiac events during follow-up was significantly higher in patients with exercise PH compared with those without exercise PH (4 years: 40 +/- 7% vs 20 +/- 5%, p <0.0001). Patients with exercise PH exhibited higher rates of cardiac events and death than those with resting PH. In a multivariate Cox proportional hazards model, exercise PH was independently associated with the occurrence of cardiac events (p <0.0001). In conclusion, in patients with secondary MR, exercise PH is determined mainly by resting SPAP, left ventricular diastolic burden, and exercise MR severity. Exercise PH is a powerful predictor of poor outcomes, with a 5.3-fold increased risk for cardiac related death during follow-up. These results highlight the added value of exercise echocardiography in secondary MR. PMID- 25784517 TI - Comparison of frequency of inflammatory bowel disease and noninfectious gastroenteritis among statin users versus nonusers. AB - Conflicting data exist regarding the effects of statin therapy on the prevalence of inflammatory bowel diseases. We aimed to examine the association of statin therapy with diagnoses of inflammatory bowel diseases and noninfectious gastroenteritis. This is a retrospective study using data of a military health care system from October 1, 2003, to March 1, 2012. Based on medication fills during fiscal year 2005, patients were divided into: (1) statin users (received at least 90-day supply of statin) and (2) nonusers (never received a statin). A propensity score-matched cohort of statin users and nonusers was created using 80 variables. Primary analysis examined the risks of being diagnosed with inflammatory bowel diseases and noninfectious gastroenteritis between statin users and nonusers in the propensity score-matched cohort. Secondary analyses examined the risk of outcomes in the whole cohort and in patients with no comorbidities according to Charlson Comorbidity Index. Of 43,438 patients meeting study criteria (13,626 statin users and 29,812 nonusers), we propensity score matched 6,342 statin users with 6,342 nonusers. For our primary analysis, 93 statin users and 92 nonusers were diagnosed with inflammatory bowel diseases (odds ratio = 1.01, 95% confidence interval = 0.76 to 1.35), and 632 statin users and 619 nonusers were diagnosed of noninfectious gastroenteritis (odds ratio = 1.02, 95% confidence interval = 0.91 to 1.15). In conclusion, the risks of inflammatory bowel diseases and noninfectious gastroenteritis among statin users and nonusers are similar after adjusting for other potential confounding factors. PMID- 25784518 TI - Effect of age on survival and causes of death after primary prevention implantable cardioverter-defibrillator implantation. AB - The benefit of implantable cardioverter-defibrillators (ICDs) remains controversial in elderly patients and may be attenuated by a greater risk of nonarrhythmic death. We examined the effect of age on outcomes after prophylactic ICD implantation. All patients with coronary artery disease or dilated cardiomyopathy implanted with an ICD for primary prevention of sudden cardiac death in 12 French medical centers were included in a retrospective observational study. The 5,534 ICD recipients were divided according to age: 18 to 59 years (n = 2,139), 60 to 74 years (n = 2,693), and >=75 years (n = 702). Greater prevalences of coronary artery disease and atrial fibrillation at the time of implant were observed with increasing age (both p <0.0001). During a mean follow up of 3.1 +/- 2.0 years, the annual mortality rate increased with age: 3.1% per year for age 18 to 59 years, 5.7% per year for age 60 to 74 years, and 7.5% per year for age >=75 years (p <0.001). Older age was independently associated with a greater risk of death (adjusted odds ratio 1.43, 95% confidence interval 1.14 to 1.80 for age 60 to 74 years; and adjusted odds ratio 1.65, 95% confidence interval 1.22 to 2.22 for age >75 years). Proportions of cardiac deaths (55.2%, 57.6%, and 57.0%, p = 0.84), including ICD-unresponsive sudden death (9.9%, 6.0%, and 10.6%, p = 0.08), and rates of appropriate ICD therapies were similar in the 3 age groups. Older age was independently associated with a higher rate of early complications and a lower rate of inappropriate therapies. In conclusion, older patients exhibited higher global mortality after ICD implantation for primary prevention, whereas rates of sudden deaths and of appropriate device therapies were similar across age groups. PMID- 25784519 TI - Usefulness of colchicine to reduce perioperative myocardial damage in patients who underwent on-pump coronary artery bypass grafting. AB - The objective of the present study was to test whether a perioperative course of colchicine, in patients who underwent standard coronary artery bypass grafting, would result in reduced postoperative increase of myocardial injury biomarker levels. Patients were prospectively randomized to colchicine or placebo starting 48 hours before scheduled coronary artery bypass grafting and for 8 days thereafter (0.5 mg twice daily). The primary outcome parameter was maximal high sensitivity troponin T (hsTnT) concentration within 48 hours after surgery. Secondary outcome measures were maximal creatine kinase-myocardial brain fraction (CK-MB) levels and area under the curve (AUC) of hsTnT and CK-MB concentrations; 59 patients were included. Maximal hsTnT was 616 pg/ml (396 to 986) in the colchicine group versus 1,613 pg/ml (732 to 2,587) in controls (p = 0.002). Maximal CK-MB was 44.6 ng/ml (36.6 to 68.8) and 93.0 ng/ml (48.0 to 182.3), respectively (p = 0.002). The median AUC for hsTnT was 40,755 pg h/ml (20,868 to 79,176) in controls versus 20,363 pg h/ml (13,891 to 31,661) in the colchicine group (p = 0.002). AUCs for CK-MB were 2,552 ng h/ml (1,564 to 4,791) in controls and 1,586 ng h/ml (1,159 to 2,073) in the colchicine group (p = 0.003). The main complaints associated with colchicine were, as expected, gastrointestinal, with 5 patients (16.7%) in the colchicine group reporting diarrhea versus 1 control (3.4%) (p = 0.195). In conclusion, a short perioperative course of colchicine was effective in attenuating postoperative increases of hsTnT and CK-MB compared with placebo. This finding, which needs confirmation in a larger clinical trial powered to assess clinical endpoints, suggests a potential role for this agent in reducing cardiac surgery-related myocardial damage. PMID- 25784520 TI - Usefulness of preoperative atrial fibrillation to predict outcome and left ventricular dysfunction after valve repair for mitral valve prolapse. AB - The aim of the study was to assess the impact of atrial fibrillation (AF) on outcome in patients who underwent mitral valve repair (MVRp) for mitral valve prolapse (MVP). Four hundred and forty-three consecutive patients underwent MVRp for organic mitral regurgitation due to MVP. Echocardiography was performed preoperatively and after surgery. Postoperative left ventricular dysfunction (LVD) was defined as left ventricular ejection fraction (LVEF) <50%. Before surgery, 187 patients (42%) had preoperative AF. After surgery, LVEF significantly decreased from 67 +/- 9% to 56 +/- 10% (p <0.0001). Compared with patients in sinus rhythm (SR), those in AF were significantly older (p <0.0001), had more severe symptoms (p = 0.004), had lower LVEF (p = 0.002), and higher EuroSCORE (p = 0.05). Compared with patients in SR, patients with AF had significantly lower 10-year survival (64 +/- 4% vs 83 +/- 3%, p = 0.001). On multivariate analysis, preoperative AF was identified as an independent predictor of overall mortality (hazard ratio 1.67; 95% confidence interval 1.15 to 2.42; p = 0.007). At 10 years, patients with paroxysmal AF had lower survival and higher heart failure rate than patients in SR (78 +/- 3% vs 66 +/- 6%) but had a better outcome compared with those with permanent AF (66 +/- 6% vs 53 +/- 6%, p = 0.022). Patients with AF had a significantly higher rate of postoperative LVD (23.3% vs 13.4%, p = 0.007). In conclusion, preoperative AF is a predictor of long-term mortality and postoperative LVD after MVRp for MVP. To improve postoperative outcome, surgery in these patients should be performed before onset of AF. PMID- 25784521 TI - Global mapping transcriptional start sites revealed both transcriptional and post transcriptional regulation of cold adaptation in the methanogenic archaeon Methanolobus psychrophilus. AB - Psychrophilic methanogenic Archaea contribute significantly to global methane emissions, but archaeal cold adaptation mechanisms remain poorly understood. Hinted by that mRNA architecture determined secondary structure respond to cold more promptly than proteins, differential RNA-seq was used in this work to examine the genome-wide transcription start sites (TSSs) of the psychrophilic methanogen Methanolobus psychrophilus R15 and its response to cold. Unlike most prokaryotic mRNAs with short 5' untranslated regions (5' UTR, median lengths of 20-40 nt), 51% mRNAs of this methanogen have large 5' UTR (>50 nt). For 24% of the mRNAs, the 5' UTR is >150 nt. This implies that post-transcriptional regulation may be significance in the psychrophile. Remarkably, 219 (14%) genes possessed multiple gene TSSs (gTSSs), and 84 genes exhibited temperature regulated gTSS selection to express alternative 5' UTR. Primer extension studies confirmed the temperature-dependent TSS selection and a stem-loop masking of ribosome binding sites was predicted from the longer 5' UTRs, suggesting alternative 5' UTRs-mediated translation regulation in the cold adaptation as well. In addition, 195 small RNAs (sRNAs) were detected, and Northern blots confirmed that many sRNAs were induced by cold. Thus, this study revealed an integrated transcriptional and post-transcriptional regulation for cold adaptation in a psychrophilic methanogen. PMID- 25784522 TI - Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers. AB - Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the alphavbeta3-integrin ligand cyclo[DKP-RGD] CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified alphaVbeta3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (alphaVbeta3-) and its subclone CCRF-CEM alphaVbeta3 (alphaVbeta3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen positive CCRF-CEM alphaVbeta3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload. PMID- 25784524 TI - Thermal Augmentation of Vancomycin Against Staphylococcal Biofilms. AB - Given the increasing evidence of safe application of elevated temperature in other clinical contexts, we consider the potential for supplemental hyperthermia to augment the effects of vancomycin against staphylococci, a major source of postoperative and posttraumatic sepsis. Laboratory reference strains and libraries of clinical blood isolates of Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus, both as planktonic cells and as established biofilms, were assessed for thermosensitivity and increased susceptibility to vancomycin in the setting of thermal treatment. In addition to viability measures, patterns of stress gene expression were assessed with quantitative polymerase chain reaction, and structural changes were measured using quantitative transmission electron microscopy. Laboratory strains of both species had reduced growth and biofilm viability at 45 degrees C, a temperature commonly used in other domains such as adjuvant treatments of malignancy. Blood isolates of S. epidermidis were consistent in this regard as well, but significant between-isolate variability in thermosensitivity was seen in blood isolates of S. aureus. Expression profiling and ultrastructural measurements confirmed that elevated temperature was a substantial stressor with or without vancomycin treatment. Our findings suggest that temperature elevations shown to be tolerated in humans in other settings hold the potential to be used as an adjuvant to antibiotic therapy against staphylococcal biofilms. PMID- 25784523 TI - Prehospital Resuscitation of Traumatic Hemorrhagic Shock with Hypertonic Solutions Worsens Hypocoagulation and Hyperfibrinolysis. AB - Impaired hemostasis frequently occurs after traumatic shock and resuscitation. The prehospital fluid administered can exacerbate subsequent bleeding and coagulopathy. Hypertonic solutions are recommended as first-line treatment of traumatic shock; however, their effects on coagulation are unclear. This study explores the impact of resuscitation with various hypertonic solutions on early coagulopathy after trauma. We conducted a prospective observational subgroup analysis of large clinical trial on out-of-hospital single-bolus (250 mL) hypertonic fluid resuscitation of hemorrhagic shock trauma patients (systolic blood pressure, <=70 mmHg). Patients received 7.5% NaCl (HS), 7.5% NaCl/6% Dextran 70 (HSD), or 0.9% NaCl (normal saline [NS]) in the prehospital setting. Thirty-four patients were included: 9 HS, 8 HSD, 17 NS. Treatment with HS/HSD led to higher admission systolic blood pressure, sodium, chloride, and osmolarity, whereas lactate, base deficit, fluid requirement, and hemoglobin levels were similar in all groups. The HSD-resuscitated patients had higher admission international normalized ratio values and more hypocoagulable patients, 62% (vs. 55% HS, 47% NS; P < 0.05). Prothrombotic tissue factor was elevated in shock treated with NS but depressed in both HS and HSD groups. Fibrinolytic tissue plasminogen activator and anti-fibrinolytic plasminogen activator inhibitor type 1 were increased by shock but not thrombin-activatable fibrinolysis inhibitor. The HSD patients had the worst imbalance between procoagulation/anticoagulation and profibrinolysis/antifibrinolysis, resulting in more hypocoagulability and hyperfibrinolysis. We concluded that resuscitation with hypertonic solutions, particularly HSD, worsens hypocoagulability and hyperfibrinolysis after hemorrhagic shock in trauma through imbalances in both procoagulants and anticoagulants and both profibrinolytic and antifibrinolytic activities. PMID- 25784525 TI - Experimental Animal Models of Traumatic Coagulopathy: A Systematic Review. AB - BACKGROUND: Perturbations in coagulation function are common following trauma and are associated with poor clinical outcomes. Traditionally considered an iatrogenic process, it is now recognized that an acute coagulation dysfunction develops prior to medical intervention. The mechanisms underlying the development of this acute traumatic coagulopathy remain poorly understood. Preclinical animal research is a necessary adjunct to improve mechanistic understanding and management of this condition. This review aims to identify and evaluate existing animal models of traumatic coagulopathy for clinical relevance. METHODS: A structured search of MEDLINE/PubMed was performed in September 2014 in accordance with the PRISMA guidelines. RESULTS: A total of 62 relevant publications describing 27 distinct models of traumatic coagulopathy were identified. Porcine models predominated, and hemodilution in isolation or in combination with hypothermia and/or acidosis was the principal mechanism for inducing coagulopathy. Acute coagulation changes in response to tissue injury and hemorrhage were evident in five publications, and pathophysiological evaluation of postulated mechanisms was performed in three studies. CONCLUSIONS: There are few clinically relevant animal models that reflect the contemporary understanding of traumatic coagulopathy. This relative deficiency highlights the need for further development of valid and reproducible animal models of trauma. Well designed models will facilitate improved mechanistic understanding and development of targeted treatment strategies for traumatic coagulopathy. PMID- 25784526 TI - Glutamine Modulates Changes in Intestinal Intraepithelial gammadeltaT-Lymphocyte Expressions in Mice With Ischemia/Reperfusion Injury. AB - This study investigated the effect of glutamine (GLN) on expressions of small intestinal intraepithelial lymphocyte (IEL) gammadeltaT-cell proinflammatory cytokines and apoptotic regulatory factor genes in a mouse model of hindlimb ischemia/reperfusion (IR) injury. Mice were assigned to a normal control group and three IR groups. Mice in the normal control group received no ischemia treatment, whereas IR groups had hindlimb ischemia for 90 min with subsequent 0 (IR0) or 24 h (IR24) of reperfusion. The IR0 group was sacrificed immediately after reperfusion. The IR24S group was injected with saline, and the IR24G group was given 0.75 g GLN/kg of body weight once via a tail vein before reperfusion. The IR24 groups were sacrificed 24 h after reperfusion. Small intestinal IEL gammadeltaT cells of the animals were isolated for further analysis. Results showed that IR injury resulted in lower small intestinal IEL gammadeltaT-cell percentages and higher proinflammatory cytokine messenger RNA expressions of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha by IEL gammadeltaT cells. Compared with the IR24S group, the IR24G group had a higher IEL gammadeltaT-cell percentage. Multiples of change of messenger RNA of proliferation gene expressions of the antiapoptotic Bcl-xl (B-cell lymphoma-extra large) and IL-7 receptor in the IR24G group were higher, whereas expressions of the keratinocyte growth factor and bacterial lectin regenerating islet-derived (Reg)IIIgamma were lower in IEL gammadeltaT cells. Histological findings also showed that damage to the intestinal mucosa was less severe in the IR group with GLN. These results indicated that a single dose of GLN administered before reperfusion maintained small intestinal IEL gammadeltaT cell populations and reduced expressions of intestinal inflammatory cytokines, which may have consequently ameliorated the severity of IR-induced small intestinal epithelial injury. PMID- 25784528 TI - Narcolepsy with Cataplexy in an Elderly Woman. AB - A 72-year-old woman was referred for a 15-year history of brief attacks of generalized weakness that occurred when she was tense or startled. During these episodes, she squatted, closed her eyes, and had difficulty speaking, but there was no disturbance of consciousness. The cerebrospinal fluid level of orexin/hypocretin was low (92 ng/L), leading to a diagnosis of narcolepsy with cataplexy according to the International Classification of Sleep Disorders (ICSD) 2 criteria. Cataplexy should be considered for sudden attacks of weakness lasting less than 2 minutes and with no alteration of consciousness. Measurement of cerebrospinal fluid levels of orexin/hypocretin is recommended when the diagnosis is uncertain. PMID- 25784527 TI - Combat: Initial Experience with a Randomized Clinical Trial of Plasma-Based Resuscitation in the Field for Traumatic Hemorrhagic Shock. AB - The existing evidence shows great promise for plasma as the first resuscitation fluid in both civilian and military trauma. We embarked on the Control of Major Bleeding After Trauma (COMBAT) trial with the support of the Department of Defense to determine if plasma-first resuscitation yields hemostatic and survival benefits. The methodology of the COMBAT study represents not only 3 years of development work but also the integration of nearly two decades of technical experience with the design and implementation of other clinical trials and studies. Herein, we describe the key features of the study design, critical personnel and infrastructural elements, and key innovations. We will also briefly outline the systems engineering challenges entailed by this study. The COMBAT trial is a randomized, placebo-controlled, semiblinded, prospective, phase IIB clinical trial conducted in a ground ambulance fleet based at a level I trauma center and part of a multicenter collaboration. The primary objective of the COMBAT trial is to determine the efficacy of field resuscitation with plasma first compared with standard of care (normal saline). To date, we have enrolled 30 subjects in the COMBAT study. The ability to achieve intervention with a hemostatic resuscitation agent in the closest possible temporal proximity to injury is critical and represents an opportunity to forestall the evolution of the "bloody vicious cycle." Thus, the COMBAT model for deploying plasma in first response units should serve as a model for randomized clinical trials of other hemostatic resuscitative agents. PMID- 25784529 TI - Dose-intensified bendamustine followed by autologous peripheral blood stem cell support in relapsed and refractory multiple myeloma with impaired bone marrow function. AB - Therapeutic options in heavily pretreated relapsed/refractory multiple myeloma patients are often very limited because of impaired bone marrow function. Bendamustine is effective in multiple myeloma and has a favourable toxicity profile. We hypothesized that dose-intensified bendamustine (180 mg/m2 , day 1 and 2) followed by autologous blood stem cell support (ASCS) would improve bone marrow function with low post-transplant toxicity in patients with severely impaired haematopoiesis. We analyzed 28 consecutive myeloma patients, with a median of three prior lines of therapy (range 2-7), who had relapsed from the last treatment with very limited bone marrow function and were therefore ineligible for conventional chemotherapy, novel agents or trial enrolment. Dose intensified bendamustine with ASCS improved haematopoiesis as reflected by increased platelet counts (median 40/nl vs 94/nl, p = 0.0004) and white blood cell counts (3.0/nl vs 4.8/nl, p = 0.02) at day +100. The median time until engraftment of platelets (>50/nl) was 11 days (0-24 days) and of white cell counts (>1.0/nl) 0 days (0-24 days). At least, a minimal response was achieved in 36% of patients. The disease stabilization rate was 50% while the median progression-free survival rate was limited to 2.14 months. Most importantly, patients were once again eligible for alternative treatments including enrolment into clinical trials. We conclude that dose-intensified bendamustine followed by ASCS is safe and feasible for multiple myeloma patients with very limited bone marrow reserve. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25784530 TI - Dynamics of behavioral disorders in transgenic mice with modeled Alzheimer's disease. AB - Age-related development of behavioral disorders in transgenic mice with modeled Alzheimer's disease carrying V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) genotype was assessed at the age of 7.5, 10 and 20 months in the following tests: open-field, plus maze, T-maze, conditioned passive avoidance response, rotarod, conflict situation with water deprivation, behavioral despair, and arecoline tremor. The main behavioral disorder in transgenic mice at all observation terms was memory impairment in conditioning with positive (but not negative) reinforcement. At the age of 7.5 and 10 months, transgenic mice also showed signs of nonspecific excitement and anxiety, depression-like state, and symptoms of cholinergic deficit. Our results suggest that appropriate age for behavioral tests in studies of effects of potential anti-Alzheimer drugs in transgenic V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) mice is 7.5-10 months. PMID- 25784533 TI - Flow cytometry reveals that the rust fungus, Uromyces bidentis (Pucciniales), possesses the largest fungal genome reported--2489 Mbp. AB - Among the Eukaryotes, Fungi have relatively small genomes (average of 44.2 Mbp across 1850 species). The order Pucciniales (Basidiomycota) has the largest average genome size among fungi (305 Mbp), and includes the two largest fungal genomes reported so far (Puccinia chrysanthemi and Gymnosporangium confusum, with 806.5 and 893.2 Mbp, respectively). In this work, flow cytometry was employed to determine the genome size of the Bidens pilosa rust pathogen, Uromyces bidentis. The results obtained revealed that U. bidentis presents a surprisingly large haploid genome size of 2489 Mbp. This value is almost three times larger than the previous largest fungal genome reported and over 50 times larger than the average fungal genome size. Microscopic examination of U. bidentis nuclei also showed that they are not as different in size from the B. pilosa nuclei when compared with the differences between other rusts and their host plants. This result further reinforces the position of the Pucciniales as the fungal group with the largest genomes, prompting studies addressing the role of repetitive elements and polyploidy in the evolution, pathological specialization and diversity of fungal species. PMID- 25784534 TI - Anthropometric, lifestyle and parental characteristics associated with the prevalence of energy intake misreporting in children: the GRECO (Greek Childhood Obesity) study. AB - The objectives of the present study were to identify childhood energy misreporting, and evaluate characteristics that are associated with its prevalence in a nationwide cross-sectional sample of Greek schoolchildren. Under the context of the GRECO (Greek Childhood Obesity) study, data from a total of 4547 children aged 10-12 years and 2318 parents were included in the analysis. Anthropometric, lifestyle and parental characteristics plus psychological concerns were investigated in relation to the prevalence of energy misreporting. Of the included children, 36 % were classified as energy under-reporters and 16 % as over-reporters. Multinomial logistic regression analysis revealed that the most important predictors of energy under-reporting (URP) were children's BMI (OR 1.11, 95 % CI 1.09, 1.14) and weight satisfaction (OR 0.87, 95 % CI 0.78, 0.97). In the case of energy over-reporting (ORP), children's BMI (OR 0.87, 95 % CI 0.84, 0.90), meal and snack consumption frequency (OR 1.52, 95 % CI 1.32, 1.75), female sex (OR 0.65, 95 % CI 0.45, 0.90), and maternal education (OR 0.95, 95 % CI 0.91, 0.99) remained as significant predictors. Additionally, parental perception that the body weight of their children was normal reduced the odds of URP (OR 0.69, 95 % CI 0.48, 0.99) and ORP (OR 0.53, 95 % CI 0.31, 0.93). In conclusion, the present study confirms that the issue of URP and ORP in childhood populations is evident and quite serious. Although there are no definite guidelines on how to use data obtained from misreporters in an epidemiological dataset, validity of reported energy intake seems to be influenced by children's BMI and weight satisfaction, as well as by parental perceptions regarding their children's weight. PMID- 25784536 TI - Stability analysis of a Komarova type model for the interactions of osteoblast and osteoclast cells during bone remodeling. AB - In order to analyze theoretically the dynamics of osteoblast and osteoclast cells in the bone remodeling process we first consider a simplified Komarova model. The existence of periodic solutions, which is consistent with the biophysical phenomenon, has been observed only numerically for the general model. By a stability analysis of the simplified model we provide sufficient conditions to obtain existence and uniqueness of positive periodic solutions. Considering recent biological evidence about the participation of another cells like osteocytes in the regulation of bone remodeling, we incorporate to the simplified model a new term as a way to model the signaling of external agents in the remodeling process. Finally, we demonstrate that this new model has stable positive non-periodic solutions. All the theoretical results are accompanied by computational simulations. PMID- 25784537 TI - Recurrent extramammary Paget's disease with an unusual histopathological finding. PMID- 25784539 TI - Diagnosis, Management and Assessment of Adults with Joint Hypermobility Syndrome: A UK-Wide Survey of Physiotherapy Practice. AB - Joint hypermobility syndrome (JHS) is a heritable disorder associated with excessive joint range of motion and pain in the absence of inflammatory joint disease. It is a relatively common cause of musculoskeletal pain but is generally understood to be under-recognized and poorly managed in clinical practice. The present study therefore aimed to identify how JHS is diagnosed, managed and assessed in routine physiotherapy practice. A survey tool was developed from similar physiotherapy surveys of musculoskeletal practice, a review of the literature, and consultation with researchers and clinicians. Paper copies of the final survey were sent to 201 randomly selected secondary care organizations across the UK and an electronic version was advertised through physiotherapy professional networks. A total of 66 responses (80% women) were received from physiotherapists, with a wide range of clinical experience. Only 32% of respondents reported that they had received formal training in JHS management. The Brighton diagnostic criteria for JHS were not often used (only 31% of respondents). The stated aims of physiotherapy and the specific interventions employed seem well matched, with a focus on advice, education, exercise and self management. Although pain relief was not reported as a high priority in terms of treatment aims, pain was most often assessed as an outcome, suggesting a mismatch between what clinicians aim to achieve and what they measure. The results suggest that reported management strategies are broadly appropriate to long-term musculoskeletal conditions but additional training specific to JHS may be required, particularly in diagnosis and assessment. PMID- 25784538 TI - The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition. AB - RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca(2+)-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders. PMID- 25784540 TI - Identification of AstG1, A LAL family regulator that positively controls ansatrienins production in Streptomyces sp. XZQH13. AB - Ansamycins is a group of type I polyketides characterized by the unique starter unit 3-amino-5-hydroxybenzoic acid. This family of secondary metabolites shows diverse biological activities, well-known members of which include rifamycin, geldanamycin, and maytansine. Previously, we isolated an AHBA synthase gene positive strain Streptomyces sp. XZQH13 containing a "silent" ansamycin biosynthetic gene cluster ast. The constitutive expression of the Large-ATP binding regulators of the LuxR family regulator gene astG1 located within the cluster triggered the expression of the biosynthetic genes. Reverse transcription PCR experiments showed that the expression of the key biosynthetic genes, astB4, astD1, and astF1, was induced in the astG1 overexpression mutant compared to the wild type. This led to the isolation of two known ansatrienins, hydroxymycotrienin A (1) and thiazinotrienomycin G (2), which were identified by analysis of the mass spectral and NMR spectral data, from the mutant. These observations suggest that astG1 is probably a pathway-specific positive regulator for the biosynthesis of ansatrienin. PMID- 25784541 TI - Domestic dogs (Canis lupus familiaris) and forensic practice. PMID- 25784542 TI - SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle. AB - Small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) that reverse protein modification by SUMO are involved in the control of numerous cellular processes, including transcription, cell division, and cancer development. However, the physiological function of SENPs in energy metabolism remains unclear. Here, we investigated the role of SENP2 in fatty acid metabolism in C2C12 myotubes and in vivo. In C2C12 myotubes, treatment with saturated fatty acids, like palmitate, led to nuclear factor-kappaB-mediated increase in the expression of SENP2. This increase promoted the recruitment of peroxisome proliferator-activated receptor (PPAR)delta and PPARgamma, through desumoylation of PPARs, to the promoters of the genes involved in fatty acid oxidation (FAO), such as carnitine-palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). In addition, SENP2 overexpression substantially increased FAO in C2C12 myotubes. Consistent with the cell culture system, muscle-specific SENP2 overexpression led to a marked increase in the mRNA levels of CPT1b and ACSL1 and thereby in FAO in the skeletal muscle, which ultimately alleviated high fat diet-induced obesity and insulin resistance. Collectively, these data identify SENP2 as an important regulator of fatty acid metabolism in skeletal muscle and further implicate that muscle SENP2 could be a novel therapeutic target for the treatment of obesity-linked metabolic disorders. PMID- 25784543 TI - Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes. AB - Elevated sympathetic nerve activity (SNA) coupled with dysregulated beta adrenoceptor (beta-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the beta-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to beta-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular beta1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial beta2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac beta-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart. PMID- 25784544 TI - Legacy Effect of Foxo1 in Pancreatic Endocrine Progenitors on Adult beta-Cell Mass and Function. AB - beta-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of beta-cells. Foxo1 is important to maintain adult beta-cells, but little is known about its role in pancreatic progenitor cells as determinants of future beta-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of beta-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded beta-cell mass. In contrast, ablation of Foxo1 in terminally differentiated beta-cells did not increase beta-cell mass nor did it affect Neurogenin3 expression. Despite the increased beta-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult beta-cell mass and function. Our results illustrate how developmental programming predisposes to beta-cell dysfunction in adults and raise questions on the desirability of increasing beta-cell mass for therapeutic purposes in type 2 diabetes. PMID- 25784545 TI - TNF-alpha Antibody Therapy in Combination With the T-Cell-Specific Antibody Anti TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddm Rat. AB - Anti-tumor necrosis factor-alpha (TNF-alpha) therapy (5 mg/kg body weight), alone or combined with the T-cell-specific antibody anti-T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased beta-cell proliferation and reduced apoptosis led to a restoration of beta-cell mass along with an immune cell infiltration-free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti-T-cell therapy, and anti-TNF alpha, as the most prominent and effective therapeutic antibody in suppressing TNF-alpha action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual beta-cell mass increased, ultimately reaching a point where the reservoir of the surviving beta cells was insufficient to allow a restoration of normal beta-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials. PMID- 25784551 TI - Structural Basis for Action of the External Chaperone for a Propeptide-deficient Serine Protease from Aeromonas sobria. AB - Subtilisin-like proteases are broadly expressed in organisms ranging from bacteria to mammals. During maturation of these enzymes, N-terminal propeptides function as intramolecular chaperones, assisting the folding of their catalytic domains. However, we have identified an exceptional case, the serine protease from Aeromonas sobria (ASP), that lacks a propeptide. Instead, ORF2, a protein encoded just downstream of asp, appears essential for proper ASP folding. The mechanism by which ORF2 functions remains an open question, because it shares no sequence homology with any known intramolecular propeptide or other protein. Here we report the crystal structure of the ORF2-ASP complex and the solution structure of free ORF2. ORF2 consists of three regions: an N-terminal extension, a central body, and a C-terminal tail. Together, the structure of the central body and the C-terminal tail is similar to that of the intramolecular propeptide. The N-terminal extension, which is not seen in other subtilisin-like enzymes, is intrinsically disordered but forms some degree of secondary structure upon binding ASP. We also show that C-terminal (DeltaC1 and DeltaC5) or N-terminal (DeltaN43 and DeltaN64) deletion eliminates the ability of ORF2 to function as a chaperone. Characterization of the maturation of ASP with ORF2 showed that folding occurs in the periplasmic space and is followed by translocation into extracellular space and dissociation from ORF2, generating active ASP. Finally, a PSI-BLAST search revealed that operons encoding subtilases and their external chaperones are widely distributed among Gram-negative bacteria, suggesting that ASP and its homologs form a novel family of subtilases having an external chaperone. PMID- 25784552 TI - The class III cyclobutane pyrimidine dimer photolyase structure reveals a new antenna chromophore binding site and alternative photoreduction pathways. AB - Photolyases are proteins with an FAD chromophore that repair UV-induced pyrimidine dimers on the DNA in a light-dependent manner. The cyclobutane pyrimidine dimer class III photolyases are structurally unknown but closely related to plant cryptochromes, which serve as blue-light photoreceptors. Here we present the crystal structure of a class III photolyase termed photolyase-related protein A (PhrA) of Agrobacterium tumefaciens at 1.67-A resolution. PhrA contains 5,10-methenyltetrahydrofolate (MTHF) as an antenna chromophore with a unique binding site and mode. Two Trp residues play pivotal roles for stabilizing MTHF by a double pi-stacking sandwich. Plant cryptochrome I forms a pocket at the same site that could accommodate MTHF or a similar molecule. The PhrA structure and mutant studies showed that electrons flow during FAD photoreduction proceeds via two Trp triads. The structural studies on PhrA give a clearer picture on the evolutionary transition from photolyase to photoreceptor. PMID- 25784554 TI - A Residue Quartet in the Extracellular Domain of the Prolactin Receptor Selectively Controls Mitogen-activated Protein Kinase Signaling. AB - Cytokine receptors elicit several signaling pathways, but it is poorly understood how they select and discriminate between them. We have scrutinized the prolactin receptor as an archetype model of homodimeric cytokine receptors to address the role of the extracellular membrane proximal domain in signal transfer and pathway selection. Structure-guided manipulation of residues involved in the receptor dimerization interface identified one residue (position 170) that in cell-based assays profoundly altered pathway selectivity and species-specific bio characteristics. Subsequent in vitro spectroscopic and nuclear magnetic resonance analyses revealed that this residue was part of a residue quartet responsible for specific local structural changes underlying these effects. This included alteration of a novel aromatic T-stack within the membrane proximal domain, which promoted selective signaling affecting primarily the MAPK (ERK1/2) pathway. Importantly, activation of the MAPK pathway correlated with in vitro stabilities of ternary ligand.receptor complexes, suggesting a threshold mean lifetime of the complex necessary to achieve maximal activation. No such dependence was observed for STAT5 signaling. Thus, this study establishes a residue quartet in the extracellular membrane proximal domain of homodimeric cytokine receptors as a key regulator of intracellular signaling discrimination. PMID- 25784553 TI - Orc1 Binding to Mitotic Chromosomes Precedes Spatial Patterning during G1 Phase and Assembly of the Origin Recognition Complex in Human Cells. AB - Replication of eukaryotic chromosomes occurs once every cell division cycle in normal cells and is a tightly controlled process that ensures complete genome duplication. The origin recognition complex (ORC) plays a key role during the initiation of DNA replication. In human cells, the level of Orc1, the largest subunit of ORC, is regulated during the cell division cycle, and thus ORC is a dynamic complex. Upon S phase entry, Orc1 is ubiquitinated and targeted for destruction, with subsequent dissociation of ORC from chromosomes. Time lapse and live cell images of human cells expressing fluorescently tagged Orc1 show that Orc1 re-localizes to condensing chromatin during early mitosis and then displays different nuclear localization patterns at different times during G1 phase, remaining associated with late replicating regions of the genome in late G1 phase. The initial binding of Orc1 to mitotic chromosomes requires C-terminal amino acid sequences that are similar to mitotic chromosome-binding sequences in the transcriptional pioneer protein FOXA1. Depletion of Orc1 causes concomitant loss of the mini-chromosome maintenance (Mcm2-7) helicase proteins on chromatin. The data suggest that Orc1 acts as a nucleating center for ORC assembly and then pre-replication complex assembly by binding to mitotic chromosomes, followed by gradual removal from chromatin during the G1 phase. PMID- 25784555 TI - Increasing adipocyte lipoprotein lipase improves glucose metabolism in high fat diet-induced obesity. AB - Lipid accumulation in liver and skeletal muscle contributes to co-morbidities associated with diabetes and obesity. We made a transgenic mouse in which the adiponectin (Adipoq) promoter drives expression of lipoprotein lipase (LPL) in adipocytes to potentially increase adipose tissue lipid storage. These mice (Adipoq-LPL) have improved glucose and insulin tolerance as well as increased energy expenditure when challenged with a high fat diet (HFD). To identify the mechanism(s) involved, we determined whether the Adipoq-LPL mice diverted dietary lipid to adipose tissue to reduce peripheral lipotoxicity, but we found no evidence for this. Instead, characterization of the adipose tissue of the male mice after HFD challenge revealed that the mRNA levels of peroxisome proliferator activated receptor-gamma (PPARgamma) and a number of PPARgamma-regulated genes were higher in the epididymal fat pads of Adipoq-LPL mice than control mice. This included adiponectin, whose mRNA levels were increased, leading to increased adiponectin serum levels in the Adipoq-LPL mice. In many respects, the adipose phenotype of these animals resembles thiazolidinedione treatment except for one important difference, the Adipoq-LPL mice did not gain more fat mass on HFD than control mice and did not have increased expression of genes in adipose such as glycerol kinase, which are induced by high affinity PPAR agonists. Rather, there was selective induction of PPARgamma-regulated genes such as adiponectin in the adipose of the Adipoq-LPL mice, suggesting that increasing adipose tissue LPL improves glucose metabolism in diet-induced obesity by improving the adipose tissue phenotype. Adipoq-LPL mice also have increased energy expenditure. PMID- 25784556 TI - Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P) IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1. AB - Inflammation induced by exposure to the common food additive carrageenan leads to insulin resistance by increase in Ser(P)(307)-insulin receptor substrate 1 (IRS1) and subsequent decline in the insulin-stimulated increase in Ser(P)(473)-AKT. Inhibition of carrageenan-induced inflammation reversed the increase in Ser(P)(307)-IRS1 but did not completely reverse the carrageenan-induced decline in Ser(P)(473)-AKT. To identify the additional mechanism responsible for the decrease in Ser(P)(473)-AKT, studies were performed in human HepG2 cells and in C57BL/6J mice. Following carrageenan, expression of GRB10 (growth factor receptor bound 10 protein), an adaptor protein that binds to the insulin receptor and inhibits insulin signaling, increased significantly. GRB10 silencing blocked the carrageenan-induced reduction of the insulin-stimulated increase in Tyr(P)-IRS1 and partially reversed the decline in Ser(P)(473)-AKT. The combination of GRB10 silencing with BCL10 silencing and the reactive oxygen species inhibitor Tempol completely reversed the decline in Ser(P)(473)-AKT. After carrageenan, GRB10 promoter activity was enhanced because of activation by GATA2. A direct correlation between Ser(P)(473)-AKT and Ser(P)(401)-GATA2 was evident, and inhibition of AKT phosphorylation by the PI3K inhibitor LY294002 blocked Ser(401) GATA2 phosphorylation and the increase in GRB10 expression. Studies indicated that carrageenan inhibited insulin signaling by two mechanisms: through the inflammation-mediated increase in Ser(P)(307)-IRS1, a negative regulator of insulin signaling, and through a transcriptional mechanism leading to increase in GRB10 expression and GRB10-inhibition of Tyr(P)-IRS1, a positive regulator of insulin signaling. These mechanisms converge to inhibit the insulin-induced increase in Ser(P)(473)-AKT. They provide internal feedback, mediated by Ser(P)(473)-AKT, Ser(P)(401)-GATA2, and nuclear GATA2, which links the opposing effects of serine and tyrosine phosphorylations of IRS1 and can modulate insulin responsiveness. PMID- 25784558 TI - Ortho-quinone methides as reactive intermediates in asymmetric bronsted Acid catalyzed cycloadditions with unactivated alkenes by exclusive activation of the electrophile. AB - An efficient method for the highly enantioselective synthesis of chiral chromanes bearing multiple stereogenic centers was developed. A chiral BINOL-based N triflylphosphoramide proved to be an effective catalyst for the in situ generation of ortho-quinone methides (o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes provided chromanes with excellent diastereo- and enantioselectivity. PMID- 25784557 TI - The c-Cbl ubiquitin ligase regulates nuclear beta-catenin and angiogenesis by its tyrosine phosphorylation mediated through the Wnt signaling pathway. AB - Wnt signaling plays important roles in both the tumor-induced angiogenesis and tumorigenesis through the transcriptionally active nuclear beta-catenin. Recently, c-Cbl was identified as a unique E3 ubiquitin ligase targeting the active nuclear beta-catenin. However, little is known about the molecular mechanisms by which c-Cbl regulates ubiquitination and degradation of active beta catenin. Here, we demonstrate that Wnt activation promotes the phosphorylation of c-Cbl at tyrosine 731(Tyr-731), which increases c-Cbl dimerization and binding to beta-catenin. Tyr-731 phosphorylation and dimerization mediate c-Cbl nuclear translocation and lead to the degradation of nuclearly active beta-catenin in the Wnt-on phase. c-Cbl activation also inhibits expression of the pro-angiogenic Wnt targets, IL-8 and VEGF. Phospho-Tyr-731-inactive mutant c-Cbl (Y731F) enhances and phosphomimetic mutant c-Cbl (Y731E) suppresses angiogenesis in zebrafish. Taken together, we have identified a novel mechanism for the regulation of active nuclear beta-catenin by c-Cbl and its critical role in angiogenesis. This mechanism can be further explored to modulate both the pathological angiogenesis and the tumorigenesis. PMID- 25784559 TI - 2,2',4,4'-Tetrabromodiphenyl ether promotes human neuroblastoma SH-SY5Y cells migration via the GPER/PI3K/Akt signal pathway. AB - Neuroblastoma is the predominant tumor of early childhood. 2,2',4,4' Tetrabromodiphenyl ether (BDE-47) has the highest concentration among all polybrominated diphenyl ether (PBDE) congeners in human body, particularly for children. Considering that accumulating evidences showed developmental neurotoxicity of PBDE, there is an urgent need to investigate the effects of BDE 47 on the development of neuroblastoma. This study revealed that BDE-47 had limited effects on the cytotoxicity while significantly increased the in vitro migration and invasion of human neuroblastoma SH-SY5Y cells. This was further confirmed by the results that BDE-47 treatment significantly downregulated the expression of E-cadherin and zona occludin-1 and upregulated the expression of matrix metalloproteinase-9 (MMP-9). Silencing of MMP-9 by specific small interfering RNA significantly abolished the BDE-47-induced migration and invasion of SH-SY5Y cells. Further, the signals G protein-coupled estrogen receptor 1 (GPER)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) mediated the BDE-47-induced upregulation of MMP-9 and in vitro migration of SH-SY5Y cells since G15 (GPER inhibitor) and LY 294002 (PI3K/Akt inhibitor) significantly abolished the effects of BDE-47. Our results revealed that BDE-47 significantly triggered the metastasis of human neuroblastoma SH-SY5Y cells via upregulation of MMP-9 by the GPER/PI3K/Akt signal pathway. This study revealed for the first time that BDE-47 can promote the migration of SH-SY5Y cells. It also provided a better understanding about the metastasis of human neuroblastoma induced by environmental endocrine disruptors. PMID- 25784560 TI - Association of Toll-like receptor 2 Arg753Gln and Toll-like receptor 1 Ile602Ser single-nucleotide polymorphisms with leptospirosis in an Argentine population. AB - Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an important role in the recognition of and subsequent immune response activation against leptospirosis in humans. The genetic polymorphism in TLR2 of an arginine to glutamine substitution at residue 753 (Arg753Gln) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to Leptospira spp. This bacterium signals through TLR2/TLR1 heterodimers in human cells. The aim of the present study was to investigate the Arg753Gln single-nucleotide polymorphism (SNP) of the TLR2 gene, and the isoleucine to serine transversion at position 602 (Ile602Ser) of the TLR1 gene (previously associated with Lyme disease), in leptospirosis patients compared to healthy controls, carrying out a retrospective case/control study. The TLR2 polymorphism adenine (A) allele was observed in 7.3% of leptospirosis patients but was not found in the control group, whereas the guanine (G) allele of the TLR1 polymorphism was found in 63.6% of patients and 41.6% of controls. Susceptibility to leptospirosis disease was increased 10.57-fold for carriers of the TLR2 G/A genotype (P=0.0493) and 3.85-fold for carriers of the TLR1 G/G genotype (P=0.0428). Furthermore, the risk of developing hepatic insufficiency and jaundice was increased 18.86- and 27.60-fold for TLR2 G/A carriers, respectively. Similarly, the risk of developing jaundice was increased 12.67-fold for TLR1 G allele carriers (G/G and T/G genotypes). In conclusion, the present data suggest that the TLR2 Arg753Gln and TLR1 Ile602Ser SNPs influence the risk of developing leptospirosis and its severity. PMID- 25784561 TI - Health-related quality of life in young survivors of childhood cancer. AB - PURPOSE: Childhood cancer and its treatment may affect health-related quality of life (HRQoL) in childhood cancer survivors, but population-based studies in young survivors are scarce. We aimed to: (1) compare HRQoL between young survivors and population norms and (2) find factors that influence parent-reported HRQoL in survivors. METHODS: As part of the Swiss Childhood Cancer Survivor Study, a questionnaire was mailed to parents of survivors aged 8-16 years, registered in the Swiss Childhood Cancer Registry, >=5 years after diagnosis. We used the KIDSCREEN-27 instrument to compare self- and parent-reported HRQoL between survivors (N = 425) and standardized norms in the five dimensions of physical well-being, psychological well-being, autonomy, peers and school environment (mean = 50, SD = 10). We then used multivariable linear regressions to test the influence of socio-demographic and cancer-related factors on HRQoL. RESULTS: Self reported physical well-being was comparable to norms. Other HRQoL dimensions were higher than norms, with the highest mean = 52.2 (p < 0.001) for school environment. Parent-reported HRQoL in survivors was comparable to population norms; only physical well-being was lower (mean = 47.1, p < 0.001), and school environment was higher (mean = 51.1, p = 0.035). Parent-reported HRQoL was lower for survivors of CNS tumors (physical well-being: beta = -5.27, p = 0.007; psychological well-being: beta = -4.39, p = 0.044; peers beta = -5.17, p = 0.028), survivors of neuroblastoma (psychological well-being beta = -5.20, p = 0.047), and survivors who had had a relapse (physical well-being beta = -5.41, p = 0.005). CONCLUSIONS: Assessing HRQoL during follow-up care, with a focus on physical well-being, specific diagnoses (e.g., CNS tumor) and late complications (e.g., relapse) might help to early identify problems and offer support to survivors with reduced HRQoL. PMID- 25784562 TI - Comparing three different approaches to the measurement of needs concerning fatigue in patients with advanced cancer. AB - PURPOSE: To identify patients having fatigue, it is necessary to assess the patients fatigue systematically. This study investigates three different approaches to the assessment of needs concerning fatigue in patients with advanced cancer and addresses the following questions. METHODS: In a cross sectional nationwide survey, patients were asked about their needs concerning fatigue in three different ways: Fatigue intensity was measured with the European Organisation for Research and Treatment of Cancer quality of life questionnaire, fatigue burden (the extent fatigue was a problem) and fatigue felt need (whether the patient experienced an unmet need regarding their fatigue) was measured with the Three-Levels-of-Needs Questionnaire. The relations between these three approaches were investigated using cross-tabulations, polychromic correlations, receiver operating curves, and area under the curve. RESULTS: In total, 1447 patients participated (61 %). Of these, 34 % reported at least quite a bit fatigue (intensity), 36 % reported at least quite a bit fatigue burden, and 35 % reported experiencing an unmet need. There was a high correlation between fatigue intensity and fatigue burden (0.91). Fatigue intensity was also correlated with experiencing an unmet need and having at least a little fatigue predicted experiencing an unmet need. CONCLUSION: Overall, no matter which approach was used, about a third of the patients had a need concerning fatigue. In nearly all cases, patients who had fatigue also experienced fatigue to be a problem. The QLQ C30 item 'Were you tired' worked as a screening tool to identify patients experiencing an unmet need concerning fatigue. PMID- 25784563 TI - Insulin pump risks and benefits: a clinical appraisal of pump safety standards, adverse event reporting and research needs. A joint statement of the European Association for the Study of Diabetes and the American Diabetes Association Diabetes Technology Working Group. AB - Insulin pump therapy, also known as continuous subcutaneous insulin infusion (CSII), is an important and evolving form of insulin delivery, which is mainly used for people with type 1 diabetes. However, even with modern insulin pumps, errors of insulin infusion can occur due to pump failure, insulin infusion set (IIS) blockage, infusion site problems, insulin stability issues, user error or a combination of these. Users are therefore exposed to significant and potentially fatal hazards: interruption of insulin infusion can result in hyperglycaemia and ketoacidosis; conversely, delivery of excessive insulin can cause severe hypoglycaemia. Nevertheless, the available evidence on the safety and efficacy of CSII remains limited. The European Association for the Study of Diabetes (EASD) and American Diabetes Association (ADA) have therefore joined forces to review the systems in place for evaluating the safety of pumps from a clinical perspective. We found that useful information held by the manufacturing companies is not currently shared in a sufficiently transparent manner. Public availability of adverse event (AE) reports on the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is potentially a rich source of safety information but is insufficiently utilised due to the current configuration of the system; the comparable database in Europe (European Databank on Medical Devices, EUDAMED) is not publicly accessible. Many AEs appear to be attributable to human factors and/or user error, but the extent to which manufacturing companies are required by regulators to consider the interactions of users with the technical features of their products is limited. The clinical studies required by regulators prior to marketing are small and over-reliant on bench testing in relation to 'predicate' products. Once a pump is available on the market, insufficient data are made publicly available on its long-term use in a real-world setting; such data could provide vital information to help healthcare teams to educate and support users, and thereby prevent AEs. As well as requiring more from the manufacturing companies, we call for public funding of more research addressing clinically important questions in relation to pump therapy: both observational studies and clinical trials. At present there are significant differences in the regulatory systems between the USA and European Union at both pre- and post-marketing stages; improvements in the European system are more urgently required. This statement concludes with a series of recommended specific actions for 'meknovigilance' (i.e. a standardised safety approach to technology) which could be implemented to address the shortcomings we highlight. PMID- 25784564 TI - Treatment Toxicity in Elderly Patients With Advanced Non-Small Cell Lung Cancer. AB - OBJECTIVES: Toxicity is a main concern limiting the use of chemotherapy and radiotherapy (RT) for elderly patients with non-small cell lung cancer (NSCLC). The objective of this study was to assess the rates of treatment-related toxicity among elderly stage IIIB and IV NSCLC patients. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results registry linked to Medicare records to identify 2596 stage IIIB and 14,803 stage IV NSCLC patients aged 70 years and above, diagnosed in 2000 or later. We compared rates of toxicity requiring hospitalization according to treatment (chemotherapy, RT, or chemoradiation [CRT]) in unadjusted and adjusted models controlling for selection bias using propensity scores. RESULTS: Among stage IIIB patients, rates of any severe toxicity were 10.1%, 23.8%, 30.4%, and 39.2% for patients who received no treatment, RT, chemotherapy alone, and CRT, respectively. In stage IV patients, rates of any severe toxicity were 31.5% versus 13.5% among those treated with and without chemotherapy, respectively. In stage IIIB patients treated with CRT, the most common toxicities was esophagitis (odds ratio, 48.5; 95% confidence interval, 6.7-350.5). Among stage IV patients treated with chemotherapy, the risk of toxicity was highest for neutropenia (odds ratio, 8.4; 95% confidence interval, 6.1-11.5). CONCLUSIONS: Toxicity was relatively common among stage IIIB patients with up to a 6-fold increase in elderly individuals treated with CRT and a 4-fold increase in toxicities among stage IV patients. This information should be helpful to guide discussions about the risk-benefit ratio of chemotherapy and RT in elderly patients with advanced NSCLC. PMID- 25784565 TI - Alcohol Abuse Decreases Pelvic Control and Survival in Cervical Cancer: An Opportunity of Lifestyle Intervention for Outcome Improvement. AB - PURPOSE: We examined the incidence and the effect of alcohol abuse on pelvic control (PC), disease-free survival (DFS), and overall survival (OS) in locally advanced cervical cancer patients undergoing definitive radiation therapy (RT). METHODS: Between 2007 and 2013, 95 patients treated with RT were reviewed, and the tumor characteristics, the RT dose, the treatment time, chemotherapy, and the number of cycles were recorded. The association between alcohol abuse and DFS, OS, and the duration of PC was analyzed using multivariable Cox proportional hazards models. RESULTS: Of the 95 patients with an average age of 54.8 years (range, 27 to 91 y), 30% were FIGO stage 1B1, 1B2, 2A, 52% stage 2B, 3A; and 18% stage 3B; 86% of the patients were treated with weekly cisplatin chemotherapy. Alcohol history showed that 10 (10.5%) patients met the CDC criteria for heavy alcohol use. With a mean follow-up time of 2 years, 85 patients (88.5%) achieved PC and 86 patients (90.5%) were free of distant metastasis. A total of 82 patients (86.3%) were alive at the last follow-up. When controlling for the total treatment time, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; hazard ratio [HR], 6.19; 95% confidence interval [CI]: 1.73, 22.18), OS (P=0.001; HR, 6.68; 95% CI: 2.10, 21.26), and PC (P=0.029; HR, 3.10; 95% CI: 1.13, 8.56) on univariable analysis. On multivariable analysis, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; HR, 10.57; 95% CI: 2.07, 53.93) and OS (P=0.001; HR, 10.80; 95% CI: 2.57, 45.40). CONCLUSIONS: In this small hypothesis-generating series of patients with heavy alcohol use, the data support the association that heavy alcohol use increases the risk of cancer recurrence and mortality. Additional research is required to better define the patient- and treatment-related factors that may be targeted for intervention. PMID- 25784566 TI - De novo sequencing, assembly and analysis of salivary gland transcriptome of Haemaphysalis flava and identification of sialoprotein genes. AB - Saliva plays an important role in feeding and pathogen transmission, identification and analysis of tick salivary gland (SG) proteins is considered as a hot spot in anti-tick researching area. Herein, we present the first description of SG transcriptome of Haemaphysalis flava using next-generation sequencing (NGS). A total of over 143 million high-quality reads were assembled into 54,357 unigenes, of which 20,145 (37.06%) had significant similarities to proteins in the Swiss-Prot database. 13,513 annotated sequences were associated with GO terms. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 14,280 unigenes were assigned to 279 KEGG pathways in total. Reads per kb per million reads (RPKM) analysis showed that there were 3035 down-regulated unigenes and 2260 up-regulated unigenes in the engorged ticks (ET) compared with the semi-engorged one (SET). Several important genes are associated with blood feeding and ingestion as secreted salivary proteins, concluding cysteine, longipain, 4D8, calreticulin, metalloproteases, serine protease inhibitor, enolase, heat shock protein and AV422 in SG, were identified. The qRT-PCR results confirmed that patterns of these genes (except for the longipain gene) expression were consistent with RNA-seq results. This de novo assembly of SG transcriptome of H. flava not only provides more chance for screening and cloning functional genes, but also forms a solid basis for further insight into the changes of salivary proteins during blood-feeding. PMID- 25784567 TI - Genetic heterogeneity and recombination in type-3 human astroviruses. AB - Human astroviruses (HAstVs) are important enteric pathogens and can be classified genetically and antigenically into eight types. During molecular surveillance for HAstVs in Italy, sequence analysis of the diagnostic region C (about 400 nucleotide in length), located on the capsid (ORF2) gene, identified a novel type 3 strain. Upon sequencing of the full-length ORF2, the type-3 HAstV strain was characterized as a novel ORF2 genetic lineage, designated as 3c. By converse, in the ORF1b the virus was more similar to type-1 HAstVs, rather than to type-3 strains, suggesting a recombination nature, with the crossover site being mapped to the ORF1b/ORF2 junction region. Region C sequences of similar type-3 HAstV identified from European and extra-European countries were retrieved in the databases, suggesting the global distribution of this novel type-3 lineage. PMID- 25784568 TI - Reliable timescale inference of HBV genotype A origin and phylodynamics. AB - The worldwide distributed Hepatitis B virus (HBV) genotype A is classified into three subgenotypes, and one quasi-subgenotype. The majority of HBV-A subgenotypes are widespread in Africa and in ethnic groups that have relatively recently emigrated from African countries, whereas HBV-A2 is highly prevalent among subjects at high risk for sexual exposure to HBV in north-western Europe and the USA. The aim of this study was to reconstruct the origin and dispersion of HBV-A subgenotypes on a reliable timescale using short-term calibration based on heterochronous sampling for HBV-A2, and long-term calibration based on historical data for the other subgenotypes. To this aim, we analysed 113 newly characterised HBV-A isolates with 247 reference sequences retrieved from a public database. The phylodynamic reconstruction was performed by a Bayesian framework. The common ancestor of the currently circulating A subgenotypes was placed in west-central Africa a mean 1057 years ago. The genotype diverged into two main clades at the beginning of the 13th century: one including all of the west-central African quasi-subgenotypes and the other corresponding to subgenotype A1, originating in east Africa and further segregating into two main subclades: an "African" and a "cosmopolitan" clade. It is likely that the slave trade was the main source the spread of cosmopolitan HBV-A1, which was exported to Asia in the 17th century as a result of Arab or Portuguese trade, and to Latin America in the 18th centuries through the trans-Atlantic slave trade. The origin of the currently circulating A2 strains dates back to the first decades of the 20th century, and the evolutionary demography analysis suggests an exponential growth of infections, between 1970s and the mid-1990s. In conclusion, the very different epidemiological and evolutionary histories of HBV-A subgenotypes justify the use of different calibration approaches to reconstruct their reciprocal phylodynamics. PMID- 25784569 TI - Genomic analysis and growth characteristic of dengue viruses from Makassar, Indonesia. AB - Dengue fever is currently the most important mosquito-borne viral disease in Indonesia. In South Sulawesi province, most regions report dengue cases including the capital city, Makassar. Currently, no information is available on the serotypes and genotypes of the viruses circulating in the area. To understand the dynamic of dengue disease in Makassar, we carried out dengue fever surveillance study during 2007-2010. A total of 455 patients were recruited, in which antigen and serological detection revealed the confirmed dengue cases in 43.3% of patients. Molecular detection confirmed the dengue cases in 27.7% of patients, demonstrating that dengue places a significant disease burden on the community. Serotyping revealed that dengue virus serotype 1 (DENV-1) was the most predominant serotype, followed by DENV-2, -3, and -4. To determine the molecular evolution of the viruses, we conducted whole-genome sequencing of 80 isolates. Phylogenetic analysis grouped DENV-2, -3 and -4 to the Cosmopolitan genotype, Genotype I and Genotype II, respectively. Intriguingly, each serotype paints a different picture of evolution and transmission. DENV-1 appears to be undergoing a clade replacement with Genotype IV being supplanted by Genotype I. The Cosmopolitan DENV-2 isolates were found to be regionally endemic and is frequently being exchanged between countries in the region. By contrast, DENV-3 and DENV-4 isolates were related to strains with a long history in Indonesia although the DENV-3 strains appear to have been following a distinct evolutionary path since approximately 1998. To assess whether the various DENV serotypes/genotypes possess different growth characteristics, we performed growth kinetic assays on selected viruses. We observed the relatively higher rate of replication for DENV-1 and -2 compared to DENV-3 and -4. Within the DENV-1, viruses from Genotype I grow faster than that of Genotype IV. This higher replication rate may underlie their ability to replace the circulation of Genotype IV in the community. PMID- 25784570 TI - Quantification of residual crystallinity in ball milled commercially sourced lactose monohydrate by thermo-analytical techniques and terahertz spectroscopy. AB - The quantification of crystallinity is necessary in order to be able to control the milling process. The use of thermal analysis for this assessment presents certain challenges, particularly in the case of crystal hydrates. In this study, the residual crystallinity on ball milling of lactose monohydrate (LMH), for periods up to 90min, was evaluated by thermo-analytical techniques (TGA, DSC) and terahertz spectroscopy (THz). In general, the results from one of the DSC analysis and the THz measurements agree showing a monotonous decrease in relative residual crystallinity with milling time (~80% reduction after 60min milling) and a slight increase at the 90min time point. However, the estimates from TGA and two other methods of analyzing DSC curve do not agree with the former techniques and show variability with significantly higher estimates for crystallinity. It was concluded that, the thermal techniques require more complex treatment of the data in the evaluation of changes in crystallinity of a milled material (in particular to account for the de-vitrification and mutarotation of the material that inevitably occurs during the measurement cycle) while the analysis of THz data is more straightforward, with the measurement having no impact on the native state of the material. PMID- 25784571 TI - Meta-Analysis of the Prevalence of Unacknowledged Rape. AB - Many sexual violence survivors do not label their experiences as rape but instead use more benign labels, such as "bad sex" or "miscommunication." A meta-analysis was conducted to estimate the mean prevalence of unacknowledged rape and to inform our understanding of methodological factors that influence the detection of this phenomenon. Studies were identified using PsycINFO, PubMED, and PILOTS and were required to report the percentage of unacknowledged rape that had occurred since the age of 14 among female survivors. Moderator variables included mean participant age, recruitment source, rape definition, and unacknowledged rape definition. Twenty-eight studies (30 independent samples) containing 5,917 female rape survivors met the inclusion criteria. Based on a random effects model, the overall weighted mean percentage of unacknowledged rape was 60.4% (95% confidence interval [55.0%, 65.6%]). There was a large amount of heterogeneity, Q(29) = 445.11, p < .001, and inconsistency (I(2) = 93.5%) among included studies. The prevalence was significantly higher among college student participants compared to noncollege participants. The findings supported that over half of all female rape survivors do not acknowledge that they have been raped. The results suggest that screening tools should use behaviorally descriptive items about sexual contact, rather than using terms such as "rape." PMID- 25784572 TI - The impact of community-based health insurance on utilization and out-of-pocket expenditures in Lao People's Democratic Republic. AB - Community-based health insurance in Lao People's Democratic Republic targets the informal workforce. Estimates of the program's impact on utilization and out-of pocket expenditures (OOPs) were obtained using a case-comparison study of 3000 households (14 804 individuals) in urban and semi-urban areas. We used propensity score matching to control for bias on observables and to account for heterogeneity. We check the sensitivity of the results using a weighted regression combined with propensity score matching, which leads to doubly robust treatment effect estimates. The results are robust across the two approaches and show that the insured have significantly higher utilization, lower OOPs and lower incidence of catastrophic expenditures, and are less likely to employ coping mechanisms. However, coverage of the scheme is extremely low, indicating negligible population level impact. Furthermore, the results show that the scheme provides greater protection to the better off than to the poor: the poor are less likely to enrol, and among the poor who are enrolled, there has been no significant impact on utilization of outpatient services, total OOPs or catastrophic expenditures. We discuss the policy implications in the context of the international debate regarding the prospects for the role of community-based health insurance in national financing strategies. PMID- 25784574 TI - Priming analogical reasoning with false memories. AB - Like true memories, false memories are capable of priming answers to insight based problems. Recent research has attempted to extend this paradigm to more advanced problem-solving tasks, including those involving verbal analogical reasoning. However, these experiments are constrained inasmuch as problem solutions could be generated via spreading activation mechanisms (much like false memories themselves) rather than using complex reasoning processes. In three experiments we examined false memory priming of complex analogical reasoning tasks in the absence of simple semantic associations. In Experiment 1, we demonstrated the robustness of false memory priming in analogical reasoning when backward associative strength among the problem terms was eliminated. In Experiments 2a and 2b, we extended these findings by demonstrating priming on newly created homonym analogies that can only be solved by inhibiting semantic associations within the analogy. Overall, the findings of the present experiments provide evidence that the efficacy of false memory priming extends to complex analogical reasoning problems. PMID- 25784575 TI - The state of cancer care in america, 2015: a report by the american society of clinical oncology. PMID- 25784576 TI - Estimating demand and unmet need for allogeneic hematopoietic cell transplantation in the United States using geographic information systems. AB - PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used therapy for many patients with hematologic malignancies and other marrow failure or immune system disorders. The purpose of this study was to quantify and visualize both the demand and unmet need for HCT. METHODS: HCT use for 2012 was described using the Center for International Blood and Marrow Transplant Research registry. Potential demand for HCT was calculated using 2012 SEER data and published literature for HCT-treatable conditions. Point locations of transplant centers were geocoded using geographic information system (GIS) software; Thiessen polygons were created to establish adult (age 20 to 74 years) and pediatric (age 0 to 19 years) market areas. Market-area population estimates were calculated using 2012 population estimates by age aggregated by census block. RESULTS: US market areas for HCTs were identified separately for transplant centers treating adult (n = 62) and pediatric patients (n = 52). Overall HCT demand among adults was 16,096, with an unmet need for HCTs of 10,276 patients. For pediatric patients, the total demand was 4,561, with an unmet need of 3,213 potential recipients. Evaluation of adult and pediatric market areas indicated that the largest unmet needs tended to be in areas with large populations. CONCLUSION: Market-area maps and statistics developed using GIS will help communicate the unmet need for HCT, inform policy, and assist transplant centers in planning for the anticipated growth in HCT use. PMID- 25784577 TI - Systematic approach to providing breast cancer survivors with survivorship care plans: a feasibility study. AB - PURPOSE: This was a feasibility study with the primary purpose to identify women with a diagnosis of breast cancer for survivorship care plan (SCP) delivery at the postoperative visit and deliver an SCP after treatment. The secondary purpose was to determine if patients' knowledge about their diagnosis, treatment, and risk for future adverse events improved with the SCP. METHODS: Sixty-seven English-speaking women older than age 18 years with stage I-III breast cancer were enrolled at their postoperative appointment. The participants' treatment was tracked through the electronic medical record; SCPs were generated based on information abstracted from the records. After treatment completion, participants received an SCP during a routine follow-up appointment. Knowledge of tumor, treatments, adverse events, and screening recommendations were assessed before receiving the SCP and 2 months later. Accuracy at baseline and follow-up were compared using the McNemar test. RESULTS: One hundred twenty-nine visits were screened to identify 75 eligible participants. Seventy-five eligible participants (100%) agreed to enroll, and 71 (95%) were given an SCP. Participants were more accurate in reporting details about their history, screening recommendations, and potential adverse events at follow-up than they were at baseline for most measures, but the only statistically significant changes were found with stage (P = .0016) and increased risk of leukemia (P = .0348). CONCLUSION: It is feasible to identify and deliver SCPs to women with breast cancer who are approached during the postoperative visit in a surgical clinic. Additionally, SCPs seem to improve patient knowledge in several areas. PMID- 25784578 TI - Challenges faced by pediatric oncology fellows when patients die during their training. AB - PURPOSE: Given the paucity of research on the experience of pediatric oncology fellows regarding patient death, the purpose of this study was to explore the specific challenges that pediatric oncology fellows face when patients die during their training. METHODS: Six pediatric oncology fellows at two academic cancer centers in Ontario, Canada, were interviewed about their experiences with patient death during their fellowship training. The grounded theory method of data collection and data analysis was used. Line-by-line coding was used to establish themes, and constant comparison was used to establish relationships among emerging codes and themes. RESULTS: Fellows reported structural challenges that included ward duty and lack of follow-up opportunities with bereaved families. Personal challenges included feelings of vulnerability as a result of being a trainee, inexperience with patient death, and feeling alone with one's reactions to patient death. Relational challenges included duration of relationships with families and with supervising staff and perceived lack of modeling on how to cope with patient deaths. CONCLUSION: Structural changes to the fellowship model can be made in order to enhance support with patient death, including informing fellows of all patient deaths and incorporating fellows into follow-up practices with bereaved families. Moreover, integrating fellows' debriefing (facilitated by grief counselors) after a patient death into fellow training, as well as greater involvement with palliative care physicians, can lessen feelings of isolation and help fellows learn effective strategies for dealing with patient deaths from experienced palliative care physicians. PMID- 25784579 TI - Outcomes and satisfaction after delivery of a breast cancer survivorship care plan: results of a multicenter trial. AB - PURPOSE: Survivorship care plans (SCPs) have been suggested to reduce fragmentation of care experienced by cancer survivors. Acceptance of SCPs is high, but trials in the United States are few. This pilot study used a quasiexperimental design to examine the outcomes achieved by breast cancer survivors receiving a standardized SCP visit at one of seven comprehensive cancer centers. MATERIALS AND METHODS: Outcomes were assessed before and again 3 months after delivery of an SCP and included survivors' use of and satisfaction with SCPs, perceived knowledge about survivorship, and assessment of the quality and coordination of survivorship care. RESULTS: One hundred thirty-nine survivors of breast cancer completed baseline and follow-up measures and received a standardized SCP visit. Participants most commonly used SCP materials to make decisions about exercise (64%), which tests to receive and when (62%), and dietary changes (62%). Only 21% shared the SCP with their primary care provider during that time. Satisfaction with the SCP was high, with 90% of participants reporting being at least satisfied with the SCP. Perceived knowledge about survivorship improved after SCP delivery, as did perceived care coordination and the provider's knowledge of the effects of cancer on survivors (all P < .001). Individuals closer to the time of diagnosis reported greater satisfaction with and use of SCPs. CONCLUSION: This study demonstrates improvements in perceived knowledge and quality of survivorship care after receipt of a comprehensive SCP. Survivors were satisfied with their SCP, and those closer to diagnosis reported greater satisfaction with and use of the materials. PMID- 25784580 TI - Perceptions of palliative care among hematologic malignancy specialists: a mixed methods study. AB - PURPOSE: Patients with hematologic malignancies are less likely to receive specialist palliative care services than patients with solid tumors. Reasons for this difference are poorly understood. METHODS: This was a multisite, mixed methods study to understand and contrast perceptions of palliative care among hematologic and solid tumor oncologists using surveys assessing referral practices and in-depth semistructured interviews exploring views of palliative care. We compared referral patterns using standard statistical methods. We analyzed qualitative interview data using constant comparative methods to explore reasons for observed differences. RESULTS: Among 66 interviewees, 23 oncologists cared exclusively for patients with hematologic malignancies; 43 treated only patients with solid tumors. Seven (30%) of 23 hematologic oncologists reported never referring to palliative care; all solid tumor oncologists had previously referred. In qualitative analyses, most hematologic oncologists viewed palliative care as end-of-life care, whereas most solid tumor oncologists viewed palliative care as a subspecialty that could assist with complex patient cases. Solid tumor oncologists emphasized practical barriers to palliative care referral, such as appointment availability and reimbursement issues. Hematologic oncologists emphasized philosophic concerns about palliative care referrals, including different treatment goals, responsiveness to chemotherapy, and preference for controlling even palliative aspects of patient care. CONCLUSION: Most hematologic oncologists view palliative care as end-of-life care, whereas solid tumor oncologists more often view palliative care as a subspecialty for comanaging patients with complex cases. Efforts to integrate palliative care into hematologic malignancy practices will require solutions that address unique barriers to palliative care referral experienced by hematologic malignancy specialists. PMID- 25784581 TI - Administration of oral chemotherapy: results from three rounds of the quality oncology practice initiative. AB - PURPOSE: Although use of oral chemotherapy is becoming more prevalent, little is known about the quality of care that patients receive when these agents are prescribed. Moreover, few practice-level systems are in place to ensure safe management of oral chemotherapy in the vulnerable population of patients with cancer. METHODS: We analyzed results from 155 practices that were voluntarily participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) program on 17 test measures of oral chemotherapy administration and management in at least one of three collection periods: spring or fall of 2012, or spring of 2013. The 17 test measures cover three domains: treatment plan documentation, patient education, and adherence/toxicity monitoring. We defined composite scores for each of the three domains. We analyzed the composite scores by secular trend and tested the difference in composite scores for the three domains. Additionally, we tested change in scores over time among practices that participated at least twice. RESULTS: The majority of data was provided by QOPI-certified practices. Overall, mean practice composite scores ranged from 66% to 68% for treatment plan documentation, 51% to 57% for patient education, and 75% to 81% for adherence/toxicity monitoring. Composite scores for practices that participated more than once did not improve significantly. CONCLUSION: The collection of oral chemotherapy test measure data is feasible. Composite scores for treatment plan documentation and patient education were not only lower, but had greater variability compared with adherence/toxicity monitoring. Improvement opportunities exist for patients who are prescribed oral chemotherapy. PMID- 25784582 TI - Improving incidence of code status documentation through process and discipline. AB - Documentation of a patient's preferred code status is a critical outcome of advance care planning. Although there is agreement that code status is valuable information, little progress has been made to increase the incidence of documented code status within the medical record in an outpatient setting. Incidence of code status documentation in the community oncology setting has not been studied. In April 2013, the US Oncology Network and McKesson Specialty Health launched a new advance care planning initiative for the purpose of promoting conversations between clinicians and patients regarding end-of-life care preferences. The program-My Choices, My Wishes-provides a systematic approach for learning about and documenting a patient's values and goals for care in the electronic health record. Code status documentation is one of several program performance measures. During the 14-month period from August 1, 2013, through September 30, 2014, collective sites participating in My Choices, My Wishes included discrete code status documentation within the medical record for 5,467 patients with metastatic disease. Although much work remains, early results show promise for improvement in incidence of code status documentation within health records in the outpatient setting. PMID- 25784583 TI - Exercise-induced downbeat nystagmus in a Korean family with a nonsense mutation in CACNA1A. AB - Episodic ataxia type 2 (EA2) is characterized by recurrent attacks of vertigo and ataxia lasting hours triggered by emotional stress or exercise. Although interictal horizontal gaze-evoked nystagmus and rebound nystagmus are commonly observed in patients with EA2, the nystagmus has been rarely reported during the vertigo attack. To better describe exercise-induced nystagmus in EA2, four affected members from three generations of a Korean family with EA2 received full neurological and neuro-otological evaluations. Vertigo was provoked in the proband with running for 10 min to record eye movements during the vertigo attack. We performed a polymerase chain reaction-based direct sequence analysis of all coding regions of CACNA1A in all participants. The four affected members had a history of exertional vertigo, imbalance, childhood epilepsy, headache, and paresthesia. The provocation induced severe vertigo and imbalance lasting several hours, and oculography documented pure downbeat nystagmus during the attack. Genetic analyses identified a nonsense mutation in exon 23 which has been registered in dbSNP as a pathogenic allele (c.3832C>T, p.R1278X) in all the affected members. Ictal downbeat nystagmus in the studied family indicates cerebellar dysfunction during the vertigo attack in EA2. In patients with episodic vertigo and ataxia, the observation of exercise-induced nystagmus would provide a clue for EA2. PMID- 25784585 TI - Targeting the erythrocytic and liver stages of malaria parasites with s-triazine based hybrids. AB - A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials. PMID- 25784584 TI - Engineering the ovarian cycle using in vitro follicle culture. AB - STUDY QUESTION: Can cultured follicles model the ovarian cycle, including follicular- and luteal-phase hormone synthesis patterns and ovulation? SUMMARY ANSWER: Under gonadotrophin stimulation, murine follicles grown in an encapsulated three-dimensional system ovulate in vitro and murine and human follicle hormone synthesis mimics follicular and luteal phases expected in vivo. WHAT IS KNOWN ALREADY: Studies of the human ovary and follicle function are limited by the availability of human tissue and lack of in vitro models. We developed an encapsulated in vitro follicle growth (eIVFG) culture system, which preserves 3D follicular structure. Thus far, the alginate system has supported the culture of follicles from mice, dog, rhesus macaque, baboon and human. These studies have shown that cultured follicles synthesize steroid hormones similar to those observed during the follicular phase in vivo. STUDY DESIGN, SIZE, DURATION: Cultured murine follicles were treated with human chorionic gonadotrophin (hCG) and epidermal growth factor (EGF) and either assayed for luteinization or removed from alginate beads and assayed for ovulation. Human follicles were also cultured, treated with follicle-stimulating hormone (FSH), hCG and EGF to mimic gonadotrophin changes throughout the ovarian cycle, and culture medium was assayed for hormone production. PARTICIPANTS/MATERIALS, SETTING, METHODS: Murine and human follicles were cultured in alginate hydrogel and hormone production [17beta-estradiol, progesterone, inhibin A, inhibin B, activin A and anti Mullerian hormone (AMH)] was quantified in medium by enzyme-linked immuno assay (ELISA). Human ovarian tissue was acquired from females between 6 and 34 years of age with a cancer diagnosis. These participants were undergoing ovarian tissue cryopreservation at National Physicians Cooperative sites as part of the Oncofertility Consortium. MAIN RESULTS AND THE ROLE OF CHANCE: When grown in this system, 96% of mouse follicles ovulated in response to hCG and released meiotically competent eggs. Ovulated follicles recapitulated transcriptional, morphologic and hormone synthesis patterns post-luteinizing hormone (LH/hCG). In addition to rodent follicles, individual human follicles secreted steroid and peptide hormones that mimicked the patterns of serum hormones observed during the menstrual cycle. LIMITATIONS, REASONS FOR CAUTION: This was a descriptive study of an in vitro model of ovulation and the ovarian hormone cycle. The ovulation studies were limited to murine tissue and further studies are needed to optimize conditions using other species. WIDER IMPLICATIONS OF THE FINDINGS: The eIVFG system reliably phenocopies the in vivo ovarian cycle and provides a new tool to study human follicle biology and the influence of cycling female hormones on other tissue systems in vitro. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIH U54 HD041857, NIH U54 HD076188, NIH UH2 E5022920, NIH UH3 TR001207 and F30 AG040916 (R.M.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. PMID- 25784586 TI - Velocity valleys enable efficient capture and spatial sorting of nanoparticle bound cancer cells. AB - The development of strategies for isolating rare cells from complex matrices like blood is important for a wide variety of applications including the analysis of bloodborne cancer cells, infectious pathogens, and prenatal testing. Due to their high colloidal stability and surface-to-volume ratio, antibody-coated magnetic nanoparticles are excellent labels for cellular surface markers. Unfortunately, capture of nanoparticle-bound cells at practical flow rates is challenging due to the small volume, and thus low magnetic susceptibility, of magnetic nanoparticles. We have developed a means to capture nanoparticle-labeled cells using microstructures which create pockets of locally low linear velocity, termed velocity valleys. Cells that enter a velocity valley slow down momentarily, allowing the magnetic force to overcome the reduced drag force and trap the cells. Here, we describe a model for this mechanism of cell capture and use this model to guide the rational design of a device that efficiently captures rare cells and sorts them according to surface expression in complex matrices with greater than 10,000-fold specificity. By analysing the magnetic and drag forces on a cell, we calculate a threshold linear velocity for capture and relate this to the capture efficiency. We find that the addition of X-shaped microstructures enhances capture efficiency 5-fold compared to circular posts. By tuning the linear velocity, we capture cells with a 100-fold range of surface marker expression with near 100% efficiency and sort these cells into spatially distinct zones. By tuning the flow channel geometry, we reduce non-specific cell adhesion by 5-fold. PMID- 25784587 TI - Potential contributions of training intensity on locomotor performance in individuals with chronic stroke. AB - BACKGROUND AND PURPOSE: Many interventions can improve walking ability of individuals with stroke, although the training parameters that maximize recovery are not clear. For example, the contribution of training intensity has not been well established and may contribute to the efficacy of many locomotor interventions. The purpose of this preliminary study was to evaluate the effects of locomotor training intensity on walking outcomes in individuals with gait deficits poststroke. METHODS: Using a randomized cross-over design, 12 participants with chronic stroke (>6-month duration) performed either high intensity (70%-80% of heart rate reserve; n = 6) or low-intensity (30%-40% heart rate reserve; n = 6) locomotor training for 12 or fewer sessions over 4 to 5 weeks. Four weeks following completion, the alternate training intervention was performed. Training intensity was manipulated by adding loads or applying resistance during walking, with similar speeds, durations, and amount of stepping practice between conditions. RESULTS: Greater increases in 6-Minute Walk Test performance were observed following high-intensity training compared with low intensity training. A significant interaction of intensity and order was also observed for 6-Minute Walk Test and peak treadmill speed, with the largest changes in those who performed high-intensity training first. Moderate correlations were observed between locomotor outcomes and measures of training intensity. CONCLUSION: This study provides the first evidence that the intensity of locomotor practice may be an important independent determinant of walking outcomes poststroke. In the clinical setting, the intensity of locomotor training can be manipulated in many ways, although this represents only 1 parameter to consider.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A90). PMID- 25784588 TI - CB[8] gated photochromism of a diarylethene derivative containing thiazole orange groups. AB - Photochromism in a diarylethene derivative (1O) can be gated by a host-guest interaction where the thiazole orange groups are bound into the hydrophobic cavity of CB[8] in water. The closed-ring isomer (1C), which cannot be obtained freely in aqueous solution, survives even when the complex is dissociated by displacement from CB[8] by competition with 1-adamantanamine hydrochloride. PMID- 25784590 TI - Erectile dysfunction in urethral stricture and pelvic fracture urethral injury patients: diagnosis, treatment, and outcomes. AB - Urethral stricture disease, pelvic fracture urethral injury (PFUI), and their various treatment options are associated with erectile dysfunction (ED). The etiology of urethral stricture disease is multifactorial and includes trauma, inflammatory, and iatrogenic causes. Posterior urethral injuries are commonly associated with pelvic fractures. There is a spectrum in the severity of both conditions and this directly impacts the treatment options offered by the surgeon. Many published studies focus on the treatment outcomes and the relatively high recurrence rates after surgical repair. This communication reviews the current knowledge of the association between ED and urethral stricture disease, as well as PFUI. The incidence, pathophysiology, and clinical ramifications of both conditions on sexual function are discussed. The treatment options for ED in those patients are reviewed and summarized. PMID- 25784589 TI - Segmentation of Retinal Layers in Sjogren-Larsson Syndrome. PMID- 25784591 TI - Sequencing current therapies in the treatment of metastatic prostate cancer. AB - The standard treatment for metastatic prostate cancer is androgen deprivation therapy. However, progressive, metastatic disease usually develops, giving rise to metastatic castration-resistant prostate cancer (mCRPC). Great improvements have been made recently in the management of mCRPC, with current approved treatments including chemotherapy, androgen receptor-targeted agents, immunotherapies and radiopharmaceuticals. While the emergence of multiple effective therapies is encouraging, devising a treatment strategy can be difficult and it is becoming increasingly important, and challenging, to identify factors that influence the ideal timing of specific therapies. Considering where to place these agents in the treatment schedule of mCRPC, or whether these agents should be sequenced or combined to derive the optimal benefit for the patient, is not yet clear. Furthermore, cross-resistance may exist between these agents, which may ultimately influence treatment decisions and sequence choices. Preliminary data are emerging regarding the safety and activity for sequential treatment regimens, but there are currently no prospective studies. As prostate cancer is highly heterogeneous clinically, it is likely that no single treatment sequence will be optimal for all patients. However, at present, there are no validated biomarkers to guide individualized treatment for mCRPC. Here we review available data for the different mCRPC treatments, discussing potential sequencing of agents and possible cross-resistance or synergy among the recently approved and emerging therapies. PMID- 25784592 TI - Vortex chain in a resonantly pumped polariton superfluid. AB - Exciton-polaritons are light-matter mixed states interacting via their exciton fraction. They can be excited, manipulated, and detected using all the versatile techniques of modern optics. An exciton-polariton gas is therefore a unique platform to study out-of-equilibrium interacting quantum fluids. In this work, we report the formation of a ring-shaped array of same sign vortices after injection of angular momentum in a polariton superfluid. The angular momentum is injected by a l = 8 Laguerre-Gauss beam. In the linear regime, a spiral interference pattern containing phase defects is visible. In the nonlinear (superfluid) regime, the interference disappears and eight vortices appear, minimizing the energy while conserving the quantized angular momentum. The radial position of the vortices evolves in the region between the two pumps as a function of the density. Hydrodynamic instabilities resulting in the spontaneous nucleation of vortex-antivortex pairs when the system size is sufficiently large confirm that the vortices are not constrained by interference when nonlinearities dominate the system. PMID- 25784593 TI - Value of a risk scoring tool to predict respiratory syncytial virus disease severity and need for hospitalization in term infants. AB - Several environmental and demographic risk factors have been validated and are used to determine the risk of acquiring severe respiratory syncytial virus (RSV) infection and subsequent hospitalization in late preterm infants born at 33-35 weeks gestational age. The applicability of the same composite model of risk factors in the term population has not been fully explored. The primary objective of this pilot study was to establish whether a risk scoring tool (RST), could predict the severity of RSV infection in term, RSV-positive infants who were hospitalized. A retrospective observational study was conducted in a pediatric unit, over 2 RSV seasons (2011-2013). A convenient sample of 72 children was selected out of a total of 111 RSV-positive cases after exclusions. The RST was applied and a score of respiratory disease severity was determined for each patient. Demographic characteristics were analyzed by standard descriptive methods, chi(2) analysis was utilized for categorical data and ANOVA for comparison between the clinical severity groups and the RST score. A P-value <0.05 was considered significant. Sixty per cent (n = 43) of all infants scored in the low-risk category compared to 26% (n = 19) in the moderate and 14% (n = 10) in the high-risk groups. RST scores were also inconsistent with disease severity. Mean (SD) RST scores for those with mild, moderate, and severe illness were 47.8 [16.4], 41.1 [20.39] and, 41.7 [19.8], respectively (P = 0.17). In conclusion, the RST did not predict accurately the clinical severity of RSV bronchiolitis in term infants nor did it correlate with risk for RSV-related hospitalization. PMID- 25784594 TI - Solid aneurysmal bone cyst on the cervical spine of a young child. AB - INTRODUCTION: Solid aneurysmal bone cyst (S-ABC) is a variant of aneurysmal bone cyst (ABC), an uncommon benign bone tumor. There are few cases described in the cervical spine in kids up today. We treated a recurrent case with neurological involvement that needed multiple surgical procedures and radiotherapy. CASE PRESENTATION: We report a case of C4 located S-ABC concerning a 2-year-old boy treated surgically by anterior and posterior approach. Three months after the initial procedure appearance of a tetraparesis led to diagnose a local recurrence treated by sclerotherapy and a second surgery. The patient had a full neurological recovery. Three months later, a follow-up CT scan showed a second recurrence requiring a new surgical revision by anterior approach and radiotherapy. OUTCOME: At 6-year follow-up after four surgical procedures, sclerotherapy and radiotherapy, the aneurysmal bone cyst has been healed. Patient had neurological impairment after a local recurrence but had full recovered after final revision surgery. PMID- 25784595 TI - Effects of shear force on intervertebral disc: an in vivo rabbit study. AB - PURPOSE: A new in vivo rabbit model was developed to investigate the effects of shear force on intervertebral disc (IVD). METHODS: Japanese white rabbits (n = 38) were used for this study. The L4/5 discs in Group A (n = 10) were subjected to a constant shear force (50 N) using a custom-made external loading device for 1 month; in Group B (n = 10) for 2 months; whereas in Group C (n = 10), loading device was attached to the spine but the discs remained unloaded. Group D (n = 8) was a non-operated intact control group. After loading, the loading devices were taken out and the animals were given X-ray and MRI examination. After X-ray and MRI examination, the animals were euthanized for histological analysis. RESULTS: After 1 and 2 months of loading, radiographic findings showed significant disc height narrowing in L4/5 discs of the animals in loading groups, and slight lumbar spondylolisthesis in some animals of Group B. MRI showed a significant decrease in nucleus pulposus (NP) area and signal intensity from T2-weighted images. Histologically, loss of normal NP cells and disorganization of the architecture of the annulus occurred, and proteoglycan stain decreased. CONCLUSIONS: The results of this study suggest that disc degeneration can be induced by hyper-physiological shear loading in the rabbit IVD. Long-term shear loading may result in structural disc failure inducing lumbar spondylolisthesis and progressive disc degeneration, which, however, has to be proven by further studies. PMID- 25784596 TI - Sagittal alignment of cervical spine in adult idiopathic scoliosis. AB - PURPOSE: Alignment of the cervical spine (CS) in adolescent idiopathic scoliosis (IS) as well as in asymptomatic adult populations has recently been studied and described as being less lordotic in the adolescent IS population. However, few studies have examined the sagittal alignment of the CS in adult IS or its association with other radiological variables and clinical relevance. The aim of this study is to analyse the sagittal alignment of CS in adult IS and its association with age, alignment of the thoracic, lumbar and global spinal column as well as health-related quality of life (HRQOL) parameters. METHODS: A retrospective review of prospectively collected data from a multicenter database was performed. Of 468 consecutive adult IS patients, 213 were included in the study; the remainder were excluded due to poor quality X-rays where the CS was not properly visible, or previous surgery. X-rays were measured for the following CS parameters: [Cranial base-C2 (C0-C2) lordosis, C2-C7 lordosis, thoracic (T1) slope, thoracic inlet angle (TIA) and odontoid (Od)-T1 offset using a measurement software]. These measurements were then evaluated for possible associations with patient age and with pre-existing alignment parameters and HRQOL scores using Pearson correlation tests. RESULTS: The average and standard deviations for CS alignment parameters were 32.3 degrees +/- 10.2 degrees for C0-C2; 5.7 degrees +/- 14.1 degrees for C2-C7; 23.9 degrees +/- 11.3 degrees for T1 slope, 70.5 degrees +/- 14.7 degrees for TIA and 20.8 degrees +/- 16.5 degrees for Od-T1 offset. CS alignment showed a significant (p < 0.05) correlation with age, T kyphosis and several other sagittal alignment parameters such as sagittal vertical axis (SVA), global tilt and T1 sagittal tilt, but not with the HRQOL parameters. CONCLUSION: The sagittal alignment of the CS in adult IS is less lordotic than the normal average while less kyphotic than that of IS of a younger age. It correlates with age, thoracic kyphosis and some global sagittal alignment parameters. These findings suggest that CS alignment is likely a component of the global sagittal alignment strongly affected by thoracic kyphosis, and most probably does not affect HRQOL by itself. PMID- 25784598 TI - Macromolecular surface design: photopatterning of functional stable nitrile oxides. AB - The efficient trapping of photogenerated thioaldehydes with functional shelf stable nitrile oxides in a 1,3-dipolar cycloaddition is a novel and versatile photochemical strategy for polymer end-group functionalization and surface modification under mild and equimolar conditions. The modular ligation in solution was followed in detail by electrospray ionization mass spectrometry (ESI MS). X-ray photoelectron spectroscopy (XPS) was employed to analyze the functionalized surfaces, whereas time-of-flight secondary-ion mass spectrometry (ToF-SIMS) confirmed the spatial control of the surface functionalization using a micropatterned shadow mask. Polymer brushes were grown from the surface in a spatially confined regime by surface-initiated atom transfer radical polymerization (SI-ATRP) as confirmed by TOF-SIMS, XPS as well as ellipsometry. PMID- 25784599 TI - Increased effect of IMiDs by addition of cytokine-induced killer cells in multiple myeloma. AB - Immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide and pomalidomide, represent the basic principle of multiple myeloma treatment. However, the development of resistance is a limiting factor. Over the last years, the efficient application of cytokine-induced killer (CIK) cells has been reported as an alternative strategy to treat hematological neoplasms. In this study, we tested for a potential synergistic effect by combining the IMiDs thalidomide, lenalidomide and pomalidomide with CIK cells in different myeloma cell lines in vitro. Myeloma cells tested with CIK cells were significantly reduced. In the combination, myeloma cells were significantly reduced compared with cells only tested with IMiDs but not to the cells tested with CIK cells. Otherwise, the number of CIK cells was significantly reduced when treated with IMiDs. Because IMiDs are active in patients with myeloma, these results lead to the expectation that combination of IMiDs and CIK cells achieve better results in the treatment of multiple myeloma compared with the single use of IMiDs. Therefore, further examinations in an in vivo setting are necessary to have a closer look on the cellular interactions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25784600 TI - Classic hallucinogens in the treatment of addictions. AB - Addictive disorders are very common and have devastating individual and social consequences. Currently available treatment is moderately effective at best. After many years of neglect, there is renewed interest in potential clinical uses for classic hallucinogens in the treatment of addictions and other behavioral health conditions. In this paper we provide a comprehensive review of both historical and recent clinical research on the use of classic hallucinogens in the treatment of addiction, selectively review other relevant research concerning hallucinogens, and suggest directions for future research. Clinical trial data are very limited except for the use of LSD in the treatment of alcoholism, where a meta-analysis of controlled trials has demonstrated a consistent and clinically significant beneficial effect of high-dose LSD. Recent pilot studies of psilocybin-assisted treatment of nicotine and alcohol dependence had strikingly positive outcomes, but controlled trials will be necessary to evaluate the efficacy of these treatments. Although plausible biological mechanisms have been proposed, currently the strongest evidence is for the role of mystical or other meaningful experiences as mediators of therapeutic effects. Classic hallucinogens have an excellent record of safety in the context of clinical research. Given our limited understanding of the clinically relevant effects of classic hallucinogens, there is a wealth of opportunities for research that could contribute important new knowledge and potentially lead to valuable new treatments for addiction. PMID- 25784597 TI - HIF-1 at the crossroads of hypoxia, inflammation, and cancer. AB - The complex cross-talk of intricate intercellular signaling networks between the tumor and stromal cells promotes cancer progression. Hypoxia is one of the most common conditions encountered within the tumor microenvironment that drives tumorigenesis. Most responses to hypoxia are elicited by a family of transcription factors called hypoxia-inducible factors (HIFs), which induce expression of a diverse set of genes that assist cells to adapt to hypoxic environments. Among the three HIF protein family members, the role of HIF-1 is well established in cancer progression. HIF-1 functions as a signaling hub to coordinate the activities of many transcription factors and signaling molecules that impact tumorigenesis. This mini review discusses the complex role of HIF-1 and its context-dependent partners under various cancer-promoting events including inflammation and generation of cancer stem cells, which are implicated in tumor metastasis and relapse. In addition, the review highlights the importance of therapeutic targeting of HIF-1 for cancer prevention. PMID- 25784601 TI - Self-harm in schizophrenia is associated with dorsolateral prefrontal and posterior cingulate activity. AB - Self-harm, such as self-cutting, self-poisoning or jumping from height, regardless of intentions, is common among people with schizophrenia. We wished to investigate brain activations relating to self-harm, in order to test whether these activations could differentiate between schizophrenia patients with self harm and those without. We used event-related functional MRI with a go/no-go response inhibition paradigm. Fourteen schizophrenia patients with a history of self-harm were compared with 14 schizophrenia patients without a history of self harm and 17 healthy control participants. In addition, we used standard clinical measures and neuropsychological tests to assess risk factors associated with self harm. The right dorsolateral prefrontal cortex (DLPFC) and the left posterior cingulate cortex differentiated all three groups; brain activation in these regions being greatest in the control group, and the self-harm patient group being greater than in the non-self-harm patient group. In the self-harm patient group, right DLPFC activity was positively correlated with severity of suicidal thinking. In addition, both patient groups showed less activation in the right orbitofrontal cortex, left ventral anterior cingulate cortex and right thalamus. This is the first study to report right DLPFC activation in association with self harm and suicidal thinking in patients with schizophrenia. This area could be a target for future neuromodulation studies to treat suicidal thinking and self harm behaviors in patients with schizophrenia. PMID- 25784602 TI - Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism. AB - The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy. PMID- 25784603 TI - Hippocampal transcriptional and neurogenic changes evoked by combination yohimbine and imipramine treatment. AB - Adjunct alpha2-adrenoceptor antagonism is a potential strategy to accelerate the behavioral effects of antidepressants. Co-administration of the alpha2 adrenoceptor antagonist yohimbine hastens the behavioral and neurogenic effects of the antidepressant imipramine. We examined the transcriptional targets of short duration (7days), combination treatment of yohimbine and imipramine (Y+I) within the adult rat hippocampus. Using microarray and qPCR analysis we observed functional enrichment of genes involved in intracellular signaling cascades, plasma membrane, cellular metal ion homeostasis, multicellular stress responses and neuropeptide signaling pathways in the Y+I transcriptome. We noted reduced expression of the alpha2A-adrenoceptor (Adra2a), serotonin 5HT2C receptor (Htr2c) and the somatostatin receptor 1 (Sstr1), which modulate antidepressant action. Further, we noted a regulation of signaling pathway genes like inositol monophosphatase 2 (Impa2), iodothyronine deiodinase 3 (Dio3), regulator of G protein signaling 4 (Rgs4), alkaline ceramidase 2 (Acer2), doublecortin-like kinase 2 (Dclk2), nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (Nfkbia) and serum/glucocorticoid-regulated kinase 1 (Sgk1), several of which are implicated in the pathophysiology of mood disorders. Comparative analysis revealed an overlap in the hippocampal regulation of Acer2, Nfkbia, Sgk1 and Impa2 between Y+I treatment, the fast-acting electroconvulsive seizure (ECS) paradigm, and the slow-onset chronic (21days) imipramine treatment. Further, Y+I treatment enhanced the quiescent neural progenitor pool in the hippocampal neurogenic niche similar to ECS, and distinct from chronic imipramine treatment. Taken together, our results provide insight into the molecular and cellular targets of short duration Y+I treatment, and identify potential leads for the development of rapid-action antidepressants. PMID- 25784605 TI - How the vortex lattice of a superconductor becomes disordered: a study by scanning tunneling spectroscopy. AB - Order-disorder transitions take place in many physical systems, but observing them in detail in real materials is difficult. In two- or quasi-two-dimensional systems, the transition has been studied by computer simulations and experimentally in electron sheets, dusty plasmas, colloidal and other systems. Here I show the different stages of defect formation in the vortex lattice of a superconductor while it undergoes an order-disorder transition by presenting real space images of the lattice from scanning tunneling spectroscopy. When the system evolves from the ordered to the disordered state, the predominant kind of defect changes from dislocation pairs to single dislocations, and finally to defect clusters forming grain boundaries. Correlation functions indicate a hexatic-like state preceding the disordered state. The transition in the microscopic vortex distribution is mirrored by the well-known spectacular second peak effect observed in the macroscopic current density of the superconductor. PMID- 25784604 TI - The effect of temporary meiotic attenuation on the in vitro maturation outcome of bovine oocytes. AB - The aim of this study was to investigate the effect of delaying maturation by extended culture of immature bovine oocytes in prematuration medium (PMC) containing single maturation inhibitor on their meiotic resumption and embryonic development. Bovine immature oocytes were cultured in M199 containing 10 MUM of either inhibitor (roscovitine, cilostamide, or forskolin) for either 72 or 120 h followed by up to 48 h in maturation media supplemented with 7.5 IU follicle stimulating hormone (FSH)/luteinizing hormone (LH). Two control groups were used. In untreated control, immature oocytes were cultured in the same medium as the experimental group without any inhibitors. In the FSH/LH control group, oocytes were cultured directly in the maturation medium supplemented with FSH/LH up to 48 h. In vitro matured oocytes were then inseminated with frozen-thawed bull sperm. Fertilization, defined as two-cell division 48 h post-insemination, and blastocyst formation were recorded. Total maturation rate for the 72-h group was 73%, 70%, 66%, and 69% for roscovitine, forskolin, cilostamide, and FSH/LH control, respectively, with no significant difference indicating that inhibitors have no negative effect on the oocyte maturation rate. The total fertilization rate for the 72-h group revealed that cilostamide (47%) and roscovitine (35%) were significantly higher than FSH/LH control (20%). The total blastocyst formation rates per inseminated oocytes revealed that among treatment groups, roscovitine (20%) had significantly higher rate than forskolin (9%). Overall, 72 h exposure period had better outcomes than 120 h in all the treated groups. In conclusion, prematuration culture of the bovine oocytes in the presence of maturation inhibitor for 72-h period at 10 MUM concentration is sufficient in improving the bovine oocyte developmental competence. PMID- 25784606 TI - Detection of BRAF mutation in Chinese tumor patients using a highly sensitive antibody immunohistochemistry assay. AB - BRAF mutations can be found in various solid tumors. But accurate and reliable screening for BRAF mutation that is compatible for clinical application is not yet available. In this study, we used an automated immunohistochemistry (IHC) staining coupled with mouse monoclonal anti-BRAF V600E (VE1) primary antibody to screen the BRAF V600E mutation in 779 tumor cases, including 611 colorectal carcinomas (CRC), 127 papillary thyroid carcinomas (PTC) and 41 malignant melanomas. Among the 779 cases, 150 cases were positive for BRAF (V600E) staining, including 38 (of 611, 6%) CRCs, 102 (of 127, 80%) PTCs and 10 (of 41, 24%) malignant melanomas. Sanger sequencing and real-time PCR confirmed the sensitivity and specificity of IHC staining for the V600E mutation are 100% and 99%, respectively. Therefore, our study demonstrates that the fully automated IHC is a reliable tool to determine BRAF mutation status in CRC, PTC and melanoma and can be used for routine clinical screen. PMID- 25784607 TI - Suspended solids and total phosphorus loads and their spatial differences in a lake-rich river basin as determined by automatic monitoring network. AB - Turbidity datasets recorded by sensors during 2009-2012 were collected in five observation sites in the 2046-km2 Karjaanjoki River Basin in southern Finland. From these and water sample-based data, total phosphorus (TP) and total suspended solids (TSS) fluxes were determined. Based on calculations made with combined sensor- and water sample-based dataset, the annual loading from the Karjaanjoki Basin in 2009-2012 varied between 11,300 and 23,900[corrected] kg of TP and 3300 8400 t of TSS. As compared with two other river basins discharging into the Baltic Sea in southern Finland, the TP loading from Karjaanjoki was low because the summed retention in the two major lakes Hiidenvesi and Lohjanjarvi was high: 48 and 49% of the TSS and TP loadings generated in their upstream catchments, respectively. Depending on how water sampling took place in relation to peak flow events, differences of annual fluxes as determined by "water samples only" vs. "sensors and water samples" data varied between -22 and 26 for TP and -31 and 39% for TSS. This study proved automatic monitoring being useful when spatial differences and lake retention of riverine fluxes are explored. Moreover, the loading estimates calculated on the base of well-functioning and well-maintained automatic monitoring system, supported with water sampling during periods when devices were off, are undoubtedly more accurate than those based on manual grab water sampling only. The findings of this study were in line with, and well contribute to, earlier Finnish and international research on automatic water quality monitoring. PMID- 25784608 TI - Public concerns about and perceptions of solid waste dump sites and selection of sanitary landfill sites in the West Bank, Palestinian territory. AB - Palestinian inhabitants have disposed of their solid wastes at open dumpsites over the past 40 years without an adequate solid waste management (SWM) plans. Recently, the Palestinian Authority initiated SWM planning to establish controlled sanitary landfills, based on a participatory approach. The purpose of this study was to assess public concerns about existing solid waste dumpsites and public perceptions of sanitary landfill site selection. The study will also take into consideration the effect of diverse social, economic, and environmental related factors of the inhabitants on sitting suitable landfill sites in three Palestinian districts in the West Bank, namely, "Nablus," "Salfit," and "Ramallah and Al-Bireh." The results of this study showed that 64.9% of the sample population are aware of the problems and potential impacts associated with random dumpsites, and 41.6% think that they are suffering from the dumps. Among the environmental, socioeconomic, and political factors, the environmental factors, air pollution in particular, are thought be the most important consideration in selecting a landfill site. The "fairness in selecting a landfill site" was chosen to be one of the most important socioeconomic factors, possibly as a reaction to the Israeli occupation and subsequent land use restrictions in the West Bank, Palestinian territory. PMID- 25784609 TI - Solid phase extraction of Cu2+, Ni2+, and Co2+ ions by a new magnetic nano composite: excellent reactivity combined with facile extraction and determination. AB - In the present study, silica magnetite mesoporous nanoparticles functionalized with a new chelating agent were synthesized and introduced as a magnetic solid phase for preconcentration of trace amounts of Cu2+, Ni2+, and Co2+ ions from aqueous solutions. Briefly, MCM-41 mesoporous-coated magnetite nano-particles (MMNPs) with particle size lower than 15 nm were synthesized via chemical co precipitation methods. Then, N-(4-methoxysalicylidene)-4,5-dinitro-1,2 phenylenediamine (HL) as a new chelating agent was synthesized and used for surface modification of mesoporous magnetic solid phase by dispersive liquid liquid functionalization (DLLF) as a new rapid method to form HL functionalized mesoporous magnetite nanoparticles (MMNPs?HL). The structure and morphology of prepared sorbent were characterized by FT-IR, XRD, VSM, and TEM. Finally, the prepared nanoparticles were utilized for preconcentration of Cu2+, Ni2+, and Co2+ ions prior to determination by atomic absorption spectrophotometery. The calibration graph was obtained under the optimized conditions with linear dynamic range of 1.0-300 MUg L(-1) and correlation coefficient (r2) of 0.998. The detection limits of this method for cobalt, nickel, and copper ions were 0.03, 0.03, and 0.04 ng/mL, respectively. Finally, the method was successfully applied to the extraction and determination of the analyte ions in natural waters and reference plant samples. PMID- 25784610 TI - Spectrophotometric characterization of dissolved organic matter in a rural watershed: the Madon River (N-E France). AB - In the last 20 years, increasing dissolved organic carbon (DOC) concentrations have been observed in several rivers and lakes in Europe. This increase has reduced the quality of the aquatic environment. In this study, UV-vis spectroscopy and synchronous fluorescence spectroscopy with a difference of 50 nm between the excitation and emission (SF50) were used to characterize the DOC in a rural river (Madon River). The specific absorbance index at 254 nm (SUVA254) which is related to the aromaticity of DOC was extracted from UV-vis spectra, whose maximum of the second derivative (occurring near 225 nm) is related to nitrates. SF50 spectra which are characterized by well-defined peaks indicated large spatial and temporal variations. Two methods were used to analyze and compare these spectra. The first method was based on the decomposition of the SF50 spectra into four Gauss functions: B1 (related to tryptophan-like fluorescence), B2 and B3 (related to humic substances), and B4 (related to chlorophyll-like substances). The second method was principal components analysis (PCA), which results yielded three principal components that accounted for 95% of the variance. Although PCA enables the consideration of the spectra without making assumptions regarding the number of fluorophores, the results from the decomposition in Gauss function were easier to interpret. PMID- 25784611 TI - Deepithelized posterior interosseous artery flap for 3-dimensional defect coverage in the hand. AB - The posterior interosseous artery (PIA) flap is a pedicle flap that can be harvested at the posterior forearm based on blood supply from the PIA and its concomitant veins. The flap can be used for posttrauma coverage of exposed bones, tendons, and defects; for treatment of a surgical wound; or as a spacer in congenital or burn-related contracture releases. The surgical technique has been reported with limited donor morbidity and few complications to cover exposed structures. In this article, we present our methods and experience using a modification of the posterior interosseous flap that was deepithelized to fill a 3-dimensional cavity in the hand. This method has been successfully used, and the example of the patient shows good outcome, function, and range of motion with no significant complications. The deepithelized PIA flap is a technique that surgeons may add to their toolbox for 3-dimensional defect coverage in the hand. It offers the following advantages: (a) technically uncomplicated; (b) does not create significant donor site morbidity; (c) does not sacrifice any major vessels; and (d) provides good cosmetic appearance, especially in the dorsum of the hand. PMID- 25784612 TI - The influence of social environment in early life on the behavior, stress response, and reproductive system of adult male Norway rats selected for different attitudes to humans. AB - The influence of social disturbance in early life on behavior, response of blood corticosterone level to restraint stress, and endocrine and morphometric indices of the testes was studied in 2-month Norway rat males from three populations: not selected for behavior (unselected), selected for against aggression to humans (tame), and selected for increased aggression to humans (aggressive). The experimental social disturbance included early weaning, daily replacement of cagemates from days 19 to 25, and subsequent housing in twos till the age of 2months. The social disturbance increased the latent period of aggressive behavior in the social interaction test in unselected males and reduced relative testis weights in comparison to the corresponding control groups. In addition, experimental unselected rats had smaller diameters of seminiferous tubules and lower blood testosterone levels. In the experimental group, tame rats had lower basal corticosterone levels, and aggressive animals had lower hormone levels after restraint stress in comparison to the control. The results suggest that the selection in two directions for attitude to humans modifies the response of male rats to social disturbance in early life. In this regard, the selected rat populations may be viewed as a model for investigation of (1) neuroendocrinal mechanisms responsible for the manifestation of aggression and (2) interaction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems in stress. PMID- 25784613 TI - Detecting primitive hematopoietic stem cells in total nucleated and mononuclear cell fractions from umbilical cord blood segments and units. AB - BACKGROUND: Rare hematopoietic stem cell populations are responsible for the transplantation engraftment process. Umbilical cord blood (UCB) is usually processed to the total nucleated cell (TNC), but not to the mononuclear cell (MNC) fraction. TNC counts are used to determine UCB unit storage, release for transplantation and correlation with time to engraftment. However, the TNC fraction contains varying concentrations of red blood cells, granulocytes, platelets and other cells that dilute and mask the stem cells from being detected. This does not allow the quality and potency of the stem cells to be reliably measured. METHODS: 63 UCB segments and 10 UCB units plus segments were analyzed for the response of both primitive lympho-hematopoietic and primitive hematopoietic stem cells in both the TNC and MNC fractions. The samples were analyzed using a highly sensitive, standardized and validated adenosine triphosphate (ATP) bioluminescence stem cell proliferation assay verified against the colony-forming unit (CFU) assay. Dye exclusion and metabolic viability were also determined. RESULTS: Regardless of whether the cells were derived from a segment or unit, the TNC fraction always produced a significantly lower and more variable stem cell response than that derived from the MNC fraction. Routine dye exclusion cell viability did not correspond with metabolic viability and stem cell response. Paired UCB segments produced highly variable results, and the UCB segment did not produce similar results to the unit. DISCUSSION: The TNC fraction underestimates the ability and capacity of the stem cells in both the UCB segment and unit and therefore provides an erroneous interpretation of the of the results. Dye exclusion viability can result in false positive values, when in fact the stem cells may be dead or incapable of proliferation. The difference in response between the segment and unit calls into question the ability to use the segment as a representative sample of the UCB unit. It is apparent that present UCB processing and testing methods are inadequate to properly determine the quality and potency of the unit for release and use in a patient. PMID- 25784615 TI - Enantioselective template-directed [2+2] photocycloadditions of isoquinolones: scope, mechanism and synthetic applications. AB - A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron-deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio-, diastereo- and enantioselectivities (up to 99% ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4-biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications. PMID- 25784614 TI - Focused ultrasound-induced blood-brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. AB - BACKGROUND: Interleukin-12 (IL-12) has long been considered to be effective in triggering an anticancer immune response, however, the dosage has been limited by potential systemic immunotoxicity. Since focused ultrasound (FUS) has been confirmed to temporally and locally open the blood-brain barrier (BBB), the purpose of this study was to elucidate the possibility of combining FUS-induced BBB opening with IL-12 delivery to enhance the anticancer immunological response for glioma treatment. METHODS: FUS energy combined with microbubble administration was delivered transcranially to open BBB, and C-6 glioma rats were used in this study. The efficacy in inducing BBB opening and the corresponding immunological response were primarily evaluated in normal animals. The anticancer immune-triggering chemokine, IL-12, was intraperitoneally administered during the treatment phase to evaluate the effect of immunological response on tumor progression. Glioma animals were sub-grouped to evaluate the effect of the immune response in suppressing glioma when IL-12 was combined with FUS-induced BBB opening. We performed flow cytometry to verify consequent immune cell population changes of peripheral/ tissue lymphocytes as well as macrophages from the animals. Brain sections of sacrificed animals were also used for histological and immunohistochemical analysis. IL-12 level among experimental groups were measured via ELISA analysis. We also analyzed survival and followed tumor progression in vivo via T2-weighted magnetic resonance imaging. RESULTS: FUS-induced BBB opening had no obvious effect on the T lymphocytes population in normal animals, either in the brain or systemically. Yet, it triggered mild changes in the tumor infiltrating lymphocyte (TIL) population, particularly in numbers of CD3+CD8+ cytotoxic T lymphocytes (CTLs) in the tumor region. IL-12 administration triggered a profound increase in all TIL populations, including CD3+CD4+ T helper cells (Th), CTL, and CD4+CD25+ regulatory T cells (Treg), but combined FUS-BBB opening with IL-12 administration produced the most significant IL-12 increase, CTL increase and CTL/Treg ratio increase, thus contributing to the most significant suppression of tumor progression and increased animal survival. CONCLUSION: This study provides evidence that FUS-BBB opening can enhance immune modulating agent delivery to the brain, which improve the anticancer immune response in brain tumor treatment. PMID- 25784617 TI - De novo branching cascades for structural and functional diversity in small molecules. AB - The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero- or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity. PMID- 25784616 TI - Phase II trial of bevacizumab + cetuximab + cisplatin with concurrent intensity modulated radiation therapy for patients with stage III/IVB head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy and tolerability of the addition of 2 monoclonal antibodies, bevacizumab and cetuximab, to 2 cycles of high-dose cisplatin administered concurrently with intensity-modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with newly diagnosed stage III/IVB (M0) HNSCC received cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2) weekly), bevacizumab (15 mg/kg, days 1 and 22), and cisplatin (50 mg/m(2) , days 1, 2, 22, and 23) concurrently with IMRT (70 Gy). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety and tolerability. RESULTS: Among 30 patients enrolled in this study, the primary tumor site was the oropharynx in 24 patients (p16 immunohistochemistry was positive in 17, negative in 1, and not done in 6 of the oropharyngeal tumors). Median age was 57 years (range, 38-77 years) and 27 patients had clinical stage IVA disease. All patients completed the full planned dose of radiation therapy. The most common >= grade 3 adverse events were lymphopenia, mucositis (functional), and dysphagia. With a median follow-up of 33.8 months, 2-year PFS was 88.5% (95% confidence interval [CI] = 68.1-96.1) and 2-year OS was 92.8% (95% CI = 74.2-98.1). CONCLUSION: The addition of bevacizumab and cetuximab to 2 cycles of cisplatin, given concurrently with IMRT, was well tolerated and was associated with favorable efficacy outcomes in this patient population. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E566-E570, 2016. PMID- 25784618 TI - Pain Management Programmes for Non-English-Speaking Black and Minority Ethnic Groups With Long-Term or Chronic Pain. AB - Increasing ethnic diversity in the UK means that there is a growing need for National Health Service care to be delivered to non-English-speaking patients. The aims of the present systematic review were to: (1) better understand the outcomes of chronic pain management programmes (PMPs) for ethnic minority and non English-speaking patients and (2) explore the perspectives on and experiences of chronic pain for these groups. A systematic review identified 26 papers meeting the inclusion criteria; no papers reported on the outcomes of PMPs delivered in the UK. Of the papers obtained, four reported on PMPs conducted outside the UK; eight reported on ethnic differences in patients seeking support from pain management services in America; and the remaining papers included literature reviews, an experimental pain study, a collaborative enquiry, and a survey of patient and clinician ratings of pain. The findings indicate a lack of research into UK-based pain management for ethnic minorities and non-English-speaking patients. The literature suggests that effective PMPs must be tailored to meet cultural experiences of pain and beliefs about pain management. There is a need for further research to explore these cultural beliefs in non-English-speaking groups in the UK. Culturally sensitive evaluations of interpreted PMPs with long term follow-up are needed to assess the effectiveness of current provision. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25784619 TI - Influence of starvation on heart contractility and corticosterone level in rats. AB - The physiological changes, including cardiac modification, that occur during starvation are not yet completely understood. The purpose of this study is to examine the effects of a 2-week starvation period on heart contractility, muscle mass, and irisin and corticosterone levels in rats. Rats in the starved group showed a significant reduction in the body, heart, kidney, and muscle weight (n = 23, p < 0.05). Blood glucose, total protein, and albumin showed a 44, 17.5, and 10.3 % reduction, respectively (p < 0.05). Lipid reserves, such as total lipid, triglyceride, and free fatty acid, were also comparably reduced (p < 0.05). However, the bilirubin, creatinine, blood urea nitrogen, and creatine kinase levels were higher than in the control group (p < 0.05). The blood irisin level was unchanged, but the stress-related corticosterone level was significantly higher in the starved group. The differences observed in M-mode echocardiography were further compared with the body-weight-matched control group. Starvation reduced the left ventricle mass; however, this difference was not significant compared with the body-weight-matched group (p > 0.05). In the starvation group, the impairment of cardiac output was dependent on the reduction in stroke volume and heart rate. Starvation induced a severe reduction in ejection fraction and fractional shortening when compared with the body-weight-matched control group (p < 0.05). In summary, prolonged starvation, which leads to a deficiency of available nutrition, increases the stress-related corticosterone level, impairs the cardiac output, and is associated with changes in cardiac morphogeometry. PMID- 25784621 TI - Participation of T cell immunoglobulin and mucin domain-3 (TIM-3) and its ligand (galectin-9) in the pathogenesis of active generalized vitiligo. AB - Vitiligo is a depigmentary disease where melanocytes of the basal layer of epidermis are selectively destroyed by immune-cell-mediated cytotoxicity. The T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) are involved in immune regulation, and their participation is not known in vitiligo. The present study revealed significant increase in the percentage of CD3+CD4+TIM3+ T cells (P < 0.05) in peripheral blood and was positively correlated with percentage body surface area involvement in aGV group. Further, increased expression of TIM-3 and its ligand galectin-9 (Gal-9) mRNA was found in peripheral blood and lesional/perilesional skin of active generalized vitiligo (aGV) compared with controls. Characteristic migration pattern of TIM-3-positive immune cells in lesional (near/in the epidermis) and perilesional (towards epidermis) skin section suggested that TIM-3+ immune cells may be involved in melanocyte destruction. Further, investigation is required to understand the role of TIM 3/Gal-9 signalling pathways in aGV and it can be targeted in the management of vitiligo. PMID- 25784623 TI - Analysis of Paris meeting redefining the "self" of the immune system. AB - Some ideas because of their intuitive appeal never die by neglect and survive because they are not amenable to experimental disproof. They can only be evaluated by weighing them against competing ideas and by invoking a credibility factor when used to explain observation. Most scientists would recommend ignoring such ideas, yet there is much to be learned by engaging their proponents in debate. The immune system viewed as an idiotype network, and its tweaking by the new school of "contextualists" is an example of such an idea. As chance would have it, the supporters of this idea gathered in a meeting, thereby permitting a cumulative analysis of this conceptualization. The goal of this essay is to compare the views of each of the speakers in light of a competing theory with the hope that a better understanding of immune responsiveness will emerge. PMID- 25784624 TI - A Single-Chain Magnet Tape Based on Hexacyanomanganate(III). AB - The tape-like chain {[(tptz)Mn(II) (H2 O)Mn(III) (CN)6 ]2 Mn(II) (H2 O)2 }n ?4n MeOH?2n H2 O based on the anisotropic building block hexacyanomanganate(III) exhibits long-range magnetic ordering below 5.1 K as well as single-chain magnetic behavior at lower temperatures with an effective energy barrier of 40.5(7) K. PMID- 25784625 TI - Death Delusions and Myoclonus: Acyclovir Toxicity. PMID- 25784626 TI - Clopidogrel reduces the inflammatory response of lung in a rat model of decompression sickness. AB - Inflammation and platelet activation are critical phenomena in the setting of decompression sickness. Clopidogrel (Clo) inhibits platelet activation and may also reduce inflammation. The goal of this study was to investigate if Clo had a protective role in decompression sickness (DCS) through anti-inflammation way. Male Sprague-Dawley rats (n=111) were assigned to three groups: control+vehicle group, DCS+vehicle, DCS+Clo group. The experimental group received 50 mg/kg of Clo or vehicle for 3 days, then compressed to 1,600 kPa (150 msw) in 28 s, maintained at 150 msw for 242 s and decompressed to surface at 3m/s. In a control experiment, rats were also treated with vehicle for 3 days and maintained at atmospheric pressure for an equivalent period of time. Clinical assessment took place over a period of 30 min after surfacing. At the end, blood samples were collected for blood cells counts and cytokine detection. The pathology and the wet/dry ratio of lung tissues, immunohistochemical detection of lung tissue CD41 expression, the numbers of P-selectin positive platelets and platelet-leukocyte conjugates in blood were tested. We found that Clo significantly reduced the DCS mortality risk (mortality rate: 11/45 with Clo vs. 28/46 in the untreated group, P<0.01). Clo reduced the lung injury, the wet/dry ratio of lung, the accumulation of platelet and leukocyte in lung, the fall in platelet count, the WBC count, the numbers of activated platelets and platelet-leukocyte complexes in peripheral blood. It was concluded that Clo can play a protective role in decompression sickness through reducing post-decompression platelet activation and inflammatory process. PMID- 25784627 TI - Concussions are associated with decreased batting performance among Major League Baseball players. AB - BACKGROUND: Concussions impair balance, visual acuity, and reaction time--all of which are required for high-level batting performance--but the effects of concussion on batting performance have not been reported. The authors examined this relationship between concussion and batting performance among Major League Baseball (MLB) players. HYPOTHESIS: Batting performance among concussed MLB players will be worse upon return to play than batting performance among players missing time for noninjury reasons. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The authors identified MLB players who sustained a concussion between 2007 and 2013 through league disabled-list records and a Baseball Prospectus database. For a comparison group, they identified players who went on paternity or bereavement leave during the same period. Using repeated measures generalized linear models, the authors compared 7 batting metrics between the 2 groups for the 2 weeks upon return, as well as 4 to 6 weeks after return, controlling for pre-leave batting metrics, number of days missed, and position. RESULTS: The authors identified 66 concussions and 68 episodes of bereavement/paternity leave to include in the analysis. In the 2 weeks after return, batting average (.235 vs .266), on-base percentage (.294 vs .326), slugging percentage (.361 vs .423), and on-base plus slugging (.650 vs .749) were significantly lower among concussed players relative to the bereavement/paternity leave players (time*group interaction, P<.05). In weeks 4 to 6 after leave, these metrics were slightly lower in concussed players but not statistically significantly so. CONCLUSION: Although concussed players may be asymptomatic upon return to play, the residual effects of concussion on the skills required for batting may still be present. Further work is needed to clarify the mechanism through which batting performance after concussion is adversely affected and to identify better measures to use for return-to-play decisions. PMID- 25784622 TI - Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. AB - Toll like receptors (TLRs) play a crucial role in regulation of innate as well as adaptive immunity. TLRs recognize a distinct but limited repertoire of conserved microbial products. Ligand binding to TLRs activates the signaling cascade and results in activation of multiple inflammatory genes. Variation in this immune response is under genetic control. Polymorphisms in genes associated with inflammatory pathway especially influence the outcome of diseases. TLR2 makes heterodimer with TLR1 or TLR6 and recognizes a wide variety of microbial ligands. In this review, we summarize studies of polymorphisms in genes encoding TLR1, TLR2, TLR4, TLR6, and most polymorphic adaptor protein, Mal/TIRAP, revealing their effect on susceptibility to diseases. PMID- 25784628 TI - Bone Marrow Edema in the Knee and Its Influence on Clinical Outcome After Matrix Based Autologous Chondrocyte Implantation: Results After 3-Year Follow-up. AB - BACKGROUND: Third-generation autologous chondrocyte implantation (ACI) is an established method for treatment of full-thickness cartilage defects in the knee joint. Subchondral bone marrow edema (BME) is frequently observed after ACI, with unknown pathogenesis and clinical relevance. PURPOSE: To investigate the occurrence and clinical relevance of BME after third-generation ACI in the knee joint during the postoperative course of 36 months. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 38 circumscribed full-thickness cartilage defects in 30 patients were included in this study. All defects were treated with third-generation ACI (Novocart 3D). A standardized MRI examination was carried out after 1.5, 3, 6, 12, 24, and 36 months. Bone marrow edema was observed in 78.9% of defects over the postoperative course, with initial occurrence in the first 12 months. The size of the BMEs were determined according to their maximum diameter and were classified as small (<1 cm), medium (<2 cm), large (<4 cm), and very large (diffuse; >4 cm). Clinical outcomes in patients were analyzed by use of the International Knee Documentation Committee (IKDC) scoring system and a visual analog scale for pain. RESULTS: There were 5.3% (n=2) small, 28.9% (n=11) medium, 34.2% (n=13) large, and 10.5% (n=4) very large BMEs. In a subgroup analysis, cartilage defects of the medial femoral condyle showed significantly higher frequency of BME than did patellar defects. Clinical scores showed significant improvements throughout the entire study course (P<.05). Clinical patient outcome did not correlate with presence of BME at any time period (P>.05). CONCLUSION: Midterm clinical results of the matrix-based third generation ACI showed a substantial amount of BME over a 36-month follow-up, but this did not correlate with worse clinical outcome. Patients with femoral cartilage defects were more often affected than were those with patellar cartilage defects. PMID- 25784629 TI - Prospective clinical and radiologic evaluation of patellofemoral matrix-induced autologous chondrocyte implantation. AB - BACKGROUND: While matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging outcomes in the treatment of knee chondral defects, there remains little available research specifically investigating its use in the patellofemoral joint. PURPOSE: To prospectively evaluate the clinical and radiologic outcome of MACI in the patellofemoral joint. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In 47 consecutive patients undergoing patellofemoral MACI, clinical (Knee injury and Osteoarthritis Outcome Score, 36 Item Short Form Health Survey, visual analog scale for pain, 6-minute walk test, knee range of motion, and strength assessment) and magnetic resonance imaging (MRI) assessments were undertaken before and 3, 12, and 24 months after surgery. The MRI was performed to assess graft infill and determine an overall MRI composite score. Results were analyzed according to (1) the patient sample overall and (2) after stratification into 4 subgroups per implant location (patella or trochlea) as well as whether or not adjunct tibial tubercle transfer for patellofemoral malalignment was required. RESULTS: The overall patient sample, as well as each of the 4 procedural subgroups, demonstrated clinically and statistically significant (P < .05) improvements over time for all clinical scores. Graft infill and the MRI composite score also demonstrated statistically significant (P < .05) improvements over time, with no evidence of a main effect for procedure group or interaction between procedure group and time. At 24 months after surgery, 40.4% (n = 19) of patients exhibited complete graft infill comparable with the adjacent native cartilage, with a further 6.4% (n = 3) demonstrating a hypertrophic graft. A further 31.9% (n = 15) of patients exhibited 50% to 100% tissue infill, and 17% (n = 8) demonstrated <50% tissue infill. Two patients (4.3%) demonstrated graft failure. At 24 months after surgery, 85% (n = 40) of patients were satisfied with the results of their MACI surgery. CONCLUSION: These results demonstrate that MACI provides improved clinical and radiologic outcomes to 24 months in patients undergoing treatment specifically for articular cartilage defects on the patella or trochlea, with and without concurrent realignment of the extensor mechanism if required. PMID- 25784630 TI - A gustatory receptor tuned to D-fructose in antennal sensilla chaetica of Helicoverpa armigera. AB - Insect gustatory systems play important roles in food selection and feeding behaviors. In spite of the enormous progress in understanding gustation in Drosophila, for other insects one of the key elements in gustatory signaling, the gustatory receptor (GR), is still elusive. In this study, we report that fructose elicits behavioral and physiological responses in Helicoverpa armigera (Harm) to fructose and identify the gustatory receptor for this sugar. Using the proboscis extension reflex (PER) assays we found that females respond to fructose following stimulation of the distal part of the antenna, where we have identified contact chemosensilla tuned to fructose in tip recording experiments. We isolated three full-length cDNAs encoding candidate HarmGRs based on comparison with orthologous GR sequences in Heliothis virescens and functionally characterized the responses of HarmGR4 to 15 chemicals when this receptor was expressed in Xenopus oocytes with two-electrode voltage-clamp recording. Among the tastants tested, the oocytes dose-dependently responded only to D-fructose (EC50 = 0.045 M). By combining behavioral, electrophysiological and molecular approaches, these results provide basic knowledge for further research on the molecular mechanisms of gustatory reception. PMID- 25784631 TI - The Lepidoptera Odorant Binding Protein gene family: Gene gain and loss within the GOBP/PBP complex of moths and butterflies. AB - Butterflies and moths differ significantly in their daily activities: butterflies are diurnal while moths are largely nocturnal or crepuscular. This life history difference is presumably reflected in their sensory biology, and especially the balance between the use of chemical versus visual signals. Odorant Binding Proteins (OBP) are a class of insect proteins, at least some of which are thought to orchestrate the transfer of odor molecules within an olfactory sensillum (olfactory organ), between the air and odor receptor proteins (ORs) on the olfactory neurons. A Lepidoptera specific subclass of OBPs are the GOBPs and PBPs; these were the first OBPs studied and have well documented associations with olfactory sensilla. We have used the available genomes of two moths, Manduca sexta and Bombyx mori, and two butterflies, Danaus plexippus and Heliconius melpomene, to characterize the GOBP/PBP genes, attempting to identify gene orthologs and document specific gene gain and loss. First, we identified the full repertoire of OBPs in the M. sexta genome, and compared these with the full repertoire of OBPs from the other three lepidopteran genomes, the OBPs of Drosophila melanogaster and select OBPs from other Lepidoptera. We also evaluated the tissue specific expression of the M. sexta OBPs using an available RNAseq databases. In the four lepidopteran species, GOBP2 and all PBPs reside in single gene clusters; in two species GOBP1 is documented to be nearby, about 100 kb from the cluster; all GOBP/PBP genes share a common gene structure indicating a common origin. As such, the GOBP/PBP genes form a gene complex. Our findings suggest that (1) the lepidopteran GOBP/PBP complex is a monophyletic lineage with origins deep within Lepidoptera phylogeny, (2) within this lineage PBP gene evolution is much more dynamic than GOBP gene evolution, and (3) butterflies may have lost a PBP gene that plays an important role in moth pheromone detection, correlating with a shift from olfactory (moth) to visual (butterfly) communication, at least regarding long distance mate recognition. These findings will be clarified by additional lepidopteran genomic data, but the observation that moths and butterflies share most of the PBP/GOBP genes suggests that they also share common chemosensory-based behavioral pathways. PMID- 25784632 TI - The dysfunctional consequences of a performance measurement system: the case of the Iranian national hospital grading programme. AB - OBJECTIVES: Performance measurement systems are increasingly used to reward and improve provider performance. However, such initiatives may also inadvertently induce a range of unintended and dysfunctional side-effects. This study explores the unintended and adverse consequences induced by the Iranian national hospital grading programme, which incorporates financial incentives for meeting nationally defined standards. METHODS: We interviewed key informants across four key groups with a legitimate interest in healthcare performance: four purposively selected hospitals; four health insurance organizations; the Iranian hospital accreditation body; and one grading agency. The transcribed interviews and field notes were analysed thematically, and subsequently, member checking was conducted. RESULTS: Seven dysfunctional consequences were identified: misrepresentation of data by hospitals; increased anxiety and stress among hospital employees; tunnel vision; financial pressures on poorly graded hospitals; incentives to purchase unnecessary equipment; erosion of public trust; and restricting access to hospital services by patients. These were caused by the way the grading system was implemented: poor standards of audit; the way in which the audit process was conducted; and the timing of audits. The pay for performance element of the grading system and the focus on structural aspects in the standards made improvement in grading particularly difficult for those hospitals that had been assessed as under-performing. CONCLUSION: Although the Iranian hospital grading system has resulted in a significant increase in the adoption of national standards, it has nevertheless induced a range of perverse outcomes. To mitigate these requires further refinement and recalibration of the system. PMID- 25784636 TI - Genomic instability: Crossing pathways at the origin of structural and numerical chromosome changes. AB - Genomic instability leads to a wide spectrum of genetic changes, including single nucleotide mutations, structural chromosome alterations, and numerical chromosome changes. The accepted view on how these events are generated predicts that separate cellular mechanisms and genetic events explain the occurrence of these types of genetic variation. Recently, new findings have shed light on the complexity of the mechanisms leading to structural and numerical chromosome aberrations, their intertwining pathways, and their dynamic evolution, in somatic as well as in germ cells. In this review, we present a critical analysis of these recent discoveries in this area, with the aim to contribute to a deeper knowledge of the molecular networks leading to adverse outcomes in humans following exposure to environmental factors. The review illustrates how several technological advances, including DNA sequencing methods, bioinformatics, and live-cell imaging approaches, have contributed to produce a renewed concept of the mechanisms causing genomic instability. Special attention is also given to the specific pathways causing genomic instability in mammalian germ cells. Remarkably, the same scenario emerged from some pioneering studies published in the 1980s to 1990s, when the evolution of polyploidy, the chromosomal effects of spindle poisons, the fate of micronuclei, were intuitively proposed to share mechanisms and pathways. Thus, an old working hypothesis has eventually found proper validation. PMID- 25784637 TI - An unusual lethal cerebrovascular complication of near hanging: traumatic injury of the vertebral artery. PMID- 25784638 TI - Remarkable improvement of selective mutism with everolimus in a patient with tuberous sclerosis complex. PMID- 25784639 TI - Plasma Heat Shock Proteins (HSPs) 70 and 47 levels in diabetic foot and its possible correlation with clinical variables in a North Indian Tertiary care hospital. AB - OBJECTIVE: HSPs have been proposed to have a role in the wound healing process, supported by finding that its expression is rapidly induced after skin is wounded in animal models. Because of this phenomenon, we have made a hypothesis that circulating HSPs will have any relationship with DFU. METHODS: The circulating levels of HSP 70 and HSP 47 were measured in diabetic patients with an ulcer (Group A: n=30), without ulcer (Group B: n=30) and healthy subjects (Group C: n=30). RESULTS: Diabetic foot ulcer showed higher median plasma level of HSP 70 [3229.01 (1984.5-4137.1) vs 1625.7 (1435.1-2253.5) vs 1025.7 (835.1-1653.5)] ng/ml and HSP 47 [2.33 (2.118-2.58) vs 0.98 (0.83-1.07) vs 0.58 (0.42-0.68) pg/ml] of the diabetic foot, diabetic control and healthy subjects. Odds ratio and risk ratio for DFU after age adjusted were BMI (>25 kg/m(2)) [OR 1.78, RR 1.35], HbA1c>7% [OR 3.37), RR 1.76], neuropathy [OR 5.79, RR 3.13], retinopathy [OR 3.44, RR 1.82], hypertension [OR 1.54, RR 1.18], and smoking cessation [OR 4.53, RR 2.09]. CONCLUSION: In the near future, it would be interesting to find out whether this high plasma HSPs precedes in early would healing mechanism and will have a relationship with type of infections and/or nature of therapy for infection in such patients. PMID- 25784640 TI - Human fetal skin fibroblasts: Extremely potent and allogenic candidates for treatment of diabetic wounds. AB - The number of patients with diabetes has been expected around 300 million by 2025 and 366 million by 2030 by WHO. On the other hand, diabetic wounds as one of the common complications of diabetes represent major health challenges. Recently, wound care biological products have been proposed for treatment of chronic wounds such as the diabetic wound. Accordingly, tissue-engineered skin substitutes have demonstrated promising effects. Some of these products have used adult skin and neonatal foreskin fibroblasts to produce a tissue-engineered skin substitute. Although adult skin and neonatal foreskin fibroblasts have demonstrated promising effects, but fetal skin fibroblasts and keratinocytes have depicted some unique and considerable properties over adult and neonatal skin cells for instance, skin regeneration with no inflammation and scar formation, low immunogenicity, more VEGF-A secretion than their adult counterparts, immunomodulatory effect by the expression of Indoleamine 2,3 dioxygenase, more resistance to oxidative and physical stresses, etc. On the other hand fetal dermal cells with intrinsic IDO dependent immunosuppressive activity have introduced them as an allogeneic alternative for treatment of chronic wounds. Therefore, based on the mentioned advantages they are ideal skin substitutes. Accordingly, we suggest that using these cells alone or in combination with biocompatible scaffolds for treatment of different types of ulcers such as diabetic wounds. PMID- 25784641 TI - General practice and the Internet revolution. Use of an Internet social network to communicate information on prevention in France. AB - The popularity of social networks and the huge number of exchanges have made them immensely important for the communication of information. This French study explored prevention in hereditary breast cancer using a social Internet network to communicate information. The principal objective was to inform French women aged from 20 to 50 years, using the social network Facebook, about the warning signs of breast cancer in cases of a predisposition to the disease due to a genetic mutation. The secondary objectives were to inform people about screening. An information page entitled "hereditary breast cancer: and if I was concerned?" was distributed in 3 different ways: from friend to friend, via groups of persons, and by targeted advertising. Four articles and 11 messages were distributed over 27 days. The total number of visits for this period amounted to 1019. A total of 81 percent of the Internauts were women and 55 percent of the visitors were aged between 25 and 44 years. Other information campaigns concerning public health issues could be conducted using this tool. A legal framework is necessary to preserve the quality of the medical information provided. This new means of communication, used for prevention purposes, will add to other frequently used methods of communication. PMID- 25784642 TI - Brain Tumor Database, a free relational database for collection and analysis of brain tumor patient information. AB - In this study, we describe the development and utilization of a relational database designed to manage the clinical and radiological data of patients with brain tumors. The Brain Tumor Database was implemented using MySQL v.5.0, while the graphical user interface was created using PHP and HTML, thus making it easily accessible through a web browser. This web-based approach allows for multiple institutions to potentially access the database. The BT Database can record brain tumor patient information (e.g. clinical features, anatomical attributes, and radiological characteristics) and be used for clinical and research purposes. Analytic tools to automatically generate statistics and different plots are provided. The BT Database is a free and powerful user friendly tool with a wide range of possible clinical and research applications in neurology and neurosurgery. The BT Database graphical user interface source code and manual are freely available at http://tumorsdatabase.altervista.org. PMID- 25784643 TI - "Multidrug-resistant tuberculosis" may be nontuberculous mycobacteria. AB - INTRODUCTION: Multidrug resistant tuberculosis (MDR-TB) presents a great challenge to public health, especially for developing countries. Some nontuberculous mycobacteria (NTM) cause the similar clinical and radiological characteristics with tuberculosis. We aimed to identify the frequency of NTM infections among subjects who were suspected to have MDR-TB due to lack of response to anti-TB treatment. METHODS: This retrospective study evaluated patients with suspected MDR-TB due to lack of sputum conversion after 2-3 month therapy with first line anti-TB treatment from 2009 through 2014. Cultures for mycobacteria were performed and identification was done to species level by phenotypic and molecular tests. The outcome of the patients with NTM disease and related risk factors for poor outcome were evaluated. RESULTS: Out of 117 consecutive strains isolated from suspected MDR-TB subjects, 35 (30%) strains were identified as NTM by using conventional and molecular approaches. Of these patients with positive NTM cultures, 32 (27%) patients met ATS/IDSA diagnostic criteria. Out of 32, 29 (90%) individuals with confirmed NTM diseases had underlying disorders including 8 subjects with malignancy, 5 with organ transplantations, and 4 with the human immunodeficiency virus. No known underlying disorder was found in 3 (9%) subjects. Treatment outcomes were available for 27 subjects, 17 (63%) of whom were cured and 10 (37%) had poor outcome including 6 (60%) who failed and 4 (40%) who died during treatment. CONCLUSION: The high costs to the patient and society should lead health care providers to consider NTM in all patients suspected of having TB. PMID- 25784644 TI - A simplified trauma triage system safely reduces overtriage and improves provider satisfaction: a prospective study. AB - BACKGROUND: Standard triage systems result in high rates of overtriage to achieve acceptably low undertriage. We previously validated optimal triage variables and used these to implement a new simplified triage system (NEW) at our hospital. METHODS: All trauma entries from May 2010 to Feb 2013 were prospectively reviewed. Calculation of the undertriage and overtriage rates was based on the need for any urgent or life-saving intervention. RESULTS: We identified 704 trauma patients. Level 1 activations were reduced from 32% (OLD) to 19% in the NEW system (P < .05). Overtriage was reduced from 79% (OLD) to 44% in the NEW system (P < .01). The undertriage rate was 1.6% in the NEW system, compared with 1.2% in the OLD system (P = nonsignificant). Of all patients, 14% (63) required a life-saving intervention. There were no deaths among undertriaged patients. CONCLUSION: The NEW simplified triage system significantly reduced the rate of overtriage, while safely maintaining a low undertriage rate. PMID- 25784646 TI - Si-CSP9 regulates the integument and moulting process of larvae in the red imported fire ant, Solenopsis invicta. AB - Chemosensory proteins (CSPs) have been predicted to be involved in development; however, direct evidence for their involvement is lacking, and genetic basis is largely unknown. To determine the function of the chemosensory protein 9 (Si CSP9) gene in Solenopsis invicta, we used RNA interference to silence Si-CSP9 in 3rd-instar larvae. The 3rd-instar larvae failed to shed their cuticle after being fed Si-CSP9-directed siRNA, and expression profiling of RNAi-treated and untreated control larvae showed that 375 genes were differentially expressed. Pathway enrichment analysis revealed that 4 pathways associated with larval development were significantly enriched. Blast analysis revealed that one fatty acid amide hydrolase (FAAH) gene was up-regulated and 4 fatty acid synthase (FAT) genes and one protein kinase DC2 gene (PKA) were down-regulated in the enriched pathways. Significantly higher expression of these genes was found in 4th-instar larvae, and Pearson correlation analysis of the expression patterns revealed significant relationships among Si-CSP9, PKA, FAAH, and FAT1-4. Moreover, we confirmed that expression levels of Si-CSP9, FAAH, and FAT1-4 were significantly reduced and that the development of 3rd-instar larvae was halted with PKA silencing. These results suggest that Si-CSP9 and PKA may be involved in the network that contributes to development of 3rd-instar larvae. PMID- 25784647 TI - Increased plant productivity and decreased microbial respiratory C loss by plant growth-promoting rhizobacteria under elevated CO2. AB - Increased plant productivity and decreased microbial respiratory C loss can potentially mitigate increasing atmospheric CO2, but we currently lack effective means to achieve these goals. Soil microbes may play critical roles in mediating plant productivity and soil C/N dynamics under future climate scenarios of elevated CO2 (eCO2) through optimizing functioning of the root-soil interface. By using a labeling technique with (13)C and (15)N, we examined the effects of plant growth-promoting Pseudomonas fluorescens on C and N cycling in the rhizosphere of a common grass species under eCO2. These microbial inoculants were shown to increase plant productivity. Although strong competition for N between the plant and soil microbes was observed, the plant can increase its capacity to store more biomass C per unit of N under P. fluorescens addition. Unlike eCO2 effects, P. fluorescens inoculants did not change mass-specific microbial respiration and accelerate soil decomposition related to N cycling, suggesting these microbial inoculants mitigated positive feedbacks of soil microbial decomposition to eCO2. The potential to mitigate climate change by optimizing soil microbial functioning by plant growth-promoting Pseudomonas fluorescens is a prospect for ecosystem management. PMID- 25784645 TI - The nature of individual differences in inhibited temperament and risk for psychiatric disease: A review and meta-analysis. AB - What makes us different from one another? Why does one person jump out of airplanes for fun while another prefers to stay home and read? Why are some babies born with a predisposition to become anxious? Questions about individual differences in temperament have engaged the minds of scientists, psychologists, and philosophers for centuries. Recent technological advances in neuroimaging and genetics provide an unprecedented opportunity to answer these questions. Here we review the literature on the neurobiology of one of the most basic individual differences-the tendency to approach or avoid novelty. This trait, called inhibited temperament, is innate, heritable, and observed across species. Importantly, inhibited temperament also confers risk for psychiatric disease. Here, we provide a comprehensive review of inhibited temperament, including neuroimaging and genetic studies in human and non-human primates. We conducted a meta-analysis of neuroimaging findings in inhibited humans that points to alterations in a fronto-limbic-basal ganglia circuit; these findings provide the basis of a model of inhibited temperament neurocircuitry. Lesion and neuroimaging studies in non-human primate models of inhibited temperament highlight roles for the amygdala, hippocampus, orbitofrontal cortex, and dorsal prefrontal cortex. Genetic studies highlight a role for genes that regulate neurotransmitter function, such as the serotonin transporter polymorphisms (5-HTTLPR), as well as genes that regulate stress response, such as corticotropin-releasing hormone (CRH). Together these studies provide a foundation of knowledge about the genetic and neural substrates of this most basic of temperament traits. Future studies using novel imaging methods and genetic approaches promise to expand upon these biological bases of inhibited temperament and inform our understanding of risk for psychiatric disease. PMID- 25784648 TI - Antiseizure Activity of Midazolam in Mice Lacking delta-Subunit Extrasynaptic GABA(A) Receptors. AB - Midazolam is a benzodiazepine anticonvulsant with rapid onset and short duration of action. Midazolam is the current drug of choice for acute seizures and status epilepticus, including those caused by organophosphate nerve agents. The antiseizure activity of midazolam is thought to result from its allosteric potentiation of synaptic GABA(A) receptors in the brain. However, there are indications that benzodiazepines promote neurosteroid synthesis via the 18-kDa cholesterol transporter protein (TSPO). Therefore, we investigated the role of neurosteroids and their extrasynaptic GABA(A) receptor targets in the antiseizure activity of midazolam. Here, we used delta-subunit knockout (DKO) mice bearing a targeted deletion of the extrasynaptic receptors to investigate the contribution of the extrasynaptic receptors to the antiseizure activity of midazolam using the 6-Hz and hippocampus kindling seizure models. In both models, midazolam produced rapid and dose-dependent protection against seizures (ED50, 0.4 mg/kg). Moreover, the antiseizure potency of midazolam was undiminished in DKO mice compared with control mice. Pretreatment with PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1 methylpropyl)-3-isoquinolinecarboxamide], a TSPO blocker, or finasteride, a 5alpha-reductase neurosteroid inhibitor, did not affect the antiseizure effect of midazolam. The antiseizure activity of midazolam was significantly reversed by pretreatment with flumazenil, a benzodiazepine antagonist. Plasma and brain levels of the neurosteroid allopregnanolone were not significantly greater in midazolam-treated animals. These studies therefore provide strong evidence that neurosteroids and extrasynaptic GABA(A) receptors are not involved in the antiseizure activity of midazolam, which mainly occurs through synaptic GABA(A) receptors via direct binding to benzodiazepine sites. This study reaffirms midazolam's use for controlling acute seizures and status epilepticus. PMID- 25784649 TI - Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor. AB - c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9 pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1beta in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3(+)CD4(+)CD25(+) regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis. PMID- 25784650 TI - Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets. AB - c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood. c-Met and RON form both activated homodimers and heterodimers with themselves and other families of phosphotyrosine kinase receptors. Inhibitors for c-Met and RON including small molecular weigh kinase inhibitors and neutralizing antibodies are in pre-clinical investigation and clinical trials. Several of the tyrosine kinase inhibitors have activity against both c-Met and RON kinases whereas the antibodies generally are target specific. As with many targeted agents used to treat solid tumors, it is likely that c-Met/RON inhibitors will have greater benefit when used in combination with chemotherapy or other targeted agents. A careful analysis of c-Met/RON expression or activity and a better elucidation of how they influence cell signaling will be useful in predicting which tumors respond best to these inhibitors as well as determining which agents can be used with these inhibitors for combined therapy. PMID- 25784651 TI - p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia. AB - MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL. PMID- 25784652 TI - Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma. AB - We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P(meta-analysis) = 9.15 * 10-4, P(heterogeneity) = 0.427). Strong correlation indicated that rs1063355 was a cis expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 * 10-6). The correlation was further validated using a public dataset. Our results highlighted the role of immune related pathway and genes in the etiology of RCC. PMID- 25784653 TI - miR-191 promotes tumorigenesis of human colorectal cancer through targeting C/EBPbeta. AB - MicroRNA-191 (miR-191), a small non-coding RNA, is involved in disease development and cancer diagnosis and prognosis. However, how miR-191 functions in colorectal cancer remains largely unclear. In this study, we show that miR-191 is highly expressed in colon tumor tissues, and that inhibition of miR-191 leads to decreased cell growth, proliferation and tumorigenicity in a xenograft model. Overexpression of miR-191 in colorectal cancer cell lines alters cell cycle progression and cell resistance to 5-Fu induced cell apoptosis. Mechanistic studies demonstrated that miR-191 directly binds to the 3'UTR of the C/EBPbeta mRNA and mediates a decrease in the mRNA and protein expression of C/EBPbeta. We further showed that C/EBPbeta induces growth arrest in a colorectal cancer cell line and that its expression is negatively correlated with the miR-191 level in patient samples. Our findings suggest that miR-191 may be a potential gene therapy target for the treatment of colorectal cancer. PMID- 25784654 TI - Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells. AB - Breast cancer is one of the leading causes of cancer death among women in the United States. Patients expressing the estrogen and progesterone receptor (ER and PR) and human epidermal growth factor 2 (HER-2) tumor markers have favorable prognosis and efficacious therapeutic options. In contrast, tumors that are negative for these markers (triple-negative) have a disproportionate share of morbidity and mortality due to lack of a validated molecular target. Deubiquitinating enzymes (DUBs) are a critical component of ubiquitin-proteasome system degradation and have been shown to be differentially expressed and activated in a number of cancers, including breast, with their aberrant activity linked to cancer prognosis and clinical outcome. We evaluated the effect of the DUB inhibitors b-AP15 and RA-9 alone and in combination with early- and late stage lysosomal inhibitors on cell viability in a panel of triple negative breast cancer (TNBC) cell lines. Our results indicate small-molecule DUB inhibitors have a profound effect on TNBC viability and lead to activation of autophagy as a cellular mechanism to compensate for ubiquitin-proteasome-system stress. Treatment with sub-optimal doses of DUB and lysosome inhibitors synergistically kills TNBC cells. This supports the evaluation of DUB inhibition, in combination with lysosomal inhibition, as a therapeutic approach for the treatment of TNBC. PMID- 25784655 TI - Stage-specific prognostic biomarkers in melanoma. AB - The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression. Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients). Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities. PMID- 25784656 TI - Glycolytic metabolism influences global chromatin structure. AB - Metabolic rewiring, specifically elevated glycolytic metabolism is a hallmark of cancer. Global chromatin structure regulates gene expression, DNA repair, and also affects cancer progression. But the interrelationship between tumor metabolism and chromatin architecture remain unclear. Here we show that increased glycolysis in cancer cells promotes an open chromatin configuration. Using complementary methods including Micrococcal nuclease (MNase) digestion assay, electron microscope and immunofluorescence staining, we demonstrate that glycolysis inhibition by pharmacological and genetic approaches was associated with induction of compacted chromatin structure. This condensed chromatin status appeared to result chiefly from histone hypoacetylation as restoration of histone acetylation with an HDAC inhibitor reversed the compacted chromatin state. Interestingly, glycolysis inhibition-induced chromatin condensation impeded DNA repair efficiency leading to increased sensitivity of cancer cells to DNA damage drugs, which may represent a novel molecular mechanism that can be exploited for cancer therapy. PMID- 25784659 TI - High rate of spontaneous normalization of celiac serology in a cohort of 446 children with type 1 diabetes: a prospective study. AB - OBJECTIVE: In children with type 1 diabetes mellitus (T1DM), elevated levels of antitissue transglutaminase (anti-tTG) antibody may spontaneously normalize, despite continued consumption of gluten. We aimed to investigate the prevalence of spontaneous normalization of anti-tTG levels and the existence of factors predictive for this outcome. RESEARCH DESIGN AND METHODS: All children referred from 2002 to 2012 were screened for celiac disease (CD) at diabetes onset and at specific intervals. In the presence of a high anti-tTG titer or clinical symptoms, children were offered endoscopy, and asymptomatic patients with a low anti-tTG titer were invited to a second serological test after 6 months of eating a gluten-containing diet. RESULTS: The study included 446 children. Of these, 65 (14.5%) became positive for celiac serology: 38 (58%) had a persistently elevated anti-tTG titer and 27 (41%) fluctuating anti-tTG titer; 18 (28%) became negative. The prevalence of positive CD autoimmunity and overt CD was 14.3% (95% CI 11-17) and 8.5% (95% CI 5-10), 15- and 8-times higher than the general pediatric population, respectively. Asymptomatic children older than 9.1 years at T1DM onset had the lowest risk to develop CD. CONCLUSIONS: Serum anti-tTG levels decreased spontaneously in 40% of children with T1DM and became negative in 20%, despite gluten consumption. This finding supports the hypothesis of a state of temporary positivity of celiac serology in children with diabetes. In absence of clinical symptoms or signs of CD, histological confirmation of the disease and the gluten-free diet should be postponed to avoid unnecessary procedures and reduce an additional psychological burden. PMID- 25784657 TI - A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer. AB - INTRODUCTION: There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI. METHODS: This phase I open label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF). RESULTS: Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3 months (range 1.6-4.0 months); median OS was 3.5 months (range 1.6-5.1 months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF. CONCLUSION: Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation. PMID- 25784661 TI - Association between cardiorespiratory fitness and the determinants of glycemic control across the entire glucose tolerance continuum. AB - OBJECTIVE: Cardiorespiratory fitness (VO2max) is associated with glycemic control, yet the relationship between VO2max and the underlying determinants of glycemic control is less clear. Our aim was to determine whether VO2max is associated with insulin sensitivity, insulin secretion, and the disposition index, a measure of compensatory pancreatic beta-cell insulin secretion relative to insulin sensitivity, in subjects representing the entire range of the glucose tolerance continuum. RESEARCH DESIGN AND METHODS: A cohort of subjects (N = 313) with heterogeneous age, sex, BMI, and glycemic control underwent measurements of body composition, HbA1c, fasting glucose, oral glucose tolerance (OGTT), and VO2max. OGTT-derived insulin sensitivity (SiOGTT), glucose-stimulated insulin secretion (GSISOGTT), and the disposition index (DIOGTT) (the product of SiOGTT and GSISOGTT) were measured, and associations between VO2max and these determinants of glycemic control were examined. RESULTS: A low VO2max was associated with high HbA1c (r = -0.33), high fasting glucose (r = -0.34), high 2 h OGTT glucose (r = -0.33), low SiOGTT (r = 0.73), and high early-phase (r = 0.34) and late-phase (r = -0.36) GSISOGTT. Furthermore, a low VO2max was associated with low early- and late-phase DIOGTT (both r = 0.41). Interestingly, relationships between VO2max and either glycemic control or late-phase GSISOGTT deteriorated across the glucose tolerance continuum. CONCLUSIONS: The association between poor cardiorespiratory fitness and compromised pancreatic beta-cell compensation across the entire glucose tolerance continuum provides additional evidence highlighting the importance of fitness in protection against the onset of a fundamental pathophysiological event that leads to type 2 diabetes. PMID- 25784660 TI - Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study. AB - OBJECTIVE: To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment. RESEARCH DESIGN AND METHODS: In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 +/- 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards. RESULTS: In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95% CI 1.04-2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20-3.03], P trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03-1.86], P-trend = 0.02), t-18:1 (1.32 [1.00 1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05-1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained. CONCLUSIONS: Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM. PMID- 25784662 TI - Effects of the lifestyle intervention program GLICEMIA in people at risk for type 2 diabetes: a cluster-randomized controlled trial. AB - OBJECTIVE: The aim of this study was to assess the efficacy of a 12-month prevention program conducted in 42 community pharmacies in reducing the risk for diabetes. RESEARCH DESIGN AND METHODS: In a cluster-randomized controlled trial in 1,092 participants, mean change in the risk for diabetes (indicated by the Finnish Diabetes Risk Score [FINDRISC]) between intervention and control groups was calculated. In the intervention program GLICEMIA, three appointments with individual counseling and five educational group sessions were combined, whereas in the control group, only information about the participants' health was obtained in three assessments. RESULTS: After adjusting for cluster structure and differences in baseline characteristics, improvement in FINDRISC in the intervention group was 0.74 points (95% CI 0.42-1.04) above the control group. CONCLUSIONS: The GLICEMIA program shows the feasibility of a pharmacy-based intervention and leads to a significant modest reduction in diabetes risk score but does not reduce the rate of diabetes progression over 1 year. PMID- 25784664 TI - Comparison of glycemic and metabolic control in youth with type 1 diabetes with and without antipsychotic medication: analysis from the nationwide German/Austrian Diabetes Survey (DPV). AB - OBJECTIVE: The objective of this study was to explore metabolic risk factors and glycemic control in youth with type 1 diabetes treated with typical or atypical antipsychotics. RESEARCH DESIGN AND METHODS: Data for 60,162 subjects with type 1 diabetes up to the age of 25 years registered in the nationwide German/Austrian Diabetes Survey were included in the analysis. BMI; HbA1c; treatment strategy; prevalence of hypertension, dyslipidemia, microalbuminuria, and retinopathy; frequency of hypoglycemia and diabetic ketoacidosis (DKA); and immigrant status among subjects treated with typical or atypical antipsychotics were compared with those without antipsychotic medication and analyzed by regression analysis. RESULTS: A total of 291 subjects with type 1 diabetes (median diabetes duration 7.2 years) received antipsychotic medications (most commonly risperidone). Subjects treated with antipsychotics had a higher BMI (P = 0.004) and dyslipidemia was more frequent (P = 0.045) compared with subjects not receiving antipsychotic medication. Frequencies of severe hypoglycemia and DKA were significantly higher in subjects receiving antipsychotics (P < 0.001). The prevalences of hypertension, microalbuminuria, and retinopathy were not different. In subjects treated with typical antipsychotics, glycemic control did not differ compared with those who did not receive antipsychotic medications. By contrast, subjects treated with atypical antipsychotics had higher HbA1c levels (P = 0.022). CONCLUSIONS: This analysis from a real-life survey demonstrated that subjects with antipsychotic medication had worse glycemic control and a higher rate of acute complications compared with those without antipsychotic medication. Health care teams caring for youth with type 1 diabetes taking antipsychotic medication need to know about these findings. We suggest monitoring metabolic risk factors as well as providing diabetes education about prevention of acute complications. PMID- 25784663 TI - Parental Characteristics Associated With Outcomes in Youth With Type 2 Diabetes: Results From the TODAY Clinical Trial. AB - OBJECTIVE: This study examined parental factors associated with outcomes of youth in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. RESEARCH DESIGN AND METHODS: Of 699 youth with type 2 diabetes in the TODAY cohort, 623 (89.1%) had a parent participate and provide data at baseline, including weight, HbA1c, blood pressure, symptoms of depression, binge eating (BE), and medical history. Youth were followed 2-6.5 years. Data were analyzed using regression models and survival curve methods. RESULTS: Parental diabetes (43.6% of parents) was associated with higher baseline HbA1c (P < 0.0001) and failure of youths to maintain glycemic control on study treatment (53.6% vs. 38.2% failure rate among those without a diabetic parent, P = 0.0002). Parental hypertension (40.6% of parents) was associated with hypertension in youth during TODAY (40.4% vs. 27.4% of youth with and without parental hypertension had hypertension, P = 0.0008) and with higher youth baseline BMI z scores (P = 0.0038). Parents had a mean baseline BMI of 33.6 kg/m(2). Parental obesity (BMI >30 kg/m(2)) was associated with higher baseline BMI z scores in the youth (P < 0.0001). Depressive symptoms in parents (20.6% of parents) were related to youth depressive symptoms at baseline only (P = 0.0430); subclinical BE in parents was related to the presence of subclinical BE (P = 0.0354) and depressive symptoms (P = 0.0326) in youth throughout the study period. CONCLUSIONS: Parental diabetes and hypertension were associated with lack of glycemic control, hypertension, and higher BMI z scores in youth. Further research is needed to better understand and address parental biological and behavioral factors to improve youth health outcomes. PMID- 25784665 TI - Hyperglycemia potentiates the slowing of gastric emptying induced by exogenous GLP-1. AB - OBJECTIVE: Acute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 also slows gastric emptying, leading to diminished glycemic excursions. The primary objective was to determine whether hyperglycemia potentiates the slowing of gastric emptying induced by GLP-1 administration. RESEARCH DESIGN AND METHODS: Ten healthy participants were studied on 4 separate days. Blood glucose was clamped at hyperglycemia using an intravenous infusion of 25% dextrose (~12 mmol/L; hyper) on 2 days, or maintained at euglycemia (~6 mmol/L; eu) on 2 days, between t = -15 and 240 min. During hyperglycemic and euglycemic days, participants received intravenous GLP-1 (1.2 pmol/kg/min) and placebo in a randomized double-blind fashion. At t = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq technetium-99m-sulfur colloid and 3 g 3-O-methyl-glucose (3 OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from t = 0 to 240 min and serum 3-OMG taken at regular intervals from t = 15 to 240 min. The areas under the curve for gastric emptying and 3-OMG were analyzed using one-way repeated-measures ANOVA with Bonferroni Holm adjusted post hoc tests. RESULTS: Hyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; P < 0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P < 0.001). There was an additive effect of GLP-1 and hyperglycemia, such that gastric emptying was markedly slower compared with GLP-1 administration during euglycemia (eu/GLP-1 vs. hyper/GLP-1; P < 0.01). CONCLUSIONS: Acute administration of exogenous GLP-1 profoundly slows gastric emptying during hyperglycemia in excess of the slowing induced by GLP-1 during euglycemia. Studies are required to determine the effects of hyperglycemia on gastric emptying with the subcutaneously administered commercially available GLP-1 agonists in patients with type 2 diabetes. PMID- 25784666 TI - Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes. AB - OBJECTIVE: We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS: We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS: KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (beta = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (beta = 0.51; P = 6.5 * 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (beta = -5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS: KIM-1 did not predict progression to end stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link. PMID- 25784667 TI - Truancy and teenage pregnancy in English adolescent girls: can we identify those at risk? AB - BACKGROUND: Truancy has been linked to risky sexual behaviours in teenagers. However, no studies in England have examined the association between truancy and teenage pregnancy, and the use of truancy as a marker of teenagers at risk of pregnancy. METHODS: Using logistic regression, we investigated the association between truancy at age 15 and the likelihood of teenage pregnancy by age 19 among 3837 female teenagers who participated in the Longitudinal Study of Young People of England. We calculated the areas under the ROC curves of four models to determine how useful truancy would be as a marker of future teenage pregnancy. RESULTS: Truancy showed a dose-response association with teenage pregnancy after adjusting for ethnicity, educational intentions at age 16, parental socioeconomic status and family composition ('several days at a time' versus 'none', odds ratio 3.48 95% confidence interval 1.90-6.36, P < 0.001). Inclusion of risk behaviours improved the accuracy of predictive models only marginally (area under the ROC curve 0.76 full model versus 0.71 sociodemographic characteristics only). CONCLUSIONS: Truancy is independently associated with teenage pregnancy among English adolescent girls. However, the discriminatory powers of models were low, suggesting that interventions addressing the whole population, rather than targeting high-risk individuals, might be more effective in reducing teenage pregnancy rates. PMID- 25784668 TI - Linkages of plant-soil feedbacks and underlying invasion mechanisms. AB - Soil microbial communities and processes have repeatedly been shown to impact plant community assembly and population growth. Soil-driven effects may be particularly pronounced with the introduction of plants to non-native ranges, as introduced plants are not typically accompanied by transference of local soil communities. Here we describe how the mechanisms by which soil community processes influence plant growth overlap with several known and well-described mechanisms of plant invasion. Critically, a given soil community process may either facilitate or limit invasion, depending upon local conditions and the specific mechanisms of soil processes involved. Additionally, as soil communities typically consist of species with short generation times, the net consequences of plant-soil feedbacks for invasion trajectories are likely to change over time, as ecological and evolutionary adjustments occur. Here we provide an overview of the ecological linkages of plant-soil feedbacks and underlying mechanisms of invasion. PMID- 25784669 TI - Meta-Analysis of Massage Therapy on Cancer Pain. AB - Cancer pain is the most common complaint among patients with cancer. Conventional treatment does not always relieve cancer pain satisfactorily. Therefore, many patients with cancer have turned to complementary therapies to help them with their physical, emotional, and spiritual well-being. Massage therapy is increasingly used for symptom relief in patients with cancer. The current study aimed to investigate by meta-analysis the effects of massage therapy for cancer patients experiencing pain. Nine electronic databases were systematically searched for studies published through August 2013 in English, Chinese, and Korean. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) and Cochrane risk-of-bias scales. Twelve studies, including 559 participants, were used in the meta-analysis. In 9 high-quality studies based on the PEDro scale (standardized mean difference, -1.24; 95% confidence interval, 1.72 to -0.75), we observed reduction in cancer pain after massage. Massage therapy significantly reduced cancer pain compared with no massage treatment or conventional care (standardized mean difference, -1.25; 95% confidence interval, 1.63 to -0.87). Our results indicate that massage is effective for the relief of cancer pain, especially for surgery-related pain. Among the various types of massage, foot reflexology appeared to be more effective than body or aroma massage. Our meta-analysis indicated a beneficial effect of massage for relief of cancer pain. Further well-designed, large studies with longer follow-up periods are needed to be able to draw firmer conclusions regarding the effectiveness. PMID- 25784670 TI - Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. AB - BACKGROUND: Polysaccharide K, also known as PSK or Krestin, is derived from the Coriolus versicolor mushroom and is widely used in Japan as an adjuvant immunotherapy for a variety of cancer including lung cancer. Despite reported benefits, there has been no English language synthesis of PSK for lung cancer. To address this knowledge gap, we conducted a systematic review of PSK for the treatment of lung cancer. METHODS: We searched PubMed, EMBASE, CINAHL, the Cochrane Library, AltHealth Watch, and the Library of Science and Technology from inception to August 2014 for clinical and preclinical evidence pertaining to the safety and efficacy of PSK or other Coriolus versicolor extracts for lung cancer. RESULTS: Thirty-one reports of 28 studies were included for full review and analysis. Six studies were randomized controlled trials, 5 were nonrandomized controlled trials, and 17 were preclinical studies. Nine of the reports were Japanese language publications. Fifteen of 17 preclinical studies supported anticancer effects for PSK through immunomodulation and potentiation of immune surveillance, as well as through direct tumor inhibiting actions in vivo that resulted in reduced tumor growth and antimetastatic effects. Nonrandomized controlled trials showed improvement of various survival measures including median survival and 1-, 2-, and 5-year survival. Randomized controlled trials showed benefits on a range of endpoints, including immune parameters and hematological function, performance status and body weight, tumor-related symptoms such as fatigue and anorexia, as well as survival. Although there were conflicting results for impact on some of the tumor-related symptoms and median survival, overall most randomized controlled trials supported a positive impact for PSK on these endpoints. PSK was safely administered following and in conjunction with standard radiation and chemotherapy. CONCLUSIONS: PSK may improve immune function, reduce tumor-associated symptoms, and extend survival in lung cancer patients. Larger, more rigorous randomized controlled trials for PSK in lung cancer patients are warranted. PMID- 25784671 TI - Gelatin modified ultrathin silk fibroin films for enhanced proliferation of cells. AB - Silk fibroin (SF) films were modified with gelatin (G) to explore if such SF/G films could enhance the surface biocompatibility of silk as cell growth biomaterials. Ultrathin films were coated from aqueous SF solutions pre-mixed with different amounts of G. It was found that the SF/G blended films after methanol treatment were highly stable in physiological conditions. The incorporation of G smoothed the surface morphology of the SF/G films formed. Surface-exposed RGD sequences were successfully identified on the SF/G films through specific recognition of an integrin-mimicking peptide (bearing the sequence of CWDDGWLC). Cell culture experiments with 3T3 fibroblasts demonstrated that SF/G films with 1.2-20% (w/w) G gave clear improvement in promoting cell attachment and proliferation over pure SF films. Films containing 10-20% (w/w) of G showed cell attachment and growth even superior to the pure G films. The differences as observed from this study suggest that due to the lack of mechanical strength associated with its high solubility, G could not work alone as a cell growth scaffold. The enhanced cellular responses from the blended SF/G films must result from improvement in film stability arising from SF and in cytocompatibility arising from G. The results thus indicate the potential of the SF/G blends in tissue engineering and biomedical engineering where physical and biological properties could be manipulated via mixing either as bulk biomaterials or for coating purposes. PMID- 25784672 TI - In vitro antimicrobial activity and biocompatibility of propolis containing nanohydroxyapatite. AB - The high number of biomaterial associated infections demands new strategies to prevent this problem. In this study the suitability of nanohydroxyapatite (nanoHA)-based surfaces containing two Brazilian extracts of propolis (green and red ones) to prevent bacterial growth and biofilm formation, as well as its non cytotoxic nature, was investigated. Optical density, colony forming units and MTT reduction assay were used to assess the materials' antibacterial activity against planktonic and sessile growth of Staphylococcus aureus. NanoHA matrix was able to absorb both types of propolis and the obtained results revealed the antibacterial effectiveness of the novel materials expressed as the reduction of bacterial growth and biofilm formation ability. Additionally, cell culture tests showed the growth of fibroblasts with high metabolic activity and without membrane damage. Therefore, these nanoHA-based surfaces containing natural products deriving from bees may be a promising bioactive biomaterial to be further studied with the aim of application to orthopaedic or dental devices. PMID- 25784673 TI - Readiness for Independent Living Among Youth on the Verge of Leaving Juvenile Correctional Facilities. AB - A growing body of literature has documented the dismal outcomes of youth placed in juvenile correctional facilities (JCFs) upon their return to the community. However, very little is known as to how well equipped are the youth with the necessary skills for reintegration. In the current study, the authors examine self-reports of readiness for independent living among adolescents in correctional settings on the verge of leaving care, and explore how individual, placement, and social support characteristics predict such perceived readiness. A sample of 116 adolescents (aged 15-20) placed in Israeli JCFs responded to structured self-report questionnaires. The results indicated that most adolescents perceived their readiness to leave care as high, with girls showing significantly lower levels of perceived readiness when compared with boys. Higher levels of self-esteem and optimism as well as support from peers and staff were related to better readiness. From these findings, implications for theory and practice are proposed. PMID- 25784674 TI - Letter to the Editor. PMID- 25784675 TI - A Practitioner's Response to: "Addressing Violence by Female Partners Is Vital to Prevent or Stop Violence Against Women: Evidence From the Multisite Batterer Intervention Evaluation," by Murray Straus, Violence Against Women, 20, 889-899. PMID- 25784676 TI - In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. AB - Elastic fibers are essential for the proper function of organs including cardiovascular tissues such as heart valves and blood vessels. Although (tropo)elastin production in a tissue-engineered construct has previously been described, the assembly to functional elastic fibers in vitro using human cells has been highly challenging. In the present study, we seeded primary isolated human vascular smooth muscle cells (VSMCs) onto 3D electrospun scaffolds and exposed them to defined laminar shear stress using a customized bioreactor system. Increased elastin expression followed by elastin deposition onto the electrospun scaffolds, as well as on newly formed fibers, was observed after six days. Most interestingly, we identified the successful deposition of elastogenesis-associated proteins, including fibrillin-1 and -2, fibulin-4 and 5, fibronectin, elastin microfibril interface located protein 1 (EMILIN-1) and lysyl oxidase (LOX) within our engineered constructs. Ultrastructural analyses revealed a developing extracellular matrix (ECM) similar to native human fetal tissue, which is composed of collagens, microfibrils and elastin. To conclude, the combination of a novel dynamic flow bioreactor and an electrospun hybrid polymer scaffold allowed the production and assembly of an elastic fiber containing ECM. PMID- 25784677 TI - Amniotic fluid-derived stem cells demonstrate limited cardiac differentiation following small molecule-based modulation of Wnt signaling pathway. AB - Amniotic fluid-derived stem cells (AFSC) are a promising cell source for regenerative medicine and cardiac tissue engineering. However, a non-xenotropic differentiation protocol has not been established for cardiac differentiation of AFSC. We tested a small molecule-based modulation of Wnt signaling for directed cardiac differentiation of AFSC. Cells were treated with inhibitors of glycogen synthase kinase 3 and Wnt production and secretion in a time-dependent and sequential manner, as has been demonstrated successful for cardiac differentiation of embryonic and induced pluripotent stem cells. Cells were then analyzed for gene and protein expression of markers along the cardiac lineage at multiple days during the differentiation protocol. At the midpoint of the differentiation, an increase in the percentage of AFSC expressing Islet-1, a transcription factor found in cardiac progenitor cells, and Nkx-2.5, a cardiac transcription factor, was observed. After a 15 d differentiation, a subpopulation of AFSC upregulated protein expression of smooth muscle actin, myosin light chain 2, and troponin I, all indicative of progression down a cardiac lineage. AFSC at the end of the differentiation also demonstrated organization of connexin 43, a key component of gap junctions, to cell membranes. However, no organized sarcomeres or spontaneous contraction were observed. These results demonstrate that small molecule-based modulation of Wnt signaling alone is not sufficient to generate functional cardiomyocytes from AFSC, though an upregulation of genes and proteins common to cardiac lineage cells was observed. PMID- 25784679 TI - Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. AB - Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21 0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate 1 risk. PMID- 25784678 TI - Lectins from opportunistic bacteria interact with acquired variable-region glycans of surface immunoglobulin in follicular lymphoma. AB - B-cell antigen receptor (BCR) expression is a key feature of most B-cell lymphomas, but the mechanisms of BCR signal induction and the involvement of autoantigen recognition remain unclear. In follicular lymphoma (FL) B cells, BCR expression is retained despite a chromosomal translocation that links the antiapoptotic gene BCL2 to the regulatory elements of immunoglobulin genes, thereby disrupting 1 heavy-chain allele. A remarkable feature of FL-BCRs is the acquisition of potential N-glycosylation sites during somatic hypermutation. The introduced glycans carry mannose termini, which create potential novel binding sites for mannose-specific lectins. Here, we investigated the effect of N-linked variable-region glycosylation for BCR interaction with cognate antigen and with lectins of different origins. N-glycans were found to severely impair BCR specificity and affinity to the initial cognate antigen. In addition, we found that lectins from Pseudomonas aeruginosa and Burkholderia cenocepacia bind and stimulate FL cells. Human exposure to these bacteria can occur by contact with soil and water. In addition, they represent opportunistic pathogens in susceptible hosts. Understanding the role of bacterial lectins might elucidate the pathogenesis of FL and establish novel therapeutic approaches. PMID- 25784680 TI - Therapeutic targeting of HES1 transcriptional programs in T-ALL. AB - Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1 induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo. PMID- 25784681 TI - How I treat refractory thrombotic thrombocytopenic purpura. AB - Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy. PMID- 25784682 TI - Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. AB - This phase 1/2 dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged >65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1 to 4; carfilzomib was IV administered on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to 9 cycles of CMP. In the phase 1 dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase 2 portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase 1 portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase 2 portion of the study, 44 patients were enrolled at the MTD. Among 50 efficacy-evaluable patients treated at the MTD, the ORR was 90%. The projected 3-year overall survival rate was 80%. The combination of CMP was observed to be effective in elderly patients with newly diagnosed MM. This trial was registered at www.clinicaltrials.gov as #NCT01279694 (Eudract identifier 2010-019462-92). PMID- 25784683 TI - Drug eluting stents match bypass surgery for mortality in registry study, but trial shows higher event rate. PMID- 25784684 TI - Continuing the Journey: Transitioning to the New Tenure-Track Faculty Role. PMID- 25784685 TI - Building Evidence in Health Informatics. PMID- 25784686 TI - Achieving Tenure: Planning for a Marathon, Not a Sprint. PMID- 25784687 TI - CT coronary angiography clarifies diagnosis in suspected angina, study shows. PMID- 25784689 TI - Co-composting of rose oil processing waste with caged layer manure and straw or sawdust: effects of carbon source and C/N ratio on decomposition. AB - Rose oil is a specific essential oil that is produced mainly for the cosmetics industry in a few selected locations around the world. Rose oil production is a water distillation process from petals of Rosa damascena Mill. Since the oil content of the rose petals of this variety is between 0.3-0.4% (w/w), almost 4000 to 3000 kg of rose petals are needed to produce 1 kg of rose oil. Rose oil production is a seasonal activity and takes place during the relatively short period where the roses are blooming. As a result, large quantities of solid waste are produced over a limited time interval. This research aims: (i) to determine the possibilities of aerobic co-composting as a waste management option for rose oil processing waste with caged layer manure; (ii) to identify effects of different carbon sources - straw or sawdust on co-composting of rose oil processing waste and caged layer manure, which are both readily available in Isparta, where significant rose oil production also takes place; (iii) to determine the effects of different C/N ratios on co-composting by the means of organic matter decomposition and dry matter loss. Composting experiments were carried out by 12 identical laboratory-scale composting reactors (60 L) simultaneously. The results of the study showed that the best results were obtained with a mixture consisting of 50% rose oil processing waste, 64% caged layer manure and 15% straw wet weight in terms of organic matter loss (66%) and dry matter loss (38%). PMID- 25784688 TI - Statins and congenital malformations: cohort study. AB - OBJECTIVE: To examine the teratogenic potential of statins. DESIGN: Cohort study. SETTING: United States. PARTICIPANTS: A cohort of 886,996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007. METHODS: We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs. RESULTS: 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses. CONCLUSIONS: Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe. PMID- 25784690 TI - Controlling chromium slag pollution utilising scavengers: a case of Shandong Province, China. AB - The problem of chromium slag pollution is a great challenge for China. It is now an urgent task for China to take effective measures to eliminate chromium slag pollution. This article examines the case of the treatment of chromium slag in Shandong Province and explores how chromium slag pollution can be eliminated in Shandong Province. It shows that the chromium slag stockpiled by the chemical plants was successfully utilised by local steel companies, who act as 'scavenger companies'. The driving mechanism, seeking a potential 'scavenger company' within the local region and the role of the local government on the case of Shandong Province are discussed. This article concludes that local steel companies can be utilised to effectively and efficiently treat the chromium slag while benefiting the steel companies. The local governments need to play multiple roles in solving the problem of chromium slag pollution. Seeking and identifying 'scavenger companies' within a region could be an important approach to reducing pollution within the region. PMID- 25784691 TI - Kinetic analysis on the non-isothermal degradation of plum stone waste by thermogravimetric analysis and integral master-plots method. AB - In this study, pyrolysis of plum stone was investigated by thermogravimetric analysis in a nitrogen atmosphere at heating rates of 5, 10, 20 and 40 degrees C min(-1). Pyrolysis characteristics and the thermal-decomposition rate were significantly affected by variation in the heating rate. However, the heating rate slightly affected the total yield of the volatile matters. Activation energy of the pyrolysis reaction was evaluated by model-free methods, Friedman and Kissingere-Akahirae-Sunose. Results of the Master-Plots method indicated that the most probable reaction model function was the nth order reaction model function as f(x) = (1-x) (3.11), A = 8.02x10(12) under a mean activation energy of 150.61 kJ mol(-1). Proximate and ultimate analysis showed that plum stone can be considered as a favourable source for energy production owing to its low moisture and ash content, and high volatile matter ratio and moderate heating value. PMID- 25784692 TI - Statins in pregnancy: new safety data are reassuring, but suspension of treatment is still advisable. PMID- 25784693 TI - IL-9 aggravates the development of atherosclerosis in ApoE-/- mice. AB - AIMS: Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. METHODS AND RESULTS: IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. CONCLUSION: Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions. PMID- 25784694 TI - Emerging translational approaches to target STAT3 signalling and its impact on vascular disease. AB - Acute and chronic inflammation responses characterize the vascular remodelling processes in atherosclerosis, restenosis, pulmonary arterial hypertension, and angiogenesis. The functional and phenotypic changes in diverse vascular cell types are mediated by complex signalling cascades that initiate and control genetic reprogramming. The signalling molecule's signal transducer and activator of transcription 3 (STAT3) plays a key role in the initiation and continuation of these pathophysiological changes. This review highlights the pivotal involvement of STAT3 in pathological vascular remodelling processes and discusses potential translational therapies, which target STAT3 signalling, to prevent and treat cardiovascular diseases. Moreover, current clinical trials using highly effective and selective inhibitors of STAT3 signalling for distinct diseases, such as myelofibrosis and rheumatoid arthritis, are discussed with regard to their vascular (side-) effects and their potential to pave the way for a direct use of these molecules for the prevention or treatment of vascular diseases. PMID- 25784695 TI - Nonribosomal peptides, key biocontrol components for Pseudomonas fluorescens In5, isolated from a Greenlandic suppressive soil. AB - Potatoes are cultivated in southwest Greenland without the use of pesticides and with limited crop rotation. Despite the fact that plant-pathogenic fungi are present, no severe-disease outbreaks have yet been observed. In this report, we document that a potato soil at Inneruulalik in southern Greenland is suppressive against Rhizoctonia solani Ag3 and uncover the suppressive antifungal mechanism of a highly potent biocontrol bacterium, Pseudomonas fluorescens In5, isolated from the suppressive potato soil. A combination of molecular genetics, genomics, and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) revealed an antifungal genomic island in P. fluorescens In5 encoding two nonribosomal peptides, nunamycin and nunapeptin, which are key components for the biocontrol activity by strain In5 in vitro and in soil microcosm experiments. Furthermore, complex microbial behaviors were highlighted. Whereas nunamycin was demonstrated to inhibit the mycelial growth of R. solani Ag3, but not that of Pythium aphanidermatum, nunapeptin instead inhibited P. aphanidermatum but not R. solani Ag3. Moreover, the synthesis of nunamycin by P. fluorescens In5 was inhibited in the presence of P. aphanidermatum. Further characterization of the two peptides revealed nunamycin to be a monochlorinated 9-amino-acid cyclic lipopeptide with similarity to members of the syringomycin group, whereas nunapeptin was a 22-amino-acid cyclic lipopeptide with similarity to corpeptin and syringopeptin. IMPORTANCE: Crop rotation and systematic pest management are used to only a limited extent in Greenlandic potato farming. Nonetheless, although plant-pathogenic fungi are present in the soil, the farmers do not experience major plant disease outbreaks. Here, we show that a Greenlandic potato soil is suppressive against Rhizoctonia solani, and we unravel the key biocontrol components for Pseudomonas fluorescens In5, one of the potent biocontrol bacteria isolated from this Greenlandic suppressive soil. Using a combination of molecular genetics, genomics, and microbial imaging mass spectrometry, we show that two cyclic lipopeptides, nunamycin and nunapeptin, are important for the biocontrol activity of P. fluorescens In5 both in vitro and in microcosm assays. Furthermore, we demonstrate that the synthesis of nunamycin is repressed by the oomycete Pythium aphanidermatum. Overall, our report provides important insight into interkingdom interference between bacteria and fungi/oomycetes. PMID- 25784696 TI - Trypanosoma brucei RRM1 is a nuclear RNA-binding protein and modulator of chromatin structure. AB - TbRRM1 of Trypanosoma brucei is a nucleoprotein that was previously identified in a search for splicing factors in T. brucei. We show that TbRRM1 associates with mRNAs and with the auxiliary splicing factor polypyrimidine tract-binding protein 2, but not with components of the core spliceosome. TbRRM1 also interacts with several retrotransposon hot spot (RHS) proteins and histones. RNA immunoprecipitation of a tagged form of TbRRM1 from procyclic (insect) form trypanosomes identified ca. 1,500 transcripts that were enriched and 3,000 transcripts that were underrepresented compared to cellular mRNA. Enriched transcripts encoded RNA-binding proteins, including TbRRM1 itself, several RHS transcripts, mRNAs with long coding regions, and a high proportion of stage regulated mRNAs that are more highly expressed in bloodstream forms. Transcripts encoding ribosomal proteins, other factors involved in translation, and procyclic specific transcripts were underrepresented. Knockdown of TbRRM1 by RNA interference caused widespread changes in mRNA abundance, but these changes did not correlate with the binding of the protein to transcripts, and most splice sites were unchanged, negating a general role for TbRRM1 in splice site selection. When changes in mRNA abundance were mapped across the genome, regions with many downregulated mRNAs were identified. Two regions were analyzed by chromatin immunoprecipitation, both of which exhibited increases in nucleosome occupancy upon TbRRM1 depletion. In addition, subjecting cells to heat shock resulted in translocation of TbRRM1 to the cytoplasm and compaction of chromatin, consistent with a second role for TbRRM1 in modulating chromatin structure. IMPORTANCE: Trypanosoma brucei, the parasite that causes human sleeping sickness, is transmitted by tsetse flies. The parasite progresses through different life cycle stages in its two hosts, altering its pattern of gene expression in the process. In trypanosomes, protein-coding genes are organized as polycistronic units that are processed into monocistronic mRNAs. Since genes in the same unit can be regulated independently of each other, it is believed that gene regulation is essentially posttranscriptional. In this study, we investigated the role of a nuclear RNA-binding protein, TbRRM1, in the insect stage of the parasite. We found that TbRRM1 binds nuclear mRNAs and also affects chromatin status. Reduction of nuclear TbRRM1 by RNA interference or heat shock resulted in chromatin compaction. We propose that TbRRM1 regulates RNA polymerase II-driven gene expression both cotranscriptionally, by facilitating transcription and efficient splicing, and posttranscriptionally, via its interaction with nuclear mRNAs. PMID- 25784697 TI - The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity. AB - Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha] and macrophage inflammatory protein 1 alpha [MIP-1alpha]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance. IMPORTANCE: Farnesol is a quorum-sensing molecule which controls morphological plasticity of the pathogenic yeast Candida albicans. As such, it is a major mediator of intraspecies communication. Here, we investigated the impact of farnesol on human innate immune cells known to be important for fungal clearance and protective immunity. We show that farnesol is able to enhance inflammation by inducing activation of neutrophils and monocytes. At the same time, farnesol impairs differentiation of monocytes into immature dendritic cells (iDC) by modulating surface phenotype, cytokine release and migrational behavior. Consequently, iDC generated in the presence of farnesol are unable to induce proper T cell responses and fail to secrete Th1 promoting interleukin 12 (IL-12). As farnesol induced down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, desensitization to GM-CSF could potentially explain transcriptional reprofiling of iDC effector molecules. Taken together, our data show that farnesol can also mediate Candida-host communication and is able to act as a virulence factor. PMID- 25784698 TI - Novel type III effectors in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that causes chronic and acute infections in immunocompromised patients. Most P. aeruginosa strains encode an active type III secretion system (T3SS), utilized by the bacteria to deliver effector proteins from the bacterial cell directly into the cytoplasm of the host cell. Four T3SS effectors have been discovered and extensively studied in P. aeruginosa: ExoT, ExoS, ExoU, and ExoY. This is especially intriguing in light of P. aeruginosa's ability to infect a wide range of hosts. We therefore hypothesized that additional T3SS effectors that have not yet been discovered are encoded in the genome of P. aeruginosa. Here, we applied a machine learning classification algorithm to identify novel P. aeruginosa effectors. In this approach, various types of data are integrated to differentiate effectors from the rest of the open reading frames of the bacterial genome. Due to the lack of a sufficient learning set of positive effectors, our machine learning algorithm integrated genomic information from another Pseudomonas species and utilized dozens of features accounting for various aspects of the effector coding genes and their products. Twelve top-ranking predictions were experimentally tested for T3SS-specific translocation, leading to the discovery of two novel T3SS effectors. We demonstrate that these effectors are not part of the injection structural complex and report initial efforts toward their characterization. IMPORTANCE: Pseudomonas aeruginosa uses a type III secretion system (T3SS) to secrete toxic proteins, termed effectors, directly into the cytoplasm of the host cell. The activation of this secretion system is correlated with disease severity and patient death. Compared with many other T3SS utilizing pathogenic bacteria, P. aeruginosa has a fairly limited arsenal of effectors that have been identified. This is in sharp contrast with the wide range of hosts that this bacterium can infect. The discovery of two novel effectors described here is an important step toward better understanding of the virulence and host evasion mechanisms adopted by this versatile pathogen and may provide novel approaches to treat P. aeruginosa infections. PMID- 25784699 TI - Erratum for Cheng et al., Ehrlichia chaffeensis proliferation begins with NtrY/NtrX and PutA/GlnA upregulation and CtrA degradation induced by proline and glutamine uptake. PMID- 25784700 TI - Intercellular diffusion of a fluorescent sucrose analog via the septal junctions in a filamentous cyanobacterium. AB - Many filamentous cyanobacteria produce specialized nitrogen-fixing cells called heterocysts, which are located at semiregular intervals along the filament with about 10 to 20 photosynthetic vegetative cells in between. Nitrogen fixation in these complex multicellular bacteria depends on metabolite exchange between the two cell types, with the heterocysts supplying combined-nitrogen compounds but dependent on the vegetative cells for photosynthetically produced carbon compounds. Here, we used a fluorescent tracer to probe intercellular metabolite exchange in the filamentous heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120. We show that esculin, a fluorescent sucrose analog, is incorporated by a sucrose import system into the cytoplasm of Anabaena cells. The cytoplasmic esculin is rapidly and reversibly exchanged across vegetative-vegetative and vegetative-heterocyst cell junctions. Our measurements reveal the kinetics of esculin exchange and also show that intercellular metabolic communication is lost in a significant fraction of older heterocysts. SepJ, FraC, and FraD are proteins located at the intercellular septa and are suggested to form structures analogous to gap junctions. We show that a DeltasepJ DeltafraC DeltafraD triple mutant shows an altered septum structure with thinner septa but a denser peptidoglycan layer. Intercellular diffusion of esculin and fluorescein derivatives is impaired in this mutant, which also shows a greatly reduced frequency of nanopores in the intercellular septal cross walls. These findings suggest that FraC, FraD, and SepJ are important for the formation of junctional structures that constitute the major pathway for feeding heterocysts with sucrose. IMPORTANCE: Anabaena and its relatives are filamentous cyanobacteria that exhibit a sophisticated form of prokaryotic multicellularity, with the formation of differentiated cell types, including normal photosynthetic cells and specialized nitrogen-fixing cells called heterocysts. The question of how heterocysts communicate and exchange metabolites with other cells in the filament is key to understanding this form of bacterial multicellularity. Here we provide the first information on the intercellular exchange of a physiologically important molecule, sucrose. We show that a fluorescent sucrose analog can be imported into the Anabaena cytoplasm by a sucrose import system. Once in the cytoplasm, it is rapidly and reversibly exchanged among all of the cells in the filament by diffusion across the septal junctions. Photosynthetically produced sucrose likely follows the same route from cytoplasm to cytoplasm. We identify some of the septal proteins involved in sucrose exchange, and our results indicate that these proteins form structures functionally analogous to metazoan gap junctions. PMID- 25784701 TI - Cyclic GMP balance is critical for malaria parasite transmission from the mosquito to the mammalian host. AB - Transmission of malaria occurs during Anopheles mosquito vector blood meals, when Plasmodium sporozoites that have invaded the mosquito salivary glands are delivered to the mammalian host. Sporozoites display a unique form of motility that is essential for their movement across cellular host barriers and invasion of hepatocytes. While the molecular machinery powering motility and invasion is increasingly well defined, the signaling events that control these essential parasite activities have not been clearly delineated. Here, we identify a phosphodiesterase (PDEgamma) in Plasmodium, a regulator of signaling through cyclic nucleotide second messengers. Reverse transcriptase PCR (RT-PCR) analysis and epitope tagging of endogenous PDEgamma detected its expression in blood stages and sporozoites of Plasmodium yoelii. Deletion of PDEgamma (pdegamma(-)) rendered sporozoites nonmotile, and they failed to invade the mosquito salivary glands. Consequently, PDEgamma deletion completely blocked parasite transmission by mosquito bite. Strikingly, pdegamma(-) sporozoites showed dramatically elevated levels of cyclic GMP (cGMP), indicating that a perturbation in cyclic nucleotide balance is involved in the observed phenotypic defects. Transcriptome sequencing (RNA-Seq) analysis of pdegamma(-) sporozoites revealed reduced transcript abundance of genes that encode key components of the motility and invasion apparatus. Our data reveal a crucial role for PDEgamma in maintaining the cyclic nucleotide balance in the malaria parasite sporozoite stage, which in turn is essential for parasite transmission from mosquito to mammal. IMPORTANCE: Malaria is a formidable threat to human health worldwide, and there is an urgent need to identify novel drug targets for this parasitic disease. The parasite is transmitted by mosquito bite, inoculating the host with infectious sporozoite stages. We show that cellular signaling by cyclic nucleotides is critical for transmission of the parasite from the mosquito vector to the mammalian host. Parasite phosphodiesterase gamma is essential for maintaining cyclic nucleotide balance, and its deletion blocks transmission of sporozoites. A deeper understanding of the signaling mechanisms involved in transmission might inform the discovery of novel drugs that interrupt this essential step in the parasite life cycle. PMID- 25784702 TI - Deficiency of the novel exopolyphosphatase Rv1026/PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis can persist for decades in the human host. Stringent response pathways involving inorganic polyphosphate [poly(P)], which is synthesized and hydrolyzed by polyphosphate kinase (PPK) and exopolyphosphatase (PPX), respectively, are believed to play a key regulatory role in bacterial persistence. We show here that M. tuberculosis poly(P) accumulation is temporally linked to bacillary growth restriction. We also identify M. tuberculosis Rv1026 as a novel exopolyphosphatase with hydrolytic activity against long-chain poly(P). Using a tetracycline-inducible expression system to knock down expression of Rv1026 (ppx2), we found that M. tuberculosis poly(P) accumulation leads to slowed growth and reduced susceptibility to isoniazid, increased resistance to heat and acid pH, and enhanced intracellular survival during macrophage infection. By transmission electron microscopy, the ppx2 knockdown strain exhibited increased cell wall thickness, which was associated with reduced cell wall permeability to hydrophilic drugs rather than induction of drug efflux pumps or altered biofilm formation relative to the empty vector control. Transcriptomic and metabolomic analysis revealed a metabolic downshift of the ppx2 knockdown characterized by reduced transcription and translation and a downshift of glycerol-3-phosphate levels. In summary, poly(P) plays an important role in M. tuberculosis growth restriction and metabolic downshift and contributes to antibiotic tolerance through altered cell wall permeability. IMPORTANCE: The stringent response, involving the regulatory molecules inorganic polyphosphate [poly(P)] and (p)ppGpp, is believed to mediate Mycobacterium tuberculosis persistence. In this study, we identified a novel enzyme (Rv1026, PPX2) responsible for hydrolyzing long-chain poly(P). A genetically engineered M. tuberculosis strain deficient in the ppx2 gene showed increased poly(P) levels, which were associated with early bacterial growth arrest and reduced susceptibility to the first-line drug isoniazid, as well as increased bacterial survival during exposure to stress conditions and within macrophages. Relative to the control strain, the mutant showed increased thickness of the cell wall and reduced drug permeability. Global gene expression and metabolite analysis revealed reduced expression of the transcriptional and translational machinery and a shift in carbon source utilization. In summary, regulation of the poly(P) balance is critical for persister formation in M. tuberculosis. PMID- 25784703 TI - Ralstonia solanacearum uses inorganic nitrogen metabolism for virulence, ATP production, and detoxification in the oxygen-limited host xylem environment. AB - Genomic data predict that, in addition to oxygen, the bacterial plant pathogen Ralstonia solanacearum can use nitrate (NO3(-)), nitrite (NO2(-)), nitric oxide (NO), and nitrous oxide (N2O) as terminal electron acceptors (TEAs). Genes encoding inorganic nitrogen reduction were highly expressed during tomato bacterial wilt disease, when the pathogen grows in xylem vessels. Direct measurements found that tomato xylem fluid was low in oxygen, especially in plants infected by R. solanacearum. Xylem fluid contained ~25 mM NO3(-), corresponding to R. solanacearum's optimal NO3(-) concentration for anaerobic growth in vitro. We tested the hypothesis that R. solanacearum uses inorganic nitrogen species to respire and grow during pathogenesis by making deletion mutants that each lacked a step in nitrate respiration (DeltanarG), denitrification (DeltaaniA, DeltanorB, and DeltanosZ), or NO detoxification (DeltahmpX). The DeltanarG, DeltaaniA, and DeltanorB mutants grew poorly on NO3( ) compared to the wild type, and they had reduced adenylate energy charge levels under anaerobiosis. While NarG-dependent NO3(-) respiration directly enhanced growth, AniA-dependent NO2(-) reduction did not. NO2(-) and NO inhibited growth in culture, and their removal depended on denitrification and NO detoxification. Thus, NO3(-) acts as a TEA, but the resulting NO2(-) and NO likely do not. None of the mutants grew as well as the wild type in planta, and strains lacking AniA (NO2(-) reductase) or HmpX (NO detoxification) had reduced virulence on tomato. Thus, R. solanacearum exploits host NO3(-) to respire, grow, and cause disease. Degradation of NO2(-) and NO is also important for successful infection and depends on denitrification and NO detoxification systems. IMPORTANCE: The plant pathogenic bacterium Ralstonia solanacearum causes bacterial wilt, one of the world's most destructive crop diseases. This pathogen's explosive growth in plant vascular xylem is poorly understood. We used biochemical and genetic approaches to show that R. solanacearum rapidly depletes oxygen in host xylem but can then respire using host nitrate as a terminal electron acceptor. The microbe uses its denitrification pathway to detoxify the reactive nitrogen species nitrite (a product of nitrate respiration) and nitric oxide (a plant defense signal). Detoxification may play synergistic roles in bacterial wilt virulence by converting the host's chemical weapon into an energy source. Mutant bacterial strains lacking elements of the denitrification pathway could not grow as well as the wild type in tomato plants, and some mutants were also reduced in virulence. Our results show how a pathogen's metabolic activity can alter the host environment in ways that increase pathogen success. PMID- 25784704 TI - Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. AB - Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans. IMPORTANCE: Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases. PMID- 25784706 TI - US consumer group criticizes proposal to allow drug makers to challenge safety information. PMID- 25784705 TI - Stress granules regulate double-stranded RNA-dependent protein kinase activation through a complex containing G3BP1 and Caprin1. AB - Stress granules (SGs) are dynamic cytoplasmic repositories containing translationally silenced mRNAs that assemble upon cellular stress. We recently reported that the SG nucleating protein G3BP1 promotes antiviral activity and is essential in double-stranded RNA-dependent protein kinase (PKR) recruitment to stress granules, thereby driving phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). Here, we delineate the mechanism for SG-dependent PKR activation. We show that G3BP1 and inactive PKR directly interact with each other, dependent on both the NTF2-like and PXXP domains of G3BP1. The G3BP1-interacting protein Caprin1 also directly interacts with PKR, regulates efficient PKR activation at the stress granule, and is also integral for the release of active PKR into the cytoplasm to engage in substrate recognition. The G3BP1-Caprin1-PKR complex represents a new mode of PKR activation and is important for antiviral activity of G3BP1 and PKR during infection with mengovirus. Our data links stress responses and their resultant SGs with innate immune activation through PKR without a requirement for foreign double-stranded RNA (dsRNA) pattern recognition. IMPORTANCE: Our previous work indicates that stress granules have antiviral activity and mediate innate immunity through functions of G3BP1; however, the mechanistic details of these functions were not resolved. We show that much of the antiviral activity of stress granules is contingent on the function of PKR in a complex with G3BP1 and Caprin1. The PKR-G3BP1-Caprin1 complex undergoes dynamic transitioning within and outside stress granules to accomplish PKR activation and translational repression. This mechanism appears to function distinctly from canonical pattern recognition of double-stranded RNA by PKR. Therefore, this mechanism bridges the stress response with innate immunity, allowing the cell to respond to many cellular stressors and amplify the pathogen pattern recognition systems of innate immunity. PMID- 25784707 TI - Physicians' personal values in determining medical decision-making capacity: a survey study. AB - Decision-making capacity (DMC) evaluations are complex clinical judgements with important ethical implications for patients' self-determination. They are achieved not only on descriptive grounds but are inherently normative and, therefore, dependent on the values held by those involved in the DMC evaluation. To date, the issue of whether and how physicians' personal values relate to DMC evaluation has never been empirically investigated. The present survey study aimed to investigate this question by exploring the relationship between physicians' value profiles and the use of risk-relative standards in capacity evaluations. The findings indicate that physicians' personal values are of some significance in this regard. Those physicians with relatively high scores on the value types of achievement, power-resource, face and conformity to interpersonal standards were more likely to apply risk-relative criteria in a range of situations, using more stringent assessment standards when interventions were riskier. By contrast, those physicians who strongly emphasise hedonism, conformity to rules and universalism concern were more likely to apply equal standards regardless of the consequences of a decision. Furthermore, it has been shown that around a quarter of all respondents do not appreciate that their values impact on their DMC evaluations, highlighting a need to better sensitise physicians in this regard. The implications of these findings are discussed, especially in terms of the moral status of the potential and almost unavoidable influence of physicians' values. PMID- 25784708 TI - Syphilitic condylomata lata mimicking anogenital warts. PMID- 25784709 TI - Comparison of benazepril and losartan on endothelial function and vascular stiffness in patients with Type 2 diabetes mellitus and hypertension: A randomized controlled trial. AB - INTRODUCTION: The purpose of this study was to compare the effects of benazepril and losartan on endothelial function and vascular stiffness, in patients with diabetes mellitus and hypertension. MATERIALS AND METHODS: We included hypertensive diabetic patients with an office systolic blood pressure (BP) ? 130 mmHg and/or diastolic BP ? 80 mmHg. Patients were rolled over to amlodipine for 6 weeks, then we performed C-reactive protein assays, BP measurement and vascular tests; next, patients were randomized to benazepril or losartan. The tests were repeated after 12 weeks. RESULTS: We randomized 14 patients to benazepril and 16 to losartan. There were no differences in systolic (139 versus 134 mmHg, p = 0.618) and diastolic (82 versus 80 mmHg, p = 0.950) BP at the end of the study. C reactive protein values were lower in the benazepril group (0.38 versus 0.42 mg/dl, p = 0.020). There was a slightly higher flow-mediated vasodilation (FMD) response in the benazepril group (45% increase, p = 0.057) than in the losartan group (19% increase, p = 0.132). Both central systolic BP (129 versus 123 mmHg, p = 0.934) and carotid-femoral pulse wave velocity (cfPWV) (8.5 versus 8.5 m/s, p = 0.280) were the same between groups. CONCLUSIONS: Hypertensive diabetic patients using benazepril had a greater reduction in C-reactive protein, and a slight improvement in FMD, than those taking losartan. PMID- 25784710 TI - Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials. AB - INTRODUCTION: The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear. METHODS: MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials. RESULTS: Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (-5.24, 95% confidence interval (CI) -8.65, -1.82 mmHg; p=0.003 and -1.96, 95% CI -3.22, -0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials. CONCLUSIONS: The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established. PMID- 25784711 TI - Assessment of the relationship between ACE I/D gene polymorphism and renal allograft survival. AB - BACKGROUND AND OBJECTIVE: The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and renal allograft survival after renal transplantation from the published reports are still debatable. This study was performed to evaluate the relationship between the ACE I/D gene polymorphism and renal allograft survival after renal transplantation using meta-analysis. METHOD: Eligible studies were identified from PubMed and Cochrane Library on 1 November 2014, and eligible studies were recruited and synthesized using a meta-analysis methodology. RESULTS: Twelve investigations were included in this meta-analysis for the assessment of the relationship between the ACE I/D gene polymorphism and renal allograft survival. In this meta analysis, the ACE I/D gene polymorphism was not associated with renal allograft survival after renal transplantation for overall populations, Caucasians, Brazilians and Africans. Interestingly, the ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. CONCLUSIONS: ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. However, more studies should be performed to confirm this association. PMID- 25784713 TI - Mental health effects of varenicline. PMID- 25784712 TI - Childhood conscientiousness predicts the social gradient of smoking in adulthood: a life course analysis. AB - BACKGROUND AND AIMS: The social gradient in smoking is well known, with higher rates among those in less advantaged socioeconomic position. Some recent research has reported that personality characteristics partly explain this gradient. However, the majority of existing work is limited by cross-sectional designs unsuitable to determine whether differences in conscientiousness are a predictor or a product of social inequalities. Adopting a life course perspective, we investigated in the current paper the influence of conscientiousness in early and mid-life on the social gradient in smoking and the role of potential confounding factors in a large longitudinal cohort study. METHODS: Using data from the 1958 National Child Development Study, we examined the extent to which two measures of conscientiousness, one assessed with a personality questionnaire at age 50 and one derived from three related items at 16 years in childhood, explained the social gradient of smoking at age 50 by comparing nested logistic regression models that included social class at birth, cognitive ability, attention and conduct problems at age 7, and educational qualification. RESULTS: Childhood conscientiousness was a significant predictor of smoking at 50 years (OR=0.86, CI (95%) 0.84 to 0.88), explaining 5.0% of the social gradient independent of all other variables. Childhood conscientiousness was a stronger predictor than adult conscientiousness, statistically accounting for the observed direct association of adult conscientiousness with smoking. CONCLUSIONS: Conscientiousness may be a predictor rather than a product of social differences in smoking. Inclusion of personality measures and adoption of a life course perspective add significantly to our understanding of health inequalities. PMID- 25784714 TI - Exploring perceptions and experiences of Bolivian health researchers with research ethics. AB - In Bolivia, there is increasing interest in incorporating research ethics into study procedures, but there have been inconsistent application of research ethics practices. Minimal data exist regarding the experiences of researchers concerning the ethical conduct of research. A cross-sectional study was administered to Bolivian health leaders with research experience (n = 82) to document their knowledge, perceptions, and experiences of research ethics committees and infrastructure support for research ethics. Results showed that 16% of respondents reported not using ethical guidelines to conduct their research and 66% indicated their institutions did not consistently require ethics approval for research. Barriers and facilitators to incorporate research ethics into practice were outlined. These findings will help inform a comprehensive rights-based research ethics education program in Bolivia. PMID- 25784716 TI - Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis. AB - Triple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, EGFR is frequently activated in a subset of TNBCs and represents a viable clinical target. Because the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared with normal breast epithelial cells. Stable knockdown (KD) of Endo II was achieved in two TNBC cell lines, and although cell viability was unaffected, defects in receptor-mediated endocytosis were observed. EGFR signaling to Erk and Akt kinases was impaired in Endo II KD cells, and this correlated with reduced rates of EGFR internalization and cell motility. Endo II KD cells also displayed defects in three dimensional (3D) cell invasion, and this correlated with impaired extracellular matrix degradation and internalization of MT1-MMP. Endo II silencing also caused a significant reduction in TNBC tumor growth and lung metastasis in mammary orthotopic tumor xenograft assays. In human breast tumor specimens, Endo II expression was highest in TNBC tumors compared with other subtypes, and at the level of gene expression, high Endo II was associated with reduced relapse-free survival in patients with basal like breast cancers. Together, these results identify a positive role for Endo II in TNBC tumor metastasis and a potential link with poor prognosis. IMPLICATIONS: Endophilin A2 and related adaptor proteins represent important signaling hubs to target in metastatic cancers. PMID- 25784718 TI - Diabetes groups call for better regulation of insulin pumps. PMID- 25784717 TI - CHCHD2 Is Coamplified with EGFR in NSCLC and Regulates Mitochondrial Function and Cell Migration. AB - Coiled-coil-helix-coiled-coil-helix domain-containing 2, a mitochondrial protein, encoded by CHCHD2 is located at chromosome 7p11.2 and proximal to the EGFR gene. Here, bioinformatic analyses revealed that CHCHD2 is consistently coamplified with EGFR in non-small cell lung carcinoma (NSCLC). In addition, CHCHD2 and EGFR protein expression levels were positively correlated and upregulated relative to normal lung in NSCLC tumor-derived xenografts. Knockdown of CHCHD2 expression in NSCLC cells attenuated cell proliferation, migration, and mitochondrial respiration. CHCHD2 protein-protein interactions were assessed by the complementary approaches of affinity purification mass spectrometry and in vivo proximity ligation. The CHCHD2 interactome includes the apparent hub proteins C1QBP (a mitochondrial protein) and YBX1 (an oncogenic transcription factor), and an overlapping set of hub-associated proteins implicated in cell regulation. IMPLICATIONS: CHCHD2 influences mitochondrial and nuclear functions and contributes to the cancer phenotype associated with 7p11.2 amplification in NSCLC. PMID- 25784715 TI - Nitric oxide generated by nitrate reductase increases nitrogen uptake capacity by inducing lateral root formation and inorganic nitrogen uptake under partial nitrate nutrition in rice. AB - Increasing evidence shows that partial nitrate nutrition (PNN) can be attributed to improved plant growth and nitrogen-use efficiency (NUE) in rice. Nitric oxide (NO) is a signalling molecule involved in many physiological processes during plant development and nitrogen (N) assimilation. It remains unclear whether molecular NO improves NUE through PNN. Two rice cultivars (cvs Nanguang and Elio), with high and low NUE, respectively, were used in the analysis of NO production, nitrate reductase (NR) activity, lateral root (LR) density, and (15)N uptake under PNN, with or without NO production donor and inhibitors. PNN increased NO accumulation in cv. Nanguang possibly through the NIA2-dependent NR pathway. PNN-mediated NO increases contributed to LR initiation, (15)NH4(+)/(15)NO3(-) influx into the root, and levels of ammonium and nitrate transporters in cv. Nanguang but not cv. Elio. Further results revealed marked and specific induction of LR initiation and (15)NH4(+)/(15)NO3(-) influx into the roots of plants supplied with NH4(+)+sodium nitroprusside (SNP) relative to those supplied with NH4(+) alone, and considerable inhibition upon the application of cPTIO or tungstate (NR inhibitor) in addition to PNN, which is in agreement with the change in NO fluorescence in the two rice cultivars. The findings suggest that NO generated by the NR pathway plays a pivotal role in improving the N acquisition capacity by increasing LR initiation and the inorganic N uptake rate, which may represent a strategy for rice plants to adapt to a fluctuating nitrate supply and increase NUE. PMID- 25784719 TI - First-in-human trial of the safety, pharmacokinetics and immunogenicity of a PEGylated anti-CD40L antibody fragment (CDP7657) in healthy individuals and patients with systemic lupus erythematosus. AB - OBJECTIVE: The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE). METHODS: This randomized, double-blind, single-dose, dose escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004-5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5-60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1. RESULTS: Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657. CONCLUSION: Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE. PMID- 25784720 TI - Neonatal invasive Haemophilus influenzae disease in England and Wales: epidemiology, clinical characteristics, and outcome. AB - BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) frequently causes noninvasive upper respiratory tract infections in children but can cause invasive disease, mainly in older adults. An increased burden of invasive NTHi disease in the perinatal period has been reported by a number of studies. Here we describe the epidemiology, clinical characteristics, and outcome of neonatal invasive H. influenzae disease in England and Wales over a 5-year period. METHODS: Public Health England conducts enhanced national surveillance of invasive H. influenzae disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed cases in infants aged <=31 days during 2009-2013. RESULTS: Overall, 118 live-born neonates had laboratory-confirmed invasive H. influenzae disease: 115 (97%) were NTHi, 2 were serotype f, and 1 was serotype b. NTHi was isolated within 48 hours of birth (early-onset) in 110 of 115 (96%) cases, and 70 of 110 (64%) presented with septicemia. Only 17 mothers (15%) had suspected bacterial infection requiring antibiotics during labor. Few (8/110 [7%]) neonates had comorbidities. The incidence of early-onset NTHi increased exponentially with prematurity, from 0.9 per 100 000 (95% confidence interval [CI], .6-1.4) in term neonates to 342 per 100 000 (95% CI, 233.9-482.7) in neonates born at <28 weeks' gestation (incidence rate ratio, 365 [95% CI, 205-659]; P < .001). Case fatality for early-onset NTHi was 19% (21/110); each additional gestational week reduced the odds of dying by 21% (odds ratio, 0.79 [95% CI, .69-.90]; P < .01). A quarter of neonates who survived experienced long-term complications. CONCLUSIONS: Early onset neonatal NTHi disease is strongly associated with premature birth and causes significant morbidity and mortality. PMID- 25784722 TI - Extending opening hours in general practice won't improve access for patients most in need. PMID- 25784721 TI - Salmeterol Efficacy and Bias in the Activation and Kinase-Mediated Desensitization of beta2-Adrenergic Receptors. AB - Salmeterol is a long-acting beta2-adrenergic receptor (beta2AR) agonist that is widely used as a bronchodilator for the treatment of persistent asthma and chronic obstructive pulmonary disease in conjunction with steroids. Previous studies demonstrated that salmeterol showed weak efficacy for activation of adenylyl cyclase; however, its efficacy in the complex desensitization of the beta2AR remains poorly understood. In this work, we provide insights into the roles played by the G protein-coupled receptor kinase/arrestin and protein kinase A in salmeterol-mediated desensitization through bioluminescence resonance energy transfer (BRET) studies of liganded-beta2AR binding to arrestin and through kinetic studies of cAMP turnover. First, BRET demonstrated a much reduced efficacy for salmeterol recruitment of arrestin to beta2AR relative to isoproterenol. The ratio of BRETISO/BRETSALM after 5-minute stimulation was 20 and decreased to 5 after 35 minutes, reflecting a progressive decline in BRETISO and a stable BRETSALM. Second, to assess salmeterol efficacy for functional desensitization, we examined the kinetics of salmeterol-induced cAMP accumulation (0-30 minutes) in human airway smooth muscle cells in the presence and absence of phosphodiesterase inhibition. Analysis of shaping of cAMP turnover for both agonists demonstrated significant salmeterol desensitization, although it was reduced relative to isoproterenol. Using an isoproterenol rescue protocol after either short-term (10 minutes) or long-term (2 and 14 hours) salmeterol pretreatments, we found that salmeterol progressively depressed isoproterenol stimulation but did not prevent subsequent rescue by isoproterenol and additional isoproterenol-mediated desensitization. Our findings reveal a complex efficacy for functional desensitization, demonstrating that although salmeterol shows weak efficacy for adenylyl cyclase activation and G protein-coupled receptor kinase/arrestin-mediated desensitization, it acts as a strong agonist in highly amplified protein kinase A-mediated events. PMID- 25784723 TI - Regional ventricular performance and exercise training in children and young adults after repair of tetralogy of Fallot: randomized controlled pilot study. AB - BACKGROUND: Public-health guidelines recommend patients with congenital heart disease to exercise. Studies have shown that patients with congenital heart disease can improve physical exercise capacity. The effect of training on regional ventricular performance has hardly been studied. We performed a pilot study to assess whether an exercise training program would result in adverse changes of regional ventricular performance in patients with corrected tetralogy of Fallot. METHODS AND RESULTS: Multicenter prospective randomized controlled pilot study in patients with tetralogy of Fallot aged 10 to 25 years. A 12-week standardized aerobic dynamic exercise training program (3 one-hour sessions per week) was used. Pre- and post-training cardiopulmonary exercise tests, MRI, and echocardiography, including tissue-Doppler imaging, were performed. Patients were randomized to the exercise group (n=28) or control group (n=20). One patient in the exercise group dropped out. Change in tissue-Doppler imaging parameters was similar in the exercise group and control group (change in right ventricle free wall peak velocity E' exercise group, 0.8+/-2.6 cm/s; control group, 0.9+/-4.1; peak velocity A' exercise group, 0.4+/-2.4 m/s; control group 4.6+/-18.1 cm/s). CONCLUSIONS: This randomized controlled pilot study provides preliminary data suggesting that regional ventricular performance is well maintained during 3 month aerobic dynamic exercise training in children and young adults with repaired tetralogy of Fallot. This information might help patients adhere to current public-health guidelines. CLINICAL TRIAL REGISTRATION: URL: http//:www.trialregister.nl. Unique identifier: NTR2731. PMID- 25784724 TI - Multimodality imaging of extensive caseating intramyocardial calcification secondary to lymphoma. PMID- 25784725 TI - Serum and urine markers of collagen degradation reflect renal fibrosis in experimental kidney diseases. AB - BACKGROUND: The extent of renal fibrosis in chronic kidney disease (CKD) is the best predictor for progression of most renal diseases. To date, no established biomarkers of renal fibrosis exist. METHODS: We measured circulating and urinary specific matrix metalloproteinase (MMP)-generated collagen type I and III degradation fragments (C1M and C3M) and an N-terminal propeptide of collagen III (Pro-C3), as markers of collagen type III production, in three rat models of CKD and fibrosis: renal mass reduction (5/6 nephrectomy), progressive glomerulonephritis (chronic anti-Thy1.1 nephritis) and adenine crystal-induced nephropathy. Healthy rats served as controls. RESULTS: In all three models, the animals developed significant CKD and renal fibrosis. Compared with healthy rats, serum C1M and C3M significantly increased in rats with 5/6 nephrectomy and adenine nephropathy (2- to 3-fold), but not with chronic anti-Thy1.1 nephritis. Urinary C1M and C3M levels increased 9- to 100-fold in all three models compared with controls. Urinary degradation markers correlated closely with renal deposition of collagen type I and type III. Pro-C3 was significantly increased only in the urine of 5/6 nephrectomy rats. CONCLUSIONS: In particular, urinary markers of MMP-driven collagen degradation, rather than collagen production markers, may represent a novel, specific and non-invasive diagnostic approach to assess kidney fibrosis. PMID- 25784726 TI - Success, significance, and social responsibility. PMID- 25784727 TI - A Reevaluation of the Role of Aedes albopictus in Dengue Transmission. PMID- 25784728 TI - Integrated Sentinel Surveillance Linking Genetic, Antigenic, and Epidemiologic Monitoring of Influenza Vaccine-Virus Relatedness and Effectiveness During the 2013-2014 Influenza Season. AB - BACKGROUND: Canada's Sentinel Physician Surveillance Network links genetic, antigenic, and vaccine effectiveness (VE) measures in an integrated platform of influenza monitoring, described here for the 2013-2014 influenza season of resurgent A(H1N1)pdm09 and late-season type B activity. METHODS: VE was estimated as [1 - odds ratio] * 100% and compared vaccination status between individuals who tested positive (cases) and those who tested negative (controls) for influenza virus. Vaccine-virus relatedness was assessed by genomic sequence analysis and hemagglutination inhibition assays. RESULTS: Analyses included 1037 controls (of whom 33% were vaccinated) and 663 cases (of whom 14% were vaccinated). A total of 415 cases tested positive for A(H1N1)pdm09 virus, 15 tested positive for A(H3N2) virus, 191 tested positive for B/Yamagata-lineage virus, 6 tested positive for B/Victoria-lineage virus, and 36 tested positive for viruses of unknown subtype or lineage. A(H1N1)pdm09 viruses belonged to clade 6B, distinguished by a K163Q substitution, but remained antigenically similar to the A/California/07/2009-like vaccine strain, with an adjusted VE of 71% (95% confidence interval [CI], 58%-80%). Most B/Yamagata-lineage viruses (83%) clustered phylogenetically with the prior (ie, 2012-2013) season's B/Wisconsin/01/2010-like clade 3 vaccine strain, while only 17% clustered with the current (ie, 2013-2014) season's B/Massachusetts/02/2012-like clade 2 vaccine strain. The adjusted VE for B/Yamagata-lineage virus was 73% (95% CI, 57%-84%), with a lower VE obtained after partial calendar-time adjustment for clade mismatched B/Wisconsin/01/2010-like virus (VE, 63%; 95% CI, 41%-77%), compared with that for clade-matched B/Massachusetts/02/2012-like virus (VE, 88%; 95% CI, 48%-97%). No A(H3N2) viruses clustered with the A/Texas/50/2012-like clade 3C.1 vaccine strain, and more than half were antigenically mismatched, but sparse data did not support VE estimation. CONCLUSIONS: VE corresponded with antigenically conserved A(H1N1)pdm09 and lineage-matched B/Yamagata viruses with clade-level variation. Surveillance linking genotypic, phenotypic, and epidemiologic measures of vaccine-virus relatedness and effectiveness could better inform predictions of vaccine performance and reformulation. PMID- 25784729 TI - Temporal Changes in Pneumococcal Colonization in HIV-infected and HIV-uninfected Mother-Child Pairs Following Transitioning From 7-valent to 13-valent Pneumococcal Conjugate Vaccine, Soweto, South Africa. AB - BACKGROUND: We investigated the impact of infant pneumococcal conjugate vaccine (PCV) immunization on pneumococcal colonization among human immunodeficiency virus (HIV)-infected and HIV-uninfected mother-child pairs. METHODS: Pneumococcal colonization was assessed in May 2010-February 2011 (period 1; 7-valent PCV era) and May 2012-April 2013 (period 2; 13-valent PCV era). Standard microbiological methods were used for pneumococcus isolation and serotyping. RESULTS: In children 0-12 years, PCV13-serotype colonization decreased from period 1 to period 2 among HIV-uninfected (adjusted odds ratio [OR], 0.32; 95% confidence interval [CI], .25 .40) and HIV-infected children (adjusted OR, 0.37; 95% CI, .28-.49), while there was an increase in nonvaccine serotype colonization. Decreases in PCV13-serotype colonization were observed in HIV-uninfected women (adjusted OR, 0.44; 95% CI, .23-.81), with a similar trend in HIV-infected women. HIV-infected compared to uninfected women had higher prevalence of overall (20.5% vs 9.7% in period 1; 13.8% vs 9.7% in period 2) and PCV13-serotype colonization (8.7% vs 5.4% in period 1; 4.8% vs 2.0% in period 2), P < .04 for all observations. CONCLUSIONS: Targeted PCV vaccination of African infants in a setting with high HIV prevalence was associated with PCV13-serotype colonization reduction, including among unvaccinated HIV-infected women. PMID- 25784730 TI - Letter to the Editor in Response to the Editorial Commentary by Dr Kenrad E. Nelson Entitled, "The Changing Epidemiology of Hepatitis A Virus Infections in the United States". PMID- 25784731 TI - Reply to Ly et al. PMID- 25784732 TI - Zoster Vaccination Increases the Breadth of CD4+ T Cells Responsive to Varicella Zoster Virus. AB - BACKGROUND: The live, attenuated varicella vaccine strain (vOka) is the only licensed therapeutic vaccine. Boost of varicella zoster virus (VZV)-specific cellular immunity is a likely mechanism of action. We examined memory CD4(+) T cell responses to each VZV protein at baseline and after zoster vaccination. METHODS: Serial blood samples were collected from 12 subjects vaccinated with Zostavax and immunogenicity confirmed by ex vivo VZV-specific T-cell and antibody assays. CD4(+) T-cell lines enriched for VZV specificity were generated and probed for proliferative responses to every VZV protein and selected peptide sets. RESULTS: Zoster vaccination increased the median magnitude (2.3-fold) and breadth (4.2-fold) of VZV-specific CD4(+) T cells one month post-vaccination. Both measures declined by 6 months. The most prevalent responses at baseline included VZV open reading frames (ORFs) 68, 4, 37, and 63. After vaccination, responses to ORFs 40, 67, 9, 59, 12, 62, and 18 were also prevalent. The immunogenicity of ORF9 and ORF18 were confirmed using peptides, defining a large number of discrete CD4 T-cell epitopes. CONCLUSIONS: The breadth and magnitude of the VZV-specific CD4(+) T-cell response increase after zoster vaccination. In addition to glycoprotein E (ORF68), we identified antigenic ORFs that may be useful components of subunit vaccines. PMID- 25784734 TI - Onco-nephrology: current concepts and future perspectives. AB - Onco-nephrology is a new and evolving subspecialized area in nephrology that deals with kidney diseases in cancer patients. As many newer cancer therapies emerge in the field of oncology, cancer patients are surviving longer than ever before. However, the benefits of the remarkable advances in cancer management have not been fully appreciated. Not only is cancer often associated with abnormalities that affect the kidney, but cancer therapy often leads to both acute and chronic kidney diseases. The development of cancer-associated kidney complications is associated with poor prognosis, whereas prompt recognition and treatment initiation are associated with improved outcomes in this population. Therefore, both nephrologists and oncologists should be familiar with the diagnosis and management of cancer-associated kidney complications. Another unique aspect of onco-nephrology is that significant improvements in predialysis and dialysis care in recent years have led to prolonged survival and a higher incidence of patients with chronic kidney disease suffering from cancer. Therefore, research is urgently needed to establish treatment for patients with chronic kidney disease. This update addresses the pathophysiology and treatment of various cancer-associated kidney complications, and highlights cancer treatment for patients with chronic kidney disease. PMID- 25784733 TI - Comparative Susceptibility of Aedes albopictus and Aedes aegypti to Dengue Virus Infection After Feeding on Blood of Viremic Humans: Implications for Public Health. AB - Aedes albopictus is secondary to Aedes aegypti as a vector of dengue viruses (DENVs) in settings of endemicity, but it plays an important role in areas of dengue emergence. This study compared the susceptibility of these 2 species to DENV infection by performing 232 direct blood-feeding experiments on 118 viremic patients with dengue in Vietnam. Field-derived A. albopictus acquired DENV infections as readily as A. aegypti after blood feeding. Once infected, A. albopictus permitted higher concentrations of DENV RNA to accumulate in abdominal tissues, compared with A. aegypti. However, the odds of A. albopictus having infectious saliva were lower than the odds observed for A. aegypti (odds ratio, 0.70; 95% confidence interval, .52-.93). These results quantitate the susceptibility of A. albopictus to DENV infection and will assist parameterization of models for predicting disease risk in settings where A. albopictus is present. PMID- 25784735 TI - Prevention and treatment of psychiatric disorders in children with chronic physical illness. PMID- 25784736 TI - Psychological interventions for mental health disorders in children with chronic physical illness: a systematic review. AB - BACKGROUND: Children with chronic physical illness are significantly more likely to develop common psychiatric symptoms than otherwise healthy children. These children therefore warrant effective integrated healthcare yet it is not established whether the known, effective, psychological treatments for symptoms of common childhood mental health disorders work in children with chronic physical illness. METHODS: EMBASE, MEDLINE, PsycINFO and CINAHL databases were searched with predefined terms relating to evidence-based psychological interventions for psychiatric symptoms in children with chronic physical illness. We included all studies (randomised and non-randomised designs) investigating interventions aimed primarily at treating common psychiatric symptoms in children with a chronic physical illness in the review. Two reviewers independently assessed the relevance of abstracts identified, extracted data and undertook quality analysis. RESULTS: Ten studies (209 children, including 70 in control groups) met the criteria for inclusion in the review. All studies demonstrated some positive outcomes of cognitive behavioural therapy for the treatment of psychiatric symptoms in children with chronic physical illness. Only two randomised controlled trials, both investigating interventions for symptoms of depression, were found. CONCLUSIONS: There is preliminary evidence that cognitive behavioural therapy has positive effects in the treatment of symptoms of depression and anxiety in children with chronic physical illness. However, the current evidence base is weak and fully powered randomised controlled trials are needed to establish the efficacy of psychological treatments in this vulnerable population. PMID- 25784737 TI - Acute rheumatic fever and rheumatic heart disease in resource-limited settings. AB - Poststreptococcal complications, such as acute rheumatic fever (ARF) and rheumatic heart disease (RHD), are common in resource-limited settings, with RHD recognised as the most common cause of paediatric heart disease worldwide. Managing these conditions in resource-limited settings can be challenging. We review the investigation and treatment options for ARF and RHD and, most importantly, prevention methods in an African setting. PMID- 25784738 TI - How effective is the use of long-term anti-TNF for paediatric IBD? Clues from real-life surveillance cohorts. PMID- 25784739 TI - Do we use antibiotics rationally? PMID- 25784740 TI - Question: is breastfeeding useful in the management of neonatal abstinence syndrome? PMID- 25784741 TI - Towards evidence based medicine for paediatricians. PMID- 25784746 TI - Use of Bayesian Markov chain Monte Carlo methods to estimate EQ-5D utility scores from EORTC QLQ data in myeloma for use in cost-effectiveness analysis. AB - BACKGROUND: Patient-reported outcome measures are an important component of the evidence for health technology appraisal. Their incorporation into cost effectiveness analyses (CEAs) requires conversion of descriptive information into utilities. This can be done by using bespoke utility algorithms. Otherwise, investigators will often estimate indirect utility models for the patient reported outcome measures using off-the-shelf utility data such as the EQ-5D or SF-6D. Numerous modeling strategies are reported; however, to date, there has been limited utilization of Bayesian methods in this context. In this article, we examine the relative advantage of the Bayesian methods in relation to dealing with missing data, relaxing the assumption of equal variances and characterizing the uncertainty in the model predictions. METHODS: Data from a large myeloma trial were used to examine the relationship between scores in each of the 19 domains of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30/QLQ-MY20 and the EQ-5D utility. Data from 1839 patients were divided 75%/25% between derivation and validation sets. A conventional ordinary least squares model assuming equal variance and a Bayesian model allowing unequal variance were estimated on complete cases. Two further models were estimated using conventional and Bayesian multiple imputation, respectively, using the full data set. Models were compared in terms of data fit, accuracy in model prediction, and characterization of uncertainty in model predictions. CONCLUSIONS: Mean EQ-5D utility weights can be estimated from the EORTC QLQ C30/QLQ-MY20 for use in CEAs. Frequentist and Bayesian methods produced effectively identical models. However, the Bayesian models provide distributions describing the uncertainty surrounding the estimated utility values and are thus more suited informing analyses for probabilistic CEAs. PMID- 25784743 TI - Interferon-alpha inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling. AB - Persistent type I IFN production occurs during chronic viral infections, such as HIV disease. As type I IFNs have antiproliferative activity, it is possible that chronic exposure to these cytokines could adversely affect T cell homeostasis. We investigated the capacity of IFN-alpha to impair T cell proliferation induced by the homeostatic cytokine, IL-7, or another common gamma-chain cytokine, IL-2, in cells from healthy human donors. We found that IL-7- or IL-2-induced proliferation of CD4(+) T cells was partially inhibited in the presence of IFN alpha. The CD4(+) T cells that were exposed to IFN-alpha also displayed attenuated induction of IL-2 and CD40L following TCR stimulation. Analyses of signaling pathways indicated that IL-7 and IL-2 induced a delayed and sustained P Akt signal that lasted for several days and was partially inhibited by IFN-alpha. In contrast, IL-7-induced P-STAT5 was not affected by IFN-alpha. Furthermore, IFN alpha had no detectable effect on P-Akt that was induced by the chemokine SDF-1. Both inhibitors of P-Akt and P-STAT5 blocked IL-7-induced T cell proliferation, confirming that both signaling pathways are important for IL-7-induced T cell proliferation. These results demonstrate that IFN-alpha can selectively inhibit cytokine-induced P-Akt as a potential mechanism to disrupt homeostasis of T lymphocytes. PMID- 25784747 TI - Defining normal ranges and centiles for heart and respiratory rates in infants and children: a cross-sectional study of patients attending an Australian tertiary hospital paediatric emergency department. AB - OBJECTIVE: Key components in the assessment of a child in the emergency department (ED) are their heart and respiratory rates. In order to interpret these signs, practitioners must know what is normal for a particular age. The aim of this paper is to develop age-specific centiles for these parameters and to compare centiles with the previously published work of Fleming and Bonafide, and the Advanced Paediatric Life Support (APLS) reference ranges. DESIGN: A retrospective cross-sectional study. SETTING: The ED of the Children's Hospital at Westmead, Australia. PATIENTS: Afebrile, Triage Category 5 (low priority) patients aged 0-15 years attending the ED. INTERVENTIONS: Centiles were developed using quantile regression analysis, with cubic B-splines to model the centiles. MAIN OUTCOME MEASURES: Centile charts were compared with previous studies by concurrently plotting the estimates. RESULTS: 668 616 records were retrieved for ED attendances from 1995 to 2011, and 111 696 heart and respiratory rates were extracted for inclusion in the analysis. Graphical comparison demonstrates that with heart rate, our 50th centile agrees with the results of Bonafide, is considerably higher than the Fleming centiles and fits well between the APLS reference ranges. With respiratory rate, our 50th centile was considerably lower than the comparison centiles in infants, becomes higher with increasing age and crosses the lower APLS range in infants and upper range in teenagers. CONCLUSIONS: Clinicians should consider adopting these centiles when assessing acutely unwell children. APLS should review their normal values for respiratory rate in infants and teenagers. PMID- 25784748 TI - Efficacy and safety of diosmectite in acute childhood diarrhoea: a meta-analysis. AB - OBJECTIVE: We evaluated the role of diosmectite as an add-on treatment to the 'recommended treatment' of acute diarrhoea in children. METHODS: We searched all published literature through the major databases: Medline via Ovid, PubMed, CENTRAL, Embase and Google Scholar till May 2014. Randomised clinical trials comparing diosmectite versus placebo were included (PROSPERO registration: CRD42014013783). MAIN OUTCOME MEASURES: The primary outcome measures were duration of acute diarrhoea (h), and day-to-day cure rates (%). The secondary outcome measures were stool output (volume), stool output (frequency) and adverse events. RESULTS: Of 384 citations retrieved, a total of 13 randomised clinical trials (2164 children, 1-60 months old) were included in the meta-analysis. A dose of 3-6 grams per day of diosmectite was given for a duration from 3 days until recovery. Compared with placebo, diosmectite significantly decreased the duration of acute diarrhoea (mean difference, -23.39; 95% CI -28.77 to -18.01), and increased the cure rate (%) at day 5 (OR, 4.44; 95% CI 1.66 to 11.84), without any increases in the risk of adverse events. Diosmectite was effective in all types of acute childhood diarrhoea except dysentery. Because, most of the trials were open-label, and there was a high possibility of publication bias, the GRADE evidence generated was of 'low quality'. CONCLUSIONS: Diosmectite may be a useful additive in the treatment of acute childhood diarrhoea. As the evidence generated was of 'low quality', future research is needed with higher quality designs before any firm recommendations can be made. TRIAL REGISTRATION NUMBER: PROSPERO registration: CRD42014013783. PMID- 25784750 TI - Urticaria pigmentosa masquerading as non-accidental injury. PMID- 25784752 TI - Not only athlete's foot survives in feet. PMID- 25784753 TI - Prognosis after revascularization for left main coronary artery disease: insights from the crystal ball. PMID- 25784754 TI - A truncation in the regulator RocA underlies heightened capsule expression in serotype M3 group A streptococci. PMID- 25784749 TI - Predicting severe motor impairment in preterm children at age 5 years. AB - OBJECTIVE: To determine whether the ability to predict severe motor impairment at age 5 years improves between birth and 18 months. DESIGN: Ancillary study of the Caffeine for Apnea of Prematurity Trial. SETTING AND PATIENTS: International cohort of very low birth weight children who were assessed sequentially from birth to 5 years. OUTCOME MEASURES: Severe motor impairment was defined as a score <5th percentile on the Movement Assessment Battery of Children (MABC), or inability to complete the MABC because of cerebral palsy. Multivariable logistic regression cumulative risk models used four sets of predictor variables: early neonatal risk factors, risk factors at 36 weeks' postmenstrual age, risk factors at a corrected age of 18 months, and sociodemographic variables. A receiver operating characteristic curve (ROC) was generated for each model, and the four ROC curves were compared to determine if the addition of the new set of predictors significantly increased the area under the curve (AUC). RESULTS: Of 1469 children, 291 (19.8%) had a severe motor impairment at 5 years. The AUC increased from 0.650 soon after birth, to 0.718 (p<0.001) at 36 weeks' postmenstrual age, and to 0.797 at 18 months (p<0.001). Sociodemographic variables did not significantly improve the AUC (AUC=0.806; p=0.07). CONCLUSIONS: Prediction of severe motor impairment at 5 years of age using a cumulative risk model improves significantly from birth to 18 months of age in children with birth weights between 500 g and 1250 g. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT00182312. PMID- 25784755 TI - Reply to "A truncation in the regulator RocA underlies heightened capsule expression in serotype M3 group A streptococci". PMID- 25784756 TI - Retraction for Xu et al., Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice. PMID- 25784758 TI - Nuclear lamins are not required for lamina-associated domain organization in mouse embryonic stem cells. AB - In mammals, the nuclear lamina interacts with hundreds of large genomic regions, termed lamina-associated domains (LADs) that are generally in a transcriptionally repressed state. Lamins form the major structural component of the lamina and have been reported to bind DNA and chromatin. Here, we systematically evaluate whether lamins are necessary for the LAD organization in murine embryonic stem cells. Surprisingly, removal of essentially all lamins does not have any detectable effect on the genome-wide interaction pattern of chromatin with emerin, a marker of the inner nuclear membrane. This suggests that other components of the lamina mediate these interactions. PMID- 25784759 TI - The use of octreotide in the treatment of chylothorax following cardiothoracic surgery. AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'Is octreotide (a long-acting somatostatin analogue) effective in patients with post-operative or traumatic chylothorax as a part of conservative management to reduce lymphorrhagia?' Altogether 180 papers were found using the reported search, of which 20 represented the best evidence to answer the clinical question. One case was reported twice and therefore was excluded, leaving us with 19 papers. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Although rare, iatrogenic and traumatic chylothorax have been well described in the literature. At present, there have been no randomized controlled clinical trials on the use of octreotide in chylothorax. Sixteen of 19 papers found octreotide to be effective in the treatment of chylothorax. Octreotide was found to have no complementary effect in three reports. Two of the papers were retrospective studies: one a randomized controlled trial in canines, and the remainder were case reports and case series. The two retrospective studies showed a success rate of 87-90% in the use of octreotide as an adjunct to conservative management for the treatment of chylothorax and hence preventing the need for further surgery. Experimental study in canines has shown significant drain reduction and earlier fistula closure, although transferability of this result to human is difficult to interpret. Twelve case reports found octreotide effective in reduction of the volume and arrest of chylothorax. Most reported benefit in 2-3 days of administration of octreotide. The general consensus is for conservative management with octreotide to be instituted for 1 week before consideration of surgery, although some authors have advocated for a large volume chylothorax, especially after oesophageal surgery with no response to conservative management with octreotide, to be operated on sooner. We concluded that octreotide is effective in the management of moderate to large volume chylothorax. PMID- 25784760 TI - Current state of emergency medicine in Fukushima 4 years after the Great East Japan Earthquake. PMID- 25784761 TI - Hubble's Law and the expanding universe. PMID- 25784762 TI - Inner workings: Hubble's quarter century in orbit has opened a universe of possibilities. PMID- 25784764 TI - Nutritional evaluation of canola meals produced from new varieties of canola seeds for poultry. AB - This study evaluated the nutritional value of 14 canola meals from new varieties of canola and compared them to conventional canola meal samples and soybean meals in chickens. Five experiments that included different sources of canola meals or soybean meals were conducted. For each experiment, a precision-fed rooster assay with conventional or cecectomized roosters was conducted to determine TMEn or amino acid digestibility. Analyzed nutritional composition of the canola meal samples indicated increases in crude protein and amino acids for all test canola meals (49.41 to 50.58% crude protein on a dry matter basis) compared to conventional canola meals (40.73 to 43.01%). All test canola meals also contained lower amounts of neutral detergent fiber and acid detergent fiber. Most test canola meals had significantly higher TMEn values than the conventional canola meals (P < 0.05), but all were lower than the soybean meal (P < 0.05). The test canola meals had higher amino acid digestibility coefficients than conventional canola meals in Experiments 1, 2, and 4 (P < 0.05), and higher concentrations of digestible amino acids in all 5 experiments. The results of this study indicated that nutritional value of the canola meal from new varieties of canola was greater than conventional canola meal for poultry. PMID- 25784765 TI - Genetic analysis of bone quality traits and growth in a random mating broiler population. AB - We report the genetic relationship between growth and bone quality traits in a random mating broiler control population. Traits studied were growth rates from week 0 to 4 [body weight gain (BWG) 0 to 4], from week 0 to 6 (BWG 0 to 6), and residual feed intake (RFI) from week 5 to 6 (RFI 5 to 6). Bone quality traits were obtained at 6 weeks of age. These traits were shank weight (SW), shank length (SL), shank diameter (SDIAM), tibia weight (TW), tibia length (TL), and tibia diameter (TDIAM). Likewise, tibia was used to obtain the tibia density (TDEN), tibia breaking strength (TBS), tibia mineral density (TMD), tibia mineral content (TMC), and tibia ash content (TAC). At the phenotypic level, growth traits were positively correlated with most of the bone quality traits except with TDEN and TAC which tended to show unfavorable associations (-0.04 to -0.31). Heritability of bone quality traits ranged from 0.08 to 0.54. The additive genetic associations of growth traits with weight, length, and diameter of shank and tibia were positive (0.37 to 0.80). A similar pattern was observed with TMD and TMC (0.06 to 0.65). In contrast, growth traits showed unfavorable genetic associations with TDEN, TBS, and TAC (-0.03 to -0.18). It was concluded that bone quality traits have an additive genetic background and they can be improved by means of genetic tools. It appears that selection for growth is negatively correlated with some traits involved in the integrity, health, and maturity of leg bones. PMID- 25784766 TI - Standardized ileal amino acid digestibility of expeller-extracted canola meal subjected to different processing conditions for starter and grower broiler chickens. AB - Six expeller-extracted canola meal (ECM) samples produced under different seed conditioning temperatures (90, 95, or 100 degrees C) and screw torques in the second press (low or high) were evaluated in a 3 * 2 factorial arrangement of treatments to determine the effect of processing on standardized ileal amino acid digestibility (SID) in 10 and 24-day-old broilers. A nitrogen-free diet was fed to determine ileal endogenous amino acid flow. Each diet was fed for 5 d to 6 replicate cages of 10 or 7 chicks, and ileal samples were collected at 10 and 24 d, respectively. The endogenous flow (mg/kg DM intake) of CP and all amino acids except Cys decreased (P < 0.01) with age. Conditioning temperature by screw torque interactions were detected (P < 0.05) for apparent ileal digestibility (AID) of CP, Arg, Ile, Lys, Phe, Thr, Ala, Asp, Glu, Pro ,and Ser at d 10, and the same trend was observed at d 24 except for Ile, Phe, Ala, and Pro (P > 0.05). Meals processed under medium conditioning temperature (95 degrees C) at either low or high screw torque had the greatest (P < 0.05) AID of CP and total amino acids. The SID values followed a similar pattern as AID at both ages. When corrected for endogenous losses, the average AID of total amino acids improved approximately 3.5 and 2.0 units, at 10 and 24 d, respectively. The AID and SID values increased (P < 0.05) with age for most AA, but the effect of age was not consistent between ECMs. A negative correlation was detected between NDF and neutral detergent-insoluble nitrogen (NDIN) content of the meals and SID values of Lys at d 24 (r = -0.79, r = -0.76; P = 0.001, respectively). Processing conditions affected CP and amino acid digestibility, likely because of alterations to the chemical composition of ECM and formation of indigestible complexes of amino acids with fiber. The AID and SID values increased with age independent of meal processing conditions. PMID- 25784767 TI - Modulating the thermostability of Endoglucanase I from Trichoderma reesei using computational approaches. AB - In the last decades, effective cellulose degradation became a major point of interest due to the properties of cellulose as a renewable energy source and the widespread application of cellulases (the cellulose degrading enzymes) in many industrial processes. Effective bioconversion of lignocellulosic biomass into soluble sugars for ethanol production requires use of thermostable and highly active cellulases. The library of current cellulases includes enzymes that can work at acidic and neutral pH in a wide temperature range. However, only few cellulases are reported to be thermostable. In order to alleviate this, we have performed a hybrid approach for the thermostabilization of a key cellulase, Endoglucanase I (EGI) from Trichoderma reesei. We combined in silico and in vitro experiments to modulate the thermostability of EGI. Four different predictive algorithms were used to set up a library of mutations. Three thermostabilizer mutations (Q126F, K272F, Q274V) were selected and molecular dynamics simulations at room temperature and high temperatures were performed to analyze the effect of the mutations on enzyme structure and stability. The mutations were then introduced into the endoglucanase 1 gene, using site-directed mutagenesis, and the effect of the mutations on enzyme structure and stability were determined. MD simulations supported the fact that Q126F, K272F and Q274V mutations have a thermostabilizing effect on the protein structure. Experimental studies validated that all of the mutants exhibited higher thermostability compared with native EGI albeit with a decrease in specific activity. PMID- 25784768 TI - Setting the record straight on measuring diagnostic errors. Reply to: 'Bad assumptions on primary care diagnostic errors' by Dr Richard Young. PMID- 25784769 TI - Anti-MDA5 dermatomyositis and progressive interstitial pneumonia. PMID- 25784770 TI - A novel biomarker for anti-androgenic activity in placenta reveals risks of urogenital malformations. AB - It has been hypothesized that the rise in male reproductive disorders over recent decades may at least be partially attributable to environmental factors, including chemical exposures, but observed associations with single chemicals were rather weak. The aim of this case-control study was to explore the relationship between exposure to mixtures of (anti-)androgenic chemicals during pregnancy and the risk of cryptorchidism and/or hypospadias in offspring, using the total effective xenobiotic burden of anti-androgens (TEXB-AA) as a biomarker. A subsample of 29 cases (16 of cryptorchidism, 12 of hypospadias, and one of both disorders) and 60 healthy controls was nested in a cohort of male newborns recruited between October 2000 and July 2002. The (anti-)androgenic activity of placenta samples collected at delivery was assessed using TEXB-AA biomarker, combined with a bioassay-directed fractionation protocol that separated endogenous hormones from most (anti-)androgenic chemicals by normal-phase HPLC. The bioassay measures the androgen-induced luciferase activity and the inhibition of this pathway by (anti-)androgens. First, we collected 27 HPLC fractions in each placenta extract, which were all tested in the bioassay. The multivariable statistical analyses indicated a statistically significant positive dose-response association between the potent anti-androgenic activity of the HPLC fraction collected during minutes 1-2 (F2) and the risk of malformations (odds ratio: 2.33, 95% CI: 1.04-5.23). This study represents a novel approach for the estimation of combined effects of the total anti-androgenic load and the associations suggest an effect of environmental pollutants on the development of fetal reproductive tract.Free Spanish abstract: A Spanish translation of this abstract is freely available at http://www.reproduction online.org/content/149/6/605/suppl/DC1. PMID- 25784771 TI - Squamous Cell Lung Carcinoma Presenting With Refractory Status Epilepticus: A Case Report of Paraneoplastic Limbic Encephalitis. AB - Lung cancer-associated paraneoplastic syndromes affecting the central nervous system present significant diagnostic and treatment challenges. In this case, the patient presented with personality change, cognitive impairment, complex partial seizures, ataxia, dyspraxia, and dysphasia. Shortly after admission, the patient suffered refractory generalized tonic-clonic seizures and a decreased level of consciousness and required intubation, ventilation, and admission to the ICU. He was subsequently diagnosed with paraneoplastic limbic encephalitis based on recognized criteria, including a compatible clinical picture, elevated protein content in his cerebrospinal fluid with negative cytology, a positive positron emission tomography-computed tomography scan showing a right upper lobe tumor, and the exclusion of other neuro-oncological complications. Histopathology confirmed the tissue diagnosis as squamous cell cancer. Initial immunotherapy with steroids and intravenous immunoglobulin and subsequent lobectomy and adjuvant chemotherapy were partially successful, leading to partial resolution of his cognitive impairment. This report highlights the diagnostic and therapeutic challenges of lung-related paraneoplastic syndromes. In addition, it illustrates the poor outcomes for patients and identifies squamous cell cancer as an extremely rare cause of paraneoplastic limbic encephalitis. PMID- 25784772 TI - Year in review 2014: mechanical ventilation. AB - Mechanical ventilation is an important and ever-evolving component of everyday critical care. Clinicians can struggle to keep up with current literature and descriptions of advancement in a way that they can apply these changes to their bedside patient care. This article serves as a review of important recent findings related to invasive mechanical ventilation and describes their relevance to bedside critical care. PMID- 25784773 TI - Year in review 2014: airway clearance. AB - The respiratory therapist has had integrated adjuncts to improve mucus clearance for decades. However, there is a lack of literature describing the impact of these interventions on specific patient populations, resulting in an inability to make recommendations about the use of devices and techniques. The purpose of this article is to review recent literature regarding airway clearance therapies in a manner that is most likely to have interest to the readers of Respiratory Care. PMID- 25784774 TI - Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling. AB - OBJECTIVE: An accelerated rate of decline in forced vital capacity (FVC) affects >50% of patients with SSc but data on the variability and determinants of this change are scarce. We sought to identify trajectories of FVC and their associated variables in SSc patients over a 12-year period. METHODS: Clinical and pulmonary function data were retrospectively collected. SSc patients with three or more FVC values were included. Group-based modelling was used to cluster similar FVC patterns into trajectories. Baseline variables were associated with the trajectories using multinomial logistic regression. The effect of CYC on FVC was examined with each trajectory as a time-varying covariate. RESULTS: In 254 SSc patients we identified seven distinct FVC trajectories: very low slow decline (5.5%), very low improve (13.8%), low fast decline (9.5%), low stable (19.7%), low-normal improve (31.1%), normal improve (16.1%) and normal stable (4.3%). Younger age and the presence of pulmonary hypertension, Interstitial lung disease and shortness of breath at baseline significantly increased the odds of declining trajectories vs the reference trajectory (low-normal improve). CYC was associated with FVC improvement in the low fast decline trajectory. CONCLUSION: The course of FVC in SSc was highly variable, with improvement and stability experienced even by those with low baseline FVC. Trajectory modelling was able to identify SSc patients who were most likely to experience FVC decline and thus could be a useful tool for patient management as well as clinical trial design. PMID- 25784775 TI - Basis for standards: ICRP activities. AB - The purpose of this chapter is to describe work achieved recently by the International Commission on Radiological Protection (ICRP) and especially by Committee 3 (Protection in Medicine) and its use for standards. In March 1960, the Board of Governors of the International Atomic Energy Agency approved the Agency's 'Health and Safety Measures', stating that the Agency's 'Basic Safety Standards' (BSS) would be based, to the extent possible, on the recommendations of the ICRP. In a similar way, the Council of the European Union took into account the new recommendations of the ICRP when adopting the new Directive 2013/59/EURATOM that laid down BSS for protection against the dangers arising from exposure to ionising radiation. The new limit for the lens of the eyes for occupational exposures has been incorporated into these international standards and several articles dealing with medical exposures: justification, optimisation, recording patient doses, the use of diagnostic reference levels, training, accidental and unintended exposures, etc. have also been included in agreement with the ICRP recommendations. PMID- 25784776 TI - On-line data collection platform for national dose surveys in diagnostic and interventional radiology. AB - According to the Bulgarian regulation for radiation protection at medical exposure, the National Centre of Radiobiology and Radiation Protection (NCRRP) is responsible for performing national dose surveys in diagnostic and interventional radiology and nuclear medicine and for establishing of national diagnostic reference levels (DRLs). The next national dose survey is under preparation to be performed in the period of 2015-16, with the aim to cover conventional radiography, mammography, conventional fluoroscopy, interventional and fluoroscopy guided procedures and CT. It will be performed electronically using centralised on-line data collection platform established by the NCRRP. The aim is to increase the response rate and to improve the accuracy by reducing human errors. The concept of the on-line dose data collection platform is presented. Radiological facilities are provided with a tool to determine local typical patient doses, and the NCRRP to establish national DRLs. Future work will include automatic retrieval of dose data from hospital picture archival and communicating system. The on-line data collection platform is expected to facilitate the process of dose audit and optimisation of radiological procedures in Bulgarian hospitals. PMID- 25784777 TI - Magnetic phase transitions and monopole excitations in spin ice under uniaxial pressure: A Monte Carlo simulation. AB - In this work, we explore the spin ice model under uniaxial pressure using the Monte Carlo simulation method. For the known spin ices, the interaction correction (delta) introduced by the uniaxial pressure varies in quite a wide range from positive to negative. When delta is positive, the ground state characterized by the ferromagnetic spin chains is quite unstable, and in real materials it serves as intermediate state connecting the ice state and the long range ordered dipolar spin ice ground state. In the case of negative delta, the system relaxes from highly degenerate ice state to ordered ferromagnetic state via a first order phase transition. Furthermore, the domain walls in such ferromagnetic state are the hotbed of the excitations of magnetic monopoles, thus indicating that the uniaxial pressure can greatly increase the monopole density. PMID- 25784778 TI - The influence of vitamin D receptor genetic variants on bone mineral density and osteoporosis in Chinese postmenopausal women. AB - Growing evidence indicates that the vitamin D receptor (VDR) gene is an important candidate gene for influencing the development of osteoporosis. The aim of the study was to evaluate the potential association between genetic variants of VDR gene and bone mineral density (BMD) and osteoporosis in Chinese postmenopausal women. The study included 970 Chinese postmenopausal women at the postmenopausal osteoporosis (482) and healthy controls (488). The BMD of lumbar spine (L(2-4) anterior-posterior view), femoral neck hip, and total hip was evaluated using the Norland XR-46 dual energy X-ray absorptiometry (DEXA). The genotypes of VDR genetic variants were determined by the created restriction site-PCR (CRS-PCR) and confirmed by DNA sequencing methods. Our data indicated that the VDR p.Glicine (Gly)14 alanine (Ala) and p.histidine (His) 305 glutanine (Gln) genetic variants were statistically associated with adjusted femoral neck hip BMD, adjusted lumbar spine BMD, and adjusted total hip BMD (P values < 0.05). Results from this study suggest that the VDR p.Gly14Ala and p.His305Gln genetic variants are significantly associated with BMD decrease in Chinese postmenopausal women and might be used as molecular markers for assessing the risk of BMD and osteoporosis. PMID- 25784779 TI - Sequence variants of peroxisome proliferator-activated receptor-gamma gene and the clinical courses of patients with end-stage renal disease. AB - BACKGROUND: PPAR-gamma single nucleotide polymorphisms (SNPs) reportedly play an important role in determining metabolic risk among diverse population. Whether PPAR-gamma SNPs affect the clinical courses in ESRD patients is unknown. METHODS: From a multicenter cohort, we identified 698 patients with prevalent ESRD between 2002 and 2003, and other 782 healthy subjects as control. Two PPAR-gamma SNPs, Pro12Ala (rs1801282) and C161T (rs3856806), were genotyped and their association with ESRD was examined. Both groups were prospectively followed until 2007, and the predictability of genotypes for the long-term survival of ESRD patients was analyzed. RESULTS: After multivariable-adjusted regression, GG genotype of Pro12Ala was significantly more likely to associate with ESRD (P < 0.001) among patients with non-diabetes-related ESRD. Cox's proportional hazard regression showed that both Pro12Ala and C161T polymorphisms were significant predictors of mortality in ESRD patients with DM (Pro12Ala: GG versus other genotypes, hazard ratio [HR] <0.01; P < 0.001; for C161T, CC versus TT genotypes, HR 2.86; P < 0.001; CT versus TT genotypes, HR 1.93; P < 0.001). CONCLUSION: This is the first and largest study to evaluate PPAR-gamma SNPs in ESRD patients. Further mechanistic study is needed to elucidate the role of PPAR-gamma among ESRD patients. PMID- 25784781 TI - A lipid mediator hepoxilin A3 is a natural inducer of neutrophil extracellular traps in human neutrophils. AB - Pulmonary exacerbations in cystic fibrosis airways are accompanied by inflammation, neutrophilia, and mucous thickening. Cystic fibrosis sputum contains a large amount of uncleared DNA contributed by neutrophil extracellular trap (NET) formation from neutrophils. The exact mechanisms of the induction of NETosis in cystic fibrosis airways remain unclear, especially in uninfected lungs of patients with early cystic fibrosis lung disease. Here we show that Hepoxilin A3, a proinflammatory eicosanoid, and the synthetic analog of Hepoxilin B3, PBT 3, directly induce NETosis in human neutrophils. Furthermore, we show that Hepoxilin A3-mediated NETosis is NADPH-oxidase-dependent at lower doses of Hepoxilin A3, while it is NADPH-oxidase-independent at higher doses. Together, these results demonstrate that Hepoxilin A3 is a previously unrecognized inducer of NETosis in cystic fibrosis lungs and may represent a new therapeutic target for treating cystic fibrosis and other inflammatory lung diseases. PMID- 25784782 TI - Estimating the attack rate of pregnancy-associated listeriosis during a large outbreak. AB - BACKGROUND: In 2011, a multistate outbreak of listeriosis linked to contaminated cantaloupes raised concerns that many pregnant women might have been exposed to Listeria monocytogenes. Listeriosis during pregnancy can cause fetal death, premature delivery, and neonatal sepsis and meningitis. Little information is available to guide healthcare providers who care for asymptomatic pregnant women with suspected L. monocytogenes exposure. METHODS: We tracked pregnancy associated listeriosis cases using reportable diseases surveillance and enhanced surveillance for fetal death using vital records and inpatient fetal deaths data in Colorado. We surveyed 1,060 pregnant women about symptoms and exposures. We developed three methods to estimate how many pregnant women in Colorado ate the implicated cantaloupes, and we calculated attack rates. RESULTS: One laboratory confirmed case of listeriosis was associated with pregnancy. The fetal death rate did not increase significantly compared to preoutbreak periods. Approximately 6,500-12,000 pregnant women in Colorado might have eaten the contaminated cantaloupes, an attack rate of ~1 per 10,000 exposed pregnant women. CONCLUSIONS: Despite many exposures, the risk of pregnancy-associated listeriosis was low. Our methods for estimating attack rates may help during future outbreaks and product recalls. Our findings offer relevant considerations for management of asymptomatic pregnant women with possible L. monocytogenes exposure. PMID- 25784783 TI - Characteristics and outcomes of fall-related open-globe injuries in pseudophakic patients. AB - AIM: We aimed to identify the characteristics and prognostic indicators of poor visual and anatomic outcome in pseudophakic patients with fall-related open-globe (OG) injuries. We used a case series design, for a total of 26 patients. METHODS: Charts of consecutive pseudophakic patients with fall-related OG injury at a single institution were reviewed. Demographics, ophthalmic history, circumstances of injury, initial best-corrected visual acuity (BCVA), examination findings, surgical interventions, and follow-up BCVA were tabulated for statistical analysis with unpaired t-tests and Fisher's exact tests. RESULTS: Nineteen patients (73%) were women. Mean (+/- standard deviation) age was 80.6+/-4.6 years (range: 61-97 years). Initial BCVA was <20/400 in 24 of 25 patients (96%). Mean ocular trauma score (OTS) was 38.54+/-10.95. OTS was lower (P=0.0017, P<0.0001, and P=0.0240) and wound size was larger (P=0.0440, 0.0145, and 0.0026) in patients with final BCVA <20/40, <20/400, and phthisis at final follow-up, respectively; compared to patients with BCVA >=20/40, 20/400, and no phthisis at final follow-up, respectively. Final BCVA <20/400 was associated with 360 degrees subconjunctival hemorrhage (SCH), retinal detachment, and proliferative vitreoretinopathy (P=0.0498, 0.0181, and 0.0310, respectively). Total hyphema, intraocular lens (IOL) damage, and IOL expulsion were associated with needing multiple surgical interventions (P=0.0345, P<0.0001, and P=0.0023, respectively). CONCLUSION: Large wound size, low OTS, 360 degrees SCH, total hyphema, posterior injury, and IOL damage are common findings that are also prognostic of poor visual and anatomic outcome in pseudophakic patients with fall-related OG injuries. Ophthalmologists dealing primarily with geriatric populations should contribute to the discussion of fall risk. PMID- 25784784 TI - Progression to macula-off tractional retinal detachment after a contralateral intraoperative intravitreal bevacizumab injection for proliferative diabetic retinopathy. PMID- 25784785 TI - Perfluoro-n-octane as a temporary intraocular tamponade in a staged approach to manage complex retinal detachments. AB - PURPOSE: To evaluate outcomes in patients with complex retinal detachments (RD) with proliferative vitreoretinopathy (PVR) requiring retinectomy using a staged approach utilizing perfluoro-n-octane (PFO) as a short-term postoperative intraocular tamponade. METHODS: Retrospective analysis. Patients who underwent 23G pars plana vitrectomy for the management of complicated RD where PFO was used as a primary temporary intraocular tamponade. Only eyes with PVR in rhegmatogenous RD or eyes with penetrating injuries or globe ruptures (ocular trauma) and subsequent RD with PVR were included. Analysis of 17 eyes of 17 consecutive patients with a minimum follow-up of 12 months during a period of 5 years. The primary outcome measure was the reattachment rate after at least 12 months of follow-up after the PFO removal. Secondary outcome measures were changes in visual acuity, complications due to PFO use, and necessity for further surgeries. RESULTS: Eight eyes with prior penetrating injuries or globe rupture and nine eyes with rhegmatogenous pathology were included. All eyes had PFO as temporary tamponade for 14 days (median), which was replaced by silicon oil. Sixteen eyes (94%) had complete and one eye partial reattachment. No redetachments occurred. All eyes retained or improved visual acuity. On average, only 2.5 procedures, including silicon oil removal, were performed. Two eyes had long-term intraocular pressure of 5 mmHg and no eye had intraocular pressure of >=21 mmHg. No long-term inflammation was observed. CONCLUSION: PFO seems to be beneficial in a staged approach to repair complex detachments when used as short term tamponade. A median period of 14 days allowed for both sufficient retinal support plus a reduction in side effects seen in long-term endotamponades. PMID- 25784786 TI - Ocular leech infestation. AB - This case report describes a female toddler with manifestations of ocular leech infestation. A 2-year-old girl was brought to our outpatient clinic with a complaint of irritable crying after being taken to a stream in Hualien 1 day previous, where she played in the water. The parents noticed that she rubbed her right eye a lot. Upon examination, the girl had good fix and follow in either eye. Slit-lamp examination showed conjunctival injection with a moving dark black brown foreign body partly attached in the lower conjunctiva. After applying topical anesthetics, the leech, measuring 1 cm in length, was extracted under a microscope. The patient began using topical antibiotic and corticosteroid agents. By 1 week after extraction, the patient had no obvious symptoms or signs, except for a limited subconjunctival hemorrhage, and no corneal/scleral involvement was observed. PMID- 25784780 TI - Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives. AB - A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behcet's disease, gout, Sjogren's syndrome, interstitial lung diseases, and Still's disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems. PMID- 25784787 TI - Ocular myiasis caused by Chrysomya bezziana - a case report. AB - Ophthalmomyiasis can have variable presentation depending on the type of fly, structures involved, and level of penetration. A 42-year-old female presented with extensive myiasis of the right eye. A lesion of 3*2 cm was noted at the medial canthus and was infested with maggots. The larvae were removed meticulously and the wound debrided. The larva isolated was that of Chrysomya bezziana (Old World screwworm). Computed tomography (CT) scan was normal. The wound was dressed regularly and healed by secondary intention. Ocular myiasis is a rare disease that can lead to life threatening consequences, such as intracranial extension. Prompt management with debridement and radical antibiotic therapy is essential. PMID- 25784788 TI - Long-term outcomes of intravitreal injection of bevacizumab for choroidal neovascularization associated with choroidal osteoma. AB - PURPOSE: To describe the outcomes of intravitreal injections of bevacizumab for choroidal neovascularization (CNV) associated with choroidal osteoma. METHODS: Retrospective consecutive case series. Three eyes of three patients were studied. All patients were treated with intravitreal injections of bevacizumab for CNV associated with choroidal osteoma. Best-corrected visual acuity, central foveal thickness, tumor thickness on spectral domain optical coherence tomography, and subretinal pigmentation around the CNV were evaluated. RESULTS: The mean number of intravitreal injections of bevacizumab was 2.0 (range 1-3). The mean follow-up time was 56.0 months (range 25-99 months). The mean LogMAR visual acuity worsened from 0.1 to 0.6. LogMAR visual acuity loss of 0.7 or worse occurred in two of three eyes. CNV was located in the subfoveal area in two eyes, and CNV was located in the juxtafoveal area in one eye. The mean central foveal thickness decreased from 407 MUm to 251 MUm. The mean tumor thickness decreased from 709 MUm to 608 MUm. All eyes had subretinal pigmentation around the CNV. CONCLUSION: Intravitreal injections of bevacizumab for subfoveal CNV associated with decalcified choroidal osteoma resulted in poor visual acuity. PMID- 25784789 TI - Outcomes of microincision vitrectomy surgery with internal limiting membrane peeling for macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To evaluate the anatomic and functional effect of microincision vitrectomy surgery (MIVS) with internal limiting membrane (ILM) peeling for macular edema secondary to branch retinal vein occlusion (BRVO). METHODS: The medical records of 101 eyes of 101 patients who had undergone MIVS with ILM peeling for macular edema secondary to BRVO were studied. Patients were classified into ischemic and non-ischemic BRVO based on angiograph. The best corrected visual acuity (BCVA) and central foveal thickness (CFT), determined by spectral domain optical coherence tomography, were evaluated at baseline and at 1, 3, 6, and 12 months postoperatively. RESULTS: Preoperative mean logarithm of the minimum angle of resolution (logMAR) BCVA +/- standard deviation (SD) was 0.52+/-0.43 and mean CFT +/- SD was 489.4+/-224.9 MUm. Postoperative mean BCVA +/ SD values were 0.41+/-0.35, 0.35+/-0.41, 0.29+/-0.36, and 0.25+/-0.41, and mean CFT values were 370.1+/-148.9, 327.5+/-157.5, 310.9+/-154.9, and 274.4+/-135.3 MUm at 1, 3, 6, 12 months, respectively. The mean BCVA was significantly improved at 3, 6, and 12 months postoperatively (all P<0.05), and the mean CFT was significantly decreased at all postoperative follow-up time points (all P<0.05). At the 12-month postoperative evaluation, BCVA had improved by 0.2 logMAR units in 50 eyes (60.0%) with ischemic BRVO and in nine eyes (50.0%) with non-ischemic BRVO. Six eyes (6.0%) experienced recurrence or persistence of macular edema at 12 months postoperatively. CONCLUSION: MIVS with ILM peeling for macular edema secondary to BRVO is effective in improving visual acuity and foveal morphology with low recurrence of macular edema. PMID- 25784790 TI - Delayed manifestation of bilateral scleral thinning after I-BRITE((r)) procedure and review of literature for cosmetic eye-whitening procedures. AB - PURPOSE: To report a case of delayed-onset bilateral scleral thinning and calcium deposition following a cosmetic ocular-whitening procedure (I-BRITE((r))). METHODS: A 33-year-old male patient with a history of right-sided ptosis repair and left-sided anterior uveitis had previously undergone bilateral I-BRITE treatment for chronic conjunctival hyperemia. Four years after the procedure, the patient was referred to our institution with bilateral scleral thinning and overlying calcific depositions. A literature review was performed through PubMed from 1980 through 2014 using the search terms 'cosmetic', 'ocular', 'conjunctivectomy', 'regional conjunctivectomy', 'I-BRITE', 'eye-whitening', 'scleritis', 'necrotizing scleritis', 'anterior uveitis', 'mitomycin C', '5 fluorouracil', and 'bevacizumab', along with associated cross-referencing from relevant articles. RESULTS: Examination of the patient revealed bilateral necrotizing scleritis within the nasal region of both eyes. Calcified plaques were also present within the areas of scleromalacia, along with epithelial defects demonstrated with fluorescein staining. Although evidence of previous intraocular inflammation was apparent within the left eye, there were no active signs of inflammation evident within either eye on initial presentation. Complication rates reported in the literature include: scleral thinning (1.8%), calcific plaque formation (2.9%), fibrovascular proliferation (13%), diplopia (1.2%), elevation of intraocular pressure (4.2%), and recurrence of conjunctival hyperemia (2.1%). CONCLUSION: Cosmetic ocular whitening procedures have an attendant high complication rate, and have been associated with several adverse postoperative complications, which have in turn generated several reservations regarding the veritable benefit of the procedure. Many postsurgical complications may demonstrate delayed apparition, varying from several months to several years after primary surgical intervention as in the case reported here. PMID- 25784791 TI - The development of the ProMAS: a Probabilistic Medication Adherence Scale. AB - Current self-report medication adherence measures often provide heavily skewed results with limited variance, suggesting that most participants are highly adherent. This contrasts with findings from objective adherence measures. We argue that one of the main limitations of these self-report measures is the limited range covered by the behaviors assessed. That is, the items do not match the adherence behaviors that people perform, resulting in a ceiling effect. In this paper, we present a new self-reported medication adherence scale based on the Rasch model approach (the ProMAS), which covers a wide range of adherence behaviors. The ProMAS was tested with 370 elderly receiving medication for chronic conditions. The results indicated that the ProMAS provided adherence scores with sufficient fit to the Rasch model. Furthermore, the ProMAS covered a wider range of adherence behaviors compared to the widely used Medication Adherence Report Scale (MARS) instrument, resulting in more variance and less skewness in adherence scores. We conclude that the ProMAS is more capable of discriminating between people with different adherence rates than the MARS. PMID- 25784792 TI - Dezocine for anesthesia and stress reduction in induced abortion. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of dezocine with regard to analgesic and stress reduction outcomes in women undergoing induced abortion. METHODS: A total of 126 women in early pregnancy (up to 14 weeks' gestation) who underwent induced abortion at Cangzhou Central Hospital from May 2012 to May 2013 were randomly assigned to a control (propofol) group (n=63) or an intervention (propofol + dezocine) group (n=63). Wake-up time, orientation force recovery time, incidence of adverse reactions, postoperative visual analog scale (VAS) score, analgesic effect, and respiratory and circulatory monitoring before the operation, 5 minutes into the operation, and 5 minutes after the operation were compared between the two groups. RESULTS: The surgical procedure and anesthesia were performed successfully in all patients. Systolic and diastolic blood pressure and oxyhemoglobin saturation in the intervention group were significantly higher than in the control group; however, heart rate was significantly lower in the intervention group than in the control group 5 minutes into the operation (all P<0.05). There were no statistically significant differences in these parameters before surgery and after recovery. The postoperative VAS score (2.82+/-0.72), Ramsay score (2.65+/-0.65), and anesthetic effect in the intervention group were better than in the control group (3.90+/-0.84 and 2.21+/-0.49, respectively), and all differences were statistically significant (P<0.05). The wake-up time (3.41+/-0.79 minutes) and orientation force recovery time (4.28+/-0.92 minutes) were all significantly shorter (P<0.05) in the intervention group than in the control group, as was the incidence of adverse reactions (7.94% versus 26.98%, respectively). CONCLUSION: Adverse reactions of propofol combined with dezocine in painless induced abortion are less while the analgesic effect is better. PMID- 25784793 TI - Determinants of non-adherence to antiretroviral therapy in adult hospitalized patients, Northwest Ethiopia. AB - AIM: The aim of this study was to assess the rate of antiretroviral therapy (ART) adherence and to identify any determinants among adult patients. METHODS: A cross sectional study was conducted on 351 ART patients in the ART clinic of the University of Gondar referral hospital. Data were collected by a pretested interviewer-administered structured questionnaire from May to June 2014. Multivariate logistic regression was used to determine factors significantly associated with adherence. RESULTS: Of 351 study subjects, women were more predominant than men (64.4% versus 35.6%). Three hundred and forty (96.9%) patients agreed and strongly agreed that the use of ART is essential in their life, and approximately 327 (93.2%) disclosed their sero-status to family. Seventy-nine (22.5%) participants were active substance users. The level of adherence was 284 (80.9%). Three hundred forty-one (97.2%) respondents had good or fair adherence. Among the reasons for missing doses were forgetfulness (29 [43.3%]), missing appointments (14 [20.9%]), running out of medicine (9 [13.4%]), depression, anger, or hopelessness (4 [6.0%]), side effects of the medicine used (2 [3.0%]), and nonbelief in the ART (2 [3.0%]). The variables found significantly associated with non-adherence were age (P-value 0.017), employment (P-value 0.02), HIV disclosure (P-value 0.04), and comfortability to take ART in the presence of others (P-value 0.02). CONCLUSION: From this study, it was determined that forgetfulness (43.3%) was the most common reason for missing doses. Also, employment and acceptance in using ART in the presence of others are significant issues observed for non-adherence. Hence, the ART counselor needs to place more emphasis on the provision and use of memory aids. PMID- 25784794 TI - In vitro studies of the toxic effects of silver nanoparticles on HeLa and U937 cells. AB - In the last decade, much attention has been paid to studies of the effect of silver nanoparticles (Ag NPs) on tumor cells. Apart from elucidation of the mechanism of NPs' interaction with mammalian cells, these studies are aimed at discovering new effective antitumor drugs. In this work, we report about the toxic effects of Ag NPs observed on two types of tumor cells: HeLa (adhesive cells) and U937 (suspension cells). The Ag NPs were obtained by an original method of biochemical synthesis. Particle size was 13.2+/-4.72 nm, and zeta potential was -61.9+/-3.2 mV. The toxicity of Ag NPs in the concentration range 0.5-8.0 MUg Ag/mL was determined by means of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and cytofluorometry after 4 and 24 hours' incubation. It was found that Ag NPs had high toxicity toward both cell types. The minimal concentrations where a toxicity effect was registered (toxicity thresholds) lied in the range 0.5-2.0 MUg Ag/mL. In parallel with the Ag NP solution, cells were incubated with water solutions of the NP stabilizer (aerosol OT) and Ag(+) ions (as silver nitrate). It was shown that aerosol-OT had no effect on the viability on HeLa cells, but was moderately toxic toward U937, though less dangerous for these cells than Ag NPs. With Ag(+) ions, for HeLa no toxic effect was observed, while for U937 they were as toxic as the Ag NPs. The data obtained indicate that Ag NPs as used in this study may prove to be useful for the creation of medicines for cancer therapy. PMID- 25784795 TI - Oral and pharyngeal bolus transit in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), may have swallowing dysfunction. OBJECTIVE: The aim of this investigation was to evaluate the oral and pharyngeal phases of swallowing in patients with COPD. METHODS: We studied 16 patients with clinical manifestations and pulmonary function tests diagnosis of COPD (mean age: 68 years) and 15 nonsmoking healthy volunteers (mean age: 65 years) with normal pulmonary function tests. All subjects were submitted to clinical and videofluoroscopic evaluation of swallowing. Each subject performed in duplicate swallows of 5 mL and 10 mL of liquid bolus, paste bolus, and a solid bolus. RESULTS: In general, the duration of the events of the pharyngeal phase of swallowing was longer in COPD patients than controls. The difference was significant in the laryngeal vestibular closure, hyoid movement, and pharyngeal transit with swallows of both volumes of liquid bolus; in oral-pharyngeal transit with 5 mL paste bolus; and in pharyngeal and oral-pharyngeal transit with solid bolus. The difference between the duration of maximal laryngeal elevation and the duration of pharyngeal transit was higher in control subjects than in patients with COPD. CONCLUSION: The results suggested that patients with COPD have a longer pharyngeal swallowing phase than normal subjects, which is associated with a decrease in the difference between the duration of maximal laryngeal elevation and the duration of pharyngeal transit. PMID- 25784796 TI - Risk factors for chronic obstructive pulmonary disease among never-smokers in Korea. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients include those who have never smoked. However, risk factors other than smoking in never-smokers have not been elucidated sufficiently. This study investigated the risk factors for COPD among never-smokers in Korea using population-based data. METHODS: The data were retrieved from the Korean National Health and Nutrition Survey IV conducted from 2007 to 2009. Among subjects aged 40 years or older who underwent appropriate pulmonary function tests, never-smokers not diagnosed with asthma and not showing a restrictive pattern on pulmonary function tests were enrolled. Risk factors of COPD in never-smokers were analyzed using logistic regression models. RESULTS: Among 24,871 participants in the representative Korean cohort, 3,473 never-smokers were enrolled. COPD patients accounted for 7.6% of the never smokers. In the logistic regression analysis, low education status (odds ratio [OR]: 2.0; 95% confidence interval [CI]: 1.2-3.2), occupational exposure (OR: 2.6; 95% CI: 1.3-5.3), a history of tuberculosis (OR: 4.5; 95% CI: 2.3-8.7), bronchiectasis (OR: 6.0; 95% CI: 1.4-25.4), male sex (OR: 4.2; 95% CI: 2.6-6.7), advanced age (60-69 years vs 40-49 years; OR: 3.8; 95% CI: 2.0-7.0), and being underweight (body mass index <18.5 vs 18.0-24.9 kg/m(2); OR: 3.1; 95% CI: 1.0 9.4) were associated with the development of COPD. CONCLUSION: Low education status, manual labor, a history of tuberculosis and bronchiectasis, as well as male sex, advanced age and being underweight were risk factors for COPD in Korean never-smokers. PMID- 25784797 TI - The COPD assessment test correlates well with the computed tomography measurements in COPD patients in China. AB - BACKGROUND: The chronic obstructive pulmonary disease (COPD) assessment test (CAT) is a validated simple instrument to assess health status, and it correlates well with the severity of airway obstruction in COPD patients. However, little is known about the relationships between CAT scores and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness in COPD patients in the People's Republic of China. METHODS: One hundred and twelve participants including 63 COPD patients and 49 normal control subjects were recruited. All participants were examined with high-resolution CT to get the measurements of emphysema (percentage of pixels below -950 HU [%LAA-950]) and airway wall thickness (wall area percentage and the ratio of airway wall thickness to total diameter). Meanwhile, they completed the CAT and modified Medical Research Council questionnaire independently. RESULTS: Significantly higher CAT scores and CT measurements were found in COPD patients compared with normal control subjects (P<0.05), and there was a tendency of higher CAT scores and CT measurements with increasing disease severity measured by GOLD staging system. Positive correlations were found between CAT scores and CT measurements (P<0.01). Using multiple linear stepwise regression, CAT score =-46.38+0.778* (wall area percentage) +0.203* (%LAA-950) (P<0.001). Meanwhile, CAT scores and CT measurements in COPD patients all positively correlated with the modified Medical Research Council grades and negatively correlated with FEV1% (P<0.01). CONCLUSION: CAT scores correlate well with the quantitative CT measurements in COPD patients, which may provide an imaging evidence that the structural changes of the lungs in this disease are associated with the health status measured by CAT. PMID- 25784799 TI - Development of an oral push-pull osmotic pump of fenofibrate-loaded mesoporous silica nanoparticles. AB - In this study, mesoporous silica nanoparticles (MSNs) were used to prepare an oral push-pull osmotic pump. Fenofibrate, the selected model drug, was firstly loaded into the MSNs, followed by a suspending agent consisting of a drug layer of push-pull osmotic pump. Fenofibrate-loaded MSNs were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption/desorption analysis, differential scanning calorimetry (DSC), powder X ray diffractometry (PXRD) analysis, and Fourier-transform infrared (FT-IR) spectroscopy. Polyethylene oxide of molecular weight (MW) 100,000 and polyethylene oxide of MW 6,000,000 were selected as the suspending agent and the expanding agent, respectively. Cellulose acetate was used as the semipermeable membrane, along with polyethylene glycol 6,000 to increase the flexibility and control the membrane permeability. The in vitro dissolution studies indicated that the osmotic pump tablet combined with MSNs was able to deliver fenofibrate in an approximately zero-order manner in 24 hours. A pharmacokinetic study showed that, although the maximum plasma concentration of the osmotic pump was lower than that of the reference formulation, the relative bioavailability was increased, indicating that the osmotic pump was more efficient than the reference tablets. Therefore, using MSNs as a carrier for poorly water-soluble drugs is an effective method for preparing osmotic pump tablets. PMID- 25784798 TI - Impact of beta-blocker selectivity on long-term outcomes in congestive heart failure patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is present in approximately one-third of all congestive heart failure (CHF) patients, and is a key cause of underprescription and underdosing of beta-blockers, largely owing to concerns about precipitating respiratory deterioration. For these reasons, the aim of this study was to evaluate the impact of beta-blockers on the long-term outcomes in CHF patients with COPD. In addition, we compared the effects of two different beta-blockers, carvedilol and bisoprolol. METHODS: The study was a retrospective, non-randomized, single center trial. Acute decompensated HF patients with COPD were classified according to the oral drug used at discharge into beta-blocker (n=86; carvedilol [n=52] or bisoprolol [n=34]) and non-beta blocker groups (n=46). The primary endpoint was all-cause mortality between the beta-blocker and non-beta-blocker groups during a mean clinical follow-up of 33.9 months. The secondary endpoints were the differences in all-cause mortality and the hospitalization rates for CHF and/or COPD exacerbation between patients receiving carvedilol and bisoprolol. RESULTS: The mortality rate was higher in patients without beta-blockers compared with those taking beta-blockers (log-rank P=0.039), and univariate analyses revealed that the use of beta-blockers was the only factor significantly correlated with the mortality rate (hazard ratio: 0.41; 95% confidence interval: 0.17-0.99; P=0.047). Moreover, the rate of CHF and/or COPD exacerbation was higher in patients treated with carvedilol compared with bisoprolol (log-rank P=0.033). In the multivariate analysis, only a past history of COPD exacerbation significantly increased the risk of re-hospitalization due to CHF and/or COPD exacerbation (adjusted hazard ratio: 3.11; 95% confidence interval: 1.47-6.61; P=0.003). CONCLUSION: These findings support the recommendations to use beta-blockers in HF patients with COPD. Importantly, bisoprolol reduced the incidence of CHF and/or COPD exacerbation compared with carvedilol. PMID- 25784800 TI - Blood-brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate. AB - In this study, the ability of a multiwalled carbon nanotube functionalized with fluorescein isothiocyanate (MWCNT-FITC) was assessed as a prospective central nervous system-targeting drug delivery system to permeate the blood-brain barrier. The results indicated that the MWCNT-FITC conjugate is able to penetrate microvascular cerebral endothelial monolayers; its concentrations in the Transwell((r)) system were fully equilibrated after 48 hours. Cell viability test, together with phase-contrast and fluorescence microscopies, did not detect any signs of MWCNT-FITC toxicity on the cerebral endothelial cells. These microscopic techniques also revealed presumably the intracellular localization of fluorescent MWCNT-FITCs apart from their massive nonfluorescent accumulation on the cellular surface due to nanotube lipophilic properties. In addition, the 1,000 ps molecular dynamics simulation in vacuo discovered the phenomenon of carbon nanotube aggregation driven by van der Waals forces via MWCNT-FITC rapid dissociation as an intermediate phase. PMID- 25784801 TI - Mesoporous calcium-silicon xerogels with mesopore size and pore volume influence hMSC behaviors by load and sustained release of rhBMP-2. AB - Mesoporous calcium-silicon xerogels with a pore size of 15 nm (MCS-15) and pore volume of 1.43 cm(3)/g were synthesized by using 1,3,5-mesitylene (TMB) as the pore-expanding agent. The MCS-15 exhibited good degradability with the weight loss of 50 wt% after soaking in Tris-HCl solution for 56 days, which was higher than the 30 wt% loss shown by mesoporous calcium-silicon xerogels with a pore size of 4 nm (MCS-4). The pore size and pore volume of MCS-15 had significant influences on load and release of recombinant human bone morphogenetic protein-2 (rhBMP-2). The MCS-15 had a higher capacity to encapsulate a large amount of rhBMP-2; it could adsorb 45 mg/g of rhBMP-2 in phosphate-buffered saline after 24 hours, which was more than twice that with MCS-4 (20 mg/g). Moreover, the MCS-15 system exhibited sustained release of rhBMP-2 as compared with MCS-4 system (showing a burst release). The MCS-15/rhBMP-2 system could promote the proliferation and differentiation of human mesenchymal stem cells, showing good cytocompatibility and bioactivity. The results indicated that MCS-15, with larger mesopore size and higher pore volume, might be a promising carrier for loading and sustained release of rhBMP-2, which could be used as bone repair material with built-in osteoinduction function in bone reconstruction. PMID- 25784802 TI - Specifically targeted delivery of protein to phagocytic macrophages. AB - Macrophages play important roles in the pathogenesis of various diseases, and are important potential therapeutic targets. Furthermore, macrophages are key antigen presenting cells and important in vaccine design. In this study, we report on the novel formulation (bovine serum albumin [BSA]-loaded glucan particles [GMP-BSA]) based on beta-glucan particles from cell walls of baker's yeast for the targeted delivery of protein to macrophages. Using this formulation, chitosan, tripolyphosphate, and alginate were used to fabricate colloidal particles with the model protein BSA via electrostatic interactions, which were caged and incorporated BSA very tightly within the beta-glucan particle shells. The prepared GMP-BSA exhibited good protein-release behavior and avoided protein leakage. The particles were also highly specific to phagocytic macrophages, such as Raw 264.7 cells, primary bone marrow-derived macrophages, and peritoneal exudate macrophages, whereas the particles were not taken up by nonphagocytic cells, including NIH3T3, AD293, HeLa, and Caco-2. We hypothesize that these tightly encapsulated protein-loaded glucan particles deliver various types of proteins to macrophages with notably high selectivity, and may have broad applications in targeted drug delivery or vaccine design against macrophages. PMID- 25784803 TI - Quantum dot-based multiplexed imaging in malignant ascites: a new model for malignant ascites classification. AB - PURPOSE: The aims of this study are to establish a new method for simultaneously detecting the interactions between cancer cells and immunocytes in malignant ascites (MA) and to propose a new model for MA classification. METHODS: A quantum dot (QD)-based multiplexed imaging technique was developed for simultaneous in situ imaging of cancer cells, lymphocytes, and macrophages. This method was first validated in gastric cancer tissues, and then was applied to MA samples from 20 patients with peritoneal carcinomatosis from gastrointestinal and gynecological origins. The staining features of MA and the interactions between cancer cells and immunocytes in the ascites were further analyzed and correlated with clinical features. RESULTS: The QD-based multiplexed imaging technique was able to simultaneously show gastric cancer cells, infiltrating macrophages, and lymphocytes in tumor tissue, and the technique revealed the distinctive features of the cancer tumor microenvironment. When this multiplexed imaging protocol was applied to MA cytology, different features of the interactions and quantitative relations between cancer cells and immunocytes were observed. On the basis of these features, MA could be classified into immunocyte-dominant type, immunocyte reactive type, cancer cell-dominant type, and cell deletion type; the four categories were statistically different in terms of the ratio of cancer cells to immunocytes (P<0.001). Moreover, in the MA, the ratio of cancer cells to immunocytes was higher for patients with gynecological and gastric cancers than for those with colorectal cancer. CONCLUSION: The newly developed QD-based multiplexed imaging technique was able to better reveal the interactions between cancer cells and immunocytes. This advancement allows for better MA classification and, thereby, allows for treatment decisions to be more individualized. PMID- 25784804 TI - Self-assembled amphotericin B-loaded polyglutamic acid nanoparticles: preparation, characterization and in vitro potential against Candida albicans. AB - In the present study, we developed a self-assembled biodegradable polyglutamic acid (PGA)-based formulation of amphotericin B (AmB) and evaluated its in vitro antifungal potential against Candida albicans. The AmB-loaded PGA nanoparticles were prepared in-house and had a mean size dimension of around 98+/-2 nm with a zeta potential of -35.2+/-7.3 mV. Spectroscopic studies revealed that the drug predominantly acquires an aggregated form inside the formulation with an aggregation ratio above 2. The PGA-based AmB formulation was shown to be highly stable in phosphate-buffered saline as well as in serum (only 10%-20% of the drug was released after 10 days). The AmB-PGA nanoparticles were less toxic to red blood cells (<15% lysis at an AmB concentration of 100 MUg/mL after 24 hours) when compared with Fungizone((r)), a commercial antifungal product. An MTT assay showed that the viability of mammalian cells (KB and RAW 264.7) was negligibly affected at AmB concentrations as high as 200 MUg/mL. Histopathological examination of mouse kidney revealed no signs of tissue necrosis. The AmB-PGA formulation showed potent antimicrobial activity similar to that of Fungizone against C. albicans. Interestingly, AmB-bearing PGA nanoparticles were found to inhibit biofilm formation to a considerable extent. In summary, AmB-PGA nanoparticles showed highly attenuated toxicity when compared with Fungizone, while retaining equivalent active antifungal properties. This study indicates that the AmB-PGA preparation could be a promising treatment for various fungal infections. PMID- 25784805 TI - Poly(ethylene glycol)-block-poly(epsilon-caprolactone)-and phospholipid-based stealth nanoparticles with enhanced therapeutic efficacy on murine breast cancer by improved intracellular drug delivery. AB - BACKGROUND: Effective anticancer drug delivery to the tumor site without rapid body clearance is a prerequisite for successful chemotherapy. 1,2-distearoyl-sn glycero-3-phospho-ethanolamine-N-(methoxy[polyethyleneglycol]-2000) (DSPE PEG2000) has been widely used in the preparation of stealth liposomes. Although PEG chains can efficiently preserve liposomes from rapid clearance by the reticuloendothelial system (RES), its application has been hindered by poor cellular uptake and unsatisfactory therapeutic effect. METHODS: To address the dilemma, we presented a facile approach to fabricate novel stealth nanoparticles generated by poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL), soybean phosphatidylcholine (SPC), and cholesterol, namely LPPs (L represented lipid and PP represented PEG-b-PCL), for the delivery of anticancer drug paclitaxel (PTX). LPPs were prepared using the thin film hydration method. Two PEG-b-PCL polymers with different molecular weights (MW; PEG2000-b-PCL2000, MW: 4,000 Da and PEG5000-b-PCL5000, MW: 10,000 Da) were used to fabricate stealth nanoparticles. Conventional PEGylated liposome (LDP2000, L represented lipid and DP2000 represented DSPE-PEG2000) composed of SPC, cholesterol, and DSPE-PEG2000 was used as the control. The physical properties, cellular uptake, endocytosis pathway, cytotoxicity, pharmacokinetics, tumor accumulation, and anticancer efficacy of free PTX, PTX-loaded LPPs, and LDP2000 were systemically investigated after injection into 4T1 breast tumor-bearing mice. RESULTS: LPPs were vesicles around 100 nm in size with negative zeta potential. With enhanced stability, LPPs achieved sustainable release of cancer therapeutics. The cellular uptake level was closely related to the PEG chain length of PEG-b-PCL; a shorter PEG chain resulted in higher cellular uptake. Moreover, the cellular internalization of LPP2000 modified by PEG2000-b-PCL2000 on 4T1 cells was 2.1-fold higher than LDP2000 due to the improved stability of LPP2000. The cytotoxicity of PTX-loaded LPP2000 was also higher than that of LDP2000 and LPP5000 as observed using a WST 8 assay, while blank LPPs showed negligible toxicity. Consistent with the results of the in vitro study, in vivo experiments showed that LPPs allowed significantly improved bioavailability and prolonged T1/2beta as compared to free PTX injection. More importantly, LPPs mainly accumulated at the tumor site, probably due to the enhanced permeation and retention effect (EPR effect). As a nanomedicine, LPP2000 (tumor inhibition rate of 75.1%) significantly enhanced the therapeutic effect of PTX in 4T1 breast tumor-bearing mice by inhibiting tumor growth compared to LDP2000 and LPP5000 (tumor inhibition rates of 56.3% and 49.5%, respectively). CONCLUSION: Modification of liposomes with PEG2000-b PCL2000 can simultaneously improve drug accumulation at the target tumor site and tumor cells, showing great promise for utilization as a PEG modification tool in the fabrication of stealth nanoparticles for cancer chemotherapy. PMID- 25784806 TI - Glioma-targeting micelles for optical/magnetic resonance dual-mode imaging. AB - Surgical resection is the primary mode for glioma treatment, while gross total resection is difficult to achieve, due to the invasiveness of the gliomas. Meanwhile, the tumor-resection region is closely related to survival rate and life quality. Therefore, we developed optical/magnetic resonance imaging (MRI) bifunctional targeted micelles for glioma so as to delineate the glioma location before and during operation. The micelles were constructed through encapsulation of hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) with polyethylene glycol-block-polycaprolactone (PEG-b-PCL) by using a solvent evaporation method, and modified with a near-infrared fluorescent probe, Cy5.5, in addition to the glioma-targeting ligand lactoferrin (Lf). Being encapsulated by PEG-b-PCL, the hydrophobic SPIONs dispersed well in phosphate-buffered saline over 4 weeks, and the relaxivity (r 2) of micelles was 215.4 mM(-1).s(-1), with sustained satisfactory fluorescent imaging ability, which might have been due to the interval formed by PEG-b-PCL for avoiding the fluorescence quenching caused by SPIONs. The in vivo results indicated that the nanoparticles with Lf accumulated efficiently in glioma cells and prolonged the duration of hypointensity at the tumor site over 48 hours in the MR image compared to the nontarget group. Corresponding with the MRI results, the margin of the glioma was clearly demarcated in the fluorescence image, wherein the average fluorescence intensity of the tumor was about fourfold higher than that of normal brain tissue. Furthermore, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay results showed that the micelles were biocompatible at Fe concentrations of 0-100 MUg/mL. In general, these optical/MRI bifunctional micelles can specifically target the glioma and provide guidance for surgical resection of the glioma before and during operation. PMID- 25784808 TI - Hypomania after augmenting venlafaxine and olanzapine with sarcosine in a patient with schizophrenia: a case study. AB - Glutamate is the main excitatory neurotransmitter in the central nervous system. Dysfunction of the glutamatergic system plays an important and well-established role in the pathogenesis of schizophrenia. Agents with glutamatergic properties such as N-methyl-D-aspartate receptor coagonists (ie, glycine, D-cycloserine) and glycine transporter type 1 inhibitors (eg, sarcosine, bitopertin) are investigated in schizophrenia with special focus on negative and cognitive symptomatology. In this article, we describe a case of a 34-year-old woman with diagnosis of schizophrenia with persistent moderate negative and cognitive symptoms, a participant of the Polish Sarcosine Study (PULSAR) treated with olanzapine (25 mg per day) and venlafaxine (75 mg per day). During ten weeks of sarcosine administration (2 g per day) the patient's activity and mood improved, but in the following 2 weeks, the patient reported decreased need for sleep, elevated mood, libido and general activity. We diagnosed drug-induced hypomania and recommended decreasing the daily dose of venlafaxine to 37.5 mg per day, which resulted in normalization of mood and activity in about 1 week. After this change, activity and mood remained stable and better than before adding sarcosine, and subsequent depressive symptoms were not noted. We describe here the second case report where sarcosine induced important affect changes when added to antidepressive and antipsychotic treatment, which supports the hypothesis of clinically important glutamate-serotonin interaction. PMID- 25784807 TI - Enhanced oral bioavailability of fenofibrate using polymeric nanoparticulated systems: physicochemical characterization and in vivo investigation. AB - BACKGROUND: The intention of this research was to prepare and compare various solubility-enhancing nanoparticulated systems in order to select a nanoparticulated formulation with the most improved oral bioavailability of poorly water-soluble fenofibrate. METHODS: The most appropriate excipients for different nanoparticulated preparations were selected by determining the drug solubility in 1% (w/v) aqueous solutions of each carrier. The polyvinylpyrrolidone (PVP) nanospheres, hydroxypropyl-beta-cyclodextrin (HP-beta CD) nanocorpuscles, and gelatin nanocapsules were formulated as fenofibrate/PVP/sodium lauryl sulfate (SLS), fenofibrate/HP-beta-CD, and fenofibrate/gelatin at the optimized weight ratios of 2.5:4.5:1, 1:4, and 1:8, respectively. The three solid-state products were achieved using the solvent evaporation method through the spray-drying technique. The physicochemical characterization of these nanoparticles was accomplished by powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and Fourier-transform infrared spectroscopy. Their physicochemical properties, aqueous solubility, dissolution rate, and pharmacokinetics in rats were investigated in comparison with the drug powder. RESULTS: Among the tested carriers, PVP, HP-beta-CD, gelatin, and SLS showed better solubility and were selected as the most appropriate constituents for various nanoparticulated systems. All of the formulations significantly improved the aqueous solubility, dissolution rate, and oral bioavailability of fenofibrate compared to the drug powder. The drug was present in the amorphous form in HP-beta-CD nanocorpuscles; however, in other formulations, it existed in the crystalline state with a reduced intensity. The aqueous solubility and dissolution rates of the nanoparticles (after 30 minutes) were not significantly different from one another. Among the nanoparticulated systems tested in this study, the initial dissolution rates (up to 10 minutes) were higher with the PVP nanospheres and HP beta-CD nanocorpuscles; however, neither of them resulted in the highest oral bioavailability. Irrespective of relatively retarded dissolution rate, gelatin nanocapsules showed the highest apparent aqueous solubility and furnished the most improved oral bioavailability of the drug (~5.5-fold), owing to better wetting and diminution in crystallinity. CONCLUSION: Fenofibrate-loaded gelatin nanocapsules prepared using the solvent-evaporation method through the spray drying technique could be a potential oral pharmaceutical product for administering the poorly water-soluble fenofibrate with an enhanced bioavailability. PMID- 25784809 TI - Cattle encephalon glycoside and ignotin injection improves cognitive impairment in APPswe/PS1dE9 mice used as multitarget anti-Alzheimer's drug candidates. AB - BACKGROUND: Cattle encephalon glycoside and ignotin injection (CEGI), a multitargeted neurotrophic drug, has been widely used in the treatment of central and peripheral nerve injuries, such as stroke, hypoxic ischemic encephalopathy, and diabetic neuropathy in the People's Republic of China. However, data regarding the effect of CEGI on Alzheimer's disease (AD) remain scarce. The present study aimed to investigate the effect of CEGI on learning and memory in an APPswe/PS1dE9 double-transgenic mouse model, a suitable animal model of AD, and elucidate its possible mechanisms. MATERIALS AND METHODS: Five-month-old APP/PS1 mice were intraperitoneally administered 6.6 mL/kg or 13.2 mL/kg of CEGI for 1 month. After 1 month of administration, all mice received Morris water maze training and a probe test. Mouse brain sections were detected by standard biochemical and immunohistochemical measures. RESULTS: CEGI treatment significantly improved the spatial learning and memory deficits and decreased cerebral amyloid-beta42 levels in brain homogenates of APP/PS1 mice. CEGI treatment elevated the activities of superoxide dismutase, and reduced the levels of malondialdehyde. CEGI attenuated neuronal damage in the hippocampus of APP/PS1 mice and upregulated protein and gene expression of Bcl-2 and the ratio of Bcl 2/Bax. CEGI treatment decreased the number of Iba1(+) activated microglia in the cortex of the APP/PS1 mice. CONCLUSION: Our results showed that CEGI prevents memory impairment, possibly by decreasing the amyloid-beta42 levels in APP/PS1 mice and inhibiting oxidative stress, apoptosis, and inflammation, making CEGI a promising therapeutic agent for AD. PMID- 25784810 TI - Adjunctive treatment with aripiprazole for risperidone-induced hyperprolactinemia. AB - BACKGROUND: Antipsychotics have been used for more than 50 years in the treatment of schizophrenia and many other psychiatric disorders. Prolactin levels usually increase in patients treated with risperidone. Aripiprazole, which has a unique effect as an antipsychotic, is a D2 receptor partial agonist. It is an atypical antipsychotic with limited extrapyramidal symptoms. Since it acts as an antagonist in hyperdopaminergic conditions and as an agonist in hypodopaminergic conditions, it does not have adverse effects on serum prolactin levels. The present study aimed to investigate the effect of aripiprazole on risperidone induced hyperprolactinemia. METHODS: This before-and-after clinical trial was performed in 30 patients. Baseline prolactin levels were measured in all patients who were candidates for treatment with risperidone. In subjects with elevated serum prolactin, aripiprazole was added to their treatment. Serum prolactin levels were measured during the first week, second week, and monthly thereafter for at least 3 months or until prolactin levels became normal. The data were analyzed using Stata version 11 software. Survival analysis and McNemar's test were also performed. RESULTS: The mean age of the participants was 30.8 years. Prolactin levels normalized in 23 (77%) participants during the study, and menstrual disturbances normalized in 25 (83.3%). Prolactin levels normalized in most patients between days 50 and 110. The median time to recovery based on normalization of prolactin was 84 days. Psychotic symptoms were present in 26 subjects at baseline, but in only two by the end of the study. CONCLUSION: The results of this study confirm the effects of aripiprazole in reducing risperidone induced hyperprolactinemia and its sequelae. Aripiprazole also led to significant improvements in psychotic symptoms when compared with those present prior to treatment with aripiprazole. PMID- 25784811 TI - Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects. AB - Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4 hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases. PMID- 25784812 TI - Sex differences in TGFB-beta signaling with respect to age of onset and cognitive functioning in schizophrenia. AB - There are studies showing that gene polymorphisms within the transforming growth factor-beta (TGF-beta) signaling constitute schizophrenia risk variants. However, the association between TGFB1 gene polymorphisms (+869T/C and +915G/C), TGF-beta level with schizophrenia course, and its symptomatology together with cognitive functioning has not been investigated so far. We included 151 patients with schizophrenia and 279 healthy controls. Cognitive functioning was assessed using Rey Auditory Verbal Learning Test, Trail Making Test (TMT)-A and TMT-B, Verbal Fluency task, Stroop test, as well as selected subtests from the Wechsler Adults Intelligence Scale - Revised, Polish adaptation (WAIS-R-Pl): Digit Symbol Coding, Digit Span Forward and Backward, and Similarities. Additionally, serum TGF-beta levels were measured in 88 schizophrenia patients and 88 healthy controls. Serum TGF-beta level was significantly higher among patients with schizophrenia in comparison with healthy controls; however, the studied polymorphisms were not associated with TGF-beta level in schizophrenia patients. Subjects carrying the +869T allele performed significantly worse in comparison with +869CC homozygotes on Stroop task, Verbal Fluency task and Digit Symbol Coding task. There was a significant difference in age of psychosis onset in female schizophrenia patients with respect to the TGFB1 +869T/C polymorphism. Additionally, adjustment for possible confounders revealed that there was a significant difference in cognitive performance on Digit Symbol Coding task with respect to the TGFB1 +869T/C polymorphism among female schizophrenia patients. Our results suggest that TGF-beta signaling might be a valid link contributing to observed differences in age of onset and the level of cognitive decline between male and female schizophrenia patients. PMID- 25784813 TI - Quality of life of patients with schizophrenia treated in foster home care and in outpatient treatment. AB - BACKGROUND: The Sveti Ivan Psychiatric Hospital in Zagreb, Croatia, offers foster home care treatment that includes pharmacotherapy, group psychodynamic psychotherapy, family therapy, and work and occupational therapy. The aim of this study is to compare the health-related quality of life of patients with schizophrenia treated in foster home care with that of patients in standard outpatient treatment. METHODS: The sample consisted of 44 patients with schizophrenia who, upon discharge from the hospital, were included in foster home care treatment and a comparative group of 50 patients who returned to their families and continued receiving outpatient treatment. All patients completed the Short Form 36 Health Survey Questionnaire on the day they completed hospital treatment, 6 months later, and 1 year after they participated in the study. The research also included data on the number of hospitalizations for both groups of patients. RESULTS: Though directly upon discharge from the hospital, patients who entered foster home care treatment assessed their health-related quality of life as poorer than patients who returned to their families, their assessments significantly improved over time. After 6 months of treatment, these patients even achieved better results in several dimensions than did patients in the outpatient program, and they also had fewer hospitalizations. These effects remained the same at the follow-up 1 year after the inclusion in the study. CONCLUSION: Notwithstanding the limitations of this study, it can be concluded that treatment in foster home care is associated with an improvement in the quality of life of patients with schizophrenia, but the same was not observed for the patients in standard outpatient treatment. We hope that these findings will contribute to an improved understanding of the influence of psychosocial factors on the functioning of patients and the development of more effective therapeutic methods aimed at improving the patients' quality of life. PMID- 25784814 TI - Protocol for audit of current Filipino practice in rehabilitation of stroke inpatients. AB - BACKGROUND: Stroke is one of the leading medical conditions in the Philippines. Over 500,000 Filipinos suffer from stroke annually. Provision of evidence-based medical and rehabilitation management for stroke patients has been a challenge due to existing environmental, social, and local health system issues. Thus, existing western guidelines on stroke rehabilitation were contextualized to draft recommendations relevant to the local Philippine setting. Prior to fully implementing the guidelines, an audit of current practice needs to be undertaken, thus the purpose of this audit protocol. METHODS: A clinical audit of current practices in stroke rehabilitation in the Philippines will be undertaken. A consensus list of data items to be captured was identified by the audit team during a 2-day meeting in 2012. These items, including patient demographics, type of stroke, time to referral for rehabilitation management, length of hospital stay, and other relevant descriptors of stroke management were included as part of the audit. Hospitals in the Philippines will be recruited to take part in the audit activity. Recruitment will be via the registry of the Philippine Academy of Rehabilitation Medicine, where 90% of physiatrists (medical doctors specialized in rehabilitation medicine) are active members and are affiliated with various hospitals in the Philippines. Data collectors will be identified and trained in the audit process. A pilot audit will be conducted to test the feasibility of the audit protocol, and refinements to the protocol will be undertaken as necessary. The comprehensive audit process will take place for a period of 3 months. Data will be encoded using MS Excel((r)). Data will be reported as means and percentages as appropriate. Subgroup analysis will be undertaken to look into differences and variability of stroke patient descriptors and rehabilitation activities. CONCLUSION: This audit study is an ambitious project, but given the "need" to conduct the audit to identify "gaps" in current practice, and the value it can bring to serve as a platform for implementation of evidence-based stroke management in the Philippines to achieve best patient and health outcomes, the audit team is more than ready to take up the challenge. PMID- 25784815 TI - Micro-ribonucleic acid 29b inhibits cell proliferation and invasion and enhances cell apoptosis and chemotherapy effects of cisplatin via targeting of DNMT3b and AKT3 in prostate cancer. AB - BACKGROUND: Micro-ribonucleic acids (miRNAs) are crucial regulators in malignant tumors. miRNA-29b (miR-29b) has been identified as a tumor suppressor in prostate cancer (PCa). However, very few studies have investigated the effects of miR-29b in PCa, especially the mechanism and its association with chemotherapy. Our study aimed to explore the role and mechanism of miR-29b in PCa. MATERIALS AND METHODS: The expression levels of miR-29b were detected in ten clinical PCa specimens and four different PCa cell lines through quantitative real-time polymerase chain reaction. After miR-29b mimics and inhibitors were successfully transfected into LNCaP, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was then used to investigate cell proliferation and cisplatin sensitivity of PCa cells. Cell cycle, cell apoptosis, and cell invasion were detected via flow cytometry, annexin V-fluorescein isothiocyanate labeling, and transwell assay, respectively. Based on bioinformatic methods, Western blot analysis, and dual luciferase reporter assay, novel target genes of miR-29b were identified. RESULTS: miR-29b was downregulated in PCa tissues compared with matched adjacent nontumor tissues. In the androgen-independent PCa cell line (LNCaP-AI), the expression of miR-29b was much lower than the androgen-dependent PCa cell line (LNCaP). Subsequent studies showed that forced expression of miR-29b inhibited cell proliferation and cell invasion and induced cell apoptosis in PCa. Upregulation of miR-29b also enhanced the chemosensitivity of PCa cells to cisplatin. Moreover, we identified DNMT3b and AKT3 as novel target genes of miR 29b in PCa. CONCLUSION: Taken together, the results showed that miR-29b plays a tumor-suppressive role in PCa. It inhibits cell biological behavior and enhances the chemotherapy effects of cisplatin through its involvement in epigenetic regulation and PI3K/AKT pathway. PMID- 25784816 TI - Single-nucleotide polymorphisms of microRNA processing machinery genes are associated with risk for gastric cancer. AB - Recent studies demonstrate that microRNA-related single-nucleotide polymorphisms (miR-SNPs) are associated with the development of numerous human cancers. In this study, we investigated six miR-SNPs in microRNA processing machinery genes, including rs11077 of the XPO5 gene, rs14035 of the RAN gene, rs3742330 of the Dicer gene, rs9623117 of the TNRC6B gene, rs197412 of the GEMIN3 gene, and rs2740348 of the GEMIN4 gene, in gastric cancer patients and subsequently evaluated their potential roles in gastric cancer risk in a case control study. The results indicate that the C/C genotype of rs14035 from RAN, the A/A genotype of rs3742330 from Dicer, and the T/T genotype of rs9623117 from TNRC6B are significantly associated with gastric cancer risk. In conclusion, these miR-SNPs can be used as predictive biomarkers in gastric cancer. PMID- 25784817 TI - Human papillomavirus 16 infection predicts poor outcome in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Previous studies indicate that human papillomavirus 16 (HPV16) infection plays a pivotal role in the etiology of esophageal squamous cell carcinoma (ESCC). We aim to detect the influence of HPV16 infection on ESCC patient prognosis. PATIENTS AND METHODS: Immunohistochemical staining for HPV16 E6 oncoprotein, the low-affinity p75 neurotrophin receptor (p75NTR), and phosphatidylinositol 3-kinase (PI3K) was performed on 103 archived surgical specimens from patients with ESCC and 54 control samples from patients with benign esophageal tumor or inflammatory lesions. All patients were from the Shaan Xi Province, People's Republic of China. RESULTS: HPV16 E6 expression was significantly higher in the ESCC group (P<0.05). HPV16 E6 expression was significantly higher in men than in women (P<0.05). p75NTR expression was higher in those aged >56 years (P<0.05). PI3K expression was higher in those with a more advanced histopathological grade (P<0.05). There was a positive correlation between HPV16 E6 and p75NTR expression (r=0.547, P<0.001) and between p75NTR and PI3K expression (r=0.364, P<0.001). In 100 evaluable patients, the 5-year overall survival (OS) rate was 11%. In patients with ESCC, HPV16 E6 and PI3K expression were negatively correlated with the 3-year OS (P<0.05), 5-year OS (P<0.05), and progression-free survival (P<0.05). CONCLUSION: HPV16 infection likely contributes to the etiology of ESCC patients in Shaan Xi, People's Republic of China. HPV16 infection status and PI3K expression levels could be useful for predicting prognosis in patients with ESCC. PMID- 25784819 TI - Electronic medical record data to identify variables associated with a fibromyalgia diagnosis: importance of health care resource utilization. AB - BACKGROUND: Diagnosis of fibromyalgia (FM) is often challenging. Identifying factors associated with an FM diagnosis may guide health care providers in implementing appropriate diagnostic and management strategies. METHODS: This retrospective study used the de-identified Humedica electronic medical record (EMR) database to identify variables associated with an FM diagnosis. Cases (n=4,296) were subjects >=18 years old with >=2 International Classification of Diseases, Ninth Revision (ICD-9) codes for FM (729.1) >=30 days apart during 2012, associated with an integrated delivery network, with >=1 encounter with a health care provider in 2011 and 2012. Controls without FM (no-FM; n=583,665) did not have the ICD-9 codes for FM. Demographic, clinical, and health care resource utilization variables were extracted from structured EMR data. Univariate analysis identified variables showing significant differences between the cohorts based on odds ratios (ORs). RESULTS: Consistent with FM epidemiology, FM subjects were predominantly female (78.7% vs 64.5%; P<0.0001) and slightly older (mean age 53.3 vs 52.7 years; P=0.0318). Relative to the no-FM cohort, the FM cohort was characterized by a higher prevalence of nearly all evaluated comorbidities; the ORs suggested a higher likelihood of an FM diagnosis (P<0.0001), especially for musculoskeletal and neuropathic pain conditions (OR 3.1 for each condition). Variables potentially associated with an FM diagnosis included higher levels of use of specific health care resources including emergency-room visits, outpatient visits, hospitalizations, and medications. Units used per subject for emergency room visits, outpatient visits, hospitalizations, and medications were also significantly higher in the FM cohort (P<0.0001), confirming resource utilization as an important variable associated with an FM diagnosis. CONCLUSION: Significant differences between the FM and no-FM cohorts were observed for nearly all the demographic, clinical, and health care resource variables, suggesting an association with FM diagnosis. These results also support use of EMR data for identifying variables associated with FM, which may help in the diagnosis and management of this condition. PMID- 25784818 TI - Epoetin beta for the treatment of chemotherapy-induced anemia: an update. AB - Epoetin beta belongs to the class of erythropoiesis-stimulating agents (ESAs) that are currently available to treat anemic patients receiving chemotherapy. Chemotherapy-induced anemia affects a high percentage of cancer patients and, due to its negative effects on disease outcome and the patient's quality of life, should be treated when first diagnosed. Initial trials with ESAs have shown efficacy in improving quality of life and reducing the need for blood transfusions in patients with chemotherapy-induced anemia. However, recent meta analyses have provided conflicting data on the impact of ESAs on survival and tumor progression. Here we provide an overview of these recent data and review the role of epoetin beta in the treatment of chemotherapy-induced anemia over the past 20 years. PMID- 25784820 TI - Estimating the hypothetical dual health impact and cost-effectiveness of the Woman's Condom in selected sub-Saharan African countries. AB - BACKGROUND: Female condoms are the only currently available woman-initiated option that offers dual protection from pregnancy and sexually transmitted infections, including HIV. The Woman's Condom is a new female condom designed to provide dual protection and to be highly pleasurable and acceptable. OBJECTIVE: We sought to estimate the potential dual health impact and cost-effectiveness of a Woman's Condom distribution program in 13 sub-Saharan African countries with HIV prevalence rates >4% among adults aged 15-49 years. We used two separate, publicly available models for this analysis, the Impact 2 model developed by Marie Stopes International and the Population Services International disability adjusted life years (DALY) calculator program. We estimated the potential numbers of pregnancies and DALYs averted when the Woman's Condom is used as a family planning method and the HIV infections and DALYs averted when it is used as an HIV prevention method. RESULTS: Programming 100,000 Woman's Condoms in each of 13 countries in sub-Saharan Africa during a 1-year period could potentially prevent 194 pregnancies and an average of 21 HIV infections in each country. When using the World Health Organization CHOosing Interventions that are Cost-Effective (WHO CHOICE) criteria as a threshold to infer the potential cost-effectiveness of the Woman's Condom, we found that the Woman's Condom would be considered cost effective. CONCLUSION: This was a first and successful attempt to estimate the impact of dual protection of female condoms. The health impact is greater for the use of the Woman's Condom as an HIV prevention method than for contraception. Dual use of the Woman's Condom increases the overall health impact. The Woman's Condom was found to be very cost-effective in all 13 countries in our sample. PMID- 25784821 TI - Ablation of idiopathic ventricular tachycardia originating from posterior mitral annulus by using electroanatomical mapping. AB - Idiopathic ventricular tachycardia (IVT) is an important type of arrhythmia, which has distinct electrocardiographic features and treatment options. Most of the cases originate from right ventricular outflow tract and less frequently from the left ventricular outflow tract. IVTs originating from mitral annulus are rare, and little is known about the efficacy of radiofrequency catheter ablation in this form. We hereby present a rare case of IVT arising from posterior mitral annulus. The electrocardiographic, electrophysiological, and electroanatomical characteristics of this tachycardia are discussed. PMID- 25784823 TI - Policy address. PMID- 25784824 TI - Guidelines for iodine prophylaxis as a protective measure: information for physicians. PMID- 25784822 TI - Use of computed tomography to determine the risk of patellar dislocation in 921 patients with patellar instability. AB - The purpose of this research was to identify reliable tomographic measurements that can detect patellofemoral abnormality and allow quantification of the risk of patellar dislocation in patients with potential patellar instability. A cross sectional study in 921 patients with anterior pain or knee instability of at least 6 months' duration was conducted from July 2001 to December 2009. All subjects were clinically evaluated and underwent radiography and computed tomography of their knees. According to their degree of dislocating patellar dysplasia, the subjects were classified into groups for statistical comparison. There was a statistically significant difference in all measurements when the groups were compared, except for external tibial torsion angle. The most sensitive and specific measurements for determining patellar instability were the trochlear groove angle, tibial tubercle-trochlear groove distance, average patellar tilt, and average patellar height. Patients with potential patellar instability, increased tibial tubercle-trochlear groove distance, and patellar height, tilt, and deviation measurements had a greater risk for patellar dislocation. The clinical relevance of this study is to determine measurements that are able to tell us about patellar dislocation risk. PMID- 25784825 TI - Enhancing International Contributions Centered on WMA Activities and Community Health. PMID- 25784826 TI - Efforts of the Japan Medical Association toward the Resolution of Vaccine Gaps. PMID- 25784827 TI - Regulatory organizations for physicians' status and administrative sanctions on physicians: - examining the framework of government administrative systems for physicians in Japan based on a questionnaire survey conducted on 13 national medical associations. AB - Society bestows professional privilege on physicians. At the same time, it expects physicians to strive constantly to improve their ethics and quality in medical expertise. In every nation, some level of government is responsible for certifying or licensing physicians and imposes strict management, including revoking licenses from inappropriate physicians or providing severe sanctions for misconduct or conduct unbecoming of a physician. In reality, however, it is difficult to reduce the number of inappropriate or indiscreet physicians, and each nation faces its own challenges. We conducted a questionnaire survey of 13 national medical associations, including some major Western countries, regarding the licensing of physicians, the organizations managing their medical practice status, and the data and grounds for administrative sanctioning of physicians. We then examined the circumstances in Japan based on the survey results and pointed out the domestic issues. PMID- 25784828 TI - Health literacy training for public health nurses in fukushima: a case-study of program adaptation, implementation and evaluation. AB - Health literacy comprises not only an individual's ability to gain access to, understand and use health information, but also health care providers' ability to make health information accessible and usable. The Fukushima nuclear accident has posed challenges related to the communication of radiation-related health information. Public health nurses are gatekeepers of community health in Japan, and have primary responsibility for communicating this complex information about science and risk to lay members of the community. A health literacy training program was designed to augment communication skills of participating nurses with two primary goals: changing communication practices and norms among public health nurses, and improving access to information for community residents. Training content incorporated an overview of health literacy skills (including numeracy), processes for assessing written materials and visual displays, as well as guidelines for text improvement. The workshop was spread across two days with two hour sessions each day. A proximal post-training evaluation survey was conducted, followed by a more distal one-month follow-up evaluation to assess the application of learned skills in practice. Twenty-six nurses in Fukushima City attended the first trial. Post-training evaluations were highly positive, with agreement from 85-100% of participants on the appropriateness and usefulness of the workshop. During a one-month follow-up, the nurses reported applying new knowledge and skills to develop written materials. However, they faced difficulties sharing their new skills with colleagues and challenges changing work norms. Participants also encountered difficulties using graphics and explaining risks in practice. This paper highlights the importance of providing health literacy training opportunities for professionals to strengthen health system's ability to accessible information and services. This program also serves as important reference for future disaster management efforts. PMID- 25784829 TI - Physicians and professional autonomy. PMID- 25784830 TI - From the Editor's Desk. PMID- 25784831 TI - Prognostic factors and treatment results of high-grade osteosarcoma in norway: a scope beyond the "classical" patient. AB - Purpose. A retrospective study of prognostic factors and treatment outcome of osteosarcoma (OS) during modern chemotherapy era with focus on patients with primary metastatic disease, nonextremity localisation, or age >40 years (nonclassical OS). Methods. A nationwide cohort, comprising 424 high-grade Norwegian bone OS patients, was based on registry sources supplemented with clinical records from hospitals involved in sarcoma management between 1975 and 2009. Results. Only 48% were younger patients with tumour in the extremities and without metastasis at diagnosis (classical OS). A considerable discrepancy in survival between classical and nonclassical OS was observed: 61% versus 26% 10 year sarcoma specific survival. Twice as many of the former received both adequate surgery and chemotherapy compared to the latter. This could only partly explain the differences in survival due to inherent chemoresistance in primary metastatic disease and a higher rate of local relapse among patients with axial tumours. Metastasis at diagnosis, increased lactate dehydrogenase, age > 40 years, and tumour size above median value were all adverse prognostic factors for overall survival. Conclusion. We confirm a dramatic difference in outcome between classical and nonclassical high-grade OS patients, but treatment variables could only partly explain the dismal outcome of the latter. PMID- 25784832 TI - Wiki-based clinical practice guidelines for the management of adult onset sarcoma: a new paradigm in sarcoma evidence. AB - In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community. PMID- 25784833 TI - Intercalary reconstruction after wide resection of malignant bone tumors of the lower extremity using a composite graft with a devitalized autograft and a vascularized fibula. AB - Introduction. Although several intercalary reconstructions after resection of a lower extremity malignant bone tumor are reported, there are no optimal methods which can provide a long-term reconstruction with fewest complications. We present the outcome of reconstruction using a devitalized autograft and a vascularized fibula graft composite. Materials and Methods. We conducted a retrospective review of 11 patients (7 males, 4 females; median age 27 years) undergoing reconstruction using a devitalized autograft (pasteurization (n = 6), deep freezing (n = 5)) and a vascularized fibula graft composite for lower extremity malignant bone tumors (femur (n = 10), tibia (n = 1)). Results. The mean period required for callus formation and bone union was 4.4 months and 9.9 months, respectively. Four postoperative complications occurred in 3 patients: 2 infections (1 pasteurized autograft, 1 frozen autograft) and 1 fracture and 1 implant failure (both in pasteurized autografts). Graft removal was required in 2 patients with infections. The mean MSTS score was 81% at last follow-up. Conclusions. Although some complications were noted in early cases involving a pasteurized autograft, our novel method involving a combination of a frozen autograft with a vascularized fibula graft and rigid fixation with a locking plate may offer better outcomes than previously reported allografts or devitalized autografts. PMID- 25784834 TI - Are we a step forward with targeted agents in resolving the enigma of mantle cell lymphoma? AB - Mantle cell lymphoma has been recognized as a distinct entity from the other non Hodgkin lymphomas in middle 1990's. It carries a worst prognosis among all mature B-cell malignancies. Cyclin D1 and recently SOX11 are the hallmarks for this disease. Even if it is highly responsive to induction treatment, it remains incurable, since it inevitably relapses. Highly aggressive approaches with stem cell transplantation can shift the survival curve for a bit, but even so the overall survival is not significantly improved in most of the cases. Small portion of patients with this heterogeneous disease have an indolent course with long-term survival. Conventional immunochemotherapy has reached its maximal possibilities, so novel target agents are absolutely warranted. The large number of ongoing early phase trials demonstrated promising results, especially emphasizing agents that target B-cell receptor. They are mostly investigated in relapsed/refractory disease, while front-line approaches with those agents need to be explored in future times. PMID- 25784835 TI - Characteristics of gastrointestinal stromal tumours, diagnostic procedure and therapeutic management and main directions of nursing practice in gastrointestinal stromal tumours. AB - Gastrointestinal stromal tumours (GIST) constitute a separate group of mesenchymal neoplasms of the gastrointestinal tract. They have been commonly recognized for a few years, they have created a new problem in medical practice. GIST are more often centred in the stomach. They equally affect female and male patients and occur mainly in patients older than 50 years of age. The clinical picture of the tumour is non-specific. Radical surgical treatment and molecularly targeted therapy with tyrosine kinase inhibitors are used in GIST treatment. Nursing practice with reference to GIST danger is connected with biopsychosocial interventions of perioperative, oncological and palliative procedures and involves the area of health education mainly oriented towards shaping preventive procedures which favour early disease detection and support therapy and recovery. PMID- 25784836 TI - Overexpression of Raf-1 in basal-like carcinoma of the breast: correlation with clinicopathology and prognosis. AB - AIM OF THE STUDY: Increased Raf-1 expression has been associated with an aggressive behaviour in some carcinomas such as pulmonary carcinoma and renal carcinoma. However, its role in breast cancer, especially in basal-like carcinoma of the breast (BLBC), has not been defined. MATERIAL AND METHODS: The current study attempted to investigate the expression pattern of Raf-1 protein in BLBC, in relation to the biological behaviour and prognosis of the carcinoma. Expression of Raf-1 was detected by immunohistochemistry in carcinoma specimens from 74 cases of BLBC, and associations between their expression and the clinicopathological characteristics were statistically assessed. RESULTS: The patients' age, tumour size, BRCA1, and p53 protein expression was not significantly different between the Raf-1-positive and Raf-1-negative expression groups (p > 0.05). The proportion of histological grade 3 tumours was not significantly higher in the Raf-1 positive group than that of grade 2 tumours (p > 0.05). However, positive cytoplasmic Raf-1 expression was positively correlated to Ki-67 expression (p < 0.05). Also, increased Raf-1 protein was found to exert an unfavourable impact on patients' axillary lymph node metastasis and overall survival (p < 0.05). CONCLUSIONS: The study implies that positive Raf-1 expression in BLBC is associated with a more aggressive phenotype and could be considered as a new prognostic biomarker for poor survival in BLBC patients. PMID- 25784837 TI - Analysis of the involvement of cytokines in allergy and breast cancer association. AB - AIM OF THE STUDY: The existence of a correlation between allergy disorders and cancer diseases has been confirmed by several epidemiological studies. Although the molecular mechanism involved in this phenomenon remains unknown, there are data indicating that certain cytokines, engaged in allergic processes, have antineoplastic activities. The aim of the present study was to explore the association between advanced breast cancer and allergic state on the molecular level. MATERIAL AND METHODS: We determined and compared the mRNA and protein expression of interleukin-1beta (IL-1beta), IL-4, IL-6, and interferon-gamma (IFN gamma), cytokines known for antitumor properties, in the blood of advanced breast cancer patients and individuals with allergic diseases related to type 2 response. In addition, we performed an in vitro assay of reactivity of peripheral blood mononuclear cells after exogenous antigen stimulation. As a preliminary to molecular analysis we conducted a questionnaire study concerning the incidence of allergy among breast cancer patients and healthy subjects without malignancy. RESULTS: The results of the survey study revealed a negative relation between breast cancer and allergy prevalence. Subsequent molecular analysis, however, did not show statistically significant differences in cytokines mRNA and protein expression levels between allergic patients and those with malignancy. The in vitro reactivity test also did not reveal marked differences between IL-1beta, IL 4 and IL-6 production after PBMC triggering with exogenous antigen. CONCLUSIONS: We concluded that the studied cytokines (IL-1beta, IL-4, IL-6, and IFN-gamma) are not engaged in breast cancer-allergy negative relation. PMID- 25784838 TI - Expression of cell adhesion molecules in laryngeal carcinoma - preliminary analysis. AB - AIM OF THE STUDY: Intercellular adhesion molecules present in immunocompetent cells as well as endothelium and tumour cells can regulate cell migration, angiogenesis, apoptosis, proliferation, and metastases in solid tumours. The aim of this study was to analyse the sICAM-1 (soluble intercellular adhesion molecule 1) and sVCAM-1 (soluble vascular cell adhesion molecule 1) expression in peripheral blood mononuclear cell (PBMC) cultures, and to find their relationships with clinicomorphological characteristics in laryngeal cancer. MATERIALS AND METHODS: The analysis included a group of 50 patients with verified squamous cell carcinoma of the larynx. The control group constituted 30 healthy volunteers. The pathological assessment included pTNM, stage, histological grade, and type of invasion according to the tumour front grading. The expression of adhesion molecules was assessed using the enzyme-linked immunosorbent assay (ELISA). RESULTS: Increased expression of sICAM-1 and sVCAM-1 was an indicator of more aggressive laryngeal carcinomas. More advanced local changes evaluated on the pT feature were connected with a higher sVCAM-1 (p = 0.017), but not sICAM-1 level. The presence of lymph node metastases correlated with a higher expression of adhesion molecules (p = 0.012 and p = 0.003, for sICAM-1 and sVCAM-1, respectively). Tumours with more diffuse growth and infiltrating with small cell groups (< 15/hpf) was characterised by the highest level of adhesive proteins (p = 0.001 and p = 0.02 for sICAM and sVCAM, respectively). Moreover, lower levels of sICAM-1 and sVCAM-1 were observed more frequently in patients who lived longer than five years after treatment. CONCLUSIONS: The study indicates the importance of the sICAM and sVCAM expression as indicators of advanced changes and prognosis in patients with laryngeal carcinoma. PMID- 25784839 TI - Cyclooxygenase-2 immunohistochemical expression in serrated polyps of the colon. AB - AIM OF THE STUDY: Cyclooxygenase-2 (COX-2) expression has been observed in a substantial percentage of classical adenomas of the large bowel. The aim of the study was to assess and compare the expression of COX-2 in serrated polyps of the colon. MATERIAL AND METHODS: One hundred and nineteen serrated polyps were analyzed. There were 83 hyperplastic polyps (HP), 19 sessile serrated polyps (SSP) and 17 traditional serrated adenomas (TSA). COX-2 expression was assessed semi-quantitatively (0-2) and each lesion was fully characterized in terms of anatomical location, size, histology, age and sex of the patient. The general estimating equation (GEE) model with logit link was used in the statistical analysis. RESULTS: Epithelial expression of COX-2 was found in 85/119 serrated polyps (71.43%): 57/83 (68.67%) HP, 16/19 (84.21%) SSP, and 12/17 (70.59%) TSA. In HP and SSP it was predominantly of weak (49/83 HP, 12/19 SSP), whereas in TSA it was mainly of medium/strong intensity (8/17). The TSA category was associated with more frequent COX-2 expression (OR = 7.00, 95% CI: 1.49-32.88, p = 0.014) than HP, but such relation was not found for SSP vs. HP (p > 0.1). No associations between COX-2 expression and clinical parameters were found. CONCLUSIONS: Immunohistochemical COX-2 expression cannot serve as a diagnostic adjunct to differentiate HP and SSP. PMID- 25784840 TI - Colorectal cancer with intestinal perforation - a retrospective analysis of treatment outcomes. AB - AIM OF THE STUDY: Colorectal cancer (CRC) is one of the leading cause of death in European population. It progresses without any symptoms in the early stages or those clinical symptoms are very discrete. The aim of this study was a retrospective analysis of treatment outcomes in patients with colorectal cancer complicated with intestinal perforation. MATERIAL AND METHODS: A retrospective analysis of patients urgently operated upon in our Division of General Surgery, because of large intestine perforation, from February 1993 to February 2013 has been made. Results were compared with a group of patients undergoing the elective surgery for colorectal cancer in the same time and Division. RESULTS: Intestinal perforation occurred more often in males (6.52% vs. 6.03%), patients with mucous component in histopathological examination (9.09% vs. 6.01%) and with clinicaly advanced CRC. Patients treated because of perforation had a five-fold higher 30 day mortality rate (9.09% vs. 1.83%), however long-term survival did not differ significantly in both groups. After resectional surgery in 874 patients an intestinal anastomosis was made. Anastomotic leakage was present in 23 (2.6%) patients. This complication occurred six-fold more frequently in a group of patients operated upon because of intestinal perforation (12.20% vs. 2.16%). CONCLUSIONS: In patients with CRC complicated with perforation of the colon in a 30-day observation significantly higher rate of complications and mortality was shown, whereas there was no difference in distant survival rates. PMID- 25784841 TI - Clinical practice in febrile neutropenia risk assessment and granulocyte colony stimulating factor primary prophylaxis of febrile neutropenia in Poland. AB - AIM OF THE STUDY: The first aim was to investigate the knowledge and awareness of oncologists concerning febrile neutropenia (FN) risk assessment and indications for granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (PP), based on current therapeutic guidelines (PTOK and EORTC). The second aim was to educate the oncologists on best practices for risk assessment and neutropenia management. MATERIAL AND METHODS: The project participants included 169 oncologists from 7 regions working in large specialist oncological centres, university hospitals, regional and city hospitals, specialist outpatient clinics, and oncological wards in small local hospitals. The participants completed a questionnaire based on seven prepared clinical cases of patients with different tumour types and patient characteristics, receiving chemotherapy (CT), and with different levels of FN risk. Participants answered questions related to FN risk assessment and G-CSF use. After completing the questionnaire, the participants proceeded to an educational module in which they were provided with an analysis of correct diagnostic and therapeutic procedures according to the PTOK and EORTC guidelines. RESULTS AND CONCLUSIONS: Febrile neutropenia risk assessment was found to be a routine procedure performed for over 90% of the clinical cases by the participant oncologists. However, the FN risk assessment of clinical cases was correct and consistent with therapeutic guidelines in only 65% of responses. Indications for G-CSF PP were properly identified in 76% of responses and it appeared that indications for G-CSF PP were more likely to be correctly identified in patients receiving high-risk or low-risk regimens than in those receiving intermediate risk regimens, where the decision to give G-CSF PP is based on additional assessment of patient risk factors. The vast majority of participants who correctly identified the need for PP administered G-CSF in accordance with the dose and schedule recommended by PTOK and EORTC. PMID- 25784842 TI - Clinical practice in secondary prophylaxis and management of febrile neutropenia in Poland: results of the febrile neutropenia awareness project. AB - AIM OF THE STUDY: This paper presents the second part of the GoPractice project involving oncologists from seven Polish provinces. The aim of this part of the project was to assess the knowledge of oncologists on indications for granulocyte colony-stimulating factor (G-CSF) secondary prophylaxis (SP) of febrile neutropenia (FN) and FN management based on current therapeutic guidelines (Polish Society of Clinical Oncology [PTOK] and European Organisation for Research and Treatment of Cancer [EORTC]). MATERIAL AND METHODS: The project involved 169 oncologists from 7 regions working in large specialist oncological centers, university hospitals, regional and city hospitals, specialist outpatient clinics and oncological wards in small, local hospitals. The participants completed a questionnaire based on 7 prepared clinical cases of patients with different tumor types and patient characteristics, receiving chemotherapy (CT) with different levels of FN risk. Participants answered questions related to FN risk assessment and G-CSF use as secondary prophylaxis (SP) and for the management of FN. After completing the questionnaire, the participants proceeded to an educational module in which they were provided with an analysis of correct diagnostic and therapeutic procedures according to the PTOK and EORTC guidelines. RESULTS AND CONCLUSIONS: Indications for G-CSF SP were generally well recognized: in nearly 90% of responses, oncologists assessed correctly indications/lack of indications for secondary prophylaxis, in accordance with guideline recommendations and Experts' opinion. However, the use of daily G-CSFs was often recommended by the study participants for the management of FN. This clinical practice is contradictory to PTOK and EORTC recommendations and may unnecessarily increase treatment costs. Changing this clinical approach may be achieved through regular training to improve guideline adherence. PMID- 25784843 TI - The effect of tumor volume on radiotherapy outcome and correlation with other prognostic factors in patients with T2 supraglottic cancer. AB - The retrospective chart review of 110 patients with T2 supraglottic cancer who underwent radiotherapy was performed to correlate tumor volume with other prognostic factors and to analyze its impact on treatment results. Patients with involved nodes, poor histopathological tumor differentiation, or hemoglobin concentration <= 14.3 g/dl had significantly larger tumors. Patients with large tumors had significantly lower 5-year local control rate, overall survival rate and presented significantly higher risk of nodal involvement and the ratio of poor histopathological differentiation of the tumor. Tumor volume significantly impacts radiotherapy outcome and should be considered to optimize treatment strategy for patients with T2 supraglottic cancer. PMID- 25784844 TI - Impact of different beam directions on intensity-modulated radiation therapy dose delivered to functioning lung tissue identified using single-photon emission computed tomography. AB - AIM OF THE STUDY: To use different beam arrangements and numbers to plan intensity-modulated radiation therapy (IMRT) and investigate their effects on low and high radiation doses delivered to the functional lung, in order to reduce radiation-induced lung damage. MATERIAL AND METHODS: Ten patients with stage I III non-small cell lung carcinoma (NSCLC) underwent IMRT. Beam arrangements were selected on the basis of orientation and dose-volume histograms to create SPECT guided IMRT plans that spared the functional lung and maintained target coverage. Four different plans, including CT-7, SPECT-7, SPECT-4, SPECT-5 with different beam arrangements, were used. The differences of conformity index (CI), heterogeneity index (HI) between the plans were analyzed, by using a paired t test. RESULTS: The seven-beam SPECT (SPECT-7) plan reduced the volume of the functional lung irradiated with at least 20 Gy (FV20) and 30 Gy (FV30) by 26.02% +/-15.45% and 14.41% +/-16.66%, respectively, as compared to the seven-beam computed tomography (CT-7) plan. The CI significantly differed between the SPECT 7 and SPECT-4 plans and between the SPECT-5 and SPECT-4 plans, but not between the SPECT-5 and SPECT-7 plans. The CIs in the SPECT-5 and SPECT-7 plans were better than that in the SPECT-4 plan. The heterogeneity index significantly differed among the three SPECT plans and was best in the SPECT-7 plan. CONCLUSIONS: The incorporation of SPECT images into IMRT planning for NSCLC greatly affected beam angles and number of beams. Fewer beams and modified beam angles achieved similar or better IMRT quality. The low-dose volumes were lower in SPECT-4. PMID- 25784845 TI - LanroNET, a non-interventional, prospective study to assess the resource utilization and cost of lanreotide autogel 120 mg in Polish patients with neuroendocrine tumors - results of interim analysis. AB - AIM OF THE STUDY: To examine characteristics and treatment patterns of symptomatic neuroendocrine tumors (NETs) patients who received lanreotide Autogel 120 mg (ATG120) administered as part of routine clinical practice. MATERIAL AND METHODS: Lanro-NET is a national, multicenter, non-interventional, observational study in the population of adult patients with symptomatic NETs treated with ATG120 for at least three months before inclusion. Data on demographic and clinical characteristics of the population, dosing interval regimen and aspects of administration were collected prospectively during 12 months. Costs were calculated from the perspective of public payer for the year 2014. RESULTS: Fifty two patients were enrolled in the study. Primary tumors were located predominantly in gastrointestinal tract (51.2%), all tumors were metastatic. The most commonly reported disease symptoms were flushing and diarrhea (55.8% of patients). 86% of patients had undergone surgery, chemotherapy and radioisotope therapy were used in 11.6% and 46.5% of patients, respectively. During the 12 months observation 12 (28%) patients received ATG120 at an extended dosing interval (> 4 weeks), the mean number of days between injections was 31.75 (SD 6.74). The cost of ATG12 was estimated at 4273.17 PLN patient/month. In all patients ATG120 was administered by nurse, 51.6% of injections in out-patient setting, 48.4% - in hospital. CONCLUSIONS: This study presents the current use of ATG120 in the population of Polish NETs patients in a realistic clinical settings. Finding that 28% of patients could be treated with extended dose intervals supports the potential for ATG120 of reducing treatment burden. PMID- 25784846 TI - Multiple metastases of renal clear cell carcinoma to the organs of the head. AB - Metastases of renal clear cell carcinoma to the organs of the head are rare. Single cases show that they can appear either shortly after or many years after radical surgery. The diagnosis of this cancer is difficult because of its insidious course; therefore, it is often diagnosed too late. Late diagnosis is associated with a high risk of distant metastases and increased mortality. The paper presents a case of a patient whose kidney tumour was diagnosed during hospitalisation at the Department of Rheumatology. Further diagnosis and surgical treatment were performed in the Department of Urology, where a left-sided nephrectomy was carried out. After two years, the patient was hospitalised in the Department of Otolaryngology due to dysphagia. The patient was subjected to fine needle biopsy, surgical biopsy, CT, and ultrasound. Metastases of renal clear cell carcinoma were diagnosed based on a histopathological examination and the results of imaging studies. Due to the extent of the tumour, diagnostics were extended to magnetic resonance imaging. The patient was qualified for tracheotomy, cytoreductive surgery, and chemoradiation. The patient was referred for further treatment at the Centre of Oncology in Bydgoszcz. PMID- 25784847 TI - Comparison between FDG-PET/CT and bone scan in bone metastasis from NSCLC. PMID- 25784848 TI - Development of the choroid plexus and blood-CSF barrier. AB - Well-known as one of the main sources of cerebrospinal fluid (CSF), the choroid plexuses have been, and still remain, a relatively understudied tissue in neuroscience. The choroid plexus and CSF (along with the blood-brain barrier proper) are recognized to provide a robust protective effort for the brain: a physical barrier to impede entrance of toxic metabolites to the brain; a "biochemical" barrier that facilitates removal of moieties that circumvent this physical barrier; and buoyant physical protection by CSF itself. In addition, the choroid plexus-CSF system has been shown to be integral for normal brain development, central nervous system (CNS) homeostasis, and repair after disease and trauma. It has been suggested to provide a stem-cell like repository for neuronal and astrocyte glial cell progenitors. By far, the most widely recognized choroid plexus role is as the site of the blood-CSF barrier, controller of the internal CNS microenvironment. Mechanisms involved combine structural diffusion restraint from tight junctions between plexus epithelial cells (physical barrier) and specific exchange mechanisms across the interface (enzymatic barrier). The current hypothesis states that early in development this interface is functional and more specific than in the adult, with differences historically termed as "immaturity" actually correctly reflecting developmental specialization. The advanced knowledge of the choroid plexus-CSF system proves itself imperative to understand a range of neurological diseases, from those caused by plexus or CSF drainage dysfunction (e.g., hydrocephalus) to more complicated late-stage diseases (e.g., Alzheimer's) and failure of CNS regeneration. This review will focus on choroid plexus development, outlining how early specializations may be exploited clinically. PMID- 25784849 TI - Plasticity in memristive devices for spiking neural networks. AB - Memristive devices present a new device technology allowing for the realization of compact non-volatile memories. Some of them are already in the process of industrialization. Additionally, they exhibit complex multilevel and plastic behaviors, which make them good candidates for the implementation of artificial synapses in neuromorphic engineering. However, memristive effects rely on diverse physical mechanisms, and their plastic behaviors differ strongly from one technology to another. Here, we present measurements performed on different memristive devices and the opportunities that they provide. We show that they can be used to implement different learning rules whose properties emerge directly from device physics: real time or accelerated operation, deterministic or stochastic behavior, long term or short term plasticity. We then discuss how such devices might be integrated into a complete architecture. These results highlight that there is no unique way to exploit memristive devices in neuromorphic systems. Understanding and embracing device physics is the key for their optimal use. PMID- 25784851 TI - Closed-loop control of a fragile network: application to seizure-like dynamics of an epilepsy model. AB - It has recently been proposed that the epileptic cortex is fragile in the sense that seizures manifest through small perturbations in the synaptic connections that render the entire cortical network unstable. Closed-loop therapy could therefore entail detecting when the network goes unstable, and then stimulating with an exogenous current to stabilize the network. In this study, a non-linear stochastic model of a neuronal network was used to simulate both seizure and non seizure activity. In particular, synaptic weights between neurons were chosen such that the network's fixed point is stable during non-seizure periods, and a subset of these connections (the most fragile) were perturbed to make the same fixed point unstable to model seizure events; and, the model randomly transitions between these two modes. The goal of this study was to measure spike train observations from this epileptic network and then apply a feedback controller that (i) detects when the network goes unstable, and then (ii) applies a state feedback gain control input to the network to stabilize it. The stability detector is based on a 2-state (stable, unstable) hidden Markov model (HMM) of the network, and detects the transition from the stable mode to the unstable mode from using the firing rate of the most fragile node in the network (which is the output of the HMM). When the unstable mode is detected, a state-feedback gain is applied to generate a control input to the fragile node bringing the network back to the stable mode. Finally, when the network is detected as stable again, the feedback control input is switched off. High performance was achieved for the stability detector, and feedback control suppressed seizures within 2 s after onset. PMID- 25784850 TI - Bisphenol A and phthalate endocrine disruption of parental and social behaviors. AB - Perinatal exposure to endocrine disrupting chemicals (EDCs) can induce promiscuous neurobehavioral disturbances. Bisphenol A and phthalates are two widely prevalent and persistent EDCs reported to lead to such effects. Parental and social behaviors are especially vulnerable to endocrine disruption, as these traits are programmed by the organizational-activational effects of testosterone and estrogen. Exposure to BPA and other EDCs disrupts normal maternal care provided by rodents and non-human primates, such as nursing, time she spends hunched over and in the nest, and grooming her pups. Paternal care may also be affected by BPA. No long-term study has linked perinatal exposure to BPA or other EDC and later parental behavioral deficits in humans. The fact that the same brain regions and neural hormone substrates govern parental behaviors in animal models and humans suggests that this suite of behaviors may also be vulnerable in the latter. Social behaviors, such as communication, mate choice, pair bonding, social inquisitiveness and recognition, play behavior, social grooming, copulation, and aggression, are compromised in animal models exposed to BPA, phthalates, and other EDCs. Early contact to these chemicals is also correlated with maladaptive social behaviors in children. These behavioral disturbances may originate by altering the fetal or adult gonadal production of testosterone or estrogen, expression of ESR1, ESR2, and AR in the brain regions governing these behaviors, neuropeptide/protein hormone (oxytocin, vasopressin, and prolactin) and their cognate neural receptors, and/or through epimutations. Robust evidence exists for all of these EDC-induced changes. Concern also exists for transgenerational persistence of such neurobehavioral disruptions. In sum, evidence for social and parental deficits induced by BPA, phthalates, and related chemicals is strongly mounting, and such effects may ultimately compromise the overall social fitness of populations to come. PMID- 25784852 TI - Segmentation of brain magnetic resonance images based on multi-atlas likelihood fusion: testing using data with a broad range of anatomical and photometric profiles. AB - We propose a hierarchical pipeline for skull-stripping and segmentation of anatomical structures of interest from T1-weighted images of the human brain. The pipeline is constructed based on a two-level Bayesian parameter estimation algorithm called multi-atlas likelihood fusion (MALF). In MALF, estimation of the parameter of interest is performed via maximum a posteriori estimation using the expectation-maximization (EM) algorithm. The likelihoods of multiple atlases are fused in the E-step while the optimal estimator, a single maximizer of the fused likelihoods, is then obtained in the M-step. There are two stages in the proposed pipeline; first the input T1-weighted image is automatically skull-stripped via a fast MALF, then internal brain structures of interest are automatically extracted using a regular MALF. We assess the performance of each of the two modules in the pipeline based on two sets of images with markedly different anatomical and photometric contrasts; 3T MPRAGE scans of pediatric subjects with developmental disorders vs. 1.5T SPGR scans of elderly subjects with dementia. Evaluation is performed quantitatively using the Dice overlap as well as qualitatively via visual inspections. As a result, we demonstrate subject-level differences in the performance of the proposed pipeline, which may be accounted for by age, diagnosis, or the imaging parameters (particularly the field strength). For the subcortical and ventricular structures of the two datasets, the hierarchical pipeline is capable of producing automated segmentations with Dice overlaps ranging from 0.8 to 0.964 when compared with the gold standard. Comparisons with other representative segmentation algorithms are presented, relative to which the proposed hierarchical pipeline demonstrates comparative or superior accuracy. PMID- 25784853 TI - Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and thyroid hormone transmembrane transporters. AB - Thyroid hormones are key players in regulating brain development. Thus, transfer of appropriate quantities of thyroid hormones from the blood into the brain at specific stages of development is critical. The choroid plexus forms the blood cerebrospinal fluid barrier. In reptiles, birds and mammals, the main protein synthesized and secreted by the choroid plexus is a thyroid hormone distributor protein: transthyretin. This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid. Maximal transthyretin synthesis in the choroid plexus occurs just prior to the period of rapid brain growth, suggesting that choroid plexus-derived transthyretin moves thyroid hormones from blood into cerebrospinal fluid just prior to when thyroid hormones are required for rapid brain growth. The structure of transthyretin has been highly conserved, implying strong selection pressure and an important function. In mammals, transthyretin binds T4 (precursor form of thyroid hormone) with higher affinity than T3 (active form of thyroid hormone). In all other vertebrates, transthyretin binds T3 with higher affinity than T4. As mammals are the exception, we should not base our thinking about the role of transthyretin in the choroid plexus solely on mammalian data. Thyroid hormone transmembrane transporters are involved in moving thyroid hormones into and out of cells and have been identified in many tissues, including the choroid plexus. Thyroid hormones enter the choroid plexus via thyroid hormone transmembrane transporters and leave the choroid plexus to enter the cerebrospinal fluid via either thyroid hormone transmembrane transporters or via choroid plexus-derived transthyretin secreted into the cerebrospinal fluid. The quantitative contribution of each route during development remains to be elucidated. This is part of a review series on ontogeny and phylogeny of brain barrier mechanisms. PMID- 25784854 TI - Increase in NF-kappaB-sensitive miRNA-146a and miRNA-155 in multiple sclerosis (MS) and pro-inflammatory neurodegeneration. PMID- 25784855 TI - Modulation of the glutamatergic transmission by Dopamine: a focus on Parkinson, Huntington and Addiction diseases. AB - Dopamine (DA) plays a major role in motor and cognitive functions as well as in reward processing by regulating glutamatergic inputs. In particular in the striatum the release of DA rapidly influences synaptic transmission modulating both AMPA and NMDA receptors. Several neurodegenerative and neuropsychiatric disorders, including Parkinson, Huntington and addiction-related diseases, manifest a dysregulation of glutamate and DA signaling. Here, we will focus our attention on the mechanisms underlying the modulation of the glutamatergic transmission by DA in striatal circuits. PMID- 25784856 TI - Update on the implication of potassium channels in autism: K(+) channelautism spectrum disorder. AB - Autism spectrum disorders (ASDs) are characterized by impaired ability to properly implement environmental stimuli that are essential to achieve a state of social and cultural exchange. Indeed, the main features of ASD are impairments of interpersonal relationships, verbal and non-verbal communication and restricted and repetitive behaviors. These aspects are often accompanied by several comorbidities such as motor delay, praxis impairment, gait abnormalities, insomnia, and above all epilepsy. Genetic analyses of autistic individuals uncovered deleterious mutations in several K(+) channel types strengthening the notion that their intrinsic dysfunction may play a central etiologic role in ASD. However, indirect implication of K(+) channels in ASD has been also reported. For instance, loss of fragile X mental retardation protein (FMRP) results in K(+) channels deregulation, network dysfunction and ASD-like cognitive and behavioral symptoms. This review provides an update on direct and indirect implications of K(+) channels in ASDs. Owing to a mounting body of evidence associating a channelopathy pathogenesis to autism and showing that nearly 500 ion channel proteins are encoded by the human genome, we propose to classify ASDs - whose susceptibility is significantly enhanced by ion channels defects, either in a monogenic or multigenic condition - in a new category named " c hannel A utism S pectrum D isorder" (channelASD; cASD) and introduce a new taxonomy (e.g., Kv x.y channelASD and likewise Nav x.y-channelASD, Cav x.y-channelASD; etc.). This review also highlights some degree of clinical and genetic overlap between K(+) channelASDs and K(+) channelepsies, whereby such correlation suggests that a subcategory characterized by a channelASD-channelepsy phenotype may be distinguished. Ultimately, this overview aims to further understand the different clinical subgroups and help parse out the distinct biological basis of autism that are essential to establish patient-tailored treatments. PMID- 25784857 TI - Fluoxetine induces alkalinization of astroglial cytosol through stimulation of sodium-hydrogen exchanger 1: dissection of intracellular signaling pathways. AB - Clinical evidence suggest astrocytic abnormality in major depression (MD) while treatment with anti-psychotic drugs affects astroglial functions. Astroglial cells are involved in pH homeostasis of the brain by transporting protons (through sodium-proton transporter 1, NHE1, glutamate transporters EAAT1/2 and proton-lactate co-transporter MCT1) and bicarbonate (through the sodium bicarbonate co-transporter NBC or the chloride-bicarbonate exchanger AE). Here we show that chronic treatment with fluoxetine increases astroglial pH i by stimulating NHE1-mediated proton extrusion. At a clinically relevant concentration of 1 MUM, fluoxetine significantly increased astroglial pH i from 7.05 to 7.34 after 3 weeks and from 7.18 to 7.58 after 4 weeks of drug treatment. Stimulation of NHE1 is a result of transporter phosphorylation mediated by several intracellular signaling cascades that include MAPK/ERK1/2, PI3K/AKT and ribosomal S6 kinase (RSK). Fluoxetine stimulated phosphorylation of ERK1/2, AKT and RSK in a concentration dependent manner. Positive crosstalk exists between two signal pathways, MAPK/ERK1/2 and PI3K/AKT activated by fluoxetine since ERK1/2 phosphrylation could be abolished by inhibitors of PI3K, LY294002 and AKT, triciribine, and AKT phosphorylation by inhibitor of MAPK, U0126. As a result, RSK phosphorylation was not only inhibited by U0126 but also by inhibitor of LY294002. The NHE1 phoshorylation resulted in stimulation of NHE1 activity as revealed by the NH4Cl-prepulse technique; the increase of NHE1 activity was dependent on fluoxetine concentration, and could be inhibited by both U0126 and LY294002. Our findings suggest that regulation of astrocytic pH i and brain pH may be one of the mechanisms underlying fluoxetine action. PMID- 25784859 TI - Direct and indirect pathways of the basal ganglia: opponents or collaborators? PMID- 25784860 TI - Development of a highly sensitive immunohistochemical method to detect neurochemical molecules in formalin-fixed and paraffin-embedded tissues from autopsied human brains. AB - Immunohistochemistry (IHC) is a valuable method for identifying discrete neurochemical molecules by the interaction of target antigens with validated antibodies tagged with a visible label (e.g., peroxidase). We have developed an immunostaining method that is highly sensitive in detection of neurochemical antigens. Our IHC method, which we call the PBTA method, involves a hybrid protocol that implements aspects of both the polymer and avidin-biotin-complex (ABC) methods in combination with biotin-tyramide amplification. When using [Met] enkephalin as a target antigen, the sensitivity of the PBTA method for IHC was more than 100-fold higher compared with the polymer and ABC methods. In addition, its sensitivity for enzyme-linked immunosorbent assay was about 1,000-fold higher compared with the ABC method. We examined the utility of our IHC method for both chromogenic and fluorescence detection systems used to visualize neurochemical peptides and proteins in formalin-fixed, paraffin-embedded tissues from autopsied human brains. The results convincingly demonstrate that under optimal conditions, our IHC method is highly sensitive without increasing non-specific background activities. Our IHC method could be a powerful tool for detection and visualization of neurochemical antigens that are present even in trace amounts in autopsied human brains. PMID- 25784861 TI - Stronger efferent suppression of cochlear neural potentials by contralateral acoustic stimulation in awake than in anesthetized chinchilla. AB - There are two types of sensory cells in the mammalian cochlea, inner hair cells, which make synaptic contact with auditory-nerve afferent fibers, and outer hair cells that are innervated by crossed and uncrossed medial olivocochlear (MOC) efferent fibers. Contralateral acoustic stimulation activates the uncrossed efferent MOC fibers reducing cochlear neural responses, thus modifying the input to the central auditory system. The chinchilla, among all studied mammals, displays the lowest percentage of uncrossed MOC fibers raising questions about the strength and frequency distribution of the contralateral-sound effect in this species. On the other hand, MOC effects on cochlear sensitivity have been mainly studied in anesthetized animals and since the MOC-neuron activity depends on the level of anesthesia, it is important to assess the influence of anesthesia in the strength of efferent effects. Seven adult chinchillas (Chinchilla laniger) were chronically implanted with round-window electrodes in both cochleae. We compared the effect of contralateral sound in awake and anesthetized condition. Compound action potentials (CAP) and cochlear microphonics (CM) were measured in the ipsilateral cochlea in response to tones in absence and presence of contralateral sound. Control measurements performed after middle-ear muscles section in one animal discarded any possible middle-ear reflex activation. Contralateral sound produced CAP amplitude reductions in all chinchillas, with suppression effects greater by about 1-3 dB in awake than in anesthetized animals. In contrast, CM amplitude increases of up to 1.9 dB were found in only three awake chinchillas. In both conditions the strongest efferent effects were produced by contralateral tones at frequencies equal or close to those of ipsilateral tones. Contralateral CAP suppressions for 1-6 kHz ipsilateral tones corresponded to a span of uncrossed MOC fiber innervation reaching at least the central third of the chinchilla cochlea. PMID- 25784858 TI - Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD (SAD). According to the "vascular hypothesis", AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorrhagic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review, we analyze the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease. PMID- 25784862 TI - A role of right middle frontal gyrus in reorienting of attention: a case study. AB - The right middle fontal gyrus (MFG) has been proposed to be a site of convergence of the dorsal and ventral attention networks, by serving as a circuit-breaker to interrupt ongoing endogenous attentional processes in the dorsal network and reorient attention to an exogenous stimulus. Here, we probed the contribution of the right MFG to both endogenous and exogenous attention by comparing performance on an orientation discrimination task of a patient with a right MFG resection and a group of healthy controls. On endogenously cued trials, participants were shown a central cue that predicted with 90% accuracy the location of a subsequent peri threshold Gabor patch stimulus. On exogenously cued trials, a cue appeared briefly at one of two peripheral locations, followed by a variable inter-stimulus interval (ISI; range 0-700 ms) and a Gabor patch in the same or opposite location as the cue. Behavioral data showed that for endogenous, and short ISI exogenous trials, valid cues facilitated responses compared to invalid cues, for both the patient and controls. However, at long ISIs, the patient exhibited difficulty in reverting to top-down attentional control, once the facilitatory effect of the exogenous cue had dissipated. When explicitly cued during long ISIs to attend to both stimulus locations, the patient was able to engage successfully in top-down control. This result indicates that the right MFG may play an important role in reorienting attention from exogenous to endogenous attentional control. Resting state fMRI data revealed that the right superior parietal lobule and right orbitofrontal cortex, showed significantly higher correlations with a left MFG seed region (a region tightly coupled with the right MFG in controls) in the patient relative to controls. We hypothesize that this paradoxical increase in cortical coupling represents a compensatory mechanism in the patient to offset the loss of function of the resected tissue in right prefrontal cortex. PMID- 25784863 TI - Top-down control and early multisensory processes: chicken vs. egg. PMID- 25784864 TI - Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype. AB - Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety-like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HTT) genotype, an established mouse model of increased anxiety like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered. PMID- 25784867 TI - The attribution of incentive salience to Pavlovian alcohol cues: a shift from goal-tracking to sign-tracking. AB - Environmental stimuli that are reliably paired with alcohol may acquire incentive salience, a property that can operate in the use and abuse of alcohol. Here we investigated the incentive salience of Pavlovian alcohol cues using a preclinical animal model. Male, Long-Evans rats (Harlan) with unrestricted access to food and water were acclimated to drinking 15% ethanol (v/v) in their home-cages. Rats then received Pavlovian autoshaping training in which the 10 s presentation of a retractable lever served as the conditioned stimulus (CS) and 15% ethanol served as the unconditioned stimulus (US) (0.2 ml/CS; 12 CS presentations/session; 27 sessions). Next, in an operant test of conditioned reinforcement, nose pokes into an active aperture delivered presentations of the lever-CS, whereas nose pokes into an inactive aperture had no consequences. Across initial autoshaping sessions, goal-tracking behavior, as measured by entries into the fluid port where ethanol was delivered, developed rapidly. However, with extended training goal-tracking diminished, and sign-tracking responses, as measured by lever-CS activations, emerged. Control rats that received explicitly unpaired CS and US presentations did not show goal-tracking or sign-tracking responses. In the test for conditioned reinforcement, rats with CS-US pairings during autoshaping training made more active relative to inactive nose pokes, whereas rats in the unpaired control group did not. Moreover, active nose pokes were positively correlated with sign-tracking behavior during autoshaping. Extended training may produce a shift in the learned properties of Pavlovian alcohol cues, such that after initially predicting alcohol availability they acquire robust incentive salience. PMID- 25784866 TI - Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with beta-adrenergic activity. AB - Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of beta-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals' performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals' performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of beta-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a beta-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a beta-adrenergic signaling. PMID- 25784868 TI - Adaptation to recent conflict in the classical color-word Stroop-task mainly involves facilitation of processing of task-relevant information. AB - To process information selectively and to continuously fine-tune selectivity of information processing are important abilities for successful goal-directed behavior. One phenomenon thought to represent this fine-tuning are conflict adaptation effects in interference tasks, i.e., reduction of interference after an incompatible trial and when incompatible trials are frequent. The neurocognitive mechanisms of these effects are currently only partly understood and results from brainimaging studies so far are mixed. In our study we validate and extend recent findings by examining adaption to recent conflict in the classical Stroop task using functional magnetic resonance imaging. Consistent with previous research we found increased activity in a fronto-parietal network comprising the medial prefrontal cortex, ventro-lateral prefrontal cortex, and posterior parietal cortex when contrasting incompatible with compatible trials. These areas have been associated with attentional processes and might reflect increased cognitive conflict and resolution thereof during incompatible trials. While carefully controlling for non-attentional sequential effects we found smaller Stroop interference after an incompatible trial (conflict adaptation effect). These behavioral conflict adaptation effects were accompanied by changes in activity in visual color-selective areas (V4, V4alpha), while there was no modulation by previous trial compatibility in a visual word-selective area (VWFA). Our results provide further evidence for the notion, that adaptation to recent conflict seems to be based mainly on enhancement of processing of the task relevant information. PMID- 25784865 TI - A perspective on neural and cognitive mechanisms of error commission. AB - Behavioral adaptation and cognitive control are crucial for goal-reaching behaviors. Every creature is ubiquitously faced with choices between behavioral alternatives. Common sense suggests that errors are an important source of information in the regulation of such processes. Several theories exist regarding cognitive control and the processing of undesired outcomes. However, most of these models focus on the consequences of an error, and less attention has been paid to the mechanisms that underlie the commissioning of an error. In this article, we present an integrative review of neuro-cognitive models that detail the determinants of the occurrence of response errors. The factors that may determine the likelihood of committing errors are likely related to the stability of task-representations in prefrontal networks, attentional selection mechanisms and mechanisms of action selection in basal ganglia circuits. An important conclusion is that the likelihood of committing an error is not stable over time but rather changes depending on the interplay of different functional neuro anatomical and neuro-biological systems. We describe factors that might determine the time-course of cognitive control and the need to adapt behavior following response errors. Finally, we outline the mechanisms that may proof useful for predicting the outcomes of cognitive control and the emergence of response errors in future research. PMID- 25784870 TI - Directional organization and shape formation: new illusions and Helmholtz's Square. AB - According to Helmholtz's Square illusion, a square appears wider when it is filled with vertical lines and higher when filled with horizontal lines (Helmholtz von, 1866). Recently, Pinna (2010a) demonstrated that the grouping of small squares on the basis of the similarity principle influences also perception of their shape and of the whole emerging shapes. The direction imparted by grouping is the main attribute that influences the shape by polarizing it in the same direction both globally and locally. The rectangle illusion is opposite to what expected on the basis of Helmholtz's Square illusion. Aim of this work is to solve the antinomy between the two sets of illusions and to demonstrate a common explanation based on the interaction between different sources of directional organization. This was accomplished by introducing some new phenomena and through phenomenological experiments proving the role played by the directional shape organization in shape formation. According to our results, Helmholtz's square illusion shows at least two synergistic sources of directional organization: the direction of the grouping of the lines due to their similarity of the luminance contrast and the direction of the grouping of the lines due to the good continuation. PMID- 25784869 TI - The trajectory of gray matter development in Broca's area is abnormal in people who stutter. AB - The acquisition and mastery of speech-motor control requires years of practice spanning the course of development. People who stutter often perform poorly on speech-motor tasks thereby calling into question their ability to establish the stable neural motor programs required for masterful speech-motor control. There is evidence to support the assertion that these neural motor programs are represented in the posterior part of Broca's area, specifically the left pars opercularis. Consequently, various theories of stuttering causation posit that the disorder is related to a breakdown in the formation of the neural motor programs for speech early in development and that this breakdown is maintained throughout life. To date, no study has examined the potential neurodevelopmental signatures of the disorder across pediatric and adult populations. The current study aimed to fill this gap in our knowledge. We hypothesized that the developmental trajectory of cortical thickness in people who stutter would differ across the lifespan in the left pars opercularis relative to a group of control participants. We collected structural magnetic resonance images from 116 males (55 people who stutter) ranging in age from 6 to 48 years old. Differences in cortical thickness across ages and between patients and controls were investigated in 30 brain regions previously implicated in speech-motor control. An interaction between age and group was found for the left pars opercularis only. In people who stutter, the pars opercularis did not demonstrate the typical maturational pattern of gradual gray matter thinning with age across the lifespan that we observed in control participants. In contrast, the developmental trajectory of gray matter thickness in other regions of interest within the neural network for speech-motor control was similar for both groups. Our findings indicate that the developmental trajectory of gray matter in left pars opercularis is abnormal in people who stutter. PMID- 25784871 TI - Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA. AB - It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = -0.37, p = 1.25 * 10(-6)) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 * 10(-4). The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development. PMID- 25784872 TI - Upper extremity proprioception in healthy aging and stroke populations, and the effects of therapist- and robot-based rehabilitation therapies on proprioceptive function. AB - The world's population is aging, with the number of people ages 65 or older expected to surpass 1.5 billion people, or 16% of the global total. As people age, there are notable declines in proprioception due to changes in the central and peripheral nervous systems. Moreover, the risk of stroke increases with age, with approximately two-thirds of stroke-related hospitalizations occurring in people over the age of 65. In this literature review, we first summarize behavioral studies investigating proprioceptive deficits in normally aging older adults and stroke patients, and discuss the differences in proprioceptive function between these populations. We then provide a state of the art review the literature regarding therapist- and robot-based rehabilitation of the upper extremity proprioceptive dysfunction in stroke populations and discuss avenues of future research. PMID- 25784873 TI - NeuroPG: open source software for optical pattern generation and data acquisition. AB - Patterned illumination using a digital micromirror device (DMD) is a powerful tool for optogenetics. Compared to a scanning laser, DMDs are inexpensive and can easily create complex illumination patterns. Combining these complex spatiotemporal illumination patterns with optogenetics allows DMD-equipped microscopes to probe neural circuits by selectively manipulating the activity of many individual cells or many subcellular regions at the same time. To use DMDs to study neural activity, scientists must develop specialized software to coordinate optical stimulation patterns with the acquisition of electrophysiological and fluorescence data. To meet this growing need we have developed an open source optical pattern generation software for neuroscience NeuroPG-that combines, DMD control, sample visualization, and data acquisition in one application. Built on a MATLAB platform, NeuroPG can also process, analyze, and visualize data. The software is designed specifically for the Mightex Polygon400; however, as an open source package, NeuroPG can be modified to incorporate any data acquisition, imaging, or illumination equipment that is compatible with MATLAB's Data Acquisition and Image Acquisition toolboxes. PMID- 25784874 TI - Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders. PMID- 25784875 TI - Diabetes impairs the vascular effects of aldosterone mediated by G protein coupled estrogen receptor activation. AB - Aldosterone promotes non-genomic effects in endothelial and vascular smooth muscle cells via activation of mineralocorticoid receptors (MR) and G protein coupled estrogen receptors (GPER). GPER activation is associated with beneficial/protective effects in the vasculature. Considering that vascular dysfunction plays a major role in diabetes-associated complications, we hypothesized that the beneficial effects mediated by vascular GPER activation, in response to aldosterone, are decreased in diabetes. Mesenteric resistance arteries from female, 14-16 weeks-old, control and diabetic (db/db) mice were used. Phenylephrine (PhE)-induced contractions were greater in arteries from db/db vs. control mice. Aldosterone (10 nM) increased maximal contractile responses to PhE in arteries from control mice, an effect elicited via activation of GPER. Although aldosterone did not increase PhE responses in arteries from db/db mice, blockade of GPER, and MR decreased PhE-induced contractile responses in db/db mesenteric arteries. Aldosterone also reduced the potency of acetylcholine (ACh)-induced relaxation in arteries from both control and db/db mice via MR-dependent mechanisms. GPER antagonism further decreased ACh-induced relaxation in the control group, but did not affect ACh responses in the diabetic group. Aldosterone increased extracellular signal-regulated kinase 1/2 phosphorylation in arteries from control and db/db mice by a GPER-dependent mechanism. GPER, but not MR, gene, and protein expression, determined by RT-PCR and immunoblotting/immunofluorescence assays, respectively, were increased in arteries from db/db mice vs. control arteries. These findings indicate that aldosterone activates both vascular MR and GPER and that the beneficial effects of GPER activation are decreased in arteries from diabetic animals. Our results further elucidate the mechanisms by which aldosterone influences vascular function and contributes to vascular dysfunction in diabetes. Financial Support: FAPESP, CNPq, and CAPES, Brazil. PMID- 25784876 TI - Identification of agonists for a group of human odorant receptors. AB - Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs) which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10%) have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs. PMID- 25784877 TI - Citrus bergamia essential oil: from basic research to clinical application. AB - Citrus bergamia Risso et Poiteau, also known as "Bergamot," is a plant belonging to the Rutaceae family, defined as a hybrid of bitter orange and lemon. It is an endemic plant of the Calabria region (Italy). Bergamot fruit is primarily used for the extraction of its essential oil (bergamot essential oil: BEO), employed in perfume, cosmetics, food, and confections. The aim of this review was to collect recent data from the literature on C. bergamia essential oil and, through a critical analysis, focus on safety and the beneficial effects on human health. Clinical studies on the therapeutic applications of BEO exclusively focus on the field of aromatherapy, suggesting that its use can be useful for reducing anxiety and stress. PMID- 25784878 TI - Corrigendum: In utero therapy for congenital disorders using amniotic fluid stem cells. AB - [This corrects the article on p. 270 in vol. 5, PMID: 25566071.]. PMID- 25784880 TI - Estimating cellular parameters through optimization procedures: elementary principles and applications. AB - Construction of quantitative models is a primary goal of quantitative biology, which aims to understand cellular and organismal phenomena in a quantitative manner. In this article, we introduce optimization procedures to search for parameters in a quantitative model that can reproduce experimental data. The aim of optimization is to minimize the sum of squared errors (SSE) in a prediction or to maximize likelihood. A (local) maximum of likelihood or (local) minimum of the SSE can efficiently be identified using gradient approaches. Addition of a stochastic process enables us to identify the global maximum/minimum without becoming trapped in local maxima/minima. Sampling approaches take advantage of increasing computational power to test numerous sets of parameters in order to determine the optimum set. By combining Bayesian inference with gradient or sampling approaches, we can estimate both the optimum parameters and the form of the likelihood function related to the parameters. Finally, we introduce four examples of research that utilize parameter optimization to obtain biological insights from quantified data: transcriptional regulation, bacterial chemotaxis, morphogenesis, and cell cycle regulation. With practical knowledge of parameter optimization, cell and developmental biologists can develop realistic models that reproduce their observations and thus, obtain mechanistic insights into phenomena of interest. PMID- 25784879 TI - Platelets and the complement cascade in atherosclerosis. AB - Atherosclerosis and its late sequels are still the number one cause of death in western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischemic stroke. Atherosclerosis is increasingly recognized as an inflammatory disease, influenced by various immune mechanisms. The complement system is part of our innate immune system, and its diverse roles in atherosclerosis have become evident over the past years. In this review we identify points of intersection between platelets and the complement system and discuss their relevance for atherosclerosis. Specifically, we will focus on roles for platelets in the onset as well as progression of the disease, a possible dual role for complement in the genesis and development of atherosclerosis, and review emerging literature revealing previously unrecognized cross-talk between platelets and the complement system and discuss its possible impact for atherosclerosis. Finally, we identify limitations of current research approaches and discuss perspectives of complement modulation in the control of the disease. PMID- 25784881 TI - Decreased Resting-State Connectivity between Neurocognitive Networks in Treatment Resistant Depression. AB - Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission after various treatment options and develop treatment resistant depression (TRD). So far, little is known about the pathophysiology of TRD. Studies in MDD patients showed aberrant functional connectivity (FC) of three "core" neurocognitive networks: the salience network (SN), cognitive control network (CCN), and default mode network (DMN). We used a cross-sectional design and performed resting-state FC MRI to assess connectivity of the SN, CCN, and both anterior and posterior DMN in 17 severe TRD, 18 non-TRD, and 18 healthy control (HC) subjects. Relative to both non-TRD and HC subjects, TRD patients showed decreased FC between the dorsolateral prefrontal cortex and angular gyrus, which suggests reduced FC between the CCN and DMN, and reduced FC between the medial prefrontal cortex and precuneus/cuneus, which suggests reduced FC between the anterior and posterior DMN. No significant differences in SN FC were observed. Our results suggest that TRD is characterized by a disturbance in neurocognitive networks relative to non-TRD and HC. PMID- 25784882 TI - NIDA Clinical Trials Network Common Data Elements Initiative: Advancing Big-Data Addictive-Disorders Research. PMID- 25784884 TI - Enactive account of pretend play and its application to therapy. AB - This paper informs therapeutic practices that use play, by providing a non standard philosophical account of pretense: the enactive account of pretend play (EAPP). The EAPP holds that pretend play activity need not invoke mental representational mechanisms; instead, it focuses on interaction and the role of affordances in shaping pretend play activity. One advantage of this re characterization of pretense is that it may help us better understand the role of shared meanings and interacting in systemic therapies, which use playing to enhance dialog in therapy rather than to uncover hidden meanings. We conclude with bringing together findings from therapeutic practice and philosophical considerations. PMID- 25784883 TI - Combined contributions of feedforward and feedback inputs to bottom-up attention. AB - In order to deal with a large amount of information carried by visual inputs entering the brain at any given point in time, the brain swiftly uses the same inputs to enhance processing in one part of visual field at the expense of the others. These processes, collectively called bottom-up attentional selection, are assumed to solely rely on feedforward processing of the external inputs, as it is implied by the nomenclature. Nevertheless, evidence from recent experimental and modeling studies points to the role of feedback in bottom-up attention. Here, we review behavioral and neural evidence that feedback inputs are important for the formation of signals that could guide attentional selection based on exogenous inputs. Moreover, we review results from a modeling study elucidating mechanisms underlying the emergence of these signals in successive layers of neural populations and how they depend on feedback from higher visual areas. We use these results to interpret and discuss more recent findings that can further unravel feedforward and feedback neural mechanisms underlying bottom-up attention. We argue that while it is descriptively useful to separate feedforward and feedback processes underlying bottom-up attention, these processes cannot be mechanistically separated into two successive stages as they occur at almost the same time and affect neural activity within the same brain areas using similar neural mechanisms. Therefore, understanding the interaction and integration of feedforward and feedback inputs is crucial for better understanding of bottom-up attention. PMID- 25784885 TI - Psychological intervention reduces self-reported performance anxiety in high school music students. AB - Music performance anxiety (MPA) can be distressing for many young people studying music, and may negatively impact upon their ability to cope with the demands and stressors of music education. It can also lead young people to give up music or to develop unhealthy coping habits in their adult music careers. Minimal research has examined the effectiveness of psychological programs to address MPA in young musicians. Sixty-two adolescents were pseudo-randomized to a cognitive behavioral (CB) group-delivered intervention or a waitlist condition. The intervention consisted of psychoeducation, cognitive restructuring and relaxation techniques, identification of strengths, goal-setting, imagery and visualization techniques to support three solo performances in front of judges. Significant reductions in self-rated MPA were found in both groups following the intervention and compared to their baseline MPA. This reduction was maintained at 2-months follow-up. There appeared to be inconsistent effects of the intervention upon judge-rated MPA, however the presence of floor effects precluded meaningful reductions in MPA. There appeared to be no effect of the intervention upon judge-rated performance quality. This study highlights the potential for group-based CB programs to be delivered within school music curricula to help young musicians develop skills to overcome the often debilitating effects of MPA. PMID- 25784886 TI - Visual and skill effects on soccer passing performance, kinematics, and outcome estimations. AB - The role of visual information and action representations in executing a motor task was examined from a mental representations approach. High-skill (n = 20) and low-skill (n = 20) soccer players performed a passing task to two targets at distances of 9.14 and 18.29 m, under three visual conditions: normal, occluded, and distorted vision (i.e., +4.0 corrective lenses, a visual acuity of approximately 6/75) without knowledge of results. Following each pass, participants estimated the relative horizontal distance from the target as the ball crossed the target plane. Kinematic data during each pass were also recorded for the shorter distance. Results revealed that performance on the motor task decreased as a function of visual information and task complexity (i.e., distance from target) regardless of skill level. High-skill players performed significantly better than low-skill players on both the actual passing and estimation tasks, at each target distance and visual condition. In addition, kinematic data indicated that high-skill participants were more consistent and had different kinematic movement patterns than low-skill participants. Findings contribute to the understanding of the underlying mechanisms required for successful performance in a self-paced, discrete and closed motor task. PMID- 25784887 TI - Integrating body movement into attractiveness research. AB - People judge attractiveness and make trait inferences from the physical appearance of others, and research reveals high agreement among observers making such judgments. Evolutionary psychologists have argued that interest in physical appearance and beauty reflects adaptations that motivate the search for desirable qualities in a potential partner. Although men more than women value the physical appearance of a partner, appearance universally affects social perception in both sexes. Most studies of attractiveness perceptions have focused on third party assessments of static representations of the face and body. Corroborating evidence suggests that body movement, such as dance, also conveys information about mate quality. Here we review evidence that dynamic cues (e.g., gait, dance) also influence perceptions of mate quality, including personality traits, strength, and overall attractiveness. We recommend that attractiveness research considers the informational value of body movement in addition to static cues, to present an integrated perspective on human social perception. PMID- 25784888 TI - Remembrance of happy things past: positive autobiographical memories are intrinsically rewarding and valuable, but not in depression. PMID- 25784889 TI - Fisher, Neyman-Pearson or NHST? A tutorial for teaching data testing. AB - Despite frequent calls for the overhaul of null hypothesis significance testing (NHST), this controversial procedure remains ubiquitous in behavioral, social and biomedical teaching and research. Little change seems possible once the procedure becomes well ingrained in the minds and current practice of researchers; thus, the optimal opportunity for such change is at the time the procedure is taught, be this at undergraduate or at postgraduate levels. This paper presents a tutorial for the teaching of data testing procedures, often referred to as hypothesis testing theories. The first procedure introduced is Fisher's approach to data testing-tests of significance; the second is Neyman-Pearson's approach tests of acceptance; the final procedure is the incongruent combination of the previous two theories into the current approach-NSHT. For those researchers sticking with the latter, two compromise solutions on how to improve NHST conclude the tutorial. PMID- 25784890 TI - Commentary: A pointer about grasping numbers. PMID- 25784891 TI - Music and health: what interventions for what results? PMID- 25784892 TI - Differential binding of colors to objects in memory: red and yellow stick better than blue and green. AB - Both evolutionary considerations and recent research suggest that the color red serves as a signal indicating an object's importance. However, until now, there is no evidence that this signaling function of red is also reflected in human memory. To examine the effect of red on memory, we conducted four experiments in which we presented objects colored in four different colors (red, green, blue, and yellow) and measured later memory for the presence of an object and for the color of an object. Across experiments, we varied the type of objects (words vs. pictures), task complexity (single objects vs. multiple objects in visual scenes), and intentionality of encoding (intentional vs. incidental learning). Memory for the presence of an object was not influenced by color. However, in all four experiments, memory for the color of an object depended on color type and was particularly high for red and yellow-colored objects and particularly low for green-colored objects, indicating that the binding of colors into object memory representations varies as a function of color type. Analyzing the observers' confidence in their color memories revealed that color not only influenced objective memory performance but also subjective confidence. Subjective confidence judgments differentiated well between correct and incorrect color memories for red-colored objects, but poorly for green-colored objects. Our findings reveal a previously unknown color effect which may be of considerable interest for both basic color research and applied settings like eyewitness testimony in which memory for color features is relevant. Furthermore, our results indicate that feature binding in memory is not a uniform process by which any attended feature is automatically bound into unitary memory representations. Rather, memory binding seems to vary across different subtypes of features, a finding that supports recent research showing that object features are stored in memory rather independently from each other. PMID- 25784893 TI - Toward an embodied science of intersubjectivity: widening the scope of social understanding research. PMID- 25784894 TI - Embodied and exbodied mind in clinical psychology. A proposal for a psycho-social interpretation of mental disorders. AB - A brief theoretical review of the current state of the art of embodiment research in clinical psychology has been expounded in order to highlight the key role that embodied conceptualization has on the understanding and explanation of several mental disorders, such as eating disorders, schizophrenia and depression. Evidence has suggested that mental disorders may be explained as disturbances of embodiment, from the disembodiment to the hyperembodiment. In order to understand how some clinical conditions are affected by cultural models, we propose and define a new framework called Exbodiment, complementary to the Embodiment approach to cognition. Mental disorder is strictly related to the subject-culture interaction that may be explained as a two way process in which embodiment and exbodiment are complementary points of view. In this perspective, embodiment may be seen as the "top-down" process, while exbodiment the "bottom-up" one. The introduction of exbodiment conceptualization highlights how subject is both receiver and interpreter of social influence. Subject is the target of a cultural pressure and, at the same time, enacts its own embodied culture in world. Exbodiment conceptualization may help clinicians to better understand and explain the role of culture in the onset and maintenance of mental disorders. PMID- 25784895 TI - Delayed disengagement of attention from snakes in children with autism. AB - In the visual search task, it is well known that detection of a tilted straight line as the target among vertical lines that act as distractors is easier than vice versa, and that detection of a snake image as the target among flower images is easier than vice versa. In this study, the degree of such search asymmetry was compared between 18 children with autism and 14 typically developing (TD) children. The results revealed that compared to TD children, children with autism were disproportionally slow when asked to detect the flower among the snake images, suggesting the possibility that they experienced difficulty of disengaging their attention from the snake images. This delayed disengagement would serve itself as an enhanced attentional bias toward snakes in children with autism that is similar to characteristics of visual search performance in anxiety patients. PMID- 25784896 TI - Clinical implications of neuroplasticity - the role of rehabilitation in multiple sclerosis. PMID- 25784897 TI - Extending injury- and disease-resistant CNS phenotypes by repetitive epigenetic conditioning. AB - Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to different preconditioning stimuli, but the duration of the induced protective phenotype is typically short-lasting, and thus is deemed as limiting its clinical applicability. Extending the period over which such adaptive epigenetic changes persist - in effect, expanding conditioning's "therapeutic window" - would significantly broaden the potential applications of such a treatment approach in patients. The frequency of the conditioning stimulus may hold the key. While transient (1-3 days) protection against CNS ischemic injury is well established preclinically following a single preconditioning stimulus, repetitively presenting preconditioning stimuli extends the duration of ischemic tolerance by many weeks. Moreover, repetitive intermittent postconditioning enhances post-ischemic recovery metrics and improves long-term survival. Intermittent conditioning is also efficacious for preventing or delaying injury in preclinical models of chronic neurodegenerative disease, and for promoting long-lasting functional improvements in a number of other pathologies as well. Although the detailed mechanisms underlying these protracted kinds of neuroplasticity remain largely unstudied, accumulating empirical evidence supports the contention that all of these adaptive phenotypes are epigenetically mediated. Going forward, additional preclinical demonstrations of the ability to induce sustained beneficial phenotypes that reduce the burden of acute and chronic neurodegeneration, and experimental interrogations of the regulatory constructs responsible for these epigenetic responses, will accelerate the identification of not only efficacious but also practical, adaptive epigenetics based treatments for individuals with neurological disease. PMID- 25784898 TI - Plant genotype-specific archaeal and bacterial endophytes but similar Bacillus antagonists colonize Mediterranean olive trees. AB - Endophytes have an intimate and often symbiotic interaction with their hosts. Less is known about the composition and function of endophytes in trees. In order to evaluate our hypothesis that plant genotype and origin have a strong impact on both, endophytes of leaves from 10 Olea europaea L. cultivars from the Mediterranean basin growing at a single agricultural site in Spain and from nine wild olive trees located in natural habitats in Greece, Cyprus, and on Madeira Island were studied. The composition of the bacterial endophytic communities as revealed by 16S rRNA gene amplicon sequencing and the subsequent PCoA analysis showed a strong correlation to the plant genotypes. The bacterial distribution patterns were congruent with the plant origins in "Eastern" and "Western" areas of the Mediterranean basin. Subsequently, the endophytic microbiome of wild olives was shown to be closely related to those of cultivated olives of the corresponding geographic origins. The olive leaf endosphere harbored mostly Proteobacteria, followed by Firmicutes, Actinobacteria, and Bacteroidetes. The detection of a high portion of archaeal taxa belonging to the phyla Thaumarchaeota, Crenarchaeota, and Euryarchaeota in the amplicon libraries was an unexpected discovery, which was confirmed by quantitative real-time PCR revealing an archaeal portion of up to 35.8%. Although the function of these Archaea for their host plant remains speculative, this finding suggests a significant relevance of archaeal endophytes for plant-microbe interactions. In addition, the antagonistic potential of culturable endophytes was determined; all isolates with antagonistic activity against the olive-pathogenic fungus Verticillium dahliae Kleb. belong to Bacillus amyloliquefaciens. In contrast to the specific global structural diversity, BOX-fingerprints of the antagonistic Bacillus isolates were highly similar and independent of the olive genotype from which they were isolated. PMID- 25784899 TI - RNA-binding proteins involved in post-transcriptional regulation in bacteria. AB - Post-transcriptional regulation is a very important mechanism to control gene expression in changing environments. In the past decade, a lot of interest has been directed toward the role of small RNAs (sRNAs) in bacterial post transcriptional regulation. However, sRNAs are not the only molecules controlling gene expression at this level, RNA-binding proteins (RBPs) play an important role as well. CsrA and Hfq are the two best studied bacterial proteins of this type, but recently, additional proteins involved in post-transcriptional control have been identified. This review focuses on the general working mechanisms of post transcriptionally active RBPs, which include (i) adaptation of the susceptibility of mRNAs and sRNAs to RNases, (ii) modulating the accessibility of the ribosome binding site of mRNAs, (iii) recruiting and assisting in the interaction of mRNAs with other molecules and (iv) regulating transcription terminator/antiterminator formation, and gives an overview of both the well-studied and the newly identified proteins that are involved in post-transcriptional regulatory processes. Additionally, the post-transcriptional mechanisms by which the expression or the activity of these proteins is regulated, are described. For many of the newly identified proteins, however, mechanistic questions remain. Most likely, more post-transcriptionally active proteins will be identified in the future. PMID- 25784900 TI - Fungal metabolic gene clusters-caravans traveling across genomes and environments. AB - Metabolic gene clusters (MGCs), physically co-localized genes participating in the same metabolic pathway, are signature features of fungal genomes. MGCs are most often observed in specialized metabolism, having evolved in individual fungal lineages in response to specific ecological needs, such as the utilization of uncommon nutrients (e.g., galactose and allantoin) or the production of secondary metabolic antimicrobial compounds and virulence factors (e.g., aflatoxin and melanin). A flurry of recent studies has shown that several MGCs, whose functions are often associated with fungal virulence as well as with the evolutionary arms race between fungi and their competitors, have experienced horizontal gene transfer (HGT). In this review, after briefly introducing HGT as a source of gene innovation, we examine the evidence for HGT's involvement on the evolution of MGCs and, more generally of fungal metabolism, enumerate the molecular mechanisms that mediate such transfers and the ecological circumstances that favor them, as well as discuss the types of evidence required for inferring the presence of HGT in MGCs. The currently available examples indicate that transfers of entire MGCs have taken place between closely related fungal species as well as distant ones and that they sometimes involve large chromosomal segments. These results suggest that the HGT-mediated acquisition of novel metabolism is an ongoing and successful ecological strategy for many fungal species. PMID- 25784902 TI - Antimicrobial activity of essential oils and carvacrol, and synergy of carvacrol and erythromycin, against clinical, erythromycin-resistant Group A Streptococci. AB - In the present study, we have evaluated the in vitro antibacterial activity of essential oils from Origanum vulgare, Thymus vulgaris, Lavandula angustifolia, Mentha piperita, and Melaleuca alternifolia against 32 erythromycin-resistant [Mininum Inhibitory Concentration (MIC) >=1 MUg/mL; inducible, constitutive, and efflux-mediated resistance phenotype; erm(TR), erm(B), and mef(A) genes] and cell invasive Group A streptococci (GAS) isolated from children with pharyngotonsillitis in Italy. Over the past decades erythromycin resistance in GAS has emerged in several countries; strains combining erythromycin resistance and cell invasiveness may escape beta-lactams because of intracellular location and macrolides because of resistance, resulting in difficulty of eradication and recurrent pharyngitis. Thyme and origanum essential oils demonstrated the highest antimicrobial activity with MICs ranging from 256 to 512 MUg/mL. The phenolic monoterpene carvacrol [2-Methyl-5-(1-methylethyl) phenol] is a major component of the essential oils of Origanum and Thymus plants. MICs of carvacrol ranged from 64 to 256 MUg/mL. In the live/dead assay several dead cells were detected as early as 1 h after incubation with carvacrol at the MIC. In single-step resistance selection studies no resistant mutants were obtained. A synergistic action of carvacrol and erythromycin was detected by the checkerboard assay and calculation of the Fractional Inhibitory Concentration (FIC) Index. A 2- to 2048 fold reduction of the erythromycin MIC was documented in checkerboard assays. Synergy (FIC Index <=0.5) was found in 21/32 strains and was highly significant (p < 0.01) in strains where resistance is expressed only in presence of erythromycin. Synergy was confirmed in 17/23 strains using 24-h time-kill curves in presence of carvacrol and erythromycin. Our findings demonstrated that carvacrol acts either alone or in combination with erythromycin against erythromycin-resistant GAS and could potentially serve as a novel therapeutic tool. PMID- 25784901 TI - Effects of 100 years wastewater irrigation on resistance genes, class 1 integrons and IncP-1 plasmids in Mexican soil. AB - Long-term irrigation with untreated wastewater can lead to an accumulation of antibiotic substances and antibiotic resistance genes in soil. However, little is known so far about effects of wastewater, applied for decades, on the abundance of IncP-1 plasmids and class 1 integrons which may contribute to the accumulation and spread of resistance genes in the environment, and their correlation with heavy metal concentrations. Therefore, a chronosequence of soils that were irrigated with wastewater from 0 to 100 years was sampled in the Mezquital Valley in Mexico in the dry season. The total community DNA was extracted and the absolute and relative abundance (relative to 16S rRNA genes) of antibiotic resistance genes (tet(W), tet(Q), aadA), class 1 integrons (intI1), quaternary ammonium compound resistance genes (qacE+qacEDelta1) and IncP-1 plasmids (korB) were quantified by real-time PCR. Except for intI1 and qacE+qacEDelta1 the abundances of selected genes were below the detection limit in non-irrigated soil. Confirming the results of a previous study, the absolute abundance of 16S rRNA genes in the samples increased significantly over time (linear regression model, p < 0.05) suggesting an increase in bacterial biomass due to repeated irrigation with wastewater. Correspondingly, all tested antibiotic resistance genes as well as intI1 and korB significantly increased in abundance over the period of 100 years of irrigation. In parallel, concentrations of the heavy metals Zn, Cu, Pb, Ni, and Cr significantly increased. However, no significant positive correlations were observed between the relative abundance of selected genes and years of irrigation, indicating no enrichment in the soil bacterial community due to repeated wastewater irrigation or due to a potential co selection by increasing concentrations of heavy metals. PMID- 25784903 TI - Nitrate ammonification in mangrove soils: a hidden source of nitrite? AB - Nitrate reduction is considered to be a minor microbial pathway in the oxidation of mangrove-derived organic matter due to a limited supply of nitrate in mangrove soils. At a limited availability of this electron acceptor compared to the supply of degradable carbon, nitrate ammonification is thought to be the preferential pathway of nitrate reduction. Mangrove forest mutually differ in their productivity, which may lead to different available carbon to nitrate ratios in their soil. Hence, nitrate ammonification is expected to be of more importance in high- compared to low-productive forests. The hypothesis was tested in flow through reactors that contain undisturbed mangrove soils from high-productive Avicennia germinans and Rhizophora mangle forests in Florida and low-productive Avicennia marina forests in Saudi Arabia. Nitrate was undetectable in the soils from both regions. It was assumed that a legacy of nitrate ammonification would be reflected by a higher ammonium production from these soils upon the addition of nitrate. Unexpectedly, the soils from the low-productive forests in Saudi Arabia produced considerably more ammonium than the soils from the high productive forests in Florida. Hence, other environmental factors than productivity must govern the selection of nitrate ammonification or denitrification. A rather intriguing observation was the 1:1 production of nitrite and ammonium during the consumption of nitrate, more or less independent from sampling region, location, sampling depth, mangrove species and from the absence or presence of additional degradable carbon. This 1:1 ratio points to a coupled production of ammonium and nitrite by one group of nitrate-reducing microorganisms. Such a production of nitrite will be hidden by the presence of active nitrite-reducing microorganisms under the nitrate-limited conditions of most mangrove forest soils. PMID- 25784904 TI - High-grain feeding causes strong shifts in ruminal epithelial bacterial community and expression of Toll-like receptor genes in goats. AB - High-grain (HG) feeding used in intensive goat production can affect the physiology of the rumen wall, but the changes induced in the epimural bacterial community and host Toll-like receptors (TLRs) are not well understood. In this study, 10 male goats were randomly allocated to two groups and fed either a hay diet (0% grain; n = 5) or an HG diet (65% grain; n = 5). The changes in the ruminal epithelial bacterial community and expression of TLRs during long-term (7 weeks) HG feeding were determined using pyrosequencing and quantitative real-time polymerase chain reaction. Principal coordinate analysis and analysis of molecular variance (AMOVA) results showed that HG feeding caused a strong shift in bacterial composition and structure. At the genus level, our data revealed that it increased the relative abundance of taxa Butyrivibrio, unclassified Clostridiales, Mogibacterium, unclassified Anaerolineaceae, and Succiniclasticum, and decreased the proportion of unclassified Ruminococcaceae, unclassified Rikenellaceae, unclassified Erysipelotrichaceae, Howardella, and unclassified Neisseriaceae. The HG-fed goats also exhibited upregulation of the relative mRNA expression of TLR2, TLR3, and TLR5 in the rumen epithelium (P < 0.05). Correlation analysis revealed that the increase in TLR expression was associated with changes in the relative abundance of ruminal epithelial bacteria. This study provides a first insight into the adaptive response of ruminal epithelial bacterial populations to HG feeding in goats and shows that these changes were associated with alterations in TLR expression. These findings provide new insight into understanding of host-microbial relationships in ruminants. PMID- 25784905 TI - VgrG2 of type VI secretion system 2 of Vibrio parahaemolyticus induces autophagy in macrophages. AB - Type VI secretion system (T6SS) is a macromolecular transenvelope machine encoded within the genomes of several proteobacteria species. Vibrio parahaemolyticus contains two putative T6SS systems, VpT6SS1 and VpT6SS2, both contributing to adherence to Caco-2 and/or HeLa cells. However, it remains unknown if these systems are involved in cellular responses. In order to exclude the effects of other virulence factors known to induce cytotoxicity or autophagy, a triple deletion mutant dTTT (with deletion of tdh, and T3SS1 and T3SS2 structural protein genes) was used as the parent strain to construct deletion mutants of T6SS genes. The mutant dTTT-DeltaicmF2, but not dTTT-DeltaicmF1, reduced autophagic response upon 4 h of infection of the macrophage. Further attempt was made to search for the possible effector proteins that might be responsible for direct induction of autophagy by deletion of the genes encoding Hcp2 and VgrG2, two putative translocons of T6SS2 of V. parahaemolyticus. Deletion of either hcp2 or vgrG2 did reduce the autophagic response. However, increased LC3-II lipidation was seen only in the macrophage cells transfected with pVgrG2, but not with pHcp2. Chloroquinine treatment increased accumulation of LC3-II, suggesting that VgrG2 enhanced autophagic flux. The fact that vgrG2 deletion led to reduced level of intracellular cAMP suggests a possible role of cAMP signaling in autophagic responses to the bacterium. We conclude that VgrG2 of V. parahaemolyticus induces autophagy in macrophages. PMID- 25784906 TI - Incorporation of membrane-anchored flagellin or Escherichia coli heat-labile enterotoxin B subunit enhances the immunogenicity of rabies virus-like particles in mice and dogs. AB - Rabies remains an important worldwide public health threat, so safe, effective, and affordable vaccines are still being sought. Virus-like particle-based vaccines targeting various viral pathogens have been successfully produced, licensed, and commercialized. Here, we designed and constructed two chimeric rabies virus-like particles (cRVLPs) containing rabies virus (RABV) glycoprotein (G), matrix (M) protein, and membrane-anchored flagellin (EVLP-F) or Escherichia coli heat-labile enterotoxin B subunit (EVLP-L) as molecular adjuvants to enhance the immune response against rabies. The immunogenicity and potential of cRVLPs as novel rabies vaccine were evaluated by intramuscular vaccination in mouse and dog models. Mouse studies demonstrated that both EVLP-F and EVLP-L induced faster and larger virus-neutralizing antibodies (VNAs) responses and elicited greater numbers of CD4(+) and CD8(+) T cells secreting IFN-gamma or IL-4 compared with a standard rabies VLP (sRVLP) containing only G and M. Moreover, cRVLPs recruited and/or activated more B cells and dendritic cells in inguinal lymph nodes. EVLP-F induced a strong, specific IgG2a response but not an IgG1 response, suggesting the activation of Th1 class immunity; in contrast, Th2 class immunity was observed with EVLP-L. The significantly enhanced humoral and cellular immune responses induced by cRVLPs provided complete protection against lethal challenge with RABV. Most importantly, dogs vaccinated with EVLP-F or EVLP-L exhibited increased VNA titers in sera and enhanced IFN-gamma and IL-4 secretion from peripheral blood mononuclear cells. Taken together, these results illustrate that when incorporated into sRVLP, membrane-anchored flagellin, and heat-labile enterotoxin B subunit possess strong adjuvant activity. EVLP-F and EVLP-L induce significantly enhanced RABV-specific humoral and cellular immune responses in both mouse and dog. Therefore, these cRVLPs may be developed as safe and more efficacious rabies vaccine candidate for animals. PMID- 25784907 TI - Proteomics as the final step in the functional metagenomics study of antimicrobial resistance. AB - The majority of clinically applied antimicrobial agents are derived from natural products generated by soil microorganisms and therefore resistance is likely to be ubiquitous in such environments. This is supported by the fact that numerous clinically important resistance mechanisms are encoded within the genomes of such bacteria. Advances in genomic sequencing have enabled the in silico identification of putative resistance genes present in these microorganisms. However, it is not sufficient to rely on the identification of putative resistance genes, we must also determine if the resultant proteins confer a resistant phenotype. This will require an analysis pipeline that extends from the extraction of environmental DNA, to the identification and analysis of potential resistance genes and their resultant proteins and phenotypes. This review focuses on the application of functional metagenomics and proteomics to study antimicrobial resistance in diverse environments. PMID- 25784908 TI - Genetic diversity and virulence of novel sequence types of Streptococcus suis from diseased and healthy pigs in China. AB - Streptococcus suis is a serious threat to swine industry and public health. In this work, a total of 62 S. suis isolates recovered from infected and healthy pigs from four provinces in northern China were classified by multilocus sequence typing into nine sequence types (STs), including six novel ones, namely, ST417, ST418, ST419, ST420, ST421, and ST422. The majority (64.5%) of these 62 isolates belong to serotype 2; all of these serotype 2 isolates can be assigned into ST1 or ST28 clonal complex, indicating at least two parallel routes of clonal dissemination of these isolates. In these serotype 2 isolates, 23 (20 from healthy pigs and three from diseased pigs) were identified as ST7 strains, which were previously characterized as the cause of streptococcal toxic shock-like syndrome. The novel ST strains lack 89 K pathogenicity island but can cause septicemia and meningitis in a mouse model, showing remarkable differences in virulence. The ST421 strain named HLB causes suppurative encephalitis. Our results highlighted the need for increased surveillance of S. suis in farm-raised pigs in northern China. PMID- 25784909 TI - The nasal microbiota in health and disease: variation within and between subjects. AB - Chronic rhinosinusitis (CRS) affects approximately 5% of the adult population in Western societies and severely reduces the patient's quality of life. The role of bacteria in the pathogenesis of this condition has not yet been established with certainty. However, recent reports of bacterial and fungal biofilms in CRS highlight a potential role for these microorganisms. In this study, 16S rRNA gene targeted amplicon pyrosequencing and qPCR were used to determine the composition and abundance, respectively, of the sinus microbiota within 9 patients with CRS and 6 healthy individuals. Within-patient variability was also investigated by sampling from anterior nares, inferior turbinate, and middle meatus on each side of the sinuses. Our results indicate that more of the variation in bacterial composition can be explained by inter-personal differences, rather than sampling location or even disease status. In addition, bacterial community diversity was significantly lower in CRS samples compared to those from healthy subjects, whereas bacterial load was not associated with disease status. Although members of the genera Corynebacterium and Staphylococcus were prevalent in the majority of samples (including healthy subjects), the large amount of variation observed between individuals, particularly within the CRS cohort, suggests that an imbalance or dysbiosis in community structure could be the driving force behind the disease. Ultimately, understanding the causes of variation within the sinus microbiota may lead to more personalized treatment options for CRS. PMID- 25784911 TI - Corrigendum: depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. AB - [This corrects the article on p. 587 in vol. 5, PMID: 25505466.]. PMID- 25784912 TI - Protecting the borders: tissue-resident memory T cells on the front line. PMID- 25784910 TI - The Inflammatory Role of Platelets via Their TLRs and Siglec Receptors. AB - Platelets are non-nucleated cells that play central roles in the processes of hemostasis, innate immunity, and inflammation; however, several reports show that these distinct functions are more closely linked than initially thought. Platelets express numerous receptors and contain hundreds of secretory products. These receptors and secretory products are instrumental to the platelet functional responses. The capacity of platelets to secrete copious amounts of cytokines, chemokines, and related molecules appears intimately related to the role of the platelet in inflammation. Platelets exhibit non-self-infectious danger detection molecules on their surfaces, including those belonging to the "toll-like receptor" family, as well as pathogen sensors of other natures (Ig- or complement receptors, etc.). These receptors permit platelets to both bind infectious agents and deliver differential signals leading to the secretion of cytokines/chemokines, under the control of specific intracellular regulatory pathways. In contrast, dysfunctional receptors or dysregulation of the intracellular pathway may increase the susceptibility to pathological inflammation. Physiological vs. pathological inflammation is tightly controlled by the sensors of danger expressed in resting, as well as in activated, platelets. These sensors, referred to as pathogen recognition receptors, primarily sense danger signals termed pathogen associated molecular patterns. As platelets are found in inflamed tissues and are involved in auto-immune disorders, it is possible that they can also be stimulated by internal pathogens. In such cases, platelets can also sense danger signals using damage associated molecular patterns (DAMPs). Some of the most significant DAMP family members are the alarmins, to which the Siglec family of molecules belongs. This review examines the role of platelets in anti-infection immunity via their TLRs and Siglec receptors. PMID- 25784914 TI - Regulation of Tissue Responses: The TWEAK/Fn14 Pathway and Other TNF/TNFR Superfamily Members That Activate Non-Canonical NFkappaB Signaling. PMID- 25784913 TI - Dendritic cell-based vaccine efficacy: aiming for hot spots. AB - Many approaches for cancer immunotherapy have targeted dendritic cells (DCs), directly or indirectly, for the induction of antitumor immune responses. DC-based vaccines have been developed using a wide variety of ex vivo DC culture conditions, antigen (Ag) source and loading strategies, maturation agents, and routes of vaccination. Adjuvants are used to activate innate immune cells at the vaccine injection site, to promote Ag transport to the draining lymph nodes (LNs) and to model adaptive immune responses. Despite years of effort, the effective induction of strong and durable antitumor T-cell responses in vaccinated patients remains a challenge. The study of vaccine interactions with other immune cells in the LNs and, more recently, in the injection site has opened new doors for understanding antitumor effector T-cell licensing and function. In this review, we will briefly discuss the relevant sites and up-to-date facts regarding possible targets for antitumor vaccine refinement. We will focus on the processes taking place at the injection site, adjuvant combinations and their role in DC based vaccines, LN homing, and modeling vaccine-induced immune responses capable of controlling tumor growth and generating immune memory. PMID- 25784915 TI - Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More? AB - The induction of central tolerance in the course of T cell development crucially depends on promiscuous gene expression (pGE) in medullary thymic epithelial cells (mTECs). mTECs express a genome-wide variety of tissue-restricted antigens (TRAs), preventing the escape of autoreactive T cells to the periphery, and the development of severe autoimmunity. Most of our knowledge of how pGE is controlled comes from studies on the autoimmune regulator (Aire). Aire activates the expression of a large subset of TRAs by interacting with the general transcriptional machinery and promoting transcript elongation. However, further factors regulating Aire-independent TRAs must be at play. Recent studies demonstrated that pGE in general and the function of Aire in particular are controlled by epigenetic and post-transcriptional mechanisms. This mini-review summarizes current knowledge of the regulation of pGE by miRNA and epigenetic regulatory mechanisms such as DNA methylation, histone modifications, and chromosomal topology. PMID- 25784916 TI - Exploring bacteria-induced growth and morphogenesis in the green macroalga order Ulvales (Chlorophyta). AB - Green macroalgae, such as Ulvales, lose their typical morphology completely when grown under axenic conditions or in the absence of the appropriate microbiome. As a result, slow growing aberrant phenotypes or even callus-like morphotypes are observed in Ulvales. The cross-kingdom interactions between marine algae and microorganisms are hence not only restricted by the exchange of macronutrients, including vitamins and nutrients, but also by infochemicals such as bacterial morphogenetic compounds. The latter are a fundamental trait mediating the mutualism within the chemosphere where the organisms interact with each other via compounds in their surroundings. Approximately 60 years ago, pilot studies demonstrated that certain bacteria promote growth, whereas other bacteria induce morphogenesis; this is particularly true for the order of Ulvales. However, only slow progress was made towards the underlying mechanism due to the complexity of, for example, algal cultivation techniques, and the lack of standardized experiments in the laboratory. A breakthrough in this research was the discovery of the morphogenetic compound thallusin, which was isolated from an epiphytic bacterium and induces normal germination restoring the foliaceous morphotypes of Monostroma. Owing to the low concentration, the purification and structure elucidation of highly biologically active morphogenetic compounds are still challenging. Recently, it was found that only the combination of two specific bacteria from the Rhodobacteraceae and Flavobacteriaceae can completely recover the growth and morphogenesis of axenic Ulva mutabilis cultures forming a symbiotic tripartite community by chemical communication. This review combines literature detailing evidences of bacteria-induced morphogenesis in Ulvales. A set of standardized experimental approaches is further proposed for the preparation of axenic algal tissues, bacteria isolation, co-cultivation experiments, and the analysis of the chemosphere. PMID- 25784917 TI - An efficient method for miRNA detection and localization in crop plants. AB - microRNAs are a class of non-coding small RNAs (sRNAs) that are important regulators of gene expression at the post-transcriptional level by mRNA cleavage or translation inhibition. Another class of sRNAs are siRNAs, which also regulate gene expression but by causing DNA methylation. This epigenetic regulatory role has been observed for some miRNAs as well. The use of sRNAs allows the development of biotechnological applications in plants. To develop these types of applications, and to better understand the natural roles they play, it is important to be able to detect and to localize these sRNAs at the plant tissue level. Sometimes, in crop plants this can be challenging. Therefore, we developed a tissue printing hybridization protocol for easy and efficient detection of sRNAs and demonstrate this by the analysis of the spatio-temporal expression patterns of the miRNAs miR159 and miR164 in fruits of various crop plants. Moreover, we show the possibility to also detect the expression of miRNAs in fruit juice using a dot blot hybridization approach. PMID- 25784918 TI - Germacrene A synthase in yarrow (Achillea millefolium) is an enzyme with mixed substrate specificity: gene cloning, functional characterization and expression analysis. AB - Terpenoid synthases constitute a highly diverse gene family producing a wide range of cyclic and acyclic molecules consisting of isoprene (C5) residues. Often a single terpene synthase produces a spectrum of molecules of given chain length, but some terpene synthases can use multiple substrates, producing products of different chain length. Only a few such enzymes has been characterized, but the capacity for multiple-substrate use can be more widespread than previously thought. Here we focused on germacrene A synthase (GAS) that is a key cytosolic enzyme in the sesquiterpene lactone biosynthesis pathway in the important medicinal plant Achillea millefolium (AmGAS). The full length encoding gene was heterologously expressed in Escherichia coli BL21 (DE3), functionally characterized, and its in vivo expression was analyzed. The recombinant protein catalyzed formation of germacrene A with the C15 substrate farnesyl diphosphate (FDP), while acyclic monoterpenes were formed with the C10 substrate geranyl diphosphate (GDP) and cyclic monoterpenes with the C10 substrate neryl diphosphate (NDP). Although monoterpene synthesis has been assumed to be confined exclusively to plastids, AmGAS can potentially synthesize monoterpenes in cytosol when GDP or NDP become available. AmGAS enzyme had high homology with GAS sequences from other Asteraceae species, suggesting that multi-substrate use can be more widespread among germacrene A synthases than previously thought. Expression studies indicated that AmGAS was expressed in both autotrophic and heterotrophic plant compartments with the highest expression levels in leaves and flowers. To our knowledge, this is the first report on the cloning and characterization of germacrene A synthase coding gene in A. millefolium, and multi-substrate use of GAS enzymes. PMID- 25784919 TI - Selenium hyperaccumulators harbor a diverse endophytic bacterial community characterized by high selenium resistance and plant growth promoting properties. AB - Selenium (Se)-rich plants may be used to provide dietary Se to humans and livestock, and also to clean up Se-polluted soils or waters. This study focused on endophytic bacteria of plants that hyperaccumulate selenium (Se) to 0.5-1% of dry weight. Terminal restriction fragment length polymorphism (T-RFLP) analysis was used to compare the diversity of endophytic bacteria of hyperaccumulators Stanleya pinnata (Brassicaceae) and Astragalus bisulcatus (Fabaceae) with those from related non-accumulators Physaria bellii (Brassicaceae) and Medicago sativa (Fabaceae) collected on the same, seleniferous site. Hyperaccumulators and non accumulators showed equal T-RF diversity. Parsimony analysis showed that T-RFs from individuals of the same species were more similar to each other than to those from other species, regardless of plant Se content or spatial proximity. Cultivable endophytes from hyperaccumulators S. pinnata and A. bisulcatus were further identified and characterized. The 66 bacterial morphotypes were shown by MS MALDI-TOF Biotyper analysis and 16S rRNA gene sequencing to include strains of Bacillus, Pseudomonas, Pantoea, Staphylococcus, Paenibacillus, Advenella, Arthrobacter, and Variovorax. Most isolates were highly resistant to selenate and selenite (up to 200 mM) and all could reduce selenite to red elemental Se, reduce nitrite and produce siderophores. Seven isolates were selected for plant inoculation and found to have plant growth promoting properties, both in pure culture and when co-cultivated with crop species Brassica juncea (Brassicaceae) or M. sativa. There were no effects on plant Se accumulation. We conclude that Se hyperaccumulators harbor an endophytic bacterial community in their natural seleniferous habitat that is equally diverse to that of comparable non accumulators. The hyperaccumulator endophytes are characterized by high Se resistance, capacity to produce elemental Se and plant growth promoting properties. PMID- 25784921 TI - Transcriptional profiling of Petunia seedlings reveals candidate regulators of the cold stress response. AB - Petunias are important ornamentals with the capacity for cold acclimation. So far, there is limited information concerning gene regulation and signaling pathways associated with the cold stress response in petunias. A custom-designed petunia microarray representing 24816 genes was used to perform transcriptome profiling in petunia seedlings subjected to cold at 2 degrees C for 0.5 h, 2 h, 24 h, and 5 d. A total of 2071 transcripts displayed differential expression patterns under cold stress, of which 1149 were up-regulated and 922 were down regulated. Gene ontology enrichment analysis demarcated related biological processes, suggesting a possible link between flavonoid metabolism and plant adaptation to low temperatures. Many novel stress-responsive regulators were revealed, suggesting that diverse regulatory pathways may exist in petunias in addition to the well-characterized CBF pathway. The expression changes of selected genes under cold and other abiotic stress conditions were confirmed by real-time RT-PCR. Furthermore, weighted gene co-expression network analysis divided the petunia genes on the array into 65 modules that showed high co expression and identified stress-specific hub genes with high connectivity. Our identification of these transcriptional responses and groups of differentially expressed regulators will facilitate the functional dissection of the molecular mechanism in petunias responding to environment stresses and extend our ability to improve cold tolerance in plants. PMID- 25784922 TI - Tradeoffs between chilling and forcing in satisfying dormancy requirements for Pacific Northwest tree species. AB - Many temperate and boreal tree species have a chilling requirement, that is, they need to experience cold temperatures during fall and winter to burst bud normally in the spring. Results from trials with 11 Pacific Northwest tree species are consistent with the concept that plants can accumulate both chilling and forcing units simultaneously during the dormant season and they exhibit a tradeoff between amount of forcing and chilling. That is, the parallel model of chilling and forcing was effective in predicting budburst and well chilled plants require less forcing for bud burst than plants which have received less chilling. Genotypes differed in the shape of the possibility line which describes the quantitative tradeoff between chilling and forcing units. Plants which have an obligate chilling requirement (Douglas-fir, western hemlock, western larch, pines, and true firs) and received no or very low levels of chilling did not burst bud normally even with long photoperiods. Pacific madrone and western redcedar benefited from chilling in terms of requiring less forcing to promote bud burst but many plants burst bud normally without chilling. Equations predicting budburst were developed for each species in our trials for a portion of western North America under current climatic conditions and for 2080. Mean winter temperature was predicted to increase 3.2-5.5 degrees C and this change resulted in earlier predicted budburst for Douglas-fir throughout much of our study area (up to 74 days earlier) but later budburst in some southern portions of its current range (up to 48 days later) as insufficient chilling is predicted to occur. Other species all had earlier predicted dates of budburst by 2080 than currently. Recent warming trends have resulted in earlier budburst for some woody plant species; however, the substantial winter warming predicted by some climate models will reduce future chilling in some locations such that budburst will not consistently occur earlier. PMID- 25784920 TI - Chromatin changes in response to drought, salinity, heat, and cold stresses in plants. AB - Chromatin regulation is essential to regulate genes and genome activities. In plants, the alteration of histone modification and DNA methylation are coordinated with changes in the expression of stress-responsive genes to adapt to environmental changes. Several chromatin regulators have been shown to be involved in the regulation of stress-responsive gene networks under abiotic stress conditions. Specific histone modification sites and the histone modifiers that regulate key stress-responsive genes have been identified by genetic and biochemical approaches, revealing the importance of chromatin regulation in plant stress responses. Recent studies have also suggested that histone modification plays an important role in plant stress memory. In this review, we summarize recent progress on the regulation and alteration of histone modification (acetylation, methylation, phosphorylation, and SUMOylation) in response to the abiotic stresses, drought, high-salinity, heat, and cold in plants. PMID- 25784923 TI - Application of Next Generation Sequencing for personalized medicine for sudden cardiac death. AB - Sudden cardiac death (SCD) is a serious public health problem. In the United States, more than 300,000 people are affected by SCD every year. Significantly, sudden deaths represent 20% of the total mortality and 50% of cardiovascular mortality in Western countries. In addition, SCD constitutes one of the most important unsolved challenges in the practice of forensic pathology because of the failure to determine the exact cause of sudden death. In young individuals, SCD is frequently caused by cardiomyopathies and channelopathies, that have generally an autosomal dominant pattern of inheritance. The impact of genetics and genetic testing on the clinical management of these diseases is unquestioned. In particular, genetic tests are an important tool for identifying pre symptomatic individuals carrying genetic variant that predisposes them to SCD. High-throughput sequencing technologies offer novel opportunities to deeper investigate the genetic background underlying these fatal diseases and to early identify individuals at risk for SCD. In this review, we provide an overview of the development of Next-Generation Sequencing (NGS) technologies and of guidelines useful to design an efficient sequencing protocol and to perform an accurate data analysis. We suggest a flow chart to follow for the set up of a genetic screening protocol for the prevention of cardiac pathologies, in particular SCD events, in young athletes. PMID- 25784924 TI - Distinct actions of ancestral vinclozolin and juvenile stress on neural gene expression in the male rat. AB - Exposure to the endocrine disrupting chemical vinclozolin during gestation of an F0 generation and/or chronic restraint stress during adolescence of the F3 descendants affects behavior, physiology, and gene expression in the brain. Genes related to the networks of growth factors, signaling peptides, and receptors, steroid hormone receptors and enzymes, and epigenetic related factors were measured using quantitative polymerase chain reaction via Taqman low density arrays targeting 48 genes in the central amygdaloid nucleus, medial amygdaloid nucleus, medial preoptic area (mPOA), lateral hypothalamus (LH), and the ventromedial nucleus of the hypothalamus. We found that growth factors are particularly vulnerable to ancestral exposure in the central and medial amygdala; restraint stress during adolescence affected neural growth factors in the medial amygdala. Signaling peptides were affected by both ancestral exposure and stress during adolescence primarily in hypothalamic nuclei. Steroid hormone receptors and enzymes were strongly affected by restraint stress in the mPOA. Epigenetic related genes were affected by stress in the ventromedial nucleus and by both ancestral exposure and stress during adolescence independently in the central amygdala. It is noteworthy that the LH showed no effects of either manipulation. Gene expression is discussed in the context of behavioral and physiological measures previously published. PMID- 25784925 TI - A snapshot of genetic and epigenetic basis of arrhythmia and heart failure. PMID- 25784927 TI - Numerical computation of homogeneous slope stability. AB - To simplify the computational process of homogeneous slope stability, improve computational accuracy, and find multiple potential slip surfaces of a complex geometric slope, this study utilized the limit equilibrium method to derive expression equations of overall and partial factors of safety. This study transformed the solution of the minimum factor of safety (FOS) to solving of a constrained nonlinear programming problem and applied an exhaustive method (EM) and particle swarm optimization algorithm (PSO) to this problem. In simple slope examples, the computational results using an EM and PSO were close to those obtained using other methods. Compared to the EM, the PSO had a small computation error and a significantly shorter computation time. As a result, the PSO could precisely calculate the slope FOS with high efficiency. The example of the multistage slope analysis indicated that this slope had two potential slip surfaces. The factors of safety were 1.1182 and 1.1560, respectively. The differences between these and the minimum FOS (1.0759) were small, but the positions of the slip surfaces were completely different than the critical slip surface (CSS). PMID- 25784926 TI - Pharmacological classes that extend lifespan of Caenorhabditis elegans. AB - Recent progress in the field of aging has resulted in ever increasing numbers of compounds that extend lifespan in Caenorhabditis elegans. Lifespan extending compounds include metabolites and synthetic compounds, as well as natural products. For many of these compounds, mammalian pharmacology is known, and for some the actual targets have been experimentally identified. In this review, we explore the data available in C. elegans to provide an overview of which pharmacological classes have potential for identification of further compounds that extend lifespan. PMID- 25784928 TI - An adaptive image enhancement technique by combining cuckoo search and particle swarm optimization algorithm. AB - Image enhancement is an important procedure of image processing and analysis. This paper presents a new technique using a modified measure and blending of cuckoo search and particle swarm optimization (CS-PSO) for low contrast images to enhance image adaptively. In this way, contrast enhancement is obtained by global transformation of the input intensities; it employs incomplete Beta function as the transformation function and a novel criterion for measuring image quality considering three factors which are threshold, entropy value, and gray-level probability density of the image. The enhancement process is a nonlinear optimization problem with several constraints. CS-PSO is utilized to maximize the objective fitness criterion in order to enhance the contrast and detail in an image by adapting the parameters of a novel extension to a local enhancement technique. The performance of the proposed method has been compared with other existing techniques such as linear contrast stretching, histogram equalization, and evolutionary computing based image enhancement methods like backtracking search algorithm, differential search algorithm, genetic algorithm, and particle swarm optimization in terms of processing time and image quality. Experimental results demonstrate that the proposed method is robust and adaptive and exhibits the better performance than other methods involved in the paper. PMID- 25784929 TI - Comparisons of Esophageal Function Tests between Chinese and British Patients with Gastroesophageal Reflux Disease. AB - Objective. To investigate the esophageal function tests in British and Chinese patients with gastroesophageal reflux disease (GERD). Methods. Patients with GERD were selected from the functional gut clinic, London, and digestive department, Beijing Chao-Yang Hospital, after taking the examinations of High-resolution Manometry and Impedance (HRiM) and 24-hour Multi-Channel Intraluminal Impedance and pH Recording (MII/pH) between 2013 and 2014. Chinese healthy volunteers who undertook HRiM were also selected as control group. Results. Fifty-nine British and 82 Chinese patients with GERD and 62 Chinese healthy volunteers were entered. Values for British patients, Chinese patients, and healthy volunteers were as follows: Lower esophageal sphincter pressure (LESP) 16.0 +/- 8.6, 16.5 +/- 10.0, and 26.4 +/- 10.9 mmHg, peristalsis (normal/small break/large break) 24/12/23, 44/10/28, and 57/1/4, total bolus transit time (TBTT) 7.3 +/- 1.3, 7.6 +/- 1.2, and 6.9 +/- 0.9 s, and complete bolus transit rate (CBTR) 66.7 +/- 37.8, 61.7 +/- 36.4, and 90.3 +/- 14.0%, respectively. Stepwise linear regression analysis showed that age, gender, and ethnicity did not have significant effect on LESP, TBTT, esophageal peristalsis, and CBTR in patients with GERD. Conclusions. British and Chinese patients with GERD presented similar values of LESP, TBTT, and impaired esophageal peristalsis and CBTR. PMID- 25784930 TI - Recurrent posterior strokes in inflammatory bowel disease patients. AB - Objective. To describe the stroke characteristics of patients with a history of inflammatory bowel disease (IBD). Background. A hypercoagulable state associated with IBD has been frequently implicated as a risk factor for ischemic stroke. Variable mechanisms and infrequent occurrence limit prospective clinical research on the association between IBD and stroke. Methods. We retrospectively reviewed consecutive patients with acute ischemic stroke presenting to our medical center from 7/2008 to 9/2013. Patients with a history of IBD were identified. Clinical variables were abstracted from our prospective stroke registry. Results. Over the period of five years we identified only three patients with a documented history of IBD. Each of these patients presented three times to our hospital with new strokes. Patients presented outside the window for intravenous tPA treatment on 8/9 admissions. Each one of our patients had posterior strokes on at least two separate occasions. Hypercoagulation panel showed elevated factor VIII with or without concomitant elevation of Von Willebrand factor (vWF) during almost every admission (8/9 admissions). Only one admission was associated with IBD flare. Conclusion. The association between IBD and posterior strokes is a novel finding. Factor VIII elevation may serve as a biomarker of a peristroke hypercoagulable state in patients with IBD. PMID- 25784932 TI - Measurement of the Physical Properties during Laparoscopic Surgery Performed on Pigs by Using Forceps with Pressure Sensors. AB - Objectives. Here we developed a unique training system, a patient specific virtual reality simulator, for laparoscopic renal surgery. To develop the simulator, it was important to first identify the physical properties of the organ. Methods. We recorded the force measured during laparoscopic surgery performed on pigs by using forceps with pressure sensors. Several sensors, including strain gauges, accelerometers, and a potentiometer, are attached to the forceps. Results. Throughout the experiment, we measured the reaction force in response to the forceps movement in real time. Conclusions. The experiment showed the possibility of digitizing these physical properties in humans as well. PMID- 25784931 TI - From molecular classification to targeted therapeutics: the changing face of systemic therapy in metastatic gastroesophageal cancer. AB - Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician's therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients. PMID- 25784933 TI - Development of a wearable-sensor-based fall detection system. AB - Fall detection is a major challenge in the public healthcare domain, especially for the elderly as the decline of their physical fitness, and timely and reliable surveillance is necessary to mitigate the negative effects of falls. This paper develops a novel fall detection system based on a wearable device. The system monitors the movements of human body, recognizes a fall from normal daily activities by an effective quaternion algorithm, and automatically sends request for help to the caregivers with the patient's location. PMID- 25784934 TI - Species differences in paraoxonase mediated hydrolysis of several organophosphorus insecticide metabolites. AB - Paraoxonase (PON1) is a calcium dependent enzyme that is capable of hydrolyzing organophosphate anticholinesterases. PON1 activity is present in most mammals and previous research established that PON1 activity differs depending on the species. These studies mainly used the organophosphate substrate paraoxon, the active metabolite of the insecticide parathion. Using serum PON1 from different mammalian species, we compared the hydrolysis of paraoxon with the hydrolysis of the active metabolites (oxons) of two additional organophosphorus insecticides, methyl parathion and chlorpyrifos. Paraoxon hydrolysis was greater than that of methyl paraoxon, but the level of activity between species displayed a similar pattern. Regardless of the species tested, the hydrolysis of chlorpyrifos-oxon was significantly greater than that of paraoxon or methyl paraoxon. These data indicate that chlorpyrifos-oxon is a better substrate for PON1 regardless of the species. The pattern of species differences in PON1 activity varied with the change in substrate to chlorpyrifos-oxon from paraoxon or methyl paraoxon. For example, the sex difference observed here and reported elsewhere in the literature for rat PON1 hydrolysis of paraoxon was not present when chlorpyrifos oxon was the substrate. PMID- 25784935 TI - Effect of weight loss on serum osteocalcin and its association with serum adipokines. AB - Studies have suggested that osteocalcin, a bone formation marker, is related to body metabolism and insulin sensitivity. Whether this relation is mediated through an interaction with adipokines remains unclear. The aim of this study was to assess the effect of weight loss on serum osteocalcin and its relation with three adipokines, adiponectin, chemerin, and resistin. Forty-nine obese nondiabetic males completed a four-month dietary program. Body mass index (BMI) decreased significantly from 39.7 +/- 7.6 to 37.8 +/- 7.6 (P < 0.001). This was associated with significant reduction in waist circumference, fasting blood glucose, HOMA-IR, total and LDL-cholesterol, bone-specific alkaline phosphatase (BAP), and resistin (P < 0.05). There was significant increase in serum adiponectin and undercarboxylated osteocalcin (uOC) (P < 0.001). The changes in uOC levels were negatively correlated with changes in serum triglycerides (r = 0.51, P < 0.001) and positively correlated with changes in BAP (r = 0.52, P < 0.001). In contrast, the changes in uOC were not correlated with changes in BMI, waist circumference, fasting blood glucose, HOMA-IR, total and LDL-cholesterol, hsCRP, vitamin D, and circulating adipokines. We concluded that the increase in serum uOC following weight loss is not related to the changes in circulating adipokines levels. PMID- 25784936 TI - High Serum IgG4 Concentrations in Patients with Hashimoto's Thyroiditis. AB - Purpose. Since recent reports suggest that Hashimoto thyroiditis (HT) may be associated with IgG4-related disease, we aimed to find out whether the measurement of serum IgG4 allows for the identification of distinct types of HT, with different clinical, sonographic, and serologic characteristics. Methods. The group studied consisted of 53 patients with HT and 28 healthy individuals who underwent thyroid ultrasonography and body composition analysis. Serum concentrations of IgG4, TSH, anti-peroxidase antibodies (TPOAb), anti-TSH receptor antibodies, TNF-alpha, TGF-beta1, Fas Ligand, TRAIL, and chemokines (CXCL9, CXCL11, and CXCL10) were measured by ELISA or radioimmunoassay. Results. The group with IgG4 level >135 IU/ml accounted for 32.5% of the patients. The signs of fibrosis were present in 27.0% of the high-IgG4 patients and in 9.1% of the normal-IgG4 group. The patients with elevated IgG4 required higher doses of L thyroxine and had significantly lower level of TPOAb (P=0.02) than the non-IgG4 HT individuals and higher TNF-alpha level in comparison with the controls (P=0.01). Conclusions. Our results suggest that the measurement of serum IgG4 allows for an identification of patients with more rapid progression of HT, requiring higher doses of L-thyroxine. Low TPOAb level and the absence of coexisting autoimmune diseases may suggest distinct pathomechanism of this type of thyroiditis. PMID- 25784937 TI - Dental treatment in patients with leukemia. AB - Dental treatment of patients with leukemia should be planned on the basis of antineoplastic therapy which can be chemotherapy with or without radiotherapy and bone marrow transplantation. Many are the oral manifestations presented by these patients, arising from leukemia and/or treatment. In addition, performing dental procedures at different stages of treatment (before, during, or after) must follow certain protocols in relation to the haematological indices of patients, aimed at maintaining health and contributing to the effectiveness of the results of antineoplastic therapy. Through a literature review, the purpose of this study was to report the hematological abnormalities present in patients with leukemia, trying to correlate them with the feasibility of dental treatment at different stages of the disease. It is concluded in this paper that dental treatment in relation to haematological indices presented by patients with leukemia must follow certain protocols, mainly related to neutrophil and platelet counts, and the presence of the dentist in a multidisciplinary team is required for the health care of this patient. PMID- 25784938 TI - Study on the Identification of Radix Bupleuri from Its Unofficial Varieties Based on Discrete Wavelet Transformation Feature Extraction of ATR-FTIR Spectroscopy Combined with Probability Neural Network. AB - The attenuated total reflection-Fourier transform infrared spectroscopy (ATR FTIR) was employed to acquire the infrared spectra of Radix Bupleuri and its unofficial varieties: the root of Bupleurum smithii Wolff and the root of Bupleurum bicaule Helm. The infrared spectra and spectra of Fourier self deconvolution (FSD), discrete wavelet transform (DWT), and probability neural network (PNN) of these species were analyzed. By the method of FSD, there were conspicuous differences of the infrared absorption peak intensity of different types between Radix Bupleuri and its unofficial varieties. But it is hard to tell the differences between the root of Bupleurum smithii Wolff and the root of Bupleurum bicaule. The differences could be shown more clearly when the DWT was used. The research result shows that by the DWT technology it is easier to identify Radix Bupleuri from its unofficial varieties the root of Bupleurum smithii Wolff and the root of Bupleurum bicaule. PMID- 25784939 TI - Fabrication of TiO2 Crystalline Coatings by Combining Ti-6Al-4V Anodic Oxidation and Heat Treatments. AB - The bio- and hemocompatibility of titanium alloys are due to the formation of a TiO2 layer. This natural oxide may have fissures which are detrimental to its properties. Anodic oxidation is used to obtain thicker films. By means of this technique, at low voltages oxidation, amorphous and low roughness coatings are obtained, while, above a certain voltage, crystalline and porous coatings are obtained. According to the literature, the crystalline phases of TiO2, anatase, and rutile would present greater biocompatibility than the amorphous phase. On the other hand, for hemocompatible applications, smooth and homogeneous surfaces are required. One way to obtain crystalline and homogeneous coatings is by heat treatments after anodic oxidation. The aim of this study is to evaluate the influence of heat treatments on the thickness, morphology, and crystalline structure of the TiO2 anodic coatings. The characterization was performed by optical and scanning electron microscopy, X-ray diffraction, and X-ray reflectometry. Coatings with different colors of interference were obtained. There were no significant changes in the surface morphology and roughness after heat treatment of 500 degrees C. Heat treated coatings have different proportions of the crystalline phases, depending on the voltage of anodic oxidation and the temperature of the heat treatment. PMID- 25784940 TI - Immune suppressive effects of tonsil-derived mesenchymal stem cells on mouse bone marrow-derived dendritic cells. AB - Mesenchymal stem cells (MSCs) are considered valuable sources for cell therapy because of their immune regulatory function. Here, we investigated the effects of tonsil-derived MSCs (T-MSCs) on the differentiation, maturation, and function of dendritic cells (DCs). We examined the effect of T-MSCs on differentiation and maturation of bone-marrow- (BM-) derived monocytes into DCs and we found suppressive effect of T-MSCs on DCs via direct contact as well as soluble mediators. Moreover, T cell proliferation, normally increased in the presence of DCs, was inhibited by T-MSCs. Differentiation of CD4(+) T cell subsets by the DC T cell interaction also was inhibited by T-MSCs. The soluble mediators suppressed by T-MSCs were granulocyte-macrophage colony-stimulating factor (GM-CSF), RANTES, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Taken together, T-MSCs exert immune modulatory function via suppression of the differentiation, maturation, and function of BM-derived DCs. Our data suggests that T-MSCs could be used as a novel source of stem cell therapy as immune modulators. PMID- 25784941 TI - CXCL13 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Inhibiting miR-23a Expression. AB - CXC chemokines are essential for osteogenic differentiation of bone mesenchymal stem cells (BMSCs) for use in bone tissue engineering and regenerative medicine in clinical settings. However, an accurate understanding of the underlying mechanisms is still needed. In this study, we analyzed the effects of CXC chemokine ligand-13 (CXCL13) on osteogenic differentiation of rat BMSCs and initiated a preliminary discussion on possible mechanisms. BMSCs were isolated from bone marrow of rat and incubated with CXCL13 recombinant protein in differentiation medium. The main osteogenesis indexes were alkaline phosphatase (ALP) activity and calcium nodes. Expression of Runx2 and CXCR5 was determined using western blot, while miRNAs were determined with quantitative-RT-PCR. Si CXCR5 was transfected into MSCs to silence CXCR5. A miRNA-23a mimic was transfected into BMSCs for overexpression of miRNA-23a. Recombinant CXCL13 induced ALP activity, deposition of calcium salts, and formation of calcium nodes, and it also increased expression of Runx2. The expression of recombinant CXCL13 suppressed expression of miRNA-23a. Overexpression of miR-23a reversed CXCL13 induced-osteogenic differentiation of BMSCs and expression of Runx2. Recombinant CXCL13 attenuated the interaction of miRNA-23a with the Runx2 3'UTR. Silencing of CXCR5 abrogated recombinant CXCL13-induced downregulation of miRNA 23a expression. In summary, CXCL13 promotes osteogenic differentiation of BMSCs by inhibiting miR-23a expression. PMID- 25784942 TI - Recent advances in the diagnosis and treatment of niemann-pick disease type C in children: a guide to early diagnosis for the general pediatrician. AB - Niemann-Pick disease (NP-C) is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI) screening tool was developed to identify suspected patients with this disease. It is especially good at recognizing the disease in patients older than four years of age. Biochemical tests involving genetic markers and Filipin staining of skin fibroblast are being employed to assist diagnosis. Therapy is mostly supportive and since 2009, the first specific therapy approved for use was Miglustat (Zavesca) aimed at stabilizing the rate of progression of neurological manifestation. The prognosis correlates with age at onset of neurological signs; patients with early onset form progress faster. The NP-C disease has heterogeneous neurovisceral manifestations. A SI is a screening tool that helps in diagnostic process. Filipin staining test is a specific biomarker diagnostic test. Miglustat is the first disease-specific therapy. PMID- 25784943 TI - Amoxicillin rash in patients with infectious mononucleosis: evidence of true drug sensitization. AB - BACKGROUND: It hasn't been clearly understood yet whether sensitization to antibiotics, the virus itself or transient loss of drug tolerance due to the virus, is responsible for the development of maculopapular exanthems following amoxicillin intake in patients with infectious mononucleosis. We aimed to examine whether sensitization to penicillin developed among patients with skin rash following amoxicillin treatment within infectious mononucleosis. METHODS: Ten patients were investigated for drug sensitization by lymphocyte transformation test and six patients were further tested by prick-, intradermal and patch tests employing the penicillin's main antigens. RESULTS: Lymphocyte transformation test showed negative results with amoxicillin, while one patient had positive reaction to cefixime. Six patients with suspected sensitization to amoxicillin were then investigated by in vivo tests. Prick tests were negative in all six patients, but the intradermal tests showed positive reactions in four patients. CONCLUSIONS: Our data demonstrate that in vitro testing is not sensitive enough in determining drug sensitization to penicillin. In vivo tests should be performed to detect sensitization and indeed with skin tests our results confirmed that sensitization to aminopenicillin may develop within infectious mononucleosis. PMID- 25784944 TI - The Clinical Efficacy and Safety of the Sahastara Remedy versus Diclofenac in the Treatment of Osteoarthritis of the Knee: A Double-Blind, Randomized, and Controlled Trial. AB - Introduction. The Sahastara (SHT) remedy is a Thai traditional medicine that has been acknowledged in the Thai National List of Essential Medicine and has been used as an alternative medicine to treat knee osteoarthritis. Although SHT remedies have been used in Thai traditional medical practices for a long period of time, there are few reports on their clinical trials. Aim of the Study. To investigate the clinical efficacy and safety of the SHT remedy in treating OA of the knee when compared to diclofenac. Methods. A phase 2, double-blind, randomized, and controlled trial study with a purpose to determine the clinical efficacy and safety of SHT in comparison with diclofenac for the treatment of knee osteoarthritis. Sixty-six patients, ages between 45 and 80 years of age, were randomly allocated into 2 groups. The SHT group received 1,000 mg of SHT powdered capsules 3 times per day, orally before meals, while another group received 25 mg of diclofenac sodium capsules 3 times a day, orally after meals for 28 days. All patients were followed up at 14 and 28 days for the evaluation of the efficacy and safety by using clinical examinations, blood tests, a visual analogue scale (VAS) for pain, and the 100-meter walktime test. Improvement on the quality of life was also assessed by the WOMAC index. Results. There were 31 and 30 patients in SHT and diclofenac groups, respectively, who had completed the study. Both medications have shown to significantly reduce the VAS for pain, and significantly improve the 100-meter walktime test and the WOMAC index score. However, there were no differences in the efficacy between the two groups. The blood chemistry showed no toxicity on renal and/or liver functions after taking SHT for 28 days but the patients who took diclofenac showed significant increases in their AST, ALT, and ALP. Systolic and diastolic blood pressure slightly increased in the diclofenac group but the SHT group did not effect on blood pressure. Conclusions. The SHT remedy is similar to diclofenac in all evaluating symptoms of OA knee. However, the SHT remedy has shown to be a good alternative treatment for OA knee with less systemic side effects when it was compared with diclofenac. PMID- 25784945 TI - Total Flavonoids from Clinopodium chinense (Benth.) O. Ktze Protect against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo. AB - Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. This study aims to investigate the protective effects of the total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC) against doxorubicin- (DOX-) induced cardiotoxicity. Male rats were intraperitoneally injected with a single dose of DOX (3 mg/kg) every 2 days for three injections. Heart samples were collected 2 weeks after the last DOX dose and then analyzed. DOX delayed body and heart growth and caused cardiac tissue injury, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. Similar experiments in H9C2 cardiomyocytes showed that doxorubicin reduced cell viability, increased ROS generation and DNA fragmentation, disrupted mitochondrial membrane potential, and induced apoptotic cell death. However, TFCC pretreatment suppressed all of these adverse effects of doxorubicin. Signal transduction studies indicated that TFCC suppressed DOX-induced overexpression of p53 and phosphorylation of JNK, p38, and ERK. Studies with LY294002 (a PI3K/AKT inhibitor) demonstrated that the mechanism of TFCC-induced cardioprotection also involves activation of PI3K/AKT. These findings indicated the potential clinical application of TFCC in preventing DOX-induced cardiac oxidative stress. PMID- 25784946 TI - Terminalia chebula Fructus Inhibits Migration and Proliferation of Vascular Smooth Muscle Cells and Production of Inflammatory Mediators in RAW 264.7. AB - Pathogenesis of atherosclerosis and neointima formation after angioplasty involves vascular smooth muscle cells (VSMCs) migration and proliferation followed by inflammatory responses mediated by recruited macrophages in the neointima. Terminalia chebula is widely used traditional medicine in Asia for its beneficial effects against cancer, diabetes, and bacterial infection. The study was designed to determine whether Terminalia chebula fructus water extract (TFW) suppresses VSMC migration and proliferation and inflammatory mediators production in macrophage (RAW 264.7). Our results showed that TFW possessed strong antioxidative effects in 1,1-diphenyl-2-picryl hydrazyl (DPPH) scavenging and lipid peroxidation assays. In addition, TFW reduced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression in RAW 264.7 cells. Also, TFW inhibited platelet-derived growth factor (PDGF-BB) induced VSMC migration as determined by wound healing and Boyden chamber assays. The antimigratory effect of TFW was due to its inhibitory effect on metalloproteinase-9 (MMP-9) expression, focal adhesion kinase (FAK) activation, and Rho-family of small GTPases (Cdc42 and RhoA) expression in VSMCs. Furthermore, TFW suppressed PDGF-BB induced VSMC proliferation by downregulation of mitogen activated protein kinases (MAPKs) signaling molecules. These results suggest that TFW could be a beneficial resource in the prevention of atherosclerosis. PMID- 25784947 TI - Cytotoxic effects of biosynthesized zinc oxide nanoparticles on murine cell lines. AB - The aim of this study is to evaluate the in vitro cytotoxic activity and cellular effects of previously prepared ZnO-NPs on murine cancer cell lines using brown seaweed (Sargassum muticum) aqueous extract. Treated cancer cells with ZnO-NPs for 72 hours demonstrated various levels of cytotoxicity based on calculated IC50 values using MTT assay as follows: 21.7 +/- 1.3 MUg/mL (4T1), 17.45 +/- 1.1 MUg/mL (CRL-1451), 11.75 +/- 0.8 MUg/mL (CT-26), and 5.6 +/- 0.55 MUg/mL (WEHI 3B), respectively. On the other hand, ZnO-NPs treatments for 72 hours showed no toxicity against normal mouse fibroblast (3T3) cell line. On the other hand, paclitaxel, which imposed an inhibitory effect on WEHI-3B cells with IC50 of 2.25 +/- 0.4, 1.17 +/- 0.5, and 1.6 +/- 0.09 MUg/mL after 24, 48, and 72 hours treatment, respectively, was used as positive control. Furthermore, distinct morphological changes were found by utilizing fluorescent dyes; apoptotic population was increased via flowcytometry, while a cell cycle block and stimulation of apoptotic proteins were also observed. Additionally, the present study showed that the caspase activations contributed to ZnO-NPs triggered apoptotic death in WEHI-3 cells. Thus, the nature of biosynthesis and the therapeutic potential of ZnO-NPs could prepare the way for further research on the design of green synthesis therapeutic agents, particularly in nanomedicine, for the treatment of cancer. PMID- 25784948 TI - Acupuncture antiarrhythmic effects on drug refractory persistent atrial fibrillation: study protocol for a randomized, controlled trial. AB - Background. Atrial fibrillation (AF) is the most common form of arrhythmia. Several trials have suggested that acupuncture may prevent AF. However, the efficacy of acupuncture for AF prevention has not been well investigated. Therefore, we designed a prospective, two-parallel-armed, participant and assessor blinded, randomized, sham-controlled clinical trial to investigate acupuncture in persistent AF (ACU-AF). Methods. A total of 80 participants will be randomly assigned to active acupuncture or sham acupuncture groups in a 1 : 1 ratio. Both groups will take the same antiarrhythmic medication during the study period. Patients will receive 10 sessions of acupuncture treatment once a week for 10 weeks. The primary endpoint is AF recurrence rate. Secondary endpoints are left atrium (LA) and left atrial appendage (LAA) changes in function and volume, and inflammatory biomarker changes. Ethics. This study protocol was approved by the institutional review boards (IRBs) of Kyung Hee University Hospital (number 1335-04). This trial is registered with clinicaltrials.gov NCT02110537. PMID- 25784949 TI - Antihypertensive effect of radix paeoniae alba in spontaneously hypertensive rats and excessive alcohol intake and high fat diet induced hypertensive rats. AB - Radix Paeoniae Alba (Baishao, RPA) has long been used in traditional Chinese medicine formulation to treat hypertension by repression the hyperfunction of liver. However, whether the RPA itself has the antihypertensive effect or not is seldom studied. This study was to evaluate the protective effect of RPA on hypertensive rats. Alcohol in conjunction with a high fat diet- (ACHFD-) induced hypertensive rats and spontaneously hypertensive rats (SHR) was constantly received either RPA extract (25 or 75 mg/kg) or captopril (15 mg/kg) all along the experiments. As a result, RPA extract (75 mg/kg) could significantly reduce systolic blood pressure of both ACHFD-induced hypertensive rats and SHR after 9 week or 4-week treatment. In ACHFD-induced hypertensive rats, the blood pressure was significantly increased and the lipid profiles in serum including triglyceride, total cholesterol, LDL-cholesterol, and HDL-cholesterol were significantly deteriorated. Also, hepatic damage was manifested by a significant increase in alanine transaminase (ALT) and aspartate transaminase (AST) in serum. The RPA extract significantly reversed these parameters, which revealed that it could alleviate the liver damage of rats. In SHR, our result suggested that the antihypertensive active of RPA extract may be related to its effect on regulating serum nitric oxide (NO) and endothelin (ET) levels. PMID- 25784950 TI - Tai chi chuan for the primary prevention of stroke in middle-aged and elderly adults: a systematic review. AB - Background. Stroke is a major healthcare problem with serious long-term disability and is one of the leading causes of death in the world. Prevention of stroke is considered an important strategy. Methods. Seven electronic databases were searched. Results. 36 eligible studies with a total of 2393 participants were identified. Primary outcome measures, TCC exercise combined with other intervention had a significant effect on decreasing the incidence of nonfatal stroke (n = 185, RR = 0.11, 95% CI 0.01 to 0.85, P = 0.03) and CCD (n = 125, RR = 0.33, 95% CI 0.11 to 0.96, P = 0.04). For the risk factors of stroke, pooled analysis demonstrated that TCC exercise was associated with lower body weight, BMI, FBG level, and decreasing SBP, DBP, plasma TC, and LDL-C level regardless of the intervention period less than half a year or more than one year and significantly raised HDL-C level in comparison to nonintervention. Compared with other treatments, TCC intervention on the basis of the same other treatments in patients with chronic disease also showed the beneficial effect on lowering blood pressure. Conclusion. The present systematic review indicates that TCC exercise is beneficially associated with the primary prevention of stroke in middle-aged and elderly adults by inversing the high risk factors of stroke. PMID- 25784951 TI - Adenosine A2A Receptors Mediate Anti-Inflammatory Effects of Electroacupuncture on Synovitis in Mice with Collagen-Induced Arthritis. AB - To study the role of adenosine A2A receptor (A2AR) in mediating the anti inflammatory effect of electroacupuncture (EA) on synovitis in collagen-induced arthritis (CIA), C57BL/6 mice were divided into five treatment groups: Sham control, CIA-control, CIA-EA, CIA-SCH58261 (A2AR antagonist), and CIA-EA SCH58261. All mice except those in the Sham-control group were immunized with collagen II for arthritis induction. EA treatment was administered using the stomach 36 and spleen 6 points, and stimulated with a continuous rectangular wave for 30 min daily. EA treatment and SCH58261 were administered daily from days 35 to 49 (n = 10). After treatment, X-ray radiography of joint bone morphology was established at day 60 and mouse blood was collected for ELISA determination of tumor necrosis factor alpha (TNF-alpha) levels. Mice were sacrificed and processed for histological examination of pathological changes of joint tissue, including hematoxylin-eosin staining and immunohistochemistry of A2AR expression. EA treatment resulted in significantly reduced pathological scores, TNF-alpha concentrations, and bone damage X-ray scores. Importantly, the anti-inflammatory and tissue-protective effect of EA treatment was reversed by coadministration of SCH58261. Thus, EA treatment exerts an anti-inflammatory effect resulting in significant protection of cartilage by activation of A2AR in the synovial tissue of CIA. PMID- 25784952 TI - Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. AB - BACKGROUND: Functional loss of blood-brain barrier (BBB) is suggested to be pivotal to pathogenesis and pathology of vascular-based neurodegenerative disorders such as Alzheimer's disease. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms. RESULTS: Immunomicroscopy analyses confirmed significantly increased capillary permeability with heightened neuroinflammation in naturally aged 24 month old mice compared to young control at 3 months of age. Aged mice showed significant attenuation in the expression of BBB tight junction proteins, occludin-1 and to lesser extent ZO-1 compared to young mice. In addition, TNF alpha in cerebral endothelial cells of aged mice was significantly elevated compared to controls and this was associated with heightened peripheral inflammation. The expression of ICAM-1 and VCAM-1 remained unelevated, and no sign of leukocyte recruitment was observed in aged mice. CONCLUSION: The BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking. PMID- 25784954 TI - Global infant formula: monitoring and regulating the impacts to protect human health. AB - Worldwide promotion of infant formula and other commercial baby foods is leading to increased use of these products, raising concerns about their impact on the health of infants. These products are made and marketed through a global system that extends beyond the control of separate nations. As the industry is increasingly globalized, there is a growing need for guidance, monitoring, and regulation. This study suggests a path toward achieving better control of infant formula and other baby foods to ensure that infants and young children everywhere are well nourished. The negotiation of a new Optional Protocol on Children's Nutrition, to be linked to the most relevant human rights treaty, the Convention on the Rights of the Child, would bring the major issues relating to infant formula and other baby foods to the attention of the global community and all national governments. PMID- 25784953 TI - The beta-3 adrenergic agonist (CL-316,243) restores the expression of down regulated fatty acid oxidation genes in type 2 diabetic mice. AB - BACKGROUND: The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype. METHODS: Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis. RESULTS: Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL 316,243 treatment. CONCLUSIONS: This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study. PMID- 25784955 TI - Early infant feeding practices in three African countries: the PROMISE-EBF trial promoting exclusive breastfeeding by peer counsellors. AB - BACKGROUND: Immediate and exclusive initiation of breastfeeding after delivery has been associated with better neonatal survival and child health and are recommended by the WHO. We report its impact on early infant feeding practices from the PROMISE-EBF trial. METHODS: PROMISE-EBF was a cluster randomised behaviour change intervention trial of exclusive breastfeeding (EBF) promotion by peer counsellors in Burkina Faso, Uganda and South Africa implemented during 2006 2008 among 2579 mother-infant pairs. Counselling started in the last pregnancy trimester and mothers were offered at least five postnatal visits. Early infant feeding practices: use of prelacteal feeds (any foods or drinks other than breast milk given within the first 3 days), expressing and discarding colostrum, and timing of initiation of breastfeeding are presented by trial arm in each country. Prevalence ratios (PR) with 95% confidence intervals (95%CI) are given. RESULTS: The proportion of women who gave prelacteal feeds in the intervention and control arms were, respectively: 11% and 36%, PR 0.3 (95% CI 0.2, 0.6) in Burkina Faso, 13% and 44%, PR 0.3 (95% CI 0.2, 0.5) in Uganda and 30% and 33%, PR 0.9 (95% CI 0.6, 1.3) in South Africa. While the majority gave colostrum, the proportion of those who expressed and discarded it in the intervention and control arms were: 8% and 12%, PR 0.7 (95% CI 0.3, 1.6) in Burkina Faso, 3% and 10%, PR 0.3 (95% CI 0.1, 0.6) in Uganda and 17% and 16%, PR 1.1 (95% CI 0.6, 2.1) in South Africa. Only a minority in Burkina Faso (<4%) and roughly half in South Africa initiated breastfeeding within the first hour with no large or statistically significant differences between the trial arms, whilst in Uganda the proportion of early initiation of breastfeeding in the intervention and control arms were: 55% and 41%, PR 0.8 (95% CI 0.7, 0.9). CONCLUSIONS: The PROMISE-EBF trial showed that the intervention led to less prelacteal feeding in Burkina Faso and Uganda. More children received colostrum and started breastfeeding early in the intervention arm in Uganda. Late breastfeeding initiation continues to be a challenge. No clear behaviour change was seen in South Africa. TRIAL REGISTRATION: NCT00397150. PMID- 25784956 TI - A Bayesian inferential approach to quantify the transmission intensity of disease outbreak. AB - BACKGROUND: Emergence of infectious diseases like influenza pandemic (H1N1) 2009 has become great concern, which posed new challenges to the health authorities worldwide. To control these diseases various studies have been developed in the field of mathematical modelling, which is useful tool for understanding the epidemiological dynamics and their dependence on social mixing patterns. METHOD: We have used Bayesian approach to quantify the disease outbreak through key epidemiological parameter basic reproduction number (R0), using effective contacts, defined as sum of the product of incidence cases and probability of generation time distribution. We have estimated R0 from daily case incidence data for pandemic influenza A/H1N1 2009 in India, for the initial phase. RESULT: The estimated R0 with 95% credible interval is consistent with several other studies on the same strain. Through sensitivity analysis our study indicates that infectiousness affects the estimate of R0. CONCLUSION: Basic reproduction number R0 provides the useful information to the public health system to do some effort in controlling the disease by using mitigation strategies like vaccination, quarantine, and so forth. PMID- 25784957 TI - In silico design of human IMPDH inhibitors using pharmacophore mapping and molecular docking approaches. AB - Inosine 5'-monophosphate dehydrogenase (IMPDH) is one of the crucial enzymes in the de novo biosynthesis of guanosine nucleotides. It has served as an attractive target in immunosuppressive, anticancer, antiviral, and antiparasitic therapeutic strategies. In this study, pharmacophore mapping and molecular docking approaches were employed to discover novel Homo sapiens IMPDH (hIMPDH) inhibitors. The Guner Henry (GH) scoring method was used to evaluate the quality of generated pharmacophore hypotheses. One of the generated pharmacophore hypotheses was found to possess a GH score of 0.67. Ten potential compounds were selected from the ZINC database using a pharmacophore mapping approach and docked into the IMPDH active site. We find two hits (i.e., ZINC02090792 and ZINC00048033) that match well the optimal pharmacophore features used in this investigation, and it is found that they form interactions with key residues of IMPDH. We propose that these two hits are lead compounds for the development of novel hIMPDH inhibitors. PMID- 25784958 TI - Fungi isolated from Miscanthus and sugarcane: biomass conversion, fungal enzymes, and hydrolysis of plant cell wall polymers. AB - BACKGROUND: Biofuel use is one of many means of addressing global change caused by anthropogenic release of fossil fuel carbon dioxide into Earth's atmosphere. To make a meaningful reduction in fossil fuel use, bioethanol must be produced from the entire plant rather than only its starch or sugars. Enzymes produced by fungi constitute a significant percentage of the cost of bioethanol production from non-starch (i.e., lignocellulosic) components of energy crops and agricultural residues. We, and others, have reasoned that fungi that naturally deconstruct plant walls may provide the best enzymes for bioconversion of energy crops. RESULTS: Previously, we have reported on the isolation of 106 fungi from decaying leaves of Miscanthus and sugarcane (Appl Environ Microbiol 77:5490-504, 2011). Here, we thoroughly analyze 30 of these fungi including those most often found on decaying leaves and stems of these plants, as well as four fungi chosen because they are well-studied for their plant cell wall deconstructing enzymes, for wood decay, or for genetic regulation of plant cell wall deconstruction. We extend our analysis to assess not only their ability over an 8-week period to bioconvert Miscanthus cell walls but also their ability to secrete total protein, to secrete enzymes with the activities of xylanases, exocellulases, endocellulases, and beta-glucosidases, and to remove specific parts of Miscanthus cell walls, that is, glucan, xylan, arabinan, and lignin. CONCLUSION: This study of fungi that bioconvert energy crops is significant because 30 fungi were studied, because the fungi were isolated from decaying energy grasses, because enzyme activity and removal of plant cell wall components were recorded in addition to biomass conversion, and because the study period was 2 months. Each of these factors make our study the most thorough to date, and we discovered fungi that are significantly superior on all counts to the most widely used, industrial bioconversion fungus, Trichoderma reesei. Many of the best fungi that we found are in taxonomic groups that have not been exploited for industrial bioconversion and the cultures are available from the Centraalbureau voor Schimmelcultures in Utrecht, Netherlands, for all to use. PMID- 25784959 TI - STAT3 acts through pre-existing nucleosome-depleted regions bound by FOS during an epigenetic switch linking inflammation to cancer. AB - BACKGROUND: Transient induction of the Src oncoprotein in a non-transformed breast cell line can initiate an epigenetic switch to a cancer cell via a positive feedback loop that involves activation of the signal transducer and activator of transcription 3 protein (STAT3) and NF-kappaB transcription factors. RESULTS: We show that during the transformation process, nucleosome-depleted regions (defined by formaldehyde-assisted isolation of regulatory elements (FAIRE)) are largely unchanged and that both before and during transformation, STAT3 binds almost exclusively to previously open chromatin regions. Roughly, a third of the transformation-inducible genes require STAT3 for the induction. STAT3 and NF-kappaB appear to drive the regulation of different gene sets during the transformation process. Interestingly, STAT3 directly regulates the expression of NFKB1, which encodes a subunit of NF-kappaB, and IL6, a cytokine that stimulates STAT3 activity. Lastly, many STAT3 binding sites are also bound by FOS and the expression of several AP-1 factors is altered during transformation in a STAT3-dependent manner, suggesting that STAT3 may cooperate with AP-1 proteins. CONCLUSIONS: These observations uncover additional complexities to the inflammatory feedback loop that are likely to contribute to the epigenetic switch. In addition, gene expression changes during transformation, whether driven by pre-existing or induced transcription factors, occur largely through pre-existing nucleosome-depleted regions. PMID- 25784960 TI - Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. AB - Autism spectrum disorder (ASD) and intellectual disability (ID) can be caused by mutations in a large number of genes. One example is SHANK3 on the terminal end of chromosome 22q. Loss of one functional copy of SHANK3 results in 22q13 deletion syndrome or Phelan-McDermid syndrome (PMS) and causes a monogenic form of ASD and/or ID with a frequency of 0.5% to 2% of cases. SHANK3 is the critical gene in this syndrome, and its loss results in disruption of synaptic function. With chromosomal microarray analyses now a standard of care in the assessment of ASD and developmental delay, and with the emergence of whole exome and whole genome sequencing in this context, identification of PMS in routine clinical settings will increase significantly. However, PMS remains a rare disorder, and the majority of physicians have never seen a case. While there is agreement about core deficits of PMS, there have been no established parameters to guide evaluation and medical monitoring of the syndrome. Evaluations must include a thorough history and physical and dysmorphology examination. Neurological deficits, including the presence of seizures and structural brain abnormalities should be assessed as well as motor deficits. Endocrine, renal, cardiac, and gastrointestinal problems all require assessment and monitoring in addition to the risk of recurring infections, dental and vision problems, and lymphedema. Finally, all patients should have cognitive, behavioral, and ASD evaluations. The objective of this paper is to address this gap in the literature and establish recommendations to assess the medical, genetic, and neurological features of PMS. PMID- 25784962 TI - New developments in urology: urology update 2014. PMID- 25784961 TI - Congenital imprinting disorders: EUCID.net - a network to decipher their aetiology and to improve the diagnostic and clinical care. AB - Imprinting disorders (IDs) are a group of eight rare but probably underdiagnosed congenital diseases affecting growth, development and metabolism. They are caused by similar molecular changes affecting regulation, dosage or the genomic sequence of imprinted genes. Each ID is characterised by specific clinical features, and, as each appeared to be associated with specific imprinting defects, they have been widely regarded as separate entities. However, they share clinical characteristics and can show overlapping molecular alterations. Nevertheless, IDs are usually studied separately despite their common underlying (epi)genetic aetiologies, and their basic pathogenesis and long-term clinical consequences remain largely unknown. Efforts to elucidate the aetiology of IDs are currently fragmented across Europe, and standardisation of diagnostic and clinical management is lacking. The new consortium EUCID.net (European network of congenital imprinting disorders) now aims to promote better clinical care and scientific investigation of imprinting disorders by establishing a concerted multidisciplinary alliance of clinicians, researchers, patients and families. By encompassing all IDs and establishing a wide ranging and collaborative network, EUCID.net brings together a wide variety of expertise and interests to engender new collaborations and initiatives. PMID- 25784963 TI - Highlights of the university of toronto urology update 2014. AB - At the University of Toronto Urology Update 2014, a faculty of Canadian and American experts presented a series of lectures covering a range of topics in the field of urology. Areas of focus included prostate cancer (PCa), functional urology, erectile dysfunction (ED), and surgical topics (e.g., percutaneous nephrolithotomy [PCNL]). PMID- 25784964 TI - Three dimensional passivated-electrode insulator-based dielectrophoresis. AB - In this study, a 3D passivated-electrode, insulator-based dielectrophoresis microchip (3D piDEP) is presented. This technology combines the benefits of electrode-based DEP, insulator-based DEP, and three dimensional insulating features with the goal of improving trapping efficiency of biological species at low applied signals and fostering wide frequency range operation of the microfluidic device. The 3D piDEP chips were fabricated by making 3D structures in silicon using reactive ion etching. The reusable electrodes are deposited on second glass substrate and then aligned to the microfluidic channel to capacitively couple the electric signal through a 100 MUm glass slide. The 3D insulating structures generate high electric field gradients, which ultimately increases the DEP force. To demonstrate the capabilities of 3D piDEP, Staphylococcus aureus was trapped from water samples under varied electrical environments. Trapping efficiencies of 100% were obtained at flow rates as high as 350 MUl/h and 70% at flow rates as high as 750 MUl/h. Additionally, for live bacteria samples, 100% trapping was demonstrated over a wide frequency range from 50 to 400 kHz with an amplitude applied signal of 200 Vpp. 20% trapping of bacteria was observed at applied voltages as low as 50 Vpp. We demonstrate selective trapping of live and dead bacteria at frequencies ranging from 30 to 60 kHz at 400 Vpp with over 90% of the live bacteria trapped while most of the dead bacteria escape. PMID- 25784965 TI - Enhanced fluorescence emitted by microdroplets containing organic dye emulsions. AB - In this paper, laser beam resonant interaction with pendant microdroplets that are seeded with a laser dye (Rhodamine 6G (Rh6G)) water solution or oily Vitamin A emulsion with Rhodamine 6G solution in water is investigated through fluorescence spectra analysis. The excitation is made with the second harmonic generated beam emitted by a pulsed Nd:YAG laser system at 532 nm. The pendant microdroplets containing emulsion exhibit an enhanced fluorescence signal. This effect can be explained as being due to the scattering of light by the sub micrometric drops of oily Vitamin A in emulsion and by the spherical geometry of the pendant droplet. The droplet acts as an optical resonator amplifying the fluorescence signal with the possibility of producing lasing effect. Here, we also investigate how Rhodamine 6G concentration, pumping laser beam energies and number of pumping laser pulses influence the fluorescence behavior. The results can be useful in optical imaging, since they can lead to the use of smaller quantities of fluorescent dyes to obtain results with the same quality. PMID- 25784966 TI - Hydrogel-based microfluidic incubator for microorganism cultivation and analyses. AB - This work presents an array of microfluidic chambers for on-chip culturing of microorganisms in static and continuous shear-free operation modes. The unique design comprises an in-situ polymerized hydrogel that forms gas and reagent permeable culture wells in a glass chip. Utilizing a hydrophilic substrate increases usability by autonomous capillary priming. The thin gel barrier enables efficient oxygen supply and facilitates on-chip analysis by chemical access through the gel without introducing a disturbing flow to the culture. Trapping the suspended microorganisms inside a gel well allows for a much simpler fabrication than in conventional trapping devices as the minimal feature size does not depend on cell size. Nutrients and drugs are provided on-chip in the gel for a self-contained and user-friendly handling. Rapid antibiotic testing in static cultures with strains of Enterococcus faecalis and Escherichia coli is presented. Cell seeding and diffusive medium supply is provided by phaseguide technology, enabling simple operation of continuous culturing with a great flexibility. Cells of Saccharomyces cerevisiae are utilized as a model to demonstrate continuous on-chip culturing. PMID- 25784967 TI - Third Stage of Labor and Acupuncture. AB - Background: Acupuncture use in obstetrics has been increasing in Western medicine, especially to alleviate complications of pregnancy, the most important cause of maternal mortality worldwide. One quarter of maternal deaths are caused by complications in the third stage of labor, an interval between complete delivery of the baby and the complete expulsion of the placenta. Methods: This review analyzes the increased acupuncture use for pregnancy complications as a potential method of reducting maternal mortality during the third stage of labor. This overview focuses on acupuncture points and techniques to manage the third stage of labor and help patients with retained placentas. Passive (or expectant) management of the third stage of labor is occasionally associated with massive obstetric hemorrhage, a major cause of maternal morbidity and mortality, especially in low-income countries. Conclusions: Active management of the third stage of labor has been shown to reduce the risk of postpartum hemorrhage. Use of acupuncture in the first and second stages of labor could lead to a faster separation of the placenta in the third stage of labor. The possible effects of acupuncture in cases of retained placentas may have significant implications for possible complications and final outcomes of labor. Further studies are needed for more conclusive results. PMID- 25784968 TI - Impact of microalbuminuria on incident coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis of prospective studies. AB - This study is to investigate the magnitude of relationship between microalbuminuria and incident coronary heart disease (CHD) and mortality in the general population by conducting a meta-analysis. A comprehensive literature search in Pubmed and Embase database was performed prior to March 2014. Only prospective studies investigating the presence of microalbuminuria and incident CHD, cardiovascular disease (CVD), and mortality and were selected. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated by the presence of microalbuminuria versus without microalbuminuria. Finally, we identified 8 prospective studies involving 114,105 individuals. Participants with microalbuminuria were associated with 69% greater risk of CVD (RR=1.69; 95% CI 1.41-2.02) and 41% greater risk of CHD (RR=1.41; 95% CI 1.17-1.69). Participants with microalbuminuria were also associated with 57% greater risk of cardiovascular mortality (RR=1.57; 95% CI 1.20-2.06) and 65% greater risk of all cause mortality (RR=1.65; 95% CI 1.45-1.88). Microalbuminuria is an independent predictor for CHD, CVD, and all-cause mortality in the general population. Early detection of microalbuminuria in the general population is likely to identify patients at increased risk of CVD and mortality. PMID- 25784969 TI - Topical and effective hemostatic medicines in the battlefield. AB - Uncontrolled hemorrhage has been considered as one of the most important factors for causing death on the battlefront. If given timely and efficient hemostatic medicines in pre-hospital setting, patients will obtain more time and chance to wait for medical treatment so as to save their lives. However, there is not a certain answer about which kind of hemostatic drugs can achieve efficacious effect to hemostasis in the battle. This review aims to summarize effective hemostatic medicines applied in battlefield from 41 articles. After analyzing and comparing the efficacy and complications of those products, we conclude that Fibrin Sealant Dressing, Celox and Woundstat are prior to other materials to stanch life-threatening extremity hemorrhage on the battlefield based on present research in the related area. Therefore, in the prevalence of some inevitable battlefield throughout the world, especially in the Middle Eastern countries, our findings suggest for the first time that the effective hemostatic device is not only a key point to link pre-hospital and hospital care but also an essential way to increase the survival rate of battlefront in the foreseeable future. PMID- 25784970 TI - A review of life quality in living donors after liver transplantation. AB - Living-donor liver transplantation (LDLT) has increasingly performed all around the world. However, LDLT donors achieve no medical benefits and are exposed to the risk of complications, and even death. The potential effects of LDLT on donor safety, donor recovery, and post-donation psychological impairment are essential to be better understood. We searched the MEDLINE database to identify articles about the quality of life (QOL) in adults after LDLT donation. Twenty-eight studies with a total of 1944 donors were included in the review. 14 of the 28 studies (50%) had a cross-sectional design, and the remaining half had a prospective design. The Physical Component Score (PCS) decreased immediately after the donation, then returned to the baseline within 6 to 12 months while the Mental Component Score (MCS) remains comparable to that of normative population throughout the procedure. Compared with the left graft (LG) donors, right graft (RG) donors were significantly older, had longer hospital stays and higher rates of postoperative complications, and a higher recipient mortality rate, while there were no difference in the PCS and MCS between the two groups. Our review clearly indicates that the LDLT donors can endure the donation procedure and return to their normal daily life without major problem in the short term. However, to improve the donor selection criteria and ensure the QOL in donors throughout donation procedure, more studies with longer follow up and larger samples are essential and predictors of poor QOL should be identified in study with sufficient response rate and ideal control groups. PMID- 25784971 TI - Total hip arthroplasty: areview of advances, advantages and limitations. AB - The therapeutic outcomes of Osteoarthritis (OA) has been unsatisfactory and often surgeries such as total hip arthroplasty (THA) is required. THA is an effective treatment for patients with end-stage arthritic hip conditions. Cemented THA has been the treatment of choice for elderly patients with OA. An improvement in Timed "Up and Go" (TUG) before surgery might contribute to a decrease in the occurrence of DVT after THA, though post-thrombotic syndrome (PTS), a chronic condition in the lower extremity does not appear to be a major complication after DVT in patients undergoing THA. For OA, four domains to be evaluated: pain, physical function, joint imaging, and patient global assessment. Thus, THA can be cost saving or, at least cost- effective in improving quality-adjusted life expectancy. The purpose of this review is to discuss the recent advances as well as advantages and limitations of THA. PMID- 25784972 TI - Periosteal osteosarcoma: a review of clinical evidence. AB - Periosteal osteosarcoma (PO) is a rare primary malignant bone tumor and a variant of osteosarcoma. It is a surface lesion without evidence of medullary involvement. The radiologic appearance of periosteal osteosarcoma is a broad based surface soft-tissue mass that causes extrinsic erosion of thickened underlying diaphyseal cortex and perpendicular periosteal reaction extending into the soft-tissue component. The tumour presents as non-homogeneous masses of speculated osteoid matrix progressively denser from the periphery to their cortical base. The average age is around 28 and the most common location is the proximal third of the femur; with all the lesions diaphyseal in location. The treatment usually indicated is amputation, but in selected cases, radical segmental resection is appropriate. Long-term disease-free survival is possible after resection of the local recurrence. Limb-salvage therapy seems to offer survival equivalent to amputation, and there does not seem to be a substantial risk of late recurrence, dedifferentiation, or disease progression. The current review also highlights on various rare occurrences of periosteal osteosarcoma including the one of calcaneum, fifth metatarsal, mandible cranium, jaws, clavicle, maxilla, sphenoid bone with extensive periosteal extension, metacarpal in a paediatric age group and bilateral metachronous periosteal osteosarcoma. Recent findings relating to genetic factors governing the pathogenesis of PO is also presented. PMID- 25784973 TI - Sensitivity of (18)F-FDG PET in evaluation of solitary pulmonary nodules. AB - INTRODUCTION: The solitary pulmonary nodule (SPN) may be an early sign of lung cancer. Due to the difficulties of radiological imaging techniques in differentiation of benign/malignant nodules, functional imaging techniques like PET-CT are required in patients diagnosed with SPN. The aim of this study was the evaluation of the role of PET-CT in differentiation of malignant/benign SPN by some characteristic findings in PET-CT. Moreover, among the nodules with histopathologically diagnosed as benign, malignant or metastatic, the SUVmax and Hounsfield Units (HU) of PET-CT imaging were also aimed to be compared to assess the role of PET-CT in discrimination of malignant/benign SPN. MATERIAL AND METHOD: Among the patients evaluated with PET-CT with the pre-diagnosis of pulmonary nodule or non-pulmonary malignancies, between July 2010 and January 2012, in Konya University Meram Medical School Nuclear Medicine Department, 241 patients (167 male, 74 female) diagnosed with pulmonary nodule were enrolled in the study. In visual evaluation of PET-CT of all patients, there was only one nodule in lung parenchyma. The diameter in cm, location as central or peripheral, regularity of borders, presence of calcification and HU and Maximum standardized uptake values (SUVmax) values with quantitative analysis of all nodules was recorded. The histopathological evaluation of nodules was available in 91 of those 241 patients and they were also recorded. RESULTS: In comparison of mean SUVmax values in regards to the characteristic findings of nodules in PET-CT, the mean SUVmax value of patients was statistically significantly higher in patients with the nodule diameter >=1 cm, centrally located nodules, or nodules with irregular borders. CONCLUSION: In malignant/benign differentiation of solitary pulmonary nodules with the diameter of higher than 1 cm, PET-CT plays an essential role; however, for the nodules smaller than 1 cm in diameter, in small, single metastatic nodules and some benign nodules with high SUVmax values, PET-CT may be unsatisfactory. However, it is clear that, in especially undetermined nodules, PET-CT is an important complementary tool in diagnosis. PMID- 25784974 TI - Advances and applications of bronchoscopic lung volume reduction. AB - Lung volume reduction surgery usually gives rise to high postoperative morbidity and impedes its further application. Recently, a plethora of bronchoscopic lung volume reduction techniques such as one-way endobronchial valves, biological sealants, thermal vapor ablation, airway bypass stents and lung volume reduction coils have been extensively used in emphysema treatment. The current data for bronchoscopic lung volume reduction although not conclusive enough do present multiple safer ways compared with conventional surgery with few serious complications, lower cost and shortened hospital care. The bronchoscopic lung volume reduction will undergo continuous development as constant randomized trials are performed to prove its full efficacy. PMID- 25784975 TI - AMPK is required for PM2.5-induced autophagy in human lung epithelial A549 cells. AB - The aim is to investigate the molecular mechanisms underlying the PM2.5-induced autophagy in human lung cancer epithelial cells (A549). The effects of the PM2.5 on morphological and biochemical markers of autophagy in A549 were analyzed by electron microscopy, GFP-LC3 puncta was observed by confocal fluorescence microscope. The effects of phosphorylation of AMPK, mTOR, AKT, ERK, JNK, and p53 on LC3II in A549 were observed following PM2.5 exposure; the role of autophagy in PM2.5-induced apoptosis was examined using 3-methyladenine and rapamycin. PM2.5 induced morphological and biochemical markers of autophagy in A549. Phosphorylation of AMPK and dephosphorylation of mTOR were observed following PM2.5 treatment, and AMPK inhibitor blocked LC3B-II expression. In addition, we demonstrated that PM2.5-induced autophagy confers a pro-survival role in host defense. PMID- 25784976 TI - Meta-analysis of studies on breast cancer risk and diet in Chinese women. AB - OBJECTIVE: A meta-analysis was carried out to summarize published data on the relationship between breast cancer and dietary factors. METHODS: Databases in Chinese (China National Knowledge Infrastructure [CNKI], China Biology Medicine [CBM], WanFang, VIP) and in English (PubMed and Web of Science) were searched for articles analyzing vegetable, fruit, soy food and fat consumption and breast cancer risk published through June 30, 2013. Random effects models were used to estimate summary odds ratios (OR) based on high versus low intake, and subgroup analysis was conducted according to region, study design, paper quality and adjustment for confounding factors to detect the potential source of heterogeneity. Every study was screened according to the inclusion criteria and exclusion criteria, evaluated in accordance with the Newcastle-Ottawa Scale. RevMan 5.2 software was used for analysis. RESULTS: Of 785 studies retrieved, 22 met inclusion criteria (13 in Chinese and 9 in English), representing 23,201 patients: 10,566 in the experimental group and 12,635 in the control group. Thirteen included studies showed vegetables consumption to be a relevant factor in breast cancer risk, OR = 0.77 (95% CI [confidence interval] 0.62-0.96). Eleven studies showed fruits consumption to be relevant, OR = 0.68 (95% CI 0.49-0.93). Significant differences were also found between those who consumed soy foods, OR = 0.68 (95% CI 0.50-0.93) and those who ate a high-fat diet, OR = 1.15 (95% CI 1.01-1.30). CONCLUSION: This analysis confirms the association between intake of vegetables, fruits, soy foods and fat and the risk of breast cancer from published sources. It's suggested that high consumption of vegetables, fruits and soy foods may reduce the risk of breast cancer, while increasing fat consumption may increase the risk. PMID- 25784977 TI - Short-term effect and adverse events of adalimumab versus placebo in inducing remission for moderate-to-severe ulcerative colitis: a meta-analysis. AB - BACKGROUND: Adalimumab is used in an attempt to maintain remission for Ulcerative colitis. This study was to evaluate the efficacy and adverse events of adalimumab compared with placebo in inducing remission of Ulcerative colitis. METHODS: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, OVID, BIOSIS, CNKI, and Google were searched. All randomized trials comparing adalimumab with placebo in inducing remission of moderate-to-severe ulcerative colitis were included. RESULTS: Two randomized controlled trials with a total of 754 participants met the inclusion criteria. The pooled risk ratio (RR) of clinical remission was 1.85 (95% confidence interval (CI) 1.26 to 2.72) following adalimumab treatment. RR of clinical response was 1.40 (95% CI 1.19 to 1.65) while that of mucosal healing was 1.23 (95% CI 1.03 to 1.47). RR of any adverse events was 1.00 (95% CI 0.93 to 1.09). CONCLUSION: Compared with placebo, administration of adalimumab may increase the proportion of patients with moderate-to-severe ulcerative colitis attaining clinical remission, clinical response and mucosal healing. Adalimumab is also tolerated well in these patients. PMID- 25784978 TI - Laparoscopic vs. laparoscopically assisted management of Meckel's diverticulum in children. AB - To investigate the management of Meckel's diverticulum in children and the feasibility of using laparoscopic and laparoscopically assisted Meckel's diverticulum resection and intestinal anastomosis according to the different subtypes classified laparoscopically. 55 symptomatic Meckel's diverticulum cases were classified into two categories, the simple and the complex types depending on Meckel's diverticulum appearance upon laparoscopic exploration. Forty-one cases of simple Meckel's diverticulum were treated with simple diverticulectomy during laparoscopy, and 14 cases of complicated Meckel's diverticulum were treated with laparoscopically assisted Meckel's diverticulum resection and intestinal anastomosis. The operation time for the laparoscopically assisted was significant longer than laparoscopic-only surgeries [45~123 min (54.57 +/- 20.17min) vs 29~78min (38.85 +/- 9.75 min)], P = 0.013. Among the 55 cases, Just one child with simple type MD during laparoscopic exploration, and presented a diverticulum with a base that was considered to be in the mesangial margin. The remaining 54 patients were cured, and follow-up for 4~36 months revealed that they did not present abdominal pain, and no hematochezia occurred as a complication. Surgery selection either laparoscopy only or transumbilical laparoscopically assisted intestinal resection and intestinal anastomosis by laparoscopic exploration for Meckel's diverticulum treatment, based on the type of Meckel's diverticulum in children, is safe, feasible, and effective. PMID- 25784979 TI - Arthroscopic transtendinous repair of articular-sided pasta (partial articular supraspinatus tendon avulsion) injury. AB - OBJECTIVE: To evaluate clinical efficacy of arthroscopic transtendinous repair of partial articular-sided PASTA (partial articular supraspinatus tendon avulsion) injury. METHODS: From February 2011 to July 2014, 12 cases of PASTA, aged 29 to 72 years with an average of 52.9 +/- 13.3 years, were treated arthoscopically. To repair PASTA, articular-sided rotator cuff tear was explored, injury site was punctured and labeled with PDS absorbable monofilament suture (Ethicon, Somerville, NJ, USA) suture, subacromial bursa was cleaned up with acromioplasty, and integrity of bursa-side rotator cuff was assessed. Then with arthroscope in glenohumeral joint, footprint of the bursa-side supraspinatus tendon was preserved, rivets were introduced into the joint through supraspinatus tendon, joint-side partial tear was sutured, and anatomical reconstruction of the rotator cuff footprint was established. The patients were followed up post-operatively for 12-36 months, average 22 +/- 7.3 months. The clinical outcomes were emulated with ASES (American Shoulder and Elbow Surgeons) Shoulder Score system and UCLA (University of California at Los Angeles) Shoulder rating scale. RESULTS: The post-operative ASES score was 89.7 +/- 5.6, higher than the pre-operative one 49.8 +/- 9.8 (t = 12.25, P <0.0001). While UCLA scale increased from the pre operative 17.3, +/- 3.3 to the post-operative 30.4 +/- 3.2 points (t = 9.87, P <0.0001), with a satisfaction rate of 11/12 (91.7%). CONCLUSION: Trans-tendon repair is ideal for PASTA with advantage of maximal preservation of the normal rotator cuff tissue, anatomical reconstruction of the rotator cuff footprint and stable fixation of tendon-bone interface. PMID- 25784980 TI - Salvianolate lyophilized injection promotes post-stroke functional recovery via the activation of VEGF and BDNF-TrkB-CREB signaling pathway. AB - Reports show that, while the mechanism remains unknown, salvianolate lyophilized injection (SLI) improves functional recovery after stroke in diabetic rats. In this study, we investigated the mechanism and effect of SLI on stroke outcome in type 1 diabetic (T1DM) rats. T1DM were induced in adult male Wistar rats by injecting streptozotocin. T1DM rats were then subjected to 90 minutes of middle cerebral artery occlusion (MCAO). SLI (10.5, 21, 42 mg/kg, respectively) was administered by tail vein injection at 24 hours after MCAO, and dayly and last for 14 days. The neurological deficit score and brain infarct volume were assessed after 14 days. Also, VEGF, BDNF, TrkB, CREB and p-CREB levels in the ischemic brain tissue were analyzed with western blot at 14 days after MCAO. SLI significantly reduced neurological deficit scores and cerebral infarct volume, and reduced lesion volumes at all time points. SLI also increased the expression of VEGF, BDNF, TrkB, CREB and p-CREB protein levels in T1DM-MCAO rats. In summary, our results demonstrate that SLI can improve functional recovery after stroke in diabetic rats, and the mechanism of treating cerebral ischemic injury is related to the activation of the VEGF, BDNF-TrkB-CREB signaling pathway. PMID- 25784981 TI - Conventional ultrasound and contrast-enhanced ultrasound in evaluating the severity of Crohn's disease. AB - OBJECTIVE: To evaluate the value of conventional ultrasound and contrast-enhanced ultrasound (CEUS) in determining the severity of active Crohn's disease. METHODS: Thirty-seven patients who were considered to be in active period of Crohn's disease were included. Conventional ultrasound was employed to measure the thicknesses of interior, exterior and the whole bowel walls. Qualitative and quantitative CEUS analysis of the interior, exterior and the whole intestinal walls were also performed. Correlations between these methods and the severity of Crohn's disease were assessed. RESULTS: Endoscopy grading system identified 19 patients with mild disease and 18 with severe disease. In discriminating severe Crohn's disease from mild disease, the cut-off value for the thickness of the entire bowel wall was 6.8 mm by receiver operating characteristic (ROC) analysis, with area under ROC (AUROC) of 0.84, sensitivity of 94.4%, specificity of 68.4%, positive predictive value (PPV) of 61.1%, negative predictive value (NPV) of 69.2%, and Youden's index of 0.628. The cut-off value for thickness of the interior intestinal wall was 4.8 mm (AUROC, 0.81; sensitivity, 88.9%; specificity, 63.2%; PPV, 85.7%; NPV, 69.6%; Youden's index, 0.521). The sensitivity, specificity, PPV, NPV, accuracy, and Youden's index of CEUS qualitative analysis were 100% (18/18), 57.9% (11/19), 64.3% (18/26), 100% (11/11), 78.4% (29/37), and 0.579, respectively. Quantitative comparison revealed that patients with mild disease and those with severe disease differed only in Imax of inner bowel wall enhancement (2746.9 +/- 911 vs. 12814.5 +/- 9802.4; P = 0.02) and Imax of entire wall enhancement (2106 +/- 660 vs. 9864 +/- 6994; P = 0.03). The cut-off value for the Imax of the entire bowel wall was 3067, with the AUROC of 0.96, sensitivity of 100%, specificity of 67.7%, PPV of 100%, NPV of 88.9%, and Youden's index of 0.677; and the cut-off value for the Imax of the interior intestinal layer was 3356, with the AUROC of 1.00, sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and Youden's index of 1.0. CONCLUSIONS: Both conventional ultrasound and CEUS are reliable methods in determining the severity of active Crohn's disease. The diagnostic performance in terms of Youden's index was highest for the Imax of the interior layer, in comparison with all other features on conventional ultrasound, qualitative CEUS, and quantitative CEUS. PMID- 25784982 TI - Bone augmentation in rabbit tibia using microfixed cobalt-chromium membranes with whole blood, tricalcium phosphate and bone marrow cells. AB - To assess bone augmentation based on a non-critical defect, 1.5 mm deep cobalt chromium (Co-Cr) barrier membranes were placed on seven adult California rabbits with three different grafting situations: whole blood, whole blood with tricalcium phosphate (TCP), and TCP mixed with bone marrow cells. Macroscopic assessment of the animals was performed once a week and densitometric studies were performed once a month. Three months post-surgery, after detaching the membranes, tibias were sectioned and followed the routine laboratory processing for decalcified sections, with inclusion in paraffin and staining by hematoxylin and eosin technique. Bone augmentation was observed for each animal, even sometimes over the Co-Cr membranes. Compact bone was mostly observed for every situation, with a higher cellular activity on those samples with bone grafts. This could be due to the presence of graft remains at the growth area. It could be concluded that blood supply to the site providing growth factors by the blood clot formation, and the placement of an osteoconductive non-resolvable membrane that favors osseoinduction, may be sufficient elements to achieve bone augmentation in a period of three months in rabbit tibia. PMID- 25784983 TI - XRCC1 genetic polymorphisms and sensitivity to platinum-based drugs in non-small cell lung cancer: an update meta-analysis based on 4708 subjects. AB - OBJECTIVE: To evaluate the correlation between genetic polymorphisms in x-ray repair cross complementing group 1 (XRCC1) and sensitivity to platinum-based chemotherapy drugs in patients with non-small cell lung cancer. METHODS: Reports published before June 2014 were retrieved from the following databases: China Biology Medicine (CBM), China Academic Journal Full-Text Database (CNKI), China Science and Technology Journal Full-Text Database (VIP), Wanfang Data, PubMed and Excerpta Medica dataBASE (EMBASE). After extracting the data and evaluating the quality, meta-analysis was performed using RevMan5.2 software. RESULTS: A total of 29 studies with 4807 patients were included. Two polymorphisms (Arg399Gln and Arg194Trp) were analyzed. Meta-analysis showed that the efficacy of chemotherapy for patients with the TT genotype [TT vs. CC, OR=1.66, 95% OR=1.66, 95 CI (1.30 2.14)] and the CT genotype [CT vs. CC, OR=1.62, 95% CI (1.35-1.93)] at codon 194 of the XRCC1 gene was significantly higher than that for patients with the CC genotype. The efficacy of chemotherapy for patients with mutant (CT+TT) genotypes was significantly higher than for patients with the wild-type (CC) genotype [TT+CT vs. CC, OR=1.63; 95% CI (1.38-1.92)]. The sensitivity to chemotherapy in patients with the AG genotype at codon 399 of the XRCC1 gene was lower than in patients with the GG genotype [AG vs. GG, OR=0.72, 95% CI (0.55-0.92)] in Chinese population. However, we did not found this association in Caucasus population. CONCLUSION: Genetic polymorphisms in the XRCC1 gene are correlated with sensitivity to platinum-based chemotherapy in patients with non-small cell lung cancer. PMID- 25784984 TI - Minimally invasive image-guided keyhole aspiration of cerebral abscesses. AB - Despite the low incidence of brain abscesses in Western nations (1-2%), the incidence in developing countries is as high as 8%. We evaluate a minimally invasive image-guided keyhole aspiration of cerebral abscesses and compare it with a series of cases treated with surgical excision. 23 patients (20 male and 3 female, aged 7-67 years) underwent image-guided burr hole aspiration of single or multiple cerebral abscesses. Patient characteristics, perioperative, and postoperative data were analyzed and compared with a second group of 22 patients (14 male and 8 female, aged 12-72) treated for cerebral abscesses with open surgical excision. In all cases, the surgical procedure was performed successfully without complication. 8 of the 23 aspiration cases were performed with the aid of iMRI. A comparison of patient demographics, duration of hospital stay, duration of antibiotic therapy, postoperative neurological recovery time, intraoperative blood loss, operative duration, length of incision, postoperative fever, repeat surgery, and mortality was performed between the aspiration and excision groups. Intraoperative blood loss, operative duration, length of incision, and postoperative fever were all significantly reduced in the aspiration group. Though, duration of hospital stay and antibiotic therapy and postoperative neurological recovery time were all increased in the aspiration group, and statistical significance was observed in all except the duration of hospital stay. This technique is a feasible and comparable minimally invasive alternative to open surgical excision and may provide reduced intraoperative blood loss, shortened operative duration, improved cosmetic outcomes, and a lessened incidence of postoperative fever. PMID- 25784985 TI - Functional characterization of OPN in human laryngeal squamous cell carcinoma and its xenograft model in nude mice. AB - BACKGROUND: Osteopontin (OPN) is involved in promotion of cancer cells by regulating various facets of tumor progression such as cell proliferation, angiogenesis and metastasis. To understand the role of OPN in laryngeal squamous cell carcinoma (LSCC), we thus explored the biological function of OPN in LSCC after silencing OPN expression by RNA interference (RNAi). METHOD: The OPN expression in tumor tissues of LSCC was determined immunohistochemically in both LSCC and adjacent normal tissues. Lentivirus vector with RNAi small hairpin gene sequence of OPN (named LV-shOPN) was transfected into Hep-2 cells and transplanted into BALB/c-nu mice. After siRNA transfection, the viability of Hep 2 cells was examined by MTS, OPN expression was detected by Western blotting, and tumor angiogenesis was assessed by microvessel densities (MVD). RESULTS: The difference of positive rate of OPN in 72 cases LSCC (54 cases, 75.0%) and adjacent normal tissues (15 cases, 20.8%) was statistically significant (P<0.001) and the OPN expression was also significantly correlated with tumor stage, grade and the presence of lymph node. Hep-2 cells infected with LV-shOPN significantly decreased OPN expression, in comparison to cells with LV-shNon transfection (as the control) (P<0.05). The constructed LV-shOPN effectively inhibited the viability of Hep-2 cell and growth of xenograft tumors in nude mice (all P<0.050). The expression of OPN and MVD was significantly decreased in xenograft tumors (all P<0.05). CONCLUSION: RNAi silencing of OPN expression can significantly inhibit tumor growth and angiogenesis of Hep-2 cells, and OPN may be considered as one of gene targeting therapy for LSCC. PMID- 25784986 TI - A study of high cell density cultivation process of recombinant Helicobacter pylori multi-epitope vaccine engineering bacteria. AB - OBJECTIVE: To establish high cell density cultivation process of recombinant Helicobacter pylori multi-epitope vaccine engineering bacteria BIB. METHODS: Based on the results of shake flask fermentation, the process was magnified into volume of a 50 L fermenter to optimize and verify the factors affecting the yield of the target protein, such as the fermentation medium, working seed inoculation amount, inducer concentration, induction starting time, induction duration, inducer adding mode and feeding strategy. RESULTS: After activated in modified TB medium at 37 degrees C for 8 h, the BIB working seed was inoculated at 5% (v/v) and was induced for expression for another 11 h by the final concentration of 5 mmol/L lactose. In growth phase, glucose at rate of 80 ml/h was used as carbon source, and in induction phase, glycerol at rate of 40 ml/h was used as carbon source; ammonia water was added dropwise to control pH at about 7.0, and revolution speed is adjusted to control the dissolved oxygen at above 30%; ultimately the output of bacterial body was 70 g/L and protein expression amount was about 32%. CONCLUSION: After high cell density cultivation of the recombinant engineering bacteria, expression and yield of the target protein rBIB significantly increased. PMID- 25784987 TI - Using acetabular fossa as a guide for anticipated inclination of uncemented cup in total hip replacement. AB - Positions of acetabular implant generally are considered to be major causative factors of dislocation. Accurate and consistent achievement of the preoperatively anticipated orientation of the acetabular cup is a great challenge in total hip replacement (THR). In the present study, we investigated the surgical application of acetabular fossa as a guide for anticipated inclination of uncemented cup, and evaluated its accuracy as an anatomic reference for achieving the preoperatively anticipated abduction of the acetabular cup in comparison with traditional device method on cadaveric specimens. Sixteen normal adult pelvic cadaveric specimens were collected. On each of the sixteen normal adult pelvic cadaveric specimens, acetabular fossa related anatomic sites were marked and studied on pelvic radiographs. Our results showed that there is close correlation between most medial aspect of acetabular sourcil and central axis of the acetabular cup at anticipated inclination of 40 degrees +/- 5 degrees . And the fossa group can achieve the preoperatively anticipated cup abduction more accurately than the device group. The current results demonstrated that acetabular fossa can be a reasonable alternative, or as a complement to the currently used methods guiding total hip replacement. PMID- 25784988 TI - Activation of protein kinase C epsilon enhanced movement ability and paracrine function of rat bone marrow mesenchymal stem cells partly at least independent of SDF-1/CXCR4 axis and PI3K/AKT pathway. AB - OBJECTS: to probe into the effects of PKCepsilon on migration and paracrine functions of stem cells and potential molecular mechanisms. METHODS: Bone Marrow mesenchymal stem cells (BMMSCs) were obtained from rat femur and passaged. mRNA and protein levels of capital proteins in PKCepsilon signaling, SDF-1/CXCR4 axis and PI3K/AKT pathway in the MSCs in different conditions treating with PKC agonist, specific PKCepsilon inhibitor, CXCR4 antagonist or PI3K inhibitor for 24 hours were analyzed by real-time PCR and western blot, and migration abilities were observed by migration assay in vitro and the changes of paracrine factors in different treatments were analyzed by protein clips assay. RESULTS: the levels of p-JNK, p-P38MAPK, SDF-1, CXCR4, PI3K and p-AKT increased significantly after treating with PKC agonist (P < 0.05) and decreased obviously after treating with specific PKCepsilon inhibitor. Migration ability and paracrine function of MSCs were enhanced in PMA group and attenuated in PKCepsilon inhibitor group, and inhibiting activity of CXCR4 or PI3K attenuated the effects of PKCepsilon, but not abolished completely. CONCLUSION: There was cross-talking between PKCepsilon signaling and SDF-1/CXCR4 axis and PI3K/AKT pathway in signal transduction of MSCs. Activating PKCepsilon could improve migration ability and paracrine function of MSCs partly at least independent of SDF-1/CXCR4 axis and PI3K/AKT pathway. PMID- 25784989 TI - TET1-mediated different transcriptional regulation in prostate cancer. AB - The recent studies demonstrated that the global 5-hydroxymethylcytosine (5 hmC) level decreased in prostate cancer (PCa) involved the 5-methylcytosine (5 mC) hydroxymethylase, Ten-eleven translocation (TET)1 reduction. 5 hmC and TET1 were both revealed a dual function in bivalent domain associated with developmental regulators in embryonic stem cell model. However, the mechanism underlying the DNA methylation and hydroxymethylation change mediated by TET1 downregulation in PCa remains unclear. Herein, using BSP to assess the 5 mC level in promoters of ten specific marker gene in PCa, our results present that Cdh1, Gstp1, Pten, Apc, Runx3 and Mgmt are observed to be hypermethylated in promoters and lower expression while Cyr61, Sema3c and Ptgs2 are reversed patterns compared to the normal prostate tissues. Furthermore, using ChIP methods to investigate the H3K4me3 and H3K27me3 patterns in promoters, these four markers are all demonstrated to be associated with Polycomb-repressed characterization and upregulated in response to TET1/PRC2 reduction in PCa. Thus, our findings reveal a distinct activating and repressive function of TET1-mediated transcriptional regulation in prostate cancer. PMID- 25784990 TI - Extrafine HFA-beclomethasone dipropionate versus budesonide for asthma: a meta analysis. AB - The small-particle inhaled corticosteroid might be a new available way to treat uncontrolled asthma. To evaluate the efficacy and safety of extrafine hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) versus budesonide (BUD) in patients with asthma, a meta-analysis was performed. A systematic search was made of PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Clinicaltrials.gov and Ovid, and a hand search of leading respiratory journals. Randomised controlled trials (RCTs) on treatment of asthma for 4 or more weeks with extrafine HFA-BDP, compared with BUD, were reviewed. Five studies involving 949 asthmatic patients met the inclusion criteria. There was no significant difference in FEV1 (SMD=-0.03L, 95% CI -0.15 to 0.10L, I(2)=0%, P=0.70), morning PEF (WMD=0.88 L/min, 95% CI -5.96 to 7.72 L/min, I(2)=0%, P=0.80), evening PEF (WMD=6.32 L/min, 95% CI -1.17 to 13.81 L/min, I(2)=33%, P=0.10) and use of rescue medication (WMD=-0.13, 95% CI -0.31 to 0.06, I(2)=41%, P=0.18) between extrafine HFA-BDP at half of the daily dose and BUD group. Individual studies reported no significant differences in asthma exacerbations and 7-point Asthma Control Questionnaire score (ACQ-7). There were no significant difference in total number of adverse events (OR=1.04, 95% CI 0.78 to 1.38, I(2)=0%, P=0.81) between the two groups. Our meta-analysis demonstrated that extrafine HFA-BDP at half of daily dose is equivalent to BUD in improving lung function and use of rescue medication, without increasing adverse events in patients with asthma. Long-term trials are required to assess the efficacy and safety of extrafine HFA-BDP. PMID- 25784991 TI - In vitro evaluation of rhBMP-2-induced expression of VEGF in human adipose derived stromal cells. AB - Bone Morphogenetic Protein 2 (BMP-2) plays a key role in skeletal development, repair and regeneration. Our previous studies indicate that recombinant human BMP 2 (rhBMP-2) can stimulate osteogenic differentiation and promote angiogenesis through the up-regulation of Vascular Endothelial Growth Factor (VEGF), while the underlying mechanism of the BMP-2 effect on human cells is not well understood. To gain a better understanding of BMP-2-induced angiogenesis, we further characterized the effect of rhBMP-2 on VEGF expression in human adipose-derived stromal cells (hASCs) by RT-PCR and ELISA. VEGF expression was induced by rhBMP-2 in a dose- and time-dependent manner, with the highest induction observed using 100 ng/ml of rhBMP-2 at 18-24 h post stimulation. In addition, Western blot analyses revealed that the phosphorylation of p38 was closely related to the expression of VEGF, and blocking the p38MAPK pathway with the specific inhibitor sb203580 resulted in the decreased VEGF expression. Our data suggest that p38 activation may be required for rhBMP-2-induced VEGF expression and angiogenesis. Information derived from this study may shed light on understanding the effect of rhBMP-2 in the angiogenesis of hASCs, which is important for designing new strategies to increase the angiogenesis of tissue engineering bone. PMID- 25784992 TI - Effects of alpha-enolase (ENO1) over-expression on malignant biological behaviors of AGS cells. AB - OBJECTIVE: To investigate the effects of alpha-Enolase (ENO1) over-expression on the proliferative and migratory abilities of AGS cells. METHODS: The target gene was cloned and mounted to the eukaryotic expression vector pcDNA3.1(+), then was transfected into gastric cancer cell lines AGS. mRNA and protein level of ENO1 in AGS cells were verified by real-time quantitative RT-PCR and Western Blot, respectively. The effects of over-expression of ENO1 on proliferative and migratory abilities of AGS cells were detected by the experiments of CCK-8, colony formation and wound healing assays. RESULTS: The eukaryotic expression vector pcDNA3.1(+)/eno1 was successfully constructed, and verified by sequencing. It was shown from the cell proliferation curves that the proliferative ability of AGS-ENO1 transfected group was higher than that of the control group after 72 hours (t = 3.44, P = 0.04), meanwhile, the number of the cell-colonies of the AGS ENO1 group were significantly greater than that of the control group (t = 5.26, P = 0.01). For the ability of migration, it was significantly enhanced in the over expression ENO1 cells than in the negative cells (t = 7.35, P < 0.001). CONCLUSION: The over-expression of ENO1 protein can enhance the abilities of proliferation and migration in gastric cancer cells of AGS, which indicates that ENO1 may be an important potential tumor-marker associated with the development of gastric cancer. PMID- 25784993 TI - Electrophysiological characteristics of paroxysmal atrial fibrillation originating from superior vena cava: a clinical analysis of 30 cases. AB - To analyze characteristics of electrocardiogram (ECG), electrophysiological intracardiac mapping and radiofrequency ablation (RF) of paroxysmal atrial fibrillation (PAF) originating from superior vena cava (SVC), aiming to investigate electrophysiological characteristics of PAF with SVC origin. Clinical data of 30 subjects (18 men and 12 women, aged, 58.6 +/- 15.5 years) with PAF of SVC origin were retrospectively analyzed; All patients underwent RF during 2006.9 2012.7. ECG of AF and atrial premature contractions (APCs), procedure and fluoroscopic time, numbers of ablation sites within SVC, complications and success rate were studied. Compared with P wave of sinus rhythm (SR), APCs of SVC origin exhibited higher amplitude in lead II (0.23 +/- 0.11 vs. 0.15 +/- 0.06 mv), III (0.19 +/- 0.09 vs. 0.13 +/- 0.08 mv), AVF (0.21 +/- 0.13 vs. 0.14 +/- 0.10 mv), V2 (0.24 +/- 0.07 vs. 0.15 +/- 0.09 mv) and V3 (0.21 +/- 0.09 vs. 0.12 +/- 0.05 mv) (P < 0.05), as well as more biphasic polarity in lead V1 (80.0% vs. 26.6%, P < 0.05) and isoelectric in AVL (60.0% vs. 6.7%, P < 0.05). In terms of left pulmonary vein (LPV) and right pulmonary vein (RPV) electrical isolation, procedure time (14.3 +/- 11.5 vs. 33.7 +/- 14.2, 28.1 +/- 6.8 min, P < 0.05), fluoroscopic time (9.6 +/- 3.8 vs. 21.1 +/- 9.3, 19.4 +/- 9.7 min, P < 0.05), ablation sites (11.2 +/- 3.1 vs. 37.1 +/- 13.7, 31.4 +/- 10.4 points, P < 0.05) of SVC isolation (SVCI) remarkably decreased compared with that of mean LPV and RPV. After the procedure, 9 patients still presented paroxymal rapid firing within the SVC in the setting of SR restoration, 2 patients developed paroxysmal atrial flutter within 1 month after completion of ablation and were controlled by antiarrhythmic drugs. The APCs and AF of SVC origin manifested distinctive ECG features, which could be helpful to distinguish SVC from other foci before ablation, the completion of SVCI required shorter procedure and fluoroscopic time, as well as less ablation points, and meanwhile, the success rate was high with less complication. PMID- 25784994 TI - Microelectrode array measurement of potassium ion channel remodeling on the field action potential duration in rapid atrial pacing rabbits model. AB - BACKGROUND: Atrial fibrillation (AF) arises from abnormalities in atrial structure and electrical activity. Microelectrode arrays (MEA) is a real-time, nondestructive measurement of the resting and action potential signal, from myocardial cells, to the peripheral circuit of electrophysiological activity. This study examined the field action potential duration (fAPD) of the right atrial appendage (RAA) by MEA in rapid atrial pacing (RAP) in the right atrium of rabbits. In addition, this study also investigated the effect of potassium ion channel blockers on fAPD. METHODS: 40 New Zealand white rabbits of either sex were randomly divided into 3 groups: 1) the control, 2) potassium ion channel blocker (TEA, 4-Ap and BaCl2), and 3) amiodarone groups. The hearts were quickly removed and right atrial appendage sectioned (slice thickness 500 MUm). Each slice was perfused with Tyrode's solution and continuously stimulated for 30 minutes. Sections from the control group were superfused with Tyrode's solution for 10 minutes, while the blocker groups and amiodarone were both treated with their respective compounds for 10 minutes each. The fAPD of RAA and action field action potential morphology were measured using MEA. RESULTS: In non-pace (control) groups, fAPD was 188.33 +/- 18.29 ms after Tyrode's solution superfusion, and 173.91 +/- 6.83 ms after RAP. In pace/potassium ion channel groups, TEA and BaCl2 superfusion prolonged atrial field action potential (fAPD) (control vs blocker: 176.67 +/- 8.66 ms vs 196.11 +/- 10.76 ms, 182.22 +/- 12.87 ms vs 191.11 +/- 13.09 ms with TEA and BaCl2 superfusion, respectively, P < 0.05). 4-AP superfusion significantly prolonged FAPD. In pace/amiodarone groups, 4-Ap superfusion extended fAPD. CONCLUSIONS: MEA was a sensitive and stable reporter for the measurement of the tissue action potential in animal heart slices. After superfusing potassium ion channel blockers, fAPD was prolonged. These results suggest that Ito, IKur and IK1 remodel and mediate RAP-induced atrial electrical remodeling. Amiodarone alter potassium ion channel activity (Ito, IKur, IK1 and IKs), shortening fAPD. PMID- 25784995 TI - Osteogenesis of bone marrow mesenchymal stem cells on strontium-substituted nano hydroxyapatite coated roughened titanium surfaces. AB - OBJECTIVE: To investigate osteogenesis of bone marrow mesenchymal stem cells (BMSCs) on strontium-substituted nano-hydroxyapatite (Sr-HA) coated roughened titanium surfaces. METHODS: Sr-HA coating and HA coating were fabricated on roughened titanium surfaces by electrochemical deposition technique and characterized by field emission scanning electron microscope (FESM). BMSCs were cultured on Sr-HA coating, HA coating and roughened titanium surfaces respectively. Cell proliferation, alkaline phosphatase (ALP) activity, mineralized nodules formation and cell osteocalcin (OC) secretion were measured. RESULTS: Electrochemically deposited Sr-HA coating and HA coating had no effect on the proliferation of BMSCs and demonstrated that the materials have a good biocompatibility. BMSCs cultured on Sr-HA coating showed increased alkaline phosphatase activity, mineralized nodules formation, and cell OC secretion compared with the other two groups. Cells cultured on HA coating also showed increased biological activity compared with the roughened group. CONCLUSION: Sr HA coated titanium surfaces by electrochemical deposition can promote osteogenesis of BMSCs in vitro and have the potential to shorten bone healing period and enhance implant osseointegration. PMID- 25784996 TI - ABCB1 (rs1128503) polymorphism and response to chemotherapy in patients with malignant tumors-evidences from a meta-analysis. AB - Numerous papers have reported ABCB1 polymorphisms are associated with the response to chemotherapy of cancers. The inconclusive results call for a comprehensive analysis, for the sample size of the published studies is comparatively small. Therefore, a comprehensive meta-analysis was performed on the basis of the published studies for an accurate estimation of such association. Altogether 8 comparative studies including 2463 cancer patients were involved in our meta-analyses. ABCB1 C1236T (rs1128503) polymorphism was shown to be associated with tumor response to chemotherapy in cancer patients under the dominant model (OR=1.72, 95% CI=1.09-2.73, P=0.177, I(2)=36.60%) and additive model (OR=1.99, 95% CI=1.39-2.85, P=0.222, I(2)=25.90%). A subgroup meta-analysis indicated a significant association under dominant model between ABCB1 C1236T (rs1128503) polymorphism and breast cancer in the Asians (OR=2.15, 95% CI=1.22 3.77, P=0.210, I(2)=33.70%). These results suggest that ABCB1 C1236T (rs1128503) might contribute to the tumor response to chemotherapy in cancers from the Asians, especially in the osteosarcoma and breast cancer. PMID- 25784997 TI - Ultrasound-guided technology versus neurostimulation for sciatic nerver block: a meta-analysis. AB - BACKGROUND: Sciatic nerve block is widely used for anesthesia and analgesia in lower limb surgery, traditional method used for sciatic nerve block is nerve stimulation guidance. Whether the use of ultrasound-guided technology can increases the success rate of sciatic nerve block and provide other benefits are not defined. This meta-analysis was aimed to clarify this issue. METHOD: We searched Pubmed, the Cochrane library and Google Scholar. A total of 10 RCTs met our inclusion criteria. The patients included underwent ultrasound-guided or nerve stimulation guidance for sciatic nerve block. We compared the success rate, vascular puncture, the time of procedure and Success rate of catheter placement. RESULTS: Ultrasound-guided technology, compared with nerve stimulation for sciatic nerve block, provided higher success rate. [RR = 1.22 95% CI: 1.04-1.42, P = 0.01], Ultrasound guidance also reduce the risk of vascular puncture. [RR = 0.13 95% CI: 0.02-0.97, P = 0.05]. However, the success rate of catheter placement [RR = 1.1095% CI: 0.93-1.29, P = 0.27] and the time of performing sciatica never block [RR = -0.17 95% CI: -1.61-1.27, P = 0.82] did not differ significantly. CONCLUSIONS: Compared to traditional nerve stimulation guidance, ultrasound guidance for sciatic nerve may improve the success rate of block and reduce the risk of vascular puncture. PMID- 25784998 TI - Magnesium-enriched hydroxyapatite as bone filler in an ameloblastoma mandibular defect. AB - The aim of this study was to evaluate the clinical performance of a magnesium enriched hydroxyapatite biomaterial used as bone substitute in a case of mandibular ameloblastoma treated with conservative surgery. A 63 year old male patient was treated for an ameloblastoma in the anterior mandibular profile. After tissue excision, the bone defect was filled with a synthetic hydroxyapatite biomaterial enriched with magnesium ions, in order to promote bone tissue regeneration and obtain a good aesthetic result. Twenty-five months after surgery, due to ameloblastoma recurrence in an area adjacent to the previously treated one, the patient underwent to a further surgery. In that occasion the surgeon performed a biopsy in the initially treated area, in order to investigate the nature of the newly-formed tissue and to evaluate the bone regenerative potential of this biomaterial by clinical, radiographic and histological analyses. The clinical, radiographic and histological evaluations showed various characteristics of bone remodeling stage with an ongoing osteogenic formation and a good osteo-integration. In conclusion, magnesium-enriched hydroxyapatite used as bone substitute in a mandibular defect due to ameloblastoma excision showed an effective bone regeneration at 25 months follow-up, demonstrating an excellent biocompatibility and a high osteo-integration property. PMID- 25784999 TI - A sutureless method for digestive tract reconstruction during pancreaticoduodenectomy in a dog model. AB - Development of pancreatic fistulas as a result of anastomotic gaps is still a major complication after pancreaticoduodenectomy, and can cause post-operative death. Therefore, safer and more effective methods of anastomosis are needed to avoid leakage and decrease mortality. MATERIALS AND METHODS: Twenty domestic dogs with body weights ranging from 15 to 25 kg were used, regardless of gender. A model of common bile duct and pancreatic duct dilatation was surgically prepared in these dogs. Pancreaticobiliary stents combined with magnetic anastomoses (PB MA), and controls were treated with fibrin glue were studied in terms of and efficacy by measurement of serum amylase, incidence of complications, and survival times. RESULTS: The mean time required to create the fibrin glue pancreaticoenterostomy was 9 +/- 2.05 min, while the mean time required to create the magnet cholangioenterostomy was 5 +/- 0.9 min. The total operative time was 2.7 +/- 0.6 h. Eighty percent of the dogs that underwent the operations were still alive for 15 days after the operations and none developed pancreatic fistulas. Examination by macroscopic observation, and hematoxylin and eosin staining of the pathological specimens showed that the anastomoses were completed healed. CONCLUSIONS: The use of a PB-MA in sutureless digestive tract reconstruction for pancreatoduodenectomy resulted in an elimination of pancreatic fistulas, and shortening of the stent removed time. In addition, the procedure is simple to perform, fast, and appears to be safe in this dog model. PMID- 25785000 TI - Obstructive sleep apnea/hypopnea syndrome increases glaucoma risk: evidence from a meta-analysis. AB - Associations between Obstructive sleep apnea/hypopnea syndrome (OSAHS) and risk of glaucoma remained controversial. Therefore, we performed this meta-analysis to investigate this association. We searched Pubmed, EMBASE, and Wangfang databases for studies before Oct. 10 2014. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association. A total of 12 studies with 36909 subjects on the association between OSAHS and glaucoma risk were included for this meta-analysis. OSAHS was associated with a significantly increased risk of glaucoma (OR = 1.65; 95% CI, 1.44-1.88; I (2) = 43%). In the race subgroup analysis, both Asians (OR = 1.78; 95% CI, 1.49-2.12; I (2) = 0%) and Caucasians (OR = 2.03; 95% CI, 1.12-3.69; I (2) = 57%) with OSAHS had increased glaucoma risk. In the subgroup analysis according to gender, both women and men were significantly associated with risk of glaucoma (OR = 1.81; 95% CI, 1.27-2.57; I (2) = 22% and OR = 1.62; 95% CI, 1.29-2.03; I (2) = 0%, respectively). In the subgroup analysis by glaucoma type, OSAHS patients showed increased primary open-angle glaucoma (POAG) risk (OR = 1.87; 95% CI, 1.54-2.33; I (2) = 0%) but not normal tension glaucoma (NTG) risk (OR = 3.57; 95% CI, 0.89 14.43; I (2) = 0%). In addition, severe OSAHS patients had an increased glaucoma risk (OR = 5.49; 95% CI, 1.04-33.83; I (2) = 0%), while mild and moderate OSAHS patients did not show significantly increased glaucoma risk. This meta-analysis suggested that the OSAHS may be a risk factor for glaucoma. PMID- 25785001 TI - Biliopancreatic duct injection of ethanol as an experimental model of acute and chronic pancreatitis in rats. AB - In the present study, we described an easily reproducable experimental pancreatits model induced by biliopancreatic duct injection of ethyl alcohol. Seventy Wistar albino rats were divided equally into seven groups randomly: the control group (group 1), acute pancreatitis groups; induced by 20% ethanol (group 2), 48% ethanol (group 3), 80% ethanol (group 4), chronic pancreatitis groups; induced by 20% ethanol (group 5), 48% ethanol (group 6) and by 80% ethanol (group 7). Acute pancreatitis groups were sacrified on postoperative day 3, while the control group and chronic pancreatitis groups were killed on postoperative day 7. Histopathologic evaluation was done, and P < 0.05 was accepted as statistically significant. All rats in group 3 developed acute pancreatitis (100%). Inflammatory infiltration of neutrophils and mononuclear cells, interstitial edema, and focal necrotic areas were seen in the pancreatic tissues. Similarly, all rats in group 6 developed chronic pancreatitis (100%). Interstitial fibrosis, lymphotic infiltration, ductal dilatation, acinar cell atrophy, periductal hyperplasia were seen in the pancreatic tissues. Mortality was seen only in group 7. The biliopancreatic ductal injection of 48% ethanol induced acute and chronic pancreatitis has 100% success rate. PMID- 25785002 TI - Association of three common BARD1 variants with cancer susceptibility: a system review and meta-analysis. AB - BARD1 has been shown to play tumor suppressive roles in human cancer. We performed this meta-analysis and firstly evaluated the association between three common BARD1 polymorphisms (Arg378Ser, Val507Met and Pro24Ser) and cancer susceptibility. We performed this meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, EMBASE, Cochrane Library, OVID and Web of Science databases was done from database inception to August 2014. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between BARD1 polymorphisms and cancer risk. On the basis of 10 studies about BARD1 polymorphisms and cancer, we found that BARD1 Val507Met (G/A) polymorphism was associated with decreased cancer susceptibility (allelic model: OR = 0.76, 95% CI: 0.66-0.87, P < 0.00001; dominant model: OR = 0.77, 95% CI: 0.65-0.91, P < 0.00001; recessive model: OR = 0.64, 95% CI: 0.55-0.74, P < 0.00001; homozygote comparison: OR = 0.58, 95% CI: 0.49-0.70, P < 0.00001; heterozygote comparison: OR = 0.85, 95% CI: 0.74-0.99 , P = 0.0008). BARD1 Pro24Ser (C/T) polymorphism was also associated decreased cancer risk in allelic model (OR = 0.72, 95% CI: 0.60-0.88, P = 0.0009), dominant model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), recessive model (OR = 0.70, 95% CI: 0.56-0.87 , P = 0.004), homozygote comparison (OR = 0.55, 95% CI: 0.39-0.78, P = 0.0007) and heterozygote comparison (OR = 0.75, 95% CI: 0.62-0.91, P = 0.004). And in our sensitivity analysis, when deleting the study performed by Capasso in 2009, we found that BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006). In conclusion, BARD1 Arg378Ser, Val507Met and Pro24Ser may be associated with decreased cancer risk. More studies with larger samples and gene-environment interactions are needed to confirm our findings. PMID- 25785003 TI - Association between nonalcoholic fatty liver disease and colorectal adenoma: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Several existing studies indicated that nonalcoholic fatty liver disease (NAFLD) may be associated with colorectal adenoma, but the results and risk factors are controversial. A systematic review of studies was conducted to explore these issues by meta-analysis. METHODS: We searched the Pubmed, Embase, Cochrane library, Medline and Web of Science databases for studies published before May 30(th), 2014. A statistical analysis was performed using RevMan 5.2 software. RESULTS: Seven studies involving 11,905 participants from different regions were included. Among them, five trials carried out subgroup of NAFLD patients in colorectal adenoma population. The result showed NAFLD was significantly correlated with adenoma of colon (Odds ratio [OR] = 1.56, 95% confidence interval [CI]: 1.22-1.99, P = 0.0003). It could be found in stratified analysis that patients had more chance to get multiple adenomas when they suffered NAFLD (Rate ratio [RR]: 1.52, 95% CI: 1.08-2.13, P = 0.02). Such risk factors of NAFLD as age, waist circumference, body mass index (BMI), disorder of lipid metabolism, hyperglycemia and high blood pressure (HBP) increased risk of colorectal adenoma (Age: mean difference [MD]: 2.81, 95% CI: 0.33-5.28; Waist: MD: 2.84, 95% CI: 2.14-3.54; BMI: MD: 0.85, 95% CI: 0.69-1.01; High-density lipoprotein: MD: -2.46, 95% CI: -3.68 to -1.24; Triglyceride: MD: 16.12, 95% CI: 8.89-23.36; Low-density lipoprotein: MD: 6.04, 95% CI: 3.60-8.48; Cholesterol: MD: 4.25, 95% CI: 0.87-7.63; Fasting glucose: MD: 2.27, 95% CI: 1.24-3.30; HBP: OR = 1.51, 95% CI: 1.22-1.88), while diabetes had no significant association with it (OR = 1.43, 95% CI: 0.94-2.17, P = 0.09). Besides, NAFLD didn't affect the location, size and advanced type of colorectal adenoma (P > 0.05). CONCLUSION: The present systematic review and meta-analysis demonstrated NAFLD was closely associated with great risk of colorectal adenoma and its number, but not with its location, size and advanced type. Waist, obesity, lipid profiles, glucose, hypertension played roles in the process of colorectal adenoma. PMID- 25785004 TI - The efficacy and safety of adding bevacizumab to cetuximab- or panitumumab-based therapy in the treatment of patients with metastatic colorectal cancer (mCRC): a meta-analysis from randomized control trials. AB - OBJECTIVE: To estimate the efficacy and safety of adding bevacizumab to cetuximab or panitumumab-based therapy in the treatment of patients with metastatic colorectal cancer (mCRC), using a meta-analysis of randomized controlled trials. METHODS: A literature search for randomized clinical trials (RCTs) was performed through Pubmed, Embase, and Web of Science (up to May 22, 2014). The outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events. Two investigators identified eligible studies and extracted data independently. The quality of the included studies was assessed by the Jadad score. Hazard ratios (HR), risk ratio (RR), and 95% confidence intervals (Cls) were calculated and pooled. RESULTS: A total of 4 RCTs with 2069 patients were included in this meta-analysis. The addition of bevacizumab to cetuximab- or panitumumab-based therapy did not significantly prolonged PFS, when compared with antibody alone. The subgroup analysis of adding bevacizumab to cetuximab-based therapy also suggested no significant benefit in PFS or in OS. Patients who received the combined therapy did not have a higher ORR (RR = 0.98, 95% CI: 0.89-1.07; P = 0.608). The incidence of grade 3/4 adverse events was not significantly higher in the bevacizumab and cetuximab/panitumumab group. CONCLUSION: The addition of bevacizumab to cetuximab- or panitumumab-based therapy did not improve PFS and OS resulting in better ORR. Thus, the combined therapy of bevacizumab with cetuximab or panitumumab is not recommended for the treatment of mCRC. However, larger scale RCTs are needed to confirm these findings. PMID- 25785005 TI - Histopathological alterations during breast carcinogenesis in a rat model induced by 7,12-Dimethylbenz (a) anthracene and estrogen-progestogen combinations. AB - Studies have shown that the development of breast cancer (BC) is a multi-step process that occurs sequentially from normal to usual hyperplasia, atypical hyperplasia, carcinoma in situ, and finally the invasive stages of carcinoma. Our study investigated the histopathological alterations in breast tissue in a Sprague-Dawley (SD) rat model induced by 7,12-Dimethylbenz (a) anthracene (DMBA) and estrogen-progestogen (E-P). Fifty rats were randomly divided into five groups (n = 10 each) and administered the E-P/DMBA combination. After the induction of BC, breast tissue samples were obtained from the rats and stained with hematoxylin-eosin (HE). Breast tissues from 10 rats and 10 human patients were obtained for comparison. The expression of P63, CK5/6 and CK34betaE12 was observed and analyzed using the SPSS 17.0 software. The HE results showed ductal epithelial hyperplasia with forming a second lumen or papillary structure, atypical hyperplasia with atypical proliferative cells, forming a cross-bridge or cribriform structure in breast tissues from the rats samples. The IHC results showed that the expression of P63 was not significantly different between rat and human breast tissue (P > 0.05), but its expression in rat and human tissue was significantly different between UDH, ADH, DCIS and IDC (P < 0.01). A similar trend was observed for the expression of CK5/6 and CK34betaE12 too. Thus, the findings in this model may reflect the histopathological changes that occur during the progression of human BC. Therefore, this model could be used for the establishment of BC models to investigate the prevention and treatment of BC. PMID- 25785006 TI - Alpha-lipoic acid attenuates trinitrobenzene sulfonic acid-induced ulcerative colitis in mice. AB - Ulcerative colitis (UC), characterized by inflammation, oxidative stress, and increased intestinal epithelial cell apoptosis, is an immunologically mediated chronic intestinal disorder. The present study was aimed at investigating the protective effects of alpha-lipoic acid (ALA) against trinitrobenzene sulfonic acid (TNBS)-induced UC and the underlying mechanism. ALA of 80 mg/kg bw/day was administered by gastric gavage to mice for 7 days after TNBS-induced UC. Our data indicated that ALA effectively facilitated recovery of pathologic changes in the colon, as evidenced by a significant increase of body weight, decrease of colon mass index and histopathological score. Furthermore, ALA significantly inhibited TNBS-induced apoptosis, which partly due to up-regulation of Bcl-2 expression, reduction of Bax expression and caspase-3, caspase-9 activity. ALA reduced malondialdehyde (MDA), nitric oxide (NO), and inducible nitric oxide synthase (iNOS) levels, and restored superoxide dismutase (SOD) activity and glutathione (GSH) content in colon tissues from TNBS-challenged mice. Additionally, phosphorylation of extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase (p38) in colon tissues were significantly inhibited by ALA treatment. In summary, we demonstrate that ALA has protective properties against TNBS-induced UC through anti-apoptosis, anti-oxidant actions, and mitogen activated protein kinase (MAPK) signaling pathway. Our present findings suggest a therapeutic potential of ALA in UC. PMID- 25785007 TI - Effect of saphenous nerve block for postoperative pain on knee surgery: a meta analysis. AB - Early post-operative mobilization is important both to reduce immobility-related complications and to get the best functional result following surgery on knee. We hypothesized that saphenous nerve block would reduce pain in this patient category compared with placebo injection. In this study, two reviewers independently searched the databases of PubMed, EMBASE, and Cochrane Library (last performed on 12 October, 2014) to retrieve eligible randomized controlled clinical trials. The primary outcomes were visual analog scale (VAS) pain scores within 24 hours after operation when at rest and at an active flexion of knee. Mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CIs) was calculated for each end point. Subgroup analysis was calculated to evaluate potential sources of heterogeneity. Nine randomized controlled trials were retrieved and analyzed. We found that VAS pain scores at rest within postoperative 24 hours were significantly decreased in saphenous nerve block group than that in placebo group (MD = -0.79; 95% CI -1.35 to -0.22; P = 0.007), as well as VAS pain scores at an active flexion of knee within postoperative 24 hours (MD = -0.92; 95% CI -1.61 to -0.22; P = 0.010). In addition, compared to placebo injection group, saphenous nerve block resulted in significantly less morphine consumption during the first postoperative 24 hours (MD = -6.56; 95% CI 11.26 to -1.86; P = 0.006). To conclude, this meta-analysis suggests that saphenous nerve block has an advantage in pain relief both at an active flexion of knee and at rest after knee surgery. Further studies are still wanted to validate these conclusions. PMID- 25785008 TI - Contribution of glutathione S-transferase gene polymorphisms to development of skin cancer. AB - BACKGROUND: Glutathione S-transferase (GST) family genes are of vital importance in maintaining cellular defence systems, protecting cells against the toxic effects of reactive oxygen produced during the synthesis of melanin, and detoxifying environmental mutagens and chemical or synthetic drugs. As no previous meta-analyses have examined the association of polymorphisms at GSTT1, GSTP1 Ile105Val with skin cancer risk and independently published studies have produced inconsistent conclusions, we were promoted to estimate the associations in the largest study to date. METHODS: Computer-assisted searches were carried out to systematically identify the studies of GST polymorphisms and skin cancer. The eligibility of studies was evaluated following the requirements of inclusion criteria. Risk of skin cancers (OR and 95% CI) was assessed with the fixed or random effects meta-analysis. MAJOR FINDINGS: The fixed effects meta-analysis of 15 studies suggested no overall association between GSTT1 null and skin cancer. Nor was there a significant association in any subgroup. However, in the stratified analysis by histologic type for GSTP1 Ile105Val, we found 1.56 times higher risk of malignant melanoma (MM) among people with the 105-Val/Val genotype (Val/Val vs. Ile/Ile: OR = 1.56, 95% CI = 1.05-2.32, pheterogeneity = 0.584). CONCLUSIONS: These statistical data demonstrate that Ile105Val polymorphism of the GSTP1 gene may have genetic contribution to the development of skin cancer, MM in particular. PMID- 25785009 TI - Additional furosemide treatment beyond saline hydration for the prevention of contrast-induced nephropathy: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: There have been conflicting results on the clinical utility of furosemide in preventing contrast-induced nephropathy (CIN). This study aimed to elucidate the effect of additional furosemide treatment beyond saline hydration on CIN post radiologic procedures by a meta-analysis of randomized controlled trials (RCTs). METHODS: The Medline, EMBASE, and Cochrane databases were systematically searched. Two reviewers independently determined the eligibility of studies that randomly assigned patients undergoing radiologic procedure to receive additional peri-procedural furosemide injection or intravenous saline hydration alone. Combined results were presented as risk ratios (RR) with 95% confidence intervals (CI) by random-effect models. RESULTS: We identified 5 RCTs including 1330 patients. Of them 659 received peri-procedural furosemide injection in addition to saline hydration, and 671 only received intravenous saline hydration (the control). Relatively small total number of dialysis events and heart failure events were reported in the included studies (n = 18 across 5 trials, n = 24 across 3 trials, respectively). Compared to the control, additional furosemide treatment did not significantly increase the incidence of CIN (RR = 1.18; 95% CI, 0.50-2.78; P = 0.71) and the risk of dialysis (RR = 1.03; 95% CI, 0.41-2.57; P = 0.95) post radiologic procedure. Furthermore, furosemide treatment appeared to decrease the occurrence of heart failure (RR = 0.35; 95% CI, 0.14-0.88; P = 0.02). CONCLUSIONS: Peri-procedural furosemide treatment in addition to saline hydration did not provide significantly prophylactic effect on CIN after radiologic procedure. Nevertheless, the process seemed likely to decrease the risk of heart failure post saline hydration. PMID- 25785010 TI - Sleep deprivation induces abnormal bone metabolism in temporomandibular joint. AB - BACKGROUND: The purpose of this study was to explore the effect of experimental sleep deprivation (SD) on the temporomandibular joint (TMJ) of rats and the possible mechanism related to abnormal bone metabolism. MATERIAL AND METHODS: SD was induced by a modified multiple platform method and assessed by serum adrenocorticotropic hormone (ACTH) level. TMJs were detached and stained with hematoxylin and eosin (H&E). Expression of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) was evaluated by quantitative reverse transcription polymerase chain reaction, H&E staining, immunohistochemical staining and enzyme linked immunosorbent assay. RESULTS: Compared with controls, SD significantly increased serum ACTH, indicating that the SD model was successful. In the SD group, H&E staining revealed greater vessel hyperplasia in the synovial membrane and thicker hypertrophic layers in condylar cartilages. Compared with controls, RNA and protein expression of the inflammatory factors IL 1beta and TNF-alpha and the bone metabolism-related factor RANKL increased in condylar cartilage in the SD group, whereas OPG and the OPG/RANKL ratio decreased. Immunohistochemical staining revealed that OPG/RANKL immunopositive cells were mainly located in hypertrophic layers. CONCLUSIONS: These results suggest that sleep deprivation might play an important role in the occurrence and development of temporomandibular disorders, which may occur through abnormal secretion of inflammatory and bone metabolism-related factors. PMID- 25785011 TI - Neural stem cells transplantation alleviate the hyperalgesia of spinal cord injured (SCI) associated with down-regulation of BDNF. AB - Transplantation of neural stem cells (NSCs) in the injured spinal cord has been shown to improve functional outcome. However, the influence of NSCs transplantation on the sensory function and analgesic behaviors has not been elucidated yet. Here, we investigated whether transplanted NSCs would improve sensory function in rats subjected to complete cord transection (T10) and explore the underlying mechanism. The rats were divided into sham, SCT (spinal cord transection), and NSC implanted groups. NSCs (3 * 10(6)/ml) were implanted into injury site at the day after operation. Mechanical (the hind paw test) and thermal (the tail-flick test) were measured at 5 weeks. Immunohistochemistry and RT-PCR were used to demonstrate that expression of Brain-derived neurotrophic factor (BDNF) in the superficial of the dorsal horn. Consequently, the tail-flick latencies and paw withdrawal thresholds in NSC implanted group exhibit a significant higher than SCT group (P < 0.05). RT-PCR demonstrate that mRNA expression of BDNF was down-regulated remarkably in NSC engrafted rats. The present findings suggest that NSC transplantation inhibits neuropathic pain associated with BDNF down-regulation. PMID- 25785012 TI - Steroid-antivirals treatment versus steroids alone for the treatment of Bell's palsy: a meta-analysis. AB - BACKGROUND: To illustrate whether the steroid-antivirals treatment could acquire a better recovery in patients with Bell's palsy than the steroids alone treatment. MATERIALS AND METHODS: We conducted an exhaustive search over Pub med/Medline, Ovid, Elsevier search engines and the Cochrane library thereby collecting the randomized controlled trials in the treatment of patients with Bell's palsy with steroid-antivirals and steroids. The qualities of relevant articles were assessed by GRADE, which was used to present the overall quality of evidence as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Two investigators evaluated these papers independently, and resolved the disagreements by discussion. At last 8 eligible papers (1816 patients included: 896 treated with steroid-antivirals and 920 treated with steroids alone) match the criteria. Owing to the result (chi(2) = 12.57, P = 0.08, I(2) = 44%) presented by the formal test for heterogeneity, the fixed effect meta-analysis model was chosen. The facial muscle recovery between the steroids-antivirals group and the steroids alone group show significant differences (OR = 1.52, 95% CI: 1.20-1.94), while the statistical outcome of adverse effect shows no statistical significance (OR = 1.28, 95% CI: 0.71-2.31). CONCLUSIONS: The present meta-analysis indicates that the steroid-antivirals treatment could improve the recovery rate in patients with Bell's palsy when comparing with the steroid alone treatment. CLINICAL SIGNIFICANCE: This meta analysis showed that the steroid-antivirals treatment achieved the better outcomes in patients with Bell's palsy. Clinicians should consider that steroid antivirals therapy is an alternative choice for the patients with Bell's palsy. PMID- 25785013 TI - Telomerase reverse transcriptase (TERT) rs2736100 polymorphism contributes to increased risk of glioma: evidence from a meta-analysis. AB - The rs2736100 polymorphism in telomerase reverse transcriptase (TERT) gene has been implicated as a risk factor for glioma in previous epidemiological studies. However, the data from these studies were inconclusive for the precise association of TERT rs2736100 with glioma. Here we employed a meta-analysis aiming to evaluate such association. The PubMed, Embase, and Web of Science were systematically searched for eligible studies. The odds ratio (OR) and 95% confidence interval (95% CI) was estimated to assess the strength of this association in fixed or random effects models. A total of 5 studies in 16 articles including 7337 cases and 12062 controls were eventually collected. Our analyses showed that there was a significant association between TERT rs2736100 polymorphism and glioma in all five genetic models(homozygous model-GG vs. TT: OR=1.64, 95% CI=1.50~1.79, P heterogeneity=0.253, I(2) =17.5%; heterozygous model GT vs. TT: OR=1.38, 95% CI=1.27~1.49, P heterogeneity=0.235, I(2) =19.1%; dominant model-GG+GT vs. TT: OR=1.46, 95% CI=1.36~1.57, P heterogeneity=0.167, I(2) =25.5%; recessive model-GG vs. GT+TT: OR=1.31, 95% CI=1.22~1.40, P heterogeneity=0.796, I(2) =0.0%; additive model-G allele vs. T allele: OR=1.27, 95% CI=1.21~1.32, P heterogeneity=0.481, I(2) =0.0%). Further subgroup analysis on control source and ethnicity, we found similar association in population based, hospital-based and Caucasians groups. The result of heterogeneity test were in acceptable range (P<0.05 and I(2) <50%). Egger's tests and Begg's funnel plot did not show any publication bias. Sensitivity analysis confirmed that our results were reliable. Taken together, our meta-analysis suggested that TERT rs2736100 polymorphism may greatly increase glioma risk. PMID- 25785014 TI - Neuroprotection of MAO-B inhibitor and dopamine agonist in Parkinson disease. AB - Parkinson disease is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta. We explored the neuroprotective effect of Selegiline and Piribedil, the Monoamine Oxidase Type B (MAO-B) and dopamine agonist to Parkinson disease (PD). After embryonic Wistar rat were induced by cerebrospinal fluid (CSF) from PD patients, Selegiline and Piribedil were administered to Wistar rat. Immunohistochemical staining, RT-PCR and western blot were adopted to analyze the changes of morphology, lactate dehydrogenase activity, tyrosine hydroxylase positive neurons rate, and tyrosine hydroxylase (TH) expression in Wistar rat. The two drugs do not affect the normal growth of dopamine neurons. Selegiline and Piribedil both decreased the injury caused by CSF of PD patients in Wistar rat. We observed decreased lactate dehydrogenase (LDH) activity, increased TH (+)/total cells ratio and increased the TH expression in treated Wistar rat with dose-dependent effects. The morphological changes of cells are consistent with above observation. Selegiline and Piribedil have neuroprotective effects to induced PD Wistar rat with dose-dependent effect. Selegiline demonstrated stronger neuroprotective effect than Piribedil, and the two drugs have potential treatment effect in clinical for PD patients. PMID- 25785015 TI - Metabolic status and personality affect the prognosis of patients with continuous ambulatory peritoneal dialysis. AB - Continuous ambulatory peritoneal dialysis (CAPD) is recognized as an effective and economical therapy for end-stage renal disease (ESRD). However, the drop-out and mortality rates of this treatment remain high. The aim of the present study was to investigate the potential effects of metabolic status and personality on the prognosis of ESRD patients receiving CAPD. A total of 835 patients (455 men and 380 women) were enrolled in the cross-sectional survey. Analysis of variance and Spearman correlations were used to analyze variables in two groups of ESRD patients: group L (dialysis duration < 3 years) and group H (dialysis duration >= 3 years). The variables included gender, age, duration of dialysis, primary diseases, blood pressure, body mass index (BMI), hemoglobin (Hb), serum albumin, Subjective Global Assessment (SGA), blood lipids, fasting blood glucose, renal function, immunoreactive parathyroid hormone (iPTH), serum phosphorus and calcium, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Kt/V, and Life Orientation Test-Revised (LOT-R) scores. Levels of DBP, BUN, glucose, CRP, SBP, SGA, TG, LDL, creatinine, iPTH, ESR, and LOT-R scores were significantly higher in group H than in Group L, whereas Hb and Kt/V were significantly lower in group H. The dialysis duration was positively correlated with the blood pressure, SGA scores, TG, LDL, PTH, CRP, and LOT-R scores, but negatively correlated with Kt/V. Our results suggest that hypertension, anemia, hypoproteinemia, SGA, TG, LDL, iPTH, CRP, Kt/V, and personalities are potentially important factors affecting the prognosis of ERSD patients with CAPD. PMID- 25785016 TI - Genetic association between leptin-2548G/A polymorphism and risk of cancer: a meta analysis. AB - OBJECTIVE: Abundance of evidence implicated that leptin may play a decisive role in cancer occurrence, but the reported results varied across the individually published studies. The objective of this study is to access to what extent the extensively studied -2548G/A polymorphism of LEP gene acts on the onset of multiple cancers. METHODS: Eligible studies included in this meta-analysis were identified electronically in PubMed and Embase, and manually in relevant literature. Crude odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated to estimate the risk of cancer associated with the -2548G/A polymorphism. RESULTS: 12 association studies with a total of 5,618 cancer cases and 6,509 healthy controls were pooled into this meta-analysis. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall cancer (OR, 1.21; 95% CI, 1.02-1.44). Following further stratified analyses, a borderline association was indicated in prostate cancer (OR, 1.18; 95% CI, 1.00-1.39), breast cancer (OR, 1.11; 95% CI, 1.00-1.22) and Caucasians (OR, 1.19; 95% CI, 1.00-1.41). CONCLUSIONS: This meta analysis reveals that the A allele of -2548G/A polymorphism may be a determinant of cancer development. PMID- 25785017 TI - Serum microRNA-128 as a biomarker for diagnosis of glioma. AB - MicroRNA-128 is down-regulated in glioma tissues, which regulates cell proliferation, self-renewal, apoptosis, angiogenesis and differentiation. This study aims at investigating the diagnostic value of serum miR-128 in human glioma. Real-time quantitative reverse transcriptase polymerase chain reaction was used to detect the expression levels of miR-128 in serum samples from 151 glioma patients, 59 postoperative patients, 52 meningioma patients and 53 normal donors. To analyze the association of miR-128 expression with clinicopathological parameters in serum samples and matched tissues, matched 151 glioma tissues were collected in the study. Receiver operating characteristic analysis (ROC) was utilized to evaluate the value of serum miR-128 as a biomarker for the early diagnosis of glioma. Results revealed that miR-128 expression was significantly decreased in glioma preoperative serum compared with normal controls and meningioma serum samples (both P < 0.001). ROC analyses showed that serum miR-128 levels were reliable in distinguishing patients with glioma from normal controls and meningioma, with the area under the curve (AUC) values of 0.9095 and 0.8283, respectively. In addition, the AUC value for discriminating glioma II-IV from I was 0.7362. Importantly, serum miR-128 expression was significantly elevated after surgery (P < 0.001), although it didn't reach to normal levels (P < 0.001). Furthermore, low miR-128 levels in serum and tissue were markedly correlated with high pathological grade and low Karnofsky Performance Status score (KPS). These findings proved that serum miR-128 could be a sensitive and specific biomarker of glioma. PMID- 25785018 TI - Role and mechanism of Sophoridine on proliferation inhibition in human glioma U87MG cell line. AB - Sophoridine, a natural product obtained from medicinal plants, which has a variety of pharmacological effects, including anti-cancer effects, and selectively induces apoptotic cell death in a variety of human cancer cells in vitro and in vivo; however, its mechanism of action needs to be further elaborated. In this study, we investigated the effects of Sophoridine on the induction of apoptosis in human Glioma U87MG cells. Here, we found that Sophoridine can significantly inhibited cell proliferation, G2/M phase arrest, induced cell apoptosis and caused reactive oxygen species (ROS) generation and GSH content reduction. Sophoridine also triggered significant down-regulated the expression of p27, CDK2, Survivin, Livin, Bcl-2, E2F1 and the transcriptional activity of FoxM1, NF-kappab and AP-1, meanwhile, up-regulated the expression of caspase-3/8, p53, Smac, c-JNK and p38-MAPK. Moreover, we found that Sophoridine significantly inhibited ubiquitin-proteasome in tumor cells. In conclusion, Sophoridine shows obvious anti-cancer activity on glioma cells by inducing cell apoptosis, inducing ROS accumulation, and activating mitochondrial signal pathways. Eventually, we believe Sophoridine could be used as a new drug for the treatment of glioma. PMID- 25785019 TI - Posterior tibial plateau fracture: a new treatment-oriented classification and surgical management. AB - PURPOSE: To establish a classification system for the different types of posterior tibial plateau fractures (PTPF), and to explore the fracture patterns and early results of treatment. METHODS: 39 PTPFs patients who received surgeries through posteromedial or (and) posterolateral knee approaches were analyzed retrospectively. RESULTS: There were 5 types of PTPFs identified in the new classification system: posteromedial split fracture (type I, 7 patients), posterolateral split fracture (type II, 5 patients), posterolateral depression fracture (type III, 11 patients), posterolateral split and depression fracture (type IV, 2 patients), and posteromedial split combined with posterolateral depression fracture (type V, 14 patients). All patients underwent surgeries safely without complications. The average follow up was 18.1 months (12-30 months). The average weight-bearing durations were 15.6 weeks (12-20 weeks). Based on Rasmussen functional scoring system, 20 cases were regarded as excellent, 14 were good, 5 were fair, and 0 was poor. There was significant change in the Rasmussen functional score before (8.38 +/- 2.87) and after surgery (24.20 +/- 3.44). According to Rasmussen radiology system, 28 cases were excellent, 8 cases were good, 3 were fair, and none was poor. There was also a significant difference detected between pre-operation (6.77 +/- 2.27) and post operation (16.41 +/- 2.65). CONCLUSION: This study presents a new classification system for the different types of PTPFs based on the treatment. The classification is clinically relevant and can be used to guide the surgical management. PMID- 25785020 TI - MicroRNA-7 inhibits metastasis and invasion through targeting focal adhesion kinase in cervical cancer. AB - MicroRNAs (miRNAs) are aberrantly expressed in cervical cancer. miR-7 has been demonstrated to function as both an oncogene and a tumor suppressor in some types of human cancers. In the present study, miR-7 was significantly downregulated in cervical cancer, especially metastatic tumors. Ectopic expression of miR-7 significantly inhibited metastasis and invasion in Hela and C33A cells. Upregulated miR-7 significantly suppressed focal adhesion kinase (FAK) at transcriptional and translational levels. Furthermore, the level of FAK was negatively correlated with miR-7 in cervical cancer tissues. In conclusion, miR-7 inhibited the metastasis and invasion of cervical cancer at least partially through targeting FAK. The findings of this study provide novel insight with potential therapeutic applications for the treatment of metastatic cervical cancer. PMID- 25785021 TI - The polymorphism (Gln261Arg) of 12-lipoxygenase and cancer risk: a meta-analysis. AB - BACKGROUND: Many studies suggest that the Gln261Arg polymorphism in 12 lipoxygenase gene is assicated with cancer susceptibility, but the results are inconclusive. This meta-analysis aimed to investigate the overall association between the Gln261Arg polymorphism in 12-lipoxygenase gene and cancer risk. METHODS: Literature search was performed in Pubmed, Embase and other databases for studies evaluating the association between the Gln261Arg polymorphism in 12 lipoxygenase gene and cancer risk. Data were extracted and statistical analysis was performed using STATA 12.0 software. RESULTS: A total of eight publications involving 8,379 subjects were included in this meta-analysis. Combined analysis revealed a significant association between this polymorphism and cancer susceptibility with an OR of 1.19 (95% CI: 1.09-1.31, P=0.000 for Gln/Gln vs. Arg/Gln + Arg/Arg). Subgroup analysis by ethnicity showed that the cancer risk associated with the Gln261Arg polymorphism in 12-lipoxygenase gene was significantly elevated among Asians (OR=1.21, 95% CI: 1.10-1.34, P=0.000 for Gln/Gln vs. Arg/Gln + Arg/Arg), but not among Caucasians. Subgroup analysis by cancer type suggested that the Gln261Arg polymorphism in 12-lipoxygenase gene is not a risk factor for colon cancer or rectal cancer. CONCLUSION: This meta analysis suggests that the Gln261Arg polymorphism in 12-lipoxygenase gene contributes to cancer susceptibility, specifically in Asian populations. More studies are needed to validate our findings. PMID- 25785022 TI - Hypoxia stimulates the proliferation of neonatal rat vascular smooth muscle cells through activation of hypoxia-inducible factor-1alpha. AB - Exposure to an adverse intrauterine environment increases the risk of cardiovascular disease later in adult life. It has been shown that hypoxia plays a critical role in vascular remodeling and directly affects vascular smooth muscle cells functions. In the present study, we aimed to investigate the effect of hypoxia on neonatal rat aorta smooth muscle cells (NRSMCs). Our study demonstrated that hypoxia stimulation at 2% oxygen could significantly enhance NRSMCs proliferation in a time dependent manner. Moreover, hypoxia treatment resulted in an increased percentage in the S + G2/M phase and decreased apoptosis rate in NRSMCs. On the molecular level, the protein levels of pro-apoptotic proteins BNIP3 and bax were obviously reduced, while the anti-apoptotic factor bcl-2 was enhanced under hypoxia condition. Furthermore, we found that hypoxia activated hypoxia-inducible factor-1alpha (HIF-1alpha) expression and subsequently promoted NRSMCs proliferation. Specific down-regulation of HIF 1alpha partly abolished the proliferative effect of hypoxia on NRSMCs growth. Taken together, the present study demonstrated that hypoxia treatment promoted NRSMCs growth through activation of HIF-1alpha, which may contribute to the understanding of the pathogenesis of atherosclerosis. PMID- 25785023 TI - Rat model of focal cerebral ischemia in the dominant hemisphere. AB - In the human brain, the dominant hemisphere is more complex than the non-dominant hemisphere. Hence, cerebral ischemia of the dominant hemisphere often leads to serious consequences. This study aims to establish a rodent model of focal cerebral ischemia in the dominant hemisphere. The quadruped feeding test was used to screen 70 male Sprague Dawley rats. From this test, 48 rats with right paw preference were selected and randomly assigned numbers. Half were assigned to the dominant hemisphere ischemia (DHI) group, and the other half were assigned to the non-dominant hemisphere ischemia (NDHI) group. The middle cerebral artery was occluded 2 h before reperfusion. Neurological functions were tested. TTC and HE staining were performed. The volume of cerebral infarction was calculated. Rats in the DHI group had significantly worse neurological scores than rats in the NDHI group (P < 0.05). TTC staining indicated ischemia had more severe consequences in the dominant hemisphere than in the non-dominant hemisphere. The dominant hippocampus indicated severe neuronal loss and disorderly cellular arrangement. The volume of cerebral infarction was also greater in the DHI group compared to the NDHI group (P < 0.05). Compared to MCA occlusion in the non dominant hemisphere, MCA occlusion in the dominant hemisphere caused greater impairment in neurological functions. The proposed rodent model is reliable and has high levels of reproducibility. Therefore, his model can be reliably for investigating the mechanism of focal cerebral ischemia in the dominant hemisphere of human brains. PMID- 25785024 TI - Differential expression of 5-HT-related genes in symptomatic pulmonary embolism patients. AB - OBJECTIVE: Whole human genome oligo microarrays were employed to systematically investigate the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signaling pathway in peripheral blood karyocytes from pulmonary embolism (PE) patients. METHODS: A total of 20 PE patients and 20 healthy subjects matched in gender and age were recruited. The human genome microarrays were performed to detect the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signal pathway of two groups. The random variance model corrected t-test was used for analysis. RESULTS: Our results showed (1) tryptophan hydroxylase (TPH1)-related gene expression was markedly down-regulated in PE patients (P < 0.01); (2) monoamine oxidases (MAO)-related gene (MAOB) expression was significantly up-regulated in PE patients (P < 0.01); (3) the expression of 17 genes of 7 5-HT receptors showed a down-regulated tendency in PE patients, and significant difference was observed in the expression of HTR1E, HTR3B, HTR4 and HTR5A between them (P < 0.05); (4) the expression of DalDAG-GEF I, Tubby, PKA and EPAC in 5-HT signal pathways was dramatically up-regulated in PE patients (P < 0.05); the expression of SPA1, RIAM, RAPL, Talin, PKC, PLC and Pyk2 was remarkably up-regulated in PE patients (P < 0.05); (5) the expression of integrin genes ITGA2B, ITGB1 and ITGB3 was significantly up-regulated in PE patients (P < 0.05). CONCLUSION: In PE patients, the expression of TPH1 and HTR4 was down-regulated as a negative feedback; the MAOB expression was up-regulated. Consistent with the expression of 5-HTR1E and 5 HTR4 and the abnormally activated Tubby, the expression of integrins in platelets was activated. PMID- 25785025 TI - Preliminary study of the effect of abnormal savda munziq on TGF-beta1 and Smad7 expression in hypertrophic scar fibroblasts. AB - BACKGROUND: To study the effect of abnormal savda munziq (ASMq) on TGF-beta1 and Smad7 expression in hypertrophic scar fibroblasts (HSFs) and to preliminarily assess the function of abnormal savda munziq in hypertrophic scar formation at the molecular biology level. METHODS: HSFs were cultured in vitro. RT-PCR and Western-blot were used to investigate the influence of 48-h treatment with ASMq at different concentrations (0 mg/mL, 0.1 mg/mL, 0.4 mg/mL, and 0.7 mg/mL) on TGF beta1 and Smad7 mRNA and protein expression levels. RESULTS: After 48-h treatment with ASMq, the expression of TGF-beta1 mRNA and protein gradually decreased in HSFs as the concentration increased. In contrary, Smad7 mRNA and protein expression were positively correlated with ASMq concentration. CONCLUSIONS: ASMq reduces TGF-beta1, increases Smad7 mRNA and protein expression through regulating TGFbeta-1/Smad signaling pathway, inhibiting HSFs proliferation and reducing extracellular collagen deposition. PMID- 25785026 TI - Target radiofrequency combined with collagenase chemonucleolysis in the treatment of lumbar intervertebral disc herniation. AB - Both target radiofrequency thermocoagulation and collagenase chemonucleolysis are effective micro-invasive therapy means for lumbar intervertebral disc herniation. In order to analyze the clinical effects of target radiofrequency thermocoagulation combined with collagenase chemonucleolysis on lumbar intervertebral disc herniation, the contents of hydroxyproline and glycosaminoglycan were measured and the histological changes of nucleus pulposus was detected in the vitro experiments. Radiofrequency thermocoagulation reduced the hydrolyzation of herniated nucleus pulposus caused by collagenase, as well as the content of hydroxyproline and glycosaminoglycan. Furthermore, 236 patients with lumbar intervertebral disc herniation were treated by target radiofrequency thermocoagulation combined with collagenase chemonucleolysis. The efficiency was evaluated according to Macnab criteria, and the index of lumbar disc herniation (IDH) was compared pre-operation with 3 months post-operation. The post-operative good rate was 66.5% (157/236) at 2 weeks post-operation, and 88.1% (208/236) at 3 months post-operation. In the post-operative follow-up exam, 86.8% of the re examined cases demonstrated smaller or ablated protrusion, with reduced IDH values from pre-operation, which was statistically significant. No serious complications were detected intra-operatively and post-operatively. In conclusion, target radiofrequency combined with collagenase chemonucleolysis was an effective and safe method for treatment of lumbar intervertebral disc herniation. PMID- 25785027 TI - Clinical and radiological character of eosinophilic cystitis. AB - PURPOSE: Eosinophilic cystitis (EC) is a rare disease and remains a poorly understood. We explored the potential etiology, clinical and radiological presentation, diagnosis and therapeutic experience with EC. MATERIALS AND METHODS: A pooled ten patients diagnosed with EC were retrospectively studied in our hospital to assess clinical presentation symptoms, radiological and pathological diagnosis, treatment and outcomes between 1998 and 2012. RESULTS: Nine patients presented with irritative urinary symptoms, one was symptomless. Allergic history were found in 2 patients, bladder mass was detected in all by radiologic tests or cystoscopy. Radiology revealed diffuse thickening of bladder wall in 7 cases among which one with bilateral hydroureteronephrosis, solitary tumor-like lesion in other 3. Elevated serum leukocytes were evident in 4 cases while elevated peripheral eosinophilias were observed in 3. One was asymptomatic and without specific therapy (group 1, 10%), transurethral resection of the lesions in one tumor-like case (10%). The other 8 cases were treated with corticosteroid and/or antihistaminics and 5 patients had excellent outcome with symptom resolution (62.5%). CONCLUSIONS: EC usually follows a benign course, most treated with corticosteroids and resulted in relief of symptoms while some may relapse. Surgery is an available choice for drug refractory or localized EC. PMID- 25785028 TI - Estimation of fetal weight by ultrasonic examination. AB - PURPOSE: This study was to evaluate the accuracy and clinical application of a new technique in the fetal weight estimation by ultrasound. METHODS: The fetal biparietal diameter (BPD), head circumference (HC) and femur length (FL) were measured by ultrasound examination within one week before delivery. Two different fetal abdominal sectors were measured for the assessment of abdominal circumference (AC). The fetal weight of 516 singleton fetuses was estimated according to above measurements and their actual birth weight was recorded after delivery. RESULTS: There were no significant differences in the fetal AC or body weight evaluated before delivery and recorded after delivery. CONCLUSION: This new technique is more convenient and applicable for the evaluation of fetal AC as compared to standard method, and seems to be reliable and accurate for the assessment of fetal weight. PMID- 25785029 TI - Prognostic and clinical significance of STAT3 and MMP9 in patients with gastric cancer: a meta-analysis of a Chinese cohort. AB - As signal transducer and activator of transcription 3 (STAT3)-mediated signaling cascade directly contributes to tumor metastasis, numerous agents targeting STAT3 are in clinical development. However, reported data on the prognostic impact of STAT3 expression vary considerably. We aim to quantitatively summarize available evidences for evaluating the association between STAT3 and STAT3-regulated target gene, matrix metalloproteinase 9 (MMP9), and the prognosis of Chinese patients with gastric cancer. Searches were applied to PubMed and the Chinese National Knowledge Infrastructure database without any language restriction. A total of 5,757 patients were included in the final analyses. All results favored an association between high STAT3 expression and poor 5-year overall survival (risk ratio = 1.845, 95% confidence interval [CI] = 1.027-3.315). The reduced survival was heavily influenced by advanced tumor invasion (OR = 2.885, 95% CI = 2.034 4.094), lymph node metastasis (OR = 5.349, 95% CI = 3.807-7.516), distant metastasis (OR = 5.873, 95% CI = 2.641-13.062), dedifferentiation (OR = 2.516, 95% CI = 1.814-3.491), tumor size (OR = 1.918, 95% CI = 1.246-2.954), and higher TNM stage (OR = 4.171, 95% CI = 2.840-6.126). Similar results were observed in the meta-analyses of MMP9, with the magnitude of effect OR > 2. Our findings indicate that STAT3 and MMP9, as measured by IHC, are associated with worse survival and potentially mark invasion and metastasis in gastric cancer, especially in Chinese patients. More significantly, these two biomarkers may be converted from candidates to the routine clinical evaluation to help predict the outcome of gastric carcinoma patients. PMID- 25785030 TI - Effect of Chuanminshen violaceum polysaccharides and its sulfated derivatives on immunosuppression induced by cyclophosphamide in mice. AB - One hundred mice were randomly divided into five groups. The mice in one group were injected with physiological saline as the normal control group. The mice in the other four groups were injected with physiological saline, sulfated Chuanminshen violaceum polysaccharides (SCVP), Chuanminshen violaceum polysaccharide (CVP) and astragalus polysaccharide (AP) once daily for 7 d and then with cyclophosphamide (CY) in the last 3 d. The serum cytokine level, apoptosis protein expressions, spleen lymphocyte proliferation, changes in peripheral blood T-cell subsets, and immune organ index were then measured. Results showed that SCVP and CVP can overcome CY-induced immunosuppression by promoting spleen lymphocyte proliferation, raising serum IFN-gamma and IL-2 levels, enlarging immune organ indexes, and decreasing excessive apoptosis. Moreover, SCVP and CVP showed the potential to treat autoimmune diseases based on CD4(+)/CD8(+) ratios. Results suggested that SCVP and CVP exhibited the potential to treat autoimmune and immunosuppression diseases. PMID- 25785031 TI - Study of functional connectivity in patients with sensorineural hearing loss by using resting-state fMRI. AB - OBJECTIVE: To determine functional connectivity of the default mode network in patients with sensorineural hearing loss (SNHL) in resting state. METHODS: The posterior cingulate cortex was selected as a seed for assessment of functional connectivity of the activated brain areas in resting state by using a seed-based correlation analysis of the resting state functional magnetic resonance imaging (fMRI) data. RESULTS: The fMRI results demonstrated that, the healthy volunteers and the patients with NSHL shared certain activated brain areas with positive functional connectivity with region of interest (ROI). However, the healthy volunteers also had positive functional connectivity with ROI in bilateral middle temporal gyrus, left anterior cingulate cortex, right inferior parietal lobule and left medial superior frontal gyrus. While the patients with SNHL did with bilateral inferior parietal lobule, left medial superior frontal gyrus, right supramarginal gyrus, and left middle temporal gyrus. Compared to controls, patients with SNHL showed increased functional connectivity in the right posterior frontal lobe, right precentral gyrus, right supramarginal gyrus and left posterior cingulate cortex, and had decreased functional connectivity in the left lingual gyrus, right cuneus lobe and right superior frontal gyrus. CONCLUSION: The posterior cingulate cortex, precuneus lobe, medial frontal gyrus, anterior cingulate cortex, temporal lobe, angular gyrus and inferior parietal lobule constitute a default mode of network in normal resting status. And patients with SNHL have abnormal functional connectivity of default mode network and cortical reorganisation in resting status. PMID- 25785032 TI - Ghrelin inhibits AngII -induced expression of TNF-alpha, IL-8, MCP-1 in human umbilical vein endothelial cells. AB - AIM: Ghrelin, a gastric peptide, is involved in several metabolic and cardiovascular processes. Emerging evidence indicates the potential involvement of ghrelin in low-grade inflammatory diseases such as atherosclerosis and hypertension. Cytokine-induced inflammation is critical in these pathological states. The growth hormone secretagogue receptor (GHSR) has been identified in blood vessels, so we predict that ghrelin might inhibit proinflammatory responses in human umbilical vein endothelial cells (HUVECs). The aim of this study is to examine the effect of ghrelin on angiotension II (AngII)-induced expression of TNF-alpha, MCP-1, IL-8 in HUVECs. METHOD: HUVECs were pretreated with ghrelin, with or without the specific antagonist of GHSR [D-Lys(3)]-GHRP-6, the selective inhibitor of nuclear factor-kappaB (NF-kappaB) PDTC, and the selective inhibitor of extracellular signal-regulated kinase (ERK1/2) PD98059. The cells were finally treated with AngII. The expression of TNF-alpha, MCP-1, IL-8 was examined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The activity of ERK1/2 and NF-kappaB was analyzed by Western blot. RESULT: our study showed that ghrelin inhibited AngII -induced expression of IL-8, TNF-alpha and MCP-1 in the HUVECs via GHSR pathway in concentration- and time-dependent manners. We also found that ghrelin inhibited AngII -induced activation of ERK1/2 and NF-kappaB. CONCLUSIONS: these results suggest that Ghrelin may play novel antiinflammatory and immunoregulatory roles in HUVECs. PMID- 25785033 TI - Influence of BsmI polymorphism in vitamin D receptor gene on the risk of fracture in Caucasian populations: a meta analysis. AB - OBJECTIVE: To gain combined risk estimates for the BsmI polymorphism in vitamin D receptor (VDR) gene associated with the risk of fractures in Caucasian population. METHODS: We performed a meta-analysis and extracted 15 eligible publications by searching the databases of Medline, EMBASE and CNKI. Summary odds ratio (OR) with 95% confidence interval (CI) was estimated by using fixed-effects model. The inconsistency index (I(2)) was performed to evaluate heterogeneity. Begg's funnel plots and Egger's test were used to assess publication bias. RESULTS: A total of 15 available studies including 5,570 subjects (1,912 cases and 3,658 controls) were included in the meta-analysis. No overall association was observed between the BsmI polymorphism in VDR gene and the susceptibility to fracture under all genetic models. When stratifying by fracture type, we did not find any significant risk, either. But in the subgroup analysis by source of control, the results from population-based groups suggested the BsmI polymorphism was associated with the increased fracture susceptibility (ORBB vs. bb = 1.22, 95% CI = 1.01-1.48, P heterogeneity = 0.912; ORB vs. b = 1.10, 95% CI = 1.00 1.20, P heterogeneity = 0.921). CONCLUSIONS: Our meta-analysis provides evidence that the BsmI polymorphism in VDR gene may not be associated with the susceptibility to fracture in Caucasian populations. Our findings need to be further confirmed in future larger and well-designed studies. PMID- 25785034 TI - Orthotopic transplantation of decellularized liver scaffold in mice. AB - End-stage liver disease is a life threatening health problem to millions of people worldwide. Orthotopic liver transplantation is the only therapy for the definitive cure at the present time. However, persistent shortage in donor organs limits the opportunity for patients to receive this treatment. Liver tissue engineering aims to overcome this restriction by generating functional tissue constructs for treatment of individuals with the end-stage liver disease. Recently, a new strategy has emerged using the natural organ scaffold as a vehicle for liver tissue engineering. This involves preparation of decellularized scaffold containing the circulatory framework of the natural organ system. Currently, surgical performance of liver scaffold transplantation with end-to side anastomosis of major vessels in small experimental animals, particularly in mice (mLBST), remains technically challenging. Here, we describe surgical techniques of mLBST that can be used for evaluation of engineered liver grafts in recipients. PMID- 25785035 TI - Proposed management protocol for ingested esophageal foreign body and aortoesophageal fistula: a single-center experience. AB - OBJECTIVE: Aortoesophageal fistula (AEF) is a life-threatening complication of foreign body ingestion. The primary objective of this study was to describe a new management protocol for infected AEFs, which combines endovascular stent grafting and mediastinal drainage using video-assisted thoracoscopic surgery (VATS). METHODS: The authors analyzed the clinical data of 22 patients with ingested foreign bodies retrospectively, developed a classification system based on multidetector computed tomography (MDCT) findings for esophageal injuries induced by foreign body ingestion, and used this system and the clinical presentation to guide treatment. RESULTS: Depending on the MDCT findings, the esophageal injuries were divided into four grades: Grade I, non-penetrating injury (six patients); Grade II, penetrating injury with minimal infection (five patients); Grade III, potential AEF (five patients); and Grade IV, definite AEF (six patients). When a foreign body was visible on MDCT, a distance of <= 2 mm between the foreign body and aortic wall indicated potential or definite AEF. When no foreign body was visible, a typical clinical presentation, especially sentinel hemorrhage, and MDCT findings were used to establish the diagnosis. Only three Grade IV patients who underwent open surgery died of severe hemorrhage within 24 h postoperatively. The others patients had a good outcome with different treatment. CONCLUSIONS: The authors' experience indicates that MDCT was useful to classify esophageal injuries caused by foreign body ingestion which predicted the risk of AEF; endovascular stent grafting and VATS-guided mediastinal drainage would be a safe and minimally invasive method for treating patients with AEF and has the potential for improved treatment options for AEFs. PMID- 25785036 TI - Clinicopathological and prognostic role of SIRT1 in breast cancer patients: a meta-analysis. AB - BACKGROUND: Silent mating type information regulation 2 homolog-1 (SIRT1) plays an important role in the progression and development of cancer, including breast cancer. However, the association between SIRT1 expression and clinicopathological parameters and prognosis in breast cancer remains inconclusive. To accurately evaluate the significance of SIRT1 expression in breast cancer, a meta-analysis based on published studies was performed. METHODS: The PubMed, Embase, ISI Web of Science, Science Direct, and Chinese National Knowledge Infrastructure databases were screened to retrieve relevant literature. The reported odds ratios (ORs) and hazard ratios (HRs) and their 95% corresponding confidence intervals (CIs) were pooled to estimate the strength of specific associations. RESULTS: Six studies involving 604 patients were included in the meta-analysis. The pooled analyses showed a significant correlation between SIRT1 expression and poor disease-free survival (DFS) (HR = 3.07, 95% CI: 1.92-4.91, Z = 4.69, P < 0.001) and overall survival (OS) (HR = 3.94, 95% CI: 2.19-7.10, Z = 4.57, P < 0.001). SIRT1 expression also significantly correlated with high TNM stage (pooled OR = 2.92, 95% CI: 1.84-4.63) and lymph node metastasis (pooled OR = 3.22, 95% CI: 0.98 10.57). CONCLUSIONS: Our meta-analysis shows that SIRT1 expression correlates with unfavorable clinical outcomes. We suggest that SIRT1 expression may have potential value in the pathological diagnosis and clinical treatment of patients with breast cancer. More studies are warranted to investigate the effect of SIRT1 on the survival of breast cancer patients. PMID- 25785037 TI - Protein expression of phospho-lim kinase-1 in patients and an experimental rat model with intractable temporal lobe epilepsy. AB - Lim kinase-1 (LIMK1) plays a critical role in dendritic spine morphogenesis and brain function. The protein expression pattern of phospho-LIMK1 (p-LIMK1), the active form of LIMK1, in intractable temporal lobe epilepsy (TLE), however, is unknown. Here we measured p-LIMK1 protein expression in thirty temporal neocortex tissue samples from intractable TLE patients, fifteen histologically normal temporal neocortex tissue samples from trauma patients without epilepsy, in the hippocampi of lithium chloride/pilocarpine-induced TLE rats, and in controls. We found that p-LIMK1 was expressed mainly in the cytoplasm of neurons. The protein expression of p-LIMK1 was significantly higher in the TLE patients and rats than in the control groups. Our results suggest that p-LIMK1 might be involved in the pathogenesis of intractable TLE. PMID- 25785038 TI - Blockage of tropomyosin receptor kinase a (TrkA) enhances chemo-sensitivity in breast cancer cells and inhibits metastasis in vivo. AB - Hyper-activation of the Neurotrophin Receptor Signaling contributes to the development and metastasis of breast cancer. The inhibition of growth factor dependent growth of breast cancer cell demonstrated a promising way for cancer therapy. In this study, the signaling pathway of tropomyosin receptor kinase A (TrkA) had been investigated for the role it played in the proliferation of chemo resistance of breast cancer cells. Small interference RNA (siRNA) was used to down-regulate the expression of TrkA in breast cancer cell and tumor xenograft mice model. Our results indicated that siRNA mediated down-regulation of TrkA lead to the proliferation inhibition of cancer cells and arrested cells cycle at G0/G1 phase via inactivation of NF-kappaBp65. Application of TrkA siRNA to cancer cell also increased the chemo-sensitivity to paclitaxel, and further promoted apoptosis in cancer cell through the activation of caspase-3. Moreover, TrkA siRNA increased the efficacy of paclitaxel and decreased the incidence of lung metastasis in tumor xenografted mice. In sum, these results indicate that TrkA signaling plays an important role in breast cancer chemo-resistance and metastasis. It could be a potential pharmacologic target to enhance the effectiveness of chemo-therapy for breast cancer. PMID- 25785039 TI - MiR-19a overexpression contributes to heart failure through targeting ADRB1. AB - Beta1-adrenoreceptor (beta1-AR) predominantly exists in the heart and beta1-AR reduction is closely related to severity of heart failure (HF). In this study, our research focused on the miRNAs that may repress beta1-AR directly, and aim to find out new markers and target molecules for HF. We first did Argonaute2 AGO2 knock down experiments and confirmed that endogenous adrenoceptor beta 1 (ADRB1) expression was suppressed by miRNAs. To further identify which miRNA suppress ADRB1 expression directly, we constructed the ADRB1 3'UTR reporter plasmid and selected sixteen candidate miRNAs. Confirmed by dual-luciferase assay and western blot, we found that miR-19a suppressed ADRB1 expression by directly targeting 3'UTR. Further expressions detection the levels of miR-19a, BNP and cAMP in 32 plasma samples of HF patients helped us to construct positive correlations between the expression levels of miR-19a and BNP or cAMP, hints miR-19a may be used as a biomarker in HF patients indicating cardiac function. In conclusion, this study confirmed miR-19a suppressed ADRB1 expression by directly targeting 3'UTR of ADRB1 and found an positive correlation between plasma miR-19a and BNP or cAMP levels in HF patients, which may contributes to fully understand the HF pathogenesis and develops new therapy for HF. PMID- 25785040 TI - Association between CTLA-4 rs231775 polymorphism and risk of colorectal cancer: a meta analysis. AB - OBJECTIVE: Many previous studies that examined the association between CTLA-4 rs231775 polymorphism and CRC risk have produced inconsistent results. In this study, a meta-analysis was performed to systematically summarize the possible association. METHODS: We identified relevant studies using PubMed, Embase, and China National Knowledge Infrastructure literature databases. Eligible studies were selected using specific criteria. Data were extracted independently by two authors. The pooled OR with 95% CI was estimated by applying the fixed-effects model to examine the association of interest. RESULTS: Eight studies were identified for the meta-analysis. In overall analysis, we observed an significantly increased CRC risk attributed to the AG genotype as compared to the AA genotype (OR: 1.17, 95% CI: 1.02-1.35 for AG vs AA). Stratified analysis according to ethnicity also showed a significant association in Caucasians under the AG vs AA model (OR: 1.22, 95% CI: 1.03-1.46). No significant heterogeneity or publication bias was tested in our meta-analysis. CONCLUSION: In conclusion, the meta-analysis suggests that rs231775 in the CTLA-4 gene may be a risk factor for CRC, especially in Caucasians. PMID- 25785041 TI - Association between chemokine receptor 5 (CCR5) delta32 gene variant and atherosclerosis: a meta-analysis of 13 studies. AB - BACKGROUND: Chemokine receptor 5 (CCR5) is one of the pro-inflammatory G protein coupled receptors. Many studies have accessed the association between CCR5 gene polymorphism and atherosclerotic disease. However, the results are conflicting and inconclusive. The aim of this study was to evaluate the association more precisely. RESEARCH DESIGN AND METHODS: Trials were retrieved through Pubmed, Embase, Medline, China National Knowledge Infrastructure, Web of Science, and Cochrane database without restrictions on language. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to describe the strength of association with atherosclerotic disease. The subgroup analysis was used to explore the heterogeneity bias among studies. RESULTS: Data were obtained from 13 case-control studies that included 5321 patients with atherosclerotic disease and 4283 control subjects. In the overall analysis, the CCR5-delta32 (Delta32) genetic variants was not associated with increased the risk of atherosclerotic disease (dominant model: OR = 0.93, 95% CI = 0.69-1.24, I(2) = 77%, P = 0.60; recessive model: OR = 1.01, 95% CI = 0.61-1.65, I(2) = 0%, P = 0.98), even after stratification for the status of CCR5-delta32 allele. However, in subgroup analysis, the association was significant for Asians population (OR: 2.29, 95% CI: 1.44-3.64, P = 0.0004). CONCLUSIONS: Our studies add to the evidence that CCR5 Delta32-positive genotype (Delta32/Delta32 or wt/Delta32) increases the risk of atherosclerotic disease in Asian population. Ethnicity difference might contribute to the inconsistency in isolated studies. PMID- 25785042 TI - Comparison of the efficacy of tenofovir disoproxil fumarate and entecavir for initial treatment of patient with chronic hepatitis B in China. AB - OBJECTIVE: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have been accepted as the standard treatment drugs for hepatitis B virus (HBV) reactivation. We aim to compare the efficacy and safety of TDF and ETV initial treatment of chronic hepatitis B (CHB) patients. METHODS: We retrospectively analyzed the efficacy and safety of TDF treatment on 33 CHB patients and of ETV treatment on 65 CHB patients by comparing the HBV DNA levels, HBV DNA undetectable rate, HBV DNA negative conversion multi-factor analysis, alanine amino transferase (ALT) normalization rate, and the adverse event incidence at weeks 4, 12, 24, 36, 48, 72 before and after treatment in each group. RESULTS: The HBV DNA levels in the ETV group were significantly lower than that in the TDF group at week 4 (95.05 +/- 39.49 versus 103.3 +/- 80.25 U/L, P = 0.005). The differences in HBV DNA levels at the other times between these two treatment groups were not statistically significant. No significant differences were observed with HBV DNA undetectable rate and ALT normalization rate between the two groups (P = 0.114, 0.656, respectively). HBV DNA negativity multi-factor analysis showed that the differences in TDF and ETV treatment were not statistically significant (P = 0.116). Therefore, the proportion of Creatine Kinase (CK) levels that were 2 times over the upper limit of normal (2ULN) showed no significant differences in any time points between the two groups (P > 0.05). CONCLUSION: TDF and ETV treatment both exhibited rapid inhibiting effects on HBV DNA replication in the early phase of naive CHB patients in Mainland China. PMID- 25785043 TI - Up-regulated miR-93 contributes to coronary atherosclerosis pathogenesis through targeting ABCA1. AB - Atherosclerosis is a chronic inflammatory disease, starting with the accumulation of white blood cells and fatty materials in the arterial wall. ABCA1, a gene promotes phospholipid and cholesterol transfer from cells to poorly lapidated ApoA1, is considered to be related to the pathogenesis of coronary atherosclerosis. Meanwhile, disturbed miRNAs were reported to be related to coronary atherosclerosis. To understand the relationship between miRNA, ABCA1 and coronary atherosclerosis pathogenesis, we first screened the miRNAs that may directly target 3'UTR of ABCA1 and miR-33a was used as positive control. Through dual luciferase assay and western blot, we confirmed that miR-93 and miR-17 repress ABCA1 expression through directly targeting 3'UTR. The serum miR-33a, miR 93 and miR-17 levels in participants were detected by qRT-PCR and a significant reduction of miR-33a and miR-93 was found in the coronary patients. After statistical analysis we identified that a negative correlation was existed in the serum miR-93 and ABCA1 levels in coronary atherosclerosis patients. Meanwhile, our results indicate that the serum miR-93 positively correlates with the serum cholesterol level. This research may give insight into understanding of coronary atherosclerosis pathogenesis and create an opportunity to the diagnosis of coronary atherosclerosis. PMID- 25785044 TI - PIAS3, an inhibitor of STAT3, has intensively negative association with the survival of gastric cancer. AB - OBJECTIVE: The present study was conducted to elucidate the prognostic prediction value of the expression of the protein inhibitor of activated signal transducer and activators of transcription 3 (PIAS3) in gastric cancer (GC). METHODS: We detected the expression of PIAS3 in GC tissue, adjacent non-tumor tissue, GC cell lines, and GES-1 cell line. Besides, both clinicopathological data and follow-up records were obtained for patients' survival analyses. RESULTS: We showed that both protein and mRNA expression of PIAS3 in GC tissue were significantly lower than those in adjacent non-tumor tissue, respectively. Besides, the relative mRNA expression value of PIAS3 in each of GC cell lines was also much lower than that in GES-1 cell line. With multivariate survival analyses, PIAS3 protein expression in GC tissues, and status of lymph node metastasis were identified to be the independently prognostic predictors of GC by using the Cox regression with bootstrapping method. CONCLUSIONS: Lower expression of PIAS3 protein, indicating the poor survival of GC, is a potential marker for prediction the prognosis of patients. PMID- 25785045 TI - Association between regulator of telomere elongation helicase 1 polymorphism and susceptibility to glioma. AB - BACKGROUND: Glioma is the most devastating type of malignant brain tumors in adults. Genetic factors play important roles in the pathogenesis of glioma. In recent years, some studies found that there were significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility, however, the results were controversial. The aim of this study was to obtain a more exact estimation of the association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma through a meta analysis. METHODS: The meta-analysis included 19 published case-control studies involving 8541 cases and 14226 controls. The included papers were searched from PubMed and Embase database. Odds ratio (OR) with 95% confidence interval (95% CI) were used to evaluate the association of regulator of telomere elongation helicase 1 rs6010620 polymorphism with glioma. RESULTS: A significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility was observed for GG vs. AA+AG (OR=1.28, 95% CI=1.14-1.43) and G vs. A (OR=1.07, 95% CI=1.03-1.10). Further subgroup analysis based on ethnicity showed similar results in Asians and Caucasians. In the subgroup analysis of source of control, a significant association between the G allele and glioma susceptibility were found in population-based group and hospital-based group. CONCLUSIONS: The meta-analysis suggested that regulator of telomere elongation helicase 1 rs6010620 polymorphism was a risk factor for glioma. And this study also suggested that rs6010620 GG genotype and G allele may be indicators for the risk of glioma. PMID- 25785046 TI - Superparamagnetic iron oxide promotes osteogenic differentiation of rat adipose derived stem cells. AB - Adult adipose tissue-derived stem cells (ADSCs) were found to hold great promise for use in bone tissue repair and regeneration. The present study aims to improve the osteogenesis of ADSCs by Superparamagnetic Iron Oxide (SPIO), which is widely used in tissue imaging. In this study, adipose-derived stem cells were harvested from 4-week-old male Sprague-Dawley (SD) rats. The proliferation rates of ADSCs labeling with or without SPIO were assessed by using trypan blue assay. The osteogenic capability was examined by employing the ALP activity detection kit. The mineralization of cells was determined by staining with Alizarin red S. Flow cytometry analysis was used to examine the cell apoptosis treated with or without SPIO. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis was utilized to detect the Runx2, Opn, Ocn and ALP genes in the cells. The results indicated that SPIO could promote rat ADSCs proliferation and reduce rat ADSCs apoptosis. Also, SPIO could significantly enhance the ALP and alizarin red staining of ADSCs in -SPIO group and +SPIO group (P < 0.01). Furthermore, we also found that the expression of Runx2, Opn, Ocn and ALP was significantly increased after SPIO treatment compared to the un-treated cells (P < 0.01). In conclusion, SPIO could promote the osteogenic differentiation of rat adipose-derived stem cells, which would also become a great potential therapeutic tool in bone tissue engineering. PMID- 25785047 TI - IL-1RA gene-transfected bone marrow-derived mesenchymal stem cells in APA microcapsules could alleviate rheumatoid arthritis. AB - OBJECTIVES: In order to investigate the encapsulation of interleukin 1 receptor antagonist (IL-RA) gene-modified mesenchymal stem cells (MSCs) in alginate-poly-L lysine (APA) microcapsules for the persistent delivery of interleukin 1 receptor antagonist (IL-RA) to treat Rheumatoid arthritis (RA). METHODS: We transfect mesenchymal stem cells with IL-RA gene, and quantify the IL-RA proteins released from the encapsulated cells followed by microencapsulation of recombinant mesenchymal stem cells, and thus observe the permeability of APA microcapsules and evaluate clinical effects after induction and treatment of collagen-induced arthritis (CIA). The concentration of IL-RA in the supernatant was determined by IL-RA ELISA kit by run in technical triplicates using samples from three separate mice. RESULTS: Encapsulated IL-RA gene-transfected cells were capable of constitutive delivery of IL-RA proteins for at least 30 days. Moreover, the APA microcapsules could inhibit the permeation of fluorescein isothiocyanate conjuncted immunoglobulin G. Also, it has been found that the APA microcapsules can significantly attenuate collagen induced arthritis after delivering of APA microcapsules to rats. CONCLUSIONS: Our results demonstrated that the nonautologous IL-RA gene-transfected stem cells are of potential utility for RA therapy. PMID- 25785048 TI - Upregulated MiR-1269 in hepatocellular carcinoma and its clinical significance. AB - OBJECTIVES: MicroRNAs (miRNAs) are small, non-coding RNAs that have been increasingly shown important roles in various classes of cancers. However, miR 1269 has not been comprehensively studied in hepatocellular carcinoma (HCC). Thus, the purpose of the study was to evaluate the relationship between the expression of miR-1269 and clinicopathological parameters in HCC patients, and to predict its potential target genes. METHODS: Total RNA was extracted from 95 pairs of HCC and matching adjacent non-cancerous tissues. The level of miR-1269 expression was detected by using quantitative real-time RT-PCR and calculated with the 2(-DeltaCq) method. Eighteen online biological databases were used for targets prediction. RESULTS: MiR-1269 expression was up-regulated in HCC tissues (1.9264+/-0.7160) compared to their non-tumor livers (1.5518+/-0.7273, P < 0.001). Level of miR-1269 was positively correlated to tumor nodes (r = 0.206, P = 0.046), metastasis (r = 0.203, P = 0.049), portal vein tumor embolus (r = 0.247, P = 0.016), vaso-invasion (r = 0.273, P = 0.008), tumor capsular infiltration (r = 0.407, P < 0.001) and expression of MTDH (r = 0.211, P = 0.005). Finally, 7 databases could be applied for the target prediction successfully. There were 9 targeted genes which had been shown concurrently by at least 4 databases: AGAP1, AGK, BPTF, C16orf74, DACT1, LIX1L, RBMS3, ZNF706 and BMPER. CONCLUSIONS: MiR-1269 may be possibly involved in the tumorigenesis and progress of HCC. MiR-1269 could also act as a potential biomarker for the prognosis prediction for HCC. PMID- 25785049 TI - Assessment of serum and urine ghrelin levels in patients with acute stroke. AB - INTRODUCTION: Ghrelin is a novel brain-gut peptide hormone consisted of 28 amino acid. In the plasma, it exists in two major molecular forms, acylated and des acyled ghrelin, filtered in glomeruli or secreted by nephrons. Primary biological effects of hormones are regulating appetite, foods intake and energy metabolism. We investigated the changing and relationships between serum and urine ghrelin levels in acute stroke patients to provide more information whether diagnostic parameter. METHODS: Thirty acute stroke patients and thirty consecutive volunteers included in study prospectively. To analyze serum and urine ghrelin levels, at the time of diagnose, all of participant blood and fresh urine (1 ml serum, 2 ml urine respectively) samples were obtained. Serum ghrelin levels analyzed ELISA technique, and urine ghrelin levels studied by validation technique. To compare quantitative data student's t test, and for qualitative data chi-square and Fisher's Exact Chi-square test was used. P<0.05 was considered statistically significant. RESULTS: Urine acyl ghrelin levels found statistically significant between patient and control groups (P=0.001), but there were no statistically significant differences between both groups (P>0.05) in serum acyl gherelin, des-acyl ghrelin and urine des-acyle ghrelin levels. CONCLUSIONS: The results indicate that urine acyl ghrelin levels may be considered as a diagnostic parameter in acute ischemic stroke patients. Further studies delineating the mechanism of these observed results are warranted. PMID- 25785050 TI - Erysipelothrix rhusiopathiae-induced aortic valve endocarditis: case report and literature review. AB - Erysipelothrix rhusiopathiae is a pathogen of zoonosis often associated with occupational exposure. Although Erysipelothrix rhusiopathiae infection has high mortality, the heart valves in humans are rarely involved. The clinical data of a case of a 65-year-old male with Erysipelothrix rhusiopathiae-induced aortic valve endocarditis was summarized retrospectively and analyzed with a literature review. Based on a literature review and our experience, cases of E. rhusiopathiae-induced aortic valve endocarditis are extremely rare and surgical treatment for this condition is useful and recommended. PMID- 25785051 TI - Apolipoprotein E knockout induced inflammatory responses related to microglia in neonatal mice brain via astrocytes. AB - More and more evidences suggestted that ApoE plays an important role in modulating the systemic and central nervous inflammatory responses. However, there is a lack of exacted mechanism of ApoE. In this study, we aimed to investigate whether apolipoprotein E (ApoE) induced inflammatory responses and apoptosis in neonatal mice brain from ApoE deficient (ApoE(-/-)) and wildtype (WT). Compared to control group, the microglia cell from ApoE(-/-) mice showed more severe inflammation and cell death such as iNOS and IL-1beta. Furthermore, anti-inflammatory such as TGF-beta, IL-10 from microglia and astrocytes in ApoE( /-) mice were decreased. On the other way, TGF-beta from astrocytes can inhibit inflammation factors secretion from microglia. Our findings suggested that the anti- inflammation factor such as IL-10 mainly from microglia and TGF-beta mainly from astrocyte is significant decreased after Loss of ApoE function in ApoE(-/-) mice which induced severe inflammation. Furthrtmore, anti- inflammation factor such as IL-10 and TGF-beta Therefore, we conclude that apolipoprotein E knockout induced inflammatory responses related to microglia in neonatal mice brain via astrocytes. PMID- 25785052 TI - Feasibility study on the application of fenestrated stent grafts in canine aortic arches. AB - OBJECTIVE: To validate the feasibility and effectiveness of applying fenestrated stent grafts in canine aortic arches. METHODS: According to the anatomic characteristics of the aortic arches from four adult beagle dogs, a straight-type aortic coated vascular stent system from Lifetech Scientific (Shenzhen) Co., Ltd. was released in vitro, after which a square window was burnt out at the back tendon of the coated vascular stent with an electrocautery pen, and the fenestrated stent grafts were then returned in the catheter and delivery sheath, following the original release path. Endovascular aortic repair (EVAR) was then performed in the canine aorta. Immediately after surgery, digital subtraction angiography (DSA) and computed tomography (CT) angiography were conducted. On day 3, the dressing was changed, and on day 7, the stitches were removed and CT angiography was reviewed. Animal autopsies were performed 2 weeks after surgery. RESULTS: DSA and CT angiography were conducted in 4 beagles immediately after the experiments. The CT angiography reviewed on day 7 after surgery and the animal autopsy performed two weeks after surgery both revealed that the fenestrated stent grafts were anchored in the canine aortic arch, the openings were aligned against the branch vessels above the aortic arch, and in each branch vessel, the blood flow was smooth, without any obvious internal leakage phenomena. CONCLUSION: An ordinary straight-type coated vascular stent, fenestrated in vitro, followed by the performance of EVAR in the canine aortic arch for in vivo stent implantation, was technically feasible. When a branch coated vascular stent cannot meet the individual needs of the wound, this technology may provide a valuable strategy for clinical thoracic aortic trauma emergencies. PMID- 25785053 TI - Child-Pugh versus MELD score for predicting the in-hospital mortality of acute upper gastrointestinal bleeding in liver cirrhosis. AB - A retrospective study was conducted to compare the performance of Child-Pugh and Model for End-Stage Liver Diseases (MELD) scores for predicting the in-hospital mortality of acute upper gastrointestinal bleeding (UGIB) in patients with liver cirrhosis. A total of 145 patients with a diagnosis of liver cirrhosis and acute UGIB between July 2013 and June 2014 were retrospectively analyzed (male/female: 94/51; mean age: 56.77+/-11.33 years; Child-Pugh class A/B/C: 46/64/35; mean Child-Pugh score: 7.88+/-2.17; mean MELD score: 7.86+/-7.22). The in-hospital mortality was 8% (11/145). Areas under receiving-operator characteristics curve (AUROC) for predicting the in-hospital mortality were compared between MELD and Child-Pugh scores. AUROCs for predicting the in-hospital mortality for Child-Pugh and MELD scores were 0.796 (95% confidence interval [CI]: 0.721-0.858) and 0.810 (95% CI: 0.736-0.870), respectively. The discriminative ability was not significant different between the two scoring systems (P=0.7241). In conclusion, Child-Pugh and MELD scores were similar for predicting the in-hospital mortality of acute UGIB in cirrhotic patients. PMID- 25785054 TI - Warm ischemia may damage peribiliary vascular plexus during DCD liver transplantation. AB - Biliary complications cause significant morbidity and mortality in liver transplantation. Warm ischemia can induce biliary duct injury. This study aimed to investigate the effects of warm ischemia on the peribiliary vascular plexus in rat liver transplantation. A total of 102 Sprague-Dawley rats were divided into three groups: sham-operation group, non-ischemic group, and ischemic group. Liver transplantation was performed in both the non-ischemic group and the ischemic group. The animals were sacrificed on day 1, 3, 7, and 14 to collect the blood and liver samples. Serum levels of bile duct obstruction, viz, alkaline phosphatase and gamma-glutamyl transpeptidase, as well as direct and indirect bilirubin were measured. Liver biopsy samples were examined with hematoxylin eosin staining and transmission electron microscopy. The levels of enzymes and bilirubin were significantly higher in the ischemic group than the non-ischemic group and sham-operated animals (P<0.05), with return to normal levels in the ischemic group after two weeks. Morphological examination showed microthrombi and endothelial damage in the bile ducts and the peribiliary vascular plexus of the ischemic group. Warm ischemia/reperfusion injury can damage the endothelium of the peribiliary vascular plexus, which might compromise the bile duct microcirculation and lead to ischemic cholangiopathy after liver transplantation. PMID- 25785055 TI - The roles of vitamin B12 and vitamin D in children with intractable epilepsy. AB - Epilepsy is a chronic neurological disorder. Antiepileptic drugs (AEDs) can cause vitamin B12 or D deficiency in children with intractable epilepsy. In this study, we measured salivary superoxide dismutase (SOD) and metalloproteinsases (MMP) levels in the patients with vitamin B12 and vitamin D treatment. Cytokines and chemokines were measured using ELISA. The mean salivary value of SOD activity in the control group was 1.75 +/- 0.21 U/ml. In the treatment group, the value was 1.33 +/- 0.18 U/ml. The salivary MMP 2, MMP 3, and MMP 9 levels of the patients with vitamin D and vitamin B12 treatment were lower than that in the patients without vitamin D and vitamin B12 treatment. Interleukin 1beta (IL-1beta), IL-6, IL-8, macrophage inflammatory protein 1beta (MIP-1beta), monocyte chemoattractant protein-1 (MCP-1) and IFN-inducible protein 10 (IP-10) were significantly decreased in the cortex of our patients with vitamin D and vitamin B12 treatment. In this study, a clear association between vitamin D and vitamin B12 treatment and epilepsy was identified. We now plan to investigate the genetic factors that underlie vitamin D and vitamin B12 treatment in patients treated with AEDs. PMID- 25785056 TI - Safe distance between electrotome and recurrent laryngeal nerve: an experimental canine model. AB - BACKGROUND: Various energy based surgical devices (ESD) like electrotome have been widely applied in thyroid surgery. This is the first canine model to determine the safety margin of using the electrotome near the recurrent laryngeal nerve (RLN) to prevent injury to this nerve during thyroid surgery. METHODS: Eighteen healthy male dogs were divided equally into three groups according to the distance between electrotome application and the RLN: Group A (5 mm), Group B (3 mm), Group C (1 mm). The parameters of evoked electromyography (EEMG) of vocal muscles between right normal RLNs and left RLNs after electrotome application at a power of 30 W for 1 second in each group were recorded and compared. The acute microstructural morphological changes of the RLNs were observed immediately after the operation under electron microscope. RESULTS: In Group B and Group C, after using the electrotome at a vertical distance of 3 mm or 1 mm from the left RLNs, the stimulating thresholds of left RLNs had a significant increase (P = 0.005; P = 0.002) compared with right normal RLNs, and there occurred obvious acute microstructural morphological changes under electron microscope for left RLNs. While there was no significant functional or histological changes for left RLNs after using the electrotome at a vertical distance of 5 mm from the RLN (P = 0.187) in Group A. CONCLUSIONS: When using the electrotome near the RLN at a power of 30W in thyroid surgery, a safety margin of more than 3 mm should be recommended. PMID- 25785057 TI - Renoprotective effects of propofol on the expression of iNOS protein in rats with ischemia reperfusion injury. AB - AIMS: This study aims to explore the pathogenesis of myocardial ischemia reperfusion injury and the treatment method. METHODS: Myocardial Ischemia reperfusion rat model was established in this study. They were divided into three groups: sham operation (SO) group, IRI control (C) group and IRI with propofol (A) group (n = 9). Myocardial infarct size was compared with HE staining method. TUNEL assay was used to detect cell apoptosis. Changes in the expression of iNOS were detected using real-time PCR and Western blotting methods. RESULTS: Myocardial infarct size of control group and propofol group was 53.03 +/- 8.90% and 34.73 +/- 7.20% respectively, there were significant differences between them (P < 0.01). Apoptotic index of two groups was 0.21 +/- 0.02 and 0.31 +/- 0.05, with statistical significance (P < 0.05). The expression levels of iNOS in propofol group reduced significantly (P < 0.05). CONCLUSION: The levels of iNOS increase in IRI rats, suggesting that the severity of myocardial failure may be correlated with iNOS; propofol can specifically inhibit iNOS and thus protect the myocardial function. PMID- 25785058 TI - Association between dietary patterns and coronary heart disease: a meta-analysis of prospective cohort studies. AB - The associations of dietary patterns with coronary heart disease (CHD) risk remain unclear. Thereby, a meta-analysis was conducted to examine potential relations between dietary patterns and CHD. PubMed and EMBASE databases were searched up to March 2014 for eligible prospective cohort studies regarding the relationships between common dietary patterns and CHD. Random-effects models were applied to calculate the summary relative risk estimates (SRRE) for the highest versus the lowest category of dietary pattern. Sensitivity analyses were conducted and publication bias was assessed using Begg or Egger's tests. Twelve prospective cohort studies were included involving 409,780 participants and 6298 CHD cases. There was an inverse association between prudent/healthy dietary pattern and CHD risk (SRRE = 0.80, 95% CI: 0.74-0.87, P-value for heterogeneity = 0.497, I(2) = 0%). Furthermore, no significant association was observed between western/unhealthy dietary pattern and risk of CHD (SRRE = 1.05, 95% CI: 0.86 1.27, P-value for heterogeneity = 0.007, I(2) = 61.9%). However, increased risk was detected between western/unhealthy dietary pattern and CHD in the United States (USA) (SRRE = 1.45, 95% CI: 1.15-1.82, P-value for heterogeneity = 0.930, I(2) = 0%). In conclusion, our analysis provides evidence of an inverse association between prudent/healthy dietary pattern and CHD risk, and suggests null association between western/unhealthy dietary pattern and CHD. However, greater adherence to western/unhealthy pattern possibily increases by 45% the risk of CHD in USA. Further efforts are warranted to confirm these findings and clarify the role of dietary patterns and CHD risk. PMID- 25785059 TI - The role of O(6)-methylguanine-DNA methyltransferase polymorphisms in colorectal cancer susceptibility: a meta analysis. AB - OBJECTIVE: O(6)-methylguanine DNA methyl-transferase gene (MGMT) is a central DNA repair mechanism with a significant role in removing DNA damage caused by alkylating agents and inhibiting human oncogenesis. Two single polymorphisms in the MGMT gene, Leu84Phe and Ile143Val, have been reported to affect DNA repair capability and enzymic activity, thereby leading to formation of different cancers. In this work, we quantitatively assess the associations between MGMT polymorphisms and risk of colorectal cancer (CRC), as previous studies has implicated inconsistencies in their results. METHODS: Analysis was performed on all usable data collected from the eligible studies that were searched in multiple bibliographical databases (PubMed, SCOPUS, and Embase). RESULTS: We obtained studies on Leu84Phe and Ile143Val, providing 6,154 and 7,371 samples, respectively. In the analysis on Leu84Phe, the SNP presented no global association with CRC at both the genotypic and the allelic level, but a trend towards an increased or decreased risk was shown in the models examined. Stratification by ethnicity revealed a significant increase in risk of CRC related to the Phe/Phe genotype in Caucasian samples (homozygote genetic model: OR=1.70, 95% CI=1.06-2.72; recessive genetic model: OR=1.80, 95% CI=1.12-2.87). CONCLUSIONS: Based on the statistical data, our meta-analysis indicates that Leu84Phe polymorphism in the MGMT gene may predispose Caucasians to CRC. PMID- 25785060 TI - Efficacy and safety of cangrelor for patients with coronary artery disease: a meta-analysis of four randomized trials. AB - BACKGROUND: The efficacy and safety of new intravenous P2Y12 inhibitor (cangrelor) for patients with coronary artery disease (CAD) remain unclear. METHODS AND RESULTS: Trials were identified in PubMed, Web of Science, Embase, and Cochrane Database searches. We included four randomized, placebo-controlled reports in the meta-analysis. The database consisted of 36, 081 patients on cangrelor compared with clopidogrel or placebo. Major adverse cardiac events (MACE) were defined as the primary efficacy endpoint and major or severe bleeding at 48 hours was defined as the primary safety endpoint. Cangrelor significantly decreased risk of MACE (OR: 0.87, P = 0.002) and stent thrombosis (OR: 0.53, P < 0.001). However, at the same time, an increase in TIMI minor bleeding (OR: 1.49, P = 0.04) and in GUSTO moderate bleeding (OR: 1.43, P = 0.04) were observed by cangrelor. CONCLUSIONS: Intravenous administration of cangrelor is benefit to reduce risk of MACE and stent thrombosis in patients with CAD excepting for increased minor bleeding events. PMID- 25785061 TI - The expression and correlation of SIRT1 and Phospho-SIRT1 in colorectal cancer. AB - SIRT1 is the homologue of sir2 in mammals, which is a nicotinamide adenine dinucleotide (NAD(+)) dependent histone deacetylase. SIRT1 is involved in many physiological processes, such as metabolism, senescence, inflammatory response, neuroprotection, and tumorigenesis by acetylating histones and multiple transcription factors. However, the exact role of SIRT1 in tumor is still under controversial. Immunohistochemistry and Western blot were performed to investigate the expressions and subcellular localizations of SIRT1 and Phospho SIRT1 in colorectal cancer tissues and adjacent normal tissues. The relationship between SIRT1 or Phospho-SIRT1 and clinicopathological characteristics was also analyzed. Real-Time PCR was performed to investigate the transcriptional level of SIRT1 mRNA in colorectal cancer tissues and adjacent normal tissues. SIRT1 and Phospho-SIRT1 were both localized in the nucleus. The expressions of SIRT1 and Phospho-SIRT1 were higher in colorectal cancer tissues than normal tissues. SIRT1 expression in cancer tissues was associated with patient age, TNM stage and mutant P53 loss. Phospho-SIRT1 expression in cancer tissues was associated with Ki67. SIRT1 and Phospho-SIRT1 were highly correlated in cancer tissues and normal tissues. The ratios of Phospho-SIRT1 and SIRT1 expression in cancer tissues were higher than normal tissues. SIRT1 mRNA level was no significant difference in cancer tissues and normal tissues. SIRT1 have a dual character in colorectal cancer, and Phospho-SIRT1 may determine the role of SIRT1 in colorectal cancer formation. PMID- 25785062 TI - MICA polymorphisms and cancer risk: a meta-analysis. AB - The major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism has been implicated in susceptibility to cancer. However, the results are inconsistent. The aim of this meta-analysis is to evaluate the association between the MICA-TM polymorphisms and cancer risk. All eligible case control studies published up to August 20, 2014 were identified by searching PubMed, Web of Science, CNKI and Wanfang databases. The cancer risk associated with the MICA polymorphism was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. 21 studies from 19 publications with 3620 cases and 4903 controls were included. Overall, no significant associations between the MICA-TM polymorphism and cancer risk were found (A4 allele: OR = 0.97, 95% CI: 0.88-1.07; A5 allele: OR = 0.91, 95% CI: 0.81-1.04; A5.1 allele: OR = 1.03, 95% CI: 0.89-1.18; A6 allele: OR = 1.05, 95% CI: 0.95-1.15; A9 allele: OR = 0.96, 95% CI: 0.80-1.14; A10 allele: OR = 0.88, 95% CI: 0.43-1.79; del: OR = 2.50, 95% CI: 0.73-8.58; A7 allele: OR = 0.93, 95% CI: 0.43-2.00). When stratified by ethnicity, similar results were observed among Asians; however, there were significant association in Caucasian population for A5 (OR = 0.77, 95% CI: 0.68-0.87) and A9 allele (OR = 0.75, 95% CI: 0.66-0.85). This meta-analysis suggests that the MICA-TM A5 and A9 alleles may be an important protective factor for cancer in Caucasian populations. PMID- 25785063 TI - Therapeutic effects of minimally invasive adjustable and locking compression plate for unstable pelvic fractures via posterior approach. AB - OBJECTIVE: Unstable pelvic fractures are clinically complex injuries. Selecting appropriate treatment remains a challenging problem for orthopedic physicians. The aim of this study is to compare the clinical effects of minimally invasive adjustable plate and locking compression plate in treatment of unstable pelvic fractures via posterior approach. METHODS: From January 2009 to June 2012, fifty six patients with unstable pelvic fractures were included. After at least 12 month follow-up, forty-four patients treated with two methods were enrolled in the study and divided into two groups: minimally invasive adjustable plate (group A) and locking compression plate (group B). Preoperative and postoperative radiography was taken to assess the fracture displacement and reduction quality. The size of incision, operation duration, blood loss, duration of X-ray exposures, Majeed postoperative functional evaluation and Lindahl postoperative reduction evaluation were analyzed. RESULTS: The mean follow-up in group A was 27.3 months (range, 13-48 months), and that in group B was 21.8 months (range, 12 42 months). There were no iatrogenic neurovascular injuries during the operations in the two groups. In group B, malunion was observed in one patient, and infection of incision was observed in one case. The operation duration, blood loss, and size of incision of group A were significantly less than that of group B. There was no significant difference in the duration of X-ray exposures between the two groups. The Majeed functional evaluation score in group A was significantly higher than that in group B. The difference of the imaging score of the retained displacement was not statistically significant. CONCLUSIONS: Both the two methods can effectively stabilize the unstable pelvic fractures. However, the minimally invasive adjustable plate has the advantages of minimally invasive, less radiation exposure, technically safe and time saving. Minimally invasive adjustable plate is a good supplementary option for treating posterior pelvic ring injuries. PMID- 25785064 TI - Molecular classification and drug resistance analysis of Escherichia coli isolated from poultry in China. AB - We aimed to understand the distribution of Escherichia coli in poultry and to reveal the virulence factors, the drug resistance and molecular epidemic regularity and characteristics of isolate strains from 6 provinces in China and to complete the characteristics of E. coli for the risk assessment. A total of 87 E. coli isolates were analyzed with 7 virulence genes by PCR drug sensitivity test in 13 kinds of antimicrobial agents and analyzed with PFGE and MLST genotyping. The PFGE genotyping of 87 isolates yielded 75 PFGE type. MLST analysis of isolates identified the 39 STs, the 7 housekeeping genes had the different variation. The most prevalent virulence genes were iucD (74.7%), followed by iss (55.2%), Irp2 (43.7%), tsh (28.7%), cva (19.5%), papC (9.2%) and vat (8.1%). All isolates were resistant to two or three antimicrobial agents highly resistant to SXT, TE (85.06%), SF (83.91%), AM (66. 67%), to fluoroquinolones (ENR, 63.22%, NOR, 50.57%) and to GM (57.47%). E. coli strains resistant spectrum was wide gene was polymorphism the distribution had a certain timeliness and regional in part region of China. These were a solid foundation for the epidemiological investigation and traceability laid. PMID- 25785065 TI - Expression profile analysis of circulating microRNAs and their effects on ion channels in Chinese atrial fibrillation patients. AB - OBJECTIVE: To investigate the changes in expression profile of circulating microRNAs (miRNAs) and the regulatory effect of atrial fibrilation (AF)-related miRNAs on ion channels. METHODS: 112 patients with AF were assigned into observation group, and another 112 non-AF people were assigned into control group. Total plasma RNAs were extracted from patients' blood samples. Differentially expressed miRNA-1s were transfected into primary-cultured neonatal rat cardiac myocytes. RESULTS: Compared with control group, significant differences were observed in 15 kinds of miRNAs in observation group. Down regulation of the expression of miRNAs included hsa-miR-328, hsa-miR-145, hsa-miR 222, hsa-miR-1, hsa-miR-162, hsa-miR-432, and hsa-miR-493b; Up-regulation of the expression included hsa-miR634, hsa-miR-664, hsa-miR-9, hsa-miR-152, hsa-miR-19, hsa-miR-454, hsa-miR-146, and hsa-miR-374a. The expression level of CACNB2 protein in miRNA-1 group was significantly lower than that in blank control group, negative control group, MTmiRNA-1 group, AMO-1 group and miRNA-1+AMO-1 cotransfection group (P < 0.05), while in AMO-1 group, the expression level of CACNB2 protein was significantly higher than that in other groups (P < 0.05). These results indicated that transfected miRNA-1 could significantly inhibit the expression of CACNB2 protein. CONCLUSIONS: Circulating miRNAs can be used in studies concerning on the regulation mechanism of the occurrence and development of AF. MiRNA-1 can decrease the intracellular Ca(2+) concentration and prevent the AF. PMID- 25785066 TI - A new model for the discrimination between ulcerative colitis and Crohn's disease. AB - Distinguishing ulcerative colitis (UC) from Crohn's disease (CD) is sometimes difficult in a clinical setting. The purpose of this study was to identify a series of independent serum markers capable of distinguishing between UC and CD. 140 UC and 174 CD patients hospitalized at The First Affiliated Hospital, College of Medicine, Zhejiang University were recruited into this study. A panel of serum markers was quantified for each patient and the Bayesian information criterion (BIC) was used to determine a discrimination model. The receiver operating characteristic (ROC) was used to evaluate the performance of the model, and the area under the ROC curve (AUC) was used to evaluate the accuracy of the model. Serum albumin (Alb), total cholesterol (TC), total calcium (TCa), platelet (Plt), glycyl proline dipeptidyl aminopeptidase (GPDA) and their ratios (Alb: Plt, Alb: GPDA, TCa: TC, and Plt: GPDA) were selected into the diagnosis model using BIC. The resulting CD/UC Index (CUI) is CUI = 1.901 + 0.425 Alb - 3.324 TC - 7.444 TCa + 0.018 Plt + 0.087 GPDA - 0.0007 Alb: Plt - 0.004 Alb: GPDA + 1.839 TC: TCa + 0.003 Plt: GPDA, with CUI > 0 incrementally favored a diagnosis of UC, while CUI < 0 corresponded to a higher likelihood of a diagnosis of CD. An average value of the AUC for the CUI model is 0.73 (95% confidence interval: 0.67-0.80). The CUI, derived from commonly available serum biomarkers, could try to differentiate UC from CD in patients with unclear clinical features as a new approach to diagnosis. PMID- 25785067 TI - Prognostic factors for surgically managed patients with stage II non-small cell lung cancer. AB - BACKGROUND: To investigate the prognostic factors in surgically managed patients with stage II non-small cell lung cancer. MATERIAL AND METHODS: A retrospective analysis of clinical data of surgically managed 93 patients with stage II non small cell lung cancer in our hospital between May 2005 and November 2009 was conducted, and prognostic factors that may impact the postoperative 5-year survival rate were statistically analyzed. RESULTS: Univariable survival analysis showed that new TNM staging, total number of dissected lymph nodes, number of dissected N1 and N2 lymph nodes and N1 lymph groups, metastasis rate of N1 lymph nodes, and 10th group of lymph nodes metastatic or not, were related to the postoperative 5-year survival rate in the patients. Multivariable survival analysis showed that the metastasis rate of N1 lymph nodes and 10th group of lymph nodes metastatic or not were independent prognostic factors for the postoperative 5-year survival rate in the patients. CONCLUSION: When patients with stage II non-small cell lung cancer are treated with surgery, the total number of dissected lymph nodes greater than 6, the number of dissected N1 lymph nodes over 5, N2 over 2, and the number of dissected N1 groups over 3, may improve their postoperative 5-year survival rate. The metastasis rate of N1 lymph nodes over 50%, and the metastasis of the 10th group of lymph nodes imply poor prognosis of the patients. PMID- 25785068 TI - Surgical approach does not influence the outcome of incidental gallbladder carcinoma. AB - Several reports claim that there is a risk that laparoscopic cholecystectomy (LC) might worsen the prognosis of unsuspected gallbladder cancer. The aim of this study was to evaluate whether the surgical approach influence the outcome in patients with incidental gallbladder carcinoma. METHODS: A retrospective study was done of 28 patients who were diagnosed with unsuspected gallbladder carcinoma who had undergone cholecystectomy for benign gallbladder disease at our institution between 1999 and 2007. 20 patients (4 men and 16 women, aged from 37 to 81 years) undergoing LC (group A) and 8 patients (6 men and 2 women, aged from 43 to 88 years) undergoing open cholecystectomy (OC) (group B) with incidental diagnosed GC. We evaluated the outcome in the two groups correlating the cumulative survival rates with tumor stage and surgical technique (LC or OC), time of diagnosis (after or during cholecystectomy). RESULTS: nine patients (69.2 %) in group A and four patients (30.8%) in group B had recurrence. Survival rate was statistically correlated to tumor stage (P<0.0001) Survival rate was statistically correlated with tumor stage but neither with the surgical approach used to perform cholecystectomy, nor with time of diagnosis (intra- or post operatively). CONCLUSION: These results would seem to lend support to the opinion that LC does not worsen the prognosis for incidental GC, regardless of whether the tumor was detected during or after cholecystectomy. PMID- 25785069 TI - Alterations of ghrelin with weights and correlation among ghrelin, cytokine and survival in patients receiving chemoradiotherapy for gastrointestinal cancers. AB - AIM: This study involved 30 patients (16 had gastric, 9 pancreatic and 5 gall bladder cancer) who had received concomitant chemoradiotherapy (CRT). Blood ghrelin and IL-6 values were compared before, in the last week of, and 3 months after CRT. Meanwhile, changes in body weight of patients were also investigated with changes in ghrelin and IL-6 levels before, in the last week of, and after radiotherapy (RT). METHODS: Informed consent of the patients and the ethical committee approval from Cukurova University Medical Faculty were taken. Blood ghrelin and IL-6 levels were measured by using the ELISA method. Survival analysis was performed by the Kaplan Maier method, and data were evaluated by using the SPSS 19.0 package. Categorical measurements were calculated as numbers and percentages, whereas numerical data were summarized as mean and standard deviation. RESULTS: The correlation between ghrelin and IL-6 values at the baseline of RT and overall survival rates at the end of the 30-month follow up was analyzed. Accordingly, ghrelin values were also changed in line with changes in patients' weights (P < 0.001). Patients with ghrelin values above 35 pg/ml before RT had longer survival rates at the end of the 30-month follow up (P = 0.001). Overall survival rates in patients with IL-6 value at or below 3.9 pg/ml before RT were longer than patients with IL-6 value above 3.9 pg/ml (P = 0.021). CONCLUSION: Therefore, the initiation of ghrelin analogue prophylactically in patients receiving chemoradiotherapy with gastrointestinal system malignancies can both prevent weight loss by increasing appetite and decrease severity of inflammation, thereby increasing survival. PMID- 25785070 TI - A common genetic variant as an effect modifier for primary angle closure glaucoma. AB - BACKGROUND: Epidemiological studies provide evidence of a genetic basis for primary angle closure glaucoma (PACG), and genome-wide association studies (GWAS) have identified various candidate genes as susceptibility loci. However, different results produced by previous studies make the role of a common genetic variant in the COL11A1 gene (rs3753841) remains elusive. Thus, we carried out a meta-analysis, attempting to determine the association of rs3753841 with PACG. METHODS: Potentially relevant studies were identified by systematical computer based searches. Selection of eligible studies was undertaken by two investigators according to inclusion criteria. The DerSimonian and Laird's method was performed to estimate pooled odds ratios (risk of PACG) under distinct genetic models. Heterogeneity was measured using the chi-square-based Q statistic test and I(2) metric. RESULTS: We found a significant association of COL11A1 rs3753841 with PACG among 26,365 subjects (5,594 cases and 20,771 controls) with Asian or Caucasian ancestry derived from a total of 15 studies. The association was more pronounced in individuals with the GG genotype (GG vs AA: odds ratio 1.26, 95% confidence interval 1.13-1.41; GG vs GA + AA: odds ratio 1.24, 95% confidence interval 1.12-1.38). In the stratified analyses, the statistical significance was retailed in Asians and the studies without Hardy-Weinberg equilibrium. CONCLUSION: Our meta-analysis including the large-scale study suggest that COL11A1 variant rs3753841 may confer higher susceptibility to PACG and provide additional insight into the mechanisms that underlie this most common subtype of glaucoma. PMID- 25785071 TI - Role of beta-isomerized C-terminal telopeptides (beta-CTx) and total procollagen type 1 amino-terminal propeptide (tP1NP) as osteosarcoma biomarkers. AB - INTRODUCTION: Few serum markers are valid and useful for the diagnosis or therapeutic effect monitoring of osteosarcoma. This study aimed to investigate the role of beta-isomerized C-terminal telopeptides (beta-CTx) and total procollagen type 1 amino-terminal propeptide (tP1NP) as serological biomarkers for osteosarcoma patients. MATERIALS AND METHODS: A total of 48 patients with osteosarcoma and 55 healthy volunteers were investigated. Serum beta-CTx and tP1NP levels were measured by electrochemiluminescence immunoassay. Data were analyzed by t test with Walth's correction and receiver operating characteristic (ROC) curve analysis. RESULTS: The baseline levels of beta-CTx and tP1NP were found to be significantly higher in patients with osteosarcoma than the healthy volunteers. The mean areas under the ROC curves were 0.919 (range, 0.864-0.973) for beta-CTx and 0.866 (range, 0.792-0.939) for tP1NP. The levels of beta-CTx and tP1NP were lower in patients with stable disease after operation than those before operation. CONCLUSION: These findings support our hypothesis that beta-CTx and tP1NP are promising serum biomarkers for diagnosing or monitoring osteosarcoma. PMID- 25785072 TI - Wound bed preparation for ischemic diabetic foot ulcer. AB - OBJECTIVE: This study is to evaluate the effect of allograft skin on wound angiogenesis and wound bed preparation of ischemic diabetic foot ulcer. METHODS: A total of 60 cases of patients with diabetic foot ulcer were randomly divided into the experimental group (n = 30) and the control group (n = 30). After debridement, in the experimental group, allograft skin was used to cover the wound while in the control group, vaseline and gauze was used to cover the wound. The wound was opened and dressed at 3, 5, 7, 14 days after operation and the growth condition of the granulation tissue was observed and recorded. RESULTS: The wound bed preparation time of the experimental group was 14.37 +/- 1.06 days, compared with the control group 25.99 +/- 4.03 days, there was statistically significant difference (t = 14.78, P < 0.0001). The mean cure time of the experimental group was 32 +/- 1.93 days and this time was significantly shortened than the control group 39.73 +/- 2.55 days (t = 12.521, P < 0.01). CONCLUSIONS: Allogeneic skin has a protective effect on the wound and could promote vascularization of ischemic diabetic foot ulcer and shorten the wound bed preparation time and treatment cycle. PMID- 25785073 TI - Comparison of laparoscopic versus open left lateral segmentectomy. AB - BACKGROUND: Although there are data in the literature about the safety and efficacy of laparoscopic liver resections, there are not many studies comparing laparoscopic versus open approaches in a case-matched design. This study was designed to compare perioperative outcomes of the left lateral segmentectomy via laparoscopic and open approach. METHODS: From January 2009 to January 2013, we performed left lateral segmentectomies in 60 patients, those excluded from analysis included previous liver resections, polycystic liver disease and liver cirrhosis. Laparoscopic left lateral segmentectomy was performed in 30 patients and open left lateral segmentectomy was performed in 20 patients. All clinical data were analyzed retrospectively. RESULTS: The mean duration of operation was 120 +/- 30.4 min in the LLS and 150 +/- 36.8 min in the OLS group, no statistically significant difference was found between the two groups. The median blood loss in LLS group was less than that in OLS group (200 +/- 22.1 ml versus 328 +/- 36.8 ml, P < 0.05). Mean post-operative hospital stay was significantly lower in LLS compared with OLS (5 +/- 0.9 vs. 8 +/- 1.0; P < 0.05). The postoperative morbidity rate was also significantly different between the groups, a tendency towards more severe complications in the OLS group compared with LLS group. CONCLUSION: Laparoscopic left lateral segmentectomy can decrease complications, shorten hospitalization time, is a minimally invasive, safe and effective way. PMID- 25785074 TI - Up-regulation of cyclin E in breast cancer via estrogen receptor pathway. AB - It is well known that cell cycle dysregulation plays an important role in breast cancer. The mechanism, however, is not fully understood. In this study, we aimed to explore whether estrogen and estrogen receptor pathway play a role in the regulation of cell cycle protein cyclin E expression, and whether the expression of cyclin E is associated with breast cancer prognosis. We first examined the level of cyclin E expression in breast cancer by immunohistochemistry. Benign fibroadenoma was used as controls. Next we cultured MCF-7 cells with different concentration of 17beta-estradiol or tamoxifen for 48 hours. Then we employ qRT PCR to determine changes of cyclin E in MCF-7 cells. Cyclin E is overexpressed in breast cancer and its expression is associated with the status of estrogen receptor and lymph node metastasis. After treatment with 17beta-estradiol, the gene expression of cyclin E was enhanced, and as the concentration increased, the enhancement increased. After treatment with tamoxifen, the gene expression of cyclin E was inhibited, and as the concentration decreased, the inhibition increased. We demonstrated that estrogen induces, while tamoxifen inhibits cyclin E expression. This indicate that estrogen receptor pathway play a critical role in cell cycle dysregulation in breast cancer. PMID- 25785075 TI - Vitamin D analog EB1089 could repair the defective bone marrow-derived mesenchymal stromal cells in patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) involves multiple factors, which result in the breakdown of self-tolerance and development of autoimmunity with organ damage. Bone marrow mesenchymal stem cells (BMMSCs) from the patients with SLE showed an impaired proliferative capacity compared with that from normal controls. In this study, we isolated BMMSCs from the patients with SLE and found that Vitamin D analog EB1089 could induce BMMSCs proliferation and mineralization deposition. Furthermore, we found that the expression of p-Smad 1/5/8 was promoted in BMMSCs with EB1089 treatment. In conclusion, our results support the notion that EB1089 promoted proliferation and osteogenic differentiation of BMMSCs by Smad 1/5/8 signaling pathway. PMID- 25785076 TI - Unpredicted effects of Ankaferd(r) on cartilage tissue. AB - OBJECTIVE: This study aims to investigate the histopathological changes secondary to the administration of Ankaferd Blood Stopper(r) (ABS) into the auricular cartilage. MATERIALS AND METHODS: Both of the auricular cartilages of thirty New Zealand rabbits were marked with tattoo ink. A 0.2-cc ABS (study group, n: 30) and 0.2 cc physiological saline (control group, n: 30) were subcutaneously infused into the right auricle and left auricle, respectively. All layers were removed at 14 days. RESULTS: The ABS group had significantly higher level of fibrosis, necrosis, foreign body reaction, inflammation, and cartilage degeneration, compared to the controls. CONCLUSION: Our study results showed that ABS administration into a closed cavity led to a significantly increased fibrosis and necrosis in the auricular cartilage. PMID- 25785077 TI - Effect evaluation of repeated debridement after endoscopic sinus surgery. AB - OBJECTIVE: To investigate the effect of early phase debridement by the different intervention frequencies on postoperative symptoms recovery and turnover of mucosa after functional endoscopic sinus surgery (FESS). METHODS: 67 patients undergone FESS were divided into intervention group and control group. Intranasal corticosteroids, macrolides antibiotics and postoperative saline douching were used in both groups. Debridement was performed on the 1(st), 4(th), 8(th) postoperative week on patients of invention group, while once per week on patients of control group. The primary outcome measure was visual analogue scale (VAS) and Lund-Kennedy Endoscopic Score (LKES) Results: On the 4(th) week, the control group presented more release on nasal block, the VAS of the two groups is 3.45 +/- 1.16 and 4.83 +/- 1.47 in the control group and intervention group respectively which was significantly different. The LKES on crust decreased more in the control group (1.12 +/- 0.64 in the control group and 1.90 +/- 0.47 in the intervention group). However, the control group complained more sever facial pain and uncomfortable; the VAS of two groups is 5.92 +/- 0.91 and 2.74 +/- 1.41 respectively. On the 8(th) week, there were no significant difference between the two groups on all domains of VAS and LKES except lower scar was shown in the control group. CONCLUSIONS: Benefit of frequent debridement during the early postoperative was not in positive correlation with patients recovering from ESS. Excessive debridement may induce more surgical trauma and cause more facial pain to patients. Therefore, in terms of subjective recovery and health care costs, appropriate extending postoperative management time and decreasing intervention frequencies will not affect the therapeutic effect of endoscopic surgery for chronic sinusitis. PMID- 25785078 TI - Expression of ATF4 and RUNX2 in periodontal tissue of pressure side during orthodontic tooth movement in rat. AB - OBJECTIVE: This study aims to explore the expression levels of ATF4 and RUNX and their interactions in periodontal tissue of the pressure side during orthodontic tooth movement. METHODS: A total of 72 SPF level male Sprague Dawley rats were used in this study, they were divided into 9 groups randomly and 8 rats in each group. The expression changes of ATF4 and RUNX2 in periodontal tissue of pressure side at different straining time point were detected with RT-PCR and Western blotting methods. The morphological changes of cells in the tissue samples were observed by HE staining. The data were analyzed with SPSS 19.0 software. RESULTS: The expression levels of ATF4 and RUNX2 increased during orthodontic tooth movement and were related with the movement time. They reached highest after straining for 24 h and began to decrease after straining for 12 d. CONCLUSIONS: The expression levels of ATF4 and RUNX2 in periodontal tissue can increase transiently induced by stress, which play a role in the process of osteogenesis and reconstruction of periodontal tissue during orthodontic tooth movement. PMID- 25785079 TI - Human cervical cancer oncogene-1 over expression in colon cancer and its clinical significance. AB - OBJECTIVE: This study was to explore the expression of human cervical cancer oncogene-1 (HCCR-1) in colon cancer and its clinical significance. METHODS: RT PCR, immunohistochemistry and Western blot assay were employed to detect HCCR-1 expression in 152 colon cancers, 43 adjacent non-cancerous tissues and 37 normal tissues. In addition, immunohistochemistry was done to detect CEA in colon cancers. RESULTS: The mRNA expression of HCCR-1 in colon cancers was higher than that in the adjacent non-cancerous tissues (P < 0.05), and the mRNA expression of HCCR-1 in adjacent non-cancerous tissues was higher than that in normal tissues (P < 0.05). The positive rate of HCCR-1 in colon cancers was 80.9%, which was higher than that in adjacent non-cancerous tissues (P < 0.05). Almost no HCCR-1 expression was observed in normal tissues, weak expression in adjacent non cancerous tissues and strong expression in colon cancers. The positive rate of HCCR-1 in colon cancer at Duke stage B-C was 87.3%, which was higher than that in stage A colon cancer (63.6%, P < 0.05). CONCLUSION: HCCR-1 is over-expressed in colon cancers, indicating that HCCR-1 may participate in occurrence and development of colon cancer and has a correlation with the pathological progress of colon cancer progression. PMID- 25785080 TI - Angiotensin-converting enzyme I/D polymorphism is a genetic biomarker of diabetic peripheral neuropathy: evidence from a meta-analysis. AB - The Angiotensin-converting enzyme (ACE) I/D polymorphism has been indicated to be correlated with peripheral neuropathy (PN) susceptibility, but study results are still debatable. Thus, a meta-analysis was conducted. Databases including PubMed, Embase and CNKI were searched. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Eight studies with 1430 cases and 1873 controls were included in this meta-analysis. The association between ACE I/D polymorphism and PN risk was significant (OR = 1.25; 95% CI 1.05-1.48; P = 0.01). When stratified by ethnicity, the significantly increased PN risk was observed in Caucasians (OR = 1.24; 95% CI 1.05-1.47; P = 0.01). In conclusion, this meta-analysis suggested that ACE I/D polymorphism was a risk factor for PN. PMID- 25785081 TI - Factor analysis on symptoms and signs of stroke based on traditional Korean Medicine theory. AB - The purpose of this study was to classify factors of symptoms and signs, which is the same implication with items of factor, from patients with stroke based on the Traditional Korean Medicine (TKM) theory by using factor analysis, and to find out the inter-relations between factors and patterns. A cross-sectional study was conducted among 2905 patients with stroke in 11 Oriental Medicine hospitals of Korea. Outcome measures comprised patterns decided by TKM doctors considering 44 items and 44 items that were based on inspection, listening and smelling, inquiry, and palpation. Factor analysis was used as statistical method for classifying 44 items, and dominant pattern of the four patterns [Qi deficiency (QD), Fire-heat (FH), Yin deficiency (YD), Dampness-phlegm (DP)] for each factor was determined by Chi-square test. Thirty-three items belonged to some factors, but 11 items did not. 14 factors were extracted. Six factors which had a negative loading were separated, and distinguished using hyphen. The fourteen factors accounted for 9.42%, 6.97%, 5.75%, 4.22%, 4.15%, 3.82%, 3.32%, 3.14%, 2.95%, 2.65%, 2.62%, 2.47%, 2.37% and 2.29% of total variance respectively, and totally 56.14%. In conclusion, there are 10 factors which belong to exclusive pattern, and 9 factors which belong to inter-related pattern. It was statistically found out that there are inter-relation between DP and QD, between DP and FH, between FH and YD, and between YD and QD for stroke patients. PMID- 25785082 TI - Noninvasive predictive models of liver fibrosis in patients with chronic hepatitis B. AB - OBJECTIVE: The aim of the present study was to establish noninvasive diagnostic models for liver fibrosis and assess their predictive accuracy (AC). METHODS: A total of 349 patients with chronic hepatitis B virus infection were evaluated, who underwent liver biopsy and pathologic examination at Beijing Ditan Hospital affiliated to Capital Medical University. Patients were subdivided in disease immune tolerant (n = 125) and immune reactive HBeAg positive (n = 224) groups. Diagnostic models were based on independent markers of liver fibrosis. Receiver operating characteristic (ROC) curves were used to set cutoff values and determine the diagnostic value of the models. RESULTS: Wang I and Wang II models were constructed using independent disease markers. Wang I model cutoff values <= 1.75 and > 5.84 were used to identify patients in the immune tolerant phase with or without significant fibrosis. The area under the ROC curve (AUC) for this model was 0.866 (95% CI, 0.790, 0.942) and an AC of 92.0% was obtained. Wang II model cutoff values <= 3.79 and > 7.06 were used to identify immune reactive HBeAg-positive patients with or without significant fibrosis. AUC was 0.872 (95% CI, 0.824, 0.920), with an AC of 88.0%. CONCLUSIONS: Both Wang models enabled noninvasive liver fibrosis assessment with reliable predictive power and reproducibility for diagnosis of fibrosis in immune tolerant and immune reactive HBeAg-positive patients. With further development, these models may provide a clinical alternative to liver biopsy. PMID- 25785083 TI - Intraoperative diagnosis of benign and malignant breast tissues by fourier transform infrared spectroscopy and support vector machine classification. AB - BACKGROUND: Fourier transform infrared (FTIR) spectroscopy has shown its unique advantages in distinguishing cancerous tissue from normal one. The aim of this study was to establish a quick and accurate diagnostic method of FTIR spectroscopy to differentiate malignancies from benign breast tissues intraoperatively. MATERIALS AND METHODS: In this study, a total of 100 breast tissue samples obtained from 100 patients were taken on surgery. All tissue samples were scanned for spectra intraoperatively before being processed for histopathological diagnosis. Standard normal variate (SNV) method was adopted to reduce scatter effects. Support vector machine (SVM) classification was used to discriminate spectra between malignant and benign breast tissues. Leave-one-out cross validation (LOOCV) was used to evaluate the discrimination. RESULTS: According to histopathological examination, 50 cases were diagnosed as fibroadenoma and 50 cases as invasive ductal carcinoma. The results of SVM algorithm showed that the sensitivity, specificity and accuracy rate of this method are 90.0%, 98.0% and 94.0%, respectively. CONCLUSIONS: FTIR spectroscopy technique in combination with SVM classification could be an accurate, rapid and objective tool to differentiate malignant from benign tumors during operation. Our studies establish the feasibility of FTIR spectroscopy with chemometrics method to guide surgeons during the surgery as an effective supplement for pathological diagnosis on frozen section. PMID- 25785084 TI - Role of blood tumor markers in predicting metastasis and local recurrence after curative resection of colon cancer. AB - AIM: To investigate the prognostic value of carcinoembryonic antigen (CEA), CA199, CA724 and CA242 in peripheral blood and local draining venous blood in colon cancer patients after curative resection. METHODS: 92 colon cancer patients who received curative resection were retrospectively analyzed. The CEA, CA199, CA724 and CA242 were detected in peripheral blood and local draining venous blood. RESULTS: Metastasis or local recurrence was found in 29 (29/92, 31.5%) patients during follow-up period. 92 patients were divided into two groups: metastasis/local recurrence group (n = 29) and non-metastasis/local recurrence group (n = 63). Peripheral venous CEA, CA199, CA724 and CA242 (p-CEA, p-CA199, p CA724 and p-CA242) were comparable between two groups (P > 0.05). The median draining venous CEA (d-CEA) in metastases/local recurrence group (23.7 +/- 6.9 ng/ml) was significantly higher than that in non-metastases/local recurrence group (18.1 +/- 6.3 ng/ml; P < 0.05), but marked differences were not observed in draining venous CA199, CA724 and CA242 (d-CA199, d-CA724 and d-CA242) between two groups (P > 0.05). The optimal cut-off value of d-CEA was 2.76 ng/ml, with the sensitivity and specificity of 90% and 40% in the prediction of metastasis or local recurrence, respectively. d-CEA correlated with tumor differentiation, T stage, TNM stage, metastasis and local recurrence. Subgroup analysis showed that, of 41 patients with stage II colon cancer, the optimal cut-off value of d-CEA was 8.78 ng/mL, and the sensitivity and specificity were 87.5% and 69.7% in the prediction of metastasis or local recurrence, respectively. CONCLUSION: d-CEA may be a prognostic factor for stage II colon cancer patients. PMID- 25785085 TI - Association of plasma Fetuin-A and clinical characteristics in patients with new onset type 2 diabetes mellitus. AB - CONTEXT: Fetuin-A is an abundant plasma protein known to inhibit insulin signaling and pathologic calcification, has emerged as a promising candidate biomarker for diabetes risk. OBJECTIVE: The objective of this study was to investigate the relationships between plasma Fetuin-A level with clinical characteristics in patients with new-onset type 2 diabetes mellitus (nT2DM). SUBJECTS AND METHODS: Plasma Fetuin-A levels, and clinical characteristics were assessed in 100 patients with nT2DM and 100 normal glucose tolerance (NGT). RESULTS: nT2DM subjects had significantly higher Fetuin-A levels than NGT subjects (368.5 +/- 15.6 vs 152.7 +/- 7.1 mg/ml, P < 0.01). In the Pearson's correlation coefficients, Fetuin-A levels and clinical parameters. Fetuin-A was positively correlated with HOMA-insulin resistance index (HOMA-IR), carotid intima media thickness(CIMT), HbA1c, triglyceride (TG), Low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), systolic blood pressure (SBP), fasting plasma glucose (FBG) and 2 h post-glucose load blood glucose (2 h OGTT) (P < 0.05 and P < 0.01), but negatively with fasting plasma insulin (FINS), 2 h plasma insulin after glucose overload (PINS), High-density lipoprotein cholesterol (HDL-C) and HOMA-beta-cell insulin secretion index (HOMA-IS) (P < 0.05 and P < 0.01). However, no significant relationships were observed between plasma Fetuin-A levels and estimated glomerular filtration rate (eGFR), age and gender in nT2DM subjects. In a multiple linear regression analysis, Fetuin-A levels were independently associated with FBG, 2 h OGTT, HOMA-IS, TG, and CIMT (R(2) = 0.6760). CIMT were negatively associated with FINS and HDL-C (r = -0.33, P = 0.008; r = -0.31, P = 0.01, respectively) in the Pearson's analyses. Moreover, they were positively associated with HOMA-IR (r = 0.28, P = 0.03). It showed significant correlations of plasma CIMT with FINS, PINS and HOMA-IR (R(2) = 0.6760). CONCLUSIONS: Our study suggests that the plasma Fetuin-A levels may be associated with macroangiopathies in nT2DM patients. Therefore, detecting early plasma Fetuin-A levels nT2DM provides an opportunity to intervene of carotid artery disease in diabetic patients and giving timely treatment for the prevention of diabetic vascular complications. PMID- 25785086 TI - Initial hepatic artery infusion and systemic chemotherapy for asymptomatic colorectal cancer with un-resectable liver metastasis. AB - PURPOSE: Hepatic arterial infusion (HAI) has been proved to be an effective strategy to increase the chances of resection for colorectal cancer patients with liver metastasis (CRCLM). Herein, we aimed to evaluate the benefits and risks of initial treatment with HAI floxuridine (FUDR) and systemic XELOX in un-resectable synchronous CRCLM. MATERIALS AND METHODS: HAI catheter systems were implanted radiologically in 54 patients with un-resectable synchronous CRCLM. Upfront HAI FUDR and systemic XELOX were delivered without primary cancer resection. Patients underwent deferred surgery when the metastatic diseases were converted to resectability, or any serious colorectal cancer-related complications occurred. RESULTS: Thirty-eight patients (70.4%) were converted to resectability and underwent staged or synchronous resection of the primary tumor and metastatic disease, with an estimated 3-year survival rate of 76% compared with 15% in un resected patients. Uni-variate analysis showed that hepatic involvement, number of lesion, and the location of primary cancer did not affect resectability rate. Only 3 patients (5.6%) required palliative surgery to treat complications related to primary cancer. CONCLUSIONS: Initial HAI FUDR and systemic XELOX are effective to help patients with CRCLM to obtain a high resection rate for asymptomatic colorectal cancer and un-resectable liver metastases, and associated with a low rate of complications related to the intact primary cancer. PMID- 25785088 TI - Intra-articular hyaluronate, tenoxicam and vitamin E in a rat model of osteoarthritis: evaluation and comparison of chondroprotective efficacy. AB - OBJECTIVE: The aim of this experimental study was to evaluate and compare the chondroprotective efficacy of intra-articular hyaluronic acid, tenoxicam and vitamin E in osteoarthritis. METHODS: An osteoarthritis model was created by anterior cruciate ligament transection and medial menisectomy in knees of 28 rats. The rats were randomized into four groups; first group served as a control group and received intra-articular injections of saline solution, intra-articular HA, intra-articular tenoxicam and intra-articular Vit E were applied to the treatment groups. First intra-articular injections were applied at second week postoperatively and repeated once a week for 5 weeks. At 8th week after the operation groups were compared based on the histologic scores of cartilage degeneration by Mankin Histological Grading Scale. RESULTS: Total cartilage degeneration score was significantly increased in the control group (P=0.004). Total Mankin scores of HA, tenoxicam and Vit E groups were significantly lower than the control group (P=0.004, P=0.016, P=0.012 respectively). There was no statistically siginificant difference between the treatment groups in terms of total Mankin scores (P>0.05). CONCLUSION: Intra-articular application of HA, tenoxicam and Vit E are chondroprotective in early osteoarthritis model in rats. Chondroprotective activity of tenoxicam and Vit E are comparable with the beneficial effects of HA on articular cartilage. PMID- 25785087 TI - MicroRNAs associated with osteoarthritis differently expressed in bone matrix gelatin (BMG) rat model. AB - Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intraarticular inflammation with synovitis, and changes in peri-articular and subchondral bone. In recent years, more and more evidence demonstrated that microRNAs (miRNAs) play important roles in the molecular mechanisms in OA by suppressing gene expression at the post-transcriptional level. In current study, histological staining of toluidine blue and cartilage-specific gene express revealed that the bone matrix gelatin (BMG) rat model could demonstrate the different development of cartilage. In current study, we tested whether some miRNAs associated with OA differently expressed in BMG rat model. We verified that miR-140 and miR-455 were associated with cartilage development, and further revealed that miR-140-5p and miR-455-3p might play more important function than miR-140-3p and miR-455-5p in the BMG rat model. Moreover, we found that miR-9 and miR-98 were involved in the endochondral ossification, suggesting they may be also the key regulators in the process of endochondral ossification. In fact, many miRNAs worked as a miRNA-mediated regulatory network in the process of cartilage development and OA. Further functional discovery will clarify the roles of individual miRNAs and their targets, and serve as a strong foundation for translating these findings to the clinic therapy for OA. PMID- 25785089 TI - Identification of B cells participated in the mechanism of postmenopausal women osteoporosis using microarray analysis. AB - To further understand the molecular mechanism of lymphocytes B cells in postmenopausal women osteoporosis. Microarray data (GSE7429) were downloaded from Gene Expression Omnibus, in which B cells were separated from the whole blood of postmenopausal women, including 10 with high bone mineral density (BMD) and 10 with low BMD. Differentially expressed genes (DEGs) between high and low BMD women were identified by Student's t-test, and P < 0.01 was used as the significant criterion. Functional enrichment analysis was performed for up- and down-regulated DEGs using KEGG, REACTOME, and Gene Ontology (GO) databases. Protein-protein interaction network (PPI) of up- and down-regulated DEGs was respectively constructed by Cytoscape software using the STRING data. Total of 169 up-regulated and 69 down-regulated DEGs were identified. Functional enrichment analysis indicated that the genes (ITPA, ATIC, UMPS, HPRT1, COX10 and COX15) might participate in metabolic pathways, MAP3K10 and MAP3K9 might participate in the activation of JNKK activity, COX10 and COX15 might involve in mitochondrial electron transport, and ATIC, UMPS and HPRT1 might involve in transferase activity. MAPK3, ITPA, ATIC, UMPS and HPRT1 with a higher degree in PPI network were identified. MAPK3, MAP3K10, MAP3K9, COX10, COX15, ATIC, UMPS and HPRT1 might participate in the pathogenesis of osteoporosis. PMID- 25785090 TI - Pure transcatheter arterial chemoembolization therapy for intrahepatic tumors causes a shrink in pulmonary metastases of hepatocellular carcinoma. AB - OBJECTIVE: Pulmonary metastasis of hepatocellular carcinoma (HCC) could be defined as advanced HCC and systematic treatment is the main therapeutic modality. However, local therapy of intrahepatic tumor, which is significantly associated with the prognosis of HCC, remains important for advanced HCC. METHODS: Twenty-six HCC patients with pulmonary metastasis underwent intrahepatic transcatheter arterial chemoembolization (TACE). We investigated the progression of lung metastastic tumors, overall survival and risk factors related to survival of these patients. RESULTS: Of the 26 patients who underwent TACE for one to four times, 10 patients achieved complete remission (CR) of intrahepatic tumors and among these 10 patients, 4 patients successfully received hepatic artery-venous shunt embolization combined with TACE. The lung metastasis lesions also achieved CR and the survival time was significantly longer than the other 22 patients. The lung metastastic lesions of the other 6 patients of intrahepatic tumors achieved stable disease (SD). Six patients acquired partial remission (PR) of intrahepatic tumors after TACE, while the lung metastastic lesions showed SD or progress disease (PD). Patients who showed CR and PR of intrahepatic tumors had longer survival time than patients with SD and PD. Portal vein tumor thrombus and size of the lung metastastic lesions were significant prognostic factors in these advanced HCC patients. CONCLUSIONS: With respect to HCC patients with lung metastasis, TACE was an effective and important therapeutic tool to control pulmonary metastatic tumor growth, and prolong the survival of advanced HCC patients, especially patients with hepatic artery-venous shunt. PMID- 25785091 TI - Elasticity of healthy Achilles tendon decreases with the increase of age as determined by acoustic radiation force impulse imaging. AB - AIMS: The objective of the study was to investigate the value of acoustic radiation force impulse (ARFI) and its application in Achilles tendon elasticity of healthy volunteers. METHODS: Bilateral Achilles tendons of 56 healthy individuals were included in the study. The subjects were divided into four age groups. Shear wave velocities (SWVs) of each tendon in the states of relaxation and tension were measured using ARFI technology. We selected the middle section of the Achilles tendon for ARFI measurement. Each Achilles tendon was examined by a musculoskeletal radiologist. Longitudinal images of each tendon were obtained by ultrasound and ARFI elastography. A quantitative assessment of the tissue stiffness was made with virtual touch tissue quantification. RESULTS: Significant differences in SWVs of Achilles tendon were found between any two age groups in the same status (P < 0.05) and between different status in subjects aged 25-35 years (P < 0.05) and 36-45 years (P < 0.05). SWV of Achilles tendon increased with increasing age in both states of relaxation and tension, which was consistent with the histological feature of ageing tendons. However, there were no significant differences between men and women within any group in the same status (P > 0.05) or between different states in subjects aged 46-55 years (P = 0.308) and 56-65 years (P = 0.362). CONCLUSIONS: ARFI imaging provides quantitative information about tendon stiffness and represents an excellent supplementary technique to B-mode ultrasound. Furthermore, the elasticity of healthy tendon decreases with increasing age in subjects without disease and long term heavy load lifting. PMID- 25785092 TI - Genetic polymorphisms of IL-6 and IL-10 genes correlate with lung cancer in never smoking Han population in China. AB - Lung cancer is one of the most common cancers in the world, especially in China. It is believed that genetic polymorphisms played a role in cancer susceptibility. Here we investigated the association of interleukin-6 (IL-6) and interleukin-10 (IL-10) gene polymorphisms with the susceptibility of lung cancer in never smoking Chinese Han population. In this study, we performed a case-control study including 330 cases of never-smoking lung cancer patients and 336 cancer-free never-smoking controls in Chinese Han population. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to identify gene polymorphisms, and then verified by sequencing method. The results indicated that the four single nucleotide polymorphisms (IL-6 -1363T/G and -572G/C, IL-10 819T/C and -592A/C) were genotyped by PCR-RFLP and confirmed by sequencing, and we found that the allelic frequencies of G in IL-6 -1363T/G, C in IL-10 -819T/C and C in IL-10 -592A/C were significantly increased in lung cancer patients, by comparing with the control group. However, there was no significant difference in the distribution of the IL-6 572G/C polymorphisms between patients and controls. In conclusion, the IL-6 -1363T/G, IL-10 -819T/C and IL-10 -592A/C polymorphisms are closely related to genetic susceptibility to lung cancer in never-smoking Chinese Han population, and these genetic variants might be used as molecular markers for detecting lung cancer susceptibility. PMID- 25785093 TI - Hydronephrosis due to ureteral endometriosis in women of reproductive age. AB - OBJECTIVE: The aim of the present study was to improve the understanding of ureteral endometriosis, and remind the clinics to be highly suspicious of it in women of reproductive age with hydronephrosis without evidence of stones and malignancy. METHODS: A retrospective analysis was performed on a database of 82 patients who underwent surgery for hydronephrosis due to ureteral endometriosis between Jan. 2007 and Apr. 2014. RESULTS: All patients evaluated in this study were divided into three groups: Group A consisted of patients between 20-30 years (n = 12), Group B comprised of patients between 31-40 years (n = 29), Group C consisted of patients between 41-50 years (n = 41). Patients in Group C had a greater prevalence of pelvic pain compared with patients in Group A and Group B (P < 0.05). However there were no differences with respect to the prevalence of other non-specific genitourinary symptoms and the urinary symptoms. Infertility was found to occur more frequently in patients in Group A compared with patients in Group B and Group C (P < 0.05). Because of the lack of specific symptoms, ureteral endometriosis was diagnosed (20.1 +/- 10.3) months on average after the patients suffered from mild hydronephrosis or mild loin pain. Preoperative examinations showed different degree of hydronephrosis, but lack of specificity. All patients underwent surgery by laparotomy or laparoscopy, such as ureterectomy with ureteroureterostomy or ureterocystoneostomy. The pathological examination confirmed the diagnosis of ureteral endometriosis. CONCLUSION: The diagnosis of ureteral endometriosis is elusive and relies heavily on clinical suspicion. Hence, women in the reproductive age, especially with infertility and pelvic pain, who have hydronephrosis without evidence of stones and malignance, should be adequately assessed via imaging techniques or diagnostic laparoscopy or cystoscopy to highly suspect the diagnosis of ureteral endometriosis. PMID- 25785095 TI - The plasma and platelet are important in reducing the mortality in surgical massive blood transfusion: a large multicenter study in China. AB - OBJECTIVE: The aim of this study was to learn the current situation of surgical massive transfusion of death and survival groups in China, which could provide the basis for the formulation of guidelines on massive transfusion. METHODS: A multicenter retrospective research for the application status of blood constituents during massive blood transfusion was conducted, the differences of fresh frozen plasma and platelet application between death group and survival group were compared, and the transfusion volume and the distribution of other blood constituents were analyses at different periods of time when red blood cells are infused between death group and survival group. RESULTS: The patients with fresh frozen plasma compare the patients with red blood cell was 1:1-2 during massive transfusion, while the dosage of platelet and cryocepitate were transfused very small. Results showed that the average amount of platelet and plasma in death group was significantly lower than those in survival group. CONCLUSION: During massive transfusion, clinicians in 20 Chinese hospitals paid more attention to the infusion of fresh frozen plasma while making the infusion of red blood cells. However, they paid little attention to the supplement of platelet and cryocepitate. The average quantity of plasma and platelet in survival group were also higher than those in death group. PMID- 25785094 TI - Evaluation of prognostic factors for secondary cytoreductive surgery in Chinese patients with recurrent epithelial ovarian carcinoma. AB - OBJECTIVE: Secondary cytoreductive surgery (SCS) is reported to be beneficial for patients with recurrent epithelial ovarian carcinoma (EOC). The current study is to evaluate risk factors that would affect the surgical optimal resection rate and prognosis of recurrent EOC after SCS in Chinese patients. METHODS: In our study, 44 patients with recurrent EOC treated with SCS at Shandong Cancer Hospital were retrospectively reviewed. Patient characteristics were collected and multivariate logistic regression was used to analyze factors that affect the optimal surgical resection rate. The overall survival rate was calculated by the Kaplan-Meier method. Cox proportional-hazards regression was used to analyze risk factors that affect the overall survival of these patients. RESULTS: 90.9% (40/44) patients achieved optimal cytoreductive surgery. Logistic regression did not find any factor that affects the optimal surgical resection rate. Among 24 cases that received chemotherapy before SCS, 18 cases achieved good response and thus had a better survival rate after SCS. Multivariate Cox proportional hazard regression analysis indicated that differentiation, the extent of surgical resection during the initial surgery, and course and efficacy of chemotherapy prior to SCS, and efficacy of chemotherapy after the first recurrence significantly correlated with survival of patients with recurrent cancer (P < 0.05; OR < 1). CONCLUSION: Selection of patients that are suitable to perform SCS will enhance the optimal surgical resection rate. The prognosis of Chinese patients with recurrent EOC after SCS is affected by histologic grade, the extent of residual disease and the effect of chemotherapy after first relapse. PMID- 25785096 TI - Expression of Yes-associated protein in liver cancer and its correlation with clinicopathological features and prognosis of liver cancer patients. AB - OBJECTIVE: To investigate the expression of Yes-associated protein (YAP) in liver cancer and its correlation with clinicopathological features and prognosis of liver cancer patients. METHODS: A total of 95 patients receiving surgery due to liver cancer were recruited. RESULTS: In 95 liver cancers, YAP expression was significantly higher than that in adjacent normal tissues. In addition, of liver cancers, 14.7% was negative for YAP (14/95), 29.5% (28/95) weakly positive, 21.1% (20/95) positive and 34.7% (33/95) strong positive, and low expression and high expression were observed in 44.2% (42/95) and 55.8% (53/95) of liver cancers, respectively. Of adjacent normal tissues, 13.7% (13/95) were negative or weakly positive for YAP. The mean survival time of patients with high YAP expression was significantly longer than that of patients with low YAP expression (Log-rank = 9.206, P < 0.01). Univariate analysis showed portal vein thrombosis (P < 0.01), metastasis (P < 0.01), American Joint Committee on Cancer Staging (AJCC) stage (P < 0.01), alpha fetoprotein (AFP) (P < 0.01) and high YAP expression (P < 0.01) were factors affecting the overall survival of liver cancer patients. However, multivariate analysis showed metastasis (P < 0.01) and high YAP expression (P < 0.01) were independent risk factors of overall survival of liver cancer patients. CONCLUSION: YAP expression increases significantly in liver cancer and it may be involved in the occurrence and development of liver cancer. YAP expression is an independent risk factor affecting the overall survival of liver cancer patients. PMID- 25785097 TI - A novel tissue-engineered bone in repairing femoral head defect and necrosis. AB - OBJECTIVE: To evaluate the therapeutic effects of AACB/BMP/bFGF, a novel tissue engineered bone, in repairing femoral head defect and necrosis in dog models. METHODS: Dog models of avascular necrosis of femoral head (ANFH) were established by liquid nitrogen freezing method. Group A was untreated; Groups B, C, and D were implanted with AACB, AACB/BMP, and AACB/BMP/bFGF complex, respectively; Group E was grafted with autologous cancellous bone. Samples were collected at 3 w, 6 w, and 12 w after operation. A series of examinations were carried out to investigate the effects of the materials in repairing femoral head defect, including anatomical observation, X-ray examination, histological analysis, and vascular immunohistochemical staining. RESULTS: Our results indicated that, compared with AACB alone and AACB/BMP, AACB/BMP/bFGF complex could exert the most efficient therapeutic effects in dog ANFH models. X-ray examination further confirmed that AACB/BMP/bFGF complex could effectively repair the injuries in dog ANFH models, almost to a comparable level with cancellous bone autografts. Moreover, histological analysis indicated that AACB/BMP/bFGF complex greatly enhanced the new bone formation, which would contribute to the healing of ANFH. Furthermore, vascular immunohistochemical staining revealed that AACB/BMP/bFGF complex could significantly stimulate the revascularization in defect areas, reflecting the post-injury healing process in these models. CONCLUSION: AACB/BMP/bFGF complex has great potential in repairing femoral head defect by enhancing osteogenesis and revascularization. The novel tissue-engineered bone would be widely used in clinical applications for ANFH treatment, especially as an alternative for autografts. PMID- 25785098 TI - Positive MACC1 expression correlates with invasive behaviors and postoperative liver metastasis in colon cancer. AB - OBJECTIVE: Metastasis-associated in colon cancer-1 (MACC1), a new gene associated with primary and metastatic colon cancer, promotes tumor cell growth as well as the development of distant metastasis. The aim of this study is to investigate the expression of MACC1 protein in colon cancer and its association with clinicopathological parameters and postoperative liver metastasis. MATERIALS AND METHODS: Expression of MACC1 protein was detected immunohistochemically in paraffin-embedded specimens of 96 cases of colon cancer. Relationship between MACC1 protein expression and clinicopathological parameters, postoperative liver metastasis were analyzed. RESULTS: Immunohistochemistry examination showed that MACC1 protein expression was significantly more abundant in colon cancer tissues than in normal colon tissues (P = 0.038), Positive rate of MACC1 expression in colon cancer tissues was increased significantly in patients with lymph node metastases (P = 0.001) and higher T stages (P = 0.006). Postoperative live metastasis-free survival period was significantly longer in negative MACC1 expression group than that of positive MACC1 expression group (36.4 +/- 2.85 vs. 28.6 +/- 2.02 months, P = 0.014). Multivariate analysis showed that MACC1 expression level is an independent prognostic factor for postoperative live metastasis-free survival (95% confidence interval [CI] =1.32-3.38, P = 0.006). CONCLUSIONS: Our results suggest that MACC1 expression level might play an important role in colon cancer invasion and MACC1 expression level is an independent biomarker for postoperative liver metastasis in patients with colon cancer. PMID- 25785099 TI - 99mTc-ECD brain perfusion SPECT imaging for the assessment of brain perfusion in cerebral palsy (CP) patients with evaluation of the effect of hyperbaric oxygen therapy. AB - OBJECTIVE: The present study was carried out to evaluate cerebral perfusion in different types of cerebral palsy (CP) patients. For those patients who underwent hyperbaric oxygen therapy, brain perfusion before and after the therapy was compared. METHODS: A total of 11 CP patients were enrolled in this study, of which 4 patients underwent oxygen therapy. Before oxygen therapy and at the end of 40 sessions of oxygen treatment, 99mTc-ECD brain perfusion single photon emission computed tomography (SPECT) was performed , and the results were compared. RESULTS: A total of 11 CP patients, 7 females and 4 males with an age range of 5-27 years participated in the study. In brain SPECT studies, all the patients showed perfusion impairments. The region most significantly involved was the frontal lobe (54.54%), followed by the temporal lobe (27.27%), the occipital lobe (18.18%), the visual cortex (18.18%), the basal ganglia (9.09%), the parietal lobe (9.09%), and the cerebellum (9.09%). Frontal-lobe hypoperfusion was seen in all types of cerebral palsy. Two out of 4 patients (2 males and 2 females) who underwent oxygen therapy revealed certain degree of brain perfusion improvement. CONCLUSION: This study demonstrated decreased cerebral perfusion in different types of CP patients. The study also showed that hyperbaric oxygen therapy improved cerebral perfusion in a few CP patients. However, it could keep the physiological discussion open and strenghten a link with other areas of neurology in which this approach may have some value. PMID- 25785100 TI - A clinical analysis of 21 cases of pen sheath bronchial foreign bodies in children. AB - OBJECTIVE: To explore the clinical characteristics of children pen sheath bronchial foreign body, andto conclude rigid bronchoscope and self-made foreign body hook in the value of diagnosis and treatment in childrenpen sheath bronchial foreign body and operating considerations. METHODS: 21 pen sheath bronchial foreign body cases diagnosed and treated by rigid bronchoscopy were retrospective analyzed. RESULTS: Under the assistance of self-made foreign body hook and latent speculum, 20 cases were successfully removed, 1 case was turned thoracotomy thoracic surgery. CONCLUSION: Rigid bronchoscopy is an effective method to finally diagnose and treat pen sheath bronchial foreign body. Using self-made foreign body hook can significantly improve the success rate of surgery and reduce occurrence of complications. PMID- 25785101 TI - Value of contrast-enhanced ultrasound in the differential diagnosis between gallbladder adenoma and gallbladder adenoma canceration. AB - OBJECTIVES: To investigate the value of contrast-enhanced ultrasound (CEUS) in the differential diagnosis between gallbladder adenomas and gallbladder adenomas canceration. METHODS: CEUS data from 34 patients (25 patients with gallbladder adenomas and 9 patients with gallbladder adenomas canceration) were retrospectively analyzed, including the characteristics of contrast arrival time, time to peak enhancement, enhancement extend, enhancement morphology and the intactness of gallbladder wall below the lesions. RESULTS: On CEIS, the contrast arrival time and the time to peak enhancement were significantly shorter in patients with gallbladder adenomas than in patients with gallbladder adenomas canceration (12.63 +/- 3.37 s vs. 18.11 +/- 3.26 s, P < 0.001; 17.42 +/- 3.69 s vs. 24.56 +/- 4.36 s, P < 0.001). The time to iso-enhancement showed no significant difference between the two groups; while the time to hypo-enhancement was significantly shorter in patients with gallbladder adenomas canceration than in patients with gallbladder adenomas (55.56 +/- 15.48 s vs. 84.71 +/- 36.07 s, P = 0.027), and the enhancement time of the liver was significantly slower in patients with gallbladder adenomas canceration than in patients with gallbladder adenomas (22.78 +/- 5.28 s vs. 16.63 +/- 4.66 s, P = 0.004). Using receiver operating characteristic (ROC) analysis, the time to peak enhancement greater than 20 s had 89% sensitivity and 84% specificity for detecting patients with gallbladder adenomas canceration. The enhancement level showed no difference between the two groups. Inhomogeneous enhancement was found in 33% (3/9) gallbladder adenoma canceration and none (0/25) of gallbladder adenoma (P < 0.01). Destruction of gallbladder wall intactness was found in 66.7% (6/9) gallbladder adenoma canceration and none (0/25) of gallbladder adenoma (P < 0.01). CONCLUSION: CEUS is useful in differentiation between gallbladder adenoma and gallbladder adenoma canceration. The time to peak enhancement, the enhancement morphology and the intactness of gallbladder wall below the lesions are the diagnostic clues in differentiating diagnosis between gallbladder adenoma and gallbladder adenoma canceration. PMID- 25785102 TI - Surgical procedure and long-term survival of hilar cholangiocarcinoma. AB - OBJECTIVE: The aim of this study was to identify the influencing factors related to outcome of patients with hilar cholangiocarcinoma. METHODS: From January 1999 to January 2009, 204 cases of hilar cholangiocarcinoma undergoing surgery were analyzed retrospectively. Bismuth-Corlette classification showed type I in 18 patients, type II in 40, type IIIa in 65, type IIIb in 54, type IV in 27. Survival analysis was performed by the Kaplan-Meier method and the relationship between each of the clinicopathologic variables and survival was assessed by the log-rank test. Multivatiate results were confirmed using Cox regression. RESULTS: Radical resection was accomplished in 161 of 204 patients (78.9%). Radical resection offered the best chance of long-term survival, with the 1-, 3-, and 5 year survival rate were 62.6%, 42.4%, 23.7%, respectively. Univariate analysis showed that lymph node metastasis, surgical margin, operative procedure and tumor differentiation were prognostic impacts. The difference was statistically significant (P < 0.05). Cox multivariate analysis showed that lymph node metastasis and surgical margin are two separate prognostic factors. CONCLUSION: Racical resection is the key to improve the long-term survival rate of hilar cholangiocarcinoma and a favorable outcome after resection is mainly determined by curative resection and the absence of lymph node metastasis. PMID- 25785103 TI - Morphometry of lumbar spinous process via three dimensional CT reconstruction in a Chinese population. AB - To investigate the morphometric data of the lumbar spinous process dimensions in Chinese population. Forty-six adult subjects (22 males, 24 females, age range 26 45 years) were studied using the method of the three dimensional CT reconstruction in our hospital. The following parameters were measured: the distance between two adjacent spinous processes (DB), distance across the two adjacent spinous processes (DA), thickness of central of spinous processes (TC), thickness of the superior margin of spinous processes (TS), thickness of the inferior margin of spinous processes (TI), and height of spinous processes (H). Variance and correlation analysis were conducted for these data. Data met with normal distribution and homogeneity of variance. Similar variation trend of the parameters of lumbar spinous process for male and female was found. DB became shorter gradually from L1-2 to L4-5, and increased at the L5-S1. DA became larger from T12-L1 to L1-2 for male and L2-3 for female, and then became shorter from L1 2 for male and L2-3 for female, respectively. The largest H of male and female were both noted at L3. TS of the adjacent spinous processes were lower than that of TI for male and female. Statistical significance between male and female were found in H, TC, TS, TI (L1, L3 and L4), and DA (except for L4-5). Compared to male, the spinous processes of female were shorter, thinner and lower. These data may be useful for clinical application and the design of interspinous implant in Chinese population. PMID- 25785104 TI - PIK3C2G copy number is associated with clinical outcomes of colorectal cancer patients treated with oxaliplatin. AB - PURPOSE: To investigate whether the copy number of PIK3C2G is associated with clinical outcomes for stage III colorectal cancer (CRC) patients treated with oxaliplatin-based chemotherapy. METHODS: A total of 142 CRC patients who received first-line oxaliplatin-based chemotherapy after curative surgery in Ruijin Hospital and The Tenth People's Hospital were recruited in this study. Patients were enrolled between June 2006 and December 2011, with follow-up to January 2014. Quantitative real-time PCR method was used to detect the copy number of PIK3C2G. Cox proportional hazards model and Kaplan-Meier curves were used to analyze the association between PIK3C2G copy number and clinical outcome. RESULTS: In patients with stage III disease, low copy number of PIK3C2G was associated with increased risk of both recurrence (HR, 2.44, 95% CI, 1.33-4.47, P=0.004) and death (HR, 2.89, 95% CI, 1.49-5.60, P=0.002). Multivariate analysis also indicated that low PIK3C2G copy number was a significant and independent predictor of OS and RFS of stage III CRC. CONCLUSIONS: PIK3C2G is capable of predicting the recurrence and overall survival of stage III CRC patients receiving oxaliplatin-based therapy. PMID- 25785105 TI - Improved Achilles tendon healing by early mechanical loading in a rabbit model. AB - OBJECTIVE: To investigate the structure and the attachment strength of a healing tendon-bone interface and the role of mechanical loading in tendon healing. METHODS: Sixty rabbits underwent unilateral detachment and repair of the Achilles tendon. Thirty animals were immobilized (Group A), and the others wereallowed loadingimmediately postoperatively (Group B). Animals were sacrificed at 4 weeks and evaluated for histological and biomechanical testing. Statistical analysis was performed with an independent t test with significance set at P = 0.05. RESULTS: The ultimate stress was greater in group B (4.598 +/- 1.321 N/mm(2)) compared with the control group (3.388 +/- 0.994 N/mm(2)) (P < 0.05). Similarly, a more organized tendon-to-bone interface with a larger area of chondrocytes was found in group B (P < 0.05). CONCLUSION: Mechanical loading improves the structure and the attachment strength of the healing tendon-to-bone interface. PMID- 25785106 TI - Correlative analyses of isolated upper lumbar disc herniation and adjacent wedge shaped vertebrae. AB - BACKGROUND: Upper lumbar disc herniation (ULDH) is easy to be misdiagnosed due to its special anatomical and atypical clinical features. Few studies have identified the relationship between ULDH and adjacent wedge-shaped vertebrae (WSV). HYPOTHESIS: WSV may have some indicative relations withULDH. PATIENTS AND METHODS: Between January 2003 and October 2013, 47 patients (27 males and 20 females; mean age, 41.2 years) with single-level ULDH (as study group) and 47 sex and age-matched healthy volunteers (as control group) were studied by radiograph. The two groups were compared with respect to age, sexual proportion, body mass index (BMI), kyphotic angle, and the proportion of WSV. Also, correlative analyses were conducted in the study group to investigate the relation between the kyphotic angle of target vertebrae and other factors including age, BMI, Cobb angle, JOA score and bone mineral density (BMD). RESULTS: The average kyphotic angle in the study group was 11 degrees (4 degrees -22 degrees ), while the average kyphotic angle in the control group was 2 degrees (0 degrees -7 degrees ). Obviously, the mean kyphotic angle in the study group was statistically larger than that in the control group (t=13.797, P<0.001). The proportion of WSV in the study group was significantly larger than that in the control group (x(2)=36.380, P<0.0001). The correlations between kyphotic angles and other items (i.e., age, BMI, BMD, Cobb angle and JOA score) in the study group and the control group were low or uncorrelated. CONCLUSIONS: WSV are indicatively associated with adjacent ULDH. Thus, ULDH should be alerted when WSV are first found in radiograph and accompanied by clinical symptoms. PMID- 25785107 TI - A comparison study of immune-inflammatory response in electroacupuncture and transcutaneous electrical nerve stimulation for patients undergoing supratentorial craniotomy. AB - OBJECTIVE: The effect of transcutaneous electrical nerve stimulation (TENS) on immuno-inflammatory response was tested and the differences between electroacupuncture (EA) and TENS in immuno-inflammatory response in patients undergoing supratentorial craniotomy were explored. METHODS: 51 patients received craniotomy were randomly divided into 3 groups: control (group C, n=18), EA (group A, n=19) and TENS (group T, n=14) groups. Blood samples were collected before anesthesia (T0) and 30 min (T1), 2 h (T2) and 4 h (T3) after induction of anesthesia to measure the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-8, IL-10, IgM, IgA and IgG. RESULTS: No significant difference existed between group A and group T during craniotomy. IgM and IgA decreased significantly in group C compared with groups A and T at T2 and T3 time points. Compared with group C, there were significant differences in TNF-alpha, IgM and IgA levels at T0 in groups A and T; no significant difference was found in the levels of IgG, IL-10 and IL-8. CONCLUSION: EA and TENS could reduce immunosuppression in patients undergoing supratentorial craniotomy and it has significance in choice of treatment in immunosuppressive therapy. PMID- 25785108 TI - Bulbocavernosus reflex and pudendal nerve somatosensory evoked potential are valuable for the diagnosis of cauda equina syndrome in male patients. AB - AIMS: This study is to assess the value of bulbocavernosus reflex (BCR) and pudendal nerve somatosensory evoked potential (SSEP) in the topical diagnosis of cauda equina syndrome (CES) with or without sphincter dysfunction in male patients. METHODS: In this study, 40 healthy male adults (control group) and 53 male adult patients (experimental group) were included. The experimental group was subdivided into sphincter subgroup (24 patients with sphincter dysfunction) and non-sphincter subgroup (29 patients without sphincter dysfunction). All subjects underwent BCR and SSEP examinations. The mean latencies of BCR and SSEP P41 were calculated and compared between the control group and the experimental group. Latencies above the average value of +2.58S were considered abnormal. The abnormality rates of BCRs and SSEPs in sphincter and non-sphincter subgroups were calculated, respectively. RESULTS: BCR and SSEP latencies in the experimental group were remarkably prolonged than those in the control group. BCR and SSEP latencies in sphincter subgroup were remarkably prolonged than those in non sphincter subgroup. Among the 106 nerves in the experimental group, 87 nerves had prolonged BCR latencies and 3 nerves had no wave elicited, with an abnormality rate of 84.9%. The abnormality rates of BCR were 95.8% and 74.1% in sphincter subgroup and non-sphincter subgroup, respectively. Among the 53 nerves in the experimental group, 39 nerves had prolonged SSEP P41 latencies and 2 nerves had no wave elicited, with an abnormality rate of 77.4%. The abnormality rates of SSEP P41 were 91.7% and 65.5% in sphincter subgroup and non-sphincter subgroup, respectively. CONCLUSIONS: Both BCR and SSEP were changed in CES patients with or without sphincter dysfunction, and they were especially changed in patients with sphincter dysfunction. BCR and SSEP are valuable in the diagnosis of cauda equina lesions and their severity in males. PMID- 25785109 TI - Concomitant ligamentous and meniscal injuries in floating knee. AB - BACKGROUND: To identify and characterize the concomitant ligamentous and meniscal injuries in floating knee. METHODS: A total of 37 cases of floating knee were enrolled. Arthroscopic or open surgical examination of the knee, Lachman test, posterior drawer's test, and varus and valgus stress tests under anesthesia were carried out to determine the incidence of knee injury. RESULTS: Through arthroscopic and open surgical examinations, a medial meniscal tear was detected in 14 (37.8%) cases and a lateral meniscal tear in 11 (29.7%). Twenty-one (56.8%) patients had anterior cruciate ligament (ACL) injury including complete injury in 6 and incomplete injury in 15 cases. Three (8.1%) patients had posterior cruciate ligament (PCL) tear, including complete injury in 1 and incomplete injury in 2. Varus and valgus stress tests revealed that 10 (27.0%) and 7 (18.9%) patients had medial and lateral collateral ligament (MCL and LCL) laxity, respectively. Lachman test showed positive in 8 (21.6%) cases. Posterior drawer test showed positive in 3 (8.1%) cases. Twenty-six (70.3%) patients had knee ligamentous injuries. ACL injury was the most common ligamentous injury. ACL injury in 15 (71.4%) cases was associated with meniscal injury, including medial meniscal injury in 9 (42.9%) and lateral meniscal injury in 6 (28.6%). CONCLUSION: Physicians should pay attention to the concomitant ligamentous and meniscal injuries in floating knee. Careful clinical examination with aid of arthroscopic examination is helpful for the early diagnosis and treatment of these injuries. PMID- 25785110 TI - Associations between human aldosterone synthase CYP11B2 (-344T/C) gene polymorphism and antihypertensive response to valsartan in Chinese patients with essential hypertension. AB - Aldosterone synthase is a mitochondrial enzyme that catalyzes the conversion of 11-deoxycorticosterone to the potent mineralocorticoid aldosterone. The gene encoding aldosterone synthase, CYP11B2, is associated with essential hypertension. But if the genetic variations in aldosterone synthesis could influence the antihypertensive response to Valsartan is not clear. A Chinese sample of 502 persons (217 women) was studied, which was divided into the hypertensive group (EH) of 345 persons and the normotensive group (NB) of 157 persons. Subjects were genotyped through the use of the polymerase chain reaction for the diallelic polymorphisms in CYP11B2. 98 persons of the essential hypertension group received 4 weeks therapy with valsartan. Blood pressure, 24 hour ambulatory blood pressure, biochemical index were also determined. The frequency of CC+CT genotypes in hypertensive group was significantly higher than that in normotensive group (P<0.05), the frequency of C allele of gene CYP11B2 ( 344T/C) in hypertensive group was significantly higher than that in normotensive group (P<0.01). The descending values of SBP (systolic blood pressure), DBP (diastolic blood pressure), MAP (mean arterial pressure), 24 h SBP (mean SBP of 24 hours), 24 h DBP (mean DBP of 24 hours), 24 h MAP (mean arterial pressure of 24 hours) of CC+CT genotype group were significantly higher than those of the TT genotype group (P<0.05). The aldosterone synthase CYP11B2 (-344T/C) gene polymorphism is associated with essential hypertension in Chinese. And the aldosterone synthase CYP11B2 (-344T/C) gene polymorphism may be the predictor of the antihypertensive response to Valsartan. PMID- 25785111 TI - Single nucleotide polymorphisms of cathepsin S and the risks of asthma attack induced by acaroid mites. AB - To investigate association between the three single nucleotide polymorphisms (SNPs, rs146456111, rs143154304 and rs147260142) in cathepsin S (Cat S) and the risks of allergic asthma attack induced by the acaroid mites in the Chinese population. A case-control study was performed in 412 cases and 454 volunteers/controls to evaluate the effects of three SNPs in Cat S on the risks of asthma attack. The genotypes were determined using polymerase chain reaction (PCR) and cleaved amplification polymorphism sequence-tagged sites (PCR-RFLP). The frequencies of genotypes and alleles in these SNPs in the asthmatic group were also analyzed between the two groups. The locus of rs146456111 in Cat S gene, the allele frequency of A and C in asthmatic group were significantly different from the control group (chi(2) = 184.425, P = 0.000), and the difference was significant regarding the distribution of the genotypes (AA, AC, and CC) between asthmatic subjects and normal controls (chi(2) = 177.915, P = 0.000). Logistic regression analysis revealed that the AC, CC, and AC + CC genotypes were significantly increased with the risk of asthma (AC vs. AA, OR = 4.013, 95% CI = 2.989-4.751, P = 0.000; CC vs. AA, OR = 3.167, 95% CI = 2.483 3.785, P = 0.000; AC + CC vs. AA, OR = 3.418, 95% CI = 2.381-4.214, P = 0.000, respectively), compared with AA genotype. Moreover, by comparison with allele A, allele C (OR = 2.187, 95% CI = 1.743-2.281, P < 0.001) tended to increase the risk of asthma; For the locus of rs143154304, compared with the allele frequency G with A in control group, there was no difference (chi(2) = 1.434, P = 0.231) in that of asthmatic group, as well as the distributions of the genotypes (AA, AG, and GG) between asthmatic subjects and normal controls (chi(2) = 1.997, P = 0.369); Logistic regression analysis showed that the AG, GG, and AG + GG genotypes were no risk to asthma (AG vs. AA, OR = 0.991, 95% CI = 0.625-1.507, P = 0.968; GG vs. AA, OR = 0.812, 95% CI = 0.525-1.258, P = 0.352; AG + GG vs. AA, OR = 0.914, 95% CI = 0.612-1.366, P = 0.660, respectively) as compared with AA genotype. By comparison with allele A, G allele (OR = 0.888, 95% CI: 0.732-1.078, P = 0.231) failed to increase the risk of asthma; The allele frequencies A and G of rs147260142 in asthma group and control group showed no significant difference (chi(2) = 0.162, P = 0.688), yet the distribution of the genotypes (AA, AG, and GG) in control group was different from that in asthmatic subjects (chi(2) = 7.520, P = 0.023); Logistic regression analysis suggested that, in compassion with AA genotype, the AG, and AG + GG genotypes appeared to increases the risk of asthma (AG vs. AA, OR = 0.630, 95% CI = 0.439-0.903, P = 0.012; AG + GG vs. AA, OR = 0.710, 95% CI = 0.507-0.996, P = 0.047); However, the GG genotype (OR = 0.843, 95% CI = 0.576-1.234, P = 0.286) and the allele G (OR = 1.040, 95% CI = 0.860-1.258, P = 0.688) were not related to the risk of asthma. The SNP of rs146456111A/C may be susceptible to the risks of asthma in the Chinese population; however, The SNPs of rs143154304A/G and rs147260142A/G may be less likely associated with the asthma attack. PMID- 25785112 TI - Common variant rs7597774 in ADD2 is associated with dilated cardiomyopathy in Chinese Han population. AB - Two polymorphisms, rs7597774 and rs1739843 in ADD2 and HSPB7 respectively, were found to be associated with dilated cardiomyopathy (DCM) in European cohorts but the results were not validated in the Chinese Han population. We aimed to test the association of the two variants with DCM in a cohort of Chinese Han population. DCM (399) and control (1384) individuals were identified from the GeneID database in China, and DNA was isolated from peripheral blood lymphocytes for genotyping. Alleles were amplified by PCR, and amplicons harboring polymorphisms rs1739843 and rs7597774 were directly genotyped using high resolution melting analysis. Statistical analysis was subsequently performed to evaluate the association of the variants with DCM. Allelic analysis demonstrated that rs7597774 was significantly related to DCM (P -adj = 0.0157), and an increased risk of DCM was specifically associated with the minor allele A (OR = 1.582). High-grade cardiac dysfunction (NYHA III/IV) was a clinical parameter significantly associated with the rs7597774 genotypes AA + AC relative to genotype CC (P = 0.021). Furthermore, DCM patients with the rs7597774 genotype AA tended to undergo more invasive medical interventions than those with the genotype CC (P = 0.008). No association was detected between rs1739843 and DCM under any allelic (P -adj = 0.407, OR = 0.920) or genotypic model. In the Chinese Han population, rs7597774 but not rs1739843 was found to be associated with DCM. This study is the first to demonstrate that underlying genotypes of rs7597774 may assist in assessing the heart functional status of DCM patients and also in the prediction of the benefit of particular therapies for these patients. PMID- 25785113 TI - XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure. AB - Aflatoxin B1 (AFB1), resulting in the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen repairing genotypes may experience an increased risk of genotoxicity. This study was aimed to investigate whether DNA repair gene xerodermapigmentosum complementation group C codon 939 polymorphism (rs2228001) affected the levels of AFB1-DNA adducts in Guangxi Population (n = 2558), from an AFB1-exposure area. AFB1-DNA adducts were measured by ELISA, and XPC codon 939 genotypes were identified by TaqMan-PCR. We found that longer AFB1-exposure years significantly increased XPC genotypes with codon 939 Gln alleles (namely, XPC-LG and -GG, odds ratios [95% confidence intervals] were 1.37 (1.15-1.63) and 1.99 (1.55-2.55), respectively) was significantly associated with higher levels of AFB1-DNA adducts. Furthermore, there was a positive joint effect between XPC genotypes and long-year AFB1 exposure in the formation of AFB1-DNA adducts. These results suggest that individuals with susceptible genotypes XPC-LG and -GG may experience an increased risk of DNA damage elicited by AFB1 exposure. PMID- 25785114 TI - Risk factors for naturally-occurring early-onset hepatocellular carcinoma in patients with HBV-associated liver cirrhosis in China. AB - AIMS: Early onset of hepatocellular carcinoma (HCC) (males and females under the age of 40 or 50 years old, respectively) has a significant prevalence and poor prognosis; however, few studies have reported the risk factors and development of HCC in such cases. METHODS: In this study, we retrospectively analyzed clinical, laboratory and demographic data from 588 treatment-naive HCC patients with hepatitis B virus (HBV)-associated liver cirrhosis (LC) and 708 age-matched HBV associated LC patients as control in Beijing 302 Hospital. RESULTS: 15.1% (89/588) of the HCC patients and 36.7% (181/708) of the LC patients were classified as early onset. Compared with age-matched LC controls, male gender (odds ratio (OR) = 2.09, P < 0.05), family history of HBV infection (OR = 2.45, P < 0.05) and alpha-fetoprotein (AFP) > 200 ng/ml (OR = 30.8, P < 0.05) were independent risk factors for early-onset HCC. Comparing late-onset LC controls, male gender (OR = 1.92, P < 0.05), age (OR = 1.04, P < 0.05), family history of HCC (OR = 2.06, P < 0.05), history of smoking (OR = 1.68, P < 0.05) and AFP > 200 ng/ml (OR = 12.0, P < 0.05) were associated with the development of naturally occurring HCC. Overall, male gender and AFP > 200 ng/ml is associated with HCC development across all ages, whereas a family history of HBV infection may identify younger HBV-associated LC patients at risk for HCC. CONCLUSION: Our data suggest that a family history of HBV infection is a unique risk factor for naturally-occurring early-onset HCC patients with HBV-associated LC, who should be considered for intensive screening programs. PMID- 25785115 TI - Elevated red blood cell distribution width in benign prostatic hyperplasia patients with metabolic syndrome. AB - Red blood distribution width (RDW) is a novel prognostic marker that reflects oxidative stress and inflammation in patients. Chronic inflammation has been proposed as a candidate mechanism between benign prostatic hyperplasia (BPH) and metabolic syndrome (MetS). However, the relationship between RDW and MetS in BPH patients is unclear. Men aged 50 year-old or older with BPH were recruited into the study. The BPH patients were classified as MetS group and non-MetS group. 69 patients without BPH and MetS were as the control group. The clinical information and RDW were measured to identify their relationship. MetS was diagnosed in 34% of the patients. The RDW values were found to be higher in the BPH group than in the control group [(13.3 +/- 0.8) vs. (12.6 +/- 0.8), P < 0.001]. The total prostate volume (TPV) and post void residual (PVR) urine volume were significantly higher in subject with MetS than in non-MetS and related with the number of metabolic abnormalities. High serum triglyceride and low serum high- density lipoprotein cholesterol (HDL-C) levels were significantly associated with TPV even adjusting for age (adjusted r = 0.373, P < 0.001, and adjusted r = 0.425, P < 0.001, respectively).There was a significant correlation between RDW and TPV (r = 0.370, P < 0.001), Body mass index (BMI) (r = 0.367, P < 0.001) and MetS (r = 0.276, P < 0.001). The data indicated that RDW was independently correlated with the presence of MetS (odd ratio 1.226, 95% confidence intervals 0.89-1.87, P < 0.001). MetS is associated with BPH development in men. The RDW level is significantly higher in patients with BPH than that in control. RDW is an independent predictor of MetS in BPH patients. PMID- 25785116 TI - Utility of plasma fibrinogen in the differential diagnosis of thyrotoxicosis. AB - BACKGROUND: A study had reported that a low TSH level is associated with elevated plasma fibrinogen (FIB) levels. Our purpose was to investigate the role of FIB in the differential diagnosis of thyrotoxicosis. METHODS: The data of 104 patients with primary thyrotoxicosis at the First Hospital of China Medical University from July 2010 to March 2011 were analyzed and divided into three groups: 45 cases of subacute thyroiditis, 50 cases of Graves' disease, and 9 cases of toxic multinodular goiter. The patients with subacute thyroiditis were followed up before and after the treatment. FIB levels of the three groups were compared. RESULTS: There was no significant difference in serum TSH, FT3 and FT4 between the patients with three different causes of thyrotoxicosis (P > 0.05). The proportion of hyperfibrinogenemia in patients with subacute thyroiditis was 98%. The FIB levels of patients with subacute thyroiditis were significantly higher than those with Graves' disease and toxic multinodular goiter (P < 0.05). Levels of ESR show a similar tendency. The FIB levels returned to normal with the remission of subacute thyroiditis. CONCLUSIONS: Elevated plasma fibrinogen is a common manifestation of the active phase of subacute thyroiditis. A FIB test can be used for the differential diagnosis of thyrotoxicosis. We can anticipate the outcome of subacute thyroiditis through the dynamic changes of FIB. PMID- 25785117 TI - Associations between polymorphisms in the IL-4 and IL-4 receptor genes and urinary carcinomas: a meta-analysis. AB - To evaluate the association between polymorphisms of interleukin-4 (IL-4) and IL 4 receptor (IL-4R) genes and risk of renal cell cancer (RCC), bladder cancer (BC), and prostate cancer (PC) based on meta-analysis. PubMed, Web of Science and SpecilalSCI(TM) were searched for studies published up to May 2014 that reported the association between IL-4 or IL-4R and RCC, BC or PC risk. Odds ratio (OR)/Hazard ratio (HR) and 95% confidence interval (CI) were analyzed to evaluate the association. Meta-analysis showed that the IL-4R polymorphism rs1805010 was associated with increased RCC risk (CC/CT vs. TT: OR=1.266, 95% CI 1.09-1.472, P=0.002). The IL-4 haplotypes, IL4-589T and IL4-33T, were associated with higher survival rate of the patients comparted with the haplotype IL-4-589C-33C (P<0.05). The IL-4 polymorphism rs2243250 was associated with an increased risk of developing multiple BCs (OR=2.52, P=0.033). The IL-4 polymorphisms rs2243228, rs2243250, and rs22272480 were significantly associated with PC risk (rs2243228 CC vs. CA/AA: OR=0.27, 95% CI 0.09-0.84, P=0.03; rs2243350 TT vs. CT/CC: OR=2.16, 95% CI 1.06-4.40, P=0.03, CC vs. CT/TT: OR=1.31, 95% CI 1.05-1.65, P=0.02; rs2227284 TT vs. GT/GG: OR=1.98, 95% CI 1.30-3.00, P=0.001). In addition, IL-4 polymorphism rs2070874 was associated with PC mortality. Three polymorphisms (rs2070874, rs1805015, and rs1801275) were not associated with RCC, BC, and PC. The IL-4R polymorphism rs1805015 might be associated with RCC risk. IL-4 rs2243250 carriers had increased risk of developing multiple BCs. IL-4 polymorphisms rs2243228, rs2243250, rs2227284, and rs2070874 were associated with PC risk or mortality. PMID- 25785118 TI - Effects of Rhubarb combined with ulinastatin on T-cell subsets in sepsis rats. AB - OBJECTIVE: The pathogenesis of sepsis, a systemic inflammatory response syndrome, is very complicated and not well understood. However, the importance of lymphocyte percentage and ratio is implicated. Rhubarb is a traditional Chinese medication and plays a role in protecting gastrointestinal mucous and controlling the SIRS damage. Ulinastatin is a protease inhibitor that prevents overproduction of inflammatory cytokines. Currently, despite numerous sepsis clinical researches, the study on the effects of combined drug therapy on sepsis is lacking. In this study, we studied Rhubarb and Ulinastatin combination treatment on T lymphocyte subsets in sepsis induced by the cecal ligation and perforation (CLP). Immunosuppression happened at the early stage of severe sepsis in the CLP rat models, as CD3(+), CD4(+), CD4(+)/CD8(+) began to decline, dropped rapidly after 24 h and continuously decreased at 36 h. CD8(+) T lymphocyte showed no significant change in all groups after CLP. The morality of CLP rats was increased with Rhubarb treatment in test dose (1.2 g/100 g). The immunosuppression state of CLP rats ameliorated with UTI treatment at early stage. The immunomodulatory properties were improved along with drug treatment, and immunities were obviously increased after 24 h, moreover, continuously increased at 36 h. The relief effect of immunosuppression after CLP showed much better in Rhubarb combined with UTI treatment than UTI monotherapy. In conclusion, the combination drug treatment facilitates the improvement of sepsis by modifying the lymphocyte percentage. PMID- 25785119 TI - Association between apparent diffusion coefficient and intervertebral disc degeneration in patients with ankylosing spondylitis. AB - PURPOSE: To assess the relation between ankylosing spondylitis (AS) and degenerative disc disease emerging in association with various intrinsic and extrinsic factors and to evaluate the correlation between degree of degeneration in intervertebral discs and apparent diffusion coefficient (ADC) values. METHODS: Thirty-five patients with AS and a control group of 35 patients were included in the study. Three hundred fifty intervertebral discs were assessed in terms of degeneration by analyzing signal intensities and morphologies on T2 weighted series of a 1.5 Tesla magnetic resonance scanner. ADC values were determined in diffusion weighted images (DWI) using a "b value of 500 s/mm(2)". Patients in the AS and control groups were compared in terms of intervertebral disc degeneration, and association between degree of degeneration and ADC values was analyzed. RESULTS: The mean of total degeneration degrees for five lumbar intervertebral discs was significantly higher in the patients with AS compared to the control group (16.77+/-4.67 vs 13.00+/-4.08, respectively; P=0.001). When intervertebral discs were analyzed separately, disc degeneration was again significantly higher in patients with AS compared to the control group, with the exception of L5-S1. Age, cholesterol level, triglyceride level, duration of disease and BASFI index were significantly associated with degree of degeneration in patients with AS. A negative correlation was determined between disc degeneration and ADC value. CONCLUSION: AS is a risk factor for degenerative disc disease due to its systemic effects, the fact it leads to posture impairment and its inflammatory effects on the vertebrae. A decrease in ADC values is observed as degeneration worsens in degenerative disc disease. PMID- 25785120 TI - rs17501976 polymorphism of CLDN1 gene is associated with decreased risk of colorectal cancer in a Chinese population. AB - The purpose of this study was to determine the relationship between polymorphisms in Claudin-1 (CLDN1) and the risk of colorectal cancer in a Chinese population. In this study, a case-control study was conducted in which polymorphisms in CLDN1 were analyzed in 50 patients with colorectal cancer (CRC) and 50 healthy individuals as controls. No rs16865344 and rs17429833 polymorphism were found among all analyzed samples. For the rs17501976 polymorphism, the TC genotype (OR = 0. 41, 95% CI = 0.18-0.91, and P = 0.045) was closely associated with the risk of colorectal cancer compared with the more common TT genotype. And the TC + CC genotypes (OR = 0.41, 95% CI = 0.18-0.91, and P = 0.045) were also significantly associated with the risk of CRC compared with the TT genotype. However, a C > T change of the rs17501976 polymorphism did not show a difference in transcription factor binding to the promoter region of CLDN1. For rs12696600 polymorphism, no significant difference was found in colorectal cancer risk between cases and controls in corresponding genotypes. Collectively, our data suggest that rs17501976 polymorphism significantly associated with a decreased susceptibility to CRC in a Chinese population. PMID- 25785121 TI - Up-regulated Reg proteins induced by Interleukin-22 treatment ameliorate acute liver injury in rat model. AB - BACKGROUND: The regenerating gene (Reg), encoding lectin-related protein, was originally isolated from a rat regenerating pancreatic islets. Interleukin-22 (IL 22), a recently identified cytokine, is produced by Th 17 cells and natural killer cells. Both of them have been shown to play an important role in controlling tissue repair. But, it is unclear whether the IL-22/Reg axis is involved in liver regeneration and the improvement of liver function in a rat model of acute liver injury. AIMS: We investigated the expression levels of Reg proteins after IL-22 stimulation in a rat model of acute liver injury, and estimated the effects of Reg proteins ameliorating acute liver injury. METHODS: Western blot was used to measure the expressions of Reg I, Reg III, Reg IV proteins after treatment with recombinant lentivirus IL-22. At the same time, the expression levels of TB, ALT, AST, endotoxin (ETM), superoxide dismutase (SOD), malondialdehyde (MDA) were detected by related reagents. RESULTS: In a rat model of acute liver injury, the expression levels of Reg I, Reg III, Reg IV proteins were increased after treatment with IL-22 recombinant lentivirus compared with treatment with lentivirus-empty vector, especially, Reg IV protein expression. Meanwhile, treatment with IL-22 recombinant lentivirus reduced serum levels of TB, ALT, AST, ETM, and decreased MAD levels in rat liver tissues, but increased SOD levels in rat liver tissues. CONCLUSION: IL-22 stimulation enhanced the expressions of Reg proteins in liver cell, especially, Reg IV protein, and ameliorated liver injury in a rat model of acute liver injury. Reg protein, especially Reg IV protein, might act as a biological mediator of immune cell derived IL-22 in the recovering mechanism of liver injury. PMID- 25785122 TI - Treatment of acutely ruptured wide-necked intracranial aneurysms using self expanding stent. AB - OBJECTIVES: To evaluate the effectiveness and safety of self-expanding stent in treatment of acutely ruptured wide-necked intracranial aneurysms in the acute stage. METHOD: Treatment of 38 patients with self-expanding stent was retrospectively analyzed. RESULTS: From January 2009 to May 2014, a total of 38 patients with 44 acutely ruptured wide-necked intracranial aneurysms were embolized with self-expanding stents at our center. Immediate post-operative imaging demonstrated that the aneurysms were densely packed in 17 patients, subtotally embolized in 2 patients, and subtotally embolized with residual aneurysm necks in 19 patients. At discharge, the patients were assessed for prognosis and the results revealed nerve dysfunction in 3 patients (7.9%), coma in 6 patients (15.8%), hospital death in 1 case (2.6%). Twenty-eight (73.7%) patients were asymptomatic at discharge. Ten of the 38 patients were followed up by angiography for a period of 3.7 months on average, which showed complete occlusion in 9 patients (90%), remnant aneurysm necks in 1 patient (10%), and no recanalization was observed in all the followed-up patients. Stent related complications also were recorded. CONCLUSION: Stent-assisted coiling is effective in treating acutely ruptured wide-necked intracranial aneurysms. Angiographic investigation and clinical follow-up is needed for evaluation of long-term clinical outcomes. PMID- 25785123 TI - Expression and clinical significance of microvessel density and its association with TWIST in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is characterized by a high frequency of nodal and distant metastasis at diagnosis. Microvessel density (MVD) is an indicator for angiogenesis that has been shown to correlate with metastasis of cancers. Evidence regarding the roles of MVD in NPC has rarely been reported. Thus, we aimed to investigate the state of angiogenesis in NPC. CD34 and TWIST were detected in sixty-five NPC specimens by immunohistochemistry, respectively. Then, MVD and its association with clinical features as well as TWIST expression have been assessed. As a result, MVD was closely related to cancer progression as reflected by distant metastasis (P < 0.05), and nevertheless, the data failed to show its association with lymph node metastasis and other clinicophathological features (P > 0.05). Interestingly, a marked correlation between TWIST positive expression with increased MVD was observed. The results suggested that MVD might play important roles in the development of NPC and TWIST might promote cancer progression by facilitating angiogenesis. Further studies are needed to confirm the results. PMID- 25785124 TI - Application of impulse oscillometry and bronchial dilation test for analysis in patients with asthma and chronic obstructive pulmonary disease. AB - Impulse oscillometry (IOS) is a good method for measuring airway resistance. The aim of this study was to assess the diagnostic contribution of IOS combined with bronchial dilation test (BDT) when distinguishing between patients with asthma and those with chronic obstructive pulmonary disease (COPD). 870 were enrolled in the study including 561 patients with asthma, 100 patients with COPD and 209 patients with chronic coughing or normal subjects. All the participants underwent routine pulmonary function tests, IOS and BDT examination. And IOS examination was before and after BDT. IOS parameters (R5, R20, R25, R35, X5, X20, X25, X35, Fres, Zrs & RP) and forced expiratory volume in one second (FEV1) were recorded. Receiver operating characteristics (ROC) curve analysis was performed to evaluate the diagnostic ability to differentiate asthma and COPD. The discriminative power of the various parameters studied was determined by means of ROC curves: the area under the curve (AUC), sensitivity and specificity. The X5, X20, X25, X35, Fres, Zrs and Rp correlated better with COPD. In particular, X5, Fres and X25 have been found to be significantly correlated with COPD. The diagnostic efficiency of X5, Fres and X25 when diagnosis COPD, expressed by ROC curve parameters, was as follows: AUC (0.725, 0.730, 0.724), sensitivity (67%, 77%, 83%) and specificity (68%, 65%, 58%), respectively. The diagnostic efficiency of Zrs, R5 and X35 when diagnosis asthma, expressed by ROC curve parameters, was as follows: AUC (0.721, 0.710, 0.695), sensitivity (62%, 72%, 53%) and specificity (72%, 61%, 76%), respectively. Our findings show, that X5, X25 and Fres may be useful for predictions and evaluations for COPD. And R5, X35 and Zrs may provide useful IOS parameters for asthma. IOS combined BDT could be useful diagnostic and differential diagnosis between asthma and COPD. PMID- 25785125 TI - Exploration of common bile duct for treating hepatic cystic echinococcosis. AB - OBJECTIVE: To compare the clinical efficacy of exploration of common bile duct through cystic duct or T type tube in CE patients. METHODS: One hundred and fifty six patients with chronic CE received decompression of biliary tract from January 2007 to December 2012 were included. Exploration of common bile duct was performed through cystic duct (n=102) or T type tube (n=54). Psychological reactions were monitored including inconvenient position alteration due to carrying of the drainage tube, anxiety of the folding and prolapse of drainage tube, folding of the drainage tube, and any pain during the body position change. RESULTS: No significant difference was noticed in the body position alteration discomfort in both groups (P>0.05). Statistical difference was noted in the anxiety of folding and prolapse of draining tube (P<0.05), and improvement of the clinical symptoms (P<0.05). CONCLUSIONS: A higher possibility of wound, enlarged tube-carrying duration, and lower sense of discomfort, were noticed in patients underwent exploration of common bile duct through T type tube. Higher sense of comfort was reported in patients received exploration of common bile duct through cystic duct tube. PMID- 25785126 TI - Application of a spontaneously closed protective stoma in an ileal pouch-anal anastomosis: a preliminary study. AB - BACKGROUND: To evaluate the application value of a spontaneously closed protective stoma (SCPS) in an ileal pouch-anal anastomosis, which is a novel procedure first performed in our hospital in 2008. MATERIALS AND METHODS: Two males cases with ulcerative colitis and one female with familial adenomatous polyposis were treated with colorectal surgery at the First Affiliated Hospital of Zhejiang University since March 2010. The surgery was designed as total proctocolectomy with an ileal pouch-anal anastomosis and SCPS. The surgical plan and procedure was determined with the patients after analyzing their hospitalized records and follow-up information. RESULTS: No operation-induced death or anastomotic leakage occurred. One patient had a persistent fever and another patient presented with postoperative urinary retention. The average time until flatulence occurred post-SCPS was 26 days, and the average time until the removal of the postoperative stomal tube was 46 days that healed well. CONCLUSIONS: An SCPS can effectively protect the anastomosis with a simple operation and avoid the second surgery. Patients with ulcerative colitis require a two-stage operation, those who were in poor health and had a long history of hormone treatment even requiring a three-stage operation. However, a one- or two-stage operation could help alleviate pain for patients who require multiple surgeries and reduce economic burden. PMID- 25785127 TI - Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in vitro fertilization. AB - INTRODUCTION: This study was to evaluate the effectiveness of PRP in the therapy of infertile women with thin endometrium (<= 7 mm). MATERIAL AND METHODS: Five women undergoing in vitro fertilization (IVF) with poor endometrial response still had thin endometrium (< 7 mm) after standard hormone replacement therapy (HRT) and had to cancel embryo transfer cycle. In addition to HRT, intrauterine infusion of PRP was performed. PRP was prepared from autologous blood by centrifugation, and 0.5-1 ml of PRP was infused into the uterine cavity on the 10(th) day of HRT cycle. If endometrial thickness failed to increase 72 h later, PRP infusion was done 1-2 times in each cycle. Embryos were transferred when the endometrium thickness reached > 7 mm. RESULTS: Successful endometrial expansion and pregnancy were observed in all the patients after PRP infusion. Intrauterine PRP infusion represent a new method for the thin endometrium with poor response. CONCLUSION: This article reported that platelet-rich plasma (PRP) was able to promote the endometrial growth and improve pregnancy outcome of patients with thin endometrium. PMID- 25785128 TI - Evaluation of mean platelet volume as a diagnostic biomarker in acute appendicitis. AB - BACKGROUND: Diagnosis of acute appendicitis remains to be challenging with up to 30% negative exploration rates. In addition to careful clinical history and physical examination, we still need easily applicable, cheap and effective biomarker. PATIENTS AND METHODS: A retrospective case-controlled study was designed in two groups, both containing 100 patients, acute appendicitis and control. Leukocyte count, neutrophil percentage, platelet count and meal platelet volume (MPV) were compared. RESULTS: MPV values for acute appendicitis and control groups were 7.4 +/- 0.9 fL (5.6-10.6) and 9.1 +/- 1.6 fL (5.1-13.1). For the diagnosis of acute appendicitis, ROC analysis revealed 74% sensitivity and 75% specificity for a cut-off value of 7.95 fL of MPV, however, the diagnostic value of leukocyte count and/or neutrophil ratio was superior. CONCLUSION: Our results suggest that, MPV value is an important parameter in the diagnosis of acute appendicitis, but in terms of sensitivity and specificity, leukocyte count and/or neutrophil percentage is superior. PMID- 25785129 TI - Sternocleidomastoid muscle flap used for repairing the dead space after supraomohyoid neck dissection. AB - Surgical site infection (SSI) is a common complication followed neck dissection and dead space is a common reason of SSI. The present study is aimed to explore whether the sternocleidomastoid muscle (SCM) flap transposition to repair the dead space in level II of neck could decrease the postoperative SSI in patients with oral squamous cell carcinoma (OSCC) underwent supraomohyoid neck dissection (SOND). Ninety-six patients with cT2-3N0 OSCC who underwent extended resection of primary cancer combined SOND and reconstructed with free flap from March 2011 to October 2014 in our department were included. Forty-eight cases underwent SCM transposition to repair the potential dead space in level II of the neck, the other 48 cases did not. The two groups were matched at age, gender, concomitant diseases, and perioperative treatments. All the patients underwent exhaustive hemostasis and careful placement of negative pressure drainage. The wound healing was observed on 7 days postoperatively. The SSI rates of neck between the two groups were compared using Fisher's exact test. The dead space in level II was observed in all the neck wounds after SOND. The neck wounds healed by primary intention in 46 cases underwent SCM flap transposition, and in 39 cases underwent routine SOND only. Two cases with SCM flap transposition and 9 cases in the group without SCM flap transposition presented SSI in neck. There was significant difference in the SSI rate between the two groups (P = 0.0248). The dead space in level II could be an important cause of SSI in neck followed SOND. Repairing of the dead space in level II using SCM flap transposition reduce the SSI rate of neck followed SOND. PMID- 25785130 TI - A novel specialized staging system for cancellous fracture healing, distinct from traditional healing pattern of diaphysis corticalfracture? AB - Metaphysis cancellous bone fracture is one of the most common fracture types in clinical orthopedic practice. The specialized healing process of cancellous bone fracture has long been ignored by the academic society. Comparing with diaphyseal cortical bone healing, cancellous bone healing showed less bone tissue necrosis, barely any hematoma formation, limited inflammation events and no external callus formation. Based on our clinical practice and preliminary study, we hypothesize that the healing process of metaphysis cancellous fracture is a distinct process which could be concluded into five overlapping stages with distinguished histological features of each other. Different from the traditional theory defining diaphyseal cortical fracture, our novel staging theory is specialized in cancellous bone tissue fully considering its unique histological features. This novel staging system may help clinical orthopedists gain specialized understanding concerning cancellous healing process and aid in their clinical evaluation and treatment to metaphysis cancellous bone fracture. PMID- 25785131 TI - Dietary products consumption in relation to serum 25-hydroxyvitamin D and selenium level in Saudi children and adults. AB - Vitamin D deficiency is a global health threat that has been associated with several chronic diseases. Selenium is an essential trace element because of role in major metabolic processes, immune function, thyroid hormone metabolism, male infertility, neoplasms and cardiovascular disease. We aimed to investigate for the first time in the Saudi population the association between vitamin D and selenium status with various dietary products consumption. A total of 259 children and 95 adults were included in this cross-sectional study. We estimated the consumption frequencies of various dietary food products using a qualitative food frequency questionnaire (FFQ) and also measured serum levels of 25 hydroxyvitamin D and selenium. Associations between variables of interest were assessed. Vitamin D deficiency and insufficiency were observed in 80% of the boys, 90% of the girls, 64% of men and 50% of women. Modest associations were found between mean serum 25 (OH) D concentration and consumption frequencies of fresh milk in children (r=0.11; P<0.05), more specifically in girls (r=0.12; P<0.05), and to the overall consumption of dairy products in women (r=0.12; P<0.05). Vitamin D status was also inversely associated with selenium in adults (r=-0.43; P<0.05). There was a significant correlation between delta changes of serum selenium, triglycerides and HDL levels (P-values <0.05). Vitamin D and selenium levels are modestly associated with dietary products consumption. Changes in selenium levels were associated with increased serum triglyceride levels, indicating a potential biomarker for cardiovascular risk and dyslipidemia. The widespread vitamin D deficiency observed in the present study highlight the need for adequate fortification of dairy products. PMID- 25785132 TI - Genetic predisposition of stroke: understanding the evolving landscape through meta-analysis. AB - Stroke, either ischemic or hemorrhagic, is the leading cause of death and morbidity worldwide. Identifying the risk factors is a prerequisite step for stroke prevention and treatment. It is believed that a major portion of the currently unidentified risk factors is of genetic origin. Consistent with this idea, numerous potential risk alleles for stroke have been reported, however, the genetic evidence so far is not conclusive. The major goal of this review is to update the current knowledge about the genetic predisposition to the common multifactorial stroke, and to provide a bird's-eye view of this fast moving field. We selectively review and meta-analyze the related English literatures in public domain (PubMed) from 2000 onward, including the original reports and meta analyses, to evaluate the genetic risk factors of common multifactorial stroke. The results indicated that we reviewed and meta-analyzed original reports and existing meta-analyses that studied the genetic predisposition to the common multifactorial stroke. Some original reports and meta-analyses were specific for ischemic stroke and others were for hemorrhagic stroke only. We also evaluated the major evolving issues in this field and discussed the future directions. In conclusion, strong evidences suggest that genetic risk factors contribute to common multifactorial stroke, and many genetic risk genes have been implicated in the literatures. However, not a single risk allele has been conclusively approved. PMID- 25785133 TI - Early- and late-onset severe pneumonia after renal transplantation. AB - BACKGROUND: The aim of this study was to clarify the distinctions in the clinical characteristics and outcomes between early- and late-onset severe pneumonia after renal transplantation requiring ICU admission. METHODS: The data were retrospectively collected in consecutive renal recipients with severe pneumonia from January 1, 2009, to December 31, 2013, in a tertiary ICU. We classified the patients according to the time of pneumonia onset as follows: early-onset severe pneumonia (E-SP) corresponded to a pulmonary infection occurring during the first year following the transplantation, and late-onset severe pneumonia (L-SP) corresponded to a pulmonary infection occurring after the first year following the transplantation. RESULTS: In the E-SP patients, fungi (42.1%) and viruses (31.6%) were the most common pathogens. Twenty-three (71.9%) patients received non-invasive ventilation (NIV), 15 (65.2%) of whom were intubated. The median duration of the ICU and hospital stays was 11 +/- 5 and 19 +/- 4 days, respectively. In the L-SP patients, bacteria (42.1%) and viruses (26.3%) were the predominant pathogens. Four of 15 (26.7%) patients failed NIV treatment. The median duration of the ICU and hospital stays was 9 +/- 3 and 16 +/- 3 days, respectively. The ICU mortality among the E-SP patients was 18.8% (6 of 32), compared with 7.1% (2 of 28) in the L-SP group (P = 0.264). CONCLUSIONS: Early onset severe pneumonia in renal transplant recipients resulted in a more serious condition, higher rate of NIV failure, longer duration of mechanical ventilation, and increased length of ICU and hospital stays. PMID- 25785134 TI - Impact of low-dose urokinase in peritoneal dialysis on serum oxidative stress, nitric oxide and endothelin in cerebral infarction complicated with uremia. AB - BACKGROUND: Cerebrovascular accident is an important cause of death in patients with chronic renal failure. METHODS: This study evaluated the interference of low dose urokinase in peritoneal dialysis solution on uremic serum superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and endothelin (ET) dynamics in patients with a cerebral infarction complicated by uremia. RESULTS: Both the urokinase and conventional treatment groups showed decreased SOD activities, increased MDA content, and elevated serum NO and ET levels at the initiation stage of treatment. Antiplatelet and cerebral protection therapy slightly reduced body MDA content and increased SOD activity at the early stage of treatment, and its effects on reducing serum NO and ET-1 are also limited. CONCLUSION: Our results revealed that a small amount of urokinase in peritoneal dialysis can reduce body MDA content, increase SOD activity and decrease serum levels of NO and ET-1 at the early stage of cerebral infarction complicated by uremia. We also found that continuous treatment for 8 weeks may provide a potential treatment of cerebral infarction complicated with uremia. PMID- 25785135 TI - The changes of von willebrand factor/a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 balance in aneurysmal subarachnoid hemorrhage. AB - The aim of this study was to investigate the role of Von Willebrand Factor/thrombospondin type I repeats-13 (VWF/ADAMTS13) balance in aSAH. Fifty eight patients with aSAH at the First Affiliated hospital of Soochow University, Suzhou, China, between January 2012 and January 2014 were eligible for the study. They were divided into delayed cerebral ischemia group (DCI group) and non delayed cerebral ischemia group (no DCI group), or cerebral vasospasm group (CVS group) and no spasm group (no CVS group), or good outcome group and poor outcome group. The control group consisted of twenty healthy people. All patients underwent CT, DSA, or (and) CTA diagnosed with intracranial subarachnoid hemorrhage which is caused by aneurysm rupture. Venous blood was drawn in tubes at 3 time points: 1 day after SAH (T1), (4+/-1) days after SAH (T2), and (9+/-1) days after SAH (T3) to determine plasma concentrations of ADAMTS13, VWF, P selectin and IL-6 via enzyme-linked immunosorbent assay (ELISA). Transcranial doppler sonography (TCD) was used to measure mean blood flow velocity of the middle cerebral artery (VMCA). Glasgow Outcome Scale (GOS) was measured before discharge. Among 58 patients, 12 (20.7%) had DCI, 40 (68.9%) had TCD evidence of CVS, and 20 (34.5%) had poor outcome. The concentrations of VWF, P-selectin and IL-6 on T1, T2 and T3 after SAH were significantly higher in DCI, CVS and poor outcome groups compared with those of the control group (P < 0.05). The concentrations of VWF, P-selectin and IL-6 were significantly higher in DCI, CVS and poor outcome groups compared with those of the no DCI, no CVS and good outcome groups. The activity of ADAMTS13 was lower in DCI and poor outcome groups compared with those of the no DCI and good outcome groups (P < 0.05). The activity of ADAMTS13 showed no difference in CVS group and no CVS group (P > 0.05). The results of our study suggest that the increased VWF and decreased ADAMTS13 activity were associated with DCI and poor outcome. The balance of VWF/ADAMTS13 could be used to predict the clinical outcome. The deficiency of ADAMTS13 can not only induce DCI but also accelerate inflammatory reaction. Our results reported in this paper may provide new insights into the possible use of ADAMTS13 as a therapeutic agent in aneurysmal subarachnoid hemorrhage. PMID- 25785136 TI - Effects of modified electroconvulsive therapy on the cognitive function and blood parameters in female patients with schizophrenia. AB - BACKGROUND: This study aimed to investigate the effects of modified electroconvulsive therapy (MECT) on cognitive function and blood parameters in female patients with schizophrenia. MATERIALS AND METHODS: Female patients with schizophrenia (n = 23) received MECT while maintaining antipsychotic therapy. 1) White blood cell (WBC), alanine aminotransferase (ALT), creatine kinase (CK) and creatine kinase MB (CKMB) were measured at 10 min before and after MECT. 2) The severity of symptoms was evaluated before and after MECT by using the Positive and Negative Symptoms Scale (PANSS) and then the therapeutic effects of MECT were assessed. 3) Single nerve psychology test was used to assess the cognitive function. RESULTS: 1) There were no significant differences in WBC, ALT, CK and CKMB before and after MECT (P > 0.05). 2) WBC, ALT and CKMB remained stable at different time points after MECT treatment (P > 0.05). But CK had statistical differences at different times before or after MECT treatment (P < 0.05). CK decreased since the first MECT and thereafter increased after the 7th treatment (P < 0.05). 3) The total score of PANSS decreased significantly after MECT (P < 0.05). 4) Digit span test showed no statistically significant differences in different time points (P > 0.05); Digital sign test and verbal fluency test showed significant differences in different times (P < 0.05). CONCLUSION: The CK figure decreased from the first to sixth MECT treatment and increased in the 7th MECT treatment, and the CKMB also increased in the 7th treatment. MECT treatment had significant effects on female patients with schizophrenia and could obviously improve patient's cognitive function. PMID- 25785137 TI - Low vitamin D status associated with dilated cardiomyopathy. AB - In recent years, a growing body of evidence supports that vitamin D plays a crucial role in various cardiovascular diseases. Cardiac muscle cells have vitamin D receptors as well as calcitriol-dependent Ca(2+) binding protein. Therefore, the vitamin D may have an effect on cardiac function. In this research, we investigated the association between vitamin D status and dilated cardiomyopathy (DCMP). We compared serum 25-hydroxy-vitamin D3 (25OHD3) concentrations in 39 patients (mean age 50.4 +/- 11.7 years, 15 women) with DCMP and in 35 healthy controls (mean age 54.6 +/- 13.2 years, 17 women). Parathyroid hormone (PTH), calcium (Ca++), phosphorus, lipid profile, albumin and echocardiographic parameters (left-ventricular (LV) ejection fraction, LV fractional shortening, LV-end-diastolic and end-systolic dimensions) were measured in all study participants. The mean serum 25OHD3 concentrations in patients with the DCMP were significantly lower in compared to healthy controls (24.1 +/- 10.4 ng/mL versus 41.4 +/- 20.9 ng/mL, P < 0.0001). PTH concentrations were significantly higher in patients with DCMP in comparison with healthy controls (90.6 +/- 29.8 pg/mL versus 49.1 +/- 18 pg/mL, P < 0.0001). Additionally, we observed a significant negative correlation between 25OHD3 concentrations and PTH concentrations, LV end-diastolic dimensions, LV end systolic dimensions (r = -0.66; P < 0.0001, r = -0.49; P < 0.0001, r = -0.50; P < 0.0001, respectively). Moreover, 25OHD3 was positively correlated with LV ejection fraction, LV fractional shortening, stroke volume, cardiac output, cardiac index (r = 0.46; P < 0.001, r = 0.44; P < 0.001, r = 0.25; P = 0.03, r = 0.37; P < 0.001, r = 0.25; P = 0.03; respectively). Our findings support that vitamin D has a potential role both in the development of DCMP and LV remodeling. PMID- 25785138 TI - Effects of fermentable dietary fiber supplementation on oxidative and inflammatory status in hemodialysis patients. AB - BACKGROUND: Increased oxidative stress, inflammation, and malnutrition are important risk factors for cardiovascular disease in hemodialysis patients. High dietary intake in soluble fiber can decrease the elevated level of serum c reactive protein in patients with chronic kidney disease. The aim of this study was to evaluate the effect of supplementation of dietary water-soluble fiber on oxidative and inflammatory status in hemodialysis patients. METHODS: In a randomized placebo-controlled trial, we examined the effects of supplementation of dietary fiber on oxidative and inflammatory status in hemodialysis patients. 124 hemodialysis patients were randomly selected and given either 10 g/d, 20 g/d of fiber or placebo for 6 weeks. Anthropometric indices and 24 h diet recall intake was assessed. The CRP, albumin, triglyceride, total cholesterol, LDL, HDL were measured before and after of the intervention. The malondialdehyde (MDA), total antioxidant capacity (T-AOC), Cu-Zn superoxidase dismutase (SOD), glutathione peroxidase (GSH-Px) high-sensitivity C-Reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) were measured. RESULTS: After 6 weeks of intervention, in 10 g and 20 g/d of fiber supplement groups, TC and LDL level and TC:LDL ratio were significantly decreased, T-AOC was significantly increased, MDA level was significantly deceased, TNF-alpha, IL-6, IL-8 and CRP level were significantly deceased. TG, HDL, SOD and GSH-Px had no change before and after the intervention. CONCLUSIONS: Dietary fermentable fiber supplementation improved lipid profile and oxidative status, decreased systemic inflammatory state of hemodialysis patients. Thus, it may decrease the risk of cardiovascular events in these patients. PMID- 25785139 TI - P53 mutations occur more commonly than KRAS mutations in colorectal adenoma. AB - TP53 and KRAS mutations are commonly found in colorectal tumors. The rates of mutation of these two genes in colorectal carcinoma were compared to better understand their contribution to the disease. Here, colorectal tissue samples were obtained from 49 patients with colorectal adenoma, 90 patients with single primary colorectal carcinoma, 32 patients with multiple primary colorectal carcinoma, and 50 healthy individuals. Real-time PCR was used to amplify exons 5 8 of TP53 and codons 12-13 (exon 1) of KRAS from each sample. Clinical and pathological features of tumor samples were recorded, and these features were compared against mutation status using multivariate logistic regression. The proportions of samples with mutations of KRAS and/or TP53 were significantly different between control individuals and those with colorectal lesions (P < 0.05). Indeed, more than 80% of carcinoma samples were positive for either a KRAS or TP53 mutation. Further, mutations in KRAS and/or TP53 were significantly more common among the two groups with confirmed carcinoma than in individuals with colorectal adenoma (P < 0.05). Interestingly, TP53 mutations were significantly more frequent than KRAS mutations in the colorectal adenoma group (P < 0.01). However, no associations were observed for the frequency of KRAS or TP53 mutations between well-differentiated and poorly-differentiated tumors, different tumor stages, or other clinical and pathological features like age, sex, family history, tumor location, and stage and grade of differentiation. In conclusion, KRAS and TP53 mutations are important contributors to colorectal cancer, and TP53 mutation appears to occur earlier than KRAS mutation. PMID- 25785140 TI - Serum biomarkers for acute hepatotoxicity of Echis pyramidum snake venom in rats. AB - Echis pyramidum is a venomous viper responsible for most cases of envenomation in Arabian Peninsula. We determined the acute phase (3-6 h) changes in serum markers of liver function including alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and bilirubin in adult male Sprague Dawley rats injected with Echis pyramidum venom (EPV) in the doses of 0.00 (control), 0.25, 0.50 and 1.00 mg/kg bodyweight. We also analyzed markers of oxidative stress including superoxide dismutase (SOD), catalase (CAT), total thiols (T-SH) and thiobarbituric acids reactive substances (TBARS) in liver. The results showed significant and dose- and time-dependent increases in serum ALT, ALP and GGT activities after a single injection of EPV. Serum bilirubin was significantly increased by medium and high doses of EVP after 3 h post-injection and then decreased at 6 h. The low dose of EPV neither affected the activity of SOD nor altered the levels of liver T-SH and TBARS, however, it significantly decreased the activity of CAT at 6 h post-injection of EPV. The medium dose of EPV significantly reduced liver SOD activity after 6 h whereas the high dose significantly reduced the SOD activity at 3 h and 6 h post-dosing. Both medium and high doses of EPV caused significant as well as dose- and time-dependent reductions in liver CAT activities. The high dose significantly reduced T-SH and increased TBARS in rat liver. Further studies are warranted to test the pharmacological potential of early phase antioxidant therapy for neutralizing the toxic effects of EPV. PMID- 25785141 TI - Molecular epidemiology of aminoglycosides resistance on Klebsiella pneumonia in a hospital in China. AB - To investigate the molecular epidemiology of aminoglycosides resistance among Klebsiella pneumonia in hospitals in China, the antibiotics resistance and the possession of extended-spectrum beta-lactamases (ESBLs) from 162 isolates were examined using Kirby-Bauer disk diffusion and PCR sequencing. Overall, 47.5% (77/162) of strains showed an ESBL phenotype. According to antibiotics resistance, ESBLs-positive K. pneumoniae showed significantly higher resistance to most antibiotics than ESBLs-negative strains (P<0.05). Moreover, 162 strains harboured aminoglycoside-modifying enzymes genes (AMEs) including aac (3)-II (n = 49), aac (6')-Ib (n = 32), ant (3")-I (n = 22) and ant (2")-I (n = 7). Overall, 11.1% (18/162) and 6.2% (10/162) of isolates carried 16S rRNA methylase genes (armA and rmtB), in which the aminoglycoside MIC was more than 256 MUg/ml. In conclusion, our study characterised aminoglycosides resistance among K. pneumoniae strains in China hospitals and revealed antibiotic resistance and the increased presence of AMEs and 16S rRNA methylase genes in K. pneumonia, enabling the prevalence of aminoglycosides resistance of K. pneumoniae to be tracked from patients. PMID- 25785142 TI - Prevalence and fluoroquinolone resistance of pseudomonas aeruginosa in a hospital of South China. AB - Pseudomonas aeruginosa is an opportunistic pathogen that poses a threat in clinical settings. This study aimed to investigate the molecular characterization and epidemiology of fluoroquinolones (FQs) resistance in P. aeruginosa isolated from South China. A total of 256 P. aeruginosa strains isolated from outpatients, emergency patients and inpatients were collected from January 2010 to December 2010 in the hospital of South China. The resistance profile of all isolated strains was screened by antibiotic-susceptibility testing, and the molecular characteristics of plasmid-mediated quinolone resistance (PMQR) and the quinolone resistance determining region (QRDR) were determined using PCR in combination with DNA sequencing. The result of antibiotic-susceptibility tests showed that most strains were sensitive to polymyxin B, piperacillin, piperacillin/tazobactam, ceftazidime and amikacin. Moreover, 65 isolates were identified as resistant to ciprofloxacin. Further analysis of QRDR revealed that the resistant strains carried at least one mutation in the gyrA (The83Ile), gyrB (Ser467Phe, Gln468His) and parC (Ser87Leu) genes, but no mutation was detected in parE. For the first time, we report here that the qnrA1 gene is associated with low levels of resistance to ciprofloxacin from clinical P. aeruginosa isolates in South China. The mutation of gyrA (at position 83) is clearly linked to the FQs resistance of P. aeruginosa. Moreover, FQs resistance of P. aeruginosa may be due to the chromosome-mediated resistance mechanism rather than PMQR. PMID- 25785143 TI - Effects of intensive insulin therapy upon pancreatic beta cell function in patients newly diagnosed with type II diabetes. AB - OBJECTIVE: This study was designed to evaluate the clinical efficacy of intensive insulin therapy for patients newly diagnosed with type 2 diabetes. METHODS: A total of 219 patients newly diagnosed with type 2 diabetes were randomly assigned into insulin group (n = 55), gliclazide group (n = 52), metformin group (n = 55) and pioglitazone group (n = 57). On the basis of diet and physical interventions, patients in the insulin group received intensive insulin therapy. Those in other three groups were given oral intake of medication. All treatment schemes endured for 12 weeks. A variety of indexes including fasting blood-glucose (FPG), FPG at 2 h after diet (FPG 2 h), hemoglobin A1 c (HbAlc), area under the curve (AUC) for insulin (insulin AUC) after glucose load, C-peptide AUC after glucose load (C peptide AUC), changes in insulin secretion index (Homa-beta) and insulin resistance index( Homa-IR) were accurately measured and statistically among different groups. RESULTS: The insulin AUC at 0-30 min, C-peptide AUC at 0-30 min and Homa-beta in the insulin group were equally significantly higher compared with those levels in the other three groups. In addition, the level of Homa-IR in the insulin, metformin and pioglitazone groups were all significantly reduced compared with the values prior to respective treatment (all P < 0.05). CONCLUSION: Compared with oral administration of hypoglycemic drugs, intensive insulin therapy is able to better improve pancreatic beta cell function and insulin resistance for newly-diagnosed type 2 diabetes patients. PMID- 25785144 TI - Correlation between diabetic lower-extremity arterial disease and diabetic neuropathy in patients with type II diabetes: an exploratory study. AB - The lower-extremity vascular injuries and neuropathy are the most salient complications of diabetes which could lead to the poor prognosis, especially for the type II diabetes. The lower extremity vascular injuries and neuropathy usually coexist, yet their correlation in the pathogenesis of lower extremity lesions has received little attention in previous studies. To investigate the correlation between the degree of lower-extremity arterial injuries and lower extremity neurological functional status in patients with type II diabetes, 32 patients with type II diabetes were examined for the mean flow velocity of the femoral artery and popliteal artery of lower extremeties, while the motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) of the bilateral common peroneal nerve, sural nerve and posterior tibial nerve were simultaneously examined. Results showed that there was moderate correlation between the mean flow velocity of lower-extremity arteries and MCV/SCV. In particular, the MCV of the right tibial nerve was strongly correlated with the average velocity of the right popliteal artery (P < 0.05). PMID- 25785145 TI - Genetic polymorphisms of interleukin-16 are associated with susceptibility to primary knee osteoarthritis. AB - Interleukin-16 (IL-16) polymorphisms have been associated with various disease states, and its activity is dysregulated in synovial fibroblasts of individuals with rheumatoid arthritis. Here, the association between genetic polymorphisms in the gene encoding IL-16 and susceptibility to primary knee osteoarthritis was investigated in the Chinese Han population. The study included 228 unrelated patients, half of whom presented with primary knee osteoarthritis (OA); the remainder was healthy individuals. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine single nucleotide polymorphisms (SNPs) in IL16 in these patients. Statistical analysis was performed using the chi-square goodness-of-fit test, Hardy-Weinberg (H-W) equilibrium, linkage disequilibrium analysis, and logistic regression analysis. The genotype distributions of three IL16 SNPs, rs11556218, rs4778889, and rs4072111, were found to be in line with Hardy-Weinberg equilibrium criteria (P > 0.05). The single-factor logistic regression analysis showed that, compared with the T/T genotype, the T/G genotype decreased the risk of primary knee OA in rs11556218 (OR = 0.37, 95% CI = 0.18~0.82) and, compared with the C/C genotype, the C/T genotype increased the risk of primary knee OA in rs4072111 (OR = 1.83, 95% CI = 1.07~3.59). There was linkage disequilibrium between rs4778889 and rs11556218 (D= 0.592, r(2) = 0.213). Finally, logistic regression analysis showed that compared to haplotype TTC, the TTT haplotype was associated with an increased risk of primary knee OA (OR = 2.10, 95% CI = 1.09-4.98); however, the GCC haplotype was associated with a reduced risk of primary knee OA (OR = 0.36, 95% CI = 0.12-0.93). Thus, the genetic polymorphisms rs11556218, rs4778889, and rs4072111 in the gene encoding IL-16 are associated with primary knee OA in Chinese Han population. PMID- 25785146 TI - Local transplantation of osteogenic pre-differentiated autologous adipose-derived mesenchymal stem cells may accelerate non-union fracture healing with limited pro metastatic potency. AB - Fracture non-union is a serious complication in orthopedic clinical practice. Mesenchymal stem cells are believed to play a vital role in fracture healing process. Among various origins of mesenchymal stem cell, adipose derived stem cells hold great promise especially in clinical milieu. However, the wide spread application of mesenchymal stem cell based therapy is impeded by the pro metastasis nature of the mesenchymal stem cell itself. Based on the findings from previous studies, we hypothesize that local transplanted osteogenic pre differentiatiated adipose stem cell may promote the non-union fracture healing. Moreover, the pre-differnetiation stem cells by down-regulating the expression of CCL5 and CCL2. This novel osteogenic pre-differnetiation technique may help clinical orthopedists to resolve the refractory non-union cases and shed new light on other stem cell based therapies to counteract to avoid the pro metastasis nature of the mesenchymal stem cells. PMID- 25785147 TI - Local administration of IKK small molecule inhibitor may enhance fracture healing in osteoporosis patient. AB - Osteoporosis is an inflammatory bone disease affecting millions of population worldwide, which often cause increased fracture risks and prolonged fracture healing. Growing evidence suggests that IKK-NF-kappaB signaling exert inhibitory influence on MSCs osteogenic differentiation and bone formation. Moreover, enhance the fracture healing process in osteoporosis patient. In the current work, IKK-NF- kappaB differentiated osteoblasts. Thus, manipulating local inflammatory IKK-NF-kappaB signaling was also found to suppress the anabolic effect of signaling in osteoporotic related fracture emerge as a promising therapy to we hypothesized to use locally delivered IKK small molecule inhibitor to augment the impaired fracture healing ability in osteoporosis patient via enhancing both MSCs osteogenic differentiation and osteoblast function. PMID- 25785148 TI - Repeated transurethral resection for non-muscle invasive bladder cancer. AB - BACKGROUND: transurethral resection of bladder tumor (TURBT) is the first-line treatment fornon-muscle-invasive bladder cancer. We aimed to investigate the effect of probable risk factors on the positive rate of the repeated transurethral resection of bladder tumor performed 4-6 weeks after an initial TURBT in patients with non-muscle invasive bladder cancer in China. METHODS: 134 patients with non-muscle invasive bladder cancer who underwent repeated TURBT within 4-6 weeks after an initial resection were included in this study. The presence of residual tumor and the correlated risk factors, the complications of the second procedure and the changes of stage and grade between the two different TURBTs were analyzed. As showed in the manuscript, of the total 134 patients, 52 had residual tumor, and upgrading occurred in 41 patients. Patients with high grade, T1 stageand residual tumor with multi-focality at the initial transurethral resection were found to be at higher risk after the second opinion. The progression and recurrence rate was significantly higher in patients with residual tumor in Re TURBT. CONCLUSION: a high rate of occurrence of residual tumor was reported in the repeated TURBT. We suggest repeated TURBT is to be recommended in patients with high grade, T1 stage or multi-focality non-muscle invasive bladder cancer. PMID- 25785149 TI - NFKB1 -94ins/del ATTG polymorphism increases osteosarcoma risk in a Chinese Han population. AB - Osteosarcoma is one of the most common bone malignancies. The Nuclear factor kappaB1 (NFKB1) gene plays an important role in the pathogenesis of osteosarcoma. The objective of this study aimed to detect the potential association between NFKB1 -94 ins/del ATTG polymorphism and osteosarcoma susceptibility in Chinese Han population. We recruited 220 osteosarcoma patients and 222 cancer-free controls in this case-control study. The NFKB1 -94 ins/del ATTG polymorphism by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients with ID genotype and II genotype showed higher risk of osteosarcoma than individuals with DD genotype (OR=1.54, 95% CI 1.00-2.44, P=0.05; OR=1.72, 95% CI 1.01-2.93, P=0.04), respectively. Subjects with ID or II genotype also showed increased risk of osteosarcoma (OR=1.60, 95% CI 1.04-2.47, P=0.03). In addition, I allele was significantly associated with osteosarcoma risk (OR=1.31, 95% CI 1.01-1.71, P=0.04). We also found that this polymorphism was significantly associated with advanced osteosarcoma risk (OR=3.43, 95% CI 1.61-7.36, P=0.001) and metastatic osteosarcoma risk (OR=2.33, 95% CI 1.22-5.03, P=0.01). In conclusion, our findings indicate that osteosarcoma is associated with the NFKB1 promoter -94ins/del ATTG polymorphism. PMID- 25785150 TI - Blood zinc, calcium and lead levels in Chinese children aged 1-36 months. AB - The aim of the study is to evaluate the blood lead (Pb), total blood calcium (Ca) levels and blood zinc (Zn) levels among children. A cross-sectional study was designed to collect healthy children age 1-36 months (Mean +/- SD: 1.4 +/- 0.3 age, 55% boys) in the study from January 2012 to September 2013. The overall mean blood Pb, Zn and Ca levels were (41.18 +/- 11.13) MUg/L, (62.18 +/- 13.33) MUmol/L and (1.76 +/- 0.13) mmol/L, respectively. The prevalence of elevated blood Pb levels and low blood Ca levels were 1.5% and 5.2%, respectively. The prevalence of Zn deficiency varied from 42% to 49% among different age group. Biomonitoring trace element levels have a significant important to children health. Our findings suggest that parents should pay more attention to the nutrition status, especially for Zn status among children. PMID- 25785151 TI - Complex reconstruction of facial deformity and function after severe gunshot injury: one case report. AB - In this report, we described clinical outcomes of a multi-stage surgery integrating multiple techniques in restoration of facial morphology and function of a 17-year-old boy with severe gunshot injuries. This multi-stage surgery was applied in treatment of one rare case of gunshot-caused complicated facial deformities involving most parts of the face (labrum, left nose wing, nasal columella, nasal septum, maxillary alveolar process, hard palate, soft palate, bilateral maxillary bones, left zygoma, suborbital bone defects) and clinical efficacy upon restoring facial form and function were retrospectively evaluated. The patient was diagnosed with massive facial defects and deformities caused by gunshot, which led to feeding difficulty, severe articulation disorders and serious facial disfigurement. To reconstruct facial form and restore functions of mastication and articulation, multiple examinations and surgical procedures including mirror imaging, rapid prototyping technique, porous titanium implants, microscopic surgical technique, dental implants, osteomyocutaneous flap, muscular flap, shifting and repairing of adjacent tissue flaps and free bone graft reconstruction were undertaken. Postoperatively, reconstruction of severe facial disfigurement and restoring basic functions including articulation and feeding for the first time and relatively sound clinical outcomes have been obtained, which may add clinical evidence to the treatment of similar cases of severe facial deformities. PMID- 25785152 TI - Efficacy of chemotherapy plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer: a meta-analysis and up-date. AB - Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide. Bevacizumab plays an important role in the treatment of metastatic CRC (mCRC). The aim of this study was to evaluate the efficacy and safety of chemotherapy plus bevacizumab as first-line treatment in patients with mCRC. Randomized-controlled clinical trials comparing the efficacy of chemotherapy plus bevacizumab or chemotherapy alone in patients with mCRC were searched using the following electronic database of PubMed, Medline, Embase and CNKI. Total 9 trials, containing 1843 patients in chemotherapy plus bevacizumab group and 1741 patients in chemotherapy alone group, were included. Our results showed that chemotherapy plus bevacizumab statistically increased the Overall response rate (ORR) in patients with mCRC (OR = 1.57, 95% CI = 1.17-2.11, P = 0.003) in a random-effects model. The complete response rate and partial response rate were statistically increased as well (P <= 0.05). Subgroup analysis by bevacizumab dosage found that bevacizumab 5 mg/kg statistically increased the ORR. Significant differences were found in PFS (HR = 0.56, 95% CI = 0.46-0.69, P < 0.00001) and OS (HR = 0.83, 95% CI = 0.76-0.91, P < 0.0001) as well. No significant difference was found in adverse events. Overall, the combination of chemotherapy and bevacizumab as first-line treatment is an effective and well tolerated regimen for patients with mCRC. PMID- 25785153 TI - A case of laryngeal angioleiomyoma and review of literature. AB - Angioleiomyoma is a rare benign vascular smooth muscle tumor that arise from the tunica media of veins and arteries. Here a case of laryngeal angioleiomyoma in a 57-year-old Chinese man is reported. The patient presented with dysphagia for one and half-month and dyspnea during the previous one week, was hospitalized for treatment with a tracheotomy and laryngofissure with the unblock mass excision. Final pathological evaluation of the neoplasm confirmed a diagnosis of laryngeal angioleiomyoma. The patient had been followed up 4 years with no recurrence of disease. This study demonstrated the clinical feature, pathology, treatment and outcome of the rare disease of laryngeal angioleiomyoma. PMID- 25785154 TI - Wernicke's encephalopathy in a patient with unresectable gastric carcinoma and literature review. AB - Wernicke's encephalopathy (WE) is a disease classically associated with nutrition deficiency. It is characterized by typical symptoms like confusion, ataxia and ophthalmoparesis, and developes due to thiamine deficieny in alcoholic patients. Recently, it has been shown that WE could ocur in patients with gastric carcinoma without a history of alcohol use. In this paper, we have made some suggestions about early diagnosis, treatment and prevention of WE by discussing the development of WE in a patient with unresectable gastric carcinoma, who had been inpatient for a long time and given radiotherapy and chemotherapy. PMID- 25785155 TI - The overwhelmingly positive response to Dasatinib of a patient with multiple blast crisis of chronic myeloid leukemia. AB - Blastic phase (BP), the terminal phase of chronic myeloid leukemia (CML), can occur in any of the hematopoietic lineages. Extramedullary blastic crisis (EBC) is a rare form of blastic crisis, which has an extremely poor prognosis. As the tyrosine kinase inhibitor (TKI), Dasatinib is a more effective treatment drug than Imatinib and Nilotinib for this type of CML, because it has greater potency and penetrates through the blood-brain barrier to reach the cerebrospinal fluid (CSF). This report examines the case of a 22-year-old woman with CML, who successively suffered from monocytic blast crisis, lymphoid blast crisis, and central nervous system EBC. She had an overwhelmingly positive response to taking Dasatinib and eventually achieved lasting complete remission. PMID- 25785156 TI - Primary hypertrophic osteoarthropathy with myelofibrosis and anemia: a case report and review of literature. AB - Primary hypertrophic osteoarthropathy (PHO) is a rare and usually benign disorder of bone and connective tissue growth. Here we present a 28-year-old male patient presenting to our hospital with PHO and symptomatic anemia. Bone marrow biopsy suggested myelofibrosis, a serious complication of PHO, which is often neglected upon admission, but may lead to life-threatening anemia. PMID- 25785157 TI - Distal ureteral atresia with ureteropelvic junction obstruction in a female child: a rare case. AB - This case report describes a distal ureteral atresia along with ureteropelvic junction obstruction which occurred in a 19-month-old female child. It is easily to be misdiagnosed as mere ureteropelvic junction obstruction and omitted the combined diagnosis of distal ureteral atresia. Dismembered pyeloplasty was done in local hospital after admission, however with the result of recurrent fever when clamp the left nephrostomy tube and Antegrade urography demonstrated distal ureteral atresia. After two months, boari flap reconstruction was performed for the patient in the Second Xiangya Hospital of Central South University, and the child had good rehabilitation in the end. To our knowledge, this is the first case report on distal ureteral atresia associated with ureteropelvic junction obstruction. PMID- 25785158 TI - Neuraxial anesthesia in the presence of clinical anticoagulation: what are our options for pediatric patients? AB - The use of local anesthesia combined with general anesthesia to provide effective perioperative analgesia continues to increase in the pediatric population. Although neurological complications resulting from peridural hemorrhage following placement of neuraxial blockade is extremely rare in the absence of co-morbid conditions, the consequences can be devastating. Therefore, caution should be exercised, especially in patients receiving antithrombotic or thrombolytic therapy. We present two patients who received unplanned anticoagulation therapy perioperatively following placement of an epidural catheter for postoperative analgesia. Potential concerns with anticoagulation therapy in patients with epidural catheters are discussed and suggestions for the care of such patients are presented. PMID- 25785159 TI - Mycoplasma pneumonia combined with pulmonary infarction in a child. AB - We reported a 9-year-old boy with mycoplasma pneumonia who developed pulmonary infarction. The child first had fever and cough, and then had difficult breathing. But, the signs of his lung were not obvious. Mycoplasma antibody IgM was positive. The child was given intravenous azithromycin for anti-infection, and intravenous low molecular weight heparin and oral warfarin for anti coagulation. Although difficult breathing was relieved, sudden cardiac arrest occurred. His parents requested to give up treatment. PMID- 25785160 TI - Arsenical keratosis caused by medication: a case report and literature. AB - Medication-induced arsenical keratosis is a rare type of arsenical keratosis. We describe here a case of 70-year-old man to explore the clinical characters, diagnosis and treatment of medication-induced arsenical keratosis in order to improve the understanding of this disease and reduce the misdiagnosis rate. The clinical characters, signs, lab findings as well as progression, diagnosis and treatment in the case of arsenical keratosis were analyzed. The patient of medication-induced arsenical keratosis suffered from chronic eczema. He has taken realgar during the treatment. His medication caused arsenical keratosis. Medication-induced arsenical keratosis is rare. Making the medication history clear and using urine arsenic detection if necessary are of significance to understand the patients' condition. It is quite effective that using Sodium Dimercaptosulphonate during the treatment without delay. PMID- 25785161 TI - Pregnancy luteoma followed with massive ascites and elevated CA125 after ovulation induction therapy: a case report and review of literatures. AB - OBJECTIVES: To report a rare case of ovarian tumor with an unusual presentation; an ovarian pregnancy luteoma with massive ascites and elevated CA125 after ovulation induction therapy. CASE PRESENTATION: A 26-year-old pregnant woman complained lower abdominal distension. Ultrasound imaging showed a solid tumor in the right adexna and massive ascites. The blood test showed elevated serum level of CA125 and androgens. The patient underwent the right salpingo-oophorectomy, and then the results of blood test were normal and ascites disappeared. CONCLUSIONS: pregnancy luteoma followed with massive ascites and increased CA125 after ovulation induction therapy is a very rare case. It is important to provide appropriate medical/surgical intervention without disturbing the pregnancy iatrogenically or causing unnecessary maternal morbidity. PMID- 25785162 TI - Endoscopic banding ligation can effectively remove the submucosal tumor. AB - Endoscopic band ligation for variceal bleeding in cirrhosis has been proved its safety and efficacy. We tried to treat submucosal tumors the gastrointestinal (GI) tract by endoscopic band ligation. The aim of this study was to evaluate the efficacy and safety of endoscopic band ligation in the treatment of submucosal tumors of the GI tract. There are 29 patients (15 men, 14 women, age range: 25-67 years old) with 30 submucosal lesions of the GI tract, including 15 lesions in the esophagus, 14 lesions in the of stomach and 1 lesion in the duodenal bulb. The average maximum diameter of the lesions was 7.78 mm (range: 2.4-23.6 mm). All submucosal lesions were successfully removed by band ligation. There is no bleeding and perforation in all patients. No recurrence was observed for the one month following-up. Endoscopic band ligation promises could be considered as a safe and effective for the treatment submucosal tumors of the GI tract, especially for the diameter of tumor < 25 mm. PMID- 25785163 TI - Treatment of pure red cell aplasia associated with multiple myeloma with biclonal gammopathy using cyclosporine A: a case report. AB - We reported a rare case of pure red cell aplasia in a 44-year-old man with multiple myeloma with biclonal gammophathy (IgG lambda and IgA lambda type) with severe anemia. After treatment with bortezomib, adriamycin, and dexamethasone, the patient achieved very good partial response with disappearance of monoclonal gammopathy. However, his anemia was not significantly improved. Bone marrow analysis revealed selective erythroid hypoplasia. Thus, cyclosporine A was administered, which resulted in a complete recovery from anemia. The present case may provide some insight into the pathogenesis of PRAC and malignant plasma cell disorder. PMID- 25785164 TI - Life-threatening intrathyroidal parathyroid adenoma. AB - Acute primary hyperparathyroidism and parathyroid crisis are characterized by life-threatening hypercalcemia, a rare disorder. A 69-year-old female patient presented at our hospital's neurology clinic with weakness, nausea, vomiting, depression, and hypercalcemia. Treatment of hypercalcemia resulted in no improvement in neurological symptoms, indicating resistance to treatment. Thyroid ultrasonography and parathyroid scintigraphy revealed hypoechoic nodules in the right lobe, pieces of nodules in the left lobe, and high serum calcium and parathyroid hormone levels. After provision of intensive medical treatment including hydration, diuresis, and bisphosphonate infusion resulted in only minimal decrease in the calcium level, urgent surgical treatment was performed. Frozen biopsy of the right intrathyroidal giant parathyroid adenoma in the right lobe confirmed initial diagnosis of primary hyperparathyroidism. Based on the biopsy findings, right parathyroidectomy and right total and left subtotal thyroidectomy were performed. Histopathologic examination revealed a parathyroid adenoma localized inside large thyroid nodules. Review of the findings resulted in diagnosis of intrathyroidal parathyroid adenoma. Symptoms of hypercalcemia improved rapidly during the postoperative period. PMID- 25785165 TI - Effect of Two Macrocephala Flavored Powder supplementation on intestinal morphology and intestinal microbiota in weaning pigs. AB - A total of 75 pigs were used to investigate effects of feeding Two Macrocephala Flavored Powder (TMFP) on small intestinal morphology, intestinal microbiota in weaning pigs. The dietary treatments were: a control diet; control diet + 3 g/kg TMFP; control diet + 0.3 g/kg colistin sulfate (ANT). The results showed that supplementation with TMFP increased (P < 0.05) villus height at duodenum, jejunum at 3 time points, increased (P < 0.05) crypt depth at duodenum, jejunum at day 14, improved villus height: crypt depth ratio (P < 0.05) in jejunum at day 21 as compared with ANT. Supplementation of TMFP and ANT had lower (P < 0.05) E. coli counts in the ileum, cecum and colon at day 7 as compared with control. Supplementation of TMFP had higher (P < 0.05) bifidobacteria counts in the ileum, cecum and colon compared with ANT, except for colon at day 21. No effect (P > 0.05) on lactobacilli in colon has been seen with supplementation of TMFP and ANT at 3 time points, while both of supplementations showed increased the number of lactobacilli in cecum at day 14 and day 21. Analysis of DGGE fingerprints indicated that a highest similarity was observed for profiles from samples taken 14 d, 21 d from TMFP. The diversity of DGGE fingerprints of TMFP was higher than those of ANT and control. The results suggest that TMFP is potential to enhancing intestinal morphology and microbiota of weaning pigs, and can be served as an effective and safe dietary additive for weaning pigs. PMID- 25785166 TI - Short-term prognostic factors in the patients after acute heart failure. AB - To explore risk factors of short-term prognosis of acute heart failure (AHF) patients and compare the difference between acute heart failure with reduced ejection fraction (AHFREF) and acute heart failure with preserved ejection fraction (AHFPEF). A retrospective analysis of medical records of AHF patients was performed. Eligible patients were at the age of more than 18 years old, excluding malignancy, acute pulmonary embolism, heart valve diseases (such as mild valvular regurgitation), severe renal insufficiency, and N-terminal pro brain natriuretic peptide (NT-proBNP) < 300 pg/ml. AHFREF group (LVEF < 0.5) and AHFPEF group (LVEF >= 0.5) were classified depending on the left ventricular ejection fraction (LVEF). The involved patients were followed up via telephone contact and consult of medical recording. Unfavorable prognosis was defined upon the cardiac death and re-hospitalization within 6 months; otherwise they had a favorable prognosis. We analyzed the impact factors of short-term prognosis, including patient's age, gender, systolic blood pressure, diastolic blood pressure, heart rate, NT-proBNP, blood glucose, heart ultrasound LVEF, cardiothoracic ration in chest radiograph, history of hypertension, coronary heart disease and diabetes mellitus, for multivariate logistic regression analysis. A total of 130 AHF patients were included in the analysis, including 79 male (60.8%) and 51 female (39.2%). The average age of all involved patients was 74.0 years [M (P 25, P 75) = 64.0, 80.0]. Fifteen cases (11.5%) had unfavorable prognosis and 35 cases (27.0%) had favorable prognosis in the AHFREF group, while the cases in the AHFPEF group were respectively 31 (23.8%) and 49 (37.7%). There was no significant difference in the short-term prognosis between the two groups (chi (2) = 1.030, P = 0.310). The short-term prognosis in AHF patients was mainly influenced by NT-proBNP (r = -0.263, P = 0.035), blood glucose (r = -0.090, P = 0.049) and systolic blood pressure (r = 0.012, P = 0.030). As for AHFREF patients, systolic blood pressure (r = 0.047, P = 0.014) and LVEF (r = 10.991, P = 0.037) were the predominant factors; as for AHFPEF patients, NT-proBNP was the major risk factor (r = -0.319, P = 0.033). High NT-proBNP, high blood sugar and low systolic blood pressure at visits are the risk factors for short-term prognosis of AHF patients. Due to different LVEF baseline levels of AHFREF and AHFPEF, the prognosis factors also vary. Low systolic blood pressure and LVEF are the risk factors of AHFREF, while high NT-proBNP is risk factor of AHFPEF. PMID- 25785167 TI - Meta-analysis of methylenetetrahydrofolate reductase polymorphism and lung cancer risk in Chinese. AB - Numerous studies have investigated association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with lung cancer (LC) susceptibility in Chinese; however, the findings are inconsistent. Therefore, we performed a meta analysis. PubMed, ISI Web of Knowledge, Chinese National Knowledge Infrastructure, and Wanfang were searched. Pooled ORs and 95% CIs were used to assess the strength of the associations. Overall, 10 studies with 2487 cases and 3228 controls investigating the MTHFR C677T polymorphism and LC risk were included. We did not find a significant association between MTHFR C677T polymorphism and LC risk. However, significantly increased LC risk was found in the population from North China, which was not found in the population from South China. In conclusion, our meta-analysis suggested that MTHFR C677T polymorphism might influence the risk of LC. PMID- 25785168 TI - Increased production of soluble vascular endothelial growth factors receptor-1 in CHO-cell line by using new combination of chitosan-protein lipid nanoparticles. AB - The soluble vascular endothelial growth factor receptor-1 (VEGFR1) or sFLT-1 has important role in antiangiogenesis. In this study, the increase expression and production of sFLT-1 fragment by newly designed ChPL-NPs nanoparticles (chitosan protein lipid) using Chinese hamster ovary cell line (CHO) was evaluated. The assessment and purification of sFLT-1 were carried out by western blotting and fast protein liquid chromatography (FPLC). Thereafter, the angiostatic effect of gene transfer of sFLT-1 in Human umbilical vein endothelial cell line (HUVEC) was evaluated. Our results showed a significance rate of transfection with ChPL-NPs (80-85%) in comparison to standard lipofectamine(2000) (65-70%) (P < 0.05). The anti-angiogenic action of sFLT-1 was observed by in-vitro culture of recombinant protein (sFLT-1; 50 ng/ml) with HUVEC cell lines (5 * 10(6)). The ChPL-NPs nanoparticles can consider a potential carrier system for large scale production of sFLT-1, which ultimately may be use as therapeutic agent in targeting solid tumor tissues. PMID- 25785169 TI - A novel approach using Neuron 6F guiding catheter for the embolization of intracranial aneurysm with coiling of the parent internal carotid artery. AB - To describe our initial experience and early outcomes with distal placement of the Neuron 6F guiding catheter through coiled ICA for aneurysmal EVT. We examined the utility of the Neuronf 70 6F guiding catheter for the embolization procedure in such cases, fourteen cases of aneurysm with coiling of the parent ICA are presented via traditional guiding catheters. With the support of 8F ENVOY guiding catheter as a shuttle sheath, the Neuron(TM) 70 6F guiding catheter was successfully placed through coiled extracranial ICA, so the mirocatheter could be delivered to a more strategic position for embolization of the aneurysm. Coiling of extracranial ICA was found as parent artery on angiogram in all patients with ruptured aneurysms. Even where there were two curvatures of more than 360 degrees in the coiled segment of the ICA, Neuron(TM) 70 6F guiding catheter could be placed through the coiling to a distal position and enabled EVT of intracranial aneurysms with no related neurological complications. Neuron guiding catheter is a useful device for embolization of aneurysm where there is coiling of parent ICA, easily placed through the coiling of the ICA and provided robust anatomical support via enhanced catheter-to-vessel wall engagement. PMID- 25785170 TI - Levels of serum superoxide dismutase and high sensitive C-reactive protein in type 2 diabetic patients with lower extremity vascular disease are enhanced by interventional treatment. AB - OBJECTIVES: This study is to determine the levels of serum superoxide dismutase (SOD) and high sensitive C-reactive protein (hs-CRP) in type 2 diabetic patients with lower extremity vascular disease before and after interventional treatment. METHODS: A total of 65 patients were enrolled in this study, including 35 mails and 30 females. Another 65 healthy individuals were used as control, including 41 males and 24 females. Lesions and degrees of stenosis were determined by computed tomography angiography. Contralateral iliac artery and proximal femoral artery occlusion were treated by retrograde femoral artery puncture. The levels of serum SOD and hs-CRP were determined by enzyme-linked immunosorbent assay. Correlation was analyzed by Pearson's test. Progression-free survival curve was analyzed by Kaplan-Meier method. RESULTS: The levels of serum SOD at 20 min, 24 hr, 7 d, and 14 d after surgery were significantly decreased compared with those before surgery (P < 0.05). The levels of serum hs-CRP at 20 min and 24 hr after surgery were increased compared with those before surgery (P < 0.05). The level of serum hs-CRP at 14 d after surgery was significantly lower than that before surgery (P < 0.05). The correlation between SOD and hs-CRP was positive before surgery (r = 0.03, P < 0.001), but negative at 24 hr after surgery (r = -0.008, P < 0.001). The levels of serum SOD were significantly lower than median value (P < 0.05), while the Levels of serum hs-CRP were significantly higher than median value (P < 0.05). CONCLUSIONS: The levels of serum SOD and hs-CRP were significantly different before and after interventional treatment. The levels of serum SOD and hs-CRP can be used as indicators for the efficacy and prognosis of interventional treatment on type 2 diabetic patients with lower extremity vascular disease. PMID- 25785171 TI - Effects of antimicrobial peptides on Staphylococcus aureus growth and biofilm formation in vitro following isolation from implant-associated infections. AB - To prevent biomaterial-associated infections, antibiotic agents are recommended for various medical conditions requiring biomaterial implants, but resistance often appears after the introduction of antibiotics into clinical use. Therefore, new strategies for the prevention or treatment for biomaterial-associated infections are required. The purpose of this study was to evaluate the effects of antimicrobial peptides on growth and biofilm formation of Staphylococcus aureus isolated from implant-associated infections. A total of 20 patients with culture proven staphylococcal infection associated with stable orthopedic implants were selected as the experimental group. S. aureus were isolated from tissue biopsies for identification, the isolated strains were mixed with Tet213 incubated at 37 degrees C and viable bactrial number of S. aureus was counted. For the biofilm formation, the broad spectrum AMP Tet213 was selected and loaded onto the Ti coating first. At the same time Ti coated with Tet213 were mixed with S. aureus in vitro to form biofilm. After 30 min, 2 h, 4 h, 6 h, 8 h, the population of S. aureus in the biofilm was counted. Tet213 showed significant antibacterial effect on 16 strains (P < 0.05, Table 1). The inhibition rate reached above 80% among 12 strains of the clinically isolated strain. In biofilm experiments, counts of the NO. 1, 2, 3, 4 strains in biofilms decreased significantly after 2 h (P < 0.05), while there was no obvious difference in counts of NO. 5 strain (P > 0.05). The broad spectrum AMP Tet213 could strongly reduce the growth and biofilm formation of S. aureus in vitro, and the use of this might be an important new approach to target implant-associated infections. PMID- 25785172 TI - Effects of insulin resistance on myometrial growth. AB - To observe the effects of insulin resistance on gonadal steroid hormone stimulation and the myometrial growth of female rats in order to elucidate the relationship between insulin resistance and the development of uterine leiomyomas. We divided 180 nonpregnant female Wistar rats into three groups as follows: group A, as the control group; group B, as the "model by exogenous sex hormone" group; and group C, as the "model by exogenous sex hormone plus insulin resistance" group. All the animals were raised for 16 weeks. Uterine coefficient and homeostasis model assessment of insulin resistance (HOMA-IR) index were calculated. Myometrial depth and expression levels of the oestrogen receptor (ER), progesterone receptor (PR), and proliferating cell nuclear antigen (PCNA) were measured. HOMA-IR index, serum oestrogen level, uterine coefficient, and myometrial depth were lower in group B than in group C (P < 0.05). The expression levels of ER, PR, and PCNA were higher in group C than in group B (P < 0.05). An auxo-action of insulin resistance in myometrial growth was observed when exogenous oestrogen and progesterone were administered to the female rats in this study. Thus, we suspected that insulin resistance may affect the development of uterine leiomyomas. PMID- 25785173 TI - Application of new packing material in endoscopic nasal surgery. AB - OBJECTIVE: To show the efficacy and comfort of pneumatic bag packing after the endoscopic nasal surgery. Pneumatic bag packing may be recommendable in terms of comfort and efficacy after endoscopic nasal surgery. Significant findings: There were statistical significant differences between the pneumatic bag packing and the expansive sponge packing regarding subjective symptoms and objective findings after surgery. CONCLUSIONS: Pneumatic bag packing may be recommendable in terms of comfort and efficacy after endoscopic nasal surgery. PMID- 25785175 TI - Comparison of the efficacy of conventional echocardiographic parameters in the diagnosis of significant coronary artery stenosis. AB - BACKGROUND: For diagnosis of significant coronary artery stenosis, the most accurate parameter among the conventional echocardiographic parameters remains unknown. OBJECTIVES: To assess the diagnostic efficacy of conventional echocardiographic parameters in the diagnosis of significant coronary artery stenosis and their correlation with the percentage of stenosis considering conventional coronary angiography as gold standard. PATIENTS AND METHODS: Seventy eight individuals were included in the study. The three echocardiographic parameters including the coronary sinus flow [flow (mL/minute)], the global left ventricular perfusion by dividing the coronary sinus flow by left ventricular mass [flow/LVM (mL/minute)] and the difference between the left ventricular mass at end diastole and peak systole using area-length calculation methods [LV (d-s) mass A-L] were assessed using receiver operating characteristic (ROC) analysis for their accuracy to distinguish between normal subjects and patients with significant (> 50%) coronary artery disease (CAD). RESULTS: Flow (mL/minute), flow/LVM (mL/minuteg) and LV (d-s) mass A-L all correlated significantly with the percentage of stenosis (r = -0.64, P < 0.001; r = -0.47, P < 0.001; r = -0.56, P < 0.001, respectively). With the use of the percentage of stenosis > 50% as the criteria to distinguish patients with or without CAD, the areas under the ROC curve for flow (mL/minute) were 0.75, while they were 0.57 for flow/LVM (mL/minuteg) and 0.59 for LV (d-s) mass A-L. The percentage of stenosis > 70% was best detected by coronary sinus flow < 198 mL/minute (sensitivity, 81.35%; specificity, 70.37%; positive predictive value, 63.63%; negative predictive value, 86.36% and accuracy, 75%; P < 0.001). CONCLUSIONS: The coronary sinus flow per minute is the most accurate parameter among the three echocardiographic parameters mentioned above for the assessment of significant stenosis of the coronary artery. PMID- 25785174 TI - Potential benefits of berberine in the management of perimenopausal syndrome. AB - Cardiovascular diseases are one of the leading causes of morbidity and mortality in women after menopause and 56% of all causes of death in Western European countries. Nowadays, with increasing life span, women spend approximately one third of their life-time in postmenopausal state; therefore, the development of new strategies to improve the prevention and treatment of menopause-associated pathologies is important topic in clinical practice. The studies to assess the safety of hormone replacement therapy in women with estrogen deficiency have not been conclusive due to the relative contraindications; therefore, hormone replacement therapy is prescribed only in selected cases and for a limited time. For this reason, today women are encouraged to use naturally available compounds to prevent or to attenuate menopausal symptoms and correlated pathologies, with fewer side effects. Among these compounds, berberine, an isoquinoline alkaloid derived from plants of the generis Berberis, has been recognized as being capable of decreasing oxidative stress, LDL, triglycerides, and insulin resistance and of improving the mood. This review describes the cellular and clinical effects associated with the use of berberine, which suggest that this molecule could be an effective natural supplement to ensure a smooth peri- and postmenopausal transition. PMID- 25785176 TI - Preliminary study on the kidney elasticity quantification in patients with chronic kidney disease using virtual touch tissue quantification. AB - BACKGROUND: Virtual touch tissue quantification (VTTQ) provides numerical measurements (shear wave velocity (SWV) values) of tissue stiffness. OBJECTIVES: The purpose of this study was to describe the SWV values of the kidney by VTTQ and to examine the clinical usefulness of this procedure in the evaluation of elasticity changes in the kidneys of patients with chronic kidney disease (CKD). PATIENTS AND METHODS: Sixty-five patients with CKD and seventy healthy participants were included in this study. A total of 270 kidneys were examined by VTTQ. The kidney elasticity was expressed as shear wave velocity. The SWV values, blood serum creatinine (Scr)/BUN and pathological findings were analyzed and compared between patients with CKD and healthy participants. RESULTS: In patients with CKD and healthy participants, the SWV values both gradually decreased from the renal cortex to the medulla and renal sinus The SWV value of the renal cortex in patients with CKD was less than that of healthy participants (P < 0.05), and the SWV value of the renal cortex in patients with renal insufficiency was significantly less than in those with normal renal function (2.46 +/- 0.15 vs. 3.45 +/- 0.26 m/s, P < 0.05). The best cutoff value for predicting renal insufficiency (Scr > 1.24 mg/dL or/and BUN > 21 mg/DL) was a SWV value of the renal cortex of less than 1.92 m/s with a sensitivity of 84.4% (95% CI: 67.2 94.7%) and a specificity of 96.8% (95% CI: 83.3-99.9%) (P < 0.001). CONCLUSION: VTTQ can sensitively detect the elasticity changes in patients with CKD, and it can effectively predict renal insufficiency. This technology provides a valuable tool for the assessment of CKD. PMID- 25785177 TI - How can a radiologist reveal more practical information using dynamic study of cavernosal artery after injection of vasoactive agents? AB - BACKGROUND: Erection is a dynamic multi-stage neurovascular phenomenon consisting of 4 phases. Conventional protocol of color Doppler study can easily overlook these ongoing dynamic events. OBJECTIVES: Here, we tried to designate patterns for these dynamic spectral waveform changes of cavernosal arteries in patients with erectile dysfunction and subsequently better describe the extent of their underlying problem. PATIENTS AND METHODS: We evaluated 59 men who were referred for post-intracavernosal injection (ICI) color Doppler investigation of suspected erectile dysfunction (ED). The demographic data and medical history were recorded. Afterwards, first scan injection was done. Then scanning of cavernosal arteries was started about one minute after the injection and was continued thereafter. For better description of temporal changes in the waveform of cavernosal arteries, new patterns were defined and used. Patients were also classified based on previously known etiologic categories (i.e. arterial insufficiency, venous leak, mixed type, and normal response). RESULTS: The mean age was 45.6 +/- 13.1 (24 to 74 ) years. Twenty-two were normal responders [considered as non-organic causes (37.3% of all patients)], 27 were classified as venous leakage, eight had arterial insufficiency and two were mixed type. Maximum PSV occurred before the fifth minute in 47 patients (92.2%). Eight patients completed all phases of erection in the first 5 minutes. We defined 8 patterns for the temporal changes in cavernosal arterial waveform. Pattern 5 was the most common pattern of venous leak; while, patterns 3 and 4 were considered as the uncommon group. Six patients demonstrated the uncommon patterns of venous leak (22.2%). Hypertension was more prevalent in the uncommon pattern of venous leak. CONCLUSIONS: We highlight the considerable role of continuous evaluation starting one minute after intra cavernosal with ICI injection of the vasoactive agent for better description of the underlying pathologies of ED especially in patients with venous leak etiology. PMID- 25785178 TI - Comparison of the Accuracy of DWI and Ultrasonography in Screening Hepatocellular Carcinoma in Patients With Chronic Liver Disease. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a neoplasm usually arising in a cirrhotic liver by a multistep carcinogenesis process. Early detection of HCC and accurate assessment of tumor burden are crucial to successful treatment planning and long-term survival. OBJECTIVES: In this study, we compared the accuracy of diffusion weighted imaging (DWI) combined with limited sequence magnetic resonance imaging (MRI) set as a potentially quick and practical MR candidate with ultrasonography (US) for screening of HCC in patients with cirrhosis. PATIENTS AND METHODS: Of 96 patients with cirrhosis, 30 who had concomitant HCC proved by pathology were selected. MRI, DWI, and US of the liver were performed for the patients. Sensitivity, specificity, and accuracy of DWI alone, limited sequences MRI alone, a combination of them, and US were calculated for the detection of HCC in these patients and then comparison between these modalities was performed. RESULTS: Combination of limited sequences MRI and DWI had the highest accuracy (94.79%) followed by DWI alone followed by limited sequence MRI alone. The least accuracy was for US (78.12%) with a statistically significant difference. CONCLUSION: Due to the significant improvement in the treatment of early stage of HCC compared to the previous decade, we suggest a fast, non invasive, more accurate, but more expensive method (HASTE, OP/IP T1W sequences MRI combined with DWI) rather than US for the screening of HCC in liver cirrhosis. PMID- 25785179 TI - Clinical and Laboratory Findings in Patients With Acute Respiratory Symptoms That Suggest the Necessity of Chest X-ray for Community-Acquired Pneumonia. AB - BACKGROUND: Pneumonia is a common illness in all parts of the world and is considered as a major cause of death among all age groups. Nevertheless, only about 5% of patients referring to their primary care physicians with acute respiratory symptoms will develop pneumonia. OBJECTIVES: This study was performed to derive practical criteria for performing chest radiographs for the evaluation of community-acquired pneumonia (CAP). PATIENTS AND METHODS: A total of 420 patients with acute respiratory symptoms and positive findings on chest radiograph were evaluated from December 2008 to December 2009. The subjects were referred to outpatient clinics or emergency departments of Birjand's medical university hospitals, Iran, and were enrolled as positive cases. A checklist was completed for each patient including their demographic information, clinical signs and symptoms (cough, sputum production, dyspnea, chest pain, fever, tachycardia, and tachypnea), abnormal findings in pulmonary auscultation and laboratory findings (erythrocyte sedimentation rate, C-reactive protein levels, and white blood cell count). An equal number of age-matched individuals with acute respiratory symptoms, but insignificant findings on chest radiography, were included as the control group. Finally, the diagnostic values of different findings were compared. RESULTS: The data showed that vital signs and physical examination findings are useful screening parameters for predicting chest radiograph findings in outpatient settings. Therefore, by implementing a prediction rule, we would be able to determine which patients would benefit from a chest X-Ray (sensitivity, 94% and specificity, 57%). CONCLUSIONS: This study's findings suggest that requesting chest radiographs might not be necessary in patients with acute respiratory symptoms unless the vital signs and/or physical examination findings are abnormal. Considering the 94% sensitivity of this rule for predicting CAP, a chest radiograph is required for patients with unreliable follow-ups or moderate to high likelihood of morbidity if CAP is not initially detected. PMID- 25785180 TI - Comparing color Doppler ultrasonography and angiography to assess traumatic arterial injuries of the extremities. AB - BACKGROUND: Traumatic events are one of the major causes of arterial injuries. Physical examination is not a good predictor of the extent of injuries and arteriography is considered as the gold standard for this purpose. In the recent years, noninvasive modalities are increasingly replacing diagnostic arteriography. Color Doppler ultrasonography (USG) is an excellent method to investigate arterial diseases. OBJECTIVES: The present study aimed to evaluate the diagnostic value of color Doppler USG compared to conventional angiography in traumatic arterial injuries of extremities. PATIENTS AND METHODS: Seventy-five patients with extremity trauma suspicious for arterial injury were examined by color Doppler USG just before angiography. Doppler pattern and flow states were assessed, then angiography was performed. The results of duplex USG were compared with angiography. RESULTS: Color Doppler USG had a sensitivity of 95% and specificity of 98% in diagnosis of arterial injury. Positive and negative predictive values of Doppler USG were 92.5% and 94.2%, respectively. CONCLUSIONS: Color Doppler USG can be used as a reliable modality with acceptable sensitivity and specificity values to screen hemodynamically stable patients with limb trauma suspicious for arterial injury. PMID- 25785181 TI - Intraosseous pleomorphic adenoma of the mandible. PMID- 25785182 TI - Ectopic mediastinal thyroid tissue with a normally located thyroid gland. AB - Ectopic thyroid tissue (ETT) is a rare entity and a challenging differential diagnosis. This is a report of a case of a mediastinal mass that was found to be an ectopic mediastinal thyroid tissue, in a 77-year-old woman who was admitted to our hospital for breast cancer management. The mediastinal mass was identified in the postsurgical computed tomography (CT) scan of the chest and was suspected as mediastinal lymph node metastasis. A CT-guided percutaneous transthoracic punch biopsy (CT-TPB) proved to be an adequate diagnostic tool to exclude malignancy and provide a definite diagnosis of the mediastinal mass. We find that CT-guided punch biopsy as a useful diagnostic alternative enabling histopathological specimens to be obtained from mediastinal masses and lymph nodes suspected of malignancy. PMID- 25785183 TI - Comparative analysis of knowledge representation and reasoning requirements across a range of life sciences textbooks. AB - BACKGROUND: Using knowledge representation for biomedical projects is now commonplace. In previous work, we represented the knowledge found in a college level biology textbook in a fashion useful for answering questions. We showed that embedding the knowledge representation and question-answering abilities in an electronic textbook helped to engage student interest and improve learning. A natural question that arises from this success, and this paper's primary focus, is whether a similar approach is applicable across a range of life science textbooks. To answer that question, we considered four different textbooks, ranging from a below-introductory college biology text to an advanced, graduate level neuroscience textbook. For these textbooks, we investigated the following questions: (1) To what extent is knowledge shared between the different textbooks? (2) To what extent can the same upper ontology be used to represent the knowledge found in different textbooks? (3) To what extent can the questions of interest for a range of textbooks be answered by using the same reasoning mechanisms? RESULTS: Our existing modeling and reasoning methods apply especially well both to a textbook that is comparable in level to the text studied in our previous work (i.e., an introductory-level text) and to a textbook at a lower level, suggesting potential for a high degree of portability. Even for the overlapping knowledge found across the textbooks, the level of detail covered in each textbook was different, which requires that the representations must be customized for each textbook. We also found that for advanced textbooks, representing models and scientific reasoning processes was particularly important. CONCLUSIONS: With some additional work, our representation methodology would be applicable to a range of textbooks. The requirements for knowledge representation are common across textbooks, suggesting that a shared semantic infrastructure for the life sciences is feasible. Because our representation overlaps heavily with those already being used for biomedical ontologies, this work suggests a natural pathway to include such representations as part of the life sciences curriculum at different grade levels. PMID- 25785184 TI - Development and application of an interaction network ontology for literature mining of vaccine-associated gene-gene interactions. AB - BACKGROUND: Literature mining of gene-gene interactions has been enhanced by ontology-based name classifications. However, in biomedical literature mining, interaction keywords have not been carefully studied and used beyond a collection of keywords. METHODS: In this study, we report the development of a new Interaction Network Ontology (INO) that classifies >800 interaction keywords and incorporates interaction terms from the PSI Molecular Interactions (PSI-MI) and Gene Ontology (GO). Using INO-based literature mining results, a modified Fisher's exact test was established to analyze significantly over- and under represented enriched gene-gene interaction types within a specific area. Such a strategy was applied to study the vaccine-mediated gene-gene interactions using all PubMed abstracts. The Vaccine Ontology (VO) and INO were used to support the retrieval of vaccine terms and interaction keywords from the literature. RESULTS: INO is aligned with the Basic Formal Ontology (BFO) and imports terms from 10 other existing ontologies. Current INO includes 540 terms. In terms of interaction-related terms, INO imports and aligns PSI-MI and GO interaction terms and includes over 100 newly generated ontology terms with 'INO_' prefix. A new annotation property, 'has literature mining keywords', was generated to allow the listing of different keywords mapping to the interaction types in INO. Using all PubMed documents published as of 12/31/2013, approximately 266,000 vaccine associated documents were identified, and a total of 6,116 gene-pairs were associated with at least one INO term. Out of 78 INO interaction terms associated with at least five gene-pairs of the vaccine-associated sub-network, 14 terms were significantly over-represented (i.e., more frequently used) and 17 under represented based on our modified Fisher's exact test. These over-represented and under-represented terms share some common top-level terms but are distinct at the bottom levels of the INO hierarchy. The analysis of these interaction types and their associated gene-gene pairs uncovered many scientific insights. CONCLUSIONS: INO provides a novel approach for defining hierarchical interaction types and related keywords for literature mining. The ontology-based literature mining, in combination with an INO-based statistical interaction enrichment test, provides a new platform for efficient mining and analysis of topic-specific gene interaction networks. PMID- 25785185 TI - Ontorat: automatic generation of new ontology terms, annotations, and axioms based on ontology design patterns. AB - BACKGROUND: It is time-consuming to build an ontology with many terms and axioms. Thus it is desired to automate the process of ontology development. Ontology Design Patterns (ODPs) provide a reusable solution to solve a recurrent modeling problem in the context of ontology engineering. Because ontology terms often follow specific ODPs, the Ontology for Biomedical Investigations (OBI) developers proposed a Quick Term Templates (QTTs) process targeted at generating new ontology classes following the same pattern, using term templates in a spreadsheet format. RESULTS: Inspired by the ODPs and QTTs, the Ontorat web application is developed to automatically generate new ontology terms, annotations of terms, and logical axioms based on a specific ODP(s). The inputs of an Ontorat execution include axiom expression settings, an input data file, ID generation settings, and a target ontology (optional). The axiom expression settings can be saved as a predesigned Ontorat setting format text file for reuse. The input data file is generated based on a template file created by a specific ODP (text or Excel format). Ontorat is an efficient tool for ontology expansion. Different use cases are described. For example, Ontorat was applied to automatically generate over 1,000 Japan RIKEN cell line cell terms with both logical axioms and rich annotation axioms in the Cell Line Ontology (CLO). Approximately 800 licensed animal vaccines were represented and annotated in the Vaccine Ontology (VO) by Ontorat. The OBI team used Ontorat to add assay and device terms required by ENCODE project. Ontorat was also used to add missing annotations to all existing Biobank specific terms in the Biobank Ontology. A collection of ODPs and templates with examples are provided on the Ontorat website and can be reused to facilitate ontology development. CONCLUSIONS: With ever increasing ontology development and applications, Ontorat provides a timely platform for generating and annotating a large number of ontology terms by following design patterns. AVAILABILITY: http://ontorat.hegroup.org/. PMID- 25785186 TI - Lymphangiogenesis and angiogenesis during human fetal pancreas development. AB - BACKGROUND: The complex endocrine and exocrine functionality of the human pancreas depends on an efficient fluid transport through the blood and the lymphatic vascular systems. The lymphatic vasculature has key roles in the physiology of the pancreas and in regulating the immune response, both important for developing successful transplantation and cell-replacement therapies to treat diabetes. However, little is known about how the lymphatic and blood systems develop in humans. Here, we investigated the establishment of these two vascular systems in human pancreas organogenesis in order to understand neovascularization in the context of emerging regenerative therapies. METHODS: We examined angiogenesis and lymphangiogenesis during human pancreas development between 9 and 22 weeks of gestation (W9-W22) by immunohistochemistry. RESULTS: As early as W9, the peri-pancreatic mesenchyme was populated by CD31-expressing blood vessels as well as LYVE1- and PDPN-expressing lymphatic vessels. The appearance of smooth muscle cell-coated blood vessels in the intra-pancreatic mesenchyme occurred only several weeks later and from W14.5 onwards the islets of Langerhans also became heavily irrigated by blood vessels. In contrast to blood vessels, LYVE1- and PDPN expressing lymphatic vessels were restricted to the peri-pancreatic mesenchyme until later in development (W14.5-W17), and some of these invading lymphatic vessels contained smooth muscle cells at W17. Interestingly, between W11-W22, most large caliber lymphatic vessels were lined with a characteristic, discontinuous, collagen type IV-rich basement membrane. Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22. CONCLUSION: Our data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards. Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development. PMID- 25785187 TI - In vitro gastrointestinal digestion study of two wheat cultivars and evaluation of xylanase supplementation. AB - BACKGROUND: The filamentous fungus Talaromyces versatilis is known to improve the metabolizable energy of wheat-based poultry diets thanks to its ability to produce a pool of CAZymes and particularly endo-beta(1,4)-xylanases. In order to appreciate their in vivo mode of action, the supplementation effect of two of its xylanases, XynD and XynB from families GH10 and GH11 respectively, have been evaluated on two different wheat cultivars Caphorn and Isengrain, which were chosen amongst 6 varieties for their difference in non starch polysaccharides content and arabinoxylan composition. RESULTS: Polysaccharides digestion was followed during 6 h along the digestive tract using the TNO gastrointestinal model-1, to mimic monogastric metabolism. Polysaccharide degradation appeared to occur mainly at the jejunal level and was higher with Isengrain than with Caphorn. For both cultivars, XynD and XynB supplementation increased notably the amount of reducing end sugars into the jejuno-ileal dialysates, which has been confirmed by a valuable increase of the soluble glucose into the jejunal dialysates. CONCLUSIONS: The amounts of arabinose and xylose into the dialysates and ileal deliveries increased consequently mainly for Caphorn, suggesting that XynD and XynB supplementation in wheat-based diet could alleviate the anti nutritional effects of arabinoxylans by limiting the physical entrapment of starch and could increase the available metabolizable energy. PMID- 25785188 TI - Development of TAP, a non-invasive test for qualitative and quantitative measurements of biomarkers from the skin surface. AB - BACKGROUND: The skin proteome contains valuable information on skin condition, but also on how skin may evolve in time and may respond to treatments. Despite the potential of measuring regulatory-, effector- and structural proteins in the skin for biomarker applications in clinical dermatology and skin care, convenient diagnostic tools are lacking. The aim of the present study was to develop a highly versatile and non-invasive diagnostic tool for multiplex measurements of protein biomarkers from the surface of skin. RESULTS: The Transdermal Analyses Patch (TAP) is a novel molecular diagnostic tool that has been developed to capture biomarkers directly from skin, which are quantitatively analyzed in spot ELISA assays. Optimisation of protocols for TAP production and biomarker analyses makes TAP measurements highly specific and reproducible. In measurements of interleukin-1alpha (IL-1alpha), IL-1 receptor antagonist (IL-1RA) and human beta defensin (hBD-1) from healthy skin, TAP appears far more sensitive than skin lavage-based methods using ELISA. No side-effects were observed using TAP on human skin. CONCLUSION: TAP is a practical and valuable new skin diagnostic tool for measuring protein-based biomarkers from skin, which is convenient to use for operators, with minimal burden for patients. PMID- 25785189 TI - Vav2 protein overexpression marks and may predict the aggressive subtype of ductal carcinoma in situ. AB - BACKGROUND: A subset of patients with ductal carcinoma in situ (DCIS) will develop invasive breast cancer (IBC). To date, there are no effective predictive biomarkers for identifying this subset with worse prognosis whose lesions are essentially indistinguishable histologically from those with favorable outcomes. We hypothesized that measurable parameters that discriminate DCIS from DCIS with concurrent invasion may serve as diagnostic biomarkers (BM) of progressive cancer in situ (CIS). RESULTS: Using a novel imaging-based method of tissue testing, we measured the relative expression levels of three candidate BM proteins specifically implicated in IBC progression - the insulin-like growth factor I receptor (IGF-IR), Ras-related protein 1 (Rap1), and Vav2 oncoprotein. Protein profiles were compared in 42 histologically normal mammary epithelial samples, 71 CIS (35 without/36 with invasion either on diagnostic biopsy or final surgical excision), and 98 IBC of known estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. The levels of the IGF IR and Rap1 protein expression were significantly elevated in ER-positive (ER+/PR+/-/HER2 -) DCIS relative to normal epithelium (P <0.0001). The IGF-IR protein expression was also significantly up regulated in HER2-positive (ER+/ /PR+/-/HER2+) DCIS relative to normal epithelium (P = 0.0002). IGF-IR and Rap1 protein expression levels were similar among DCIS patients without or with concurrent invasion. Vav2 upregulation in DCIS relative to normal group was not associated with steroid hormone receptor and HER2 status, but was associated with the presence of concurrent invasion, including microinvasion (invasive foci of less than 1 mm). DCIS with high Vav2 were more than twice as likely to progress to invasive cancers as DCIS with low Vav2 (odds ratio, 2.42; 95% CI, 1.26-4-65; P =0.008). Furthermore, a receiver operating characteristic curve analysis revealed moderate ability of Vav2 protein expression measurements in DCIS to predict the existence of invasion concurrent with DCIS (area under the curve, 0.71; 95% CI, 0.59- 0.84). CONCLUSIONS: Our novel findings hold promise for utilizing Vav2 protein as a predictive BM for differentiating progressive from non-progressive DCIS. PMID- 25785190 TI - First attempt to implement ophthalmia neonatorum prophylaxis in angola: microorganisms, efficacy, and obstacles. AB - Purpose. To determine the efficacy of povidone-iodine (P-I) prophylaxis for ophthalmia neonatorum (ON) in Angola and to document maternal prevalence and mother-to-child transmission rates. Methods. Endocervical samples from mothers (n = 317) and newborn conjunctival smears (n = 245) were analysed by multiplex polymerase chain reaction (PCR) for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG). Newborns were randomized into a noninterventional group and an interventional group that received a drop of P-I 2.5% bilaterally after conjunctival smear collection. Mothers were trained to identify signs of ON and attend a follow-up visit. Results. Forty-two newborns had ocular pathology, and 11 (4.4%) had clinical signs of ON at the time of delivery. Maternal PCR was positive for MG (n = 19), CT (n = 8), and NG (n = 2). Six newborns were positive for CT (n = 4), MG (n = 2), and NG (n = 1). Mother-to child transmission rates were 50% for CT and NG and 10.5% for MG. Only 16 newborns returned for follow-up. Conclusions. Lack of maternal compliance prevented successful testing of prophylactic P-I efficacy in ON prevention. Nevertheless, we documented the prevalence and mother-to-child transmission rates for CT, NG, and MG. These results emphasize the need to develop an effective Angolan educational and prophylactic ON program. PMID- 25785191 TI - Clinical and spectral-domain optical coherence tomography findings of patients with incomplete visual recovery after anatomically successful retinal detachment surgery. AB - Purpose. To identify causes of incomplete visual recovery in patients with anatomically successful retinal detachment surgery. Methods. This was a retrospective study of 61 eyes of 61 patients with at least 12-month follow-up and complete preoperative, intraoperative, and postoperative record. Postoperative visual acuity (VA) more than 0.18 logMAR was considered as incomplete visual recovery. Complete ophthalmic examination and Spectral-Domain OCT (SD-OCT) imaging were performed at last follow-up. Results. Twenty-nine eyes (47.5%) had a postoperative VA < 0.18 logMAR and 32 eyes (52.5%) had a postoperative VA >= 0.18 logMAR. Mean follow-up was 32.8 +/- 17.3 months. Incomplete visual recovery was strongly correlated with presence of macular pathology (P = 0.002), a detached macula preoperatively (P = 0.02), retinotomy (P = 0.025), and pars plana vitrectomy and use of silicon oil as a tamponade agent (P = 0.009). Also, although there was a strong correlation between ellipsoid zone disruption and incomplete visual recovery, a distinct, more course pathology could be identified in all cases of poor visual recovery related to edema, thickening, or atrophy of the macula. Conclusion. The careful postoperative evaluation of the macula using biomicroscopy and SD-OCT can help in diagnosis of alterations that can be associated with incomplete visual recovery. PMID- 25785192 TI - Cognitive Outcomes following Transcatheter Aortic Valve Implantation: A Systematic Review. AB - Severe aortic stenosis is the most common valvular heart disease in the elderly in the Western world and contributes to a large proportion of all deaths over the age of 70. Severe aortic stenosis is conventionally treated with surgical aortic valve replacement; however, the less invasive transcatheter aortic valve implantation (TAVI) is suggested for those at high surgical risk. While TAVI has been associated with improved survival and favourable outcomes, there is a higher incidence of cerebral microembolisms in TAVI patients. This finding is of concern given mechanistic links with cognitive decline, a symptom highly prevalent in those with cardiovascular disease. This paper reviews the literature assessing the possible link between TAVI and cognitive changes. Studies to date have shown that global cognition improves or remains unchanged over 3 months following TAVI while individual cognitive domains remain preserved over time. However, the association between TAVI and cognition remains unclear due to methodological limitations. Furthermore, while these studies have largely focused on memory, cognitive impairment in this population may be predominantly of vascular origin. Therefore, cognitive assessment focusing on domains important in vascular cognitive impairment, such as executive dysfunction, may be more helpful in elucidating the association between TAVI and cognition in the long term. PMID- 25785193 TI - Association of serum bisphenol a with hypertension in thai population. AB - Objective. The present study aimed to examine the association between serum BPA and hypertension and evaluated whether it was influenced by estradiol level. Methods. A subsample of 2588 sera randomly selected from the Thai National Health Examination Survey IV, 2009, was measured for serum BPA and estradiol. Logistic regression was used to examine the association controlling for age, sex, diabetes, body mass index, and estradiol level. Results. Compared with the lowest quartile, the adjusted odds ratio (AOR) of hypertension for the fourth quartile of serum BPA was 2.16 (95% CI 1.31, 3.56) in women and 1.44 (0.99, 2.09) in men. There was no interaction between serum BPA and estradiol level. For analysis using log(BPA) as a continuous variable, the AOR per unit change in log(BPA) was 1.09 (95% CI 1.02, 1.16). Among postmenopausal women, the AOR for the fourth quartile of BPA was 2.33 (95% CI 1.31, 4.15) and, for premenopausal women, it was 2.12 (95% CI 0.87, 5.19). Conclusion. Serum BPA was independently associated with hypertension in women and was not likely to be affected by estrogen; however, its mechanism related to blood pressure needs further investigation. PMID- 25785194 TI - Peritoneal carcinomatosis: intraoperative parameters in open (coliseum) versus closed abdomen HIPEC. AB - BACKGROUND: Peritoneal carcinomatosis (PC) is associated with a poor prognosis. Cytoreductive surgery (CRS) and HIPEC play an important role in well-selected patients with PC. The aim of the study is to present the differences in the intraoperative parameters in patients who received HIPEC in two different manners, open versus closed abdomen. PATIENTS AND METHODS: The population includes 105 patients with peritoneal carcinomatosis from colorectal, gastric, and ovarian cancer, sarcoma, mesothelioma, and pseudomyxoma peritonei. Group A (n = 60) received HIPEC using the open technique and Group B (n = 45) received HIPEC with the closed technique. The main end points were morbidity, mortality, and overall hospital stay. RESULTS: There were two postoperative deaths (3.3%) in the open group versus no deaths in the closed group. Twenty-two patients in the open group (55%) had grade III-IV complications versus 18 patients in the closed group (40%). There are more stable intraoperative conditions in the closed abdomen HIPEC in CVP, pulse rate, and systolic pressure parameters. CONCLUSIONS: Both methods are equal in the HIPEC procedures. Perhaps the closed method is the method of choice for frail patients due to more stable hemodynamic parameters. PMID- 25785196 TI - Two ports laparoscopic inguinal hernia repair in children. AB - Introduction. Several laparoscopic treatment techniques were designed for improving the outcome over the last decade. The various techniques differ in their approach to the inguinal internal ring, suturing and knotting techniques, number of ports used in the procedures, and mode of dissection of the hernia sac. Patients and Surgical Technique. 90 children were subjected to surgery and they undergone two-port laparoscopic repair of inguinal hernia in children. Technique feasibility in relation to other modalities of repair was the aim of this work. 90 children including 75 males and 15 females underwent surgery. Hernia in 55 cases was right-sided and in 15 left-sided. Two patients had recurrent hernia following open hernia repair. 70 (77.7%) cases were suffering unilateral hernia and 20 (22.2%) patients had bilateral hernia. Out of the 20 cases 5 cases were diagnosed by laparoscope (25%). The patients' median age was 18 months. The mean operative time for unilateral repairs was 15 to 20 minutes and bilateral was 21 to 30 minutes. There was no conversion. The complications were as follows: one case was recurrent right inguinal hernia and the second was stitch sinus. Discussion. The results confirm the safety and efficacy of two ports laparoscopic hernia repair in congenital inguinal hernia in relation to other modalities of treatment. PMID- 25785195 TI - Implementation of a robotic surgical program in gynaecological oncology and comparison with prior laparoscopic series. AB - BACKGROUND: Robotic surgery in gynaecological oncology is a rapidly developing field as it offers several technical advantages over conventional laparoscopy. An audit was performed on the outcome of robotic surgery during our learning curve and compared with recent well-established laparoscopic procedure data. METHOD: Following acquisition of the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, California, USA), we prospectively analysed all cases performed over the first six months by one experienced gynaecologist who had been appropriately trained and mentored. Data on age, BMI, pathology, surgery type, blood loss, morbidity, return to theatre, hospital stay, and readmission rate were collected and compared with a consecutive series over the preceding 6 months performed laparoscopically by the same team. RESULTS: A comparison of two consecutive series was made. The mean age was somewhat different, 55 years in the robotic versus 69 years in the laparoscopic group, but obesity was a feature of both groups with a mean of BMI 29.3 versus 28.06, respectively. This difference was not statistically significant (P = 0.54). Three subgroups of minimal access surgical procedures were performed: total hysterectomy and bilateral salpingooophorectomy (TH + BSO), total hysterectomy and bilateral salpingooophorectomy plus bilateral pelvic lymphadenectomy (TH + BSO + BPLND), and radical hysterectomy plus bilateral pelvic lymphadenectomy (RH + BPLND). The mean time taken to perform surgery for TH + BSO was longer in the robotic group, 151.2 min compared to 126.3 min in the laparoscopic group. TH + BSO + BPLND surgical time was similar to 178.3 min in robotic group and 176.5 min in laparoscopic group. RH + BPLND surgical time was similar, 263.6 min (robotic arm) and 264.0 min (laparoscopic arm). However, the numbers in this initial analysis were small especially in the last two subgroups and do not allow for statistical analysis. The rate of complications necessitating intervention (Clavien-Dindo classification grade 2/3) was higher in the robotic arm (22.7%) compared to the laparoscopic approach (4.5%). The readmission rate was higher in the robotic group (18.2%) compared to the laparoscopic group (4.5%). The return to theatre in the robotic group was 18.2% and 4.5% in laparoscopic group. Uncomplicated robotic surgery hospital stay appeared to be shorter, 1.3 days compared to the uncomplicated laparoscopic group, 2.5 days. There was no conversion to the open procedure in either arm. Estimated blood loss in all cases was less than 100 mL in both groups. CONCLUSION: Robotic surgery is comparable to laparoscopic surgery in blood loss; however, the hospital stay in uncomplicated cases appears to be longer in the laparoscopic arm. Surgical robotic time is equivalent to laparoscopic in complex cases but may be longer in cases not requiring lymph node dissection. The robotic surgery team learning curve may be associated with higher rate of morbidity. Further research on the benefits to the surgeon is needed to clarify the whole picture of this versatile novel surgical approach. PMID- 25785197 TI - Early metacarpal bone mineral density loss using digital x-ray radiogrammetry and 3-tesla wrist MRI in established rheumatoid arthritis: a longitudinal one-year observational study. AB - Objectives. Early change in rheumatoid arthritis (RA) is characterised by periarticular osteopenia. We investigated the relationship of early metacarpal digital X-ray radiogrammetry bone mineral density (DXR-BMD) change rate (RC-BMD, mg/cm(2)/month) to longitudinal changes in hand and feet radiographic and wrist MRI scores over 1 year. Materials and Methods. 10 RA patients completed the study and had wrist 3T-MRI and hand and feet X-rays at various time points over 1 year. MRI was scored by RAMRIS, X-ray was done by van der Heijde modified Sharp scoring, and RC-BMD was analysed using dxr-online. Results. There was good correlation amongst the two scorers for MRI measures and ICC for erosions: 0.984, BME: 0.943, and synovitis: 0.657. Strong relationships were observed between RC BMD at 12-week and 1-year change in wrist marrow oedema (BME) (r = 0.78, P = 0.035) but not with erosion, synovitis, or radiographic scores. Conclusion. Early RC-BMD correlates with 1-year wrist BME change, which is a known predictor of future erosion and joint damage. However, in our pilot study, early RC-BMD did not show relationships to MRI erosion or radiographic changes over 1 year. This may reflect a slower kinetic in the appearance of MRI/radiographic erosions, generating the hypothesis that RC-BMD may be a more sensitive and early structural prognostic marker in RA follow-up. PMID- 25785198 TI - Quantitative Proteomics and Lipidomics Analysis of Endoplasmic Reticulum of Macrophage Infected with Mycobacterium tuberculosis. AB - Even though endoplasmic reticulum (ER) stress associated with mycobacterial infection has been well studied, the molecular basis of ER as a crucial organelle to determine the fate of Mtb is yet to be established. Here, we have studied the ability of Mtb to manipulate the ultrastructural architecture of macrophage ER and found that the ER-phenotypes associated with virulent (H37Rv) and avirulent (H37Ra) strains were different: a rough ER (RER) with the former against a smooth ER (SER) with the later. Further, the functional attributes of these changes were probed by MS-based quantitative proteomics (133 ER proteins) and lipidomics (8 phospholipids). Our omics approaches not only revealed the host pathogen cross talk but also emphasized how precisely Mtb uses proteins and lipids in combination to give rise to characteristic ER-phenotypes. H37Ra-infected macrophages increased the cytosolic Ca(2+) levels by attenuating the ATP2A2 protein and simultaneous induction of PC/PE expression to facilitate apoptosis. However, H37Rv inhibited apoptosis and further controlled the expression of EST-1 and AMRP proteins to disturb cholesterol homeostasis resulting in sustained infection. This approach offers the potential to decipher the specific roles of ER in understanding the cell biology of mycobacterial infection with special reference to the impact of host response. PMID- 25785199 TI - Outcome of concurrent occult hemothorax and pneumothorax in trauma patients who required assisted ventilation. AB - Background. The management and outcomes of occult hemopneumothorax in blunt trauma patients who required mechanical ventilation are not well studied. We aimed to study patients with occult hemopneumothorax on mechanical ventilation who could be carefully managed without tube thoracostomy. Methods. Chest trauma patients with occult hemopneumothorax who were on mechanical ventilation were prospectively evaluated. The presence of hemopneumothorax was confirmed by CT scanning. Hospital length of stay, complications, and outcome were recorded. Results. A total of 56 chest trauma patients with occult hemopneumothorax who were on ventilatory support were included with a mean age of 36 +/- 13 years. Hemopneumothorax was managed conservatively in 72% cases and 28% underwent tube thoracostomy as indicated. 29% of patients developed pneumonia, 16% had Acute Respiratory Distress Syndrome (ARDS), and 7% died. Thickness of hemothorax, duration of mechanical ventilation, and development of ARDS were significantly associated with tube thoracostomy in comparison to no-chest tube group. Conclusions. The majority of occult hemopneumothorax can be carefully managed without tube thoracostomy in patients who required positive pressure ventilation. Tube thoracotomy could be restricted to those who had evidence of increase in the size of the hemothorax or pneumothorax on follow-up chest radiographs or developed respiratory compromise. PMID- 25785200 TI - In silico analysis of bioethanol overproduction by genetically modified microorganisms in coculture fermentation. AB - Lignocellulosic biomass is an attractive sustainable carbon source for fermentative production of bioethanol. In this context, use of microbial consortia consisting of substrate-selective microbes is advantageous as it eliminates the negative impacts of glucose catabolite repression. In this study, a detailed in silico analysis of bioethanol production from glucose-xylose mixtures of various compositions by coculture fermentation of xylose-selective Escherichia coli strain ZSC113 and glucose-selective wild-type Saccharomyces cerevisiae is presented. Dynamic flux balance models based on available genome scale metabolic networks of the microorganisms have been used to analyze bioethanol production and the maximization of ethanol productivity is addressed by computing optimal aerobic-anaerobic switching times. A set of genetic engineering strategies for ethanol overproduction by E. coli strain ZSC113 have been evaluated for their efficiency in the context of batch coculture process. Finally, simulations are carried out to determine the pairs of genetically modified E. coli strain ZSC113 and S. cerevisiae that significantly enhance ethanol productivity in batch coculture fermentation. PMID- 25785201 TI - Immediate weight-bearing after ankle fracture fixation. AB - We believe that a certain subset of surgical ankle fracture patients can be made weight-bearing as tolerated immediately following surgery. Immediate weight bearing as tolerated (IWBAT) allows patients to return to ambulation and activities of daily living faster and may facilitate rehabilitation. A prospectively gathered orthopaedic trauma database at a Level 1 trauma center was reviewed retrospectively to identify patients who had ORIF after unstable ankle injuries treated by the senior author. Patients were excluded if they were not IWBAT based on specific criteria or if they did meet followup requirement. Only 1/26 patients was noted to have loss of fixation. This was found at the 6-week followup and was attributed to a missed syndesmotic injury. At 2-week followup, 2 patients had peri-incisional erythema that resolved with a short course of oral antibiotics. At 6-week followup, 20 patients were wearing normal shoes and 6 patients continued to wear the CAM Boot for comfort. To conclude, IWBAT in a certain subset of patients with stable osteosynthesis following an ankle fracture could potentially be a safe alternative to a period of protected weight-bearing. PMID- 25785203 TI - Dual prosthetic heart valve presented with chest pain: a case report of coronary thromboembolism. AB - Coronary embolism from a prosthetic heart valve is a rare but remarkable cause of acute coronary syndrome. There is no definite management of an entity like this. Here we report a case of 54-year-old male with a history of rheumatic heart disease with dual prosthetic heart valve and atrial fibrillation who developed chest pain from acute myocardial infarction. The laboratory values showed inadequate anticoagulation. Cardiac catheterization and thrombectomy with the aspiration catheter were chosen to be the treatment for this patient, and it showed satisfactory outcome. PMID- 25785202 TI - Npas4 expression in two experimental models of the barrel cortex plasticity. AB - Npas4 has recently been identified as an important factor in brain plasticity, particularly in mechanisms of inhibitory control. Little is known about Npas4 expression in terms of cortical plasticity. In the present study expressions of Npas4 and the archetypal immediate early gene (IEG) c-Fos were investigated in the barrel cortex of mice after sensory deprivation (sparing one row of whiskers for 7 days) or sensory conditioning (pairing stimulation of one row of whiskers with aversive stimulus). Laser microdissection of individual barrel rows allowed for analysis of IEGs expression precisely in deprived and nondeprived barrels (in deprivation study) or stimulated and nonstimulated barrels (in conditioning study). Cortex activation by sensory conditioning was found to upregulate the expression of both Npas4 and c-Fos. Reorganization of cortical circuits triggered by removal of selected rows of whiskers strongly affected c-Fos but not Npas4 expression. We hypothesize that increased inhibitory synaptogenesis observed previously after conditioning may be mediated by Npas4 expression. PMID- 25785204 TI - Subacute right ventricle perforation by pacemaker lead presenting with left hemothorax and shock. AB - Cardiac perforation by pacemaker is a rare but potentially fatal complication. Acute perforations occurring within twenty-four hours of insertion of pacemaker can lead to hemopericardium, cardiac tamponade, and death. Hemothorax occurring as an acute complication of pacemaker insertion is reported but extremely rare. Previously, hemothorax and shock as a subacute complication following pacemaker insertion have not been reported. We report the case of an 85-year-old patient who presented with shock from hemothorax caused by pacemaker perforation, two weeks after insertion. Device interrogation showed normal function. Chest X-ray and echocardiogram missed lead dislocation and the diagnosis was made on computed tomogram (CT) of the chest. Following surgical repair, a new ventricular pacemaker was placed transvenously in the right ventricular septum. This case illustrates that CT scan of the chest should be performed in all patients in whom cardiac perforation by pacemaker is suspected but not diagnosed on chest X-ray and echocardiogram. Normal functioning of pacemaker on device interrogation does not exclude perforation. PMID- 25785205 TI - Nitric oxide-sensitive pulmonary hypertension in congenital rubella syndrome. AB - Persistent pulmonary hypertension is a very rare presentation of congenital virus infection. We discuss the case of complete congenital rubella syndrome presenting at echocardiography with pulmonary hypertension that worsened after ductus ligation. Cardiac catheterization showed a normal pulmonary valve and vascular tree but a PAP = 40 mmHg. The infant promptly responded to inhaled nitric oxide while on mechanical ventilation and was later shifted to oral sildenafil. It is not clear whether our observation may be due to direct viral damage to the endothelium or to the rubella virus increasing the vascular tone via a metabolic derangement. PMID- 25785206 TI - A modified design for posterior inlay-retained fixed dental prosthesis. AB - The aim of this paper is to report a clinical case with bilateral missing mandibular second premolars that were restored by metal-ceramic inlay-retained fixed dental prostheses. The first prosthesis was of a traditional design and the second was of a modified design. The suggested design is created by modifying the retainer wings of the traditional resin-bonded inlay-retained fixed dental prosthesis and covering the wings with composite resin. The modified design is relatively conservative, esthetic and provides an extra element for the retention of posterior metal-ceramic inlay-retained fixed dental prostheses. PMID- 25785207 TI - Sarcomatoid (spindle cell) carcinoma of tongue: a report of two cases. AB - Sarcomatoid Carcinoma (SC) is an unusual and aggressive variant of squamous cell carcinoma, which frequently recurs and metastasizes; for this reason, the right diagnosis is very important. It is considered to be a biphasic tumor made up of cells from squamous and spindle cells carcinoma with a sarcomatous aspect, but of epithelial origin. The diagnosis often represents a clinical-pathological challenge where the study with immunohistochemical technique (IHC) is key to the histopathological diagnosis. The reported cases related to oral mucosa are limited. In this work we present two SC cases where the use of IHC allowed us to achieve a conclusive diagnosis. PMID- 25785208 TI - Unilateral oral mucous membrane pemphigoid: refractory atypical presentation successfully treated with intravenous immunoglobulins. AB - A 57-year-old male presented with a 6-month history of blisters and painful erosions on the right buccal mucosa. No skin or other mucosal involvement was seen. The findings of histopathological and direct immunofluorescence examinations were sufficient for the diagnosis of oral mucous membrane pemphigoid in the context of adequate clinical correlation. No response was seen after topical therapies and oral corticosteroids or dapsone. Intravenous immunoglobulin was started and repeated every three weeks. Complete remission was achieved after three cycles and no recurrence was seen after two years of follow-up. The authors report a rare unilateral presentation of oral mucous membrane pemphigoid on the right buccal and hard palate mucosa, without additional involvement during a period of five years. Local trauma or autoimmune factors are possible etiologic factors for this rare disorder, here with unique presentation. PMID- 25785209 TI - Case Reports That Illustrate the Efficacy of SGLT2 Inhibitors in the Type 1 Diabetic Patient. AB - SGLT2 inhibitors are only approved for use in adults with type 2 diabetes. However, because SGLT2 inhibitors have a mechanism of action that does not require the presence of endogenous insulin, these drugs should also be efficacious in type 1 diabetes where endogenous insulin production is greatly reduced or absent. Herein, I present five cases which illustrate the benefits of utilizing an SGLT2 inhibitor with type 1 diabetes. In these cases the use of SGLT2 inhibitors resulted not only in better glycemic control in most patients but also in some patients' less hypoglycemia, weight loss, and decreased doses of insulin. In type 1 diabetes Candida albicans vaginitis and balanitis may occur more frequently than in type 2 diabetes. These cases show that a large randomized clinical trial of SGLT2 inhibitors in type 1 diabetes needs to be performed. PMID- 25785210 TI - Hyperhemolysis Syndrome without Underlying Hematologic Disease. AB - Introduction. Hyperhemolysis is characterized by a life-threatening hemolytic transfusion reaction, with hemoglobin (Hb) and hematocrit (Hct) dropping markedly lower than before transfusion. This phenomenon, commonly described in sickle cell disease, is a rare occurrence in patients without hemoglobinopathies. Case Report. A 55-year-old male presented to the hospital after a motorcycle crash and received 10 units of cross-matched blood for active bleeding. The patient was blood group O, with a negative antibody screen. Ten days later, he represented complaining of dyspnea and was found to have a hematocrit of 12%. The direct antiglobulin test was positive for anti-immunoglobin G and complement. Indirect antiglobulin test was positive for anti-Jka alloantibodies. The presence of Jka antigen was revealed in one unit of previously transfused blood; patient's RBCs were negative for the Jka antigen. Laboratory data demonstrated findings consistent with DHTR, as well as reticulopenia and elevated ferritin levels. He continued to show signs of active hemolysis, requiring a total of 4 subsequent units of pRBCs. Each transfusion precipitated a drop in Hb and Hct to levels lower than before transfusion; once transfusions were held, the patient slowly recovered. Discussion. Hyperhemolysis in the setting of a DHTR can occur in patients without hematologic disease. PMID- 25785211 TI - A proven case of cutaneous rhizopus infection presenting with severe limb pain very soon after induction treatment in a patient with acute lymphoblastic leukemia. AB - Objective and Importance. Invasive mucormycosis may complicate the course of patients with hematologic malignancies and has a very high mortality rate. Early diagnosis and aggressive approach combined with surgical and medical treatment have paramount importance for cure. Clinical Presentation. We report here a case of a patient with acute lymphoblastic leukemia presenting with a subcutaneous mass lesion which was sampled by an ultrasound guided needle biopsy. The pathology showed microorganisms with aseptate hyphae with wide, irregular walls and more or less branching with highly vertical angles which suggested a mold infection. The specimen was also cultured where Rhizopus spp. grew. Conclusion. Posaconazole 200 mg QID was commenced. She recovered from neutropenia and pain on day 20 of treatment. After 4 courses of hyper-CVAD chemotherapy, the remaining soft tissue mass was removed surgically and she underwent allogeneic HSCT from a full matched sibling donor under secondary prophylaxis. PMID- 25785212 TI - Cutaneous ulcer as leading symptom of systemic cytomegalovirus infection. AB - Cytomegalovirus (CMV) infection rarely manifests with skin ulcerations. We describe a case report of a 64-year-old woman with chronic immunosuppression for treatment of mixed connective tissue disease, presenting with new onset leg ulcerations after a recent change in immunosuppressive regimen. She subsequently developed fulminant hepatitis, encephalopathy, and pancytopenia and was found to have severe systemic CMV viremia. Skin ulcer biopsy was positive by immunohistochemical staining for CMV infected endothelial cells. Both systemic disease and skin ulcer rapidly improved after stopping immunosuppression and administering intravenous ganciclovir. New onset skin ulcers in an immunosuppressed individual, especially with recent changes in immunosuppressive regimen, should raise the suspicion of reactivation of CMV. PMID- 25785213 TI - A rare case of primary amenorrhea with two etiologies, hypothalamic amenorrhea, transverse vaginal septum, and no hematocolpos. AB - We reported a rare case of hypothalamic amenorrhea and transverse vaginal septum. A 28-year-old woman presented with primary amenorrhea and no complaint of abdominal pain. Laparoscopy revealed a small rudimentary uterus with streak ovaries and a vaginal pouch. The patient with diagnosis of Mayer-Rokitansky Kuster-Hauser (MRKH) syndrome was subjected to a vaginoplasty in another fertility center. In our institute, after two courses of estrogen and progesterone, sonography revealed hematocolpos, while, under anesthesia, transverse vaginal septum was resected. Hysteroscopy revealed normal uterine cavity. She became pregnant 5 months postoperatively with controlled ovarian stimulation (COS) in conjunction with intrauterine insemination, and she has two healthy babies now. This case highlights the importance of careful evaluation of all primary amenorrheas. Clinicians should be aware of presence of more than one etiology which causes atypical presentations and accomplishes a systematic strategy for the evaluation of amenorrhea potential to avoid long-term side effects of a misdiagnosis. PMID- 25785214 TI - Intra-articular giant synovial osteochondroma: case reports of the ankle and knee joint. AB - Two cases of giant intra-articular osteochondromas (knee and ankle joint) are reported; pathologically they are rare representations of synovial chondromatosis. A 17-year-old man presented with a tumorous mass which had been localized in his left ankle for many years, increasing in volume during the last months. The lesion was removed by posteromedial ankle arthrotomy. The second case was observed in a 39-year-old woman with a slow-growing mass in her right knee joint. The lesion was removed from the Hoffa fat pad by open anteromedial arthrotomy. PMID- 25785215 TI - Tibial tubercle fracture in a 14-year-old athlete with bilateral lower pole bipartite patella and osgood-schlatter disease. AB - We present a case of tibial tubercle fracture in a young male athlete with both bilateral bipartite patella at the lower pole (Saupe type I) and Osgood-Schlatter disease. Open reduction and internal fixation were performed to restore the extensor mechanism of the knee. PMID- 25785216 TI - Conservative management for lingual thyroid ectopic. AB - Lingual thyroid gland is a rare clinical entity. The presence of an ectopic thyroid gland located at the base of the tongue may be presented with symptoms like dysphagia, dysphonia, and upper airway obstruction. We are introducing a case of an 8-year-old girl who had lingual thyroid that presented dysphagia and foreign body sensation in the throat. The diagnostic was reached with clinical examination, thyroid scintigraphy with Tc(99m) and ultrasound. A laryngoscopy was performed which confirmed a spherical mass at base of tongue. Investigation should include thyroid function tests. In this case we observed subclinical hypothyroidism. There are different types of surgical approaches for the treatment of this condition; however, the treatment with Levothyroxine Sodium allowed the stabilization of TSH levels and clinical improvement of symptoms in a follow-up of 2 years. PMID- 25785217 TI - Successful treatment with mycophenolate mofetil and tacrolimus in juvenile severe lupus nephritis. AB - Lupus nephritis (LN) of juvenile onset often has severe disease presentation. Despite aggressive induction therapy, up to 20% of patients with LN are resistant to initial therapy and up to 44% suffer a renal relapse. However, there is no consensus on an appropriate therapeutic regimen for refractory LN. We report a 13 year-old girl with recurrent LN who was not taking her medications. At age of 11 years, she was diagnosed with LN classified as International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV G (A) + V. She was treated with prednisolone and MMF after nine methylprednisolone pulses. Nineteen months later, she was admitted to the hospital with generalized edema. Her symptoms were nephrotic syndrome and acute renal dysfunction. She received three methylprednisolone pulses for 3 days, followed by oral prednisolone and MMF. Twenty-seven days after the three methylprednisolone pulses, her acute renal dysfunction was improved, but the nephrotic syndrome was not improved. A second biopsy showed diffuse lupus nephritis classified as the predominant finding of ISN/RPS class V. We added tacrolimus to the MMF. Four months after adding tacrolimus, the nephrotic syndrome improved. We conclude that adding tacrolimus to the treatment regimen for LN resistant to MMF is effective. PMID- 25785218 TI - Ultrasonographic and scintigraphic findings of thyroid hemiagenesis in a child: report of a rare male case. AB - Thyroid hemiagenesis is a rare congenital anomaly in which one lobe of thyroid gland fails to develop. It is much rarer in males. There is a higher incidence of associated thyroid disorders in patients with thyroid hemiagenesis; therefore early and prompt diagnosis is important for children. We present the ultrasonographic and scintigraphic findings of thyroid hemiagenesis in an eight year-old-boy. On ultrasonography (US), left lobe of the thyroid gland could not be demonstrated and the right lobe showed minimal hyperplasia. Its echogenicity was normal and no nodule was seen. On thyroid scintigraphy, left lobe of thyroid gland or any ectopic thyroid tissue could not be demonstrated, while the right lobe showed minimal hyperplasia. Without performing any invasive procedure, we enrolled the child in a follow-up program with the guidance of US and scintigraphy, which were effective both in making the final diagnosis of thyroid hemiagenesis and in evaluating the current status of the present thyroid tissue. In conclusion, if only one thyroid lobe is detected in a pediatric case initially with US or scintigraphy, the diagnosis of thyroid hemiagenesis should be suggested and, before any unnecessary or invasive attempt, the other complementary method (scintigraphy/US) should be performed. PMID- 25785219 TI - Refractory rheumatic disorder: atypical postpregnancy osteoporosis. AB - This is a case report on a young patient with severe osteoporosis that was initially revealed when she presented with polyarthralgia during her second pregnancy. Postpartum, the pain increased and her X-ray did not show any abnormalities. A bone scintigraphy was performed. It indicated an inflammatory rheumatic disorder. Six months after partum, an investigation of right coxalgia revealed a spontaneous basicervical fracture. Given the persistent polyarthralgia, the patient underwent a new scintigraphy, which revealed areas of what looked to be old rib and L1 fractures. A subsequent full body magnetic resonance imaging (MRI) scan revealed signal abnormalities that could indicate multiple lower limb bone fractures. Despite exhaustive biological, radiological, and histological testing, no secondary cause for the osteoporosis was found. The patient was started on teriparatide. We finally concluded that, despite the atypical presentation, the patient was suffering from postpregnancy osteoporosis. It is possible that the frequency of occurrence of this still poorly understood disease is underestimated. PMID- 25785220 TI - Pure squamous cell carcinoma of the duodenum. AB - Primary carcinomas of the small intestine are extremely rare neoplasms. Most of these are adenocarcinomas. Primary squamous cell carcinoma (SCC) of small intestine is exceptionally rare with only occasional case reports in the literature. We report here a surgically treated patient with squamous cell carcinoma arising from duodenal diverticula in the third part of the duodenum. PMID- 25785221 TI - Amyand's Hernia Complicated by Omental Infarct Presenting as Acute Scrotum: Report of a Case and Review of the Literature. AB - Inguinal hernia with acute appendicitis known as Amyand's hernia is uncommon. It may clinically manifest as acute scrotum, inguinal lymphadenitis, or strangulated hernia. The presentation of Amyand's hernia with acute scrotum has been rarely described. Also, the manifestation of infarcted omentum in the inguinal hernia has been described in one case previously. However, the coexistence of perforated appendix with infarcted omentum in the hernia sac which manifests acute scrotum has not been described previously. Herein, we described a case of a 5-year-old boy, admitted with right tense, painful, and erythematous scrotum in the emergency room. The diagnosis of herniated appendicitis was performed preoperatively by ultrasound. Moreover, the ischemic omentum was confirmed during surgery. PMID- 25785222 TI - Fungal pulmonary valve endocarditis masquerading as a pulmonary embolism. AB - Septic pulmonary emboli (SPE) can be a difficult clinical entity to distinguish from thromboembolic pulmonary embolism (TPE) in a patient with history of IV drug abuse (IVDA). We present a case of a patient who presented with failure to thrive and presumed diagnosis of recurrent PE that ultimately was discovered to have fungal pulmonary valve endocarditis resulting in a right ventricular outflow obstruction. This required replacement of the pulmonary valve and repair of the right ventricular outflow tract. This case highlights difficulty in differentiating pulmonary valve endocarditis with septic emboli from chronic PE in a patient with a complex medical history. PMID- 25785223 TI - Papillary Carcinoma Occurrence in a Thyroglossal Duct Cyst with Synchronous Papillary Thyroid Carcinoma without Cervical Lymph Node Metastasis: Two-Cases Report. AB - Background. We present two rare cases of papillary carcinomas which appeared in thyroglossal duct cysts. These cases highlight that thyroglossal duct cyst can serve as malignancy of thyroid gland. Methods. A retrospective case report was carried out on 2 patients at Cipto Mangunkusumo Hospital. Results. A 57-year-old man presented with enlarged right anterior and midline neck mass, which preoperatively were diagnosed as thyroglossal duct cyst (TDC) and nontoxic multinodular goiter. A total thyroidectomy and Sistrunk procedure were performed. In the second case, a 35-year-old woman presented with a lump which occurred at anterior neck region without palpable mass at the thyroid. Preoperatively, it was diagnosed as TDC. Sistrunk procedure was performed, followed by total thyroidectomy a month after the first operation. Histopathology showed papillary thyroid carcinoma in both patients. Conclusion. The occurrence of carcinoma in TDC is very rare but should always be considered as an option in making diagnosis for a neck mass. PMID- 25785224 TI - Morel-lavallee lesion: report of a case of unknown mechanism. AB - Morel-Lavallee lesions are cystic lesions occurring between the subcutaneous tissue and the underlying layer of a fascia. The most frequent mechanism of occurrence is posttraumatic, usually after degloving injuries. The chain of events leading to the occurrence of this lesion is the formation of a potential space between the subcutaneous tissue and the firmly attached deep fascia, which in turn fills with blood and/or lymph and/or necrotic fat, secondary to disruption of the capillaries. We present a case of a 74-year-old male patient with a cystic lesion of the lateral surface of his left thigh increasing in size over a period of six months. Despite the meticulous history acquisition, we were unable to reveal any alleged mechanism of injury of the area. The patient underwent an MRI which revealed an ovoid cyst. The patient underwent surgical excision of the cyst. The pathology examination revealed a simple cyst, lined by a fibrous capsule and filled with serosanguineous fluid, thus confirming the diagnosis. The patient made a full recovery and since has been asymptomatic. PMID- 25785225 TI - Whole-Body Electromyostimulation to Fight Osteopenia in Elderly Females: The Randomized Controlled Training and Electrostimulation Trial (TEST-III). AB - Whole-body electromyostimulation (WB-EMS) has been shown to be effective in increasing muscle strength and mass in elderly women. Because of the interaction of muscles and bones, these adaptions might be related to changes in bone parameters. 76 community-living osteopenic women 70 years and older were randomly assigned to either a WB-EMS group (n = 38) or a control group (CG: n = 38). The WB-EMS group performed 3 sessions every 14 days for one year while the CG performed gymnastics containing identical exercises without EMS. Primary study endpoints were bone mineral density (BMD) at lumbar spine (LS) and total hip (thip) as assessed by DXA. After 54 weeks of intervention, borderline nonsignificant intergroup differences were determined for LS-BMD (WB-EMS: 0.6 +/- 2.5% versus CG -0.7 +/- 2.5%, P = .051) but not for thip-BMD (WB-EMS: -1.1 +/- 1.9% versus CG: -0.8 +/- 2.3%, P = .771). With respect to secondary endpoints, there was a gain in lean body mass (LBM) of 1.5% (P = .006) and an increase in grip strength of 8.4% (P = .000) in the WB-EMS group compared to CG. WB-EMS effects on bone are less pronounced than previously reported effects on muscle mass. However, for subjects unable or unwilling to perform intense exercise programs, WB-EMS may be an option for maintaining BMD at the LS. PMID- 25785226 TI - Associations of polyunsaturated Fatty Acid intake with bone mineral density in postmenopausal women. AB - A secondary analysis of cross-sectional data was analyzed from 6 cohorts (Fall 1995-Fall 1997) of postmenopausal women (n = 266; 56.6 +/- 4.7 years) participating in the Bone Estrogen Strength Training (BEST) study (a 12-month, block-randomized, clinical trial). Bone mineral density (BMD) was measured at femur neck and trochanter, lumbar spine (L2-L4), and total body BMD using dual energy X-ray absorptiometry (DXA). Mean dietary polyunsaturated fatty acids (PUFAs) intakes were assessed using 8 days of diet records. Multiple linear regression was used to examine associations between dietary PUFAs and BMD. Covariates included in the models were total energy intake, body weight at year 1, years after menopause, exercise, use of hormone therapy (HT), total calcium, and total iron intakes. In the total sample, lumbar spine and total body BMD had significant negative associations with dietary PUFA intake at P < 0.05. In the non-HT group, no significant associations between dietary PUFA intake and BMD were seen. In the HT group, significant inverse associations with dietary PUFA intake were seen in the spine, total body, and Ward's triangle BMD, suggesting that HT may influence PUFA associations with BMD. This study is registered with clinicaltrials.gov, identifier: NCT00000399. PMID- 25785227 TI - The Genetic Link between Parkinson's Disease and the Kynurenine Pathway Is Still Missing. AB - Background. There is substantial evidence that the kynurenine pathway (KP) plays a role in the normal physiology of the brain and is involved in the pathology of neurodegenerative disorders such as Huntington's disease and Parkinson's disease (PD). Objective. We set out to investigate the potential roles in PD of single nucleotide polymorphisms (SNPs) from one of the key enzymes of the KP, kynurenine 3-monooxygenase (KMO). Methods. 105 unrelated, clinically definitive PD patients and 131 healthy controls were enrolled to investigate the possible effects of the different alleles of KMO. Fluorescently labeled TaqMan probes were used for allele discrimination. Results. None of the four investigated SNPs proved to be associated with PD or influenced the age at onset of the disease. Conclusions. The genetic link between the KP and PD is still missing. The investigated SNPs presumably do not appear to influence the function of KMO and probably do not contain binding sites for regulatory proteins of relevance in PD. This is the first study to assess the genetic background behind the biochemical alterations of the kynurenine pathway in PD, directing the attention to this previously unexamined field. PMID- 25785228 TI - Early Freezing of Gait: Atypical versus Typical Parkinson Disorders. AB - In 18 months, 850 patients were referred to Muhammad Ali Parkinson Center (MAPC). Among them, 810 patients had typical Parkinson disease (PD) and 212 had PD for <=5 years. Among the 212 patients with early PD, 27 (12.7%) had freezing of gait (FOG). Forty of the 850 had atypical parkinsonism. Among these 40 patients, all of whom had symptoms for <=5 years, 12 (30.0%) had FOG. FOG improved with levodopa in 21/27 patients with typical PD but did not improve in the 12 patients with atypical parkinsonism. FOG was associated with falls in both groups of patients. We believe that FOG unresponsive to levodopa in typical PD resembles FOG in atypical parkinsonism. We thus compared the 6 typical PD patients with FOG unresponsive to levodopa plus the 12 patients with atypical parkinsonism with the 21 patients with typical PD responsive to levodopa. We compared them by tests of locomotion and postural stability. Among the patients with FOG unresponsive to levodopa, postural stability was more impaired than locomotion. This finding leads us to believe that, in these patients, postural stability, not locomotion, is the principal problem underlying FOG. PMID- 25785229 TI - Chemical Composition and Seasonality of Aromatic Mediterranean Plant Species by NMR-Based Metabolomics. AB - An NMR-based metabolomic approach has been applied to analyse seven aromatic Mediterranean plant species used in traditional cuisine. Based on the ethnobotanical use of these plants, the approach has been employed in order to study the metabolic changes during different seasons. Primary and secondary metabolites have been detected and quantified. Flavonoids (apigenin, quercetin, and kaempferol derivatives) and phenylpropanoid derivatives (e.g., chlorogenic and rosmarinic acid) are the main identified polyphenols. The richness in these metabolites could explain the biological properties ascribed to these plant species. PMID- 25785230 TI - Determination of Matrine in Rat Plasma after Oral Administration of Novel Korean Herbal Medicine KIOM-MA128 and Application of PK. AB - KIOM-MA128 is a novel Korean herbal medicine with antiatopic, anti-inflammatory, and antiasthmatic effects. Matrine is thought to be a potential chemical marker of KIOM-MA128, but pharmacokinetic studies on KIOM-MA128 had not been performed. This study describes a simple and rapid method using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to determine the concentration of matrine in rats plasma after administration of KIOM-MA128. The isocratic mobile phase consisted of methanol and distilled water, and the flow rate was 0.15 mL/min. The accuracy and precision of the assay, as well as stability tests, were performed in accordance with FDA regulations for the validation of bioanalytical methods. The half-life and T max of matrine after administration of KIOM-MA128 were 4.29 +/- 2.20 h and 1.8 +/- 1.23 h, respectively. C max and AUCinf of matrine after administration of KIOM-MA128 at 4 g/kg and 8 g/kg were 595.10 +/- 182.91 ng/mL, 5336.77 +/- 1503.84 ng/mL.h and 850.46 +/- 120 ng/mL, 9583.10 +/- 888.92 ng/mL.h, respectively. The validated method was successfully applied to a pharmacokinetic study in rats after oral administration of KIOM-MA128. PMID- 25785231 TI - Electrochemical Studies for Cation Recognition with Diazo-Coupled Calix[4]arenes. AB - The electrochemical properties of diazophenylcalix[4]arenes bearing ortho carboxyl group (o-CAC) and ortho-ester group (o-EAC), respectively, in the presence of various metal ions were investigated by voltammetry in CH3CN. o-CAC and o-EAC showed voltammetric changes toward divalent metal ions and no significant changes with monovalent alkali metal ions. However, o-CAC preferentially binds with alkaline earth and transition metal ions, whereas no significant changes in voltammetric signals are observed in o-EAC with alkaline earth metal ions. o-EAC only binds with other transition metal ions. This can be explained on metal ion complexation-induced release of proton from the azophenol to the quinone-hydrazone tautomer followed by internal complexation of the metal ion with aid of nitrogen atoms and ortho-carbonyl groups in the diazophenylazocalix[4]arenes. PMID- 25785232 TI - Phytochemical Analysis and Anti-Inflammatory Activity of the Extracts of the African Medicinal Plant Ximenia caffra. AB - A method was developed for identification and quantification of polyphenols in the leaves of Ximenia caffra using HPLC/UV/MS. Based on analyzing the MS and UV data and in comparison to the authentic standards, a total of 10 polyphenols were identified and quantified, including gallic acid, catechin, quercetin, kaempferol, and their derivatives. The total content of these compounds was found to be approximately 19.45 mg/g in the leaf and the most abundant is quercetin rutinoside (9.08 mg/g). The total phenolic content as measured by Folin-Ciocalteu assay was 261.87 +/- 7.11 mg GAE/g and the total antioxidant capacity as measured in vitro was 1.46 +/- 0.01 mmol Trolox/g. The antiproliferative effect of the leaf extract was measured by MTS assay with IC50 value of 239.0 +/- 44.5 MUg/mL. Cell-based assays show that the leaf extract inhibits the mRNA expression of proinflammatory genes (IL-6, iNOS, and TNF-alpha) by using RT-qPCR, implying its anti-inflammatory effects. It was further demonstrated that the underlying therapeutic mechanism involves the suppression of NF-kappaB, a shared pathway between cell death and inflammation. PMID- 25785233 TI - Fast HPLC-MS/MS Method for Determining Penicillin Antibiotics in Infant Formulas Using Molecularly Imprinted Solid-Phase Extraction. AB - The dairy cattle may suffer from different infections relatively often, but the inflammation of the mammary gland is very important to the farmer. These infections are frequently treated with penicillin antimicrobial drugs. However, their use may result in the presence of residues in animal products, such as milk powder and/or infant formulas, and it represents a potential risk for consumers. To monitor this, the EU has defined safe maximum residue limits (MRLs) through Commission Regulation (EU) number 37/2010. Although LC-MS is a trustful option for confirmation and quantification of antibiotics, the analysis of real samples with complex matrices frequently implies previous clean-up steps. In this work, precipitation polymerization has been used and different molecularly imprinted polymer (MIP) sorbents were tested and optimized for the fast and simultaneous solid-phase extraction (MISPE) of eight common penicillins (ampicillin, amoxicillin, oxacillin, penicillin G, penicillin V, cloxacillin, dicloxacillin, and nafcillin). The extracts were analyzed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and the applicability of these polymers as sorbents for the extraction of penicillins at MRL levels in milk powder (infant formulas) was proved. The limits of detection and quantification were below the legal tolerances, except for LOQ for oxacillin and cloxacillin. PMID- 25785234 TI - Coffee, Genetic Variants, and Parkinson's Disease: Gene-Environment Interactions. AB - Studies of gene-environment interactions may help us to understand the disease mechanisms of common and complex diseases such as Parkinson's disease (PD). Sporadic PD, the common form of PD, is thought to be a multifactorial disorder caused by combinations of multiple genetic factors and environmental or life style exposures. Since one of the most extensively studied life-style factors in PD is coffee/caffeine intake, here, the studies of genetic polymorphisms with life-style interactions of sporadic PD are reviewed, focusing on coffee/caffeine intake. PMID- 25785235 TI - Depression and Cognitive Impairment Are Associated with Low Education and Literacy Status and Smoking but Not Caffeine Consumption in Urban African Americans and White Adults. AB - Background: Recent research has linked caffeine consumption with a lower risk for depression and cognitive decline. However, no studies have examined the relationship in an African American compared to a white, socioeconomically diverse representative urban sample. Methods: Data from a cross-sectional study were used to determine the associations of caffeine use with depressive symptomatology and cognition in a sample of 1,724 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. The United States Department of Agriculture's Automated Multiple Pass Method was used by trained interviewers to collect two, in-person 24-hour dietary recalls. Depressive symptoms and global cognition were assessed using two well-validated measures: the Center for Epidemiologic Studies Depressive Scale (CES-D) and Mini Mental State Examination (MMSE), respectively. Usual caffeine intake was based on both recalls. Data were analyzed with t- and chi-square tests, correlation analysis, and ordinal logistic regression. Results: African Americans consumed significantly less caffeine than did whites (89.0+/-3.2 and 244.0+/-8.7 mg respectively). Caffeine consumption was not associated with depressive symptomatology or global cognition. Age, less than 5th grade literacy, and less than high school education were significantly associated with both depressive symptoms and cognitive function. Smokers had a 43% greater risk for depression but only a 3% higher risk for cognitive impairment. Conclusion: The low level of dietary caffeine intake in combination with smoking among HANDLS study participants may have influenced the lack of association with depressive symptomatology or global cognition. For this sample, low literacy and education appear more highly associated with depressive symptoms and cognitive function than caffeine intake. PMID- 25785236 TI - Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring. AB - Significance: When a cutaneous injury occurs, the wound heals via a dynamic series of physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. The final stage can take many months, yet the new ECM forms a scar that never achieves the flexibility or strength of the original tissue. In certain circumstances, the normal scar is replaced by pathological fibrotic tissue, which results in hypertrophic or keloid scars. These scars cause significant morbidity through physical dysfunction and psychological stress. Recent Advances and Critical Issues: The cutaneous ECM comprises a complex assortment of proteins that was traditionally thought to simply provide structural integrity and scaffolding characteristics. However, recent findings show that the ECM has multiple functions, including, storage and delivery of growth factors and cytokines, tissue repair and various physiological functions. Abnormal ECM reconstruction during wound healing contributes to the formation of hypertrophic and keloid scars. Whereas adult wounds heal with scarring, the developing foetus has the ability to heal wounds in a scarless fashion by regenerating skin and restoring the normal ECM architecture, strength, and function. Recent studies show that the lack of inflammation in fetal wounds contributes to this perfect healing. Future Directions: Better understanding of the exact roles of ECM components in scarring will allow us to produce therapeutic agents to prevent hypertrophic and keloid scars. This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation. PMID- 25785237 TI - Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions. AB - Significance: The pathogenesis of fibrogenic wound and connective tissue healing is complex and incompletely understood. Common observations across a vast array of human and animal models of fibroproliferative conditions suggest neuroinflammatory mechanisms are important upstream fibrogenic events. Recent Advances: As detailed in this review, mast cell hyperplasia is a common observation in fibrotic tissue. Recent investigations in human and preclinical models of hypertrophic wound healing and post-traumatic joint fibrosis provides evidence that fibrogenesis is governed by a maladaptive neuropeptide-mast cell myofibroblast signaling pathway. Critical Issues: The blockade and manipulation of these factors is providing promising evidence that if timed correctly, the fibrogenic process can be appropriately regulated. Clinically, abnormal fibrogenic healing responses are not ubiquitous to all patients and the identification of those at-risk remains an area of priority. Future Directions: Ultimately, an integrated appreciation of the common pathobiology shared by many fibrogenic connective tissue conditions may provide a scientific framework to facilitate the development of novel antifibrotic prevention and treatment strategies. PMID- 25785240 TI - Safety and Feasibility of Intermittent Electrical Stimulation for the Prevention of Deep Tissue Injury. AB - Objective: To investigate the safety, feasibility, and acceptability of a novel treatment, intermittent electrical stimulation (IES), for preventing deep tissue injury (DTI) in different healthcare settings. Approach: Testing was conducted in an acute rehabilitation unit of a general hospital, a tertiary rehabilitation hospital, a long-term care facility, and homecare (HC). IES was delivered through surface electrodes placed either directly on the gluteal muscles or through mesh panels inside a specialized garment. Study participants at risk for DTI used the system for an average of 4 weeks. Outcome measures included skin reaction to long term stimulation, demands on the caregiver, stability of induced muscle contraction, and acceptability as part of the users' daily routine. Results: A total of 48 study participants used the IES system. The system proved to be safe and feasible in all four clinical settings. No pressure ulcers were observed in any of the participants. There was no difference between the clinical settings in patient positioning, ease of finding optimal stimulation site, and patient acceptance. Although donning and doffing time was longer in the long-term care and HC settings than the acute rehabilitation unit and tertiary rehabilitation facility, time required to apply the IES system was <18 min (including data collection). The patients and caregivers did not find the application disruptive and indicated that the stimulation was acceptable as part of their daily routine in over 97% of the time. Innovation and Conclusion: We demonstrated the safety, feasibility, and acceptability of a novel method of IES to prevent DTI in a continuum of healthcare settings. PMID- 25785239 TI - Provisional Matrix Deposition in Hemostasis and Venous Insufficiency: Tissue Preconditioning for Nonhealing Venous Ulcers. AB - Significance: Chronic wounds represent a major burden on global healthcare systems and reduce the quality of life of those affected. Significant advances have been made in our understanding of the biochemistry of wound healing progression. However, knowledge regarding the specific molecular processes influencing chronic wound formation and persistence remains limited. Recent Advances: Generally, healing of acute wounds begins with hemostasis and the deposition of a plasma-derived provisional matrix into the wound. The deposition of plasma matrix proteins is known to occur around the microvasculature of the lower limb as a result of venous insufficiency. This appears to alter limb cutaneous tissue physiology and consequently drives the tissue into a 'preconditioned' state that negatively influences the response to wounding. Critical Issues: Processes, such as oxygen and nutrient suppression, edema, inflammatory cell trapping/extravasation, diffuse inflammation, and tissue necrosis are thought to contribute to the advent of a chronic wound. Healing of the wound then becomes difficult in the context of an internally injured limb. Thus, interventions and therapies for promoting healing of the limb is a growing area of interest. For venous ulcers, treatment using compression bandaging encourages venous return and improves healing processes within the limb, critically however, once treatment concludes ulcers often reoccur. Future Directions: Improved understanding of the composition and role of pericapillary matrix deposits in facilitating internal limb injury and subsequent development of chronic wounds will be critical for informing and enhancing current best practice therapies and preventative action in the wound care field. PMID- 25785241 TI - Range of motion of the intact lumbar segment: a multivariate study of 42 lumbar spines. AB - BACKGROUND: A thorough understanding of the biomechanical characteristics of the healthy human spine is critical in furthering the treatment of spinal pathology. The goal of this study was to investigate the motion of the intact lumbar spine segment as measured by range of motion (ROM), and to investigate the dependencies thereof on gender and intervertebral level. MATERIALS AND METHODS: Kinematic data was obtained for 42 human lumbar segments (L1-S1) in response to a pure-moment loading protocol in flexion extension (FE), lateral bending (LB) and axial torsion (AT). Data was obtained for 204 individual functional spinal units (91 female, 113 male). Multivariate analysis of variance was conducted to detect differences between genders and intervertebral levels in each mode of loading. Correlations between ROM and donor demographics, including height, weight, and age, were conducted. RESULTS: ROM was significantly greater for females than for males in FE, LB and AT (p<0.001). ROM tended to increase down the vertebral column in FE. L3-4 FE ROM was significantly greater than L1-2 (p=0.024), and L4-5 and L5-S1 FE ROM were significantly greater than for every other level (p<0.003). LB ROM tended to be greater toward the center of the segment with L2-3, L3-4 and L4-5 ROM being significantly greater than both L1-2 (p<0.001) and L5-S1 (p=0.006, p<0.001, p=0.043, respectively). A similar trend was found for AT, however only L1-2 was significantly less than all other levels (p=0.042, p<0.001, p<0.001, and p=0.034 for L2-3, L3-4, L4-5, and L5-S1 respectively). CONCLUSION: The significant differences in lumbar ROM between male and female spine segments and between the intervertebral levels must be taken into account in study design in order to prevent biases in outcomes. The significant differences in ROM between levels may also have critical implications in the design of spinal implants, particularly those designed to maintain or restore healthy motion. PMID- 25785238 TI - Proteoglycans in Normal and Healing Skin. AB - Significance: Proteoglycans have a distinct spatial localization in normal skin and are essential for the correct structural development, organization, hydration, and functional properties of this tissue. The extracellular matrix (ECM) is no longer considered to be just an inert supportive material but is a source of directive, spatial and temporal, contextual information to the cells via components such as the proteoglycans. There is a pressing need to improve our understanding of how these important molecules functionally interact with other matrix structures, cells and cellular mediators in normal skin and during wound healing. Recent Advances: New antibodies to glycosaminoglycan side chain components of skin proteoglycans have facilitated the elucidation of detailed localization patterns within skin. Other studies have revealed important proliferative activities of proteinase-generated fragments of proteoglycans and other ECM components (matricryptins). Knockout mice have further established the functional importance of skin proteoglycans in the assembly and homeostasis of the normal skin ECM. Critical Issues: Our comprehension of the molecular and structural complexity of skin as a complex, dynamic, constantly renewing, layered connective tissue is incomplete. The impact of changes in proteoglycans on skin pathology and the wound healing process is recognized as an important area of pathobiology and is an area of intense investigation. Future Directions: Advanced technology is allowing the development of new artificial skins. Recent knowledge on skin proteoglycans can be used to incorporate these molecules into useful adjunct therapies for wound healing and for maintenance of optimal tissue homeostasis in aging skin. PMID- 25785242 TI - Sacroiliac Joint Fusion Using Triangular Titanium Implants vs. Non-Surgical Management: Six-Month Outcomes from a Prospective Randomized Controlled Trial. AB - BACKGROUND: Sacroiliac (SI) joint pain is a prevalent, underdiagnosed cause of lower back pain. SI joint fusion can relieve pain and improve quality of life in patients who have failed nonoperative care. To date, no study has concurrently compared surgical and non-surgical treatments for chronic SI joint dysfunction. METHODS: We conducted a prospective randomized controlled trial of 148 subjects with SI joint dysfunction due to degenerative sacroiliitis or sacroiliac joint disruptions who were assigned to either minimally invasive SI joint fusion with triangular titanium implants (N=102) or non-surgical management (NSM, n=46). SI joint pain scores, Oswestry Disability Index (ODI), Short-Form 36 (SF-36) and EuroQol-5D (EQ-5D) were collected at baseline and at 1, 3 and 6 months after treatment commencement. Six-month success rates, defined as the proportion of treated subjects with a 20-mm improvement in SI joint pain in the absence of severe device-related or neurologic SI joint-related adverse events or surgical revision, were compared using Bayesian methods. RESULTS: Subjects (mean age 51, 70% women) were highly debilitated at baseline (mean SI joint VAS pain score 82, mean ODI score 62). Six-month follow-up was obtained in 97.3%. By 6 months, success rates were 81.4% in the surgical group vs. 23.9% in the NSM group (difference of 56.6%, 95% posterior credible interval 41.4-70.0%, posterior probability of superiority >0.999). Clinically important (>=15 point) ODI improvement at 6 months occurred in 75% of surgery subjects vs. 27.3% of NSM subjects. At six months, quality of life improved more in the surgery group and satisfaction rates were high. The mean number of adverse events in the first six months was slightly higher in the surgical group compared to the non-surgical group (1.3 vs. 1.0 events per subject, p=0.1857). CONCLUSIONS: Six-month follow up from this level 1 study showed that minimally invasive SI joint fusion using triangular titanium implants was more effective than non-surgical management in relieving pain, improving function and improving quality of life in patients with SI joint dysfunction due to degenerative sacroiliitis or SI joint disruptions. CLINICAL RELEVANCE: Minimally invasive SI joint fusion is an acceptable option for patients with chronic SI joint dysfunction due to degenerative sacroiliitis and sacroiliac joint disruptions unresponsive to non-surgical treatments. PMID- 25785245 TI - A new mouse avatar model of non-small cell lung cancer. AB - INTRODUCTION: Lung cancer remains the leading cause of tumor-related deaths, despite advances in the understanding of the disease pathogenesis and in its clinical treatment. It is crucial to develop novel technologies to discover disease biomarkers and predict individual therapy response. MATERIALS AND METHODS: We established 48 patients-derived tumor xenografts (PDTXs) implanted in the subrenal capsule of immunodeficient mice using thin, precision-cut tumor tissue slices, derived from five patients affected by non-small cell lung cancer. Twenty-six tissue slices were immediately processed and implanted at sample recovery [patients-derived tumor xenografts derived from fresh tissue (dPDTX)], whereas the remaining sections were cultured on specific organotypic supports at 37 degrees C and 5% CO2 for 24 h before grafting [patients-derived tumor xenografts derived from cultured tissue (cPDTX)]. At sacrifice, xenografts tissue morphology, proliferation (Ki67), and histotype markers were analyzed. Oncogenic miRNAs profiles were assessed in PDTXs, human tumors, and serum from one patient. RESULTS: Xenografts retained the original cancer features and there were no differences between dPDTXs and cPDTXs. Squamous cell carcinoma (SCC) xenografts showed a higher engraftment rate than adenocarcinoma (AC)-derived tumors. At basal time, Ki67 levels were higher in SCCs than in ACs, and the expression levels of genes associated to a stem cell-like phenotype were also more expressed in SCC samples. The analysis of oncogenic miRNAs showed that circulating miR-19b, -21, and -210 levels were correlated with higher Ki67 expression in xenografts. CONCLUSION: Our study implemented the PDTX model with thin, precision-cut tumor slices from small tumors, which could be useful for clinical applications and predictive purposes. The different engraftment success is likely determined by tumor histotype, high proliferation index, and the expression of genes essential for cancer stem cells maintenance. Our PDTXs model could be a valid tool to expand primary tumors for the discovery of new biomarkers and explore therapeutic options. PMID- 25785244 TI - Prostate cancer and neuroendocrine differentiation: more neuronal, less endocrine? AB - Neuroendocrine differentiation (NED) marks a structural and functional feature of certain cancers, including prostate cancer (PCa), whereby the malignant tissue contains a significant proportion of cells displaying neuronal, endocrine, or mixed features. NED cells produce, and can secrete, a cocktail of mediators commonly encountered in the nervous system, which may stimulate and coordinate cancer growth. In PCa, NED appears during advanced stages, subsequent to treatment, and accompanies treatment resistance and poor prognosis. However, the term "neuroendocrine" in this context is intrinsically vague. This article seeks to provide a framework on which a unified view of NED might emerge. First, we review the mutually beneficial interplay between PCa and neural structures, mainly supported by cell biology experiments and neurological conditions. Next, we address the correlations between PCa and neural functions, as described in the literature. Based upon the integration of clinical and basic observations, we suggest that it is legitimate to seek for true neural differentiation, or neuromimicry, in cancer progression, most notably in PCa cells exhibiting what is commonly described as NED. PMID- 25785243 TI - ISASS Policy Statement - Lumbar Artificial Disc. AB - PURPOSE: The primary goal of this Policy Statement is to educate patients, physicians, medical providers, reviewers, adjustors, case managers, insurers, and all others involved or affected by insurance coverage decisions regarding lumbar disc replacement surgery. PROCEDURES: This Policy Statement was developed by a panel of physicians selected by the Board of Directors of ISASS for their expertise and experience with lumbar TDR. The panel's recommendation was entirely based on the best evidence-based scientific research available regarding the safety and effectiveness of lumbar TDR. PMID- 25785246 TI - Current Understanding of BRAF Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas. AB - The mitogen-activated protein kinase (MAPK) pathway is known to play a key role in the initiation and maintenance of many tumors as well as normal development. This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway. BRAF is one of three RAF kinases which act as downstream effectors of growth factor signaling leading to cell cycle progression, proliferation, and survival. Initially reported as a point mutation (V600E) in the majority of metastatic melanomas, other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer, colon carcinomas, hairy cell leukemia, and more recently in gliomas. The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK. This review describes the molecular biology of BRAF in the context of pediatric low-grade gliomas, the role of BRAF as a diagnostic marker, the prognostic implications of BRAF, and evidence for therapeutic targeting of BRAF. PMID- 25785247 TI - Molecular heterogeneity in glioblastoma: potential clinical implications. AB - Glioblastomas, (grade 4 astrocytomas), are aggressive primary brain tumors characterized by histopathological heterogeneity. High-resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed. PMID- 25785248 TI - An observational study on infective endocarditis: a single center experience. AB - BACKGROUND: Cloning of microorganisms on heart endothelium can lead to infective endocarditis (IE). The prototypic lesion of infective endocarditis, the vegetation is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells. OBJECTIVES: The aim of this study was to evaluate patients with IE and also focusing on echocardiographic data and comparison between TTE (transthoracic echocardiography) and TEE (transesophageal echocardiography) of native and prosthetic valve endocarditis and the final impact of IE (infective endocarditis) in these patients with endocarditis. PATIENTS AND METHODS: All patients with IE admitted to our center between 2007 and 2010 were studied. All echocardiographies were performed by the same echocardiographer. Echocardiography and lab tests were performed for all patients. We used SPSS 16 for data analysis. RESULTS: We studied 35 patients, 45% male and 55% female with a mean age of 56.36 +/- 12.44 years. Fever (80%) and chills (65.7%) were the most common symptoms. There was only a positive blood culture and enterococci sensitive to vancomycin and amoxicillin. The most involved valve was mitral (54.2%) and then aortic valve (48.5%) (two patients had vegetation on both aortic and mitral valves). In this study, specificity and sensitivity of TEE were 100% and 88.6%. Six patients (17.1%) died and six patients needed surgery. CONCLUSIONS: Endocarditis is an important disease with a high mortality rate if not treated appropriately. Therefore, these patients need more attention. In echocardiography, vegetation and complications of IE such as abscess and paravalvular leakage can be detected. PMID- 25785249 TI - Factors influencing prolonged ICU stay after open heart surgery. AB - BACKGROUND: There are different risk factors that affect the intensive care unit (ICU) stay after cardiac surgery. OBJECTIVES: The aim of this study was to evaluate possible risk factors influencing prolonged ICU stay in a large referral hospital. PATIENTS AND METHODS: We conducted a case-control study to determinate causes of prolonged ICU stay in 280 adult patients undergoing cardiac surgery in a tertiary care center for cardiovascular patients, Tehran, Iran. These patients were divided into two groups according to ICU stay <= 96 and > 96 hours. We evaluated perioperative risk factors of ICU stay > 96 hours. RESULTS: Among the 280 patients studied, 184 (65.7%) had stayed <= 96 hours and 96 (34.3%) had stayed > 96 hours in ICU. Frequency of prolonged ICU stay was 34.2% in patients undergoing coronary artery bypass graft (CABG), 30.8% in patients with valve surgery, and 44.8% in patients with CABG plus valve surgery. Patients with > 96 hours of ICU stay received more blood transfusion and intravenous inotropes. They also had longer anesthesia, cardiopulmonary bypass, and postoperative intubation time. There were higher incidence of postoperative tamponade, re-exploration, re intubation, hemodialysis, and hypotension in this group (P < 0.05 for all comparisons). CONCLUSIONS: In this study, about one-third of patients had prolonged ICU stay. Factors influencing prolonged ICU stay were medical and some non-medical factors. In the present study, up to 30% of the patients had a prolonged ICU stay of > 96 hours. Additional data from well-designed investigations are needed for further assessment of the factors influencing prolonged ICU stay after cardiac surgery. PMID- 25785250 TI - LV Dyssynchrony Assessed With Phase Analysis on Gated Myocardial Perfusion SPECT Can Predict Response to CRT in Patients With End-Stage Heart Failure. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment in patients with end-stage heart failure and wide QRS complex. However, about 30% of patients do not benefit from CRT (non-responder). Recent studies with tissue Doppler imaging yielded disappointing results in predicting CRT responders. Phase analysis was developed to allow assessment of LV dyssynchrony by gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (GMPS). OBJECTIVES: The aim of present study was to investigate the role of quantitative GMPS-derived LV dyssynchrony data to predict CRT responder. PATIENTS AND METHODS: Thirty eligible patients for CRT implantation underwent GMPS and echocardiography. Response to CRT was evaluated six months after the device implantation. Clinical response to CRT was defined as 50 meters increase in 6 minute walking test (6-MWT) distance. Echocardiographic response to CRT was defined as >= 15% decrease in left ventricular end-systolic volume (LVESV). The lead position was considered concordant if it was positioned at the area of latest mechanical activation, and discordant if located outside the area of latest mechanical activation. RESULTS: Clinical response to CRT was observed in 74% of patients. However, only 57% of patients were responder according to the echo criteria. There were statistically significant differences between CRT responders and non-responders for GMPS-derived variables, including phased histogram bandwidth (PHB), phase SD (PSD), and Entropy. Moreover, a cutoff value of 112 degrees for PHB with a sensitivity of 72% and specificity of 70%, a cutoff value of 21 degrees for PSD with a sensitivity of 90% and specificity of 74%, and a cutoff of 52% for Entropy with a sensitivity of 90% and a specificity of 80% were considered to discriminate responders and non-responders. CRT response was more likely in patients with concordant LV lead position compared to those with discordant LV lead position. CONCLUSIONS: GMPS-derived LV dyssynchrony variables can predict response to CRT with good sensitivity and specificity. PMID- 25785251 TI - Echocardiographic evaluation of cardiac function in ischemic rats: value of m mode echocardiography. AB - BACKGROUND: Echocardiography is a well-established diagnostic tool for a safe, reproducible and accurate evaluation of cardiac anatomy, hemodynamics and function in clinical practice. OBJECTIVES: We sought to demonstrate the efficacy and feasibility of M-mode echocardiography to evaluate cardiac structure and function in normal and MI-induced adult rats. MATERIALS AND METHODS: All animal procedures were approved by the ethics committee of Tehran University of Medical Sciences and the investigation conformed to the "Guide for the Care and Use of Laboratory Animals" published by the United States National Institutes of Health. Forty-eight male Wistar rats weighing 280-300 grams were obtained from a single breeding colony. The statistical analyses were performed using SPSS 20.0. RESULTS: Echocardiographic measurements were possible in all rats before and after the operation. In our survey, we studied echocardiographic alterations in rats after MI induction. Changes can be seen in all echocardiographic mean values after myocardial infarction (MI), but significant decrease (P < 0.01) of Fractional shortening and Ejection Fraction as well as significant increase (P < 0.05) of end systolic diameter and systolic volume after left anterior descending coronary artery (LAD) ligation can be good signs of MI induction. CONCLUSIONS: In light of our results, it can be concluded that we succeeded in establishing a precise echocardiographic method to confidently assess the success of LAD ligation surgery in rats. It is feasible to thoroughly monitor the functional efficiency of regional therapeutic interventions such as intra-myocardial stem cell injection. PMID- 25785252 TI - Persistent isolated right atrial standstill associated with left atrial tachycardia. AB - INTRODUCTION: Atrial standstill is a rare condition, characterized by absence of atrial electrical and mechanical activity evident in surface electrocardiography echocardiography, or fluoroscopy, which is associated with unresponsiveness of atria to maximal output electrical stimulation. This condition can be present with thromboembolic complication, low cardiac output, and sometimes palpitation. CASE PRESENTATION: Here we presented a woman with right atrial stand still and left atrial tachycardia. It was confirmed by electrocardiogram, echocardiography, and intracardiac electrogram in basal state and during maximal output electrical stimulation. We treated her by implanting pacemaker to control bradycardia, oral calcium channel blocker to control palpitation episodes, and anticoagulation. CONCLUSIONS: Atrial standstill can be present partially that can be localized in one atrium and is associated with tachycardia in the other atrium. PMID- 25785253 TI - Investigation the relationship between self-care and readmission in patients with chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is associated with unpredictably increased prevalence of hospital admissions. Self-care is one of the most important aspects of management for patients with CHF. Self-care adequacy has led to increased satisfaction, independence in daily activities, reduced stress, and morbidity. OBJECTIVES: We aimed to assess the relationship between self-care behavior and readmission rate in patients with heart failure. PATIENTS AND METHODS: A total of 287 patients with a diagnosis of systolic CHF with a left ventricular ejection fraction less than 35% admitted for acute heart failure were enrolled. The self-care behavior was assessed using SCHFI questionnaires that have three domains (self-care maintenance, self-care management, and self-care confidence). An acquired score greater than 70 was considered as proper self-care index. The study population was followed over three months after discharge for readmission. RESULTS: This study showed that self-care behavior was improper in our study population. More than 75% of patients had a score less than 70 in the different domains for self-care. The multivariable regression analyses showed a significant relationship between self-care management (beta = 1.6, P = 0.006, OR (CI) = 2.66 (1.37-5.1) and self-care confidence (beta = 0.9, P = 0.02, OR (CI) = 2.01 (1.1-3.68) and readmission rate. CONCLUSIONS: We concluded that a good administration program such as education and a surveillance plan for the improvement of self-care behaviors would reduce hospital readmissions in patients with heart failure. PMID- 25785254 TI - Accuracy of cardiogoniometry compared with electrocardiography in the diagnosis of coronary artery disease. AB - BACKGROUND: Cardiogoniometry (CGM) is a novel spatiotemporal electrocardiographic method utilizing computer-assisted three-dimensional data on cardiac potentials. OBJECTIVES: This study compares the accuracy of CGM and electrocardiography (ECG) by detecting coronary artery disease (CAD) with reference to angiography as a well-known gold standard. PATIENTS AND METHODS: A total of 390 patients undergoing coronary angiography with CAD were enrolled. CGM was performed a few hours prior to coronary angiography. A standard 12-lead ECG was recorded after the CGM. The CGM and ECG results were recorded and analyzed by an independent investigator blinded to all patient data and the results of the coronary angiography. RESULTS: The coronary angiography showed a normal coronary artery in 263 patients (67.4%). A median of CGM score was 1 (0-2), the minimum score was 0 and maximum score was 8. A total of 90 patients (31%) showed predefined ST segment/T-wave changes in the resting 12-lead ECG. CGM yielded a sensitivity of 84% and specificity of 81% and the ECG yielded a sensitivity of 29% and specificity of 67% when compared with the coronary angiography. CONCLUSIONS: CGM is a non-invasive technique recently developed for quantitative three-dimensional vectorial analysis of myocardial activity and detection of ischemia and infarction. This technique is clearly more sensitive and more specific than a standard resting 12-lead ECG. PMID- 25785255 TI - Failure to reach the optimal temperature during cryoablation due to refrigerant cylinder problem. AB - INTRODUCTION: Pulmonary vein (PV) isolation is considered as a key to atrial fibrillation (AF) treatment. Cryoballoon ablation is an effective therapy for PV isolation for AF with minimal side effects and was approved by the US Food and Drug Administration (FDA) several years ago. Successful isolation of PVs during cryoablation depends on the balloon temperature and helps in early identification of noneffective cryoballoon applications. A lower balloon temperature has been associated with long-term success in isolation of PVs. CASE PRESENTATION: At the start of the procedure, the cryoconsole displayed "low refrigerant level". After a few cycles of successful cryoballoon applications, for a fresh application for a new PV, the optimal temperature was not obtained in spite of obtaining good grade of occlusion and ostial positioning for right inferior pulmonary vein (RIPV). Later, immediately after changing the refrigerant cylinder, suitable temperature was obtained. We faced this situation thrice in a span of eight months. CONCLUSION: Low refrigerant level may cause nonoptimal temperature during cryoablation, which can be resolved by premature change of a gas cylinder. PMID- 25785256 TI - The Age of Reason for Gated SPECT MPI to Deal With Cardiac Dyssynchrony. PMID- 25785257 TI - Assessment of bone defects in anterior shoulder instability. AB - Glenohumeral bone defects are a common finding in shoulder instability and they are strongly correlated with recurrence of dislocation and failure following arthroscopic Bankart repair. Most authors agree that open surgery should be considered in the presence of certain conditions: glenoid bone loss > 25%, a lesion involving > 30% of the humeral head, an engaging Hill-Sachs lesion, bipolar bone lesions even without engagement. A careful imaging evaluation must therefore be performed in order to identify, quantify and characterize the bone defects. Even though magnetic resonance has important additional value in the assessment of the glenoid labrum and rotator cuff, computed tomography scan is the examination of choice for studying bone defects. Several methods have been proposed to quantify the extent of the glenoid bone defect; the most accurate ones utilize two-dimensional computed tomography images with multiplanar reconstructions (PICO method) or more sophisticated three-dimensional reconstruction software. Conversely, the literature lacks studies that accurately quantify humeral bone defects and, above all, that demonstrate definitively the clinical and prognostic significance of the lesion location and size. PMID- 25785258 TI - Comparison between the Acute Pulmonary Vascular Effects of Oxygen with Nitric Oxide and Sildenafil. AB - OBJECTIVE: Right heart catheterization is performed in patients with pulmonary arterial hypertension to determine the severity of disease and their pulmonary vascular reactivity. The acute pulmonary vascular effect of inhaled nitric oxide is frequently used to identify patients who will respond favorably to long-term vasodilator therapy. This study sought to determine whether the acute pulmonary vascular effects of oxygen with nitric oxide and intravenous sildenafil are similar. METHODS: A retrospective, descriptive study of 13 individuals with pulmonary hypertension who underwent heart catheterization and acute vasodilator testing was performed. The hemodynamic measurements during five phases (21-53% oxygen, 100% oxygen, 100% oxygen with 20 ppm nitric oxide, 21-51% oxygen, and 21 51% oxygen with 0.05-0.29 mg/kg intravenous sildenafil) of the procedures were compared using analysis of variance. A linear regression analysis and a Bland Altman plot were used to compare the percent change in mean pulmonary arterial pressure and the percent change in pulmonary vascular resistance from baseline with oxygen and nitric oxide, and from baseline with sildenafil. RESULTS: Mean pulmonary arterial pressure and pulmonary vascular resistance acutely decreased with 100% oxygen with nitric oxide and 21-51% oxygen with sildenafil. Pulmonary blood flow during sildenafil was greater than pulmonary blood flow during 100% oxygen and 100% oxygen with nitric oxide. The pH, right atrial pressure, and left atrial pressure did not change during the five phase of heart catheterization. Mean pulmonary arterial pressure (millimeter of mercury, mean +/- standard error of the mean) was 38 +/- 4 during 21-53% oxygen, 32 +/- 3 during 100% oxygen, 29 +/- 2 during 100% oxygen with nitric oxide, 37 +/- 3 during 21-51% oxygen, and 32 +/- 2 during 21-51% oxygen with sildenafil. There was not a significant correlation between the percent change in pulmonary vascular resistance from baseline with oxygen and nitric oxide, and from baseline with sildenafil (r (2) = 0.011, p = 0.738). The Bland Altman analysis demonstrated statistical agreement between the effects of oxygen with nitric oxide and sildenafil. However, differences were large enough to limit the interchangeable use of these vasodilators in a clinical setting. CONCLUSION: Oxygen with nitric oxide and sildenafil decreased pulmonary vascular resistance. However, the pulmonary vascular effects of oxygen and nitric oxide do not reliably predict the acute response to sildenafil. Additional studies are needed to determine whether the acute response to sildenafil can be used to predict the long-term response to treatment with an oral phosphodiesterase V inhibitor. PMID- 25785259 TI - Differentiated Typology of Sex Work and Implication for HIV Prevention Programs among Female Sex Workers in Nepal. AB - BACKGROUND: Sex work in exchange for kind and cash has long been practiced in Nepal. The HIV prevention program in Nepal is focused mainly on these two typologies of sex work. There might be more typologies of sex work beyond streets and establishments seeking research and programmatic attention. The objective of the study is to explore the differentiated typologies of sex work. METHODS: This is a cross-sectional study conducted using a qualitative technique. Researchers carried out eight Focus Group Discussions with female sex workers (FSWs) (n = 50) in different places of Tanahu district. Data were analyzed using a deductive thematic analysis approach. RESULTS: We identified a more differentiated typology of sex work. Private contact-based sex work and the covert sex work on the cruising areas along the major highways were common. Sex work has become easier to operate with the advent of new technologies such as cell phone. With limited role of facilitation by brokers and pimps, now FSWs are better off and have longer duration of relationship with clients. Soft prostitution was common, as FSWs complemented their income through sex work. CONCLUSION: The conventional mode of peer and outreach educational approach needs to be further strengthened and modified according to the changing typology of sex work. HIV testing sites need to be further expanded to cruising areas along the highways. PMID- 25785260 TI - The Journey toward Voluntary Public Health Accreditation Readiness in Local Health Departments: Leadership and Followership Theories in Action. AB - Local health department directors' intent on getting their organizations ready for accreditation must embrace the blurring of leader/follower lines and create an accreditation readiness team fueled not by traditional leader or follower roles but by teamship. PMID- 25785261 TI - Effect of sodium benzoate preservative on micronucleus induction, chromosome break, and Ala40Thr superoxide dismutase gene mutation in lymphocytes. AB - Sodium benzoate is food preservative that inhibits microbial growth. The effects of sodium benzoate preservative on micronucleus induction, chromosome break, and Ala40Thr superoxide dismutase gene mutation in lymphocytes were studied. Sodium benzoate concentrations of 0.5, 1.0, 1.5, and 2.0 mg/mL were treated in lymphocyte cell line for 24 and 48 hrs, respectively. Micronucleus test, standard chromosome culture technique, PCR, and automated sequencing technique were done to detect micronucleus, chromosome break, and gene mutation. The results showed that, at 24- and 48-hour. incubation time, sodium benzoate concentrations of 1.0, 1.5, and 2.0 mg/mL increased micronucleus formation when comparing with the control group (P < 0.05). At 24- and 48-hour. incubation time, sodium benzoate concentrations of 2.0 mg/mL increased chromosome break when comparing with the control group (P < 0.05). Sodium benzoate did not cause Ala40Thr (GCG->ACG) in superoxide dismutase gene. Sodium benzoate had the mutagenic and cytotoxic toxicity in lymphocytes caused by micronucleus formation and chromosome break. PMID- 25785262 TI - Molecular dynamics, monte carlo simulations, and langevin dynamics: a computational review. AB - Macromolecular structures, such as neuraminidases, hemagglutinins, and monoclonal antibodies, are not rigid entities. Rather, they are characterised by their flexibility, which is the result of the interaction and collective motion of their constituent atoms. This conformational diversity has a significant impact on their physicochemical and biological properties. Among these are their structural stability, the transport of ions through the M2 channel, drug resistance, macromolecular docking, binding energy, and rational epitope design. To assess these properties and to calculate the associated thermodynamical observables, the conformational space must be efficiently sampled and the dynamic of the constituent atoms must be simulated. This paper presents algorithms and techniques that address the abovementioned issues. To this end, a computational review of molecular dynamics, Monte Carlo simulations, Langevin dynamics, and free energy calculation is presented. The exposition is made from first principles to promote a better understanding of the potentialities, limitations, applications, and interrelations of these computational methods. PMID- 25785263 TI - The HDAC inhibitor Vorinostat diminishes the in vitro metastatic behavior of Osteosarcoma cells. AB - Osteosarcoma (OS) is the most common primary malignancy of bone and affects patients in the first two decades of life. The greatest determinant of survival is the presence of pulmonary metastatic disease. The role of epigenetic regulation in OS, specifically the biology of metastases, is unknown. Our previous study with the murine OS cell populations K7M2 and K12 demonstrated a significant correlation of metastatic potential with the DNA methylation level of tumor suppressor genes. In the current study, we investigated if the histone deacetylase (HDAC) inhibitor, vorinostat, could regulate the metastatic potential of highly metastatic OS cells. Our results revealed that vorinostat treatment of highly metastatic K7M2 OS cells was able to greatly reduce the proliferation and metastatic potential of the cells. Morphological features related to cell motility and invasion were changed by vorinostat treatment. In addition, the gene expressions of mTOR, ALDH1, and PGC-1 were downregulated by vorinostat treatment. These data suggest that vorinostat may be an effective modulator of OS cell metastatic potential and should be studied in preclinical models of metastatic OS. PMID- 25785264 TI - Differential regulation of proinflammatory mediators following LPS- and ATP induced activation of monocytes from patients with antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by recurrent thrombosis and pregnancy morbidity in association with the presence of antiphospholipid antibodies. Growing evidence supports the involvement of monocytes in APS pathogenesis. Inflammatory activation of monocytes promotes thrombus formation and other APS complications. However, mechanisms underlying their activation are poorly investigated. We aimed to determine transcriptional activity of monocytes after exposing them to low concentrations of lipopolysaccharide (LPS) and LPS + adenosine triphosphate (ATP) using comparative qRT-PCR. The results showed that LPS significantly increased transcriptional levels of TLR2, IL-23, CCL2, CXCL10, IL-1beta, and IL-6 in APS cells, while, in cells from healthy donors, LPS resulted in IL-6 and STAT3 elevated mRNAs. Double stimulation of the cells resulted in decreased mRNA levels of NLRP3 in monocytes isolated from healthy donors and CCL2, IL-1beta in APS cells. By contrast, TLR2 mRNAs were elevated in both investigated groups after culture of the cells with LPS + ATP. Thus, the findings indicate increased sensitivity of APS cells to LPS that may contribute to thrombus formation and enhance development or progression of autoimmune processes. Low concentrations of ATP diminish LPS-induced inflammatory state of APS monocytes which might be a potential mechanism which regulates inflammatory state of the cells. PMID- 25785265 TI - Structural characterization and in vitro antioxidant activity of kojic dipalmitate loaded w/o/w multiple emulsions intended for skin disorders. AB - Multiple emulsions (MEs) are intensively being studied for drug delivery due to their ability to load and increase the bioavailability of active lipophilic antioxidant, such as kojic dipalmitate (KDP). The aim of this study was to structurally characterize developed MEs by determining the average droplet size (Dnm) and zeta potential (ZP), performing macroscopic and microscopic analysis and analyzing their rheological behavior and in vitro bioadhesion. Furthermore, the in vitro safety profile and antioxidant activity of KDP-loaded MEs were evaluated. The developed MEs showed a Dnm of approximately 1 micrometer and a ZP of -13 mV, and no change was observed in Dnm or ZP of the system with the addition of KDP. KDP-unloaded MEs exhibited ''shear thinning" flow behavior whereas KDP-loaded MEs exhibited Newtonian behavior, which are both characteristic of antithixotropic materials. MEs have bioadhesion properties that were not influenced by the incorporation of KDP. The results showed that the incorporation of KDP into MEs improved the safety profile of the drug. The in vitro antioxidant activity assay suggested that MEs presented a higher capacity for maintaining the antioxidant activity of KDP. ME-based systems may be a promising platform for the topical application of KDP in the treatment of skin disorders. PMID- 25785266 TI - Roles of osteopontin gene polymorphism (rs1126616), osteopontin levels in urine and serum, and the risk of urolithiasis: a meta-analysis. AB - Objective. Previous studies have investigated the relationships between osteopontin gene polymorphism rs1126616 and OPN levels and urolithiasis, but the results were controversial. Our study aimed to clarify such relationships. Methods. A meta-analysis was performed by searching the databases Pubmed, Embase, and Web of Science for relevant studies. Crude odds ratios (ORs) or standardised mean differences with 95% confidence intervals (CIs) were calculated to evaluate the strength of association. Publication bias was estimated using Begg's funnel plots and Egger's regression test. Results. Overall, a significantly increased risk of urolithiasis was associated with OPN gene polymorphism rs1126616 for all the genetic models except recessive model. When stratified by ethnicity, the results were significant only in Turkish populations. For OPN level association, a low OPN level was detected in the urine of urolithiasis patients in large sample size subgroup. Results also indicated that urolithiasis patients have lower OPN level in serum than normal controls. Conclusion. This meta-analysis revealed that the T allele of OPN gene polymorphism increased susceptibility to urolithiasis. Moreover, significantly lower OPN levels were detected in urine and serum of urolithiasis patients than normal controls, thereby indicating that OPN has important functions in the progression of urolithiasis. PMID- 25785267 TI - Corrigendum to "neurogenesis and increase in differentiated neural cell survival via phosphorylation of Akt1 after fluoxetine treatment of stem cells". PMID- 25785269 TI - Control of avian coccidiosis: future and present natural alternatives. AB - Numerous efforts to date have been implemented in the control of avian coccidiosis caused by the Eimeria parasite. Since the appearance of anticoccidial chemical compounds, the search for new alternatives continues. Today, no product is available to cope with the disease; however, the number of products commercially available is constantly increasing. In this review, we focus on natural products and their anticoccidial activity. This group comprises fatty acids, antioxidants, fungal and herbal extracts, and immune response modulators with proven anticoccidial activity, many of which exist as dietary supplements. Additionally, we offer an overview of the poultry industry and the economic cost of coccidiosis as well as the classical strategies used to control the disease. PMID- 25785268 TI - Prospects of HA-based universal influenza vaccine. AB - Current influenza vaccines afford substantial protection in humans by inducing strain-specific neutralizing antibodies (Abs). Most of these Abs target highly variable immunodominant epitopes in the globular domain of the viral hemagglutinin (HA). Therefore, current vaccines may not be able to induce heterosubtypic immunity against the divergent influenza subtypes. The identification of broadly neutralizing Abs (BnAbs) against influenza HA using recent technological advancements in antibody libraries, hybridoma, and isolation of single Ab-secreting plasma cells has increased the interest in developing a universal influenza vaccine as it could provide life-long protection. While these BnAbs can serve as a source for passive immunotherapy, their identification represents an important step towards the design of such a universal vaccine. This review describes the recent advances and approaches used in the development of universal influenza vaccine based on highly conserved HA regions identified by BnAbs. PMID- 25785270 TI - Inhibition of adhesion, proliferation, and invasion of primary endometriosis and endometrial stromal and ovarian carcinoma cells by a nonhyaluronan adhesion barrier gel. AB - Endometriosis is a chronic disease of women in the reproductive age, defined as endometrial cells growing outside of the uterine cavity and associated with relapses. Relapses are hypothesized to correlate with incomplete surgical excision or result from nonrandom implantation of new endometrial implants in adjacent peritoneum. Thus, surgical excision could lead to free endometriotic cells or tissue residues, which readhere, grow, and invade into recurrent lesions. Barrier agents are frequently used to prevent postoperative adhesions. We tested if the absorbable cell adhesion barrier gel Intercoat consisting of polyethylene oxide and sodium carboxymethyl cellulose could inhibit cellular adhesion, proliferation, and invasion of primary endometriosis and endometrial cells. Due to an association of endometriosis with ovarian carcinoma, we tested two ovarian carcinoma cell lines. Prior to cell seeding, a drop of the barrier gel was placed in cell culture wells in order to test inhibition of adherence and proliferation or coated over a polymerized collagen gel to assay for prevention of invasion. Results showed that the barrier gel significantly inhibited cell adherence, proliferation, and invasion of endometriosis and endometrial stromal cells as well as ovarian carcinoma cells in culture. Our findings could help to prevent local cell growth/invasion and possible consequent recurrences. PMID- 25785271 TI - The results of adductor magnus tenodesis in adolescents with recurrent patellar dislocation. AB - Recurrent dislocation of the patella is a common orthopaedic problem which occurs in about 44% of cases after first-time dislocation. In most cases of first-time patellar dislocation, the medial patellofemoral ligament (MPFL) becomes damaged. Between 2010 and 2012, 33 children and adolescents (39 knees) with recurrent patellar dislocation were treated with MPFL reconstruction using the adductor magnus tendon. The aim of our study is to assess the effectiveness of this surgical procedure. The outcomes were evaluated functionally (Lysholm knee scale, the Kujala Anterior Knee Pain Scale, and isokinetic examination) and radiographically (Caton index, sulcus angle, congruence angle, and patellofemoral angle). Four patients demonstrated redislocation with MPFL graft failure, despite the fact that patellar tracking was found to be normal before the injury, and the patients had not reported any symptoms. Statistically significant improvements in Lysholm and Kujala scales, in patellofemoral and congruence angle, were seen (P < 0.001). A statistically significant improvement in the peak torque of the quadriceps muscle and flexor was observed for 60 degrees /sec and 180 degrees /sec angular velocities (P = 0.01). Our results confirm the efficacy of MPFL reconstruction using the adductor magnus tendon in children and adolescents with recurrent patellar dislocation. PMID- 25785272 TI - The current testing protocols for biomechanical evaluation of lumbar spinal implants in laboratory setting: a review of the literature. AB - In vitro biomechanical investigations have become a routinely employed technique to explore new lumbar instrumentation. One of the most important advantages of such investigations is the low risk present when compared to clinical trials. However, the best use of any experimental data can be made when standard testing protocols are adopted by investigators, thus allowing comparisons among studies. Experimental variables, such as the length of the specimen, operative level, type of loading (e.g., dynamic versus quasistatic), magnitude, and rate of load applied, are among the most common variables controlled during spinal biomechanical testing. Although important efforts have been made to standardize these protocols, high variability can be found in the current literature. The aim of this investigation was to conduct a systematic review of the literature to identify the current trends in the protocols reported for the evaluation of new lumbar spinal implants under laboratory setting. PMID- 25785273 TI - Hypergravity stimulation enhances PC12 neuron-like cell differentiation. AB - Altered gravity is a strong physical cue able to elicit different cellular responses, representing a largely uninvestigated opportunity for tissue engineering/regenerative medicine applications. Our recent studies have shown that both proliferation and differentiation of C2C12 skeletal muscle cells can be enhanced by hypergravity treatment; given these results, PC12 neuron-like cells were chosen to test the hypothesis that hypergravity stimulation might also affect the behavior of neuronal cells, in particular promoting an enhanced differentiated phenotype. PC12 cells were thus cultured under differentiating conditions for either 12 h or 72 h before being stimulated with different values of hypergravity (50 g and 150 g). Effects of hypergravity were evaluated at transcriptional level 1 h and 48 h after the stimulation, and at protein level 48 h from hypergravity exposure, to assess its influence on neurite development over increasing differentiation times. PC12 differentiation resulted strongly affected by the hypergravity treatments; in particular, neurite length was significantly enhanced after exposure to high acceleration values. The achieved results suggest that hypergravity might induce a faster and higher neuronal differentiation and encourage further investigations on the potential of hypergravity in the preparation of cellular constructs for regenerative medicine and tissue engineering purposes. PMID- 25785274 TI - Cross-platform evaluation of commercial real-time SYBR green RT-PCR kits for sensitive and rapid detection of European bat Lyssavirus type 1. AB - This study evaluates the performance of five two-step SYBR Green RT-qPCR kits and five one-step SYBR Green qRT-PCR kits using real-time PCR assays. Two real-time thermocyclers showing different throughput capacities were used. The analysed performance evaluation criteria included the generation of standard curve, reaction efficiency, analytical sensitivity, intra- and interassay repeatability as well as the costs and the practicability of kits, and thermocycling times. We found that the optimised one-step PCR assays had a higher detection sensitivity than the optimised two-step assays regardless of the machine used, while no difference was detected in reaction efficiency, R (2) values, and intra- and interreproducibility between the two methods. The limit of detection at the 95% confidence level varied between 15 to 981 copies/uL and 41 to 171 for one-step kits and two-step kits, respectively. Of the ten kits tested, the most efficient kit was the Quantitect SYBR Green qRT-PCR with a limit of detection at 95% of confidence of 20 and 22 copies/uL on the thermocyclers Rotor gene Q MDx and MX3005P, respectively. The study demonstrated the pivotal influence of the thermocycler on PCR performance for the detection of rabies RNA, as well as that of the master mixes. PMID- 25785275 TI - Clinical characteristics, treatment patterns, and outcomes of primary canaliculitis among patients in Beijing, China. AB - BACKGROUND: Canaliculitis may cause punctal or canalicular swelling, discharge, erythema, and sometimes concretions. This study examined the clinical characteristics, treatment patterns, and outcomes of primary canaliculitis from patients at a top-rated hospital in Beijing, China. METHODS: Medical records of 16 patients (retrospective case series) were studied. RESULTS: This study included four males and twelve females with a median age of 72.5 years. The mean and the median follow-up time were 10.4 months and 6 months, respectively. The mostly observed clinical symptoms were epiphora with discharge (94%), while the mostly observed signs included pouting punctum (75%) and punctal regurgitation of concretions under syringing (75%). Only the symptoms of one patient among those with conservative therapy completely resolved within two-year follow-up. Curettage therapy was found to partly resolve the clinical symptoms and signs within the follow-up of four weeks. Fifteen patients finally received curettage with punctoplasty, and symptoms completely resolved in fourteen patients after one surgery. CONCLUSIONS: Syringing with pressing of lacrimal sac area may help better diagnosis of canaliculitis. Additionally, curettage with punctoplasty is recommended for thorough removal of concretions and complete resolution of canaliculitis. PMID- 25785276 TI - Polymorphisms of GLP-1 receptor gene and response to GLP-1 analogue in patients with poorly controlled type 2 diabetes. AB - AIM: The relationship between genetic polymorphisms of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) gene and unresponsiveness to GLP-1 analogue treatment in patients with poorly controlled type 2 diabetes mellitus (DM) is unclear. METHODS: Thirty-six patients with poorly controlled type 2 DM were enrolled and they received six days of continuous subcutaneous insulin infusion for this study. After the normalization of blood glucose in the first 3 days, the patients then received a combination therapy with injections of the GLP-1 analogue, exenatide, for another 3 days. All 13 exons and intron-exon boundaries of the GLP1R gene were amplified to investigate the association. RESULTS: The short tandem repeat at 8GA/7GA (rs5875654) had complete linkage disequilibrium (LD, with r2 = 1) with single nucleotide polymorphism (SNP) rs761386. Quantitative trait loci analysis of GLP1R gene variation with clinical response of GLP1 analogue showed the missense rs3765467 and rs761386 significantly associated with changes in the standard deviation of plasma glucose (SDPG(baseline) - SDPG(treatment with GLP-1 analogue)) (P = 0.041 and 0.019, resp.). The reported P values became insignificant after multiple testing adjustments. CONCLUSION: The variable response to the GLP-1 analogue was not statistically correlated with polymorphisms of the GLP1R gene in patients with poorly controlled type 2 DM. PMID- 25785277 TI - Ameliorative effect of allopurinol on vascular complications of insulin resistance. AB - The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo) on experimentally induced insulin resistance (IR) and vascular complications. Rats were divided into four groups: control, IR, allopurinol treated IR (IR-Allo), and allopurinol-treated control (Allo). IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-alpha and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-alpha, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion. PMID- 25785278 TI - Women's views on their diagnosis and management for borderline gestational diabetes mellitus. AB - INTRODUCTION: Little is known about women's views relating to a diagnosis of borderline gestational diabetes mellitus (GDM) and the subsequent management. This study aimed to explore women's experiences after being diagnosed with borderline GDM, their attitudes about treatment, and factors important to them for achieving any lifestyle changes. METHODS: We conducted face-to-face, semistructured interviews with women diagnosed with borderline GDM. RESULTS: A total of 22 women were interviewed. After a diagnosis of borderline GDM, 14 (64%) women reported not being concerned or worried. Management of borderline GDM was thought by 21 (95%) women to be very important or important. Eighteen (82%) women planned to improve their diet and/or exercise to manage their borderline GDM. The most frequently mentioned enabler for achieving intended lifestyle change was being more motivated to improve the health of their baby and/or themselves (15 women). The most frequent barrier was tiredness and/or being physically unwell (11 women). CONCLUSIONS: A diagnosis of borderline GDM caused some concern to one third of women interviewed. The majority of women believed managing their borderline GDM was important and they planned to improve their lifestyle. Women's own and their babies' future health were powerful motivators for lifestyle change. PMID- 25785279 TI - Animal models of diabetic macrovascular complications: key players in the development of new therapeutic approaches. AB - Diabetes mellitus is a lifelong, incapacitating metabolic disease associated with chronic macrovascular complications (coronary heart disease, stroke, and peripheral vascular disease) and microvascular disorders leading to damage of the kidneys (nephropathy) and eyes (retinopathy). Based on the current trends, the rising prevalence of diabetes worldwide will lead to increased cardiovascular morbidity and mortality. Therefore, novel means to prevent and treat these complications are needed. Under the auspices of the IMI (Innovative Medicines Initiative), the SUMMIT (SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools) consortium is working on the development of novel animal models that better replicate vascular complications of diabetes and on the characterization of the available models. In the past years, with the high level of genomic information available and more advanced molecular tools, a very large number of models has been created. Selecting the right model for a specific study is not a trivial task and will have an impact on the study results and their interpretation. This review gathers information on the available experimental animal models of diabetic macrovascular complications and evaluates their pros and cons for research purposes as well as for drug development. PMID- 25785281 TI - Sodium-glucose linked transporter-2 inhibitors in chronic kidney disease. AB - SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD) the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD. PMID- 25785282 TI - Conjunctival flap covering combined with antiviral and steroid therapy for severe herpes simplex virus necrotizing stromal keratitis. AB - Herpes simplex virus (HSV) necrotizing stromal keratitis is a common type of herpetic stromal keratitis (HSK). Antiviral medication alone cannot control the disease, and corticosteroid eye drops may aggravate the ulcer and result in corneal perforation. Amniotic membrane transplantation effectively treats superficial corneal ulcer resulting from necrotizing stromal HSK. However, the efficacy of this approach seems to be limited for more serious cases. This study presented the clinical treatment of severe HSV necrotizing stromal keratitis (ulcer depth greater than half of the corneal stroma) by conjunctival flap covering surgery in 25 patients (25 eyes) combined with antivirus and corticosteroid treatment at Shandong Eye Hospital from January 2007 to December 2013. Clinical results showed that the mean best spectacle-corrected visual acuity improved from preoperative 20/333 to postoperative 20/40 (P < 0.05). All patients recovered ocular surface stabilization. There was recurrence in two eyes, which was cured with antiviral medication. Conjunctival flap covering combined with antivirus and corticosteroid treatment is effective in treating severe HSV necrotizing stromal keratitis. PMID- 25785280 TI - Inflammatory cytokines in diabetic nephropathy. AB - Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy. PMID- 25785283 TI - Does probability guided hysteroscopy reduce costs in women investigated for postmenopausal bleeding? AB - OBJECTIVE: To evaluate whether a model to predict a failed endometrial biopsy in women with postmenopausal bleeding (PMB) and a thickened endometrium can reduce costs without compromising diagnostic accuracy. DESIGN, SETTING, AND POPULATION: Model based cost-minimization analysis. METHODS: A decision analytic model was designed to compare two diagnostic strategies for women with PMB: (I) attempting office endometrial biopsy and performing outpatient hysteroscopy after failed biopsy and (II) predicted probability of a failed endometrial biopsy based on patient characteristics to guide the decision for endometrial biopsy or immediate hysteroscopy. Robustness of assumptions regarding costs was evaluated in sensitivity analyses. MAIN OUTCOME MEASURES: Costs for the different strategies. RESULTS: At different cut-offs for the predicted probability of failure of an endometrial biopsy, strategy I was generally less expensive than strategy II. The costs for strategy I were always ? 460; the costs for strategy II varied between ? 457 and ? 475. At a 65% cut-off, a possible saving of ? 3 per woman could be achieved. CONCLUSIONS: Individualizing the decision to perform an endometrial biopsy or immediate hysteroscopy in women presenting with postmenopausal bleeding based on patient characteristics does not increase the efficiency of the diagnostic work-up. PMID- 25785284 TI - Cross-cultural adaptation and validation of the Serbian version of the ICS SF male questionnaire. AB - INTRODUCTION: The objective of this study was to cross-culturally adapt and validate ICS male SF questionnaire to Serbian language. MATERIALS AND METHODS: This study included 91 male patients with lower urinary tract symptoms and 24 men with similar age and with confirmed absence of LUTS. ICS male SF questionnaire was translated from English to Serbian language and then back-translated to English. RESULTS: Internal consistency was high in both dimensions, voiding (Cronbach's alpha = 0.916) and incontinence (Cronbach's alpha = 0.763). Comparison of the average scores between patients and controls revealed significant differences in both dimensions: voiding (med = 8 versus med = 0; P < 0.001) and incontinence (med = 3 versus med = 0; P < 0.001). Interclass correlation revealed high testretest validity in both dimensions, voiding ICC = 0.992 (P < 0.001) and incontinece ICC = 0.989 (P < 0.001). Correlation analysis revealed high agreement between ICS male SF voiding dimension and IPSS questionnaire (rho = 0.943; P < 0.001). CONCLUSION: The Serbian version of male ICS SF questionnaire showed acceptable reliability and validity. The ICS male SF questionnaire could be used in routine practice as an easy and comprehensive tool for assessment of LUTS. PMID- 25785285 TI - Integrated production and distribution scheduling problems related to fixed delivery departure dates and weights of late orders. AB - We consider an integrated production and distribution scheduling problem faced by a typical make-to-order manufacturer which relies on a third-party logistics (3PL) provider for finished product delivery to customers. In the beginning of a planning horizon, the manufacturer has received a set of orders to be processed on a single production line. Completed orders are delivered to customers by a finite number of vehicles provided by the 3PL company which follows a fixed daily or weekly shipping schedule such that the vehicles have fixed departure dates which are not part of the decisions. The problem is to find a feasible schedule that minimizes one of the following objective functions when processing times and weights are oppositely ordered: (1) the total weight of late orders and (2) the number of vehicles used subject to the condition that the total weight of late orders is minimum. We show that both problems are solvable in polynomial time. PMID- 25785287 TI - [Comment on "The relative performance characteristics of the logistic European System for Cardiac Operative Risk Evaluation score and the Society of Thoracic Surgeons score in the Placement of Aortic Transcatheter Valves trial"]. PMID- 25785288 TI - Mobile health technologies. Preface. PMID- 25785286 TI - Penile rehabilitation after pelvic cancer surgery. AB - Erectile dysfunction is the most common complication after pelvic radical surgery. Rehabilitation programs are increasingly being used in clinical practice but there is no high level of evidence supporting its efficacy. The principle of early penile rehabilitation stems from animal studies showing early histological and molecular changes associated with penile corporal hypoxia after cavernous nerve injury. The concept of early penile rehabilitation was developed in late nineties with a subsequent number of clinical studies supporting early pharmacologic penile rehabilitation. These studies included all available phosphodiesterase type 5 inhibitors, intracavernosal injection and intraurethral use of prostaglandin E1 and to lesser extent vacuum erectile devices. However, these studies are of small number, difficult to interpret, and often with no control group. Furthermore, no studies have proven an in vivo derangement of endothelial or smooth muscle cell metabolism secondary to a prolonged flaccid state. The purpose of the present report is a synthetic overview of the literature in order to analyze the concept and the rationale of rehabilitation program of erectile dysfunction following radical pelvic surgery and the evidence of such programs in clinical practice. Emphasis will be placed on penile rehabilitation programs after radical cystoprostatectomy, radical prostatectomy, and rectal cancer treatment. Future perspectives are also analyzed. PMID- 25785289 TI - Response. PMID- 25785290 TI - Response. PMID- 25785291 TI - Response. PMID- 25785292 TI - [Paresthesias of the upper respiratory tract]. AB - This review concerns the modern views of etiology, diagnostics, and treatment of the patients presenting with paresthesias of the upper respiratory tract. Various concepts of etiology of this pathology are described along with the relevant diagnostic and therapeutic approaches. Special attention is given to the debatable aspects of diagnostics and treatment of the patients complaining of the feeling of a lump in the throat ("globus sensation"). The opinions of the domestic and foreign authors concerning this problem are considered. The necessity of the search for the new additional therapeutic procedures for the treatment of paresthesias of the upper respiratory tract, including the non medicamental modalities, is substantiated. It is concluded that the development of the new adequate diagnostic and therapeutic algorithm is indispensable for the enhancement of the effectiveness of the management of the patients with paresthesias of the upper respiratory tract and complaints of "globus sensation". PMID- 25785293 TI - [The modern view of the clinical significance of tensor tympani muscle]. AB - The objective of the present work was analyse the modern views of the role of tensor tympani muscle in the development of otic pathology. In this context, the authors discuss tenotomy of the middle ear muscles for the treatment of Meniere's disease, diagnostics and clinical aspects of middle ear myoclonus, and tonic tensor tympani syndrome. PMID- 25785294 TI - [I memory of L.A. Luchikhin]. PMID- 25785295 TI - [In Process Citation]. PMID- 25785296 TI - [In Process Citation]. PMID- 25785297 TI - [Epidemiological surveillance of Pertussis: the experience of Argentina and its relevance for the other countries in the region]. PMID- 25785298 TI - [Not Available]. PMID- 25785299 TI - Solvent exfoliation of electronic-grade, two-dimensional black phosphorus. AB - Solution dispersions of two-dimensional (2D) black phosphorus (BP)--often referred to as phosphorene--are achieved by solvent exfoliation. These pristine, electronic-grade BP dispersions are produced with anhydrous organic solvents in a sealed-tip ultrasonication system, which circumvents BP degradation that would otherwise occur via solvated O2 or H2O. Among conventional solvents, N methylpyrrolidone (NMP) is found to provide stable, highly concentrated (~0.4 mg/mL) BP dispersions. Atomic force microscopy, scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy show that the structure and chemistry of solvent-exfoliated BP nanosheets are comparable to mechanically exfoliated BP flakes. Additionally, residual NMP from the liquid-phase processing suppresses the rate of BP oxidation in ambient conditions. Solvent-exfoliated BP nanosheet field-effect transistors exhibit ambipolar behavior with current on/off ratios and mobilities up to ~10(4) and ~50 cm(2) V(-1) s(-1), respectively. Overall, this study shows that stable, highly concentrated, electronic-grade 2D BP dispersions can be realized by scalable solvent exfoliation, thereby presenting opportunities for large-area, high-performance BP device applications. PMID- 25785300 TI - TPOX Triallelic Genotype: An Interesting Pattern to Be Noted in Bone Marrow Transplantation Monitoring. AB - AIMS: TPOX triallelic genotypic pattern has been described in the setting of forensic and paternity testing but not in bone marrow transplantation (BMT) monitoring for graft engraftment. MATERIALS AND METHODS: A total of 50 cases have been studied using the AmpFLSTR((r)) IdentifilerTM polymerase chain reaction amplification kit as part of the workup of patients and donors before and after BMT at the American University of Beirut Medical Center. RESULTS: Of the 50 studied cases, 49 showed typical allelic patterns of the variable short tandem repeats detected by the assay; however, one single patient showed a biallelic TPOX genotype in the pre-BMT specimen but a triallelic pattern in the post-BMT sample. CONCLUSION: Triallelic patterns of TPOX should also be considered in the context of BMT monitoring testing where misinterpretation of the allelic pattern can lead to wrong unwanted conclusions related to the graft condition and proper quantification of donor DNA. PMID- 25785301 TI - Synthesis and properties of benzophospholo[3,2-b]benzofuran derivatives. AB - Benzophospholo[3,2-b]benzofuran (BPBF) derivatives were studied as a new family of phosphole-containing pi-conjugated organic materials. The versatile reactivity of the trivalent phosphorus center of the parent BPBF offered access to a variety of derivatives by simple chemical modifications. The diversity-oriented synthetic route was also developed to allow facile access to BPBFs with a different substituent on the phosphorus center. Photophysical properties were revealed based on UV-vis and photoluminescence spectroscopies and theoretical calculation. The characteristic property of BPBF derivatives is highly efficient photoluminescence. In particular, phosphole oxide derivatives demonstrated intense blue fluorescence with high quantum yield over 85% even in the solid state. PMID- 25785302 TI - Beyond entropy: magnetic forces induce formation of quasicrystalline structure in binary nanocrystal superlattices. AB - Here, it is shown that binary superlattices of Co/Ag nanocrystals with the same size, surface coating, differing by their type of crystallinity are governed by Co-Co magnetic interactions. By using 9 nm amorphous-phase Co nanocrystals and 4 nm polycrystalline Ag nanocrystals at 25 degrees C, triangle-shaped NaCl-type binary nanocrystal superlattices are produced driven by the entropic force, maximizing the packing density. By contrast, using ferromagnetic 9 nm single domain (hcp) Co nanocrystals instead of amorphous-phase Co, dodecagonal quasicrystalline order is obtained, together with less-packed phases such as the CoAg13 (NaZn13-type), CoAg (AuCu-type), and CoAg3 (AuCu3-type) structures. On increasing temperature to 65 degrees C, 9 nm hcp Co nanocrystals become superparamagnetic, and the system yields the CoAg3 (AuCu3-type) and CoAg2 (AlB2 type) structures, as observed with 9 nm amorphous Co nanocrystals. Furthermore, by decreasing the Co nanocrystal size from 9 to 7 nm, stable AlB2-type binary nanocrystal superlattices are produced, which remain independent of the crystallinity of Co nanocrystals with the superparamagnetic state. PMID- 25785303 TI - Expression of multiple horizontally acquired genes is a hallmark of both vertebrate and invertebrate genomes. AB - BACKGROUND: A fundamental concept in biology is that heritable material, DNA, is passed from parent to offspring, a process called vertical gene transfer. An alternative mechanism of gene acquisition is through horizontal gene transfer (HGT), which involves movement of genetic material between different species. HGT is well-known in single-celled organisms such as bacteria, but its existence in higher organisms, including animals, is less well established, and is controversial in humans. RESULTS: We have taken advantage of the recent availability of a sufficient number of high-quality genomes and associated transcriptomes to carry out a detailed examination of HGT in 26 animal species (10 primates, 12 flies and four nematodes) and a simplified analysis in a further 14 vertebrates. Genome-wide comparative and phylogenetic analyses show that HGT in animals typically gives rise to tens or hundreds of active 'foreign' genes, largely concerned with metabolism. Our analyses suggest that while fruit flies and nematodes have continued to acquire foreign genes throughout their evolution, humans and other primates have gained relatively few since their common ancestor. We also resolve the controversy surrounding previous evidence of HGT in humans and provide at least 33 new examples of horizontally acquired genes. CONCLUSIONS: We argue that HGT has occurred, and continues to occur, on a previously unsuspected scale in metazoans and is likely to have contributed to biochemical diversification during animal evolution. PMID- 25785304 TI - Skin imprinting in silica plates: a potential diagnostic methodology for leprosy using high-resolution mass spectrometry. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which primarily infects macrophages and Schwann cells, affecting skin and peripheral nerves. Clinically, the most common form of identification is through the observation of anesthetic lesions on skin; however, up to 30% of infected patients may not present this clinical manifestation. Currently, the gold standard diagnostic test for leprosy is based on skin lesion biopsy, which is invasive and presents low sensibility for suspect cases. Therefore, the development of a fast, sensible and noninvasive method that identifies infected patients would be helpful for assertive diagnosis. The aim of this work was to identify lipid markers in leprosy patients directly from skin imprints, using a mass spectrometric analytical strategy. For skin imprint samples, a 1 cm(2) silica plate was gently pressed against the skin of patients or healthy volunteers. Imprinted silica lipids were extracted and submitted to direct infusion electrospray ionization high-resolution mass spectrometry (ESI-HRMS). All samples were differentiated using a lipidomics-based data workup employing multivariate data analysis, which helped electing different lipid markers, for example, mycobacterial mycolic acids, inflammatory and apoptotic molecules were identified as leprosy patients' markers. Otherwise, phospholipids and gangliosides were pointed as healthy volunteers' skin lipid markers, according to normal skin composition. Results indicate that silica plate skin imprinting associated with ESI-HRMS is a promising fast and sensible leprosy diagnostic method. With a prompt leprosy diagnosis, an early and effective treatment could be feasible and thus the chain of leprosy transmission could be abbreviated. PMID- 25785305 TI - The optimization based dynamic and cyclic working strategies for rechargeable wireless sensor networks with multiple base stations and wireless energy transfer devices. AB - In this paper, the optimal working schemes for wireless sensor networks with multiple base stations and wireless energy transfer devices are proposed. The wireless energy transfer devices also work as data gatherers while charging sensor nodes. The wireless sensor network is firstly divided into sub networks according to the concept of Voronoi diagram. Then, the entire energy replenishing procedure is split into the pre-normal and normal energy replenishing stages. With the objective of maximizing the sojourn time ratio of the wireless energy transfer device, a continuous time optimization problem for the normal energy replenishing cycle is formed according to constraints with which sensor nodes and wireless energy transfer devices should comply. Later on, the continuous time optimization problem is reshaped into a discrete multi-phased optimization problem, which yields the identical optimality. After linearizing it, we obtain a linear programming problem that can be solved efficiently. The working strategies of both sensor nodes and wireless energy transfer devices in the pre-normal replenishing stage are also discussed in this paper. The intensive simulations exhibit the dynamic and cyclic working schemes for the entire energy replenishing procedure. Additionally, a way of eliminating "bottleneck" sensor nodes is also developed in this paper. PMID- 25785306 TI - Bio-optics based sensation imaging for breast tumor detection using tissue characterization. AB - The tissue inclusion parameter estimation method is proposed to measure the stiffness as well as geometric parameters. The estimation is performed based on the tactile data obtained at the surface of the tissue using an optical tactile sensation imaging system (TSIS). A forward algorithm is designed to comprehensively predict the tactile data based on the mechanical properties of tissue inclusion using finite element modeling (FEM). This forward information is used to develop an inversion algorithm that will be used to extract the size, depth, and Young's modulus of a tissue inclusion from the tactile data. We utilize the artificial neural network (ANN) for the inversion algorithm. The proposed estimation method was validated by a realistic tissue phantom with stiff inclusions. The experimental results showed that the proposed estimation method can measure the size, depth, and Young's modulus of a tissue inclusion with 0.58%, 3.82%, and 2.51% relative errors, respectively. The obtained results prove that the proposed method has potential to become a useful screening and diagnostic method for breast cancer. PMID- 25785308 TI - Robust optimization of a MEMS accelerometer considering temperature variations. AB - A robust optimization approach for a MEMS accelerometer to minimize the effects of temperature variations is presented. The mathematical model of the accelerometer is built. The effects of temperature variations on the output performance of the accelerometer are determined, and thermal deformation of the accelerometer is analyzed. The deviations of the output capacitance and resonance frequency due to temperature fluctuations are calculated and discussed. The sensitivity analysis method is employed to determine the design variables for robust optimization and find out the key structural parameters that have most significant influence on the output capacitance and resonance frequency of the accelerometer. The mathematical model and procedure for the robust optimization of the accelerometer are proposed. The robust optimization problem is solved and discussed. The robust optimization results show that an optimized accelerometer with high sensitivity, high temperature robustness and decoupling structure is finally obtained. PMID- 25785307 TI - Label-free, single molecule resonant cavity detection: a double-blind experimental study. AB - Optical resonant cavity sensors are gaining increasing interest as a potential diagnostic method for a range of applications, including medical prognostics and environmental monitoring. However, the majority of detection demonstrations to date have involved identifying a "known" analyte, and the more rigorous double blind experiment, in which the experimenter must identify unknown solutions, has yet to be performed. This scenario is more representative of a real-world situation. Therefore, before these devices can truly transition, it is necessary to demonstrate this level of robustness. By combining a recently developed surface chemistry with integrated silica optical sensors, we have performed a double-blind experiment to identify four unknown solutions. The four unknown solutions represented a subset or complete set of four known solutions; as such, there were 256 possible combinations. Based on the single molecule detection signal, we correctly identified all solutions. In addition, as part of this work, we developed noise reduction algorithms. PMID- 25785309 TI - A model-based 3D template matching technique for pose acquisition of an uncooperative space object. AB - This paper presents a customized three-dimensional template matching technique for autonomous pose determination of uncooperative targets. This topic is relevant to advanced space applications, like active debris removal and on-orbit servicing. The proposed technique is model-based and produces estimates of the target pose without any prior pose information, by processing three-dimensional point clouds provided by a LIDAR. These estimates are then used to initialize a pose tracking algorithm. Peculiar features of the proposed approach are the use of a reduced number of templates and the idea of building the database of templates on-line, thus significantly reducing the amount of on-board stored data with respect to traditional techniques. An algorithm variant is also introduced aimed at further accelerating the pose acquisition time and reducing the computational cost. Technique performance is investigated within a realistic numerical simulation environment comprising a target model, LIDAR operation and various target-chaser relative dynamics scenarios, relevant to close-proximity flight operations. Specifically, the capability of the proposed techniques to provide a pose solution suitable to initialize the tracking algorithm is demonstrated, as well as their robustness against highly variable pose conditions determined by the relative dynamics. Finally, a criterion for autonomous failure detection of the presented techniques is presented. PMID- 25785310 TI - Assessment of human respiration patterns via noncontact sensing using Doppler multi-radar system. AB - Human respiratory patterns at chest and abdomen are associated with both physical and emotional states. Accurate measurement of the respiratory patterns provides an approach to assess and analyze the physical and emotional states of the subject persons. Not many research efforts have been made to wirelessly assess different respiration patterns, largely due to the inaccuracy of the conventional continuous-wave radar sensor to track the original signal pattern of slow respiratory movements. This paper presents the accurate assessment of different respiratory patterns based on noncontact Doppler radar sensing. This paper evaluates the feasibility of accurately monitoring different human respiration patterns via noncontact radar sensing. A 2.4 GHz DC coupled multi-radar system was used for accurate measurement of the complete respiration patterns without any signal distortion. Experiments were carried out in the lab environment to measure the different respiration patterns when the subject person performed natural breathing, chest breathing and diaphragmatic breathing. The experimental results showed that accurate assessment of different respiration patterns is feasible using the proposed noncontact radar sensing technique. PMID- 25785311 TI - Improved local ternary patterns for automatic target recognition in infrared imagery. AB - This paper presents an improved local ternary pattern (LTP) for automatic target recognition (ATR) in infrared imagery. Firstly, a robust LTP (RLTP) scheme is proposed to overcome the limitation of the original LTP for achieving the invariance with respect to the illumination transformation. Then, a soft concave convex partition (SCCP) is introduced to add some flexibility to the original concave-convex partition (CCP) scheme. Referring to the orthogonal combination of local binary patterns (OC_LBP), the orthogonal combination of LTP (OC_LTP) is adopted to reduce the dimensionality of the LTP histogram. Further, a novel operator, called the soft concave-convex orthogonal combination of robust LTP (SCC_OC_RLTP), is proposed by combing RLTP, SCCP and OC_LTP. Finally, the new operator is used for ATR along with a blocking schedule to improve its discriminability and a feature selection technique to enhance its efficiency. Experimental results on infrared imagery show that the proposed features can achieve competitive ATR results compared with the state-of-the-art methods. PMID- 25785312 TI - Proteomics analysis of EV71-infected cells reveals the involvement of host protein NEDD4L in EV71 replication. AB - Enterovirus 71 (EV71) is a human enterovirus that has seriously affected the Asia Pacific area for the past two decades. EV71 infection can result in mild hand foot-and-mouth disease and herpangina and may occasionally lead to severe neurological complications in children. However, the specific biological processes that become altered during EV71 infection remain unclear. To further explore host responses upon EV71 infection, we identified proteins differentially expressed in EV71-infected human glioblastoma SF268 cells using isobaric mass tag (iTRAQ) labeling coupled with multidimensional liquid chromatography-mass spectrometry (LC-MS/MS). Network analysis of proteins altered in cells infected with EV71 revealed that the changed biological processes are related to protein and ion transport, regulation of protein degradation, and homeostatic processes. We confirmed that the levels of NEDD4L and PSMF1 were increased and reduced, respectively, in EV71-infected cells compared to mock-infected control cells. To determine the physiological relevance of our findings, we investigated the consequences of EV71 infection in cells with NEDD4L or PSMF1 depletion. We found that the depletion of NEDD4L significantly reduced the replication of EV71, whereas PSMF1 knockdown enhanced EV71 replication. Collectively, our findings provide the first evidence of proteome-wide dysregulation by EV71 infection and suggest a novel role for the host protein NEDD4L in the replication of this virus. PMID- 25785313 TI - Preprint publication option. PMID- 25785315 TI - Medullary carcinoma of the thyroid with axillary metastasis: a case report. AB - We report a case of axillary lymph node metastasis as a consequence of medullary thyroid carcinoma (MTC) in a 42-year-old man. On January 2009, the patient was referred to us for the management of right cervical lymph node enlargement. Total thyroidectomy was performed with right-sided functional neck dissection. Postoperative histopathology revealed MTC in the right lobe of the thyroid, with extrathyroidal extension and right-sided neck metastases. Multiple left cervical, mediastinal, and right axillary lymphadenopathies were detected at the third year follow-up exam. Left-sided functional neck dissection, axillary lymph node dissection, and mediastinal lymph node dissection were performed, and the pathologic outcomes revealed as the metastatic dissemination of MTC. After a disease-free term for 1 year, multiple metastatic lesions were detected in the patient. PMID- 25785316 TI - Intravenous lidocaine for effective pain relief after a laparoscopic colectomy: a prospective, randomized, double-blind, placebo-controlled study. AB - A perioperative intravenous lidocaine infusion has been reported to decrease postoperative pain. The goal of this study was to evaluate the effectiveness of intravenous lidocaine in reducing postoperative pain for laparoscopic colectomy patients. Fifty-five patients scheduled for an elective laparoscopic colectomy were randomly assigned to 2 groups. Group L received an intravenous bolus injection of lidocaine 1.5 mg/kg before intubation, followed by 2 mg/kg/h continuous infusion during the operation. Group C received the same dosage of saline at the same time. Postoperative pain was assessed at 2, 4, 8, 12, 24, and 48 hours after surgery by using the visual analog scale (VAS). Fentanyl consumption by patient-controlled plus investigator-controlled rescue administration and the total number of button pushes were measured at 2, 4, 8, 12, 24, and 48 hours after surgery. In addition, C-reactive protein (CRP) levels were checked on the operation day and postoperative days 1, 2, 3, and 5. VAS scores were significantly lower in group L than group C until 24 hours after surgery. Fentanyl consumption was lower in group L than group C until 12 hours after surgery. Moreover, additional fentanyl injections and the total number of button pushes appeared to be lower in group L than group C (P < 0.05). The CRP level tended to be lower in group L than group C, especially on postoperative day 1 and 2 and appeared to be statistically significant. The satisfaction score was higher in group L than group C (P = 0.024). Intravenous lidocaine infusion during an operation reduces pain after a laparoscopic colectomy. PMID- 25785317 TI - A case of recurrent Cronkhite-Canada syndrome containing colon cancer. AB - Cronkhite-Canada syndrome (CCS) is a very rare disease which may cause malignant transformation. A combination regimen including corticosteroids are common therapy for CCS, however the decrease of medicine may lead to CCS relapse and also may contribute to malignant transformation of the polyps in gastrointestinal tract. We retrospectively analyze one case of recurrent CCS from the first time of treatment after resection of colon cancer and readjust the usage of corticoids, the patient recovered well. The nine months follow-up showed non gastrointestinal tumor occurred or relapsed. We believe close follow-up should be taken when CCS patients are making medicine dosage alteration and tumor marker such as CEA may be included in the surveillance examination. When improvement using conservative treatment can be neither obtained nor is expected, the use of surgery should be considered. PMID- 25785318 TI - Usability of elective laparoscopic sigmoidectomy and feasibility of single incision laparoscopic surgery for sigmoid volvulus: report of three cases. AB - A therapeutic guideline for sigmoid volvulus (SV) has not been established, and the most recommended surgical procedure for SV has not been determined. Our objective is to assess the usability of elective laparoscopic sigmoidectomy and the feasibility of single-incision laparoscopic surgery for SV following endoscopic reduction. SV typically affects the elderly and accounts for 1% to 7% of intestinal obstructions in Western countries. We report on 3 patients with SV who underwent elective laparoscopic sigmoidectomy following endoscopic reduction, and we first describe single-port surgery for SV. We discuss the 3 patients (a 79 year-old male, an 88-year-old female, and a 67-year-old female) with SV who underwent elective laparoscopic sigmoidectomy following endoscopic reduction. All 3 patients underwent laparoscopic sigmoidectomy, and 2 patients underwent single port laparoscopic surgery without complications. Recurrence of volvulus was not seen during the course of 12 to 24 months. In experienced hands, elective laparoscopic sigmoidectomy after colonoscopic detorsion is a valuable alternative, and single-port surgery is also feasible. PMID- 25785319 TI - Colonic Perforation Caused by Methicillin-Resistant Staphylococcus aureus Enteritis After Total Gastrectomy: A Case Report. AB - A 68-year-old man underwent total gastrectomy and splenectomy for adenocarcinoma and low anterior resection for carcinoma in tubulo-villous adenoma of the rectum. Broad-spectrum antibiotics were administered for postoperative pancreatic fistula. Methicillin-resistant Staphylococcus aureus enteritis occurred on the 50th postoperative day and cecal perforation followed. The patient underwent construction of cecostomy with peritoneal drainage, and vancomycin was administered orally and per cecostomy for 2 weeks. The patient recovered well and was discharged at 35 days after re-operation in good general condition. PMID- 25785320 TI - Single-incision Plus One Port Laparoscopic Total Mesorectal Excision and Bilateral Pelvic Node Dissection for Advanced Rectal Cancer--A Medial Umbilical Ligament Approach. AB - We prove the safety and feasibility of single-incision plus 1 port (SILS+1) laparoscopic total mesorectal excision (TME) + lateral pelvic lymph node dissection (LPLD) via a medial umbilical approach for rectal cancer. Only a few reports have been published about single-incision multiport laparoscopic low anterior resection with LPLD. Recently, minimally invasive surgery such as single incision plus 1 port (SILS + 1) for advanced rectal cancer has been reported as safe and feasible. To our knowledge, this is the first reported case of SILS + 1 used for LPLD. A wound protector was inserted through a 30-mm transumbilical incision. Next, a single-port access device was mounted to the wound protector and 3 ports (5 mm each) were placed. A 12-mm port was inserted in the right lower quadrant. Super-low anterior resection of the rectum and bilateral LPLD and temporary ileostomy were performed with SILS + 1, with a blood loss of 50 mL and a total surgical time of 525 minutes. The time for right lateral dissection was 74 minutes; the time for left lateral dissection was 118 minutes. The total number of dissected lymph nodes was 57 and the number of lateral lymph nodes dissected was 21 (8 left pelvic lymph nodes, 13 right pelvic lymph nodes). No postoperative anastomotic insufficiency or voiding dysfunction was observed. We have documented the safety and feasibility of SILS + 1-TME + LPLD via a medial umbilical approach for rectal cancer. PMID- 25785321 TI - Laparoscopic sigmoid colectomy for a patient with sigmoid colon cancer and crossed-fused renal ectopia: a case report. AB - Crossed-fused renal ectopia (CFRE) is a very rare congenital renal malformation. This condition comprises several anatomic anomalies, including unilateral ureteral intersection of the midline, anteriorly-placed renal pelvises, and aberrant renal blood vessels, all of which increase the difficulty of colectomy. This report describes a case of laparoscopic sigmoidectomy with sufficient lymphadenectomy for a patient with sigmoid colon cancer and left-sided L-shaped CFRE. Preoperative computed tomography demonstrated that the origin of the inferior mesenteric artery (IMA) was free from anomalies and that the tumor did not invade surrounding organs. Therefore, we planned conventional laparoscopic sigmoid colectomy with D3 lymphadenectomy. Division of IMA at its origin and anterior colon resection was successfully performed by careful mobilization of the mesocolon to avoid exposing the retroperitoneal organs. To our knowledge, this is the first case report of laparoscopic colectomy for a patient with CFRE. Sufficient preoperative assessment of anatomic anomalies enabled successful surgery. PMID- 25785322 TI - Successfully treated intra-abdominal abscess caused by fish bone with perforation of ascending colon: a case report. AB - Ingestion of a foreign body is not uncommon, but rarely results in perforation of the gastrointestinal tract. The most common sites of perforation are reportedly the narrowest parts of the bowel, and perforation of the right side of the colon is rare. We report herein the case of a 69-year-old man who presented with an 8 week history of right upper abdominal pain. Laboratory data revealed inflammation at the first hospital visit. Computed tomography revealed a hypodense lesion containing a hyperdense foreign body in the abdomen. Intra-abdominal abscess caused by foreign body perforation was diagnosed. After administering antibiotics for 2 weeks, surgery was performed. Symptoms had resulted from perforation of the ascending colon by a fish bone. PMID- 25785323 TI - Hybrid laparoscopic and anterior approach for postsurgical inguinal hernia after iliofemoral arterial bypass. AB - Laparoscopic hernia repair has become popular due to its rapid recovery time, fewer postoperative complications, and less chronic pain compared with conventional approaches. Currently, laparoscopic hernia repair is also used for more complex pathogenesis, including extra-anatomic bypass surgery for femoral artery. To the best of our knowledge, cases of inguinal hernia after femoral arterial bypass are extremely rare. We report the case of a 77-year-old Japanese man who was diagnosed with inguinal hernia after a previous left external iliac artery-right common femoral artery bypass. We used a hybrid laparoscopic and anterior approach, and the procedure was completed successfully without perioperative complications. A laparoscopic approach is useful for the diagnosis and treatment of inguinal hernia after extra-anatomic bypass surgery for femoral artery. While complicated, the addition of anterior reinforcement should be considered in cases of insufficient preperitoneal repair using transabdominal preperitoneal patch plasty. PMID- 25785324 TI - Temporary Diverting Ileostomy via the Umbilicus: a Small Case Series. AB - The umbilicus, a natural orifice, which is used as an access port during laparoscopic surgery, can be used as a stoma site with potential superior cosmetic results as one less incision is then required. Our objective was to assess the efficacy and safety of the umbilical stoma in a selected group of patients. This is a prospective case series in hospital patients admitted as emergency or elective. Patients who underwent laparoscopic colorectal surgery with a planned ileostomy at Box Hill Hospital were approached and invited to participate in the study, with the stoma being fashioned on the umbilicus. Outcomes of interest included demographics, the details regarding the original indication for operation, operative and hospital related outcomes, postoperative bowel related complications, and other surgical and medical complications. Outcomes of a total of 10 (5 males) patients who underwent umbilical covering ileostomy during the study period were analyzed. Two patients with ulcerative colitis had the second stage of their operation converting their end stomas to loop stoma. These were counted twice, totaling 12 stomas in 10 patients. Three patients had their umbistomas after receiving neoadjuvant treatment for rectal cancer. The median period patients have had umbistomas is 113 days. Overall morbidity during the initial operation was low, except for 1 patient who had a small bowel injury. There was no mortality. Minor peristomal skin changes were the most common postoperative complication. Three patients had their stomas reversed with excellent cosmesis. Umbistomas appear to be a safe and effective way to fashion covering stomas post laparoscopic surgery and save the patient an added incision with excellent cosmetic results. PMID- 25785325 TI - Posttraumatic transdiaphragmatic intercostal hernia: report of a case and review of the literature. AB - Intercostal hernias are rare, and usually occur following injuries of the thoracic wall. The scope of this report is to present a case of a 53-year-old obese patient that developed a transdiaphragmatic intercostal hernia. The patient presented with a palpable, sizeable, reducible mass in the right lateral thoracic wall, with evident bowel sounds in the area, 6 months after a motor-vehicle accident. On computed tomography (CT), the hernia sac contained part of the liver and part of the ascending colon. A surgical repair of the defect was performed, using a prosthetic patch. The patient's postoperative course was uneventful and she remains recurrence free at 12 months after surgery. Intercostal hernias should be suspected following high-impact injuries of the thoracic wall, and CT scans will facilitate the diagnosis of intercostal hernia. We consider the surgical repair of the defect, with placement of a prosthetic mesh, as the treatment of choice to ensure a favorable outcome. PMID- 25785326 TI - A free terminal ileal perforation from active crohn disease in pregnancy: a diagnostic challenge. AB - The surgical management of the complications of Crohn disease is often challenging. These difficulties are compounded in pregnancy by competing interests of the mother and the baby. In this report, we describe the presentation and surgical management of a patient in her second trimester with active Crohn disease who required emergent surgical intervention. She had presented with the uncommon complication of a free perforation in the presence of active untreated disease. PMID- 25785327 TI - Visceral organ resection during femoral hernia surgery is a predictor of morbidity. AB - Reports on the outcomes of emergency and elective femoral hernia surgery are scarce. Most studies do not distinguish femoral hernia from other types of groin hernia; studies of femoral hernia alone are few in number. The main objective of the present study was to identify factors affecting morbidity of femoral hernia patients. We retrospectively analyzed data on 80 patients who underwent femoral hernia surgery between June 2009 and June 2013. Patients who did and did not experience morbidity were compared in terms of age, sex, hernia location, the presence of any comorbid disease, the type of anesthesia employed, the operative technique used, the type of surgical intervention, and performance of small bowel resection. Forty-three patients (53.8%) underwent emergency surgery because of incarceration. Of these, 18 (41.9%) experienced strangulation and underwent resection. Postoperative complications developed in 11 patients (13.8%). Upon multiple logistic regression analysis, visceral organ resection (of the small bowel and/or omentum) was the only independent predictor of significant morbidity (P < 0.05; odds ratio [OR]: 14.010, 95% confidence interval [CI]: 1.001-196.143). When diagnosed, femoral hernias should be electively repaired as soon as possible. The cumulative probability of strangulation rises over time. A requirement for bowel resection seems to significantly increase morbidity. PMID- 25785328 TI - Pseudosarcoma of the thigh: a rare case of massive localized lymphedema. AB - Massive localized lymphedema, also called pseudosarcoma, is a rare condition associated with morbid obesity. Accurate identification of this entity helps the physician make the distinction between this condition and other soft tissue tumors, especially with the increasing rate of obesity worldwide. Obesity and increased caloric intake lead to storage of the excess energy in the form of adipose tissue. The excess adipose tissue disturbs the lymphatic vessels, leading to massive edema localized mostly in the lower extremity, reaching a substantial size and weight that interferes with the quality of life of the individual in question. The mass can cause cosmetic but more importantly functional and structural defects, leading to altered biomechanics with increased risk of deep vein thromboembolism. Below is a presentation of a patient presenting with complaint of a massive medial thigh mass. After much investigation, consultation, and use of diagnostic radiologic modalities it was diagnosed as what is referred to in the literature as massive localized lymphedema, or pseudosarcoma. This mass was managed by surgical excision and the diagnosis was further confirmed by pathologic analysis. After the excision, our patient regained his ability to ambulate on his own, with the help of a rehabilitation program and physical therapy. Massive localized lymphedema needs to be on the differential diagnosis of any morbidly obese patient presenting with mass, especially in the lower extremities. Adequate knowledge about this condition enables the physician to make the distinction between pseudosarcoma and true soft tissue sarcomas. PMID- 25785329 TI - How to Avoid Nontherapeutic Laparotomy in Patients With Multiple Organ Failure of Unknown Origin. The Role of CT Scan Revisited. AB - Diagnosis of intra-abdominal diseases in critically ill patients remains a clinical challenge. Physical examination is unreliable whereas exploratory laparotomy may aggravate patient's condition and delay further evaluation. Only a few studies have investigated the place of computed tomography (CT) on this hazardous situation. We aimed to evaluate the ability of CT to prevent unnecessary laparotomy during the management of critically ill patients. Charts of all consecutive patients who had undergone an emergency nontherapeutic laparotomy from 1996 to 2013 were retrospectively studied and patient's demographic, clinical characteristics, and surgical findings were collected. During this period 59 patients had an unnecessary laparotomy. Fifty-one patients had at least one preoperative imaging and 36 had a CT scan. CT scans were interpreted to be normal (n = 12), with minor anomalies (n = 10), or major anomalies (pneumoperitoneum, portal venous gas/pneumatosis intestinalis, thickened gallbladder wall, and small bowel obstruction signs). Surgical exploration was performed through laparotomy (n = 55) or laparoscopy. Overall mortality was 37% with a median survival after surgery of 7 days. In univariate analysis, hospitalization in ICU before surgical exploration was the only factor related to death. In our series CT scans, objectively interpreted, helped avoid unnecessary surgical exploration in 61% of our patients. PMID- 25785330 TI - Risk of surgical site infection in older patients in a cohort survey: targets for quality improvement in antibiotic prophylaxis. AB - The aims of the present study were to: (1) assess surgical site infection (SSI) incidence in a cohort of surgical patients and (2) estimate the compliance with national guidelines for perioperative antibiotic prophylaxis (PAP). SSIs, among the most common health care-associated infections, are an important target for surveillance and an official priority in several European countries. SSI commonly complicates surgical procedures in older people and is associated with substantial attributable mortality and costs. The implementation of PAP guidelines is difficult among surgeons, and failure to comply with the standard of care has been widely reported. A 12-month prospective survey was performed in accordance with the methods, protocols, and definitions of the Hospital in Europe Link for Infection Control through Surveillance (HELICS) protocol. The compliance of the current PAP practices with the published national guidelines was assessed. A total of 249 patients were enrolled. The cumulative SSI incidence was 3.2 per 100 operative procedures. Cumulative compliance for PAP was 12.4%. Overall, only infection risk index >= 1 was confirmed as a significant risk factor for SSI (odds ratio, 6.65; 95% confidence interval, 1.04-42.59; P = 0.045). When only older patients (age >65 years) were considered, no significant risk factors for SSI were identified. Our study indicates an overall inadequate compliance with PAP recommendations, thus highlighting the need to develop multimodal and targeted intervention programs to improve compliance with PAP guidelines. PMID- 25785331 TI - Immunoglobulin G4-related sclerosing cholangitis mimicking hilar cholangiocarcinoma diagnosed with following bile duct resection: report of a case. AB - We report a rare case of immunoglobulin G4 (IgG4)-related sclerosing cholangitis without other organ involvement. A 69-year-old-man was referred for the evaluation of jaundice. Computed tomography revealed thickening of the bile duct wall, compressing the right portal vein. Endoscopic retrograde cholangiopancreatography showed a lesion extending from the proximal confluence of the common bile duct to the left and right hepatic ducts. Intraductal ultrasonography showed a bile duct mass invading the portal vein. Hilar bile duct cancer was initially diagnosed and percutaneous transhepatic portal vein embolization was performed, preceding a planned right hepatectomy. Strictures persisted despite steroid therapy. Therefore, partial resection of the common bile duct following choledochojejunostomy was performed. Histologic examination showed diffuse and severe lymphoplasmacytic infiltration, and abundant plasma cells, which stained positive for anti-IgG4 antibody. The final diagnosis was IgG4 sclerosing cholangitis. Types 3 and 4 IgG4 sclerosing cholangitis remains a challenge to differentiate from cholangiocarcinoma. A histopathologic diagnosis obtained with a less invasive approach avoided unnecessary hepatectomy. PMID- 25785332 TI - Heterotopic pancreatic pseudocyst radiologically mimicking gastrointestinal stromal tumor. AB - Heterotopic pancreas is a relatively common variant of foregut embryologic dystopia that can be described as pancreatic tissue found outside the normal anatomic location, being independent from vascular supply of normal pancreas. Having all features of pancreatic tissue except for the major duct structures, this ectopic tissue may be clinically recognized when pathologic changes take place. Inflammation, hemorrhagic or obstructive states, and eventually malignancy related problems may become a diagnostic challenge for clinician and finally lead to consequences of misdiagnosis. In this article we will discuss a case of heterotopic pancreatic tissue located in gastric cardia, which was diagnosed preoperatively as gastrointestinal stromal tumor. PMID- 25785333 TI - Differentiated thyroid cancer with liver metastases: lessons learned from managing a series of 14 patients. AB - Liver metastases from differentiated thyroid carcinoma (LMDTC) are rare and usually occur in disseminated metastatic disease. The aim of this study was to review the diagnosis and management of LMDTC. Between 1995 and 2011, 14 patients with a mean age of 59.7 years (+/-10.2) were treated for LMDTC. Data were retrospectively reviewed and analyzed. Seven patients had distant metastases at diagnosis, including 2 with synchronous liver lesions. The average time of onset of LMDTC from initial diagnosis was 52.2 months (+/49.5). All LMDTC were discovered during routine radiologic monitoring. Histologic analysis confirmed LMDTC in 5 patients. Eight patients received tyrosine kinase inhibitors, 1 patient underwent resection of their LMDTC after chemotherapy. Six patients (disseminated metastases, significant comorbidities) did not receive any specific treatment. The median survival after diagnosis of LMDTC was 17.4 months (+/-3.3): 23.6 months (+/-2.9) for patients who underwent chemotherapy versus 3.9 months (+/-0.9) for patients who did not receive any specific treatment (P < 0.001). Developing DTC liver metastasis is a very poor prognostic sign. Chemotherapy by TKIs, especially, hold promise in the cure of LMDTC for selected patients. PMID- 25785334 TI - Quantification of pancreatic stiffness on intraoperative ultrasound elastography and evaluation of its relationship with postoperative pancreatic fistula. AB - "Soft pancreas" has often been reported as a predictive factor for postoperative pancreatic fistula (POPF) after pancreatectomy. However, pancreatic stiffness is judged subjectively by surgeons, without objective criteria. In the present study, pancreatic stiffness was quantified using intraoperative ultrasound elastography, and its relevance to POPF and histopathology was investigated. Forty-one patients (pancreatoduodenectomy, 30; distal pancreatectomy, 11) who underwent intraoperative elastography during pancreatectomy were included. The elastic ratio was determined at the pancreatic resection site (just above the portal vein) and at the remnant pancreas (head or tail). Correlations between the incidence of POPF and patient characteristics, operative variables, and the elastic ratio were examined. In addition, the relationship between the elastic ratio and the percentage of the exocrine gland at the resection stump was investigated. For pancreatoduodenectomy patients, main pancreatic duct diameter < 3.2 mm and elastic ratio < 2.09 were significant risk factors for POPF. In addition, the elastic ratio, but not main pancreatic duct diameter, was significantly associated with the percentage of exocrine gland area at the pancreatic resection stump. Pancreatic stiffness can be quantified using intraoperative elastography. Elastography can be used to diagnose "soft pancreas" and may thus be useful in predicting the occurrence of POPF. PMID- 25785335 TI - Improvement in Pulmonary Function of Chronic Obstructive Pulmonary Disease (COPD) Patients With Osteoporotic Vertebral Compression Fractures (OVCFs) After Kyphoplasty Under Local Anesthesia. AB - To investigate the changes in respiratory function of COPD patients with osteoporotic vertebral compression fractures (OVCFs) after kyphoplasty (KP). Pain scores, pulmonary function parameters (PFT), and local kyphotic angle (LKA) were measured in 31 older patients (25 women, 6 men) with OVCFs before, 3 days after and 3 months after kyphoplasty. The preoperative and postoperative (3 days, 3 months) PFT parameters were as follows: % pred FVC, 74.33 +/- 12.35, 85.23.8 +/- 13.23, and 84.86 +/- 14.01; % pred FEV1, 60.23 +/- 11.2, 60.02 +/- 11.90, and 60.78 +/- 12.70; FEV1/FVC ratio (%), 68.22 +/- 16.74, 59.56 +/- 13.23, and 60.77 +/- 12.28, % pred MVV 52.46 +/- 14.37, 55.23 +/- 15.68, and 62.12 +/- 14.48, respectively. The preoperative mean VAS score was 8.01 +/- 1.41 and significantly decreased to 2.52 +/- 0.89 and 2.34 +/- 0.78 at 3 days, 3 months after kyphoplasty, respectively. The preoperative local kyphotic angle degree was 21.96 +/- 5.75 degrees , significantly decreased to 13.48 +/- 6.12 degrees 3 days after KP, and maintained 3 month after KP. The decrease in the VAS scores correlated with the PFT parameters; however, there were no significant correlations between the PFT parameters and the LKA, the VAS scores and the LKA. Kyphoplasty under local anesthesia is a safety treatment for the COPD patients with OVCFS, and is able to improve the lung function impaired by OVCFs. PMID- 25785336 TI - Surgical removal of an intracardiac sewing needle in a 13-month-old Chinese girl: report of a case. AB - Sewing needles, albeit rare in the case of penetrating cardiac injury, are highly lethal; especially in children, because the injury is difficult to diagnose and treat. We herein present the case of a 13-month-old girl who was injured by a sewing needle inserted in the myocardium; it is the first report of its kind from mainland China. The 13-month-old girl was referred to our hospital with a range of symptoms, including convulsions, diarrhea, and cough. Chest X-ray and echocardiogram revealed a needle located below the aortic valve, passing through the ventricular septum and aortic root. Surgical removal of the needle was performed under extracorporeal circulation. No hemorrhage or arrhythmia was seen, so the operation was ended, and the patient was discharged 8 days after the surgery. An early diagnosis and intervention proved to be lifesaving for this patient with a penetrating cardiac injury. We hope this case can provide a reference for the treatment of similar situations. PMID- 25785337 TI - Prenatal and postnatal ultrasonographic findings of the torsioned ovarian cyst: a case report and brief literature review. AB - Cystic and solid tumors of the ovary are rare during the newborn period and infancy. We present the case of a term female infant born to a mother of 28 years of age and found to have a cystic abdominal mass through prenatal sonographic evaluation in the third trimester. The complex cyst was also demonstrated by postnatal abdominal ultrasonography. Laparotomy revealed a large cystic mass with a torsed right ovary. Pathologic examination of cyst revealed hemorrhagic necrosis with ovarian torsion. PMID- 25785338 TI - EASEPort NPWT System to Enhance Skin Graft Survival--A Simple Assembly. AB - Skin graft has been known to be prone to failure. This study was aimed to make a simplification of the negative pressure wound therapy (NPWT), which follows EASEPort (effective, affordable, safe, easily handled, and portable) concept to support the take of skin graft. The design of the EASEPort-NPWT was then made and technically verified. Thereafter, an animal experimental study comparing the EASEPort-NPWT to the classic tie-over technique on skin graft over exudative wound was conducted. The EASEPort-NPWT was verified to be able to yield and sustain the subatmospheric pressure needed. In the animal study, the treatment group showed better skin graft survival rate (97.55 +/- 11.18% take) than the control group (54.88 +/- 19.73%) on day-7. Histopathology examination showed good quality of the skin structures taken from the treatment group, which was better than the structures of the skin in the control group. In summary, this study has been able to fulfill its objective to create a device following EASEPort concept. Subsequently, the EASEPort-NPWT was able to enhance skin graft survival rate in exudative wound. PMID- 25785339 TI - Dysfunction in Patients With Small-for-Size Grafts After Living Donor Liver Transplantation. AB - The relationship between postoperative percentage fall of platelet (PLT) counts and graft dysfunction after living donor liver transplantation (LDLT) in recipients with small-for-size (SFS) graft has not been fully evaluated. We retrospectively studied 50 adult-to-adult LDLT recipients with a graft-to recipient weight ratio of <0.8% between 1999 and 2011. Graft dysfunction was defined as the presence of hyperbilirubinemia, coagulopathy, or ascites on 3 consecutive days during the first postoperative week. Each clinical sign of dysfunction was assigned 1 point. Postoperative percentage fall in PLT counts, graft dysfunction score, and postoperative complications according to the Clavien Dindo classification were investigated. Overall, 31 patients (62%) exhibited a PLT count fall of more than 50%, and 19 (38%) patients exhibited a PLT count fall of less than 50% at postoperative day (POD) 3. Receiver operating characteristic curve analysis indicated that at POD 3, the cutoff value of PLT count fall was 56% for a graft dysfunction score of 2 or 3 (sensitivity, 70%; specificity, 63.3%). Fourteen of 20 patients (70%) with a dysfunction score of 2 or 3 and 11 of 30 patients (37%) with a dysfunction score of 0 or 1 showed a fall in PLT count >56% at POD 3 (P = 0.021). Grade 2 to 5 complications were more observed in patients with a dysfunction score of 2 or 3 than in patients with a dysfunction score of 0 or 1 (P < 0.001). The fall of PLT count at POD 3 >56% is an ominous sign that can predict the graft dysfunction after LDLT in recipients with SFS graft. PMID- 25785340 TI - Complete abdominal wall disruption with herniation following blunt injury: case report and review of the literature. AB - Acute traumatic abdominal wall hernia (TAWH) is a rare type of hernia that occurs after a low- or high-velocity impact of the abdominal wall against a blunt object. With few cases reported, a consensus in diagnosis and management has not been established in the literature. A systematic review of the literature for adult cases of traumatic abdominal wall hernia due to blunt abdominal trauma was undertaken. All original articles were reviewed and data were compiled and tabulated qualitatively. Diagnostic imaging modalities and their reported description of the abdominal wall hernia were detailed correlated with the laparotomy findings. We also report a case of TAWH following blunt abdominal trauma, and describe integration of this management into clinical practice. Fifty five cases of adult TAWH were found in the English literature. Most hernias contained either small bowel (69%) or large bowel (36%), with 16% of TAWH containing both. Concurrent intra-abdominal injuries were seen in 60% of cases, with an almost equal number of associated bowel (44%) and solid organ (35%) injuries. Twenty percent of diagnosis of TAWH was delayed, ranging from 2 days to 9 years. While TAWH is uncommon, a high index of suspicion is required in patients who present with blunt abdominal trauma. A staging system for TAWH can facilitate appropriate management priorities and treatment. CT scanning is crucial in the diagnosis of TAWH, and aids in definitive management of these patients. The literature supports immediate surgical exploration for most TAWH. PMID- 25785341 TI - Successful salvage of the upper limb after crush injury requiring nine operations: a case report. AB - Emergency treatment of amputation is one of the most frequently used therapeutic methods for patients with severe upper limb crush injury with a mangled extremity severity score (MESS) of more than 7. With the development of advanced surgical repair techniques and reconstructive technology, cases that once required amputation can now be salvaged with appropriate management, and some limb functions may also be reserved. A patient with a severe upper limb crush injury with a MESS score of 10 was treated in our hospital. The limb was salvaged after 9 surgeries over 10 months. The follow-up visits over the next 18 months post injury showed that the shoulder joint functions were rated as "excellent" (90) according to the Neer score, the Harris hip evaluation (HHS) for elbow joint functions was "good" (80), and the patient was very satisfied with the overall therapeutic outcome. We conclude from the successful outcome of this extreme injury that salvage attempts should be the first management choice for upper limbs with complex injuries to save as much function as possible. Amputation should only be adopted when the injury is life-threatening or no more function can be saved. The level of evidence was V. PMID- 25785342 TI - Transurethral electric coagulation combined with retroperitoneal laparoscopic nephroureterectomy for upper urinary urothelial carcinoma. AB - Retroperitoneal laparoscopic nephroureterectomy (LNU) combined with transurethral electric resection of ipsilateral bladder cuff is widely accepted to treat the upper urinary tract urothelial carcinoma (UUT-UC). To reduce the local recurrence rate, we improved the procedure from electric resection to electric coagulation. From May 2008 to July 2012, of all the 156 retroperitoneal LNU patients, 76 cases (test group) were performed with LNU combined with electric coagulation, and 80 cases (control group) were with electric resection. For the clinical outcomes, the hospital stay in the test group was shorter (5.2 +/- 2.6 days versus 8.2 +/- 3.4 days; P < 0.05), and the 1-year tumor recurrence rate was much lower (1.6% versus 13.3%, P < 0.05). There was no difference in operation time and blood loss between groups. Retroperitoneal LNU combined with electric coagulation is technically feasible and safe with lower tumor recurrence rate and shorter hospital stay. PMID- 25785343 TI - Management of priapism in adult men. AB - This study aims to present the management of priapism in adult men in Port Harcourt, Nigeria. All patients who presented with priapism in 2 hospitals in Port Harcourt from July 2007 to April 2014 were prospectively studied. Treatment was assigned based on clinical presentation. Data analyzed included: age on clinical presentation, risk factor, mode, and outcome of management. There were 18 patients aged 17 to 60 years (median age: 30 years). Three patients (16.7%) presented with stuttering priapism. Most of the patients presented after 24 hours of onset. Sixteen patients (89.9%) had hematological disorders. Five patients (27.8%) took suspected aphrodisiac medications. Seven patients (38.9%) were managed conservatively. The rest achieved detumescence following glandulo cavernous shunting. Erectile function after treatment was satisfactory in 5 patients (27.8%). The commonest cause of priapism in Port Harcourt was hematological disorder. Most of the patients presented late. Prevalence of erectile dysfunction after treatment was high. PMID- 25785344 TI - Cutaneous metastases from esophageal adenocarcinoma. AB - The aim of this study is to present 2 rare cases of cutaneous metastases originated from adenocarcinoma of the gastro-esophageal junction, thus, underline the need for early diagnosis and possible treatment of suspicious skin lesions among patients with esophageal malignancy. Metastatic cancer to the skin originated from internal malignancies, mostly lung cancer, breast cancer, and colorectal cancer, constitute 0.5 to 9% of all metastatic cancers. (5, 8, 15) Skin metastases, mainly from squamous cell carcinomas of the esophagus, are rarely reported. Cutaneous metastasis is a finding indicating progressiveness of the disease. (17) More precisely, median survival is estimated approximately 4.7 months. (2, 14) This study is a retrospective review of 2 cases of patients with adenocarcinoma of the esophagus and a review of the literature. Two patients aged 60 and 32 years old, respectively, underwent esophagectomy. Both pathologic reports disclosed adenocarcinoma of the gastro-esophageal junction staged T3 N2 M0 (stage IIIB). During follow-up time, the 2 patients were diagnosed with cutaneous metastases originated from the primary esophageal tumor 11 and 4 months after surgery, respectively. The first patient is alive 37 months after diagnosis, while the second one died 16 months after surgery. Cutaneous metastasis caused by esophageal adenocarcinoma is possible. Therefore, follow-up of patients who were diagnosed with esophageal malignancy and underwent esophagectomy is mandatory in order to reveal early surgical stages. PMID- 25785345 TI - A case of mixed adenoneuroendocrine carcinoma of the stomach with focal intestinal metaplasia and hypergastrinemia. AB - Among neuroendocrine neoplasms, mixed exocrine and endocrine characteristics with at least 30% of each component are classified into mixed adenoneuroendocrine carcinoma (MANEC), according to the 2010 World Health Organization classification. We experienced a rare case of MANEC of the stomach with focal intestinal metaplasia and hypergastrinemia. A 76-year-old Japanese male was diagnosed as having gastric adenocarcinoma and underwent total gastrectomy. The pathologic diagnosis was MANEC of the stomach accompanied by unusual mucosal atrophy without Helicobacter pylori infection, the characteristics of which were different from both type A and type B atrophic gastritis. The patient has a history of long-term use of a proton pump inhibitor. Additional serum chemistry examination using preoperatively obtained plasma from the patient revealed hypergastrinemia. The mechanism of gastric MANEC carcinogenesis is still unclear, but that might be correlated with unusual intestinal metaplasia and hypergastrinemia in this case. PMID- 25785346 TI - A Case of G-CSF-Producing Histiocytic Sarcoma of the Stomach. AB - No reports have been published to date regarding primary gastric granulocyte colony-stimulating factor (G-CSF)-producing histiocytic sarcoma. We encountered a case of primary gastric histiocytic sarcoma that also fulfilled the criteria for a G-CSF-producing tumor. A 75-year-old man was diagnosed with gastric cancer with poorly differentiated adenocarcinoma. The patient's white blood cell count was elevated to 20,700/MUL, and the G-CSF level was elevated to 380 pg/mL. A computed tomography scan showed hepatic infiltration; therefore, a preoperative diagnosis of T4 (liver) N2H0M0 cStage IV gastric cancer was made, and surgery was performed. No. 11d lymphatic metastasis was noted, resulting in invasion of the pancreatic tail, and combined resection of the liver, pancreas, and spleen was conducted with complete gastrectomy. The results of hematoxylin-eosin and immunohistochemical staining were subsequently assessed. On discharge, the G-CSF level had fallen to 22.7 pg/mL. Currently, the patient is still alive and has experienced no recurrence approximately 4 years after the operation. PMID- 25785347 TI - Complete resection of a complicated huge mesenteric lymphangioma guided by mesenteric computed tomography angiography with three-dimensional reconstruction: report of a case. AB - We herein describe the case of an adult with a complicated huge lymphangioma of the small bowel mesentery. Computed tomography (CT) confirmed a 45 * 30 * 14 cm multiple and separate, mixed and solid cystic tumor without enhancement by contrast medium in the abdominal cavity. Mesenteric CT angiography with three dimensional (3D) reconstruction showed that the tumor did not involve the first jejunal artery, although the tumor did involve the subsequent jejunal and ileal arteries and the corresponding segment of the small bowel. Under anatomic guidance based on mesenteric CT angiography with 3D reconstruction, we were able to successfully excise the tumor. Mesenteric lymphangioma should be excised even when the tumor is asymptomatic. Mesenteric CT angiography with 3D reconstruction is useful for the surgical treatment of huge mesenteric tumors. PMID- 25785349 TI - Association between breastfeeding and breast cancer risk: evidence from a meta analysis. AB - BACKGROUND: Quantification of the association between breastfeeding and breast cancer risk is still conflicting. Therefore, we conducted a meta-analysis to summarize the evidence from epidemiological studies of breastfeeding with the risk of breast cancer. MATERIALS AND METHODS: Pertinent studies were identified by a search of PubMed between January 1, 2008 and July 31, 2014. The random effect model was used. Sensitivity analysis, subgroups analysis, and publication bias were conducted. RESULTS: Twenty-four articles with 27 studies involving 13,907 breast cancer cases were included in this meta-analysis. Pooled results suggested that breastfeeding was inversely [corrected] associated with the risk of breast cancer. The summary relative risk (RR) of breast cancer for the ever compared with never categories of breastfeeding was 0.613 (95% confidence interval [CI], 0.442-0.850). An inverse association was also found for the longest compared with the shortest categories of breastfeeding with the risk of breast cancer (RR=0.471; 95% CI, 0.368-0.602). No evidence of publication bias was found. CONCLUSIONS: Findings from this meta-analysis suggest that breastfeeding, particularly a longer duration of breastfeeding, was inversely associated with risk of breast cancer. PMID- 25785348 TI - Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts. AB - Oncogene-induced senescence (OIS) is an important tumor suppression mechanism preventing uncontrolled proliferation in response to aberrant oncogenic signaling. The profound functional and morphological remodelling of the senescent cell involves extensive changes. In particular, alterations in protein ubiquitination during senescence have not been systematically analyzed previously. Here, we report the first global ubiquitination profile of primary human cells undergoing senescence. We employed a well-characterized in vitro model of OIS, primary human fibroblasts expressing oncogenic RAS. To compare the ubiquitinome of RAS-induced OIS and controls, ubiquitinated peptides were enriched by immune affinity purification and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified 4,472 ubiquitination sites, with 397 sites significantly changed (>3 standard deviations) in senescent cells. In addition, we performed mass spectrometry analysis of total proteins in OIS and control cells to account for parallel changes in both protein abundance and ubiquitin levels that did not affect the percentage of ubiquitination of a given protein. Pathway analysis revealed that the OIS-induced ubiquitinome alterations mainly affected 3 signaling networks: eIF2 signaling, eIF4/p70S6K signaling, and mTOR signaling. Interestingly, the majority of the changed ubiquitinated proteins in these pathways belong to the translation machinery. This includes several translation initiation factors (eIF2C2, eIF2B4, eIF3I, eIF3L, eIF4A1) and elongation factors (eEF1G, eEF1A) as well as 40S (RPS4X, RPS7, RPS11 and RPS20) and 60S ribosomal subunits (RPL10, RPL11, RPL18 and RPL35a). In addition, we observed enriched ubiquitination of aminoacyl-tRNA ligases (isoleucyl-, glutamine , and tyrosine-tRNA ligase), which provide the amino acid-loaded tRNAs for protein synthesis. These results suggest that ubiquitination affects key components of the translation machinery to regulate protein synthesis during OIS. Our results thus point toward ubiquitination as a hitherto unappreciated regulatory mechanism during OIS. PMID- 25785350 TI - Analysis of veterinary drug and pesticide residues in animal feed by high resolution mass spectrometry: comparison between time-of-flight and Orbitrap. AB - The use of medium-high-resolution mass spectrometers (M-HRMS) provides many advantages in multi-residue analysis. A comparison between two mass spectrometers, medium-resolution (MRMS) time-of-flight (TOF) and high-resolution (HRMS) Orbitrap, has been carried out for the analysis of toxic compounds in animal feed. More than 300 compounds belonging to several classes of veterinary drugs (VDs) and pesticides have been determined in different animal feed samples using a generic extraction method. The use of a clean-up procedure has been evaluated in both instruments, and several validation parameters have been established, such as the matrix effect, linearity, recovery and sensitivity. Finally, both instruments have been used during the analysis of 18 different feed samples (including chicken, hen, rabbit and horse). Some VDs (sulfadiazine, trimethoprim, robenidine and monensin sodium) and one pesticide (chlorpyrifos) have been identified. In general, better results were obtained using the Orbitrap, such as sensitivity (1-12.5 ug kg(-1)) and recovery values (60-125%). Moreover, this analyser had several software tools, which reduced the time for data processing and were easy to use, performing quick screening for more than 450 compounds in less than 5 min. However, some disadvantages such as the high cost and a decrease in the number of detected compounds at low concentrations must be taken into account. PMID- 25785351 TI - Structural characterization and biological activities of a novel polysaccharide from cultured Cordyceps militaris and its sulfated derivative. AB - A novel polysaccharide (CMPA90-1; compound 1) was isolated from the cultured fruiting bodies of Cordyceps militaris. The chemical structure of compound 1 was elucidated by acid hydrolysis, periodate oxidation, Smith degradation, and methylation analysis, along with Fourier transform infrared spectroscopy, high performance anion-exchange chromatography coupled with pulsed amperometric detection, gas chromatography-mass spectrometry, and one-dimensional [(1)H and (13)C nuclear magnetic resonance (NMR)] and two-dimensional NMR (heteronuclear single-quantum coherence and heteronuclear multiple-bond correlation). Sulfation of compound 1 by the chlorosulfonic acid-pyridine (CSA-Pyr) method led to synthesis of its sulfated analogue (CMPA90-M1; compound 2). The ultrastructures of both compounds 1 and 2 were further characterized by scanning electron microscopy and atomic force microscopy. The results of antioxidant assays showed that compounds 1 and 2 exhibited free-radical-scavenging effects, ferrous-ion chelating ability, and reducing power. Also, in the cytotoxicity assay, compounds 1 and 2 showed inhibitory activity against A549 cells, with IC50 values of 39.08 and 17.33 MUg/mL, respectively. PMID- 25785352 TI - Highlights from Faraday Discussion 170: challenges and opportunities of modern mechanochemistry, Montreal, Canada, 2014. AB - The Faraday Discussion Mechanochemistry: From Functional Solids to Single Molecules which took place 21-23 May 2014 in Montreal, Canada, brought together a diversity of academic and industrial researchers, experimentalists and theoreticians, students, as well as experienced researchers, to discuss the changing face of mechanochemistry, an area with a long history and deep connections to manufacturing, that is currently undergoing vigorous renaissance and rapid expansion in a number of areas, including supramolecular chemistry, smart polymers, metal-organic frameworks, pharmaceutical materials, catalytic organic synthesis, as well as mineral and biomass processing and nanoparticle synthesis. PMID- 25785353 TI - Theoretical derivation of anodizing current and comparison between fitted curves and measured curves under different conditions. AB - Anodic TiO2 nanotubes have been studied extensively for many years. However, the growth kinetics still remains unclear. The systematic study of the current transient under constant anodizing voltage has not been mentioned in the original literature. Here, a derivation and its corresponding theoretical formula are proposed to overcome this challenge. In this paper, the theoretical expressions for the time dependent ionic current and electronic current are derived to explore the anodizing process of Ti. The anodizing current-time curves under different anodizing voltages and different temperatures are experimentally investigated in the anodization of Ti. Furthermore, the quantitative relationship between the thickness of the barrier layer and anodizing time, and the relationships between the ionic/electronic current and temperatures are proposed in this paper. All of the current-transient plots can be fitted consistently by the proposed theoretical expressions. Additionally, it is the first time that the coefficient A of the exponential relationship (ionic current j(ion) = A exp(BE)) has been determined under various temperatures and voltages. And the results indicate that as temperature and voltage increase, ionic current and electronic current both increase. The temperature has a larger effect on electronic current than ionic current. These results can promote the research of kinetics from a qualitative to quantitative level. PMID- 25785355 TI - Infection Rate of Intramedullary Nailing in Closed Fractures of the Femoral Diaphysis After Temporizing External Fixation in an Austere Environment. AB - OBJECTIVES: To determine the infection rate of intramedullary (IM) nailing of closed diaphyseal femur fractures after temporary stabilization with external fixation in an austere combat environment. DESIGN: Retrospective case series. SETTING: Iraq and Afghanistan Theater and Military Medical Treatment Centers in the United States and Landstuhl, Germany. PATIENTS: Military personnel who underwent temporizing external fixation of a closed diaphyseal femur fracture (OTA 32) with later conversion to an IM nail between 2003 and 2012. INTERVENTION: Patients were identified from the Joint Theater Trauma Registry and Department of Defense electronic medical record, and a retrospective review was performed. MAIN OUTCOME MEASUREMENTS: Variables measured included age, gender, mechanism of injury, Injury Severity Score, associated injuries (to include thoracic and abdominal injuries), base deficit, history of massive transfusion, date of injury, date and place of external and IM fixations, time to conversion procedure, report of superficial or deep infection, report of fracture union, and date of last follow-up. RESULTS: One hundred twenty-two patients, mean age 25 (18 43) years, sustained 125 closed femoral diaphyseal fractures from May 2003 to July 2012. External fixation was performed at a mean of 0.2 days (median of the day of injury) and a range of 0-3 days. Mean time to IM nail conversion procedure was 6.9 (1-20) days. Infection rate was 2.5%, with a P of 0.188. Average follow up was 41.4 (12-119) months. CONCLUSIONS: Acceptable low infection rates can be achieved after IM nailing of closed diaphyseal femur fractures treated with initial external fixation in an austere combat environment. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25785356 TI - Low Complication Rates Associated With the Application of Lower Extremity Traction Pins. AB - OBJECTIVE: To quantify the infection risks of temporary lower extremity traction pins and compare these rates to nationwide and institution-specific surgical site infection rates. Additionally, to qualitatively describe pin site infections and to analyze the impact of traction pins on infection risks at associated open reduction internal fixation (ORIF) surgical sites. DESIGN: A retrospective case control study. SETTING: Level I Urban University Trauma Center. PATIENTS: One hundred sixty-nine cases of traction pin application occurring in 157 unique patients extracted from a trauma patient database. INTERVENTION: Bedside application of a traction pin in the femur or tibia. MAIN OUTCOME MEASUREMENTS: Rates of 90-day and 1-year minor and major infections at pin insertion locations and at ORIF wounds associated with traction pins. RESULTS: A single infection, a septic knee, was reported. There were no superficial infections or osteomyelitis cases observed. The 90-day and 1-year rates of infection were identical with a per pin infection rate of 0.6% [95% confidence interval (CI), 0.1%-3.4%], a minor infection rate of 0.0% (95% CI, 0.0%-2.3%), and a major infection rate of 0.6% (95% CI, 0.1%-3.4%). Observed rates were lower than, but statistically similar to, nationwide infection rates for open reduction procedures and similar to institution-specific infection rates for arthroplasty procedures. Infection rates at associated ORIF wounds were not increased in comparison with nationwide controls. Pin placement played a definitive role in the infection observed. CONCLUSIONS: Temporary lower extremity traction pins have low infection rates and can be safely placed at the bedside. Careful pin placement and review of postinsertion radiographs is necessary to avoid iatrogenic infection. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25785357 TI - Patient-Based and Surgical Risk Factors for 30-Day Postoperative Complications and Mortality After Ankle Fracture Fixation. AB - OBJECTIVE: The purpose was to calculate the incidence rates and determine risk factors for 30-day postoperative mortality and morbidity after ankle fracture open reduction and internal fixation (ORIF). METHODS: The NSQIP database was queried to identify patients undergoing ankle fracture ORIF from 2006 to 2011, with extraction patient-based or surgical variables and a 30-day clinical course. Multivariable logistic regression analysis identified significant predictors on outcome measures. RESULTS: Mean age was 50.3 (+/-18.2) years while diabetes mellitus (12.8%) and body mass index >=40 kg/m(2) (9.2%) were documented from a total of 3328 patients identified. The 30-day mortality rate was 0.30%, and complications occurred in 5.1%. Chronic obstructive pulmonary disease [odds ratio (OR): 4.23, 95% confidence interval (CI): 1.19-15.06] and a nonindependent functional status before surgery (OR: 2.25, 95% CI: 1.13-4.51) were the sole independent predictors of mortality and major local complications, respectively. Major local complications occurred in 2.2% of patients, and significant predictors were peripheral vascular disease (OR: 6.14; 95% CI: 1.95-19.35), open wound (OR: 5.04; 95% CI: 2.25-11.27), nonclean wound classification (OR: 3.02; 95% CI: 1.31-6.93), and smoking (OR: 2.85; 95% CI: 1.42-5.70). Independent predictors of hospital stay >3 days were cardiac disease, age 70 years or older, open wound, partially/totally dependent functional status, American Society of Anesthesiologists (ASA) classification >=3, body mass index >=40 kg/m(2), bimalleolar or trimalleolar ankle fracture pattern, female sex, and diabetes. CONCLUSIONS: Chronic obstructive pulmonary disease increased the risk of mortality after ankle fracture ORIF. Risk factors for postoperative complications included peripheral vascular disease, open wound, nonclean wound classification, age 70 years or older, and ASA classification >=3. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25785358 TI - Posterior Malleolar Fracture Patterns. AB - OBJECTIVE: To characterize posterior malleolar fracture morphology using Cole fracture mapping and to study reliability of quantification of 3-dimensional computed tomography (CT)-modeling for posterior malleolar fractures with respect to quantification of fragment size (in cubic millimeter) and true articular involvement (in square millimeter). METHODS: CT scans of a consecutive series of 45 patients with an ankle fracture involving the posterior malleolus were reconstructed to calculate (1) fracture maps, (2) fragment volume, (3) articular surface of the posterior malleolar fragment, (4) articular surface of intact tibia, and (5) articular surface of the medial malleolus by 3 independent observers. Three-dimensional animation of this technique is shown on www.traumaplatform.org. RESULTS: Fracture mapping revealed (1) a continuous spectrum of posterolateral oriented fracture lines and (2) fragments with posterolateral to posteromedial oriented fracture lines extending into the medial malleolus. Reliability of measurements of the volume and articular surface of posterior malleolar fracture fragments was defined as almost perfect according to the categorical system of Landis (interclass coefficient, range, 0.978-1.000). CONCLUSIONS: Mapping of posterior malleolar fractures revealed a continuous spectrum of Haraguchi III to I fractures and identified Haraguchi type II as a separate pattern. Quantification of 3-dimensional CT-modeling is reliable to assess fracture characteristics of posterior malleolar fracture fragments. Morphology might be more important than posterior malleolar fracture size alone for clinical decision making. PMID- 25785359 TI - Coronoid Fractures. AB - Fractures of the coronoid process of the ulna are usually part of a more complex injury. The type of coronoid fracture corresponds with a specific pattern of injury with known pitfalls and recommended treatments. Tip fractures usually correspond with dislocation of the elbow and fracture of the radial head (the so called terrible triad of the elbow because it is prone to redislocation, subluxation, and arthrosis) and are best repaired with a suture passed through drill holes along with repair or replacement of the fractured radial head and reattachment of the lateral collateral ligament to the lateral epicondyle. Anteromedial fractures are usually part of a subluxation injury and are best addressed with a medial buttress plate and reattachment of the lateral collateral ligament. Large basilar coronoid fractures are usually part of an olecranon fracture-dislocation and are usually repaired with 1 or 2 plates and screws. Tenuous fixation is protected with temporary external fixation or cross-pinning of the joint because healing of the coronoid with concentric elbow alignment is critical. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 25785360 TI - Biocompatible hydrogel nanocomposite with covalently embedded silver nanoparticles. AB - Bionanocomposite materials, combining the properties of biopolymers and nanostructured materials, are attracting interest of the wider scientific community due to their potential application in design of implants, drug delivery systems, and tissue design platforms. Herein, we report on the use of maleimide coated silver nanoparticles (Ag NPs) as cocross-linkers for the preparation of a bionanocomposite gelatin based hydrogel. Diels-Alder cycloaddition of benzotriazole maleimide (BTM) functionalized Ag NPs and furan containing gelatin in combination with additional amide coupling resulted in stable and biocompatible hybrid nanocomposite. The storage moduli values for the hydrogel are nearly three times higher than that of control hydrogel without NPs indicating a stabilizing role of the covalently bound NPs. Finally, the swelling and drug release properties of the materials as well as the biocompatibility and toxicity tests indicate the biomedical potential of this type of material. PMID- 25785361 TI - Food for thought: edible gardens in New Zealand primary and secondary schools. AB - ISSUE ADDRESSED: School gardens are a potentially important health promotion tool, allowing the growth and consumption of fruit and vegetables to be embedded within the students' educational experience. This study aimed to investigate the implementation of edible gardens in New Zealand (NZ) primary and secondary schools. METHODS: A questionnaire mailed to principals from a randomly selected sample of 764 NZ schools included questions on whether or not the school had a garden and, if so, what produce was grown; how long the garden had been in place; how harvested crops were distributed; and curriculum integration. RESULTS: Among 491 responding schools (64.3% response rate), 52.9% currently had an edible garden - with most gardens started in the previous two years. Vegetables, herbs and tree fruit were commonly grown. Gardens were integrated into curriculum subjects, cooking lessons, recipes and messages promoting increased fruit and vegetable consumption. CONCLUSIONS: Edible gardens were common within NZ schools, though often relatively new, and were used for teaching in a variety of curriculum areas. SO WHAT?: Given the current popularity of school gardens, there are opportunities to deliver health promotion messages regarding consumption of fruit and vegetables, and for these to be reinforced by real life experience growing and preparing healthy food. PMID- 25785363 TI - Bipolar resistive switching behavior of an amorphous Ge2Sb2Te5 thin films with a Te layer. AB - The mechanism of bipolar resistive switching (BRS) of amorphous Ge2Sb2Te5 (GST) thin films sandwiched between inert electrodes (Ti and Pt) was examined. Typical bipolar resistive switching behavior with a high resistance ratio (~10(3)) and reliable switching characteristics was achieved. High-resolution transmission electron microscopy revealed the presence of a conductive Te-filament bridging between the top and bottom electrodes through an amorphous GST matrix. The conduction mechanism analysis showed that the low-resistance state was semiconducting and dominated by band transport, whereas Poole-Frenkel conduction governed the carrier transport in the high-resistance state. Thus, the BRS behavior can be attributed to the formation and rupture of the semiconducting conductive Te bridge through the migration of the Te ions in the amorphous GST matrix under a high electric field. The Te ions are provided by the thin (~5 nm) Te-rich layer formed at the bottom electrode interface. PMID- 25785362 TI - Metabolic syndrome and its components as predictors of nonalcoholic fatty liver disease in a northern urban Han Chinese population: a prospective cohort study. AB - OBJECTIVES: To explore the longitudinal effect of metabolic syndrome (MetS) and its components on the development of non-alcoholic fatty liver disease (NAFLD) and to evaluate the significance of MetS and its components as early markers of NAFLD risk in a northern urban Han Chinese population. MATERIALS AND METHODS: A total of 15,791 cohort members without NAFLD at baseline were included in the current study between 2005 and 2011. The baseline characteristics of the cohort were compared by MetS status at baseline and NAFLD status after follow-up. Cox proportional hazards models were used to estimate the unadjusted or adjusted hazard ratios (HRs) for development of NAFLD among individuals with MetS compared with individuals without MetS at baseline. RESULTS: During 51,652 person-years of follow-up, 3913 (24.78%) new cases of NAFLD occurred between 2005 and 2011. In the unadjusted model, the HR (95% confidence interval [CI]) for NAFLD was 2.51 (2.30, 2.73). After adjusting for gender, age, diet, smoking status, and regular exercise, the HR was 1.94 (1.78, 2.13). Gender differences were observed, with adjusted HRs (95% CIs) of 1.89 (1.71, 2.09) and 1.72 (1.43, 2.07) among males and females, respectively. Compared with individuals without MetS components, the HRs were 1.92 (1.76, 2.09), 2.64 (2.40, 2.90) and 3.51 (3.15, 3.91) for individuals with one, two, or three or more MetS components, respectively. Moreover, participants with obesity or hyperlipidemia had a higher risk of NAFLD than patients with hypertension or hyperglycemia, with HRs of 2.03 (1.83, 2.25) for obesity, 1.94 (1.72, 2.19) for hyperlipidemia, and 3.01 (2.68, 3.37) for these factors in combination. CONCLUSION: The present study indicates that MetS and its components independently predict the risk of NAFLD in a northern urban Han Chinese population and suggests that people with MetS or its component should initiate lifestyle changes to prevent the development of NAFLD. PMID- 25785364 TI - Intramolecular O-H...O?C hydrogen bond energy via the molecular tailoring approach to RAHB structures. AB - A method for the calculation of the intramolecular hydrogen bond (HB) energy (EHB) by molecular tailoring approach for hydroxycarbonyl aliphatic compounds has been used for compounds with resonance-assisted hydrogen bonding (RAHB). The intramolecular hydrogen bond energies estimated for 229 structures (of 186 compounds) range from 8.2 to 26.3 kcal/mol and show correlation with the geometry descriptors of hydrogen bonds, with the calculated frequencies as well as with topological parameters obtained from the atoms in molecules (AIM) theory. These correlations differ significantly from obtained formerly for saturated nonenolizable structures and prove the special character of the resonance assisted hydrogen-bonded systems. PMID- 25785365 TI - Tramadol for postoperative pain treatment in children. AB - BACKGROUND: According to current recommendations a multimodal approach is believed to be the gold standard for postoperative pain treatment in children. However, several surveys in the last few years demonstrated that postoperative pain in children is still a serious problem, mainly because opioids are avoided. One of the reasons for this is the fear of severe adverse events following opioid administration. Tramadol is a weak mu-opioid agonist and inhibits reuptake of noradrenaline and serotonin (5HT). Because of a relatively wide therapeutic window and a ceiling effect with a lower risk for severe adverse events (for example respiratory depression) tramadol is a widely used opioid in children. However, the exact efficacy and occurrence of adverse events following tramadol (in comparison with placebo or other opioids) for postoperative pain treatment in children and adolescents are currently not clear. OBJECTIVES: To assess the effectiveness and side effect profile of tramadol for postoperative pain relief in children and adolescents undergoing different surgical procedures. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 6), MEDLINE via PubMed (January 1966 to July 2014) and EMBASE via Ovid (January 1947 to July 2014). There were no restrictions regarding language or date of publication. The reference lists of all included trials were checked for additional studies. SELECTION CRITERIA: All randomised controlled clinical trials investigating the perioperative administration of tramadol compared to placebo or other opioids for postoperative pain treatment in children and adolescents were included. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the study eligibility, performed the data extraction and assessed the risk of bias of included trials. MAIN RESULTS: Twenty randomised controlled trials involving 1170 patients were included in this systematic review. The overall risk of bias in included trials was assessed as unclear, because concealment of allocation processes and blinding of outcome assessors were poorly described. Due to inconsistent outcome reporting, data from 17 included trials could be pooled for some endpoints only. Eight trials compared tramadol administration with placebo and five trials found that the need for rescue analgesia in the postoperative care unit (PACU) was reduced in children receiving tramadol (RR 0.40; 95% CI 0.20 to 0.78; low quality evidence). Only one trial investigated the number of patients with moderate to severe pain, but a non validated pain scale was used (very low quality evidence). Four trials compared morphine with tramadol administration. There was no clear evidence of difference in the need for rescue analgesia in the PACU (RR 1.25; 95% CI 0.83 to 1.89; low quality evidence) with tramadol compared with morphine. No trials could be pooled for the outcome 'number of patients with moderate to severe pain'. Three trials were included for the comparison of tramadol with nalbuphine. There was no clear evidence for the need for rescue analgesia in the PACU (RR 0,63; 95% CI 0.16 to 2.45; low quality evidence). Only one trial reported the number of patients with moderate to severe pain, but used a non-validated pain scale (very low quality evidence). Two out of six included trials, which compared pethidine with tramadol, reported the number of children with a need for rescue analgesia within the PACU and showed no clear evidence (RR 0.93; 95% CI 0.43 to 2.02; very low quality evidence). Two trials reported the number of patients with moderate to severe pain and showed a lower RR in patients treated with tramadol (RR 0.64; 95% CI 0.36 to 1.16; low quality evidence). Only one trial was included, which compared tramadol with fentanyl, reporting the number of patients with the need for rescue analgesia (very low quality evidence). Generally, adverse events were poorly reported. Most data could be pooled for the comparison with placebo focusing on the RR for postoperative nausea and vomiting (PONV) in the postoperative care unit and 24 h postoperation. Children treated with tramadol, compared to placebo, did not show clear evidence of benefit for PONV in the postoperative care unit (RR 0.84; 95% CI 0.28 to 2.52; moderate quality evidence) and 24 h postoperation (RR 0.78; 95% CI 0.54 to 1.12; moderate quality evidence). AUTHORS' CONCLUSIONS: The overall evidence regarding tramadol for postoperative pain in children is currently low or very low and should be interpreted with caution due to small studies and methodological problems (different validated and non-validated pain scales with different pain triggers, missing sample size calculations and missing intention-to-treat analysis). Nevertheless, we demonstrated that tramadol administration might provide appropriate analgesia when compared to placebo; this is based on results showing reduced rescue analgesia in children treated with tramadol compared to placebo. In contrast, the evidence regarding the comparison with other opioids (for example morphine) was uncertain. Adverse events were only poorly reported, so an accurate risk-benefit analysis was not possible. PMID- 25785366 TI - Toxicity and accumulation of Cu and ZnO nanoparticles in Daphnia magna. AB - There is increasing recognition that the wide use of nanoparticles, such as Cu (CuNPs) and ZnO nanoparticles (ZnONPs), may pose risks to the environment. Currently there is insufficient insight in the contribution of metal-based nanoparticles and their dissolved ions to the overall toxicity and accumulation. To fill in this gap, we combined the fate assessment of CuNPs and ZnONPs in aquatic test media with the assessment of toxicity and accumulation of ions and particles present in the suspensions. It was found that at the LC50 level of Daphnia magna exposed to the nanoparticle suspensions, the relative contributions of ions released from CuNPs and ZnONPs to toxicity were around 26% and 31%, respectively, indicating that particles rather than the dissolved ions were the major source of toxicity. It was additionally found that at the low exposure concentrations of CuNPs and ZnONPs (below 0.05 and 0.5 mg/L, respectively) the dissolved ions were predominantly accumulated, whereas at the high exposure concentrations (above 0.1 mg/L and 1 mg/L, respectively), particles rather than the released ions played a dominant role in the accumulation process. Our results thus suggest that consideration on the contribution of dissolved ions to nanoparticle toxicity needs to be interpreted with care. PMID- 25785367 TI - Trichosporon inkin as an Emergent Pathogen in Patients With Severe Pemphigus. AB - IMPORTANCE: To our knowledge, these are the first reports of bloodstream infections by Trichosporon inkin in patients with pemphigus. OBSERVATIONS: Trichosporon inkin, a novel organism causing bloodstream infection, was detected in 2 patients with pemphigus. An elderly man with pemphigus foliaceus died despite treatment with liposomal amphotericin B, 3 mg/kg/d, and a young girl with pemphigus vulgaris responded to treatment with voriconazole, 8 mg/kg/d, for 24 days. One of the T inkin isolates had a minimal inhibitory concentration of 2 mg/L against amphotericin B, suggesting resistance to the drug. CONCLUSIONS AND RELEVANCE: Delayed suspicion of invasive infection by T inkin may result in a poor outcome in patients with severe forms of pemphigus. This opportunistic infection is highly refractory to conventional potent antifungal treatment. PMID- 25785368 TI - Enriched inhibition of cancer and stem-like cancer cells via STAT-3 modulating niclocelles. AB - We describe for the first time a therapeutic strategy to target stem-like cancer cells via STAT-3 modulation using a nanomedicine approach. Niclocelle, a niclosamide loaded rigid core mixed micelle, was synthesized from a self assembled well-defined amphiphilic diblock copolymer and an FDA-approved signal transducer and activator of transcription factor 3. Followed by a rigorous physico-chemical characterization, niclocelles were evaluated biologically for cytotoxicity and apoptosis in human melanoma (C32) and breast cancer (MDA-MB231 and MCF-7) cells. Niclocelles were found to selectively reduce the CD44+ stem cell population in C32 cells via STAT-3 modulation. PMID- 25785369 TI - On the potential for fibronectin/phosphorylcholine coatings on PTFE substrates to jointly modulate endothelial cell adhesion and hemocompatibility properties. AB - The use of biomolecules as coatings on biomaterials is recognized to constitute a promising approach to modulate the biological response of the host. In this work, we propose a coating composed by 2 biomolecules susceptible to provide complementary properties for cardiovascular applications: fibronectin (FN) to enhance endothelialization, and phosphorylcholine (PRC) for its non thrombogenic properties. Polytetrafluoroethylene (PTFE) was selected as model substrate mainly because it is largely used in cardiovascular applications. Two approaches were investigated: 1) a sequential adsorption of the 2 biomolecules and 2) an adsorption of the protein followed by the grafting of phosphorylcholine via chemical activation. All coatings were characterized by immunofluorescence staining, X-Ray Photoelectron Spectroscopy and Scanning Electron Microscopy analyses. Assays with endothelial cells showed improvement on cell adhesion, spreading and metabolic activity on FN-PRC coatings compared with the uncoated PTFE. Platelets adhesion and activation were both reduced on the coated surfaces when compared with uncoated PTFE. Moreover, clotting time tests exhibited better hemocompatibility properties of the surfaces after a sequential adsorption of FN and PRC. In conclusion, FN-PRC coating improves cell adhesion and non thrombogenic properties, thus revealing a certain potential for the development of this combined deposition strategy in cardiovascular applications. PMID- 25785370 TI - Orientation and density control of bispecific anti-HER2 antibody on functionalized carbon nanotubes for amplifying effective binding reactivity to cancer cells. AB - Nanomaterial bioconjugates have gained unabated interest in the field of sensing, imaging and therapy. As a conjugation process significantly affects the biological functions of proteins, it is crucial to attach them to nanomaterials with control over their orientation and the nanomaterial-to-protein ratio in order to amplify the binding efficiency of nanomaterial bioconjugates to targets. Here, we describe a targeting nanomaterial platform utilizing carbon nanotubes functionalized with a cotinine-modified dextran polymer and a bispecific anti HER2 * cotinine tandem antibody. This new approach provides an effective control over antibody orientation and density on the surface of carbon nanotubes through site-specific binding between the anti-cotinine domain of the bispecific tandem antibody and the cotinine group of the functionalized carbon nanotubes. The developed synthetic carbon nanotube/bispecific tandem antibody conjugates (denoted as SNAs) show an effective binding affinity against HER2 that is three orders of magnitude higher than that of the carbon nanotubes bearing a randomly conjugated tandem antibody prepared by carbodiimide chemistry. As the density of a tandem antibody on SNAs increases, their effective binding affinity to HER2 increases as well. SNAs exhibit strong resonance Raman signals for signal transduction, and are successfully applied to the selective detection of HER2 overexpressing cancer cells. PMID- 25785371 TI - Development of telerehabilitation application with designated consultation categories. AB - Telerehabilitation (TR) is getting ever more popular because it is effective in bringing rehabilitation services to rural populations by means of audiovisual systems and its initial implementation studies presented encouraging results. TR is proven to be helpful, with benefits in terms of reduced travel time, cost, and availability of specialists' support in local communities. However, TR systems that are usable under low-bandwidth network environments are rare. This article introduces the development of a TR system with customized consultation categories for users to choose from, depending on requirements. Each category, with its preset parameter values, is discussed in detail by demonstrating relevant rehabilitation exercises. A novel bandwidth adaptation algorithm is also presented for optimal utilization of the dynamic network conditions, which ensures the system functionality even under narrow-bandwidth environments. Experiment results show that the system is able to perform effectively in each consultation category while the rehabilitation exercises are being performed. The proposed algorithm is also verified for its ability to adapt the content quality and effectively utilize the network under constrained conditions. A survey conducted on the video quality of the system under low-bandwidth conditions shows encouraging results for a large scale deployment of the application. PMID- 25785372 TI - Tetranuclear ruthenium(II) complexes with oligo-oxyethylene linkers as one- and two-photon luminescent tracking non-viral gene vectors. AB - To prolong the observation time, increase the penetration depth and decrease self absorption and phototoxicity, two-photon luminescent vectors have emerged as promising tools for tracking gene delivery in living cells. Herein, we report four new tetranuclear Ru(ii) complexes based on oligo-oxyethylene and polybenzimidazole as one- and two- photon luminescent tracking non-viral gene vectors. In such a molecular design, the oligo-oxyethylene, polybenzimidazole and Ru(ii) polypyridyl complexes were expected to render the vectors with increased cell permeability, biocompatibility, proton buffering capacity and one- and two photon luminescence. Corresponding DNA interaction studies showed that the ability of the complexes to condense DNA decreased with increasing oligo oxyethylene lengths. Additionally, all complexes protected DNA. The complexes were investigated as one- and two-photon tracking non-viral gene vectors in living cells and showed proper cellular uptake, good luciferase expression and low cytotoxicity. PMID- 25785373 TI - Selective detection of tyrosine-containing proximally phosphorylated motifs using an antenna-free Tb3+ luminescent sensor. AB - We herein report the first application of Tb(3+) for the selective detection of an important subset of the phosphoproteome, namely, proximally di-phosphorylated peptide motifs where at least one phosphorylated residue is tyrosine. PMID- 25785374 TI - The Clinical Role of Intraoperative Core Temperature in Free Tissue Transfer. AB - BACKGROUND: Lengthy microvascular procedures carry hypothermia risk, yet limited published data evaluate the overall impact of core temperature on patient and flap morbidity. Although hypothermia may contribute to complications, warming measures are challenged by conflicting reports of intraoperative hypothermia improving anastomotic patency. METHODS: A retrospective review included all free flaps performed by plastic surgeons at an academic medical center from December 2005 to December 2010. Intraoperative core temperatures were measured by esophageal probe, and median values recorded over 5-minute intervals yielded a case mean (Tavg), maximum (Tmax), and nadir (Tmin). Outcomes included flap failure, pedicle thrombosis, recipient site infection and complications associated with patient, and flap morbidity. Analysis used Student t test, Fisher exact test, Probit, and logistic regression. RESULTS: Of 156 consecutive free tissue transfers, the median Tavg, Tmax, and Tmin were 36.5 degrees C, 37.1 degrees C, and 35.8 degrees C, respectively. The flap failure rate was 7.7% (12/156) and pedicle thrombosis occurred in 9 (6%) cases. Core temperatures did not associate with overall flap failure or pedicle thrombosis but recipient site infection occurred in 21 (13%) patients who had significantly lower mean core temperatures (Tavg=36.0 degrees C, P<0.01). Lower Tavg and Tmax significantly predicted recipient site infection (P<0.01 and P<0.05, respectively). Cut-point analysis revealed significant increases in recipient site infection risk at Tavg less than 37.0 degrees C (P=0.026) and Tmin less than or equal to 34.5 degrees C (P=0.020). CONCLUSIONS: Intraoperative hypothermia posed significant risk of flap infection with no benefit to anastomotic patency in free tissue transfer. PMID- 25785375 TI - The Role of the Distal Runoff Vessel of the Descending Branch of the Lateral Circumflex Femoral System in Anterolateral Thigh Flap Surgery: A Case Series and Literature Review. AB - BACKGROUND: As a distal portion of the descending branch of the lateral circumflex femoral system (LCFS), the role of the distal runoff vessel in anterolateral thigh (ALT) flap surgery has long been overlooked. Recently, however, the distal runoff vessel has been increasingly used in many aspects of ALT flap surgery, and it has exhibited superior properties in solving some difficult problems. METHODS: Fourteen ALT flaps using the distal runoff vessel of the descending branch of the LCFS for extremity defects were retrospectively reviewed, and recent reports on using the distal runoff vessel were reviewed to determine the role of this vessel in ALT flap surgery. RESULTS: In our series, the distal runoff vessel was used as a flow-through pattern in 10 cases, as a recombined chimeric flap in 2 cases, and as a backup vessel for flap salvage in 2 cases. All of the ALT flaps completely survived. None of the donor sites presented with additional morbidity as a result of harvesting the distal runoff vessel. In the literature review, the following are 5 other options for using the distal runoff vessel: in interposition artery and vein grafts, as the pedicle of the reverse-flow ALT flap, as the recipient vessel, to avoid twisting, and as a monitoring method. CONCLUSIONS: The distal runoff vessel of the descending branch of the LCFS could be used for many aspects of the ALT flap surgery, and this vessel plays an irreplaceable role in some difficult reconstruction surgeries. PMID- 25785376 TI - The prominent antihelix and helix--the myth of the 'overcorrected' ear in otoplasty. AB - BACKGROUND: Classic teaching of ear anatomy in the context of otoplasty states that if the antihelical fold is more prominent than the helical fold after surgery then the ear is "overcorrected." We set out to explore the role of the antihelix in normal ear anatomy, its relevance to aesthetic perceptions of the ear, and a snapshot of its incidence in nonoperated ears. METHODS: To readily identify junior staff in our department, their color photographs, names, and contact details are posted on every ward. Using digital methods, we cropped the left ear out of the source images, making them unidentifiable. Clinical and nonclinical staff in our unit were asked to choose their favorite and their least favorite ears based on their aesthetic appeal. Responses were tabulated and the 2 most popular ears were compared. RESULTS: The preferred ear did not conform to the traditional dogma because it had a prominent antihelix and was statistically significant when compared to other choices. We also noted that a prominent antihelix is common among the general population and among colleagues within the department, and hence "normal." Also interesting was that the helix of the ear chosen as the most aesthetic was also the ear where the helix was almost touching the side of the head. CONCLUSIONS: We found that when judging the aesthetic nature of the "virgin" ear, antihelical fold prominence did not appear to be a negative attribute. Indeed, we noted that a prominent antihelix was a common attribute, and we conclude that this was a normal variant without undue negative aesthetic stigma. A surgically corrected ear should not necessarily be regarded as a poor outcome simply on the basis of antihelical prominence. Furthermore, we postulate that patients who have a prominent antihelix might be part of a spectrum of individuals who might have had the subtype of prominent ears featuring a deep conchal bowl. Finally, although not tested directly, it appears that we do not have an idea of our own ear shape, as none of the participants was able to recognize their own ear from the photographs. PMID- 25785377 TI - Rise in microsurgical free-flap breast reconstruction in academic medical practices. AB - BACKGROUND: Previous studies have examined national trends in breast reconstruction, using various data sets demonstrating increases in implant-based reconstruction and decreases in autologous reconstruction. However, academic breast reconstruction practices have never been specifically characterized. The University Health Consortium-Association of American Medical Colleges Faculty Practice Solutions Center database contains comprehensive, factual billing and coding data from 90 academic medical centers in the United States, and has been used to characterize practice patterns of various academic surgical specialties. OBJECTIVE: To describe breast reconstruction trends unique to academic surgical practices, using the Faculty Practice Solutions Center database. METHODS: Annual data for defined breast reconstruction procedures (current procedural terminology codes: 19340, 19342, 19357, 19361, 19364, 19366, 19367, 19369, and 19380) performed by university plastic surgeons during calendar years 2007 to 2013 were included in the study. RESULTS: From 2007 to 2013, a 2-fold increase in the number of breast reconstruction procedures was observed (from a mean of 45.3 to 94.2 procedures per surgeon). During this period, implant-based reconstructions and autologous reconstructions rose in tandem (28.9-44.6 and 11.4-19.3, respectively), with a preserved 2.5:1 ratio between the 2 categories each year. When compared to reconstructions overall, the proportion of both implant reconstruction and autologous reconstruction procedures declined, since revision and other types of reconstructions increased (11% of all reconstructions in 2007 vs 32% in 2013). With regard to autologous reconstruction, microsurgical free flaps (mostly comprised of deep inferior epigastric artery perforator flaps) have supplanted latissimus flaps as the favored modality and comprised 13% to 14% of breast reconstruction cases overall from 2011 to 2013. CONCLUSION: In contrast to national trends, university-based plastic surgeons are performing a growing number of microsurgical free flaps as the preferred method for autologous breast reconstruction. Whereas implant-based reconstructions still predominate in academic practices, the trend of increasing preference toward implant-based reconstructions has slowed in recent years and revision reconstructions are on the rise. PMID- 25785378 TI - Sexual and Overall Quality of Life Improvements After Surgical Correction of "Buried Penis". AB - BACKGROUND: "Buried penis" is an increasing burden in our population with many possible etiologies. Although surgical correction of buried penis can be rewarding and successful for the surgeon, the psychological and functional impact of buried penis on the patient is less understood. METHODS: The study's aim was to evaluate the sexual satisfaction and overall quality of life before and after buried penis surgery in a single-surgeon's patient population using a validated questionnaire (Changes in Sexual Functioning Questionnaire short-form). RESULTS: Using Likert scales generated from the questionnaire and 1-tailed paired t test analysis, we found that there was significantly improved sexual function after correction of a buried penis. Variables individually showed that there was significant improvement with sexual pleasure, urinating, and with genital hygiene postoperatively. There were no significant differences concerning frequency of pain with orgasms. CONCLUSIONS: Surgical correction of buried penis significantly improves the functional, sexual, and psychological aspects of patient's lives. PMID- 25785379 TI - Three-dimensional computer-assisted orthognathic surgery: experience of 37 patients. AB - PURPOSE: Three-dimensional computer-assisted orthognathic surgery has been applied to improve planning and outcome. This study presents our experience with this promising modality for simulation of surgery, prefabrication of positioning guides, and navigation of the surgery. METHODS: Thirty-seven patients who received surgical simulation and intraoperative navigation for 2-jaw orthognathic surgery were recruited. Preoperative 3-dimensional cone-beam computed tomographic images were used for surgical simulation and design of intraoperative guidance. An initial surgical plan was developed and transferred for 3-dimensional virtual surgery. Modification of the surgical plan was made if facial symmetry and skeletal harmony or collision of ramus segments were concerned. The result of virtual surgery was used to design and manufacture positioning guides and perform preoperative navigation planning. During the operation, the positioning guides were used to transfer the virtual planning to actual surgery, and a real-time navigation system was used to confirm the predetermined position of the maxillomandibular complex. For assessment of the computer-assisted surgical system, the simulation image was superimposed to the postoperative image for comparison. RESULTS: The computer-assisted orthognathic surgery was successfully carried out in all patients. The initial surgical plan was modified in 17 patients in whom the position of maxillomandibular complex was changed. The positioning guides were helpful in controlling the spatial position of the maxillomandibular complex. The BrainLabTR navigation system was useful to further confirm the position of the facial bone. Superimposition of the simulation and postoperative images revealed satisfactory result with acceptable errors. The difference ranged from 0.05 to 1.46 mm, with a mean value of 0.66 mm, for patients using the positioning guides; and the difference ranged from 0.07 to 2.30 mm, with a mean value of 1.20 mm, for patients using the navigation system. Overall, patient and doctor satisfaction was high. CONCLUSION: This computer assisted orthognathic surgery system helps to improve surgical planning, reduce surgical difficulty, facilitate positioning and fixation of the maxillomandibular complex, and improve outcome. PMID- 25785380 TI - High risk of rhabdomyolysis and acute kidney injury after traumatic limb compartment syndrome. AB - PURPOSE: Rhabdomyolysis often occurs after traumatic compartment syndrome, and high morbidity and mortality have been reported with the acute kidney injury that develops subsequently. We focused on the risk factors for rhabdomyolysis and acute kidney injury in patients with traumatic compartment syndrome. We also analyzed the relation between renal function and rhabdomyolysis in these patients. MATERIALS AND METHODS: A retrospective chart review was conducted from January 2006 to March 2012. Inpatients with traumatic compartment syndrome were included. We evaluated patients' demographics, history of illicit drugs use or alcohol consumption, mechanism of injury, symptoms, serum creatine kinase levels, and kidney function. RESULTS: A total of 52 patients with a mean age of 40.9 years were included; 23 patients had rhabdomyolysis (44.2%), of which 9 patients developed acute kidney injury (39.1%). Significant predictive factors for rhabdomyolysis were history of illicit drugs or alcohol use (P=0.039; odds ratio, 5.91) and ischemic injury (P=0.005). We found a moderate correlation between serum creatine kinase levels and serum creatinine levels (R=0.57; P<0.0001). The correlation coefficient (R) between serum creatine kinase levels and the estimated creatinine clearance rate was -0.45. Rhabdomyolysis was a predisposing factor for acute kidney injury (P=0.011; odds ratio, 8.68). Four patients with rhabdomyolysis required a short period of renal replacement therapy. CONCLUSION: A high percentage of patients with traumatic compartment syndrome developed rhabdomyolysis (44.2%). Patients with rhabdomyolysis had a higher possibility of developing acute kidney injury (39.1%), and rhabdomyolysis was correlated to renal function. Early diagnosis, frequent monitoring, and aggressive treatment are suggested once compartment syndrome is suspected. The overall prognosis is good with early diagnosis and proper treatment. PMID- 25785381 TI - Professionalism in plastic surgery: attitudes, knowledge, and behaviors in medical students compared to surgeons in training and practice--one, but not the same. AB - INTRODUCTION: Professionalism is now recognized as a core competency of surgical education and is required for certification and licensure. However, best teaching methods remain elusive, because (1) ethical standards are not absolute, and (2) learning and teaching styles vary considerably-both of which are influenced by cultural and generational forces. We sought to compare attitudes, knowledge, and behaviors in fourth year medical students, compared to surgeons in training and practice, focusing on issues related to professionalism in plastic surgery. METHODS: Fourth year medical students participating in a capstone course (n = 160), surgical residents (n = 219), and attending surgeons (n = 99) at a single institution were asked to complete a questionnaire regarding surgical professionalism. Participants (1) identified components of professionalism, (2) cited examples of unprofessional behavior, (3) ranked the egregiousness of 30 scenarios, and (4) indicated best educational practices. Cohorts were compared using t test and chi, with statistical significance assigned to P values less than 0.05. RESULTS: Compared to surgeons in training or practice, medical students were younger (27.8 vs 38.0 years, P < 0.001) and more often female (51.1% vs 36.6%, P < 0.03). Both groups cited "a body of ethics" as the defining component of professionalism. Respondents from both groups agreed that professionalism could be taught, learned, and assessed. Surgeons (94.3%) had observed unprofessional behavior, as did 88.0% of students; "poor anger management," "dishonesty," and "bullying" were the most common examples. Compared to students, however, surgeons were more likely to witness substance and physical abuse (P < 0.05). From the list of 30 scenarios, both groups picked the following as the most egregious, although in different order: working while impaired, fraudulent billing, dating a patient, lying on rounds, self-prescribing, and sexual harassment. Both students and surgeons agreed that the following scenarios were unethical: "fraudulent billing while on a mission trip" (84% vs 90%, NS), "showing inaccurate preop/postop photos" (70% vs 75%, NS), and "failing to disclose a conflict of interest" (56% vs 57%). Students and surgeons disagreed that the following scenarios were egregious: "owning biotech stock in a company whose product the surgeon uses" (33% vs 13%, P < 0.01), and "offering a breast augmentation as part of a charity raffle" (45% vs 58%, P < 0.05). Both students and surgeons agreed "advertising on a highway billboard was NOT unprofessional (87% vs 85%, NS). CONCLUSIONS: Despite differences in age and sex, medical students and surgeons have similar attitudes about professionalism in plastic surgery, but differ in their knowledge and observations. Understanding cultural and generational factors may help educators teach and model cognitive and behavioral aspects of professionalism. The fact that some clearly egregious behaviors are not viewed as unethical by individual students, trainees, and surgeons, and that such behavior continues to be observed, indicates the need to improve our efforts in promoting professionalism in plastic surgery. PMID- 25785382 TI - What Is the Ideal Free Flap for Soft Tissue Reconstruction? A Ten-Year Experience of Microsurgical Reconstruction Using 334 Latissimus Dorsi Flaps From a Universal Donor Site. AB - Microsurgical free tissue transfer is regarded as the best available method of tissue reconstruction for intractable defects. The ideal soft tissue flap is thought to be the anterolateral thigh flap. On the basis of 334 procedures involving the latissimus dorsi (LD) flap, we discuss the advantages of the LD flap over the current universal option, and we aimed to establish whether the LD could also gain universal status in all reconstructive fields.Three hundred thirty-four reconstructive procedures using the LD flap were performed in 322 patients between September 2002 and July 2012. In accordance with defect characteristics, we performed 334 procedures using flaps, which included the LD muscle flap with skin graft, the myocutaneous flap, the muscle-sparing flap, the perforator flap, the chimeric flap, and the 2-flap technique using the serratus anterior branch.Flap-related complications occurred in 21 patients (6.3%), including total and partial flap failure. In 253 cases, the donor site was closed primarily, and in the remaining cases, we used split-thickness skin grafts. Donor site complications occurred in 20 cases (6%). In 11 of the 182 cases, no suitable perforators were identified during surgery.The advantages of the LD as a donor site include the possibility of various harvesting positions without position change, versatility of components, availability of muscle to fill extensive defects, and presence of thick fascia to enable full abdominal reconstruction. On the basis of our experience, we concluded that this flap has the potential to be used as widely as, or in preference to, the anterolateral thigh flap in most reconstructive areas. PMID- 25785383 TI - Herpes simplex 1 stomatitis after cleft palate repair: a case report and guidelines for management. AB - Herpes simplex virus (HSV) primary infection and reactivation has been associated with the inflammation and transient decrease in immunocompetence after surgery and local trauma. In addition, HSV infection is known to impair wound healing, increase risk of scarring, and impede connective tissue graft transplantation. To our knowledge, this is the first case of HSV infection complicating cleft palate repair presented in literature. In this report, we present a case of primary HSV infection occurring in a healthy 26-month-old patient after repair of the secondary cleft palate with mucoperichondrial flaps and V-Y pushback. The patient developed high fever on postoperative day 1, which was followed by perioral vesicular lesions and multiple intraoral ulcerations involving the lips, palate, and posterior pharynx. Unknown to the surgeons, the patient was exposed to HSV before surgery by a sibling with orolabial HSV infection. The infective cause was ascertained via polymerase chain reaction for HSV-1 DNA, and the infection was treated with topical and intravenous acyclovir for 1 week. The patient recovered well with adequate flap healing, good aesthetic outcome, and no complications on 1-month follow-up. This report underscores the importance of prompt recognition of herpetic infections in the patient with craniofacial surgery and reviews the association and complications of HSV infection in surgical healing. Early identification with prompt antiviral therapy and meticulous wound care are essential to ameliorate the scarring and delayed wound healing associated with HSV infection. PMID- 25785384 TI - Palliative reconstructive surgery may improve quality of life in high functioning noncurable head and neck oncologic patients. AB - BACKGROUND: Treatment recommendations for palliative patients are guided by functional status and individual needs. The projected success of palliative procedures relies on estimating the risk: benefit ratio, which weighs the expected improvement in life quality to the frailty, metabolic status, and the individual's ability to heal after surgery. Terminal patients have less time in which to judge outcomes; therefore, the timeframe in which we assess these metrics should be modified according to prognosis. We emphasize efficiency over simplicity for reconstructive palliative surgery. METHODS: We reviewed the literature and supply a representative case to contribute our experiences for the palliative reconstructive surgeon to use in the evaluation and treatment of incurable patients. RESULTS: Palliative reconstructive surgery carries higher perioperative risk than standard reconstructive surgery; however, aggressive surgical management can improve quality of life. We find the Palliative Performance Scale-a functional, prognostic tool-to be a helpful metric for preoperative evaluation. CONCLUSIONS: Reconstructive palliative surgery can improve quality of life in dying patients (ie, pain, wound hygiene, and so on) and may even improve survival. We advocate prioritizing efficiency in completing the reconstructive process, which may not be the simplest or least invasive. PMID- 25785385 TI - Surgical Treatment of Angiosarcoma of the Scalp With Superficial Parotidectomy. PMID- 25785386 TI - Patient access in plastic surgery: an operational and financial analysis of service-based interventions to improve ambulatory throughput in an academic surgery practice. AB - INTRODUCTION: Inefficient patient throughput in a surgery practice can result in extended new patient backlogs, excessively long cycle times in the outpatient clinics, poor patient satisfaction, decreased physician productivity, and loss of potential revenue. This project assesses the efficacy of multiple throughput interventions in an academic, plastic surgery practice at a public university. METHODS: We implemented a Patient Access and Efficiency (PAcE) initiative, funded and sponsored by our health care system, to improve patient throughput in the outpatient surgery clinic. Interventions included: (1) creation of a multidisciplinary team, led by a project redesign manager, that met weekly; (2) definition of goals, metrics, and target outcomes; 3) revision of clinic templates to reflect actual demand; 4) working down patient backlog through group visits; 5) booking new patients across entire practice; 6) assigning a physician's assistant to the preoperative clinic; and 7) designating a central scheduler to coordinate flow of information. Main outcome measures included: patient satisfaction using Press-Ganey surveys; complaints reported to patient relations; time to third available appointment; size of patient backlog; monthly clinic volumes with utilization rates and supply/demand curves; "chaos" rate (cancellations plus reschedules, divided by supply, within 48 hours of booked clinic date); patient cycle times with bottleneck analysis; physician productivity measured by work Relative Value Units (wRVUs); and downstream financial effects on billing, collection, accounts receivable (A/R), and payer mix. We collected, managed, and analyzed the data prospectively, comparing the pre-PAcE period (6 months) with the PAcE period (6 months). RESULTS: The PAcE initiative resulted in multiple improvements across the entire plastic surgery practice. Patient satisfaction increased only slightly from 88.5% to 90.0%, but the quarterly number of complaints notably declined from 17 to 9. Time to third available new patient appointment dropped from 52 to 38 days, whereas the same metric for a preoperative appointment plunged from 46 to 16 days. The size of the new patient backlog fell from 169 to 110 patients, and total monthly clinic volume climbed from 574 to 766 patients. Our "chaos" rate dropped from 12.3% to 1.8%. Mean patient cycle time in the clinic decreased dramatically from 127 to 44 minutes. Mean monthly productivity for the practice increased from 2479 to 2702 RVUs. Although our collection rate did not change, days in A/R dropped from 66 to 57 days. Mean monthly charges increased from U.S. $535,213 to U.S. $583,193, and mean monthly collections improved from U.S. $181,967 to U.S. $210,987. Payer mix remained unchanged. CONCLUSIONS: Implementation of a PAcE initiative, focusing on outpatient clinic throughput, yields significant improvements in access to care, patient satisfaction as measured by complaints, physician productivity, and financial performance. An academic, university-based, plastic surgery practice can use throughput interventions to deliver timely care and to enhance financial viability. PMID- 25785387 TI - Temporary Relocation of the Testes in Anteromedial Thigh Pouches Facilitates Delayed Primary Scrotal Wound Closure in Fournier Gangrene With Extensive Loss of Scrotal Skin-Experience With 12 Cases. AB - AIMS AND OBJECTIVES: To share our experience on the use of temporary testicular thigh pouches to facilitate scrotal wound closure in Fournier gangrene with extensive loss of scrotal skin. PATIENTS AND METHODS: Patients seen over a 10 year period who had extensive (>50%) loss of scrotal skin precluding delayed primary closure of the residual scrotal skin over the testes were documented. Patients had serial debridement as required with scrotal wound dressing until healthy granulation tissue was achieved. The testes were placed temporarily in anteromedial thigh pouches to allow for scrotal wound closure. In the postoperative period, the testes were gradually massaged back into the residual scrotal pouch, thus acting as natural tissue expanders. RESULTS: Mean patient age was 38.1 +/- 10.0 years. Mean duration of admission was 24.4 +/- 4.7 days. Identified predisposing factors were ischiorectal fossa abscess in 2 patients and urethral stricture in 1 patient. The rest were idiopathic. Mean Fournier gangrene severity index was 6.0 +/- 1.3. Mean number of debridements was 2.3 +/- 0.5. There was no mortality. The residual scrotal pouches expanded sufficiently over time (3-8 months) to accommodate the testes. Normal testicular volume was maintained in all patients. Mean testicular volume was 19.0 +/- 3.2 cm. Follow-up was for 14.8 +/- 9.7 months. CONCLUSIONS: Temporarily relocating the testes in anteromedial thigh pouches facilitates scrotal wound closure in Fournier gangrene with extensive loss of scrotal skin and obviates the need for specialized reconstructive surgery. PMID- 25785388 TI - Stuck in a moment: an ex ante analysis of patient complaints in plastic surgery, used to predict malpractice risk profiles, from a large cohort of physicians in the patient advocacy reporting system. AB - INTRODUCTION: Unsolicited patient complaints (UPCs) serve as a powerful predictor of increased risk of malpractice claims, and reductions in UPCs, through targeted physician interventions, lower incidence of lawsuits and decrease cost of risk management. We analyzed UPCs, verified by trained counselors in patient relations, to determine the malpractice risk of plastic surgeons, compared to dermatologists, all surgeons, and all physicians, from a national patient complaint registry. METHODS: We examined the patient complaint profiles and risk scores of 31,077 physicians (3935 surgeons, 338 plastic and reconstructive surgeons, and 519 dermatologists), who participated in the Patient Advocacy Reporting System, a national registry of UPCs. Patient complaint data were collected from 70 community and academic hospitals across 29 states, from 2009 to 2012. In addition to determining the specific complaint mix for plastic surgery compared to all physicians, each physician was assigned a patient complaint risk score, based on a proprietary weighted-sum algorithm, with a score higher than 70, indicative of high risk for malpractice claims. Patient complaint profiles and risk scores were compared between all groups, using Wilcoxon rank and chi analysis. P values less than 0.05 were assigned statistical significance. RESULTS: Over this 4-year period, the majority of plastic surgeons (50.8%) did not generate any patient complaints, but those who did received an average of 9.8 complaints from 4.8 patients. The percentage of physicians at high risk for malpractice claims, based upon the Patient Advocacy Reporting System index score of patient complaints, was as follows: all physicians, 2.0%; all surgeons, 4.1%; plastic and reconstructive surgeons, 2.4%; dermatologists, 1.4%. Physicians (from 2012 only) who were identified by their sponsoring institutions as "reconstructive" plastic surgeons (n = 41) were 5 times as likely to have a high risk score, compared to physicians who were identified as "plastic" surgeons (n = 233), and were more likely to practice within an academic health care system that had a level 1 trauma center and a plastic surgery residency program. The overall mix of patient complaints from plastic and reconstructive surgeons was nearly the same as the national cohort of all physicians: care and treatment, 49%; communication, 19%; accessibility and availability, 14%; money or payment issues, 9%; and concern for patient/family, 9%. CONCLUSIONS: "Reconstructive" plastic surgeons are at increased risk for UPCs, compared to most physicians, especially dermatologists. Because UPCs are a robust proxy for malpractice risk, targeted interventions to decrease patient complaints may improve patient satisfaction and reduce malpractice claims and risk management activity. Monitoring UPCs may permit early identification of high-risk surgeons before malpractice claims accumulate. PMID- 25785389 TI - Lymph node flap based on the right transverse cervical artery as a donor site for lymph node transfer: reply. PMID- 25785390 TI - Self-Inflicted Burns in Soldiers: The Singapore Experience. PMID- 25785391 TI - Accessibility of Academic Plastic Surgeons as Mentors to Medical Students. PMID- 25785392 TI - Oral bioavailability and pharmacodynamic activity of hesperetin nanocrystals generated using a novel bottom-up technology. AB - In the present study, nanocrystalline solid dispersion (NSD) was developed to enhance the release rate and oral bioavailability of hesperetin (HRN). NSD of HRN was prepared using a novel bottom-up technology platform. It is a spray drying based technology to generate solid particles, containing drug nanocrystals dispersed in small molecule excipients. HRN and mannitol were used in a 5:5 ratio, and an average crystallite size of HRN in NSD with mannitol was found to be 137.3 +/- 90.0 nm. An in vitro release study revealed a statistically significant release rate enhancement for HRN nanocrystals (46.3 MUg/mL/min) as compared to that of the control (29.5 MUg/mL/min). Further, a comparative oral bioavailability study of NSD and control in Sprague-Dawley rats established significant improvement in Cmax and oral bioavailability (AUC0-infinity) by 1.79- and 2.25-fold, respectively, for HRN nanocrystals. The findings of oral bioavailability were corroborated by intestinal uptake and Caco-2 cell uptake studies, wherein HRN, when administered in nanocrystalline form, showed higher penetration in intestinal mucosa and higher uptake in Caco-2 cells. Finally, the therapeutic efficacy of HRN nanocrystals was tested by a reactive oxygen species (ROS) generation assay and carrageenan induced anti-inflammatory model. HRN nanocrystals markedly inhibited ROS generation in MCF-7 cells, and carrageenan induced inflammation in rats. The process of NSD formation was found to be based on classical nucleation theory wherein mannitol contributed to NSD formation by acting as a plasticizer and crystallization inducer, and by providing sites for heterogeneous nucleation/crystallization. PMID- 25785395 TI - Vibrational properties of Ti3C2 and Ti3C2T2 (T = O, F, OH) monosheets by first principles calculations: a comparative study. AB - We present a comparative study on the static and dynamical properties of bare Ti3C2 and T-terminated Ti3C2T2 (T = O, F, OH) monosheets using density functional theory calculations. First, the crystal structures are optimized to be of trigonal configurations (P3[combining macron]m1), which are thermodynamically and dynamically stable. It is demonstrated that the terminations modulate the crystal structures through valence electron density redistribution of the atoms, particularly surface Ti (Ti2) in the monosheets. Second, lattice dynamical properties including phonon dispersion and partial density of states (PDOS) are investigated. Phonon PDOS analysis shows a clear collaborative feature in the vibrations, reflecting the covalent nature of corresponding bonds in the monosheets. In the bare Ti3C2 monosheet, there is a phonon band gap between 400 and 500 cm(-1), while it disappears in Ti3C2O2 and Ti3C2(OH)2 as the vibrations associated with the terminal atoms (O and OH) bridge the gap. Third, both Raman (Eg and A1g) and infrared-active (Eu and A2u) vibrational modes are predicted and conclusively assigned. A comparative study indicates that the terminal atoms remarkably influence the vibrational frequencies. Generally, the terminal atoms weaken the vibrations in which surface Ti atoms are involved while strengthening the out-of-plane vibration of C atoms. Temperature-dependent micro Raman measurements agree with the theoretical prediction if the complexity in the experimentally obtained lamellae for the Raman study is taken into account. PMID- 25785393 TI - A passive heat maintenance strategy implemented during a simulated half-time improves lower body power output and repeated sprint ability in professional Rugby Union players. AB - Reduced physical performance has been observed following the half-time period in team sports players, likely due to a decrease in muscle temperature during this period. We examined the effects of a passive heat maintenance strategy employed between successive exercise bouts on core temperature (Tcore) and subsequent exercise performance. Eighteen professional Rugby Union players completed this randomised and counter-balanced study. After a standardised warm-up (WU) and 15 min of rest, players completed a repeated sprint test (RSSA 1) and countermovement jumps (CMJ). Thereafter, in normal training attire (Control) or a survival jacket (Passive), players rested for a further 15 min (simulating a typical half-time) before performing a second RSSA (RSSA 2) and CMJ's. Measurements of Tcore were taken at baseline, post-WU, pre-RSSA 1, post-RSSA 1 and pre-RSSA 2. Peak power output (PPO) and repeated sprint ability was assessed before and after the simulated half-time. Similar Tcore responses were observed between conditions at baseline (Control: 37.06+/-0.05 degrees C; Passive: 37.03+/ 0.05 degrees C) and for all other Tcore measurements taken before half-time. After the simulated half-time, the decline in Tcore was lower (-0.74+/-0.08% vs. 1.54+/-0.06%, p<0.001) and PPO was higher (5610+/-105 W vs. 5440+/-105 W, p<0.001) in the Passive versus Control condition. The decline in PPO over half time was related to the decline in Tcore (r = 0.632, p = 0.005). In RSSA 2, best, mean and total sprint times were 1.39+/-0.17% (p<0.001), 0.55+/-0.06% (p<0.001) and 0.55+/-0.06% (p<0.001) faster for Passive versus Control. Passive heat maintenance reduced declines in Tcore that were observed during a simulated half time period and improved subsequent PPO and repeated sprint ability in professional Rugby Union players. PMID- 25785396 TI - Contact charge electrophoresis: experiment and theory. AB - Contact charge electrophoresis (CCEP) uses steady electric fields to drive the continuous, oscillatory motion of conductive particles and droplets between two or more electrodes. These rapid oscillations can be rectified to direct the motion of objects within microfluidic environments using low-power, dc voltage. Here, we compare high precision experimental measurements of CCEP within a microfluidic system to equally detailed theoretical predictions on the motion of a conductive particle between parallel electrodes. We use a simple, capillary microfluidic platform that combines high-speed imaging with precision electrical measurements to enable the synchronized acquisition of both the particle location and the electric current due to particle motion. The experimental results are compared to those of a theoretical model, which relies on a Stokesian dynamics approach to accurately describe both the electrostatic and hydrodynamic problems governing particle motion. We find remarkable agreement between theory and experiment, suggesting that particle motion can be accurately captured by a combination of classical electrostatics and low-Reynolds number hydrodynamics. Building on this agreement, we offer new insight into the charge transfer process that occurs when the particle nears contact with an electrode surface. In particular, we find that the particle does not make mechanical contact with the electrode but rather that charge transfer occurs at finite surface separations of >0.1 MUm by means of an electric discharge through a thin lubricating film. We discuss the implications of these findings on the charging of the particle and its subsequent dynamics. PMID- 25785397 TI - Deep-red emissive crescent-shaped fluorescent dyes: substituent effect on live cell imaging. AB - A series of crescent-shaped fluorescent dyes (CP1-CP6) were synthesized by hybridizing coumarin and pyronin moieties with different amino substituents at both ends. The molecular structures and photophysical properties of these fluorescent dyes were investigated through X-ray diffraction, absorption spectroscopy, and fluorescence spectroscopy. Results show that the fluorescent dyes exhibited crescent-shaped structures, deep-red emissions (approximately 650 nm), and significant Stokes shifts. In live-cell-imaging experiments, CP1 stains mitochondria, whereas CP3 and CP6 stain the lysosomes in a cytoplasm and the RNA in nucleoli. The relationships between different amino substituent groups and the imaging properties of CP dyes were discussed as well. Additionally, findings from the cytotoxicity and photostability experiments on living cells indicated the favorable biocompatibility and high photostability of the CP dyes. PMID- 25785398 TI - The nurse's role in medication safety. PMID- 25785399 TI - Support for the family of a patient in crisis. PMID- 25785402 TI - Dying in America: a nursing response to the IOM's call to action. PMID- 25785403 TI - Assessing accurate BP measurement: size and technique matter! PMID- 25785404 TI - Prepping for NCLEX? Eight tips to get you started. PMID- 25785405 TI - Informatics leadership: the role of the CNIO. PMID- 25785409 TI - Unmasking Moebius syndrome. PMID- 25785410 TI - Driving Miss (or Mr.) Daisy. PMID- 25785411 TI - Finding peace in Monet's gardens. PMID- 25785412 TI - Measles: what you need to know. PMID- 25785413 TI - Sidestep the perils of PCA in post-op patients. PMID- 25785415 TI - Long-term quality of life and risk factors for recurrence after laparoscopic repair of paraesophageal hernia. AB - IMPORTANCE: Laparoscopic repair of paraesophageal hernia (PEH) has been shown to result in excellent relief of symptoms and improved quality of life (QOL) despite a relatively high radiographically identified recurrence rate. OBJECTIVE: To assess potential risk factors for recurrence and long-term change in QOL after laparoscopic repair of PEH. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective study of 111 patients who underwent elective laparoscopic repair of type III PEH with biological mesh buttressed over a primary cruroplasty from April 3, 2009, through July 31, 2014, at the Department of Surgery, Johns Hopkins University of Medicine. We administered a modified version of a validated gastroesophageal reflux disease-specific QOL tool to patients before and at 2, 12, and 36 months after the procedure. Higher QOL scores represent greater severity of symptoms. An upper gastrointestinal tract barium-contrast radiographic examination was performed at 1 year to assess for recurrence. Demographic factors, comorbidities, and preoperative radiographic findings were analyzed as possible indicators for recurrence using logistic regression. MAIN OUTCOMES AND MEASURES: Quality of life, measured by the gastroesophageal reflux disease-specific QOL tool, and recurrence, defined as a PEH of greater than 2 cm. RESULTS: Median patient age was 61 years, 63.1% of patients were women, and 81.1% of patients were white. Four patients required reoperation, of which only 1 was for symptomatic recurrent PEH. The mean follow-up time for the 36-month QOL assessment was 43.5 months. The overall preoperative and 2-, 12-, and 36-month QOL scores were 28.50, 10.18, 9.74, and 10.58, respectively (P < .001). Recurrences were found in 19 of the 70 patients (27%) who completed the 1-year radiographic examination. Compared with baseline, all individual symptoms improved significantly except for early satiety (mean [SD] score, 3.18 [1.88] at baseline vs 2.07 [1.70] at the 36-month follow-up; P = .07), nausea (1.69 [1.63] vs 0.77 [1.25]; P = .08), pain with swallowing (1.06 [1.50] vs 0.53 [0.90]; P = .73), and bloating/gas (3.28 [1.71] vs 2.23 [1.72]; P = .05) at the 36-month QOL assessment. Although not statistically significant, preoperative hernias containing most of the stomach were more likely to recur after repair when compared with those involving gastric cardia and fundus (odds ratio, 3.74 [95% CI, 0.93-15.14]; P = .06). CONCLUSIONS AND RELEVANCE: Overall, laparoscopic repair of PEH with biological mesh results in excellent long-term QOL. The cause of recurrence is likely multifactorial and individualized to each patient. Further evaluation of novel techniques and unidentified patient factors is needed. PMID- 25785416 TI - Double-blind peer review. PMID- 25785419 TI - Viral mechanisms: Tat modulates DAT. PMID- 25785424 TI - Photosynthesis: Dissipating energy by carotenoids. PMID- 25785425 TI - Carbohydrates: Translation from sticky to sweet. PMID- 25785426 TI - GPCRs: Heterodimer-specific signaling. PMID- 25785428 TI - Erratum: Chemical biologists rush to San Francisco for the ICBS. PMID- 25785429 TI - Corrigendum: Arginine-rhamnosylation as new strategy to activate translation elongation factor P. PMID- 25785427 TI - Regulation of the oncoprotein Smoothened by small molecules. AB - The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein-coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO. PMID- 25785430 TI - Erratum: Coordinated gripping of substrate by subunits of an AAA+ proteolytic machine. PMID- 25785431 TI - Corrigendum: Chemical biologists rush to San Francisco for the ICBS. PMID- 25785432 TI - Isolation of lactic acid bacteria from pao cai, a Chinese traditional fermented vegetable, with inhibitory activity against Salmonella associated with fresh-cut apple, using a modelling study. AB - AIMS: To isolate lactic acid bacteria (LAB) from pao cai, a Chinese traditional fermented vegetable, with outstanding inhibitory activity against Salmonella inoculated on fresh-cut apple, using a modelling method. METHODS AND RESULTS: Four kinds of pao cai were selected. A total of 122 isolates exhibited typical LAB characteristics: Gram-positive and catalase negative, among which 104 (85.24%) colonies showed antibacterial activity against Salmonella by the well diffusion assay. Four colonies showing maximum antibacterial radius against Salmonella were selected to co-inoculate with Salmonella on fresh-cut apple and stored at 10 degrees C, further identified as three strains of Lactobacillus plantarum and one strain of Lactobacillus brevis by 16s rRNA gene sequence analysis. The modified Gompertz model was employed to analyse the growth of the micro-organisms on apple wedges. Two of the four selected strains showed antagonistic activity against Salmonella on fresh-cut apple, one of which, RD1, exhibited best inhibitory activity (Salmonella were greatly inhibited when co inoculated with RD1 at 10 degrees C at 168 h). No deterioration in odour or appearance of the apple piece was observed by the triangle test when fresh-cut apple was inoculated with RD1. CONCLUSIONS: The mathematical modelling method is essential to select LAB with outstanding inhibitory activity against Salmonella associated with fresh-cut apple. LAB RD1 holds promise for the preservation of fresh-cut apple. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provided a new method on fresh-cut product preservation. Besides, to make the LAB isolating procedure a more correct one, this study first added the mathematical modelling method to the isolating procedure. PMID- 25785433 TI - Radiation dose to the heart in paediatric interventional cardiology. AB - Recent ICRP publications have reviewed evidence for induction of heart disease. Studies suggest the threshold dose to the heart may be as low as 500 mGy. Doses to the heart from paediatric interventional procedures performed in Glasgow between April 2012 and July 2013 to correct congenital heart defects were investigated to assess the level of potential risk of cardiovascular disease. For common procedures, doses were found to be typically less than 50 mGy, with the highest dose in the period for which data are available estimated to be 330 mGy. These results suggest that any increased risk due to paediatric interventional cardiology is likely to be small, but cumulative doses over a number of years could reach the threshold for effects. PMID- 25785434 TI - Within-host stochastic emergence dynamics of immune-escape mutants. AB - Predicting the emergence of new pathogenic strains is a key goal of evolutionary epidemiology. However, the majority of existing studies have focussed on emergence at the population level, and not within a host. In particular, the coexistence of pre-existing and mutated strains triggers a heightened immune response due to the larger total pathogen population; this feedback can smother mutated strains before they reach an ample size and establish. Here, we extend previous work for measuring emergence probabilities in non-equilibrium populations, to within-host models of acute infections. We create a mathematical model to investigate the emergence probability of a fitter strain if it mutates from a self-limiting strain that is guaranteed to go extinct in the long-term. We show that ongoing immune cell proliferation during the initial stages of infection causes a drastic reduction in the probability of emergence of mutated strains; we further outline how this effect can be accurately measured. Further analysis of the model shows that, in the short-term, mutant strains that enlarge their replication rate due to evolving an increased growth rate are more favoured than strains that suffer a lower immune-mediated death rate ('immune tolerance'), as the latter does not completely evade ongoing immune proliferation due to inter parasitic competition. We end by discussing the model in relation to within-host evolution of human pathogens (including HIV, hepatitis C virus, and cancer), and how ongoing immune growth can affect their evolutionary dynamics. PMID- 25785435 TI - Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention deficit/hyperactivity disorder and their unaffected siblings. AB - IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (beta = -31.92; 95% CI, 52.69 to -11.16; P = .0027) and a 3% smaller total gray matter volume (beta = 22.51; 95% CI, -35.07 to -9.96; P = .0005), while total white matter volume was unaltered (beta = -10.10; 95% CI, -20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. CONCLUSIONS AND RELEVANCE: Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD. PMID- 25785436 TI - Dissociation of SHP-1 from spinophilin during platelet activation exposes an inhibitory binding site for protein phosphatase-1 (PP1). AB - We have recently shown that a critical regulatory node in the platelet signaling network lies immediately downstream of platelet receptors for thrombin and TxA2. This node is comprised of a scaffold protein (spinophilin, SPL), a protein tyrosine phosphatase (SHP-1), and either of the two members of the Regulators of G protein Signaling family predominantly expressed in platelets (RGS10 or RGS18). The SPL/RGS/SHP-1 complex is present in resting platelets, dissociating when thrombin or TxA2, but not ADP or collagen, activate SHP-1 and release RGS10 and RGS18 to dampen signaling. Here we demonstrate an additional regulatory role for spinophilin, showing that dissociation of SHP-1 from spinophilin is followed by an increase in the binding of spinophilin to PP1, a serine/threonine phosphatase whose binding site maps to a region close to the SHP-1 binding site. The increase in PP1 binding to spinophilin is limited to platelet agonists that cause dissociation of the complex and is selective for the alpha and gamma isoforms of PP1. Studies in cell culture show that SHP-1 and PP1 can compete for binding to spinophilin and that binding inhibits PP1 activity since over-expression of wild type spinophilin, but not spinophilin with a disabled PP1 binding site, causes an increase in the phosphorylation of myosin light chain, a well-characterized PP1 substrate. Collectively, these results indicate that in addition to regulating RGS protein availability in resting platelets, spinophilin can serve as a time dependent, agonist- and isoform-selective regulator of PP1, inhibiting its activity when decay of the SPL/RGS/SHP-1 complex releases SHP-1 from spinophilin, exposing a binding site for PP1. PMID- 25785437 TI - Biophysical induction of vascular smooth muscle cell podosomes. AB - Vascular smooth muscle cell (VSMC) migration and matrix degradation occurs with intimal hyperplasia associated with atherosclerosis, vascular injury, and restenosis. One proposed mechanism by which VSMCs degrade matrix is through the use of podosomes, transient actin-based structures that are thought to play a role in extracellular matrix degradation by creating localized sites of matrix metalloproteinase (MMP) secretion. To date, podosomes in VSMCs have largely been studied by stimulating cells with phorbol esters, such as phorbol 12,13 dibutyrate (PDBu), however little is known about the physiological cues that drive podosome formation. We present the first evidence that physiological, physical stimuli mimicking cues present within the microenvironment of diseased arteries can induce podosome formation in VSMCs. Both microtopographical cues and imposed pressure mimicking stage II hypertension induce podosome formation in A7R5 rat aortic smooth muscle cells. Moreover, wounding using a scratch assay induces podosomes at the leading edge of VSMCs. Notably the effect of each of these biophysical stimuli on podosome stimulation can be inhibited using a Src inhibitor. Together, these data indicate that physical cues can induce podosome formation in VSMCs. PMID- 25785438 TI - Direct determination of phosphatase activity from physiological substrates in cells. AB - A direct and continuous approach to determine simultaneously protein and phosphate concentrations in cells and kinetics of phosphate release from physiological substrates by cells without any labeling has been developed. Among the enzymes having a phosphatase activity, tissue non-specific alkaline phosphatase (TNAP) performs indispensable, multiple functions in humans. It is expressed in numerous tissues with high levels detected in bones, liver and neurons. It is absolutely required for bone mineralization and also necessary for neurotransmitter synthesis. We provided the proof of concept that infrared spectroscopy is a reliable assay to determine a phosphatase activity in the osteoblasts. For the first time, an overall specific phosphatase activity in cells was determined in a single step by measuring simultaneously protein and substrate concentrations. We found specific activities in osteoblast like cells amounting to 116 +/- 13 nmol min(-1) mg(-1) for PPi, to 56 +/- 11 nmol min(-1) mg(-1) for AMP, to 79 +/- 23 nmol min(-1) mg(-1) for beta-glycerophosphate and to 73 +/- 15 nmol min(-1) mg(-1) for 1-alpha-D glucose phosphate. The assay was also effective to monitor phosphatase activity in primary osteoblasts and in matrix vesicles. The use of levamisole--a TNAP inhibitor--served to demonstrate that a part of the phosphatase activity originated from this enzyme. An IC50 value of 1.16 +/- 0.03 mM was obtained for the inhibition of phosphatase activity of levamisole in osteoblast like cells. The infrared assay could be extended to determine any type of phosphatase activity in other cells. It may serve as a metabolomic tool to monitor an overall phosphatase activity including acid phosphatases or other related enzymes. PMID- 25785439 TI - Ecological and sociodemographic determinants of house infestation by Triatoma infestans in indigenous communities of the Argentine Chaco. AB - BACKGROUND: The Gran Chaco ecoregion, a hotspot for Chagas and other neglected tropical diseases, is home to >20 indigenous peoples. Our objective was to identify the main ecological and sociodemographic determinants of house infestation and abundance of Triatoma infestans in traditional Qom populations including a Creole minority in Pampa del Indio, northeastern Argentina. METHODS: A cross-sectional survey determined house infestation by timed-manual searches with a dislodging aerosol in 386 inhabited houses and administered questionnaires on selected variables before full-coverage insecticide spraying and annual vector surveillance. We fitted generalized linear models to two global models of domestic infestation and bug abundance, and estimated coefficients via multimodel inference with model averaging. PRINCIPAL FINDINGS: Most Qom households were larger and lived in small-sized, recently-built, precarious houses with fewer peridomestic structures, and fewer livestock and poultry than Creoles'. Qom households had lower educational level and unexpectedly high residential mobility. House infestation (31.9%) was much lower than expected from lack of recent insecticide spraying campaigns and was spatially aggregated. Nearly half of the infested houses examined had infected vectors. Qom households had higher prevalence of domestic infestation (29.2%) than Creoles' (10.0%), although there is large uncertainty around the adjusted OR. Factors with high relative importance for domestic infestation and/or bug abundance were refuge availability, distance to the nearest infested house, domestic insecticide use, indoor presence of poultry, residential overcrowding, and household educational level. CONCLUSIONS AND SIGNIFICANCE: Our study highlights the importance of sociodemographic determinants of domestic infestation such as overcrowding, education and proximity to the nearest infested house, and corroborates the role of refuge availability, domestic use of insecticides and household size. These factors may be used for designing improved interventions for sustainable disease control and risk stratification. Housing instability, household mobility and migration patterns are key to understanding the process of house (re)infestation in the Gran Chaco. PMID- 25785440 TI - Staple foods consumption and irritable bowel syndrome in Japanese adults: a cross sectional study. AB - BACKGROUND: Carbohydrates can cause gastrointestinal symptoms due to incomplete absorption in the small bowel. Thus, high-carbohydrate diets may induce symptoms of irritable bowel syndrome (IBS). OBJECTIVE: This observational and cross sectional study assessed the association between consumption of several carbohydrate-enriched staple foods, such as rice, Japanese wheat noodles, Chinese noodles, bread, pasta, and buckwheat noodles, and the prevalence of IBS in Japanese adults. SUBJECTS AND METHODS: One thousand and eighty-two (837 men) Japanese adult employees aged 19-85 were included in this cross-sectional study conducted in 2011. IBS diagnosis was based on the Rome III criteria. Consumption of staple foods was assessed using a brief self-administered diet history questionnaire, and divided into three categories (low, middle, high) depending on their distribution. RESULTS: In the multivariate analysis, daily consumption of rice (odds ratios [ORs] and [95% confidence interval (CI)]: middle, 1.36 [0.93 1.99]; high, 1.67 [1.12-2.49]; P for trend = 0.01), bread (middle, 1.88 [1.28 2.75]; high, 1.63 [1.10-2.41]; P for trend = 0.01), pasta (middle, 1.47 [1.01 2.15]; high, 1.68 [1.12-2.52]; P for trend = 0.01), and buckwheat noodles (middle, 1.76 [1.18-2.61]; high, 1.98 [1.31-3.00]; P for trend = 0.001) were associated with higher prevalence of IBS after adjustment for socio-demographic, anthropometric, and lifestyle-related factors. Buckwheat noodles, but not other staple foods, retained an association with the prevalence of IBS even after adjustment for daily intake of carbohydrates or plant proteins. CONCLUSIONS: This cross-sectional study demonstrated that the consumption of staple foods, such as rice, bread, pasta, and buckwheat noodles is associated with the prevalence of IBS. Of these, the consumption of buckwheat noodles, but not other staple foods, is associated with IBS independent of carbohydrate or plant protein contents. PMID- 25785442 TI - Correction: Predicting epileptic seizures in advance. PMID- 25785441 TI - The hypolipidemic and pleiotropic effects of rosuvastatin are not enhanced by its association with zinc and selenium supplementation in coronary artery disease patients: a double blind randomized controlled study. AB - OBJECTIVE: Statins treatment may modify the levels of zinc and selenium, minerals that can improve vascular function and reduce oxidative damage and inflammation in atherosclerotic patients. This study aimed to evaluate the effects of rosuvastatin, alone or associated with zinc and selenium supplementation, on lipid profile, antioxidant enzymes and mineral status in coronary artery disease patients. MATERIAL AND METHODS: A double-blind randomized clinical trial was performed in which patients (n = 76) were treated with 10 mg rosuvastatin over 4 months associated or not with zinc (30 mg/d) and selenium (150 MUg/d) supplementation. The following parameters were analyzed before and after the intervention: anthropometric measurements, lipid profile, high sensitivity C reactive protein (hs-CRP), electronegative low density lipoprotein (LDL(-)) concentrations, activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), zinc and selenium concentrations in blood plasma and erythocytes. Significance was determined using an alpha of 5% (two-tailed). RESULTS: We found that rosuvastatin therapy was efficient in reducing total cholesterol, LDL cholesterol, non-HDL cholesterol, triglycerides, and hs-CRP independently of mineral supplementation. Neither treatment was associated with significant changes in LDL(-). Similarly, the antioxidant enzymes GPx and SOD activity were unchanged by treatments. Neither treatment was associated with significant differences in concentrations of zinc or selenium in blood plasma and erythocytes of studied groups. CONCLUSION: Rosuvastatin treatment did not affect zinc and selenium levels in coronary artery disease patients. The zinc and selenium supplementation at doses used in this study did not change lipid profile or SOD and GPx activity in patients receiving rosuvastatin. Further studies should be focused on testing alternative doses and supplements in different populations to contribute for a consensus on the ideal choice of antioxidants to be used as possible complementary therapies in atherosclerotic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01547377. PMID- 25785443 TI - The inhibitory effect of the hepatitis B virus singly-spliced RNA-encoded p21.5 protein on HBV nucleocapsid formation. AB - Hepatitis B virus (HBV) is the smallest DNA virus and the major cause of acute and chronic hepatitis. The 3.2 kb HBV viral genome generates four major species of unspliced viral transcript as well as several alternatively spliced RNAs. A 2.2 kb singly-spliced RNA is the most abundant spliced RNA and is widely expressed among all HBV genotypes. The expression of the singly-spliced RNA, as well as that of its encoded protein HBSP, is strongly associated with hepatopathology during HBV infection. Here, we report a novel inhibitory role of a p21.5 protein, which is encoded by a 2.2 kb singly-spliced RNA, in the modulation of HBV replication. We show that overexpression of the singly-spliced RNA is able to efficiently inhibit HBV replication. Furthermore, a mutation in the ATG start codon of the precore region completely abolishes the inhibitory effect of the singly-spliced RNA, indicating that a viral protein (p21.5) derived from the singly-spliced RNA is the mediator of the inhibition. Furthermore, p21.5 is able to form a homodimer that interacts with core dimers forming hybrid viral assembly components. Sucrose gradient fractionation revealed that co-expression of p21.5 resulted in a spread distribution pattern of core proteins ranging from low to high sucrose densities. When compared with p22, p21.5 is almost ten times more efficient at destabilizing HBV nucleocapsid assembly in Huh7 cells overexpressing either p21.5 or p22 protein. Moreover, in vivo expression of p21.5 protein by tail vein injection was found to decrease the amount of nucleocapsid in the livers of HBV-expressing BALB/c mice. In conclusion, our study reveals that the HBV 2.2 kb singly-spliced RNA encodes a 21.5 kDa viral protein that significantly interferes with the assembly of nucleocapsids during HBV nucleocapsid formation. These findings provide a possible strategy for elimination of HBV particles inside cells. PMID- 25785445 TI - Combined antigen-specific interferon-gamma and interleukin-2 release assay (FluoroSpot) for the diagnosis of Mycobacterium tuberculosis infection. AB - BACKGROUND: To evaluate interleukin (IL)-2 and interferon (IFN)-gamma secreting T cells in parallel for the differentiation of latent infection with Mycobacterium tuberculosis infection (LTBI) from active tuberculosis. METHODS: Following ex vivo stimulation of peripheral blood mononuclear cells (PBMC) with M. tuberculosis-specific antigens early secretory antigenic target (ESAT)-6 and culture filtrate protein (CFP)-10, immune responses were assessed by enzyme linked immunospot IFN-gamma release assay (EliSpot-IGRA) and a novel dual cytokine detecting fluorescence-linked immunospot (FluoroSpot) in 18 patients with pulmonary tuberculosis, 10 persons with previously cured tuberculosis, 25 individuals with LTBI and 16 healthy controls. RESULTS: Correlation of IFN-gamma+ spot-forming cells in EliSpot-IGRA and FluoroSpot were R2 = 0.67 for ESAT-6 and R2 = 0.73 for CFP-10. The number of IL-2- IFN-gamma+ producing cells was higher in patients with tuberculosis compared with past tuberculosis (CFP-10-induced p = 0.0068) or individuals with LTBI (ESAT-6-induced p = 0.0136). A cutoff value of >16 CFP-10-induced IFN-gamma+ secreting cells/200.000 PBMC in the EliSpot-IGRA discriminated with highest sensitivity and specificity (89% and 76%, respectively). However, overlap in cytokine responses precludes distinction between the cohorts on an individual basis. CONCLUSIONS: Combined analysis of IFN gamma and IL-2 secretion by antigen specific T-cells does not allow a reliable differentiation between different states of M. tuberculosis infection in clinical practice. PMID- 25785444 TI - Some like it fat: comparative ultrastructure of the embryo in two demosponges of the genus Mycale (order Poecilosclerida) from Antarctica and the Caribbean. AB - During embryogenesis, organisms with lecithotrophic indirect development usually accumulate large quantities of energetic reserves in the form of yolk that are necessary for larval survival. Since all sponges have lecithotrophic development, yolk formation is an ineludible step of their embryogenesis. Sponge yolk platelets have a wide range of morphological forms, from entirely lipid or protein platelets to a combined platelet showing both lipids and proteins and even glycogen. So far, there are no comparative studies on the nature and content of yolk in congeneric species of sponges inhabiting contrasting environments, which could have putative effects on the larval adaptation to environmental conditions. Here, we have taken advantage of the worldwide distribution of the sponge genus Mycale, in order to compare the embryogenesis and yolk formation in two species inhabiting contrasting latitudinal areas: M. acerata from Antarctic waters and M. laevis from the Caribbean. We have compared their brooded embryos and larvae using scanning and transmission electron microscopy, and calculated their energetic signatures based on the nature of their yolk. While the general morphological feature of embryos and larvae of both species were very similar, the main difference resided in the yolk nature. The Antarctic species, M. acerata, showed exclusively lipid yolk, whereas the Caribbean species, M. laevis, showed combined platelets of lipids and proteins and less frequently protein yolk platelets. The larvae of M. acerata were estimated to possess a two-fold energetic signature compared to that of M. laevis, which may have important ecological implications for their survival and for maintaining large population densities in the cold waters of the Southern Ocean. PMID- 25785446 TI - A single naturally occurring 2'-O-methylation converts a TLR7- and TLR8 activating RNA into a TLR8-specific ligand. AB - TLR7 and TLR8 recognize RNA from pathogens and lead to subsequent immune stimulation. Here we demonstrate that a single naturally occurring 2'-O methylation within a synthetic 18s rRNA derived RNA sequence prevents IFN-alpha production, however secretion of proinflammatory cytokines such as IL-6 is not impaired. By analysing TLR-deficient plasmacytoid dendritic cells and performing HEK293 genetic complementation assays we could demonstrate that the single 2'-O methylation containing RNA still activated TLR8 but not TLR7. Therefore this specific 2'-O-ribose methylation in rRNA converts a TLR7/TLR8 ligand to an exclusively TLR8-specific ligand. Interestingly, other modifications at this position such as 2'-O-deoxy or 2'-fluoro had no strong modulating effect on TLR7 or TLR8 activation suggesting an important role of 2'-O-methylation for shaping differential TLR7 or TLR8 activation. PMID- 25785449 TI - Relationship between television viewing and language delay in toddlers: evidence from a Korea national cross-sectional survey. AB - PURPOSE: This study investigated the relationship between 2-year-old children's exposure to TV and language delay. METHODS: The subjects of this study were 1,778 toddlers (906 males and 872 females) who participated in the Panel Study on Korean Children conducted in 2010. The linguistic ability of the toddlers was measured with the K-ASQ (Korean-Ages and Stages Questionnaire). The relationship between the amount of young children's exposure to TV and language delay was analyzed with Poisson regression. RESULTS: The average daily TV watching time of 2-year-old Korean toddlers in this study was 1.21 hours. After all confounding variables were adjusted, toddlers with over 2 hours and less than 3 hours of TV watching time had 2.7 times more risk (RR = 2.74, 95% CI: 1.13-6.65) of language delay than those with less than 1 hour of TV watching time. Those with more than 3 hours of TV watching time had approximately 3 times (RR = 3.03, 95% CI: 1.12 8.21) more risk (p<0.05). In addition, the risk of language delay increased proportionately with the increase in toddlers' TV watching time (p = 0.004). CONCLUSION: Two-year-old Korean toddlers' average daily TV watching time of more than 2 hours was related with language delay. PMID- 25785447 TI - Genome-wide association mapping for yield and other agronomic traits in an elite breeding population of tropical rice (Oryza sativa). AB - Genome-wide association mapping studies (GWAS) are frequently used to detect QTL in diverse collections of crop germplasm, based on historic recombination events and linkage disequilibrium across the genome. Generally, diversity panels genotyped with high density SNP panels are utilized in order to assay a wide range of alleles and haplotypes and to monitor recombination breakpoints across the genome. By contrast, GWAS have not generally been performed in breeding populations. In this study we performed association mapping for 19 agronomic traits including yield and yield components in a breeding population of elite irrigated tropical rice breeding lines so that the results would be more directly applicable to breeding than those from a diversity panel. The population was genotyped with 71,710 SNPs using genotyping-by-sequencing (GBS), and GWAS performed with the explicit goal of expediting selection in the breeding program. Using this breeding panel we identified 52 QTL for 11 agronomic traits, including large effect QTLs for flowering time and grain length/grain width/grain-length breadth ratio. We also identified haplotypes that can be used to select plants in our population for short stature (plant height), early flowering time, and high yield, and thus demonstrate the utility of association mapping in breeding populations for informing breeding decisions. We conclude by exploring how the newly identified significant SNPs and insights into the genetic architecture of these quantitative traits can be leveraged to build genomic-assisted selection models. PMID- 25785448 TI - Low levels of microbial translocation marker LBP are associated with sustained viral response after anti-HCV treatment in HIV-1/HCV co-infected patients. AB - BACKGROUND: Microbial translocation (MT) contributes to immune activation during HIV and HCV infections. We investigated the kinetics of MT markers during anti HCV and anti-HIV treatments, and if baseline plasma levels of lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) could predict anti-HCV treatment outcome. METHODS: Plasma from 78 HIV-infected patients was evaluated for LPS, LBP and sCD14. The patients starting anti-HCV treatment (with ongoing antiretroviral (ART) treatment) were categorized into sustained viral responders (SVR; n = 21) or non-responders (NR; n = 15) based on treatment outcome. ART starting subjects--were categorized into chronically HCV-infected (CH; n = 24) and mono-infected (HIV; n = 18), based on the HCV infection status. Samples were collected before start (at baseline) of pegylated-interferon alpha/ribavirin (peg-IFN/RBV) or antiretroviral-therapy and two years after treatment start (at follow up). chi2-test, non-parametric statistics and logistic regression were applied to determine the associations with treatment response and changes of the soluble markers. RESULTS: Plasma levels of LPS and sCD14 were elevated in all subjects before antiviral-treatment but remained unchanged at follow-up. Elevated levels of LBP were present in patients with HIV and HIV/HCV co-infection and were reduced by ART. Additionally, higher levels of LBP were present at baseline in NR vs. SVR. Higher levels of LBP at baseline were associated with non-response to peg-IFN/RBV treatment in both bivariate (OR: 0.19 95% CI: 0.06-0.31, p = 0.004) and multivariate analysis (OR: 1.43, 95% CI: 1.1 1.86, p = 0.07). CONCLUSION: In HIV/HCV co-infected patients high baseline LBP levels are associated with non-response to peg-IFN/RBV therapy. Plasma LBP (decreased by ART) may be a more relevant MT marker than LPS and sCD14. PMID- 25785450 TI - Infarction of the corpus callosum: a retrospective clinical investigation. AB - OBJECTIVES: The aim of this study was to investigate patients with ischemic infarctions in the territory of the corpus callosum to advance our understanding of this rare stroke subtype by providing comprehensive descriptive and epidemiological data. METHODS: From January 1, 2010 to June 30, 2014, all cases of acute ischemic stroke diagnosed by clinical manifestation and diffusion weighted imaging in Dalian Municipal Central Hospital were investigated. The patients presenting with corpus callosum infarctions were selected and further allocated into genu and/or body and splenium infarction groups. Proportion, lesion patterns, clinical features, risk factors and etiology of corpus callosum infarction were analyzed. RESULTS: Out of 1,629 cases, 59 patients (3.6%) with corpus callosum infarctions were identified by diffusion weighted imaging, including 7 patients who had ischemic lesions restricted to the corpus callosum territory. Thirty six patients had lesions in the splenium (61.0%). Corpus callosum infarction patients suffered from a broad spectrum of symptoms including weakness and/or numbness of the limbs, clumsy speech, and vertigo, which could not be explained by lesions in corpus callosum. A classical callosal disconnection syndrome was found in 2 out of all patients with corpus callosum infarctions. Statistical differences in the risk factor and infarct pattern between the genu and/or body group and splenium group were revealed. CONCLUSION: Corpus callosum infarction and the callosal disconnection syndrome were generally rare. The most susceptible location of ischemic corpus callosum lesion was the splenium. Splenium infarctions were often associated with bilateral cerebral hemisphere involvement (46.2%). The genu and/or body infarctions were associated with atherosclerosis. The most common cause of corpus callosum infarction probably was embolism. PMID- 25785451 TI - Loss from treatment for drug resistant tuberculosis: risk factors and patient outcomes in a community-based program in Khayelitsha, South Africa. AB - BACKGROUND: A community based drug resistant tuberculosis (DR-TB) program has been incrementally implemented in Khayelitsha, a high HIV and TB burden community in South Africa. We investigated loss from treatment (LFT), and post treatment outcomes of DR-TB patients in this setting. METHODOLOGY: LFT, defined as interruption of treatment for >=2 consecutive months was assessed among patients initiating DR-TB treatment for the first time between January 2009 and July 2011. Patients were traced through routine data sources to identify those who subsequently restarted treatment and those who died. Additional information on patient status and survival after LTF was obtained from community DR-TB counselors and from the national death registry. Post treatment outcomes were observed until July 2013. RESULTS: Among 452 patients initiating treatment for the first time within the given period, 30% (136) were LFT, with 67% retention at 18 months. Treatment was restarted in 27 (20%) patients, with additional resistance recorded in 2/25 (8%), excluding two with presumed DR-TB. Overall, 34 (25%) patients died, including 11 who restarted treatment. Males and those in the age category 15-25 years had a greater hazard of LFT; HR 1.93 (95% CI 1.35-2.75), and 2.43 (95% CI 1.52-3.88) respectively. Older age (>35 years) was associated with a greater hazard of death; HR 3.74 (1.13- 12.37) post treatment. Overall two year survival was 62%. It was lower (45%) in older patients, and was 92% among those who received >12 months treatment. CONCLUSION: LFT was high, occurred throughout the treatment period and was particularly high among males and those aged 15-25 years. Overall long term survival was poor. High rates of LFT should however not preclude scale up of community based care given its impact in increasing access to treatment. Further research is needed to support retention of DR-TB patients on treatment, even within community based treatment programs. PMID- 25785452 TI - Impact of community based peer support in type 2 diabetes: a cluster randomised controlled trial of individual and/or group approaches. AB - BACKGROUND: Diabetes peer support, where one person with diabetes helps guide and support others, has been proposed as a way to improve diabetes management. We have tested whether different diabetes peer support strategies can improve metabolic and/or psychological outcomes. METHODS: People with type 2 diabetes (n = 1,299) were invited to participate as either 'peer' or 'peer support facilitator' (PSF) in a 2x2 factorial randomised cluster controlled trial across rural communities (130 clusters) in England. Peer support was delivered over 8-12 months by trained PSFs, supported by monthly meetings with a diabetes educator. Primary end point was HbA1c. Secondary outcomes included quality of life, diabetes distress, blood pressure, waist, total cholesterol and weight. Outcome assessors and investigators were masked to arm allocation. Main factors were 1:1 or group intervention. Analysis was by intention-to-treat adjusting for baseline. RESULTS: The 4 arms were well matched (Group n = 330, 1:1(individual) n = 325, combined n = 322, control n = 322); 1035 (79.7%) completed the mid-point postal questionnaire and 1064 (81.9%) had a final HbA1c. A limitation was that although 92.6% PSFs and peers were in telephone contact, only 61.4% of intervention participants attended a face to face session. Mean baseline HbA1c was 57 mmol/mol (7.4%), with no significant change across arms. Follow up systolic blood pressure was 2.3 mm Hg (0.6 to 4.0) lower among those allocated group peer-support and 3.0 mm Hg (1.1 to 5.0) lower if the group support was attended at least once. There was no impact on other outcomes by intention to treat or significant differences between arms in self-reported adherence or medication. CONCLUSIONS: Group diabetes peer support over 8-12 months was associated with a small improvement in blood pressure but no other significant outcomes. Long term benefits should be investigated. TRIAL REGISTRATION: ISRCTN.com ISRCTN6696362166963621. PMID- 25785454 TI - An integrative approach to the study of filamentous oligomeric assemblies, with application to RecA. AB - Oligomeric macromolecules in the cell self-organize into a wide variety of geometrical motifs such as helices, rings or linear filaments. The recombinase proteins involved in homologous recombination present many such assembly motifs. Here, we examine in particular the polymorphic characteristics of RecA, the most studied member of the recombinase family, using an integrative approach that relates local modes of monomer/monomer association to the global architecture of their screw-type organization. In our approach, local modes of association are sampled via docking or Monte Carlo simulations. This enables shedding new light on fiber morphologies that may be adopted by the RecA protein. Two distinct RecA helical morphologies, the so-called "extended" and "compressed" forms, are known to play a role in homologous recombination. We investigate the variability within each form in terms of helical parameters and steric accessibility. We also address possible helical discontinuities in RecA filaments due to multiple monomer-monomer association modes. By relating local interface organization to global filament morphology, the strategies developed here to study RecA self assembly are particularly well suited to other DNA-binding proteins and to filamentous protein assemblies in general. PMID- 25785453 TI - Non-viral generation of marmoset monkey iPS cells by a six-factor-in-one-vector approach. AB - Groundbreaking studies showed that differentiated somatic cells of mouse and human origin could be reverted to a stable pluripotent state by the ectopic expression of only four proteins. The resulting pluripotent cells, called induced pluripotent stem (iPS) cells, could be an alternative to embryonic stem cells, which are under continuous ethical debate. Hence, iPS cell-derived functional cells such as neurons may become the key for an effective treatment of currently incurable degenerative diseases. However, besides the requirement of efficacy testing of the therapy also its long-term safety needs to be carefully evaluated in settings mirroring the clinical situation in an optimal way. In this context, we chose the long-lived common marmoset monkey (Callithrix jacchus) as a non human primate species to generate iPS cells. The marmoset monkey is frequently used in biomedical research and is gaining more and more preclinical relevance due to the increasing number of disease models. Here, we describe, to our knowledge, the first-time generation of marmoset monkey iPS cells from postnatal skin fibroblasts by non-viral means. We used the transposon-based, fully reversible piggyback system. We cloned the marmoset monkey reprogramming factors and established robust and reproducible reprogramming protocols with a six-factor in-one-construct approach. We generated six individual iPS cell lines and characterized them in comparison with marmoset monkey embryonic stem cells. The generated iPS cells are morphologically indistinguishable from marmoset ES cells. The iPS cells are fully reprogrammed as demonstrated by differentiation assays, pluripotency marker expression and transcriptome analysis. They are stable for numerous passages (more than 80) and exhibit euploidy. In summary, we have established efficient non-viral reprogramming protocols for the derivation of stable marmoset monkey iPS cells, which can be used to develop and test cell replacement therapies in preclinical settings. PMID- 25785455 TI - Protective effect of remote limb ischemic perconditioning on the liver grafts of rats with a novel model. AB - BACKGROUND: Remote ischemic conditioning (RIC) is a known manual conditioning to decrease ischemic reperfusion injury (IRI) but not increase ischemic time. Here we tried to establish a rat RIC model of liver transplantation (LT), optimize the applicable protocols and investigate the protective mechanism. METHODS: The RIC model was developed by a standard tourniquet. Sprague-Dawley rats were assigned randomly to the sham operated control (N), standard rat liver transplantation (OLT) and RIC groups. According to the different protocols, RIC group was divided into 3 subgroups (10 min*3, n = 6; 5 min*3, n = 6; 1 min*3, n = 6) respectively. Serum transaminases (ALT, AST), creatine kinase (CK), histopathologic changes, malondialdehyde (MDA), myeloperoxidase (MPO) and expressions of p-Akt were evaluated. RESULTS: Compared with the OLT group, the grafts subjected to RIC 5min*3 algorithm showed significant reduction of morphological damage and improved the graft function. Also, production of reactive oxygen species (MDA) and neutrophil accumulation (MPO) were markedly depressed and p-Akt was upregulated. CONCLUSION: In conclusion, we successfully established a novel model of RIC in rat LT, the optimal RIC 5min*3 algorithm seemed to be more efficient to alleviate IRI of the liver graft in both functional and morphological categories, which due to its antioxidative, anti-inflammation activities and activating PI3K Akt pathway. PMID- 25785456 TI - Detection of EML4-ALK in lung adenocarcinoma using pleural effusion with FISH, IHC, and RT-PCR methods. AB - Anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein like 4 (EML4) gene rearrangements occur in approximately 5% of non-small-cell lung cancers (NSCLC), leading to the overexpression of anaplastic lymphoma kinase and predicting a response to the targeted inhibitor, crizotinib. Malignant pleural effusion occurs in most patients with advanced lung cancer, especially adenocarcinoma, and tissue samples are not always available from these patients. We attempted to clarify the feasibility of detecting the EML4-ALK fusion gene in pleural effusion cells using different methods. We obtained 66 samples of pleural effusion from NSCLC patients. The pleural effusion fluid was centrifuged, and the cellular components obtained were formalin fixed and paraffin embedded. The EML4 ALK fusion gene status was determined with fluorescent in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). EML4-ALK was detected in three of 66 patient samples (4.5%) with RT-PCR. When the RT-PCR data were used as the standard, one false positive and one false negative samples were identified with IHC; and one false negative sample was identified with FISH. These results suggest that a block of pleural effusion cells can be used to detect the EML4-ALK fusion gene. IHC had good sensitivity, but low specificity. FISH had low sensitivity, but high specificity. RT-PCR is a good candidate method for detecting EML4-ALK in blocks of pleural effusion cells from lung cancer patients. PMID- 25785458 TI - Correction: Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. PMID- 25785457 TI - Gulf War agent exposure causes impairment of long-term memory formation and neuropathological changes in a mouse model of Gulf War Illness. AB - Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long term time points post-exposure. No cognitive deficits were observed at the short term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans. PMID- 25785459 TI - The spatial properties of L- and M-cone inputs to electroretinograms that reflect different types of post-receptoral processing. AB - We studied the spatial arrangement of L- and M-cone driven electroretinograms (ERGs) reflecting the activity of magno- and parvocellular pathways. L- and M cone isolating sine wave stimuli were created with a four primary LED stimulator using triple silent substitution paradigms. Temporal frequencies were 8 and 12 Hz, to reflect cone opponent activity, and 30, 36 and 48 Hz to reflect luminance activity. The responses were measured for full-field stimuli and for different circular and annular stimuli. The ERG data confirm the presence of two different mechanisms at intermediate and high temporal frequencies. The responses measured at high temporal frequencies strongly depended upon spatial stimulus configuration. In the full-field conditions, the L-cone driven responses were substantially larger than the full-field M-cone driven responses and also than the L-cone driven responses with smaller stimuli. The M-cone driven responses at full-field and with 70 degrees diameter stimuli displayed similar amplitudes. The L- and M-cone driven responses measured at 8 and 12 Hz were of similar amplitude and approximately in counter-phase. The amplitudes were constant for most stimulus configurations. The results indicate that, when the ERG reflects luminance activity, it is positively correlated with stimulus size. Beyond 35 degrees retinal eccentricity, the retina mainly contains L-cones. Small stimuli are sufficient to obtain maximal ERGs at low temporal frequencies where the ERGs are also sensitive to cone-opponent processing. PMID- 25785461 TI - Correction: Estrogen induces global reorganization of chromatin structure in human breast cancer cells. PMID- 25785460 TI - A predictive model for corticosteroid response in individual patients with MS relapses. AB - OBJECTIVES: To derive a simple predictive model to guide the use of corticosteroids in patients with relapsing remitting MS suffering an acute relapse. MATERIALS AND METHODS: We analysed individual patient randomised controlled trial data (n=98) using a binary logistic regression model based on age, gender, baseline disability scores [physician-observed: expanded disability status scale (EDSS) and patient reported: multiple sclerosis impact scale 29 (MSIS-29)], and the time intervals between symptom onset or referral and treatment. RESULTS: Based on two a priori selected cut-off points (improvement in EDSS >= 0.5 and >= 1.0), we found that variables which predicted better response to corticosteroids after 6 weeks were younger age and lower MSIS-29 physical score at the time of relapse (model fit 71.2% - 73.1%). CONCLUSIONS: This pilot study suggests two clinical variables which may predict the majority of the response to corticosteroid treatment in patients undergoing an MS relapse. The study is limited in being able to clearly distinguish factors associated with treatment response or spontaneous recovery and needs to be replicated in a larger prospective study. PMID- 25785462 TI - Adapting to a warmer ocean--seasonal shift of baleen whale movements over three decades. AB - Global warming poses particular challenges to migratory species, which face changes to the multiple environments occupied during migration. For many species, the timing of migration between summer and winter grounds and also within-season movements are crucial to maximise exploitation of temporarily abundant prey resources in feeding areas, themselves adapting to the warming planet. We investigated the temporal variation in the occurrence of fin (Balaenoptera physalus) and humpback whales (Megaptera novaeangliae) in a North Atlantic summer feeding ground, the Gulf of St. Lawrence (Canada), from 1984 to 2010 using a long term study of individually identifiable animals. These two sympatric species both shifted their date of arrival at a previously undocumented rate of more than 1 day per year earlier over the study period thus maintaining the approximate 2 week difference in arrival of the two species and enabling the maintenance of temporal niche separation. However, the departure date of both species also shifted earlier but at different rates resulting in increasing temporal overlap over the study period indicating that this separation may be starting to erode. Our analysis revealed that the trend in arrival was strongly related to earlier ice break-up and rising sea surface temperature, likely triggering earlier primary production. The observed changes in phenology in response to ocean warming are a remarkable example of phenotypic plasticity and may partly explain how baleen whales were able to survive a number of changes in climate over the last several million years. However, it is questionable whether the observed rate of change in timing can be maintained. Substantial modification to the distribution or annual life cycle of these species might be required to keep up with the ongoing warming of the oceans. PMID- 25785463 TI - The inhibitory effect of selenium nanoparticles on protein glycation in vitro. AB - Selenium nanoparticles (Se NPs) possess well-known excellent biological activities and low toxicity, and have been employed for numerous applications except as inhibitors to protein glycation. Herein, the present study is carried out to investigate the inhibitory effect of Se NPs on protein glycation in a bovine serum albumin (BSA)/glucose system. By measuring the amount of glucose covalently bound onto BSA, the formation of fructosamine and fluorescent products, it is found that Se NPs can hinder the development of protein glycation in a dose-dependent but time-independent manner under the selected reaction conditions (55 degrees C, 40 h). And after comparing the increase of inhibitory rate in different stages, it is observed that Se NPs show the greatest inhibitory effect in the early stage, then in the advanced stage, but no effect in the intermediate stage. Fourier transform infrared spectroscopy characterization of Se NPs collected after glycation and determination of .OH influence and glyoxal formation show that the mechanism for the inhibitory efficacy of Se NPs is related to their strong competitive activity against available amino groups in proteins, their great scavenging activity on reactive oxygen species and their inhibitory effect on alpha-dicarbonyl compounds' formation. In addition, it is proved that Se NPs protect proteins from structural modifications in the system and they do not exhibit significant cytotoxicity towards BV-2 and BRL-3A cells at low concentrations (10 and 50 MUg mL(-1)). Consequently, Se NPs may be suitable for further in vivo studies as novel anti-glycation agents. PMID- 25785466 TI - Mini-open repair of achilles rupture in the national football league. AB - Tears of the Achilles tendon in professional athletes are an infrequent yet devastating injury. Historical studies have demonstrated not only a poor rate of return to competitive play but have also noted significant declines in performance for those able to return. While classic treatment of these injuries in the competitive athlete has been an open, locked suture repair, this article reports on a consecutive series of professional football athletes who underwent mini-open repair. All athletes returned to professional football, with seven out of nine (78%) returning to National Football League (NFL) competition. Average return to play was 273 days (8.9 months), with one athlete returning at 166 days (5.4 months). There have been no reruptures and no sural nerve or wound healing complications. Although limited in number currently, mini-open repair in NFL athletes has allowed successful return to competitive play with no reruptures and a trend toward faster return to play compared with historical open repair outcomes. PMID- 25785464 TI - Emergent toxins in North Atlantic temperate waters: a challenge for monitoring programs and legislation. AB - Harmful Algal Blooms (HAB) are complex to manage due to their intermittent nature and their severe impact on the economy and human health. The conditions which promote HAB have not yet been fully explained, though climate change and anthropogenic intervention are pointed as significant factors. The rise of water temperature, the opening of new sea canals and the introduction of ship ballast waters all contribute to the dispersion and establishment of toxin-producing invasive species that promote the settling of emergent toxins in the food-chain. Tetrodotoxin, ciguatoxin, palytoxin and cyclic imines are commonly reported in warm waters but have also caused poisoning incidents in temperate zones. There is evidence that monitoring for these toxins exclusively in bivalves is simplistic and underestimates the risk to public health, since new vectors have been reported for these toxins and as well for regulated toxins such as PSTs and DSTs. In order to avoid public health impacts, there is a need for adequate monitoring programs, a need for establishing appropriate legislation, and a need for optimizing effective methods of analysis. In this review, we will compile evidence concerning emergent marine toxins and provide data that may indicate the need to restructure the current monitoring programs of HAB. PMID- 25785465 TI - Isolation and preliminary characterization of proteinaceous toxins with insecticidal and antibacterial activities from black widow spider (L. tredecimguttatus) eggs. AB - The eggs of black widow spider (L. tredecimguttatus) have been demonstrated to be rich in toxic proteinaceous components. The study on such active components is of theoretical and practical importance. In the present work, using a combination of multiple biochemical and biological strategies, we isolated and characterized the proteinaceous components from the aqueous extract of the black widow spider eggs. After gel filtration of the egg extract, the resulting main protein and peptide peaks were further fractionated by ion exchange chromatography and reversed-phase high performance liquid chromatography. Two proteinaceous components, named latroeggtoxin-III and latroeggtoxin-IV, respectively, were purified to homogeneity. Latroeggtoxin-III was demonstrated to have a molecular weight of about 36 kDa. Activity analysis indicated that latroeggtoxin-III exhibited neurotoxicity against cockroaches but had no obvious effect on mice, suggesting that it is an insect-specific toxin. Latroeggtoxin-IV, with a molecular weight of 3.6 kDa, was shown to be a broad-spectrum antibacterial peptide, showing inhibitory activity against all five species of bacteria tested, with the highest activity against Staphylococcus aureus. Finally, the implications of the proteinaceous toxins in egg protection and their potential applications were analyzed and discussed. PMID- 25785467 TI - Equivalent pain relief with and without resection of the posterior tibial tendon in adult flatfoot reconstruction. AB - Transfer of the flexor digitorum longus (FDL) is indicated to compensate for the loss of posterior tibial tendon (PTT) function in the treatment of adult acquired flatfoot deformity (AAFD). The aim of this study was to determine the effect of PTT resection on pain relief following surgical treatment of stage II AAFD. A retrospective review of patients who underwent surgical treatment for stage II AAFD was performed. Patients were divided into two groups based on whether the degenerated PTT was resected or left in situ. A visual analog scale (VAS) score for pain was recorded for each patient preoperatively. Concomitant surgical procedures and the incidence of postoperative pain were also reported for each group. Deformity correction was assessed with standard weight-bearing radiographs. Thirty-four patients with a mean follow-up of 14 months were included in the study. There was no difference in preoperative VAS pain scores, and patients in both groups demonstrated excellent pain relief postoperatively. Five patients in the PTT resection group and one patient in the PTT in situ group reported lateral-sided foot pain postoperatively. Resection of the PTT did not significantly affect postoperative pain relief. Future prospective studies are needed to determine whether resection of the degenerated PTT is necessary at the time of surgery for stage II AAFD. PMID- 25785468 TI - Biomechanical comparison of prophylactic medial malleolar fixation in total ankle arthroplasty. AB - The purpose of this study was to compare the biomechanical properties of two common forms of prophylactic fixation of the medial malleolus during total ankle arthroplasty (TAA). Ten matched pairs of cadaveric lower extremities were fixed with a single cannulated cortical screw or a one-third tubular plate after preparation for TAA. Ten unmatched single cadaver lower extremities were used as the control. A transverse load was applied to the medial malleolus. Bone mineral density, peak loads at fracture, and fracture pattern were noted. There was no statistically significant difference in peak load to failure between either fixation cohorts or between the fixation cohort and the control cohort. There was a moderate positive correlation between bone mineral density and peak load for all three experimental groups. The peak load was significantly (p = .035) increased in male cadavers. Fractures occurred almost exclusively at the apex of the tibial and malleolar cuts with a vertical fracture pattern. PMID- 25785469 TI - Total ankle arthroplasty and perioperative pain. AB - Total ankle arthroplasty is a procedure that has been shown to greatly improve patient quality of life. However, it is associated with moderate to severe postoperative pain. Commonly used strategies for pain control include opioids, multimodal analgesia with nonsteroidal anti-inflammatory drugs, acetaminophen and gabapentinoids, and regional anesthetic techniques such as peripheral nerve blocks. Nerve blocks in particular afford high-quality relief from pain while avoiding many of the side effects of traditional systemic therapies. This review highlights the state-of-the-art practice for providing postoperative analgesia following total ankle arthroplasty. PMID- 25785470 TI - Liposomal bupivacaine in hallux valgus surgery: a multimodal pain management adjunct. AB - The objective of this study was to review the use of liposomal bupivacaine as a multimodal pain management adjunct following hallux valgus surgery. The study was a prospective review of a consecutive series of patients who underwent hallux valgus surgery and received liposomal bupivacaine. From postoperative day (POD) 1 to 4, pain scores, number of narcotic rescue pills used, and adverse events were recorded. Wound complications, narcotic refills, and unscheduled clinic and emergency room (ER) visits or hospital admissions for pain were also recorded. The average pain rating was <3.4 (+/-2.4) during POD 1 to 4. Four patients (28.6%) reported never experiencing pain (Numeric Rating Scale <=1). Seventy-one percent used narcotic rescue pills on POD 1. There were no unscheduled office or ER visits or hospital admissions. One adverse event and one wound complication occurred. Liposomal bupivacaine may be a safe and useful adjunct in a multimodal pain regimen for patients undergoing hallux valgus surgery. More rigorous studies are needed to determine its efficacy, safety profile, and cost-effectiveness compared to placebo. PMID- 25785471 TI - Heterotopic ossification following total ankle replacement: clinical significance and factors affecting its formation. AB - Little is known about the clinical significance of heterotopic ossification after total ankle replacement and the factors contributing to its occurrence. This study documented the incidence of heterotopic ossification in a large ankle arthroplasty series; identified potentially related patient, implant, and operative factors; and determined the strength of association of those factors with the clinical outcome. Ninety ankles in 88 primary ankle arthroplasty patients were followed for an average of 32.4 months. Scandinavian Total Ankle Replacement, Salto-Talaris, and INBONE ankle implants were used at the surgeon's discretion. Heterotopic ossification was measured and classified using methods previously described for total hip arthroplasty. Incidence, location, severity, predisposing factors, and outcomes were documented, and correlation between ossification severity and each examined factor was determined. Eighty percent and 95.6% of ankles showed heterotopic ossification on anteroposterior and lateral views, respectively, and 97.8% showed evidence on either anteroposterior or lateral views. Ossification grades 4 and 3 were most common, predominantly located at the medial gutter and posterior to the tibial component. No preoperative variables were associated with heterotopic ossification, but its presence on lateral radiographs correlated with insufficient coverage of the tibial or talar component. Only three ankles required heterotopic ossification resection because of recalcitrant pain. The incidence of heterotopic ossification following primary total ankle arthroplasty was higher in this series than previously reported. PMID- 25785472 TI - Classification of metatarsophalangeal joint plantar plate injuries: history and physical examination variables. AB - Although metatarsophalangeal (MTP) plantar plate tears are common, they are still often missed. The purpose of this study is to find the best clinical variables to define and grade the plantar plate injuries. Sixty-eight patients (100 MTP joints) were graded arthroscopically and divided into five groups (0 to IV) according to the anatomical classification. Their medical records were reviewed to establish correlations of clinical findings with the anatomical lesions. The positive correlations found were acute pain, widening of the interdigital space, loss of ground touch, positivity of the MTP joint drawer test, reduction of the toe purchase, and toe supination. The drawer test is the most reliable and accurate tool to classify and grade the plantar plate lesion, followed by ground touch and rotational deformities. It is possible to improve the accuracy of diagnosis of plantar plate tears by means of the combination of both clinical history and physical examination data. PMID- 25785473 TI - Normal anatomic variants of the acetabular labrum. AB - Within the past two decades, magnetic resonance imaging (MRI) has evolved into an integral part of noninvasive diagnostic testing for evaluation of musculoskeletal disorders. With the advancements in imaging and coil technology, assessment of small and spatially complex structures, such as the acetabular labrum, became possible. Labral tears are being diagnosed with increasing frequency with MRI. However, the medical literature reveals erratic sensitivity and specificity values of MRI, including MR arthrography, in identifying labral tears. This finding could be partly attributable to false-positive results caused by normal anatomic variants of the acetabular labrum. Additional challenges are introduced by the lack of consensus on the existence and the distributions of the normal anatomic variants of the labrum in MRI and orthopedic literature. In this article, the spectrum and incidence of these variations are discussed with emphasis on MRI features of the variant anatomy and the labral tears. PMID- 25785474 TI - Administration technique of liposomal bupivacaine for total ankle arthroplasty. AB - Liposomal bupivacaine, a slow-releasing form of bupivacaine, is proving to be effective and safe for postsurgical pain management. It can provide great benefit and patient satisfaction because of its long-duration local analgesia by a single infiltration for up to 72 hours. A technical tip and application considerations of liposomal bupivacaine in total ankle arthroplasties are described. PMID- 25785475 TI - Longitudinal Lisfranc injury. AB - Most Lisfranc or tarsometatarsal (TMT) joint injuries result from a horizontally directed force in which the metatarsals are displaced relative to the midfoot. The injury pattern that is described in this article is one of a longitudinal force through the first ray and cuneiform. A reliable measure to recognize the longitudinal Lisfranc variant injury has been the height difference between the distal articular surfaces of the first and second cuneiform bones in an anteroposterior (AP) weight-bearing radiograph. This measure helps identify subtle injuries in which there is a proximal and medial subluxation of the first cuneiform-metatarsal complex. Delayed diagnosis and treatment have been associated with poorer results and significant functional consequences. This article describes a simple radiographic measurement to recognize the longitudinal injury pattern and to aid in determining whether operative intervention is required. PMID- 25785476 TI - Efficiency Enhancement of PbS Quantum Dot/ZnO Nanowire Bulk-Heterojunction Solar Cells by Plasmonic Silver Nanocubes. AB - For improvement of solar cell performance, it is important to make efficient use of near-infrared light, which accounts for ~40% of sunlight energy. Here we introduce plasmonic Ag nanocubes (NCs) to colloidal PbS quantum dot/ZnO nanowire (PbS QD/ZnO NW) bulk-heterojunction solar cells, which are characterized by high photocurrents, for further improvement in the photocurrent and power conversion efficiency (PCE) in the visible and near-infrared regions. The Ag NCs exhibit strong far field scattering and intense optical near field in the wavelength region where light absorption of PbS QDs is relatively weak. Photocurrents of the solar cells are enhanced by the Ag NCs particularly in the range 700-1200 nm because of plasmonic enhancement of light absorption and possible facilitation of exciton dissociation. As a result of the optimization of the position and amount of Ag NCs, the PCE of PbS QD/ZnO NW bulk-heterojunction solar cells is improved from 4.45% to 6.03% by 1.36 times. PMID- 25785477 TI - Diphenylalanine self assembly: novel ion mobility methods showing the essential role of water. AB - The mechanism and driving forces behind the formation of diphenylalanine (FF) nanotubes have attracted much attention in the past decades. The hollow structure of the nanotubes suggests a role for water during the self-assembly process. Here, we use novel ion-mobility mass spectrometry methods to probe the early oligomers formed by diphenylalanine peptides. Interestingly, water-bound oligomers are observed in nano-electrospray ionization (ESI) mass spectra in the absence of bulk solvent. In addition, ligated water clusters transit the ion mobility cell but (often) dissociate before detection. These water molecules are shown to be essential for the formation of diphenylalanine oligomers larger than the dimer. The ligated water molecules exist in the solvent free environment either as neutral water or as protonated water clusters, depending on the composition of solvent from which they are sprayed. Water adduction helps stabilize conformers that are otherwise energetically unstable ultimately leading to the assembly of FF nanotubes. PMID- 25785479 TI - A Diels-Alder reaction triggered by a [4 + 3] metallacycloaddition. AB - The Tp(Me2)Ir(III) complex 1-OH2 (Tp(Me2) = hydrotris(3,5 dimethylpyrazolyl)borate), which contains a labile molecule of water and an iridium-bonded alkenyl moiety (-C(R)?C(R)-(R=CO2Me)) as part of a benzo-annulated five-membered iridacycle, reacts readily with the conjugated dienes butadiene and 2,3-dimethylbutadiene to afford the corresponding Diels-Alder products. Experimental and DFT studies are in accordance with an initial [4 + 3] cyclometalation reaction between the diene and the five-coordinated 16-electron organometallic fragment 1 (generated from 1-OH2 by facile water dissociation). The reaction can be extended to a related TpIr(III) complex (Tp = hydrotris(pyrazolyl)borate) that also features a labile ligand (i.e., 2-THF). PMID- 25785478 TI - Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities. AB - Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 A resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model. PMID- 25785480 TI - Strong photocurrent enhancements in plasmonic organic photovoltaics by biomimetic nanoarchitectures with efficient light harvesting. AB - We propose the biomimetic moth-eye nanoarchitectures as a novel plasmonic light harvesting structure for further enhancing the solar-generated photocurrents in organic photovoltaics (OPVs). The full moth-eye nanoarchitectures are composed of two-dimensional hexagonal periodic grating arrays on surfaces of both the front zinc oxide (ZnO) and rear active layers, which are prepared by a simple and cost effective soft imprint nanopatterning technique. For the 380 nm period ZnO and 650 nm period active gratings (i.e., ZnO(P380)/Active(P650)), the poly(3 hexylthiophene-2,5-diyl):indene-C60 bis-adduct (P3HT:ICBA)-based plasmonic OPVs exhibit an improvement of the absorption spectrum compared to the pristine OPVs over a broad wavelength range of 350-750 nm, showing absorption enhancement peaks at wavelengths of ~370, 450, and 670 nm, respectively. This leads to a considerable increase of short-circuit current density (Jsc) from 10.9 to 13.32 mA/cm(2), showing a large Jsc enhancement percentage of ~22.2%. As a result, the strongly improved power conversion efficiency (PCE) of 6.28% is obtained compared to that (i.e., PCE = 5.12%) of the pristine OPVs. For the angle-dependent light absorption characteristics, the plasmonic OPVs with ZnO(P380)/Active(P650) have a better absorption performance than that of the pristine OPVs at incident angles of 20-70 degrees . For optical absorption characteristics and near-field intensity distributions of plasmonic OPVs, theoretical analyses are also performed by a rigorous coupled-wave analysis method, which gives a similar tendency with the experimentally measured data. PMID- 25785481 TI - Survey on public awareness, attitudes, and barriers for herpes zoster vaccination in South Korea. AB - A cross-sectional study was performed to assess current public awareness of herpes zoster (HZ) and its vaccine, determine the factors that influence people's intention regarding HZ vaccination, and investigate the barriers for vaccination by changing decisions with sequential questions regarding knowledge, cost, and physician's recommendation in the Department of Infectious Diseases, Korea University Guro Hospital, in South Korea, between August 23 and September 15 of 2013. Among 603 subjects who completed the survey, 85.7% and 43.6% subjects were aware of HZ and HZ vaccination, respectively. Women, younger age group, those with higher income or higher education levels were more likely to be aware of HZ. Overall, 85.8% of subjects aware of HZ were willing to be vaccinated or vaccinate their parents. The main obstacles for the increased acceptance toward vaccination were the high cost and low perceived risk, which decreased acceptance to 60.2%. However, physician's recommendation reversed 69.5% of the refusal to accept HZ vaccine. These results indicate that expanding public education and physician's recommendations are important factors aimed at increasing HZ vaccine coverage rate. PMID- 25785482 TI - Infrared multiphoton dissociation spectroscopy of a gas-phase complex of uranyl and 3-oxa-glutaramide: an extreme red-shift of the [O?U?O](2+) asymmetric stretch. AB - The gas-phase complex UO2(TMOGA)2(2+) (TMOGA = tetramethyl-3-oxa-glutaramide) prepared by electrospray ionization was characterized by infrared multiphoton dissociation (IRMPD) spectroscopy. The IRMPD spectrum from 700-1800 cm(-1) was interpreted using a computational study based on density functional theory. The predicted vibrational frequencies are in good agreement with the measured values, with an average deviation of only 8 cm(-1) (<1%) and a maximum deviation of 21 cm(-1) (<2%). The only IR peak assigned to the linear uranyl moiety was the asymmetric nu3 mode, which appeared at 965 cm(-1) and was predicted by DFT as 953 cm(-1). This nu3 frequency is red-shifted relative to bare uranyl, UO2(2+), by ca. 150 cm(-1) due to electron donation from the TMOGA ligands. Based on the degree of red-shifting, it is inferred that two TMOGA oxygen-donor ligands have a greater effective gas basicity than the four monodentate acetone ligands in UO2(acetone)4(2+). The uranyl nu3 frequency was also computed for uranyl coordinated by two TMGA ligands, in which the central Oether of TMOGA has been replaced by CH2. The computed nu3 for UO2(TMGA)2(2+), 950 cm(-1), is essentially the same as that for UO2(TMOGA)2(2+), suggesting that electron donation to uranyl from the Oether of TMOGA is minor. The computed nu3 asymmetric stretching frequencies for the three actinyl complexes, UO2(TMOGA)2(2+), NpO2(TMOGA)2(2+) and PuO2(TMOGA)2(2+), are comparable. This similarity is discussed in the context of the relationship between nu3 and intrinsic actinide-oxygen bond energies in actinyl complexes. PMID- 25785483 TI - Multiannual top-down estimate of HFC-23 emissions in East Asia. AB - Trifluoromethane (CHF3, HFC-23), with a 100-year global warming potential (GWP) of 12400, is regulated under the Kyoto Protocol. HFC-23 emissions in East Asia, especially in China, are currently thought to represent the majority of global HFC-23 emissions. This study provides both a bottom-up emission inventory and the multiannual top-down estimate of HFC-23 emissions in East Asia during 2007-2012. The new bottom-up inventory yields improved simulated HFC-23 mixing ratios compared to previous bottom-up inventories. The top-down estimate uses inverse modeling to further improve the model-measurement agreement. Results show that China contributed 94-98% of all HFC-23 emissions in East Asia. Annual a posteriori emissions from China were around 6.3 Gg/yr during the period 2007-2010 after which they increased to 7.1 +/- 0.7 Gg/yr in 2011 and 8.8 +/- 0.8 Gg/yr in 2012. For the first time, this study also provides a top-down estimate of HFC 23/HCFC-22 (chlorodifluoromethane, CHClF2) coproduction ratios in non-CDM (Clean Development Mechanism) HCFC-22 production plants as well as in all HCFC-22 production plants in China. PMID- 25785484 TI - A Feasibility study on Combining Internet-Based Cognitive Behaviour Therapy with Physical Exercise as Treatment for Panic Disorder--Treatment Protocol and Preliminary Results. AB - Internet-based cognitive behaviour therapy (ICBT) is a recommended, cost effective and efficacious treatment for panic disorder (PD). However, treatment effects in psychiatric settings indicate that a substantial proportion fail to achieve remission. Physical exercise improves symptoms in patients with PD, and acts through mechanisms that can augment the effect of ICBT. The feasibility of combining these two interventions has not previously been investigated, and this was the aim of this study. The intervention comprised guided ICBT combined with one weekly session of supervised and two weekly sessions of unsupervised physical exercise for a total of 12 weeks. Treatment rationale, procedures and protocols are presented together with preliminary results for four patients with PD who have currently finished treatment. Quantitative and qualitative results are reported on the feasibility of adhering to the treatments, treatment outcome as assessed by clinician rating and estimation of reliable and clinically significant change for outcome measures, and participants' satisfactions with the combined treatment. The preliminary results indicate that the combined treatment is feasible to complete, and that the combination is perceived by the participants as beneficial. PMID- 25785485 TI - Classification Accuracy of Sequentially Administered WAIS-IV Short Forms. AB - A Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) short form (SF) may be effective for ruling out subnormal intelligence. To create a useful SF, subtest administration should follow the order prescribed in the manual and, depending upon individual performance, be terminated after completion of 2, 3, 4, or 5 subtests. One hundred and twenty-two patients completed the WAIS-IV. In two analyses, Full-Scale IQs (FSIQs) <=69 and <=79 were classified as impairment. Classification accuracy statistics indicated that all SFs using both cutoff scores exceeded the base rate (i.e., 14% and 34%) of subnormal intelligence, with hit rates ranging from 84% to 95%. The FSIQ cutoff of <=69 had poor sensitivity for detecting impaired intellectual functioning with the 2-, 3-, 4-, and 5 subtest SFs; specificity, positive predictive value (PPV), and negative predictive value (NPV) were excellent for each SF. With the FSIQ cutoff of <=79, sensitivity was strong to excellent for the 3-, 4-, and 5-subtest SFs as were specificity, PPV, and NPV. PMID- 25785486 TI - Circulating tumor cell levels are elevated in colorectal cancer patients with high tumor burden in the liver. AB - BACKGROUND: Metastatic spread is the most common cause of cancer-related death in colorectal cancer (CRC) patients, with the liver being the mostly affected organ. Circulating tumor cells (CTCs) are a prognostic marker in stage IV CRC. We hypothesized that tumor burden in the liver correlates with CTC quantity. METHODS: Blood (7.5 ml) was prospectively collected from 24 patients with novel stage IV CRC diagnosis. Baseline EpCAM+ CTCs were analyzed with the FDA-approved CellSearch(r) system. Clinicopathological data were collected, and hepatic tumor burden was determined by radiographic liver volumetry with contrast-enhanced CT scans. CRC primary tumors were immunohistochemically stained for EpCAM expression with BerEP4 monoclonal antibody. Statistical analyses were performed using 2 sample T-test, non-parametric Wilcoxon Rank-Sum test, and Fisher's exact test. RESULTS: CTCs were detected n 17 (71%) of 24 patients. The overall mean CTC number as determined by EpCAM-based CellSearch(r) detection was 6.3 (SEM 2.9). High baseline CTC numbers (>=3) correlated significantly with a high tumor/liver ratio (>=30%), and with high serum CEA levels, as determined by two-sample T-test on log-transformed data and by Fisher's Exact test on categorical data analysis (P < 0.05). The CRC primary tumors were consistently expressing EpCAM by immunostaining. CONCLUSIONS: High tumor burden in the liver and high baseline serum CEA levels are associated with high number of baseline CTCs in stage IV CRC patients. Future studies should further investigate the biological role and expression patterns of single CTCs in cancer patients to further improve personalized treatment strategies. PMID- 25785487 TI - Intrapartum synthetic oxytocin reduce the expression of primitive reflexes associated with breastfeeding. AB - AIM: Several synthetic peptide manipulations during the time surrounding birth can alter the specific neurohormonal status in the newborn brain. This study is aimed at assessing whether intrapartum oxytocin administration has any effect on primitive neonatal reflexes and determining whether such an effect is dose dependent. MATERIALS AND METHODS: A cohort prospective study was conducted at a tertiary hospital. Mother-infant dyads who received intrapartum oxytocin (n=53) were compared with mother-infant dyads who did not receive intrapartum oxytocin (n=45). Primitive neonatal reflexes (endogenous, antigravity, motor, and rhythmic reflexes) were quantified by analyzing videotaped breastfeeding sessions in a biological nurturing position. Two observers blind to the group assignment and the oxytocin dose analyzed the videotapes and assesed the newborn's state of consciousness according to the Brazelton scale. RESULTS: The release of all rhythmic reflexes (p=0.01), the antigravity reflex (p=0.04), and total primitive neonatal reflexes (p=0.02) in the group exposed to oxytocin was lower than in the group not exposed to oxytocin. No correlations were observed between the dose of oxytocin administered and the percentage of primitive neonatal reflexes released (r=0.03; p=0.82). CONCLUSIONS: Intrapartum oxytocin administration might inhibit the expression of several primitive neonatal reflexes associated with breastfeeding. This correlation does not seem to be dose-dependent. PMID- 25785488 TI - Effectiveness of hand sorting, flotation/washing, dehulling and combinations thereof on the decontamination of mycotoxin-contaminated white maize. AB - Maize is one of the major staple foods of Sub-Saharan Africa and is consumed as whole or dehulled grain. In this region, where the environmental conditions favour fungal growth and mycotoxin production, the majority of the population are subsistence consumers who, unfortunately, have little or no access to mycotoxin testing of their food. In an attempt to develop feasible reduction strategies in dietary mycotoxin exposure of the population, a three-factorial design experiment was conducted to examine and compare the efficacy of hand sorting, flotation, dehulling and combinations thereof in removing naturally occurring aflatoxins, fumonisins, nivalenol, deoxynivalenol and alternariol in shelled white maize. Regression analysis was used to determine the significant (p < 0.05) process variables on the removal of mycotoxins from the maize. Results from this experiment indicated that hand sorting had the greatest effect on mycotoxin removal, while flotation yielded the least effect. In particular hand sorting left < 6% of aflatoxin B1 and < 5% of fumonisin B1. Based on these results, hand sorting of maize grains is being recommended as a last line of defence against mycotoxin exposure among subsistence consumers. PMID- 25785489 TI - Steroidal 5alpha-Reductase Inhibitors: A Comparative 3D-QSAR Study Review. PMID- 25785490 TI - Prostate cancer incidence and agriculture practices in Georgia, 2000-2010. AB - BACKGROUND: Georgia has prostate cancer incidence rates consistently above the national average. A notable portion of Georgia's economy is rooted in agricultural production, and agricultural practices have been associated with an increased risk of prostate cancer. METHODS: Statistical analyses considered county age-adjusted prostate cancer incidence rates as the outcome of interest and three agricultural variables (farmland as percent of county land, dollars spent per county acre on agriculture chemicals, and dollars spent per county acre on commercial fertilizers) as exposures of interest. Multivariate linear regression models analyzed for each separately. Data were obtained from National Cancer Institute Surveillance, Epidemiology and End Results (SEER) 2000-2010, United States Department of Agriculture (USDA) 1987 Agriculture Survey, and 2010 US Census. RESULTS: In counties with equal to or greater than Georgia counties' median percent African-American population (27%), dollars per acre spent on agriculture chemicals was significantly associated (P = 0.04) and dollars spent of commercial fertilizers was moderately associated (P = 0.07) with elevated prostate cancer incidence rates. There was no association between percent of county farmland and prostate cancer rates. CONCLUSION: This study identified associations between prostate cancer incidence rates, agriculture chemical expenditure, and commercial fertilizer expenditure in Georgia counties with a population comprised of more than 27% of African Americans. PMID- 25785491 TI - Reduced bone mass accrual in mouse model of repetitive mild traumatic brain injury. AB - Traumatic brain injury (TBI) can affect bone by influencing the production/actions of pituitary hormones and neuropeptides that play significant regulatory roles in bone metabolism. Previously, we demonstrated that experimental TBI exerted a negative effect on the skeleton. Since mild TBI (mTBI) accounts for the majority of TBI cases, this study was undertaken to evaluate TBI effects using a milder impact model in female mice. Repetitive mTBI caused microhemorrhaging, astrocytosis, and increased anti-inflammatory protective actions in the brain of the impacted versus control mice 2 wk after the first impact. Serum levels of growth regulating insulin-like growth factor 1 (IGF-I) were reduced by 28.9%. Bone mass was reduced significantly in total body as well as individual skeletons. Tibial total cortical density was reduced by 7.0%, which led to weaker bones, as shown by a 31.3% decrease in femoral size adjusted peak torque. A 27.5% decrease in tibial trabecular bone volume per total volume was accompanied by a 34.3% (p = 0.07) decrease in bone formation rate (BFR) per total area. Based on our data, we conclude that repetitive mTBI exerted significant negative effects on accrual of both cortical and trabecular bone mass in mice caused by a reduced BFR. PMID- 25785492 TI - Comparative Biodistribution and Pharmacokinetic Analysis of Cyclosporine-A in the Brain upon Intranasal or Intravenous Administration in an Oil-in-Water Nanoemulsion Formulation. AB - The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague-Dawley rats using an oil-in water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood-brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity. PMID- 25785494 TI - Spreading of a droplet over a nonisothermal substrate: multiple scaling regimes. AB - We envisage the spreading behavior of a two-dimensional droplet under a thin-film based paradigm, under a perfect wetting condition, while the droplet is placed over a nonisothermal substrate. Starting from the onset of thin-film behavior (or equivalently beyond the inertia-dominated initial stage), we identify the existence of mutually contrasting multiple scaling regimes defining the spreading behavior at different time scales. This is attributable to the time-stage-wise upsurge of capillarity or thermocapillarity over the other. In particular, the spreading behavior is characterized by the foot-width (w) evolution with time (t) in a power-law fashion w ~ t(alpha), with alpha being the spreading exponent, defining the rate of spreading. Following pertinent thin-film and subsequent similarity analysis, we identify different asymptotes of alpha over disparate temporal scales, leading to the characterization of different scaling regimes over the entire spreading event starting from the inception of thin-film behavior. Reported literature data are found to correspond well to the present interpretations and estimations. PMID- 25785493 TI - Simultaneous inference of cancer pathways and tumor progression from cross sectional mutation data. AB - Recent cancer sequencing studies provide a wealth of somatic mutation data from a large number of patients. One of the most intriguing and challenging questions arising from this data is to determine whether the temporal order of somatic mutations in a cancer follows any common progression. Since we usually obtain only one sample from a patient, such inferences are commonly made from cross sectional data from different patients. This analysis is complicated by the extensive variation in the somatic mutations across different patients, variation that is reduced by examining combinations of mutations in various pathways. Thus far, methods to reconstruct tumor progression at the pathway level have restricted attention to known, a priori defined pathways. In this work we show how to simultaneously infer pathways and the temporal order of their mutations from cross-sectional data, leveraging on the exclusivity property of driver mutations within a pathway. We define the pathway linear progression model, and derive a combinatorial formulation for the problem of finding the optimal model from mutation data. We show that with enough samples the optimal solution to this problem uniquely identifies the correct model with high probability even when errors are present in the mutation data. We then formulate the problem as an integer linear program (ILP), which allows the analysis of datasets from recent studies with large numbers of samples. We use our algorithm to analyze somatic mutation data from three cancer studies, including two studies from The Cancer Genome Atlas (TCGA) on large number of samples on colorectal cancer and glioblastoma. The models reconstructed with our method capture most of the current knowledge of the progression of somatic mutations in these cancer types, while also providing new insights on the tumor progression at the pathway level. PMID- 25785495 TI - A generic magnetic microsphere platform with "clickable" ligands for purification and immobilization of targeted proteins. AB - While much effort has been made to prepare magnetic microspheres (MMs) with surface moieties that bind to affinity tags or fusion partners of interest in the recombinant proteins, it remains a challenge to develop a generic platform that is capable of incorporating a variety of capture ligands by a simple chemistry. Herein, we developed core-shell structured magnetic microspheres with a high magnetic susceptibility and a low nonspecific protein adsorption. Surface functionalization of these MMs with azide groups facilitates covalent attachment of alkynylated ligands on their surfaces by "click" chemistry and creates a versatile platform for selective purification and immobilization of recombinant proteins carrying corresponding affinity tags. The general applicability of the approach was demonstrated in incorporating four widely used affinity ligands with different reactive groups (-CHO, -SH, -COOH, and -NH2) onto the MMs platform for purification and immobilization of targeted proteins. The azide-functionalized MMs would be applicable for a variety of ligands and substrates that are amenable to alkynylation modification. PMID- 25785497 TI - Feasibility of delivering a dance intervention for subacute stroke in a rehabilitation hospital setting. AB - Dance can be a promising treatment intervention used in rehabilitation for individuals with disabilities to address physical, cognitive and psychological impairments. The aim of this pilot study was to determine the feasibility of a modified dance intervention as an adjunct therapy designed for people with subacute stroke, in a rehabilitation setting. Using a descriptive qualitative study design, a biweekly 45-min dance intervention was offered to individuals with a subacute stroke followed in a rehabilitation hospital, over 4 weeks. The dance intervention followed the structure of an usual dance class, but the exercises were modified and progressed to meet each individual's needs. The dance intervention, delivered in a group format, was feasible in a rehabilitation setting. A 45-min dance class of moderate intensity was of appropriate duration and intensity for individuals with subacute stroke to avoid excessive fatigue and to deliver the appropriate level of challenge. The overall satisfaction of the participants towards the dance class, the availability of space and equipment, and the low level of risks contributed to the feasibility of a dance intervention designed for individuals in the subacute stage of post-stroke recovery. PMID- 25785496 TI - Interventions to reduce harm from smoking with families in infancy and early childhood: a systematic review. AB - Exposure to adult smoking can have deleterious effects on children. Interventions that assist families with smoking cessation/reduction and environmental tobacco smoke (ETS) avoidance can improve child health outcomes and reduce the risk of smoking initiation. The purpose of this review was to describe the state of the science of interventions with families to promote smoke-free home environments for infants and young children, including parent smoking reduction and cessation interventions, ETS reduction, and anti-smoking socialisation interventions, using the socio-ecological framework as a guide. A systematic review of peer-reviewed articles identified from journal databases from 2000 to 2014 was undertaken. Of 921 articles identified, 28 were included in the review. Considerable heterogeneity characterised target populations, intervention types, complexity and intensity, precluding meta-analysis. Few studies used socio-ecological approaches, such as family theories or concepts. Studies in early parenthood (child age newborn to one year) tended to focus on parent smoking cessation, where studies of families with children aged 1-5 years were more likely to target household SHSe reduction. Results suggest that interventions for reduction in ETS may be more successful than for smoking cessation and relapse prevention in families of children aged less than 5 years. There is a need for a range of interventions to support families in creating a smoke free home environment that are both tailored and targeted to specific populations. Interventions that target the social and psychodynamics of the family should be considered further, particularly in reaching vulnerable populations. Consideration is also required for approaches to interventions that may further stigmatise families containing smokers. Further research is required to identify successful elements of interventions and the contexts in which they are most effective. PMID- 25785498 TI - Breastfeeding, bottle feeding practices and malocclusion in the primary dentition: a systematic review of cohort studies. AB - The World Health Organization recommends exclusive breast feeding for at least six months. However, there is no scientific evidence of the benefits of breast feeding for oral health in children under primary dentition. This study aimed to search for scientific evidence regarding the following question: is bottle feeding associated with malocclusion in the primary dentition compared to children that are breastfed? An electronic search was performed in seven databases. The systematic review included 10 cohort studies. It was not possible to conduct meta-analysis; therefore a qualitative analysis was assessed. The majority of studies evaluated feeding habits by means of questionnaires and conducted a single examination. Three studies observed that bottle feeding was significantly associated with overjet and posterior crossbite. Studies reported several cut-off times for breastfeeding (varying from 1 month up to 3 years of age) and several types of malocclusion. Controlling for non-nutritive sucking habits was reported for only half of the studies and this may have led to biased results. The scientific evidence could not confirm a specific type of malocclusion associated with the feeding habits or an adequate time of breastfeeding to benefit the children against malocclusion. Further cohort studies are needed to confirm this evidence. PMID- 25785499 TI - Perceived and objectively measured physical activity and sedentary time among South Asian women in the UK. AB - INTRODUCTION: Limited self-report data suggest that South Asian (SA) women fail to meet physical activity (PA) recommendations. Recent research using objective measures reveals SA women living in the UK have higher PA levels than previously reported, and a pattern of under-reporting PA and sedentary time (ST). There is limited research on SA women's understanding and experiences of PA/ST, and the cultural contexts and conditions within which they occur. Therefore the aims of this mixed-methods study were to compare perceived PA and ST to objectively measured data and explore PA- and ST-specific contexts, experiences, and sources of PA and ST amongst SA women in the UK. METHODS: 24 women were purposively sampled to participate in a semi-structured interview from a larger study of 140 women who wore an accelerometer for 7 days. Demographic and anthropometric data were also collected. RESULTS: Notable qualitative themes on contextualisation were of adequate PA as "keeping busy" or "being healthy", and of ST as "lazy" or "resting in old age". Few participants reported being sedentary, and most believed they were sufficiently physically active. Objectively measured PA/ST indicated that 66% women were less active than perceived (with regard to duration and intensity), with none able to estimate duration of ST. DISCUSSION: Findings suggest that overall, SA women have contextualisations of PA/ST that may not coincide with those of researchers, health professionals and policy makers, and lack awareness of the intensity of PA in which they engage and the health risks of high levels of ST. These findings highlight the need for objective measures of PA and ST in this population combined with in-depth qualitative assessments to provide more accurate assessments of these behaviours. This information can subsequently be used to develop health promotion messages and interventions focusing on increasing duration and/or intensity levels of daily activities (e.g., walking, housework) and reducing ST in this population. PMID- 25785500 TI - Doses to LiF :Ti, Mg chips encapsulated in plastic extremity rings as a result of radon gas exposure. AB - Previous studies measured the effects of (222)Rn on various thermoluminescent dosemeters (TLDs). This study quantified the effects of (222)Rn on LiF : Ti,Mg chips encapsulated in plastic extremity rings. For 28 d, one batch of TLDs was left in a chamber with high radon levels, and another batch in a control chamber with normal background radon levels. A few TLDs in each batch were removed from the rings for direct exposure to the ambient air in each chamber. Passive continuous radon monitors (CRMs) recorded the (222)Rn levels. TLDs were processed using a third-party dosimetry company, CRM data were analysed, and the relationship between integrated (222)Rn concentration and TLD response was determined. The batch of TLDs in the experimental chamber showed a weak response to (222)Rn gas, which was in the order of 0.5 nSv Bq(-1) m(3) d(-1). PMID- 25785501 TI - Occupational determinants of methicillin-resistant Staphylococcus aureus colonization among healthcare workers: a longitudinal study in a rehabilitation center. AB - BACKGROUND Staphylococcus aureus carriage among healthcare workers (HCWs) is a concern in hospital settings, where it may provide a reservoir for later infections in both patients and staff. Earlier studies have shown that the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) carriage in HCWs is highly variable, depending notably on location, hospital department type, MRSA prevalence among patients, and type of contacts with patients. However, MRSA incidence in HCWs and its occupational determinants have seldom been studied. METHODS A prospective, observational cohort study was conducted between May and October 2009 in a French rehabilitation center hospital. HCWs and patients were screened weekly for S. aureus nasal carriage. Methicillin-susceptible S. aureus and MRSA prevalence and incidence were estimated and factors associated with MRSA acquisition were identified using generalized estimating equation regression methods. RESULTS Among 343 HCWs included in the analysis, the average prevalence was 27% (95% CI, 24%-29%) for methicillin-susceptible S. aureus and 10% (8%-11%) for MRSA. We observed 129 MRSA colonization events. According to the multivariable analysis, high MRSA prevalence level among patients and HCW occupation were significantly associated with MRSA acquisition in HCWs, with assistant nurses being more at risk than nurses (odds ratio, 2.2; 95% CI, 1.4 3.6). CONCLUSIONS Our findings may help further our understanding of the transmission dynamics of MRSA carriage acquisition in HCWs, suggesting that it is notably driven by carriage among patients and by the type of contact with patients. PMID- 25785502 TI - Composition-property relationships in multifunctional hollow mesoporous carbon nanosystems for PH-responsive magnetic resonance imaging and on-demand drug release. AB - The construction of intelligent stimuli-responsive nanosystems can substantially improve the sensitivity/resolution/specificity of diagnostic imaging and enhance the therapeutic efficiency of chemotherapy for cancer treatment. This work reports on a generic construction strategy to achieve a multiple stimuli responsive theranostic system for cancer simply by optimizing the chemical compositions of inorganic nanoplatforms to avoid the tedious and complicated synthetic procedure for traditional organic or organic/inorganic nanosystems. Based on the "breaking up" nature of manganese oxides and specific features of the carbonaceous framework to interact with aromatic drug molecules, manganese oxide nanoparticles were elaborately integrated into hollow mesoporous carbon nanocapsules by a simple in situ framework redox strategy to realize concurrent pH-sensitive T1-weighted magnetic resonance imaging (MRI) and pH-/HIFU-responsive on-demand drug release. The ultrasensitive disease-triggered MRI performance has been successfully demonstrated by a 52.5-fold increase of longitudinal relaxivity (r1 = 10.5 mM(-1) s(-1)) and on nude mice 4T1 xenograft. The pH- and HIFU triggered doxorubicin release and enhanced therapeutic outcome against multidrug resistance of cancer cells were systematically confirmed. In particular, the fabricated inorganic composite nanocapsules were found to feature unique biological behaviours, such as antimetastasis effect, extremely low hemolysis against red blood cells and high in vivo histocompatibility. This report on the successful construction of a pure inorganic nanosystem with multiple stimuli responsivenesses may pave the way to new methods for the development of intelligent nanofamilies for cancer therapy. PMID- 25785503 TI - "H2 sponge": pressure as a means for reversible high-capacity hydrogen storage in nanoporous Ca-intercalated covalent organic frameworks. AB - We explore the potential and advantages of Ca-intercalated covalent organic framework-1 (CaCOF-1) as a 3-dimensional (3D) layered material for reversible hydrogen storage. Density functional theory calculations show that by varying the interlayer distance of CaCOF-1, a series of metastable structures can be achieved with the interlayer distance falling in the range of 4.3-4.8 A. When four hydrogen molecules are adsorbed on each Ca, a high hydrogen uptake of 4.54 wt% can be produced, with the binding energy falling in the ideal range of 0.2-0.6 eV per H2. While H2 absorption is a spontaneous process under H2 rich conditions, tuning the interlayer distance by reasonable external pressure could compress CaCOF-1 to release all of the hydrogen molecules and restore the material to its original state for recyclable use. This provides a new method for gradual, controllable extraction of hydrogen molecules in covalent organic frameworks, satisfying the practical demand for reversible hydrogen storage at ambient temperatures. PMID- 25785504 TI - Orotic acid as a useful supramolecular synthon for the fabrication of an OPV based hydrogel: stoichiometry dependent injectable behavior. AB - A facile hydrogelation of a p-pyridylenevinylene derivative (PV) bearing oxyethylene chains in the presence of orotic acid (OA) occurs via various non covalent interactions. Depending on the PV : OA molar ratio, the hydrogel shows vesicle to either cluster-type aggregate or fiber transformation. Visual color tuning, stimuli-responsiveness and injectable properties of the hydrogel are also observed. PMID- 25785505 TI - Zinc oxide as a defect-dominated material in thin films for photovoltaic applications--experimental determination of defect levels, quantification of composition, and construction of band diagram. AB - In the present work, thin ZnO layers were synthesized by the sol-gel method with subsequent spin-coating on Si(100). We show that the detailed analysis of lab recorded photoemission spectra in combination with Kelvin probe data yielded the work function, ionization energy, and valence band - Fermi level separation - and hence enabled the construction of band diagrams of the examined layers. With small modifications in preparation, very different films can be obtained. One set shows a homogeneous depth-dependent n carrier distribution, and another a significant carrier concentration gradient from n-type conductivity to almost metal-like n(+) character. Likewise, the surface morphology can be tuned from a uniform, compact surface with spherical single-nm sized grain-like features to a structured surface with 5-10 nm tall crystallites with (002) dominating crystal orientation. Based on the band-bending and the energy levels observed, defects of contradictory nature, i.e. acceptor-donor-trap (ADT) properties, were identified. These defects may be groups of point defects, with opposite character. The ADT states affect the energy levels of the oxide layers and due to their nature cannot be considered in the photoemission experiment as mutually independent. The versatile nature of the synthesis provides us with the opportunity to tune the properties with a high degree of freedom, at low processing costs, yielding layers with an exotic electronic structure. Such layers are interesting candidates for applications in photovoltaic and nanoelectronic devices. PMID- 25785506 TI - Palladium-catalyzed Hiyama coupling reaction of arylsulfonyl hydrazides under oxygen. AB - Palladium-catalyzed Hiyama cross-coupling reactions of various arylsulfonyl hydrazides with a wide variety of aryl silanes have been achieved in good to excellent yields under simple conditions. The newly developed catalytic system does not require the use of expensive silver- or copper-based stoichiometric oxidants and can be accelerated by the addition of TBAT under an atmosphere of oxygen. The reported Hiyama-type coupling reactions are tolerant to common functional groups, making these transformations attractive alternatives to the traditional cross-coupling approaches. PMID- 25785507 TI - Ag plasmonic nanostructures and a novel gel electrolyte in a high efficiency TiO2/CdS solar cell. AB - A novel photoanode architecture with plasmonic silver (Ag) nanostructures embedded in titania (TiO2), which served as the wide band gap semiconducting support and CdS quantum dots (QDs), as light absorbers, is presented. Ag nanostructures were prepared by a polyol method and are comprised of clumps of nanorods, 15-35 nm wide, interspersed with globular nanoparticles and they were characterized by a face centered cubic lattice. Optimization of Ag nanostructures was achieved on the basis of a superior power conversion efficiency (PCE) obtained for the cell with a Ag/TiO2/CdS electrode encompassing a mixed morphology of Ag nano-rods and particles, relative to analogous cells with either Ag nanoparticles or Ag nanorods. Interfacial charge transfer kinetics was unraveled by fluorescence quenching and lifetime studies. Ag nanostructures improve the light harvesting ability of the TiO2/CdS photoanode via (a) plasmonic and scattering effects, which induce both near- and far-field enhancements which translate to higher photocurrent densities and (b) charging effects, whereby, photoexcited electron transfer from TiO2 to Ag is facilitated by Fermi level equilibration. Owing to the spectacular ability of Ag nanostructures to increase light absorption, a greatly increased PCE of 4.27% and a maximum external quantum efficiency of 55% (at 440 nm) was achieved for the cell based on Ag/TiO2/CdS, greater by 42 and 66%, respectively, compared to the TiO2/CdS based cell. In addition, the liquid S(2-) electrolyte was replaced by a S(2-) gel containing fumed silica, and the redox potential, conductivity and p-type conduction of the two were deduced to be comparable. Although the gel based cells showed diminished solar cell performances compared to their liquid counterparts, nonetheless, the Ag/TiO2/CdS electrode continued to outperform the TiO2/CdS electrode. Our studies demonstrate that Ag nanostructures effectively capture a significant chunk of the electromagnetic spectrum and aid QD solar cells in delivering high power conversion efficiencies. PMID- 25785509 TI - Erythrodermic Epidermolysis Bullosa Acquisita. PMID- 25785512 TI - Incorrect academic degree. PMID- 25785514 TI - Metal-enhanced luminescence of silicon quantum dots: effects of nanoparticles and molecular electron donors and acceptors on the photofading kinetics. AB - Alkyl-capped silicon quantum dots (SiQDs) show enhanced luminescence when drop cast as films on glass slides in mixtures with Ag or Au nanoparticles or the electron donor ferrocene (Fc). Metal enhancement of quantum dot photoluminescence (PL) is known to arise from a combination of the intense near-field associated with the surface plasmon of the metal on the rate of absorption and the decrease in the lifetime of the excited state. Here we present evidence that an additional factor is also involved: electron transfer from the metal to the quantum dot. Under CW irradiation with an argon ion laser at 488 nm, SiQDs undergo a reversible photofading of the PL as the particles photoionize. A steady-state condition is established by the competition between photoionization and electron hole recombination. The fading of the initial PL I0 to the steady-state value Iinfinity can be modelled by a simple first order decay with a lognormal distribution of rates, which reflects the heterogeneity of the sample. In the presence of Ag and Au nanoparticles, the modal rate constants of photofading increase by factors of up to 4-fold and the ratio I0/Iinfinity decreases by factors up to 5-fold; this is consistent with an increase in the rate of electron hole recombination facilitated by the metal nanoparticles acting as sources of electrons. Further support for this interpretation comes from the enhancement in PL observed in photofading experiments with films of SiQDs mixed with Fc; this compound is a well-known one-electron donor, but shows no plasmon band which complicates the estimation of PL enhancement with Ag NPs. PMID- 25785510 TI - Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms. AB - IMPORTANCE: The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype. OBJECTIVE: To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing. DESIGN, SETTING, AND PARTICIPANTS: The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10,000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children's hospital health care network, between November 1, 2009 to November 30, 2011. A subsample of 1445 youths underwent neuroimaging, including functional magnetic resonance imaging tasks examined herein. Participants were youth aged 11 to 22 years old identified through structured interview as having PS features (PS group) (n = 260) and typically developing (TD) comparison youth without significant psychopathology (TD group) (n = 220). MAIN OUTCOMES AND MEASURES: Two functional magnetic resonance imaging paradigms were used: a fractal n-back working memory task probing executive system function and an emotion identification task probing amygdala responses to threatening faces. RESULTS: In the n-back task, working memory evoked lower activation in the PS group than the TD group throughout the executive control circuitry, including dorsolateral prefrontal cortex (cluster corrected P < .05). Within the PS group, dorsolateral prefrontal cortex activation correlated with cognitive deficits (r = .32, P < .001), but no correlation was found with positive symptom severity. During emotion identification, PS demonstrated elevated responses to threatening facial expressions in amygdala, as well as left fusiform cortex and right middle frontal gyrus (cluster-corrected P < .05). The response in the amygdala correlated with positive symptom severity (r = .16, P = .01) but not with cognitive deficits. CONCLUSIONS AND RELEVANCE: The pattern of functional abnormalities observed in the PS group is similar to that previously found in schizophrenia and help seeking risk samples. Specific circuit dysfunction during cognitive and emotion processing tasks is present early in the development of psychopathology and herein could not be attributed to chronic illness or medication confounds. Hypoactivation in executive circuitry and limbic hyperactivation to threat could reflect partly independent risk factors for PS symptoms, with the former relating to cognitive deficits that increase the risk for developing psychotic symptoms and the latter contributing directly to positive psychotic symptoms. PMID- 25785515 TI - From lesions to viral clones: biological and molecular diversity amongst autochthonous Brazilian vaccinia virus. AB - Vaccinia virus (VACV) has had an important role for humanity because of its use during the smallpox eradication campaign. VACV is the etiologic agent of the bovine vaccinia (BV), an emerging zoonosis that has been associated with economic, social, veterinary and public health problems, mainly in Brazil and India. Despite the current and historical VACV importance, there is little information about its circulation, prevalence, origins and maintenance in the environment, natural reservoirs and diversity. Brazilian VACV (VACV-BR) are grouped into at least two groups based on genetic and biological diversity: group 1 (G1) and group 2 (G2). In this study, we went to the field and investigated VACV clonal diversity directly from exanthemous lesions, during BV outbreaks. Our results demonstrate that the G1 VACV-BR were more frequently isolated. Furthermore, we were able to co-detect the two variants (G1 and G2) in the same sample. Molecular and biological analysis corroborated previous reports and confirmed the co-circulation of two VACV-BR lineages. The detected G2 clones presented exclusive genetic and biological markers, distinct to reference isolates, including VACV-Western Reserve. Two clones presented a mosaic profile, with both G1 and G2 features based on the molecular analysis of A56R, A26L and C23L genes. Indeed, some SNPs and INDELs in A56R nucleotide sequences were observed among clones of the same virus population, maybe as a result of an increased mutation rate in a mixed population. These results provide information about the diversity profile in VACV populations, highlighting its importance to VACV evolution and maintenance in the environment. PMID- 25785517 TI - Lithium Electrodeposition Dynamics in Aprotic Electrolyte Observed in Situ via Transmission Electron Microscopy. AB - Electrodeposited metallic lithium is an ideal negative battery electrode, but nonuniform microstructure evolution during cycling leads to degradation and safety issues. A better understanding of the Li plating and stripping processes is needed to enable practical Li-metal batteries. Here we use a custom microfabricated, sealed liquid cell for in situ scanning transmission electron microscopy (STEM) to image the first few cycles of lithium electrodeposition/dissolution in liquid aprotic electrolyte at submicron resolution. Cycling at current densities from 1 to 25 mA/cm(2) leads to variations in grain structure, with higher current densities giving a more needle like, higher surface area deposit. The effect of the electron beam was explored, and it was found that, even with minimal beam exposure, beam-induced surface film formation could alter the Li microstructure. The electrochemical dissolution was seen to initiate from isolated points on grains rather than uniformly across the Li surface, due to the stabilizing solid electrolyte interphase surface film. We discuss the implications for operando STEM liquid-cell imaging and Li-battery applications. PMID- 25785516 TI - Human endogenous retrovirus group E and its involvement in diseases. AB - Human endogenous retrovirus group E (HERV-E) elements are stably integrated into the human genome, transmitted vertically in a Mendelian manner, and are endowed with transcriptional activity as alternative promoters or enhancers. Such effects are under the control of the proviral long terminal repeats (LTR) that are organized into three HERV-E phylogenetic subgroups, namely LTR2, LTR2B, and LTR2C. Moreover, HERV-E expression is tissue-specific, and silenced by epigenetic constraints that may be disrupted in cancer, autoimmunity, and human placentation. Interest in HERV-E with regard to these conditions has been stimulated further by concerns regarding the capacity of HERV-E elements to modify the expression of neighboring genes and/or to produce retroviral proteins, including immunosuppressive env peptides, which in turn may induce (auto) antibody (Ab) production. Finally, better understanding of HERV-E elements may have clinical applications for prevention, diagnosis, prognosis, and therapy. PMID- 25785518 TI - Characterization of covalent bond formation between PPARgamma and oxo-fatty acids. AB - Covalent modification of proteins is important for normal cellular regulation. Here, we report on the covalent modification of peroxisome proliferator-activated receptor gamma (PPARgamma), an important drug target, by oxo-fatty acids. In this study, ESI mass spectroscopy showed that the reactivities of oxo-fatty acids with PPARgamma are different from one another and that these behaviors are related to the structure of the fatty acids. X-ray crystallography showed that three oxo fatty acids all bound to the same residue of PPARgamma (Cys285), but displayed different hydrogen bonding modes. Moreover, fatty acids formed covalent bonds with both PPARgamma moieties in the homodimer, one in an active conformation and the other in an alternative conformation. These two conformations may explain why covalently bound fatty acids show partial rather than full agonist activity. PMID- 25785519 TI - Interaction of sodium bicarbonate and Na+/H+ exchanger inhibition in the treatment of acute metabolic acidosis in pigs. AB - OBJECTIVE: Administration of NaHCO3 does not improve cellular function or reduce the mortality of acute lactic acidosis. This might be related to aggravation of intracellular acidosis, but it could also be due to activation of Na+/H+ exchanger with a deleterious increment in intracellular calcium ([Ca2+]i). This study examined the impact of coadministration of NaHCO3 and a selective inhibitor of Na+/H+ exchanger, sabiporide on cardiovascular function, changes in proinflammatory cytokines, and organ function in a model of acute lactic acidosis produced by hemorrhagic hypotension followed by infusion of lactic acid. DESIGN: Experimental, prospective study. SETTING: Medical Center research laboratory. SUBJECTS: Male Yorkshire pigs. INTERVENTIONS: Anesthetized pigs were subjected to hypovolemia for 30 minutes and followed by DL-lactic acid infusion, and then either saline or sodium bicarbonate was infused. MEASUREMENTS AND MAIN RESULTS: Hypovolemia followed by a DL-lactic acid infusion resulted in severe acidemia with a blood pH~6.8. Administration of NaHCO3 did not improve cardiovascular performance or decrease the levels of proinflammatory responses, whereas administration of sabiporide prior to acid or NaHCO3 infusion improved cardiopulmonary performance and blood oxygenation, reduced nuclear factor-kappaB activation, neutrophil accumulation, and proinflammatory cytokine production, and attenuated organ injury. Exposure of rat cardiac myocytes to a pH of 7.2 led to a marked increase of [Ca2+]i, and release of lactate dehydrogenase from cells which were further augmented after increase in external pH by addition of NaHCO3. Both the increase in [Ca2+]i and release of lactate dehydrogenase were attenuated in the presence of sabiporide. CONCLUSIONS: Coadministration of Na/H exchanger inhibitor with sodium bicarbonate improves cardiovascular performances, reduces proinflammatory responses, and attenuates organ injury. This improvement in these variables appears to be related to prevention of a rise in intracellular calcium occurring after both exposures to acid and bicarbonate. PMID- 25785521 TI - Middle East respiratory syndrome: knowledge to date. AB - OBJECTIVE: To provide a conceptual and clinical review of Middle East respiratory syndrome. DATA SOURCES: Peer-reviewed articles were identified through searches of PubMed using the terms "Middle East respiratory syndrome," "coronavirus respiratory illness in Saudi Arabia," and "novel (beta) coronavirus and human coronavirus Erasmus Medical Center". In addition, articles were searched on the websites of the World Health Organization and the U.S. Centers for Disease Control and Prevention using the terms "Middle East respiratory syndrome" and "novel coronavirus in Middle East." The reference lists of these articles and relevant review articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Final references were selected for inclusion in the review on the basis of their relevance. DATA SYNTHESIS: The emerging Middle East respiratory syndrome coronavirus causes severe pulmonary disease with multiorgan involvement and a high fatality rate. Within months after its emergence, Middle East respiratory syndrome coronavirus was reported in several countries worldwide in people who had traveled from the Middle East. Middle East respiratory syndrome coronavirus is considered a zoonotic virus that has crossed the species barrier to humans, but the pathogenesis and the routes of transmission are not completely understood. There is currently no recommended treatment for Middle East respiratory syndrome coronavirus, although supportive treatment has played an important role. CONCLUSIONS: This syndrome has raised global public health concerns about the dissemination of an emerging infectious disease and highlights the need for a coordinated global response to contain such a disease threat. PMID- 25785520 TI - Coping Strategies and Posttraumatic Stress Symptoms in Post-ICU Family Decision Makers. AB - OBJECTIVE: To assess the coping strategies used by family decision makers of adult critical care patients during and after the critical care experience and the relationship of coping strategies to posttraumatic stress symptoms experienced 60 days after hospitalization. DESIGN: A single-group descriptive longitudinal correlational study. SETTING: Medical, surgical, and neurological ICUs in a large tertiary care university hospital. PATIENTS: Consecutive family decision makers of adult critical care patients from August 2012 to November 2013. Study inclusion occurred after the patient's fifth day in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Family decision makers of incapacitated adult ICU patients completed the Brief COPE instrument assessing coping strategy use 5 days after ICU admission and 30 days after hospital discharge or death of the patient and completed the Impact of Event Scale-Revised assessing posttraumatic stress symptoms 60 days after hospital discharge. Seventy seven family decision makers of the eligible 176 completed all data collection time points of this study. The use of problem-focused (p=0.01) and emotion focused (p<0.01) coping decreased over time while avoidant coping (p=0.20) use remained stable. Coping strategies 30 days after hospitalization (R2=0.50, p<0.001) were better predictors of later posttraumatic stress symptoms than coping strategies 5 days after ICU admission (R2=0.30, p=0.001) controlling for patient and decision-maker characteristics. The role of decision maker for a parent and patient death were the only noncoping predictors of posttraumatic stress symptoms. Avoidant coping use 30 days after hospitalization mediated the relationship between patient death and later posttraumatic stress symptom severity. CONCLUSIONS: Coping strategy use is a significant predictor of posttraumatic stress symptom severity 60 days after hospitalization in family decision makers of ICU patients. PMID- 25785522 TI - Improving the Accuracy of Cardiovascular Component of the Sequential Organ Failure Assessment Score. AB - OBJECTIVES: The Sequential Organ Failure Assessment score is an attractive risk prediction model because of its simplicity and graded assessment of morbidity and mortality. Due to changes in clinical practice over time, the cardiovascular component of the Sequential Organ Failure Assessment score no longer accurately reflects current clinical practice. To address this limitation, we developed and validated a modified cardiovascular component of the Sequential Organ Failure Assessment score that takes into account all vasoactive agents used in current clinical practice, uses shock index as a substitute for mean arterial pressure, and incorporates serum lactate as a biomarker for shock states. DESIGN: Retrospective cohort. SETTING: Mayo Clinic, Rochester, MN. PATIENTS: Adult patients admitted to one of six ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Score performance was assessed via area under the receiver operator characteristic curve. A total of 16,386 ICU admissions were included: 9,204 in the derivation cohort and 7,182 in the validation cohort. area under the receiver operator characteristic curve was significantly higher for modified cardiovascular component of the Sequential Organ Failure Assessment score than for cardiovascular component of the Sequential Organ Failure Assessment for in ICU mortality (0.801 vs 0.718; difference = 0.083; p < 0.001), in-hospital mortality (0.783 vs 0.651; difference = 0.132; p < 0.001), and 28-day mortality (0.737 vs 0.655; difference = 0.082; p < 0.001). When modified cardiovascular component of the Sequential Organ Failure Assessment score was added to the remaining Sequential Organ Failure Assessment components, the modified Sequential Organ Failure Assessment score again outperformed the existing Sequential Organ Failure Assessment score: in-ICU mortality (0.836 vs 0.822; difference = 0.014; p < 0.001), in-hospital mortality (0.799 vs 0.784; difference = 0.015; p < 0.001), and 28-day mortality (0.798 vs 0.783; difference = 0.015; p < 0.001). Similar results were seen in the validation cohort. CONCLUSIONS: The modified cardiovascular component of the Sequential Organ Failure Assessment score outperforms the existing cardiovascular component of the Sequential Organ Failure Assessment score in predicting patient outcomes and improves the overall performance of the Sequential Organ Failure Assessment model. This score is easily calculated, includes serum lactate as a biomarker for shock states, and incorporates all vasopressors used in current clinical practice. PMID- 25785523 TI - Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. AB - Opioid use in chronic pain treatment is complex, as patients may derive both benefit and harm. Identification of individuals currently using opioids in a problematic way is important given the substantial recent increases in prescription rates and consequent increases in morbidity and mortality. The present review provides updated and expanded information regarding rates of problematic opioid use in chronic pain. Because previous reviews have indicated substantial variability in this literature, several steps were taken to enhance precision and utility. First, problematic use was coded using explicitly defined terms, referring to different patterns of use (ie, misuse, abuse, and addiction). Second, average prevalence rates were calculated and weighted by sample size and study quality. Third, the influence of differences in study methodology was examined. In total, data from 38 studies were included. Rates of problematic use were quite broad, ranging from <1% to 81% across studies. Across most calculations, rates of misuse averaged between 21% and 29% (range, 95% confidence interval [CI]: 13%-38%). Rates of addiction averaged between 8% and 12% (range, 95% CI: 3%-17%). Abuse was reported in only a single study. Only 1 difference emerged when study methods were examined, where rates of addiction were lower in studies that identified prevalence assessment as a primary, rather than secondary, objective. Although significant variability remains in this literature, this review provides guidance regarding possible average rates of opioid misuse and addiction and also highlights areas in need of further clarification. PMID- 25785525 TI - Validity of the decoding-encoding screener for dyslexia. AB - PURPOSE: The Decoding-Encoding Screener for Dyslexia (DESD) was developed to identify children who may have reading difficulties. The purpose of this study was to evaluate the validity of the DESD using two standardized tests of reading ability in school-aged children. METHODS: Thirty-one children aged 9 to 15 years enrolled in the study. Each child completed the DESD and two standardized reading assessments, the Wide Range Achievement Test-Third Edition (WRAT-3) and the Gray Oral Reading Test-Fourth Edition (GORT-4). Pearson correlations were used to compare the DESD Reading Test with the WRAT-3 and GORT-4, and Spearman correlation coefficients were used to measure the associations between the DESD Spelling Scale and the WRAT-3 and GORT-4. RESULTS: Pearson correlation coefficients between the DESD Reading Test standard score and WRAT-3 Spelling subtest and GORT-4 were large, with the exception of the WRAT-3 Word Reading subtest, which had a small correlation. Spearman rank correlations between the DESD Spelling score and the GORT-4 and WRAT-3 Spelling subtest were large to very large, but only a moderate correlation was found with the WRAT-3 Word Reading subtest. CONCLUSIONS: The DESD Reading Test and Spelling Scale had significant correlations with the WRAT-3 Spelling subtest and GORT-4. However, the small correlation between the DESD Reading Test and the WRAT-3 Word Reading subtest indicates that some caution should be used when interpreting the results of the DESD Reading Test. Therefore, practitioners may find the DESD Spelling Scale to be a more useful tool in identifying children who may have reading difficulties. PMID- 25785524 TI - Induction of long-term potentiation and long-term depression is cell-type specific in the spinal cord. AB - The underlying mechanism of chronic pain is believed to be changes in excitability in spinal dorsal horn (DH) neurons that respond abnormally to peripheral input. Increased excitability in pain transmission neurons, and depression of inhibitory neurons, are widely recognized in the spinal cord of animal models of chronic pain. The possible occurrence of 2 parallel but opposing forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) was tested in 2 types of identified DH neurons using whole-cell patch-clamp recordings in mouse spinal cord slices. The test stimulus was applied to the sensory fibers to evoke excitatory postsynaptic currents in identified spinothalamic tract neurons (STTn) and GABAergic neurons (GABAn). Afferent conditioning stimulation (ACS) applied to primary afferent fibers with various stimulation parameters induced LTP in STTn but LTD in GABAn, regardless of stimulation parameters. These opposite responses were further confirmed by simultaneous dual patch-clamp recordings of STTn and GABAn from a single spinal cord slice. Both the LTP in STTn and the LTD in GABAn were blocked by an NMDA receptor antagonist, AP5, or an intracellular Ca chelator, BAPTA. Both the pattern and magnitude of intracellular Ca after ACS were almost identical between STTn and GABAn based on live-cell calcium imaging. The results suggest that the intense sensory input induces an NMDA receptor-dependent intracellular Ca increase in both STTn and GABAn, but produces opposing synaptic plasticity. This study shows that there is cell type-specific synaptic plasticity in the spinal DH. PMID- 25785526 TI - Comparison of three types of images for the detection of retinal nerve fiber layer defects. AB - PURPOSE: To compare the clinical effectiveness of three types of images for detecting retinal nerve fiber layer (RNFL) defects. METHODS: Three image sets of 100 subjects (9 normal control subjects, 16 glaucoma suspects, and 75 glaucoma patients) were produced using color fundus photography, typical red-free RNFL photography, and blue reflectance RNFL photography with confocal scanning laser ophthalmoscopy (CSLO). A total of 300 images were rated twice in random order by five independent evaluators who were masked to the patient characteristics; each image was rated as normal, having a diffuse RNFL defect, or showing a wedge RNFL defect. Intraobserver and interobserver agreement, sensitivity, specificity, accuracy, and area under the curve were assessed. An additional analysis was performed for identifying differences in two black-and-white RNFL photographs. RESULTS: The results showed high intraobserver agreement, with relatively low interobserver agreements among the five evaluators. Blue reflectance RNFL photography with CSLO demonstrated the best performance in sensitivity, specificity, accuracy, and area under the curve. Blue reflectance RNFL images showed better accuracy than red-free RNFL images especially in subjects with wedge defects and in advanced glaucomatous cases. CONCLUSIONS: The RNFL images produced using blue reflectance with CSLO showed the best performance for the detection of RNFL defects, especially in cases with wedge defects and advanced glaucoma stages. PMID- 25785528 TI - Efficacy of antimicrobials against biofilms of Achromobacter and Pseudomonas. AB - PURPOSE: Achromobacter xylosoxidans and Pseudomonas aeruginosa biofilms can develop in ophthalmic products and accessories such as contact lens cases, leading to the development of ocular infections. This study evaluated the efficacy of the antimicrobials polyaminopropyl biguanide (PAPB) and benzalkonium chloride (BAK) against A. xylosoxidans and P. aeruginosa biofilms. METHODS: Biofilms of A. xylosoxidans and P. aeruginosa used as a comparative control were formed by incubating the bacteria on contact lens cases and on coverslips in phosphate-buffered saline. The biofilms were then exposed to PAPB and BAK for 5 minutes and 4 hours. After exposure, alginate swabs were used to remove the biofilms from the lens cases and the bacteria were plated on tryptic soy agar for determination of survivors. Also, after exposure to these disinfectants, the A. xylosoxidans and P. aeruginosa biofilms were stained with SYTO 9 and propidium iodide. Using a confocal microscope with a 488-nm laser, the number of cells with damaged cell membranes was determined. RESULTS: After 5 minutes of exposure to BAK or PAPB, A. xylosoxidans biofilms were more resistant to the antimicrobial effects of these disinfectants than P. aeruginosa biofilms. After 4 hours, both organisms were reduced by more than 3 logs after exposure to either BAK or PAPB. Confocal microscopy studies revealed that BAK was more effective at damaging A. xylosoxidans and P. aeruginosa cell membranes than PAPB at the concentrations used in ophthalmic products. CONCLUSIONS: Biofilms of the emerging pathogen A. xylosoxidans were more resistant to the disinfectants PAPB and BAK than biofilms of P. aeruginosa. Because of the emergence of A. xylosoxidans and the demonstrated greater resistance to the common ophthalmic preservatives BAK and PAPB than the standard Gram-negative organism P. aeruginosa, A. xylosoxidans biofilms should be assessed in antimicrobial challenge tests to assure the safety of multiuse ophthalmic products. PMID- 25785527 TI - Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye. AB - PURPOSE: Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)-related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. CASE REPORTS: Case 1. A 61-year old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. CONCLUSIONS: Long-term treatment with topical rebamipide and diquafosol can improve dry eye in patients with cGVHD or OCP-like disease. PMID- 25785529 TI - LASIK-induced aberrations: comparing corneal and whole-eye measurements. AB - PURPOSE: To compare the change in aberrations produced by laser-assisted in situ keratomileusis (LASIK) measured by either front surface corneal aberrometry or Hartmann-Shack whole-eye aberrometry. METHODS: This was a retrospective case series from consecutive patients treated with LASIK at the London Vision Clinic, London, UK. Corneal and ocular wavefront data were collected before and after LASIK for myopia and hyperopia. To control for centration of corneal and whole eye aberration measurements, only patients with pupil offset (measured as the distance between the corneal vertex and the entrance pupil center) of 0.25 mm or less were recruited. Corneal front surface wavefront was obtained from a Placido based corneal topography system (Atlas), and whole-eye wavefront was measured by Hartmann-Shack aberrometry (WASCA) before and at least 3 months after surgery. All aberrations were calculated up to the fourth order for the 6-mm pupil diameter. Change in HORMS (higher-order root mean square [RMS]) and all individual Zernike coefficients from the second to the fourth order were compared. RESULTS: One hundred myopic eyes and 50 hyperopic eyes were included for analysis. For myopic LASIK, the change measured by corneal aberrometry or whole-eye aberrometry differed on average by 0.077 MUm for HORMS, by 0.024 MUm for secondary astigmatism, and by 0.065 MUm for spherical aberration (p <= 0.003). For hyperopic LASIK, there was no statistically significant difference between the change measured by corneal aberrometry and whole-eye aberrometry for third- and fourth-order individual Zernike coefficients (p >= 0.034). However, the change in HORMS measured by whole-eye aberrometry was 0.095 MUm greater than that measured by corneal aberrometry (p < 0.001). CONCLUSIONS: This study demonstrated that when measuring the change in higher-order aberrations induced by LASIK, corneal front surface aberrometry measurement was not interchangeable with whole-eye ocular aberrometry. PMID- 25785530 TI - Evaluation of the Waggoner Computerized Color Vision Test. AB - PURPOSE: Clinical color vision evaluation has been based primarily on the same set of tests for the past several decades. Recently, computer-based color vision tests have been devised, and these have several advantages but are still not widely used. In this study, we evaluated the Waggoner Computerized Color Vision Test (CCVT), which was developed for widespread use with common computer systems. METHODS: A sample of subjects with (n = 59) and without (n = 361) color vision deficiency (CVD) were tested on the CCVT, the anomaloscope, the Richmond HRR (Hardy-Rand-Rittler) (4th edition), and the Ishihara test. The CCVT was administered in two ways: (1) on a computer monitor using its default settings and (2) on one standardized to a correlated color temperature (CCT) of 6500 K. Twenty-four subjects with CVD performed the CCVT both ways. Sensitivity, specificity, and correct classification rates were determined. RESULTS: The screening performance of the CCVT was good (95% sensitivity, 100% specificity). The CCVT classified subjects as deutan or protan in agreement with anomaloscopy 89% of the time. It generally classified subjects as having a more severe defect compared with other tests. Results from 18 of the 24 subjects with CVD tested under both default and calibrated CCT conditions were the same, whereas the results from 6 subjects had better agreement with other test results when the CCT was set. CONCLUSIONS: The Waggoner CCVT is an adequate color vision screening test with several advantages and appears to provide a fairly accurate diagnosis of deficiency type. Used in conjunction with other color vision tests, it may be a useful addition to a color vision test battery. PMID- 25785531 TI - Biometric and intraocular pressure change after cataract surgery. AB - PURPOSE: To evaluate changes in ocular biometric parameters with optical biometry and intraocular pressure (IOP) by Goldmann tonometry after uneventful phacoemulsification in normotensive eyes. METHODS: This prospective study was composed of 117 eyes of 117 patients who had undergone uncomplicated phacoemulsification and foldable intraocular lens implantation. The measurements were obtained preoperatively and 1 month postoperatively. Axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), pupil diameter (PD), and lens thickness were measured by the LenStar optical biometer, and IOP was measured by Goldmann applanation tonometry. The relationships between IOP change and ocular biometric parameters were evaluated. RESULTS: Mean age was 64.73 +/- 10.83 years; 45 patients were women (38.46%) and 72 patients were men (61.54%). Comparing preoperative and postoperative 1-month measurements, the mean AL, PD, and IOP decreased (p < 0.01), whereas ACD (p < 0.01) and CCT (p > 0.05) increased. Intraocular pressure change correlated positively with AL change (p < 0.05) and PD change (p < 0.05) and preoperative IOP (p < 0.01) and preoperative CCT (p < 0.05). Anterior chamber depth change correlated positively with preoperative ACD (p < 0.01) and negatively with preoperative PD (p < 0.05). Pupil diameter change positively correlated with preoperative PD (p < 0.01). Regression analyses showed that preoperative IOP significantly associated with postoperative IOP reduction according to the standardized coefficient beta (-0.649). CONCLUSIONS: Anterior segment morphometry changed and IOP decreased after phacoemulsification. The preoperative IOP may be the best parameter for estimating postoperative IOP reduction. PMID- 25785532 TI - Attitudes and barriers to evidence-based practice in optometry educators. AB - PURPOSE: Evidence-based practice (EBP) is an essential component of good quality, patient-centered health care. This requires practitioners to acquire EBP skills and knowledge during undergraduate and continuing education. Evidence-based practice education exists in a range of health care disciplines, including optometry. Evidence-based practice education, however, depends on relevant skills and knowledge in educators. Courses and workshops exist for the development of EBP teaching skills in some areas of health care but not in optometry. Here, we describe a pilot workshop designed to enhance the teaching of EBP and to investigate the perspectives of optometric educators on EBP including their attitudes and perceived barriers to EBP and its teaching. METHODS: Twenty-seven optometric educators including 8 facilitators participated. Of these, 14 were academics (including the 8 facilitators) and 13 were practitioners. Evidence based practice attitudes were assessed using the Evidence-Based Practice Attitude Scale-50 with appropriate modifications for optometry. Workshop design incorporated strategies to trigger discussion among participants. A nominal group technique was used to identify, prioritize, and reach consensus on barriers to EBP. RESULTS: Although some participants expressed reservations about EBP, a common understanding of the contemporary definition of EBP emerged in educators. Thirty-five barriers to EBP were identified; "time" was selected in the top five barriers by most participants and attracted the highest total score, well above any other barrier (negative attitude to EBP, volume of evidence, integration with clinical practice, and lack of lifelong learning mind-set). Attitudes toward EBP were generally positive and negatively correlated with age and time since graduation, respectively. CONCLUSIONS: A group of optometrists and academics new to implementing education in EBP displayed positive attitudes to EBP but considered that its application and teaching could be significantly hindered by a lack of time to access and appraise the large volume of available research evidence in the field of eye care. PMID- 25785533 TI - Peripheral prism glasses: effects of moving and stationary backgrounds. AB - PURPOSE: Unilateral peripheral prisms for homonymous hemianopia (HH) expand the visual field through peripheral binocular visual confusion, a stimulus for binocular rivalry that could lead to reduced predominance and partial suppression of the prism image, thereby limiting device functionality. Using natural-scene images and motion videos, we evaluated whether detection was reduced in binocular compared with monocular viewing. METHODS: Detection rates of nine participants with HH or quadranopia and normal binocularity wearing peripheral prisms were determined for static checkerboard perimetry targets briefly presented in the prism expansion area and the seeing hemifield. Perimetry was conducted under monocular and binocular viewing with targets presented over videos of real-world driving scenes and still frame images derived from those videos. RESULTS: With unilateral prisms, detection rates in the prism expansion area were significantly lower in binocular than in monocular (prism eye) viewing on the motion background (medians, 13 and 58%, respectively, p = 0.008) but not the still frame background (medians, 63 and 68%, p = 0.123). When the stimulus for binocular rivalry was reduced by fitting prisms bilaterally in one HH and one normally sighted subject with simulated HH, prism-area detection rates on the motion background were not significantly different (p > 0.6) in binocular and monocular viewing. CONCLUSIONS: Conflicting binocular motion appears to be a stimulus for reduced predominance of the prism image in binocular viewing when using unilateral peripheral prisms. However, the effect was only found for relatively small targets. Further testing is needed to determine the extent to which this phenomenon might affect the functionality of unilateral peripheral prisms in more real-world situations. PMID- 25785534 TI - Different amounts of alcohol consumption and cataract: a meta-analysis. AB - PURPOSE: To evaluate the association between different amounts of alcohol consumption and the risk of age-related cataract. METHODS: We searched PubMed and Embase from their inception until May 2014 for case-control or cohort studies with data on alcohol consumption and age-related cataract. Heavy alcohol consumption was defined as more than two standard drinks per day, which is equal to a daily intake of 20 g of alcohol or 140 g per week. Moderate consumption was defined as less than 20 g of alcohol per day but more than never any. We performed separate meta-analyses for the associations of moderate or heavy alcohol consumption with age-related cataract under a random-effects model, respectively. RESULTS: Five case-control and five cohort studies were identified through comprehensive literature search. In the meta-analysis of 10 studies, the associations between moderate alcohol consumption and age-related cataract were marginally nonsignificant (pooled relative risk, 0.88; 95% confidence interval, 0.74 to 1.05; I = 82.1%), whereas heavy alcohol consumption was associated with an increased risk of age-related cataract (pooled relative risk, 1.26; 95% confidence interval, 1.06 to 1.50; I = 58.9%). The association between heavy alcohol consumption and cataract was stronger in case-control than in cohort studies. Adjusting for smoking as a potential confounder attenuated the association between heavy alcohol consumption and cataract. CONCLUSIONS: Heavy alcohol consumption significantly increased the risk of age-related cataract, whereas moderate consumption may be protective for this ocular condition. Clinically, information on a patient's alcohol drinking history might be valuable to general physicians and ophthalmologists when there is a diagnosis of age related cataract and should be collected on a routine basis in eye clinics. PMID- 25785535 TI - Self-refraction accuracy with adjustable spectacles among children in Ghana. AB - PURPOSE: To determine the accuracy of self-refraction (SR) in myopic teenagers, we compared visual and refractive outcomes of self-refracting spectacles (FocusSpecs) with those obtained using cycloplegic subjective refraction (CSR) as a gold standard. METHODS: A total of 203 eligible schoolchildren (mean [+/-SD] age, 13.8 [+/-1.0] years; 59.1% were female) completed an examination consisting of SR with FocusSpecs adjustable spectacles, visual acuity with the logMAR (logarithm of the minimum angle of resolution) chart, cycloplegic retinoscopy, and CSR. Examiners were masked to the SR findings. Wilcoxon signed rank test and paired Student t test were used to compare measures across refraction methods (95% confidence intervals [CIs]). RESULTS: The mean (+/-SD) spherical equivalent refractive error measured by CSR and SR was -1.22 (+/-0.49) diopters (D) and 1.66 (+/-0.73) D, respectively, a statistically significant difference of -0.44 D (p < 0.001, t = 15.517). The greatest proportion of participants was correctable to visual acuity greater than or equal to 6/7.5 (logMAR 0.1) in the better eye by CSR (99.0%; 95% CI, 96.5 to 99.7%), followed by cycloplegic retinoscopy (94.1%; 95% CI, 90.0 to 96.6%) and SR (85.2%; 95% CI, 79.7 to 89.5%). These proportions differed significantly from each other (p < 0.001, Wilcoxon signed rank test). Myopic inaccuracy of greater than 0.50 D and greater than or equal to -1.00 D was present in 29 (15.3%) and 16 (8.4%) right eyes, respectively, with SR. In logistic regression models, failure to achieve visual acuity greater than or equal to 6/7.5 in right eyes with SR was significantly associated with age (odds ratio, 1.92; 95% CI, 1.12 to 3.28; p = 0.017) and spherical power (odds ratio, 0.017; 95% CI, 0.005 to 0.056; p < 0.001). CONCLUSIONS: Self-refraction offers acceptable visual and refractive results for young people in a rural setting in Ghana, although myopic inaccuracy in the more negative direction occurred in some children. PMID- 25785536 TI - Genes in dizygote twins with Bowman layer corneal dystrophy. AB - PURPOSE: To report a de novo R124C mutation of transforming growth factor beta induced (TGFBI) gene in one of dizygotic twins with corneal dystrophy of the Bowman layer. CASE REPORT: An 11-year-old boy was one of dizygotic twins and had a history of bilateral blurred vision and recurrent corneal erosion. Examination of the visual acuity demonstrated 20/40 in his each eye. Biomicroscopy showed bilaterally central corneal subepithelial opacities and some dot opacities in the superficial stroma. Anterior segment optical coherence tomography demonstrated most hyperreflective opacities at the subepithelial layer with some interspersed opacities in the superficial stroma. Confocal microscopy revealed irregular hyperreflective materials in the Bowman layer and the superficial stroma. Several rough filaments were found in the middle layer of stroma, corresponding to a feature of amyloid lattice. The corneas of his parents and dizygotic sister were clear. Sequencing of the TGFBI gene revealed an R124C mutation in the affected boy but not in his three healthy family members. CONCLUSIONS: A de novo R124C mutation of the TGFBI gene may occur in one of dizygotic twins. Patients with an R124C mutation may have clinical features like corneal dystrophy of the Bowman layer. Confocal microscopy can be used to detect subclinical lattice lines, thereby facilitating differential diagnosis. PMID- 25785537 TI - Refractive error and ocular parameters: comparison of two SD-OCT systems. AB - PURPOSE: Spectral domain optical coherence tomography (OCT) was used to examine the influence of refractive error (RE) on foveal retinal and choroidal thicknesses and scleral canal width (SCW). The performance of the Cirrus and Bioptigen spectral domain OCT instruments was compared in the same eyes. METHODS: Both eyes of 40 healthy human subjects, aged 22 to 38 years, were dilated and imaged, with the Cirrus OCT, using 6-mm five-line rasters collapsed into one line, one centered on the fovea and one bisecting the optic nerve head. Seventy two of the same eyes were imaged with the Bioptigen OCT, using 6- by 6-mm scans, one centered on the fovea and one on the optic nerve head. Subfoveal retinal and choroidal thicknesses and SCW were measured. Axial lengths (ALs) and REs were obtained using an IOLMaster and a Grand Seiko autorefractor, respectively. RESULTS: Only right eyes were included in analyses. Spherical equivalent REs ranged from -12.18 to +8.12 diopters (mean [+/-SD], -3.44 [+/-4.06] diopters), and ALs ranged from 20.56 to 29.17 mm (mean [+/-SD], 24.86 [+/-1.91] mm). Myopia was associated with relatively thin choroids at the fovea (p < 0.05) but normal retinal thickness. Scleral canal width was significantly correlated with AL as measured with the Bioptigen OCT (p < 0.05). Retinal and choroidal thicknesses recorded with the Bioptigen OCT tended to be smaller than values obtained with the Cirrus OCT (mean difference, 5.63 and 24.76 MUm, respectively), whereas the converse was true for the SCW (mean difference, 25.45 MUm). CONCLUSIONS: The finding that high myopes tend to have a thinner subfoveal choroid is consistent with previous studies. That high myopia was linked to enlarged scleral canals may help to explain the increased risk of glaucoma in myopia. Observed differences obtained with the Cirrus and Bioptigen instruments urge caution in comparing results collected with different instruments. PMID- 25785539 TI - Which ratio of areas improves vision quality in simultaneous focus optics? AB - PURPOSE: To evaluate the impact of the center optical zone diameter (COZD) of center-near bifocal optics on the through-focus subjective quality of vision. METHODS: Subjective image quality was assessed by 14 young, normally sighted subjects. Computed images of three high-contrast 20/50 letters were generated, across a range of object vergences from +2 diopters (D) to -4 D in 0.25-D steps. The center near optical zone addition power was +2.50 D, and the diameter of this center zone was varied in 10% steps to cover from 0% (single vision distance) to 90% of the 4.5-mm pupil diameter. Subjects rated image clarity of these computed images on a 0 to 5 scale, through a 3-mm pupil to limit the effect of their own aberrations. RESULTS: To quantify the efficiency of bifocal optics, we calculated the area under the through-focus subjective quality of vision curve. A criterion higher than 2 was judged to be an acceptable level of quality of vision, normalized by the naked eye condition. The average benefit of the optical profiles is highly subject dependent (i.e., from 0.8 to 1.9), potentially explaining why some subjects are not satisfied with simultaneous vision multifocal corrections. Averaged across subjects, the best benefit (i.e., 1.42) was obtained with a COZD covering 40% of the pupil area, whereas the 20, 30, and 50% profiles provide slightly lower benefit (i.e., ~1.35). A COZD covering 20% of the pupil area equalized distance and near quality of vision. CONCLUSIONS: Quality of vision with bifocal optics is highly subject dependent. Peripheral rays do not seem to play an important role in the through-focus quality of vision, as the central pupil area is more heavily weighted in determining subjective image quality. PMID- 25785538 TI - Effects of optical blur reduction on equivalent intrinsic blur. AB - PURPOSE: To determine the effect of optical blur reduction on equivalent intrinsic blur, an estimate of the blur within the visual system, by comparing optical and equivalent intrinsic blur before and after adaptive optics (AO) correction of wavefront error. METHODS: Twelve visually normal subjects (mean [+/ SD] age, 31 [+/-12] years) participated in this study. Equivalent intrinsic blur (sigmaint) was derived using a previously described model. Optical blur (sigmaopt) caused by high-order aberrations was quantified by Shack-Hartmann aberrometry and minimized using AO correction of wavefront error. RESULTS: sigmaopt and sigmaint were significantly reduced and visual acuity was significantly improved after AO correction (p <= 0.004). Reductions in sigmaopt and sigmaint were linearly dependent on the values before AO correction (r >= 0.94, p <= 0.002). The reduction in sigmaint was greater than the reduction in sigmaopt, although it was marginally significant (p = 0.05). sigmaint after AO correlated significantly with sigmaint before AO (r = 0.92, p < 0.001), and the two parameters were related linearly with a slope of 0.46. CONCLUSIONS: Reduction in equivalent intrinsic blur was greater than the reduction in optical blur after AO correction of wavefront error. This finding implies that visual acuity in subjects with high equivalent intrinsic blur can be improved beyond that expected from the reduction in optical blur alone. PMID- 25785540 TI - Design of a highly selective quenched activity-based probe and its application in dual color imaging studies of cathepsin S activity localization. AB - The cysteine cathepsins are a group of 11 proteases whose function was originally believed to be the degradation of endocytosed material with a high degree of redundancy. However, it has become clear that these enzymes are also important regulators of both health and disease. Thus, selective tools that can discriminate between members of this highly related class of enzymes will be critical to further delineate the unique biological functions of individual cathepsins. Here we present the design and synthesis of a near-infrared quenched activity-based probe (qABP) that selectively targets cathepsin S which is highly expressed in immune cells. Importantly, this high degree of selectivity is retained both in vitro and in vivo. In combination with a new green-fluorescent pan-reactive cysteine cathepsin qABP we performed dual color labeling studies in bone marrow-derived immune cells and identified vesicles containing exclusively cathepsin S activity. This observation demonstrates the value of our complementary cathepsin probes and provides evidence for the existence of specific localization of cathepsin S activity in dendritic cells. PMID- 25785542 TI - Nutrient Composition and In Vitro Antioxidant Properties of Harungana madagascariensis Stembark Extracts. AB - The stembarks of Harungana madagascariensis were analyzed for their content of chemical constituents, antinutrients, vitamin levels, and in vitro antioxidant properties in two solvent systems. Phytochemical screening revealed higher levels of alkaloids, saponins, and flavonoids in the methanolic (MHM) extract than in the dichloromethane (DCM) extract. The methanolic extract had higher contents of minerals, vitamins, and antinutrients except K, vitamin B1, and phytic acid, respectively. Antioxidant potentials of the stembark extracts were assessed by the 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, metal chelating activity, and ferric reducing power. The methanolic extract showed a better antioxidant activity (IC50=87.66+/-0.97 MUg/mL) in the DPPH system. The metal chelating activity was higher in the methanolic extract (92.4% at 20 mg/mL), but lower than the control ethylenediaminetetraacetic acid (EDTA). The methanolic extract also showed greater ferric reducing power and was richer in phenolics (132.24+/-0.61 mgGAE/g) and flavonoids (259.05+/-2.85 mgQE/g). Antinutrient analysis of the extracts indicated low levels of phytic acid, oxalates, and hydrocyanides below the lethal doses. The LD50 (i.p. mice) of the extracts showed relatively low toxicity in the range 1000-1414 mg/kg. These results support the ethnomedicinal uses of this plant in the treatment of diseases related to oxidative stress and suggest that consumption of H. madagascariensis is not harmful nutritively. PMID- 25785543 TI - A bifunctional, site-isolated metal-organic framework-based tandem catalyst. AB - Herein, we present the synthesis of a metal-organic framework-based tandem catalyst that contains two distinct catalytic domains. Zn(II)-based IRMOF-9 Irdcppy-NH2 (IRMOF = isoreticular metal-organic framework) has both organocatalytic amine and organometallic Ir(I) groups that were incorporated by both pre- and postsynthetic functionalization methods. The isolated amine and Ir(I) sites of IRMOF-9-Irdcppy-NH2 are shown to be independently catalytically active for performing a Knoevenagel condensation and allylic N-alkylation, respectively. More importantly, IRMOF-9-Irdcppy-NH2 can act as a tandem catalyst for both of these organic transformations in a one-pot reaction, which cannot be achieved efficiently using the combined, homogeneous analogues. PMID- 25785541 TI - Host response to Candida albicans bloodstream infection and sepsis. AB - Candida albicans is a major cause of bloodstream infection which may present as sepsis and septic shock - major causes of morbidity and mortality world-wide. After invasion of the pathogen, innate mechanisms govern the early response. Here, we outline the models used to study these mechanisms and summarize our current understanding of innate immune responses during Candida bloodstream infection. This includes protective immunity as well as harmful responses resulting in Candida induced sepsis. Neutrophilic granulocytes are considered principal effector cells conferring protection and recognize C. albicans mainly via complement receptor 3. They possess a range of effector mechanisms, contributing to elimination of the pathogen. Neutrophil activation is closely linked to complement and modulated by activated mononuclear cells. A thorough understanding of these mechanisms will help in creating an individualized approach to patients suffering from systemic candidiasis and aid in optimizing clinical management. PMID- 25785544 TI - Evaluation of the Generalizability of the Number of Abnormal Scores and the Overall Test Battery Mean as Measures of Performance Validity to a Different Test Battery. AB - Davis, Axelrod, McHugh, Hanks, and Millis (2013) documented that in a battery of 25 tests, producing 15, 10, and 5 abnormal scores at 1, 1.5, and 2 standard deviations below the norm-referenced mean, respectively, and an overall test battery mean (OTBM) of T <= 38 accurately identifies performance invalidity. However, generalizability of these findings to other samples and test batteries remains unclear. This study evaluated the use of abnormal scores and the OTBM as performance validity measures in a different sample that was administered a 25 test battery that minimally overlapped with Davis et al.'s test battery. Archival analysis of 48 examinees with mild traumatic brain injury seen for medico-legal purposes was conducted. Producing 18 or more, 7 or more, and 5 or more abnormal scores at 1, 1.5, and 2 standard deviations below the norm-referenced mean, respectively, and an OTBM of T <= 40 most accurately classified examinees; however, using Davis et al.'s proposed cutoffs in the current sample maintained specificity at or near acceptable levels. Due to convergence across studies, producing >=5 abnormal scores at 2 standard deviations below the norm-referenced mean is the most appropriate cutoff for clinical implementation; however, for batteries consisting of a different quantity of tests than 25, an OTBM of T <= 38 is more appropriate. PMID- 25785545 TI - IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells. PMID- 25785546 TI - Prolonged duration of breastfeeding does not affect lipid profile in adulthood. AB - BACKGROUND: The Hertfordshire study suggested that age of weaning and methods of infant feeding may influence adult serum low-density lipoprotein cholesterol (LDL C) and mortality from ischemic heart disease in men. Although breastfeeding <1 year appeared to be protective compared with formula, prolonged breastfeeding (>1 year) was associated with increased LDL-C and mortality. This study tested the effect of breastfeeding duration on lipid profile in young adults. MATERIALS AND METHODS: Adult volunteers whose mothers could recall the age at which their child was weaned were recruited. We excluded patients with known dyslipidemia, dyslipidemia in a first-degree relative, obesity (body mass index [BMI] >30 kg/m(2)), pregnant or within 3 months of a previous pregnancy, subjects taking medications that may affect lipid profile, or subjects with a chronic medical condition. Nutritional questionnaires and number of weekly hours of exercise were recorded. Lipid profiles were obtained after a night fast. RESULTS: The three groups (no breastfeeding, breastfeeding 0-6 months, or breastfeeding >9 months) did not differ in terms of age, gender, BMI, level of education, amount of exercise, and dietary style. By stepwise background multiple regression analysis taking into account exercise, nutritional habitus, age, BMI, gender, and socioeconomic status, blood lipids were not affected by duration of breastfeeding. CONCLUSIONS: Duration of breastfeeding does not affect lipid profiles in young adults. These findings do not support negative messages on the long-term effect of prolonged lactation generated by the Hertfordshire study. PMID- 25785547 TI - Older People with Access to Hand-Held Devices: Who Are They? AB - INTRODUCTION: Multiple comorbid conditions among older patients require frequent physician office and emergency room visits, at times leading to hospitalization. In recent years, mobile health (m-health) systems utilizing hand-held devices (e.g., smartphones) have been developed, which could be used for health-related interventions. This study investigates sociodemographic and clinical characteristics of individuals who have or have not accessed Internet via hand held devices. MATERIALS AND METHODS: Adults older than 65 years of age who participated in the Health Tracking survey of the Pew Internet and American Life Project in 2012 were included in the analysis. Data were analyzed for prevalence of Internet access via hand-held devices and differences in sociodemographic and clinical characteristics. Different online health information seeking behavior is also reported. RESULTS: In the weighted sample size of 3,116 responses, 472 (15.1%) had access to Internet via hand-held devices. Those with such an access were younger and had higher income and education and better overall quality of life and quality of life at the time of answering the survey. They were more likely to be female and married or living as married. Those with diabetes or significant change in physical condition in the prior year were less likely to have such an access. In the multivariate analysis, older or diabetic individuals had lower probability of such access. Higher likelihood of access was associated with higher income and education, being married, female gender, better quality of life, higher number of comorbid illnesses, and emergency room visit or hospital admission in the last 12 months. CONCLUSIONS: Investigators should pay attention to sociodemographic and clinical disparities of older adults to develop feasible m-health interventions. PMID- 25785548 TI - Tapering opioid prescriptions and reducing polypharmacy for inpatients with spinal cord injury at Rancho Los Amigos National Rehabilitation Center. PMID- 25785549 TI - The Uyghur population and genetic susceptibility to type 2 diabetes: potential role for variants in CDKAL1, JAZF1, and IGF1 genes. AB - Substantial evidence suggests that type 2 diabetes mellitus (T2DM) is a multi factorial disease with a strong genetic component. A list of genetic susceptibility loci in populations of European and Asian ancestry has been established in the literature. Little is known on the inter-ethnic contribution of such established functional polymorphic variants. We performed a case-control study to explore the genetic susceptibility of 16 selected T2DM-related SNPs in a cohort of 102 Uyghur objects (51 cases and 51 controls). Three of the 16 SNPs showed significant association with T2DM in the Uyghur population. There were significant differences between the T2DM and control groups in frequencies of the risk allelic distributions of rs7754840 (CDKAL1) (p=0.014), rs864745 (JAZF1) (p=0.032), and rs35767 (IGF1) (p=0.044). Carriers of rs7754840-C, rs35767-A, and rs864745-C risk alleles had a 2.32-fold [OR (95% CI): 1.19-4.54], 2.06-fold [OR (95% CI): 1.02-4.17], 0.48-fold [OR (95% CI): 0.24-0.94] increased risk for T2DM, respectively. The cumulative risk allelic scores of these 16 SNPs differed significantly between the T2DM patients and the controls [17.1+/-8.1 vs. 15.4+/ 7.3; OR (95%CI): 1.27(1.07-1.50), p=0.007]. This is the first study to evaluate genomic variation at 16 SNPs in respective T2DM candidate genes for the Uyghur population compared with other ethnic groups. The SNP rs7754840 in CDKAL1, rs864745 in JAZF1, and rs35767 in IGF1 might serve as potential susceptibility loci for T2DM in Uyghurs. We suggest a broader capture and study of the world populations, including who that are hitherto understudied, are essential for a comprehensive understanding of the genetic/genomic basis of T2DM. PMID- 25785550 TI - Following the transient reactions in lithium-sulfur batteries using an in situ nuclear magnetic resonance technique. AB - A fundamental understanding of electrochemical reaction pathways is critical to improving the performance of Li-S batteries, but few techniques can be used to directly identify and quantify the reaction species during disharge/charge cycling processes in real time. Here, an in situ (7)Li NMR technique employing a specially designed cylindrical microbattery was used to probe the transient electrochemical and chemical reactions occurring during the cycling of a Li-S system. In situ NMR provides real time, semiquantitative information related to the temporal evolution of lithium polysulfide allotropes during both discharge/charge processes. This technique uniquely reveals that the polysulfide redox reactions involve charged free radicals as intermediate species that are difficult to detect in ex situ NMR studies. Additionally, it also uncovers vital information about the (7)Li chemical environments during the electrochemical and parasitic reactions on the Li metal anode. These new molecular-level insights about transient species and the associated anode failure mechanism are crucial to delineating effective strategies to accelerate the development of Li-S battery technologies. PMID- 25785551 TI - Patterns of total cost and economic consequences of progression for patients with newly diagnosed multiple myeloma. AB - BACKGROUND: Few studies have addressed the cost patterns of patients with multiple myeloma (MM) before and after first relapse. This US claims analysis evaluated, from a US health plan perspective, patterns of total direct costs of care from treatment initiation to progression for patients with MM treated with novel agents, using time to next therapy (TTNT) as a proxy measure for progression. METHODS: A retrospective study was conducted using a large US claims database, evaluating patients with claims for MM between 2006 and 2013. Patients with claims for stem cell transplant (SCT) were excluded. The analysis focused on patients receiving lenalidomide (LEN) or bortezomib (BORT) based treatment, for whom complete claim history was available through initiation of subsequent treatment. Average patient monthly direct costs were determined, including medical and pharmacy costs, and total cost patterns over quarterly time periods were calculated. RESULTS: The study population comprised 2843 patients with newly diagnosed MM (NDMM) and 1361 with relapsed MM. Total monthly cost for patients with NDMM declined steadily, from $15,734 initially to $5082 at 18+ months after therapy. Upon initiation of second-line therapy, total monthly costs rose to $13,876 and declined to $6446 18 months later. Although NDMM cost levels for individual ordinal months were similar between the LEN and BORT groups, TTNT was longer for LEN-based treatments (37 months). The BORT-treated cohort had higher average monthly total costs for NDMM and for the common time period through 37 months after initiation of therapy ($7534 vs $10,763 for LEN and BORT, respectively). Key limitations of this study, in addition to the lack of mortality and staging information available from claims data, include the definition of TTNT based on change in treatment or a defined gap in therapy prior to retreatment, which may differ from actual time of progression in some patients. CONCLUSIONS: For patients with NDMM receiving either LEN- or BORT-based treatment without SCT, followed until TTNT, total direct monthly costs (drug + medical) declined steadily over time. Monthly costs returned to near initial levels when patients began second-line therapy and then followed a similar pattern of decline. Due to the longer TTNT for patients initiated on LEN and the associated longer period of below-average costs, patients initiated with LEN based treatments had mean monthly total costs >$3200 lower than total costs for patients initiated on BORT during the first 3 years after starting treatment, cumulating to nearly $120,000 in lower costs for patients initiated on LEN. PMID- 25785552 TI - Dynamics of the evaporative dewetting of a volatile liquid film confined within a circular ring. AB - The dewetting dynamics of a toluene film confined within a copper ring on a deformable PMMA film is studied. The toluene film experiences evaporation and dewetting, which leads to the formation of a circular contact line around the center of the copper ring. The contact line recedes smoothly toward the copper ring at a constant velocity until reaching a dynamic "stick" state to form the first circular polymer ridge. The average receding velocity is found to be dependent on the dimensions of the copper ring (the copper ring diameter and the cross-sectional diameter of the copper wire) and the thickness of the PMMA films. A model is presented to qualitatively explain the evaporative dewetting phenomenon. PMID- 25785553 TI - Preconditioning of model biocarriers by soluble pollutants: a QCM-D study. AB - Preconditioning of a biocarrier surface is the first step in triggering biofilm formation in attached-growth bioreactors. However, the quantification and control of this step as influenced by solution conditions and biocarrier properties have been rarely explored. In this paper, deposition behaviors of soluble pollutants on the model biocarriers polystyrene (PS) and polyamide (PA) were performed using a quartz crystal microbalance with dissipation monitoring (QCM-D). Three types of wastewater from municipal and industrial wastewater treatment plants and 12 synthetic wastewaters with different configurations of model macromolecules (bovine serum albumin and sodium alginate) and ionic compositions (Na(+) and Ca(2+)) were prepared. Results showed that high organic contents (protein and humic acid) in real wastewater increased deposition compared to the impact of ions on the two types of carriers. For synthetic wastewater, an interesting phenomenon was observed in that the presence of Ca(2+) can transform a thin and rigid adlayer into a denser and viscoelastic one on the surface of PS with low organic contents, yet a viscoelastic adlayer can directly form on PS and an increase in the ionic strength hinders deposition in the presence of high organic contents. The deposition of solutes on PA produces a thicker and viscoelastic adlayer that is strengthened an elevated concentration of organic materials. Additionally, a weakening effect of Ca(2+) on deposition was revealed under high ionic strength. This is the first demonstration of control strategies for preconditioning hydrophilic and hydrophobic biocarriers under different water quality conditions and has important implications for the design of a start-up process for biofilm formation in attached-growth bioreactors. PMID- 25785554 TI - Metal-free synthesis of indole via NIS-mediated cascade C-N bond formation/aromatization. AB - A novel rapid synthesis of indoles from N-Ts-2-alkenylanilines has been described; the reaction involves a NIS-mediated cascade C-N bond formation/aromatization, and a series of indoles with various functional groups have been synthesized in good to excellent yields under mild conditions without any other additives or catalysts. PMID- 25785555 TI - Transurethral radiofrequency collagen denaturation for the treatment of women with urinary incontinence. AB - BACKGROUND: Transurethral radiofrequency collagen denaturation is a relatively novel, minimally invasive device-based intervention used to treat individuals with urinary incontinence (UI). No systematic review of the evidence supporting its use has been published to date. OBJECTIVES: To evaluate the efficacy of transurethral radiofrequency collagen denaturation, compared with other interventions, in the treatment of women with UI.Review authors sought to compare the following.* Transurethral radiofrequency collagen denaturation versus no treatment/sham treatment.* Transurethral radiofrequency collagen denaturation versus conservative physical treatment.* Transurethral radiofrequency collagen denaturation versus mechanical devices (pessaries for UI).* Transurethral radiofrequency collagen denaturation versus drug treatment.* Transurethral radiofrequency collagen denaturation versus injectable treatment for UI.* Transurethral radiofrequency collagen denaturation versus other surgery for UI. SEARCH METHODS: We conducted a systematic search of the Cochrane Incontinence Group Specialised Register (searched 19 December 2014), EMBASE and EMBASE Classic (January 1947 to 2014 Week 50), Google Scholar and three trials registries in December 2014, along with reference checking. We sought to identify unpublished studies by handsearching abstracts of major gynaecology and urology meetings, and by contacting experts in the field and the device manufacturer. SELECTION CRITERIA: Randomised and quasi-randomised trials of transurethral radiofrequency collagen denaturation versus no treatment/sham treatment, conservative physical treatment, mechanical devices, drug treatment, injectable treatment for UI or other surgery for UI in women were eligible. DATA COLLECTION AND ANALYSIS: We screened search results and selected eligible studies for inclusion. We assessed risk of bias and analysed dichotomous variables as risk ratios (RRs) with 95% confidence intervals (CIs) and continuous variables as mean differences (MDs) with 95% CIs. We rated the quality of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. MAIN RESULTS: We included in the analysis one small sham-controlled randomised trial of 173 women performed in the United States. Participants enrolled in this study had been diagnosed with stress UI and were randomly assigned to transurethral radiofrequency collagen denaturation (treatment) or a sham surgery using a non functioning catheter (no treatment). Mean age of participants in the 12-month multi-centre trial was 50 years (range 22 to 76 years).Of three patient-important primary outcomes selected for this systematic review, the number of women reporting UI symptoms after intervention was not reported. No serious adverse events were reported for the transurethral radiofrequency collagen denaturation arm or the sham treatment arm during the 12-month trial. Owing to high risk of bias and imprecision, we downgraded the quality of evidence for this outcome to low. The effect of transurethral radiofrequency collagen denaturation on the number of women with an incontinence quality of life (I-QOL) score improvement >= 10 points at 12 months was as follows: RR 1.11, 95% CI 0.77 to 1.62; participants = 142, but the confidence interval was wide. For this outcome, the quality of evidence was also low as the result of high risk of bias and imprecision.We found no evidence on the number of women undergoing repeat continence surgery. The risk of other adverse events (pain/dysuria (RR 5.73, 95% CI 0.75 to 43.70; participants = 173); new detrusor overactivity (RR 1.36, 95% CI 0.63 to 2.93; participants = 173); and urinary tract infection (RR 0.95, 95% CI 0.24 to 3.86; participants = 173) could not be established reliably as the trial was small. Evidence was insufficient for assessment of whether use of transurethral radiofrequency collagen denaturation was associated with an increased rate of urinary retention, haematuria and hesitancy compared with sham treatment in 173 participants. The GRADE quality of evidence for all other adverse events with available evidence was low as the result of high risk of bias and imprecision.We found no evidence to inform comparisons of transurethral radiofrequency collagen denaturation with conservative physical treatment, mechanical devices, drug treatment, injectable treatment for UI or other surgery for UI. AUTHORS' CONCLUSIONS: It is not known whether transurethral radiofrequency collagen denaturation, as compared with sham treatment, improves patient-reported symptoms of UI. Evidence is insufficient to show whether the procedure improves disease specific quality of life. Evidence is also insufficient to show whether the procedure causes serious adverse events or other adverse events in comparison with sham treatment, and no evidence was found for comparison with any other method of treatment for UI. PMID- 25785556 TI - Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene. AB - The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered. PMID- 25785557 TI - Picocyanobacteria from a clade of marine Cyanobium revealed bioactive potential against microalgae, bacteria, and marine invertebrates. AB - The production of bioactive compounds either toxic or with pharmacological applications by cyanobacteria is well established. However, picoplanktonic forms within this group of organisms have rarely been studied in this context. In this study, the toxicological potential of picocyanobacteria from a clade of marine Cyanobium strains isolated from the Portuguese coast was examined using different biological models. First, strains were identified by applying morphological and molecular approaches and cultured under lab conditions. A crude extract and three fractions reflecting a preliminary segregation of lipophilic metabolites were tested for toxicity with the marine microalga Nannochloropsis sp., the bacteria Pseudomonas sp., the brine shrimp Artemia salina, and fertilized eggs of the sea urchin Paracentrotus lividus. No significant apparent adverse effects were noted against Artemia salina. However, significant adverse effects were found in all other assays, with an inhibition of Nannochloropsis sp. and Pseudomonas sp. growth and marked reduction in Paracentrotus lividus larvae length. The results obtained indicated that Cyanobium genus may serve as a potential source of interesting bioactive compounds and emphasize the importance of also studying smaller picoplanktonic fractions of marine cyanobacteria. PMID- 25785558 TI - Combined effects of fine particulate matter and lipopolysaccharide on apoptotic responses in NR8383 macrophages. AB - Alveolar macrophages (AM) are the predominant lung cells responsible for both ingestion and clearance of inhaled particulate matter (PM). The aims of this study were (1) to examine effects of fine PM on rat NR8383 cell line apoptosis, and (2) to determine whether NR8383 cell functions are further affected when exposed to fine PM in the presence of inflammation induced by lipopolysaccharide (LPS). Standard Reference Material 2786 (SRM 2786) for fine PM was used to measure the following parameters: cytotoxicity, apoptotic rate, Bax/Bcl-2 expression, nitric oxide (NO) production, and reactive oxygen species (ROS) generation in NR8383 cells. Data showed that SRM 2786 alone induced damage and apoptosis in NR8383 cells in a concentration-dependent manner as demonstrated by significant decrease in expression of Bcl-2 and increase in expression of Bax, suggesting fine PM might trigger apoptosis involving a mitochondria-mediated apoptotic pathway. In addition, there was elevated production of free radicals, such as NO and ROS, suggesting oxidative stress plays a role in the observed apoptotic responses. Further, LPS pretreatment enhanced apoptosis of NR8383 cells induced by SRM 2786. Consequently, data indicate that SRM 2786 triggered cell apoptosis in NR8383 cells, probably by mechanisms involving oxidative stress, as evidenced by elevated NO and ROS levels, while the degree of apoptosis was further aggravated by inflammation. PMID- 25785559 TI - Flaxseed suppressed prostatic epithelial proliferation in a rat model of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH), a disease occurring frequently among elderly males, is a slow progressive enlargement of the fibromuscular and epithelial structures of the prostate gland. Dietary factors may influence the prostate and exert an influence on prostatic growth and disease. The current study was undertaken to investigate the protective effect of dietary flaxseed supplementation against testosterone-induced prostatic hyperplasia in male rats. Forty male Wistar rats were divided into 5 groups: (1) untreated control; (2) treatment with testosterone propionate (TP) to induce prostate enlargement; (3) TP-treated group fed a diet containing 5% milled flaxseed; (4) TP-treated group fed a diet containing 10% milled flaxseed; and (5) TP-treated group fed a diet containing 20 ppm finasteride. Treatment with TP significantly increased the absolute and relative weights of different prostatic lobes, serum testosterone (T), and testosterone/estradiol ratio, as well as prostatic vascular endothelial growth factor (VEGF) expression, RNA synthesis per cell, and epithelial cell proliferation, detected as Ki67 labeling. Histopathological examination did not reveal marked differences in acinar morphology in ventral prostate, whereas morphometric analysis showed significantly increased epithelial cell height. Co administration of flaxseed or finasteride with TP significantly reduced prostatic VEFG, epithelial cell proliferation, and RNA/DNA ratio, along with a significant increase in serum T and testosterone/estradiol ratio compared with TP-only treated rats. Our results indicate that flaxseed, similar to the 5alpha-reductase inhibitor finasteride, blocked TP-induced prostate enlargement in a rat model of BPH, likely through suppression of prostatic VEFG and cellular proliferation. PMID- 25785560 TI - Genotoxicity assessment of reactive and disperse textile dyes using human dermal equivalent (3D cell culture system). AB - Thousands of dyes are marketed daily for different purposes, including textile dyeing. However, there are several studies reporting attributing to dyes deleterious human effects such as DNA damage. Humans may be exposed to toxic dyes through either ingestion of contaminated waters or dermal contact with colored garments. With respect to dermal exposure, human skin equivalents are promising tools to assess in vitro genotoxicity of dermally applied chemicals using a three dimensional (3D) model to mimic tissue behavior. This study investigated the sensitivity of an in-house human dermal equivalent (DE) for detecting genotoxicity of textile dyes. Two azo (reactive green 19 [RG19] and disperse red 1[DR1]) dyes and one anthraquinone (reactive blue 2 [RB2]) dye were analyzed. RG19 was genotoxic for DE in a dose-responsive manner, whereas RB2 and DR1 were nongenotoxic under the conditions tested. These findings are not in agreement with previous genotoxicological assessment of these dyes carried out using two dimensional (2D) cell cultures, which showed that DR1 was genotoxic in human hepatoma cells (HepG2) and RG19 was nongenotoxic for normal human dermal fibroblasts (NHDF). These discrepant results probably may be due to differences between metabolic activities of each cell type (organ-specific genotoxicity, HepG2 and fibroblasts) and the test setup systems used in each study (fibroblasts cultured at 2D and three-dimensional [3D] culture systems). Genotoxicological assessment of textile dyes in context of organ-specific genotoxicity and using in vitro models that more closely resemble in vivo tissue architecture and physiology may provide more reliable estimates of genotoxic potential of these chemicals. PMID- 25785561 TI - In situ analysis of melt-drawing behavior of ultrahigh molecular weight polyethylene films with different molecular weights: roles of entanglements on oriented crystallization. AB - Ultrahigh molecular weight polyethylene (UHMW-PE) films having different molecular weights (MWs) were melt-drawn at 150 degrees C. The stress-strain curve for higher-MW film exhibits higher stress on the characteristic plateau region and a subsequent steeper increase of stress due to strain hardening. Structural changes during such melt-drawing were analyzed using in situ wide angle X-ray diffraction measurements. Hexagonal crystallization occurs at the beginning of the plateau region, independent of the sample MW. Once this hexagonal reflection intensity is saturated, it remains constant even at the later stage of draw. In contrast, orthorhombic reflection intensities gradually increase with increasing draw strain. Both of these oriented crystallizations into plateau hexagonal and increasing orthorhombic forms are accelerated with increasing MW. Correspondingly, the higher amount of extended chain crystals (ECCs) was confirmed from morphological observation for the resultant melt-drawn films of the higher-MW sample. Deep entanglements can effectively transmit the applied stress; thus, the oriented amorphous melts induce rapid hexagonal crystallization with disentangling shallow entanglements, which subsequently transforms into orthorhombic form. Such hexagonal crystallization plays the role of a thermodynamic pathway for growing such ECCs, where the stable orthorhombic form gradually accumulates with increasing draw strain. PMID- 25785562 TI - The effects of marine carbohydrates and glycosylated compounds on human health. AB - Marine organisms have been recognized as a valuable source of bioactive compounds with industrial and nutraceutical potential. Recently, marine-derived carbohydrates, including polysaccharides and low molecular weight glycosylated oligosaccharides, have attracted much attention because of their numerous health benefits. Moreover, several studies have reported that marine carbohydrates exhibit various biological activities, including antioxidant, anti-infection, anticoagulant, anti-inflammatory, and anti-diabetic effects. The present review discusses the potential industrial applications of bioactive marine carbohydrates for health maintenance and disease prevention. Furthermore, the use of marine carbohydrates in food, cosmetics, agriculture, and environmental protection is discussed. PMID- 25785565 TI - Uncovering the pKa dependent fluorescence quenching of carbon dots induced by chlorophenols. AB - Fluorescence quenching induced by targets is always an alluring strategy to elucidate the possible photoluminescence origin of carbon dots. In this study, a new kind of N, S co-doped carbon dots (NSCDs) was synthesized and the fluorescence of NSCDs was surprisingly found to be quenched by chlorophenols (CPs) in a pKa dependent mode. Detailed investigation of this behavior demonstrated that phenolate was the responsible species and N and/or S dopants in NSCDs failed to play a role in the fluorescence quenching. Further evidence uncovered that the quenching was a static one, where a non-fluorescent intermediate was formed between electron-deficient C=O on the CDs surface and the electron-rich phenolic oxygen anion of chlorophenolate via nucleophilic addition. Moreover, one of the main photoluminescence origins of this kind of CDs was derived, namely surface emissive sites mostly attributed to carbonyl groups. PMID- 25785563 TI - Conformational analysis of misfolded protein aggregation by FRET and live-cell imaging techniques. AB - Cellular homeostasis is maintained by several types of protein machinery, including molecular chaperones and proteolysis systems. Dysregulation of the proteome disrupts homeostasis in cells, tissues, and the organism as a whole, and has been hypothesized to cause neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). A hallmark of neurodegenerative disorders is formation of ubiquitin-positive inclusion bodies in neurons, suggesting that the aggregation process of misfolded proteins changes during disease progression. Hence, high-throughput determination of soluble oligomers during the aggregation process, as well as the conformation of sequestered proteins in inclusion bodies, is essential for elucidation of physiological regulation mechanism and drug discovery in this field. To elucidate the interaction, accumulation, and conformation of aggregation-prone proteins, in situ spectroscopic imaging techniques, such as Forster/fluorescence resonance energy transfer (FRET), fluorescence correlation spectroscopy (FCS), and bimolecular fluorescence complementation (BiFC) have been employed. Here, we summarize recent reports in which these techniques were applied to the analysis of aggregation-prone proteins (in particular their dimerization, interactions, and conformational changes), and describe several fluorescent indicators used for real-time observation of physiological states related to proteostasis. PMID- 25785566 TI - On the feasibility of utilizing active personal dosimeters worn on the chest to estimate occupational eye lens dose in x-ray angiography. AB - The International Commission on Radiological Protection (ICRP) has recommended that the occupational dose limit to the eye lens be substantially reduced. To ensure compliance with these recommendations, monitoring of the occupational eye lens dose is essential in certain hospital work environments. For assessment of the eye lens dose it is recommended to use a supplementary dosimeter placed at a position adjacent to the eye(s). Wearing a dosimeter at eye level can, however, be impractical and distributing and managing additional dosimeters over long periods of time is cumbersome and costly for large clinical sites. An attractive alternative is to utilize active personal dosimeters (APDs), which are routinely used by clinical staff for real-time monitoring of the personal dose equivalent rate (H(p)(10)). In this work, a formalism for the determination of eye lens dose from the response of such APD's worn on the chest is proposed and evaluated. The evaluation is based on both phantom and clinical measurements performed in an x ray angiography suite for interventional cardiology. The main results show that the eye lens dose to the primary operator and to the assisting clinical staff can be conservatively estimated from the APD response as D(eye)(conductor) = 2.0 APD chest and D(eye)(assisting) = 1.0 APD chest, respectively. However, care should be exercised for particularly short assisting staff and if radiation protection shields are misused. These concerns can be greatly mitigated if the clinical staff are provided with adequate radiation protection training. PMID- 25785564 TI - Osteoarthritis in the XXIst century: risk factors and behaviours that influence disease onset and progression. AB - Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by "low-grade inflammation" in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder. PMID- 25785568 TI - Simple coordination complex-derived three-dimensional mesoporous graphene as an efficient bifunctional oxygen electrocatalyst. AB - 3D mesoporous graphene (mesoG) was synthesized from [Ni2(EDTA)] (EDTA = ethylenediaminetetraacetate). The material is comprised of interconnected 4 nm sized hollow carbon shells composed of 3-4 layers of graphene and exhibits high bifunctional electrocatalytic activity as well as high durability for use in oxygen evolution and reduction reactions. PMID- 25785569 TI - Theoretical understanding of two-photon-induced fluorescence of isomorphic nucleoside analogs. AB - We use ab initio Density Functional Theory (DFT) and Time-dependent DFT (TDDFT) calculations for a detailed understanding of one-photon absorption (1PA) and two photon absorption (2PA) cross sections of eight different nucleoside analogs. The results are compared and contrasted with the available experimental data. Our calculated results show that the low energy peaks in the absorption spectra mainly arise because of the pi-pi* electronic transition of the nucleoside analogs. The emission spectra of the nucleoside analogs are also calculated using TDDFT methods. The calculated absorption and emission spectra in the presence of a solvent follow the same trend as those found experimentally. Our results demonstrate that the nucleoside analogs show significantly different electronic and optical properties, although their bonding aspects towards Watson-Crick base pairing remain the same. We also derive the microscopic details of the origin of nonlinear optical properties of the nucleoside analogs. PMID- 25785567 TI - Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity. AB - A general strategy was developed for the intracellular delivery of linear peptidyl ligands through fusion to a cell-penetrating peptide and cyclization of the fusion peptides via a disulfide bond. The resulting cyclic peptides are cell permeable and have improved proteolytic stability. Once inside the cell, the disulfide bond is reduced to produce linear biologically active peptides. This strategy was applied to generate a cell-permeable peptide substrate for real-time detection of intracellular caspase activities during apoptosis and an inhibitor for the CFTR-associated ligand (CAL) PDZ domain as a potential treatment for cystic fibrosis. PMID- 25785570 TI - Copper-mediated tandem reaction of beta-ketoesters/ketones with tertiary amines for the synthesis of 2,3-dihydrofurans. AB - A copper-mediated tandem reaction of beta-ketoesters/ketones with tertiary amines was achieved, which provides a simple and efficient approach to the synthesis of 2,3-dihydrofuran derivatives. In this tandem reaction, the tertiary amine not only offers the methylene moiety but also serves as the base. PMID- 25785571 TI - Synthesis and Lewis acidity of fluorophosphonium cations. AB - A series of fluorophosphonium salts, [R3PF][X] (R = alkyl or aryl; X = FB(C6F5)3, [B(C6F5)4]), have been prepared by reactions of phosphine/borane frustrated Lewis pairs (FLPs) with XeF2 or difluorophosphoranes with [Et3Si][B(C6F5)4]. As the substituents bound to phosphorus become increasingly electron withdrawing, the corresponding fluorophosphonium salts are shown to be increasingly Lewis acidic. Calculations were also performed to determine the relative fluoride ion affinities (FIA) of these fluorophosphonium cations. PMID- 25785572 TI - Release of proteins and enzymes from vesicular compartments by alternating magnetic fields. AB - The magnetic release of catalytically active enzymes from vesicular compartments within aggregated nanomaterials has been demonstrated. These nanomaterials, magnetic nanoparticle-vesicle aggregates (MNPVs), were formed by the self assembly of biotinylated silica-coated Fe3O4 nanoparticles, biotinylated vesicles and tetrameric avidin. The unique features of nanoscale magnetite allow adhesion between membranes to be combined with magnetically triggered transit of reagents across membranes. Adding short spacers between the adhesive biotin groups and the nanoparticle or vesicle surfaces was found to strengthen binding to avidin, with binding of avidin to biotinylated bilayers and biotinylated nanoparticles monitored by quartz crystal microgravimetry with dissipation (QCM-D). Three different reagents were released from the vesicle compartments of MNPVs by a pulse of alternating magnetic field, with the release of a dye modelling the release of small molecule substrates, and the release of cytochrome c modelling the release of biological polymers, such as enzymes. To confirm that enzymes could be released and maintain activity, trypsin was encapsulated and shown to digest casein after magnetically triggered release. PMID- 25785573 TI - Separating the need for intraoperative consultation from the fear of out-of network billing: the myth of drive-by doctoring. PMID- 25785574 TI - Chronic, Painful, Nonhealing Ulcer on the Right Arm Following Minor Trauma. PMID- 25785576 TI - Psychosocial work environment and risk of ischemic stroke and coronary heart disease: a prospective longitudinal study of 75 236 construction workers. AB - OBJECTIVES: The present study aimed to investigate whether different dimensions of psychosocial stress, as measured by the job demand-control model (JDC), were associated with increased risks of ischemic stroke and coronary heart disease (CHD). METHODS: A cohort of 75 236 male construction workers was followed from 1989-2004. Exposure to psychosocial stress was determined by a questionnaire answered in 1989-1993. Events of ischemic stroke and CHD were found by linkage to the Swedish Causes of Death and National Patient registers. Hazard ratios (HR) were obtained from Cox regression models, adjusted for age, smoking habits, body mass index and systolic blood pressure. RESULTS: There were 1884 cases of CHD and 739 cases of ischemic stroke. Regarding ischemic stroke, no association was found between job demands [HR 1.12, 95% confidence interval (95% CI) 0.89-1.40, highest versus lowest quintile] or job control (HR 1.04, 95% CI 0.82-1.32, lowest versus highest quintile). Regarding CHD, job demands were associated to CHD (HR 1.18, 95% CI 1.02-1.37, highest vs. lowest quintile), but no consistent trend was seen among quintiles. The results were inconsistent in relation to job control. The division of JDC into four categories showed no significant associations with either ischemic stroke or CHD. CONCLUSIONS: This exploratory study showed no significant associations between psychosocial work environment and ischemic stroke, and the associations between job demands and control and CHD were inconsistent and weak. The combination of job control and job demand showed no significant associations with either ischemic stroke or CHD. PMID- 25785575 TI - Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity. AB - IMPORTANCE: Major depressive disorder (MDD) has been linked to imbalanced communication among large-scale brain networks, as reflected by abnormal resting state functional connectivity (rsFC). However, given variable methods and results across studies, identifying consistent patterns of network dysfunction in MDD has been elusive. OBJECTIVE: To investigate network dysfunction in MDD through a meta analysis of rsFC studies. DATA SOURCES: Seed-based voxelwise rsFC studies comparing individuals with MDD with healthy controls (published before June 30, 2014) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE) and authors contacted for additional data. STUDY SELECTION: Twenty-seven seed-based voxel-wise rsFC data sets from 25 publications (556 individuals with MDD and 518 healthy controls) were included in the meta-analysis. DATA EXTRACTION AND SYNTHESIS: Coordinates of seed regions of interest and between-group effects were extracted. Seeds were categorized into seed-networks by their location within a priori functional networks. Multilevel kernel density analysis of between-group effects identified brain systems in which MDD was associated with hyperconnectivity (increased positive or reduced negative connectivity) or hypoconnectivity (increased negative or reduced positive connectivity) with each seed-network. RESULTS: Major depressive disorder was characterized by hypoconnectivity within the frontoparietal network, a set of regions involved in cognitive control of attention and emotion regulation, and hypoconnectivity between frontoparietal systems and parietal regions of the dorsal attention network involved in attending to the external environment. Major depressive disorder was also associated with hyperconnectivity within the default network, a network believed to support internally oriented and self-referential thought, and hyperconnectivity between frontoparietal control systems and regions of the default network. Finally, the MDD groups exhibited hypoconnectivity between neural systems involved in processing emotion or salience and midline cortical regions that may mediate top-down regulation of such functions. CONCLUSIONS AND RELEVANCE: Reduced connectivity within frontoparietal control systems and imbalanced connectivity between control systems and networks involved in internal or external attention may reflect depressive biases toward internal thoughts at the cost of engaging with the external world. Meanwhile, altered connectivity between neural systems involved in cognitive control and those that support salience or emotion processing may relate to deficits regulating mood. These findings provide an empirical foundation for a neurocognitive model in which network dysfunction underlies core cognitive and affective abnormalities in depression. PMID- 25785577 TI - Orientation relationship in WC-Co composite nanoparticles synthesized by in situ reactions. AB - Using the nanoscale violet tungsten oxide as the tungsten source, the WC-Co composite powder was synthesized by the in situ reactions. The particle size of the WC-Co composite powder has a narrow distribution with the mean particle size below 100 nm, and the single composite particle has a nanocrystalline structure with a mean grain size smaller than 10 nm. The detailed characterizations of the nanoparticle microstructure reveal that the orientation relationship and coherence at the interfaces can form during the in situ reactions and further inherit in the consolidated cemented carbide bulk material. The favorable crystallographic characteristics of the WC-Co composite nanoparticles play a significant role in the enhancement of the mechanical properties of the prepared cemented carbide bulk material. PMID- 25785578 TI - Effect of pregabalin in preventing secondary damage in traumatic brain injury: an experimental study. AB - BACKGROUND: In this study we aimed to explore the effects of pregabalin on a traumatic brain injury model in rats. MATERIAL AND METHODS: This study included 40 adult male Sprague-Dawley rats randomized into 4 groups, each of which contained equal numbers of animals. The control group had no head trauma and thus was not treated. The trauma group had head trauma but was not treated. The pregabalin group had no head trauma but was treated by pregabalin. The trauma + pregabalin group had head trauma treated with pregabalin. The biopsy samples taken from the study animals were histopathologically examined for the presence of edema, inflammation, and neuronal damage. RESULTS: All animals in the trauma group had edema, inflammation, and neuronal damage. Four subjects in the control group, 6 in the pregabalin group, and 4 in the trauma + pregabalin group had edema; inflammation was present in 1 subject in the control group, 3 subjects in the pregabalin group, and 3 subjects in the trauma + pregabalin group; neuronal damage existed in 1 subject in the control group, 1 subject in the pregabalin group, and 6 subjects in the trauma+pregabalin group. The trauma group had significantly higher edema and neuronal damage scores than the other groups. Similarly, inflammation was significantly more prevalent in the trauma group than the control and trauma+pregabalin groups. CONCLUSIONS: The results of the present study indicated anti-edema, anti-inflammatory, and neuroprotective effects of pregabalin in an experimental head trauma model in rats. Pregabalin may thus be beneficial in humans with acute TBI by relieving concomitant edema and inflammation. PMID- 25785579 TI - Factors Affecting Health-Related Quality of Life in Patients With Cholangiocarcinoma in the Northeastern Region of Thailand. AB - BACKGROUND: Cholangiocarcinoma (CCA) remains a major health problem and causes high mortality in Northeastern Thailand. Patients with CCA have a poor prognosis, and little is known about their health-related quality of life (HRQOL) and its determinants. OBJECTIVE: The objective of this study was to investigate factors affecting HRQOL and its changes over time among CCA patients. METHODS: Two hundred thirty-seven patients with CCA were recruited during a 6-month period in 2011 in 5 tertiary hospitals in 4 provinces of northeastern Thailand. Health related quality of life after diagnosis of CCA was measured by the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire (Thai version 4). The HRQOL score of CCA patients at different times after diagnosis was compared by repeated-measures analysis of variance. Generalized estimating equation was used to identify factors affecting HRQOL among CCA patients. RESULTS: Of 237 eligible patients registered, 99 confirmed cases completed follow-up at 2 months. Overall HRQOL varied over time, with the score at baseline being significantly lower than 1 and 2 months later. An adjusted analysis showed that patients who were 60 to 69 years old had higher HRQOL scores than did younger patients. Patients using alternative medicine had lower HRQOL scores than did those who did not. CONCLUSIONS: Health-related quality-of-life scores among CCA patients changed over time and were related to age at recruitment and use of alternative medicine. IMPLICATIONS FOR PRACTICE: Healthcare providers should carefully communicate about the diagnosis and its implications. Patients with CCA, especially younger patients and those who have used traditional medicine, may benefit from counseling and help with mobilizing family and social support. PMID- 25785580 TI - The Meaning and Experience of Patients Undergoing Rectal High-Dose-Rate Brachytherapy. AB - BACKGROUND: High-dose-rate (HDR) brachytherapy is a precise form of radiation therapy that targets cancerous tumors by directly applying the radiation source at the site or directly next to the tumor. Patients often experience but underreport pain and anxiety related to cancer treatments. At present, there is no research available concerning the pervasiveness and intensity of patients' pain and anxiety during rectal brachytherapy. OBJECTIVE: The aim of this study was to examine patients' thoughts, emotions, coping strategies, physical sensations, and needs during rectal HDR brachytherapy treatment. METHODS: Twenty five patients with rectal cancer were interviewed using a semi-structured qualitative interview following the completion of their brachytherapy treatment delivered at a Montreal-based hospital in Quebec, Canada. RESULTS: The experiences of pain and discomfort varied greatly between patients and were linked to the meaning patients attributed to the treatment itself, sense of time, the body's lithotomic position, insertion of the treatment applicator, and the patients' sense of agency and empowerment during the procedure. Patients drew upon a variety of internal and external resources to help them cope with discomfort. CONCLUSION: Staff need to know about the variation in the physical and emotional experiences of patients undergoing this treatment. IMPLICATIONS FOR PRACTICE: Clinical teams can tailor their procedural behavior (eg, using certain language, psychosocial interventions) according to patients' needs to increase patients' comfort and ultimately improve their experience of HDR rectal brachytherapy. PMID- 25785581 TI - The Caregiver's Role Across the Bone Marrow Transplantation Trajectory. AB - BACKGROUND: Approximately 50 000 people undergo bone marrow transplants (BMTs) each year worldwide. With the move to more outpatient and home care, family caregivers are playing an ever-increasing role. However, there is little information regarding the needs and well-being of caregivers of individuals undergoing BMT. OBJECTIVE: The study purpose was to gain a better understanding of the BMT experience across the trajectory from the perspective of the family caregiver. METHODS: Qualitative interviews were conducted with 15 family caregivers during and 4 months after BMT. Interviews were recorded, transcribed verbatim, and analyzed using a content analysis approach. RESULTS: Uncertainty and need for more information were 2 major underlying themes noted across the early BMT trajectory. Caregivers reported feeling overwhelmed and juggling multiple roles, including (a) "interpreter," which included obtaining and translating medical information to their partner, family, and social network; (b) "organizer," which included arranging and coordinating medical appointments (pre- and post-BMT) for the patient, but also juggling the needs of immediate and extended family members; and (c) "clinician," which included assessing and identifying changes in their significant other, with many reporting that they had to be "vigilant" about or "on top of" any changes. Caregivers also reported the most challenging aspects of their role were to "be strong for everyone" and "finding balance." CONCLUSIONS: Our results underscore the unique needs of family caregivers as a consequence of BMT. IMPLICATIONS FOR PRACTICE: A greater understanding of the adaptation of caregivers will lead to the development of effective interventions for families going through BMT. PMID- 25785583 TI - Correction: Mammalian Ste20-like kinase and SAV1 promote 3T3-L1 adipocyte differentiation by activation of PPARgamma. PMID- 25785582 TI - Cell cycle- and cancer-associated gene networks activated by Dsg2: evidence of cystatin A deregulation and a potential role in cell-cell adhesion. AB - Cell-cell adhesion is paramount in providing and maintaining multicellular structure and signal transmission between cells. In the skin, disruption to desmosomal regulated intercellular connectivity may lead to disorders of keratinization and hyperproliferative disease including cancer. Recently we showed transgenic mice overexpressing desmoglein 2 (Dsg2) in the epidermis develop hyperplasia. Following microarray and gene network analysis, we demonstrate that Dsg2 caused a profound change in the transcriptome of keratinocytes in vivo and altered a number of genes important in epithelial dysplasia including: calcium-binding proteins (S100A8 and S100A9), members of the cyclin protein family, and the cysteine protease inhibitor cystatin A (CSTA). CSTA is deregulated in several skin cancers, including squamous cell carcinomas (SCC) and loss of function mutations lead to recessive skin fragility disorders. The microarray results were confirmed by qPCR, immunoblotting, and immunohistochemistry. CSTA was detected at high level throughout the newborn mouse epidermis but dramatically decreased with development and was detected predominantly in the differentiated layers. In human keratinocytes, knockdown of Dsg2 by siRNA or shRNA reduced CSTA expression. Furthermore, siRNA knockdown of CSTA resulted in cytoplasmic localization of Dsg2, perturbed cytokeratin 14 staining and reduced levels of desmoplakin in response to mechanical stretching. Both knockdown of either Dsg2 or CSTA induced loss of cell adhesion in a dispase based assay and the effect was synergistic. Our findings here offer a novel pathway of CSTA regulation involving Dsg2 and a potential crosstalk between Dsg2 and CSTA that modulates cell adhesion. These results further support the recent human genetic findings that loss of function mutations in the CSTA gene result in skin fragility due to impaired cell-cell adhesion: autosomal-recessive exfoliative ichthyosis or acral peeling skin syndrome. PMID- 25785584 TI - Entrapment bias of arthropods in Miocene amber revealed by trapping experiments in a tropical forest in Chiapas, Mexico. AB - All entomological traps have a capturing bias, and amber, viewed as a trap, is no exception. Thus the fauna trapped in amber does not represent the total existing fauna of the former amber forest, rather the fauna living in and around the resin producing tree. In this paper we compare arthropods from a forest very similar to the reconstruction of the Miocene Mexican amber forest, and determine the bias of different trapping methods, including amber. We also show, using cluster analyses, measurements of the trapped arthropods, and guild distribution, that the amber trap is a complex entomological trap not comparable with a single artificial trap. At the order level, the most similar trap to amber is the sticky trap. However, in the case of Diptera, at the family level, the Malaise trap is also very similar to amber. Amber captured a higher diversity of arthropods than each of the artificial traps, based on our study of Mexican amber from the Middle Miocene, a time of climate optimum, where temperature and humidity were probably higher than in modern Central America. We conclude that the size bias is qualitatively independent of the kind of trap for non-extreme values. We suggest that frequent specimens in amber were not necessarily the most frequent arthropods in the former amber forest. Selected taxa with higher numbers of specimens appear in amber because of their ecology and behavior, usually closely related with a tree-inhabiting life. Finally, changes of diversity from the Middle Miocene to Recent time in Central and South America can be analyzed by comparing the rich amber faunas from Mexico and the Dominican Republic with the fauna trapped using sticky and Malaise traps in Central America. PMID- 25785585 TI - Optimal cut-off points of fasting plasma glucose for two-step strategy in estimating prevalence and screening undiagnosed diabetes and pre-diabetes in Harbin, China. AB - To identify optimal cut-off points of fasting plasma glucose (FPG) for two-step strategy in screening abnormal glucose metabolism and estimating prevalence in general Chinese population. A population-based cross-sectional study was conducted on 7913 people aged 20 to 74 years in Harbin. Diabetes and pre-diabetes were determined by fasting and 2 hour post-load glucose from the oral glucose tolerance test in all participants. Screening potential of FPG, cost per case identified by two-step strategy, and optimal FPG cut-off points were described. The prevalence of diabetes was 12.7%, of which 65.2% was undiagnosed. Twelve percent or 9.0% of participants were diagnosed with pre-diabetes using 2003 ADA criteria or 1999 WHO criteria, respectively. The optimal FPG cut-off points for two-step strategy were 5.6 mmol/l for previously undiagnosed diabetes (area under the receiver-operating characteristic curve of FPG 0.93; sensitivity 82.0%; cost per case identified by two-step strategy Y261), 5.3 mmol/l for both diabetes and pre-diabetes or pre-diabetes alone using 2003 ADA criteria (0.89 or 0.85; 72.4% or 62.9%; Y110 or Y258), 5.0 mmol/l for pre-diabetes using 1999 WHO criteria (0.78; 66.8%; Y399), and 4.9 mmol/l for IGT alone (0.74; 62.2%; Y502). Using the two-step strategy, the underestimates of prevalence reduced to nearly 38% for pre diabetes or 18.7% for undiagnosed diabetes, respectively. Approximately a quarter of the general population in Harbin was in hyperglycemic condition. Using optimal FPG cut-off points for two-step strategy in Chinese population may be more effective and less costly for reducing the missed diagnosis of hyperglycemic condition. PMID- 25785586 TI - Oxygen therapy use in older adults with chronic obstructive pulmonary disease. AB - RATIONALE: Oxygen therapy improves survival and function in severely hypoxemic chronic obstructive pulmonary disease (COPD) patients based on two landmark studies conducted over 40 years ago. We hypothesize that oxygen users in the current era may be very different. We examined trends and subject characteristics associated with oxygen therapy use from 2001-2010 in the United States. METHODS: We examined Medicare beneficiaries with COPD who received oxygen from 2001 to 2010. COPD subjects were identified by: 1) >=2 outpatient visits >30 days apart within one year with an encounter diagnosis of COPD; or 2) an acute care hospitalization with COPD as the primary or secondary discharge diagnosis. Oxygen therapy and sustained oxygen therapy were defined as >=1 and >=11 claims for oxygen, respectively, in the durable medical equipment file in a calendar year. Primary outcome measures were factors associated with oxygen therapy and sustained oxygen therapy over the study period. RESULTS: Oxygen therapy increased from 33.7% in 2001 to 40.5% in 2010 (p-value of trend <0.001). Sustained oxygen therapy use increased from 19.5% in 2001, peaked in 2008 to 26.9% and declined to 18.5% in 2010. The majority of subjects receiving oxygen therapy and sustained oxygen therapy were female. Besides gender, factors associated with any oxygen use or sustained oxygen therapy were non-Hispanic white race, low socioeconomic status and >=2 comorbidities. CONCLUSIONS: Any oxygen use among fee-for service Medicare beneficiaries with COPD is high. Current users of oxygen are older females with multiple comorbidities. Decline in sustained oxygen therapy use after 2008 may be related to reimbursement policy change. PMID- 25785587 TI - Elimination of lymphatic filariasis in the Gambia. AB - BACKGROUND: The prevalence of Wuchereria bancrofti, which causes lymphatic filariasis (LF) in The Gambia was among the highest in Africa in the 1950s. However, surveys conducted in 1975 and 1976 revealed a dramatic decline in LF endemicity in the absence of mass drug administration (MDA). The decline in prevalence was partly attributed to a significant reduction in mosquito density through the widespread use of insecticidal nets. Based on findings elsewhere that vector control alone can interrupt LF, we asked the question in 2013 whether the rapid scale up in the use of insecticidal nets in The Gambia had interrupted LF transmission. METHODOLOGY/PRINCIPAL FINDING: We present here the results of three independently designed filariasis surveys conducted over a period of 17 years (1997-2013), and involving over 6000 subjects in 21 districts across all administrative divisions in The Gambia. An immunochromatographic (ICT) test was used to detect W. bancrofti antigen during all three surveys. In 2001, tests performed on stored samples collected between 1997 and 2000, in three divisions, failed to show positive individuals from two divisions that were previously highly endemic for LF, suggesting a decline towards extinction in some areas. Results of the second survey conducted in 2003 showed that LF was no longer endemic in 16 of 21 districts surveyed. The 2013 survey used a WHO recommended LF transmission verification tool involving 3180 6-7 year-olds attending 60 schools across the country. We demonstrated that transmission of W. bancrofti has been interrupted in all 21 districts. CONCLUSIONS: We conclude that LF transmission may have been interrupted in The Gambia through the extensive use of insecticidal nets for malaria control for decades. The growing evidence for the impact of malaria vector control activities on parasite transmission has been endorsed by WHO through a position statement in 2011 on integrated vector management to control malaria and LF. PMID- 25785588 TI - Quantitative evaluation of human cerebellum-dependent motor learning through prism adaptation of hand-reaching movement. AB - The cerebellum plays important roles in motor coordination and learning. However, motor learning has not been quantitatively evaluated clinically. It thus remains unclear how motor learning is influenced by cerebellar diseases or aging, and is related with incoordination. Here, we present a new application for testing human cerebellum-dependent motor learning using prism adaptation. In our paradigm, the participant wearing prism-equipped goggles touches their index finger to the target presented on a touchscreen in every trial. The whole test consisted of three consecutive sessions: (1) 50 trials with normal vision (BASELINE), (2) 100 trials wearing the prism that shifts the visual field 25 degrees rightward (PRISM), and (3) 50 trials without the prism (REMOVAL). In healthy subjects, the prism-induced finger-touch error, i.e., the distance between touch and target positions, was decreased gradually by motor learning through repetition of trials. We found that such motor learning could be quantified using the "adaptability index (AI)", which was calculated by multiplying each probability of [acquisition in the last 10 trials of PRISM], [retention in the initial five trials of REMOVAL], and [extinction in the last 10 trials of REMOVAL]. The AI of cerebellar patients less than 70 years old (mean, 0.227; n = 62) was lower than that of age-matched healthy subjects (0.867, n = 21; p < 0.0001). While AI did not correlate with the magnitude of dysmetria in ataxic patients, it declined in parallel with disease progression, suggesting a close correlation between the impaired cerebellar motor leaning and the dysmetria. Furthermore, AI decreased with aging in the healthy subjects over 70 years old compared with that in the healthy subjects less than 70 years old. We suggest that our paradigm of prism adaptation may allow us to quantitatively assess cerebellar motor learning in both normal and diseased conditions. PMID- 25785589 TI - Widening consumer access to medicines: a comparison of prescription to non prescription medicine switch in Australia and New Zealand. AB - BACKGROUND: Despite similarities in health systems and Trans-Tasman Harmonization of medicines scheduling, New Zealand is more active than Australia in 'switching' (reclassifying) medicines from prescription to non-prescription. OBJECTIVES: To identify and compare enablers and barriers to switch in New Zealand and Australia. METHODS: We conducted and analyzed 27 in-depth personal interviews with key participants in NZ and Australia and international participants previously located in Australia, and analyzed records of meetings considering switches (2000-2013). Analysis of both sets of data entailed a heuristic qualitative approach that embraced the lead researcher's knowledge and experience. RESULTS: The key themes identified were conservatism and political influences in Australia, and an open attitude, proactivity and flexibility in NZ. Pharmacist-only medicine schedules and individuals holding a progressive attitude were proposed to facilitate switch in both countries. A pharmacy retail group drove many switches in NZ ('third-party switch'), unlike Australia. Barriers to switch in both countries included small market sizes, funding of prescription medicines and cost of doctor visits, and lack of market exclusivity. In Australia, advertising limitations for pharmacist-only medicines reportedly discouraged industry from submitting switch applications. Perceptions of pharmacy performance could help or hinder switches. CONCLUSION: Committee and regulator openness to switch, and confidence in pharmacy appear to influence consumer access to medicines. The pharmacist-only medicine schedule in Australasia and the rise of third-party switch and flexibility in switch in NZ could be considered elsewhere to enable switch. PMID- 25785591 TI - Vitamin D Deficiency in Slipped Upper Femoral Epiphysis: Time to Physeal Fusion. AB - BACKGROUND: Slipped upper femoral epiphysis (SUFE) has an incidence of 1 to 7 per 100,000 adolescents in the United Kingdom and its link with obesity is well established. With an increasing number of pediatric orthopaedic patients presenting with vitamin D deficiency, the aim of our study was to establish the prevalence of vitamin D deficiency in SUFE patients presenting to an orthopaedic department in the United Kingdom and whether a low vitamin D level increases the time to proximal femoral physeal fusion after surgical fixation. METHODS: A total of 27 pediatric patients, with a female to male ratio of 17:10 and a mean age of 11.5 years (SD=1.99), range 8 to 16 years, presented with a SUFE and their vitamin D level was assessed during the study period, June 2007 to July 2012 (inclusive). The majority of these patients (85.2%) were assessed as vitamin D deficient, with a serum 25-(OH)D<52 nmol/L. The time taken for >50% physeal fusion on anteroposterior radiography after surgical fixation reported in the literature is 9.6 months, with no reported vitamin D deficiency or insufficiency. RESULTS: In our study, the median time to physeal fusion in the vitamin D deficient and vitamin D-insufficient patients was 25 months (interquartile range, 17 to 43 mo; mean of 29 mo, SD=16.8). A negative correlation was also observed between vitamin D level and the time taken for physeal fusion after surgical fixation. CONCLUSIONS: We conclude that a high prevalence of vitamin D deficiency has been observed in our SUFE patients. Comparing the time taken for physeal closure of 9.6 months in the literature with vitamin D-deficient patients, this is prolonged. Indeed, a negative correlation has been shown between vitamin D level and time to physeal fusion. This study highlights the need for regular vitamin D status assessment in SUFE patients to allow early implementation of treatment with vitamin D supplementation. The impact of vitamin D screening and supplementation on SUFE outcomes should be investigated further. PMID- 25785592 TI - Reliability and Validity of the Adapted Turkish Version of the Early-onset Scoliosis-24-Item Questionnaire (EOSQ-24). AB - INTRODUCTION: Early-onset scoliosis (EOS) can have negative effects on the developing thorax, lungs, and quality of life in general. Children with EOS can face various health problems and require recurring hospitalization and surgeries. Radiographic parameters are insufficient to evaluate the severity and efficacy of treatment in EOS. Early-onset Scoliosis Questionnaire (EOSQ)-24 questionnaire is a new instrument developed for this specific age group. To date, reliability of this questionnaire has not yet been interrogated in wide patient groups from different cultures. The aim of this study was to evaluate the validity and reliability of culturally adapted Turkish version of the EOSQ-24. METHODS: Forward translation and back translation of the English version of the EOSQ-24 was done, and all steps for cross-cultural adaptation process were performed properly by an expert committee. Turkish version of the EOSQ-24 and Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) were applied to 61 (24 male, 37 female) EOS patients. The average age of these patients was 9.1 +/- 3.1 years (0.4 to 14.3 y), and 50 of them had undergone surgical treatment. Data quality was assessed by mean, median, percentage of missing data, and extent of ceiling and floor effects. Reliability was assessed by internal consistency using Cronbach's alpha and item-total correlations. The construct validity was evaluated by comparing the results of the EOSQ-24 with the Turkish version of the CHQ-PF-50. Subgroup analyses were applied for sex, diagnosis, treated/untreated, mobilization ability, and complications. RESULTS: The item response to the EOSQ 24 was high with a small number of missing answers (1.6% to 3.3%). Of the 24 items, 22 were evenly distributed. This resulted in a floor effect in 0% to 21.7% of patients, and a ceiling effect in 1.6% to 68.3%. The calculated Cronbach's alpha for the 24-item scale was 0.909, indicating excellent reliability. Construct validity showed that high correlations between the EOSQ and the CHQ by means of similar domains. Correlation coefficient was between 0.348 and 0.688 (P=0.0001). Subgroup analyses also showed significant difference in treated/untreated patients (P=0.032) and mobilization ability (P=0.001). DISCUSSION: The Turkish adaptation of the EOSQ-24 exhibits favorable psychometric properties and excellent reliability, validating its use in this population. PMID- 25785590 TI - Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma. AB - Medulloblastoma (MB) is the most common malignant pediatric brain tumor. While the pathways that are deregulated in MB remain to be fully characterized, amplification and/or overexpression of the MYCN gene, which is has a critical role in cerebellar development as a regulator of neural progenitor cell fate, has been identified in several MB subgroups. Phenotypically, aberrant expression of MYCN is associated with the large-cell/anaplastic MB variant, which accounts for 5-15% of cases and is associated with aggressive disease and poor clinical outcome. To better understand the role of MYCN in MB in vitro and in vivo and to aid the development of MYCN-targeted therapeutics we established tumor-derived neurosphere cell lines from the GTML (Glt1-tTA/TRE-MYCN-Luc) genetically engineered mouse model. A fraction of GTML neurospheres were found to be growth factor independent, expressed CD133 (a marker of neural stem cells), failed to differentiate upon MYCN withdrawal and were highly tumorigenic when orthotopically implanted into the cerebellum. Principal component analyzes using single cell RNA assay data suggested that the clinical candidate aurora-A kinase inhibitor MLN8237 converts GTML neurospheres to resemble non-MYCN expressors. Correlating with this, MLN8237 significantly extended the survival of mice bearing GTML MB allografts. In summary, our results demonstrate that MYCN plays a critical role in expansion and survival of aggressive MB-propagating cells, and establish GTML neurospheres as an important resource for the development of novel therapeutic strategies. PMID- 25785593 TI - Community-acquired Methicillin-resistant Staphylococcus aureus Musculoskeletal Infections: Emerging Trends Over the Past Decade. AB - BACKGROUND: The emergence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has altered the management of pediatric musculoskeletal infections. Yet, institution-to-institution differences in MRSA virulence may exist, suggesting a need to carefully examine local epidemiological characteristics. The purpose of this study was to compare MRSA and methicillin sensitive S. aureus (MSSA) musculoskeletal infections with respect to prevalence and complexity of clinical care over the past decade at a single children's hospital. METHODS: We retrospectively reviewed a series of patients presenting to The Children's Hospital of Philadelphia with a diagnosis of osteomyelitis, septic arthritis, or both over a 10-year period. Inclusion criteria were S. aureus (SA) infections proven by positive culture of blood, bone, or joint aspirate. Exclusion criteria were non-SA infectious etiologies. Hospital-acquired infections were also not included to exclusively evaluate acute, community acquired cases. Data related to hospital course, laboratory values, and number of surgical interventions were collected and compared between MRSA and MSSA cohorts. RESULTS: In our series of pediatric patients, we identified 148 cases of acute, community-acquired musculoskeletal SA infections (MRSA, n=37 and MSSA, n=111). The prevalence of MRSA musculoskeletal infections increased from 11.8% in 2001 to 2002 to 34.8% in 2009 to 2010. Compared with MSSA, MRSA infections resulted in higher presenting C-reactive protein levels (10.4 vs. 7.8 mg/L, P=0.04), longer inpatient stays (10 vs. 5 d, P<0.01), multiple surgical procedures (n>1) (38% vs. 14%, P<0.01), increased sequelae (27% vs. 6%, P<0.01), and more frequent admissions to the intensive care unit (16% vs. 3%, P<0.01). CONCLUSIONS: At our institution over the past decade, we found an approximate 3-fold rise in community-acquired pediatric MRSA musculoskeletal infections accompanied by an elevated risk for complications during inpatient management. Awareness of the epidemiological trends of MRSA within the local community may guide parental counseling and facilitate timely and accurate clinical diagnosis and treatment. LEVEL OF EVIDENCE: Level II-prognostic retrospective study. PMID- 25785594 TI - Acetabular Remodeling After a Varus Derotational Osteotomy in Children With Cerebral Palsy. AB - BACKGROUND: The optimal surgical intervention for hip dysplasia in cerebral palsy (CP) is controversial. The purpose of this study was to determine (1) whether an isolated varus derotation osteotomy (VDRO) for the treatment of CP hip dysplasia allows for acetabular remodeling as measured by acetabular depth ratio (ADR), (2) the predictive factors for acetabular remodeling after an isolated VDRO for the treatment of CP hip dysplasia, and (3) to establish the normal ADR in typical children for comparison. METHODS: Eighty-seven CP patients (174 hips) treated with an isolated VDRO between 2003 and 2009 were retrospectively reviewed. The average age at surgery was 4.6 years (range, 2.4 to 10.6 y) and the average follow-up period was 5.1 years (range, 1.1 to 9.9 y). Acetabular remodeling was assessed on radiographs by the ADR. Changes in preoperative and postoperative ADR were analyzed using linear mixed-effects models. Patients were divided into 2 different groups for the postoperative ADR analysis: Gross Motor Function Classification System (GMFCS) levels I, II, and III compared with GMFCS levels IV and V. The progression of ADR versus age was determined in a set of 917 normal children (1834 hips) for comparison. RESULTS: There was a statistically significant increase (improvement) in ADR postsurgically for the collective CP set (P<0.001) and for both GMFCS categories (I/II/III, IV/V: P<0.001). GMFCS level, sex, and intraoperative neck shaft angle (NSA) were determined to be significant predictors for postoperative ADR improvement. GMFCS level was the most significant predictor for an increase in ADR after surgery (P<0.001). Less improvement in ADR was observed in patients of GMFCS levels IV and V compared with patients of GMFCS levels I, II, and III (P<0.001). A lower intraoperative NSA resulted in greater postoperative increase in ADR (P<0.05). CONCLUSIONS: Overall, isolated VDRO allowed for acetabular remodeling in CP hip dysplasia. Acetabular remodeling was increased in patients of GMFCS levels I, II, and III compared with patients of GMFCS levels IV and V. Increased varization at the time of VDRO improved acetabular remodeling. This study recommends considering GMFCS level and intraoperative NSA during surgical planning for CP hip dysplasia. PMID- 25785595 TI - Fracture of the Lateral Process of the Talus in Children: A Kind of Ankle Injury With Frequently Missed Diagnosis. AB - OBJECTIVE: To analyze the clinical characteristics, the treatment, and the outcome of lateral process fracture of the talus in children. METHODS: From March 2011 to October 2013, 12 children with lateral process fracture of the talus were treated in our hospital. The study contained 3 female and 9 male patients, including 8 patients affected on the left side and 4 on the right side. The age at the time of injury ranged from 8 to 13 years. Concomitant injuries included undisplaced calcaneus fractures in 1 case and distal fibula epiphysis injury in 1 case. The patients presented to our hospital from 2 hours to 2 months after injury. All cases were classified by the Hawkins fracture system. Treatment included immobilization and not bearing weight for 4 weeks for nondisplaced fractures or open reduction and fixation for significantly displaced fractures. Therapeutic effects were evaluated on the basis of the AOFAS (The American Orthopaedic Foot and Ankle Society) Ankle Hindfoot Scale. RESULTS: Seven of the cases were initially diagnosed in our department, and the diagnosis was missed in 5 cases. The missed diagnosis rate was 42%. All patients were followed up for 18 months on an average. Follow-up radiographs did not show avascular necrosis of the talus, nonunion, and malunion in any patient. The mean AOFAS hindfoot score was 96 points. The clinical result was found to be excellent in 10 patients, good in 1 patient, and fair in 1 patient (the success rate was 92%). CONCLUSIONS: The lateral process of talus fracture is a frequently missed injury. The diagnosis must rely on thorough check-ups combined with standard radiographs and computed tomographic scan. Depending on the type and the displacement of the fracture, proper treatment options could be implemented for desirable clinical effects. PMID- 25785596 TI - Correction: Neurotrophic requirements of human motor neurons defined using amplified and purified stem cell-derived cultures. PMID- 25785597 TI - A memristor SPICE model accounting for synaptic activity dependence. AB - In this work, we propose a new memristor SPICE model that accounts for the typical synaptic characteristics that have been previously demonstrated with practical memristive devices. We show that this model could account for both volatile and non-volatile memristance changes under distinct stimuli. We then demonstrate that our model is capable of supporting typical STDP with simple non overlapping digital pulse pairs. Finally, we investigate the capability of our model to simulate the activity dependence dynamics of synaptic modification and present simulated results that are in excellent agreement with biological results. PMID- 25785598 TI - The influence of maternal islet beta-cell autoantibodies in conjunction with gestational hyperglycemia on neonatal outcomes. AB - OBJECTIVE: To determine the predictive value of the presence of maternal islet beta-cell autoantibodies with respect to neonatal outcomes. METHODS: A total of 311 pregnant women with abnormal 75 g oral glucose tolerance test (OGTT) results were enrolled in this study. Maternal glutamic acid decarboxylase autoantibodies (GADA), islet cell autoantibodies (ICA) and insulin autoantibodies (IAA) were tested in fasting blood both on the day following the routine OGTT and before delivery. The birth weight, Apgar score, blood glucose and outcomes of each neonate were later evaluated and recorded. RESULTS: 1. In this study, 33.9% of the pregnant women with gestational hyperglycemia had detectable levels of one or more types of anti-islet cell antibodies in the third trimester. The proportion of women who produced GADA and/or ICA was significantly higher in the group of women with gestational hyperglycemia than in the control group (P<0.05). The groups similarly differed in the proportion of women who tested positive for any anti-islet cell antibody (P<0.05). 2. Of the patients in our study, those who produced GADA exhibited an increase in uterine and umbilical arterial pulsatility indexes (PIs) during the third trimesters compared with the control group (P?0.05). Additionally, an increased frequency of fetal growth restriction (FGR) was observed in the infants of women who produced IAA during pregnancy compared with those without autoantibodies (P?0.05). 3. The rate of newborn admission to the neonatal intensive care unit (NICU) was significantly associated with the presence of maternal ICA during the third trimester (OR, 6.36; 95% CI, 1.22 33.26). 4. The incidence of neonatal asphyxia was associated with the presence of maternal GADA in both the second (OR, 10.44; 95% CI, 1.46-74.92) and the third (OR, 8.33; 95% CI, 1.45-47.82) trimesters. CONCLUSION: Approximately one-third of the women with gestational hyperglycemia produced anti-islet cell antibodies. The incidence of FGR was higher in women with gestational hyperglycemia who produced IAA than in those without autoantibodies. Maternal ICA production in the third trimester was a risk factor for the subsequent admission of newborns to the NICU. Furthermore, the presence of maternal GADA placed the neonate at increased risk for asphyxia. PMID- 25785599 TI - Effects of ovarian hormones and oral contraceptive pills on cardiac vagal withdrawal at the onset of dynamic exercise. AB - The purpose of this study was to investigate the effects of the ovarian hormones and the use of oral contraceptive pills (OCP) on cardiac vagal withdrawal at the onset of dynamic exercise. Thirty physically active women aged 19-32 years were divided into two groups: OCP users (n = 17) and non-OCP users (n = 13). Participants were studied randomly at three different phases of the menstrual cycle: early follicular (day 3.6 +/- 1.2; range 1-5), ovulatory (day 14.3 +/- 0.8; range 13-16) and midluteal (day 21.3 +/- 0.8; range 20-24), according to endogenous (in non-OCP users) or exogenous (in OCP users) estradiol and progesterone variations. The cardiac vagal withdrawal was represented by the cardiac vagal index (CVI), which was obtained by the 4-s exercise test. Additionally, resting heart rate, systolic (SBP) and diastolic blood pressure (DBP) were obtained. The CVI was not significantly different between the three phases of the menstrual cycle in either the non-OCP users (early follicular: 1.58 +/- 0.1; ovulatory: 1.56 +/- 0.1; midluteal: 1.58 +/- 0.1, P > 0.05) or OCP users (early follicular: 1.47 +/- 0.1; ovulatory: 1.49 +/- 0.1; midluteal: 1.47 +/- 0.1, P > 0.05) (mean +/- SEM). Resting cardiovascular responses were not affected by hormonal phase or OCP use, except that the SBP was higher in the OCP users than non-OCP users in all phases of the cycle (P < 0.05). In summary, our results demonstrate that cardiac vagal withdrawal at the onset of dynamic exercise was not impacted by the menstrual cycle or OCP use in physically active women. PMID- 25785600 TI - Therapeutic implications from sensitivity analysis of tumor angiogenesis models. AB - Anti-angiogenic cancer treatments induce tumor starvation and regression by targeting the tumor vasculature that delivers oxygen and nutrients. Mathematical models prove valuable tools to study the proof-of-concept, efficacy and underlying mechanisms of such treatment approaches. The effects of parameter value uncertainties for two models of tumor development under angiogenic signaling and anti-angiogenic treatment are studied. Data fitting is performed to compare predictions of both models and to obtain nominal parameter values for sensitivity analysis. Sensitivity analysis reveals that the success of different cancer treatments depends on tumor size and tumor intrinsic parameters. In particular, we show that tumors with ample vascular support can be successfully targeted with conventional cytotoxic treatments. On the other hand, tumors with curtailed vascular support are not limited by their growth rate and therefore interruption of neovascularization emerges as the most promising treatment target. PMID- 25785601 TI - Emotional bookkeeping and high partner selectivity are necessary for the emergence of partner-specific reciprocal affiliation in an agent-based model of primate groups. AB - Primate affiliative relationships are differentiated, individual-specific and often reciprocal. However, the required cognitive abilities are still under debate. Recently, we introduced the EMO-model, in which two emotional dimensions regulate social behaviour: anxiety-FEAR and satisfaction-LIKE. Emotional bookkeeping is modelled by providing each individual with partner-specific LIKE attitudes in which the emotional experiences of earlier affiliations with others are accumulated. Individuals also possess fixed partner-specific FEAR attitudes, reflecting the stable dominance hierarchy. In this paper, we focus on one key parameter of the model, namely the degree of partner selectivity, i.e. the extent to which individuals rely on their LIKE attitudes when choosing affiliation partners. Studying the effect of partner selectivity on the emergent affiliative relationships, we found that at high selectivity, individuals restricted their affiliative behaviours more to similar-ranking individuals and that reciprocity of affiliation was enhanced. We compared the emotional bookkeeping model with a control model, in which individuals had fixed LIKE attitudes simply based on the (fixed) rank-distance, instead of dynamic LIKE attitudes based on earlier events. Results from the control model were very similar to the emotional bookkeeping model: high selectivity resulted in preference of similar-ranking partners and enhanced reciprocity. However, only in the emotional bookkeeping model did high selectivity result in the emergence of reciprocal affiliative relationships that were highly partner-specific. Moreover, in the emotional bookkeeping model, LIKE attitude predicted affiliative behaviour better than rank-distance, especially at high selectivity. Our model suggests that emotional bookkeeping is a likely candidate mechanism to underlie partner-specific reciprocal affiliation. PMID- 25785603 TI - Disentangling the impact of social groups on response times and movement dynamics in evacuations. AB - Crowd evacuations are paradigmatic examples for collective behaviour, as interactions between individuals lead to the overall movement dynamics. Approaches assuming that all individuals interact in the same way have significantly improved our understanding of pedestrian crowd evacuations. However, this scenario is unlikely, as many pedestrians move in social groups that are based on friendship or kinship. We test how the presence of social groups affects the egress time of individuals and crowds in a representative crowd evacuation experiment. Our results suggest that the presence of social groups increases egress times and that this is largely due to differences at two stages of evacuations. First, individuals in social groups take longer to show a movement response at the start of evacuations, and, second, they take longer to move into the vicinity of the exits once they have started to move towards them. Surprisingly, there are no discernible time differences between the movement of independent individuals and individuals in groups directly in front of the exits. We explain these results and discuss their implications. Our findings elucidate behavioural differences between independent individuals and social groups in evacuations. Such insights are crucial for the control of crowd evacuations and for planning mass events. PMID- 25785602 TI - Mechanisms of immunity in post-exposure vaccination against Ebola virus infection. AB - Ebolaviruses can cause severe hemorrhagic fever that is characterized by rapid viral replication, coagulopathy, inflammation, and high lethality rates. Although there is no clinically proven vaccine or treatment for Ebola virus infection, a virus-like particle (VLP) vaccine is effective in mice, guinea pigs, and non human primates when given pre-infection. In this work, we report that VLPs protect Ebola virus-infected mice when given 24 hours post-infection. Analysis of cytokine expression in serum revealed a decrease in pro-inflammatory cytokine and chemokine levels in mice given VLPs post-exposure compared to infected, untreated mice. Using knockout mice, we show that VLP-mediated post-exposure protection requires perforin, B cells, macrophages, conventional dendritic cells (cDCs), and either CD4+ or CD8+ T cells. Protection was Ebola virus-specific, as marburgvirus VLPs did not protect Ebola virus-infected mice. Increased antibody production in VLP-treated mice correlated with protection, and macrophages were required for this increased production. However, NK cells, IFN-gamma, and TNF-alpha were not required for post-exposure-mediated protection. These data suggest that a non replicating Ebola virus vaccine can provide post-exposure protection and that the mechanisms of immune protection in this setting require both increased antibody production and generation of cytotoxic T cells. PMID- 25785604 TI - Altered localization of p120 catenin in the cytoplasm rather than the membrane correlates with poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND: P120 catenin (p120ctn), a regulator of cell adhesion, has previously been found in many malignancies, and suggested a role in invasion, metastasis and survival. The aim of this study was to investigate correlations between altered localization of p120ctn and clinical-pathological characteristics in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemical staining for p120ctn was performed on tissue samples from 118 patients with ESCC. The expression of p120ctn was scored for intensity and cellular localization by Image-pro Plus 6.0. Correlations between immunohistochemical staining of p120ctn and pathological characteristics and clinical prognosis were determined using SPSS 18.0 software. RESULTS: Membrane expression of p120ctn in ESCCs was lower than that in adjacentnormal esophageal epithelial tissues (P = 0.041), while overall cellular expression of p120ctn was not different between the two tissue types (P = 0.787). Furthermore, neither overall cellular expression nor localized membrane expression was associated with histological and clinical variables. The high ratio of membrane expression to overall cellular expression (M/C) of p120ctn was inversely associated with lymph node invasion (P = 0.001), tumor differentiation (P = 0.012) and advanced tumor stage (P = 0.005); however, it was poorly associated with T stage (P = 0.274). The high M/C ratio of p120ctn was inversely correlated with poor survival; the 5-year OS (overall survival) and the 5-year DFS (disease free survival) for the high M/C ratio group were significantly higher than those of the low M/C ratio group (41.0% vs. 6.7%, P = 0.000; 44.1% vs. 24.9%, P = 0.007). Both the M/C ratio of p120ctn and N status were independent variables for the prediction of overall survival (P = 0.007 and P = 0.027). The M/C of p120ctn predicted a 0.49-fold risk of ESCC death (p = 0.007, 95% CI 0.29-0.83). CONCLUSIONS: The reduced M/C ratio of p120ctn acted as an independent prognostic factor for ESCC patient survival and for the migration and invasive behavior of the disease. PMID- 25785606 TI - Real-time dynamics of emerging actin networks in cell-mimicking compartments. AB - Understanding the cytoskeletal functionality and its relation to other cellular components and properties is a prominent question in biophysics. The dynamics of actin cytoskeleton and its polymorphic nature are indispensable for the proper functioning of living cells. Actin bundles are involved in cell motility, environmental exploration, intracellular transport and mechanical stability. Though the viscoelastic properties of actin-based structures have been extensively probed, the underlying microstructure dynamics, especially their disassembly, is not fully understood. In this article, we explore the rich dynamics and emergent properties exhibited by actin bundles within flow-free confinements using a microfluidic set-up and epifluorescence microscopy. After forming entangled actin filaments within cell-sized quasi two-dimensional confinements, we induce their bundling using three different fundamental mechanisms: counterion condensation, depletion interactions and specific protein protein interactions. Intriguingly, long actin filaments form emerging networks of actin bundles via percolation leading to remarkable properties such as stress generation and spindle-like intermediate structures. Simultaneous sharing of filaments in different links of the network is an important parameter, as short filaments do not form networks but segregated clusters of bundles instead. We encounter a hierarchical process of bundling and its subsequent disassembly. Additionally, our study suggests that such percolated networks are likely to exist within living cells in a dynamic fashion. These observations render a perspective about differential cytoskeletal responses towards numerous stimuli. PMID- 25785605 TI - Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin. AB - A new series of compounds characterized by the presence of a 2 methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3 (3',4',5'-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2 methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3-27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate. PMID- 25785608 TI - A non-parametric peak calling algorithm for DamID-Seq. AB - Protein-DNA interactions play a significant role in gene regulation and expression. In order to identify transcription factor binding sites (TFBS) of double sex (DSX)-an important transcription factor in sex determination, we applied the DNA adenine methylation identification (DamID) technology to the fat body tissue of Drosophila, followed by deep sequencing (DamID-Seq). One feature of DamID-Seq data is that induced adenine methylation signals are not assured to be symmetrically distributed at TFBS, which renders the existing peak calling algorithms for ChIP-Seq, including SPP and MACS, inappropriate for DamID-Seq data. This challenged us to develop a new algorithm for peak calling. A challenge in peaking calling based on sequence data is estimating the averaged behavior of background signals. We applied a bootstrap resampling method to short sequence reads in the control (Dam only). After data quality check and mapping reads to a reference genome, the peaking calling procedure compromises the following steps: 1) reads resampling; 2) reads scaling (normalization) and computing signal-to noise fold changes; 3) filtering; 4) Calling peaks based on a statistically significant threshold. This is a non-parametric method for peak calling (NPPC). We also used irreproducible discovery rate (IDR) analysis, as well as ChIP-Seq data to compare the peaks called by the NPPC. We identified approximately 6,000 peaks for DSX, which point to 1,225 genes related to the fat body tissue difference between female and male Drosophila. Statistical evidence from IDR analysis indicated that these peaks are reproducible across biological replicates. In addition, these peaks are comparable to those identified by use of ChIP-Seq on S2 cells, in terms of peak number, location, and peaks width. PMID- 25785607 TI - A meta-analysis of gene expression signatures of blood pressure and hypertension. AB - Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. PMID- 25785609 TI - 'Bee hotels' as tools for native pollinator conservation: a premature verdict? AB - Society is increasingly concerned with declining wild bee populations. Although most bees nest in the ground, considerable effort has centered on installing 'bee hotels'--also known as nest boxes or trap nests--which artificially aggregate nest sites of above ground nesting bees. Campaigns to 'save the bees' often promote these devices despite the absence of data indicating they have a positive effect. From a survey of almost 600 bee hotels set up over a period of three years in Toronto, Canada, introduced bees nested at 32.9% of sites and represented 24.6% of more than 27,000 total bees and wasps recorded (47.1% of all bees recorded). Native bees were parasitized more than introduced bees and females of introduced bee species provisioned nests with significantly more female larva each year. Native wasps were significantly more abundant than both native and introduced bees and occupied almost 3/4 of all bee hotels each year; further, introduced wasps were the only group to significantly increase in relative abundance year over year. More research is needed to elucidate the potential pitfalls and benefits of using bee hotels in the conservation and population dynamics of wild native bees. PMID- 25785611 TI - Efficacy of landiolol for the treatment of junctional ectopic tachycardia resulting from sepsis. AB - Junctional ectopic tachycardia, after surgery for CHD, is a serious arrhythmia that can cause increased morbidity and mortality. We report a case of junctional ectopic tachycardia, preceded by sepsis, in a 4-year-old girl, 31 months after open-heart surgery. She was successfully treated using low-dose landiolol hydrochloride. PMID- 25785612 TI - Correction: Electrical stimulation over bilateral occipito-temporal regions reduces N170 in the right hemisphere and the composite face effect. PMID- 25785610 TI - Effect of lysine to arginine mutagenesis in the V3 loop of HIV-1 gp120 on viral entry efficiency and neutralization. AB - HIV-1 infection is characterized by an ongoing replication leading to T lymphocyte decline which is paralleled by the switch from CCR5 to CXCR4 coreceptor usage. To predict coreceptor usage, several computer algorithms using gp120 V3 loop sequence data have been developed. In these algorithms an occupation of the V3 positions 11 and 25, by one of the amino acids lysine (K) or arginine (R), is an indicator for CXCR4 usage. Amino acids R and K dominate at these two positions, but can also be identified at positions 9 and 10. Generally, CXCR4-viruses possess V3 sequences, with an overall positive charge higher than the V3 sequences of R5-viruses. The net charge is calculated by subtracting the number of negatively charged amino acids (D, aspartic acid and E, glutamic acid) from the number of positively charged ones (K and R). In contrast to D and E, which are very similar in their polar and acidic properties, the characteristics of the R guanidinium group differ significantly from the K ammonium group. However, in coreceptor predictive computer algorithms R and K are both equally rated. The study was conducted to analyze differences in infectivity and coreceptor usage because of R-to-K mutations at the V3 positions 9, 10 and 11. V3 loop mutants with all possible RRR-to-KKK triplets were constructed and analyzed for coreceptor usage, infectivity and neutralization by SDF-1alpha and RANTES. Virus mutants R9R10R11 showed the highest infectivity rates, and were inhibited more efficiently in contrast to the K9K10K11 viruses. They also showed higher efficiency in a virus-gp120 paired infection assay. Especially V3 loop position 9 was relevant for a switch to higher infectivity when occupied by R. Thus, K-to-R exchanges play a role for enhanced viral entry efficiency and should therefore be considered when the viral phenotype is predicted based on V3 sequence data. PMID- 25785613 TI - Caring: a compassionate gesture. PMID- 25785614 TI - Unbundling the mystery of bundled payment programs. PMID- 25785615 TI - Improving transition of care for veterans after total joint replacement. AB - BACKGROUND: Patients transitioning from hospital to home are at risk for readmission to the hospital. Readmissions are costly and occur too often. Standardized discharge education processes have shown to decrease readmissions. PURPOSE: The purpose of this quality improvement project was to utilize evidence based practice changes to decrease 30-day all-cause readmissions after total joint replacement. METHODS: Review of literature revealed that improved discharge education can decrease unnecessary readmissions after discharge. A quality improvement project was developed including standardized total joint replacement discharge education, teach-back education methodology, and improved postdischarge telephone follow-up. The quality improvement project was initiated and outcomes were evaluated. OUTCOMES: Improving coordination of the discharge process, enhanced education for patients/caregivers, and postdischarge follow-up decreased total joint replacement readmissions. PMID- 25785617 TI - The use of tranexamic acid in joint replacement surgery. AB - Perioperative bleeding is a prevalent risk of elective joint replacement surgery that can lead to allogeneic blood transfusions, delayed discharge, and slowed physical therapy progress. Antifibrinolytics such as tranexamic acid (TXA) have been used in various surgical procedures to reduce bleeding; however, the use of TXA in orthopaedic surgery is not widespread. The purpose of this article is to determine whether the use of TXA in joint replacement surgery reduces total blood loss and lowers the need for allogeneic blood transfusions without adding additional surgical risk and cost. All reviewed meta analyses and systematic reviews analyzed did show a statistically significant reduction in total blood loss and reduction in the need for allogeneic blood transfusions. Therefore, researchers conclude that intravenous TXA use does decrease total blood loss and allogeneic blood transfusion needs. Thus, its use should be included in orthopaedic clinical practice guidelines due to its overall positive effect on outcomes. PMID- 25785619 TI - Measuring functional performance at discharge from hospital after total joint arthroplasty as a pre-requisite for planning early rehabilitation: a prognostic study. AB - BACKGROUND: The autonomy achieved by discharge after total knee and hip arthroplasty is important for planning early rehabilitation. PURPOSE: Describe functional performance using the Iowa Level of Assistance (ILOA) scale and investigate possible prognostic factors. METHODS: A prospective cohort study design was used. Autonomy at discharge was measured using the ILOA scale. Postoperative factors such as time to remove surgical drains, the length of hospitalization, preoperative physical therapy, and the number of physiotherapy treatments were collected. RESULTS: The sample was composed of 452 patients: 191 men (42.3%) and 261 women (57.7%). The mean ILOA score was 12.34 (SD = 5.4), representing a level of autonomy of 68.4%. Gait speed was the activity with the highest score and it ranged from 0.26 m/s to 0.32 m/s. Based on univariate and multivariate analysis, gender and age were the only significant variables to influence achieving autonomy at discharge. CONCLUSION: The rehabilitative program in its acute phase should be planned with particular attention paid to elderly women, unifying the physiotherapy protocol for total hip arthroplasty (THA) and total knee arthroplasty (TKA), reviewing the modalities of preoperative treatment sessions and with a specific training for the speed gait. PMID- 25785620 TI - Gentle persuasive approaches: introducing an educational program on an orthopaedic unit for staff caring for patients with dementia and delirium. AB - Gentle Persuasive Approaches in Dementia Care (GPA), a curriculum originally designed for long-term care, was introduced into an acute care setting. This person-centered approach to supporting and responding to persons with behaviors associated with dementia was shown to be applicable for staff on an orthopaedic surgery unit where they had reported significant challenges and care burdens when faced with behaviors such as shouting, explosiveness, and resistance to care. Staff confidence in their ability to care for persons with behaviors increased after attending the 1-day GPA workshop, and they reported being highly satisfied with the curriculum, found it to be applicable to their practice, indicated that it was also useful for patients with delirium, and would recommend it to others. Some of the staff on the orthopaedic unit became certified GPA coaches. The passion of those champions, along with demonstrated success of the program on their unit, contributed to its spread to other units, including rehabilitation and acute medicine. PMID- 25785622 TI - Limb position significantly affects safety distance during cast removal. AB - BACKGROUND: Unintentional cast saw injuries are attributable to casting material or improper removal technique. Another factor associated with the risk of injury is the "safety distance," the distance between the inner perimeter of the cast and the patient's skin. METHODS: Nine patients with lower leg casts around the knee/ankle were examined. Safety distance was measured using a standard depth gauge at 6-10 spots along the limb. The safety distance at each spot was measured in both supine and lateral-decubitus positions. Limb position was termed "safe" with the saw coming directly from above; a "dangerous" position was considered when the saw was coming from the side. RESULTS: The mean safety distance in the "safe position" was 17.02 mm +/- 4.66 mm, compared with 14.34 mm +/- 3.85 mm in the "dangerous position" (Delta = 2.7 mm; p < .0001). CONCLUSIONS: Proper positioning of a patient during cast-splitting, with the saw in the nondependent, safe aspect of the limb, can significantly increase the safety distance and minimize skin injuries. PMID- 25785623 TI - Posterior dislocation of the sternoclavicular joint: a case study. PMID- 25785628 TI - Assessment of regeneration potential in the clonal macrophyte Miscanthus sacchariflorus (Poaceae) after burial disturbance based on bud bank size and sprouting capacity. AB - The demography of the bud bank and its sprouting capacity are important for understanding the population dynamics of clonal plants and their potential responses to disturbances. To this end, we investigated the size and composition of the bud bank of Miscanthus sacchariflorus (Maxim.) Hack. immediately after flooding (November), in winter (January), in spring (March), and before flooding (May) in the wetlands of Dongting Lake. We then examined the sprouting capacity of axillary buds after sediment burial at 0, 5, 10, 15, and 20 cm. Total bud density of M. sacchariflorus ranged from 2524 buds m(-2) in November to 4293 buds m(-2) in March. Rhizome segments with inactive axillary buds, which represented the majority of the bud population (88.7% in November, 93.3% in May), did not sprout during the 140 days of the experiment (n = 250). The sprouting ratio was the highest for active axillary buds buried at 0 cm (64%) and decreased when buried at 10-20 cm (34%-40%). Due to the large number of active axillary buds in the bud bank (211-277 buds m(-2) from November to the following March), M. sacchariflorus could completely replace its aboveground shoot population, except in May (142 buds m(-2)). Increasing burial depth delayed bud emergence and reduced the growth period of shoots; however, burial depth did not affect the resulting plant height and only reduced the accumulated biomass at 20 cm. Therefore, the belowground bud bank and its strong sprouting capacity are important factors in the maintenance of local populations and colonization of new habitats for M. sacchariflorus after burial disturbances. The present methodology, which combined measurements of bud bank demography and sprouting capacity, may reflect the regeneration potential of clonal plants after burial disturbances. PMID- 25785629 TI - Growth kinetics and transmission potential of existing and emerging field strains of infectious laryngotracheitis virus. AB - Attenuated live infectious laryngotracheitis virus (ILTV) vaccines are widely used in the poultry industry to control outbreaks of disease. Natural recombination between commercial ILTV vaccines has resulted in virulent recombinant viruses that cause severe disease, and that have now emerged as the dominant field strains in important poultry producing regions in Australia. Genotype analysis using PCR-restriction fragment length polymorphism has shown one recombinant virus (class 9) has largely replaced the previously dominant class 2 field strain. To examine potential reasons for this displacement we compared the growth kinetics and transmission potential of class 2 and class 9 viruses. The class 9 ILTV grew to higher titres in cell culture and embryonated eggs, but no differences were observed in entry kinetics or egress into the allantoic fluid from the chorioallantoic membrane. In vivo studies showed that birds inoculated with class 9 ILTV had more severe tracheal pathology and greater weight loss than those inoculated with the class 2 virus. Consistent with the predominance of class 9 field strains, birds inoculated with 10(2) or 10(3) plaque forming units of class 9 ILTV consistently transmitted virus to in-contact birds, whereas this could only be seen in birds inoculated with 10(4) PFU of the class 2 virus. Taken together, the improved growth kinetics and transmission potential of the class 9 virus is consistent with improved fitness of the recombinant virus over the previously dominant field strain. PMID- 25785631 TI - Photogenerated excitons in plain core CdSe nanocrystals with unity radiative decay in single channel: the effects of surface and ligands. AB - A systematic and reproducible method was developed to study the decay dynamics of an exciton, a photogenerated electron-hole pair, in semiconductor nanocrystals in solution. Results revealed that the excitons in plain core CdSe nanocrystals in either zinc-blende or wurtzite or mixed lattice structures could be reproducibly prepared to decay radiatively in unity quantum yield and in single channel. The single-channel lifetime was found to increase monotonically by increasing size of the CdSe nanocrystals, with zinc-blende ones increasing in a relatively slow pace. Surface inorganic stoichiometry was found to be a sensitive parameter to affect the exciton decay dynamics for all crystal structures with different sizes. Excess Se (Cd) sites on the surface were found to induce short (long) lifetime channels for the excitons. Both types of traps reduced the quantum yield of the radiative decay of the excitons, and the hole traps associated with Se sites were nearly not emissive. With optimal surface inorganic stoichiometry, primary amines were identified as "ideal" organic ligands for CdSe core nanocrystals to achieve unity radiative decay of excitons in single channel in comparison to other types of neutral ligands commonly applied in the field. PMID- 25785630 TI - A global phylogeny of leafmining Ectoedemia moths (Lepidoptera: Nepticulidae): exploring host plant family shifts and allopatry as drivers of speciation. AB - BACKGROUND: Host association patterns in Ectoedemia (Lepidoptera: Nepticulidae) are also encountered in other insect groups with intimate plant relationships, including a high degree of monophagy, a preference for ecologically dominant plant families (e.g. Fagaceae, Rosaceae, Salicaceae, and Betulaceae) and a tendency for related insect species to feed on related host plant species. The evolutionary processes underlying these patterns are only partly understood, we therefore assessed the role of allopatry and host plant family shifts in speciation within Ectoedemia. METHODOLOGY: Six nuclear and mitochondrial DNA markers with a total aligned length of 3692 base pairs were used to infer phylogenetic relationships among 92 species belonging to the subgenus Ectoedemia of the genus Ectoedemia, representing a thorough taxon sampling with a global coverage. The results support monophyletic species groups that are congruent with published findings based on morphology. We used the obtained phylogeny to explore host plant family association and geographical distribution to investigate if host shifts and allopatry have been instrumental in the speciation of these leafmining insects. SIGNIFICANCE: We found that, even though most species within species groups commonly feed on plants from one family, shifts to a distantly related host family have occasionally occurred throughout the phylogeny and such shifts are most commonly observed towards Betulaceae. The largest radiations have occurred within species groups that feed on Fagaceae, Rosaceae, and Salicaceae. Most species are restricted to one of the seven global biogeographic regions, but within species groups representatives are commonly found in different biogeographic regions. Although we find general patterns with regard to host use and biogeography, there are differences between clades that suggest that different drivers of speciation, and perhaps drivers that we did not examine, have shaped diversity patterns in different clades. PMID- 25785632 TI - Integrated electrochemical microsystems for genetic detection of pathogens at the point of care. AB - The capacity to achieve rapid, sensitive, specific, quantitative, and multiplexed genetic detection of pathogens via a robust, portable, point-of-care platform could transform many diagnostic applications. And while contemporary technologies have yet to effectively achieve this goal, the advent of microfluidics provides a potentially viable approach to this end by enabling the integration of sophisticated multistep biochemical assays (e.g., sample preparation, genetic amplification, and quantitative detection) in a monolithic, portable device from relatively small biological samples. Integrated electrochemical sensors offer a particularly promising solution to genetic detection because they do not require optical instrumentation and are readily compatible with both integrated circuit and microfluidic technologies. Nevertheless, the development of generalizable microfluidic electrochemical platforms that integrate sample preparation and amplification as well as quantitative and multiplexed detection remains a challenging and unsolved technical problem. Recognizing this unmet need, we have developed a series of microfluidic electrochemical DNA sensors that have progressively evolved to encompass each of these critical functionalities. For DNA detection, our platforms employ label-free, single-step, and sequence specific electrochemical DNA (E-DNA) sensors, in which an electrode-bound, redox reporter-modified DNA "probe" generates a current change after undergoing a hybridization-induced conformational change. After successfully integrating E-DNA sensors into a microfluidic chip format, we subsequently incorporated on-chip genetic amplification techniques including polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) to enable genetic detection at clinically relevant target concentrations. To maximize the potential point-of care utility of our platforms, we have further integrated sample preparation via immunomagnetic separation, which allowed the detection of influenza virus directly from throat swabs and developed strategies for the multiplexed detection of related bacterial strains from the blood of septic mice. Finally, we developed an alternative electrochemical detection platform based on real-time LAMP, which not is only capable of detecting across a broad dynamic range of target concentrations, but also greatly simplifies quantitative measurement of nucleic acids. These efforts represent considerable progress toward the development of a true sample-in-answer-out platform for genetic detection of pathogens at the point of care. Given the many advantages of these systems, and the growing interest and innovative contributions from researchers in this field, we are optimistic that iterations of these systems will arrive in clinical settings in the foreseeable future. PMID- 25785634 TI - Correction: Genetic and morphological divergence in three strains of brook trout Salvelinus fontinalis commonly stocked in Lake Superior. PMID- 25785633 TI - Prevalence and risk factors of diabetes and diabetic retinopathy in Liaoning province, China: a population-based cross-sectional study. AB - AIM: To evaluate the prevalence and risk factors of diabetes and diabetic retinopathy (DR) in northeast area of China with a population-based study. METHODS: A population of 3173 (aged from 20 to 80 years old) was stratified by geographical location and age in Liaoning province, China. Prediabetes and diabetes were diagnosed according to the guideline of American Diabetes Association. Retinal photographs were obtained by using digital non-mydriatic camera for the presence and grading of DR according to the modified ETDRS Airlie house classification. Blood samples and comprehensive questionnaires were obtained for evaluation of laboratory results and risk factors. RESULTS: The prevalence of prediabetes and diabetes was 20.7% and 10.4%, respectively. Among diabetes patients, DR prevalence was 11.9%. Age, obesity, total cholesterol, triglycerides, hypertension, living in rural areas and diabetes family history are all risk factors for prediabetes and diabetes. Waist-to-hip circumference rate served as a better obesity index to estimate diabetes risk compared with body mass index and waist circumference. Among all risk factors that we investigated, only the length of diabetes history was associated with the incidence of DR. However, DR prevalence in the newly discovered patients in rural areas was significantly higher than that in urban areas. CONCLUSION: According to this study, 1 in 10 people has diabetes, 2 in 10 people have prediabetes, and 1 in 10 diabetics has DR in Liaoning province. In rural areas, diabetes was poorly recognized with limited medical resources, which probably resulted in more diabetes patient at a high risk of DR. PMID- 25785636 TI - Spin crossover behavior in a series of iron(III) alkoxide complexes. AB - The synthesis, crystal structures, magnetic behavior, and electron paramagnetic resonance studies of five new Fe(III) spin crossover (SCO) complexes are reported. The [Fe(III)N5O] coordination core is constituted of the pentadentate ligand bztpen (N5) and a series of alkoxide anions (ethoxide, propoxide, n butoxide, isobutoxide, and ethylene glycoxide). The methoxide derivative previously reported by us is also reinvestigated. The six complexes crystallize in the orthorhombic Pbca space group and show similar molecular structures and crystal packing. The coordination octahedron is strongly distorted in both the high- and low-temperature structures. The structural changes upon spin conversion are consistent with those previously observed for [Fe(III)N4O2] SCO complexes of the Schiff base type, except for the Fe-O(alkoxide) bond distance, which shortens significantly in the high-spin state. Application of the Slichter-Drickamer thermodynamic model to the experimental SCO curves afforded reasonably good simulations with typical enthalpy and entropy variations ranging in the intervals DeltaH = 6-13 kJ mol(-1) and DeltaS = 40-50 J mol(-1) K(-1), respectively. The estimated values of the cooperativity parameter Gamma, found in the interval 0 2.2 kJ mol(-1), were consistent with the nature of the SCO. Electron paramagnetic resonance spectroscopy confirmed the transformation between the high-spin and low spin states, characterized by signals at g ~ 4.47 and 2.10, respectively. Electrochemical analysis demonstrated the instability of the Fe(II) alkoxide derivatives in solution. PMID- 25785635 TI - Prolonged pre-incubation increases the susceptibility of Galleria mellonella larvae to bacterial and fungal infection. AB - Galleria mellonella larvae are widely used for assessing the virulence of microbial pathogens and for measuring the in vivo activity of antimicrobial agents and produce results comparable to those that can be obtained using mammals. The aim of the work described here was to ascertain the effect of pre incubation at 15 degrees C for 1, 3, 6 or 10 weeks on the susceptibility of larvae to infection with Candida albicans and Staphylococcus aureus. Larvae infected with C. albicans after 1 week pre-incubation at 15 degrees C showed 73.3 +/- 3.3% survival at 24 hours post-infection while those infected after 10 weeks pre-incubation showed 30 +/- 3.3% survival (P < 0.01). Larvae infected with S. aureus after 1 week pre-incubation showed 65.5 +/- 3.3% survival after 24 hours while those infected after 10 weeks pre-incubation showed 13.3 +/- 3.3% (P < 0.001). Analysis of the haemocyte density in larvae pre-incubated for 3-10 weeks showed a reduction in haemocytes over time but a proportionate increase in the density of granular haemocytes in the population as determined by FACS analysis. Proteomic analysis revealed decreased abundance of proteins associated with metabolic pathways (e.g. malate dehydrogenase, fructose-1,6-bisphosphatase, glyceraldehyde-3-phosphate dehydrogenase) and prophenoloxidase. G. mellonella larvae are a useful in vivo model system but the duration of the pre-incubation stage significantly affects their susceptibility to microbial pathogens possibly as a result of altered metabolism. PMID- 25785637 TI - The panel management questionnaire: a tool to measure panel management capability. AB - Primary care practices are turning toward team-based strategies such as panel management, in which nonclinicians address routine preventive and chronic disease care tasks for a group of patients. No known validated instruments have been published for measuring panel management implementation. The authors developed the 12-item Panel Management Questionnaire (PMQ) measuring 4 domains. Data were assembled from self-administered cross-sectional surveys of 136 staff and 204 clinicians in 9 county and 5 university adult primary care clinics. Staff and clinician PMQ scores in each clinic were correlated. The clinic-level median PMQ score was positively associated with a composite clinic quality measure. PMID- 25785638 TI - Expanding Access to Care and Improving Quality in the Mid-Atlantic States Safety Net Clinics: Kaiser Permanente's Community Ambassador Program. AB - The Community Ambassador Program (CAP) in the Mid-Atlantic States Region places Kaiser Permanente-employed nurse practitioners, midwives, and physician assistants to work in the safety-net clinics and share best practices through a long-term community collaboration. The authors conducted an evaluation of 18 safety-net clinics that participated in the CAP in 2012. The Community Ambassadors provided an estimated 32,249 encounters to 11,988 patients. Performance was at or near 90% for 2 adult quality measures (weight screening and tobacco use assessment). For breast cancer screenings, however, performance among the Community Ambassadors was much lower (48%). The program expanded access and improved quality of care. PMID- 25785639 TI - Alcohol intake, beverage choice, and cancer: a cohort study in a large kaiser permanente population. AB - The authors studied incident cancer risk from 1978 to 1985 and through follow-up in 2012 relative to light-to-moderate and heavy drinking and to the choice of alcoholic beverage in a cohort of 124,193 persons. With lifelong abstainers as referent, heavy drinking (>= 3 drinks per day) was associated with increased risk of 5 cancer types: upper airway/digestive tract, lung, female breast, colorectal, and melanoma, with light-to-moderate drinking related to all but lung cancer. PMID- 25785640 TI - Big data, miniregistries: a rapid-turnaround solution to get quality improvement data into the hands of medical specialists. AB - The cost to build and to maintain traditional registries for many dire, complex, low-frequency conditions is prohibitive. The authors used accessible technology to develop a platform that would generate miniregistries (small, routinely updated datasets) for surveillance, to identify patients who were missing elected utilization and to influence clinicians to change practices to improve care. The platform, tested in 5 medical specialty departments, enabled the specialists to rapidly and effectively communicate clinical questions, knowledge of disease, clinical workflows, and improve opportunities. Each miniregistry required 1 to 2 hours of collaboration by a specialist. Turnaround was 1 to 14 days. PMID- 25785641 TI - Use of ERC-1671 Vaccine in a Patient with Recurrent Glioblastoma Multiforme after Progression during Bevacizumab Therapy: First Published Report. AB - Glioblastoma multiforme is a highy aggressive tumor that recurs despite resection, focal beam radiation, and temozolamide chemotherapy. ERC-1671 is an experimental treatment strategy that uses the patient's own immune system to attack the tumor cells. The authors report preliminary data on the first human administration of ERC-1671 vaccination under a single-patient, compassionate-use protocol. The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies. PMID- 25785642 TI - Maintenance of Certification Part IV Quality-Improvement Project for Hypertension Control: A Preliminary Retrospective Analysis. AB - Fifty-two American Board of Family Medicine and 19 American Board of Internal Medicine certified physicians completed projects to increase the percentage of hypertensive patients on their patient panels who had controlled blood pressure. Mean panel blood pressure control improved from 79.49% to 84.64%. The choice of improvement option was not associated with the level of improvement or with the participant's perception of the workload related to completing the project. PMID- 25785643 TI - Cdk5 controls IL-2 gene expression via repression of the mSin3a-HDAC complex. AB - Cyclin-dependent kinase 5 (Cdk5) is a unique member of a family of serine/threonine cyclin-dependent protein kinases. We previously demonstrated disruption of Cdk5 gene expression in mice impairs T-cell function and ameliorates T-cell-mediated neuroinflammation. Here, we show Cdk5 modulates gene expression during T-cell activation by impairing the repression of gene transcription by histone deacetylase 1 (HDAC1) through specific phosphorylation of the mSin3a protein at serine residue 861. Disruption of Cdk5 activity in T cells enhances HDAC activity and binding of the HDAC1/mSin3a complex to the IL-2 promoter, leading to suppression of IL-2 gene expression. These data point to essential roles for Cdk5 in regulating gene expression in T-cells and transcriptional regulation by the co-repressor mSin3a. PMID- 25785644 TI - Effects of Industrial Processes on Antioxidant Power and Polyphenols Profile in Cherry Tomato Cultivar. AB - The antioxidant capacity and the polyphenolic profile of fresh and processed cherry tomatoes were analyzed with the aim of investigating the effect of industrial processes on the nutritional qualities of fruits. The results exhibited a decrease of antioxidant activity mainly in the lipophilic fraction of processed tomatoes compared with fresh products. No great difference in the antioxidant capacity was detected in the hydrophilic and methanolic extracts of fresh tomatoes and processed tomato juices. Moreover, a decrease of polyphenolic content, estimated by means of high-performance liquid chromatography analysis and Folin-Ciocalteu method, was observed in all tomato juices. The overall polyphenolic profile of both fresh and processed tomatoes did not change significantly and, among all juices, a higher polyphenolic content was detected in juice containing peels and seeds in comparison to those without. From our data on antioxidant power and the bioactive metabolite content, tomato juice could be used as a valid and easily available source of antioxidants in everyday diet to preserve human health. PMID- 25785646 TI - Child-Directed Interaction Training for Young Children With Autism Spectrum Disorders: Parent and Child Outcomes. AB - This study examined the efficacy of the Child-Directed Interaction Training (CDIT) phase of Parent-Child Interaction Therapy for children with an Autism Spectrum Disorder (ASD). Thirty mother-child dyads with children ages 3-7 years with a diagnosis of ASD participated in this randomized controlled study. Following manualized CDIT, statistically significant and meaningful improvements in child disruptive behavior and social awareness as well as maternal distress associated with child disruptive behavior occurred. Across 8 sessions, mothers learned to provide positive attention to their children's appropriate social and play behaviors. Both child and parent changes were maintained at 6-week follow up. A relatively brief, time-limited, and accessible intervention may be efficacious for improving child and parent behaviors in families of young children with ASD. By decreasing child disruptive behaviors, CDIT may also help to prepare children to benefit further from future interventions. PMID- 25785645 TI - Targeting alpha-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies. AB - OBJECTIVE: Reducing the burden of alpha-synuclein oligomeric species represents a promising approach for disease-modifying therapies against synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. However, the lack of efficient drug discovery strategies that specifically target alpha-synuclein oligomers has been a limitation to drug discovery programs. RESEARCH DESIGN AND METHODS: Here we describe an innovative strategy that harnesses the power of bimolecular protein-fragment complementation to monitor synuclein-synuclein interactions. We have developed two robust models to monitor alpha-synuclein oligomerization by generating novel stable cell lines expressing alpha-synuclein fusion proteins for either fluorescent or bioluminescent protein-fragment complementation under the tetracycline-controlled transcriptional activation system. MAIN OUTCOME MEASURES: A pilot screen was performed resulting in the identification of two potential hits, a p38 MAPK inhibitor and a casein kinase 2 inhibitor, thereby demonstrating the suitability of our protein-fragment complementation assay for the measurement of alpha-synuclein oligomerization in living cells at high throughput. CONCLUSIONS: The application of the strategy described herein to monitor alpha-synuclein oligomer formation in living cells with high throughput will facilitate drug discovery efforts for disease-modifying therapies against synucleinopathies and other proteinopathies. PMID- 25785647 TI - In Vitro Evaluation of Titanium Exfoliation During Simulated Surgical Insertion of Dental Implants. AB - Dissolution of titanium wear particles in the oral environment, and their accumulation in the surrounding tissues have been associated with failure of dental implants (DI). The goal of this study is to investigate the effect of mechanical forces involved in surgical insertion of DI on surface wear and metal particle generation. It was hypothesized that mechanical factors associated with implant placement can lead to the generation of titanium particles in the oral environment. The testing methodology for surface evaluation employed simulated surgical insertion, followed by removal of DI in different densities of simulated bone material. Torsional forces were monitored for the insertion and removal of DI. The surface of the simulated bone materials was inspected with optical microscopy to detect traces of metallic particles that may have been generated during the procedure. Further characterization of the composition of powders collected from osteotomy cavities was conducted with powder X-ray diffraction. The results showed that the different densities of simulated bone material affected the torsional forces associated with implant insertion. However, the mechanical factors involved in the implant insertion/removal procedure did not generate wear particles, as confirmed by powder X-ray experiments. PMID- 25785648 TI - Feasibility of unilateral breastfeeding. PMID- 25785649 TI - Toxicity mechanisms identification via gene set enrichment analysis of time series toxicogenomics data: impact of time and concentration. AB - The advance in high-throughput "toxicogenomics" technologies, which allows for concurrent monitoring of cellular responses globally upon exposure to chemical toxicants, presents promises for next-generation toxicity assessment. It is recognized that cellular responses to toxicants have a highly dynamic nature, and exhibit both temporal complexity and dose-response shifts. Most current gene enrichment or pathway analysis lack the recognition of the inherent correlation within time series data, and may potentially miss important pathways or yield biased and inconsistent results that ignore dynamic patterns and time sensitivity. In this study, we investigated the application of two score metrics for GSEA (gene set enrichment analysis) to rank the genes that consider the temporal gene expression profile. One applies a novel time series CPCA (common principal components analysis) to generate scores for genes based on their contributions to the common temporal variation among treatments for a given chemical at different concentrations. Another one employs an integrated altered gene expression quantifier-TELI (transcriptional effect level index) that integrates altered gene expression magnitude over the exposure time. By comparing the GSEA results using two different ranking metrics for examining the dynamic responses of reporter cells treated with various dose levels of three model toxicants, mitomycin C, hydrogen peroxide, and lead nitrate, the analysis identified and revealed different toxicity mechanisms of these chemicals that exhibit chemical-specific, as well as time-aware and dose-sensitive nature. The ability, advantages, and disadvantages of varying ranking metrics were discussed. These findings support the notion that toxicity bioassays should account for the cells' complex dynamic responses, thereby implying that both data acquisition and data analysis should look beyond simple traditional end point responses. PMID- 25785650 TI - Factors associated with the use of a teleconsultation system in Brazilian primary care. AB - BACKGROUND: The Telehealth Network of Minas Gerais (TNMG) is a public telehealth service that provides support to primary healthcare in Minas Gerais, Brazil, performing teleconsultation and tele-electrocardiography. The aim of this study was to assess teleconsultation requests received by the TNMG and to investigate the factors associated with low teleconsultation utilization in most municipalities. MATERIALS AND METHODS: A cross-sectional study was carried out including 214 municipalities. Indicators were defined to analyze teleconsultation requests. A structured questionnaire was used to investigate factors associated with teleconsultation utilization, which were analyzed by multivariate analysis through a decision tree algorithm (chi-squared automatic interaction detector) to the entire population of the study and logistic regression for municipalities that had used the system during the analyzed period. RESULTS: From May to September 2009, 1,954 teleconsultations were performed. The average number (+/ standard deviation) of teleconsultations per municipality was 1.71 (+/-1.50) per month. The majority of the users were located in remote regions with a low Human Development Index. The decision tree showed "conduction of sufficient training" (p=0.0015) as the factor with the greatest positive impact on teleconsultation utilization, followed by "ability to discuss clinical cases outside the teleconsultation system" (p=0.0192). Logistic regression analysis revealed two factors associated with increased use of the system: "complexity of the system" (odds ratio=3.35; 95% confidence interval [CI], 1.58-7.09) and whether they considered that the "service helps to solve everyday problems" (odds ratio=4.37; 95% CI, 1.14-16.69). CONCLUSIONS: The study of factors associated with the low use of the teleconsultation system of the TNMG may help policy makers define strategies to improve the use of teleconsultation services. PMID- 25785651 TI - Comparison of bone prefabrication with vascularized periosteal flaps, hydroxyapatite, and bioactive glass in rats. AB - BACKGROUND: Periosteal flaps possess osteoprogenitor cells and an osteoinductive potential that can be further augmented by combination with a biodegradable scaffold; therefore, various osteoconductive and osteostimulative biomaterials are frequently combined with periosteal flaps in studies of bone prefabrication. An experimental study was designed to determine and compare the contribution of bioactive glass and hydroxyapatite to osteoneogenesis in rats when combined with a periosteal flap. MATERIALS AND METHODS: In 60 Sprague Dawley rats, saphenous artery periosto-fasciocutaneous island flaps were transposed to abdomen. In group 1, the flap was left alone, in group 2, an empty artificial pocket made of Gore Tex (W. L. Gore & Associates, Inc.; Flagstaff, AZ) was sutured onto the periosteal layer, and in groups 3 and 4, the pocket was filled with bioactive glass and hydroxyapatite, respectively. Following sampling for histological analysis, a 4-point scoring system was used to grade inflammatory cell infiltration, osteogenesis, angiogenesis, and cell migration into the bioactive material. RESULTS: The combination of the periosteal flap with any of the bioactive materials resulted in significantly higher percentages of animals exhibiting osteogenesis (80% in hydroxyapatite group and 93.3% in the bioactive glass group; p = 0.0000528) and angiogenesis. Comparison of the bioactive material groups revealed that a significantly higher proportion of animals in the bioactive glass group exhibited moderate or severe inflammation (80 vs. 20%; p = 0.002814). CONCLUSION: Periosteal flaps prefabricated with hydroxyapatite or bioactive glass in rats exhibit osteogenic capacities that are not dependent on direct bone contact or proximity to vascular bony tissue. The innate capacity of the periosteal flap when utilized alone for osteoneogenesis was found to be rather insufficient. PMID- 25785652 TI - Delayed implant augmentation of breast free flaps. AB - BACKGROUND: Two commonly used breast reconstruction techniques are (1) implant based and (2) abdominal tissue-based procedures. When the two modalities are combined, the result is a unique construct that shares advantages and disadvantages of both approaches. Combining breast flaps and implants has been reported, yet the specific techniques associated with a reliable outcome remain unclear. MATERIALS AND METHODS: Between July 2010 and 2014, a review of all patients who underwent delayed implant augmentation of a breast free flap reconstruction by the senior author was performed. Data were collected on patient characteristics, implants used, timing of reconstruction, and position of implant relative to the flap. RESULTS: During the study period, 101 patients underwent breast reconstruction with 161 abdominal free flaps. Of these, 12 patients (12%) and 17 flaps (11%) had delayed implant augmentation. Of the 17 augmented flaps, 12 had expanders placed before final implant placement. Eleven implants were placed in the subflap position and 6 in the subpectoralis major position. The mean final implant size was 296.5 mL (range, 125-510 mL). At a mean follow-up of 17.1 months, there was one expander removed before complete expansion for impending extrusion and one silicone gel implant revision for malposition. CONCLUSION: The results of delayed breast flap implant augmentation can be reliable and generate results that may not be obtainable with flaps or implants alone. Admittedly, the addition of an implant to a flap reconstruction exposes the patient to implant-related complications that would otherwise have been circumvented by a pure autologous reconstruction. PMID- 25785653 TI - Three-dimensional venous visualization with phase-lag computed tomography angiography for reconstructive microsurgery. AB - BACKGROUND: Most free flap reconstruction complications involve vascular compromise. Evaluation of vascular anatomy provides considerable information that can potentially minimize these complications. Previous reports have shown that contrast-enhanced computed tomography is effective for understanding three dimensional arterial anatomy. However, most vascular complications result from venous thromboses, making imaging of venous anatomy highly desirable. METHODS: The phase-lag computed tomography angiography (pl-CTA) technique involves 64 channel (virtually, 128-channel) multidetector CT and is used to acquire arterial images using conventional CTA. Venous images are three-dimensionally reconstructed using a subtraction technique involving combined venous phase and arterial phase images, using a computer workstation. RESULTS: This technique was used to examine 48 patients (12 lower leg reconstructions, 34 head and neck reconstructions, and 2 upper extremity reconstructions) without complications. The pl-CTA technique can be used for three-dimensional visualization of peripheral veins measuring approximately 1 mm in diameter. CONCLUSION: The pl-CTA information was especially helpful for secondary free flap reconstructions in the head and neck region after malignant tumor recurrence. In such cases, radical dissection of the neck was performed as part of the first operation, and many vessels, including veins, were resected and used in the first free-tissue transfer. The pl-CTA images also allowed visualization of varicose changes in the lower leg region and helped us avoid selecting those vessels for anastomosis. Thus, the pl-CTA-derived venous anatomy information was useful for exact evaluations during the planning of free-tissue transfers. PMID- 25785654 TI - A Novel Preoperative Planning Technique Using a Combination of CT Angiography and Three-Dimensional Printing for Complex Toe-to-Hand Reconstruction. AB - BACKGROUND: Microsurgical toe-to-hand transplantation is a reasonable salvage procedure after failed replantation, though no consensus exists on proper donor toe length for restoration of hand function and optimal donor flap needed for recipient site healing. The purpose of this study was to introduce a novel technique for preoperative planning in complicated toe-to-hand reconstruction and to assess feasibility in four cases. METHODS: Computed tomography (CT) angiography was used to map donor site vasculature, whereas CT data were used to create three-dimensional (3D) soft tissue and skeletal models for injured and uninjured hands. Based on the reformatted model (mirror of uninjured hand), soft tissue and finger skeleton models were generated using a 3D printer. An adhesive plaster model was placed on the donor site to determine osteotomy level and incision markings. The skeletal model was used to determine the length of the donor foot resection. Four complex amputation cases were included to illustrate clinical feasibility and early functional and cosmetic outcomes. RESULTS: In all four cases, thumb and fingers were reconstructed successfully and all flaps survived. No arterial or venous thrombosis or major donor morbidity were observed. Functional and cosmetic outcomes were satisfactory with similarly satisfactory static two-point discrimination, key pinch and grip strength, and Michigan Hand Outcomes Questionnaire scores. CONCLUSION: This novel microsurgical toe-to-hand reconstruction methodology, as introduced in this study, showed promising functional and cosmetic outcomes. Application of this technique in complex hand injuries has the potential to increase surgical efficiency, minimize procedural morbidity, and improve reproducibility. PMID- 25785655 TI - Use of small gap anastomosis for the repair of peripheral nerve injury by cutting and sleeve jointing the epineurium. AB - BACKGROUND: Although epineurium neurorrhaphy is the most reliable and conventional method for the repair of peripheral nerve injury and is accepted as the gold standard, it is still far from ideal. Many attempts have been made to develop nerve anastomosis techniques. The aim of this study was to investigate the use of small gap anastomosis performed by cutting and sleeve jointing the epineurium for nerve repair. METHODS: A 12-week study was performed using small gap anastomosis via cutting and sleeve jointing the epineurium, compared with epineurium neurorrhaphy in situ, to repair a rat sciatic nerve rupture. Three experimental groups were included: sham control (n = 8), small gap anastomosis (n = 16), and epineurium neurorrhaphy (n = 16). About 12 weeks after surgery, recovery was assessed with walking track analysis, electrophysiology, hematoxylin and eosin staining, immunohistochemistry, and electron microscopy. RESULTS: The sciatic nerve functional index observed in the small gap anastomosis group was significantly higher than that in the epineurium neurorrhaphy group (p < 0.05). In vivo electrophysiological analysis confirmed that the small gap anastomosis group showed a significantly higher conduction velocity than the epineurium neurorrhaphy group (p < 0.05). Postoperative morphometric analysis revealed better results after small gap anastomosis compared with epineurium neurorrhaphy. CONCLUSION: Small gap anastomosis via cutting and sleeve jointing the epineurium could be an alternative to epineurium neurorrhaphy for the repair of peripheral nerve injury, particularly, considering that the epineurium originates from native tissue that provides a suitable microenvironment for the selective regeneration of axons. PMID- 25785656 TI - Role of bromide in hydrogen peroxide oxidation of CTAB-stabilized gold nanorods in aqueous solutions. AB - In recent years hydrogen peroxide has often been used as the oxidizing agent to tune the resonance wavelength of gold nanorods (AuNRs) through anisotropic shortening in the presence of cetyltrimethylammonium bromide (CTAB). However, a complete picture of the reaction mechanism remains elusive. In this work, we present a systematic study on the mechanism of the AuNR oxidation by revealing the important role of bromide. Hydrogen peroxide slowly oxidizes bromide into elemental bromine. The latter two form tribromide, which exhibits a characteristic 272 nm absorption peak. The peak intensity, representing the concentration of tribromide, is found to have a linear correlation with the oxidation rate of AuNRs. Tribromide approaches AuNRs through conjugating strongly with CTA cationic micelles, which leads to the oxidation occurring on the surface of AuNRs. In contrast, the CTA micelles protect AuNRs from the direct oxidation by hydrogen peroxide. Our findings are believed to provide new insights into the reaction mechanism occurring in the relevant CTAB-AuNR systems, which can be important for understanding the principles governing the reaction dynamics. PMID- 25785657 TI - Molecular motions in supercooled and glassy ibuprofen: deuteron magnetic resonance and high-resolution rheology study. AB - Using deuteron nuclear magnetic resonance, the molecular motions of specifically isotope-labeled ibuprofen were probed at the carboxylic group and at the methin group next to it. Spin relaxometry revealed slight differences between the molecular motions of the two isotopomers that are rationalized with reference to the hydrogen bonding of the COOH moiety. In the glassy state, a small-angle jump process among about four sites, related to the so-called gamma-process, was identified using stimulated-echo spectroscopy. Indications for a Debye-like process, previously found to leave a weak signature in the dielectric loss, could not unambiguously be detected in magnetic resonance or shear mechanical experiments carried out for supercooled liquid ibuprofen. PMID- 25785658 TI - Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients. AB - BACKGROUND: Little is known about the influence of exogenous insulin and actual glucose levels on the release of endogenous insulin in insulin-treated type 2 diabetes mellitus (T2DM) patients. This study investigated the interaction among serum endogenous insulin (s-EI), serum exogenous insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. STUDY DESIGN AND METHODS: Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8+/-3.8 kg/m(2)) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU/h) as a continuous subcutaneous insulin infusion (CSII) during a 10-h period on two occasions with different duration of hyperglycemia: (1) transient hyperglycemia for 2 h (visit TH) and (2) continuous hyperglycemia for 12 h (visit CH). RESULTS: During steady state the variances of plasma glucose (p-glucose), s-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first 100 min of both visits when s-IAsp was undetectable (adjusted R(2)=0.9). A complex but statistically significant interaction among s IAsp, s-EI, p-glucose, and patients was observed during measurable s-IAsp levels (adjusted R(2)=0.70). CONCLUSIONS: Endogenous and exogenous insulin showed higher variation during continuous hyperglycemia. Significantly lower levels of exogenous insulin were observed following CSII during continuous hyperglycemia compared with transient hyperglycemia. Endogenous insulin levels could in a complex way be explained by an individual interaction among p-glucose and serum exogenous insulin, if present. PMID- 25785659 TI - Online Vision as a Function of Real-Time Limb Velocity: Another Case for Optimal Windows. AB - The efficiency of online visuomotor processes was investigated by manipulating vision based on real-time upper limb velocity. Participants completed rapid reaches under two control (full vision, no vision) and three experimental visual window conditions. The experimental visual windows were early: 0.8-1.4 m/s, middle: above 1.4 m/s, and late: 1.4 to 0.8 m/s. The results indicated that endpoint consistency comparable to that of full-vision trials was observed when using vision from the early (43 ms) and middle (89 ms) windows, but vision from the middle window entailed a longer deceleration phase (i.e., a temporal cost). The late window was not useful to implement online trajectory amendments. This study provides further support for the idea of early visuomotor control, which may involve multiple online control processes during voluntary movement. PMID- 25785660 TI - Corticosteroid therapy for nephrotic syndrome in children. AB - BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the mortality rate to around 3%. However corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2003, 2005 and 2007. OBJECTIVES: The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children 1) children in their initial episode of SSNS, and 2) children who experience a relapsing course of SSNS. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 26 February 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) performed in children (three months to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: Ten new studies were identified so a total of 34 studies (3033 total participants) were included in the 2015 review update. The risk of bias attributes were frequently poorly performed. Low risk of bias was reported in 18 studies for sequence generation, 16 studies for allocation concealment, seven for performance and detection bias, 15 for incomplete reporting and 16 for selective reporting. Three months or more of prednisone significantly reduced the risk of frequently relapsing nephrotic syndrome (FRNS) (6 studies, 582 children: RR 0.68, 95% CI 0.47 to 1.00) and of relapse by 12 to 24 months (8 studies, 741 children: RR 0.80, 95% CI 0.64 to 1.00) compared with two months. Five or six months of prednisone significantly reduced the risk of relapse (7 studies, 763 children: RR 0.62, 95% CI 0.45 to 0.85) but not FRNS (5 studies, 591 children: RR 0.78, 95% CI 0.50 to 1.22) compared with three months. However there was significant heterogeneity in the analyses. Subgroup analysis stratified by risk of bias for allocation concealment showed that the risk for FRNS did not differ significantly between two or three months of prednisone and three to six months among studies at low risk of bias but was significantly reduced in extended duration studies compared with two or three months in studies at high risk or unclear risk of bias. There were no significant differences in the risk of adverse effects between extended duration and two or three months of prednisone. Four studies found that in children with FRNS, daily prednisone during viral infections compared with alternate-day prednisone or no treatment significantly reduced the rate of relapse. AUTHORS' CONCLUSIONS: In this 2015 update the addition of three well-designed studies has changed the conclusion of this review. Studies of long versus shorter duration of corticosteroids have heterogeneous treatment effects, with the older high risk of bias studies tending to over-estimate the effect of longer course therapy, compared with more recently published low risk of bias studies. Among studies at low risk of bias, there was no significant difference in the risk for FRNS between prednisone given for two or three months and longer durations or total dose of therapy indicating that there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.The risk of relapse in children with FRNS is reduced by the administration of daily prednisone at onset of an upper respiratory tract or viral infection. Three additional studies have increased the evidence supporting this conclusion. This management strategy may be considered for children with FRNS. A paucity of data on prednisone use in relapsing nephrotic syndrome remains. In particular there are no data from RCTs evaluating the efficacy and safety of prolonged courses of low dose alternate-day prednisone although this management strategy is recommended in current guidelines. PMID- 25785661 TI - Controlled lanthanide-organic framework nanospheres as reversible and sensitive luminescent sensors for practical applications. AB - Two novel 3D frameworks were synthesized, and further nanosized to form nanospheres. Studies revealed that is the first MOF-based luminescent sensor for detecting cyclohexane, and this is also the first time that quick regeneration, high sensitivity, high yield, and easy nanocrystallization of MOF-based luminescent sensors have been simultaneously realized. PMID- 25785662 TI - Interface chemistry and molecular bonding of functional ethoxysilane-based self assembled monolayers on magnesium surfaces. AB - The modification of magnesium implants with functional organic molecules is important for increasing the biological acceptance and for reducing the corrosion rate of the implant. In this work, we evaluated by a combined experimental and theoretical approach the adsorption strength and geometry of a functional self assembled monolayer (SAM) of hydrolyzed (3-aminopropyl)triethoxysilane (APTES) molecules on a model magnesium implant surface. In time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS), only a minor amount of reverse attachment was observed. Substrate-O-Si signals could be detected, as well as other characteristic APTES fragments. The stability of the SAM upon heating in UHV was investigated additionally. Density-functional theory (DFT) calculations were used to explore the preferred binding mode and the most favorable binding configuration of the hydrolyzed APTES molecules on the hydroxylated magnesium substrate. Attachment of the molecules via hydrogen bonding or covalent bond formation via single or multiple condensation reactions were considered. The impact of the experimental conditions and the water concentration in the solvent on the thermodynamic stability of possible APTES binding modes is analyzed as a function of the water chemical potential of the environment. Finally, the influence of van der Waals contributions to the adsorption energy will be discussed. PMID- 25785663 TI - Influence of nanopore surface charge and magnesium ion on polyadenosine translocation. AB - We investigate the influence of a nanopore surface state and the addition of Mg(2+) on poly-adenosine translocation. To do so, two kinds of nanopores with a low aspect ratio (diameter ~3-5 nm, length 30 nm) were tailored: the first one with a negative charge surface and the second one uncharged. It was shown that the velocity and the energy barrier strongly depend on the nanopore surface. Typically if the nanopore and polyA exhibit a similar charge, the macromolecule velocity increases and its global energy barrier of entrance in the nanopore decreases, as opposed to the non-charged nanopore. Moreover, the addition of a divalent chelating cation induces an increase of energy barrier of entrance, as expected. However, for a negative nanopore, this effect is counterbalanced by the inversion of the surface charge induced by the adsorption of divalent cations. PMID- 25785664 TI - Canadian Health Measures Survey: A tool for immigrant health research? AB - BACKGROUND: The Canadian Health Measures Survey (CHMS) fills important health information gaps, but the feasibility of using it for immigrant research is unknown. DATA AND METHODS: Weighted estimates of socio-demographic variables by immigrant status from the combined cycles 1 and 2 of the CHMS (2007 to 2009 and 2009 to 2011) were compared with distributions from the 2006 Census and the 2011 National Household Survey (NHS). Weighted CHMS estimates of selected self reported health indicators among immigrants were compared with corresponding data from the 2009/2010 Canadian Community Health Survey (CCHS) by age group, sex, broad world region of origin, and period of arrival. Z-scores were used to detect statistical significance between the CHMS and CCHS estimates. RESULTS: The CHMS immigrant sample is generally similar to the average of 2006 Census/2011 NHS samples, but it contains higher percentages of recent immigrants, 30- to 49-year olds, and immigrants from South/Central America. Estimates of selected self reported health and health behaviour variables from the CHMS and the CCHS were similar overall, with minor differences at subgroup levels, and some inconclusive results due to high variability. INTERPRETATION: The combined CHMS immigrant sample can be used for health research. However, it is necessary to ensure that variables of interest meet sample size and prevalence requirements, especially at the subgroup level. PMID- 25785665 TI - A spatial analysis of COPD prevalence, incidence, mortality and health service use in Ontario. AB - BACKGROUND: Risk factors for chronic obstructive pulmonary disease (COPD) include smoking, occupational exposure and air pollution, which vary geographically, but relatively little is known about how COPD varies spatially. DATA AND METHODS: This population-based ecological analysis examines physician-diagnosed COPD prevalence, incidence, mortality, and health care services use in Ontario over a 10-year period. Data were mapped and analyzed at the sub-Local Health Integration Network level (n = 141). Comparative morbidity figures were calculated and analyzed for local clusters of high and low rates of COPD health and health service use outcomes. RESULTS: A total of 722,494 individuals were identified as having COPD over the study period. Clusters of high rates in health outcomes and in most indicators of health service use emerged in northern parts of Ontario and in industrial and more rural agricultural areas. Clusters of low rates were centered on major urban and suburban areas. An exception was COPD-specific physician visits, which were lower in northern areas suggesting greater reliance on acute care. INTERPRETATION: This study highlights the need for research focused on explaining the spatial patterns identified here. PMID- 25785666 TI - Oxidative cross-coupling of pyridine N-oxides and ethers between C(sp(2)) H/C(sp(3))-H bonds under transition-metal-free conditions. AB - A novel and efficient method based on the cross-coupling reactions of pyridine N oxides with ethers between C(sp(2))-H/C(sp(3))-H bonds in the presence of TBHP was developed. The strategy provides an alternative approach to the pyridine moiety under transition-metal-free conditions. PMID- 25785667 TI - Electrical control of memristance and magnetoresistance in oxide magnetic tunnel junctions. AB - Electric-field control of magnetic and transport properties of magnetic tunnel junctions has promising applications in spintronics. Here, we experimentally demonstrate a reversible electrical manipulation of memristance, magnetoresistance, and exchange bias in Co/CoO-ZnO/Co magnetic tunnel junctions, which enables the realization of four nonvolatile resistance states. Moreover, greatly enhanced tunneling magnetoresistance of 68% was observed due to the enhanced spin polarization of the bottom Co/CoO interface. The ab initio calculations further indicate that the spin polarization of the Co/CoO interface is as high as 73% near the Fermi level and plenty of oxygen vacancies can induce metal-insulator transition of the CoO(1-v) layer. Thus, the electrical manipulation mechanism on the memristance, magnetoresistance and exchange bias can be attributed to the electric-field-driven migration of oxygen ions/vacancies between very thin CoO and ZnO layers. PMID- 25785668 TI - Effects of polymer graft properties on protein adsorption and transport in ion exchange chromatography: a multiscale modeling study. AB - Multiscale simulation is used to study the adsorption of lysozyme onto ion exchangers obtained by grafting charged polymers into a porous matrix, in systems with various polymer properties and strengths of electrostatic interaction. Molecular dynamics simulations show that protein partitioning into the polymer filled pore space increases with the overall charge content of the polymers, while the diffusivity in the pore space decreases. However, the combination of greatly increased partitioning and modestly decreased diffusion results in macroscopic transport rates that increase as a function of charge content, as the large concentration driving force due to enhanced pore space partitioning outweighs the reduction in the pore space diffusivity. Matrices having greater charge associated with the grafted polymers also exhibit more diffuse intraparticle concentration profiles during transient adsorption. In systems with a high charge content per polymer and a low protein loading, the polymers preferentially partition toward the surface due to favorable interactions with the surface-bound protein. These results demonstrate the potential of multiscale modeling to illuminate qualitative trends between molecular properties and the adsorption equilibria and kinetic properties observable on macroscopic scales. PMID- 25785669 TI - Theoretical research on the effect of regulated pi-conjugation on the photophysical properties of Ir(III) complexes. AB - In this work, the effect of regulated host and auxiliary ligand pi-conjugation on the photophysical properties of a series of Ir(III) carbene complexes is examined by using the start-of-the-art theoretical methods. According to our results, all of the lowest-lying and strongest absorption peaks can be assigned as having a mixed ligand-to-ligand/metal-to-ligand charge transfer (LLCT/MLCT) character, but the different ways of introducing phenyl have a great effect on the absorption wavelength variation. In addition, the charge transfer characteristics of lowest lying emission have some minute differences. In addition, when the extended pi conjugation is broken, the emission wavelength can be effectively retained due to the similar emission charge transfer related electronic density distribution of occupied molecular orbitals and unoccupied molecular orbitals. However, the larger pi-conjugation can give rise to remarkably blue-shifted emission. This blue-shifted emission can be attributed to the alteration in the transition character due to intense interactions between nearly degenerate unoccupied molecular orbitals. Through the evaluation of the spin-orbit coupling (SOC) effect, we can gain a deeper understanding of the radiative decay rate processes. These results reveal that the larger pi-conjugation can also lead to higher quantum efficiency due to the larger radiative decay and the smaller nonradiative decay rate. Our theoretical studies highlight the role of pi-conjugation of the host and auxiliary ligand, and thus, can pave the way for the design of novel and efficient blue phosphorescent materials. PMID- 25785670 TI - "Surviving is not the same as living": cancer and Sobrevivencia in Puerto Rico. AB - "Cancer survivorship" is an evolving concept that has been elaborated to a large extent in the mainland U.S. through the work of national advocacy organizations, and it has served as a source of cohesion for many people who have experienced cancer. However, anthropologists and other social scientists have argued that dominant meanings of survivorship-such as the idea of "cancer as a gift" or the role of positive thinking in influencing the disease course-reflect distinctively American cultural values, and survivorship outside the U.S. has remained largely unexplored even while the concept has gained some traction globally. This paper explores how the concepts of "survivorship" and "survivor" are engaged in the setting of Puerto Rico, an unincorporated territory of the U.S., and how well they are seen to explain the nature of post-treatment life. Ethnographic fieldwork for this study was conducted over 12 months split between two field visits (2 months and 10 months) between June 2010 and March 2012 in San Juan, the capital city, and Ponce, a smaller city on the southern coast. This paper is based on interviews with 23 participants treated for cancer as young adults. Participants drew from many of the prevailing discourses of survivorship-such as transformation and the importance of optimism-as well as from what they understood to be distinctive aspects of Puerto Rican culture and identity, in the crafting of a local understanding of post-treatment life. Support organizations played a key role in shaping roles and expectations associated with having had cancer, and in solidifying particular views of survivorship more broadly. PMID- 25785671 TI - Ni-catalyzed highly chemo-, regio-, and enantioselective decarboxylative aldol reaction of beta,gamma-unsaturated alpha-ketoesters with beta-ketoacids. AB - A novel Ni-catalyzed decarboxylative aldol reaction of beta,gamma-unsaturated alpha-ketoesters with beta-ketoacids is reported. The reaction proceeds smoothly with high chemo-, regio-, and enantioselectivity. This protocol provides a convenient approach to access enantioenriched chiral tertiary alcohols. PMID- 25785672 TI - Pentaborate(1-) salts templated by substituted pyrrolidinium cations: synthesis, structural characterization, and modelling of solid-state H-bond interactions by DFT calculations. AB - The synthesis and characterization of a series of pentaborate(1-) salts of substituted pyrrolidinium cations [C4H8NH2][B5O6(OH)4] (), [C4H8NMe2][B5O6(OH)4] () [C4H8NMeH][B5O6(OH)4] (), [(2-CH2OH)C4H7NH2][B5O6(OH)4] () is reported. All compounds were characterized by single-crystal XRD studies with (1/2CH3COCH3) and (1/2H2O) solvated. TGA/DSC analysis of the pentaborates showed that they thermally decomposed in air at 800 degrees C to 2.5 B2O3, in a 2 step process involving dehydration (<250 degrees C) and oxidative decomposition (250-600 degrees C). BET analysis of materials derived thermally from the pentaborates and had internal porosities of <1 m(2) g(-1), indicating they were non-porous. All compounds show extensive supramolecular H-bonded anionic lattices. H-bond interactions are described in detail and motifs found in these and in other pentaborate structures have been examined and modelled by DFT calculations. These calculations confirm that H-bonds interactions in pentaborates are moderately strong (ca. -10 to -21 kJ mol(-1)) and are likely to dominate the energetics of their templated syntheses. PMID- 25785673 TI - Transition to surgical residency: a multi-institutional study of perceived intern preparedness and the effect of a formal residency preparatory course in the fourth year of medical school. AB - PURPOSE: To evaluate interns' perceived preparedness for defined surgical residency responsibilities and to determine whether fourth-year medical school (M4) preparatory courses ("bootcamps") facilitate transition to internship. METHOD: The authors conducted a multi-institutional, mixed-methods study (June 2009) evaluating interns from 11 U.S. and Canadian surgery residency programs. Interns completed structured surveys and answered open-ended reflective questions about their preparedness for their surgery internship. Analyses include t tests comparing ratings of interns who had and had not participated in formal internship preparation programs. The authors calculated Cohen d for effect size and used grounded theory to identify themes in the interns' reflections. RESULTS: Of 221 eligible interns, 158 (71.5%) participated. Interns self-reported only moderate preparation for most defined care responsibilities in the medical knowledge and patient care domains but, overall, felt well prepared in the professionalism, interpersonal communication, practice-based learning, and systems-based practice domains. Interns who participated in M4 preparatory curricula had higher self-assessed ratings of surgical technical skills, professionalism, interpersonal communication skills, and overall preparation, at statistically significant levels (P < .05) with medium effect sizes. Themes identified in interns' characterizations of their greatest internship challenges included anxiety or lack of preparation related to performance of technical skills or procedures, managing simultaneous demands, being first responders for critically ill patients, clinical management of predictable postoperative conditions, and difficult communications. CONCLUSIONS: Entering surgical residency, interns report not feeling prepared to fulfill common clinical and professional responsibilities. As M4 curricula may enhance preparation, programs facilitating transition to residency should be developed and evaluated. PMID- 25785674 TI - Culture Matters in Successful Curriculum Change: An International Study of the Influence of National and Organizational Culture Tested With Multilevel Structural Equation Modeling. AB - PURPOSE: National culture has been shown to play a role in curriculum change in medical schools, and business literature has described a similar influence of organizational culture on change processes in organizations. This study investigated the impact of both national and organizational culture on successful curriculum change in medical schools internationally. METHOD: The authors tested a literature-based conceptual model using multilevel structural equation modeling. For the operationalization of national and organizational culture, the authors used Hofstede's dimensions of culture and Quinn and Spreitzer's competing values framework, respectively. To operationalize successful curriculum change, the authors used two derivates: medical schools' organizational readiness for curriculum change developed by Jippes and colleagues, and change-related behavior developed by Herscovitch and Meyer. The authors administered a questionnaire in 2012 measuring the described operationalizations to medical schools in the process of changing their curriculum. RESULTS: Nine hundred ninety-one of 1,073 invited staff members from 131 of 345 medical schools in 56 of 80 countries completed the questionnaire. An initial poor fit of the model improved to a reasonable fit by two suggested modifications which seemed theoretically plausible. In sum, characteristics of national culture and organizational culture, such as a certain level of risk taking, flexible policies and procedures, and strong leadership, affected successful curriculum change. CONCLUSIONS: National and organizational culture influence readiness for change in medical schools. Therefore, medical schools considering curriculum reform should anticipate the potential impact of national and organizational culture. PMID- 25785675 TI - Changes in medical students' exposure to and attitudes about drug company interactions from 2003 to 2012: a multi-institutional follow-up survey. AB - PURPOSE: To ascertain whether changes occurred in medical student exposure to and attitudes about drug company interactions from 2003-2012, which factors influence exposure and attitudes, and whether exposure and attitudes influence future plans to interact with drug companies. METHOD: In 2012, the authors surveyed 1,269 third-year students at eight U.S. medical schools. Items explored student exposure to, attitudes toward, and future plans regarding drug company interactions. The authors compared 2012 survey data with their 2003 survey data from third-year students at the same schools. RESULTS: The 2012 response rate was 68.2% (866/1,269). Compared with 2003, in 2012, students were significantly less frequently exposed to interactions (1.6/month versus 4.1/month, P < .001), less likely to feel entitled to gifts (41.8% versus 80.3%, P < .001), and more apt to feel gifts could influence them (44.3% versus 31.2%, P < .001). In 2012, 545/839 students (65.0%) reported private outpatient offices were the main location of exposure to pharmaceutical representatives, despite spending only 18.4% of their clerkship-rotation time there. In 2012, 310/703 students (44.1%) were unaware their schools had rules restricting interactions, and 467/837 (55.8%) planned to interact with pharmaceutical representatives during residency. CONCLUSIONS: Students in 2012 had less exposure to drug company interactions and were more likely to have skeptical attitudes than students in 2003. These changes are consistent with national organizations' recommendations to limit and teach about these interactions. Continued efforts to study and influence students' and physician role models' exposures to and attitudes about drug companies are warranted. PMID- 25785676 TI - Access and Selection: Canadian Perspectives on Who Will Be Good Doctors and How to Identify Them. AB - PURPOSE: How to best select future doctors and the implications of selection for equity and access are timely, relevant, and complex issues that fundamentally affect other aspects of medical education such as curriculum design and social accountability. The authors thus conducted an environmental scan of practices related to access and selection in Canadian medical schools. METHOD: The authors drew and built on a literature review, key informant interviews, and expert panel discussions conducted as part of the 2008-2009 Future of Medical Education in Canada project to detail the empirical basis for prioritizing the study of access and selection, the evidence base of current practices, and implications for medical schools. RESULTS: Data clustered around four principles: (1) selection criteria must address current attributes and future potential, (2) access to medical school and diversity within the class are linked to a school's social accountability framework, (3) sound instruments and protocols are necessary to maximize reliability and validity, and (4) medical schools must be accountable for the effectiveness of their admissions processes. Although initiatives addressing barriers exist, ongoing challenges include recruitment and selection for overall diversity, adoption of better criteria for nonacademic achievement, and empirical validation of selection processes. CONCLUSIONS: Evidence-based selection processes can optimize the provision of broadly competent physicians for a given population. Schools must work to minimize systematic barriers for specific groups. Although this analysis provides a Canadian perspective, the principles and implications are relevant to medical education institutions elsewhere. PMID- 25785677 TI - AM Last Page: combined specialty residency programs. PMID- 25785678 TI - Creating, curating, and sharing online faculty development resources: the medical education in cases series experience. AB - PROBLEM: It is difficult to engage clinicians in continuing medical education that does not focus on clinical expertise. Evolving online technologies (e.g., massive open online courses [MOOCs]) are disrupting and transforming medical education, but few online nonclinical professional development resources exist. APPROACH: In August 2013, the Academic Life in Emergency Medicine Web site launched the Medical Education in Cases (MEdIC) series to engage clinicians in an online professional development exercise. Each month, a complex, realistic scenario featuring a nonclinical medical education dilemma is published with accompanying discussion questions. A weeklong discussion is moderated on Twitter and the Web site. This discussion is curated to create a community commentary, which is published alongside presolicited expert responses. Case resources are available for download. OUTCOMES: The first six MEdIC cases (published August 2013-January 2014) emphasized different CanMEDS and/or Accreditation Council on Graduate Medical Education competencies. Median reader engagement metrics (interquartile range 25%-75%) in the first week following publication were 861 (634-1,114) pageviews, 767 (518-953) unique visitors from 326 (218-405) cities in 45 (32-50) countries, 30 (24-39) comments, 52 (40-56) tweets, 17 (13-30) Facebook Likes, and 5 (5-7) Google Plus +1s. NEXT STEPS: The MEdIC series is proof of concept that online activities can engage clinicians in nonclinical professional development. The early experience suggests the connectivist nature of MEdIC allows for crowdsourcing solutions to ill-defined problems via the wisdom of readers. This methodology may also be effective for other nonclinical and medical education topics. PMID- 25785679 TI - A new conceptual framework for academic health centers. AB - Led by the Affordable Care Act, the U.S. health care system is undergoing a transformative shift toward greater accountability for quality and efficiency. Academic health centers (AHCs), whose triple mission of clinical care, research, and education serves a critical role in the country's health care system, must adapt to this evolving environment. Doing so successfully, however, requires a broader understanding of the wide-ranging roles of the AHC. This article proposes a conceptual framework through which the triple mission is expanded along four new dimensions: health, innovation, community, and policy. Examples within the conceptual framework categories, such as the AHCs' safety net function, their contributions to local economies, and their role in right-sizing the health care workforce, illustrate how each of these dimensions provides a more robust picture of the modern AHC and demonstrates the value added by AHCs. This conceptual framework also offers a basis for developing new performance metrics by which AHCs, both individually and as a group, can be held accountable, and that can inform policy decisions affecting them. This closer examination of the myriad activities of modern AHCs clarifies their essential role in our health care system and will enable these institutions to evolve, improve, be held accountable for, and more fully serve the health of the nation. PMID- 25785680 TI - Nutrition Education in an Era of Global Obesity and Diabetes: Thinking Outside the Box. AB - In an era when rates of obesity, diabetes, and other lifestyle-related diseases challenge medical educators and governments worldwide, it is necessary to consider novel educational strategies, both didactic and experiential, whereby current and future health professionals can be better prepared to proactively advise and teach patients enhanced self-care skills (e.g., diet, movement, stress management, and enhanced behavioral change).In this Perspective, the authors summarize current circumstances involving rising rates of obesity and diabetes worldwide, the lack of nutrition- and lifestyle-related curricular requirements for professional medical certification, societal trends regarding modern food culture and food availability in health care settings, and the misalignment of financial incentives to promote health.The authors assess what elements of self care should or should not be required within future curricula and certification exams. They consider how best to educate trainees about diet and how to "translate" nutrition, exercise, and behavioral science knowledge into practical advice. They explore several ideas for reforming nutrition education, including "teaching kitchens" as required laboratory classes for nutrition and lifestyle instruction, wearable technologies for tracking behaviors and physiological data relating to lifestyle choices, and the prospect of hospitals and other medical venues serving as exemplars of healthy, delicious food options. Finally, the authors argue that "salutogenesis"-the study of the creation and maintenance of health and well-being-should assume its rightful position alongside the study of "pathogenesis"-disease diagnosis and treatment-in medical education and practice. PMID- 25785681 TI - "Beginning with the end in mind": imagining personal retirement speeches to promote professionalism. AB - PROBLEM: The goal of teaching professionalism in medicine is to transform a theoretical concept into an internalized and actualized identity. Many trainees struggle with professionalism in the abstract, particularly when instruction methods are didactic and disconnected from personal experience. APPROACH: The authors aim to demonstrate the feasibility of having interns frame a personal definition of professionalism based on a reflective technique called "beginning with the end in mind." Interns composed remarks that might be used to introduce them at their own retirement ceremony following a career in medicine. This "career eulogies" exercise was introduced to groups of six interns during the first third of the internship year as part of a two-week curriculum focused on professional development. Two investigators independently coded the written introductions, identifying emergent themes through content analysis. OUTCOMES: Of the 19 interns in an internal medicine residency program (2012-13), 17 participated in the exercise. Six themes emerged from the data: aligning behaviors with core values, achieving excellence in medicine, changing the world and giving back, valuing teamwork and relationships, realizing work-life balance, and appreciating a career in medicine. These themes correlate with accepted published definitions of professionalism. NEXT STEPS: The personal reflections produced through this exercise allow physicians to begin to formulate their professional self-conception. Extensions of this work might include linking such forms of critical reflection to individualized learning plans and updating the speeches over time. Further research on "reflecting forward" may determine its impact as a complement to traditional narrative reflection. PMID- 25785682 TI - A schematic representation of the professional identity formation and socialization of medical students and residents: a guide for medical educators. AB - Recent calls to focus on identity formation in medicine propose that educators establish as a goal of medical education the support and guidance of students and residents as they develop their professional identity. Those entering medical school arrive with a personal identity formed since birth. As they proceed through the educational continuum, they successively develop the identity of a medical student, a resident, and a physician. Each individual's journey from layperson to skilled professional is unique and is affected by "who they are" at the beginning and "who they wish to become."Identity formation is a dynamic process achieved through socialization; it results in individuals joining the medical community of practice. Multiple factors within and outside of the educational system affect the formation of an individual's professional identity. Each learner reacts to different factors in her or his own fashion, with the anticipated outcome being the emergence of a professional identity. However, the inherent logic in the related processes of professional identity formation and socialization may be obscured by their complexity and the large number of factors involved.Drawing on the identity formation and socialization literature, as well as experience gained in teaching professionalism, the authors developed schematic representations of these processes. They adapted them to the medical context to guide educators as they initiate educational interventions, which aim to explicitly support professional identity formation and the ultimate goal of medical education-to ensure that medical students and residents come to "think, act, and feel like a physician." PMID- 25785684 TI - Understanding chemical expansion in perovskite-structured oxides. AB - In this work, chemical expansion in perovskite oxides was characterized in detail, motivated, inter alia, by a desire to understand the lower chemical expansion coefficients observed for perovskites in comparison to fluorite structured oxides. Changes in lattice parameter and in local atomic arrangements taking place during compositional changes of perovskites, i.e., stoichiometric expansion, were investigated by developing an empirical model and through molecular dynamics and density functional theory atomistic simulations. An accurate empirical expression for predicting lattice constants of perovskites was developed, using a similar approach to previous reports. From this equation, analytical expressions relating chemical expansion coefficients to separate contributions from the cation and anion sublattices, assuming Shannon ionic radii, were developed and used to isolate the effective radius of an oxygen vacancy, rV. Using both experimental and simulated chemical expansion coefficient data, rV for a variety of perovskite compositions was estimated, and trends in rV were studied. In most cases, rV was slightly smaller than or similar to the radius of an oxide ion, but larger than in the fluorite structured materials. This result was in good agreement with the atomistic simulations, showing contractive relaxations of the closest oxide ions towards the oxygen vacancy. The results indicate that the smaller chemical expansion coefficients of perovskites vs. fluorites are largely due to the smaller change in cation radii in perovskites, given that the contraction around the oxygen vacancy appears to be less in this structure. Limitations of applicability for the model are discussed. PMID- 25785683 TI - Dexamethasone added to local lidocaine for infiltration along the spinal-epidural needle pathway decreases incidence and severity of backache after gynecological surgery. AB - BACKGROUND: The aim of this study was to evaluate the effect of dexamethasone added to local lidocaine infiltration on incidence and severity of backache after combined spinal-epidural anesthesia for gynecological surgery. MATERIAL AND METHODS: We randomly allocated 160 patients to receive either local lidocaine infiltration along the pathway of the spinal-epidural needle (Group L) or local dexamethasone and lidocaine infiltration (Group DL). The incidence and scores for back pain were evaluated on the first, second, and third day (acute lumbago) and first, second, and sixth month (chronic lumbago) after surgery. Fentanyl consumption for management of back pain was recorded. RESULTS: The incidence of acute, subacute, and chronic back pain was significantly lower in the DL group than the L group (P<0.05 for all comparisons). The VAS score for back pain on the first and second day and first and second month, were significantly lower in the DL group than the L group (P=0.0028, P=0.017; P<0.001, both), but there were no significant differences on the third day and sixth month. Fentanyl consumption in the first 3 postoperative days was significantly lower in the DL group than in the L group (P<0.001). The incidence of back pain during the first, second, and sixth month in patients who did not have preoperative lumbago were significantly lower in the DL group than in the L group (P<0.001, both). CONCLUSIONS: Addition of dexamethasone to local lidocaine infiltration effectively decreases the incidence and severity of back pain after combined spinal-epidural anesthesia implemented for gynecological surgery. PMID- 25785685 TI - The use of hand gestures to communicate about nonpresent objects in mind among children with autism spectrum disorder. AB - PURPOSE: The current study examined whether children with autism spectrum disorder (ASD), in comparison with typically developing children, perceive and produce gestures to identify nonpresent objects (i.e., referent-identifying gestures), which is crucial for communicating ideas in a discourse. METHOD: An experimenter described the uses of daily-life objects to 6- to 12-year-old children both orally and with gestures. The children were then asked to describe how they performed daily activities using those objects. RESULTS: All children gestured. A gesture identified a nonpresent referent if it was produced in the same location that had previously been established by the experimenter. Children with ASD gestured at the specific locations less often than typically developing children. Verbal and spatial memory were positively correlated with the ability to produce referent-identifying gestures for all children. However, the positive correlation between Raven's Children Progressive Matrices score and the production of referent-identifying gestures was found only in children with ASD. CONCLUSIONS: Children with ASD might be less able to perceive and produce referent-identifying gestures and may rely more heavily on visual-spatial skills in producing referent-identifying gestures. The results have clinical implications for designing an intervention program to enhance the ability of children with ASD to communicate about nonpresent objects with gestures. PMID- 25785686 TI - How simple is too simple? Computational perspective on importance of second-shell environment for metal-ion selectivity. AB - The metal-ion selectivity in biomolecules represents one of the most important phenomena in bioinorganic chemistry. The open question to what extent is the selectivity in the complex bioinorganic structures such as metallopeptides determined by the first-shell ligands of the metal ion is answered herein using six model peptides complexed with the set of divalent metal ions (Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Hg(2+)) and their various first-shell representations. By calculating the differences among the free energies of complexation of metal ions in these peptides and their model (truncated) systems it is quantitatively shown that the definition of the first shell is paramount to this discussion and revolves around the chemical nature of the binding site. Despite the vast conceivable diversity of peptidic structures, that suggest certain fluidity of this definition, major contributing factors are identified and assessed based on their importance for capturing metal-ion selectivity. These factors include soft/hard character of ligands and various non-covalent interactions in the vicinity of the binding site. The relative importance of these factors is considered and specific suggestions for effective construction of the models are made. The relationship of first-shell models and their corresponding parent peptides is discussed thoroughly, both with respect to their chemical similarity and potential disparity introduced by generally "non alignable" conformational flexibility of the two systems. It is concluded that, in special cases, this disparity can be negligible and that heeding the chemical factors contributing to selectivity during construction of the model can successfully result in models that retain the affinity profile for various metal ions with high fidelity. PMID- 25785687 TI - Experimental assessment of the water quality influence on the phosphorus uptake of an invasive aquatic plant: biological responses throughout its phenological stage. AB - Understanding how an invasive plant can colonize a large range of environments is still a great challenge in freshwater ecology. For the first time, we assessed the relative importance of four factors on the phosphorus uptake and growth of an invasive macrophyte Elodea nuttallii (Planch.) St. John. This study provided data on its phenotypic plasticity, which is frequently suggested as an important mechanism but remains poorly investigated. The phosphorus uptake of two Elodea nuttallii subpopulations was experimentally studied under contrasting environmental conditions. Plants were sampled in the Rhine floodplain and in the Northern Vosges mountains, and then maintained in aquaria in hard (Rhine) or soft (Vosges) water. Under these conditions, we tested the influence of two trophic states (eutrophic state, 100 MUg x l(-1) P-PO4(3-) and hypertrophic state, 300 MUg x l(-1) P-PO4(3-)) on the P metabolism of plant subpopulations collected at three seasons (winter, spring and summer). Elodea nuttallii was able to absorb high levels of phosphorus through its shoots and enhance its phosphorus uptake, continually, after an increase of the resource availability (hypertrophic > eutrophic). The lowest efficiency in nutrient use was observed in winter, whereas the highest was recorded in spring, what revealed thus a storage strategy which can be beneficial to new shoots. This experiment provided evidence that generally, the water trophic state is the main factor governing P uptake, and the mineral status (softwater > hardwater) of the stream water is the second main factor. The phenological stage appeared to be a confounding factor to P level in water. Nonetheless, phenology played a role in P turnover in the plant. Finally, phenotypic plasticity allows both subpopulations to adapt to a changing environment. PMID- 25785688 TI - Cross-sectional study on antibiotic usage in pigs in Germany. AB - To be able to analyze the relationship between the level of resistance and the use of antimicrobials, it is necessary to collect detailed data on antimicrobial usage. For this reason, data on antimicrobial use on 495 pig farms from entire Germany were collected and analyzed. In Germany, each application and dispensing of medicines to food-producing animals is documented in detail obligatorily by the veterinarian. This information was collected retrospectively for the year 2011. The analyses undertook separate examinations on the age groups sow, piglet, weaner and fattening pig; both the route of administration and indication per active ingredient, and active ingredient class, were evaluated. In total, 20,374 kg of antimicrobial substances were used in the study population. Tetracyclines were used in highest amounts, followed by beta-lactams, trimethoprim-sulfonamides and macrolides. Concerning the frequency of using an active substance per animal, polypeptides were most commonly administered. In all age groups, respiratory infections were the main indication for using antimicrobials, followed by intestinal diseases in piglets, weaners and fattening pigs and diseases of reproductive organs in sows. Over a period of 100 days, the median number of treatment days with one antimicrobial substance for piglets was 15 days, for weaners about 6 days, for fattening pigs about 4 days and for sows about 1 day. A multifactorial ANOVA was conducted to investigate which factors are associated with the treatment frequency. The factors "veterinarian" and "age group" were related to the treatment frequency, just as the interaction between "veterinarian" and "farm size" as well as the interaction between "veterinarian" and "age group". PMID- 25785689 TI - DNA adenine methyltransferase facilitated diffusion is enhanced by protein-DNA "roadblock" complexes that induce DNA looping. AB - The genomes of all cells are intimately associated with proteins, which are important for compaction, scaffolding, and gene regulation. Here we show that pre existing protein-DNA complexes (roadblocks) diminish and-interestingly-enhance the ability of particular sequence-specific proteins to move along DNA to locate their binding sites. We challenge the bacterial DNA adenine methyltransferase (Dam, recognizes 5'-GATC-3') with tightly bound EcoRV ENase-DNA complexes, which bend DNA. A single EcoRV roadblock does not alter processive (multiple modifications) methylation by Dam. This result disfavors a reliance on heavily touted mechanisms involving sliding or short hops for Dam. Specific conformations of two EcoRV roadblocks cause an increase in processivity. The histone-like leucine-responsive regulatory protein (Lrp) binds DNA nonspecifically as an octamer, and also increases Dam's processivity. These results can be explained by our prior demonstration that Dam moves over large regions (>300 bp) within a single DNA molecule using an "intersegmental hopping" mechanism. This mechanism involves the protein hopping between looped DNA segments. Both roadblock systems can cause the DNA to loop and therefore facilitate intersegmental hopping. For Lrp, this only occurs when the Dam sites are separated (by >134bp) such that they can be looped around the protein. Intersegmental hopping may well be a general mechanism for proteins that navigate long distances along compacted DNA. Unlike Dam, EcoRI ENase (recognizes 5'-GAATTC-3') relies extensively on a sliding mechanism, and as expected, Lrp decreases its processivity. Our systematic use of protein roadblocks provides a powerful strategy to differentiate between site location mechanisms. PMID- 25785691 TI - Body fat accumulation in zebrafish is induced by a diet rich in fat and reduced by supplementation with green tea extract. AB - Fat-rich diets not only induce obesity in humans but also make animals obese. Therefore, animals that accumulate body fat in response to a high-fat diet (especially rodents) are commonly used in obesity research. The effect of dietary fat on body fat accumulation is not fully understood in zebrafish, an excellent model of vertebrate lipid metabolism. Here, we explored the effects of dietary fat and green tea extract, which has anti-obesity properties, on body fat accumulation in zebrafish. Adult zebrafish were allocated to four diet groups and over 6 weeks were fed a high-fat diet containing basal diet plus two types of fat or a low-fat diet containing basal diet plus carbohydrate or protein. Another group of adult zebrafish was fed a high-fat diet with or without 5% green tea extract supplementation. Zebrafish fed the high-fat diets had nearly twice the body fat (visceral, subcutaneous, and total fat) volume and body fat volume ratio (body fat volume/body weight) of those fed low-fat diets. There were no differences in body fat accumulation between the two high-fat groups, nor were there any differences between the two low-fat groups. Adding green tea extract to the high-fat diet significantly suppressed body weight, body fat volume, and body fat volume ratio compared with the same diet lacking green tea extract. 3 Hydroxyacyl-coenzyme A dehydrogenase and citrate synthase activity in the liver and skeletal muscle were significantly higher in fish fed the diet supplemented with green tea extract than in those fed the unsupplemented diet. Our results suggest that a diet rich in fat, instead of protein or carbohydrate, induced body fat accumulation in zebrafish with mechanisms that might be similar to those in mammals. Consequently, zebrafish might serve as a good animal model for research into obesity induced by high-fat diets. PMID- 25785690 TI - Human beta-defensin 4 with non-native disulfide bridges exhibit antimicrobial activity. AB - Human defensins play multiple roles in innate immunity including direct antimicrobial killing and immunomodulatory activity. They have three disulfide bridges which contribute to the stability of three anti-parallel beta-strands. The exact role of disulfide bridges and canonical beta-structure in the antimicrobial action is not yet fully understood. In this study, we have explored the antimicrobial activity of human beta-defensin 4 (HBD4) analogs that differ in the number and connectivity of disulfide bridges. The cysteine framework was similar to the disulfide bridges present in MU-conotoxins, an unrelated class of peptide toxins. All the analogs possessed enhanced antimicrobial potency as compared to native HBD4. Among the analogs, the single disulfide bridged peptide showed maximum potency. However, there were no marked differences in the secondary structure of the analogs. Subtle variations were observed in the localization and membrane interaction of the analogs with bacteria and Candida albicans, suggesting a role for disulfide bridges in modulating their antimicrobial action. All analogs accumulated in the cytosol where they can bind to anionic molecules such as nucleic acids which would affect several cellular processes leading to cell death. Our study strongly suggests that native disulfide bridges or the canonical beta-strands in defensins have not evolved for maximal activity but they play important roles in determining their antimicrobial potency. PMID- 25785692 TI - Inferring cetacean population densities from the absolute dynamic topography of the ocean in a hierarchical Bayesian framework. AB - We inferred the population densities of blue whales (Balaenoptera musculus) and short-beaked common dolphins (Delphinus delphis) in the Northeast Pacific Ocean as functions of the water-column's physical structure by implementing hierarchical models in a Bayesian framework. This approach allowed us to propagate the uncertainty of the field observations into the inference of species habitat relationships and to generate spatially explicit population density predictions with reduced effects of sampling heterogeneity. Our hypothesis was that the large-scale spatial distributions of these two cetacean species respond primarily to ecological processes resulting from shoaling and outcropping of the pycnocline in regions of wind-forced upwelling and eddy-like circulation. Physically, these processes affect the thermodynamic balance of the water column, decreasing its volume and thus the height of the absolute dynamic topography (ADT). Biologically, they lead to elevated primary productivity and persistent aggregation of low-trophic-level prey. Unlike other remotely sensed variables, ADT provides information about the structure of the entire water column and it is also routinely measured at high spatial-temporal resolution by satellite altimeters with uniform global coverage. Our models provide spatially explicit population density predictions for both species, even in areas where the pycnocline shoals but does not outcrop (e.g. the Costa Rica Dome and the North Equatorial Countercurrent thermocline ridge). Interannual variations in distribution during El Nino anomalies suggest that the population density of both species decreases dramatically in the Equatorial Cold Tongue and the Costa Rica Dome, and that their distributions retract to particular areas that remain productive, such as the more oceanic waters in the central California Current System, the northern Gulf of California, the North Equatorial Countercurrent thermocline ridge, and the more southern portion of the Humboldt Current System. We posit that such reductions in available foraging habitats during climatic disturbances could incur high energetic costs on these populations, ultimately affecting individual fitness and survival. PMID- 25785693 TI - An integrated approach for platoon-based simulation and its feasibility assessment. AB - Research on developing mathematical and simulative models to evaluate performance of signalized arterials is still ongoing. In this paper, an integrated model (IM) based on Rakha vehicle dynamics and LWR model is proposed. The IM which imitates actuated performance measurement in signalized arterials is described using continuous timed Petri net with variable speeds (VCPN). This enables systematic discretized description of platoon movement from an upstream signalized intersection towards a downstream signalized intersection. The integration is based on the notion that speed and travel time characteristics in a link can be provided using Rakha model. This will assist the LWR to estimate arrival profiles of vehicles at downstream intersection. One immediate benefit of the model is that platoon arrival profile obtained from the IM can be directly manipulated to estimate queues and delays at the target intersection using input-output analysis without considering the effect of shockwaves. This is less tedious as compared to analysing the LWR model through tracing trajectory of shockwave. Besides, time parameters of a platoon could be estimated for self-scheduling control approach from a cycle to cycle basis. The proposed IM is applied to a test intersection where simulated queues and average delays from the IM are compared with the platoon dispersion model (PDM) implemented in TRANSYT, cell transmission model (CTM) and HCM2000 for both under-saturated and oversaturated situations. The comparisons yielded acceptable and reasonable results, thus ascertained the feasibility and validity of the model. PMID- 25785694 TI - Simultaneous measurement and quantitation of 4-hydroxyphenylacetic acid and dopamine with fast-scan cyclic voltammetry. AB - Caged compounds have been used extensively to investigate neuronal function in a variety of preparations, including cell culture, ex vivo tissue samples, and in vivo. As a first step toward electrochemically measuring the extent of caged compound photoactivation while also measuring the release of the catecholamine neurotransmitter, dopamine, fast-scan cyclic voltammetry at carbon-fiber microelectrodes (FSCV) was used to electrochemically characterize 4 hydroxyphenylacetic acid (4HPAA) in the absence and presence of dopamine. 4HPAA is a by-product formed during the process of photoactivation of p-hydroxyphenacyl based caged compounds, such as p-hydroxyphenylglutamate (pHP-Glu). Our data suggest that the oxidation of 4HPAA occurs through the formation of a conjugated species. Moreover, we found that a triangular waveform of -0.4 V to +1.3 V to 0.4 V at 600 V s(-1), repeated every 100 ms, provided an oxidation current of 4HPAA that was enhanced with a limit of detection of 100 nM, while also allowing the detection and quantitation of dopamine within the same scan. Along with quantifying 4HPAA in biological preparations, the results from this work will allow the electrochemical measurement of photoactivation reactions that generate 4HPAA as a by-product as well as provide a framework for measuring the photorelease of electroactive by-products from caged compounds that incorporate other chromophores. PMID- 25785695 TI - Teaching the Simple Suture to Medical Students for Long-term Retention of Skill. AB - IMPORTANCE: Instructional methods for the simple suture technique vary widely and are seldom based on educational research. Published data indicate that video primers and structured instruction and evaluation decrease learning time and improve skill acquisition. OBJECTIVES: To determine the amount of practice needed to attain simple suture proficiency and to identify the optimal teaching schedule for retention of skill. DESIGN, SETTING, AND PARTICIPANTS: First-year and second year medical students at the Icahn School of Medicine at Mount Sinai with little to no suturing experience were randomly divided into 2 equal groups, with one being taught on day 1 and tested for proficiency on day 30 (control group) and the other being taught on day 1 and tested for proficiency on days 10, 20, and 30 (experimental group). Students were evaluated using the objective structured assessment of technical skills method and a checklist. Those initially not proficient on a given day were immediately prompted to practice and retest. This cycle continued until proficiency was achieved for that day. The study was conducted from April 7, 2014, to June 30, 2014. MAIN OUTCOMES AND MEASURES: Simple suture proficiency at 30 days and the mean number of practice sutures needed for proficiency on day 1. RESULTS: All students ultimately achieved proficiency. The mean (SD) number of practice sutures required to achieve proficiency at the initial training was 41 (15). Students in the control group had a 0% pass rate at the 30-day initial proficiency test, while students in the experimental group had a 91.7% pass rate at day 30 (P < .001). There were no differences in instructional time, cumulative number of sutures, or objective structured assessment of technical skills scores at proficiency between groups across the study. CONCLUSIONS AND RELEVANCE: Single instructional sessions may not be sufficient to maintain simple suture proficiency over the course of a 30 day elective. We propose the use of preparatory instructional videos, followed by instructor demonstration to introduce the technique. Independent practice with intermittent evaluation and critique allows for skill acquisition and time efficiency at the initial training. Students should view instructional videos and practice at least 10 repetitions every 10 days to maintain their skill. PMID- 25785696 TI - Woman with abdominal pain. PMID- 25785697 TI - Involvement of neutrophil hyporesponse and the role of Toll-like receptors in human immunodeficiency virus 1 protection. AB - OBJECTIVES: Neutrophils contribute to pathogen clearance through pattern recognition receptors (PRRs) activation. However, the role of PRRs in neutrophils in both HIV-1-infected [HIV-1(+)] and HIV-1-exposed seronegative individuals (HESN) is unknown. Here, a study was carried out to evaluate the level of PRR mRNAs and cytokines produced after activation of neutrophils from HIV-1(+), HESN and healthy donors. METHODS: The neutrophils were stimulated with specific agonists for TLR2, TLR4 and TLR9 in the presence of HIV-1 particles. Pro inflammatory cytokine production, expression of neutrophil activation markers and reactive oxygen species (ROS) production were analyzed in neutrophils from HESN, HIV-1(+) and healthy donors (controls). RESULTS: We found that neutrophils from HESN presented reduced expression of PRR mRNAs (TLR4, TLR9, NOD1, NOD2, NLRC4 and RIG-I) and reduced expression of cytokine mRNAs (IL-1beta, IL-6, IL-18, TNF-alpha and TGF-beta). Moreover, neutrophils from HESN were less sensitive to stimulation through TLR4. Furthermore, neutrophils from HESN challenged with HIV-1 and stimulated with TLR2 and TLR4 agonists, produced significantly lower levels of reactive oxygen species, versus HIV-1(+). CONCLUSIONS: A differential pattern of PRR expression and release of innate immune factors in neutrophils from HESN is evident. Our results suggest that lower neutrophil activation can be involved in protection against HIV-1 infection. PMID- 25785698 TI - The 5-HTTLPR confers susceptibility to anorexia nervosa in Han Chinese: evidence from a case-control and family-based study. AB - Accumulating evidence has implied that serotonin system dysfunction may be involved in the etiology of anorexia nervosa (AN). Serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is the genetic variant coding for the serotonin transporter and has a modulatory effect on its expression. This study aimed to investigate the possible association between the 5-HTTLPR and the susceptibility and severity of AN in Han Chinese using a case-control (255 patients and 351 controls) and family based study (198 trios). Eating disorder examination was used to measure the severity of AN behavioral symptoms. For the case-control study, the 5-HTTLPR showed significant association with AN in our sample (genotypic P = 0.03). The frequency of S allele was significantly higher in patients than that in controls (OR = 1.38, 95%CI: 1.06-1.79, P = 0.017). For the family-based study, the S allele of 5-HTTLPR was preferentially transmitted rather than non-transmitted from the parents to affected offspring (P = 0.013). The results of ANCOVA test revealed no significant association between the 5 HTTLPR polymorphism and severity of AN. Our findings suggested that 5-HTTLPR is able to confer susceptibility to AN in Han Chinese. PMID- 25785700 TI - Structure of Physical Fitness Among Young Female Basketball Players (Trends of Changes in 2006-2013). AB - The aim of this study was to identify trends of changes in the structure and levels of motor effects among young women basketball players in 2006-2013. These changes were examined in the context of comprehensive development of functional, fitness-related, and technical fundamentals with respect to requirements of specific training adopted as typical for targeted sports training stage. The research material was collected in 2006-2013 among young basketball players from the Greater Poland region. The study evaluated 169 girls (mean +/- SD: age = 15.5 +/- 0.5 years; height = 173.5 +/- 5.8 cm; weight = 60.2 +/- 7.9 kg). The measurements focused on the structure of motor effects in the athletes studied. For this purpose, the study used the International Physical Fitness Test. The study found that overall physical fitness of young women basketball players has been declining year by year. On the one hand, this might have been caused by the tendency for regression in motor modifications across generations that have been observed among populations. On the other hand, changes in weight-height ratio toward increasing obesity have also been observed. The results may serve as a kind of expertise about the structure of motor development of successive age groups of sports talented young women in light of training objectives at the targeted sports training stage as compared with trends typical for the general population. By describing the results of long-term research, this article offers a way of detecting possible positive or negative tendencies at a relatively early stage. PMID- 25785699 TI - Establishment of hairy root cultures by Agrobacterium rhizogenes mediated transformation of Isatis tinctoria L. For the efficient production of flavonoids and evaluation of antioxidant activities. AB - In this work, Isatis tinctoria hairy root cultures (ITHRCs) were established as an alternative source for flavonoids (FL) production. I. tinctoria hairy root line V was found to be the most efficient line and was further confirmed by the PCR amplification of rolB, rolC and aux1 genes. Culture parameters of ITHRCs were optimized by Box-Behnken design (BBD), and eight bioactive FL constituents (rutin, neohesperidin, buddleoside, liquiritigenin, quercetin, isorhamnetin, kaempferol and isoliquiritigenin) were quali-quantitatively determined by LC MS/MS. Under optimal conditions, the total FL accumulation of ITHRCs (24 day-old) achieved was 438.10 MUg/g dry weight (DW), which exhibited significant superiority as against that of 2 year-old field grown roots (341.73 MUg/g DW). Additionally, in vitro antioxidant assays demonstrated that ITHRCs extracts exhibited better antioxidant activities with lower IC50 values (0.41 and 0.39, mg/mL) as compared to those of field grown roots (0.56 and 0.48, mg/mL). To the best of our knowledge, this is the first report describing FL production and antioxidant activities from ITHRCs. PMID- 25785701 TI - Effects of hyperbaric oxygen on muscle fatigue after maximal intermittent plantar flexion exercise. AB - The purpose of this study was to investigate the effects of hyperbaric oxygen (HBO) treatment on muscle fatigue after maximal intermittent plantar flexion exercise. Twenty healthy male volunteers (aged from 21 to 24 years) were randomly assigned to either HBO or normoxic group and were blinded to their treatment and group assignment. The HBO group breathed 100% oxygen under 2.5 atmosphere absolute (ATA) for 60 minutes, whereas the normoxic group breathed room air under 1.2 ATA for 70 minutes. The subjects performed a fatigue test, which consisted of 50 maximal unilateral isometric plantar flexions, before and after intervention. Surface electromyography was recorded from triceps surae muscle. Subjects performed maximal voluntary contractions of isometric plantar flexions, and voluntary activation and twitch contractile properties were evaluated with cutaneous tibial nerve stimuli before and after intervention. Compared with initial values during repetitions 4-10, the plantar flexion torque during repetitions 41-50 decreased to 88.5 and 83.2% after HBO and normoxic treatment, respectively. A smaller decrease in muscle force was observed in the HBO group compared with the normoxic group. No differences in function between treatment groups were observed after nerve stimulation. These results suggest that HBO contributes to sustained force production due to suppressing the muscle fatigue progression. In practice, HBO can contribute to the prevention of excess fatigue of agonist muscles for specific exercises involving repeated jumping. PMID- 25785702 TI - Testing and Training of the Eggbeater Kick Movement in Water Polo: Applicability of a New Method. AB - In water polo, many of the technical actions and the contacts with the opponent take place in quasi-vertical floating position using 2 types of lower limb actions: the eggbeater kick is used most often in fighting and passing and the breaststroke kick in jumping and throwing. The aim of this study was to identify a new system to evaluate and to train the eggbeater kick movement and to verify its applicability. Twenty amateur players and 22 elite players participated in the study. A jacket, homemade and easy to make, allowing the application of an overload submerged in water but not hindering breathing or mobility, was used. Standard anthropometry and a test consisting of different trials of the eggbeater kick action until exhaustion with an increasing overload (5, 7.5, 10, 12.5, 15, and 17.5 kg) were collected. Time to exhaustion and the overload estimated maximum value (OEMV) at second 2 were determined for each load. Body weight, height, and lower limb muscle performance of the elite and nonelite players were significantly different from each other (p <= 0.05). The effectiveness of the different measured variables in both subgroups and that of the OEMV was evaluated with receiver operating characteristic (ROC) curve analysis. Areas under the ROC curve for the different overloads were 0.72 (0.53-0.92) for 5 kg, 0.80 (0.68 0.90) for 7.5 kg, 0.87 (0.77-0.91) for 10 kg, and 0.88 (0.84-0.92) for 12.5 kg overload. Our results show that the test is sensitive enough and therefore can be used to plan and control training and injury recovery. PMID- 25785703 TI - Carbohydrate and Caffeine Mouth Rinses Do Not Affect Maximum Strength and Muscular Endurance Performance. AB - Oral carbohydrate (CHO) rinsing has beneficial effects on endurance performance and caffeine (CAF) mouth rinsing either independently or in conjunction with CHO may enhance sprinting performance. However, the effects of CHO and CAF mouth rinses on resistance exercise have not been examined previously. The purpose of this study was to investigate the effects of CHO and CAF rinsing on maximum strength and muscular endurance performance. Fifteen recreationally resistance trained males completed an exercise protocol, which involved a 1 repetition maximum (RM) bench press followed by 60% of their 1RM to failure in a double blind, randomized, counterbalanced crossover design. Before exercise, 25 ml of a 6% (15 g; 0.20 +/- 0.02 g.kg(-1)) CHO, 1.2% (300 mg; 3.9 +/- 0.3 mg.kg(-1)) CAF, carbohydrate with caffeine (C + C) solutions, or water (placebo; PLA) were rinsed for 10 seconds. During the remaining session, no solution was rinsed (control; CON). All solutions were flavored with (200 mg) sucralose. Felt arousal was recorded pre- and post-rinse, and rating of perceived exertion (RPE) was recorded immediately after the repetitions to failure. There were no significant differences in 1RM (p = 0.808; etap(2)= 0.02), the number of repetitions performed (p = 0.682; etap(2)= 0.03), or the total exercise volume (p = 0.482; etap(2)= 0.03) between conditions. Rating of perceived exertion was similar for all trials (p = 0.330; etap(2)= 0.08), whereas Felt arousal increased as a consequence of rinsing (p = 0.001; etap(2)= 0.58), but was not different between trials (p = 0.335; etap(2)= 0.08). These results suggest that rinsing with a CHO and CAF solution either independently or combined has no significant effect on maximum strength or muscular endurance performance. PMID- 25785704 TI - Variations in Star Excursion Balance Test Performance Between High School and Collegiate Football Players. AB - The Star Excursion Balance Test (SEBT) is a reliable inexpensive tool used to assess dynamic postural control deficits and efficacy in the prediction of musculoskeletal injuries, but with little previous consideration for performance differences across age and skill levels. The purpose of this study was to examine differences in SEBT scores between high school and collegiate football players. Three-hundred eighteen high school football players and 180 National Collegiate Athletic Association Division I collegiate football players volunteered to participate. Star Excursion Balance Test scores were obtained bilaterally for anterior (ANT), posterolateral (PL), and posteromedial (PM) directions, and for an overall composite (COMP) score. The mean of 3 trials from each leg was normalized to stance leg length and presented as a percentage score. Bilaterally averaged scores were compared between high school and collegiate football players using separate independent t-tests. A multiple linear backward regression determined the amount of variance in SEBT scores explained by age, mass, and height. Compared with collegiate athletes, high school athletes had lower PL (72.8 +/- 11.4% vs. 77.1 +/- 10.2%; p < 0.001), PM (83.5 +/- 10.2% vs. 86.7 +/- 10.7%; p = 0.001), and COMP (75.4 +/- 8.5% vs. 78.0 +/- 7.4%; p = 0.001) scores. Anterior scores did not differ between high school (69.9 +/- 7.9%) and collegiate (70.3 +/- 7.1%) athletes (p = 0.545). Age, mass, and height were not meaningful contributors to ANT (R = 0.089; p < 0.001), PL (R = 0.032; p < 0.001), PM (R = 0.030; p = 0.002), and COMP (R = 0.048; p < 0.001) variances. Disparity between high school and collegiate athletes should be considered when using the SEBT to identify risk of or deficits related to lower extremity injury in football players. PMID- 25785705 TI - Peak Power Output Test on a Rowing Ergometer: A Methodological Study. AB - We aimed to examine the reliability and validity of the peak power output test on a rowing ergometer (Concept II Model D Inc.) and to establish the "optimal resistance" at which this peak power output was observed in 87 participants with varying levels of physical activity and rowing expertise: 15 male and 12 female physically inactive students (age: 21 +/- 2 years), 16 male and 20 female physically active students (age: 23 +/- 2 years), and 15 male and 9 female trained rowers (age: 19 +/- 2 years). The participants performed countermovement jump (CMJ) test on a force plate, followed by 3 maximal-effort rowing trials using the lowest, medium, and the highest adjustable resistance settings (i.e., "1", "5," and "10" on the resistance control dial on the ergometer) in randomized order. The test proved to be reliable (coefficients of variation: 2.6-6.5%; intraclass correlation coefficients: 0.87-0.98). The correlation coefficients between CMJ peak power and rowing peak power (both in watts per kilogram) were fairly consistent across all 3 groups of participants and resistance levels, ranging between r = 0.70 and r = 0.78. Finally, the highest power output was observed at the highest resistance setting in 2 nonathletic groups (p < 0.01), whereas rowers seem to produce the highest power output at the moderate resistance setting. We conclude that the power output test on a Concept II rowing ergometer may serve as a reliable and valid tool for assessing whole-body peak power output in untrained individuals and rowing athletes. PMID- 25785706 TI - Postexercise Hypotension After Continuous, Aerobic Interval, and Sprint Interval Exercise. AB - We examined the effects of 3 exercise bouts, differing markedly in intensity, on postexercise hypotension (PEH). Eleven young adults (age: 24.6 +/- 3.7 years) completed 4 randomly assigned experimental conditions: (a) control, (b) 30-minute steady-state exercise (SSE) at 75-80% maximum heart rate (HRmax), (4) aerobic interval exercise (AIE): four 4-minute bouts at 90-95% HRmax, separated by 3 minutes of active recovery, and (d) sprint interval exercise (SIE): six 30-second Wingate sprints, separated by 4 minutes of active recovery. Exercise was performed on a cycle ergometer. Blood pressure (BP) was measured before exercise and every 15-minute postexercise for 3 hours. Linear mixed models were used to compare BP between trials. During the 3-hour postexercise, systolic BP (SBP) was lower (p < 0.001) after AIE (118 +/- 10 mm Hg), SSE (121 +/- 10 mm Hg), and SIE (121 +/- 11 mm Hg) compared with control (124 +/- 8 mm Hg). Diastolic BP (DBP) was also lower (p < 0.001) after AIE (66 +/- 7 mm Hg), SSE (69 +/- 6 mm Hg), and SIE (68 +/- 8 mm Hg) compared with control (71 +/- 7 mm Hg). Only AIE resulted in sustained (>2 hours) PEH, with SBP (120 +/- 9 mm Hg) and DBP (68 +/- 7 mm Hg) during the third-hour postexercise being lower (p <= 0.05) than control (124 +/- 8 and 70 +/- 7 mm Hg). Although all exercise bouts produced similar reductions in BP at 1-hour postexercise, the duration of PEH was greatest after AIE. PMID- 25785707 TI - Validity and reliability of hand and electronic timing for 40-yd sprint in college football players. AB - The 40-yd sprint is the premier event for evaluating sprint speed among football players at all competitive levels. Some questions remain concerning the validity of hand timing compared with electronic timing, as well as the lack of assessment and reliability of each method. The purpose of this study was to evaluate the validity of hand timing by experienced and novice timers compared with electronic timing and to establish the reliability and smallest worthwhile difference (SWD) of each method for the 40-yd sprint. National Collegiate Athletic Association (NCAA) Division I college football players (n = 81) ran two 40-yd sprint trials, with each being timed electronically (touch pad start and infrared beam stop) and with hand-held stopwatches by 2 experienced and 4 novice timers. There was no significant difference between trials timed electronically or by experienced and novice timers. Hand timing (experienced = 4.90 +/- 0.34 seconds; novice = 4.86 +/ 0.33 seconds) produced a significantly faster 40-yd sprint time than electronic timing (5.12 +/- 0.35 seconds) by 0.22 +/- 0.07 and 0.26 +/- 0.08 seconds, respectively. Relative reliability was extremely high for all comparisons with intraclass correlation coefficient >0.987. The SWD was 0.12 seconds with electronic timing and 0.14 seconds with hand timing. In conclusion, hand timing produces faster sprint times than electronic timing in college football players, independent of timer experience. Repeated 40-yd sprint trials have high relative reliability regardless of timing method. A meaningful change in 40-yd sprint performance is dependent on timing method used. PMID- 25785708 TI - Relative contributions of strength, anthropometric, and body composition characteristics to estimated propulsive force in young male swimmers. AB - The purpose of this study was to determine the relative contributions of isokinetic forearm flexion (FLX) and extension (EXT) peak torque (PT) at 180 degrees .s, height (HT), percent body fat (%BF), and fat-free mass (FFM) to the prediction of estimated propulsive force (EPF) and which of these variables should be a focus of training in young male swimmers. Thirty young male swimmers (mean age +/- SD = 12.4 +/- 2.7 years) volunteered for this study. The subjects were members of local swimming clubs who competed in the front crawl. The swimmers were measured for FLX and EXT PT at 180 degrees .s, HT, body mass (BM), arm muscle area (AMA), arm circumference, triceps skinfold, %BF, and FFM. Arm muscle area was used to calculate EPF. Zero-order correlations and stepwise multiple regression analyses were used to examine the relationships among variables and the relative contributions of FLX, EXT, HT, %BF, and FFM to the prediction of EPF. Forearm flexion PT at 180 degrees .s, EXT, BM, HT, FFM, AMA, and EPF were significantly intercorrelated (r = 0.83-1.00). In addition, 4 variables contributed significantly to the prediction of EPF (standardized regression coefficients = FFM [1.00], FLX [0.92], EXT [-0.62], and HT [-0.35]). Percent body fat did not contribute to any of the stepwise models. These findings suggested that age-related increases in HT and FFM, as well as training for increases in FLX and EXT strength may improve propulsive force and swimming performance in young male swimmers. PMID- 25785709 TI - Distinguishing schizophrenia from posttraumatic stress disorder with psychosis. AB - PURPOSE OF REVIEW: Co-occurrence of psychotic symptoms with symptoms typically thought of as posttraumatic stress disorder (PTSD) is well known, and there has been considerable debate whether this represents a psychotic subtype or a comorbid psychotic disorder. RECENT FINDINGS: Psychotic symptoms typical of schizophrenia occur with a higher than expected frequency in PTSD. A large genome wide association study (GWAS) has identified a collection of genes associated with PTSD, and these genes overlap with those identified as increasing the risk of developing schizophrenia. SUMMARY: Up to 70% of returning veterans experience symptoms of PTSD. These individuals also fall within the peak age range for the onset of schizophrenia. PTSD with psychosis may occur for several reasons: trauma increases one's risk for schizophrenia and PTSD; patients with schizophrenia have a higher incidence of PTSD and may present with characteristic psychotic symptoms overlapping with psychosis in schizophrenia. Secondary to symptom overlap, there may be substantial misdiagnosis of psychotic disorders as PTSD, or nonidentification of a comorbid psychotic disorder. This overlap calls into question traditional diagnostic boundaries with implications for initial and long term treatment of PTSD and psychosis. This review will discuss the recent literature relating to the association of PTSD with schizophrenia. PMID- 25785710 TI - Ambiguous findings concerning potential advantages of depot antipsychotics: in search of clinical relevance. AB - PURPOSE OF REVIEW: We review the recent literature on the comparative efficacy/effectiveness of antipsychotic long-acting injections (LAIs) vs. oral antipsychotics. Randomized controlled trials (RCTs), mirror-image studies and cohort studies are reviewed, and the strength and weaknesses of each design discussed. RECENT FINDINGS: The data are conflicting and differ by trial design. RCTs tend to show equivalence for the two treatments, whereas mirror-image studies and cohort studies are more likely to show benefits for LAIs, although a prescribing/channelling bias in cohort studies suggests that LAIs are prescribed to more severely ill patients. Two recent, large RCTs, in a more real-world treatment setting, found a longer time to relapse or treatment failure with a LAI versus oral antipsychotics. SUMMARY: Each of the three trial designs has strengths and weaknesses. The traditional RCT does not seem to be the gold standard to compare the effectiveness of oral antipsychotics and LAIs because of selective recruitment and altered ecology of the treatment. Conversely, weaknesses of observational studies include lack of blinding and difficulty disentangling the effect of treatment from prescribing bias and confounders. The best approach to determining comparative effectiveness may be a pragmatic RCT with broad inclusion criteria and minimal exclusion criteria and minimal assessment following baseline assessment and randomization. PMID- 25785711 TI - Correction: Generation and characterization of induced pluripotent stem cells from aid-deficient mice. PMID- 25785712 TI - Proposed systematic nomenclature for orbitides. AB - Orbitides are short (5-11 amino acid residue), ribosomally synthesized homodetic plant cyclic peptides characterized by N-to-C amide bonds rather than disulfide bonds. Orbitides can be discovered using mass spectrometry of plant extracts or by identifying DNA sequences coding for the precursor protein. The number of orbitides that have been characterized to date, by a number of different research groups, is modest. The nomenclatural system currently used for the Type VI cyclic peptides has been developed in an ad hoc fashion and is somewhat arbitrary. We propose a systematic naming system specifically for the Type VI cyclic peptides that reflects the taxonomic name of the species producing the orbitides and a numbering system that enables systematic representation of amino acid residues and modifications. The proposed naming system emulates the IUPAC Nomenclature for Natural Products and UniProt, both of which use abbreviations of taxonomic names for the compounds in question. Nomenclature for post-translational modifications also follows the IUPAC precedent, as well as the cyclic peptide literature. Furthermore, the proposed system aims to maintain agreement with the precedents set by the pre-existing literature. An example of the proposed nomenclature is provided using the methionine-containing homodetic peptides of Linum usitatissimum (flaxseed). PMID- 25785713 TI - Translational arrest due to cytoplasmic redox stress delays adaptation to growth on methanol and heterologous protein expression in a typical fed-batch culture of Pichia pastoris. AB - RESULTS: We have followed a typical fed-batch induction regime for heterologous protein production under the control of the AOX1 promoter using both microarray and metabolomic analysis. The genetic constructs involved 1 and 3 copies of the TRY1 gene, encoding human trypsinogen. In small-scale laboratory cultures, expression of the 3 copy-number construct induced the unfolded protein response (UPR) sufficiently that titres of extracellular trypsinogen were lower in the 3 copy construct than with the 1-copy construct. In the fed-batch-culture, a similar pattern was observed, with higher expression from the 1-copy construct, but in this case there was no significant induction of UPR with the 3-copy strain. Analysis of the microarray and metabolomic information indicates that the 3-copy strain was undergoing cytoplasmic redox stress at the point of induction with methanol. In this Crabtree-negative yeast, this redox stress appeared to delay the adaptation to growth on methanol and supressed heterologous protein production, probably due to a block in translation. CONCLUSION: Although redox imbalance as a result of artificially imposed hypoxia has previously been described, this is the first time that it has been characterised as a result of a transient metabolic imbalance and shown to involve a stress response which can lead to translational arrest. Without detailed analysis of the underlying processes it could easily have been mis-interpreted as secretion stress, transmitted through the UPR. PMID- 25785714 TI - Isolation and identification of an extracellular subtilisin-like serine protease secreted by the bat pathogen Pseudogymnoascus destructans. AB - White nose syndrome (WNS) is a cutaneous fungal disease of bats. WNS is responsible for unprecedented mortalities in North American cave bat populations. There have been few descriptions of enzyme activities that may function in WNS host/pathogen interactions, while no study has isolated and described secreted proteases. To address the hypothesis that Pseudogymnoascus destructans secretes extracellular proteases that function in wing necrosis during WNS infection, the object of this study was to culture P. destructans on various media, then isolate and structurally identify those proteases accumulated stably in the culture medium. We found a single dominant protease activity on minimal nutrient broth enriched with protein substrates, which was strongly inhibited by phenylmethylsulfonyl fluoride. This P. destructans serine protease (PdSP1) was isolated by preparative isoelectric focusing and concanavalin A lectin affinity chromatography. PdSP1 showed a molecular weight 27,900 (estimated by SDS-PAGE), broad pH optimum 6-8, and temperature optimum 60 degrees C. Structural characterization of PdSP1 by MALDI-TOF MS, Orbitrap MS/MS, and Edman amino terminal peptide sequencing matched it directly to a hypothetical protein accession from the sequenced P. destructans genome that is further identified as a MEROPS family S8A subtilisin-like serine peptidase. Two additional isoforms, PdSP2 and PdSP3, were identified in the P. destructans genome with 90% and 53% homology, respectively. P. destructans S8A serine proteases showed closer sequence conservation to P. pannorum and plant pathogenic fungi than to human pathogenic dermatophytes. Peptide-specific polyclonal antibodies developed from the PdSP1 sequence detected the protein in western blots. These subtilisin-like serine proteases are candidates for further functional studies in WNS host pathogen interaction. PMID- 25785715 TI - Lipid metabolism: fatty acids on the move. PMID- 25785717 TI - Development: Switching off WNT with precision. PMID- 25785716 TI - Signalling scaffolds and local organization of cellular behaviour. AB - Cellular responses to environmental cues involve the mobilization of GTPases, protein kinases and phosphoprotein phosphatases. The spatial organization of these signalling enzymes by scaffold proteins helps to guide the flow of molecular information. Allosteric modulation of scaffolded enzymes can alter their catalytic activity or sensitivity to second messengers in a manner that augments, insulates or terminates local cellular events. This Review examines the features of scaffold proteins and highlights examples of locally organized groups of signalling enzymes that drive essential physiological processes, including hormone action, heart rate, cell division, organelle movement and synaptic transmission. PMID- 25785719 TI - Maternal mortality in Colombia in 2011: a two level ecological study. AB - OBJECTIVE: Maternal mortality reduction is a Millennium Development Goal. In Colombia, there is a large disparity in the maternal mortality ratio (MMR) between and into departments (states) and also between municipalities. We examined socioeconomics variables at the municipal and departmental levels which could be associated to the municipal maternal mortality in Colombia. METHODS: A multilevel ecology study was carried out using different national data sources in Colombia. The outcome variable was the MMR at municipal level in 2011 with multidimensional poverty at municipal and department level as the principal independent variables and other measures of the social and economic characteristics at municipal and departmental level were also considered explicative variables (overall fertility municipal rate, percentage of local rural population, health insurance coverage, per capita territorial participation allocated to the health sector, transparency index and Gini coefficient). The association between MMR and socioeconomic contextual conditions at municipal and departmental level was assessed using a multilevel Poisson regression model. RESULTS: The MMR in the Colombian municipalities was associated significantly with the multidimensional poverty (relative ratio of MMR: 3.52; CI 95%: 1.09 11.38). This association was stronger in municipalities from departments with the highest poverty (relative ratio of MMR: 7.14; CI 95%: 2.01-25.35). Additionally, the MMR at municipal level was marginally associated with municipally health insurance coverage (relative ratio of MMR: 0.99; CI 95%: 0.98-1.00), and significantly with transparency index at departmental level (relative ratio of MMR: 0.98; CI 95%: 0.97-0.99). CONCLUSION: Poverty and transparency in a contextual level were associated with the increase of the municipal MMR in Colombia. The results of this study are useful evidence for informing the public policies discussion and formulation processes with a differential approach. PMID- 25785718 TI - A novel class of mitochondria-targeted soft electrophiles modifies mitochondrial proteins and inhibits mitochondrial metabolism in breast cancer cells through redox mechanisms. AB - Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration in vitro. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins. PMID- 25785720 TI - A novel host-proteome signature for distinguishing between acute bacterial and viral infections. AB - Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP), and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL) (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91), which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96). The signature was superior to any of the individual proteins (P<0.001), as well as routinely used clinical parameters and their combinations (P<0.001). It remained robust across different physiological systems, times from symptom onset, and pathogens (AUCs 0.87-1.0). The accurate differential diagnosis provided by this novel combination of viral- and bacterial induced proteins has the potential to improve management of patients with acute infections and reduce antibiotic misuse. PMID- 25785722 TI - Changes in and patterns of smoking exposure in an elderly urban population in Beijing: 2001-2010. AB - OBJECTIVE: The study aims to explore the patterns and changes of active and passive smoking in the elderly population. METHODS: Two cross-sectional surveys with representative samples of urban populations, aged between 60 and 95 years old, were conducted in 2001 and 2010 in Beijing. A current smoker was defined as a person who smoked a tobacco product at the time of the survey, and a passive smoker was defined as a person who had been exposed to smoke exhaled by a smoker for more than 15 minutes per day more than once per week. RESULTS: A total of 2,277 participants in 2001 and 2,102 participants in 2010 completed the survey. The current smoking prevalence changed slightly in males (24.7 vs. 21.2%, P = 0.081), while the prevalence in females decreased significantly from 8.8% (95% CI: 7.3-10.3%) in 2001 to 4.1% (95% CI: 3.0-5.2%) in 2010 (P<0.001). The prevalence of passive smoking was 30.5% (95% CI: 28.6-32.4%) in 2001 and 30.0% (95% CI: 28.1-32.0%) in 2010. The main source of secondhand smoke switched from a spouse in 2001 to offspring in 2010. This trend was observed in both sexes. Passive smoking in males from a smoking spouse decreased from 5.7% to 2.4% (P<0.001), while that from smoking offspring increased from 7.3 to 14.5% (P<0.001). Passive smoking in females from a spouse decreased from 30.6 to 17.6%, while that from offspring increased from 5.3 to 15.4% (P<0.001). CONCLUSION: Offspring became the main source of secondhand smoke for the elderly. Our findings demonstrated the importance of implementing smoking prevention programs, to educate older adults who live with a smoking spouse and/or offspring. PMID- 25785723 TI - Clinical course of diabetic ketoacidosis in hypertriglyceridemic pancreatitis. AB - OBJECTIVES: Hypertriglyceridemic pancreatitis (HP) is an uncommon condition accounting for 1% to 4% of cases of acute pancreatitis, mostly associated with poor glycemic control. Diabetic ketoacidosis (DKA) may complicate the clinical course of HP. Our objective was to identify clinical and demographic differences between HP and DKA patients compared with those without DKA. METHODS: Fifty-five patients with HP were included. Diabetic ketoacidosis was diagnosed in 8 patients. We analyzed the severity, hospital stay, delay in oral intake, duration of insulin infusion, complete blood cell count, and triglyceride levels. RESULTS: Diabetic ketoacidosis was associated with a more severe HP. There were no differences in hospital stay, delay in oral intake, or duration of insulin treatment in both groups. Serum amylase, lipase, and triglyceride levels were similar. Previous diagnosis of diabetes mellitus, higher Ranson and APACHE II scores, and higher serum glucose level at admission were the only predictive risk factors for DKA and HP. CONCLUSIONS: Coexistence of DKA does not modify the clinical course of HP, although a more severe episode of HP in DKA patients. Diabetic ketoacidosis was associated with higher insulin doses, without impact in triglyceride levels. Diabetic ketoacidosis and HP should be considered when a previous diagnosis of diabetes mellitus and a severe HP are present. PMID- 25785721 TI - Octopamine regulates antennal sensory neurons via daytime-dependent changes in cAMP and IP3 levels in the hawkmoth Manduca sexta. AB - The biogenic amine octopamine (OA) mediates reward signals in olfactory learning and memory as well as circadian rhythms of sleep and activity. In the crepuscular hawkmoth Manduca sexta, OA changed pheromone detection thresholds daytime dependently, suggesting that OA confers circadian control of olfactory transduction. Thus, with enzyme-linked immunosorbent assays we searched hawkmoth antennae for daytime-dependent changes in the concentration of OA and its respective second messengers. Antennal stimulation with OA raised cAMP- and IP3 levels. Furthermore, antennae expressed daytime-dependent changes in the concentration of OA, with maxima at Zeitgebertime (ZT) 20 when moths were active and also maximal concentrations of cAMP occurred. Maximal IP3 levels at ZT 18 and 23 correlated with maximal flight activity of male moths, while minimal IP3 levels at dusk correlated with peaks of feeding activity. Half maximal effective concentration (EC50) for activation of the OA-receptor decreased during the moth's activity phase suggesting daytime-dependent changes in OA receptor sensitivity. With an antiserum against tyramine, the precursor of OA, two centrifugal neurons were detected projecting out into the sensory cell layer of the antenna, possibly mediating more rapid stimulus-dependent OA actions. Indeed, in fast kinetic assays OA receptor stimulation increased cAMP concentrations within 50 msec. Thus, we hypothesize that fast, stimulus-dependent centrifugal control of OA-release in the antenna occurs. Additional slow systemic OA actions might be based upon circadian release of OA into the hemolymph mediating circadian rhythms of antennal second messenger levels. The resulting rhythms of odor sensitivity are suggested to underlie circadian rhythms in odor-mediated behavior. PMID- 25785724 TI - Serum IgG4 elevation in pancreatic cancer: diagnostic and prognostic significance and association with autoimmune pancreatitis. AB - OBJECTIVE: Serum IgG4 (sIgG4) elevation, more common to autoimmune pancreatitis (AIP), occurs in some patients with pancreatic cancer (PaC). We investigated whether sIgG4 could differentiate AIP from PaC, its role in prognostication, and the concomitant occurrence of AIP and PaC. METHODS: We identified all patients with PaC (n = 548) and with type 1 AIP (n = 99) with sIgG4 measurements from 2001 to 2011. We compared demographics and sIgG4 profiles in these groups. Among patients with PaC, we compared resectability and mortality with and without elevated sIgG4. We reviewed AIP and PaC tissue specimens to identify concomitant occurrence of both diseases. RESULTS: Patients with AIP were more likely to have elevation in sIgG4 (65% vs 10.4%, P < 0.001) and sIgG4 more than 2 times upper limit of normal (40% vs 2.4%, P < 0.001). Patients with PaC with sIgG4 elevation were more commonly male compared with those with normal sIgG4 (81% vs 53%). Both groups were similarly aged with similar rates of resectability and mortality. No evidence of concurrent PaC and AIP was found. CONCLUSIONS: Mild elevations in sIgG4 cannot distinguish AIP from PaC. Elevations more than 2 times upper limit of normal appear more commonly in AIP. Serum IgG4 elevation has no prognostic significance in PaC. We could not identify a relationship between AIP and PaC. PMID- 25785726 TI - Access point selection game with mobile users using correlated equilibrium. AB - One of the most important issues in wireless local area network (WLAN) systems with multiple access points (APs) is the AP selection problem. Game theory is a mathematical tool used to analyze the interactions in multiplayer systems and has been applied to various problems in wireless networks. Correlated equilibrium (CE) is one of the powerful game theory solution concepts, which is more general than the Nash equilibrium for analyzing the interactions in multiplayer mixed strategy games. A game-theoretic formulation of the AP selection problem with mobile users is presented using a novel scheme based on a regret-based learning procedure. Through convergence analysis, we show that the joint actions based on the proposed algorithm achieve CE. Simulation results illustrate that the proposed algorithm is effective in a realistic WLAN environment with user mobility and achieves maximum system throughput based on the game-theoretic formulation. PMID- 25785725 TI - Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1. AB - The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function. PMID- 25785728 TI - Correction: Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism. PMID- 25785727 TI - Choline and betaine intake and colorectal cancer risk in Chinese population: a case-control study. AB - BACKGROUND: Few studies have examined the association of choline and betaine intake with colorectal cancer risk, although they might play an important role in colorectal cancer development because of their role as methyl donors. The aim of this study was to examine the relationship between consumption of choline and betaine and colorectal cancer risk in a Chinese population. METHODOLOGY/PRINCIPAL FINDINGS: A case-control study was conducted between July 2010 and December 2013 in Guangzhou, China. Eight hundred and ninety consecutively recruited colorectal cancer cases were frequency matched to 890 controls by age (5-year interval) and sex. Dietary information was assessed with a validated food frequency questionnaire by face-to-face interviews. The logistic regression model was used to estimate multivariate odds ratios (ORs) and 95% confidence intervals (CIs). Total choline intake was inversely associated with colorectal cancer risk after adjustment for various lifestyle and dietary factors. The multivariate-adjusted OR was 0.54 (95%CI = 0.37-0.80, Ptrend <0.01) comparing the highest with the lowest quartile. No significant associations were observed for betaine or total choline+betaine intakes. For choline-containing compounds, lower colorectal cancer risk was associated with higher intakes of choline from phosphatidylcholine, glycerophosphocholine and sphingomyelin but not for free choline and phosphocholine. The inverse association of total choline intake with colorectal cancer risk was observed in both men and women, colon and rectal cancer. These inverse associations were not modified by folate intake. CONCLUSIONS: These results indicate that high intake of total choline is associated with a lower risk of colorectal cancer. PMID- 25785730 TI - Correction: Insights from the genome annotation of Elizabethkingia anophelis from the malaria vector Anopheles gambiae. PMID- 25785729 TI - A multilevel model to estimate the within- and the between-center components of the exposure/disease association in the EPIC study. AB - In a multicenter study, the overall relationship between exposure and the risk of cancer can be broken down into a within-center component, which reflects the individual level association, and a between-center relationship, which captures the association at the aggregate level. A piecewise exponential proportional hazards model with random effects was used to evaluate the association between dietary fiber intake and colorectal cancer (CRC) risk in the EPIC study. During an average follow-up of 11.0 years, 4,517 CRC events occurred among study participants recruited in 28 centers from ten European countries. Models were adjusted by relevant confounding factors. Heterogeneity among centers was modelled with random effects. Linear regression calibration was used to account for errors in dietary questionnaire (DQ) measurements. Risk ratio estimates for a 10 g/day increment in dietary fiber were equal to 0.90 (95%CI: 0.85, 0.96) and 0.85 (0.64, 1.14), at the individual and aggregate levels, respectively, while calibrated estimates were 0.85 (0.76, 0.94), and 0.87 (0.65, 1.15), respectively. In multicenter studies, over a straightforward ecological analysis, random effects models allow information at the individual and ecologic levels to be captured, while controlling for confounding at both levels of evidence. PMID- 25785732 TI - Correction: an evolutionary analysis of the Secoviridae family of viruses. PMID- 25785731 TI - Impaired glucose metabolism among those with and without diagnosed diabetes and mortality: a cohort study using Health Survey for England data. AB - BACKGROUND: The extent that controlled diabetes impacts upon mortality, compared with uncontrolled diabetes, and how pre-diabetes alters mortality risk remain issues requiring clarification. METHODS: We carried out a cohort study of 22,106 Health Survey for England participants with a HbA1C measurement linked with UK mortality records. We estimated hazard ratios (HRs) of all-cause, cancer and cardiovascular disease (CVD) mortality and 95% confidence intervals (CI) using Cox regression. RESULTS: Average follow-up time was seven years and there were 1,509 deaths within the sample. Compared with the non-diabetic and normoglycaemic group (HbA1C <5.7% [<39 mmol/mol] and did not indicate diabetes), undiagnosed diabetes (HbA1C >=6.5% [>=48 mmol/mol] and did not indicate diabetes) inferred an increased risk of mortality for all-causes (HR 1.40, 1.09-1.80) and CVD (1.99, 1.35-2.94), as did uncontrolled diabetes (diagnosed diabetes and HbA1C >=6.5% [>=48 mmol/mol]) and diabetes with moderately raised HbA1C (diagnosed diabetes and HbA1C 5.7-<6.5% [39-<48 mmol/mol]). Those with controlled diabetes (diagnosed diabetes and HbA<5.7% [<39 mmol/mol]) had an increased HR in relation to mortality from CVD only. Pre-diabetes (those who did not indicate diagnosed diabetes and HbA1C 5.7-<6.5% [39-<48 mmol/mol]) was not associated with increased mortality, and raised HbA1C did not appear to have a statistically significant impact upon cancer mortality. Adjustment for BMI and socioeconomic status had a limited impact upon our results. We also found women had a higher all-cause and CVD mortality risk compared with men. CONCLUSIONS: We found higher rates of all cause and CVD mortality among those with raised HbA1C, but not for those with pre diabetes, compared with those without diabetes. This excess differed by sex and diabetes status. The large number of deaths from cancer and CVD globally suggests that controlling blood glucose levels and policies to prevent hyperglycaemia should be considered public health priorities. PMID- 25785733 TI - Antimicrobial Activity of Plectasin NZ2114 in Combination with Cell Wall Targeting Antibiotics Against VanA-Type Enterococcus faecalis. AB - Antimicrobial peptide plectasin targeting bacterial cell wall precursor Lipid II has been reported to be active against benzylpenicillin-resistant Streptococcus pneumoniae but less potent against vancomycin-resistant enterococci than their susceptible counterparts. The aim of this work was to test plectasin NZ2114 in combination with cell wall targeting antibiotics on vancomycin-resistant Enterococcus faecalis. The activity of antibiotic combinations was evaluated against VanA-type vancomycin-resistant E. faecalis strain BM4110/pIP816-1 by disk agar-induction, double-disk assay, determination of fractional inhibitory concentration (FIC) index, and time-kill curve. The results indicated that plectasin NZ2114 was synergistic in combination with teicoplanin, moenomycin, and dalbavancin but not with vancomycin, telavancin, penicillin G, bacitracin, ramoplanin, daptomycin, and fosfomycin. To gain an insight into the synergism, we tested other cell wall antibiotic combinations. Interestingly, synergy was observed between teicoplanin or moenomycin and the majority of the antibiotics tested; however, vancomycin was only synergistic with penicillin G. Other cell wall active antibiotics such as ramoplanin, bacitracin, and fosfomycin did not synergize. It appeared that most of the synergies observed involved inhibition of the transglycosylation step in peptidoglycan synthesis. These results suggest that teicoplanin, dalbavancin, vancomycin, and telavancin, although they all bind to the C-terminal D-Ala-D-Ala of Lipid II, might act on different stages of cell wall synthesis. PMID- 25785735 TI - An exclusively organometallic {FeNO}(7) complex with tetracarbene ligation and a linear FeNO unit. AB - The iron(II) complex 1 of a macrocyclic tetracarbene binds NO to form a low-spin (S = (1)/2) {FeNO}(7) complex (2) with a linear FeNO unit and a short Fe-NO bond. IR, electron paramagnetic resonance, and Mossbauer spectroscopies as well as density functional theory calculations suggest some Fe(I)NO(+) character and reveal that the singly occupied molecular orbital of 2, resulting from the sigma antibonding interaction of Fe dz(2) and the NO lone pair, is largely iron-based. Reduction yields a quite stable {FeNO}(8) species (3); both 2 and 3 feature very low Mossbauer isomer shifts (~0.0 mm.s(-1)). PMID- 25785734 TI - Selection of peptide mimics of HIV-1 epitope recognized by neutralizing antibody VRC01. AB - The ability to induce anti-HIV-1 antibodies that can neutralize a broad spectrum of viral isolates from different subtypes seems to be a key requirement for development of an effective HIV-1 vaccine. The epitopes recognized by the most potent broadly neutralizing antibodies that have been characterized are largely discontinuous. Mimetics of such conformational epitopes could be potentially used as components of a synthetic immunogen that can elicit neutralizing antibodies. Here we used phage display technology to identify peptide motifs that mimic the epitope recognized by monoclonal antibody VRC01, which is able to neutralize up to 91% of circulating primary isolates. Three rounds of biopanning were performed against 2 different phage peptide libraries for this purpose. The binding specificity of selected phage clones to monoclonal antibody VRC01 was estimated using dot blot analysis. The putative peptide mimics exposed on the surface of selected phages were analyzed for conformational and linear homology to the surface of HIV-1 gp120 fragment using computational analysis. Corresponding peptides were synthesized and checked for their ability to interfere with neutralization activity of VRC01 in a competitive inhibition assay. One of the most common peptides selected from 12-mer phage library was found to partially mimic a CD4-binding loop fragment, whereas none of the circular C7C-mer peptides was able to mimic any HIV-1 domains. However, peptides identified from both the 12-mer and C7C-mer peptide libraries showed rescue of HIV-1 infectivity in the competitive inhibition assay. The identification of epitope mimics may lead to novel immunogens capable of inducing broadly reactive neutralizing antibodies. PMID- 25785736 TI - The white collar complex is involved in sexual development of Fusarium graminearum. AB - Sexual spores (ascospores) of Fusarium graminearum, a homothallic ascomycetous fungus, are believed to be the primary inocula for epidemics of the diseases caused by this species in cereal crops. Based on the light requirement for the formation of fruiting bodies (perithecia) of F. graminearum under laboratory conditions, we explored whether photoreceptors play an important role in sexual development. Here, we evaluated the roles of three genes encoding putative photoreceptors [a phytochrome gene (FgFph) and two white collar genes (FgWc-1 and FgWc-2)] during sexual development in F. graminearum. For functional analyses, we generated transgenic strains lacking one or two genes from the self-fertile Z3643 strain. Unlike the wild-type (WT) and add-back strains, the single deletion strains (DeltaFgWc-1 and DeltaFgWc-2) produced fertile perithecia under constant light on complete medium (CM, an unfavorable medium for sexual development) as well as on carrot agar (a perithecial induction condition). The expression of mating-type (MAT) genes increased significantly in the gene deletion strains compared to the WT under both conditions. Deletion of FgFph had no significant effect on sexual development or MAT gene expression. In contrast, all of the deletion strains examined did not show significant changes in other traits such as hyphal growth, mycotoxin production, and virulence. A split luciferase assay confirmed the in vivo protein-protein interactions among three photoreceptors along with FgLaeA, a global regulator of secondary metabolism and fungal development. Introduction of an intact copy of the A. nidulans LreA and LreB genes, which are homologs of FgWc-1 and FgWc-2, into the DeltaFgWc-1 and DeltaFgWc-2 strains, respectively, failed to repress perithecia formation on CM in the gene deletion strains. Taken together, these results demonstrate that FgWc 1 and FgWc-2, two central components of the blue-light sensing system, negatively regulate sexual development in F. graminearum, which differs from the regulation pattern in A. nidulans. PMID- 25785737 TI - The seascape of demersal fish nursery areas in the North Mediterranean Sea, a first step towards the implementation of spatial planning for trawl fisheries. AB - The identification of nursery grounds and other essential fish habitats of exploited stocks is a key requirement for the development of spatial conservation planning aimed at reducing the adverse impact of fishing on the exploited populations and ecosystems. The reduction in juvenile mortality is particularly relevant in the Mediterranean and is considered as one of the main prerequisites for the future sustainability of trawl fisheries. The distribution of nursery areas of 11 important commercial species of demersal fish and shellfish was analysed in the European Union Mediterranean waters using time series of bottom trawl survey data with the aim of identifying the most persistent recruitment areas. A high interspecific spatial overlap between nursery areas was mainly found along the shelf break of many different sectors of the Northern Mediterranean indicating a high potential for the implementation of conservation measures. Overlap of the nursery grounds with existing spatial fisheries management measures and trawl fisheries restricted areas was also investigated. Spatial analyses revealed considerable variation depending on species and associated habitat/depth preferences with increased protection seen in coastal nurseries and minimal protection seen for deeper nurseries (e.g. Parapenaeus longirostris 6%). This is partly attributed to existing environmental policy instruments (e.g. Habitats Directive and Mediterranean Regulation EC 1967/2006) aiming at minimising impacts on coastal priority habitats such as seagrass, coralligenous and maerl beds. The new knowledge on the distribution and persistence of demersal nurseries provided in this study can support the application of spatial conservation measures, such as the designation of no-take Marine Protected Areas in EU Mediterranean waters and their inclusion in a conservation network. The establishment of no-take zones will be consistent with the objectives of the Common Fisheries Policy applying the ecosystem approach to fisheries management and with the requirements of the Marine Strategy Framework Directive to maintain or achieve seafloor integrity and good environmental status. PMID- 25785739 TI - Aging-related systemic manifestations in COPD patients and cigarette smokers. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is often associated with age-related systemic abnormalities that adversely affect the prognosis. Whether these manifestations are linked to the lung alterations or are independent complications of smoking remains unclear. OBJECTIVES: To look for aging-related systemic manifestations and telomere shortening in COPD patients and smokers with minor lung destruction responsible for a decline in the diffusing capacity for carbon monoxide (DLCO) corrected for alveolar volume (KCO). METHODS: Cross sectional study in 301 individuals (100 with COPD, 100 smokers without COPD, and 101 nonsmokers without COPD). MEASUREMENTS AND MAIN RESULTS: Compared to control smokers, patients with COPD had higher aortic pulse-wave velocity (PWV), lower bone mineral density (BMD) and appendicular skeletal muscle mass index (ASMMI), and shorter telomere length (TL). Insulin resistance (HOMA-IR) and glomerular filtration rate (GFR) were similar between control smokers and COPD patients. Smokers did not differ from nonsmokers for any of these parameters. However, smokers with normal spirometry but low KCO had lower ASMMI values compared to those with normal KCO. Moreover, female smokers with low KCO, had lower BMD and shorter TL compared to those with normal KCO. CONCLUSIONS: Aging-related abnormalities in patients with COPD are also found in smokers with minor lung dysfunction manifesting as a KCO decrease. Decreased KCO might be useful, particularly among women, for identifying smokers at high risk for aging-related systemic manifestations and telomere shortening. PMID- 25785738 TI - Differences in energy balance-related behaviours in European preschool children: the ToyBox-study. AB - BACKGROUND: The aim of the current study was to compare levels of energy balance related behaviours (physical activity, sedentary behaviour, and dietary behaviours (more specifically water consumption, sugar-sweetened beverage consumption and unhealthy snacking)) in four- to six-year-old preschoolers from six European countries (Belgium, Bulgaria, Germany, Greece, Poland, and Spain) within the ToyBox cross-sectional study. METHODS: A sample of 4,045 preschoolers (4.77 +/- 0.43 years; 52.2% boys) had valid physical activity data (steps per day), parents of 8,117 preschoolers (4.78 +/- 0.46 years; 53.0% boys) completed a parental questionnaire with questions on sedentary behaviours (television viewing, computer use, and quiet play), and parents of 7,244 preschoolers (4.77 +/- 0.44 years; 52.0% boys) completed a food frequency questionnaire with questions on water consumption, sugar-sweetened beverage consumption and unhealthy snacking. RESULTS: The highest levels of physical activity were found in Spain (12,669 steps/day on weekdays), while the lowest levels were found in Bulgaria and Greece (9,777 and 9,656 steps/day on weekdays, respectively). German preschoolers spent the least amount of time in television viewing (43.3 min/day on weekdays), while Greek preschoolers spent the most time in television viewing (88.5 min/day on weekdays). A considerable amount of time was spent in quiet play in all countries, with the highest levels in Poland (104.9 min/day on weekdays), and the lowest levels in Spain (60.4 min/day on weekdays). Belgian, German, and Polish preschoolers had the lowest intakes of water and the highest intakes of sugar-sweetened beverages. The intake of snacks was the highest in Belgian preschoolers (73.1 g/day) and the lowest in Greek preschoolers (53.3 g/day). CONCLUSIONS: Across six European countries, differences in preschoolers' energy balance-related behaviours were found. Future interventions should target European preschoolers' energy balance-related behaviours simultaneously, but should apply country-specific adaptations. PMID- 25785740 TI - Aurora A inhibition by MNL8054 promotes centriole elongation during Drosophila male meiosis. AB - Aurora A kinase plays an important role in several aspects of cell division, including centrosome maturation and separation, a crucial step for the correct organization of the bipolar spindle. Although it has long been showed that this kinase accumulates at the centrosome throughout mitosis its precise contribution to centriole biogenesis and structure has until now not been reported. It is not surprising that so little is known, due to the small size of somatic centrioles, where only dramatic structural changes may be identified by careful electron microscopy analysis. Conversely, centrioles of Drosophila primary spermatocytes increase tenfold in length during the first prophase, thus making any change easily detectable. Therefore, we examined the consequence of the pharmacological inhibition of Aurora A by MLN8054 on centriole biogenesis during early Drosophila gametogenesis. Here, we show that depletion of this kinase results in longer centrioles, mainly during transition from prophase to prometaphase of the first meiosis. We also found abnormal ciliogenesis characterized by irregularly growing axonemal doublets. Our results represent the first documentation of a potential requirement of Aurora A in centriole integrity and elongation. PMID- 25785741 TI - Nasal cytological changes as late effects of radiotherapy for nasopharyngeal cancer. AB - BACKGROUND: Radiation therapy is a cornerstone in nasopharyngeal cancer treatment. However, it can induce acute and long-term adverse effects, such as acute mucositis and late submucosal fibrosis. Late toxicities could not only affect submucosa but also mucosal cells, determining long-term cytological changes. OBJECTIVE: Evaluation of delayed nasal cytological alterations in patients who underwent radiation therapy for nasopharyngeal carcinoma (NPC). METHODS: In this case-control study, we analyzed 30 healthy subjects and 30 patients treated with chemotherapy and radiotherapy for NPC between 2003 and 2011, with a median follow-up of 59 months. All subjects underwent symptoms anamnestic evaluation (rhinorrea, nasal obstruction), endoscopic fiber optic nasal examination, skin-prick tests, and nasal scraping for cytological exam. RESULTS: A higher percentage of rhinorrhea, nasal obstruction, mucosal hyperemia, and presence of nasopharyngeal secretions at fiber optic endoscopic exam was found in radiated subjects (p < 0.05). Nasal cytology analysis demonstrated a higher percentage of neutrophilic inflammation and squamous cell metaplasia and mucous cell metaplasia in treated patients (p < 0.05). No cytological atypia was seen. No statistically significant correlation between nasal cytological changes and objective findings, patients' age, tobacco smoking, and gastroesophageal reflux has been found in the radiotherapy group (p > 0.05). CONCLUSION: Radiation therapy induces late nasal mucosal changes, which may be related to clinical consequences, such as abundant mucus production and its consequent endonasal stagnation. In the future, detailed knowledge of cytological changes in patients' nasal mucosa could represent a key prerequisite for the choice of effective interventions for late radiation-induced rhinitis. PMID- 25785742 TI - Plasma vitamin D levels of patients with allergic rhino-conjunctivitis with positive skin prick test. AB - BACKGROUND: Allergic rhino-conjunctivitis (ARC) and allergic rhinitis are inflammatory diseases that develop through immunoglobulin E in the rhino-ocular mucosa due to allergy. The main symptoms are runny nose, nasal congestion, sneezing, itchy nose, and conjunctivitis. OBJECTIVE: This study was designed to evaluate plasma 25-hydroxyvitamin D levels in patients with ARC. STUDY DESIGN: This study was planned as a prospective and cross sectional study. This study was performed in a tertiary referral center. METHODS: This observational study involved 42 patients with ARC and 35 consecutive, age- and sex-matched healthy subjects. Patients in both groups underwent skin-prick test. Plasma 25 hydroxyvitamin D levels of all subjects were quantified with electrochemiluminescence technique. Results were compared between the groups and p < 0.05 was considered as statistically significant. RESULTS: Group one included 42 ARC patients (15 male, 27 female, ages between 12 and 43, average age 25.7 +/- 8.6); group two included 35 healthy people (15 male, 20 female, ages between 12 and 44, average age 26.9 +/- 9.1). Plasma 25-hydroxyvitamin D levels of the subjects with ARC group (7.33 +/- 3.61 ng/mL, standard error mean: 0.55, range 3.17-13.68 ng/mL) were significantly lower than the control group (13.37 +/- 5.42 ng/mL, standard error mean: 0.91, range 6.84-25.92 ng/mL) (p = 0.010, Independent Samples test). CONCLUSIONS: We found lower plasma vitamin D levels in patients with ARC when compared with the control group. PMID- 25785743 TI - Development of Taiwan Smell Identification Test: a quick office-based smell screening test for Taiwanese. AB - BACKGROUND: Objective smell tests not only identify levels of smelling ability but also provide information on changes in olfaction after treatment. Odor identification is strongly socially and culturally dependent; therefore, the odorants used in a smell identification test should be familiar to the test population. We developed this smell test for Taiwanese populations with two aims: the test odors should be familiar to Taiwanese and the test should be easily and quickly administered in a busy clinic. METHODS: Additives that are familiar to Taiwanese people were selected for this smell identification test. Subsequently, the test was validated with the traditional Chinese version of the University of Pennsylvania Smell Identification Test (TC-UPSIT). Finally, this Taiwan Smell Identification Test (TWSIT) was implemented in daily clinical use, and cut-off points of "normosmia," "hyposmia," and "anosmia" were established. RESULTS: A total of 1000 subjects were included in the market survey to identify commonly recognized odors. Eight odorants with identification rate greater than 95% were selected. The TWSIT is an array of multiple-choice questions to select the odor. In addition, patient also reported the strength of the odor. The full score was 48. Thirty-seven patients simultaneously received both TWSIT and TC-UPSIT, and the correlation was high (r = 0.874). Based on the testing results of an additional 187 subjects, we concluded that scores of 47-48, 15-44, and 2-12 corresponded to normosmia, hyposmia, and anosmia, respectively. Patients with scores falling in the gaps require retesting at a later time. CONCLUSION: The TWSIT is a quick, office-based, and useful odor identification tool for Taiwanese. The experience of developing a culturally specific olfaction test like the TWSIT can be applied in different countries and cultures. PMID- 25785744 TI - A pilot study of the Self-Administered Computerized Olfactory Testing System. AB - BACKGROUND: The Self-Administered Computerized Olfactory Testing System (SCOTS) was developed recently to perform the olfactory threshold test under computer control. The aim of this study was to evaluate the validity and test-retest reliability of the SCOTS. METHODOLOGY: A total of 180 subjects were tested for olfactory thresholds using an odor detection threshold test and the SCOTS. There were 60 normosmic volunteers, 60 hyposmic patients, and 60 anosmic patients. Among them, 30 normosmic subjects were retested with the SCOTS at least 1 day after the first test occasion. The olfactory threshold test and retest results from the SCOTS were compared. RESULTS: The mean olfactory threshold attained from the SCOTS was -5.48 for normosmic subjects, -3.18 for hyposmic patients, and -2 for anosmic patients. The olfactory thresholds among the normosmic, hyposmic, and anosmic patients were significantly different (p < .001). The correlation coefficient between the olfactory thresholds of an odor detection threshold test and the SCOTS was 0.809 (p < .001). The test-retest correlation for the SCOTS based olfactory thresholds was strong (r = 0.671; p < .001). CONCLUSION: Our results show that on the basis of its validity and test-retest reliability, the SCOTS was appropriate for self-administered tests of the olfactory threshold. PMID- 25785745 TI - Nasal air-conditioning after partial turbinectomy: myths versus facts. AB - BACKGROUND: Turbinectomy, although a common procedure, is often accused of having a negative impact in all nasal functions. This study is the first in vivo study that evaluates objectively the effect of partial turbinectomy on nasal air conditioning capacity. METHODS: In total, 57 patients with prior partial inferior turbinectomy and 28 healthy controls were examined. Intranasal temperature and humidity values were measured at the level of the head of inferior and middle turbinate. Nasal patency was evaluated by means of acoustic rhinometry. The clinical assessment was completed with nasal endoscopy and the Nasal Obstruction Symptom Evaluation questionnaire for subjective evaluation of nasal patency. RESULTS: Significant changes of temperature were found in both detection sites with 13% reduced heating capacity of the air at the level of the inferior and 19% at the level of the middle turbinate, respectively. No similar results were found for humidity measurements. No correlations were found between air-conditioning values and acoustic rhinometry results for both study groups. Nasal endoscopy revealed normal healing in all patients. No major complications were reported by the patients. Their subjective ratings of nasal obstruction were similar to healthy controls. CONCLUSION: Partial turbinectomy seems to have a negative impact on intranasal air heating but not to humidification. This effect has no impact on clinical condition and subjective perception of surgical outcome. PMID- 25785746 TI - Editorial: new perspectives in the pathogenesis and management of rhinologic and allergic airway disease. PMID- 25785747 TI - Superoxide dismutase reduces the inflammatory response to Aspergillus and Alternaria in human sinonasal epithelial cells derived from patients with chronic rhinosinusitis. AB - BACKGROUND: Aspergillus fumigatus and Alternaria alternata are ubiquitous environmental fungal allergens that can exacerbate airway inflammation and contribute to the disease process in patients with chronic rhinosinusitis (CRS). These antigens have been shown to induce human sinonasal epithelial cells (HSNECs) to promote a proinflammatory response, but what is unclear is a means by which to reduce these effects. Inhaled pathogens can induce HSNECs to produce reactive oxygen species (ROS) that trigger cytokine production. OBJECTIVE: This study aimed to determine whether the free radical scavenger superoxide dismutase (SOD) could reduce HSNEC-derived inflammation, as measured by interleukin (IL)-6 and IL-8 production, in response to Aspergillus or Alternaria exposure. METHODS: Sinus tissue explants were collected at the time of surgery from control patients (n = 7) and patients with CRS with nasal polyps (CRSwNP) (n = 9). HSNECs were cultured from the explants and treated with Aspergillus, Alternaria, and SOD for 24 hours. Cell supernatants and lysates were collected, and IL-6 and IL-8 concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: In control and CRSwNP HSNECs, Aspergillus and Alternaria both increased cytokine production (p < 0.05), as measured by IL-6 and IL-8 concentration. SOD treatment reduced the inflammatory response to fungal antigen exposure from CRSwNP HSNECs but not control HSNECs. In CRSwNP patients, SOD significantly decreased IL-6 and IL-8 production after Alternaria exposure and IL-8 after Aspergillus exposure (p < 0.05). CONCLUSIONS: When HSNECs from CRSwNP patients are treated with SOD concurrently with Aspergillus or Alternaria, SOD treatment decreases the fungal antigen-induced inflammatory response. The ability to attenuate inflammation induced by common fungal allergens with SOD treatment could provide a novel therapeutic or preventative approach for patients with CRS or other allergic inflammatory airway diseases. PMID- 25785748 TI - Factors associated with the development and remission of allergic diseases in an epidemiological survey of high school students in Japan. AB - BACKGROUND: Allergic diseases are an important health problem for children and adults. It is important to know how allergic diseases develop and remit from infancy to adolescence. Early intervention is effective in treating allergic diseases. OBJECTIVE: We performed a large-scale questionnaire survey of high school students in Fukui Prefecture, Japan, and analyzed the factors associated with the development and remission of allergic diseases. METHODS: A total of 21,802 students participated in the epidemiologic survey, and the valid response rate was 89.3% (19,461). We applied an inverse probability weighting method with propensity scores. RESULTS: The present prevalence rate of allergic rhinitis (AR) was 19.2%. The remission rate of AR was 15.3%. Only children and firstborns had a significantly higher risk of developing symptoms of allergic diseases [only child: AR, 1.37; bronchial asthma (BA), 1.30; food allergy (FA), 1.33 and firstborn: AR, 1.38; BA, 1.10]. Constipation was an associated factor for development of atopic dermatitis (AD) (1.17) and AR (1.17), regular intake of lactic acid bacteria was not an associated factor for development of allergic diseases but was a factor for remission of AD (1.22). Hypohidrosis was an associated factor for development of AD (1.25). High academic performance was an associated factor for development of AR (1.20) but was a negative factor for development of BA (0.89). The values in parentheses are significant adjusted odds ratios. CONCLUSION: This epidemiologic survey showed that the hygiene hypothesis and intestinal bacterial flora might influence the development of symptoms and remission of allergic diseases. PMID- 25785749 TI - Clustering of chronic rhinosinusitis symptomatology reveals novel associations with objective clinical and demographic characteristics. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is associated with varied head and neck symptomatology and quality-of-life impairments that are not necessarily correlated with each other or with objective measures of disease. OBJECTIVE: To determine how clustering patterns of CRS symptoms associate with objective clinical findings. METHODS: Symptom scores from 193 Sinonasal Outcomes Test-22 (SNOT-22) questionnaires, from 177 consecutive CRS patients, were analyzed by principal component analysis (PCA) to uncover fewer and physiologically understandable latent components. Univariate and multivariate regressions were made with patients' demographic characteristics, nasal polyposis, comorbid allergic rhinitis, asthma, gastro-esophageal reflux disease (GERD) or depression, and Lund-Mackay scoring of sinus computed tomography (CT) results. RESULTS: Four principal components (PCs), heavily weighted on sleep symptoms, nasal symptoms, otologic symptoms, and emotional function symptoms, respectively, are found to primarily describe the variability in patients' SNOT-22 scores. SNOT-22 subset scores reflecting sleep, nasal, otologic, and emotional function symptoms were constructed from corresponding PCs. Only female gender associated with the total SNOT-22 score (p = 0.004), whereas only Lund-Mackay score associated with the nasal subset score (p = 0.015). Allergic rhinitis only associated with the otologic subset score (p = 0.005), whereas only asthma associated with the emotional function subset score (p = 0.027). None of the measured covariates were associated with the sleep subset score. CONCLUSION: Variability in SNOT-22 scores from CRS patients may be explained by the independent presence of sleep, nasal, otologic, and emotional function symptoms, with which we find novel clinical and demographic associations. These findings may represent clinical evidence for distinct pathophysiologic processes that differentially cause specific CRS symptomatology. PMID- 25785750 TI - Clinical considerations in the use of sublingual immunotherapy for allergic rhinitis. AB - BACKGROUND: Allergen immunotherapy (AIT) has been in practice for more than 100 years. However, research in novel routes and delivery methods of immunotherapy to treat allergic rhinitis (AR) and conjunctivitis has only recently occurred in the United States, where the predominant form of AIT provided is largely via a subcutaneous immunotherapy (SCIT) route. AIT may prevent new sensitizations, improve symptoms, decrease medication usage, and prevent allergic asthma. Although AIT is the only potentially curative treatment for AR, access and adherence continue to be problematic. Only a fraction of eligible patients actually undergo treatment, and attrition rates are high. An obvious limitation of SCIT includes the requirement of regular injections to be provided in the physician's office due to the potential for anaphylaxis. Sublingual immunotherapy (SLIT) for home administration has been investigated as a potential alternative to address this limitation of SCIT. METHODS: A literature review was performed including the current findings from randomized clinical trials and meta-analyses with a discussion of the most recent evidence for the efficacy, safety, and dosing of allergen SLIT. RESULTS: The current data suggest that SLIT is effective for treatment of seasonal allergies, can potentially prevent asthma, and has a favorable safety profile. Head-to-head studies, however, are few, and comparative effectiveness still remains to be answered. Optimal treatment algorithms for SLIT have not yet been established, with wide variation in dosage selection and schedules. Similarly to SCIT, only a few allergens such as ragweed and grass pollen have been found to be effective in large clinical trials. CONCLUSION: Recent data indicate that SLIT is an effective treatment modality for seasonal AR, improve quality of life, and can potentially prevent asthma but head-to head studies comparing SLIT to SCIT are needed. PMID- 25785751 TI - Immunodeficiency in chronic sinusitis: recognition and treatment. AB - Chronic rhinosinusitis (CRS) is estimated to affect over 35 million people. However, not all patients with the diagnosis respond to standard medical and surgical treatments. Although there are a variety of reasons a patient may be refractory to therapy, one possible etiology is the presence of an underlying immunodeficiency. This review will focus on the description, recognition, and treatment of several antibody deficiencies associated with CRS, including common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency, and specific antibody deficiency (SAD). The diagnosis of antibody deficiency in patients with CRS is important because of the large clinical implications it can have on sinus disease management. CVID is treated with immunoglobulin replacement, whereas SAD may be managed symptomatically and sometimes with prophylactic antibiotics and/or immunoglobulin replacement. PMID- 25785752 TI - Maternofetal transfer of antibodies and the influence of maternal atopic status on the neonate. AB - BACKGROUND: Epidemiologic evidence has shown that sensitization of allergic diseases develops early in life, even before birth. The gestational environment, including maternal atopic status and transplacentally transferred antibodies to allergens, may be of importance in the sensitization process. OBJECTIVE: To investigate maternofetal transfer of antibodies and the influence of maternal atopic status on the neonatal immune response. METHODS: Fifty-seven healthy pregnant women who underwent elective cesarean section (ECS) were recruited. Total and specific IgE (Phadiatop) levels in cord blood (CB) and maternal blood (MB) were determined using the ImmunoCAP assay. MB- and CB-specific IgG1 and IgA1 antibodies against ovalbumin and house dust mite were analyzed by enzyme linked immunosorbent assay. The cytokines, interleukin (IL)-13, interferon (IFN)-gamma, and IL-10 in the supernatant of cultured CB mononuclear cells were quantified by enzyme linked immunosorbent assay. Two subgroups were defined based on the maternal levels of specific IgE (atopic group, Phadiatop IgE more than or equal to 0.35 kilo international units of allergen-specific antibody (KUA)/L; nonatopic group, Phadiatop IgE less than 0.35 KUA/L). RESULTS: Although total IgE was detectable in all MB samples, it could only be detected in 7% (4/57) of the CB samples. Specific IgE was detectable in all MB samples but undetectable in all CB samples. There was no correlation of total IgE between mothers and their neonates. The concentrations of IL-10, IL-13, and allergen-specific IgG1 and IgA1 in the CB samples did not differ significantly between the atopic and nonatopic groups. IFN-gamma was undetectable in the CB samples. CONCLUSIONS: Maternal IgE cannot be transferred to the child in utero. Maternal atopic status has no significant effect on neonatal immune responses. PMID- 25785753 TI - The blood-brain barrier and nasal drug delivery to the central nervous system. AB - BACKGROUND: The blood-brain barrier (BBB) is a highly efficient system that separates the central nervous system (CNS) from general circulation and promotes selective transport of molecules that are essential for brain function. However, it also limits the distribution of systemically administered therapeutics to the brain; therefore, there is a restricted number of drugs available for the treatment of brain disorders. Several drug-targeting strategies have been developed to attempt to bypass the BBB, but none has proved sufficiently effective in reaching the brain. METHODS: The objective of this study is to generally review these strategies of drug administration to the CNS. RESULTS: Noninvasive methods of drug delivery, such as chemical and biologic transport systems, do not represent a feasible platform, whereas for most drugs, it is still not possible to achieve therapeutic levels within the brain tissue after intravenous or oral administration, and the use of higher potency or more concentrated doses may cause serious toxic side effects. Direct intrathecal drug delivery through a catheter into the CNS also presents several problems. Intranasal drug delivery is a potential alternative method due to the direct transport into the cerebrospinal fluid (CSF) compartment along the olfactory pathway, but the study's conclusions are controversial. An endoscopic intranasal surgical procedure using established skull base surgery reconstruction techniques based on the use of a nasal mucosa surgical flap as the only obstacle between the nose and the subarachnoid space has appeared as a potential solution to increase the absorption of intranasal drugs to the CNS. CONCLUSION: Despite extensive efforts to develop new techniques to cross the BBB, none has proved sufficiently effective in reaching the brain, whereas minimizing adverse effects and the endoscopic mucosal grafting technique offers new potential promise. PMID- 25785754 TI - Surgical management of vasomotor rhinitis: a systematic review. AB - BACKGROUND: Vasomotor rhinitis (VMR) is one of the most prevalent forms of nonallergic rhinitis. In the past, when maximal medical therapy failed, surgical options were limited. Vidian neurectomy (VN) was one option; however, it was fraught with complications and limited success. The advent of endoscopic sinus surgery revitalized interest in surgical procedures for VMR. This study was designed to review the available literature and assess the safety and efficacy of surgery on the vidian and posterior nasal nerves for treatment of VMR and when possible, compare the different approaches to one another in regard to safety and efficacy. METHODS: A systematic review was performed of English language articles using Ovid and PubMed. Search terms included "endoscopic vidian neurectomy," "vidian neurectomy," "endoscopic posterior nasal neurectomy" (EPNN), and "posterior nasal neurectomy." Only clinical trials performed on humans with safety and or efficacy data were included. Independent extraction of articles by two authors using predefined data fields was performed. Safety defined by complication rates and efficacy defined as objective improvement on outcomes scores along with the overall length of benefit were the primary measures of treatment effect. The Preferred Reporting Items for Systematic Reviews and Meta Analysis statement for reporting systematic reviews was followed. RESULTS: In comparison with open VN, endoscopic techniques were not associated with any long term sequelae. Rhinorrhea and nasal obstruction were shown to improve after endoscopic VN (EVN) and the benefits were maintained for several years after surgery. CONCLUSION: EVN is well tolerated, safe, and effective in a majority of patients. Overall, the literature has shown that the endoscopic approach is associated with less morbidity than the traditional transantral approach. Currently, no literature exists on the effect of EPNN in patients with vasomotor rhinitis and further study is needed to elucidate the efficacy of this procedure in this subset of patients. PMID- 25785755 TI - Systematic review and metaanalysis of middle meatal packing after endoscopic sinus surgery. AB - OBJECTIVE: The objective of this systematic review was to evaluate synechiae formation in patients who underwent packing in the middle meatus at the completion of endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) or recurrent acute rhinosinusitis. DATA SOURCES: PubMed and Ovid. REVIEW METHODS: Prospective randomized controlled studies of ESS with the placement of middle meatal packing were reviewed and included for analysis. Metaanalysis of the pooled data was performed. RESULTS: Eighteen prospective, randomized, controlled trials met inclusion criteria, resulting in a total of 925 subjects. Although there was a trend toward decreased risk of synechiae formation in the patients who underwent placement of middle meatal packing postoperatively (RR = 0.544), this did not achieve statistical significance on metaanalysis (p = 0.052). CONCLUSIONS: This systematic review and metaanalysis suggests that use of middle meatal packing does not significantly reduce the risk of synechiae formation after ESS. There was, however, significant heterogeneity of the data analyzed, and the difference between groups was just short of statistical significance in our metaanalysis. Additional prospective randomized studies on this topic will further elucidate the utility of middle meatal packing. PMID- 25785756 TI - Surgical outcomes of primary and revision augmentation rhinoplasty using a processed fascia lata. AB - BACKGROUND: Dorsal augmentation is the most commonly performed procedure in rhinoplasty for Asian patients. Due to the anatomic features of the Asian nose, the use of nonautologous materials to obtain a proper degree of augmentation is inevitable in most cases. Because the use of nonautologous materials possesses a higher risk of complications, surgeons are concerned about selecting suitable materials for the procedure, especially in revision rhinoplasty. Therefore, this study was designed to evaluate the suitability and usefulness of a homologous material, Tutoplast-processed fascia lata (TPFL), in revision augmentation rhinoplasty. METHODS: Retrospective analysis of 104 rhinoplasty patients (primary, 86; revision, 18) who had undergone dorsal augmentation using TPFL was conducted. The comparison of surgical outcomes between primary and revision surgery was made using objective [dorsal height (DH) and radix height (RH), complication rate] and subjective (patient satisfaction) parameters. RESULTS: The degree of augmentation represented by DH and RH was comparable between primary and revision rhinoplasty using TPFL. In comparing the rate of postoperative complications, only minor incidents were noted, in six cases after primary surgery and in one case after revision surgery. Patient satisfaction was measured in both primary and revision augmentation, with a significant difference observed between the two groups (40.57 +/- 9.25 versus 31.48 +/- 7.59; p < 0.05). CONCLUSION: TPFL is a feasible implant material that delivers suitable augmentation and patient satisfaction with minimal morbidity in both primary and revision rhinoplasty. PMID- 25785757 TI - Modeling alterations in sinonasal physiology after skull base surgery. AB - BACKGROUND: Endonasal endoscopic skull base surgery (EESBS) often requires significant alterations in intranasal anatomy. For example, posterior septectomy (PS) with middle turbinate resection (MTR) is frequently performed to provide access to large sellar and clival tumors. However, little is known about the alterations that occur in sinonasal physiology. This study was designed to assess changes in sinonasal physiology after virtually performed endoscopic skull base surgery. METHODS: Three-dimensional models of the sinonasal passage were created from computed tomography scans in three subjects with varying anatomy: no SD (SD), right anterior SD, and left anterior SD, respectively. Four additional surgery types were performed virtually on each model: endoscopic transsphenoidal approach (ETSA) with small (1 cm) PS (smPS), ETSA with complete (2 cm) PS, ETSA with smPS and right MTR, and ETSA with complete PS and right MTR. Computational fluid dynamics (CFD) simulations were performed on the 3 presurgery and 12 virtual surgery models to assess changes from surgery types. RESULTS: Increased nasal airflow corresponded to amount of tissue removed. Effects of MTR on unilateral airflow allocation were unchanged in subject with no SD, worsened in leftward SD, and reversed in rightward SD. Severity of airflow and mucosal wall interactions trended with amount of tissue removed. MTR hindered flow interactions with the olfactory mucosa in subjects with SD. CONCLUSION: CFD simulations on virtual surgery models are able to reasonably detect changes in airflow patterns in the computer-generated nasal models. In addition, each patient's unique anatomy influences the magnitude and direction of these changes after virtual EESBS. Once future studies can reliably correlate CFD parameters with patient symptoms, CFD will be a useful clinical tool in surgical planning and maximizing patient outcomes. PMID- 25785758 TI - Comparative analysis of quality-of-life metrics after endoscopic surgery for sinonasal neoplasms. AB - BACKGROUND: The objective of this study was to evaluate the postoperative quality of life (QOL) after endoscopic resection of sinus and skull base neoplasms using validated outcomes measures and to perform correlation of the various metrics to better discern their efficacy. Prospective QOL data collection and retrospective chart review were performed. METHODS: QOL data were collected using the 20-item Sino-Nasal Outcome Test (SNOT-20), Anterior Skull Base Questionnaire (ASBQ), European Quality-of-Life-5 Dimension (EQ-5D) questionnaire, and Lund-Kennedy endoscopic (LKE) score in 71 patients with sinonasal and skull base tumors. RESULTS: The mean age was 53 years and mean follow-up was 14.5 months at the time QOL data were collected. Benign and malignant tumors represented 39 (54.9%) and 32 (45.1%) cases, respectively. Twenty malignancies (62.5%) were stage T3 or T4, and 23 required postoperative chemotherapy and radiation (CRT). Factors indicating worsened postoperative QOL included malignant histopathology, T3 or T4 tumors, and the use of postoperative CRT (p < 0.05). There was a strong correlation of ASBQ with EQ-5D and SNOT-20 scores (r < -0.5) and a moderate correlation between the SNOT-20 and EQ-5D (r > 0.3), and the LKE had moderate correlation with SNOT-20 (r > 0.3) and weak correlation to the ASBQ (r > -0.3) and EQ-5D (r < 0.3). CONCLUSION: Patients who have undergone endoscopic resection of sinonasal tumors have quantifiable QOL changes as measured by various validated metrics. This study shows that concurrent use of these instruments may better discern QOL outcomes after endoscopic tumor surgery. PMID- 25785760 TI - Correction. PMID- 25785761 TI - Cloud and traditional videoconferencing technology for telemedicine and distance learning. AB - INTRODUCTION: Cloud-based videoconferencing versus traditional systems are described for possible use in telemedicine and distance learning. MATERIALS AND METHODS: Differences between traditional and cloud-based videoconferencing systems are examined, and the methods for identifying and testing systems are explained. Findings are presented characterizing the cloud conferencing genre and its attributes versus traditional H.323 conferencing. RESULTS: Because the technology is rapidly evolving and needs to be evaluated in reference to local needs, it is strongly recommended that this or other reviews not be considered substitutes for personal hands-on experience. CONCLUSIONS: This review identifies key attributes of the technology that can be used to appraise the relevance of cloud conferencing technology and to determine whether migration from traditional technology to a cloud environment is warranted. An evaluation template is provided for assessing systems appropriateness. PMID- 25785763 TI - Stepwise Tactile Localization and Wedge Resections for Deep Pulmonary Nodules during Video-Assisted Thoracoscopic Surgery. AB - This article details a modified method of tactile localization for deep pulmonary nodules of less than 20 mm size and at a distance of more than 15 mm from the visceral pleura. Sixteen patients with deep nodules were successfully located and underwent subsequent thoracoscopic wedge resection. This technique is a continuance of the traditional finger-tough method, which can be an effective complementary technique. PMID- 25785762 TI - Valeriana officinalis Extracts Ameliorate Neuronal Damage by Suppressing Lipid Peroxidation in the Gerbil Hippocampus Following Transient Cerebral Ischemia. AB - As a medicinal plant, the roots of Valeriana officinalis have been used as a sedative and tranquilizer. In the present study, we evaluated the neuroprotective effects of valerian root extracts (VE) on the hippocampal CA1 region of gerbils after 5 min of transient cerebral ischemia. Gerbils were administered VE orally once a day for 3 weeks, subjected to ischemia/reperfusion injury, and continued on VE for 3 weeks. The administration of 100 mg/kg VE (VE100 group) significantly reduced the ischemia-induced spontaneous motor hyperactivity 1 day after ischemia/reperfusion. Four days after ischemia/reperfusion, animals treated with VE showed abundant cresyl violet-positive neurons in the hippocampal CA1 region when compared to the vehicle or 25 mg/kg VE-treated groups. In addition, the VE treatment markedly decreased microglial activation in the hippocampal CA1 region 4 days after ischemia. Compared to the other groups, the VE100 group showed the lowest level of lipid peroxidation during the first 24 h after ischemia/reperfusion. In summary, the findings in this study suggest that pretreatment with VE has protective effects against ischemic injury in the hippocampal pyramidal neurons by decreasing microglial activation and lipid peroxidation. PMID- 25785764 TI - Reply by the Authors of the Original Article. PMID- 25785765 TI - A Comment on the Pulmonary Contusion Model. PMID- 25785766 TI - "Blame it on the Comorbidities": A 5-Year Follow-Up of 53 Chronic Dialysis Dependent Patients Who Underwent Cardiac Surgery. AB - Objectives This study evaluates midterm survival rates and risk factors for mortality of chronic dialysis-dependent patients undergoing cardiac surgery. Methods Fifty-three dialysis-dependent patients (34 males, aged 67 +/- 12 years) with end-stage renal disease operated within March 2007 and May 2012 were analyzed retrospectively. Survival rates were calculated using Kaplan-Meier methods. Predictors of midterm survival were identified with multivariate Cox regression analysis. Results Twenty-three patients received isolated coronary artery bypass graft surgery, 17 received isolated valve replacement, and 13 received combined procedures. Thirty-day mortality was 24.5% (n = 13). Follow-up was complete for 94.3% (n = 50). Survival rates at 1, 3, and 5 years were: 82, 50, and 17%, respectively. Neither age, gender, poor ejection fraction, emergency, ECC/X-clamp (cross-clamp) time, nor use of left internal thoracic artery or right internal thoracic artery had any influence on midterm survival. Causes of death within midterm follow-up period were related to cardiac events in 16% and neurological events in 16%. In the majority (47%), cause of death was associated with peripheral arterial disease (PAD).The only comorbidity, which could be identified as a significant risk factor, was PAD (p = 0.035). Five patients underwent successful renal transplantation within the follow-up period. Conclusion Although 30-day mortality in this high-risk patient population was increased, midterm survival rates were comparable to the results described in the literature. Cause of death within midterm follow-up period was mostly noncardiac related. Given the limited number of patients, predictors for enhanced 30-day mortality, such as preoperative myocardial infarction, prolonged extracorporeal circulation, operation time, and diabetes mellitus, did not have an influence on midterm survival. PMID- 25785767 TI - Aortic Dissections Type A during Sexual Intercourse in Male Patients: Accident or Systematic Coincidence? Examination of 365 Patients with Acute Aortic Dissection within 20 Years. AB - OBJECTIVES: Physical exercise accompanied by arterial hypertension is known to trigger acute aortic dissections. As a booster effect, mental stress leads to aggravation of hypertensive crisis. The aim of the study was to evaluate whether stress factors during sexual intercourse play any role as a catalyst in patients with acute type A aortic dissections. Concerning this subject, only two case reports have been published. METHODS: A total of 365 patients with acute type A aortic dissections, operated between January 1993 and July 2014, were analyzed retrospectively. The main focus was to identify the provoking situation before onset of symptoms. A total of 247 patients were males and mean age was 60.2 years (range, 17.0-91.9 years). Of the total cohort, 86 patients (24%) were younger than 50 years (68 males) and 184 patients (50%) were younger than 60 years (149 males). RESULTS: The explicit trigger could not be determined in 24% of the patients. In majority of the patients, onset of symptoms occurred during physical exercises, such as sports or lifting of heavy weights (68%), without a significant difference between males and females. In only 8% of the patients, symptoms occurred at rest. In 0.9%, Marfan syndrome was evident. Eleven of 68 males < 50 years (16%) and 17 of 149 males < 60 years (11%) but none among females (p = 0.03) experienced sudden onset of symptoms during sexual intercourse. CONCLUSION: Combined physical and emotional stress during sexual intercourse seems to present a meaningful promoter effect for acute aortic dissections, especially in younger males, but not in females. Despite self evidence of this phenomenon, frequency of this sensitive issue appears to be surprisingly high. PMID- 25785768 TI - A Single Institution Evaluation of the Performance of Two Different Chest Drainage Systems in Pediatric Patients after Surgery for Congenital Heart Disease. AB - BACKGROUND: The study compares the efficacy and advantages of two different drainage systems in pediatric patients during surgery for congenital heart disease (CHD). METHODS: A total of 200 consecutive pediatric patients (< 16 years) were enrolled; in 100 patients we used a polyvinyl chloride drain (PVCD) and in the other 100 we used a silicone drain (SD). Demographics, drain's technical data, and postoperative complications and costs were evaluated. A pain score was calculated in patients older than 6 years. RESULTS: The SDs were significantly smaller when compared with PVCDs (median of 1.63 vs. 3.09 French/kg, p = 0.0006), were kept in site for a median shorter period (23 vs. 40 hours, p = 0.002), drained more thoracic spaces (median of 2 vs. 1, p < 0.0001), and were associated to a lower pain score (p = 0.01). The overall drain-related complication rate was lower for the SD group than for the PVCD group (3 vs. 9%, p = 0.1) as well as the drain-related adverse event required additional interventional maneuvers (0 vs. 6%, p = 0.04). Patients who were treated with a PVCD reported a higher perceived pain score than patients treated with a SD, both at the time when the drain was in site (p = 0.016) and during the drain's removal (p = 0.0001). CONCLUSION: SDs can be used safely in pediatric patients during surgery for CHD. Sizes required are smaller than other conventional drains and multiple cavities can be drained with a single tube. The use of SD is associated to a lower complication rate, lower requirement of additional procedures, and lesser perceived pain from the patient, when compared with other more traditional drains. PMID- 25785769 TI - Less Invasive Quick Open Stenting using a J Graft Open Stent for Distal Arch Aneurysms. AB - A new device of aortic stent graft made in Japan has been available since July 2014. Here, we describe a novel, unique surgical technique named "less invasive quick open stenting" at a rectal temperature of 28 degrees C without any cerebral perfusion for treating distal arch aneurysms. All 12 patients were discharged from the intensive care unit within 24 hours after surgery without any complications. This technique aids in the exclusion of atherosclerotic plaques on the aortic wall and shortens the duration of circulatory arrest; moreover, it represents a very attractive option to prevent recurrent nerve injury. PMID- 25785770 TI - Spanning breadth and depth in ASSAY and Drug Development Technologies. PMID- 25785771 TI - Development and validation of semiautomated 96-well transport assay using LLC-PK1 cells transfected with human P-glycoprotein for high-throughput screening. AB - Transport assays using P-gp-expressing cell lines are commonly used to identify P gp substrates and inhibitors in drug discovery. The P-gp cell-based assay is performed manually in 12- or 24-well plates and requires improvement for high throughput screening. In this study, we established an efficient semiautomated 96 well transport assay using LLC-PK1 cells transfected with human P-gp. The protocol was optimized with a microplate washer for exchanging media and buffer to enhance throughput. P-gp substrates and inhibitors, and the paracellular marker Dextran Texas Red(r) were used to validate the 96-well transport assay. Cell monolayer integrity after washing by a microplate washer was confirmed by measuring paracellular permeability of Dextran Texas Red. Permeability and net flux ratio of the P-gp substrates and the inhibitory potency of the P-gp inhibitors were comparable in 24- and 96-well plates. The regression value of net flux ratio of P-gp substrates was high between the two formats (r2=0.99). The optimized 96-well transport assay using the microplate washer was found to be an efficient high-throughput screening tool that provided the same quality data as the 24-well plate for the identification of P-gp substrates and inhibitors in drug discovery. PMID- 25785772 TI - Validation of miniaturized one-step reverse transcription qPCR assays for high throughput screening and comparison to a reporter gene methodology. AB - Quantitative real-time polymerase chain reaction (PCR) is regarded as the gold standard for molecular profiling and target identification, but not in the context of high-throughput screening owing to limitations on workflow, cost of reagents, and miniaturization opportunities. Recent advances have moved reverse transcription quantitative PCR (RT-qPCR) forward, such as improvements in liquid handling, the launch of higher throughput platforms, and the release of one-step products. These one-step reagents enable the user to go straight from a cellular assay format to qPCR without the need for cumbersome and potentially expensive multistep RNA purification protocols. Our aim was to investigate the use of a one step accelerated workflow to measure the levels of epidermal growth factor receptor (EGFR) and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) gene expression using lysates generated by the RealTime ready Cell Lysis kit in downstream quantitative RT-qPCR. We present, for the first time, data from a vendor-independent one-step 1536 workflow that compares reporter gene and RT-qPCR screening approaches for oncology drug discovery. We also demonstrate a miniaturized and high-throughput workflow that could enable future application of this sensitive assay technology, with particular impact against phenotypic assays and those using rare cell types. PMID- 25785773 TI - Remembering and telling self-consistent and self-discrepant memories. AB - It has been argued that memories that are inconsistent with one's self would differ from those that are consistent with the self. The present study addresses retrieval, phenomenology, rehearsal and narrative characteristics of autobiographical memories that are consistent versus discrepant with one's self. One hundred participants were asked to recall one self-consistent and one self discrepant memory as well as an episode of telling these memories to others. They also filled out the Autobiographical Memory Questionnaire and the Centrality of Event Scale for each memory. Results showed no difference between self-consistent and self-discrepant memories in retrieval time, specificity or phenomenology. However, self-discrepant memory narratives contained more meaning-making statements and less autonomy than self-consistent memories. Compared to self consistent memories, self-discrepant memories were told to fewer people, and listener responses were more negative when they were told. Results are discussed in relation to the functions these memories serve. PMID- 25785775 TI - A 75-year-old female with ulceration of breast skin. AB - An elderly female presented to a North Carolina wound care center (Sandhills Center for Wound Healing and Hyperbaric Medicine, Hamlet, NC) with ulcerative lesions of both breasts. After a thorough investigation, an Internet search yielded a list of possible causes, of which candidiasis exacerbated by friction seemed the most likely diagnosis. However, a biopsy diagnosed bullous pemphigoid. This reinforces the point that a biopsy of an unusual lesion is a valuable diagnostic tool to investigate suspected malignancy, wounds in unusual locations or with unusual appearance, and wounds not responding to treatment. PMID- 25785776 TI - Effect of alertness level and backrest elevation on skin interface pressure. AB - INTRODUCTION: Critically ill patients may experience reduced mobility and sensation related to various pharmacologic therapies and treatments, making this patient population especially susceptible to pressure ulcers. An alert patient may be better able to reposition in response to discomfort, therefore preventing the development of pressure ulcers. However, little is known about the effect of an individual's alertness level on skin interface pressures. This study describes the effect of alertness level and backrest elevation on skin interface pressures. MATERIALS AND METHODS: Fifty healthy participants were recruited from the Virginia Commonwealth University (Richmond, VA) population. Participants simulated each of 2 alertness levels (sedated or alert) while in 3 backrest elevations (30 degrees , 45 degrees , or 60 degrees ). Activity level, backrest elevation, and interface pressures were recorded continuously for 30 seconds. Random effects models were used to examine the effects of alertness level and backrest elevation on average and peak pressure. Participants had a mean age of 30 and 82% were female. RESULTS: There was a significant interaction between alertness level and angle as related to average pressure (P < 0.0001) and peak pressure (P < 0.0001). Increases in backrest elevation increased average pressure and peak pressure. Interface pressures were generally greater when participants were simulating the alert state. CONCLUSION: These findings may indicate that interface pressure is a poor indicator of patient discomfort. Higher body mass index (BMI) was associated with higher average pressure (P < 0.0001), but lower peak pressure (P < 0.0001), suggesting better pressure distribution across the patient's body area. These findings are similar to previous studies in which low BMI is associated with increased pressure ulcer risk. . PMID- 25785777 TI - Hypochlorous Acid: an ideal wound care agent with powerful microbicidal, antibiofilm, and wound healing potency. AB - INTRODUCTION: Chronic wounds and the infections associated with them are responsible for a considerable escalation in morbidity and the cost of health care. Infection and cellular activation and the relation between cells are 2 critical factors in wound healing. Since chronic wounds offer ideal conditions for infection and biofilm production, good wound care strategies are critical for wound healing. Topical antiseptics in chronic wounds remain in widespread use today. These antiseptics are successful in microbial eradication, but their cytotoxcity is a controversial issue in wound healing. OBJECTIVE: The aim of this study was to investigate the effect of stabilized hypochlorous acid solution (HOCl) on killing rate, biofilm formation, antimicrobial activity within biofilm against frequently isolated microorganisms and migration rate of wounded fibroblasts and keratinocytes. MATERIALS AND METHODS: Minimal bactericidal concentration of stabilized HOCl solution for all standard microorganisms was 1/64 dilution and for clinical isolates it ranged from 1/32 to 1/64 dilutions. RESULTS: All microorganisms were killed within 0 minutes and accurate killing time was 12 seconds. The effective dose for biofilm impairment for standard microorganisms and clinical isolates ranged from 1/32 to 1/16. Microbicidal effects within the biofilm and antibiofilm concentration was the same for each microorganism. CONCLUSION: The stabilized HOCl solution had dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone iodine and media alone. These features lead to a stabilized HOCl solution as an ideal wound care agent. PMID- 25785774 TI - Adequately diversified dietary intake and iron and folic acid supplementation during pregnancy is associated with reduced occurrence of symptoms suggestive of pre-eclampsia or eclampsia in Indian women. AB - BACKGROUND/OBJECTIVE: Pre-eclampsia or Eclampsia (PE or E) accounts for 25% of cases of maternal mortality worldwide. There is some evidence of a link to dietary factors, but few studies have explored this association in developing countries, where the majority of the burden falls. We examined the association between adequately diversified dietary intake, iron and folic acid supplementation during pregnancy and symptoms suggestive of PE or E in Indian women. METHODS: Cross-sectional data from India's third National Family Health Survey (NFHS-3, 2005-06) was used for this study. Self-reported symptoms suggestive of PE or E during pregnancy were obtained from 39,657 women aged 15-49 years who had had a live birth in the five years preceding the survey. Multivariable logistic regression analysis was used to estimate the association between adequately diversified dietary intake, iron and folic acid supplementation during pregnancy and symptoms suggestive of PE or E after adjusting for maternal, health and lifestyle factors, and socio-demographic characteristics of the mother. RESULTS: In their most recent pregnancy, 1.2% (n=456) of the study sample experienced symptoms suggestive of PE or E. Mothers who consumed an adequately diversified diet were 34% less likely (OR: 0.66; 95% CI: 0.51-0.87) to report PE or E symptoms than mothers with inadequately diversified dietary intake. The likelihood of reporting PE or E symptoms was also 36% lower (OR: 0.64; 95% CI: 0.47-0.88) among those mothers who consumed iron and folic acid supplementation for at least 90 days during their last pregnancy. As a sensitivity analysis, we stratified our models sequentially by education, wealth, antenatal care visits, birth interval, and parity. Our results remained largely unchanged: both adequately diversified dietary intake and iron and folic acid supplementation during pregnancy were associated with a reduced occurrence of PE or E symptoms. CONCLUSION: Having a adequately diversified dietary intake and iron and folic acid supplementation in pregnancy was associated with a reduced occurrence of symptoms suggestive of PE or E in Indian women. PMID- 25785778 TI - A 5-year retrospective study of descriptors associated with identification of stage I and suspected deep tissue pressure ulcers in persons with darkly pigmented skin. AB - BACKGROUND: As skin assessment is critical to pressure ulcer prevention, it is essential that practitioners performing skin assessments understand individuals with dark skin tones may represent at-risk persons. In addition, visual cues commonly associated with the identification of stage I and suspected deep tissue injury (sDTI) pressure ulcers may not be sufficient in persons with darkly pigmented skin. OBJECTIVE: The purpose of this study was to identify common descriptors associated with stage I and sDTI pressure ulcers in persons with darkly pigmented skin, to determine whether the National Pressure Ulcer Advisory Panel (NPUAP) definitions are adequate, and to identify additional descriptors that might aid practitioners in identifying pressure ulcers in this at-risk population. METHODS: A 5-year retrospective review of 96 subjects with 274 stage I or sDTI pressure ulcers was conducted at an acute care facility. A literature search aided in identifying descriptors associated with pressure ulcers in persons with darkly pigmented skin. Computer-queried records targeted subjects matching the descriptors of "African American," "Asian," "Hispanic," "American Indian," "Alaskan Native,""Native Hawaiian," or "Pacific Islander" descent; with a "stage I or sDTI" and a "WOCN consult" from "March-2008 through March-2013." The pressure ulcer documentation of 9 wound, ostomy, and continence nurses (WOCNs) was analyzed. RESULTS: Stage I and sDTIs presentations were varied. However, the majority of pressure ulcers were associated with descriptors consistent with NPUAP staging guidelines. For stage I pressure ulcers, the prevailing presentation was nonblanchable erythema in 66 (75%) cases and intact skin in all 88 (100%) cases. Contrary to NPUAP guidelines, the blanching effect was commonly present. Stage I pressure ulcers also presented with normal color in 17 (11.4%) instances and were accompanied by bogginess, pain, and induration. For sDTI pressure ulcers, the prevailing color presentation was purple discoloration in 130 (70%) of the 186 cases. Intact skin was observed in 140 (75.3%) cases of the 186 cases. CONCLUSION: Contrary to NPUAP guidelines, this study showed sDTIs can have a break in the skin, with 26 (14%) ulcers demonstrating this. This suggests the NPUAP definition may benefit from revision to improve the accuracy of sDTI identification among persons with darkly pigmented skin. PMID- 25785779 TI - Effects of lytic polysaccharide monooxygenase oxidation on cellulose structure and binding of oxidized cellulose oligomers to cellulases. AB - In nature, polysaccharide glycosidic bonds are cleaved by hydrolytic enzymes for a vast array of biological functions. Recently, a new class of enzymes that utilize an oxidative mechanism to cleave glycosidic linkages was discovered; these enzymes are called lytic polysaccharide monooxygenases (LPMO). These oxidative enzymes are synergistic with cocktails of hydrolytic enzymes and are thought to act primarily on crystalline regions, in turn providing new sites of productive attachment and detachment for processive hydrolytic enzymes. In the case of cellulose, the homopolymer of beta-1,4-d-glucose, enzymatic oxidation occurs at either the reducing end or the nonreducing end of glucose, depending on enzymatic specificity, and results in the generation of oxidized chemical substituents at polymer chain ends. LPMO oxidation of cellulose is thought to produce either a lactone at the reducing end of glucose that can spontaneously or enzymatically convert to aldonic acid or 4-keto-aldose at the nonreducing end that may further oxidize to a geminal diol. Here, we use molecular simulation to examine the effect of oxidation on the structure of crystalline cellulose. The simulations highlight variations in behaviors depending on the chemical identity of the oxidized species and its location within the cellulose fibril, as different oxidized species introduce steric effects that disrupt local crystallinity and in some cases reduce the work needed for polymer decrystallization. Reducing-end oxidations are easiest to decrystallize when located at the end of the fibril, whereas nonreducing end oxidations readily decrystallize from internal cleavage sites despite their lower solvent accessibility. The differential in decrystallization free energy suggests a molecular mechanism consistent with experimentally observed LPMO/cellobiohydrolase synergy. Additionally, the soluble oxidized cellobiose products released by hydrolytic cellulases may bind to the active sites of cellulases with different affinities relative to cellobiose itself, which potentially affects hydrolytic turnover through product inhibition. To examine the effect of oxidation on cello-oligomer binding, we use thermodynamic integration to compute the relative change in binding free energy between the hydrolyzed and oxidized products in the active site of Family 7 and Family 6 processive glycoside hydrolases, Trichoderma reesei Cel7A and Cel6A, which are key industrial cellulases and commonly used model systems for fungal cellulases. Our results suggest that the equilibrium between the two reducing end oxidized products, favoring the linear aldonic acid, may increase product inhibition, which would in turn reduce processive substrate turnover. In the case of LMPO action at the nonreducing end, oxidation appears to lower affinity with the nonreducing end specific cellulase, reducing product inhibition and potentially promoting processive cellulose turnover. Overall, this suggests that oxidation of recalcitrant polysaccharides by LPMOs accelerates degradation not only by increasing the concentration of chain termini but also by reducing decrystallization work, and that product inhibition may be somewhat reduced as a result. PMID- 25785780 TI - AcpM, the meromycolate extension acyl carrier protein of Mycobacterium tuberculosis, is activated by the 4'-phosphopantetheinyl transferase PptT, a potential target of the multistep mycolic acid biosynthesis. AB - Modification of acyl carrier proteins (ACP) or domains by the covalent binding of a 4'-phosphopantetheine (4'-PP) moiety is a fundamental condition for activation of fatty acid synthases (FASes) and polyketide synthases (PKSes). Binding of 4' PP is mediated by 4' phosphopantetheinyl transfersases (PPTases). Mycobacterium tuberculosis (Mtb) possesses two essential PPTases: acyl carrier protein synthase (Mtb AcpS), which activates the multidomain fatty acid synthase I (FAS I), and Mtb PptT, an Sfp-type broad spectrum PPTase that activates PKSes. To date, it has not been determined which of the two Mtb PPTases, AcpS or PptT, activates the meromycolate extension ACP, Mtb AcpM, en route to the production of mycolic acids, the main components of the mycobacterial cell wall. In this study, we tested the enzymatic activation of a highly purified Mtb apo-AcpM to Mtb holo AcpM by either Mtb PptT or Mtb AcpS. By using SDS-PAGE band shift assay and mass spectrometry analysis, we found that Mtb PptT is the PPTase that activates Mtb AcpM. We measured the catalytic activity of Mtb PptT toward CoA, using an activation assay of a blue pigment synthase, BpsA (a nonribosomal peptide synthase, NRPS). BpsA activation by Mtb PptT was inhibited by Mtb apo-AcpM through competition for CoA, in accord with Mtb AcpM activation. A structural model of the putative interaction between Mtb PptT and Mtb AcpM suggests that both hydrophobic and electrostatic interactions stabilize this complex. To conclude, activation of Mtb AcpM by Mtb PptT reveals a potential target of the multistep mycolic acid biosynthesis. PMID- 25785781 TI - Resistance to Sulfonamides and Dissemination of sul Genes Among Salmonella spp. Isolated from Food in Poland. AB - Antimicrobial resistance of pathogenic bacteria, including Salmonella spp., is an emerging problem of food safety. Antimicrobial use can result in selection of resistant organisms. The food chain is considered a route of transmission of resistant pathogens to humans. In many European countries, sulfonamides are one of the most commonly used antimicrobials. The aim of our investigation was to assess the prevalence of sul genes and plasmid occurrence among sulfonamide resistant Salmonella spp. Eighty-four sulfonamide-resistant isolates were collected in 2008 and 2013 from retail products in Poland. Minimal inhibitory concentration of all of these isolates was >=1024 MUg/mL. Resistant isolates were tested for the presence of sul1, sul2, sul3, and int1 genes by using multiplex polymerase chain reaction. In total, 44.0% (37/84) isolates carried the sul1 gene, 46.4% (39/84) were sul2 positive, while the sul3 gene was not detected in any of the sulfonamide-resistant isolates tested. It was found that 3.6% (3/84) of resistant Salmonella spp. contained sul1, sul2, and intI genes. All 33 intI positive isolates carried the sul1 gene. Eleven of the sulfonamide-resistant isolates were negative for all the sul genes. Most of the sulfonamide-resistant Salmonella spp. harbored plasmids; only in eight isolates were no plasmids detected. Generally, the size of the plasmids ranged from approximately 2 kb to >=90 kb. Our results revealed a relatively a high prevalence of sulfonamides resistant Salmonella spp. isolated from retail food. Additionally, we have detected a high dissemination of plasmids and class 1 integrons that may enhance the spread of resistance genes in the food chain. PMID- 25785782 TI - SCN8A mutations in Chinese children with early onset epilepsy and intellectual disability. AB - OBJECTIVE: Mutations in SCN8A, a voltage-gated sodium-channel type VIII alpha subunit gene, have recently been recognized as one of the pathogenic mechanisms leading to epilepsy and intellectual/developmental disabilities (IDDs). The aim of this study was to detect SCN8A mutations in Chinese patients with epilepsy of unknown etiology and ID/DD. METHODS: We used targeted next-generation sequencing to identify SCN8A mutations in Chinese patients with epilepsy of unknown etiology and IDDs. A filter process was performed to prioritize rare variants of potential functional significance. Sanger sequencing confirmed the variants and determined the parental origin. We followed all patients with SCN8A mutations in our cohort and analyzed their clinical data. RESULTS: Five de novo SCN8A mutations were identified, including four novel mutations (p.Ala890Thr, p.Leu407Phe, p.Arg850Gln, and p.Ser1596Cys) and one reported (p.Arg1617Gln). Polyphen2 and SIFT software predicted that all five mutations probably damaged Nav1.6 protein function; Mutation Taster indicated that all mutations were disease-causing. Three of these five patients were controlled well by sodium channel blockers (SCBs). Two of these three patients remained seizure free for 6 and 1.5 months, respectively. One patient had sudden unexpected death in epilepsy (SUDEP) at the age of 1 year and 4 months. SIGNIFICANCE: Five SCN8A mutations were first reported in Chinese patients with epilepsy and ID/DD, expanding the phenotype and mutation spectrum of SCN8A mutations. Although three of these patients were controlled well by SCBs in our study, the effectiveness of SCBs should be validated in more patients with epilepsy caused by SCN8A mutations in the future. One of our five patients had sudden unexpected death in epilepsy SUDEP, suggesting that we should pay more attention to SUDEP in epileptic patients with SCN8A mutations. PMID- 25785783 TI - Health, Wellbeing and Social Sciences. AB - For social interventions aimed at improving nutrition behavior evidence from randomized trials is essential but cannot be the only approach of research activities. Interventions on dietary habits require considerations on food security, economic and environmental sustainability, and a broad meaning of wellbeing which includes, but also goes beyond, health effects. The model of research in nutrition requires a new consideration of observational studies, mainly through different analytical models. Nutrition and food studies need research programs where medical (nutrition and health), psychology (how we behave), economics (how resources are used and their impact on wellbeing) and sociology (how social determinant shape behavior) collaborate. PMID- 25785784 TI - Synergistic effects of Ir-Au/TiO2 catalysts in the total oxidation of propene: influence of the activation conditions. AB - Iridium was added to the Au/TiO2 system to try to enhance its catalytic activity in the reaction of propene oxidation, performed under conditions close to those used in the studies of decomposition of volatile organic compounds (1200 ppm propene and 9 vol% O2 in He). Titania supported Ir-Au (Ir/Au = 1) was prepared by sequential deposition-precipitation with urea (DPU) of Ir then Au. The effect of the activation conditions (hydrogen or air at 400 degrees C) was investigated. The study of the activation conditions of Ir-Au/TiO2 showed that activation under hydrogen at 400 degrees C generated a catalyst more active than the monometallic ones, while Ir-Au/TiO2 activated in air remained as poorly active as Au/TiO2. TEM characterization showed the formation of metallic particles of similar size (2-3 nm) in both monometallic Au/TiO2 and bimetallic Ir-Au/TiO2. Characterization especially by DRIFTS using CO as a probe molecule suggests the presence of Ir-Au interaction, IrO2-Au(0) interaction when the sample is calcined and Ir(0)-Au(0) bimetallic particles when it is reduced. XPS and TPR characterization techniques showed that gold hinders to some extent the reoxidation of iridium in the reduced bimetallic Ir-Au/TiO2 catalyst. The enhanced catalytic activity of the reduced bimetallic Ir-Au/TiO2 catalyst is attributed to a surface Ir(0)-Au(0) synergism. PMID- 25785785 TI - Microalgae cultivation on wastewater digestate: beta-estradiol and 17alpha ethynylestradiol degradation and transformation products identification. AB - Selenastrum capricornutum and Chlamydomonas reinhardtii were tested for possible biodegradation of the hormones beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2) when cultured in anaerobic digester centrate (ADC). Neither ADC nor the hormones had a negative or toxic effect on the microalgae growth but enhanced it. E2 and EE2 biodegradation was evaluated under different culture conditions. After 7 days of treatment, between 88% and 100% of E2 was removed by S. capricornutum. Overall, 42 and 54% of the removal was attributed to biodegradation processes, while the rest of the removal was due to adsorption onto the algae biomass. For EE2, removals between 60 and 95%, depending on the culture conditions, were achieved, with biodegradation accounting for 20-54% of the removal. E2 and EE2 were completely removed in the experiments performed with C. reinhardtii, except for EE2 in the presence of ADC, which decreased to 76%. However, C. reinhardtii presented higher adsorption percentages: 86% and 71% after 7 days for E2 and EE2, respectively. Transformation products (TPs) of E2 and EE2 generated in each treatment were also monitored. Two TPs were tentatively proposed as degradation products of E2 and EE2 by the algae. In addition, the removal of 26 endocrine disruptors and related pollutants present in the centrate was also monitored: bisphenol A was completely removed, whereas tris(2-butoxyethyl)phosphate was only removed in the absence of hormones. PMID- 25785786 TI - Synthesis of ultrastable copper sulfide nanoclusters via trapping the reaction intermediate: potential anticancer and antibacterial applications. AB - Copper-based nanomaterials have broad applications in electronics, catalysts, solar energy conversion, antibiotics, tissue imaging, and photothermal cancer therapy. However, it is challenging to prepare ultrasmall and ultrastable CuS nanoclusters (NCs) at room temperature. In this article, a simple method to synthesize water-soluble, monodispersed CuS NCs is reported based on the strategy of trapping the reaction intermediate using thiol-terminated, alkyl-containing short-chain poly(ethylene glycol)s (HS-(CH2)11-(OCH2CH2)6-OH, abbreviated as MUH). The MUH-coated CuS NCs have superior stability in solutions with varied pH values and are stable in pure water for at least 10 months. The as-prepared CuS NCs were highly toxic to A549 cancer cells at a concentration of higher than 100 MUM (9.6 MUg/mL), making them be potentially applicable as anticancer drugs via intravenous administration by liposomal encapsulation or by direct intratumoral injection. Besides, for the first time, CuS NCs were used for antibacterial application, and 800 MUM (76.8 MUg/mL) CuS NCs could completely kill the E. coli cells through damaging the cell walls. Moreover, the NCs synthesized here have strong near-infrared (NIR) absorption and can be used as a candidate reagent for photothermal therapy and photoacoustic imaging. The method of trapping the reaction intermediate for simple and controlled synthesis of nanoclusters is generally applicable and can be widely used to synthesize many metal-based (such as Pt, Pd, Au, and Ag) nanoclusters and nanocrystals. PMID- 25785787 TI - Cascade couplings of N-alkyl-N-methacryloyl benzamides with ethers and benzenesulfonohydrazides to generate isoquinoline-1,3(2H,4H)-dione derivatives. AB - Two radical-mediated cascade couplings of N-alkyl-N-methacryloylbenzamides with different ethers and arylsulfonohydrazides to generate ether- and arylsulfonyl substituted isoquinoline-1,3(2H,4H)-dione derivatives were developed. Both casccades proceeded via initially triggered functionalization of the alkene functions of the N-alkyl-N-methacryloylbenzamides, followed by ortho radical cyclizations onto the aromatic ring to give isoquinoline-1,3(2H,4H)-dione derivatives in good yields. These highly functionalized drug-like molecules will be valuable in drug discovery in the future. PMID- 25785788 TI - A Pilot SMART for Developing an Adaptive Treatment Strategy for Adolescent Depression. AB - This pilot study was conducted to assess the feasibility and acceptability of 4 adaptive treatment strategies (ATSs) for adolescent depression to plan for a subsequent full-scale clinical trial. The ATSs aim to address 2 questions that arise when personalizing treatment: (a) For adolescents treated with Interpersonal Psychotherapy for depressed adolescents (IPT-A; Mufson et al., 2004 ), at what time point should therapists make the determination that the adolescent is not likely to respond if the initial treatment plan is continued (week 4 or week 8)? (b) For adolescents who are judged to need their treatment augmented, should the therapist increase the number of IPT-A sessions or add pharmacotherapy (fluoxetine)? A 16-week pilot sequential multiple assignment randomized trial (SMART) was conducted with 32 adolescents (M age = 14.9) who had a diagnosis of major depressive disorder, dysthymic disorder, or depressive disorder not otherwise specified. Adolescents were primarily female (75%) and Caucasian (84.4%). Data regarding the feasibility and acceptability of the study and treatment procedures and treatment response rates were collected. Week 4 was the more feasible and acceptable decision point for assessing need for a change to treatment. Adolescents, parents, and therapists reported a range of attitudes about medication and more intensive therapy as treatment options. Results from the pilot study have yielded additional research questions for the full-scale SMART and will improve our ability to successfully conduct the trial. PMID- 25785789 TI - Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. AB - BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease. A newer form of ventilation called high frequency oscillatory ventilation has been shown in experimental studies to result in less lung injury. OBJECTIVES: The objective of this review was to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) on the incidence of chronic lung disease (CLD), mortality and other complications associated with prematurity and assisted ventilation in preterm infants who were mechanically ventilated for respiratory distress syndrome (RDS). SEARCH METHODS: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conference and symposia proceedings; and from expert informants and handsearching of journals by The Cochrane Collaboration, mainly in the English language. The search was updated in January 2009 and again in November 2014. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomisation and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the review authors. The standard effect measures were relative risk (RR) and risk difference (RD). From 1/RD the number needed to benefit (NNTB) to produce one outcome was calculated. For all measures of effect, 95% confidence intervals (CIs) were used. For interpretation of subgroup analyses, a P value for subgroup differences as well as the I(2) statistic for between-subgroup heterogeneity were calculated. Meta-analysis was performed using both a fixed-effect and a random effects model. Where heterogeneity was over 50%, the random-effects model RR was also reported. MAIN RESULTS: Nineteen eligible studies involving 4096 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 to 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The risk of CLD in survivors at term equivalent gestational age was significantly reduced with the use of HFOV but this effect was inconsistent across studies, even after the meta-analysis was restricted to studies that applied a high lung volume strategy with HFOV. Subgroup analysis by HFOV strategy showed a similar effect in trials with a more strict lung volume recruitment strategy, targeting a very low fraction of inspired oxygen (FiO2), and trials with a less strict lung volume recruitment strategy and with a somewhat higher or unspecified target FiO2. Subgroup analyses by age at randomisation, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy (lung protective or not) could not sufficiently explain the heterogeneity. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial emphysema, occurred more frequently in the HFOV group, whereas the risk of severe retinopathy of prematurity was significantly reduced.Although in some studies an increased risk of severe grade intracranial haemorrhage and periventricular leukomalacia was found, the overall meta-analysis revealed no significant differences in effect between HFOV and CV. The short-term neurological morbidity with HFOV was only found in the subgroup of two trials not using a high volume strategy with HFOV. Most trials did not find a significant difference in long-term neurodevelopmental outcome, although one recent trial showed a significant reduction in the risk of cerebral palsy and poor mental development. AUTHORS' CONCLUSIONS: There is evidence that the use of elective HFOV compared with CV results in a small reduction in the risk of CLD, but the evidence is weakened by the inconsistency of this effect across trials. Probably many factors, both related to the intervention itself as well as to the individual patient, interact in complex ways. In addition, the benefit could be counteracted by an increased risk of acute air leak. Adverse effects on short term neurological outcomes have been observed in some studies but these effects are not significant overall. Most trials reporting long-term outcome have not identified any difference. PMID- 25785790 TI - Role of balance ability and confidence in prosthetic use for mobility of people with lower-limb loss. AB - For people with lower-limb loss, impaired balance is common and limits prosthetic function within the community. This cross-sectional study (1) analyzed relationships among prosthetic use for mobility, balance ability and confidence, and amputation-related variables and (2) determined multivariate models to identify level of prosthetic use. Subjects included 46 community-dwelling adults (mean age 56.2 yr) with limb loss (91.3% unilateral) of varied levels (52.2% transtibial) and etiologies (69.6% vascular). A three-variable linear regression model including balance ability, balance confidence, and years since amputation explained 63.7% of variance in the Houghton scale of prosthetic use score. A logistic regression model including the 14-task Berg Balance Scale, balance confidence, years since amputation, age, and number of comorbidities correctly differentiated between people who had reached a satisfactory level of prosthetic use or not 89.1% of the time. The first three variables demonstrated moderate accuracy with positive likelihood ratios from 2.34 to 4.35. The regression model was further reduced to correctly classify 87.0% of cases with three balance ability tasks (retrieving objects from floor, turning to look behind, and placing alternate foot on stool), balance confidence, and numbers of comorbidities. Logistic models that include balance ability, balance confidence, and numbers of comorbidities can identify level of prosthetic use in people with lower-limb loss. Increased balance confidence and ability when retrieving objects from floor, turning to look behind, and placing alternate foot on stool were most indicative of successful prosthetic use for mobility. PMID- 25785791 TI - The support effect on the size and catalytic activity of thiolated Au25 nanoclusters as precatalysts. AB - In this study, 6-mercaptohexanoic (MHA) protected Au25(MHA)18 nanoclusters (or thiolated Au NCs) deposited on various inorganic supports, including hydroxyapatite (HAP), TiO2 (Degussa P25), activated carbon (AC), pyrolyzed graphene oxide (PGO), and fumed SiO2 were prepared via a conventional impregnation method. Following that, calcination under a N2 stream was conducted to produce surface ligand free, highly dispersed Au NCs catalysts. The effects of supports on the size and catalytic activity of Au NCs were systematically investigated. No obvious size growth was observed for Au NCs on HAP and P25 after thermally induced ligand removal, due to the strong interaction between the metal and the supports. However, severe aggregations of Au NCs were seen after thermal treatment on three other supports, including AC, PGO, and SiO2. The removal of surface thiol ligands from the Au NCs is crucial to catalyze nitrobenzene hydrogenation, where only calcined Au/HAP and Au/P25 exhibited good catalytic activity. On the other hand, all the supported Au NCs were active for the styrene oxidation, where Au/HAP exhibited the best catalytic performance. Altogether, both the size effect and metal-support interaction are crucial for the design of supported Au NCs as efficient catalysts for targeted reactions. PMID- 25785792 TI - Investigating cannabis use normalization by distinguishing between experimental and regular use: a multilevel study in 31 countries. AB - OBJECTIVE: This research examined whether national population-level cannabis frequency rates moderate the strength of the relationship between individual level psychosocial and behavioral risk factors (poor parental communication, bullying, fighting, etc.) and different levels of adolescent cannabis use (abstinence, experimental use, and regular use). METHOD: Data from the 2009/2010 Health Behaviour in School-Aged Children survey (N = 62,009, age = 15 years) from 31 countries were analyzed using multinomial hierarchical linear modeling. RESULTS: Analyses showed that adolescents who reported experimental cannabis use and who lived in relatively high cannabis frequency countries were less likely than their counterparts in low cannabis frequency countries to present some of the cannabis-related psychosocial and behavioral risk factors. Conversely, regular cannabis use tended to occur among high-risk adolescents to an equal degree in high and low cannabis frequency countries. CONCLUSIONS: The findings suggest that the normality of cannabis use in the youth population is important to consider when investigating the relationship between risk factors and cannabis use. PMID- 25785793 TI - Event-specific cannabis use and use-related impairment: the relationship to campus traditions. AB - OBJECTIVE: Despite high rates of college cannabis use, little work has identified high-risk cannabis use events. For instance, Mardi Gras (MG) and St. Patrick's Day (SPD) are characterized by more college drinking, yet it is unknown whether they are also related to greater cannabis use. Further, some campuses may have traditions that emphasize substance use during these events, whereas other campuses may not. Such campus differences may affect whether students use cannabis during specific events. The present study tested whether MG and SPD were related to more cannabis use at two campuses with different traditions regarding MG and SPD. Further, given that Campus A has specific traditions regarding MG whereas Campus B has specific traditions regarding SPD, cross-campus differences in event-specific use were examined. METHOD: Current cannabis-using undergraduates (N = 154) at two campuses completed an online survey of event specific cannabis use and event-specific cannabis-related problems. RESULTS: Participants used more cannabis during MG and SPD than during a typical weekday, typical day on which the holiday fell, and a holiday unrelated to cannabis use (Presidents' Day). Among those who engaged in event-specific use, MG and SPD cannabis use was greater than typical weekend use. Campus differences were observed. For example, Campus A reported more cannabis-related problems during MG than SPD, whereas Campus B reported more problems during SPD than MG. CONCLUSIONS: Specific holidays were associated with more cannabis use and use related problems. Observed between-campus differences indicate that campus traditions may affect event-specific cannabis use and use-related problems. PMID- 25785794 TI - School and work status, drug-free workplace protections, and prescription drug misuse among Americans ages 15-25. AB - OBJECTIVE: We assessed the prevalence and characteristics of prescription drug misuse among youth ages 15-25 to examine differences by student and employment status, and associations with workplace antidrug policies and programs. METHOD: Multivariate logistic regressions analyzed associations in weighted data on the 20,457 young adults in the combined 2004-2008 National Surveys on Drug Use and Health. Demographic controls included sex, race, community size, and age group. RESULTS: After we accounted for demographic controls, at ages 15-25, students were less likely than nonstudents to misuse prescription drugs. Segmenting student from nonstudent groups, working consistently was associated with a further reduction in misuse for those ages 18-25. When we controlled for demographics and substance use history, both Employee Assistance Program (EAP) services and awareness that one's employer had a drug-free workplace policy were associated with significantly lower misuse of prescription drugs (OR = 0.85 for each program, 95% CI [0.73, 1.00] and [0.72, 1.00]). Associations of workplace antidrug policies and programs with marijuana use and with Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria for alcohol abuse and dependence contrasted sharply with these patterns. All four aspects were significantly associated with lower marijuana use. None was associated with problem drinking. CONCLUSIONS: Protective effects of drug-free workplace policy and EAPs persist after other substance use was controlled for. Comparing the effects of workplace programs on illicit drug use and problem drinking versus prescription misuse suggests that those protective associations do not result from selection bias. Thus, drug-free workplace policies and EAPs appear to help protect younger workers against prescription misuse. If workplace substance use disorder programs focused prevention messages and interventions on prescription drug misuse, their impact on misuse might increase. PMID- 25785795 TI - Is orientation week a gateway to persistent alcohol use in university students? A preliminary investigation. AB - OBJECTIVE: Orientation Week is common at many universities throughout the world and is a way to introduce students to their new environment. Despite some benefits, Orientation Week is often typified by heavy alcohol use. Although typically viewed as a "one-time" event, the higher levels of drinking that students engage in during Orientation Week may persist into the academic year. We investigated this possibility in the present study. METHOD: Freshman-year students (n = 143; 41% male) residing in a dormitory were surveyed about their alcohol intake before university. During Orientation Week, students were sent a daily text message asking about the number of drinks they consumed the previous night. Then, during the academic year, students were sent one text message each month to record their weekend drinking. RESULTS: Participants consumed a higher number of standard drinks during Orientation Week (M = 26.0, SD = 28.6) than they did either before entering university (M = 13.1, SD = 13.6) or during the academic year (M = 6.4, SD = 8.5). For male students, but not female students, higher Orientation Week drinking uniquely contributed to higher rates of drinking during the academic year when controlling for pre-university drinking (b = 0.122, p < .001). Students who drank at low levels before entering university were particularly susceptible to the negative effects of Orientation Week drinking. CONCLUSIONS: Orientation Week may act as a gateway for male students, as drinking during Orientation Week predicted their subsequent drinking throughout the academic year. Based on these findings, Orientation Week could be a prime period for interventions aimed at curbing academic-year drinking. PMID- 25785797 TI - Costs of screening and brief intervention for illicit drug use in primary care settings. AB - OBJECTIVE: In this article, the authors estimate implementation costs for illicit drug screening and brief intervention (SBI) and identify a key source of variation in cost estimates noted in the alcohol SBI literature. This is the first study of the cost of SBI for drug use only. METHOD: Using primary data collected from a clinical trial of illicit drug SBI (n = 528) and a hybrid costing approach, we estimated a per-service implementation cost for screening and two models of brief intervention. A taxonomy of activities was first compiled, and then resources and prices were attached to estimate the per activity cost. Two components of the implementation cost, direct service delivery and service support costs, were estimated separately. RESULTS: Per-person cost estimates were $15.61 for screening, $38.94 for a brief negotiated interview, and $252.26 for an adaptation of motivational interviewing. (Amounts are in 2011 U.S. dollars.) Service support costs per patient are 5 to 7.5 times greater than direct service delivery costs per patient. Ongoing clinical supervision costs are the largest component of service support costs. CONCLUSIONS: Implementation cost estimates for illicit drug brief intervention vary greatly depending on the brief intervention method, and service support is the largest component of SBI costs. Screening and brief intervention cost estimates for drug use are similar to those published for alcohol SBI. Direct service delivery cost estimates are similar to costs at the low end of the distribution identified in the alcohol literature. The magnitude of service support costs may explain the larger cost estimates at the high end of the alcohol SBI cost distribution. PMID- 25785796 TI - The prospective association between sipping alcohol by the sixth grade and later substance use. AB - OBJECTIVE: Although there is a clear association between early use of alcohol and short- and long-term adverse outcomes, it is unclear whether consumption of minor amounts of alcohol (less than a full drink) at a young age is prognostic of risk behaviors in later adolescence. METHOD: Data were taken from 561 students enrolled in an ongoing prospective web-based study on alcohol initiation and progression (55% female; 25% White non-Hispanic). Based on a combination of monthly and semiannual surveys, we coded whether participants sipped alcohol before sixth grade and examined associations between early sipping and alcohol consumption by fall of ninth grade, as well as other indices of problem behavior. Participants also reported on the context of the first sipping event. RESULTS: The prevalence of sipping alcohol by fall of sixth grade was 29.5%. Most participants indicated that their first sip took place at their own home, and the primary source of alcohol was an adult, usually a parent. Youth who sipped alcohol by sixth grade had significantly greater odds of consuming a full drink, getting drunk, and drinking heavily by ninth grade than nonsippers. These associations held even when we controlled for temperamental, behavioral, and environmental factors that contribute to proneness for problem behavior, which suggests that sipping is not simply a marker of underlying risk. CONCLUSIONS: Our findings that early sipping is associated with elevated odds of risky behaviors at high school entry dispute the idea of sipping as a protective factor. Offering even just a sip of alcohol may undermine messages about the unacceptability of alcohol consumption for youth. PMID- 25785798 TI - Perceived racial discrimination and negative-mood-related drinking among African American college students. AB - OBJECTIVE: Research consistently shows a positive association between racial discrimination and problematic alcohol use among African Americans, but little is known about the micro-processes linking this pernicious form of stress to drinking. One possibility is that the cumulative effects of discrimination increase individuals' likelihood of negative-mood-related drinking. In the current study, we examined whether individual differences in lifetime perceived racial discrimination among African American college students moderate relations between daily negative moods and evening alcohol consumption in both social and nonsocial contexts. METHOD: Data came from an online daily diary study of 441 African Americans (58% female) enrolled at a historically black college/university. Lifetime discrimination was measured at baseline. For 30 days, students reported the number of drinks they consumed the night before both socially and nonsocially, as well as their daytime level of negative mood. RESULTS: In support of the hypotheses, only men who reported higher (vs. lower) lifetime discrimination showed a positive association between daily negative mood and that evening's level of nonsocial drinking. Contrary to expectation, women who reported higher (vs. lower) discrimination showed a negative association between daily negative mood and nonsocial drinking. Neither daily negative mood nor lifetime discrimination predicted level of social drinking. CONCLUSIONS: These findings provide further evidence that the cumulative impact of racial discrimination may produce a vulnerability to negative-mood-related drinking--but only for African American men. Importantly, these effects emerged only for nonsocial drinking, which may further explain the robust association between discrimination and problematic alcohol use. PMID- 25785799 TI - Modifying alcohol expectancies of Hispanic children: examining the effects of expectancy-targeted, developmentally congruous prevention videos. AB - OBJECTIVE: Children's expectations about the effects of alcohol consumption are known to predict the amount of alcohol they consume as adults. Previous research has used videotaped interventions to modify children's alcohol expectancies and found that puppet actors had the expected effect of decreasing children's positive alcohol expectancies, whereas adult actors did not. The current study sought to enhance the methods and outcomes of previous research by developing brief prevention videos that focus on pre-selected negative and sedating alcohol expectancies and include youth actors and age-relevant scenarios. METHOD: Using a 2 * 2 factorial design (actor's age [youth or adult] * scenario relevance [youth or adult]), we examined the alcohol expectancies of 183 Hispanic third-, fourth-, and fifth-grade students (50% girls) in a public school setting. Expectancies were assessed before, immediately following the intervention, and 1 month later. The intervention consisted of four 8-minute videos based on beliefs associated with expectancies related to low alcohol consumption and a control group video about school bus safety. RESULTS: Positive alcohol expectancies were significantly lower directly after the intervention than at baseline. At 1-month follow-up, this effect decreased but was still significant. CONCLUSIONS: The current study adds to existing findings that expectancies can be modified in children, using interventions that are extremely brief, low-cost, and linked to research in children's cognitive and social development. In addition, it appears that children of different ages and genders respond differently to varying components of prevention media. PMID- 25785800 TI - Adolescent social networks: general and smoking-specific characteristics associated with smoking. AB - OBJECTIVE: Converging lines of research suggest that adolescents' smoking behaviors are strongly influenced by the characteristics of their social network and the social processes their network facilitates. The primary goal of this study was to conduct a detailed comparison of the social networks of adolescent smokers and nonsmokers to determine what aspects relate the most to smoking status. A secondary goal was to conduct within-group analyses to examine relationships between key measures of behavior-specific social support and (a) smoking susceptibility among nonsmokers, and (b) readiness to quit smoking among smokers. METHOD: A matched sample of 190 adolescent smokers and nonsmokers (Mage = 16.8 years; 51% female) completed a questionnaire in which they nominated and reported on up to 10 important people in their lives. This measure allowed us to examine adolescents' overall networks (both peers and family) and to investigate numerous aspects, including general network characteristics (e.g., size of network, average contact with network members), social support (e.g., importance of people in the network), and the pervasiveness of smoking in the network (e.g., percentage of smoking peers). RESULTS: The pervasiveness of smoking in adolescents' social network was the strongest distinguisher of smokers versus nonsmokers. In addition, behavior-specific social support was strongly associated with susceptibility to initiate smoking among nonsmokers and readiness to quit among smokers. CONCLUSIONS: This research offers insight into potential targets for prevention and early intervention by demonstrating how social networks can both promote and attenuate risk for smoking. PMID- 25785801 TI - What predicts early smoking milestones? AB - OBJECTIVE: As many cigarette smokers begin experimenting before age 16, prevention efforts require a comprehensive understanding of smoking predictors during adolescence. Research has made many advances in understanding the predictors of smoking initiation, yet more precision is still needed to determine whether the patterns of prediction differ across early smoking milestones. The purpose of this study was to use a sample of young adolescents to examine the predictors of two key milestones in smoking initiation: first puff and first cigarette. METHOD: Data came from an ongoing, prospective project examining psychosocial factors related to adolescent substance use. At Time 1 (T1), the sample was 1,023 Rhode Island middle school students (ages 10-15 years; M = 12.2). T1 measures included empirically supported risk and protective factors, as well as current smoking. Follow-up surveys assessed smoking behavior over the ensuing year (T2 smoking). RESULTS: Cigarette availability was the most robust predictor of smoking milestones, increasing the likelihood of both first puff and first cigarette in cross-sectional and prospective analyses. Multivariable analyses also showed specificity, where some factors were only associated with one time point (e.g., age and T1 puff and cigarette), whereas others were only associated with one milestone (e.g., parental monitoring and whole cigarette at both time points). CONCLUSIONS: This study found different patterns of predictors for two early smoking milestones. Such findings are the first to suggest that puff and whole cigarette are distinct smoking milestones and reaffirm arguments that researchers should distinguish the various stages of smoking initiation when examining the broader period of onset/initiation. PMID- 25785802 TI - Measuring peer socialization for adolescent substance use: a comparison of perceived and actual friends' substance use effects. AB - OBJECTIVE: There has been an increase in the use of social network analysis in studies of peer socialization effects on adolescent substance use. Some researchers argue that social network analyses provide more accurate measures of peer substance use, that the alternate strategy of assessing perceptions of friends' drug use is biased, and that perceptions of peer use and actual peer use represent different constructs. However, there has been little research directly comparing the two effects, and little is known about the extent to which the measures differ in the magnitude of their influence on adolescent substance use, as well as how these two effects may be redundant or separate constructs. METHOD: Using Waves I and II of the National Longitudinal Study of Adolescent Health (Add Health) saturated subsample, we directly compared effects of perception of friends' use (PFU) and actual friends' use (AFU) on alcohol, cigarette, and marijuana initiation and persistence of use 1 year later. We also examined potential moderating effects of friendship quality and individual use on the relationship between perceived and actual friends' substance use and outcomes. RESULTS: Results indicated that, overall, PFU effects were larger than AFU effects; however, these effects did not significantly differ in magnitude for most models. In addition, interaction effects differed for different substances and usage outcomes, indicating the meaning of PFU and AFU constructs (and thus, different types of peer socialization) may change based on substance and type of use. CONCLUSIONS: These results highlight the multifaceted nature of peer influence on substance use and the importance of assessing multiple aspects of peer socialization while accounting for distinct contexts related to specific substances and use outcomes. PMID- 25785803 TI - Alcohol sensitivity moderates the indirect associations between impulsive traits, impaired control over drinking, and drinking outcomes. AB - OBJECTIVE: The purpose of this study was to examine impaired control over drinking behavior as a mediator of unique pathways from impulsive traits to alcohol outcomes in young adults. We also sought to investigate the moderating influence of self-reported sensitivity to alcohol on these pathways. METHOD: Young adult heavy drinkers (N = 172; 82 women) recruited from the community completed self-report measures of impulsive traits (positive urgency, negative urgency, sensation seeking), alcohol sensitivity (Self-Rating of the Effects of Alcohol scale), impaired control over drinking, and alcohol use and problems. Multiple-groups path analysis was used to analyze the data. RESULTS: Path coefficients between urgency and impaired control were larger for individuals with lower versus higher self-reported sensitivity to alcohol. The same was true for the association between impaired control and alcohol problems. For participants lower on alcohol sensitivity, significant indirect paths were observed from both positive and negative urgency to all alcohol outcomes (quantity, frequency, and problems) mediated via impaired control. For participants higher on alcohol sensitivity, only the paths from negative urgency (but not positive urgency) to the three alcohol outcomes via impaired control were statistically significant. Sensation seeking was not uniquely associated with impaired control. CONCLUSIONS: The findings indicate that relatively low sensitivity to the pharmacological effects of alcohol may strengthen the association between urgency--especially positive urgency--and impaired control, supporting the notion that personality and level of response to alcohol may interact to increase risk for impaired control over drinking. PMID- 25785804 TI - Differences in subjective response to alcohol by gender, family history, heavy episodic drinking, and cigarette use: refining and broadening the scope of measurement. AB - OBJECTIVE: Subjective response to alcohol (SR) has been shown to differ by gender, family history of alcoholism, drinking status, and cigarette smoking status. However, the requisite statistical basis for making mean-level comparisons (scalar measurement invariance; MI) has not been established for any SR measure, making it impossible to determine whether observed differences reflect true differences or measurement bias. Secondary data analyses were conducted to evaluate (a) MI of the Subjective Effects of Alcohol Scale (SEAS) by gender, family history, heavy drinking status, and cigarette smoking status using multigroup confirmatory factor analysis; and (b) the impact of these group-level variables on SR using multivariate general linear modeling. A central strength, the SEAS assesses novel high arousal negative (HIGH-; e.g., aggressive) and low arousal positive effects (LOW+; e.g., relaxed) in addition to commonly assessed high arousal positive [HIGH+; e.g., sociable] and low arousal negative effects [LOW-; e.g., woozy]). METHOD: A total of 215 young adults reported on SR during a placebo-controlled alcohol administration study in a simulated bar setting (target blood alcohol concentration = .08%). RESULTS: Scalar MI was achieved for each group. After consuming alcohol, family history-positive individuals reported stronger HIGH- effects and female smokers reported weaker LOW+ effects than their counterparts. Heavy episodic drinkers and family history-positive females reported weaker LOW- effects than their counterparts. CONCLUSIONS: The SEAS permits meaningful SR comparisons within several important groups. SR differences largely were observed on the novel SEAS subscales, highlighting the importance of assessing a full range of SR. PMID- 25785805 TI - Effects of aging on frontal white matter microstructure in alcohol use disorder and associations with processing speed. AB - OBJECTIVE: The number of older adults with alcohol use disorder (AUD) is expected to significantly increase in the coming years. Both aging and AUD have been associated with compromised white matter microstructure, although the extent of combined AUD and aging effects is unclear. This study investigated interactions between aging and AUD in cerebral white matter integrity using diffusion tensor imaging (DTI). METHOD: All participants (44 recently detoxified participants with AUD and 28 healthy controls; ages 31-64 years) completed neurocognitive testing and a DTI scan. Regions of interests were identified on Tract-Based Spatial Statistics images. Hierarchical multiple regression was used to examine interactions between age and AUD status on DTI values [e.g., fractional anisotropy (FA)]. RESULTS: Significant Age * AUD interactions were found across several prefrontal white matter regions (R(2)Delta = 5%-9%). Regional FA was negatively associated with age in the AUD group (rs = -.33 - -.53) but not in the control group (rs = .18 - -.32). This pattern remained after adjusting for lifetime history of drinking and recent drinking. Lifetime alcohol consumption negatively correlated with frontal white matter integrity in the AUD group (rs = .33 - -.40). Finally, processing speed was significantly slower in the AUD group versus controls (p = .001) and was positively correlated with FA values in frontal white matter regions (rs = .34-.53). CONCLUSIONS: Cumulative alcohol consumption may affect frontal white matter integrity, and persons with AUD may be more prone to reductions in frontal white matter integrity with advancing age. These reductions in frontal white matter integrity may contribute to reductions in processing speed. PMID- 25785806 TI - Influence of mother-daughter attachment on substance use: a longitudinal study of a Latina community-based sample. AB - OBJECTIVE: Advancing our initial, cross-sectional study, which showed that adult Latinas' mother-daughter attachment relates to their substance use, the current, longitudinal study tests whether mother and daughter attachment scores at baseline predict their substance use over time. METHOD: We analyzed data from a convenience sample of 133 Latina adult mothers (mean age = 52 years, SD = 10) and 133 Latina adult daughters (mean age = 27, SD = 9) at baseline and at 5-year and 6-year follow-ups after baseline (attrition rate = 16%). Multilevel longitudinal modeling was used to examine the effect of mother-daughter attachment at baseline on their substance use over time. RESULTS: Each unit of increase in the attachment score at baseline is associated with a 0.28 drink decrease in monthly alcohol use (p < .05) and a lower likelihood of being a heavy alcohol or other drug user [exp(beta) = 0.97, p < .01] compared with average attachment score at baseline (M = 91.52, SD = 18.00). Time and older age at baseline are associated with decreased substance use. Being born outside the United States is associated with decreased risk of heavy alcohol or other drug use. Being a mother is associated with increased substance use. CONCLUSIONS: The findings of this longitudinal study on adult Latinas indicate that mother-daughter attachment has long-lasting effects on substance use trajectories among adult Latinas. Future research should focus on (a) investigating social and cultural factors mediating this relationship and (b) greater substance use among Latina mothers compared with daughters. PMID- 25785807 TI - Anxiety sensitivity and pre-cessation smoking processes: testing the independent and combined mediating effects of negative affect-reduction expectancies and motives. AB - OBJECTIVE: Anxiety sensitivity appears to be relevant in understanding the nature of emotional symptoms and disorders associated with smoking. Negative reinforcement smoking expectancies and motives are implicated as core regulatory processes that may explain, in part, the anxiety sensitivity-smoking interrelations; however, these pathways have received little empirical attention. METHOD: Participants (N = 471) were adult treatment-seeking daily smokers assessed for a smoking-cessation trial who provided baseline data; 157 participants provided within-treatment (pre-cessation) data. Anxiety sensitivity was examined as a cross-sectional predictor of several baseline smoking processes (nicotine dependence, perceived barriers to cessation, severity of prior withdrawal-related quit problems) and pre-cessation processes including nicotine withdrawal and smoking urges (assessed during 3 weeks before the quit day). Baseline negative-reinforcement smoking expectancies and motives were tested as simultaneous mediators via parallel multiple mediator models. RESULTS: Higher levels of anxiety sensitivity were related to higher levels of nicotine dependence, greater perceived barriers to smoking cessation, more severe withdrawal-related problems during prior quit attempts, and greater average withdrawal before the quit day; effects were indirectly explained by the combination of both mediators. Higher levels of anxiety sensitivity were not directly related to pre-cessation smoking urges but were indirectly related through the independent and combined effects of the mediators. CONCLUSIONS: These empirical findings bolster theoretical models of anxiety sensitivity and smoking and identify targets for nicotine dependence etiology research and cessation interventions. PMID- 25785808 TI - A daily measure of positive and negative alcohol expectancies and evaluations: documenting a two-factor structure and within- and between-person variability. AB - OBJECTIVE: Despite the documented importance of alcohol outcome expectancies in predicting alcohol use and related consequences, little research has explored within-person variability in expectancies. This article details the construction and psychometric analysis of a measure of alcohol expectancies specifically designed for daily assessment. METHOD: We developed a 15-item instrument to measure the likelihood of experiencing various outcomes from drinking, as well as the subjective evaluation of these outcomes. College students (N = 352; mean age = 19.7 years, SD = 1.26; 53.4% female) participated in a yearlong study wherein they completed three computerized interviews daily via mobile phones for 2 weeks in each academic quarter. Multilevel exploratory factor analysis was used to examine dimensionality at between-person and within-person levels, and generalizability coefficients were calculated to establish reliability. RESULTS: Intraclass correlation coefficients were generally between .30 and .40, demonstrating both between-person and within-person variability. Exploratory factor analysis resulted in a two-factor solution of positive and negative effects of alcohol, and two items with equivocal loadings were dropped from the final scale. The two subscales showed excellent reliabilities at within- and between- person levels, and the measure demonstrated good convergent and discriminant validity with a commonly used expectancy measure. CONCLUSIONS: Drinkers hold many expectations about the effects of alcohol, and measures are needed that are designed to capture both stable and context-dependent aspects of these beliefs. Results demonstrated significant day-to-day variation in the strength and valuation of alcohol expectancies, and the scale demonstrated good psychometric properties that establish its appropriateness for use in daily process studies of alcohol use. PMID- 25785809 TI - Development and validation of the East Africa Alcohol Expectancy Scale (AFEXS). AB - OBJECTIVE: The purpose of this study was to develop and validate the East Africa Alcohol Expectancy Scale (AFEXS), a measure of alcohol expectancies for use with HIV-positive adults in East Africa. METHOD: The study was conducted in several phases. The first involved development of the scale and an exploratory factor analysis (EFA) with a total of 209 HIV-positive, Ugandan men (n = 120) and women (n = 89). The second phase involved a confirmatory factor analysis (CFA) as well as validity analyses with a second, demographically similar, sample of 181 HIV positive Ugandan men (n = 109) and women (n = 72). All participants were recruited from two ongoing cohort studies taking place at an HIV clinic in rural southwestern Uganda. RESULTS: The EFA resulted in a 13-item, three-factor scale that explained 67% of the variance and showed excellent internal consistency (alpha = .89). The CFA showed good model fit with a final 11-item scale, chi(2)(41) = 68.60, p = .004; comparative fit index = .97; root mean square error of approximation = .06, 90% CI [.03, .09], that again showed excellent internal consistency and yielded the following three factors: sex-related (alpha = .94), release of inhibition (alpha = .61), and negative expectancies (alpha = .73). CONCLUSIONS: The AFEXS is the first psychometrically validated alcohol expectancy scale available for use in Africa. The extent to which the AFEXS can be used with other populations and with adults from countries outside of East Africa requires ongoing validation. PMID- 25785810 TI - Use of alcohol mixed with energy drinks and its consequences: a response to Patrick et al. (2014). PMID- 25785811 TI - Use of alcohol mixed with energy drinks and its consequences: the authors respond. PMID- 25785812 TI - Erratum to: A systematic review of risk and protective factors associated with nonmedical use of prescription drugs among youth in the United States: a social ecological perspective. PMID- 25785813 TI - Room temperature N-arylation of amino acids and peptides using copper(I) and beta diketone. AB - A mild and efficient method for the N-arylation of zwitterionic amino acids, amino acid esters and peptides is described. The procedure provides the first room temperature synthesis of N-arylated amino acids and peptides using CuI as a catalyst, diketone as a ligand, and aryl iodides as coupling partners. The method is equally applicable for using relatively inexpensive aryl bromides as coupling partners at 80 degrees C. Using this procedure, electronically and sterically diverse aryl halides, containing reactive functional groups were efficiently coupled in good to excellent yields. PMID- 25785814 TI - Modulating the self-assembly of amphiphilic X-shaped block copolymers with cyclodextrins: structure and mechanisms. AB - Inclusion complexes between cyclodextrins and polymers-so-called pseudopolyrotaxanes (PPR)-are at the origin of fascinating supramolecular structures, which are finding increasing uses in biomedical and technological fields. Here we explore the impact of both native and a range of modified cyclodextrins (CD) on the self-assembly of X-shaped poly(ethylene oxide) poly(propylene oxide) block copolymers, so-called Tetronics or poloxamines, by focusing on Tetronic 904 (T904, Mw 6700). The effects are markedly dependent on the type and arrangement of the substituents on the macrocycle. While native CDs drive the formation of a solid PPR, most substituted CDs induce micellar breakup, with dimethylated beta-CD (DIMEB) having the strongest impact and randomly substituted CDs a much weaker disruptive effect. Using native alpha-CD as a "molecular trap", we perform competitive binding experiments-where two types of CDs thread together onto the polymer chains-to establish that DIMEB indeed has the highest propensity to form an inclusion complex with the polymer, while hydroxypropylated CDs do not thread. 1D (1)H NMR and ROESY experiments confirm the formation of a soluble PPR with DIMEB in which the CD binds preferentially to the PO units, thus providing the drive for the observed demicellization. A combination of dynamic light scattering (DLS) and small-angle neutron scattering (SANS) is used to extract detailed structural parameters on the micelles. A binding model is proposed, which exploits the chemical shifts of selected protons from the CD in conjunction with the Hill equation, to prove that the formation of the PPR is a negatively cooperative process, in which threaded DIMEBs hamper the entrance of subsequent macrocycles. PMID- 25785815 TI - General nanomoulding with bulk metallic glasses. AB - Bulk metallic glasses (BMGs) are ideal for nanomoulding as they possess desirable strength for molds as well as for moldable materials and furthermore lack intrinsic size limitations. Despite their attractiveness, only recently Pt-based BMGs have been successfully molded into pores ranging 10-100 nm (Kumar et al 2009 Nature 457 868-72). Here, we introduce a quantitative theory, which reveals previous challenges in filling nanosized pores. This theory considers, in addition to a viscous and a capillary term, also oxidation, which becomes increasingly more important on smaller length scales. Based on this theory we construct a nanomoulding processing map for BMG, which reveals the limiting factors for BMG nanomoulding. Based on the quantitative prediction of the processing map, we introduce a strategy to reduce the capillary effect through a wetting layer, which allows us to mold non-noble BMGs below 1 MUm in air. An additional benefit of this strategy is that it drastically facilitates demoulding, one of the main challenges of nanomoulding in general. PMID- 25785816 TI - Entropy-based model for miRNA isoform analysis. AB - MiRNAs have been widely studied due to their important post-transcriptional regulatory roles in gene expression. Many reports have demonstrated the evidence of miRNA isoform products (isomiRs) in high-throughput small RNA sequencing data. However, the biological function involved in these molecules is still not well investigated. Here, we developed a Shannon entropy-based model to estimate isomiR expression profiles of high-throughput small RNA sequencing data extracted from miRBase webserver. By using the Kolmogorov-Smirnov statistical test (KS test), we demonstrated that the 5p and 3p miRNAs present more variants than the single arm miRNAs. We also found that the isomiR variant, except the 3' isomiR variant, is strongly correlated with Minimum Free Energy (MFE) of pre-miRNA, suggesting the intrinsic feature of pre-miRNA should be one of the important factors for the miRNA regulation. The functional enrichment analysis showed that the miRNAs with high variation, particularly the 5' end variation, are enriched in a set of critical functions, supporting these molecules should not be randomly produced. Our results provide a probabilistic framework for miRNA isoforms analysis, and give functional insights into pre-miRNA processing. PMID- 25785817 TI - Homoleptic borates and aluminates containing the difluorophosphato ligand - [M(O2PF2)x](y-) - synthesis and characterization. AB - Weakly coordinating anions (WCAs) with the difluorophosphato ligand (O2PF2) were the target of this study. Initial experiments were conducted towards the preparation of homoleptic aluminates of the well-studied [Al(OR)4](-)-type. The preparation of the initial target structure Li[Al(O2PF2)4] failed due to the remaining Lewis acidic character of the central aluminum atom. Instead, the formation of Li3[Al(O2PF2)6] and Al(O2PF2)3 was observed with hexacoordinate aluminum atoms and verified by NMR, IR and X-ray crystallography. A possible mechanism towards these compounds was postulated in the solvent induced dismutation of the tetracoordinate Li[Al(O2PF2)4]. A singly charged WCA was realized by the exchange of the central aluminum atom for boron. The [B(O2PF2)4]( ) anion was prepared starting from BH3.S(CH3)2 and boron tribromide leading to the protic room temperature Ionic Liquid (IL) [H(S(CH3)2)][B(O2PF2)4] and the neat liquid Bronsted acid H[B(O2PF2)4], respectively, representing a significantly improved synthesis with regard to the first experiments of Dove et al. The basicity of the [B(O2PF2)4](-) anion and its WCA quality were investigated on the basis of the IR-spectroscopic NH-scale and the salt [H(N(Oct)3)][B(O2PF2)4] that places it better than all oxyanions and close to the carboranate based WCAs. A pathway to the solvent free pure Li[B(O2PF2)4] salt was established on a multi-gram scale with excellent purities enabling electrochemical applications (verified by NMR, IR, X-ray crystallography and cyclovoltammetry). PMID- 25785818 TI - A Sudden and Concerning Increase in the Use of Electronic Brachytherapy for Skin Cancer. PMID- 25785819 TI - Giant magnetoresistance in zigzag MoS2 nanoribbons. AB - Using first principles calculations based on density functional theory, we investigated the transport properties of zigzag MoS2 nanoribbons with parallel and antiparallel spin configurations. The results show that the parallel configuration has conventional metallic properties while the antiparallel configuration presents semiconductor properties. Consequently, the conduction calculations predict that the zigzag MoS2 nanoribbons exhibit the giant magnetoresistance effect with a value over four orders of magnitude at room temperature by altering the configuration from the parallel to the antiparallel spin junction. By analyzing the spin-resolved band structures of zigzag MoS2 nanoribbons, we clarify that the orbital mismatching near the Fermi level between spin up and spin down is a key factor to generate this large magnetoresistance. Our results indicate that the giant magnetoresistance effect in the zigzag MoS2 nanoribbons remains robust to the change in the ribbon widths and lengths. PMID- 25785820 TI - Economic and health implications of routine CBCT examination before surgical removal of the mandibular third molar in the Danish population. AB - OBJECTIVES: This epidemiological study aimed to analyse economical and societal consequences in Denmark if CBCT is used routinely as a diagnostic method before removal of the mandibular third molar. Furthermore, the aim was to calculate the excess cancer incidence from this practice. METHODS: 17 representative dental clinics in the regions of Denmark were visited by two observers, who registered the total number of patients in each clinic, the number of removed mandibular third molars from patients' files together with the age and gender of these patients. The data were collected from 2008 to 2014. The total number of removed mandibular third molars in Denmark each year was derived from the collected data and information on patients' contacts with dentists from Statistics Denmark as a sum of contributions from each region. The contribution of a region was obtained as the number of removed mandibular third molars in the selected clinics in the region times the ratio of the number of patients in the selected clinics in the region to the total number of patients with contact to a general practitioner in the region in 2011. Existing knowledge on the costs for panoramic and CBCT imaging was used to calculate total costs. The cancer incidence was calculated from lifetime attributable risk curves based on linear risk assumptions. RESULTS: The selected clinics included 109,686 patients, and 1369 mandibular third molars had been surgically removed. Using data from Statistics Denmark gave an estimated annual number of removed mandibular third molars of 36,882 at a total cost of ?6,633,400. The additional cancer incidence was estimated to be approximately 0.46 per year. CONCLUSIONS: The data should be used in a cost-effectiveness analysis of the clinical efficacy of CBCT imaging before removal of mandibular third molars. PMID- 25785821 TI - 3-T MRI safety assessments of magnetic dental attachments and castable magnetic alloys. AB - OBJECTIVES: To assess the safety of different magnetic dental attachments during 3-T MRI according to the American Society for Testing and Materials F2182-09 and F2052-06e1 standard testing methods and to develop a method to determine MRI compatibility by measuring magnetically induced torque. METHODS: The temperature elevations, magnetically induced forces and torques of a ferromagnetic stainless steel keeper, a coping comprising a keeper and a cast magnetic alloy coping were measured on MRI systems. RESULTS: The coping comprising a keeper demonstrated the maximum temperature increase (1.42 degrees C) for the whole-body-averaged specific absorption rate and was calculated as 2.1 W kg-1 with the saline phantom. All deflection angles exceeded 45 degrees . The cast magnetic alloy coping had the greatest deflection force (0.33 N) during 3-T MRI and torque (1.015 mN m) during 0.3-T MRI. CONCLUSIONS: The tested devices showed minimal radiofrequency (RF)-induced heating in a 3-T MR environment, but the cast magnetic alloy coping showed a magnetically induced deflection force and torque approximately eight times that of the keepers. For safety, magnetic dental attachments should be inspected before and after MRI and large prostheses containing cast magnetic alloy should be removed. Although magnetic dental attachments may pose no great risk of RF-induced heating or magnetically induced torque during 3-T MRI, their magnetically induced deflection forces tended to exceed acceptable limits. Therefore, the inspection of such devices before and after MRI is important for patient safety. PMID- 25785822 TI - Measuring absorbed dose for i-CAT CBCT examinations in child, adolescent and adult phantoms. AB - OBJECTIVES: Design and construct child and adolescent head phantoms to measure the absorbed doses imparted during dental CBCT and compare with the absorbed dose measured in an adult phantom. METHODS: A child phantom was developed to represent the smallest patients receiving CBCT, usually for craniofacial developmental concerns, and an adolescent phantom was developed to represent healthy orthodontic patients. Absorbed doses were measured using a thimble ionization chamber for the custom-built child and adolescent phantoms and compared with measurements using a commercially available adult phantom. Imaging was performed with an i-CAT Next Generation (Imaging Sciences International, Hatfield, PA) CBCT using two different fields of view covering the craniofacial complex (130 mm high) or maxilla/mandible (60 mm high). RESULTS: Measured absorbed doses varied depending on the location of the ionization chamber within the phantoms. For CBCT images obtained using the same protocol for all phantoms, the highest absorbed dose was measured in all locations of the small child phantom. The lowest absorbed dose was measured in the adult phantom. CONCLUSIONS: Images were obtained with the same protocol for the adult, adolescent and child phantoms. A consistent trend was observed with the highest absorbed dose being measured in the smallest phantom (child), while the lowest absorbed dose was measured in the largest phantom (adult). This study demonstrates the importance of child-sizing the dose by using dedicated paediatric protocols optimized for the imaging task, which is critical as children are more sensitive to harmful effects of radiation and have a longer life-span post-irradiation for radiation-induced symptoms to develop than do adults. PMID- 25785823 TI - Reply to the Comment on "Decomposition mechanisms of trinitroalkyl compounds: a theoretical study from aliphatic to aromatic nitro compounds" by G. Fayet, P. Rotureau, B. Minisini, Phys. Chem. Chem. Phys., 2014, 16, 6614. PMID- 25785825 TI - Palladium-catalyzed amination of 2,3,3-trifluoroallyl esters: synthesis of trifluoromethylenamines via an intramolecular fluorine shift and CF3 group construction. AB - The palladium-catalyzed reaction of 2,3,3-trifluoroallyl esters with several types of amines afforded trifluoromethylenamines, which were formed by the addition of a nitrogen nucleophile at the C-2 position and the intramolecular construction of the trifluoromethyl group via the fluorine atom shift from the C 2 to the C-3 position. PMID- 25785826 TI - Television viewing, walking speed, and grip strength in a prospective cohort study. AB - PURPOSE: Television (TV) watching is the most prevalent sedentary leisure time activity in the United Kingdom. We examined associations between TV viewing time, measured over 10 yr, and two objective measures of physical capability, usual walking speed (UWS) and grip strength. METHODS: Community-based participants (n = 8623; 48-92 yr old) enrolled in the European Prospective Investigation of Cancer Norfolk study attended a third health examination (3HC, 2006-2011) for measurement of maximum grip strength (Smedley dynamometer) and UWS. TV viewing time was estimated using a validated questionnaire (n = 6086) administered during two periods (3HC, 2006-2007; 2HC, 1998-2000). Associations between physical capability and TV viewing time category (<2, 2 < 3, 3 < 4, and >=4 h.d) at the 3HC, 2HC, and using an average of the two measures were explored. Sex-stratified analyses were adjusted for age, physical activity, anthropometry, wealth, comorbidity, smoking, and alcohol intake and combined if no sex-TV viewing time interactions were identified. RESULTS: Men and women who watched the least TV at the 2HC or 3HC walked at a faster usual pace than those who watched the most TV. There was no evidence of effect modification by sex (Pinteraction = 0.09), and in combined analyses, participants who watched for <2 h.d on average walked 4.29 cm.s (95% confidence interval, 2.56-6.03) faster than those who watched for >=4 h.d, with evidence of a dose-response association (Ptrend < 0.001). However, no strong associations with grip strength were found. CONCLUSIONS: TV viewing time predicted UWS in older adults. More research is needed to inform public health policy and prospective associations between other measures of sedentariness, such as total sitting time or objectively measured sedentary time, and physical capability should be explored. PMID- 25785827 TI - Green tea polyphenol (-)-epigallocatechin-3-gallate restores Nrf2 activity and ameliorates crescentic glomerulonephritis. AB - Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3 weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p JNK, p-ERK1/2 and p-P38 as well as restoration of PPARgamma and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress. PMID- 25785828 TI - Rapid adaptation of rat brain and liver metabolism to a ketogenic diet: an integrated study using (1)H- and (13)C-NMR spectroscopy. AB - The ketogenic diet (KD) is an effective alternative treatment for refractory epilepsy in children, but the mechanisms by which it reduces seizures are poorly understood. To investigate how the KD modifies brain metabolism, we infused control (CT) and 7-day KD rats with either [1-(13)C]glucose (Glc) or [2,4 (13)C2]beta-hydroxybutyrate (beta-HB). Specific enrichments of amino acids (AAs) measured by (1)H- and (13)C-NMR in total brain perchloric acid extracts were similar between CT and KD rats after [1-(13)C]Glc infusion whereas they were higher in KD rats after [2,4-(13)C2]beta-HB infusion. This suggests better metabolic efficiency of ketone body utilization on the KD. The relative rapid metabolic adaptation to the KD included (1) 11%-higher brain gamma-amino butyric acid (GABA)/glutamate (Glu) ratio versus CT, (2) liver accumulation of the ketogenic branched-chain AAs (BCAAs) leucine (Leu) and isoleucine (ILeu), which were never detected in CT, and (3) higher brain Leu and ILeu contents. Since Glu and GABA are excitatory and inhibitory neurotransmitters, respectively, higher brain GABA/Glu ratio could contribute to the mechanism by which the KD reduces seizures in epilepsy. Increased BCAA on the KD may also contribute to better seizure control. PMID- 25785829 TI - Perfusion single photon emission computed tomography in a mouse model of neurofibromatosis type 1: towards a biomarker of neurologic deficits. AB - Neurofibromatosis type 1 (NF1) is a single-gene disorder affecting neurologic function in humans. The NF1+/- mouse model with germline mutation of the NF1 gene presents with deficits in learning, attention, and motor coordination, very similar to NF1 patients. The present study performed brain perfusion single photon emission computed tomography (SPECT) in NF1+/- mice to identify possible perfusion differences as surrogate marker for altered cerebral activity in NF1. Cerebral perfusion was measured with hexamethyl-propyleneamine oxime (HMPAO) SPECT in NF1+/- mice and their wild-type littermates longitudinally at juvenile age and at young adulthood. Histology and immunohistochemistry were performed to test for structural changes. There was increased HMPAO uptake in NF1 mice in the amygdala at juvenile age, which reduced to normal levels at young adulthood. There was no genotype effect on thalamic HMPAO uptake, which was confirmed by ex vivo measurements of F-18-fluorodeoxyglucose uptake in the thalamus. Morphologic analyses showed no major structural abnormalities. However, there was some evidence of increased density of microglial somata in the amygdala of NF1 deficient mice. In conclusion, there is evidence of increased perfusion and increased density of microglia in juvenile NF1 mice specifically in the amygdala, both of which might be associated with altered synaptic plasticity and, therefore, with cognitive deficits in NF1. PMID- 25785830 TI - Metabolic connectivity as index of verbal working memory. AB - Positron emission tomography (PET) data are commonly analyzed in terms of regional intensity, while covariant information is not taken into account. Here, we searched for network correlates of healthy cognitive function in resting state PET data. PET with [(18)F]-fluorodeoxyglucose and a test of verbal working memory (WM) were administered to 35 young healthy adults. Metabolic connectivity was modeled at a group level using sparse inverse covariance estimation. Among 13 WM relevant Brodmann areas (BAs), 6 appeared to be robustly connected. Connectivity within this network was significantly stronger in subjects with above-median WM performance. In respect to regional intensity, i.e., metabolism, no difference between groups was found. The results encourage examination of covariant patterns in FDG-PET data from non-neurodegenerative populations. PMID- 25785831 TI - Comparison of velocity- and acceleration-selective arterial spin labeling with [15O]H2O positron emission tomography. AB - In the last decade spatially nonselective arterial spin labeling (SNS-ASL) methods such as velocity-selective ASL (VS-ASL) and acceleration-selective ASL have been introduced, which label spins based on their flow velocity or acceleration rather than spatial localization. Since labeling also occurs within the imaging plane, these methods suffer less from transit delay effects than traditional ASL methods. However, there is a need for validation of these techniques. In this study, a comparison was made between these SNS-ASL techniques with [(15)O]H2O positron emission tomography (PET), which is regarded as gold standard to measure quantitatively cerebral blood flow (CBF) in humans. In addition, the question of whether these techniques suffered from sensitivity to arterial cerebral blood volume (aCBV), as opposed to producing pure CBF contrast, was investigated. The results show high voxelwise intracranial correlation (0.72 to 0.89) between the spatial distribution of the perfusion signal from the SNS ASL methods and the PET CBF maps. A similar gray matter (GM) CBF was measured by dual VS-ASL compared with PET (46.7 +/- 4.1 versus 47.1 +/- 6.5 mL/100 g/min, respectively). Finally, only minor contribution of aCBV patterns in GM to all SNS ASL methods was found compared with pseudo-continuous ASL. In conclusion, VS-ASL provides a similar quantitative CBF, and all SNS-ASL methods provide qualitatively similar CBF maps as [(15)O]H2O PET. PMID- 25785832 TI - Time-resolved FT-IR microspectroscopy of protein aggregation induced by heat shock in live cells. AB - Maintaining the correct folding of cellular proteins is essential for preserving cellular homeostasis. Protein dishomeostasis, aberrant protein folding, and protein aggregation are indeed involved in several diseases including cancer, aging-associated, and neurodegenerative disorders. Accumulation of protein aggregates can also be induced from a variety of stressful conditions, such as temperature increase or oxidative stress. In this work, we monitored by Fourier transform-infrared (FT-IR) microspectroscopy the response of live breast cancer MCF-7 and mammary breast adenocarcinoma MDA-MB 231 cell lines to severe heat shock (HS), caused by the rise of the cellular medium temperature from 37 +/- 0.5 degrees C to 42 +/- 0.5 degrees C. Through the study of the time-evolution of the second derivatives of the spectra and by the 2D correlation analysis of FT-IR absorbance data, we were able to identify a common sudden heat-shock response (HSR) among the two cell lines. The hyperfluidization of mammalian cell membranes, the transient increment of the signal lipids, as well as the alteration of proteome profile were all monitored within the first 40 min of stress application, while the persistent intracellular accumulation of extended beta-folded protein aggregates was detected after 40 min up to 2 h. As a whole, this paper offers a further prove of the diagnostic capabilities of FT-IR microspectroscopy for monitoring in real-time the biochemical rearrangements undergone by live cells upon external stimulation. PMID- 25785833 TI - Knockdown of CDK2AP1 in primary human fibroblasts induces p53 dependent senescence. AB - Cyclin Dependent Kinase-2 Associated Protein-1 (CDK2AP1) is known to be a tumor suppressor that plays a role in cell cycle regulation by sequestering monomeric CDK2, and targeting it for proteolysis. A reduction of CDK2AP1 expression is considered to be a negative prognostic indicator in patients with oral squamous cell carcinoma and also associated with increased invasion in human gastric cancer tissue. CDK2AP1 overexpression was shown to inhibit growth, reduce invasion and increase apoptosis in prostate cancer cell lines. In this study, we investigated the effect of CDK2AP1 downregulation in primary human dermal fibroblasts. Using a short-hairpin RNA to reduce its expression, we found that knockdown of CDK2AP1 in primary human fibroblasts resulted in reduced proliferation and in the induction of senescence associated beta-galactosidase activity. CDK2AP1 knockdown also resulted in a significant reduction in the percentage of cells in the S phase and an accumulation of cells in the G1 phase of the cell cycle. Immunocytochemical analysis also revealed that the CDK2AP1 knockdown significantly increased the percentage of cells that exhibited gamma H2AX foci, which could indicate presence of DNA damage. CDK2AP1 knockdown also resulted in increased mRNA levels of p53, p21, BAX and PUMA and p53 protein levels. In primary human fibroblasts in which p53 and CDK2AP1 were simultaneously downregulated, there was: (a) no increase in senescence associated beta galactosidase activity, (b) decrease in the number of cells in the G1-phase and increase in number of cells in the S-phase of the cell cycle, and (c) decrease in the mRNA levels of p21, BAX and PUMA when compared with CDK2AP1 knockdown only fibroblasts. Taken together, this suggests that the observed phenotype is p53 dependent. We also observed a prominent increase in the levels of ARF protein in the CDK2AP1 knockdown cells, which suggests a possible role of ARF in p53 stabilization following CDK2AP1 knockdown. Altogether, our results show that knockdown of CDK2AP1 in primary human fibroblasts reduced proliferation and induced premature senescence, with the observed phenotype being p53 dependent. PMID- 25785834 TI - Posture affects how robots and infants map words to objects. AB - For infants, the first problem in learning a word is to map the word to its referent; a second problem is to remember that mapping when the word and/or referent are again encountered. Recent infant studies suggest that spatial location plays a key role in how infants solve both problems. Here we provide a new theoretical model and new empirical evidence on how the body - and its momentary posture - may be central to these processes. The present study uses a name-object mapping task in which names are either encountered in the absence of their target (experiments 1-3, 6 & 7), or when their target is present but in a location previously associated with a foil (experiments 4, 5, 8 & 9). A humanoid robot model (experiments 1-5) is used to instantiate and test the hypothesis that body-centric spatial location, and thus the bodies' momentary posture, is used to centrally bind the multimodal features of heard names and visual objects. The robot model is shown to replicate existing infant data and then to generate novel predictions, which are tested in new infant studies (experiments 6-9). Despite spatial location being task-irrelevant in this second set of experiments, infants use body-centric spatial contingency over temporal contingency to map the name to object. Both infants and the robot remember the name-object mapping even in new spatial locations. However, the robot model shows how this memory can emerge -not from separating bodily information from the word-object mapping as proposed in previous models of the role of space in word-object mapping - but through the body's momentary disposition in space. PMID- 25785835 TI - Mutations in PRPS1 causing syndromic or nonsyndromic hearing impairment: intrafamilial phenotypic variation complicates genetic counseling. AB - BACKGROUND: PRPS1 encodes isoform I of phosphoribosylpyrophosphate synthetase (PRS-I), a key enzyme in nucleotide biosynthesis. Different missense mutations in PRPS1 cause a variety of disorders that include PRS-I superactivity, nonsyndromic sensorineural hearing impairment, Charcot-Marie-Tooth disease, and Arts syndrome. It has been proposed that each mutation would result in a specific phenotype, depending on its effects on the structure and function of the enzyme. METHODS: Thirteen Spanish unrelated families segregating X-linked hearing impairment were screened for PRPS1 mutations by Sanger sequencing. In two positive pedigrees, segregation of mutations was studied, and clinical data from affected subjects were compared. RESULTS: We report two novel missense mutations in PRPS1, p.Ile275Thr and p.Gly306Glu, which were found in the propositi of two unrelated Spanish families, both subjects presenting with nonsyndromic hearing impairment. Further investigation revealed syndromic features in other hemizygous carriers from one of the pedigrees. Sequencing of genes that are functionally related to PRPS1 did not reveal any candidate variant that might act as a phenotype modifier. CONCLUSION: This case of intrafamilial phenotypic variation associated with a single PRPS1 mutation complicates the genotype-phenotype correlations, which makes genetic counseling of mutation carriers difficult because of the wide spectrum of severity of the associated disorders. PMID- 25785836 TI - Identification of metE as a second target of the sRNA scr5239 in Streptomyces coelicolor. AB - While transcriptional regulation of the primary and secondary metabolism of the model organism Streptomyces coelicolor is well studied, little is still known about the role small noncoding RNAs (sRNAs) play in regulating gene expression in this organism. Here, we report the identification of a second target of the sRNA scr5239, an sRNA highly conserved in streptomycetes. The 159 nt long sRNA binds its target, the mRNA of the cobalamin independent methionine synthase metE (SCO0985), at the 5' end of its open reading frame thereby repressing translation. We show that a high methionine level induces expression of scr5239 itself. This leads, in a negative feedback loop, to the repression of methionine biosynthesis. In contrast to the first reported target of this sRNA, the agarase dagA, this interaction seems to be conserved in a wide number of streptomycetes. PMID- 25785837 TI - Investigation of the saturation pulse artifact in non-enhanced MR angiography of the lower extremity arteries at 7 Tesla. AB - When performing non-enhanced time-of-flight MR angiography of the lower extremity arteries at 7 T with cardiac triggering, the acquisition time is a crucial consideration. Therefore, in previous studies, saturation RF pulses were applied only every second TR. In the axial source images a slight artifact with an appearance similar to aliasing could be observed. The purpose of this study was to investigate the origin of this artifact. The reason for the artifact is supposed to be related to the two effective TRs during acquisition caused by the sparsely applied saturation RF pulse. Several sequence variants were simulated and implemented within the sequence source code to examine this hypothesis. An adaptation of the excitation flip angles for each TR as well as a correction factor for the k-space data was calculated. Additionally, a different ordering of the k-space data during acquisition was implemented as well as the combination of the latter with the k-space correction factor. The observations from the simulations were verified using both a static and a flow phantom and, finally, in a healthy volunteer using the same measurement setup as in previous volunteer and patient studies. Of all implemented techniques, only the reordering of the k space was capable of suppressing the artifact almost completely at the cost of creating a ringing artifact. The phantom measurements showed the same results as the simulations and could thus confirm the hypothesis regarding the origin of the artifact. This was additionally verified in the healthy volunteer. The origin of the artifact could be confirmed to be the periodic signal variation caused by two effective TRs during acquisition. PMID- 25785840 TI - Radiofrequency ablation near the bone-muscle interface alters soft tissue lesion dimensions. AB - BACKGROUND AND OBJECTIVES: Radiofrequency (RF) lesions are safe and effective in the treatment of spine pain; however, models developed to study factors affecting lesion dimensions have been performed in homogeneous media that may not accurately simulate human anatomy and electrophysiology. We present a novel ex vivo porcine model for performing RF lesion studies and report the influence of bone on projection of RF ablation lesions into soft tissue. METHODS: Radiofrequency lesions were performed in porcine rib specimens using monopolar 18 gauge, 10-mm straight active tip cannula, with a lesion temperature of 80 degrees C for 150 seconds. Ten lesions were performed in pure porcine muscle tissue and abutting porcine rib bone with surrounding muscle. Lesions were exposed with dissection and measured with digital calipers. RESULTS: Maximal effective lesion radius approximately doubled against the bone compared with the pure muscle group (mean, 5.65 mm [95% CI, 5.43-5.87 mm] vs 2.68 mm [95% CI, 2.55-2.81 mm], P < .0001), although this was seen only in a vertical direction and not horizontally. In addition, the prelesion and postlesion impedance of the bone-muscle interface was consistently higher than the muscle-only interface (mean, 165.6 Ohm [95% CI, 146.6-184.6 Ohm] vs 137.8 Ohm [95% CI, 135.5-140.1 Ohm], P = 0.004; 144.3 Ohm [95% CI, 134.3-154.3 Ohm] vs 124.3 Ohm [95% CI, 119.3-129.3 Ohm], P = 0.001). Other dimensions and estimated volume were not significantly different. CONCLUSIONS: Bone adjacent to RF lesions alters the surrounding electrophysiological environment causing RF lesions to project further perpendicularly from the needle axis, vertically to bone, than previously expected. This phenomenon should be considered in the future modeling and clinical practice of RF. PMID- 25785839 TI - Human malignant melanoma-derived progestagen-associated endometrial protein immunosuppresses T lymphocytes in vitro. AB - Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow's 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-gamma secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment. PMID- 25785838 TI - Stromal cells positively and negatively modulate the growth of cancer cells: stimulation via the PGE2-TNFalpha-IL-6 pathway and inhibition via secreted GAPDH E-cadherin interaction. AB - Fibroblast-like stromal cells modulate cancer cells through secreted factors and adhesion, but those factors are not fully understood. Here, we have identified critical stromal factors that modulate cancer growth positively and negatively. Using a cell co-culture system, we found that gastric stromal cells secreted IL-6 as a growth and survival factor for gastric cancer cells. Moreover, gastric cancer cells secreted PGE2 and TNFalpha that stimulated IL-6 secretion by the stromal cells. Furthermore, we found that stromal cells secreted glyceraldehyde 3 phosphate dehydrogenase (GAPDH). Extracellular GAPDH, or its N-terminal domain, inhibited gastric cancer cell growth, a finding confirmed in other cell systems. GAPDH bound to E-cadherin and downregulated the mTOR-p70S6 kinase pathway. These results demonstrate that stromal cells could regulate cancer cell growth through the balance of these secreted factors. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy. PMID- 25785841 TI - The Requisites of Needle-to-Nerve Proximity for Ultrasound-Guided Regional Anesthesia: A Scoping Review of the Evidence. AB - This scoping review examines the literature to determine whether the position of the needle tip relative to the target nerve is accurately and reliably detected during ultrasound (US)-guided regional anesthesia. The requisites for successful and safe needle tip positioning relative to the target nerve include accurate and reliable needle presentation by the machine, needle interpretation by the operator, nerve presentation by the machine, and nerve interpretation by the operator. Failure to visualize the needle tip is a common occurrence, frequently prompting operators to use needle and probe maneuvers, which are not necessarily based on evidence. Needle tip interpretation often relies on surrogate indicators that have not been validated. The acoustic resolution of modern portable US machines limits the extent to which nerve microanatomy can be reliably presented. Finally, our interpretation of the sonographic end points for local anesthetic injection that best balance success and safety for US-guided regional anesthesia continues to evolve. WHAT'S NEW: In order to determine whether or not the position of the needle tip relative to the target nerve is accurately and reliably detected during US-guided regional anesthesia, the available literature is reviewed and interpreted to address the following 4 questions. PMID- 25785843 TI - Optoelectronic Studies of Methylammonium Lead Iodide Perovskite Solar Cells with Mesoporous TiO2: Separation of Electronic and Chemical Charge Storage, Understanding Two Recombination Lifetimes, and the Evolution of Band Offsets during J-V Hysteresis. AB - Methylammonium lead iodide (MAPI) cells of the design FTO/sTiO2/mpTiO2/MAPI/Spiro OMeTAD/Au, where FTO is fluorine-doped tin oxide, sTiO2 indicates solid-TiO2, and mpTiO2 is mesoporous TiO2, are studied using transient photovoltage (TPV), differential capacitance, charge extraction, current interrupt, and chronophotoamperometry. We show that in mpTiO2/MAPI cells there are two kinds of extractable charge stored under operation: a capacitive electronic charge (~0.2 MUC/cm(2)) and another, larger charge (40 MUC/cm(2)), possibly related to mobile ions. Transient photovoltage decays are strongly double exponential with two time constants that differ by a factor of ~5, independent of bias light intensity. The fast decay (~1 MUs at 1 sun) is assigned to the predominant charge recombination pathway in the cell. We examine and reject the possibility that the fast decay is due to ferroelectric relaxation or to the bulk photovoltaic effect. Like many MAPI solar cells, the studied cells show significant J-V hysteresis. Capacitance vs open circuit voltage (V(oc)) data indicate that the hysteresis involves a change in internal potential gradients, likely a shift in band offset at the TiO2/MAPI interface. The TPV results show that the V(oc) hysteresis is not due to a change in recombination rate constant. Calculation of recombination flux at V(oc) suggests that the hysteresis is also not due to an increase in charge separation efficiency and that charge generation is not a function of applied bias. We also show that the J-V hysteresis is not a light driven effect but is caused by exposure to electrical bias, light or dark. PMID- 25785842 TI - Comparison of perioperative outcomes for epidural versus intravenous patient controlled analgesia after radical cystectomy. AB - BACKGROUND AND OBJECTIVES: The use of patient-controlled epidural analgesia after various operations has been associated with an early return of bowel function, thus decreasing patients' length of stay (LOS). The primary aim of this study was to compare LOS after radical cystectomy between patients who received epidural analgesia versus those who received intravenous patient-controlled analgesia. Our secondary analysis included the assessment of other metrics such as total opioid requirements, pain scores, return of bowel function, and complication rates between the 2 groups. METHODS: We conducted a retrospective review using the electronic medical records of 308 patients who underwent radical cystectomies at Memorial Sloan Kettering between 2006 and 2011. We aimed to understand if epidural analgesia was associated with a reduced LOS compared with patient controlled intravenous opioid analgesia. We also aimed to identify performance improvements as a function of epidural analgesia status using various metrics such as pain management, bowel function return, and complication rates. We used both univariate and multivariate analyses to identify if epidural analgesia was associated with meaningful differences in the aforementioned metrics. RESULTS: Median age at radical cystectomy, body mass index, sex, American Society of Anesthesiologists score, and T stage were similar for both groups. For our primary objective of LOS, we found no significant difference between the 2 cohorts (8 vs 7 days, P = 0.2). Analysis of our secondary outcome measures revealed that epidural analgesia use was associated with less total opioid requirement for the first 3 postoperative days (PODs) (P = 0.0001). In addition, epidural analgesia was found to be associated with improved postoperative pain scores compared with intravenous patient-controlled analgesia on PODs 1 (P = 0.0001) and 2 (P = 0.004), and there was a slight improvement on POD 3, but this was not significant (P = 0.77). In contrast, we found no difference between pain management types with regard to proportion of patients who experienced a delay in gastrointestinal recovery, fluid bolus requirements within the first 3 perioperative days, rates of infection, pulmonary complications, and grade 3 or greater complications. CONCLUSIONS: We have demonstrated that, despite significant improvements in initial pain control and less opioid requirement with patient-controlled epidural analgesia, there was no association between analgesic approach and LOS, return of bowel function, or complications. PMID- 25785844 TI - What can the brain teach us about winemaking? An fMRI study of alcohol level preferences. AB - Over the last few decades, wine makers have been producing wines with a higher alcohol content, assuming that they are more appreciated by consumers. To test this hypothesis, we used functional magnetic imaging to compare reactions of human subjects to different types of wine, focusing on brain regions critical for flavor processing and food reward. Participants were presented with carefully matched pairs of high- and low-alcohol content red wines, without informing them of any of the wine attributes. Contrary to expectation, significantly greater activation was found for low-alcohol than for high-alcohol content wines in brain regions that are sensitive to taste intensity, including the insula as well as the cerebellum. Wines were closely matched for all physical attributes except for alcohol content, thus we interpret the preferential response to the low-alcohol content wines as arising from top-down modulation due to the low alcohol content wines inducing greater attentional exploration of aromas and flavours. The findings raise intriguing possibilities for objectively testing hypotheses regarding methods of producing a highly complex product such as wine. PMID- 25785845 TI - Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. AB - PURPOSE: Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. METHODS: Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an 90Y- or 177Lu labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. RESULTS: The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. CONCLUSION: 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models. PMID- 25785846 TI - Thermally induced osteocyte damage initiates a remodelling signaling cascade. AB - Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47 degrees C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47 degrees C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis followed by a cascade of remodelling responses. PMID- 25785847 TI - In vivo investigations of the effect of short- and long-term recombinant growth hormone treatment on DNA-methylation in humans. AB - Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p<0.0001, unadjusted paired t-test), which nevertheless did not retain significance after adjustment for multiple testing. An individualized evaluation strategy led to the identification of 2350 CpG and 3 CpH sites showing methylation differences of at least 10% in more than 2 of the 24 analyzed sample pairs. To investigate the long term effects of rhGH treatment on the DNA-methylome, we analyzed peripheral blood cells from an independent cohort of 36 rhGH treated children born small for gestational age (SGA) as compared to 18 untreated controls. Median treatment interval was 33 months. In line with the groupwise comparison in the short-term treated cohort no differentially methylated targets reached the level of significance in the long-term treated cohort. We identified marked intra individual responses of DNA-methylation to short-term rhGH treatment. These responses seem to be predominately associated with immunologic functions and show considerable inter-individual heterogeneity. The latter is likely the cause for the lack of a rhGH induced homogeneous DNA-methylation signature after short- and long-term treatment, which nevertheless is well in line with generally assumed safety of rhGH treatment. PMID- 25785848 TI - Changes in spatial patterns of Caragana stenophylla along a climatic drought gradient on the Inner Mongolian Plateau. AB - Few studies have investigated the influence of water availability on plant population spatial patterns. We studied changes in the spatial patterns of Caragana stenophylla along a climatic drought gradient within the Inner Mongolian Plateau, China. We examined spatial patterns, seed density, "nurse effects" of shrubs on seedlings, transpiration rates and water use efficiency (WUE) of C. stenophylla across semi-arid, arid, and intensively arid zones. Our results showed that patches of C. stenophylla populations shifted from a random to a clumped spatial pattern towards drier environments. Seed density and seedling survival rate of C. stenophylla decreased from the semi-arid zone to the intensively arid zone. Across the three zones, there were more C. stenophylla seeds and seedlings underneath shrub canopies than outside shrub canopies; and in the intensively arid zone, there were almost no seeds or seedlings outside shrub canopies. Transpiration rates of outer-canopy leaves and WUE of both outer-canopy and inner-canopy leaves increased from the semi-arid zone to the intensively arid zone. In the intensively arid zone, transpiration rates and WUE of inner-canopy leaves were significantly lower and higher, respectively, than those of outer canopy leaves. We conclude that, as drought stress increased, seed density decreased, seed proportions inside shrubs increased, and "nurse effects" of shrubs on seedlings became more important. These factors, combined with water saving characteristics associated with clumped spatial patterns, are likely driving the changes in C. stenophylla spatial patterns. PMID- 25785849 TI - Impacts of surface water diversions for marijuana cultivation on aquatic habitat in four northwestern California watersheds. AB - Marijuana (Cannabis sativa L.) cultivation has proliferated in northwestern California since at least the mid-1990s. The environmental impacts associated with marijuana cultivation appear substantial, yet have been difficult to quantify, in part because cultivation is clandestine and often occurs on private property. To evaluate the impacts of water diversions at a watershed scale, we interpreted high-resolution aerial imagery to estimate the number of marijuana plants being cultivated in four watersheds in northwestern California, USA. Low altitude aircraft flights and search warrants executed with law enforcement at cultivation sites in the region helped to validate assumptions used in aerial imagery interpretation. We estimated the water demand of marijuana irrigation and the potential effects water diversions could have on stream flow in the study watersheds. Our results indicate that water demand for marijuana cultivation has the potential to divert substantial portions of streamflow in the study watersheds, with an estimated flow reduction of up to 23% of the annual seven-day low flow in the least impacted of the study watersheds. Estimates from the other study watersheds indicate that water demand for marijuana cultivation exceeds streamflow during the low-flow period. In the most impacted study watersheds, diminished streamflow is likely to have lethal or sub-lethal effects on state- and federally-listed salmon and steelhead trout and to cause further decline of sensitive amphibian species. PMID- 25785850 TI - Correction: Biased transmission of sex chromosomes in the aphid Myzus persicae is not associated with reproductive mode. PMID- 25785852 TI - Syntheses of tricyanofluoroborates M[BF(CN)3] (M = Na, K): (CH3)3SiCl catalysis, countercation effect, and reaction intermediates. AB - Potassium tricyanofluoroborate, K[BF(CN)3], which is the starting material for tricyanofluoroborate room-temperature ionic liquids [N. Ignat'ev et al. J. Fluorine Chem., submitted] was obtained on a molar scale (140 g) from Na[BF4] and (CH3)3SiCN with a purity of up to 99.9%. The initial product of the reaction that was catalyzed by (CH3)3SiCl was Na[BF(CN)3].(CH3)3SiCN that was characterized by multinuclear NMR and vibrational spectroscopy, elemental analysis, differential scanning calorimetry, and single-crystal X-ray diffraction. Na[BF(CN)3].(CH3)3SiCN was converted to K[BF(CN)3] via a simple extraction protocol. The catalytic effect of (CH3)3SiCl was evaluated and some intermediates of the reaction, including the isocyanoborate anion [BF(NC)(CN)2](-), were identified using multinuclear NMR and vibrational spectroscopy. K[BF2(CN)2] also reacted with (CH3)3SiCN in the presence of (CH3)3SiCl, to result in K[BF(CN)3]. The interpretation of the experimental observations was supported by data derived from density functional theory (DFT) calculations. In addition, the influence of selected countercations of the tetrafluoroborate anion on the progress of the (CH3)3SiCl-catalyzed reaction was studied. The fastest reaction was observed for Na[BF4], while the conversion of [BF4](-) to [BF(CN)3](-) was slower with the countercation K(+). Li[BF4] and [Et4N][BF4] were converted under the reaction conditions applied to Li[BF2(CN)2] and [Et4N][BF2(CN)2] only. PMID- 25785851 TI - Granulin knock out zebrafish lack frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis pathology. AB - Loss of function mutations in granulin (GRN) are linked to two distinct neurological disorders, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). It is so far unknown how a complete loss of GRN in NCL and partial loss of GRN in FTLD can result in such distinct diseases. In zebrafish, there are two GRN homologues, Granulin A (Grna) and Granulin B (Grnb). We have generated stable Grna and Grnb loss of function zebrafish mutants by zinc finger nuclease mediated genome editing. Surprisingly, the grna and grnb single and double mutants display neither spinal motor neuron axonopathies nor a reduced number of myogenic progenitor cells as previously reported for Grna and Grnb knock down embryos. Additionally, grna-/-;grnb-/- double mutants have no obvious FTLD- and NCL-related biochemical and neuropathological phenotypes. Taken together, the Grna and Grnb single and double knock out zebrafish lack any obvious morphological, pathological and biochemical phenotypes. Loss of zebrafish Grna and Grnb might therefore either be fully compensated or only become symptomatic upon additional challenge. PMID- 25785853 TI - Correction: Multiple hits for the association of uterine fibroids on human chromosome 1q43. PMID- 25785855 TI - Comparison of current diagnostic criteria for acute-on-chronic liver failure. AB - BACKGROUND AND AIMS: Currently, acute-on-chronic liver failure (ACLF) has been defined differently by Asia-Pacific Association for the Study of the Liver (APASL) and Chinese Medical Association (CMA) in the East, as well as EASL Chronic Liver Failure (EASL-CLIF) Consortium in the West. This study aimed to compare current different diagnostic criteria for ACLF and to determine predictors of the progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium. METHODS: We retrospectively analyzed clinical data from 394 eligible cirrhotic patients fulfilling at least APASL criteria for ACLF at enrollment. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank test. Independent predictors of disease progression were determined using univariate analysis and multivariate Cox regression analysis. RESULTS: The 90-day mortality rate was 13.1% in patients with ACLF at enrollment defined by APASL alone, 25.3% in patients with ACLF at enrollment defined by both APASL and CMA but not EASL-CLIF Consortium, and 59.3% in patients with ACLF at enrollment defined by EASL-CLIF Consortium in addition to APASL. Baseline Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) score, and the maximum rising rates of CLIF-SOFA score, Model for End-Stage Liver Disease-Sodium (MELD Na) score and total bilirubin were independent predictors of progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium. CONCLUSION: Different diagnostic criteria for ACLF caused different patient prognosis. So, it is imperative to formulate a unifying diagnostic criteria for ACLF worldwide, thus attaining early identification and treatment, and eventual improvement in survival of ACLF patients. Baseline CLIF-SOFA score, and the maximum rising rates of CLIF-SOFA score, MELD-Na score and total bilirubin may early predict post enrollment development of EASL-CLIF ACLF. PMID- 25785854 TI - Escape from X inactivation varies in mouse tissues. AB - X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape genes in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a binomial model to assess allelic expression, we demonstrate a continuum between complete silencing and expression from the inactive X (Xi). The validity of the RNA-seq approach was verified using RT-PCR with species-specific primers or Sanger sequencing. Both common escape genes and genes with significant differences in XCI status between tissues were identified. Such genes may be candidates for tissue-specific sex differences. Overall, few genes (3-7%) escape XCI in any of the mouse tissues examined, suggesting stringent silencing and escape controls. In contrast, an in vitro system represented by the embryonic-kidney-derived Patski cell line showed a higher density of escape genes (21%), representing both kidney-specific escape genes and cell-line specific escape genes. Allele-specific RNA polymerase II occupancy and DNase I hypersensitivity at the promoter of genes on the Xi correlated well with levels of escape, consistent with an open chromatin structure at escape genes. Allele-specific CTCF binding on the Xi clustered at escape genes and was denser in brain compared to the Patski cell line, possibly contributing to a more compartmentalized structure of the Xi and fewer escape genes in brain compared to the cell line where larger domains of escape were observed. PMID- 25785857 TI - Three-dimensional flow of nanofluid induced by an exponentially stretching sheet: an application to solar energy. AB - This work deals with the three-dimensional flow of nanofluid over a bi directional exponentially stretching sheet. The effects of Brownian motion and thermophoretic diffusion of nanoparticles are considered in the mathematical model. The temperature and nanoparticle volume fraction at the sheet are also distributed exponentially. Local similarity solutions are obtained by an implicit finite difference scheme known as Keller-box method. The results are compared with the existing studies in some limiting cases and found in good agreement. The results reveal the existence of interesting Sparrow-Gregg-type hills for temperature distribution corresponding to some range of parametric values. PMID- 25785856 TI - Dynamic adjustment of stimuli in real time functional magnetic resonance imaging. AB - The conventional fMRI image analysis approach to associating stimuli to brain activation is performed by carrying out a massive number of parallel univariate regression analyses. fMRI blood-oxygen-level dependent (BOLD) signal, the basis of these analyses, is known for its low signal-noise-ratio and high spatial and temporal signal correlation. In order to ensure accurate localization of brain activity, stimulus administration in an fMRI session is often lengthy and repetitive. Real-time fMRI BOLD signal analysis is carried out as the signal is observed. This method allows for dynamic, real-time adjustment of stimuli through sequential experimental designs. We have developed a voxel-wise sequential probability ratio test (SPRT) approach for dynamically determining localization, as well as decision rules for stopping stimulus administration. SPRT methods and general linear model (GLM) approaches are combined to identify brain regions that are activated by specific elements of stimuli. Stimulus administration is dynamically stopped when sufficient statistical evidence is collected to determine activation status across regions of interest, following predetermined statistical error thresholds. Simulation experiments and an example based on real fMRI data show that scan volumes can be substantially reduced when compared with pre-determined, fixed designs while achieving similar or better accuracy in detecting activated voxels. Moreover, the proposed approach is also able to accurately detect differentially activated areas, and other comparisons between task-related GLM parameters that can be formulated in a hypothesis-testing framework. Finally, we give a demonstration of SPRT being employed in conjunction with a halving algorithm to dynamically adjust stimuli. PMID- 25785858 TI - Ecological niche transferability using invasive species as a case study. AB - Species distribution modeling is widely applied to predict invasive species distributions and species range shifts under climate change. Accurate predictions depend upon meeting the assumption that ecological niches are conserved, i.e., spatially or temporally transferable. Here we present a multi-taxon comparative analysis of niche conservatism using biological invasion events well documented in natural history museum collections. Our goal is to assess spatial transferability of the climatic niche of a range of noxious terrestrial invasive species using two complementary approaches. First we compare species' native versus invasive ranges in environmental space using two distinct methods, Principal Components Analysis and Mahalanobis distance. Second we compare species' native versus invaded ranges in geographic space as estimated using the species distribution modeling technique Maxent and the comparative index Hellinger's I. We find that species exhibit a range of responses, from almost complete transferability, in which the invaded niches completely overlap with the native niches, to a complete dissociation between native and invaded ranges. Intermediate responses included expansion of dimension attributable to either temperature or precipitation derived variables, as well as niche expansion in multiple dimensions. We conclude that the ecological niche in the native range is generally a poor predictor of invaded range and, by analogy, the ecological niche may be a poor predictor of range shifts under climate change. We suggest that assessing dimensions of niche transferability prior to standard species distribution modeling may improve the understanding of species' dynamics in the invaded range. PMID- 25785859 TI - Effect of soil moisture content on the splash phenomenon reproducibility. AB - One of the methods for testing splash (the first phase of water erosion) may be an analysis of photos taken using so-called high-speed cameras. The aim of this study was to determine the reproducibility of measurements using a single drop splash of simulated precipitation. The height from which the drops fell resulted in a splash of 1.5 m. Tests were carried out using two types of soil: Eutric Cambisol (loamy silt) and Orthic Luvisol (sandy loam); three initial pressure heads were applied equal to 16 kPa, 3.1 kPa, and 0.1 kPa. Images for one, five, and 10 drops were recorded at a rate of 2000 frames per second. It was found that (i) the dispersion of soil caused by the striking of the 1st drop was significantly different from the splash impact caused by subsequent drops; (ii) with every drop, the splash phenomenon proceeded more reproducibly, that is, the number of particles of soil and/or water that splashed were increasingly close to each other; (iii) the number of particles that were detached during the splash were strongly correlated with its surface area; and (iv) the higher the water film was on the surface the smaller the width of the crown was. PMID- 25785860 TI - The CodacsTM direct acoustic cochlear implant actuator: exploring alternative stimulation sites and their stimulation efficiency. AB - This work assesses the efficiency of the Codacs system actuator (Cochlear Ltd., Sydney Australia) in different inner ear stimulation modalities. Originally the actuator was intended for direct perilymph stimulation after stapedotomy using a piston prosthesis. A possible alternative application is the stimulation of middle ear structures or the round window (RW). Here the perilymph stimulation with a K-piston through a stapes footplate (SFP) fenestration (N = 10) as well as stimulation of the stapes head (SH) with a Bell prosthesis (N = 9), SFP stimulation with an Omega/Aerial prosthesis (N = 8) and reverse RW stimulation (N = 10) were performed in cadaveric human temporal bones (TBs). Codacs actuator output is expressed as equivalent sound pressure level (eq. SPL) using RW and SFP displacement responses, measured by Laser Doppler velocimetry as reference. The axial actuator coupling force in stimulation of stapes and RW was adjusted to ~5 mN. The Bell prosthesis and Omega/Aerial prosthesis stimulation generated similar mean eq. SPLs (Bell: 127.5-141.8 eq. dB SPL; Omega/Aerial: 123.6-143.9 eq. dB SPL), being significantly more efficient than K-piston perilymph stimulation (108.6-131.6 eq. dB SPL) and RW stimulation (108.3-128.2 eq. dB SPL). Our results demonstrate that SH, SFP and RW are adequate alternative stimulation sites for the Codacs actuator using coupling prostheses and an axial coupling force of ~5 mN. Based on the eq. SPLs, all investigated methods were adequate for in vivo hearing aid applications, provided that experimental conditions including constant coupling force will be implemented. PMID- 25785861 TI - IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators. AB - Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-beta, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling. PMID- 25785862 TI - Obesity impairs gammadelta T cell homeostasis and antiviral function in humans. AB - Obese patients are susceptible to increased morbidity and mortality associated with infectious diseases such as influenza A virus. gammadelta T cells and memory alphabeta T cells play key roles in reducing viral load by rapidly producing IFN gamma and lysing infected cells. In this article we analyze the impact of obesity on T lymphocyte antiviral immunity. Obese donors exhibit a reduction in gammadelta T cells in the peripheral blood. The severity of obesity negatively correlates with the number of gammadelta T cells. The remaining gammadelta T cells have a skewed maturation similar to that observed in aged populations. This skewed gammadelta T cell population exhibits a blunted antiviral IFN-gamma response. Full gammadelta T cell function can be restored by potent stimulation with 1-Hydroxy-2-methyl-buten-4yl 4-diphosphate (HDMAPP), suggesting that gammadelta T cells retain the ability to produce IFN-gamma. Additionally, gammadelta T cells from obese donors have reduced levels of IL-2Ralpha. IL-2 is able to restore gammadelta T cell antiviral cytokine production, which suggests that gammadelta T cells lack key T cell specific growth factor signals. These studies make the novel finding that the gammadelta T cell antiviral immune response to influenza is compromised by obesity. This has important implications for the development of therapeutic strategies to improve vaccination and antiviral responses in obese patients. PMID- 25785864 TI - Correction: Rapid losses of surface elevation following tree girdling and cutting in tropical mangroves. PMID- 25785863 TI - A model for growth of a single fungal hypha based on well-mixed tanks in series: simulation of nutrient and vesicle transport in aerial reproductive hyphae. AB - Current models that describe the extension of fungal hyphae and development of a mycelium either do not describe the role of vesicles in hyphal extension or do not correctly describe the experimentally observed profile for distribution of vesicles along the hypha. The present work uses the n-tanks-in-series approach to develop a model for hyphal extension that describes the intracellular transport of nutrient to a sub-apical zone where vesicles are formed and then transported to the tip, where tip extension occurs. The model was calibrated using experimental data from the literature for the extension of reproductive aerial hyphae of three different fungi, and was able to describe different profiles involving acceleration and deceleration of the extension rate. A sensitivity analysis showed that the supply of nutrient to the sub-apical vesicle-producing zone is a key factor influencing the rate of extension of the hypha. Although this model was used to describe the extension of a single reproductive aerial hypha, the use of the n-tanks-in-series approach to representing the hypha means that the model has the flexibility to be extended to describe the growth of other types of hyphae and the branching of hyphae to form a complete mycelium. PMID- 25785866 TI - Climate-based models for pulsed resources improve predictability of consumer population dynamics: outbreaks of house mice in forest ecosystems. AB - Accurate predictions of the timing and magnitude of consumer responses to episodic seeding events (masts) are important for understanding ecosystem dynamics and for managing outbreaks of invasive species generated by masts. While models relating consumer populations to resource fluctuations have been developed successfully for a range of natural and modified ecosystems, a critical gap that needs addressing is better prediction of resource pulses. A recent model used change in summer temperature from one year to the next (DeltaT) for predicting masts for forest and grassland plants in New Zealand. We extend this climate based method in the framework of a model for consumer-resource dynamics to predict invasive house mouse (Mus musculus) outbreaks in forest ecosystems. Compared with previous mast models based on absolute temperature, the DeltaT method for predicting masts resulted in an improved model for mouse population dynamics. There was also a threshold effect of DeltaT on the likelihood of an outbreak occurring. The improved climate-based method for predicting resource pulses and consumer responses provides a straightforward rule of thumb for determining, with one year's advance warning, whether management intervention might be required in invaded ecosystems. The approach could be applied to consumer-resource systems worldwide where climatic variables are used to model the size and duration of resource pulses, and may have particular relevance for ecosystems where global change scenarios predict increased variability in climatic events. PMID- 25785868 TI - Influence of resistance training combined with daily consumption of an egg-based or bagel-based breakfast on risk factors for chronic diseases in healthy untrained individuals. AB - OBJECTIVE: Egg consumption is often discouraged due to cholesterol content; however, recent studies have not demonstrated a clear adverse influence of eggs on blood lipids. Furthermore, exercise training promotes improved lipids and blood pressure. The purpose of the study was to examine the effect of eating an isoenergetic (400 kcal) egg-based (including two eggs per day) versus bagel-based breakfasts, daily, combined with resistance training three times per week, prior to breakfast, on plasma lipids, glucose, insulin, insulin sensitivity and blood pressure in untrained individuals. METHODS: Twenty-five healthy adult men and women (18-35 years of age) participated in the twelve week study following random assignment to study groups. Lipids and blood pressure were examined at baseline and after 6 and 12 weeks. RESULTS: Plasma triglycerides (TG) decreased significantly in the egg- based breakfast (EBB) group from baseline to six weeks (p = 0.011) and from six to twelve weeks (p = 0.045). A significant (p = 0.033) decrease in insulin sensitivity was observed in the bagel-based breakfast (BBB) group from zero to six weeks. No significant effects on systolic blood pressure, diastolic blood pressure, total cholesterol, high density lipoprotein- cholesterol or low density lipoprotein cholesterol were detected. CONCLUSION: Overall, daily breakfasts including two eggs for twelve weeks did not adversely affect lipids during a resistance training program and promoted improvements in plasma TG. PMID- 25785867 TI - Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation. AB - We recently demonstrated that conditioned media (CM) from osteocytes enhances myogenic differentiation of myoblasts, suggesting that signaling from bone may be important for skeletal muscle myogenesis. The effect of CM was closely mimicked by prostaglandin E2 (PGE2), a bioactive lipid mediator in various physiological or pathological conditions. PGE2 is secreted at high levels by osteocytes and such secretion is further enhanced under loading conditions. Although four types of receptors, EP1 to EP4, mediate PGE2 signaling, it is unknown whether these receptors play a role in myogenesis. Therefore, in this study, the expression of EPs in mouse primary myoblasts was characterized, followed by examination of their roles in myoblast proliferation by treating myoblasts with PGE2 or specific agonists. All four PGE2 receptor mRNAs were detectable by quantitative real-time PCR (qPCR), but only PGE2 and EP4 agonist CAY 10598 significantly enhance myoblast proliferation. EP1/EP3 agonist 17-phenyl trinor PGE2 (17-PT PGE2) and EP2 agonist butaprost did not have any significant effects. Moreover, treatment with EP4 antagonist L161,982 dose-dependently inhibited myoblast proliferation. These results were confirmed by cell cycle analysis and the gene expression of cell cycle regulators. Concomitant with the inhibition of myoblast proliferation, treatment with L161,982 significantly increased intracellular reactive oxygen species (ROS) levels. Cotreatment with antioxidant N-acetyl cysteine (NAC) or sodium ascorbate (SA) successfully reversed the inhibition of myoblast proliferation and ROS overproduction caused by L161,982. Therefore, PGE2 signaling via the EP4 receptor regulates myogenesis by promoting myoblast proliferation and blocking this receptor results in increased ROS production in myoblasts. PMID- 25785869 TI - Spatial variation in age structure among colonies of a marine snake: the influence of ectothermy. AB - Several tetrapod lineages that have evolved to exploit marine environments (e.g. seals, seabirds, sea kraits) continue to rely upon land for reproduction and, thus, form dense colonies on suitable islands. In birds and mammals (endotherms), the offspring cannot survive without their parents. Terrestrial colonies contain all age classes. In reptiles (ectotherms), this constraint is relaxed, because offspring are independent from birth. Hence, each age class has the potential to select sites with characteristics that favour them. Our studies of sea snakes (sea kraits) in the lagoon of New Caledonia reveal marked spatial heterogeneity in age structure among colonies. Sea krait colonies exhibit the endothermic 'seal seabird' pattern (mixed-age classes within populations) only where the lagoon is narrow. Where the lagoon is wide, most snake colonies are comprised primarily of a single age cohort. Nurseries are located near the coast, adult colonies offshore and mixed colonies in-between. We suggest that ectothermy allows individuals to utilize habitats that are best suited to their own ecological requirements, a flexibility not available to endothermic marine taxa with obligate parental care. PMID- 25785882 TI - The n-Butanol Fraction and Rutin from Tartary Buckwheat Improve Cognition and Memory in an In Vivo Model of Amyloid-beta-Induced Alzheimer's Disease. AB - This study examined the beneficial effects of the n-butanol fraction and rutin extracted from tartary buckwheat (TB) on learning and memory deficits in a mouse model of amyloid beta (Abeta)-induced Alzheimer's disease (AD). Learning and memory were assessed using the T-maze, object recognition, and Morris water maze tests. Animals administered Abeta showed impaired cognition and memory, which were alleviated by oral administration of an n-butanol fraction and rutin extracted from TB. Similarly, Abeta-induced increases in nitric oxide formation and lipid peroxidation in the brain, liver, and kidneys were attenuated by treatment with n-butanol fraction and rutin from TB in addition to antioxidant effects observed in control (nonAbeta-treated) animals. The results of the present study suggest that the n-butanol fraction and rutin extracted from TB are protective against and have possible therapeutic applications for the treatment of AD. PMID- 25785883 TI - Selective heterogeneous catalytic hydrogenation of ketone (C?O) to alcohol (OH) by magnetite nanoparticles following Langmuir-Hinshelwood kinetic approach. AB - Magnetite nanoparticles were successfully synthesized and effectively employed as heterogeneous catalyst for hydrogenation of ketone moiety to alcohol moiety by NaBH4 under the microwave radiation process. The improvement was achieved in percent recovery of isopropyl alcohol by varying and optimizing reaction time, power of microwave radiations and amount of catalyst. The catalytic study revealed that acetone would be converted into isopropyl alcohol (IPA) with 99.5% yield in short period of reaction time, using 10 MUg of magnetite NPs (Fe3O4). It was observed that the catalytic hydrogenation reaction, followed second-order of reaction and the Langmuir-Hinshelwood kinetic mechanism, which elucidated that both reactants get adsorb onto the surface of silica coated magnetite nanocatalyst to react. Consequently, the rate-determining step was the surface reaction of acetone and sodium borohydride. The current study revealed an environment friendly conversion of acetone to IPA on the basis of its fast, efficient, and highly economical method of utilization of microwave irradiation process and easy catalyst recovery. PMID- 25785885 TI - Characterization of antimicrobial resistance and extended-spectrum beta-lactamase genes in Escherichia coli isolated from chickens. AB - Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli have been frequently isolated from food-producing animals and pose a serious threat to human health. This study collected 195 ESBL-producing E. coli isolates from 20 chicken farms and 3 live-bird markets located in Northeast China (Heilongjiang, Liaoning, Jilin) and Jiangsu province from February 2011 to October 2013. ESBL genes, including blaCTX-M, blaTEM, and blaSHV, were detected and characterized, and the susceptibilities of these strains to various antimicrobial agents were determined. One hundred ninety-one of these isolates carried 1 or more bla genes. blaCTX-M, blaTEM-1, and blaSHV-5 were identified in 183, 121, and 2 isolates, respectively. The most common blaCTX-M genes were blaCTX-M-15 (68 strains), blaCTX-M-65 (41 strains), blaCTX-M-55 (35 strains), blaCTX-M-14 (32 strains), followed by blaCTX-M-3, blaCTX-M-13, blaCTX-M-79, and blaCTX-M-101, as well as the chimeric genes blaCTX-M-64, blaCTX-M-123, and blaCTX-M-132. Fifteen strains (7.7%) co-harboring CTX-M-1 group and CTX-M-9 group genes were detected in 195 ESBL-producing strains. Pulsed-field gel electrophoresis of 45 strains showed that these CTX-M-producing isolates belonged to 34 different types. To our knowledge, this is the first study to report the blaSHV-5 gene in E. coli isolated from chickens in China. Conjugation experiments demonstrated that the blaCTX-M and blaTEM genes could be transferred to E. coli strain J53, while conjugative transfer of the blaSHV-5 gene from two isolates was not detectable. blaCTX-M genes are carried by many kinds of transferable and untypable plasmids. Our findings demonstrate that the CTX-M enzymes are predominant in both type and quantity. PMID- 25785884 TI - Quantitative Connection between Ensemble Thermodynamics and Single-Molecule Kinetics: A Case Study Using Cryogenic Electron Microscopy and Single-Molecule Fluorescence Resonance Energy Transfer Investigations of the Ribosome. AB - At equilibrium, thermodynamic and kinetic information can be extracted from biomolecular energy landscapes by many techniques. However, while static, ensemble techniques yield thermodynamic data, often only dynamic, single-molecule techniques can yield the kinetic data that describe transition-state energy barriers. Here we present a generalized framework based upon dwell-time distributions that can be used to connect such static, ensemble techniques with dynamic, single-molecule techniques, and thus characterize energy landscapes to greater resolutions. We demonstrate the utility of this framework by applying it to cryogenic electron microscopy (cryo-EM) and single-molecule fluorescence resonance energy transfer (smFRET) studies of the bacterial ribosomal pre translocation complex. Among other benefits, application of this framework to these data explains why two transient, intermediate conformations of the pre translocation complex, which are observed in a cryo-EM study, may not be observed in several smFRET studies. PMID- 25785886 TI - Statistical foundations for model-based adjustments. AB - Most epidemiology textbooks that discuss models are vague on details of model selection. This lack of detail may be understandable since selection should be strongly influenced by features of the particular study, including contextual (prior) information about covariates that may confound, modify, or mediate the effect under study. It is thus important that authors document their modeling goals and strategies and understand the contextual interpretation of model parameters and model selection criteria. To illustrate this point, we review several established strategies for selecting model covariates, describe their shortcomings, and point to refinements, assuming that the main goal is to derive the most accurate effect estimates obtainable from the data and available resources. This goal shifts the focus to prediction of exposure or potential outcomes (or both) to adjust for confounding; it thus differs from the goal of ordinary statistical modeling, which is to passively predict outcomes. Nonetheless, methods and software for passive prediction can be used for causal inference as well, provided that the target parameters are shifted appropriately. PMID- 25785887 TI - Fitness of the US workforce. AB - Fitness matters for the prevention of premature death, chronic diseases, productivity loss, excess medical care costs, loss of income or family earnings, and other social and economic concerns. The workforce may be viewed as a corporate strategic asset, yet its fitness level appears to be relatively low and declining. Over the past half-century, obesity rates have doubled, physical activity levels are below par, and cardiorespiratory fitness often does not meet minimum acceptable job standards. During this time, daily occupational energy expenditure has decreased by more than 100 calories. Employers should consider best practices and design workplace wellness programs accordingly. Particular attention should be paid to human-centered cultures. Research should address ongoing surveillance needs regarding fitness of the US workforce and close gaps in the evidence base for fitness and business-relevant outcomes. Policy priorities should consider the impact of both state and federal regulations, adherence to current regulations that protect and promote worker health, and the introduction of incentives that allow employers to optimize the fitness of their workforce through supportive legislation and organizational policies. PMID- 25785888 TI - Food system policy, public health, and human rights in the United States. AB - The US food system functions within a complex nexus of social, political, economic, cultural, and ecological factors. Among them are many dynamic pressures such as population growth, urbanization, socioeconomic inequities, climate disruption, and the increasing demand for resource-intensive foods that place immense strains on public health and the environment. This review focuses on the role that policy plays in defining the food system, particularly with regard to agriculture. It further examines the challenges of making the food supply safe, nutritious, and sustainable, while respecting the rights of all people to have access to adequate food and to attain the highest standard of health. We conclude that the present US food system is largely unhealthy, inequitable, environmentally damaging, and insufficiently resilient to endure the impacts of climate change, resource depletion, and population increases, and is therefore unsustainable. Thus, it is imperative that the US embraces policy reforms to transform the food system into one that supports public health and reflects the principles of human rights and agroecology for the benefit of current and future generations. PMID- 25785889 TI - Regulating chemicals: law, science, and the unbearable burdens of regulation. AB - The challenges of regulating industrial chemicals remain unresolved in the United States. The Toxic Substances Control Act (TSCA) of 1976 was the first legislation to extend coverage to the regulation of industrial chemicals, both existing and newly registered. However, decisions related to both law and science that were made in passing this law inevitably rendered it ineffectual. Attempts to fix these shortcomings have not been successful. In light of the European Union's passage of innovative principles and requirements for chemical regulation, it is no longer possible to deny the opportunity and need for reform in US law and practice. PMID- 25785890 TI - The haves, the have-nots, and the health of everyone: the relationship between social inequality and environmental quality. AB - A growing body of literature suggests that more unequal societies have more polluted and degraded environments, perhaps helping explain why more unequal societies are often less healthy. We summarize the mechanisms by which inequality can lead to environmental degradation and their relevance for public health. We review the evidence of a relationship between environmental quality and social inequality along the axes of income, wealth, political power, and race and ethnicity. Our review suggests that the evidence is strongest for air- and water quality measures that have more immediate health implications; evidence is less strong for more dispersed pollutants that have longer-term health impacts. More attention should be paid in research and in practice to links among inequality, the environment, and health, including more within-country studies that may elucidate causal pathways and points of intervention. We synthesize common metrics of inequality and methodological considerations in an effort to bring cohesion to such efforts. PMID- 25785891 TI - Identifying the effects of environmental and policy change interventions on healthy eating. AB - Obesity has been characterized as a disease. Strategies to change the incidence and prevalence of this disease include a focus on changing physical and social environments, over and above individual-level strategies, using a multilevel or systems approach. We focus our attention on evidence published between 2008 and 2013 on the effectiveness of interventions in nutrition environments, i.e., environmental interventions designed to influence the intake of healthful foods and amount of energy consumed. An overarching socioecological framework that has guided much of this research was used to characterize different types of environmental strategies. Intervention examples in each area of the framework are provided with a discussion of key findings and related conceptual and methodological issues. The emphasis in this review is on adults, but clearly this literature is only one part of the picture. Much research has been focused on child-specific interventions, including environmental interventions. Some evidence suggests effectiveness of policy-based or other types of interventions that aim to regulate or restructure environments to promote healthy dietary choices, and these strategies would apply to both children and adults. Opportunities to evaluate these policy changes in adults' social and physical environments are rare. Much of the existing research has been with children. As conceptual and methodological issues continue to be identified and resolved, we hope that future research in this domain will identify environmental strategies that can be included in intervention toolboxes to build healthy nutrition environments for both adults and children. PMID- 25785892 TI - Mobile text messaging for health: a systematic review of reviews. AB - The aim of this systematic review of reviews is to identify mobile text-messaging interventions designed for health improvement and behavior change and to derive recommendations for practice. We have compiled and reviewed existing systematic research reviews and meta-analyses to organize and summarize the text-messaging intervention evidence base, identify best-practice recommendations based on findings from multiple reviews, and explore implications for future research. Our review found that the majority of published text-messaging interventions were effective when addressing diabetes self-management, weight loss, physical activity, smoking cessation, and medication adherence for antiretroviral therapy. However, we found limited evidence across the population of studies and reviews to inform recommended intervention characteristics. Although strong evidence supports the value of integrating text-messaging interventions into public health practice, additional research is needed to establish longer-term intervention effects, identify recommended intervention characteristics, and explore issues of cost-effectiveness. PMID- 25785894 TI - Assessing and changing organizational social contexts for effective mental health services. AB - Culture and climate are critical dimensions of a mental health service organization's social context that affect the quality and outcomes of the services it provides and the implementation of innovations such as evidence-based treatments (EBTs). We describe a measure of culture and climate labeled Organizational Social Context (OSC), which has been associated with innovation, service quality, and outcomes in national samples and randomized controlled trials (RCTs) of mental health and social service organizations. The article also describes an empirically supported organizational intervention model labeled Availability, Responsiveness, and Continuity (ARC), which has improved organizational social context, innovation, and effectiveness in five RCTs. Finally, the article outlines a research agenda for developing more efficient and scalable organizational strategies to improve mental health services by identifying the mechanisms that link organizational interventions and social context to individual-level service provider intentions and behaviors associated with innovation and effectiveness. PMID- 25785895 TI - Tax-exempt hospitals and community benefit: new directions in policy and practice. AB - The current community benefit standard for nonprofit hospital tax exemption has been the subject of mounting criticism. Many different constituencies have advanced the view that in its present form it fails to ensure that nonprofit hospitals provide adequate benefits to their communities in exchange for their tax exemption. In contrast, hospitals have often expressed the concern that the community benefit standard in its current form is vague and therefore difficult to comply with. Various suggestions have been made regarding how the existing community benefit standard could be improved or even replaced. In this article, we first discuss the historical and legal development of the community benefit standard. We then present the key controversies that have emerged in recent years and the policy responses attempted thus far. Finally, we evaluate possible future policy directions, which reform efforts could follow. PMID- 25785893 TI - Sleep as a potential fundamental contributor to disparities in cardiovascular health. AB - Optimal sleep is integral to health but is commonly not obtained. Despite its wide-ranging public health impact, sleep health is considered only rarely by policy makers, employers, schools, and others whose policies and structures can adversely affect sleep. An inadequate duration of sleep and poor-quality sleep are prevalent in minority and low-income populations, and may be fundamental to racial and socioeconomic status inequities that contribute to a range of health conditions, including cardiovascular disease (CVD). This review examines the relationship between sleep and disparities in CVD. We describe the public health importance of sleep and the role of sleep duration, as well as the two most common disorders (sleep apnea and insomnia) as risk factors for a number of chronic diseases. We use a multilevel model focused on population health and health disparities, which is based on the notion that individual behaviors, such as sleep, are influenced by complex and dynamic interrelations among individuals and their physical and social environments. We also describe modifiable factors that contribute to insufficient sleep and circadian misalignment, propose potential interventions in various sectors (e.g., neighborhoods, schools, workplaces) that can address social structures that contribute to disparities, and recommend areas for future research. Integrating sleep into public health research will identify novel approaches for closing gaps in health disparities. PMID- 25785896 TI - Self-assembly of a nine-residue amyloid-forming peptide fragment of SARS corona virus E-protein: mechanism of self aggregation and amyloid-inhibition of hIAPP. AB - Molecular self-assembly, a phenomenon widely observed in nature, has been exploited through organic molecules, proteins, DNA, and peptides to study complex biological systems. These self-assembly systems may also be used in understanding the molecular and structural biology which can inspire the design and synthesis of increasingly complex biomaterials. Specifically, use of these building blocks to investigate protein folding and misfolding has been of particular value since it can provide tremendous insights into peptide aggregation related to a variety of protein misfolding diseases, or amyloid diseases (e.g., Alzheimer's disease, Parkinson's disease, type-II diabetes). Herein, the self-assembly of TK9, a nine residue peptide of the extra membrane C-terminal tail of the SARS corona virus envelope, and its variants were characterized through biophysical, spectroscopic, and simulated studies, and it was confirmed that the structure of these peptides influences their aggregation propensity, hence, mimicking amyloid proteins. TK9, which forms a beta-sheet rich fibril, contains a key sequence motif that may be critical for beta-sheet formation, thus making it an interesting system to study amyloid fibrillation. TK9 aggregates were further examined through simulations to evaluate the possible intra- and interpeptide interactions at the molecular level. These self-assembly peptides can also serve as amyloid inhibitors through hydrophobic and electrophilic recognition interactions. Our results show that TK9 inhibits the fibrillation of hIAPP, a 37 amino acid peptide implicated in the pathology of type-II diabetes. Thus, biophysical and NMR experimental results have revealed a molecular level understanding of peptide folding events, as well as the inhibition of amyloid-protein aggregation are reported. PMID- 25785897 TI - Adoption of clinical decision support in multimorbidity: a systematic review. AB - BACKGROUND: Patients with multiple conditions have complex needs and are increasing in number as populations age. This multimorbidity is one of the greatest challenges facing health care. Having more than 1 condition generates (1) interactions between pathologies, (2) duplication of tests, (3) difficulties in adhering to often conflicting clinical practice guidelines, (4) obstacles in the continuity of care, (5) confusing self-management information, and (6) medication errors. In this context, clinical decision support (CDS) systems need to be able to handle realistic complexity and minimize iatrogenic risks. OBJECTIVE: The aim of this review was to identify to what extent CDS is adopted in multimorbidity. METHODS: This review followed PRISMA guidance and adopted a multidisciplinary approach. Scopus and PubMed searches were performed by combining terms from 3 different thesauri containing synonyms for (1) multimorbidity and comorbidity, (2) polypharmacy, and (3) CDS. The relevant articles were identified by examining the titles and abstracts. The full text of selected/relevant articles was analyzed in-depth. For articles appropriate for this review, data were collected on clinical tasks, diseases, decision maker, methods, data input context, user interface considerations, and evaluation of effectiveness. RESULTS: A total of 50 articles were selected for the full in depth analysis and 20 studies were included in the final review. Medication (n=10) and clinical guidance (n=8) were the predominant clinical tasks. Four studies focused on merging concurrent clinical practice guidelines. A total of 17 articles reported their CDS systems were knowledge-based. Most articles reviewed considered patients' clinical records (n=19), clinical practice guidelines (n=12), and clinicians' knowledge (n=10) as contextual input data. The most frequent diseases mentioned were cardiovascular (n=9) and diabetes mellitus (n=5). In all, 12 articles mentioned generalist doctor(s) as the decision maker(s). For articles reviewed, there were no studies referring to the active involvement of the patient in the decision-making process or to patient self management. None of the articles reviewed adopted mobile technologies. There were no rigorous evaluations of usability or effectiveness of the CDS systems reported. CONCLUSIONS: This review shows that multimorbidity is underinvestigated in the informatics of supporting clinical decisions. CDS interventions that systematize clinical practice guidelines without considering the interactions of different conditions and care processes may lead to unhelpful or harmful clinical actions. To improve patient safety in multimorbidity, there is a need for more evidence about how both conditions and care processes interact. The data needed to build this evidence base exist in many electronic health record systems and are underused. PMID- 25785899 TI - Bipolar host with multielectron transport benzimidazole units for low operating voltage and high power efficiency solution-processed phosphorescent OLEDs. AB - Two soluble bipolar host materials (mCP-BPBI and CP-QPBI), comprising different proportions of hole-transporting carbazole and electron-transporting benzimidazole, were synthesized. Their thermal, physical, and electrochemical properties were characterized. The designated bulky star-shaped structures efficiently suppress the direct intramolecular interaction between the donor and acceptor subunits to give high triplet energies. Through computational studies, varying the ratio of hole- and electron-transporting moieties could significantly change the carrier injection/transporting abilities and charge balance properties of the host materials. Indeed, CP-QPBI with more benzimidazole units shows extremely enhanced current density at the same voltage when compared to mCP-BPBI. The operating voltage of solution-processed phosphorescent light-emitting diodes with CP-QPBI as host were dramatically reduced by ~3 V compared with the similar devices of mCP-BPBI. At the same time, the power efficiencies were improved for 2 2.5 times at the corresponding voltage. Importantly, both blue and green devices maintain their high efficiencies even at brightness up to 1000 cd m(-2), which clearly demonstrates that the new strategy applied to improve electron transporting ability and charge-balance property of the solution-processable host material by tuning the ratio of donor and acceptor unit is profitable. PMID- 25785898 TI - Calcium Homeostasis and Ionic Mechanisms in Pulmonary Fibroblasts. AB - Fibroblasts are key cellular mediators of many chronic interstitial lung diseases, including idiopathic pulmonary fibrosis, scleroderma, sarcoidosis, drug induced interstitial lung disease, and interstitial lung disease in connective tissue disease. A great deal of effort has been expended to understand the signaling mechanisms underlying the various cellular functions of fibroblasts. Recently, it has been shown that Ca(2+) oscillations play a central role in the regulation of gene expression in human pulmonary fibroblasts. However, the mechanisms whereby cytosolic [Ca(2+)] are regulated and [Ca(2+)] oscillations transduced are both poorly understood. In this review, we present the general concepts of [Ca(2+)] homeostasis, of ionic mechanisms responsible for various Ca(2+) fluxes, and of regulation of gene expression by [Ca(2+)]. In each case, we then also summarize the original findings that pertain specifically to pulmonary fibroblasts. From these data, we propose an overall signaling cascade by which excitation of the fibroblasts triggers pulsatile release of internally sequestered Ca(2+), which, in turn, activates membrane conductances, including voltage-dependent Ca(2+) influx pathways. Collectively, these events produce recurring Ca(2+) oscillations, the frequency of which is transduced by Ca(2+) dependent transcription factors, which, in turn, orchestrate a variety of cellular events, including proliferation, synthesis/secretion of extracellular matrix proteins, autoactivation (production of transforming growth factor-beta), and transformation into myofibroblasts. That unifying hypothesis, in turn, allows us to highlight several specific cellular targets and therapeutic intervention strategies aimed at controlling unwanted pulmonary fibrosis. The relationships between Ca(2+) signaling events and the unfolded protein response and apoptosis are also explored. PMID- 25785900 TI - Silica-mediated synthesis of indolinooxazolidine-based molecular switches. AB - A novel and convenient method for the synthesis of photochromic compounds is reported here. It is based on the use of commercially available untreated silica, as an efficient catalyst to perform the condensation between indolinooxazolidine derivatives and aromatic aldehydes under solvent-free conditions. The scope and limitations of this transformation were investigated and several novel photochromic indolinooxazolidines were synthesized. This methodology can also be applied to the synthesis of other photoactive compounds such as spiropyrans or spirooxazines. According to our working protocol the reaction did not require any solvent or additional reagents and gave the products within 10 min in isolated yields of up to 90%. PMID- 25785901 TI - Effect of dielectrophoretic force on swimming bacteria. AB - Dielectrophoresis (DEP) has been applied widely in bacterial manipulation such as separating, concentrating, and focusing. Previous studies primarily focused on the collective effects of DEP force on the bacterial population. However, the influence of DEP force on the swimming of a single bacterium had not been investigated. In this study, we present a model to analyze the effect of DEP force on a swimming helically flagellated bacterium, particularly on its swimming direction and velocity. We consider a simple DEP force that acts along the X direction, and its strength as well as direction varies with the X- and Y positions. Resistive force theory is employed to compute the hydrodynamic force on the bacterium's flagellar bundle, and the effects of both DEP force and rotational diffusion on the swimming of the bacterium are simultaneously taken into consideration using the Fokker-Planck equation. We show the mechanism of how DEP force alters the orientation and velocity of the bacterium. In most cases, the DEP force dominantly influences the orientation of the swimming bacterium; however, when the DEP force strongly varies along the Y-direction, the rotational diffusion is also responsible for determining the bacterium's reorientation. More interestingly, the variance of DEP force along the Y-direction causes the bacterium to experience a translational velocity perpendicular to its primary axis, and this phenomenon could be utilized to focus the bacteria. Finally, we show the feasibility of applying our findings to achieve bacterial focusing. PMID- 25785902 TI - Transporting Evidence-Based Parenting Programs for Child Problem Behavior (Age 3 10) Between Countries: Systematic Review and Meta-Analysis. AB - There has been rapid global dissemination of parenting interventions, yet little is known about their effectiveness when transported to countries different from where they originated, or about factors influencing success. This is the first systematic attempt to address this issue, focusing on interventions for reducing child behavior problems. Stage 1 identified evidence-based parenting interventions showing robust effects in systematic reviews; Stage 2 identified trials of these interventions in a new country. Systematic review/meta-analysis of transported programs was followed by subgroup analyses by trial- and country level cultural, resource, and policy factors. We found 17 transported trials of 4 interventions, originating in United States or Australia, tested in 10 countries in 5 regions, (n = 1,558 children). Effects on child behavior were substantial (SMD -.71) in the (14) randomized trials, but nonsignificant in the (3) nonrandomized trials. Subgroup analyses of randomized trials found no association between effect size and participant or intervention factors (e.g., program brand, staffing). Interventions transported to "western" countries showed comparable effects to trials in origin countries; however, effects were stronger when interventions were transported to culturally more distant regions. Effects were higher in countries with survival-focused family/childrearing values than those ranked more individualistic. There were no differences in effects by country level policy or resource factors. Contrary to common belief, parenting interventions appear to be at least as effective when transported to countries that are more different culturally, and in service provision, than those in which they were developed. Extensive adaptation did not appear necessary for successful transportation. PMID- 25785903 TI - Bio-inspired design of electrocatalysts for oxalate oxidation: a combined experimental and computational study of Mn-N-C catalysts. AB - We report a novel non-platinum group metal (non-PGM) catalyst derived from Mn and amino- antipyrine (MnAAPyr) that shows electrochemical activity towards the oxidation of oxalic acid comparable to Pt with an onset potential for oxalate oxidation measured to be 0.714 +/- 0.002 V vs. SHE at pH = 4. The material has been synthesized using a templating Sacrificial Support Method with manganese nitrate and 4-aminoantipyrine as precursors. This catalyst is a nano-structured material in which Mn is atomically dispersed on a nitrogen-doped graphene matrix. XPS studies reveal high abundance of pyridinic, Mn-Nx, and pyrrolic nitrogen pointing towards the conclusion that pyridinic nitrogen atoms coordinated to manganese constitute the active centers. Thus, the main features of the MnAAPyr catalyst are it exhibits similarity to the active sites of naturally occurring enzymes that are capable of efficient and selective oxidation of oxalic acid. Density functional theory in plane wave formalism with Perdew, Burke and Ernzerhof functional was further used to study the stability and activity of different one-metal active centers that could exist in the catalyst. The results show that the stability of the Mn-Nx sites changes in the following order: MnN4 > MnN3C > MnN2C2 > MnN3. Based on the overpotentials of 0.64 V and 0.71 V vs. SHE, calculated using the free energy diagrams for the oxalate oxidation mechanism, we could conclude that the MnN3C and MnN2C2 sites are most probable Mn-Nx sites responsible for the reported catalytic activity of the new catalyst. PMID- 25785904 TI - Calcinosis cutis presenting in the context of long-term therapy for chronic myeloid leukemia: a case report and review of the literature. AB - Calcinosis cutis is a poorly understood process in which calcium salts deposit in the skin and subcutaneous tissues. Due to its multifactorial pathogenesis, several subtypes and potential etiologies have been described. Presented here is a case of bilateral pretibial calcinosis cutis in a patient on long-term tyrosine kinase inhibitor therapy for chronic myeloid leukemia. The patient initially presented with a right tibial ulceration treated with multiple surgical debridements, antibiotics, and negative pressure wound therapy. The wound was ultimately closed with a split-thickness skin graft. Relevant literature is examined and several possible mechanisms are discussed. PMID- 25785906 TI - Evidence corner: evidence links nicotine use to surgical site infections. PMID- 25785905 TI - A comparative study of spray keratinocytes and autologous meshed split-thickness skin graft in the treatment of acute burn injuries. AB - BACKGROUND: ReCell (Avita Medical, Northridge, CA) is an autologous cell harvesting (ACH) device that enables a thin split-thickness skin biopsy to be processed to produce a cell population that includes a mixed population of keratinocytes, melanocytes, Langerhans cells, and papillary dermal fibroblasts for immediate delivery via a spray applicator onto a prepared skin surface. MATERIALS AND METHODS: In this Institutional Review Board-approved US Food and Drug Administration phase 2 study, the authors prospectively evaluated the treatment of partial-thickness burns in patients with two 320 cm2 areas, 1 area treated with the ACH device and the other with a meshed split-thickness skin graft (MSTSG) as a control. The authors compared the treatment areas for graft take, pigmentation, and color match to surrounding healthy tissue, scarring, and pain. RESULTS: In this preliminary study, 10 patients were treated with this protocol. Eight patients had 100% take to both treatment areas and 2 patients had significant non-take and graft loss attributable to underexcised wound beds and difficulty with the spray applicator. Pigmentation and color match ratings were identical at week 52 and the Modified Vancouver Scar Scale scores were comparable. One subject rated the autologous cell harvesting site as having a better appearance, while the remaining subjects rated their ACH and MSTSG sites' appearances as being comparable. In early follow-up visits, pain ratings were slightly elevated in the ACH group due to graft healing; however, in visits following week 2, pain ratings at the ACH and MSTSG sites were rated similarly by all patients. CONCLUSION: This preliminary report describes an early experience with the ACH device and the treatment of partial-thickness burn injuries. In this 10-patient series, patients benefitted from having a decreased donor site size and comparable outcomes with MSTSG treatment. While this preliminary underpowered study has provided positive results, there is a learning curve with choosing the proper wound for treatment with the ACH device, as well as with using the device. PMID- 25785907 TI - The increasing role of epidermal grafting utilizing a novel harvesting system in chronic wounds. AB - Skin grafting techniques range from harvesting full-thickness to split-thickness grafts to grafts containing only epidermis. All of these autologous tissues have their place on the reconstructive ladder. However, the use of full-thickness and split-thickness grafts as coverage over chronic wounds remains limited by a number of factors, including the need for anesthesia, a surgically trained physician, and an operating room in which to perform the procedure; pain and damage associated with the donor site; and severe patient comorbidities. Epidermal grafting offers an option for autografts and uses only a minimal amount of superficial epidermis from the donor site. Although successful use of epidermal grafting has been reported in pigmentation disorders, as well as burns and chronic wounds, previous harvesting methods have been described as cumbersome and time consuming. An automated epidermal harvesting system is now commercially available and involves a tool that applies both heat and suction concurrently to normal skin to induce epidermal micrograft formation. The new tool allows quick harvest and transfer of the epidermal micrografts at the bedside without anesthesia, with minimal donor site healing time and patient discomfort. The use of epidermal grafts in chronic wounds and the harvesting technique are reviewed here. PMID- 25785908 TI - Correction: A new topology of the HK97-like fold revealed in Bordetella bacteriophage by cryoEM at 3.5 A resolution. PMID- 25785909 TI - Comment on "Decomposition mechanisms of trinitroalkyl compounds: a theoretical study from aliphatic to aromatic nitro compounds" by G. Fayet, P. Rotureau, B. Minisini, Phys. Chem. Chem. Phys., 2014, 16, 6614. PMID- 25785910 TI - Design and development of solar power-assisted manual/electric wheelchair. AB - Wheelchairs are an essential assistive device for many individuals with injury or disability. Manual wheelchairs provide a relatively low-cost solution to the mobility needs of such individuals. Furthermore, they provide an effective means of improving the user's cardiopulmonary function and upper-limb muscle strength. However, manual wheelchairs have a loss gross mechanical efficiency, and thus the risk of user fatigue and upper-limb injury is increased. Electric-powered wheelchairs reduce the risk of injury and provide a more convenient means of transportation. However, they have a large physical size and are relatively expensive. Accordingly, the present study utilizes a quality function deployment method to develop a wheelchair with a user-selectable manual/electric propulsion mode and an auxiliary solar power supply system. The auxiliary solar power supply increased the travel range of the wheelchair by approximately 26% compared with that of a wheelchair powered by battery alone. Moreover, the wheelchair has a modular design and can be disassembled and folded for ease of transportation or storage. Overall, the present results suggest that the proposed wheelchair provides an effective and convenient means of meeting the mobility needs of individuals with mobility difficulties. PMID- 25785911 TI - Pb6Ba2(BO3)5X (X = Cl, Br): new borate halides with strong predicted optical anisotropies derived from Pb(2+) and (BO3)(3.). AB - Two new borate halides, Pb6Ba2(BO3)5X (X = Cl, Br), have been synthesized by solid-state reactions and their structures determined by single-crystal X-ray diffraction. They are isostructural and feature 3D frameworks composed of alternate stacking of [PbBO] and [PbBOX] layers which are connected by 10 coordinated Ba atoms along the c direction. First-principles calculations show that both compounds have a large birefringence of 0.1582 and 0.1810 at 532 nm, respectively. The large birefringence originates from the strong optical anisotropies of the Pb(2+) cations and (BO3)(3-) groups based on the real-space atom-cutting analysis. The IR and UV-Vis-NIR diffuse reflectance spectroscopy, as well as thermal stability analyses of both compounds, were performed. PMID- 25785912 TI - Highly flexible, nonflammable and free-standing SiC nanowire paper. AB - Flexible paper-like semiconductor nanowire materials are expected to meet the criteria for some emerging applications, such as components of flexible solar cells, electrical batteries, supercapacitors, nanocomposites, bendable or wearable electronic or optoelectronic components, and so on. As a new generation of wide-bandgap semiconductors and reinforcements in composites, SiC nanowires have advantages in power electronic applications and nanofiber reinforced ceramic composites. Herein, free-standing SiC nanowire paper consisting of ultralong single-crystalline SiC nanowires was prepared through a facile vacuum filtration approach. The ultralong SiC nanowires were synthesized by a sol-gel and carbothermal reduction method. The flexible paper composed of SiC nanowires is ~100 nm in width and up to several hundreds of micrometers in length. The nanowires are intertwisted with each other to form a three-dimensional network like structure. SiC nanowire paper exhibits high flexibility and strong mechanical stability. The refractory performance and thermal stability of SiC nanowire paper were also investigated. The paper not only exhibits excellent nonflammability in fire, but also remains well preserved without visible damage when it is heated in an electric oven at a high temperature (1000 degrees C) for 3 h. With its high flexibility, excellent nonflammability, and high thermal stability, the free-standing SiC nanowire paper may have the potential to improve the ablation resistance of high temperature ceramic composites. PMID- 25785913 TI - Heterostructured core-shell ZnMn2O4 nanosheets@carbon nanotubes' coaxial nanocables: a competitive anode towards high-performance Li-ion batteries. AB - In this study, we rationally designed a rapid, low-temperature yet general synthetic methodology for the first time, involving in situ growth of two dimensional (2D) birnessite-type MnO2 nanosheets (NSs) upon each carbon nanotube (CNT), and we designed the subsequent phase transformation into untrathin mesoporous ZnMn2O4 NSs with a thickness of ~2-3 nm at room temperature to efficiently fabricate heterostructured core-shell ZnMn2O4 NSs@CNT coaxial nanocables with well-dispersed and tunable ZnMn2O4 loading. The underlying insights into the low-temperature formation mechanism of the unique core-shell hybrid nanoarchitectures were tentatively proposed here. When utilized as a high performance anode for advanced LIBs, the resultant core-shell ZnMn2O4@CNTs' coaxial nanocables (~84.5 wt.% loading) exhibited large specific discharge capacity (~1033 mAh g(-1)), good rate capability (~528 mAh g(-1)) and excellent cycling stability (average capacity degradation of only ~5.2% per cycle) at a high current rate of 1224 mA g(-1), originating from the distinct core-shell synergetic effect of fast electronic delivery and from the large electrode/electrolyte contacting surfaces/interfaces provided by three dimensional entangling coaxial CNT-based nanonetwork topology. PMID- 25785915 TI - Micromechanical cohesion force between gas hydrate particles measured under high pressure and low temperature conditions. AB - To prevent hydrate plugging conditions in the transportation of oil/gas in multiphase flowlines, one of the key processes to control is the agglomeration/deposition of hydrate particles, which are determined by the cohesive/adhesive forces. Previous studies reporting measurements of the cohesive/adhesive force between hydrate particles used cyclopentane hydrate particles in a low-pressure micromechanical force apparatus. In this study, we report the cohesive forces of particles measured in a new high-pressure micromechanical force (MMF) apparatus for ice particles, mixed (methane/ethane, 74.7:25.3) hydrate particles (Structure II), and carbon dioxide hydrate particles (Structure I). The cohesive forces are measured as a function of the contact time, contact force, temperature, and pressure, and determined from pull-off measurements. For the measurements performed of the gas hydrate particles in the gas phase, the determined cohesive force is about 30-35 mN/m, about 8 times higher than the cohesive force of CyC5 hydrates in the liquid CyC5, which is about 4.3 mN/m. We show from our results that the hydrate structure (sI with CO2 hydrates and sII with CH4/C2H6 hydrates) has no influence on the cohesive force. These results are important in the deposition of a gas-dominated system, where the hydrate particles formed in the liquid phase can then stick to the hydrate deposited in the wall exposed to the gas phase. PMID- 25785914 TI - Nano-enabled bioanalytical approaches to ultrasensitive detection of low abundance single nucleotide polymorphisms. AB - Single nucleotide polymorphisms (SNPs) constitute the most common types of genetic variations in the human genome. A number of SNPs have been linked to the development of life threatening diseases including cancer, cardiovascular diseases and neurodegenerative diseases. The ability for ultrasensitive and accurate detection of low abundant disease-related SNPs in bodily fluids (e.g. blood, serum, etc.) holds a significant value in the development of non-invasive future biodiagnostic tools. Over the past two decades, nanomaterials have been utilized in a myriad of biosensing applications due to their ability of detecting extremely low quantities of biologically important biomarkers with high sensitivity and accuracy. Of particular interest is the application of such technologies in the detection of SNPs. The use of various nanomaterials, coupled with different powerful signal amplification strategies, has paved the way for a new generation of ultrasensitive SNP biodiagnostic assays. Over the past few years, several ultrasensitive SNP biosensors capable of detecting specific targets down to the ultra-low regimes (ca. aM and below) and therefore holding great promises for early clinical diagnosis of diseases have been developed. This mini review will highlight some of the most recent, significant advances in nanomaterial-based ultrasensitive SNP sensing technologies capable of detecting specific targets on the attomolar (10(-18) M) regime or below. In particular, the design of novel, powerful signal amplification strategies that hold the key to the ultrasensitivity is highlighted. PMID- 25785916 TI - C60 as an active smart spacer material on silver thin film substrates for enhanced surface plasmon coupled emission. AB - In this study, we present the use of C60 as an active spacer material on a silver (Ag) based surface plasmon coupled emission (SPCE) platform. In addition to its primary role of protecting the Ag thin film from oxidation, the incorporation of C60 facilitated the achievement of a 30-fold enhancement in the emission intensity of rhodamine B (RhB) fluorophore. The high signal yield was attributed to the unique pi-pi interactions between C60 thin films and RhB, which enabled efficient transfer of energy of RhB emission to Ag plasmon modes. Furthermore, minor variations in the C60 film thickness yielded large changes in the enhancement and angularity properties of the SPCE signal, which can be exploited for sensing applications. Finally, the low-cost fabrication process of the Ag-C60 thin film stacks render C60 based SPCE substrates ideal, for the economic and simplistic detection of analytes. PMID- 25785917 TI - Copper-catalyzed aerobic cascade cycloamination and acyloxylation: a direct approach to 4-acyloxy-1H-pyrazoles. AB - A novel direct transformation of hydrazones to acyloxylated pyrazoles by copper catalyzed regioselective olefinic C(sp(2))-H bond cycloamination and acyloxylation was performed under mild conditions, which combines the formation of the pyrazole skeleton and installation of an acyloxyl group in a single step, using facile carboxylic acids as the acyloxylation reagents. PMID- 25785918 TI - Comparison of dynamic contrast-enhanced MRI parameters of breast lesions at 1.5 and 3.0 T: a pilot study. AB - OBJECTIVE: To compare dynamic contrast-enhanced (DCE) MRI parameters from scans of breast lesions at 1.5 and 3.0 T. METHODS: 11 patients underwent paired MRI examinations in both Philips 1.5 and 3.0 T systems (Best, Netherlands) using a standard clinical fat-suppressed, T1 weighted DCE-MRI protocol, with 70-76 s temporal resolution. Signal intensity vs time curves were fit with an empirical mathematical model to obtain semi-quantitative measures of uptake and washout rates as well as time-to-peak enhancement (TTP). Maximum percent enhancement and signal enhancement ratio (SER) were also measured for each lesion. Percent differences between parameters measured at the two field strengths were compared. RESULTS: TTP and SER parameters measured at 1.5 and 3.0 T were similar; with mean absolute differences of 19% and 22%, respectively. Maximum percent signal enhancement was significantly higher at 3 T than at 1.5 T (p = 0.006). Qualitative assessment showed that image quality was significantly higher at 3 T (p = 0.005). CONCLUSION: Our results suggest that TTP and SER are more robust to field strength change than other measured kinetic parameters, and therefore measurements of these parameters can be more easily standardized than measurements of other parameters derived from DCE-MRI. Semi-quantitative measures of overall kinetic curve shape showed higher reproducibility than do discrete classification of kinetic curve early and delayed phases in a majority of the cases studied. ADVANCES IN KNOWLEDGE: Qualitative measures of curve shape are not consistent across field strength even when acquisition parameters are standardized. Quantitative measures of overall kinetic curve shape, by contrast, have higher reproducibility. PMID- 25785919 TI - 3-T diffusion tensor imaging (DTI) of normal uterus in young and middle-aged females during the menstrual cycle: evaluation of the cyclic changes of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values. AB - OBJECTIVE: To evaluate cyclic changes of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of normal uterus in different age groups during the menstrual cycle, and the correlation with serum female hormone levels. METHODS: 29 normal volunteers accepted diffusion tensor imaging of the uterus on menstrual phase (MP), follicular phase (FP), ovulatory phase (OP) and luteal phase. FA and ADC values of different uterine layers on midsagittal images were measured. Differences between two age groups during the menstrual cycle were evaluated using liner mixed models and one-way analysis of variance. Pearson correlation analysis compared variation of FA and ADC values with serum female hormone levels measured in MP. RESULTS: During menstrual cycle, endometrial FA values declined, whereas ADC values increased with significant differences (p < 0.05). Serum oestradiol (E) levels correlated moderately with variations of FA values between MP-FP (p = 0.045; r = 0.389) and MP-OP (p = 0.008; r = 0.511). FA and ADC values of junctional zones showed no significant difference (p > 0.05) as well as FA values of myometrium (p = 0.0961), while ADC values of myometrium showed significant increase from menstrual phase to luteal phase (p < 0.05). FA and ADC values of uterine three zonal structures showed significant differences (p < 0.05) at each phase during the menstrual cycle. No significant difference of FA and ADC values was found between age groups (p > 0.05). CONCLUSION: Dynamic changes of uterine FA and ADC values were observed during menstrual cycle. Variation of FA values between MP-FP, MP-OP correlated moderately with serum E levels. ADVANCES IN KNOWLEDGE: No publications on the relationship between FA and ADC values and the female hormone levels were found; our study prospectively investigated the cyclic changes of FA and ADC values of the normal uterus and the correlation with the basic serum female hormone levels in MP. PMID- 25785920 TI - Functional outcomes of patients with amputation receiving chronic dialysis for end-stage renal disease. AB - OBJECTIVE: The aim of this study was to compare the rehabilitation length of stay and functional outcome of patients with amputation on chronic dialysis with a similar group of patients not on dialysis. DESIGN: This was a retrospective cohort study. Twenty-five patients with amputations on chronic dialysis and 25 nonrenal controls with amputation were included in the two groups. Primary outcome measures were Functional Independence Measure scores through discharge and follow-up, the percentage of patients fitted with a prosthesis, the number of patients able to ambulate independently indoors or outdoors or operate a wheelchair, and acute and rehabilitation length of stay for inpatients. Comorbidities and complications in end-stage renal disease (ESRD) patients with amputation on chronic dialysis vs. those without renal disease were also evaluated. RESULTS: Eleven women and 14 men were included in each group. The study group patients were younger than non-ESRD controls (54 +/- 12 and 61 +/- 11 yrs, respectively; P = 0.05). No significant differences were found between the groups in sex, race, amputation etiology, or comorbidities, except minor amputations of toes and fingers, which were performed more often in the ESRD group compared with the non-ESRD group (14 and 2, respectively; P = 0.0003). Functional Independence Measure score was higher in the non-ESRD group on discharge (112.1 +/- 7.6 vs. 107.5 +/- 7.7; P = 0.04) and follow-up (111.3 +/- 10.7 vs. 104.4 +/- 8.7; P = 0.02). The number of patients able to ambulate indoors and outdoors or operate wheelchair independently on discharge was not statistically different between the groups. Length of stay was higher in the ESRD group (153 +/- 67 vs. 105 +/- 42 days; P = 0.04). CONCLUSIONS: Patients with limb amputations on chronic dialysis had significantly longer length of stay and lower Functional Independence Measure scores compared with the non-ESRD group. It is suggested that current practices may need to be adjusted to accommodate the complex rehabilitation needs of the ESRD patient population. PMID- 25785921 TI - Clinical and economic characteristics of total hip replacement patients with high health care costs and high health care use. AB - OBJECTIVE: The aims of this study were to confirm whether total hip arthroplasty (THA) patients with muscle atrophy/weakness (MAW) have high health care costs and resource use and to identify the characteristics that contribute to these high costs and use. DESIGN: This study analyzed claims from United States patients who underwent THA identified from commercial (n = 25,249) and Medicare (n = 22,472) insurance databases to compare demographics, health care costs, and resource use among patients with or without MAW. The patients were classified into three separate cohorts: pre-MAW (having MAW during the 12 mos before THA), post-MAW (having MAW during the 12 mos after THA, and no-MAW (no MAW claim). Characteristics of the THA patients associated with high health care costs were examined by multiple logistic regression, and subgroups of patients with high cost and high resource use were identified by classification and regression tree analyses. RESULTS: Health care use and costs were significantly higher for the THA patients with MAW, who had greater likelihood of inpatient and emergency department use and stays at skilled nursing facilities than the no-MAW patients. Classification and regression tree identified subgroups of high-cost patients as those with MAW having extended hospital stays and more outpatient visits. CONCLUSIONS: THA patients with MAW are at greater risk for high health care costs and resource consumption, including longer hospital stays, increased outpatient visits, and stays at skilled nursing and inpatient rehabilitation facilities. PMID- 25785922 TI - Physical therapy with drug treatment in Bell palsy: a focused review. AB - The physical therapy (PT) associated with standard drug treatment (SDT) in Bell palsy has never been investigated. Randomized controlled trials or quasirandomized controlled trials have compared facial PT (except treatments such as acupuncture and osteopathic) combined with SDT against a control group with SDT alone. Participants included those older than 15 yrs with a clinical diagnosis of Bell palsy, and the primary outcome measure was motor function recovery by the House-Brackmann scale. The methodologic quality of each study was also independently assessed by two reviewers using the PEDro scale. Four studies met the inclusion criteria. Three trials indicate that PT in association with SDT supports higher motor function recovery than SDT alone between 15 days and 1 yr of follow-up. On the other hand, one trial showed that electrical stimulation added to conventional PT with SDT did not influence treatment outcomes. The present review suggests that the current practice of Bell palsy treatment by PT associated with SDT seems to have a positive effect on grade and time recovery compared with SDT alone. However, there is very little quality evidence from randomized controlled trials, and such evidence is insufficient to decide whether combined treatment is beneficial in the management of Bell palsy. PMID- 25785923 TI - Do not rush to return to sports after trigger finger injection. AB - Trigger finger, or digital stenosing tenosynovitis, is a common hand problem. A widely accepted treatment is steroid injection into the flexor tendon sheath. This can cause rupture of the flexor tendon. However, to the best of our knowledge, there is no report on tendon rupture after a single corticosteroid injection. Moreover, there are no guidelines for patients with tendinopathy who want to return to sports after corticosteroid injection. Clinicians who perform local steroid injections for tendinopathy treatment should be aware of the possible dangers of tendon rupture and should confirm that steroids are not administrated into the tendon. Patients should also be warned about returning to sports prematurely and should be encouraged to gradually resume sports after the injection to prevent further damage. Herein, we report an unusual case of flexor digitorum profundus rupture after a single corticosteroid injection in a 57-yr old male golfer and we also present a review of the literature. PMID- 25785924 TI - Delayed diagnosis of severe traumatic brain injury. PMID- 25785925 TI - Outcomes of paraesophageal hernia repair. PMID- 25785926 TI - Comparative kinetics of the 3-buten-1-ol and 1-butene reactions with OH radicals: a density functional theory/RRKM investigation. AB - The compared kinetics of the reactions of unsaturated alcohols and alkenes with OH radicals is a topic of great interest from both the theoretical chemistry and the atmospheric chemistry points of view. The enhanced reactivity of an unsaturated alcohol, with respect to its alkene analogue, toward OH radicals has been previously demonstrated, at 298 K, by experimental and theoretical research. In this work, a new comparative investigation of such reactions is performed for 3-buten-1-ol and 1-butene. The model assumes that the overall kinetics is governed by the first OH addition steps of the mechanism. Calculations have been performed at the DFT level, employing the BHandHLYP functional and the cc-pVDZ and aug-cc-pVDZ basis sets, and the rate coefficients have been determined on the basis of the microcanonical variational transition state theory. The rate coefficients obtained for the OH reactions with 3-buten-1-ol (kOH(31BO)) and 1 butene (kOH(1B)) at 298.15 K are lower than the experimental rate coefficient available in the literature, showing deviations of 18% and 25%, respectively. Negative temperature dependence is verified for these rate coefficients. The kOH(31BO)/kOH(1B) ratios have also been investigated as a function of the temperature, suggesting that at room temperature the unsaturated alcohol reacts with the OH radicals faster than 1-butene, by a factor of 1.2, but at higher temperatures (400-500 K), the alkene should react faster, and that the stabilization of prebarrier complexes and saddle points due to hydrogen bonds is no longer an important factor to govern the reactivity of the unsaturated alcohol toward OH radicals, with respect to the alkene analogue. PMID- 25785927 TI - A ratiometric fluorescent probe for in situ quantification of basal mitochondrial hypochlorite in cancer cells. AB - A ratiometric fluorescent probe () for ClO(-) based on the conjugate of coumarin rhodamine was presented, which could sense ClO(-) with fast response (within 5 s), high sensitivity and excellent selectivity. More importantly, is the first mitochondria-targeted ratiometric fluorescent probe to image exogenous and endogenous ClO(-). PMID- 25785928 TI - Adipose Tissue Insulin Action and IL-6 Signaling after Exercise in Obese Mice. AB - INTRODUCTION: Adipose tissue insulin action is impaired in obesity and is associated with inflammation, macrophage infiltration, and polarization toward a proinflammatory phenotype. Acute exercise can reduce markers of adipose inflammation, including interleukin (IL) 6, in parallel with improvements in insulin action; however, others have provided evidence that IL-6 has anti inflammatory properties. PURPOSE: This study aimed to examine the relation between IL-6 signaling, macrophage infiltration, and polarization and insulin action in inguinal fat after acute exercise in obese, insulin-resistant mice. METHODS: Male C57BL/6 mice were fed a low-fat diet (10% kcal lard) or a high-fat diet (HFD, 60% kcal lard) for 7 wk and then underwent an acute bout of exercise (2-h treadmill running: 15 m.min, 5% incline). RESULTS: The HFD resulted in increased body mass, glucose intolerance, and attenuated insulin-induced AKT Thr308 phosphorylation in inguinal fat. This was accompanied by increases in indices of macrophage infiltration (F4/80, CD68, and monocyte chemoattractant protein-1 expression) and polarization toward an M1 phenotype (increased expression of CD11c, CD11c/galactose-type C-type lectin 1, and inducible nitric oxide synthase). Immunofluorescence imaging demonstrated increased F4/80- and CD11c-positive cells with the HFD. Two hours after exercise, the insulin-induced activation of AKT Th308 phosphorylation was recovered in HFD mice. This was accompanied by an upregulation of IL-6 and IL-10 signaling, as demonstrated by increased expression of IL-6, IL-10, and SOCS3 as well as STAT3 phosphorylation. Furthermore, acute exercise resulted in a shift toward reduction in M1 polarization indicated by a decrease in the ratio of CD11c to galactose-type C type lectin 1 mRNA as well as a decline in F4/80- and CD11c-positive cells. CONCLUSIONS: The results suggest a link between exercise-induced increases in IL 6, reductions in indices of M1 macrophages, and increased IL-10, a reputed anti inflammatory cytokine with insulin-sensitizing properties. PMID- 25785929 TI - Utilization and Harmonization of Adult Accelerometry Data: Review and Expert Consensus. AB - PURPOSE: This study aimed to describe the scope of accelerometry data collected internationally in adults and to obtain a consensus from measurement experts regarding the optimal strategies to harmonize international accelerometry data. METHODS: In March 2014, a comprehensive review was undertaken to identify studies that collected accelerometry data in adults (sample size, n >= 400). In addition, 20 physical activity experts were invited to participate in a two-phase Delphi process to obtain consensus on the following: unique research opportunities available with such data, additional data required to address these opportunities, strategies for enabling comparisons between studies/countries, requirements for implementing/progressing such strategies, and value of a global repository of accelerometry data. RESULTS: The review identified accelerometry data from more than 275,000 adults from 76 studies across 36 countries. Consensus was achieved after two rounds of the Delphi process; 18 experts participated in one or both rounds. The key opportunities highlighted were the ability for cross country/cross-population comparisons and the analytic options available with the larger heterogeneity and greater statistical power. Basic sociodemographic and anthropometric data were considered a prerequisite for this. Disclosure of monitor specifications and protocols for data collection and processing were deemed essential to enable comparison and data harmonization. There was strong consensus that standardization of data collection, processing, and analytical procedures was needed. To implement these strategies, communication and consensus among researchers, development of an online infrastructure, and methodological comparison work were required. There was consensus that a global accelerometry data repository would be beneficial and worthwhile. CONCLUSIONS: This foundational resource can lead to implementation of key priority areas and identification of future directions in physical activity epidemiology, population monitoring, and burden of disease estimates. PMID- 25785930 TI - Do Short Spurts of Physical Activity Benefit Cardiovascular Health? The CARDIA Study. AB - BACKGROUND: For optimal health benefits, moderate- to vigorous-intensity physical activity (MVPA) is recommended in sustained bouts lasting >=10 min. However, short spurts of MVPA lasting <10 min are more common in everyday life. It is unclear whether short spurts of MVPA further protect against the development of hypertension and obesity in middle-age adults beyond bouted MVPA. METHODS: Objectively measured physical activity was collected in the Coronary Artery Risk Development in Young Adults study at the 20-yr (2005-2006) examination, and blood pressure and BMI were collected at the 20- and 25-yr (2010-2011) examinations. Time spent in MVPA was classified as either bouted MVPA, i.e., >=10 continuous minutes or short spurts of MVPA, i.e., <10 continuous minutes. To examine the association of short spurts of MVPA with incident hypertension and obesity over 5 yr, we calculated risk ratios adjusted for bouted MVPA and potential confounders. RESULTS: Among 1531 and 1251 participants without hypertension and obesity, respectively, at year 20 (age, 45.2 +/- 3.6 yr; 57.3% women; body mass index, 29.0 +/- 7.0 kg.m(-2)), 14.8% and 12.1% developed hypertension and obesity by year 25. Study participants in the highest tertile of short spurts of MVPA were 31% less likely to develop hypertension 5 yr later (risk ratio = 0.69 (0.49 0.96)) compared with those in the lowest tertile. There was no statistically significant association of short spurts of MVPA with incident obesity. CONCLUSIONS: These findings support the notion that accumulating short spurts of MVPA protects against the development of hypertension but not obesity in middle age adults. PMID- 25785931 TI - Loss of Adipocyte VEGF Impairs Endurance Exercise Capacity in Mice. AB - PURPOSE: Reducing vascular endothelial growth factor (VEGF) in adipose tissue alters adipose vascularity and metabolic homeostasis. We hypothesized that this would also affect metabolic responses during exercise-induced stress and that adipocyte-specific VEGF-deficient (adipoVEGF-/-) mice would have impaired endurance capacity. METHODS: Endurance exercise capacity in adipoVEGF-/- (n = 10) and littermate control (n = 11) mice was evaluated every 4 wk between 6 and 24 wk of age using a submaximal endurance run to exhaustion at 20 m.min(-1) at 10 degrees incline. Maximal running speed, using incremental increases in speed at 30-s intervals, was tested at 25 and 37 wk of age. RESULTS: White and brown adipose tissue capillarity were reduced by 40% in adipoVEGF-/-, and no difference in skeletal muscle capillarity was observed. Endurance run time to exhaustion was 30% lower in adipoVEGF-/- compared with that in controls at all time points (P < 0.001), but no difference in maximal running speed was observed between the groups. After exercise (1 h at 50% maximum running speed), adipoVEGF-/- mice displayed lower circulating insulin (P < 0.001), lower glycerol (P < 0.05), and tendency for lower blood glucose (P = 0.06) compared with controls. There was no evidence of altered oxidative damage or changes in carnitine palmitoyltransferase 1beta expression in skeletal muscle of adipoVEGF-/- mice. CONCLUSIONS: These data suggest that VEGF-mediated deficits in adipose tissue blunt the availability of lipid substrates during endurance exercise, which likely reduced endurance performance. Surprisingly, we also found an unchanged basal blood glucose despite lower circulating insulin in adipoVEGF-/- mice, suggesting that loss of adipocyte VEGF can blunt insulin release and/or increase basal insulin sensitivity. PMID- 25785933 TI - Tile-based Fisher ratio analysis of comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC * GC-TOFMS) data using a null distribution approach. AB - Comprehensive two-dimensional (2D) gas chromatography coupled with time-of-flight mass spectrometry (GC * GC-TOFMS) is a versatile instrumental platform capable of collecting highly informative, yet highly complex, chemical data for a variety of samples. Fisher-ratio (F-ratio) analysis applied to the supervised comparison of sample classes algorithmically reduces complex GC * GC-TOFMS data sets to find class distinguishing chemical features. F-ratio analysis, using a tile-based algorithm, significantly reduces the adverse effects of chromatographic misalignment and spurious covariance of the detected signal, enhancing the discovery of true positives while simultaneously reducing the likelihood of detecting false positives. Herein, we report a study using tile-based F-ratio analysis whereby four non-native analytes were spiked into diesel fuel at several concentrations ranging from 0 to 100 ppm. Spike level comparisons were performed in two regimes: comparing the spiked samples to the nonspiked fuel matrix and to each other at relative concentration factors of two. Redundant hits were algorithmically removed by refocusing the tiled results onto the original high resolution pixel level data. To objectively limit the tile-based F-ratio results to only features which are statistically likely to be true positives, we developed a combinatorial technique using null class comparisons, called null distribution analysis, by which we determined a statistically defensible F-ratio cutoff for the analysis of the hit list. After applying null distribution analysis, spiked analytes were reliably discovered at ~1 to ~10 ppm (~5 to ~50 pg using a 200:1 split), depending upon the degree of mass spectral selectivity and 2D chromatographic resolution, with minimal occurrence of false positives. To place the relevance of this work among other methods in this field, results are compared to those for pixel and peak table-based approaches. PMID- 25785932 TI - Ruta graveolens L. induces death of glioblastoma cells and neural progenitors, but not of neurons, via ERK 1/2 and AKT activation. AB - Glioblastoma multiforme is a highly aggressive brain tumor whose prognosis is very poor. Due to early invasion of brain parenchyma, its complete surgical removal is nearly impossible, and even after aggressive combined treatment (association of surgery and chemo- and radio-therapy) five-year survival is only about 10%. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases, including cancer. Here, we report that the water extract of Ruta graveolens L., commonly known as rue, induces death in different glioblastoma cell lines (U87MG, C6 and U138) widely used to test novel drugs in preclinical studies. Ruta graveolens' effect was mediated by ERK1/2 and AKT activation, and the inhibition of these pathways, via PD98058 and wortmannin, reverted its antiproliferative activity. Rue extract also affects survival of neural precursor cells (A1) obtained from embryonic mouse CNS. As in the case of glioma cells, rue stimulates the activation of ERK1/2 and AKT in A1 cells, whereas their blockade by pharmacological inhibitors prevents cell death. Interestingly, upon induction of differentiation and cell cycle exit, A1 cells become resistant to rue's noxious effects but not to those of temozolomide and cisplatin, two alkylating agents widely used in glioblastoma therapy. Finally, rutin, a major component of the Ruta graveolens water extract, failed to cause cell death, suggesting that rutin by itself is not responsible for the observed effects. In conclusion, we report that rue extracts induce glioma cell death, discriminating between proliferating/undifferentiated and non proliferating/differentiated neurons. Thus, it can be a promising tool to isolate novel drugs and also to discover targets for therapeutic intervention. PMID- 25785934 TI - Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe. AB - BACKGROUND: There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. AIM: To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. METHODS: We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases >=3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance. RESULTS: Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible. CONCLUSIONS: Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance. PMID- 25785935 TI - Vaccination with human papillomavirus pseudovirus-encapsidated plasmids targeted to skin using microneedles. AB - Human papilloma virus-like particles (HPV VLP) serve as the basis of the current licensed vaccines for HPV. We have previously shown that encapsidation of DNA expressing the model antigen M/M2 from respiratory syncytial virus (RSV) in HPV pseudovirions (PsV) is immunogenic when delivered intravaginally. Because the HPV capsids confer tropism for basal epithelium, they represent attractive carriers for vaccination targeted to the skin using microneedles. In this study we asked: 1) whether HPV16 VLP administered by microneedles could induce protective immune responses to HPV16 and 2) whether HPV16 PsV-encapsidated plasmids delivered by microneedles could elicit immune responses to both HPV and the antigen delivered by the transgene. Mice immunized with HPV16 VLP coated microneedles generated robust neutralizing antibody responses and were protected from HPV16 challenge. Microneedle arrays coated with HPV16-M/M2 or HPV16-F protein (genes of RSV) were then tested and dose-dependent HPV and F-specific antibody responses were detected post-immunization, and M/M2-specific T-cell responses were detected post RSV challenge, respectively. HPV16 PsV-F immunized mice were fully protected from challenge with HPV16 PsV and had reduced RSV viral load in lung and nose upon intranasal RSV challenge. In summary, HPV16 PsV-encapsidated DNA delivered by microneedles induced neutralizing antibody responses against HPV and primed for antibody and T-cell responses to RSV antigens encoded by the encapsidated plasmids. Although the immunogenicity of the DNA component was just above the dose response threshold, the HPV-specific immunity was robust. Taken together, these data suggest microneedle delivery of lyophilized HPV PsV could provide a practical, thermostable combined vaccine approach that could be developed for clinical evaluation. PMID- 25785936 TI - Upregulation of glycolytic enzymes, mitochondrial dysfunction and increased cytotoxicity in glial cells treated with Alzheimer's disease plasma. AB - Alzheimer's disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia. PMID- 25785938 TI - Mother and offspring in conflict: why not? AB - A gene mediating interactions between mouse mothers and their pups has recently been claimed to support coadaptation rather than the kinship theory of genomic imprinting. This Formal Comment argues that this claim is unfounded. PMID- 25785937 TI - Increased eicosanoid levels in the Sugen/chronic hypoxia model of severe pulmonary hypertension. AB - Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX 2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established. PMID- 25785939 TI - EEG findings of reduced neural synchronization during visual integration in schizophrenia. AB - Schizophrenia patients exhibit well-documented visual processing deficits. One area of disruption is visual integration, the ability to form global objects from local elements. However, most studies of visual integration in schizophrenia have been conducted in the context of an active attention task, which may influence the findings. In this study we examined visual integration using electroencephalography (EEG) in a passive task to elucidate neural mechanisms associated with poor visual integration. Forty-six schizophrenia patients and 30 healthy controls had EEG recorded while passively viewing figures comprised of real, illusory, or no contours. We examined visual P100, N100, and P200 event related potential (ERP) components, as well as neural synchronization in the gamma (30-60 Hz) band assessed by the EEG phase locking factor (PLF). The N100 was significantly larger to illusory vs. no contour, and illusory vs. real contour stimuli while the P200 was larger only to real vs. illusory stimuli; there were no significant interactions with group. Compared to controls, patients failed to show increased phase locking to illusory versus no contours between 40 60 Hz. Also, controls, but not patients, had larger PLF between 30-40 Hz when viewing real vs. illusory contours. Finally, the positive symptom factor of the BPRS was negatively correlated with PLF values between 40-60 Hz to illusory stimuli, and with PLF between 30-40 Hz to real contour stimuli. These results suggest that the pattern of results across visual processing conditions is similar in patients and controls. However, patients have deficits in neural synchronization in the gamma range during basic processing of illusory contours when attentional demand is limited. PMID- 25785940 TI - An alpha-MSH analog in erythropoietic protoporphyria. PMID- 25785944 TI - Leonard C. Harber (1927-2014). PMID- 25785945 TI - Next-generation sequencing for mutation detection in heritable skin diseases: the paradigm of pseudoxanthoma elasticum. AB - Next-generation sequencing applied either to the entire genome or to a subset, such as a whole exome, has revolutionized the search for pathogenic mutations in heritable diseases, including genodermatoses. In this issue, Hosen et al. applied whole-exome sequencing to identify potential pathogenic mutations in four candidate genes associated with pseudoxanthoma elasticum, the prototype of ectopic mineralization disorders. The study highlights the advantages of this approach over traditional Sanger sequencing, including expedience and cost, but it also illustrates some of the challenges encountered in implementing this rapidly evolving technology. PMID- 25785946 TI - The double life of connexin channels: single is a treat. AB - Although several genetic diseases are caused by mutations in channels made by connexin family members, there has been little progress in the development and validation of therapeutic options. An in vitro study in this issue of JID suggests that an anti-malarial drug may be beneficial in keratitis-ichthyosis deafness, a severe conexin channel disease associated with potentially fatal recurrent infections. PMID- 25785947 TI - When the circadian clock meets the melanin pigmentary system. AB - Silencing of BMAL1 and PER1 stimulates melanogenic activity of follicular and epidermal melanocytes, indicating a novel role for peripheral circadian clock processes in the regulation of melanin pigmentation. Linking the expression levels of BMAL1/PER1 with changes in melanogenesis opens exciting opportunities to study the role of the local molecular clock in modulation of melanocyte functions in the hair follicle and the epidermis with attendant effects on epidermal barrier functions in general. PMID- 25785948 TI - Hsp90 inhibitor can inhibit UV carcinogenesis. AB - Extensive exposure to solar UVR is a well-recognized etiologic factor for cutaneous non-melanoma skin cancer. In this issue of the Journal, Singh et al. show that topical treatment of the skin with 17-[allylamino]-17 demethoxygeldanamycin (17AAG), a heat-shock protein 90 (Hsp90) inhibitor, prevents UVR-induced squamous cell carcinomas (SCCs) in mice. The inhibitory effect of 17AAG on SCC was associated with the inhibition of the UVR-induced (i) hyperplastic response, (ii) Hsp90beta-PKCE interaction, and (iii) pStat3 and pAkt expression in mouse skin. PMID- 25785949 TI - Focus on early detection to reduce melanoma deaths. AB - Thin fatal melanomas are a relatively new clinical and public health concern, representing an estimated 20% of melanoma deaths. Understanding this phenomenon will require a multi-pronged approach, including in-depth investigation of its behavioral and biological underpinnings. As we proceed with relevant studies, the benefits in lives saved will grow via early detection. PMID- 25785950 TI - Montagna Symposium 2014-skin aging: molecular mechanisms and tissue consequences. PMID- 25785951 TI - Cells to surgery quiz: April 2015. PMID- 25785952 TI - JID VisualDx Quiz: April 2015. PMID- 25785953 TI - The use of luminex assays to measure cytokines. PMID- 25785954 TI - Correction: Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation via beta-catenin signaling. PMID- 25785955 TI - Comparison of Clinical Outcomes of 1- and 2-Level Total Disc Replacement: Four Year Results From a Prospective, Randomized, Controlled, Multicenter IDE Clinical Trial. AB - STUDY DESIGN: A prospective, randomized, multicenter Food and Drug Administration Investigation Device Exemption study using total disc replacement as surgical treatment of degenerative disc disease at 1 or 2 contiguous levels of the cervical spine. OBJECTIVE: To evaluate the safety and effectiveness of total disc replacement at single or 2 contiguous levels through 48 months of follow-up. SUMMARY OF BACKGROUND DATA: Cervical total disc replacement has been shown to be a safe and effective alternative to anterior cervical discectomy and fusion at 24 months. Its motion-preserving capabilities may avoid accelerating adjacent segment pathology and thereby lower the rate of associated complications. METHODS: Patients were randomized in a 2:1 ratio (total disc replacement [TDR]: anterior cervical discectomy and fusion [ACDF]) at 24 sites. Ultimately, 164 patients received TDR at 1 level and 225 patients received TDR at 2 contiguous levels. An additional 24 patients (15 one-level, 9 two-level) were treated with TDR as training cases.Outcome measures included neck disability index, visual analogue scale neck and arm pain, Short Form 12-item Health Survey (SF-12) Mental Composite Score (MCS) and Physical Composite Score (PCS), range of motion, major complication rates, and secondary surgery rates. Patients received follow-up examinations at regular intervals through 4 years after surgery. RESULTS: Preoperative characteristics were statistically similar for the 1- and 2-level patient groups. Four-year follow-up rates were 83.1% (1-level) and 89.0% (2 level). There was no statistically significant difference between 1- and 2-level TDR groups for all clinical outcome measures. Both TDR groups experienced significant improvement at each follow-up when compared with preoperative scores. One case of migration was reported in the 2-level TDR group. CONCLUSION: A 4-year post hoc comparison of 1- and 2-level TDR patients concurrently enrolled in a 24 center, Food and Drug Administration Investigation Device Exemption clinical trial indicated no statistical differences between groups in clinical outcomes, overall complication rates, and subsequent surgery rates. LEVEL OF EVIDENCE: 1. PMID- 25785956 TI - Has a Mono- or Bisegmental Lumbar Spinal Fusion Surgery an Influence on Self Assessed Quality of Life, Trunk Range of Motion, and Gait Performance? AB - STUDY DESIGN: This investigation prospectively compared self-assessed quality of life and biomechanical measures of physical function before and after spinal fusion surgery in 26 adult patients with symptomatic lumbar degenerative disease. OBJECTIVE: The objective was to demonstrate that (1) due to a reduction of low back pain, quality of life as well as gait parameters would improve after a spinal fusion surgery and (2) gait performance is more similar to that observed in healthy controls at the same age, whereas trunk range of motion remains unchanged after surgery. SUMMARY OF BACKGROUND DATA: Current outcome evaluations of spinal fusion surgery are based on radiological changes and self-report questionnaires. However, these traditional measures do not sufficiently assess the functionality. METHODS: Twenty-six patients with a mean age of 59.3 (SD: 10.1) years and 20 healthy subjects at the same age were evaluated. Before and approximately 6 months after a mono- or bisegmental spinal fusion surgery, patients completed self-report questionnaires and biomechanical assessments of gait analysis and trunk range of motion in the 3 principal planes of the body. RESULTS: Results indicated an improvement in quality of life as well as an increased pain-free walking distance, walking speed, step length, and maximum hip extension during the stance phase of gait. Anterior pelvis and thorax tilt were significantly reduced after the surgery without significant differences compared with the control group. Regarding the trunk range of motion, we observed a decrease in maximum forward flexion and an increase in the fingertip-floor distance after surgery. CONCLUSION: The study results show that lumbar spinal fusion is a useful procedure to improve patient's quality of life and gait performance. Although we performed only mono- and 2-level fusions, the sagittal alignment of the pelvis and thorax during walking was normalized. Clinical gait analysis contributes to the advancement of our knowledge regarding the functional changes after a spinal fusion surgery. LEVEL OF EVIDENCE: 2. PMID- 25785957 TI - Predicting In-Hospital Mortality in Elderly Patients With Cervical Spine Fractures: A Comparison of the Charlson and Elixhauser Comorbidity Measures. AB - STUDY DESIGN: Retrospective analysis of nationally representative data collected for the National Hospital Discharge Survey. OBJECTIVE: To compare the performance of the Charlson and Elixhauser comorbidity-based measures for predicting in hospital mortality after cervical spine fractures. SUMMARY OF BACKGROUND DATA: Mortality occurring as a consequence of cervical spine fractures is very high in the elderly. The Charlson comorbidity measure has been associated with an increased risk of mortality, but its predictive accuracy has yet to be compared with the more recent and increasingly used Elixhauser measure. METHODS: Using the National Hospital Discharge Survey for the years 1990 through 2007, we identified all patients aged 65 years or older hospitalized with a diagnosis of cervical spine fracture. The association of each Charlson and Elixhauser comorbidity with mortality was assessed in bivariate analysis using chi tests. Two main multivariable logistic regression models were constructed, with in-hospital mortality as the dependent variable and 1 of the 2 comorbidity-based measures (as well as age, sex, and year of admission) as independent variables. A base model that included only age, sex, and year of admission was also evaluated. The discriminative ability of the models was quantified using the area under the receiver operating characteristic curve (AUC). RESULTS: Among an estimated 111,564 patients admitted for cervical spine fractures, 7.6% died in the hospital. Elixhauser comorbidity adjustment provided better prediction of in hospital case mortality (AUC = 0.852, 95% confidence interval: 0.848-0.856) than the Charlson model (AUC = 0.823, 95% confidence interval: 0.819-0.828) and the base model with no comorbidities (AUC = 0.785, 95% confidence interval: 0.781 0.790). In terms of relative improvement in predictive ability, the Elixhauser model performed 43% better than the Charlson model. CONCLUSION: The Elixhauser comorbidity risk adjustment method performed numerically better than the widely used Charlson measure in predicting in-hospital mortality after cervical spine fractures. LEVEL OF EVIDENCE: N/A. PMID- 25785958 TI - The Evolution of Sagittal Spinal Alignment in Sitting Position During Childhood. AB - STUDY DESIGN: This is a cross-sectional descriptive study. OBJECTIVE: The purposes of this study are to describe normative data of the sagittal plane in the sitting position within the pediatric population and document the evolution of sagittal alignment during the growth. SUMMARY OF BACKGROUND DATA: Surgical procedures addressing the deformity aim to make the maximal correction on the coronal and transverse planes and to restore the physiological curves on the sagittal plane. Prerequisite for sagittal plane reconstruction is to know the physiological values. METHODS: Children between 3 and 17 years of age, followed by pediatrics unit for nonskeleton disease with lateral radiographs of the entire spine and pelvis on sitting positions, were included to the study. Children with history of surgery or disease that may affect spine development were excluded. Children were evaluated in 4 age groups (3-6, 7-9, 10-12, and 13-17 yr) in terms of spinal sagittal alignment on sitting position. RESULTS: Of the screened, 124 children (49 girls, 75 boys) were included. Descriptive statistics of all possible segmental angles were summarized. Thoracic kyphosis and lumbar lordosis values were lower on sitting position than on standing position. Thoracic segmental angulations steadily increased from T1-T2 to midthoracic segments and then decreased in caudal direction. Moreover, lumbar segmental angulations steadily increased in cephalocaudal direction. Sacral slope, L4-S1 angulation, and T1-T12 and T1-S1 distance tend to increase as the age increases. CONCLUSION: Sagittal spinal alignment in the sitting position is different than that in the standing position and it changes as the child grows. There is a statistically significant difference between different age groups, especially at the cervicothoracic, thoracolumbar, and lumbosacral junctions. These findings should be taken into consideration for young nonambulatory patients who require spinal instrumentation and/or fusion. LEVEL OF EVIDENCE: 2. PMID- 25785959 TI - The Molecular Feature of HOX Gene Family in the Intramedullary Spinal Tumors. AB - STUDY DESIGN: The expression of HOXB13 and HOXA9 proteins was detected. OBJECTIVE: The purpose of this study was to investigate the molecular signature of spinal ependymoma (EPN) and astrocytoma, 2 most common types of intramedullary spinal tumor. SUMMARY OF BACKGROUND DATA: Intramedullary spinal tumor is unusual. It leads to high neurological morbidity and mortality without treatment. Till now, its molecular feature has been elucidated up to a little extent. METHODS: A total of 37 cases of spinal EPN, including 12 myxopapillary EPNs (MEPNs), 18 classic EPNs, and 7 anaplastic EPNs, and another 12 cases of astrocytoma were selected for this study. Immunohistochemical analysis of a large cohort of patients providing clinical tumor samples was performed to compare the expression of HOXB13 and HOXA9 not only between spinal EPN and astrocytoma but also among all 3 World Health Organization grades of spinal EPN. RESULTS: The results showed that HOXB13 and HOXA9 were selectively expressed in spinal EPN instead of astrocytoma. Furthermore, we found the strongest positive response of HOXB13 in MEPN whereas that of HOXA9 was ubiquitously detected in all subgroups of EPN. CONCLUSION: Both specificity and sensitivity of HOXB13 in MEPN indicated that HOXB13 might be a diagnostic marker to distinguish MEPN from other 2 types of EPN and a promising therapeutic target for MEPN. The strong immunoreactivity of HOXA9 in spinal EPN suggested an indispensable role in the progression of spinal EPN, and further research on its molecular function will provide new clues for the development of treatment options. LEVEL OF EVIDENCE: N /A. PMID- 25785960 TI - Analysis of the Fracture Mechanism of Ti-6Al-4V Alloy Rods That Failed Clinically After Spinal Instrumentation Surgery. AB - STUDY DESIGN: Retrieval analysis of 2 Ti-6Al-4V alloy rods that fractured after spinal instrumentation surgery. OBJECTIVE: To determine the mechanism that underlies fractures of Ti-6Al-4V alloy rods after spinal instrumentation surgery from a materials science viewpoint. SUMMARY OF BACKGROUND DATA: Rod failures after spinal instrumentation surgery are often reported and many case-based studies have been published. However, the details of the mechanism that underlies the fractures have not yet been fully elucidated. METHODS: Two patients, a 71 year-old female and an 11-year-old male, underwent radiography and removal of their fractured rods. The latter patient had been treated using the growing-rod method. Metallurgical failure analysis of the retrieved rods was conducted, and material properties were compared between the unused and fractured rods. RESULTS: The microstructures and mechanical properties of the Ti-6Al-4V alloy rods that failed after spinal instrumentation surgery were similar to those of unused rods. Analysis of the fracture surfaces clearly identified fatigue cracking in both cases that would have lowered the resistance of the rods to failures caused by external stresses. Shot blasting the surfaces of Ti-6Al-4V alloy rods and bending the rods to fit particular contours, which is always conducted during spinal instrumentation surgery, probably introduced fatigue cracking because the alloy is highly notch sensitive. CONCLUSION: Improvements should be made to rod design and/or rod material, because the fatigue resistance of titanium alloys is intrinsically lower than that of other commercially available rod materials, including cobalt-chromium alloys. These imperfections may have greater consequences for the growing-rod method and pseudarthrosis, where the rods are not completely fixed, and they subsequently suffer from severe long-arm moments. LEVEL OF EVIDENCE: N/A. PMID- 25785961 TI - The Rapid and Progressive Degeneration of the Cervical Multifidus in Whiplash: An MRI Study of Fatty Infiltration. AB - STUDY DESIGN: Single-center prospective longitudinal study. OBJECTIVE: To study the (1) temporal development of muscle fatty infiltrates (MFI) in the cervical multifidi after whiplash, (2) differences in multifidi MFI between those who recover or report milder pain-related disability and those who report moderate/severe symptoms at 3 months, and (3) predictive value of multifidi MFI outcomes. SUMMARY OF BACKGROUND DATA: The temporal development of MFI on conventional magnetic resonance image has been shown to be associated with specific aspects of pain and psychological factors. The replication of such findings has yet to be explored longitudinally. METHODS: Thirty-six subjects with whiplash injury were enrolled at less than 1 week postinjury and classified at 3 months using percentage scores on the Neck Disability Index as recovered/mild (0% 28%) or severe (>=30%). A fat/water magnetic resonance imaging measure, patient self-report of pain-related disability, and post-traumatic stress disorder were collected at less than 1 week, 2 weeks, and 3 months postinjury. The effects of time and group (per Neck Disability Index) and the interaction of time by group on MFI were determined. Receiver operating characteristic curve analysis was used to determine a cut-point for MFI at 2 weeks to predict outcome at 3 months. RESULTS: There was no difference in MFI across groups at enrolment. MFI values were significantly higher in the severe group than those in the recovered/mild group at 2 weeks and 3 months. The receiver operating characteristic curve analysis indicated that MFI levels of 20.5% or above resulted in a sensitivity of 87.5% and a specificity of 92.9% for predicting outcome at 3 months. CONCLUSION: Consistent with previous evidence, muscle degeneration occurs soon after injury but only in those patients with poor functional recovery. This study provides further evidence that (1) multifidi MFI occur in tandem with known predictive risk factors (older age, pain-related disability, and post-traumatic stress disorder) and (2) routine imaging protocols may need to be reconsidered in the vast majority of patients after whiplash. LEVEL OF EVIDENCE: 3. PMID- 25785962 TI - Differentiation of Human Ligamentum Flavum Stem Cells Toward Nucleus Pulposus Like Cells Induced by Coculture System and Hypoxia. AB - STUDY DESIGN: Human ligamentum flavum (LF)-derived stem cells (LFSCs) and nucleus pulposus cells (NPCs) were cocultured under normoxia or hypoxia. OBJECTIVE: To isolate and identify human LFSCs and determine whether they can differentiate into NPCs when cocultured with NPCs under hypoxia. SUMMARY OF BACKGROUND DATA: Mesenchymal stem cell (MSC)-based therapies have been proposed as a biological treatment for intervertebral disc degeneration. MSCs derived from various tissues are leading candidates for cell-based therapies, but such cells have not been reported in LF. METHODS: LF cells were isolated from patient samples and cultured using culture flasks coated with fibronectin, and their identity was confirmed using flow cytometry. The cells were induced to differentiate into osteoblasts, chondrocytes, and adipocytes, and their morphology, immunophenotype, cell proliferation capacity, cell cycle, and expression of stem cell-specific genes were compared with those of bone marrow-MSCs (BM-MSCs) derived from the same patients. NPCs and LFSCs were cocultured in 1-MUm-pore-size insert transwell culture systems under hypoxia (2% O2) or normoxia. CD24 expression was measured by flow cytometry and confocal microscopy assay. On day 14, reverse transcription polymerase chain reaction was used for comparing the expression of chondrogenic genes (Sox-9, collagen-II, aggrecan) and novel marker genes (KRT19, CA12, FOXF1, HIF-1alpha) between the 2 groups. RESULTS: LFSCs were obtained using the fibronectin differential-adhesion assay. The morphology of LFSCs was altered, and their immunophenotype, multilineage induction, cell proliferation capacity, cell cycle, and stem cell-specific gene expression were closely related-but not identical-to BM-MSCs, CD24 expression was highly significant in the differentiated LFSCs. RT/Real-time polymerase chain reaction revealed that compared with LFSCs grown under normoxia, hypoxia-treated LFSCs expressed higher levels of Sox-9, collagen-II, aggrecan, KRT19, CA12, and HIF-1alpha genes except FOXF1. CONCLUSION: Stem cells were identified in human LF, and LFSCs cocultured with NPCs were successfully differentiated into NP-like cells under hypoxia. This potentially provides new cell candidates for cell-based regenerative medicine and tissue engineering. LEVEL OF EVIDENCE: N/A. PMID- 25785963 TI - Analysis of Delays to Surgery for Cervical Spinal Cord Injuries. AB - STUDY DESIGN: A retrospective study of surgically treated patients with cervical spinal cord injury (SCI) from the National Trauma Data Bank Research Data Set. OBJECTIVE: To determine how time to surgery differs between SCI subtypes, where delays before surgery occur, and what factors are associated with delays. SUMMARY OF BACKGROUND DATA: Studies have shown that patients with cervical SCI undergoing surgery within 24 hours after injury have superior neurological outcomes to patients undergoing later surgery, with most evidence coming from the incomplete SCI subpopulation. METHODS: Surgically treated patients with cervical SCI from 2011 and 2012 were identified in National Trauma Data Bank Research Data Set and divided into subpopulations of complete, central, and other incomplete SCIs. Relationships between surgical timing and patient and injury characteristics were analyzed using multivariate regression. RESULTS: A total of 2636 patients with cervical SCI were identified: 803 with complete SCI, 950 with incomplete SCI, and 883 with central SCI. The average time to surgery was 51.1 hours for patients with complete SCI, 55.3 hours for patients with incomplete SCI, and 83.1 hours for patients with central SCI. Only 44% of patients with SCI underwent surgery within the first 24 hours after injury, including only 49% of patients with incomplete SCI.The vast majority of time between injury and surgery was after admission, rather than in the emergency department or in the field. Upper cervical SCIs and greater Charlson Comorbidity Index were associated with later surgery in all 3 SCI subpopulations. CONCLUSION: The majority of patients with SCI do not undergo surgery within the first 24 hours after injury, and the majority of delays occur after inpatient admission. Factors associated with these delays highlight areas of focus for expediting care in these patient populations. LEVEL OF EVIDENCE: 4. PMID- 25785964 TI - The Impact of Renal Impairment on Short-term Morbidity Risk Following Lumbar Spine Surgeries. AB - STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To determine a cutoff below which worsening renal function is associated with increased risk of morbidity and to determine the types and magnitude of morbidity associated with renal impairment. SUMMARY OF BACKGROUND DATA: Renal impairment is associated with an increased risk of morbidity after lumbar spine surgery. However, the degree to which increasing levels of renal dysfunction are associated with morbidity has not been well defined. METHODS: A large, multicenter, clinical registry was queried for all adult patients undergoing lumbar spine surgery in 2012, and 13,576 cases were identified. An estimated glomerular filtration rate (eGFR) was calculated for each patient. Propensity scores were used to match patients on the basis of preoperative comorbidities and the procedure-type performed. The incidence of 30-day morbidity was then compared between patients with no or mild renal impairment (eGFR >=60 mL/min/1.73 m) and those with moderate or severe disease (eGFR <60 mL/min/1.73 m). Separately, the morbidity risk associated with eGFR was analyzed as a continuous variable. RESULTS: The risk of morbidity increased with worsening eGFR in an inverse logarithmic fashion (R = 0.84), and the magnitude of risk increased substantially for eGFR below 60 mL/min/1.73 m (odds ratio of >=1.8). There was a 26% relative increase in morbidity for patients with moderate to severe renal impairment, as compared with the propensity score-matched cohort of patients with no or mild disease (5% absolute increase, 24% vs. 19%, P = 0.004). Wound complications (3% vs. 2.1%), reoperation rates (4.6% vs. 3.3%), and need for blood transfusions (16.3% vs. 12.8%) trended higher in patients with moderate or severe disease, but only the need for blood transfusion reached significance. Patients with preoperative moderate or serve renal impairment were 10 times more likely to develop acute renal failure postoperatively (0.6% vs. 0.06%, P = 0.01). CONCLUSION: Thirty-day morbidity risk after lumbar spine surgery is strongly associated with renal impairment. These data may be useful for preoperative patient counseling, and surgeons should consider the relative magnitude of risks and benefits before operating on a patient with severe renal disease, particularly in elective cases. LEVEL OF EVIDENCE: 3. PMID- 25785965 TI - Myocardial mitochondrial and contractile function are preserved in mice lacking adiponectin. AB - Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion and to exaggerated cardiac hypertrophy following pressure overload, entities that are causally linked to mitochondrial dysfunction. In skeletal muscle, lack of adiponectin results in impaired mitochondrial function. Thus, it was our objective to investigate whether adiponectin deficiency impairs mitochondrial energetics in the heart. At 8 weeks of age, heart weight-to-body weight ratios were not different between adiponectin knockout (ADQ-/-) mice and wildtypes (WT). In isolated working hearts, cardiac output, aortic developed pressure and cardiac power were preserved in ADQ-/- mice. Rates of fatty acid oxidation, glucose oxidation and glycolysis were unchanged between groups. While myocardial oxygen consumption was slightly reduced (-24%) in ADQ-/- mice in isolated working hearts, rates of maximal ADP-stimulated mitochondrial oxygen consumption and ATP synthesis in saponin-permeabilized cardiac fibers were preserved in ADQ-/- mice with glutamate, pyruvate or palmitoyl-carnitine as a substrate. In addition, enzymatic activity of respiratory complexes I and II was unchanged between groups. Phosphorylation of AMP-activated protein kinase and SIRT1 activity were not decreased, expression and acetylation of PGC-1alpha were unchanged, and mitochondrial content of OXPHOS subunits was not decreased in ADQ /- mice. Finally, increasing energy demands due to prolonged subcutaneous infusion of isoproterenol did not differentially affect cardiac contractility or mitochondrial function in ADQ-/- mice compared to WT. Thus, mitochondrial and contractile function are preserved in hearts of mice lacking adiponectin, suggesting that adiponectin may be expendable in the regulation of mitochondrial energetics and contractile function in the heart under non-pathological conditions. PMID- 25785966 TI - DNA polymerase-mediated synthesis of unbiased threose nucleic acid (TNA) polymers requires 7-deazaguanine to suppress G:G mispairing during TNA transcription. AB - Threose nucleic acid (TNA) is an unnatural genetic polymer capable of undergoing Darwinian evolution to generate folded molecules with ligand-binding activity. This property, coupled with a nuclease-resistant backbone, makes TNA an attractive candidate for future applications in biotechnology. Previously, we have shown that an engineered form of the Archaean replicative DNA polymerase 9 degrees N, known commercially as Therminator DNA polymerase, can copy a three letter genetic alphabet (A,T,C) from DNA into TNA. However, our ability to transcribe four-nucleotide libraries has been limited by chain termination events that prevent the synthesis of full-length TNA products. Here, we show that chain termination is caused by tG:dG mispairing in the enzyme active site. We demonstrate that the unnatural base analogue 7-deazaguanine (7dG) will suppress tGTP misincorporation by inhibiting the formation of Hoogsteen tG:dG base pairs. DNA templates that contain 7dG in place of natural dG residues replicate with high efficiency and >99% overall fidelity. Pre-steady-state kinetic measurements indicate that the rate of tCTP incorporation is 5-fold higher opposite 7dG than dG and only slightly lower than dCTP incorporation opposite either 7dG or dG. These results provide a chemical solution to the problem of how to synthesize large, unbiased pools of TNA molecules by polymerase-mediated synthesis. PMID- 25785967 TI - Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections. AB - BACKGROUND: Skin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear. METHODS: We enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of treatment. RESULTS: A total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, -2.6 percentage points; 95% confidence interval [CI], -10.2 to 4.9; P=0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, -1.2 percentage points; 95% CI, -7.6 to 5.1; P=0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups. CONCLUSIONS: We found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.). PMID- 25785968 TI - Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. AB - BACKGROUND: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor beta1 (TGF beta1) due to high levels of SMAD7, an inhibitor of TGF-beta1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. METHODS: In a double blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. RESULTS: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. CONCLUSIONS: We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.). PMID- 25785969 TI - Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. AB - BACKGROUND: Pneumococcal polysaccharide conjugate vaccines prevent pneumococcal disease in infants, but their efficacy against pneumococcal community-acquired pneumonia in adults 65 years of age or older is unknown. METHODS: In a randomized, double-blind, placebo-controlled trial involving 84,496 adults 65 years of age or older, we evaluated the efficacy of 13-valent polysaccharide conjugate vaccine (PCV13) in preventing first episodes of vaccine-type strains of pneumococcal community-acquired pneumonia, nonbacteremic and noninvasive pneumococcal community-acquired pneumonia, and invasive pneumococcal disease. Standard laboratory methods and a serotype-specific urinary antigen detection assay were used to identify community-acquired pneumonia and invasive pneumococcal disease. RESULTS: In the per-protocol analysis of first episodes of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 persons in the PCV13 group and 90 persons in the placebo group (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5), nonbacteremic and noninvasive community-acquired pneumonia occurred in 33 persons in the PCV13 group and 60 persons in the placebo group (vaccine efficacy, 45.0%; 95.2% CI, 14.2 to 65.3), and invasive pneumococcal disease occurred in 7 persons in the PCV13 group and 28 persons in the placebo group (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8). Efficacy persisted throughout the trial (mean follow-up, 3.97 years). In the modified intention-to-treat analysis, similar efficacy was observed (vaccine efficacy, 37.7%, 41.1%, and 75.8%, respectively), and community acquired pneumonia occurred in 747 persons in the PCV13 group and 787 persons in placebo group (vaccine efficacy, 5.1%; 95% CI, -5.1 to 14.2). Numbers of serious adverse events and deaths were similar in the two groups, but there were more local reactions in the PCV13 group. CONCLUSIONS: Among older adults, PCV13 was effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease but not in preventing community-acquired pneumonia from any cause. (Funded by Pfizer; CAPITA ClinicalTrials.gov number NCT00744263.). PMID- 25785971 TI - Fibrosis--a common pathway to organ injury and failure. PMID- 25785970 TI - Brain swelling and death in children with cerebral malaria. AB - BACKGROUND: Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS: We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS: Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS: Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.). PMID- 25785972 TI - Images in clinical medicine. Disseminated zoster. PMID- 25785974 TI - Choosing an antibiotic for skin infections. PMID- 25785973 TI - Case records of the Massachusetts General Hospital. Case 9-2015. A 31-year-old man with personality changes and progressive neurologic decline. PMID- 25785975 TI - Oral SMAD7 antisense drug for Crohn's disease. PMID- 25785976 TI - A new antibiotic and the evolution of resistance. PMID- 25785977 TI - Why is there no generic insulin? Historical origins of a modern problem. PMID- 25785978 TI - Intraarterial treatment for acute ischemic stroke. PMID- 25785979 TI - Intraarterial treatment for acute ischemic stroke. PMID- 25785980 TI - Intraarterial treatment for acute ischemic stroke. PMID- 25785981 TI - Intraarterial treatment for acute ischemic stroke. PMID- 25785982 TI - Intraarterial treatment for acute ischemic stroke. PMID- 25785983 TI - Intraarterial treatment for acute ischemic stroke. PMID- 25785984 TI - Detection of drug-resistant tuberculosis by Xpert MTB/RIF in Swaziland. PMID- 25785986 TI - Images in clinical medicine. Nasal myiasis. PMID- 25785987 TI - Correction to impact of d-orbital occupation on metal-carbon bond functionalization. PMID- 25785989 TI - Correction: Alginate microencapsulated hepatocytes optimised for transplantation in acute liver failure. PMID- 25785988 TI - A decline in benthic foraminifera following the deepwater horizon event in the northeastern Gulf of Mexico. AB - Sediment cores were collected from three sites (1000-1200 m water depth) in the northeastern Gulf of Mexico from December 2010 to June 2011 to assess changes in benthic foraminiferal density related to the Deepwater Horizon (DWH) event (April July 2010, 1500 m water depth). Short-lived radioisotope geochronologies (210Pb, 234Th), organic geochemical assessments, and redox metal concentrations were determined to relate changes in sediment accumulation rate, contamination, and redox conditions with benthic foraminiferal density. Cores collected in December 2010 indicated a decline in density (80-93%). This decline was characterized by a decrease in benthic foraminiferal density and benthic foraminiferal accumulation rate (BFAR) in the surface 10 mm relative to the down-core mean in all benthic foraminifera, including the dominant genera (Bulimina spp., Uvigerina spp., and Cibicidoides spp.). Cores collected in February 2011 documented a site-specific response. There was evidence of a recovery in the benthic foraminiferal density and BFAR at the site closest to the wellhead (45 NM, NE). However, the site farther afield (60 NM, NE) recorded a continued decline in benthic foraminiferal density and BFAR down to near-zero values. This decline in benthic foraminiferal density occurred simultaneously with abrupt increases in sedimentary accumulation rates, polycyclic aromatic hydrocarbon (PAH) concentrations, and changes in redox conditions. Persistent reducing conditions (as many as 10 months after the event) in the surface of these core records were a possible cause of the decline. Another possible cause was the increase (2-3 times background) in PAH's, which are known to cause benthic foraminifera mortality and inhibit reproduction. Records of benthic foraminiferal density coupled with short-lived radionuclide geochronology and organic geochemistry were effective in quantifying the benthic response and will continue to be a valuable tool in determining the long-term effects of the DWH event on a larger spatial scale. PMID- 25785990 TI - Anti-angiogenic effect of metformin in mouse oxygen-induced retinopathy is mediated by reducing levels of the vascular endothelial growth factor receptor Flk-1. AB - PURPOSE: To evaluate the effect of metformin on vascular changes in oxygen induced retinopathy (OIR) in mouse, and to elucidate the possible underlying mechanism. METHODS: OIR mice were treated with metformin by intraperitoneal injection from postnatal day 12 (P12) to P17 or P21. At P17 and P21, vessel formation and avascular areas were assessed using retinal flat mounts. Levels of vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assays, and the effects of metformin on VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) were assessed. The effects of metformin on the levels of Flk1 (VEGF receptor-2) and phosphorylated Flk1 (pFlk1) were measured by Western blotting (HUVECs) and immunohistochemistry (retinal tissue). RESULTS: Retinal morphologic changes were analyzed between two groups (saline-treated OIR; metformin-treated OIR). Metformin treatment did not change the extent of avascular areas at P17. However, at P21, when OIR pathology was markedly improved in the saline-treated group, OIR pathology still remained in the metformin-treated OIR group. VEGF expression levels did not differ between metformin- and saline-treated OIR groups at P17 and P21, but Flk1 levels were significantly reduced in the metformin group compared with saline-treated OIR group. Moreover, metformin inhibited VEGF-induced cell proliferation and decreased levels of Flk1 and pFlk1, consistent with the interpretation that metformin inhibits vascular growth by reducing Flk1 levels. CONCLUSION: Metformin exerts anti-angiogenesis effects and delays the normal vessel formation in the recovery phase of OIR in mice, likely by suppressing the levels of Flk1. PMID- 25785991 TI - Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis. AB - BACKGROUND: Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis. METHODS: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-beta1 (TGF-beta1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. RESULTS: Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-beta1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis. CONCLUSION: TGF-beta1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis. PMID- 25785992 TI - Magnetic resonance imaging assessment of effective ablated volume following high intensity focused ultrasound. AB - Under magnetic resonance (MR) guidance, high intensity focused ultrasound (HIFU) is capable of precise and accurate delivery of thermal dose to tissues. Given the excellent soft tissue imaging capabilities of MRI, but the lack of data on the correlation of MRI findings to histology following HIFU, we sought to examine tumor response to HIFU ablation to determine whether there was a correlation between histological findings and common MR imaging protocols in the assessment of the extent of thermal damage. Female FVB mice (n = 34), bearing bilateral neu deletion tumors, were unilaterally insonated under MR guidance, with the contralateral tumor as a control. Between one and five spots (focal size 0.5 * 0.5 * 2.5 mm3) were insonated per tumor with each spot receiving approximately 74.2 J of acoustic energy over a period of 7 seconds. Animals were then imaged on a 7T MR scanner with several protocols. T1 weighted images (with and without gadolinium contrast) were collected in addition to a series of T2 weighted and diffusion weighted images (for later reconstruction into T2 and apparent diffusion coefficient maps), immediately following ablation and at 6, 24, and 48 hours post treatment. Animals were sacrificed at each time point and both insonated/treated and contralateral tumors removed and stained for NADH diaphorase, caspase 3, or with hematoxylin and eosin (H&E). We found the area of non-enhancement on contrast enhanced T1 weighted imaging immediately post ablation correlated with the region of tissue receiving a thermal dose CEM43 >= 240 min. Moreover, while both tumor T2 and apparent diffusion coefficient values changed from pre-ablation values, contrast enhanced T1 weighted images appeared to be more senstive to changes in tissue viability following HIFU ablation. PMID- 25785993 TI - Breastfeeding and maternal hypertension and diabetes: a population-based cross sectional study. AB - OBJECTIVE: This study aimed to assess the association of breastfeeding and maternal hypertension and diabetes in Beijing, China. SUBJECTS AND METHODS: A cross-sectional study was conducted in four urban communities of Beijing, China, with 9,128 parous women 40-81 years of age who had had only one lifetime birth. Each participant completed a detailed survey and accepted blood pressure measurement and blood glucose testing. Moreover, self-reported hypertension and diabetes were confirmed by review of medical records. RESULTS: After the analysis was adjusted for the potential confounders, including age, body mass index (BMI), waist to hip ratio (WHR), working status, educational level, drinking, smoking, family history of hypertension, age of menarche, menopause, oral contraceptive use, age of child-bearing, and postpartum BMI, the odd ratio (OR) of hypertension was 1.18 (95% confidence interval [CI], 1.05-1.32) for women who did not breastfeed, compared with women who did. In addition, the ORs for >0 to 6 months, >6 to 12 months, and >12 months of breastfeeding were 0.87 (95% CI, 0.76-0.99), 0.83 (95% CI, 0.68-1.00), and 0.79 (95% CI, 0.65-0.97), respectively, compared with women who did not breastfeed. With adjustment for age, WHR, working status, educational level, family history of diabetes, and postpartum BMI, women who did not breastfeed increased the risk of diabetes (OR=1.30; 95% CI, 1.11-1.53) compared with women who did. Moreover, women who breastfed for >0 to 6 months (OR=0.81; 95% CI, 0.67-0.98) and >6 to 12 months (OR=0.46; 95% CI, 0.26-0.84) had a lower risk of diabetes, compared with women who did not breastfeed. CONCLUSIONS: Chinese mothers who did not breastfeed were more likely to develop hypertension and diabetes in later life. PMID- 25785994 TI - The non-benzodiazepine anxiolytic drug etifoxine causes a rapid, receptor independent stimulation of neurosteroid biosynthesis. AB - Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus investigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tetrahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR) receptor antagonist flumazenil, the translocator protein (TSPO) antagonist PK11195 or the GABAA receptor antagonist bicuculline. In addition, the stimulatory effects of etifoxine and the triakontatetraneuropeptide TTN, a TSPO agonist, were additive, indicating that these two compounds act through distinct mechanisms. Etifoxine also induced a rapid stimulation of neurosteroid biosynthesis from frog hypothalamus homogenates, a preparation in which membrane receptor signalling is disrupted. In conclusion, the present study demonstrates that etifoxine stimulates neurosteroid production through a membrane receptor-independent mechanism. PMID- 25785995 TI - Characterization of functional antibody and memory B-cell responses to pH1N1 monovalent vaccine in HIV-infected children and youth. AB - OBJECTIVES: We investigated immune determinants of antibody responses and B-cell memory to pH1N1 vaccine in HIV-infected children. METHODS: Ninety subjects 4 to <25 years of age received two double doses of pH1N1 vaccine. Serum and cells were frozen at baseline, after each vaccination, and at 28 weeks post-immunization. Hemagglutination inhibition (HAI) titers, avidity indices (AI), B-cell subsets, and pH1N1 IgG and IgA antigen secreting cells (ASC) were measured at baseline and after each vaccination. Neutralizing antibodies and pH1N1-specific Th1, Th2 and Tfh cytokines were measured at baseline and post-dose 1. RESULTS: At entry, 26 (29%) subjects had pH1N1 protective HAI titers (>=1:40). pH1N1-specific HAI, neutralizing titers, AI, IgG ASC, IL-2 and IL-4 increased in response to vaccination (p<0.05), but IgA ASC, IL-5, IL-13, IL-21, IFNgamma and B-cell subsets did not change. Subjects with baseline HAI >=1:40 had significantly greater increases in IgG ASC and AI after immunization compared with those with HAI <1:40. Neutralizing titers and AI after vaccination increased with older age. High pH1N1 HAI responses were associated with increased IgG ASC, IFNgamma, IL-2, microneutralizion titers, and AI. Microneutralization titers after vaccination increased with high IgG ASC and IL-2 responses. IgG ASC also increased with high IFNgamma responses. CD4% and viral load did not predict the immune responses post vaccination, but the B-cell distribution did. Notably, vaccine immunogenicity increased with high CD19+CD21+CD27+% resting memory, high CD19+CD10+CD27+% immature activated, low CD19+CD21-CD27-CD20-% tissue-like, low CD19+CD21-CD27 CD20-% transitional and low CD19+CD38+HLADR+% activated B-cell subsets. CONCLUSIONS: HIV-infected children on HAART mount a broad B-cell memory response to pH1N1 vaccine, which was higher for subjects with baseline HAI>=1:40 and increased with age, presumably due to prior exposure to pH1N1 or to other influenza vaccination/infection. The response to the vaccine was dependent on B cell subset distribution, but not on CD4 counts or viral load. TRIAL REGISTRATION: ClinicalTrials.gov NCT00992836. PMID- 25785996 TI - Cyclin A1 regulates the interactions between mouse haematopoietic stem and progenitor cells and their niches. AB - It remains poorly understood how the haematopoietic stem/progenitor cells (HSPC) are attracted to their niches and the functional consequences of such interaction. In the present study, we show that the cell cycle regulator cyclin A1 in association with vascular endothelial growth factor receptor 1 (VEGFR1), is required for HSPC and their niches to maintain their function and proper interaction. In the absence of cyclin A1, the HSPC in the BM are increased in their frequency and display an increased migratory and homing ability. Concomitantly, the ability of the endosteal and central BM niche zones to attract and home the wild-type HSPC is significantly reduced in cyclin A1-null mice as compared to the wild-type controls. The impaired proliferation and homing of HSPC in the BM of cyclin A1-null mice are attributed to the increased density of microvessels in the endosteal and central BM niche zones, which is associated with the increased VEGFR1 expression. Thus, modulation of cyclin A1 and VEGFR1 in HSPC and their niches may provide new insights into therapeutic approaches. PMID- 25785997 TI - Interaction of streaming and attention in human auditory cortex. AB - Serially presented tones are sometimes segregated into two perceptually distinct streams. An ongoing debate is whether this basic streaming phenomenon reflects automatic processes or requires attention focused to the stimuli. Here, we examined the influence of focused attention on streaming-related activity in human auditory cortex using magnetoencephalography (MEG). Listeners were presented with a dichotic paradigm in which left-ear stimuli consisted of canonical streaming stimuli (ABA_ or ABAA) and right-ear stimuli consisted of a classical oddball paradigm. In phase one, listeners were instructed to attend the right-ear oddball sequence and detect rare deviants. In phase two, they were instructed to attend the left ear streaming stimulus and report whether they heard one or two streams. The frequency difference (DeltaF) of the sequences was set such that the smallest and largest DeltaF conditions generally induced one- and two-stream percepts, respectively. Two intermediate DeltaF conditions were chosen to elicit bistable percepts (i.e., either one or two streams). Attention enhanced the peak-to-peak amplitude of the P1-N1 complex, but only for ambiguous DeltaF conditions, consistent with the notion that automatic mechanisms for streaming tightly interact with attention and that the latter is of particular importance for ambiguous sound sequences. PMID- 25785998 TI - Correction: The conserved nhaAR operon is drastically divergent between B2 and non-B2 Escherichia coli and is involved in extra-intestinal virulence. PMID- 25785999 TI - A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human. AB - Aging is defined as the accumulation of progressive organ dysfunction. Controlling the rate of aging by clarifying the complex pathways has a significant clinical importance. Nowadays, sirtuins have become famous molecules for slowing aging and decreasing age-related disorders. In the present study, we analyzed the SIRT1 gene polymorphisms (rs7895833 A>G, rs7069102 C>G and rs2273773 C>T) and its relation with levels of SIRT1, eNOS, PON-1, cholesterol, TAS, TOS, and OSI to demonstrate the association between genetic variation in SIRT1 and phenotype at different ages in humans. We observed a significant increase in the SIRT1 level in older people and found a significant positive correlation between SIRT1 level and age in the overall studied population. The oldest people carrying AG genotypes for rs7895833 have the highest SIRT1 level suggesting an association between rs7895833 SNP and lifespan longevity. Older people have lower PON-1 levels than those of adults and children which may explain the high levels of SIRT1 protein as a compensatory mechanism for oxidative stress in the elderly. The eNOS protein level was significantly decreased in older people as compared to adults. There was no significant difference in the eNOS level between older people and children. The current study is the first to demonstrate age-related changes in SIRT1 levels in humans and it is important for a much better molecular understanding of the role of the longevity gene SIRT1 and its protein product in aging. It is also the first study presenting the association between SIRT1 expression in older people and rs7895833 in SIRT1 gene. PMID- 25786001 TI - When ideology trumps: a case for evidence-based health policies. PMID- 25786000 TI - A Plasmodium phospholipase is involved in disruption of the liver stage parasitophorous vacuole membrane. AB - The coordinated exit of intracellular pathogens from host cells is a process critical to the success and spread of an infection. While phospholipases have been shown to play important roles in bacteria host cell egress and virulence, their role in the release of intracellular eukaryotic parasites is largely unknown. We examined a malaria parasite protein with phospholipase activity and found it to be involved in hepatocyte egress. In hepatocytes, Plasmodium parasites are surrounded by a parasitophorous vacuole membrane (PVM), which must be disrupted before parasites are released into the blood. However, on a molecular basis, little is known about how the PVM is ruptured. We show that Plasmodium berghei phospholipase, PbPL, localizes to the PVM in infected hepatocytes. We provide evidence that parasites lacking PbPL undergo completely normal liver stage development until merozoites are produced but have a defect in egress from host hepatocytes. To investigate this further, we established a live cell imaging-based assay, which enabled us to study the temporal dynamics of PVM rupture on a quantitative basis. Using this assay we could show that PbPL deficient parasites exhibit impaired PVM rupture, resulting in delayed parasite egress. A wild-type phenotype could be re-established by gene complementation, demonstrating the specificity of the PbPL deletion phenotype. In conclusion, we have identified for the first time a Plasmodium phospholipase that is important for PVM rupture and in turn for parasite exit from the infected hepatocyte and therefore established a key role of a parasite phospholipase in egress. PMID- 25786002 TI - Mandatory cancer risk warnings on alcoholic beverages: what are the ethical issues? AB - The link between alcohol consumption and cancer is well established, but public awareness of the risk remains low. Mandated warning labels have been suggested as a way of ensuring "informed choice" about alcohol consumption. In this article we explore various ethical issues that may arise in connection with cancer warning labels on alcoholic beverages; in particular we highlight the potentially questionable autonomy of alcohol consumption decisions (either with or without labels) and consider the implications if the autonomy of drinking behavior is substantially compromised. Our discussion demonstrates the need for the various ethical issues to be considered and addressed in any decision to mandate cancer warning labels. PMID- 25786003 TI - Alcohol, liberty, and societal change: what should we do about our drinking problem? PMID- 25786004 TI - Weighing the ethical considerations of autonomy and efficacy with respect to mandatory warning labels. PMID- 25786005 TI - Cancer warnings on alcohol: is cancer the issue and are labels the solution? PMID- 25786006 TI - Caution! Warning labels about alcohol and pregnancy: unintended consequences and questionable effectiveness. PMID- 25786007 TI - How should we ethically justify alcohol warning labels? Thinking more broadly about risk, benefit, and efficacy. PMID- 25786008 TI - Evaluating public health effectiveness of alcohol label warnings. PMID- 25786009 TI - The social determinants of health: why should we care? AB - A growing body of empirical research examines the effects of the so-called "social determinants of health" (SDH) on health and health inequalities. Several high-profile publications have issued policy recommendations to reduce health inequalities based on a specific interpretation of this empirical research as well as a set of normative assumptions. This article questions the framework defined by these assumptions by focusing on two issues: first, the normative judgments about the (un)fairness of particular health inequalities; and second, the policy recommendations issued on this basis. We argue that the normative underpinnings of the approach are insufficiently supported and that the policy recommendations do not necessarily follow from the arguments provided. Furthermore, while many of the policies recommended-such as improving people's living conditions and reducing inequalities in wealth and power-are justified in their own right, the way these recommendations are tied to health is problematic. PMID- 25786010 TI - Why we should care about the social determinants of health. PMID- 25786011 TI - Justice and tragedy: the avoidability of health inequalities. PMID- 25786012 TI - Nondistributive social factors, noneconomic distributive factors. PMID- 25786013 TI - Just deserts or icing on the cake? Addressing the social determinants of health. PMID- 25786014 TI - Noncomparative justice regarding health and its social determinants. PMID- 25786015 TI - The social determinants of health: why we should care. PMID- 25786016 TI - Caring about the social determinants of health. PMID- 25786017 TI - Evaluating health inequalities: residual worries. PMID- 25786018 TI - Power hierarchies and social status: on the normative significance of social epidemiology. PMID- 25786019 TI - HESC and equitable residues. PMID- 25786020 TI - The evidence suggests we should care about social inequalities in health. PMID- 25786021 TI - The naturalistic fallacy in ethical discourse on the social determinants of health. PMID- 25786022 TI - The social gradient in health: missed opportunities or unjust inequalities? PMID- 25786023 TI - Response to open peer commentaries on "ritual male infant circumcision and human rights". PMID- 25786024 TI - Male-biased aganglionic megacolon in the TashT mouse line due to perturbation of silencer elements in a large gene desert of chromosome 10. AB - Neural crest cells (NCC) are a transient migratory cell population that generates diverse cell types such as neurons and glia of the enteric nervous system (ENS). Via an insertional mutation screen for loci affecting NCC development in mice, we identified one line-named TashT-that displays a partially penetrant aganglionic megacolon phenotype in a strong male-biased manner. Interestingly, this phenotype is highly reminiscent of human Hirschsprung's disease, a neurocristopathy with a still unexplained male sex bias. In contrast to the megacolon phenotype, colonic aganglionosis is almost fully penetrant in homozygous TashT animals. The sex bias in megacolon expressivity can be explained by the fact that the male ENS ends, on average, around a "tipping point" of minimal colonic ganglionosis while the female ENS ends, on average, just beyond it. Detailed analysis of embryonic intestines revealed that aganglionosis in homozygous TashT animals is due to slower migration of enteric NCC. The TashT insertional mutation is localized in a gene desert containing multiple highly conserved elements that exhibit repressive activity in reporter assays. RNAseq analyses and 3C assays revealed that the TashT insertion results, at least in part, in NCC-specific relief of repression of the uncharacterized gene Fam162b; an outcome independently confirmed via transient transgenesis. The transcriptional signature of enteric NCC from homozygous TashT embryos is also characterized by the deregulation of genes encoding members of the most important signaling pathways for ENS formation Gdnf/Ret and Edn3/Ednrb-and, intriguingly, the downregulation of specific subsets of X-linked genes. In conclusion, this study not only allowed the identification of Fam162b coding and regulatory sequences as novel candidate loci for Hirschsprung's disease but also provides important new insights into its male sex bias. PMID- 25786026 TI - REVIEW: Can habitat selection predict abundance? AB - Habitats have substantial influence on the distribution and abundance of animals. Animals' selective movement yields their habitat use. Animals generally are more abundant in habitats that are selected most strongly. Models of habitat selection can be used to distribute animals on the landscape or their distribution can be modelled based on data of habitat use, occupancy, intensity of use or counts of animals. When the population is at carrying capacity or in an ideal-free distribution, habitat selection and related metrics of habitat use can be used to estimate abundance. If the population is not at equilibrium, models have the flexibility to incorporate density into models of habitat selection; but abundance might be influenced by factors influencing fitness that are not directly related to habitat thereby compromising the use of habitat-based models for predicting population size. Scale and domain of the sampling frame, both in time and space, are crucial considerations limiting application of these models. Ultimately, identifying reliable models for predicting abundance from habitat data requires an understanding of the mechanisms underlying population regulation and limitation. PMID- 25786025 TI - Internet and computer-based cognitive behavioral therapy for anxiety and depression in youth: a meta-analysis of randomized controlled outcome trials. AB - BACKGROUND: Anxiety and depression in children and adolescents are undertreated. Computer- and Internet-based cognitive behavioral treatments (cCBT) may be an attractive treatment alternative to regular face-to-face treatment.This meta analysis aims to evaluate whether cCBT is effective for treating symptoms of anxiety and depression in youth. METHODS AND FINDINGS: We conducted systematic searches in bibliographical databases (Pubmed, Cochrane controlled trial register, PsychInfo) up to December 4, 2013. Only randomized controlled trials in which a computer-, Internet- or mobile-based cognitive behavioral intervention targeting either depression, anxiety or both in children or adolescents up to the age of 25 were compared to a control condition were selected. We employed a random-effects pooling model in overall effect analyses and a mixed effect model for sub-group analyses. Searches resulted in identifying 13 randomized trials, including 796 children and adolescents that met inclusion criteria. Seven studies were directed at treating anxiety, four studies at depression, and two were of a transdiagnostic nature, targeting both anxiety and depression. The overall mean effect size (Hedges' g) of cCBT on symptoms of anxiety or depression at post-test was g=0.72 (95% CI:0.55-0.90, numbers needed to be treated (NNT)=2.56). Heterogeneity was low (I2=20.14%, 95% CI: 0-58%). The superiority of cCBT over controls was evident for interventions targeting anxiety (g=0.68; 95% CI: 0.45 0.92; p < .001; NNT=2.70) and for interventions targeting depression (g=0.76; 95% CI: 0.41-0.12; p < .001; NNT=2.44) as well as for transdiagnostic interventions (g=0.94; 95% CI: 0.23-2.66; p < .001; NNT=2.60). CONCLUSIONS: Results provide evidence for the efficacy of cCBT in the treatment of anxiety and depressive symptoms in youth. Hence, such interventions may be a promising treatment alternative when evidence based face-to-face treatment is not feasible. Future studies should examine long-term effects of treatments and should focus on obtaining patient-level data from existing studies, to perform an individual patient data meta-analysis. PMID- 25786027 TI - Antimicrobial resistance: the major contribution of poor governance and corruption to this growing problem. AB - OBJECTIVES: To determine how important governmental, social, and economic factors are in driving antibiotic resistance compared to the factors usually considered the main driving factors-antibiotic usage and levels of economic development. DESIGN: A retrospective multivariate analysis of the variation of antibiotic resistance in Europe in terms of human antibiotic usage, private health care expenditure, tertiary education, the level of economic advancement (per capita GDP), and quality of governance (corruption). The model was estimated using a panel data set involving 7 common human bloodstream isolates and covering 28 European countries for the period 1998-2010. RESULTS: Only 28% of the total variation in antibiotic resistance among countries is attributable to variation in antibiotic usage. If time effects are included the explanatory power increases to 33%. However when the control of corruption indicator is included as an additional variable, 63% of the total variation in antibiotic resistance is now explained by the regression. The complete multivariate regression only accomplishes an additional 7% in terms of goodness of fit, indicating that corruption is the main socioeconomic factor that explains antibiotic resistance. The income level of a country appeared to have no effect on resistance rates in the multivariate analysis. The estimated impact of corruption was statistically significant (p< 0.01). The coefficient indicates that an improvement of one unit in the corruption indicator is associated with a reduction in antibiotic resistance by approximately 0.7 units. The estimated coefficient of private health expenditure showed that one unit reduction is associated with a 0.2 unit decrease in antibiotic resistance. CONCLUSIONS: These findings support the hypothesis that poor governance and corruption contributes to levels of antibiotic resistance and correlate better than antibiotic usage volumes with resistance rates. We conclude that addressing corruption and improving governance will lead to a reduction in antibiotic resistance. PMID- 25786028 TI - In vivo therapeutic protection against influenza A (H1N1) oseltamivir-sensitive and resistant viruses by the iminosugar UV-4. AB - Our lead iminosugar analog called UV-4 or N-(9-methoxynonyl)-1-deoxynojirimycin inhibits activity of endoplasmic reticulum (ER) alpha-glucosidases I and II and is a potent, host-targeted antiviral candidate. The mechanism of action for the antiviral activity of iminosugars is proposed to be inhibition of ER alpha glucosidases leading to misfolding of critical viral glycoproteins. These misfolded glycoproteins would then be incorporated into defective virus particles or targeted for degradation resulting in a reduction of infectious progeny virions. UV-4, and its hydrochloride salt known as UV-4B, is highly potent against dengue virus in vitro and promotes complete survival in a lethal dengue virus mouse model. In the current studies, UV-4 was shown to be highly efficacious via oral gavage against both oseltamivir-sensitive and -resistant influenza A (H1N1) infections in mice even if treatment was initiated as late as 48-72 hours after infection. The minimal effective dose was found to be 80-100 mg/kg when administered orally thrice daily. UV-4 treatment did not affect the development of protective antibody responses after either influenza infection or vaccination. Therefore, UV-4 is a promising candidate for further development as a therapeutic intervention against influenza. PMID- 25786029 TI - Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability. AB - Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability. PMID- 25786030 TI - Low physical activity and high screen time can increase the risks of mental health problems and poor sleep quality among Chinese college students. AB - OBJECTIVE: To test the independent and interactive associations of physical activity (PA) and screen time (ST) with self-reported mental health and sleep quality among Chinese college students. METHOD: Data were collected in October, 2013. The gender, age, residential background, body mass index (BMI), perceived family economy and perceived study burden were obtained from a total of 4747 college students (41.6% males and 58.4% females). The outcomes were self-reported PA status, ST, anxiety, depression, psychopathological symptoms and sleep quality. Analyses were conducted with logistic regression models. RESULTS: Overall, 16.3%, 15.9% and 17.3% of the students had psychological problems, such as anxiety, depression and psychopathological symptoms, respectively. The prevalence of poor sleep quality was 9.8%. High ST was significantly positively associated with anxiety (OR=1.38, 95%CI: 1.15-1.65), depression (OR=1.76, 95%CI: 1.47-2.09), psychopathological symptoms (OR=1.69, 95%CI: 1.43-2.01) and poor sleep quality (OR=1.32, 95%CI: 1.06-1.65). High PA was insignificantly negatively associated with anxiety, depression, psychopathological symptoms and poor sleep. Low PA and high ST were independently and interactively associated with increased risks of mental health problems and poor sleep quality (p<0.05 for all). CONCLUSION: Interventions are needed to reduce ST and increase PA in the lifestyles of young people. Future research should develop and measure the impacts of interventions and their potential consequences on sleep, health, and well being. PMID- 25786031 TI - 1H-NMR and MS based metabolomics study of the intervention effect of curcumin on hyperlipidemia mice induced by high-fat diet. AB - Curcumin, a principle bioactive component of Curcuma longa L, is well known for its anti-hyperlipidemia effect. However, no holistic metabolic information of curcumin on hyperlipidemia models has been revealed, which may provide us an insight into the underlying mechanism. In the present work, NMR and MS based metabolomics was conducted to investigate the intervention effect of curcumin on hyperlipidemia mice induced by high-fat diet (HFD) feeding for 12 weeks. The HFD induced animals were orally administered with curcumin (40, 80 mg/kg) or lovastatin (30 mg/kg, positive control) once a day during the inducing period. Serum biochemistry assay of TC, TG, LDL-c, and HDL-c was conducted and proved that treatment of curcumin or lovastatin can significantly improve the lipid profiles. Subsequently, metabolomics analysis was carried out for urine samples. Orthogonal Partial Least Squares-Discriminant analysis (OPLS-DA) was employed to investigate the anti-hyperlipidemia effect of curcumin and to detect related potential biomarkers. Totally, 35 biomarkers were identified, including 31 by NMR and nine by MS (five by both). It turned out that curcumin treatment can partially recover the metabolism disorders induced by HFD, with the following metabolic pathways involved: TCA cycle, glycolysis and gluconeogenesis, synthesis of ketone bodies and cholesterol, ketogenesis of branched chain amino acid, choline metabolism, and fatty acid metabolism. Besides, NMR and MS based metabolomics proved to be powerful tools in investigating pharmacodynamics effect of natural products and underlying mechanisms. PMID- 25786032 TI - Treatment outcomes in eyes with polypoidal choroidal vasculopathy with poor baseline visual acuity. AB - PURPOSE: To evaluate treatment outcomes of intravitreal vascular endothelial growth factor (VEGF) in eyes with polypoidal choroidal vasculopathy (PCV) that exhibited poor baseline visual acuity. METHODS: This retrospective, observational study included 47 eyes with treatment-naive PCV with baseline visual acuity of 20/200 or worse treated with intravitreal anti-VEGF. Eyes were divided into 2 groups according to the presence of submacular hemorrhage (hemorrhage and no hemorrhage groups). The best-corrected visual acuity (BCVA) at baseline was compared with that measured at 3 and 6 months after treatment. RESULTS: A mean of 3.3+/-0.9 intravitreal anti-VEGF injections were performed during the 6-month follow-up period. In the hemorrhage group (n=23), 6 patients additionally underwent pneumatic displacement with or without intravitreal tissue plasminogen activator. The logarithm of minimal angle of resolution BCVA at diagnosis, 3, and 6 months was 1.47+/-0.49, 0.91+/-0.79, and 0.81+/-0.83, respectively. Compared with baseline, BCVA was significantly better at 3 and 6 months (P=0.007 and P=0.001, respectively). In the no-hemorrhage group (n=24), the BCVA at defined time points was 1.23+/-0.32, 1.06+/-0.33, and 1.02+/-0.35, respectively. BCVA was significantly better at 3 and 6 months compared with baseline (P=0.006 and P=0.025, respectively). CONCLUSIONS: Intravitreal anti-VEGF was found to be beneficial in PCV eyes with poor baseline visual acuity, regardless of the presence of submacular hemorrhage. The magnitude of visual improvement was relatively greater in eyes with submacular hemorrhage. PMID- 25786034 TI - Correction: First record of the myrmicine ant genus Meranoplus Smith, 1853 (Hymenoptera: Formicidae) from the Arabian Peninsula with description of a new species and notes on the zoogeography of southwestern Kingdom Saudi Arabia. PMID- 25786033 TI - Mechanical properties of the compass depressors of the sea-urchin Paracentrotus lividus (Echinodermata, Echinoidea) and the effects of enzymes, neurotransmitters and synthetic tensilin-like protein. AB - The compass depressors (CDs) of the sea-urchin lantern are ligaments consisting mainly of discontinuous collagen fibrils associated with a small population of myocytes. They are mutable collagenous structures, which can change their mechanical properties rapidly and reversibly under nervous control. The aims of this investigation were to characterise the baseline (i.e. unmanipulated) static mechanical properties of the CDs of Paracentrotus lividus by means of creep tests and incremental force-extension tests, and to determine the effects on their mechanical behaviour of a range of agents. Under constant load the CDs exhibited a three-phase creep curve, the mean coefficient of viscosity being 561+/-365 MPa.s. The stress-strain curve showed toe, linear and yield regions; the mean strain at the toe-linear inflection was 0.86+/-0.61; the mean Young's modulus was 18.62+/-10.30 MPa; and the mean tensile strength was 8.14+/-5.73 MPa. Hyaluronidase from Streptomyces hyalurolyticus had no effect on creep behaviour, whilst chondroitinase ABC prolonged primary creep but had no effect on secondary creep or on any force-extension parameters; it thus appears that neither hyaluronic acid nor sulphated glycosaminoglycans have an interfibrillar load transfer function in the CD. Acetylcholine, the muscarinic agonists arecoline and methacholine, and the nicotinic agonists nicotine and 1-[1-(3,4-dimethyl-phenyl) ethyl]-piperazine produced an abrupt increase in CD viscosity; the CDs were not differentially sensitive to muscarinic or nicotinic agonists. CDs showed either no, or no consistent, response to adrenaline, L-glutamic acid, 5 hydroxytryptamine and gamma-aminobutyric acid. Synthetic echinoid tensilin-like protein had a weak and inconsistent stiffening effect, indicating that, in contrast to holothurian tensilins, the echinoid molecule may not be involved in the regulation of collagenous tissue tensility. We compare in detail the mechanical behaviour of the CD with that of mammalian tendon and highlight its potential as a model system for investigating poorly understood aspects of the ontogeny and phylogeny of vertebrate collagenous tissues. PMID- 25786035 TI - The prognostic value of plasma galectin-3 in chronic heart failure patients is maintained when treated with mineralocorticoid receptor antagonists. AB - OBJECTIVE: Galectin-3 (Gal-3) is considered as a myocardial fibrosis biomarker with prognostic value in heart failure (HF). Since aldosterone is a neurohormone with established fibrotic properties, we aimed to investigate if mineralocorticoid receptor antagonists (MRAs) would modulate the prognostic value of Gal-3. METHODS: The IBLOMAVED cohort comprised 427 eligible chronic HF patients (CHF) with echocardiography and heart failure biomarkers assessments (BNP). After propensity score matching CHF patients for cardiovascular risk factors, to form balanced groups, Gal-3 levels were measured at baseline in plasma from patients treated with MRAs (MRA-Plus, n=101) or not (MRA-Neg, n=101). The primary end point was all-cause mortality with a follow-up of 3 years. RESULTS: Gal-3 in plasma from these patients were similar with median values of 14.0 ng/mL [IQR, 9.9-19.3] and 14.4 ng/mL [IQR, 12.3-19.8] (P = 0.132) in MRA-Neg and MRA-Plus, respectively. Patients with Gal-3 <=17.8 ng/mL had an HR of 1 (reference group) and 1.5 [0.4-5.7] in MRA-Neg and MRA-Plus, respectively (p=0.509). Patients with Gal-3 >= 17.8 ng/mL had an HR of 7.4 [2.2-24.6] and 9.0 [2.9-27.8] in MRA-Plus and MRA-Neg, respectively (p=0.539) and a median survival time of 2.4 years [95%CI,1.8-2.4]. Multivariate Cox proportional hazard analysis confirmed that MRA and the interaction term between MRA treatment and Gal-3 >17.8 ng/mL were not factors associated with survival. CONCLUSIONS: MRA treatment did not impair the prognostic value of Gal-3 assessed with a 17.8 ng/mL cut off. Gal 3 levels maintained its strong prognostic value in CHF also in patients treated with MRAs. The significance of the observed lack of an interaction between Gal-3 and treatment effect of MRAs remains to be elucidated. PMID- 25786036 TI - Identification of livestock-associated methicillin-resistant Staphylococcus aureus isolates in Korea and molecular comparison between isolates from animal carcasses and slaughterhouse workers. AB - This study was undertaken to screen methicillin-resistant Staphylococcus aureus (MRSA) in animal carcasses and slaughterhouse workers and characterize MRSA isolates identified during 2010-2012 in Korea. A total of 830 (16.4%) S. aureus and 65 (1.3%) MRSA were isolated from 9669 carcass samples. MRSA was more frequently detected in chicken carcasses (1.2%) than in cattle (0.3%) and pig carcasses (0.6%). The prevalence of MRSA in workers was 6.9% (4/58) in chicken slaughterhouse workers, but no MRSA was detected in pig and cattle slaughterhouse workers (0/41). Two different lineages of MRSA were identified (i.e., human associated type [ST5, ST59, and ST72] and livestock-associated [LA] type [ST398, ST541, and ST692]); only LA MRSA was observed in chicken carcasses, whereas both types were found in cattle and pig carcasses and workers. All human-associated MRSA isolates carried enterotoxin and/or leukotoxin genes, whereas LA MRSA types did not carry these genes, except ST692 type. However, all LA MRSA isolates were multiresistant, whereas human-associated types were susceptible or resistant to fewer than two antimicrobials except ST5. Furthermore, one or more resistance genes were attributed for resistance to aminoglycosides (aac(6')-Ie-aph(2"), ant(4')-Ia, and aph(3')-IIIa), tetracycline [tet(K), tet(L), tet(M), and tet(S)], macrolide-lincosamide-streptogramin B (ermA, ermB, ermC, and ermT), lincosamide [lnu(B)], phenicol-lincosamide-oxazolidinone-pleuromutilin-streptogramin A (cfr), chloramphenicol (fexA), and fusidic acid [fus(C)]. To our knowledge, this is the first report of tet(S) gene in MRSA isolates and first detection of a unique (ST692) type of MRSA in occupational workers. Detection of new types of human associated and LA MRSA with multiple resistance and virulence genes in food animal products constitutes a potential threat to public health. PMID- 25786037 TI - Immunohistochemical localization of LLC1 in human tissues and its limited expression in non-small cell lung cancer. AB - We have shown both LLC1 expression in the lung epithelium by in situ hybridization and its inactivation in lung cancer by epigenetic modification. However, LLC1 protein's cellular localization or its role in normal lung or cancer tissues has not yet been evaluated. In the present study, a monoclonal antibody against recombinant LLC1 was produced, and immunohistochemical staining was performed on arrays including various human tissues, normal lung and non small cell lung cancer (NSCLC) tissues for LLC1 localization. The immunohistochemical results showed LLC1 expression in the cilia of normal-airway epithelial cells and in the cytoplasm of type II pneumocytes in bronchiectatic patients, but no expression in most of the NSCLC tissues, which is consistent with our previous report positing LLC1 as a tumor suppressor. However, LLC1 over expression in NSCLC cell lines NCI-H1299 and NCI-H23 did not show any change in proliferation or migration, which does not indicate any LLC1 tumor-suppressor role. As for the other human tissues, LLC1 was localized in renal tubular cells, pancreatic acinar cells, and epithelial cells of the stomach, duodenum, and gallbladder. In summary, our findings suggest that LLC1 is not a tumor suppressor, and that it is localized in the cilia of the normal lung epithelium but is absent in most NSCLC cases, probably due to the loss of cilia during lung carcinogenesis. PMID- 25786038 TI - Stream measurements locate thermogenic methane fluxes in groundwater discharge in an area of shale-gas development. AB - The environmental impacts of shale-gas development on water resources, including methane migration to shallow groundwater, have been difficult to assess. Monitoring around gas wells is generally limited to domestic water-supply wells, which often are not situated along predominant groundwater flow paths. A new concept is tested here: combining stream hydrocarbon and noble-gas measurements with reach mass-balance modeling to estimate thermogenic methane concentrations and fluxes in groundwater discharging to streams and to constrain methane sources. In the Marcellus Formation shale-gas play of northern Pennsylvania (U.S.A.), we sampled methane in 15 streams as a reconnaissance tool to locate methane-laden groundwater discharge: concentrations up to 69 MUg L(-1) were observed, with four streams >= 5 MUg L(-1). Geochemical analyses of water from one stream with high methane (Sugar Run, Lycoming County) were consistent with Middle Devonian gases. After sampling was completed, we learned of a state regulator investigation of stray-gas migration from a nearby Marcellus Formation gas well. Modeling indicates a groundwater thermogenic methane flux of about 0.5 kg d(-1) discharging into Sugar Run, possibly from this fugitive gas source. Since flow paths often coalesce into gaining streams, stream methane monitoring provides the first watershed-scale method to assess groundwater contamination from shale-gas development. PMID- 25786039 TI - Key mechanisms mediating fibromyalgia. PMID- 25786040 TI - From Mitchell's causalgia to complex regional pain syndromes: 150 years of definitions and theories. PMID- 25786041 TI - The rs3771863 single nucleotide polymorphism of the TACR1 gene is associated to a lower risk of sicca syndrome in fibromyalgia patients. AB - OBJECTIVES: Fibromyalgia (FM) has been associated with affective spectrum disorders and other chronic pain disorders, which tend to co-occur in individuals and co-aggregate among families. The objective of our study was to investigate the genetic risk factors associated with the presence of related symptoms and with disease severity in subjects affected with FM. METHODS: Two independent cohorts of subjects diagnosed with FM according to the 1990 ACR criteria were studied. A genetic array composed of 320 single nucleotide polymorphisms (SNPs) was analysed in a discovery cohort comprised by 564 patients, and the most suggestive variants were genotyped in a replication cohort, comprised by 397 subjects. The associated conditions and related symptoms analysed were: the presence of depression, sleep disorders, headache, myofascial syndrome, irritable bowel syndrome, chronic fatigue syndrome, vertiginous syndrome, chronic cystitis, and sicca syndrome. FM severity was assessed by the Fibromyalgia Impact Questionnaire and the Hospital Anxiety and Depression Scale. Analyses were adjusted by elapsed time from pain onset, and a meta-analysis was performed to pool the results. RESULTS: Minor allele of the rs3771863 SNP from the TACR1 gene showed a significant association with a lower risk of sicca syndrome (pooled and adjusted OR 0.56, [95%CI 0.42-0.76], p=0.00022). CONCLUSIONS: Our findings indicate a role of the TACR1 gene in the development of sicca syndrome in subjects affected with FM. PMID- 25786042 TI - Vagal modulation and symptomatology following a 6-month aerobic exercise program for women with fibromyalgia. AB - OBJECTIVES: To examine the effects of a supervised aerobic exercise programme on heart rate variability (HRV) parameters and symptom severity in women with fibromyalgia (FM). METHODS: Thirty-two women with FM were randomly allocated to one of two groups: aerobic exercise (AE) or usual care control for 24 weeks. Women allocated to AE performed two aerobic exercise sessions per week of 45-60 min duration including 15-20 min of steady-state aerobic exercise at 60-65% of predicted maximum heart rate (HRmax) and 15 min of interval training at 75-80% HRmax (six repetitions of 1.5 min, with 1 min interpolated rest intervals). Cardiac autonomic modulation was assessed using power spectral analysis of HRV. Symptom severity was assessed by a 10 cm visual analogue scale (VAS) for pain, sleep disturbances, stiffness, anxiety and depression. RESULTS: After 24 weeks, the women in the exercise group showed an increase (4.8 +/- 0.2 to 5.2 +/- 0.2) in total power (LnTP, p<0.001), low frequency power (LnLF, p<0.01), high frequency power (LnHF, p<0.001), and the root-mean-square of successive R-R intervals (rMSSD, p<0.001). In addition, significant group-by-time interaction effects were observed for LnHF (p=0.036) and LnLF/HF (p=0.014). Improvements in anxiety and depression were also observed in AE versus control patients. CONCLUSIONS: These results show that a programme of aerobic exercise training induced changes in cardiac autonomic nervous system modulation in FM and that these changes in HRV parameters were accompanied by changes in anxiety and depression. PMID- 25786043 TI - Inter-accelerometer comparison to measure physical activity and sedentary time in female fibromyalgia patients: the al-Andalus project. AB - OBJECTIVES: The purpose of the current study was to compare physical activity (PA) levels and sedentary time between two accelerometers, the SenseWear Pro3 Armband (SWA) and the Actigraph GT1M, in Spanish female fibromyalgia patients. METHODS: Patients wore the SWA and the Actigraph for 7 consecutive days. Total minutes/day spent in sedentary, light, moderate and moderate-to-vigorous PA were analysed. The agreement between the SWA and the Actigraph were assessed by using Bland-Altman plots. RESULTS: Total PA, light, moderate, and moderate-vigorous PA levels in total-week, weekdays and weekends were higher (all, p <= 0.001), and sedentary time in total-week, weekdays and weekends lower (all, p<0.001) for the SWA when compared to the Actigraph. Concordance correlation coefficients between the SWA and the Actigraph ranged from 0.12 to 0.45 and Pearson's correlation coefficients ranged from 0.28 to 0.77. The Bland-Altman plots showed an overall lack of agreement between both methods. CONCLUSIONS: The present study showed that the SWA and the Actigraph provide different estimates of PA and sedentary time in Spanish female fibromyalgia patients. Caution must be taken when using different devices and the location on the body must be noted. Our results suggest that the PA levels and sedentary time provided by both devices should be interpreted independently across studies. PMID- 25786044 TI - Relationship between sympathetic activity and pain intensity in fibromyalgia. AB - OBJECTIVES: Fibromyalgia (FM) is a syndrome characterised by chronic musculoskeletal pain, hyperalgesia on specific areas of tenderness (tender points) and by an autonomic nervous system dysfunction consistent with sympathetic overactivity. It is not known whether there is any relationship between the amount of cardiovascular sympathetic activity and the magnitude of pain. Our objective was to assess this potential relationship in patients with FM. METHODS: Electrocardiogram, finger blood pressure, respiration and post ganglionic sympathetic discharge activity (muscle sympathetic nerve activity, MSNA) were continuously recorded at rest in 25 patients with primary FMS. The autonomic profile was assessed by MSNA and spectral indices of cardiac sympathetic (LFRR) and vagal (HFRR) modulation and of sympathetic vasomotor control (LF-SAP) computed by spectrum analysis of RR and systolic arterial pressure (SAP) variability. Cardiac baroreflex function was evaluated by the index alpha (alphaLF). Baroreceptor modulation of the sympathetic vasomotor control (sBRS) was assessed by the MSNA/diastolic pressure relationship. RESULTS: Pain intensity was linearly correlated with LFRR/HFRR (r2 = 0.21; p=0.03), LFSAP (r2 = 0.26; p=0.02) and MSNA (burst rate) (r2 = 0.45; p=0.003). Pain intensity was inversely correlated with the alphaLF index (r2 = 0.24; p=0.02) and the sBRS (r2 = 0.28; p=0.03). Thus, the higher the sympathetic drive to the heart and vessels, the higher the magnitude of chronic pain. Also, the gains of both the cardiac and MSNA baroreceptor control were inversely related to the pain intensity. CONCLUSIONS: These findings raise the theoretical possibility that in FM patients the use of anti-adrenergic agents might lessen chronic pain intensity by reducing the underlying excessive sympathetic activity. PMID- 25786045 TI - Agreement between self-reported sleep patterns and actigraphy in fibromyalgia and healthy women. AB - OBJECTIVES: To examine the agreement between objective (accelerometer) and subjective measures of sleep in fibromyalgia women (FW) and healthy women (HW). To identify explanatory variables of the discrepancies between the objective and subjective measures in FW and in HW. METHODS: 127 diagnosed FW and 53 HW filled the Fibromyalgia Impact Questionnaire (FIQ) and wore the SenseWear Pro Armband (SWA) for 7 days in order to assess sleep over the last week. Participants completed the Pittsburgh Sleep Quality Index (PSQI) when the SWA was returned. RESULTS: The SWA showed greater total duration (74 vs. 88 min/day) and average duration (7 vs. 9 min) of wake after sleep onset in FW compared with HW. The PSQI showed poorer sleep quality in all the variables studied in FW than in HW (all, p<0.001), except time in bed. There was a lack of inter-method agreement for total sleep time, sleep time without naps and sleep latency in FW. Age and educational status explained the inter-method mean difference in sleep time in FW. High discrepancy in sleep time between the SWA and the PSQI was related to higher FIQ scores (p<0.05). CONCLUSIONS: The objective measure only showed higher frequency and average duration of wake after sleep onset in FW compared with HW. The agreement between the SWA and the PSQI measures of sleep were poor in the FW group. Age, educational level and the impact of fibromyalgia might be explanatory variables of the inter-method discrepancies in FW. PMID- 25786046 TI - Hyperexcitability in pain matrices in patients with fibromyalgia. AB - OBJECTIVES: Emerging evidence associates fibromyalgia (FM) with pain system dysfunction. In this study, using laser evoked potentials (LEPs) and paired laser stimuli, we tested excitability in the pain matrices and sought possible changes in patients with FM. METHODS: In 20 patients with FM and 15 healthy subjects, after recording control nociceptive system-mediated Adelta- and C-fibre-related LEPs, we measured excitability in the pain matrices by testing the Adelta-LEP conditioned by a preceding C-LEP. RESULTS: No difference was found in control LEP amplitudes for Adelta- or C-fibres between patients and healthy subjects. Conversely, the Adelta-LEP amplitude, conditioned by a preceding C-LEP, was significantly higher in patients than in healthy subjects (p<0.001). CONCLUSIONS: Objective evidence from increased conditioned Adelta-LEP amplitudes reflecting hyperexcitability in the pain matrices in FM, provides diagnostically useful information and might help in developing new therapeutic approaches. PMID- 25786047 TI - Effects of a hydrotherapy programme on symbolic and complexity dynamics of heart rate variability and aerobic capacity in fibromyalgia patients. AB - OBJECTIVES: To evaluate the effects of a hydrotherapy programme on aerobic capacity and linear and non-linear dynamics of heart rate variability (HRV) in women with fibromyalgia syndrome (FMS). METHODS: 20 women with FMS and 20 healthy controls (HC) took part in the study. The FMS group was evaluated at baseline and after a 16-week hydrotherapy programme. All participants underwent cardiopulmonary exercise testing on a cycle ergometer and RR intervals recording in supine and standing positions. The HRV was analysed by linear and non-linear methods. The current level of pain, the tender points, the pressure pain threshold and the impact of FMS on quality of life were assessed. RESULTS: The FMS patients presented higher cardiac sympathetic modulation, lower vagal modulation and lower complexity of HRV in supine position than the HC. Only the HC decreased the complexity indices of HRV during orthostatic stimulus. After a 16-week hydrotherapy programme, the FMS patients increased aerobic capacity, decreased cardiac sympathetic modulation and increased vagal modulation and complexity dynamics of HRV in supine. The FMS patients also improved their cardiac autonomic adjustments to the orthostatic stimulus. Associations between improvements in non-linear dynamics of HRV and improvements in pain and in the impact of FMS on quality of life were found. CONCLUSIONS: A 16-week hydrotherapy programme proved to be effective in ameliorating symptoms, aerobic functional capacity and cardiac autonomic control in FMS patients. Improvements in the non linear dynamics of HRV were related to improvements in pain and in the impact of FMS on quality of life. PMID- 25786048 TI - A randomised controlled trial comparing duloxetine and acetyl L-carnitine in fibromyalgic patients: preliminary data. AB - OBJECTIVES: Fibromyalgia syndrome (FMS) is a chronic disorder characterised by widespread musculoskeletal pain, troubled sleep, disturbed mood, and fatigue. Recently published reviews have demonstrated that it is influenced by various psychological aspects, and antidepressants are now considered the treatment of choice for most patients. The aim of this randomised controlled trial was to compare the effects of duloxetine and acetyl L-carnitine on pain, depression, anxiety and well-being in FMS patients. METHODS: Sixty-five female outpatients with FMS diagnosed by a rheumatologist were recruited between January 2011 and May 2012, and randomised to receive duloxetine 60 mg/day or acetyl L-carnitine 1500 mg/day (500 mg t.i.d.). Drug efficacy and side effects were assessed by the same psychiatrist at baseline, and four and 12 weeks later. RESULTS: Both drugs led to a general clinical improvement, with positive effects on pain and depressive symptoms; but neither induced a significant improvement in anxiety. Both drugs had a positive effect on the physical component of the quality of life, but only duloxetine improved the psychological component. CONCLUSIONS: Although they need to be confirmed by further studies, these preliminary findings confirm the efficacy of duloxetine, and suggest that acetyl L-carnitine is also efficacious in improving depressive symptoms, pain, and the quality of life of FMS patients. PMID- 25786049 TI - Self-reported childhood maltreatment, lifelong traumatic events and mental disorders in fibromyalgia syndrome: a comparison of US and German outpatients. AB - OBJECTIVES: The robustness of findings on retrospective self-reports of childhood maltreatment and lifetime traumatic experiences of adults with fibromyalgia syndrome (FMS) has not been demonstrated by transcultural studies. This is the first transcultural study to focus on the associations between FMS, childhood maltreatment, lifetime psychological traumas, and potential differences between countries adjusting for psychological distress. METHODS: 71 age-and sex-matched US and German FMS outpatients were compared. Childhood maltreatment were assessed by the Childhood Trauma Questionnaire and potential, traumatic experiences by the trauma list of the Munich Composite International Diagnostic Interview. Potential posttraumatic stress disorder (PTSD) was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders IV-TR symptom criteria by the Posttraumatic Diagnostic Scale. Potential depressive and anxiety disorder were assessed by the Patient Health Questionnaire PHQ 4. RESULTS: US and German patients did not significantly differ in the amount of self-reported childhood maltreatment (emotional, physical and sexual abuse or neglect) or in the frequency of lifetime traumatic experiences. No differences in the frequency of potential anxiety, depression, and PTSD were seen. Psychological distress fully accounted for group differences in emotional and sexual abuse and emotional and physical neglect. CONCLUSIONS: The study demonstrated the transcultural robustness of findings on the association of adult FMS with self-reports of childhood maltreatment and lifelong traumatic experiences. These associations are mainly explained by current psychological distress. PMID- 25786050 TI - Web/Internet-based telemonitoring of a randomized controlled trial evaluating the time-integrated effects of a 24-week multicomponent intervention on key health outcomes in patients with fibromyalgia. AB - OBJECTIVES: The aims of the study were to assess the efficacy of a multicomponent intervention and evaluate the feasibility and user acceptance of an internet based home telemedical surveillance system for the evaluation of pain and other key health outcomes in patients with fibromyalgia (FM). METHODS: The study involved 76 FM patients who were randomised to usual care or the multicomponent exercise programme, which consisted of 24 twice-weekly sessions of combined aerobic, muscle strength training exercises and education. All the patients completed the revised version of the Fibromyalgia Impact Questionnaire (FIQR) and the self-administered Fibromyalgia Activity Score (FAS). A predefined website allowed authorised users to enter data via a personal computer (PC) and Internet browser. The differences between the groups were assessed using the Mann-Whitney U-test and Fisher's exact test, and the correlations were analysed using Spearman's rank correlation test. RESULTS: The multicomponent intervention led to a clinically relevant difference in improvement in comparison with the standard approach. It markedly improved the FIQR symptom subscale score, significantly increased the time-integrated area under the curve (AUC) of the FAS scores, and led to a greater benefit in terms of fatigue and the quality of sleep. The mean change in the AUC of the total FIQR score closely correlated with the changes in the AUC of the total FAS score. CONCLUSIONS: The multicomponent approach to FM was effective in treating the key symptoms and maintaining the improvements in the short term, and telemonitoring proved to be an easyto-use solution for patient-centred data acquisition. PMID- 25786051 TI - Algo-dysfunctional syndromes: a critical digest of the recent literature. AB - The etiopathogenesis of the algo-dysfunctional syndromes, which include chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome, is still debated, but it is widely accepted that it is best described by a multifactorial model that include genes, environmental factors such as external infections, inflammation, dietary habits, impaired endogenous cortisol production, the aberrant activation of some areas of the central nervous system, and small peripheral nervous fibre damage. This complexity suggests that they should be managed by means of a multidisciplinary approach involving the use of both pharmacological and non-pharmacological treatments. The aim of this review is to discuss the most recent scientific acquisitions concerning these syndromes and their treatment. PMID- 25786052 TI - The inflammatory hypothesis of mood spectrum broadened to fibromyalgia and chronic fatigue syndrome. AB - OBJECTIVES: The present paper aimed at reviewing literature data on the inflammatory hypothesis of mood spectrum, as well as the overlapping features with some chronic rheumatologic disorders, in particular fibromyalgia and chronic fatigue syndrome. METHODS: A literature search was carried out for English papers published in the years 2000-2014, while using the following words: mood spectrum, depression, bipolar disorders, fibromyalgia, chronic fatigue syndrome, neurotransmitters, inflammation, neuroinflammation, cytokines. RESULTS: Overlapping features were highlighted between mood spectrum, fibromyalgia and chronic fatigue syndrome suggesting common underlying mechanisms at pathophysiological level involving both central nervous and the immune systems. CONCLUSIONS: Taken together, the literature would suggest that the borders between different medical domains should be reconsidered in the light of common processes linking them. PMID- 25786053 TI - Fibromyalgia and nutrition: what news? AB - Fibromyalgia syndrome (FM) is a chronic, generalised pain condition usually accompanied by several associated symptoms, such as fatigue, sleep disturbance, headache, irritable bowel syndrome and mood disorders. Different medical treatments are used to treat fibromyalgia and the recent guidelines suggest that the optimal treatment consists in a multidisciplinary approach with a combination of pharmacological and non-pharmacological treatment modalities. Among non pharmacological treatment, nutrition is a promising tool for FM patients. The aim of this review is to update the present knowledge about fibromyalgia and nutrition by means of a systematic search performed on Medline from January 2000 to December 2014. Nutritional deficiencies have been described in FM patients and the benefits of specific diet and nutritional supplementation are shown. Obesity and overweight, often present in FM patients, are related to the severity of FM worsening the quality of life in terms of higher pain, fatigue, worsened sleep quality and higher incidence of mood disorders. Weight control is thus an effective tool to improve the symptoms. Moreover, it seems reasonable to eliminate some foods from the diet of FM patients, for example excitotoxins. Non coeliac gluten sensitivity is increasingly recognised as a frequent condition with similar manifestations which overlap with those of FM. The elimination of gluten from the diet of FM patients is recently becoming a potential dietary intervention for clinical improvement. In summary, this review reveals the potential benefit of specific dietary interventions as non-pharmacological tools as part of a multidisciplinary treatment for FM patients. PMID- 25786054 TI - The therapeutic approach to complex regional pain syndrome: light and shade. AB - Complex regional pain syndrome (CRPS) is a highly painful, limb-confined condition that usually arises after a trauma although its causes remain unknown. It is associated with a particularly poor quality of life, and considerable healthcare and societal costs. Its distinct combination of abnormalities includes limb-confined inflammation and tissue hypoxia, sympathetic dysregulation, small fibre damage, serum autoantibodies, central sensitisation and cortical reorganisation, which place it at the crossroads of disciplines including rheumatology, pain medicine and neurology. The significant scientific and clinical advances made over the past 10 years promise an improved understanding of the causes of CRPS, and for more effective treatments. This review summarises the currently available treatments. The therapeutic approach is multidisciplinary, and involves educating patients about the condition, sustaining or restoring limb function, reducing pain, and providing psychological support. This paper describes the systemic drug treatments, grouped on the basis of their real or presumed antinociceptive mechanisms and reported actions without making any formal distinction between CRPS types I and II. PMID- 25786055 TI - MR Imaging-Transrectal US Fusion for Targeted Prostate Biopsies: Implications for Diagnosis and Clinical Management. AB - Cancer of the prostate gland is a common but heterogeneous disease requiring individualized risk stratification for optimal clinical management. However, transrectal ultrasonography (US)-guided biopsy-the standard of care for diagnosis of prostate cancer-frequently fails to detect aggressive tumors or provide reliable parameters for pretreatment risk stratification. Multiparametric magnetic resonance (MR) imaging is the most accurate imaging technique for prostate cancer detection and local staging. Recently, different approaches have been developed to allow targeted biopsies of areas that are suspicious for cancer at MR imaging, including direct MR imaging guidance and MR imaging-transrectal US fusion, which can be achieved with cognitive fusion or software assistance. Regardless of the technique used, targeted prostate biopsies have the potential to increase detection of clinically relevant prostate cancer and provide more reliable risk stratification in patients with known cancer. The authors discuss the shortcomings of traditional diagnostic workup for prostate cancer, the rationale for targeted prostate biopsies, the different techniques available for targeting suspicious areas seen at MR imaging, and the clinical contexts in which targeted prostate biopsies might be useful. In addition, they discuss opportunities and challenges associated with MR imaging-transrectal US fusion biopsy, as well as questions that need to be addressed before formal incorporation of this technique into practice guidelines. PMID- 25786056 TI - Treatment effects produced by the Twin-block appliance vs the Forsus Fatigue Resistant Device in growing Class II patients. AB - OBJECTIVE: To compare the dentoskeletal changes produced by the Twin-block appliance (TB) followed by fixed appliances vs the Forsus Fatigue Resistant Device (FRD) in combination with fixed appliances in growing patients having Class II division 1 malocclusion. MATERIALS AND METHODS: Twenty-eight Class II patients (19 females and 9 males; mean age, 12.4 years) treated consecutively with the TB followed by fixed appliances were compared with a group of 36 patients (16 females and 20 males; mean age, 12.3 years) treated consecutively with the FRD in combination with fixed appliances and with a sample of 27 subjects having untreated Class II malocclusion (13 females and 14 males; mean age, 12.2 years). Mean observation interval was 2.3 years in all groups. Cephalometric changes were compared among the three groups by means of ANOVA and Tukey's post hoc tests. RESULTS: The FRD produced a significant restraint of the maxilla compared with the TB and control samples (SNA, -1.1 degrees and -1.8 degrees , respectively). The TB sample exhibited significantly greater mandibular advancement and greater increments in total mandibular length than either the FRD or control groups (SNB, 1.9 degrees and 1.5 degrees , respectively; and Co-Gn, 2.0 mm and 3.4 mm, respectively). The FRD produced a significantly greater amount of proclination of the mandibular incisors than what occurred with the TB or the control samples (2.9 degrees and 5.6 degrees , respectively). CONCLUSION: The TB appliance produced greater skeletal effects in terms of mandibular advancement and growth stimulation while the Forsus caused significant proclination of the mandibular incisors. PMID- 25786057 TI - Using the fluorescence red edge effect to assess the long-term stability of lyophilized protein formulations. AB - Nanosecond relaxation processes in sugar matrices are causally linked through diffusional processes to protein stability in lyophilized formulations. Long-term protein degradation rates track mean-squared displacement (?u(2)?) of hydrogen atoms in sugar glasses, a parameter describing dynamics on a time scale of picoseconds to nanoseconds. However, measurements of ?u(2)? are usually performed by neutron scattering, which is not conducive to rapid formulation screening in early development. Here, we present a benchtop technique to derive a ?u(2)? surrogate based on the fluorescence red edge effect. Glycerol, lyophilized trehalose, and lyophilized sucrose were used as model systems. Samples containing 10(-6) mole fraction of rhodamine 6G, a fluorophore, were excited at either 532 nm (main peak) or 566 nm (red edge), and the ?u(2)? surrogate was determined based the corresponding Stokes shifts. Results showed reasonable agreement between ?u(2)? from neutron scattering and the surrogate from fluorescence, although deviations were observed at very low temperatures. We discuss the sources of the deviations and suggest technique improvements to ameliorate these. We expect that this method will be a valuable tool to evaluate lyophilized sugar matrices with respect to their ability to protect proteins from diffusion-limited degradation processes during long-term storage. Additionally, the method may have broader applications in amorphous pharmaceutical solids. PMID- 25786058 TI - Nerve guidance conduits from aligned nanofibers: improvement of nerve regeneration through longitudinal nanogrooves on a fiber surface. AB - A novel fibrous conduit consisting of well-aligned nanofibers with longitudinal nanogrooves on the fiber surface was prepared by electrospinning and was subjected to an in vivo nerve regeneration study on rats using a sciatic nerve injury model. For comparison, a fibrous conduit having a similar fiber alignment structure without surface groove and an autograft were also conducted in the same test. The electrophysiological, walking track, gastrocnemius muscle, triple immunofluorescence, and immunohistological analyses indicated that grooved fibers effectively improved sciatic nerve regeneration. This is mainly attributed to the highly ordered secondary structure formed by surface grooves and an increase in the specific surface area. Fibrous conduits made of longitudinally aligned nanofibers with longitudinal nanogrooves on the fiber surface may offer a new nerve guidance conduit for peripheral nerve repair and regeneration. PMID- 25786059 TI - Transition-metal-free hydration of nitriles using potassium tert-butoxide under anhydrous conditions. AB - Potassium tert-butoxide acts as a nucleophilic oxygen source during the hydration of nitriles to give the corresponding amides under anhydrous conditions. The reaction proceeds smoothly for a broad range of substrates under mild conditions, providing an efficient and economically affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an ionic mechanism have been proposed for the hydration process. PMID- 25786060 TI - mHealthApps: A Repository and Database of Mobile Health Apps. AB - BACKGROUND: The market of mobile health (mHealth) apps has rapidly evolved in the past decade. With more than 100,000 mHealth apps currently available, there is no centralized resource that collects information on these health-related apps for researchers in this field to effectively evaluate the strength and weakness of these apps. OBJECTIVE: The objective of this study was to create a centralized mHealth app repository. We expect the analysis of information in this repository to provide insights for future mHealth research developments. METHODS: We focused on apps from the two most established app stores, the Apple App Store and the Google Play Store. We extracted detailed information of each health-related app from these two app stores via our python crawling program, and then stored the information in both a user-friendly array format and a standard JavaScript Object Notation (JSON) format. RESULTS: We have developed a centralized resource that provides detailed information of more than 60,000 health-related apps from the Apple App Store and the Google Play Store. Using this information resource, we analyzed thousands of apps systematically and provide an overview of the trends for mHealth apps. CONCLUSIONS: This unique database allows the meta-analysis of health-related apps and provides guidance for research designs of future apps in the mHealth field. PMID- 25786061 TI - Cytotoxic and antibacterial angucycline- and prodigiosin-analogues from the deep sea derived Streptomyces sp. SCSIO 11594. AB - Two new C-glycoside angucyclines, marangucycline A (1) and marangucycline B (2), along with three known compounds, dehydroxyaquayamycin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), have been identified as products of the deep sea sediment strain Streptomyces sp. SCSIO 11594. New structures were elucidated on the basis of HRESIMS, 1D and 2D NMR analyses and comparisons to previously reported datasets. Compounds 2 and 4 displayed in vitro cytotoxicity against four cancer cell lines A594, CNE2, HepG2, MCF-7 superior to those obtained with cisplatin, the positive control. Notably, compound 2 bearing a keto-sugar displayed significant cytotoxicity against cancer cell lines with IC50 values ranging from 0.24 to 0.56 MUM; An IC50 value of 3.67 MUM was found when using non cancerous hepatic cell line HL7702, demonstrating the cancer cell selectivity of 2. Compounds 1-3 were proved to have weak antibacterial activities against Enterococcus faecalis ATCC29212 with an MIC value of 64.0 MUg/mL. Moreover, 3 displayed selective antibacterial activity against methicillin-resistant Staphylococcus epidermidis shhs-E1 with an MIC value of 16.0 MUg/mL. PMID- 25786062 TI - Inventory of fatty acid desaturases in the pennate diatom Phaeodactylum tricornutum. AB - The diatom Phaeodactylum is rich in very long chain polyunsaturated fatty acids (PUFAs). Fatty acid (FA) synthesis, elongation, and desaturation have been studied in depth in plants including Arabidopsis, but for secondary endosymbionts the full picture remains unclear. FAs are synthesized up to a chain length of 18 carbons inside chloroplasts, where they can be incorporated into glycerolipids. They are also exported to the ER for phospho- and betaine lipid syntheses. Elongation of FAs up to 22 carbons occurs in the ER. PUFAs can be reimported into plastids to serve as precursors for glycerolipids. In both organelles, FA desaturases are present, introducing double bonds between carbon atoms and giving rise to a variety of molecular species. In addition to the four desaturases characterized in Phaeodactylum (FAD2, FAD6, PtD5, PtD6), we identified eight putative desaturase genes. Combining subcellular localization predictions and comparisons with desaturases from other organisms like Arabidopsis, we propose a scheme at the whole cell level, including features that are likely specific to secondary endosymbionts. PMID- 25786063 TI - The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11, 15-cembratetraen-17,2-olide(LS 1) through the activation of TGF-beta signaling in SNU-C5/5-FU, fluorouracil resistant human colon cancer cells. AB - The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS 1) from Lobophytum sp. has been already reported in HT-29 human colorectal cancer cells. In this study, we examined the effect of LS-1 on the apoptosis induction of SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells. Furthermore, we investigated whether the apoptosis-induction effect of LS-1 could arise from the activation of the TGF-beta pathway. In SNU-C5/5-FU treated with LS-1 of 7.1 MUM (IC50), we could observe the various apoptotic characteristics, such as the increase of apoptotic bodies, the increase of the sub-G1 hypodiploid cell population, the decrease of the Bcl-2 level, the increase of procaspase-9 cleavage, the increase of procaspase-3 cleavage and the increase of poly(ADP ribose) polymerase cleavage. Interestingly, the apoptosis-induction effect of LS 1 was also accompanied by the increase of Smad-3 phosphorylation and the downregulation of c-Myc in SNU-C5/5-FU. LS-1 also increased the nuclear localization of phospho-Smad-3 and Smad-4. We examined whether LS-1 could downregulate the expression of carcinoembryonic antigen (CEA), a direct inhibitor of TGF-beta signaling. LS-1 decreased the CEA level, as well as the direct interaction between CEA and TGF-betaR1 in the apoptosis-induction condition of SNU-C5/5-FU. To examine whether LS-1 can induce apoptosis via the activation of TGF-beta signaling, the SNU-C5/5-FU cells were treated with LS-1 in the presence or absence of SB525334, a TGF-betaRI kinase inhibitor. SB525334 inhibited the effect of LS-1 on the apoptosis induction. These findings provide evidence demonstrating that the apoptosis-induction effect of LS-1 results from the activation of the TGF-beta pathway via the downregulation of CEA in SNU-C5/5-FU. PMID- 25786064 TI - Structural analysis and anti-complement activity of polysaccharides from Kjellmaniella crsaaifolia. AB - Two polysaccharides, named KCA and KCW, were extracted from Kjellmaniella crassifolia using dilute hydrochloric acid and water, respectively. Composition analysis showed that these polysaccharides predominantly consisted of fucose, with galactose, mannose and glucuronic acid as minor components. After degradation and partial desulfation, electrospray ionization mass spectrometry (ESI-MS) was performed, which showed that the polysaccharides consisted of sulfated fucooligosaccharides, sulfated galactofucooligosaccharides and methyl glycosides of mono-sulfated/multi-sulfated fucooligosaccharides. The structures of the oligomeric fragments were further characterized by electrospray ionization collision-induced dissociation tandem mass spectrometry (ESI-CID-MS2 and ESI-CID MS3). Moreover, the activity of KCA and KCW against the hemolytic activity of both the classical and alternative complement pathways was determined. The activity of KCA was found to be similar to KCW, suggesting that the method of extraction did not influence the activity. In addition, the degraded polysaccharides (DKCA and DKCW) displayed lower activity levels than the crude polysaccharides (KCA and KCW), indicating that molecular weight had an effect on activity. Moreover, the desulfated fractions (ds-DKCA and ds-DKCW) showed less or no activity, which confirmed that sulfate was important for activity. In conclusion, polysaccharides from K. crassifolia may be good candidates for the treatment of diseases involving the complement pathway. PMID- 25786065 TI - Astaxanthin protects steroidogenesis from hydrogen peroxide-induced oxidative stress in mouse Leydig cells. AB - Androgens, especially testosterone produced in Leydig cells, play an essential role in development of the male reproductive phenotype and fertility. However, testicular oxidative stress may cause a decline in testosterone production. Many antioxidants have been used as reactive oxygen species (ROS) scavengers to eliminate oxidative stress to protect steroidogenesis. Astaxanthin (AST), a natural extract from algae and plants ubiquitous in the marine environment, has been shown to have antioxidant activity in many previous studies. In this study, we treated primary mouse Leydig cells or MA-10 cells with hydrogen peroxide (H2O2) to cause oxidative stress. Testosterone and progesterone production was suppressed and the expression of the mature (30 kDa) form of StAR protein was down-regulated in MA-10 cells by H2O2 and cAMP co-treatment. However, progesterone production and expression of mature StAR protein were restored in MA 10 cells by a one-hour pretreatment with AST. AST also reduced ROS levels in cells so that they were lower than the levels in untreated controls. These results provide additional evidence of the potential health benefits of AST as a potential food additive to ease oxidative stress. PMID- 25786066 TI - New antimicrobial bromotyrosine analogues from the sponge Pseudoceratina purpurea and its predator Tylodina corticalis. AB - Bioassay-guided fractionation of extracts from temperate Australian collections of the marine sponge Pseudoceratina purpurea resulted in the isolation and characterisation of two new and six known bromotyrosine-derived alkaloids with antibiotic activity. Surprisingly, a single specimen of the mollusc Tylodina corticalis, which was collected while feeding on P. purpurea, contained only a few of the compounds found in the sponge suggesting selective accumulation and chemical modification of sponge metabolites. PMID- 25786067 TI - Solvent separating secondary metabolites directly from biosynthetic tissue for surface-assisted laser desorption ionisation mass spectrometry. AB - Marine bioactive metabolites are often heterogeneously expressed in tissues both spatially and over time. Therefore, traditional solvent extraction methods benefit from an understanding of the in situ sites of biosynthesis and storage to deal with heterogeneity and maximize yield. Recently, surface-assisted mass spectrometry (MS) methods namely nanostructure-assisted laser desorption ionisation (NALDI) and desorption ionisation on porous silicon (DIOS) surfaces have been developed to enable the direct detection of low molecular weight metabolites. Since direct tissue NALDI-MS or DIOS-MS produce complex spectra due to the wide variety of other metabolites and fragments present in the low mass range, we report here the use of "on surface" solvent separation directly from mollusc tissue onto nanostructured surfaces for MS analysis, as a mechanism for simplifying data annotation and detecting possible artefacts from compound delocalization during the preparative steps. Water, ethanol, chloroform and hexane selectively extracted a range of choline esters, brominated indoles and lipids from Dicathais orbita hypobranchial tissue imprints. These compounds could be quantified on the nanostructured surfaces by comparison to standard curves generated from the pure compounds. Surface-assisted MS could have broad utility for detecting a broad range of secondary metabolites in complex marine tissue samples. PMID- 25786069 TI - Top-down silicon microcantilever with coupled bottom-up silicon nanowire for enhanced mass resolution. AB - A stepped cantilever composed of a bottom-up silicon nanowire coupled to a top down silicon microcantilever electrostatically actuated and with capacitive or optical readout is fabricated and analyzed, both theoretically and experimentally, for mass sensing applications. The mass sensitivity at the nanowire free end and the frequency resolution considering thermomechanical noise are computed for different nanowire dimensions. The results obtained show that the coupled structure presents a very good mass sensitivity thanks to the nanowire, where the mass depositions take place, while also presenting a very good frequency resolution due to the microcantilever, where the transduction is carried out. A two-fold improvement in mass sensitivity with respect to that of the microcantilever standalone is experimentally demonstrated, and at least an order-of-magnitude improvement is theoretically predicted, only changing the nanowire length. Very close frequency resolutions are experimentally measured and theoretically predicted for a standalone microcantilever and for a microcantilever-nanowire coupled system. Thus, an improvement in mass sensing resolution of the microcantilever-nanowire stepped cantilever is demonstrated with respect to that of the microcantilever standalone. PMID- 25786068 TI - General features of the retinal connectome determine the computation of motion anticipation. AB - Motion anticipation allows the visual system to compensate for the slow speed of phototransduction so that a moving object can be accurately located. This correction is already present in the signal that ganglion cells send from the retina but the biophysical mechanisms underlying this computation are not known. Here we demonstrate that motion anticipation is computed autonomously within the dendritic tree of each ganglion cell and relies on feedforward inhibition. The passive and non-linear interaction of excitatory and inhibitory synapses enables the somatic voltage to encode the actual position of a moving object instead of its delayed representation. General rather than specific features of the retinal connectome govern this computation: an excess of inhibitory inputs over excitatory, with both being randomly distributed, allows tracking of all directions of motion, while the average distance between inputs determines the object velocities that can be compensated for. PMID- 25786070 TI - Evaluation of the intrinsic charge carrier transporting properties of linear- and bent-shaped pi-extended benzo-fused thieno[3,2-b]thiophenes. AB - The intrinsic charge carrier transporting properties of two isomeric linear- and bent-shaped 7-ring benzo-fused thieno[3,2-b] thiophenes and their octyl substituted analogues were newly investigated using flash-photolysis (FP-) and field-induced (FI-) time-resolved microwave conductivity (TRMC) techniques. FP TRMC study in the solid state revealed that octyl-substitution potentially improved the photoconductivity due to the enhanced crystalline lamellar packing. After this screening process, local-scale hole mobilities at the thienoacene poly(methylmethacrylate) insulator interfaces were precisely recorded using FI TRMC, reaching up to 4.5 cm(2) V(-1) s(-1) for the linear-shaped non-alkylated thienoacene. The combination of FP- and FI-TRMC measurements provides a rapid and quantitative evaluation scheme even for a variety of compounds with some issues in the processing conditions, leading to the optimized structure of the compounds used as active (interfacial) layers in practical electronic devices. PMID- 25786071 TI - Why ice-binding type I antifreeze protein acts as a gas hydrate crystal inhibitor. AB - Antifreeze proteins (AFPs) prevent ice growth by binding to a specific ice plane. Some AFPs have been found to inhibit the formation of gas hydrates which are a serious safety and operational challenge for the oil and gas industry. Molecular dynamics simulations are used to determine the mechanism of action of the winter flounder AFP (wf-AFP) in inhibiting methane hydrate growth. The wf-AFP adsorbs onto the methane hydrate surface via cooperative binding of a set of hydrophobic methyl pendant groups to the empty half-cages at the hydrate/water interface. Each binding set is composed of the methyl side chain of threonine and two alanine residues, four and seven places further down in the sequence of the protein. Understanding the principle of action of AFPs can lead to the rational design of green hydrate inhibitor molecules with potential superior performance. PMID- 25786072 TI - Analysis of sphingosine kinase activity in single natural killer cells from peripheral blood. AB - Sphingosine-1-phosphate (S1P), a lipid second messenger formed upon phosphorylation of sphingosine by sphingosine kinase (SK), plays a crucial role in natural killer (NK) cell proliferation, migration, and cytotoxicity. Dysregulation of the S1P pathway has been linked to a number of immune system disorders and therapeutic manipulation of the pathway has been proposed as a method of disease intervention. However, peripheral blood NK cells, as identified by surface markers (CD56(+)CD45(+)CD3(-)CD16) consist of a highly diverse population with distinct phenotypes and functions and it is unknown whether the S1P pathway is similarly diverse across peripheral blood NK cells. In this work, we measured the phosphorylation of sphingosine-fluorescein (SF) and subsequent metabolism of S1P fluorescein (S1PF) to form hexadecanoic acid fluorescein (HAF) in 111 single NK cells obtained from the peripheral blood of four healthy human subjects. The percentage of SF converted to S1PF or HAF was highly variable amongst the cells ranging from 0% to 100% (S1PF) and 0% to 97% (HAF). Subpopulations of cells with varying levels of S1PF formation and metabolism were readily identified. Across all subjects, the average percentage of SF converted to S1PF or HAF was 37 +/- 36% and 12 +/- 19%, respectively. NK cell metabolism of SF by the different subjects was also distinct with hierarchical clustering suggesting two possible phenotypes: low (<20%) or high (>50%) producers of S1PF. The heterogeneity of SK and downstream enzyme activity in NK cells may enable NK cells to respond effectively to a diverse array of pathogens as well as incipient tumor cells. NK cells from two subjects were also loaded with S1PF to assess the activity of S1P phosphatase (S1PP), which converts S1P to sphingosine. No NK cells (n = 41) formed sphingosine, suggesting that S1PP was minimally active in peripheral blood NK cells. In contrast to the SK activity, S1PP activity was homogeneous across the peripheral blood NK cells, suggesting a bias in the SK pathway towards proliferation and migration, activities supported by S1P. PMID- 25786073 TI - Understanding stand-to-sit maneuver: implications for motor system neuroprostheses after paralysis. AB - Standing up, standing, and walking functions can be restored to people with spinal cord injury by contracting the paralyzed hip, knee, and ankle muscles with electrical stimulation. Restoring these functions using electrical stimulation requires controlled activation to provide coordinated movements. However, the stand-to-sit (STS) maneuver involves eccentric contractions of the quadriceps to control lowering of the body to the seated position, which is difficult to achieve with stimulation alone and presents unique challenges to lower-limb neuroprostheses. In this study, we examined the biomechanics of the STS maneuver in five nondisabled individuals and five users of an implanted neuroprosthesis. Neuroprosthesis users relied heavily on their upper limbs during STS, with peak supporting forces approximately 25% body weight, and exhibited an average vertical acceleration at the impact six times higher than that of the nondisabled subjects (p < 0.001). Sitting with stimulation resulted in impact forces at initial contact with the seating surface averaging 1.4 times body weight and representing an average of twice the impact forces of the nondisabled subjects (p < 0.001). These results indicate a need for additional interventions to better control descent, minimize impact, and gently transition from standing to sitting to achieve a more natural movement and reduce the risk of injury. PMID- 25786074 TI - Two-dimensional TiS2 nanosheets for in vivo photoacoustic imaging and photothermal cancer therapy. AB - Recently, transition metal dichalcogenides (TMDCs) have attracted significant attention in nanomedicine owing to their intriguing properties. In this study, TiS2 nanosheets, a new TMDC nanomaterial, are synthesized by a bottom-up solution phase method and then modified with polyethylene glycol (PEG), obtaining TiS2-PEG with high stability in physiological solutions and no appreciable in vitro toxicity. Due to their high absorbance in the near-infrared (NIR) region, TiS2 PEG nanosheets could offer a strong contrast in photoacoustic imaging, which uncovers the high tumor uptake and retention of these nanosheets after systemic administration into tumor-bearing mice. We further apply TiS2-PEG nanosheets for in vivo photothermal therapy, which are able to completely eradicate the tumors in mice upon intravenous injection of TiS2-PEG followed by NIR laser irradiation. Our work indicates that TiS2 nanosheets with appropriate surface coating (e.g. PEGylation) would be a promising new class of photothermal agents for imaging guided cancer therapy. PMID- 25786076 TI - A retrospective study of the effects of clostridial collagenase ointment and negative pressure wound therapy for the treatment of chronic pressure ulcers. AB - Nonhealing, chronic pressure ulcers present a continuous challenge in the global health care venue, with decreased mobility and the effects of aging on skin placing the elderly at particular risk. Debridement is an important process to decrease risk of infection and promote healing. Enzymatic debridement with, for example, clostridial collagenase ointment (CCO) has been shown to assist with the achievement and maintenance of a clean wound bed in preparation for closure. Negative pressure wound therapy (NPWT) has also been used successfully for the treatment of wounds. Although conclusive research has demonstrated positive independent effects of both CCO and NPWT as treatments for chronic pressure ulcers, there are no known published studies that have investigated the 2 as a conjunctive treatment. MATERIALS AND METHODS: A retrospective analysis of 114 adult patients was conducted to assess wound healing of chronic pressure ulcers in a setting with medically complex patients. Two groups were established comparing those who received NPWT alone to those who received NPWT plus CCO. The study sample included 67 patients treated with NPWT + CCO and 47 patients who received only NPWT. RESULTS: Results were similar for both treatment groups with mean values indicating the cohorts were closely aligned with respect to wound size, complexity, length of long-term acute care hospital stay, and duration of NPWT. The patients who received NPWT + CCO demonstrated statistically significant changes in several key areas including initial Bates-Jensen Wound Assessment Tool (BWAT) score, changes in the overall BWAT score and in the necrotic tissue domain. CONCLUSION: Data analysis from this retrospective study indicates patients who received both therapies (NPWT + CCO) demonstrated improved outcomes in speed of debridement and rate of wound closure compared to those who received NPWT alone. PMID- 25786075 TI - Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. AB - IMPORTANCE: Antipsychotic medications are associated with increased mortality in older adults with dementia, yet their absolute effect on risk relative to no treatment or an alternative psychotropic is unclear. OBJECTIVE: To determine the absolute mortality risk increase and number needed to harm (NNH) (ie, number of patients who receive treatment that would be associated with 1 death) of antipsychotic, valproic acid and its derivatives, and antidepressant use in patients with dementia relative to either no treatment or antidepressant treatment. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-control study was conducted in the Veterans Health Administration from October 1, 1998, through September 30, 2009. Participants included 90,786 patients 65 years or older with a diagnosis of dementia. Final analyses were conducted in August 2014. EXPOSURES: A new prescription for an antipsychotic (haloperidol, olanzapine, quetiapine, and risperidone), valproic acid and its derivatives, or an antidepressant (46,008 medication users). MAIN OUTCOMES AND MEASURES: Absolute change in mortality risk and NNH over 180 days of follow-up in medication users compared with nonmedication users matched on several risk factors. Among patients in whom a treatment with medication was initiated, mortality risk associated with each agent was also compared using the antidepressant group as the reference, adjusting for age, sex, years with dementia, presence of delirium, and other clinical and demographic characteristics. Secondary analyses compared dose adjusted absolute change in mortality risk for olanzapine, quetiapine, and risperidone. RESULTS: Compared with respective matched nonusers, individuals receiving haloperidol had an increased mortality risk of 3.8% (95% CI, 1.0%-6.6%; P < .01) with an NNH of 26 (95% CI, 15-99); followed by risperidone, 3.7% (95% CI, 2.2%-5.3%; P < .01) with an NNH of 27 (95% CI, 19-46); olanzapine, 2.5% (95% CI, 0.3%-4.7%; P = .02) with an NNH of 40 (95% CI, 21-312); and quetiapine, 2.0% (95% CI, 0.7%-3.3%; P < .01) with an NNH of 50 (95% CI, 30-150). Compared with antidepressant users, mortality risk ranged from 12.3% (95% CI, 8.6%-16.0%; P < .01) with an NNH of 8 (95% CI, 6-12) for haloperidol users to 3.2% (95% CI, 1.6% 4.9%; P < .01) with an NNH of 31 (95% CI, 21-62) for quetiapine users. As a group, the atypical antipsychotics (olanzapine, quetiapine, and risperidone) showed a dose-response increase in mortality risk, with 3.5% greater mortality (95% CI, 0.5%-6.5%; P = .02) in the high-dose subgroup relative to the low-dose group. When compared directly with quetiapine, dose-adjusted mortality risk was increased with both risperidone (1.7%; 95% CI, 0.6%-2.8%; P = .003) and olanzapine (1.5%; 95% CI, 0.02%-3.0%; P = .047). CONCLUSIONS AND RELEVANCE: The absolute effect of antipsychotics on mortality in elderly patients with dementia may be higher than previously reported and increases with dose. PMID- 25786077 TI - Sentinel node mapping in Marjolin's ulcers: is it feasible? AB - INTRODUCTION: This study evaluated the feasibility of sentinel node biopsy in Marjolin's ulcers using peritumoral injection of the radiotracer and blue dye. MATERIALS AND METHODS: Ten patients with Marjolin's ulcers (5 male and 5 females) ranging in age from 39-65 years, and who were candidates for surgical removal of their tumors, were included in this study. The patients received 2 mCi technetium 99m (99mTc) antimony sulfide colloid in 2 divided doses subcutaneously in the peritumoral region. Immediately after anesthesia induction, 1 cc patent blue V in 2 divided doses was also injected in the same fashion as the radiotracer. Lymphatic mapping and sentinel node biopsy was performed using a gamma probe. Any hot and/or blue lymph nodes were harvested as a sentinel node. Primary lesions were then excised and wounds grafted with a splitthickness skin graft. RESULTS: A sentinel node could be identified on the lymphoscintigraphy images in only 2 patients. Sentinel node mapping was successful during surgery in these 2 patients. None of the harvested sentinel nodes were blue. CONCLUSION: Lymphatic mapping and sentinel node biopsy do not seem feasible in Marjolin's ulcers located in areas of extensive burn scarring due to a low detection rate. Larger studies are needed to validate the results of this study. PMID- 25786078 TI - Comparison of health care costs and hospital readmission rates associated with negative pressure wound therapies. AB - OBJECTIVE: A retrospective national claims database analysis evaluated total and wound-related costs (eg, hospital readmission rates) for patients with chronic wounds treated with negative pressure wound therapy (NPWT), comparing NPWT-V (V.A.C. Therapy, KCI, an Acelity company, San Antonio, TX) and NPWT-O (other non KCI models of NPWT, the brands of which were not known to the researchers). METHODS: Patients with >= 1 NPWT claim from January 2009-June 2012 in outpatient settings in the United States were included, if they had continuous medical and pharmacy benefits for 12 months before the initial index date of their NPWT claim and at least 3 months post index. Mean total health care costs were assessed at 3 months and 12 months; wound-related hospital readmission rates were assessed at 3 months and 6 months. Cost differences between cohorts were analyzed by t test and readmission rates were analyzed by chi-square test. RESULTS: At 3 months, the cohort of NPWT-V patients was significantly younger (59.2 vs 63.6 years, P < 0.01). The same patients were followed at 3, 6, and 12 months, although some fell out as time progressed. At the 3-month assessment, mean comorbidity scores did not differ between the NPWT-V group and the NPWT-O groups (3.38 vs 3.66). Total costs were lower for NPWT-V vs NPWT-O at 3 months ($35,498 vs $39,722, respectively; P = 0.08) and 12 months ($80,768 vs $111,212; P = 0.03). Significantly lower inpatient (P = 0.01), emergency room (P < 0.01), and home (P = 0.05) costs, despite higher (P = 0.04) NPWT costs, accounted for lower 12-month NPWT-V total costs. Wound-related readmission rates were significantly lower for NPWT-V at 3 months (5% vs 8%; P <= 0.01) and 6 months (6% vs 11%; P <= 0.01). For all wound types, NPWT-O patients had a 17-fold higher rate of switching to alternate NPWT models compared with NPWT-V patients. CONCLUSION: In this retrospective analysis, NPWT-V patients had lower total costs, lower wound related costs, and lower hospital readmission rates than NPWT-O patients at all time points assessed. PMID- 25786079 TI - Results of a retrospective comparative study: material cost for managing a series of large wounds in subjects with serious morbidity with a hydrokinetic fiber dressing or negative pressure wound therapy. AB - This retrospective observational study analyzed lesions with regard to healing trends and cost of materials. MATERIALS AND METHODS: The observed lesions were mostly postsurgical or stage IV pressure ulcers in patients with serious morbidity. The wounds were treated with a hydrokinetic fiber dressing (sorbion Sachet S, sorbion Gmbh & Co, a BSN medical company, Senden, Germany) (n = 26) or negative pressure wound therapy (NPWT) (n = 16). RESULTS: Primary healing trends (ie, reduction of wound size, change from necrosis to granulation tissue, and change from granulation tissue to epithelium) and secondary healing trends (ie, periwound conditions) were similar for wounds treated with the hydrokinetic dressing when compared to wounds treated with NPWT. Cost of materials was substantially lower for wounds treated with the hydrokinetic fiber dressing compared to the NPWT, with cost reductions of $1,640 (348%) to $2,242 (1794%) per wound, depending on the criteria used for the analysis. CONCLUSION: In this set of wounds, the hydrokinetic fiber dressing was shown to lead to similar healing results while providing substantial reductions of the cost of materials. For the types of wounds presented in this observational study, the hydrokinetic fiber dressing seems to be an effective substitution for negative pressure wound therapy. PMID- 25786080 TI - In situ monitoring of laser-induced periodic surface structures formation on polymer films by grazing incidence small-angle X-ray scattering. AB - The formation of laser-induced periodic surface structures (LIPSS) on model spin coated polymer films has been followed in situ by grazing incidence small-angle X ray scattering (GISAXS) using synchrotron radiation. The samples were irradiated at different repetition rates ranging from 1 up to 10 Hz by using the fourth harmonic of a Nd:YAG laser (266 nm) with pulses of 8 ns. Simultaneously, GISAXS patterns were acquired during laser irradiation. The variation of both the GISAXS signal with the number of pulses and the LIPSS period with laser irradiation time is revealing key kinetic aspects of the nanostructure formation process. By considering LIPSS as one-dimensional paracrystalline lattice and using a correlation found between the paracrystalline disorder parameter, g, and the number of reflections observed in the GISAXS patterns, the variation of the structural order of LIPSS can be assessed. The role of the laser repetition rate in the nanostructure formation has been clarified. For high pulse repetition rates (i.e., 10 Hz), LIPSS evolve in time to reach the expected period matching the wavelength of the irradiating laser. For lower pulse repetition rates LIPSS formation is less effective, and the period of the ripples never reaches the wavelength value. Results support and provide information on the existence of a feedback mechanism for LIPSS formation in polymer films. PMID- 25786081 TI - Differential expression of miR-499 and validation of predicted target genes in the testicular tissue of swine at different developmental stages. AB - microRNAs (miRNAs) represent a newly identified class of nonprotein-coding ~ 22 nt small RNA that plays important roles in multiple biological processes by degrading targeted mRNA or repressing mRNA translation. This study observed the morphology of swine testicular tissue at different developmental stages (including 1-day old, 1-7 month old) by Hematoxylin-eosin staining. We also examined the expression of miR-499 and its target genes (CYLC1, DMRT1, QKI, XRN2, ZNF313) in samples of tissue slices using quantitative reverse-transcription polymerase chain reaction, which showed that miR-499 had a significant negative correlation with QKI gene. Then, the proteins of QKI gene expression were determined by western blot, which were consistent with results of quantitative polymerase chain reaction (qPCR) detection. Therefore, the luciferase reporter gene system was used to verify correlation between miR-499 and QKI gene. Activity of luciferase was significantly lower in miR-499 co-transfected with pmiR-RB REPORT-QKI-WT group than the miR-499 co-transfected with pmiR-RB-REPORT-QKI mut/si groups, indicating that target sequence of miR-499 existed in 3'UTR of QKI gene. Furthermore, the expressions of miR-499 and QKI were detected in testicular cells that were transfected with miR-499, miR-499 negative control and untreated. The results showed that the diameter of convoluted seminiferous tubule growth increased with age. Significantly different expressions of miR-499 and its target genes were found in swine testicular tissue at different developmental stages (p<0.05), overexpressing miR-499 analysis, suggesting that miR-499 was negatively correlated to the expression of QKI (p<0.05). In conclusion, QKI is a target gene of miR-499. PMID- 25786082 TI - Abrupt loss of MLH1 and PMS2 expression in endometrial carcinoma: molecular and morphologic analysis of 6 cases. AB - Given that endometrial cancer (EC) is often the sentinel cancer for female Lynch syndrome patients, we have successfully implemented universal screening of ECs and have previously shown that this is the preferred method to identify these patients. However, during the course of universal screening of EC, we encountered 6 cases with an unusual pattern of mismatch-repair protein immunohistochemistry that has not been previously described in this setting. In these 6 cases, there was an abrupt loss of MLH1 and PMS2 expression in a portion of the tumor. In 3 cases, marked histologic differences were identified between the areas of the tumor with retained expression and areas with loss of expression. In 2 cases, the areas with loss of expression were of higher grade (1 demonstrated solid growth and the other demonstrated increased nuclear atypia with diffuse p53 expression). In 4 tumors, histologic features associated with microsatellite instability (MSI) were present, including increased intraepithelial lymphocytes. The areas with loss of and retained MLH1/PMS2 expression were separately microdissected and assessed for MSI and MLH1 promoter methylation. The areas with loss of MLH1 and PMS2 more commonly demonstrated MSI compared with the areas with intact expression (83% vs. 33%). MLH1 promoter methylation analysis demonstrated heterogenous hypermethylation, as all areas with loss of MLH1/PMS2 expression had more extensive methylation of MLH1 compared with those areas with retained expression. In summary, we describe the histologic and molecular features of 6 cases of EC with abrupt loss of MLH1 and PMS2 expression and demonstrate that heterogenous methylation of the MLH1 promoter results in this distinct and unusual pattern of immunohistochemical expression. PMID- 25786083 TI - Hepatic arteriolosclerosis: a small-vessel complication of diabetes and hypertension. AB - Liver involvement in diabetes is well recognized in the form of steatohepatitis and glycogenic hepatopathy. More recently, sinusoidal fibrosis, even in the absence of steatosis, has also been suggested to be associated with diabetes (diabetic hepatosclerosis); however, case-control studies are lacking. In addition, microangiopathy (hyaline arteriolosclerosis), a well-known complication of diabetes, has not been well studied in liver. Therefore, we undertook a cross sectional blinded study with the specific aim of evaluating the association between hepatic sinusoidal fibrosis and hepatic arteriolosclerosis (HA) with diabetes. Liver biopsy findings from 89 diabetic patients obtained between January 2006 and December 2009 were compared with those of 89 nondiabetic patients matched by age and hepatitis C virus infection status. Patients with cirrhosis, liver mass, right heart failure, significant alcohol use, or insufficient available clinical information were excluded. Medical records were reviewed for the presence of diabetes, body mass index, diabetes treatment, and comorbidities at the time of biopsy (eg, underlying liver disease, hypertension, dyslipidemia). Liver biopsies were evaluated blinded to all clinical data (including presence or absence of diabetes) for a variety of histologic features, especially patterns of fibrosis and HA. Diabetic patients had a higher average body mass index (33 vs. 30 m/kg, P=0.0039), prevalence of hypertension (78% vs. 33%, P<0.0001), and dyslipidemia (52% vs. 20%, P<0.0001). Among diabetic patients, 87% had type 2 diabetes, and 57% used insulin. Whereas sinusoidal fibrosis, with or without steatosis, was not significantly associated with the presence of diabetes, HA was significantly more prevalent among diabetic patients compared with controls: 45% versus 29% (P=0.0298). The presence of both diabetes and hypertension had a significant odds for HA: with an adjusted odds ratio of 2.632 (95% confidence interval, 1.178-5.878; P=0.0183). Biliary changes were associated with HA in some cases (10.6%).In this study, we describe the histopathologic entity of HA for the first time. It is a small-vessel complication (microangiopathy) of the liver observed mainly in patients with diabetes who also have arterial hypertension. The clinical and prognostic implications of this finding, particularly regarding liver injury, remain to be further investigated. PMID- 25786084 TI - Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis. AB - Chordoid glioma of the third ventricle (CG3V) is a rare tumor developing in a stereotyped localization. It has been related to the circumventricular organ of the lamina terminalis, in the anterior part of the third ventricle, but its oncogenesis is poorly understood. TTF-1 transcription factor is involved in the development and adult physiology of the ventral forebrain. We studied the histopathologic and immunohistochemical features of a multicentric series of 17 cases of CG3V. We described additional histologic patterns (solid, fibrosing, and fusiform) to the typical chordoid pattern. TTF-1 was constantly expressed in CG3V, as in developing and adult lamina terminalis. The anti-TTF-1 SPT24 clone was more sensitive than the 8G7G3/1 clone. No mutation of IDH1 R132, IDH2 R172, or BRAF V600 codons was found. We showed TTF-1 as a useful marker for the diagnosis of CG3V and the understanding of its oncogenesis. PMID- 25786086 TI - Incidental Pelvic and Para-aortic Lymph Node Lymphangioleiomyomatosis Detected During Surgical Staging of Pelvic Cancer in Women Without Symptomatic Pulmonary Lymphangioleiomyomatosis or Tuberous Sclerosis Complex. AB - Extrapulmonary lymphangioleiomyomatosis (LAM) is a rare neoplasm of spindle cells exhibiting melanocytic and myoid differentiation that arises as a mass in the mediastinum, retroperitoneum, uterine wall, and/or intraperitoneal lymph nodes. Many patients also have pulmonary LAM, tuberous sclerosis complex (TSC), and/or other neoplasms of the perivascular epithelioid cell tumor family. This study reports 26 patients with clinically occult LAM involving pelvic/para-aortic lymph nodes removed from women undergoing surgical staging of a uterine (17), ovarian (5), cervical (3), or urinary bladder (1) neoplasm. None of the patients exhibited symptoms of pulmonary LAM, and the median patient age (56 y) was older than what would be expected for patients presenting with pulmonary LAM. Only 2/26 patients had TSC. Four patients also had uterine LAM. One of these 4 had uterine perivascular epithelioid cell tumor, and 1 had vaginal angiomyolipoma. In all 26 patients the lymph node LAM was grossly occult, measured 3.5 mm on average (1 to 19 mm), and involved either a single lymph node (12/26) or multiple lymph nodes (14/26). HMB45 was positive in 24/25 cases, mostly in a focal or patchy distribution. Other melanocytic markers included MiTF (12/14) and MelanA (2/12). Myoid markers included smooth muscle actin (23/23) and desmin (15/16), mostly in a diffuse distribution. Estrogen receptor was positive in all cases tested, as was D240 expression in the lymphatic endothelium lining the spindle cell bundles. Concurrent findings in the involved lymph nodes included metastatic carcinoma (3/26), endosalpingiosis (3/26), and reactive lymphoid hyperplasia (13/26). This study demonstrates that clinically occult lymph node LAM can be detected during surgical staging of pelvic cancer and is not commonly associated with pulmonary LAM or TSC, although these patients should still be formally evaluated for both of these diseases. PMID- 25786085 TI - Perineural Invasion Is an Independent Pathologic Indicator of Recurrence in Vulvar Squamous Cell Carcinoma. AB - OBJECTIVES: Vulvar squamous cell carcinoma (vSCC) is a gynecologic malignancy diagnosed in nearly 4500 women in the United States each year. Current criteria for treatment planning provide inadequate assessment of aggressive vSCC cases, resulting in insufficient use of adjuvant treatments and high rates of vSCC recurrence. Perineural invasion (PNI) is a pathologic feature inconsistently included in the assessment of vSCC, because its relevance to clinical outcomes in these women is not well defined. The purpose of this study was to determine the association between PNI and relevant clinical parameters such as recurrence. METHODS: A total of 103 cases of vSCC were evaluated for PNI using pathology report review and immunohistochemistry dual-chromogen staining for S100 and AE1/3. Medical records were reviewed for clinical and follow-up data. Data were analyzed using univariate and multivariate logistic regression statistical methods. RESULTS: Patients with vSCC containing PNI had a greater risk for cancer recurrence than those whose tumors did not contain PNI (odds ratio=2.8, P=0.0290). There was no significant correlation between the presence of PNI and nodal involvement, stage, or lymphovascular invasion. Tumors with PNI had greater depth of invasion (DOI) (P=0.0047); however, DOI was not associated with recurrence (P=0.2220). When analyzed using a multivariable logistic regression model, PNI was an independent predictor of recurrence in vSCC (adjusted odds ratio=2.613, P=0.045). CONCLUSIONS: PNI is an independent indicator of risk for recurrence in vSCC. The association of PNI with increased risk for recurrence, independent of DOI, nodal involvement, lymphovascular invasion, or stage, should encourage practicing pathologists to thoroughly search for and report the presence of PNI in vSCC. PMID- 25786087 TI - Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer. AB - A multistep model of disease progression and genomic landscape has been firmly established for colorectal cancer (CRC) primaries, but the genetic makeup of related metastases and the dynamics of genetic changes during metastatic progression are scarcely known. To address these issues, we used multigene high coverage next-generation sequencing of 24 microsatellite-stable CRC primaries, matched normal tissue, and related multiple metastases to nodes, liver, lung, and brain with a CRC-specific gene panel to infer the degree of clonal evolution during metastatic progression of the disease. Somatic mutations were detected in 40% of CRC-related genes, and we observed a striking 100% genetic concordance between primary and multiple secondary sites for APC, KRAS, FBXW7, PIK3CA, BRAF, SMAD4, and ACVR2A. Except for true de novo mutations in 4 cases (affecting SYNE1, CTNNB1, TP53, and PTEN), all remaining cases (84.4%) shared the genetic lesions of the primary tumors with all investigated metastases irrespective of the site of metastasis or time lapse between primary tumor resection and the occurrence of metastatic spread. Putative biomarkers and druggable targets were identified in 25% of the cases. Our data proves that genetic alterations occurring early in CRC carcinogenesis are remarkably stable during metastatic progression, indicating (i) a very low degree of genetic heterogeneity between primary and multiple secondary sites with respect to CRC driver mutations and (ii) that genetic interrogation of archived primary tumor samples appears to be sufficient for the application of cancer precision medicine in the metastatic setting. PMID- 25786088 TI - Association of postoperative hyperglycemia with outcomes among patients with complex ventral hernia repair. AB - IMPORTANCE: Patients with medically complex conditions undergoing repair of large or recurrent hernia of the abdominal wall are at risk for early postoperative hyperglycemia, which may serve as an early warning for delays in recovery and for adverse outcomes. OBJECTIVE: To evaluate postoperative serum glucose level as a predictor of outcome after open ventral hernia repair in patients with major medical comorbidities. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective medical record review of 172 consecutive patients who underwent open ventral hernia repair at Penn State Milton S. Hershey Medical Center, an academic tertiary referral center, from May 1, 2011, through November 30, 2013. We initially identified patients by medical complexity and repair requiring a length of stay of longer than 1 day. MAIN OUTCOMES AND MEASURES: Postoperative recovery variables, including time to the first solid meal, length of stay, total costs of hospitalization, and surgical site occurrence. RESULTS: Postoperative serum glucose values were available for 136 patients (79.1%), with 130 (95.6%) obtained within 48 hours of surgery. Among these patients, Ventral Hernia Working Group grade distributions included 8 patients with grade 1, 79 with grade 2, 41 with grade 3, and 8 with grade 4. Fifty-four patients (39.7%) had a postoperative glucose level of at least 140 mg/dL, and 69 patients (50.7%) required insulin administration. Both outcomes were associated with delays in the interval to the first solid meal (glucose level, >=140 vs <140 mg/dL: mean [SD] delay, 6.4 [5.3] vs 5.6 [8.2] days; P = .01; >=2 insulin events vs <2: 6.5 [5.5] vs 5.4 [8.4] days; P = .02); increased length of stay (glucose level, >=140 vs <140 mg/dL: mean [SD], 8.0 [6.0] vs 6.9 [8.2] days; P = .008; >=2 insulin events vs <2: 8.3 [6.1] vs 6.5 [8.4] days; P < .001); increased costs of hospitalization (glucose level, >=140 vs <140 mg/dL: mean [SD], $31 307 [$20 875] vs $22 508 [$22 531]; P < .001; >=2 insulin events vs <2: $31 943 [$22 224] vs $20 651 [$20 917]; P < .001); and possibly increased likelihood of surgical site occurrence (glucose level, >=140 vs <140 mg/dL: 37.5% [21 of 56 patients] vs 22.5% [18 of 80 patients]; P = .06; >=2 insulin events vs <2: 36.4% [24 of 66 patients] vs 21.4% [15 of 70 patients]; P = .06). Not all patients with diabetes mellitus developed postoperative hyperglycemia or needed more intense insulin therapy; however, 46.4% of the patients who developed postoperative hyperglycemia were not previously known to have diabetes mellitus, although most had at least 1 clinical risk factor for a prediabetic condition. CONCLUSIONS AND RELEVANCE: Postoperative hyperglycemia was associated with outcomes in patients in this study who underwent complex ventral hernia repair and may serve as a suitable target for screening, benchmarking, and intervention in patient groups with major comorbidities. PMID- 25786089 TI - Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins. AB - Parallel affinity screening of a DNA-encoded chemical library against rat, bovine and human serum albumin allowed the identification of small-molecule ligands with distinctive binding specificities to the individual proteins. PMID- 25786090 TI - H2 saturation on palladium clusters. AB - The interaction of PdN clusters (N = 2, 3, 4, 7, and 13) with multiple H2 adsorbate molecules is investigated using density functional theory with the hybrid PBE0 functional. The optimal structure for each PdNH2(L) complex is determined systematically via a sequential addition of H2 units. The adsorption energy for each successive H2 addition is computed to determine the maximum number of molecules that can be stably added to a PdN at T = 0 K. The Gibbs free energy is then used to determine the saturation coverage at finite temperature. For N = 2, 3, and 4, a single H2 is found to dissociate, and up to two additional molecular H2 units per Pd atom can bind stably to the clusters at 0 K. At 300 K, one H2 unit dissociates, and only one additional H2 molecular unit per Pd atom is stably bound. For N = 7 and T = 0 K, two H2 units dissociate, and 11 additional H2 units bind molecularly. At 300 K, two units dissociate, and eight are bound molecularly. For N = 3, 4, and 7, we find that an additional H2 unit may dissociate if the underlying cluster structure rearranges. Eight H2 units dissociate on Pd13 at 0 K. At least one additional H2 binds molecularly at 0 K, but none bind at 300 K. This suggests that only dissociated H2 units will stably bind to larger Pd particles at room temperature. The influence of molecularly adsorbed H2 units on the migration of dissociated H atoms is investigated in a preliminary way. Both barrier heights and the relative stability of local minima of Pd4H2(L) are found to be affected by the degree of molecular H2 coverage. PMID- 25786092 TI - Influence of leptomeningeal collateral pattern on the prognostic value of mismatch in acute anterior circulation stroke. AB - OBJECTIVE: This study aimed to investigate whether and to what degree leptomeningeal collateral flow as detected on angiography influences the prognostic value of computed tomography perfusion-estimated mismatch in interventional treatment of acute anterior circulation stroke. METHODS: Thirty eight consecutive patients with acute anterior circulation stroke who received interventional neuroradiologic treatment were assigned one of 2 groups depending on the patient's degree of collateral flow (18 patients with poor collaterals, 20 patients with high degree collaterals) according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grading system. In a multiregression model, we investigated a possible interaction between 2 independent variables mismatch ratio and degree of collateral flow using a "centered" variable approach. RESULTS: The mismatch ratio per se showed a significant correlation with final clinical outcome (beta coefficient, -0.79; P = 0.02); whereas, there was no interaction shown between mismatch degree of collateral flow (beta coefficient, 0.54; P = 0.1). CONCLUSIONS: This study suggests that the predictive value of computed tomography perfusion-estimated mismatch is not influenced by the degree of leptomeningeal collateral flow. PMID- 25786093 TI - The active extravasation of contrast (spot sign) depicted on multidetector computed tomography angiography might predict structural vascular etiology and mortality in secondary intracranial hemorrhage. AB - OBJECTIVE: Intracerebral hemorrhage (ICH) occurs in 10% to 15% of all strokes and is accompanied by high rates of mortality, disability, and neurological sequelae. Our aim was to assess the presence and prognostic implications of the active extravasation of contrast within the hemorrhage (spot sign) in a series of patients with secondary ICH. METHODS: We analysed 59 subjects who arrived at a tertiary hospital with secondary ICH and a brain parenchyma hemorrhage greater than 2.0 cm in any axis. RESULTS: Spot sign was observed in 11 subjects, including 8 patients with saccular aneurysm, 1 with arteriovenous malformation, 1 with coagulation disorder and 1 with venous sinus thrombosis. A 37.5% mortality rate was documented in the spot sign-negative group, whereas the presence of this imaging finding was followed by an 81.8% in-hospital mortality rate. CONCLUSIONS: Spot sign was correlated with vascular etiology and was a predictor of mortality in our series of patients. PMID- 25786094 TI - X-ray dark-field vector radiography-a novel technique for osteoporosis imaging. AB - X-ray dark-field vector radiography (XVR) has emerged as an imaging technique which can efficiently yield dark-field scatter images of high quality, even with conventional X-ray tube sources. The XVR yields direction-dependent information about the X-ray scattering of the trabecular bone microstructure without the requirement of resolving the micrometer size structures directly causing the scattering. In this pilot study, we demonstrated that XVR-based degree of anisotropy correlated with femoral bone strength in the context of osteoporosis. PMID- 25786095 TI - Reduction of fetal dose in computed tomography using anterior shields. AB - OBJECTIVE: The objective of this study was to assess the potential of anterior in beam bismuth shields placed on the abdomen and the pelvis of a RANDO phantom to decrease radiation dose to a simulated fetus. METHODS: Thermal luminescent dosimeters irradiated in a RANDO phantom were used to measure radiation dose at 0 weeks and 18 weeks after conception. An 18-week gestation was simulated by adding the corresponding equivalent of super-stuff to account for additional subcutaneous tissue. To assess image quality, a 461A body phantom with low contrast resolution phantom insert was used. The minimum size of low contrast resolution target visualize was recorded with no shielding and 25-cm-wide shielding. RESULTS: With shields, there was a radiation dose reduction of 19% to 23% at 0-week gestation and 16% to 24% at 18-week gestation. No qualitative difference was found in low contrast detectability with the shields. CONCLUSIONS: These shields reduce fetal radiation exposure early in pregnancy with acceptable image quality. PMID- 25786096 TI - Oxidation and hydration of U3O8 materials following controlled exposure to temperature and humidity. AB - Chemical signatures correlated with uranium oxide processing are of interest to forensic science for inferring sample provenance. Identification of temporal changes in chemical structures of process uranium materials as a function of controlled temperatures and relative humidities may provide additional information regarding sample history. In this study, a high-purity alpha-U3O8 sample and three other uranium oxide samples synthesized from reaction routes used in nuclear conversion processes were stored under controlled conditions over 2-3.5 years, and powder X-ray diffraction analysis and X-ray absorption spectroscopy were employed to characterize chemical speciation. Signatures measured from the alpha-U3O8 sample indicated that the material oxidized and hydrated after storage under high humidity conditions over time. Impurities, such as uranyl fluoride or schoepites, were initially detectable in the other uranium oxide samples. After storage under controlled conditions, the analyses of the samples revealed oxidation over time, although the signature of the uranyl fluoride impurity diminished. The presence of schoepite phases in older uranium oxide material is likely indicative of storage under high humidity and should be taken into account for assessing sample history. The absence of a signature from a chemical impurity, such as uranyl fluoride hydrate, in an older material may not preclude its presence at the initial time of production. LA-UR-15-21495. PMID- 25786097 TI - Parathyroidectomy and survival among Japanese hemodialysis patients with secondary hyperparathyroidism. AB - Parathyroidectomy (PTx) drastically improves biochemical parameters and clinical symptoms related to severe secondary hyperparathyroidism (SHPT) but the effect of PTx on survival has not been adequately investigated. Here we analyzed data on 114,064 maintenance hemodialysis patients from a nationwide registry of the Japanese Society for Dialysis Therapy to evaluate the associations of severity of SHPT and history of PTx with 1-year all-cause and cardiovascular mortality. We then compared the mortality rate between 4428 patients who had undergone PTx and 4428 propensity score-matched patients who had not despite severe SHPT. During a 1-year follow-up, 7926 patients of the entire study population died, of whom 3607 died from cardiovascular disease. Among patients without a history of PTx, severe SHPT was associated with an increased risk for all-cause and cardiovascular mortality. However, such an increased risk of mortality was not observed among patients with a history of PTx. In the propensity score-matched analysis, patients who had undergone PTx had a 34% and 41% lower risk for all-cause and cardiovascular mortality, respectively, compared to the matched controls. The survival benefit associated with PTx was robust in several sensitivity analyses and consistent across subgroups, except for those who had persistent postoperative SHPT. Thus, successful PTx may reduce the risk for all-cause and cardiovascular mortality in hemodialysis patients with severe, uncontrolled SHPT. PMID- 25786099 TI - The risk of hospitalization and modality failure with home dialysis. AB - While home dialysis is being promoted, there are few comparative effectiveness studies of home-based modalities to guide patient decisions. To address this, we matched 1116 daily home hemodialysis (DHD) patients by propensity scores to 2784 contemporaneous USRDS patients receiving home peritoneal dialysis (PD), and compared hospitalization rates from cardiovascular, infectious, access-related or bleeding causes (prespecified composite), and modality failure risk. We performed similar analyses for 1187 DHD patients matched to 3173 USRDS patients receiving in-center conventional hemodialysis (CHD). The composite hospitalization rate was significantly lower with DHD than with PD (0.93 vs. 1.35/patient-year, hazard ratio=0.73 (95% CI=0.67-0.79)). DHD patients spent significantly fewer days in hospital than PD patients (5.2 vs. 9.2 days/patient-year), and significantly more DHD patients remained admission-free (52% DHD vs. 32% PD). In contrast, there was no significant difference in hospitalizations between DHD and CHD (DHD vs. CHD: 0.93 vs. 1.10/patient-year, hazard ratio 0.92 (0.85-1.00)). Cardiovascular hospitalizations were lower with DHD than with CHD (0.68 (0.61-0.77)), while infectious and access hospitalizations were higher (1.15 (1.04-1.29) and 1.25 (1.08-1.43), respectively). Significantly more PD than DHD patients switched back to in-center HD (44% vs. 15%; 3.4 (2.9-4.0)). In this prevalent cohort, home DHD was associated with fewer admissions and hospital days than PD, and a substantially lower risk of modality failure. PMID- 25786098 TI - Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. AB - Autosomal-dominant polycystic kidney disease (ADPKD) affects up to 12 million individuals and is the fourth most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management of its manifestations. Yet, diagnosis, evaluation, prevention, and treatment vary widely and there are no broadly accepted practice guidelines. Barriers to translation of basic science breakthroughs to clinical care exist, with considerable heterogeneity across countries. The Kidney Disease: Improving Global Outcomes Controversies Conference on ADPKD brought together a panel of multidisciplinary clinical expertise and engaged patients to identify areas of consensus, gaps in knowledge, and research and health-care priorities related to diagnosis; monitoring of kidney disease progression; management of hypertension, renal function decline and complications; end-stage renal disease; extrarenal complications; and practical integrated patient support. These are summarized in this review. PMID- 25786101 TI - Kidney donation after circulatory death (DCD): state of the art. AB - The use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to markedly increase kidney transplants performed. However, this potential is not being realized because of concerns that DCD kidneys are inferior to those from donation after brain-death (DBD) donors. The United Kingdom has developed a large and successful controlled DCD kidney transplant program that has allowed for a substantial increase in kidney transplant numbers. Here we describe recent trends in DCD kidney donor activity in the United Kingdom, outline aspects of the donation process, and describe donor selection and allocation of DCD kidneys. Previous UK Transplant Registry analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, short- and medium-term transplant outcomes are similar in recipients of kidneys from DCD and DBD donors. We present an updated, extended UK registry analysis showing that longer-term transplant outcomes in DCD donor kidneys are also similar to those for DBD donor kidneys, and that transplant outcomes for kidneys from expanded-criteria DCD donors are no less favorable than for expanded-criteria DBD donors. Accordingly, the selection criteria for use of kidneys from DCD donors should be the same as those used for DBD donors. The UK experience suggests that wider international development of DCD kidney transplantation programs will help address the global shortage of deceased donor kidneys for transplantation. PMID- 25786100 TI - Migration of smooth muscle cells from the arterial anastomosis of arteriovenous fistulas requires Notch activation to form neointima. AB - A major factor contributing to failure of arteriovenous fistulas (AVFs) is migration of smooth muscle cells into the forming neointima. To identify the source of smooth muscle cells in neointima, we created end-to-end AVFs by anastomosing the common carotid artery to the jugular vein and studied neural crest-derived smooth muscle cells from the carotid artery, which are Wnt1 positive during development. In Wnt1-cre-GFP mice, smooth muscle cells in the carotid artery but not the jugular vein are labeled with GFP. About half of the cells were GFP-positive in the neointima, indicating their migration from the carotid artery to the jugular vein in AVFs created in these mice. As fibroblast specific protein-1 (FSP-1) regulates smooth muscle cell migration, we examined FSP-1 in failed AVFs and polytetrafluoroethylene grafts from patients with end stage kidney disease or from AVFs in mice with chronic kidney disease. In smooth muscle cells of AVFs or polytetrafluoroethylene grafts, FSP-1 and activation of Notch1 are present. In smooth muscle cells, Notch1 increased RBP-Jkappa transcription factor activity and RBP-Jkappa stimulated FSP-1 expression. Conditional knockout of RBP-Jkappa in smooth muscle cells or general knockout of FSP-1 suppressed neointima formation in AVFs in mice. Thus, the artery of AVFs is the major source of smooth muscle cells during neointima formation. Knockout of RBP-Jkappa or FSP-1 ameliorates neointima formation and might improve AVF patency during long-term follow-up. PMID- 25786102 TI - Prevalence of chronic kidney disease in two major Indian cities and projections for associated cardiovascular disease. AB - India is experiencing an alarming rise in the burden of noncommunicable diseases, but data on the incidence of chronic kidney disease (CKD) are sparse. Using the Center for Cardiometabolic Risk Reduction in South Asia surveillance study (a population-based survey of Delhi and Chennai, India) we estimated overall, and age-, sex-, city-, and diabetes-specific prevalence of CKD, and defined the distribution of the study population by the Kidney Disease Improving Global Outcomes (KDIGO) classification scheme. The likelihood of cardiovascular events in participants with and without CKD was estimated by the Framingham and Interheart Modifiable Risk Scores. Of the 12,271 participants, 80% had complete data on serum creatinine and albuminuria. The prevalence of CKD and albuminuria, age standardized to the World Bank 2010 world population, was 8.7% (95% confidence interval: 7.9-9.4%) and 7.1% (6.4-7.7%), respectively. Nearly 80% of patients with CKD had an abnormally high hemoglobin A1c (5.7 and above). Based on KDIGO guidelines, 6.0, 1.0, and 0.5% of study participants are at moderate, high, or very high risk for experiencing CKD-associated adverse outcomes. The cardiovascular risk scores placed a greater proportion of patients with CKD in the high-risk categories for experiencing cardiovascular events when compared with participants without CKD. Thus, 1 in 12 individuals living in two of India's largest cities have evidence of CKD, with features that put them at high risk for adverse outcomes. PMID- 25786104 TI - Nucleotides with altered hydrogen bonding capacities impede human DNA polymerase eta by reducing synthesis in the presence of the major cisplatin DNA adduct. AB - Human DNA polymerase eta (hPol eta) contributes to anticancer drug resistance by catalyzing the replicative bypass of DNA adducts formed by the widely used chemotherapeutic agent cis-diamminedichloroplatinum (cisplatin). A chemical basis for overcoming bypass-associated resistance requires greater knowledge of how small molecules influence the hPol eta-catalyzed bypass of DNA adducts. In this study, we demonstrated how synthetic nucleoside triphosphates act as hPol eta substrates and characterized their influence on hPol eta-mediated DNA synthesis over unmodified and platinated DNA. The single nucleotide incorporation efficiency of the altered nucleotides varied by more than 10-fold and the higher incorporation rates appeared to be attributable to the presence of an additional hydrogen bond between incoming dNTP and templating base. Finally, full-length DNA synthesis in the presence of increasing concentrations of synthetic nucleotides reduced the amount of DNA product independent of the template, representing the first example of hPol eta inhibition in the presence of a platinated DNA template. PMID- 25786103 TI - Mortality amongst patients with influenza-associated severe acute respiratory illness, South Africa, 2009-2013. AB - INTRODUCTION: Data on the burden and risk groups for influenza-associated mortality from Africa are limited. We aimed to estimate the incidence and risk factors for in-hospital influenza-associated severe acute respiratory illness (SARI) deaths. METHODS: Hospitalised patients with SARI were enrolled prospectively in four provinces of South Africa from 2009-2013. Using polymerase chain reaction, respiratory samples were tested for ten respiratory viruses and blood for pneumococcal DNA. The incidence of influenza-associated SARI deaths was estimated at one urban hospital with a defined catchment population. RESULTS: We enrolled 1376 patients with influenza-associated SARI and 3% (41 of 1358 with available outcome data) died. In patients with available HIV-status, the case fatality proportion (CFP) was higher in HIV-infected (5%, 22/419) than HIV uninfected individuals (2%, 13/620; p = 0.006). CFPs varied by age group, and generally increased with increasing age amongst individuals >5 years (p<0.001). On multivariable analysis, factors associated with death were age-group 45-64 years (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.01-16.3) and >=65 years (OR 6.5, 95%CI 1.2-34.3) compared to 1-4 year age-group who had the lowest CFP, HIV-infection (OR 2.9, 95%CI 1.1-7.8), underlying medical conditions other than HIV (OR 2.9, 95%CI 1.2-7.3) and pneumococcal co-infection (OR 4.1, 95%CI 1.5 11.2). The estimated incidence of influenza-associated SARI deaths per 100,000 population was highest in children <1 year (20.1, 95%CI 12.1-31.3) and adults aged 45-64 years (10.4, 95%CI 8.4-12.9). Adjusting for age, the rate of death was 20-fold (95%CI 15.0-27.8) higher in HIV-infected individuals than HIV-uninfected individuals. CONCLUSION: Influenza causes substantial mortality in urban South Africa, particularly in infants aged <1 year and HIV-infected individuals. More widespread access to antiretroviral treatment and influenza vaccination may reduce this burden. PMID- 25786105 TI - Correlates of pro-drinking practices in drinking parents of adolescents in Hong Kong. AB - INTRODUCTION AND AIMS: Parental alcohol-related practices are important risk factors of adolescent drinking, but little is known about the factors associated with these parental pro-drinking practices (PPDPs). We investigated the correlates of 9 PPDPs in drinking parents of adolescents in Hong Kong. METHODS: A total of 2200 students (age 14.8+/-2.0; boys 63.2%) participated in a school based cross-sectional survey in 2012. Analysis was restricted to 1087 (61.8%) students with at least 1 drinking parent as PPDPs were much more common in these families. Logistic regression was used to identify correlates of each PPDP. RESULTS: Among 1087 students, the prevalence of PPDPs ranged from 8.2% for training drinking capacity to 65.7% for seeing parents drink. Only 14.8% of students had not experienced any of these practices. More frequent maternal drinking predicted parental training of drinking capacity. Older age predicted helping parents buy alcohol and parental encouragement of drinking. Adolescent girls were more likely to have received parental training of drinking capacity than boys. Higher perceived family affluence was associated with hearing parents saying benefits of drinking, and helping parents open bottle and pour alcohol. CONCLUSIONS: PPDPs were associated with parental drinking frequency and various socio-demographic factors. These results have implications on alcohol control programmes involving parents to tailor messages for reducing PPDPs based on the characteristics of adolescents and parents. PMID- 25786106 TI - Aspartame sensitivity? A double blind randomised crossover study. AB - BACKGROUND: Aspartame is a commonly used intense artificial sweetener, being approximately 200 times sweeter than sucrose. There have been concerns over aspartame since approval in the 1980s including a large anecdotal database reporting severe symptoms. The objective of this study was to compare the acute symptom effects of aspartame to a control preparation. METHODS: This was a double blind randomized cross over study conducted in a clinical research unit in United Kingdom. Forty-eight individual who has self reported sensitivity to aspartame were compared to 48 age and gender matched aspartame non-sensitive individuals. They were given aspartame (100mg)-containing or control snack bars randomly at least 7 days apart. The main outcome measures were acute effects of aspartame measured using repeated ratings of 14 symptoms, biochemistry and metabonomics. RESULTS: Aspartame sensitive and non-sensitive participants differed psychologically at baseline in handling feelings and perceived stress. Sensitive participants had higher triglycerides (2.05 +/- 1.44 vs. 1.26 +/- 0.84mmol/L; p value 0.008) and lower HDL-C (1.16 +/- 0.34 vs. 1.35 +/- 0.54 mmol/L; p value 0.04), reflected in 1H NMR serum analysis that showed differences in the baseline lipid content between the two groups. Urine metabonomic studies showed no significant differences. None of the rated symptoms differed between aspartame and control bars, or between sensitive and control participants. However, aspartame sensitive participants rated more symptoms particularly in the first test session, whether this was placebo or control. Aspartame and control bars affected GLP-1, GIP, tyrosine and phenylalanine levels equally in both aspartame sensitive and non-sensitive subjects. CONCLUSION: Using a comprehensive battery of psychological tests, biochemistry and state of the art metabonomics there was no evidence of any acute adverse responses to aspartame. This independent study gives reassurance to both regulatory bodies and the public that acute ingestion of aspartame does not have any detectable psychological or metabolic effects in humans. TRIAL REGISTRATION: ISRCTN Registry ISRCTN39650237. PMID- 25786108 TI - BitPhylogeny: a probabilistic framework for reconstructing intra-tumor phylogenies. AB - Cancer has long been understood as a somatic evolutionary process, but many details of tumor progression remain elusive. Here, we present BitPhylogenyBitPhylogeny, a probabilistic framework to reconstruct intra-tumor evolutionary pathways. Using a full Bayesian approach, we jointly estimate the number and composition of clones in the sample as well as the most likely tree connecting them. We validate our approach in the controlled setting of a simulation study and compare it against several competing methods. In two case studies, we demonstrate how BitPhylogeny BitPhylogeny reconstructs tumor phylogenies from methylation patterns in colon cancer and from single-cell exomes in myeloproliferative neoplasm. PMID- 25786107 TI - Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and beta cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications. PMID- 25786109 TI - Over-expression of calpastatin inhibits calpain activation and attenuates post infarction myocardial remodeling. AB - BACKGROUND: Calpain is activated following myocardial infarction and ablation of calpastatin (CAST), an endogenous inhibitor of calpains, promotes left ventricular remodeling after myocardial infarction (MI). The present study aimed to investigate the effect of transgenic over-expression of CAST on the post infarction myocardial remodeling process. METHOD: We established transgenic mice (TG) ubiquitously over-expressing human CAST protein and produced MI in TG mice and C57BL/6J wild-type (WT) littermates. RESULTS: The CAST protein expression was profoundly upregulated in the myocardial tissue of TG mice compared with WT littermates (P < 0.01). Overexpression of CAST significantly reduced the infarct size (P < 0.01) and blunted MI-induced interventricular hypertrophy, global myocardial fibrosis and collagen I and collagen III deposition, hypotension and hemodynamic disturbances at 21 days after MI. Moreover, the MI-induced up regulation and activation of calpains were obviously attenuated in CAST TG mice. MI-induced down-regulation of CAST was partially reversed in TG mice. Additionally, the MI-caused imbalance of matrix metalloproteinases and their inhibitors was improved in TG mice. CONCLUSIONS: Transgenic over-expression of CAST inhibits calpain activation and attenuates post-infarction myocardial remodeling. PMID- 25786111 TI - Coadaptation between mother and offspring: why not? AB - A Formal Comment has challenged the interpretation of a study into an imprinted gene, maintaining that conflict, rather than mother-offspring co-adaptation, provides a better mechanistic explanation. Here authors of the original Research Article reply. PMID- 25786110 TI - Recognition of Neisseria meningitidis by the long pentraxin PTX3 and its role as an endogenous adjuvant. AB - Long pentraxin 3 (PTX3) is a non-redundant component of the humoral arm of innate immunity. The present study was designed to investigate the interaction of PTX3 with Neisseria meningitidis. PTX3 bound acapsular meningococcus, Neisseria derived outer membrane vesicles (OMV) and 3 selected meningococcal antigens (GNA0667, GNA1030 and GNA2091). PTX3-recognized microbial moieties are conserved structures which fulfil essential microbial functions. Ptx3-deficient mice had a lower antibody response in vaccination protocols with OMV and co-administration of PTX3 increased the antibody response, particularly in Ptx3-deficient mice. Administration of PTX3 reduced the bacterial load in infant rats challenged with Neisseria meningitidis. These results suggest that PTX3 recognizes a set of conserved structures from Neisseria meningitidis and acts as an amplifier/endogenous adjuvant of responses to this bacterium. PMID- 25786113 TI - Correction: MysiRNA-Designer: a workflow for efficient siRNA design. PMID- 25786112 TI - Saturated fatty acids modulate autophagy's proteins in the hypothalamus. AB - Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell-line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity. PMID- 25786115 TI - Improvement in long-term breastfeeding for very preterm infants. AB - INTRODUCTION: The extensive health benefits of breastfeeding preterm infants for both mother and infant have been widely reported. However, establishing and maintaining breastfeeding for very preterm (VP) infants remain challenging. The aim of this study was to examine changes in breastfeeding of VP infants over time. SUBJECTS AND METHODS: Breastfeeding questionnaires were administered to two cohorts of parents of VP infants (<32 weeks) cared for at the tertiary perinatal or surgical neonatal unit in Western Australia. Of these, 488 infants were included in cohort 1 (C1) (births from January 1, 1990 to June 30, 1992) and 253 in cohort 2 (C2) (from January 1, 2011 to September 14, 2012). RESULTS: More mothers (96.8%) initiated breastfeeding in C2 compared with those in C1 (65.6%) (p<0.001). Additionally, 41.4% of mothers in C2 breastfed for more than 6 months, relative to 25.8% in C1 (p<0.001). The benefits of breastfeeding were endorsed by more women in C2 (45.8%) compared with C1 (11.4%) (p<0.01). Reasons for stopping feeding remained largely consistent. CONCLUSIONS: Significant improvements were evident in the initiation and duration of breastfeeding of the VP infant over time. This improvement was associated with attitudinal shifts in mothers about the benefits of breastfeeding. PMID- 25786114 TI - In-silico analysis of inflammatory bowel disease (IBD) GWAS loci to novel connections. AB - Genome-wide association studies (GWASs) for many complex diseases, including inflammatory bowel disease (IBD), produced hundreds of disease-associated loci the majority of which are noncoding. The number of GWAS loci is increasing very rapidly, but the process of translating single nucleotide polymorphisms (SNPs) from these loci to genomic medicine is lagging. In this study, we investigated 4,734 variants from 152 IBD associated GWAS loci (IBD associated 152 lead noncoding SNPs identified from pooled GWAS results + 4,582 variants in strong linkage-disequilibrium (LD) (r2 >=0.8) for EUR population of 1K Genomes Project) using four publicly available bioinformatics tools, e.g. dbPSHP, CADD, GWAVA, and RegulomeDB, to annotate and prioritize putative regulatory variants. Of the 152 lead noncoding SNPs, around 11% are under strong negative selection (GERP++ RS >=2); and ~30% are under balancing selection (Tajima's D score >2) in CEU population (1K Genomes Project)--though these regions are positively selected (GERP++ RS <0) in mammalian evolution. The analysis of 4,734 variants using three integrative annotation tools produced 929 putative functional SNPs, of which 18 SNPs (from 15 GWAS loci) are in concordance with all three classifiers. These prioritized noncoding SNPs may contribute to IBD pathogenesis by dysregulating the expression of nearby genes. This study showed the usefulness of integrative annotation for prioritizing fewer functional variants from a large number of GWAS markers. PMID- 25786116 TI - Phosphorylation of CHO1 by Lats1/2 regulates the centrosomal activation of LIMK1 during cytokinesis. AB - Large tumor suppressor 1 and 2 (Lats1/2) regulate centrosomal integrity, chromosome segregation and cytokinesis. As components of the centralspindlin complex, the kinesin-like protein CHO1 and its splicing variant MKLP1 colocalize with chromosome passenger proteins and GTPases and regulate the formation of the contractile ring and cytokinesis; however, the regulatory mechanisms of CHO1/MKLP1 remain elusive. Here, we show that Lats1/2 phosphorylate Ser716 in the F-actin-interacting region of CHO1, which is absent in MKLP1. Phosphorylated CHO1 localized to the centrosomes and midbody, and the actin polymerization factor LIM kinase 1 (LIMK1) was identified as its binding partner. Overexpression of constitutively phosphorylated and non-phosphorylated CHO1 altered the mitotic localization and activation of LIMK1 at the centrosomes in HeLa cells, leading to the inhibition of cytokinesis through excessive phosphorylation of Cofilin and mislocalization of Ect2. These results suggest that Lats1/2 stringently control cytokinesis by regulating CHO1 phosphorylation and the mitotic activation of LIMK1 on centrosomes. PMID- 25786117 TI - Highly selective separation and purification of anthocyanins from bilberry based on a macroporous polymeric adsorbent. AB - Powdered bilberry extract (United States Pharmacopoeia, USP35-NF30), which is prepared from ripe bilberry fruits (Vaccinium myrtillus L.), is the main ingredient of drugs alleviating visual fatigue and diabetic retinopathy because of the rich anthocyanins (purity of 36%). In this study, a method based on a macroporous polymeric adsorbent was established to obtain anthocyanin compounds from bilberry, in which the purity of the anthocyanins was improved to 96%, conducive to further pharmacological research and improvement of the efficiency of the drug. On the basis of the structure of anthocyanins, we designed a series of macroporous polymeric adsorbents based on the copolymerization of divinylbenzene (DVB) and ethylene glycol dimethyl acrylate (EGDMA). In this situation, EGDMA not only regulated the polarity of the adsorbent but also acted as the cross-linking agent to ensure the matrix structure of the adsorbent, which had a high specific surface area and could provide more interaction sites during adsorption with anthocyanins. Among the synthesized polymeric adsorbents with different contents of EGDMA, the one with 20% EGDMA content (DE-20) was demonstrated to exhibit optimal adsorption capacity and selectivity to anthocyanins compared to various commercial adsorbents through static adsorption and desorption experiments. In addition, the optimum condition of the dynamic adsorption-desorption experiment was further explored. The results indicated that the purity of anthocyanins after rinsing with 20% ethanol was determined to be approximately 96% at a desorption ratio of 83%, which was clearly higher than that in powdered bilberry extract. The established separation and purification method of anthocyanins with high purity is expected to be applied in industrial production. PMID- 25786118 TI - Serum levels of monocyte chemoattractant protein-1 and all-cause and cardiovascular mortality among patients with coronary artery disease. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine at multiple phases of atherosclerosis in animals, but human studies are few and inconsistent. The aim of this study is to investigate the association of serum MCP-1 with all-cause and cardiovascular disease (CVD) mortality among coronary artery disease (CAD) patients and determine whether this biomarker can add secondary prognostic value to standard risk predictors. METHODS: MCP-1 was measured at baseline in 1411 CAD patients who were 40-85 years of age. Cox proportional hazards regression models were used to estimate the association of MCP-1 levels with death risk. RESULTS: During a median follow-up of 3.3 years, 117 deaths were recorded, 88 of which were due to CVD. The multivariable-adjusted hazard ratios across tertiles of MCP-1 were 1.51 (95% confidence intervals [CI] 0.89-2.58), 1.00, and 2.11 (95% CI 1.31-3.40) for all-cause mortality, and 1.50 (95% CI 0.80-2.81), 1.00, and 2.21 (95% CI 1.27-3.87) for CVD mortality. The addition of serum MCP-1 to the fully adjusted model increased the C-index by 0.009 (p<0.0001) for all-cause mortality and 0.008 (p<0.0001) for CVD mortality and significantly improved the predictive ability by 12.1% (P = 0.006) on all cause mortality and 12.6% (P = 0.003) on CVD mortality using the net reclassification improvement method. CONCLUSIONS: Both lower and higher MCP-1 levels are associated with an increased risk of all-cause and CVD mortality among CAD patients. More research is needed to confirm its clinical relevance. PMID- 25786119 TI - Mitogenomes from The 1000 Genome Project reveal new Near Eastern features in present-day Tuscans. AB - BACKGROUND: Genetic analyses have recently been carried out on present-day Tuscans (Central Italy) in order to investigate their presumable recent Near East ancestry in connection with the long-standing debate on the origins of the Etruscan civilization. We retrieved mitogenomes and genome-wide SNP data from 110 Tuscans analyzed within the context of The 1000 Genome Project. For phylogeographic and evolutionary analysis we made use of a large worldwide database of entire mitogenomes (>26,000) and partial control region sequences (>180,000). RESULTS: Different analyses reveal the presence of typical Near East haplotypes in Tuscans representing isolated members of various mtDNA phylogenetic branches. As a whole, the Near East component in Tuscan mitogenomes can be estimated at about 8%; a proportion that is comparable to previous estimates but significantly lower than admixture estimates obtained from autosomal SNP data (21%). Phylogeographic and evolutionary inter-population comparisons indicate that the main signal of Near Eastern Tuscan mitogenomes comes from Iran. CONCLUSIONS: Mitogenomes of recent Near East origin in present-day Tuscans do not show local or regional variation. This points to a demographic scenario that is compatible with a recent arrival of Near Easterners to this region in Italy with no founder events or bottlenecks. PMID- 25786120 TI - In vitro matured oocytes are more susceptible than in vivo matured oocytes to mock ICSI induced functional and genetic changes. AB - BACKGROUND: Concerns regarding the safety of ICSI have been intensified recently due to increased risk of birth defects in ICSI born children. Although fertilization rate is significantly higher in ICSI cycles, studies have failed to demonstrate the benefits of ICSI in improving the pregnancy rate. Poor technical skill, and suboptimal in vitro conditions may account for the ICSI results however, there is no report on the effects of oocyte manipulations on the ICSI outcome. OBJECTIVE: The present study elucidates the influence of mock ICSI on the functional and genetic integrity of the mouse oocytes. METHODS: Reactive Oxygen Species (ROS) level, mitochondrial status, and phosphorylation of H2AX were assessed in the in vivo matured and IVM oocytes subjected to mock ICSI. RESULTS: A significant increase in ROS level was observed in both in vivo matured and IVM oocytes subjected to mock ICSI (P<0.05-0.001) whereas unique mitochondrial distribution pattern was found only in IVM oocytes (P<0.01-0.001). Importantly, differential H2AX phosphorylation was observed in both in vivo matured and IVM oocytes subjected to mock ICSI (P <0.001). CONCLUSION: The data from this study suggests that mock ICSI can alter genetic and functional integrity in oocytes and IVM oocytes are more vulnerable to mock ICSI induced changes. PMID- 25786121 TI - Preventive effect of Lactobacillus reuteri CRL1324 on Group B Streptococcus vaginal colonization in an experimental mouse model. AB - AIMS: To assess the preventive effect of different intravaginal (i.va.) doses of Lactobacillus reuteri CRL1324 against vaginal colonization by Group B Streptococcus (GBS) in a murine experimental model. METHODS AND RESULTS: The major virulence factors of four vaginal GBS clinical isolates were determined to select the most virulent strain and set up a murine model of streptococcal vaginal colonization. Later, the effect of four and seven doses of 10(8) viable cells of Lact. reuteri CRL1324 i.va. administered, prior to the GBS challenge was studied. Seven doses of lactobacilli were able to significantly reduce the number of viable GBS cells, while four doses showed no preventive effect. Both doses reduced the leucocyte influx induced by GBS. Seven doses caused a slight increase in the Lact. reuteri CRL1324 vaginal colonization compared with four doses and reduced murine vaginal pH compared to control mice. CONCLUSIONS: Lactobacillus reuteri CRL1324 evidenced a preventive effect on GBS vaginal colonization in an experimental mouse model. SIGNIFICANCE AND IMPACTS OF THE STUDY: Maternal GBS colonization is one of the most important risk factors for developing disease in newborns. Lactobacillus reuteri CRL1324 could be considered as a new biological agent to reduce infections caused by this micro-organism. PMID- 25786123 TI - Fat residue and use-wear found on Acheulian biface and scraper associated with butchered elephant remains at the site of Revadim, Israel. AB - The archaeological record indicates that elephants must have played a significant role in early human diet and culture during Palaeolithic times in the Old World. However, the nature of interactions between early humans and elephants is still under discussion. Elephant remains are found in Palaeolithic sites, both open-air and cave sites, in Europe, Asia, the Levant, and Africa. In some cases elephant and mammoth remains indicate evidence for butchering and marrow extraction performed by humans. Revadim Quarry (Israel) is a Late Acheulian site where elephant remains were found in association with characteristic Lower Palaeolithic flint tools. In this paper we present results regarding the use of Palaeolithic tools in processing animal carcasses and rare identification of fat residue preserved on Lower Palaeolithic tools. Our results shed new light on the use of Palaeolithic stone tools and provide, for the first time, direct evidence (residue) of animal exploitation through the use of an Acheulian biface and a scraper. The association of an elephant rib bearing cut marks with these tools may reinforce the view suggesting the use of Palaeolithic stone tools in the consumption of large game. PMID- 25786122 TI - Curcumin and emodin down-regulate TGF-beta signaling pathway in human cervical cancer cells. AB - Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF beta signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-beta signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-beta and Wnt/beta-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-beta on beta-catenin (an important player in Wnt/beta-catenin signaling) and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-beta signaling pathway by decreasing the expression of TGF-beta Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-beta by inhibiting the TGF-beta induced migration and invasion. Expression of downstream effectors of TGF-beta signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug) upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-beta activates Wnt/beta-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting beta-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer. PMID- 25786124 TI - Noninvasive method for measuring local pulse wave velocity by dual pulse wave Doppler: in vitro and in vivo studies. AB - OBJECTIVES: To evaluate the validity and reproducibility of a noninvasive dual pulse wave Doppler (DPWD) method, which involves simultaneous recording of flow velocity of two independent sample volumes with a measurable distance, for measuring the local arterial pulse wave velocity (PWV) through in vitro and in vivo studies. METHODS: The DPWD mode of Hitachi HI Vision Preirus ultrasound system with a 5-13MHz transducer was used. An in vitro model was designed to compare the PWV of a homogeneous rubber tubing with the local PWV of its middle part measured by DPWD method. In the in vivo study, local PWV of 45 hypertensive patients (25 male, 49.8+/-3.1 years) and 45 matched healthy subjects (25 male, 49.3+/-3.0 years) were investigated at the left common carotid artery (LCCA) by DPWD method. RESULTS: In the in vitro study, the local PWV measured by DPWP method and the PWV of the homogeneous rubber tubing did not show statistical difference (5.16 +/- 0.28 m/s vs 5.03 +/- 0.15 m/s, p = 0.075). The coefficient of variation (CV) of the intra- and inter- measurements for local PWV were 3.46% and 4.96%, for the PWV of the homogeneous rubber tubing were 0.99% and 1.98%. In the in vivo study, a significantly higher local PWV of LCCA was found in the hypertensive patients as compared to that in healthy subjects (6.29+/-1.04 m/s vs. 5.31+/-0.72 m/s, P = 0.019). The CV of the intra- and inter- measurements in hypertensive patients were 2.22% and 3.94%, in healthy subjects were 2.07% and 4.14%. CONCLUSIONS: This study demonstrated the feasibility of the noninvasive DPWD method to determine the local PWV, which was accurate and reproducible not only in vitro but also in vivo studies. This noninvasive echocardiographic method may be illuminating to clinical use. PMID- 25786125 TI - Tenotomy or tenodesis for the long head of biceps lesions in shoulders: a systematic review and meta-analysis. AB - BACKGROUND: Both tenotomy and tenodesis have been widely used for the treatment of long head of biceps tendon (LHBT) lesions, but the optimal strategy remains considerably controversial. In this meta-analysis of published studies, we compared the results of the two procedures. METHODS: A literature search that compared tenotomy with tenodesis was performed using MEDLINE, and Embase until August 2014. A total of 7 studies reporting data on 622 subjects were included. Study quality was evaluated using the PEDro critical appraisal tool and the NO quality assessment tool. RESULTS: Data synthesis showed higher functional outcomes, a lower complication rate, and longer surgical time in patients managed with tenodesis compared to tenotomy (Constant score, P = 0.02; Popeye sign, P < 0.001; cramp pain, P = 0.04; surgical time, P < 0.001, respectively). CONCLUSION: This meta-analysis indicates that tenodesis results in better arm function and lower incidences of cramp pain and Popeye sign in LHBT lesions, while the procedure required longer surgical time compared to tenotomy. More sufficiently powered studies would be required to further determine the optimal strategy. PMID- 25786126 TI - A mechanistic tumor penetration model to guide antibody drug conjugate design. AB - Antibody drug conjugates (ADCs) represent novel anti-cancer modalities engineered to specifically target and kill tumor cells expressing corresponding antigens. Due to their large size and their complex kinetics, these therapeutic agents often face heterogeneous distributions in tumors, leading to large untargeted regions that escape therapy. We present a modeling framework which includes the systemic distribution, vascular permeability, interstitial transport, as well as binding and payload release kinetics of ADC-therapeutic agents in mouse xenografts. We focused, in particular, on receptor dynamics such as endocytic trafficking mechanisms within cancer cells, to simulate their impact on tumor mass shrinkage upon ADC administration. Our model identified undesirable tumor properties that can impair ADC tissue homogeneity, further compromising ADC success, and explored ADC design optimization scenarios to counteract upon such unfavorable intrinsic tumor tissue attributes. We further demonstrated the profound impact of cytotoxic payload release mechanisms and the role of bystander killing effects on tumor shrinkage. This model platform affords a customizable simulation environment which can aid with experimental data interpretation and the design of ADC therapeutic treatments. PMID- 25786127 TI - Assessment of chronic sublethal effects of imidacloprid on honey bee colony health. AB - Here we present results of a three-year study to determine the fate of imidacloprid residues in hive matrices and to assess chronic sublethal effects on whole honey bee colonies fed supplemental pollen diet containing imidacloprid at 5, 20 and 100 MUg/kg over multiple brood cycles. Various endpoints of colony performance and foraging behavior were measured during and after exposure, including winter survival. Imidacloprid residues became diluted or non-detectable within colonies due to the processing of beebread and honey and the rapid metabolism of the chemical. Imidacloprid exposure doses up to 100 MUg/kg had no significant effects on foraging activity or other colony performance indicators during and shortly after exposure. Diseases and pest species did not affect colony health but infestations of Varroa mites were significantly higher in exposed colonies. Honey stores indicated that exposed colonies may have avoided the contaminated food. Imidacloprid dose effects was delayed later in the summer, when colonies exposed to 20 and 100 MUg/kg experienced higher rates of queen failure and broodless periods, which led to weaker colonies going into the winter. Pooled over two years, winter survival of colonies averaged 85.7, 72.4, 61.2 and 59.2% in the control, 5, 20 and 100 MUg/kg treatment groups, respectively. Analysis of colony survival data showed a significant dose effect, and all contrast tests comparing survival between control and treatment groups were significant, except for colonies exposed to 5 MUg/kg. Given the weight of evidence, chronic exposure to imidacloprid at the higher range of field doses (20 to 100 MUg/kg) in pollen of certain treated crops could cause negative impacts on honey bee colony health and reduced overwintering success, but the most likely encountered high range of field doses relevant for seed-treated crops (5 MUg/kg) had negligible effects on colony health and are unlikely a sole cause of colony declines. PMID- 25786128 TI - Increasing prevalence of diabetes during pregnancy in South Carolina. AB - BACKGROUND: The objective of our study was to examine the prevalence of diabetes during pregnancy at the population level in SC from January 1996 through December 2008. METHODS: The study included 387,720 non-Hispanic white (NHW), 232,278 non Hispanic black (NHB), and 43,454 Hispanic live singleton births. Maternal inpatient hospital discharge codes from delivery (91.59%) and prenatal information (i.e., Medicaid [42.91%] and SC State Health Plan [SHP] [5.98%]) were linked to birth certificate data. Diabetes during pregnancy included gestational and preexisting, defined by prenatal and maternal inpatient International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes (i.e., 64801-64802, 64881-64882, or 25000-25092) or report on the birth certificate. RESULTS: Diabetes prevalence from any source increased from 5.02% (95% confidence interval [CI]: 4.82-5.22) in 1996 to 8.37% (95% CI: 8.15-8.60) in 2008. Diabetes prevalence, standardized for maternal age and race/ethnicity from 1996 through 2008, increased from 3.38% (95% CI: 3.29-3.47) to 5.81% (95% CI: 5.71-5.91) using birth certificate data, from 3.99% (95% CI: 3.89-4.10) to 6.69% (95% CI: 6.58-6.80) using hospital discharge data, and from 4.74% (95% CI: 4.52-4.96) to 8.82% (95% CI: 8.61-9.03) using Medicaid data. Comparing birth certificate to hospital discharge, Medicaid, and SHP data, Cohen's kappa in 2008 was 0.73 (95% CI: 0.72-0.75), 0.64 (95% CI: 0.62-0.66), and 0.59 (95% CI: 0.54-0.65), respectively. CONCLUSIONS: An increasing prevalence of diabetes during pregnancy is reported, as well as substantial lack of agreement in reporting of diabetes prevalence across administrative databases. Prevalence of reported diabetes during pregnancy is impacted by screening, diagnostic, and reporting practices across different data sources, as well as by actual changes in prevalence over time. PMID- 25786129 TI - Proteome-wide lysine acetylation in cortical astrocytes and alterations that occur during infection with brain parasite Toxoplasma gondii. AB - Lysine acetylation is a reversible post-translational modification (PTM) that has been detected on thousands of proteins in nearly all cellular compartments. The role of this widespread PTM has yet to be fully elucidated, but can impact protein localization, interactions, activity, and stability. Here we present the first proteome-wide survey of lysine acetylation in cortical astrocytes, a subtype of glia that is a component of the blood-brain barrier and a key regulator of neuronal function and plasticity. We identified 529 lysine acetylation sites across 304 proteins found in multiple cellular compartments that largely function in RNA processing/transcription, metabolism, chromatin biology, and translation. Two hundred and seventy-seven of the acetylated lysines we identified on 186 proteins have not been reported previously in any other cell type. We also mapped an acetylome of astrocytes infected with the brain parasite, Toxoplasma gondii. It has been shown that infection with T. gondii modulates host cell gene expression, including several lysine acetyltransferase (KAT) and deacetylase (KDAC) genes, suggesting that the host acetylome may also be altered during infection. In the T. gondii-infected astrocytes, we identified 34 proteins exhibiting a level of acetylation >2-fold and 24 with a level of acetylation <2 fold relative to uninfected astrocytes. Our study documents the first acetylome map for cortical astrocytes, uncovers novel lysine acetylation sites, and demonstrates that T. gondii infection produces an altered acetylome. PMID- 25786130 TI - Examining the evolution of the regulatory circuit controlling secondary metabolism and development in the fungal genus Aspergillus. AB - Filamentous fungi produce diverse secondary metabolites (SMs) essential to their ecology and adaptation. Although each SM is typically produced by only a handful of species, global SM production is governed by widely conserved transcriptional regulators in conjunction with other cellular processes, such as development. We examined the interplay between the taxonomic narrowness of SM distribution and the broad conservation of global regulation of SM and development in Aspergillus, a diverse fungal genus whose members produce well-known SMs such as penicillin and gliotoxin. Evolutionary analysis of the 2,124 genes comprising the 262 SM pathways in four Aspergillus species showed that most SM pathways were species specific, that the number of SM gene orthologs was significantly lower than that of orthologs in primary metabolism, and that the few conserved SM orthologs typically belonged to non-homologous SM pathways. RNA sequencing of two master transcriptional regulators of SM and development, veA and mtfA, showed that the effects of deletion of each gene, especially veA, on SM pathway regulation were similar in A. fumigatus and A. nidulans, even though the underlying genes and pathways regulated in each species differed. In contrast, examination of the role of these two regulators in development, where 94% of the underlying genes are conserved in both species showed that whereas the role of veA is conserved, mtfA regulates development in the homothallic A. nidulans but not in the heterothallic A. fumigatus. Thus, the regulation of these highly conserved developmental genes is divergent, whereas-despite minimal conservation of target genes and pathways the global regulation of SM production is largely conserved. We suggest that the evolution of the transcriptional regulation of secondary metabolism in Aspergillus represents a novel type of regulatory circuit rewiring and hypothesize that it has been largely driven by the dramatic turnover of the target genes involved in the process. PMID- 25786131 TI - Third-generation electrokinetically pumped sheath-flow nanospray interface with improved stability and sensitivity for automated capillary zone electrophoresis mass spectrometry analysis of complex proteome digests. AB - We have reported a set of electrokinetically pumped sheath flow nanoelectrospray interfaces to couple capillary zone electrophoresis with mass spectrometry. A separation capillary is threaded through a cross into a glass emitter. A side arm provides fluidic contact with a sheath buffer reservoir that is connected to a power supply. The potential applied to the sheath buffer drives electro-osmosis in the emitter to pump the sheath fluid at nanoliter per minute rates. Our first generation interface placed a flat-tipped capillary in the emitter. Sensitivity was inversely related to orifice size and to the distance from the capillary tip to the emitter orifice. A second-generation interface used a capillary with an etched tip that allowed the capillary exit to approach within a few hundred micrometers of the emitter orifice, resulting in a significant increase in sensitivity. In both the first- and second-generation interfaces, the emitter diameter was typically 8 MUm; these narrow orifices were susceptible to plugging and tended to have limited lifetime. We now report a third-generation interface that employs a larger diameter emitter orifice with very short distance between the capillary tip and the emitter orifice. This modified interface is much more robust and produces much longer lifetime than our previous designs with no loss in sensitivity. We evaluated the third-generation interface for a 5000 min (127 runs, 3.5 days) repetitive analysis of bovine serum albumin digest using an uncoated capillary. We observed a 10% relative standard deviation in peak area, an average of 160,000 theoretical plates, and very low carry-over (much less than 1%). We employed a linear-polyacrylamide (LPA)-coated capillary for single-shot, bottom-up proteomic analysis of 300 ng of Xenopus laevis fertilized egg proteome digest and identified 1249 protein groups and 4038 peptides in a 110 min separation using an LTQ-Orbitrap Velos mass spectrometer; peak capacity was ~330. The proteome data set using this third-generation interface-based CZE-MS/MS is similar in size to that generated using a commercial ultraperformance liquid chromatographic analysis of the same sample with the same mass spectrometer and similar analysis time. PMID- 25786134 TI - The association between state attachment security and state Mindfulness. AB - Recent research suggests that attachment and mindfulness are related, though the nature of this association is unclear. Here we present two studies examining whether there is a causal relationship between state attachment and state mindfulness. Study 1 investigated the effects of experimentally increasing state mindfulness on state attachment security. State mindfulness was successfully enhanced, but this led to no change in state attachment security. Study 2 investigated the effects of experimentally enhancing state attachment security on state mindfulness. State attachment security was successfully enhanced, but this did not lead to any change in state mindfulness. These findings suggest that there is not a direct, immediate causal relationship between state attachment and state mindfulness as a result of brief experimental manipulations. Future research should examine these associations in longer term interventions. PMID- 25786133 TI - STEP levels are unchanged in pre-frontal cortex and associative striatum in post mortem human brain samples from subjects with schizophrenia, bipolar disorder and major depressive disorder. AB - Increased protein levels of striatal-enriched tyrosine phosphatase (STEP) have recently been reported in postmortem schizophrenic cortex. The present study sought to replicate this finding in a separate cohort of postmortem samples and to extend observations to striatum, including subjects with bipolar disorder and major depressive disorder in the analysis. No statistically significant changes between disease and control subjects were found in STEP mRNA or protein levels in dorsolateral prefrontal cortex or associative striatum. Although samples were matched for several covariates, postmortem interval correlated negatively with STEP protein levels, emphasizing the importance of including these analyses in postmortem studies. PMID- 25786132 TI - Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury. AB - Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/ mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID- 25786135 TI - Biosynthesis of the diterpenoid lycosantalonol via nerylneryl diphosphate in Solanum lycopersicum. AB - We recently reported that three genes involved in the biosynthesis of monoterpenes in trichomes, a cis-prenyltransferase named neryl diphosphate synthase 1 (NDPS1) and two terpene synthases (TPS19 and TPS20), are present in close proximity to each other at the tip of chromosome 8 in the genome of the cultivated tomato (Solanum lycopersicum). This terpene gene "cluster" also contains a second cis-prenyltransferase gene (CPT2), three other TPS genes, including TPS21, and the cytochrome P450-oxidoreductase gene CYP71BN1. CPT2 encodes a neryneryl diphosphate synthase. Co-expression in E. coli of CPT2 and TPS21 led to the formation of the diterpene lycosantalene, and co-expression in E. coli of CPT2, TPS21 and CYP71BN1 led to the formation of lycosantalonol, an oxidation product of lycosantalene. Here we show that maximal expression of all three genes occurs in the petiolule part of the leaf, but little expression of these genes occurs in the trichomes present on the petiolules. While lycosantalene or lycosantalonol cannot be detected in the petiolules of wild-type plants (or anywhere else in the plant), lycosantalene and lycosantalonol are detected in petiolules of transgenic tomato plants expressing CPT2 under the control of the 35S CaMV promoter. These results suggest that lycosantalene and lycosantalonol are produced in the petiolules and perhaps in other tissues of wild-type plants, but that low rate of synthesis, controlled by the rate-limiting enzyme CPT2, results in product levels that are too low for detection under our current methodology. It is also possible that these compounds are further modified in the plant. The involvement of CPT2, TPS21 and CYP71BN1 in a diterpenoid biosynthetic pathway outside the trichomes, together with the involvement of other genes in the cluster in the synthesis of monoterpenes in trichomes, indicates that this cluster is further evolving into "sub-clusters" with unique biochemical, and likely physiological, roles. PMID- 25786136 TI - Nephroprotective effect of heparanase in experimental nephrotic syndrome. AB - BACKGROUND: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model. METHODS: BALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity. RESULTS: ADR injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice. CONCLUSIONS: Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury. PMID- 25786137 TI - Synergistic plasmonic effects of metal nanoparticle-decorated PEGylated graphene oxides in polymer solar cells. AB - Metal nanostructures that trigger plasmonic near-field effects are often incorporated in organic photovoltaic devices (OPVs) to improve their light harvesting ability. These nanostructures usually can be positioned in two different locations in a device: (i) within the photon absorption layers and (ii) at the interfaces between the active layer and the metal electrodes. In this study, we developed amphiphilic gold nanoparticles (Au NPs) for use in dual plasmonic nanostructures within OPVs. We employed graphene oxide as the template to anchor the Au NPs, thereby avoiding their aggregation. Furthermore, we added poly(ethylene glycol) (PEG) bis(amine) to the synthesis medium to improve the solubility of the nanocomposites, such that they could be dispersed well in water and in several organic solvents. Accordingly, we could incorporate the PEGylated Au NP/graphene oxides readily into both the buffer layer and photoactive layer of OPVs, which, as a result, exhibited obvious enhancements in their photocurrents and overall device efficiencies. Moreover, we observed different spectral enhancement regions when we positioned the nanocomposites at different locations, reflecting the different dielectric environments surrounding the NPs; this unexpected behavior should assist in enhancing the broadband absorption of solar irradiation. PMID- 25786139 TI - Controlled synthesis and synergistic effects of graphene-supported PdAu bimetallic nanoparticles with tunable catalytic properties. AB - Graphene-supported bimetallic nanoparticles are promising nanocatalysts, which can show strong and tunable catalytic activity and selectivity. Herein room temperature-ionic-liquid-assisted metal sputtering is utilized to synthesize PdAu bimetallic nanoparticles on graphene with bare surface, small size, high surface density and controlled Pd-to-Au ratio. This controllable synthetic approach is green-chemistry compatible and totally free of additives and byproducts. The supported PdAu nanoparticles show excellent catalytic capabilities for both oxidation and reduction reactions, strongly dependent on the Pd-to-Au ratio. A strong correlation among catalytic performance, bimetallic composition and charge redistribution in the PdAu nanoparticles has been demonstrated. The results suggest that sufficient Au d-holes appear to be significant to the catalysis of oxidation reaction, and a metallic Pd surface is critical to the catalysis of reduction reaction. By the present method, the bimetallic combination can be tailored for distinct types of catalytic reactions. PMID- 25786138 TI - miR-29a/b enhances cell migration and invasion in nasopharyngeal carcinoma progression by regulating SPARC and COL3A1 gene expression. AB - Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with a genetic predisposition, Epstein-Barr virus infection and chromosomal abnormalities. Recently, several miRNAs have been shown to target specific mRNAs to regulate NPC development and progression. However, the involvement of miRNAs in processes leading to NPC migration and invasion remains to be elucidated. We predicted that miR-29a/b are associated with dysregulated genes controlling NPC through an integrated interaction network of miRNAs and genes. miR-29a/b over-expression in NPC cell lines had no significant effect on proliferation, whereas miR-29b mildly increased the percentage of cells in the G1 phase with a concomitant decrease in the percentage of cells in S phase. Furthermore, we demonstrated that miR-29a/b might be responsible for increasing S18 cell migration and invasion, and only COL3A1 was identified as a direct target of miR-29b despite the fact that both SPARC and COL3A1 were inhibited by miR-29a/b over-expression. Meanwhile, SPARC proteins were increased in metastatic NPC tissue and are involved in NPC progression. Unexpectedly, we identified that miRNA-29b expression was elevated in the serum of NPC patients with a high risk of metastasis. The 5-year actuarial overall survival rates in NPC patients with high serum miR-29b expression was significantly shorter than those with low serum miR-29b expression; therefore, serum miR-29b expression could be a promising prognostic marker. PMID- 25786140 TI - Genetic Relatedness Among Escherichia coli Pathotypes Isolated from Food Products for Human Consumption in Cartagena, Colombia. AB - Foodborne pathogens are a leading cause of mild-to-severe gastrointestinal illnesses worldwide. Escherichia coli pathotypes have been known to cause gastrointestinal illnesses in children less than 5 years old in Colombia. However, insufficient information is available on the prevalence of E. coli contamination of food products and the kind of E. coli food product reservoirs. The two objectives of this study were designed to address this issue. The first objective was to ascertain coliform, E. coli, and pathogenic E. coli contamination of food products readily available for human consumption in Cartagena, Colombia. The second objective was to evaluate the relationship between pathogenic E. coli isolated from food products and those isolated from cases of diarrhea in children. Food product samples consisting of pasteurized milk, unpasteurized fruit juice, ground beef, cheese, and vegetables were obtained at four retail stores. The food samples were cultured in liquid media and tested for the presence of coliforms and E. coli. E. coli isolates were tested by polymerase chain reaction for the presence of pathogenic E. coli. Coliforms, E. coli, and E. coli intestinal pathotypes contamination were detected in 88.4%, 53%, and 2.1% of food product samples, respectively. Ground beef and cheese were the only food samples contaminated with E. coli intestinal pathotypes including enteropathogenic (EPEC), Shiga toxin-producing (STEC), and enterotoxigenic E. coli (ETEC). Closed multilocus sequencing typing relationships between diarrheagenic E. coli isolates from food products and from individuals with diarrhea suggest that food products readily available at public markets in Cartagena can transmit ETEC and possibly EPEC and STEC. We demonstrated that a high proportion of food products for human consumption available at public markets in Cartagena are contaminated with coliforms, E. coli, and E. coli intestinal pathogens. Furthermore, food products containing E. coli intestinal pathogens may be involved in the transmission of foodborne illnesses among children in Cartagena, Colombia. PMID- 25786141 TI - PAMAM dendrimers and graphene: materials for removing aromatic contaminants from water. AB - We present results from experiments and atomistic molecular dynamics simulations on the remediation of naphthalene by polyamidoamine (PAMAM) dendrimers and graphene oxide (GrO). Specifically, we investigate 3rd-6th generation (G3-G6) PAMAM dendrimers and GrO with different levels of oxidation. The work is motivated by the potential applications of these emerging nanomaterials in removing polycyclic aromatic hydrocarbon contaminants from water. Our experimental results indicate that GrO outperforms dendrimers in removing naphthalene from water. Molecular dynamics simulations suggest that the prominent factors driving naphthalene association to these seemingly disparate materials are similar. Interestingly, we find that cooperative interactions between the naphthalene molecules play a significant role in enhancing their association to the dendrimers and GrO. Our findings highlight that while selection of appropriate materials is important, the interactions between the contaminants themselves can also be important in governing the effectiveness of a given material. The combined use of experiments and molecular dynamics simulations allows us to comment on the possible factors resulting in better performance of GrO in removing polyaromatic contaminants from water. PMID- 25786142 TI - Identification and characterization of bifunctional proline racemase/hydroxyproline epimerase from archaea: discrimination of substrates and molecular evolution. AB - Proline racemase (ProR) is a member of the pyridoxal 5'-phosphate-independent racemase family, and is involved in the Stickland reaction (fermentation) in certain clostridia as well as the mechanisms underlying the escape of parasites from host immunity in eukaryotic Trypanosoma. Hydroxyproline epimerase (HypE), which is in the same protein family as ProR, catalyzes the first step of the trans-4-hydroxy-L-proline metabolism of bacteria. Their substrate specificities were previously considered to be very strict, in spite of similarities in their structures and catalytic mechanisms, and no racemase/epimerase from the ProR superfamily has been found in archaea. We here characterized the ProR-like protein (OCC_00372) from the hyperthermophilic archaeon, Thermococcus litoralis (TlProR). This protein could reversibly catalyze not only the racemization of proline, but also the epimerization of 4-hydroxyproline and 3-hydroxyproline with similar kinetic constants. Among the four (putative) ligand binding sites, one amino acid substitution was detected between TlProR (tryptophan at the position of 241) and natural ProR (phenylalanine). The W241F mutant showed a significant preference for proline over hydroxyproline, suggesting that this (hydrophobic and bulky) tryptophan residue played an importance role in the recognition of hydroxyproline (more hydrophilic and bulky than proline), and substrate specificity for hydroxyproline was evolutionarily acquired separately between natural HypE and ProR. A phylogenetic analysis indicated that such unique broad substrate specificity was derived from an ancestral enzyme of this superfamily. PMID- 25786143 TI - Novel R pipeline for analyzing Biolog Phenotypic MicroArray data. AB - Data produced by Biolog Phenotype MicroArrays are longitudinal measurements of cells' respiration on distinct substrates. We introduce a three-step pipeline to analyze phenotypic microarray data with novel procedures for grouping, normalization and effect identification. Grouping and normalization are standard problems in the analysis of phenotype microarrays defined as categorizing bacterial responses into active and non-active, and removing systematic errors from the experimental data, respectively. We expand existing solutions by introducing an important assumption that active and non-active bacteria manifest completely different metabolism and thus should be treated separately. Effect identification, in turn, provides new insights into detecting differing respiration patterns between experimental conditions, e.g. between different combinations of strains and temperatures, as not only the main effects but also their interactions can be evaluated. In the effect identification, the multilevel data are effectively processed by a hierarchical model in the Bayesian framework. The pipeline is tested on a data set of 12 phenotypic plates with bacterium Yersinia enterocolitica. Our pipeline is implemented in R language on the top of opm R package and is freely available for research purposes. PMID- 25786144 TI - Chronic obstructive pulmonary disease phenotypes. Past, present, and future. PMID- 25786145 TI - Methacholine challenge. PD20 versus PC20. PMID- 25786146 TI - Under one roof: care for children with asthma from the hospital to home. PMID- 25786147 TI - Counting the cost of intensive care unit survivorship after acute lung injury. PMID- 25786148 TI - Endobronchial ultrasound-guided transbronchial needle aspiration for staging patients with lung cancer with clinical N0 disease. PMID- 25786149 TI - "You can't always get what you want..." the Mycobacterium abscessus issue. Name versus function. PMID- 25786150 TI - Field walking tests in chronic respiratory disease. PMID- 25786151 TI - Anchored to asthma. PMID- 25786152 TI - Personalized bronchial stent therapy. PMID- 25786153 TI - Cardiac tamponade in severe pulmonary hypertension. A therapeutic challenge revisited. PMID- 25786154 TI - Prevalence of Escherichia coli carriage in the oropharynx of ambulatory children and adults with and without upper respiratory symptoms. PMID- 25786155 TI - Thoracic imaging: a primer for physicians by wallace T. Miller, Jr., M.D. PMID- 25786156 TI - High on-off ratio improvement of ZnO-based forming-free memristor by surface hydrogen annealing. AB - In this work, a high-performance, forming-free memristor based on Au/ZnO nanorods/AZO (Al-doped ZnO conductive glass) sandwich structure has been developed by rapid hydrogen annealing treatment. The Ron/Roff rate is dramatically increased from ~10 to ~10(4) after the surface treatment. Such an enhanced performance is attributed to the introduced oxygen vacancies layer at the top of ZnO nanorods. The device also exhibits excellent switching and retention stability. In addition, the carrier migration behavior can be well interpreted by classical trap-controlled space charge limited conduction, which verifies the forming of conductive filamentary in low resistive state. On this basis, Arrhenius activation theory is adopted to explain the drifting of oxygen vacancies, which is further confirmed by the time pertinence of resistive switching behavior under different sweep speed. This fabrication approach offers a useful approach to enhance the switching properties for next-generation memory applications. PMID- 25786157 TI - CT Evaluation of Small-Diameter Coronary Artery Stents: Effect of an Integrated Circuit Detector with Iterative Reconstruction. AB - PURPOSE: To use suitable objective methods of analysis to assess the influence of the combination of an integrated-circuit computed tomographic (CT) detector and iterative reconstruction (IR) algorithms on the visualization of small (<=3-mm) coronary artery stents. MATERIALS AND METHODS: By using a moving heart phantom, 18 data sets obtained from three coronary artery stents with small diameters were investigated. A second-generation dual-source CT system equipped with an integrated-circuit detector was used. Images were reconstructed with filtered back-projection (FBP) and IR at a section thickness of 0.75 mm (FBP75 and IR75, respectively) and IR at a section thickness of 0.50 mm (IR50). Multirow intensity profiles in Hounsfield units were modeled by using a sum-of-Gaussians fit to analyze in-plane image characteristics. Out-of-plane image characteristics were analyzed with z upslope of multicolumn intensity profiles in Hounsfield units. Statistical analysis was conducted with one-way analysis of variance and the Student t test. RESULTS: Independent of stent diameter and heart rate, IR75 resulted in significantly increased xy sharpness, signal-to-noise ratio, and contrast-to-noise ratio, as well as decreased blurring and noise compared with FBP75 (eg, 2.25-mm stent, 0 beats per minute; xy sharpness, 278.2 vs 252.3; signal-to-noise ratio, 46.6 vs 33.5; contrast-to-noise ratio, 26.0 vs 16.8; blurring, 1.4 vs 1.5; noise, 15.4 vs 21.2; all P < .001). In the z direction, the upslopes were substantially higher in the IR50 reconstructions (2.25-mm stent: IR50, 94.0; IR75, 53.1; and FBP75, 48.1; P < .001). CONCLUSION: The implementation of an integrated-circuit CT detector provides substantially sharper out-of-plane resolution of coronary artery stents at 0.5-mm section thickness, while the use of iterative image reconstruction mostly improves in plane stent visualization. PMID- 25786159 TI - Chemoenzymatic asymmetric synthesis of 1,4-benzoxazine derivatives: application in the synthesis of a levofloxacin precursor. AB - A versatile and general route has been developed for the asymmetric synthesis of a wide family of 3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazines bearing different pattern substitutions in the aromatic ring. Whereas hydrolases were not suitable for resolution of these racemic cyclic nitrogenated amines, alternative chemoenzymatic strategies were designed through independent pathways leading to both amine antipodes. On one hand, bioreduction of 1-(2-nitrophenoxy)propan-2 ones allowed the recovery of the enantiopure (S)-alcohols in high yields using the alcohol dehydrogenase from Rhodococcus ruber (ADH-A), whereas evo-1.1.200 ADH led to their counterpart (R)-enantiomers also with complete selectivity and quantitative conversion. Alternatively, lipase-catalyzed acetylation of these racemic alcohols, and the complementary hydrolysis of the acetate analogues, gave access to the corresponding optically enriched products with high stereodiscrimination. Particularly attractive was the design of a chemoenzymatic strategy in six steps for the production of (S)-(-)-7,8-difluoro-3-methyl-3,4 dihydro-2H-benzo-[b][1,4]oxazine, which is a key precursor of the antimicrobial agent Levofloxacin. PMID- 25786158 TI - Comparative genomic analysis of buffalo (Bubalus bubalis) NOD1 and NOD2 receptors and their functional role in in-vitro cellular immune response. AB - Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are innate immune receptors that recognize bacterial cell wall components and initiate host immune response. Structure and function of NLRs have been well studied in human and mice, but little information exists on genetic composition and role of these receptors in innate immune system of water buffalo--a species known for its exceptional disease resistance. Here, a comparative study on the functional domains of NOD1 and NOD2 was performed across different species. The NOD mediated in-vitro cellular responses were studied in buffalo peripheral blood mononuclear cells, resident macrophages, mammary epithelial, and fibroblast cells. Buffalo NOD1 (buNOD1) and buNOD2 showed conserved domain architectures as found in other mammals. The domains of buNOD1 and buNOD2 showed analogy in secondary and tertiary conformations. Constitutive expressions of NODs were ubiquitous in different tissues. Following treatment with NOD agonists, peripheral lymphocytes showed an IFN-gamma response along-with production of pro inflammatory cytokines. Alveolar macrophages and mammary epithelial cells showed NOD mediated in-vitro immune response through NF-kappaB dependent pathway. Fibroblasts showed pro-inflammatory cytokine response following agonist treatment. Our study demonstrates that both immune and non-immune cells could generate NOD-mediated responses to pathogens though the type and magnitude of response depend on the cell types. The structural basis of ligand recognition by buffalo NODs and knowledge of immune response by different cell types could be useful for development of non-infective innate immune modulators and next generation anti-inflammatory compounds. PMID- 25786160 TI - Antimicrobial and antioxidant activities and phenolic profile of Eucalyptus globulus Labill. and Corymbia ficifolia (F. Muell.) K.D. Hill & L.A.S. Johnson leaves. AB - This study was performed to evaluate the in vitro antimicrobial and antioxidant activities and the phenolic profile of Eucalytus globulus Labill. and Corymbia ficifolia (F. Muell.) K.D. Hill & L.A.S. Johnson leaves. Both leave extracts contain significant amounts of phenolic compounds, mainly flavonoids. Qualitative and quantitative analyses of the phenolic compounds were performed using a HPLC/MS method. The main flavonoid was hyperoside and its highest amount was found in E. globulus (666.42 +/- 5.02 MUg/g dw plant material). Regarding the flavonol profile, myricetin was the dominant compound and its highest amount was found in C. ficifolia leaves (124.46 +/- 0.24 MUg/g dw plant material). The antioxidant activity was evaluated by DPPH, TEAC, hemoglobin ascorbate peroxidase activity inhibition (HAPX) and inhibition of lipid peroxidation catalyzed by cytochrome c assays, revealing an important antioxidant potential for both species. In the antimicrobial assays, C. ficifolia extract was found to be more active than E. globulus against both Gram-positive and Gram-negative bacterial strains with the exception of Bacillus subtilis. The results of the present study provide new valuable data regarding the bioactivities of these medicinal species. PMID- 25786161 TI - Chemical composition and biological activities of the essential oil of Skimmia laureola leaves. AB - The composition of the essential oil from leaves of Skimmia laureola was determined by GC and GC-MS. Twenty-eight components were identified, accounting for 93.9% of the total oil. The oil is mainly composed of monoterpenes (93.5%), of which monoterpene hydrocarbons and oxygenated monoterpenes represent 11.0% and 82.5%, respectively. Sesquiterpenes constitute only 0.3% of the total oil. Linalyl acetate is the main component (50.5%), with linalool (13.1%), geranyl acetate (8.5%) and cis-p-menth-2-en-1-ol (6.2%) as other principal constituents. The essential oil showed a significant antispasmodic activity, in a dose range of 0.03-10 mg/mL. The essential oil also possesses antibacterial and antifungal activities against some pathogenic strains. The phytotoxic and cytotoxic activities were also assessed. PMID- 25786162 TI - Protective effects of Labisia pumila var. alata on biochemical and histopathological alterations of cardiac muscle cells in isoproterenol-induced myocardial infarction rats. AB - The study was designed to evaluate the cardioprotective effects of the standardized aqueous and 80% ethanol extracts of Labisia pumila var. alata (LPva) in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. The extracts were administered to Wistar rats orally for 28 days with three doses (100, 200 and 400 mg/kg of body weight) prior to ISO (85 mg/kg)-induced MI in two doses on day 29 and 30. The sera and hearts were collected for biochemical and histopathological analysis after the rats were sacrificed 48 h after the first induction. The main components of the extracts, gallic acid, alkylresorcinols and flavonoids were identified and quantitatively analyzed in the extracts by using a validated reversed phase HPLC method. The extracts showed significant protective effects as pretreated rats showed a significant dose-dependent decrease (p < 0.05) in cardiac enzyme activities, i.e., cardiac troponin I (cTnI), creatine kinase MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), alanine transaminase (ALT) and aspartate transaminase (AST), when compared with ISO-control rats. There were significant rises (p < 0.05) in the activity of oxidase enzymes, i.e., glutathione peroxide (GPx), catalase (CAT) and superoxide dismutase (SOD) of the pretreated rats, when compared with ISO-control group. Histopathological examination showed an improvement in membrane cell integrity in pre-treated rats compared to untreated rats. The major components of LPva extracts can be used as their biomarkers and contributed to the cardioprotective effects against ISO induced MI rats. PMID- 25786163 TI - Cyclic comonomers for the synthesis of carboxylic acid and amine functionalized poly(L-lactic acid). AB - Degradable aliphatic polyesters such as poly(lactic acid) are widely used in biomedical applications, however, they lack functional moieties along the polymer backbone that are amenable for functionalization reactions or could be the basis for interactions with biological systems. Here we present a straightforward route for the synthesis of functional alpha-omega epoxyesters as comonomers for lactide polymerization. Salient features of these highly functionalized epoxides are versatility in functionality and a short synthetic route of less than four steps. The alpha-omega epoxyesters presented serve as a means to introduce carboxylic acid and amine functional groups into poly(lactic acid) polymers via ring-opening copolymerization. PMID- 25786164 TI - QM/MM calculations with deMon2k. AB - The density functional code deMon2k employs a fitted density throughout (Auxiliary Density Functional Theory), which offers a great speed advantage without sacrificing necessary accuracy. Powerful Quantum Mechanical/Molecular Mechanical (QM/MM) approaches are reviewed. Following an overview of the basic features of deMon2k that make it efficient while retaining accuracy, three QM/MM implementations are compared and contrasted. In the first, deMon2k is interfaced with the CHARMM MM code (CHARMM-deMon2k); in the second MM is coded directly within the deMon2k software; and in the third the Chemistry in Ruby (Cuby) wrapper is used to drive the calculations. Cuby is also used in the context of constrained-DFT/MM calculations. Each of these implementations is described briefly; pros and cons are discussed and a few recent applications are described briefly. Applications include solvated ions and biomolecules, polyglutamine peptides important in polyQ neurodegenerative diseases, copper monooxygenases and ultra-rapid electron transfer in cryptochromes. PMID- 25786165 TI - In vitro neuroprotective activities of compounds from Angelica shikokiana Makino. AB - Angelica shikokiana is widely marketed in Japan as a dietary food supplement. With a focus on neurodegenerative conditions such as Alzheimer's disease, the aerial part was extracted and through bio-guided fractionation, fifteen compounds [alpha-glutinol, beta-amyrin, kaempferol, luteolin, quercetin, kaempferol-3-O glucoside, kaempferol-3-O-rutinoside, methyl chlorogenate, chlorogenic acid, hyuganin E, 5-(hydroxymethyl)-2-furaldehyde, beta-sitosterol-3-O-glucoside, adenosine (isolated for the first time from A. shikokiana), isoepoxypteryxin and isopteryxin] were isolated. Isolated compounds were evaluated for in vitro neuroprotection using acetylcholine esterase inhibitory, protection against hydrogen peroxide and amyloid beta peptide (Abeta25-35)-induced neurotoxicity in neuro-2A cells, scavenging of hydroxyl radicals and intracellular reactive oxygen species and thioflavin T assays. Quercetin showed the strongest AChE inhibition (IC50 value = 35.5 uM) through binding to His-440 and Tyr-70 residues at the catalytic and anionic sites of acetylcholine esterase, respectively. Chlorogenic acid, its methyl ester, quercetin and luteolin could significantly protect neuro 2A cells against H2O2-induced neurotoxicity and scavenge hydroxyl radical and intracellular reactive oxygen species. Kaempferol-3-O-rutinoiside, hyuganin E and isoepoxypteryxin significantly decreased Abeta25-35-induced neurotoxicity and Th T fluorescence. To the best of our knowledge, this is the first report about neuroprotection of hyuganin E and isoepoxypteryxin against Abeta25-35-induced neurotoxicity. PMID- 25786166 TI - Identification of the valid reference genes for quantitative RT-PCR in annual ryegrass (Lolium multiflorum) under salt stress. AB - Annual ryegrass (Lolium multiflorum) is a cool-season annual grass cultivated worldwide for its high yield and quality. With the areas of saline soil increasing, investigation of the molecular mechanisms of annual ryegrass tolerance under salt stress has become a significant topic. qRT-PCR has been a predominant assay for determination of the gene expression, in which selecting a valid internal reference gene is a crucial step. The objective of present study was to evaluate and identify suitable reference genes for qRT-PCR in annual ryegrass under salt stress. The results calculated by RefFinder indicated that eEF1A(s) was the most stable reference gene in leaves, whereas EF1-a was the least stable; meanwhile, TBP-1 was the most optimal in roots and in all samples, and the eIF-5A shouldn't be utilized for normalization of the gene expression. eEF1A(s) is more suitable than TBP-1 as reference gene in leaves when verified with P5CS1 and Cyt-Cu/Zn SOD genes. We should choose optimal reference genes in specific tissues instead of the most stable one selected from different conditions and tissues. PMID- 25786167 TI - A broken krebs cycle in macrophages. AB - Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states. PMID- 25786168 TI - CD5 helps aspiring regulatory T cells ward off unwelcome cytokine advances. AB - The role of co-receptor molecules in the generation of inducible regulatory T cells (iTregs) remains incompletely defined. In this issue of Immunity, Henderson et al. (2015) show that CD5 regulates iTreg cell induction by rendering emerging iTreg cells refractory to signals mediated by effector-differentiating cytokines. PMID- 25786169 TI - HIF1alpha allows monocytes to take a breather during sepsis. AB - How the immune system is negatively affected by sepsis is not fully understood. In this issue of Immunity, Shalova et al. (2015) show that during human sepsis monocytes upregulate hypoxia-inducible factor-alpha (HIF1-alpha) activity and acquire an immunosuppressive phenotype while retaining anti-bacterial and wound healing properties. PMID- 25786170 TI - Infected cells call their killers to the scene of the crime. AB - Effector CD8(+) T cells scan tissues to locate and kill infected host cells. In this issue of Immunity, Hickman et al. (2015) show that the exploration is not random: infected monocytes attract their assassins by secreting chemokines, which accelerates clearance of epicutaneous vaccinia virus infection. PMID- 25786171 TI - Cigarette smoke resets the Alarmin IL-33 in COPD. AB - Cigarette smoke and infection are the major drivers of chronic obstructive pulmonary disease. In this issue of Immunity, Kearley et al. (2015) demonstrate that smoke exposure alters the lung microenvironment leading to an interleukin-33 dependent proinflammatory disease exacerbation. PMID- 25786172 TI - CNS injury: IL-33 sounds the alarm. AB - Central nervous system trauma induces marked inflammation that has beneficial and deleterious consequences. In a recent issue of Neuron, Gadani et al. (2015) show that injured spinal cord releases the alarmin IL-33 to drive chemokines that recruit monocytes and promote recovery. PMID- 25786173 TI - Mitochondria in the regulation of innate and adaptive immunity. AB - Mitochondria are well appreciated for their role as biosynthetic and bioenergetic organelles. In the past two decades, mitochondria have emerged as signaling organelles that contribute critical decisions about cell proliferation, death, and differentiation. Mitochondria not only sustain immune cell phenotypes but also are necessary for establishing immune cell phenotype and their function. Mitochondria can rapidly switch from primarily being catabolic organelles generating ATP to anabolic organelles that generate both ATP and building blocks for macromolecule synthesis. This enables them to fulfill appropriate metabolic demands of different immune cells. Mitochondria have multiple mechanisms that allow them to activate signaling pathways in the cytosol including altering in AMP/ATP ratio, the release of ROS and TCA cycle metabolites, as well as the localization of immune regulatory proteins on the outer mitochondrial membrane. In this Review, we discuss the evidence and mechanisms that mitochondrial dependent signaling controls innate and adaptive immune responses. PMID- 25786174 TI - Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. AB - Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc associated modules. Correspondingly, glutamine deprivation or inhibition of N glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes. PMID- 25786175 TI - Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. AB - Long-lived "memory-like" NK cells have been identified in individuals infected by human cytomegalovirus (HCMV), but little is known about how the memory-like NK cell pool is formed. Here, we have shown that HCMV-infected individuals have several distinct subsets of memory-like NK cells that are often deficient for multiple transcription factors and signaling proteins, including tyrosine kinase SYK, for which the reduced expression was stable over time and correlated with epigenetic modification of the gene promoter. Deficient expression of these proteins was largely confined to the recently discovered FcRgamma-deficient NK cells that display enhanced antibody-dependent functional activity. Importantly, FcRgamma-deficient NK cells exhibited robust preferential expansion in response to virus-infected cells (both HCMV and influenza) in an antibody-dependent manner. These findings suggest that the memory-like NK cell pool is shaped and maintained by a mechanism that involves both epigenetic modification of gene expression and antibody-dependent expansion. PMID- 25786177 TI - CD5 instructs extrathymic regulatory T cell development in response to self and tolerizing antigens. AB - Self-reactive T cells can escape thymic deletion and therefore some of these potentially autoaggressive T cells need to convert into regulatory T (Treg) cells to help control responses against self. However, it remains unknown how peripheral self-reactive T cells are specifically instructed to become Treg cells. We report that CD5, whose expression is upregulated in T cells by self and tolerizing antigens in the thymus and periphery, governed extrathymic Treg cell development. CD5 modified effector cell-differentiating signals that inhibit Treg cell induction. Treg cell conversion of Cd5(-/-) and CD5(lo) T cells was inhibited by even small amounts of interleukin-4 (IL-4), IL-6, and interferon gamma (IFN-gamma) produced by bystander lymphocytes, while CD5(hi) T cells resisted this inhibition of Treg cell induction. Our findings further revealed that CD5 promoted Treg cell induction by blocking mechanistic target of rapamycin (mTOR) activation. Therefore CD5 instructs extrathymic Treg cell development in response to self and tolerizing antigens. PMID- 25786176 TI - Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. AB - The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets. PMID- 25786178 TI - Local triggering of the ICOS coreceptor by CD11c(+) myeloid cells drives organ inflammation in lupus. AB - The inducible T cell costimulator (ICOS) is a potent promoter of organ inflammation in murine lupus. ICOS stimulates T follicular helper cell differentiation in lymphoid tissue, suggesting that it might drive autoimmunity by enhancing autoantibody production. Yet the pathogenic relevance of this mechanism remains unclear. It is also unknown whether other ICOS-induced processes might contribute to lupus pathology. Here we show that selective ablation of ICOS ligand (ICOSL) in CD11c(+) cells, but not in B cells, dramatically ameliorates kidney and lung inflammation in lupus-prone MRL.Fas(lpr) mice. Autoantibody formation was largely unaffected by ICOSL deficiency in CD11c(+) cells. However, ICOSL display by CD11c(+) cells in inflamed organs had a nonredundant role in protecting invading T cells from apoptosis by elevating activity of the PI3K-Akt signaling pathway, thereby facilitating T cell accrual. These findings reveal a mechanism that locally sustains organ inflammation in lupus. PMID- 25786179 TI - Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. AB - Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL 33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33 dependent exaggerated proinflammatory response to infection, exacerbating disease. PMID- 25786181 TI - Plasmonic enhancement of the upconversion fluorescence in YVO4:Yb3+, Er3+ nanocrystals based on the porous Ag film. AB - The upconversion luminescence (UCL) enhancement based on the surface plasmonic resonance (SPR) of noble metals is a promising way to improve UCL efficiency. However, it is still a challenge to achieve stable and effective UCL enhancement. Here, we present the preparation of the porous Ag/YVO4:Yb(3+), Er(3+) composite film via a simple double annealing method. It is exciting to observe that a maximum 36-fold ((2)H11/2-(4)I15/2) and 30-fold ((4)S3/2-(4)I15/2) UCL enhancement in the porous Ag/YVO4:Yb(3+), Er(3+) composite film, attributed to the effective coupling between SPR and the excitation light by adjusting the SPR peak to the excitation wavelength, controlling the effective coupling distance and improving the scattering-absorption ratio. Furthermore, the enhancement factor strongly depended on the excitation power and the Er(3+) concentration. PMID- 25786182 TI - Implementing quality initiatives in healthcare organizations: drivers and challenges. AB - PURPOSE: Various quality initiatives seem to have successful implementation in some healthcare organizations yet fail in others. This paper sets out to study the literature trying to understand drivers and challenges facing quality initiatives implementation in healthcare organizations then compare findings from literature with those of a structured questionnaire answered by 60 representatives from 18 hospitals. Finally it proposes a framework that mitigates challenges and utilizes drivers to ensure best implementation results. DESIGN/METHODOLOGY/APPROACH: Literature regarding implementing various quality initiatives in the healthcare sector was reviewed. Representatives from several healthcare organizations were surveyed. Results from both approaches are compared to highlight the key challenges and drivers facing implementers. FINDINGS: This research reveals that internal factors related to leadership and employees greatly affect quality initiative success or failure. Design and relevance play a major role in successful implementation. PRACTICAL IMPLICATIONs: This research offers healthcare professionals greater success when implementing certain quality initiatives by taking success/failure factors into consideration. A general framework for successful implementation in the healthcare sector is provided. ORIGINALITY/VALUE: This article uncovers reasons behind success or failure in a comprehensive and practical way. It also explores how most popular quality initiatives are applied in hospitals. PMID- 25786180 TI - Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. AB - Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion inhibitory activity and protective immunity. PMID- 25786183 TI - Patient satisfaction and resident postgraduate year status. AB - PURPOSE: Patient satisfaction has been recognized as an important variable affecting healthcare behavior. However, there are limited data on the relationship between doctor post-graduate year (PGY) status and patient satisfaction with provider interpersonal skills and humanistic qualities. The authors aims to assess this relationship using an American Board of Internal Medicine (ABIM) questionnaire. DESIGN/METHODOLOGY/APPROACH: Participants were: patients attending a primary care clinic at a large urban academic hospital; and physicians treating them. The survey questionnaire was the ABIM patient satisfaction instrument; ten questions pertaining to humanistic qualities and communication skills with responses from poor to excellent. Mann Whitney U test and multi-variable logistic regression analyses were used to explore score differences by PGY level. FINDINGS: The postgraduate year one (PGY1) had higher patient-satisfaction levels compared to PGY2/PGY3 residents. The PGY1 level residents were more likely to score in the 90th percentile and this remained constant even after adjusting for confounders. RESEARCH LIMITATIONS/IMPLICATIONS: The research was a single-center study and may have been subject to confounding factors such as patient personality types and a survey ceiling effect. The survey's cross-sectional nature may also be a potential limitation. Practical implications - Patient satisfaction varies significantly with PGY status. Though clinical skills may improve with increasing experience, findings imply that interpersonal and humanistic qualities may deteriorate. ORIGINALITY/VALUE: The study is the first to assess patient satisfaction with PGY status and provides evidence that advanced trainees may need support to keep their communication skills and humanistic qualities from deteriorating as stressors increase to ensure optimal patient satisfaction. PMID- 25786184 TI - Concurrent implementation of quality improvement programs. AB - PURPOSE: Competing activities and projects can interfere with implementing new knowledge and approaches. The purpose, therefore, was to investigate processes and impact related to implementing two concurrent quality initiatives in a Swedish hospital. These were a regionally initiated, system-wide organizational learning programme called the Dynamic and Viable Organization (DVO) and a national initiative on stopping healthcare-associated and hospital-acquired infections (SHAI). Both undertakings aspired to increase staff competence in systematic improvement approaches. DESIGN/METHODOLOGY/APPROACH: Multiple methods were applied including surveys, observations, interviews, process diaries, documents and organizational measurements. Respondents were unit managers, change facilitators and improvement team members. FINDINGS: Even though both initiatives shared the same improvement approach, there was no strong indication that they were strategically combined to benefit each other. The initiatives existed side by side with some coordination and some conflict. Despite absent management strategies to utilize the national SHAI initiative, positive developments in QI culture and communication were reported. The current study illustrates the inherent difficulties coordinating change initiatives, even in favourable circumstances. ORIGINALITY/VALUE: This article addresses the lesser studied but common situation of coinciding and competing projects in organizations. PMID- 25786185 TI - Healthcare quality indicators--a systematic review. AB - PURPOSE: The purpose of this paper is to review the literature on quality model development, validation and limitations. DESIGN/METHODOLOGY/APPROACH: The systematic literature review used online journal indexes between January 1995 and April 2010. International studies focusing on multiple functional domains and those in which development methods were selected. Two reviewers assessed all studies and 18 were shortlisted. FINDINGS: Literature reviews, peer reviews, questionnaires and expert panels are the most frequently used model development methods. Expert judges were widely used to validate the models. The most important limitation was that key indicators were missing. ORIGINALITY/VALUE: Existing healthcare quality models are not comprehensive and there is no consensus on targets, clinical areas or diseases. PMID- 25786186 TI - Burnout syndrome during residency in internal medicine and pediatrics in a country without working time directive. AB - PURPOSE: The purpose of this paper is to demonstrate burnout syndrome among internal medicine and pediatrics residents in a country that does not have the working time directive (WTD) and also to determine the risk factors and consequent impact on efficient functioning in clinical areas. DESIGN/METHODOLOGY/APPROACH: A 57-item questionnaire was given to internal medicine and pediatrics residents. Responses from 22 pediatrics and 33 internal medicine residents were evaluated. FINDINGS: Demographic findings, burnout scores, having hobbies, social activities and reading books unrelated to medicine were similar between the two groups. Six pediatrics residents (27.3 per cent) and 11 (33.3 per cent) internal medicine residents met the criteria for clinically significant burnout. Personal accomplishment scores and reading books unrelated to medicine were found to be related to burnout. ORIGINALITY/VALUE: Burnout is a syndrome characterized by depersonalization, emotional exhaustion and a low sense of personal accomplishment. It is important to document burnout in countries where WTDs are not implemented. Further studies might demonstrate burnout's effect on patient safety, service quality and physician's performance. PMID- 25786187 TI - Expanding a Canadian community health centre. AB - PURPOSE: The current study's purpose is to examine, through a case study, a community health centre board's governance during an expansion period with particular attention to the organizational and internal board relations that contribute to or inhibit expansion. DESIGN/METHODOLOGY/APPROACH: All board members on the slate during the expansion were invited to participate in one semi structured interview. Administrative data (board documentation and correspondence) were also used to inform the study. Discourse analysis was used to analyze the data. FINDINGS: While board members agreed with the expansion they acknowledge that the expansion process should be examined. Board members identified missing board skill sets, comfort with governance and low organizational understanding as personal barriers to an enhanced process. External barriers included: absent decision support tools; documentation and information availability and historical decision making processes. RESEARCH LIMITATIONS/IMPLICATIONS: Half the board members agreed to participate in the interviews. Of those declining, 30 percent cited difficulties during the expansion period as their rationale for withdrawing. ORIGINALITY/VALUE: Findings add to: the limited publications regarding primary healthcare service expansion; and understanding expansion and volunteer board members' roles and their governance process during this time. PMID- 25786188 TI - Technology and medication errors: impact in nursing homes. AB - PURPOSE: The purpose of this paper is to study a medication distribution technology's (MDT) impact on medication errors reported in public nursing homes in Quebec Province. DESIGN/METHODOLOGY/APPROACH: The work was carried out in six nursing homes (800 patients). Medication error data were collected from nursing staff through a voluntary reporting process before and after MDT was implemented. The errors were analysed using: totals errors; medication error type; severity and patient consequences. A statistical analysis verified whether there was a significant difference between the variables before and after introducing MDT. FINDINGS: The results show that the MDT detected medication errors. The authors' analysis also indicates that errors are detected more rapidly resulting in less severe consequences for patients. PRACTICAL IMPLICATIONS: MDT is a step towards safer and more efficient medication processes. Our findings should convince healthcare administrators to implement technology such as electronic prescriber or bar code medication administration systems to improve medication processes and to provide better healthcare to patients. ORIGINALITY/VALUE: Few studies have been carried out in long-term healthcare facilities such as nursing homes. The authors' study extends what is known about MDT's impact on medication errors in nursing homes. PMID- 25786189 TI - Post deposition annealing of epitaxial Ce(1-x)Pr(x)O(2-delta) films grown on Si(111). AB - In this work the structural and morphological changes of Ce1-xPrxO2-delta (x = 0.20, 0.35 and 0.75) films grown on Si(111) due to post deposition annealing are investigated by low energy electron diffraction combined with a spot profile analysis. The surface of the oxide films exhibit mosaics with large terraces separated by monoatomic steps. It is shown that the Ce/Pr ratio and post deposition annealing temperature can be used to tune the mosaic spread, terrace size and step height of the grains. The morphological changes are accompanied by a phase transition from a fluorite type lattice to a bixbyite structure. Furthermore, at high PDA temperatures a silicate formation via a polycrystalline intermediate state is observed. PMID- 25786190 TI - Variabilities and uncertainties in characterising water transport kinetics in glassy and ultraviscous aerosol. AB - We present a comprehensive evaluation of the variabilities and uncertainties present in determining the kinetics of water transport in ultraviscous aerosol droplets, alongside new measurements of the water transport timescale in sucrose aerosol. Measurements are performed on individual droplets captured using aerosol optical tweezers and the change in particle size during water evaporation or condensation is inferred from shifts in the wavelength of the whispering gallery mode peaks at which spontaneous Raman scattering is enhanced. The characteristic relaxation timescale (tau) for condensation or evaporation of water from viscous droplets following a change in gas phase relative humidity can be described by the Kohlrausch-Williams-Watts function. To adequately characterise the water transport kinetics and determine tau, sufficient time must be allowed for the particle to progress towards the final state. However, instabilities in the environmental conditions can prevent an accurate characterisation of the kinetics over such long time frames. Comparison with established thermodynamic and diffusional water transport models suggests the determination of tau is insensitive to the choice of thermodynamic treatment. We report excellent agreement between experimental and simulated evaporation timescales, and investigate the scaling of tau with droplet radius. A clear increase in tau is observed for condensation with increase in drying (wait) time. This trend is qualitatively supported by model simulations. PMID- 25786191 TI - An extended siderophore suite from Synechococcus sp. PCC 7002 revealed by LC ICPMS-ESIMS. AB - Siderophores are thought to play an important role in iron cycling in the ocean, but relatively few marine siderophores have been identified. Sensitive, high throughput methods hold promise for expediting the discovery and characterization of new siderophores produced by marine microbes. We developed a methodology for siderophore characterization that combines liquid chromatography (LC) inductively coupled plasma mass spectrometry (ICPMS) with high resolution electrospray ionization mass spectrometry (ESIMS). To demonstrate this approach, we investigated siderophore production by the marine cyanobacteria Synechococcus sp. PCC 7002. Three hydroxamate siderophores, synechobactin A-C, have been previously isolated and characterized from this strain. These compounds consist of an iron binding head group attached to a fatty acid side chain of variable length (C12, C10, and C8 respectively). In this study, we detected six iron-containing compounds in Synechococcus sp. PCC 7002 media by LC-ICPMS. To identify the molecular ions of these siderophores, we aligned the chromatographic retention times of peaks from the LC-ICPMS chromatogram with features detected from LC ESIMS spectra using an algorithm designed to recognize metal isotope patterns. Three of these compounds corresponded to synechobactins A (614 m/z), B (586 m/z), and C (558 m/z). The MS2 spectra of these compounds revealed diagnostic synechobactin fragmentation patterns which were used to confirm the identity of the three unknown compounds (600, 628, and 642 m/z) as new members of the synechobactin suite with side chain lengths of 11, 13, and 14 carbons. These results demonstrate the potential of combined LCMS techniques for the identification of novel iron-organic complexes. PMID- 25786192 TI - Multidisciplinary approach to converting power chair into motorized prone cart. AB - Pressure ulcers remain a major source of morbidity and mortality in veterans with neurologic impairment. Management of pressure ulcers typically involves pressure relief over skin regions containing wounds, but this can lead to loss of mobility and independence when the wounds are located in regions that receive pressure from sitting. An innovative, low-cost, multidisciplinary effort was undertaken to maximize quality of life in a veteran with a thoracic-4 level complete spinal cord injury and a stage 4 ischial wound. The person's power wheelchair was converted into a motorized prone cart, allowing navigation of the Department of Veterans Affairs spinal cord injury hospital ward and improved socialization while relieving pressure on the wound. Physical and occupational therapy assisted with the reconfiguration of the power chair and verified safe transfers into the chair and driving of the device. Psychology verified positive psychosocial benefit, while nursing and physician services verified an absence of unwanted pain or skin injury resulting from use of the device. Further investigation of ways to apply this technique is warranted to improve the quality of life of persons with pressure ulcers. PMID- 25786193 TI - Further neuroimaging evidence for the deficit subtype of schizophrenia: a cortical connectomics analysis. AB - IMPORTANCE: The clinical heterogeneity of schizophrenia has hindered neurobiological investigations aimed at identifying neural correlates of the disorder. OBJECTIVE: To identify network-based biomarkers across the spectrum of impairment present in schizophrenia by separately evaluating individuals with deficit and nondeficit subtypes of this disorder. DESIGN, SETTING, AND PARTICIPANTS: A university hospital network-based neuroimaging study was conducted between February 1, 2007, and February 28, 2012. Participants included patients with schizophrenia (n = 128) and matched healthy controls (n = 130) from two academic centers and patients with bipolar I disorder (n = 39) and matched healthy controls (n = 43) from a third site. Patients with schizophrenia at each site in the top quartile on the proxy scale for the deficit syndrome were classified as having deficit schizophrenia and those in the bottom quartile were classified as having nondeficit schizophrenia. EXPOSURE: All participants underwent magnetic resonance brain imaging. MAIN OUTCOMES AND MEASURES: Network level properties of cortical thickness were assessed in each group. Interregional cortexwide coupling was compared among the groups, and graph theoretical approaches were used to assess network density and node degree, betweenness, closeness, and eigenvector centrality. RESULTS: Stronger frontoparietal and frontotemporal coupling was found in patients with deficit schizophrenia compared with those with nondeficit schizophrenia (17 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate) and in patients with deficit schizophrenia compared with healthy controls (49 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate). Participants with nondeficit schizophrenia and bipolar I disorder did not show significant differences in coupling relative to those in the control groups (for both comparisons, 0 of 1326 pairwise relationships were significantly different, P > .05; 5% false discovery rate). The networks formed from patients with deficit schizophrenia demonstrated increased density of connections relative to controls and nondeficit patients (range, 0.07-0.45 in controls, 0.09-0.43 in the nondeficit group, and 0.18-0.67 in the deficit group). High centrality nodes were identified in the supramarginal, middle, and superior temporal and inferior frontal regions in deficit schizophrenia networks based on ranking of 4 centrality metrics. High centrality regions were identified as those that ranked in the top 10 in 50% or more of the thresholded networks in 3 or more of the centrality measures. Network properties were similar in patients with deficit schizophrenia from both study sites. CONCLUSIONS AND RELEVANCE: Patients with schizophrenia at one end of a spectrum show characteristic signatures of altered intracortical relationships compared with those at the other end of that spectrum, patients with bipolar I disorder, and healthy individuals. Cortical connectomic approaches can be used to reliably identify neural signatures in clinically heterogeneous groups of patients. PMID- 25786194 TI - Telomere shortening in Down syndrome patients--when does it start? AB - Down syndrome (DS) is one of the most common aneuploidy. In general population, its prevalence is 1:600-1:800 live births. It is caused by a trisomy of chromosome 21. DS is phenotypically manifested by premature aging, upward slant to the eyes, epicanthus, flattened face, and poor muscle tone. In addition to physical changes, this syndrome is characterized by early onset of diseases specific to old age, such as Alzheimer's disease, vision and hearing problems, and precocious menopause. Since DS symptoms include premature aging, the shortening of telomeres might be one of the markers of cellular aging. Consequently, the aim of the study was to determine the length of the telomeres in leukocytes from the blood of juvenile patients with DS (n=68) compared to an age-matched control group (n=56) and also to determine the diagnostic or predictive value for this parameter. We show that, for the first time, in juveniles, the average relative telomere length in studied subjects is significantly longer than in the control group (50.46 vs. 40.56, respectively arbitrary units [AU]; p=0.0026). The results provide interesting basis for further research to determine the causes and consequences of telomere maintaining and the dynamics of this process in patients with DS. PMID- 25786195 TI - Direct oligonucleotide-photosensitizer conjugates for photochemical delivery of antisense oligonucleotides. AB - Activation of photosensitizers in endosomes enables release of therapeutic macromolecules into the cytosol of the target cells for pharmacological actions. In this study, we demonstrate that direct conjugation of photosensitizers to oligonucleotides (ONs) allows spatial and temporal co-localization of the two modalities in the target cells, and thus leads to superior functional delivery of ONs. Further, light-activated delivery of an anticancer ON caused cancer cell killing via modulation of an oncogene and photodynamic therapy. PMID- 25786197 TI - Rh/Cu-catalyzed multiple C-H, C-C, and C-N bond cleavage: facile synthesis of pyrido[2,1-a]indoles from 1-(pyridin-2-yl)-1H-indoles and gamma-substituted propargyl alcohols. AB - An unusual Rh/Cu-catalyzed synthesis of pyrido[2,1-a]indoles starting from 1 (pyridin-2-yl)-1H-indoles and gamma-substituted propargyl alcohols was presented. The multi-step cascade transformations formally involve the cleavage of two C-H, three C-C, and one C-N bonds with concomitant construction of two C-H, four C-C, and one C-N bonds with excellent chemoselectivity in one-pot reaction. PMID- 25786196 TI - Effect of Repetitive Transcranial Magnetic Stimulation on fMRI Resting-State Connectivity in Multiple System Atrophy. AB - Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been used to treat neurological and psychiatric conditions. Although results of rTMS intervention are promising, so far, little is known about the rTMS effect on brain functional networks in clinical populations. In this study, we used a whole-brain connectivity analysis of resting-state functional magnetic resonance imaging data to uncover changes in functional connectivity following rTMS intervention and their association with motor symptoms in patients with multiple system atrophy (MSA). Patients were randomized to active rTMS or sham rTMS groups and completed a 10-session 5-Hz rTMS treatment over the left primary motor area. The results showed significant rTMS-related changes in motor symptoms and functional connectivity. Specifically, (1) significant improvement of motor symptoms was observed in the active rTMS group, but not in the sham rTMS group; and (2) several functional links involving the default mode, cerebellar, and limbic networks exhibited positive changes in functional connectivity in the active rTMS group. Moreover, the positive changes in functional connectivity were associated with improvement in motor symptoms for the active rTMS group. The present findings suggest that rTMS may improve motor symptoms by modulating functional links connecting to the default mode, cerebellar, and limbic networks, inferring a future therapeutic candidate for patients with MSA. PMID- 25786198 TI - Novel imidazolium and imidazolinium salts containing the 9-nickelafluorenyl anion -synthesis, structures and reactivity. AB - Investigation of the properties of carbene complexes is one of the most important fields of modern coordination chemistry. In this paper, we propose the convenient synthesis of NHC-nickel compounds. The 9-nickelafluorenyllithium complex reacts with imidazolium or imidazolinium salts to afford 9-nickelafluorenyl-NHC salts via ionic metathesis with very good yields (66-92%). These compounds can be isomerised at elevated temperatures to give Ni-NHC complexes with excellent yields (88-91%), probably via nickel mediated hydrogen transfer to the biphenyl moiety. In this reaction, the nickelacyclic ring itself serves as a base in the deprotonation of the carbene precursor. DFT calculations show the thermodynamic instability of the synthesized salts, with Gibbs free energy differences for 1 of -84 kJ mol(-1) at 298 K and -167 kJ mol(-1) at 374 K. The obtained salts and carbene complexes are relatively air and moisture stable in the solid state. PMID- 25786200 TI - Cooperation between adsorbates accounts for the activation of atomic layer deposition reactions. AB - Atomic layer deposition (ALD) is a technique for producing conformal layers of nanometre-scale thickness, used commercially in non-planar electronics and increasingly in other high-tech industries. ALD depends on self-limiting surface chemistry but the mechanistic reasons for this are not understood in detail. Here we demonstrate, by first-principle calculations of growth of HfO2 from Hf(N(CH3)2)4-H2O and HfCl4-H2O and growth of Al2O3 from Al(CH3)3-H2O, that, for all these precursors, co-adsorption plays an important role in ALD. By this we mean that previously-inert adsorbed fragments can become reactive once sufficient numbers of molecules adsorb in their neighbourhood during either precursor pulse. Through the calculated activation energies, this 'cooperative' mechanism is shown to have a profound influence on proton transfer and ligand desorption, which are crucial steps in the ALD cycle. Depletion of reactive species and increasing coordination cause these reactions to self-limit during one precursor pulse, but to be re-activated via the cooperative effect in the next pulse. This explains the self-limiting nature of ALD. PMID- 25786199 TI - Unconscious race and social class bias among acute care surgical clinicians and clinical treatment decisions. AB - IMPORTANCE: Significant health inequities persist among minority and socially disadvantaged patients. Better understanding of how unconscious biases affect clinical decision making may help to illuminate clinicians' roles in propagating disparities. OBJECTIVE: To determine whether clinicians' unconscious race and/or social class biases correlate with patient management decisions. DESIGN, SETTING, AND PARTICIPANTS: We conducted a web-based survey among 230 physicians from surgery and related specialties at an academic, level I trauma center from December 1, 2011, through January 31, 2012. INTERVENTIONS: We administered clinical vignettes, each with 3 management questions. Eight vignettes assessed the relationship between unconscious bias and clinical decision making. We performed ordered logistic regression analysis on the Implicit Association Test (IAT) scores and used multivariable analysis to determine whether implicit bias was associated with the vignette responses. MAIN OUTCOMES AND MEASURES: Differential response times (D scores) on the IAT as a surrogate for unconscious bias. Patient management vignettes varied by patient race or social class. Resulting D scores were calculated for each management decision. RESULTS: In total, 215 clinicians were included and consisted of 74 attending surgeons, 32 fellows, 86 residents, 19 interns, and 4 physicians with an undetermined level of education. Specialties included surgery (32.1%), anesthesia (18.1%), emergency medicine (18.1%), orthopedics (7.9%), otolaryngology (7.0%), neurosurgery (7.0%), critical care (6.0%), and urology (2.8%); 1.9% did not report a departmental affiliation. Implicit race and social class biases were present in most respondents. Among all clinicians, mean IAT D scores for race and social class were 0.42 (95% CI, 0.37-0.48) and 0.71 (95% CI, 0.65-0.78), respectively. Race and class scores were similar across departments (general surgery, orthopedics, urology, etc), race, or age. Women demonstrated less bias concerning race (mean IAT D score, 0.39 [95% CI, 0.29-0.49]) and social class (mean IAT D score, 0.66 [95% CI, 0.57-0.75]) relative to men (mean IAT D scores, 0.44 [95% CI, 0.37-0.52] and 0.82 [95% CI, 0.75-0.89], respectively). In univariate analyses, we found an association between race/social class bias and 3 of 27 possible patient-care decisions. Multivariable analyses revealed no association between the IAT D scores and vignette-based clinical assessments. CONCLUSIONS AND RELEVANCE: Unconscious social class and race biases were not significantly associated with clinical decision making among acute care surgical clinicians. Further studies involving real physician-patient interactions may be warranted. PMID- 25786201 TI - A retrospective comparison of the influence of surgical clipping and endovascular embolization on recovery of oculomotor nerve palsy in patients with posterior communicating artery aneurysms. AB - BACKGROUND: Oculomotor nerve palsy (ONP) is a common symptom of posterior communicating artery aneurysms (PcomAAs). Surgical clipping and endovascular embolization are used to treat PcomAAs with ONP. OBJECTIVE: To analyze the impact of these 2 techniques on recovery of ONP caused by PcomAAs. METHODS: The clinical data for 176 patients with intracranial PcomAAs with ONP admitted to the Department of Neurosurgery, Sichuan Provincial People's Hospital, between June 2008 and May 2013 who undergone surgical clipping or endovascular embolization were studied retrospectively. The 2 treatment groups were compared with respect to age, sex, aneurysm size, levels of hypertension and hyperlipidemia, preadmission ONP duration, subarachnoid hemorrhage (SAH), complete ONP, postoperative recovery time from ONP symptoms, and degree of recovery. The follow up duration was a minimum of 12 months. Multivariate Cox regression was used for analysis. RESULTS: A total of 132 patients were treated by surgical clipping, and 44 were treated by endovascular embolization. Significant differences were found in postoperative recovery time (83.87 +/- 34.70 days for clipping and 137.45 +/- 44.94 days for embolization, P < .001) and recovery rates (130 [98.5%] for clipping and 30 [68.2%] for embolization, P < .001). The period between ONP onset and admission was associated with recovery. Postoperative complications included significant cerebral vasospasms (6 in the clipping group and 2 in the embolization group) and hydrocephalus (16 in the clipping group and 9 in the embolization group). CONCLUSION: Simultaneous elimination of 2 injury mechanisms, compression and pulsation, when treating the oculomotor nerve by surgical clipping may be more advantageous than endovascular embolization to treat ONP caused by PcomAA. PMID- 25786202 TI - Central serous chorioretinopathy in Susac syndrome. AB - We report central serous chorioretinopathy (CSC) in a patient with Susac syndrome. The diagnosis of Susac syndrome was based on the results of funduscopy, brain magnetic resonance imaging, and audiometric testing. Our case demonstrates that possible choroidal involvement in Susac syndrome may lead to the development of CSC. PMID- 25786203 TI - Tonsillar Herniation After Lumbar Puncture in Idiopathic Intracranial Hypertension. AB - A 30-year-old woman with coexisting renal tubular acidosis and idiopathic intracranial hypertension (IIH), treated with acetazolamide, experienced coning (cerebellar tonsillar herniation) after a lumbar puncture (LP). Brain magnetic resonance imaging at initial diagnosis of IIH showed minor tonsillar descent and computed tomographic venography revealed hypoplasia of the left transverse sinus. The patient previously had three uneventful LPs, all of which showed high opening pressures and normal cerebrospinal fluid composition. In retrospect, it was noted that her serum bicarbonate had fallen to 9 mmol/L (normal: 22-28 mm/L) 1 week before the LP. We hypothesize that the combination of cerebral edema (due to worsening metabolic acidosis), poor venous drainage, and preexisting minor tonsillar descent contributed to her post-LP coning. PMID- 25786204 TI - Investigation on the Origin of Sperm DNA Fragmentation: Role of Apoptosis, Immaturity and Oxidative Stress. AB - Sperm DNA fragmentation (sDF) represents a threat to male fertility, human reproduction and the health of the offspring. The causes of sDF are still unclear, even if apoptosis, oxidative assault and defects in chromatin maturation are hypothesized. Using multicolor flow cytometry and sperm sorting, we challenged the three hypothesized mechanisms by simultaneously evaluating sDF and signs of oxidative damage (8-hydroxy, 2'-deoxyguanosine [8-OHdG] and malondialdehyde [MDA]), apoptosis (caspase activity and cleaved poly[ADP-ribose] polymerase [cPARP]) and sperm immaturity (creatine phosphokinase [CK] and excess of residual histones). Active caspases and c-PARP were concomitant with sDF in a high percentage of spermatozoa (82.6% +/- 9.1% and 53.5% +/- 16.4%, respectively). Excess of residual histones was significantly higher in DNA fragmented sperm versus sperm without DNA fragmentation (74.8% +/- 17.5% and 37.3% +/- 16.6%, respectively, p < 0.005), and largely concomitant with active caspases. Conversely, oxidative damage was scarcely concomitant with sDF in the total sperm population, at variance with live sperm, where 8-OHdG and MDA were clearly associated to sDF. In addition, most live cells with active caspase also showed 8-OHdG, suggesting activation of apoptotic pathways in oxidative-injured live cells. This is the first investigation on the origin of sDF directly evaluating the simultaneous presence of the signs of the hypothesized mechanisms with DNA breaks at the single cell level. The results indicate that the main pathway leading to sperm DNA breaks is a process of apoptosis, likely triggered by an impairment of chromatin maturation in the testis and by oxidative stress during the transit in the male genital tract. These findings are highly relevant for clinical studies on the effects of drugs on sDF and oxidative stress in infertile men and for the development of new therapeutic strategies. PMID- 25786205 TI - Spectacle: fast chromatin state annotation using spectral learning. AB - Epigenomic data from ENCODE can be used to associate specific combinations of chromatin marks with regulatory elements in the human genome. Hidden Markov models and the expectation-maximization (EM) algorithm are often used to analyze epigenomic data. However, the EM algorithm can have overfitting problems in data sets where the chromatin states show high class-imbalance and it is often slow to converge. Here we use spectral learning instead of EM and find that our software Spectacle overcame these problems. Furthermore, Spectacle is able to find enhancer subtypes not found by ChromHMM but strongly enriched in GWAS SNPs. Spectacle is available at https://github.com/jiminsong/Spectacle. PMID- 25786206 TI - Identification of communal oviposition pheromones from the black fly Simulium vittatum. AB - The suite of pheromones that promote communal oviposition by Simulium vittatum, a North American black fly species, was identified and characterized using gas chromatography-mass spectrometry, electrophysiological, and behavioral bioassays. Behavioral assays demonstrated that communal oviposition was induced by egg derived compounds that were active at short range and whose effect was enhanced through direct contact. Three compounds (cis-9-tetradecen-1-ol, 1-pentadecene, and 1-tridecene) were identified in a non-polar solvent extract of freshly deposited S. vittatum eggs that were capable of inducing the oviposition response. Electroantennography demonstrated that two of these three compounds (1 pentadecene and 1-tridecene) actively stimulated antennal neurons. Identification of the oviposition pheromones of this family may be helpful in developing control measures for nuisance black flies and for medically-important species such as Simulium damnosum sensu lato. PMID- 25786207 TI - Identification and validation of reference genes for quantification of target gene expression with quantitative real-time PCR for tall fescue under four abiotic stresses. AB - Tall fescue (Festuca arundinacea Schreb.) is widely utilized as a major forage and turfgrass species in the temperate regions of the world and is a valuable plant material for studying molecular mechanisms of grass stress tolerance due to its superior drought and heat tolerance among cool-season species. Selection of suitable reference genes for quantification of target gene expression is important for the discovery of molecular mechanisms underlying improved growth traits and stress tolerance. The stability of nine potential reference genes (ACT, TUB, EF1a, GAPDH, SAND, CACS, F-box, PEPKR1 and TIP41) was evaluated using four programs, GeNorm, NormFinder, BestKeeper, and RefFinder. The combinations of SAND and TUB or TIP41 and TUB were most stably expressed in salt-treated roots or leaves. The combinations of GAPDH with TIP41 or TUB were stable in roots and leaves under drought stress. TIP41 and PEPKR1 exhibited stable expression in cold treated roots, and the combination of F-box, TIP41 and TUB was also stable in cold-treated leaves. CACS and TUB were the two most stable reference genes in heat-stressed roots. TIP41 combined with TUB and ACT was stably expressed in heat stressed leaves. Finally, quantitative real-time polymerase chain reaction (qRT PCR) assays of the target gene FaWRKY1 using the identified most stable reference genes confirmed the reliability of selected reference genes. The selection of suitable reference genes in tall fescue will allow for more accurate identification of stress-tolerance genes and molecular mechanisms conferring stress tolerance in this stress-tolerant species. PMID- 25786208 TI - Cost-effectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: the Multi Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated. OBJECTIVE: To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines. METHODS: We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC>=1 and CAC>=100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a "treat all" strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas. RESULTS: We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC>=1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC>=100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use. CONCLUSION: Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients' risks of CVD. PMID- 25786210 TI - Adjusting for one issue while ignoring others can make things worse. PMID- 25786209 TI - A newly designed curcumin analog Y20 mitigates cardiac injury via anti inflammatory and anti-oxidant actions in obese rats. AB - Obesity is strongly associated with the cause of structural and functional changes of the heart in both human and animal models. Oxidative stress and inflammation play a critical role in the development of obesity-induced cardiac disorders. Curcumin is a natural product from Curcuma Longa with multiple bioactivities. In our previous study, in order to reach better anti-inflammatory and anti-oxidant dual activities, we designed a new mono-carbonyl curcumin analog, Y20, via the structural modification with both trifluoromethyl and bromine. This study was designed to investigate the protective effects of Y20 on obesity-induced cardiac injury and its underlying mechanisms. In high fat diet fed rats, oral administration of Y20 at 20 mg/kg or curcumin at 50 mg/kg significantly decreased the cardiac inflammation and oxidative stress and eventually improved the cardiac remodeling by mitigating cardiac disorganization, hypertrophy, fibrosis and apoptosis. Y20 at 20 mg/kg showed comparable and even stronger bioactivities than curcumin at 50 mg/kg. The beneficial actions of Y20 are closely associated with its ability to increase Nrf2 expression and inhibit NF-kappaB activation. Taken together, these results suggest that Y20 may have a great therapeutic potential in the treatment of obesity-induced cardiac injury using Nrf2 and NF-kappaB as the therapeutic targets for treating obesity-related disorders. PMID- 25786211 TI - Cell cycle-dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas. AB - Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5, giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitors balancing self renewal and lineage-specific differentiation has never been described. Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contribution of individual cells to the global behaviour and demonstrate three modes of progenitor divisions: symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitor and an endocrine progenitor. Quantitative analysis shows that the endocrine differentiation process is consistent with a simple model of cell cycle-dependent stochastic priming of progenitors to endocrine fate. The findings provide insights to define control parameters to optimize the generation of beta-cells in vitro. PMID- 25786212 TI - Strategies for individual phenotyping of linoleic and arachidonic acid metabolism using an oral glucose tolerance test. AB - The ability to restore homeostasis upon environmental challenges has been proposed as a measure for health. Metabolic profiling of plasma samples during the challenge response phase should offer a profound view on the flexibility of a phenotype to cope with daily stressors. Current data modeling approaches, however, struggle to extract biological descriptors from time-resolved metabolite profiles that are able to discriminate between different phenotypes. Thus, for the case of oxylipin responses in plasma upon an oral glucose tolerance test we developed a modeling approach that incorporates a priori biological pathway knowledge. The degradation pathways of arachidonic and linoleic acids were modeled using a regression model based on a pseudo-steady-state approximated model, resulting in a parameter A that summarizes the relative enzymatic activity in these pathways. Analysis of the phenotypic parameters As suggests that different phenotypes can be discriminated according to preferred relative activity of the arachidonic and linoleic pathway. Correlation analysis shows that there is little or no competition between the arachidonic and linoleic acid pathways, although they share the same enzymes. PMID- 25786213 TI - Microscale characterization and trace element distribution in bacteriogenic ferromanganese coatings on sand grains from an intertidal zone of the East China Sea. AB - An ancient wood layer dated at about 5600 yr BP by accelerator mass spectrometry (AMS) 14C was discovered in an intertidal zone of the East China Sea. Extensive and horizontally stratified sediments with black color on the top and yellowish red at the bottom, and some nodule-cemented concretions with brown surface and black inclusions occurred in this intertidal zone. Microscale analysis methods were employed to study the microscale characterization and trace element distribution in the stratified sediments and concretions. Light microscopy, scanning electron microscopy (SEM) and backscattered electron imaging (BSE) revealed the presence of different coatings on the sand grains. The main mineral compositions of the coatings were ferrihydrite and goethite in the yellowish-red parts, and birnessite in the black parts using X-ray powder diffraction (XRD). SEM observations showed that bacteriogenic products and bacterial remnants extensively occurred in the coatings, indicating that bacteria likely played an important role in the formation of ferromanganese coatings. Post-Archean Australian Shale (PAAS)-normalized middle rare earth element (MREE) enrichment patterns of the coatings indicated that they were caused by two sub-sequential processes: (1) preferentially release of Fe-Mn from the beach rocks by fermentation of ancient woods and colloidal flocculation in the mixing water zone and (2) preferential adsorption of MREE by Fe-Mn oxyhydroxides from the seawater. The chemical results indicated that the coatings were enriched with Sc, V, Cr, Co, Ni, Cu, Zn, Ba, especially with respect to Co, Ni. The findings of the present study provide an insight in the microscale features of ferromanganese coatings and the Fe-Mn biogeochemical cycling during the degradation of buried organic matter in intertidal zones or shallow coasts. PMID- 25786214 TI - Child maltreatment experience among primary school children: a large scale survey in Selangor state, Malaysia. AB - Official reports of child maltreatment in Malaysia have persistently increased throughout the last decade. However there is a lack of population surveys evaluating the actual burden of child maltreatment, its correlates and its consequences in the country. This cross sectional study employed 2 stage stratified cluster random sampling of public primary schools, to survey 3509 ten to twelve year old school children in Selangor state. It aimed to estimate the prevalence of parental physical and emotional maltreatment, parental neglect and teacher- inflicted physical maltreatment. It further aimed to examine the associations between child maltreatment and important socio-demographic factors; family functioning and symptoms of depression among children. Logistic regression on weighted samples was used to extend results to a population level. Three quarters of 10-12 year olds reported at least one form of maltreatment, with parental physical maltreatment being most common. Males had higher odds of maltreatment in general except for emotional maltreatment. Ethnicity and parental conflict were key factors associated with maltreatment. The study contributes important evidence towards improving public health interventions for child maltreatment prevention in the country. PMID- 25786215 TI - Two arginine residues suppress the flexibility of nucleosomal DNA in the canonical nucleosome core. AB - The dynamics of nucleosomes containing either canonical H3 or its centromere specific variant CENP-A were investigated using molecular dynamics simulations. The simulations showed that the histone cores were structurally stable during simulation periods of 100 ns and 50 ns, while DNA was highly flexible at the entry and exit regions and partially dissociated from the histone core. In particular, approximately 20-25 bp of DNA at the entry and exit regions of the CENP-A nucleosome exhibited larger fluctuations than DNA at the entry and exit regions of the H3 nucleosome. Our detailed analysis clarified that this difference in dynamics was attributable to a difference in two basic amino acids in the alphaN helix; two arginine (Arg) residues in H3 were substituted by lysine (Lys) residues at the corresponding sites in CENP-A. The difference in the ability to form hydrogen bonds with DNA of these two residues regulated the flexibility of nucleosomal DNA at the entry and exit regions. Our exonuclease III assay consistently revealed that replacement of these two Arg residues in the H3 nucleosome by Lys enhanced endonuclease susceptibility, suggesting that the DNA ends of the CENP-A nucleosome are more flexible than those of the H3 nucleosome. This difference in the dynamics between the two types of nucleosomes may be important for forming higher order structures in different phases. PMID- 25786216 TI - High connectivity in Rastrelliger kanagurta: influence of historical signatures and migratory behaviour inferred from mtDNA cytochrome b. AB - Phylogeographic patterns and population structure of the pelagic Indian mackerel, Rastrelliger kanagurta were examined in 23 populations collected from the Indonesian-Malaysian Archipelago (IMA) and the West Indian Ocean (WIO). Despite the vast expanse of the IMA and neighbouring seas, no evidence for geographical structure was evident. An indication that R. kanagurta populations across this region are essentially panmictic. This study also revealed that historical isolation was insufficient for R. kanagurta to attain migration drift equilibrium. Two distinct subpopulations were detected between the WIO and the IMA (and adjacent populations); interpopulation genetic variation was high. A plausible explanation for the genetic differentiation observed between the IMA and WIO regions suggest historical isolation as a result of fluctuations in sea levels during the late Pleistocene. This occurrence resulted in the evolution of a phylogeographic break for this species to the north of the Andaman Sea. PMID- 25786217 TI - Consensus forecasting of species distributions: the effects of niche model performance and niche properties. AB - Ensemble forecasting is advocated as a way of reducing uncertainty in species distribution modeling (SDM). This is because it is expected to balance accuracy and robustness of SDM models. However, there are little available data regarding the spatial similarity of the combined distribution maps generated by different consensus approaches. Here, using eight niche-based models, nine split-sample calibration bouts (or nine random model-training subsets), and nine climate change scenarios, the distributions of 32 forest tree species in China were simulated under current and future climate conditions. The forecasting ensembles were combined to determine final consensual prediction maps for target species using three simple consensus approaches (average, frequency, and median [PCA]). Species' geographic ranges changed (area change and shifting distance) in response to climate change, but the three consensual projections did not differ significantly with respect to how much or in which direction, but they did differ with respect to the spatial similarity of the three consensual predictions. Incongruent areas were observed primarily at the edges of species' ranges. Multiple stepwise regression models showed the three factors (niche marginality and specialization, and niche model accuracy) to be related to the observed variations in consensual prediction maps among consensus approaches. Spatial correspondence among prediction maps was the highest when niche model accuracy was high and marginality and specialization were low. The difference in spatial predictions suggested that more attention should be paid to the range of spatial uncertainty before any decisions regarding specialist species can be made based on map outputs. The niche properties and single-model predictive performance provide promising insights that may further understanding of uncertainties in SDM. PMID- 25786218 TI - Transport infrastructure shapes foraging habitat in a raptor community. AB - Transport infrastructure elements are widespread and increasing in size and length in many countries, with the subsequent alteration of landscapes and wildlife communities. Nonetheless, their effects on habitat selection by raptors are still poorly understood. In this paper, we analyzed raptors' foraging habitat selection in response to conventional roads and high capacity motorways at the landscape scale, and compared their effects with those of other variables, such as habitat structure, food availability, and presence of potential interspecific competitors. We also analyzed whether the raptors' response towards infrastructure depends on the spatial scale of observation, comparing the attraction or avoidance behavior of the species at the landscape scale with the response of individuals observed in the proximity of the infrastructure. Based on ecological hypotheses for foraging habitat selection, we built generalized linear mixed models, selected the best models according to Akaike Information Criterion and assessed variable importance by Akaike weights. At the community level, the traffic volume was the most relevant variable in the landscape for foraging habitat selection. Abundance, richness, and diversity values reached their maximum at medium traffic volumes and decreased at highest traffic volumes. Individual species showed different degrees of tolerance toward traffic, from higher abundance in areas with high traffic values to avoidance of it. Medium sized opportunistic raptors increased their abundance near the traffic infrastructures, large scavenger raptors avoided areas with higher traffic values, and other species showed no direct response to traffic but to the presence of prey. Finally, our cross-scale analysis revealed that the effect of transport infrastructures on the behavior of some species might be detectable only at a broad scale. Also, food availability may attract raptor species to risky areas such as motorways. PMID- 25786219 TI - Correction: A chitin-like component on sclerotic cells of fonsecaea pedrosoi inhibits dectin-1-mediated murine Th17 development by masking beta-glucans. PMID- 25786220 TI - Differential subcellular localization renders HAI-2 a matriptase inhibitor in breast cancer cells but not in mammary epithelial cells. AB - The type 2 transmembrane serine protease matriptase is under tight control primarily by the actions of the integral membrane Kunitz-type serine protease inhibitor HAI-1. Growing evidence indicates that HAI-2 might also be involved in matriptase inhibition in some contexts. Here we showed that matriptase inhibition by HAI-2 depends on the subcellular localizations of HAI-2, and is observed in breast cancer cells but not in mammary epithelial cells. HAI-2 is co-expressed with matriptase in 21 out of 26 human epithelial and carcinoma cells examined. HAI-2 is also a potent matriptase inhibitor in solution, but in spite of this, HAI-2 inhibition of matriptase is not observed in all contexts where HAI-2 is expressed, unlike what is seen for HAI-1. Induction of matriptase zymogen activation in mammary epithelial cells results in the formation of matriptase-HAI 1 complexes, but matriptase-HAI-2 complexes are not observed. In breast cancer cells, however, in addition to the appearance of matriptase-HAI-1 complex, three different matriptase-HAI-2 complexes, are formed following the induction of matriptase activation. Immunofluorescent staining reveals that activated matriptase is focused at the cell-cell junctions upon the induction of matriptase zymogen activation in both mammary epithelial cells and breast cancer cells. HAI 2, in contrast, remains localized in vesicle/granule-like structures during matriptase zymogen activation in human mammary epithelial cells. In breast cancer cells, however, a proportion of the HAI-2 reaches the cell surface where it can gain access to and inhibit active matriptase. Collectively, these data suggest that matriptase inhibition by HAI-2 requires the translocation of HAI-2 to the cell surface, a process which is observed in some breast cancer cells but not in mammary epithelial cells. PMID- 25786222 TI - Experimental study of the irrational phase synchronization of coupled nonidentical mechanical metronomes. AB - It has recently been observed in numerical simulations that the phases of two coupled nonlinear oscillators can become locked into an irrational ratio, exhibiting the phenomenon of irrational phase synchronization (IPS) [Phys. Rev. E 69, 056228 (2004)]. Here, using two coupled nonidentical periodic mechanical metronomes, we revisit this interesting phenomenon through experimental studies. It is demonstrated that under suitable couplings, the phases of the metronomes indeed can become locked into irrational ratios. Numerical simulations confirm the experimental observations and also reveal that in the IPS state, the system dynamics are chaotic. Our studies provide a solid step toward further studies of IPS. PMID- 25786221 TI - Phosphorescence monitoring of hypoxic microenvironment in solid-tumors to evaluate chemotherapeutic effects using the hypoxia-sensitive iridium (III) coordination compound. AB - OBJECTIVES: To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo. METHODS: A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results. RESULTS: BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice. CONCLUSIONS: We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis. PMID- 25786223 TI - Short-term treatment with diminazene aceturate ameliorates the reduction in kidney ACE2 activity in rats with subtotal nephrectomy. AB - Angiotensin converting enzyme (ACE) 2 is an important modulator of the renin angiotensin system (RAS) through its role to degrade angiotensin (Ang) II. Depletion of kidney ACE2 occurs following kidney injury due to renal mass reduction and may contribute to progressive kidney disease. This study assessed the effect of diminazine aceturate (DIZE), which has been described as an ACE2 activator, on kidney ACE2 mRNA and activity in rats with kidney injury due to subtotal nephrectomy (STNx). Sprague Dawley rats were divided into Control groups or underwent STNx; rats then received vehicle or the DIZE (s.c. 15 mg/kg/day) for 2 weeks. STNx led to hypertension (P<0.01), kidney hypertrophy (P<0.001) and impaired kidney function (P<0.001) compared to Control rats. STNx was associated with increased kidney cortical ACE activity, and reduced ACE2 mRNA in the cortex (P<0.01), with reduced cortical and medullary ACE2 activity (P<0.05), and increased urinary ACE2 excretion (P<0.05) compared to Control rats. Urinary ACE2 activity correlated positively with urinary protein excretion (P<0.001), and negatively with creatinine clearance (P=0.04). In STNx rats, DIZE had no effect on blood pressure or kidney function, but was associated with reduced cortical ACE activity (P<0.01), increased cortical ACE2 mRNA (P<0.05) and increased cortical and medullary ACE2 activity (P<0.05). The precise in vivo mechanism of action of DIZE is not clear, and its effects to increase ACE2 activity may be secondary to an increase in ACE2 mRNA abundance. In ex vivo studies, DIZE did not increase ACE2 activity in either Control or STNx kidney cortical membranes. It is not yet known if chronic administration of DIZE has long-term benefits to slow the progression of kidney disease. PMID- 25786224 TI - Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: a genome-wide association study. AB - Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women's Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38x10(-4)), although the UHS WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47x10(-7) vs. P<5.0x10(-8)) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9x10(-5)); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8x10(-5)); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies. PMID- 25786226 TI - In the right place at the right time: habitat representation in protected areas of South American Nothofagus-dominated plants after a dispersal constrained climate change scenario. AB - In order to assess the effects of climate change in temperate rainforest plants in southern South America in terms of habitat size, representation in protected areas, considering also if the expected impacts are similar for dominant trees and understory plant species, we used niche modeling constrained by species migration on 118 plant species, considering two groups of dominant trees and two groups of understory ferns. Representation in protected areas included Chilean national protected areas, private protected areas, and priority areas planned for future reserves, with two thresholds for minimum representation at the country level: 10% and 17%. With a 10% representation threshold, national protected areas currently represent only 50% of the assessed species. Private reserves are important since they increase up to 66% the species representation level. Besides, 97% of the evaluated species may achieve the minimum representation target only if the proposed priority areas were included. With the climate change scenario representation levels slightly increase to 53%, 69%, and 99%, respectively, to the categories previously mentioned. Thus, the current location of all the representation categories is useful for overcoming climate change by 2050. Climate change impacts on habitat size and representation of dominant trees in protected areas are not applicable to understory plants, highlighting the importance of assessing these effects with a larger number of species. Although climate change will modify the habitat size of plant species in South American temperate rainforests, it will have no significant impact in terms of the number of species adequately represented in Chile, where the implementation of the proposed reserves is vital to accomplish the present and future minimum representation. Our results also show the importance of using migration dispersal constraints to develop more realistic future habitat maps from climate change predictions. PMID- 25786225 TI - Economic and disease burden of dengue in Mexico. AB - BACKGROUND: Dengue imposes a substantial economic and disease burden in most tropical and subtropical countries. Dengue incidence and severity have dramatically increased in Mexico during the past decades. Having objective and comparable estimates of the economic burden of dengue is essential to inform health policy, increase disease awareness, and assess the impact of dengue prevention and control technologies. METHODS AND FINDINGS: We estimated the annual economic and disease burden of dengue in Mexico for the years 2010-2011. We merged multiple data sources, including a prospective cohort study; patient interviews and macro-costing from major hospitals; surveillance, budget, and health data from the Ministry of Health; WHO cost estimates; and available literature. We conducted a probabilistic sensitivity analysis using Monte Carlo simulations to derive 95% certainty levels (CL) for our estimates. Results suggest that Mexico had about 139,000 (95%CL: 128,000-253,000) symptomatic and 119 (95%CL: 75-171) fatal dengue episodes annually on average (2010-2011), compared to an average of 30,941 symptomatic and 59 fatal dengue episodes reported. The annual cost, including surveillance and vector control, was US$170 (95%CL: 151-292) million, or $1.56 (95%CL: 1.38-2.68) per capita, comparable to other countries in the region. Of this, $87 (95%CL: 87-209) million or $0.80 per capita (95%CL: 0.62-1.12) corresponds to illness. Annual disease burden averaged 65 (95%CL: 36-99) disability-adjusted life years (DALYs) per million population. Inclusion of long-term sequelae, co-morbidities, impact on tourism, and health system disruption during outbreaks would further increase estimated economic and disease burden. CONCLUSION: With this study, Mexico joins Panama, Puerto Rico, Nicaragua, and Thailand as the only countries or areas worldwide with comprehensive (illness and preventive) empirical estimates of dengue burden. Burden varies annually; during an outbreak, dengue burden may be significantly higher than that of the pre-vaccine level of rotavirus diarrhea. In sum, Mexico's potential economic benefits from dengue control would be substantial. PMID- 25786227 TI - Isotherm modelling, kinetic study and optimization of batch parameters using response surface methodology for effective removal of Cr(VI) using fungal biomass. AB - Biosorption is a promising alternative method to replace the existing conventional technique for Cr(VI) removal from the industrial effluent. In the present experimental design, the removal of Cr(VI) from the aqueous solution was studied by Aspergillus niger MSR4 under different environmental conditions in the batch systems. The optimum conditions of biosorption were determined by investigating pH (2.0) and temperature (27 degrees C). The effects of parameters such as biomass dosage (g/L), initial Cr(VI) concentration (mg/L) and contact time (min) on Cr(VI) biosorption were analyzed using a three parameter Box Behnken design (BBD). The experimental data well fitted to the Langmuir isotherm, in comparison to the other isotherm models tested. The results of the D-R isotherm model suggested that a chemical ion-exchange mechanism was involved in the biosorption process. The biosorption process followed the pseudo-second-order kinetic model, which indicates that the rate limiting step is chemisorption process. Fourier transform infrared (FT-IR) spectroscopic studies revealed the possible involvement of functional groups, such as hydroxyl, carboxyl, amino and carbonyl group in the biosorption process. The thermodynamic parameters for Cr(VI) biosorption were also calculated, and the negative ?Go values indicated the spontaneous nature of biosorption process. PMID- 25786228 TI - Multilevel effects of wealth on women's contraceptive use in Mozambique. AB - OBJECTIVE: This paper analyzes the impact of wealth on the use of contraception in Mozambique unmixing the contextual effects due to community wealth from the individual effects associated with the women's situation within the community of residence. METHODS: Data from the 2011 Mozambican Demographic and Health Survey on women who are married or living together are analyzed for the entire country and also for the rural and urban areas separately. We used single level and multilevel probit regression models. FINDINGS: A single level probit regression reveals that region, religion, age, previous fertility, education, and wealth impact contraceptive behavior. The multilevel analysis shows that average community wealth and the women's relative socioeconomic position within the community have significant positive effects on the use of modern contraceptives. The multilevel framework proved to be necessary in rural settings but not relevant in urban areas. Moreover, the contextual effects due to community wealth are greater in rural than in urban areas and this feature is associated with the higher socioeconomic heterogeneity within the richest communities. CONCLUSION: This analysis highlights the need for the studies on contraceptive behavior to specifically address the individual and contextual effects arising from the poverty-wealth dimension in rural and urban areas separately. The inclusion in a particular community of residence is not relevant in urban areas, but it is an important feature in rural areas. Although the women's individual position within the community of residence has a similar effect on contraceptive adoption in rural and urban settings, the impact of community wealth is greater in rural areas and smaller in urban areas. PMID- 25786229 TI - Cysteine Protease Profiles of the Medicinal Plant Calotropis procera R. Br. revealed by de novo transcriptome analysis. AB - Calotropis procera R. Br., a traditional medicinal plant in India, is a promising source of commercial proteases, because the cysteine proteases from the plant exhibit high thermo-stability, broad pH optima, and plasma-clotting activity. Though several proteases such as Procerain, Procerain B, CpCp-1, CpCp-2, and CpCp 3 have been isolated and characterized, the information of their transcripts is limited to cDNAs encoding their mature peptides. Due to this limitation, in this study, to determine the cDNA sequences encoding full open reading frame of these cysteine proteases, transcripts were sequenced with an Illumina Hiseq2000 sequencer. A total of 171,253,393 clean reads were assembled into 106,093 contigs with an average length of 1,614 bp and an N50 of 2,703 bp, and 70,797 contigs with an average length of 1,565 bp and N50 of 2,082 bp using Trinity and Velvet Oases software, respectively. Among these contigs, we found 20 unigenes related to papain-like cysteine proteases by BLASTX analysis against a non-redundant NCBI protein database. Our expression analysis revealed that the cysteine protease contains an N-terminal pro-peptide domain (inhibitor region), which is necessary for correct folding and proteolytic activity. It was evident that expression yields using an inducible T7 expression system in Escherichia coli were considerably higher with the pro-peptide domain than without the domain, which could contribute to molecular cloning of the Calotropis procera protease as an active form with correct folding. PMID- 25786230 TI - Syntactic priming in American Sign Language. AB - Psycholinguistic studies of sign language processing provide valuable opportunities to assess whether language phenomena, which are primarily studied in spoken language, are fundamentally shaped by peripheral biology. For example, we know that when given a choice between two syntactically permissible ways to express the same proposition, speakers tend to choose structures that were recently used, a phenomenon known as syntactic priming. Here, we report two experiments testing syntactic priming of a noun phrase construction in American Sign Language (ASL). Experiment 1 shows that second language (L2) signers with normal hearing exhibit syntactic priming in ASL and that priming is stronger when the head noun is repeated between prime and target (the lexical boost effect). Experiment 2 shows that syntactic priming is equally strong among deaf native L1 signers, deaf late L1 learners, and hearing L2 signers. Experiment 2 also tested for, but did not find evidence of, phonological or semantic boosts to syntactic priming in ASL. These results show that despite the profound differences between spoken and signed languages in terms of how they are produced and perceived, the psychological representation of sentence structure (as assessed by syntactic priming) operates similarly in sign and speech. PMID- 25786233 TI - Correction: Natural variation in fish transcriptomes: comparative analysis of the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio). PMID- 25786232 TI - Compensation for retinal vessel density reduces the variation of circumpapillary RNFL in healthy subjects. AB - This work intends to assess circumpapillary retinal vessel density (RVD) at a 3.46 mm diameter circle and correlate it with circumpapillary retinal nerve fiber layer (RNFL) thickness measured with Fourier-Domain Optical Coherence Tomography. Furthermore, it aims to evaluate the reduction of intersubject variability of RNFL when considering RVD as a source of information for RNFL distribution. For that, 106 healthy subjects underwent circumpapillary RNFL measurement. Using the scanning laser ophthalmoscope fundus image, thickness and position of retinal vessels were assessed and integrated in a 256-sector RVD profile. The relationship between local RVD value and local RNFL thickness was modeled by linear regression. RNFL was then compensated for RVD variation by regression formulas. A strong statistically significant intrasubject correlation was found for all subjects between RVD and RNFL profiles (mean R = 0.769). In the intersubject regression analysis, 247 of 256 RNFL sectors showed a statistically significant positive correlation with RVD (mean R = 0.423). RVD compensation of RNFL resulted in a relative reduction of up to 20% of the intersubject variance. In conclusion, RVD in a 3.46 mm circle has a clinically relevant influence on the RNFL distribution. RVD may be used to develop more individualized normative values for RNFL measurement, which might improve early diagnosis of glaucoma. PMID- 25786231 TI - Aberrant functional connectome in neurologically asymptomatic patients with end stage renal disease. AB - PURPOSE: This study aimed to investigate the topological organization of intrinsic functional brain networks in patients with end-stage renal disease (ESRD). MATERIALS AND METHODS: Resting-state functional MRI data were collected from 22 patients with ESRD (16 men, 18-61 years) and 29 age- and gender-matched healthy controls (HCs, 19 men, 32-61 years). Whole-brain functional networks were obtained by calculating the interregional correlation of low-frequency fluctuations in spontaneous brain activity among 1,024 parcels that cover the entire cerebrum. Weighted graph-based models were then employed to topologically characterize these networks at different global, modular and nodal levels. RESULTS: Compared to HCs, the patients exhibited significant disruption in parallel information processing over the whole networks (P < 0.05). The disruption was present in all the functional modules (default mode, executive control, sensorimotor and visual networks) although decreased functional connectivity was observed only within the default mode network. Regional analysis showed that the disease disproportionately weakened nodal efficiency of the default mode components and tended to preferentially affect central or hub-like regions. Intriguingly, the network abnormalities correlated with biochemical hemoglobin and serum calcium levels in the patients. Finally, the functional changes were substantively unchanged after correcting for gray matter atrophy in the patients. CONCLUSION: Our findings provide evidence for the disconnection nature of ESRD's brain and therefore have important implications for understanding the neuropathologic substrate of the disease from disrupted network organization perspective. PMID- 25786234 TI - Demographics of the disappearing bottlenose dolphin in Argentina: a common species on its way out? AB - Populations of the once common bottlenose dolphin (Tursiops truncatus) in Argentina have precipitously declined throughout the country in the past decades. Unfortunately, local declines of common species are easily overlooked when establishing priorities for conservation. In this study, demographics of what may well be the last remaining resident population in the country were assessed using mark-recapture analysis (Pollock's Robust Design) of a photo-identification dataset collected during 2006-2011 in Bahia San Antonio (Patagonia, Argentina). Total abundance, corrected for unmarked individuals, ranged from 40 (95%CI: 16.1 98.8) to 83 (95%CI = 45.8-151.8) individuals and showed a decrease over the years. Adult survival rates varied between 0.97 (+/- 0.037 SE) and 0.99 (+/- 0.010 SE). Average calving interval equalled 3.5 +/- 1.03 years, with 3.5 births/year in the entire population and a minimum annual birth rate of 4.2%. However, data suggest that calves may have been born and lost before being documented, underestimating birth rate, calf mortality, and possibly the number of reproductive females. Either way, the recruitment rate of calves appears to be insufficient to support the size of the population. This population is relatively small and declining. Considering the disappearance of populations north and south of the study area, an incessant decline will have severe consequences for the continuous existence of this species in Argentina, indicating an urgent need for serious conservation efforts. This study provides insight into how the failure to recognize local population declines can threaten the national (and eventually the international) status of a common species like the bottlenose dolphin. PMID- 25786235 TI - PhyloWGS: reconstructing subclonal composition and evolution from whole-genome sequencing of tumors. AB - Tumors often contain multiple subpopulations of cancerous cells defined by distinct somatic mutations. We describe a new method, PhyloWGS, which can be applied to whole-genome sequencing data from one or more tumor samples to reconstruct complete genotypes of these subpopulations based on variant allele frequencies (VAFs) of point mutations and population frequencies of structural variations. We introduce a principled phylogenic correction for VAFs in loci affected by copy number alterations and we show that this correction greatly improves subclonal reconstruction compared to existing methods. PhyloWGS is free, open-source software, available at https://github.com/morrislab/phylowgs. PMID- 25786236 TI - Preoperative radiologic classification of convexity meningioma to predict the survival and aggressive meningioma behavior. AB - BACKGROUND: A subgroup of meningioma demonstrates clinical aggressive behavior. We set out to determine if the radiological parameters can predict histopathological aggressive meningioma, and propose a classification to predict survival and aggressive meningioma behavior. METHODS: A retrospective review of medical records was conducted for patients who underwent surgical resection of their convexity meningioma. WHO-2007 grading was used for histopathological diagnosis. Preoperative radiologic parameters were analyzed, each parameter was scored 0 or 1. Signal intensity on diffusion weighted MRI (DWI) (hyperintensity=1), heterogeneity on T1-weighted gadolinium enhanced MRI (heterogeneity=1), disruption of arachnoid at brain-tumor interface=1 and peritumoral edema (PTE) on T2-weighted MRI (presence of PTE=1) and tumor shape (irregular shape=1). Multivariate logistic regression analyses were conducted to determine association of radiological parameters to histopathological grading. Kaplan-Meier and Cox regression models were used to determine the association of scoring system to overall survival and progression free survival (PFS). Reliability of the classification was tested using Kappa co-efficient analysis. RESULTS: Hyperintensity on DWI, disruption of arachnoid at brain-tumor interface, PTE, heterogenicitiy on T1-weighted enhanced MRI and irregular tumor shape were independent predictors of non-grade I meningioma. Mean follow-up period was 94.6 months (range, 12-117 months). Median survival and PFS in groups-I, II and III was 114.1+/-1.2 and 115.7+/- 0.8, 88+/- 3.3 and 58.5+/-3.9, 43.2+/- 5.1 and 18.2+/-1.7 months respectively. In cox regression analysis model, age (P<0.0001, OR-1.039, CI-1.017-0.062), WHO non-grade-I meningioma (P=0.017, OR-3.014, CI 1.217-7.465), radiological classification groups II (P=0.002, OR-6.194, CI-1.956 19.610) and III (P<0.0001, OR-21.658, CI-5.701-82.273) were independent predictors of unfavorable survival outcomes. CONCLUSIONS: Preoperative radiological classification can be used as a supplement to the histopathological grading. Group-I meningiomas demonstrate benign radiological, histopathological and clinical features; group-III demonstrates aggressive features. Group-II meningiomas demonstrate intermediate features; the need for more aggressive follow-up and/or treatment should be further investigated. PMID- 25786237 TI - Lens status influences the association between CFH polymorphisms and age-related macular degeneration: findings from two population-based studies in Singapore. AB - AIMS: To determine the differential effects of genetic polymorphism in CFH and ARMS2 on risk of age-related macular degeneration (AMD) between phakic vs. pseudophakic/aphakic eyes. METHODS: 9,529 eyes of 4,918 participants from the Singapore Malay Eye Study and Singapore Indian Eye Study were analyzed. Participants had detailed eye examinations, including slit-lamp examinations and dilated fundus photography. AMD grading was performed according to the Wisconsin age-related maculopathy grading system. Lens status was defined. Single nucleotide polymorphisms (SNPs) rs10801555 (Y402H) within CFH and rs3750847 in ARMS2 were assessed. The main outcome measure was early AMD or any AMD. RESULTS: No significant associations between the CFH Y402H genotypes and early AMD were found in phakic individuals. In contrast, among pseudophakic/aphakic individuals, the CFH Y402H risk genotypes were significantly associated with higher odds of early AMD, with an OR of 1.57 (95% CI: 1.07-2.29) for GA genotype and 2.40 (95% CI: 1.25-4.61) for AA genotype, compared to those with GG genotype. There was significant interaction between pseudophakic/aphakic status and CFH Y402H variant on risk of early AMD (p = 0.037), adjusting for age, gender, and the first 5 genetic principal components. No significant interaction was found between lens status and ARMS2 rs3750847. CONCLUSIONS: CFH genetic polymorphism and pseudophakic/aphakic status may have a potential synergistic effect on early AMD, suggesting roles for the complement system and related pathways in the pathogenesis of AMD in eyes after cataract surgery. PMID- 25786238 TI - Design and evaluation of optimized artificial HIV-1 poly-T cell-epitope immunogens. AB - A successful HIV vaccine in addition to induction of antibody responses should elicit effective T cell responses. Here we described possible strategies for rational design of T-cell vaccine capable to induce high levels of both CD4+ and CD8+ T- cell responses. We developed artificial HIV-1 polyepitope T-cell immunogens based on the conserved natural CD8+ and CD4+ T cell epitopes from different HIV-1 strains and restricted by the most frequent major human leukocyte antigen (HLA) alleles. Designed immunogens contain optimized core polyepitope sequence and additional "signal" sequences which increase epitope processing and presentation to CD8+ and CD4+ T-lymphocytes: N-terminal ubiquitin, N-terminal signal peptide and C-terminal tyrosine motif of LAMP-1 protein. As a result we engineered three T cell immunogens - TCI-N, TCI-N2, and TCI-N3, with different combinations of signal sequences. All designed immunogens were able to elicit HIV specific CD4+ and CD8+ T cell responses following immunization. Attachment of either ubiquitin or ER-signal/LAMP-1 sequences increased both CD4+ and CD8+ mediated HIV-specific T cell responses in comparison with polyepitope immunogen without any additional signal sequences. Moreover, TCI-N3 polyepitope immunogen with ubiquitin generated highest magnitude of HIV-specific CD4+ and CD8+ T cell responses in our study. Obtained data suggests that attachment of signal sequences targeting polyepitope immunogens to either MHC class I or MHC class II presentation pathways may improve immunogenicity of T-cell vaccines. These results support the strategy of the rational T cell immunogen design and contribute to the development of effective HIV-1 vaccine. PMID- 25786239 TI - Overexpressing CYP71Z2 enhances resistance to bacterial blight by suppressing auxin biosynthesis in rice. AB - BACKGROUND: The hormone auxin plays an important role not only in the growth and development of rice, but also in its defense responses. We've previously shown that the P450 gene CYP71Z2 enhances disease resistance to pathogens through regulation of phytoalexin biosynthesis in rice, though it remains unclear if auxin is involved in this process or not. METHODOLOGY AND PRINCIPAL FINDINGS: The expression of CYP71Z2 was induced by Xanthomonas oryzae pv. oryzae (Xoo) inoculation was analyzed by qRT-PCR, with GUS histochemical staining showing that CYP71Z2 expression was limited to roots, blades and nodes. Overexpression of CYP71Z2 in rice durably and stably increased resistance to Xoo, though no significant difference in disease resistance was detected between CYP71Z2-RNA interference (RNAi) rice and wild-type. Moreover, IAA concentration was determined using the HPLC/electrospray ionization/tandem mass spectrometry system. The accumulation of IAA was significantly reduced in CYP71Z2 overexpressing rice regardless of whether plants were inoculated or not, whereas it was unaffected in CYP71Z2-RNAi rice. Furthermore, the expression of genes related to IAA, expansin and SA/JA signaling pathways was suppressed in CYP71Z2 overexpressing rice with or without inoculation. CONCLUSIONS AND SIGNIFICANCE: These results suggest that CYP71Z2-mediated resistance to Xoo may be via suppression of IAA signaling in rice. Our studies also provide comprehensive insight into molecular mechanism of resistance to Xoo mediated by IAA in rice. Moreover, an available approach for understanding the P450 gene functions in interaction between rice and pathogens has been provided. PMID- 25786240 TI - A longitudinal functional neuroimaging study in medication-naive depression after antidepressant treatment. AB - Recent studies have indicated the potential clinical use of near infrared spectroscopy (NIRS) as a tool in assisting the diagnosis of major depressive disorder (MDD); however, it is still unclear whether NIRS signal changes during cognitive task are state- or trait-dependent, and whether NIRS could be a neural predictor of treatment response. Therefore, we conducted a longitudinal study to explore frontal haemodynamic changes following antidepressant treatment in medication-naive MDD using 52-channel NIRS. This study included 25 medication naive individuals with MDD and 62 healthy controls (HC). We performed NIRS scans before and after antidepressant treatment and measured changes of [oxy-Hb] activation during a verbal fluency task (VFT) following treatment. Individuals with MDD showed significantly decreased [oxy-Hb] values during a VFT compared with HC in the bilateral frontal and temporal cortices at baseline. There were no [oxy-Hb] changes between pre- and post-antidepressant treatment time points in the MDD cohort despite significant improvement in depressive symptoms. There was a significant association between mean [oxy-Hb] values during a VFT at baseline and improvement in depressive symptoms following treatment in the bilateral inferior frontal and middle temporal gyri in MDD. These findings suggest that hypofrontality response to a VFT may represent a potential trait marker for depression rather than a state marker. Moreover, the correlation analysis indicates that the NIRS signals before the initiation of treatment may be a biological marker to predict patient's clinical response to antidepressant treatment. The present study provides further evidence to support a potential application of NIRS for the diagnosis and treatment of depression. PMID- 25786241 TI - Genetic analysis of the CDI pathway from Burkholderia pseudomallei 1026b. AB - Contact-dependent growth inhibition (CDI) is a mode of inter-bacterial competition mediated by the CdiB/CdiA family of two-partner secretion systems. CdiA binds to receptors on susceptible target bacteria, then delivers a toxin domain derived from its C-terminus. Studies with Escherichia coli suggest the existence of multiple CDI growth-inhibition pathways, whereby different systems exploit distinct target-cell proteins to deliver and activate toxins. Here, we explore the CDI pathway in Burkholderia using the CDIIIBp1026b system encoded on chromosome II of Burkholderia pseudomallei 1026b as a model. We took a genetic approach and selected Burkholderia thailandensis E264 mutants that are resistant to growth inhibition by CDIIIBp1026b. We identified mutations in three genes, BTH_I0359, BTH_II0599, and BTH_I0986, each of which confers resistance to CDIIIBp1026b. BTH_I0359 encodes a small peptide of unknown function, whereas BTH_II0599 encodes a predicted inner membrane transport protein of the major facilitator superfamily. The inner membrane localization of BTH_II0599 suggests that it may facilitate translocation of CdiA-CTIIBp1026b toxin from the periplasm into the cytoplasm of target cells. BTH_I0986 encodes a putative transglycosylase involved in lipopolysaccharide (LPS) synthesis. ?BTH_I0986 mutants have altered LPS structure and do not interact with CDI+ inhibitor cells to the same extent as BTH_I0986+ cells, suggesting that LPS could function as a receptor for CdiAIIBp1026b. Although ?BTH_I0359, ?BTH_II0599, and ?BTH_I0986 mutations confer resistance to CDIIIBp1026b, they provide no protection against the CDIE264 system deployed by B. thailandensis E264. Together, these findings demonstrate that CDI growth-inhibition pathways are distinct and can differ significantly even between closely related species. PMID- 25786242 TI - Prioritizing therapeutics for lung cancer: an integrative meta-analysis of cancer gene signatures and chemogenomic data. AB - Repurposing FDA-approved drugs with the aid of gene signatures of disease can accelerate the development of new therapeutics. A major challenge to developing reliable drug predictions is heterogeneity. Different gene signatures of the same disease or drug treatment often show poor overlap across studies, as a consequence of both biological and technical variability, and this can affect the quality and reproducibility of computational drug predictions. Existing algorithms for signature-based drug repurposing use only individual signatures as input. But for many diseases, there are dozens of signatures in the public domain. Methods that exploit all available transcriptional knowledge on a disease should produce improved drug predictions. Here, we adapt an established meta analysis framework to address the problem of drug repurposing using an ensemble of disease signatures. Our computational pipeline takes as input a collection of disease signatures, and outputs a list of drugs predicted to consistently reverse pathological gene changes. We apply our method to conduct the largest and most systematic repurposing study on lung cancer transcriptomes, using 21 signatures. We show that scaling up transcriptional knowledge significantly increases the reproducibility of top drug hits, from 44% to 78%. We extensively characterize drug hits in silico, demonstrating that they slow growth significantly in nine lung cancer cell lines from the NCI-60 collection, and identify CALM1 and PLA2G4A as promising drug targets for lung cancer. Our meta-analysis pipeline is general, and applicable to any disease context; it can be applied to improve the results of signature-based drug repurposing by leveraging the large number of disease signatures in the public domain. PMID- 25786243 TI - Dystrophic spinal deformities in a neurofibromatosis type 1 murine model. AB - Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/ ;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36 60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population. PMID- 25786245 TI - Science classroom inquiry (SCI) simulations: a novel method to scaffold science learning. AB - Science education is progressively more focused on employing inquiry-based learning methods in the classroom and increasing scientific literacy among students. However, due to time and resource constraints, many classroom science activities and laboratory experiments focus on simple inquiry, with a step-by step approach to reach predetermined outcomes. The science classroom inquiry (SCI) simulations were designed to give students real life, authentic science experiences within the confines of a typical classroom. The SCI simulations allow students to engage with a science problem in a meaningful, inquiry-based manner. Three discrete SCI simulations were created as website applications for use with middle school and high school students. For each simulation, students were tasked with solving a scientific problem through investigation and hypothesis testing. After completion of the simulation, 67% of students reported a change in how they perceived authentic science practices, specifically related to the complex and dynamic nature of scientific research and how scientists approach problems. Moreover, 80% of the students who did not report a change in how they viewed the practice of science indicated that the simulation confirmed or strengthened their prior understanding. Additionally, we found a statistically significant positive correlation between students' self-reported changes in understanding of authentic science practices and the degree to which each simulation benefitted learning. Since SCI simulations were effective in promoting both student learning and student understanding of authentic science practices with both middle and high school students, we propose that SCI simulations are a valuable and versatile technology that can be used to educate and inspire a wide range of science students on the real-world complexities inherent in scientific study. PMID- 25786244 TI - Association studies of calcium-sensing receptor (CaSR) polymorphisms with serum concentrations of glucose and phosphate, and vascular calcification in renal transplant recipients. AB - BACKGROUND: Cardiovascular disease is the major cause of death in renal transplant recipients (RTRs) and linked to arterial calcification. The calcium sensing receptor (CaSR), a G-protein coupled receptor, plays a pivotal role in extracellular calcium homeostasis and is expressed in the intimal and medial layers of the arterial wall. We investigated whether common CASR gene variants are predictors for aortic and coronary artery calcification or influence risk factors such as serum calcium, phosphate and glucose concentrations in RTRs. METHODS: Two hundred and eighty four RTRs were investigated for associations between three CASR promoter region single nucleotide polymorphisms (SNPs) (rs115759455, rs7652589, rs1501899), three non-synonymous CASR coding region SNPs (A986S, R990G, Q1011E), and aortic and coronary artery calcium mass scores, cardiovascular outcomes and calcification risk factors that included serum phosphate, calcium, total cholesterol and glucose concentrations. RESULTS: Multivariate analysis revealed that RTRs homozygous for the minor allele (SS) of the A986S SNP, when compared to those homozygous for the major allele (AA), had raised serum glucose concentrations (8.7+/-5.4 vs. 5.7+/-2.1 mmol/L, P<0.05). In addition, RTRs who were heterozygous (CT) at the rs115759455 SNP, when compared to those homozygous for the major allele (CC), had higher serum phosphate concentrations (1.1+/-0.3 vs. 1.0+/-0.2 mmol/L, P<0.05). CASR SNPs were not significant determinants for aortic or coronary artery calcification, and were not associated with cardiovascular outcomes or mortality in this RTR cohort. CONCLUSIONS: Common CASR SNPs may be independent predictors of serum glucose and phosphate concentrations, but are not determinants of vascular calcification or cardiovascular outcomes. PMID- 25786246 TI - Serum phthalate levels and time to pregnancy in couples from Greenland, Poland and Ukraine. AB - Phthalates are ubiquitous industrial chemicals that have been associated with altered reproductive function in rodents. Several human studies have reported an inverse association between male testosterone and phthalate levels. Our aim was to investigate time to pregnancy (TTP) according to serum levels of diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) metabolites in both partners. In 2002-2004 we enrolled 938 pregnant women and 401 male spouses from Greenland, Poland and Ukraine. Six oxidized metabolites of DEHP and DiNP were summarized for each of the two parent compounds to provide proxies of the internal exposure. We used Cox discrete-time models to estimate fecundability ratios (FR) and 95% confidence intervals (95% CIs) for men and women according to their proxy-DEHP or -DiNP serum levels adjusted for a fixed set of covariates. The FR was slightly elevated among women with high levels of DEHP (FR=1.14, 95% CI 1.00;1.30) suggesting a shorter TTP in these women. The FR was unrelated to DiNP in women, whereas the results for men were inconsistent pointing in opposite directions. First-time pregnant women from Greenland with high serum DiNP levels had a longer TTP. This study spanning large contrast in environmental exposure does not indicate adverse effects of phthalates on couple fecundity. The shorter TTP in women with high levels of DEHP metabolites is unexplained and needs further investigation. PMID- 25786247 TI - Use of smokeless tobacco by Indian women aged 18-40 years during pregnancy and reproductive years. AB - OBJECTIVES: This paper discusses patterns of daily smokeless tobacco (SLT) use and correlates of poly SLT use among married women aged 18-40 years in a Mumbai slum community with implications for tobacco control. METHODS: Using a mixed methods approach, the study included a structured survey with 409 daily SLT users and in-depth interviews with 42 women. Participants for the survey were selected using a systematic sampling procedure (one woman in every fourth eligible household). Univariate and bivariate analysis, and multiple logistic regressions were conducted to identify demographic and social factors associated with women's use of poly SLT products. To illustrate survey results, in-depth interviews were analyzed using Atlas ti software. RESULTS: Sixty-four percent of the women surveyed used only one type of SLT; of these, 30% used mishri, 32% used pan with tobacco and the rest used chewed tobacco (11%), gul (17%) or gutkha (10%). Thirty six percent used more than one type of SLT. Poly SLT users chewed or rubbed 50% more tobacco as compared to single users (mean consumption of tobacco per day: 9.54 vs. 6.49 grams; p<0.001). Women were more likely to be poly SLT users if they were illiterate as compared to literate (adjusted odds ratio [AOR]=1.67; 95% confidence interval [CI]=1.07-2.71), if they had lived in Mumbai for 10 years or more, versus less than ten years (AOR=1.67, 95% CI=1.03-2.71); and if their husband was a poly SLT user as compared to a non SLT user (AOR=2.78, 95% CI=1.63 4.76). No differences were noted between pregnant and non-pregnant women in SLT consumption patterns. CONCLUSIONS: Tobacco control policies and programs must focus specifically on both social context and use patterns to address SLT use among women of reproductive age with special attention to poly SLT users, an understudied and vulnerable population. PMID- 25786248 TI - Scientific basis for use of Pyrus pashia Buch.-Ham. ex D. Don. fruit in gastrointestinal, respiratory and cardiovascular ailments. AB - BACKGROUND: Pyrus pashia Buch.-Ham. ex D. Don. has been used conventionally by many communities in the Himalayan region for the management of gastrointestinal, respiratory, and vascular complications. Set against this background, this study was carried out to justify the scientific basis to validate folkloric uses of fruits of Pyrus pashia Buch.-Ham. ex D. Don. (Pp.Cr) in traditional systems of medicine. METHODS: The crude ethanol extract of fruits of Pyrus pashia Buch.-Ham. ex D. Don. (Pp.Cr) was tested in vitro on isolated rabbit jejunum, tracheal, and aorta preparations. The responses of tissues were recorded using isotonic transducers coupled with a PowerLab data acquisition system. RESULTS: The Pp.Cr on application (0.01-5.0 mg/ml) to isolated rabbit jejunum preparation exhibited relaxation through decrease in magnitude and frequency of spontaneous contractions. The Pp.Cr also exerted a relaxant (0.01-5.0 mg/ml) effect on K+ (80 mM) induced contractions in isolated rabbit jejunum preparations and caused shifting of the Ca2+ curves (1.0-3.0 mg/ml) toward right in a manner similar to that of verapamil (3 MUM), possibly suggesting presence of Ca2+ channel blocking activity. Subsequently, Pp.Cr in a concentration-dependent fashion (0.01-10.0 mg/ml) caused relaxation of CCh (1 MUM) and K+ (80 mM) induced contractions in isolated rabbit tracheal preparations in a manner comparable to that of dicyclomine, suggesting that the observed relaxant effect is likely to be mediated through antimuscarinic and/or Ca2+ channel blocking activities. Moreover, when evaluated against isolated rabbit aortic preparations, the Pp.Cr in concentrations up to 10 mg/ml exhibited a contractile response that was found to be abolished subsequent to pretreatment of isolated tissue preparation with cyproheptadine (1 MUM), phentolamine (1 MUM), and losartan (1 MUM), suggesting that Pp.Cr may have some alpha-adrenergic, muscarinic, serotonergic, and angiotensin II activities. CONCLUSIONS: The aqueous ethanolic extract of Pyrus pashia (Pp.Cr) exhibited spasmolytic, bronchodilator, and vaso-constrictive activities possibly through different mechanisms. The spasmolytic and bronchodilator activities are likely to be mediated through blockade of Ca2+ channels, while vasoconstrictive activity may be due to presence of a alpha adrenergic, muscarinic, serotonergic, and angiotensin II agonistic component. PMID- 25786249 TI - The association between alcohol consumption patterns and health-related quality of life in a nationally representative sample of South Korean adults. AB - This study examined the relationship between alcohol consumption and health related quality of life (HRQOL) in a nationally representative sample of middle aged to older South Koreans. Data collected from 3,408 men and 3,361 women aged >= 40 years were obtained from the 2010 and 2011 Korea National Health and Nutrition Examination Survey. Based on the World Health Organization guidelines, the participants were categorized into zones I (0-7), II (8-15), III (16-19), or IV (20-40) according to their Alcohol Use Disorders Identification Test (AUDIT) scores, with a higher zone indicating a higher level of alcohol consumption. Data collected from the AUDIT and EuroQol 5-Dimension (EQ-5D) test were subjected to multiple regression analysis in order to examine the relationship between alcohol consumption patterns and health-related quality of life, and to identify intersex and interzone differences. Significant intersex differences were found for the mean total AUDIT and EQ-5D scores and the proportion of participants rating their pain/discomfort and impairment in mobility and usual activities as "moderate" or "severe" (p < 0.001). The analysis of the EQ-5D scores by alcohol consumption pattern and sex suggested the existence of an inverted U-shaped relationship between the total AUDIT and EQ-5D scores. The HRQOL of moderate alcohol drinkers was higher than that of non-drinkers and heavy drinkers. The results of this study will be valuable in designing appropriate interventions to increase the HRQOL impaired by the harmful use of alcohol, in comparing HRQOL among different countries, and in implementing alcohol-related health projects. PMID- 25786250 TI - Non-egalitarian allocations among preschool peers in a face-to-face bargaining task. AB - In face-to-face bargaining tasks human adults almost always agree on an equal split of resources. This is due to mutually recognized fairness and equality norms. Early developmental studies on sharing and equality norms found that egalitarian allocations of resources are not common before children are 5 or 6 years old. However, recent studies have shown that in some face-to face collaborative situations, or when recipients express their desires, children at much younger ages choose equal allocations. We investigated the ability of 3.5 and 5-year-olds to negotiate face-to-face, whether to collaborate to obtain an equal or an unequal distribution of rewards. We hypothesized that the face-to face interaction and interdependency between partners would facilitate egalitarian outcomes at both ages. In the first experiment we found that 5-year olds were more egalitarian than 3.5-year-olds, but neither of the age classes shared equally. In the second experiment, in which we increased the magnitude of the inequality, we found that children at both ages mostly agreed on the unequal distribution. These results show that communication and face-to-face interactions are not sufficient to guarantee equal allocations at 3-5 years of age. These results add to previous findings suggesting that in the context of non collaboratively produced resources it is only after 5 years of age that children use equality norms to allocate resources. PMID- 25786251 TI - The examination of the musculoskeletal system based only on the evaluation of pelvic-hip complex muscle and trunk flexibility may lead to failure to screen children for generalized joint hypermobility. AB - OBJECTIVE: The aim of the study was to evaluate whether the clinical assessment of the pelvic-hip complex muscle and trunk flexibility is sufficient for diagnosing generalized joint hypermobility (GJH). DESIGN: A cross-sectional study. SETTING: Center of Body Posture in Olsztyn, North East Poland. PARTICIPANTS: The study included 136 females and 113 males aged 10-13 years. MAIN OUTCOME MEASURES: In order to assess muscle flexibility, the straight leg raise (SLR) test (for hamstring) and modified Thomas test for one- (O-JHF) and two joint (T-JHF) hip flexors were performed. To evaluate trunk flexibility the fingertip-to-floor (FTF) and lateral trunk flexion (LTF) tests were used. The GJH occurrence was assessed with the use of nine-point Beighton scale (threshold value >=5 points for females, >=4 for males). The analysis was carried out separately for females and males. RESULTS: There were no significant differences between females with versus without GJH, and males with versus without GJH regarding SLR (p = 0.86, p = 0.19 for females and males, respectively), O-JHF (p = 0.89, p = 0.35 for females and males, respectively), T-JHF (p = 0.77, p = 0.4 for females and males, respectively), FTF (p = 0.19, p = 0.84 for females and males, respectively) and LTF (p = 0.58, p = 0.35 for females and males, respectively) tests results. CONCLUSIONS: Clinical examination of the pelvic-hip complex muscles and trunk flexibility by use of SLR, O-JHF, T-JHF, FTF and LTF revealed to be insufficient in diagnosing GJH in children aged 10-13 years. Thus, the Beighton scale should be considered a standard element of physiotherapeutic examination of the musculoskeletal system in children and youth. PMID- 25786253 TI - Artificial warthog burrows used to sample adult and immature tsetse (Glossina spp) in the Zambezi Valley of Zimbabwe. AB - BACKGROUND: The biology of adult tsetse (Glossina spp), vectors of trypanosomiasis in Africa, has been extensively studied - but little is known about larviposition in the field. METHODOLOGY/PRINCIPAL FINDINGS: In September November 1998, in the hot-dry season in Zimbabwe's Zambezi Valley, we used artificial warthog burrows to capture adult females as they deposited larvae. Females were subjected to ovarian dissection and were defined as perinatal flies, assumed to have entered burrows to larviposit, if oocyte sizes indicated >95% pregnancy completion. Perinatal flies were defined as full-term pregnant if there was a late third instar larva in utero, or postpartum if the uterus was empty. All other females were defined as pre-full-term pregnant (pre-FT). Of 845 G. m. morsitans captured, 91% (765) were female and 295/724 (41%) of females dissected were perinatal flies. By contrast, of 2805 G. pallidipes captured only 71% (2003) were female and only 33% (596/1825) of females were perinatal. Among all perinatal females 67% (596/891) were G. pallidipes. Conversely, in burrows not fitted with traps - such that flies were free to come and go - 1834 (59%) of pupae deposited were G. m. morsitans and only 1297 (41%) were G. pallidipes. Thus, while more full-term pregnant G. pallidipes enter burrows, greater proportions of G. m. morsitans larviposit in them, reflecting a greater discrimination among G. pallidipes in choosing larviposition sites. Catches of males and pre-FT females increased strongly with temperatures above 32 degrees C, indicating that these flies used burrows as refuges from high ambient temperatures. Conversely, catches of perinatal females changed little with maximum temperature but declined from late September through November: females may anticipate that burrows will be inundated during the forthcoming wet season. Ovarian age distributions of perinatal and pre-FT females were similar, consistent with all ages of females larvipositing in burrows with similar probability. CONCLUSIONS/SIGNIFICANCE: Artificial warthog burrows provide a novel method for collecting tsetse pupae, studying tsetse behaviour at larviposition, assessing the physiological status of female tsetse and their larvae, and of improving understanding of the physiological dynamics of terminal pregnancy, and population dynamics generally, with a view to improving methods of trypanosomiasis control. PMID- 25786252 TI - Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia. AB - IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation. PMID- 25786254 TI - Population regulation in Magellanic penguins: what determines changes in colony size? AB - Seabirds are often studied at individual colonies, but the confounding effects of emigration and mortality processes in open populations may lead to inappropriate conclusions on the mechanisms underlying population changes. Magellanic penguin (Spheniscus magellanicus) colonies of variable population sizes are distributed along the Argentine coastline. In recent decades, several population and distributional changes have occurred, with some colonies declining and others newly established or increasing. We integrated data of eight colonies scattered along ~600 km in Northern Patagonia (from 41 degrees 26'S, 65 degrees 01'W to 45 degrees 11'S, 66 degrees 30'W, Rio Negro and Chubut provinces) and conducted analysis in terms of their growth rates, production of young and of the dependence of those vital rates on colony age, size, and location. We contrasted population trends estimated from abundance data with those derived from population modeling to understand if observed growth rates were attainable under closed population scenarios. Population trends were inversely related to colony size, suggesting a density dependent growth pattern. All colonies located in the north--which were established during the last decades--increased at high rates, with the smallest, recently established colonies growing at the fastest rate. In central-southern Chubut, where colonies are the oldest, the largest breeding aggregations declined, but smaller colonies remained relatively stable. Results provided strong evidence that dispersal played a major role in driving local trends. Breeding success was higher in northern colonies, likely mediated by favorable oceanographic conditions. However, mean foraging distance and body condition of chicks at fledging were influenced by colony size. Recruitment of penguins in the northern area may have been triggered by a combination of density dependence, likely exacerbated by less favorable oceanographic conditions in the southern sector. Our results reaffirm the idea that individual colony trends do not provide confident indicators of population health, highlighting the need to redefine the scale for the study of population changes. PMID- 25786255 TI - Hygienisation and nutrient conservation of sewage sludge or cattle manure by lactic acid fermentation. AB - Manure from animal farms and sewage sludge contain pathogens and opportunistic organisms in various concentrations depending on the health of the herds and human sources. Other than for the presence of pathogens, these waste substances are excellent nutrient sources and constitute a preferred organic fertilizer. However, because of the pathogens, the risks of infection of animals or humans increase with the indiscriminate use of manure, especially liquid manure or sludge, for agriculture. This potential problem can increase with the global connectedness of animal herds fed imported feed grown on fields fertilized with local manures. This paper describes a simple, easy-to-use, low-tech hygienization method which conserves nutrients and does not require large investments in infrastructure. The proposed method uses the microbiotic shift during mesophilic fermentation of cow manure or sewage sludge during which gram-negative bacteria, enterococci and yeasts were inactivated below the detection limit of 3 log10 cfu/g while lactobacilli increased up to a thousand fold. Pathogens like Salmonella, Listeria monocytogenes, Staphylococcus aureus, E. coli EHEC O:157 and vegetative Clostridium perfringens were inactivated within 3 days of fermentation. In addition, ECBO-viruses and eggs of Ascaris suum were inactivated within 7 and 56 days, respectively. Compared to the mass lost through composting (15-57%), the loss of mass during fermentation (< 2.45%) is very low and provides strong economic and ecological benefits for this process. This method might be an acceptable hygienization method for developed as well as undeveloped countries, and could play a key role in public and animal health while safely closing the nutrient cycle by reducing the necessity of using energy-inefficient inorganic fertilizer for crop production. PMID- 25786256 TI - Anomalous gray matter structural networks in patients with hepatitis B virus related cirrhosis without overt hepatic encephalopathy. AB - BACKGROUND AND PURPOSE: Increasing evidence suggests that cirrhosis may affect the connectivity among different brain regions in patients before overt hepatic encephalopathy (OHE) occurs. However, there has been no study investigating the structural reorganization of these altered connections at the network level. The primary focus of this study was to investigate the abnormal topological organization of the structural network in patients with hepatitis B virus-related cirrhosis (HBV-RC) without OHE using structural MRI. METHODS: Using graph theoretical analysis, we compared the global and regional topological properties of gray matter structural networks between 28 patients with HBV-RC without OHE and 30 age-, sex- and education-matched healthy controls. The structural correlation networks were constructed for the two groups based on measures of gray matter volume. RESULTS: The brain network of the HBV-RC group exhibited a significant decrease in the clustering coefficient and reduced small-worldness at the global level across a range of network densities. Regionally, brain areas with altered nodal degree/betweenness centrality were observed predominantly in association cortices (frontal and temporal regions) (p < 0.05, uncorrected), including a significantly decreased nodal degree in the inferior temporal gyrus (p < 0.001, uncorrected). Furthermore, the HBV-RC group exhibited a loss of association hubs and the emergence of an increased number of non-association hubs compared with the healthy controls. CONCLUSION: The results of this large-scale gray matter structural network study suggest reduced topological organization efficiency in patients with HBV-RC without OHE. Our findings provide new insight concerning the mechanisms of neurobiological reorganization in the HBV-RC brain from a network perspective. PMID- 25786257 TI - Spatial, temporal, and density-dependent components of habitat quality for a desert owl. AB - Spatial variation in resources is a fundamental driver of habitat quality but the realized value of resources at any point in space may depend on the effects of conspecifics and stochastic factors, such as weather, which vary through time. We evaluated the relative and combined effects of habitat resources, weather, and conspecifics on habitat quality for ferruginous pygmy-owls (Glaucidium brasilianum) in the Sonoran Desert of northwest Mexico by monitoring reproductive output and conspecific abundance over 10 years in and around 107 territory patches. Variation in reproductive output was much greater across space than time, and although habitat resources explained a much greater proportion of that variation (0.70) than weather (0.17) or conspecifics (0.13), evidence for interactions among each of these components of the environment was strong. Relative to habitat that was persistently low in quality, high-quality habitat buffered the negative effects of conspecifics and amplified the benefits of favorable weather, but did not buffer the disadvantages of harsh weather. Moreover, the positive effects of favorable weather at low conspecific densities were offset by intraspecific competition at high densities. Although realized habitat quality declined with increasing conspecific density suggesting interference mechanisms associated with an Ideal Free Distribution, broad spatial heterogeneity in habitat quality persisted. Factors linked to food resources had positive effects on reproductive output but only where nest cavities were sufficiently abundant to mitigate the negative effects of heterospecific enemies. Annual precipitation and brooding-season temperature had strong multiplicative effects on reproductive output, which declined at increasing rates as drought and temperature increased, reflecting conditions predicted to become more frequent with climate change. Because the collective environment influences habitat quality in complex ways, integrated approaches that consider habitat resources, stochastic factors, and conspecifics are necessary to accurately assess habitat quality. PMID- 25786259 TI - Bayesian inference on proportional elections. AB - Polls for majoritarian voting systems usually show estimates of the percentage of votes for each candidate. However, proportional vote systems do not necessarily guarantee the candidate with the most percentage of votes will be elected. Thus, traditional methods used in majoritarian elections cannot be applied on proportional elections. In this context, the purpose of this paper was to perform a Bayesian inference on proportional elections considering the Brazilian system of seats distribution. More specifically, a methodology to answer the probability that a given party will have representation on the chamber of deputies was developed. Inferences were made on a Bayesian scenario using the Monte Carlo simulation technique, and the developed methodology was applied on data from the Brazilian elections for Members of the Legislative Assembly and Federal Chamber of Deputies in 2010. A performance rate was also presented to evaluate the efficiency of the methodology. Calculations and simulations were carried out using the free R statistical software. PMID- 25786258 TI - Drug synergy drives conserved pathways to increase fission yeast lifespan. AB - Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms. PMID- 25786260 TI - The potential distribution of invading Helicoverpa armigera in North America: is it just a matter of time? AB - Helicoverpa armigera has recently invaded South and Central America, and appears to be spreading rapidly. We update a previously developed potential distribution model to highlight the global invasion threat, with emphasis on the risks to the United States. The continued range expansion of H. armigera in Central America is likely to change the invasion threat it poses to North America qualitatively, making natural dispersal from either the Caribbean islands or Mexico feasible. To characterise the threat posed by H. armigera, we collated the value of the major host crops in the United States growing within its modelled potential range, including that area where it could expand its range during favourable seasons. We found that the annual value of crops that would be exposed to H. armigera totalled approximately US$78 billion p.a., with US$843 million p.a. worth growing in climates that are optimal for the pest. Elsewhere, H. armigera has developed broad-spectrum pesticide resistance; meaning that if it invades the United States, protecting these crops from significant production impacts could be challenging. It may be cost-effective to undertake pre-emptive biosecurity activities such as slowing the spread of H. armigera throughout the Americas, improving the system for detecting H. armigera, and methods for rapid identification, especially distinguishing between H. armigera, H. zea and potential H. armigera x H. zea hybrids. Developing biological control programs, especially using inundative techniques with entomopathogens and parasitoids could slow the spread of H. armigera, and reduce selective pressure for pesticide resistance. The rapid spread of H. armigera through South America into Central America suggests that its spread into North America is a matter of time. The likely natural dispersal routes preclude aggressive incursion responses, emphasizing the value of preparatory communication with agricultural producers in areas suitable for invasion by H. armigera. PMID- 25786261 TI - ADAMTS expression in colorectal cancer. AB - ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). By acting on a large panel of extracellular substrates, they control several cell functions such as fusion, adhesion, proliferation and migration. Through their thrombospondin motifs they also possess anti-angiogenic properties. We investigated whether ADAMTSs participate in colorectal cancer progression and invasion. Their expression was investigated at both mRNA and protein levels. Using RT-PCR, the expression of ADAMTS-1, -4, -5 and ADAMTS-20 was estimated in colorectal tumors of different cancer stage and anatomic site and 3 cell lines of different aggressiveness. An overexpression of ADAMTS-4 and -5 was observed, especially in tissue samples, whereas ADAMTS-1 and -20 were found to be down-regulated. Western blot analysis further supported the RT-PCR findings, revealing in addition the degradation of ADAMTS-1 and -20 in cancer. In situ expression and localization of ADAMTS-1, -4, 5 and -20 was also investigated by immunohistochemical analysis. Our data suggest a positive correlation between ADAMTS-4 and -5 expression and cancer progression, in contrast with the anti-angiogenic members of the family, ADAMTS-1 and -20, which were found to be down-regulated. Our findings support the notion that overexpression of ADAMTS-4 and ADAMTS-5 in colorectal cancer might be a possible invasive mechanism of cancer cells in order to degrade proteoglycans of ECM. PMID- 25786263 TI - GPU-accelerated compartmental modeling analysis of DCE-MRI data from glioblastoma patients treated with bevacizumab. AB - The compartment model analysis using medical imaging data is the well-established but extremely time consuming technique for quantifying the changes in microvascular physiology of targeted organs in clinical patients after antivascular therapies. In this paper, we present a first graphics processing unit-accelerated method for compartmental modeling of medical imaging data. Using this approach, we performed the analysis of dynamic contrast-enhanced magnetic resonance imaging data from bevacizumab-treated glioblastoma patients in less than one minute per slice without losing accuracy. This approach reduced the computation time by more than 120-fold comparing to a central processing unit based method that performed the analogous analysis steps in serial and more than 17-fold comparing to the algorithm that optimized for central processing unit computation. The method developed in this study could be of significant utility in reducing the computational times required to assess tumor physiology from dynamic contrast-enhanced magnetic resonance imaging data in preclinical and clinical development of antivascular therapies and related fields. PMID- 25786262 TI - Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. AB - INTRODUCTION: Subjective memory complaints are common with aging. Docosahexaenoic acid (DHA; 22:6 n-3) is a long-chain polyunsaturated fatty acid (LCPUFA) and an integral part of neural membrane phospholipids that impacts brain structure and function. Past research demonstrates a positive association between DHA plasma status/dietary intake and cognitive function. OBJECTIVES: The current meta analysis was designed to determine the effect of DHA intake, alone or combined with eicosapentaenoic acid (EPA; 20:5 n-3), on specific memory domains: episodic, working, and semantic in healthy adults aged 18 years and older. A secondary objective was to systematically review/summarize the related observational epidemiologic literature. METHODS: A systematic literature search of clinical trials and observational studies that examined the relationship between n-3 LCPUFA on memory outcomes in healthy adults was conducted in Ovid MEDLINE and EMBASE databases. Studies of subjects free of neurologic disease at baseline, with or without mild memory complaints (MMC), were included. Random effects meta analyses were conducted to generate weighted group mean differences, standardized weighted group mean differences (Hedge's g), z-scores, and p-values for heterogeneity comparing DHA/EPA to a placebo. A priori sub-group analyses were conducted to evaluate the effect of age at enrollment, dose level, and memory type tested. RESULTS: Episodic memory outcomes of adults with MMC were significantly (P<.004) improved with DHA/EPA supplementation. Regardless of cognitive status at baseline, > 1 g/day DHA/EPA improved episodic memory (P<.04). Semantic and working memory changes from baseline were significant with DHA but no between group differences were detected. Observational studies support a beneficial association between intake/blood levels of DHA/EPA and memory function in older adults. CONCLUSION: DHA, alone or combined with EPA, contributes to improved memory function in older adults with mild memory complaints. PMID- 25786265 TI - The cloudy future of science publishing. PMID- 25786264 TI - Effects of prolonged hypertrophic resistance training on acute endocrine responses in young and older men. AB - The present study investigated changes in acute serum hormone responses to a resistance exercise bout following a prolonged period of hypertrophic resistance training in young (YM) and older men (OM). Subjects performed a 5 * 10RM leg press exercise protocol before and after 20 weeks of hypertrophic resistance training. In YM, the acute responses in growth hormone were greater compared with before training (p < .05), and cortisol concentration did not increase after training. Endocrine responses in OM were similar before and after training. Greater acute growth hormone responses after training were associated with larger gains in lean mass in the entire subject group (r = .596, p = .019). These findings suggest that, in general, YM demonstrate greater adaptability within the endocrine system compared with OM. However, adaptability in growth hormone response was associated with larger training-induced gains independent of age. PMID- 25786266 TI - [Fatal castleman disease complicated of hemophagocytic syndrome]. PMID- 25786267 TI - [Topographic features of lingual nerve and incidence of its injury by lower third molars extraction]. PMID- 25786268 TI - [The role of occlusal disorders in development of temporomandibular joint dysfunction]. AB - Currently Temporomandibular joint (TMJ) dysfunction is a very highly discussed topic by both researchers and clinicians. the incidence of the of TMJ is dysfunctions still not very well established because of heterogeneity of the diagnostic criteria used by different authors. This article is dedicated to the analysis of basic theories of the etiology of the aforementioned pathology, including overview of main pathophysiological mechanisms of the TMJ, dysfunctions occlusive disorders in particular. The main problem being analyzed is the use and efficacy of the electronic axiography in successful diagnostic and therapy of the TMJ dysfunction. PMID- 25786269 TI - [Effect of mouth breathing on the severity of morphological and functional changes of dental system in patients with otolaryngologic pathology]. AB - The study included 282 patients aged 5 to 14 years with pathology of the pharyngeal tonsil. Diagnostic algorithm is presented. The study results allowed elaboration of complex rehabilitation of nasal breathing and miodynamic equilibrium in the maxillofacial region by means of elastopositioner. PMID- 25786270 TI - [Diagnostics and treatment of patients with II class malocclusion associated with obstructive sleep apnea syndrome]. PMID- 25786271 TI - [The analysis of the structure, types and volumes of dental care provided to adults with tongue disorders by obligatory medical insurance program]. AB - This article presents the data about the structure, the types and volumes of dental care provided to adults with tongue disorders by obligatory medical insurance program. The study showed that treatment of tongue disorders in conditions of the municipal dental polyclinic is practically not carried out. There are 7 types of services provided to patients with these disorders, and only 3 of them could be attributed to treatment manipulations. PMID- 25786274 TI - Etymologia: Bonferroni correction. PMID- 25786275 TI - Cubism and research synthesis. PMID- 25786276 TI - [Surgical treatment of hyperparathyroidism]. PMID- 25786277 TI - [Tumor recurrence after surgical treatment of colon cancer]. PMID- 25786278 TI - [Cardiac surgery in patients of elderly and senile age]. PMID- 25786279 TI - [Academician of the academy of medical sciences of the USSA A.V. Vishnevskiy (1874 - 1948) and his contribution into Russian surgery (by the 140th anniversary of his birth)]. PMID- 25786280 TI - [Professor Nicholaj Safronovich Makokha (by the 100th anniversary of his birth)]. PMID- 25786281 TI - [Clinical investigations of innovative technologies of pancreatic cancer treatment]. PMID- 25786282 TI - [Robot-assisted liver surgery]. PMID- 25786283 TI - [Choice of diaphragm plasty for acquired relaxation with evidence-based medicine]. PMID- 25786284 TI - [Neck injuries]. PMID- 25786285 TI - Communication between general practitioners and radiologists: opinions, experience, promises, pitfalls. AB - PURPOSE: Studies encompassing the views and aspirations of general practitioners (GPs) concerning the radiology report are rare. We present the results of a large scale survey among GPs in Flanders, Belgium, and examine its implications for the communication between radiologists and GPs. MATERIALS AND METHODS: GPs were invited by e-mail to participate in a survey on the radiology report. Respondents could state their degree of agreement with 46 statements. Besides that, they could freely make suggestions to improve the report. Quantitative results were examined to determine majority convictions. Free text suggestions were searched for motives and convictions. RESULTS: Of 1323 GPs invited, 282 completed forms were prepared for analysis. 96.8% considered the report an indispensable tool. 85.5% were satisfied with it. Itemized reporting of complex examinations was favoured by a very large majority. 83 GPs (29.4%) made suggestions for improvement. Much emphasis was put upon the clinical role of the radiologist. The need to mark key images, to mention meaningful normal findings, to structure the report and to facilitate communication was also frequently mentioned. CONCLUSION: GPs expect the radiologist to think as a clinician and offer clinical answers. An automated electronic information chain may contribute to realize this objective but direct communication should always remain possible. PMID- 25786286 TI - Comparative Doppler flow measurements of the ulnar artery and of the postanastomotic radial artery in radiocephalic arteriovenous fistulas to detect steal syndromes. AB - OBJECTIVE: This study aims to assess whether a comparison of the Doppler flow measurements of the ulnar artery and of the postanastomotic radial artery can help detect steal syndromes at the level of native dialysis fistulas of the wrist. PATIENTS AND METHODS: We have prospectively analyzed 35 distal radiocephalic arteriovenous fistulas presenting with postanastomotic radial artery Doppler inversion of flow. The flows of the ulnar artery and of the postanastomotic radial artery have been measured and compared. Subsequent clinical examination to detect any sign of ischemia at the hand level was performed and the results of medical imaging were confronted with the clinical data. RESULTS: A steal syndrome was discovered in a total of 6 patients (17%), 4 patients out of 23 displaying an ulnar flow lower than the postanastomotic radial one and 2 patients among 12 with an ulnar flow higher than the radial one. Sensitivity, specificity, positive predictive value and negative predictive value of the test were 67%, 34%, 17% and 83%, respectively. Paradoxically, the mean intensity of ulnar flow deficiency has been measured at 40% among true positive patients and at 70% among false positive ones. We have not been able to identify any difference, be it in terms of systolic upstroke time, maximum systolic speed, telediastolic speed or in terms of global architecture of the curves between the Doppler waveforms of 4 true positive and 4 false positive patients. CONCLUSION: The comparative Doppler study of the flows of the ulnar and postanastomotic radial arteries does not enable us to detect steal syndromes at the level of wrist dialysis fistulas. Hence we consider that a systematic study of the postanastomotic radial artery flow, during routine Doppler examination of distal dialysis fistulas, proves superfluous. PMID- 25786287 TI - Endovenous laser ablation treatment with 980 nm diode laser for saphenous vein insufficiency: 6 months follow up results. AB - OBJECTIVE: Superficial venous insufficiency is a common problem associated with varicose veins which, if untreated, may progress to venous ulceration. Endovenous laser ablation (EVLA) is a new, minimally invasive method for management of superficial venous insufficiency and varicose veins. The aim of this study was to demonstrate the effectiveness of 980 nm EVLA for treatment of symptomatic saphenous venous insufficiency and to present its early outcomes. METHODS: Thirty eight great saphenous veins and 5 small saphenous veins in 40 patients with saphenofemoral reflux were treated with 980 nm diode endovenous laser equipment. The diameter and length of the vein treated, total laser energy and energy density (Joules/cm) delivered were recorded. To determine the severity of the venous disease Venous Clinical Severity Score (VCSS) and Visual Analogue Scale (VAS) were used. Patients were followed up for 6 months after the procedure. Complications were recorded prospectively. RESULTS: Forty-three saphenous veins in 40 patients were treated. The mean age of the patients was 39.9 (range 21-72) years. The mean diameter and length of the veins were 4.9 mm (range, 3.5 to 8.5 mm) and 30.2 cm (range, 16 to 50 cm), respectively. At 6 months follow-up, total occlusion rate was 95.4% (41/43), and recanalization rate was 4.6%. Significant decrease was observed for VCSS and VAS scores after the procedure. No major complication was detected. CONCLUSION: EVLA treatment for superficial venous insufficiency is safe and can be carried out under local anaesthesia in an outpatient setting with good patient satisfaction and low complication rates. PMID- 25786288 TI - The effectiveness of whole body magnetic resonance imaging (diffusion-weighted imaging and fat saturated T2-weighted imaging) in the evaluation of patients with newly diagnosed malignancies in comparison with positron emission tomography computed tomography. AB - PURPOSE: To evaluate the effectiveness of WB-MRI for the detection of primary and metastatic lesions in comparison to PET-CT in patients with newly diagnosed malignancies MATERIAL AND METHODS: In this prospective study, 36 patients were evaluated between August 2008 and October 2012. The findings of WB-MRI (DWI and fat saturated T2 weighted images) were compared to the findings of PET-CT re- garding the primary lesions and metastasis. Sensitivity, specificity, positive and negative predictive values were calculated. To assess the aggreement between PET-CT and WB-MRI, kappa analysis was performed. RESULTS: The sensitivity, specificity, positive and negative predictive values for WB-DWI for the detection of primary and metastatic lesions in comparison to PET-CT were 96%, 89%, 97% and 84%, respectively. These are calculated as 96%, 56%, 90% and 77%, for fat saturated T2W images. According to kappa analysis, the agreement between PET-CT and WB-DWI was excellent (chi = 0.83), but between PET-CT and fat-saturated T2 weighted images, it was moderate (chi = 0.58). CONCLUSION: Providing both morphogical and functional data, WB-MRI with DWI is emerging as a promising alternative imaging tool in the evaluation of cancer patients and may become complementary to PET-CT in several clinical applications. PMID- 25786289 TI - Intramedullary lipoma of the cervico-thoracic spinal cord. AB - Most of the spinal cord lipomas reported in the literature are intradural extramedullary, and true intramedullary lipomas are very rare. We present a case of intramedullary spinal cord lipoma of the cervico-thoracic region with extensions over many spinal segments. Magnetic resonance (MR) examination showed an intramedullary lipoma of the cervico-thoracic spinal cord of both high T1 and T2-weighted signal intensity and suppression on fat saturation sequence. MR imaging assessment is critical in the detection of intramedullary lipomas which may present without any neurological deficit at an early stage. Early diagnosis may lead to prevention of the irreversible deterioration of neurological functions. PMID- 25786290 TI - A case of a rare aortic arch variation: the avian form. AB - Variations in the branching pattern of the aortic arch are multiple. The avian form is an extremely rare anatomical variation with only a few reported cases in the literature. Herein we report a case of avian variation with two branches arising from the aortic arch: a bicarotid trunk and a common origin for bilateral subclavian arteries. PMID- 25786291 TI - The role of magnetic resonance imaging in the prenatal management of a lymphatic malformation. AB - We report the magnetic resonance imaging (MRI) findings in a case of extensive fetal lymphatic malformation involving the upper left arm and axillo-thoraco abdominal wall found on routine prenatal ultrasound (US) examination at 22 weeks of gestation. MRI clearly reveals the tumor extent and tissue characteristics, and thick-slab T2-weighted MRI has the capacity to provide more information on the cystic lesion on global overview. PMID- 25786292 TI - Radiologic diagnosis of a type-III pleuropulmonary blastoma. AB - Pleuropulmonary blastoma (PPB) is a rare and aggressive dysontogenic neoplasm, occurring in children under the age of 6 years in most cases. CT and MRI findings are well-known, a mixed solid and cystic lesion with variable contrast enhancement and a necrotic centre. We report the radiologic features of type III PPB case. PMID- 25786293 TI - Aortopulmonary window: a rare congenital heart disease. AB - We report the case of a 3,5 month-old infant presented at cardiology consultation of our institution for investigation of a heart murmur associated with failure to thrive and respiratory distress. Echocardiogram showed dilatation of left heart cavities, patent foramen ovale, small muscular ventricular septal defect and pulmonary hypertension. Angio-CT was performed on a 64-slice CT to better characterize the congenital heart disease. Aortopulmonary window was diagnosed and surgically corrected. Patient evolution was good with discharge 10 days after surgery. The authors review the literature and stress the importance of angio-CT in pre-operative evaluation. PMID- 25786294 TI - Extensive myelitis after oral polio vaccination: MRI features. AB - A 7-year-old boy presented with fever and ataxia 20 days after oral polio vaccination. Magnetic resonance imaging showed extensive myelitis, involving both anterior and posterior horns of the gray matter. Complete posttreatment recovery was evident. Postvaccinal myelitis after oral polio vaccination, of either infectious or immune mediated etiology, is very rare entity that should be promptly recognized in order to initiate adequate treatment. PMID- 25786295 TI - Spontaneous life-threatening hemobilia during acute liver failure successfully treated with transarterial embolization. AB - A 28-year-old patient admitted with jaundice, vomiting and deteriorating coagulopathy was diagnosed with acute liver failure. After listing for urgent transplantation, he developed Boerhaave's syndrome and massive hemobilia, two life-threatening complications. Massive hemobilia secondary to a fistula between the right hepatic artery and the right bile duct occurred several days after transjugular biopsy and was controlled with fluid resuscitation, transfusion and arterial embolization. Two days later he was transplanted successfully, and is currently doing well after more than 72 months. Aggressive treatment of potentially reversible complications during acute liver failure whilst awaiting transplantation is mandatory to allow survival of these patients. PMID- 25786296 TI - Giant perivascular spaces: utility of MR in differentiation from other cystic lesions of the brain. AB - Perivascular or Virchow-Robin spaces (VR) of the brain are fluid-filled, pial lined spaces that accompany the cerebral vessels as they pass from subarachnoid space into the brain parenchyma. They are visualized on routine MR examinations as CSF intensity spaces and are normally < 2 mm in size. These spaces may rarely enlarge massively and can be mistaken for more ominous pathologic processes on CT scan and even on MRI, but careful examination on special sequences and follow-up examination can clear the uncertainty. We describe a case of a young male who presented with mildly progressive neurological symptoms and the imaging findings were typical of enlarged VR spaces. Patient was advised follow up and is doing well. PMID- 25786297 TI - Mass-forming intrahepatic cholangiocarcinoma presenting with painful obstructive hemobilia. AB - We report a very rare case of acute obstructive hemobilia caused by bleeding of a mass-forming intrahepatic cholangiocarcinoma in a 75-year old man. The prompt complete emergency diagnosis was made by ultrasound and confirmed by MDCT. The features of hemobilia and intrahepatic cholangiocarcinoma are briefly reviewed. PMID- 25786298 TI - Multiple calcified nodules in pulmonary amyloidosis. PMID- 25786299 TI - A rare cause of posterolateral elbow pain: radio- humeral plica syndrome with typical MRI findings. PMID- 25786300 TI - Rasmussen aneurysm. PMID- 25786301 TI - Traumatic avulsion of the trochanter minor in a 15-year-old boy: an uncommon injury. PMID- 25786302 TI - Incidentally discovered optic nerve head drusen. PMID- 25786303 TI - Eosinophilic cystitis mimicking bladder tumor. PMID- 25786304 TI - Focal autoimmune pancreatitis. PMID- 25786305 TI - Frontotemporal lobar dementia in a young woman. PMID- 25786306 TI - An unusual complication of ureteral double-J stent placement: ureteral perforation. PMID- 25786307 TI - Misplacement of ephrostomy tube into the inferior vena cava after percutaneous nephrolithotomy. PMID- 25786308 TI - [Super-species genetic systems]. AB - Genetic integration of diverse organisms results in generation of three types of the super-species systems of heredity: metagenome (set of genetic factors of the microbial community which occupies a certain ecological niche), symbiogenome (functionally integrated system of the partners' symbiotic genes) and hologenome (entire hereditary system of a symbiotically originated organism). The integrity of metagenome is based on the cross-regulation and horizontal transfer of genes in co-evolving organisms which in the soil microbial communities are accompanied by maintenance of the stable extracellular DNA pool. Formation of symbiogenome is related to the highly specific partners' signaling interactions which are responsible for development of the joint metabolic pathways based on the specialized cellular and tissue structures. Transitions of symbiogenome into hologenome are due to the endosymbiotic gene transfer from microsymbionts to their hosts. In symbiotic bacteria, these transitions are coupled with establishments of multi-component, reduced and rudimentary genomes revealed for the ecologically obligatory symbionts, genetically obligatory symbionts, and cellular organelles, respectively. Their evolution is related to the stringency of transmission of microsymbionts by hosts increased from pseudo-vertical (via environment) to the trans-embryonic (via embryos and the surrounding tissues) and trans-ovarian transmission (via germ cells) which are culminated in the cytoplasmic inheritance of cellular organelles. We suggest the hypothesis about generation of endophytic plant symbiogenome on the basis of soil metagenome subjected to the control of host by its involvement into the quorum sensing auto regulation of microbial community. PMID- 25786309 TI - [What's wrong with "development of isolating mechanisms" (and its special case in form of "reinforcement")?]. AB - Examined are the conceptual grounds of the "reinforcement" model that play an important role in explanatory schemes of the theory of evolution. According to the current views, reinforcement (of obstacles for crossing under natural selection when there occurs a repeated contact with hybridization between two substantially divergent forms, up to the level where started hybridization is terminated and the forms become unable to cross) should be a common or even frequent phenomenon. In fact, reinforcement turns out to be a rare event needed to be specially searched for, all such events are dubious, etc. Here, empirical data on reinforcement pro and contra are analyzed, using mostly ornithological (and some other zoological) materials. It is shown that in most cases where the theory predicts reinforcement to occur, it does not happen. On the contrary, something quite opposite is observed--selection for non-crossing enhancement does not stop up the leaks in gene pools of the forms that are due to their hybridization within the zone of a repeated contact, but instead the stable hybrid zone is established which serve as a conduit for gene exchange between the forms. Through hybridization, those forms can adopt strange genes, remaining, at that, their isolation at the level of separate species. This is achieved through the system of self-non-self recognition in population system of both forms being in contact. Within the zone of a repeated contact, conditions are usually such that individuals repeatedly make mistakes forming mixed pairs and producing hybrids, i.e., at the level of individuals, self-non-self recognition is often inefficient, especially at the range edges, in zone of repeated contact and such. Efficient recognition, that ensures species separateness even under conditions of continuing hybridization, takes place upon inclusion of individuals of different origin--phenotypically 'pure' ones, hybrids, and backcrosses--into spatio ethologic population structure of both forms, upon acquisition of territories by established groups, their inclusion in flocks and other intra-population associations of resident individuals. At that, groups of both forms predominantly incorporate their 'own' ('pure') phenotypes and reject 'strange' ones, including hybrids of intermediate phenotype. If the forms have attained the species level of separateness, hybrids do not form their own stable groups, but try to individually inset themselves into the habitation of both parents, which turns out to be not so successful as compared with phenotypically 'pure' individuals of the given form. Thereby, hybrids happen to be directly excluded from the population system of both forms even if hybridization goes on and produces them in sufficient quantity while hybrids and backcrosses themselves are not inferior to 'pure' individuals either in survivorship or reproductive success (those ones who became residents have occupied a territory and are reproducing). It is shown that usual examples of reinforcement are not only sparse but could be explained differently. Particularly, 'splitting up' of a population system which gives rise to two forms of different ecology with following strengthening/enhancement of the divergence through sexual selection is better explained by our model of self-non self recognition than by reinforcement. Relying on this concept, the conclusion is drawn that the model of non-crossing 'reinforcement' in zones of a repeated contact with hybridization is not supported by the data, as well as the model of character displacement that follows from it. Apparently, the reasons behind its popularity consist in conformity with the 'ideology' of a more general theory that is agreed upon by most researchers, and corresponds, in whole, to known facts (in this case, the theory of modern evolutionary synthesis). PMID- 25786310 TI - [Population dynamics of thrushes and seasonal resource partition]. AB - We studied seasonal population dynamics in birds using four thrush species from the Yenisei middle taiga region as an example. Long-term data on bird route censuses, capture-mark-recapture, and nest observa- tions were incorporated in the analysis. Particularly, methodological problems that complicate a direct comparison between assessed numbers at different phases of the annual cycle are considered. The integrated analysis of the results allowed comparing changes in numbers, energy expenditure, age structure, migrating status, and density distribution of selected populations during the snowless period and relating them to seasonal changes in food resource abundance. Thrush population numbers within the breeding range, and their energy consumption in the Yenisei middle taiga proportionately reflect the seasonal change in abundance of food resources. The compliance between resource intake and carrying capacity of the environment is attained by: timing of arrival and departure regarding to the species' range of tolerance; change in numbers as a result of reproduction and mortality; change in numbers due to habitat changes and long-distance movements; increasing energetic expenditures during reproduction and molt; timing, intensity and replication of nesting attempts; timing of molt and proportion of molting individuals in a population; individual variations of the annual cycle. Reproductive growth of local bird populations is not fast enough to catch up with seasonal growth of ecosystems productivity. Superabundance of invertebrates at the peak of the season offers a temporal niche which, on the one hand, is suitable for species capable of diet switching, while, on the other hand, may be used by specialized consumers, namely tropical migrants for whom, at high resource level, a shortened breeding period suffices. PMID- 25786311 TI - [Major histocompatibility complex (MHC) in mammals' and its importance for studies of rare species (with Felidae family as an example)]. AB - Major histocompatibility complex (MHC) appears to be a suitable tool for solving various tasks of popu- lationgenetics. Information on genetic basis of immunity facilitates understanding of evolutionary his- tory and assessment of current state and prospects of studied population/species survival. On the one hand, MHC variability is maintained through pathogen dependent mechanisms, i.e., directional selection of individuals resistant to diseases, that are present in the environment and balancing selection which gives advantage to those individuals carrying unusual or rare alleles of MHC genes. On the other hand, MHC genes have an influence on reproduction efficiency of individuals. Because of MHC polygeny, its studying requires an application of methods that introduce additional stages between amplification of a certain gene segment and its sequencing. In the article, different tech- niques of allele separation are considered, as well as a simplified version of MHC variability analysis based on the examination of microsatellite loci. Despite the high information value of MHC, it is still not used in zoological studies as often as it deserves. Using as an example predatory mammals of Felidae family which contains quite a few threatened species, we show that a majority of studies on MHC in wild cats is descriptive ones and only few of them deal with genes comparative analysis. The rise of interest to the studies of major histocompatibility complex in non-model species may help not only in solving the fundamental problems of evolution and phylogenetic structure of the family but also in planning the measures for conservation of rare and endangered species exposed to various anthropogenic stresses. PMID- 25786313 TI - [Review of: V.G. Onipchenko "Functional Phytocenology: Synecology of Plants"]. PMID- 25786312 TI - [Age of maturity in alpine herbaceous perennials, the North-West Caucasus]. AB - Sod transplantation experiment was carried out for 24 years in alpine communities, Teberda Reserve, the North-West Caucasus, Russia. Age of maturity (AOM) was estimated as a period between first registra- tion of a species on.a permanent plot and flowering shoot appearance. Mean species AOM varied from 2.3 years (Antennaria dioica with clonal propagation) to 13.7 years for Taraxacum stevenii (non-clonal plant). General gradient of alpine plant traits and population strategies was determined. It represents a continuum ranging from ruderal--stress-tolerants (shorter AOM, clonality, shorter leaf life span, low rate of mycorrhizal infection, low regrowth ability, low generative shoot number, low specific leaf area and leaf nitrogen content) to competitor--stress-tolerants (longer AOM, longer leaf life span, higher rate of mycorrhizal infection, higher regrowth ability, high generative shoot number, high specific leaf area and leaf nitrogen content). PMID- 25786314 TI - [Development of sociality in the superfamily of bees (Hymenoptera, Apoidea)]. AB - Regularities of the appearance of family have been analyzed in the superfamily of bees. It is shown that conversion of family in the highly organized eusocial bee species into the biological unit is coupled to perfection of instincts of care of offspring of the female-founderess and to an increase its lifespan duration at enhancement of various forms of domination. There is substantiated the concept that development of offspring of the dominating females under similar conditions ruling out intranest competition as well as enhancement of interconnection and interdependence between members of the family has led to the appearance of family selection. PMID- 25786315 TI - [Catecholaminergic neurons of mammalian brain and neuromelanin]. AB - Brain catecholaminergic neurons belong to the most extensively studied populations of nerve cells. Presence of a pigment neuromelanin in their cytoplasm is a specific morphological feature of these neurons in many mammalian species. Elucidation of the role of neuromelanin is of importance for comparative neurobiology, as it is absent in neurons of another neurotransmitter systems and, moreover, even in catecholaminergic neurons of some laboratory animals, which limits the possibility of experimental verification of existing hypotheses of its functions under physiological and pathological conditions. For recent years, neuromelanin is an object of particular interest in the scientific community involved in research of neurotoxicity and modeling the Parkinson's disease. The present review summarizes and analyzes new data on the structure and functions of neuromelanin and its probable role in pathogenesis of Parkinson's disease is discussed. PMID- 25786316 TI - [Adaptive reactions of lipid metabolism in native and alien female representatives of Tofalaria population living under extreme environmental conditions]. AB - Peculiarities of the state of lipid metabolism and of processes of lipid peroxidation--the antioxidant protection have been considered in female representatives of the native and alien population of Tofalaria in the age aspects. The obtained data indicate specificity of changes of level of parameters lipid metabolism not only in response to duration of effect of climatic factors, but also depending on belonging to different ethnic groups. Thus, in girls of the natural population of Tofalaria there is noted activation of adaptational compensatory processes as compared with the alien ones, which is expressed as a significant decrease of atherogenic blood fractions and the general activation of the system of antioxidant protection. However, with age, in both ethnic groups a change of character of reactions of lipid peroxidation and lipid metabolism is noted, which is more expressed in the alien population. PMID- 25786317 TI - [Attenuation of inhibitory influence of hormones on adenylyl cyclase systems in the myocardium and brain of rats with obesity and type 2 diabetes mellitus and effect of intranasal insulin on it]. AB - The functional state of the adenylyl cyclase signaling system (ACSS) and its regulation by hormones, the inhibitors of adenylyl cyclase (AC)--somatostatin (SST) in the brain and myocardium and 5-nonyloxytryptamine (5-NOT) in the brain of rats of different ages (5- and 7-month-old) with experimental obesity and a combination of obesity and type 2 diabetes mellitus (DM2), and the effect of long term treatment of animals with intranasally administered insulin (II) on ACSS were studied. It was shown that the basal AC activity in rats with obesity and DM2 was increased in the myocardium, and to the lesser extent in the brain, the treatment with II reducing this parameter. The AC stimulating effects of forskolin are decreased in the myocardium, but not in the brain, of rats with obesity and DM2. The treatment with II restored the AC action of forskolin in the 7-month-old animals, but has little effect on it in the 5-month-old rats. In obesity the basal AC activity and its stimulation by forskolin varied insignificantly and weakly changed in treatment of animals with II. The AC inhibitory effects of SST and 5-NOT in the investigated pathology are essentially attenuated, the effect of SST to the greatest extent, which we believe to be associated with a reduction in the functional activity of Gi-proteins. The II treatment of animals with obesity and with a combination of obesity and DM2 restored completely or partially the AC inhibiting effects of hormones, to the greatest extent in the brain. Since impaired functioning of ACSS is one of the causes of the metabolic syndrome and DM2, their elimination by treatments with II can be an effective approach to treat these diseases and their CNS and cardiovascular system complications. PMID- 25786318 TI - [Coupling of membranous and metabolic functions in nucleated erythrocytes of Scorpaena porcus L. in hypoxia (experiments in vivo and in vitro)]. AB - Effect of hypoxia (diapason of 0.57-8.17 mg O2 l(-1)) on functional characteristics of nucleated erythrocytes of the benthonic marine fish Scorpaena porcus L. was studied under conditions in vivo and in vitro. It has been established that characteristic of cellular system of this species is a balanced unhibition of membranous and metabolic functions under conditions of external deficit of oxygen (experiments in vivo). This is expressed in the ability of cells to maintain within norm the intracellular ATP concentration and transmembrane gradients for Na+ and K+ with low activities of Na+, K(+)-ATPase and hexokinase. This phenomenon seems to be based on the process of a decrease of the number of functioning ion channel at the level of the cell cytoplasmic membrane; this process reduces energy expenditure for maintenance of cationic gradients (the phenomenon of metabolic arrest). The same is also indicated by an increase of intensity of fluorescence of FDA and R123 in the scorpaena erythrocytic suspensions in hypoxia (experiments in vitro). Mechanisms underlying this phenomenon are discussed. PMID- 25786319 TI - [Seasonal changes in mechanical resistance of erythrocytes of the long-tailed ground squirrel (Citellus undulatus)]. AB - Seasonal changes of relative blood reticulocyte counts, free plasma hemoglobin and mechanical erythrocyte resistance were studied in the long-tailed ground squirrel (Citellus undulatus), under different functional conditions (winter hibernation, forced arousal in winter, and summer activity). A significant increase in reticulocyte counts in the ground squirrel blood was observed in April and October, indicating enhancement of erythropoeisis. This conclusion is also confirmed by a significant increase in free plasma hemoglobin at these periods. It has been also shown that erythrocytes of hibernating and forcibly awaken winter ground squirrels have a significantly lower mechanical resistance in comparison with those of active summer animals. The obtained data indicate that during the periods preceding the onset of winter hibernation and transition to summer activity there occurs a seasonal replacement of the erythrocyte pool by a pool more adapted to performance of functions in the novel functional state of the animal-hibernator. PMID- 25786320 TI - [Asymmetry and spatial specificity of auditory aftereffects following adaptation to signals simulating approach and withdrawal of sound sources]. AB - The spatial specificity of auditory approaching and withdrawing aftereffects was investigated in an anechoic chamber. The adapting and testing stimuli were presented from loudspeakers located in front of the subject at the distance of 1.1 m (near) and 4.5 m (far) from the listener's head. Approach and withdrawal of stimuli were simulated by increasing or decreasing the amplitude of the wide noise impulse sequence. The listeners were required to determine the movement direction of test stimulus following each 5-s adaptation period. The listeners' "withdrawal" responses were used for psychometric functions plotting and for quantitative assessment of auditory aftereffect. The data summarized for all 8 participants indicated that the asymmetry of approaching and withdrawing aftereffects depended on spatial localization of adaptor and test. The asymmetry of aftereffects was largest when adaptor and test were presented from the same loudspeaker (either near or far). Adaptation to the approach induced a directionally dependent displacement of the psychometric functions relative to control condition without adaptation and adaptation to the withdrawal was not. The magnitude of approaching aftereffect was greater when adaptor and test were located in near spatial domain than when they came from far domain. When adaptor and test were presented from the distinct loudspeakers, magnitude approaching aftereffect was decreasing in comparison to the same spatial localization, but after adaptation to withdrawal it was increasing. As a result, the directionally dependent displacements of the psychometric functions relative to control condition were observed after adaptation as to approach and to withdrawal. The discrepancy of the psychometric functions received after adaptation to approach and to withdrawal at near and far spatial domains was greater under the same localization of adaptor and test in comparison to their distinct localization. We assume that the peculiarities of approaching and withdrawing aftereffects observed reflect their spatial specificity. It is possible that spatial peculiarities of approaching and withdrawing aftereffects can be associated with specialized mechanisms for analysis of motion at the different distance from subject. PMID- 25786321 TI - [Turtle isthmic complex of visual nuclei: immunohistochemical study of gamma aminobutyric acid, choline acetyltransferase, calcium-binding proteins and cytochrome oxidase activity]. AB - The distribution of the immunoreactivity for gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), calcium-binding proteins (CaBPr) and histochemistry of cytochrome oxidase activity (CO) was studied in turtles (Testudo horsfieldi, Emys orbicularis) isthmal complex of visual nuclei. Magnocellular nucleus (IMc) was shown to reveal mainly the strongly stained GABA , parvalbumin (PV)-ir neurons and CO-positive cells, as well as variable both in number and degree of intensity of ChAT-, cal- bindin (CB)-, and calretinin (CR) ir cells. After the local tracer injection into the optic tectum GABA-ir neurons containing also retrograde label were found in IMc. The most caracteristic of the parvocellular nucleus (IPc) was the content of strongly stained ChAT-ir neurons, dense GABA-ir and CO-active terminal fields, as well as the neurons variable by the amount and the degree of immunoreactivity for CaBPr and GABA. Principal similarity in these features in the turtle IMc and IPc and of those in the avian isthmal nuclei of the same name allows suggesting their homology and consequently the same participation in selective processing of the visual information flow. The comparison with lower vertebrates confirms the evolutionary conservatism of visual isthmal complex among vertebrates and the existence of its progressive differentiation in the process of evolution. PMID- 25786322 TI - [Analysis of development of morphofunctional interconnections between CART- and AGRP-ergic neurons with dopaminergic structures in ontogenesis of mammals]. AB - There are obtained data indicating that morphogenesis and, probably, formation of structurally functional interaction of the CART- and dopaminergic neurons occur as early as during embryonic development. Meanwhile development of the AGRergic system and formation of its structural and functional communications are observed in the course of postnatal development of rat. Analysis of literature and re- sults of our own investigation show that differentiation of dopaminergic neurons in hypothalamus and midbrain occurs on the background of development of CARTergic neurons and in the absence of AGRP. Taking into account our data on activating action of the CART-peptide and inhibitory effect of AGRP on dopaminergic brain neurons, we believe that the leading component at formation of functional interactions of these systems is the later maturing AGRPergic system. PMID- 25786323 TI - [Protective effect of GM1 ganglioside against toxic action of glutamate on cerebellar granule cells]. PMID- 25786324 TI - [Phylogeny of peptide regulation: the beginning]. AB - Analyzing existing literature sources and his own experimental data, the author has concluded that (i) regulatory peptides arise solely as a result of cleavage of protein precursors, but not by non-ribosomal synthesis; (ii) the peptide regulation of physiological functions emerged as a part of autocrine regulation system almost simultaneously with life itself; peptide paracrine regulation appeared in the colonial prokaryotes, and peptide endocrine regulation in the multicellular eukaryotes; (iii) the regulatory peptides and their receptors could occur either sequentially (in any order) or simultaneously; (iv) conservatism of the primary structure of regulatory peptides is not significantly different from that of proteins; (v) the regulatory peptides are presented in the most evolutionarily ancient species wider than specialists think. PMID- 25786325 TI - Effect of elite physical exercise by triathletes on seven catabolites of DNA oxidation. AB - The oxidized nucleoside 8-hydroxy-2'-deoxyguanosine has been widely studied as a marker of DNA oxidation; however, data on the occurrence of other metabolites in plasma that are related to DNA damage are scarce. We have applied an improved, sensitive, robust, and reliable method, involving solid phase extraction and ultrahigh-performance liquid chromatography (UHPLC)-tandem mass spectrometry (MS/MS), to the precise quantitation of seven metabolites in the plasma of 15 elite triathletes after a 2-week training program. All compounds were eluted in the first 1.6 min, with limits of detection and quantification ranging between 0.001 and 0.3 ng.mL(-1) and 0.009 and 0.6 ng.mL(-1), respectively. Four compounds were detected in plasma: guanosine-3'-5'-cyclic monophosphate, 8-hydroxyguanine, 8-hydroxy-2'-deoxyguanosine, and 8-nitroguanosine. After two weeks of training, 8 hydroxyguanine exhibited the highest increase (from 0.031 +/- 0.008 nM to 0.036 +/- 0.012 nM) (p < 0.05), which could be related to the enhanced activity of DNA repairing enzymes that excise this oxidized base. Increased levels of guanosine 3'-5'-cyclic monophosphate and 8-hydroxy-2'-deoxyguanosine were also observed. In contrast, levels of 8-nitroguanosine (p < 0.05) were significantly reduced, which might be a protective measure as this compound strongly stimulates the generation of superoxide radicals, and its excess is related to pathologies such as microbial (viral) infections and other inflammatory and degenerative disorders. The results obtained indicate an induced adaptive response to the increased oxidative stress related to elite training, and point to the benefits associated with regular exercise. PMID- 25786327 TI - Mate locating and access behaviour of the parasitic pea crab, Nepinnotheres novaezelandiae, an important parasite of the mussel Perna canaliculus. AB - Pea crabs are globally ubiquitous symbionts in the marine environment that cause serious economic impact in the aquaculture production of several major bivalve species. However, little is known about their host-parasite interactions, especially the mating behaviour of these parasites that could prove useful for controlling their infestation in aquaculture. In this study, the mate location behaviour of male New Zealand pea crabs, Nepinnotheres novaezelandiae (Filhol, 1885), was observed when dwelling in its preferred host, the commercially important green-lipped mussel, Perna canaliculus. Given the cryptic behaviour of the male crabs, a novel trapping system was developed to determine whether male crabs would exit their mussel hosts in response to an upstream female crab. The presence of receptive female crabs placed upstream successfully attracted 60% of male crabs from their host over 24 h. Observations of the nocturnal mate-finding behaviour of male crabs were made in darkness using infrared video recordings. Males spent on average 49 min on empty hosts and never left a mussel containing a female conspecific once found, spending 200 min on average to gain entry to the mussel. Male crabs were often observed stroking the mantle edge of the mussel whilst attempting to gain entry, successfully increasing mussel valve gape during entry from 3.7 to 5.5 mm. A pheromone-based mate location system is likely used by this crab to greatly reduce the risks associated with the location of females. PMID- 25786326 TI - Genetic polymorphism of merozoite surface protein-1 in Plasmodium falciparum isolates from patients with mild to severe malaria in Libreville, Gabon. AB - We assessed Plasmodium (P.) falciparum allelic diversity based on clinical severity and age. The study was conducted from 2011 to 2012 in Libreville, Gabon where malaria prevalence was 24.5%. The polymorphism of the merozoite surface protein-1 (msp1) locus was analyzed in isolates from patients with complicated and uncomplicated malaria. Blood was collected on filter paper. After DNA extraction, genotyping of the msp1 gene was performed using nested PCR. The K1, Ro33, and Mad20 allelic families were detected in 71 (63%), 64 (57%), and 38 (34%) of the 112 analyzed samples, respectively. Overall, 17 K1 and 11 Mad20 alleles were detected. There was no association between msp1 allelic families and age. Mad20 allelic diversity increased with the severity of malaria. The number of K1 and Mad20 alleles decreased with age. The multiplicity of infection (MOI) was 1-6 genotypes and the complexity of infection (COI) 1.8 +/- 1. The COI differed based on age: it was 1.9 (+/-1.1) in the isolates from adults, 1.8 (+/ 1.1) in those from 0-5 year-old children, whereas it tended to be lower (1.6 +/- 0.8) in those from 6-15 year-old children. Extensive genetic diversity is found in P. falciparum strains circulating in Libreville. The number of specific msp1 alleles increased with clinical severity, suggesting an association between the diversity and the severity of malaria. PMID- 25786328 TI - Lrp1/LDL Receptor Play Critical Roles in Mannose 6-Phosphate-Independent Lysosomal Enzyme Targeting. AB - Most lysosomal enzymes require mannose 6-phosphate (M6P) residues for efficient receptor-mediated lysosomal targeting. Although the lack of M6P residues results in missorting and hypersecretion, selected lysosomal enzymes reach normal levels in lysosomes of various cell types, suggesting the existence of M6P-independent transport routes. Here, we quantify the lysosomal proteome in M6P-deficient mouse fibroblasts (PT(ki)) using Stable Isotope Labeling by Amino acids in Cell culture (SILAC)-based comparative mass spectrometry, and find unchanged amounts of 20% of lysosomal enzymes, including cathepsins D and B (Ctsd and Ctsb). Examination of fibroblasts from a new mouse line lacking both M6P and sortilin, a candidate for M6P-independent transport of lysosomal enzymes, revealed that sortilin does not act as cargo receptor for Ctsb and Ctsd. Using fibroblast lines deficient for endocytic lipoprotein receptors, we could demonstrate that both LDL receptor and Lrp1 mediate the internalization of non-phosphorylated Ctsb and Ctsd. Furthermore, the presence of Lrp1 inhibitor increased the secretion of Ctsd from PT(ki) cells. These findings establish Lrp1 and LDL receptors in M6P-independent secretion-recapture targeting mechanism for lysosomal enzymes. PMID- 25786329 TI - Two mutations in the 5'-flanking region of the KITLG gene are associated with litter size of dairy goats. AB - In this study, Xinong Saanen (SN) and Guanzhong (GZ) dairy goat breeds were used to detect single nucleotide polymorphisms (SNPs) in the 5'-flanking region of the KITLG gene by DNA sequencing and primer-introduced restriction analysis polymerase chain reaction. Two novel SNPs (g.13090G>T and g.13664C>A) were identified (GenBank Accession no. KM658964). Furthermore, g.13090G>T and g.13664C>A loci were closely linked in SN and GZ breeds (r(2) > 0.33). Association analysis results showed that g.13090G>T and g.13664C>A SNPs significantly affected litter size (P < 0.05). The litter size of individuals with the combined genotype GG/CC from both dairy goat breeds was greater than that of individuals with TT/AA in average parity (P < 0.05). Known biochemical and physiological functions, along with our results, indicated that GG/CC could be used in marker-assisted selection to choose individuals with greater litter size from both breeds. These results extend the spectrum of genetic variation in the caprine KITLG gene and may contribute to genetic resources and breeding of goats. PMID- 25786330 TI - Facial pigmentation as a biomarker of carotid atherosclerosis in middle-aged to elderly healthy Japanese subjects. AB - BACKGROUND/PURPOSE: Perceived age may be a better predictor of mortality rate than chronological age. We have demonstrated that perceived age was a significant biomarker for carotid atherosclerosis in Japanese. However, it remains to be determined which skin parameter is associated with atherosclerosis. The purpose of this study is to analyze the relationship between 10 facial skin-aging parameters and atherosclerosis in 169 middle-aged to elderly Japanese women who participated. METHODS: Facial photographs were taken under a shadowless lamp from three directions using a high-resolution digital camera. The digital images of each subject were analyzed using computer software and various parameters of skin aging such as pigmentation, wrinkles, and skin color were quantified. Carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured as indices for atherosclerosis. RESULTS: Facial pigmentation showed a significant correlation with carotid IMT, even after correction for age (r = 0.13, P = 0.03), and with visceral fat area. Stepwise regression analysis indicated that facial pigmentation was associated with carotid IMT via visceral fat area. CONCLUSION: Facial pigmentation may be a useful biomarker for carotid atherosclerosis in Japanese women. PMID- 25786331 TI - Economic outcomes among Medicare patients receiving bioengineered cellular technologies for treatment of diabetic foot ulcers. AB - OBJECTIVE: To assess the real-world medical services utilization and associated costs of Medicare patients with diabetic foot ulcers (DFUs) treated with Apligraf (bioengineered living cellular construct (BLCC)) or Dermagraft (human fibroblast derived dermal substitute (HFDS)) compared with those receiving conventional care (CC). METHODS: DFU patients were selected from Medicare de-identified administrative claims using ICD-9-CM codes. The analysis followed an 'intent-to treat' design, with cohorts assigned based on use of (1) BLCC, (2) HFDS, or (3) CC (i.e., >=1 claim for a DFU-related treatment procedure or podiatrist visit and no evidence of skin substitute use) for treatment of DFU in 2006-2012. Propensity score models were used to separately match BLCC and HFDS patients to CC patients with similar baseline demographics, wound severity, and physician experience measures. Medical resource use, lower-limb amputation rates, and total healthcare costs (2012 USD; from payer perspective) during the 18 months following treatment initiation were compared among the resulting matched samples. RESULTS: Data for 502 matched BLCC-CC patient pairs and 222 matched HFDS-CC patient pairs were analyzed. Increased costs associated with outpatient service utilization relative to matched CC patients were offset by lower amputation rates (-27.6% BLCC, -22.2% HFDS), fewer days hospitalized (-33.3% BLCC, -42.4% HFDS), and fewer emergency department visits (-32.3% BLCC, -25.7% HFDS) among BLCC/HFDS patients. Consequently, BLCC and HFDS patients had per-patient average healthcare costs during the 18-month follow-up period that were lower than their respective matched CC counterparts (-$5253 BLCC, -$6991 HFDS). LIMITATIONS: Findings relied on accuracy of diagnosis and procedure codes contained in the claims data, and did not account for outcomes and costs beyond 18 months after treatment initiation. CONCLUSION: These findings suggest that use of BLCC and HFDS for treatment of DFU may lower overall medical costs through reduced utilization of costly healthcare services. PMID- 25786332 TI - Estimating the predictive validity of diabetic animal models in rosiglitazone studies. AB - For therapeutic studies, predictive validity of animal models - arguably the most important feature of animal models in terms of human relevance - can be calculated retrospectively by obtaining data on treatment efficacy from human and animal trials. Using rosiglitazone as a case study, we aim to determine the predictive validity of animal models of diabetes, by analysing which models perform most similarly to humans during rosiglitazone treatment in terms of changes in standard diabetes diagnosis parameters (glycosylated haemoglobin [HbA1c] and fasting glucose levels). A further objective of this paper was to explore the impact of four covariates on the predictive capacity: (i) diabetes induction method; (ii) drug administration route; (iii) sex of animals and (iv) diet during the experiments. Despite the variable consistency of animal species based models with the human reference for glucose and HbA1c treatment effects, our results show that glucose and HbA1c treatment effects in rats agreed better with the expected values based on human data than in other species. Induction method was also found to be a substantial factor affecting animal model performance. The study concluded that regular reassessment of animal models can help to identify human relevance of each model and adapt research design for actual research goals. PMID- 25786333 TI - Levels of antibodies against human heat shock protein (HSP) 60 in patients with glaucoma in Poland. AB - BACKGROUND: Although elevated intraocular pressure is a major risk factor for the development of glaucoma, there is increasing evidence that the immune system may be involved in the development of normal-tension glaucoma (NTG). The aim of this study was to determine if NTG is associated with elevated levels of antibodies against human heat shock protein (HSP) 60. MATERIAL AND METHODS: The study was conducted in 139 subjects (35 subjects with NTG [Group 1], 34 subjects with primary open-angle glaucoma /POAG/ [Group 2], 24 subjects with autoimmune rheumatic diseases [Group 3], and 36 healthy controls [Group 4]). All subjects had complete ophthalmologic examination (visual acuity, slit-lamp examination, tonometry, gonioscopy; visual-field examination, and optical coherence tomography /OCT/ of the optic nerve head and the macula). Blood samples were collected for the measurements of serum levels of antibodies against human HSP60. RESULTS: The subjects with rheumatic diseases had the highest median serum level of antibodies against HSP60 - 20.49 ng/mL. The values in the subjects with NTG, POAG, and in controls were 18.79 ng/mL, 18.61 ng/mL and 17.61 ng/mL, respectively (p=0.96). CONCLUSIONS: This study does not confirm the hypothesis that normal-tension glaucoma is associated with elevated blood levels of antibodies against human heat shock protein (HSP) 60. PMID- 25786334 TI - Predicting mental disorders from hypothalamic-pituitary-adrenal axis functioning: a 3-year follow-up in the TRAILS study. AB - BACKGROUND: Hypothalamic-pituitary-adrenal axis functioning, with cortisol as its major output hormone, has been presumed to play a key role in the development of psychopathology. Predicting affective disorders from diurnal cortisol levels has been inconclusive, whereas the predictive value of stress-induced cortisol concentrations has not been studied before. The aim of this study was to predict mental disorders over a 3-year follow-up from awakening and stress-induced cortisol concentrations. METHOD: Data were used from 561 TRAILS (TRacking Adolescents' Individual Lives Survey) participants, a prospective cohort study of Dutch adolescents. Saliva samples were collected at awakening and half an hour later and during a social stress test at age 16. Mental disorders were assessed 3 years later with the Composite International Diagnostic Interview (CIDI). RESULTS: A lower cortisol awakening response (CAR) marginally significantly predicted new disorders [odds ratio (OR) 0.77, p = 0.06]. A flat recovery slope predicted disorders with a first onset after the experimental session (OR 1.27, p = 0.04). Recovery revealed smaller, non-significant ORs when predicting new onset affective or anxiety disorders, major depressive disorder, or dependence disorders in three separate models, corrected for all other new onsets. CONCLUSIONS: Our results suggest that delayed recovery and possibly reduced CAR are indicators of a more general risk status and may be part of a common pathway to psychopathology. Delayed recovery suggests that individuals at risk for mental disorders perceived the social stress test as less controllable and less predictable. PMID- 25786336 TI - Expansion load: recessive mutations and the role of standing genetic variation. AB - Expanding populations incur a mutation burden - the so-called expansion load. Previous studies of expansion load have focused on codominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations, we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis, whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to codominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions. PMID- 25786335 TI - Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. AB - We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy. PMID- 25786337 TI - Pemphigus and associated comorbidities: a cross-sectional study. AB - BACKGROUND: Pemphigus is a rare autoimmune blistering disease, reported to be associated with other coexisting and autoimmune diseases, including thyroid diseases, rheumatoid arthritis, alopecia areata, vitiligo, systemic lupus erythematosus, scleroderma and rare entities such as myasthenia gravis. AIM: To identify and describe patients with pemphigus with a diagnosed comorbidity, and to quantify the risk of additional comorbidities. METHODS: This was a cross sectional study of patients with pemphigus treated at a tertiary referral centre. Prevalence rates of 15 comorbid diseases were calculated. Age-standardized prevalence ratio (SPR) and 95% CI were calculated in comparison with prevalence rates in the general Canadian population using data from the Canadian Community Health Survey. Data were analysed using SAS software. RESULTS: In total, 295 patients were identified. An increased risk of hypothyroidism (n = 38, SPR = 1.53, 95% CI 1.08-2.10) and inflammatory bowel disease (IBD) (SPR = 1.48, 95% CI 0.40-3.80), and a two-fold increased risk of diabetes (SPR = 2.20, 95% CI 1.64 2.87) were observed. CONCLUSIONS: Patients with pemphigus have a higher incidence of hypothyroidism, IBD and diabetes compared with the general population. As part of pemphigus investigations and surveillance, investigating for these conditions may be considered. PMID- 25786338 TI - Periodic eye opening and upward eye deviation accompanied by burst-suppression, as an isolated clinical manifestation of acute post-hypoxic myoclonus. AB - Various movement disorders have been described following hypoxic-ischaemic brain injury. Here, we present a 72-year-old female patient who developed periodic opening and upward deviation of the eyes as an isolated clinical finding, within 24 hours after cardio-pulmonary arrest. These movements were accompanied by burst suppression on EEG, and both clinical and electrophysiological findings were suppressed 18 hours after intravenous levetiracetam infusion. The strictly periodic nature of both EEG discharges and eye opening with vertical deviation suggest a cause due to either activation of a subcortical/brainstem pacemaker reciprocally stimulating the cortex, or, alternatively, post-anoxic burst activity of viable cortical neural networks, somehow stimulating the relevant oculomotor nuclei. Together with previous similar cases, our case expands the spectrum of post-resuscitation myoclonus syndromes with the addition of this rare isolated oculopalpebral subtype. [Published with video sequence]. PMID- 25786339 TI - The sociologist and the state. An assessment of Pierre Bourdieu's sociology. AB - This paper provides an assessment of Pierre Bourdieu's sociology based on a reading of his posthumously published lectures on the state in Sur l'Etat. It argues that the state was a foundational element in Bourdieu's rendition of the symbolic order of everyday life. As such, the state becomes equally pivotal in Bourdieu's sociology, the applicability of which rests on the existence of the state, which stabilizes the social fields and their symbolic action that constitute the object of sociology. The state, which Bourdieu considers a 'meta' ordering principle in social life, ensures that sociology has a well-ordered object of study, vis-a-vis which it can posit itself as 'meta-meta'. The state thus functions as an epistemic guarantee in Bourdieu's sociology. A critical analysis of Bourdieu's sociology of the state offers the chance of a more fundamental overall assessment of Bourdieu's conception of sociology that has relevance for any critical sociological perspective that rests on the assumption of a meta-social entity, such as the state in Bourdieu's work, as a final ordering instance. PMID- 25786340 TI - The influence of various reef sounds on coral-fish larvae behaviour. AB - The swimming behaviour of coral-reef fish larvae from 20 species of 10 different families was tested under natural and artificial sound conditions. Underwater sounds from reef habitats (barrier reef, fringing reef and mangrove) as well as a white noise were broadcasted in a choice chamber experiment. Sixteen of the 20 species tested significantly reacted to at least one of the habitat playback conditions, and a range of responses was observed: fishes were (1) attracted by a single sound but repelled by none (e.g. white-banded triggerfish Rhinecanthus aculeatus was attracted by the barrier-reef sound), (2) repelled by one or more sounds but attracted by none (e.g. bridled cardinalfish Pristiapogon fraenatus was repelled by the mangrove and the bay sounds), (3) attracted by all sounds (e.g. striated surgeonfish Ctenochaetus striatus), (4) attracted and repelled by several sounds (e.g. whitetail dascyllus Dascyllus aruanus was attracted by the barrier-reef sound and repelled by the mangrove sound) and (5) not influenced by any sound (e.g. convict surgeonfish Acanthurus triostegus). Overall, these results highlight two settlement strategies: a direct selection of habitats using sound (45% of the species), or a by-default selection by avoidance of certain sound habitats (35%). These results also clearly demonstrated the need to analyse the influence of sounds at the species-specific level since congeneric and confamilial species can express different behaviours when exposed to the same sounds. PMID- 25786341 TI - Calcipotriol/betamethasone dipropionate ointment compared with tacrolimus ointment for the treatment of erosive pustular dermatosis of the scalp: a split lesion comparison. PMID- 25786342 TI - Interchangeability among five devices that measure anterior eye distances. AB - PURPOSE: The aim was to study the interchangeability of various devices that measure anterior chamber depth (ACD) and white-to-white (WTW) distance. METHODS: Eighty right eyes of eighty patients aged 20 to 40 years were included. Their spherical equivalent ranged from -4.25 to +1.00 dioptres. Each eye's ACD and the WTW distance were measured using the following devices: a Castroviejo surgical calliper, CA-200F Corneal Analyser, Orbscan II, Pentacam HR and IOLMaster 500. RESULTS: The Pentacam HR measured significantly greater ACD (p < 0.01) than the other two devices, whereas IOLMaster 500 and Orbscan II yielded comparable (p > 0.01) distances. Nonetheless, in every device comparison, the mean difference was within clinically acceptable limits. The device comparison showed that for WTW distance measurements IOLMaster 500 yields the greatest value (p < 0.01), whereas CA-200F Corneal Analyser yields the smallest one (p < 0.01). CONCLUSION: Pentacam HR, Orbscan II and IOLMaster 500 can be used interchangeably to measure ACD, whereas Orbscan II, IOLMaster 500, Castroviejo surgical calliper and CA-200F Corneal Analyser cannot be considered interchangeable, when it comes to measuring WTW distance. PMID- 25786343 TI - Skin phototype: a new perspective. AB - Cutaneous phototype is considered mainly related to cutaneous pigmentation and to the eumelanin/pheomelanin ratio, which is mostly genetically determined by the melanocortin 1 receptor (MC1R) polymorphisms. However, data in literature indicate that, in addition to stimulation of eumelanin synthesis, the MC1R signalling activates antioxidant, DNA repair and survival pathways. New emerging aspects regarding photoprotection and skin phototypes are going beyond those features connected to the melanin content in the skin. Important new findings link the MC1R to nuclear receptors activation, shedding light on new extra melanogenic effects dependent on the alpha-melanocyte-stimulating hormone (alpha MSH) activity and new ways through which such functions are modulated. These evidences indicate that several factors including melanin play a part in defining the basis for individual sun sensitivity, suggesting that the cutaneous phototype represents a 'biochemical fingerprint'. PMID- 25786344 TI - IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation. AB - INTRODUCTION: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of function mutation in KCNQ1, the gene encoding the pore-forming alpha-subunit of the IKs channel (KV 7.1), was the first ion channel dysfunction to be associated with familial AF. We hypothesized that early-onset lone AF is associated with a high prevalence of mutations in KCNQ1. METHODS AND RESULTS: We bidirectionally sequenced the entire coding sequence of KCNQ1 in 209 unrelated patients with early-onset lone AF (<40 years) and investigated the identified mutations functionally in a heterologous expression system. We found 4 nonsynonymous KCNQ1 mutations (A46T, R195W, A302V, and R670K) in 4 unrelated patients (38, 31, 39, and 36 years, respectively). None of the mutations were present in the control group (n = 416 alleles). No other mutations were found in genes previously associated with AF. The mutations A46T, R195W, and A302V have previously been associated with long-QT syndrome. In line with previous reports, we found A302V to display a pronounced loss-of-function of the IKs current, while the other mutants exhibited a gain-of-function phenotype. CONCLUSIONS: Mutations in the IKs channel leading to gain-of-function have previously been described in familial AF, yet this is the first time a loss-of-function mutation in KCNQ1 is associated with early-onset lone AF. These findings suggest that both gain-of-function and loss-of-function of cardiac potassium currents enhance the susceptibility to AF. PMID- 25786347 TI - Foot pain and swelling after minor traumatic injury. AB - Necrotizing fasciitis is a rare bacterial infection of the fascia and surrounding soft tissue, which carries a mortality rate as high as 20%, even in well appearing patients [1]. Classically, this diagnosis must be made with computed tomography or magnetic resonance,but recent literature shows that ultrasonography, readily available in the emergency department, may be adequate for diagnosis [2]. We present a case of a 48-year-old man who presented with a painful rash. We used his clinical presentation and ultrasound to make the diagnosis,which was later corroborated with plain radiograph findings. He was taken immediately to the operating room for extensive debridement.He was discharged 8 days later in good condition. PMID- 25786345 TI - p53-dependent expression of CXCR5 chemokine receptor in MCF-7 breast cancer cells. AB - Elevated expression of chemokine receptors in tumors has been reported in many instances and is related to a number of survival advantages for tumor cells including abnormal activation of prosurvival intracellular pathways. In this work we demonstrated an inverse correlation between expression levels of p53 tumor suppressor and CXCR5 chemokine receptor in MCF-7 human breast cancer cell line. Lentiviral transduction of MCF-7 cells with p53 shRNA led to elevated CXCR5 at both mRNA and protein levels. Functional activity of CXCR5 in p53-knockdown MCF-7 cells was also increased as shown by activation of target gene expression and chemotaxis in response to B-lymphocyte chemoattractant CXCL13. Using deletion analysis and site-directed mutagenesis of the cxcr5 gene promoter and enhancer elements, we demonstrated that p53 appears to act upon cxcr5 promoter indirectly, by repressing the activity of NFkappaB transcription factors. Using chromatin immunoprecipitation and reporter gene analysis, we further demonstrated that p65/RelA was able to bind the cxcr5 promoter in p53-dependent manner and to directly transactivate it when overexpressed. Through the described mechanism, elevated CXCR5 expression may contribute to abnormal cell survival and migration in breast tumors that lack functional p53. PMID- 25786348 TI - Relationship of newborn weight loss to milk supply concern and anxiety: the impact on breastfeeding duration. AB - Milk supply concern is the most common reason for breastfeeding discontinuation and maternal anxiety is also associated with reduced breastfeeding duration. Newborn excess weight loss (EWL) could trigger milk supply concern and anxiety and might be amenable to modification. Our objective was to determine the relationship between EWL and the development of milk supply concern and anxiety and the effect of such development on breastfeeding duration. We conducted a cohort analysis using data previously obtained from a randomised controlled trial comparing two post-hospital discharge follow-up strategies. For 1107 well, singleton infants born at >=34 weeks, we extracted data on all inpatient infant weights. EWL was defined as the loss of >=10% of birthweight. We surveyed mothers to obtain data on state anxiety and milk supply concern at birth and at 2 weeks. Our final outcome was breastfeeding at 6 months. Seventy (6.3%) infants developed EWL during the birth hospitalisation. At 2 weeks, milk supply concern and positive anxiety screen were more common (42% and 18%, respectively) among mothers whose infants had had EWL than among mothers whose infants had not had EWL (20% and 6%, respectively) (P < 0.001 for each comparison). Mothers with milk supply concern at 2 weeks were much less likely to be breastfeeding at 6 months, with odds ratio of 0.47 (0.30, 0.74) in multivariate analysis. EWL may increase milk supply concern and anxiety and these may reduce breastfeeding duration. Ameliorating EWL might alleviate milk supply concern and anxiety and improve breastfeeding duration. PMID- 25786349 TI - Development of carotenoid storage cells in Bixa orellana L. seed arils. AB - The arils of Bixa orellana L. seeds contain carotenoid storage cells (CSCs). The main compounds in these cells include bixin and norbixin, which are important pigments in the food and pharmaceutical industries. Although many studies have been conducted on these chemical constituents, the cellular events that occur during the development of the carotenoid-accumulating cells in the arils and their relationship with the final carotenoid accumulation in the vacuoles remain unknown. In this study, the development of the CSCs in B. orellana arils was analyzed by light and transmission electron microscopy. Carotenoids formed in specialized cells, whose number and size increased during aril development. At various stages of development, the cytoplasm of the CSCs contained chromoplasts that held an extensive network of tubules and plastoglobules. Next to the chromoplasts, lipid droplets may fuse one another to form osmiophilic bodies. In addition, vesicles were observed next to the tonoplast. At the final stages of development, both the osmiophilic bodies and vesicles, which became quadrangular or rectangular, were stored in the vacuoles of the CSCs. This study reported for the first time the occurrence of different storage unit types within the vacuole of carotenoid storage cells. PMID- 25786351 TI - Different locations of RANTES and its receptors on mouse epididymal spermatozoa. AB - Our previous study showed that the chemokine regulated upon activation normal T cell expressed and secreted (RANTES) originating from the mouse epididymis bound to the midpiece of luminal spermatozoa. The present study was undertaken to investigate the association between RANTES and epididymal spermatozoa and to determine whether the association is mediated by the RANTES receptors CCR1, CCR3 or CCR5. The use of reverse transcription polymerase chain reaction (RT-PCR), immunohistochemical staining and immunofluorescent staining demonstrated that RANTES secreted by apical and narrow cells of mouse epididymal ducts was associated with luminal spermatozoa. Flow cytometric analysis and immunofluorescent labelling revealed that the association between RANTES and spermatozoa of different regions weakened gradually as the spermatozoa moved along the epididymis. Moreover, CCR1, CCR3 and CCR5 were expressed in epididymal spermatozoa and located on the head of epididymal spermatozoa, while RANTES was generally located at the midpiece. In conclusion, RANTES and its receptors were not in the same sperm location, suggesting that RANTES binding to mouse epididymal spermatozoa is independent of CCR1, CCR3 and CCR5. PMID- 25786350 TI - Early osmotic, antioxidant, ionic, and redox responses to salinity in leaves and roots of Indian mustard (Brassica juncea L.). AB - Salt-stress-induced alterations in osmotic, ionic, and redox responses were studied in the early period of treatment (30 min to 5 days) in seedlings of Brassica juncea L. Roots and shoots under mild (50 mM) and severe (250 mM) NaCl stress were analyzed for growth, oxidative stress, osmolyte accumulation, antioxidant defense, and redox state. Growth reduction was less pronounced in the early time period of salt stress while oxidative damage increased linearly and in a sustained manner under severe stress up to 6 h. An early and transient reactive oxygen species (ROS) burst, as evidenced by superoxide and hydrogen peroxide level was observed, followed by activation of enzymatic antioxidant system (GPX, SOD, CAT, and GR) in both root and shoot. The enzymatic activity was not affected much under mild stress particularly at early phase; however, severe stress induced a significant increase in the activity of antioxidant enzymes. Root ascorbate was progressively accumulated, and its redox state maintained in the early time phase of treatment under mild stress while increase in root and shoot glutathione content was recorded under mild stress at 5 days when the active ascorbate pool decreased. While early period of salt stress showed significant Na(+) accumulation over control, plants subjected to mild stress measured less Na(+) accumulation up to 5 days compared to severely stressed plants. The results showed an early induction of differential responses to salt stress in roots and shoots of Brassica which include growth limitations, reduced relative water content, increased osmolytes, redox state, and antioxidant system, and a significant Na(+) increase. The results also indicate that roots and shoots may have distinct mechanisms of responses to salt stress. PMID- 25786352 TI - Line defects and quantum Hall plateaus in graphene. AB - Line defects in graphene can be either tailored-growth or arise naturally and are at the center of many discussions. Here we study the multiterminal conductance of graphene with an extended line defect in the quantum Hall regime analyzing the effects of the geometry of the setup, disorder and strain on the quantum Hall plateaus. We show that the defect turns out to affect the local and non-local conductance in very different ways depending on the geometrical configuration. When the defect is parallel to the sample edges one gets an equivalent circuit formed by parallel resistors. In contrast, when the defect bridges opposite edges, the Hall conductance may remain unaltered depending on the geometry of the voltage/current probes. The role of disorder, strain and the microscopic details of the defect in our results is also discussed. We show that the defect provides a realization of the electrical analog of an optical beam splitter. Its peculiar energy dependent inter-edge transmission allows it to be turned on or off at will and it may be used for routing the chiral edge states. PMID- 25786353 TI - Humor styles and personality: A meta-analysis of the relation between humor styles and the Big Five personality traits. AB - This research summarizes the knowledge generated in social psychology and positive psychology about the relationship between humor styles, personality and wellbeing. Specifically, a meta-analysis was performed with the results of 15 studies on humor styles measured by the Humor Styles Questionnaire (Martin, Puhlik-Doris, Larsen, Gray & Weir, 2003) in correlation with the personality traits measured by the Big Five Personality model (measured with different scales). Following the steps presented by Rosenthal (1991) for meta-analysis in the case of correlational research, we calculated the total mean r as an indicator of effect size. Results show that affiliative humor has a strong and homogeneous relation to neuroticism and extraversion. The homogeneity and heterogeneity found between variables and possible explanations are discussed in the conclusion. PMID- 25786354 TI - Growth rates in a captive population of Tonkean macaques. AB - Measuring variations in body mass is necessary to gain a deeper understanding of the evolution of life-history patterns, and it provides information on the timing of sexual maturity and the development of sexual dimorphism. In this study, we collected longitudinal data on body mass from infancy to adulthood in a captive population of Tonkean macaques (Macaca tonkeana). Tests to evaluate whether social group, maternal age, and dominance rank influenced growth rates showed that they had no significant effect. We investigated the timing and magnitude of breaking points in the growth paths of males and females, and checked whether these breaking points could correspond to specific reproductive and morphological developmental events. We found that male and female Tonkean macaques have roughly equivalent body masses until around the age of four, when males go through an adolescent growth spurt and females continue to grow at a constant rate. Males not only grow faster than females, but they also continue to grow for nearly one and a half years after females have attained their full body mass. Growth rate differences account for approximately two-thirds of the body mass sexual dimorphism; only the remaining third results from continued male growth beyond the age where full body mass is reached in females. We also discovered remarkable correspondences between the timing of testicular enlargement and the adolescent growth spurt in males, and between dental development and slowdown breaking points in both sexes. PMID- 25786355 TI - Ligand effects on the electrochemical behavior of [Fe2(CO)5(L){MU (SCH2)2(Ph)P=O}] (L = PPh3, P(OEt)3) hydrogenase model complexes. AB - In this paper we study the influence of substituting one CO ligand in [Fe2(CO)6{MU-(SCH2)2(Ph)P=O}] (1) by better sigma-donor L ligands affording [Fe2(CO)5(L){MU-(SCH2)2(Ph)P=O}] {L = PPh3 (2) and P(OEt)3 (3)} in relation to the steric interactions and the voltammetric behavior. Cyclic voltammetric investigations under N2 and CO showed remarkable differences in the electrochemical behaviour of complexes 2 and 3: (i) Complex 2 tends to expel PPh3 upon reduction whereas complex 3 exhibits chemical reversibility and (ii) Under CO, complex 3 reacts with CO affording a new compound P, which shows a reversible wave at E1/2 ~ -0.9 V (vs. ferrocenium/ferrocene couple). The presence of CO assists the formation of 1 after electrochemically induced loss of PPh3 during the voltammetric experiment of 2. Using DFT calculations we provide an explanation for the difference in stabilities between the Fe-PPh3 and Fe-P(OEt)3 bonds. PMID- 25786356 TI - Unilateral suppression of probable antipsychotic drug-induced parkinsonism. PMID- 25786358 TI - 3D proton transfer augments bio-photocurrent generation. AB - An enhancement of the photocurrent is achieved in a biohybrid nanocomposite consisting of nanovesicle reconstituted proteorhodopsin and potassium phosphotungstate nanoparticles. With the observation of an accelerated protein photocycle and elevated proton conductivity, this improvement of the photo electric performance is attributed to the construction of a 3D proton-transfer framework. PMID- 25786357 TI - Porencephaly in dogs and cats: relationships between magnetic resonance imaging (MRI) features and hippocampal atrophy. AB - Porencephaly is the congenital cerebral defect and a rare malformation and described few MRI reports in veterinary medicine. MRI features of porencephaly are recognized the coexistence with the unilateral/bilateral hippocampal atrophy, caused by the seizure symptoms in human medicine. We studied 2 dogs and 1 cat with congenital porencephaly to characterize the clinical signs and MRI, and to discuss the associated MRI with hippocampal atrophy. The main clinical sign was the seizure symptoms, and all had hippocampal atrophy at the lesion side or the larger defect side. There is association between hippocampal atrophy or the cyst volume and the severe of clinical signs, and it is suggested that porencephaly coexists with hippocampal atrophy as well as humans in this study. PMID- 25786359 TI - Plasmon coupled Fabry-Perot lasing enhancement in graphene/ZnO hybrid microcavity. AB - The response of graphene surface plasmon (SP) in the ultraviolet (UV) region and the realization of short-wavelength semiconductor lasers not only are two hot research areas of great academic and practical significance, but also are two important issues lacked of good understanding. In this work, a hybrid Fabry-Perot (F-P) microcavity, comprising of monolayer graphene covered ZnO microbelt, was constructed to investigate the fundamental physics of graphene SP and the functional extension of ZnO UV lasing. Through the coupling between graphene SP modes and conventional optical microcavity modes of ZnO, improved F-P lasing performance was realized, including the lowered lasing threshold, the improved lasing quality and the remarkably enhanced lasing intensity. The underlying mechanism of the improved lasing performance was proposed based on theoretical simulation and experimental characterization. The results are helpful to design new types of optic and photoelectronic devices based on SP coupling in graphene/semiconductor hybrid structures. PMID- 25786360 TI - [More income inequalities means more HIV-AIDS. An advocacy for Gini coefficients beside 0.3]. PMID- 25786361 TI - Drug resistance in cancer therapy. PMID- 25786362 TI - Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer. AB - Paclitaxel is a potent chemotherapeutic agent for treating refractory prostate cancer. However, its prolonged treatment develops multidrug resistance. Since lapatinib interacts with and inhibits P-gp activity, our objective was to determine whether the combination therapy of these two drugs can synergistically treat resistant prostate cancer. Our recently synthesized lipopolymer, poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft dodecanol) (PEG-PCD), was used to efficiently load both drugs into PEG-PCD micelles since they are hydrophobic. Lapatinib inhibited P-gp function but not its expression. Co-treatment of DU145-TXR cells with 0.5 MUM paclitaxel and 5 MUM lapatinib resulted in up to 138-fold reversal compared to paclitaxel alone. These formulations killed almost 70% and 80% of DU145-TXR cells when 0.5 MUM paclitaxel was combined with lapatinib at a dose of 1 and 5 MUM, respectively, while monotherapy had no effect. Combination therapy induced apoptosis and cell cycle arrest at mitotic phase. Xenograft tumor growth in athymic nude mice was significantly regressed when PEG-PCD micelles carrying lapatinib and paclitaxel were given intravenously twice a week. Furthermore, this combination therapy synergistically decreased antiangiogenic activity compared to the control or their monotherapy. In conclusion, lipopolymeric micelles carrying lapatinib and paclitaxel have the potential to treat resistant prostate cancer and can successfully deliver drugs to tumors while minimizing toxic effects associated with solubilizing agents. PMID- 25786363 TI - Nanostructured reverse hexagonal liquid crystals sustain plasma concentrations for a poorly water-soluble drug after oral administration. AB - Reverse hexagonal (H2) liquid crystals formed from selachyl alcohol were demonstrated to sustain the absorption of the poorly water-soluble drug cinnarizine (CZ) after oral administration to rats. When CZ was administered as a bolus lipid solution in selachyl alcohol, the T max was observed to be 23.5 +/- 5.9 h, significantly longer than the control suspension (1 h). Administration of selachyl alcohol as dispersed nanoparticles (hexosomes) also resulted in a sustained plasma profile, with drug concentrations maintained from 20 to 40 ng/mL over the first 24 h after administration. Sustained absorption of CZ from the selachyl alcohol hexosomes led to a significant enhancement (p < 0.05) in oral bioavailability (F% = 17%) compared to the control CZ suspension (9%). Analysis of selachyl alcohol hexosomes using small-angle x-ray scattering indicated that neither the presence of CZ (7 mg/g) nor simulated intestinal fluid altered the H2 nanostructure. Selachyl alcohol is not susceptible to digestion. Prolonged absorption from the selachyl alcohol-based H2 systems was attributed to the non digestible nature of the lipid, similar to non-digestible phytantriol cubic (V2) systems previously reported. Furthermore, the likely presence of non-sink conditions in the gastric compartment provides a drug reservoir requiring gastric emptying to stimulate drug release from the formulation. This study highlights the potential use of non-digestible liquid crystalline systems generally and nanostructured liquid crystalline particles in particular as novel sustained oral drug delivery systems. PMID- 25786364 TI - A drug-laden elastomer for surgical treatment of anal fistula. AB - Anal fistula is a common surgical problem with high incidence and causes suffering to patients. The management of high and complex anal fistula is challenging. The purpose of this work is to develop drug-laden elastomer not only to act as seton in the surgical management of anal fistula but also provide painkilling effect during the treatment. Elastic silicone bands were fabricated with different concentrations of lidocaine, with different in vitro drug release profiles. Muscle cutting experiment showed that the drug-laden elastic silicone bands were as effective as the surgical rubber bands in cutting function. Preliminary clinical trial indicated that the drug-laden silicone bands can be used as setons with analgesic effect in the treatment of anal fistula. The findings showed that the drug-laden elastic silicone bands are potentially useful as seton for surgical treatment of anal fistula. PMID- 25786365 TI - Protective effects of nanoparticulate coenzyme Q10 and curcumin on inflammatory markers and lipid metabolism in streptozotocin-induced diabetic rats: a possible remedy to diabetic complications. AB - Diabetes and its complications have been linked to increased levels of free radicals and systemic pro-inflammatory cytokines and to an altered lipid profile. Coenzyme Q10 and curcumin are potent antioxidants and anti-inflammatory agents but are underutilized clinically because of their poor bioavailability when administered orally. We have recently developed poly(D,L-lactic-co-glycolic acid) based nanoparticles in which we have encapsulated coenzyme Q10 and curcumin to increase the oral bioavailability and therapeutic efficacy of the antioxidant molecules. These formulations when tested in streptozotocin-induced diabetic rats demonstrated protective effects on inflammatory markers as well as lipid metabolism. Coenzyme Q10 nanoparticulates reduced only C-reactive protein levels, whereas curcumin nanoparticles reduced levels of C-reactive protein, interleukin 6 and tumor necrosis factor-alpha. Administration of both nanoparticulates resulted in significant reductions of plasma triglycerides and total cholesterol and an increase in high-density lipoprotein cholesterol. Together, these data indicate the promise of coenzyme Q10 and curcumin in diabetes when delivered through nanoparticulate formulations. PMID- 25786366 TI - The influence of sample drying procedures on mercury concentrations analyzed in soils. AB - Methods commonly used for soil sample preparation may be unsuitable for measuring Hg concentrations due to the possible loss of volatile Hg species when drying at higher temperatures. Here, the effects of freeze-drying, air drying at 25 degrees C and oven-drying at 105 degrees C on Hg concentrations in two soil types and three standard reference materials were tested. Two soils with different levels of Hg contamination and three reference materials were examined. A systematic decrease of Hg concentrations was observed in air-dried (24 %) and oven-dried (3 %) contaminated upland soils in comparison to freeze-dried control samples. The 105 degrees C oven drying also led to loss of Hg from reference materials (5 %-8 % in comparison with the certified Hg concentration). Different results from the drying of sterilized reference materials and natural soils were probably related to the extent of microbiological activity, demonstrating the importance of this parameter in sample preparation for Hg analysis. PMID- 25786367 TI - Prognostic significance of ADAM17 expression in patients with gastric cancer who underwent curative gastrectomy. AB - BACKGROUNDS: A disintegrin and metalloproteinase (ADAM) 17 has been indicated to be an indispensable regulator of cellular events from proliferation to migration. Although prognostic importance of ADAM17 expression has been investigated in several tumours, its clinical utility as a useful prognostic molecular marker remains unclear in gastric cancer. In the current study, we evaluated the expression of ADAM17 and its prognostic significance in gastric cancer patients after curative gastrectomy. METHODS: The prognostic significance of ADAM17 expression was analysed immunohistochemically in 156 patients with gastric cancer who had undergone curative gastrectomy, and the relationship between its expression and clinicopathological factors was also evaluated. RESULTS: High ADAM17 expression was detected in 79 patients (51 %), whereas low expression was found in 77 cases (49 %). There was significant correlation between gender, histology, lymph node metastasis, vascular invasion, the presence of recurrence and high ADAM17 expression. Recurrence in patients with high ADAM17 expression was significantly higher than that for patients with low ADAM17 expression (p = 0.032). The median disease-free survival (DFS) time for patients with tumours with high ADAM17 expression was worse than that of patients with tumours with low ADAM17 expression (16.6 vs. 44.2 months, p = 0.004). In addition, patients with low ADAM17 expression had a higher median overall survival (OS) (49.6 vs. 26.9 months, p = 0.019) compared to those with high ADAM17 expression. Multivariate analysis indicated that the rate of ADAM17 expression was an independent prognostic factor for DFS, in addition to the already known important clinicopathological prognostic indicator. But the prognostic importance of ADAM17 expression could not be proved by multivariate analysis for OS. CONCLUSIONS: The potential value of ADAM17 expression as a useful molecular marker in gastric cancer progression should be evaluated comprehensively; it may predict recurrence and poor prognosis in patients with gastric cancer after curative resection. PMID- 25786369 TI - A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients. AB - OBJECTIVE: Secondary hyperparathyroidism (SHPT) is a frequent complication of chronic kidney disease. We evaluated AMG 416, a long-acting peptide agonist of the calcium-sensing receptor, to assess its safety, tolerability, and efficacy and to determine a safe and effective starting dose for subsequent phase 2 studies. The study was not designed to titrate AMG 416 dosing to achieve a specific PTH treatment goal. RESEARCH DESIGN AND METHODS: This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation study designed to evaluate the safety and efficacy of AMG 416 administered thrice weekly by IV bolus at the end of hemodialysis for up to 4 weeks. Eligible subjects were enrolled in one of three cohorts and treated with 5 mg of AMG 416 or placebo for 2 weeks (Cohort 1) or 5 or 10 mg of AMG 416 or placebo for 4 weeks (Cohorts 2 and 3). The primary endpoint was mean percentage change from baseline in PTH during the efficacy assessment phase (EAP) in Cohorts 2 and 3. RESULTS: Analysis of the primary endpoint showed that treatment with AMG 416 at 10 mg (Cohort 2) and 5 mg (Cohort 3) for up to 4 weeks resulted in mean 49.4% and 33.0% reductions from baseline in PTH during the efficacy assessment phase, respectively (p < 0.05 for both cohorts compared to placebo group within the cohort). A substantial proportion of subjects treated with AMG 416 achieved PTH <=300 pg/mL and >=30% reduction in PTH from baseline in both cohorts. The observed decreases in serum corrected calcium were well tolerated and serum phosphate levels also tended to decrease. CONCLUSIONS: The present clinical findings support the continued development of AMG 416 as a treatment for SHPT in hemodialysis patients. PMID- 25786368 TI - ZNF32 inhibits autophagy through the mTOR pathway and protects MCF-7 cells from stimulus-induced cell death. AB - ZNF32 is a recently identified zinc finger protein and its functions remain largely unknown. Autophagy has been shown to affect cell proliferation and survival. Here, we innovatively show the effect of ZNF32 on cell autophagy and autophagy-associated cell death in breast carcinoma cells and also elucidate its underlying mechanisms. We examined the autophagic activity and LC3 II expression in human carcinoma cell lines with increased or decreased ZNF32 expression. Pharmacological inhibition (rapamycin) or activation (EGF) assays were used to investigate the function of the AKT/mTOR pathway during this process. H2O2- and diamide-induced MCF-7 cell death models were used to elucidate the role of ZNF32 associated autophagy in breast carcinoma cell death. Our results show that increasing ZNF32 expression in MCF-7 cells inhibits autophagy initiation by activating the AKT/mTOR pathway, and further reduced autophagy-associated cell death and maintained MCF-7 cell survival. Conversely, impairing ZNF32 expression by transfecting ZNF32 siRNA strongly promoted autophagy, further augmenting autophagy-associated cell death. Furthermore, correlations between ZNF32 and autophagy were observed in both MCF-7 xenograft tumors and in breast cancer patients. In conclusion, ZNF32 acts as an effective autophagy inhibitor to protect breast cancer cells from excessive stimulus-autophagy-induced cell death. PMID- 25786370 TI - Shi Zhang Qiao. PMID- 25786371 TI - In vivo biocompatibility evaluation of electrospun composite scaffolds by subcutaneous implantation in rat. AB - In vivo biocompatibility of nanofibrous poly-L-lactic acid (P), poly-L-lactic acid/gelatin (PG), poly-L-lactic acid/hydroxyapatite (PH), and poly-L-lactic acid/gelatin/hydroxyapatite (PGH) scaffolds, useful in regenerative medicine and drug delivery, was evaluated by subcutaneous implantation in both male and female rats (n = 5) for up to 90 days. The body weight of each animal in the study was evaluated on a weekly basis, and no significant difference was noticed. Total and differential leukocyte counts displayed no inflammatory reaction due to scaffold implantation. Gross observation and histology of necropsied vital organs exhibited normal morphology of cell types and tissue, denying any systemic adverse reaction on distal organs. Histology of subcutaneous tissue surrounding scaffolds was done to assess any local toxic effect of implants and found all scaffolds to be compatible and nontoxic. Moreover, no remnant of scaffolds was observed in any of the histological sections, suggesting all scaffolds to be biodegradable. All the results in this study confirm that nanofibrous scaffolds P, PG, PH, and PGH are biocompatible and safe for bone tissue engineering application. PMID- 25786372 TI - Polymer-controlled release of tobramycin from bone graft void filler. AB - Despite clinical, material, and pharmaceutical advances, infection remains a major obstacle in total joint revision surgery. Successful solutions must extend beyond bulk biomaterial and device modifications, integrating locally delivered pharmaceuticals and physiological cues at the implant site, or within large bone defects with prominent avascular spaces. One approach involves coating clinically familiar allograft bone with an antibiotic-releasing rate-controlling polymer membrane for use as a matrix for local drug release in bone. The kinetics of drug release from this system can be tailored via alterations in the substrate or the polymeric coating. Drug-loaded polycaprolactone coating releases bioactive tobramycin from both cadaveric-sourced cancellous allograft fragments and synthetic hybrid coralline ceramic bone graft fragments with similar kinetics over a clinically relevant 6-week timeframe. However, micron-sized allograft particulate provides extended bioactive tobramycin release. Addition of porogen polyethylene glycol to the polymer coating formulation changes tobramycin release kinetics without significant impact on released antibiotic bioactivity. Incorporation of oil-microencapsulated tobramycin into the polymer coating did not significantly modify tobramycin release kinetics. In addition to releasing inhibitory concentrations of tobramycin, antibiotic-loaded allograft bone provides recognized beneficial osteoconductive potential, attractive for decreasing orthopedic surgical infections with improved filling of dead space and new bone formation. PMID- 25786373 TI - Killing bacteria within biofilms by sustained release of tetracycline from triple layered electrospun micro/nanofibre matrices of polycaprolactone and poly(ethylene-co-vinyl acetate). AB - We report the controlled release of the antibiotic tetracycline (tet) HCl from a triple-layered electrospun matrix consisting of a central layer of poly(ethylene co-vinyl acetate (PEVA) sandwiched between outer layers of poly-epsilon caprolactone (PCL). These micro/nanofibre layers with tet successfully encapsulated (essentially quantitatively at 3 and 5 % w/w) in each layer, efficiently inhibited the growth of a panel of bacteria, including clinical isolates, as shown by a modified Kirby-Bauer disc assay. Furthermore, they demonstrated high biological activity in increasingly complex models of biofilm formation (models that are moving closer to the situation in a wound) by stopping biofilm formation, by killing preformed biofilms and killing mature, dense biofilm colonies of Staphylococcus aureus MRSA252. Tet is clinically useful with potential applications in wound healing and especially in complicated skin and skin-structure infections; electrospinning provides good encapsulation efficiency of tet within PCL/PEVA/PCL polymers in micro/nanofibre layers which display sustained antibiotic release in formulations that are anti-biofilm. PMID- 25786374 TI - Zein/polycaprolactone electrospun matrices for localised controlled delivery of tetracycline. AB - We report the controlled release of the antibiotic tetracycline (Tet) from triple layered (3L) electrospun matrices consisting of zein or a zein/PCL blend, where the drug was loaded into the central layer with the two outer layers acting as diffusion barriers. These fibrous matrices successfully encapsulated Tet and efficiently inhibited the growth of a clinical isolate, the methicillin-resistant Staphylococcus aureus strain MRSA252, as demonstrated in a modified Kirby-Bauer disc assay over 5 days. Whilst untreated zein fibres are unstable in an aqueous environment, rapidly shrinking due to plasticisation and film formation, blending zein with PCL stabilised the electrospun matrices and prevented them from shrinking. These 3L formulations display sustained antibiotic release and provide a proof of concept for zein-based polymeric matrices as wound dressings to treat or prevent bacterial infection. This is the first demonstration of the controlled release of a clinically used antibiotic from electrospun zein-based matrices. PMID- 25786375 TI - Delineating intracellular pharmacokinetics of paclitaxel delivered by PLGA nanoparticles. AB - Although many studies have shown that drug delivery and efficacy can be improved by nano-sized drug carriers, we understand little regarding their pharmacokinetics (PK). PK calculations for drugs delivered by carriers are more complex than those for drug-only solutions. The overall PK depends on many factors, including drug-release rate and the PK of both the drug itself and the carrier. We built a mathematical model to describe the intracellular PK of paclitaxel delivered by nanoparticles. Paclitaxel was incorporated into poly (lactic-co-glycolic acid) nanoparticles, which were chemically labeled with a fluorescence probe for quantification. PK profiles of drug alone, nanoparticles alone, and drug delivered by nanoparticles were studied in human breast cancer MCF7 cells. Simulated results from the model were similar to observed data, indicating that the model was properly developed. The model clearly and quantitatively represented the effects of relative factors, such as drug dose, drug-release kinetics, and nanoparticle PK, on the PK of paclitaxel delivered by nanoparticles. We also used this model to estimate the intracellular drug-release rate, which was found to be slightly slower than the in vitro release rate in this study. This mathematical model could be used to provide guidelines to design, evaluate, and optimize nano-sized drug carriers. PMID- 25786376 TI - Niosomes as a vesicular carrier for topical administration of minoxidil: formulation and in vitro assessment. AB - Niosomes are reported to increase the skin permeation and bioavailability of topically applied drug molecules. However, very few studies were reported for nanometer-sized niosome vesicles. The aim of the present study was to prepare minoxidil-loaded niosomal formulation using ethanol injection method. Surfactant screening showed that only Span 60, Span 20, and Tween 20 with cholesterol have capability of nano size vesicle formation. The formed niosomes were characterized for entrapment efficiency, vesicle size, scanning electron microscope, and physical stability. By modulation of surfactant and cholesterol ratio maximum entrapment up to 34.70 +/- 1.1 % with size of 470 +/- 27 nm was obtained (Span 60/cholesterol ratio of 1:2). The vesicle size obtained was between 150 and 800 nm that was depending on cholesterol ratio and type of nonionic surfactant employed. The in vitro skin permeation study showed that an increase in cholesterol concentration in niosome vesicles increases minoxidil skin retention. Niosome formulation prepared with 1:2 ratio of Span 60 and cholesterol showed 17.21 +/- 3.2 % skin retention of minoxidil, which is more than eightfold as compared to control minoxidil gel. PMID- 25786378 TI - Reachable workspace reflects dynamometer-measured upper extremity strength in facioscapulohumeral muscular dystrophy. AB - INTRODUCTION: It is not known whether a reduction in reachable workspace closely reflects loss of upper extremity strength in facioscapulohumeral muscular dystrophy (FSHD). In this study we aimed to determine the relationship between reachable workspace and quantitative upper extremity strength measures. METHODS: Maximal voluntary isometric contraction (MVIC) testing of bilateral elbow flexion and shoulder abduction by hand-held dynamometry was performed on 26 FSHD and 27 control subjects. In addition, Kinect sensor-based 3D reachable workspace relative surface areas (RSAs) were obtained. Loading (500-g weight) effects on reachable workspace were also evaluated. RESULTS: Quantitative upper extremity strength (MVIC of elbow flexion and shoulder abduction) correlated with Kinect acquired reachable workspace RSA (R = 0.477 for FSHD, P = 0.0003; R = 0.675 for the combined study cohort, P < 0.0001). Progressive reduction in RSA reflected worsening MVIC measures. Loading impacted the moderately weak individuals the most with additional reductions in RSA. CONCLUSIONS: Reachable workspace outcome measure is reflective of upper extremity strength impairment in FSHD. PMID- 25786377 TI - Diseases originate and terminate by genes: unraveling nonviral gene delivery. AB - The world is driving in to the era of transformation of chemical therapeutic molecules to biological genetic material therapeutics, and that is where the biological drugs especially "genes" come into existence. These genes worked as "magical bullets" to specifically silence faulty genes responsible for progression of diseases. Viral gene delivery research is far ahead of nonviral gene delivery technique. However, with more advancement in polymer science, new ways are opening for better and efficient nonviral gene delivery. But efficient delivery method is always considered as a bottleneck for gene delivery as success of which will decide the fate of gene in cells. During the past decade, it became evident that extracellular as well as intracellular barriers compromise the transfection efficiency of nonviral vectors. The challenge for gene therapy research is to pinpoint the rate-limiting steps in this complex process and implement strategies to overcome the biological physiochemical and metabolic barriers encountered during targeting. The synergy between studies that investigate the mechanism of breaking in and breaking out of nonviral gene delivery carrier through various extracellular and intracellular barriers with desired characteristics will enable the rational design of vehicles and revolutionize the treatment of various diseases. PMID- 25786380 TI - Case of dermatophyte abscess caused by Trichophyton rubrum: a case report and review of the literature. AB - A 54-year-old Japanese man without apparent immunosuppression presented with nodules with purulent drainage on the right lower leg. He had ringworm of the right leg and tinea unguium. A biopsy specimen of the nodule showed intradermal abscesses with fungal elements, and Trichophyton rubrum was cultured from both the pus and the biopsy specimen. Treatment with oral terbinafine resolved the nodules. Dermatophyte abscess is a rare, deep and invasive dermatophytosis, which is often associated with immunocompromised conditions. We provide a review of the literature including Japanese cases. PMID- 25786379 TI - Transcription Factor Brn-3b Overexpression Enhances Neurite Outgrowth in PC12 Cells Under Condition of Hypoxia. AB - Transcription factor Brn-3b plays a key role in retinal ganglion cell differentiation, survival, and axon outgrowth during development. However, the precise role of Brn-3b in the normal adult retina as well as during neurodegeneration is unclear. In the current study, the effect of overexpression of Brn-3b was assessed in vitro, in PC12 cells under conditions of normoxia and hypoxia. Immunoblot analysis showed that overexpression of Brn-3b in PC12 cells as well as 661W cells produced significant increase in the growth cone marker, growth-associated protein-43 (GAP-43), and acetylated-tubulin (ac-TUBA). In addition, an increased immunostaining for GAP-43 and ac-TUBA was observed in PC12 cells overexpressing Brn-3b, which was accompanied by a marked increase in neurite outgrowth, compared to PC12 cells overexpressing the empty vector. In separate experiments, one set of PC12 cells transfected either with a Brn-3b expression vector or an empty vector was subjected to conditions of hypoxia for 2 h, while another set of similarly transfected PC12 cells was maintained in normoxic conditions. It was found that the upregulation of GAP-43 and ac-TUBA in PC12 cells overexpressing Brn-3b under conditions of normoxia was sustained under conditions of hypoxia. Immunocytochemical analysis revealed not only an upregulation of GAP-43 and ac-TUBA, but also increased neurite outgrowth in PC12 cells transfected with Brn-3b as compared to PC12 cells transfected with empty vector in both normoxia and hypoxia. The findings have implications for a potential role of Brn-3b in neurodegenerative diseases in which hypoxia/ischemia contribute to pathophysiology of the disease. PMID- 25786381 TI - Sulfur and Nitrogen Co-Doped Graphene for Metal-Free Catalytic Oxidation Reactions. AB - Sulfur and nitrogen co-doped reduced graphene oxide (rGO) is synthesized by a facile method and demonstrated remarkably enhanced activities in metal-free activation of peroxymonosulfate (PMS) for catalytic oxidation of phenol. Based on first-order kinetic model, S-N co-doped rGO (SNG) presents an apparent reaction rate constant of 0.043 +/- 0.002 min(-1) , which is 86.6, 22.8, 19.7, and 4.5 fold as high as that over graphene oxide (GO), rGO, S-doped rGO (S-rGO), and N doped rGO (N-rGO), respectively. A variety of characterization techniques and density functional theory calculations are employed to investigate the synergistic effect of sulfur and nitrogen co-doping. Co-doping of rGO at an optimal sulfur loading can effectively break the inertness of carbon systems, activate the sp(2) -hybridized carbon lattice and facilitate the electron transfer from covalent graphene sheets for PMS activation. Moreover, both electron paramagnetic resonance (EPR) spectroscopy and classical quenching tests are employed to investigate the generation and evolution of reactive radicals on the SNG sample for phenol catalytic oxidation. This study presents a novel metal free catalyst for green remediation of organic pollutants in water. PMID- 25786382 TI - Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination. AB - It has been proposed that the adult dorsal root ganglia (DRG) harbor neural stem/progenitor cells (NPCs) derived from the neural crest. However, the thorough characterization of their stemness and differentiation plasticity was not addressed. In this study, we investigated adult DRG-NPC stem cell properties overtime, and their fate when ectopically grafted in the central nervous system. We compared them in vitro and in vivo to the well-characterized adult spinal cord NPCs derived from the same donors. Using micro-dissection and neurosphere cultures, we demonstrate that adult DRG-NPCs have quasi unlimited self-expansion capacities without compromising their tissue specific molecular signature. Moreover, they differentiate into multiple peripheral lineages in vitro. After transplantation, adult DRG-NPCs generate pericytes in the developing forebrain but remyelinating Schwann cells in response to spinal cord demyelination. In addition, we show that axonal and endothelial/astrocytic factors as well astrocytes regulate the fate of adult DRG-NPCs in culture. Although the adult DRG NPC multipotency is restricted to the neural crest lineage, their dual responsiveness to developmental and lesion cues highlights their impressive adaptive and repair potentials making them valuable targets for regenerative medicine. PMID- 25786383 TI - Topical glucocorticoid or pimecrolimus treatment suppresses thymic stromal lymphopoietin-related allergic inflammatory mechanism in an oxazolone-induced atopic dermatitis murine model. AB - Congenitally or early impaired skin barrier as the first event starting the 'atopic march' in atopic dermatitis (AD) patients can increase allergen penetration that results in sensitization, even in the airways, followed by asthma and allergic rhinitis. Thymic stromal lymphopoietin (TSLP) is a cytokine existing in high levels in AD skin and is considered as a novel therapeutic target for atopic disease. We generated oxazolone (Ox)-induced AD-like (Ox-AD) hairless mice and divided them into four groups according to the therapeutic challenges: topical glucocorticoid, pimecrolimus, emollient, and control (acetone only treated). We assessed the functional studies of skin barrier, epidermal expressions of differentiation markers, IL-1alpha, TNF-alpha, proteinase activated receptor-2 (PAR-2), TSLP and antimicrobial peptides (AMP), and serum IgE in each group. Topical glucocorticoid or pimecrolimus treatment improved AD like skin lesions and barrier functions, and restored the epidermal expression of differentiation markers, IL-1alpha, TNF-alpha, PAR-2, and TSLP, in Ox-AD mice. The improvement was relatively better with the glucocorticoid than pimecrolimus. Epidermal AMP expression was restored by topical glucocorticoid, but not pimecrolimus. Our result showed that topical glucocorticoid or pimecrolimus improved the AD-like skin lesions and barrier impairment by suppressing TSLP related allergic inflammation. PMID- 25786385 TI - Emerging infections and the cytology laboratory. PMID- 25786384 TI - Gold carbene or carbenoid: is there a difference? AB - By reviewing the recent progress on the elucidation of the structure of gold carbenes and the definitions of metal carbenes and carbenoids, we recommend to use the term gold carbene to describe gold carbene-like intermediates, regardless of whether the carbene or carbocation extreme resonance dominates. Gold carbenes, because of the weak metal-to-carbene pi-back-donation and their strongly electrophilic reactivity, could be classified into the broader family of Fischer carbenes, although their behavior and properties are very specific. PMID- 25786386 TI - Fabrication of Fluoropolymer Microtubes via RAFT Copolymerization of N,N' Methylene Bisacrylamide Gel Fibers and Fluoromonomer. AB - Fluoropolymer microtubes with a smooth surface were fabricated in more than 70 % yield via reversible addition fragmentation chain transfer (RAFT) co polymerization of N,N'-methylene bisacrylamide (MBA) gel fibers as both template and monomer, 2-(perfluoro-3-methylbutyl)ethyl acrylate (R-3420) as co-monomer, and pentaerythritol tetraacrylate (PET4A) as cross-linker. The resulting fluoropolymer microtubes were characterized fully by SEM, TEM, EDS, XPS, and FT IR. The influence of the monomer composition on the yields and morphologies of the tubes were investigated in detail. The results indicated that polymer microtubes with a smooth surface were obtained at suitable amounts of R-3420 and PET4A. Because of the decreased solubility of MBA gel fibers, the wall thickness increased as more R-3420 was used. In the presence of PET4A, the solution polymerization could be facilitated and more R-3420 could be attached onto the tubes based on FT-IR analysis. The water contact angle and swelling ratio measurements both revealed the low hydrophilicity and high lipophilicity of the fluoropolymer microtubes, which made the sample able to absorb toluene selectively in a water/toluene two-phase system. PMID- 25786387 TI - Diagnosis of Cushing's disease. AB - Diagnosis of Cushing's disease frequently remains a challenge. In this review we critically appraise the clinical features, biochemical tests, and imaging modalities used for this purpose. We outline recommendations for approaches to clinical investigation, with a particular focus on developments made within the last two years. PMID- 25786388 TI - A functional electrical stimulation system improves knee control in crouch gait. AB - BACKGROUND: Crouch gait is a major sagittal plane deviation in children diagnosed with cerebral palsy (CP). It is defined as a combination of excessive ankle dorsiflexion and knee and hip flexion throughout the stance phase. To the best of our knowledge, functional electrical stimulation (FES) has not been used to decrease the severity of crouch gait in CP subjects and assist in achieving lower limb extension. PURPOSE: To evaluate the short- and long-term effects of FES to the quadriceps muscles in preventing crouch gait and achieving ankle plantar flexion, knee and hip extension at the stance phase. METHODS: An 18-year-old boy diagnosed with CP diplegia [Gross Motor Function Classification System (GMFCS) level II] was evaluated. The NESS L300((r)) Plus neuroprosthesis system provided electrical stimulation of the quadriceps muscle. A three-dimensional gait analysis was performed using an eight-camera system measuring gait kinematics and spatiotemporal parameters while the subject walked shod only, with ground reaction ankle foot orthotics (GRAFOs) and using an FES device. RESULTS: Walking with the FES device showed an increase in the patient's knee extension at midstance and increased knee maximal extension at the stance phase. In addition, the patient was able to ascend and descend stairs with a "step-through" pattern immediately after adjusting the FES device. CONCLUSIONS: This report suggests that FES to the quadriceps muscles may affect knee extension at stance and decrease crouch gait, depending on the adequate passive range of motion of the hip, knee extension, and plantar flexion. Further studies are needed in order to validate these results. PMID- 25786389 TI - Current questions on space and time encoding. AB - The Nobel Prize in Physiology or Medicine 2014 celebrated the groundbreaking findings on place cells and grid cells by John O'Keefe and May-Britt Moser and Edvard Moser. These findings provided an essential foothold for understanding the cognitive encoding of space and time in episodic memory function. This foothold provides a closer view of a broad new world of important research questions raised by the phenomena of place cells and grid cells. These questions concern the mechanisms of generation of place and grid cell firing, including sensory influences, circuit dynamics and intrinsic properties. Similar questions concern the generation of time cells. In addition, questions concern the functional role of place cells, grid cells and time cells in mediating goal-directed behavior and episodic memory function. PMID- 25786391 TI - [Dos and don'ts for crystalloids in intensive care medicine. Can too much water be bad?]. AB - Notwithstanding the use of colloids, crystalloids have a firm position in today's intensive care: In addition to the substitution as a basic requirement of the human organism or drug carriers, they are primarily used for volume replacement. A common complication is the development of interstitial edema, which is due to the composition of these solutions and the permeability of the glycocalyx.With the large variety available on the market, bicarbonate-based precursor isotonic balanced full electrolyte solutions have become established in the meantime. The use of 0.9% saline solution is regarded as obsolete. With low cost and a good safety profile, a few relevant aspects, e.g., the risk of hypervolemia and electrolyte imbalance, must be taken into account in the use of crystalloids. PMID- 25786390 TI - Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice. AB - With a view toward reduction of graft loss, we explored pancreatic islet transplantation within fibrin matrices rendered pro-angiogenic by incorporation of minimal doses of vascular endothelial growth factor-A165 and platelet-derived growth factor-BB presented complexed to a fibrin-bound integrin-binding fibronectin domain. Engineered matrices allowed for extended release of pro angiogenic factors and for their synergistic signaling with extracellular matrix binding domains in the post-transplant period. Aprotinin addition delayed matrix degradation and prolonged pro-angiogenic factor availability within the graft. Both subcutaneous (SC) and epididymal fat pad (EFP) sites were evaluated. We show that in the SC site, diabetes reversal in mice transplanted with 1,000 IEQ of syngeneic islets was not observed for islets transplanted alone, while engineered matrices resulted in a diabetes median reversal time (MDRT) of 38 days. In the EFP site, the MDRT with 250 IEQ of syngeneic islets within the engineered matrices was 24 days versus 86 days for islets transplanted alone. Improved function of engineered grafts was associated with enhanced and earlier (by day 7) angiogenesis. Our findings show that by engineering the transplant site to promote prompt re-vascularization, engraftment and long-term function of islet grafts can be improved in relevant extrahepatic sites. PMID- 25786392 TI - Natural and synthetic compound anti-Trichomonas vaginalis: an update review. AB - Trichomonas vaginalis is a flagellate protozoan that causes trichomonosis, a sexually transmitted disease of worldwide importance. However, the infection has long received much less attention than other parasitic and sexually transmitted diseases. This negligence leads to poor diagnosis and underestimated prevalence values, and consequently, it has been associated to increasing acquisition and transmission of HIV, pregnancy outcomes, infertility, pelvic inflammatory disease, and cervical and prostate cancer. In view of increased resistance to drugs belonging to the nitroimidazole class, new treatment alternatives are urgently needed. Natural products provide an immeasurable wealth of active molecules, and a great number of new drugs have been originated from these compounds. In addition, new synthetic products or derivatives from old drugs also provide an alternative to treat trichomonosis. Albeit many studies have been performed with natural products against T. vaginalis, none of them progressed to clinical trials. Overall, inadequate financial investments are made, and no alternative treatment for trichomonosis has been discovered; meanwhile, hundreds of thousands of people will remain infected and suffering the serious consequences of this nonviral STD. Thus, it is highlighted that clinical trials for better understanding the potential in vitro are necessary and urgent in order to furnish a new therapeutic alternative for trichomonosis treatment. The current review attempts to give an overview on the potential of natural and synthetic products as antitrichomonal. PMID- 25786393 TI - Transmission electron microscopic observations on ultrastructural alterations in Schistosoma mansoni adult worms recovered from C57BL/6 mice treated with radiation-attenuated vaccine and/or praziquantel in addition to passive immunization with normal and vaccinated rabbit sera against infection. AB - Although the current treatment of schistosomiasis relies largely on praziquantel (PZQ), it has not been successful in significantly reducing the overall rate of disease cases, one of the suggested reasons being the inevitable resistance to PZQ. Previous studies showed that radiation-attenuated vaccine provides protection against Schistosoma mansoni in a host of various species. In the present study, we evaluated the effect of various vaccination strategies in C57BL/6 mice, including single or multiple vaccination strategy, subcurative dose (20 mg/kg) of PZQ, and a combination of single vaccination with subcurative dose of PZQ. Treatment either with subcurative dose of PZQ or with a single vaccination of attenuated cercariae (500 per mouse), caused significant reduction in total worm burden, hepatic, and intestinal ova counts of 43.03, 73.2, and 59.5 and 37.97, 52.02, and 26.3%, respectively. Furthermore, tegumental changes were observed. In multiple vaccinated group, there was an extensive lysis in tegumental layers. High deformations in gastrodermis, testis cells, vitelline cells, and oocytes were recorded. Also, this study is to explore the role of humoral immunity using highly resistant rabbits that had been exposed to three immunizations with ultraviolet (UV)-irradiated cercariae (8000 per rabbit in each immunization), and their sera were tested for their ability to transfer protection. The reduction in challenge worm burden had reached 32.76-43.64% when compared with recipients of normal serum or no serum. The reduction in hepatic and intestinal ova counts reached to 74.4 and 71.08% in group immunized with vaccinated rabbit sera. Swelling and extensive lysis of tegumental layers, gastrodermis lumen, spermatocytes, and deformation of oocytes were recorded with more severity than that recorded in normal rabbit sera group. Our findings recorded that multiple vaccination strategy is the most effective strategy then passive transfer of vaccinated rabbit. This gives guiding in the design the appropriate therapeutic strategy. PMID- 25786394 TI - Intravenous Furosemide for Acute Decompensated Congestive Heart Failure: What Is the Evidence? AB - Use of intravenous furosemide rather than oral administration in acute decompensated congestive cardiac failure is universally recommended in international guidelines. We argue that this recommendation is not supported by the existing evidence, and suggest that trials should be performed to determine whether larger doses of oral furosemide should be prescribed prior to an IV switch. This could reduce length of hospital admissions and allow for more patients to be managed in the primary care setting. PMID- 25786395 TI - Inhibitory effects of relaxin on cardiac fibroblast-to-myofibroblast transition: an electrophysiological study. AB - NEW FINDINGS: What is the central question of this study? Fibroblast-to myofibroblast transition is a key mechanism in the reparative response to tissue damage, but myofibroblast persistence in the wound leads to fibrosis and organ failure. The role of relaxin as an antifibrotic agent capable of counteracting the acquisition of biophysical features of differentiated myofibroblasts deserves further investigation. What is the main finding and its importance? Electrophysiological analysis showed that relaxin, administered during profibrotic treatment, hyperpolarizes the membrane potential and attenuates delayed rectifier and inwardly rectifying K(+) currents, which usually increase in the transition to myofibroblasts. These findings provide further clues to the therapeutic potential of relaxin in fibrosis. The hormone relaxin (RLX) is produced by the heart and may be involved in endogenous mechanisms of cardiac protection against ischaemic injury and fibrosis. Recent findings in cultured cardiac stromal cells suggest that RLX can inhibit fibroblast-to-myofibroblast transition, thereby counteracting fibrosis. In order to explore its efficiency as an antifibrotic agent further, we designed the present study to investigate whether RLX may influence the electrophysiological events associated with differentiation of cardiac stromal cells to myofibroblasts. Primary cardiac proto myofibroblasts and NIH/3T3 fibroblasts were induced to myofibroblasts by transforming growth factor-beta1, and the electrophysiological features of both cell populations were investigated by whole-cell patch clamp. We demonstrated that proto-myofibroblasts and myofibroblasts express different membrane passive properties and K(+) currents. Here, we have shown, for the first time, that RLX (100 ng ml(-1) ) significantly reduced both voltage- and Ca(2+) -dependent delayed-rectifier and inward-rectifying K(+) currents that are typically increased in myofibroblasts compared with proto-myofibroblasts, suggesting that this hormone can antagonize the biophysical effects of transforming growth factor beta1 in inducing myofibroblast differentiation. These newly recognized effects of RLX on the electrical properties of cardiac stromal cell membrane correlate well with its well-known ability to suppress myofibroblast differentiation, further supporting the possibility that RLX may be used for the treatment of cardiac fibrosis. PMID- 25786396 TI - Surface chemistry and effects on bone regeneration of a novel biomimetic synthetic bone filler. AB - The paper presents results of physico-chemical and biological investigations of a surface-engineered synthetic bone filler. Surface analysis confirms that the ceramic phosphate granules present a collagen nanolayer to the surrounding environment. Cell cultures tests show that, in agreement with literature reports, surface-immobilized collagen molecular cues can stimulate progression along the osteogenic pathway of undifferentiated human mesenchymal cells. Finally, in vivo test in a rabbit model of critical bone defects shows statistically significant increase of bone volume and mineral apposition rate between the biomimetic bone filler and collagen-free control. All together, obtained data confirm that biomolecular surface engineering can upgrade the properties of implant device, by promoting more specific and targeted implant-host cells interactions. PMID- 25786397 TI - The synergistic effects of Chinese herb and injectable calcium silicate/beta tricalcium phosphate composite on an osteogenic accelerator in vitro. AB - This study investigates the physicochemical and biological effects of traditional Chinese medicines on the beta-tricalcium phosphate (beta-TCP)/calcium silicate (CS) composites of bone cells using human dental pulp cell. CS is an osteoconductive and bioactive material. For this research we have combined beta TCP and CS and check its effectiveness, a series of beta-TCP/CS composites with different ratios of Xu Duan (XD) were prepared to make new bioactive and biodegradable biocomposites for bone repair. XD has been used in Traditional Chinese Medicine for hundreds of years as an antiosteoporosis, tonic and antiaging agent for the therapy of low back pain, traumatic hematoma, threatened abortion and bone fractures. Formation of bone-like apatite, the diametral tensile strength, and weight loss of composites were considered before and after immersion in simulated body fluid (SBF). In addition, we also examined the effects of XD released from beta-TCP/CS composites and in vitro human dental pulp cell (hDPCs) and studied its behavior. The results show the XD-contained paste did not give any demixing when the weight ratio of XD increased to 5-10 % due to the filter-pressing effect during extrusion through the syringe. After immersion in SBF, the microstructure image showed a dense bone-like apatite layer covered on the beta-TCP/CS/XD composites. In vitro cell experiments shows that the XD rich composites promote human dental pulp cells (hDPCs) proliferation and differentiation. However, when the XD quantity in the composite is more than 5 %, the amount of cells and osteogenesis protein of hDPCs were stimulated by XD released from beta-TCP/CS composites. The combination of XD in degradation of beta-TCP and osteogenesis of CS gives strong reason to believe that these calcium based composite cements may prove to be promising bone repair materials. PMID- 25786398 TI - Photocrosslinked layered gelatin-chitosan hydrogel with graded compositions for osteochondral defect repair. AB - A layered gelatin-chitosan hydrogel with graded composition was prepared via photocrosslinking to simulate the polysaccharide/collagen composition of the natural tissue and mimic the multi-layered gradient structure of the cartilage bone interface tissue. Firstly, gelatin and carboxymethyl chitosan were reacted with glycidyl methacrylate (GMA) to obtain methacrylated gelatin (Gtn-GMA) and carboxymethyl chitosan (CS-GMA). Then, the mixed solutions of Gtn-GMA in different methacrylation degrees with CS-GMA were prepared to form the superficial, transitional and deep layers of the hydrogel, respectively under the irradiation of ultraviolet light, while polyhedral oligomeric silsesquioxane was introduced in the deep layer to improve the mechanical properties. Results suggested that the pore sizes of the superficial, transitional and deep layers of the layered hydrogel were 115 +/- 30, 94 +/- 34, 51 +/- 12 MUm, respectively and their porosities were all higher than 80 %. The compressive strengths of them were 165 +/- 54, 565 +/- 50 and 993 +/- 108 kPa, respectively and the strain of the gradient hydrogel decreased along the thickness direction, similar to the natural tissue. The in vitro cytotoxicity results showed that the hydrogel had good cytocompatibility and the in vivo repair results of osteochondral defect demonstrated remarkable recovery by using the gradient gelatin-chitosan hydrogel, especially when the hydrogel loading transforming growth factor-beta1. Therefore, it was suggested that the prepared layered gelatin-chitosan hydrogel in this study could be potentially used to promote cartilage-bone interface tissue repair. PMID- 25786400 TI - Pathophysiology of Clinical Symptoms in Acute Viral Respiratory Tract Infections. AB - In this article we discuss the pathophysiology of common symptoms of acute viral respiratory infections (e.g., sneezing, nasal discharge, sore throat, cough, muscle pains, malaise, and mood changes). Since clinical symptoms are not sufficient to determine the etiology of viral respiratory tract infections, we believe that the host defense mechanisms are critical for the symptomatology. Consequently, this review of literature is focused on the pathophysiology of respiratory symptoms regardless of their etiology. We assume that despite a high prevalence of symptoms of respiratory infection, their pathogenesis is not widely known. A better understanding of the symptoms' pathogenesis could improve the quality of care for patients with respiratory tract infections. PMID- 25786399 TI - Biotechnologically produced microbial alginate dressings show enhanced gel forming capacity compared to commercial alginate dressings of marine origin. AB - Marine alginate fibre dressings are well established in wound management. Alginate fibres can absorb plenty of wound exudate due to their gel forming abilities and ion exchange. Alginates from bacteria have never been studied for medical applications so far, although the microbial polymer raises expectations for improved gelling capacity due to its unique O-acetylation. To prove the gelling capacity of bacterial alginate, we extracted the co-polymer from fermentation of the soil bacterium Azotobacter vinelandii ATCC 9046, cultivated on crude glycerol as an alternative carbon source. Bacterial alginate was isolated in high purity and extruded by a wet spinning method. Fibre structure and properties were characterised by infrared spectroscopy, NMR, GPC, scanning electron microscopy and tensile testing. The fibres could be processed into biocompatible needle web dressings, which showed more than twice the gel formation in saline compared to commercial dressings made of marine alginates. Gelled dressings of bacterial alginate formed stable hydrogels of sufficient shape and strength for wound healing applications. This work suggests that the increased gel formation of bacterial alginate from A. vinelandii may be optimal for the preparation of novel wound dressings. PMID- 25786401 TI - Evaluation of Airway Inflammation in Compost Workers Exposed to Bioaerosols Using Exhaled Breath Condensate and Fractional Exhaled Nitric Oxide. AB - Occupational bioaerosol exposures are capable to cause respiratory diseases. We studied the relationship between exposure to bioaerosols and biomarkers' concentration in exhaled breath condensate (EBC) and fractional exhaled nitric oxide (FeNO) in 119 bioaerosol-exposed compost workers taking into account atopy and smoking habits. Atopy was classified according to specific IgE concentrations to common inhalant allergens (sx1). Bioaerosol exposure was estimated according to job title, duration of employment, results of ambient monitoring at the workplaces, and shift time worked under protection of filtered air supply. Concentrations of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and acid-base balance (pH) in EBC and FeNO were assessed in 59 never-smoking (NS) and 60 smoking (S) compost workers. We found that atopic subjects were equally distributed among NS and S (n=16 each). Levels of 8-iso-PGF2alpha were significantly higher in workers considered highly exposed to bioaerosols than in low exposed workers (86.6 (66.1; 128.8) pg/mL vs. 74.4 (56.3; 96.7) pg/mL, p=0.047). No associations could be observed between exposures and biomarkers concerning compost workers in total, but there were some in atopic workers (duration of employment and FeNO: r=0.376, p=0.041; filtered air supply and FeNO: r=-0.335, p=0.071). Smokers had significantly lower pH values compared to NS (non-atopic, p=0.041; atopic p=0.050). In conclusion, EBC and FeNO might be useful tools for monitoring of inflammation due to bioaerosol exposures, especially in atopic subjects. Besides smoking also atopy should be considered when investigating airway inflammation. PMID- 25786402 TI - Evaluation of the Activity of Influenza and Influenza-Like Viruses in the Epidemic Season 2013/2014. AB - Infections caused by respiratory viruses can have different clinical symptoms, while specific set of symptoms can be induced by different viruses. Despite usually mild course of disease, some viruses causing certain disease entity can result in serious complications. Therefore, quick and appropriate diagnostic is crucial for administering proper treatment. In the epidemic season 2013/2014, 2,497 specimens were tested. Infections caused by influenza viruses were confirmed in 9.8%, while infections caused by influenza-like viruses (ILI) in 13.2%. The co-domination of A/H1N1/pdm09 (29.4%) with A/H3N2/ (30.6%) was observed among circulating subtypes of influenza virus type A. Analysis of positive specimens categorized into 7 age groups indicated that most of morbidity to influenza was noted in the age intervals: 26-44 (22.9%) and 45-64 years old (21.6%). Considering infections caused by influenza-like viruses, the highest amount of positive cases was registered in the age group 0-4 years old (92.7%) with the highest ratio of RSV (87.9%) and PIV-3 (10.5%). Judging by the epidemiological and virological indicators, the 2013/14 influenza season was mild and only low virus activity was reported in Poland as well as in most European countries. Still, 9,000 hospitalizations and 17 deaths were registered in Poland during this epidemic season. PMID- 25786403 TI - Plasma Fibrinolysis Parameters in Smokers and Non-smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. AB - Cardiovascular diseases (CVD) are an important cause of morbidity and mortality worldwide. Parameters of coagulation and fibrinolysis are risk factors of CVD and might be affected by cigarette smoking. Aim of our study was to analyze the effect of cigarette smoking on parameters of fibrinolysis in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study as well as the use of these parameters for risk prediction. We determined plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen (t-PA), protein C activity, and D-dimers in 3,316 LURIC patients. Smoking status was assessed by a questionnaire and measurement of plasma cotinine concentration. Cox regression was used to assess the effect of parameters on mortality. We found that of the 3,316 LURIC patients 777 were AS and 1,178 NS. Within the observation period of 10 years (median) 221 AS and 302 NS died. In male AS vs. NS, PAI-1 (19.0 (10.0-35.0) vs. 15.0 (9.0-29.0) U/ml; p=0.026) and t-PA antigen (12.7 (9.6-16.3) vs. 11.6 (8.9-14.6) MUg/l; p=0.020) were slightly increased, while t-PA activity was slightly decreased (0.63 (0.30 1.05) vs. 0.68 (0.42-1.10) U/l; p=0.005). In female AS vs. NS, t-PA antigen (10.5 (8.3-13.9) vs. 11.5 (8.8-15.0) MUg/l; p=0.025) and protein C (108.0+/-24.1% vs. 118.0+/-25.7%; p=0.004) were decreased. All parameters except for protein C were predictive for mortality in AS. Fully adjusted hazard ratios (95% CI) were 1.14 (1.04-1.25), 1.19 (1.06-1.34), and 1.29 (1.11-1.49) per 1SD increase for D-dimer, t-PA, and PAI-1, respectively. Including fibrinolysis parameters in risk prediction models for mortality improved the area-under-the-curve (AUC) significantly compared with the conventional risk factors. In conclusion, we found alterations in the fibrinolytic system in smokers, which were more pronounced in male AS. PAI-1, t-PA and D-dimers were significant predictors of mortality in AS in LURIC and should be included into the assessment of cardiovascular risk particularly in patients at risk. PMID- 25786404 TI - Atrial Fibrillation and Gastro-Oesophageal Reflux Disease - Controversies and Challenges. AB - Atrial fibrillation and gastro-oesophageal reflux are common manifestations in daily practice. The atria and the oesophagus are closely located and have similar nerve innervations. Over the last years, it has been observed that atrial fibrillation development and reflux disease could be related. Atrial fibrillation occurrence could be due to vagal nerve overstimulation. This, in association with vagal nerve-mediated parasympathetic stimulation, has also been observed in patients with gastro-oesophageal reflux. These mechanisms, in addition to inflammation, seem to be implicated in the pathophysiology of both diseases. Despite these associations supported by clinical and experimental studies, this relationship is still considered controversial. This review summarizes critical data regarding the association of gastro-oesophageal reflux and atrial fibrillation as well as their clinical implications. PMID- 25786405 TI - Dynamic airway pressure-time curve profile (Stress Index): a systematic review. AB - The assessment of respiratory mechanics at the bedside is necessary in order to identify the most protective ventilatory strategy. Indeed in the last 20 years, adverse effects of positive ventilation to the lung structures have led to a reappraisal of the objectives of mechanical ventilation. The ventilator setting requires repeated readjustment over the period of mechanical ventilation dependency and careful respiratory monitoring to minimize the risks, preventing further injury and permitting the lung and airways healing. Among the different methods that have been proposed and validated, the analysis of dynamic P-t curve (named Stress Index, SI) represents an adequate tool available at the bedside, repeatable and, therefore, able to identify the amount of overdistension occurring in the daily clinical practice, when modifying positive end-expiratory pressure. In this review we will analyze the evidence that supports respiratory mechanics assessment at the bedside and the application of the dynamic P/t curve profile (SI) to optimize protective ventilation in patients with acute respiratory failure. PMID- 25786406 TI - Improve reporting of female genital mutilation, MPs tell doctors. PMID- 25786407 TI - US Republicans' budget would cut Medicaid and Medicare and repeal health reform law. PMID- 25786409 TI - Epilepsia partialis continua of the abdominal muscles due to cerebrovascular disease. AB - Two elderly men, with previous history of cerebrovascular disease, were admitted to the emergency department due to focal motor status epilepticus with persistent myoclonic jerks of one side of the body. In both cases, the clinical picture evolved into a unilateral and isolated arrhythmic myoclonus of the abdominal muscles with preserved consciousness. These involuntary movements resolved with antiepileptic drugs. Although cerebrovascular disease is one of the most common causes of epilepsia partialis continua, reported cases in the literature with predominant abdominal involvement have a different aetiology. The neuroimaging and electroencephalographic findings showed a wide spectrum of different localizations and aetiologies associated with this particular type of epileptic seizure. Indeed, the pathophysiology of focal motor seizures involving the abdominal muscles is still a matter of discussion. In our second case, we present a patient with epilepsia partialis continua of the abdominal wall with an occipital focus, which, to the best of our knowledge, has not been previously reported. [Published with video sequences]. PMID- 25786410 TI - A case of papular elastolytic giant cell granuloma: A mini-review of reported cases. PMID- 25786408 TI - The optimization of treatment and management of schizophrenia in Europe (OPTiMiSE) trial: rationale for its methodology and a review of the effectiveness of switching antipsychotics. AB - BACKGROUND: Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. METHODS: We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choices of the OPTiMiSE trial. RESULTS: We found 10 RCTs on switching antipsychotic drugs. No trial was conclusive and none was concerned with first-episode schizophrenia. In OPTiMiSE, 500 first episode patients are treated with amisulpride for 4 weeks, followed by a 6-week double-blind RCT comparing continuation of amisulpride with switching to olanzapine and ultimately a 12-week clozapine treatment in nonremitters. A subsequent 1-year RCT validates psychosocial interventions to enhance adherence. DISCUSSION: Current literature fails to provide basic guidance for the pharmacological treatment of schizophrenia. The OPTiMiSE trial is expected to provide a basis for clinical guidelines to treat patients with a first episode of schizophrenia. PMID- 25786411 TI - Not just a number: effect of age on fertility, pregnancy and offspring vigour in thoroughbred brood-mares. AB - Advancing age can adversely affect a thoroughbred brood-mare's reproductive efficiency and influence the commercial and athletic potential of her progeny. Causes for the decline in fertility include decreased oocyte and embryo quality, anatomical defects and endometrial degeneration. In addition, evidence exists that as the age of a dam increases, her foals will be at increased risk of morbidity and mortality during the neonatal period. Health issues can have lasting and deleterious effects on surviving foals, including decreased sale value and reduced athletic performance. The purpose of this review is to evaluate the association between mare age, fertility and offspring vigour in thoroughbred horses. PMID- 25786412 TI - Neural correlates of prenatal stress in young women. AB - BACKGROUND: Prenatal stress is hypothesized to have a disruptive impact on neurodevelopmental trajectories, but few human studies have been conducted on the long-term neural correlates of prenatal exposure to stress. The aim of this study was to explore the relationship between prenatal stress exposure and gray-matter volume and resting-state functional connectivity in a sample of 35 healthy women aged 14-40 years. METHOD: Voxel-based morphometry and functional connectivity analyses were performed on the whole brain and in specific regions of interest (hippocampus and amygdala). Data about prenatal/postnatal stress and obstetric complications were obtained by interviewing participants and their mothers, and reviewing obstetric records. RESULTS: Higher prenatal stress was associated with decreased gray-matter volume in the left medial temporal lobe (MTL) and both amygdalae, but not the hippocampus. Variance in gray-matter volume of these brain areas significantly correlated with depressive symptoms, after statistically adjusting for the effects of age, postnatal stress and obstetric complications. Prenatal stress showed a positive linear relationship with functional connectivity between the left MTL and the pregenual cortex. Moreover, connectivity between the left MTL and the left medial-orbitofrontal cortex partially explained variance in the depressive symptoms of offspring. CONCLUSIONS: In young women, exposure to prenatal stress showed a relationship with the morphometry and functional connectivity of brain areas involved in the pathophysiology of depressive disorders. These data provide evidence in favor of the hypothesis that early exposure to stress affects brain development and identified the MTL and amygdalae as possible targets of such exposure. PMID- 25786413 TI - Tuning the elastic nonlinearities in composite nanomaterials. AB - The possibility of tuning the nonlinear effective response of composite materials and structures is of great importance for developing new concepts such as soft metamaterials, acoustic diodes, nonlinear waveguides and phononic crystals. In this paper we develop a homogenization technique for dispersions of nonlinear particles in a soft matrix able to take account of second and third order elastic nonlinearities. Based on this method, we prove the possibility to strongly amplify a given particles nonlinearity (either the second or the third one) under specific conditions concerning the linear response of the two constituents (particles and matrix). We finally give a realistic example based on a population of porous polymer particles embedded in a PDMS matrix. PMID- 25786414 TI - Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma. AB - Neuroblastoma (NB), although rare, accounts for 15% of all paediatric cancer mortality. Unusual among cancers, NBs lack a consistent set of gene mutations and, excluding large-scale chromosomal rearrangements, the genome seems to be largely intact. Indeed, many interesting features of NB suggest that it has little in common with adult solid tumours but instead has characteristics of a developmental disorder. NB arises overwhelmingly in infants under 2 years of age during a specific window of development and, histologically, NB bears striking similarity to undifferentiated neuroblasts of the sympathetic nervous system, its likely cells of origin. Hence, NB could be considered a disease of development arising when neuroblasts of the sympathetic nervous system fail to undergo proper differentiation, but instead are maintained precociously as progenitors with the potential for acquiring further mutations eventually resulting in tumour formation. To explore this possibility, we require a robust and flexible developmental model to investigate the differentiation of NB's presumptive cell of origin. Here, we use Xenopus frog embryos to characterise the differentiation of anteroventral noradrenergic (AVNA) cells, cells derived from the neural crest. We find that these cells share many characteristics with their mammalian developmental counterparts, and also with NB cells. We find that the transcriptional regulator Ascl1 is expressed transiently in normal AVNA cell differentiation but its expression is aberrantly maintained in NB cells, where it is largely phosphorylated on multiple sites. We show that Ascl1's ability to induce differentiation of AVNA cells is inhibited by its multi-site phosphorylation at serine-proline motifs, whereas overexpression of cyclin dependent kinases (CDKs) and MYCN inhibit wild-type Ascl1-driven AVNA differentiation, but not differentiation driven by a phospho-mutant form of Ascl1. This suggests that the maintenance of ASCL1 in its multiply phosphorylated state might prevent terminal differentiation in NB, which could offer new approaches for differentiation therapy in NB. PMID- 25786416 TI - Sedative effects of intramuscular alfaxalone administered to cats. AB - The sedative effects of intramuscular (IM) alfaxalone in 2-hydroxypropyl-beta cyclodextrin (alfaxalone-HPCD) were evaluated in cats. The cats were treated with alfaxalone-HPCD in five occasions with a minimum 14-day interval between treatments: an IM injection of 1.0 mg/kg (IM1), 2.5 mg/kg (IM2.5), 5 mg/kg (IM5) or 10 mg/kg (IM10), or an intravenous injection of 5 mg/kg (IV5). The sedative effects were evaluated subjectively using a composite measurement scoring system (a maximum score of 16). Cardio-respiratory variables were measured non invasively. The median sedation scores peaked at 10 min (score 9), 15 min (score 14), 10 min (score 16), 10 to 20 min (score 16) and 2 to 5 min (score 16) after the IM1, IM2.5, IM5, IM10 and IV5 treatments, respectively. The IM5 treatment produced longer lasting sedation, compared to the IV5 treatment. Durations of maintenance of lateral recumbency after the IM10 treatment (115 +/- 22 min) were longer than those after the IM2.5 (40 +/- 15 min), IM5 (76 +/- 21 min) and IV5 treatments (50 +/- 5 min). Cardio-respiratory variables remained within clinically acceptable ranges, except for each one cat that showed hypotension (<60 mmHg) after the IM10 and IV5 treatments. Tremors, ataxia and opisthotonus like posture were observed during the early recovery period after the IM2.5, IM5, IM10 and IV5 treatments. In conclusion, IM alfaxalone-HPCD produced dose dependent and clinically relevant sedative effect at 2.5 to 10 mg/kg in healthy cats. Hypotension may occur at higher IM doses of alfaxalone-HPCD. PMID- 25786417 TI - [Medical education and training in geriatrics: the challenge for the future]. PMID- 25786415 TI - Of mice, flies--and men? Comparing fungal infection models for large-scale screening efforts. AB - Studying infectious diseases requires suitable hosts for experimental in vivo infections. Recent years have seen the advent of many alternatives to murine infection models. However, the use of non-mammalian models is still controversial because it is often unclear how well findings from these systems predict virulence potential in humans or other mammals. Here, we compare the commonly used models, fruit fly and mouse (representing invertebrate and mammalian hosts), for their similarities and degree of correlation upon infection with a library of mutants of an important fungal pathogen, the yeast Candida glabrata. Using two indices, for fly survival time and for mouse fungal burden in specific organs, we show a good agreement between the models. We provide a suitable predictive model for estimating the virulence potential of C. glabrata mutants in the mouse from fly survival data. As examples, we found cell wall integrity mutants attenuated in flies, and mutants of a MAP kinase pathway had defective virulence in flies and reduced relative pathogen fitness in mice. In addition, mutants with strongly reduced in vitro growth generally, but not always, had reduced virulence in flies. Overall, we demonstrate that surveying Drosophila survival after infection is a suitable model to predict the outcome of murine infections, especially for severely attenuated C. glabrata mutants. Pre-screening of mutants in an invertebrate Drosophila model can, thus, provide a good estimate of the probability of finding a strain with reduced microbial burden in the mouse host. PMID- 25786418 TI - [Pulmonary hypertension in the elderly]. AB - In the past decade, a significant improvement has been done in the management of pulmonary arterial hypertension, a devastating disease. Beside the aging population, one of the next challenges is to develop a specific management of a pulmonary hypertension's suspicion, in the aged patients. In fact, recent data have shown that if pulmonary hypertension were mostly related to chronic heart or lung failure, or pulmonary embolism, some elderly may in fact develop a real pulmonary arterial hypertension. Because of the potential therapies which may be proposed, the evaluation of a pulmonary hypertension's suspicion in the elderly needs a stringent evaluation by trained physicians, in collaboration with geriatricians. PMID- 25786419 TI - [Appropriateness of direct admissions to acute care geriatric unit for nursing home patients: an adaptation of the AEPf GRID]. AB - The patient population staying in nursing homes is increasingly vulnerable and dependent and should benefit from a direct access to an acute care geriatric unit. Nevertheless, the easy access by a simple phone call from the general practitioner to the geriatrician, as well as the lack of orientation of these patients by emergency units, might lead to inappropriate admissions. This work studied the appropriateness of direct admissions of 40 patients living in nursing home in an acute care geriatric unit. Based on the AEPf assessment grid, 82.5% of these admissions were considered as appropriate (52.5%) or justified (30% based on an expert panel decision), and 17.5% were inappropriate. In conclusion, the process of direct admission does not seem to increase the rate of inappropriate admissions. Some actions could decrease this rate: implementation of geriatric mobile teams or psychogeriatric mobile teams intervening in nursing home, a better and more adapted use of ambulatory structures, a better information to the general practitioners. In order to reduce the intervention of the panel of experts, an adaptation of the AEPf assessment grid to these geriatric patients has been proposed. The "AEPg" assessment grid should benefit from a validation study. PMID- 25786420 TI - [The fight against malnutrition in older adults: new aproaches in dentistry]. AB - A minimal oral treatment aiming a clean and comfortable mouth could be very helpful in malnutrition control of dependent elderly persons. In such a case, it is necessary and generally it is enough to perform dental scaling and/or extractions with anxiolytic premedication (oral or rectal diazepam). Most of times, such minimal dental care can be performed at bedside, avoiding patient's stress and displacement to a dental surgery. The nursing staff can reassure the residents and their families on the absence of dentures, because saliva would be even more important than teeth. Actually, there is a tight relation between oral health, saliva, drugs, food texture and nutritional state of person. The notion of saliva includes two important criteria: 1) saliva-bacteria in the saliva, 2) fluid saliva-oral biofilm covering mucous membranes. All factors which change saliva secretion or inhibit oral bacteria community may lead to malnutrition. Several studies performed in hospital geriatric wards and in retirement homes allowed us to identify the following iatrogenic causes for malnutrition: 1) inappropriate preservation of teeth or dentures which may lead to oral reservoir (Candida albicans yeast-hyphal transition, antibiotic resistance genes transfer); 2) excessive uses of antiseptic mouthwashes for oral hygiene (leading to oral biofilm inhibition which is a cause of xerostomia); 3) drugs crushed in food (alteration of food taste and alteration of the oral biofilm); 4) exclusive recourse to a soft or mixed texture of food (alternative solutions exist, such as texture-adapted protein rich cookies). All these iatrogenic practices raise the possibility of formation of thick microbial communities in the mouth. This would explain why, despite attentive oral care, most of nurses and nurse's aides feel that in retirement homes the oral hygiene of the many residents is insufficient. PMID- 25786421 TI - [Representation and practice about "chimical restraints": qualitative study with 50 health worker]. AB - The term "chemical restraints" seems to be used in medical practice, but does not have the same meaning for all French health care professionals. In available literature it is considered as use of psychotropic medications for behavioral disorders. We used qualitative research method based on semi-directive interviews, in order to better understand meaning of "chemical restraint" term for geriatric medical and paramedical personnel. This term is well understood, rarely used, wrong for some professional because "drugs do not hold". The term of "physical restraint" has a more tangible reality. The term of "sedation of psychocomportemental troubles" is more common and seems to have a less pejorative connotation. In practice chemical restraint may correspond to emergency use of benzodiazepines or neuroleptics by injection at doses leading to the patient's sedation without his consent. PMID- 25786422 TI - [Cost evaluation of hospital inpatient stays induced by injuries due to falls for elderly people]. AB - Thirty percent of people aged 65 and older, living at home fall at least once a year. Few economic data are available in Belgium on this issue. We evaluated the cost borne by social security. 823 inpatient stays aged 65 and more, from home and admitted for injuries after a fall were selected. We observe an average (SD) age of 81 years. The proportion of women is 76%. 75% of admissions are related to fractures. 18% of patients are 'institutionalized' after falls. The death rate is 6%. The median (Q1-Q3) of cost is ? 4.182 (2.385-6.820), for a length of stay median (Q1-Q3) of 11 days (4-25). The cost of hospital stays is estimated at ?135 millions. Based on population projections, the cost could be estimated at ? 243 millions in 2050. The overall cost of the treatment of these lesions is much more important, because costs are also generated after the hospitalization. PMID- 25786423 TI - [Quality of life of elderly people on oral anticoagulant for atrial fibrillation: VKA versus direct oral anticoagulants]. AB - Atrial fibrillation (AF) is the most common arrhythmia. Its prevalence increases with age and increases the risk of stroke and systemic embolism. Few data are currently available on the quality of life (QOL) of anticoagulated patients with the advent of direct oral anticoagulants (DOAC). Our study aims to describe levels of QOL in elderly patients with AF receiving oral anticoagulants and compare QOL of patients treated with vitamin K antagonists (VKA) and DOAC. This prospective study included patients of 65 years and over, receiving anticoagulants for AF (VKA or DOAC) from general practice (n=70) or cardiac practice (n=30). The patients completed a self-administered questionnaire that included demographic, geriatric data and a QOL standardized scale: the anti-clot treatment scale (ACTS) 17 items exploring two dimensions "Burdens" and "Benefits". Eighty-nine patients were enrolled: 61 were taking VKA and 28 taking DOAC. Our two groups were comparable for all demographic and clinical characteristics studied. Our patients' mean scores were 48.6+/-12.1 on Burdens and 9.7+/-3.8 on Benefits. Burdens and Benefits scores were significantly better for patients treated with DOAC compared to patients with VKA (p<0.0001 and p<0.01, respectively). Anticoagulation in the elderly should be encouraged given the high thrombotic risk of AF. No matter what kind of molecule is chosen if in accordance to good guidance. Patients treated with ACOD seem to have a better QOL, but these results should be confirmed through larger randomized studies. PMID- 25786424 TI - [Triage risk screening tool (TRST) in screening elderly patients requiring the intervention of a mobile geriatric team: results of a pilot study]. AB - Improving care and health course for hospitalized elderly patients is one of the tasks set out in the "Rapport du parcours de sante des PAERPA" (elderly people with or at risk of functional decline). Identification of the needs of a mobile geriatric team (MGT) intervention for the patients remain difficult in emergency department and in medical surgical units. A screening tool is needed and should be simple and fast to use. Its implementation implies that it is efficient and previously validated. The aim of our study was to evaluate the validity and predictive performances of the Triage risk stratification tool (TRST) for identify patients aged over 75 years, requiring the intervention of the MGT. This is a prospective, national, multicenter study including consecutive patients aged 75 years and older, hospitalized in emergency services and medical-surgical units in September and October 2013. The TRST was considered positive when the score was greater than 2 of 5 points. A supplementary question with binary answer (yes/no) was asked to MGT, in order to define if MGT intervention was useful. This issue has served as a "gold standard" for assessing the validity and predictive test performance. In emergency departments, the TRST was performed in 427 patients, 347 were positive. Results showed high sensitivity (79%), and poor specificity (19%) of the test in emergency units, showing that TRST did not permit to identify patients requiring MGT intervention. In contrast, the TRST seems more performant in medical-surgical (n=63 patients) units with good predictive performances (positive predictive value 90% and negative predictive value 87%). The specificity of TRST in emergency services is insufficient to generalize its use. However, performances of the TRST in other units are encouraging to propose a validation as part of a national research project. PMID- 25786425 TI - [Age-prospective memory-paradox: explanatory hypotheses]. AB - Prospective memory is a complex cognitive function requiring to remember a planned action. For example, this function is particularly important for elderly people to remember taking medication at the appropriate time. The comparison of the performance of old and young peoples on different prospective memory tasks led to two contradictory results, a configuration that has been dubbed "age prospective memory-paradox". The first set of results of the age-prospective memory-paradox configuration is in keeping with the effects of aging on cognitive functioning, older peoples generally performing less well than younger peoples on laboratory prospective memory tasks. The second set of results is at odds with the first one, as older peoples generally perform better than younger peoples on naturalistic prospective memory tasks. The aim of the present paper is to expose the main explanatory hypotheses of the age related deficit on laboratory prospective memory tasks in one hand and on the age related benefit on naturalistic prospective memory tasks on the other hand. Concerning laboratory prospective memory tasks, the main hypothesis is that the detrimental effect of age would be principally due to negative influence of age on executive control processes and retrospective memory processes involved in this kind of tasks. With respect to naturalistic prospective memory tasks, a higher motivational level and the fact that older people have more frequently recourse to external memory aids and to compensation strategies could explain the better results of older people. PMID- 25786426 TI - [Jean-Baptiste Vincent Laborde (1830-1903), forgotten neurologist and neurophysiologist]. AB - Jean-Baptiste Vincent Laborde (1830-1903), native of Buzet, in Gascony, undertook his medical studies in Paris and was nominated "externe" (1854) then "interne" (1858) of Paris hospitals. His main "patrons" were Alfred Velpeau (1795-1867), Auguste Nelaton (1807-1873), Jean-Baptiste Bouillaud (1796-1881), Pierre-Olive Rayer (1793-1867), Joseph-Francois Malgaigne (1806-1865), Pierre Carl Edouard Potain (1825-1901), Ernest Charles Lasegue (1816-1883) and Leon Rostan (1790 1866). In 1864 he defended his thesis on the essential paralysis of childhood. He then worked in the physiology laboratory of Professor Jules Auguste Beclard (1818 1887), and became "chef des travaux" of physiology at the Paris faculty of medicine. In 1890, he was nominated to the chair of Biological anthropology at the Paris school of anthropology. His main works focused on the rhythmic tractions of the tongue in cases of apparent death, the understanding of the etiology of brain softening he attributed to vascular occlusions by atheroma and the discovery of connections between the cranial nuclei of common (III) and external (VI) oculomotor nerves and the struggle against the use of ceruse, against tuberculosis and especially against alcoholism. In addition, he made a career in journalism: since 1874 he had been the founder, director and editor-in chief of the weekly newspaper The Medical Tribune, whose aim was to "combine to a fair extent, science and progress with the practice of medicine." Finally, Laborde was a convinced Republican, a friend of Leon Gambetta's (1838-1882). For him, democracy was the "ideal of civilized nations" and he showed deep hatred for the "Commune of Paris". Finally, he was a determined free thinker, who ran the Society for mutual autopsy for a while and who was attached to civil funerals and cremation. PMID- 25786427 TI - [REM sleep behavior disorder in dementia with Lewy bodies]. AB - REM sleep behavior disorder (RBD) is included in the diagnostic criteria for dementia with Lewy bodies (DLB), and is useful for being distinguished from Alzheimer's disease. However, RBD can precede DLB for a few years and be a warning symptom when associated with visuospatial disorders and hypometabolism in occipital regions by SPECT. When RBD are associated with dangerous behaviors or increased risk of fall out of bed, they must be treated. However, RBD can be difficult to be differentiated from hallucinations related to nocturnal delirium, both symptoms being frequently associated. PMID- 25786428 TI - [Artificial intelligence meeting neuropsychology. Semantic memory in normal and pathological aging]. AB - Artificial intelligence (IA) is the subject of much research, but also many fantasies. It aims to reproduce human intelligence in its learning capacity, knowledge storage and computation. In 2014, the Defense Advanced Research Projects Agency (DARPA) started the restoring active memory (RAM) program that attempt to develop implantable technology to bridge gaps in the injured brain and restore normal memory function to people with memory loss caused by injury or disease. In another IA's field, computational ontologies (a formal and shared conceptualization) try to model knowledge in order to represent a structured and unambiguous meaning of the concepts of a target domain. The aim of these structures is to ensure a consensual understanding of their meaning and a univariant use (the same concept is used by all to categorize the same individuals). The first representations of knowledge in the AI's domain are largely based on model tests of semantic memory. This one, as a component of long term memory is the memory of words, ideas, concepts. It is the only declarative memory system that resists so remarkably to the effects of age. In contrast, non specific cognitive changes may decrease the performance of elderly in various events and instead report difficulties of access to semantic representations that affect the semantics stock itself. Some dementias, like semantic dementia and Alzheimer's disease, are linked to alteration of semantic memory. We propose in this paper, using the computational ontologies model, a formal and relatively thin modeling, in the service of neuropsychology: 1) for the practitioner with decision support systems, 2) for the patient as cognitive prosthesis outsourced, and 3) for the researcher to study semantic memory. PMID- 25786429 TI - [Verbal and gestural communication in interpersonal interaction with Alzheimer's disease patients]. AB - Communication can be defined as a verbal and non verbal exchange of thoughts and emotions. While verbal communication deficit in Alzheimer's disease is well documented, very little is known about gestural communication, especially in interpersonal situations. This study examines the production of gestures and its relations with verbal aspects of communication. Three patients suffering from moderately severe Alzheimer's disease were compared to three healthy adults. Each one were given a series of pictures and asked to explain which one she preferred and why. The interpersonal interaction was video recorded. Analyses concerned verbal production (quantity and quality) and gestures. Gestures were either non representational (i.e., gestures of small amplitude punctuating speech or accentuating some parts of utterance) or representational (i.e., referring to the object of the speech). Representational gestures were coded as iconic (depicting of concrete aspects), metaphoric (depicting of abstract meaning) or deictic (pointing toward an object). In comparison with healthy participants, patients revealed a decrease in quantity and quality of speech. Nevertheless, their production of gestures was always present. This pattern is in line with the conception that gestures and speech depend on different communicational systems and look inconsistent with the assumption of a parallel dissolution of gesture and speech. Moreover, analyzing the articulation between verbal and gestural dimensions suggests that representational gestures may compensate for speech deficits. It underlines the importance for the role of gestures in maintaining interpersonal communication. PMID- 25786430 TI - [Altered identification with relative preservation of emotional prosody production in patients with Alzheimer's disease]. AB - Patients with Alzheimer's disease (AD) show cognitive and behavioral disorders, which they and their caregivers have difficulties to cope with in daily life. Psychological symptoms seem to be increased by impaired emotion processing in patients, this ability being linked to social cognition and thus essential to maintain good interpersonal relationships. Non-verbal emotion processing is a genuine way to communicate, especially so for patients whose language may be rapidly impaired. Many studies focus on emotion identification in AD patients, mostly by means of facial expressions rather than emotional prosody; even fewer consider emotional prosody production, despite its playing a key role in interpersonal exchanges. The literature on this subject is scarce with contradictory results. The present study compares the performances of 14 AD patients (88.4+/-4.9 yrs; MMSE: 19.9+/-2.7) to those of 14 control subjects (87.5+/-5.1 yrs; MMSE: 28.1+/-1.4) in tasks of emotion identification through faces and voices (non linguistic vocal emotion or emotional prosody) and in a task of emotional prosody production (12 sentences were to be pronounced in a neutral, positive, or negative tone, after a context was read). The Alzheimer's disease patients showed weaker performances than control subjects in all emotional recognition tasks and particularly when identifying emotional prosody. A negative relation between the identification scores and the NPI (professional caregivers) scores was found which underlines their link to psychological and behavioral disorders. The production of emotional prosody seems relatively preserved in a mild to moderate stage of the disease: we found subtle differences regarding acoustic parameters but in a qualitative way judges established that the patients' productions were as good as those of control subjects. These results suggest interesting new directions for improving patients' care. PMID- 25786431 TI - Disentangling the relationship of the Australian marsupial orders using retrotransposon and evolutionary network analyses. AB - The ancestors to the Australian marsupials entered Australia around 60 (54-72) Ma from Antarctica, and radiated into the four living orders Peramelemorphia, Dasyuromorphia, Diprotodontia, and Notoryctemorphia. The relationship between the four Australian marsupial orders has been a long-standing question, because different phylogenetic studies have not been able to consistently reconstruct the same topology. Initial in silico analysis of the Tasmanian devil genome and experimental screening in the seven marsupial orders revealed 20 informative transposable element insertions for resolving the inter- and intraordinal relationships of Australian and South American orders. However, the retrotransposon insertions support three conflicting topologies regarding Peramelemorphia, Dasyuromorphia, and Notoryctemorphia, indicating that the split between the three orders may be best understood as a network. This finding is supported by a phylogenetic reanalysis of nuclear gene sequences, using a consensus network approach that allows depicting hidden phylogenetic conflict, otherwise lost when forcing the data into a bifurcating tree. The consensus network analysis agrees with the transposable element analysis in that all possible topologies regarding Peramelemorphia, Dasyuromorphia, and Notoryctemorphia in a rooted four-taxon topology are equally well supported. In addition, retrotransposon insertion data support the South American order Didelphimorphia being the sistergroup to all other living marsupial orders. The four Australian orders originated within 3 Myr at the Cretaceous-Paleogene boundary. The rapid divergences left conflicting phylogenetic information in the genome possibly generated by incomplete lineage sorting or introgressive hybridization, leaving the relationship among Australian marsupial orders unresolvable as a bifurcating process millions of years later. PMID- 25786432 TI - Increased expression of X-linked genes in mammals is associated with a higher stability of transcripts and an increased ribosome density. AB - Mammalian sex chromosomes evolved from the degeneration of one homolog of a pair of ancestral autosomes, the proto-Y. This resulted in a gene dose imbalance that is believed to be restored (partially or fully) through upregulation of gene expression from the single active X-chromosome in both sexes by a dosage compensatory mechanism. We analyzed multiple genome-wide RNA stability data sets and found significantly longer average half-lives for X-chromosome transcripts than for autosomal transcripts in various human cell lines, both male and female, and in mice. Analysis of ribosome profiling data shows that ribosome density is higher on X-chromosome transcripts than on autosomal transcripts in both humans and mice, suggesting that the higher stability is causally linked to a higher translation rate. Our results and observations are in accordance with a dosage compensatory upregulation of expressed X-linked genes. We therefore propose that differential mRNA stability and translation rates of the autosomes and sex chromosomes contribute to an evolutionarily conserved dosage compensation mechanism in mammals. PMID- 25786433 TI - Mutation bias, rather than binding preference, underlies the nucleosome associated G+C% variation in eukaryotes. AB - The effects of genetic content on epigenetic status have been extensively studied, but how epigenetic status affects genetic content is not well understood. As a key epigenetic factor the nucleosome structure is highly correlated with local G+C% in eukaryotic genomes. The prevailing explanation to the pattern is that nucleosome occupancy favors higher G+C% sequences more than lower G+C% sequences. However, recent observation of a biased mutation spectrum caused by nucleosome occupancy suggests that the higher G+C% of nucleosomal DNA might be the evolutionary consequence of nucleosome occupancy. To distinguish the two explanations, we examined data from an in vitro nucleosome reconstitution experiment in which histones are incubated with yeast Saccharomyces cerevisiae and Escherichia coli genomic DNA, the former has been shaped by nucleosome structure while the latter has not. There is a strong positive correlation between nucleosome density and G+C% for the yeast DNA, an observation consistent with in vivo data, and such a pattern nearly vanishes for E. coli genomic DNA, suggesting that biased mutation, rather than biased occupancy, explains the most nucleosome-associated G+C% variation in eukaryotic genomes. PMID- 25786434 TI - Maintaining Specimen Integrity for G6PD Screening by Cytofluorometric Assays. AB - Cytochemical staining remains an efficient way of identifying females who are heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD) gene. G6PD is highly polymorphic with certain alleles resulting in low intracellular G6PD activity in red blood cells. Low intracellular G6PD activity is associated with a risk of severe hemolysis when exposed to an oxidative stress such as fava beans, certain drugs and infections. Heterozygous females express the enzyme from both X-chromosome alleles resulting in two red blood cell populations each with G6PD enzyme characteristics representative of each allele; for example, normal and deficient. Cytochemical staining is the only way to determine the relative representation of each allele in red blood cells, a feature that is critical when assessing the risk for severe hemolysis when exposed to an oxidant such as the anti-malarial drug primaquine. This letter discusses red blood cell integrity with respect to the cytofluorometric assays for G6PD activity. An approach to making this test more robust is suggested. The approach makes this test more reliable and extends its use to a broader range of blood specimens. PMID- 25786435 TI - Structural analysis of alterations in zebrafish muscle differentiation induced by simvastatin and their recovery with cholesterol. AB - In vitro studies show that cholesterol is essential to myogenesis. We have been using zebrafish to overcome the limitations of the in vitro approach and to study the sub-cellular structures and processes involved during myogenesis. We use simvastatin--a drug widely used to prevent high levels of cholesterol and cardiovascular disease--during zebrafish skeletal muscle formation. Simvastatin is an efficient inhibitor of cholesterol synthesis that has various myotoxic consequences. Here, we employed simvastatin concentrations that cause either mild or severe morphological disturbances to observe changes in the cytoskeleton (intermediate filaments and microfilaments), extracellular matrix and adhesion markers by confocal microscopy. With low-dose simvastatin treatment, laminin was almost normal, and alpha-actinin was reduced in the myofibrils. With high simvastatin doses, laminin and vinculin were reduced and appeared discontinuous along the septa, with almost no myofibrils, and small amounts of desmin accumulating close to the septa. We also analyzed sub-cellular alterations in the embryos by electron microscopy, and demonstrate changes in embryo and somite size, septa shape, and in myofibril structure. These effects could be reversed by the addition of exogenous cholesterol. These results contribute to the understanding of the mechanisms of action of simvastatin in muscle cells in particular, and in the study of myogenesis in general. PMID- 25786436 TI - An infant with aphallia and its associated complication: A rare case report and review of literature. AB - Complete penile agenesis (aphallia) is a very rare congenital anomaly. Around 80 cases have been reported to date. Diagnosis of this rare anomaly is made by clinical examination, but treatment options and parental counselling for gender assignment is difficult and challenging for the treating doctor. We report a case of an infant with complete penile agenesis with recto-urethral fistula, who was referred on day 6 of life. This baby developed obstructive uropathy which required vesicostomy. Surgical management consists of gender assignment after discussing in detail the pertinent situation with the parents and accepting their final decision. PMID- 25786437 TI - Periorbital necrotising fasciitis in infants: Presentation and management of six cases. AB - PURPOSE: To present the clinical features and management of infants presenting with periorbital necrotising fasciitis (NF). METHODS: Retrospective case series. RESULTS: Six children were studied. The age at presentation was in the range of 5 11 months (median, 8 months). All children presented with acute onset eyelid inflammation and necrosis with fever, lethargy and poor oral intake. The management included intravenous antibiotics and repeated surgical debridement. The infection healed by 2-3 weeks in all cases, resulting in cicatricial ectropion and lagophthalmos. Full thickness skin grafting (with a Hughes tarso conjunctival graft in one child) was performed in all patients at 3-5 weeks subsequently. Repeat surgery was required in three children. Adequate globe coverage and cosmesis was achieved in five children. CONCLUSION: NF of eyelids is a potentially fatal infection that requires urgent and vigorous management and heals with sequelae that may need more than one surgical intervention over a period of time. Adequate cosmetic and functional outcomes can be achieved. PMID- 25786438 TI - Operative management of splenic rupture and hepatic flexure injury during diagnostic colonoscopy in a patient with adenocarcinoma of the cecum. AB - Diagnostic colonoscopy has evolved to become the gold standard for the screening for carcinoma and other diseases of the colon. Injuries to the colon are rare and may be managed in a variety of ways. This includes observation and bowel rest or operative intervention and repair. Other organs are at risk during colonoscopy. The present report describes a patient who underwent colonoscopy for the work-up of anaemia. Following colonoscopy she developed signs of haemorrhagic shock and was found to have haemoperitoneum. She underwent surgery, and adenocarcinoma of the cecum was identified and managed during exploration. The clinical management is described. PMID- 25786439 TI - Endometrioma in a virgin abdomen masquerading as an intramuscular lipoma. AB - Endometriosis is the presence of endometrial tissue outside the uterine cavity. It has been previously reported in the abdominal wall secondary to gynaecological surgery. We present the case of a 32-year woman with endometrioma of the abdominal wall masquerading as an intramuscular lipoma with no previous surgical history. PMID- 25786440 TI - Primary umbilical endometriosis: a cause of a painful umbilical nodule. AB - A female patient presented with a painful swelling in the umbilicus. Ultrasonography demonstrated a hypodense nodule of 1.8 cm. Surgical exploration revealed a subcutaneous, dark discoloured, lobulated swelling at the bottom of the umbilicus, which turned out to be primary umbilical endometriosis (PUE). Primary umbilical endometriosis is a rare and benign disorder, caused by the presence of ectopic endometrial tissue in the umbilicus, which can present as a painful, discoloured swelling in the umbilicus. The clinical distinction between primary umbilical endometrioses and other causes of an umbilical nodule is difficult. Additional imaging modalities do not show any pathognomonic signs for establishing this diagnose. Surgical exploration and excision are a safe and definitive treatment of primary umbilical endometrioses. This case highlights the importance of including PUE in the differential diagnosis of women with a painful umbilical nodule. PMID- 25786441 TI - Complications of polymers on drug-eluting stents: looking toward polymer-free drug-eluting stents. PMID- 25786442 TI - Hypereosinophilic syndrome in the tyrosine kinase inhibitor era. PMID- 25786443 TI - Urgent computed tomography for determining the optimal timing of colonoscopy in patients with acute lower gastrointestinal bleeding. AB - OBJECTIVE: We evaluated the diagnostic performance of computed tomography (CT) as an initial radiologic test for assessing the optimal timing of colonoscopy in patients with acute lower gastrointestinal bleeding (LGIB) and investigated the effectiveness of contrast-enhanced (CE) CT for detecting colonic diverticular bleeding. METHODS: This was a retrospective study of 1,604 consecutive patients who visited or were referred to St. Marianna University Hospital due to acute LGIB and underwent colonoscopy within three months after presentation between September 2004 and December 2012. The clinicopathological data of the subjects were obtained from their medical records. RESULTS: Among the 1,604 patients presenting with LGIB, 879 (55%) underwent a CT scan. Elective colonoscopy was considered in cases in which typical colonic wall thickening was observed on CT, suggesting colonic inflammation or malignancy (239 patients; 27%). The diagnoses in the elective cases included ischemic colitis (38%), infectious colitis (8%), inflammatory bowel disease (8%) and malignancy (5%). Urgent colonoscopy was performed after the CT examination in 640 cases (73%). The most common presumptive CT diagnosis was diverticulum (402/640; 63%). Of the 638 patients who underwent CE-CT, diverticula were observed in 346 cases, including 104 cases of extravasation indicating ongoing diverticular bleeding. Among these 104 patients, the site of bleeding was identified in 71 subjects (68%) during colonoscopy. The rate of detection of the bleeding source on colonoscopy was significantly higher in the patients with extravasation on CE-CT than in those without extravasation on CE-CT (68% vs. 20%, respectively; p<0.001). CONCLUSION: Urgent CT is useful for determining the optimal timing of colonoscopy in cases of acute LGIB. CE-CT may be used to depict the presence and location of active hemorrhage and provides useful information for subsequent colonoscopy, especially in patients with diverticular bleeding. PMID- 25786444 TI - Effects of esomeprazole on sleep in patients with gastroesophageal reflux disease as assessed on actigraphy. AB - OBJECTIVE: Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although treatment with proton pump inhibitors (PPIs) helps to improve GERD symptoms and subjective sleep parameters, the effects of PPI therapy on objective sleep parameters are conflicting. The aim of this study was to examine the effects of esomeprazole treatment on GERD symptoms and sleep parameters assessed using actigraphs and questionnaires. METHODS: Thirteen patients with GERD received 20 mg of esomeprazole once daily for two weeks. The patients wore actigraphs from three days before the initiation of PPI treatment to the end of therapy. They were also asked to answer the following self-reported questionnaires: Frequency Scale for the Symptoms of GERD (FSSG), Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Objective sleep parameters were evaluated using actigraphy. RESULTS: Treatment with esomeprazole significantly decreased the total FSSG score, including the scores for reflux and dysmotility, as well as the ESS score, although it had no effect on the PSQI score. After the second week of treatment, esomeprazole significantly decreased the wake time (from 47.5+/-39.6 min to 36.0+/-27.1 min) and sleep latency period (from 19.5+/-19.8 min to 9.9+/-10.2 min) and increased the percentage of sleep time (from 89.1+/-8.8% to 91.9+/-6.3%); however, improvements were not noted in all objective parameters. CONCLUSION: Esomeprazole treatment significantly improves various objective sleep parameters in Japanese patients with GERD. Further placebo-controlled randomized trials are needed to obtain detailed results. PMID- 25786445 TI - Clinical characteristics of very elderly patients at hemodialysis initiation. AB - OBJECTIVE: The patient's clinical features at hemodialysis initiation can affect their prognosis in the subsequent dialysis period; however, these features have not been fully elucidated in very elderly subjects. The purpose of this study was to clarify the clinical characteristics associated with cardiovascular and chronic kidney disease at hemodialysis initiation. METHODS: Twenty consecutive very elderly patients with end-stage renal disease (ESRD) (>=80 years; VE group) and 35 consecutive control patients with ESRD (<60 years; control group) were included in this study. All patients had started maintenance hemodialysis therapy at our institution. We evaluated the clinical characteristics, laboratory data, thoracic aortic calcification (TAC) and echocardiographic parameters, including aortic valve calcification (AVC), mitral valve calcification and mitral annular calcification (MAC). RESULTS: The diastolic blood pressure was significantly lower and pulse pressure values were significantly higher in the VE group than in the control group, whereas the estimated glomerular filtration rate and cardiac function were comparable between the two groups. Despite having lower serum phosphate and calcium-phosphate product levels, the VE group exhibited more severe TAC, AVC and MAC than the control group. Furthermore, the duration of hospitalization was significantly shorter in the very elderly patients followed by nephrologists than in those who were not. CONCLUSION: Our findings suggest that atherosclerotic lesions are more severe in very elderly patients at hemodialysis initiation. PMID- 25786446 TI - Hepatitis B e antigen and hepatitis B surface antigen seroclearance with the emergence of lamivudine-associated and core mutations following CD4 elevation in a patient with hepatitis B and HIV. AB - Obtaining a better understanding of the mechanisms associated with hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) loss in patients with hepatitis B virus (HBV) is important for treating patients with chronic hepatitis B. We herein describe the case of a patient with HBV and human immunodeficiency virus whose chronic hepatitis was stabilized due to HBe and HBs seroconversion with the emergence of lamivudine-associated and core mutations after CD4 elevation. A full-length HBV DNA analysis indicated that HBsAg had been lost after the development of the rtS143T mutation, which corresponded to the emergence of the sF134L and core mutations. The details of this case shed some light on the mechanisms associated with HBsAg and HBeAg clearance. PMID- 25786447 TI - Isoniazid-induced acute liver failure during preventive therapy for latent tuberculosis infection. AB - Treating latent tuberculosis infection is a strategy for eliminating tuberculosis, and isoniazid is recommended as preventive therapy. However, concerns have been raised regarding the application of isoniazid due to its toxicity, particularly hepatotoxicity; however, biochemical monitoring is not routinely performed during treatment. We herein present a case of fatal isoniazid induced acute liver failure. The patient's liver function was not periodically examined and isoniazid therapy was continued for 10 days despite the onset of symptoms associated with hepatitis. The patient died four months after hospitalization. It is essential to consider the potential toxicities of isoniazid and establish strategies to prevent acute liver failure. PMID- 25786448 TI - Sneddon-Wilkinson disease induced by sorafenib in a patient with advanced hepatocellular carcinoma. AB - Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC), although it is known to cause a variety of dermatologic adverse events. Subcorneal pustular dermatosis (SCPD), also known as Sneddon-Wilkinson disease, is a rare skin eruption that accompanies various systemic disorders and may become chronically progressive. We herein describe the case of a patient who developed SCPD after sorafenib administration. The dermatologic reaction was improved by the cessation of sorafenib and worsened by its readministration. Clinicians treating HCC patients with sorafenib should be aware of the possibility of SCPD. PMID- 25786449 TI - Rivaroxaban therapy resulting in the resolution of right atrial thrombosis resistant to ordinary control with warfarin in a patient with atrial fibrillation. AB - A 72-year-old man with non-valvular atrial fibrillation and metastatic liver and lung cancer after surgery for colon cancer developed thrombosis in the right atrium one month after decreasing the dose of warfarin due to the introduction of double anti-platelet therapy for coronary stent implantation. Restoring the warfarin dose with ordinary control for two months did not result in any changes in the size of the thrombus; however, the subsequent substitution of rivaroxaban (oral treatment with a direct Factor Xa inhibitor) for warfarin ultimately resolved the thrombosis. PMID- 25786450 TI - Suspicion of superior mesenteric artery syndrome in a patient with severe gastric dilatation after catheter ablation. AB - Catheter ablation is a widely used treatment for atrial fibrillation. Gastric hypomotility due to periesophageal vagal plexus injury is a consequence of the extracardiac penetration of ablative energy. Some affected patients develop severe gastric dilatation requiring hospitalization. However, most previous reports have stated the cause of the subject's condition to be "unknown" or described the symptoms using obscure terms, such as "paralytic" or "gastroparesis." For example, one report stated that a few sites of severe gastric dilatation were secondary to "pyloric spasms;" however, no illustrations were provided in the paper. "Superior mesenteric artery syndrome" is a suspected cause of such dilatation. PMID- 25786451 TI - Anaplastic thyroid carcinoma accompanied by uncontrollable eosinophilia. AB - Anaplastic thyroid carcinoma is a rare disease, and cases associated with eosinophilia are even rarer. We herein report a case of anaplastic thyroid carcinoma accompanied by remarkable and uncontrollable eosinophilia. A 71-year old man was diagnosed with end-stage anaplastic thyroid carcinoma. Throughout the aggressive clinical course of the cancer, eosinophilia dramatically progressed and became extremely refractory to steroid treatment. We measured the serum levels of hematopoietic cytokines potentially involved in eosinophilia, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5. Although the GM-CSF level was moderately elevated, both the IL-3 and IL-5 levels were within the normal ranges. In this case, the patient's eosinophilia may have been related to his severe dyspnea and was likely responsible for the allergic reaction to the anticancer drug. Therefore, it is essential to elucidate the etiology of eosinophilia in patients with thyroid cancer in order to improve the treatment for patients with anaplastic thyroid carcinoma. PMID- 25786452 TI - Poorly-controlled acromegaly accompanied by subclinical adrenal Cushing's syndrome after surgery for multiple endocrine tumors. AB - A 48-year-old woman diagnosed with acromegaly 21 years earlier presented at our hospital with a left adrenal tumor. Her medical history included breast cancer, thyroid cancer and an incompletely resected growth hormone (GH)-producing pituitary adenoma. Endocrinological and radiological examinations revealed subclinical adrenal Cushing's syndrome. She subsequently underwent left adrenalectomy, followed by glucocorticoid replacement therapy. Her GH and insulin like growth factor-1 levels were insufficiently controlled, and pegvisomant was administered in addition to octreotide acetate. Following adrenalectomy, a giant hepatic hemangioma and papillary thyroid carcinoma in the residual right lobe developed, indicating the high risk of tumor development in patients with acromegaly. PMID- 25786453 TI - Insulinoma in a patient with chronic renal failure due to type 2 diabetes mellitus treated effectively with diazoxide. AB - A 63-year-old man was diagnosed with diabetes mellitus at 42 years of age. He subsequently exhibited poor blood glucose control for a prolonged period, and his renal failure worsened. He therefore underwent hemodialysis and abdominal magnetic resonance imaging, which revealed a mass in the pancreatic tail. The immunoreactive insulin and C-peptide immunoreactivity levels were significantly elevated, and the results of a fasting test led to a diagnosis of insulinoma. The patient received treatment with oral diazoxide and continuous glucose monitoring (CGM), which resulted in the resolution of the hypoglycemia. This is a rare case of renal failure in which the CGM findings showed improvements in the blood glucose level after diazoxide administration. PMID- 25786454 TI - CAPD peritonitis caused by co-infection with Cellulosimicrobium cellulans (Oerskovia xanthineolytica) and Enterobacter cloacae: a case report and literature review. AB - A 50-year-old woman with end-stage renal disease on continuous ambulatory peritoneal dialysis was admitted with abdominal pain, fever and cloudy peritoneal fluid. The diagnosis was peritonitis, and the causative bacteria were Cellulosimicrobium cellulans and Enterobacter cloacae. She was subsequently treated with the administration of intraperitoneal antibiotics and removal of the infected indwelling catheter. We herein report a case of Cellulosimicrobium cellulans and Enterobacter cloacae co-infection in a patient with peritonitis and review the relevant literature. PMID- 25786455 TI - A novel UMOD gene mutation associated with uromodulin-associated kidney disease in a young woman with moderate kidney dysfunction. AB - Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by a mutation in the uromodulin (UMOD) gene, leading to end-stage renal disease. We herein report the case of a family with UAKD caused by a novel mutation (C135G) in the UMOD gene. A 31-year-old woman had a low estimated glomerular filtration rate (59.7 mL/min per 1.73 m(2)). Her father, grandfather and paternal aunt had received maintenance hemodialysis therapy since their 40's. This case underscores the importance of performing genetic testing in young patients even in cases involving only moderate abnormalities in the kidney function. PMID- 25786456 TI - Diagnostic challenges during pretreatment long-term follow-up in a patient with FIP1L1-PDGFRA-positive eosinophilia. AB - Obtaining a precise characterization of eosinophilia is crucial, as successful treatment relies on the underlying etiology of the disease. Platelet-derived growth factor receptor alpha-related disorders were first specified in 2008 as a distinct group of clonal eosinophilic disorders with exceptional responsiveness to imatinib. We herein present the case of a man with myeloid neoplasm and eosinophilia in whom a definitive diagnosis could not be adequately made based on histopathological features who was ultimately diagnosed only after extensive molecular analyses and successfully treated with imatinib. In addition, we discuss the diagnostic and therapeutic approaches to treating patients presenting with eosinophilia. PMID- 25786457 TI - Bone marrow metastasis of rhabdomyosarcoma mimicking acute leukemia: a case report and review of the literature. AB - Bone marrow metastasis of rhabdomyosarcoma has been reported to be difficult to distinguish from acute leukemia. We herein describe a case of rhabdomyosarcoma with bone marrow metastasis mimicking acute lymphoblastic leukemia. A 29-year-old woman was admitted with thrombocytopenia, blast-like cells in the peripheral blood and a coagulation disorder. Bone marrow aspirates showed 94.8% blast-like cell infiltration (CD45(-), myeloperoxidase(-), and CD56(+)), and CT scan revealed the presence of an infiltrating mass in the nasal cavity. Based on a biopsy of the nasal cavity, the patient was diagnosed with rhabdomyosarcoma exhibiting bone marrow metastasis. She received chemotherapy, followed by radiation therapy, and has since remained alive for 26 months, as of the last follow-up. PMID- 25786458 TI - Therapy-related leukemia with Inv(16)(p13.1q22) and type D CBFB/MYH11 developing after exposure to irinotecan-containing chemoradiotherapy. AB - A 40-year-old woman developed therapy-related acute myeloid leukemia (t-AML) with inv(16)(p13.1q22) and a rare type D form of core-binding factor beta-subunit gene myosin heavy chain 11 gene (CBFB-MYH11) fusion transcript approximately 2.5 years after receiving chemoradiotherapy for uterine cervical cancer. t-AML with inv(16)(p13.1q22) and rare non-type A CBFB-MYH11 typically develops after exposure to a topoisomerase II inhibitor, with a short period of latency of one to five years. As the patient had no history of exposure to topoisomerase II inhibitors, among her previously used chemotherapeutics, the topoisomerase I inhibitor, irinotecan, was speculated to be the most plausible cause of t-AML in this case. The present case suggests that irinotecan may cause t-AML resembling that associated with topoisomerase II inhibitors. PMID- 25786459 TI - Late onset post-transfusion hepatitis E developing during chemotherapy for acute promyelocytic leukemia. AB - We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease. PMID- 25786460 TI - Dialister pneumosintes bacteremia caused by dental caries and sinusitis. AB - A 62-year-old Japanese woman was hospitalized at the Department of Senology for positive signals on two sets of blood cultures obtained in the Emergency Department. The initial physical examination with enhanced computed tomography of the chest and abdomen did not identify the infectious source. Dialister pneumosintes was identified on 16S rRNA sequencing, and dental caries with sinusitis were subsequently diagnosed based on a dental examination and magnetic resonance imaging. History taking with respect to dental hygiene and oral examinations should be performed in daily clinical practice, especially in immunosuppressed patients. PMID- 25786461 TI - Bacteremia with an iliopsoas abscess and osteomyelitis of the femoral head caused by Enterococcus avium in a patient with end-stage kidney disease. AB - A 70-year-old man on hemodialysis for end-stage kidney disease due to polycystic kidney disease presented with hip pain on extension and a high C-reactive protein level. Further examinations revealed an iliopsoas abscess and femoral head osteomyelitis caused by Enterococcus avium (E. avium) detected in blood and pus cultures. Complete resolution of the infection with ampicillin-resistant E. avium required six months of vancomycin therapy and two surgical drainage procedures. There have been no previous case reports in which both blood and abscess cultures confirmed E. avium infection. Careful attention should be paid to the detection of non-specific symptoms in patients on hemodialysis, with blood cultures being essential in such cases. PMID- 25786462 TI - Asymptomatic colonic anisakiasis. PMID- 25786463 TI - Nonocclusive mesenteric ischemia following abdominal aortic aneurysm repair. PMID- 25786464 TI - Intracoronary embolization of the coating polymer on a cardiovascular device. PMID- 25786465 TI - Persistent left superior vena cava (PLSVC) with anomalous hepatic venous drainage. PMID- 25786466 TI - Mediastinal radiation therapy-induced multiple cardiovascular diseases. PMID- 25786467 TI - Tubulointerstitial nephritis caused by chronic lymphocytic leukemia. PMID- 25786468 TI - Saddle pulmonary embolism as the initial manifestation of pancreatic cancer. PMID- 25786469 TI - Arthritis mutilans in a patient with juvenile idiopathic arthritis. PMID- 25786470 TI - Imported Lyme disease. PMID- 25786471 TI - Abdominal shooting star. PMID- 25786472 TI - Peroxiredoxin 2, glutathione peroxidase, and catalase in the cytosol and membrane of erythrocytes under H2O2-induced oxidative stress. AB - Erythrocytes are continuously exposed to risk of oxidative injury due to oxidant oxygen species. To prevent damage, they have antioxidant agents namely, catalase (Cat), glutathione peroxidase (GPx), and peroxiredoxin 2 (Prx2). Our aim was to contribute to a better understanding of the interplay between Prx2, Cat, and GPx under H2O2-induced oxidative stress, by studying their changes in the red blood cell cytosol and membrane, in different conditions. These three enzymes were quantified by immunoblotting. Malondialdehyde, that is, lipoperoxidation (LPO) in the erythrocyte membrane, and membrane-bound hemoglobin (MBH) were evaluated, as markers of oxidative stress. We also studied the erythrocyte membrane protein profile, to estimate how oxidative stress affects the membrane protein structure. We showed that under increasing H2O2 concentrations, inhibition of the three enzymes with or without metHb formation lead to the binding of Prx2 and GPx (but not Cat) to the erythrocyte membrane. Prx2 was detected mainly in its oxidized form and the linkage of metHb to the membrane seems to compete with the binding of Prx2. Catalase played a major role in protecting erythrocytes from high exogenous flux of H2O2, since whenever Cat was active there were no significant changes in any of the studied parameters. When only Cat was inhibited, Prx2 and GPx were unable to prevent H2O2-induced oxidative stress resulting in increasing MBH and membrane LPO. Additionally, the inhibition of one or more of these enzymes induced changes in the anchor/linker proteins of the junctional complexes of the membrane cytoskeleton-lipid bilayer, which might lead to membrane destabilization. PMID- 25786473 TI - Association of vitamin D deficiency with acute lower respiratory tract infections in newborns. AB - OBJECTIVE: To determine the association between serum 25-hydroxy vitamin D [25(OH)D] levels and acute respiratory tract infections (ALRTI) in newborns. STUDY DESIGN: The study group consisted of 30 term newborns with ALRTI who were admitted to our neonatal intensive care unit. Controls were 30 healthy newborns with the same age as the study group. Newborns and their mothers were tested for serum 25(OH)D levels, with a low level defined as <=15 ng/mL. RESULTS: The groups were similar in gestational week, birthweight, postnatal age and gender. Forty three of the 60 infants (including study and control) had low 25(OH)D levels. The median 25(OH)D levels were lower [9.5 ng/mL (IQR = 7.9-12.2)] in the study group than those of the control group [15.5 ng/mL (IQR: 12-18)] (p = 0.0001). The median serum 25(OH)D levels in the mothers of the study group were also lower than those in the mothers of the control group [11.6 ng/mL (IQR = 9.4-15.8) and 17.3 ng/mL (IQR = 13.7-20.6), respectively] (p = 0.0001). CONCLUSION: Lower blood 25(OH)D levels might be associated with increased risk of ALRTI in term newborn babies. Appropriate vitamin D supplementation during pregnancy and early childhood may enhance newborns' respiratory health. PMID- 25786474 TI - The metabolomics of necrotising enterocolitis in preterm babies: an exploratory study. AB - OBJECTIVE: No single diagnostic investigation is currently available for necrotising enterocolitis (NEC). We implemented a novel, untargeted, exploratory study to determine whether metabolomics can reveal early biomarker(s) of NEC. The effect of gestational age on the metabolome was also investigated. METHODS: Two serum samples were obtained from 12 preterm babies (born <30 weeks gestation) and eight term controls: sample "A" at <=1 week of age and sample "B" once fully fed. Samples were subjected to gas chromatography-mass spectrometry. Metabolomic data was analysed by principal component analysis (PCA), univariate and network analysis. RESULTS: Sixteen metabolite features significantly differed when B samples were compared between preterm babies who subsequently developed NEC and preterm/term controls (p value <0.05). Of these seven metabolites were linked to up-regulation of IL-1beta. Significant differences in 54 metabolite features (p value <0.05) were observed between preterm and term metabolomes. Of these, 12 metabolite features were linked to one network involved in carbohydrate/lipid metabolism (p = 1 * 10(-30)). CONCLUSIONS: Metabolomic differences were observed in preterm babies at risk of NEC. However, sample sizes were insufficient to confidently identify a biomarker. Network modelling of preterm and term metabolomes suggest possible nutritional deficiency and altered pro-insulin action in preterm babies. PMID- 25786475 TI - "How to conquer a mountain with multiple sclerosis". How a climbing expedition to Machu Picchu affects the way people with multiple sclerosis experience their body and identity: a phenomenological analysis. AB - BACKGROUND: People with multiple sclerosis (MS) frequently complain of chronic or fluctuating fatigue, sometimes accompanied by pain. From a phenomenological point of view, both fatigue and pain are seen as aspects of suffering which adversely affect the physical, psychological, social and even existential dimensions of the individual life. OBJECTIVE: The present study discusses changes in identity and body awareness in people with MS who completed a 5-d trekking to Machu Picchu in Peru in 2012, after having completed a physical training schedule for several months. METHOD AND DESIGN: All nine participants took part in a focus group organized after the trip. The Interpretative Phenomenological Analysis (IPA) was used to gain insight in their experiences and to refine pre-existing theoretical understanding of body awareness and identity. RESULTS: Our phenomenological analysis clarified how aspects of the participants' identity and body experience before, during and after the journey influenced major daily themes as "body", "lived body", "behaviour" and "relationship" and how this contributed to a meaningful experience. When participants describe how they started looking at their own identity more consciously after being watched through the others' eyes, this resulted in a joyful transcending of their bodily power and endurance. In general, our data suggest that the more extreme, positive lived body experiences during the expedition were necessary for optimizing daily "routine" functioning. CONCLUSION: Participating in Machu Picchu expedition appeared to have a deep and profound effect on body awareness and identity. Participants experienced their body once again as theirs, owning it and above all, allowing it to be a source of strength, joy and meaningfulness. While MS determined their lives prior to the journey, they now could look at MS as a part of what they are, without totally being absorbed in it. So being a patient with MS before, resulted in merely having MS after the climb. Implications for Rehabilitation Patients experience illness as a disruption of their previous life. A phenomenological approach deals with the lived experience and the concept of body awareness, the meaningful experience of living in the world through the body. This approach complements biomedical viewpoints as providing different. Suffering from a chronic and unpredictable disease like multiple sclerosis (MS) can disturb the implicit and harmonious relation between the body, the mind and the world, already at an early stage. Factors including physical training, professional guidance, social support, becoming a role model and completing a unique expedition outside of national and natural comfort borders may contribute to changes in body and identity experience. PMID- 25786476 TI - A narrative synthesis investigating the use and value of social support to promote physical activity among individuals with schizophrenia. AB - PURPOSE: To review and synthesise the literature detailing the use of social support to facilitate physical activity participation in individuals with schizophrenia. METHOD: A systematic review of major electronic databases was conducted to identify literature regarding the use of social support to promote physical activity among people with schizophrenia. A narrative synthesis was undertaken in four stages, including development of a theory, developing a preliminary synthesis, exploring relationships and assessing the robustness of the synthesis. RESULTS: From a total of 110 studies, 23 met the inclusion criteria including 883 individuals with schizophrenia. Informational support was the most documented form of social support, followed by emotional, esteem and tangible. Providers included research personnel, healthcare professionals, family members and peers. Details of the content of the different dimensions of functional support are given. Social support appears to have an important role to help individuals with schizophrenia initiate, comply and adhere with exercise interventions. Social support may have an indirect benefit on weight maintenance. However, due to the limitations of the selected literature, it was difficult ascertain what the (in)direct benefit of social support are on health outcomes. CONCLUSIONS: Social support appears to play a pivotal role in initiating physical activity as well as ensuring compliance and adherence to physical activity. Future research is required to investigate the optimal type and mode of delivery of social support on health outcomes. IMPLICATIONS FOR REHABILITATION: Limited evidence is available that considers the role, value and use of social support within physical activity interventions for individuals with schizophrenia. Social support appears most likely to aid an individual's initiation, adherence and compliance to physical activity interventions. There may be an indirect benefit of social support on maintaining or enhancing health outcomes. PMID- 25786477 TI - The rate of X-ray-induced DNA double-strand break repair in the embryonic mouse brain is unaffected by exposure to 50 Hz magnetic fields. AB - PURPOSE: Following in utero exposure to low dose radiation (10-200 mGy), we recently observed a linear induction of DNA double-strand breaks (DSB) and activation of apoptosis in the embryonic neuronal stem/progenitor cell compartment. No significant induction of DSB or apoptosis was observed following exposure to magnetic fields (MF). In the present study, we exploited this in vivo system to examine whether exposure to MF before and after exposure to 100 mGy X rays impacts upon DSB repair rates. MATERIALS AND METHODS: 53BP1 foci were quantified following combined exposure to radiation and MF in the embryonic neuronal stem/progenitor cell compartment. Embryos were exposed in utero to 50 Hz MF at 300 MUT for 3 h before and up to 9 h after exposure to 100 mGy X-rays. Controls included embryos exposed to MF or X-rays alone plus sham exposures. RESULTS: Exposure to MF before and after 100 mGy X-rays did not impact upon the rate of DSB repair in the embryonic neuronal stem cell compartment compared to repair rates following radiation exposure alone. CONCLUSIONS: We conclude that in this sensitive system MF do not exert any significant level of DNA damage and do not impede the repair of X-ray induced damage. PMID- 25786478 TI - Influenza viruses with B/Yamagata- and B/Victoria-like neuraminidases are differentially affected by mutations that alter antiviral susceptibility. AB - OBJECTIVES: The burden of disease due to influenza B is often underestimated. Clinical studies have shown that oseltamivir, a widely used neuraminidase inhibitor (NAI) antiviral drug, may have reduced effectiveness against influenza B viruses. Therefore, it is important to study the effect of neuraminidase mutations in influenza B viruses that may further reduce NAI susceptibility, and to determine whether these mutations have the same effect in the two lineages of influenza B viruses that are currently circulating (B/Yamagata-like and B/Victoria-like). METHODS: We characterized the effect of 16 amino acid substitutions across five framework residues and four monomeric interface residues on the susceptibility to four different NAIs (oseltamivir, zanamivir, peramivir and laninamivir). RESULTS: Framework residue mutations E117A and E117G conferred highly reduced inhibition to three of the four NAIs, but substantially reduced neuraminidase activity, whereas other framework mutations retained a greater level of NA activity. Mutations E105K, P139S and G140R of the monomeric interface were also found to cause highly reduced inhibition, but, interestingly, their effect was substantially greater in a B/Victoria-like neuraminidase than in a B/Yamagata-like neuraminidase, with some susceptibility values being up to 1000 fold different between lineages. CONCLUSIONS: The frequency and the effect of key neuraminidase mutations on neuraminidase activity and NAI susceptibility can differ substantially between the two influenza B lineages. Therefore, future surveillance, analysis and interpretation of influenza B virus NAI susceptibility should consider the B lineage of the neuraminidase in the same manner as already occurs for different influenza A neuraminidase subtypes. PMID- 25786479 TI - Can cytokine adsorber treatment affect antibiotic concentrations? A case report. PMID- 25786480 TI - Third-generation cephalosporin resistance conferred by a chromosomally encoded blaCMY-23 gene in the Escherichia coli ST131 reference strain EC958. AB - OBJECTIVES: Escherichia coli ST131 is a globally disseminated MDR clone originally identified due to its association with the blaCTX-M-15 gene encoding an ESBL. It is thus assumed that blaCTX-M-15 is the major determinant for resistance to beta-lactam antibiotics in this clone. The complete sequence of EC958, a reference strain for E. coli ST131, revealed that it contains a chromosomally located blaCMY-23 gene with an upstream ISEcp1 element as well as several additional plasmid-encoded beta-lactamase genes. Here, we examined the genetic context of the blaCMY-23 element in EC958 and other E. coli ST131 strains and investigated the contribution of blaCMY-23 to EC958 resistance to a range of beta-lactam antibiotics. METHODS: The genetic context of blaCMY-23 and its associated mobile elements was determined by PCR and sequencing. Antibiotic susceptibility testing was performed using Etests. The activity of the blaCMY-23 promoter was assessed using lacZ reporter assays. Mutations were generated using lambda-Red-recombination. RESULTS: The genetic structure of the ISEcp1-IS5-blaCMY 23 mobile element was determined and localized within the betU gene on the chromosome of EC958 and five other E. coli ST131 strains. The transcription of blaCMY-23, driven by a previously defined promoter within ISEcp1, was significantly higher than other beta-lactamase genes and could be induced by cefotaxime. Deletion of the blaCMY-23 gene resulted in enhanced susceptibility to cefoxitin, cefotaxime and ceftazidime. CONCLUSIONS: This is the first known report to demonstrate the chromosomal location of blaCMY-23 in E. coli ST131. In EC958, CMY-23 plays a major role in resistance to third-generation cephalosporins and cephamycins. PMID- 25786481 TI - Antibiotic penetration and bacterial killing in a Pseudomonas aeruginosa biofilm model. AB - OBJECTIVES: Treating biofilm infections successfully is a challenge. We hypothesized that biofilms may be considered as independent compartments with particular pharmacokinetics. We therefore studied the pharmacokinetics and pharmacodynamics of tobramycin in a seaweed alginate-embedded biofilm model. METHODS: Seaweed alginate beads containing Pseudomonas aeruginosa were cultured in LB medium, sampled at day 1, 3, 5 or 7 and examined for the effect of treatment with tobramycin for 30 min. Treated beads were homogenized and the number of cfu was determined. The antibiotic concentration in the solution of homogenized beads was measured. Finally, beads were examined for live cells by Syto9 staining and for dead cells by propidium iodide staining using a confocal laser scanning microscope. RESULTS: The antibiotic level in each bead was relatively stable (range 30-42 mg/L; MIC = 1.5 mg/L). There were fewer cfu in the tobramycin-treated beads than the non-treated beads (P < 0.016) and bacterial killing was reduced as the culture period increased from 1 to 7 days. Throughout the study period, increasing size and more superficial positioning of the microcolonies within the beads were demonstrated by confocal laser scanning microscopy. More dead cells (measured by propidium iodide staining) were observed in the treated group of beads, which supports the results obtained by culture. CONCLUSIONS: The present study, simulating the clinical pharmacokinetics of tobramycin, demonstrates fast absorption of tobramycin in an in vitro biofilm model. In addition, this model system enables parallel investigation of pharmacokinetics and pharmacodynamics, providing a model for testing new treatment strategies. PMID- 25786482 TI - Antibiotic therapy in the management of atopic dermatitis. AB - Atopic dermatitis (AD), also known as atopic eczema, is a syndrome characterized by a chronic eczematous dermatitis, with associated pruritus, characteristic age specific morphology and distribution of lesions and recurrent nature. Secondary infections in patients with AD are very common and difficult to treat. S. aureus colonizes almost all eczematous lesions in atopic patients and releases several super-antigens and exotoxins (i.e., toxic shock syndrome toxin-1, enterotoxins A D, etc.), which sustain inflammatory reactions and promote tachyphylaxis. The topical antibiotics most commonly prescribed for mild/moderate secondary infections are gentamicin, fusidic acid and mupirocine. This article reviews existing therapeutic options and provides guidance for the management of secondary skin infection among patients with AD. PMID- 25786483 TI - Cyclosporine in psoriasis: comparison of a 25-year real-world Italian experience to current European guidelines. AB - Cyclosporine (CsA) is an effective and safe therapeutic option in various dermatoses in both adults and children. Over the last 25 years, Italian dermatologists have gained relevant experience about the use of CsA in the treatment of psoriasis and atopic dermatitis, and an Italian Consensus Conference has recently provided recommendations in adult patients. A comparison between these real-world indications and current European guidelines is hereby provided. PMID- 25786484 TI - Cognitive and perceptual responses during passive heat stress in younger and older adults. AB - We tested the hypothesis that attention, memory, and executive function are impaired to a greater extent in passively heat-stressed older adults than in passively heat-stressed younger adults. In a randomized, crossover design, 15 older (age: 69 +/- 5 yr) and 14 younger (age: 30 +/- 4 yr) healthy subjects underwent passive heat stress and time control trials. Cognitive tests (outcomes: accuracy and reaction time) from the CANTAB battery evaluated attention [rapid visual processing (RVP), choice reaction time (CRT)], memory [spatial span (SSP), pattern recognition memory (PRM)], and executive function [one touch stockings of Cambridge (OTS)]. Testing was undertaken on two occasions during each trial, at baseline and after internal temperature had increased by 1.0 +/- 0.2 degrees C or after a time control period. For tests that measured attention, reaction time during RVP and CRT was slower (P <= 0.01) in the older group. During heat stress, RVP reaction time improved (P < 0.01) in both groups. Heat stress had no effect (P >= 0.09) on RVP or CRT accuracy in either group. For tests that measured memory, accuracy on SSP and PRM was lower (P < 0.01) in the older group, but there was no effect of heat stress (P >= 0.14). For tests that measured executive function, overall, accuracy on OTS was lower, and reaction time was slower in the older group (P <= 0.05). Reaction time generally improved during heat stress, but there was no effect of heat stress on accuracy in either group. These data indicate that moderate increases in body temperature during passive heat stress do not differentially compromise cognitive function in younger and older adults. PMID- 25786486 TI - Therapeutic value of spinal cord stimulation in irritable bowel syndrome: a randomized crossover pilot study. AB - Irritable bowel syndrome (IBS) is characterized by abdominal pain and changed bowel habits. Spinal cord stimulation (SCS) has been used for treatment of chronic pain syndromes. Animal studies have shown SCS to reduce the reaction to colonic balloon distension, known to be increased in IBS patients. To elucidate the potential for SCS as treatment for IBS, a pilot study was performed. Ten IBS patients (age 26-56 yr) were recruited. A SCS system with a four-polar electrode was implanted at the T5-T8 level. After a 2-wk run-in, a randomized, crossover design SCS during 6 wk was compared with no stimulation, with an ensuing stimulation period for 12 wk; total study period 28 wk. Patients recorded pain level, pain attacks, diarrheas, and global quality of life in a diary. At end of the study patients could choose to retain their SCS system or have it removed. Nine patients completed the whole trial. During stimulation periods the median pain scores were significantly reduced from visual analogue scale (VAS) 7 (4-8) to 3 (2.5-7) and to 4 (2-6) during early and late stimulation periods, respectively (P < 0.03-0.04). Pain attacks were numerically reduced. A few patients reported reduced number of diarrheas. After study termination, six patients chose to retain their SCS system. To conclude, SCS is a minimally invasive treatment option for pain in IBS. With SCS the pain level was reduced though with merely a trend for number of attacks and diarrheas. The efficacy of SCS in IBS pain indicates a possible usefulness in other painful bowel disorders. PMID- 25786485 TI - Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats. AB - The objective of this study was to determine the potential role of astrocyte derived ketone bodies in regulating the early changes in caloric intake of diet induced-obese (DIO) versus diet-resistant (DR) rats fed a 31.5% fat high-energy (HE) diet. After 3 days on chow or HE diet, DR and DIO rats were assessed for their ventromedial hypothalamic (VMH) ketone bodies levels and neuronal ventromedial hypothalamic nucleus (VMN) sensing using microdialysis coupled to continuous food intake monitoring and calcium imaging in dissociated neurons, respectively. DIO rats ate more than DR rats over 3 days of HE diet intake. On day 3 of HE diet intake, DR rats reduced their caloric intake while DIO rats remained hyperphagic. Local VMH astrocyte ketone bodies production was similar between DR and DIO rats during the first 6 h after dark onset feeding but inhibiting VMH ketone body production in DR rats on day 3 transiently returned their intake of HE diet to the level of DIO rats consuming HE diet. In addition, dissociated VMN neurons from DIO and DR rats were equally sensitive to the largely excitatory effects of beta-hydroxybutyrate. Thus while DR rats respond to increased VMH ketone levels by decreasing their intake after 3 days of HE diet, this is not the case of DIO rats. These data suggest that DIO inherent leptin resistance prevents ketone bodies inhibitory action on food intake. PMID- 25786487 TI - No effect of NOS inhibition on skeletal muscle glucose uptake during in situ hindlimb contraction in healthy and diabetic Sprague-Dawley rats. AB - Nitric oxide (NO) has been shown to be involved in skeletal muscle glucose uptake during contraction/exercise, especially in individuals with Type 2 diabetes (T2D). To examine the potential mechanisms, we examined the effect of local NO synthase (NOS) inhibition on muscle glucose uptake and muscle capillary blood flow during contraction in healthy and T2D rats. T2D was induced in Sprague Dawley rats using a combined high-fat diet (23% fat wt/wt for 4 wk) and low-dose streptozotocin injections (35 mg/kg). Anesthetized animals had one hindlimb stimulated to contract in situ for 30 min (2 Hz, 0.1 ms, 35 V) with the contralateral hindlimb rested. After 10 min, the NOS inhibitor, N(G)-nitro-l arginine methyl ester (l-NAME; 5 MUM) or saline was continuously infused into the femoral artery of the contracting hindlimb until the end of contraction. Surprisingly, there was no increase in skeletal muscle NOS activity during contraction in either group. Local NOS inhibition had no effect on systemic blood pressure or muscle contraction force, but it did cause a significant attenuation of the increase in femoral artery blood flow in control and T2D rats. However, NOS inhibition did not attenuate the increase in muscle capillary recruitment during contraction in these rats. Muscle glucose uptake during contraction was significantly higher in T2D rats compared with controls but, unlike our previous findings in hooded Wistar rats, NOS inhibition had no effect on glucose uptake during contraction. In conclusion, NOS inhibition did not affect muscle glucose uptake during contraction in control or T2D Sprague-Dawley rats, and this may have been because there was no increase in NOS activity during contraction. PMID- 25786488 TI - Insight into the number of pre-malignancies and malignancies of the skin in a hospital population in the Netherlands. AB - BACKGROUND: Skin cancer incidence is rising, placing a burden on healthcare systems worldwide. This problem may even be more extensive than expected, since registration of (pre)malignancies of the skin is poor. OBJECTIVE: To provide insight into the numbers of (pre)malignancies in patients with actinic keratosis (AK) or basal cell carcinoma (BCC) in 2 university and 2 general hospitals. METHODS: The types and numbers of previous tumours and of tumours during a two year follow-up were collected from 574 patients. RESULTS: Mean time between the first diagnosed (pre)malignancy and time of inclusion was 6.6 years. Overall, 60% had multiple types of (pre)malignancies. In BCC patients, 61% had multiple BCCs, in patients with squamous cell carcinoma (SCC), 40% had multiple SCCs. The combination 'BCC and SCC' occurred in 10%, 'BCC and AK' in 47%, 'SCC and AK' in 14%. CONCLUSION: High numbers of patients with multiple (pre)malignancies were found in this patient population in university and general hospitals, which may well reflect the Dutch hospital population. We conclude that skin cancer patients are more extensively affected than was expected up till now. Consequently, the management of skin cancer may be in need of adaptation in near future and the question arises whether dermatologists have the capacity for providing care for all these patients. PMID- 25786489 TI - Autoimmune encephalitis and anti-GAD/GABA-A receptor antibodies. PMID- 25786490 TI - Effects of aging on gene expression and mitochondrial DNA in the equine oocyte and follicle cells. AB - We hypothesised that advanced mare age is associated with follicle and oocyte gene alterations. The aims of the study were to examine quantitative and temporal differences in mRNA for LH receptor (LHR), amphiregulin (AREG) and epiregulin (EREG) in granulosa cells, phosphodiesterase (PDE) 4D in cumulus cells and PDE3A, G-protein-coupled receptor 3 (GPR3), growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and mitochondrial (mt) DNA in oocytes. Samples were collected from dominant follicles of Young (3-12 years) and Old (>=20 years) mares at 0, 6, 9 and 12h after administration of equine recombinant LH. LHR mRNA declined after 0h in Young mares, with no time effect in Old mares. For both ages, gene expression of AREG was elevated at 6 and 9h and EREG was expression was elevated at 9h, with higher expression in Old than Young mares. Cumulus cell PDE4D expression increased by 6h (Old) and 12h (Young). Oocyte GPR3 expression peaked at 9 and 12h in Young and Old mares, respectively. Expression of PDE3A increased at 6h, with the increase greater in oocytes from Old than Young mares at 6 and 9h. Mean GDF9 and BMP15 transcripts were higher in Young than Old, with a peak at 6h. Copy numbers of mtDNA did not vary over time in oocytes from Young mares, but a temporal decrease was observed in oocytes from Old mares. The results support an age-associated asynchrony in the expression of genes that are essential for follicular and oocyte maturation before ovulation. PMID- 25786491 TI - Delayed acquisition of non-adjacent vocalic distributional regularities. AB - The ability to compute non-adjacent regularities is key in the acquisition of a new language. In the domain of phonology/phonotactics, sensitivity to non adjacent regularities between consonants has been found to appear between 7 and 10 months. The present study focuses on the emergence of a posterior-anterior (PA) bias, a regularity involving two non-adjacent vowels. Experiments 1 and 2 show that a preference for PA over AP (anterior-posterior) words emerges between 10 and 13 months in French-learning infants. Control experiments show that this bias cannot be explained by adjacent or positional preferences. The present study demonstrates that infants become sensitive to non-adjacent vocalic distributional regularities between 10 and 13 months, showing the existence of a delay for the acquisition of non-adjacent vocalic regularities compared to equivalent non adjacent consonantal regularities. These results are consistent with the CV hypothesis, according to which consonants and vowels play different roles at different linguistic levels. PMID- 25786492 TI - Combined external pressure and Cu-substitution studies on BaFe2As2 single crystals. AB - We report a combined study of external pressure and Cu-substitution on BaFe2As2 single crystals grown by the in-flux technique. At ambient pressure, the Cu substitution is known to suppress the spin density wave (SDW) phase in pure BaFe2As2(T(SDW) ~ 140 K) and to induce a superconducting (SC) dome with a maximum transition temperature T(c)(max) ? 4.2 K. This T(c)(max) is much lower than the T(c) ~ 15-28 K achieved in the case of Ru, Ni and Co substitutions. Such a lower T(c) is attributed to a Cu(2+) magnetic pair-breaking effect. The latter is strongly suppressed by applied pressure, as shown herein, Tc can be significantly enhanced by applying high pressures. In this work, we investigated the pressure effects on Cu(2+) magnetic pair-breaking in the BaFe(2-x)Cu(x)As2 series. Around the optimal concentration (x(opd) = 0.11), all samples showed a substantial increase of T(c) as a function of pressure. Yet for those samples with a slightly higher doping level (over-doped regime), T(c) presented a dome-like shape with maximum T(c) ? 8 K. Remarkably interesting, the under-doped samples, e.g. x = 0.02 display a maximum pressure induced T(c) ? 30 K which is comparable to the maximum T(c)'s found for the pure compound under external pressures. Furthermore, the magnetoresistance effect as a function of pressure in the normal state of the x = 0.02 sample also presented an evolution consistent with the screening of the Cu(2+) local moments. These findings demonstrate that the Cu(2+) magnetic pair breaking effect is completely suppressed by applying pressure in the low concentration regime of Cu(2+) substituted BaFe2As2. PMID- 25786493 TI - Synthesis and evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting Janus kinase 3. AB - Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5 position and substitution of a cyclohexylamino group at the C4-position of the 1H pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity. PMID- 25786494 TI - Commentary on Muscle dysmorphia as an addiction: a response to Grant (2015) and Nieuwoudt (2015). AB - BACKGROUND: Following the publication of our paper 'Muscle Dysmorphia: Could it be classified as an addiction to body image?' in the Journal of Behavioral Addictions, two commentaries by Jon Grant and Johanna Nieuwoudt were published in response to our paper. METHOD: Using the 'addiction components model', our main contention is that muscle dysmorphia (MD) actually comprises a number of different actions and behaviors and that the actual addictive activity is the maintaining of body image via a number of different activities such as bodybuilding, exercise, eating certain foods, taking specific drugs (e.g., anabolic steroids), shopping for certain foods, food supplements, and purchase or use of physical exercise accessories. This paper briefly responds to these two commentaries. RESULTS: While our hypothesized specifics relating to each addiction component sometimes lack empirical support (as noted explicitly by both Nieuwoudt and Grant), we still believe that our main thesis (that almost all the thoughts and behaviors of those with MD revolve around the maintenance of body image) is something that could be empirically tested in future research by those who already work in the area. CONCLUSIONS: We hope that the 'Addiction to Body Image' model we proposed provides a new framework for carrying out work in both empirical and clinical settings. The idea that MD could potentially be classed as an addiction cannot be negated on theoretical grounds as many people in the addiction field are turning their attention to research in new areas of behavioral addiction. PMID- 25786495 TI - Getting stuck with pornography? Overuse or neglect of cybersex cues in a multitasking situation is related to symptoms of cybersex addiction. AB - BACKGROUND AND AIMS: Some individuals consume cybersex contents, such as pornographic material, in an addictive manner, which leads to severe negative consequences in private life or work. One mechanism leading to negative consequences may be reduced executive control over cognition and behavior that may be necessary to realize goal-oriented switching between cybersex use and other tasks and obligations of life. METHODS: To address this aspect,we investigated 104 male participants with an executive multitasking paradigm with two sets: One set consisted of pictures of persons, the other set consisted of pornographic pictures. In both sets the pictures had to be classified according to certain criteria. The explicit goal was to work on all classification tasks to equal amounts, by switching between the sets and classification tasks in a balanced manner. RESULTS: We found that less balanced performance in this multitasking paradigm was associated with a higher tendency towards cybersex addiction. Persons with this tendency often either overused or neglected working on the pornographic pictures. DISCUSSION: The results indicate that reduced executive control over multitasking performance, when being confronted with pornographic material, may contribute to dysfunctional behaviors and negative consequences resulting from cybersex addiction. However, individuals with tendencies towards cybersex addiction seem to have either an inclination to avoid or to approach the pornographic material, as discussed in motivational models of addiction. PMID- 25786496 TI - Sexual compulsion--relationship with sex, attachment and sexual orientation. AB - BACKGROUND AND AIMS: Sexual addiction, also known as hypersexual disorder, is associated with serious psychosocial problems for many people. METHODS: This study used questionnaires to investigate the effects of gender, sexual orientation and attachment (avoidance and anxiety) on sexual compulsion among 100 heterosexual and homosexual men and women. RESULTS: A positive correlation was found between anxious attachment and sexual compulsivity (r =0.46; p < 0.01) and a positive correlation between avoidant attachment and sexual compulsivity (r = 0.39; p L 0.01) in all participants. Secondly, an analysis of covariance showed a gender by sexual orientation interaction effect [F(1,103) = 6.39, p < 0.01] but no attachment effect on sexual compulsivity. A follow-up comparison showed that lesbian women had higher rates of sexual compulsivity than heterosexual women [t(2, 50) = 5.08, p < 0.001] whereas there was non-significant difference in sexual compulsivity between homosexual and heterosexual men [t(2, 50) = 1.30,p = N.S.]. DISCUSSION: The results provide preliminary evidence for an association between attachment and sexual compulsivity and the effects of gender and sexual orientation on sexual compulsivity. PMID- 25786497 TI - Fortune telling addiction: Unfortunately a serious topic about a case report. AB - BACKGROUND: Constant social change brings about new forms of behavior, such as smartphone use, social networking,indoor tanning, cosmetic surgery, etc., that could become excessive or even lead to new forms of addictive disorders. METHODS: We report the case of a woman who starts consulting for "clairvoyance addiction". We then discuss the addictive nature of her disorder, based on several classifications of addiction. RESULTS: The patient fulfilled the criteria for addiction and her clinical features were typical of that of addicted people. Other differential diagnoses were discussed. CONCLUSION: As for any addictive behavior, the interaction of several risk factors should be considered.They are related to the individual himself, but also to the object of addiction and to the socio-environmental context. In this case, all the conditions were met for fortune telling use to become addictive. PMID- 25786499 TI - Distinct germination response of endangered and common arable weeds to reduced water potential. AB - Arable weeds are one of the most endangered species groups in Europe. Modern agriculture and intensive land-use management are the main causes of their dramatic decline. However, besides the changes in land use, climate change may further challenge the adaptability of arable weeds. Therefore, we investigated the response pattern of arable weeds to different water potential and temperature regimes during the phase of germination. We expected that endangered arable weeds would be more sensitive to differences in water availability and temperature than common arable weeds. To this end, we set up a climate chamber experiment where we exposed seeds of five familial pairs of common and endangered arable weed species to different temperatures (5/15, 10/20 degrees C) and water potentials (0.0 to 1.2 MPa). The results revealed a significant relationship between the reaction of arable weed species to water availability and their Red List status. The effects of reduced water availability on total germination, mean germination time and synchrony were significantly stronger in endangered than in common arable weeds. Therefore, global climate change may present a further threat to the survival of endangered arable weed species. PMID- 25786500 TI - Radiographic analysis of hexapod external fixators: fundamental differences between the Taylor Spatial Frame and TrueLok-Hex. AB - Hexapod circular external fixators are extremely accurate at correcting deformities in three dimensions. In order to exploit this accuracy, however, the surgeon must be able to accurately analyse the deformity and mounting parameters on post-operative radiographs. A Sawbone(r) model was created to simulate a mid shaft tibial fracture with deformity. A 180 mm ring was applied oblique to the proximal segment of the Sawbone(r) model, in both the sagittal and coronal planes. Standard radiographs were taken of the model and analysed using the described Taylor Spatial Frame and TrueLok-Hex methods. The TrueLok-Hex software allows the surgeon the ability to program reference rings that are not orthogonally mounted. Apart from this software difference, the described analysis methods resulted in variation in all translational measurements for both deformity and mounting parameters. In conclusion, the radiographic analysis of the Taylor Spatial Frame and TrueLok-Hex are fundamentally different. These differences must be appreciated in order to use these systems effectively. PMID- 25786501 TI - Vagotomy prevents the effect of probiotics on caspase activity in a model of postmyocardial infarction depression. AB - BACKGROUND: Myocardial infarction (MI) is associated with apoptosis in the amygdala and, ultimately, with clinical signs of depression. Different treatments have proven to be beneficial in preventing depression, including combination of the probiotics Lactobacillus helveticus and Bifidobacterium longum for prophylaxis. We have speculated previously that the benefit of these probiotics is due to their anti-inflammatory properties, and evidence suggests that an intact vagus nerve is important for this effect to occur. This study was designed to ascertain vagus nerve involvement in the beneficial influence of probiotics on caspase activities in our post-MI animal model of depression. METHODS: Probiotics and/or vehicle were administered daily to male adult rats, 14 days before MI and until euthanasia. Vagotomy was performed in subgroups of rats 40 min before MI. They were sacrificed after 3 days of reperfusion, and MI size was assessed along with caspase-3 and -8 activities in the amygdala. KEY RESULTS: Probiotics had no effect on infarct size but vagotomy increased it. Caspase-3 and caspase-8 activities in the amygdala were higher in MI than in sham-operated rats, and this outcome was reversed by probiotics. The beneficial influence of probiotics was abolished by vagotomy. CONCLUSIONS & INFERENCES: Our data indicate that the effect of probiotics on caspase activities in the amygdala after MI depends on an intact vagus nerve. PMID- 25786502 TI - Galactomyces fermentation filtrate prevents T helper 2-mediated reduction of filaggrin in an aryl hydrocarbon receptor-dependent manner. AB - BACKGROUND: The aryl hydrocarbon receptor (AhR) recognizes diverse small molecules such as dioxins, tryptophan photoproducts and phytochemicals. It also plays crucial roles in epidermal homeostasis by upregulating epidermal barrier proteins. In preliminary screening, we found that Galactomyces fermentation filtrate (GFF), a cosmetic compound, was capable of activating AhR. AIM: To examine whether GFF upregulates the expression of the filaggrin and loricrin genes, FLG and LOR, in an AhR-dependent manner. METHODS: The activation (cytoplasmic to nuclear translocation) of AhR was confirmed by immunofluorescence study and by upregulation of an AhR-specific marker, cytochrome P450-1A1 (CYP1A1). Gene expression levels were compared by quantitative reverse transcription PCR with or without GFF, interleukin (IL)-4 or IL-13 in normal human keratinocytes. AhR or control knockdown was carried out by transfection with AhR or control small interfering RNA. The protein expression of FLG and LOR was examined by immunohistochemistry using a three-dimensional epidermal equivalent treated with or without GFF or T helper (Th)2 cytokines. RESULTS: GFF induced the nuclear translocation of AhR with significant and dose-dependent upregulation of CYP1A1, FLG and LOR gene expression. The enhancing effects of GFF were abolished in AhR-knockdown keratinocytes. Th2 cytokines decreased expression of genes for FLG and LOR, and this expression was completely restored in the presence of GFF. The downregulated expression of the FLG gene with its restoration by GFF was also evident in the epidermal equivalent. GFF also upregulated the gene expression of genes encoding occludin, claudin-1 and 4, and kallikrein 5 and 7. CONCLUSIONS: Use of GFF is feasible to prevent the Th2 mediated reduction of FLG in an AhR-dependent fashion. PMID- 25786503 TI - Anti-tubercular agents from Glycyrrhiza glabra. AB - Bioactivity guided isolation of Glycyrrhiza glabra (Leguminosae / Fabaceae) roots resulted in the characterization of 18beta-glycyrrhetinic acid as a major anti tubercular agent. Further, GA-1 was semi-synthetically converted into its nine derivatives, which were in-vitro evaluated for their antitubercular potential against Mycobacterium tuberculosis H37Rv using BACTEC-460 radiometric susceptibility assay. All the derivatives were active, but the benzylamide (GA-8, MIC 12.5MUg/ml) and ethyl oxylate (GA-3, MIC 25.0 MUg/ml) derivatives were significantly active against the pathogen. This was further supported by the molecular docking studies, which showed adequate docking (LibDock) scores for GA 3 (120.3) and GA-8 (112.6) with respect to the standard anti-tubercular drug, rifampicin (92.94) on the DNA-directed RNA polymerase subunit beta (rpoB) target site. Finally, the in silico pharmacokinetic and drug-likeness studies showed that GA-3 and GA- 8 possesses drug-like properties. This is the first ever report on the anti-tubercular potential of GA and its derivatives. These results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non toxic natural product. PMID- 25786504 TI - Glycolipids: isolated from Oplismenus burmannii induce glucose uptake in L6 GLUT4myc myotube cells. AB - Bioactivity guided separation of combined n-hexane and chloroform extracts of Oplismenus burmannii resulted in the isolation and characterization of five new glycoglycerolipids, (2S)-1,2,6'-tri- O-hexadecanoyl-3-O-beta-D-galactopyranosyl glycerol (1a), (2S)-1,2,6'-tri-O-[(9Z,12Z)-octadeca-9,12- dienoyl]-3-O-beta-D galactopyranosyl glycerol (1b), (2S)-1,6'-di-O-[(9Z,12Z)-octadeca-9,12-dienoyl]-3 O-beta-D-galactopyranosyl glycerol (2b), (2S)-1,6'-di-O-[(9Z,12Z,15Z)-octadeca 9,12,15-trienoyl]-3-O-beta-D-galactopyranosyl glycerol (2c), and (2S)-1,2-di-O [(9Z,12Z)-octadeca-9,12-dienoyl]-3-O-(6- sulpho-alpha-D)-quinovopyranosyl glycerol (3b) along with five known glycoglycerolipids (1c, 2a, 3a, 3c and 4), a cerebroside (5), three monoacylglycerols (6a-c) and alpha-linoleic acid (7). The isolated compounds, 1-5 were in-vitro tested for their antihyperglycemic potential in terms of increase in 2-deoxyglucose uptake in L6-GLUT4myc myotube cells. The results showed that compounds, 1-5 were showing 1.52 (P<0.05), 1.50 (P<0.05), 1.28, 1.49 (P<0.05) and 1.50 (P<0.05) fold increase in the glucose uptake at concentration of 10 MUg/mL and 1.71 (P<0.001), 1.74 (P<0.001), 1.50 (P<0.05), 1.76 (P<0.001) and 1.74 (P<0.001) fold increase in the glucose uptake at concentration of 25 MUg/mL respectively. However, standard drug Rosiglitazone increases the glucose uptake by 1.59 fold at the concentration of 10MUM. Further work on optimization of the anti-diabetic lead is under progress. PMID- 25786505 TI - Homology modeling of MDR1 gene MDR1_ENTHI of E. histolytica & its molecular docking with anti-entamoeba histolytica agents. AB - To investigate the theoretical model of the three-dimensional structure of multidrug resistance protein 1(P-glycoprotein, expressed by MDR1 gene of E. histolytica) and its molecular docking with anti-amoebic agents. The theoretical model of multidrug resistance protein 1(P-glyoprotein, expressed by MDR1 gene of E. histolytica) was predicted by homology modeling on the structure of the 3G61. Docking studies were performed to investigate the interaction of p-glycoprotein with antiamoebic gents. MRPEH1F is significant model for p-glycoprotein and have total of 114 amino acid residues. The model is well supported by cross validation data generated after analyzing criss-cross residues, local geometry check as well as ramachandran plot. Molecular docking of MRPEH1F revealed that all the test molecules have strong binding affinity along with significant interactions. Henceforth, none of the molecules will probably be effective for the multidrug resistant strains of E. histolytica. PMID- 25786506 TI - Towards the development of anticancer drugs from andrographolide: semisynthesis, bioevaluation, QSAR analysis and pharmacokinetic studies. AB - Isolation of andrographolide from Andrographis paniculata, preparation of a library of derivatives via 1,3-dipolar cycloaddition of andrographolide with azomethine ylides generated from isatin derivatives or acenaphthoquinone and seconday alpha-amino acids, evaluation of the anticancer potential of the products, quantitative structure activity relationship studies and pharmacokinetic parameter determination have been described. 2D QSAR studies revaled that steric effects and van der Waals interactions play major roles in the determination of antiproliferative activity of these derivatives. 3D QSAR study predicted that the benzyl substitution at N20 position may be important for higher steric interaction. Pharmacokinetic studies with two most potent analogues revealed moderate chemical stability but poor aqueous solubility, metabolic stability and permeability with significant CYP3A4 inhibition. PMID- 25786507 TI - Crystallographic study and biological evaluation of 1,4-dimethyl-N alkylcarbazoles. AB - The 9-(bromoalkyl)-1,4-dimethyl-9H-carbazole (2a-d) derivatives, characterized by the presence of five or seven methylenic spacer groups bonded to the carbazole nitrogen, have been synthesized from the corresponding 1,4- dimethyl-9H-carbazole and appropriate dibromoalkane following a general synthetic method. All the prepared species have been fully characterized by means of IR, and (1)H and (13)C NMR spectroscopy, GC-MS and Elemental analysis. Good crystals of the 2c have been obtained and the crystal structure has been solved by means of X-ray diffractometry. In order to study the cytotoxic effect of 2a, 2b, 2c, 2d carbazole derivatives on A2780 ovarian cancer cells, we performed MTT assay after exposure of this cell population to those compounds in a concentration range from 1 to 10MUM. Finally, we want to verify whether the cytotoxic effect of the 2c carbazole is mediated by apoptotic mechanisms, by performing chromatin condensation assay on the A2780 cell cultures upon the carbazole treatment at concentration of 10 MUM for 72h. All together our data demonstrate that carbazole derivatives exert inhibitory effects on ovarian cancer cell growth, highlighting a stronger and a dose-dependent anti proliferative activity displayed by 2c carbazole, designating this compound, as a better candidate in the treatment of human ovarian cancer. PMID- 25786508 TI - Molecular modeling based semi-synthesis and in vitro evaluation of anticancer activity in indolyl chalcones. AB - A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against four human cancer cell lines. Compounds 1a, 1b, 1d, 1f-1j, 2c, 2e, 2i showed significant cytotoxicity. Chalcones 1b and 1d were identified as the most potent and selective anticancer agents with IC50 values <1ug/ml and 1.51ug/ml, against WRL-68 cell line, respectively. PMID- 25786509 TI - Synthesis, antimicrobial, anticancer evaluation of 2-(aryl)-4- thiazolidinone derivatives and their QSAR studies. AB - A new class of 4-thiazolidinones clubbed with quinozolinone nucleus has been synthesized. The title compounds were screened for their in vitro antimicrobial and anticancer potentials. Results of antimicrobial and anticancer study revealed that compounds 7 (pMICam = 1.69 MUM/ml) and 2 (IC50 = 12.83 MUM) were found to be the most potent antimicrobial and anticancer agents respectively. QSAR studies indicated that antimicrobial activity of synthesized 4-thiazolidinone derivatives was governed by the electronic parameters, dipole moment (MU), energy of highest occupied molecular orbital (HOMO), lipophilic parameter, log P and topological parameter, valence third order molecular connectivity index ((3)chi(v)). PMID- 25786510 TI - (6-bromo-1,4-dimethyl-9H-carbazol-3-yl-methylene)-hydrazine (carbhydraz) acts as a GPER agonist in breast cancer cells. AB - Estrogens control a wide number of aspects of human physiology and play a key role in multiple diseases, including cancer. Estrogens act by binding to and activating the cognate receptor (ER), however numerous studies have revealed that the G protein-coupled receptor named GPR30/GPER mediates also estrogen signals. As ER and GPER share the ability to bind to same compounds, the use of GPER selective ligands has allowed a better understanding of the biological responses mediated by GPER. In the present study, we designed and synthesized two novel carbazole derivatives and then investigated their ability to interact with and activate the GPER-mediated transduction pathway in breast cancer cells. Both compounds did not activate the classical ER in MCF7 cells, whereas one of the two compounds synthesized triggered through GPER the rapid ERK activation in ER negative SkBr3 cells, demonstrating a good affinity for GPER in docking studies. The characterization of this novel selective GPER agonist could represent a potential useful tool to provide further insights into the physiopathological role exerted by GPER. PMID- 25786511 TI - Comparative Analysis of the Public Health Role of Two Types of Death Investigation Systems in Texas: Application of Essential Services. AB - The purpose of this research was to assess the practices of death investigation agencies in Texas and to investigate the differences between justices of the peace (JPs) and medical examiner perceptions of their role and responsibilities. A survey was conducted in which justices of the peace and medical examiners (MEs) were questioned on their agency's policies and practices in regard to essential services provided using a recently published 50-item instrument subdivided into 10 essential services areas. The study used a quantitative descriptive cross sectional design in which nonparametric analysis was used to ascertain differences between groups. The sample size for analysis was composed of 10 (83%) ME offices and 112 (15.5%) JPs. This statewide study found significant differences between MEs and JPs. These differences reflect the variation in educational background, understanding and implementation of essential services, and the appreciation of the needs of a system to be both collaborative and independent. PMID- 25786513 TI - Erratum. PMID- 25786512 TI - Acute atorvastatin is hepatoprotective against ischaemia-reperfusion injury in mice by modulating eNOS and microparticle formation. AB - BACKGROUND & AIMS: Steatosis accentuates the severity of hepatic ischaemia reperfusion injury (IRI); 'statins' (HMG-CoA reductase inhibitors) protect the heart and brain against post-ischaemic injury. We tested whether short-term administration of atorvastatin protects fatty livers in obese mice against IRI. METHODS: Mice with dietary or genetic simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) were subjected to 60 min partial hepatic ischaemia/24 h reperfusion. Atorvastatin was injected intravenously (5 mg/kg) 1 h before IRI. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, iNOS/eNOS expression, eNOS activity and thromboxane B2 (TXB2) production were determined. RESULTS: Ischaemia-reperfusion injury was exaggerated by two- to five-fold in SS and NASH compared with lean liver. Atorvastatin pretreatment conferred 70-90% hepatic protection in all animals. Atorvastatin increased post-ischaemic eNOS mRNA/protein and strikingly enhanced eNOS activity (by phospho-eNOS). It also attenuated microparticle (MP) production, NF-kappaB activation, significantly dampened post-ischaemic thromboxane B2 production, induction of TNF-alpha, IL-6, MIP-1a, MCP-1, GM-CSF and vascular cell adhesion molecule-1 (VCAM), with a resultant reduction on macrophage and polymorphonuclear neutrophil recruitment. Up-regulation of HMGB1 and TLR4 after IRI was marked in fatty livers; 1 h pretreatment with atorvastatin reduced HMGB1 and TLR4 expression in all livers. CONCLUSIONS: Acute (1 h) atorvastatin administration is highly hepatoprotective against IRI in NASH, fatty and lean livers. Key mechanisms include suppression of inflammation by prevention of NF-kappaB activation, microvascular protection via eNOS activation and suppression of TXB2 and MP release. Short-term intravenous statin treatment is a readily available and effective preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease, and merits clinical trials in at-risk patients. PMID- 25786514 TI - HBV infection is associated with greater mortality in hospitalised patients compared to HCV infection or alcoholic liver disease. AB - BACKGROUND: Little is known about outcomes of Hepatitis B virus (HBV)-related hospitalisations. AIM: To compare the characteristics and outcomes of hospitalised HBV patients to those with Hepatitis C virus (HCV) infection and alcoholic liver disease (ALD), and to examine variables associated with poor outcomes. METHODS: Using the 2011 US Nationwide Inpatient Sample, we identified hospitalised patients with HBV, HCV or ALD-related admissions using ICD-9-CM codes. We compared liver-related complications between the three groups. Multivariable regression was performed to identify factors associated with in hospital mortality and length of stay. RESULTS: A total of 22 843 HBV, 203 300 HCV and 244 383 ALD-related discharges were included. Cirrhosis was noted less commonly in those with HBV (69.1%) compared to HCV (83.9%) or ALD (80.9%) (P < 0.001). In contrast, hepatocellular cancer and acute liver failure were more common with HBV (16.5% and 5.2%) compared to HCV (10.4% and 2.8%) or ALD (2.5% and 4.9%) respectively (P < 0.0001). On multivariable analysis, adjusting for demographics, liver and nonliver comorbidity, HBV infection was associated with higher mortality compared to HCV infection [Odds ratio (OR) 1.21, 95% CI: 1.04 1.39) or ALD (OR: 1.21, 95% CI: 1.05-1.40). Length of hospital stay was greater with HBV compared to HCV (+0.54 days) or ALD (+0.36 days). Among those with HBV, significant factors associated with mortality included renal failure, hepatocellular cancer, respiratory failure, ascites, coagulopathy and acute liver failure. CONCLUSION: Patients hospitalised with HBV infection represent a particularly high-risk group with poor in-hospital outcomes and increased mortality compared to HCV infection or alcoholic liver disease. PMID- 25786516 TI - MITF regulation - more hints from Wnt. PMID- 25786515 TI - Association of late-night carbohydrate intake with glucose tolerance among pregnant African American women. AB - Obesity and late-night food consumption are associated with impaired glucose tolerance. Late-night carbohydrate consumption may be particularly detrimental during late pregnancy because insulin sensitivity declines as pregnancy progresses. Further, women who were obese (Ob) prior to pregnancy have lower insulin sensitivity than do women of normal weight (NW). The aim of this study is to test the hypothesis that night-time carbohydrate consumption is associated with poorer glucose tolerance in late pregnancy and that this association would be exacerbated among Ob women. Forty non-diabetic African American women were recruited based upon early pregnancy body mass index (NW, <25 kg m(-2) ; Ob, >=30 kg m(-2) ). Third trimester free-living dietary intake was assessed by food diary, and indices of glucose tolerance and insulin action were assessed during a 75-g oral glucose tolerance test. Women in the Ob group reported greater average 24-h energy intake (3055 kcal vs. 2415 kcal, P < 0.05). Across the whole cohort, night-time, but not day-time, carbohydrate intake was positively associated with glucose concentrations after the glucose load and inversely associated with early phase insulin secretion (P < 0.05). Multiple linear regression modelling within each weight group showed that the associations among late-night carbohydrate intake, glucose concentrations and insulin secretion were present only in the Ob group. This is the first study to report an association of night-time carbohydrate intake specifically on glucose tolerance and insulin action during pregnancy. If replicated, these results suggest that late-night carbohydrate intake may be a potential target for intervention to improve metabolic health of Ob women in late pregnancy. PMID- 25786518 TI - Focal choroidal excavation with changes in shape and alterations of inner retina during long follow-up in an eye with polypoidal choroidal vasculopathy. PMID- 25786517 TI - Length of the Mitral Isthmus But Not Anatomical Location of Ablation Line Predicts Bidirectional Mitral Isthmus Block in Patients Undergoing Catheter Ablation of Persistent Atrial Fibrillation: A Randomized Controlled Trial. AB - INTRODUCTION: Mitral isthmus (MI) ablation is an effective option in patients undergoing ablation for persistent atrial fibrillation (AF). Achieving bidirectional conduction block across the MI is challenging, and predictors of MI ablation success remain incompletely understood. We sought to determine the impact of anatomical location of the ablation line on the efficacy of MI ablation. METHODS AND RESULTS: A total of 40 consecutive patients (87% male; 54 +/- 10 years) undergoing stepwise AF ablation were included. MI ablation was performed in sinus rhythm. MI ablation was performed from the left inferior PV to either the posterior (group 1) or the anterolateral (group 2) mitral annulus depending on randomization. The length of the MI line (measured with the 3D mapping system) and the amplitude of the EGMs at 3 positions on the MI were measured in each patient. MI block was achieved in 14/19 (74%) patients in group 1 and 15/21 (71%) patients in group 2 (P = NS). Total MI radiofrequency time (18 +/- 7 min vs. 17 +/- 8 min; P = NS) was similar between groups. Patients with incomplete MI block had a longer MI length (34 +/- 6 mm vs. 24 +/- 5 mm; P < 0.001), a higher bipolar voltage along the MI (1.75 +/- 0.74 mV vs. 1.05 +/- 0.69 mV; P < 0.01), and a longer history of continuous AF (19 +/- 17 months vs. 10 +/- 10 months; P < 0.05). In multivariate analysis, decreased length of the MI was an independent predictor of successful MI block (OR 1.5; 95% CI 1.1-2.1; P < 0.05). CONCLUSIONS: Increased length but not anatomical location of the MI predicts failure to achieve bidirectional MI block during ablation of persistent AF. PMID- 25786519 TI - Effect of radiation on the nutritional and microbial qualities of salted and sun dried Sharpfin barracuda (Sphyraena acutipinnis). AB - PURPOSE: To evaluate the effect of low-dose gamma irradiation (5 kGy) on the nutritional and microbial qualities of sun dried fin fish, Sharpfin barracuda (Sphyraena acutipinnis). MATERIALS AND METHODS: Salted and sun-dried S. acutipinnis with 25.8% moisture content were exposed to total body irradiation with a dose of 5 kGy. Control groups were non-irradiated and both the control and irradiated samples were stored under ambient temperature. One week after irradiation, the control and irradiated samples were analyzed for nutritional, microbial and organoleptic properties. The data were statistically analyzed. RESULTS: The proximate composition and quality parameters like free fatty acid (FFA), Trimethyl amine nitrogen (TMA-N) and total volatile base nitrogen (TVB-N) were significantly different (p < 0.05). The organoleptic qualities of the irradiated fish products were good. Total bacterial count was reduced, whereas Salmonella, Vibrio and fungi were totally eliminated after irradiation. CONCLUSIONS: The irradiation helps to improve the quality and safety of sun-dried fishes. The process would not only reduce the risk resulting from pathogens but also would destroy many of the spoilage agents like bacteria, insects, parasites, moulds and yeasts which are known to be the main cause of food losses in developing countries. PMID- 25786520 TI - Further development of LLNA:DAE method as stand-alone skin-sensitization testing method and applied for evaluation of relative skin-sensitizing potency between chemicals. AB - To date, there has been no well-established local lymph node assay (LLNA) that includes an elicitation phase. Therefore, we developed a modified local lymph node assay with an elicitation phase (LLNA:DAE) to discriminate true skin sensitizers from chemicals that gave borderline positive results and previously reported this assay. To develop the LLNA:DAE method as a useful stand-alone testing method, we investigated the complete procedure for the LLNA:DAE method using hexyl cinnamic aldehyde (HCA), isoeugenol, and 2,4-dinitrochlorobenzene (DNCB) as test compounds. We defined the LLNA:DAE procedure as follows: in the dose-finding test, four concentrations of chemical applied to dorsum of the right ear on days 1, 2, and 3 and dorsum of both ears on day 10. Ear thickness and skin irritation score were measured on days 1, 3, 5, 10, and 12. Local lymph nodes were excised and weighed on day 12. The test dose for the primary LLNA:DAE study was selected as the dose that gave the highest left ear lymph node weight in the dose-finding study, or the lowest dose that produced a left ear lymph node of over 4 mg. This procedure was validated using nine different chemicals. Furthermore, qualitative relationship was observed between the degree of elicitation response in the left ear lymph node and the skin sensitizing potency of 32 chemicals tested in this study and the previous study. These results indicated that LLNA:DAE method was as first LLNA method that was able to evaluate the skin sensitizing potential and potency in elicitation response. PMID- 25786521 TI - Cadmium up-regulates transcription of the steroidogenic acute regulatory protein (StAR) gene through phosphorylated CREB rather than SF-1 in K28 cells. AB - Cadmium is a widely used heavy metal in industry and affects the male reproductive system of animals, including humans, as a result of occupational and environmental exposures. However, the molecular mechanism underlying its effect on steroidogenesis in gonads remains unclear. In this study, we demonstrated that exposure of K28 mouse testicular Leydig tumor cells to cadmium led to a significant increase in the mRNA level, promoter activity and protein level of the steroidogenic acute regulatory protein (StAR), an essential factor for steroid biosynthesis. It has been well documented that StAR gene transcription is regulated by multiple transcription factors, including cAMP-responsive element binding protein (CREB) family members and SF-1. Cadmium treatment caused an increase in CREB phosphorylation but did not alter the CREB protein level in the nucleus. EMSA studies revealed that cadmium-induced phosphorylated CREB formed specific complexes with the proximal region of the StAR gene promoter. Furthermore, co-transfection with a CREB expression plasmid significantly increased cadmium-induced StAR promoter activity. However, the nuclear level and the affinity of SF-1 protein for the StAR proximal promoter were dramatically decreased upon exposure to cadmium. Taken together, these results suggest that cadmium up-regulates StAR gene expression through phosphorylated CREB rather than through SF-1 in mouse testicular Leydig cells. PMID- 25786522 TI - Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients. AB - Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS). PMID- 25786523 TI - Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid-supplemented diet. AB - The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and 3 methylcholanthrene (3-MC) on fatty liver were examined in rats. Treating rats with orotic acid caused marked accumulation of lipid droplets in the liver. This effect of orotic acid was almost eradicated by co-treatment with DHEAS and PB. While DHEAS or PB alone also alleviated fatty liver, treatment with 3-MC caused little effect on a reduction in lipid droplets. Histopathological examinations revealed numerous peroxisomes in the liver of rats treated with DHEAS. In addition, a significant increase in the expression on hepatic CYPs was observed in rats the fatty liver of which was attenuated. Regarding other enzymes associated with hepatic fatty acid oxidation, the expression levels of sirtuin 1, sirtuin 6, and carnitine palmitoyltransferase 1 were also upregulated most markedly by treatment with DHEAS alone. Thus, the attenuation in fatty liver observed in the present study is likely due to peroxisome proliferation and the induction of fatty acid-metabolizing enzymes by DHEAS and typical CYP inducers. PMID- 25786524 TI - In silico risk assessment for skin sensitization using artificial neural network analysis. AB - The sensitizing potential of chemicals is usually identified and characterized using in vivo methods such as the murine local lymph node assay (LLNA). Due to regulatory constraints and ethical concerns, alternatives to animal testing are needed to predict the skin sensitization potential of chemicals. For this purpose, an integrated evaluation system employing multiple in vitro and in silico parameters that reflect different aspects of the sensitization process seems promising. We previously reported that LLNA thresholds could be well predicted by using an artificial neural network (ANN) model, designated iSENS ver. 2 (integrating in vitro sensitization tests version 2), to analyze data obtained from in vitro tests focused on different aspects of skin sensitization. Here, we examined whether LLNA thresholds could be predicted by ANN using in silico-calculated descriptors of the three-dimensional structures of chemicals. We obtained a good correlation between predicted LLNA thresholds and reported values. Furthermore, combining the results of the in vitro (iSENS ver. 2) and in silico models reduced the number of chemicals for which the potency category was under-estimated. In conclusion, the ANN model using in silico parameters was shown to be have useful predictive performance. Further, our results indicate that the combination of this model with a predictive model using in vitro data represents a promising approach for integrated risk assessment of skin sensitization potential of chemicals. PMID- 25786525 TI - Dysfunction of blood pressure regulation in hyperhomocyteinemia model in rats. AB - Hyperhomocysteinemia (HHC) has been reported to be one of risk factors for cardiovascular disease. We investigated the effects of HHC on blood pressure regulation and its association with damage to the thoracic aorta and imbalance of redox in plasma in rats. Rats were fed a methionine enriched diet (Met diet) or a methionine and cholesterol (Met+Chol diet) enriched diet for 16 weeks to create a subchronic HHC model, in which the plasma concentration of homocysteine was about 7 times higher than that of control rats. The increase in systolic blood pressure (Delta-SBP) from sympathetic stimulation by L-epinephrine was 2- to 3-fold larger in HHC model in rats than that in control rats after several weeks of the treatment. These findings suggest that HHC deteriorates vaso-regulatory function, which could bring on an increased risk of cardiovascular events in humans. In addition, some of the elastic lamellae in the aorta were disrupted in the HHC group. However, the content of cross-linkages which give elasticity and mechanical strength in the lamellae, was not significantly different between HHC and control rats. Also plasma concentrations of thiobarbituric acid reactive substance and glutathione as indicators for redox balance in plasma were not different. In conclusion, the deterioration of vaso-regulation in HHC model in rats might be caused by the damage to elastic lamellae in the aorta, and not by oxidative stresses. PMID- 25786526 TI - Bongkrekic acid as a selective activator of the peroxisome proliferator-activated receptor gamma (PPARgamma) isoform. AB - Bongkrekic acid (BKA), an antibiotic isolated from Pseudomonas cocovenans, is an inhibitory molecule of adenine nucleotide translocase. Since this translocase is a core component of the mitochondrial permeability transition pore (MPTP) formed by apoptotic stimuli, BKA has been used as a tool to abrogate apoptosis. However, the other biochemical properties of BKA have not yet been resolved. Although the definition of a fatty acid is a carboxylic acid (-COOH) with a long hydrocarbon chain (tail), when focused on the chemical structure of BKA, the molecule was revealed to be a branched unsaturated tricarboxylic acid that resembled the structure of polyunsaturated fatty acids (PUFAs). Peroxisome proliferator activated receptors (PPARs) consist of a subfamily of three isoforms: alpha, beta, and gamma, the ligands of which include PUFAs. Using completely synthesized BKA together with simplified BKA derivatives (purity: > 98%), we herein demonstrated the utility of BKA as a selective activator of the human PPARgamma isoform, which may not be associated with the anti-apoptotic nature of BKA. We also discussed the possible usefulness of BKA. PMID- 25786527 TI - Oral administration of Brazilian propolis exerts estrogenic effect in ovariectomized rats. AB - Propolis, a natural product derived from plants by honeybees, is a mixture of several hundred chemicals, including flavonoids, coumaric acids, and caffeic acids, some of which show estrogen-like activity. In this study, the estrogenic activity of crude ethanolic extract of Brazilian propolis was determined using several in vitro and in vivo assays. Propolis was found to bind to human estrogen receptors (ERs). Furthermore, propolis induced the expression of estrogen responsive genes in ER-positive MCF-7 and Ishikawa cells. These in vitro assays suggest that propolis exerts estrogenic activity; therefore, in vivo experiments were conducted using ovariectomized rats. Oral administration of propolis (55 or 550 mg/kg/day for 3 days) significantly increased uterine wet weight and luminal epithelium thickness in comparison with the corresponding values in the corn oil treated control group. Moreover, propolis induced ductal cell proliferation in the mammary glands. These effects were completely inhibited by full ER antagonist ICI 182,780, confirming that the effects of propolis are mediated by the ER. Our data show that oral intake of propolis induces estrogenic activity in ER expressing organs in vivo and suggest that Brazilian propolis is a useful dietary source of phytoestrogens and a promising treatment for postmenopausal symptoms. PMID- 25786528 TI - Biodistribution of gold nanoparticles in mice and investigation of their possible translocation by nerve uptake around the alveolus. AB - The effect of nanoparticles in the environment on our health is a cause of concern. The greatest concern with respect to the biological effect of nanoparticles is that they remain in the body and invade tissues, overcoming the protective mechanisms of the body. It is generally believed that nanoparticles invading a living body move into the blood and are carried by the bloodstream to all organs. However, some studies have shown that the inhaled nanoparticles directly translocate to the central nervous system by nerve uptake. Here quantification of the amount of migration of nanoparticles to organs in short time spans (1, 3, and 6 hr) was attempted by animal experiments. Furthermore, the possibility of migration of nanoparticles through the nerves that project around the alveolus, including the nodose ganglion and dorsal root ganglion (DRG), was investigated. Gold (Au) nanoparticles (15 nm) were administered to mice by intratracheal instillation and tail vein injection. After tail vein injection, most nanoparticles were distributed in the liver. After intratracheal instillation, approximately 80% of detected nanoparticles remained in the lungs at 1 hr and were believed to be translocated to digestive organs, including the stomach and intestine, at 3 and 6 hr. With respect to quantification in ganglia, the levels in most samples were lower than the limit of quantification of inductively coupled plasma mass spectrometry (ICP-MS). However, Au nanoparticles were detected in DRG in only some samples of intratracheal instillation. Therefore, this suggests the possibility of translocation of nanoparticles to DRG via nerves. PMID- 25786529 TI - Hand1-Luc embryonic stem cell test (Hand1-Luc EST): a novel rapid and highly reproducible in vitro test for embryotoxicity by measuring cytotoxicity and differentiation toxicity using engineered mouse ES cells. AB - The embryonic stem cell test (EST) is a promising alternative method for evaluating embryotoxicity of test chemicals by measuring cytotoxicity and differentiation toxicity using mouse ES cells. Differentiation toxicity is analyzed by microscopically counting the beating of embryonic bodies after 10 days of culture. However, improvements are necessary to reduce the laborious manipulations involved and the time required to obtain results. We have previously reported the successful stable transfection of ES cells (ES-D3) with the heart and neural crest derivatives expressed transcript 1 (Hand1) gene and the establishment of a 96-well multi-plate-based new EST with luciferase reporter assay 6 days after treatment with test chemicals. Now, we propose an even more rapid and easier EST, named Hand1-Luc EST. We established another cell line to monitor the Hand1 gene expression via a luciferase reporter gene. By mRNA analysis and luciferase assay, we examined in detail the luciferase activity during cell differentiation, which allowed us to reduce the time of measurement from day 6 to day 5 (120 hr). Furthermore, the protocol was improved, with, among others, the measurement of cytotoxicity and differentiation toxicity taking place in the same 96-well round bottom plate instead of two different plates. With the positive control, 5-fluorouracil (5-FU), and 9 test chemicals, data with high reproducibility and very low variation (CV < 50%) in the relevant endpoints were obtained. This study shows that the Hand1-Luc EST could provide an accurate and sensitive short-term test for prediction of embryotoxicants by measuring cytotoxicity and differentiation toxicity from the same sample. PMID- 25786530 TI - Induced adverse effects of prenatal exposure to silver nanoparticles on neurobehavioral development of offspring of mice. AB - Steadily increased use of silver nanoparticles (Ag-NPs), has increased the amount of its exposure to humans and animals. Current scarce knowledge about the influences of prenatal exposure to Ag-NPs on postnatal outcomes, motivated us to investigate whether being exposed to it during pregnancy has any effects on neurobehavioral development of the adult offspring. Thirty virgin female NMRI mice were mated and treated subcutaneously once every three days from gestation day 3 until delivery, by 0, 0.2 and 2 mg/kg of bodyweight (BW) of Ag-NPs. Behavioral functions of adult offspring including spatial memory, passive avoidance learning, stress, anxiety-like behaviors and locomotor activities were assessed by commonly used neurobehavioral paradigms and the results were compared according to treatment and sex. Prenatal exposure to Ag-NPs significantly impaired their cognitive behavior in the Morris water maze. Although no evidence was observed indicating more anxiety-like behaviors in the treated offspring in the elevated plus maze, the number of defecations and leanings in the open field assay and number of passages in the light-dark box were greater in groups prenatally treated by Ag-NPs. Most of the impairments were more apparent in the offspring which had been prenatally exposed to high doses of Ag-NPs, particularly female ones. The present study indicated that the exposure of pregnant animals to Ag-NPs may lead to various neurobehavioral disorders in their offspring. Thus, more attention should be paid to avoid exposure to Ag-NPs, especially from pregnant females. PMID- 25786531 TI - Artificial neural network analysis for predicting human percutaneous absorption taking account of vehicle properties. AB - An in silico method for predicting percutaneous absorption of cosmetic ingredients was developed by using artificial neural network (ANN) analysis to predict the human skin permeability coefficient (log Kp), taking account of the physicochemical properties of the vehicle, and the apparent diffusion coefficient (log D). Molecular weight and octanol-water partition coefficient (log P) of chemicals, and log P of the vehicles, were used as molecular descriptors for predicting log Kp and log D of 359 samples, for which literature values of either or both of log Kp and log D were available. Adaptivity of the ANN model was evaluated in comparison with a multiple linear regression model (MLR) by calculating the root-mean-square (RMS) errors. Accuracy and robustness were confirmed by 10-fold cross-validation. The predictive RMS errors of the ANN model were smaller than those of the MLR model (log Kp; 0.675 vs 0.887, log D; 0.553 vs 0.658), indicating superior performance. The predictive RMS errors for log Kp and log D with the ANN model after 10-fold cross-validation analysis were 0.723 and 0.606, respectively. Moreover, we estimated the cumulative amounts of chemicals permeated into the skin during 24 hr (Q24hr) from the values of log Kp and log D by applying Fick's law of diffusion. Our results suggest that this newly established ANN analysis method, taking account of the property of the vehicle, could contribute to non-animal risk assessment of cosmetic ingredients by providing a tool for calculating Q24hr, which is required for evaluating the margin of safety. PMID- 25786532 TI - Identification of immune response-related genes and signalling pathways in spleen of Vibrio parahaemolyticus-infected Epinephelus fuscoguttatus (Forskal) by next generation sequencing. PMID- 25786533 TI - Food insecurity: experience in a tertiary health center in Turkey. AB - AIM: Aim of the study was to determine food insecurity in families presenting to our hospital and the sociodemographic characteristics of those families. METHODS: A survey consisting of 18 questions was administered to the parents of the patients applying to our hospital's pediatric polyclinic in September 01-30, 2011. The administered survey was adapted by us to Turkish from the Household Food Security Survey Module of the American Ministry of Agriculture. The survey was administered to all patients by the same researcher. RESULTS: The study enrolled 283 families. Of the parents filling out the survey 208 (73.5%) were mothers, 53 (18.7%) were fathers and 22 (7.8%) other relatives (grandmother, aunt and uncle). Eighty-two (29%) families were determined to be food secure, 58 (20.5%) borderline food secure, 86 (30.4%) food insecure and 57 (20.1%) severely food insecure. CONCLUSION: Food insecurity ratio in the families presenting to our hospital was found to be fairly high. In our country studies associated with food insecurity should be conducted in larger areas and a higher number of families should be enrolled. PMID- 25786534 TI - Left ventricular non-compaction progression to dilated cardiomyopathy following acute myocarditis in an early infant twin. AB - Left ventricular non-compaction (LVNC), previously termed "spongy myocardium", is an abnormal interruption of myocardial compaction in early embryogenesis. It is now considered to be an important etiology of pediatric cardiomyopathy. Here, we report a case of 3-month-old twins with acute viral myocarditis, in which one of the twins, who had LVNC that progressed rapidly to dilated cardiomyopathy (DCMP) even after maximal medical therapy. The twin without LVNC recovered almost completely after supportive medical therapy. Although several reports have suggested that genetic abnormalities are associated with this disease, genetic research is needed to confirm this. This is the first report of LVNC in twins at 3 months of age who developed DCMP following acute fulminant myocarditis. In addition, this report highlights the fact that LVNC can be an important cause of DCMP, which can be rapidly aggravated after acute viral myocarditis during early infancy. PMID- 25786536 TI - Author's response. PMID- 25786535 TI - Radiological pitfalls of age estimation in adopted children: a case report. AB - Age estimation has a relevant importance in assessing adopted children, also in cases where the age of the minor seems unquestioned, since pathological conditions may radically alter bodily growth. This may lead to an incorrect age evaluation, with consequent social and psychological problems linked to an inadequate collocation in public school. This study aims at exposing a case report concerning age estimation for a newly adopted child from Cambodia; previous clinical documentation reported information suggesting possible malnutrition, which was verified by the observation of a general disalignment of bone and dental structures. This example shows the importance of a thorough forensic evaluation of adopted children from other countries in order to verify the possible environmental modification of physiological growth even where it seems not to be needed, and represents a caveat for clinical and social personnel dealing with adoption procedures. PMID- 25786537 TI - Restless legs syndrome in psoriasis: an unexpected comorbidity. AB - BACKGROUND: Restless legs syndrome (RLS) is characterized by unpleasant sensations in the legs and an uncontrollable urge to move them in order to gain relief. Higher frequencies of RLS have been reported in systemic lupus, multiple sclerosis, rheumatoid arthritis and atopic dermatitis. OBJECTIVES: Since the disease-related stress present in psoriasis is similar to the stress of those diseases, we aimed to study the frequency of RLS in a German cohort of patients with psoriasis. METHODS: 300 patients with psoriasis and 300 healthy controls were evaluated for RLS symptoms in this study. RESULTS: While 17% (n = 51) of patients with psoriasis reported symptoms of RLS, only 4% (n = 12) of individuals without psoriasis suffered from RLS symptoms (95% confidence interval: 0.08 - 0.18, p<0.01). In patients with psoriasis and RLS the average RLS score was 16.0 +/- 9.2 whereas individuals with RLS in the control group had an average RLS score of 13.5 +/- 7.1. CONCLUSIONS: Our findings indicate an increased frequency of RLS in patients with psoriasis, suggesting screening patients with psoriasis for the presence of RLS as a well-treatable co-morbidity. PMID- 25786538 TI - Maintaining integrity of germline DNA: individuals age, species do not. AB - All life forms are under constant assault, resulting in an accumulation of damage within each individual, in both somatic and germline cells. The obvious causes are: (1) mutations from radiation, chemical reactions like peroxidation and errors in replicating genetic material; (2) injury due to environmental insults, such as chemical alteration of proteins by reactive oxygen species; (3) epigenetic errors, such as failure of appropriate maintenance methylation of cytosines of DNA; and (4) numerous other problems, including retroviral invasions, inflammation and unhealthy microbiomes. Collectively, these phenomena constitute aging and/or certain disease states. Nature has developed numerous mechanisms to counteract these problems, such as proofreading enzymes, ubiquitous antioxidants and apoptotic death of unfit cells. However, none of these is completely effective. Although individuals accumulate damage, species usually do not become increasingly damaged; however, this could be one of the mechanisms for eventual extinction or evolution to a different species, the apparent fate of essentially all species. Nevertheless, germline DNA appears to remain sufficiently pristine to maintain fairly stable phenotypes over many generations. How do species avoid accumulating damage when composed of individuals that do? One broad answer seems to be reproductive redundancy followed by elimination of defects through the death of gametes, embryos, fetuses, neonates and postpubertal individuals, with the culling pressure increasing as potential parents age. Another major force appears to be evolutionary pressure; individuals that best fit the environment out-reproduce those that fit less well. What is impressive is that older and older parents continue to have offspring that are nearly as pristine as those of younger parents, even though their germline cells have continued to age. Although the offspring of old parents are not as fit, on average, as those of young parents, differences are small and, in some species, compensated for by superior parenting with accumulated experience. To conclude, it appears that species do not age, even though they are composed of individuals whose somatic and germline cells have aged. PMID- 25786539 TI - An educational measure to significantly increase critical knowledge regarding interfacility patient transfers. AB - BACKGROUND: Patient transfers among medical facilities are high-risk situations. Despite this, there is very little training of physicians regarding the medical and legal aspects of transport medicine. OBJECTIVES: To examine the effects of a one hour, educational intervention on Emergency Medicine (EM) residents' and Critical Care (CC) fellows' knowledge regarding the medical and legal aspects of interfacility patient transfers. METHODS: Prior to the intervention, physician knowledge regarding 12 key concepts in patient transfer was assessed using a pre test instrument. A one hour, interactive, educational session followed immediately thereafter. Following the intervention, a post-intervention test was given between two and four weeks after delivery. Participants were also asked to describe any prior transportation-medicine-related education, their opinions as they relate to the relevance of the topic, and their comfort levels with patient transfers before and after the intervention. RESULTS: Only a minority of participants had received any formal training in patient transfers prior to the intervention, despite dealing with patient transfers on a frequent, often daily, basis. Both groups improved in several categories on the post-intervention test. They reported improved comfort levels with the medicolegal aspects of interfacility patient transfers after the intervention and felt well-prepared to manage transfers in their daily practice. CONCLUSION: A one hour, educational intervention objectively increased EM and CC physician trainees' understanding of some of the medicolegal aspects of interfacility patient transfers. The study demonstrated a lack of previous training on this important topic and improved levels of comfort with transfers after study participation. PMID- 25786540 TI - Increase in transgene expression by pluronic L64-mediated endosomal/lysosomal escape through its membrane-disturbing action. AB - For efficient transgene delivery and expression, internalized nucleic acids should quickly escape from cellular endosomes and lysosomes to avoid enzymatic destruction and degradation. Here, we report a novel strategy for safe and efficient endosomal/lysosomal escape of transgenes mediated by Pluronic L64, a neutral amphiphilic triblock copolymer. L64 enhanced the permeability of biomembranes by structural disturbance and pore formation in a concentration- and time-dependent manner. When applied at optimal concentration, it rapidly reached the endosome/lysosome compartments, where it facilitated escape of the transfection complex from the compartments and dissociation of the complex. Therefore, when applied properly, L64 not only significantly increased polyethylenimine- and liposome-mediated transgene expression, but also decreased the cytotoxicity occasioned by transfection process. Our studies revealed the function and mechanism of neutral amphiphilic triblock copolymer as potent mediator for safe and efficient gene delivery. PMID- 25786541 TI - Expression of N-methyl-D-aspartate receptor subunits in the bovine ovum: ova as a potential source of autoantigens causing anti-NMDAR encephalitis. AB - Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis. PMID- 25786542 TI - Erythropoietin gene expression: developmental-stage specificity, cell-type specificity, and hypoxia inducibility. AB - Erythrocytes play an essential role in the delivery of oxygen from the lung to every organ; a decrease in erythrocytes (anemia) causes hypoxic stress and tissue damage. To maintain oxygen homeostasis in adult mammals, when the kidney senses hypoxia, it secretes an erythroid growth factor, erythropoietin (Epo), which stimulates erythropoiesis in the bone marrow. Recently, studies using genetically modified mice have shown that the in vivo expression profile of the Epo gene changes dramatically during development. The first Epo-producing cells emerge in the neural crest and neuroepithelium of mid-stage embryos and support primitive erythropoiesis in the yolk sac. Subsequently, Epo from the hepatocytes stimulates erythropoiesis in the fetal liver of later stage embryos in a paracrine manner. In fact, erythroid lineage cells comprise the largest cell population in the fetal liver, and hepatocytes are distributed among the erythroid cell clusters. Adult erythropoiesis in the bone marrow requires Epo that is secreted by renal Epo-producing cells (REP cells). REP cells are widely distributed in the renal cortex and outer medulla. Hypoxia-inducible Epo production both in hepatocytes and REP cells is controlled at the gene transcription level that is mainly mediated by the hypoxia-inducible transcription factor (HIF) pathway. These mouse studies further provide insights into the molecular mechanisms of the cell-type specific, hypoxia-inducible expression of the Epo gene, which involves multiple sets of cis- and trans-regulatory elements. PMID- 25786543 TI - Thermal, magnetic and electronic properties of non-centrosymmetric YbPt2B. AB - Ternary YbPt2B crystallizes in the non-centrosymmetric hexagonal CePt2B-type structure (space group P6(2)22). Electrical resistivity, specific heat and magnetic measurements reveal a magnetic instability at 5.6 K. Furthermore, a spin reorientation of presumably a ferromagnetic type occurs around 1.5 K. The behaviour at low temperature is governed by a rather weak Kondo effect, T(K) ? 1 K, in the presence of strong crystalline electric field splitting, with a doublet ground state. Besides, the complex magnetic behaviour presumably results from a Dzyaloshinskii-Moriya interaction triggered by the absence of inversion symmetry in the crystal structure. Scaling according to the de Gennes factor traces back magnetic ordering in YbPt2B to the Rudermann-Kittel-Kasuya-Yoshida (RKKY) interaction and the smooth evolution of the lattice constants and the unit cell volume of REPt2B (RE = rare earths) refers to the 4f(13) electronic configuration of Yb in YbPt2B. PMID- 25786544 TI - Sleep and nursing care activities in an intensive care unit. AB - This study aimed to describe the quality of sleep of non-intubated patients and the night-time nursing care activities in an intensive care unit. The study also aimed to evaluate the effect of nursing care activities on the quality of sleep. An overnight polysomnography was performed in 21 alert, non-intubated, non sedated adult patients, and all nursing care activities that involved touching the patient were documented by the bedside nurse. The median (interquartile range) amount of sleep was 387 (170, 486) minutes. The portion of deep non-rapid eye-movement (non-REM) sleep varied from 0% to 42% and REM sleep from 0% to 65%. The frequency of arousals and awakenings varied from two to 73 per hour. The median amount of nursing care activities was 0.6/h. Every tenth activity presumably awakened the patient. Patients who had more care activities had more light N1 sleep, less light N2 sleep, and less deep sleep. Nursing care was often performed while patients were awake. However, only 31% of the intervals between nursing care activities were over 90 min. More attention should be paid to better clustering of care activities. PMID- 25786545 TI - Lack of IDH1 mutation in astroblastomas suggests putative origin from ependymoglial cells? AB - Astroblastomas are extremely rare neuroepithelial tumors of uncertain histogenesis, affecting children and young adults, and constitute a new addition to the WHO 2000 classification of CNS tumors. We report the largest series of nine cases diagnosed in a single institute over the last 13 years and review published literature. Mean age at presentation was 12.8 years (range: 22 months to 27years). Seven out of nine cases were supratentorial (frontal/frontoparietal three, parieto-occipital - three, parafalcine - one), one was intraventricular and another was optochaismatic/suprasellar. Five cases were high grade (anaplastic) astroblastomas with Ki-67 labeling index of 8-10%. Immunohistochemical and ultrastructural evidence suggesting origin from cells intermediate between ependymocytes and astrocytes is presented. The histogenetic origin of these tumors remains speculative. But the lack of Isocitrate dehydrogenase 1 (IDH1) mutation as detected by immunohistochemistry in this study, which is similar to ependymomas supports putative origin from ependymoglial cells. Out of the nine cases, recurrence was noted in one case, 12 months after gross total resection with progression to high grade in the recurrent tumor. There is no recommended treatment protocol due to the rarity of this entity and prognostic factors are yet to be established. PMID- 25786546 TI - The synthesis of condensed C-PDA-g-C3N4 composites with superior photocatalytic performance. AB - Carbonized polydopamine-graphitic carbon nitride (C-PDA-g-C3N4) composites have been synthesised via in situ polymerization of dopamine (DA) on the surface of melamine followed by carbonization and condensation for the first time. The obtained C-PDA-g-C3N4 composites display enhanced crystallinity and superior photocatalytic performance. PMID- 25786547 TI - Binding of a biosynthetic intermediate to AtrA modulates the production of lidamycin by Streptomyces globisporus. AB - The control of secondary production in streptomycetes involves the funneling of environmental and physiological signals to the cluster-situated (transcriptional) regulators (CSRs) of the biosynthetic genes. For some systems, the binding of biosynthetic products to the CSR has been shown to provide negative feedback. Here we show for the production of lidamycin (C-1027), a clinically relevant antitumor agent, by Streptomyces globisporus that negative feedback can extend to a point higher in the regulatory cascade. We show that the DNA-binding activity of the S. globisporus orthologue of AtrA, which was initially described as a transcriptional activator of actinorhodin biosynthesis in S. coelicolor, is inhibited by the binding of heptaene, a biosynthetic intermediate of lidamycin. Additional experiments described here show that S. globisporus AtrA binds in vivo as well as in vitro to the promoter region of the gene encoding SgcR1, one of the CSRs of lidamycin production. The feedback to the pleiotropic regulator AtrA is likely to provide a mechanism for coordinating the production of lidamycin with that of other secondary metabolites. The activity of AtrA is also regulated by actinorhodin. As AtrA is evolutionarily conserved, negative feedback of the type described here may be widespread within the streptomycetes. PMID- 25786548 TI - Osteotome Sinus Floor Elevation without Grafting: A 10-Year Prospective Study. AB - BACKGROUND: Little is known about the long-term outcome of implants placed in the atrophic maxilla using osteotome sinus floor elevation (OSFE) without grafting. PURPOSE: The study aims to evaluate the long-term efficiency of the procedure and stability of the peri-implant bone formed following implant placement without grafting into resorbed posterior maxilla. MATERIALS AND METHODS: Twenty-five implants (<=10 mm in length) were placed in 17 patients using OSFE without grafting. The mean residual bone height was 5.4 +/- 2.3 mm. Bone levels were evaluated at 1, 3, 5, and 10 years using periapical radiographs. RESULTS: Fifteen patients (23 implants) participated in the 10-year examination. All implants fulfilled the survival criteria. Following surgery, the implant sites gained endo sinus bone (mean: 3.0 +/- 1.4 mm). The mean crestal bone loss (CBL) was limited to 1.0 +/- 0.9 mm. The difference in mean endo-sinus bone gain and CBL was statistically significant between 1 and 10 years, but not between 3 and 5, 3 and 10, and 5 and 10 years. CONCLUSIONS: At 10 years, the implant survival rate was 100%. Endo-sinus bone was mainly gained during the first year. This study demonstrates the long-term predictability of OSFE without grafting and simultaneous implant placement. PMID- 25786550 TI - CONDITIONING FACTORS FOR HIGH CARDIOVASCULAR RISK IN PATIENTS WITH CUSHING SYNDROME. AB - OBJECTIVE: To characterize the alterations in carbohydrate and lipoprotein metabolism, to evaluate markers of lipoprotein functionality, and to identify the presence of novel atherogenic risk factors in patients with Cushing syndrome (CS) in comparison with sex- and age-matched controls. METHODS: In an open, cross sectional study, 32 nontreated patients with active CS were consecutively recruited from the Endocrinology Service at "Jose de San Martin" Clinical Hospital, University of Buenos Aires, Argentina, between April 11, 2010 and December 11, 2012. The patients were compared with sex- and age-matched controls. RESULTS: Versus controls, patients with CS presented with excess weight, central obesity, and hypercortisolism. They also exhibited an insulin-resistant state, with high resistin levels (median [interquartile range], 16 [10 to 22] ng/mL versus 6 [5 to 9] ng/mL; P<.0001), a more atherogenic lipoprotein profile, high oxidized low-density lipoprotein levels (oxLDL; mean +/- SD, 100 +/- 31 U/L versus 75 +/- 32 U/L; P<.05) and high sensitive C-reactive protein levels (median [interquartile range], 1.2 [0.6 to 3.1] mg/L versus 0.6 [0.3 to 1.1] mg/L; P<.05), and increased leukocyte count (mean +/- SD, 9.5 +/- 2.6 * 10(3) cells/MUL versus 6.5 +/- 1.4 * 10(3) cells/MUL; P<.0001). Multivariate analyses showed that the increase in waist circumference was associated with both the diagnosis of CS and the degree of insulin resistance. Resistin concentration was related to a greater extent to the diagnosis of CS than to homeostasis model assessment insulin resistance. Triglyceride and oxLDL levels were only significantly associated with the diagnosis of CS. CONCLUSION: Hypercortisolism is related to the increase observed in triglycerides and oxLDL levels, and, in combination with insulin resistance, acts to increase waist circumference and amplify the inflammatory process, key factors for the development of cardiovascular disease. PMID- 25786551 TI - EFFECTIVENESS AND OUTCOMES OF CURRENT PRACTICE IN TREATING VITAMIN D DEFICIENCY IN PATIENTS LISTED FOR LIVER TRANSPLANTATION. AB - OBJECTIVE: Vitamin D deficiency is prevalent in cirrhotic patients awaiting liver transplantation (LT). Optimal vitamin D management for these patients remains undefined. We sought to determine the effectiveness of our practice in addressing vitamin D deficiency in LT patients. METHODS: This retrospective study included 127 patients who received a first LT between July 2010 and July 2011. Outcomes measured included readmission rates, fractures, and functional status post-LT. 25 Hydroxyvitamin D (25-OH D) deficiency was stratified as: mild (20-30 ng/mL), moderate (15-19.9 ng/mL), and severe (<15 ng/mL). We estimated the amount of vitamin D supplementation required for each patient. RESULTS: At LT evaluation, 107 patients (84%) had vitamin D deficiency, and 74% remained vitamin D deficient at LT. Only 62% received vitamin D supplementation pre-LT. Moderate and severe deficiencies were less common at LT and rare 4 months post-LT. There was an association between improvement in vitamin D deficiency category at LT and increased vitamin D (>400,000 IU total) supplementation (P = .004). We found no association between vitamin D deficiency at LT and functional status, fractures, or readmissions post-LT. Patients receiving induction immunosuppressant therapy with basiliximab had a significantly greater degree of worsening in bone mineral density (BMD) post-LT. CONCLUSION: Moderate-to-severe vitamin D deficiency was very prevalent in a cohort of patients undergoing evaluation for LT. Deficiency was improved with increased vitamin D replacement therapy. Vitamin D deficiency at LT was not associated with worse bone or functional outcomes post-LT. The influence of basiliximab on bone health post-LT requires further evaluation. PMID- 25786552 TI - CIRCULATING THYROID-STIMULATING HORMONE RECEPTOR MESSENGER RNA AS A MARKER OF TUMOR AGGRESSIVENESS IN PATIENTS WITH PAPILLARY THYROID MICROCARCINOMA. AB - BACKGROUND: We have previously shown that thyroid-stimulating hormone receptor messenger RNA (TSHR mRNA) is detectable in the peripheral blood of patients with papillary thyroid microcarcinoma (PTmC). The aim of this study was to analyze the utility of TSHR mRNA status as a marker of tumor aggressiveness in patients with PTmC. METHODS: Preoperative TSHR mRNA values were obtained in 152 patients who underwent thyroidectomy and were found to have PTmC on final pathology. Clinical parameters were analyzed from an institutional review board-approved database using chi(2) and t tests. RESULTS: Preoperatively, TSHR mRNA was detected in the peripheral blood in 46% of patients, which was less than that for macroscopic papillary thyroid carcinoma (PTC) (80%) but higher than for benign thyroid disease (18%) (P<.001). The focus of cancer was larger in the TSHR mRNA-positive group compared to the negative group (0.41 vs. 0.30 cm, respectively, P = .015). The prevalence of tall-cell variant was higher in the TSHR mRNA positive group. The rates of lymph node (LN) metastasis (16% vs. 10%), multifocality (46% vs. 49%), and extra-thyroidal extension (10% vs. 5%) were similar between the TSHR mRNA-positive and-negative groups, respectively. In patients 45 years or older, rate of LN metastasis was higher in those who were TSHR mRNA positive (10%) versus negative (2%) (P = .039). TSHR mRNA positivity predicted a higher likelihood of radioactive iodine treatment (36% vs. 17%, P = .009) postoperatively. CONCLUSION: This study shows that TSHR mRNA, which is a marker of circulating thyroid cancer cells, is detectable in about half of patients with PTmC. The positivity of this marker predicts a higher likelihood of LN involvement in patients with PTmC who are 45 years or older. PMID- 25786553 TI - 1,5-ANHYDROGLUCITOL AND NEONATAL COMPLICATIONS IN PREGNANCY COMPLICATED BY DIABETES. AB - OBJECTIVE: To determine the association of 1,5-anhydroglucitol (1,5-AG) with neonatal birth weight (NBW) and neonatal hypoglycemia (+NH) in pregnancies complicated by diabetes. METHODS: We assessed a retrospective cohort of 102 females, 17 with gestational diabetes (GDM), 48 with type 1 diabetes mellitus (T1DM), and 37 with type 2 diabetes mellitus (T2DM). 1,5-AG and glycated hemoglobin A1C (A1C) values throughout pregnancy were extracted. Linear regression was used to assess their association with NBWs z-scores adjusting for maternal age, ethnicity and body mass index (BMI). +NH was defined by a note in the infant record, glucose <1.7 mmol/L in the first 24 h, or <2.5 mmol/L in the first 48 h after birth. A t test or Welch's approximate t test was used to compare the mean 1,5-AG and A1C of mothers with +NH versus those without (-NH), adjusted for gestational age and analyzed by diabetes type and across trimesters. RESULTS: Mean 1,5-AG significantly differed across groups: T1DM 3.77 +/- 2.82 MUg/mL, T2DM 5.73 +/- 4.38 MUg/mL, GDM 8.89 +/- 4.39 MUg/mL (P<.0001), suggesting less glucose exposure in GDM relative to T1DM or T2DM. A negative linear association was found between mean 1,5-AG and z-scores (R= -0.28, P = .005. In contrast, the association between mean A1C and z-scores was weaker (R = 0.15, P = .14). The mean 1,5-AG tended to be lower in the +NH cohort versus -NH (P = .08), and this was statistically significant (P = .01) among subjects with GDM. CONCLUSION: The association of 1,5-AG with complications related to glycemic exposure supports the notion of its utility as an adjunct glycemic biomarker in pregnancies complicated by diabetes and across trimesters. PMID- 25786554 TI - TREATMENT WITH CINACALCET INCREASES PLASMA ADIPONECTIN CONCENTRATION IN HEMODIALYZED PATIENTS WITH CHRONIC KIDNEY DISEASE AND SECONDARY HYPERPARATHYROIDISM. AB - OBJECTIVE: Cinacalcet increases calcium-sensing receptor (CaSR) sensitivity to serum calcium. CaSR is expressed by adipocytes, and adiponectin is an adipokine with antiatherogenic and insulin-sensitizing properties. The aim of this study was to assess the influence of a 3-month cinacalcet regimen on plasma adiponectin concentration in hemodialyzed patients (HDP) with chronic kidney disease (CKD) and secondary hyperparathyroidism (sHPT). METHODS: Plasma adiponectin, advanced oxidation protein products (AOPP), serum interleukin-6 (IL-6) and C-reactive protein (CRP) concentrations were assessed in 65 HDP with sHPT treated with cinacalcet (30-120 mg/day) before the first dose and after 3 months of treatment. RESULTS: There was a significant decrease in serum parathyroid hormone (PTH) concentration: from 1,089 (891-1,286) pg/mL to 775 (574-976) pg/mL after 3 months of treatment (P<.0001). The treatment was associated with a significant (P = .048) increase in plasma adiponectin concentration from 16.9 (14.4-19.5) MUg/mL to 17.8 (15.0-20.6) MUg/mL. Significant (P = .03) reduction of plasma AOPP concentration was observed from 186.7 (156.7-216.7) pg/mL to 162.6 (141.2-183.9) pg/mL. CONCLUSIONS: A 3-month cinacalcet regimen increased plasma adiponectin concentrations in HDP with sHPT. Increased adiponectinemia in these patients may be related to reduced oxidative stress. PMID- 25786555 TI - MENSTRUAL AND REPRODUCTIVE FUNCTION IN WOMEN WITH TYPE 1 DIABETES. AB - OBJECTIVE: Menstrual irregularities, reproductive abnormalities, and androgen excess are reported to be more prevalent in women with type 1 diabetes (T1D). The objective of this study was to investigate the prevalence of menstrual irregularities, reproductive abnormalities, and androgen excess among women with T1D and their age-matched controls. METHODS: A survey requesting information regarding menstrual and reproductive histories was administered to all participants. Results were stratified according to age (18 to 40, 40 to 50, and >50 years). RESULTS: There were no significant differences between women with and without diabetes in age at menarche, cycle length, or androgen excess in any group. Women who self-reported difficulty with glycemic control were more likely to report irregular menses than controls (P = .04). Among women who reported ever being pregnant, there were fewer pregnancies (P = .02) and live births (P = .002) in women with T1D. Women with T1D reported a lower frequency of oral contraceptive use (P = .003), despite being less likely to smoke (P = .016). CONCLUSION: Menstrual and reproductive abnormalities were not observed more frequently in women with T1D in this study. Subtle but measurable differences in menstrual and reproductive function were confined to the subgroup of women who perceived poor control of their diabetes. Additional prospective studies of T1D and menstrual and reproductive function would be useful. PMID- 25786556 TI - Postoperative hypocalcemia after thyroidectomy: can it be prevented? PMID- 25786557 TI - THE RATIONALE FOR USE OF INCRETINS IN THE MANAGEMENT OF NEW ONSET DIABETES AFTER TRANSPLANTATION (NODAT). AB - OBJECTIVE: Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed. METHODS: The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia. RESULTS: Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation. CONCLUSION: Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management. PMID- 25786558 TI - Radiotherapy vs. Radiosurgery in Treating Patients with Acromegaly: Systematic Review and Meta-Analysis. AB - OBJECTIVE: When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence to compare outcomes with SRS and RT in patients with acromegaly. METHODS: We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum IGF-1 and GH levels, biochemical remission, all-cause mortality, hypopituitarism, headaches and secondary malignancies. We pooled outcomes using the random-effects model. RESULTS: The final search yielded 30 eligible studies enrolling 2464 patients. When compared to RT, SRS was associated with a non-significant increase in remission rate at the latest follow-up period (52% vs. 36%; p = 0.14), and a significantly lower follow-up IGF-1 level (decline of - 409.72 MUg/1 vs. -102 MUg/1; p = 0.002). SRS was associated with lower incidence of hypopituitarism than RT; however the difference was not statistically significant [(32% vs.51%, respectively; p = 0.05). CONCLUSIONS: SRS may be associated with better biochemical remission and lower risk of hypopituitarism with at least one deficient axis when compared with RT; however, the confidence in such evidence is very low due to the non-comparative nature of the studies, high heterogeneity, and imprecision. PMID- 25786559 TI - OVOTESTICULAR DISORDER OF SEX DEVELOPMENT: A SINGLE-CENTER EXPERIENCE. AB - OBJECTIVE: Ovotesticular disorder of sex development (OT DSD) is a rare disorder of sex development characterized by the presence in the same individual of both histologically proven testis and ovary. There are scant data from the Indian subcontinent regarding this disorder. The aim of this study was to describe the clinical, biochemical, imaging, cytogenetic, surgical, and histopathologic findings and outcomes of patients with OT DSD from Western India. METHODS: The records of patients referred to our center for disorders of sex development between 2005 and 2013 were reviewed, and 7 patients were found to have histologically proven OT DSD. RESULTS: The median age at presentation was 8 years (range, 2 months to 25 years). Clinical presentation varied from genital ambiguity and inguinal swelling at birth to gynecomastia and cyclical hematuria after puberty. Karyotype was 46, XX in 6 patients and 46, XY in 1 patient. All patients underwent pelvic ultrasonography, laparoscopy, and surgery for removal of gonads not congruous with the chosen sex of rearing. Gender assignment for all the patients was done by the parents at birth, which was mainly influenced by the external genitalia and sociocultural influences, with 5 out of the 7 patients being reared as males. There was no evidence of gonadal tumors in our study. CONCLUSION: OT DSD should be considered as one of the differential diagnoses in cases of ambiguous genitalia with nonpalpable or asymmetrical gonads, pubertal gynecomastia, and cyclical hematuria, irrespective of the karyotype or internal genitalia. PMID- 25786560 TI - Gastrointestinal hormone research - with a Scandinavian annotation. AB - Gastrointestinal hormones are peptides released from neuroendocrine cells in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gut, which makes it the largest hormone-producing organ in the body. Modern biology makes it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization or differentiated posttranslational maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gut. Gut hormone genes are also widely expressed outside the gut, some only in extraintestinal endocrine cells and cerebral or peripheral neurons but others also in other cell types. The extraintestinal cells may release different bioactive fragments of the same prohormone due to cell specific processing pathways. Moreover, endocrine cells, neurons, cancer cells and, for instance, spermatozoa secrete gut peptides in different ways, so the same peptide may act as a blood-borne hormone, a neurotransmitter, a local growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein-coupled receptors that are expressed in the cell membranes also outside the digestive tract. Thus, gut hormones not only regulate digestive functions, but also constitute regulatory systems operating in the whole organism. This overview of gut hormone biology is supplemented with an annotation on some Scandinavian contributions to gastrointestinal hormone research. PMID- 25786561 TI - Prevalence and correlates of rest tremor in essential tremor: cross-sectional survey of 831 patients across four distinct cohorts. AB - BACKGROUND AND PURPOSE: Essential tremor (ET) is amongst the most commonly encountered neurological disorders. Its hallmark feature is kinetic tremor. However, other tremors may also occur in ET patients, creating considerable diagnostic confusion amongst treating physicians. Hence, characterizing the prevalence and clinical accompaniments of these other tremors is of value. Surprisingly, there are few data on the prevalence of rest tremor in ET patients, and even fewer data on the clinical correlates of such tremor. METHODS: Eight hundred and thirty-one patients in four distinct settings (population, genetics study, study of environmental epidemiology, brain bank) underwent a detailed videotaped neurological examination that was reviewed by a senior movement disorders neurologist. Rest tremor was evaluated in several positions (seated, standing, lying down). RESULTS: The prevalence of rest tremor whilst seated or standing was lowest in the population-based setting (1.9%), highest in the brain bank study (46.4%) and intermediate in the remaining two settings (9.6% and 14.7%, respectively). Rest tremor was restricted to the arms and was not observed in the legs. Rest tremor was associated with older age, longer disease duration (in some studies), greater tremor severity and, to some extent, the presence of cranial tremors. CONCLUSIONS: Rest tremor can be a common clinical feature of ET. Its prevalence is highly dependent on the setting in which patients are evaluated, ranging from as low as 1% to nearly 50%. Rest tremor seems to emerge as a clinical feature with advancing disease. The anatomical substrates for this type of tremor remain unknown at present. PMID- 25786562 TI - MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis. AB - AIMS: From the viewpoint of histogenesis, lung adenocarcinoma can be subdivided into two groups: terminal respiratory unit (TRU) and non-TRU types. We recently reported a non-TRU type adenocarcinoma designated as ciliated adenocarcinoma (we now prefer central type adenocarcinoma). We suggest reasons that mucinous adenocarcinoma should encompass central type adenocarcinoma to represent its biological characteristics as non-TRU type adenocarcinoma. METHODS AND RESULTS: Mucin (MUC)5AC and MUC5B were expressed more significantly in non-TRU type adenocarcinoma (P < 0.01). Thirty-five (76.1%) and 45 cases (97.8%) of 46 non-TRU type adenocarcinoma showed positivity for MUC5AC and MUC5B. Twelve (7.6%) and eight (5.1%) cases of 157 TRU type adenocarainoma showed positivity for MUC5B and MUC5AC. NKX2-1 gene expression was measured with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). DeltaDeltaCt of NKX2-1 gene expression was 6.79 for TRU type adenocarcinoma and 0.6 for non-TRU type adenocarcinoma. Overall survival and disease-free survival were poorer in non-TRU type adenocarcinoma (P = 0.02 and P = 0.03). A multivariate test also showed that non-TRU type adenocarcinoma is an independent prognostic factor (P = 0.04). CONCLUSION: MUC5AC and MUC5B were specific makers for non-TRU adenocarcinoma, including both central type adenocarcinoma and mucinous adenocarcinoma. We suggest that non-TRU type adenocarcinoma presents a poorer prognosis, so it should be regarded separately from TRU type adenocarcinoma. PMID- 25786563 TI - Conditioned medium of demineralized freeze-dried bone activates gene expression in periodontal fibroblasts in vitro. AB - BACKGROUND: Demineralized bone matrix (DBM) is used for the treatment of osseous defects. Conditioned medium from native bone chips can activate transforming growth factor (TGF)-beta signaling in mesenchymal cells. The aim of this study is to determine whether processing of native bone into DBM affects the activity of the conditioned medium. METHODS: Porcine cortical bone blocks were subjected to defatting, different concentrations of hydrochloric acid, and various temperatures. DBM was lyophilized, ground, and placed into culture medium. Human gingiva and periodontal fibroblasts were exposed to the respective conditioned medium obtained from DBM (DBCM). Changes in the expression of TGF-beta target genes were determined. RESULTS: DBCM altered the expression of TGF-beta target genes (e.g., adrenomedullin, pentraxin 3, KN motif and ankyrin repeat domains 4, interleukin 11, NADPH oxidase 4, and BTB [POZ] domain containing 11) by at least five-fold. The response was observed in fibroblasts from both sources. Defatting lowered the activity of DBCM. The TGF-beta receptor type I kinase inhibitor SB431542 [4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2 yl)benzamide] but not the inhibitor of bone morphogenetic protein receptor dorsomorphin, blocked the effects of DBCM on gene expression. Moreover, conditioned medium obtained from commercial human DBM modulated the expression of TGF-beta target genes. CONCLUSION: The findings suggest that the DBCM can activate TGF-beta signaling in oral fibroblasts. PMID- 25786564 TI - Level of Interleukin-35 in Gingival Crevicular Fluid, Saliva, and Plasma in Periodontal Disease and Health. AB - BACKGROUND: A novel member of the interleukin (IL)-12 family, IL-35 is an important inhibitory cytokine released by regulatory T cells. The aim of this study is to evaluate gingival crevicular fluid (GCF), saliva, and plasma levels of IL-35 in periodontal disease and health. METHODS: Samples of GCF, whole saliva, and plasma were obtained from systemically healthy, non-smoking individuals with gingivitis (n = 20) or chronic periodontitis (CP) (n = 20) and periodontally healthy individuals (n = 20). Full-mouth clinical periodontal measurements, including probing depth (PD), bleeding on probing, gingival index, and plaque index (PI), were also recorded. Enzyme-linked immunosorbent assay was used to determine IL-35 levels in the samples. Data were tested statistically by analysis of variance and Pearson rank correlation test. RESULTS: All clinical parameters were significantly higher in the CP group than the healthy and gingivitis groups (P <0.001). The GCF total amount of IL-35 was significantly higher in the CP group than the other groups (P = 0.04), whereas the GCF concentration of IL-35 was significantly higher in the healthy group than the other groups (P = 0.002). There were significant differences among the study groups in terms of salivary IL-35 level (P <0.001), with the highest level observed in the healthy group and the lowest in the CP group. There was no statistical difference between groups in plasma levels of IL-35 (P >0.05). There was a positive correlation between GCF total amount of IL-35 and PD (r = 0.338, P = 0.03) and PI (r = 0.374, P = 0.005) parameters. CONCLUSIONS: IL-35 could have an important role in suppressing periodontal inflammation and maintaining periodontal health. Additional studies are required to evaluate its role in periodontal diseases. PMID- 25786565 TI - Efficacy of locally delivered 1.2% rosuvastatin gel to non-surgical treatment of patients with chronic periodontitis: a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Chronic periodontitis (CP) is an inflammatory condition affecting tooth-supporting tissues and alveolar bone that surround the tooth, leading to formation of a deepened gingival sulcus that is highly prone to pathologic changes and, ultimately, bone resorption and tooth loss. In the literature, several pharmacologic agents have been administered via local delivery routes directly into diseased sites, affirming improvement in periodontal status. Therefore, this study aims to determine the clinical effectiveness of subgingivally delivered 1.2% rosuvastatin (RSV) gel incorporated into a methylcellulose vehicle for its controlled release into intrabony defect (IBD) sites as an adjunct to scaling and root planing (SRP) for treatment of patients with CP. METHODS: Sixty-five patients were categorized into two treatment groups: group 1, SRP plus 1.2 mg RSV; group 2, SRP plus placebo. Clinical parameters, including modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL), were recorded at baseline (before SRP) and at 1, 3, 4, and 6 months. Radiologic assessment of IBD fill was analyzed at baseline and after 6 months using software. RESULTS: There was significant improvement in both study groups. At 6 months, there was a greater decrease in mSBI scores in group 1 (3.71 +/- 0.24) compared to group 2 (1.48 +/- 0.33). The mean decrease in PD from baseline to 6 months was 4.04 +/- 0.34 and 1.31 +/- 0.24 mm in groups 1 and 2, respectively. Mean CAL gain from baseline to 6 months was 4.2 +/- 0.17 and 1.4 +/ 0.15 mm in groups 1 and 2, respectively. In group 1, there was a greater decrease in mean IBD (2.23 +/- 0.32 mm, 48.58%) compared to group 2 (0.46 +/- 0.02 mm, 10.02%). All patients tolerated the drug without any adverse reaction. CONCLUSION: Rosuvastatin in situ gel (1.2%), when delivered locally into IBD/pocket sites, showed a greater reduction than placebo in PD and gingival index, along with increased gain in CAL. PMID- 25786566 TI - Effect of non-surgical periodontal treatment on visfatin concentrations in serum and gingival crevicular fluid of patients with chronic periodontitis and type 2 diabetes mellitus. AB - BACKGROUND: This study aims to assess visfatin concentrations in serum and gingival crevicular fluid (GCF) and investigate this relationship in patients with type 2 diabetes mellitus (T2DM) and chronic periodontitis (CP) before and after non-surgical periodontal treatment. METHODS: Fifty-four patients with T2DM and CP were recruited. The patients were randomly divided into two groups: treatment and control. Serum and GCF visfatin concentrations and glycated hemoglobin (HbA1c) levels were measured by enzyme-linked immunosorbent assay at different time points (at baseline and 3 and 6 months after non-surgical periodontal treatment). RESULTS: Serum and GCF visfatin concentrations showed no significant differences between the groups at baseline (t test, P >0.05). A significant decline of visfatin in the treatment group was found in serum and GCF 3 months after non-surgical periodontal treatment (t test, P <0.01). Baseline and 3-month HbA1c levels were not significantly different, but at 6 months, a statistically significant difference was detected (t test, P >0.05). CONCLUSIONS: The data suggest that non-surgical periodontal treatment is helpful for glucose control, an effect that may be associated with reduced visfatin in patients with T2DM and periodontitis. Furthermore, the data suggest that visfatin may be considered an inflammatory marker for periodontal diseases. PMID- 25786568 TI - Strategies to overcome statin intolerance. AB - This editorial discusses several options to overcome statin intolerance in clinical practice. For example, switching to a different statin, changing statin dosing, using lipid-lowering drugs other than statins (e.g., ezetimibe, bile acid sequestrants and fibrates, alone or in combination), or combining statins with other lipid-lowering drugs. The authors focus on the potential mechanisms involved in statin-related myopathy. New lipid-lowering drugs currently in development (e.g., cholesterol ester transfer protein inhibitors [anacetrapib] and proprotein convertase subtilisin/kexin 9 inhibitors) inhibitors may help in the management of statin intolerance while achieving low-density lipoprotein cholesterol targets as set out by the guidelines. PMID- 25786567 TI - Preservation of protein fluorescence in embedded human dendritic cells for targeted 3D light and electron microscopy. AB - In this study, we present a correlative microscopy workflow to combine detailed 3D fluorescence light microscopy data with ultrastructural information gained by 3D focused ion beam assisted scanning electron microscopy. The workflow is based on an optimized high pressure freezing/freeze substitution protocol that preserves good ultrastructural detail along with retaining the fluorescence signal in the resin embedded specimens. Consequently, cellular structures of interest can readily be identified and imaged by state of the art 3D confocal fluorescence microscopy and are precisely referenced with respect to an imprinted coordinate system on the surface of the resin block. This allows precise guidance of the focused ion beam assisted scanning electron microscopy and limits the volume to be imaged to the structure of interest. This, in turn, minimizes the total acquisition time necessary to conduct the time consuming ultrastructural scanning electron microscope imaging while eliminating the risk to miss parts of the target structure. We illustrate the value of this workflow for targeting virus compartments, which are formed in HIV-pulsed mature human dendritic cells. PMID- 25786570 TI - Inter-individual differences in HLA expression can impact the CDC crossmatch. AB - How human leucocyte antigen (HLA) expression levels on human lymphocytes relate to clinically relevant in vitro cytotoxicity testing has not been defined. Here, cross-sectional (n = 14) and longitudinal (n = 6) semi-quantitative assessment of HLA expression on lymphocytes was performed. Complement-dependent cytotoxicity (CDC) and cellular allo-reactivity were assessed vis-a-vis target cells with defined levels of HLA expression. On CD4(+) and CD8(+) T-cells, and on B-cells, intra-individual HLA levels varied <=1.5-fold, whereas inter-individual HLA expression varied 2.34-fold and 2.07-fold on CD4(+) and CD8(+) T-cells, respectively, and 2.90-fold on B-cells. Importantly, CDC crossmatch reactions induced by anti-HLA-A2 monoclonal antibody as well as patient sera solely containing HLA-A2 antibodies were significantly impacted by HLA-A2 expression levels on donor cells. Likewise, cytotoxicity of HLA-A2 reactive effector cells was induced proportionate to availability of HLA-A2. These data demonstrate that human HLA expression on lymphocytes from healthy blood donors is fairly stable intra-individually, yet varies significantly from person to person. Variability in HLA expression levels can impact functional cytotoxic reactions in vitro, including the widely used CDC crossmatch assay. Prospective studies are required to test the clinical relevance of this finding. PMID- 25786572 TI - Two novel HLA alleles, HLA-A*30:02:01:03 and HLA-C*08:113, identified in a South African bone marrow donor. AB - Genomic sequencing of HLA-A*30:02:01:03, an intronic variant, and HLA-C*08:113, an exonic variant. PMID- 25786571 TI - Gene expression changes in HLA mismatched mixed lymphocyte cultures reveal genes associated with allorecognition. AB - Human leucocyte antigen (HLA) compatibility is the main factor determining the occurrence of graft-vs-host disease (GVHD) in patients. It has also been shown that minor histocompatibility antigen differences as well as genetic polymorphisms that are not sequenced by standard methodology for HLA typing can play a role. We used mixed lymphocyte cultures (MLCs) as a functional cellular test and investigated gene expression changes driven by HLA incompatibility in an effort to better understand the mechanisms involved in the disease. Gene expression profile of HLA matched and HLA mismatched MLC identified differentially regulated genes and pathways. We found that a great number of genes related to immune function were differentially regulated; these genes were also found to be associated with GVHD and graft rejection. The majority of differentially regulated genes were interferon-gamma (IFNgamma)-inducible genes and IFNgamma neutralisation in MLCs abrogated their induction. The microRNA-155, a recently identified target for acute GVHD (aGVHD), was also found to be significantly induced in HLA mismatched MLC but not in the matched setting and its induction was not diminished by blocking IFNgamma. In this proof-of-principle study we show gene expression changes in mismatched MLC that represent alloreactive responses, correlate with markers involved in GVHD and can potentially be useful in the study of the biological processes involved in this disease. PMID- 25786573 TI - A new HLA-B allele, B*49:34, sequenced in a Spanish individual. AB - HLA-B*49:34 shows one nucleotide difference regarding B*49:01:01 at codon 66 (ATC>GTC, I66>V66). PMID- 25786574 TI - Optic Nerve Sheath Diameter Measurement to Identify High-Risk Patients for Spinal Ischemia after Endovascular Thoracoabdominal Aortic Aneurysm Repair. AB - BACKGROUND & PURPOSE: Thoracic endovascular aortic repair (TEVAR) is associated with a reasonable risk of spinal ischemia. As cerebrospinal fluid pressure (CSFP) is correlated with the rate of paraplegia, a non-invasive method to estimate CSFP could help to estimate the patient's individual risk and guide the therapeutic approach. The quantification of the optic nerve sheath diameter (ONSD) using ocular sonography (OS) could be a suitable technique and was examined in the present study. METHODS: 28 patients with TEVAR were included. Five consecutive measurements of the ONSD were performed in each patient. The first before the intervention ("baseline"), the next immediately postinterventional at the intensive care unit (post1), measurements 3, 4 (post2, post3) on day 1 and 2 after the intervention and number 5 (post4) before discharge. Statistical analysis was done using the Wilcoxon-test. A p-value < 0.05 was considered statistically significant. RESULTS: A significant increase between baseline and post1-measurements (right eye: p = 0.006; left eye: p = 0.02) could be detected. A significant decrease was detected between post1 and post3 (right eye: p = 0.02; left eye: p < 0.01). A group of 5 patients had an additional increase of ONSD from post1 to post2, one of these patients developed a permanent paraplegia. Patients with spinal catheters had significantly lower ONSDs at nearly all time points. CONCLUSION: The present study is the first to prospectively examine and prove the possibility to monitor CSFP changes in patients with TEVAR associated transient spinal edema using OS. Systematic factors as artificial ventilation and body positioning did not have a significant effect. PMID- 25786575 TI - Expression of anti-tumor necrosis factor alpha (TNFalpha) single-chain variable fragment (scFv) in Spirodela punctata plants transformed with Agrobacterium tumefaciens. AB - Therapeutic antibodies against tumor necrosis factor alpha (TNFalpha) have been considered effective for some of the autoimmune diseases such as rheumatoid arthritis, Crohn's diseases, and so on. But associated limitations of the current therapeutics in terms of cost, availability, and immunogenicity have necessitated the need for alternative candidates. Single-chain variable fragment (scFv) can negate the limitations tagged with the anti-TNFalpha therapeutics to a greater extent. In the present study, Spirodela punctata plants were transformed with anti-TNFalpha through in planta transformation using Agrobacterium tumefaciens strain, EHA105. Instead of cefotaxime, garlic extract (1 mg/mL) was used to remove the agrobacterial cells after cocultivation. To the best of our knowledge, this report shows for the first time the application of plant extracts in transgenic plant development. 95% of the plants survived screening under hygromycin. ScFv cDNA integration in the plant genomic DNA was confirmed at the molecular level by PCR. The transgenic protein expression was followed up to 10 months. Expression of scFv was confirmed by immunodot blot. Protein expression levels of up to 6.3% of total soluble protein were observed. beta-Glucuronidase and green fluorescent protein expressions were also detected in the antibiotic resistant plants. The paper shows the generation of transgenic Spirodela punctuata plants through in planta transformation. PMID- 25786576 TI - A combinatorial approach of comprehensive QTL-based comparative genome mapping and transcript profiling identified a seed weight-regulating candidate gene in chickpea. AB - High experimental validation/genotyping success rate (94-96%) and intra-specific polymorphic potential (82-96%) of 1536 SNP and 472 SSR markers showing in silico polymorphism between desi ICC 4958 and kabuli ICC 12968 chickpea was obtained in a 190 mapping population (ICC 4958 * ICC 12968) and 92 diverse desi and kabuli genotypes. A high-density 2001 marker-based intra-specific genetic linkage map comprising of eight LGs constructed is comparatively much saturated (mean map density: 0.94 cM) in contrast to existing intra-specific genetic maps in chickpea. Fifteen robust QTLs (PVE: 8.8-25.8% with LOD: 7.0-13.8) associated with pod and seed number/plant (PN and SN) and 100 seed weight (SW) were identified and mapped on 10 major genomic regions of eight LGs. One of 126.8 kb major genomic region harbouring a strong SW-associated robust QTL (Caq'SW1.1: 169.1 171.3 cM) has been delineated by integrating high-resolution QTL mapping with comprehensive marker-based comparative genome mapping and differential expression profiling. This identified one potential regulatory SNP (G/A) in the cis-acting element of candidate ERF (ethylene responsive factor) TF (transcription factor) gene governing seed weight in chickpea. The functionally relevant molecular tags identified have potential to be utilized for marker-assisted genetic improvement of chickpea. PMID- 25786577 TI - Effect of visual biofeedback of posterior tongue movement on articulation rehabilitation in dysarthria patients. AB - Articulation is driven by various combinations of movements of the lip, tongue, soft palate, pharynx and larynx, where the tongue plays an especially important role. In patients with cerebrovascular disorder, lingual motor function is often affected, causing dysarthria. We aimed to evaluate the effect of visual biofeedback of posterior tongue movement on articulation rehabilitation in dysarthria patients with cerebrovascular disorder. Fifteen dysarthria patients (10 men and 5 women; mean age, 70.7 +/- 10.3 years) agreed to participate in this study. A device for measuring the movement of the posterior part of the tongue was used for the visual biofeedback. Subjects were instructed to produce repetitive articulation of [ka] as fast and steadily as possible between a lungful with/without visual biofeedback. For both the unaffected and affected sides, the range of ascending and descending movement of the posterior tongue with visual biofeedback was significantly larger than that without visual biofeedback. The coefficient of variation for these movements with visual biofeedback was significantly smaller than that without visual biofeedback. With visual biofeedback, the range of ascent exhibited a significant and strong correlation with that of descent for both the unaffected and affected sides. The results of this study revealed that the use of visual biofeedback leads to prompt and preferable change in the movement of the posterior part of the tongue. From the standpoint of pursuing necessary rehabilitation for patients with attention and memory disorders, visualization of tongue movement would be of marked clinical benefit. PMID- 25786578 TI - Feasibility of Extended-interval Follow-up for Patients Receiving Warfarin. AB - AIMS: The 2012 American College of Chest Physician Evidence-Based Management of Anticoagulant Therapy guidelines suggest an international normalized ratio (INR) testing interval of up to 12 weeks, rather than every 4 weeks, for patients with consistently stable INRs while taking vitamin K antagonists. We aimed to examine the feasibility of extended-interval follow-up in a real-world setting. METHODS: Patients receiving stable warfarin therapy for >= 12 weeks at baseline began extended-interval follow-up with visits occurring at 6 weeks, 14 weeks, and every 12 weeks thereafter to a maximum of 68 weeks or until they were no longer suitable for extended-interval follow-up. A single INR excursion >0.3 from goal was permitted if a reversible precipitating factor was identified and the INR was expected to return to goal without dose adjustment. The primary outcome was the proportion of patients completing all study follow-up visits. RESULTS: Of 48 patients enrolled, 47 had evaluable data. The most common indication for anticoagulation was atrial fibrillation/flutter (53.2%). At baseline, mean prior warfarin treatment duration was 6.7 +/- 6 years and median number of weeks on a stable regimen was 24 weeks (IQR, 19-37.5). Eleven patients (23%) completed all study follow-up visits, whereas 17 (36%) did not maintain a stable INR past the 14-week follow-up. CONCLUSION: A large proportion of patients with previously stable (>= 3 months) INRs were not able to maintain stable INRs during extended interval follow-up. More research is needed to identify patient characteristics predictive of success with extended-interval follow-up prior to broad implementation. PMID- 25786579 TI - A combination of targeted enrichment methodologies for whole-exome sequencing reveals novel pathogenic mutations. AB - Whole-exome sequencing (WES) is a useful method to identify disease-causing mutations, however, often no candidate mutations are identified using commonly available targeted probe sets. In a recent analysis, we also could not find candidate mutations for 20.9% (9/43) of our pedigrees with congenital neurological disorder using pre-designed capture probes (SureSelect V4 or V5). One possible cause for this lack of candidates is that standard WES cannot sequence all protein-coding sequences (CDS) due to capture probe design and regions of low coverage, which account for approximately 10% of all CDS regions. In this study, we combined a selective circularization-based target enrichment method (HaloPlex) with a hybrid capture method (SureSelect V5; WES), and achieved a more complete coverage of CDS regions (~97% of all CDS). We applied this approach to 7 (SureSelect V5) out of 9 pedigrees with no candidates through standard WES analysis and identified novel pathogenic mutations in one pedigree. The application of this effective combination of targeted enrichment methodologies can be expected to aid in the identification of novel pathogenic mutations previously missed by standard WES analysis. PMID- 25786580 TI - The impact of concomitant genomic alterations on treatment outcome for trastuzumab therapy in HER2-positive gastric cancer. AB - Clinical benefit from trastuzumab and other anti-human epidermal growth factor receptor-2 (HER2) therapies in patients with HER2-positive gastric cancer (GC) remains limited by primary or acquired resistance. We aimed to investigate the impact of concomitant molecular alterations to HER2 amplification on the clinical outcome of trastuzumab-treated patients. Using immunohistochemistry (IHC), copy number variations (CNVs), and Ion Ampliseq Cancer Panel, we analyzed the status of concomitant alterations in 50 HER2-positive advanced GC patients treated with trastuzumab in combination with other chemotherapeutic agents. The percentage of tumor samples with at least one concomitant alteration was 40% as assessed by IHC, 16% by CNVs, and 64% by Ampliseq sequencing. Median progression-free survival (PFS) was 8.0 months (95% confidence interval, 4.8-11.3). Patients were divided into two subgroups according to PFS values with a cutoff point of 8 months; results show that concomitant genomic alterations do not correlate with trastuzumab response. However, CNVs of CCNE1 significantly correlated (p < 0.05) with a shorter survival time. Our findings indicate that additional alterations implemented for prediction of clinical benefit from HER2-targeting agents in GC remained unclear. Further studies will be needed to elucidate the role of each specific biomarker and to optimize therapeutic approaches. PMID- 25786581 TI - The Paradoxical Relationship between White Matter, Psychopathology and Cognition in Schizophrenia: A Diffusion Tensor and Proton Spectroscopic Imaging Study. AB - White matter disruption has been repeatedly documented in schizophrenia consistent with microstructural disorganization (reduced fractional anisotropy (FA)) and axonal dysfunction (reduced N-acetylaspartate NAAc). However, the clinical significance of these abnormalities is poorly understood. Diffusion tensor and proton spectroscopic imaging where used to assess FA, axial diffusivity and radial diffusivity (RD), and supra-ventricular white matter NAAc, respectively, in 64 schizophrenia and 64 healthy subjects. Schizophrenia patients had reduced FA across several regions, with additional regions where FA correlated positively with positive symptoms severity. These regions included genu, body and splenium of corpus callosum, anterior and superior corona radiata, superior longitudinal and inferior fronto-occipital fasciculi, and internal capsule. The FA/symptoms relationships corresponded with opposite correlations between RD and positive symptoms. The schizophrenia group (SP group) had progressively reduced NAAc with age, and NAAc correlated negatively with positive symptoms. Cognition correlated positively with both FA and NAAc in controls, whereas in the SP group it had a negative correlation with NAAc and no significant relationship with FA. Antipsychotic dose did not account for the results. Correlates of psychosis, cognitive and negative symptoms can be found in white matter. The significant correlations between positive symptoms in schizophrenia and diffusion and NAAc measures suggest decreased axonal density with increased glial cells and higher myelination in this subpopulation. A separate set of abnormal relationships between cognition and FA/RD, as well as with NAAc, converge to suggest that in schizophrenia, white matter microstructure supports the two core illness domains: psychosis and cognitive/negative symptoms. PMID- 25786584 TI - The employment of IVF techniques for establishment of sodium, copper and selenium impact upon human sperm quality. AB - We analysed sodium (Na), copper (Cu) and selenium (Se) levels in human semen and glutathione peroxidase activity (GPx) in seminal plasma and examined their relationships with sperm quality. Semen samples were obtained from men (n=168) undergoing routine infertility evaluation. The study design included two groups based on standard ejaculate parameters: Group I (n=39) with normal ejaculates (normozoospermia) and Group II (n=129) with a pathological spermiogram. Se concentration (but not Na or Cu) and GPx activity were significantly higher in normozoospermic males than in those with a pathological spermiogram and also in males with correct sperm motility and normal sperm morphology than in asthenozoospermic and teratozoospermic males. There were significant correlations between sperm motility, Se and GPx, between rapid progressive motility and Cu, between sperm motility and Na, between normal sperm morphology and Se and Cu and between sperm concentration and Cu and GPx. Significant correlations were found between Na and Cu, between Na and Se and between Cu and Se in human semen in relation to alcohol consumption and tobacco use. Na, Cu, Se and GPx are related to sperm characteristics and male fertility and their survey could improve male infertility diagnosis. PMID- 25786582 TI - Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism. AB - Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF(Met/Met)) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF(Met/Met) mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF(Met/Met) mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers. PMID- 25786583 TI - [Surgical treatment of tibialis anterior tendon rupture]. AB - INTRODUCTION: Tibialis anterior tendon rupture is rare, with only a few cases and small series having been reported in the literature. In this article, cases reported in the literature from 1997-2012 are reviewed and patients treated by the author are presented. MATERIALS: Cases published from 1997-2012 needing surgical treatment for tibialis anterior tendon rupture were retrospectively reviewed. In all, 32 articles with a total of 44 reported cases and 5 patients from our own practice were included. Patient-specific data (e.g., age, trauma, secondary diagnosis, and time to surgery), surgical technique, operative result, and documented complications were also evaluated. RESULTS: The mean age (MA) of the patients (30 men and 19 women) undergoing treatment was 58 years. A total of 17 patients presented as a result of adequate trauma (MA 52) and 32 patients without or minor trauma (MA 62). In 16 patients (33 %), a primary tendon suture was selected, while in 11 patients (22 %) osseous refixation techniques were performed. In 21 patients (43 %), plastic reconstruction was necessary. Total recovery was observed in 69 % of patients (n = 34); 26 % (n = 13) had moderate limitations. Complications were reported in 12 % of cases (n = 6), thereof one re rupture. CONCLUSION: Good to excellent results were observed in tibialis anterior tendon ruptures reconstruction. No associations between surgical treatment and outcome were observed. The selection of the surgical technique depended on rupture mechanism, location, size, tendon constitution, rupture age, and surgeon's experience. PMID- 25786586 TI - Efficacy and Safety of Hospital-Based Intravenous Immunoglobulin and Home-Based Self-Administered Subcutaneous Immunoglobulin in Polish Children with Primary Immunodeficiency Diseases. PMID- 25786585 TI - Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques. AB - PURPOSE: The threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. The study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques. MATERIALS AND METHODS: Animals received a single total-body irradiation (TBI) exposure at doses of 0, 2 or 5 Gy with scheduled necropsies at 5 days, 8 weeks and 24 weeks post-exposure. Blood and lymphoid tissues were evaluated for morphologic, cellular, and molecular responses. RESULTS: Irradiated animals developed symptoms of acute hematopoietic syndrome, and reductions in thymus weight, thymopoiesis, and bone marrow cellularity. Acute, transient increases in plasma monocyte chemoattractant protein 1 (MCP-1) were observed in 5 Gy animals along with dose-dependent alterations in messenger ribonucleic acid (mRNA) signatures in thymus, spleen, and lymph node. Expression of T cell markers was lower in thymus and spleen, while expression of macrophage marker CD68 (cluster of differentiation 68) was relatively elevated in lymphoid tissues from irradiated animals. CONCLUSIONS: Ovariectomized female macaques exposed to moderate doses of radiation experienced increased morbidity, including acute, dose-dependent alterations in systemic and tissue-specific biomarkers, and increased macrophage/T cell ratios. The effects on mortality exceeded expectations based on previous studies in males, warranting further investigation. PMID- 25786587 TI - Role of saliva in the caries experience and calculus formation of young patients undergoing hemodialysis. AB - OBJECTIVES: The aims of this study were to investigate the caries experience, periodontal status, oral hygiene habits, and salivary parameters of children and adolescents undergoing hemodialysis (HD) and to compare them with their healthy counterparts. METHODS: Fifty-two HD patients were matched for age, sex, ethnicity, and social class with 52 healthy subjects for analysis of the number of decayed, missing and filled teeth, plaque and gingival index, dental calculus accumulation, measurements of pocket depth, clinical attachment level, gingival recession, and bleeding on probing. Stimulated saliva samples were collected to assess salivary flow rate, pH and buffer capacity, and salivary concentrations of calcium, phosphate, and urea by colorimetric method. RESULTS: HD patients had lower dental caries (p = 0.004), greater plaque and calculus accumulation (p = 0.001), and reported flossing less often than the controls (p = 0.013). Regarding salivary analysis, HD patients showed significantly higher values of pH, buffer capacity, and salivary urea concentration when compared to the controls (p = 0.001). CONCLUSION: HD patients had lower caries experience, higher accumulation of dental plaque, and calculus deposition than their healthy counterparts, probably due to the differences found in their salivary biochemical parameters. CLINICAL SIGNIFICANCE: A significant number of children and adolescents undergoing hemodialysis are candidates for kidney transplantation and should receive complete pre-transplant dental exams and dental treatment. Our results open the way for the development of an individualized dental protocol for these patients with preventive measures and treatment of the poor oral health in HD patients. PMID- 25786588 TI - Arginase activity in peripheral blood of patients with intestinal schistosomiasis, Wonji, Central Ethiopia. AB - Morbidity and mortality caused by schistosomiasis usually results from immunopathology. But the underlying mechanisms are not yet clearly understood. Th2-type immune response is thought to be dominant during chronic schistosomiasis, and upregulation of arginase-I is one component of this milieu. A cohort study was conducted to assess arginase activity in peripheral blood of humans with intestinal schistosomiasis in Wonji-Shoa Sugar Estate, Central Ethiopia. Laboratory-confirmed 30 Schistosoma mansoni-infected patients and 18 apparently healthy controls were recruited. Faecal egg count was carried out by Kato-Katz technique. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood. Activity of arginase in plasma and PBMC lysates was measured, and results were compared with that of controls. Twenty-one of 30 patients had light infection, whereas moderate and heavy intensity infections were observed in eight and only one patient(s), respectively. A significant increase in both PBMC (patients: 59.96 + 82.99, controls: 25.44 + 24.6 mU/mg protein, P < 0.0001) and plasma (patients: 1.61 + 2.19, controls: 0.31 + 0.73 mU/mL plasma, P < 0.0001) arginase activity was observed during human S. mansoni infection. Arginase activity increases in peripheral blood of patients with intestinal schistosomiasis. PMID- 25786589 TI - Intensity-modulated whole abdomen irradiation following adjuvant carboplatin/taxane chemotherapy for FIGO stage III ovarian cancer : four-year outcomes. AB - INTRODUCTION: A prospective study to assess toxicity and survival outcomes after intensity-modulated whole-abdominal irradiation (IM-WAI) following surgery and adjuvant intravenous carboplatin/taxane chemotherapy in advanced FIGO stage III ovarian cancer. PATIENTS AND METHODS: Between 2006 and 2009, 16 patients with optimally resected FIGO stage III ovarian cancer, who had received six cycles of adjuvant carboplatin/taxane chemotherapy were treated with consolidation IM-WAI. Radiotherapy was delivered to a total dose of 30 Gy in 1.5-Gy fractions, using step-and-shoot (n = 3) or helical tomotherapy (n = 13). The first 10 patients were treated within a phase I trial; the following patients received the same treatment modality. The target volume included the entire peritoneal cavity, the diaphragm, the liver capsule, and the pelvic and para-aortic node regions. Organs at risk were kidneys, liver, heart, and bone marrow. RESULTS: Median follow-up was 44 months (range 19.2-67.2 months). No grade 4 toxicities occurred during IM WAI. Common Toxicity Criteria for Adverse Events (CTCAE) grade 3 toxicities were: diarrhea (25 %), leucopenia (19 %), nausea/vomiting (6 %), and thrombocytopenia (6 %). No toxicity-related treatment break was necessary. Small bowel obstruction occurred in a total of 6 patients: in 3 cases (19 %) due to postsurgical adhesions and in 3 cases due to local tumor recurrence (19 %). Median recurrence free survival (RFS) was 27.6 months (95 % confidence interval, CI = 24-44 months) and median overall survival (OS) was 42.1 months (95 %CI = 17-68 months). The peritoneal cavity was the most frequent site of initial failure. CONCLUSION: Consolidation IM-WAI following surgery and adjuvant chemotherapy is feasible and can be performed with manageable acute and late toxicity. The favorable RFS outcome is promising and justifies further clinical trials. PMID- 25786590 TI - Plant lipid biology and biotechnology. PMID- 25786591 TI - A highly efficient maize nucellus protoplast system for transient gene expression and studying programmed cell death-related processes. AB - KEY MESSAGE: Conditions for the isolation and transfection of maize nucellus protoplasts were established. We demonstrated its utilization for protein expression, localization, protein-protein interaction, and the investigation of PCD-related processes. Plant protoplasts are an important and versatile cell system that is widely used in the analysis of gene characterization and diverse signaling pathways. Programmed cell death (PCD) occurs throughout the life of plants from embryogenesis to fertilization. The maize nucellus undergoes typical PCD during development of the embryo sac. The nucellus protoplast shows potential for use in research of PCD-related processes. No studies have reported previously the isolation and transfection of nucellus protoplasts. In this study, conditions for the isolation and transfection of maize nucellus protoplasts were established. The maize protoplast system can be used for protein expression, localization, and protein-protein interaction. We applied this system to investigate PCD-related processes. Quantitative real-time PCR analysis revealed that transient expression of MADS29 in the maize nucellus protoplast increases Cys-protease gene transcript level. In addition, beta-glucuronidase and luciferase activity assays showed that MADS29 could enhance the promoter activities of the Cys-protease gene. Thus, we demonstrated the potential of a highly efficient maize nucellus protoplast system for transient gene expression and investigation of PCD-related processes. PMID- 25786592 TI - Late paradoxical development of pyoderma gangrenosum in a psoriasis patient treated with infliximab. PMID- 25786593 TI - Comment on: "Use of the Fluocinolone Acetonide Intravitreal Implant for the Treatment of Noninfectious Posterior Uveitis: 3-Year Results of a Randomized Clinical Trial in a Predominantly Asian Population". PMID- 25786594 TI - Air pollution, athletic health and performance at the Olympic Games. AB - The objective of this study was to briefly review air pollution and its effects on athletes' health and performance and to examine air quality (AQ) at specific Olympic Summer Games between 1964 and 2008. It will focus on any attempts made by the cities hosting these Olympics to improve AQ for the Games and if undertaken, how successful these were. The author had a medical role at five of the seven Olympic Games that will be examined and hence has personal experiences. Information was obtained from the readily accessible official reports of the Olympic Games, relevant published papers and books and the internet. For each of these seven Olympic Games, monitoring AQ was far below current acceptable standards and for the majority, minimal or no data on major pollutants was available. From what can be ascertained, at these Games, AQ varied but was less than optimal in most if not all. Nevertheless, there were few reported or known unfavorable effects on the health of Olympic athletes. To date, there have been few reported consequences of sub-optimal AQ at Olympic Games. The focus on AQ at Olympic Games has gradually increased over the past five decades and is expected to continue into the future. PMID- 25786596 TI - Advances in image-guided drug delivery. PMID- 25786595 TI - Dietary Adherence, Glycemic Control, and Psychological Factors Associated with Binge Eating Among Indigenous and Non-Indigenous Chileans with Type 2 Diabetes. AB - BACKGROUND: Despite the strong association between obesity and binge eating, limited research has examined the implications of binge eating on dietary adherence and psychological factors in ethnically diverse type 2 diabetes patients. PURPOSE: This study investigated the prevalence of binge eating and its association with dietary adherence, glycemic control, and psychological factors among indigenous and non-indigenous type 2 diabetes patients in Chile. METHOD: Participants were 387 indigenous (Mapuche) and non-indigenous (non-Mapuche) adults with type 2 diabetes. Self-report measures of binge eating, dietary adherence, diet self-efficacy, body image dissatisfaction, and psychological well being were administered. Participants' weight, height, and glycemic control (HbA(1c)) were also obtained. RESULTS: Approximately 8 % of the type 2 diabetes patients reported binge eating. The prevalence among Mapuche patients was 4.9 %, and among non-Mapuche patients, it was 9.9 %. Compared to non-binge eaters, binge eating diabetes patients had greater body mass index values, consumed more high fat foods, were less likely to adhere to their eating plan, and reported poorer body image and emotional well-being. CONCLUSION: Results of this study extend previous research by examining the co-occurrence of binge eating and type 2 diabetes as well as the associated dietary behaviors, glycemic control, and psychological factors among indigenous and non-indigenous patients in Chile. These findings may increase our understanding of the health challenges faced by indigenous populations from other countries and highlight the need for additional research that may inform interventions addressing binge eating in diverse patients with type 2 diabetes. PMID- 25786597 TI - Magnetic nanoparticles and their applications in image-guided drug delivery. AB - Magnetic iron oxide nanoparticles have been shown to be suitable for use as theranostic agents owing to their intrinsic diagnostic capabilities in magnetic resonance imaging (MRI) applications, hyperthermia properties, and ability to deliver drugs via magnetic attraction and/or systemic delivery. In addition, surface modifications are easily introduced through conjugation with targeting moieties (e.g., antibodies, peptides, or aptamers), genes, or therapeutic drugs to provide multimodal functionalities. Such valuable characteristics apply to image-guided drug delivery, especially MRI-guided drug delivery-a form of individualized therapy in which imaging methods are used to guide and monitor delivery of therapeutic agents to target tissues. This review summarizes the intrinsic physicochemical properties and pharmacokinetics of magnetic nanoparticles and highlights recent reports describing theranostic systems, including magnetic nanoparticle-based nanoplatforms, and their applications in MRI-guided drug delivery. PMID- 25786599 TI - Fluorescently labeled microbubbles for facilitating translational molecular ultrasound studies. AB - Microbubbles (MB) are routinely used as contrast agents for functional and molecular ultrasound (US) imaging. For molecular US imaging, MB are functionalized with antibodies or peptides, in order to visualize receptor expression by angiogenic or inflamed endothelium. In general, initial in vitro binding studies with targeted MB are performed using phase contrast microscopy. Difficulties in the identification of MB in standard phase contrast microscopy, however, generally result in high variability, high observer dependency, and low reproducibility. To overcome these shortcomings, we here describe a simple post loading strategy for labeling polymer-based MB with fluorophores, and we show that the use of rhodamine-loaded MB in combination with fluorescence microscopy substantially reduces the variability and the observer dependency of in vitro binding studies. In addition, we demonstrate that rhodamine-loaded MB can also be used for in vivo and ex vivo experimental setups, e.g., for analyzing MB binding to inflamed carotids using two-photon laser scanning microscopy, and for validating the binding of VEGFR2-targeted MB to tumor endothelium. These findings demonstrate that fluorescently labeled MB substantially facilitate translational molecular US studies, and they suggest that a similar synthetic strategy can be exploited for preparing drug-loaded MB, to enable image-guided, targeted, and triggered drug delivery to tumors and to sites of inflammation. PMID- 25786598 TI - Image-guided drug delivery in lung cancer. AB - Lung cancer continues to be the number one cause of cancer-related deaths in the USA. Early identification of the disease, availability of more effective drugs, and improved delivery of such drugs specifically to cancer cells are needed to decrease lung cancer-associated morbidity and mortality. The concept of image guided drug delivery (IGDD), which envisions the utilization of imaging techniques for quantitative assessments of tumor-targeted drug delivery and therapeutic response, has the potential to make a significant impact in lung cancer. While the anatomic and physiological features of the lung pose distinct problems for imaging drug delivery, several new techniques are emerging that have the potential to overcome these problems. X-ray is a routinely used technique for diagnosing lung cancer; however, positron emission tomography (PET) and magnetic resonance imaging (MRI) are complementary approaches. PET- and MRI-based techniques (such as functional MRI) offer the possibility of imaging the delivery of specific molecules to cancer tissues in the lung. This paper reviews fundamentals of imaging with an emphasis on MRI and to some extent PET, since it will be argued that these techniques are the most promising for development in IGDD for lung cancer. Finally, key literature contributions will be highlighted, which exemplify the current successes in this area. PMID- 25786600 TI - Bispecific antibody complex pre-targeted delivery of polymer-drug conjugates for cancer therapy. AB - The pretargeting approach using bispecific affibody-antibody complex (BAAC) and targeting of chemotherapeutic drug loaded polymers have been used in breast cancer cell cultures to demonstrate targeted chemotherapy and reduce toxicity to non-pretargeted cancer and cardiac cells. HER2/neu-positive BT-474 and -negative BT-20 human mammary carcinoma cell lines were pretargeted with BAAC and targeted with multi-doxorubicin (Dox) loaded polyglutamic acid (PGA) site specifically modified with diethylene triamine pentaacetic acid (DTPA) (D-Dox-PGA) at the N terminal of PGA. Toxicity to embryonic cardiocytes and human mammary carcinoma cells were assessed. BAAC was prepared by covalent conjugation of anti-HER2/neu affibody and anti-DTPA Fab via the thioether linkage. N-terminal DTPA modified polyglutamic acid was conjugated with doxorubicin via the amide bonds. Reduction in cardiotoxicity and IC50 of D-Dox-PGA and free Dox were determined in embryonic cardiocyte H9C2 cultures. Enhanced targeted tumor toxicity was demonstrated in BT 474 human mammary carcinoma cell line pretargeting with BAAC followed by targeting with D-Dox-PGA and compared to D-Dox-PGA alone with no pretargeting or free Dox. No enhanced targeted tumor toxicity was observed in HER2/neu negative BT-20 cells. IC50 of D-Dox-PGA and free Dox on embryonic cardiocytes was 15.75 and 1.20 MUg/ml, respectively. When BT-474 and BT-20 cells were pretargeted with BAAC followed by targeting with D-Dox-PGA, higher tumor cell-killing was seen only in BT-474 cells. Pretargeting with BAAC resulted in greater tumor cell death in BT-474 human breast cancer cells due to specific targeted delivery of D-Dox PGA than cancer cells treated with D-Dox-PGA without pretargeting or treatment with free doxorubicin. In vitro targeted delivery of polymer drug conjugate resulted in highly specific, targeted HER2/neu positive BT-474 cancer cell death. Such a pretargeting and targeting approach using prodrug polymers may allow development of very efficient, lower non-target toxicity, and image-guided targeted therapy since these polymers can also be labeled with radioisotopes. PMID- 25786601 TI - ["To be a good doctor": how are medical students prepared for the future]. PMID- 25786602 TI - Achievement of physical activity recommendation and activity levels in students of human medicine compared with the general Austrian population aged between 20 and 29 years. AB - Weekly 150 min of moderate to vigorous physical activity and muscle-strengthening activities are a major public health goal. The International Physical Activity Questionnaire-short form was applied in 467 students of the 4th year at the Medical University of Vienna and compared with subsamples of data from the Austrian Health Interview Survey, 795 subjects with and 1131 subjects without higher education aged 20-29 years. Median values for weekly total energy expenditure were 3083, 3048, and 3816 MET-minutes (P < 0.001) in medical students, higher and lower educated subjects of the general population. Energy expenditure with vigorous intensity was highest in medical students. A total of 39.4 % of medical students reached the minimum requirements of the national physical activity recommendations. Although medical students are taught those recommendation and are aware of their health benefits, only a minority reach them. If medical students engage in physical activity, they do it with higher intensity than the general population. PMID- 25786604 TI - Imaging of physeal bars in children. AB - The growth plate, also known as the physis or epiphyseal plate, is essential for longitudinal growth of bones in the immature skeleton. A variety of insults to the growth plate from trauma to infection to idiopathic causes can lead to physeal bar formation, an interruption in normal growth plate cartilage, where a bony or fibrous bridge develops between the metaphysis and epiphysis. This bridge restricts subsequent bone growth, leading to limb shortening and/or angular deformities. Early recognition of the presence of a physeal bar can help direct appropriate surgical management to restore linear growth of the bone. PMID- 25786603 TI - Apple russeting as seen through the RNA-seq lens: strong alterations in the exocarp cell wall. AB - Russeting, a commercially important defect in the exocarp of apple (Malus * domestica), is mainly characterized by the accumulation of suberin on the inner part of the cell wall of the outer epidermal cell layers. However, knowledge on the underlying genetic components triggering this trait remains sketchy. Bulk transcriptomic profiling was performed on the exocarps of three russeted and three waxy apple varieties. This experimental design was chosen to lower the impact of genotype on the obtained results. Validation by qPCR was carried out on representative genes and additional varieties. Gene ontology enrichment revealed a repression of lignin and cuticle biosynthesis genes in russeted exocarps, concomitantly with an enhanced expression of suberin deposition, stress responsive, primary sensing, NAC and MYB-family transcription factors, and specific triterpene biosynthetic genes. Notably, a strong correlation (R(2) = 0.976) between the expression of a MYB93-like transcription factor and key suberin biosynthetic genes was found. Our results suggest that russeting is induced by a decreased expression of cuticle biosynthetic genes, leading to a stress response which not only affects suberin deposition, but also the entire structure of the cell wall. The large number of candidate genes identified in this study provides a solid foundation for further functional studies. PMID- 25786605 TI - Extratesticular masses in children: taking ultrasound beyond paratesticular rhabdomyosarcoma. AB - Extratesticular cystic and solid scrotal masses are commonly encountered in pediatrics. The most common extratesticular malignancy is paratesticular rhabdomyosarcoma. The remainder of the common pathologies encountered -- appendage torsion, epididymitis and varicoceles -- are mostly benign. These frequently encountered benign lesions are confidently differentiated from paratesticular rhadbomyosarcoma using high-frequency scrotal sonography in combination with clinical features. Less commonly encountered extratesticular masses may not be as easily classified; however, these also have distinguishing features that can enable differentiation from malignancy. This review discusses the sonographic findings, and relevant clinical and pathological manifestations of the more unusual extratesticular masses encountered in two tertiary pediatric institutions during a 10-year period. While these extratesticular pathologies are encountered relatively infrequently, recognition of their manifestations enables appropriate management. PMID- 25786606 TI - Acanthocephalans of the genus Centrorhynchus (Palaeacanthocephala: Centrorhynchidae) of birds of prey (Falconiformes) and owls (Strigiformes) in Slovakia. AB - Three species of thorny-headed worms of the genus Centrorhynchus were found to parasitize birds of prey and owls in the territory of the Slovakia during the years 2012-2014. Out of 286 examined bird individuals belonging to 23 species, only Buteo buteo, Buteo rufinus, Falco tinnunculus (Falconiformes), Asio otus, Strix aluco, Strix uralensis and Tyto alba (Strigiformes) were infected by acanthocephalans. All the bird species except for S. aluco represent new host records for Slovakia. The most prevalent acanthocephalan Centrorhynchus aluconis was detected in all 15 examined birds of non-migratory Ural owl S. uralensis (P = 100%); however, it was found occasionally also in two individuals of the tawny owl S. aluco (P = 20%), one long-eared owl A. otus (P = 7.7%), one barn owl T. alba (P = 33.3%) and the common buzzard B. buteo (P = 0.8%). Two other thorny headed worms occurred exclusively in Falconiformes in raw or mixed infections: Centrorhynchus buteonis was found in 11 individuals of B. buteo (P = 9.2%), and two birds (B. buteo and B. rufinus) were parasitized simultaneously by C. buteonis and the species Centrorhynchus globocaudatus. Moreover, the latest, relatively rare acanthocephalan was found alone in two common kestrels F. tinnunculus (P = 2.7%). Regarding intensity of infection, it ranged from a single female of C. buteonis, C. globocaudatus or C. aluconis per host (four cases) to a maximum of 82 C. aluconis per an Ural owl. The difference in acanthocephalan species spectrum between birds of prey and owls in Slovakia was apparent. PMID- 25786607 TI - Tetracapsuloides bryosalmonae infection affects the expression of genes involved in cellular signal transduction and iron metabolism in the kidney of the brown trout Salmo trutta. AB - Tetracapsuloides bryosalmonae is an enigmatic endoparasite which causes proliferative kidney disease in various species of salmonids in Europe and North America. The life cycle of the European strain of T. bryosalmonae generally completes in an invertebrate host freshwater bryozoan and vertebrate host brown trout (Salmo trutta) Linnaeus, 1758. Little is known about the gene expression in the kidney of brown trout during the developmental stages of T. bryosalmonae. In the present study, quantitative real-time PCR was applied to quantify the target genes of interest in the kidney of brown trout at different time points of T. bryosalmonae development. PCR primers specific for target genes were designed and optimized, and their gene expression levels were quantified in the cDNA kidney samples using SYBR Green Supermix. Expression of Rab GDP dissociation inhibitor beta, integral membrane protein 2B, NADH dehydrogenase 1 beta subcomplex subunit 6, and 26S protease regulatory subunit S10B were upregulated significantly in infected brown trout, while the expression of the ferritin M middle subunit was downregulated significantly. These results suggest that host genes involved in cellular signal transduction, proteasomal activities, including membrane transporters and cellular iron storage, are differentially upregulated or downregulated in the kidney of brown trout during parasite development. The gene expression pattern of infected renal tissue may support the development of intraluminal sporogonic stages of T. bryosalmonae in the renal tubular lumen of brown trout which may facilitate the release of viable parasite spores to transmit to the invertebrate host bryozoan. PMID- 25786608 TI - The influence of conidial Pr1 protease on pathogenicity potential of Metarhizium anisopliae senso latu to ticks. AB - Pr1 is a subtilisin-like protease produced by Metarhizium spp. entomopathogenic fungi, and it is recognized as heavily involved in the initial steps of the fungal invasion of arthropod-host cuticles. In the current study, correlation was sought between mortality of tick larvae and conidial Pr1 levels of one Metarhizium anisopliae senso latu (s.l.) isolate (CG 148). Conidia with different levels of pr1 gene expression and enzymatic activity were obtained by producing them on either artificial medium (to yield low Pr1 activity) or on Rhipicephalus microplus cadavers (to yield high Pr1 activity). Conidial proteolytic activity was assessed using N-suc-ala-ala-pro-phe-rhoNA as the chromogenic substrate, and pr1 expression was profiled by qPCR using three genes (gpd, try, and tef) as reference genes. Pr1 enzymatic (proteolytic) activity on conidia obtained from tick cadavers was 36 U mg(-1) in comparison to 4 U mg(-1) on conidia from PDA medium. Also, pr1 gene expression level was ten times higher in conidia from tick cadavers compared to PDA medium. Bioassays of M. anisopliae s.l. CG 148 spores with elevated Pr1 proteolytic activity and gene expression levels did not demonstrate increased virulence (= significant change percent mortality of tick larvae). The minimal levels of Pr1 on conidia produced on artificial medium was adequate to afford high levels of virulence, and the elevated amounts of the enzyme on tick-cadaver-produced conidia did not induce elevated larval mortality. As long as some Pr1 activity was present, fungal virulence of isolate CG 148 against tick larvae was not elevated by increased levels of conidial Pr1. PMID- 25786610 TI - Magnetic and magnetothermal properties, and the magnetic phase diagram of single crystal holmium along the easy magnetization direction. AB - The magnetic and magnetothermal properties of holmium single crystal have been investigated from 4.2 to 300 K in magnetic fields up to 100 kOe using magnetization and heat capacity data measured along the easy magnetization direction, which is the crystallographic b-axis, i.e. [112-0] direction. The magnetic phase diagram of Ho has been refined by examining data measured using a high purity single crystal. PMID- 25786609 TI - Malaria DNA vaccine gp96NTD-CSP elicits both CSP-specific antibody and CD8(+) T cell response. AB - It is ideal for the pre-erythrocytic stage subunit vaccine to induce both CSP specific antibody and CD8(+) T cell response. Here, we designed a novel malaria DNA vaccine gp96NTD-CSP, which was constructed by fusing the full-length of CSP with the N-terminal domain of gp96 that deleted the endoplasmic reticulum localized motif KDEL, and investigated its protective efficacy. We found that the fusion protein gp96NTD-CSP was mainly distributed on the surface of eukaryotic cells after transfection and could be sensed as a "danger signal" by the host immune system. Interestingly, both liver parasite burden and parasitemia in mice immunized with gp96NTD-CSP were significantly lower than those in the mice immunized either with gp96NTD, CSP, or gp96NTD-SYVPSAEQI, which was constructed by fusing the CSP-specific CD8(+) T cell epitope with the N-terminal domain of gp96 deleted with KDEL. Consistently, both the level of CSP-specific antibody and the frequency of IFN-gamma secreted-CSP-specific CD8(+) T cells were much higher in mice immunized with gp96NTD-CSP than those in the mice immunized either with gp96NTD, CSP, or gp96NTD-SYVPSAEQI. Our results suggest that the malaria DNA vaccine gp96NTD-CSP could induce both humoral and cellular immune responses, which is attributed to the adjuvant effect of gp96NTD and full-length CSP. PMID- 25786612 TI - RNA interference-based therapeutics and diagnostics. PMID- 25786611 TI - [Results of surgical treatment for pulmonary aspergilloma]. AB - INTRODUCTION: Aspergilloma results from the development, inside preexisting pulmonary cavities, of aspergillus spores. It is most commonly manifested by hemoptysis. The goal of this retrospective study is to report our surgical experience of this disease. PATIENTS AND METHODS: From January 2004 to December 2008, 35 patients underwent surgery at the same center for pulmonary aspergilloma. We examined the epidemiological, clinical, paraclinical, therapeutic, and outcome data. RESULTS: The patients' median age was 43.37 years (range: 20-70 years), 28 were male. The average time to consultation was 19.35 months (1-120 months), and all patients had a history of pulmonary tuberculosis. Hemoptysis was the symptom observed most often, in 54.3% of patients, followed by bronchorrhea. Aspergillus serology was positive for 22 patients. The standard radiological image was found in 20 patients. We performed 14 lobectomies, 1 bilobectomy, 1 segmentectomy, 1 bisegmentectomy, 3 lobectomies with segmentectomies, 1 bilobectomy with segmentectomy, and 14 pleuropneumonectomies. In one case, the pulmonary artery was damaged and repaired. The average duration of intensive care was 3.54 days (2-7 days) and of total hospitalization, 17.33 days (7-48). Complications were: empyema (3 cases), a large air leak (1 case), parietal suppuration (5 cases), and pleural effusion, which was drained (3 cases). There was no postoperative mortality. After 35 months (1-72), one case of recurrent hemoptysis by reinfestation was observed. Three patients died of respiratory failure, one at 6 months and the other two at 1 year after the surgery. CONCLUSION: Despite the associated morbidity, surgical treatment of pulmonary aspergilloma must be proposed systematically to these subjects presenting hemoptysis. PMID- 25786613 TI - RNA interference-based therapeutics and diagnostics. PMID- 25786615 TI - Profiling of circulating microRNAs for prostate cancer biomarker discovery. AB - Prostate cancer (PC) is the most frequent cancer in men in the Western world. Currently, serum prostate-specific antigen levels and digital rectal examinations are used to indicate the need for diagnostic prostate biopsy, but lack in specificity and sensitivity. Thus, many men undergo unnecessary biopsy, and better and less invasive tools for PC detection are needed. Furthermore, whereas aggressive PC should be treated immediately to prevent dissemination, indolent PC often does not progress and overtreatment should be avoided. Currently, the best predictors of aggressiveness are Gleason score and T-stage of the primary PC. Better tools to assess PC aggressiveness could aid in treatment decisions. Recently, circulating miRNAs have been suggested as potential new biomarkers for PC with diagnostic and prognostic potential. Here, to identify new serum miRNA biomarker candidates for PC, we performed genome-wide miRNA profiling of serum samples from 13 benign prostatic hyperplasia (BPH) control patients and 31 PC patients. Furthermore, we carefully reviewed the literature on circulating miRNA biomarkers for PC. Our results confirmed the de-regulation of miR-141 and miR 375, two of the most well-documented candidate miRNA markers for PC. Moreover, we identified several new potential serum miRNA markers for PC and developed three novel and highly specific (100 %) miRNA candidate marker panels able to identify 84 % of all PC patients (miR-562/miR-210/miR-501-3p/miR-375/miR-551b), 80 % of patients with disseminated PC when compared to BPH patients (let-7a*/miR-210/miR 562/miR-616), and 75 % of disseminated PC patients when compared to localized PC patients (miR-375/miR-708/miR-1203/miR-200a), demonstrating high potential of serum miRNAs for diagnosing and staging of PC. PMID- 25786614 TI - The application of RNAi-based treatments for inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic, relapsing, idiopathic inflammation of the gastrointestinal tract with no permanent cure. Present immunosuppressive and anti-inflammatory therapies are often ineffective and associated with severe side effects. An RNA interference (RNAi)-based approach in which small interfering RNA (siRNA) mediates specific downregulation of key molecular targets of the IBD inflammatory process may offer a precise, potent and safer alternative to conventional treatments. This review describes the aetiology of Crohn's disease and ulcerative colitis and the cellular and molecular basis for current treatments to highlight target candidates for an RNAi-based approach. Promising preclinical studies support an RNAi application; however, optimal siRNA designs that maximise potency and development of enabling technologies for site- and cellular-specific delivery are prerequisites for clinical translation. PMID- 25786616 TI - Overcoming obstacles in microRNA delivery towards improved cancer therapy. AB - MicroRNAs (miRNAs) are small noncoding RNAs found to govern nearly every biological process. They frequently acquire a gain or a loss of function in cancer, hence playing a causative role in the development and progression of cancer. There are major obstacles on the way for the successful delivery of miRNA, which include low cellular uptake of the RNA and endosomal escape, immunogenicity, degradation in the bloodstream, and rapid renal clearance. The delivered miRNA needs to be successfully routed to the target organ, enter the cell and reach its intracellular target in an active form. Consequently, in order to exploit the promise of RNA interference, there is an urgent need for efficient methods to deliver miRNAs. These can be divided into three main categories: complexation, encapsulation, and conjugation. In this review, we will discuss the special considerations for miRNA delivery for cancer therapy, focusing on nonviral delivery systems: lipid, polymeric, and inorganic nanocarriers. PMID- 25786617 TI - Multifunctional polyion complex micelle featuring enhanced stability, targetability, and endosome escapability for systemic siRNA delivery to subcutaneous model of lung cancer. AB - For systemic small interfering RNA (siRNA) delivery to tumor mass, a multifunctional polyion complex micelle was constructed with a block copolymer bearing a targeting ligand and a micelle-stabilizing moiety as well as an endosome-disrupting cationic unit. The block copolymer was comprised of poly(ethylene glycol) (PEG) and a polyaspartamide derivative with flanking cationic tetraethylenepentamine (TEP) moiety (PAsp(TEP)), in which the distal ends of PEG and PAsp(TEP) were further installed with cyclic RGD (cRGD) peptide ligand and cholesteryl (Chol) moiety, respectively. The resulting polymer was confirmed to form siRNA-loaded micelle with a diameter of sub 50 nm and a narrow size distribution. In the stability assays with fluorescently labeled siRNA, the terminal Chol moiety significantly suppressed both the rapid dissociation of the micelles in the serum-containing medium and their rapid elimination from the bloodstream, presumably due to its hydrophobic interactions in the micellar core. Moreover, the targeting cRGD ligand, associated with the stabilizing moiety, significantly enhanced the accumulation of siRNA-loaded micelle in a subcutaneous lung (A549) tumor, compared to a non-targeted control, after systemic administration. Ultimately, significant tumor growth inhibition was achieved by systemic administration of the targeted/stabilized micelle incorporating polo like kinase 1 (Plk1) siRNA with negligible liver toxicity, consistent with the significant sequence-specific gene silencing of Plk1 in the tumor tissue. These results demonstrated the therapeutic potential of cRGD-PEG-PAsp(TEP)-Chol/siRNA micelle for systemic siRNA delivery toward cancer therapy. PMID- 25786619 TI - Gene silencing and antitumoral effects of Eg5 or Ran siRNA oligoaminoamide polyplexes. AB - Two antitumoral siRNAs (directed against target genes Eg5 and Ran) complexed with one of three sequence-defined cationic oligomers were compared in gene silencing in vitro and antitumoral in vivo efficacy upon intratumoral injection. Two lipo oligomers (T-shape 49, i-shape 229) and the three-arm oligomer 386 were chosen because of their high efficiency in previous marker gene silencing screens. The oligomers showed very similar target-specific gene knockdown in murine neuroblastoma cells. Silencing persisted only for a short period (maximum on day 1 at mRNA and day 2 at protein level) triggering siRNA specific in vitro tumor cell killing. The fastest onset of protein knockdown and strongest antitumoral effect was mediated by oligomer 386. Tumor growth reduction in vivo was evaluated in the subcutaneous Neuro2A mouse model. Intratumoral injections of either Eg5 or Ran siRNA/oligomer 49 polyplexes led to reduced tumor growth and prolonged survival of mice compared to control siRNA and buffer treatment. Target knockdown was evidenced in tumors by mitotic Aster formation for Eg5 knockdown and apoptotic TUNEL stain for Ran knockdown. Ran siRNA displayed better antitumoral efficacy and was chosen for in vivo comparison of the oligomers. A very clear order of antitumoral activity (oligomer 386 > 49 > 229) was observed. In summary, the similar in vitro gene silencing efficiencies on mRNA level by the tested oligomers did not correlate with the observed therapeutic effects in vivo. Oligomer 386 with the fastest onset of protein knockdown and best in vitro cell killing mediated the best in vivo antitumoral efficacy. PMID- 25786618 TI - Lipid nanoparticle delivery systems for siRNA-based therapeutics. AB - Therapeutics based on small interfering RNA (siRNA) have a huge potential for the treatment of disease but requires sophisticated delivery systems for in vivo applications. Lipid nanoparticles (LNP) are proven delivery systems for conventional small molecule drugs with over eight approved LNP drugs. Experience gained in the clinical development of LNP for the delivery of small molecules, combined with an understanding of the physical properties of lipids, can be applied to design LNP systems for in vivo delivery of siRNA. In particular, cationic lipids are required to achieve efficient encapsulation of oligonucleotides; however, the presence of a charge on LNP systems can result in toxic side effects and rapid clearance from the circulation. To address these problems, we have developed ionizable cationic lipids with pKa values below 7 that allow oligonucleotide encapsulation at low pH (e.g., pH 4) and a relatively neutral surface at physiological pH. Further optimization of cationic lipids to achieve maximized endosomal destabilization following uptake has resulted in LNP siRNA systems that can silence genes in hepatocytes at doses as low as 0.005 mg siRNA/kg body weight in mouse models. These systems have been shown to be highly effective clinically, with promising results for the treatment of hypercholesterolemia and transthyretin-induced amyloidosis among others. More LNP siRNA therapeutics, targeting different tissues and diseases, are expected to become available in the near future. PMID- 25786620 TI - Toxicity profiling of several common RNAi-based nanomedicines: a comparative study. AB - RNAi-based nanomedicine platforms (RNPs) have progressed from tools to study gene expression in vitro into clinical trials. Numerous RNPs strategies have been documented with an efficient ability to condense RNAi payloads and induce potent gene silencing. Moreover, some of these RNPs have been explored in various animal models, and some have even made it to the clinic. Still, there is lack of a clinically approved RNAi-based delivery strategy most probably due to unpredicted clinical toxicity. In this study, we prepared common RNPs such as cationic liposomes, polyamines, and hyaluronan-coated lipid-based nanoparticles and tested these strategies for global toxicity parameters such as changes in bodyweight, liver enzyme release, and hematological profiling. We found that polyamines such as polyethyleneimine and Poly-L-lysine released high levels of liver enzymes into the serum and reduced C57BL/6 mice bodyweight upon three intravenous injections. In addition, these polyamines dramatically reduced the total number of leukocytes, suggesting an immune suppression mechanism, while cationic liposomes, which also increased liver enzymes levels in the serum, elevated the total number of leukocytes probably by activation of Toll-like receptors 2 and 4. Coating the liposomes with hyaluronan, a hydrophilic glycosaminoglycan, provided a protective layer and did not induce adverse effects upon multiple intravenous injections. These findings suggest that there is an urgent need to develop gold standards for nanotoxicity in the field of RNAi that will be embraced by the RNAi community. PMID- 25786622 TI - Batesian mimics influence the evolution of conspicuousness in an aposematic salamander. AB - Conspicuousness, or having high contrast relative to the surrounding background, is a common feature of unpalatable species. Several hypotheses have been proposed to explain the occurrence of conspicuousness, and while most involve the role of conspicuousness as a direct signal of unpalatability to potential predators, one hypothesis suggests that exaggerated conspicuousness may evolve in unpalatable species to reduce predator confusion with palatable species (potential Batesian mimics). This hypothesis of antagonistic coevolution between palatable and unpalatable species hinges on the 'cost of conspicuousness', in which conspicuousness increases the likelihood of predation more in palatable species than in unpalatable species. Under this mimicry scenario, four patterns are expected: (i) mimics will more closely resemble local models than models from other localities, (ii) there will be a positive relationship between mimic and model conspicuousness, (iii) models will be more conspicuous in the presence of mimics, and (iv) when models and mimics differ in conspicuousness, mimics will be less conspicuous than models. We tested these predictions in the salamander mimicry system involving Notophthalmus viridescens (model) and one colour morph of Plethodon cinereus (mimic). All predictions were supported, indicating that selection for Batesian mimicry not only influences the evolution of mimics, but also the evolution of the models they resemble. These findings indicate that mimicry plays a large role in the evolution of model warning signals, particularly influencing the evolution of conspicuousness. PMID- 25786621 TI - Antimicrobial peptide protegrin-3 adopt an antiparallel dimer in the presence of DPC micelles: a high-resolution NMR study. AB - A tendency to dimerize in the presence of lipids was found for the protegrin. The dimer formation by the protegrin-1 (PG-1) is the first step for further oligomeric membrane pore formation. Generally there are two distinct model of PG 1 dimerization in either a parallel or antiparallel beta-sheet. But despite the wealth of data available today, protegrin dimer structure and pore formation is still not completely understood. In order to investigate a more detailed dimerization process of PG-1 and if it will be the same for another type of protegrins, in this work we used a high-resolution NMR spectroscopy for structure determination of protegrin-3 (RGGGL-CYCRR-RFCVC-VGR) in the presence of perdeuterated DPC micelles and demonstrate that PG-3 forms an antiparallel NCCN dimer with a possible association of these dimers. This structural study complements previously published solution, solid state and computational studies of PG-1 in various environments and validate the potential of mean force simulations of PG-1 dimers and association of dimers to form octameric or decameric beta-barrels. PMID- 25786623 TI - Six-core versus twelve-core prostate biopsy: a retrospective study comparing accuracy, oncological outcomes and safety. AB - AIMS: To compare sextant and 12 core transrectal ultrasound-guided (TRUS) prostate biopsies for detecting prostate cancer (PCa) and to determine whether 12 core prostate biopsies are associated with a higher incidence of insignificant prostate cancer and complications. METHODS: A retrospective study was performed on all patients with a positive TRUS biopsy for prostate cancer between January 2011 and December 2013. Group A underwent a sextant core prostate biopsy and group B underwent a 12-core prostate biopsy. Outcome variables were cancer detection rates, oncological outcomes, incidence of clinically insignificant PCa and incidence of biopsy associated complications. Exclusion criteria included a negative TRUS biopsy and metastatic prostate cancer. RESULT: In total 718 prostate biopsies were performed and 286 patients met inclusion criteria (143 patients in each group). The overall cancer detection rate was 43 % in group A compared to 53 % in group B (p = 0.03). In group A, 31 (21.7 %) patients proceeded to open retropubic radical prostatectomy (RRP) compared to 36 (25.2 %) in group B (p = 0.7). Sextant biopsies were associated with a significantly higher rate of upgrading compared to 12-core biopsies in RRP specimens (51.6 versus 25 % respectively, p < 0.01). The incidence of clinically insignificant PCa was 10.5 % in group A versus 14.7 % in group B (p = 0.2). The incidence of urosepsis post biopsy was 0.7 % in both groups (n = 1). CONCLUSION: Twelve-core biopsies were associated with higher PCa cancer detection rates, greater accuracy for Gleason grading and no differences for detecting clinically insignificant PCa or urosepsis compared to sextant biopsies. PMID- 25786624 TI - Systematic analysis to identify a key role of CDK1 in mediating gene interaction networks in cervical cancer development. AB - OBJECTIVE: This study aims to identify corresponding differentially expressed genes in cervical cancer by comparing gene expression profiles between normal and cervical cancer samples. METHOD: To identify differentially expressed genes in cervical cancer, two groups of Affymetrix microarray data available online were analyzed. One group consisted of 43 carcinomatous cervical epithelial cell samples, and the other was composed of 17 healthy cervical epithelial cell samples, both from the Amerindian. R packages-GO.db, KEGG.db and KEGGREST were used to detect GO categories and KEGG pathways with significant overrepresentation in differentially expressed genes comparing with the whole genome. Cytoscape was utilized to construct biological networks. RESULTS: By comparing gene expression profile of normal and cervical cancer samples, 122 differentially expressed genes were identified including 46 up-regulated genes and 76 down-regulated genes. Using the identified differentially expressed genes, a large and a small biological network was constructed. In addition, 402 GO biological processes and 9 KEGG pathways were over-represented. Top significant biological processes included cell cycle and cell proliferation. Moreover, top significant KEGG pathways were oocyte meiosis, cell cycle and progesterone mediated oocyte maturation. Most importantly, CDK1 frequently appeared in these processes and pathways, which indicated its significant role in the progression of cervical cancer. CONCLUSION: CDK1 plays a comprehensive role in mediating genetic networks implicated in the progression of cervical cancer. Novel therapeutics targeting CDK1 or its related pathways might help improve prognosis of advanced stage cervical cancer. PMID- 25786625 TI - Ethnicity and patient satisfaction with tuberculosis care: A cross-sectional study. AB - Patients presenting in major tuberculosis (TB) centres in two Australian metropolitan hospitals and three central hospitals in Malawi were interviewed for health and other information, including their satisfaction with nursing care. The main objective of the study was to investigate differences in satisfaction rates among ethnically similar and different patients coming from two dissimilar health systems. A multivariable Generalized Estimating Equations model was constructed to identify sociodemographic and health-related factors associated with dissatisfaction, while focusing on ethnic differences between and within each country. The Australian and Malawian patients were similar in age, gender, marital status, and employment. However, the Malawians were mostly inpatients, with recurrent TB episodes, and were more seriously ill with impaired physical and mental wellbeing. Nonetheless, being Australian was more associated with dissatisfaction observed in all components of care. However, Australian ethnic minorities were less dissatisfied than their Anglo-Saxon or European counterparts, being more similar to Malawian patients irrespective of the health care provided. Our study suggests that patients coming from similar ethnic backgrounds may express similar satisfaction irrespective of the health system they belong to. PMID- 25786626 TI - [In Process Citation]. PMID- 25786627 TI - [In Process Citation]. PMID- 25786628 TI - [The differences in speciality preferences and career determinant factors between first- and fifth-year medical school students]. AB - AIM: In Japan, the imbalance in the medical workforce has caused a deterioration of rural medicine. We explored the differences in speciality preferences and career determinant factors among students to identify keys to increase the recruitment of physicians to rural areas. METHODS: We conducted a survey of first and fifth-year medical students, using a questionnaire enquiring about their specialty preference and career determinant factors. The data were analyzed with a chi-square test. RESULTS: A higher percentage of first-year students preferred to be basic medicine scientists, while fifth-year students considered internal medicine subspecialities, obstetrics and gynecology, anesthesia, and ophthalmology to be the most desirable. The factor analysis yielded five factors responsible for these findings; high social approval of the specialty, working hours, income, advice from senior classmates and doctors, and the work environment. The percentage of students who considered rural practice as a choice for thier future plan and had an awareness of the collapse of rural medicine was lower in the fifth-year students than in the first-year students. CONCLUSION: To increase the medical work force in provincial areas, it is necessary to strengthen not only the medical system with regard to general medicine, but also to offer better medical education in rural areas. More information about rural practice should therefore be transmitted to medical students. PMID- 25786629 TI - [Investigation of the effects of intervention by therapists at night on convalescent rehabilitation units]. AB - AIM: This study sought to investigate the influence of intervention by therapists at night on the patient's ADL's, number of falls, etc. On convalescent rehabilitation units in order to examine the efficacy of the intervention. METHODS: The study subjects included patients hospitalized on 11 convalescent rehabilitation units. The period of intervention by the therapists at night and the period of no intervention were each set for three months. The improvements in the ADL scores during each period were compared, and the changes in the number of falls were examined. In addition, a questionnaire survey was conducted among the night shift staff in order to examine the need for intervention. RESULTS: The patients who received intervention by therapists at night showed higher scores for BI, FIM, etc. and fewer falls than those treated without intervention. The results of the questionnaire survey indicated differences between the therapists and other professionals regarding their attitude toward working the night shift. CONCLUSIONS: Our findings suggest that intervention by therapists at night results in favorable outcomes, e.g., improvements in the patient's ADL's and a reduction in the number of falls. Although there are issues to be discussed with respect to raising awareness among therapists and concerns regarding work-related problems, intervention by therapists at night has the possibility to be used as a new treatment strategy on rehabilitation units. PMID- 25786630 TI - [Reliability and validity of the Japanese version of the AD8]. AB - AIM: The AD8 is a brief, sensitive informant interview tool for detecting dementia. However, there are no reports of a Japanese version of the AD8. Our aim was to establish the reliability and validity of the AD8 for screening for dementia in older adults 75 years of age or older in Japan. METHODS: We acquired the author's permission to translate the AD8 from English to Japanese. A total of 572 community residents 75 years of age or older living in Kurihara, Northern Japan agreed to participate in this study. Of these participants, 214 scored a Clinical Dementia Rating (CDR) of 0 (healthy), 289 scored a CDR of 0.5 (mild cognitive impairment) and 69 scored a CDR of 1 or above (dementia). Analysis 1. Reliability of the Japanese version of the AD8. Analysis 2. Validity of the AD8: Receiver operating characteristic (ROC) curve for nondemented (CDR 0+0.5) vs. demented (CDR 1 or above) individuals. RESULTS: For the Japanese version of the AD8, the Cronbach' s coefficient alpha was 0.88 and the Guttman's split half method coefficient was 0.85. For the patients with CDR values of 0+0.5 vs. 1 or above, the area under the ROC curve was 0.89 (p<0.0001) and the cut-off score was 1/2, with a sensitivity of 88.4% and specificity of 68.4%. CONCLUSIONS: We established the reliability and validity of the Japanese version of the AD8 for screening for dementia in older adults 75 years of age or older in the community. PMID- 25786631 TI - [Validity and reliability of the "Trail Making Peg" test as a performance measurement for evaluating the cognitive function]. AB - AIM: To investigate the validity and reliability of a novel performance test, called the "Trail Making Peg" (TMP) test, for evaluating the cognitive function. METHODS: We recruited 632 community-dwelling older adults (mean age: 73.3+/-5.2 years) as subjects for the assessment of the validity of the test and 319 adults (mean age: 73.1+/-5.2 years) as subjects for the assessment of reliability. Five cognitive tests (5-Cog) were used to evaluate the cognitive function, and the degree of cognitive decline was delineated for subjects scoring below 1 SD from the mean 5-Cog score. A receiver operating characteristic analysis was employed to calculate the cut-off point. RESULTS: There were no sex differences in the TMP scores (P=0.951), and the TMP and 5-Cog scores were found to correlate significantly (r=-0.63) with each other. The Trail Making Peg test demonstrated an area under the curve of 0.855 for discriminating between non-cognitive decline and cognitive decline. At this cutoff point, the sensitivity was 85% and the specificity was 69%. The intraclass correlation coefficient of the TMP was 0.746. CONCLUSIONS: The TMP exhibits sufficient validity and reliability. Our results suggest that TMP is a useful screening test for detecting cognitive decline. PMID- 25786632 TI - [Communication with important others regarding their preferences for end-of-life care]. AB - AIM: Our aim in this study was to explore individual factors that make it likely for Japanese older adults to engage in communication with important other persons regarding their preferences for end-of-life care. METHODS: We conducted a questionnaire survey of outpatients at Tokyo Metropolitan Geriatric Hospital in the last six days of March 2012. Nine-hundred and sixty-eight outpatients consented in writing to participate in this survey. Two items on the questionnaire concerned the participants' attempts to communicate their preferences regarding end-of-life care; that is, whether they had discussed this issue with their significant others and whether they had written notes indicating how they want to be cared for in the final days of their lives. RESULTS: The participants who had designated a surrogate decision-maker were more likely to report answers of both than only discussion (OR=2.52) and less likely to reports answers of no communication than only discussion (OR=0.37). In addition, (a) those who did not wish to rely on artificial nutrition or hydration (OR=0.68) and (b) those who often thought about their death were more likely to be in the only discussion group than in the no communication group, although these factors were not significantly associated with whether the participants were likely to be in the both or only discussion groups. CONCLUSIONS: Our findings indicate that individuals often attempt to clarify their preferences in order to make it easier for their significant others to make end-of-life care decision on their behalf, so that they may receive their desired care. PMID- 25786633 TI - [Prospective study of cognitive decline assessed using the mini-mental state examination and the risk of incident long-term care insurance among community dwelling older Japanese]. AB - AIM: We examined the longitudinal association between the change in the Mini Mental State Examination (MMSE) score per year and the incidence of a certified need for care in the long-term care insurance system among community-dwelling older Japanese subjects. METHODS: A total of 773 adults 65 years of age or older who participated in a baseline survey (2002 to 2007) underwent MMSE reevaluation at least once until Wave-1 (2003 to 2008). The incidence of a certified need for care in the long-term care insurance system until Wave-2 (Wave-1 to 2013) was examined in all subjects. RESULTS: During an average follow-up of 1,195 days (baseline survey to Wave-1), the change in the MMSE score per year was greater than 0 in 511 (66.1%) participants, 0 to -0.5 in 94 (12.2%) participants, -0.5 to -1 in 66 (8.5%) participants, -1 to -2 in 56 (7.2%) participants, and less than 2 in 46 (6.0%) participants. During an average follow-up of 1,802 days (Wave-1 to Wave-2), 104 participants (13.5%) were newly certified with a need for care in the long-term care insurance system. After controlling for important confounders, elders with a change in the MMSE score of 0 to -0.5, -0.5 to -1, -1 to -2 and less than -2 per year were 1.73 (95% confidence interval, 0.93-3.23), 1.94 (1.01 3.45), 1.95 (1.02-3.76) and 3.16 (1.68-5.98) times as likely to be newly certified with a need for care in the long-term care insurance system, respectively, compared those with a change in the score greater than 0. CONCLUSIONS: The extent of change in the MMSE score per year independently predicted the incident certified need for care in the long-term care insurance system in a general population of older Japanese subjects. A decrease of greater than 0.5 points per year may be a useful cutoff value for clinically evaluating elders. PMID- 25786637 TI - Questions about and speculations on the incidence of idiopathic polyhydramnios by fetal gender. PMID- 25786638 TI - Reply to "Questions about and speculations on the incidence of idiopathic polyhydramnios by fetal gender". PMID- 25786639 TI - Discovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach. AB - Streptococcus pneumoniae is a leading cause of life-threatening bacterial infections, especially in young children in developing countries. Pneumococcal infections can be treated with beta-lactam antibiotics, but rapid emergence of multidrug-resistant strains of S. pneumoniae over the past two decades has emphasized the need to identify novel drug targets. Pneumococcal surface antigen A (PsaA) is one such target, found on the cell surface of S. pneumoniae. It functions as a high-affinity substrate-binding protein, facilitating acquisition of Mn(2+), which has an important role in protecting S. pneumoniae from reactive oxygen species and, hence, oxidative stress. Consequently, PsaA is essential for bacterial survival and an important virulence factor, which makes it a promising target for antibiotic drug development. To design novel PsaA inhibitors, we used a combination of de novo fragment-based drug discovery and in silico virtual screening methods. We profiled a collection of low molecular weight compounds that were selected based on their structural diversity and ability to bind to apo PsaA in a virtual docking experiment. The screening resulted in two initial hits that were further optimized by structural variation to improve their potency while maintaining their ligand efficiency and favorable physicochemical properties. The optimized hits were validated using a cell-based assay and molecular dynamics simulations. We found that virtual screening substantially augmented fragment-based drug design approaches, leading to the identification of novel pneumococcal PsaA inhibitors. PMID- 25786640 TI - Late-onset glucocorticoid-responsive circulatory collapse in preterm infants: clinical characteristics of 14 patients. AB - Preterm infants may develop acute systemic hypotension that responds to glucocorticoid therapy, but not to volume loading or vasopressors, during the postnatal period. This condition is termed late-onset circulatory collapse (LCC) that develops a few weeks after birth in relatively stable infants. LCC may cause periventricular leukomalacia, periventricular necrosis in the white matter. The aim of this study was to identify the clinical characteristics of LCC. We retrospectively reviewed the clinical data of infants with LCC. Among 41 infants born at < 29 weeks of gestation between 2010 and 2014, we identified 14 infants (median gestational age 25.6 weeks) with LCC. All infants were stable before the acute onset of circulatory collapse at a median age of 21 days, which is characterized by the decreased physical activity, systolic blood pressure (12 mmHg decrease), urine output (76% decrease), and serum sodium level (4 mEq/L decrease), and the increased resistance index in the cerebral and renal arteries on Doppler ultrasonography. Both left ventricular dimension and contraction were well preserved. Three infants developed hyperkalemia. The median time from the initial hydrocortisone dose to improvements was 4 h (interquartile range 3-5 h). Hydrocortisone therapy was effective, but had to be withdrawn slowly to prevent relapse. The median duration of hydrocortisone therapy was 23 days. There was no evidence of periventricular leukomalacia in any of the infants. None of the infants developed adrenal insufficiency during the follow-up period. During the acute stage of LCC, the main priority is the early initiation of glucocorticoid therapy. PMID- 25786641 TI - Investigating the Robustness and Diagnostic Potential of Extracellular Matrix Remodelling Biomarkers in Alkaptonuria. AB - BACKGROUND AND AIM: Alkaptonuria (AKU) clinical manifestations resemble severe arthritis. The Suitability of Nitisinone in Alkaptonuria 1 (SONIA 1) study is a dose-finding trial for nitisinone treatment of AKU patients. We tested a panel of serum and urinary biomarkers reflecting extracellular matrix remodelling (ECMR) of cartilage, bone and connective tissue in SONIA 1 patients to identify non invasive and diagnostic biomarkers of tissue turnover in AKU. METHODS: Fasted serum and urine were retrieved from 40 SONIA 1 patients and 44 healthy controls. Established biomarkers of bone remodelling (CTX-I, P1NP, OC), cartilage remodelling (CTX-II, C2M, AGNx1) and inflammation (CRPM) as well as exploratory biomarkers of ECMR (C6M, VCANM, MIM, TIM) were measured at baseline in serum and urine by means of enzyme-linked immunosorbent assays (ELISAs) or automated systems (Elecsys 2010). RESULTS: The levels of bone resorption (CTX-I) and cartilage degradation (C2M) were elevated in AKU patients as compared to controls (p > 0.0001 and p = 0.03, respectively). Also tissue inflammation (CRPM) was elevated in AKU patients (p = 0.01). In addition all four exploratory biomarkers of ECMR (C6M, VCANM, MIM, TIM) were elevated in AKU patients compared to healthy controls. CTX-II was the only biomarker to be reduced in AKU patients. TIM was the only marker that showed a higher concentration than the normal assay range in AKU patients. CONCLUSIONS: We have identified new potential biomarkers for assessment of cartilage, bone and cardiovascular remodelling in AKU and demonstrated the robustness of the assays used to measure the biomarker concentration in biological fluids. PMID- 25786642 TI - Age-Related Deviation of Gait from Normality in Alkaptonuria. AB - Alkaptonuria is a rare metabolic disease leading to systemic changes including early and severe arthropathy which affects mobility. For unknown reasons, the onset of degenerative changes is delayed to around 30 years of age when both objective and subjective symptoms develop. In order to complement description of the structural changes in alkaptonuria with measures of movement function, clinical gait analysis was added to the list of assessments in 2013. The aim of this study was to describe the deviation of gait from normality as a function of age in patients with alkaptonuria. Three-dimensional movement of reflective markers attached to joints were captured during walking in 39 patients and 10 controls. Subsequent to processing the data to emphasise the shape of marker trajectories, the mean Movement Deviation Profile was generated for all participants. This single number measure gives the deviation of a patient's gait from a distributed definition of gait normality. Results showed that gait deviation roughly follows a sigmoid profile with minimal increase of gait deviations in a younger patient group and an abrupt large increase around the second half of the 4th decade of life. Larger variations of gait deviations were found in the older group than in the younger group suggesting a complex interaction of multiple factors which determine gait function after symptoms manifest. Continued gait analysis of adults with AKU, extended to younger adults and children with AKU, is expected to complete understanding of both the natural history of alkaptonuria and how interventions can affect movement function. PMID- 25786643 TI - Development and psychometric evaluation of the Primary Health Care Engagement (PHCE) Scale: a pilot survey of rural and remote nurses. AB - AIM: To report the development and psychometric evaluation of a scale to measure rural and remote (rural/remote) nurses' perceptions of the engagement of their workplaces in key dimensions of primary health care (PHC). BACKGROUND: Amidst ongoing PHC reforms, a comprehensive instrument is needed to evaluate the degree to which rural/remote health care settings are involved in the key dimensions that characterize PHC delivery, particularly from the perspective of professionals delivering care. METHODS: This study followed a three-phase process of instrument development and psychometric evaluation. A literature review and expert consultation informed instrument development in the first phase, followed by an iterative process of content evaluation in the second phase. In the final phase, a pilot survey was undertaken and item discrimination analysis employed to evaluate the internal consistency reliability of each subscale in the preliminary 60-item Primary Health Care Engagement (PHCE) Scale. The 60-item scale was subsequently refined to a 40-item instrument. FINDINGS: The pilot survey sample included 89 nurses in current practice who had experience in rural/remote practice settings. Participants completed either a web-based or paper survey from September to December, 2013. Following item discrimination analysis, the 60-item instrument was refined to a 40-item PHCE Scale consisting of 10 subscales, each including three to five items. Alpha estimates of the 10 refined subscales ranged from 0.61 to 0.83, with seven of the subscales demonstrating acceptable reliability (alpha ? 0.70). The refined 40-item instrument exhibited good internal consistency reliability (alpha=0.91). The 40-item PHCE Scale may be considered for use in future studies regardless of locale, to measure the extent to which health care professionals perceive their workplaces to be engaged in key dimensions of PHC. PMID- 25786644 TI - Individualised dietary counselling for nutritionally at-risk older patients following discharge from acute hospital to home: a systematic review and meta analysis. AB - BACKGROUND: Many older patients are undernourished after hospitalisation. Undernutrition impacts negatively on physical function and the ability of older patients to perform activities of daily living at home after discharge from acute hospital. The present study aimed to evaluate the evidence for an effect of individualised dietary counselling following discharge from acute hospital to home on physical function, and, second, on readmissions, mortality, nutritional status, nutritional intake and quality of life (QoL), in nutritionally at-risk older patients. METHODS: A systematic review of randomised controlled trials was conducted. The overall quality of the evidence was assessed according to Grading of Recommendations Assessment, Development and Evaluation system (GRADE) criteria. RESULTS: Four randomised controlled trials (n = 729) were included. Overall, the evidence was of moderate quality. Dietitians provided counselling in all studies. Meta-analyses showed a significant increase in energy intake [mean difference (MD) = 1.10 MJ day(-1), 95% confidence interval (CI) = 0.66-1.54, P < 0.001], protein intake (MD = 10.13 g day(-1), 95% CI = 5.14-15.13, P < 0.001) and body weight (BW) (MD = 1.01 kg, 95% CI = 0.08-1.95, P = 0.03). Meta-analyses revealed no significant effect on physical function assessed using hand grip strength, and similarly on mortality. Narrative summation of effects on physical function using other instruments revealed inconsistent effects. Meta-analyses were not conducted on QoL and readmissions as a result of a lack of data. CONCLUSIONS: Individualised dietary counselling by dietitians following discharge from acute hospital to home improved BW, as well as energy and protein intake, in older nutritionally at-risk patients, although without clearly improving physical function. The effect of this strategy on physical function and other relevant clinical outcomes warrants further investigation. PMID- 25786645 TI - Editorial Comment to Improvement of overactive bladder symptoms after tension free vaginal mesh operation in women with pelvic organ prolapse: Correlation with preoperative urodynamic findings. PMID- 25786646 TI - Correction: unexpected optical activity of cerium in Y2O3:Ce(3+), Yb(3+), Er(3+) up and down-conversion system. PMID- 25786647 TI - A template-confined fabrication of controllable gold nanoparticles based on the two-dimensional nanostructure of macrocycles. AB - An amine-substituted macrocycle , a rigid hexagonal ring, self-assembled into network architecture on the surface, which could be used as a molecular template to directly fabricate gold nanoparticles (AuNPs) with narrow size distribution (2.2 +/- 0.1 nm). This work demonstrated a new pathway for the formation of controllable AuNPs on the surface. PMID- 25786650 TI - CMS asserts broad authority over physician prescribing practices. PMID- 25786651 TI - Persistent back pain after percutaneous vertebroplasty. PMID- 25786652 TI - Self-assembled autophagy-inducing polymeric nanoparticles for breast cancer interference in-vivo. AB - A peptide-conjugated poly(beta-amino ester) that self-assembles into micelle-like nanoparticles is prepared by a convenient and modular supramolecular approach. The polymer-beclin-1 (P-Bec1) nanoparticles display enhanced cytotoxicity to breast cancer cells through induction of autophagy. This approach overcomes two major limitations of the haploinsufficient tumor suppressor Bec1 compared to small-molecule drugs: poor delivery to tumors owing to enzymatic degradation, and unstable, non-specific bio-distribution and targeting in the tumor tissues. PMID- 25786653 TI - Deep metabotyping of the murine gastrointestinal tract for the visualization of digestion and microbial metabolism. AB - Despite the gut's longitudinal specialization for digestion and microbiome organization, most studies focus on the analysis of its end product, feces. To determine the metabolic and physiological functions of different sections of the gut, we aimed to define a comprehensive list of characteristic metabolites for the physiological gut sections and to quantify the selected pathways. We investigated the metabolic composition of seven different gut sections from four C57Bl/6N mice with nontargeted metabolite profiling using high-resolution NMR spectroscopy, which returned a comprehensive metabolite overview with a single analytical measurement per sample. Here we deliver a list of characteristic metabolites, describe metabolite changes along the gut, and highlight the site specificity for selected metabolite pathways. We find that the largest metabolic changes happen in the cecum, where the microbiome produces microbial metabolites. Furthermore, we show the evolution of bile acids along the gut and describe their site-specific conversion. We establish a metabolic basis for future investigations of metabolic perturbations, which can be introduced by dietary challenges or gene knockouts and provide valuable information for tailored study design and targeted sample collection. PMID- 25786654 TI - Towards understanding directed evolution: more than half of all amino acid positions contribute to ionic liquid resistance of Bacillus subtilis lipase A. AB - Ionic liquids (ILs) are attractive (co-)solvents for biocatalysis. However, in high concentration (>10 % IL), enzymes usually show decreased activity. No general principles have been discovered to improve IL resistance of enzymes by protein engineering. We present a systematic study to elucidate general engineering principles by site saturation mutagenesis on the complete gene bsla. Screening in presence of four [BMIM]-based ILs revealed two unexpected lessons on directed evolution: 1) resistance improvement was obtainable at 50-69 % of all amino acid positions, thus explaining the success of small sized random mutant libraries; 2) 6-13 % of substitutions led to improved resistance. Among these, 66 95 % were substitutions by chemically different amino acids (e.g., aromatic to polar/aliphatic/charged amino acids), thus indicating that mutagenesis methods introducing such changes should, at least for lipases like BSLA, be favored to improve IL resistance. PMID- 25786655 TI - Sarcoid polyneuropathy masquerading as chronic inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: Sarcoid polyneuropathy is a rare and clinically heterogeneous disorder that may be the initial presentation of sarcoidosis. METHODS: We report the clinical, electrophysiological, and pathological findings of a patient who carried a diagnosis of sensory-predominant chronic inflammatory demyelinating polyneuropathy (CIDP) for over a decade but was ultimately found to have sarcoid polyneuropathy. RESULTS: A 36-year-old man presented with a several-week history of gait difficulty and muscle cramps. He had a diagnosis of CIDP but had not received lasting benefit from steroid-sparing immunosuppressive drugs. Electrodiagnostic studies were consistent with a chronic demyelinating polyradiculoneuropathy with conduction blocks. After he developed systemic symptoms, tissue biopsies revealed granulomatous disease. Symptoms improved with steroid therapy. CONCLUSIONS: Sarcoid polyneuropathy presents a diagnostic challenge, but, in patients with atypical neuropathy, characteristic systemic symptoms, or a poor response to standard treatment, nerve and muscle biopsies can help diagnose this treatable disorder. PMID- 25786656 TI - Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancer. AB - BACKGROUND: Imatinib mesylate is a chemotherapeutic drug that inhibits the tyrosine kinase activity of c-KIT and has been successfully used to treat leukemias and some solid tumors. However, its application for treatment of hormone-refractory prostate cancer (HRPC) has shown modest effectiveness and did not follow the outcomes in cultured cells or animal models. Moreover, the molecular pathways by which imatinib induces cytotoxicity in prostate cancer cells are poorly characterized. METHODS: Two cell line models of HRPC (DU145 and PC3) were exposed to 20 MUM of imatinib for 6-72 hr. MTS assay was used to assess cell viability during the course of experiment. Gene expression analysis of c KIT, cell-cycle and apoptosis regulators, and angiogenic factors was determined by means of real-time PCR, western blot, and/or immunocytochemistry. The enzymatic activity of the apoptosis effector, caspase-3, was determined by a colorimetric assay. RESULTS: Imatinib significantly decreased the viability of DU145 cells but paradoxically augmented the viability of PC3 cells. DU145 cells displayed diminished expression of anti-apoptotic Bcl-2 protein and augmented levels of caspase-8 and -9, as well as, increased enzymatic activity of caspase-3 in response to imatinib. No differences existed on the expression levels of apoptosis-related proteins in PC3 cells treated with imatinib, though the activity of caspase-3 was decreased. The mRNA levels of angiogenic factor VEGF were decreased in DU145-treated cells, whereas an opposite effect was seen in PC3. In addition, it was shown that DU145 and PC3 cells present a differential expression of c-KIT protein variants. CONCLUSION: DU145 and PC3 cells displayed a contradictory behavior in response to imatinib, which was underpinned by a distinct expression pattern (or activity) of target regulators of cell-cycle, apoptosis, and angiogenesis. The paradoxical effect of imatinib in PC3 cells may be related with the differential expression of c-KIT protein variants. Moreover, the present findings helped to understand the discrepancies in the efficacy of imatinib as therapeutic option in HRPC. PMID- 25786658 TI - Surface Profile Control of FeNiPt/Pt Core/Shell Nanowires for Oxygen Reduction Reaction. AB - Monodisperse core/shell FeNiPt/FePt nanowires (4.5 * 20-50 nm) are synthesized by seed-mediated growth of FePt over the pre-made 2.5 nm wide FeNiPt nanowires. The surface profile of the FeNiPt/FePt nanowires is tailored by acid and thermal treatment. The FeNiPt/Pt-skin nanowires show higher activities than the FeNiPt/Pt skeleton nanowires. PMID- 25786657 TI - Replication of 13q31.1 association in nonsyndromic cleft lip with cleft palate in Europeans. AB - Genome wide association (GWA) studies have successfully identified at least a dozen loci associated with orofacial clefts. However, these signals may be unique to specific populations and require replication to validate and extend findings as a prelude to etiologic SNP discovery. We attempted to replicate the findings of a recent meta-analysis of orofacial cleft GWA studies using four different ancestral populations. We studied 946 pedigrees (3,436 persons) of European (US white and Danish) and Asian (Japanese and Mongolian) origin. We genotyped six SNPs that represented the most significant P-value associations identified in published studies: rs742071 (1p36), rs7590268 (2p21), rs7632427 (3p11.1), rs12543318 (8q21.3), rs8001641 (13q31.1), and rs7179658 (15q22.2). We directly sequenced three non-coding conserved regions 200 kb downstream of SPRY2 in 713 cases, 438 controls, and 485 trios from the US, Mongolia, and the Philippines. We found rs8001641 to be significantly associated with nonsyndromic cleft lip with cleft palate (NSCLP) in Europeans (P-value = 4 * 10(-5), ORtransmission = 1.86 with 95% confidence interval: 1.38-2.52). We also found several novel sequence variants in the conserved regions in Asian and European samples, which may help to localize common variants contributing directly to the risk for NSCLP. This study confirms the prior association between rs8001641 and NSCLP in European populations. PMID- 25786660 TI - A novel colorimetric fluoride sensor based on a semi-rigid chromophore controlled by hydrogen bonding. AB - A novel semi-rigid latent chromophore E1, containing an amide subunit activated by an adjacent semi-rigid intramolecular hydrogen-bonding (IHB) unit, was designed for the detection of fluoride ion by the 'naked-eye' in CH3CN. Comparative studies on structural analogs (E2, E3, and E4) provided significant insight into the structural and functional role of the amide N-H and IHB segment in the selective recognition of fluoride ions. The deprotonation of the amide N-H followed by the enhancement of intramolecular charge transfer (ICT) induced the colorimetric detection of E1 for fluoride ion. PMID- 25786659 TI - Oral fluid with three modes of collection and plasma methamphetamine and amphetamine enantiomer concentrations after controlled intranasal l methamphetamine administration. AB - Methamphetamine is included in drug testing programmes due to its high abuse potential. d-Methamphetamine is a scheduled potent central nervous system stimulant, while l-methamphetamine is the unscheduled active ingredient in the over-the-counter nasal decongestant Vicks(r) VapoInhalerTM. No data are available in oral fluid (OF) and few in plasma after controlled Vicks(r) VapoInhalerTM administration. We quantified methamphetamine and amphetamine enantiomers in OF collected with two different devices and plasma via a fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Additionally, OF were analyzed with an on-site screening device. Sixteen participants received 7 Vicks(r) VapoInhalerTM doses according to manufacturer's recommendations. Specimens were collected before and up to 32 h after the first dose. No d methamphetamine or d-amphetamine was detected in any sample. All participants had measurable OF l-methamphetamine with median maximum concentrations 14.8 and 16.1 MUg/L in QuantisalTM and Oral-Eze(r) devices, respectively, after a median of 5 doses. One participant had measurable OF l-amphetamine with maximum concentrations 3.7 and 5.5 MUg/L after 6 doses with the QuantisalTM and Oral Eze(r) devices, respectively. There were no positive DrugTest(r) 5000 results. In the cutoff range 20-50 MUg/L methamphetamine with amphetamine >=limit of detection, 3.1-10.1% of specimens were positive; first positive results were observed after 1-4 doses. Two participants had detectable plasma l methamphetamine, with maximum observed concentrations 6.3 and 10.0 MUg/L after 2 and 5 doses, respectively. Positive OF and plasma methamphetamine results are possible after Vicks(r) VapoInhalerTM administration. Chiral confirmatory analyses are necessary to rule out VapoInhalerTM intake. Implementing a selective d-methamphetamine screening assay can help eliminate false-positive OF results. PMID- 25786661 TI - The mantle of the heavens: Reflections on the 2014 Nobel Prize for medicine or physiology. AB - The award of the Nobel Prize in Medicine or Physiology in 2014 for the discovery of place and grid cells was both a personal award to three great scientists and also a mark of the maturity of systems neuroscience as a discipline. This article offers both personal and scientific reflections on these discoveries, detailing both how getting to know all three winners had an impact on my life and the research questions that we shared in common work together. It ends with brief reflections on three important outstanding questions. PMID- 25786662 TI - Dr. J. Lester Gabrilove: a master clinician, scientist, and educator (1916-2014). PMID- 25786663 TI - Effects of Palonosetron on Perioperative Cardiovascular Complications in Patients Undergoing Noncardiac Surgery With General Anesthesia: A Retrospective Cohort Study. AB - We retrospectively investigated whether palonosetron administered during the induction of general anesthesia is associated with an increased risk of perioperative cardiovascular complications in a single tertiary center cohort consisting of 4,517 palonosetron-exposed patients and 4,517 propensity score matched patients without palonosetron exposure. The primary endpoint was a composite of perioperative cardiovascular complications, including intraoperative cardiac arrhythmia, intraoperative cardiac death, and myocardial injury within the first postoperative week, and there was no significant difference between the groups (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 0.92-1.19). As secondary endpoints, intraoperative cardioversion, cardiac compression, use of cardiovascular drugs, postoperative hospital stay, and in-hospital mortality showed no differences between the groups. However, the palonosetron group showed decreased intraoperative hypotension (OR = 0.88; 95% CI = 0.79-0.97) and length of postoperative intensive care unit (ICU) stay (4.26 +/- 9.86 vs. 6.14 +/- 16.75; P = 0.026). Palonosetron did not increase the rate of perioperative cardiovascular complications, and can therefore be used safely during anesthetic induction. PMID- 25786664 TI - Concise review: transplantation of cultured oral mucosal epithelial cells for treating limbal stem cell deficiency-current status and future perspectives. AB - A number of diseases and external factors can deplete limbal stem cells, causing pain and visual loss. Ten years have passed since the first transplantation of cultured oral mucosal epithelial cells in humans, representing the first autologous cell-based therapy for severe bilateral limbal stem cell deficiency. Its steady increase in popularity since then can be attributed to the accumulating evidence of its efficacy in reverting limbal stem cell deficiency. In this review, the focus is on clinical, and to a lesser degree laboratory, features of cultured oral mucosal epithelial transplants over the past 10 years. Comparisons with other available technologies are made. Avenues for research to stimulate further improvements in clinical results and allow worldwide distribution of limbal stem cell therapy based on oral mucosal cells are discussed. These include storage and transportation of cultured oral mucosal epithelial sheets and in vivo culture of oral mucosal epithelial cells. PMID- 25786665 TI - Alcohol and amyotrophic lateral sclerosis: a possible neuroprotective effect. PMID- 25786666 TI - Alkaline-earth metal cations as structure building blocks for molecular cages with entrapment and controlled release of quintuple ionic aggregates. AB - Currently, main-group metal cations are totally neglected as the structure building blocks for the self-assembly of supramolecular coordination metallocages due to the lack of directional bonding. However, here we show that a common Arrhenius acid-base neutralization allows the alkaline-earth metal cations to act as charged binders, easily connecting two or more highly directional anionic transition-metal-based metalloligands to coordination polymers. With a metal salt such as K(+) PF6 (-) added during the neutralization, the main-group metal connected skeleton can be templated by the largest yet reported ionic-aggregate anion, K2 (PF6 )3 (-) , formed from KPF6 in solution, into molecular metallocages, encapsulating the ion. Crystal-structure details, DFT-calculation results, and controlled-release behavior support the presence of K2 (PF6 )3 (-) as a guest in the cage. Upon removal of PF6 (-) ions, the cage stays intact. Other ions like BF4 (-) can be put back in. PMID- 25786667 TI - Direct Synthesis of Porous Nanorod-Type Graphitic Carbon Nitride/CuO Composite from Cu-Melamine Supramolecular Framework towards Enhanced Photocatalytic Performance. AB - Facile and direct synthesis of porous nanorod-type graphitic carbon nitride/CuO composite (CuO-g-C3 N4 ) has been achieved by using a Cu-melamine supramolecular framework as a precursor. The CuO-g-C3 N4 nanocomposite demonstrated improved visible-light-driven photocatalytic activities. The results indicate that metal melamine supramolecular frameworks can be promising precursors for the preparation of efficient g-C3 N4 nanocomposite photocatalysts. PMID- 25786668 TI - Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat. AB - NEW FINDINGS: What is the central question of this study? The aim was to determine whether the accumulation of ceramide contributes to skeletal muscle insulin resistance in the JCR obese rat. What is the main finding and its importance? Our main new finding is that ceramides accumulate only in slow-twitch skeletal muscle in the JCR obese rat and that reducing ceramide content in this muscle type by inhibition of serine palmitoyl transferase-1 halts the progression of insulin resistance in this rat model predisposed to early development of type 2 diabetes. Our findings highlight the importance of assessing insulin signalling/sensitivity and lipid intermediate accumulation in different muscle fibre types. It has been postulated that insulin resistance results from the accumulation of cytosolic lipid metabolites (i.e. diacylglycerol/ceramide) that impede insulin signalling and impair glucose homeostasis. De novo ceramide synthesis is catalysed by serine palmitoyl transferase-1. Our aim was to determine whether de novo ceramide synthesis plays a role during development of insulin resistance in the JCR:LA-cp obese rat. Ten-week-old JCR:LA-cp obese rats were supplemented with either vehicle or the serine palmitoyl transferase-1 inhibitor l-cycloserine (360 mg l(-1) ) in their drinking water for a 2 week period, and glycaemia was assessed by meal tolerance testing. Treatment of JCR:LA cp obese rats with l-cycloserine improved their plasma glucose and insulin levels during a meal tolerance test. Examination of muscle lipid metabolites and protein phosphorylation patterns revealed differential signatures in slow-twitch (soleus) versus fast-twitch muscle (gastrocnemius), in that ceramide levels were increased in soleus but not gastrocnemius muscles of JCR:LA-cp obese rats. Likewise, improved glycaemia in l-cycloserine-treated JCR:LA-cp obese rats was associated with enhanced Akt and pyruvate dehydrogenase signalling in soleus but not gastrocnemius muscles, probably as a result of l-cycloserine reducing elevated ceramides in this muscle type. Potential mechanisms of ceramide-mediated insulin resistance involve activation of atypical protein kinase Czeta/lambda and protein phosphatase 2A; however, neither of these was altered in muscles of JCR:LA-cp obese rats. Our results suggest a key role for ceramide in the development of insulin resistance in the JCR:LA-cp obese rat, while supporting serine palmitoyl transferase-1 inhibition as a novel target for treatment of obesity-associated insulin resistance. PMID- 25786669 TI - Evaluation of four methods of assigning species and genus to medically important bacteria using 16S rRNA gene sequence analysis. AB - The four methods for assigning bacterial species are the Clinical and Laboratory Standards Institute (CLSI), modified CLSI (mCLSI), phylogenetic analysis (PA) and closest match (CM) methods, these are used to identify the genus and species using 16S rRNA gene sequence results. In this study, the results of identification by these four methods of 37 aerobic reference strains, 30 anaerobic reference strains, 15 Acinetobacter reference strains and 167 Acinetobacter clinical strains were compared. The rates of accurate identification to the species level using the CLSI, mCLSI, PA and CM methods were as follows: 24.3, 86.5, 86.5 and 89.2%, respectively, for the 37 aerobic reference strains; 73.3%, 96.7%, 90.0% and 93.3%, respectively, for the 30 anaerobic reference strains; 40.0%, 93.3%, 100% and 93.3%, respectively, for the 15 Acinetobacter reference strains; and 53.9%, 90.4%, 95.8% and 90.4%, respectively, for the 167 Acinetobacter clinical strains. The rates of accurate identification to the genus level using the CLSI, mCLSI, PA, and CM methods were as follows: 91.9%, 91.9%, 94.6% and 91.9%, respectively, for the 37 aerobic reference strains; 100%, 100%, 100% and 100%, respectively, for all of the 30 anaerobic reference strains, 15 Acinetobacter reference strains and the 167 Acinetobacter clinical strains. The mCLSI is the most practical and pragmatic method for identification of species based on 16S rRNA sequences for hospital, research or industry laboratories because it performs well and involves a simple procedure. PMID- 25786670 TI - Two novel alpha2 gene mutations causing altered amino acid sequences produce a mild (Hb Kinshasa, HBA2: c.428A > T) and severe (HBA2: c.342-345insCC) alpha thalassemia phenotype. AB - We describe two novel alpha2 gene mutations that result in an altered amino acid sequence. In case 1, the alpha2 stop codon was mutated from TAA > TTA (HBA2: c.428A > T), resulting in an alpha2 protein chain extension of 31 amino acids. The new hemoglobin (Hb) variant was named Hb Kinshasa for the place of origin of the patient. This patient was also a carrier of Hb S (HBB: c.20A > T), which was expressed at reduced levels, but had an otherwise normal blood count. For cases 2 and 3, an alpha2 frameshift mutation caused a premature alpha2 protein chain termination at position 133 (HBA2: c.342-345insCC). The phenotype of this mutation seems to be rather severe as judged by the pronounced microcytosis and hypochromia observed in case 2. In addition, the father of this patient (case 3) also carried a beta(0)-thalassemia (beta(0)-thal) mutation (HBB: c.118C > T). PMID- 25786671 TI - Time-resolved biofilm deformation measurements using optical coherence tomography. AB - The interaction of shear stress with the biofilm leads to a dynamic deformation, which is related to the structural and material characteristics of biofilms. We show how optical coherence tomography can be used as an imaging technique to investigate the time-resolved deformation on the biofilm mesoscale as well as to estimate mechanical properties of the biofilm. For the first time time-resolved deformation from cross-sectional views of the inner biofilm structure could be shown. Changes in the biofilm structure and rheological properties were calculated from cross sections in real-time and time-lapsed measurements. Heterotrophic biofilms were grown in a flow cell set-up at low shear stress of tauw = 0.01 Pa. By applying higher shear stress elastic and viscoelastic behavior of biofilms were quantified. Deformation led to a change in biofilm conformation and allowed to estimate rheological properties. Assuming an ideal wall shear stress calculation, the shear modulus G = 29.7 +/- 1.7 Pa and the Young's modulus E = 36.0 +/- 2.6 Pa were estimated. PMID- 25786672 TI - Neuro-protective effects of cerium and yttrium oxide nanoparticles on high glucose-induced oxidative stress and apoptosis in undifferentiated PC12 cells. AB - OBJECTIVE: Oxidative stress has been recognized as the major factor for the development of diabetes and its complications. Cerium oxide and Yttrium oxide nanoparticles are known as free radicals scavengers. The aim of this study was to investigate the protective effect of CeO2 and Y2O3 on oxidative stress induced by high glucose in undifferentiated rat pheochromocytoma (PC12) cells. METHODS: In this study, undifferentiated PC12 cells were exposed to high glucose (25 mg/ml, 24 hours) and the protective effects of CeO2 and Y2O3 nanoparticles were evaluated. The viability of undifferentiated PC12 cells was determined by MTT assay. The levels of reactive oxygen species (ROS) were measured using 2,7 dichlorodihydrofluorescein diacetate (DCF). The expression levels of pro apoptotic Bax, anti-apoptotic Bcl-2 and caspase3 proteins were also detected by western blotting. Total antioxidant power (TAP), total thiol molecules (TTM) and lipid peroxidation (LPO) were also evaluated. RESULTS: CeO2 and Y2O3 increased survival of undifferentiated PC12 cells exposed to high glucose-induced oxidative stress. CeO2 and Y2O3 pre-treatment decreased ROS production, LPO, Bax and caspase-3 proteins expression. Both nanoparticles have also increased the TTM and Bcl-2 protein expression. DISCUSSION: These findings suggest that CeO2 and Y2O3 protect the undifferentiated PC12 cells against the oxidative stress and apoptosis induced by high glucose. PMID- 25786673 TI - Anatomical Variations in the Posterior Circle of Willis and Vascular Pathologies in Isolated Unilateral Thalamic Infarction. AB - BACKGROUND AND PURPOSE: To characterize relations between configurations of the posterior part of the Circle of Willis (CoW) and the occurrence of unilateral thalamic infarction. METHODS: From a magnetic resonance imaging report database, we identified and analyzed 111 patients with acute isolated unilateral thalamic infarction on diffusion-weighted imaging (DWI). Vascular pathologies were noted on magnetic resonance angiography (MRA) and the diameter of the posterior communicating artery (PComA) and the P1 and P2 segments of the posterior cerebral artery determined. RESULTS: Most infarctions were observed in the territory of the inferolateral arteries (70.2%), followed by the paramedian (16.3%), tuberothalamic (8.7%), and posterior choroidal arteries (4.8%). Relevant vascular pathologies included stenosis of the basilar artery (4.5%), P1 segment stenosis (4.5%)/occlusion (.9%), and P2 segment stenosis (14.4%)/occlusion (4.5%). Paramedian thalamic infarction was associated with ipsilateral P1 segment hypoplasia/absence (P < .001); tuberothalamic infarction with ipsilateral PComA hypoplasia/absence (P = .08). Furthermore, the diameter of the relevant CoW segment was smaller in patients with ipsilateral thalamic infarction. CONCLUSIONS: Assessment of CoW configuration on MRA may be helpful to understand the appearance of unilateral thalamic stroke independent from stroke etiology. A smaller diameter of the relevant CoW segment might be a risk factor for ipsilateral thalamic stroke in the corresponding thalamic vascular territory. PMID- 25786674 TI - Long-term durability of pericardial valves in the aortic position in younger patients: when does reoperation become necessary? AB - BACKGROUND: We sought to assess the long-term durability of pericardial valves in patients at age <65 years undergoing aortic valve replacement (AVR), and to determine the timing of redo operations due to structural valve deterioration (SVD). METHODS: From 1986 to 2001, a total of 574 adult patients underwent AVR with pericardial valves in nine hospitals in Japan. Of these, 53 patients were at age <65 years (group Y). These patients were compared with those of age >= 65 (group O, n = 521). RESULTS: The mean follow-up duration was 9.5 years in group Y and 8.1 years in group O. Freedom from reoperation due to SVD was 100% at five years, 90.8% at 10 years, and 47.2% at 15 years in group Y, and 99.3% at five years, 97.4% at 10 years, and 94.4% at 15 years in group O (log-rank test, p < 0.01). In those who required redo AVR in group Y (n = 12), the mean time from initial operation to reoperation was 12.1 years. The reoperation-free survival curve started to decline after eight years postoperation in group Y. CONCLUSIONS: Redo AVR started to become necessary eight years after surgery in the patients who underwent AVR with pericardial valve at age <65 years. In addition, approximately half of those patients required reoperation due to SVD by 15 years postoperatively. PMID- 25786675 TI - The somatotopy of tic inhibition: Where and how much? AB - BACKGROUND: Tics are the hallmark feature of Tourette syndrome. The basic phenomenological and neurophysiological characteristics of tics have been widely investigated. Interestingly, the spatial distribution of tics across different body parts has received little attention. No previous study has investigated whether the capacity for voluntary tic inhibition also varies across body parts. METHODS: We analyzed video sequences of 26 adolescents with Tourette syndrome in a "tic freely" condition, and in a "voluntary tic inhibition" condition, to obtain absolute tic counts for different body parts. Two measures of the spatial distribution of tics were then analyzed. Linear regression analyses were employed to investigate the relation between the contribution of each body part to overall tic behavior and the ability to inhibit tics in that body part, averaged over our patient group. RESULTS: Tic distribution across patients showed a characteristic somatotopic pattern, with the face most strongly represented. A significant negative relation was found between the ability to inhibit tics and pooled tic frequency across body parts. The body parts that exhibited the fewest tics were the ones for which tic inhibition was most effective. CONCLUSIONS: Our data are consistent with the idea that tic recruitment order reflects a "tic generator" spreading across a somatotopic map in the brain. Voluntary tic inhibition did not simply cause a proportional reduction of tics in each body part. Rather, the least affected body parts showed most effective voluntary tic inhibition. The results are discussed in terms of signal and noise within cortical-subcortical motor loops. PMID- 25786676 TI - Clinical aspects of indirect immunofluorescence for autoimmune diseases. AB - Because the most common term used in conversations considering autoimmunity is autoantibodies, it is well-expected that the indirect immunofluorescence assay, which detects antibodies directed against various antigens, is one of our most impressive techniques for investigating autoimmune diseases (AIDs). Roughly speaking, the current literature corroborates that this immunopathologic investigation means that autoantibodies detection makes a considerable contribution to both diagnostic and prognostic aspects of AIDs in the clinical setting. However, it varies between different AIDs, autoantibodies, ethnicities or detection methodologies. Directly focusing on the indirect immunofluorescence assay, we present evidence to support this multidimensional variation regarding the subject via reviewing briefly the best-investigated autoantibodies in the well-documented AIDs, including vasculitis, inflammatory bowel disease, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, systemic lupus erythematosus and Sjogren's syndrome. PMID- 25786677 TI - High survival of mouse oocytes/embryos after vitrification without permeating cryoprotectants followed by ultra-rapid warming with an IR laser pulse. AB - Vitrification is now the main route to the cryopreservation of human and animal oocytes and preimplantation embryos. A central belief is that for success, the cells must be placed in very high concentrations of cryoprotective solutes and must be cooled extremely rapidly. We have shown recently that these beliefs are incorrect. Over 90% of mouse oocytes and embryos survive being cooled relatively slowly even in solutions containing only 1/3(rd) the normal solute concentrations, provided that they are warmed ultra-rapidly at 10(7) degrees C/min by a laser pulse. Nearly all vitrification solutions contain both permeating and non-permeating solutes, and an important question is whether the former protect because they permeate the cells and promote intracellular vitrification (as is almost universally believed), or because they osmotically withdraw a large fraction of intracellular water prior to cooling. The answer for the mouse system is clearly the latter. When oocytes or embryos are placed in 1 molal concentrations of the impermeable solute sucrose, they osmotically lose ~85% of their cellular water in less than 2 minutes. If the cells are then cooled rapidly to -196 degrees C, nearly 90% remain viable after warming, again provided that the warming is ultra rapid. PMID- 25786678 TI - Pre-operative fibrinogen supplementation in cardiac surgery patients. More is not always better. PMID- 25786679 TI - Transversus abdominis plane block vs. wound infiltration in Caesarean section: a randomised controlled trial. AB - BACKGROUND: Multiple studies suggest that transversus abdominis plane (TAP) block (without intrathecal morphine) after Caesarean section (CS) reduces post operative morphine consumption. In our study, we wanted to compare the analgesic effect of TAP block with infiltration of the wound after CS. METHODS: We included 60 pregnant women scheduled for elective CS under spinal anaesthesia in a randomised, single-centre, double-blind study. Thirty patients received ultrasound-guided TAP block using 20 ml bupivacaine 0.25% with adrenaline 5 MUg/ml bilaterally and 20 ml normal saline as wound infiltration (TAP group). The other 30 patients (the control group) received normal saline 20 ml bilaterally in the TAP, and 20 ml bupivacaine 0.25% with adrenaline 5 MUg/ml as wound infiltration. The main outcome was cumulative morphine consumption at 48 h after surgery. In addition, continuous morphine consumption, pain scores and side effects were registered. RESULTS: Fifty-seven patients completed the study. Cumulative morphine consumption at 48 h (mean+/-standard deviation) was 41+/-34 mg in the TAP group and 38+/-27 mg in the control group (P=0.7); a difference of 3 mg (95% confidence interval -13 to 19 mg). Morphine consumption at any time up to 48 h was virtually identical in both groups. Side effects were similar, except for a higher degree of sedation in the TAP group (P=0.04). CONCLUSION: Compared with wound infiltration with local anaesthetics, TAP block did not reduce cumulative morphine consumption following CS. The TAP block was associated with more pronounced sedation. PMID- 25786680 TI - Peripheral venous lactate at admission is associated with in-hospital mortality, a prospective cohort study. AB - BACKGROUND: The prognostic value of blood lactate as a predictor of adverse outcome in the acutely ill patient is unclear. The aim of this study was to investigate if a peripheral venous lactate measurement, taken at admission, is associated with in-hospital mortality in acutely ill patients with all diagnosis. Furthermore, we wanted to investigate if the test improves a triage model in terms of predicting in-hospital mortality. METHODS: We retrieved a cohort of 2272 adult patients from a prospectively gathered acute admission database. We performed regression analysis to evaluate the association between the relevant covariates and the outcome measure: in-hospital mortality. RESULTS: Lactate as a continuous variable was a risk for in-hospital mortality with an odds ratio (OR) of 1.40 [95% confidence interval (CI) 1.25-1.57, P<0.0001]. OR for in-hospital mortality increased with increasing lactate levels from 2.97 (95% CI 1.55-5.72, P<0.001) for lactate between 2 mmol/l and 4 mmol/l, to 7.77 (95% CI 3.23-18.66, P<0.0001) for lactate>4 mmol/l. If the condition was non-compensated (i.e. pH<7.35), OR for in-hospital mortality increased to 19.99 (7.26-55.06, P<0.0001). Patient with a blood lactate at 4 mmol/l or more had a risk of in-hospital mortality equivalent to the patients in the most urgent triage category. CONCLUSION: We found elevated admission peripheral venous lactate to be independently associated with in-hospital mortality in the acutely ill patient admitted to the emergency department. Patients with a lactate>4 mmol/l at hospital admission should be considered triaged to the most urgent triage category. PMID- 25786682 TI - Correlation of two-photon in vivo imaging and FIB/SEM microscopy. AB - Advances in the understanding of brain functions are closely linked to the technical developments in microscopy. In this study, we describe a correlative microscopy technique that offers a possibility of combining two-photon in vivo imaging with focus ion beam/scanning electron microscope (FIB/SEM) techniques. Long-term two-photon in vivo imaging allows the visualization of functional interactions within the brain of a living organism over the time, and therefore, is emerging as a new tool for studying the dynamics of neurodegenerative diseases, such as Alzheimer's disease. However, light microscopy has important limitations in revealing alterations occurring at the synaptic level and when this is required, electron microscopy is mandatory. FIB/SEM microscopy is a novel tool for three-dimensional high-resolution reconstructions, since it acquires automated serial images at ultrastructural level. Using FIB/SEM imaging, we observed, at 10 nm isotropic resolution, the same dendrites that were imaged in vivo over 9 days. Thus, we analyzed their ultrastructure and monitored the dynamics of the neuropil around them. We found that stable spines (present during the 9 days of imaging) formed typical asymmetric contacts with axons, whereas transient spines (present only during one day of imaging) did not form a synaptic contact. Our data suggest that the morphological classification that was assigned to a dendritic spine according to the in vivo images did not fit with its ultrastructural morphology. The correlative technique described herein is likely to open opportunities for unravelling the earlier unrecognized complexity of the nervous system. PMID- 25786683 TI - The promyelinating properties of androstenediol in gliotoxin-induced demyelination in rat corpus callosum. AB - AIMS: Experimental evidence has shown that the adrenal steroid hormone, androstenediol, dampens the symptoms of demyelination. However, the cellular and molecular effects of androstenediol are not yet known. In the present study, we investigated the cellular and subcellular effects of this hormone in a gliotoxin induced demyelination model. METHODS: Male Sprague Dawley rats received 2 MUl of either saline or the gliotoxin ethidium bromide (EB, 0.04%) into the corpus callosum. These rats received daily subcutaneous injections of either oil or androstenediol (5 mg/kg). Their brains were collected at 2, 7, 14 and 28 days post-EB injection. Demyelinated lesions were assessed using Luxol fast blue staining. Immunofluorescent staining was used to investigate the number of oligodendrocyte progenitor cells, their maturation and microglial activation at the lesion site. Remyelination was further explored using transmission electron microscopy. The expression levels of total and phosphorylated MBP isoforms and CNPase were explored using western blot. RESULTS: Androstenediol decreased the size of demyelinated lesions in the corpus callosum at 7 and 14 days post-EB injection. It enhanced the number of oligodendrocyte precursor cells, promoted an increase in the number of mature oligodendrocytes and reduced microglial activation. Androstenediol also stimulated the phosphorylation of MBP at the site of the lesion and promoted remyelination of the affected axons. CONCLUSIONS: These data strongly suggest that androstenediol is endowed with promyelinating properties in a model of focal gliotoxin-induced demyelination. It induces its promyelinating effects by enhancing the number of oligodendrocyte precursor cells and their maturation at the lesion site. PMID- 25786684 TI - Limbus- versus fornix-based trabeculectomy for open-angle glaucoma eyes with prior ocular surgery: the Collaborative Bleb-Related Infection Incidence and Treatment Study. AB - We compared the surgical successes of limbus- and fornix-based trabeculectomies in open-angle glaucoma (OAG) eyes that had prior ocular surgery in the Collaborative Bleb-Related Infection Incidence and Treatment Study (CBIITS), Japan. From the 1,098 glaucoma eyes in 34 clinical centers in CBIITS, 195 OAG eyes that had undergone previous trabeculectomy and/or lens extraction were included. Limbus- or fornix-based trabeculectomy with mitomycin C were performed. Surgical failure (IOP >= 21, 18, or 15 mmHg for criterion A, B or C, respectively; <20% decrease from baseline; reoperation for glaucoma; or loss of light perception vision) was counted. There were 106 and 89 eyes treated with limbus- and fornix-based trabeculectomies, respectively. At 3 years, IOP (mean +/ SD) was 12.5 +/- 5.9 and 14.1 +/- 6.4 mmHg and the cumulative probabilities of failure during 3 years were 30.2% and 50.5% for criterion A, 40.3% and 57.4% for criterion B, and 57.9% and 65.8% for criterion C in the limbus- and the fornix based group, respectively. Fornix-based incisions were associated with surgical failure in Cox-proportional multivariable analysis for criterion A [relative risk (RR) = 1.96], and B [RR = 1.60]. Limbus-based trabeculectomy had a higher probability of success in OAG eyes with prior ocular surgery. PMID- 25786685 TI - Inhibition of CD40-induced N-Ras activation reduces leishmania major infection. AB - Leishmania major is a parasite that resides and replicates in macrophages. We previously showed that the parasite enhanced CD40-induced Raf-MEK-ERK signaling but inhibited PI3K-MKK-p38MAPK signaling to proleishmanial effects. As Raf and PI3K have a Ras-binding domain but exert opposite effects on Leishmania infection, we examined whether Ras isoforms had differential roles in Leishmania infection. We observed that L. major enhanced N-Ras and H-Ras expression but inhibited K-Ras expression in macrophages. L. major infection enhanced N-Ras activity but inhibited H-Ras and K-Ras activity. TLR2 short hairpin RNA or anti TLR2 or anti-lipophosphoglycan Abs reversed the L. major-altered N-Ras and K-Ras expressions. Pam3CSK4, a TLR2 ligand, enhanced N-Ras expression but reduced K-Ras expression, indicating TLR2-regulated Ras expression in L. major infection. Whereas N-Ras silencing reduced L. major infection, K-Ras and H-Ras silencing enhanced the infection both in macrophages in vitro and in C57BL/6 mice. BALB/c derived macrophages transduced with lentivirally expressed N-Ras short hairpin RNA and pulsed with L. major-expressed MAPK10 enhanced MAPK10-specific Th1-type response. CD40-deficient mice primed with these macrophages had reduced L. major infection, accompanied by higher IFN-gamma but less IL-4 production. As N-Ras is activated by Sos, a guanine nucleotide exchange factor, we modeled the N-Ras-Sos interaction and designed two peptides from their interface. Both the cell permeable peptides reduced L. major infection in BALB/c mice but not in CD40 deficient mice. These data reveal the L. major-enhanced CD40-induced N-Ras activation as a novel immune evasion strategy and the potential for Ras isoform targeted antileishmanial immunotherapy and immunoprophylaxis. PMID- 25786686 TI - Profiling of the three circulating monocyte subpopulations in human obesity. AB - Three subpopulations of circulating monocytes have been described: CD14(2+)CD16( ) (classical monocytes [CM]), CD14(2+)CD16(+) (intermediate monocytes [IM]), and CD14(+)CD16(2+) (nonclassical monocytes [NCM]). We previously showed that obesity is associated with an increased proportion of IM and NCM. Our objective is to decipher the migratory and inflammatory functions of each monocyte subset in obesity-related low-grade inflammation. Twenty-six healthy, normal-weight and nondiabetic volunteers (C) and 40 obese nondiabetic (Ob) individuals were included in this study. We explored the gene expression profile of 18 inflammatory genes in each subset of C and Ob subjects and measured protein expression of the upregulated genes. We then tested their functional response to TLR signaling in both groups. We showed an increased expression of CX3CR1 in all monocyte subpopulations and of CCR2 and CCR5 in CM and IM in the Ob group. We found negative correlation between CCR2 and CX3CR1 expressions and high-density lipoprotein-cholesterol, whereas CCR5 expression was positively linked to obesity related metabolic traits. Production of inflammatory proteins upon bacterial LPS and viral ssRNA stimulation was higher in CM and NCM of the Ob group compared with the C group. Our work highlights an enhanced inflammatory phenotype of monocytes with a higher response to TLR4 and TLR8 stimulations in obesity. Moreover, it suggests an increased migration capacity of CM and IM subpopulations. PMID- 25786687 TI - Cholera toxin, and the related nontoxic adjuvants mmCT and dmLT, promote human Th17 responses via cyclic AMP-protein kinase A and inflammasome-dependent IL-1 signaling. AB - We have examined the molecular pathways involved in the adjuvant action of cholera toxin (CT) and two novel nontoxic molecules, multiple-mutated CT (mmCT) and double-mutant heat-labile toxin (dmLT) on human T cell responses. Human PBMCs or isolated monocytes were stimulated in vitro with CT, mmCT, or dmLT plus a polyclonal stimulus (staphylococcal enterotoxin B) or specific bacterial Ags, and effects on expression of cytokines and signaling molecules were determined. CT, mmCT, and dmLT strongly enhanced IL-17A and to a lesser extent IL-13 responses, but had little effect on IFN-gamma production or cell proliferation. Intracellular cytokine staining revealed that the enhanced IL-17A production was largely confined to CD4(+) T cells and coculture experiments showed that the IL 17A promotion was effectively induced by adjuvant-treated monocytes. Relative to CT, mmCT and dmLT induced at least 100-fold lower levels of cAMP, yet this cAMP was enough and essential for the promotion of Th17 responses. Thus, inhibition of cAMP-dependent protein kinase A was abolished, and stimulation with a cAMP analog mimicked the adjuvant effect. Furthermore, CT, mmCT, and dmLT induced IL-1beta production and caspase-1 activation in monocytes, which was associated with increased expression of key proinflammatory and inflammasome-related genes, including NLRP1, NLRP3, and NLRC4. Inflammasome inhibition with a specific caspase-1 inhibitor, or blocking of IL-1 signaling by IL-1 receptor antagonist, abrogated the Th17-promoting effect. We conclude that CT, mmCT, and dmLT promote human Th17 responses via cAMP-dependent protein kinase A and caspase 1/inflammasome-dependent IL-1 signaling. PMID- 25786688 TI - A critical role for dendritic cells in the evolution of IL-1beta-mediated murine airway disease. AB - Chronic airway inflammation and fibrosis, known as airway remodeling, are defining features of chronic obstructive pulmonary disease and are refractory to current treatments. How and whether chronic inflammation contributes to airway fibrosis remain controversial. In this study, we use a model of chronic obstructive pulmonary disease airway disease utilizing adenoviral delivery of IL 1beta to determine that adaptive T cell immunity is required for airway remodeling because mice deficient in alpha/beta T cells (tcra(-/-)) are protected. Dendritic cells (DCs) accumulate around chronic obstructive pulmonary disease airways and are critical to prime adaptive immunity, but they have not been shown to directly influence airway remodeling. We show that DC depletion or deficiency in the crucial DC chemokine receptor ccr6 both protect from adenoviral IL-1beta-induced airway adaptive T cell immune responses and fibrosis in mice. These results provide evidence that chronic airway inflammation, mediated by accumulation of alpha/beta T cells and driven by DCs, is critical to airway fibrosis. PMID- 25786689 TI - Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes. AB - Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi scidIL2rgamma(null) mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26(+)CD26(+)CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL 26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26(+)CD26(+)CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy. PMID- 25786690 TI - Molecular evolution of hypoallergenic hybrid proteins for vaccination against grass pollen allergy. AB - More than 10% of the population in Europe and North America suffer from IgE associated allergy to grass pollen. In this article, we describe the development of a vaccine for grass pollen allergen-specific immunotherapy based on two recombinant hypoallergenic mosaic molecules, designated P and Q, which were constructed out of elements derived from the four major timothy grass pollen allergens: Phl p 1, Phl p 2, Phl p 5, and Phl p 6. Seventeen recombinant mosaic molecules were expressed and purified in Escherichia coli using synthetic genes, characterized regarding biochemical properties, structural fold, and IgE reactivity. We found that depending on the arrangement of allergen fragments, mosaic molecules with strongly varying IgE reactivity were obtained. Based on an extensive screening with sera and basophils from allergic patients, two hypoallergenic mosaic molecules, P and Q, incorporating the primary sequence elements of the four grass pollen allergens were identified. As shown by lymphoproliferation experiments, they contained allergen-specific T cell epitopes required for tolerance induction, and upon immunization of animals induced higher allergen-specific IgG Abs than the wild-type allergens and a registered monophosphoryl lipid A-adjuvanted vaccine based on natural grass pollen allergen extract. Moreover, IgG Abs induced by immunization with P and Q inhibited the binding of patients' IgE to natural allergens from five grasses better than IgG induced with the wild-type allergens or an extract-based vaccine. Our results suggest that vaccines based on the hypoallergenic grass pollen mosaics can be used for immunotherapy of grass pollen allergy. PMID- 25786691 TI - FOXO1 regulates dendritic cell activity through ICAM-1 and CCR7. AB - The transcription factor FOXO1 regulates cell function and is expressed in dendritic cells (DCs). We investigated the role of FOXO1 in activating DCs to stimulate a lymphocyte response to bacteria. We show that bacteria induce FOXO1 nuclear localization through the MAPK pathway and demonstrate that FOXO1 is needed for DC activation of lymphocytes in vivo. This occurs through FOXO1 regulation of DC phagocytosis, chemotaxis, and DC-lymphocyte binding. FOXO1 induces DC activity by regulating ICAM-1 and CCR7. FOXO1 binds to the CCR7 and ICAM-1 promoters, stimulates CCR7 and ICAM-1 transcriptional activity, and regulates their expression. This is functionally important because transfection of DCs from FOXO1-deleted CD11c.Cre(+)FOXO1(L/L) mice with an ICAM-1-expressing plasmid rescues the negative effect of FOXO1 deletion on DC bacterial phagocytosis and chemotaxis. Rescue with both CCR7 and ICAM-1 reverses impaired DC homing to lymph nodes in vivo when FOXO1 is deleted. Moreover, Ab production following injection of bacteria is significantly reduced with lineage-specific FOXO1 ablation. Thus, FOXO1 coordinates upregulation of DC activity through key downstream target genes that are needed for DCs to stimulate T and B lymphocytes and generate an Ab defense to bacteria. PMID- 25786693 TI - Extreme variability in clinical penetrance for a splice-site Plakophilin-2 mutation in a Bangladeshi family. PMID- 25786694 TI - Epigenetics: Chromatin marks the spot. PMID- 25786692 TI - The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. AB - The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2 dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9. PMID- 25786695 TI - Genomic instability: Building bridges. PMID- 25786698 TI - [Scoring systems for assessment of 30-day mortality after colorectal cancer surgery]. AB - Post-operative mortality from colorectal cancer depends on multiple factors and varies across countries and hospitals. Pre-operative risk prediction can be helpful in surgical decision-making. Several scoring systems have been developed to predict the risk of post-operative mortality. The Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality (P-POSSUM) model and a revised Association of Colo-proctology of Great Britan and Ireland (ACPGBI) model are the most accurate predictors in colorectal cancer surgery. No scoring systems have been validated in the Danish population. PMID- 25786699 TI - [Inhibition of the protein PCSK9 is a promising target in the prevention of cardiovascular disease]. AB - Recent research in genetics has revealed that PCSK9 - which codes for proprotein convertase subtilisin/kexin type 9 (PCSK9) - plays a major role in cholesterol regulatory pathways. Normal genetic variations in PCSK9 have a great impact on low-density lipoprotein cholesterol levels and hence the risk of cardio-vascular disease. This has led to huge efforts in inhibiting PCSK9. Recent clinical phase II trials with monoclonal antibodies against PCSK9 have shown great results for lowering low-density lipoprotein cholesterol levels making the inhibition of PCSK9 a promising target in the prevention of cardiovascular disease. PMID- 25786700 TI - [Periconceptional folic acid prophylaxis and neural tube defects]. AB - Neural tube defects (NTD) affect 60-70 pregnancies each year in Denmark. Folic acid (FA) intake can reduce the risk of NTD in pregnancy. The Danish Health and Medicines Authority recommends Danish women to take 0.4 mg of FA daily periconceptionally. Several studies have found low compliance regarding FA supplementation. In more than 70 countries around the world FA fortification of food products has been introduced and in USA and Canada this has lead to a decrease in NTD. FA fortification has not yet been introduced in Denmark. A revision of national Danish recommendations is needed. PMID- 25786697 TI - Targeting liver X receptors in cancer therapeutics. AB - Members of the nuclear receptor superfamily of ligand-dependent transcription factors carry out vital cellular functions and are highly druggable therapeutic targets. Liver X receptors (LXRs) are nuclear receptor family members that function in cholesterol transport, glucose metabolism and the modulation of inflammatory responses. There is now accumulating evidence to support the involvement of LXRs in a variety of malignancies and the potential efficacy of their ligands in these diseases. This Review summarizes the discovery and characterization of LXRs and their ligands, their effects and mechanisms in preclinical cancer models, and the future directions of basic and translational LXR research in cancer therapeutics. PMID- 25786696 TI - Haematological malignancies: at the forefront of immunotherapeutic innovation. AB - The recent successes of cancer immunotherapies have stimulated interest in the potential widespread application of these approaches; haematological malignancies have provided both initial proofs of concept and an informative testing ground for various immune-based therapeutics. The immune-cell origin of many of the blood malignancies provides a unique opportunity both to understand the mechanisms of cancer immune responsiveness and immune evasion, and to exploit these mechanisms for therapeutic purposes. PMID- 25786701 TI - [Dupuytren's disease treatment]. AB - Dupuytren's disease is a hereditary fibroproliferative disease commonly affecting the palmar fascia of the hand, which results in progressive and irreversibly fixed flexion contractures of the hand. It may occur in the sole of the foot or in the penis. Generally, treatment has been up against a high frequency of complications and recurrence, but promising results are reported from less invasive treatment options, e.g. needle fasciotomy and enzymatic fasciotomy with collagenase. This is a detailed, comparative review of available non-operative and surgical treatments with focus on the enzymatic fasciotomy. PMID- 25786702 TI - [Pharmaceutical drugs containing lactose can as a rule be used by persons with lactose intolerance]. AB - Lactose is often used as an excipient in pharmaceutical drugs. Current evidence indicates that the amount of lactose in most drugs is not sufficient to cause symptoms in persons with lactose intolerance, although interindividual differences in sensitivity probably exist. Patient preferences and/or suboptimal treatment adherence could be reasons for considering lactose-free drug alternatives. PMID- 25786703 TI - Relation between financial market structure and the real economy: comparison between clustering methods. AB - We quantify the amount of information filtered by different hierarchical clustering methods on correlations between stock returns comparing the clustering structure with the underlying industrial activity classification. We apply, for the first time to financial data, a novel hierarchical clustering approach, the Directed Bubble Hierarchical Tree and we compare it with other methods including the Linkage and k-medoids. By taking the industrial sector classification of stocks as a benchmark partition, we evaluate how the different methods retrieve this classification. The results show that the Directed Bubble Hierarchical Tree can outperform other methods, being able to retrieve more information with fewer clusters. Moreover,we show that the economic information is hidden at different levels of the hierarchical structures depending on the clustering method. The dynamical analysis on a rolling window also reveals that the different methods show different degrees of sensitivity to events affecting financial markets, like crises. These results can be of interest for all the applications of clustering methods to portfolio optimization and risk hedging [corrected]. PMID- 25786704 TI - Exposure to a 900 MHz electromagnetic field for 1 hour a day over 30 days does change the histopathology and biochemistry of the rat testis. AB - PURPOSE: To investigate the effect of exposure to a 900 megahertz (MHz) electromagnetic field (EMF) on the rat testicle. MATERIALS AND METHODS: Twenty four adult male rats were divided into control, sham and EMF groups. The EMF group rats were exposed to 900 MHz EMF (1 h/30 day), and testicles were extracted at the end of the experiment. Malondialdehyde, superoxide dismutase, catalase and glutathione levels and apoptotic index and histopathological damage scores were compared. RESULTS: Histopathologically, EMF group rats exhibited vacuoles in seminiferous tubules basal membrane and edema in the intertubular space. Seminiferous tubule diameters and germinal epithelium thickness were both smaller, and apoptotic index was higher, in the EMF group than in the other groups. Malondialdehyde, superoxide dismutase, catalase and glutathione values in the EMF group decreased significantly compared to those of the control group. CONCLUSIONS: The results show that exposure to 900 MHz EMF causes alterations in adult rat testicular morphology and biochemistry. PMID- 25786705 TI - Mental health of adolescents before and after the death of a parent or sibling. AB - The death of a parent or sibling (family bereavement) is associated with mental health problems in approximately, 25 % of the affected children. However, it is still unknown whether mental health problems of family-bereaved adolescents are predicted by pre-existing mental health problems, pre-loss family functioning, or multiple bereavements. In this study, a prospective longitudinal assessment of change in mental health following bereavement was done in a large representative sample from the 'Tracking Adolescents Individual Lives Survey' (TRAILS). This is a four-wave prospective cohort study of Dutch adolescents (n = 2230) of whom 131 (5.9 %) had experienced family bereavement at the last wave (T4). Family-bereaved adolescents reported more internalizing problems, within 2 years after family bereavement, compared to the non-bereaved peers, while taking into account the level of internalizing problems before the bereavement. A clinically relevant finding was that 22 % new cases were found in family-bereaved, in comparison to 5.5 % new cases in non-bereaved. Low SES predicted more internalizing problems in family-bereaved but not in non-bereaved adolescents. Family functioning, reported by the adolescent, did not predict mental health problems within 2 years. Multiple family bereavements predicted fewer externalizing problems. In conclusion, internalizing problems increase in adolescents after family bereavement in comparison to non-bereaved and these can be predicted by pre-loss factors. Awareness among professionals regarding the risks for aggravation of mental health problems after family loss is needed. PMID- 25786706 TI - Trajectories of Posttraumatic Growth and Associated Characteristics in Women with Breast Cancer. AB - BACKGROUND: Cancer survivors may experience posttraumatic growth (PTG), positive psychological changes resulting from highly stressful events; however, the longitudinal course of PTG is poorly understood. PURPOSE: The purpose of the present study was to determine trajectories of PTG in breast cancer survivors and associated characteristics. METHODS: Women (N = 653) participating in a longitudinal observational study completed questionnaires within 8 months of breast cancer diagnosis and 6, 12, and 18 months later. Group-based modeling identified PTG trajectories. Chi-square tests and ANOVA detected group differences in demographic, medical, and psychosocial variables. RESULTS: Six trajectory groups emerged. Three were stable at different levels of PTG, two increased modestly, and one increased substantially over time. Trajectory groups differed by age, race, receipt of chemotherapy, illness intrusiveness, depressive symptoms, active-adaptive coping, and social support. CONCLUSIONS: This first examination of PTG trajectories in US cancer survivors elucidates heterogeneity in longitudinal patterns of PTG. Future research should determine whether other samples exhibit similar trajectories and whether various PTG trajectories predict mental and physical health outcomes. PMID- 25786708 TI - Vascular-targeted photodynamic therapy with TOOKAD(r) Soluble in localized prostate cancer: standardization of the procedure. AB - INTRODUCTION: Vascular-targeted photodynamic therapy with TOOKAD((r)) Soluble is an innovative focal therapy procedure assessed in localized prostate cancer treatment. MATERIALS AND METHODS: This mini-invasive technique destroys targeted tissues using a photosensitizer [TOOKAD((r)) Soluble (WST11), STEBA Biotech] activated by laser light in the presence of oxygen. Its application for prostate cancer requires intravenous infusion of TOOKAD((r)) Soluble and the illumination of the targeted area by transperineal optical fibers inserted under trans-rectal ultrasound guidance under general anesthesia. CONCLUSION: Based on the experience gained through hundreds of procedures, we describe here the standardized technique of vascular-targeted photodynamic therapy with TOOKAD((r)) Soluble defined during the phase II and III trials. PMID- 25786707 TI - The structure of PccH from Geobacter sulfurreducens - a novel low reduction potential monoheme cytochrome essential for accepting electrons from an electrode. AB - The structure of cytochrome c (GSU3274) designated as PccH from Geobacter sulfurreducens was determined at a resolution of 2.0 A. PccH is a small (15 kDa) cytochrome containing one c-type heme, found to be essential for the growth of G. sulfurreducens with respect to accepting electrons from graphite electrodes poised at -300 mV versus standard hydrogen electrode. with fumarate as the terminal electron acceptor. The structure of PccH is unique among the monoheme cytochromes described to date. The structural fold of PccH can be described as forming two lobes with the heme sandwiched in a cleft between the two lobes. In addition, PccH has a low reduction potential of -24 mV at pH 7, which is unusual for monoheme cytochromes. Based on difference in structure, together with sequence phylogenetic analysis, we propose that PccH can be regarded as a first characterized example of a new subclass of class I monoheme cytochromes. The low reduction potential of PccH may enable the protein to be redox active at the typically negative potential ranges encountered by G. sulfurreducens. Because PccH is predicted to be located in the periplasm of this bacterium, it could not be involved in the first step of accepting electrons from the electrode but is very likely involved in the downstream electron transport events in the periplasm. PMID- 25786710 TI - Theoretical and Computational Strategies for the Study of the Molecular Imprinting Process and Polymer Performance. AB - The development of in silico strategies for the study of the molecular imprinting process and the properties of molecularly imprinted materials has been driven by a growing awareness of the inherent complexity of these systems and even by an increased awareness of the potential of these materials for use in a range of application areas. Here we highlight the development of theoretical and computational strategies that are contributing to an improved understanding of the mechanisms underlying molecularly imprinted material synthesis and performance, and even their rational design. PMID- 25786711 TI - Molecularly Imprinted Polymers for Catalysis and Synthesis. AB - The area of biomimetic catalysis based on molecular imprinted polymers has progressed considerably over the last two decades, with research efforts focused on developing catalysts for challenging reactions and on understanding the key factors in template structure and polymer morphology that influence efficiency and selectivity. Recent advances and significant achievements in the field presented in this chapter are organized according to four topics: hydrolytic reactions of challenging substrates, oxidase mimics, metallo-enzyme mimics, and polymers that display unusual reactivity, such as in the case of reactions for which enzymes don't exist, such as Diels-Alder and Kemp elimination. For each theme, significant examples for recent literature are presented and discussed. PMID- 25786709 TI - Low prevalence of HPV detection and genotyping in non-muscle invasive bladder cancer using single-step PCR followed by reverse line blot. AB - PURPOSE: To clarify the role of human papillomavirus (HPV) in non-muscle invasive bladder cancer, HPV-DNA was scrutinized in formalin-fixed, paraffin-embedded (FFPE) bladder cancer tissue using single-step PCR (HPV L1) for HPV detection, followed by reverse line blot (RLB) for genotyping. METHODS: A total of 186 patients who underwent transurethral resection of the bladder due to primary, non muscle invasive bladder cancer from 2006 to 2009 were reviewed. A positive control group of 22 cervical tissues with cervical carcinoma was included. RESULTS: Histology confirmed urothelial carcinoma in all patients: primary CIS, pTa, pT1 and pTa + pT1 in 14 (7.5 %), 134 (72 %), 36 (19.4 %) and two (1.1 %) patients, respectively. A total of 119 (63.9 %) of them were classified as low risk, while 67 (36.1 %) were high-risk cancers. Tumor recurrence and progression (>=pT2) were seen in 79 and 11 patients (mean follow-up 45 months). The presence of HPV-DNA by single-step PCR was detected in four (2.2 %) patients. HPV 16 and HPV 6 were positive in two (1.1 %) and one (0.6 %) patient, respectively In one case, no HPV genotype listed on the RLB assay could be identified. In the control group, the HPV infection rate was 100 %: HPV 16 in 12 (54.6 %) patients, HPV 16/18 in four (18.3 %) patients, HPV 18 in two (9.1 %) patients, HPV 16/45 in one patient (4.5 %), HPV 18/33 in one (4.5 %) patient, HPV 16/33 in one (4.5 %) patient and HPV 33 in one (4.5 %) patient. CONCLUSIONS: Our study demonstrates low prevalence of HPV infection in FFPE bladder cancer tissue, arguing against the etiological role of HPV in non-muscle urothelial carcinogenesis. PMID- 25786712 TI - Rheology of Lignocellulose Suspensions and Impact of Hydrolysis: A Review. AB - White biotechnologies have several challenges to overcome in order to become a viable industrial process. Achieving highly concentrated lignocellulose materials and releasing fermentable substrates, with controlled kinetics in order to regulate micro-organism activity, present major technical and scientific bottlenecks. The degradation of the main polymeric fractions of lignocellulose into simpler molecules is a prerequisite for an integrated utilisation of this resource in a biorefinery concept. The characterisation methods and the observations developed for rheology, morphology, etc., that are reviewed here are strongly dependent on the fibrous nature of lignocellulose, are thus similar or constitute a good approach to filamentous culture broths. This review focuses on scientific works related to the study of the rheological behaviour of lignocellulose suspensions and their evolution during biocatalysis. In order to produce the targeted molecules (synthon), the lignocellulose substrates are converted by enzymatic degradation and are then metabolised by micro-organisms. The dynamics of the mechanisms is limited by coupled phenomena between flow, heat and mass transfers in regard to diffusion (within solid and liquid phases), convection (mixing, transfer coefficients, homogeneity) and specific inhibitors (concentration gradients). As lignocellulose suspensions consist of long entangled fibres for the matrix of industrial interest, they exhibit diverse and complex properties linked to this fibrous character (rheological, morphological, thermal, mechanical and biochemical parameters). Among the main variables to be studied, the rheological behaviour of such suspensions appears to be determinant for process efficiency. It is this behaviour that will determine the equipment to be used and the strategies applied (substrate and biocatalysis feed, mixing, etc.). This review provides an overview of (i) the rheological behaviour of fibrous materials in suspension, (ii) the methods and experimental conditions for their measurements, (iii) the main models used and (iv) their evolution during biocatalytic reactions with a focus on enzymatic hydrolysis. PMID- 25786713 TI - Erosive pustular dermatosis of the scalp and thigh associated with skin graft recipient and donor sites. PMID- 25786714 TI - Comparison of systemic mycophenolate mofetil with topical clobetasol in lichen planopilaris: a parallel-group, assessor- and analyst-blinded, randomized controlled trial. AB - INTRODUCTION: Lichen planopilaris (LPP) is the most common cause of inflammatory immune-mediated cicatricial alopecia. If not diagnosed and treated properly, it may lead to irreversible hair loss with a devastating impact on quality of life. However, treatment can be a challenge. In an area lacking these sorts of studies, we conducted a randomized controlled trial (RCT) to study the tolerability and therapeutic effects of topical clobetasol versus systemic mycophenolate mofetil (MMF). METHODS: A randomized, assessor- and analyst-blinded controlled trial was conducted in 60 patients with LPP in Razi Dermatology Hospital, Tehran, Iran, between February and December 2013. Patients were treated with clobetasol lotion 0.05 % applied at night or oral MMF 2 g/day and were followed for 6 months. The Lichen Planopilaris Activity Index (LPPAI) was the primary measure of response to treatment. RESULTS: Systemic MMF and topical clobetasol were equally effective in reducing the LPPAI over 6 months of treatment. Treatment tolerability was excellent in both groups and no serious irreversible adverse effects were detected. Satisfaction with treatment rose in the MMF group over time; however, it declined in the clobetasol group. CONCLUSION: Given the similar efficacy profiles, topical clobetasol seems to be a more suitable and reasonable choice for treatment of LPP than MMF. PMID- 25786715 TI - Teaching old dogma with new tricks and technology: educational paradigm shifts in graduate medical education. PMID- 25786716 TI - Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model. AB - Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. Recently, we showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated siBcl 2-lipoplex in DLD-1 solid tumor mouse model. In this study, to extend our work, we investigated the effect of metronomic S-1 dosing on the intratumoral accumulation and, thereby, therapeutic efficacy of PEG-coated siAgo2-lipoplex in Lewis lung carcinoma cells (LLCC) solid tumor mouse model. Also, we tried to elucidate the probable mechanism of the enhanced intratumoral accumulation of PEG coated siRNA-lipoplexes induced by S-1 combination therapy. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG coated siAgo2-lipoplexes into a LLCC solid tumor. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes resulted in potent tumor growth suppression. These findings offer proof-of-concept for the improved systemic delivery of PEG-coated siRNA-lipoplexes by metronomic S-1 dosing in whatever tumor model used, and this may pose a promising therapeutic strategy to conquer cancer progression. PMID- 25786717 TI - Sampling of disease biomarkers from skin for theranostic applications. AB - Dermatological diseases including psoriasis, eczema, infections, and cancer collectively constitute a large category of human conditions. The large area and ease of access of skin open excellent opportunities for theranostic applications, that is, diagnosis as well as therapy of the disease. Such applications can be based on evaluation of skin's molecular composition in terms of proteins, nucleic acids, and small molecules. Currently, however, such molecular information is not used in clinical practice. To bring this molecular information to routine clinical dermatology, it is essential to develop convenient and minimally invasive methods for rapid sampling molecules from skin. Here, we demonstrate an ultrasonic sampling technique that can recover a wide variety of biomolecules from skin in a minimally invasive manner. We show that ultrasound can retrieve nearly all major tissue constituents, including structural and functional proteins (cytokines, keratins, etc.), lipids (polar and non-polar lipids), and nucleic acids (DNA and RNA). Comparative analyses of skin's molecular constituents obtained by ultrasonic sampling and skin homogenate showed high resemblance between the two biomolecular profiles, enabling us to build a unique molecular signature of skin. Using different mouse models of dermatological conditions, the ultrasonic analysis for changes in the molecular composition of skin confirmed specific regulation of several established biomarkers. PMID- 25786718 TI - A novel nanoparticle formulation overcomes multiple types of membrane efflux pumps in human breast cancer cells. AB - Multidrug resistance (MDR) in cancer cells can involve overexpression of different types of membrane drug efflux pumps and other drug resistance mechanisms. Hence, inhibition of one resistance mechanism may not be therapeutically effective. Previously we demonstrated a new polymer lipid hybrid nanoparticle (PLN) system was able to circumvent drug resistance of P glycoprotein (P-gp) overexpressing breast cancer cells. The objectives of the present study were 2-fold: (1) to evaluate the ability of the PLN system to overcome two other membrane efflux pumps-multidrug resistance protein 1 (MRP1+) and breast cancer resistance protein (BCRP+) overexpressed on human breast cancer cell lines MCF7 VP (MRP1+) and MCF7 MX (BCRP+); and (2) to evaluate possible synergistic effects of doxorubicin (Dox)-mitomycin C (MMC) in these cell lines. These objectives were accomplished by measuring in vitro cellular uptake, intracellular trafficking, and cytotoxicity (using a clonogenic assay and median effect analysis), of Dox, MMC, or Dox-MMC co-loaded PLN. Treatment of MDR cells with PLN encapsulating single anticancer agents significantly enhanced cell kill compared to free Dox or MMC solutions. Dox-MMC co-loaded PLN were 20-30-folds more effective in killing MDR cells than free drugs. Co-encapsulated Dox-MMC was more effective in killing MDR cells than single agent-encapsulated PLN. Microscopic images showed perinuclear localization of fluorescently labelled PLN in all cell lines. These results are consistent with our previous results for P gp overexpressing breast cancer cells suggesting the PLN system can overcome multiple types of membrane efflux pumps increasing the cytotoxicity of Dox-MMC at significantly lower doses than free drugs. PMID- 25786719 TI - Evaluation of a perforated drug delivery system in mice for prolonged and constant release of a hydrophilic drug. AB - A drug delivery system (DDS) consisting of a perforated microtube (polyimide, inside diameter = 1.8 mm, tube length = 20 mm, hole size = 0.15 mm) was characterized in vitro and in vivo for its usefulness for long-term release of hydrophilic drugs at a constant rate. Sodium fluorescein mixed with stearic acid was used as the model drug. The DDS was packed with sodium fluorescein and stearic acid in ratios of 50:50, 40:60, and 25:75, respectively, and in vitro drug release studies were performed in saline. Linear release rates with R (2) > 0.9700 were obtained for all groups. Release rates of 1,077.3 +/- 264.6, 342.6 +/ 146.4, and 14.4 +/- 7.0 MUg/day for sodium fluorescein were obtained from the three groups, respectively. After monitoring the in vitro release of fluorescein for 11 days, 7 tubes from the 40:60 group were implanted subcutaneously in each individual mice to study the in vivo release of fluorescein from the tubes by measuring the fluorescein in the urine for 84 days. An initial rapid release during the first 4 days was followed by a near zero order fluorescence from the tubes (R (2) = 0.9870). Following completion of the study, the DDSs were retrieved for histology. Morphological analysis indicated no clinical adverse reaction at the site of device implantation specific to the device. The DDS was found to be biocompatible and capable of long-term constant release of a hydrophilic drug such as sodium fluorescein. PMID- 25786720 TI - Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model. AB - Quercetin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Qu-NP) were prepared by emulsion-diffusion-evaporation method and characterized as 179.9 +/- 11.2 nm in size with 0.128 as polydispersity index, more than 86% drug entrapment efficiency, and zeta potential was -6.06 +/- 1.51 mV. D-Trehalose (5% w/v) was found to be a suitable cryoprotectant for lyophilization of Qu-NP, and antioxidant assays indicated that Qu-NP were able to retain the antioxidant property similar to that of free drug at equivalent concentration after formulation development. In vitro release study of Qu-NP showed a controlled release pattern of quercetin. An enhanced oral bioavailability (523% relative increase) was observed in pharmacokinetic study with a 6-day sustained release from Qu-NP as compared to quercetin suspension, which indicated the reduced dosing frequency. Efficacy in diabetic rats suggested that same dose of Qu-NP on every fifth day was sufficient to bring effect similar to daily dose of oral quercetin suspension, and the same effect was also observed for catalase and superoxide dismutase levels in pancreas and kidneys. Thus, the system offers an efficacious oral therapy with reduced dose and dosing frequency for treatment of diabetes and is hence patient compliant. PMID- 25786721 TI - Suppression of cytokine gene expression and improved therapeutic efficacy of microemulsion-based tacrolimus cream for atopic dermatitis. AB - Tacrolimus ointment being occlusive is known to give higher dermal penetration but offers limited patient acceptance in treatment of atopic dermatitis, especially in tropical countries. Hence, the aim of this study was to develop, characterize, and evaluate a microemulsion-based cream formulation of tacrolimus against ointment in hapten-induced murine model of dermatitis. Tacrolimus-loaded microemulsion having mean globule size below 25 nm was mixed with cetomacrogol cream base. The microemulsion-based cream exhibited a significantly faster drug release through semipermeable cellulose acetate membrane in comparison to commercially available ointment. The drug retention in rodent and human cadaver skin with cream was almost twofold greater in comparison to the commercially available ointment. Further, in vivo evaluation using a fluorescent marker revealed a greater and deeper accumulation of marker in skin with cream. In vivo studies in mice revealed a prompt and significant reduction in ear swelling. The reduction in inflammatory cytokine gene expression as evaluated by semiquantitative reverse transcriptase polymerase chain reaction was also significantly higher with cream. The better efficacy of cream was reflected in histopathology as well as in morphological observations at the site of application. Thus, microemulsion-based cream presents a possibility of development of an efficacious cream vehicle and a scope for dose reduction which needs to be confirmed in clinical studies. PMID- 25786722 TI - [Perineoscrotal gangrene after a snake bite: a case report]. AB - The authors describe a case of perinoscrotal gangrene in a patient who had been bitten by a snake. He was treated with antivenom immunotherapy and surgery. The outcome was good. They present a brief review of the literature regarding the epidemiological, clinical, and treatment issues. PMID- 25786723 TI - State Variation in the Delivery of Comprehensive Services for Medicaid Beneficiaries with Schizophrenia and Bipolar Disorder. AB - Medicaid beneficiaries with schizophrenia and bipolar disorder require a range of services and supports. This descriptive study used 2007 Medicaid claims data from 21 states and the District of Columbia to examine the extent to which this population received guideline-concordant medications, medication monitoring, outpatient mental health care, and preventive physical health care. More than 80 % of beneficiaries in each state filled at least one prescription for a guideline concordant medication during the year but, on average, only 57 % of those with schizophrenia and 45 % of those with bipolar disorder maintained a continuous supply of medications. Roughly 25 % did not have an outpatient mental health visit during the year (excluding case management and some other services); in some states more than half did not have such a visit. Only 11 % of beneficiaries received a physical health examination or health behavior counseling when claims codes were used to identify these services rather than all primary care physician visits. Less than 5 % of beneficiaries maintained their supply of medications, received medication monitoring and had an outpatient mental health visit, physical health examination or received health behavior counseling during the year. Although these rates of service utilization are likely conservative and the data predate recent efforts to integrate care, the findings underscore the need for quality improvement efforts targeted to this population and may provide a baseline for monitoring progress. PMID- 25786724 TI - Bioavailability, bioequivalence, and in vitro-in vivo correlation of oxybutynin transdermal patch in rabbits. AB - The first objective of the proposed research work includes comparative bioavailability and bioequivalence evaluation of oxybutynin transdermal patch with respect to different permeation enhancers. The second objective was to evaluate different in vitro methods along with synthetic membranes toward development of an in vitro-in vivo correlation. Oleic acid (fatty acid), Soluphor P (2-pyrrolidone, cosolvent), menthol (volatile oil), and dipropylene glycol (plasticizer) were selected as representatives from different classes of permeation enhancers. A random, crossover, single-dose pharmacokinetic study was carried out on male New Zealand white rabbits to determine bioavailability and bioequivalence. The obtained pharmacokinetic data were correlated with in vitro drug release using convolution-deconvolution approach. All developed formulations were found to be bioequivalent with respect to the marketed patch (Oxytrol(r)) on the basis of level of C max, AUC0-96, and AUCtotal (0.8-1.25). A biphasic linear correlation was obtained pertaining to differential diffusion behavior of the drug in vivo during the experimental timeframe. Because of close resemblance to skin, Cuprophan(r) membrane was found to be more suitable for developing an IVIVC than Millipore(r) membrane. PMID- 25786725 TI - Fabrication and statistical optimization of a polysaccharide-based sublingual film of buprenorphine hydrochloride for breakthrough pain management: in vitro and in vivo performance. AB - A typical breakthrough pain episode is severe, categorized by a fast onset, typically reaches peak intensity instantly, and lasts for an average duration of about 30 min. The research work includes the use of opioid for the treatment of breakthrough pain with special emphasis on the development of rapidly dissolving sublingual film formulation of buprenorphine hydrochloride (BPH). BPH is an opioid analgesic with low oral bioavailability due to less absorption and first pass metabolism. The clear and transparent sublingual films were prepared using a film-forming polymer (pullulan) with a plasticizer (PEG 400). The formulation was optimized statistically using 3(2) randomized full factorial design. The optimized film formulation showed desired mechanical properties (tensile strength of 25 N/m(2)) and a minimum disintegration time of 16 s. Differential scanning calorimetry and X-ray diffraction studies confirmed the uniform distribution of the drug in polymeric matrices. Morphological study showed the absence of drug crystals on polymeric surface. The relative bioavailability of the film formulation was increased by 10 % with respect to tablet formulation due to rapid T max (0.08 h for film while 0.15 h for tablet), which was confirmed by in vivo studies performed on rabbits. The present technology could be a promising alternative to conventional drug delivery systems and traditional routes of administration for breakthrough pain management. PMID- 25786726 TI - Reliability and accuracy of intradermal injection by Mantoux technique, hypodermic needle adapter, and hollow microneedle in pigs. AB - We compared the ability of three intradermal delivery devices to administer an intended dose to pig skin in vivo and target that dose to the dermal rather than subcutaneous layers. The three devices were a standard hypodermic needle and syringe for the Mantoux technique, an adapter designed to facilitate proper hypodermic needle and syringe use, and a hollow microneedle. Reliability was determined as the percentage of the administered dose that entered the skin, as opposed to remaining in the device or on the skin surface. The intradermal adapter (97.6 +/- 1.5 % delivered, mean +/- standard deviation), Mantoux technique (95.4 +/- 4.9 %), and hollow microneedle (94.9 +/- 0.3 %) exhibited similar reliability. Accuracy was determined as the percentage of the dose that entered the skin that localized in the dermis. All three devices achieved similar accuracy: hollow microneedle (99 +/- 12 % delivered to the dermis, median +/- standard deviation), Mantoux technique (97 +/- 16 %), and intradermal adapter (92 +/- 21 %). We conclude that intradermal injection by all three methods studied provided reliable delivery to the skin and provided accurate localization of delivery within the dermis. Next-generation designs of these devices have now received clearance from the FDA and are used as medical products and/or in clinical trials. PMID- 25786727 TI - Investigation of the transdermal transport of charged local anesthetics in the presence of triterpene saponin glycosides. AB - Percutaneous absorption and transdermal delivery of water-soluble drugs have proven to be challenging due to their low permeability through skin. Avicins which are triterpene saponin glycosides (TSGs) derived from the desert plant Acacia victoriae have not been investigated to date as chemical penetration enhancers due to their higher molecular weight (MW 2,000 Da). It was recently shown that avicins exhibit remarkable mobility across skin lipids in spite of their large size due to their unique chemical structure. In this study, the permeation of local anesthetics, lidocaine-HCl, prilocaine-HCl, and bupivacaine HCL from aqueous vehicle, across full-thickness porcine skin was investigated in the presence of F094-a mixture of avicins. F094 was capable of enhancing the permeability of all three anesthetics from aqueous formulations at extremely low concentrations ranging from 0.1 to 1 % w/v. The enhancement, which ranged from 2- to 5-fold, was surprisingly independent of molecular weight of the anesthetics and showed clear correlation with aqueous phase solubility of the anesthetics. Since F094 was found to have no impact on the octanol/water partition coefficients of the anesthetics, this suggests that TSGs like avicins most likely impact the aqueous pathways (pericellular/pores within lipids) and as such represent an alternative means of enhancing the transdermal transport of charged drugs from water-based formulations. PMID- 25786728 TI - In vitro evaluation of polyethylene glycol based microparticles containing azithromycin. AB - The objectives of the present investigation are (1) to screen the liquid and solid polyethylene glycol (PEG) molecules able to produce microparticles by cold or hot dispersion method either with or without other excipients, and (2) to evaluate the in vitro activities [like thermodegradation at three different storage conditions, dissolution using a membrane-free dissolution model in artificial tear fluid or phosphate buffer solution of pH 7.4, and zone-inhibition assay using Eschericella coli and red blood cells (RBC) rupturing assay] of azithromycin (AZM)-loaded microparticles in comparison to AZM alone. Adding chitosan and propylene glycol into PEG 6000 led to the formation of spherical shaped microparticles. Keeping the drug alone in phosphate buffer solution of pH 7.4 at three different storage conditions did show degradation and thus precipitation whereas incorporating the drug into microparticles did not. The microparticles showed a drug release profile that was completely in a retarded style when compared to the release profile of drug alone. The antimicrobial activity of AZM was not affected after incorporating it into microparticles as shown in the zone-inhibition assay. Nevertheless, the microparticles reduced markedly the RBC rupturing property of the drug in comparison to drug in phosphate buffer solution of pH 7.4 (hemolysis percentage values of 27.41 +/- 4.1and 43.11 +/- 7.6, respectively). This indicates that the microparticles prepared based on PEG, chitosan and propylene glycol could be of a suitable carrier to protect AZM from thermodegradation, to provide retardation in drug release, to preserve antimicrobial activity, and to reduce RBC rupturing effect of the drug. PMID- 25786729 TI - An injectable, in situ forming type II collagen/hyaluronic acid hydrogel vehicle for chondrocyte delivery in cartilage tissue engineering. AB - In this study, chondrocytes were encapsulated into an injectable, in situ forming type II collagen/hyaluronic acid (HA) hydrogel cross-linked with poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4SPEG) and supplemented with the transforming growth factor beta1 (TGFbeta1). The chondrocyte-hydrogel constructs were cultured in vitro for 7 days and studied for cell viability and proliferation, morphology, glycosaminoglycan production, and gene expression. Type II collagen/HA/4SPEG formed a strong and stable hydrogel, and the chondrocytes remained viable during the encapsulation process and for the 7-day culture period. In addition, the encapsulated cells showed spherical morphology characteristic for chondrocytic phenotype. The cells were able to produce glycosaminoglycans into their extracellular matrix, and the gene expression of type II collagen and aggrecan, genes specific for differentiated chondrocytes, increased over time. The results indicate that the studied composite hydrogel with incorporated chondrogenic growth factor TGFbeta1 is able to maintain chondrocyte viability and characteristics, and thus, it can be regarded as potential injectable cell delivery vehicle for cartilage tissue engineering. PMID- 25786730 TI - Controlled release of glial cell line-derived neurotrophic factor from poly(epsilon-caprolactone) microspheres. AB - Glial cell line-derived neurotrophic factor (GDNF), a growth factor expressed in the central nervous system, promotes the survival of both dopaminergic and motor neurons, making it a promising candidate for neurodegenerative disease therapy. Although GDNF is currently being evaluated in clinical trials for the treatment of Parkinson's disease (PD), the current delivery method using catheter implantation has certain limitations in terms of delivering GDNF safely and effectively. As a proof of concept, we encapsulated GDNF into poly(epsilon caprolactone) (PCL) microspheres to enable controlled drug release for 25 days. First, microspheres were loaded with bovine serum albumin (BSA) to determine the optimal fabrication conditions necessary to achieve the desired release rates of protein. BSA was then used as a carrier protein to preserve GDNF activity during the fabrication process in the presence of organic solvents. GDNF-encapsulated microspheres were created and characterized using scanning electron microscopy. Next, the in vitro release of GDNF along with microsphere morphology was tracked over 25 days. Finally, the bioactivity of the released GDNF was confirmed using PC12 cells. This work demonstrates the potential of such microspheres for the delivery of bioactive GDNF with the end goal of developing a suitable, clinically relevant formulation for injection to appropriate regions of the brain in PD patients. PMID- 25786731 TI - Development and optimization of solid self-nanoemulsifying drug delivery system (S-SNEDDS) using Scheffe's design for improvement of oral bioavailability of nelfinavir mesylate. AB - The present research was aimed at development and evaluation of self nanoemulsifying drug delivery system (SNEDDS) for improving bioavailability of nelfinavir mesylate (NFV), a protease inhibitor exhibiting pH dependent solubility and variable oral bioavailability. Maisine 35-1, Cremophor RH-40, and Labrasol were identified as oil, surfactant, and co-surfactant that had best solubility for NFV. Scheffe's mixture design was used to optimize the amount of components in liquid self-nanoemulsifying drug delivery system (L-SNEDDS) by taking their amounts as independent variable, whereas globule size, drug loading, and percent transmittance were taken as dependent variable. Optimized NFV-L SNEDDS was then adsorbed on Neusilin US2 to form solid self-nanoemulsifying drug delivery system (S-SNEDDS). NFV loaded L-SNEDDS and S-SNEDDS were characterized for various physicochemical properties, and solid-state properties were determined through differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy studies. In vitro dissolution using simulated gastric fluid and simulated intestinal fluid, ex vivo drug release study, and in vivo study were performed for pure NFV and NFV-S-SNEDDS. NFV-S-SNEDDS showed more than 90 % drug release in 20 min during drug release studies irrespective of pH of the dissolution medium. In vivo study revealed significant difference between release of NFV from suspension and NFV-L-SNEDDS and NFV-S-SNEDDS when given to rabbits (p < 0.001). NFV-L-SNEDDS and NFV-S-SNEDDS were subjected to stability study as per ICH guidelines, and NFV-S-SNEDDS was found to be stable during the period of study. S-SNEDDS could serve as a potential drug delivery system for NFV. PMID- 25786732 TI - Biopharmaceutical considerations and characterizations in development of colon targeted dosage forms for inflammatory bowel disease. AB - Colon targeted dosage forms have been extensively studied for the localized treatment of inflammatory bowel disease. These dosage forms not only improve the therapeutic efficacy but also reduce the incidence of adverse drug reactions and hence improve the patient compliance. However, complex and highly variable gastro intestinal physiology limits the clinical success of these dosage forms. Biopharmaceutical characteristics of these dosage forms play a key role in rapid formulation development and ensure the clinical success. The complexity in product development and clinical success of colon targeted dosage forms are based on the biopharmaceutical characteristics such as physicochemical properties of drug substances, pharmaceutical characteristics of dosage form, physiological conditions and pharmacokinetic properties of drug substances as well as drug products. Various in vitro and in vivo techniques have been employed in past to characterize the biopharmaceutical properties of colon targeted dosage forms. This review focuses on the factors influencing the biopharmaceutical performances of the dosage forms, in vitro characterization techniques and in vivo studies. PMID- 25786733 TI - How will climate change influence grapevine cv. Tempranillo photosynthesis under different soil textures? AB - While photosynthetic responses to elevated CO2, elevated temperature, or water availability have previously been reported for grapevine as responses to single stress factors, reports on the combined effect of multiple stress factors are scarce. In the present work, we evaluated effects of simulated climate change [CC; 700 ppm CO2, 28/18 degrees C, and 33/53% relative humidity (RH), day/night] versus current conditions (375 ppm CO2, 24/14 degrees C, and 45/65% RH), water availability (well-irrigated vs. water deficit), and different types of soil textures (41, 19, and 8% of soil clay contents) on grapevine (Vitis vinifera L. cv. Tempranillo) photosynthesis. Plants were grown using the fruit-bearing cutting model. CC increased the photosynthetic activity of grapevine plants grown under well-watered conditions, but such beneficial effects of elevated CO2, elevated temperature, and low RH were abolished by water deficit. Under water deficit conditions, plants subjected to CC conditions had similar photosynthetic rates as those grown under current conditions, despite their higher sub-stomatal CO2 concentrations. As expected, water deficit reduced photosynthetic activity in association with inducing stomatal closure that prevents water loss. Evidence for photosynthetic downregulation under elevated CO2 was observed, with decreases in photosynthetic capacity and leaf N content and increases in the C/N ratio in plants subjected to CC conditions. Soil texture had no marked effects on photosynthesis and did not modify the photosynthetic response to CC and water deficit conditions. However, in mature well-irrigated plants grown in the soils with the highest sand content, an important decrease in stomatal conductance was observed as well as a slight decrease in the utilization of absorbed light in photosynthetic electron transport (measured as photochemical quenching), possibly related to a low water-retention capacity of these soils even under well-watered conditions. PMID- 25786734 TI - Response to Gao et al: Interobserver reliability of Doppler-based resistive index. PMID- 25786735 TI - Magnetic correlations beyond the Heisenberg model in an Fe monolayer on Rh(0 0 1). AB - Motivated by a recent experimental observation of a complex magnetic structure (Takada et al 2013 J. Magn. Magn. Mater. 329 95) we present a theoretical study of the magnetic structure of an Fe monolayer deposited on Rh(0 0 1). We use a classical spin Hamiltonian with parameters obtained from ab initio calculations and go beyond the usual anisotropic Heisenberg model by including isotropic biquadratic interactions. Zero-temperature Landau-Lifshitz-Gilbert spin dynamics simulations lead to a complex collinear spin configuration that, however, contradicts experimental findings. We thus conclude that higher order multi-spin interactions are likely needed to account for the magnetic ordering of the system. PMID- 25786737 TI - Separation and purification of the antioxidant compound hispidin from mushrooms by molecularly imprinted polymer. AB - A new molecularly imprinted polymer (MIP), prepared by hispidin as the template molecule, was synthesized and applied as an adsorbent phase for solid phase extraction (SPE) to isolate and enrich hispidin from eight species of mushrooms. The optimization of synthesis and the adsorption behaviors of the MIPs were investigated in detail. In comparison with C18-SPE, MIP-SPE displayed high selectivity and good affinity for hispidin for extract of Phellinus igniarius. The antioxidant activity of the extracts after using the MIPs was evaluated by free radical scavenging activity, and inhibition of erythrocyte hemolysis, and lipid peroxidation. This developed method provided a rapid, selective, and effective approach for separation and enrichment of active compounds from the natural products. PMID- 25786736 TI - FLIPPER, a combinatorial probe for correlated live imaging and electron microscopy, allows identification and quantitative analysis of various cells and organelles. AB - Ultrastructural examination of cells and tissues by electron microscopy (EM) yields detailed information on subcellular structures. However, EM is typically restricted to small fields of view at high magnification; this makes quantifying events in multiple large-area sample sections extremely difficult. Even when combining light microscopy (LM) with EM (correlated LM and EM: CLEM) to find areas of interest, the labeling of molecules is still a challenge. We present a new genetically encoded probe for CLEM, named "FLIPPER", which facilitates quantitative analysis of ultrastructural features in cells. FLIPPER consists of a fluorescent protein (cyan, green, orange, or red) for LM visualization, fused to a peroxidase allowing visualization of targets at the EM level. The use of FLIPPER is straightforward and because the module is completely genetically encoded, cells can be optimally prepared for EM examination. We use FLIPPER to quantify cellular morphology at the EM level in cells expressing a normal and disease-causing point-mutant cell-surface protein called EpCAM (epithelial cell adhesion molecule). The mutant protein is retained in the endoplasmic reticulum (ER) and could therefore alter ER function and morphology. To reveal possible ER alterations, cells were co-transfected with color-coded full-length or mutant EpCAM and a FLIPPER targeted to the ER. CLEM examination of the mixed cell population allowed color-based cell identification, followed by an unbiased quantitative analysis of the ER ultrastructure by EM. Thus, FLIPPER combines bright fluorescent proteins optimized for live imaging with high sensitivity for EM labeling, thereby representing a promising tool for CLEM. PMID- 25786738 TI - Comparative genome analysis reveals genetic adaptation to versatile environmental conditions and importance of biofilm lifestyle in Comamonas testosteroni. AB - Comamonas testosteroni is an important environmental bacterium capable of degrading a variety of toxic aromatic pollutants and has been demonstrated to be a promising biocatalyst for environmental decontamination. This organism is often found to be among the primary surface colonizers in various natural and engineered ecosystems, suggesting an extraordinary capability of this organism in environmental adaptation and biofilm formation. The goal of this study was to gain genetic insights into the adaption of C. testosteroni to versatile environments and the importance of a biofilm lifestyle. Specifically, a draft genome of C. testosteroni I2 was obtained. The draft genome is 5,778,710 bp in length and comprises 110 contigs. The average G+C content was 61.88 %. A total of 5365 genes with 5263 protein-coding genes were predicted, whereas 4324 (80.60 % of total genes) protein-encoding genes were associated with predicted functions. The catabolic genes responsible for biodegradation of steroid and other aromatic compounds on draft genome were identified. Plasmid pI2 was found to encode a complete pathway for aniline degradation and a partial catabolic pathway for chloroaniline. This organism was found to be equipped with a sophisticated signaling system which helps it find ideal niches and switch between planktonic and biofilm lifestyles. A large number of putative multi-drug-resistant genes coding for abundant outer membrane transporters, chaperones, and heat shock proteins for the protection of cellular function were identified in the genome of strain I2. In addition, the genome of strain I2 was predicted to encode several proteins involved in producing, secreting, and uptaking siderophores under iron limiting conditions. The genome of strain I2 contains a number of genes responsible for the synthesis and secretion of exopolysaccharides, an extracellular component essential for biofilm formation. Overall, our results reveal the genomic features underlying the adaption of C. testosteroni to versatile environments and highlighting the importance of its biofilm lifestyle. PMID- 25786739 TI - Crystal structure of Bacillus fastidious uricase reveals an unexpected folding of the C-terminus residues crucial for thermostability under physiological conditions. AB - Bacillus fastidious uricase (BF uricase) containing 322 amino acid residues exhibited high stability under physiological conditions. Its crystal structure was solved to 1.4-A resolution, showing homotetramer containing two homodimers. After the intersubunit antiparallel beta-sheet in its homodimer, each subunit had a total of 18 C-terminus residues forming an alpha-helix (Q305-A313) and random coil (S314-L322) on surface to bury other two alpha-helices (I227-T238 and I244 R258). In comparison, reported crystal structures of Arthrobacter globiformis and Aspergillus flavus uricases had atomic coordinates of only some C-terminus residues, while the crystal structures of all the other uricases accessible before September 2014 missed atomic coordinates of all their C-terminus residues, after the intersubunit antiparallel beta-sheets. In each homodimer of BF uricase, H-bonds were found between E311 and Y249 and between Y319 and D257; electrostatic interaction networks were found to surround D307 plus R310 and intersubunit R3, K312 plus D257, E318 plus K242, and L322 plus R258. Amino acid mutations that disrupted those interactions when R3 and D307 were reserved caused moderate decreases of activity at pH 9.2 while negligible decreases of activity at pH 7.4, but destroyed stability at pH 7.4 while slightly decreased stability at pH 9.2. Such structural information guided the fusion of 6His-tag to the C-terminus of the mutant L322D with SNSNSN as a linker to reserve the activity and stability. Hence, the folding of the C-terminus residues is crucial for thermal stability of BF uricase under physiological conditions; these new structural insights are valuable for molecular engineering of uricases. PMID- 25786740 TI - Trade-offs in female signal apparency to males offer alternative anti-harassment strategies for colour polymorphic females. AB - Colour polymorphisms are known to influence receiver behaviour, but how they affect a receiver's ability to detect and recognize individuals in nature is usually unknown. I hypothesized that polymorphic female damselflies represent an evolutionary stable strategy, maintained by trade-offs between the relative apparency of morphs to male receivers. Using field experiments on Enallagma hageni and focal studies of E. hageni and Enallagma boreale, I tested for the first time the predictions that (i) green heteromorphs and blue andromorphs gain differential protection from sexual harassment via background crypsis and sexual mimicry, respectively, and (ii) female morphs behaviourally optimize their signal apparency to mate-searching males. First, based on male reactions elicited by females, against a high-contrast background, the two morphs did not differ in being detected by males, and once detected, they did not differ in being recognized (eliciting sexual reactions). However, on green ferns, heteromorphs were less likely to be detected (elicited only fly-bys) than andromorphs, but once detected, the morphs did not differ in being recognized. In contrast, when perched on a dowel with two male signal distractors, andromorphs were detected less often, and once detected, they were recognized less often than heteromorphs. Second, in fields where females foraged, andromorphs perched higher on vegetation than heteromorphs and were more often in the vicinity of males. Neither harassment rates nor evasive behaviours differed between morphs. Males aggregated in high density near shore where solitary females were rare. Equilibrium frequencies of these and other colour morphs should reflect the relative ease with which receivers detect and recognize them in the context where they are encountered. PMID- 25786741 TI - Chronic pain and comorbid mental health conditions: independent associations of posttraumatic stress disorder and depression with pain, disability, and quality of life. AB - Both posttraumatic stress disorder (PTSD) and depression are highly comorbid with chronic pain and have deleterious effects on pain and treatment outcomes, but the nature of the relationships among chronic pain, PTSD, and depression has not been fully elucidated. This study examined 250 Veterans Affairs primary care patients with moderate to severe chronic musculoskeletal pain who participated in a randomized controlled pain treatment trial. Baseline data were analyzed to examine the independent associations of PTSD and major depression with multiple domains of pain, psychological status, quality of life, and disability. PTSD was strongly associated with these variables and in multivariate models, PTSD and major depression each had strong independent associations with these domains. PTSD demonstrated similar relationships as major depression with psychological, quality of life, and disability outcomes and significant but somewhat smaller associations with pain. Because PTSD and major depression have independent negative associations with pain, psychological status, quality of life, and disability, it is important for clinicians to recognize and treat both mental disorders in patients with chronic pain. PMID- 25786742 TI - Reconstruction Using a Pedunculated Gastric Tube with Duodenal Transection After Esophagectomy and Pharyngolaryngectomy. AB - BACKGROUND: Gastric conduit ischemia is sometimes correlated with anastomosis related morbidities after esophagectomy and pharyngolaryngectomy.1 (-) 5 A lack of connection between the right and left gastroepiploic vessels and intraoperative injury to these vessels could cause conduit ischemia. In addition, tensioned anastomosis due to a short gastric tube also could contribute to anastomotic leaks. This report introduces a reconstruction technique using a pedunculated gastric tube with duodenal transection for these cases. METHODS: Creation of a gastric tube in the greater curvature of the stomach is performed with linear staplers. Only the right gastroepiploic vessels are preserved. The gastric tube is finally fashioned with a width of approximately 4 cm. The peripheral right gastroepiploic vessels to the pylorus are sacrificed. After the bulbs are transected, a pedunculated gastric tube is moved, with confirmation whether it has sufficient length for anastomosis in the neck. After the anal side of the gastric tube is transected, Roux-en-Y gastrointestinal anastomosis is performed. Finally, esophagogastric or pharyngogastric anastomosis is performed. RESULTS: Between November 2011 and September 2014, 18 patients underwent the reported reconstruction technique due to short gastric tubes in 10 patients and a lack of connection between the right and left gastroepiploic vessels in 8 patients. Anastomotic leaks occurred in three patients (16.7 %), conduit necrosis in no patients, and strictures in no patients, respectively. Two patients had an anastomotic grade 2 leak, and one patient had an anastomotic grade 3 leak. CONCLUSION: The current reconstruction technique is a good alternative for patients at risk of conduit ischemia and patients with a short gastric tube after esophagectomy and pharyngolaryngectomy. PMID- 25786743 TI - Octreoscan Versus FDG-PET for Neuroendocrine Tumor Staging: A Biological Approach. AB - BACKGROUND: Clinicians may order Octreoscan or positron emission tomography (PET) scan for staging patients with neuroendocrine tumors (NETs). (111)In-Octreoscan (Octreoscan) identifies tumors by radiolabeled targeting of somatostatin receptors, while 18F-fluorodeoxyglucose-positron emission tomography ((18)FDG PET) measures differential tissue glucose transport. We assessed the sensitivity of both nuclear imaging modalities with pathologic correlation to define the best initial choice for NET staging after standard cross-sectional imaging. METHODS: We identified all patients diagnosed with NETs of gastrointestinal or pancreatic origin who underwent nuclear imaging staging by Octreoscan and/or PET from 2000 to 2013. Imaging results were correlated with tumor differentiation and grade of pathology specimens. RESULTS: Imaging and pathology results were identified for 153 patients. Of these, 131 underwent Octreoscan, 43 underwent PET, and 21 patients had both performed. Overall sensitivity of Octreoscan and PET for NET detection was similar (77 vs. 72 %; p = not significant). For well-differentiated NETs, Octreoscan (n = 124) demonstrated sensitivity of 80 vs. 60 % (p = 0.28) for PET (n = 30). For poorly-differentiated NETs, Octreoscan (n = 7) proved significantly less sensitive than PET (n = 13) (57 vs. 100 %; p = 0.02). The sensitivity of Octreoscan versus PET varied similarly when analyzed by WHO tumor grade: Grade 1 (79 vs. 52 %; p = 0.16), Grade 2 (85 vs. 86 %; p = not significant), and Grade 3 (57 vs. 100 %; p = 0.02). CONCLUSIONS: Tumor differentiation can be used to guide selection of nuclear imaging modalities for staging gastrointestinal and pancreatic NETs. Octreoscan appears more sensitive than (18)FDG-PET for well-differentiated NETs, whereas (18)FDG-PET demonstrates superior sensitivity for poorly-differentiated NETs. PMID- 25786744 TI - Surgical Management of Cricotracheal Invasion by Papillary Thyroid Carcinoma. AB - BACKGROUND: In general, patients with papillary thyroid carcinoma (PTC) have an excellent postoperative prognosis. Those with cricoid and/or tracheal PTC invasion, however, are at a higher risk of postoperative morbidity and airway insufficiency. METHODS: We investigated postoperative airway outcomes, locoregional recurrence, and survival rates in patients with PTC who underwent cricotracheal resection. The records of PTC patients who underwent surgery at our institution between 1981 and 2009 were reviewed retrospectively, and 110 patients with cricotracheal invasion were enrolled. Curative resection was performed in all patients, and cricotracheal function was preserved or reconstructed when possible. RESULTS: Of the 110 patients, 57 and 53 patients had superficial and intraluminal invasion of the larynx, respectively. After the initial surgery, the 10-year disease-specific survival rates were 90.8 and 44.4 % in patients with superficial and intraluminal invasion of the cricotracheal area, respectively. Only six patients (5.5 %) had an isolated upper aerodigestive tract recurrence. Five patients were managed with an additional window resection as salvage surgery. Consequently, only one patient (0.9 %) underwent total laryngectomy. Altogether, 31 patients (28.0 %) had a permanent stoma, 9 and 15 of which were caused by cricotracheal invasion and invasion of other aerodigestive structures, respectively. CONCLUSIONS: Window resection for intraluminal cricotracheal invasion by PTC produced good surgical outcomes that resulted in a low local recurrence rate and survival rates that resembled those associated with other surgical treatments. Treatment of multiple organ invasion of the aerodigestive tract was necessary to improve postoperative functional outcomes in these patients. PMID- 25786745 TI - Renal Function is Associated with Nephrometry Score After Partial Nephrectomy: A Study Using Diethylene Triamine Penta-Acetic Acid (DTPA) Renal Scanning. AB - PURPOSE: The aim of this study was to evaluate the effect of renal tumor anatomical characteristics on renal function change after partial nephrectomy using the scoring systems and the glomerular filtration rate (GFR) estimated from diethylene triamine penta-acetic acid (DTPA) scans. METHODS: Patients who underwent DTPA renal scans before and after partial nephrectomy from January 2009 to December 2011 were identified retrospectively. The anatomical characteristics of renal tumors were standardized using the RENAL, PADUA and C-index scoring systems. Associations between scoring systems and change in GFRs were evaluated using a correlation coefficient. Predictors of GFR change and postoperative new onset chronic kidney disease (CKD) after partial nephrectomy were assessed. RESULTS: A total of 185 patients with a mean tumor size of 2.6 cm (median 2.3, range 0.5-10) were identified. Mean ischemia time was 21.5 min. The last DTPA renal scan was performed at a mean follow-up duration of 23.3 months after surgery, and the mean decrease in GFR was 8.1 ml/min. By multivariable analysis, preoperative GFR (beta = -039; p < 0.001), RENAL complexity score (beta = -5.32; p < 0.001), and C-index complexity (beta = -5.19; p < 0.001) were independent predictors of decreased GFR on DTPA. Of 175 patients in whom preoperative estimated GFR (eGFR) was > 60 ml/min/1.73 m(2), CKD developed in 14 (8 %) patients after surgery. Independent factors predicting new-onset CKD were preoperative eGFR (odds ratio [OR] 0.91; p = 0.047), age (OR 1.13; p = 0.003), and diabetes (OR 5.10; p = 0.038). CONCLUSIONS: Although each scoring system describing the complexity of renal tumors correlates with change in GFR after partial nephrectomy, RENAL and C-index score were significantly predictive of GFR reduction. PMID- 25786746 TI - Erratum to: The Ability to Diagnose Intrahepatic Cholangiocarcinoma Definitively Using Novel Branched DNA-Enhanced Albumin RNA In Situ Hybridization Technology. PMID- 25786747 TI - Efficacy of conservative management in patients with right colonic diverticulitis. AB - BACKGROUND: Although right colonic diverticulitis is more common than sigmoid diverticulitis, and its incidence has been increasing in Asian countries, there is no definitive treatment strategy for right colonic diverticulitis. This retrospective clinical study assessed the effect of conservative management in patients with right colonic diverticulitis. METHODS: Of the 169 patients who were diagnosed with right colonic diverticulitis at Chonbuk National University Hospital, South Korea, from 2005 to 2012, 152 patients evaluated by abdominopelvic computed tomography (CT) and managed conservatively were included. CT findings were categorized by modified Hinchey classification, with stages Ib, II, III and IV, as well as fistula and obstruction defined as complicated diverticulitis. Factors associated with recurrence of diverticulitis were determined. RESULTS: The mean age of 152 patients (87 males, 65 females) was 42.9 +/- 13.8 years, median follow-up interval was 61 months (range, 17-113 months). At diagnosis, five patients (3.3%) had complicated diverticulitis. After treatment of first attack, 15 patients (9.9%) experienced recurrence of right colonic diverticulitis, including 10 (6.6%) within 12 months. Fourteen of these patients were successfully treated conservatively, whereas one failed conservative management and required surgical resection. Statistical analysis found no variables related to recurrence of right colonic diverticulitis. CONCLUSION: Right colonic diverticulitis has a low rate of complicated diverticulitis at first attack and a low recurrence rate, with most recurrences being uncomplicated. Therefore, conservative management is effective in patients with right colonic diverticulitis. Close follow-up of patients for 12 months is required because most recurrences may occur within 12 months. PMID- 25786748 TI - Translational control mechanisms in angiogenesis and vascular biology. AB - Among the multiple modes of regulation of gene expression, translational control is arguably the least investigated and understood, and its role in vascular biology and pathobiology is not an exception. Here, we review recent studies that have revealed exciting translational regulatory phenomena and mechanisms involving novel RNA binding proteins and microRNA machinery in vascular biology. From these studies, the importance of translational regulation in angiogenesis, atherosclerosis, and blood pressure maintenance is beginning to emerge. We believe that the recent development of powerful techniques such as ribosome profiling and translating ribosome affinity purification (TRAP) will motivate and facilitate additional research in these areas. PMID- 25786749 TI - [Two cases of ischemic cerebrovascular disease with only memory disturbance as neurological symptom and abnormal MR findings]. AB - Case 1 involved a 77-year-old man admitted to our hospital after he lost almost all memory of work on the day before. Diffusion-weighted imaging (DWI) revealed spotty hyperintensities in the bilateral hippocampi, which were considered responsible for the amnesia. Transesophageal echocardiography (TEE) showed severe aortic arch atheroma, 6.8 mm in diameter with extension to the branch. Aortogenic embolism to the bilateral hippocampi was diagnosed. Case 2 involved a 66-year-old woman admitted to our hospital because she had lost all memory of the 5 hours she was out. She had transient anterograde amnesia. DWI revealed no ischemic lesions, but magnetic resonance angiography (MRA) revealed branch occlusion of the right posterior cerebral artery. MRA on hospital day 7 revealed partial recanalization. TEE showed aortic arch atheroma of 3.9 mm in diameter with extension to the branch. In both cases, aortogenic embolism to the hippocampus might have been causally related to transient memory disturbance. In patients with acute memory disturbance, the possibility of ischemic stroke should be considered. PMID- 25786750 TI - [Dramatic seizure reduction with levetiracetam in adult Dravet syndrome: a case report]. AB - A 28 year-old man who had been diagnosed as having Dravet syndrome (DS) since his childhood by a pediatric hospital was referred to our department from the local pediatric clinic. Until then, his seizures were medically intractable, and generalized tonic-clonic convulsions had occurred monthly even when administered enough valproate, zonisamide and clorazepate. After adding levetiracetam (LEV) to his drug regimen at the age of 29, the seizures disappeared for more than one year. LEV was found to be effective in this adult patient as well as in a series of children affected with DS. PMID- 25786751 TI - [A case of true neurogenic thoracic outlet syndrome accompanied by an aberrant right subclavian artery]. AB - A 65-year-old woman experienced progressive intrinsic muscle wasting on the right hand over a period of 7 years. The distribution of muscular atrophy and weakness was consistent with the area innervated by the right C8 and Th1 nerve roots. Neurophysiological examination suggested a right lower trunk lesion. An elongated right transverse process of the C7 vertebra and an aberrant subclavian artery were detected on computed tomography images, and the right lower trunk of the brachial plexus appeared to be lifted upward on magnetic resonance images. The patient was diagnosed with true neurogenic thoracic outlet syndrome. A fibrous band extending from the elongated transverse process was found during surgery, and symptoms did not progress further after resection of the band. True neurogenic thoracic outlet syndrome can cause monomelic amyotrophy, and localized neuroimaging and detailed neurophysiological examination were useful for diagnosis. PMID- 25786752 TI - [Ross syndrome presenting with asymptomatic tonic pupils]. AB - A 66-year-old woman presented with asymptomatic tonic pupils and areflexia when she was admitted to our hospital due to vertigo. She had also noticed heat intolerance and decreased sweating on her right side since she was approximately 10 years old. Both sides of each eye contracted in the pilocarpine eye drop test, while sweating on the face and left chest decreased. She was thus diagnosed with Ross syndrome. When acethylcholine was administered intracutaneously, sweating of the left subclavian and left peri-umbilical areas decreased. During an electrogastrogram, the average muscle contraction frequency was decreased and the incidence of bradygastria increased. Blood flow of the skin of the left forefinger (but not right) increased at rest and the reaction in the blood flow on deep breathing decreased. A skin biopsy of the left upper arm showed atrophy of pilosebaceous and sweat glands. Despite treatment with intravenous immunoglobulin, the patient's deficits did not improve. The lesions typical of Ross syndrome may be associated with many parts of the autonomic nervous system. PMID- 25786753 TI - [Multiple cerebral infarctions in a patient with hypereosinophilic syndrome with Loffler endocarditis: a case report]. AB - An 82-year-old woman with a history of asthma was admitted to our hospital because of dyspnea. On admission, laboratory testing showed a white blood cell count of 17,700/MUl with hypereosinophilia of 9,204/MUl (52% of all white blood cells). Various examinations, including a bone marrow biopsy for the cause of eosinophilia, were unremarkable. The patient was diagnosed with hypereosinophilic syndrome (HES). Treatment with intravenous methylprednisolone was initiated. The patient's eosinophil count normalized within 1 day. On the 6th day, she developed left-sided hemiparesis. Magnetic resonance imaging (MRI) of the brain showed acute multiple infarcts in arterial border zones of bilateral cerebral and cerebellar hemispheres, and in bilateral basal ganglia and the thalamus. Magnetic resonance angiography was normal. Coagulation factors were normal, except for an elevated D-dimer level (12.9 MUg/ml). A transthoracic echocardiogram showed thickening of the left ventricular endocardium with immobile thrombus, compatible with Loffler endocarditis. Treatment with oral prednisolone was started at 30 mg/day and then tapered to a maintenance dose of 5 mg/day. Anticoagulation was concurrently started for prevention of stroke. Ten months later, an echocardiogram showed that the thrombus had decreased in size, and MRI revealed no new cerebral infarctions. The cause of cerebral infarction in patients with hypereosinophilia is thought to be thromboembolism or cerebrovascular endothelial toxicity of eosinophils. In this patient, the cerebral infarcts may have been the result of embolism from the left ventricular thrombus. Because HES with Loffler endocarditis is frequently associated with a poor prognosis, cardiovascular problems should be evaluated and treatment started as soon as possible. PMID- 25786754 TI - [A case of pure-sensory-type Guillain-Barre syndrome with galactocerebroside antibody]. AB - A 67-year-old man noticed paresthesia in both legs in July 2011. Three days later, he was found on a street where he was unable to stand up. On admission, the deep sensation in both legs was severely disturbed, but their muscle strength remained normal. Cranial nerves and autonomic functions were normal. The deep tendon reflexes were diminished in both legs. Magnetic resonance imaging of the spine was normal. Motor nerve conduction studies revealed normal conduction velocity, amplitude, and F-wave latency. However, sensory nerve conduction studies revealed severe reduction of amplitude in the upper and lower extremities. Cerebrospinal fluid analysis showed normal cell counts but elevated protein levels. Screening for glycolipid antibodies showed a selective increase of galactocerebroside (Gal-C) IgG antibody. We diagnosed him with pure-sensory type Guillain-Barre syndrome (GBS). We administered intravenous immunoglobulin (IVIG) for 5 days. After IVIG therapy, his gait disturbance improved slightly but the disturbance of deep sensation remained severe and he was transferred to a rehabilitation ward 53 days after admission. To the best of our knowledge, this is the first report of a case of pure-sensory-type GBS with Gal-C antibody alone. This case suggests a close relationship between Gal-C antibody and sensory nerve disturbance. PMID- 25786755 TI - [Reversible changes on MR images in a patient with metronidazole-induced encephalopathy]. AB - A 66-year-old woman was diagnosed with a brain abscess. The abscess was drained by sterotactic catheter insertion. She was administered metronidazole at a dose of 2 g/day. On the 30th day of treatment, she had nausea that gradually progressed. On the 45th day, she developed a disturbance of consciousness and was admitted to our department. She was in stuporous state, and had slight vestibular and cerebellar dysfunctions. Diffusion-weighted and FLAIR brain MR images showed bilateral symmetrical high signals in the splenium of the corpus callosum (SCC), cerebellar dentate nucleus, and inferior colliculus. The apparent diffusion coefficient (ADC) map was reduced in the SCC, but not in the other locations. The peak of lactate on MR spectroscopy was increased in the SCC. The clinical presentation and image changes of the patient were thought to be most consistent with metronidazole toxicity. Metronidazole was discontinued, and her condition improved rapidly. She was discharged 14 days later. The lesions in her cerebellar dentate nucleus and inferior colliculus, suspected to be vasogenic edema, had disappeared 5 to 10 days later, whereas the lesion in the SCC, which gradually diminishing, could still be faintly detected 40 days later, which corresponded to our suspicion of cytotoxic edema. PMID- 25786756 TI - [Five years after mortality of atrial fibrillation in community-dwelling Japanese aged 40 years or older in Japan]. AB - A community-based study was conducted to estimate the prevalence of atrial fibrillation (AF) in Japanese adults aged >=40 years in Kurashiki-city at 2006. We investigated mortality of adult residents with AF in Kurashiki city after 5 years from the previous study. In 1,164 adult residents with AF, 279 persons (24.0%) were dead in this survey. The cause of death was summarized as follow; cancer was 24%, cardiac disease without hypertension was 24%, ischemic stroke 11%, stroke without ischemic stroke was 6%, pneumonia was 13%, and freak accident was 3%. Residents with AF were dead of many another courses than cardio cerebrovascular disease. When atrial fibrillation was diagnosed, we should be evaluate the heart by a cardiovascular specialist and evaluate patient's general medical condition. PMID- 25786757 TI - [Dyskinesia-hyperpyrexia syndrome in a patient with Parkinson's disease: a case report]. AB - Non-physiological, excessive dopaminergic stimulation can cause dyskinesia hyperpyrexia syndrome (DHS), which was initially reported by Gil-Navarro and Grandas in 2010. A 70-years-old woman with a 13-years history of Parkinson's disease (PD) was hospitalized due to difficulty walking, despite being treated with levodopa/carbidopa (600 mg/day), immediate-release pramipexole (3 mg/day), and selegiline (5 mg/day). Immediate-release pramipexole was changed to extended release pramipexole without changing the dose or levodopa equivalent dose (LED). The patient's adherence to drugs was good. The parkinsonism gradually improved and the patient was discharged. One month later, the patient developed severe generalized athetotic dyskinesia with visual hallucinations and hyperpyrexia that lasted for a week, and she was readmitted to hospital. On admission, the patient was conscious but slightly disoriented. Body temperature was 40.3 degrees C with hyperhidrosis. Leukocyte count in the peripheral blood was 1.78*10(4)/ml and serum creatine kinase was >3*10(4) U/l. Chest survey, whole-body computed tomography, and cranial magnetic resonance imaging showed no abnormalities. The patient was diagnosed with DHS and treated by tapering the oral administration of dopaminergic drugs, including extended-release pramipexole. Her clinical condition recovered without dyskinesia, and serum creatine kinase level swiftly normalized. DHS and resemblant conditions are reported to occur in long-term PD patients with motor complications. In advanced stage PD, loss of dopaminergic neurons impairs the dopamine holding capacity of the striatum and exogenous dopaminergic drugs can result in uncontrollable and excessive fluctuations in dopamine concentration. Our case recommends caution when switching to long-acting dopaminergic drugs, even if the dose is unchanged, could lead to excessive dopaminergic stimulation. This case highlights the importance of considering both the LED and the duration of action of dopaminergic drugs when adjusting medication. PMID- 25786758 TI - Left ventricular hypertrabeculation/noncompaction in juvenile neuronal ceroid lipofuscinosis. PMID- 25786759 TI - Juvenile neuronal ceroid-lipofuscinosis with hypertrophic cardiomyopathy and left ventricular noncompaction: a case report. PMID- 25786764 TI - [Editor's note]. PMID- 25786765 TI - Sexual dimorphism in socioeconomic differences regarding the risk factors, symptomatology and management of patients with stable coronary artery disease in Poland. AB - BACKGROUND: Relationships between socioeconomic status (SES) and the risk factors, applied treatment and outcomes of patients with coronary artery disease (CAD) have been demonstrated in Western European countries, however analogous evidence is missing from Eastern and Central European countries. The aim of the study was to investigate SES gradients regarding the risk factors, symptoms and management of patients with stable CAD in Poland, separately in men and women. METHODS: We analyzed the data of 2,593 participants of the RECENT study. SES was assessed based on the level of education attainment: university, secondary school or primary school. RESULTS: Socioeconomic differences in risk profile were most markedly seen in women: lower the education, higher body mass index (p < 0.01), systolic and diastolic blood pressure (p < 0.05), resting heart rate (p < 0.01), and greater prevalence of heart failure (p < 0.05) and dyslipidemia (p < 0.05). Importantly, smoking habit was the most frequent in women who graduated from univer-sity (p < 0.01). In men, socioeconomic gradients were only seen within resting heart rate (p < 0.01), LDL cholesterol level (p < 0.05) and smoking habit (p < 0.05). In both genders, better education was associated with less severe symptoms of angina and more frequent use of statins (p < 0.05). CONCLUSIONS: SES stratified based on education level differentiates patients with stable CAD in Poland regarding their risk profile, symptom control and the use of statins. Sexual dimorphism is found mainly within SES gradients regarding the prevalence of risk factors. PMID- 25786766 TI - Atrial thrombi detection prior to pulmonary vein isolation: diagnostic accuracy of cardiac computed tomography versus transesophageal echocardiography. AB - BACKGROUND: Patients routinely undergo transesophageal echocardiography (TEE) prior to pulmonary vein isolation (PVI) in order to rule out the presence of intra-atrial thrombi. Cardiac computed tomography (CCT) is also routinely conducted prior to the procedure to determine cardiac anatomy. Although it has been demonstrated that CCT can also rule out intra-atrial thrombi, the use of CCT for thrombi detection is controversial. The primary objective was to determine the utility of CCT for detection of atrial thrombi as compared to TEE. METHODS: Patients who underwent PVI between 2010 and 2011 with CTs and TEEs complet-ed within 3 days of each other were retrospectively identified. TEE reports were analyzed, while CCTs were interpreted by a cardiologist specializing in CCTs. Severe spontaneous echo contrast or thrombus detected on TEE were considered positive, as were filling defects found on CCT. RESULTS: A total of 51 patients undergoing PVI (mean age 59.4 +/- 9.5 years; 75% male; ejection fraction 60 +/- 12%) had both TEE and CCT in timely fashion. By TEE, 0 left atrial ap-pendage (LAA) thrombi were identified with mild to moderate spontaneous echo contrast in 4 patients. By CCT, 2 definite LAA thrombi were identified and thrombi in 4 patients could not be ruled out. Specificity, positive predictive value, and negative predictive value for CCT were 88%, 0%, and 100%, respectively. CONCLUSIONS: CCT is an effective tool in ruling out atrial thrombi prior to PVI. TEE should be completed only if CCT is positive. PMID- 25786767 TI - Current and future role of echocardiography in arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited progressive cardiomyopathy, clinically characterized by ventricular arrhythmias and increased risk of sudden cardiac death. Echocardiography has a role in the diagnosis and prognosis of ARVD/C. However, in the current era of magnetic resonance imaging (MRI), the role of echocardiography in ARVD/C patients and family member screening is subject to debate. Relatively novel echocardiographic techniques, such as three-dimensional right ventricular (3D-RV) imaging and tissue deformation imaging, may improve the diagnostic and prognostic performance of echocardiography in these patients. 3D-RV imaging provides more insights on RV anatomy and global function compared to conventional echocardiography. Subtle RV regional wall motion abnormalities, and mechanical dyssynchrony, are accurately measured by tissue deformation imaging. Several studies suggest an incremental value of novel echocardiographic parameters in addition to conventional measurements. Moreover, new parameters indicating subtle RV dysfunction, and mechanical dyssynchrony, are of predictive value and could help in risk stratification of ARVD/C patients. New robust parameters, derived from 3D-RV echocardiography and RV tissue deformation imaging, in combination with established conventional parameters, suggest that there is a current and future role for echocardiography in ARVD/C supplementing MRI. PMID- 25786768 TI - Evaluating impact of a multi-dimensional education programme on perceived performance of primary care professionals in diabetes care. AB - AIM: The purpose of this study is to evaluate an educational programme, 'Diabetes Connect: Connecting Professions', which was developed to enhance communication across primary care networks, to support best practice in clinical interventions and progress multidisciplinary team work to benefit patients in diabetes care. METHODS: A total of 26 workshops were successfully delivered for 309 primary care professionals across the state of Queensland in Australia from November 2011. It consists of two separate, but complementary training elements: a series of online clinical education training modules and state-wide interprofessional learning workshops developed to enhance professional competencies. The evaluation design included completion of online surveys by the participants at two time points: first upon registering for the online modules or workshops; second, one week after attending a workshop. The survey included questions to evaluate the change in role performance measures. FINDINGS: Overall, significant increases in participants' current knowledge, perceived ability to adopt this knowledge at work and willingness to change professional behaviour in the short term were observed. CONCLUSION: The study suggests that for maximum benefit both, workshop and online training, should be combined and made available widely. Future programmes should use a randomised trial design to test the delivery model. PMID- 25786769 TI - Esomeprazole inhibits the pentagastrin-stimulated secretion of gastric acid in healthy Japanese volunteers. AB - Gastroesophageal reflux disease (GERD) is a common disease, in which the reflux of gastric acid causes mucosal damage of the esophagus and/or troublesome symptoms. Esomeprazole, a proton pump inhibitor, has been used for treatment of GERD in Japan since 2011; namely, only little is known about its effect on gastric acid secretion in Japanese. We, therefore, assessed the relationship between dose and timing of esomeprazole administration and gastric acid inhibition in 11 healthy male Japanese volunteers by directly examining gastric acid secretion capacity. In this randomized, open-label, three-way crossover study, the subjects were dosed with esomeprazole 10 mg or 20 mg once a day (q.d.), or 20 mg twice a day (b.i.d.) for 14 days, and pentagastrin-stimulated gastric acid secretion was measured by endoscopic gastrin test. At steady states, gastric acid inhibition rates were significantly higher in esomeprazole 20 mg b.i.d. (median 100.0%, interquartile range [IQR] 99.4-100%, P = 0.027) or 20 mg q.d. (100.0%, IQR 99.7-100%, P = 0.016), compared with 10 mg q.d. (98.4%, IQR 84.4-100%). At trough states, esomeprazole 20 mg b.i.d. showed significantly higher gastric acid inhibition (99.6%, IQR 99.0-100%) than did 20 mg q.d. (84.2%, IQR 76.4-88.8%, P = 0.002) or 10 mg q.d. (64.9%, IQR 59.1-76.7%, P = 0.001). Thus, esomeprazole 20 mg b.i.d. was sufficient to inhibit > 99% gastric acid secretion in healthy subjects. We propose that esomeprazole 20 mg b.i.d. is effective for treating Japanese patients with refractory GERD who require long lasting gastric acid inhibition. PMID- 25786770 TI - Rosettes and other white shiny structures in polarized dermoscopy: histological correlate and optical explanation. AB - BACKGROUND: Rosettes are a specific form of a white shiny structure seen with polarized dermoscopy. The precise morphological correlate and optical explication are not known. OBJECTIVE: To estimate the frequency of rosettes in ex vivo dermoscopy and to find explication and morphologic correlate of this dermoscopic feature. METHODS: A series of 6108 consecutive skin biopsies were examined with ex vivo dermoscopy and when rosettes were present serial transverse sections with polarization were examined. RESULTS: In this series of 6108 consecutive skin biopsies, rosettes were found on ex vivo dermoscopy in 63 cases. When multiple we observed that they are always oriented at the same angle. Transverse sections with polarization of these lesions proved that smaller rosettes are mainly caused by polarizing horny material in adnexal openings, and larger rosettes by concentric perifollicular fibrosis. CONCLUSIONS: Rosettes are an optical effect of crossed polarization by concentric fibrosis or horny material and hence are not lesion-specific. PMID- 25786771 TI - Bioremediation of the oil spill polluted marine intertidal zone and its toxicity effect on microalgae. AB - Custom-designed devices with 0.6 m (L) * 0.3 m (W) * 0.4 m (H) and a microbial consortium were applied to simulate bioremediation on the oil spill polluted marine intertidal zone. After the bioremediation, the removal efficiency of n alkanes and polycyclic aromatic hydrocarbon homologues in crude oil evaluated by GC-MS were higher than 58% and 41% respectively. Besides, the acute toxicity effects of crude oil on three microalgae, i.e. Dicrateria sp., Skeletonema costatum and Phaeodactylum tricornutum, varied with concentration. The effects of microbe and surfactant treated water on the three microalgae followed a decreasing order: the microbial consortium plus Tween-80 > the microbial consortium > Tween-80. During 96 h, the cell densities of the three microalgae in treated seawater increased from 4.0 * 10(5), 1.0 * 10(5) and 2.5 * 10(5) cells per mL to 1.7 * 10(6), 8.5 * 10(5) and 2.5 * 10(6) cells per mL, respectively, which illustrated that the quality of seawater contaminated by crude oil was significantly improved by the bioremediation. PMID- 25786772 TI - Sudden cardiac death in athletes. PMID- 25786773 TI - Youth mental health services will get overhaul and L1.25bn over five years. PMID- 25786774 TI - Relationship between Dietary Approaches to Stop Hypertension score and Alternative Healthy Eating Index score with plasma asymmetrical dimethylarginine levels in patients referring for coronary angiography. AB - BACKGROUND: Asymmetrical dimethyl arginine (ADMA) is a competitive inhibitor in the production of nitric oxide (NO) from arginine and NO plays an important role in the preservation of vascular dilation. Elevated ADMA is a strong predictive factor for coronary artery disease (CAD). Dietary Approaches to Stop Hypertension (DASH) and Alternative Healthy Eating Index (AHEI) patterns contain factors that may influence plasma ADMA levels. The present study examined the association between the DASH score and AHEI score with plasma ADMA concentration in people with suspected heart disease selected for coronary angiography. METHODS: This cross-sectional study was conducted in 148 people aged 40-80 years who were referred for coronary angiography. The DASH diet score and AHEI score were calculated for each individual based on food groups. Plasma ADMA levels were measured by high-performance liquid chromatography. RESULTS: ADMA concentrations were higher in the CAD group compared to the non-CAD group [0.98 (0.37) MUmol L( 1) compared to 0.84 (0.42) MUmol L(-1) ; P = 0.02]. There was a significant negative association between the quartile DASH score and ADMA concentration (standardised beta = -0.172, P = 0.038). The ADMA concentration was lower in patients who were at the highest quartile of DASH score compared to patients with the lowest quintile score. The ADMA concentration and quartiles of AHEI score were not significantly associated. CONCLUSIONS: Higher scores of the DASH diet are associated with lower plasma ADMA levels and with reduced coronary artery stenosis. PMID- 25786775 TI - Radio frequency identification-enabled capabilities in a healthcare context: An exploratory study. AB - Increasingly, the adoption and use of radio frequency identification systems in hospital settings is gaining prominence. However, despite the transformative impact that radio frequency identification has in healthcare settings, few studies have examined how and why this change may occur. The purpose of this study is to systematically understand how radio frequency identification can transform work practices in an operational process that directly impacts cost and operational efficiency and indirectly contributes to impacting patient safety and quality of care. We leverage an interdisciplinary framework to explore the contextual characteristics that shape the assimilation of radio frequency identification in healthcare settings. By linking the use of radio frequency identification with specific contextual dimensions in healthcare settings, we provide a data-driven account of how and why radio frequency identification can be useful in inventory management in this setting. In doing so, we also contribute to recent work by information systems scholars who argue for a reconfiguration of conventional assumptions regarding the role of technology in contemporary organizations. PMID- 25786777 TI - Small gold nanoparticles for interfacial Staudinger-Bertozzi ligation. AB - Small gold nanoparticles (AuNPs) that possess interfacial methyl-2 (diphenylphosphino)benzoate moieties have been successfully synthesized (Staudinger-AuNPs) and characterized by multi-nuclear MR spectroscopy, transmission electron microscopy (TEM), UV-Vis spectroscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy (XPS). In particular, XPS was remarkably sensitive for characterization of the novel nanomaterial, and in furnishing proof of its interfacial reactivity. These Staudinger-AuNPs were found to be stable to the oxidation of the phosphine center. The reaction with benzyl azide in a Staudinger-Bertozzi ligation, as a model system, was investigated using (31)P NMR spectroscopy. This demonstrated that the interfacial reaction was clean and quantitative. To showcase the potential utility of these Staudinger AuNPs in bioorganic chemistry, a AuNP bioconjugate was prepared by reacting the Staudinger-AuNPs with a novel azide-labeled CRGDK peptide. The CRGDK peptide could be covalently attached to the AuNP efficiently, chemoselectively, and with a high loading. PMID- 25786776 TI - Impairment of hepatic nuclear factor-4alpha binding to the Stim1 promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells. AB - The present study was carried out to investigate if hepatic nuclear factor (HNF)4alpha contributed to the high glucose-induced increase in stromal interacting molecule (STIM)1 protein abundance in glomerular mesangial cells (MCs). Western blot and immunofluorescence experiments showed HNF4alpha expression in MCs. Knockdown of HNF4alpha using a small interfering RNA approach significantly increased mRNA expression levels of both STIM1 and Orai1 and protein expression levels of STIM1 in cultured human MCs. Consistently, overexpression of HNF4alpha reduced expressed STIM1 protein expression in human embryonic kidney-293 cells. Furthermore, high glucose treatment did not significantly change the abundance of HNF4alpha protein in MCs but significantly attenuated HNF4alpha binding activity to the Stim1 promoter. Moreover, knockdown of HNF4alpha significantly augmented store-operated Ca(2+) entry, which is known to be gated by STIM1 and has recently been found to be antifibrotic in MCs. In agreement with those results, knockdown of HNF4alpha significantly attenuated the fibrotic response of high glucose. These results suggest that HNF4alpha negatively regulates STIM1 transcription in MCs. High glucose increases STIM1 expression levels by impairing HNF4alpha binding activity to the Stim1 promoter, which subsequently releases Stim1 transcription from HNF4alpha repression. Since the STIM1-gated store-operated Ca(2+) entry pathway in MCs has an antifibrotic effect, inhibition of HNF4alpha in MCs might be a potential therapeutic option for diabetic kidney disease. PMID- 25786778 TI - Real-world variability in dabigatran levels in patients with atrial fibrillation: reply. PMID- 25786779 TI - Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells. AB - In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 MUg ml(-1) (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. PMID- 25786780 TI - Dioxygenation of cysteamine to hypotaurine at a tris(pyrazolyl)borate iron(ii) unit - cysteamine dioxygenase mimicking? AB - A novel complex Tp(Me,Ph)Fe(SCH2CH2NH2) has been synthesized as a speculative model for ADO. Indeed its reaction with O2 led to the dioxygenation of the S atom and thus to hypotaurine. This finding may allow us to draw conclusions on the constitution of the ADO active site, whose structure is still unknown. PMID- 25786781 TI - An optoelectronic resistive switching memory with integrated demodulating and arithmetic functions. AB - A multifunctional optoelectronic resistive switching memory, composed of a simple ITO/CeO2- x/AlOy/Al structure, is demonstrated. Arising from the photo-induced detrapping, electrode-injection and retrapping of electrons in the CeO2-x/AlOy/Al interfacial region, the device shows broadband, linear, and persistent photoresponses that can be used for the integration of demodulating, arithmetic, and memory functions in a single device for future optoelectronic interconnect systems. PMID- 25786782 TI - Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo. AB - We recently demonstrated that siRNAs conjugated to triantennary N acetylgalactosamine (GalNAc) induce robust RNAi-mediated gene silencing in the liver, owing to uptake mediated by the asialoglycoprotein receptor (ASGPR). Novel monovalent GalNAc units, based on a non-nucleosidic linker, were developed to yield simplified trivalent GalNAc-conjugated oligonucleotides under solid-phase synthesis conditions. Synthesis of oligonucleotide conjugates using monovalent GalNAc building blocks required fewer synthetic steps compared to the previously optimized triantennary GalNAc construct. The redesigned trivalent GalNAc ligand maintained optimal valency, spatial orientation, and distance between the sugar moieties for proper recognition by ASGPR. siRNA conjugates were synthesized by sequential covalent attachment of the trivalent GalNAc to the 3'-end of the sense strand and resulted in a conjugate with in vitro and in vivo potency similar to that of the parent trivalent GalNAc conjugate design. PMID- 25786783 TI - The expression of an immune-related phenoloxidase gene is modulated in Ciona intestinalis ovary, test cells, embryos and larva. AB - Two distinct Ciona intestinalis phenoloxidases (CinPO1, 2) had previously been cloned and sequenced. The CinPO2 is involved in innate immunity and is expressed by inflammatory hemocytes that populate the tunic and pharynx vessels as a response to LPS inoculation. In situ hybridization and immunohistochemistry assays on histological section, showed that the expression of this gene and the produced protein are shared with oogenesis, embryogenesis and larval morphogenesis. Intriguingly, upregulation of gene transcription was found in the test cell layer that envelopes the ovary follicle, ovulated egg, and gastrula, as well as it was modulated in the zygotic nucleus of outer balstomers of 32-cell embryo, neurula presumptive epidermis tissue and larval mesenchyme. The anti CinPO2 antibodies, specific for adult inflammatory cells, recognize epitopes in the cytoplasm of ovarian oocytes, ovulated eggs, development stages and larval mesenchyme. The overall findings disclose the precocious activation of the CinPO2 immunity-related gene, and show a developmentally programmed expression of this phenoloxidase. Furthermore, these findings support the multifunctional roles of immunity-related genes and allows us to explore new perspectives on ascidian development and immunity. PMID- 25786784 TI - Should patients with asymptomatic pompe disease be treated? A nationwide study in France. AB - INTRODUCTION: Acid alpha-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available. It is not known whether patients diagnosed at an asymptomatic stage should be treated to prevent progression of the disease. METHODS: We investigated 7 patients with asymptomatic Pompe disease identified from the French Pompe registry. RESULTS: The patients had a mean age of 45 (range 24-75) years, a median follow-up duration of 2 (range 1-22) years, and normal clinical examination, pulmonary function tests (PFTs), and echocardiography. All presented with at least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and muscle MRI abnormalities, suggesting that subclinical myopathy was present in all cases. CONCLUSIONS: Asymptomatic Pompe disease may remain clinically silent for decades, and affected patients should be monitored closely for overt myopathy using clinical examination, PFTs, and muscle MRI to determine when to start ERT. PMID- 25786785 TI - Renal denervation--hypes and hopes. AB - Catheter-based renal denervation (RDN) is a novel invasive approach in the treatment of resistant hypertension. It is considered a minimally invasive and safe procedure which, as shown by initial experimental and clinical trials, is able not only to reduce blood pressure but also to modify its risk factors by modulation of autonomic nervous system. Recently published results of a randomized Symplicity HTN-3 trial, which failed to demonstrate RDN-induced reduction of blood pressure at six months, decreased the initial enthusiasm regarding RDN and raised a question about real efficacy of this procedure. Nevertheless, still there are some other conditions characterized by increased sympathetic tone such as heart failure, atrial fibrillation, or ventricular arrhythmias that may benefit from RDN. Furthermore, novel therapeutical approach toward RDN using adapted electrophysiological or new specially designed electrodes may improve effectiveness of RDN procedure. PMID- 25786786 TI - Imaging the Predicted Isomerism of Oligo(aniline)s: A Scanning Tunneling Microscopy Study. AB - The self-assembly of two emeraldine base tetra(aniline) derivatives is investigated using scanning tunneling microscopy. A combination of the scanning tunneling microscopy data and calculations reveals the presence of predicted cis/trans isomerism in this oxidation state. This isomerism is shown to hinder self-assembly into ordered structures, and provides indications as to why the properties of these materials, and their parent polymer, polyaniline, remain unfulfilled. PMID- 25786787 TI - An updated look at actin dynamics in filopodia. AB - Cells dynamically interact with and probe their environment by growing finger like structures named filopodia. The dynamics of filopodia are mainly caused by the actin rich core or shaft which sits inside the filopodial membrane and continuously undergoes changes like growth, shrinking, bending, and rotation. Recent experiments combining advanced imaging and manipulation tools have provided detailed quantitative data on the correlation between mechanical properties of filopodia, their molecular composition, and the dynamic architecture of the actin structure. These experiments have revealed how retrograde flow and twisting of the actin shaft within filopodia can generate traction on external substrates. Previously, the mechanism behind filopodial pulling was mainly attributed to retrograde flow of actin, but recent experiments have shown that rotational dynamics can also contribute to the traction force. Although force measurements have indicated a step-like behavior in filopodial pulling, no direct evidence has been provided to link this behavior to a molecular motor like myosin. Therefore, the underlying biochemical and mechanical mechanisms behind filopodial force generation still remain to be resolved. PMID- 25786788 TI - Navigating the circuitry of the brain's GPS system: Future challenges for neurophysiologists. AB - The discovery of the brain's navigation system creates a compelling challenge for neurophysiologists: how do we map the circuitry of a system that can only be definitively identified in awake, behaving animals? Do grid and border cells in the entorhinal cortex correspond to the two classes of principal cell found there, stellate and pyramidal cells? In the hippocampus, does the diversity seen in pyramidal cell subtypes have functional correlates in the place cell system? How do interneurons regulate the activity of spatially tuned principal cells in the hippocampal and entorhinal circuits? Here, we discuss recent literature relating the cellular circuitry of these circuits to in vivo studies of the brain's navigation system, and the role that interneurons have in regulating the activity of principal cells in these circuits. We propose that studying in vitro models of neuronal oscillations in the entorhinal cortex and hippocampus can provide useful insights for bridging the gap in understanding that exists in relating in vivo and behavioral studies to circuit function at the cellular level. PMID- 25786789 TI - meso-Ester Corroles. AB - The introduction of ester groups on the 5- and 15-meso positions of corroles stabilizes them against oxidation and induces a redshift of their absorption and emission spectra. These effects are studied through the photophysical and electrochemical characterization of up to 16 different 5,15-diester corroles, in which the third meso position is free or occupied by an aryl group, a long alkyl chain, or an ester moiety. Single-crystal X-ray structure analysis of five 5,15 diestercorroles and DFT and time-dependent DFT calculations show that the strong electron-withdrawing character of the 5,15 ester substituents is reinforced by their pi overlap with the macrocyclic aromatic system. The crystal packing of corroles 2, 4, 6, 9, and 15 features short distances between chromophores that are stacked into columns thanks to the low steric hindrance of meso-ester groups. This close packing is partially due to intermolecular interactions that involve inner hydrogen and nitrogen atoms, and thereby, stabilize a single, identical corrole tautomeric form. PMID- 25786790 TI - Proteins involved in more domain types tend to be more essential. AB - Investigation of essential proteins is significantly valuable for understanding of cellular life, drug design and other practical purposes. In most of current studies, essential proteins are generally mined in protein-protein interaction (PPI) networks with diverse topology features. In this study, we investigate what kind of proteins is inclined to be essential from a new perspective. The investigation implies that protein essentiality is correlated with protein domains, which are functional, structural and evolutionary units of proteins. Proteins with a larger Number of Domain Types (NDT) tend to be essential. The analyses on 22 species show that essential proteins identified by NDT are much more than those identified by ten random identifications. The consideration of the structural feature makes us less dependent on network data and thus enables us to investigate protein essentiality of more species with incomplete and/or inconsistent network data. PMID- 25786791 TI - Classification methods for the analysis of LH-PCR data associated with inflammatory bowel disease patients. AB - The human gut is one of the most densely populated microbial communities in the world. The interaction of microbes with human host cells is responsible for several disease conditions and of criticality to human health. It is imperative to understand the relationships between these microbial communities within the human gut and their roles in disease. In this study we analyse the microbial communities within the human gut and their role in Inflammatory Bowel Disease (IBD). The bacterial communities were interrogated using Length Heterogeneity PCR (LH-PCR) fingerprinting of mucosal and luminal associated microbial communities for a class of healthy and diseases patients. PMID- 25786792 TI - Looking into the genome of Thermosynechococcus elongatus (thermophilic cyanobacteria) with codon selection and usage perspective. AB - Genome analysis of thermophilic cyanobacterium, Thermosynechococcus elongatus BP 1 revealed factors ruling choices of codons in this organism. Multiple parameters like Nc, GC3s, RSCU, Codon Adaptation Index (CAI), optimal and rare codons, codon pair context and amino acid usage were analysed and compositional constraint was identified as major factor. Wide range of Nc values for the same GC3 content suggested the role of translational selection. Mutational bias is suggested at synonymous position. Among optimal codons for translation, most were GC-ending. Seven codons (AGA, AGG, AUA, UAA, UAG, UCA and UGA) were found to have least occurrence in the entire genome and except stop codons all were A-ending (exception AGG). Most widely used codon-pair in the genome are G-ending or C ending and A-ending or U-ending codons make pair with G-ending or C-ending codons. Amino acids which are largely distributed in T. elongatus tend to use G ending or C-ending codons most frequently. Findings showed cumulative role of translational selection, translational accuracy and gene expression levels with mutational bias as key player in codon selection pattern of this organism. PMID- 25786793 TI - Preclinical evaluation and molecular docking of 2,5-di-tert-butyl-1,4 benzoquinone (DTBBQ) from Streptomyces sp. VITVSK1 as a potent antibacterial agent. AB - The incidence of bacterial disease has increased tremendously in the last decade, because of the emergence of drug resistance strains within the bacterial pathogens. The present study was to investigate the antibacterial compound 2,5-di tert-butyl-1,4-benzoquinone (DTBBQ) isolated from marine Streptomyces sp. VITVSK1 as a potent antibacterial agent. The antibacterial potential of DTBBQ was investigated against RNA Polymerase (PDB ID-1I6V) by in silico molecular docking tools. Results of our study showed the high affinity interaction between DTBBQ and RNA polymerase and also confirmed the drug likeliness of DTBBQ using ADMET in silico pharmacology tools. Our findings suggest that DTBBQ could be used as antibacterial drug to defend the emerging antibacterial resistance. PMID- 25786794 TI - Artificial neural networks for dihedral angles prediction in enzyme loops: a novel approach. AB - Structure prediction of proteins is considered a limiting step and determining factor in drug development and in the introduction of new therapies. Since the 3D structures of proteins determine their functionalities, prediction of dihedral angles remains an open and important problem in bioinformatics, as well as a major step in discovering tertiary structures. This work presents a method that predicts values of the dihedral angles phi and psi for enzyme loops based on data derived from amino acid sequences. The prediction of dihedral angles is implemented through a neural network based mining mechanism. The amino acid sequence data represents 6342 enzyme loop chains with 18,882 residues. The initial neural network input was a selection of 115 features and the outputs were the predicted dihedral angles phi and psi. The simulation results yielded a 0.64 Pearson's correlation coefficient. After feature selection through determining insignificant features, the input feature vector size was reduced to 45, while maintaining close to identical performance. PMID- 25786795 TI - HDVDB: a data warehouse for hepatitis delta virus. AB - Hepatitis Delta Virus (HDV) is an RNA virus and causes delta hepatitis in humans. Although a lot of data is available for HDV, but retrieval of information is a complicated task. Current web database 'HDVDB' provides a comprehensive web resource for HDV. The database is basically concerned with basic information about HDV and disease caused by this virus, genome structure, pathogenesis, epidemiology, symptoms and prevention, etc. Database also supplies sequence data and bibliographic information about HDV. A tool 'siHDV Predict' to design the effective siRNA molecule to control the activity of HDV, is also integrated in database. It is a user friendly information system available at public domain and provides annotated information about HDV for research scholars, scientists, pharma industry people for further study. PMID- 25786796 TI - Combining classifiers generated by multi-gene genetic programming for protein fold recognition using genetic algorithm. AB - In this study the problem of protein fold recognition, that is a classification task, is solved via a hybrid of evolutionary algorithms namely multi-gene Genetic Programming (GP) and Genetic Algorithm (GA). Our proposed method consists of two main stages and is performed on three datasets taken from the literature. Each dataset contains different feature groups and classes. In the first step, multi gene GP is used for producing binary classifiers based on various feature groups for each class. Then, different classifiers obtained for each class are combined via weighted voting so that the weights are determined through GA. At the end of the first step, there is a separate binary classifier for each class. In the second stage, the obtained binary classifiers are combined via GA weighting in order to generate the overall classifier. The final obtained classifier is superior to the previous works found in the literature in terms of classification accuracy. PMID- 25786797 TI - Subgroups of multiple sclerosis patients with larger treatment benefits: a meta analysis of randomized trials. AB - BACKGROUND AND PURPOSE: No subgroups of patients with higher treatment effects have been clearly detected in multiple sclerosis (MS). The aim of the present work was to evaluate whether there are subgroups of relapsing-remitting MS (RRMS) patients who are more responsive to treatments. METHODS: All published randomized clinical trials in RRMS reporting a subgroup analysis of treatment effect were collected. Two main outcomes, the annualized relapse rate (ARR) and the disability progression, were studied. The treatment effect in each subgroup was reported as a relative effect (RE), defined as the treatment effect in the subgroup relative to the overall effect. A meta-analysis was run to compare the RE between subgroups. RESULTS: Six trials (6693 RRMS patients) were included. Treatment effects on ARR were significantly higher in younger than in older subjects (RE = 0.83 vs. RE = 1.30, P < 0.001), in patients with than those without gadolinium activity (RE = 0.86 vs. RE = 1.15, P = 0.005) and in patients with lower than in those with higher Expanded Disability Status Scale (RE = 0.96 vs. RE = 1.23, P = 0.02), and on disability progression in younger than in older subjects (RE = 0.82 vs. RE = 1.28, P = 0.017). CONCLUSIONS: This study formally shows that in RRMS higher treatment effects are associated with characteristics of earlier (lower age and Expanded Disability Status Scale) and more active (higher gadolinium activity) disease. PMID- 25786798 TI - CHD2 is Required for Embryonic Neurogenesis in the Developing Cerebral Cortex. AB - Chromodomain helicase DNA-binding protein 2 (CHD2) has been associated with a broad spectrum of neurodevelopmental disorders, such as autism spectrum disorders and intellectual disability. However, it is largely unknown whether and how CHD2 is involved in brain development. Here, we demonstrate that CHD2 is predominantly expressed in Pax6(+) radial glial cells (RGs) but rarely expressed in Tbr2(+) intermediate progenitors (IPs). Importantly, the suppression of CHD2 expression inhibits the self-renewal of RGs and increases the generation of IPs and the production of neurons. CHD2 mediates these functions by directly binding to the genomic region of repressor element 1-silencing transcription factor (REST), thereby regulating the expression of REST. Furthermore, the overexpression of REST rescues the defect in neurogenesis caused by CHD2 knockdown. Taken together, these findings demonstrate an essential role of CHD2 in the maintenance of the RGs self-renewal levels, the subsequent generation of IPs, and neuronal output during neurogenesis in cerebral cortical development, suggesting that inactivation of CHD2 during neurogenesis might contribute to abnormal neurodevelopment. PMID- 25786799 TI - Using the Watchman device to close the left atrial appendage reduces risk of stroke in atrial fibrillation, compared to using warfarin. PMID- 25786800 TI - Cotrimoxazole is associated with sudden death in older patients receiving inhibitors of renin-angiotensin system. PMID- 25786801 TI - Conventional bronchoscopic techniques in sarcoidosis: not too far behind. PMID- 25786802 TI - Teenager with chest pain and swollen neck: a leave-it-alone condition. AB - A 19-year-old boy with shortness of breath and chest pain after strenuous exercise presented to emergency department . On physical examination, the neck and shoulders appeared to be swollen. There was crepitus on skin palpation. Chest X-ray disclosed diffuse subcutaneous emphysema and pneumomediastinum. CT showed additional finding of air in epidural space. The patient was discharged after 2 days of hospitalisation with conservative treatment uneventfully. Pneumorrhachis is usually caused by abrupt increase in intrathoracic pressure in instance of forceful vomiting, cough or asthma attack in an otherwise healthy young adult. It is usually accompanied with pneumomediastinum. The management of epidural pneumatosis should be tailored according to its primary cause. For most patients with pneumorrhachis associated to a spontaneous pneumomediastinum without neurological symptoms, this condition is generally self-limited. For epidural free air of large volume that causes neurological deficits, surgical laminectomy may be indicated. PMID- 25786803 TI - Oral health and dental care in aged care facilities in New South Wales, Australia. Part 3 concordance between residents' perceptions and a professional dental examination. AB - OBJECTIVES: To determine the perceptions of dental care held by the residents in aged care facilities (ACFs) in New South Wales (NSW) and to compare these perceptions with clinical observations. BACKGROUND: No specific data exist relating to NSW residents' perceptions of dental care compared with a clinical examination. Planning for appropriate oral health programs in ACFs necessitate such data. MATERIALS AND METHODS: Four Area Health Services of Sydney and 25 low care ACFs were selected from which representative residents were sampled who completed a survey and underwent a basic dental examination. RESULTS: Of the subjects (25 males, 96 females), 76.9% had never received a dental visit as entering the ACF; 14.1% suffered from dental pain; 69.4% wore dentures and of these 18.3% required assistance in cleaning. Dentures were cleaned twice/day in 54.9% of cases. Natural teeth were reported present in 71.9% of residents, and 85.1% did not require assistance in cleaning. Appropriate dental care facilities and dry mouth were most frequent problems highlighted. Clinical examinations showed that 69% were denture wearers; oral hygiene and denture hygiene were considered good in 15.7% of cases. A high level of concordance existed between self-reports and examination. CONCLUSIONS: Increased awareness about oral health across leadership, caregivers and residents with appropriate dental health education and dedicated space within facilities would provide a much needed improvement for addressing oral health issues of the ACF residents. This might be the right time to plan for the future challenges that will need to be met by the NSW care system. PMID- 25786804 TI - Consolidated bioprocessing of starchy substrates into ethanol by industrial Saccharomyces cerevisiae strains secreting fungal amylases. AB - The development of a yeast strain that converts raw starch to ethanol in one step (called Consolidated Bioprocessing, CBP) could significantly reduce the commercial costs of starch-based bioethanol. An efficient amylolytic Saccharomyces cerevisiae strain suitable for industrial bioethanol production was developed in this study. Codon-optimized variants of the Thermomyces lanuginosus glucoamylase (TLG1) and Saccharomycopsis fibuligera alpha-amylase (SFA1) genes were delta-integrated into two S. cerevisiae yeast with promising industrial traits, i.e., strains M2n and MEL2. The recombinant M2n[TLG1-SFA1] and MEL2[TLG1 SFA1] yeast displayed high enzyme activities on soluble and raw starch (up to 8118 and 4461 nkat/g dry cell weight, respectively) and produced about 64 g/L ethanol from 200 g/L raw corn starch in a bioreactor, corresponding to 55% of the theoretical maximum ethanol yield (g of ethanol/g of available glucose equivalent). Their starch-to-ethanol conversion efficiencies were even higher on natural sorghum and triticale substrates (62 and 73% of the theoretical yield, respectively). This is the first report of direct ethanol production from natural starchy substrates (without any pre-treatment or commercial enzyme addition) using industrial yeast strains co-secreting both a glucoamylase and alpha amylase. PMID- 25786805 TI - MRI-Defined Corpus Callosal Atrophy in Multiple Sclerosis: A Comparison of Volumetric Measurements, Corpus Callosum Area and Index. AB - OBJECTIVE: To compare corpus callosum area (CCA) and corpus callosum index (CCI) in terms of feasibility and their performance as biomarkers for cognitive and physical disability in multiple sclerosis (MS). A secondary aim was to compare these two methods with volumetric measurements. METHODS: This study was based on a cohort of 37 MS patients and a group of age- and gender-matched healthy controls. Physical disability was assessed with the expanded disability status scale (EDSS) and cognitive disability with the symbol digit modalities test (SDMT). CCA and CCI were assessed on midsagittal brain MRI by 3 raters with varying radiological experience. Volumes of the brain, gray and white matter, corpus callosum, and MS lesions were acquired with Freesurfer and Lesion Segmentation Toolbox for Statistical Parametric Mapping. RESULTS: CCA and CCI were obtained within seconds with excellent intra- and inter-rater agreement, and outperformed volumetric measurements. CCA had the strongest correlations with both SDMT (r = .82, P < .001) and EDSS (r = -.56, P < .001), and the highest accuracy in differentiating patients from controls (95%) and relapse-remitting MS from progressive forms of MS (77%). CCI performed less well (r = .73, P < .001; r = -.45, P < .001; 94%; 71%). CCA also outperformed the volumetric measurements in these regards. CONCLUSIONS: CCA is a time-effective and robust biomarker that has stronger correlations with both EDSS and information processing speed than CCI and volumetric measurements that are commonly used as outcome measures in MS research and clinical trials. PMID- 25786806 TI - Emotions are not always contagious: Longitudinal spreading of self-pride and group pride in homogeneous and status-differentiated groups. AB - The members of task groups are emotionally more similar to each other than to others outside the group; yet, little is known about the conditions under which this emotional similarity emerges. In two longitudinal studies, we tested the idea that emotions only spread when they contain information that is relevant to all group members. We compared the spreading of group pride (relevant) with self pride (not relevant). The first study followed emotions in 68 task groups (N = 295) across 4 moments. Multilevel cross-lagged path analyses showed that group members mutually influenced each other's group pride, but not self-pride. The second study followed emotions in 27 task groups (N = 195) across 3 moments in time. Longitudinal social network analyses showed that group members adjusted their group pride, but not their self-pride, to members they perceived to be more influential. Findings from both studies are consistent with a social referencing account of emotion spreading. PMID- 25786807 TI - Choice of Peripheral Venoarterial Extra-Corporeal Membrane Oxygenation Cannulation Site in Patients Above 15 kilograms. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving measure for pediatric patients with cardiopulmonary failure. The option of cannulating neck vessels versus those of the groin exists for patients over 15 kg; however, each carries the risk for complications. We present a single-center experience comparing the risks and benefits of these alternate peripheral ECMO cannulation sites. METHODS: All pediatric patients supported by venoarterial (VA) ECMO via peripheral cannulation from January 2006 to May 2013 were retrospectively reviewed, excluding those weighing less than 15 kg. We compared complications of neck versus groin cannulation sites, including neurologic dysfunction, limb ischemia, and in-hospital mortality. Univariate analysis and multivariable logistic regression were performed to identify factors for complications including mortality. RESULTS: Thirty-six patients (median age 10.8 years, interquartile range: 6.0-15.8) were cannulated for VA ECMO. Forty-four percent were cannulated via neck vessels and 47% were cannulated via groin. Nine percent were cannulated at both sites. Overall survival was 72% at decannulation and 67% at hospital discharge. No statistically significant survival difference between groin and neck cannulation subgroups was found. Rate of neurologic injury was higher in neck (25%) versus groin (12%) cannulation, but this was not statistically significant (p = 0.52). Extremity ischemia occurred in five patients having groin cannulation (29%, p = 0.04). CONCLUSIONS: Neck cannulation is a valuable alternative to groin vessels in patients above 15 kg. Risk of limb ischemia with groin cannulation is significant, and must be considered when choosing the cannulation site for ECMO support. PMID- 25786809 TI - Erratum: correction to: a pivotal moment in Alzheimer's disease and dementia: how global unity of purpose and action can beat the disease by 2025. PMID- 25786810 TI - Magnetic inhomogeneity on a triangular lattice: the magnetic-exchange versus the elastic energy and the role of disorder. AB - Inhomogeneity in the ground state is an intriguing, emergent phenomenon in magnetism. Recently, it has been observed in the magnetostructural channel of the geometrically frustrated alpha-NaMnO2, for the first time in the absence of active charge degrees of freedom. Here we report an in-depth numerical and local probe experimental study of the isostructural sister compound CuMnO2 that emphasizes and provides an explanation for the crucial differences between the two systems. The experimentally verified, much more homogeneous, ground state of the stoichiometric CuMnO2 is attributed to the reduced magnetoelastic competition between the counteracting magnetic-exchange and elastic-energy contributions. The comparison of the two systems additionally highlights the role of disorder and allows the understanding of the puzzling phenomenon of phase separation in uniform antiferromagnets. PMID- 25786808 TI - Low-variance RNAs identify Parkinson's disease molecular signature in blood. AB - The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection. PMID- 25786811 TI - Effect of high-volume systematic local infiltration analgesia in Caesarean section: a randomised, placebo-controlled trial. AB - BACKGROUND: Pain after Caesarean section is often treated with opioids with a risk of side effects. Wound infiltration with local anaesthetics is effective and has few side effects, but volume vs. dose concentration has not been examined. METHODS: Ninety patients scheduled for elective Caesarean section included in a randomised, double-blinded, placebo-controlled trial receiving infiltration with 50 ml ropivacaine 0.5% or 125 ml ropivacaine 0.2% or 50 ml 0.9% saline (placebo) during surgery. Surgery was performed under lumbar spinal anaesthesia. Primary endpoint was post-operative pain. Secondary endpoints were rescue analgesic, post operative nausea and vomiting, time spent in the postanesthesia care unit (PACU) and time to first mobilisation. RESULTS: No difference in pain response between groups, but time until maximum pain score was prolonged in the ropivacaine 0.5% group compared with the placebo group (P = 0.0493). The administration of ketobemidone at 24 h post-operatively in the ropivacaine 0.5% group was reduced compared with the placebo group (P = 0.020), and between the ropivacaine 0.2% group and the ropivacaine 0.5% group (P = 0.044). No significant differences between groups were found concerning time spent in the PACU, to first mobilisation or in number of women with nausea/vomiting (P >= 0.05). No complications related to ropivacaine were observed. CONCLUSIONS: Systematic infiltration with a high concentration, low volume compared with low concentration, high volume showed no significant effect on post-operative pain intensity. However, a statistically significant, but clinically limited opioid sparing effect was demonstrated compared with placebo in the high concentration, low volume group. PMID- 25786812 TI - Stereological reconstruction of polycrystalline materials. AB - Laguerre tessellations are suitable models for many polycrystalline materials. In this work, we present a reconstruction-based approach to fit a spatial Laguerre tessellation model to a plane section of a cellular material under the condition that one section of the model resembles the observed section of the material. To account for this special requirement, we introduce a novel Euclidean distance based criterion for the model fitting. The model fitting itself is based on Simulated Annealing. If the structure under consideration is a Laguerre tessellation, we found a nearly perfect reconstruction of its spatial cell characteristics in the model. Even for a real sample of a sintered alumina the observed section is captured quite well by the model. PMID- 25786813 TI - Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease. AB - AIMS: Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest gamma-aminobutyric acid (GABA)-ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. METHODS: Histochemical, immunohistochemical and immunofluorescent assays were performed on post-mortem brain tissue from 10 patients and 10 age-matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. RESULTS: We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. CONCLUSIONS: We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease. PMID- 25786814 TI - Presence of albuminuria predicts left ventricular mass in patients with chronic systemic arterial hypertension. AB - BACKGROUND: Increased left ventricular mass (LVM) is known to predict cardiovascular morbidity and mortality. LVM is high in patients with advanced kidney disease. Our aim was to study the relationship between renal parameters and LVM in hypertensive subjects at high risk of cardiovascular disease. DESIGN: Cardiac MRI was performed in 527 patients participating in the single-centre SMART cohort study. Participants free from previous symptomatic coronary heart disease but with a history of hypertension were recruited. Subjects were screened for cardiovascular risk factors in a standardized way. Multivariable linear regression was used to study the relationship of both estimated glomerular filtration rate (eGFR) and presence of albuminuria with left ventricular mass. RESULTS: Mean LVM was 121 g for men (SD 26) and 87 g for women (SD 20). Mean eGFR was 82 mL/min/1.73 m(2) (SD 19). A total of 73 patients (14%) had albuminuria. After adjusting for known determinants of LVM (height, weight, sex and age) eGFR did not relate to LVM while presence of albuminuria did (mean change in LVM per 10 mL/min/1.73 m(2) change in eGFR 0.79 g, 95% CI -0.33 to 1.91, P = 0.17, mean change in LVM in presence vs. absence of albuminuria 9.9 g, 95% CI 4.33 to 15.45, P = 0.001). Additional adjustment for systolic blood pressure did not change results (B for eGFR 0.54, 95% CI -0.58 to 1.66, P = 0.35, B for albuminuria 9.09, 95% CI 3.57 to 14.60, P = 0.001). CONCLUSIONS: In this study in hypertensive patients with high vascular risk, albuminuria was related to increased LVM and eGFR was not. PMID- 25786815 TI - Simultaneous stent expansion/balloon deflation technique to salvage failed balloon remodeling. AB - Herniation, with possible embolization, of coils into the parent vessel following aneurysm coiling remains a frequent challenge. For this reason, balloon or stent assisted embolization remains an important technique. Despite the use of balloon remodeling, there are occasions where, on deflation of the balloon, some coils, or even the entire coil mass, may migrate. We report the successful use of a simultaneous adjacent stent deployment bailout technique in order to salvage coil prolapse during balloon remodeling in three patients. Case No 1 was a wide neck left internal carotid artery bifurcation aneurysm, measuring 9 mm*7.9 mm*6 mm with a 5 mm neck. Case No 2 was a complex left superior hypophyseal artery aneurysm, measuring 5.3 mm*4 mm*5 mm with a 2.9 mm neck. Case No 3 was a ruptured right posterior communicating artery aneurysm, measuring 4 mm*4 mm*4.5 mm with a 4 mm neck. This technique successfully returned the prolapsed coil mass into the aneurysm sac in all cases without procedural complications. The closed cell design of the Enterprise VRD (Codman and Shurtleff Inc, Raynham, Massachusetts, USA) makes it ideal for this bailout technique, by allowing the use of an 0.021 inch delivery catheter (necessary for simultaneous access) and by avoiding the possibility of an open cell strut getting caught on the deflated balloon. We hope this technique will prove useful to readers who may find themselves in a similar predicament. PMID- 25786816 TI - Endogenous endophthalmitis with a visual acuity of 6/6. AB - A 43-year-old man suffering from Klebsiella liver abscess and bacteraemia presented with left eye visual disturbance a few days after admission. His visual acuity was 6/6. There was a whitish subretinal mass located at the temporal periphery without vitritis. His visual acuity dropped to 6/120 with marked vitritis 1 day later and a diagnosis of a subretinal abscess was made. The vitreous cultures were negative. Response was suboptimal with intravitreal antibiotics, and retinotomy, vitrectomy, antibiotic irrigation and silicone oil tamponade were required. His vision gradually improved to 6/60 with silicone oil in situ. This case illustrates the rare presentation of a subretinal abscess in endogenous endophthalmitis with no initial associated vitritis, and the importance of maintaining a high level of suspicion despite good visual acuity on presentation in cases with relevant history. Early detection and intervention, and close monitoring may salvage the patient's vision in such cases. PMID- 25786817 TI - A delayed presentation of bilateral leg compartment syndrome following non-stop dancing. AB - We present the case of a young man with a 48 h delayed presentation of bilateral lower limb acute compartment syndrome (ACS) affecting the anterior compartments following an extended period of dancing at a music festival. On making the diagnosis of ACS, the patient was immediately taken to theatre for fasciotomies and compartmental decompression. Repeat look fasciotomies revealed further necrosis to the muscles of the anterior compartments bilaterally and, effectively, all the muscle bellies within the anterior compartments were excised. The patient has been left with a significant functional deficit and disability. This case highlights the importance of timely diagnosis of ACS as delay in presentation can impact significantly on subsequent functional outcome and quality of life. PMID- 25786818 TI - Pain and activity limitations in women and men with contemporary treated early RA compared to 10 years ago: the Swedish TIRA project. AB - OBJECTIVES: To study differences regarding pain and activity limitations during the 3 years following diagnosis in women and men with contemporary treated early RA compared with their counterparts who were diagnosed 10 years earlier. METHOD: This study was based on patients recruited to the Early Intervention in RA (TIRA) project. In the first cohort (TIRA-1) 320 patients were included in time for diagnosis during 1996-1998 and 463 patients were included in the second cohort (TIRA-2) during 2006-2009. Disease activity, pain intensity (Visual Analogue Scale, VAS), bodily pain (BP) in the 36-item Short Form Health Survey (SF-36), activity limitations (Health Assessment Questionnaire, HAQ), and medication were reported at inclusion and at follow-up after 1, 2, and 3 years. RESULTS: Disease activity, pain, and activity limitations were pronounced at inclusion across both genders and in both cohorts, with some improvement observed during the first year after diagnosis. Disease activity did not differ between cohorts at inclusion but was significantly lower at the follow-ups in the TIRA-2 cohort, in which the patients were prescribed traditional disease-modifying anti-rheumatic drugs (DMARDs) and biological agents more frequently. In TIRA-2, patients reported significantly lower pain and activity limitations at all follow-ups, with men reporting lower pain than women. Women reported significantly higher activity limitations at all time points in TIRA-2. CONCLUSIONS: Pain and activity limitations were still pronounced in the contemporary treated early RA cohort compared with their counterparts diagnosed 10 years earlier and both of these factors need to be addressed in clinical settings. PMID- 25786819 TI - Clinical outcomes after high-flex versus conventional total knee arthroplasty. AB - PURPOSE: To compare clinical outcomes after high-flex versus conventional total knee arthroplasty (TKA). METHODS: A systematic review and meta-regression were performed to compare post-operative outcomes between the two types of prostheses. Relevant randomized controlled trials were identified from MEDLINE and Scopus up to November, 2014. RESULTS: Fourteen of 369 studies were eligible; 14, 7, 6, 5, 3, 12 and 7 studies were included in the pooling of maximum knee flexion, Knee Society Knee Score (KS), Knee Society Function Score (FS), Hospital for Special Surgery score (HSS), short-form (SF) physical activity score, post-operative complications (DVT, fractures, infection) and revision TKA, respectively. The high-flex TKA had 1.97 degrees [95% confidence interval (CI) 0.37, 3.57], -0.86 (95% CI -1.65, 0.07) and -1.34 (-2.57, -0.11) higher mean maximum knee flexion, KS and FS when compared to conventional TKA. However, there were non-significant differences in HSS, SF-36 (physical), complications and revision TKA. CONCLUSION: This study suggests that there are improvements in post-operative knee range of motion and knee scores in high-flex TKA implants when compared to conventional TKA implants; however, the difference was very small and therefore might not have any clinical impact. Therefore, conventional TKA can be used as a substitute. However, cost-effective analysis should be performed to make appropriate selections in the future. There are no statistically significant differences in terms of HSS, quality of life, complications and revisions between the groups. LEVEL OF EVIDENCE: I. PMID- 25786820 TI - Peroneal tendinosis as a predisposing factor for the acute lateral ankle sprain in runners. AB - PURPOSE: A painful episode in the region of the peroneal tendons, within the retromalleolar groove, is a common precipitating event of an acute lateral ankle sprain. A forefoot striking pattern is suspected to cause peroneal tendinosis. The aim of this study is to analyse the role of peroneal tendinosis as a predisposing factor for ankle sprain trauma in runners. METHODS: Fifty-eight runners who had experienced acute ankle sprain trauma, with pre-existing pain episodes for up to 4 weeks in the region of the peroneal tendons, were assessed clinically. Fractures were excluded by conventional radiography. An magnetic resonance imaging (MRI) scan had been performed within 14 days after the traumatic event and was subsequently evaluated by two experienced radiologists. RESULTS: MRI revealed peroneal tendinosis in 55 patients (95% of the total study population). Peroneus brevis (PB) tendinosis was found in 48 patients (87% of all patients with peroneal tendinosis), and peroneus longus (PL) tendinosis was observed in 42 cases (76%). Thirty-five patients (64%) had combined PB and PL tendinosis. A lesion of the anterior talofibular ligament was found to be the most common ligament injury associated with peroneal tendinosis (29 cases; 53%), followed by a lesion of the calcaneofibular ligament (16 cases; 29%) and a lesion of the posterior tibiofibular ligament (13 cases; 24%). CONCLUSION: The results of this study reflect the correlation between peroneal tendinosis and ankle sprain trauma. Injuries of one or more ligaments are associated with further complications. A period of rest or forbearance of sports as well as adequate treatment of the peroneal tendinosis is essential to prevent subsequent ankle injuries, especially in runners. Modification of the running technique would also be beneficial. LEVEL OF EVIDENCE: IV. PMID- 25786821 TI - Opening wedge high tibial osteotomy using a monoaxial dynamic external fixator. AB - PURPOSE: To prospectively assess midterm results in 37 patients (41 knees) who were treated with opening wedge high tibial osteotomy (OW-HTO) with the use of a monoaxial dynamic external fixator (MDEF) for medial knee osteoarthritis. METHODS: Clinical and subjective evaluations were performed using the IKDC and KOOS evaluation forms and the modified Knee Society Clinical Rating System (KSS). Pin tract infections were evaluated according to Checketts-Otterburns classification. Radiographic evaluation included long-standing AP lower limb, standard lateral, Rosenberg and Merchant views. RESULTS: Thirty-six patients (40 knees) were evaluated at a mean follow-up period of 7 years. Ten patients (25 %) developed a minor pin tract infection. Subjective KOOS and IKDC scores showed statistically significant improvement. Clinical evaluation with IKDC and KSS forms showed no patient with instability or a range-of-motion deficit worst than pre-operatively. At MDEF removal, the mechanical axis was on average 4.5 degrees valgus; anatomical axis 6.8 degrees valgus; the Mikulicz' line crossed the tibial plateau on average at 64 % of the width of the tibial plateau measured from medial; the posterior slope 5 degrees ; the metaphyseal varus 4.3 degrees ; and the Insall/Salvati ratio 1.02. At latest follow-up, five patients had a loss of correction of 1 degrees -2 degrees on mechanical axis and one patient had a loss of correction of 3 degrees on mechanical axis and 4 % of mechanical axis on tibial plateau. CONCLUSIONS: The use of a MDEF to perform an OW-HTO showed a good maintenance of correction achieved with satisfactory midterm outcome results in all patients but three who underwent total knee replacement. The only severe post operative complication was one case of non-union in a heavy smoker. LEVEL OF EVIDENCE: Prospective and therapeutic study, Level IV. PMID- 25786822 TI - Risk factors for knee instability after anterior cruciate ligament reconstruction. AB - PURPOSE: The objective of this study was to estimate risk factors that influence postoperative instability after anterior cruciate ligament (ACL) reconstruction using multivariate logistic regression analysis. METHODS: A total of 152 consecutive patients with symptomatic ACL insufficiency underwent arthroscopic ACL reconstruction between 2005 and 2011. Loss to follow-up and previous ligament reconstruction were exclusion criteria, resulting in 131 patients remaining for this retrospective study. The median follow-up was 55 months (range 25-100 months). Patients were sorted into two groups by anterior translation on stress radiograph and pivot shift test grade and were analysed for the statistical significance of various risk factors including age at surgery, gender, body mass index, preoperative instability, time from injury to surgery, single-bundle reconstruction with preserved abundant remnant versus double-bundle reconstruction with scanty remnant, and concomitant ligament, meniscus, and articular cartilage injury with use of multivariate logistic regression analysis. RESULTS: Time from injury to surgery over 12 weeks was found to be a significant risk factor for postoperative instability [p < 0.001, adjusted odds ratio (OR) 6.22; 95 % confidence interval (CI) 2.14-18.06)]. Grade 2 injury of medial collateral ligament (MCL) was also a risk factor (p = 0.02, adjusted OR 13.60; 95 % CI 1.24-148.25). The other variables were not found to be a significant risk factor. CONCLUSIONS: Among the risk factor variables, concomitant grade 2 MCL injury and surgical delay of more than 12 weeks from injury were significant risk factors for postoperative knee instability after ACL reconstruction. The overall results suggest that surgery <12 weeks from injury and meticulous attention to concomitant MCL injury should be considered. LEVEL OF EVIDENCE: Retrospective case-control study, Level III. PMID- 25786823 TI - Is meniscal allograft transplantation chondroprotective? A systematic review of radiological outcomes. AB - PURPOSE: The primary aim of this systematic review was to examine the hypothesis that meniscal allograft transplantation is chondroprotective by identifying and appraising studies that have assessed the progression of osteoarthritis following meniscal allograft transplantation. The secondary aim was to identify and appraise radiological measures of meniscal allograft integrity following surgery. METHODS: Clinical studies on human participants undergoing meniscal allograft transplantation with a minimum follow-up of 6 months were included. The primary outcome measure was any radiological osteoarthritis progression measure. Secondary outcomes included magnetic resonance measures of meniscal integrity including meniscal size, shape, healing, extrusion and signal intensity. RESULTS: Thirty-eight studies with 1056 allografts were included. The weighted mean joint space loss was 0.032 mm at 4.5 years across 11 studies. Other radiological classification systems were reported in small numbers and with variable progression rates. Meniscal extrusion was present in nearly all cases, but was not associated with clinical or other radiological outcomes. Meniscal healing rates were high, although the size, shape and signal intensity were commonly altered from that of the native meniscus. The quality of the included studies was low, with a high risk of bias. CONCLUSION: There is some evidence to support the hypothesis that meniscal allograft transplantation reduces the progression of osteoarthritis, although it is unlikely to be as effective as the native meniscus. If this is proven, there may be a role for prophylactic meniscal allograft transplantation in selected patients. Well-designed randomised controlled trials are needed to further test this hypothesis. LEVEL OF EVIDENCE: Systematic review of studies, Level IV. PMID- 25786824 TI - Treatment of patella baja by a modified Z-plasty. AB - PURPOSE: The purpose of this study was to evaluate the efficiency of a modified Z plasty for patellar tendon lengthening for the treatment of patella baja. Rather than adapting only two tendon reins according to the conventional Z-plasty method, the modified Z-plasty provides four reins to enable multifold overlapping of the tendon tissue. METHODS: Between 2010 and 2012, a modified Z-plasty procedure was performed in four patients suffering from patella baja. Physical examinations and standardized scoring instruments served as the evaluation measures. RESULTS: The median preoperative CD ratio of 0.53 (range 0.43-0.62) was corrected to 1.03 (range 1-1.06) after a median follow-up of 34 months (range 23 41 months). The median preoperative flexion of 108 degrees (range 80-135 degrees ) improved to 143 degrees (range 110-145 degrees ) compared with the flexion of 145 degrees (range 140-145 degrees ) of the unaffected knee. No patients showed any signs of extension lag. The median Lysholm score improved from 49 (range 22 80) to 91 (range 67-95), and the Tegner activity level improved from 2 (range 0 6) to 6 (range 2-6). The median VAS status for pain decreased from an average of 8.5 (range 4-10) to 1 (range 0-2). No complications were observed. CONCLUSION: The modified Z-plasty procedure is a valuable technique for the treatment of patella baja, especially if allografts are not available. This procedure allowed for early mobilization and achieved excellent clinical results. LEVEL OF EVIDENCE: IV. PMID- 25786825 TI - Comparison of outcomes after UKA in patients with and without chondrocalcinosis: a matched cohort study. AB - PURPOSE: Chondrocalcinosis can be associated with an inflammatory arthritis and aggressive joint destruction. There is uncertainty as to whether chondrocalcinosis represents a contraindication to unicompartmental knee arthroplasty (UKA). This study reports the outcome of a consecutive series of patients with chondrocalcinosis and medial compartment osteoarthritis treated with UKA matched to controls. METHODS: Between 1998 and 2008, 88 patients with radiological chondrocalcinosis (R-CCK) and 67 patients with histological chondrocalcinosis (H-CCK) were treated for end-stage medial compartment arthritis with Oxford UKA. One-to-two matching was performed to controls, treated with UKA, but without evidence of chondrocalcinosis. Functional outcome and implant survival were assessed in each group. RESULTS: The mean follow-up was 10 years. The mean Oxford Knee Score (OKS) at final follow-up was 43, 41 and 41 in H-CCK, R CCK and control groups (change from baseline OKS was 21, 18 and 15, respectively). The change was significantly higher in H-CCK than in control but was not significantly different in R-CCK. Ten-year survival was 96 % in R-CCK, 86 % in H-CCK and 98 % in controls. Although the survival in H-CCK was significantly worse than in control, only one failure was due to disease progression. CONCLUSION: The presence of R-CCK does not influence functional outcome or survival following UKA. Pre-operative radiological evidence of CCK should not be considered to be a contraindication to UKA. H-CCK is associated with significantly improved clinical outcomes but also a higher revision rate compared with controls. LEVEL OF EVIDENCE: Case control study, Level III. PMID- 25786826 TI - Anterior cruciate ligament reconstruction; is a tourniquet necessary? A randomized controlled trial. AB - PURPOSE: This work aimed at studying the effect of tourniquet use on surgical performance and peri-operative outcomes of anatomic single-bundle ACL reconstruction. METHODS: Eighty-four patients undergoing ACL surgery were randomized into two groups: the tourniquet (A) group and the non-tourniquet (B) group. Post-operative pain, need for analgesics, the volume of blood obtained in the drain, girth diameter changes in the thigh and calf, muscle strength and amount of haemarthrosis were used as outcome measures to compare the two groups. RESULTS: Fifty-eight patients were available for analysis. In the A group, the degree of pain and need to analgesics was significantly higher at 4 and 10 h. The volume measured in the surgical drain, at 24 h post-operative, was higher in the A group (p = 0.001). The calf and thigh girth diameters at 2 weeks showed a highly significant girth difference between the two groups (p = 0.001). CONCLUSION: This study showed that tourniquet use in ACL reconstruction increases immediate post-operative symptoms of pain and haemarthrosis and that the effects on muscle strength are only temporary. The tourniquet can be replaced by using of a mixture of morphine and adrenaline with no interference with the quality of visibility, nor operative time. LEVEL OF EVIDENCE: I. PMID- 25786827 TI - Investigations concerning cavitation and frost fatigue in clonal 84K poplar using high-resolution cavitron measurements. AB - Both drought and freezing-thawing of stems induce a loss of hydraulic conductivity (percentage loss of conductivity [PLC]) in woody plants. Drought induced PLC is often accompanied by physical damage to pit membranes, causing a shift in vulnerability curves (cavitation fatigue). Hence, if cavitated stems are flushed to remove embolisms, the next vulnerability curve is different (shifted to lower tensions). The 84K poplar (Populus alba * Populus glandulosa) clone has small vessels that should be immune from frost-induced PLC, but results demonstrated that freezing-thawing in combination with tension synergistically increased PLC. Frost fatigue has already been defined, which is similar to cavitation fatigue but induced by freezing. Frost fatigue caused a transition from a single to a dual Weibull curve, but drought-fatigued stems had single Weibull curves shifted to lower tensions. Studying the combined impact of tension plus freezing on fatigue provided evidence that the mechanism of frost fatigue may be the extra water tension induced by freezing or thawing while spinning stems in a centrifuge rather than direct ice damage. A hypothesis is advanced that tension is enhanced as ice crystals grow or melt during the freeze or thaw event, respectively, causing a nearly identical fatigue event to that induced by drought. PMID- 25786828 TI - Unique aspects of the structure and dynamics of elementary Ibeta cellulose microfibrils revealed by computational simulations. AB - The question of how many chains an elementary cellulose microfibril contains is critical to understanding the molecular mechanism(s) of cellulose biosynthesis and regulation. Given the hexagonal nature of the cellulose synthase rosette, it is assumed that the number of chains must be a multiple of six. We present molecular dynamics simulations on three different models of Ibeta cellulose microfibrils, 18, 24, and 36 chains, to investigate their structure and dynamics in a hydrated environment. The 36-chain model stays in a conformational space that is very similar to the initial crystalline phase, while the 18- and 24-chain models sample a conformational space different from the crystalline structure yet similar to conformations observed in recent high-temperature molecular dynamics simulations. Major differences in the conformations sampled between the different models result from changes to the tilt of chains in different layers, specifically a second stage of tilt, increased rotation about the O2-C2 dihedral, and a greater sampling of non-TG exocyclic conformations, particularly the GG conformation in center layers and GT conformation in solvent-exposed exocyclic groups. With a reinterpretation of nuclear magnetic resonance data, specifically for contributions made to the C6 peak, data from the simulations suggest that the 18- and 24-chain structures are more viable models for an elementary cellulose microfibril, which also correlates with recent scattering and diffraction experimental data. These data inform biochemical and molecular studies that must explain how a six-particle cellulose synthase complex rosette synthesizes microfibrils likely comprised of either 18 or 24 chains. PMID- 25786830 TI - First principles simulation of temperature dependent electronic transition of FM AFM phase BFO. AB - Understanding how temperature affects the electronic transitions of BFO is important for design of BiFeO3 (BFO)-based temperature-sensitive device. Hitherto, however, there have been only very limited reports of the quantitative simulation. Here, we used density functional theory (DFT) and two-dimensional correlation analysis (2D-CA) techniques to calculate the systematic variations in electronic transitions of BFO crystal, over a range of temperature (50~1500 K). The results suggest that the heat accumulation accelerates the O-2p(4) orbital splitting, inducing the Fe(3+)-3d(5) -> Fe(2+)-3d(5)d(0) charge disproportionation. The origin is observed as the temperature-dependent electron transfer process changes from threefold degeneracy to twofold degeneracy. Additionally, the crystallographic orientation (111) can be used to control the 2p-hole-induced electronic transition as O -> unoccupied Fe(3+)-3d(5), in comparison to the O -> Bi-6p(3) + Fe(3+)-3d(5)d(0) on the orientations (001) and (101). This study offers new perspective on the improvement of BFO-based temperature-sensitive device. PMID- 25786829 TI - Autophagy supports biomass production and nitrogen use efficiency at the vegetative stage in rice. AB - Much of the nitrogen in leaves is distributed to chloroplasts, mainly in photosynthetic proteins. During leaf senescence, chloroplastic proteins, including Rubisco, are rapidly degraded, and the released nitrogen is remobilized and reused in newly developing tissues. Autophagy facilitates the degradation of intracellular components for nutrient recycling in all eukaryotes, and recent studies have revealed critical roles for autophagy in Rubisco degradation and nitrogen remobilization into seeds in Arabidopsis (Arabidopsis thaliana). Here, we examined the function of autophagy in vegetative growth and nitrogen usage in a cereal plant, rice (Oryza sativa). An autophagy-disrupted rice mutant, Osatg7 1, showed reduced biomass production and nitrogen use efficiency compared with the wild type. While Osatg7-1 showed early visible leaf senescence, the nitrogen concentration remained high in the senescent leaves. (15)N pulse chase analysis revealed suppression of nitrogen remobilization during leaf senescence in Osatg7 1. Accordingly, the reduction of nitrogen available for newly developing tissues in Osatg7-1 likely led its reduced leaf area and tillers. The limited leaf growth in Osatg7-1 decreased the photosynthetic capacity of the plant. Much of the nitrogen remaining in senescent leaves of Osatg7-1 was in soluble proteins, and the Rubisco concentration in senescing leaves of Osatg7-1 was about 2.5 times higher than in the wild type. Transmission electron micrographs showed a cytosolic fraction rich with organelles in senescent leaves of Osatg7-1. Our results suggest that autophagy contributes to efficient nitrogen remobilization at the whole-plant level by facilitating protein degradation for nitrogen recycling in senescent leaves. PMID- 25786831 TI - Understanding the azeotropic diethyl carbonate-water mixture by structural and energetic characterization of DEC(H2O)(n) heteroclusters. AB - Diethyl carbonate (DEC) is an oxygenated fuel additive. During its synthesis through a promising green process, a DEC-water azeotrope is formed, which decreases DEC production efficiency in the gas phase. Molecular information about this system is scarce but could be of benefit in understanding (and potentially improving) the synthetic process. Therefore, we report a detailed computational study of the conformers of DEC, and their microsolvation with up to four water molecules, with the goal of understanding the observed 1:3 DEC:H2O molar ratio. The most stable DEC conformers (with mutual energy differences < 1.5 kcal mol( 1)) contribute to the energetic and structural properties of the complexes. An exhaustive stochastic exploration of each potential energy surface of DEC-(H2O)n, (where n = 1, 2, 3, 4) heteroclusters discovered 3, 8, 7, and 4 heterodimers, heterotrimers, heterotetramers, and heteropentamers, respectively, at the MP2/6 311++G(d,p) level of theory. DEC conformers and energies of the most stable structures at each heterocluster size were refined using CCSD(T)/6-311++G(d,p). Energy decomposition, electron density topology, and cooperative effects analyses were carried out to determine the relationship between the geometrical features of the heteroclusters and the non-covalent interaction types responsible for their stabilization. Our findings show that electrostatic and exchange energies are responsible for heterocluster stabilization, and also suggest a mutual weakening among hydrogen bonds when more than three water molecules are present. All described results are complementary and suggest a structural and energetic explanation at the molecular level for the experimental molar ratio of 1:3 (DEC:H2O) for the DEC-water azeotrope. PMID- 25786832 TI - Electronic effects of the substituent on the dioxygen-activating abilities of substituted iron tetraphenylporphyrins: a theoretical study. AB - A density functional theoretical (DFT) method was applied to understand the effects of the substituent on dioxygen activation by a series of substituted iron tetraphenylporphyrins [FeT(o/p-R)PP (o = ortho-substituted, p = para-substituted; R = -H, -Cl, -NO2, -CH3, -OCH3)]. The ground states (GS) of the dioxygen adducts of the substituted iron tetraphenylporphyrins [FeT(o/p-R)PPO2] were determined at the B3LYP/6-31G(d) level without any symmetry constraints. Binding energy calculations indicated that the presence of electron-withdrawing substituents at the para position favors O2 binding. Calculations of the O-O bond length of the adsorbed dioxygen revealed that the influence of the p-substituent on the activation of dioxygen decreases in the order p-CH3 > p-Cl > p-OCH3 > -H > p-NO2, while the influence of the o-substituent decreases in the order o-NO2 > o-CH3 > o Cl > o-OCH3 > -H. The low-lying excited states (LLES) of the FeT(o/p-R)PPO2 adducts suggest that the ability to activate dioxygen decreases in the order o CH3 > o-OCH3 = -H > o-NO2 > o-Cl for o-substituents and p-CH3 > p-Cl > -H > p-NO2 > p-OCH3 for p-substituents. NBO charge population analysis and spin density analysis showed that substitution caused more beta-electrons to be transferred from the iron tetraphenylporphyrin to the dioxygen, which enhanced dioxygen activation. Spin density analysis confirmed that the beta-electron population at the adsorbed dioxygen is an accurate indicator of the degree of dioxygen activation. The trend observed in porphyrin catalytic activity as the substituent on the dioxygen adduct was varied is consistent with the trend in the binding energy. It is clear that substituents at the ortho and para positions in these dioxygen adducts play different roles in dioxygen activation. PMID- 25786834 TI - [In Process Citation]. PMID- 25786833 TI - Role of liposome and peptide in the synergistic enhancement of transfection with a lipopolyplex vector. AB - Lipopolyplexes are of widespread interest for gene therapy due to their multifunctionality and high transfection efficiencies. Here we compared the biological and biophysical properties of a lipopolyplex formulation with its lipoplex and polyplex equivalents to assess the role of the lipid and peptide components in the formation and function of the lipopolyplex formulation. We show that peptide efficiently packaged plasmid DNA forming spherical, highly cationic nanocomplexes that are taken up efficiently by cells. However, transgene expression was poor, most likely due to endosomal degradation since the polyplex lacks membrane trafficking properties. In addition the strong peptide-DNA interaction may prevent plasmid release from the complex and so limit plasmid DNA availability. Lipid/DNA lipoplexes, on the other hand, produced aggregated masses that showed poorer cellular uptake than the polyplex but contrastingly greater levels of transgene expression. This may be due to the greater ability of lipoplexes relative to polyplexes to promote endosomal escape. Lipopolyplex formulations formed spherical, cationic nanocomplexes with efficient cellular uptake and significantly enhanced transfection efficiency. The lipopolyplexes combined the optimal features of lipoplexes and polyplexes showing optimal cell uptake, endosomal escape and availability of plasmid for transcription, thus explaining the synergistic increase in transfection efficiency. PMID- 25786835 TI - [In Process Citation]. PMID- 25786836 TI - [Polypharmacy to the elderly prevails]. AB - The risk of chronic diseases increases with age which may result in an increased need for pharmacological treatment: polypharmacy. Polypharmacy to the elderly is particularly challenging due to altered pharmacokinetics and -dynamics, and is associated with numerous problems such as poor compliance/adherence, drug interactions, adverse drug reactions, increased mortality and hospitalization. Beers criteria and STOPP/START criteria are tools which can be used as guidance in medication of the elderly, but they cannot replace a structured medical review, which should be individualized. PMID- 25786837 TI - [Teminal care in a nursing home]. AB - This article focuses on patients with limited life expectancy who no longer benefit from preventive medication but not yet qualify for palliative care - a time frame often referred to as End-of-Life (EOL). The purpose of this article is to identify and assess international guidelines for prescribing in EOL. No relevant clinical trials were available, but we found advice mainly based on logic assumptions and thoughts. Optimal prescribing for EOL patients remains mostly unexplored. Our study revealed two pivotal questions: How do we identify EOL patients, and what specific drugs should be removed? PMID- 25786838 TI - [Acute hospital admissions from nursing homes]. AB - Nursing home residents are frail patients who experience frequent hospital admission with an increased risk for acute confusion, iatrogenic adverse events, nosocomial infections, decline in ADL and death during hospitalization. Avoidance of unnecessary admissions for this vulnerable group of patients are an important part of good quality medical care and may be effective in reducing health-care costs. Danish studies are needed in order to implement efficient interventions aiming at reducing unnecessary admissions. PMID- 25786839 TI - [Prevalence of depression and dementia among nursing home residents]. AB - The population of older adults will increase in the coming years and the number of elderly in nursing homes is expected to rise considerably. The most frequent psychiatric diseases among nursing home residents are depression and dementia. We examined the prevalence of depression and dementia in nursing home populations reported in literature reviews. The included studies were published from 1986 to 2014. At least one out of ten persons living in a nursing home seems to have depression and more have depressive symptoms. Three out of four residents in nursing homes suffer from dementia. PMID- 25786840 TI - [Health care to nursing homes by general practitioners]. AB - In Denmark we used to have one GP employed at every nursing home. In 1996 it was politically decided that the patients should keep their usual GP. As a consequence GPs have patients at several nursing homes, and the nursing homes must collaborate with several GPs who are not a part of their staff. A new model is described where a small group of GPs are sharing the patients on their lists and as group provide health care to the nursing home. Taking care of elderly people at nursing homes today is complicated, and it is argued that a careful plan is necessary when moving in. PMID- 25786841 TI - [Medical focus on nursing homes]. AB - Older people living in nursing homes in Denmark are among the most frail. The mean age at moving in is 84 years. Mean time living in nursing homes is 25 months for men and 32 for women. The dwellers can choose their usual general practitioner but change in organisation is now being evaluated. Medical focus is dementia, prevention of delirium, falls and especially the medical treatment. Polypharmacy is a huge challenge. Collaboration and communication with nursing staff is essential in order to do prevention, rehabilitation and palliation among the frail dwellers. PMID- 25786842 TI - [Urinary tract infection in elderly residents of long-term care facilities]. AB - Urinary tract infection is the most prevalent bacterial infection among residents in Danish long-term care facilities, and it is the most common reason for antibiotic therapy as prevention or treatment in this population. Diagnosis and management of urinary tract infection in the elderly is challenging because of benign asymptomatic bacteriuria, chronic indwelling urinary tract catheters, cognitive impairment and other co-morbidities. This review covers updated information on diagnosis, treatment and prophylaxis of urinary tract infection in elderly residents of long-term care facilities. PMID- 25786843 TI - [Hepatocellular adenoma - new classification and recommendations]. AB - Hepatocellular adenoma (HCA) is a rare benign hepatocellular tumour developed in an otherwise healthy liver. The two main complications are bleeding from the HCA or malignant transformation to hepatocellular carcinoma (HCC). Risk factors for HCC include gender (men), size (> 8 cm) and subtype. Based on new molecular genetic analyses this review describes a new classification of adenomas using both genotype and phenotype. We want to provide an update on adenomas and give updated recommendations for diagnosis and treatment. PMID- 25786844 TI - [Severe constipation caused by an abnormally angled coccyx]. AB - Constipation is a common disease among patients in all age groups, and the pathology can vary. This case report describes a 26-year-old female with severe constipation for six years. She was referred to a centre for spine surgery with a coccyx compressing her rectum causing constipation. The symptoms developed six years previously after a trauma, progressed during pregnancy and after giving birth. X-ray showed a 90-degree anterior angulated coccyx compressing the rectum. She was treated with resection of the coccyx, and symptoms disappeared after surgery. PMID- 25786845 TI - [Certain foreign bodies can remain in the stomach without complications]. AB - It is usually recommended that swallowed foreign bodies with a length of more than 6 cm be endoscopically removed from the stomach. In this case report five cutlery knives had been ingested by a female patient with borderline personality disorder who repeatedly ingested foreign objects. It was considered too risky to remove the knives endoscopically and they were left in situ. After three years, without admission due to the knives or other swallowed foreign bodies, the patient spontaneously vomited two of the five, now very eroded, knives. Later, the remaining knives were removed at a hospital abroad. PMID- 25786846 TI - [Coronary artery dissection following blunt chest trauma]. AB - A previously healthy 38-year-old man was admitted to hospital with chest pain. The day before the patient had been to a karate session and had received multiple punches and kicks to the chest region. An ECG showed Q-waves in V1 and V2 and flattening of the T-waves in V1-V6. Levels of cardiac enzyme markers were elevated. The patient subsequently underwent coronary angiography with supplemental optical coherence tomography that revealed a bifurcate dissection involving the proximal parts of left ramus interventricularis anterior and circumflex coronary artery. Two drug-eluting stents were implanted with good angiographic result. PMID- 25786847 TI - [Bicycle helmet prevents brain damage]. AB - The relatively small and declining incidence of traffic-related death accidents in Scandinavia is a result of targeted infra-structural measures and policies. Bicycle accidents represent a large fraction of the total traffic accident load and are often underreported in statistics. We argue that there is scientific evidence of bicycle helmet efficacy with a protective effect on serious brain injury of 63-88%. There is no consensus in favour of the effect of bicycle helmet legislation, although a Cochrane review from 2007 showed a significant reduction of injuries among children. PMID- 25786848 TI - Opportunities and ethical challenges for the practice of medicine in the digital era. AB - Technological advances have been a driving force in the practice of medicine. From the discovery of x-rays' medical applications to the utilization of dialysis and surgical transplantation of organs, technology has presented new opportunities, and at times, ethical challenges for physicians. In recent years, the increased proliferation of social media tools has had a significant impact on how people engage with one another, and how they want to engage with their healthcare providers. Medical schools have begun to examine some of the issues surrounding use of social media in the context of professionalism in their curricula. Many of the physicians already in practice are left to grapple with how to learn about and wield social media in not only a professional capacity and their personal lives, but often where the two intersect. This paper will explore both opportunities for social media engagement and ethical concerns such usage presents to physicians and in particular to those in the field of musculoskeletal medicine. PMID- 25786849 TI - The impact of hypoxia on bacterial infection. AB - Tissue hypoxia is a common microenvironmental feature during inflammation associated with bacterial infection. Hypoxia has recently been shown to play an important role in both innate and adaptive host immunity through the regulation of transcription factors, including hypoxia-inducible factor and nuclear factor kappaB, in both infiltrating immunocytes and inflamed resident cells. Recent studies have suggested that, by regulating these important immune effector pathways in host tissues, hypoxia can significantly alter the process of bacterial infection and subsequent disease progression. Although hypoxia is often beneficial in terms of reducing the development of infection, its net effect depends on a number of factors, including the nature of the pathogen and the characteristics of the infection encountered. In this minireview, we will discuss the impact of local tissue hypoxia and the resulting activation of hypoxia sensitive pathways on bacterial infection by a range of pathogens. Furthermore, we will review how this knowledge may be used to develop new approaches to anti infective therapeutics. PMID- 25786851 TI - Residents'corner February 2015. Editorial: 2015 Renewal of the Resident Board. PMID- 25786850 TI - Biochemical characteristics and modulation by external and internal factors of aminopeptidase-N activity in the hepatopancreas of a euryhaline burrowing crab. AB - Strikingly, in spite of its physiological importance, information about occurrence, biochemical characteristics and mechanisms of regulation of aminopeptidase-N (APN) in the hepatopancreas of intertidal euryhaline crabs is still lacking. In this work, we determined the occurrence, biochemical characteristics, response to environmental salinity and dopamine of APN in the hepatopancreas of the euryhaline crab Neohelice granulata (Dana 1851) from the open mudflat of Mar Chiquita coastal lagoon (Buenos Aires province, Argentina). APN activity was maximal at pH and temperature range of 7.6-9.0 and 37-45 degrees C, respectively. APN activity exhibited Michaelis-Menten kinetics (apparent Km = 0.19 +/- 0.10 mM) (pH 7.6, 37 degrees C) and appeared to be sensitive to bestatin (I 50 = 15 mM) and EDTA (I 50 = 9 mM). In crabs acclimated to 10 psu (hyper-regulation conditions) and 37 psu (hypo-regulation conditions), APN activity was about 45 and 160% higher, respectively, than in 35 psu (osmoconformation). APN activity in the hepatopancreas was stimulated in vitro (about 137%) by 10(-4) M dopamine. Higher dopamine concentrations produced a similar extent of increase. The responses of APN activity to salinity and dopamine in vitro suggest the role of APN in digestive adjustments upon hyper and hypo-regulatory conditions and its modulation via direct mechanisms on hepatopancreas by dopamine. PMID- 25786852 TI - beta-Cyclodextrin-assisted extraction of polyphenols from vine shoot cultivars. AB - This work optimized the beta-cyclodextrin (beta-CD)-assisted extraction process of polyphenols from vine shoots. The efficiency of beta-CD was compared to that of ethanol in terms of the quantity and antioxidant capacity (AC) of the extracted polyphenols. Response surface methodology permitted the optimization of the beta-CD concentration, time, and temperature. The optimal polyphenol content (PC) [5.8 mg of gallic acid equivalent (GAE)/g of dry matter (DM)] and AC [3146 micromolar trolox equivalent per milliliter (MUMTE)] were initially obtained with Syrah cultivar after an extraction of 48 h at 66.6 degrees C with a 37.7 mg/mL aqueous beta-CD solvent. The same PC (5.8 mg of GAE/g of DM) was reached with 50% ethanol/water solvent after 1.65 h. However, a lower AC was found with ethanol (2000 MUMTE) compared to beta-CD. A comparison of the PC and AC of four different vine shoot cultivars was realized. Our results clearly show the capacity of beta CD to amplify polyphenol extraction from vine shoots. PMID- 25786855 TI - The SMC' is a highly accurate approximation to the ancestral recombination graph. AB - Two sequentially Markov coalescent models (SMC and SMC') are available as tractable approximations to the ancestral recombination graph (ARG). We present a Markov process describing coalescence at two fixed points along a pair of sequences evolving under the SMC'. Using our Markov process, we derive a number of new quantities related to the pairwise SMC', thereby analytically quantifying for the first time the similarity between the SMC' and the ARG. We use our process to show that the joint distribution of pairwise coalescence times at recombination sites under the SMC' is the same as it is marginally under the ARG, which demonstrates that the SMC' is, in a particular well-defined, intuitive sense, the most appropriate first-order sequentially Markov approximation to the ARG. Finally, we use these results to show that population size estimates under the pairwise SMC are asymptotically biased, while under the pairwise SMC' they are approximately asymptotically unbiased. PMID- 25786853 TI - Interplay between histone H3 lysine 56 deacetylation and chromatin modifiers in response to DNA damage. AB - In Saccharomyces cerevisiae, histone H3 lysine 56 acetylation (H3K56Ac) is present in newly synthesized histones deposited throughout the genome during DNA replication. The sirtuins Hst3 and Hst4 deacetylate H3K56 after S phase, and virtually all histone H3 molecules are K56 acetylated throughout the cell cycle in hst3? hst4? mutants. Failure to deacetylate H3K56 causes thermosensitivity, spontaneous DNA damage, and sensitivity to replicative stress via molecular mechanisms that remain unclear. Here we demonstrate that unlike wild-type cells, hst3? hst4? cells are unable to complete genome duplication and accumulate persistent foci containing the homologous recombination protein Rad52 after exposure to genotoxic drugs during S phase. In response to replicative stress, cells lacking Hst3 and Hst4 also displayed intense foci containing the Rfa1 subunit of the single-stranded DNA binding protein complex RPA, as well as persistent activation of DNA damage-induced kinases. To investigate the basis of these phenotypes, we identified histone point mutations that modulate the temperature and genotoxic drug sensitivity of hst3? hst4? cells. We found that reducing the levels of histone H4 lysine 16 acetylation or H3 lysine 79 methylation partially suppresses these sensitivities and reduces spontaneous and genotoxin-induced activation of the DNA damage-response kinase Rad53 in hst3? hst4? cells. Our data further suggest that elevated DNA damage-induced signaling significantly contributes to the phenotypes of hst3? hst4? cells. Overall, these results outline a novel interplay between H3K56Ac, H3K79 methylation, and H4K16 acetylation in the cellular response to DNA damage. PMID- 25786854 TI - The aggregation-prone intracellular serpin SRP-2 fails to transit the ER in Caenorhabditis elegans. AB - Familial encephalopathy with neuroserpin inclusions bodies (FENIB) is a serpinopathy that induces a rare form of presenile dementia. Neuroserpin contains a classical signal peptide and like all extracellular serine proteinase inhibitors (serpins) is secreted via the endoplasmic reticulum (ER)-Golgi pathway. The disease phenotype is due to gain-of-function missense mutations that cause neuroserpin to misfold and aggregate within the ER. In a previous study, nematodes expressing a homologous mutation in the endogenous Caenorhabditis elegans serpin, srp-2, were reported to model the ER proteotoxicity induced by an allele of mutant neuroserpin. Our results suggest that SRP-2 lacks a classical N terminal signal peptide and is a member of the intracellular serpin family. Using confocal imaging and an ER colocalization marker, we confirmed that GFP-tagged wild-type SRP-2 localized to the cytosol and not the ER. Similarly, the aggregation-prone SRP-2 mutant formed intracellular inclusions that localized to the cytosol. Interestingly, wild-type SRP-2, targeted to the ER by fusion to a cleavable N-terminal signal peptide, failed to be secreted and accumulated within the ER lumen. This ER retention phenotype is typical of other obligate intracellular serpins forced to translocate across the ER membrane. Neuroserpin is a secreted protein that inhibits trypsin-like proteinase. SRP-2 is a cytosolic serpin that inhibits lysosomal cysteine peptidases. We concluded that SRP-2 is neither an ortholog nor a functional homolog of neuroserpin. Furthermore, animals expressing an aggregation-prone mutation in SRP-2 do not model the ER proteotoxicity associated with FENIB. PMID- 25786856 TI - Regulation of pattern formation and gene amplification during Drosophila oogenesis by the miR-318 microRNA. AB - Pattern formation during epithelial development requires the coordination of multiple signaling pathways. Here, we investigate the functions of an ovary enriched miRNA, miR-318, in epithelial development during Drosophila oogenesis. mir-318 maternal loss-of-function mutants were female-sterile and laid eggs with abnormal morphology. Removal of mir-318 disrupted the dorsal-anterior follicle cell patterning, resulting in abnormal dorsal appendages. mir-318 mutant females also produced thin and fragile eggshells due to impaired chorion gene amplification. We provide evidence that the ecdysone signaling pathway activates expression of miR-318 and that miR-318 cooperates with Tramtrack69 to control the switch from endocycling to chorion gene amplification during differentiation of the follicular epithelium. The multiple functions of miR-318 in oogenesis illustrate the importance of miRNAs in maintaining cell fate and in promoting the developmental transition in the female follicular epithelium. PMID- 25786857 TI - [Stomach cancer: Epidemiological, clinical and histological aspects at the Lome Campus teaching hospital (Togo)]. AB - PURPOSE: To describe the epidemiological, clinical, and histological aspects of stomach cancer in the gastroenterology department of University Hospital Campus of Lome (Togo). METHODS: This retrospective descriptive and analytical study reviewed records of patients hospitalized for stomach cancer over an 8-year period. RESULTS: With 32 cases among the 250 gastrointestinal tract cancers over the study period, stomach cancer accounted for the largest proportion (12.8%) of these cases. The sex ratio was 2.5 and the mean age of patients was 58.82 years (range: 32 to 85 years). The clinical picture was dominated by epigastric pain (44%). Ulcerative budding lesions were most common, especially in the pyloric antrum (72%). Adenocarcinoma was the most common histological type (94%). Thirteen of our patients were transferred to the visceral surgery department for palliative care. Nine more were lost to follow-up after release against medical advice due to lack of financial support. Five patients died (16%) during hospitalization. CONCLUSION: Stomach cancer is common in Togo and ranks first among gastrointestinal cancers in our department. Training hepatogastroenterologists and providing adequate technical facilities, on the one hand, and early recognition of warning signs and a reduction in the cost of gastrointestinal endoscopies, on the other, could improve the survival of patients with gastric cancer in Togo. PMID- 25786858 TI - Prospective randomized controlled trial comparing the outcomes and costs of two eyecare adherence interventions in diabetes patients. AB - OBJECTIVE: Diabetic retinopathy is one of the leading causes of vision impairment among adults in the USA. While it is suggested that diabetics receive annual dilated fundus examinations (DFE), many patients do not adhere to these recommendations. This paper investigates the outcomes and costs of an educational and telephone intervention on DFE follow-up adherence in patients with diabetes. METHODS: In a prospective trial, 356 diabetic patients due for a DFE at an urban eye clinic were randomly assigned to usual care (UC; reference case), mailed intervention (MI), or telephone intervention (TI). UC patients (n = 119) received a standard form letter. MI patients (n = 117) received a personalized letter encouraging scheduling of an eye examination with an educational brochure about diabetic eye disease. TI patients (n = 120) received personal calls (up to three attempts) to schedule a follow-up with standard form letter. The primary outcome was obtaining a DFE within 90 days of suggested return. Costs (US$ 2013) included time costs for staff, phone charges, supplies, and postage. Since TI involved greater cost components compared to MI, univariate sensitivity analysis examined the impact of reducing phone costs. RESULTS: Patients were mostly female (66 %) and African American (70 %) with a mean age of 61 years. TI patients were more likely to schedule DFE [65 vs. 42 %; relative risk (RR) 1.54; CI 1.20-1.96; P < 0.001] versus UC patients. Obtaining a DFE within 90 days of suggested return was also significantly higher among TI patients compared to UC patients (51 vs. 36 %, RR 1.41; CI 1.05-1.89; P = 0.024). MI patients were slightly less likely to schedule DFE versus UC patients (38 vs. 42 %, RR 0.90; CI 0.66-1.22; P = NSS) and obtain a DFE (32 vs. 36 %; RR 0.90; CI 0.63-1.28; P = NSS). The total cost of TI was US$798.28 or US$6.65/patient and the cost/follow-up DFE was US$26.05. Sensitivity analyses revealed that the cost/follow-up can be greatly reduced but remains greater compared to UC (US$2.76 if US$0.25/call, US$11.13 if $1/call; US$22.29 if US$2/call). CONCLUSIONS: Personal phone assistance in scheduling DFE follow-up is more effective but also more costly. Follow-up research has been initiated to determine whether automated phone reminders can achieve similar effectiveness at a lower cost. PMID- 25786859 TI - Modularity enhances the rate of evolution in a rugged fitness landscape. AB - Biological systems are modular, and this modularity affects the evolution of biological systems over time and in different environments. We here develop a theory for the dynamics of evolution in a rugged, modular fitness landscape. We show analytically how horizontal gene transfer couples to the modularity in the system and leads to more rapid rates of evolution at short times. The model, in general, analytically demonstrates a selective pressure for the prevalence of modularity in biology. We use this model to show how the evolution of the influenza virus is affected by the modularity of the proteins that are recognized by the human immune system. Approximately 25% of the observed rate of fitness increase of the virus could be ascribed to a modular viral landscape. PMID- 25786860 TI - Worldwide Burden of Gastric Cancer Attributable to Tobacco Smoking in 2012 and Predictions for 2020. AB - BACKGROUND: The heterogeneous patterns and trends in tobacco consumption contribute to regional and gender differences in the burden of gastric cancer attributable to smoking. AIMS: To estimate the proportion and absolute number of gastric cancer cases that can be attributed to smoking in different countries, in 2012 and 2020. METHODS: Population attributable fractions (PAFs) were computed for 118 countries, using data of smoking prevalence in 2002 and 2011 and published estimates of the magnitude of the association between smoking and gastric cancer, assuming a time lag of ~10 years. RESULTS: For men, the highest PAF estimates in 2012 were observed in Eastern Asia and the lowest in North America, whereas for women the highest were in Western Europe and the lowest in Africa. Very high Human Development Index (HDI) countries presented the lowest median PAF in men (very high vs. high, medium, and low HDI: 17.2 vs. 20.8 %, p = 0.014) and the highest median PAF in women (very high vs. high, medium, and low HDI: 4.3 vs. 1.8 %, p < 0.001). Estimates for 2020 show a decrease in median PAFs, but the estimated absolute number of cases attributable to smoking in the countries analyzed increased for men (~154,000 vs. ~160,000) and decreased for women (~6200 vs. ~5600). CONCLUSIONS: Smoking accounts for a larger number of gastric cancer cases among men, and gender differences are expected to increase in the next decade, despite the decrease in PAFs. Intensified efforts to control smoking are needed to further reduce the burden of gastric cancer. PMID- 25786861 TI - Psychosocial Impact of Lynch Syndrome on Affected Individuals and Families. AB - INTRODUCTION: Lynch syndrome is the most common hereditary colorectal cancer syndrome, conferring a heightened risk not only of colon cancer but also of various extracolonic tumors. Studies in hereditary breast cancer have shown a negative psychological impact for patients testing positive for BRCA1 or BRCA2 mutations, but there is a paucity of literature looking at psychosocial impact of LS testing for probands and families. METHODS: A literature search of PubMed English-language articles was performed using the keywords "Lynch syndrome" combined with "psychological impact," "depression," and "anxiety." RESULTS: Lynch syndrome mutation carriers, whether or not they have had cancer, suffer a transient increase in depression and anxiety scores post-disclosure, which seem to normalize by 6-12 months. Younger patients with higher colorectal cancer risk perception, higher education level, married, and employed are more likely to accept genetic testing. Major motivators for testing are predicting one's own risk of cancer and risk to offspring. Carrier status influences family planning, and there is growing interest for preimplantation genetic diagnosis. CONCLUSIONS: Psychosocial ramifications of LS mutation positivity need to be explored further. PMID- 25786862 TI - Drug delivery to the CNS. PMID- 25786863 TI - Delivering drugs to the central nervous system: an overview. AB - Developing therapies for the brain is perhaps the greatest challenge facing modern medicine today. While a great many potential therapies show promise in animal models, precious few make it to approval or are even studied in human patients. The particular challenges to the translation of neurotherapeutics to the clinic are many, but a major barrier is difficulty in delivering therapeutics into the brain. The goal of this workshop was to present ways to deliver therapeutics to the brain, including the limitations of each method, and describe ways to track their delivery, safety, and efficacy. Solving the problem of delivery will aid translation of therapeutics for patients suffering from neurodegeneration and other disorders of the brain. PMID- 25786864 TI - Drug transport into the central nervous system: using newer findings about the blood-brain barriers. AB - The blood-brain barriers (BBBs) represent one of the biggest challenges for the effective delivery of drugs today. Discoveries made in the last 30 years offer new strategies for central nervous system (CNS) drug development, but have yet to be fully incorporated into the field. Here, we examine seven recently discovered aspects of the BBB and how they have been or could be developed for drug delivery. These areas are brain-to-blood (efflux) transporters, immune cell trafficking into the brain under physiologic conditions, mechanisms by which antibodies can access the CNS, Trojan horse delivery systems, blood-to-brain transport systems for biologicals, lectin interactions and ligand modifications that enhance BBB penetration, and secretory capacities of cells comprising the BBBs. PMID- 25786865 TI - Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice. AB - Intranasal administration, which bypasses the blood-brain barrier and minimizes systemic exposure, is a non-invasive alternative for targeted drug delivery to the brain. While identification of metal dysregulation in Alzheimer's brain has led to the development of therapeutic metal-binding agents, targeting to the brain has remained an issue. The purpose of this study was to both determine concentrations of deferoxamine (DFO), a high-affinity iron chelator, reaching the brains of mice after intranasal administration and to determine its efficacy in a mouse model of spatial memory loss. Intranasal administration of DFO (2.4 mg) labeled with (59)Fe (75 MUCi) to C57 mice resulted in micromolar concentrations at 30 min within brain parenchyma. After 3 months of intranasal DFO treatment, 2.4 mg three times per week, 48-week-old APP/PS1 mice had significantly reduced escape latencies in Morris water maze compared to vehicle-treated mice. This is the first report that intranasal DFO improves spatial memory in a mouse model of Alzheimer's disease and demonstrates that intranasal DFO reaches the brain in therapeutic doses. PMID- 25786866 TI - Safety evaluation of chronic intrathecal administration of heparan N-sulfatase in juvenile cynomolgus monkeys. AB - An intrathecal (IT) formulation of recombinant human heparan N-sulfatase (HNS) is under development for the treatment of the neurological symptoms of mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo A disease), the defining clinical feature of this disorder. Since the average age of MPS IIIA patients is 4.5 years, the pivotal toxicology studies for HNS were conducted in juvenile cynomolgus monkeys to evaluate the effects on the developing brain. Monkeys were implanted with an IT-lumbar drug delivery device and dosed every other week by slow bolus administration (1.5, 4.5, or 8.3 mg/dose HNS for 6 months; 12 doses), with device and vehicle controls receiving phosphate-buffered saline or vehicle, respectively. Eight animals per group (four/sex) were necropsied at 3 and 6 months (device control group necropsied at 3 months), and eight animals from the vehicle group and the three HNS-dosed groups were necropsied 1 month after the final IT dose. No HNS-related clinical signs or gross central nervous system lesions were observed. Compared with controls, there were cellular infiltrates of slight-to-minimal mean severity in the meninges/perineurium surrounding the brain/spinal cord correlating with transient increases in cerebrospinal fluid (CSF) leukocytes, predominantly eosinophils, which largely resolved 1 month after the final dose. These changes were not associated with any adverse morphological changes in the brain or spinal cord. There appeared to be a dose-related trend toward higher mean CSF HNS levels and in tissue HNS activity levels in the brain, spinal cord, and liver. The no-observed-adverse-effect-level was 8.3 mg/dose given every other week, the highest dose administered. PMID- 25786867 TI - Delivery of proteins to CNS as seen and measured by positron emission tomography. AB - Presently, there are no effective treatments for several diseases involving the central nervous system (CNS). While several novel molecular approaches are being developed, many of them require delivery of macromolecular or supramolecular agents to the CNS tissues protected by the blood-brain and blood-arachnoid barriers. A variety of approaches that are being developed for overcoming or bypassing the barriers are based on complex transfer processes. The delivery of biopharmaceuticals and other macromolecules and particulates to the CNS, especially through the leptomeningeal (intrathecal) route, includes a variety of stages, such as leptomeningeal propagation, drainage to the systemic circulation, and penetration into the CNS. The investigation of complex pharmacokinetics that includes convective, as well as diffusional and active transfer processes, greatly benefit from real-time non-invasive in vivo monitoring of the drug transport. Pharmacological positron emission tomography (PET) imaging, which enables such monitoring, plays an increasingly significant role in drug delivery and biopharmacology. PET is a powerful tool for quantitative in vivo tracking of molecules labeled with positron-emitting radionuclides. The high sensitivity, format, and accuracy of the data (similar to those of conventional tissue sampling biodistribution studies) make PET a readily adoptable pharmacological technique. In contrast to the conventional studies, PET also allows for longitudinal nonterminal same-animal studies. The latter may not only improve the data statistics, but also enable preclinical studies (especially in large and/or rare animals) not feasible under the conventional approach. This paper is intended to demonstrate the character of data that can be obtained by PET and to demonstrate how the main patterns of the leptomeningeal route pharmacokinetics can be investigated using this method. Examples of data processing are taken from our recent studies of five model proteins in rats and nonhuman primates. PMID- 25786868 TI - Investigation of intrathecal transport of NPT002, a prospective therapeutic based on phage M13, in nonhuman primates. AB - Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer's, Parkinson's, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-beta, tau and alpha synuclein. For CNS applications, NPT002 requires delivery to the brain parenchyma, the target tissue. NPT002 is an elongated ~950 nm particle that cannot penetrate into the brain from the blood. Furthermore, phage particles, due to their size, cannot be effectively transported in vivo by diffusion. Considering the physiology of the leptomeningeal space, intrathecal administration appears to be a promising convection-driven avenue for NPT002 delivery. In this paper, we use positron emission tomography to investigate the transport of NPT002 in Macaca fascicularis. The data suggest that approximately 50 % of the administered dose can reach the cerebral leptomeningeal space after a single lumbar intrathecal injection. A biologically significant fraction of the phage then enters the brain, resulting in potentially therapeutic cortical and subcortical exposure. PMID- 25786869 TI - Intravaginal HPV DNA vaccination with electroporation induces local CD8+ T-cell immune responses and antitumor effects against cervicovaginal tumors. AB - Therapeutic human papillomavirus (HPV) vaccines have the potential to inhibit the progression of an established HPV infection to precancer and cancer lesions by targeting HPV oncoproteins. We have previously developed a therapeutic DNA vaccine encoding calreticulin (CRT) linked to E7, CRT/E7 DNA vaccine, for use in the treatment of HPV-associated lesions. Since the transfection efficiency of DNA vaccines administered in vivo is typically low, we examined the use of electroporation as well as different routes of administration to enhance antigen specific tumor control. We tested the effects of the CRT/E7 DNA vaccine administered intramuscularly or intravaginally, with or without electroporation, on the generation of CD8+ T-cell immunity and therapeutic antitumor effects in HPV16 E7-expressing cervicovaginal tumor-bearing mice. We found that intravaginal vaccination of CRT/E7 DNA followed by electroporation-induced potent E7-specific CD8(+) T-cell responses in the cervicovaginal tract, compared with intramuscular injection followed by electroporation. Furthermore, tumor-bearing mice vaccinated intravaginally followed by electroporation had an enhanced survival, antitumor effects and local production of IFN-gamma+CD8+ T cells compared with those vaccinated intramuscularly with electroporation. Thus, we show that intravaginal CRT/E7 DNA vaccination followed by electroporation generates the most potent therapeutic antitumor effects against an orthotopic E7-expressing tumor model. The current study will have significant clinical implications once a clinically applicable electroporation device for intravaginal use becomes available. PMID- 25786870 TI - Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K mediated in vivo selection. AB - Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector-transduced human repopulating cells is needed. Human CD34(+) human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rgamma(null) mice, and selected in vivo for gene-modified cells. The retroviral insertion site profile of repopulating clones was examined using modified genomic sequencing PCR. We observed polyclonal repopulation with no evidence of clonal dominance even with the use of a strong internal spleen focus forming virus promoter known to be genotoxic. Our data supports the use of FV vectors with MGMTP140K for HSC gene therapy but also suggests additional safety features should be developed and evaluated. PMID- 25786871 TI - beta-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. AB - Protection of beta cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non redundant manner. Here we employed beta-cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to overexpress an artificial PDL1-CTLA4Ig polyprotein or interleukin 10 (IL10). beta-Cell-targeted expression of PDL1 CTLA4Ig or IL10 preserved beta-cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received major histocompatibility complex (MHC)-matched allo-islets, with or without pretreatment of the PDL1 CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus the present study demonstrates the potent immuno suppressive effects of beta-cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity. PMID- 25786872 TI - A new method to monitor antigen-specific CD8+ T cells, avoiding additional target cells and the restriction to human leukocyte antigen haplotype. AB - Therapeutic vaccination of cancer patients with dendritic cells aims at inducing a strong tumor-specific T-cell response. Testing new target antigens for their immunogenicity is crucial to evaluate their suitability for this approach. Here we demonstrate a comfortable and reliable method to detect antigen-specific CD8(+) T-cell responses without the knowledge of the precise T-cell epitope and without the usage of additional target cells. We used the CD8(+) T cells themselves and electroporated them with RNA encoding the respective tumor antigen. The cells expressed, processed and presented the antigen and were capable of stimulating each other in functional readouts. For the model antigen MelanA, the number of interferon-gamma-secreting cells obtained with this method highly correlated with the numbers obtained by exogenous peptide loading (R(2)=0.8). The method was also applicable for the tumor-associated antigen Wilms' tumor protein 1. This system is quick and easy to perform, independent of the donors human leukocyte antigen type and circumvents the need for additional cells as targets. It can be used in preclinical research to test new antigens for their immunogenic potential and for immunomonitoring in cancer patients. PMID- 25786873 TI - Expression of an engineered soluble coxsackievirus and adenovirus receptor by a dimeric AAV9 vector inhibits adenovirus infection in mice. AB - Immunosuppressed (IS) patients, such as recipients of hematopoietic stem cell transplantation, occasionally develop severe and fatal adenovirus (Ad) infections. Here, we analyzed the potential of a virus receptor trap based on a soluble coxsackievirus and Ad receptor (sCAR) for inhibition of Ad infection. In vitro, a dimeric fusion protein, sCAR-Fc, consisting of the extracellular domain of CAR and the Fc portion of human IgG1 and a monomeric sCAR lacking the Fc domain, were expressed in cell culture. More sCAR was secreted into the cell culture supernatant than sCAR-Fc, but it had lower Ad neutralization activity than sCAR-Fc. Further investigations showed that sCAR-Fc reduced the Ad infection by a 100-fold and Ad-induced cytotoxicity by ~20-fold. Not only was Ad infection inhibited by sCAR-Fc applied prior to infection, it also inhibited infection when used to treat ongoing Ad infection. In vivo, sCAR-Fc was delivered to IS mice by an AAV9 vector, resulting in persistent and high (>40 MUg ml(-1)) sCAR-Fc serum levels. The sCAR-Fc serum concentration was sufficient to significantly inhibit hepatic and cardiac wild-type Ad5 infection. Treatment with sCAR-Fc did not induce side effects. Thus, sCAR-Fc virus receptor trap may be a promising novel therapeutic for treatment of Ad infections. PMID- 25786875 TI - Proceedings of the Drug Delivery Australia 2012 symposium : Venue: Monash Institute of Pharmaceutical Sciences, Melbourne, Australia 26-27th November, 2012. PMID- 25786874 TI - The mitochondrial transporter of ascorbic acid functions with high affinity in the presence of low millimolar concentrations of sodium and in the absence of calcium and magnesium. AB - We recently reported that U937 cell mitochondria express a functional Na+ dependent ascorbic acid (AA) transporter recognised by anti-SVCT2 antibodies. The present study confirms and extends these observations by showing that this transporter is characterised by a Km and a pH-dependence comparable with that reported for the plasma membrane SVCT2. In isolated mitochondria, Na+ increased AA transport rate in a cooperative manner, revealed by a sigmoid curve and a Hill coefficient of 2, as also observed in intact Raw 264.7 cells (uniquely expressing SVCT2). There was however a striking difference on the Na+ concentrations necessary to reach saturation, i.e., 1 or 100 mM for the mitochondrial and plasma membrane transporters, respectively. Furthermore the mitochondrial, unlike the plasma membrane, transporter was fully active also in the absence of added Ca++ and/or Mg++. Taken together, the results presented in this study indicate that the U937 cell mitochondrial transporter of AA, because of its very low requirement for Na+ and independence for Ca++ and Mg++, displays kinetic characteristics surprisingly similar with those of the plasma membrane SVCT2. PMID- 25786876 TI - First in man bioavailability and tolerability studies of a silica-lipid hybrid (Lipoceramic) formulation: a Phase I study with ibuprofen. AB - Clinical trials addressing the viability of lipid and nanoparticle-based solid dosage forms for the oral delivery of poorly water-soluble drugs are limited to date. This Phase I study aimed to assess the comparative tolerability and oral pharmacokinetics of a novel silica nanoparticle-lipid hybrid formulation encapsulating ibuprofen (i.e., Lipoceramic-IBU) with reference to a commercial tablet (i.e., Nurofen(r)). The test (Lipoceramic-IBU) and reference (Nurofen(r)) ibuprofen formulations were characterised for physicochemical properties and in vitro solubilisation performance prior to the clinical study. A randomised, double-blinded, one-period single oral dose (20 mg ibuprofen) study was performed in 16 healthy male subjects under fasting conditions. Encapsulation of ibuprofen in a molecularly dispersed form in the Lipoceramic nanostructured silica-lipid matrices was shown to produce superior drug solubilisation in comparison to Nurofen(r) and the pure drug during a two-step dissolution (or solubilisation) study in aqueous buffers of pH 1.2 followed by pH 6.5. Pharmacokinetic profiles revealed an approximately 1.95-fold increased bioavailability (p=0.02) and a 1.5 fold higher maximum plasma concentration (p=0.14) for Lipoceramic-IBU with reference to Nurofen(r). Review of the safety assessments, including physical examinations, clinical laboratory tests and reports of adverse events, confirmed negligible acute side effects related to the administration of blank and ibuprofen-loaded Lipoceramic formulations. This first in man study of a dry lipid and nanoparticle-based formulation successfully demonstrated the safe use and effectiveness of the nanostructured Lipoceramic microparticles in mimicking the food effects for optimising the oral absorption of poorly water-soluble compounds. PMID- 25786877 TI - Iontophoretic skin permeation of peptides: an investigation into the influence of molecular properties, iontophoretic conditions and formulation parameters. AB - The transdermal route offers advantages for delivery of peptides and proteins. However, these polar and large molecules do not permeate the skin barrier well. Various enhancement methods have been employed to address this problem. Iontophoresis is one of the methods that shows promise but its application to peptide delivery has yet to be fully explored. This study investigates the effects of different molecular properties and iontophoretic conditions on the skin permeation of peptides. In this study, the permeation of alanine-tryptophan dipeptide (MW 276 Da), alanine-alanine-proline-valine tetrapeptide (MW 355 Da), Argireline(r) (Acetyl hexapeptide-3, MW 889 Da) and Triptorelin acetate (decapeptide, MW 1311 Da) through excised human skin under passive or iontophoretic current of 0.4 mA was investigated. The effects of pH change (3.0 7.4, to provide different net negative, neutral, and positive charges) to the peptide, donor concentration (1-10 mg/ml), background electrolyte (34-137 mM NaCl and/or 5-20 mM HEPES) and current direction (anodal vs cathodal) were also studied. Peptides were analysed by high-performance liquid chromatography or liquid scintillation counting. Iontophoresis led up to a 30 times increase in peptide permeation relative to passive permeation for the peptides. Electroosmosis was an important determinant of the total flux for the high molecular weight charged peptides. Electrorepulsion was found to be considerable for low molecular weight charged moieties. Permeation was decreased at lower pH, possibly due to decreased electroosmosis. Results also showed that 10 times increase in donor peptide concentration increases permeation of peptides by about 2-4 times and decreases iontophoretic permeability coefficients by about 2.5-5 times. The addition of extra background electrolyte decreased the iontophoretic permeation coefficient of peptides by 2-60 times. This study shows that iontophoretic permeation of peptides is affected by a number of parameters that can be optimized for effective transdermal peptide delivery. PMID- 25786878 TI - Consideration of the efficacy of non-ionic vesicles in the targeted delivery of oral vaccines. AB - The fundamentals of this research were to exploit non-ionic surfactant technology for delivery and administration of vaccine antigens across the oral route and to gain a better understanding of vaccine trafficking. Using a newly developed method for manufacture of non-ionic surfactant vesicles (niosomes and bilosomes) lower process temperatures were adopted thus reducing antigen exposure to potentially damaging conditions. Vesicles prepared by this method offered high protection to enzymatic degradation, with only ~10 % antigen loss measured when vesicles incorporating antigen were exposed to enzyme digestion. Interestingly, when formulated using this new production method, the addition of bile salt to the vesicles offered no advantage in terms of stability within simulated gastro intestinal conditions. Considering their ability to deliver antigen to their target site, results demonstrated that incorporation of antigen within vesicles enhanced delivery and targeting of the antigen to the Peyer's Patch, again with niosomes and bilosomes offering similar efficiency. Delivery to both the Peyer's patches and mesentery lymphatics was shown to be dose dependent at lower concentrations, with saturation kinetics applying at higher concentrations. This demonstrates that in the formulation of vaccine delivery systems, the lipid/antigen dose ratio is not only a key factor in production cost, but is equally a key factor in the kinetics of delivery and targeting of a vaccine system. PMID- 25786879 TI - Design, synthesis and characterisation of mannosylated ovalbumin lipid core peptide self-adjuvanting vaccine delivery system. AB - Peptide-based vaccine delivery can be hampered by rapid peptidase activity and poor inherent immunogenicity. The self-adjuvanting lipid core peptide system (LCP) has been shown to confer improved stability and immunogenicity on peptide epitopes of group A Streptococcus, Chlamydia, hookworm, and malaria pathogens. However, various diseases, including cancer, still require targeted delivery of their vaccine candidates. For this reason, we have selected two model peptides (ovalbumin CD4(+) and/or CD8(+) T cell epitopes), and incorporated two or four copies of either epitope into our LCP vaccine. Optimised glycosylation of ovalbumin peptides yielded 46 % when microwave-assisted double coupling with 2 eq of carbohydrate derivative, activated by N,N-diisopropylethylamine and (O benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, was performed. All ovalbumin peptides were successfully synthesised and purified in 11-55 % yields by Fmoc- or Boc-chemistry using solid-phase peptide synthesis. The mannosylated ovalbumin peptides were nontoxic to human erythrocytes in haemolytic assay (<2 % haemolysis) and showed increased (up to 20-fold) stability in plasma. PMID- 25786880 TI - Concurrent oral and inhalation drug delivery using a dual formulation system: the use of oral theophylline carrier with combined inhalable budesonide and terbutaline. AB - A novel approach to concurrently deliver oral and inhaled drugs as a single formulation is presented. A triple therapy containing theophylline (THEO; orally delivered) with budesonide (BUD) and terbutaline (TERB; as single and co-spray dried inhaled powders) was prepared as an ordered mix, with THEO acting as a carrier. The aerosolisation performance of THEO formulations containing BUD and TERB alone, physical mix and co-spray-dried powder was evaluated using a next generation impactor (NGI). Physicochemical properties were investigated using electron microscopy, laser diffraction, dynamic vapour sorption and thermal analysis. NGI analysis indicated that >99 % of the THEO powder was >4.46 MUm, with >90 % dissolved within 5 min. Particle size analysis showed TEB and BUD samples were of a suitable size for inhalation. Thermal and moisture analysis suggested powders to be stable at room temperature up to 70 % RH. Aerosol studies indicated a different performance of BUD and TERB depending on the mixing procedure. The co-spray-dried formulation showed the highest performance, with a fine particle fraction (<=4.46 MUm) of BUD and TERB of 34.39 +/- 3.56 and 33.61 +/- 5.67 %, respectively. Such observations suggest that this multicomponent drug delivery system could be developed to concomitantly deliver oral and inhaled drugs, an approach that, to date, does not exist. Ultimately, this technology potentially reduces the requirement for multiple therapies and increases patient compliance. PMID- 25786881 TI - A slow cooling rate of indomethacin melt spatially confined in microcontainers increases the physical stability of the amorphous drug without influencing its biorelevant dissolution behaviour. AB - Amorphous indomethacin was prepared by melting the gamma-form of indomethacin, spatially confined within microcontainers (inner diameter of 223 MUm), followed by cooling of the melt at a rate of 14, 23 or 36 K/min. The physical stability of the amorphous indomethacin within microcontainers was investigated using Raman microscopy. Furthermore, the dissolution behaviour of confined amorphous indomethacin was evaluated in biorelevant intestinal media at pH 6.5. After 30 days of storage, 10.3 +/- 1.2 % of the amorphous indomethacin cooled at 14 K/min and confined within microcontainers was found to be crystalline. When the melt of indomethacin was cooled at 23 or 36 K/min, 20.7 +/- 1.5 and 31.0 +/- 2.6 % of the indomethacin were found to be crystalline after storage for 30 days. Scanning electron microscopy showed a smooth surface of amorphous indomethacin within the microcontainers when cooling the melt at 14 K/min, whereas cracks and an uneven surface were observed when cooling at rates of 23 and 36 K/min. The uneven surface is hypothesised to be the main reason for the lower physical stability, as the cracks could act as nucleation sites for crystal growth. The rate of cooling was not seen to have any effect on the dissolution of amorphous indomethacin from the microcontainers. PMID- 25786883 TI - A mini-review on novel intraperiodontal pocket drug delivery materials for the treatment of periodontal diseases. AB - Periodontal disease is defined as chronic inflammatory condition characterized by the destruction of the periodontal tissues causing loss of connective tissue attachment, loss of alveolar bone, and the formation of pathological pockets around the diseased teeth. The use of systemic antibiotics has been advocated for its treatment, but concerns emerged with respect to adverse drug reactions and its contribution to bacterial resistance. Thus local drug delivery devices have been developed that aim to deliver a high concentration of antimicrobial drugs directly to the affected site, while minimizing drug's systemic exposure. A burst release of antimicrobial agent from carrier, resulting in a short and inadequate exposure of bacteria residing in periodontal pocket to the agent, remains the main challenge of current local delivery systems for the treatment of periodontal disease. This review aims to investigate and compare different local antimicrobial delivery systems with regard to the treatment of periodontal disease. PMID- 25786882 TI - Self-assembled structures formed during lipid digestion: characterization and implications for oral lipid-based drug delivery systems. AB - There is increasing interest in the use of lipid-based formulations for the delivery of poorly water-soluble drugs. After ingestion of the formulation, exposure to the gastrointestinal environment results in dispersion and digestion processes, leading to the production of amphiphilic digestion products that form self-assembled structures in the aqueous environment of the intestine. These structures are crucial for the maintenance of drug in a solubilized state prior to absorption. This review describes the structural techniques used to study such systems, the structures formed in assembled 'equilibrium' compositions where components are combined in expected ratios representative of the endpoint of digestion, structures formed using dynamic in vitro 'non-equilibrium' digestion models where the composition and hence structures present change over time and observations from ex vivo aspirated samples. Possible future directions towards an improved understanding of the structural aspects of lipid digestion are proposed. PMID- 25786884 TI - Phyllodes tumour among participants in screening mammography. AB - BACKGROUND: In screening, the distinction between phyllodes tumour (PT) and fibroadenoma (FA) is imprecise, often needing surgery. METHODS: In this retrospective cohort study and literature review, we wished to (i) present our experience with PT diagnosed among screening participants; (ii) identify discriminating features between FA and PT; (iii) assess the efficacy of cancer screening in identifying PT; and (iv) for women diagnosed with PT, determine appropriate breast cancer screening schedules. RESULTS: During a 23.7 years time frame, PT was diagnosed in 30 women, reflecting an incidence of 2.53 per 100 000 women screened. Only 22 (73.3%) PT were found by screening. The remaining eight (26.7%) presented as interval tumours. Thirteen PT were benign, eight borderline and nine malignant. Six of eight (75%) malignant PT were symptomatic. A circumscribed mass, mean diameter 34.7 mm, was the dominant finding. Enlargement (14 imaging, seven clinical) was documented in 21 (70%) cases. Diagnostic open biopsy was required in 67.9%. Follow-up of at least 12 months is available in 20 cases. Only two developed recurrence. One woman died of metastatic PT and one PT recurred locally. CONCLUSION: The extreme rarity of PT in screening contrasts with the prevalence of FAs. The peak incidence of PT in women is 40-50, whereas screening is targeted at women 50-74. Two yearly screening mammography is not designed to detect PT reliably. In particular, malignant PT grows rapidly and becomes symptomatic. Women with benign PT can continue with screening. Women with borderline and malignant PT should resume screening after 5 years of specialist surveillance. PMID- 25786885 TI - Erratum to: A new computerized adaptive test advancing the measurement of health related quality of life (HRQoL) in children: the Kids-CAT. PMID- 25786886 TI - Interpreting SF-12 mental component score: an investigation of its convergent validity with CESD-10. AB - OBJECTIVE: To examine the convergent validity of Mental Component Scale of the Short-Form 12 (SF-12 MCS) with the Center for Epidemiologic Studies Depression Scale (CESD-10). The CESD-10 is a screening tool for probably clinically significant depression in the Chinese population. METHODS: Data were obtained from a household survey carried out in Hong Kong. A two-stage stratified sampling method successfully interviewed 1795 adult subjects from 1239 households. Data on SF-12 MCS and the CESD-10 were extracted. Receiver operating characteristics (ROC) analyses were performed to examine the convergent validity of SF-12 MCS against the CESD-10 threshold for probably clinically significant depression for the younger to middle-aged, late middle-aged and older population cohorts. RESULTS: ROC analysis indicated the excellent convergent validity of SF-12 MCS with the CESD-10 threshold for identifying probably clinically significant depression, with the area under curve ranged from 0.81 to 0.85. The optimal cutoff scores for depression among the younger to middle age group, late middle age group and older age group were 48.1, 50.2 and 50.2, respectively, with sensitivities ranged from 77 to 83 % and specificities ranged from 73 to 78 %. Bootstrapping estimates of the mean difference indicated no significant difference in the optimal cutoff scores between these age cohorts. CONCLUSION: SF 12 is a widely adopted measure to capture the health profile of Chinese population. The study findings indicated the satisfactory performance of the SF 12 MCS in identifying probably clinical depression. Future study is warrant to examine the diagnostic validity of the SF-12 MCS by using gold standard to assess clinical depression. PMID- 25786887 TI - Introduction to special section on patient engagement. PMID- 25786888 TI - 1D Measurement of Sodium Ion Flow in Hydrogel After a Bath Concentration Jump. AB - NMR is used to measure sodium flow driven by a 1D concentration gradient inside poly-acrylamid (pAA) hydrogel. A sodium concentration jump from 0.5 M NaCl to 0 M NaCl is applied at the bottom of a cylindrical pAA sample. The sodium level and hydrogen level are measured as a function of time and position inside the sample for 5 days. Then a reversed step is applied, and ion flow is measured for another 5 days. During the measurement, the cylindrical sample is radially confined and allowed to swell in the axial direction. At the same time, sodium and moisture in the sample are measured on a 1D spatial grid in the axial direction. A quadriphasic mixture model (Huyghe and Janssen in Int J Eng Sci 35:793, 1997) is used to simulate the results and estimate the diffusion coefficient of sodium and chloride. The best fit results were obtained for D[Formula: see text] cm(2)/s and D[Formula: see text] cm(2)/s, at 25 degrees centigrade. Different time constants were observed for swelling and deswelling. PMID- 25786889 TI - First results of Endonasal dilatation of the Eustachian tube (EET) in patients with chronic obstructive tube dysfunction. AB - For years, several surgical and non-surgical therapeutic strategies in Eustachian tube dysfunction have been described. The Endonasal dilatation of the Eustachian tube (EET) utilising a balloon catheter is a feasible option in patients with symptoms of chronic obstructive Eustachian tube dysfunction. However, long-term results in a large series are missing. In a prospective case series, 217 patients (342 cases) with symptoms of chronic Eustachian tube dysfunction underwent uni- or bilateral EET at the ENT Department of the University of Hamburg, Germany, between September 2010 and April 2013. A tube score consisting of the type of tympanogram and the R value of the tubomanometry was used to evaluate pre- and postoperative tube function. All patients underwent follow-up with a post operative interval of 3-12 months. The mean value of the pre-treatment tube score was 2.23 +/- 1.147 and significantly improved to 2.68 +/- 1.011 1 year after EET. There was a significant increase in the tube score during follow-up. The co variables time period, tympanoplasty and pressure range showed a significant impact on the tube score. EET is a minimally invasive and effective treatment of chronic obstructive tube dysfunction. It is a safe procedure without causing significant complications. Nevertheless, long-term results of larger, placebo controlled multicentre studies are needed to confirm its effectiveness. PMID- 25786890 TI - Removal of Surrogate Bacteriophages and Enteric Viruses from Seeded Environmental Waters Using a Semi-technical Ultrafiltration Unit. AB - Experiments to determine the removal of viruses in different types of water (surface water from two reservoirs for drinking water treatment, treated groundwater and groundwater contaminated with either 5 or 30 % of wastewater) by ultrafiltration were performed with a semi-technical ultrafiltration unit. Concentrations of human adenoviruses (HAdVs), murine norovirus (MNV), and the bacteriophages MS2, PhiX174 and PRD1 were measured in the feed water and the filtrate, and log removal values were calculated. Bacteria added to the feed water were not detected in the filtrates. In contrast, in most cases viruses and bacteriophages were still present in the filtrates: log removal values were in the range of 1.4-6.3 depending on virus sizes and water qualities. Best removals were observed with bacteriophage PRD1 and HAdVs, followed by MNV and phages MS2 and PhiX174. Virus size, however, was not the only criterion for efficient removal. In diluted wastewater as compared to drinking water and uncontaminated environmental waters, virus removal was clearly higher for all viruses, most likely due to higher membrane fouling. For quality assessment purposes of membrane filtration efficiencies with regard to the elimination of human viruses the small bacteriophages MS2 and PhiX174 should be used as conservative viral indicators. PMID- 25786891 TI - Transcriptional changes during Daphnia pulex development indicate that the maturation decision resembles a rate more than a threshold. AB - Maturation is a critical developmental process, and the age and size at which it occurs have important fitness consequences. Although maturation is remarkably variable, certain mechanisms, including a minimum size or state threshold, are proposed to underlie the process across a broad diversity of taxa. Recent evidence suggests that thresholds may themselves be developmentally plastic, and in the crustacean Daphnia pulex it is unclear whether maturation follows a threshold or is a gradual process more akin to a rate. Changes in gene expression across four instars before and during maturation were compared in a cDNA microarray experiment. Developmental stage was treated statistically both as a discontinuous and as a continuous variable, to determine whether genes showed gradual or discrete changes in expression. The continuous analysis identified a greater number of genes with significant differential expression (45) than the discontinuous analysis (11). The majority of genes, including those coding for histones, factors relating to transcription and cell cycle processes, and a putative developmental hormone showed continuous increases or decreases in expression from the first to the fourth instars that were studied, suggestive of a prolonged and gradual maturation process. Three genes coding for a fused vitellogenin/superoxide dismutase showed increases in expression following the second instar and coincided with the posited maturation threshold, but even their expression increased in a continuous fashion. PMID- 25786892 TI - Multiple roles of a male-specific compound in the sexual behavior of the dried bean beetle, Acanthoscelides obtectus. AB - Males of Acanthoscelides obtectus (Coleoptera: Chrysomelidae, Bruchinae) emit methyl (E,R)-2,4,5-tetradecatrienoate that attracts females for mating. This study identified further roles for this compound in the sexual behavior of A. obtectus. Earlier observations revealed that males touched females with their antennae while tandem-running with them and initiated mounting and copulation, whereas they showed no such behavior toward other males. A series of subsequent laboratory choice tests were set up to establish if certain cuticular compounds aid contact sex recognition in A. obtectus. Males chose virgin females over other males. The activity toward females could be eliminated by rinsing with hexane, but was regained by application of female extract onto previously rinsed females. Gas chromatographic (GC) comparison of hexane extracts revealed the presence of two male-specific compounds, methyl (E,R)-2,4,5-tetradecatrienoate and octadecanal, which were absent from the behaviorally active female samples. Of the two compounds, methyl (E,R)-2,4,5-tetradecatrienoate was found to be responsible for the inhibition of male sexual behavior, similar to that observed with crude male extracts applied to virgin females. Furthermore, males preferred virgin over mated females. GC analyses revealed the presence of methyl (E,R) 2,4,5-tetradecatrienoate in mated females in amounts sufficient to curtail mating attempts. It appears that methyl (E,R)-2,4,5-tetradecatrienoate, besides being a male-produced sex pheromone, acts as a male-recognition signal in A. obtectus. Males also transfer it onto females during mating, resulting in mated females being avoided by courting males. PMID- 25786893 TI - A Biologically Active Analog of the Sex Pheromone of the Emerald Ash Borer, Agrilus planipennis. AB - The emerald ash borer, Agrilus planipennis (Coleoptera: Buprestidae) (EAB), is an invasive species causing unprecedented levels of mortality to ash trees in its introduced range. The female-produced sex pheromone of EAB has been shown to contain the macrocyclic lactone (3Z)-dodecen-12-olide. This compound and its geometrical isomer, (3E)-dodecen-12-olide, have been demonstrated previously to be EAG active and, in combination with a host-derived green leaf volatile, (3Z) hexenol, to be attractive to male EAB in green prism traps deployed in the ash tree canopy. In the current study, we show that the saturated analog, dodecan-12 olide, is similarly active, eliciting an antennal response and significant attraction of EAB in both olfactometer and trapping bioassays in green traps with (3Z)-hexenol. Conformational modeling of the three lactones reveals that their energies and shapes are very similar, suggesting they might share a common receptor in EAB antennae. These findings provide new insight into the pheromone ecology of this species, highlighting the apparent plasticity in response of adults to the pheromone and its analog. Both of the unsaturated isomers are costly to synthesize, involving multistep, low-yielding processes. The saturated analog can be made cheaply, in high yield, and on large scale via Mitsunobu esterification of a saturated omega-hydroxy acid or more simply by Baeyer Villiger oxidation of commercially available cyclododecanone. The analog can thus provide an inexpensive option as a lure for detection surveys as well as for possible mitigation purposes, such as mating disruption. PMID- 25786894 TI - Lipase active site covalent anchoring of Rh(NHC) catalysts: towards chemoselective artificial metalloenzymes. AB - A Rh(NHC) phosphonate complex reacts with the lipases cutinase and Candida antarctica lipase B resulting in the first (soluble) artificial metalloenzymes formed by covalent active site-directed hybridization. When compared to unsupported complexes, these new robust hybrids show enhanced chemoselectivity in the (competitive) hydrogenation of olefins over ketones. PMID- 25786895 TI - Clinical, histopathological, dermatoscopic and digital microscopic features of dermatofibroma: a retrospective analysis of 200 lesions. AB - BACKGROUND: Dermatology literature lacks a study investigating both histopathological and dermatoscopic features of dermatofibroma. OBJECTIVE: To analyse histopathological, dermatoscopic and digital microscopic features of dermatofibromas. METHODS: Two hundred dermatofibromas and 190 patients were included and retrospectively evaluated. Nine histopathological and ten dermatoscopic patterns were used to classify the lesions. We identified four different types of dermatofibroma in digital microscopy. RESULTS: The mean age of the patients was 42.18 +/- 13.72 years. Dermatofibroma was more common in females (67%) and the male to female ratio was 1:1.97. The most common location was leg (41%). The most frequent histopathological variant was fibrocollagenous type (49%). Grenz zone was the most common histopathological finding (89%). The most frequent digital microscopic type was type 1 (63%). CONCLUSIONS: We found that palisading variant displayed only pattern 6 in dermatoscopy and cellular variant showed type 3 significantly in digital microscopy. PMID- 25786896 TI - A Comprehensive, Automatically Updated Fungal ITS Sequence Dataset for Reference Based Chimera Control in Environmental Sequencing Efforts. AB - The nuclear ribosomal internal transcribed spacer (ITS) region is the most commonly chosen genetic marker for the molecular identification of fungi in environmental sequencing and molecular ecology studies. Several analytical issues complicate such efforts, one of which is the formation of chimeric-artificially joined-DNA sequences during PCR amplification or sequence assembly. Several software tools are currently available for chimera detection, but rely to various degrees on the presence of a chimera-free reference dataset for optimal performance. However, no such dataset is available for use with the fungal ITS region. This study introduces a comprehensive, automatically updated reference dataset for fungal ITS sequences based on the UNITE database for the molecular identification of fungi. This dataset supports chimera detection throughout the fungal kingdom and for full-length ITS sequences as well as partial (ITS1 or ITS2 only) datasets. The performance of the dataset on a large set of artificial chimeras was above 99.5%, and we subsequently used the dataset to remove nearly 1,000 compromised fungal ITS sequences from public circulation. The dataset is available at http://unite.ut.ee/repository.php and is subject to web-based third party curation. PMID- 25786897 TI - Immune and oxidative response to linseed in the diet of periparturient Holstein cows. AB - The aim of this research was to determine the influence of dietary replacement of n-6 with n-3 polyunsaturated fatty acids on cellular immunity and oxidative stress in the transition period dairy cows. The experiment was conducted on 20 dairy Holstein cows from 3 +/- 1 weeks before parturition until the 6th week of lactation. Both groups were fed an iso-energetic and iso-nitrogenous diet. Soybean meal from control (C) group was replaced with linseed in the experimental (LS) group. Cellular immunity and oxidative stress were measured on days -10, 1, 21 and 42 relative to parturition. During the entire experimental period, the proportion of CD45+ cells was lower (P<0.05) in LS group compared with the C group. The phagocytosis ability and phagocytosis index of cows fed with n-3 fatty acids were significantly reduced (P<0.05) compared with the group of cows fed with n-6 fatty acids. The most severe decrease in phagocytosis ability was on day -10 and 1 relative to parturition. The activity of superoxide dismutase (P<0.05) and plasma glutathione peroxidase (P<0.05) increased around calving, although activities were not influenced by dietary treatment. Increased malondialdehyde concentration (P<0.05) was influenced by dietary n-3 fatty acids and the time relative to parturition. The immune suppression was most pronounced during periparturient period. In that matter we can conclude that not only dietary n-3 fatty acids but also oxidative stress, which reached peak at time of parturition, contributed to the reduced cellular immunity during the periparturient period. PMID- 25786899 TI - Site-specific nanopatterning of functional metallic and molecular arbitrary features in nanofluidic channels. AB - We established a versatile method for site-specific nanopatterning of functional metallic and molecular arbitrary features in glass nanofluidic channels, with well-controlled feature sizes ranging from tens to hundreds of nanometers and precisely controlled placements in the range of several tens of nanometers. With the method, we achieved the fabrication of quasi-0D, quasi-1D, 2D, and 3D gold nanopatterns in nanofluidic channels, as well as a high-density fluorescent molecular nanoarray in arrayed femtoliter nanofluidic channels. The method opens the way for precise functionalization of nanofluidic channels, which has been greatly challenging in the field of nanofluidics. PMID- 25786900 TI - Small intestinal fungal overgrowth. AB - Small intestinal fungal overgrowth (SIFO) is characterized by the presence of excessive number of fungal organisms in the small intestine associated with gastrointestinal (GI) symptoms. Candidiasis is known to cause GI symptoms particularly in immunocompromised patients or those receiving steroids or antibiotics. However, only recently, there is emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained GI symptoms. Two recent studies showed that 26 % (24/94) and 25.3 % (38/150) of a series of patients with unexplained GI symptoms had SIFO. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear but small intestinal dysmotility and use of proton pump inhibitors has been implicated. However, further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth, both in healthy subjects and in patients with otherwise unexplained GI symptoms. Importantly, whether eradication or its treatment leads to resolution of symptoms remains unclear; at present, a 2-3-week course of antifungal therapy is recommended and may be effective in improving symptoms, but evidence for eradication is lacking. PMID- 25786901 TI - Screening for malignancy in primary sclerosing cholangitis (PSC). AB - Primary sclerosing cholangitis (PSC) is a frequently progressive and fatal disease. Death from cancer occurs in a significant subset of patients with PSC. Patients with PSC have a 10 to 15 % lifetime risk of developing cholangiocarcinoma (CCA). About one third of CCAs are present in the first year after a diagnosis of PSC; the remainder are present with a frequency of about 1.5 % each year. Patients with concomitant PSC and inflammatory bowel disease (IBD) have a 4-fold higher risk of colorectal cancer (CRC) than patients with IBD alone and a 10-fold higher risk of CRC than the general population. The risk does not diminish with liver transplantation. This patient population also has a high frequency of carcinoma in gallbladder mass lesions. The risk for hepatocellular carcinoma (HCC) in the presence of cirrhosis is uncertain-two large cohort studies suggest that HCC is not as common as in other causes of cirrhosis. Although AASLD guidelines do not recommend routine screening for liver tumors in patients with PSC, we recommend MRI/MRCP and serum CA 19-9 levels in patients with PSC every 6 months to screen for CCA, HCC, pancreatic cancer, and gallbladder cancer. Screening colonoscopy at the diagnosis of PSC and surveillance colonoscopies every 1-2 years should be performed in those with PSC and IBD. PMID- 25786902 TI - Correction: Tuning temperature responsive poly(2-alkyl-2-oxazoline)s by supramolecular host-guest interactions. PMID- 25786903 TI - Long-term effects of anti-reflux surgery on the physiology of the esophagogastric junction. AB - BACKGROUND: Studies performed shortly after anti-reflux surgery have demonstrated that the reduction of reflux episodes is caused by a decrease in the rate of transient lower esophageal sphincter relaxations (TLESRs) and a decrease in the distensibility of the esophagogastric junction (EGJ). We aimed to assess the long term effects of surgical fundoplication on the physiology of the EGJ. METHODS: We included 18 patients who underwent surgical fundoplication >5 years before and 10 GERD patients who did not have surgery. Patients underwent 90-min combined high resolution manometry and pH-impedance monitoring, and EGJ distensibility was assessed. RESULTS: Post-fundoplication patients exhibited a lower frequency of reflux events than GERD patients (2.0 +/- 0.5 vs 15.1 +/- 4.3, p < 0.05). The rate of TLESRs (6.1 +/- 0.9 vs 12.6 +/- 1.0, p < 0.05) and their association with reflux (28.3 +/- 9.0 vs 74.9 +/- 6.9 %, p < 0.05) was lower in post fundoplication patients than in GERD patients. EGJ distensibility was significantly lower in post-fundoplication patients than in GERD patients. Recurrence of GERD symptoms after fundoplication was not associated with an increased number of reflux episodes, nor was it associated with an increased distensibility of the EGJ or an increase in the number of TLESRs. CONCLUSION: More than 5 years after anti-reflux surgery, patients still exhibit a lower rate of TLESRs and a reduced distensibility of the EGJ compared with medically treated GERD patients. These data suggest that the effects of surgical fundoplication on EGJ physiology persist at the long term and underlie the persistent reduction of reflux events. PMID- 25786904 TI - Perioperative outcome of unilateral versus bilateral inguinal hernia repairs in TAPP technique: analysis of 15,176 cases from the Herniamed Registry. AB - INTRODUCTION: Following repair of a unilateral inguinal hernia, there is a risk of 1% per year of onset of an inguinal hernia on the other side. Comparison of bilateral with unilateral TAPP operation in a high-volume center found that morbidity and reoperation rates were only marginally higher for bilateral TAPP operation. Some authors are calling for prophylactic operation of the contralateral side. METHODS: Between September 2009 and April 2013, data were entered into the Herniamed Registry on 15,176 patients who had undergone TAPP operation. Of these patients, 10,887 had been operated on because of a unilateral (71.7%) and 4289 because of a bilateral (28.3%) inguinal hernia. RESULTS: A significant difference was noted in the rate of postoperative complications occurring within 30 days, which was 4.9% for bilateral compared with 3.9% for unilateral inguinal hernia (p = 0.009). The postoperative complications necessitated reoperation in 0.9% of patients after unilateral and in 1.9% of patients after bilateral inguinal hernia repair, thus attesting to the significantly higher risk presented by bilateral inguinal hernia repair (p = <0.001).Multivariate analysis confirmed the highly significant influence of bilateral TAPP on increased reoperation rates due to complications (p > 0.0001). The odds ratio was 2.13 (95% CI 1.58-2.86). Comparison of the results from a high volume center with those from the Herniamed Registry showed that perioperative complication rates were markedly higher. CONCLUSION: Perioperative outcome of bilateral TAPP operation demonstrates significantly worse postoperative complication and reoperation rates compared with unilateral TAPP. Likewise, the results were markedly unfavorable compared with those of a high-volume center. If a bilateral hernia repair should be attempted in those patients with only a unilateral hernia, these data give the surgeon more information on how to better prepare a patient and obtain consent preoperatively. PMID- 25786905 TI - Do we need antibiotic prophylaxis in endoscopic inguinal hernia repair? Results of the Herniamed Registry. AB - INTRODUCTION: The use of antibiotic prophylaxis in inguinal hernia repair is a controversial issue. Accepted randomized controlled trials or registry data with specific analysis of endoscopic repaired patients do not exist. PATIENT AND METHODS: The data presented in this study compared the prospectively collected data from the Herniamed Registry on all patients who had undergone unilateral, bilateral or recurrent repair of inguinal hernias using either endoscopic or open techniques between September 1, 2009, and March 5, 2014. In total, 85,033 patients were enrolled. Of these patients, 48,201 (56.7 ) had an endoscopic and 36,832 (43.3%) an open repair. The target variables analyzed were impaired wound healing and deep infections with mesh involvement within 30 days after the operation. RESULTS: Analysis of the patient group with endoscopic/laparoscopic inguinal hernia repair (n = 48,201) did not identify any significant influence of antibiotic prophylaxis on postoperative impaired wound healing, which occurred in 53 cases (p = 0.6431). Nor was it possible to identify any significant impact of antibiotic prophylaxis on the deep infections seen in 27 cases (p = 0.8409). Analysis of the open inguinal hernia repair group revealed that, unlike the laparoscopic/endoscopic group, antibiotic prophylaxis had a significant impact on the postoperative impaired wound healing and deep infection rates. The risk of postoperative impaired wound healing with antibiotic prophylaxis was significantly lower [OR 0.677 (0.479; 0.958), p = 0.027]. CONCLUSION: The positive impact of the endoscopic/laparoscopic technique on avoidance of impaired wound healing and deep infections with mesh involvement is already so great that antibiotic prophylaxis has no additional benefit. In contrast, antibiotic prophylaxis should be administered for open inguinal hernia repair. PMID- 25786907 TI - Polypyrrole nanoprobes with low non-specific protein adsorption for intracellular mRNA detection and photothermal therapy. AB - In this work, we discovered that polypyrrole nanoparticles (PPy NPs) displayed a low non-specific protein adsorption. We herein present the first PPy NP-based biosensing platform for intracellular mRNA detection in living cells. We also demonstrate that PPy NPs exhibit high NIR absorbance and can be utilized for cancer photothermal therapy. PMID- 25786906 TI - SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. We investigated changes in expression of microRNAs (miRNAs) and the genes they regulate in tissues of patients with HSCR. Quantitative real-time PCR and immunoblot analyses were used to measure levels of miRNA, mRNAs, and proteins in colon tissues from 69 patients with HSCR and 49 individuals without HSCR (controls). Direct interactions between miRNAs and specific mRNAs were indentified in vitro, while the function role of miR-218-1 was investigated by using miR-218 transgenic mice. An increased level of miR-218-1 correlated with increased levels of SLIT2 and decreased levels of RET and PLAG1 mRNA and protein. The reductions in RET and PLAG1 by miR-218-1 reduced proliferation and migration of SH-SY5Y cells. Overexpression of the secreted form of SLIT2 inhibited cell migration via binding to its receptor ROBO1. Bowel tissues from miR-218-1 transgenic mice had nerve fibre hyperplasia and reduced numbers of gangliocytes, compared with wild-type mice. Altered miR 218-1 regulation of SLIT2, RET and PLAG1 might be involved in the pathogenesis of HSCR. PMID- 25786908 TI - Resolving Weak Light of Sub-picowatt per Square Centimeter by Hybrid Perovskite Photodetectors Enabled by Noise Reduction. AB - A highly sensitive hybrid perovskite photodetector is demonstrated to be able to directly resolve light irradiance down to sub-picowatts per square centimeter, in good accordance with the calculated noise equivalent power, which is enabled by electron and hole transport layer engineering, especially the trap passivation effect of the double fullerene layer. PMID- 25786909 TI - Genome mining of the hitachimycin biosynthetic gene cluster: involvement of a phenylalanine-2,3-aminomutase in biosynthesis. AB - Hitachimycin is a macrolactam antibiotic with (S)-beta-phenylalanine (beta-Phe) at the starter position of its polyketide skeleton. To understand the incorporation mechanism of beta-Phe and the modification mechanism of the unique polyketide skeleton, the biosynthetic gene cluster for hitachimycin in Streptomyces scabrisporus was identified by genome mining. The identified gene cluster contains a putative phenylalanine-2,3-aminomutase (PAM), five polyketide synthases, four beta-amino-acid-carrying enzymes, and a characteristic amidohydrolase. A hitA knockout mutant showed no hitachimycin production, but antibiotic production was restored by feeding with (S)-beta-Phe. We also confirmed the enzymatic activity of the HitA PAM. The results suggest that the identified gene cluster is responsible for the biosynthesis of hitachimycin. A plausible biosynthetic pathway for hitachimycin, including a unique polyketide skeletal transformation mechanism, is proposed. PMID- 25786910 TI - Preventing, rather than treating, stress in doctors under investigation. PMID- 25786911 TI - Motion control of the rabbit ankle joint with a flat interface nerve electrode. AB - INTRODUCTION: A flat interface nerve electrode (FINE) has been shown to improve fascicular and subfascicular selectivity. A recently developed novel control algorithm for FINE was applied to motion control of the rabbit ankle. METHODS: A 14-contact FINE was placed on the rabbit sciatic nerve (n = 8), and ankle joint motion was controlled for sinusoidal trajectories and filtered random trajectories. To this end, a real-time controller was implemented with a multiple channel current stimulus isolator. RESULTS: The performance test results showed good tracking performance of rabbit ankle joint motion for filtered random trajectories and sinusoidal trajectories (0.5 Hz and 1.0 Hz) with <10% average root-mean-square (RMS) tracking error, whereas the average range of ankle joint motion was between -20.0 +/- 9.3 degrees and 18.1 +/- 8.8 degrees . CONCLUSIONS: The proposed control algorithm enables the use of a multiple-contact nerve electrode for motion trajectory tracking control of musculoskeletal systems. PMID- 25786912 TI - Thrombolysis in acute ischaemic stroke: time for a rethink? PMID- 25786913 TI - Renal safety of intravenous gadolinium-enhanced magnetic resonance imaging in patients awaiting liver transplantation. AB - Renal dysfunction in cirrhosis carries a high morbidity and mortality. Given the potential risk of contrast-induced nephropathy associated with iodinated intravenous contrast used in computed tomography (CT), alternate contrast modalities for abdominal imaging in liver transplant candidates need to be examined. The purpose of this study was to examine the renal safety of magnetic resonance imaging (MRI) with gadolinium in patients awaiting liver transplantation. The study involved a retrospective analysis of 352 patients of abdominal MRI with low-dose gadobenate dimeglumine (MultiHance) (0.05 mmol/kg) in patients with cirrhosis and without renal replacement therapy at a single center during the period from 2007 to 2013. For each case, serum creatinine before and within a few days after the MRI were compared. In addition, the patients were analyzed for the development of nephrogenic systemic fibrosis (NSF), a reported complication of gadolinium in chronic kidney disease. The pre-MRI serum creatinine values ranged from 0.36 to 4.86 mg/dL, with 70 patients (20%) having values >= 1.5 mg/dL. A comparison of the pre- and post-MRI serum creatinine values did not demonstrate a clinically significant difference (mean change = 0.017 mg/dL; P = 0.38), including those patients with a pre-MRI serum creatinine >= 1.5 mg/dL. In addition, no cases of NSF were noted. In conclusion, our findings suggest that MRI with low-dose gadobenate dimeglumine (MultiHance) is a nonnephrotoxic imaging modality in liver transplant candidates, and its use can be cautiously expanded to liver transplant candidates with concomitant renal insufficiency. PMID- 25786914 TI - Predicting prolonged hospital stay after laparoscopic cholecystectomy. AB - INTRODUCTION: Widespread application of laparoscopic cholecystectomy (LC) has resulted in a high complication rate and leads to prolonged hospital stays. This study aimed to investigate the preoperative and intraoperative clinical factors that relate to prolongation of hospital stay. METHODS: We studied 370 patients who underwent LC for gallbladder disease between 2008 and 2012. Clinical risk factors were retrospectively collected. The clinical pathway for LC was indicated for all patients, and they were divided into two groups according to postoperative length of stay (LOS): the normal duration group (LOS <=5 days) and the long duration (LD) group (LOS >=6 days). Multiple regression analysis was used to predict risk factors that identified hospital prolongation to create a LOS prediction score. RESULTS: The normal duration group was 236 patients and the LD group was 134. Seventeen patients (4.6%) required conversion from laparoscopic to open surgery. LOS was 4.82 days in the normal duration group and 12.08 days in the LD group. In the LD group, 18.7% of the patients stayed more than 14 days, but no patients were readmitted. Thirteen clinical factors were statistically different between the two groups. ASA score and LC difficulty were the most predictive risk factors for LOS prolongation. LOS prediction score consisted of eight variables selected from 13 factors; it helped determine the likelihood of whether a patients' hospital stay was prolonged (sensitivity, 82.1%; specificity, 75.0%). CONCLUSION: Thirteen factors closely related to hospital stay duration and LOS prediction score could predict the prolongation of a patient's hospital stay. PMID- 25786915 TI - ALIX Rescues Budding of a Double PTAP/PPEY L-Domain Deletion Mutant of Ebola VP40: A Role for ALIX in Ebola Virus Egress. AB - Ebola (EBOV) is an enveloped, negative-sense RNA virus belonging to the family Filoviridae that causes hemorrhagic fever syndromes with high-mortality rates. To date, there are no licensed vaccines or therapeutics to control EBOV infection and prevent transmission. Consequently, the need to better understand the mechanisms that regulate virus transmission is critical to developing countermeasures. The EBOV VP40 matrix protein plays a central role in late stages of virion assembly and egress, and independent expression of VP40 leads to the production of virus-like particles (VLPs) by a mechanism that accurately mimics budding of live virus. VP40 late (L) budding domains mediate efficient virus-cell separation by recruiting host ESCRT and ESCRT-associated proteins to complete the membrane fission process. L-domains consist of core consensus amino acid motifs including PPxY, P(T/S)AP, and YPx(n)L/I, and EBOV VP40 contains overlapping PPxY and PTAP motifs whose interactions with Nedd4 and Tsg101, respectively, have been characterized extensively. Here, we present data demonstrating for the first time that EBOV VP40 possesses a third L-domain YPx(n)L/I consensus motif that interacts with the ESCRT-III protein Alix. We show that the YPx(n)L/I motif mapping to amino acids 18-26 of EBOV VP40 interacts with the Alix Bro1-V fragment, and that siRNA knockdown of endogenous Alix expression inhibits EBOV VP40 VLP egress. Furthermore, overexpression of Alix Bro1-V rescues VLP production of the budding deficient EBOV VP40 double PTAP/PPEY L-domain deletion mutant to wild-type levels. Together, these findings demonstrate that EBOV VP40 recruits host Alix via a YPx(n)L/I motif that can function as an alternative L domain to promote virus egress. PMID- 25786916 TI - Seroepidemiological Prevalence of Multiple Species of Filoviruses in Fruit Bats (Eidolon helvum) Migrating in Africa. AB - Fruit bats are suspected to be a natural reservoir of filoviruses, including Ebola and Marburg viruses. Using an enzyme-linked immunosorbent assay based on the viral glycoprotein antigens, we detected filovirus-specific immunoglobulin G antibodies in 71 of 748 serum samples collected from migratory fruit bats (Eidolon helvum) in Zambia during 2006-2013. Although antibodies to African filoviruses (eg, Zaire ebolavirus) were most prevalent, some serum samples showed distinct specificity for Reston ebolavirus, which that has thus far been found only in Asia. Interestingly, the transition of filovirus species causing outbreaks in Central and West Africa during 2005-2014 seemed to be synchronized with the change of the serologically dominant virus species in these bats. These data suggest the introduction of multiple species of filoviruses in the migratory bat population and point to the need for continued surveillance of filovirus infection of wild animals in sub-Saharan Africa, including hitherto nonendemic countries. PMID- 25786917 TI - Structural and Functional Studies on the Marburg Virus GP2 Fusion Loop. AB - Marburg virus (MARV) and the ebolaviruses belong to the family Filoviridae (the members of which are filoviruses) that cause severe hemorrhagic fever. Infection requires fusion of the host and viral membranes, a process that occurs in the host cell endosomal compartment and is facilitated by the envelope glycoprotein fusion subunit, GP2. The N-terminal fusion loop (FL) of GP2 is a hydrophobic disulfide-bonded loop that is postulated to insert and disrupt the host endosomal membrane during fusion. Here, we describe the first structural and functional studies of a protein corresponding to the MARV GP2 FL. We found that this protein undergoes a pH-dependent conformational change, as monitored by circular dichroism and nuclear magnetic resonance. Furthermore, we report that, under low pH conditions, the MARV GP2 FL can induce content leakage from liposomes. The general aspects of this pH-dependent structure and lipid-perturbing behavior are consistent with previous reports on Ebola virus GP2 FL. However, nuclear magnetic resonance studies in lipid bicelles and mutational analysis indicate differences in structure exist between MARV and Ebola virus GP2 FL. These results provide new insight into the mechanism of MARV GP2-mediated cell entry. PMID- 25786918 TI - CA1-specific deletion of NMDA receptors induces abnormal renewal of a learned fear response. AB - CA1 hippocampal N-methyl-d-aspartate-receptors (NMDARs) are necessary for contextually related learning and memory processes. Extinction, a form of learning, has been shown to require intact hippocampal NMDAR signalling. Renewal of fear expression can occur after fear extinction training, when the extinguished fear stimulus is presented in an environmental context different from the training context and thus, renewal is dependent on contextual memory. In this study, we show that a Grin1 knock-out (loss of the essential NR1 subunit for the NMDAR) restricted to the bilateral CA1 subfield of the dorsal hippocampus does not affect acquisition of learned fear, but does attenuate extinction of a cued fear response even when presented in the extinction-training context. We propose that failure to remember the (safe) extinction context is responsible for the abnormal fear response and suggest it is a dysfunctional renewal. The results highlight the difference in outcome of extinguished fear memory resulting from a partial rather than complete loss of function of the hippocampus and suggest a potential mechanism for abnormally increased fear expression in PTSD. PMID- 25786919 TI - Glutaraldehyde fixation preserves the trend of elasticity alterations for endothelial cells exposed to TNF-alpha. AB - Among the users of atomic force microscopy based techniques, there is an ongoing discussion, whether cell elasticity measurements performed on fixed cells could be used for determination of the relative elasticity changes of the native (unfixed) cells subjected to physiologically active external agents. In this article, we present a case, for which the legitimacy of cell fixation for elasticity measurements is justified. We provide an evidence that the alterations of cell elasticity triggered by tumor necrosis factor alpha (TNF-alpha) in EA.hy926 endothelial cells are preserved after glutaraldehyde (GA) fixation. The value of post-fixation elasticity parameter is a product of the elasticity parameter obtained for living cells and a constant value, dependent on the GA concentration. The modification of the initial value of elasticity parameter caused by remodeling of the cortical actin cytoskeleton is reflected in the elasticity measurements performed on fixed cells. Thus, such fixation procedure may be particularly helpful for experiments, where the influence of an external agent on the cell cortex should be assessed and AFM measurements of living cells are problematic or better statistics is needed. PMID- 25786920 TI - Bio-Inspired Chemical Fabrication of Stretchable Transparent Electrodes. AB - Stretchable and transparent electrodes are fabricated by chemical deposition of metal thin films on natural veins of leaves at ambient conditions. These vein based transparent electrodes show excellent electro-optical property (0.9 Omega sq(-1) at 83% T) even at 50% tensile strains, ideal for flexible and stretchable optoelectronic devices. PMID- 25786921 TI - Auditory brainstem response of the Japanese house bat (Pipistrellus abramus). AB - Auditory brainstem responses (ABR) to high frequencies encompassing the species' vocal repertoire were recorded from the inferior colliculus of the Japanese house bat, Pipistrellus abramus. Amplitudes of tone pips were systematically decreased to obtain a threshold of response at different tone frequencies. The compiled audiogram has a broad U-shape over the frequency range from 4 to 80 kHz, with low thresholds between 20 and 50 kHz. The most sensitive frequency region of 35-50 kHz occurs at the quasi-constant-frequency terminal portion of the bat's downsweeping frequency-modulated echolocation pulses. Good sensitivity extending down to 20 kHz includes the frequency range of the first harmonic of communication sounds. The ABR audiogram does not show distinct, narrow peaks of greater sensitivity at the dominant frequencies in species vocalizations. Latencies of peaks in ABR responses lengthened as stimuli were attenuated. At 40 kHz, response latencies traded with amplitude by -7 to -9 MUs/dB, a value smaller than measured in another frequency-modulated bat using lower frequencies for echolocation. These results have implications for understanding the significance of amplitude-latency trading in a comparative context. PMID- 25786922 TI - Dynamic time warping and sparse representation classification for birdsong phrase classification using limited training data. AB - Annotation of phrases in birdsongs can be helpful to behavioral and population studies. To reduce the need for manual annotation, an automated birdsong phrase classification algorithm for limited data is developed. Limited data occur because of limited recordings or the existence of rare phrases. In this paper, classification of up to 81 phrase classes of Cassin's Vireo is performed using one to five training samples per class. The algorithm involves dynamic time warping (DTW) and two passes of sparse representation (SR) classification. DTW improves the similarity between training and test phrases from the same class in the presence of individual bird differences and phrase segmentation inconsistencies. The SR classifier works by finding a sparse linear combination of training feature vectors from all classes that best approximates the test feature vector. When the class decisions from DTW and the first pass SR classification are different, SR classification is repeated using training samples from these two conflicting classes. Compared to DTW, support vector machines, and an SR classifier without DTW, the proposed classifier achieves the highest classification accuracies of 94% and 89% on manually segmented and automatically segmented phrases, respectively, from unseen Cassin's Vireo individuals, using five training samples per class. PMID- 25786923 TI - Eigenbeam analysis of the diversity in bat biosonar beampatterns. AB - A quantitative analysis of the interspecific variability in bat biosonar beampatterns has been carried out on 267 numerical predictions of emission and reception beampatterns from 98 different species. Since these beampatterns did not share a common orientation, an alignment was necessary to analyze the variability in the shape of the patterns. To achieve this, beampatterns were aligned using a pairwise optimization framework based on a rotation-dependent cost function. The sum of the p-norms between beam-gain functions across frequency served as a figure of merit. For a representative subset of the data, it was found that all pairwise beampattern alignments resulted in a unique global minimum. This minimum was found to be contained in a subset of all possible beampattern rotations that could be predicted by the overall beam orientation. Following alignment, the beampatterns were decomposed into principal components. The average beampattern consisted of a symmetric, positionally static single lobe that narrows and became progressively asymmetric with increasing frequency. The first three "eigenbeams" controlled the beam width of the beampattern across frequency while higher rank eigenbeams account for symmetry and lobe motion. Reception and emission beampatterns could be distinguished (85% correct classification) based on the first 14 eigenbeams. PMID- 25786924 TI - Perceptual thresholds for the effects of room modes as a function of modal decay. AB - Room modes cause audible artifacts in listening environments. Modal control approaches have emerged in scientific literature over the years and, often, their performance is measured by criteria that may be perceptually unfounded. Previous research has shown modal decay as a key perceptual factor in detecting modal effects. In this work, perceptual thresholds for the effects of modes as a function of modal decay have been measured in the region between 32 and 250 Hz. A test methodology has been developed to include modal interaction and temporal masking from musical events, which are important aspects in recreating an ecologically valid test regime. This method has been deployed in addition to artificial test stimuli traditionally used in psychometric studies, which provide unmasked, absolute thresholds. For artificial stimuli, thresholds decrease monotonically from 0.9 s at 32 Hz to 0.17 s at 200 Hz, with a knee at 63 Hz. For music stimuli, thresholds decrease monotonically from 0.51 s at 63 Hz to 0.12 s at 250 Hz. Perceptual thresholds are shown to be dependent on frequency and to a much lesser extent on level. The results presented here define absolute and practical thresholds, which are useful as perceptually relevant optimization targets for modal control methods. PMID- 25786925 TI - The effects of stage absorption on reverberation times in opera house seating areas. AB - The effects of stage absorption on reverberation times in opera houses were investigated using computer simulations and scale model measurements. The reverberation time (RT) was measured in stalls seating with and without variable stage elements (e.g., fly curtains, side curtains, cycloramas, and stage sets). The absorption coefficients of the walls and ceiling of the stage houses were varied accordingly. It was found that variable stage elements have a significant influence on reverberation times in seating areas, particularly for a reverberant stage house, due to the low absorption of the walls and ceiling in the stage house. It was also found that the absorption coefficients of the walls and ceiling should be over 0.5 to avoid RT decreases of over 10% due to the absorption of the variable stage elements. In addition, coupled room effects were investigated both with and without variable stage elements and the results show that double slope was not found in the opera houses investigated in this study. PMID- 25786926 TI - Influence of wall scattering on the early fine structures of measured room impulse responses. AB - The effects of wall diffusing elements on sound-field diffuseness were investigated in a tenth-scale model hall and in a real recital hall. Acoustical measurements were carried out in both halls to measure the surface diffusivity of the lateral walls. In the scale model, the surfaces of the lateral walls and the soffits were covered with diffusers; in the recital hall, the front halves of both lateral walls were treated using reflective panels and absorptive materials. Objective characteristics were investigated using conventional room acoustic parameters and the number of peaks (Np) computed for the measured impulse responses, which were recorded under diffusive, reflective, and absorptive conditions. In addition, as a measure of the diffuse sound fields, the relative standard deviations (RSDs) of the acoustical parameters were investigated. The diffusive surfaces caused a decrease in the standard deviation of the early decay time and an increase in the Np at higher frequency bands. Auditory experiments using a paired comparison method revealed that the perception of subjective diffuseness could be quantified by using Np. In addition, one listener group's preference was correlated with Np and varied depending on different wall surface treatments. PMID- 25786927 TI - Two-compartment passive frequency domain cochlea model allowing independent fluid coupling to the tectorial and basilar membranes. AB - The cochlea is a spiral-shaped, liquid-filled organ in the inner ear that converts sound with high frequency selectivity over a wide pressure range to neurological signals that are eventually interpreted by the brain. The cochlear partition, consisting of the organ of Corti supported below by the basilar membrane and attached above to the tectorial membrane, plays a major role in the frequency analysis. In early fluid-structure interaction models of the cochlea, the mechanics of the cochlear partition were approximated by a series of single degree-of-freedom systems representing the distributed stiffness and mass of the basilar membrane. Recent experiments suggest that the mechanical properties of the tectorial membrane may also be important for the cochlea frequency response and that separate waves may propagate along the basilar and tectorial membranes. Therefore, a two-dimensional two-compartment finite difference model of the cochlea was developed to investigate the independent coupling of the basilar and tectorial membranes to the surrounding liquid. Responses are presented for models using two- or three-degree-of-freedom stiffness, damping, and mass parameters derived from a physiologically based finite element model of the cochlear partition. Effects of changes in membrane and organ of Corti stiffnesses on the individual membrane responses are investigated. PMID- 25786928 TI - Nonlinear attenuation and dispersion in human calcaneus in vitro: statistical validation and relationships to microarchitecture. AB - Through-transmission measurements were performed on 30 human calcaneus samples in vitro. Nonlinear attenuation and dispersion measurements were investigated by estimating 95% confidence intervals of coefficients of polynomial expansions of log magnitude and phase of transmission coefficients. Bone mineral density (BMD) was measured with dual x-ray absorptiometry. Microarchitecture was measured with microcomputed tomography. Statistically significant nonlinear attenuation and nonzero dispersion were confirmed for a clinical bandwidth of 300-750 kHz in 40% 43% of bone samples. The mean linear coefficient for attenuation was 10.3 dB/cm MHz [95% confidence interval (CI): 9.0-11.6 dB/cm MHz]. The mean quadratic coefficient for attenuation was 1.6 dB/cm MHz(2) (95% CI: 0.4-2.8 dB/cm MHz(2)). Nonlinear attenuation provided little information regarding BMD or microarchitecture. The quadratic coefficient for phase (which is related to dispersion) showed moderate correlations with BMD (r = -0.65; 95% CI: -0.82 to 0.36), bone surface-to-volume ratio (r = 0.47; 95% CI: 0.12-0.72) and trabecular thickness (r = -0.40; 95% CI: -0.67 to -0.03). Dispersion was proportional to bone volume fraction raised to an exponent of 2.1 +/- 0.2, which is similar to the value for parallel nylon-wire phantoms (2.4 +/- 0.2) and supports a multiple scattering model for dispersion. PMID- 25786929 TI - Tailoring the excitation of fundamental flexural guide waves in coated bone by phase-delayed array: two-dimensional simulations. AB - The fundamental flexural guided wave (FFGW) enables ultrasonic assessment of cortical bone thickness. In vivo, it is challenging to detect this mode, as its power ratio with respect to disturbing ultrasound is reduced by soft tissue covering the bone. A phase-delayed ultrasound source is proposed to tailor the FFGW excitation in order to improve its power ratio. This situation is analyzed by 2D finite-element simulations. The soft tissue coating (7-mm thick) was simulated as a fluid covering an elastic plate (bone, 2-6 mm thick). A six element array of emitters on top of the coating was excited by 50-kHz tone bursts so that each emitter was appropriately delayed from the previous one. Response was recorded by an array of receivers on top of the coating, 20-50 mm away from the closest emitter. Simulations predicted that such tailored/phase-delayed excitations should improve the power ratio of FFGW by 23 +/- 5 dB, independent of the number of emitters (N). On the other hand, the FFGW magnitude should increase by 5.8 +/- 0.5 dB for each doubling of N. This suggests that mode tailoring based on phase-delayed excitation may play a key role in the development of an in vivo FFGW assessment. PMID- 25786930 TI - Enhanced correlation between quantitative ultrasound and structural and mechanical properties of bone using combined transmission-reflection measurement. AB - Quantitative ultrasound (QUS) is capable of predicting the principal structural orientation of trabecular bone; this orientation is highly correlated with the mechanical strength of trabecular bone. Irregular shape of bone, however, would increase variation in such a prediction, especially under human in vivo measurement. This study was designed to combine transmission and reflection modes of QUS measurement to improve the prediction for the structural and mechanical properties of trabecular bone. QUS, mechanical testing, and micro computed tomography (MUCT) scanning were performed on 24 trabecular bone cubes harvested from a bovine distal femur to obtain the mechanical and structural parameters. Transmission and reflection modes of QUS measurement in the transverse and frontal planes were performed in a confined 60 degrees angle range with 5 degrees increment. The QUS parameters, attenuation (ATT) and velocity (UV), obtained from transmission mode, were normalized to the specimen thickness acquired from reflection mode. Analysis of covariance showed that the combined transmission-reflection modes improved prediction for the structural and Young's modulus of bone in comparison to the traditional QUS measurement performed only in the medial-lateral orientation. In the transverse plane, significant improvement between QUS and MUCT was found in ATT vs bone surface density (BS/BV) (p < 0.05), ATT vs trabecular thickness (Tb.Th) (p < 0.01), ATT vs degree of anisotropy (DA) (p < 0.05), UV vs trabecular bone number (Tb.N) (p < 0.05), and UV vs Tb.Th (p < 0.001). In the frontal plane, significant improvement was found in ATT vs structural model index (SMI) (p < 0.01), ATT vs bone volume fraction (BV/TV) (p < 0.01), ATT vs BS/BV (p < 0.001), ATT vs Tb.Th (p < 0.001), ATT vs DA (p < 0.001), and ATT vs modulus (p < 0.001), UV vs SMI (p < 0.01), UV vs BV/TV (p < 0.05), UV vs BS/BV (p < 0.05), UV vs Tb.Th (p < 0.01), UV vs trabecular spacing (p < 0.05), and UV vs modulus (p < 0.01). These data suggested that the combined transmission-reflection QUS method is capable of providing information more relevant to the structural and mechanical properties of trabecular bone. PMID- 25786931 TI - Scattering by single physically large and weak scatterers in the beam of a single element transducer. AB - Quantitative ultrasound techniques are generally applied to characterize media whose scattering sites are considered to be small compared to a wavelength. In this study, the backscattered response of single weakly scattering spheres and cylinders with diameters comparable to the beam width of a 2.25 MHz single element transducer were simulated and measured in the transducer focal plane to investigate the impact of physically large scatterers. The responses from large single spherical scatterers at the focus were found to closely match the plane wave response. The responses from large cylindrical scatterers at the focus were found to differ from the plane-wave response by a factor of f(-1). Normalized spectra from simulations and measurements were in close agreement: the fall-off of the responses as a function of lateral position agreed to within 2 dB for spherical scatterers and to within 3.5 dB for cylindrical scatterers. In both measurement and simulation, single scatterer diameter estimates were biased by less than 3% for a more highly focused transducer compared to estimates for a more weakly focused transducer. The results suggest that quantitative ultrasound techniques may produce physically meaningful size estimates for media whose response is dominated by scatterers comparable in size to the transducer beam. PMID- 25786932 TI - Measurement with verification of stationary signals and noise in extremely quiet environments: measuring below the noise floor. AB - It can be problematic to measure stationary acoustic sound pressure level in any environment when the target level approaches or lies below the minimum measureable sound pressure level of the measurement system itself. This minimum measureable level, referred to as the inherent measurement system noise floor, is generally established by noise emission characteristics of measurement system components such as microphones, preamplifiers, and other system circuitry. In this paper, methods are presented and shown accurate measuring stationary levels within 20 dB above and below this system noise floor. Methodology includes (1) measuring inherent measurement system noise, (2) subtractive energy based, inherent noise adjustment of levels affected by system noise floor, and (3) verifying accuracy of inherent noise adjustment technique. While generalizable to other purposes, the techniques presented here were specifically developed to quantify ambient noise levels in very quiet rooms used to evaluate free-field human hearing thresholds. Results obtained applying the methods to objectively measure and verify the ambient noise level in an extremely quiet room, using various measurement system noise floors and analysis bandwidths, are presented and discussed. The verified results demonstrate the adjustment method can accurately extend measurement range to 20 dB below the measurement system noise floor, and how measurement system frequency bandwidth can affect accuracy of reported noise levels. PMID- 25786933 TI - Modeling guided elastic waves in generally anisotropic media using a spectral collocation method. AB - Guided waves are now well established for some applications in the non destructive evaluation of structures and offer potential for deployment in a vast array of other cases. For their development, it is important to have reliable and accurate information about the modes that propagate for particular waveguide structures. Essential information that informs choices of mode transducer, operating frequencies, and interpretation of signals, among other issues, is provided by the dispersion curves of different modes within various combinations of geometries and materials. In this paper a spectral collocation method is successfully used to handle the more complicated and realistic waveguide problems that are required in non-destructive evaluation; many pitfalls and limitations found in root-finding routines based on the partial wave method are overcome by using this approach. The general cases presented cover anisotropic homogeneous perfectly elastic materials in flat and cylindrical geometry. Non-destructive evaluation applications include complex waveguide structures, such as single or multi-layered fiber composites, lined, bonded and buried structures. For this reason, arbitrarily multi-layered systems with both solid and fluid layers are also addressed as well as the implementation of interface models of imperfect boundary conditions between layers. PMID- 25786934 TI - Relationships between pressure, flow, lip motion, and upstream and downstream impedances for the trombone. AB - This experimental study investigates ten subjects playing the trombone in the lower and mid-high range of the instrument, B?2 to F4. Several techniques are combined to show the pressures and the impedance spectra upstream and downstream of the lips, the acoustic and total flows into the instrument, the component of the acoustic flow due to the sweeping motion of the lips, and high speed video images of the lip motion and aperture. The waveforms confirm that the inertance of the air in the channel between the lips is usually negligible. For lower notes, the flow caused by the sweeping motion of the lips contributes substantially to the total flow into the mouthpiece. The phase relations among the waveforms are qualitatively similar across the range studied, with no discontinuous behavior. The players normally played at frequencies about 1.1% above that of the impedance peak of the bore, but could play below as well as above this frequency and bend from above to below without discontinuity. The observed lip motion is consistent with two-degree-of-freedom models having varying effective lengths. These provide insight into why lips can auto-oscillate with an inertive or compliant load, or without a downstream resonator. PMID- 25786935 TI - A violin shell model: vibrational modes and acoustics. AB - A generic physical model for the vibro-acoustic modes of the violin is described treating the body shell as a shallow, thin-walled, guitar-shaped, box structure with doubly arched top and back plates. comsol finite element, shell structure, software is used to identify and understand the vibrational modes of a simply modeled violin. This identifies the relationship between the freely supported plate modes when coupled together by the ribs and the modes of the assembled body shell. Such coupling results in a relatively small number of eigenmodes or component shell modes, of which a single volume-changing breathing mode is shown to be responsible for almost all the sound radiated in the monopole signature mode regime below ~1 kHz for the violin, whether directly or by excitation of the Helmholtz f-hole resonance. The computations describe the influence on such modes of material properties, arching, plate thickness, elastic anisotropy, f-holes cut into the top plate, the bass-bar, coupling to internal air modes, the rigid neck fingerboard assembly, and, most importantly, the soundpost. Because the shell modes are largely determined by the symmetry of the guitar-shaped body, the model is applicable to all instruments of the violin family. PMID- 25786936 TI - A finite element model of the tuning slot of labial organ pipes. AB - An acoustic model suitable for the characterization of tuning slots of labial organ pipes is presented in this paper. Since the tuning slot arrangement is similar (but not identical) to that of toneholes in woodwind instruments, the adaptability of the well-established tonehole model for the specific problem is examined. A numerical model utilizing the finite element (FE) and perfectly matched layer techniques is set up for the simulation of tuning slots with design parameters varying over a wide range. Analytical tonehole models and the proposed numerical tuning slot model are both combined with analytical one-dimensional waveguide models to predict the acoustic behavior of tuning slot pipes. Comparison to measurements carried out on experimental pipes proves that the hybrid waveguide/FE model can predict the most important properties of the tuning slot pipe with good accuracy. The finite element method (FEM) also overcomes the limitations of traditional tonehole models relying on the equivalent T-circuit approximation. By means of the FE model the eigenfrequency-structure and its impact on the character of the sound can be foretold in the design phase, by which a more efficient scaling of tuning slot pipes can be achieved. PMID- 25786937 TI - Spectral and modulation indices for annoyance-relevant features of urban road single-vehicle pass-by noises. AB - The models that relate noise annoyance assessments to noise signal parameters are mainly based on energy-related indices (e.g., LDEN). However, various studies have shown that sound characteristics of environmental noises linked to temporal and spectral signal features also influence noise annoyance responses. In order to enhance noise annoyance models, an adequate perception-related characterization of these influential acoustical features is essential. On the basis of urban road single-vehicle pass-by noises, this study will show the identification of noise characteristics that rely on spectral and temporal signal properties and that are related to noise annoyance. Based on a semantic differential test with a verbalization task, it will be shown that the sensation dull/shrill, related to the spectral content of the noises and the modulation related sensations sputtering and nasal are linked to annoyance. The sensation dull/shrill could be characterized using the index TETC (Total Energy of Tonal Components within critical bands from 16 to 24 barks). The correlation of sputtering and nasal sensations with psychoacoustic indices was unsatisfactory. Two alternative indices are proposed to improve the characterization of these specific sensations. It is shown that noise annoyance assessment benefits from taking the TETC index and the sputtering and nasal indices into account. PMID- 25786938 TI - Strong localization of an acoustic wave in a sub-wavelength slot between two plates. AB - The dispersion relation of the acoustic field in a sub-wavelength slot (its width is smaller than the acoustic wavelength) between two identical plates immersed in an inviscid liquid is theoretically analyzed. Each plate has a phononic crystal structure consisting of periodical grooves drilled in one of outer sides of each plate. It is found that highly localization of acoustic energy can be achieved in the sub-wavelength slot when a traveling acoustic wave is incident upon the slots. The associate physical principle is as follows: The lowest anti-symmetric non-leaky A0 mode of the Lamb wave of each individual thin plate propagating as an evanescent wave extends to the liquid from opposite direction; when the width of the slot is much smaller than the characteristic decay length of the evanescent wave in the liquid, the constructive interference of evanescent waves of the both plates takes place, leading to a strong acoustic field in the slot. This system has potential to serve as an excellent candidate for the ultrasensitive microscopic chemical/biological stimulators and sensors. PMID- 25786939 TI - Finite amplitude standing waves in resonators terminated by a general impedance. AB - A general inhomogeneous Burgers equation describing finite-amplitude standing waves in resonators terminated by a general impedance is derived. This model equation can be used for modeling of nonlinear acoustic processes connected with some methods for enhancement of Q-factor of acoustic resonators. One of them is the method based on using a second-harmonics absorber. For better understanding of this method, it is convenient to know at least an approximate analytical solution of the model equation. This work presents some approximate solutions, which improve and extend the solutions that have been published previously. The solutions are compared with results obtained by numerical integration of the corresponding equations. PMID- 25786940 TI - Wind fence enclosures for infrasonic wind noise reduction. AB - A large porous wind fence enclosure has been built and tested to optimize wind noise reduction at infrasonic frequencies between 0.01 and 10 Hz to develop a technology that is simple and cost effective and improves upon the limitations of spatial filter arrays for detecting nuclear explosions, wind turbine infrasound, and other sources of infrasound. Wind noise is reduced by minimizing the sum of the wind noise generated by the turbulence and velocity gradients inside the fence and by the area-averaging the decorrelated pressure fluctuations generated at the surface of the fence. The effects of varying the enclosure porosity, top condition, bottom gap, height, and diameter and adding a secondary windscreen were investigated. The wind fence enclosure achieved best reductions when the surface porosity was between 40% and 55% and was supplemented by a secondary windscreen. The most effective wind fence enclosure tested in this study achieved wind noise reductions of 20-27 dB over the 2-4 Hz frequency band, a minimum of 5 dB noise reduction for frequencies from 0.1 to 20 Hz, constant 3-6 dB noise reduction for frequencies with turbulence wavelengths larger than the fence, and sufficient wind noise reduction at high wind speeds (3-6 m/s) to detect microbaroms. PMID- 25786941 TI - Wave propagation in a waveguide containing restrictions with circular arc shape. AB - A multimodal method is used to analyze the wave propagation in waveguides containing restrictions (or corrugations) with circular arc shapes. This is done using a geometrical transformation which transforms the waveguide with complex geometry in the real space to a straight waveguide in the transformed space, or virtual space. In this virtual space, the Helmholtz equation has a modified structure which encapsulates the complexity of the geometry. It is solved using an improved modal method, which was proposed in a paper by A. Maurel, J.-F. Mercier, and S. Felix [Proc. R. Soc. A 470, 20130743 (2014)], that increases the accuracy and convergence of usual multimodal formulations. Results show the possibility to solve the wave propagation in a waveguide with a high density of circular arc shaped scatterers. PMID- 25786943 TI - Factors limiting vocal-tract length discrimination in cochlear implant simulations. AB - Perception of voice characteristics allows normal hearing listeners to identify the gender of a speaker, and to better segregate speakers from each other in cocktail party situations. This benefit is largely driven by the perception of two vocal characteristics of the speaker: The fundamental frequency (F0) and the vocal-tract length (VTL). Previous studies have suggested that cochlear implant (CI) users have difficulties in perceiving these cues. The aim of the present study was to investigate possible causes for limited sensitivity to VTL differences in CI users. Different acoustic simulations of CI stimulation were implemented to characterize the role of spectral resolution on VTL, both in terms of number of channels and amount of channel interaction. The results indicate that with 12 channels, channel interaction caused by current spread is likely to prevent CI users from perceiving VTL differences typically found between male and female speakers. PMID- 25786942 TI - Interaural envelope correlation change discrimination in bilateral cochlear implantees: effects of mismatch, centering, and onset of deafness. AB - Bilateral cochlear implant (CI) listeners can perform binaural tasks, but they are typically worse than normal-hearing (NH) listeners. To understand why this difference occurs and the mechanisms involved in processing dynamic binaural differences, interaural envelope correlation change discrimination sensitivity was measured in real and simulated CI users. In experiment 1, 11 CI (eight late deafened, three early deafened) and eight NH listeners were tested in an envelope correlation change discrimination task. Just noticeable differences (JNDs) were best for a matched place-of-stimulation and increased for an increasing mismatch. In experiment 2, attempts at intracranially centering stimuli did not produce lower JNDs. In experiment 3, the percentage of correct identifications of antiphasic carrier pulse trains modulated by correlated envelopes was measured as a function of mismatch and pulse rate. Sensitivity decreased for increasing mismatch and increasing pulse rate. The experiments led to two conclusions. First, envelope correlation change discrimination necessitates place-of stimulation matched inputs. However, it is unclear if previous experience with acoustic hearing is necessary for envelope correlation change discrimination. Second, NH listeners presented with CI simulations demonstrated better performance than real CI listeners. If the simulations are realistic representations of electrical stimuli, real CI listeners appear to have difficulty processing interaural information in modulated signals. PMID- 25786944 TI - Comparing methods of modeling near field fluid coupling in the cochlea. AB - As well as generating the far field pressure, which allows wave propagation in the cochlea, the vibration of an individual element of the basilar membrane (BM) will also generate a near field pressure, which increases its mass and gives rise to local longitudinal coupling. This paper compares the efficiency and accuracy of a number of different methods of calculating the near field pressure distribution, and explores the connections between them. In particular it is shown that a common approximation to the wavenumber description of the near field pressure is equivalent, in the spatial domain, to an exponential decay away from the point of excitation. Two important properties of the near field pressure are its maximum amplitude, which is finite if the vibrating element has a finite length, and the value of its spatial integral, which determines the added mass on the BM due to the fluid loading. These properties are calculated as a function of the BM width relative to the width of the fluid chamber. By parameterizing the near field pressure variation in this way, it can be readily incorporated into coupled models of the cochlea, without the considerable computational expense of calculating the full three dimensional pressure field. PMID- 25786945 TI - Exploring the source of the mid-level hump for intensity discrimination in quiet and the effects of noise. AB - Intensity discrimination Weber fractions (WFs) measured for short, high-frequency tones in quiet are larger at mid levels than at lower or higher levels. The source of this "mid-level hump" is a matter of debate. One theory is that the mid level hump reflects basilar-membrane compression, and that WFs decrease at higher levels due to spread-of-excitation cues. To test this theory, Experiment 1 measured the mid-level hump and growth-of-masking functions to estimate the basilar membrane input/output (I/O) function in the same listeners. Results showed the initial rise in WFs could be accounted for by the change in I/O function slope, but there was additional unexplained variability in WFs. Previously, Plack [(1998). J. Acoust. Soc. Am. 103(5), 2530-2538] showed that long-duration notched noise (NN) presented with the tone reduced the mid-level hump even with a temporal gap in the NN. Plack concluded the results were consistent with central profile analysis. However, simultaneous, forward, and backward NN were not examined separately, which may independently test peripheral and central mechanisms of the NN. Experiment 2 measured WFs at the mid-level hump in the presence of NN and narrowband noise of different durations and temporal positions relative to the tone. Results varied across subjects, but were consistent with more peripheral mechanisms. PMID- 25786946 TI - Effects of inherent envelope fluctuations in forward maskers for listeners with normal and impaired hearing. AB - Gaussian noise simultaneous maskers yield higher masked thresholds for pure tones than low-fluctuation noise simultaneous maskers for listeners with normal hearing. This increased masking effectiveness is thought to be due to inherent fluctuations in the temporal envelope of Gaussian noise, but effects of fluctuating forward maskers are unknown. Because differences in forward masking due to age and hearing loss are known, the current study assessed effects of masker envelope fluctuations for forward maskers in younger and older adults with normal hearing and older adults with hearing loss. Detection thresholds were measured in these three participant groups for a pure-tone probe in quiet and in Gaussian and low-fluctuation noise forward maskers with either 1 or 1/3 equivalent rectangular bandwidths. Higher masked thresholds were obtained for forward maskers with greater inherent envelope fluctuations for younger adults with normal hearing. This increased effectiveness of highly fluctuating forward maskers was similar for older adults with normal and impaired hearing. Because differences in recovery from forward masking between listeners with normal and impaired hearing may relate to differences in cochlear nonlinearities, these results suggest that mechanisms other than cochlear nonlinearities may be responsible for recovery from rapid masker envelope fluctuations. PMID- 25786947 TI - Subjective and objective rating of spectrally different pseudorandom noises- implications for speech masking design. AB - Artificial sound masking is increasingly used in open-plan offices to improve speech privacy and to reduce distraction caused by speech sounds. Most of the masking sounds are based on pseudorandom continuous noise filtered to a specific spectrum that should be optimized in respect with speech masking efficiency and comfort. The aim of this study was to increase basic understanding regarding the comfort. The second aim was to determine how well objective rating methods (15 different noise indices) predict the subjective ratings. Twenty-three subjects rated the loudness, disturbance, pleasantness, and six other subjective measures of 11 spectrally different noises in laboratory conditions. Speech was not present during the experiment. All sounds were presented at 42 dB LAeq within 50 10,000 Hz. Unexpectedly, the subjects were most satisfied with sounds having emphasis on low frequencies. A sound having a slope of -7 dB per octave increment resulted in the highest satisfaction. Changes in subjective ratings were reasonably well predicted by five noise indices, while many well-known noise indices frequently used in building design underperformed in this task. The results are expected to benefit in the design of masking sounds and other appliances. PMID- 25786948 TI - A theory to explain some physiological effects of the infrasonic emissions at some wind farm sites. AB - For at least four decades, there have been reports in scientific literature of people experiencing motion sickness-like symptoms attributed to low-frequency sound and infrasound. In the last several years, there have been an increasing number of such reports with respect to wind turbines; this corresponds to wind turbines becoming more prevalent. A study in Shirley, WI, has led to interesting findings that include: (1) To induce major effects, it appears that the source must be at a very low frequency, about 0.8 Hz and below with maximum effects at about 0.2 Hz; (2) the largest, newest wind turbines are moving down in frequency into this range; (3) the symptoms of motion sickness and wind turbine acoustic emissions "sickness" are very similar; (4) and it appears that the same organs in the inner ear, the otoliths may be central to both conditions. Given that the same organs may produce the same symptoms, one explanation is that the wind turbine acoustic emissions may, in fact, induce motion sickness in those prone to this affliction. PMID- 25786949 TI - An integrated analysis-synthesis array system for spatial sound fields. AB - An integrated recording and reproduction array system for spatial audio is presented within a generic framework akin to the analysis-synthesis filterbanks in discrete time signal processing. In the analysis stage, a microphone array "encodes" the sound field by using the plane-wave decomposition. Direction of arrival of plane-wave components that comprise the sound field of interest are estimated by multiple signal classification. Next, the source signals are extracted by using a deconvolution procedure. In the synthesis stage, a loudspeaker array "decodes" the sound field by reconstructing the plane-wave components obtained in the analysis stage. This synthesis stage is carried out by pressure matching in the interior domain of the loudspeaker array. The deconvolution problem is solved by truncated singular value decomposition or convex optimization algorithms. For high-frequency reproduction that suffers from the spatial aliasing problem, vector panning is utilized. Listening tests are undertaken to evaluate the deconvolution method, vector panning, and a hybrid approach that combines both methods to cover frequency ranges below and above the spatial aliasing frequency. Localization and timbral attributes are considered in the subjective evaluation. The results show that the hybrid approach performs the best in overall preference. In addition, there is a trade-off between reproduction performance and the external radiation. PMID- 25786950 TI - A multistage minimum variance distortionless response beamformer for noise reduction. AB - This paper develops a multistage approach to the implementation of the minimum variance distortionless response (MVDR) beamformer. It first divides the microphone array of M sensors into M/2 subarrays with each subarray having only two microphones, and a two-channel MVDR beamformer is performed with each subarray. The M/2 subarrays' outputs are then treated as the inputs of M/4 subarrays of two channels in the next stage. Similarly, a two-channel MVDR beamformer is performed with each subarray in the second stage. This process is repeated till the last stage that has only a single output. This multistage MVDR beamformer has the following properties: (1) Its performance is identical to that of the conventional MVDR beamformer in spatially uncorrelated noise; (2) it is much more robust than the conventional MVDR beamformer in diffuse noise, i.e., it has a significantly higher white noise gain as compared to the traditional MVDR beamformer; and (3) its complexity is an order of magnitude smaller than that of the traditional MVDR beamformer. This basic principle can also be easily generalized to the case where every subarray has more than two microphones. PMID- 25786952 TI - Effects of manipulating the signal-to-noise envelope power ratio on speech intelligibility. AB - Jorgensen and Dau [(2011). J. Acoust. Soc. Am. 130, 1475-1487] suggested a metric for speech intelligibility prediction based on the signal-to-noise envelope power ratio ( SNRenv), calculated at the output of a modulation-frequency selective process. In the framework of the speech-based envelope power spectrum model (sEPSM), the SNRenv was demonstrated to account for speech intelligibility data in various conditions with linearly and nonlinearly processed noisy speech, as well as for conditions with stationary and fluctuating interferers. Here, the relation between the SNRenv and speech intelligibility was investigated further by systematically varying the modulation power of either the speech or the noise before mixing the two components, while keeping the overall power ratio of the two components constant. A good correspondence between the data and the corresponding sEPSM predictions was obtained when the noise was manipulated and mixed with the unprocessed speech, consistent with the hypothesis that SNRenv is indicative of speech intelligibility. However, discrepancies between data and predictions occurred for conditions where the speech was manipulated and the noise left untouched. In these conditions, distortions introduced by the applied modulation processing were detrimental for speech intelligibility, but not reflected in the SNRenv metric, thus representing a limitation of the modeling framework. PMID- 25786951 TI - Timelapse ultrasonic tomography for measuring damage localization in geomechanics laboratory tests. AB - Variation of mechanical properties in materials can be detected non-destructively using ultrasonic measurements. In particular, changes in elastic wave velocity can occur due to damage, i.e., micro-cracking and particles debonding. Here the challenge of characterizing damage in geomaterials, i.e., rocks and soils, is addressed. Geomaterials are naturally heterogeneous media in which the deformation can localize, so that few measurements of acoustic velocity across the sample are not sufficient to capture the heterogeneities. Therefore, an ultrasonic tomography procedure has been implemented to map the spatial and temporal variations in propagation velocity, which provides information on the damage process. Moreover, double beamforming has been successfully applied to identify and isolate multiple arrivals that are caused by strong heterogeneities (natural or induced by the deformation process). The applicability of the developed experimental technique to laboratory geomechanics testing is illustrated using data acquired on a sample of natural rock before and after being deformed under triaxial compression. The approach is then validated and extended to time-lapse monitoring using data acquired during plane strain compression of a sample including a well defined layer with different mechanical properties than the matrix. PMID- 25786953 TI - A kinematic study of critical and non-critical articulators in emotional speech production. AB - This study explores one aspect of the articulatory mechanism that underlies emotional speech production, namely, the behavior of linguistically critical and non-critical articulators in the encoding of emotional information. The hypothesis is that the possible larger kinematic variability in the behavior of non-critical articulators enables revealing underlying emotional expression goal more explicitly than that of the critical articulators; the critical articulators are strictly controlled in service of achieving linguistic goals and exhibit smaller kinematic variability. This hypothesis is examined by kinematic analysis of the movements of critical and non-critical speech articulators gathered using eletromagnetic articulography during spoken expressions of five categorical emotions. Analysis results at the level of consonant-vowel-consonant segments reveal that critical articulators for the consonants show more (less) peripheral articulations during production of the consonant-vowel-consonant syllables for high (low) arousal emotions, while non-critical articulators show less sensitive emotional variation of articulatory position to the linguistic gestures. Analysis results at the individual phonetic targets show that overall, between- and within emotion variability in articulatory positions is larger for non-critical cases than for critical cases. Finally, the results of simulation experiments suggest that the postural variation of non-critical articulators depending on emotion is significantly associated with the controls of critical articulators. PMID- 25786955 TI - The effect of exposure to a single vowel on talker normalization for vowels. AB - The current work investigated the role of single vowels in talker normalization. Following initial training to identify six talkers from the isolated vowel /i/, participants were asked to identify vowels in three different conditions. In the blocked-talker conditions, the vowels were blocked by talker. In the mixed-talker conditions, vowels from all six talkers were presented in random order. The precursor mixed-talker conditions were identical to the mixed-talker conditions except that participants were provided with either a sample vowel or just the written name of a talker before target-vowel presentation. In experiment 1, the precursor vowel was always spoken by the same talker as the target vowel. Identification accuracy did not differ significantly for the blocked and precursor mixed-talker conditions and both were better than the pure mixed-talker condition. In experiment 2, half of the trials had a precursor spoken by the same talker as the target and half had a different talker. For the same-talker precursor condition, the results replicated those in experiment 1. In the different-talker precursor, no benefit was observed relative to the pure-mixed condition. In experiment 3, only the written name was presented as a precursor and no benefits were observed relative to the pure-mixed condition. PMID- 25786954 TI - Using speech sounds to test functional spectral resolution in listeners with cochlear implants. AB - In this study, spectral properties of speech sounds were used to test functional spectral resolution in people who use cochlear implants (CIs). Specifically, perception of the /ba/-/da/ contrast was tested using two spectral cues: Formant transitions (a fine-resolution cue) and spectral tilt (a coarse-resolution cue). Higher weighting of the formant cues was used as an index of better spectral cue perception. Participants included 19 CI listeners and 10 listeners with normal hearing (NH), for whom spectral resolution was explicitly controlled using a noise vocoder with variable carrier filter widths to simulate electrical current spread. Perceptual weighting of the two cues was modeled with mixed-effects logistic regression, and was found to systematically vary with spectral resolution. The use of formant cues was greatest for NH listeners for unprocessed speech, and declined in the two vocoded conditions. Compared to NH listeners, CI listeners relied less on formant transitions, and more on spectral tilt. Cue weighting results showed moderately good correspondence with word recognition scores. The current approach to testing functional spectral resolution uses auditory cues that are known to be important for speech categorization, and can thus potentially serve as the basis upon which CI processing strategies and innovations are tested. PMID- 25786956 TI - Effect of musical experience on learning lexical tone categories. AB - Previous studies suggest that musicians show an advantage in processing and encoding foreign-language lexical tones. The current experiments examined whether musical experience influences the perceptual learning of lexical tone categories. Experiment I examined whether musicians with no prior experience of tonal languages differed from nonmusicians in the perception of a lexical tone continuum. Experiment II examined whether short-term perceptual training on lexical tones altered the perception of the lexical tone continuum differentially in English-speaking musicians and nonmusicians. Results suggested that (a) musicians exhibited higher sensitivity overall to tonal changes, but perceived the lexical tone continuum in a manner similar to nonmusicians (continuously), in contrast to native Mandarin speakers (categorically); and (b) short-term perceptual training altered perception; however, there were no significant differences between the effects of training on musicians and nonmusicians. PMID- 25786957 TI - Divided attention disrupts perceptual encoding during speech recognition. AB - Performing a secondary task while listening to speech has a detrimental effect on speech processing, but the locus of the disruption within the speech system is poorly understood. Recent research has shown that cognitive load imposed by a concurrent visual task increases dependency on lexical knowledge during speech processing, but it does not affect lexical activation per se. This suggests that "lexical drift" under cognitive load occurs either as a post-lexical bias at the decisional level or as a secondary consequence of reduced perceptual sensitivity. This study aimed to adjudicate between these alternatives using a forced-choice task that required listeners to identify noise-degraded spoken words with or without the addition of a concurrent visual task. Adding cognitive load increased the likelihood that listeners would select a word acoustically similar to the target even though its frequency was lower than that of the target. Thus, there was no evidence that cognitive load led to a high-frequency response bias. Rather, cognitive load seems to disrupt sublexical encoding, possibly by impairing perceptual acuity at the auditory periphery. PMID- 25786958 TI - Visual speech information: a help or hindrance in perceptual processing of dysarthric speech. AB - This study investigated the influence of visual speech information on perceptual processing of neurologically degraded speech. Fifty listeners identified spastic dysarthric speech under both audio (A) and audiovisual (AV) conditions. Condition comparisons revealed that the addition of visual speech information enhanced processing of the neurologically degraded input in terms of (a) acuity (percent phonemes correct) of vowels and consonants and (b) recognition (percent words correct) of predictive and nonpredictive phrases. Listeners exploited stress based segmentation strategies more readily in AV conditions, suggesting that the perceptual benefit associated with adding visual speech information to the auditory signal-the AV advantage-has both segmental and suprasegmental origins. Results also revealed that the magnitude of the AV advantage can be predicted, to some degree, by the extent to which an individual utilizes syllabic stress cues to inform word recognition in AV conditions. Findings inform the development of a listener-specific model of speech perception that applies to processing of dysarthric speech in everyday communication contexts. PMID- 25786959 TI - Phoneme restoration and empirical coverage of interactive activation and adaptive resonance models of human speech processing. AB - Grossberg and Kazerounian [(2011). J. Acoust. Soc. Am. 130, 440-460] present a model of sequence representation for spoken word recognition, the cARTWORD model, which simulates essential aspects of phoneme restoration. Grossberg and Kazerounian also include simulations with the TRACE model presented by McClelland and Elman [(1986). Cognit. Psychol. 18, 1-86] that seem to indicate that TRACE cannot simulate phoneme restoration. Grossberg and Kazerounian also claim cARTWORD should be preferred to TRACE because of TRACE's implausible approach to sequence representation (reduplication of time-specific units) and use of non modulatory feedback (i.e., without position-specific bottom-up support). This paper responds to Grossberg and Kazerounian first with TRACE simulations that account for phoneme restoration when appropriately constructed noise is used (and with minor changes to TRACE phoneme definitions), then reviews the case for reduplicated units and feedback as implemented in TRACE, as well as TRACE's broad and deep coverage of empirical data. Finally, it is argued that cARTWORD is not comparable to TRACE because cARTWORD cannot represent sequences with repeated elements, has only been implemented with small phoneme and lexical inventories, and has been applied to only one phenomenon (phoneme restoration). Without evidence that cARTWORD captures a similar range and detail of human spoken language processing as alternative models, it is premature to prefer cARTWORD to TRACE. PMID- 25786962 TI - Rhythmic variability between speakers: articulatory, prosodic, and linguistic factors. AB - Between-speaker variability of acoustically measurable speech rhythm [%V, DeltaV(ln), DeltaC(ln), and Deltapeak(ln)] was investigated when within-speaker variability of (a) articulation rate and (b) linguistic structural characteristics was introduced. To study (a), 12 speakers of Standard German read seven lexically identical sentences under five different intended tempo conditions (very slow, slow, normal, fast, very fast). To study (b), 16 speakers of Zurich Swiss German produced 16 spontaneous utterances each (256 in total) for which transcripts were made and then read by all speakers (4096 sentences; 16 speaker * 256 sentences). Between-speaker variability was tested using analysis of variance with repeated measures on within-speaker factors. Results revealed strong and consistent between-speaker variability while within-speaker variability as a function of articulation rate and linguistic characteristics was typically not significant. It was concluded that between-speaker variability of acoustically measurable speech rhythm is strong and robust against various sources of within-speaker variability. Idiosyncratic articulatory movements were found to be the most plausible factor explaining between-speaker differences. PMID- 25786961 TI - The contribution of phonation type to the perception of vocal emotions in German: an articulatory synthesis study. AB - Vocal emotions are signaled by specific patterns of prosodic parameters, most notably pitch, phone duration, intensity, and phonation type. Phonation type was so far the least accessible parameter in emotion research, because it was difficult to extract from speech signals and difficult to manipulate in natural or synthetic speech. The present study built on recent advances in articulatory speech synthesis to exclusively control phonation type in re-synthesized German sentences spoken with seven different emotions. The goal was to find out to what extent the sole change of phonation type affects the perception of these emotions. Therefore, portrayed emotional utterances were re-synthesized with their original phonation type, as well as with each purely breathy, modal, and pressed phonation, and then rated by listeners with respect to the perceived emotions. Highly significant effects of phonation type on the recognition rates of the original emotions were found, except for disgust. While fear, anger, and the neutral emotion require specific phonation types for correct perception, sadness, happiness, boredom, and disgust primarily rely on other prosodic parameters. These results can help to improve the expression of emotions in synthesized speech and facilitate the robust automatic recognition of vocal emotions. PMID- 25786960 TI - Three speech sounds, one motor action: evidence for speech-motor disparity from English flap production. AB - The assumption that units of speech production bear a one-to-one relationship to speech motor actions pervades otherwise widely varying theories of speech motor behavior. This speech production and simulation study demonstrates that commonly occurring flap sequences may violate this assumption. In the word "Saturday," a sequence of three sounds may be produced using a single, cyclic motor action. Under this view, the initial upward tongue tip motion, starting with the first vowel and moving to contact the hard palate on the way to a retroflex position, is under active muscular control, while the downward movement of the tongue tip, including the second contact with the hard palate, results from gravity and elasticity during tongue muscle relaxation. This sequence is reproduced using a three-dimensional computer simulation of human vocal tract biomechanics and differs greatly from other observed sequences for the same word, which employ multiple targeted speech motor actions. This outcome suggests that a goal of a speaker is to produce an entire sequence in a biomechanically efficient way at the expense of maintaining parity within the individual parts of the sequence. PMID- 25786963 TI - Nonlinear guided wave propagation in prestressed plates. AB - The measurement of stress in a structure presents considerable interest in many fields of engineering. In this paper, the diagnostic potential of nonlinear elastic guided waves in a prestressed plate is investigated. To do so, an analytical model is formulated accounting for different aspects involved in the phenomenon. The fact that the initial strains can be finite is considered using the Green Lagrange strain tensor, and initial and final configurations are not merged, as it would be assumed in the infinitesimal strain theory. Moreover, an appropriate third-order expression of the strain energy of the hyperelastic body is adopted to account for the material nonlinearities. The model obtained enables to investigate both the linearized case, which gives the variation of phase and group velocity as a function of the initial stress, and the nonlinear case, involving second-harmonic generation as a function of the initial state of stress. The analysis is limited to Rayleigh-Lamb waves propagating in a plate. Three cases of initial prestress are considered, including prestress in the direction of the wave propagation, prestress orthogonal to the direction of wave propagation, and plane isotropic stress. PMID- 25786964 TI - Experimental investigation of the accuracy of a vibroacoustic model for sandwich composite panels. AB - This paper presents a detailed experimental validation of a general laminate model to predict the vibroacoustic behavior of flat sandwich-composite panels. The accuracy of the model is investigated using a thin and a thick sandwich panel over a large frequency band. Several indicators are compared including the structural wavenumber, modal density, damping loss factor, radiation efficiency, and sound transmission loss. The accuracy of a simpler model based on identifying effective properties of an equivalent orthotropic panel from the General Laminate Model is also discussed. Results show that the vibroacoustic behaviors of flat sandwich-composite panels are accurately estimated using the used model and compare well to the equivalent panel model (for total transmission loss). This experimental investigation is generic and can be used as a benchmark to validate other sandwich models. PMID- 25786965 TI - Sound absorption of a rib-stiffened plate covered by anechoic coatings. AB - Underwater vehicles are often equipped with anechoic coatings to absorb the sound waves of active sonar and attenuate the noise emitted from the vessels. Rubber layers with periodically distributed air cavities are widely used as anechoic coatings. In this paper, the sound absorption of anechoic coatings embedded with doubly periodic cavities and backed with periodically rib-stiffened plates is investigated using a finite element method (FEM) with Bloch-periodic boundary conditions. Numerical results given by the FEM are compared with those of a simplified transfer impedance approach to explain the shifting of the main absorption peak. Further a simplified FEM approach, which reduces calculation time significantly and maintains the reasonable accuracy, is proposed for a comparison. The results indicate that the plate and the ribs can have significant impacts on the absorption performance of anechoic coatings, especially at low frequencies. PMID- 25786966 TI - Treatment of ice cover and other thin elastic layers with the parabolic equation method. AB - The parabolic equation method is extended to handle problems involving ice cover and other thin elastic layers. Parabolic equation solutions are based on rational approximations that are designed using accuracy constraints to ensure that the propagating modes are handled properly and stability constrains to ensure that the non-propagating modes are annihilated. The non-propagating modes are especially problematic for problems involving thin elastic layers. It is demonstrated that stable results may be obtained for such problems by using rotated rational approximations [Milinazzo, Zala, and Brooke, J. Acoust. Soc. Am. 101, 760-766 (1997)] and generalizations of these approximations. The approach is applied to problems involving ice cover with variable thickness and sediment layers that taper to zero thickness. PMID- 25786967 TI - Towards a complete physically based forecast model for underwater noise related to impact pile driving. AB - An approach for the prediction of underwater noise caused by impact pile driving is described and validated based on in situ measurements. The model is divided into three sub-models. The first sub-model, based on the finite element method, is used to describe the vibration of the pile and the resulting acoustic radiation into the surrounding water and soil column. The mechanical excitation of the pile by the piling hammer is estimated by the second sub-model using an analytical approach which takes the large vertical dimension of the ram into account. The third sub-model is based on the split-step Pade solution of the parabolic equation and targets the long-range propagation up to 20 km. In order to presume realistic environmental properties for the validation, a geoacoustic model is derived from spatially averaged geological information about the investigation area. Although it can be concluded from the validation that the model and the underlying assumptions are appropriate, there are some deviations between modeled and measured results. Possible explanations for the observed errors are discussed. PMID- 25786968 TI - Low-salinity-induced surface sound channel in the western sea of Jeju Island during summer. AB - Surface salinity in the western sea of Jeju Island in Korea becomes low due to the inflow of the Chinese coastal waters during summer. One of the characteristics of low salinity water is the formation of a surface sound channel (SSC) due to the decrease in sound speed by salinity. However, a quantitative analysis between low salinity water and SSC has not been fully investigated yet. In this paper, a temperature-salinity (T-S) gradient diagram is introduced in order to assess SSC formation and its acoustic characteristics are also investigated through a case study of low salinity waters. Maximum angles of limiting rays were less than 4.6 degrees and low frequency cutoffs were higher than 2.0 kHz for the SSCs formed in low salinity water. When the salinity gradients were large (>0.5 psu/m), a SSC was formed more efficiently than other cases whose salinity gradients were small. On the other hand, a SSC was not formed in spite of highly positive salinity gradients when the amount of temperature gradients was negatively high enough (<-0.5 degrees C/m). However, the acoustic energy transfer in the surface ducts was dependent on frequency and position of source. PMID- 25786969 TI - A two-hydrophone range and bearing localization algorithm with performance analysis. AB - An automated, passive algorithm for detecting and localizing small boats using two hydrophones mounted on the seabed is outlined. This extends previous work by Gebbie et al. [(2013). J. Acoust. Soc. Am. 134, EL77 - EL83] in which a similar two-hydrophone approach is used to produce an ambiguity surface of likely target locations leveraging multipath analysis and knowledge of the local bathymetry. The work presented here improves upon the prior approach using particle filtering to automate detection and localization processing. A detailed analysis has also been conducted to determine the conditions and limits under which the improved approach can be expected to yield accurate range and unambiguous bearing information. Experimental results in 12 m of water allow for a comparison of different separation distances between hydrophones, and the Bayesian Cramer-Rao lower bound is used to extrapolate the performance expected in 120 m water. This work demonstrates the conditions under which a low cost, passive, sparse array of hydrophones can provide a meaningful small boat detection and localization capability. PMID- 25786970 TI - Comment on "Relative variance of the mean squared pressure in multimode media: rehabilitating former approaches" [J. Acoust. Soc. Am. 136, 2621-2629 (2014)]. AB - Models for the statistics of responses in finite reverberant structures, and in particular, for the variance of the mean square pressure in reverberation rooms, have been studied for decades. It is therefore surprising that a recent communication has claimed that the literature has gotten the simplest of such calculations very wrong. Monsef, Cozza, Rodrigues, Cellard, and Durocher [(2014). J. Acoust. Soc. Am. 136, 2621-2629] have derived a modal-based expression for the relative variance that differs significantly from expressions that have been accepted since 1969. This Comment points out that the Monsef formula is clearly incorrect, and then for the interested reader, points out the subtle place where they made their mistake. PMID- 25786971 TI - A record "longest echo" within the Inchindown oil despository. AB - In 2013, Guinness World Records awarded tank number 1 at the Inchindown oil despository, Ross-shire, Scotland, the record for the "longest echo" at 75 s. Guinness World Records calls it the longest echo because that was the name of the record that was broken, however, the correct name for the phenomenon measured is reverberation. This Letter has been written to document this unique acoustic space where the reverberation time is 112 s at 125 Hz, to detail the methodology for those who wish to attempt to break the record, and to discuss why the tank is so uniquely reverberant. PMID- 25786972 TI - Erratum: The diffracted field near the edge of a thin screen [J. Acoust. Soc. Am. 134(6), 4303-4306 (2013)]. PMID- 25786976 TI - Postsynthetic exterior decoration of an organic cage by copper(I)-catalysed A3 coupling and detection of nitroaromatics. AB - A new synthetic protocol based on one-pot, copper(I)-catalysed multicomponent reaction of formaldehyde, secondary amine and terminal alkyne has been employed to postsynthetically modify a self-assembled nanoscopic organic cage. By employing this synthetic strategy, three new cages appended with phenyl-, xylyl- and naphthyl-acetylene moieties have been synthesised. The resulting modified cages were characterised by using a range of spectroscopic techniques. The synthesised cages were fluorescent and thus one of them was tested to explore the potential use of such compounds as chemosensors for the detection of nitroaromatics. Experimental findings suggest a high selective quenching of initial fluorescence intensity in the presence of nitroaromatic compounds. Furthermore, it has been observed that among the various nitroaromatics tested, nitrophenolic compounds have better quenching ability. PMID- 25786977 TI - Susceptibility vessel sign on T2* magnetic resonance imaging and recanalization results of mechanical thrombectomy with stent retrievers: a multicentre cohort study. AB - BACKGROUND AND PURPOSE: The susceptibility vessel sign (SVS) on T2*-weighted magnetic resonance imaging has been reported in several studies as a negative predictor of early recanalization after intravenous thrombolysis. The meaning of SVS regarding the results of mechanical thrombectomy with stent retrievers was investigated. METHODS: Susceptibility vessel sign presence and length were studied in 153 acute ischaemic stroke patients (82 men; mean +/- SD age 59 +/- 17 years, baseline National Institutes of Health Stroke Scale score 17.2 +/- 6.5) from three stroke centres, treated with either mechanical thrombectomy alone (n = 84) or bridging therapy (n = 69). Variables were compared between recanalizers, defined as thrombolysis in cerebral infarction (TICI) scores >=2b, and non recanalizers (TICI<2b). RESULTS: The SVS was present in 113 (73.8%) patients. There was no association between the presence of SVS and recanalization, obtained in 86 (56.2%) patients, in the whole population [odds ratio (OR) 1.24, 95% confidence interval (CI) 0.53-2.92, P = 0.84) and in treatment subgroups (bridging: OR = 0.91, 95% CI 0.29-2.87, P = 1.0; thrombectomy alone: OR = 1.85, 95% CI 0.48-7.16, P = 0.54). However, in SVS+ patients, recanalization decreased with SVS length (OR 0.94 for each additional mm, 95% CI 0.89-0.99; P = 0.02). CONCLUSIONS: The success of recanalization in acute stroke patients treated with stent retrievers was related to thrombus length but not to the presence of SVS. PMID- 25786978 TI - TGFBIp regulates differentiation of EPC (CD133(+) C-kit(+) Lin(-) cells) to EC through activation of the Notch signaling pathway. AB - Endothelial progenitor cells (EPCs) in the circulatory system have been suggested to maintain vascular homeostasis and contribute to adult vascular regeneration and repair. These processes require that EPCs recognize the extracellular matrix (ECM), migrate, differentiate, and undergo tube morphogenesis. The ECM plays a critical role by providing biochemical and biophysical cues that regulate cellular behavior. Here, we tested the importance of transforming growth factor beta-induced protein (TGFBIp) in regulation of the differentiation and angiogenic potential of human cord blood-derived EPCs (CD133(+) C-kit(+) Lin(-) cells). EPCs displayed increased endothelial differentiation when plated on TGFBIp compared to fibronectin. EPCs also exhibited increased adhesion and migration upon TGFBIp stimulation. Moreover, TGFBIp induced phosphorylation of the intracellular signaling molecules SRC, FAK, AKT, JNK, and ERK in EPCs. Using integrin neutralizing antibodies, we showed that the effects of TGFBIp on EPCs are mediated by integrins alpha4 and alpha5. Furthermore, TGFBIp increased the adhesion, migration, and tube formation of CD34(+) mouse bone marrow stem cells in vitro. Gene expression analysis of EPCs plated on TGFBIp revealed that EPCs stimulated by TGFBIp exhibit increased expression of Notch ligands, such as delta like 1 (DLL1) and Jagged1 (JAG1), through nuclear factor-kappa B signaling activation. Collectively, our findings demonstrate, for the first time, that locally generated TGFBIp at either wounds or tumor sites may contribute to differentiation and angiogenic function of EPCs by augmenting the recruitment of EPCs and regulating the expression of endothelial genes DLL1 and JAG1. PMID- 25786979 TI - Sequential metabolic phases as a means to optimize cellular output in a constant environment. AB - Temporal changes of gene expression are a well-known regulatory feature of all cells, which is commonly perceived as a strategy to adapt the proteome to varying external conditions. However, temporal (rhythmic and non-rhythmic) changes of gene expression are also observed under virtually constant external conditions. Here we hypothesize that such changes are a means to render the synthesis of the metabolic output more efficient than under conditions of constant gene activities. In order to substantiate this hypothesis, we used a flux-balance model of the cellular metabolism. The total time span spent on the production of a given set of target metabolites was split into a series of shorter time intervals (metabolic phases) during which only selected groups of metabolic genes are active. The related flux distributions were calculated under the constraint that genes can be either active or inactive whereby the amount of protein related to an active gene is only controlled by the number of active genes: the lower the number of active genes the more protein can be allocated to the enzymes carrying non-zero fluxes. This concept of a predominantly protein-limited efficiency of gene expression clearly differs from other concepts resting on the assumption of an optimal gene regulation capable of allocating to all enzymes and transporters just that fraction of protein necessary to prevent rate limitation. Applying this concept to a simplified metabolic network of the central carbon metabolism with glucose or lactate as alternative substrates, we demonstrate that switching between optimally chosen stationary flux modes comprising different sets of active genes allows producing a demanded amount of target metabolites in a significantly shorter time than by a single optimal flux mode at fixed gene activities. Our model-based findings suggest that temporal expression of metabolic genes can be advantageous even under conditions of constant external substrate supply. PMID- 25786980 TI - Urinary proteomic biomarkers to predict cardiovascular events. AB - PURPOSE: We have previously demonstrated associations between the urinary proteome profile and coronary artery disease (CAD) in cross-sectional studies. Here, we evaluate the potential of a urinary proteomic panel as a predictor of CAD in the hypertensive atherosclerotic cardiovascular disease (HACVD) substudy population of the Anglo-Scandinavian Cardiac Outcomes Trial study. EXPERIMENTAL DESIGN: Thirty-seven cases with primary CAD endpoint were matched for sex and age to controls who had not reached a CAD endpoint during the study. Spot urine samples were analyzed using CE coupled to Micro-TOF MS. A previously developed 238-marker CE-MS model for diagnosis of CAD (CAD238 ) was assessed for its predictive potential. RESULTS: Sixty urine samples (32 cases; 28 controls; 88% male, mean age 64 +/- 5 years) were analyzed. There was a trend toward healthier values in controls for the CAD model classifier (-0.432 +/- 0.326 versus -0.587 +/- 0.297, p = 0.170), and the CAD model showed statistical significance on Kaplan-Meier survival analysis p = 0.021. We found 190 individual markers out of 1501 urinary peptides that separated cases and controls (AUC >0.6). Of these, 25 peptides were also components of CAD238 . CONCLUSION AND CLINICAL RELEVANCE: A urinary proteome panel originally developed in a cross-sectional study predicts CAD endpoints independent of age and sex in a well-controlled prospective study. PMID- 25786981 TI - Prognostic evaluation of percentage variation of metabolic tumor burden calculated by dual-phase (18) FDG PET-CT imaging in patients with head and neck cancer. AB - BACKGROUND: The purpose of this study was to investigate the prognostic value of percentage variation of metabolic tumor burden in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Patients referred to undergo (18) fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT for staging of HNSCC were included in this study. Using a dual-phase method, standardized uptake value maximum (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were recorded and respectively used to calculate retention index (RI), %DeltaMTV, and %DeltaTLG. Recurrence-free survival (RFS) was determined by Kaplan Meier method and compared with studied PET parameters in univariate and multivariate. RESULTS: Seventy patients (61 men/9 women; 62.9 +/- 9.1 years old) were included. In univariate, SUVmax, RI, MTV, and TLG (p <= .0001) were significantly correlated with RFS, unlike %DeltaMTV (p = 137) and %DeltaTLG (p = .517). In multivariate, RI (p = .005) and MTV (p = .022) persisted as independent prognostic factors. CONCLUSION: Our results did not prove a prognostic interest of percentage variation of metabolic tumor burden in patients with HNSCC but confirmed that RI and MTV are independently correlated with RFS. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E600-E606, 2016. PMID- 25786982 TI - An integrated model-based software for FUS in moving abdominal organs. AB - Focused ultrasound surgery (FUS) is a non-invasive method for tissue ablation that has the potential for complete and controlled local tumour destruction with minimal side effects. The treatment of abdominal organs such as the liver, however, requires particular technological support in order to enable a safe, efficient and effective treatment. As FUS is applied from outside the patient's body, suitable imaging methods, such as magnetic resonance imaging or diagnostic ultrasound, are needed to guide and track the procedure. To facilitate an efficient FUS procedure in the liver, the organ motion during breathing and the partial occlusion by the rib cage need to be taken into account in real time, demanding a continuous patient-specific adaptation of the treatment configuration. Modelling the patient's respiratory motion and combining this with tracking data improves the accuracy of motion predictions. Modelling and simulation of the FUS effects within the body allows the use of treatment planning and has the potential to be used within therapy to increase knowledge about the patient status. This article describes integrated model-based software for patient-specific modelling and prediction for FUS treatments of moving abdominal organs. PMID- 25786983 TI - Lumbar lipomeningomyelocele associated with multiple cafe au lait spots: a case report. AB - We report on a child with several cafe au lait spots in association with a lumbar lipomeningomyelocele as an apparently new association. Cutaneous markers, the identification of which plays a crucial role in the early diagnosis and management of spinal malformations, can accompany occult spinal dysraphism. Herein we report a case of lumbar lipomeningomyelocele associated with an overlying cafe au lait spot that served as a marker of occult spinal dysraphism. The patient also had segmental cafe au lait spots on the face, making the association unique. PMID- 25786990 TI - MULTIDETECTOR-ROW COMPUTED TOMOGRAPHIC CHARACTERISTICS OF PRESUMED PREURETERAL VENA CAVA IN CATS. AB - Preureteral vena cava (circumcaval ureter, retrocaval ureter) occurs in a third of the feline population and has been associated with ureteral strictures in humans. The aim of this retrospective cross-sectional study was to describe the contrast-enhanced multidetector row computed tomographic (MDCT) characteristics of presumed preureteral vena cava in a group of cats. Medical records from two institutions located in different continents were searched from 2010-2013 for cases with complete contrast-enhanced MDCT examinations of the abdomen (i.e. included the entire course of the ureters and prerenal and renal segments of the caudal vena cava) and a diagnosis of preureteral caudal vena cava. For cases meeting inclusion criteria, CT scan data were retrieved and characteristics of the preureteral caudal vena cava were recorded. Presence of concomitant renal or ureteral diseases was also recorded. A total of 272 cats had contrast-enhanced abdominal CT scans during the study period and of these, 68 cats (22.43 +/- 4.96%) had a diagnosis of presumed preureteral vena cava. In all affected cats, a "reverse-J ureter" was observed, i.e. a ureter running medially at the level of L4-5, passing dorsally to the caudal vena cava and then exiting ventrally between the caudal vena cava and aorta returning to its normal position. Having a preureteral vena cava resulted in an increased risk for concurrent urinary signs (OR = 3.00; CI: 95%; 1.28-6.99; P = 0.01). Findings supported the use of contrast enhanced MDCT for characterizing morphology of preureteral vena cava and its relation with ureters in cats. PMID- 25786991 TI - Coupling limonene formation and oxyfunctionalization by mixed-culture resting cell fermentation. AB - Metabolic engineering strategies mark a milestone for the fermentative production of bulk and fine chemicals. Yet, toxic products and volatile reaction intermediates with low solubilities remain challenging. Prominent examples are artificial multistep pathways like the production of perillyl acetate (POHAc) from glucose via limonene. For POHAc, these limitations can be overcome by mixed culture fermentations. A limonene biosynthesis pathway and cytochrome P450 153A6 (CYP153A6) as regioselective hydroxylase are used in two distinct recombinant E. coli. POHAc formation from glucose in one recombinant cell was hindered by ineffective coupling of limonene synthesis and low rates of oxyfunctionalization. The optimization of P450 gene expression led to the formation of 6.20 +/- 0.06 mg gcdw (-1) POHAc in a biphasic batch cultivation with glucose as sole carbon and energy source. Increasing the spatial proximity between limonene synthase and CYP153A6 by a genetic fusion of both enzymes changed the molar limonene/POHAc ratio from 3.2 to 1.6. Spatial separation of limonene biosynthesis from its oxyfunctionalization improved POHAc concentration 3.3-fold to 21.7 mg L(-1) as compared to a biphasic fermentation. Mixed-cultures of E. coli BL21 (DE3) containing the limonene biosynthesis pathway and E. coli MG1655 harboring either CYP153A6, or alternatively a cymene monooxygenase, showed POHAc formation rates of 0.06 or 0.11 U gcdw (-1) , respectively. This concept provides a novel framework for fermentative syntheses involving toxic, volatile, or barely soluble compounds or pathway intermediates. PMID- 25786992 TI - Bacterial Colonization of Thrombosed Dialysis Arteriovenous Grafts. AB - In the absence of obvious infection, an abandoned arteriovenous graft (AVG) is generally left in place. This has been thought to be the best solution in view of the surgical procedure that would be required for its removal. However, there are reports of occult infection in these retained AVGs that can lead to significant infectious complications. In addition, there is evidence that abandoned, retained AVGs may contribute to the inflammatory state that exist in association with dialysis patients. This observational report of 100 cases of thrombosed AVG in which the thrombus was cultured at the time of thrombectomy demonstrated a significant degree of bacterial colonization in these cases without evidence of bacteremia. It is proposed that this could be the mechanism by which occult infection in an abandoned, retained AVGs occurs. PMID- 25786993 TI - The embodiment of emotional words in a second language: An eye-movement study. AB - The hypothesis that word representations are emotionally impoverished in a second language (L2) has variable support. However, this hypothesis has only been tested using tasks that present words in isolation or that require laboratory-specific decisions. Here, we recorded eye movements for 34 bilinguals who read sentences in their L2 with no goal other than comprehension, and compared them to 43 first language readers taken from our prior study. Positive words were read more quickly than neutral words in the L2 across first-pass reading time measures. However, this emotional advantage was absent for negative words for the earliest measures. Moreover, negative words but not positive words were influenced by concreteness, frequency and L2 proficiency in a manner similar to neutral words. Taken together, the findings suggest that only negative words are at risk of emotional disembodiment during L2 reading, perhaps because a positivity bias in L2 experiences ensures that positive words are emotionally grounded. PMID- 25786994 TI - How can molecular diagnostics contribute to the elimination of human African trypanosomiasis? AB - A variety of molecular diagnostic tests for human African trypanosomiasis (HAT) (sleeping sickness) has been developed. Some are effectively used for research and confirmation diagnosis in travel medicine, usually following non-standardized protocols. Others have become commercially available as diagnostic kits. WHO aims to eliminate HAT as a public health problem by the year 2020, and zero transmission by the year 2030. This article gives an overview of the recent progress in molecular diagnostics for sleeping sickness, including the most recent data on test performances. Also discussed is how molecular diagnostics can play an important role in the process toward the elimination of HAT. PMID- 25786995 TI - Repetitive transcranial magnetic stimulation of the primary motor cortex in the treatment of motor signs in Parkinson's disease: A quantitative review of the literature. AB - Parkinson's disease (PD) is a progressive disorder characterized by the emergence of motor deficits. In light of the voluminous and conflicting findings in the literature, the aim of the present quantitative review was to examine the effects of repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) in the treatment of motor signs in PD. Studies meeting inclusion criteria were analyzed using meta-analytic techniques and the Unified Parkinson's Disease Rating Scale (UPDRS) sections II and III were used as outcome measures. In order to determine the treatment effects of rTMS, the UPDRS II and III scores obtained at baseline, same day, to 1 day post rTMS treatment (short term follow-up) and 1-month post stimulation (long-term follow-up) were compared between the active and sham rTMS groups. Additionally, the placebo effect was evaluated as the changes in UPDRS III scores in the sham rTMS groups. A placebo effect was not demonstrated, because sham rTMS did not improve motor signs as measured by UPDRS III. Compared with sham rTMS, active rTMS targeting the M1 significantly improved UPDRS III scores at the short-term follow-up (Cohen's d of 0.27, UPDRS III score improvement of 3.8 points). When the long-term follow-up UPDRS III scores were compared with baseline scores, the standardized effect size between active and sham rTMS did not reach significance. However, this translated into a significant nonstandardized 6.3-point improvement on the UPDRS III. No significant improvement in the UPDRS II was found. rTMS over the M1 may improve motor signs. Further studies are needed to provide a definite conclusion. PMID- 25786996 TI - [The effects of DNA methylation on the homeostasis in vascular diseases]. AB - Homeostasis is fundamental to maintain normal physiological functions in our body. Internal and external physical, chemical and biologial changes can cause dysregulation of vascular homeostasis, which is closely associated with the homeostasis of oxygen supply, blood transportation and lipid metabolism. Subsequent epigenetic modifications are able to lead to abnormal structures and function of vessels. DNA methylation has been shown to play a vital role in the development of vascular diseases. In addition, 5-hydroxymethylcytosine (5hmC) and N(6)-methyladenine (m(6)A), as new epigenetic modifications, provide additional clues for vascular diseases. In this review, we summarize the effects of DNA methylation on the homeostasis dysregulation in the vascular diseases. PMID- 25786997 TI - [Correlation between primary cilium and Wnt signaling pathway]. AB - Primary cilium is a microtubule-based organelle,which develops from the mother centriole of the centrosome. It is an antenna-like structure that anchors at the cell membrance, protruding from the cell surface. Primary cilium acts as a sensory organelle that receives different kinds of signals from the environment and transmits signals to cells to elicit cellular responses. Recent studies have revealed that primary cilium play an important role in transmitting Wnt signaling, which is critical for embryonic development. Dysfunction of primary cilium deregulates Wnt signaling, causing a series of pathological changes in different organs of the embryo, resulting in ciliopathies. In this review, we summarize correlation among primary cilium,Wnt/beta-catenin signaling,Wnt/PCP signaling and ciliopathies. Current therapies in ciliopathies are also discussed. Highlights on these researches will encourage the development of Wnt-associated diagnostic tools and therapy for ciliopathies. PMID- 25786998 TI - [MicroRNAs in the regulation of brown adipocyte differentiation]. AB - MicroRNAs (miRNAs), a class of endogenous non-coding RNA about 22 nucleotide long, regulate gene expression at the post-transcription level by inhibiting the translation or inducing the degradation of their target mRNAs in organisms. There are two types of adipose tissues: brown and white. White adipose tissues store energy in the form of triglycerides (TGs), while brown adipose tissues catabolize TGs to generate energy. Brown adipose tissues are of great importance to the research of obesity and related metabolic diseases due to their function of preventing people from obesity. A lot of studies have revealed that miRNAs play crucial roles in regulating brown adipocyte differentiation and are modulated by lots of transcription factors and environmental factors, which form a complex regulatory network maintaining the homeostasis of adipose tissues. In this review, we summarize the latest studies of miRNAs in brown adipocyte differentiation, which might provide new strategies for the treatment of obesity and other related diseases. PMID- 25786999 TI - [Mechanism of 5'-to-3' degradation of eukaryotic and prokaryotic mRNA]. AB - RNA degradation plays an important role in modulating gene expression and it affects multiple biological processes. There are three common degradation mechanisms of eukaryotic and prokaryotic mRNA: endonucleolytic, 5'-to-3' and 3' to-5' exonucleolytic degradation. Differences do exist between the two kingdoms. For example, although the 5'-to-3' exoribonucleolytic degradation is the primary degradation mechanism of eukaryotic mRNA, it plays a minimal role in bacteria, and only in Gram-positive bacteria. Recently, novel RNA degradation mechanisms have been revealed, such as a new eukaryotic mRNA decapping mode mediated by 3' uridylation and a new 3'-to-5' degradation pathway independent of exosome. These accumulating discoveries not only deepen the insight of mRNA degradation mechanisms, but also may contribute to the development of novel therapeutic drugs targeting parasites, viruses or cancer. In this review, we summarize the current knowledge of 5'-to-3' exonucleolytic degradation pathway of eukaryotic and prokaryotic mRNA, and its future therapeutic perspectives. PMID- 25787000 TI - [The principle and application of the single-molecule real-time sequencing technology]. AB - Last decade witnessed the explosive development of the third-generation sequencing strategy, including single-molecule real-time sequencing (SMRT), true single-molecule sequencing (tSMSTM) and the single-molecule nanopore DNA sequencing. In this review, we summarize the principle, performance and application of the SMRT sequencing technology. Compared with the traditional Sanger method and the next-generation sequencing (NGS) technologies, the SMRT approach has several advantages, including long read length, high speed, PCR-free and the capability of direct detection of epigenetic modifications. However, the disadvantage of its low accuracy, most of which resulted from insertions and deletions, is also notable. So, the raw sequence data need to be corrected before assembly. Up to now, the SMRT is a good fit for applications in the de novo genomic sequencing and the high-quality assemblies of small genomes. In the future, it is expected to play an important role in epigenetics, transcriptomic sequencing, and assemblies of large genomes. PMID- 25787001 TI - [Correlation between type 2 diabetes and DNA methylation and mRNA expression of APN in abdominal adipose tissues in Xinjiang Uygur population]. AB - To investigate the relationship between type 2 diabetes mellitus (T2DM) onset and development and mRNA expression and promoter methylation of adiponectin (APN) gene in abdominal adipose tissues of Xinjiang Uygur population, abdominal adipose tissues of omentum were collected and divided into control, obesity and T2DM groups. The status of APN promoter methylation was detected by denaturing high performance liquid chromatography (DHPLC), while the mRNA expression level of APN was detected by RT-PCR. Results show that methylation positive rate of APN was at the lowest level in control, middel in obesity and highest in T2DM groups, and the differences are statistically significant. Comparing the APN mRNA relative copy number of adipose tissue in each group, we found that the relative copy number of APN in control group is significantly higher than that of obesity and T2DM groups. There is a negative correlation between the mRNA expression level of APN in abdominal adipose tissue and fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c) and triglyceride (TG) level. There is a negative correlation in DNA promoter methylation and mRNA expression of APN gene. Relative copy number of APN in DNA methylation positive group is significantly lower than that of the negative group. In conclusion, increased APN promoter methylation results in decreased mRNA expression, which induces glucose and lipid metabolic disorder, thus contributing to the initiation and development of T2DM in Xinjiang Uygur population. PMID- 25787002 TI - [Regulation of autophagy on dendritic cells during rat liver regeneration by IPA]. AB - To understand the mechanism underlying autophagy in regulating dendritic cells during rat liver regeneration, we used the method of percoll density gradient centrifugation combined with immunomagnetic bead to isolate dendritic cells, the Rat Genome 230 2.0 Array to determine the expression changes of autophagy-related genes, and Ingenuity Pathway Analysis 9.0 (IPA) to determine the autophagy activities. The results indicated that LC3, BECN1, ATG7 and SQSTM1 genes had significant expression changes during rat liver regeneration. There were 593 genes related to autophagy, among which 210 genes were identified as significant. We also showed that the activity of autophagy was enhanced in the priming phase and teminal phase of liver regeneration, weakened in the proliferative stage by comparative analysis method of IPA. The autophagy-related physiological activities mainly included RNA expression, RNA transcription, cell differentiation and proliferation, involving in PPARalpha/RXRalpha activation, acute phase response signaling, TREM1 signaling, IL-6 signaling, IL-8 signaling and IL-1 signaling, whose activities were increased or decreased in liver regeneration. Cluster analysis found that P53 and AMPK signaling participated in the regulation of dendritic cells autophagy, with AMPK signaling in the priming phase of liver regeneration, and both signaling pathways in the terminal phase. We conclude that dendritic cells autophagy played an important role in initiation of the immune response in priming phase and depletion of dendritic cells in late phase during rat liver regeneration. PMID- 25787003 TI - [The identification and verification of species-specific microRNAs and their precursors in Lampetra japonica]. AB - MicroRNAs (miRNAs) negatively regulate genes which are involved in various biological processes of metabolism at both transcriptional and post transcriptional levels. In recent years, the existence and function of miRNAs have been extensively studied in plants and animals with the application of deep sequencing and microarray technology. In this study, small RNAs from leucocytes of Lampetra japonica (L. japonica) were sequenced using the second generation high-throughput sequencing technology. A total of 5 207 787 small RNA sequences were identified, and 4 739 346 of them assembled into 10 989 variants. Based on sequence similarity analysis, the sequences of these variants matched known miRNAs of 306 conserved families, among which 6 conserved miRNA family members expressed at an extremely high level which reflected the conservatism of miRNAs among species. In addition, 70 unannotated sequences were predicted to be new miRNAs, and 34 of them were further verified expressing in antigen-treated L. japonica leucocytes by miRNA microarray assay. Moreover, the minimal folding free energy indexes for 16 of the 34 miRNA precursors exceed 0.85, indicating the existence of species-specific miRNAs in L. japonica which may play important roles in regulating, growth, development and disease response of L. japonica leukocytes. PMID- 25787004 TI - [Comparative analysis of population genetic structure of Potato virus Y from different hosts]. AB - Nucleotide sequences of P3 and pipo genes of Potato virus Y (PVY) from potato and tobacco were compared to investigate the effect of hosts on the population genetic structure. Meanwhile, mutation, natural selection and gene flow were evaluated to determine evolutionary forces responsible for the population genetic dynamics. The fixation indices of population differentiation (FST) of PVY from tobacco and potato were 0.116 and 0.120, respectively with significant difference, suggesting a moderate genetic differentiation between the two populations. Genetic variation analysis showed that nucleotide identities in P3 and pipo genes among the viral isolates from tobacco were respectively in the range of 85.2%-100% and 76.5%-100% while that from potato were respectively in the range of 95.7%-100% and 93.0%-100%, indicating higher genetic variation in PVY from tobacco than that from potato. Moreover, purifying selection was detected on the majority of polymorphic sites within P3 gene, suggesting that most of mutations in the gene were harmful and consequently being eliminated by natural selection. Conversely, positive selection was detected on two polymorphic sites, suggesting that these two mutations were beneficial to PVY. Neither purifying nor positive selection was detected in pipo gene, indicating neutral evolution of the gene. The values of gene flow (Nm) between PVY populations from tobacco and potato in P3 and pipo genes were 1.91 and 1.83, respectively, suggesting strong gene flow also contributes significantly to the population genetic dynamics of PVY population. In summary, this study indicates there was a significant genetic variation in PVY hosted by tobacco and potato, and mutation, natural selection and gene flow all contribute to the genetic diversity and population dynamic of the virus. PMID- 25787005 TI - [The effects of TorR protein on initiation of DNA replication in Escherichia coli]. AB - The two-component systems, which could sense and respond to environmental changes, widely exist in bacteria as a signal transduction pathway. The bacterial CckA/CtrA, ArcA/ArcB and PhoP/PhoQ two-component systems are associated with initiation of DNA replication and cell division, however, the effects of the TorS/TorR system on cell cycle and DNA replication remains unknown. The TorS/TorR system in Escherichia coli can sense changes in trimethylamine oxide (TMAO) concentration around the cells. However, it is unknown if it also affects initiation of DNA replication. We detected DNA replication patterns in DeltatorS and DeltatorR mutant strains by flow cytometry. We found that the average number of replication origins (oriCs) per cell and doubling time in DeltatorS mutants were the same while the average number of oriCs in DeltatorR mutants was increased compared with that in wild-type cells. These results indicated that absence of TorR led to an earlier initiation of DNA replication than that in wild type cells. Strangely, neither overexpression of TorR nor co-expression of TorR and TorS could restore DeltatorR mutant phenotype to the wild type. However, overexpression of SufD in both wild type and DeltatorR mutants promoted initiation of DNA replication, while mutation of SufD delayed it in DeltatorR mutants. Thus, TorR may affect initiation of DNA replication indirectly through regulating gene expression of sufD. PMID- 25787006 TI - [Study on tests of genetics experiments in universities]. AB - Based on the present situation and the development of experiment tests in universities, we introduced a reform in tests of genetics experiments. According to the teaching goals and course contents of genetics experiment, the tests of genetics experiments contain four aspects on the performance of students: the adherence to the experimental procedures, the depth of participation in experiment, the quality of experiment report, and the mastery of experiment principles and skills, which account for 10 %, 20 %, 40 % and 30 % in the total scores, respectively. All four aspects were graded quantitatively. This evaluation system has been tested in our experiment teaching. The results suggest that it has an effect on the promotion of teaching in genetics experiments. PMID- 25787007 TI - Implications of the causality principle for ultra chiral metamaterials. AB - Chiral metamaterials - artificial subwavelength structures with broken mirror symmetry - demonstrate outstanding degree of optical chirality that exhibits sophisticated spectral behavior and can eventually reach extreme values. Based on the fundamental causality principle we show how one can unambiguously relate the metamaterial circular dichroism and optical activity by the generalized Kramers Kronig relations. Contrary to the conventional relations, the generalized ones provide a unique opportunity of extracting information on material-dependent zeroes of transmission coefficient in the upper half plane of complex frequency. We illustrate the merit of the formulated relations by applying them to the observed ultra chiral optical transmission spectra of subwavelength arrays of chiral holes in silver films. Apart from the possibility of precise verification of experimental data, the relations enable resolving complex eigenfrequencies of metamaterial intrinsic modes and resonances. PMID- 25787008 TI - Novel A219P mutation of hydroxymethylbilane synthase identified in a Chinese woman with acute intermittent porphyria and syndrome of inappropriate antidiuretic hormone. AB - Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (approved gene symbol HMBS), also known as porphobilinogen deaminase (PBGD). AIP is characterised by intermittent attacks of abdominal pain, vomiting, and neurological complaints. The highly variable symptomatic presentation of AIP causes confusion with other diseases and results in a high misdiagnosis rate (68% in China) and delayed effective treatments. Based on biochemical and genetic analysis of two Chinese families, a new and a previously reported HMBS mutation were identified in patients with AIP and syndrome of inappropriate antidiuretic hormone (SIADH). The novel HMBS mutation is the 655G>C point mutation (A219P). In addition, the 973C>T point mutation (R325X), which had been previously reported in two Danish families, was identified. PMID- 25787009 TI - New data-driven method from 3D confocal microscopy for calculating phytoplankton cell biovolume. AB - Confocal laser scanner microscopy coupled with an image analysis system was used to directly determine the shape and calculate the biovolume of phytoplankton organisms by constructing 3D models of cells. The study was performed on Biceratium furca (Ehrenberg) Vanhoeffen, which is one of the most complex-shaped phytoplankton. Traditionally, biovolume is obtained from a standardized set of geometric models based on linear dimensions measured by light microscopy. However, especially in the case of complex-shaped cells, biovolume is affected by very large errors associated with the numerous manual measurements that this entails. We evaluate the accuracy of these traditional methods by comparing the results obtained using geometric models with direct biovolume measurement by image analysis. Our results show cell biovolume measurement based on decomposition into simple geometrical shapes can be highly inaccurate. Although we assume that the most accurate cell shape is obtained by 3D direct biovolume measurement, which is based on voxel counting, the intrinsic uncertainty of this method is explored and assessed. Finally, we implement a data-driven formula based approach to the calculation of biovolume of this complex-shaped organism. On one hand, the model is obtained from 3D direct calculation. On the other hand, it is based on just two linear dimensions which can easily be measured by hand. This approach has already been used for investigating the complexities of morphology and for determining the 3D structure of cells. It could also represent a novel way to generalize scaling laws for biovolume calculation. PMID- 25787010 TI - Pseudomonas glareae sp. nov., a marine sediment-derived bacterium with antagonistic activity. AB - An aerobic, Gram-negative, motile, rod-shaped bacterium designated KMM 9500(T) was isolated from a sediment sample collected from the Sea of Japan seashore. Comparative 16S rRNA gene sequence analysis affiliated strain KMM 9500(T) to the genus Pseudomonas as a distinct subline clustered with Pseudomonas marincola KMM 3042(T) and Pseudomonas segetis KCTC 12331(T) sharing the highest similarities of 98 and 97.9 %, respectively. Strain KMM 9500(T) was characterized by mainly possessing ubiquinone Q-9, and by the predominance of C18:1 omega7c, C16:1 omega7c, and C16:0 followed by C12:0 in its fatty acid profile. Polar lipids consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unknown aminophospholipid, and unknown phospholipids. Strain KMM 9500(T) was found to inhibit growth of Gram-negative and Gram-positive indicatory microorganisms. Based on the phylogenetic analysis and distinctive phenotypic characteristics, strain 9500(T) is concluded to represent a novel species of the genus Pseudomonas, for which the name Pseudomonas glareae sp. nov. is proposed. The type strain of the species is strain KMM 9500(T) (=NRIC 0939(T)). PMID- 25787011 TI - Receiving Versus Being Denied a Pregnancy Termination and Subsequent Alcohol Use: A Longitudinal Study. AB - AIM: Research finds women who terminate pregnancies are at risk of subsequent problematic alcohol use, but methodological and conceptual problems are common. This study examines the relationship between receiving versus being denied termination and subsequent alcohol use. METHODS: Data are from a prospective, longitudinal study of US women seeking pregnancy terminations. Participants presented just before a facility's gestational limit and received terminations (Near Limits, n = 452) or just beyond the limit and were denied terminations (Turnaways, n = 231). RESULTS: Groups did not differ in alcohol use before pregnancy recognition. One week after termination-seeking (Turnaways still pregnant, Near Limits not), Turnaways had lower odds of any and binge alcohol use, but did not differ on 1+ problem symptoms. Over 2.5 years, both Near Limits and Turnaways increased any and binge alcohol use, with Turnaways increasing more rapidly. The groups did not converge again on any or binge use. For Near Limits, any alcohol use surpassed the pre-pregnancy recognition level, but binge use did not. Changes in problem symptoms over time were not evident for either group. CONCLUSION: While women who had a termination were more likely to report any and binge alcohol use than women who had a child, this difference was due to a reduction in consumption among women having the child rather than an increase in consumption among women having a termination. Thus, assertions that having a termination leads women to increase alcohol use to cope with having had a termination are not supported. PMID- 25787012 TI - Professional's Attitudes Do Not Influence Screening and Brief Interventions Rates for Hazardous and Harmful Drinkers: Results from ODHIN Study. AB - AIMS: To determine the relation between existing levels of alcohol screening and brief intervention rates in five European jurisdictions and role security and therapeutic commitment by the participating primary healthcare professionals. METHODS: Health care professionals consisting of, 409 GPs, 282 nurses and 55 other staff including psychologists, social workers and nurse aids from 120 primary health care centres participated in a cross-sectional 4-week survey. The participants registered all screening and brief intervention activities as part of their normal routine. The participants also completed the Shortened Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ), which measure role security and therapeutic commitment. RESULTS: The only significant but small relationship was found between role security and screening rate in a multilevel logistic regression analysis adjusted for occupation of the provider, number of eligible patients and the random effects of jurisdictions and primary health care units (PHCU). No significant relationship was found between role security and brief intervention rate nor between therapeutic commitment and screening rate/brief intervention rate. The proportion of patients screened varied across jurisdictions between 2 and 10%. CONCLUSION: The findings show that the studied factors (role security and therapeutic commitment) are not of great importance for alcohol screening and BI rates. Given the fact that screening and brief intervention implementation rate has not changed much in the last decade in spite of increased policy emphasis, training initiatives and more research being published, this raises a question about what else is needed to enhance implementation. PMID- 25787013 TI - Elevated C reactive protein in adults predicts the later development of late onset or very-late-onset schizophrenia. PMID- 25787014 TI - Relationships of diversity, disparity, and their evolutionary rates in squirrels (Sciuridae). AB - Several theories predict that rapidly diversifying clades will also rapidly diverge phenotypically; yet, there are also reasons for suspecting that diversification and divergence might not be correlated. In the widely distributed squirrel clade (Sciuridae), we test for correlations between per lineage speciation rates, species richness, disparity, and a time-invariant measure of disparity that allows for comparing rates when evolutionary modes differ, as they do in squirrels. We find that species richness and speciation rates are not correlated with clade age or with each other. Disparity appears to be positively correlated with clade age because young, rapidly diversifying Nearctic grassland clades are strongly pulled to a single stable optimum but older, slowly diversifying Paleotropical forest clades contain lineages that diverge along multiple ecological and morphological lines. That contrast is likely due to both the environments they inhabit and their phylogenetic community structure. Our results argue against a shared explanation for diversity and disparity in favor of geographically mediated modes of speciation and ecologically mediated modes of phenotypic evolution. PMID- 25787016 TI - Verruciform xanthoma on the penis: an unusual location. PMID- 25787015 TI - bFGF regulates autophagy and ubiquitinated protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway. AB - Autophagy is involved in the development and/or progression of many diseases, including myocardial ischemia/reperfusion (I/R). In this study, we hypothesized a protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and ubiquitinated protein accumulation is involved in the myocardial I/R model. Our results showed that bFGF improved heart function recovery and increased the survival of cardiomyocytes in myocardial I/R model. The protective effect of bFGF is related to the inhibition of LC3II levels. Additionally, bFGF enhances the clearance of Ub by p62 and increases the survival of H9C2 cells. Moreover, silencing of p62 partially blocks the clearance of Ub and abolishes the anti-apoptosis effect of bFGF. An shRNA against the autophagic machinery Atg7 increased the survival of H9C2 cells co-treated with bFGF and rapamycin. bFGF activates the downstream signaling of the PI3K/Akt/mTOR pathway. These results indicate that the role of bFGF in myocardial I/R recovery is related to the inhibition of excessive autophagy and increased ubiquitinated protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new direction for bFGF drug development for heart disease and identifies protein signaling pathways involved in bFGF action. PMID- 25787017 TI - In vitro epithelial organoid generation induced by substrate nanotopography. AB - The extracellular matrix (ECM) exhibits tissue-specific topography and composition and plays a crucial role in initiating the biochemical and biomechanical signaling required for organizing cells into distinct tissues during development. How single cells assemble into structures featuring specific shapes in response to external cues is poorly understood. We examined the effect of substrate nanotopography on the morphogenesis of several types of epithelial cells and found that in response to the topography, Calu-3 and MDCK-II cells formed organoids that closely resemble their morphology in vivo. This finding represents the first demonstration that substrate nanotopography, one of the first physical cues detected by cells, can by itself induce epithelial tissue like organization. Our results provide insights, in terms of a new aspect of ECM topography, into the design of future tissue-engineering systems and the study of mechanosignaling in the epithelium during normal development and tumor progression. PMID- 25787018 TI - Staphylococcus aureus small colony variants in diabetic foot infections. AB - Background : Staphylococcus aureus (S. aureus) is one of the major pathogens causing chronic infections. The ability of S. aureus to acquire resistance to a diverse range of antimicrobial compounds results in limited treatment options, particularly in methicillin-resistant S. aureus (MRSA). A mechanism by which S. aureus develops reduced susceptibility to antimicrobials is through the formation of small colony variants (SCVs). Infections by SCVs of S. aureus are an upcoming problem due to difficulties in laboratory diagnosis and resistance to antimicrobial therapy. Methods : A prospective study was performed on 120 patients diagnosed with both type 2 diabetes mellitus and infected diabetic foot ulcers. The study was carried out from July 2012 to December 2013 in Hospital General de Mexico. The samples were cultured in blood agar, mannitol salt agar, and MacConkey agar media, and incubated at 37 degrees C in aerobic conditions. Results : We describe the first known cases of diabetic foot infections caused by MRSA-SCVs in patients diagnosed with type 2 diabetes mellitus and infected diabetic foot ulcers. In all of our cases, the patients had not received any form of gentamicin therapy. Conclusions : The antibiotic therapy commonly used in diabetic patients with infected diabetic foot ulcers fails in the case of MRSA SCVs because the intracellular location protects S. aureus-SCVs from the host's defenses and also helps them resist antibiotics. The cases studied in this article add to the spectrum of persistent and relapsing infections attributed to MRSA-SCVs and emphasizes that these variants may also play a relevant role in diabetic foot infections. PMID- 25787019 TI - Isolation and identification of a gene encoding 4-hydroxyphenylpyruvate dioxygenase from the red-brown pigment-producing bacterium Alteromonas stellipolaris LMG 21856. AB - We describe the isolation and identification of a gene encoding 4 hydroxyphenylpyruvate dioxygenase (HPPD (EC 1.13.11.27)) from the red-brown pigment-producing bacterium Alteromonas stellipolaris LMG 21856. HPPD directs the synthesis of 2,5-dihydroxyphenylacetic acid (homogentisic acid (HGA)). The sequence of the deduced peptide showed homology to HPPDs from other strains of Alteromonas; the greatest similarity was to the hypothetical HPPD from Alteromonas sp. SN2. As observed for HPPDs from other sources, expression of the A. stellipolaris HPPD gene in Escherichia coli cells could be detected by the gradual development of a brown pigment in cultures as a result of the spontaneous oxidation and polymerization of HGA. PMID- 25787021 TI - GM130 is a parallel tetramer with a flexible rod-like structure and N-terminally open (Y-shaped) and closed (I-shaped) conformations. AB - GM130 is a cytoplasmic peripheral membrane protein localized on the cis side of the Golgi apparatus. GM130 is proposed to function as a membrane skeleton, maintaining the structure of the Golgi apparatus, and as a vesicle tether that facilitates vesicle fusion to the Golgi membrane. More than 60% of the GM130 molecule is believed to exist as coiled-coil structures with a probability above 90%, based on its primary amino acid sequence. The predicted coiled-coil region was similar to that of yeast Uso1p and its mammalian homolog, p115, both of which form coiled-coil homodimers. Therefore, GM130 has long been thought to form a homodimer with a rod-like shape. However, our biochemical and electron microscopical analyses revealed that GM130 is a parallel homotetramer with a flexible rod-like structure with I- and Y-shaped conformations. The structure of the N-terminal region may interchange between an open conformation (branched or Y shaped) and a closed conformation (non-branched or I-shaped), possibly with the help of interacting molecules. This conformational change may alter the oligomeric state of the GM130 molecules and the function of GM130 in the vesicle tethering and the maintenance of the Golgi structure. PMID- 25787020 TI - Beneficial effects of losartan for prevention of paroxysmal atrial fibrillation in patients with sick sinus syndrome: analysis with memory function of pacemaker. AB - Renin-angiotensin system (RAS) inhibitors may be useful in preventing the occurrence of paroxysmal atrial fibrillation (PAF). However, evaluation of such effect is difficult because many PAF episodes are asymptomatic and not all episodes are detected by intermittent electrocardiographic monitoring. A pacemaker has been developed with dedicated functions for AF detection and electrocardiogram storage. Accordingly, we examined the effect of losartan, an angiotensin receptor blocker on PAF occurrence using this new modality. We enrolled 70 consecutive patients who had undergone dual-chamber pacemaker implantation for sick sinus syndrome. Finally, 62 patients participated in the study. Thirty patients were randomized to the losartan group (mean 43 +/- 12 mg/day) and 32 patients to the control group. They were followed up for 3 months. The frequency, the maximum duration and the total duration of PAF recorded by the stored electrocardiograms for the last 1 month during the observation period and study period were compared between the two groups. The change in the frequency of PAF from the observation period in the losartan and control groups was similar ( 35 +/- 25 vs. -67 +/- 62 times; NS). However, the change in the maximum duration and the total duration of PAF was significantly shorter in the losartan group than in the control group (-493 +/- 158 vs. -10 +/- 69 min; p < 0.05, and -4007 +/- 2334 vs. 1119 +/- 714 min; p < 0.05, respectively). Losartan suppressed the maximum duration and the total duration of PAF in patients with sick sinus syndrome without hemodynamic changes. This is the first study to show the effect of a renin-angiotensin system inhibitor on the secondary prevention of PAF using the dedicated functions of a pacemaker for PAF detection and electrocardiogram storage. PMID- 25787022 TI - Residents' corner February 2015. Editorial: What's new this month? PMID- 25787023 TI - Total phenolic contents, antioxidant activities, and lipid fractions from berry pomaces obtained by solid-state fermentation of two Sambucus species with Aspergillus niger. AB - The aim of this study was to investigate the effect of solid-state fermentation (SSF) by Aspergillus niger on phenolic contents and antioxidant activity in Sambucus nigra L. and Sambucus ebulus L. berry pomaces. The effect of fermentation time on the total fats and major lipid classes (neutral and polar) was also investigated. During the SSF, the extractable phenolics increased with 18.82% for S. ebulus L. and 11.11% for S. nigra L. The levels of antioxidant activity of methanolic extracts were also significantly enhanced. The HPLC-MS analysis indicated that the cyanidin 3-sambubioside-5-glucoside is the major phenolic compound in both fermented Sambucus fruit residues. In the early stages of fungal growth, the extracted oils (with TAGs as major lipid fraction) increased with 12% for S. nigra L. and 10.50% for S. ebulus L. The GC-MS analysis showed that the SSF resulted in a slight increase of the linoleic and oleic acids level. PMID- 25787024 TI - [Pernicious anemia: diagnosis and course in Burkina Faso]. AB - Pernicious anemia (also known as Biermer disease or anemia, Addison or Addisonian anemia, and Addison-Biermer anemia) is an autoimmune atrophic gastritis responsible for vitamin B12 malabsorption due to a deficiency of intrinsic factor. We report eight cases of pernicious anemia in Burkina Faso, collected over a 44-month period. The three criteria for diagnosis of pernicious anemia were: vitamin B12 deficiency, gastric disease (gastric histology) with presence of anti-intrinsic factor, and/or anti-gastric parietal cell antibodies in serum. All patients had anemia, with a mean hemoglobin level of 8.75 g/100 mL. The average mean corpuscular volume (MCV) was 122.1 fL the average mean corpuscular hemoglobin (MCH) 39.3 pg, the mean reticulocyte count 12.069 10(9)/L reticulocytes, and the mean rate of megaloblast marrow cells 17.2%. The serum vitamin B12 level ranged from 35 to 71 pmol/L. Antibodies against intrinsic factor were found in all eight patients. All ABO blood groups were present with a predominance (4 cases) of group O. Endoscopy found a normal fundic mucosa in three patients. Histology showed gastric atrophy and intestinal metaplasia for six patients (85.7%). Under B12 vitamin therapy, the course was favorable in all patients; seven patients also had 10 days of iron therapy. We recommend a gastric biopsy even in the absence of macroscopic gastric lesions on the upper gastrointestinal endoscopy. PMID- 25787025 TI - Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: focus on drug-drug interactions. AB - Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies. PMID- 25787026 TI - An anatomy of the way composite scores work. AB - Recently, epidemiologists tend to focus on the association of health outcomes with combinations of exposures (composites), defined a-priori or a-posteriori. Such composites appear often in nutritional (dietary patterns) and genetic (genetic scores) epidemiology. The estimated associations, however, have not been linked to those of the components of the composite, at least in a systematic way. We considered composites (X) which are linear combinations of more than one exposures (components of the composite) and explored the association of X with a linear heath outcome (Y) in terms of the associations of its individual components with Y. We showed that: (1) the association of X with Y is a weighted average of the associations of the components of X with Y; (2) the weights depend on the estimated covariance matrix of the components, and on the scalar used for the linear combination, and; (3) when components are binary variables and X is a simple sum of its components, the weights depend solely on the proportion of "1"s that are present in each component and are common with the others. Using data from a cohort study in Greece we illustrated these properties for: (1) the a priori Mediterranean diet score; (2) an a-priori genetic predisposition score, and; (3) an a-posteriori dietary pattern. Our findings may be important in interpreting estimated associations of composites with health outcomes, or, in designing composites that are expected to capture most of the associations of their components with health outcomes (new genetic scores, or composites of biomarkers). PMID- 25787027 TI - Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites. AB - Evolutionary-rate variation among sites within proteins depends on functional and biophysical properties that constrain protein evolution. It is generally accepted that proteins must be able to fold stably in order to function. However, the relationship between stability constraints and among-sites rate variation is not well understood. Here, we present a biophysical model that links the thermodynamic stability changes due to mutations at sites in proteins ([Formula: see text]) to the rate at which mutations accumulate at those sites over evolutionary time. We find that such a 'stability model' generally performs well, displaying correlations between predicted and empirically observed rates of up to 0.75 for some proteins. We further find that our model has comparable predictive power as does an alternative, recently proposed 'stress model' that explains evolutionary-rate variation among sites in terms of the excess energy needed for mutants to adopt the correct active structure ([Formula: see text]). The two models make distinct predictions, though, and for some proteins the stability model outperforms the stress model and vice versa. We conclude that both stability and stress constrain site-specific sequence evolution in proteins. PMID- 25787028 TI - [Differential diagnosis of oral mucosal erosions and ulcers in children]. AB - BACKGROUND: Oral ulcers and erosions are of great clinical importance because they are common in childhood and adolescence and generally painful. They can be related to harmless conditions, such as recurrent aphthous stomatitis. On the other hand, they can be associated with severe systemic diseases making an early diagnosis and initiation of treatment necessary. OBJECTIVES: We herein focus on the systematic presentation of differential diagnoses of oral ulcers and erosions in pediatric patients and present clues in the history and clinical features that are helpful to establish the diagnosis. CONCLUSIONS: Patient's age at the beginning of the symptoms, differentiation between acute and chronic course, distribution of mucosal lesions, additional involvement of the skin, extracutaneous symptoms, general condition of the patient, comorbidities and medication may be determining factors of the correct diagnosis. In children and adolescents aphthous stomatitis, infections and trauma are the most frequent causes of oral ulcerations or erosions of the mucous membranes. PMID- 25787030 TI - Engineering solid lipid nanoparticles for improved drug delivery: promises and challenges of translational research. AB - Nanotechnology is expected to revolutionize existing drug delivery. Many nanostructured systems have been employed for drug delivery and yielded some promising results. Solid lipid nanoparticles (SLN) have been looked at as a potential drug carrier system since last two decades. SLN do not show biotoxicity as they are prepared from physiological lipids. SLN are especially useful in drug delivery as they can enhance the absorption of drugs and improves the bioavailability of both hydrophilic and lipophilic drugs. This paper presents an overview about the various classes of SLN, comparison with available drug carrier systems, different ways of production, in vivo fate and biodistribution and various applications of SLN. Besides, aspects of stability, hurdles and strategies for SLN manufacturing with potential of clinical translation are also discussed. PMID- 25787031 TI - Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous infusions of large volumes of immunoglobulin in a swine model. AB - Many patients with primary immunodeficiency disease (PIDD) require lifelong immunoglobulin (Ig) replacement therapy. Home-based subcutaneous (SC) infusion provides advantages to patients with PIDD compared to hospital-based intravenous infusion. One limitation of current practice with SCIg infusion is the need for small-volume infusions at multiple injection sites on a frequent basis. A method was developed for large-volume SC infusion that uses preinfusion of recombinant human hyaluronidase (rHuPH20) to facilitate fluid dispersion. Miniature swine was used as a preclinical model to assess the effects of rHuPH20-facilitated infusions, of a single monthly dose, on fluid dispersion, infusion-related pressure, swelling, induration, and tissue damage. Preinfusion of vehicle (control) or rHuPH20 (75 U/g Ig) was performed simultaneously on contralateral abdominal sites on each animal, followed by infusion of 300 mL 10 % Ig (30 g) at each site. Compared to control infusions, rHuPH20 significantly reduced infusion pressure and induration (p < 0.05) and accelerated postinfusion Ig dispersion. Histological evaluation of infusion site tissue showed moderate to severe swelling for the control. Swelling after rHuPH20-facilitated infusion was mild on day 1 and had completely resolved shortly thereafter. Laser Doppler imaging of control infusion sites revealed local cutaneous hypoperfusion during Ig infusion, which was reduced almost 7-fold (p < 0.05) with the use of rHuPH20. These results demonstrate that rHuPH20-facilitated Ig infusion is associated with improved dispersion of Ig, resulting in reduced tissue pressure, induration, and reduced risk of tissue damage from mechanical trauma or local ischemia, thus enabling SC administration of large volumes of Ig at a single site. PMID- 25787029 TI - Clinical therapeutics for phenylketonuria. AB - Phenylketonuria was amongst the first of the metabolic disorders to be characterised, exhibiting an inborn error in phenylalanine metabolism due to a functional deficit of the enzyme phenylalanine hydroxylase. It affects around 700,000 people around the globe. Mutations in the gene coding for hepatic phenylalanine hydroxylase cause this deficiency resulting in elevated plasma phenylalanine concentrations, leading to cognitive impairment, neuromotor disorders and related behavioural symptoms. Inception of low phenylalanine diet in the 1950s marked a revolution in the management of phenylketonuria and has since been a vital element of all therapeutic regimens. However, compliance to dietary therapy has been found difficult and newer supplement approaches are being examined. The current development of gene therapy and enzyme replacement therapeutics may offer promising alternatives for the management of phenylketonuria. This review outlines the pathological basis of phenylketonuria, various treatment regimes, their associated challenges and the future prospects of each approach. Briefly, novel drug delivery systems which can potentially deliver therapeutic strategies in phenylketonuria have been discussed. PMID- 25787032 TI - Goserelin loaded nanoparticles inhibit growth and induce apoptosis in human prostate cancer cell lines. AB - Goserelin acetate (Gos) is a synthetic analogue of luteinizing hormone-releasing hormone (LHRH) used in treatment of prostate cancer. The objective of this study is to investigate the in vitro cytotoxic effect of Goserelin loaded nanoparticles on both androgen dependent and androgen independent cell lines. Goserelin causes cell death of prostate cancer cell lines by inducing apoptosis. Treatment of Goserelin loaded nanoparticles inhibited the proliferation of LNCaP and DU145 in the dose-dependent manner, however did not affect the cell proliferation in PC-3 cell lines. Blank nanoparticles exhibited negligible cytotoxicity on cell lines. In addition, immunocytochemical studies indicated that Gos induced apoptosis in prostate cancer cells. The presence and characteristics of LHRH receptors and their messenger ribonucleic acid (mRNA) expression in human prostate cancer cell line LNCaP were investigated by polymerase chain reaction. Changes in nuclear morphology and DNA fragmentation associated with Gos induced apoptosis were clearly seen in both LNCaP and DU145 cell lines by DNA studies. The PCR product of the expected size of 319 bp for human LHRH receptors was obtained in cell line sample. Goserelin loaded nanoparticles are the potential tool for site specific delivery for prostate cancer treatment. PMID- 25787033 TI - Polycaprolactone scaffold as targeted drug delivery system and cell attachment scaffold for postsurgical care of limb salvage. AB - In this paper, a dual-function drug-laden polycaprolactone scaffold, which can serve as both targeted drug delivery system and attachment platform for tissue regeneration for the postsurgical care of limb salvage procedure, was developed with a simple and solvent-free molding technique. Scaffolds of varying surface architecture were created using poly(ethylene glycol) diacrylate microneedle arrays. A model drug, rhodamine B, was incorporated homogenously into the scaffold. In vitro drug release studies showed that rhodamine B was released in a slow and sustained manner for 112 days. Its release rate was affected by drug loading and scaffold surface architecture. Release of rhodamine B from the scaffolds followed the Higuchi diffusion model. Other drugs, namely, doxorubicin and lidocaine hydrochloride, were also effectively loaded into and released from the scaffolds. Cell attachment study demonstrated potential for the scaffolds to provide attachment platforms for tissue regeneration. PMID- 25787034 TI - Intravenous fasudil improves in-hospital mortality of patients with right heart failure in severe pulmonary hypertension. AB - The in-hospital mortality of severe pulmonary hypertension (PH) with right heart failure (RHF) is high despite the use of vasoactive and PH-specific therapies. We conducted a prospective analysis evaluating the safety and outcomes of fasudil hydrochloride (Chuan Wei) therapy in acute RHF. PH patients hospitalized between April 2009 and November 2010 were treated with 30 mg of i.v. fasudil three times daily over 30 min, until they experienced relief of RHF symptoms. Adverse and serious adverse events were recorded. Odds ratios (ORs) and 95% confidence intervals were calculated for both in-hospital mortality and re-hospitalization. Multivariate adjustments were made for age, gender and World Health Organization functional class. There were no significant differences between the fasudil group and the control group in demographics, hemodynamics, and PH-specific and vasoactive therapies. Of the 209 study patients, 3 of the 74 patients (4.1%) in the fasudil arm died, and 19 of the 135 patients (14.1%) in the control arm died (P=0.005). Fasudil decreased both in-hospital mortality (OR=0.258 (0.074-0.903); P=0.034) and 30-day re-hospitalization (OR=0.200 (0.059-0.681); P=0.010). Fasudil was well tolerated; one patient discontinued treatment. Intravenous fasudil may be given safely in patients with PH and acute RHF, and may reduce the rates of both in-hospital mortality and 30-day re-hospitalization. PMID- 25787035 TI - The combination of abdominal obesity and high-sensitivity C-reactive protein predicts new-onset hypertension in the general Japanese population: the Tanno Sobetsu study. AB - The aim of this study was to examine whether the combination of abdominal obesity and high serum levels of high-sensitivity C-reactive protein (hsCRP) improves the prediction of new-onset hypertension in the general Japanese population. Participants in the Tanno-Sobetsu study, a prospective cohort study, were enrolled. Of 1516 subjects aged 30 years or older in 2002, those with hypertension or abnormal hsCRP levels were excluded, and the remaining 705 subjects were included in the present analyses. Abdominal obesity (AO) and high hsCRP levels were defined by the Japanese criteria of waist circumference and median hsCRP values, respectively. Subjects were followed up on for a maximum of 4.5 years, and the hazard ratio (HR) for new-onset hypertension was calculated using the Cox proportional hazard model. The HR for new-onset hypertension after adjustment for age, sex, fasting plasma glucose, alcohol intake, smoking, treatment for dyslipidemia and high normal blood pressure at baseline was significantly higher in the group with AO and high hsCRP (HR=1.44, 95% CI: 1.00 2.07) compared with the reference group, a group with no AO and low hsCRP; AO alone or high hsCRP alone was not associated with a significant increase in the HR. Similar trends for the increase in the HR by AO and high hsCRP were observed in separate analyses of men and women, although the differences did not reach statistical significance. Co-presence of AO and a high level of hsCRP is associated with a high risk for new-onset hypertension in the general population. PMID- 25787036 TI - Relationship between salt intake as estimated by a brief self-administered diet history questionnaire (BDHQ) and 24-h urinary salt excretion in hypertensive patients. AB - Assessing an individual's salt intake is necessary for providing guidance with respect to salt restriction. However, the methods that exist for assessing salt intake have both merits and limitations. Therefore, the evaluation methods should be selected for their appropriateness to the patients and the environment of the medical facilities. The purpose of the present study was to investigate the validity of a brief self-administered diet-history questionnaire (BDHQ) by comparing the responses with 24-h urinary salt excretion. A total of 136 hypertensive outpatients (54 men and 82 women) were included in this study. All subjects were given the BDHQ and performed 24-h home urine collection. The energy adjusted salt intake as assessed by the BDHQ was 12.3 (95% confidence interval: 11.8-12.9) g per day, and the urinary salt excretion evaluated by 24-h urinary collection was 9.0 (8.4-9.5) g per day. The energy-adjusted salt intake assessed by the BDHQ correlated significantly with the urinary salt excretion evaluated by 24-h urinary collection (r=0.34, P<0.001). In conclusion, the estimated salt intake evaluated by the BDHQ weakly, but significantly, correlated with 24-h urinary salt excretion. In clinical practice, it seems important to utilize both methods to assess an individual's salt intake in order to provide adequate guidance for salt restriction. PMID- 25787037 TI - Impact of nocturnal heart rate variability on cerebral small-vessel disease progression: a longitudinal study in community-dwelling elderly Japanese. AB - Recent evidence has shown an effect of ambulatory heart rate (HR) on cardiovascular events and mortality. Our objective was to determine whether ambulatory HR was related to the progression of cerebral small-vessel disease (SVD) or cognitive decline in community-dwelling elderly people. A cohort of 190 community-dwelling elderly people underwent an ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI) and cognitive testing at baseline, with MRI and cognitive tests repeated 4 years later. HR variability in ABPM was quantified by the s.d. (s.d. and the root mean square of successive differences (RMSSD), and the relationship between HR variability and the progression of SVD/cognitive decline was investigated. We also assessed the association of nighttime HR variability and nocturnal HR dipping. The nighttime RMSSD of participants with the progression of SVD was significantly higher than that of those without progression of SVD (P<0.05). Moreover, nighttime RMSSD was independently associated with the progression of SVD (1 b.p.m. increment: odds ratio=1.13, 95% confidence interval=1.04-1.24, P<0.01). We failed to confirm an association between cognitive decline and nighttime HR variability. However, s.d. in the daytime and 24-h HR were independently related to cognitive decline (P<0.05). Nocturnal HR dipping was least in the top quartiles of nighttime HR variability, with a monotonic trend of nocturnal HR dipping that was dependent on the quartiles of nighttime HR variability indices (P<0.01). Increased HR variability during the night is a predictor of the progression of SVD in community-dwelling elderly people. PMID- 25787038 TI - Determinants of concentric left ventricular hypertrophy in patients with resistant hypertension: RESIST-POL study. AB - Left ventricular hypertrophy, especially concentric hypertrophy, has been shown to be an independent factor of cardiovascular diseases in patients with hypertension. Obstructive sleep apnea (OSA) and/or metabolic syndrome (MS) are common in patients with resistant hypertension (RHTN). The aim of this study was to evaluate factors associated with concentric hypertrophy in patients with RHTN. Data from 155 patients (92M, 63F) was analyzed. All patients underwent a thorough examination including: biochemical evaluations, ambulatory blood pressure monitoring, polysomnography and echocardiography. MS was defined by The Adult Treatment Panel III. Clinically significant OSA was defined as apnea/hypopnea index (AHI)>15 events per hour. Left ventricular mass index (LVMI) and relative wall thickness (RWT) were calculated. Four types of LV geometry were distinguished based on the LVMI and RWT. Patients were divided into four groups based on the LV geometric patterns: group 1 (normal geometry) (n=38, 24.4%); group 2 (concentric remodeling) (n=40, 25.8%); group 3 (eccentric hypertrophy) (n=26, 16.8%); and group 4 (concentric hypertrophy) (n=51, 33%). MS was found in 64% and OSA (AHI>15) in 43.2% of patients. Factors independently associated with concentric hypertrophy were: age (OR-1.51; 95% CI-1.00-2.27; P<0.04), OSA>15 events per hour (OR-2.73; 95% CI-1.26-5.93; P=0.01) and nighttime systolic blood pressure (SBP) (OR-1.69; 95% CI-1.32-2.17; P=0.0001). Concentric hypertrophy was the most common type of left ventricular disorder in patients with RHTN. Nighttime SBP and clinically significant OSA were independently associated with concentric hypertrophy in patients with RHTN. PMID- 25787039 TI - Genetic variations in the vitamin-D receptor (VDR) gene in preeclampsia patients in the Chinese Han population. AB - Previous studies have indicated that vitamin D deficiency is linked to a risk of preeclampsia (PE). The aim of our study was to investigate the association between genetic variations in the vitamin-D receptor (VDR) gene and the susceptibility to PE in the Chinese Han population. We examined the genotypes VDR rs2228570, rs11568820 and rs1544410 in 402 PE patients and 554 normal pregnant women in the third trimester by TaqMan allelic discrimination real-time polymerase chain reaction. The clinical data of the individuals were collected to enable genotype-phenotype analysis. A significant statistical difference in the genotypic frequencies of rs2228570 between cases and controls was found (chi(2)=13.750, P=0.001). The G allele was the risk factor for the risk of PE (chi(2)=9.456, P=0.002, OR=1.137, 95% CI 1.111-1.610). There was no difference in the genotypic and allelic distributions of rs11568820 and rs1544410 between the two groups (P> 0.05). Our results provide evidence for a possible link between VDR and the development of PE in the Chinese Han population. PMID- 25787040 TI - Considerations for SphygmoCor radial artery pulse wave analysis: side selection and peripheral arterial blood pressure calibration. AB - Methods employed for pulse wave analysis (PWA) and peripheral blood pressure (PBP) calibration vary. The purpose of this study was to evaluate the agreement of SphygmoCor PWA parameters derived from radial artery tonometry when considering (1) timing (before vs. after tonometry) and side selection (ipsilateral vs. contralateral limb) for PBP calibration and (2) side selection for tonometry (left vs. right arm). In 34 subjects (aged 21.9 +/- 2.3 years), bilateral radial artery tonometry was performed simultaneously on three instances. PBP assessment via oscillometric sphygmomanometry in the left arm only and both arms simultaneously occurred following the first and second instances of tonometry, respectively. Significant within arm differences in PWA parameters derived before and after PBP measurement were observed in the right arm only (for example, aortic systolic blood pressure, Delta=0.38 +/- 0.64 mm Hg). Simultaneously captured bilateral PWA variables demonstrated significant between arm differences in 88% (14/16) and 56% (9/16) of outcome variables when calibrated to within arm and equivalent PBP, respectively. Moreover, the right arm consistently demonstrated lower values for clinical PWA variables (for example, augmentation index, bias=-2.79%). However, 26% (n=9) of participants presented with clinically significant differences (>10 mm Hg) in bilateral PBP and their exclusion from analysis abolished most between arm differences observed. SphygmoCor PWA in the right radial artery results in greater variability independent of the timing of PBP measurement and magnitude of calibration pressures in young subjects. Moreover, bilateral PBP measurement is imperative to identify subjects in whom a significant difference in bilateral PWA outcomes may exist. PMID- 25787041 TI - Randomized clinical trial to assess the effectiveness of remote patient monitoring and physician care in reducing office blood pressure. AB - The effectiveness of remote patient monitoring and physician care for the treatment of hypertension has not been demonstrated in a randomized clinical trial. The objective of this study was to evaluate the effectiveness of remote patient monitoring with or without remote physician care in reducing office blood pressure in patients with hypertension. A total of 374 hypertensive patients over 20 years of age were randomized into the following three groups: group (1) control, the patients received usual clinical care with home BP monitoring; group (2) the patients were remotely monitored and received office follow-up; and group (3) the patients received remote monitoring without physician office care using the remote monitoring device. For each group, in-office follow-up care was scheduled every 8 weeks for 24 weeks. The primary end point was the difference in sitting SBP at the 24-week follow-up. No difference between the three groups was observed in the primary end point (adjusted mean sitting SBP was as follows: group 1: -8.9+/-15.5 mm Hg, group 2: -11.3+/-15.9 mm Hg, group 3: -11.6+/-19.8 mm Hg, (NS). Significant differences in achieving the target BP at the 24th week of follow-up were observed between groups 1 and 2. The subjects over 55-years old had a significant decrease in the adjusted mean sitting SBP in groups 2 and 3 compared with that of the control group. Remote monitoring alone or remote monitoring coupled with remote physician care was as efficacious as the usual office care for reducing blood pressure with comparable safety and efficacy in hypertensive patients. PMID- 25787043 TI - Aldosterone and abnormal left ventricular geometry in chronic kidney disease. PMID- 25787042 TI - CYBA (p22phox) variants associate with blood pressure and oxidative stress markers in hypertension: a replication study in populations of diverse altitudes. AB - CYBA (p22(phox)) is an integral constituent of the NADPH oxidases and is consequently a main component of oxidative stress, which is strongly associated with hypertension. This study investigates the contribution of CYBA polymorphisms toward the complex etiology of hypertension in two ethnically different populations, one located at a high altitude and the other at a low altitude. The significance of CYBA single nucleotide polymorphisms and their correlation with clinical and biochemical phenotypes were investigated in age- and ethnicity matched unrelated permanent high-altitude residents (>3500 m) comprising 245 controls and 241 patients. The results were replicated in a second population comprising 935 controls and 545 patients who lived at a low altitude (<200 m). The analysis of covariance revealed that CYBA risk alleles and their haplotypes, rs8854A/rs9932581G/rs4873C and rs8854G/rs9932581G/rs4873C, were positively correlated with clinical parameters, for example, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP), and biochemical parameters, for example, 8-isoPGF2alpha level, and inversely correlated with catalase activity in patients compared with controls (P?0.01, each). Conversely, the protective alleles and their haplotype, rs8854G/rs9932581A/rs4873T, were inversely correlated with SBP, DBP, MAP and 8-isoPGF2alpha level, and positively correlated with catalase activity (P?0.001, each). Furthermore, correlation analysis between the clinical and biochemical parameters revealed a positive correlation of SBP, DBP and MAP with 8-isoPGF2alpha levels and a negative correlation with catalase activity in both populations (P<0.0001, each). CYBA (p22(phox)) variants influence the markers of oxidative stress and are associated with hypertension. PMID- 25787044 TI - Does reduced myocardial efficiency in systemic hypertensive-hypertrophy correlate with increased left-ventricular wall thickness? AB - Elevated systemic blood pressure, and the attendant development of pathologic left ventricular (LV) hypertrophy, ultimately culminates in heart failure and death. In clinical studies, a reduction of myocardial efficiency has been implicated in systemic hypertensive-hypertrophy. However, it is uncertain whether reduced efficiency correlates with LV wall thickness. Hence, we performed experiments on isolated working hearts of spontaneously hypertensive rats (SHRs) a widely-used experimental model of human hypertensive-hypertrophy. We contrasted their mechanoenergetic performance with that of Wistar controls at two ages: Adult (9 months) and Aged (post-18 months). The use of animal hearts allowed us to perform experiments over a wide range of afterloads. We found that mechanoenergetic performance (coronary and aortic flows, work output and oxygen consumption) declined with age. The peak efficiency of the Adult SHR was essentially similar to that of Control, but that for the Aged SHR was lower, compared with that of age-matched Wistar rats. All variables, including peak efficiency, obtained from the failing Aged SHR hearts (which also developed right ventricular hypertrophy), were greatly reduced. Our data reveal that peak efficiency of the Aged SHR, upon transitioning from compensated hypertrophy to failure, diminishes sharply, arising from compromised flows-both aortic and coronary. We further show that the reduction of myocardial efficiency in hypertensive-hypertrophy does not correlate with LV wall thickness, but instead is inversely correlated with whole-heart mass. The latter relation may serve as a prognostic and diagnostic tool in the clinical setting. PMID- 25787046 TI - Editors' welcome. PMID- 25787047 TI - The problem with repurposing: Is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? AB - If it is not feasible to develop licensed drugs to the stage that they can actually be prescribed for a new indication, can we justify, either ethically or economically, the undertaking of proof-of-concept studies using off-patent medications? Without a financial incentive it is very difficult to repurpose off patent drugs for a new indication. Therefore, we need a political solution to allow the repurposing of off-patent drugs by other stakeholders or Big Pharma. PMID- 25787045 TI - Modulation of the QT interval duration in hypertension with antihypertensive treatment. AB - The duration of the QT interval as measured by 12-lead electrocardiography is a measure of myocardial repolarization and is widely used to describe cardiac abnormalities, to determine the presence of cardiac toxicity and to evaluate drug safety. In hypertension, the QT interval is a predictor of the risk of both coronary events and cardiovascular death, after adjusting for the effects of additional risk factors. The mechanism of QT interval prolongation is multifactorial and includes cardiomyocyte hypertrophy and increased left ventricular mass, with accompanying changes in left ventricular transmural dispersion of repolarization, as well as changes in the tone of the autonomic nervous system of some patients with hypertension and mechano-electrical feedback, although this mechanism is less likely. Antihypertensive drugs vary in their effect on QT interval duration. The mechanisms underlying their effect depend on changes in left ventricular mass and autonomic nervous system tone, as well as changes in the activity of cardiac ion channels. Although blood pressure reduction is the primary goal of antihypertensive drug therapy and although the choice of antihypertensive drug treatment regimens varies among different individuals, the data regarding the disparate effects of antihypertensive drugs on the duration of the QT interval warrant consideration when implementing long term pharmacotherapy for hypertension. PMID- 25787048 TI - The need for a disease-specific prospective pregnancy registry for multiple sclerosis (MS). AB - Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age with an approximately 3:1 female to male ratio. Although pregnancy is not contraindicated in MS, data are limited regarding pregnancy outcome among MS patients, and the safety or risk to the fetus associated with most maternal MS treatments, such as disease modifying therapies (DMTs), during pregnancy is unknown. We review available epidemiological and registry data on MS and pregnancy and discuss the need to initiate a North American Multiple Sclerosis Pregnancy Registry that will prospectively identify pregnancies in women with MS, obtain information on the disease, and its treatment during gestation and lactation and follow the children to determine their health status. PMID- 25787049 TI - Patients report worse MS symptoms after menopause: findings from an online cohort. AB - BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown. OBJECTIVE: To investigate patient reported impact of menopause in a large online research platform, PatientsLikeMe (PLM). METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM's prospectively collected patient reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores. RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p<=0.01) in regressions adjusting for age, disease type and duration. CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings. PMID- 25787050 TI - Health-related quality of life in patients with longstanding 'benign multiple sclerosis'. AB - BACKGROUND: We explored health-related quality of life (HRQoL) and psychosocial aspects in a cohort of patients with a history of longstanding benign MS (BMS). METHODS: Patients with BMS (EDSS<=3 after 20 years disease duration) were re assessed 25-30 years post-MS symptom onset for: EDSS, HRQoL (MSQoL-54), depression (Beck Depression Inventory-II), and fatigue (Modified Fatigue Impact Scale). Associations between these measures and patient characteristics (age, disease duration, 'benign status' [remained benign (EDSS<=3) vs no longer benign (EDSS>3)]) were examined. RESULTS: Of the 61 patients included, 36 (49%) remained benign and 25 (41%) progressed (EDSS>3). Overall, physical and mental HRQoL scores were positively associated with each other (r=0.63; p<0.0001) and both negatively correlated with fatigue (r=-0.76 and -0.44, respectively; p<0.0005) and depression (r=-0.55 and -0.77; p<0.0001). Patients who remained benign reported better physical HRQoL vs those no longer benign (mean (SD)=67.3+/-18.1 vs 50.7+/-19.9, p=0.001), but not mental health (mean (SD)=67.4+/-19.3 vs 65.0+/ 20.6, p=0.639). Generally, neither age nor disease duration was strongly associated with HRQoL (r<0.35). CONCLUSION: Lower self-reported physical or mental HRQoL was associated with worsening fatigue and depression. However, EDSS progression was associated with the physical, but not mental aspects of HRQoL. Patient-reported HRQoL in 'benign MS' provides insight on the impact of MS beyond EDSS alone. PMID- 25787051 TI - Integrity of hypothalamic fibers and cognitive fatigue in multiple sclerosis. AB - Cognitive fatigue is a common and disabling symptom of multiple sclerosis (MS), but little is known about its pathophysiology. The present study investigated whether the posterior hypothalamus, which is considered as the waking center, is associated with MS-related cognitive fatigue. We analyzed the integrity of posterior hypothalamic fibers in 49 patients with relapsing-remitting MS and 14 healthy controls. Diffusion tensor imaging (DTI) parameters were calculated for fibers between the posterior hypothalamus and, respectively, the mesencephalon, pons and prefrontal cortex. In addition, DTI parameters were computed for fibers between the anterior hypothalamus and these regions and for the corpus callosum. Cognitive fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions. Analyses of variance with repeated measures were performed to investigate the impact of cognitive fatigue on diffusion parameters. Cognitively fatigued patients (75.5%) showed a significantly lower mean axial and radial diffusivity for fibers between the posterior hypothalamus and the mesencephalon than cognitively non-fatigued patients (Group(*)Target area(*)Diffusion orientation: F=4.047; p=0.023). For fibers of the corpus callosum, MS patients presented significantly higher axial and radial diffusivity than healthy controls (Group(*)Diffusion orientation: F=9.904; p<0.001). Depressive mood, used as covariate, revealed significant interaction effects for anterior hypothalamic fibers (Target area(*)Diffusion orientation(*)Depression: F=5.882; p=0.021; Hemisphere(*)Diffusion orientation(*) Depression: F=8.744; p=0.008). Changes in integrity of fibers between the posterior hypothalamus and the mesencephalon appear to be associated with MS-related cognitive fatigue. These changes might cause an altered modulation of hypothalamic centers responsible for wakefulness. Furthermore, integrity of anterior hypothalamic fibers might be related to depression in MS. PMID- 25787052 TI - Spinal cord atrophy in multiple sclerosis and relationship with disability across clinical phenotypes. AB - BACKGROUND: Several studies have shown a relationship between spinal cord atrophy and clinical disability in patients with multiple sclerosis (MS). OBJECTIVES: We examined the correlation between cervical cord cross-sectional area at the C2 vertebral level (CSA-C2) and the expanded disability status scale (EDSS) in patients with relapsing-remitting and progressive forms of MS. The latter included both secondary and primary progressive MS patients. METHODS: A total of 150 patients with MS were recruited from the Wayne State University MS clinic. Ninety-three had relapsing-remitting MS and 57 patients had progressive MS. MRI scan of the cervical cord was obtained for each patient. Correlation studies and multivariate regression analysis was performed, blinded to clinical status. RESULTS: The mean age was 41.3 year old, 64.6% were women, mean disease duration was 11.2 years, CSA-C2 was 80.2mm(2) and mean EDSS was 3.8. There was significant correlation between CSA-C2 and EDSS (r -0.75, p<0.0001). Sub-group analysis showed CSA-C2 was 68.6mm(2) and 87.3mm(2) in the progressive and relapsing remitting groups, respectively (p<0.0001). Multivariable regression showed that CSA-C2 was a significant predictor of disability independent of disease duration, and phenotype. CONCLUSIONS: Our study demonstrates that CSA-C2 has a strong correlation with clinical disability in both RRMS and progressive MS. Greater spinal cord atrophy was seen in patients with progressive than relapsing remitting MS. CSA-C2, disease duration, and phenotype are independent predictors of disability. PMID- 25787053 TI - Cervical cord area measurement using volumetric brain magnetic resonance imaging in multiple sclerosis. AB - BACKGROUND: In multiple sclerosis (MS), recent work suggests that cervical cord atrophy is more consistently correlated with physical disability than brain white matter lesion load and atrophy. Although spinal cord imaging has not been routinely obtained in many clinical trial and research studies, brain volumetric imaging usually has and includes the upper cervical cord. OBJECTIVES: Using volumetric T1-weighted brain images, we investigated cross-sectional area measures in the uppermost cervical cord and compared them with areas at the standard C2/3 level. METHODS: Using T1-weighted brain scans from 13 controls and 37 people with MS, and an active surface technique, cross-sectional area was measured over 5mm and 1mm cord segments at C2/3, below the level of odontoid peg, and 2cm and 2.5cm below the pons. Brain volume was also measured. RESULTS: Cord area measurements were most reliable in a 5mm segment 2.5cm below the pons (inter rater coefficient of variation 1.5%, intraclass correlation coefficient 0.99). Cord area at this level correlated more with that at C2/3 area than with brain volume (r=0.811 with C2/3, r=0.502 with brain volume). CONCLUSION: Whereas the standard C2/3 level is often not within the field of view on brain images, the level 2.5cm below the pons usually is, and measurement at this level may be a good way to investigate upper cervical cord atrophy when only brain images are available. PMID- 25787054 TI - CD20+ T cells in multiple sclerosis. PMID- 25787055 TI - Epstein-Barr virus candidate genes and multiple sclerosis. AB - BACKGROUND: Previous infection with Epstein-Barr virus (EBV) and a history of infectious mononucleosis (IM) have been previously associated with an increased risk of multiple sclerosis (MS). Whether there are common genetic factors that may partially explain these associations has not been thoroughly explored. OBJECTIVE: To investigate whether select polymorphisms in genes associated with IM susceptibility are related to MS risk-a self-reported history of IM or antibody titer against Epstein-Barr virus nuclear antigen 1 (anti-EBNA1). METHODS: A case-control study including 1213 MS cases and 454 controls enrolled in the Accelerated Cure Project for MS (ACP) Repository. Select polymorphisms in HLA-A, SH2D1A and IL15RA and anti-EBNA1 Ab titers were measured using stored blood samples provided by participants. Generalized linear models were used to assess the associations between select polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titers. RESULTS: No significant associations were observed between the selected polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titer. CONCLUSION: It is unlikely that any of the studied polymorphisms contribute to the explaining the association between anti-EBNA1 Ab titer or history of IM and MS. PMID- 25787056 TI - Serum BDNF levels are not reliable correlates of neurodegeneration in MS patients. PMID- 25787057 TI - Therapy Optimization in Multiple Sclerosis: a cohort study of therapy adherence and risk of relapse. AB - OBJECTIVES: The objective of the Therapy Optimization in MS (TOP MS) Study was to prospectively assess the relationship between MS disease-modifying therapy (DMT) adherence and MS relapse risk over 2 years. METHODS: Potential participants were recruited for TOP MS by specialty pharmacies who dispensed glatiramer acetate and beta interferons for MS nationwide. Signed IRB-approved informed consents were returned to the pharmacies. TOP MS used electronic data capture with monthly patient entries. Adherence, measured by medication possession ratio (MPR), was derived from pharmacy shipment records. Logistic regression examined the association between protocol-defined relapses and DMT MPR (<0.5; >0.5-<0.9; >0.9). RESULTS: TOP MS enrolled 3151 persons with MS, and 2410 completed the full 2 years. Across all therapies, the mean MPR for the 2-year completer cohort of 2049 who maintained the same DMT was 0.9+0.2 (range: 0.1-1.0), with 63.8% reaching a 2-year MPR >0.9. Evaluated by categories of MPR, the proportion of participants remaining relapse-free for 24 months increased with increasing MPR, and the proportion with >1 relapses declined with increasing levels of MPR (p<0.0008). Regression analysis revealed the odds of relapse for a patient in the MPR >0.9 MPR group was 64% that of a patient in the MPR <0.5 category (p=0.02). Use of >1 DMT prior to the current one was an independent predictor of relapse. CONCLUSIONS: The study provides class III evidence that improvement in adherence to DMT for MS is associated with improved clinical outcomes as measured by relapse reduction. PMID- 25787058 TI - A pragmatic approach to dealing with fingolimod-related lymphopaenia in Europe. PMID- 25787059 TI - Useless hand syndrome with astereognosis in multiple sclerosis. AB - We report on a patient with multiple sclerosis (MS) who developed bilateral useless hand syndrome (UHS) and astereognosis. Clinical features of UHS in our patient are similar to limb-kinetic apraxia with astereognosis. Cervical T1 weighted magnetic resonance imaging revealed a gadolinium-enhanced lesion at the level of C3-C4, mainly involving the posterior cord. This patient suggests that posterior cord lesions at high cervical levels cause UHS and astereognosis in MS, involving the sensorimotor integration needed to execute complex finger movements. PMID- 25787060 TI - Do neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways? AB - INTRODUCTION: Interferon-beta (IFNbeta) is currently the most used disease modifying treatment for relapsing-remitting multiple sclerosis (RRMS), but it can lead to the production of neutralising antibodies (NABs) against IFNbeta. CLINICAL CASE: A lady with a past history of genital herpes was diagnosed with RRMS, started IFNbeta treatment with a good initial response. Three years later her treatment was interrupted to become pregnant. After delivery she restarted IFNbeta; she had more reactivations of genital herpes and experienced intermittent sensory symptoms often coinciding with herpes reactivation. High NABs titres against IFNbeta were found. Since the introduction of famciclovir as prophylactic antiviral therapy and a switch from IFNbeta to glatiramer acetate, herpes reactivations ceased and she had no further MS relapses. CONCLUSION: Exacerbations of genital herpes coinciding with MS relapses suggest a potential link between the development of NABs and inhibition of anti-viral action of endogenous IFNbeta. This case highlights that NABs not only decreases exogenous IFNbeta treatment efficacy, but may also interfere with anti-viral properties of endogenous IFNbeta. Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in humans. PMID- 25787061 TI - TNNI3K in cardiovascular disease and prospects for therapy. AB - Cardiovascular diseases are an important cause of morbidity and mortality worldwide and the global burden of these diseases continues to grow. Therefore new therapies are urgently needed. The role of protein kinases in disease, including cardiac disease, is long recognized, making kinases important therapeutic targets. We here review the knowledge gathered in the last decade about troponin I-interacting kinase (TNNI3K), a kinase with cardiac-restricted expression that has been implicated in various cardiac phenotypes and diseases including heart failure, cardiomyopathy, ischemia/reperfusion injury and conduction of the cardiac electrical impulse. PMID- 25787062 TI - Outcomes of the house advancement flap for pilonidal sinus. AB - BACKGROUND: Many surgical techniques have been described for the treatment of pilonidal sinus, yet rates of recurrence and prolonged wound healing remain high and consensus on the optimal technique is lacking. This retrospective study evaluates outcomes of the use of the house advancement flap in the treatment of pilonidal sinus including time to wound healing, sinus recurrence, wound infection and flap necrosis. METHOD: Thirty-three consecutive patients who underwent excision and house advancement flap for pilonidal sinus, of whom seven patients (21%) had recurrent pilonidal sinus disease following previous surgical intervention, were reviewed retrospectively. Follow-up ranged from 4 to 59 months (mean 28 months). RESULTS: All 33 patients completed a follow-up survey. Age at time of operation ranged from 14 to 44 years with a mean of 25 years. No patients developed wound infection or flap necrosis. Four patients (12%) failed to achieve primary wound healing; mean time to wound healing for the remaining 29 patients was 62 days. Recurrence of pilonidal sinus occurred in eight patients (24%), at a mean time of 22 months post-operatively. CONCLUSION: The house advancement flap achieves primary wound closure in almost 90% of cases with few acute post operative complications. However delayed wound healing and sinus recurrence remain issues with this technique and it appears to have little advantage over other primary closure techniques. PMID- 25787063 TI - Nanomedicine for glaucoma: sustained release latanoprost offers a new therapeutic option with substantial benefits over eyedrops. AB - Glaucoma is a chronic progressive optic neuropathy that is characterized by optic nerve changes and visual field loss. Elevated intraocular pressure (IOP) is the main modifiable risk factor. Chronic instillation of daily eyedrops to lower IOP is the primary treatment of choice, although it requires patient adherence and correct performance. We have developed a nanoliposome drug delivery system for the longer term delivery of latanoprost. In the present open-label, pilot study, the safety and efficacy of a single subconjunctival injection of liposomal latanoprost was evaluated in six subjects with a diagnosis of either ocular hypertension (OHT) or primary open-angle glaucoma (POAG). Subconjunctival injection of liposomal latanoprost was well tolerated by all six subjects. From a baseline IOP of 27.55 +/- 3.25 mmHg, the mean IOP decreased within 1 h to 14.52 +/- 3.31 mmHg (range 10-18 mmHg). This represented a mean decrease of 13.03 +/- 2.88 mmHg (range 9-17 mmHg), or 47.43 +/- 10.05 % (range 37-63 %). A clinically and statistically significant IOP reduction (>=20 % IOP reduction, P = 0.001 to 0.049) was observed through 3 months after injection. The nanomedicine reported here is the first nanocarrier formulation that has an extended duration of action in humans, beyond a couple of weeks. The findings in this study open up a new treatment modality, which will greatly enhance patient compliance and improve treatment outcomes. The current study provides the evidence and support for further clinical studies of liposomal latanoprost in the treatment of glaucoma. PMID- 25787064 TI - Pharmacokinetics of ketorolac tromethamine compression-coated tablets for colon delivery. AB - Present research efforts are focused in developing compression-coated ketorolac tromethamine tablets to improve the drug levels in colon by retarding the drug release in the stomach and small intestine. To achieve this objective, core tablets containing ketorolac tromethamine were prepared by direct compression and compression coated with sodium alginate. The developed tablets were evaluated for physical properties, in vitro drug release, X-ray imaging, and pharmacokinetic studies in human volunteers. Based on the in vitro drug release study, the optimized formulation showed very little drug release (6.75 +/- 0.49 %) in the initial lag period of 5 h, followed by progressive release up to 97.47 +/- 0.93 % within 24 h. The X-ray imaging of tablets in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. From the pharmacokinetic study, the C max of colon-targeted tablets was 3,486.70 ng/ml at T max 10 h, whereas in the case of immediate-release tablets, the C max of 4,506.31 ng/ml at T max 2 h signifies the ability of compression coated tablets to target the colon. In conclusion, compression-coated tablets are suitable to deliver ketorolac tromethamine to the colon. PMID- 25787065 TI - Rapid Reconstitution Packages (RRPs) implemented by integration of computational fluid dynamics (CFD) and 3D printed microfluidics. AB - Rapid Reconstitution Packages (RRPs) are portable platforms that integrate microfluidics for rapid reconstitution of lyophilized drugs. Rapid reconstitution of lyophilized drugs using standard vials and syringes is an error-prone process. RRPs were designed using computational fluid dynamics (CFD) techniques to optimize fluidic structures for rapid mixing and integrating physical properties of targeted drugs and diluents. Devices were manufactured using stereo lithography 3D printing for micrometer structural precision and rapid prototyping. Tissue plasminogen activator (tPA) was selected as the initial model drug to test the RRPs as it is unstable in solution. tPA is a thrombolytic drug, stored in lyophilized form, required in emergency settings for which rapid reconstitution is of critical importance. RRP performance and drug stability were evaluated by high-performance liquid chromatography (HPLC) to characterize release kinetics. In addition, enzyme-linked immunosorbent assays (ELISAs) were performed to test for drug activity after the RRPs were exposed to various controlled temperature conditions. Experimental results showed that RRPs provided effective reconstitution of tPA that strongly correlated with CFD results. Simulation and experimental results show that release kinetics can be adjusted by tuning the device structural dimensions and diluent drug physical parameters. The design of RRPs can be tailored for a number of applications by taking into account physical parameters of the active pharmaceutical ingredients (APIs), excipients, and diluents. RRPs are portable platforms that can be utilized for reconstitution of emergency drugs in time-critical therapies. PMID- 25787066 TI - Evaluation of gatifloxacin pluronic micelles and development of its formulation for ocular delivery. AB - The purpose of the present study was to enhance the solubility of gatifloxacin by developing self-assembling pluronic micelles of gatifloxacin for ocular delivery, to overcome the problem of poor bioavailability and therefore lesser therapeutic response exhibited by conventional ophthalmic solutions of the drug. Gatifloxacin was loaded in micelles by solid dispersion method using Pluronic F127 and evaluated for particle size, drug loading, loading efficiency, in vitro transcorneal permeation study, in vitro drug release, solubility studies, microbiological studies, ex vivo mucoadhesive strength, and ocular safety studies. The drug loading and drug loading efficiency studies revealed that gatifloxacin/Pluronic F127 ratio of 0.25/2.52 g offered good drug loading (9.96 %), high loading efficiency (90 %), and acceptable particle size of 176 nm (polydispersity index 0.345). Hen's egg test chorioallantoic membrane (HET-CAM) assay with 0 score in 8 h and ocular safety test with score of 2 indicate the nonirritant property of the developed pluronic micelles. In vitro transcorneal permeation studies through excised goat cornea indicated increase in ocular availability with no corneal damage. In vitro drug release data of optimized formulation provided sustained release over a period of 8 h. Optimized formulation was found to possess acceptable transcorneal permeation and antimicrobial efficacy when compared to marketed eye drops. The solubility studies of gatifloxacin from these lyophilized pluronic micelles revealed 18.67 fold increase in comparison to gatifloxacin suspension in water. The pluronic micelles could enhance ocular bioavailability of gatifloxacin, prolong its residence time in the eyes, and may lead to reduced instillation frequency, thereby resulting in better patient compliance. PMID- 25787067 TI - Receptor-mediated hepatocyte-targeted delivery of primaquine phosphate nanocarboplex using a carbohydrate ligand. AB - Primaquine phosphate is a drug of choice for the treatment of malarial relapse. However, poor drug concentration in the hepatocytes and dose-related toxicity pose severe limitations. We report a nanocarboplex of primaquine phosphate by a simple in situ process using dextran sulphate as a carbohydrate polymer and pullulan as an asialoglycoprotein receptor ligand. Our aim was to preferentially enhance accumulation of the nanocarboplex in the hepatocytes. The in situ pullulan-anchored primaquine nanocarboplex was prepared by simple addition of a solution of dextran sulphate and pullulan with stabilizer to a measured quantity of primaquine phosphate in a vial, followed by shaking to obtain the primaquine phosphate nanocarboplex ready for injection. The nanocarboplex was characterized and evaluated in vivo for pharmacokinetics and biodistribution in the rat model. Specific uptake by hepatocytes in the liver was also quantified. Increase in t 1/2 with significant uptake in the RES organ was observed. More importantly, anchoring pullulan favored high liver uptake and preferential accumulation in the hepatocytes with a hepatocytes/nonparenchymal cells ratio of 75:25. The in situ primaquine phosphate nanocarboplex anchored with pullulan provides both a significant technological advantage and the desired targeting to the hepatocytes. PMID- 25787068 TI - Celecoxib nanosuspension: single-step fabrication using a modified nanoprecipitation method and in vivo evaluation. AB - Conventional nanoprecipitation process involves addition of water miscible organic solvent containing drug to an aqueous phase containing hydrophilic surfactants to yield drug nanosuspension. However, nanosuspensions obtained with conventional nanoprecipitation process have very low colloidal stability. The objective of the present investigation was to fabricate drug nanosuspensions with good colloidal stability using a modified nanoprecipitation method. Celecoxib, a hydrophobic anti-inflammatory agent with low oral bioavailability, was used as a model drug for this investigation. The conventional nanoprecipitation method did not result in the nanosizing of the celecoxib. Incorporation of surface active lipophiles such as Labrafil 1944 CS (oleolyl macrogol glycerides) along with hydrophilic surfactants during nanoprecipitation process could successfully nanosize the celecoxib. The particle size of the nanosuspensions was influenced by the various parameters of the nanoprecipitation process and also by the concentration of the lipophilic stabilizer. The celecoxib nanosuspension was characterized by transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction. Saturation solubility of celecoxib was dramatically improved in pH 1.2 buffer when formulated as nanosuspensions. The celecoxib nanosuspesnsion showed significantly higher in vitro dissolution rate and in vivo anti-inflammatory activity as compared to that of celecoxib-marketed formulation. PMID- 25787069 TI - Development of sustained-release formulations processed by hot-melt extrusion by using a quality-by-design approach. AB - In this study, a quality-by-design (QbD) approach was used to optimize the development of paracetamol (PMOL) sustained-release formulations manufactured by hot-melt extrusion (HME). For the purpose of the study, in-line near-infrared (NIR) spectroscopy as a process analytical technology (PAT) was explored while a design of experiment (DoE) was implemented to assess the effect of the process critical parameters and to identify the critical quality attributes (CQA) of the extrusion processing. Blends of paracetamol, ethyl cellulose (EC) and Compritol(r) 888 ATO (C888) were processed using a twin screw extruder to investigate the effect of screw speed, feed rate and drug loading on the dissolution rates and particle size distribution. The principal component analysis (PCA) of the NIR collected signal revealed the optimum extrusion processing parameters. Furthermore, the integration of the DoE experiments demonstrated that drug loading has a significant effect on the only quality attribute, which was the PMOL dissolution rate. This QbD approach was employed as a paradigm for the development of pharmaceutical formulations via HME processing. PMID- 25787070 TI - Stress and cortisol in disaster evacuees: an exploratory study on associations with social protective factors. AB - Though cumulative emotional and physical effects of disasters may diminish evacuees' short and long-term mental and physical health, social factors may buffer such consequences. We approached survivors of the October 2007 San Diego, California firestorms. We gathered data during the evacuation and 3 months afterward. Questionnaires measured social support as well as PTSD, depression, and anxiety symptoms. Saliva samples were used to assess the stress hormone, cortisol. Analyses, adjusting for age, gender, and socioeconomic status, showed PTSD symptoms were associated with flattening of the diurnal cortisol rhythm during evacuation. Secondary analyses showed those reporting a family emphasis on moral and religious values had lower psychological distress. Though anxiety symptoms had significantly decreased in the overall sample at follow-up, blunted cortisol rhythms persisted among those individuals with continued high anxiety. Results highlight a possible psychological, and perhaps a physiological, benefit of social and existential factors in disaster situations. Future work should explore the role of psychosocial factors and stress physiology in the development of long-term health concerns among individuals exposed to disaster. PMID- 25787071 TI - Automated Greulich-Pyle bone age determination in children with chronic kidney disease. AB - BACKGROUND: Growth restriction and retarded bone age are common findings in children with chronic kidney disease (CKD). We compared the automated BoneXpertTM method with the manual assessment of an X-ray of the non-dominant hand. METHODS: In this retrospective multicenter study, 359 patients with CKD stages 2-5, aged 2 14.5 (girls) or 2.5-17 years (boys) were included. Bone age was determined manually by three experts (according to Greulich and Pyle). Automated determination of bone age was performed using the image analysis software BoneXpertTM. RESULTS: There was a strong correlation between the automatic and the manual method (r = 0.983, p < 0.001). The automatic method tended to generate higher bone age values (0.64 +/- 0.73 years) in the younger patients (4-5 years) and to underestimate retardation or acceleration of bone age. The so-called "bone health index" (BHI) was reduced in comparison to the reference population. Bone health index standard deviation score (BHI-SDS) was not related to the stage of CKD, but weakly negatively correlated with plasma PTH concentrations (r = 0.12, p = 0.019). CONCLUSIONS: BoneXpertTM allows an objective, time-saving, and in general valid bone age assessment in children with CKD. Possible underestimation of retarded or accelerated bone age should be taken into account. Validation of the BHI needs further study. PMID- 25787072 TI - Urothelial carcinoma of the urinary bladder in pediatric patients: a long-term follow-up. AB - OBJECTIVES: To report our experience and long-term follow-up data on pediatric patients with urothelial carcinoma (UC) of the urinary bladder. METHODS: In this retrospective study, perioperative and long-term follow-up data of nine pediatric patients with neoplasms of urothelial origin within the urinary bladder between 1980 and 2014 were analyzed. Cystoscopy was performed under general anesthesia, and transurethral resection of the bladder tumors was carried out in the same session. Adult follow-up protocols were used for all patients. RESULTS: Urothelial carcinoma of the urinary bladder was histologically verified in five male (66%) and three female (33%) patients. In one patient, papillary urothelial neoplasm of low malignant potential was detected. Median patient age at the time of diagnosis was 12 years (4-18 years). Mean tumor size was 2.2 cm (1.5-4 cm). After a median follow-up of 60 months (10-121 months), no recurrence was observed among our patients. CONCLUSION: Urothelial carcinoma of the urinary bladder in pediatric patients is a rare condition. Due to lack of substantial data, it is difficult to establish tailored management strategies. Most patients present with low-grade, low-stage disease. Being the most common symptom, macroscopic hematuria should be clarified with cystoscopy in pediatric age group. PMID- 25787073 TI - Do preoperative serum C-reactive protein levels predict the definitive pathological stage in patients with clinically localized prostate cancer? AB - PURPOSE: The serum C-reactive protein (CRP) level correlates with the clinical prognosis in patients with kidney, penile and metastatic castration-resistant prostate cancer (PC). We prospectively evaluated the preoperative CRP level as a predictive marker for an advanced tumor stage or high-grade cancer in patients with clinically localized PC. METHODS: The study evaluated 629 patients with clinically localized PC who underwent radical prostatectomy between 2010 and 2013. Exclusion criteria were signs of systemic infection, symptoms of an autoimmune disease or neoadjuvant androgen deprivation. RESULTS: Poorly differentiated PC tends to be more common in patients with elevated CRP levels (15.5 vs. 9.5%, p = 0.08). Analogously, patients with a Gleason score >=8 PC had significantly higher median CRP levels than those with a Gleason score <=7 PC (1.9 vs. 1.2 mg/l, p = 0.03). However, neither uni- nor multivariate analysis showed an association between the preoperative CRP level and the presence of a locally advanced tumor stage, lymph node metastases or a positive surgical margin. CRP also failed to correlate with the initial PSA level and the clinical tumor-associated findings. Moreover, multivariate analysis relativized the association between an elevated CRP level and poor tumor differentiation. CONCLUSION: In patients with clinically localized PC, CRP does not appear to possess the predictive value and it was shown to have patients with other tumor entities or advanced PC. PMID- 25787074 TI - The Atomic Structure of the HIV-1 gp41 Transmembrane Domain and Its Connection to the Immunogenic Membrane-proximal External Region. AB - The membrane-proximal external region (MPER) C-terminal segment and the transmembrane domain (TMD) of gp41 are involved in HIV-1 envelope glycoprotein mediated fusion and modulation of immune responses during viral infection. However, the atomic structure of this functional region remains unsolved. Here, based on the high resolution NMR data obtained for peptides spanning the C terminal segment of MPER and the TMD, we report two main findings: (i) the conformational variability of the TMD helix at a membrane-buried position; and (ii) the existence of an uninterrupted alpha-helix spanning MPER and the N terminal region of the TMD. Thus, our structural data provide evidence for the bipartite organization of TMD predicted by previous molecular dynamics simulations and functional studies, but they do not support the breaking of the helix at Lys-683, as was suggested by some models to mark the initiation of the TMD anchor. Antibody binding energetics examined with isothermal titration calorimetry and humoral responses elicited in rabbits by peptide-based vaccines further support the relevance of a continuous MPER-TMD helix for immune recognition. We conclude that the transmembrane anchor of HIV-1 envelope is composed of two distinct subdomains: 1) an immunogenic helix at the N terminus also involved in promoting membrane fusion; and 2) an immunosuppressive helix at the C terminus, which might also contribute to the late stages of the fusion process. The unprecedented high resolution structural data reported here may guide future vaccine and inhibitor developments. PMID- 25787075 TI - Transcriptional Regulation, Metal Binding Properties and Structure of Pden1597, an Unusual Zinc Transport Protein from Paracoccus denitrificans. AB - ATP-binding cassette (ABC) transporters of the cluster 9 family are ubiquitous among bacteria and essential for acquiring Zn(2+) and Mn(2+) from the environment or, in the case of pathogens, from the host. These rely on a substrate-binding protein (SBP) to coordinate the relevant metal with high affinity and specificity and subsequently release it to a membrane permease for translocation into the cytoplasm. Although a number of cluster 9 SBP structures have been determined, the structural attributes conferring Zn(2+) or Mn(2+) specificity remain ambiguous. Here we describe the gene expression profile, in vitro metal binding properties, and crystal structure of a new cluster 9 SBP from Paracoccus denitrificans we have called AztC. Although all of our results strongly indicate Zn(2+) over Mn(2+) specificity, the Zn(2+) ion is coordinated by a conserved Asp residue only observed to date as a metal ligand in Mn(2+)-specific SBPs. The unusual sequence properties of this protein are shared among close homologues, including members from the human pathogens Klebsiella pneumonia and Enterobacter aerogenes, and would seem to suggest a subclass of Zn(2+)-specific transporters among the cluster 9 family. In any case, the unusual coordination environment of AztC expands the already considerable range of those available to Zn(2+)-specific SBPs and highlights the presence of a His-rich loop as the most reliable indicator of Zn(2+) specificity. PMID- 25787076 TI - Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. AB - Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial, and clinically reliable therapies are not available. A trigger of muscle protein loss is the Jak/Stat pathway, and indeed, we found that conditioned medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates Stat3 (p-Stat3) in C2C12 myotubes. We identified two proteolytic pathways that are activated in muscle by p-Stat3; one is activation of caspase-3, and the other is p-Stat3 to myostatin, MAFbx/Atrogin-1, and MuRF-1 via CAAT/enhancer-binding protein delta (C/EBPdelta). Using sequential deletions of the caspase-3 promoter and CHIP assays, we determined that Stat3 activation increases caspase-3 expression in C2C12 cells. Caspase-3 expression and proteolytic activity were stimulated by p-Stat3 in muscles of tumor-bearing mice. In mice with cachexia caused by Lewis lung carcinoma or C26 tumors, knock-out of p-Stat3 in muscle or with a small chemical inhibitor of p-Stat3 suppressed muscle mass losses, improved protein synthesis and degradation in muscle, and increased body weight and grip strength. Activation of p-Stat3 stimulates a pathway from C/EBPdelta to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBPdelta KO decreases the expression of MAFbx/Atrogin-1 and myostatin, while increasing muscle mass and grip strength. In conclusion, cancer stimulates p-Stat3 in muscle, activating protein loss by stimulating caspase-3, myostatin, and the ubiquitin-proteasome system. These results could lead to novel strategies for preventing cancer-induced muscle wasting. PMID- 25787077 TI - The coordinate cellular response to insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-2 (IGFBP-2) is regulated through vimentin binding to receptor tyrosine phosphatase beta (RPTPbeta). AB - Insulin-like growth factor-binding protein-2 (IGFBP-2) functions coordinately with IGF-I to stimulate cellular proliferation and differentiation. IGFBP-2 binds to receptor tyrosine phosphatase beta (RPTPbeta), and this binding in conjunction with IGF-I receptor stimulation induces RPTPbeta polymerization leading to phosphatase and tensin homolog inactivation, AKT stimulation, and enhanced cell proliferation. To determine the mechanism by which RPTPbeta polymerization is regulated, we analyzed the protein(s) that associated with RPTPbeta in response to IGF-I and IGFBP-2 in vascular smooth muscle cells. Proteomic experiments revealed that IGF-I stimulated the intermediate filament protein vimentin to bind to RPTPbeta, and knockdown of vimentin resulted in failure of IGFBP-2 and IGF-I to stimulate RPTPbeta polymerization. Knockdown of IGFBP-2 or inhibition of IGF IR tyrosine kinase disrupted vimentin/RPTPbeta association. Vimentin binding to RPTPbeta was mediated through vimentin serine phosphorylation. The serine threonine kinase PKCzeta was recruited to vimentin in response to IGF-I and inhibition of PKCzeta activation blocked these signaling events. A cell-permeable peptide that contained the vimentin phosphorylation site disrupted vimentin/RPTPbeta association, and IGF-I stimulated RPTPbeta polymerization and AKT activation. Integrin-linked kinase recruited PKCzeta to SHPS-1-associated vimentin in response to IGF-I and inhibition of integrin-linked kinase/PKCzeta association reduced vimentin serine phosphorylation. PKCzeta stimulation of vimentin phosphorylation required high glucose and vimentin/RPTPbeta-association occurred only during hyperglycemia. Disruption of vimetin/RPTPbeta in diabetic mice inhibited RPTPbeta polymerization, vimentin serine phosphorylation, and AKT activation in response to IGF-I, whereas nondiabetic mice showed no difference. The induction of vimentin phosphorylation is important for IGFBP-2-mediated enhancement of IGF-I-stimulated proliferation during hyperglycemia, and it coordinates signaling between these two receptor-linked signaling systems. PMID- 25787078 TI - Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system. AB - Peripheral neuroinflammation caused by activated immune cells can provoke neuropathic pain. Herein, we investigate the actions of macrophages and T cells through glucocorticoid-induced tumor neurosis factor receptor ligand (GITRL) and its receptor (GITR) in neuropathic pain. After partial sciatic nerve ligation (PSL) in enhanced green fluorescent protein (eGFP) chimeric mice generated by the transplantation of eGFP(+) bone marrow cells, eGFP(+) macrophages, and T cells markedly migrated to the injured site after PSL. Administration of agents to deplete macrophages (liposome-clodronate and Clophosome-A(TM)) or T cells (anti CD4 antibody and FTY720) could suppress PSL-induced thermal hyperalgesia and tactile allodynia. The expression levels of co-stimulatory molecules GITRL and GITR were increased on infiltrating macrophages and T cells, respectively. The perineural injection of a GITRL neutralizing antibody that could inhibit the function of the GITRL-GITR pathway attenuated PSL-induced neuropathic pain. Additionally, the induction of inflammatory cytokines and the accumulation of GITR(+) T cells in the injured SCN were abrogated after macrophage depletion by Clophosome-A(TM). In conclusion, GITRL expressed on macrophages drives cytokine release and T cell activation, resulting in neuropathic pain via GITR-dependent actions. The GITRL-GITR pathway might represent a novel target for the treatment of neuropathic pain. PMID- 25787079 TI - Acetylation stimulates the epithelial sodium channel by reducing its ubiquitination and degradation. AB - The epithelial Na(+) channel (ENaC) functions as a pathway for Na(+) absorption in the kidney and lung, where it is crucial for Na(+) homeostasis and blood pressure regulation. ENaC is regulated in part through signaling pathways that control the ubiquitination state of ENaC lysines. A defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension. Here we determined that alpha-, beta-, and gammaENaC are also substrates for lysine acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, enhanced ENaC acetylation and increased ENaC abundance in the total cell lysate and at the cell surface. Moreover, TSA increased ENaC current in Fischer rat thyroid and kidney collecting duct epithelia. We found that HDAC7 is expressed in the kidney collecting duct, supporting a potential role for this histone deacetylase in ENaC regulation. HDAC7 overexpression reduced ENaC abundance and ENaC current, whereas ENaC abundance and current were increased by silencing of HDAC7. ENaC and HDAC7 form a complex, as detected by coimmunoprecipitation. We observed a reciprocal relationship between acetylation and ubiquitination; TSA reduced ENaC ubiquitination, whereas HDAC7 increased ubiquitination. By reducing ENaC ubiquitination, TSA decreased the rate of ENaC degradation. Thus, acetylation increases epithelial Na(+) absorption by antagonizing ENaC ubiquitination. This stabilizes ENaC, and hence, increases its abundance at the cell surface. PMID- 25787080 TI - Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation. AB - Zinc is an essential trace element with wide-ranging biological functions, whereas the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. The upstream activator of Hh signaling, the Hh ligand, originates from Hh autoprocessing, which converts the Hh precursor protein to the Hh ligand. In an in vitro Hh autoprocessing assay we show that zinc inhibits Hh autoprocessing with a Ki of 2 MUm. We then demonstrate that zinc inhibits Hh autoprocessing in a cellular environment with experiments in primary rat astrocyte culture. Solution NMR reveals that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autoprocessing, and isothermal titration calorimetry provided the thermodynamics of the binding. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand. PMID- 25787081 TI - Wild-type human gammaD-crystallin promotes aggregation of its oxidation mimicking, misfolding-prone W42Q mutant. AB - Non-native protein conformers generated by mutation or chemical damage template aggregation of wild-type, undamaged polypeptides in diseases ranging from amyotrophic lateral sclerosis to cancer. We tested for such interactions in the natively monomeric human eye lens protein gammad-crystallin, whose aggregation leads to cataract disease. The oxidation-mimicking W42Q mutant of gammad crystallin formed non-native polymers starting from a native-like state under physiological conditions. Aggregation occurred in the temperature range 35-45 degrees C, in which the mutant protein began to lose the native conformation of its N-terminal domain. Surprisingly, wild-type gammad-crystallin promoted W42Q polymerization in a catalytic manner, even at mutant concentrations too low for homogeneous nucleation to occur. The presence of wild-type protein also downshifted the temperature range of W42Q aggregation. W42Q aggregation required formation of a non-native intramolecular disulfide bond but not intermolecular cross-linking. Transient WT/W42Q binding may catalyze this oxidative misfolding event in the mutant. That a more stable variant in a mixture can specifically promote aggregation of a less stable one rationalizes how extensive aggregation of rare damaged polypeptides can occur during the course of aging. PMID- 25787082 TI - Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs. AB - Increased expression of metadherin (MTDH, also known as AEG-1 and 3D3/LYRIC) has been associated with drug resistance, metastasis, and angiogenesis in a variety of cancers. However, the specific mechanisms through which MTDH is involved in these processes remain unclear. To uncover these mechanisms, we generated Mtdh knock-out mice via a targeted disruption of exon 3. Homozygous Mtdh knock-out mice are viable, but males are infertile. The homozygous male mice present with massive loss of spermatozoa as a consequence of meiotic failure. Accumulation of gamma-H2AX in spermatocytes of homozygous Mtdh knock-out mice confirms an increase in unrepaired DNA breaks. We also examined expression of the DNA repair protein Rad18, which is regulated by MTDH at the post-transcriptional level. In testes from Mtdh exon 3-deficient mice, Rad18 foci were increased in the lumina of the seminiferous tubules. The Piwi-interacting RNA (piRNA)-interacting protein Mili was expressed at high levels in testes from Mtdh knock-out mice. Accordingly, genome-wide small RNA deep sequencing demonstrated altered expression of piRNAs in the testes of Mtdh knock-out mice as compared with wild type mice. In addition, we observed significantly reduced expression of microRNAs (miRNAs) including miR-16 and miR-19b, which are known to be significantly reduced in the semen of infertile men. In sum, our observations indicate a crucial role for MTDH in male fertility and the DNA repair mechanisms required for normal spermatogenesis. PMID- 25787083 TI - Grip Strength and Cognitive Abilities: Associations in Old Age. AB - OBJECTIVES: Both physical functioning and cognitive abilities are important for well-being, not least in old age. Grip strength is often considered an indicator of general vitality and, as such, may predict cognitive functioning. Few longitudinal studies have examined the relationship between grip strength and cognition, especially where specific cognitive abilities have been targeted. METHOD: Participants (n = 708, age range: 40-86 years at baseline) came from the population-based longitudinal Swedish Adoption/Twin Study of Aging. We used a longitudinal follow-up of 6 waves during 20 years. For the analyses, we used latent growth modeling, where latent growth trajectories were fitted to the cognitive traits (verbal ability, spatial ability, processing speed, and memory) or to the grip strength values and each, respectively, treated as time-varying covariates of the other trait. RESULTS: Results supported a longitudinal influence of grip strength on changes in cognitive function. Grip strength performance was associated with change in the 4 cognitive abilities after age 65 years. DISCUSSION: A rather stable connection was found between grip strength and cognitive abilities starting around 65 years of age. The starting period suggests that the association may be due to lifestyle changes, such as retirement, or to acceleration of the aging processes. PMID- 25787084 TI - Influence of pulmonary hypertension on survival in advanced lung disease. AB - BACKGROUND: Effects of pulmonary hypertension (PH) in advanced lung disease remain unclear. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 to assess survival lung transplant candidates to determine influence of PH in advanced lung disease. Thresholds included mean pulmonary artery pressure >= 25 mmHg (mild PH) and 35 mmHg (severe PH). RESULTS: Of 12,405 listed possible candidates, 10,158 were used for univariate analysis, 7050 for Kaplan-Meier (KM) function, 6196 for multivariate Cox models, and 5328 (mild PH) and 1910 (severe PH) for propensity score matching (PSM). For mild and severe PH, univariate revealed that PH was associated with survival difference (HR = 1.530, 95% CI 1.416, 1.654, p < 0.001) and (HR = 2.033, 95% CI 1.851, 2.232, p < 0.001), respectively. KM function curves demonstrated a significant difference for mild PH (Log-rank test: Chi square (df = 1): 117.76, p < 0.0001) and severe PH (Log-rank test: Chi square (df = 1): 230.91, p < 0.0001). Multivariate Cox models also found a significant increased risk for death for mild PH (HR = 1.750, 95% CI 1.606, 1.907, p < 0.001) and severe PH (HR = 2.088, 95% CI 1.879, 2.319, p < 0.001). PSM confirmed this increased risk for death for mild PH (HR = 1.695, 95% CI 1.502, 1.914, p < 0.001) and severe PH (HR = 1.976, 95% CI 1.641, 2.379, p < 0.001). CONCLUSIONS: PH is associated with significant increased risk for death in patients with advanced lung disease. PMID- 25787085 TI - Polymorphisms in HLA-DRB1 gene and the risk of tuberculosis: a meta-analysis of 31 studies. AB - PURPOSE: The HLA-DRB1 gene polymorphisms have been implicated in susceptibility to tuberculosis (TB). However, a large number of studies have reported inconclusive results. This study was conducted to investigate the relationship of HLA-DRB1 gene polymorphisms and TB risk by a meta-analysis. METHODS: A search was performed in Embase, PubMed, Wanfang Database, and China National Knowledge Internet (CNKI) up to Jul 30, 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. Statistical analyses were calculated by STATA 11.0 software. RESULTS: All 31 articles involving 3,416 cases and 4,515 controls were identified. The pooled results indicated a significant association between HLA-DRB1*04 (OR 1.22, 95% CI 1.00-1.48, P = 0.048), *09 (OR 1.50, 95% CI 1.08-2.08, P = 0.016), *10 (OR 1.23, 95% CI 1.01-1.49, P = 0.035), *11 (OR 0.72, 95% CI 0.53-0.99, P = 0.044), *15 (OR 1.40, 95% CI 1.14-1.73, P = 0.001), and *16 (OR 1.33, 95% CI 1.08-1.63, P = 0.007) gene polymorphisms and TB risk. In addition, the results also show no significant association between HLA DRB1*01 (P = 0.748), *03 (P = 0.947), *07 (P = 0.966), *08 (P = 0.440), *12 (P = 0.288), *13 (P = 0.241), and *14 (P = 0.551) gene polymorphisms and TB risk. CONCLUSIONS: This study suggested that the HLA-DRB1*04, *09, *10, *15, and *16 gene polymorphisms may contribute to the risk of TB, especially in the East Asian. But the HLA-DRB1*11 gene polymorphism may be a protective factor for TB risk. Unfortunately, there is no significant association between the HLA-DRB1*01, *03, *07, *08, *12, *13, and *14 gene polymorphisms and TB risk. PMID- 25787086 TI - Ionization controls for biomineralization-inspired CO2 chemical looping at constant room temperature. AB - Living organisms such as corals can carry out CO2 looping efficiently via biomineralization under ambient conditions. Inspired by this natural process, we establish a solution system of calcium acetate-ethanol-water (Ca(Ac)2-C2H5OH-H2O) for CO2 chemical looping at constant room temperature. The CO2 capture is achieved by its reaction with Ca(Ac)2 to form calcium carbonate (CaCO3) mineral and HAc in the binary solvent with a high C2H5OH content. However, an increase in the H2O content in the system triggers acetic acid (HAc)-induced CaCO3 dissolution to release CO2. The system can be recovered for CO2 capture readily by the replenishment of C2H5OH. This biomimetic mineralization-based CO2 capture/release is controlled by the ionization states of the electrolytes, and is precisely regulated in the C2H5OH-H2O binary solvent. Our attempt highlights the fundamental principle of solution chemistry in reaction control and provides a bioinspired strategy for CO2 capture/release with very low cost and easy availability. PMID- 25787088 TI - Processing-Structure-Property Relationships in Laser-Annealed PbSe Nanocrystal Thin Films. AB - As nanocrystal (NC) synthesis techniques and device architectures advance, it becomes increasingly apparent that new ways of connecting NCs with each other and their external environment are required to realize their considerable potential. Enhancing inter-NC coupling by thermal annealing has been a long-standing challenge. Conventional thermal annealing approaches are limited by the challenge of annealing the NC at sufficiently high temperatures to remove surface-bound ligands while at the same time limiting the thermal budget to prevent large-scale aggregation. Here we investigate nonequilibrium laser annealing of NC thin films that enables separation of the kinetic and thermodynamic aspects of nanocrystal fusion. We show that laser annealing of NC assemblies on nano- to microsecond time scales can transform initially isolated NCs in a thin film into an interconnected structure in which proximate dots "just touch". We investigate both pulsed laser annealing and laser spike annealing and show that both annealing methods can produce "confined-but-connected" nanocrystal films. We develop a thermal transport model to rationalize the differences in resulting film morphologies. Finally we show that the insights gained from study of nanocrystal mono- and bilayers can be extended to three-dimensional NC films. The basic processing-structure-property relationships established in this work provide guidance to future advances in creating functional thin films in which constituent NCs can purposefully interact. PMID- 25787089 TI - Using qualitative and mixed methodologies to explore hierarchy in the operating room. PMID- 25787090 TI - Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia. AB - Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4 repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDP Type B. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD. PMID- 25787091 TI - Psychosocial Responses to being Identified as a Balanced Chromosomal Translocation Carrier: a Qualitative Investigation of Parents in Japan. AB - Undergoing chromosome analysis and receiving the results may have various psychosocial effects. To identify the impact on balanced translocation carriers identified through affected offspring, we conducted semi-structured interviews with eleven parents at Saitama Children's Medical Center. The results of the interviews were analyzed qualitatively by the KJ (Kawakita Jiro) method. Categories and subcategories of the various thoughts, emotions and responses experienced by balanced chromosomal translocation carriers were extracted. Participants' reactions were mixed, and appeared to be interrelated in some cases. Parents' reactions were sometimes ambivalent with regard to effects on reproductive issues and disclosure of test results. We recommend genetic counseling before and after carrier testing to help parents cope with the mixed and complex thoughts and feelings that arise upon being identified as a carrier. PMID- 25787092 TI - Correction: Light-driven conformational regulation of human telomeric G quadruplex DNA in physiological conditions. PMID- 25787093 TI - Prevalence of Germline BAP1, CDKN2A, and CDK4 Mutations in an Australian Population-Based Sample of Cutaneous Melanoma Cases. AB - Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the sample. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence. PMID- 25787094 TI - Photolithographic patterning of 3D-formed polycarbonate films for targeted cell guiding. AB - A facile photolithographic platform for the design of cell-guiding polymeric substrates is introduced. Specific areas of the substrate are photo-deactivated for the subsequent growth of bioresistant polymer brushes, creating zones for cell proliferation, and protein adhesion. PMID- 25787087 TI - KDM1 class flavin-dependent protein lysine demethylases. AB - Flavin-dependent, lysine-specific protein demethylases (KDM1s) are a subfamily of amine oxidases that catalyze the selective posttranslational oxidative demethylation of methyllysine side chains within protein and peptide substrates. KDM1s participate in the widespread epigenetic regulation of both normal and disease state transcriptional programs. Their activities are central to various cellular functions, such as hematopoietic and neuronal differentiation, cancer proliferation and metastasis, and viral lytic replication and establishment of latency. Interestingly, KDM1s function as catalytic subunits within complexes with coregulatory molecules that modulate enzymatic activity of the demethylases and coordinate their access to specific substrates at distinct sites within the cell and chromatin. Although several classes of KDM1-selective small molecule inhibitors have been recently developed, these pan-active site inhibition strategies lack the ability to selectively discriminate between KDM1 activity in specific, and occasionally opposing, functional contexts within these complexes. Here we review the discovery of this class of demethylases, their structures, chemical mechanisms, and specificity. Additionally, we review inhibition of this class of enzymes as well as emerging interactions with coregulatory molecules that regulate demethylase activity in highly specific functional contexts of biological and potential therapeutic importance. PMID- 25787095 TI - Molecular effects of supraphysiological doses of doping agents on health. AB - Performance-enhancing drugs (PEDs) gained wide popularity not only among sportsmen but also among specific subsets of population, such as adolescents. Apart from their claimed effects on athletic performance, they are very appealing due to the body shaping effect exerted on fat mass and fat-free mass. Besides the "underestimated" massive misuse of PEDs, the short- as well as long-term consequences of such habits remain largely unrecognized. They have been strictly associated with serious adverse effects, but molecular mechanisms are yet to be elucidated. Here, we analyze the current understanding of the molecular effects of supraphysiological doses of doping agents in healthy biological systems, at genomic and proteomic levels, in order to define the molecular sensors of organ/tissue impairment, determined by their misuse. The focus is put on the anabolic androgenic steroids (AASs), specifically testosterone (T) and its most potent derivative dihydrotestosterone (DHT), and on the peptide hormones, specifically the growth hormone (GH) and the insulin-like growth factor-1 (IGF 1). A map of molecular targets is defined and the risk incidence for human health is taken into account. PMID- 25787096 TI - Shift-work disorder and sleep-related environmental factors in the manufacturing industry. AB - The aim of this study was to examine the relationship between shift-work disorder (SWD) and environmental and somatic factors related to falling asleep among rapidly rotating shift workers in a manufacturing industry.A total of 556 male workers were recruited to complete a self-administered questionnaire regarding age, shift work experience, lifestyle, and family structure; the Epworth sleepiness scale (ESS); the Pittsburgh sleep quality index (PSQI); and the Horne and Ostberg questionnaire, a questionnaire for environmental and somatic factors related to falling asleep. We classified workers according to having SWD or not, and compared workers with SWD with those without this disorder in terms of all items covered in the aforementioned questionnaires. A total of 208 workers (62.8%) working rapidly rotating shifts were diagnosed with SWD. The ESS and PSQI scores and scores for environmental and somatic factors were significantly higher in workers with SWD than in those without this disorder. The ESS scores and scores for environmental and somatic factors were also associated with SWD in the logistic regression analyses. We suggest that susceptibility to SWD in the manufacturing industry may be associated with environmental and somatic factors related to falling asleep. PMID- 25787097 TI - Stress fracture of the navicular bone in a patient with cerebral palsy: a case report. AB - A 14-year-old girl with cerebral palsy (spastic diplegia) underwent examination due to a chief complaint of right foot pain, and was diagnosed with a stress fracture of the central one third of the navicular bone. The fracture was considered to have developed due to repeated loading on the navicular bone as a result of an equinus gait.Therefore, she underwent osteosynthesis and Achilles tendon lengthening to correct the equinus deformity. Following our review of the current literature, we did not identify any reports of stress fracture of the navicular bone in cerebral palsy. We believe that in cases where cerebral palsy patients with paralytic equinus complain of foot pain, the possibility of stress fracture of the navicular bone should be considered. PMID- 25787098 TI - Pregnancy after hysteroscopic metroplasty under laparoscopy in a woman with complete septate uterus: a case report. AB - A 31-year-old nulligravid woman with a 3 year history of infertility visited our hospital. After consultation and a transvaginal ultrasound and MR imaging, her uterine anomaly was identified as complete septate uterus: class V (a) by the American Fertility Society (AFS). She had a doubled uterine cervix and a vaginal septum. Hysteroscopic metroplasty was performed with the aid of a laparoscopy. Both tubal patencies were confirmed with indigocarmine in a laparoscopic image. Laparoscopic electronic cautery was also done on the left ovarian endometrioma (stage 1 endometriosis; the revised American Society for Reproductive Medicine (rASRM) classification 4 point minimal). We distrained an intrauterine device in the uterine cavity and removed it after two cycles of menstruation. The patient subsequently became pregnant during her third menstrual cycle and the current progress of her pregnancy is favorable. PMID- 25787099 TI - Work improvement factors for the amelioration of work ability, with a focus on individual capacity to deal with stress in an IT company. AB - The aim of this study was to explore factors that ameliorate work ability by focusing on workers' capacity to deal with stress.The subjects were 1,330 workers from the Japanese information technology (IT) sector. Each subject completed questionnaires in 2011 and 2012 that consisted of the work ability index (WAI), the three-item sense of coherence (SOC), and the Mental Health Improvement and Reinforcement Research of Recognition (MIRROR). The results of the WAI were also obtained in 2013. The median SOC score in 2011 was used to divide the subjects into two groups, the Low SOC group and the High SOC group, then we verified the factors that contributed to improved work ability in both of these groups over a two-year period. Results indicate that an improvement in work ability in the Low SOC group could be predicted by giving workers opportunities for education or training, by making efforts to reduce the stress of commuting, by clarifying their assignments, and by establishing support systems when troubles occur. For the High SOC group, such improvements could be predicted by giving workers job control, by giving education or training for the promotion of their abilities, and by establishing a system for assuming responsibility. In conclusion, improvements in the work environment can increase the work ability of Japanese IT workers in conformity with their capacity to deal with stress. PMID- 25787100 TI - Effects of various pharmacological agents on the function of norepinephrine transporter. AB - The norepinephrine transporter is selectively expressed in noradrenergic nerve terminals, where it can exert spatial and temporal control over the action of norepinephrine. The norepinephrine transporter mediates the termination of neurotransmission via the reuptake of norepinephrine released into the extracellular milieu. In the present brief review, we report our recent studies about the effects of various pharmacological agents such as fasudil, nicotine, pentazocine, ketamine and genistein on norepinephrine transporter function. PMID- 25787101 TI - Case of alcoholic ketoacidosis accompanied with severe hypoglycemia. AB - We report a 55 year old Japanese man with a history of alcohol abuse, who was in a near fasting state for the previous few days.He was admitted to our hospital with abrupt disturbance of consciousness. He presented disturbance of consciousness with extreme hypoglycemia and ketoacidosis with high beta hydroxybutyric acid concentration. Taking into account his living history, we diagnosed with alcoholic ketoacidosis (AKA). Symptoms ameliorated with glucose injection and fluid loading. AKA patients show abdominal pain, nausea or vomiting, but they are usually alert and lucid despite the severe acidosis. This case, however, presented comatose status caused by hypoglycemia. Poor oral intake of this patient was assumed to be the cause of hypoglycemia. Alcoholism may cause hypoglycemia accompanying with AKA, due to a low carbohydrate intake, the inhibition of gluconeogenesis, and reduced hepaticglycogen storage as seen in this case. Here, we report a case of AKA that demonstrated hypoglycemia with the literature review. PMID- 25787102 TI - [Case of graves' disease with remarkable psychiatric symptoms]. AB - A 42-year-old woman visited our hospital with palpitations, excessive sweating, and finger tremors in March 2011. She was diagnosed with Graves' disease based on the following test results: thyroid stimulating hormone < 0.01 MUU/ml, free thyroxine 6.15 ng/ml, and thyrotropin receptor antibody 7.8 U/ml. Treatment with methimazole 30 mg and propranolol 30 mg was started, and her thyroid function showed improvement. However, significant manic symptoms, irritability, hallucinations, and delusions were noted, and she was hospitalized for her own protection in May 2011. Although treatment with aripiprazole 24 mg and lithium 400 mg was started, the hallucinatory and delusional symptoms persisted, necessitating adjustment of the antipsychotics. Her psychiatric symptoms showed amelioration in July 2011 after improvement in her thyroid function, and she was discharged from our hospital. After discharge, her thyroid function remained normal with methimazole 10 mg, and administration of the antipsychotics was discontinued. Affective psychotic symptoms such as altered mood and activity are frequently observed in cases with Graves' disease, but there have been few reports describing cases with full-blown psychiatric disorders manifesting with features such as hallucinations and delusions as the chief symptoms requiring hospitalized treatment, as in the present case. In symptomatic psychosis associated with Graves' disease, prolonged psychiatric symptoms might develop, and close cooperation with psychiatrists is thus important. PMID- 25787103 TI - Secondary adrenocortical insufficiency complicated by marked hypercalcemia and eosinophilia: a case report. AB - A 56 year old female was admitted to a local hospital after developing symptoms, including generalized fatigue, nausea and vomiting, from trauma. She was relocated to our hospital because she developed other symptoms, including disturbance of consciousness from hypercalcemia and a rash over her entire body. Her clinical symptoms (disturbance of consciousness, loss of appetite, nausea, vomiting, decrease in blood pressure, fever) and examination findings (low blood cortisol levels (1.2 MUg/dl ), hypercalcemia (11.0 mg/dl ), peripheral blood eosinophilia (1,600 /MUl )) lead to a diagnosis of adrenal insufficiency. In addition, a skin biopsy indicated eosinophilic infiltration, although her condition improved in the end with an oral dose of 30 mg/day of prednisolone. Hypercalcemia and peripheral blood eosinophilia are commonly known examination findings for adrenocortical insufficiency, but it is rare for either of these to be present as clinical symptoms. PMID- 25787105 TI - There Is Something in the Air: Testing the Efficacy of a new Olfactory Stress Relief Method (AromaStick(r)). AB - In recent years, aromatherapy has become increasingly popular for clinical treatment and therapeutic management of both acute and chronic stress. It targets distinct and unique neurobiological characteristics of the olfactory system, which is tightly linked to emotions and information processing as well as the autonomous nervous system. Yet, depending on the mode of application, aromatherapeutic interventions show varying degrees of therapeutic effectiveness. In a series of five experiments, the effects of a new mode of aromatherapeutic application (inhaler) was investigated, which is specifically designed to directly stimulate the olfactory system and to reduce the activity of the sympathetic nervous system. Overall, the application of the inhaler showed consistent and large psychological and physiological effects. It also clearly outperformed other stress management techniques, like progressive muscle relaxation, Bach flowers or passive resting periods (natural control). The effects occurred shortly after very few inhalations, drastically reduced stress related biomarkers (i.e. blood pressure, heart rate and cortisol) and considerably enhanced well-being. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25787106 TI - Rituximab in the treatment of 38 patients with Pemphigus with long-term follow up. PMID- 25787107 TI - Facile fabrication of microsphere-polymer brush hierarchically three-dimensional (3D) substrates for immunoassays. AB - We propose a facile UV strategy to construct a hierarchically three-dimensional (3D) substrate that comprises a polystyrene (PS) microsphere layer on the cycloolefin polymer (COP) substrate and densely packed hydrophilic polymer brushes grafting from this 3D backbone. This hierarchical substrate gives a high antibody loading capacity and 3D manner of analyte capture, therefore enhancing detection signal while reducing background noise. PMID- 25787108 TI - Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl-2/Bax pathway. AB - OBJECTIVES: The aim of this study was to identify whether arsenic (As) exposure could induce hippocampal neural apoptosis in vivo. METHODS: Sixty-four mice were randomly divided into 4 groups of 16 each. Group 1 orally received drinking water alone as a control. Groups 2-4 were given arsenic trioxide (As2O3) orally at the doses of 1 ppm, 2 ppm and 4 ppm, respectively. All the treatments continued for 60 days. Morphological changes in the hippocampus were observed by HE staining. Apoptosis in the hippocampus was examined by TUNEL assay and transmission electron microscopy. The expression levels of Bcl-2 and Bax genes and their proteins in the hippocampus were determined by real-time PCR and Western blotting. The activity of caspase-3 was determined by spectrophotometry. RESULTS: Abnormal histopathological changes and apoptosis were found in the hippocampus of As-exposed mice. The expressions of the Bcl-2 gene and its protein in the hippocampus of As-exposed mice were significantly lower than those in the control group (p<0.05). However, the expressions of the Bax gene and its protein, and the expression ratio of Bax/Bcl-2 in the hippocampus were significantly higher in the groups exposed to As than in the control group (p<0.05). Moreover, the activity of caspase-3 in the hippocampus of mice exposed to As was higher than that in the control (p<0.05). CONCLUSIONS: These results indicate that subchronic exposure to As induces apoptosis in the hippocampus of mice by disturbing normal Bax/Bcl-2 regulatory pathways. Meanwhile, it is suggested that the induced apoptosis in the hippocampus may be at least partly responsible for As-induced neurotoxicity. PMID- 25787109 TI - Acute dermal toxicity and sensitization studies of novel nano-enhanced UV absorbers. AB - BACKGROUND: Many employees working outside are exposed to the harmful effects of UV radiation. A growing problem is also sensitization to textile materials and allergic reactions to active compounds. Groups of inorganic UV blockers with nanoparticles may provide superior properties over organic UV absorbers with relatively less potential of provoking dermatitis. OBJECTIVES: To assess acute dermal irritation and sensitization of nano UV absorbers. MATERIALS & METHODS: Five UV absorbers with nano-sized particles (Z11, TiO2 - SiO2 [TDPK], TK44, TK11, A8G) and 2 vehicles (paste-based on 10% PEG, and dispersion with 1% HEC) were tested. Acute dermal irritation was tested using group of 3 rabbits for each absorber. The sensitization study was carried out on groups of 15 guinea pigs for each tested textile with a UV absorber showing an Ultraviolet Protection Factor (UPF)>40. This research was designed according to OECD Test Guideline No. 404 and 406, and 21 rabbits and 60 guinea pigs were used in the study. RESULTS: In acute dermal irritation, Z11 and A8G modifiers and the analyzed paste gave results of 0.047 to 0.33 which classifies them as barely perceptible irritants, whereas the other analyzed modifiers and dispersion gave results of 0.00 and were classified as nonirritating. Only the textile with TK 11 did not have UPF>40. The analyzed barrier materials were classified as nonsenitizers (TDPK, A8G) or mild sensitizers (TK44, Z11). CONCLUSIONS: None of the analyzed materials or modifiers induced major skin reactions in animals. Therefore, they present low risk of provoking skin reactions in humans. PMID- 25787110 TI - Intra- and intermolecular dispersion interactions in [N]cycloparaphenylenes: do they influence their structural and electronic properties? AB - Cycloparaphenylenes (CPPs) are nanosized structures with unique isolated and bulk properties, and are synthetic targets for the template-driven bottom-up synthesis of carbon nanotubes. Thus, a systematic understanding of the supramolecular order at the nanoscale is of utmost relevance for molecular engineering. In this study, it is found that intramolecular noncovalent (dispersion) interactions must be taken into account for obtaining accurate estimates of the structural and optoelectronic properties of [n]CPP compounds, and their influence as the number of repeat units increases from n=4 to n=12 is also analyzed, both in the gas phase and in solution. The supramolecular self-assembly, for which both intra- and intermolecular noncovalent interactions are relevant, of [6]CPP is also investigated by calculating the binding energies of dimers taken along several crystal directions. These are also used to estimate the cohesive energy of the crystal, which is compared to the value obtained by means of dispersion-corrected DFT calculations using periodic boundary conditions. The reasonable agreement between both computational strategies points towards a first estimate of the [6]CPP cohesive energy of around 50 kcal mol(-1) . PMID- 25787111 TI - Construction and characterization of yeast two-hybrid cDNA library derived from LFBK cell line. AB - The cDNA libraries are indispensable and critical tools for performing protein protein interaction studies. In this study, a high quality yeast two-hybrid cDNA library from the LFBK cell line was constructed and characterized. LFBK cell line was originally derived from the swine kidney cells and is highly susceptible to foot-and-mouth disease virus (FMDV) infection. The total RNA was extracted from the LFBK cells and the switching mechanism at the 5' end of RNA template (SMART) technique was employed for the cDNA synthesis. Subsequently, double stranded cDNA was amplified by long-distance PCR, purified and co-transformed with pGADT7-rec vector in yeast strain Y187. The quality parameters of the constructed library were evaluated to qualify the constructed library. Nucleotide sequencing of the randomly selected clones from the library confirmed the swine genotype of LFBK cell line. The LFBK cDNA library was mated with the 2C protein of FMDV in yeast two-hybrid (YTH) system and several putative interaction partners were identified in the preliminary screening. The LFBK library was observed to be of high quality and could potentially be applied to protein interaction studies between FMDV and the host cells using YTH system. PMID- 25787112 TI - Update on Neurological Manifestations of HTLV-1 Infection. AB - The human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects 10-20 million persons around the world. Initially associated with the hematological malignancy adult T cell leukemia/lymphoma (ATLL), HTLV-1 is also the cause of a chronic progressive myelopathy named "HTLV-1-associated myelopathy/tropical spastic paraparesis" (HAM/TSP). HAM/TSP arises as the tip of the iceberg of an assortment of neurological syndromes triggered by the virus such as inflammatory myopathies, polyneuropathies, amyotrophic lateral sclerosis (ALS)-like syndromes, dysautonomia, and cognitive impairment. HAM/TSP typifies a chronic progressive spastic paraparesis with neurogenic bladder and minimal sensory signs. The neuropathology of HAM/TSP is concentrated in the thoracic spinal cord and is typically biphasic. Initially, there is a perivascular lymphocytic cuffing and mild parenchymal mononuclear infiltrates. Subsequently, this is replaced by gliosis and scarring. The neuropathogenesis of HTLV-1 is still partially understood. At present, the therapy of HAM/TSP remains basically symptomatic. PMID- 25787113 TI - Role of taurine in the pathogenesis of obesity. AB - Taurine is a sulfur-containing amino acid that is present in mammalian tissues in millimolar concentrations. Taurine is involved in a diverse array of biological and physiological functions, including bile salt conjugation, osmoregulation, membrane stabilization, calcium modulation, anti-oxidation, and immunomodulation. The prevalence of obesity and being overweight continues to rise worldwide at an alarming rate. Obesity is associated with a higher risk of metabolic and cardiovascular diseases, cancer, and other clinical conditions. Ingestion of taurine has been shown to alleviate metabolic diseases such as hyperlipidemia, diabetes, hypertension, and obesity in animal models. A global epidemiological survey showed that 24-h urinary taurine excretion, as a marker of dietary taurine intake, was inversely associated with BMI, blood pressure, and plasma cholesterol in humans. In addition, taurine chloramine, an endogenous product derived from activated neutrophils, has been reported to suppress obesity-induced oxidative stress and inflammation in adipocytes. Synthetic activity and concentration of taurine in adipose tissues and plasma have been shown to decrease in humans and animals during the development of obesity, suggesting a relationship between taurine deficiency and obesity. In this review, I summarize the effects of taurine on the progression of obesity in animal models and humans. Furthermore, I discuss possible mechanisms underlying the antiobesity effects of taurine. PMID- 25787114 TI - Prevalence of morphological and mechanical stiffness alterations of mid Achilles tendons in asymptomatic marathon runners before and after a competition. AB - OBJECTIVE: To determine the prevalence of morphological and mechanical stiffness alterations at the mid Achilles tendon in asymptomatic marathon runners before and after a competition. To assess the relationship between pre-existing Achilles tendon alterations and pain after running. MATERIALS AND METHODS: All marathon runners from a local running club who were participating in the Melbourne Marathon 2013 (full marathon category) were invited for conventional ultrasound and sonoelastography 1 week leading up to the marathon and again within 3 days post-marathon. Another group of active, healthy individuals not involved in running activities were recruited as controls. Intratendinous morphological (tendon thickness, hypoechogenicities), Doppler as well as stiffness properties of the Achilles were recorded. Achilles tendon pain was evaluated using the visual analogue scale (VAS) and Victorian Institute of Sports Assessment-Achilles (VISA-A). RESULTS: Twenty-one asymptomatic runners (42 Achilles tendons) and 20 healthy controls (40 Achilles tendons) were examined. On the pre-marathon evaluation, runners showed significantly more morphological changes on B-mode ultrasound compared to the controls (p < 0.001). Marathon running induced a significant reduction in tendon stiffness (p = 0.049) and an increase in Doppler signals (p = 0.036). Four runners (4/21, 19%) reported Achilles tendon pain after the race [VAS 4.0 (+/-1.9), VISA 74.2 (+/-10.1)]. Reduced tendon stiffness at baseline was associated with post-marathon Achilles tendon pain (p = 0.016). CONCLUSION: Marathon runners demonstrate a higher prevalence of morphological alterations compared to non-runners. Marathon running caused a significant change in Achilles tendon stiffness and Doppler signals. Pre-existing soft Achilles tendon properties on sonoelastography may be a predisposing risk for development of symptoms post-running. PMID- 25787115 TI - Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth. AB - Emerging evidence shows that glioblastoma multiforme (GBM) originates from cancer stem cells (CSCs). Characterization of CSC-specific signalling pathways would help identify new therapeutic targets and perhaps lead to the development of more efficient therapies selectively targeting CSCs. Here; we successfully dedifferentiated two patient-derived GBM cell lines into CSC-like cells (induced glioma stem cells, iGSCs) through expression of Oct4, Sox2 and Nanog transcription factors. Transformed cells exhibited significant suppression of epidermal growth factor receptor and its downstream pathways. Compared with parental GBM cells, iGSCs formed large neurospheres even in the absence of exogenous mitogens; they exhibited significant sensitivity to salinomycin and chemoresistance to temozolomide. Further characterization of iGSCs revealed induction of NOTCH1 and Wnt/beta-catenin signalling and expression of CD133, CD44 and ALDH1A1. Our results indicate that iGSCs may help us understand CSC physiology and lead to development of potential therapeutic interventions aimed at differentiating tumour cells to render them more sensitive to chemotherapy or other standard agents. PMID- 25787116 TI - Household Animal and Human Medicine Use and Animal Husbandry Practices in Rural Bangladesh: Risk Factors for Emerging Zoonotic Disease and Antibiotic Resistance. AB - Animal antimicrobial use and husbandry practices increase risk of emerging zoonotic disease and antibiotic resistance. We surveyed 700 households to elicit information on human and animal medicine use and husbandry practices. Households that owned livestock (n = 265/459, 57.7%) reported using animal treatments 630 times during the previous 6 months; 57.6% obtained medicines, including antibiotics, from drug sellers. Government animal healthcare providers were rarely visited (9.7%), and respondents more often sought animal health care from pharmacies and village doctors (70.6% and 11.9%, respectively), citing the latter two as less costly and more successful based on past performance. Animal husbandry practices that could promote the transmission of microbes from animals to humans included the following: the proximity of chickens to humans (50.1% of households reported that the chickens slept in the bedroom); the shared use of natural bodies of water for human and animal bathing (78.3%); the use of livestock waste as fertilizer (60.9%); and gender roles that dictate that females are the primary caretakers of poultry and children (62.8%). In the absence of an effective animal healthcare system, villagers must depend on informal healthcare providers for treatment of their animals. Suboptimal use of antimicrobials coupled with unhygienic animal husbandry practices is an important risk factor for emerging zoonotic disease and resistant pathogens. PMID- 25787117 TI - Frequency of food group consumption and risk of allergic disease and sensitization in schoolchildren in urban and rural China. AB - BACKGROUND: Diet is a potential determinant of allergic diseases. OBJECTIVE: To examine in schoolchildren the association between food intake and allergic diseases and determine whether there is effect of environment - rural vs. urban. METHODS: A questionnaire survey was performed in 11 473 children aged 7-12 years in 20 schools from urban Guangzhou and rural Shaoguan, China. A nested case control group, 402 from Guangzhou and 349 from Shaoguan, was recruited. Food ingestion frequency data were collected. Serum-specific IgE to 34 food and airborne allergens was determined. Associations between food ingestion frequency and clinical outcomes were sought by logistic analyses. RESULTS: The prevalence of self-reported asthma (6.6% vs. 2.5%), rhinitis (23.2% vs. 5.3%) and eczema (34.1% vs. 25.9%) was significantly higher in Guangzhou subjects compared to Shaoguan, whereas prevalence of food hypersensitivity (9.7% vs. 9.2%) and food allergy (4.0% vs. 3.5%) was not significantly different. In this case-control study, seafood and fruits were two major food groups causing food hypersensitivity. Urban children consumed more milk, egg, chocolate, fruits, vegetable and cereals compared to rural children. Significantly higher percentage of Guangzhou children was sensitized to egg and milk, whereas more Shaoguan children were sensitized to seafood, nuts and seeds, fruit, vegetables, legumes and cereals. High consumption of milk (OR 2.604, 95 CI% 1.569-4.322, P < 0.001) and vegetables (OR 0.382, 95% CI 0.180-0.809, P = 0.012) were positively and reversely associated with asthma, respectively. CONCLUSION: Difference in prevalence of asthma but not food allergy was observed. Diets of schoolchildren are affected by disease-related modification and country's urbanization. High vegetable intake and low milk intake might protect against asthma. PMID- 25787119 TI - High prevalence of increased nerve vascularization in healthy individuals. PMID- 25787118 TI - A novel Cre recombinase reporter mouse strain facilitates selective and efficient infection of primary immune cells with adenoviral vectors. AB - Replication-deficient recombinant adenoviruses are potent vectors for the efficient transient expression of exogenous genes in resting immune cells. However, most leukocytes are refractory to efficient adenoviral transduction as they lack expression of the coxsackie/adenovirus receptor (CAR). To circumvent this obstacle, we generated the R26/CAG-CARDelta1(StopF) (where R26 is ROSA26 and CAG is CMV early enhancer/chicken beta actin promoter) knock-in mouse line. This strain allows monitoring of in situ Cre recombinase activity through expression of CARDelta1. Simultaneously, CARDelta1 expression permits selective and highly efficient adenoviral transduction of immune cell populations, such as mast cells or T cells, directly ex vivo in bulk cultures without prior cell purification or activation. Furthermore, we show that CARDelta1 expression dramatically improves adenoviral infection of in vitro differentiated conventional and plasmacytoid dendritic cells (DCs), basophils, mast cells, as well as Hoxb8-immortalized hematopoietic progenitor cells. This novel dual function mouse strain will hence be a valuable tool to rapidly dissect the function of specific genes in leukocyte physiology. PMID- 25787120 TI - Caterpillar-Inspired Design and Fabrication of A Self-Walking Actuator with Anisotropy, Gradient, and Instant Response. AB - A caterpillar-mimetic bilayer actuator is reported, based on a wrinkled polydimethylsiloxane elastomer decorated with a hydroresponsive polyelectrolyte brush. The actuator can fold ultrafast into complex three-dimensional structures upon a change in relative humidity of the surrounding air. The folding direction is determined by the geometry of the actuator, the orientation of the wrinkles, and the gradient in polymer height on the surface. And some unique structures such as helicoid and gradient can be obtained that are seldom reported in the case of bilayered devices. The adaptive bending movement is very fast, anisotropic, highly efficient, and reversible. When the environmental humidity is repeatedly cycled up and down, the small device walks on a surface with a roughness gradient, which is reminiscent of the muscle-like movements. PMID- 25787121 TI - Efficacy of locally-delivered 1% metformin gel in the treatment of intrabony defects in patients with chronic periodontitis: a randomized, controlled clinical trial. AB - OBJECTIVE: Metformin (MF), used for the treatment of type 2 diabetes mellitus, has shown to possess properties favoring osteoblastic proliferation. The present study was designed to investigate the effectiveness of MF 1% gel as an adjunct to scaling and root planing in the treatment of intrabony defects in patients with chronic periodontitis. METHODS: The study comprised 65 individuals divided into two groups: 1% MF with SRP and placebo gel with SRP. Clinical parameters were evaluated at baseline, 3 months, and 6 months; they included plaque index, modified sulcus bleeding index, probing depth (PD), and clinical attachment level (CAL). Intrabony defect depth (IBD) was evaluated at the end of 6 months using computer-aided software. RESULTS: The mean PD reduction, CAL gain, and IBD depth reduction were found to be greater in the MF group than in the placebo group at all visits. The percentage of defect depth reduction was significantly greater in the MF group (26.8 +/- 5.52%) than in the placebo sites (4.79 +/- 2.30%, P < 0.001). CONCLUSION: One percent MF was found to significantly improve clinical and radiographic parameters in intrabony defects in patients with chronic periodontitis. PMID- 25787122 TI - Immobilized catalysts for iridium-catalyzed allylic amination: rate enhancement by immobilization. AB - The first immobilized catalyst for Ir-catalyzed asymmetric allylic aminations is described. The catalyst is a cationic (pi-allyl)Ir complex bound by cation exchange to an anionic silica gel support. Preparation of the catalyst is facile, and the supported catalyst displayed considerably enhanced activity compared with the parent homogeneous catalyst. Up to 43 consecutive amination runs were possible in recycling experiments. PMID- 25787123 TI - Measurement of tumor blood flow in head and neck squamous cell carcinoma by pseudo-continuous arterial spin labeling: comparison with dynamic contrast enhanced MRI. AB - PURPOSE: To investigate the feasibility of tumor blood flow (TBF) measurement in head and neck squamous cell carcinoma (HNSCC) using pseudo-continuous arterial spin labeling (pCASL) in a comparison with dynamic contrast-enhanced (DCE) perfusion. MATERIALS AND METHODS: We prospectively scanned 18 patients with HNSCC using 3T magnetic resonance imaging (MRI) with both pCASL and DCE perfusion. Quantitative TBF value in the whole-tumor region of interest (ROI), and regional TBF in the ROIs of the central and peripheral areas in the tumor were respectively measured. Relative TBF value in the whole-tumor ROI was also calculated. We determined the correlation and agreement between each measured TBF by pCASL and DCE perfusion using Pearson's correlation coefficients, intraclass correlation coefficients (ICC), and Bland-Altman analysis. RESULTS: In the whole tumor ROIs, significant correlation was observed between the absolute TBF values (r = 0.72, P < 0.01), with an ICC of 0.72; moreover, higher correlation was observed in the relative TBF (r = 0.79). The correlation was higher in the peripheral ROI (r = 0.70) than the central ROI (r = 0.65), with an ICC of 0.62 and 0.54, respectively. Bland-Altman plots revealed the underestimation of TBF by pCASL in central ROIs. CONCLUSION: TBF measurement by pCASL was feasible in patients with HNSCC. J. Magn. Reson. Imaging 2015;41:1-1. (c) 2014 Wiley Periodicals, Inc. PMID- 25787125 TI - World Bank Group's support to the Ebola virus response effort. PMID- 25787124 TI - Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines. AB - Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown. Using an unbiased proteomic approach, we investigated the effects of chronic intermittent ethanol (CIE) exposure on neuroadaptations in postsynaptic density (PSD)-enriched proteins in the NAc of ethanol-dependent mice. Compared with controls, CIE exposure significantly changed expression levels of 50 proteins in the PSD-enriched fraction. Systems biology and functional annotation analyses demonstrated that the dysregulated proteins are expressed at tetrapartite synapses and critically regulate cellular morphology. To confirm this latter finding, the density and morphology of dendritic spines were examined in the NAc core of ethanol-dependent mice. We found that CIE exposure and withdrawal differentially altered dendrite diameter and dendritic spine density and morphology. Through the use of quantitative proteomics and functional annotation, these series of experiments demonstrate that ethanol dependence produces neuroadaptations in proteins that modify dendritic spine morphology. In addition, these studies identified novel PSD-related proteins that contribute to the neurobiological mechanisms of ethanol dependence that drive maladaptive structural plasticity of NAc neurons. PMID- 25787127 TI - Ternary Ag/MgO-SiO2 catalysts for the conversion of ethanol into butadiene. PMID- 25787130 TI - Rosuvastatin: winner in the statin wars, patients' health notwithstanding. PMID- 25787126 TI - Cell Mechanosensitivity to Extremely Low-Magnitude Signals Is Enabled by a LINCed Nucleus. AB - A cell's ability to recognize and adapt to the physical environment is central to its survival and function, but how mechanical cues are perceived and transduced into intracellular signals remains unclear. In mesenchymal stem cells (MSCs), high-magnitude substrate strain (HMS, >=2%) effectively suppresses adipogenesis via induction of focal adhesion (FA) kinase (FAK)/mTORC2/Akt signaling generated at FAs. Physiologic systems also rely on a persistent barrage of low-level signals to regulate behavior. Exposing MSC to extremely low-magnitude mechanical signals (LMS) suppresses adipocyte formation despite the virtual absence of substrate strain (<0.001%), suggesting that LMS-induced dynamic accelerations can generate force within the cell. Here, we show that MSC response to LMS is enabled through mechanical coupling between the cytoskeleton and the nucleus, in turn activating FAK and Akt signaling followed by FAK-dependent induction of RhoA. While LMS and HMS synergistically regulated FAK activity at the FAs, LMS-induced actin remodeling was concentrated at the perinuclear domain. Preventing nuclear actin cytoskeleton mechanocoupling by disrupting linker of nucleoskeleton and cytoskeleton (LINC) complexes inhibited these LMS-induced signals as well as prevented LMS repression of adipogenic differentiation, highlighting that LINC connections are critical for sensing LMS. In contrast, FAK activation by HMS was unaffected by LINC decoupling, consistent with signal initiation at the FA mechanosome. These results indicate that the MSC responds to its dynamic physical environment not only with "outside-in" signaling initiated by substrate strain, but vibratory signals enacted through the LINC complex enable matrix independent "inside-inside" signaling. PMID- 25787131 TI - Agminated flexural melanocytic nevi: a late sequela of Langerhans cell histiocytosis? AB - Agminated flexural melanocytic nevi in children with a history of Langerhans cell histiocytosis (LCH) are rare and thought to be coincidental or related to systemic chemotherapy. We report on an 11-year-old boy in remission from LCH, treated with only topical steroids, who presented years later with an eruption of melanocytic nevi in the bilateral inguinal and axillary regions. Rather than coincidence, we hypothesize that agminated flexural melanocytic nevi are a late sequela of LCH, possibly resulting from immune tolerance or a reaction to local inflammation. PMID- 25787132 TI - Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. AB - BACKGROUND: Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy. METHODS AND RESULTS: We identified a proband with an epileptic encephalopathy, complex movement disorder and a combined mitochondrial respiratory chain enzyme deficiency. The child presented with neurological regression, complex movement disorder and intractable seizures. A combined deficiency of mitochondrial complexes I, III and IV was noted in liver tissue, along with increased mitochondrial DNA content in skeletal muscle. Incomplete assembly of complex V, using blue native polyacrylamide gel electrophoretic analysis and complex I, using western blotting, suggested a disorder of mitochondrial transcription or translation. Exome sequencing identified compound heterozygous mutations in CARS2, a mitochondrial aminoacyl tRNA synthetase. Both mutations affect highly conserved amino acids located within the functional ligase domain of the cysteinyl-tRNA synthase. A specific decrease in the amount of charged mt-tRNA(Cys) was detected in patient fibroblasts compared with controls. Retroviral transfection of the wild-type CARS2 into patient skin fibroblasts led to the correction of the incomplete assembly of complex V, providing functional evidence for the role of CARS2 mutations in disease aetiology. CONCLUSIONS: Our findings indicate that mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy. PMID- 25787133 TI - Mechanical cues in orofacial tissue engineering and regenerative medicine. AB - Cleft lip and palate patients suffer from functional, aesthetical, and psychosocial problems due to suboptimal regeneration of skin, mucosa, and skeletal muscle after restorative cleft surgery. The field of tissue engineering and regenerative medicine (TE/RM) aims to restore the normal physiology of tissues and organs in conditions such as birth defects or after injury. A crucial factor in cell differentiation, tissue formation, and tissue function is mechanical strain. Regardless of this, mechanical cues are not yet widely used in TE/RM. The effects of mechanical stimulation on cells are not straight-forward in vitro as cellular responses may differ with cell type and loading regime, complicating the translation to a therapeutic protocol. We here give an overview of the different types of mechanical strain that act on cells and tissues and discuss the effects on muscle, and skin and mucosa. We conclude that presently, sufficient knowledge is lacking to reproducibly implement external mechanical loading in TE/RM approaches. Mechanical cues can be applied in TE/RM by fine tuning the stiffness and architecture of the constructs to guide the differentiation of the seeded cells or the invading surrounding cells. This may already improve the treatment of orofacial clefts and other disorders affecting soft tissues. PMID- 25787134 TI - Initial design and physical characterization of a polymeric device for osmosis driven delayed burst delivery of vaccines. AB - Achieving the combination of delayed and immediate release of a vaccine from a delivery device without applying external triggers remains elusive in implementing single administration vaccination strategies. Here a means of vaccine delivery is presented, which exploits osmosis to trigger delayed burst release of an active compound. Poly(epsilon-caprolactone) capsules of 2 mm diameter were prepared by dip-coating, and their burst pressure and release characteristics were evaluated. Burst pressures (in bar) increased with wall thickness (t in mm) following Pburst = 131(.) t + 3(.) 4 (R(2) = 0.93). Upon immersion in PBS, glucose solution-filled capsules burst after 8.7 +/- 2.9 days. Copolymers of hydrophobic epsilon -caprolactone and hydrophilic polyethylene glycol were synthesized and their physico-chemical properties were assessed. With increasing hydrophilic content, the copolymer capsules showed increased water uptake rates and maximum weight increase, while the burst release was earlier: 5.6 +/- 2.0 days and 1.9 +/- 0.2 days for 5 and 10 wt% polyethylene glycol, respectively. The presented approach enables the reproducible preparation of capsules with high versatility in materials and properties, while these vaccine delivery vehicles can be prepared separately from, and independently of the active compound. PMID- 25787135 TI - Generation and Characterization of Human Monoclonal Antibodies Targeting Anthrax Protective Antigen following Vaccination with a Recombinant Protective Antigen Vaccine. AB - The anthrax protective antigen (PA) is the central component of the three-part anthrax toxin, and it is the primary immunogenic component in the approved AVA anthrax vaccine and the "next-generation" recombinant PA (rPA) anthrax vaccines. Animal models have indicated that PA-specific antibodies (AB) are sufficient to protect against infection with Bacillus anthracis. In this study, we investigated the PA domain specificity, affinity, mechanisms of neutralization, and synergistic effects of PA-specific antibodies from a single donor following vaccination with the rPA vaccine. Antibody-secreting cells were isolated 7 days after the donor received a boost vaccination, and 34 fully human monoclonal antibodies (hMAb) were identified. Clones 8H6, 4A3, and 22F1 were able to neutralize lethal toxin (LeTx) both in vitro and in vivo. Clone 8H6 neutralized LeTx by preventing furin cleavage of PA in a dose-dependent manner. Clone 4A3 enhanced degradation of nicked PA, thereby interfering with PA oligomerization. The mechanism of 22F1 is still unclear. A fourth clone, 2A6, that was protective only in vitro was found to be neutralizing in vivo in combination with a toxin enhancing antibody, 8A7, which binds to domain 3 of PA and PA oligomers. These results provide novel insights into the antibody response elicited by the rPA vaccine and may be useful for PA-based vaccine and immunotherapeutic cocktail design. PMID- 25787136 TI - Identification of pertussis-specific effector memory T cells in preschool children. AB - Whooping cough remains a problem despite vaccination, and worldwide resurgence of pertussis is evident. Since cellular immunity plays a role in long-term protection against pertussis, we studied pertussis-specific T-cell responses. Around the time of the preschool acellular pertussis (aP) booster dose at 4 years of age, T-cell memory responses were compared in children who were primed during infancy with either a whole-cell pertussis (wP) or an aP vaccine. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with pertussis vaccine antigens for 5 days. T cells were characterized by flow-based analysis of carboxyfluorescein succinimidyl ester (CFSE) dilution and CD4, CD3, CD45RA, CCR7, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) expression. Before the aP preschool booster vaccination, both the proliferated pertussis toxin (PT)-specific CD4(+) and CD8(+) T-cell fractions (CFSE(dim)) were higher in aP- than in wP-primed children. Post-booster vaccination, more pertussis-specific CD4(+) effector memory cells (CD45RA(-) CCR7(-)) were induced in aP-primed children than in those primed with wP. The booster vaccination did not appear to significantly affect the T-cell memory subsets and functionality in aP-primed or wP-primed children. Although the percentages of Th1 cytokine producing cells were alike in aP- and wP-primed children pre-booster vaccination, aP-primed children produced more Th1 cytokines due to higher numbers of proliferated pertussis-specific effector memory cells. At present, infant vaccinations with four aP vaccines in the first year of life result in pertussis specific CD4(+) and CD8(+) effector memory T-cell responses that persist in children until 4 years of age and are higher than those in wP-primed children. The booster at 4 years of age is therefore questionable; this may be postponed to 6 years of age. PMID- 25787139 TI - Persistent Median Artery As A Cause Of Nonmaturing AV Fistula. AB - A 68-year-old right handed male with End-Stage Renal Disease with a left radiocephalic fistula created 8 months ago was referred for the evaluation of a nonmaturing access. Patient had an arterial anastomosis lesion that underwent successful angioplasty. Diagnostic arteriogram of the AV access extremity revealed the presence of a short radial artery and dominant common interosseous artery manifesting as a persistent median artery in the distal forearm and was anastomosed to the fistula and then continues as the median-ulnar superficial arch in the palm. Balloon angioplasty of the common interosseous artery led to a complication when the distal 30 cm of the 0.018 guide wire fractured and had to be retrieved using a snare device. In addition to anticipating and treating the common complications of vascular access procedures, it is also important to be aware of the anomalies of the distal forearm arterial anatomy and perform a detailed arterial evaluation prior to creating the arterio-venous anastomosis. PMID- 25787137 TI - Vaccines for Nontypeable Haemophilus influenzae: the Future Is Now. AB - Infections due to nontypeable Haemophilus influenzae result in enormous global morbidity in two clinical settings: otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD). Recurrent otitis media affects up to 20% of children and results in hearing loss, delays in speech and language development and, in developing countries, chronic suppurative otitis media. Infections in people with COPD result in clinic and emergency room visits, hospital admissions, and respiratory failure. An effective vaccine would prevent morbidity, help control health care costs, and reduce antibiotic use, a major contributor to the global crisis in bacterial antibiotic resistance. The widespread use of the pneumococcal conjugate vaccines is causing a relative increase in H. influenzae otitis media. The partial protection against H. influenzae otitis media induced by the pneumococcal H. influenzae protein D conjugate vaccine represents a proof of principle of the feasibility of a vaccine for nontypeable H. influenzae. An ideal vaccine antigen should be conserved among strains, have abundant epitopes on the bacterial surface, be immunogenic, and induce protective immune responses. Several surface proteins of H. influenzae have been identified as potential vaccine candidates and are in various stages of development. With continued research, progress toward a broadly effective vaccine to prevent infections caused by nontypeable H. influenzae is expected over the next several years. PMID- 25787138 TI - High-level cellular and humoral immune responses in Guinea pigs immunized intradermally with a heat-inactivated varicella-zoster virus vaccine. AB - The threat of varicella and herpes zoster in immunocompromised individuals necessitates the development of a safe and effective varicella-zoster virus (VZV) vaccine. The immune responses of guinea pigs to the intradermal (i.d.) or subcutaneous (s.c.) administration of a heat-inactivated or live VZV vaccine were investigated. Relative to nonimmunized animals, a single 399-PFU dose of vaccine induced nonsignificant increases in gamma interferon (IFN-gamma), granzyme B, and perforin mRNA expression in the splenocytes of all groups, while two i.d. administrations of the inactivated vaccine increased IFN-gamma mRNA expression significantly (P < 0.005). A single 1,995-PFU dose significantly increased the expression of IFN-gamma mRNA in the groups receiving the vaccine either i.d. (P < 0.005) or s.c. (P < 0.05), that of granzyme B mRNA in the groups immunized i.d. with the inactivated (P < 0.005) or live (P < 0.005) vaccine, and that of perforin mRNA in the animals that received the inactivated vaccine i.d. (P < 0.005). Importantly, increases in the expression of IFN-gamma (P = 0.025), granzyme B (P = 0.004), and perforin (P > 0.05) mRNAs were observed in the animals immunized i.d. with 1,995 PFU of inactivated vaccine relative to those immunized s.c. with the same dose. The proportion of animals expressing IFN-gamma mRNA mirrored the proportion expressing IFN-gamma protein (correlation coefficient of 0.88). VZV glycoprotein-specific and virus-neutralizing antibodies were produced with no significant intergroup differences. A booster i.d. administration of the 399-PFU dose of heat-inactivated vaccine enhanced the antibody responses. These results demonstrate that i.d. administration of an inactivated VZV vaccine can be an efficient mode of immunization against VZV. PMID- 25787140 TI - Networks of prospective thoughts: The organisational role of emotion and its impact on well-being. AB - Recent research has shown that many prospective thoughts are organised in networks of related events, but the relational dimensions that contribute to the formation of such networks are not fully understood. Here, we investigated the organisational role of emotion by using cues of different valence for eliciting event networks. We found that manipulating the emotional valence of cues influenced the characteristics of events within networks, and that members of a network were more similar to each other on affective components than they were to members of other networks. Furthermore, a substantial proportion of events within networks were part of thematic clusters and cluster membership significantly modulated the impact of represented events on current well-being, in part through an intensification of the emotion felt when thinking about these events. These findings demonstrate that emotion contributes to the organisation of future thoughts in networks that can affect people's well-being. PMID- 25787141 TI - Deoxynivalenol (Vomitoxin)-Induced Cholecystokinin and Glucagon-Like Peptide-1 Release in the STC-1 Enteroendocrine Cell Model Is Mediated by Calcium-Sensing Receptor and Transient Receptor Potential Ankyrin-1 Channel. AB - Food refusal is a hallmark of exposure of experimental animals to the trichothecene mycotoxin deoxynivalenol (DON), a common foodborne contaminant. Although studies in the mouse suggest that DON suppresses food intake by aberrantly inducing the release of satiety hormones from enteroendocrine cells (EECs) found in the gut epithelium, the underlying mechanisms for this effect are not understood. To address this gap, we employed the murine neuroendocrine tumor STC-1 cell line, a widely used EEC model, to test the hypothesis that DON-induced hormone exocytosis is mediated by G protein-coupled receptor (GPCR)-mediated Ca(2+) signaling. The results indicate for the first time that DON elicits Ca(2) dependent secretion of cholecystokinin (CCK) and glucagon-like peptide-1(7-36) amide (GLP-1), hormones that regulate food intake and energy homeostasis and that are products of 2 critical EEC populations--I cells of the small intestine and L cells of the large intestine, respectively. Furthermore, these effects were mediated by the GPCR Ca(2+)-sensing receptor (CaSR) and involved the following serial events: (1)PLC-mediated activation of the IP3 receptor and mobilization of intracellular Ca(2+) stores, (2) activation of transient receptor potential melastatin-5 ion channel and resultant L-type voltage-sensitive Ca(2+) channel facilitated extracellular Ca(2+) entry, (3) amplification of extracellular Ca(2+) entry by transient receptor potential ankyrin-1 channel activation, and finally (4) Ca(2+)-driven CCK and GLP-1 excytosis. These in vitro findings provide a foundation for future investigation of mechanisms by which DON and other trichothecenes modulate EEC function in ex vivo and in vivo models. PMID- 25787142 TI - Evaluating the dual target binding capabilities of immobilized aptamers using flow cytometry. AB - In the current study, the authors quantify the binding activity of particle immobilized DNA aptamers to their nucleotide and non-nucleotide targets. For the purposes of this work, DNA and vascular endothelial growth factor (VEGF) binding analysis was carried out for VEGF-binding aptamers and compared to that of an ampicillin-binding aptamer as well as a non-aptamer DNA probe. Binding analysis followed incubation of one target type, coincubation of both DNA and VEGF targets, and serial incubations of each target type. Moreover, recovery of aptamer binding activity following displacement of the DNA target from aptamer:DNA duplexes was also explored. Flow cytometry served as the quantitative tool to directly monitor binding events of both the DNA target and protein target to the various aptamer and non-aptamer functionalized particles. The current work demonstrates how processing steps such as annealing and binding history of particle-immobilized aptamers can affect subsequent binding activity. To this end, the authors demonstrate the ability to fully recover DNA target binding activity capabilities and to partially recover protein target binding activity. PMID- 25787144 TI - Goodness-of-fit tests and model diagnostics for negative binomial regression of RNA sequencing data. AB - This work is about assessing model adequacy for negative binomial (NB) regression, particularly (1) assessing the adequacy of the NB assumption, and (2) assessing the appropriateness of models for NB dispersion parameters. Tools for the first are appropriate for NB regression generally; those for the second are primarily intended for RNA sequencing (RNA-Seq) data analysis. The typically small number of biological samples and large number of genes in RNA-Seq analysis motivate us to address the trade-offs between robustness and statistical power using NB regression models. One widely-used power-saving strategy, for example, is to assume some commonalities of NB dispersion parameters across genes via simple models relating them to mean expression rates, and many such models have been proposed. As RNA-Seq analysis is becoming ever more popular, it is appropriate to make more thorough investigations into power and robustness of the resulting methods, and into practical tools for model assessment. In this article, we propose simulation-based statistical tests and diagnostic graphics to address model adequacy. We provide simulated and real data examples to illustrate that our proposed methods are effective for detecting the misspecification of the NB mean-variance relationship as well as judging the adequacy of fit of several NB dispersion models. PMID- 25787145 TI - Apathy in Parkinson's disease: A systematic review and meta-analysis. AB - Apathy is a frequently reported neuropsychiatric symptom in Parkinson's disease (PD), but its prevalence and clinical correlates are debated. We aimed to address these issues by conducting a systematic review and meta-analysis. Embase, Medline/PubMed, and PsychINFO databases were searched for relevant studies. Data were extracted by two independent observers, using predefined extraction forms tailored specifically to the research question. From 1,702 titles and abstracts, 23 studies were selected. Meta-analysis showed a prevalence of apathy in PD of 39.8% (n = 5,388, 905% CI 34.6-45.0%). Apathy was associated with higher age (3.3 years, 95% CI = 1.7-4.9), lower mean Mini-Mental State Evaluation (MMSE) score ( 1.4 points, 95% CI = -2.1 to -0.8), an increased risk of co-morbid depression (relative risk [RR] = 2.3, 95% CI = 1.9-2.8), higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (6.5 points, 95% CI = 2.6-10.3), and more severe disability (Hedges-G = 0.5, 95% CI = 0.3-0.6). Half of the patients with apathy had concomitant depression (57.2%, 95% CI = 49.4-64.9%), and this estimate was similar after exclusion of patients with cognitive impairment (52.5%, 95% CI = 42.2%-62.8%). In conclusion, we found that apathy affects almost 40% of patients with PD. Several factors influence reported prevalence rates, contributing to the considerable heterogeneity in study results. Half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self-care, and reduce cognitive impairment by improving executive functioning. PMID- 25787143 TI - Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis. AB - The current status of therapeutic vaccines for autoimmune diseases is reviewed with rheumatoid arthritis as the focus. Therapeutic vaccines for autoimmune diseases must regulate or subdue responses to common self-antigens. Ideally, such a vaccine would initiate an antigen-specific modulation of the T-cell immune response that drives the inflammatory disease. Appropriate animal models and types of T helper cells and signature cytokine responses that drive autoimmune disease are also discussed. Interpretation of these animal models must be done cautiously because the means of initiation, autoantigens, and even the signature cytokine and T helper cell (Th1 or Th17) responses that are involved in the disease may differ significantly from those in humans. We describe ligand epitope antigen presentation system vaccine modulation of T-cell autoimmune responses as a strategy for the design of therapeutic vaccines for rheumatoid arthritis, which may also be effective in other autoimmune conditions. PMID- 25787146 TI - Bayesian function-on-function regression for multilevel functional data. AB - Medical and public health research increasingly involves the collection of complex and high dimensional data. In particular, functional data-where the unit of observation is a curve or set of curves that are finely sampled over a grid-is frequently obtained. Moreover, researchers often sample multiple curves per person resulting in repeated functional measures. A common question is how to analyze the relationship between two functional variables. We propose a general function-on-function regression model for repeatedly sampled functional data on a fine grid, presenting a simple model as well as a more extensive mixed model framework, and introducing various functional Bayesian inferential procedures that account for multiple testing. We examine these models via simulation and a data analysis with data from a study that used event-related potentials to examine how the brain processes various types of images. PMID- 25787147 TI - Fast universal quantum gates on microwave photons with all-resonance operations in circuit QED. AB - Stark shift on a superconducting qubit in circuit quantum electrodynamics (QED) has been used to construct universal quantum entangling gates on superconducting resonators in previous works. It is a second-order coupling effect between the resonator and the qubit in the dispersive regime, which leads to a slow state selective rotation on the qubit. Here, we present two proposals to construct the fast universal quantum gates on superconducting resonators in a microwave-photon quantum processor composed of multiple superconducting resonators coupled to a superconducting transmon qutrit, that is, the controlled-phase (c-phase) gate on two microwave-photon resonators and the controlled-controlled phase (cc-phase) gates on three resonators, resorting to quantum resonance operations, without any drive field. Compared with previous works, our universal quantum gates have the higher fidelities and shorter operation times in theory. The numerical simulation shows that the fidelity of our c-phase gate is 99.57% within about 38.1 ns and that of our cc-phase gate is 99.25% within about 73.3 ns. PMID- 25787148 TI - Seamless stitching of tile scan microscope images. AB - For diagnostic purposes, optical imaging techniques need to obtain high resolution images of extended biological specimens in reasonable time. The field of view of an objective lens, however, is often smaller than the sample size. To image the whole sample, laser scanning microscopes acquire tile scans that are stitched into larger mosaics. The appearance of such image mosaics is affected by visible edge artefacts that arise from various optical aberrations which manifest in grey level jumps across tile boundaries. In this contribution, a technique for stitching tiles into a seamless mosaic is presented. The stitching algorithm operates by equilibrating neighbouring edges and forcing the brightness at corners to a common value. The corrected image mosaics appear to be free from stitching artefacts and are, therefore, suited for further image analysis procedures. The contribution presents a novel method to seamlessly stitch tiles captured by a laser scanning microscope into a large mosaic. The motivation for the work is the failure of currently existing methods for stitching nonlinear, multimodal images captured by our microscopic setups. Our method eliminates the visible edge artefacts that appear between neighbouring tiles by taking into account the overall illumination differences among tiles in such mosaics. The algorithm first corrects the nonuniform brightness that exists within each of the tiles. It then compensates for grey level differences across tile boundaries by equilibrating neighbouring edges and forcing the brightness at the corners to a common value. After these artefacts have been removed further image analysis procedures can be applied on the microscopic images. Even though the solution presented here is tailored for the aforementioned specific case, it could be easily adapted to other contexts where image tiles are assembled into mosaics such as in astronomical or satellite photos. PMID- 25787149 TI - Commentary to Choi et al. (2015): CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver. PMID- 25787150 TI - Long-term arsenite exposure induces premature senescence in B cell lymphoma A20 cells. AB - Chronic arsenite exposure induces immunosuppression, but the precise mechanisms remain elusive. Our previous studies demonstrated that arsenite exposure for 24 h induces G0/G1 arrest in mouse B lymphoma A20 cells and the arrest is caused through induction of cyclin-dependent kinase inhibitor p16(INK4a) followed by accumulation of an Rb family protein, p130. In this study, we further investigated the consequences of long-term arsenite exposure of A20 cells. The results demonstrated that exposure to 10 MUM sodium arsenite up to 14 days induces a great increase in G0/G1 arrest, irreversible cell growth suppression, cellular morphological changes and positive staining for senescence-associated beta-galactosidase. The long-term arsenite exposure also induced up-regulation of p16(INK4a) followed by robust accumulation of p130 and activation of the p53 pathway. Knockdown experiments with siRNA showed that p130 accumulation is essential for cell cycle arrest by long-term arsenite exposure. Since p16(INK4a) and the p53 pathway are known to be activated by DNA damage, we investigated the involvement of DNA damage formation by long-term arsenite exposure. We found that a variety of DNA repair-related genes were significantly down-regulated from 24 h of arsenite exposure and activation-induced cytidine deaminase was greatly up regulated after long-term arsenite exposure. Consistent with these findings, long term arsenite exposure increased a DNA double-strand break marker, gamma-H2AX and increased mutation frequency in a Bcl6 gene region. These results revealed that long-term arsenite exposure induces premature senescence through DNA damage increase and p130 accumulation in lymphoid cells. PMID- 25787151 TI - Ketoconazole induces apoptosis in rat cardiomyocytes through reactive oxygen species-mediated parkin overexpression. AB - Azole antifungals such as ketoconazole are generally known to induce a variety of heart function side effects, e.g., long-QT syndrome and ventricular arrhythmias. However, a clear mechanism for the action of ketoconazole in heart cells has not been reported. In the present study, we assessed the correlation between ketoconazole-induced apoptosis and the alteration of genes in response to ketoconazole in rat cardiomyocytes. Cardiomyocyte viability was significantly inhibited by treatment with ketoconazole. Ketoconazole also stimulated H2O2 generation and TUNEL-positive apoptosis in a dose-dependent manner. DNA microarray technology revealed that 10,571 genes were differentially expressed by more than threefold in ketoconazole-exposed cardiomyocytes compared with untreated controls. Among these genes, parkin, which encodes a component of the multiprotein E3 ubiquitin ligase complex, was predominantly overexpressed among those classified as apoptosis- and reactive oxygen species (ROS)-related genes. The expression of parkin was also elevated in cardiomyocytes treated with exogenous H2O2. Moreover, cell viability and apoptosis in response to ketoconazole were inhibited in cardiomyocytes treated with ROS inhibitors and transfected with parkin siRNA. From the present findings, we concluded that ketoconazole may increase the expression of parkin via the ROS-mediated pathway, which consequently results in the apoptosis and decreased viability of cardiomyocytes. PMID- 25787152 TI - High-content screening technology for studying drug-induced hepatotoxicity in cell models. AB - High-content screening is the application of automated microscopy and image analysis to both cell biology and drug discovery. Over the last decade, this technique has emerged as a useful technology that allows the simultaneous measurement of different parameters at a single-cell level. Hepatotoxicity is a compelling reason for drug nonapprovals and withdrawals. It is recognized that the safety of a compound cannot be based on a single in vitro assay, and existing methods are not predictive of drug-induced toxicity. However, different HCS assays have been recently demonstrated as being powerful for identifying different mechanisms implicated in drug-induced toxicity with high sensitivity and specificity. These assays integrate the data obtained from different cell function indicators and can be easily incorporated into basic screening processes for the safety evaluation and selection of drug candidates; thus, they contribute greatly to lessen the likelihood of drug failure. Exploring the use of cellular imaging technology in drug-induced liver injury by reviewing the different tests proposed provides evidence that this technology has a strong impact on drug discovery. PMID- 25787153 TI - The evolution of life cycle complexity in aphids: Ecological optimization or historical constraint? AB - For decades, biologists have debated why many parasites have obligate multihost life cycles. Here, we use comparative phylogenetic analyses of aphids to evaluate the roles of ecological optimization and historical constraint in the evolution of life cycle complexity. If life cycle complexity is adaptive, it should be evolutionarily labile, that is, change in response to selection. We provide evidence that this is true in some aphids (aphidines), but not others (nonaphidines)-groups that differ in the intensity of their relationships with primary hosts. Next, we test specific mechanisms by which life cycle complexity could be adaptive or a constraint. We find that among aphidines there is a strong association between complex life cycles and polyphagy but only a weak correlation between life cycle complexity and reproductive mode. In contrast, among nonaphidines the relationship between life cycle complexity and host breadth is weak but the association between complex life cycles and sexual reproduction is strong. Thus, although the adaptiveness of life cycle complexity appears to be lineage specific, across aphids, life cycle evolution appears to be tightly linked with the evolution of other important natural history traits. PMID- 25787154 TI - Isolation of a spontaneous cerulenin-resistant sake yeast with both high ethyl caproate-producing ability and normal checkpoint integrity. AB - In the brewing of high-quality sake such as Daiginjo-shu, the cerulenin-resistant sake yeast strains with high producing ability to the flavor component ethyl caproate have been used widely. Genetic stability of sake yeast would be important for the maintenance of both fermentation properties of yeast and quality of sake. In eukaryotes, checkpoint mechanisms ensure genetic stability. However, the integrity of these mechanisms in sake yeast has not been examined yet. Here, we investigated the checkpoint integrity of sake yeasts, and the results suggested that a currently used cerulenin-resistant sake yeast had a defect in spindle assembly checkpoint (SAC). We also isolated a spontaneous cerulenin-resistant sake yeast FAS2-G1250S mutant, G9CR, which showed both high ethyl caproate-producing ability and integrity/intactness of the checkpoint mechanisms. Further, morphological phenotypic robustness analysis by use of CalMorph supported the genetic stability of G9CR. Finally, we confirmed the high quality of sake from G9CR in an industrial sake brewing setting. PMID- 25787155 TI - Permanent chemotherapy-induced nonscarring alopecia and premature ovarian failure. PMID- 25787156 TI - The Medical Symptom Validity Test Measures Effort Not Ability in Children: A Comparison Between Mild TBI and Fetal Alcohol Spectrum Disorder Samples. AB - Inadequate effort during neuropsychological examination results in inaccurate representations of an individual's true abilities and difficulties. As such, performance validity tests (PVTs) are strongly recommended as standard practice during adult-based evaluations. One concern with using PVTs with children is that failure reflects immature cognitive ability rather than non-credible effort. The current study examined performance on the Medical Symptom Validity Test (MSVT) in two large pediatric clinical samples with strikingly different neuropsychological profiles: (1) mild traumatic brain injury (mTBI; n = 510) and (2) fetal alcohol spectrum disorder (FASD; n = 120). Despite higher IQ scores and reading ability, the mTBI group performed significantly worse than the FASD group on all effort indices. Sixteen percent of the mTBI group failed the MSVT, whereas only 5% of the FASD group did. Our findings support the idea that the MSVT measures effort, not ability, in most cases and help to justify incorporating PVTs into pediatric neuropsychological batteries. PMID- 25787157 TI - Replacement of Ser108 in Plasmodium falciparum enolase results in weak Mg(II) binding: role of a parasite-specific pentapeptide insert in stabilizing the active conformation of the enzyme. AB - A distinct structural feature of Plasmodium falciparum enolase (Pfeno) is the presence of a five amino acid insert -104EWGWS108- that is not found in host enolases. Its conservation among apicomplexan enolases has raised the possibility of its involvement in some important physiological function(s). Deletion of this sequence is known to lower k(cat)/K(m), increase K(a) for Mg(II) and convert dimer into monomers (Vora HK, Shaik FR, Pal-Bhowmick I, Mout R & Jarori GK (2009) Arch Biochem Biophys 485, 128-138). These authors also raised the possibility of the formation of an H-bond between Ser108 and Leu49 that could stabilize the apo Pfeno in an active closed conformation that has high affinity for Mg(II). Here, we examined the effect of replacement of Ser108 with Gly/Ala/Thr on enzyme activity, Mg(II) binding affinity, conformational states and oligomeric structure and compared it with native recombinant Pfeno. The results obtained support the view that Ser108 is likely to be involved in the formation of certain crucial H bonds with Leu49. The presence of these interactions can stabilize apo-Pfeno in an active closed conformation similar to that of Mg(II) bound yeast enolase. As predicted, S108G/A-Pfeno variants (where Ser108-Leu49 H-bonds are likely to be disrupted) were found to exist in an open conformation and had low affinity for Mg(II). They also required Mg(II) induced conformational changes to acquire the active closed conformational state essential for catalysis. The possible physiological relevance of apo-Pfeno being in such an active state is discussed. PMID- 25787158 TI - Indole diketopiperazines from endophytic Chaetomium sp 88194 induce breast cancer cell apoptotic death. AB - Diketopiperazines are important secondary metabolites of the fungi with variety bioactivities. Several species belonging to genus Chaetomium produce compounds of this class, such as chetomin. To identify new antitumor agents, secondary metabolites of fungus Chaetomium sp 88194 were investigated and three new indole diketopiperazines, Chaetocochins G (1), Oidioperazines E (2) and Chetoseminudin E (3), along with two known compounds Chetoseminudins C (4) and N-acetyl-beta oxotryptamine (5), were obtained. Chaetocochins G and Chetoseminudin E were recrystallized in CHCl3 containing a small amount of MeOH, and their structures with absolute configuration were established by spectroscopic data interpretation and single-crystal X-ray diffraction analysis. The absolute configuration of Oidioperazines E was defined by comparing of experimental and calculated electronic circular dichroism spectra. These isolates were also evaluated the anticancer activity, and Chaetocochins G displayed more potent cytotoxicity in MCF-7 cells than the common chemotherapeutic agent (5-fluorouracil) associated with G2/M cell cycle arrest. More importantly, Chaetocochins G induced cell apoptotic death via caspase-3 induction and proteolytic cleavage of poly (ADP ribose) polymerase, concomitantly with increased Bax and decreased Bcl-2 expression. Our findings suggested that indole diketopiperazines from endophytic Chaetomium sp 88194 may be potential resource for developing anti-cancer reagents. PMID- 25787159 TI - [Ocular tumors in Togo: epidemiological, clinical, and histopathological features observed at the Lome Teaching Hospital of Sylvanus Olympio]. AB - PURPOSE: To describe the epidemiological, clinical, and histopathological features of ocular tumors in Togo. METHODS: We have a retrospective and descriptive study of the ocular specimens registered in the pathology laboratory from January 1, 2006, to December 31, 2010. The frequency of ocular tumors, the patients' age and sex, the department from which the specimen came, the sampling procedure, and the histopathological patterns were analyzed. RESULTS: During the study period, 80 ocular specimens were recorded among a total of 6000, for a frequency of 1.33%. Histopathological results were available for 45 cases in our sample. The mean age was 30.9 +/- 15.1 years, and the sex ratio 0.88 (21M/24F). The two teaching hospitals in Lome furnished 73.4% of the ocular specimens. The most common site was the conjunctiva, accounting for 75.5% of the cases. Benign tumors represented 69.9% of the histological diagnoses. Papilloma was the histopathological diagnosis in 33.3% of cases. CONCLUSION: Ocular tumors are relatively common, occur at any age, and are located most often in the conjunctiva. Close collaboration between the pathologist and the ophthalmologist is essential for the best management of these tumors. PMID- 25787161 TI - Residents' corner February 2015. sQUIZ your knowledge! A case of cutaneous plasmacytosis with mast cell infiltration. PMID- 25787160 TI - Trace determination of lead in lipsticks and hair dyes using microwave-assisted dispersive liquid-liquid microextraction and graphite furnace atomic absorption spectrometry. AB - OBJECTIVE: A novel microwave-assisted dispersive liquid-liquid microextraction (MADLLME) technique according to the solidification of a floating organic droplet (SFO) and graphite furnace atomic absorption spectrometry (GFAAS) used for the extraction and determination of lead ions in lipsticks and hair dyes made in different countries. Lipstick and hair dye samples of different brands and colours were collected from local market in Kermanshah, Iran. METHODS: After sample treatment with microwave-assisted acid digestion, an appropriate mixture of acetone, 1-undecanol and diethyl dithiophosphoric acid was injected rapidly into the aqueous sample containing lead ions, and as a result, cloudy mixture was formed. After centrifugation, the test tube was cooled for few minutes. The solidified 1-undecanol on top of the solution was transferred into a suitable vial and injected into the analytical instrument. RESULTS: Under the optimum experimental conditions (extraction solvent: 30 MUL of 1-undecanol; disperser solvent: 500 MUL of acetone; ligand concentration: 0.15% (v/v); pH: ~1.5 and without salt added), the enhancement factor of 96 was obtained. The calibration graphs were linear in the range of 0.3-50 MUg kg(-1) with a correlation coefficient (r(2) ) more than 0.995. The detection limit was 0.1 MUg kg(-1) . Consequently, the developed method was successfully applied to extract and determine lead ions in the lipsticks and hair dyes, and favourable results were obtained. The proposed method which applied in cosmetics showed excellent relative recoveries (90-109.7%) with relative standard deviations <8.3% (n = 3) for all samples. CONCLUSION: The study revealed that the concentration of lead found in lipsticks and hair dyes on the Kermanshah market is far below the recommended limits as applied in Germany (20 mg kg(-1) ) and Canada (10 mg kg(-1) ) and confirmed that very low levels of lead are technically available in the final cosmetic products. PMID- 25787162 TI - Surveillance after neoadjuvant therapy in advanced rectal cancer with complete clinical response can have comparable outcomes to total mesorectal excision. AB - PURPOSE: While the standard of care for patients with rectal cancer who sustain a complete clinical response (cCR) to chemoradiotherapy (CRT) remains proctectomy with total mesorectal excision, data suggests that non-operative management may be a safe alternative. The purpose of this study is to compare outcomes between patients treated with CRT that attained a cCR and opted for a vigilant surveillance to those of the patients who had a complete pathologic response (cPR) following proctectomy. METHOD: This is a retrospective review of patients treated for adenocarcinoma of the rectum who achieved either a cCR or a cPR following CRT. Patients with a cCR were enrolled in an active surveillance program which included regularly scheduled exams, proctoscopy, serum carcinoembryonic antigen (CEA), endorectal ultrasound, and cross-sectional imaging. Outcomes were compared to those patients who underwent proctectomy with a cPR. Our primary outcome measures were post-treatment complications, recurrence, and survival. RESULTS: We reviewed 18 patients who opted for surveillance after cCR and 30 patients who underwent proctectomy after a cPR. No non-operative patients had a documented treatment complication, while 17 patients with cPR suffered significant morbidity. There were two recurrences in the active surveillance group, one local and once distant, both treated by salvage resection with no associated mortality at 54 and 62 months. In the cPR group, one patient had a distant recurrence 24 months after surgery which was managed non operatively. This patient died of unrelated causes 35 months after surgery. CONCLUSIONS: Active surveillance can be a safe option that avoids the morbidity associated with proctectomy and preserves oncologic outcomes. PMID- 25787163 TI - Necrotizing myonecrosis secondary to hematogenous spread of gas gangrene following colonic perforation. PMID- 25787164 TI - Rectal follicular lymphoma. PMID- 25787165 TI - Surgical diagnosis of idiopathic cecal ulcer: presentation of two clinical cases. PMID- 25787166 TI - The correlation of major risk factors and clinicopathological characteristics in colorectal cancer patients under the age of 50. PMID- 25787167 TI - A comparison of various artificial intelligence approaches performance for estimating suspended sediment load of river systems: a case study in United States. AB - Accurate and reliable suspended sediment load (SSL) prediction models are necessary for planning and management of water resource structures. More recently, soft computing techniques have been used in hydrological and environmental modeling. The present paper compared the accuracy of three different soft computing methods, namely, artificial neural networks (ANNs), adaptive neuro-fuzzy inference system (ANFIS), coupled wavelet and neural network (WANN), and conventional sediment rating curve (SRC) approaches for estimating the daily SSL in two gauging stations in the USA. The performances of these models were measured by the coefficient of correlation (R), Nash-Sutcliffe efficiency coefficient (CE), root-mean-square error (RMSE), and mean absolute percentage error (MAPE) to choose the best fit model. Obtained results demonstrated that applied soft computing models were in good agreement with the observed SSL values, while they depicted better results than the conventional SRC method. The comparison of estimation accuracies of various models illustrated that the WANN was the most accurate model in SSL estimation in comparison to other models. For example, in Flathead River station, the determination coefficient was 0.91 for the best WANN model, while it was 0.65, 0.75, and 0.481 for the best ANN, ANFIS, and SRC models, and also in the Santa Clara River, amounts of this statistical criteria was 0.92 for the best WANN model, while it was 0.76, 0.78, and 0.39 for the best ANN, ANFIS, and SRC models, respectively. Also, the values of cumulative suspended sediment load computed by the best WANN model were closer to the observed data than the other models. In general, results indicated that the WANN model could satisfactorily mimic phenomenon, acceptably estimate cumulative SSL, and reasonably predict peak SSL values. PMID- 25787168 TI - Relationship between structural features and water chemistry in boreal headwater streams--evaluation based on results from two water management survey tools suggested for Swedish forestry. AB - Forestry may cause adverse impacts on water quality, and the forestry planning process is a key factor for the outcome of forest operation effects on stream water. To optimise environmental considerations and to identify actions needed to improve or maintain the stream biodiversity, two silvicultural water management tools, BIS+ (biodiversity, impact, sensitivity and added values) and Blue targeting, have been developed. In this study, we evaluate the links between survey variables, based on BIS+ and Blue targeting data, and water chemistry in 173 randomly selected headwater streams in the hemiboreal zone. While BIS+ and Blue targeting cannot replace more sophisticated monitoring methods necessary for classifying water quality in streams according to the EU Water Framework Directive (WFD, 2000/60/EC), our results lend support to the idea that the BIS+ protocol can be used to prioritise the protection of riparian forests. The relationship between BIS+ and water quality indicators (concentrations of nutrients and organic matter) together with data from fish studies suggests that this field protocol can be used to give reaches with higher biodiversity and conservation values a better protection. The tools indicate an ability to mitigate forestry impacts on water quality if the operations are adjusted to this knowledge in located areas. PMID- 25787169 TI - The SEMONT continuous monitoring of daily EMF exposure in an open area environment. AB - Wireless networks traffic has experienced a considerable growth in recent years. Likewise, it is to be expected that billions of objects will be connected to the Internet in years to come, many of them wirelessly. Such increase in a number of wireless connections and the inevitability of wireless communications in proximity of users highlight the healthcare concern on electromagnetic field (EMF) exposure. Thus, the intelligent monitoring systems, such as the Serbian Electromagnetic Field Monitoring Network-SEMONT-have been required to be developed and utilized for continuous and real-time EMF monitoring, as well as for the assessment of the potential in situ daily exposure of population. This paper presents the results of the SEMONT initial campaign of continuous monitoring of the high-frequency electric field strength over the campus of the University of Novi Sad, as an open area environment. Several locations, most frequently visited by the student population in their everyday activities, have been monitored during the rush hour in order to determine the fluctuation of daily exposure on this, usually considered, highly sensitive area. The results of monitoring suggest that potential exposure is far below the allowable limit, regarding reference levels prescribed by the Serbian legislation for the general population. PMID- 25787170 TI - Extracellular and intracellular factors regulating the migration direction of a chemotactic cell in traveling-wave chemotaxis. AB - This report presents a simple model that describes the motion of a single Dictyostelium discoideum cell exposed to a traveling wave of cyclic adenosine monophosphate (cAMP). The model incorporates two types of responses to stimulation by cAMP: the changes in the polarity and motility of the cell. The periodic change in motility is assumed to be induced by periodic cAMP stimulation on the basis of previous experimental studies. Consequently, the net migration of the cell occurs in a particular direction with respect to wave propagation, which explains the migration of D. discoideum cells in aggregation. The wave period and the difference between the two response times are important parameters that determine the direction of migration. The theoretical prediction compared with experiments presented in another study. The transition from the single-cell state of the population of D. discoideum cells to the aggregation state is understood to be a specific example of spontaneous breakage of symmetry in biology. PMID- 25787171 TI - Delivering regeneration. PMID- 25787172 TI - A reagent to facilitate protein recovery from cells and tissues. AB - Collection of cytosolic proteins from cells and tissues is the first and essential step in many bioanalytical assays that play a key role in medical applications such as diagnostics, theranostics, and regenerative medicine. Dissolution of cell and tissue constituents without deactivation of their constituents, especially proteins, is a challenging task. Here, we report on a recently identified cell and tissue lysis agent in terms of its ability to solubilize cells and tissues as well as preservation of cellular proteins, particularly enzymes. The lysis agent comprises a mixture of a zwitterionic surfactant, N-decyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (DPS) and a non ionic surfactant, Brij 30 (B30). Mixtures of DPS and B30 successfully solubilized keratinocytes and human vascular endothelial cells in vitro while preserving detectable quantities of cellular enzymes including glyceraldehyde 3-phosphate dehydrogenase and lactate dehydrogenase for at least 4 h. Mixtures of DPS and B30 were also effective in solubilizing tissues, especially tough tissues such as skin in vitro. Collectively, the mixture of DPS/B30 was effective in solubilizing cells and tissues while preserving its constituent proteins, which opens up its applications for use in studying the effect of environmental factors on tissue proteomics. As an example, the ability of DPS/B30 to detect alterations in skin proteins in response to UV exposure was assessed. These studies revealed that UV exposure induce upregulation of a number of inflammatory, apoptotic and stress activated proteins as well as downregulation of cell cycle progression proteins. PMID- 25787173 TI - Electrospun collagen and its applications in regenerative medicine. AB - In recent years, electrospinning has increased in popularity as a processing technique for obtaining nanometer-to-micron diameter polymer fibers collected to form a nonwoven scaffold. It possesses the ability to process collagen into nanofibrous scaffolds which have been used for a number of applications, such as artificial vascular grafts and for wound repair. This paper offers a review of some of the basic yet essential aspects of producing nanofibrous scaffolds of collagen by electrospinning. A primer to collagen structure, cross-linking techniques, and electrospinning principles is provided, along with some of the many applications of these unique materials. PMID- 25787174 TI - Substrate elasticity modulates TGF beta stimulated re-differentiation of expanded human articular chondrocytes. AB - Substrate elasticity has emerged as important biomaterial design parameter. In particular, it has been reported that on soft substrates (~4 kPa) freshly isolated porcine chondrocytes better maintain their phenotype than on stiffer ones (>20 kPa). Thus, we investigated whether this also applies to re differentiating, expanded/de-differentiated (EDD) human articular chondrocytes (HAC). EDD HAC were seeded onto Type I collagen functionalized poly acrylamide (PA) films with a Young's modulus of 0.26 +/- 0.08 kPa (soft), 21.32 +/- 0.79 kPa (intermediately stiff) and 74.88 +/- 5.13 kPa (stiff), or type I collagen-coated plastic dishes (TCPS w/CI). Cells were cultured for 7 to 14 days in chondrogenic medium supplemented with transforming growth factor beta-1 (TGF-beta1) and assessed for attachment, initial adhesion strength, proliferation, morphology as well as for expression of type I and II collagen at mRNA and type II collagen on protein level. Attachment and adhesion strength was similar on the different PA substrates and proliferation remained marginal (<1 doubling/week). On intermediately stiff to infinitely stiff substrates EDD HAC assumed a spindle shaped, fibroblastic morphology, whereas on the soft substrate they remained more spherical, as assessed by shape factor analysis, and had a reduced spreading area (up to 3.2-fold). F-actin organization on the soft substrate was restricted cortically, while on the stiffer substrates F-actin assembled into stress fibers. While type II collagen mRNA expression on the soft substrate was (similar to that in aggregate culture and) 18-fold higher than on TCPS w/CI, it was not detectable on protein level. On all substrates, in the absence of TGF-beta1 type II collagen mRNA remained at levels expressed by EDD HAC. In summary, substrate elasticity modulated the TGF-beta1 stimulated re-differentiation of EDD HAC. Mechanical compliance is thus an important parameter to be coupled with the delivery of appropriate morphogens in designing biomaterials for cartilage engineering and repair. PMID- 25787175 TI - Low-density expansion protects human synovium-derived stem cells from replicative senescence: a preliminary study. AB - Our hypothesis in this study is that low seeding density expansion could retain human synovium-derived stem cell (hSDSC) "stemness", defined as higher proliferation and multi-differentiation capacity; retention of "stemness" probably occurs through the mitogen-activated protein kinase (MAPK) signaling pathway. hSDSCs were expanded in conventional plastic flasks for two consecutive passages at either low or high density (30 or 3,000 cells/cm(2)). Expanded cells were assessed for the effect of seeding density on their morphology, proliferation, apoptosis, stem cell surface markers, and multi-lineage differentiation capacity (chondrogenic, adipogenic, and osteogenic differentiation) using flow cytometry, biochemical analysis, histology, immunostaining, and real-time polymerase chain reaction. The MAPK signaling pathway (Erk1/2, p38, and JNK) and senescence-associated markers (p21 and caveolin) were also evaluated for their role in cell density-based monolayer expansion using western blot. Our data suggested that low seeding density expansion yielded hSDSCs with enhanced proliferation and multi-differentiation capacity compared to those grown at high seeding density, despite the fact that the cells expanded at both high and low density had lower osteogenic capacity. Low seeding density also down-regulated Erk1/2 and JNK expression and up regulated p38 expression, which might be responsible for the retained "stemness" in the cells expanded at low density. Low seeding density expansion could retain hSDSC proliferation and multi-differentiation capacity and protect cells from replicative senescence. PMID- 25787176 TI - Anti-platelet and tissue engineering approaches to biomaterial blood compatibilization: how well have these been translated into the clinic? AB - In this article, we provide an update on the various approaches to "blood compatibilization", and include both passive and active approaches to compatibilizing biomaterials in contact with blood. Broadly speaking, the surface modification approaches involved either repel platelets or attract endothelial cells. For platelet-repelling surfaces, heparin immobilization seems to be the most successful approach. At least two such surfaces have been approved by the health authorities in various countries for applications involving short-term contact with blood. For active endothelialization, ex vivo seeding with autologous cells has been translated into the clinic, while selective endothelial cell capture is a promising approach. In spite of over 30 years of research in this area, a truly intrinsically non-clotting surface has not been developed yet; certain promising avenues have been indicated by the research, which we will critically assess here. PMID- 25787177 TI - Gene transfection to spheroid culture system on micropatterned culture plate by polyplex nanomicelle: a novel platform of genetically-modified cell transplantation. AB - Three-dimensional (3D) cellular spheroids have attracted much attention as a transplantation procedure because the increased cell-to-cell interaction in spheroids enhances cell survival and its functions after the transplantation into the body. Furthermore, the potency of spheroidal cells may be further improved by introducing transgenes to augment cellular functions as well as enhance the paracrine effects by secreting key proteins involved in the essential cellular signaling cascades. In this study, we organized a new platform for genetically modified cell transplantation by combining a microfabricated culture system for 3D spheroid formation with a newly developed non-viral transfection system, polyplex nanomicelle. After transfection of Gaussia luciferase using the nanomicelle, the prolonged luciferase expression was obtained for more than a month with continuous albumin secretion from the hepatocyte spheroids to the level comparable with control spheroids receiving no transfection. In contrast, by the transfection using FuGENE HD, a commercially available lipid-based reagent, the luciferase expression was obtained, yet the albumin secretion was significantly decreased with disintegration of the spheroid architecture. To assess the feasibility of the hepatocyte spheroids for in vivo transplantation, the spheroids were recovered by the use of micropatterned culture plate functionalized with thermosensitive polymer and dispersed into Matrigel(TM) Matrix. The luciferase expression as well as albumin secretion was maintained for more than a month from the spheroids in the Matrix. Thus, the combination of spheroid cell culture on micropatterned plates with gene introduction using polyplex nanomicelle is a promising platform for genetically-modified cell transplantation to achieve sustained transgene expression with maintaining innate cell functions. PMID- 25787178 TI - An antibody fragment functionalized dendritic PEGylated poly(2 (dimethylamino)ethyl diacrylate) as a vehicle of exogenous microRNA. AB - The translation of interfering RNA to the clinic requires more effective delivery agents to enable safe and efficient delivery. The aim of this work was to create a multi-functional delivery agent using deactivation enhanced ATRP synthesis of poly(dimethylamino)ethyl methacrylate (pDMAEMA)-co-PEGMEA/PEGDA (pD-b-P/DA) with linear pDMAEMA as a macro-initiator. The pD-b-P/DA was characterized for its potential to bind synthetic microRNA mimics to form structures and reacted with antibody-derived fragments (Fabs) using Michael-type addition. Conjugation of antibody fragments was verified using SDS-PAGE. Functional delivery of these interfering RNA complexes was proven using a dual luciferase reporter assay. Functional silencing of a reporter gene was improved by complexation of microRNA mimics with pD-b-P/DA alone and with Fab-decorated pD-b-P/DA. The improved silencing with Fab-decorated pD-b-P/DA was evident at 48 h but disappeared at 96 h. The resultant agent enables complexation of nucleic acid (microRNA mimic) and facile conjugation of antibody fragments via a Michael-type addition. In conclusion, this platform is effective at silencing in this reporter system and has potential as an effective delivery system of interfering RNA. PMID- 25787179 TI - Health care in a homophobic climate: the SPEND model for providing sexual health services to men who have sex with men where their health and human rights are compromised. AB - We present a model for developing health services for men who have sex with men (MSM) in sub-Saharan Africa and other places where MSM are heavily stigmatized and marginalized. The processes of the SPEND model include Safe treatment for sexually transmissible infections (STIs) and HIV; Pharmacy sites for treatment of STIs in countries where pharmacies and drug stores are the source of medical advice and treatment; Education in sexual health issues for health professionals to reduce discrimination against MSM patients; Navigation for patients who have HIV and are rejected or discriminated against for treatment; and Discrimination reduction through educating potential leaders in tertiary education in issues of human sexuality. Supporting empirical evidence from qualitative and quantitative studies is summarized, and barriers to implementation are discussed. Health care for MSM is one of the casualties of anti-homosexual social and legal climates. There is no amnesty for MSM in health care settings, where the stigma and discrimination that they face in the rest of society is replicated. Such conditions, however, make it necessary to consider ways of providing access to health care for MSM, especially where rates of HIV and STIs in MSM populations are high, and stigma and discrimination encourages high proportions of MSM to marry. This in itself enhances the status of MSM as an important bridge population for STIs including HIV. Where anti-homosexual laws encourage, or are believed to encourage, the reporting of MSM to authorities, health care may be seen as an agent of authority rather than an agency for care. PMID- 25787180 TI - 'You can't stay away from your family': a qualitative study of the ongoing ties and future plans of South African health workers in the United Kingdom. AB - BACKGROUND: Migration of African-trained health workers to countries with higher health care worker densities adds to the severe shortage of health personnel in many African countries. Policy initiatives to reduce migration levels are informed by many studies exploring the reasons for the original decision to migrate. In contrast, there is little evidence to inform policies designed to facilitate health workers returning home or providing other forms of support to the health system of their home country. OBJECTIVE: This study explores the links that South African-trained health workers who now live and work in the United Kingdom maintain with their country of training and what their future migration plans may be. DESIGN: Semi-structured interviews were conducted with South African trained health workers who are now living in the United Kingdom. Data extracts from the interviews relating to current links with South Africa and future migration plans were studied. RESULTS: All 16 participants reported strong ongoing ties with South Africa, particularly through active communication with family and friends, both face-to-face and remotely. Being South African was a significant part of their personal identity, and many made frequent visits to South Africa. These visits sometimes incorporated professional activities such as medical work, teaching, and charitable or business ventures in South Africa. The presence and location of family and spouse were of principal importance in helping South African-trained health care workers decide whether to return permanently to work in South Africa. Professional aspirations and sense of duty were also important motivators to both returning and to being involved in initiatives remotely from the United Kingdom. CONCLUSIONS: The main barrier to returning home was usually the development of stronger family ties in the United Kingdom than in South Africa. The issues that prompted the original migration decision, such as security and education, also remained important reasons to remain in the United Kingdom as long as they were perceived as unresolved at home. However, the strong residual feeling of identity and regular ongoing communication meant that most participants expressed a sense of duty to their home country, even if they were unlikely to return to live there full-time. This is a resource for training and short-term support that could be utilised to the benefit of African health care systems. PMID- 25787182 TI - Monocyte:T-cell interaction regulates human T-cell activation through a CD28/CD46 crosstalk. AB - T-cell activation requires engagement of the T-cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T-cell activation was reported several decades ago and the molecular mechanisms involved have now been well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T-cell differentiation from producing some IFNgamma to secreting some potent anti inflammatory IL-10, acquiring a so-called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T cell activation and IL-10 production. The observation that CD46 cleavage was reduced when PBMCs were costimulated compared with purified CD4(+) T cells led us to hypothesize that interactions between different cell types within the PBMCs were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4(+) T cells are cocultured with autologous monocytes. Indeed, monocyte: T-cell cocultures impaired CD46-mediated T-cell differentiation and coactivation, by reducing downregulation of surface CD46, lowering induction of the early activation marker CD69, as well as reducing the levels of IL-10 secretion. Blocking of CD86 could partly restore CD69 expression and cytokine secretion, demonstrating that the CD28: CD86 pathway regulates CD46 activation. Direct concomitant ligation of CD28 and CD46 on CD4(+) T cells also modulated CD46 expression and regulated cytokine production. These data identify a crosstalk between two main costimulatory pathways and provide novel insights into the regulation of human T-cell activation. PMID- 25787183 TI - Review: higher caffeine intake during pregnancy increases risk of low birth weight. PMID- 25787184 TI - Editors' welcome. PMID- 25787185 TI - On the origin of EDSS. AB - The origin of EDSS, the Expanded Disability Status Scale for multiple sclerosis, was some 30 years before its only publication in 1983 when we were trying to assess a potential treatment and found no published methods. Findings from the complete neurologic examinations in over 200 patients were consolidated into mutually exclusive but all-inclusive neurophysiologic entities called Functional Systems (FS), and these provided the basis for an 11 step 0-10 rank order scale, the Disability Status Scale (DSS). This was used successfully, as well as in the first two Class I treatment trials performed, with the second one also incorporating the 8 FS. Both measures were part of an assessment of a natural history series derived from men hospitalized for MS in the US Army in World War II and followed for some 20 years. Describing each of the 8 FS as affected (1) or normal (0) defined 256 possible patterns of involvement for all patients. Half the patients at diagnosis had one of the 14 most common patterns. Each FS worsened in frequency and severity of involvement in correlation with the DSS, which overall showed a unimodal distribution, until in another series of patients 16 years post onset bimodality first appeared. Observations that the 11 step DSS might have too few steps for treatment trials led to the EDSS of 20 steps with each grade between 1 and 9 divided into two. The system of EDSS+FS to summarize all the CNS involvement as defined by objective findings on neurologic examination thereafter remained unchanged to the present. I just learned that the unpublished system copyrighted in Switzerland as "neurostatus" has been called and referenced as my EDSS. It is not. PMID- 25787186 TI - Cardiovascular autonomic dysfunction in multiple sclerosis: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: The definition of cardiovascular autonomic dysfunction in patients with multiple sclerosis is controversial. Thus, its true prevalence is unknown. We performed a systematic review and meta-analysis to compare the proportion of patients with multiple sclerosis that would be diagnosed with cardiovascular dysautonomia using a definition of at least one abnormal cardiac autonomic test vs. at least two abnormal studies. METHODS: We searched PubMed, Embase, and Scopus from 1980 to December 2013 for publications reporting abnormal autonomic tests in patients with multiple sclerosis. We performed random-effects meta-analyses for calculating the proportion of patients diagnosed with autonomic dysfunction with both definitions. RESULTS: We included 16 studies comprising 611 patients with multiple sclerosis, assessing >=3 cardiovascular autonomic tests. The proportion of patients with autonomic dysfunction was two-fold higher (p=0.006) when using the definition of only one abnormal autonomic test (42.1%) compared to that using at least two abnormal results (18.8%). CONCLUSIONS: We found a wide variation in the proportion of patients with multiple sclerosis diagnosed with cardiovascular dysautonomia by using the two definitions. Consensus is needed to define autonomic dysfunction in patients with multiple sclerosis. In the meantime, we encourage investigators to report results using both thresholds. PMID- 25787187 TI - Multiple sclerosis: the role of melatonin and N-acetylserotonin. AB - Multiple sclerosis (MS) is an immune mediated disorder that is under intensive investigation in an attempt to improve on available treatments. Many of the changes occurring in MS, including increased mitochondrial dysfunction, pain reporting and depression may be partly mediated by increased indoleamine 2,3 dioxygenase, which drives tryptophan to the production of neuroregulatory tryptophan catabolites and away from serotonin, N-acetylserotonin and melatonin production. The consequences of decreased melatonin have classically been attributed to circadian changes following its release from the pineal gland. However, recent data shows that melatonin may be produced by all mitochondria containing cells to some degree, including astrocytes and immune cells, thereby providing another important MS treatment target. As well as being a powerful antioxidant, anti-inflammatory and antinociceptive, melatonin improves mitochondrial functioning, partly via increased oxidative phosphorylation. Melatonin also inhibits demyelination and increases remyelination, suggesting that its local regulation in white matter astrocytes by serotonin availability and apolipoprotein E4, among other potential factors, will be important in the etiology, course and treatment of MS. Here we review the role of local melatonin and its precursors, N-acetylserotonin and serotonin, in MS. PMID- 25787189 TI - Subclinical MRI disease activity influences cognitive performance in MS patients. AB - BACKGROUND: The pathological mechanisms underlying cognitive dysfunction in multiple sclerosis (MS) are not yet fully understood and, in addition to demyelinating lesions and gray-matter atrophy, subclinical disease activity may play a role. OBJECTIVE: To evaluate the contribution of asymptomatic gadolinium enhancing lesions to cognitive dysfunction along with gray-matter damage and callosal atrophy in relapsing-remitting MS (RRMS) patients. METHODS: Forty-two treated RRMS and 30 controls were evaluated. MRI (3T) variables of interest were brain white-matter and cortical lesion load, cortical and deep gray-matter volumes, corpus callosum volume and presence of gadolinium-enhancing lesions. Outcome variables included EDSS, MS Functional Composite (MSFC) subtests and the Brief Repeatable Battery of Neuropsychological tests. Cognitive dysfunction was classified as deficits in two or more cognitive subtests. Multivariate regression analyses assessed the contribution of MRI metrics to outcomes. RESULTS: Patients with cognitive impairment (45.2%) had more cortical lesions and lower gray-matter and callosal volumes. Patients with subclinical MRI activity (15%) had worse cognitive performance. Clinical disability on MSFC was mainly associated with putaminal atrophy. The main independent predictors for cognitive deficits were high burden of cortical lesions and number of gadolinium-enhancing lesions. CONCLUSIONS: Cognitive dysfunction was especially related to high burden of cortical lesions and subclinical disease activity. Cognitive studies in MS should look over subclinical disease activity as a potential contributor to cognitive impairment. PMID- 25787190 TI - Unmet needs of multiple sclerosis patients in the community. AB - BACKGROUND: There is no evidence that disease modifying therapies (DMTs) are beneficial in progressive (non-relapsing) MS. However, these patients may benefit from multidiscipliniary interventions, and require financial and community support. Non-pharmacological needs of MS patients may be overlooked during fund allocation, and identification of unmet needs is important to optimise care and inform governmental resource distribution. AIM: To identify unmet needs of MS patients in 3 areas during an Irish epidemiology study. PATIENTS AND METHODS: Observational study in 3 regions in Ireland: South Dublin SCD (an urban area), Donegal DGL and Wexford WEX (rural counties).A validated Needs Assessment Questionnaire (NAQ) was completed by MS patients at research clinics, or by telephone if unable to attend. RESULTS: We identified 632 patients with multiple sclerosis: 23% SCD (urban), 30.8% WEX, and 46.2% DGL.MS subtype was relapsing remitting (RR) in 51.1%, secondary progressive (SP) in 39.7%, and primary progressive (PP) in 9.2%. EDSS was 6.5 in 14%. NAQ was completed by 325 (49.9%).Group A: 155 (47.7%) reported no unmet needs relating to MS.Group B: 170 (52.3%) reported unmet needs relating to MS,including all in a group continuing to use disease-modifying therapy without benefit (EDSS>6.5).Number of unmet needs per patient in group B: 1 need 27%, >=2 needs 73%, >=5 24%.Unmet needs overall correlated with EDSS >6.5 (p<0.001),MS subtype: RR 36.4%/SP 69.8%/PP 59.5% (p<0001),increased age (p 0.003) and MS duration (p 0.003). Multivariate analysis: presence of unmet needs related to higher EDSS (p<0.001), rural residence (p<0.05), SPMS (p<0.05).Financial unmet needs frequency differed by county: DGL 23.9%, WEX 17%, SCD 10.4% (p 0.045) and marital status: 24% single, 13.5% married (p 0.03).Multivariate analysis: related to rural residence (p<0.05), being single (p<0.05).Occupational therapy (OT) unmet needs frequency differed by subtype:RR 6%/SP 24.5%/ PP 19% (p 0.001), MS duration: 19.7 v 14.8y (p 0.003)and increasing age: 52.5 v 45.8y (p 0.0006).Multivariate analysis: rural, older age, higher EDSS (p<0.05).Physiotherapy unmet needs frequency differed by subtype: RR 17.2%/SP 43.4%/PP 31.7% (p<0.001), MS duration (p<0.001), and age (p 0.002).Multivariate analysis: related to higher EDSS (p<0.001).Employment unmet needs frequency differed by gender:male 22.9%, female 12.8% (p 0.02).Social unmet needs frequency differed by subtype: RR 12%/SP 39.2%/PP 32.5%, MS duration and age (p 0.001): multivariate analysis: SPMS (p<0.001). DISCUSSION: More than 50% reported unmet needs relating to MS: suggesting non-pharmacological needs are not optimally addressed, particularly in older, single, rural residents, with greater EDSS and progressive non-relapsing MS. Physiotherapy offers significant benefits, but is the most frequently reported unmet need.These findings highlight the need for increased fund allocation, especially for development of community supports and multidisciplinary/ social services.Identifying unmet needs may help inform health service planning, and emphasises particular need for improved resources in a high risk group of MS patients. PMID- 25787191 TI - Relationship between muscle strength parameters and functional capacity in persons with mild to moderate degree multiple sclerosis. AB - BACKGROUND: Maximal muscle strength has been shown to be an important predictor of functional capacity for persons with multiple sclerosis (PwMS). Another muscle strength parameter known to be important for functional capacity in other patient groups is rate of force development (RFD) in knee extensors and flexors. This has not been investigated for PwMS. Thus, the purpose of this study was to investigate the relationship between RFD and maximal muscle strength of knee extensors and flexors and measures of functional capacity in PwMS. METHODS: 35 PwMS (Expanded Disability Status Scale 2-4) underwent isokinetic dynamometry to determine RFD and maximal isometric and isokinetic muscle strength for both legs. Furthermore all participants performed timed 25 foot walk tests (T25FWT), two minute walk tests (2MWT), stairclimb tests and 5-time sit-to-stand (5STS) tests to determine functional capacity. Multiple linear regressions were performed to determine which muscle strength parameter would serve as a stronger predictor of walking performance. RESULTS: Both RFD and maximal muscle strength correlated with functional capacity. Correlations were strongest for knee extensors and flexors of the weaker leg, while no clear ranking of the influence of the knee extensors vs. flexors on walking was evident. Multiple linear regressions showed that maximal isokinetic strength of the weaker leg is a better predictor for T25FWT and 2MWT performance than RFD. CONCLUSIONS: Maximal muscle strength of the weaker leg is the better predictor of walking performance in persons with mild to moderate multiple sclerosis. RFD, although also important for functional capacity, is a less strong predictor. Maximal strength of the knee extensors, rather than the knee flexors, predicted performance in the stairclimb and 5STS tests. PMID- 25787188 TI - Regional gray matter atrophy in relapsing remitting multiple sclerosis: baseline analysis of multi-center data. AB - Regional gray matter (GM) atrophy in multiple sclerosis (MS) at disease onset and its temporal variation can provide objective information regarding disease evolution. An automated pipeline for estimating atrophy of various GM structures was developed using tensor based morphometry (TBM) and implemented on a multi center sub-cohort of 1008 relapsing remitting MS (RRMS) patients enrolled in a Phase 3 clinical trial. Four hundred age and gender matched healthy controls were used for comparison. Using the analysis of covariance, atrophy differences between MS patients and healthy controls were assessed on a voxel-by-voxel analysis. Regional GM atrophy was observed in a number of deep GM structures that included thalamus, caudate nucleus, putamen, and cortical GM regions. General linear regression analysis was performed to analyze the effects of age, gender, and scanner field strength, and imaging sequence on the regional atrophy. Correlations between regional GM volumes and expanded disability status scale (EDSS) scores, disease duration (DD), T2 lesion load (T2 LL), T1 lesion load (T1 LL), and normalized cerebrospinal fluid (nCSF) were analyzed using Pearson's correlation coefficient. Thalamic atrophy observed in MS patients compared to healthy controls remained consistent within subgroups based on gender and scanner field strength. Weak correlations between thalamic volume and EDSS (r=-0.133; p<0.001) and DD (r=-0.098; p=0.003) were observed. Of all the structures, thalamic volume moderately correlated with T2 LL (r=-0.492; P-value<0.001), T1 LL (r=-0.473; P-value<0.001) and nCSF (r=-0.367; P-value<0.001). PMID- 25787192 TI - High doses of biotin in chronic progressive multiple sclerosis: a pilot study. AB - BACKGROUND: No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. OBJECTIVES: The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. STUDY DESIGN: Uncontrolled, non-blinded proof of concept study METHODS: 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. RESULTS: In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment's onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment's onset. CONCLUSIONS: These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. PMID- 25787193 TI - Fabry disease mimicking multiple sclerosis: Lessons from two case reports. AB - Fabry disease is an X-linked lysosomal storage disorder that can mimic multiple sclerosis. We present two cases of heterozygous adult women where clinical and radiological features initially suggested a diagnosis of multiple sclerosis. This led us to review the early clinical course and neurological features of Fabry disease and highlight the importance of assessing non-neurologic (systemic) symptoms when considering a diagnosis of multiple sclerosis and the need for specialist interpretation of neuroradiological findings. PMID- 25787194 TI - Teaching case: a man with a progressive gait impairment and visual compromise. AB - Primary progressive multiple sclerosis can present with a wide variety of symptoms. We report a case of a 52-year-old man presenting with visual symptoms and gait impairment in whom a diagnosis of a primary progressive multiple sclerosis was established. Symptomatic treatment with dalfampridine was started but did not result in a considerable improvement. Gait disorders in multiple sclerosis are common and can have a considerable effect over the patient's quality of life. Dalfampridine is the first drug approved for the symptomatic treatment of gait in MS, although only a 40% of patients show an objective response to this medication. Primary progressive multiple sclerosis represents a therapeutic challenge. Currently, there are no disease modifying treatments approved but there are several medications undergoing assessment for this indication. Further research in the underlying pathophysiology of PPMS will help us develope more successful disease-modifying treatments. Meanwhile, a symptomatic approach should be offered in order to improve the patient's quality of life. PMID- 25787196 TI - Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis: 1-Year Results From the All-Comers NOTION Randomized Clinical Trial. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an option in certain high-risk surgical patients with severe aortic valve stenosis. It is unknown whether TAVR can be safely introduced to lower-risk patients. OBJECTIVES: The NOTION (Nordic Aortic Valve Intervention Trial) randomized clinical trial compared TAVR with surgical aortic valve replacement (SAVR) in an all-comers patient cohort. METHODS: Patients >= 70 years old with severe aortic valve stenosis and no significant coronary artery disease were randomized 1:1 to TAVR using a self-expanding bioprosthesis versus SAVR. The primary outcome was the composite rate of death from any cause, stroke, or myocardial infarction (MI) at 1 year. RESULTS: A total of 280 patients were randomized at 3 Nordic centers. Mean age was 79.1 years, and 81.8% were considered low-risk patients. In the intention-to-treat population, no significant difference in the primary endpoint was found (13.1% vs. 16.3%; p = 0.43 for superiority). The result did not change in the as-treated population. No difference in the rate of cardiovascular death or prosthesis reintervention was found. Compared with SAVR-treated patients, TAVR treated patients had more conduction abnormalities requiring pacemaker implantation, larger improvement in effective orifice area, more total aortic valve regurgitation, and higher New York Heart Association functional class at 1 year. SAVR-treated patients had more major or life-threatening bleeding, cardiogenic shock, acute kidney injury (stage II or III), and new-onset or worsening atrial fibrillation at 30 days than did TAVR-treated patients. CONCLUSIONS: In the NOTION trial, no significant difference between TAVR and SAVR was found for the composite rate of death from any cause, stroke, or MI after 1 year. (Nordic Aortic Valve Intervention Trial [NOTION]; NCT01057173). PMID- 25787197 TI - Randomized Trial of Stents Versus Bypass Surgery for Left Main Coronary Artery Disease: 5-Year Outcomes of the PRECOMBAT Study. AB - BACKGROUND: In a previous randomized trial, we found that percutaneous coronary intervention (PCI) was not inferior to coronary artery bypass grafting (CABG) for the treatment of unprotected left main coronary artery stenosis at 1 year. OBJECTIVES: This study sought to determine the 5-year outcomes of PCI compared with CABG for the treatment of unprotected left main coronary artery stenosis. METHODS: We randomly assigned 600 patients with unprotected left main coronary artery stenosis to undergo PCI with a sirolimus-eluting stent (n = 300) or CABG (n = 300). The primary endpoint was a major adverse cardiac or cerebrovascular event (MACCE: a composite of death from any cause, myocardial infarction, stroke, or ischemia-driven target vessel revascularization) and compared on an intention to-treat basis. RESULTS: At 5 years, MACCE occurred in 52 patients in the PCI group and 42 patients in the CABG group (cumulative event rates of 17.5% and 14.3%, respectively; hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 0.84 to 1.90; p = 0.26). The 2 groups did not differ significantly in terms of death from any cause, myocardial infarction, or stroke as well as their composite (8.4% and 9.6%; HR, 0.89; 95% CI, 0.52 to 1.52; p = 0.66). Ischemia-driven target vessel revascularization occurred more frequently in the PCI group than in the CABG group (11.4% and 5.5%, respectively; HR: 2.11; 95% CI: 1.16 to 3.84; p = 0.012). CONCLUSIONS: During 5 years of follow-up, our study did not show significant difference regarding the rate of MACCE between patients who underwent PCI with a sirolimus-eluting stent and those who underwent CABG. However, considering the limited power of our study, our results should be interpreted with caution. (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease [PRECOMBAT]; NCT00422968). PMID- 25787198 TI - Perioperative Results and Complications in 15,964 Transcatheter Aortic Valve Replacements: Prospective Data From the GARY Registry. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has evolved into a routine procedure with good outcomes in high-risk patients. OBJECTIVES: TAVR complication rates were evaluated based on prospective data from the German Aortic Valve Registry (GARY). METHODS: From 2011 to 2013, a total of 15,964 TAVR procedures were registered. We evaluated the total cohort for severe vital complications (SVCs), including the following: death on the day of intervention, conversion to sternotomy, low cardiac output that required mechanical support, aortic dissection, and annular rupture; technical complications of the procedures (TCOs), such as repositioning or retrieval of the valve prosthesis and embolization of the prosthesis; and other complications. RESULTS: Mean patient age was 81 +/- 6 years, 54% of the patients were women, the median logistic Euroscore I was 18.3, the German aortic valve score was 5.6, and the Society of Thoracic Surgeons score was 5.0. Overall in-hospital mortality was 5.2%, whereas SVCs occurred in 5.0% of the population. Independent predictors for SVCs were female sex, pre-operative New York Heart Association functional class IV, ejection fraction <30%, pre-operative intravenous inotropes, arterial vascular disease, and higher degree of calcifications. TCOs occurred in 4.7% of patients and decreased significantly from 2011 to 2013. An emergency sternotomy was performed in 1.3% of the patients; however, multivariate analysis did not identify any predictors for conversion to sternotomy. CONCLUSIONS: The all-comers GARY registry revealed good outcomes after TAVR and a regression in complications. Survival of approximately 60% of patients who experienced SVCs or who required sternotomy underlines the need for heart team-led indication, intervention, and follow-up care of TAVR patients. PMID- 25787199 TI - Benefits and Risks of Extended Duration Dual Antiplatelet Therapy After PCI in Patients With and Without Acute Myocardial Infarction. AB - BACKGROUND: The benefits and risks of prolonged dual antiplatelet therapy may be different for patients with acute myocardial infarction (MI) compared with more stable presentations. OBJECTIVES: This study sought to assess the benefits and risks of 30 versus 12 months of dual antiplatelet therapy among patients undergoing coronary stent implantation with and without MI. METHODS: The Dual Antiplatelet Therapy Study, a randomized double-blind, placebo-controlled trial, compared 30 versus 12 months of dual antiplatelet therapy after coronary stenting. The effect of continued thienopyridine on ischemic and bleeding events among patients initially presenting with versus without MI was assessed. The coprimary endpoints were definite or probable stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) moderate or severe bleeding. RESULTS: Of 11,648 randomized patients (9,961 treated with drug-eluting stents, 1,687 with bare-metal stents), 30.7% presented with MI. Between 12 and 30 months, continued thienopyridine reduced stent thrombosis compared with placebo in patients with and without MI at presentation (MI group, 0.5% vs. 1.9%, p < 0.001; no MI group, 0.4% vs. 1.1%, p < 0.001; interaction p = 0.69). The reduction in MACCE for continued thienopyridine was greater for patients with MI (3.9% vs. 6.8%; p < 0.001) compared with those with no MI (4.4% vs. 5.3%; p = 0.08; interaction p = 0.03). In both groups, continued thienopyridine reduced MI (2.2% vs. 5.2%, p < 0.001 for MI; 2.1% vs. 3.5%, p < 0.001 for no MI; interaction p = 0.15) but increased bleeding (1.9% vs. 0.8%, p = 0.005 for MI; 2.6% vs. 1.7%, p = 0.007 for no MI; interaction p = 0.21). CONCLUSIONS: Compared with 12 months of therapy, 30 months of dual antiplatelet therapy reduced the risk of stent thrombosis and MI in patients with and without MI, and increased bleeding. (The Dual Antiplatelet Therapy Study [The DAPT Study]; NCT00977938). PMID- 25787200 TI - Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. AB - AIM: To assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. METHODS: This phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: At week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, -0.57% with fasiglifam 25 mg and -0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group. CONCLUSIONS: Fasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed. PMID- 25787201 TI - Gelatin nanoparticles enhance the neuroprotective effects of intranasally administered osteopontin in rat ischemic stroke model. AB - As a leading cause of death and adult disability, ischemic stroke requires the development of non-invasive, long-acting treatments. Osteopontin (OPN) is an endogenous protein shown to have neuroprotective effects in the post-ischemic brain of rats when administered through the non-invasive, intranasal pathway. Previously, gelatin microspheres (GMSs) have been shown to enhance the neuroprotective effects of OPN when used as a carrier during instrastriatal administration, but GMSs are generally too large to enter the brain parenchyma following intranasal administration. Here, gelatin nanoparticles (GNPs) were investigated as a carrier for intranasal delivery of an OPN peptide for the treatment of ischemic stroke. We not only successfully fabricated GNPs with a uniform shape, but also demonstrated the ability of these GNPs to pass into the brain parenchyma following intranasal administration. Critically, the use of GNPs as a carrier allowed for a 71.57 % reduction in mean infarct volume and extended the therapeutic window of intranasally administered OPN peptide to at least 6 h post-middle cerebral artery occlusion (MCAO). Our findings support the development of GNPs as a promising drug delivery platform for the intranasal treatment of ischemic stroke and, potentially, other neurologic disorders. PMID- 25787202 TI - Treatment of cutaneous candidiasis through fluconazole encapsulated cubosomes. AB - Cubosomes encapsulating fluconazole were prepared by emulsification method and characterized for particle size, entrapment efficiency, SEM, in vitro release, skin irritation studies, and confocal laser scanning microscopy. The cubosomes prepared were 257.2 +/- 2.94 nm in size and with drug entrapment efficiency of 66.2 +/- 2.69 %. The prepared formulation was characterized for surface morphology by SEM analysis which revealed their smooth surface. The cumulative percentage of fluconazole from cubosomes permeated via dialysis membrane (molecular weight cutoff (MWCO) 12-14 kD) showed 76.86 % cumulative drug release, while fluconazole solution showed release up to 91.04 % in 24 h in phosphate buffered saline (PBS) (pH 6.5), and sustained release is obtained after 24 h in case of cubosomes. The animal studies also revealed that the cubosomes are non irritant and have sustained antifungal activity. PMID- 25787203 TI - Self-assembled polymer vesicles in deciding action of Zn-sulfanilamide allergenicity. AB - Allergic reactions to sulfonamide-based drugs are quite common; hence, medications containing sulfonamides are prescribed carefully. Metal ion complexation may block the nitrogen binding site of sulfonamide by complexation and reduce such responses. In this study, trace concentrations of Zn were found to bind with sulfanilamide at pH ~ 1. The complexation was studied in water as well as in vesicular medium of polyethylene glycol (PEG) and a block copolymer, PPG-PEG-PPG. The binding constants (k) of Zn-sulfanilamide complex were determined in water, PEG, and PPG-PEG-PPG block copolymer media. The values suggest that complexation occurs best in water followed by PPG-PEG-PPG, PEG #4000, and PEG #12000. Though the binding constants are high in water and block copolymer media, the complex is not very stable as the absorbance value for the complex was found to decline with time. The same complex when prepared in polymer matrix shows higher stability. The results prompted us to explore the extraction possibilities of the Zn-sulfanilamide complex by using aqueous biphasic extraction systems comprising the polymers against sodium sulfate solution. The complex was analyzed for its allergenic response in different media by competitive enzyme-linked immunosorbent assay (ELISA) technique. The allergic response of the compounds in the respective media is the resultant of the binding constant and the stability of the complex in that particular medium. PMID- 25787204 TI - Pouch drug delivery systems for dermal and transdermal administration. AB - In this work, we have designed and investigated a new carrier for dermal and transdermal drug delivery. The delivery system is composed of high (>60 %) ethanol concentration, phospholipid, polymer, and water. The system forms a structured matrix following non-occluded application on the skin. We call these structured carriers as pouch drug delivery systems (PDDS). The pouch-structured matrix was characterized by electron microscopy, (31)P-NMR and FTIR. The new delivery system exhibits a number of properties adequate for the design of improved dermal and transdermal drug administration for various treatments. Lidocaine PDDS dry faster and has an enhanced dermal drug delivery when compared to a clinical-used product. These proprieties are important for the prevention of premature ejaculation. Results obtained in pharmacodynamics test carried out with brotizolam PDDS in a mice-sleeping model and with ibuprofen PDDS in fevered rats indicated a prolonged hypnotic and antipyretic effect, respectively. The carrier was found nonirritant in tests carried out on EpiDerm(TM) skin model. PMID- 25787205 TI - Enhanced insulin absorption from sublingual microemulsions: effect of permeation enhancers. AB - Microemulsions of insulin (50 IU/mL) comprising permeation enhancers were formulated for sublingual delivery. Circular dichroism (CD) spectra indicated conformational stability, while chemical stability was confirmed by high performance liquid chromatography (HPLC). CD spectra of insulin in combination with permeation enhancers revealed attenuation of molar ellipticity at 274 nm in the order TCTP > TC-AOT > TC > TC-NMT > Sol P > insulin solution. The molar ellipticity ratios at 208/222 nm confirmed dissociation of insulin in the microemulsions with the same rank order. Matrix-assisted laser diffraction ionization mass spectra (MALDI) revealed a significant shift in intensity signals towards monomer and dimers with a substantially high ratio of monomers, especially in the presence of the TCTP and TC-AOT. Permeation through porcine sublingual mucosa correlated with the dissociation data. A high correlation between the ratio of molar ellipticity at 208/222 nm and serum glucose levels (r (2) > 0.958) and serum insulin levels (r (2) > 0.952) strongly suggests the role of dissociation of insulin on enhanced absorption. While all microemulsions revealed a reduction in serum glucose levels and increase in serum insulin levels, significant differences were observed with the TCTP and TC-AOT microemulsions. High pharmacological availability >60 % and bioavailability >55 % compared to subcutaneous insulin at a low dose of 2 IU/kg appears highly promising. The data clearly suggests the additional role of the permeation enhancers on dissociation of insulin on enhanced sublingual absorption from the microemulsions. PMID- 25787206 TI - Core-shell nanoparticulate formulation of gemcitabine: lyophilization, stability studies, and in vivo evaluation. AB - Core-shell nanoparticulate formulation of gemcitabine was prepared by incorporating gemcitabine in a hydrophilic bovine serum albumin (BSA) core surrounded by hydrophobic poly(DL-lactic acid-co-glycolic acid) (PLGA) shell with a particle size of 243 nm and encapsulation efficiency of 40.5 %. Prepared formulations were lyophilized, wherein several cryoprotectants were screened for product attributes such as cake appearance, reconstitution with water, and size constancy. Trehalose was screened as a lyoprotectant, which showed stability for 6 months at 5 degrees C and 25 degrees C/60 % relative humidity (RH) conditions. However, an increase in particle size was observed at accelerated conditions (40 degrees C/75 % RH). In vitro evaluation of these nano formulations in MCF-7 breast cancer cells showed enhanced cellular uptake (90 %) as compared to GEMCITE(r) uptake (51 %) in 6 h along with reduced IC50 value at 72 h (16 MUM versus 30 MUM). In vivo studies in Sprague Dawley rats showed C max, t 1/2, and area under the curve (AUC) at 2.55 MUg/ml, 13.6 h, and 28,322.5 MUg/l/h, respectively, whereas GEMCITE(r) at the same dose showed significantly lower corresponding values at 1.94 MUg/ml, 6.89 h, and 13,967 MUg/l/h. In the same study, AUC and C max of inactive metabolite of gemcitabine (dFdU) were reduced by 33 and 42 %, respectively, for these nanoparticles compared to GEMCITE(r). In 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer model, significantly reduced tumor growth was observed in gemcitabine-loaded nanoparticle-treated animals compared with GEMCITE(r)-treated animal at equivalent dose (121 versus 243 % in 30 days). The results indicated that our core-shell nanoparticles are more effective for tumor reduction compared to marketed formulation of gemcitabine, GEMCITE(r). PMID- 25787207 TI - Formulation development, optimization, and evaluation of sustained release tablet of valacyclovir hydrochloride by combined approach of floating and swelling for better gastric retention. AB - The present study is intended to enhance gastric retention of sustained release tablet of valacyclovir hydrochloride by combined approach of floating and swelling. The tablets are prepared by direct compression method. Polyethylene oxide (Polyox WSR 303) is selected as the swelling matrix agent. Sodium starch glycolate (SSG) is used as swelling enhancer, and sodium bicarbonate is used as an effervescent agent for floating. A 3(2) full factorial design is applied to systematically optimize the formulation. The concentration of Polyox WSR 303 (X 1) and concentration of SSG (X 2) are selected as independent variables. The percentage drug release at 12 h, floating lag time, and maximum percentage swelling are selected as dependent variables. Formulations are evaluated for hardness, friability, floating lag time, total floating time, percentage swelling, in vitro drug release, and in vivo floating study. The results indicated that X 1 and X 2 significantly affected the drug release properties, floating lag times, and maximum percentage swelling. Release rate decreases as the concentration of Polyox increased. Regression analysis and numerical optimization are performed to identify the best formulation. Formulation F5 prepared with Polyox WSR 303 (15 %) and SSG (10 %) is found to be the best formulation. F5 followed zero-order release mechanism. Swelling and floating gastroretentive tablets of valacyclovir HCl are successfully formulated with controlled delivery to stomach with an aim of increasing the mean residence time in the upper part of GIT where the drug has its absorption window. PMID- 25787208 TI - Psychological Factors Involved in Sexual Desire, Sexual Activity, and Sexual Satisfaction: A Multi-factorial Perspective. AB - This study explored the role of psychological trait factors in sexual desire and sexual activity. In particular, it investigated how these factors may contribute to maintaining a balance between motivational aspects and self-control abilities, as both have been considered important in relation to adaptive sexuality. Moreover, the study explored the relationship between sexual desire, activity, and satisfaction. Participants completed questionnaires assessing sexual desire (dyadic, solitary), sexual activity (with a partner, alone), sexual satisfaction, approach and avoidance motivation, attachment, self-control, sensation seeking, and mindfulness. Cluster analyses, based on participants' level of sexual desire and sexual activity, highlighted three distinct profiles for each gender related to different types of psychological functioning: (a) participants with high dyadic sexual desire and activity were the most sexually satisfied, showed optimal psychological functioning, and were characterized by a balance between motivational tendencies to seek positive rewards and self-control abilities (high approach motivation, secure attachment, high self-control, high mindfulness); (b) participants with high dyadic and solitary sexual desire and activity were moderately satisfied and showed a type of psychological functioning predominantly characterized by impulsivity (an overly high motivation to obtain rewards in women, and low self-control in men); (c) participants with low dyadic sexual desire and activity were the least sexually satisfied and were characterized by high motivation to avoid negative consequences and low self-control (high avoidance motivation, insecure attachment, and poor mindfulness). These results shed further light on how fundamental psychological factors contribute to explain the individual variability in sexual desire, activity, and satisfaction. PMID- 25787209 TI - Association between coffee consumption and an oxidative stress marker in women. AB - BACKGROUND: Coffee is one of the major dietary modulators of oxidative stress conditions. Whether coffee consumption is associated with oxidative stress markers, such as derivatives of reactive oxygen metabolites (d-ROMs), remains to be investigated in women, despite one recent report describing their significant association in men. METHODS: A total of 415 women (49 +/- 9 years) attending a general clinic were evaluated regarding their self-reported coffee consumption habits and blood d-ROMs levels. RESULTS: Women who reported >= 3 cups/day of coffee consumption displayed a lower d-ROMs level than those who reported consuming 0-2 cups/day (336 +/- 67 vs. 358 +/- 80 Carr U; p < 0.05). In the multivariate-adjusted analysis, the association between coffee consumption and the d-ROMs level remained to be significant (p < 0.05). CONCLUSIONS: Daily coffee consumption (i.e., >= 3 cups) may be associated with a reduced oxidative stress status, as measured by the d-ROMs level, among women. PMID- 25787210 TI - Ischemic stroke: the impact of renal dysfunction on 1-year mortality. AB - BACKGROUND: Atherosclerosis is accelerated in patients with different stages of chronic renal failure. Renal dysfunction predicts mortality in patients with myocardial infarction and congestive heart failure. Less is known about the impact of renal dysfunction on mortality after ischemic stroke. The aim of the study was to investigate the impact of renal dysfunction on 1-year mortality. PATIENTS AND METHODS: All 390 patients (207 men and 183 women) suffered from ischemic stroke in 1-year period were included in our study. Telephonic follow-up after 1 year was performed. The mean age of our patients was 71.0 +/- 11.6 years, ranged from 36 to 96 years. Glomerular filtration rate (GFR) was calculated according to abbreviated Modification of Diet in Renal Disease formula. At admission and at discharge National Institutes of Health Stroke Scale (NIHSS) were performed. RESULTS: The mean GFR in our patients was 66.0 +/- 20.68 ml/min/1.73 m(2). There were 123 (31.5 %) deaths in 1-year period. Patients who died were older (P < 0.001), had higher NIHSS at admission and at discharge (both P < 0.001), higher high-sensitive C-reactive protein (P = 0.002), lower albumin (P < 0.001), lower GFR (P = 0.044), had more frequent atrial fibrillation (P < 0.001), and were less frequent actual smokers (P = 0.003). No differences in presence of diabetes and hypertension, high-density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides between patients who died or survived were found. With Cox multivariable regression analysis age (P = 0.037), gender (P = 0.005), NIHSS at admission (P = 0.005) and discharge (P < 0.001), albumin (P = 0.005) and also GFR (P = 0.025) were predictors of 1-year mortality. CONCLUSIONS: In patients with ischemic stroke, renal dysfunction (decreased GFR) was associated with 1-year mortality. GFR was independent predictor of mortality. PMID- 25787211 TI - Focus points in prevention actions against legal substances' abuse. AB - AIM: To determine the factors associated with alcohol and tobacco abuse in Slovenian general population. MATERIAL AND METHODS: We performed an observational cross-sectional study in a representative sample of 1002 Slovenian inhabitants in June 2011. It was performed using a method of computer-assisted telephone interview. The telephone interview consisted of questions about the prevalence and duration of preselected health-related symptoms in the past month, questions about the presence of chronic diseases, question about the presence of current smoking, EQ-5D questionnaire and AUDIT-C questionnaire. RESULTS: Risky drinking was found in 103 (14.3 %) of the sample and smoking was found in 226 (22.6 %) of the sample. Men reported risky drinking more often when compared with women (17.7 vs. 10.5 %, P = 0.007). Multivariate analysis showed that male sex, current tobacco smoking, lower education level, self-reported presence of anxiety/depression and self-reported presence of muscle pain and excessive fatigue in the past month were independently associated with risky drinking and that male sex, lower education and income, the presence of chronic disease, self reported problems in daily activities, risky drinking, self-reported troubles in sleeping and restless leg syndrome were independently associated with current tobacco smoking. CONCLUSION: Risky alcohol drinking and smoking are still major public health problems in Slovenia and are associated with known demographic risk factors but also with some symptoms of somatoform disorders. These findings should be incorporated into the guidelines for family physicians as the important focus points for screening and intervening against legal substances' abuse in their patients. PMID- 25787212 TI - Relation of fragmented QRS to tissue Doppler-derived parametersin patients with familial Mediterranean fever. AB - BACKGROUND: Familial Mediterranean fever (FMF) may pose a risk for cardiovascular diseases due to continuous inflammatory status observed during the course of the disease. Recently, the presence of fragmented QRS (fQRS) has been recognized as a predictor of myocardial fibrosis. In this study, we aim to investigate the frequency of fQRS and its relation to Doppler-based indices. METHODS: This study consisted of 80 FMF patients and 30 healthy control subjects. fQRS pattern was defined as the presence of additional R waves or RSR', evidenced by notched R or S wave on electrocardiography (ECG). The patient and the control groups underwent conventional echocardiography and tissue Doppler echocardiography. RESULTS: There was no significant difference between groups regarding age (29 +/- 12 vs 29 +/- 15). FMF patients exhibited a statistically higher frequency of fQRS (% 56 vs % 13) (p < 0.01). E/Em ratio showed a statistically significant increase in the FMF group with fQRS (p < 0.0001), while the mean Em value was markedly lower (p < 0.0001). CONCLUSIONS: FMF patients displayed a statistically significant increase in frequency of fQRS. Doppler-derived diastolic index was statistically significantly impaired in FMF patients with fQRS as compared with the patients without fQRS. In conclusion, fQRS might be a new noninvasive marker for cardiac involvement in FMF patients. PMID- 25787213 TI - Giant left ventricular aneurysm after recurrent mitral valve replacement. AB - Left ventricular pseudoaneurysm after mitral valve replacement has been reported in various studies; however, as far as we know, a true aneurysm after redo mitral valve replacement has not been reported in any article yet. We herein present a patient who developed a true aneurysm and atrioventricular complete block after third surgery of mitral valve. DDD pacemaker was implanted, albeit the patient refused reoperation for aneurysmectomy. PMID- 25787214 TI - Prevalence of isolated systolic hypertension (ISH) in Slovene hypertensive patients: insights from the "Quality of Healthcare in Slovenia" project. AB - OBJECTIVES: The aim of the present study was mainly to evaluate age- and gender dependent isolated systolic hypertension (ISH) prevalence before and during antihypertensive treatment, and to evaluate pulse pressure (PP) distributions during antihypertensive treatment in almost 20,000 Slovene hypertensive patients. METHODS: The study was conducted as part of the "Quality of Healthcare in Slovenia" project, in agreement with the National Medical Ethics Committee of the Republic of Slovenia. Appropriate statistical analyses and evaluations were performed. RESULTS: The prevalence of ISH before the treatment was 19.6 % (17.0 % for men and 21.4 % for women) and it was significantly (p < 0.001) higher during the treatment (29.6 %; 26.4 % for men and 31.9 % for women). The mean PP before the treatment for the whole study patient sample was (71.2 +/- 16.9) mmHg and was significantly (p < 0.001) reduced during the treatment to (57.4 +/- 12.5) mmHg. CONCLUSION: With regard to high ISH in treated Slovene hypertensive patients, quality of ISH control may not be optimal and should be improved. On the other hand, the adequate arterial hypertension (AH) control (systolic blood pressure (SBP) < 140 mmHg and diastolic blood pressure (DBP) < 90 mmHg) was achieved in 55.6 % of patients. Our observations may have useful therapeutic implications in the management of AH, particularly ISH in the elderly. PMID- 25787215 TI - Prevalence of vitamin D deficiency in Slovak women with polycystic ovary syndrome and its relation to metabolic and reproductive abnormalities. AB - OBJECTIVE: To investigate prevalence of vitamin D deficiency and its relation to clinical, anthropometrical, and biochemical findings in polycystic ovary syndrome (PCOS) and controls. DESIGN: Case-control prospective observational study. SETTINGS: Department of Internal medicine, L.P. University hospital. PATIENT(S): 99 PCOS women and 66 controls. MAIN OUTCOME MEASURE(S): 25-hydroxyvitamin D level (25(OH)D), anthropometric, endocrine, and metabolic parameters in both groups. RESULTS: There was no significant difference in 25(OH)D levels between PCOS women and controls (24.79 +/- 10.77 vs 25.07 +/- 10.14 ng/ml, p = 0.868) and also in the prevalence of 25(OH)D deficiency in both groups (80 vs 70 %; p = 0.138). Vitamin D-deficient PCOS patients had significantly higher body mass index (BMI), fasting insulin, and homeostasis model assessment-insulin resistance (median [quartiles]: 2.24 [1.38; 3.51] vs 1.23 [0.79; 1.66]; p< 0.05, age-and BMI adjusted p = 0.036) and borderline higher glycemia (4.7 +/- 0.5 vs 4.5 +/- 0.4 mmol/l; p = 0.05; p_adj = 0.95) compared with vitamin D-deficient controls. PCOS women with metabolic syndrome (MS) had lower serum 25(OH)D compared with those without MS (20.6 +/- 8.3 vs 25.9 +/- 11.3 ng/ml, p = 0.049). 25(OH)D correlated positively with high-density lipoprotein cholesterol in all subjects (r = 0.159, p = 0.043) and negatively with luteinizing hormone/follicle-stimulating hormone ratio (r = - 0.211, p = 0.037). CONCLUSION: Insulin resistance and other metabolic abnormalities in PCOS women seem to be related to PCOS rather than to vitamin D deficiency. PMID- 25787216 TI - Predictors of 1-year visual outcome in OCT analysis comparing ranibizumab monotherapy versus combination therapy with PDT in exsudative age-related macular degeneration. AB - AIM: The aim of this study was to find predictive factors of 1-year visual outcome, analyzing novel optical coherence tomography (OCT) biomarkers in exsudative age-related macular degeneration (choroidal neovascularization (CNV)) in two groups of different treatment modalities. METHODS: In all, 34 consecutive patients with new-onset CNV were randomized 1:1 to receive either ranibizumab monotherapy or ranibizumab combined with photodynamic therapy (PDT) with verteporfin. After three initial injections with ranibizumab, re-treatment was performed according to an as-needed scheme; PDT was performed once at baseline. Best-corrected visual acuity (BCVA) and OCT parameters like central macular volume (CMV), central macular thickness (or central retinal thickness (CRT)), subretinal and intraretinal fluid, fibrovascular lesion thickness, or inner segment/outer segment (IS/OS) junction were analyzed. RESULTS: After 12 months, a visual gain of 6.1 letters was found in the monotherapy group, whereas patients in the combination therapy group lost - 4.8 letters from baseline to the 12-month visit. CMV and CRT decreased considerably between baseline and month 2-3 in both groups, with a following slight increase until month 12. Additional application of PDT had negative effect to 12-month BCVA, whereas higher baseline BCVA and integrity of the IS/OS junction at month 12 had positive effect to 12-month BCVA. CONCLUSIONS: Better baseline BCVA and the integrity of IS/OS junction at 12-month visit were the most important predictive factors for final BCVA. Combination therapy caused worse final BCVA and a higher degree of IS/OS disruption. PMID- 25787217 TI - Quantifying the effects of geographical and environmental factors on distribution of stream bacterioplankton within nature reserves of Fujian, China. AB - Bacterioplankton are important components of freshwater ecosystems and play essential roles in ecological functions and processes; however, little is known about their geographical distribution and the factors influencing their ecology, especially in stream ecosystems. To examine how geographical and environmental factors affect the composition of bacterioplankton communities, we used denaturing gradient gel electrophoresis and clone sequencing to survey bacterioplankton communities in 31 samples of streamwater from seven nature reserves in Fujian province, southeast China. Our results revealed that dominant bacterioplankton communities exhibited a distinct geographical pattern. Further, we provided evidence for distance decay relationships in bacterioplankton community similarity and found similar community gradients in response to elevation and latitude. Both redundancy analyses and Mantel tests showed that bacterioplankton community composition was significantly correlated with both environmental (electrical conductivity, total phosphorus, and PO4-P) and geographical factors (latitude, longitude, and elevation). Variance partitioning further showed that the joint effect of geographical and environmental factors explained the largest proportion of the variation in distribution of bacterioplankton communities (13.6 %), followed by purely geographical factors (11.2 %), and purely environmental factors (0.6 %). The Betaproteobacteria were the most common taxa in the streams, followed by Firmicutes and Gammaproteobacteria. Therefore, our results suggest that the biogeographical patterns of stream bacterioplankton communities across the Fujian nature reserves are more influenced by geographical factors than by local physicochemical properties. PMID- 25787218 TI - The impact of aluminum, fluoride, and aluminum-fluoride complexes in drinking water on chronic kidney disease. AB - It is suspected that drinking water containing fluoride and aluminum results in negative health effects especially on brain, liver, and kidney. In this investigation, the effect of F, Al, and AlFx complex on chronic kidney disease (CKD) was investigated. Mice were treated either with WHO recommended or slightly higher F and Al levels in drinking water. Treatment solutions contained 0.05-10.0 mg/L of F, 0.08-10.0 mg/L of Al, or 0.07-15 mg/L of AlFx, and the treatment period was 42 weeks. Blood urea level and creatinine levels were investigated as a measure of malfunction of kidneys. Histopathological evaluations of kidney tissues were carried out to assess the extent of damage that F, Al, and AlFx complex could cause. It was demonstrated that the treated drinking water containing F and Al with par with WHO or moderately above the WHO levels or AlFx in low level (0.07-15 mg/L) does not lead to CKD in mice. PMID- 25787219 TI - Surface properties of beached plastics. AB - Studying plastic characteristics in the marine environment is important to better understand interaction between plastics and the environment. In the present study, high-density polyethylene (HDPE), polyethylene terephalate (PET), and polyvinyl chloride (PVC) samples were collected from the coastal environment in order to study their surface properties. Surface properties such as surface functional groups, surface topography, point of zero charge, and color change are important factors that change during degradation. Eroded HDPE demonstrated an altered surface topography and color and new functional groups. Eroded PET surface was uneven, yellow, and occasionally, colonized by microbes. A decrease in Fourier transform infrared (FTIR) peaks was observed for eroded PET suggesting that degradation had occurred. For eroded PVC, its surface became more lamellar and a new FTIR peak was observed. These surface properties were obtained due to degradation and could be used to explain the interaction between plastics, microbes, and pollutants. PMID- 25787220 TI - Remediation of nitrate-contaminated water by solid-phase denitrification process a review. AB - The paper presents a compilation of various autotrophic and heterotrophic ways of solid-phase denitrification. It covers a complete understanding of various pathways followed during denitrification process. The paper gives a brief review on various governing factors on which the process depends. It focuses mainly on the solid-phase denitrification process, its applicability, efficiency, and disadvantages associated. It presents a critical review on various methodologies associated with denitrification process reported in past years. A comparative study has also been carried out to have a better understanding of advantages and disadvantages of a particular method. We summarize the various organic and inorganic substances and various techniques that have been used for enhancing denitrification process and suggest possible gaps in the research areas whi'ch are worthy of future research. PMID- 25787221 TI - The impact of chronic cough: a cross-sectional European survey. AB - PURPOSE: Studies that investigate the impact of chronic cough have largely focused on patients attending secondary care. Our aim was to investigate the opinions of the wider general population across Europe. METHODS: An internet survey was made available in 12 languages on the European Lung Foundation website, between January 2012 and April 2013. RESULTS: Of 1120 respondents from 29 different European countries, 67 % were female, mean age 51 years (SD 15), median cough duration 2-5 years. The majority of respondents reported cough impacted their quality of life, mood and ability to undertake activities. Despite 72 % of respondents having visited their doctor >=3 times, only 53 % had received a diagnosis. Asthma was the most common diagnosis (23 %). Most respondents reported limited or no effectiveness of medications. 88 % of respondents reported that they would like more information to be available on chronic cough. CONCLUSIONS: Chronic cough has a negative impact on quality of life. Further work is needed to raise awareness, promote management strategies, develop effective treatments and consider the educational and support needs of patients with chronic cough. PMID- 25787222 TI - In situ evidence of pulmonary endothelial activation in patients with granulomatosis with polyangiitis and systemic sclerosis. AB - INTRODUCTION: The aim of this study was to investigate the in situ pulmonary endothelial activation in lung lesions of granulomatosis with polyangiitis (GPA) and systemic sclerosis (SScl). METHODS: We examined the endothelial expression of ICAM-1, VCAM-1, and E-selectin using immunohistochemistry on formalin-fixed, paraffin-embedded sections of lung lesions of GPA, interstitial lung disease associated with SScl and controls. RESULTS: A significantly enhanced expression of ICAM-1 and E-selectin was observed in GPA and SScl pulmonary endothelium compared to controls. VCAM-1 was more pronouncedly expressed in GPA compared to SScl. CONCLUSION: These observations are an evidence of in situ pulmonary vascular endothelial activation in lesions of GPA and SScl, adding information to the pathogenic knowledge of both diseases. PMID- 25787223 TI - Knowledge and practice of colorectal screening in a suburban group of Iraqi American women. AB - Colorectal cancer (CRC) was the second most common cancer among women in 2008, accounting for 571,000 cases, and 9.4% of all cancer cases afflicting women worldwide. According to the World Health Organization (WHO) and the Iraqi National Cancer Registry (INCR), Iraq has seen a steady rise in CRC rates among its general population over the past several decades. Despite Iraq's increasing national incidence of CRC and the growth of the US' Iraqi immigrant population over the last 10 years, little remains known about the prevalence of CRC among the latter population, their knowledge of CRC and associated risk factors, or their behavioral intent and practices regarding CRC screening. The aims of this study were to (1) examine the knowledge of and adherence to National Cancer Institute screening recommendations for CRC among a population of Iraqi women living in the Washington D.C. Metropolitan Area and (2) test the efficacy of a one-time educational intervention conducted using linguistically and culturally appropriate materials to raise awareness of, and promote future adherence to, CRC screening methods. This descriptive study used a pre/post design with a 12-month follow-up. Following extensive dissemination of information regarding the study in the Iraqi American community in the study location, 50 women were initially recruited, of whom 32 participated in the study. The study's findings revealed that the participants generally had low baseline levels of CRC screening adherence and preventive knowledge that significantly improved after the intervention as demonstrated by pre- and post-assessments of knowledge and behavior. These findings could be used to raise awareness (1) among clinicians regarding the need for early detection and screening of and referral for CRC treatment among Iraqi American women and (2) among Iraqi American women about risk factors for this disease and the importance of early detection and screening. The study also highlights the need for a larger study of knowledge, attitudes, and perceptions among both this population and the clinicians who serve them. PMID- 25787224 TI - Pores with longitudinal irregularities distinguish objects by shape. AB - The resistive-pulse technique has been used to detect and size objects which pass through a single pore. The amplitude of the ion current change observed when a particle is in the pore is correlated with the particle volume. Up to date, however, the resistive-pulse approach has not been able to distinguish between objects of similar volume but different shapes. In this manuscript, we propose using pores with longitudinal irregularities as a sensitive tool capable of distinguishing spherical and rod-shaped particles with different lengths. The ion current modulations within resulting resistive pulses carry information on the length of passing objects. The performed experiments also indicate the rods rotate while translocating, and displace an effective volume that is larger than their geometrical volume, and which also depends on the pore diameter. PMID- 25787225 TI - Determinants of Eye Care Utilization in Rural South-eastern Nigeria. AB - To determine the barriers and incentives to eye care utilization (ECU) in Abagana, a rural south-eastern Nigerian community. The study was a population based cross-sectional mixed method (quantitative and qualitative) survey of adult inhabitants of Abagana, in July-August, 2011. Data on respondents' socio demographics, barriers and incentives to ECU were collected, and analysed using descriptive and comparative statistics. A p < 0.05 was considered statistically significant. Qualitative data were obtained from focus group discussions and in depth interviews and analyzed using ATLAS.ti software. The 549 respondents (males 224) were aged 49.8 +/- 15.9 SD years (range 18-93 years). Overall, orthodox eye care had ever been sought by 42.4%, and 46.4% of those who reported change in vision. Lack of awareness-31.8%, cost-18.0%, and fatalistic attitudes-15.9% were the main ECU barriers. Possession of health insurance (OR 11.49; 95% CI 4.21 31.34; p = 0.001), family history of eye disorder (OR 3.27, 95% CI 2.03-5.26; p = 0.001), noticed change in vision (OR 11.30; 95% CI 1.42-90.09; p = 0.022), current eye disease (OR 4.06; 95% CI 2.29-7.19; p = 0.001) and systemic co morbidity (OR 4.33; 95% CI 2.67-7.02; p = 0.001) were the incentives to ECU. To enhance the low ECU in Abagana community, educational interventions on eye health maintenance and eye health seeking behaviours, and measures to reduce eye care cost are recommended. PMID- 25787226 TI - Soft landing of cell-sized vesicles on solid surfaces for robust vehicle capture/release. AB - Based on a concept of a smooth and steady landing of fragile objects without destruction via a soft cushion, we have developed a model for the soft landing of deformable lipid giant unilamellar vesicles (GUVs) on solid surfaces. The foundation for a successful soft landing is a solid substrate with a two-layer coating, including a bottom layer of positively charged lysozymes and an upper lipid membrane layer. We came to a clear conclusion that anionic GUVs when sedimented on a surface, the vesicle rupture occurs upon the direct contact with the positively charged lysozyme layer due to the strong coulombic interactions. In contrast, certain separation distances was achieved by the insertion of a soft lipid membrane cushion between the charged GUVs and the lysozyme layer, which attenuated the coulombic force and created a mild buffer zone, ensuring the robust capture of GUVs on the substrate without their rupture. The non-covalent bonding facilitated a fully reversible stimuli-responsive capture/release of GUVs from the biomimetic solid surface, which has never been demonstrated before due to the extreme fragility of GUVs. Moreover, the controllable capture/release of cells has been proven to be of vital importance in biotechnology, and similarity the present approach to capture/release cells is expected to open the previously inaccessible avenues of research. PMID- 25787227 TI - Access and use of psychotropic medicines in low-resource settings. AB - Improving access and rational use of essential medicines at all levels of care is a global challenge. Key issues related to the provision and rational use of psychotropic medicines have recently been analysed by Padmanathan et al. who conducted a survey of the psychotropic medicines management cycle in Bihar, the third most populous state of India with approximately 104 million people, of whom 88.7% live in rural areas. It was found that availability, distance and cost were the main barriers to access and utilisation. Travelling was reported to be particularly problematic because it is expensive and may also be unfeasible for service users who are acutely ill. In this commentary, the results of this survey are discussed in view of their global policy implications for low-resource settings. PMID- 25787228 TI - The influence of water on the optical properties of single-layer molybdenum disulfide. AB - Adsorbed molecules can significantly affect the properties of atomically thin materials. Physisorbed water plays a significant role in altering the optoelectronic properties of single-layer MoS2 , one such 2D film. Here the distinct quenching effect of adsorbed water on the photoluminescence of single layer MoS2 is demonstrated through scanning-probe and optical microscopy. PMID- 25787231 TI - Metabolic adaptations in diabetic endothelial cells. AB - In healthy individuals, the endothelium plays a fundamental role in normal health in the maintenance of vascular homeostasis. Endothelial cell (EC) dysfunction results in the development of several pathologies. In diabetes, in particular, sustained hyperglycemia, a characteristic of diabetes, contributes to EC dysfunction and consequently mediates the pathogenesis of diabetes-associated micro- and macrovasculopathies. Hyperglycemia-induced EC dysfunction is triggered by elevated levels of oxidative stress derived from several mechanisms, with the mitochondria as a key source, and is exacerbated by a subsequent hyperglycemia induced self-perpetuating cycle of oxidative stress and aberrant metabolic memory. Recent reports have highlighted the importance of metabolic pathways in EC and suggested the therapeutic potential of targeting EC metabolism. This review focuses on the current knowledge regarding differences in the metabolism of healthy ECs vs. diabetes-associated dysfunctional ECs, and outlines how EC metabolism may be targeted for therapeutic benefit. PMID- 25787229 TI - High mortality rate in hemodialysis patients who undergo invasive cardiovascular procedures related to peripheral artery disease - community-based observational study in Kumamoto Prefecture - . AB - BACKGROUND: Cardiovascular disease is a major cause of mortality in hemodialysis patients. The aim was to assess the relationship of various invasive cardiovascular procedures (ICP) to clinical outcome in hemodialysis patients. METHODS AND RESULTS: A total of 5,813 patients at 76 facilities were on maintenance hemodialysis in Kumamoto Prefecture. Of these, 4,807 patients at 58 institutions were enrolled. Of 4,807 patients, 212 ICP (4.4%) were performed for various cardiovascular diseases in 189 patients (3.9%). ICP included PCI (n=80), endovascular treatment (n=59), radiofrequency catheter ablation (n=8), implantation of permanent pacemaker (n=15) and ICD (n=5), thoracotomy for valvular diseases (n=16), CABG (n=14), bypass surgery for peripheral artery disease (PAD; n=8), and artificial vessel replacement for aneurysm or aortic dissection (n=7). The overall mortality rate was 10.1% (19/189 patients). The mortality rate was highest in patients who underwent ICP for PAD, compared with other ICP (PAD, 18.2%; non-PAD, 6.7%, P=0.017). Infection and PAD were significant predictors of mortality (infection: OR, 8.30; 95% CI: 1.29-65.13, P=0.027; PAD: OR, 3.76; 95% CI: 1.35-10.48, P=0.012). The presence of inflammation/malnutrition factors was associated with high mortality (OR, 15.49; 95% CI: 3.22-74.12, P=0.0006). CONCLUSIONS: In this community-based registry study of 4,807 hemodialysis patients, the mortality rate of PAD patients was high despite ICP. PMID- 25787230 TI - Decreased Intrathoracic Impedance Associated With OptiVol Alert Can Diagnose Increased B-Type Natriuretic Peptide - MOMOTARO (Monitoring and Management of OptiVol Alert to Reduce Heart Failure Hospitalization) Study - . AB - BACKGROUND: Ambulatory measurement of intrathoracic impedance (ITI) with an implanted device may detect increases in pulmonary fluid retention early, but the clinical utility of this method is not well established. The goal of this study was to test whether conventional ITI-derived parameters can diagnose fluid retention that may cause early stage heart failure (HF). METHODS AND RESULTS: HF patients implanted with high-energy devices with OptiVol (Medtronic) monitoring were enrolled in this study. Patients were monitored remotely. At both baseline and OptiVol alert, patients were assessed on standard examinations, including analysis of serum brain natriuretic peptide (BNP). From April 2010 to August 2011, 195 patients from 12 institutes were enrolled. There were 154 primary OptiVol alert events. BNP level at the alerts was not significantly different from that at baseline. Given that ITI was inversely correlated with log BNP, we added a criterion specifying that the OptiVol alert is triggered only when ITI decreases by >=4% from baseline. This change improved the diagnostic potential of increase in BNP at OptiVol alert (sensitivity, 75%; specificity, 88%). CONCLUSIONS: BNP increase could not be identified based on OptiVol alert. Decrease in ITI >=4% compared with baseline, in addition to the alert, however, may be a useful marker for the likelihood of HF (Clinical trial info: UMIN000003351). PMID- 25787232 TI - Neurocognitive evaluation of long term survivors of atypical teratoid rhabdoid tumors (ATRT): The Canadian registry experience. AB - BACKGROUND: Because atypical teratoid rhabdoid tumor(ATRT) is a rare disease of infancy carrying a grim prognosis, focus on long-term outcome, especially neurocognitive remained very limited. With new era of multimodality therapy, an increasing proportion of patients are now long-term survivors. PROCEDURE: Retrospective review of neuropsychological (NP) status of survivors from the Canadian ATRT registry. RESULTS: Among 77 patients diagnosed between 1995-2012, 16(22%) were survivors. Formal NP assessments were available in eight patients. Partial information on academic achievement was available on three additional patients. There were four girls and seven boys diagnosed at a median age of 27.5 months. Seven patients underwent complete resection and three had metastatic disease. All but one received sequential high dose chemotherapy. Five patients received intrathecal chemotherapy. Three patients underwent radiation. Median age at time of formal NP assessment was 7.6 years (3.9-9.8). Full Scale Intellectual Quotient (FSIQ) ranged from less than 50-119 (mean 78). Simple expressive and receptive language appeared relatively preserved. Three recently diagnosed patients (median time assessment from diagnosis 2.6 years (1.6-4.7)) had average to high average FSIQ, academic and visual spatial skills, visual, and verbal memory. Five other patients diagnosed earlier and tested at a median time of 4.9 years (3.3-8.3) post-diagnosis had a FSIQ ranging from <50 to 71. Approximately 50% of their scores were in the impaired range. CONCLUSION: Overall this cohort appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognitive outcome are needed in the current context where treatment strategies include adjuvant radiation. PMID- 25787233 TI - Functional dissection of virus-human crosstalk mediated by miRNAs based on the VmiReg database. AB - Recently, a number of viruses have been shown to encode microRNAs (miRNAs), and they play important roles in several biological processes, enhancing the intricacies of the virus-host crosstalk. However, systematically deciphering the characteristics of crosstalk mediated by viral and human miRNAs has been hampered by the lack of high-confidence targets. Here, a user-friendly platform is developed to provide experimentally validated and predicted target genes of viral miRNAs as well as their functions, named VmiReg. To explore the virus-human crosstalk meditated by miRNAs, validated human cellular targets of viral and cellular miRNAs are analyzed. As a result, target genes of viral miRNAs are prone to be silenced by human miRNAs. Two kinds of targets have globally significantly high functional similarities and are more often found simultaneously in many important biological functions, even in disease genes, particularly cancer genes, and essential genes. In addition, viral and human miRNA targets are in close proximity within the protein-protein interaction network, indicating frequent communication via physical interactions to participate in the same functions. Finally, multiple dense modules intuitively exhibit crosstalk between viral and cellular miRNAs. Furthermore, most co-regulated genes tend to be in important locations of modules. The lymphoma-related module is one of the typical examples. Our study suggests that the functional importance of cellular genes targeted by viral miRNAs and the intricate virus-host crosstalk mediated by miRNAs may be performed via the sharing of target genes or physical interactions, providing a new direction in further researching the roles of miRNAs in infection. PMID- 25787234 TI - Tofacitinib, a novel JAK3 inhibitor, as a potential cause of distal symmetric polyneuropathy. PMID- 25787235 TI - Acid-labile boronate-bridged dextran-bortezomib conjugate with up-regulated hypoxic tumor suppression. AB - An acid-labile dextran-bortezomib conjugate (Dex-BTZ), i.e., a macromolecularized proteasome inhibitor, is synthesized by a boron esterification reaction. The prodrug exhibits intracellular acidity-accelerated BTZ release, and up-regulated inhibition efficacies toward hypoxic tumor in vitro and in vivo through both NF kappaB- and ERS-mediated apoptosis signaling pathways. PMID- 25787236 TI - Breakfast Skipping is Positively Associated With Incidence of Type 2 Diabetes Mellitus: Evidence From the Aichi Workers' Cohort Study. AB - BACKGROUND: Skipping breakfast has been suspected as a risk factor for type 2 diabetes (T2DM), but the associations are not entirely consistent across ethnicities or sexes, and the issue has not been adequately addressed in the Japanese population. METHODS: We followed 4631 participants (3600 men and 1031 women) in a work-site cohort of participants aged 35-66 years in 2002 through 2011 for T2DM development. Frequency of eating breakfast was self-reported and was subsequently dichotomized to breakfast skippers, who eat breakfast 3-5 times/week or less, and to eaters. Cox proportional hazards models were used to adjust for potential confounding factors, including dietary factors, smoking and other lifestyles, body mass index (BMI), and fasting blood glucose (FBG) at baseline. RESULTS: During 8.9 years of follow-up, 285 T2DM cases (231 men and 54 women) developed. Compared to participants who reported eating breakfast every day, maximally-adjusted hazard ratios and 95% confidence intervals (CI) of those with the frequency of almost every day and 3-5, 1-2, and 0 days/week were: 1.06 (95% CI, 0.73-1.53), 2.07 (95% CI, 1.20-3.56), 1.37 (95% CI, 0.82-2.29), and 2.12 (95% CI, 1.19-3.76), respectively. In a dichotomized analysis, breakfast skipping was positively associated with T2DM incidence (maximally-adjusted hazard ratio 1.73; 95% CI, 1.24-2.42). The positive associations were found in both men and women, current and non-current smokers, normal weight and overweight (BMI >= 25 kg/m(2)), and normal glycemic status and impaired fasting glycemic status (FBG 110 to <126 mg/dL) individuals at baseline (Ps for interaction all >0.05). CONCLUSIONS: The present study in middle-aged Japanese men and women suggests that skipping breakfast may increase the risk of T2DM independent of lifestyles and baseline levels of BMI and FBG. PMID- 25787237 TI - Effect of individual omega-3 fatty acids on the risk of prostate cancer: a systematic review and dose-response meta-analysis of prospective cohort studies. AB - Epidemiological studies have suggested inconsistent associations between omega-3 polyunsaturated fatty acids (n-3 PUFAs) and prostate cancer (PCa) risk. We performed a dose-response meta-analysis of prospective observational studies investigating both dietary intake and circulating n-3 PUFAs and PCa risk. PubMed and EMBASE prior to February 2014 were searched, and 16 publications were eligible. Blood concentration of docosahexaenoic acid, but not alpha-linolenic acid or eicosapentaenoic acid, showed marginal positive association with PCa risk (relative risk for 1% increase in blood docosahexaenoic acid concentration: 1.02; 95% confidence interval, 1.00-1.05; I(2) = 26%; P = 0.05 for linear trend), while dietary docosahexaenoic acid intake showed a non-linear positive association with PCa risk (P < 0.01). Dietary alpha-linolenic acid was inversely associated with PCa risk (relative risk for 0.5 g/day increase in alpha-linolenic acid intake: 0.99; 95% confidence interval, 0.98-1.00; I(2) = 0%; P = 0.04 for linear trend), which was dominated by a single study. Subgroup analyses indicated that blood eicosapentaenoic acid concentration and blood docosahexaenoic acid concentration were positively associated with aggressive PCa risk and nonaggressive PCa risk, respectively. Among studies with nested case-control study designs, a 0.2% increase in blood docosapentaenoic acid concentration was associated with a 3% reduced risk of PCa (relative risk 0.97; 95% confidence interval, 0.94-1.00; I(2) = 44%; P = 0.05 for linear trend). In conclusion, different individual n-3 PUFA exposures may exhibit different or even opposite associations with PCa risk, and more prospective studies, especially those examining dietary n-3 PUFAs and PCa risk stratified by severity of cancer, are needed to confirm the results. PMID- 25787238 TI - Impact of mannose-binding lectin 2 polymorphism on the risk of hepatocellular carcinoma: a case-control study in Chinese Han population. AB - BACKGROUND: Mannose-binding lectin2 (MBL2) is implicated in the host immune response, but there are limited data about MBL2 polymorphisms and hepatocellular carcinoma (HCC) risk. This study aimed to investigate the relationship between the MBL2 rs7096206 polymorphism and HCC risk in a Chinese Han population. METHODS: A population-based case-control study of 220 HCC patients and 220 age- and gender-matched healthy control subjects from a Chinese Han population was conducted. Genomic DNA was extracted from blood samples, and the presence of the MBL2 polymorphism rs7096206 was assessed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Conditional logistic regression was performed to assess the risk of HCC by determining odds ratios and 95% confidence intervals (CIs). RESULTS: The odds of HCC among carriers of CG and GG genotypes were 7.33 (95% CI, 2.53-21.29) and 12.48 (95% CI, 2.08-74.90), respectively. In the dominant genetic model, GG+CG carriers had an approximately 8-fold increased risk (95% CI, 2.83-22.62) compared with those with the CC genotype. The G allele was significantly associated with elevated HCC risk, with an odds ratio of 6.83 (95% CI, 2.90-16.10). CONCLUSIONS: Our findings suggest that the MBL2 polymorphism rs7096206 is associated with HCC susceptibility and has the potential to serve as a biomarker to detect populations at increased HCC risk. PMID- 25787239 TI - Association between eating speed and metabolic syndrome in a three-year population-based cohort study. AB - BACKGROUND: Metabolic syndrome has received increased global attention over the past few years. Eating behaviors, particularly eating speed, have long been of interest as factors that contribute to the development of obesity and diabetes. The aim of this study was to assess the relationship between eating speed and incidence of metabolic syndrome among middle-aged and elderly Japanese people. METHODS: A total of 8941 community residents from Soka City in Saitama Prefecture, aged from 40 to 75 years and without a diagnosis of metabolic syndrome, participated in the baseline survey in 2008 and were followed until 2011. Anthropometric measurements and lifestyle factors were measured at baseline and follow-up. The association between eating speed and incidence of metabolic syndrome was evaluated using Cox proportional hazards models adjusted for potential confounding variables. RESULTS: During the 3-year follow-up, 647 people were diagnosed with metabolic syndrome (25.0 cases/1000 person-years). The incidence rates of metabolic syndrome among non-fast-eating and fast-eating participants were 2.3% and 3.1%, respectively. The multivariate-adjusted hazard ratio for incidence of metabolic syndrome in the fast-eating group compared to the not-fast-eating group was 1.30 (95% confidence interval [CI], 1.05-1.60) after adjustment for the potential confounding factors. Eating speed was significantly correlated with waist circumference and high-density lipoprotein cholesterol (HDL-C) components of metabolic risk factors. Hazard ratios in the fast-eating group compared with the reference group were 1.35 (95% CI, 1.10-1.66) for waist circumference and 1.37 (95% CI, 1.12-1.67) for HDL-C. CONCLUSIONS: Eating speed was associated with the incidence of metabolic syndrome. Eating slowly is therefore suggested to be an important lifestyle factor for preventing metabolic syndrome among the Japanese. PMID- 25787240 TI - Profile of Non-communicable Disease Risk Factors Among Young People in Palau. AB - BACKGROUND: Although non-communicable diseases (NCDs) have become the predominant health problems of Palauan society, there have been no comprehensive data on NCD risk factors available to develop effective control strategies. Therefore, the first Palauan national STEPwise approach to risk factor Surveillance (STEPS) was completed in mid-2013 to provide information on its adult population aged 25 to 64 years. This study aims to obtain corresponding data from the younger adults aged 18 to 24 years, who remained to be surveyed. METHODS: We conducted an epidemiological study, targeting the 18- to 24-year-old age group. A survey station and a mobile team were established to recruit voluntary participants dwelling in Koror. A slightly modified WHO STEPS instrument was used, including a structured questionnaire for behavioral risk factors, physical measurements, and blood tests. RESULTS: A total of 356 young people were recruited during the survey. In both sexes, nearly half of the participants were overweight/obese. The prevalence of hypertension was higher in men than in women (17.6% vs 1.7%). Raised blood glucose and impaired fasting glucose were observed in 3.5% and 5.2% of the total participants, respectively. About 36% of the subjects were observed to have raised levels of total cholesterol. More than 70% of the young people were current tobacco users, in terms of all kinds of tobacco products. CONCLUSIONS: The current survey, for the first time, revealed a high prevalence of NCD risk factors, especially overweight/obesity and tobacco use, among young people in Palau. This indicates that swift measures against NCDs are required even in this young age group. PMID- 25787241 TI - Dietary patterns and serum gamma-glutamyl transferase in Japanese men and women. AB - BACKGROUND: Although specific foods and nutrients have been examined as potential determinants of serum gamma-glutamyl transferase (GGT) concentrations, the relationship between dietary patterns and GGT remains unknown. The present cross sectional study aimed to determine relationships between dietary patterns and GGT concentrations, and the effects of lifestyle factors on GGT. METHODS: Relationships between dietary patterns and GGT were analyzed in 9803 Japanese individuals (3723 men and 6080 women age 40-69 years) without a history of liver diseases or elevated serum aminotransferase. We examined major dietary patterns by factor analysis of 46 items determined from a validated, short food frequency questionnaire. RESULTS: We defined dietary patterns as healthy, Western, seafood, bread, and dessert. The healthy pattern was inversely related to GGT in men (odds ratio [OR] for highest vs lowest quartile, 0.72; 95% confidence interval [CI], 0.57-0.92; P < 0.01 for trend) and women (OR 0.82; 95% CI, 0.66-1.0; P = 0.05 for trend), whereas the seafood pattern was positively related to GGT in men (OR 1.27; 95% CI, 1.01-1.61; P = 0.03 for trend) and women (OR 1.21; 95% CI, 0.98 1.49; P = 0.05 for trend). Male-specific inverse associations with GGT were found for bread and dessert patterns (OR 0.63; 95% CI, 0.50-0.80 and OR 0.53; 95% CI, 0.41-0.68, respectively; P < 0.01 for both trends). Seafood or bread patterns and alcohol consumption significantly interacted with GGT in men (P = 0.03 and <0.01 for interaction, respectively) and between the dessert pattern and body mass index or smoking habit in women (P = 0.03 and <0.01, respectively, for interaction). CONCLUSIONS: Dietary patterns may be important determinants of GGT, and their possible clinical implications warrant further investigation. PMID- 25787242 TI - Mapping Bias Overestimates Reference Allele Frequencies at the HLA Genes in the 1000 Genomes Project Phase I Data. AB - Next-generation sequencing (NGS) technologies have become the standard for data generation in studies of population genomics, as the 1000 Genomes Project (1000G). However, these techniques are known to be problematic when applied to highly polymorphic genomic regions, such as the human leukocyte antigen (HLA) genes. Because accurate genotype calls and allele frequency estimations are crucial to population genomics analyses, it is important to assess the reliability of NGS data. Here, we evaluate the reliability of genotype calls and allele frequency estimates of the single-nucleotide polymorphisms (SNPs) reported by 1000G (phase I) at five HLA genes (HLA-A, -B, -C, -DRB1, and -DQB1). We take advantage of the availability of HLA Sanger sequencing of 930 of the 1092 1000G samples and use this as a gold standard to benchmark the 1000G data. We document that 18.6% of SNP genotype calls in HLA genes are incorrect and that allele frequencies are estimated with an error greater than +/-0.1 at approximately 25% of the SNPs in HLA genes. We found a bias toward overestimation of reference allele frequency for the 1000G data, indicating mapping bias is an important cause of error in frequency estimation in this dataset. We provide a list of sites that have poor allele frequency estimates and discuss the outcomes of including those sites in different kinds of analyses. Because the HLA region is the most polymorphic in the human genome, our results provide insights into the challenges of using of NGS data at other genomic regions of high diversity. PMID- 25787243 TI - Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma. AB - BRAF V600E mutations have been reported in several histiocytic and dendritic cell neoplasms. In this case series, we report BRAF V600E-positive histiocytic and dendritic cell neoplasms in association with lymphomas and lymphoid proliferations. This is a review of cases with immunohistochemistry for BRAF V600E, with additional immunohistochemistry to categorize tumors. We report the first case of BRAF V600E-positive indeterminate cell tumor in association with angioimmunoblastic T-cell lymphoma. We also report a case of BRAF V600E-positive interdigitating dendritic cell sarcoma in a patient with positive B-cell polymerase chain reaction. It is unclear if these neoplasms developed as transdifferentiation of lymphoid neoplasms or if they developed independently. These cases illustrate the expanding spectrum of BRAF V600E-positive histiocytic and dendritic cell tumors and suggest that attention should be paid to lymphomas for possible coincident presentation of these disorders. PMID- 25787244 TI - Phytosterol oxidation products in enriched foods: Occurrence, exposure, and biological effects. AB - Hypercholesterolemia is an important risk factor for the development of cardiovascular diseases. Dietary intake of phytosterols/phytostanols and their fatty acid esters results in a reduction of the LDL and total plasma cholesterol levels. Therefore, these constituents are added to a broad spectrum of foods. As in the case of cholesterol, thermo-oxidative treatment of phytosterols may result in the formation of phytosterol oxidation products (POPs), i.e. keto-, hydroxy-, and epoxy-derivatives. This review summarizes and evaluates the current knowledge regarding POPs in the light of the potentially increasing dietary exposure to these constituents via the consumption of foods enriched with phytosterols/phytostanols and their esters. Data on the occurrence of POPs and approaches to assess the potential intake of POPs resulting from the consumption of enriched foods are described. The knowledge on the uptake of POPs and the presently available data on the impact of the consumption of enriched foods on the levels of POPs in humans are discussed. Biological effects of POPs, such as potential proatherogenic properties or the loss of the cholesterol-lowering effects compared to nonoxidized phytosterols, are discussed. Finally, knowledge gaps are outlined and recommendations for further research needed for a safety assessment of POPs are presented. PMID- 25787245 TI - Soft-tissue rim sign. PMID- 25787246 TI - Coffee bean sign. PMID- 25787247 TI - Special section introduction: elastography. PMID- 25787248 TI - Modulating the Solubilities of Ionic Liquid Components in Aqueous-Ionic Liquid Biphasic Systems: A Q-NMR Investigation. AB - Aqueous-ionic liquid (A-IL) biphasic systems have been examined in terms of deuterated water, acid, and IL cation and anion mutual solubilities in the upper (water-rich, in mole fraction) and lower phase of aqueous/IL biphasic systems at ambient temperature. The biphasic mixtures were composed of deuterated acids of various concentrations (mainly DCl, DNO(3), and DClO(4) from 10(-2) to 10(-4) M) and five ionic liquids of the imidazolium family with a hydrophobic anion (CF(3)SO(2))(2) N(-), that is, [C1 Cn im][Tf(2)N], (n=2, 4, 6, 8 and 10). The analytical techniques applied were (1) H NMR, (19) F NMR, Karl-Fischer titration, pH potentiometry for IL cations and anions, and water and acid determination. The effects of the ionic strength (MU=0.1 M NaCl and NaNO(3) as well as MU=0.1 M, 0.2 M and 0.4 M NaClO(4), according to the investigated acid), the nature of the IL cation, and the nature of the mineral acid on the solubilities of the (D(2)O, D(+), Tf(2)N(-), C1 Cn im(+)) entities in the lower or upper phases were determined. The addition of sodium perchlorate was found to enhance the Tf(2)N(-) solubility while inhibiting the solubility of the ionic liquid cation. Differences in IL cation and anion solubilities of up to 42 mM were evidenced. The consequences for the characterization of the aqueous biphasic system, the solvent extraction process of the metal ions, and the ecological impact of the ILs are discussed. PMID- 25787249 TI - Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. AB - To examine whether the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is altered in the endothelial cells in response to glucose and the significance of such alteration. We incubated human umbilical vein endothelial cells with media containing various glucose levels. We found an increase in MALAT1 expression peaking after 12 hrs of incubation in high glucose. This increase was associated with parallel increase in serum amyloid antigen 3 (SAA3), an inflammatory ligand and target of MALAT1 and was further accompanied by increase in mRNAs and proteins of inflammatory mediators, tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Renal tissue from the diabetic animals showed similar changes. Such cellular alterations were prevented following MALAT1 specific siRNA transfection. Results of this study indicate that LncRNA MALAT1 regulates glucose-induced up-regulation of inflammatory mediators IL-6 and TNF-alpha through activation of SAA3. Identification of such novel mechanism may lead to the development of RNA-based therapeutics targeting MALAT1 for diabetes-induced micro and macro vascular complications. PMID- 25787251 TI - Correction. PMID- 25787250 TI - Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin producing adenomas. AB - Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal beta-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion. PMID- 25787252 TI - Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia. AB - Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 * 10(12)) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL. PMID- 25787253 TI - Weak lasing in one-dimensional polariton superlattices. AB - Bosons with finite lifetime exhibit condensation and lasing when their influx exceeds the lasing threshold determined by the dissipative losses. In general, different one-particle states decay differently, and the bosons are usually assumed to condense in the state with the longest lifetime. Interaction between the bosons partially neglected by such an assumption can smear the lasing threshold into a threshold domain--a stable lasing many-body state exists within certain intervals of the bosonic influxes. This recently described weak lasing regime is formed by the spontaneously symmetry breaking and phase-locking self organization of bosonic modes, which results in an essentially many-body state with a stable balance between gains and losses. Here we report, to our knowledge, the first observation of the weak lasing phase in a one-dimensional condensate of exciton-polaritons subject to a periodic potential. Real and reciprocal space photoluminescence images demonstrate that the spatial period of the condensate is twice as large as the period of the underlying periodic potential. These experiments are realized at room temperature in a ZnO microwire deposited on a silicon grating. The period doubling takes place at a critical pumping power, whereas at a lower power polariton emission images have the same periodicity as the grating. PMID- 25787254 TI - Three-dimensional architecture of extended synaptotagmin-mediated endoplasmic reticulum-plasma membrane contact sites. AB - The close apposition between the endoplasmic reticulum (ER) and the plasma membrane (PM) plays important roles in Ca(2+) homeostasis, signaling, and lipid metabolism. The extended synaptotagmins (E-Syts; tricalbins in yeast) are ER anchored proteins that mediate the tethering of the ER to the PM and are thought to mediate lipid transfer between the two membranes. E-Syt cytoplasmic domains comprise a synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain followed by five C2 domains in E-Syt1 and three C2 domains in E-Syt2/3. Here, we used cryo-electron tomography to study the 3D architecture of E-Syt-mediated ER PM contacts at molecular resolution. In vitrified frozen-hydrated mammalian cells overexpressing individual E-Syts, in which E-Syt-dependent contacts were by far the predominant contacts, ER-PM distance (19-22 nm) correlated with the amino acid length of the cytosolic region of E-Syts (i.e., the number of C2 domains). Elevation of cytosolic Ca(2+) shortened the ER-PM distance at E-Syt1-dependent contacts sites. E-Syt-mediated contacts displayed a characteristic electron-dense layer between the ER and the PM. These features were strikingly different from those observed in cells exposed to conditions that induce contacts mediated by the stromal interaction molecule 1 (STIM1) and the Ca(2+) channel Orai1 as well as store operated Ca(2+) entry. In these cells the gap between the ER and the PM was spanned by filamentous structures perpendicular to the membranes. Our results define specific ultrastructural features of E-Syt-dependent ER-PM contacts and reveal their structural plasticity, which may impact on the cross-talk between the ER and the PM and the functions of E-Syts in lipid transport between the two bilayers. PMID- 25787255 TI - Structural basis for the enhancement of virulence by viral spindles and their in vivo crystallization. AB - The great benefits that chemical pesticides have brought to agriculture are partly offset by widespread environmental damage to nontarget species and threats to human health. Microbial bioinsecticides are considered safe and highly specific alternatives but generally lack potency. Spindles produced by insect poxviruses are crystals of the fusolin protein that considerably boost not only the virulence of these viruses but also, in cofeeding experiments, the insecticidal activity of unrelated pathogens. However, the mechanisms by which spindles assemble into ultra-stable crystals and enhance virulence are unknown. Here we describe the structure of viral spindles determined by X-ray microcrystallography from in vivo crystals purified from infected insects. We found that a C-terminal molecular arm of fusolin mediates the assembly of a globular domain, which has the hallmarks of lytic polysaccharide monooxygenases of chitinovorous bacteria. Explaining their unique stability, a 3D network of disulfide bonds between fusolin dimers covalently crosslinks the entire crystalline matrix of spindles. However, upon ingestion by a new host, removal of the molecular arm abolishes this stabilizing network leading to the dissolution of spindles. The released monooxygenase domain is then free to disrupt the chitin rich peritrophic matrix that protects insects against oral infections. The mode of action revealed here may guide the design of potent spindles as synergetic additives to bioinsecticides. PMID- 25787257 TI - Secretome of gingival epithelium in response to subgingival biofilms. AB - Periodontitis is the chronic inflammatory destruction of periodontal tissues as a result of bacterial biofilm formation on the tooth surface. Proteins secreted by the gingival epithelium challenged by subgingival biofilms represent an important initial response for periodontal inflammation. The aim of this in vitro study was to characterize the whole secreted proteome of gingival epithelial tissue challenged by subgingival biofilms, and to evaluate the differential effects of the presence of the red-complex species in the biofilm. Multi-layered human gingival epithelial cultures were challenged with a 10-species in vitro biofilm model or its seven-species variant excluding the red complex. Liquid chromatography-tandem mass spectrometry for label-free quantitative proteomics was applied to identify and quantify the secreted epithelial proteins in the culture supernatant. A total of 192 proteins were identified and quantified. The biofilm challenge resulted in more secreted proteins being downregulated than upregulated. Even so, presence of the red complex in the biofilm was responsible for much of this downregulatory effect. Over 24 h, the upregulated biological processes were associated with inflammation and apoptosis, whereas the downregulated processes were associated with the disruption of epithelial tissue integrity and impairment of tissue turnover. Over 48 h, negative regulation of several metabolic processes and degradation of various molecular complexes was further intensified. Again, many of these biological regulations were attributed to the presence of the red complex. In conclusion, the present study provides the secreted proteome profile of gingival epithelial tissue to subgingival biofilms, and identifies a significant role for the red-complex species in the observed effects. PMID- 25787256 TI - Ribosomal frameshifting and dual-target antiactivation restrict quorum-sensing activated transfer of a mobile genetic element. AB - Symbiosis islands are integrative and conjugative mobile genetic elements that convert nonsymbiotic rhizobia into nitrogen-fixing symbionts of leguminous plants. Excision of the Mesorhizobium loti symbiosis island ICEMlSym(R7A) is indirectly activated by quorum sensing through TraR-dependent activation of the excisionase gene rdfS. Here we show that a +1 programmed ribosomal frameshift (PRF) fuses the coding sequences of two TraR-activated genes, msi172 and msi171, producing an activator of rdfS expression named Frameshifted excision activator (FseA). Mass-spectrometry and mutational analyses indicated that the PRF occurred through +1 slippage of the tRNA(phe) from UUU to UUC within a conserved msi172 encoded motif. FseA activated rdfS expression in the absence of ICEMlSym(R7A), suggesting that it directly activated rdfS transcription, despite being unrelated to any characterized DNA-binding proteins. Bacterial two-hybrid and gene-reporter assays demonstrated that FseA was also bound and inhibited by the ICEMlSym(R7A) encoded quorum-sensing antiactivator QseM. Thus, activation of ICEMlSym(R7A) excision is counteracted by TraR antiactivation, ribosomal frameshifting, and FseA antiactivation. This robust suppression likely dampens the inherent biological noise present in the quorum-sensing autoinduction circuit and ensures that ICEMlSym(R7A) transfer only occurs in a subpopulation of cells in which both qseM expression is repressed and FseA is translated. The architecture of the ICEMlSym(R7A) transfer regulatory system provides an example of how a set of modular components have assembled through evolution to form a robust genetic toggle that regulates gene transcription and translation at both single-cell and cell-population levels. PMID- 25787258 TI - Cell wall proteomic of Brachypodium distachyon grains: A focus on cell wall remodeling proteins. AB - Cell walls play key roles during plant development. Following their deposition into the cell wall, polysaccharides are continually remodeled according to the growth stage and stress environment to accommodate cell growth and differentiation. To date, little is known concerning the enzymes involved in cell wall remodeling, especially in gramineous and particularly in the grain during development. Here, we investigated the cell wall proteome of the grain of Brachypodium distachyon. This plant is a suitable model for temperate cereal crops. Among the 601 proteins identified, 299 were predicted to be secreted. These proteins were distributed into eight functional classes; the class of proteins that act on carbohydrates was the most highly represented. Among these proteins, numerous glycoside hydrolases were found. Expansins and peroxidases, which are assumed to be involved in cell wall polysaccharide remodeling, were also identified. Approximately half of the proteins identified in this study were newly discovered in grain and were not identified in the previous proteome analysis conducted using the culms and leaves of B. distachyon. Therefore, the data obtained from all organs of B. distachyon infer a global cell wall proteome consisting of 460 proteins. At present, this is the most extensive cell wall proteome of a monocot species. PMID- 25787259 TI - Alcohol use among immigrants in Ontario, Canada. AB - INTRODUCTION AND AIMS: This study examined prevalence of alcohol consumption among immigrants and the Canadian-born populations of Ontario by ethnic origin, and the association between ethnicity, country of birth, age at arrival, length of residence in Canada and drinking measures. DESIGN AND METHODS: Data were derived from the Centre for Addiction and Mental Health (CAMH) Monitor, a cross sectional survey of Ontario adults, conducted between January 2005 and December 2010 (n = 13,557). RESULTS: The prevalence of alcohol consumption and risk drinking was generally lower among foreign-born than Canadian-born respondents, but significant variations across ethnic groups were found. In general, foreign born respondents of European descent reported higher rates of alcohol use and risk drinking than foreign-born respondents from other ethnic groups. We also observed that ethnicity effects varied by whether or not respondents were born in Canada, and by the age at which they arrived in Canada. DISCUSSION AND CONCLUSIONS: While previous studies generally found an increase in immigrants' alcohol consumption with years in Canada, our data suggest that longer duration of residence may have either positive or negative effects on immigrants' alcohol use, depending on the country of origin/traditional drinking pattern. More research is needed to explore determinants of alcohol use and risk drinking among immigrants and to identify those groups at highest risk. PMID- 25787260 TI - Measurement of intramuscular fat by muscle echo intensity. AB - INTRODUCTION: The aim of this study was to compare ultrasound echo intensity (EI) with high-resolution T1 -weighted MRI and to establish calibration equations to estimate percent intramuscular fat from EI. METHODS: Thirty-one participants underwent both ultrasound and MRI testing of 4 muscles: rectus femoris (RF); biceps femoris (BF); tibialis anterior (TA); and medial gastrocnemius (MG). RESULTS: Strong correlations were found between MRI percent fat and muscle EI after correcting for subcutaneous fat thickness (r = 0.91 in RF, r = 0.80 in BF, r = 0.80 in TA, r = 0.76 in MG). Three types of calibration equations were established. CONCLUSIONS: Muscle ultrasound is a practical and reproducible method that can be used as an imaging technique for examination of percent intramuscular fat. Future ultrasound studies are needed to establish equations for other muscle groups to enhance its use in both research and clinical settings. PMID- 25787265 TI - Modeling the initiation of others into injection drug use, using data from 2,500 injectors surveyed in Scotland during 2008-2009. AB - The prevalence of injection drug use has been of especial interest for assessment of the impact of blood-borne viruses. However, the incidence of injection drug use has been underresearched. Our 2-fold aim in this study was to estimate 1) how many other persons, per annum, an injection drug user (IDU) has the equivalent of full responsibility (EFR) for initiating into injection drug use and 2) the consequences for IDUs' replacement rate. EFR initiation rates are strongly associated with incarceration history, so that our analysis of IDUs' replacement rate must incorporate when, in their injecting career, IDUs were first incarcerated. To do so, we have first to estimate piecewise constant incarceration rates in conjunction with EFR initiation rates, which are then combined with rates of cessation from injecting to model IDUs' replacement rate over their injecting career, analogous to the reproduction number of an epidemic model. We apply our approach to Scotland's IDUs, using over 2,500 anonymous injector participants who were interviewed in Scotland's Needle Exchange Surveillance Initiative during 2008-2009. Our approach was made possible by the inclusion of key questions about initiations. Finally, we extend our model to include an immediate quit rate, as a reasoned compensation for higher-than expected replacement rates, and we estimate how high initiates' quit rate should be for IDUs' replacement rate to be 1. PMID- 25787264 TI - Pooled results from 5 validation studies of dietary self-report instruments using recovery biomarkers for potassium and sodium intake. AB - We pooled data from 5 large validation studies (1999-2009) of dietary self-report instruments that used recovery biomarkers as referents, to assess food frequency questionnaires (FFQs) and 24-hour recalls (24HRs). Here we report on total potassium and sodium intakes, their densities, and their ratio. Results were similar by sex but were heterogeneous across studies. For potassium, potassium density, sodium, sodium density, and sodium:potassium ratio, average correlation coefficients for the correlation of reported intake with true intake on the FFQs were 0.37, 0.47, 0.16, 0.32, and 0.49, respectively. For the same nutrients measured with a single 24HR, they were 0.47, 0.46, 0.32, 0.31, and 0.46, respectively, rising to 0.56, 0.53, 0.41, 0.38, and 0.60 for the average of three 24HRs. Average underreporting was 5%-6% with an FFQ and 0%-4% with a single 24HR for potassium but was 28%-39% and 4%-13%, respectively, for sodium. Higher body mass index was related to underreporting of sodium. Calibration equations for true intake that included personal characteristics provided improved prediction, except for sodium density. In summary, self-reports capture potassium intake quite well but sodium intake less well. Using densities improves the measurement of potassium and sodium on an FFQ. Sodium:potassium ratio is measured much better than sodium itself on both FFQs and 24HRs. PMID- 25787267 TI - The first lutetacyclopentadienes: synthesis, structure, and diversified insertion/C-H activation reactivity. AB - The first well-defined lutetacyclopentadienes are synthesised from pentamethylcyclopentadienyl lithium (Cp*Li), 1,4-dilithio-1,3-butadienes, and LuCl3. The lutetacyclopentadiene shows excellent reactivity towards some small molecules, such as pivalaldehyde, Se, carbon dioxide, and isonitrile to efficiently construct 3-, 5-, 7-, 8-, and 9-membered rare-earth metallacycles. Both monoinsertion and double-insertion of two Lu-Csp2 bonds are observed. Specially, the reaction between lutetacyclopentadiene and isonitrile afforded [3,5,5]-fused metallacycles. The distinguished reactivity can be attributed to the highly ionic character and the cooperative reactivity of two Lu-Csp2 bonds. PMID- 25787266 TI - The Impact of Implementation Fidelity on Mortality Under a CD4-Stratified Timing Strategy for Antiretroviral Therapy in Patients With Tuberculosis. AB - Among patients with tuberculosis and human immunodeficiency virus type 1, CD4 stratified initiation of antiretroviral therapy (ART) is recommended, with earlier ART in those with low CD4 counts. However, the impact of implementation fidelity to this recommendation is unknown. We examined a prospective cohort study of 395 adult patients diagnosed with tuberculosis and human immunodeficiency virus between August 2007 and November 2009 in Kinshasa, Democratic Republic of the Congo. ART was to be initiated after 1 month of tuberculosis treatment at a CD4 count of <100 cells/mm(3) or World Health Organization stage 4 (other than extrapulmonary tuberculosis) and after 2 months of tuberculosis treatment at a CD4 count of 100-350 cells/mm(3). We used the parametric g-formula to estimate the impact of implementation fidelity on 6-month mortality. Observed implementation fidelity was low (46%); 54% of patients either experienced delays in ART initiation or did not initiate ART, which could be avoided under perfect implementation fidelity. The observed mortality risk was 12.0% (95% confidence interval (CI): 8.2, 15.7); under complete (counterfactual) implementation fidelity, the mortality risk was 7.8% (95% CI: 2.4, 12.3), corresponding to a risk reduction of 4.2% (95% CI: 0.3, 8.1) and a preventable fraction of 35.1% (95% CI: 2.9, 67.9). Strategies to achieve high implementation fidelity to CD4-stratified ART timing are needed to maximize survival benefit. PMID- 25787268 TI - Diagnosis of asthma: clinical assessment. AB - BACKGROUND: Asthma is a common condition that presents with varied symptomatology and exam findings. The diagnosis of asthma is made through a combination of clinical assessment and diagnostic testing. METHODS: A literature review was conducted through PubMed, focusing on systematic reviews and practice parameters. The highest-quality studies and those including the highest number of patients were included. References were reviewed for additional relevant articles. RESULTS: Patients with asthma present with the symptoms of cough, dyspnea, and wheezing. The physical exam can demonstrate hyperinflation, wheezing, and increased work of breathing, but most patients will present with a normal pulmonary exam because they are between episodes. The symptoms and examination of patients with asthma varies greatly from patient to patient and within the same patient over time. The diagnosis of asthma in the pediatric population may be more difficult because the classic symptoms may not be present in many of those patients. CONCLUSION: The diagnosis of asthma is made in the setting of clinical history, physical exam, and diagnostic testing. The astute physician will rely on all 3 of these factors when making the diagnosis. PMID- 25787269 TI - Temporal assessment of pancreatic blood flow and perfusion following secretin stimulation using noninvasive MRI. AB - PURPOSE: To dynamically quantify pancreatic perfusion and flow within the arteries supplying the pancreas in response to secretin stimulation. MATERIALS AND METHODS: Twelve healthy male subjects were scanned at 1.5T with arterial spin labeling to measure tissue perfusion and phase contrast magnetic resonance imaging (MRI) to measure vessel flow. Superior mesenteric (SMA), gastroduodenal (GDA), common hepatic (HA), and splenic (SA) arterial flow and pancreatic perfusion were serially measured for 50 minutes following 1 IU/kg intravenous secretin. The significance of differences between timepoints was tested using a repeated measures one-way analysis of variance (ANOVA). RESULTS: Baseline blood flow (mean +/- SEM or median [IQR]) for SMA, HA, SA, and GDA was 7.6 +/- 1.3, 4.0 +/- 0.5, 8.2 +/- 0.8, and 0.9 (0.8-1.4) ml/s, respectively. Baseline pancreatic perfusion was 200 +/- 25 ml/100g/min. Blood flow increased in the SMA (234%, P < 0.0001) and GDA (155%, P = 0.015) immediately after secretin injection. Reduced HA blood flow was observed after 10 minutes (P = 0.066) with no change in SA flow (P = 0.533). Increased pancreatic perfusion was maintained for 40 minutes after injection with a maximal increase at 5 minutes (16.8%, P = 0.025). CONCLUSION: Intravenous secretin resulted in significant temporal changes in pancreatic perfusion and arterial blood flow. PMID- 25787270 TI - Power and sample size determination for group comparison of patient-reported outcomes using polytomous Rasch models. AB - The analysis of patient-reported outcomes or other psychological traits can be realized using the Rasch measurement model. When the objective of a study is to compare groups of individuals, it is important, before the study, to define a sample size such that the group comparison test will attain a given power. The Raschpower procedure (RP) allows doing so with dichotomous items. The RP is extended to polytomous items. Several computational issues were identified, and adaptations have been proposed. The performance of this new version of RP is assessed using simulations. This adaptation of RP allows obtaining a good estimate of the expected power of a test to compare groups of patients in a large number of practical situations. A Stata module, as well as its implementation online, is proposed to perform the RP. Two versions of the RP for polytomous items are proposed (deterministic and stochastic versions). These two versions produce similar results in all of the tested cases. We recommend the use of the deterministic version, when the measure is obtained using small questionnaires or items with a few number of response categories, and the stochastic version elsewhere, so as to optimize computing time. PMID- 25787271 TI - Icariin promotes angiogenic differentiation and prevents oxidative stress-induced autophagy in endothelial progenitor cells. AB - Reduced tissue levels of endothelial progenitor cells (EPCs) and functional impairment of endothelium are frequently observed in patients with diabetes and cardiovascular disease. The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Hence attention has increasingly been paid to enhance mobilization and differentiation of EPCs for therapeutic purposes. The aim of this study was to investigate whether Icariin, a natural bioactive component known from traditional Chinese Medicine, can induce angiogenic differentiation and inhibit oxidative stress induced cell dysfunction in bone marrow-derived EPCs (BM-EPCs), and, if so, through what mechanisms. We observed that treatment of BM-EPCs with Icariin significantly promoted cell migration and capillary tube formation, substantially abrogated hydrogen peroxide (H2 O2 )-induced apoptotic and autophagic programmed cell death that was linked to the reduced intracellular reactive oxygen species levels and restored mitochondrial membrane potential. Icariin downregulated endothelial nitric oxide synthase 3, as well as nicotinamide-adenine dinucleotide phosphate-oxidase expression upon H2 O2 induction. These antiapoptotic and antiautophagic effects of Icariin are possibly mediated by restoring the loss of mammalian target of rapamycin /p70S6K/4EBP1 phosphorylation as well as attenuation of ATF2 and ERK1/2 protein levels after H2 O2 treatment. In summary, favorable modulation of the angiogenesis and redox states in BM-EPCs make Icariin a promising proangiogenic agent both enhancing vasculogenesis and protecting against endothelial dysfunction. PMID- 25787272 TI - Rabin8 suppresses autophagosome formation independently of its guanine nucleotide exchange activity towards Rab8. AB - Macroautophagy is a bulk degradation system conserved from yeast to human. In budding yeast, the guanine nucleotide-exchange factor (GEF) Sec2p is required for autophagy. We examined the role of Rabin8 (a mammalian ortholog of Sec2p) with Rab8-GEF activity in autophagy in mammalian cells. Unexpectedly, depletion of Rabin8 promoted nutrient starvation-induced autophagosome formation, indicating that Rabin8 suppresses autophagosome formation. Depletion of Rab8 did not affect autophagosome formation, and expression of a Rabin8 GEF-domain mutant reverted the Rabin8 depletion-induced increase in autophagosomes, indicating that Rabin8 suppresses autophagosome formation independently of its Rab8-GEF activity. Nuclear Dbf2-related (NDR) kinases phosphorylate Rabin8 at Ser-272. The non phosphorylatable Rabin8-S272A mutant did not revert the Rabin8 depletion-induced increase in autophagosomes, suggesting that Ser-272 phosphorylation of Rabin8 is involved in its suppressive function in autophagy. Depletion of NDR kinases enhanced autophagosome formation and reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity, suggesting that NDR kinases suppress autophagosome formation by increasing mTORC1 activity, in addition to phosphorylating Rabin8. Expression of a C-terminal fragment of Rabin8, but not that of Sec2p, suppressed nutrient starvation-induced autophagosome formation. Thus, contrary to the stimulative role of yeast Sec2p, Rabin8 has a suppressive function in autophagy in mammalian cells through its non-conserved C-terminal region. PMID- 25787273 TI - Navigating life. AB - The discoveries of "place cells" in the hippocampus and "grid cells" in the entorhinal cortex are landmark achievements in relating behavior to neural activity, permitting analysis of a powerful system for spatial representation in the brain. The contributions of this work include not only the empirical findings but also the approach this work pioneered of examining neural activity in complex behaviors with real ecological validity in freely moving animals, and of attempting to place the findings in the larger context of how the neural representations of space are used in service of real-world behavior, namely what the Nobel committee described as permitting us to "navigate our way through a complex environment." These discoveries and approaches have had far-ranging impact on and implications for work in human cognitive neuroscience, where we see (1) confirmation in humans that the hippocampus and overlying MTL cortex are critically engaged in supporting a relational representation of space, and that it can be used for flexible spatial navigation and (2) evidence that these regions are also critically involved in aspects of relational memory not limited to space, and in the flexible use of hippocampal memory extending beyond spatial navigation. Recent work, using tasks that emphasize the requirement for the active use of memory in online processing, just as spatial navigation has long placed such a requirement on rodents, suggests that the hippocampus and related MTL cortex can support the navigating of environments even more complex than what is needed in spatial navigation. It allows us to use memory in guiding upcoming actions and choices to act optimally in and on the world, permitting us to navigate life in all its beautiful complexity. PMID- 25787274 TI - Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition. AB - BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations. METHODS: Clinical questions (CQs) were proposed in seven topics. Recommendation, grade of recommendation and statement for each CQ were discussed and finalized by evidence-based approach. Recommendation was graded to grade 1 (strong) and 2 (weak) according to the concept of GRADE system. RESULTS: The 29 CQs covered seven topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, (6) radiation therapy, and (7) pathology. In 27 CQs, 19 recommendations were rated strong and 11 recommendations weak. Each CQ included the statement of how the recommendation was graded. CONCLUSIONS: This guideline provides recommendation for important clinical aspects based on evidence. Future collaboration with cancer registry will be a key for assessment of the guidelines and establishment of new evidence. Free full-text articles and a mobile application of this guideline are available via http://www.jshbps.jp/en/guideline/biliary-tract2.html. PMID- 25787275 TI - SLAM- and nectin-4-independent noncytolytic spread of canine distemper virus in astrocytes. AB - Measles and canine distemper viruses (MeV and CDV, respectively) first replicate in lymphatic and epithelial tissues by using SLAM and nectin-4 as entry receptors, respectively. The viruses may also invade the brain to establish persistent infections, triggering fatal complications, such as subacute sclerosis pan-encephalitis (SSPE) in MeV infection or chronic, multiple sclerosis-like, multifocal demyelinating lesions in the case of CDV infection. In both diseases, persistence is mediated by viral nucleocapsids that do not require packaging into particles for infectivity but are directly transmitted from cell to cell (neurons in SSPE or astrocytes in distemper encephalitis), presumably by relying on restricted microfusion events. Indeed, although morphological evidence of fusion remained undetectable, viral fusion machineries and, thus, a putative cellular receptor, were shown to contribute to persistent infections. Here, we first showed that nectin-4-dependent cell-cell fusion in Vero cells, triggered by a demyelinating CDV strain, remained extremely limited, thereby supporting a potential role of nectin-4 in mediating persistent infections in astrocytes. However, nectin-4 could not be detected in either primary cultured astrocytes or the white matter of tissue sections. In addition, a bioengineered "nectin-4 blind" recombinant CDV retained full cell-to-cell transmission efficacy in primary astrocytes. Combined with our previous report demonstrating the absence of SLAM expression in astrocytes, these findings are suggestive for the existence of a hitherto unrecognized third CDV receptor expressed by glial cells that contributes to the induction of noncytolytic cell-to-cell viral transmission in astrocytes. IMPORTANCE: While persistent measles virus (MeV) infection induces SSPE in humans, persistent canine distemper virus (CDV) infection causes chronic progressive or relapsing demyelination in carnivores. Common to both central nervous system (CNS) infections is that persistence is based on noncytolytic cell to-cell spread, which, in the case of CDV, was demonstrated to rely on functional membrane fusion machinery complexes. This inferred a mechanism where nucleocapsids are transmitted through macroscopically invisible microfusion events between infected and target cells. Here, we provide evidence that CDV induces such microfusions in a SLAM- and nectin-4-independent manner, thereby strongly suggesting the existence of a third receptor expressed in glial cells (referred to as GliaR). We propose that GliaR governs intercellular transfer of nucleocapsids and hence contributes to viral persistence in the brain and ensuing demyelinating lesions. PMID- 25787276 TI - Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection. AB - Epstein-Barr virus (EBV) infects most of the world's population and is causally associated with several human cancers, but little is known about how EBV genetic variation might influence infection or EBV-associated disease. There are currently no published wild-type EBV genome sequences from a healthy individual and very few genomes from EBV-associated diseases. We have sequenced 71 geographically distinct EBV strains from cell lines, multiple types of primary tumor, and blood samples and the first EBV genome from the saliva of a healthy carrier. We show that the established genome map of EBV accurately represents all strains sequenced, but novel deletions are present in a few isolates. We have increased the number of type 2 EBV genomes sequenced from one to 12 and establish that the type 1/type 2 classification is a major feature of EBV genome variation, defined almost exclusively by variation of EBNA2 and EBNA3 genes, but geographic variation is also present. Single nucleotide polymorphism (SNP) density varies substantially across all known open reading frames and is highest in latency associated genes. Some T-cell epitope sequences in EBNA3 genes show extensive variation across strains, and we identify codons under positive selection, both important considerations for the development of vaccines and T-cell therapy. We also provide new evidence for recombination between strains, which provides a further mechanism for the generation of diversity. Our results provide the first global view of EBV sequence variation and demonstrate an effective method for sequencing large numbers of genomes to further understand the genetics of EBV infection. IMPORTANCE: Most people in the world are infected by Epstein-Barr virus (EBV), and it causes several human diseases, which occur at very different rates in different parts of the world and are linked to host immune system variation. Natural variation in EBV DNA sequence may be important for normal infection and for causing disease. Here we used rapid, cost-effective sequencing to determine 71 new EBV sequences from different sample types and locations worldwide. We showed geographic variation in EBV genomes and identified the most variable parts of the genome. We identified protein sequences that seem to have been selected by the host immune system and detected variability in known immune epitopes. This gives the first overview of EBV genome variation, important for designing vaccines and immune therapy for EBV, and provides techniques to investigate relationships between viral sequence variation and EBV-associated diseases. PMID- 25787277 TI - Phosphorylation controls the nuclear-cytoplasmic shuttling of influenza A virus nucleoprotein. AB - The nucleoprotein (NP) is a major component of the viral ribonucleoprotein (vRNP) complex. During the replication of influenza virus, the vRNP complex undergoes nuclear-cytoplasmic shuttling, during which NP serves as one of the determinants. To date, many phosphorylation sites on NP have been identified, but the biological functions of many of these phosphorylation sites remain unknown. In the present study, the functions of the phosphorylation sites S9, Y10, and Y296 were characterized. These residues are highly conserved, and their phosphorylation was essential for virus growth in cell culture and in a mouse model by regulating the activity of the viral polymerase and the nuclear cytoplasmic shuttling of NP. The phosphorylation and dephosphorylation of S9 and Y10 controlled nuclear import of NP by affecting the binding affinity between NP and different isoforms of importin-alpha. In addition, the phosphorylation of Y296 caused nuclear retention of NP by reducing the interaction between NP and CRM1. Furthermore, tyrosine phosphorylation of NP during the early stage of virus infection was ablated when Y296 was mutated to F. However, at later stages of infection, it was weakened by the Y10F mutation. Taken together, the present data indicate that the phosphorylation and dephosphorylation of NP control the shuttling of NP between the nucleus and the cytoplasm during virus replication. IMPORTANCE: It is well known that phosphorylation regulates the functions of viral proteins and the life cycle of influenza A virus. As NP is the most abundant protein in the vRNP complex of influenza A virus, several phosphorylation sites on this protein have been identified. However, the functions of these phosphorylation sites were unknown. The present study demonstrates that the phosphorylation status of these sites on NP can mediate its nuclear-cytoplasmic shuttling, which drives the trafficking of vRNP complexes in infected cells. The present data suggest that the phosphorylated residues of NP are multistep controllers of the virus life cycle and new targets for the design of anti-influenza drugs. PMID- 25787278 TI - Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket. AB - The deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N- and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors. IMPORTANCE: Enfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41 dependent fusion. PMID- 25787279 TI - Dengue Virus Infection with Highly Neutralizing Levels of Cross-Reactive Antibodies Causes Acute Lethal Small Intestinal Pathology without a High Level of Viremia in Mice. AB - Severe dengue virus (DENV)-associated diseases can occur in patients who have preexisting DENV antibodies (Abs) through antibody-dependent enhancement (ADE) of infection. It is well established that during ADE, DENV-antibody immune complexes (ICs) infect Fcgamma receptor-bearing cells and increase the systemic viral burden that can be measured in the blood. For protection against infection with DENV serotypes 1 to 4, strongly neutralizing Abs must be elicited to overcome the effect of ADE. Clinical observations in infants who have maternal DENV Abs or recent phase II/III clinical trials with a leading tetravalent dengue vaccine suggested a lack of correlation between Ab neutralization and in vivo disease prevention. In addressing this gap in knowledge, we found that inoculation of ICs formed with serotype cross-reactive Abs that are more than 98% neutralized in vitro promotes high mortality in AG129 mice even though peak viremia was lower than that in direct virus infection. This suggests that the serum viremia level is not always correlated with disease severity. We further demonstrated that infection with the ICs resulted in increased vascular permeability, specifically in the small intestine, accompanied with increased tissue viral load and cytokine production, which can be suppressed by anti-tumor necrosis factor alpha (anti-TNF alpha) Abs. Flow cytometric analysis identified increased infection in CD11b(int) CD11c(int/hi) CD103(-) antigen-presenting cells by IC inoculation, suggesting that these infected cells may be responsible for the increase in TNF-alpha production and vascular permeability in the small intestine that lead to mortality in mice. Our findings may have important implications for the development of dengue therapeutics. IMPORTANCE: We examined the relationship between the neutralizing level of Abs at the time of infection and subsequent disease progression in a mouse model in order to understand why patients who are shown to have a neutralizing quantity of Abs still allow sufficient DENV replication to induce severe dengue manifestations, which sometimes do not correlate with viremia level. Strikingly, we found that high mortality was induced in AG129 mice by the increase in TNF-alpha-induced vascular permeability accompanied by an increased viral load, specifically in the small intestine, even when the initial infection level is suppressed to less than 5% and the peak viremia level is not enhanced. This suggests that ADE overcomes the protective efficacy of Abs in a tissue-dependent manner that leads to severe small intestinal pathology. Our findings may serve to address the pathogenic role of Abs on severe dengue disease and also help to develop safe Ab-based therapeutic strategies. PMID- 25787280 TI - Receptor usage and cell entry of porcine epidemic diarrhea coronavirus. AB - Porcine epidemic diarrhea coronavirus (PEDV) has significantly damaged America's pork industry. Here we investigate the receptor usage and cell entry of PEDV. PEDV recognizes protein receptor aminopeptidase N from pig and human and sugar coreceptor N-acetylneuraminic acid. Moreover, PEDV infects cells from pig, human, monkey, and bat. These results support the idea of bats as an evolutionary origin for PEDV, implicate PEDV as a potential threat to other species, and suggest antiviral strategies to control its spread. PMID- 25787281 TI - Emergence of Highly Pathogenic Avian Influenza A(H5N1) Virus PB1-F2 Variants and Their Virulence in BALB/c Mice. AB - Influenza A viruses (IAVs) express the PB1-F2 protein from an alternate reading frame within the PB1 gene segment. The roles of PB1-F2 are not well understood but appear to involve modulation of host cell responses. As shown in previous studies, we find that PB1-F2 proteins of mammalian IAVs frequently have premature stop codons that are expected to cause truncations of the protein, whereas avian IAVs usually express a full-length 90-amino-acid PB1-F2. However, in contrast to other avian IAVs, recent isolates of highly pathogenic H5N1 influenza viruses had a high proportion of PB1-F2 truncations (15% since 2010; 61% of isolates in 2013) due to several independent mutations that have persisted and expanded in circulating viruses. One natural H5N1 IAV containing a mutated PB1-F2 start codon (i.e., lacking ATG) was 1,000-fold more virulent for BALB/c mice than a closely related H5N1 containing intact PB1-F2. In vitro, we detected expression of an in frame protein (C-terminal PB1-F2) from downstream ATGs in PB1-F2 plasmids lacking the well-conserved ATG start codon. Transient expression of full-length PB1-F2, truncated (24-amino-acid) PB1-F2, and PB1-F2 lacking the initiating ATG in mammalian and avian cells had no effect on cell apoptosis or interferon expression in human lung epithelial cells. Full-length and C-terminal PB1-F2 mutants colocalized with mitochondria in A549 cells. Close monitoring of alterations of PB1-F2 and their frequency in contemporary avian H5N1 viruses should continue, as such changes may be markers for mammalian virulence. IMPORTANCE: Although most avian influenza viruses are harmless for humans, some (such as highly pathogenic H5N1 avian influenza viruses) are capable of infecting humans and causing severe disease with a high mortality rate. A number of risk factors potentially associated with adaptation to mammalian infection have been noted. Here we demonstrate that the protein PB1-F2 is frequently truncated in recent isolates of highly pathogenic H5N1 viruses. Truncation of PB1-F2 has been proposed to act as an adaptation to mammalian infection. We show that some forms of truncation of PB1-F2 may be associated with increased virulence in mammals. Our data support the assessment of PB1-F2 truncations for genomic surveillance of influenza viruses. PMID- 25787282 TI - A Single Amino Acid Substitution in the NS2A Protein of Japanese Encephalitis Virus Affects Virus Propagation In Vitro but Not In Vivo. AB - We identified a unique amino acid of NS2A113, phenylalanine, that affects the efficient propagation of two Japanese encephalitis virus strains, JaTH160 and JaOArS982, in neuroblastoma Neuro-2a cells but not in cell lines of extraneural origin. This amino acid did not affect viral loads in the brain or survival curves in mice. These findings suggest that virus propagation in vitro may not reflect the level of virus neuroinvasiveness in vivo. PMID- 25787283 TI - A Japanese encephalitis virus genotype 5 molecular clone is highly neuropathogenic in a mouse model: impact of the structural protein region on virulence. AB - Japanese encephalitis virus (JEV) strains can be separated into 5 genotypes (g1 to g5) based on sequence similarity. JEV g5 strains have been rarely isolated and are poorly characterized. We report here the full characterization of a g5 virus generated using a cDNA-based technology and its comparison with a widely studied g3 strain. We did not observe any major differences between those viruses when their infectious cycles were studied in various cell lines in vitro. Interestingly, the JEV g5 strain was highly pathogenic when inoculated to BALB/c mice, which are known to be largely resistant to JEV g3 infection. The study of chimeric viruses between JEV g3 and g5 showed that there was a poor viral clearance of viruses that express JEV g5 structural proteins in BALB/c mice blood, which correlated with viral invasion of the central nervous system and encephalitis. In addition, using an in vitro model of the blood-brain barrier, we were able to show that JEV g5 does not have an enhanced capacity for entering the central nervous system, compared to JEV g3. Overall, in addition to providing a first characterization of the understudied JEV g5, our work highlights the importance of sustaining an early viremia in the development of JEV encephalitis. IMPORTANCE: Genotype 5 viruses are genetically and serologically distinct from other JEV genotypes and can been associated with human encephalitis, which warrants the need for their characterization. In this study, we characterized the in vitro and in vivo properties of a JEV g5 strain and showed that it was more neuropathogenic in a mouse model than a well-characterized JEV g3 strain. The enhanced virulence of JEV g5 was associated with poor viral clearance but not with enhanced crossing of the blood-brain barrier, thus providing new insights into JEV pathogenesis. PMID- 25787284 TI - Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East respiratory syndrome coronavirus infection. AB - Middle East respiratory syndrome (MERS) is a highly lethal pulmonary infection. Serum from convalescent MERS patients may provide some benefit but is not readily available. In contrast, nearly all camels in the Middle East have been infected with MERS-CoV. Here, we show that sera obtained from MERS-immune camels augment the kinetics of MERS-CoV clearance and reduce the severity of pathological changes in infected lungs, with efficacy proportional to the titer of MERS-CoV neutralizing serum antibody. IMPORTANCE: Middle East respiratory syndrome, caused by a coronavirus, is highly lethal, with a case fatality rate of 35 to 40%. No specific therapy is available, and care is generally supportive. One promising approach is passive administration of sera from convalescent human MERS patients or other animals to exposed or infected patients. The vast majority of, if not all, camels in the Middle East have been infected with MERS-CoV, and some contain high titers of antibody to the virus. Here, we show that this antibody is protective if delivered either prophylactically or therapeutically to mice infected with MERS-CoV, indicating that this may be a useful intervention in infected patients. PMID- 25787285 TI - What is the reservoir of emergent human norovirus strains? AB - Since 1996, there have been at least six human norovirus pandemics. All of the pandemic strains are genetically related, segregating in the genogroup II, genotype 4 (GII.4) cluster within the Norovirus genus. Evidence indicates that these strains are closely related but antigenically distinct, supporting immune driven viral evolution. Thus, norovirus vaccines will likely require periodic reformulation to protect from newly emergent strains. A major obstacle is that the reservoir of emergent strains is unknown. Noroviruses display tight species specificity and there is no evidence supporting zoonotic transmission, so an animal reservoir is considered unlikely. Moreover, available data indicate minimal viral diversity in most natural human infections. In this Gem, we discuss the widely speculated idea that chronically infected immunocompromised individuals are norovirus reservoirs and provide a rationale for the theory that elderly and malnourished hosts may also represent norovirus reservoirs. PMID- 25787286 TI - Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques. AB - Macrophages regulate tissue immunity, orchestrating the initiation and resolution of antimicrobial immune responses and repair of damaged tissue architecture. Their dysfunction can, thus, manifest in either pro- and anti-inflammatory responses. Indeed, despite the importance of macrophage function in health and disease, the role of tissue-resident macrophages in human immunodeficiency virus (HIV) disease progression remains incompletely defined. Here, we use flow cytometry to assess the phenotypes and functions of macrophages isolated from the spleens, axillary lymph nodes, colons, jejuna, and livers of healthy and chronically simian immunodeficiency virus (SIV)-infected Asian macaques, the prominent nonhuman primate model for HIV infection. Our data demonstrate that macrophages from healthy animals exhibit considerable phenotypic and functional heterogeneity across tissues and across a variety of stimuli. Further, our analysis reveals changes in the lipopolysaccharide (LPS) responsiveness of macrophages isolated from SIV-infected animals. We anticipate that our findings will inform future research into macrophage-directed immunity across a variety of primate diseases. IMPORTANCE: These findings highlight the functional and phenotypic heterogeneity of tissue macrophages in different anatomic sites and as a result of SIV infection. We believe that our data will lead to novel therapeutic interventions aimed at altering the proinflammatory capacity of tissue macrophages in progressively HIV-infected individuals. PMID- 25787287 TI - Diversity of Viruses Infecting the Green Microalga Ostreococcus lucimarinus. AB - The functional diversity of eukaryotic viruses infecting a single host strain from seawater samples originating from distant marine locations is unknown. To estimate this diversity, we used lysis plaque assays to detect viruses that infect the widespread species Ostreococcus lucimarinus, which is found in coastal and mesotrophic systems, and O. tauri, which was isolated from coastal and lagoon sites from the northwest Mediterranean Sea. Detection of viral lytic activities against O. tauri was not observed using seawater from most sites, except those close to the area where the host strain was isolated. In contrast, the more cosmopolitan O. lucimarinus species recovered viruses from locations in the Atlantic and Pacific Oceans and the Mediterranean Sea. Six new O. lucimarinus viruses (OlVs) then were characterized and their genomes sequenced. Two subgroups of OlVs were distinguished based on their genetic distances and on the inversion of a central 32-kb-long DNA fragment, but overall their genomes displayed a high level of synteny. The two groups did not correspond to proximity of isolation sites, and the phylogenetic distance between these subgroups was higher than the distances observed among viruses infecting O. tauri. Our study demonstrates that viruses originating from very distant sites are able to infect the same algal host strain and can be more diverse than those infecting different species of the same genus. Finally, distinctive features and evolutionary distances between these different viral subgroups does not appear to be linked to biogeography of the viral isolates. IMPORTANCE: Marine eukaryotic phytoplankton virus diversity has yet to be addressed, and more specifically, it is unclear whether diversity is connected to geographical distance and whether differential infection and lysis patterns exist among such viruses that infect the same host strain. Here, we assessed the genetic distance of geographically segregated viruses that infect the ubiquitous green microalga Ostreococcus. This study provides the first glimpse into the diversity of predicted gene functions in Ostreococcus viruses originating from distant sites and provides new insights into potential host distributions and restrictions in the world oceans. PMID- 25787288 TI - Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection. AB - Pathogen-specific neutralizing antibodies protect against many viral infections and can potentially prevent human immunodeficiency virus (HIV) transmission in humans. However, neutralizing antibodies have so far only been shown to protect nonhuman primates (NHP) against lentiviral infection when given shortly before challenge. Thus, the clinical utility and feasibility of passive antibody transfer to confer long-term protection against HIV-1 are still debated. Here, we investigate the potential of a broadly neutralizing HIV-1 antibody to provide long-term protection in a NHP model of HIV-1 infection. A human antibody was simianized to avoid immune rejection and used to sustain therapeutic levels for ~5 months. Two months after the final antibody administration, animals were completely protected against viral challenge. These findings demonstrate the feasibility and potential of long-term passive antibody for protection against HIV-1 in humans and provide a model to test antibody therapies for other diseases in NHP. IMPORTANCE: Antibodies against HIV are potential drugs that may be able to prevent HIV infection in humans. However, the long-term protective capacity of antibodies against HIV has not been assessed. Here, we repetitively administered a macaque version of a human anti-HIV antibody to monkeys, after which the antibody persisted in the blood for >5 months. Moreover, the antibody could be sustained at protective levels for 108 days, conferring protection 52 days after the last dose in a monkey model of HIV infection. Thus, passive antibody transfer can provide durable protection against infection by viruses that cause AIDS in primates. PMID- 25787291 TI - Who should pay for doctor support services? PMID- 25787290 TI - Polycystic Ovary Syndrome: Special Diagnostic and Therapeutic Considerations for Children. AB - Polycystic ovary syndrome (PCOS) is an endocrine syndrome with variable phenotypic expression and important systemic associations and sequelae, including obesity, insulin resistance, infertility, risk of endometrial cancer, and possible risk of cardiovascular events. PCOS is recognized as a condition influenced by genetic and environmental factors and distinct manifestations in all stages of life, including the prenatal period, childhood, adolescence, and adulthood. Identification of this disorder in childhood and adolescence has received growing attention, in part because of emerging evidence of the benefit of early intervention, but the diagnosis and management of PCOS in children and adolescents can be challenging. Diagnostic and therapeutic considerations of PCOS in children are reviewed to enhance identification and evaluation of patients suspected of having this disorder. When a diagnosis of PCOS is suspected in a child but cannot be confirmed, a provisional diagnosis is strongly recommended so as to prompt ongoing monitoring with an emphasis on important early interventions such as obesity reduction. PMID- 25787289 TI - Highly divergent hepaciviruses from African cattle. AB - The hepatitis C virus (HCV; genus Hepacivirus) is a highly relevant human pathogen. Unique hepaciviruses (HV) were discovered recently in animal hosts. The direct ancestor of HCV has not been found, but the genetically most closely related animal HVs exist in horses. To investigate whether other peridomestic animals also carry HVs, we analyzed sera from Ghanaian cattle for HVs by reverse transcription-PCR (RT-PCR). Nine of 106 specimens from different sampling sites contained HV RNA (8.5%) at median viral loads of 1.6 * 10(5) copies/ml. Infection seemed unrelated to cattle age and gender. Near-full-genome sequencing of five representative viruses confirmed taxonomic classifications. Cattle HVs formed two distinct phylogenetic lineages that differed by up to 17.7% on the nucleotide level in the polyprotein-encoding region, suggesting cocirculation of different virus subtypes. A conserved microRNA122-binding site in the 5' internal ribosomal entry site suggested liver tropism of cattle HVs. Phylogenetic analyses suggested the circulation of HVs in cattle for several centuries. Cattle HVs were genetically highly divergent from all other HVs, including HCV. HVs from genetically related equine and bovine hosts were not monophyletic, corroborating host shifts during the evolution of the genus Hepacivirus. Similar to equine HVs, the genetic diversity of cattle HVs was low compared to that of HCV genotypes. This suggests an influence of the human-modified ecology of peridomestic animals on virus diversity. Further studies should investigate the occurrence of cattle HVs in other geographic areas and breeds, virus pathogenicity in cattle, and the potential exposure of human risk groups, such as farmers, butchers, and abattoir workers. IMPORTANCE: HCV (genus Hepacivirus) is a major human pathogen, causing liver failure and cancer. Unique hepaciviruses (HVs) were discovered over the last few years in animals, but the direct ancestor of HCV has not been found. The animal HV most closely related to HCV so far originated from horses, suggesting that other livestock animals also harbor HVs. Therefore, we investigated African cattle and discovered previously unknown HVs at high prevalence and viral loads. Because of the agricultural importance of cattle, it may be relevant to investigate HV pathogenicity. The frequent exposure of humans to cattle also may warrant investigations of the zoonotic potential of these viruses. Evolutionary analyses suggested that cattle HVs have existed for centuries. Despite the genetic relatedness of their animal hosts, HVs from cattle and horses were not phylogenetically related, corroborating frequent host shifts during the evolution of the genus Hepacivirus. PMID- 25787292 TI - High Concentrations of Uric Acid Inhibit Endothelial Cell Migration via miR-663 Which Regulates Phosphatase and Tensin Homolog by Targeting Transforming Growth Factor-beta1. AB - BACKGROUND: Whether microRNAs participate in endothelial dysfunction HUA remains unknown. A previous study indicated that miR-663 was the most significantly differentially expressed endothelial microRNA under HUA conditions. Some studies have demonstrated that the miR-663 target gene and TGF-beta1, promoted endothelial cell migration by inhibiting PTEN deleted on chromosome 10. Therefore, we hypothesized that HUA inhibits endothelial migration via miR-663, which regulates PTEN by targeting TGF-beta1. METHODS: PCR analysis was performed to determine miR-663 expression levels. A luciferase assay was performed to validate whether miR-663 targets TGF-beta1 directly. Western blot analysis was performed to determine TGF-beta1 and PTEN expression levels. An miR-663 inhibitor and TGF-beta1- and PTEN-specific siRNAs were transfected into EA.hy926 cells to inhibit miR-663, TGF-beta1, and PTEN expression, respectively. A wound healing assay was performed to determine the migratory ability of EA.hy926 cells. RESULTS: miR-663 had higher expression levels in HUA-stimulated endothelial cells and in the sera of hyperuricemic patients and animals. TGF-beta1 was targeted directly by miR-663. Endothelial miR-663 was up-regulated under HUA conditions, and HUA inhibited endothelial cell migration via miR-663, which targeted TGF beta1. Thus, TGF-beta1 regulated cell migration in a PTEN-dependent manner. CONCLUSION: HUA inhibits endothelial cell migration via miR-663, which regulates PTEN by targeting TGF-beta1. PMID- 25787293 TI - Intraoperative radiotherapy in early breast cancer. AB - BACKGROUND: Intraoperative radiotherapy (IORT) constitutes a paradigm shift from the conventional 3-5 weeks of whole-breast external beam radiotherapy (EBRT). IORT enables delivery of radiation at the time of excision of the breast tumour, targeting the area at highest risk of recurrence, while minimizing excessive radiation exposure to healthy breast tissue. The rationale for IORT is based on the observation that over 90 per cent of local recurrences after breast conserving surgery occur at or near the original operation site. METHODS: This article reviews trials of IORT delivered with different techniques and devices. RESULTS: IORT is a very attractive option for delivering radiotherapy, reducing the traditional fractionated treatment to a single fraction administered at the time of surgery. IORT has been shown to be associated with reduced toxicity and has several potential benefits over EBRT. Only two randomized clinical trials have been published to date. The TARGIT-A and ELIOT trials have demonstrated that IORT is associated with a low rate of local recurrence, although higher than that after EBRT (TARGIT-A: 3.3 versus 1.3 per cent respectively, P = 0.042; ELIOT: 4.4 versus 0.4 per cent, P < 0.001). However, the local recurrence rate for IORT fell within the predefined 2.5 per cent non-inferiority margin in TARGIT-A, and the 7.5 per cent equivalence margin in ELIOT. CONCLUSION: Longer follow-up data from existing trials, optimization of patient criteria and cost-effectiveness analyses are needed. Based on the current evidence, IORT can be offered as an alternative to EBRT to selected patients within agreed protocols, and outcomes should be monitored within national registries. PMID- 25787294 TI - Pre-existing Arterial Micro-Calcification Predicts Primary Unassisted Arteriovenous Fistula Failure in Incident Hemodialysis Patients. AB - Vascular access micro-calcification is a risk factor for cardiovascular morbidity and mortality in hemodialysis (HD) patients but its influence on vascular access patency is still undetermined. Our study aimed to determine the impact of arterial micro-calcification (AMiC) on the patency of vascular access in HD patients. One-hundred fourteen HD patients receiving arteriovenous fistula (AVF) operation were included in this study. During the operation, we obtained partial arterial specimen and performed pathological examination by von Kossa stain to identify AMiC. We compared primary unassisted AVF failure within 1 year between positive and negative AMiC groups, and performed Cox regression analysis for evaluating risk factor of AVF failure. The incidence of AMiC was 37.7% and AVF failure occurred in 45 patients (39.5%). The AVF failure rate within 1 year was greater in the positive AMiC group than those in the negative AMiC group (53.5% vs. 31.0%, p = 0.02). Kaplan-Meier analysis showed that the positive AMiC group had a lower AVF patency rate than the negative AMiC group (p = 0.02). The presence of AMiC was an independent risk factor for AVF failure. In conclusion, preexisting AMiC of the vascular access is associated with primary unassisted AVF failure in incident HD patients. PMID- 25787295 TI - Explaining effervescence: Investigating the relationship between shared social identity and positive experience in crowds. AB - We investigated the intensely positive emotional experiences arising from participation in a large-scale collective event. We predicted such experiences arise when those attending a collective event are (1) able to enact their valued collective identity and (2) experience close relations with other participants. In turn, we predicted both of these to be more likely when participants perceived crowd members to share a common collective identity. We investigated these predictions in a survey of pilgrims (N = 416) attending a month-long Hindu pilgrimage festival in north India. We found participants' perceptions of a shared identity amongst crowd members had an indirect effect on their positive experience at the event through (1) increasing participants' sense that they were able to enact their collective identity and (2) increasing the sense of intimacy with other crowd members. We discuss the implications of these data for how crowd emotion should be conceptualised. PMID- 25787296 TI - Hepatoprotective effect of kaempferol against alcoholic liver injury in mice. AB - Kaempferol is a biologically active component present in various plants. The hepatoprotective effect of kaempferol in drug-induced liver injury has been proven, while its effect against alcoholic liver injury (ALI) remains unclear. Hence, the present study aimed to evaluate the effect of kaempferol against ALI in mice. The experimental ALI mice model was developed and the mice were treated with different doses of kaempferol for 4 weeks. The liver functions were observed by monitoring the following parameters: Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) levels in serum; histopathological studies of liver tissue; oxidative stress by hydrogen peroxide (H2O2), superoxide dismutase (SOD) and glutathione (GSH); the lipid peroxidation status by malondialdehyde (MDA) and lipid accumulation by triglyceride (TG) level in serum; and the expression levels and activities of a key microsomal enzyme cytochrome 2E1 (CYP2E1), by both in vitro and in vivo methods. The ALI mice (untreated) showed clear symptoms of liver injury, such as significantly increased levels of oxidative stress, lipid peroxidation and excessive CYP2E1 expression and activity. The mice treated with different kaempferol dosages exhibited a significant decrease in the oxidative stress as well as lipid peroxidation, and increased anti-oxidative defense activity. The kaempferol treatment has significantly reduced the expression level and activity of hepatic CYP2E1, thus indicating that kaempferol could down regulate CYP2E1. These findings show the hepatoprotective properties of kaempferol against alcohol-induced liver injury by attenuating the activity and expression of CYP2E1 and by enhancing the protective role of anti-oxidative defense system. PMID- 25787297 TI - Effects of the total saponins from Dioscorea nipponica on immunoregulation in aplastic anemia mice. AB - Dioscorea nipponica Makino, a popular folk medicine, exerts anti-inflammation properties. The present study investigated the therapeutic effect of the total saponins from Dioscorea nipponica Makino (TSDN) on aplastic anemia (AA) and possible immune regulation mechanisms. Using a mouse model of AA, three different doses of TSDN were orally administrated for 14 consecutive days. We first demonstrated that TSDN was found to be effective in alleviating pancytopenia with a hypocellular bone marrow as compared with AA model group. Moreover, gastrogavage administration of a medium dose of TSDN was found to dramatically increase the percentage of CD4(+) cells in bone marrow nucleated cells (BMNC) and restore the CD4(+)/CD8(+) ratio. The pro-inflammatory cytokine concentrations of IL-2 and IFN-gamma were significantly decreased, and anti-inflammatory cytokine IL-4 was significantly increased in culture supernatant of BMNC. Further investigations showed that TSDN obviously inhibited Fas-FasL-induced BMNC apoptosis as well as effectively suppressed intracellular apoptosis protein of caspase-3 and -8 expressions. Taken together, these findings suggested that TSDN could alleviate AA by elevating the CD4(+)/CD8(+) T-cell ratio, inhibiting inflammatory Th1-cytokines, and exerting anti-apoptosis effects. PMID- 25787298 TI - Danhong injection in the treatment of acute coronary syndrome: a systematic review and meta-analysis. AB - To systematically evaluate the efficacy and safety of Danhong injection (DH) in treating acute coronary syndrome (ACS), randomized controlled trials (RCTs) regarding ACS treated by DH were searched in Chinese and English electronic databases from inception until June 2013. Two reviewers independently retrieved RCTs and extracted information. The Cochrane risk of bias method was used to assess the quality of the included studies, and a meta-analysis was conducted with Review Manager 5.2 software. About 26 RCTs with 2660 participants were included. The methodological quality was usually not high, and only one study used a randomized, double-blinded method. The meta-analysis indicated that on the basis of conventional therapy with Western medicine (WM), DH was more effective in increasing the total effective rate [RR = 1.24, 95%CI (1.17, 1.32), p < 0.00001]. Additionally, DH can decrease inflammatory cytokines, including high sensitive C-reactive protein (Hs-CRP) and interleukin-6 (IL-6), lower plasma viscosity, plasma endothelin-1 (ET-1) and brain natriuretic peptide (BNP), reduce the generation of myeloperoxidase (MPO), and decrease the number of T-wave inversion. There were no adverse drug reactions (ADR) reported in the experimental group, while one case occurred in the control group. Based on the systematic review, DH combined with WM was effective in the treatment of ACS. However, the safety of DH in the treatment of ACS should be further carefully interpreted by more large-scale and double-blind RCTs. PMID- 25787299 TI - JSI-124 (Cucurbitacin I) inhibits tumor angiogenesis of human breast cancer through reduction of STAT3 phosphorylation. AB - Breast cancer (BC) is the most frequently diagnosed type of cancer all over the world. Angiogenesis, a physiological or pathological process characterized by the sprouting of new blood vessels from existing vessels, plays a vital role in tumor nutrition. In this work, we used JSI-124 (Cucurbitacin I), a selective JAK/STAT3 signaling pathway inhibitor, to investigate the role of STAT3 in tumor angiogenesis of a human BC cell line in vitro. JSI-124 inhibited cell viability, proliferation, adhesion, migration and tube formation of a human BC cell line MDA MB-468. After transfection with pMXs-Stat3C, a dominant active mutant, the inhibitory effects of JSI-124 on MDA-MB-468 were abolished. Furthermore, JSI-124 reduced the phosphorylation of STAT3. These results suggested that JSI-124 inhibited tumor angiogenesis of the human BC cell line in vitro through the reduction of STAT3 phosphorylation. In addition, JSI-124 could reduce VEGF transcription and secretion, suggesting that JSI-124 is also involved in the inhibition of the VEGF autocrine loop in the tumor microenvironment. PMID- 25787300 TI - Improved peripheral nerve regeneration in streptozotocin-induced diabetic rats by oral lumbrokinase. AB - We assessed the therapeutic effects of lumbrokinase, a group of enzymes extracted from the earthworm, on peripheral-nerve regeneration using well-defined sciatic nerve lesion paradigms in diabetic rats induced by the injection of streptozotocin (STZ). We found that lumbrokinase therapy could improve the rats' circulatory blood flow and promote the regeneration of axons in a silicone rubber conduit after nerve transection. Lumbrokinase treatment could also improve the neuromuscular functions with better nerve conductive performances. Immunohistochemical staining showed that lumbrokinase could dramatically promote calcitonin gene-related peptide (CGRP) expression in the lamina I-II regions in the dorsal horn ipsilateral to the injury and cause a marked increase in the number of macrophages recruited within the distal nerve stumps. In addition, the lumbrokinase could stimulate the secretion of interleukin-1 (IL-1), nerve growth factor (NGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) in dissected diabetic sciatic nerve segments. In conclusion, the administration of lumbrokinase after nerve repair surgery in diabetic rats was found to have remarkable effects on promoting peripheral nerve regeneration and functional recovery. PMID- 25787301 TI - Anti-oxidative and anti-inflammatory effects of Lobelia chinensis in vitro and in vivo. AB - Lobelia chinensis Lour (LcL) is a popular herb that has been widely used as folk medicine in China for the treatment of fever, lung cancer, and inflammation for hundreds of years. Recently, several studies have shown that the anti inflammatory properties were correlated with the inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) from the NF-kappaB pathway. The aim of this study was to evaluate the anti-oxidative and anti-inflammatory activities of L. chinensis. Both suppressive activities on LPS-induced nitric oxide production in RAW264.7 macrophages in vitro and the acute rat lung injury model in vivo were studied. The results showed that the methanol extract of LcL and its fractions within the range of 62.5-250 MUg/mL did not induce cytotoxicity (p < 0.001). The ethyl acetate fraction of LcL showed better NO inhibition activity than other fractions. On the other hand, the Lc-EA (62.5, 125, 250 mg/kg) pretreated rats showed a decrease in the pro-inflammatory cytokines (TNF-alpha, IL-beta, IL-6) and inhibited iNOS, COX-2 expression through the NF-kappaB pathway. These results suggested that L. chinensis exhibited an anti-inflammatory effect through the NF kappaB pathways. PMID- 25787302 TI - MicroRNA-145-targeted drug and its preventive effect on pulmonary arterial hypertension (patent WO2012153135 A1). AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a disease of various etiologies, characterized by progressive vascular remodeling that leads to right ventricular hypertrophy and heart failure. Although modern therapy improves life quality of patients, prognosis of PAH remains poor with a high mortality rate. Overexpression of microRNA (miR)-145, which was found in PAH patients, leads to progression of vascular remodeling. The current patent proposes a strategy using antisense oligonucleotides (ASOs) against miR-145 for prevention and treatment of PAH. AREAS COVERED: Overexpression of miR-145 was shown in chronic hypoxia mouse models and PAH patients. Genetic ablation of miR-145 in hypoxic mice led to improved hemodynamic and vascular remodeling parameters. Furthermore, miR-145 inhibition by ASOs has been performed in chronic hypoxia mouse models. The experiments showed improved systolic right ventricular pressure and a decreased percentage of vascular remodeling. EXPERT OPINION: Although the mouse model does not display the full pathology of PAH, the inhibition of miR-145 by modified ASOs is promising for prevention and reversion of vascular remodeling. Whether such ASOs can be efficiently delivered and will prevent progression of PAH pathology and may lead to an extended lifespan of PAH patients remains to be elucidated. PMID- 25787303 TI - Doctors' suicides: economic considerations and beyond. PMID- 25787304 TI - Pallidal stimulation for myoclonus-dystonia: Ten years' outcome in two patients. PMID- 25787305 TI - Potassium 2-(1-hydroxypentyl)-benzoate inhibits ADP-induced rat platelet aggregation through P2Y1-PLC signaling pathways. AB - Potassium 2-(1-hydroxypenty1)-benzoate (dl-PHPB) is a new drug candidate for treatment of ischemic stroke with antiplatelet effect. In this study, we investigated the mechanisms of dl-PHPB in inhibiting platelet aggregation. The ADP-activated P2Y1-Gq-PLC and P2Y12-Gi-AC pathways were observed, respectively. Intravenous injection of dl-PHPB (1.3, 3.9, 12.9 mg/kg) significantly inhibited ADP-, collagen-, and arachidonic acid-induced rat platelet aggregation in a dose dependent manner, and dl-PHPB had a relatively more potent inhibitory effect on ADP-induced rat platelet aggregation than other agonists. Dl-PHPB also showed a decreased expression of CD62P (a marker for platelet activation) mediated by ADP. Both dl-PHPB and ticlopidine (P2Y12 receptor antagonist) decreased cytoplasmic Ca(2+) concentration. But, dl-PHPB did not reverse the inhibition of PGE1-induced platelet cAMP formation by ADP, which was different from ticlopidine. Further, dl PHPB instead of ticlopidine showed increasing phospholipase C-beta phosphorylation (ser(1105)). The m-3M3FBS, a phospholipase C activator, attenuated the inhibitory effect of dl-PHPB on ADP-induced platelet aggregation and enhanced IP1 accumulation in rat platelets. Dl-PHPB decreased IP1 accumulation induced by ADP but had no effect on IP1 level enhanced by m-3M3FBS. Our results suggest that dl-PHPB has a potent antiplatelet effect, which is mainly through blockade of P2Y1 receptor-PLC-IP3 pathway and decreasing cytoplasmic calcium. PMID- 25787306 TI - Early crocodylomorph increases top tier predator diversity during rise of dinosaurs. AB - Triassic predatory guild evolution reflects a period of ecological flux spurred by the catastrophic end-Permian mass extinction and terminating with the global ecological dominance of dinosaurs in the early Jurassic. In responding to this dynamic ecospace, terrestrial predator diversity attained new levels, prompting unique trophic webs with a seeming overabundance of carnivorous taxa and the evolution of entirely new predatory clades. Key among these was Crocodylomorpha, the largest living reptiles and only one of two archosaurian lineages that survive to the present day. In contrast to their existing role as top, semi aquatic predators, the earliest crocodylomorphs were generally small-bodied, terrestrial faunivores, occupying subsidiary (meso) predator roles. Here we describe Carnufex carolinensis a new, unexpectedly large-bodied taxon with a slender and ornamented skull from the Carnian Pekin Formation (~231 Ma), representing one of the oldest and earliest diverging crocodylomorphs described to date. Carnufex bridges a problematic gap in the early evolution of pseudosuchians by spanning key transitions in bauplan evolution and body mass near the origin of Crocodylomorpha. With a skull length of >50 cm, the new taxon documents a rare instance of crocodylomorphs ascending to top-tier predator guilds in the equatorial regions of Pangea prior to the dominance of dinosaurs. PMID- 25787307 TI - Automated image analysis of nuclear atypia in high-power field histopathological image. AB - AIMS: We developed a computer-aided technique to study nuclear atypia classification in high-power field haematoxylin and eosin stained images. METHODS AND RESULTS: An automated technique for nuclear atypia score (NAS) calculation is proposed. The proposed technique uses sophisticated digital image analysis and machine-learning methods to measure the NAS for haematoxylin and eosin stained images. The proposed technique first segments all nuclei regions. A set of morphology and texture features is extracted from presegmented nuclei regions. The histogram of each feature is then calculated to characterize the statistical information of the nuclei. Finally, a support vector machine classifier is applied to classify a high-power field image into different nuclear atypia classes. A set of 1188 digital images was analysed in the experiment. We successfully differentiated the high-power field image with NAS1 versus non-NAS1, NAS2 versus non-NAS2 and NAS3 versus non-NAS3, with area under receiver-operating characteristic curve of 0.90, 0.86 and 0.87, respectively. In three classes evaluation, the average classification accuracy was 78.79%. We found that texture based feature provides best performance for the classification. CONCLUSION: The automated technique is able to quantify statistical features that may be difficult to be measured by human and demonstrates the future potentials of automated image analysis technique in histopathology analysis. PMID- 25787308 TI - Modeling and quantifying frequency-dependent fitness in microbial populations with cross-feeding interactions. AB - Coexistence of two or more populations by frequency-dependent selection is common in nature, and it often arises even in well-mixed experiments with microbes. If ecology is to be incorporated into models of population genetics, then it is important to represent accurately the functional form of frequency-dependent interactions. However, measuring this functional form is problematic for traditional fitness assays, which assume a constant fitness difference between competitors over the course of an assay. Here, we present a theoretical framework for measuring the functional form of frequency-dependent fitness by accounting for changes in abundance and relative fitness during a competition assay. Using two examples of ecological coexistence that arose in a long-term evolution experiment with Escherichia coli, we illustrate accurate quantification of the functional form of frequency-dependent relative fitness. Using a Monod-type model of growth dynamics, we show that two ecotypes in a typical cross-feeding interaction-such as when one bacterial population uses a byproduct generated by another-yields relative fitness that is linear with relative frequency. PMID- 25787309 TI - Biotechnological interventions in Withania somnifera (L.) Dunal. AB - Withania somnifera is one of the most valued plants and is extensively used in Indian, Unani, and African systems of traditional medicine. It possess a wide array of therapeutic properties including anti-arthritic, anti-aging, anti cancer, anti-inflammatory, immunoregulatory, chemoprotective, cardioprotective, and recovery from neurodegenerative disorders. With the growing realization of benefits and associated challenges in the improvement of W. somnifera, studies on exploration of genetic and chemotypic variations, identification and characterization of important genes, and understanding the secondary metabolites production and their modulation has gained significant momentum. In recent years, several in vitro and in vivo preclinical studies have facilitated the validation of therapeutic potential of the phytochemicals derived from W. somnifera and have provided necessary impetus for gaining deeper insight into the mechanistic aspects involved in the mode of action of these important pharmaceutically active constituents. The present review highlights some of the current developments and future prospects of biotechnological intervention in this important medicinal plant. PMID- 25787311 TI - Juvenile xanthogranuloma with bilateral retinal detachment. PMID- 25787310 TI - Phytonutrient diet supplementation promotes beneficial Clostridia species and intestinal mucus secretion resulting in protection against enteric infection. AB - Plant extracts, or phytonutrients, are used in traditional medicine practices as supplements to enhance the immune system and gain resistance to various infectious diseases and are used in animal production as health promoting feed additives. To date, there are no studies that have assessed their mechanism of action and ability to alter mucosal immune responses in the intestine. We characterized the immunomodulatory function of six phytonutrients: anethol, carvacrol, cinnamaldehyde, eugenol, capsicum oleoresin and garlic extract. Mice were treated with each phytonutrient to assess changes to colonic gene expression and mucus production. All six phytonutrients showed variable changes in expression of innate immune genes in the colon. However only eugenol stimulated production of the inner mucus layer, a key mucosal barrier to microbes. The mechanism by which eugenol causes mucus layer thickening likely involves microbial stimulation as analysis of the intestinal microbiota composition showed eugenol treatment led to an increase in abundance of specific families within the Clostridiales order. Further, eugenol treatment confers colonization resistance to the enteric pathogen Citrobacter rodentium. These results suggest that eugenol acts to strengthen the mucosal barrier by increasing the thickness of the inner mucus layer, which protects against invading pathogens and disease. PMID- 25787313 TI - On the Incorrect Statistical Calculations of the Kinetica Software Package in Imbalanced Designs. AB - This regulatory note supports the previous findings that suggest that the software package Kinetica, up to version 5.0.10, provides incorrect results for the 90% confidence intervals for the ratio test/reference where the groups are imbalanced in 2 * 2 crossover designs and parallel designs. The incorrect calculation results from using the simplified formula that is shown as an example in the Canadian guideline for a balanced dataset, but which provides an erroneous point estimate and confidence interval width in cases of imbalanced designs. Importantly, this software is rarely used for regulatory submissions in the European Union according to the search conducted in the Spanish Agency for Medicines and Health Care Products. According to our data, the error is minor if the imbalance between groups is small. However, the error may be relevant if the sample size is small and the imbalance is large. Therefore, bioequivalence studies should be reanalyzed by regulatory agencies to confirm the submitted results. PMID- 25787312 TI - Subclinical atherosclerosis and obesity phenotypes among Mexican Americans. AB - BACKGROUND: Data on the influence of obesity on atherosclerosis in Hispanics are inconsistent, possibly related to varying cardiometabolic risk among obese individuals. We aimed to determine the association of obesity and cardiometabolic risk with subclinical atherosclerosis in Mexican-Americans. METHODS AND RESULTS: Participants (n=503) were drawn from the Cameron County Hispanic Cohort. Metabolic health was defined as <2 of the following: blood pressure >=130/85; triglyceride >=150 mg/dL; high-density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women); fasting glucose >=100 mg/dL; homeostasis model assessment of insulin resistance value >5.13; or high-sensitivity C-reactive protein >3 mg/L. Carotid intima media thickness (cIMT) was measured. A high proportion of participants (77.8%) were metabolically unhealthy; they were more likely to be male, older, with fewer years of education, and less likely to meet daily recommendations regarding fruit and vegetable servings. One-third (31.8%) had abnormal carotid ultrasound findings. After adjusting for covariates, mean cIMT varied across the obesity phenotypes (P=0.0001); there was no difference among the metabolically unhealthy regardless of whether they were obese or not. In multivariable analysis, after adjusting for covariates, cardiometabolic risk (P=0.0159), but not obesity (P=0.1446), was significantly associated with subclinical atherosclerosis. CONCLUSIONS: In Mexican-Americans, cardiometabolic risk has a greater effect on early atherosclerosis development than body mass index. Non-obese but metabolically unhealthy participants had similar development of subclinical atherosclerosis as their obese counterparts. Interventions to maintain metabolic health among obese and non-obese patients may be a more important goal than weight loss alone. PMID- 25787314 TI - Heavy drinking days and mental health: an exploration of the dynamic 10-year longitudinal relationship in a prospective cohort of untreated heavy drinkers. AB - BACKGROUND: Identifying dominant processes that underlie the development of other processes is important when evaluating the temporal sequence between disorders. Such information not only improves our understanding of etiology but also allows for effective intervention strategies to be tailored. The temporal relationship between alcohol intake and mental health remains poorly understood, particularly in nonclinical samples. The purpose of this study was to disentangle the dominant temporal sequence between mental health and frequency of heavy drinking days. METHODS: We report a 10-year (1997 to 2007) prospective cohort study of 500 respondents (74% male) from the Birmingham Untreated Heavy Drinkers project. Participants were aged 25 to 55 years at baseline, drinking a minimum of 50/35 U.K. units of alcohol for men/women on a weekly basis, and were not seeking treatment for their alcohol use upon recruitment into the study. Heavy drinking days were defined as consuming 10/7+ U.K. units of alcohol in a single day for men/women. Mental health was assessed using the mental health component score of the SF-36 questionnaire. Dynamic longitudinal structural equation models were used to test competing theoretical models (frequency of heavy drinking days leading to changes in mental health scores and vice versa) and a reciprocal relationship (both mental health scores and the frequency of heavy drinking days influencing changes in each other). RESULTS: A model whereby mental health scores were predictors of change in the frequency of heavy drinking days was of best fit. In this model, mental health scores were negatively related to change in heavy drinking days (beta -0.80, SE 0.28) indicating that those with higher mental health scores (i.e., better functioning) made larger reductions in the number of heavy drinking days over time. CONCLUSIONS: Mental health appears to be the stronger underlying process in the relationship between mental health and frequency of heavy drinking days. PMID- 25787315 TI - Selectively-informed particle swarm optimization. AB - Particle swarm optimization (PSO) is a nature-inspired algorithm that has shown outstanding performance in solving many realistic problems. In the original PSO and most of its variants all particles are treated equally, overlooking the impact of structural heterogeneity on individual behavior. Here we employ complex networks to represent the population structure of swarms and propose a selectively-informed PSO (SIPSO), in which the particles choose different learning strategies based on their connections: a densely-connected hub particle gets full information from all of its neighbors while a non-hub particle with few connections can only follow a single yet best-performed neighbor. Extensive numerical experiments on widely-used benchmark functions show that our SIPSO algorithm remarkably outperforms the PSO and its existing variants in success rate, solution quality, and convergence speed. We also explore the evolution process from a microscopic point of view, leading to the discovery of different roles that the particles play in optimization. The hub particles guide the optimization process towards correct directions while the non-hub particles maintain the necessary population diversity, resulting in the optimum overall performance of SIPSO. These findings deepen our understanding of swarm intelligence and may shed light on the underlying mechanism of information exchange in natural swarm and flocking behaviors. PMID- 25787316 TI - [Role of laparoscopy in the diagnosis of peritoneal tuberculosis in endemic areas]. AB - The aim of our study is to demonstrate the difficulties of diagnosis of peritoneal tuberculosis in endemic areas and the value of laparoscopy for diagnostic confirmation. We report a retrospective study of 60 cases of peritoneal tuberculosis, collected from January 2004 to December 2009. The patients' median age was 41 years, and the sex ratio 0.4. The dominant reasons for consultation were pain and abdominal distension. Abdominal ultrasound found ascites in all patients. Computed tomography (CT) was performed in 30 patients and confirmed the ultrasound data. Paracentesis of the ascites took place in all patients, collecting exudative fluid in all cases; lymphocytes predominance in 83%. Screening for Mycobacterium tuberculosis in the ascites on direct examination and after culture was performed in 43 cases and negative in all of them. Surgical biopsy was performed laparoscopically in 29 patients and by laparotomy in 31 patients. Histological examination of the peritoneal biopsies confirmed the diagnosis of peritoneal tuberculosis in all cases. PMID- 25787317 TI - Residents' corner February 2015. DeRmpath & Clinic--Leukocytoclastic vasculitis. PMID- 25787318 TI - Terahertz spectroscopy and computational investigation of the flufenamic acid/nicotinamide cocrystal. AB - Terahertz spectroscopy probes the low-frequency vibrations that are sensitive to both the intermolecular and intramolecular interactions of molecules in the solid state. Thus, terahertz spectroscopy can be a useful tool in the investigation of crystalline pharmaceutical compounds, where slight changes in the packing arrangement can modify the overall effectiveness of a drug formulation. This is especially true for cases of polymorphic systems, hydrates/solvates, and cocrystals. In this work, the cocrystal of flufenamic acid with nicotinamide was investigated using terahertz spectroscopy and solid-state density functional theory. The solid-state simulations enable understanding of the low-frequency vibrations seen in the terahertz spectra, while also providing insight into the energetics involved in the formation of the cocrystal. The comparison of the cocrystal to the pure forms of the molecular components reveals that the cocrystal has better overall binding energy, driven by increased intermolecular hydrogen bond strength and greater London dispersion forces and that the trifluoromethyl torsional potential is significantly different between the studied solids. PMID- 25787319 TI - LTR-retrotransposons and inter-retrotransposon amplified polymorphism (IRAP) analysis in Lilium species. AB - LTR-retrotransposons are ubiquitous and highly abundant in plant genomes. Moreover, LTR-retrotransposons can often cause genome obesity in plants. Although Lilium species have been known carrying large genomes among flowering plants, reports on the LTR-retrotransposons in Lilium species are rather limited. We isolated a novel Ty3/gypsy-like retrotransposon, LIRE-del, and two Ty1/copia-like retrotransposons, a LIRE-del and an unclassified, from a fosmid clone of Lilium longiflorum. Decayed internal ORF sequences indicated that they were non autonomous elements. IRAP protocol was developed based on the LTR sequences of the isolated LTR-retrotransposons. Fourteen primer combinations showed clear distinctive PCR amplification bands that were highly informative in the analysis of species relationship among Lilium species. The phylogenetic relationship based on the IRAP profile revealed some discordant with phylogenetic studies based on the ITS sequences of 45S ribosomal gene and matK gene variations in a few species. Thus, the phylogenetic relationship among Lilium species may need to be re-evaluated with other tools such as cross compatibility and selectively neutral genetic markers. PMID- 25787320 TI - Topographical and mechanical characterization of living eukaryotic cells on opaque substrates: development of a general procedure and its application to the study of non-adherent lymphocytes. AB - The mechanical behavior of living murine T-lymphocytes was assessed by atomic force microscopy (AFM). A robust experimental procedure was developed to overcome some features of lymphocytes, in particular their spherical shape and non adherent character. The procedure included the immobilization of the lymphocytes on amine-functionalized substrates, the use of hydrodynamic effects on the deflection of the AFM cantilever to monitor the approaching, and the use of the jumping mode for obtaining the images. Indentation curves were analyzed according to Hertz's model for contact mechanics. The calculated values of the elastic modulus are consistent both when considering the results obtained from a single lymphocyte and when comparing the curves recorded from cells of different specimens. PMID- 25787321 TI - [Acute myeloid leukemia]. AB - In recent years, the development of novel molecular techniques has been instrumental in deciphering the genetic heterogeneity of acute myeloid leukemia (AML) as well as in gaining important insights into the pathomechanisms of AML. Genetic diagnostics has become an essential component in the initial work-up for disease classification, prognostication, and genotype-specific therapies. A major prerequisite for such individualized treatment strategies is a rapid pretherapeutic genetic analysis, which includes screening for the recurrent AML associated gene fusions as well as mutations in the genes NPM1, FLT3, and CEBPA. Some of these molecular markers can be used for monitoring minimal residual disease and therefore provide clinically relevant information. There is an increasing number of promising molecularly targeted therapies in clinical development for distinct genetic AML subgroups. Solid data exist for the combination of all-trans retinoic acid and arsentrioxid in the treatment of acute promyelocytic leukemia; the addition of the immunoconjugate gemtuzumab ozogamicin (GO) to induction therapy has been shown to improve outcome in cytogenetic low- and intermediate-risk AML. Furthermore, there are encouraging data on the combination of intensive chemotherapy with tyrosine kinase inhibitors in patients with AML harboring FLT3 mutations or with core-binding factor AML. Other novel therapeutic approaches address mutations or alterations in epigenetic regulators, such as IDH or DOT1L inhibitors. The comprehensive characterization of the underlying genetic mechanisms is essential for the development of novel target specific compounds with the aim of improving outcome in AML patients. PMID- 25787322 TI - [Hairy cell leukemia]. AB - Hairy cell leukemia was initially described as a distinct entity in 1958. It is rare B-cell malignancy characterized by an indolent course. Advances in the treatment and understanding of the biology of hairy cell leukemia have made the disease exquisitely amenable to treatment. This review summarizes the present understanding of hairy cell leukemia with a particular focus on the development of novel and targeted approaches to treatment. PMID- 25787324 TI - Evaluation of new bi-functional terpolymeric nanoparticles for simultaneous in vivo optical imaging and chemotherapy of breast cancer. AB - Successful development of a nanoparticulate system for cancer chemotherapy requires detailed knowledge of its biodistribution, clearance and anti-tumour efficacy in vivo. Herein we developed new bi-functional nanoparticles for simultaneous in vivo optical imaging and delivery of the anticancer drug doxorubicin (Dox) for enhanced chemotherapy. Two types of nanoparticles were synthesized, namely preformed nanoparticles (PF-NPs) and self-assembled nanoparticles (SA-NPs). The PF-NPs were prepared by cross-linking graft polymerization of methacrylic acid and polysorbate 80 with starch (PMAA-PS 80-g St) and then loading the particles with Dox. The SA-NPs were formed upon addition of Dox to non-cross-linked PMAA-PS 80-g-St. A near infrared fluorescent probe was conjugated with the PMAA unit of the nanoparticles. The biodistribution, tumour targeting and pharmacokinetics of the Dox-loaded nanoparticles in mice were determined by in vivo/ex vivo fluorescence imaging and ex vivo fluorescence microscopy. The anti-tumour efficacy of the nanoparticles was investigated using a murine orthotopic breast cancer model. PF-NPs had an average hydrodynamic diameter and zeta potential of 137 +/- 3 nm and -38 +/- 1 mV, respectively. These values were measured at 62 +/- 5 nm and -35 +/- 5 mV for SA-NPs. PF-NPs exhibited a porous morphology while the SA-NPs appeared to have a denser structure. SA-NPs outperformed the PF-NPs in terms of blood circulation, tumour uptake and penetration. PF-NPs and SA-NPs exhibited no systemic toxicity and inhibited tumour growth significantly better than the free Dox solution with SA-NPs being the best, attributable to their excellent tumour uptake and penetration. This work demonstrates the usefulness of these bi-functional nanoparticles as nanotheranostics. PMID- 25787325 TI - Microemulsion-based antifungal gel delivery to nail for the treatment of onychomycosis: formulation, optimization, and efficacy studies. AB - Onychomycosis is the most common nail disease affecting nail plate and nail bed. Onychomycosis causes onycholysis which creates cavity between the nail plate and nail bed, where drug formulations could be applied, providing a direct contact of drug with the nail bed facilitating drug delivery on the infected area. The purpose of the present study was to design and evaluate the potential of microemulsion-based gel as colloidal carrier for itraconazole for delivery into onycholytic nails for effective treatment of onychomycosis. Itraconazole-loaded microemulsions were prepared and optimized using D-optimal design. The microemulsion containing 6.24 % oil, 36 % Smix, and 57.76 % water was selected as the optimized batch (MEI). The globule size and drug loading of the optimized batch were 48.2 nm and 12.13 mg/ml, respectively. Diffused reflectance FTIR studies were performed to study drug-excipient incompatibility. Ex vivo permeation studies were carried out using bovine hoof and human cadaver skin as models for nail plate and nail bed, respectively. Microemulsion-based itraconazole gel (MBGI) showed better penetration and retention in human skin as well as bovine hoof as compared to commercial preparation (market formulation, MFI). The cumulative amount of itraconazole permeated from the MBGI after 12 h was 73.39 +/- 3.55 MUg cm(-2) which was 1.8 times more than MF. MBGI showed significantly higher ex vivo antifungal activity (P < 0.05) against Candida albicans and Trichophyton rubrum when compared to MFI. Stability studies showed that MBGI was stable at refrigeration and room temperature for 3 months. It was concluded that drug-loaded gel could be a promising formulation for effective treatment of onychomycosis. PMID- 25787323 TI - Aptamer-conjugated polymeric nanoparticles for targeted cancer therapy. AB - Recent advances in cancer nanotechnology have led to the emergence of aptamer enabled technologies to diagnose and treat cancer. Aptamers with their high binding sensitivity and specificity are highly attractive for a wide variety of applications in molecular targeting. Aptamer-escorted drug-loaded polymeric nanoparticles represent a promising technology, which facilitates controlled release and targeted approach to deliver drugs to the desired site with marginal or any collateral damage. By properly integrating these nanobased approaches with the established cancer research findings could help to resolve some of the existing problems in the current conventional cancer therapy. In this review, we discuss the progresses achieved in the aptamer mediated nanoparticle drug delivery and properties of nanoparticles, which play a significant role in developing the aptamer-nanoparticle bioconjugates. In addition, we highlight the recent preclinical works involving these bioconjugates as cancer therapeutics. PMID- 25787326 TI - Electrospun matrices for localised controlled drug delivery: release of tetracycline hydrochloride from layers of polycaprolactone and poly(ethylene-co vinyl acetate). AB - We report the controlled release of tetracycline (Tet) HCl from a three-layered electrospun matrix for the first time. Five formulations of electrospun poly epsilon-caprolactone (PCL) and poly(ethylene-co-vinyl acetate) (PEVA) have been designed, prepared as micro/nanofibre layers, and assayed for the controlled release of the clinically useful antibiotic Tet HCl with potential applications in wound healing and especially in complicated skin and skin-structure infections. Tet HCl was also chosen as a model drug possessing a good ultraviolet (UV) chromophore and capable of fluorescence together with limited stability. Tet HCl was successfully incorporated (essentially quantitatively at 3 %, w/w) and provided controlled release from multilayered electrospun matrices. The Tet HCl release test was carried out by a total immersion method on 2 * 2 cm(2) electrospun fibrous mats in Tris or phosphate-buffered saline heated to 37 degrees C. The formulation PCL/PEVA/PCL with Tet HCl in each layer gave a large initial (burst) release followed by a sustained release. Adding a third layer to the two-layered formulations led to release being sustained from 6 days to more than 15 days. There was no detectable loss of Tet chemical stability (as shown by UV and NMR) or bioactivity (as shown by a modified Kirby-Bauer disc assay). Using Tet HCl-sensitive bacteria, Staphylococcus aureus (ATCC 25923), the Tet HCl loaded three-layered matrix formulations were still showing significantly higher antibacterial effects on days 4 and 5 than commercially available Antimicrobial Susceptibility Test Discs of Tet HCl. Electrospinning provides good encapsulation efficiency of Tet HCl within PCL/PEVA/PCL polymers in micro/nanofibre layers which display sustained antibiotic release. PMID- 25787327 TI - Development of a UC781 releasing polyethylene vinyl acetate vaginal ring. AB - UC781 is potent, hydrophobic, non-nucleotide reverse transcriptase inhibitor (NNRTI) against the human immunodeficiency virus (HIV). UC781 is currently being investigated for use as a potential HIV microbicide. A study in rhesus macaques demonstrated that a 100-mg UC781-loaded silicone elastomer vaginal ring released limited amounts of UC781 into the vaginal fluid and tissue after 28 days. The reason for this was due to the hydrophobic nature and limited aqueous solubility of UC781. This study describes the manufacture of UC781-loaded polyethylene vinyl acetate (PEVA) vaginal rings, which have an improved in vitro release rate of UC781 when compared to UC781-loaded silicone elastomer vaginal rings. The study demonstrates that the UC781 in the PEVA rings is mostly in its amorphous form due to the rings being manufactured above UC781's melting point. Furthermore, the rings do not show any signs of UC781 degradation, such as the presence of UC22. PMID- 25787328 TI - SLN approach for nose-to-brain delivery of alprazolam. AB - In the present study, alprazolam-loaded solid lipid nanoparticles were prepared and characterized. They were evaluated for their efficiency in nose-to-brain targeting and biodistribution in a suitable animal model after intranasal delivery. Solid lipid nanoparticles may offer an improvement to nose-to-brain drug delivery since they are able to protect the encapsulated drug from biological and/or chemical degradation. The distribution of the drug to different organs was recorded through biodistribution studies in male Wistar rats and gamma scintigraphy imaging in New Zealand rabbits by tagging the formulation with radioactive substance (99m)Tc. The radioactivity count of various organs was taken as a function of the drug concentration. The study reveals that alprazolam can be rapidly transferred to the brain via intranasal route, bypassing the blood brain barrier and a direct nose-to-brain transfer. The enhanced rate and extent of transport may help in reducing the dose and dosing frequency, thereby providing ease for ambulatory patients. PMID- 25787329 TI - Relationship between structural alerts in NSAIDs and idiosyncratic hepatotoxicity: an analysis of spontaneous report data from the WHO database. AB - BACKGROUND: Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the drug molecule that are susceptible to bioactivation resulting in RMs. The relationship, however, between metabolic activation of SAs in drugs with in vivo toxicity measured as disproportionate reporting of adverse drug reactions (ADRs) to the WHO VigiBaseTM database has never been studied. OBJECTIVE: The objective of this study was to investigate whether reported associations of hepatotoxicity between NSAIDs with SAs and NSAIDs with mitigated SAs are disproportionately present in the ADR reporting VigiBaseTM database of the WHO collaborating center (the Uppsala Monitoring Centre). The extent of disproportionality of these associations is compared with associations of NSAIDs and hemorrhage, an ADR not associated with the forming of RMs. METHODS: We calculated the reporting odds ratios for five NSAIDs [bromfenac (withdrawn), lumiracoxib (withdrawn), diclofenac, ibuprofen, and naproxen] associated with the MedDRA preferred terms: hepatic failure, hepatic function abnormal, hepatic necrosis, and hepatitis. The disproportionality of the association of these ADRs is compared with the preferred term hemorrhage. RESULTS: The results show that hepatotoxicity is more disproportionately reported in the WHO database for NSAIDs with SAs (bromfenac, lumiracoxib, diclofenac) than for NSAIDs where SAs are mitigated (ibuprofen and naproxen). This difference in reporting between NSAIDs with SAs and with mitigated SAs is not observed for the ADR hemorrhage, an ADR not associated with the forming of RMs. CONCLUSIONS: This study shows that although spontaneous reports have many limitations, the findings are in line with previous research on the reactive metabolite concept. Whether SAs and the number of SAs in the NSAIDs actually play a role in the observed hepatotoxicity must be investigated in future studies. PMID- 25787331 TI - Slower phloem transport in gymnosperm trees can be attributed to higher sieve element resistance. AB - In trees, carbohydrates produced in photosynthesizing leaves are transported to roots and other sink organs over distances of up to 100 m inside a specialized transport tissue, the phloem. Angiosperm and gymnosperm trees have a fundamentally different phloem anatomy with respect to cell size, shape and connectivity. Whether these differences have an effect on the physiology of carbohydrate transport, however, is not clear. A meta-analysis of the experimental data on phloem transport speed in trees yielded average speeds of 56 cm h(-1) for angiosperm trees and 22 cm h(-1) for gymnosperm trees. Similar values resulted from theoretical modeling using a simple transport resistance model. Analysis of the model parameters clearly identified sieve element (SE) anatomy as the main factor for the significantly slower carbohydrate transport speed inside the phloem in gymnosperm compared with angiosperm trees. In order to investigate the influence of SE anatomy on the hydraulic resistance, anatomical data on SEs and sieve pores were collected by transmission electron microscopy analysis and from the literature for 18 tree species. Calculations showed that the hydraulic resistance is significantly higher in the gymnosperm than in angiosperm trees. The higher resistance is only partially offset by the considerably longer SEs of gymnosperms. PMID- 25787330 TI - Contrasting drought-response strategies in California redwoods. AB - We compared the physiology and growth of seedlings originating from different Sequoia sempervirens (D. Don.) Endl. (coast redwood) and Sequoiadendron giganteum (Lindl.) Buchh. (giant sequoia) populations subjected to progressive drought followed by a recovery period in a controlled greenhouse experiment. Our objective was to examine how multiple plant traits interact to influence the response of seedlings of each species and seed population to a single drought and recovery cycle. We measured soil and plant water status, leaf gas exchange, stem embolism and growth of control (well-watered) and drought-stressed (water withheld) seedlings from each population at the beginning, middle and end of a 6 week drought period and again 2 weeks after re-watering. The drought had a significant effect on many aspects of seedling performance, but water-stressed seedlings regained most physiological functioning by the end of the recovery period. Sequoiadendron seedlings exhibited a greater degree of isohydry (water status regulation), lower levels of stem embolism, higher biomass allocation to roots and lower sensitivity of growth to drought compared with Sequoia. Only minor intra-specific differences were observed among populations. Our results show that seedlings of the two redwood species exhibit contrasting drought response strategies that align with the environmental conditions these trees experience in their native habitats, and demonstrate trade-offs and coordination among traits affecting plant water use, carbon gain and growth under drought. PMID- 25787332 TI - Oil palm water use: calibration of a sap flux method and a field measurement scheme. AB - Oil palm (Elaeis guineensis Jacq.) water use was assessed by sap flux density measurements with the aim to establish the method and derive water-use characteristics. Thermal dissipation probes were inserted into leaf petioles of mature oil palms. In the laboratory, we tested our set-up against gravimetric measurements and derived new parameters for the original calibration equation that are specific to oil palm petioles. In the lowlands of Jambi, Indonesia, in a 12-year-old monoculture plantation, 56 leaves on 10 palms were equipped with one sensor per leaf. A 10-fold variation in individual leaf water use among leaves was observed, but we did not find significant correlations to the variables trunk height and diameter, leaf azimuthal orientation, leaf inclination or estimated horizontal leaf shading. We thus took an un-stratified approach to determine an appropriate sampling design to estimate stand transpiration (Es, mm day(-1)) rates of oil palm. We used the relative standard error of the mean (SEn, %) as a measure for the potential estimation error of Es associated with sample size. It was 14% for a sample size of 13 leaves to determine the average leaf water use and four palms to determine the average number of leaves per palm. Increasing these sample sizes only led to minor further decreases of the SEn of Es. The observed 90-day average of Es was 1.1 mm day(-1) (error margin +/- 0.2 mm day( 1)), which seems relatively low, but does not contradict Penman-Monteith-derived estimates of evapotranspiration. Examining the environmental drivers of Es on an intra-daily scale indicates an early, pre-noon maximum of Es rates (11 am) due to a very sensitive reaction of Es to increasing vapor pressure deficit in the morning. This early peak is followed by a steady decline of Es rates for the rest of the day, despite further rising levels of vapor pressure deficit and radiation; this results in pronounced hysteresis, particularly between Es and vapor pressure deficit. PMID- 25787333 TI - Human papilloma virus-infected genital warts in a girl with Costello syndrome. PMID- 25787334 TI - The impact of 'negative data'. PMID- 25787335 TI - Considerations in the sterile manufacture of polymeric microneedle arrays. AB - We describe, for the first time, considerations in the sterile manufacture of polymeric microneedle arrays. Microneedles (MN) made from dissolving polymeric matrices and loaded with the model drugs ovalbumin (OVA) and ibuprofen sodium and hydrogel-forming MN composed of "super-swelling" polymers and their corresponding lyophilised wafer drug reservoirs loaded with OVA and ibuprofen sodium were prepared aseptically or sterilised using commonly employed sterilisation techniques. Moist and dry heat sterilisation, understandably, damaged all devices, leaving aseptic production and gamma sterilisation as the only viable options. No measureable bioburden was detected in any of the prepared devices, and endotoxin levels were always below the US Food & Drug Administration limits (20 endotoxin units/device). Hydrogel-forming MN were unaffected by gamma irradiation (25 kGy) in terms of their physical properties or capabilities in delivering OVA and ibuprofen sodium across excised neonatal porcine skin in vitro. However, OVA content in dissolving MN (down from approximately 101.1 % recovery to approximately 58.3 % recovery) and lyophilised wafer-type drug reservoirs (down from approximately 99.7 % recovery to approximately 60.1 % recovery) was significantly reduced by gamma irradiation, while the skin permeation profile of ibuprofen sodium from gamma-irradiated dissolving MN was markedly different from their non-irradiated counterparts. It is clear that MN poses a very low risk to human health when used appropriately, as evidenced here by low endotoxin levels and absence of microbial contamination. However, if guarantees of absolute sterility of MN products are ultimately required by regulatory authorities, it will be necessary to investigate the effect of lower gamma doses on dissolving MN loaded with active pharmaceutical ingredients and lyophilised wafers loaded with biomolecules in order to avoid the expense and inconvenience of aseptic processing. PMID- 25787336 TI - RGD-conjugated solid lipid nanoparticles inhibit adhesion and invasion of alphavbeta3 integrin-overexpressing breast cancer cells. AB - alphavbeta3 integrin receptors expressed on cancer cell surfaces play a crucial role in promoting tumor angiogenesis and cancer cell metastasis. Thus, cyclic arginyl-glycyl-aspartic acid (cRGD) peptides have been explored as a alphavbeta3 integrin receptor-specific targeting moiety for the targeted delivery of nanoparticle-loaded therapeutics. However, our previous study showed that cyclic RGD could act as a double-edged sword that, on one hand, extended the retention of cRGD-modified solid lipid nanoparticles (RGD-SLNs) at alphavbeta3 integrin receptor overexpressing breast carcinoma, and yet on the other hand, decreased the amount of tumor accumulation of RGD-SLNs attributable to the greater uptake by the mononuclear phagocyte system (MPS). Therefore, we aimed to optimize the RGD-decorated nanoparticle systems for (1) inhibiting alphavbeta3 integrin receptor overexpressing tumor cell metastasis and (2) increasing nanoparticle accumulation to tumor site. SLNs with cRGD content ranging from 0 to 10 % mol of total polyethyleneglycol (PEG) chains were synthesized. The binding of RGD-SLNs with alphavbeta3 integrin receptors increased with increasing cRGD concentration on the nanoparticles. RGD-SLNs were demonstrated to inhibit MDA-MB-231 cell adhesion to fibronectin and invasion through Matrigel. In vivo whole-body fluorescence imaging revealed that 1 % cRGD on the SLNs' surface had maximum tumor accumulation with extended tumor retention among all formulations tested in an orthotopic MDA-MB-231/EGFP breast tumor model. This work has laid a foundation for further development of anticancer drug-loaded optimized cRGD nanoparticle formulations for the treatment of breast cancer metastasis. PMID- 25787337 TI - Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques. AB - This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82-860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo-in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism. PMID- 25787338 TI - Medicinal facilities to B16F10 melanoma cells for distant metastasis control with a supramolecular complex by DEAE-dextran-MMA copolymer/paclitaxel. AB - The resistance of cancer cells to chemotherapeutic drugs (MDR) is a major problem to be solved. A supramolecular DEAE-dextran-MMA copolymer (DDMC)/paclitaxel (PTX) complex was obtained by using PTX as the guest and DDMC as the host having 50-300 nm in diameter. The drug resistance of B16F10 melanoma cells to paclitaxel was observed, but there is no drug resistance of melanoma cells to the DDMC/PTX complex in vitro. The cell death rate was determined using Michaelis-Menten kinetics, as the DDMC/PTX complex promoted allosteric supramolecular reaction to tubulin. The DDMC/PTX complex showed a very superior anti-cancer activity to paclitaxel alone in vivo. The median survival time (MST) of the saline, PTX, DDMC/PTX4 (particle size, 50 nm), and DDMC/PTX5 (particle size, 290 nm) groups were 120 h (T/C, 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed the twofold effectiveness of PTX alone (p < 0.036). Histochemical analysis indicated that the administration of DDMC/PTX complex decreased distant metastasis and increased the survival of mice. A mouse of DDMC/PTX4 group in vivo was almost curing after small dermatorrhagia owing to its anti-angiogenesis, and it will be the hemorrhagic necrotic symptom of tumor by the release of "tumor necrosis factor alpha (TNF-alpha)" cytokine. As the result, the medicinal action of the DDMC/PTX complex will suppress the tumor-associated action of M2 macrophages and will control the metastasis of cancer cells. PMID- 25787339 TI - Development and optimization of novel controlled-release pioglitazone provesicular powders using 32 factorial design. AB - This work aimed at studying a novel controlled drug delivery proniosomal formulation of pioglitazone for treatment of diabetes type-2. The effects of independent variables like type of surfactant and ratio of surfactants/cholesterol were studied using 3(2) factorial design. The provesicular powders were characterized regarding their encapsulation efficiency, vesicle size, morphology, and in vitro drug release. The revealed optimal provesicular powder was exposed to stability testing and in vivo performance evaluation. Results showed that F6 was selected as the optimal formulation, and its in vivo hypoglycemic effect on normal healthy and STZ-induced diabetic albino rats was investigated. F6 proniosomal formulation exhibited a significantly higher % decrease (56.18 % for STZ-induced diabetic albino rats) of blood glucose level (BGL) than Actos(r) (32. % for STZ-induced diabetic albino rats). Higher % decrease of BGL with longer t max and lower AUC0-24 confirms the development of a successful proniosomal pioglitazone formulation. PMID- 25787340 TI - Effect of gamma irradiation on drug releasing from nano-bioactive glass. AB - In this work, we studied the effect of gamma irradiation on nano-bioactive glass (NBG) structure, bioactivity, drug loading efficiency, and drug release kinetic. Gamma irradiation was mainly introduced as a safe and cheap method to tailor the drug loading and release efficiencies. NBG was investigated before and after gamma irradiation with two doses 25 and 50 kGy. Vancomycin antibiotic was used as a drug model, and different kinetic models (first order, Higuchi, Hixson-Crowell, and Baker-Lonsdale models) were used to study the mechanism of drug release. It was found that G25 sample showed the lowest affinity for vancomycin adsorption, but it showed the highest release rate. Also, vancomycin was released from all samples by diffusion mechanism from spherically shaped carrier. On the other hand, the bioactivity of NBG was not altered by gamma irradiation; in contrary, newly formed apatite layers were more well-crystalline. PMID- 25787342 TI - Estimation of human age using N-glycan profiles from bloodstains. AB - Protein glycosylation is the most common epiproteomic modification involved in numerous physiological and pathological processes. Previous studies reported strong associations between human plasma N-glycans and age, prompting us to evaluate the potential application of this biological phenomenon in the field of forensics. Blood from 526 blood donors from different parts of Croatia was collected on bloodstain cards during the period 2004-2007 and stored at 4 degrees C for 6-9 years. Glycosylation profiles of the bloodstains were analysed using hydrophilic interaction ultra performance liquid chromatography (HILIC-UPLC) and divided into 38 glycan groups (GP1-GP38). A statistically significant correlation between N-glycan profiles of bloodstains and chronological age was found and a statistical model that can be used for the age prediction was designed (Age = 75.59 - 5.15 * (GP4)(2)+ 17.07 * GP6 - 5.30 * (GP10)(2) - 16.56 * GP16 + 20.07 * GP20 - 7.54 * (GP20)(2) + 16.47 * GP22). This model explains 47.78% of the variation in age, with a prediction error of 9.07 years. Our findings demonstrate that analysing the N-glycan profile could be a new tool in forensics, offering an approximate human age estimation from dried bloodstains found at a crime scene. PMID- 25787341 TI - Cellular senescence: from growth arrest to immunogenic conversion. AB - Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a pro-inflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, well-established triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established "atypical" senescent states that may occur independent of DNA damage. PMID- 25787343 TI - A novel mutation in EED associated with overgrowth. AB - In a patient suspected clinically to have Weaver syndrome, we ruled out mutations in EZH2 and NSD1, then identified a previously undescribed de novo mutation in EZH2's partner protein EED. Both proteins are members of the Polycomb Repressive Complex 2 that maintains gene silencing. On the basis of the similarities of the patient's phenotype to Weaver syndrome, which is caused by de novo mutations in EZH2, and on other lines of evidence including mouse Eed hypomorphs, we characterize this mutation as probably pathogenic for a Weaver-like overgrowth syndrome. This is the first report of overgrowth and related phenotypes associated with a constitutional mutation in human EED. PMID- 25787344 TI - Short-term efficacy of N-carbamylglutamate in a patient with N-acetylglutamate synthase deficiency. AB - N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error regarding the urea cycle, however, its diagnosis is important as it can be effectively treated by N-carbamylglutamate. We evaluated a patient with NAGS deficiency who harbored two novel NAGS mutations and who showed excellent responsiveness during 1 year of N-carbamylglutamate treatment. PMID- 25787345 TI - Erratum to: umbilical cord blood for autologous transfusion in the early postnatal ontogeny: analysis of cell composition and viability during long-term culturing. PMID- 25787346 TI - Microfluidic two-dimensional separation of proteins combining temperature gradient focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. AB - A two-dimensional separation system is presented combining scanning temperature gradient focusing (TGF) and sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) in a PDMS/glass microfluidic chip. Denatured proteins are first focused and separated in a 15 mm long channel via TGF with a temperature range of 16-47 degrees C and a pressure scanning rate of -0.5 Pa/s and then further separated via SDS-PAGE in a 25 mm long channel. A side channel is designed at the intersection between the two dimensions to continuously inject SDS into the gel, allowing SDS molecules to be compiled within the focused bands. Separation experiments are performed using several fluorescently labeled proteins with single point detection. Experimental results show a dramatic improvement in peak capacity over one-dimensional separation techniques. PMID- 25787347 TI - Responding to the public health consequences of the Ukraine crisis: an opportunity for global health diplomacy. AB - INTRODUCTION: Peace and stability in Eastern Europe is now at a crossroads with the rapidly deteriorating foreign policy crisis continuing to unfold in the Ukraine. However, largely overlooked in the context of other foreign policy and diplomatic priorities are the serious public health consequences for the region following the annexation of Crimea and the subsequent decision to ban opioid substitution therapy in the disputed territory. DISCUSSION: On 1 May 2014, the Republic of Crimea officially announced it would end access to opioid substitution therapy, an essential harm reduction tool recognized by international organizations and virtually all other European countries. The policy development marks a critical reversal in the region's fight against its growing HIV epidemic and also threatens years of public health gains aimed at providing evidence-based and integrated treatment approaches to combat drug dependence and HIV. Beyond these risks, the Ukrainian conflict could also negatively impact control of other infectious diseases that are converging with HIV and injection drug use, such as multidrug-resistant tuberculosis and hepatitis C virus. The continuing conflict is also likely to have a significant negative impact on Ukraine's fragile public health system leading to even worse population health outcomes than currently experienced by the country. CONCLUSIONS: In response to this crisis, the application of global health diplomacy principles represents a possible route of advocacy to ensure that HIV prevention, humane treatment of substance using populations, and improving public health outcomes in the region are pursued among concerned international stakeholders. In order to be effective, global health diplomacy efforts must be coordinated and advocated in all forms of diplomatic engagement, including at the core, multistakeholder and informal levels and through existing channels such as the different human rights bodies of the United Nations as well as amongst other actors. Hence, the Ukraine crisis represents a critical moment for the practice and advancement of global health diplomacy in order to ensure global public health priorities are given their rightful place in foreign policy making to hopefully help in bringing resolution to the current conflict. PMID- 25787348 TI - Analyzing the hydrodynamic and crowding evolution of aqueous hydroxyapatite gelatin networks: Digging deeper into bone scaffold design variables. AB - The hydration of the polypeptide network is a determinant factor to be controlled on behalf of the design of precise functional tissue scaffolding. Here we present an exhaustive study of the hydrodynamic and crowding evolution of aqueous gelatin hydroxyapatite systems with the aim of increasing the knowledge about the biomimesis of collagen mineralization; and how it can be manipulated for the preparation of collagenous derived frameworks with specific morphological characteristics. The solution's density and viscosity evaluation measurements in combination with spectroscopic techniques revealed that there is a progressive association of protein chain that can be influenced by the amount of hydroxyapatite nanorods. Gelatin and additives' concentration effect on the morphology of the gelatin scaffolds was investigated. Transverse and longitudinal sections of the obtained scaffolds were taken and analyzed using optical microscopy. It can be seen that the porous size and shape of gelatin assemblies can be easily adjusted by controlling the gelatin/HAp ratio in the solution used as template in agreement with our statement. PMID- 25787349 TI - Author's response to: Bozzetti F, Nutrition, hydration, and patient's preferences at the end of life. PMID- 25787350 TI - A comparative study on the structural, optical and magnetic properties of Fe3O4 and Fe3O4@SiO2 core-shell microspheres along with an assessment of their potentiality as electrochemical double layer capacitors. AB - Herein, we report a comprehensive and comparative study on the crystal structure, and microstructural, optical, magnetic, hyperfine and electrochemical properties of Fe3O4 microspheres (S1) of diameter ~418 nm and Fe3O4@SiO2 core-shell microspheres (S2) of diameter ~570 nm. Each asymmetric unit of the crystalline Fe3O4 has one cation vacancy at the octahedral [B] site. At 300 K the saturation magnetization and coercivity of ferrimagnetically ordered S1 and S2 are 63.5, 38.5 emu g(-1) and 200 and 120 Oe, respectively. We have shown that the synthesis procedure, morphology, surface properties, interparticle interaction manifesting the collective properties of the nanoparticle assembly and the average size of individual Fe3O4 nanoparticles forming the spherical ensemble play a crucial role in determining the magnetic properties of Fe3O4 and Fe3O4@SiO2 microspheres while the diameter of the microsphere does not have significant influence on magnetic properties of such a system. Further, the photoluminescence intensity of Fe3O4 microspheres gets significantly enhanced upon SiO2 coating. A cyclic voltammetric study suggests that S1 can act as a good electrical double layer capacitor (EDLC) above a scan rate of 0.04 V s(-1) while S2 exhibits excellent performance as EDLC in a scan range from 0.01 to 0.06 V s(-1). Thus, S2 is a potential candidate for fabrication of EDLCs. PMID- 25787351 TI - Post-immigration Changes in Social Capital and Substance Use Among Recent Latino Immigrants in South Florida: Differences by Documentation Status. AB - Changing social capital among recent Latino immigrants (RLIs) influences substance use post-immigration. This was a longitudinal study of 476 South/Central American RLIs examining social capital and substance use changes pre to post-immigration. Self-reported measures of social capital and substance use were compared between surveys administered within 1 year of immigration and 2 years post-immigration. Post-immigration, social capital, hazardous drinking and illicit drug use decreased. Women were less likely to engage in hazardous drinking [adjusted odds ratio (AOR) .32, p < .001], and less likely to use illicit drugs (AOR .67, p = .01). Documented individuals with higher levels of 'business' social capital had increased odds of illicit drug use (AOR 2.20, p < .05). Undocumented individuals with higher levels of 'friend and others' social capital had decreased risk for hazardous drinking and illicit drug use (AOR .55, p < .01; AOR .56, p < .05). Documentation status moderated the relationship between social capital and substance use. RLIs can be targeted for primary prevention of substance abuse. PMID- 25787352 TI - Migrant Selectivity or Cultural Buffering? Investigating the Black Immigrant Health Advantage in Low Birth Weight. AB - Prior studies on population health have reported an "immigrant health advantage" in which immigrants tend to show better health outcomes compared to their native born racial/ethnic counterparts. Migrant selectivity and cultural buffering have been proposed as explanations for this relative advantage, predominantly in studies that focus on Latino immigrants' health in the US. This study adds to the relatively scant literature on black immigrant health advantage by comparing the two hypotheses (migrant selectivity and cultural buffering) as related to black immigrant health. The effect of nativity on infant low birth weight is tested using data from the US Fragile Families and Child Wellbeing Study. Results indicate that immigrant black mothers do have relatively better health outcomes that may result from cultural buffering, which reduces their risky health behaviors. PMID- 25787669 TI - Sub-terahertz frequency-domain spectroscopy reveals single-grain mobility and scatter influence of large-area graphene. AB - The response of individual domains in wafer-sized chemical vapor deposition graphene is measured by contactless sub-terahertz interferometry, observing the intrinsic optical conductance and reaching very high mobility values. It is shown that charged scatterers limit the mobility, validating previous theoretical predictions, and sub-terahertz quality assessment is demonstrated, as necessary for large-scale applications in touchscreens, as well as wearable and optoelectronic devices. PMID- 25787668 TI - In vitro effects of sodium nitroprusside and leptin on norepinephrine-induced vasoconstriction in human internal mammary artery. AB - AIM: The biological and pharmacological properties of vessels used in coronary artery bypass graft (CABG) surgery are as important as their mechanical properties. The aim of this study was to investigate the possible role of protein kinase C (PKC)-dependent mechanisms in leptin-induced relaxation in the human internal mammary artery (IMA). METHODS: IMA rings, obtained from patients undergoing CABG surgery, were suspended in isolated tissue baths containing Krebs Henseleit solution, which were continuously gassed with 95% O2 and 5% CO2 at 37( degrees )C. RESULTS: The IMA rings were pre-contracted with increasing concentrations of norepinephrine (NE 10(-9)-10(-4) mol/l) and the relaxation responses to sodium nitroprusside (SNP), a nitrosovasodilator, and leptin were studied in the presence and absence of a PKC inhibitor. Leptin (1 uM) caused a dose-dependent relaxation in NE pre-contracted IMA rings. Pre-treatment with a PKC inhibitor significantly attenuated this vasorelaxatory response to leptin in human isolated IMA. CONCLUSION: It was found that SNP and leptin caused significant relaxation of the NE pre-contracted human IMA rings, and PKC was probably the sub-cellular mediator for this effect. Our findings may have clinical or pharmacological importance as it could be hypothesised that obese subjects who have a left IMA bypass graft would have better myocardial perfusion. PMID- 25787670 TI - New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics. AB - OBJECTIVES: Patients with a bicuspid aortic valve (BAV) present with various phenotypes of the valve, the aortic root (AoR) and/or the ascending aorta (AAo) and various valve haemodynamics (vHs). The aim of the present study was to investigate the association between the above parameters. METHODS: Between February 1999 and April 2014, the preoperative aortographies of 828 surgical patients with BAV were evaluated. The exact BAV type was classified intraoperatively according to the number and spatial orientation of the raphes. RESULTS: On analysis of BAV phenotypes and aortic configurations, a weak pattern was revealed (P = 0.01) only for BAV type 0 and AoR dilatation. Including haemodynamics, certain significant patterns emerged: in insufficient BAVs, AoR dilatation was significantly more frequent in type 0, type 1 LR and type 1 RN, whereas AoR + AAo dilatation was more frequent in BAV type 1 LR. In stenotic BAVs, AAo dilatation alone was observed significantly more frequently in BAV type 1 LR and type 0. Combined vHs were associated with AAo and AoR + AAo dilatation in BAV type 2/unicuspid only. CONCLUSIONS: Associations between the two parameters, BAV type and aortic configuration, were only weak. With the inclusion of haemodynamics significant associations emerged but were not exclusive. In stenotic BAVs, aortic dilatation was more localized to AAo only, supporting the valve-related flow turbulence theory. Insufficient (even trace insufficient) BAVs and also combined lesions in BAV type 2/unicuspid were associated with a more extensive aortopathy (AoR + AAo) in younger patients, indicating a more aggressive gene-related aortopathy. PMID- 25787671 TI - Impact of stage migration and practice changes on high-risk prostate cancer: results from patients treated with radical prostatectomy over the last two decades. AB - OBJECTIVE: To evaluate the impact of year of surgery on clinical, pathological and oncological outcomes of patients with high-risk prostate cancer. PATIENTS AND METHODS: We evaluated 1 033 patients with clinically high-risk prostate cancer, defined as the presence of at least one of the following risk factors: preoperative prostate-specific antigen (PSA) level >20 ng/mL, and/or clinical stage >=T3, and/or biopsy Gleason score >=8. Patients were treated between 1990 and 2013 at a single institution. The year-by-year trends in clinical and pathological characteristics were examined. Multivariable Cox regression analysis was used to test the relationship between year of surgery and oncological outcomes. RESULTS: We observed a decrease over time in the proportion of patients with high-risk disease (preoperative PSA >20 ng/mL or clinical stage cT3). A trend in the opposite direction was seen for biopsy Gleason score >=8 tumours. We observed a considerable increase in the median number of lymph nodes removed, which was associated with an increased rate of lymph node invasion (LNI). On multivariable Cox regression analysis, year of surgery was associated with a reduced risk of biochemical recurrence (hazard ratio [HR] per 5-year interval 0.90, 95% confidence interval [CI] 0.84-0.96; P = 0.01) and distant metastasis (HR per 5-year interval 0.91, 95% CI 0.83-0.99; P = 0.039), after adjusting for age, preoperative PSA, pathological stage, LNI, surgical margin status, and pathological Gleason score. CONCLUSIONS: In this single-centre study, an increased diagnosis of localized and less extensive high-grade prostate cancer was observed over the last two decades. Patients with high-risk disease who were selected for radical prostatectomy showed better cancer control over time. Better definitions of what constitutes high-risk prostate cancer among contemporary patients are needed. PMID- 25787672 TI - Circulating platelet-neutrophil aggregates play a significant role in Kawasaki disease. AB - BACKGROUND: Circulating platelet-neutrophil aggregates play a crucial role in amplifying acute inflammation and could promote adverse effects involving vascular injury. The aim of this study was to evaluate the role of platelet neutrophil aggregates in Kawasaki disease (KD). METHODS AND RESULTS: Forty patients with KD (30 intravenous immunoglobulin [IVIG] responders and 10 IVIG non responders), 7 febrile patients with bacterial infections, and 9 normal volunteers were analyzed. Thirty-three patients with KD were treated with IVIG, and 7 were treated with IVIG plus prednisolone. We evaluated the rate of platelet neutrophil aggregates and measured the platelet factor 4 (PF4) and beta thromboglobulin (beta-TG) levels. The rate of platelet-neutrophil aggregates was significantly higher in patients with KD than those with bacterial infection and normal volunteers. The rate of platelet-neutrophil aggregates was significantly higher in patients with coronary artery abnormalities (CAA) than in those without CAA, and was correlated with PF4 and beta-TG levels in patients with KD. Comparing time-course analysis, the rate of platelet-neutrophil aggregates was significantly decreased in patients treated with IVIG plus prednisolone than in those treated with IVIG alone. CONCLUSIONS: The findings demonstrate that platelet-neutrophil aggregates are significantly present in higher rates and are closely related to pathological developments of CAA in KD. Additional prednisolone treatment for patients in the acute phase of KD could suppress platelet-neutrophil aggregates, indicating that platelet-neutrophil aggregates would inhibit amplified reciprocal vascular inflammatory activation. PMID- 25787673 TI - Coronary functional tests in the catheterization laboratory - pathophysiological and clinical relevance. AB - Coronary angiography has long been the only diagnostic tool for the invasive assessment of coronary artery disease. Yet it does not allow establishing the functional severity of epicardial stenoses or vasomotor disorders of the epicardial arteries or coronary microcirculation. Functional tests in the catheterization laboratory have recently emerged as an important adjunct to coronary angiography for providing a comprehensive evaluation of the coronary circulation. In this review, we will describe and interpret the key functional tests used in current clinical practise in different clinical settings. PMID- 25787674 TI - Extremely low levels of serum uric acid are associated with endothelial dysfunction in humans. PMID- 25787675 TI - Persistent racial and ethnic differences in location of death for children with cancer. AB - BACKGROUND: Approximately one in 285 children will be diagnosed with cancer before reaching their 20th birthday. While both oncologists and parents report a preference that these children die at home rather than in a hospital, there are limited data exploring this issue in depth. PROCEDURE: We performed a retrospective analysis of national-level data from 1999 to 2011 from the National Center for Health Statistics "Underlying Cause of Death" database. Characteristics investigated included sex, race, age, ethnicity, cancer type, geographic location, and population density where the child lived. RESULTS: Of the 2,130 children with a death attributable to neoplasm in 2011, 37.6% (95% CI, 35.5-39.6%) died at home compared to 36.9% (95% CI, 35.0-38.8%) in 1999. In 2011, there were statistically significant racial differences between white, black, and Hispanic children across nearly every age group, with white children consistently most likely to die at home. Children of non-Hispanic origin were significantly more likely to die at home than Hispanic children (40.3% vs. 29.3%, P < 0.001). Children with CNS tumors are more likely to die at home than children with neoplasms as a whole, while children with leukemia are less likely. Statistically significant differences by race and ethnicity persist regardless of cancer type. CONCLUSIONS: There has been no significant change in the rate of children with cancer who die at home over the past decade. Racial and ethnic differences have persisted in end of life care for children with cancer with white non-Hispanic children being most likely to die at home. PMID- 25787676 TI - Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening. AB - Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes. Agonists of both the bile acid receptors increase insulin sensitivity and control glucose, lipids and bile acid homeostasis. The current study deals with the identification of novel dual agonists using ligand and structure-based virtual screening. Initially, an experimentally proven well-known dual agonist of FXR and TGR5, namely INT-767, was docked into the binding sites of FXR and TGR5 to determine the protein residues important for ligand binding. The docked complexes FXRINT-767 and TGR5INT-767 were used to generate e pharmacophore hypotheses. Ligand-based virtual screening was carried out using the hypothetical e-pharmacophore model against the ChemBridge database. Further, structure-based virtual screening was performed with screened hits to find potential agonists of FXR and TGR5. A total of four best agonists were identified based on their affinity and mode of interactions with the receptors. The binding mode of these compounds with both receptors was analyzed in detail. Furthermore, molecular dynamics, ADME toxicity prediction, density functional theory and binding free energy calculations were carried out to rank the compounds. Based on the above analyses, the most potent compound, ChemBridge_9149693, was selected for further in vitro studies. The results of in vitro assays suggested that ChemBridge_9149693 is a potent and promising drug for the treatment of type II diabetes. Thus, the compound could be used for further drug design and development of dual agonists of FXR and TGR5. PMID- 25787677 TI - Bis(triphenylphosphine)silver(i) perrhenate, a cyclic dimer. AB - The 1 : 4 and 1 : 2 complexes of silver perrhenate and triphenylphosphine, [(Ph3P)4Ag](+) ReO4(-) and [(Ph3P)2AgReO4]2, have been prepared and their structures determined in the solid state by X-ray diffraction. The former is composed of independent ions, while in the latter the ions are aggregated into cyclic dimers. The silver centers are tetracoordinated including contact with two bridging perrhenate anions, setting this structure apart from that of its gold analogue [(Ph3P)2Au](+) ReO4(-) where the gold centers are strictly two coordinate. PMID- 25787678 TI - Primary cicatricial alopecia and inflammatory bowel disease - is there a link? PMID- 25787679 TI - Epidemiology of chronic kidney disease, with special emphasis on chronic kidney disease of uncertain etiology, in the north central region of Sri Lanka. AB - BACKGROUND: The aim of the study was to identify the epidemiology of chronic kidney disease of uncertain etiology in Sri Lanka. METHODS: A cross-sectional study was carried out by analyzing health statistics, and three cohort studies were conducted (n = 15 630, 3996, and 2809) to analyze the demographic information, age-specific prevalence, etiology, and stage of presentation. We screened 7604 individuals for chronic kidney disease of uncertain etiology. RESULTS: The results showed that the male:female ratio was 2.4:1, the mean age of patients was 54.7 +/- 8 years, 92% of the patients were farmers, and 93% consumed water from shallow dug wells. Familial occurrence was common (36%). The prevalence of chronic kidney disease in different age groups was 3% in those aged 30-40 years; 7% in those aged 41-50 years, 20% in those aged 51-60 years, and 29% in those older than 60 years. Chronic kidney disease of uncertain etiology was diagnosed in 70.2% of patients, while 15.7% and 9.6% were due to hypertension and diabetic mellitus, respectively. The majority of patients were stage 4 (40%) at first presentation, while 31.8% were stage 3 and 24.5% were stage 5. Stage 1 and 2 presentation accounted for only 3.4%. CONCLUSIONS: Low prevalence of CKDU was noticed (1.5%) among those who consumed water from natural springs. Prevalence was highest among males, rice farming communities, and those presenting at later disease stages. PMID- 25787680 TI - Randomized controlled trial of conventional versus modern surgical dressings following primary total hip and knee replacement. AB - PURPOSE: We prospectively compared two types of dressing (conventional gauze based versus absorbing hydrofibre) after primary total hip (THA) or knee (TKA) arthroplasties. METHODS: Eighty candidates for THA (n = 40) or TKA (s = 40) were randomized: gauze-based versus hydrofibre absorbing (Aquacel(r), ConvaTec). The two groups were comparable at baseline. RESULTS: There was a statistically significant decrease of dressing changes in the hydrofibre group (p = 0.0006). Two patients from the conventional group presented minor wound complications. Nurses' satisfaction was significantly higher in the hydrofibre group considering the adherence (p = 0.04) and flexibility (p = 0.03). Patients experienced a higher satisfaction with respect to ease of movement (p = 0.01) in the hydrofibre group. The cosmetic appearance of the scars six weeks after surgery was found to be similar between groups. CONCLUSIONS: Our findings support an overall improved comfort for the patients and the medical staff by using hydrofibre dressings after primary THA and TKA. The reduction of required dressing changes was observed also. PMID- 25787681 TI - History of femoral head fracture and coronal fracture of the femoral condyles. AB - The first known description of the coronal fracture of the lateral femoral condyle was published by Busch in 1869. Hoffa used Busch's drawing in the first edition of his book in 1888 and accompanied it only with one sentence. A full case history of this fracture pattern was described by Braun in 1891. However, Braun's article fell into oblivion and so the fracture was popularized only in the fourth edition of Hoffa's textbook, particularly thanks to the drawing, rather than the brief description. Therefore, a fracture of the posterior femoral condyle, or more specifically, of the lateral condyle, could properly be called "Busch-Hoffa fracture". Femoral head fracture was initially described by Birkett in 1869. Of essential importance in this respect were the publications by Christopher in 1924 and, particularly, Pipkin's study of 1957, including his classification that is still in use today. A historically correct eponym for a femoral head fracture would therefore be "Birkitt-Pipkin fracture". PMID- 25787682 TI - Response to comments on Maffulli and Del Buono: Release of the medial head of the gastrocnemius for Achilles tendinopathy in sedentary patients. PMID- 25787684 TI - The effect of femoral neck osteotomy on femoral component position of a primary cementless total hip arthroplasty. AB - PURPOSE: The aim of this study was to quantify the femoral canal diameter and version at different femoral neck osteotomy locations, and to investigate the effect of the osteotomy plane on femoral component position in total hip arthroplasty (THA). METHODS: Preoperative and postoperative three-dimensional models were reconstructed in 15 patients (19 hips) who underwent primary cementless THA with tapered non-anatomical femoral stem. On the pre-operative models, the osteotomy plane was simulated at different levels (-5, 0, 5, and 10 mm from the femoral saddle [piriformis fossa]) and angles (30, 40, 50, and 60 degrees from the femoral anatomical axis). Medullary canal version and mediolateral diameter were measured on the osteotomy surfaces. On the postoperative models, the femoral neck osteotomy plane, stem anteversion and alignment were measured. RESULTS: The average canal diameter ranged from 22.8 to 26.3 mm at different osteotomy levels and from 20.8 to 29.0 mm at different osteotomy angles. The average canal version ranged from 11.4 to 23.2 degrees at different resection levels and from 12.8 to 21 degrees at different resection angles. The femoral stem anteversion was correlated with neck osteotomy angle (R = 0.72), whereas stem alignment in frontal plane (varus/valgus) was correlated with neck osteotomy level (R = 0.87). CONCLUSIONS: The femoral neck osteotomy plane in THA affects the postoperative stem position due to the complex morphology of the proximal femoral medullary canal, suggesting that both femoral neck resection level and angle should be considered in optimizing femoral component alignment in THA patients. PMID- 25787683 TI - Does balloon kyphoplasty improve the global spinal alignment in osteoporotic vertebral fracture? AB - PURPOSE: Balloon kyphoplasty (BKP) has been a well-accepted procedure in the treatment of osteoporotic vertebral compression fracture (OVCF), whereas it remains unclear whether or not this procedure has an impact on the global spinal alignment. The purpose of this study is to evaluate the effect of BKP on the global spinal alignment in OVCF. METHODS: Fifty-six consecutive patients who had undergone BKP for symptomatic OVCF were retrospectively reviewed with a mean follow-up of 32 months. They were seven males and 49 females with a mean age of 75 years. Radiographic assessment was performed using upright whole spine radiographs. The parameters included vertebral kyphosis, mid-vertebral body height and global sagittal spinal alignment (C7 plumb line deviation). Clinical outcomes were evaluated using visual analog scale of back pain. RESULTS: Fifty one of 56 patients (91.1 %) achieved immediate pain relief. Vertebral kyphosis significantly decreased from 18 to 14 degrees, but 43 patients (76.8 %) still had more than 10 degrees of local kyphosis. Subsequent vertebral compression fractures were observed in seven patients (12.5 %). Anterior deviation of a C7 plumb line (C7PL) was 3.1 cm pre-operatively, 3.1 cm postoperatively, and significantly increased to 5.9 cm at the final follow-up. Consistent results were obtained in those with pre-operative sagittal imbalance (>5 cm anterior deviation of C7PL) and with pre-existing OVCFs. CONCLUSIONS: BKP contributed to immediate pain relief, but did not improve the global sagittal spinal alignment after OVCF. This procedure should be solely indicated for painful OVCF or non-union, and could not be expected to restore the global sagittal alignment. PMID- 25787685 TI - Abnormal inhibition-excitation imbalance in migraine. AB - BACKGROUND: People with migraine show increased surround suppression of perceived contrast, a perceptual analogue of centre-surround antagonistic interactions in visual cortex. A proposed mechanism is that cortical 'hyperexcitability' or 'hyperresponsivity', a prominent theory in the migraine literature, drives abnormal excitatory-inhibitory balance to give increased local inhibition. The purpose of this cross-sectional study was to determine whether cortical hyperresponsivity and excitatory-inhibitory imbalance manifests in the visual cortical response of migraine sufferers. METHODS: Interictal steady-state visual evoked potentials (VEPs) in response to 0 to 97% contrast were recorded in 30 migraine participants (15 without aura, 15 with aura) and 21 non-headache controls. Monotonicity indices were calculated to determine response saturation or supersaturation. Contrast gain was modelled with a modified saturating hyperbolic function to allow for variation in excitation and inhibition. RESULTS: A greater proportion of migraine participants (43%) than controls (14%) exhibited significant VEP supersaturation at high contrast, based on monotonicity index (chi-square, p = 0.028). Supersaturation was also evident by the trend for greater suppressive exponent values in migraine compared to control individuals (Mann-Whitney rank sum, p = 0.075). CONCLUSIONS: Supersaturation in migraine is consistent with excess excitation (hyperresponsivity) driving increased network inhibition and provides support for excitatory-inhibitory imbalance as a pathophysiological disturbance in migraine. PMID- 25787686 TI - Infratrochlear neuralgia. AB - INTRODUCTION: The infratrochlear nerve supplies the medial aspect of the upper eyelid, the superolateral aspect of the nose and the lacrimal caruncle. This nerve may contribute to the pain stemming from the trochlea, but infratrochlear neuralgia has not been identified as a specific cause of pain. METHODS: Over a 10 year period we have been recruiting patients with pain in the internal angle of the orbit that did not show features of trochlear pain. RESULTS: Seven patients (six female, one male; mean age, 46.1 +/- 18.9) presented with pain in the territory of the infratrochlear nerve. The pain appeared in the internal angle of the orbit and upper eyelid (n = 3), the superolateral aspect of the nose (n = 3), or the lacrimal caruncle (n = 1). All patients had a paroxysmal pain, with the attacks lasting five to 30 seconds. Pain attacks were mostly spontaneous, but two patients had triggers. Between attacks, all patients had local allodynia. Pain did not increase with vertical eye movements. Six patients were treated with gabapentin with complete response, and one patient experienced long-lasting relief with an anesthetic blockade of the infratrochlear nerve. CONCLUSION: Infratrochlear neuralgia should be considered as a possible cause of pain in the internal angle of the orbit. PMID- 25787687 TI - Expanding capacity for hepatitis C treatment in the United States: team-based care and use of nonphysician providers. AB - Hepatitis C treatment is rapidly evolving with significant improvements in patient outcomes. With an estimated prevalence of over 3 million persons living with chronic hepatitis C in the United States, it is anticipated that there will be an increase in the number of persons seeking care and treatment for chronic hepatitis C infection. Current systems of care may be overburdened with people seeking care for chronic hepatitis C virus (HCV). Interprofessional models of care have been shown to be feasible and effective in treating different populations affected by chronic HCV. Use of interprofessional teams, integrated models of care, and greater use of nonphysician providers offer a potential solution for expanding capacity to comprehensive HCV treatment and care in the United States. PMID- 25787688 TI - Branched-chain amino acids modulate the expression of hepatic fatty acid metabolism-related genes in female broiler chickens. AB - SCOPE: The effects and roles of branched-chain amino acids (BCAAs) in hepatic fat metabolism are still unknown. METHODS AND RESULTS: Here, we used broiler chickens, in which lipogenesis occurs essentially in the liver as in human, to investigate the effects of three levels of BCAAs (control "C," low "L" and exogenous supplemented diet "L+S") on growth, carcass traits, immunity, and hepatic fat metabolism. Despite the same productive performance, immunity, and plasma BCAA levels between all groups, low BCAA levels significantly downregulated the hepatic expression of lipogenic genes particularly acetyl-CoA carboxylase alpha (ACCalpha) and stearoyl-coA desaturase 1 (p = 0.0036 and p = 0.0008, respectively) and upregulated the hepatic expression of mitochondrial beta-oxidation- (uncoupling protein and NRF-1, p < 0.05) and dynamic-related genes (DNM1, p < 0.05). Concomitant with these changes, low BCAA levels increased the phosphorylation of AMP-activated protein kinase (AMPK)alpha(Thr172), ACCalpha(Ser79), and forkhead box protein O1 (FoxO1(Ser256)) and decreased the phosphorylation of mTOR(Ser2481) and P70 S6 kinase (Thr389). The mRNA abundance of the transcription factors SREBP1/2, peroxisome proliferator activated receptor alpha/beta, and FoxO1 were also increased in the liver of L group compared to the control. CONCLUSION: Together our data indicate that low BCAA levels inhibit fatty acid synthesis and enhanced fatty acid beta-oxidation in the liver of female broiler chickens and these effects were probably mediated through AMPK mTOR-FoxO1 pathway. PMID- 25787689 TI - Potato leafroll virus structural proteins manipulate overlapping, yet distinct protein interaction networks during infection. AB - Potato leafroll virus (PLRV) produces a readthrough protein (RTP) via translational readthrough of the coat protein amber stop codon. The RTP functions as a structural component of the virion and as a nonincorporated protein in concert with numerous insect and plant proteins to regulate virus movement/transmission and tissue tropism. Affinity purification coupled to quantitative MS was used to generate protein interaction networks for a PLRV mutant that is unable to produce the read through domain (RTD) and compared to the known wild-type PLRV protein interaction network. By quantifying differences in the protein interaction networks, we identified four distinct classes of PLRV plant interactions: those plant and nonstructural viral proteins interacting with assembled coat protein (category I); plant proteins in complex with both coat protein and RTD (category II); plant proteins in complex with the RTD (category III); and plant proteins that had higher affinity for virions lacking the RTD (category IV). Proteins identified as interacting with the RTD are potential candidates for regulating viral processes that are mediated by the RTP such as phloem retention and systemic movement and can potentially be useful targets for the development of strategies to prevent infection and/or viral transmission of Luteoviridae species that infect important crop species. PMID- 25787690 TI - Novel use of platelet-rich fibrin matrix and MTA as an apical barrier in the management of a failed revascularization case. AB - METHOD: We report management of a failed revascularization/revitalization case, which could be due to inadequate removal of biofilm and bacteria in dentinal tubules. The use of an apical matrix barrier in form of a platelet-rich fibrin (PRF) membrane for stabilization of MTA in root end apexification procedure is described. The canal was cleansed of old MTA present in the cervical third using H files, irrigated using saline and finally irrigated with 2.5% NaOCl and saline. To obtain canal disinfection, calcium hydroxide paste was temporized in the canal. In subsequent appointments, PRF was placed at the root tip followed by 5 mm apical plug with mineral trioxide aggregate. One week later, the root canal was obturated with thermoplasticized gutta-percha. A 6-month and a 2-year follow ups showed reduction of periapical radiolucency and adequately functional tooth. RESULTS: One-visit apexification techniques provide an alternative treatment for failed revascularization cases. Follow up confirmed complete healing periradicularly. CONCLUSION: Apexification in one step using an apical barrier of PRF and a plug of MTA can be considered a predictable treatment and may be an alternative to long-term revascularization failures. PMID- 25787691 TI - Dietary linoleic acid requirements in the presence of alpha-linolenic acid are lower than the historical 2 % of energy intake value, study in rats. AB - Previous studies on rats and human subjects have established that the linoleic acid (LA) requirement is 2 % of the total energy intake (en%), but is obtained in the absence of alpha-linolenic acid (ALA) and consequently appear to be overestimated. This raises questions since a recent study including ALA has suggested to divide the historical value by four. However, this recent study has remained inconclusive because the animals used were not totally LA-deficient animals. For the first time, the present study was especially designed using physiological and biochemical markers and performed in two steps: (1) to achieve a specific n-6 fatty acid deficiency model using growing male rats fed either a 0 en% from LA/0 en% from ALA (0LA/0ALA), 0LA/0.5ALA or 2LA/0.5ALA diet, born from female rats fed a 0LA/0.5ALA diet; and (2) to refine the required level of LA in the presence of ALA using rats fed either a 0LA/0ALA, 0.5LA/0.5ALA, 1LA/0.5ALA, 1.5LA/0.5ALA diet, born from female rats fed a 0LA/0.5ALA diet. The first step shows that the best LA deficiency model was obtained using rats fed the 0LA/0ALA diet, born from female rats fed the 0LA/0.5ALA diet. The second step demonstrates that in growing rats, LA deficiency was corrected with an intake of 1-1.5 en% from LA and 0.5 en% from ALA. These data suggest that the requirements in humans should be revisited, considering the presence of ALA to set up the recommendation for LA. PMID- 25787692 TI - Directed evolution of lambda integrase activity and specificity by genetic derepression. AB - Advances in genome engineering are attendant on the development of novel enzyme variants with programed substrate specificities and improved activity. We have devised a novel selection method, wherein the activity of a recombinase deletes the gene encoding an inhibitor of an enzyme conferring a selectable phenotype. By using beta-lactamase and the beta-lactamase inhibitor protein, the selection couples recombinase activity to Escherichia coli survival in the presence of ampicillin. Using this method, we generated lambda integrase variants displaying improved in vitro recombination of a non-cognate substrate present in the human genome. One generalist integrase variant displaying enhanced catalytic activity was further used in a facile, single-step transformation method to introduce transgenes up to 8.5 kb into the unique endogenous attB site of common laboratory E.coli strains. PMID- 25787693 TI - A qualitative inquiry of Malawian radio listeners' attitudes and perceived outcomes of alcohol use using a mobile data collection platform. AB - INTRODUCTION AND AIMS: Alcohol use has been associated with an increased risk of human immunodeficiency virus (HIV) transmission in sub-Saharan Africa. Despite this association, there are little data on drinking behaviours in Malawi, a country located in southern Africa. Utilising alternative techniques of data collection, such as mobile technology, may be necessary to eliminate this dearth of information. We use listeners' text messages (SMS) in response to a Malawian radio show to assess listeners' attitudes and perceived outcomes of drinking. DESIGN AND METHODS: Mobile phones provide a novel, low-cost platform from which to gather qualitative data directly from target audiences. To demonstrate the utility of a mobile data collection approach, we analysed listener feedback in the form of SMS in response to a Malawian radio show. RESULTS: As emergent themes indicate that the perceived outcomes of consumption affect different levels within a social system, results are stratified within a socioecological framework to identify perceived individual, household and community level outcomes. DISCUSSION AND CONCLUSIONS: As the perceived effects of consumption are numerous and impact a wide swath of communities, alcohol consumption must be addressed through multiple levels. The utilisation of anonymous text responses as a data collection methodology may provide an innovative way to understand contributing factors, such as alcohol consumption, to HIV risk exposure. [Rooney M, Limaye RJ. A qualitative inquiry of Malawian radio listeners' attitudes and perceived outcomes of alcohol use using a mobile data collection platform. Drug Alcohol Rev 2015;34:477-82]. PMID- 25787695 TI - Blood as the carrier of ischemic tolerance in rat brain. AB - This study provides clear evidence that the factor inducing tolerance to ischemia is transmitted via the circulating blood. By using the remote ischemia and the cross-circulation model, the tolerance to ischemia was transmitted from donor to recipient. For this study, the following experimental groups were designed: I, sham control group; II, group of tolerant hindlimb tourniquet-treated rats; III, positive control group; IV, control for cross-circulation influence; preconditioned animals: V, tolerant animals subjected to middle cerebral artery occlusion (MCAO); VI, tolerant animals cross-circulated with SHC, followed by MCAO; VII, SHC animals cross-circulated with tolerant animals and subsequently subjected to MCAO; VIII, tolerant animals cross-circulated with ischemic rats, followed by MCAO; IX, SHC animals cross-circulated with ischemic animals and subjected to MCAO; postconditioned animals: X, ischemic animals treated with a remote limb tourniquet; XI, ischemic animals cross-circulated with SHC control rats; and XII, ischemic animals cross-circulated with tolerant rats. Results confirmed that remote ischemia induced reduction of infarct volume in the preconditioned (V, 60%) as well as in the postconditioned group (X, 52%). Significant diminution was also observed in group XII (56.6%). In the preconditioned group, decreased infarct volume was detected in groups VI and VII (about 65%) and in group IX (about 50%). The greatest infarct reduction (84%) was induced by the presence of ischemic blood in a tolerant rat before ischemia induction. In summary, the factor inducing tolerance to ischemia is generated by remote ischemia and by ischemia itself; from the site of origin to the rest of the body, it is transported by the systemic blood circulation and can be transferred from animal to animal. The effect of conditioning with two different ischemic events (brain and hindlimb ischemia) led to a cumulative, stronger tolerance response. PMID- 25787696 TI - Enhancing Phosphate Diester Cleavage by a Zinc Complex through Controlling Nucleophile Coordination. AB - Metal-ion complexes are the most effective artificial catalysts capable of cleaving phosphate diesters under mild aqueous conditions. A central strategy for making these complexes highly reactive has been to use ligand-based alcohols that are coordinated to the ion, providing an ionised nucleophile under neutral conditions but at the expense of deactivating it. We have created a highly reactive Zn complex that is 350-fold more reactive than an alcohol analogue by preventing the nucleophile binding to the metal ion. This strategy successfully delivers the benefits of efficient nucleophile delivery without strongly deactivating the metal ion Lewis acidity nor the oxyanion nucleophilicity. Varying the leaving group reveals that the transition state of the reaction is much further advanced than the reaction with hydroxide. PMID- 25787697 TI - Stimulated jitter analysis in the early diagnosis of infant botulism. PMID- 25787698 TI - Inflammatory cytokines and biomarkers of cartilage metabolism 8 years after anterior cruciate ligament reconstruction: results from operated and contralateral knees. AB - BACKGROUND: Patients who sustain an acute anterior cruciate ligament (ACL) rupture are at increased risk to develop posttraumatic arthritis (PTA) in the injured knee whether the ACL is reconstructed or treated nonoperatively. Inflammatory cytokines and cartilage degradation biomarkers are elevated at the time of acute injury and postoperatively. This suggests that one mechanism for PTA may be an inflammatory degradative process initiated on the acute injury and sustained for some length of time independent of whether adequate joint stability is restored. HYPOTHESIS: Inflammatory cytokines and biomarkers of cartilage degradation are elevated in the synovial fluid several years after reconstruction of the ACL, indicating an ongoing imbalance between extracellular matrix destruction and repair. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: In 11 patients who had undergone ACL reconstruction 8 years earlier, knee synovial fluid was aspirated from the operated knee and the contralateral nonoperated knee. The synovial fluid was analyzed for interleukin (IL)-1beta, IL 6, tumor necrosis factor (TNF)-alpha, sulfated glycosaminoglycans (sGAG), aggrecan neoepitope fragment (ARGS-aggrecan), and cartilage oligomeric matrix protein (COMP). At follow-up, the patients underwent bilateral weightbearing radiographs and bilateral MRIs of their knees. RESULTS: No significant differences between the operated and the contralateral knee were found for the synovial fluid concentrations of IL-1beta, IL-6, TNF-alpha, sGAG, ARGS-aggrecan, or COMP. There were significantly more radiographically visible osteoarthritic changes in the operated knees compared with the contralateral knees. MRIs revealed that all grafts and all contralateral ACLs were intact and, furthermore, that there was significantly more meniscal and cartilage damage in the index knees than the contralateral knees. CONCLUSION: Eight years after ACL reconstruction, there were no significant differences in inflammatory cytokines and biomarkers for cartilage degeneration between the nonoperated and the ACL reconstructed knee, even though there were more osteoarthritic changes and meniscal and cartilage damage in the operated knee, as seen on weightbearing radiographs and MRI. PMID- 25787699 TI - Relations of meaning in life and sense of coherence to distress in cancer patients: a meta-analysis. AB - OBJECTIVE: Cancer patients report high rates of distress. The related constructs of meaning in life (MiL) and sense of coherence (SOC) have long been recognized as important factors in the psychological adjustment to cancer; however, both constructs' associations with distress have not been quantitatively reviewed or compared in this population. Informed by Park's integrated meaning-making model and Antonovsky's salutogenic model, the goals of this meta-analysis were the following: (1) to compare the strength of MiL-distress and SOC-distress associations in cancer patients; and (2) to examine potential moderators of both associations (i.e., age, gender, ethnicity, religious affiliation, disease stage, and time since diagnosis). METHODS: A literature search was conducted using electronic databases. Overall, 62 records met inclusion criteria. The average MiL distress and SOC-distress associations were quantified as Pearson's r correlation coefficients and compared using a one-way ANOVA. RESULTS: Both MiL and SOC demonstrated significant, negative associations with distress (r = -0.41, 95% CI: -0.47 to -0.35, k = 44; and r = -0.59, 95% CI: -0.67 to -0.51, k = 18, respectively). Moreover, the MiL-distress association was significantly smaller than the SOC-distress association (Qb = 10.42, df = 1, p < 0.01). Neither association varied by the tested moderators. CONCLUSIONS: Findings provide support for the clinical relevance of MiL and SOC across demographic and medical subgroups of cancer patients. The strength of the SOC-distress association suggests that incorporating aspects of SOC (e.g., the perceived manageability of life circumstances) into meaning-centered interventions may improve their effectiveness for distressed cancer patients. PMID- 25787700 TI - Do recognizable lifetime eating disorder phenotypes naturally occur in a culturally asian population? A combined latent profile and taxometric approach. AB - BACKGROUND: We examined whether empirically derived eating disorder (ED) categories in Hong Kong Chinese patients (N = 454) would be consistent with recognizable lifetime ED phenotypes derived from latent structure models of European and American samples. METHOD: We performed latent profile analysis (LPA) using indicator variables from data collected during routine assessment, and then applied taxometric analysis to determine whether latent classes were qualitatively versus quantitatively distinct. RESULTS: Latent profile analysis identified four classes: (i) binge/purge (47%); (ii) non-fat-phobic low-weight (34%); (iii) fat-phobic low-weight (12%); and (iv) overweight disordered eating (6%). Taxometric analysis identified qualitative (categorical) distinctions between the binge/purge and non-fat-phobic low-weight classes, and also between the fat-phobic and non-fat-phobic low-weight classes. Distinctions between the fat-phobic low-weight and binge/purge classes were indeterminate. CONCLUSION: Empirically derived categories in Hong Kong showed recognizable correspondence with recognizable lifetime ED phenotypes. Although taxometric findings support two distinct classes of low weight EDs, LPA findings also support heterogeneity among non-fat-phobic individuals. PMID- 25787701 TI - Study of cardiovascular disease biomarkers among tobacco consumers, part 2: biomarkers of biological effect. AB - An age-stratified, cross-sectional study was conducted in the US among healthy adult male cigarette smokers, moist snuff consumers, and non-tobacco consumers to evaluate cardiovascular biomarkers of biological effect (BoBE). Physiological assessments included flow-mediated dilation, ankle-brachial index, carotid intima media thickness and expired carbon monoxide. Approximately one-half of the measured serum BoBE showed statistically significant differences; IL-12(p70), sICAM-1 and IL-8 were the BoBE that best differentiated among the three groups. A significant difference in ABI was observed between the cigarette smokers and non tobacco consumer groups. Significant group and age effect differences in select biomarkers were identified. PMID- 25787702 TI - Study of cardiovascular disease biomarkers among tobacco consumers. Part 3: evaluation and comparison with the US National Health and Nutrition Examination Survey. AB - Cardiovascular disease (CVD) biomarkers of biological effect (BoBE), including hematologic biomarkers, serum lipid-related biomarkers, other serum BoBE, and one physiological biomarker, were evaluated in adult cigarette smokers (SMK), smokeless tobacco consumers (STC), and non-consumers of tobacco (NTC). Data from adult males and females in the US National Health and Nutrition Examination Survey and a single site, cross-sectional study of healthy US males were analyzed and compared. Within normal clinical reference ranges, statistically significant differences were observed consistently for fibrinogen, C-reactive protein (CRP), hematocrit, mean cell volume, mean cell hemoglobin, hemoglobin, white blood cells, monocytes, lymphocytes, and neutrophils in comparisons between SMK and NTC; for CRP, white blood cells, monocytes, and lymphocytes in comparisons between SMK and STC; and for folate in comparisons with STC and NTC. Results provide evidence for differences in CVD BoBE associated with the use of different tobacco products, and provide evidence of a risk continuum among tobacco products and support for the concept of tobacco harm reduction. PMID- 25787703 TI - Study of cardiovascular disease biomarkers among tobacco consumers, part 1: biomarkers of exposure. AB - A study was conducted to evaluate biomarkers of biological effect and physiological assessments related to cardiovascular disease (CVD) among adult male cigarette smokers (SMK), moist snuff consumers (MSC) and non-consumers of tobacco (NTC). Additionally, biomarkers of tobacco and tobacco smoke exposure (BoE) were measured in spot urines and are reported here. Except for the BoE to nicotine and NNK, BoE were generally greater in SMK compared with MSC, and BoE were generally not different in comparisons of MSC and NTC. Results demonstrated that MSC had lower systemic exposures to many harmful and potentially harmful constituents than SMK, which is consistent with epidemiological data that indicate a differential in CVD risk between these groups. PMID- 25787705 TI - Determinants of improved survival after oesophagectomy for cancer. AB - BACKGROUND: Survival after oesophagectomy for cancer seems to be improving. This study aimed to identify the most important contributors to this change. METHODS: Patients who underwent oesophagectomy from 1999 to 2010 were extracted from the Netherlands Cancer Registry. Four time periods were compared: 1999-2001 (period 1), 2002-2004 (period 2), 2005-2007 (period 3) and 2008-2010 (period 4). Hospital type, tumour location, tumour type, tumour differentiation, neoadjuvant therapy, operation type, (y)pT category, involvement of surgical resection margins, number of removed lymph nodes and number of involved lymph nodes were investigated in relation to trends in survival using multivariable analysis. RESULTS: A total of 4382 patients were identified. Two-year overall survival rates improved from 49.3 per cent in period 1 to 58.4, 56.2 and 61.0 per cent in periods 2, 3 and 4 respectively (P < 0.001). Multivariable survival analysis revealed that the improvement in survival between periods 3 and 4 was related to the introduction of neoadjuvant therapy. The improvement in survival between periods 1 and 2 could not be explained completely by the factors studied. The number of examined lymph nodes increased, especially between periods 2 and 3, but this increase was not associated with the improvement in survival. CONCLUSION: The observed increase in long-term survival after surgery for oesophageal cancer between 1999 and 2010 in the Netherlands is difficult to explain fully, although the recent increase seems to be partly attributable to the introduction of neoadjuvant therapy. PMID- 25787704 TI - Bridging the gap between spatial and mnemonic views of the hippocampal formation. AB - While it has long been recognized that medial temporal lobe structures are important for memory formation, studies in rodents have also identified exquisite spatial representations in these regions in the form of place cells in the hippocampus and grid cells in the entorhinal cortex. Spatial representations entail neural activity that is observed when the rat is in a given physical location, and these representations are thought to form the basis of navigation via path integration. Recent studies in nonhuman primates have suggested that similar kinds of spatial representations can be identified, even in the absence of physical movement through an environment. Here, I will highlight some recent work that addresses similarities and differences between spatial responses as identified in rodents and primates. I will also discuss areas of opportunity for future research to further our understanding of the function of the hippocampal formation. PMID- 25787706 TI - Extensive Intracranial Arteriovenous Malformation in a Child with Aplasia Cutis Congenita. AB - We report on a child with multiple lesions of membranous aplasia cutis congenita of the scalp since birth who developed an extensive intracranial arteriovenous malformation several years later. Even in the absence of other clues to suggest intracranial anomalies, children with multiple scalp defects should be carefully surveyed and followed up in the long term. PMID- 25787709 TI - Frequency and characteristics of infectious diseases in internationally adopted children: a retrospective study in Nantes from 2010 to 2012. AB - BACKGROUND AND AIMS: Internationally adopted children are more susceptible to developing and carrying acute or chronic infectious diseases. Specialized consultations exist in the main French cities; however, specialized consultation with a pediatrician is not mandatory. The main objective of this study was to determine the frequency and characteristics of infections (bacterial, viral, and parasitic) among a group of international adoptees in Nantes over a 3-year period. METHODS: A retrospective chart review was conducted of internationally adopted children who went through the Medical Guidance for Adopted Children Consultation between 2010 and 2012. RESULTS: A total of 133 children were included in the study. Of these, 55% had an infectious disease; 8% were severe infections. We found a frequency of 38% [confidence interval (CI) 95% 30-46] for parasitic intestinal and 35% (CI 95% 27-43) for dermatologic infections. African children were more likely to have infections that required hospitalization [odds ratio (OR) = 12, p = 0.004, CI 95% 1.3-113.7] and more likely to carry extended spectrum beta-lactamase-producing bacteria. CONCLUSION: The frequency of infectious diseases, and sometimes severe diseases, found among our cohort of internationally adopted children highlights the need for systematic, specialized medical care. PMID- 25787707 TI - Dynamic gene expression in the song system of zebra finches during the song learning period. AB - The brain circuitry that controls song learning and production undergoes marked changes in morphology and connectivity during the song learning period in juvenile zebra finches, in parallel to the acquisition, practice and refinement of song. Yet, the genetic programs and timing of regulatory change that establish the neuronal connectivity and plasticity during this critical learning period remain largely undetermined. To address this question, we used in situ hybridization to compare the expression patterns of a set of 30 known robust molecular markers of HVC and/or area X, major telencephalic song nuclei, between adult and juvenile male zebra finches at different ages during development (20, 35, 50 days post-hatch, dph). We found that several of the genes examined undergo substantial changes in expression within HVC or its surrounds, and/or in other song nuclei. They fit into broad patterns of regulation, including those whose expression within HVC during this period increases (COL12A1, COL 21A1, MPZL1, PVALB, and CXCR7) or decreases (e.g., KCNT2, SAP30L), as well as some that show decreased expression in the surrounding tissue with little change within song nuclei (e.g. SV2B, TAC1). These results reveal a broad range of molecular changes that occur in the song system in concert with the song learning period. Some of the genes and pathways identified are potential modulators of the developmental changes associated with the emergence of the adult properties of the song control system, and/or the acquisition of learned vocalizations in songbirds. PMID- 25787708 TI - Molecular portrait of breast cancer in China reveals comprehensive transcriptomic likeness to Caucasian breast cancer and low prevalence of luminal A subtype. AB - The recent dramatic increase in breast cancer incidence across China with progressive urbanization and economic development has signaled the urgent need for molecular and clinical detailing of breast cancer in the Chinese population. Our analyses of a unique transethnic collection of breast cancer frozen specimens from Shanghai Fudan Cancer Center (Chinese Han) profiled simultaneously with an analogous Caucasian Italian series revealed consistent transcriptomic data lacking in batch effects. The prevalence of Luminal A subtype was significantly lower in Chinese series, impacting the overall prevalence of estrogen receptor (ER)-positive disease in a large cohort of Chinese/Caucasian patients. Unsupervised and supervised comparison of gene and microRNA (miRNA) profiles of Chinese and Caucasian samples revealed extensive similarity in the comprehensive taxonomy of transcriptional elements regulating breast cancer biology. Partition of gene expression data using gene lists relevant to breast cancer as "intrinsic" and "extracellular matrix" genes identified Chinese and Caucasian subgroups with equivalent global gene and miRNA profiles. These findings indicate that in the Chinese and Caucasian groups, breast neoplasia and the surrounding stromal characteristics undergo the same differentiation and molecular processes. Transcriptional similarity across transethnic cohorts may simplify translational medicine approaches and clinical management of breast cancer patients worldwide. PMID- 25787710 TI - Basal cell carcinomas on sun-protected vs. sun-exposed body sites: a comparison of phenotypic and environmental risk factors. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in White populations. There are indications that risk factors for BCC may differ according to the anatomic site of the tumour but this is not well understood. PURPOSE: To compare phenotypic and environmental risk factors for BCCs arising on sun-protected sites with that of those on sun-exposed sites. METHODS: We conducted a case-case study in which people who had been diagnosed with incident BCC were recruited between February 2012 and September 2013 in Brisbane, Australia. RESULTS: Fair skin (OR: 4.50; 95% CI: 1.22, 16.59), having more than 15 lesions frozen/burnt off compared to less than 5 (OR: 5.68; 95% CI: 1.78, 18.08) and severe acne (OR: 5.25; 95% CI: 1.34, 20.56) were associated with increased risk of BCC on sun-protected sites. The presence of more than 5 nevi on the body was associated with decreased risk (OR: 0.28; 95% CI: 0.11, 0.71). CONCLUSIONS: BCCs on sun-protected sites arise as a result of excessive sun exposure, most likely combined with phenotypic susceptibility. The strong negative association with nevi also suggests that there are constitutional factors that underlie the propensity for BCCs to arise on these body sites. PMID- 25787712 TI - A gestational diet high in fat-soluble vitamins alters expression of genes in brain pathways and reduces sucrose preference, but not food intake, in Wistar male rat offspring. AB - High intakes of multivitamins (HV) during pregnancy by Wistar rats increase food intake, body weight, and characteristics of the metabolic syndrome in male offspring. In this study, high-fat soluble vitamins were fed in combination during gestation to test the hypothesis that they partially account for the effects of the HV diet. Pregnant Wistar rats (14-16/group) were fed a recommended multivitamin diet (1-fold all vitamins) or high-fat soluble vitamin diet (HFS; 10 fold vitamins A, D, E, and K) during pregnancy. Offspring body weight, food intake, and preference as well as expression of selected genes in the hypothalamus and hippocampus were evaluated at birth, weaning, and 14 weeks postweaning. Body weight and food intake were not affected but sucrose preference decreased by 4% in those born to dams fed the HFS gestational diet. Gene expressions of the hypothalamic anorexogenic pro-opiomelanocortin (Pomc) and orexogenic neuropeptide Y (Npy) (~30% p = 0.008, ~40% p = 0.007) were increased in weaning and adult rats, respectively. Hippocampal dopaminergic genes (35%-50% p < 0.05) were upregulated at birth and 14 weeks postweaning. DNA hypermethylation (2% p = 0.006) was observed in the dopamine receptor 1 (Drd1) promoter region. We conclude that a gestational diet high in vitamins A, D, E, and K does not show the effects of the HV diet on body weight or food intake but may affect the development of higher hedonic regulatory pathways associated with food preference. PMID- 25787713 TI - Henrietta Bowden-Jones: extrovert, optimistic, driven. PMID- 25787711 TI - Principles of designing interpretable optogenetic behavior experiments. AB - Over the last decade, there has been much excitement about the use of optogenetic tools to test whether specific cells, regions, and projection pathways are necessary or sufficient for initiating, sustaining, or altering behavior. However, the use of such tools can result in side effects that can complicate experimental design or interpretation. The presence of optogenetic proteins in cells, the effects of heat and light, and the activity of specific ions conducted by optogenetic proteins can result in cellular side effects. At the network level, activation or silencing of defined neural populations can alter the physiology of local or distant circuits, sometimes in undesired ways. We discuss how, in order to design interpretable behavioral experiments using optogenetics, one can understand, and control for, these potential confounds. PMID- 25787714 TI - Perceptions of Duchenne and non-Duchenne smiles: A meta-analysis. AB - A meta-analysis was conducted to compare perceptions of Duchenne smiles, smiles that include activation of the cheek raiser muscle that creates crow's feet around the eyes, with perceptions of non-Duchenne smiles, smiles without cheek raiser activation. In addition to testing the overall effect, moderator analyses were conducted to test how methodological, stimulus-specific and perceiver specific differences between studies predicted the overall effect size. The meta analysis found that, overall, Duchenne smiles and people producing Duchenne smiles are rated more positively (i.e., authentic, genuine, real, attractive, trustworthy) than non-Duchenne smiles and people producing non-Duchenne smiles. The difference between Duchenne and non-Duchenne smiles was greater when the stimuli were videos rather than photographs, when smiles were elicited naturally rather than through posing paradigms and when Duchenne and non-Duchenne smiles were not matched for intensity of the lip corner puller in addition to other perceiver and methodological moderators. PMID- 25787715 TI - The centrosome: a prospective entrant in cancer therapy. AB - INTRODUCTION: The centrosome plays an essential role in the cell cycle. The centrosome and its associated proteins assist in nucleating and organizing microtubules. A structural or a functional aberration in the centrosome is known to cause abnormal cell proliferation leading to tumors. Therefore, the centrosome is considered as a promising anti-cancer target. AREAS COVERED: This review begins with a brief introduction to the centrosome and its role in the cell cycle. We elaborate on the centrosome-associated proteins that regulate microtubule dynamics. In addition, we discuss the centrosomal protein kinase targets such as cyclin-dependent, polo-like and aurora kinases. Inhibitors targeting these kinases are undergoing clinical trials for cancer chemotherapy. Further, we shed light on new approaches to target the centrosomal proteins for cancer therapy. EXPERT OPINION: Insights into the functioning of the centrosomal proteins will be extremely beneficial in validating the centrosome as a target in cancer therapy. New strategies either as a single entity or in combination with current chemotherapeutic agents should be researched or exploited to reveal the promises that the centrosome holds for future cancer therapy. PMID- 25787716 TI - The contribution of mammography screening to breast cancer incidence trends in the United States: an updated age-period-cohort model. AB - BACKGROUND: The impact of screening mammography on breast cancer incidence is difficult to disentangle from cohort- and age-related effects on incidence. METHODS: We developed an age-period-cohort model of ductal carcinoma in situ (DCIS) and invasive breast cancer incidence in U.S. females using cancer registry data. Five functions were included in the model to estimate stage-specific effects for age, premenopausal birth cohorts, postmenopausal birth cohorts, period (for all years of diagnosis), and a mammography period effect limited to women ages >= 40 years after 1982. Incidence with and without the mammography period effect was calculated. RESULTS: More recent birth cohorts have elevated underlying risk compared with earlier cohorts for both pre- and postmenopausal women. Comparing models with and without the mammography period effect showed that overall breast cancer incidence would have been 23.1% lower in the absence of mammography in 2010 (95% confidence intervals, 18.8-27.4), including 14.7% (9.5-19.3) lower for invasive breast cancer and 54.5% (47.4-59.6) lower for DCIS. Incidence of distant-staged breast cancer in 2010 would have been 29.0% (13.1 48.1) greater in the absence of mammography screening. CONCLUSIONS: Mammography contributes to markedly elevated rates of DCIS and early-stage invasive cancers, but also contributes to substantial reductions in the incidence of metastatic breast cancer. IMPACT: Mammography is an important tool for reducing the burden of breast cancer, but future work is needed to identify risk factors accounting for increasing underlying incidence and to distinguish between indolent and potentially lethal early-stage breast cancers that are detected via mammography. PMID- 25787717 TI - Study of inelastic mean free path of metal nanostructures using energy filtered transmission electron microscopy imaging. AB - We report a simple method for measuring the inelastic mean free path of nanostructures of known geometry using energy filtered transmission electron microscopy imaging. The mean free path of inelastic electrons was measured by using systems having known symmetry, such as cylindrical or cubic, combined with Poisson statistics without employing the knowledge of microscope parameters, namely the convergence angle and the collection angle. Having inherent symmetry of such systems, their absolute thickness can be measured from their two dimensional projection images. We have calculated mean free path of inelastic scattering of electrons in gold, silver and nickel doing case study research by employing gold nanorod, silver nanocube and nickel nanorod lying on a carbon coated TEM grid at two different electron energies (viz. 200 and 300 keV) following this alternative approach. Results obtained using such alternative approach were verified using microscope parameters. PMID- 25787718 TI - Preventing overdiagnosis: the myth, the music, and the medical meeting. PMID- 25787719 TI - First-principles investigations of chirality in trimetallic alloy clusters: AlMnAun (n = 1-7). AB - Chirality, also called handedness, plays a crucial role in function ranging from biological self-assembly schemes, organic polymer functionalities, to optical material designs. In this Article, we demonstrated a first-principles investigation of chirality in magnetic AlMnAun(0/+1/-1) (n = 1-7) clusters. Optimized structures of the AlMnAun clusters exhibit configurational combinations between AlAun+1 and MnAun+1 clusters, indicating a subtle but equal competition between Au-Al and Au-Mn interactions in the alloy clusters. High magnetic moments are equal to or greater than 4MUB in AlMnAun clusters due to the presence of the Mn dopant. Chirality turns up with the forms of right-handed and left-handed in stable AlMnAu5, AlMnAu6, and AlMnAu7 clusters. As a result, reflection symmetries are found in vibrational Raman and circular dichroism spectra of these chiral pairs. The present study shows that chiral magnetic clusters can be composed by doping two heteroatoms with one intrinsic magnetic dopant into small gold clusters. PMID- 25787720 TI - Home-based care, technology, and the maintenance of selves. AB - In this paper, I will argue that there is a deep connection between home-based care, technology, and the self. Providing the means for persons (especially older persons) to receive care at home is not merely a kindness that respects their preference to be at home: it is an important means of extending their selfhood and respecting the unique selves that they are. Home-based technologies like telemedicine and robotic care may certainly be useful tools in providing care for persons at home, but they also have important implications for sustaining selfhood in ways that are of value to individuals and those who care for them. I will argue, by appealing to Hilde Lindemann's notion of "holding" persons' identities in place, that technological interventions are not only useful tools for improving and sustaining health and good care at home, but that they may also help to extend our personal identities and relational capacities in ways that are practically and ethically good. Because of these important goods, I will claim that there is a prima facie moral duty to do this "holding" work and that it is best done by family members and loved ones who are well suited to the job because of their history and relationship with the individual that needs to be "held" in place. PMID- 25787722 TI - Residents' corner February 2015. Clues in DeRmoscopy: Dermoscopy of amelanotic cutaneous melanoma metastases. PMID- 25787721 TI - Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin. AB - Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30-50% of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin angiotensin-aldosterone system, the sympathetic nervous system and the arginine vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context. PMID- 25787723 TI - A high concentration of triiodothyronine attenuates the stimulatory effect on hemin-induced erythroid differentiation of human erythroleukemia K562 cells. AB - Although thyroid hormone is a known stimulator of erythropoietic differentiation, severe anemia is sometimes observed in patients with hyperthyroidism and this mechanism is not fully understood. The aim of this study was to investigate the effect of triiodothyronine (T3) on hemin-induced erythropoiesis. Human erythroleukemia K562 cells were used as an erythroid differentiation model. Cell differentiation was induced by hemin and the effect of pre-incubation with T3 (0.1 to 100 nM) was analyzed by measuring the benzidine-positive rate, hemoglobin content, CD71 expression (transferrin receptor), and mRNA expression for transcription factors related to erythropoiesis and thyroid hormone receptors (TRs). Hemin, a promoter of erythroid differentiation, increased the levels of mRNAs for TRalpha, TRbeta, and retinoid X receptor alpha (RXRalpha), as well as those for nuclear factor-erythroid 2 (NFE2), GATA-binding protein 1 (GATA1) and GATA-binding protein 2 (GATA2). Lower concentrations of T3 had a stimulatory effect on hemin-induced hemoglobin production (1 and 10 nM), CD71 expression (0.1 nM), and alpha-globin mRNA expression (1 nM), while a higher concentration of T3 (100 nM) abrogated the stimulatory effect on these parameters. T3 at 100 nM did not affect cell viability and proliferation, suggesting that the abrogation of erythropoiesis enhancement was not due to toxicity. T3 at 100 nM also significantly inhibited expression of GATA2 and RXRalpha mRNA, compared to 1 nM T3. We conclude that a high concentration of T3 attenuates the classical stimulatory effect on erythropoiesis exerted by a low concentration of T3 in hemin-induced K562 cells. PMID- 25787724 TI - [Therapy of dementia with antipsychotics and antidepressives]. AB - In dementia depressive symptoms, anxiety, hallucinations and delusions often occur and are accompanied by unspecific behavioral changes. A targeted pharmacotherapy is complicated by the underlying cognitive impairment and physical comorbidities. The current review focusses on recent evidence on the use of antidepressives and antipsychotics for psychotic disturbances, agitation and depression in dementia and analyzes currently published randomized controlled clinical trials and meta-analyses. The evidence on the use of antipsychotics for different indications favors risperidone, with lower evidence levels for quetiapine and aripiprazole, whereas haloperidol should be avoided. Increased mortality and the risk of cerebrovascular events due to antipsychotics are of major concern. With respect to antidepressives, the benefit of antidepressive pharmacotherapy in dementia is critically discussed because of limited efficacy and increased side effects; however, selective serotonin reuptake inhibitors (SSRI), such as citalopram and sertraline have demonstrated efficacy on neuropsychiatric behavioral symptoms in general. These conclusions on the risk benefit ratio of antidepressives and antipsychotics in dementia are in accordance with the recommendations of the German Society of Neurology and German Association for Psychiatry, Psychotherapy and Psychosomatics (DGN/DGPPN) S3 guidelines on the treatment of dementia. PMID- 25787725 TI - [Sarcopenia and frailty in neurology]. AB - Sarcopenia and frailty are common geriatric syndromes and are associated with adverse health outcome and impaired health-related quality of life. Co occurrences of these two syndromes with age-related neurological diseases are potentially high but not well investigated. Moreover, it is not well understood how these syndromes interact with neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke. This article introduces the currently most accepted concepts of sarcopenia and frailty, discusses the potential relevance of the syndromes for geriatric patients and presents examples of studies that investigated potential interactions between these geriatric and neurological syndromes and conditions. First results indicate that (i) the co occurrence of these geriatric syndromes and age-related neurological diseases is high, (ii) sarcopenia and frailty can influence the clinical state of neurological diseases to a relevant extent and (iii) at least some common causes and pathophysiological processes confer the geriatric and neurological conditions. In conclusion, profound knowledge about the interaction of sarcopenia, frailty and age-associated neurological conditions is currently not available. Such knowledge would have an enormous potential for improved therapy of these neurological conditions. PMID- 25787726 TI - [Is the use of placebo as control group in MS drug trials still appropriate?]. PMID- 25787727 TI - Predictors of cure among HIV co-infected multidrug-resistant TB patients at Sizwe Tropical Disease Hospital Johannesburg, South Africa. AB - BACKGROUND: The global incidence of multidrug-resistant tuberculosis (MDR-TB) is rising, especially among HIV infected patients, despite intervention programs. Limited data are available on outcomes of MDR-TB treatment, specifically in a cohort of HIV co-infected patients in sub-Saharan Africa. The objective of this study was to determine the predictors of cure among MDR-TB HIV co-infected patients. METHODS: A retrospective review of 1200 medical records of HIV co infected MDR-TB patients was performed at Sizwe Tropical Disease Hospital, Johannesburg covering the period 2007 to 2010. Logistic regression analysis was done to identify predictors of cure. RESULTS: Of 1137 patients included in the analysis, 29.8% (339/1137) were cured, 16.5% (188/1137) completed treatment, 22.3% (254/1137) defaulted treatment, 2.9% (33/1137) failed treatment and 22.7% (258/1137) died while on treatment. The remaining 5.7% (65/1137) were transferred out or still-on-treatment. There was a significant interaction between sex and timing of antiretroviral treatment (ART) initiation (p=0.008). Factors predicting cure were male patients on ART prior to commencing MDR-TB treatment (OR 1.87, [1.11-3.13]), CD4(+) cell counts between 201-349 (OR 2.06, [1.10-3.84]) and >= 350 cells/mm3 (OR 1.98, [0.98-3.97]). Negative predictors of cure included the presence of cavitary lesions on chest x-rays (OR 0.55, [0.38-0.78]) and modified individualised regimen at baseline (OR 0.62, [0.42-0.92]). CONCLUSIONS: Cure was higher in males on ART prior to initiating MDR-TB treatment compared with males on ART after initiating MDR-TB treatment. The inverse was the case among females. Therefore, future research should explore the biological and behavioural mechanisms that may possibly be responsible for this observed trend. This will help improve MDR-TB treatment outcomes in HIV co-infected patients on ART. PMID- 25787728 TI - Controlled release of an extract of Calendula officinalis flowers from a system based on the incorporation of gelatin-collagen microparticles into collagen I scaffolds: design and in vitro performance. AB - Aiming to develop biological skin dresses with improved performance in the treatment of skin wounds, acellular collagen I scaffolds were modified with polymeric microparticles and the subsequent loading of a hydroglycolic extract of Calendula officinalis flowers. Microparticles made of gelatin-collagen were produced by a water-in-oil emulsion/cross-linking method. Thereafter, these microparticles were mixed with collagen suspensions at three increasing concentrations and the resulting mixtures lyophilized to make microparticle loaded porous collagen scaffolds. Resistance to enzymatic degradation, ability to associate with the C. officinalis extract, and the extract release profile of the three gelatin-collagen microparticle-scaffold prototypes were assessed in vitro and compared to collagen scaffolds without microparticles used as control. Data indicated that the incorporation of gelatin-collagen microparticles increased the resistance of the scaffolds to in vitro enzymatic degradation, as well as their association with the C. officinalis flower extract. In addition, a sharp decrease in cytotoxicity, as well as more prolonged release of the extract, was attained. Overall results support the potential of these systems to develop innovative dermal substitutes with improved features. Furthermore, the gelatin-collagen mixture represents a low-cost and scalable alternative with high clinical transferability, especially appealing in developing countries. PMID- 25787729 TI - Multifunctional nanoparticles for use in theranostic applications. AB - Theranostics is a promising field that combines therapeutics and diagnostics into single multifunctional formulations. This field is driven by advancements in nanoparticle systems capable of providing the necessary functionalities. By utilizing these powerful nanomedicines, the concept of personalized medicine can be realized by tailoring treatment strategies to the individual. This review gives a brief overview of the components of a theranostic system and the challenges that designing truly multifunctional nanoparticles present. Considerations when choosing a class of nanoparticle include the size, shape, charge, and surface chemistry, while classes of nanoparticles discussed are polymers, liposomes, dendrimers, and polymeric micelles. Targeting to disease states can be achieved either through passive or active targeting which uses specific ligands to target receptors that are overexpressed in tumors and common targeting elements are presented. To image the interactions with disease states, contrast agents are included in the nanoparticle formulation. Imaging options include optical imaging techniques, computed tomography, nuclear based, and magnetic resonance imaging. The interplay between all of these components needs to be carefully considered when designing a theranostic system. PMID- 25787730 TI - Urate crystal degradation for treatment of gout: a nanoparticulate combination therapy approach. AB - The objective of the present work was to develop polymeric nanoparticles of uricase and aceclofenac (NSAID) and to incorporate them into gel, for delivering drugs to synovial joints, for effective treatment of Gout. Nanoparticles containing uricase and aceclofenac were prepared by double emulsion solvent evaporation method and emulsion solvent evaporation, using PLGA (50:50) as carrier, respectively. Process parameters were optimized using Taguchi L4 orthogonal array and L9 array, respectively. The formulations were characterized for particle size, entrapment efficiency, surface charge, in vitro drug release, ex vivo drug permeation, and urate crystal degradation activity. The particle size and entrapment efficiency for optimized batch was found to be 228.8 nm and 81.26% for uricase nanoparticles and 288.5 nm and 85.36% for aceclofenac nanoparticles, respectively. The developed nanoparticles formulations displayed zero order and Higuchi release kinetics with non-Fickian diffusion, respectively. The in vivo studies were performed in rabbit model. Topical application of gel containing polymeric uricase nanoparticles alone and a combination of both, uricase nanoparticles and aceclofenac nanoparticles in rabbit model test groups, provided complete removal of urate crystals and inflammation within 40 and 25 days of treatment, respectively. The combination treatment therapy resulted in effective treatment of gout due to degradation of crystals and anti-inflammatory response. PMID- 25787731 TI - Influence of cholesterol on liposome stability and on in vitro drug release. AB - Cholesterol plays a strategic role in liposome composition; however, the quantity used to achieve an appropriate formulation has not been yet clarified. Therefore, by screening arrangement of lipids and cholesterol ratio, the main aim of this study is to investigate the most suitable amount of cholesterol in lipids in order to prepare stable and controlled drug release vehicles. For the preparation of liposomes, DMPC, DPPC and DSPC phospholipids were used and combined with different molar ratios of cholesterol (e.g. 100, 80-20, 70-30, 60-40 and 50-50%). Stability studies were conducted by storing the formulations at 37 and 50 degrees C for 30 days and by analysing them by AFM, DLS and FT-IR. By detecting the two most stable formulations from the stability results, drug encapsulation and in vitro release studies in PBS were performed by encapsulating atenolol and quinine. The release results were validated using a simulation model to ensure the reliability and suitable interpretation of the data. The generated model showed a good correlation between the prediction and the in vitro obtained results. By using 70:30% ratio (known in literature as 2:1), it is possible to reach the most stable formulation to guarantee a controlled and reproducible release for drugs with different physicochemical characteristics and pharmaceutical applications. PMID- 25787732 TI - Preparation and characterization of pH-sensitive methyl methacrylate-g starch/hydroxypropylated starch hydrogels: in vitro and in vivo study on release of esomeprazole magnesium. AB - In the present study, novel hydrogels were prepared through graft copolymerization of methyl methacrylate onto starch and hydroxypropylated starch for intestinal drug delivery. The successful grafting has been confirmed by FTIR, NMR spectroscopy, and elemental analysis. Morphological examination of copolymeric hydrogels by scanning electron microscopy (SEM) confirms the macroporous nature of the copolymers. The high decomposition temperature was observed in thermograms indicating the thermal stability of the hydrogels. To attain a hydrogel with maximum percent graft yield, the impact of reaction variables like concentration of ceric ammonium nitrate as initiator and methyl methacrylate as monomer were consistently optimized. X-ray powder diffraction and differential scanning calorimetric analysis supported the successful entrapment of the drug moiety (esomeprazole magnesium; proton pump inhibitor) within the hydrogel network. Drug encapsulation efficiency of optimized hydrogels was found to be >78%. Furthermore, swelling capacity of copolymeric hydrogels exhibited a pH-responsive behavior which makes the synthesized hydrogels potential candidates for controlled delivery of medicinal agents. In vitro drug release was found to be sustained up to 14 h with 80-90% drug release in pH 6.8 solution; however, the cumulative release was 40-45% in pH 1.2. The gastrointestinal transit behavior of optimized hydrogel was determined by gamma scintigraphy, using (99m)Tc as marker. The amount of radioactive tracer released from the labeled hydrogel was minimal when the hydrogel was in the stomach, whereas it increased as hydrogel reached in intestine. Well-correlated results of in vitro and in vivo analysis proved their controlled release behavior with preferential delivery into alkaline pH environment. PMID- 25787733 TI - Paediatricians' opinions of microneedle-mediated monitoring: a key stage in the translation of microneedle technology from laboratory into clinical practice. AB - Microneedle (MN) arrays could offer an alternative method to traditional drug delivery and blood sampling methods. However, acceptance among key end-users is critical for new technologies to succeed. MNs have been advocated for use in children and so, paediatricians are key potential end-users. However, the opinions of paediatricians on MN use have been previously unexplored. The aim of this study was to investigate the views of UK paediatricians on the use of MN technology within neonatal and paediatric care. An online survey was developed and distributed among UK paediatricians to gain their opinions of MN technology and its use in the neonatal and paediatric care settings, particularly for MN mediated monitoring. A total of 145 responses were obtained, with a completion response rate of 13.7 %. Respondents believed an alternative monitoring technique to blood sampling in children was required. Furthermore, 83 % of paediatricians believed there was a particular need in premature neonates. Overall, this potential end-user group approved of the MN technology and a MN-mediated monitoring approach. Minimal pain and the perceived ease of use were important elements in gaining favour. Concerns included the need for confirmation of correct application and the potential for skin irritation. The findings of this study provide an initial indication of MN acceptability among a key potential end user group. Furthermore, the concerns identified present a challenge to those working within the MN field to provide solutions to further improve this technology. The work strengthens the rationale behind MN technology and facilitates the translation of MN technology from lab bench into the clinical setting. PMID- 25787734 TI - Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists. AB - Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen. PMID- 25787735 TI - Nanofiber-mediated release of retinoic acid and brain-derived neurotrophic factor for enhanced neuronal differentiation of neural progenitor cells. AB - The treatment of an injured central nervous system using stem-cell-based regenerative medicine still faces considerable hurdles that need to be overcome. Chief among which is the lack of efficient strategies to generate functional neurons from stem cells. The sustained delivery of biochemical cues and synergistic topographical signaling from electrospun nanofibrous scaffolds may be a potential strategy to enhance neuronal differentiation of stem cells for therapeutic purposes. In this study, retinoic acid (RA) and brain-derived neurotrophic factor (BDNF) were encapsulated into a copolymer of epsilon caprolactone and ethyl ethylene phosphate to form a multifunctional, electrospun nanofibrous scaffold. Sustained release of RA and BDNF was achieved for at least 7 and 14 days, respectively. Despite lower cumulative release of drugs as compared to bolus delivery to plain nanofibers (at least 2* and 50* lower for RA and BDNF, respectively), nanofiber-mediated delivery of RA and/or BDNF resulted in similar capacity for neuronal differentiation of mouse neural progenitor cells (NPCs). In addition, nanofiber topography significantly increased neuronal differentiation (with BDNF, 47.4% Map2(+) cells on 2D vs. 53.4 to 56.5% on nanofibers, p < 0.05) and reduced glial cell differentiation. BDNF was a more potent inducer of neuronal differentiation than RA. RA supplementation alone resulted in minimal effect on NPC differentiation, and dual supplementation of RA and BDNF did not further enhance the neuronal differentiation of NPCs. Collectively, the results suggest that synergistic effects of nanofiber topography and sustained delivery of RA and/or BDNF may contribute towards the design of a multifunctional artificial stem cell niche for NPC neuronal differentiation. PMID- 25787737 TI - Evans blue nanocarriers visually demarcate margins of invasive gliomas. AB - Aggressive surgical resection is the primary therapy for glioma. However, aggressive resection may compromise functional healthy brain tissue. Currently, there are no objective cues for surgeons to distinguish healthy tissue from tumor and determine tumor borders; surgeons skillfully rely on subjective means such as tactile feedback. This often results in incomplete resection and recurrence. The objective of the present study was to design, develop, and evaluate, in vitro and in vivo, a nanoencapsulated visible dye for intraoperative, visual delineation of tumor margins in an invasive tumor model. Liposomal nanocarriers containing Evans blue dye (nano-EB) were developed, characterized, and tested for safety in vitro and in vivo. 3RT1RT2A glioma cells were implanted into brains of Fischer 344 rats. Nano-EB or EB solution was injected via tail vein into tumor-bearing animals. To assess tumor staining, tissue samples were analyzed visibly and using fluorescence microscopy. Area, perimeter ratios, and Manders overlap coefficients were calculated to quantify extent of staining. Nano-EB clearly marked tumor margins in the invasive tumor model. Area ratio of nano-EB staining to tumor was 0.89 +/- 0.05, perimeter ratio was 0.94 +/- 0.04, Manders R was 0.51 +/- 0.08, and M1 was 0.97 +/- 0.06. Microscopic tumor border inspection under high magnification verified that nano-EB did not stain healthy tissue. Nano-EB clearly aids in distinguishing tumor tissue from healthy tissue in an invasive tumor model, while injection of unencapsulated EB results in false identification of healthy tissue as tumor due to diffusion of dye from the tumor into healthy tissue. PMID- 25787736 TI - Clinical translation of controlled protein delivery systems for tissue engineering. AB - Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed. PMID- 25787738 TI - Engineered VEGF-releasing PEG-MAL hydrogel for pancreatic islet vascularization. AB - Biofunctionalized polyethylene glycol maleimide (PEG-MAL) hydrogels were engineered as a platform to deliver pancreatic islets to the small bowel mesentery and promote graft vascularization. VEGF, a potent stimulator of angiogenesis, was incorporated into the hydrogel to be released in an on-demand manner through enzymatic degradation. PEG-MAL hydrogel enabled extended in vivo release of VEGF. Isolated rat islets encapsulated in PEG-MAL hydrogels remained viable in culture and secreted insulin. Islets encapsulated in PEG-MAL matrix and transplanted to the small bowel mesentery of healthy rats grafted to the host tissue and revascularized by 4 weeks. Addition of VEGF release to the PEG-MAL matrix greatly augmented the vascularization response. These results establish PEG-MAL engineered matrices as a vascular-inductive cell delivery vehicle and warrant their further investigation as islet transplantation vehicles in diabetic animal models. PMID- 25787739 TI - Electrospinning strategies of drug-incorporated nanofibrous mats for wound recovery. AB - Electrospun nanofibrous mats have recently been employed as drug reservoirs for their unique features, such as high surface-to-volume ratios and easy fabrication process. We describe herein various methods of fabricating drug- and gene encapsulated nanofibrous meshes, which can be prepared by electrospinning. The electrospinning process of nanofibrous mats is affected by many parameters, including viscosity and ejection speeds of the polymeric solutions and the electrical potential applied to the system. Both single- and dual-nozzle systems are widely employed in the preparation of electrospun nanofibers encapsulating drugs and genes, which are usually incorporated into the electrospun mats either by physical mixing with polymeric solutions before electrospinning or by physical incorporation after electrospinning. Various strategies have been tailored to maintain the bioactivity of proteins for tissue regeneration before and after electrospinning. Nucleic acids, such as DNA and siRNA, are also incorporated into nanofibrous meshes to enhance tissue regeneration by expressing transgenes or silencing domestic genes in specific tissues. Drug- or gene-incorporated nanofibrous meshes can greatly increase tissue regeneration rates and reduce scar formation in normal and diabetic wounds. Hybrid nanofibers, with multiple cell layers or hydrogels, have also been used to improve wound healing efficiency by increasing cell infiltration. PMID- 25787740 TI - The incorporation of bFGF mediated by heparin into PCL/gelatin composite fiber meshes for guided bone regeneration. AB - The concept of guided bone regeneration facilitated by barrier membranes has been widely considered to achieve enhanced bone healing in maxillofacial surgery. However, the currently available membranes are limited in their active regulation of cellular activities. In this study, we fabricated polycaprolactone/gelatin composite electrospun nanofibers incorporated with basic fibroblast growth factor (bFGF) to direct bone regeneration. The fibrous morphology was maintained after the crosslinking and subsequent conjugation of heparin. Release of bFGF from electrospun nanofibers without heparin resulted in a spontaneous burst, while the heparin-mediated release of bFGF decreased the burst release in 24 h. The bFGF released from the nanofibers enhanced the proliferation and migration of human mesenchymal stem cells as well as the tubule formation of human umbilical cord blood cells. The subcutaneous implantation of fibers incorporated with bFGF mobilized a large number of cells positive for CD31 and smooth muscle alpha actin within 2 weeks. The effect of the nanofibers incorporated with bFGF on bone regeneration was evaluated on a calvarial critical size defect model. As compared to the mice that received fibers without bFGF, which presented minimal new bone formation (5.36 +/- 3.4 % of the defect), those that received implants of heparinized nanofibers incorporated with 50 or 100 ng/mL bFGF significantly enhanced new bone formation (10.82 +/- 2.2 and 17.55 +/- 6.08 %). Taken together, our results suggest that the electrospun nanofibers incorporating bFGF have the potential to be used as an advanced membrane that actively enhances bone regeneration. PMID- 25787741 TI - Gene delivery of osteoinductive signals to a human fetal osteoblast cell line induces cell death in a dose-dependent manner. AB - Gene delivery provides a powerful tool for regulating tissue regeneration by activating or inhibiting specific genes associated with targeted signaling pathways. Up-regulating bone morphogenetic protein-2 (BMP-2) or silencing GNAS and Noggin gene expression in stem cells has been shown to enhance osteogenic differentiation and bone tissue formation. However, few studies have examined how such gene delivery would influence other differentiated cell types residing in the bone. In this study, we examined the effects of DNA delivery of BMP-2 and siRNA delivery of GNAS or Noggin on a widely used human fetal osteoblast cell line (hFOB1.19) using biomaterials-mediated gene delivery. Our results showed that both GNAS and Noggin siRNA delivery increased cell death in hFOB1.19 in a dose-dependent manner. In particular, groups treated with the highest doses of BMP-2, siGNAS or siNoggin showed a more than 50% decline in cell proliferation and a 90% decline in cell viability compared to untransfected and sham DNA/siRNA transfected controls. TUNEL staining showed that BMP-2, siGNAS or siNoggin induced cell apoptosis in hFOBs. In contrast, cells transfected using sham DNA or siRNA showed no noticeable cell death or apoptosis. These results elucidate the nuanced responses of progenitor and immortalized cell populations to the delivery of exogenous osteoinductive genes. In particular, they highlight the differences between immortalized and primary cell lines and underscore the importance of targeted gene delivery mechanisms in the regeneration of injured bone tissue. PMID- 25787744 TI - Analysis of features associated with equivocal diagnosis and diagnostic discordance of Spitz naevi over an 18-year period. AB - BACKGROUND: Distinguishing Spitz naevi from malignant melanoma can pose diagnostic dilemmas and atypical subtypes present particular challenges to both clinicians and pathologists. OBJECTIVES: We aimed to review our institutional experience of Spitz naevi, to characterise demographics and analyse the clinical and histological features associated with difficult/equivocal diagnosis of such lesions. Additionally we evaluated discordant cases following expert opinion at a second institution. MATERIALS & METHODS: Data was retrospectively analysed on all cases of Spitz naevi treated over an 18-year period (1991-2009). Equivocal cases, (where a diagnosis of classical Spitz naevi could not be confidently made) were identified. The original/provisional diagnosis and second histopathological opinions were compared. RESULTS: 148 cases were identified 112 lesions were classical Spitz naevi. 36 lesions (24.3%) posed diagnostic difficulty (equivocal cases). These equivocal cases tended to occur in the lower limbs, have brown pigmentation, be smaller in size (<6mm) and occur in older (>24 years) patients. Clinical sub-types and gender were not associated with equivocal cases. Of the 36 equivocal cases, the second opinion in 23 cases (63.9%) concurred with the original diagnosis. Of the remaining 13 cases (discordant cases), 10 cases that were originally deemed malignant were reported as benign after the second opinion. Two benign lesions were reclassified as malignant. CONCLUSION: A firm histological diagnosis of Spitz naevi cannot be made with certainty in nearly a quarter of cases. Thus, additional external analysis for a second opinion should be sought for these equivocal cases. PMID- 25787743 TI - Fucoidan in a 3D scaffold interacts with vascular endothelial growth factor and promotes neovascularization in mice. AB - The aim of this study was to functionalize 3D porous cross-linked scaffolds with natural non-animal sulfated polysaccharide fucoidans in order to allow a delivery of vascular endothelial growth factor (VEGF) and potentiate its angiogenic activity. Microporous (20 MUm) and macroporous (200 MUm) scaffolds were functionalized with low, medium, or high molecular weight fucoidans (named LMWF, MMWF, and HMWF, respectively). In vitro, addition of fucoidans promoted endothelial progenitor cells proliferation in both micro- and macroporous scaffolds. While control scaffolds without fucoidans loaded with VEGF165 (100 ng) showed a fast burst release in PBS during the first 24 h, MMWF significantly reduced the VEGF165 release (p < 0.001). Surface plasmon resonance experiments confirmed a direct interaction between MMWF and VEGF165, characterized by an affinity K D (K d/K a) of 1 * 10(-9) M. In a subcutaneous angiogenesis model in mice, fucoidan functionalized scaffolds showed a more intense vascularization response than control groups. Expression of isolectin-B4 and alpha-smooth muscle actin, as well as confinement of erythrocytes, demonstrated the neoformed blood vessels functionality. There was a significant difference in neovessel area and neovessel density between MMWF scaffolds or VEGF165 scaffolds and MMWF+VEGF165 scaffolds (p < 0.001 for all cases). Here, we demonstrate that fucoidan sequesters VEGF165 and delivers biological cues promoting angiogenesis. In conclusion, this study shows that hydrogels functionalized with fucoidan can direct the formation of mature vasculature through a local release of VEGF165 and can be a useful tool in ischemic tissues to guide therapeutic angiogenesis. PMID- 25787745 TI - 'Tri-leaflet mitral valve morphology': a new phenotypic expression in hypertrophic cardiomyopathy? PMID- 25787742 TI - Integration of drug, protein, and gene delivery systems with regenerative medicine. AB - Regenerative medicine has the potential to drastically change the field of health care from reactive to preventative and restorative. Exciting advances in stem cell biology and cellular reprogramming have fueled the progress of this field. Biochemical cues in the form of small molecule drugs, growth factors, zinc finger protein transcription factors and nucleases, transcription activator-like effector nucleases, monoclonal antibodies, plasmid DNA, aptamers, or RNA interference agents can play an important role to influence stem cell differentiation and the outcome of tissue regeneration. Many of these biochemical factors are fragile and must act intracellularly at the molecular level. They require an effective delivery system, which can take the form of a scaffold (e.g., hydrogels and electrospun fibers), carrier (viral and nonviral), nano- and microparticle, or genetically modified cell. In this review, we will discuss the history and current technologies of drug, protein, and gene delivery in the context of regenerative medicine. Next, we will present case examples of how delivery technologies are being applied to promote angiogenesis in nonhealing wounds or prevent angiogenesis in age related macular degeneration. Finally, we will conclude with a brief discussion of the regulatory pathway from bench to bedside for the clinical translation of these novel therapeutics. PMID- 25787746 TI - Mechanisms of neuroimmune gene induction in alcoholism. AB - RATIONALE: Alcoholism is a primary, chronic relapsing disease of brain reward, motivation, memory, and related circuitry. It is characterized by an individual's continued drinking despite negative consequences related to alcohol use, which is exemplified by alcohol use leading to clinically significant impairment or distress. Chronic alcohol consumption increases the expression of innate immune signaling molecules (ISMs) in the brain that alter cognitive processes and promote alcohol drinking. OBJECTIVES: Unraveling the mechanisms of alcohol induced neuroimmune gene induction is complicated by positive loops of multiple cytokines and other signaling molecules that converge on nuclear factor kappa light-chain-enhancer of activated B cells and activator protein-1 leading to induction of additional neuroimmune signaling molecules that amplify and expand the expression of ISMs. RESULTS: Studies from our laboratory employing reverse transcription polymerase chain reaction (RT-PCR) to assess mRNA, immunohistochemistry and Western blot analysis to assess protein expression, and others suggest that ethanol increases brain neuroimmune gene and protein expression through two distinct mechanisms involving (1) systemic induction of innate immune molecules that are transported from blood to the brain and (2) the direct release of high-mobility group box 1 (HMGB1) from neurons in the brain. Released HMGB1 signals through multiple receptors, particularly Toll-like receptor (TLR) 4, that potentiate cytokine receptor responses leading to a hyperexcitable state that disrupts neuronal networks and increases excitotoxic neuronal death. Innate immune gene activation in brain is persistent, consistent with the chronic relapsing disease that is alcoholism. Expression of HMGB1, TLRs, and other ISMs is increased several-fold in the human orbital frontal cortex, and expression of these molecules is highly correlated with each other as well as lifetime alcohol consumption and age of drinking onset. CONCLUSIONS: The persistent and cumulative nature of alcohol on HMGB1 and TLR gene induction support their involvement in alcohol-induced long-term changes in brain function and neurodegeneration. PMID- 25787747 TI - Effect of ceftriaxone and topiramate treatments on naltrexone-precipitated morphine withdrawal and glutamate receptor desensitization in the rat locus coeruleus. AB - RATIONALE: Morphine withdrawal is associated with a hyperactivity of locus coeruleus (LC) neurons by an elevated glutamate neurotransmission in this nucleus. We postulate that reductions in the amount of glutamate in the LC by enhancing its reuptake or inhibiting its release could attenuate the behavioral and cellular consequences of morphine withdrawal. OBJECTIVES: We investigated the effect of chronic treatment with ceftriaxone (CFT), an excitatory amino acid transporter (EAAT2) enhancer, and acute administration of topiramate (TPM), a glutamate release inhibitor, on morphine withdrawal syndrome and withdrawal induced glutamate receptor (GluR) desensitization in LC neurons from morphine dependent rats. METHODS: Morphine withdrawal behavior was measured after naltrexone administration in rats implanted with a morphine (200 mg kg(-1)) emulsion for 3 days. GluR desensitization in the LC was assessed by performing concentration-effect curves for glutamate by extracellular electrophysiological recordings in vitro. RESULTS: Treatments with CFT or TPM reduced, in a dose related manner, the total behavioral score of naltrexone-precipitated morphine withdrawal. CFT and TPM, at doses that were effective in behavioral tests, also reduced the induction of GluR desensitization normally occurring in LC neurons from morphine-dependent rats. Acute treatment with the specific EAAT2 inhibitor dihydrokainic acid (DHK) prevented the effect of CFT on withdrawal syndrome and GluR desensitization. Perfusion with TPM inhibited KCl-evoked but not glutamate induced activation of LC neurons in vitro. CONCLUSIONS: Our results suggest that a reduction of synaptic concentrations of glutamate by enhancing EAAT2-mediated uptake or inhibiting glutamate release alleviates the behavioral response and the cellular changes in the LC during opiate withdrawal. PMID- 25787748 TI - Prognostic role of serum carbohydrate antigen 19-9 levels in patients with resectable hepatocellular carcinoma. AB - Serum levels of carbohydrate antigen 19-9 (CA 19-9) were shown to be associated with poorer prognosis in several cancers, but the prognostic role of CA 19-9 levels in patients with hepatocellular carcinoma was unclear. A retrospective cohort of 97 patients with resectable hepatocellular carcinoma was performed to assess the prognostic role of CA 19-9 levels on overall survival in hepatocellular carcinoma. Both Kaplan-Meier product-limit method and multivariate analysis were performed to determine the prognostic role of CA 19-9 levels. The results indicated that among those 97 patients, 24 (24.7%) had elevated preoperative CA 19-9 levels (>=37 U/mL). Elevated serum CA 19-9 levels did not correlate with patient age, gender, tumor size, tumor stage, diabetes, and hepatitis B virus (HBV) infection. Kaplan-Meier product-limit method showed that patients with elevated CA 19-9 levels had poorer survival than those with normal CA 19-9 levels (log-rank test P < 0.001). Multivariate analysis showed that elevated CA 19-9 level was a significantly independent predictor of poorer overall survival (hazard ratio [HR] = 2.56; 95% confidence interval [95% CI] 1.41 4.64, P = 0.002). In addition, tumor stages and multiple tumors were also independent predictors of poorer overall survival in hepatocellular carcinoma (P < 0.01). In conclusion, serum CA 19-9 levels have an independent prognostic role in patients with resectable hepatocellular carcinoma. Elevated CA 19-9 level is significantly associated with poorer overall survival in hepatocellular carcinoma. PMID- 25787749 TI - Squalene epoxidase (SQLE) promotes the growth and migration of the hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor response to chemotherapy. It is very important to identify novel therapeutic targets. Squalene epoxidase (SQLE), one of the rate-limiting enzymes in the cholesterol biosynthesis, recently has been found to be involved in the tumorigenesis. However, its expression profile and function in the progression of HCC remain largely unknown. Here, we found that the expression of SQLE was upregulated in the HCC tissues. Moreover, overexpression of SQLE in HCC cells promoted cell proliferation and migration, while downregulation of SQLE inhibited the tumorigenicity of HCC cells in vitro and in vivo. Mechanistically, SQLE positively regulated the ERK signaling. Taken together, our study suggests that SQLE is a promising therapeutic target in HCC. PMID- 25787750 TI - A Huaier polysaccharide reduced metastasis of human hepatocellular carcinoma SMMC 7721 cells via modulating AUF-1 signaling pathway. AB - TP-1 is a polysaccharide from one famous fungus Huaier. Treatment with TP-1 significantly inhibited the cell growth, adhesion, migration, and motility of SMMC-7721 cells in a dose-dependent manner. Real-time quantitative RT-PCR revealed a dose-dependent decrease in RNA-binding factor 1 (AUF-1) and astrocyte elevated gene-1 (AEG-1) messenger RNA (mRNA) levels in TP-1-treated SMMC-7721 cells, which is consistent with their protein expression detected by Western blotting. On the contrary, microRNA-122 (miR-122) expression increased in SMMC 7721 cells following TP-1 treatment. Moreover, TP-1 treatment at three doses apparently increased epithelial marker E-cadherin protein expression but decreased the mesenchymal marker N-cadherin protein level. In addition, the hematoxylin-eosin (H & E) staining showed that the TP-1 significantly inhibited the lung metastasis of liver cancer in mice orthotopic implanted with SMMC-7721 tumor tissue. Taken together, these findings proved the inhibitory effect of TP-1 on the growth and metastasis of SMMC-7721 cells, and TP-1 might be offered for future application as a powerful chemopreventive agent against hepatocellular carcinoma (HCC) metastasis. PMID- 25787756 TI - Surface chemical immobilization of bioactive peptides on synthetic polymers for cardiac tissue engineering. AB - The aim of this work was the development of new synthetic polymeric systems, functionalized by surface chemical modification with bioactive peptides, for myocardial tissue engineering. Polycaprolactone and a poly(ester-ether-ester) block copolymer synthesized in our lab, polycaprolactone-poly(ethylene oxide) polycaprolactone (PCL-PEO-PCL), were used as the substrates to be modified. Two pentapeptides, H-Gly-Arg-Gly-Asp-Ser-OH (GRGDS) from fibronectin and H-Tyr-Ile Gly-Ser-Arg-OH (YIGSR) from laminin, were used for the functionalization. Polymeric membranes were obtained by casting from solutions and then functionalized by means of alkaline hydrolysis and subsequent coupling of the bioactive molecules through 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride/N-hydroxysuccinimide chemistry. The hydrolysis conditions, in terms of hydrolysis time, temperature, and sodium hydroxide concentration, were optimized for the two materials. The occurrence of the coupling reaction was demonstrated by infrared spectroscopy, as the presence on the functionalized materials of the absorption peaks typical of the two peptides. The peptide surface density was determined by chromatographic analysis and the distribution was studied by infrared chemical imaging. The results showed a nearly homogeneous peptide distribution, with a density above the minimum value necessary to promote cell adhesion. Preliminary in vitro cell culture studies demonstrated that the introduction of the bioactive molecules had a positive effect on improving C2C12 myoblasts growth on the synthetic materials. PMID- 25787755 TI - Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells. AB - SCOPE: In vitro and in vivo studies suggest that dietary anthocyanins modulate cardiovascular disease risk; however, given anthocyanins extensive metabolism, it is likely that their degradation products and conjugated metabolites are responsible for this reported bioactivity. METHODS AND RESULTS: Human vascular endothelial cells were stimulated with either oxidized LDL (oxLDL) or cluster of differentiation 40 ligand (CD40L) and cotreated with cyanidin-3-glucoside and 11 of its recently identified metabolites, at 0.1, 1, and 10 MUM concentrations. Protein and gene expression of IL-6 and VCAM-1 was quantified by ELISA and RT qPCR. In oxLDL-stimulated cells the parent anthocyanin had no effect on IL-6 production, whereas numerous anthocyanin metabolites significantly reduced IL-6 protein levels; phase II conjugates of protocatechuic acid produced the greatest effects (>75% reduction, p <= 0.05). In CD40L-stimulated cells the anthocyanin and its phase II metabolites reduced IL-6 protein production, where protocatechuic acid-4-sulfate induced the greatest reduction (>96% reduction, p <= 0.03). Similarly, the anthocyanin and its metabolites reduced VCAM-1 protein production, with ferulic acid producing the greatest effect (>65% reduction, p <= 0.04). CONCLUSION: These novel data provide evidence to suggest that anthocyanin metabolites are bioactive at physiologically relevant concentrations and have the potential to modulate cardiovascular disease progression by altering the expression of inflammatory mediators. PMID- 25787757 TI - The problem of infective endocarditis after transcatheter pulmonary valve implantation. PMID- 25787758 TI - The Effectiveness of the Within Our Reach Relationship Education Program for Couples: Findings from a Federal Randomized Trial. AB - This study examined the effectiveness of a couple-based relationship education program, Within Our Reach. Secondary data (n = 3,609) were analyzed from the federal Supporting Healthy Marriage project. Couples were randomly assigned to receive Within Our Reach and associated services or to a no-treatment (treatment as-usual) control group. Those assigned to Within Our Reach reported better couple and individual outcomes on 8 of 12 outcomes measured (M ES = .15) at the 12-month follow-up and 6 of 10 outcomes measured at the 30-month follow-up (M ES = .14), including higher relationship happiness, more warmth and support, more positive communication, less negative behavior and emotion, less psychological abuse, less physical assault (for men), lower psychological distress (for women), and less infidelity. They were also less likely to report that their marriage was in trouble. These effects were generally small in size and many were replicated across the two follow-ups. There were no significant differences between those assigned to Within Our Reach versus control on cooperative parenting, severe psychological assault, or percent married. Implications for future research, programming, and policy are discussed. PMID- 25787759 TI - Two-step naked-eye detection of lectin by hierarchical organization of soft nanotubes into liquid crystal and gel phases. AB - Depending on the concentration of a lectin analyte, supramolecular soft nanotubes, bearing recognition sites immobilized on the outer surface through ethylene glycol chains, hierarchically organized into naked-eye-detectable liquid crystals and hydrogels. PMID- 25787760 TI - Sponsors meet scientists to speed pediatric medicines development. AB - The Point-Person Project, a child-health research initiative, enables rapid response to opportunities for participation in multicenter pediatric clinical trials. PMID- 25787761 TI - Small RNA: from development to regeneration. AB - A microRNA cluster that targets the Hippo pathway can reintroduce terminally differentiated cardiomyocytes into the cell cycle, promoting heart regeneration (Tian et al., this issue). PMID- 25787763 TI - Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti. AB - Dengue is the most common arboviral infection of humans and is a public health burden in more than 100 countries. Aedes aegypti mosquitoes stably infected with strains of the intracellular bacterium Wolbachia are resistant to dengue virus (DENV) infection and are being tested in field trials. To mimic field conditions, we experimentally assessed the vector competence of A. aegypti carrying the Wolbachia strains wMel and wMelPop after challenge with viremic blood from dengue patients. We found that wMelPop conferred strong resistance to DENV infection of mosquito abdomen tissue and largely prevented disseminated infection. wMel conferred less resistance to infection of mosquito abdomen tissue, but it did reduce the prevalence of mosquitoes with infectious saliva. A mathematical model of DENV transmission incorporating the dynamics of viral infection in humans and mosquitoes was fitted to the data collected. Model predictions suggested that wMel would reduce the basic reproduction number, R0, of DENV transmission by 66 to 75%. Our results suggest that establishment of wMelPop-infected A. aegypti at a high frequency in a dengue-endemic setting would result in the complete abatement of DENV transmission. Establishment of wMel-infected A. aegypti is also predicted to have a substantial effect on transmission that would be sufficient to eliminate dengue in low or moderate transmission settings but may be insufficient to achieve complete control in settings where R0 is high. These findings develop a framework for selecting Wolbachia strains for field releases and for calculating their likely impact. PMID- 25787762 TI - MG53-mediated cell membrane repair protects against acute kidney injury. AB - Injury to the renal proximal tubular epithelium (PTE) represents the underlying consequence of acute kidney injury (AKI) after exposure to various stressors, including nephrotoxins and ischemia/reperfusion (I/R). Although the kidney has the ability to repair itself after mild injury, insufficient repair of PTE cells may trigger inflammatory and fibrotic responses, leading to chronic renal failure. We report that MG53, a member of the TRIM family of proteins, participates in repair of injured PTE cells and protects against the development of AKI. We show that MG53 translocates to acute injury sites on PTE cells and forms a repair patch. Ablation of MG53 leads to defective membrane repair. MG53 deficient mice develop pronounced tubulointerstitial injury and increased susceptibility to I/R-induced AKI compared to wild-type mice. Recombinant human MG53 (rhMG53) protein can target injury sites on PTE cells to facilitate repair after I/R injury or nephrotoxin exposure. Moreover, in animal studies, intravenous delivery of rhMG53 ameliorates cisplatin-induced AKI without affecting the tumor suppressor efficacy of cisplatin. These findings identify MG53 as a vital component of reno-protection, and targeting MG53-mediated repair of PTE cells represents a potential approach to prevention and treatment of AKI. PMID- 25787764 TI - A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. AB - In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. We show that the microRNA cluster miR302-367 is important for cardiomyocyte proliferation during development and is sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. In mice, loss of miR302-367 led to decreased cardiomyocyte proliferation during development. In contrast, increased miR302-367 expression led to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal reexpression of miR302-367 reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. However, long-term expression of miR302-367 induced cardiomyocyte dedifferentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. This limitation can be overcome by transient systemic application of miR302-367 mimics, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury. Our data demonstrate the ability of microRNA-based therapeutic approaches to promote mammalian cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation. PMID- 25787765 TI - Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. AB - The skin of an adult human contains about 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice, but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human-engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All nonrecirculating resident memory T cells (TRM) expressed CD69, but most were CD4(+), CD103(-), and located in the dermis, in contrast to studies in mice. Both CD4(+) and CD8(+) CD103(+) TRM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103(-) TRM. TRM of both types had more potent effector functions than recirculating T cells. We observed two distinct populations of recirculating T cells, CCR7(+)/L selectin(+) central memory T cells (TCM) and CCR7(+)/L-selectin(-) T cells, which we term migratory memory T cells (TMM). Circulating skin-tropic TMM were intermediate in cytokine production between TCM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant TCM and TMM induced distinct inflammatory skin lesions, and TMM were depleted more slowly from skin after alemtuzumab, suggesting that TMM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities. PMID- 25787766 TI - Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. AB - The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics. PMID- 25787767 TI - Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. AB - Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel 1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma. PMID- 25787768 TI - Neointimal hyperplasia in allogeneic and autologous venous grafts is not different in nature. AB - Neointimal hyperplasia, transplant rejection and thus immunogenicity of allografts are possible reasons for poorer patency rates in cryopreserved venous allografts for peripheral bypass surgery in comparison with autologous venous grafts. To expand the limited knowledge from human allografts, we histologically investigated allogeneic and autologous venous grafts in arterial location. Specimens of allogeneic and autologous venous graft stenosis, harvested 6 months after bypass implantation, were immunohistochemically characterized. Examination of the lesions showed a uniform morphological pattern. A continuous endothelial layer, tissue fibrosis and a thickened neointima with monocytes and dedifferentiated vascular smooth muscle cells were seen in both conduits with very low cell turnover and the absence of acute and chronic inflammation. Neoangiogenesis with CD34-positive endothelium was abundant in the vessel media. The morphological patterns of allogeneic and autologous neointima formation are similar. Consequently, neointimal hyperplasia in venous grafts may reflect a uniform physiological host response of non-immunological factors with the reasons for poorer clinical outcome of cryopreserved allografts yet to be elucidated. PMID- 25787769 TI - Facile synthesis of three-dimensional structured carbon fiber-NiCo2O4-Ni(OH)2 high-performance electrode for pseudocapacitors. AB - Two-dimensional textured carbon fiber is an excellent electrode material and/or supporting substrate for active materials in fuel cells, batteries, and pseudocapacitors owing to its large surface area, high porosity, ultra-lightness, good electric conductivity, and excellent chemical stability in various liquid electrolytes. And Nickel hydroxide is one of the most promising active materials that have been studied in practical pseudocapacitor applications. Here we report a high-capacitance, flexible and ultra-light composite electrode that combines the advantages of these two materials for pseudocapacitor applications. Electrochemical measurements demonstrate that the 3D hybrid nanostructured carbon fiber-NiCo2O4-Ni(OH)2 composite electrode shows high capacitance, excellent rate capability. To the best of our knowledge, the electrode developed in this work possesses the highest areal capacitance of 6.04 F cm(-2) at the current density of 5 mA cm(-2) among those employing carbon fiber as the conductor. It still remains 64.23% at 40 mA cm(-2). As for the cycling stability, the initial specific capacitance decreases only from 4.56 F cm(-2) to 3.35 F cm(-2) after 1000 cycles under a current density of 30 mA cm(-2). PMID- 25787770 TI - Enzyme with a memory for its substrate? PMID- 25787771 TI - Pernicious anaemia presenting as hyperpigmentation. AB - An adult East Asian woman presented with sudden onset of hyperpigmented macules on her oral mucosal surfaces, palms and soles, in association with hypoguesia and loss of weight. This was found to be associated with underlying severe vitamin B12 deficiency secondary to pernicious anaemia. PMID- 25787772 TI - Olanzapine: evaluation of the in vivo cytogenetic effect. AB - BACKGROUND/AIMS: Olanzapine (OLZ), an atypical antipsychotic, is licensed for use in the treatment of schizophrenia and other psychiatric disorders. METHODS: OLZ cytogenetic effects were investigated by evaluating the frequency of Sister Chromatid Exchanges (SCEs) and Proliferation Rate Index (PRI) in cultured lymphocytes of schizophrenic patients who were under treatment of OLZ. SCE estimation is one of the most sensitive biomarkers of potential cytotoxicity, while PRI is used as a valuable marker of cytostatic activity. RESULTS: Our results showed a statistically significant increase of SCEs in the cultured lymphocytes of patients (p < 0,001) compared to the lymphocytes of healthy donors, a statistically significant increase of SCEs (p < 0.001) in the lymphocytes of smoker patients compared to those of non-smoker patients and a statistically significant increase of SCEs (p < 0.001) in the lymphocytes of chronic recipients of OLZ compared to those of the patients with recent initiation of treatment. We did not detect any statistically significant differences with respect to PRI between the various groups examined. CONCLUSIONS: Our results indicate a mild cytotoxic-but not cytostatic-effect of OLZ which was more prominent in smokers and in chronically treated patients. That effect should be taken into consideration by psychiatrists upon assessing the benefit/risk ratio of their prescriptions. PMID- 25787773 TI - A Review: Phytochemicals Targeting JAK/STAT Signaling and IDO Expression in Cancer. AB - Cancer remains a major health problem worldwide. Among many other factors, two regulatory defects that are present in most cancer cells are constitutive activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and the induction of indoleamine 2, 3-dioxygenase (IDO), an enzyme that catalyzes tryptophan degradation, through JAK/STAT signaling. Cytokine signaling activates STAT proteins in regulating cell proliferation, differentiation, and survival through modulation of target genes. Many phytochemicals can inhibit both JAK/STAT signaling and IDO expression in antigen presenting cells by targeting different pathways. Some of the promising phytochemicals that are discussed in this review include resveratrol, cucurbitacin, curcumin, (-)-epigallocatechin gallate, and others. It is now evident that phytochemicals play key roles in inhibition of tumor proliferation and development and provide novel means for therapeutic targeting of cancer. PMID- 25787774 TI - Polyoxometalate-conductive polymer composites for energy conversion, energy storage and nanostructured sensors. AB - The exchange of electric charges between a chemical reaction centre and an external electrical circuit is critical for many real-life technologies. This perspective explores the "wiring" of highly redox-active molecular metal oxide anions, so-called polyoxometalates (POMs) to conductive organic polymers (CPs). The major synthetic approaches to these organic-inorganic hybrid materials are reviewed. Typical applications are highlighted, emphasizing the current bottlenecks in materials development. Utilization of the composites in the fields of energy conversion, electrochemical energy storage, sensors and nanoparticle "wiring" into conductive materials are discussed. The outlook section presents the authors' views on emerging fields of research where the combination of POMs and CPs can be expected to provide novel materials for groundbreaking new technologies. These include light-weight energy storage, high-sensitivity toxin sensors, artificial muscles, photoelectrochemical devices and components for fuel cells. PMID- 25787775 TI - Expression of mucin 1 possessing a 3'-sulfated core1 in recurrent and metastatic breast cancer. AB - Breast cancer is the most frequent cancer threatening the lives of women between the ages of 30 and 64. The cancer antigen 15-3 assay (CA15-3) has been widely used for the detection of breast cancer recurrence; however, its sensitivity and specificity are inadequate. We previously found that the breast cancer cell line YMBS secretes mucin 1 possessing 3'-sulfated core1 (3Score1-MUC1) into the medium. Therefore, we here evaluated whether 3Score1-MUC1 is secreted into the blood streams of breast cancer patients, and whether it can serve as an improved breast cancer marker. We developed a lectin-sandwich immunoassay, called Gal4/MUC1, using a 3'-sulfated core1-specific galectin-4 and a MUC1 monoclonal antibody. Using the Gal4/MUC1 assay method, we found that 3Score1-MUC1 was profoundly expressed in the blood streams of patients with recurrent and/or metastatic breast cancer. The positive ratio of the Gal4/MUC1 assay was higher than that of the CA15-3 assay in both primary (n = 240) and relapsed (n = 43) patients, especially in the latter of which the positive ratio of Gal4/MUC1 was 86%. whereas that of CA15-3 was 47%. Furthermore, serum Gal4/MUC1 levels could more sensitively reflect the recurrence of primary breast cancer patients after surgery. Therefore, the Gal4/MUC1 assay should be an excellent alternative to the CA15-3 tumor marker for tracking the recurrence and metastasis of breast cancer. PMID- 25787776 TI - Evidence for different, host-dependent functioning of Rx against both wild-type and recombinant Pepino mosaic virus. AB - The potato Rx gene provides resistance against Pepino mosaic virus (PepMV) in tomato; however, recent work has suggested that the resistance conferred may not be durable. Resistance breaking can probably be attributed to multiple mutations observed to accumulate in the capsid protein (CP) region of resistance-breaking isolates, but this has not been confirmed through directed manipulation of an infectious PepMV clone. The present work describes the introduction of two specific mutations, A-T78 and A-T114, into the coat protein minimal elicitor region of an Rx-controlled PepMV isolate of the EU genotype. Enzyme-linked immunosorbent assay (ELISA) and phenotypic evaluation were conducted in three Rx expressing and wild-type solanaceous hosts: Nicotiana benthamiana, Nicotiana tabacum and Solanum lycopersicum. Mutation A-T78 alone was sufficient to confer Rx-breaking activity in N. benthamiana and S. lycopersicum, whereas mutation A T114 was found to be associated, in most cases, with a secondary A-D100 mutation to break Rx-mediated resistance in S. lycopersicum. These results suggest that the need for a second, fitness-restoring mutation may be dependent on the PepMV mutant under consideration. Both mutations conferred Rx breaking in S. lycopersicum, whereas neither conferred Rx breaking in N. tabacum and only A-T78 allowed Rx breaking in N. benthamiana, suggesting that Rx may function in a different manner depending on the genetic background in which it is present. PMID- 25787777 TI - Short-term blood pressure variability over 24 h and target organ damage in middle aged men and women. AB - Blood pressure variability (BPV) has been associated with cardiovascular events; however, the prognostic significance of short-term BPV remains uncertain. As uncertainty also remains as to which measure of variability most accurately describes short-term BPV, this study explores different indices and investigates their relationship with subclinical target organ damage (TOD). We used data from the Mitchelstown Study, a cross-sectional study of Irish adults aged 47-73 years (n=2047). A subsample (1207) underwent 24-h ambulatory BP monitoring (ABPM). As measures of short-term BPV, we estimated the s.d., weighted s.d. (wSD), coefficient of variation (CV) and average real variability (ARV). TOD was documented by microalbuminuria and electrocardiogram (ECG) left ventricular hypertrophy (LVH). There was no association found between any measure of BPV and LVH in both unadjusted and fully adjusted logistic regression models. Similar analysis found that ARV (24 h, day and night), s.d. (day and night) and wSD were all univariately associated with microalbuminuria and remained associated after adjustment for age, gender, smoking, body mass index (BMI), diabetes and antihypertensive treatment. However, when the models were further adjusted for the mean BP the association did not persist for all indices. Our findings illustrate choosing the appropriate summary measure, which accurately captures that short-term BPV is difficult. Despite discrepancies in values between the different measures, there was no association between any indexes of variability with TOD measures after adjustment for the mean BP. PMID- 25787778 TI - Interactions between plasma homocysteine and arterial stiffness in chronic kidney disease in community-dwelling individuals: The Maine-Syracuse Study. AB - Plasma homocysteine (tHcy) is associated with kidney disease. However, few, if any, studies have examined homocysteine in relation to arterial stiffness, with stratification by the presence or absence of early-stage chronic kidney disease (CKD). The aim of this study was to examine prospective associations between tHcy and carotid-femoral pulse wave velocity (PWV) in persons with and without early stage CKD in a sample of community-living individuals free from end-stage renal disease, dialysis, stroke and dementia. We conducted a prospective study with 498 participants of the Maine-Syracuse Longitudinal Study (mean age 61 years). Levels of tHcy were positively related to PWV measured 4-5 years later for participants with early-stage CKD (estimated glomerular filtration rate <60 ml min(-1) per 1.73 m(2)). Statistical adjustment was made for multiple confounders, including demographic factors, PWV-related variables and cardiovascular risk factors (b=4.27, 95% confidence interval: 0.23-8.31, P=0.04). These associations were not observed in persons free from CKD. Plasma tHcy is an important predictor of arterial stiffness, as indexed by PWV, in community-living individuals with modest CKD. PMID- 25787779 TI - Ambulatory BP monitoring and clinic BP in predicting small-for-gestational-age infants during pregnancy. AB - The significance of ambulatory blood pressure (ABP) monitoring during pregnancy has not been established. We performed a prospective study to elucidate whether ABP measures are associated with small-for-gestational-age birth weight (SGA). We studied 146 pregnant women who were seen for maternal medical checkups or suspected hypertension. ABP monitoring was performed for further assessment of hypertension. The outcome measure was SGA. The subjects were classified by their medical history and ABP as having preeclampsia or gestational hypertension (n=68 cases), chronic hypertension (n=48) or white-coat hypertension (n=30). There were 50 (34.2%) cases of SGA by the fetal growth reference standard. In multivariable logistic regression analyses adjusting for age, body mass index, the presence of prior pregnancy, current smoking habit and the use of antihypertensive medications, 24-h SBP (per 10 mm Hg (odds ratio (OR): 1.74; 95% confidence interval (CI): 1.28-2.38; P<0.001)) was more closely associated with SGA than clinic BP (OR: 1.40; 95% CI: 0.92-2.13; P=0.11). The results were essentially the same if 24-h BP was replaced by awake or sleep SBP. Ambulatory diastolic BP showed the same tendency. However, abnormal circadian rhythm was not associated with the outcome. In conclusion, ambulatory BP monitoring measures performed during pregnancy were more closely associated with SGA than clinic BP. PMID- 25787780 TI - Arterial compliance may be reduced by ingestion of red wine. AB - The aim of this study was to assess the effect of alcohol on blood pressure and arterial compliance over 24 h in a group of volunteers, comparing the same group of subjects on two consecutive but separate days, one with alcohol intake (alcohol day) and one free of alcohol (control day). We studied 18 healthy subjects (mean age 34.2 years, range 25-53). The subjects received the two days in random order. On the alcohol day, the subjects were asked to drink two glasses of red wine (12% ethanol) between 1830 hours and 0430 hours. Measurements of heart rate, blood pressure and QKD interval (Q wave to Korotkoff (K) sound, diastolic phase (D) using Diasys Integra (Novacor, France)) were recorded (usually 1500 hours to 1500 hours). Three 'ingestion' periods were defined, from 1500 hours to 1830 hours ('before'), 1900 hours to 0430 hours ('during') and from 0430 hours to the following afternoon ('after') on both the alcohol day and on the control day. Red wine increased heart rate during alcohol ingestion and reduced arterial compliance after ingestion. The significant effect of interaction between day and ingestion period on heart rate, diastolic blood pressure and QKD were found, suggesting that the differences in response among the ingestion periods depended on whether alcohol has been consumed that day. For the first time our study indicates the effect of alcohol on 24 h arterial stiffness in a healthy group of volunteers. PMID- 25787782 TI - Analytical and microbiological characterization of paper samples exhibiting foxing stains. AB - This work comprises the use of a multi-analytical approach combined with microbiological studies to characterize six paper samples, containing foxing stains, from the 20th century, regarding their cellulose matrix, fillers, and sizing materials, and to evaluate possible paper degradation that might have occurred during the foxing stains. Photography under different illuminations and optical microscopy were used for morphological characterization of the paper samples and foxing stains. Scanning electron microscopy coupled energy dispersive spectroscopy (SEM-EDS) was of particular importance for defining the presence of fiber disorder and disruption on the surface of some of the stains, and localized accumulations of mineral-like particles on the surface of others. SEM-EDS, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FT-IR), and energy dispersive X-ray fluorescence (EDXRF) were used for the identification of mineral fillers, whereas sizing agents were analyzed using ATR-FT-IR. EDXRF results showed that no differences, within the standard deviation, were found in iron and copper contents between the foxed and unfoxed areas. Fungi belonging to the genus Penicillium spp. were found in all the paper samples. Unfoxed areas presented lower contamination than the foxed areas. PMID- 25787781 TI - Comparison of adiposity measures in the identification of children with elevated blood pressure in Guangzhou, China. AB - To differentiate the screening potential of waist circumference (WC), waist-to hip ratio (WHR), waist-to-height ratio (WHtR) and body mass index (BMI) for the presence of elevated blood pressure (BP) in Chinese children. A total of 2799 boys and 2672 girls aged 6-10 years participated in this cross-sectional study. Weight, height, WC and hip circumference were measured, and WHR, WHtR and BMI were calculated. Elevated BP was defined as systolic BP and/or diastolic BP ? 95 th percentile for age and gender. Both linear and logistic regression showed that WC had the strongest associations with BP values or risk of elevated BP, and the association was more substantial in boys than in girls. The area under receiver operating curves for the presence of elevated BP were highest for WC (0.770, 95% confidence interval: 0.754-0.785) in boys. In girls, WC, BMI and WHtR showed similar discriminatory capacity for elevated BP and were slightly higher than that of WHR. The optimal cutoff values of WC were 71.1 th percentile for boys and 83.5th percentile for girls. WC was a simple and sensitive measure in the identification of elevated BP regardless of sex in children in Guangzhou, China. PMID- 25787783 TI - Cellulose films: designing template-free nanoporous cellulose films on semiconducting surfaces. AB - In this work, we report the preparation of ultrathin submicro- and nanoporous cellulose films onto Si (100). The effect of different experimental conditions of preparation on the film surface morphology was studied, namely the role of the film casting method (spin- versus dip-coating), solvent (toluene or tetrahydrofuran), substrate pretreatment (hydrophilicity degree), and regeneration procedure with HCl vapors (two consecutive dips followed by regeneration or regeneration after each dip). The surface morphological structures presented in this work were never obtained before without the use of templates. A rather regular two-dimensional pore network was obtained onto the less hydrophilic Si substrate (contact angle?68 degrees ), after two consecutive dips (with an intercalary rotation of 180o) in trimethylsilyl cellulose diluted in toluene and regeneration at the end. All the surfaces were characterized by atomic force microscopy. PMID- 25787784 TI - Effects of preheating and cooling durations on roll-to-roll hot embossing erratum. PMID- 25787785 TI - Multiply disadvantaged: Health and service utilisation factors faced by homeless injecting drug consumers in Australia. AB - INTRODUCTION AND AIMS: Homelessness status is strongly correlated with higher rates of substance use. Few studies, however, examine the complex relationship between housing status and substance use in people who inject drugs (PWID). This study extends previous research by comparing the physical and mental health status and service utilisation rates between stably housed and homeless PWID. DESIGN AND METHODS: A cross-sectional sample of 923 PWID were recruited for the 2012 Illicit Drug Reporting System. Multivariate models were generated addressing associations between homelessness and the domains of demographics; substance use; and health status, service utilisation and criminal justice system contact, with significant correlates entered into a final multivariate model. RESULTS: Two thirds of the PWID sample were male. The median age was 39 years and 16% identified as Indigenous. Almost one-quarter (23%) reported that they were homeless. Homeless PWID were significantly more likely to be unemployed [adjusted odds ratio (AOR) 2.83, 95% confidence interval (CI) 1.26, 6.34], inject in public (AOR 2.01, 95% CI 1.38, 3.18), have poorer mental health (AOR 0.98, 95% CI 0.97, 1.00), report schizophrenia (AOR 2.31, 95% CI 1.16, 4.60) and have a prison history (AOR 1.53, 95% CI 1.05, 2.21) than stably housed PWID. DISCUSSION AND CONCLUSIONS: Findings highlight the challenge of mental health problems for homeless PWID. Our results demonstrate that further research that evaluates outcomes of housing programs accommodating PWID, particularly those with comorbid mental health disorders, is warranted. Results also emphasise the need to better utilise integrated models of outreach care that co-manage housing and mental health needs. PMID- 25787786 TI - An adaptive Hidden Markov model for activity recognition based on a wearable multi-sensor device. AB - Human activity recognition is important in the study of personal health, wellness and lifestyle. In order to acquire human activity information from the personal space, many wearable multi-sensor devices have been developed. In this paper, a novel technique for automatic activity recognition based on multi-sensor data is presented. In order to utilize these data efficiently and overcome the big data problem, an offline adaptive-Hidden Markov Model (HMM) is proposed. A sensor selection scheme is implemented based on an improved Viterbi algorithm. A new method is proposed that incorporates personal experience into the HMM model as a priori information. Experiments are conducted using a personal wearable computer eButton consisting of multiple sensors. Our comparative study with the standard HMM and other alternative methods in processing the eButton data have shown that our method is more robust and efficient, providing a useful tool to evaluate human activity and lifestyle. PMID- 25787787 TI - Effect of Dermal Thickness on Scars in Women with Type III-IV Fitzpatrick Skin. AB - BACKGROUND: Both patients and physicians desire minimal scarring after surgical procedures. The removal of foreign bodies from around the wound, prevention of infection, and wound closure without tension is recommended for reducing scarring. The reasons underlying the differing appearance of scars between different anatomical regions of the same individual are not fully understood. Moreover, to our knowledge, the relationship between incision width and dermal thickness in different anatomical regions has yet to be investigated. Hence, in the present study, we aimed to determine the effect of dermal thickness on scar formation. METHODS: Fifty patients who were treated and followed up for breast hypertrophy between 2010 and 2013 were retrospectively investigated. In all patients, a 2 * 2-cm skin biopsy specimen was obtained from the medial right breast at the horizontal line of the T scar. A routine superomedial pedicle breast reduction was subsequently performed. The extracted excision materials and skin biopsy specimens were examined pathologically. Dermal thickness was measured from the starting point of the subcutaneous tissue to the end point of the epidermis, at four different sites. The average dermal thickness was then calculated for each patient. The skin color of all patients was determined according to the Fitzpatrick classification. Scar width was measured in three different regions, including a combination of the vertical and horizontal portions of the T scar and the flap confluence. After the measurements, the scars were evaluated for vascularity, pigmentation, elasticity, thickness, and height by two plastic surgeons and a clinical nurse, who were blinded to patient data. RESULTS: The mean age of the 50 female patients was 40.8 years (range 18-65 years). The average follow-up period was 16 months (range 12-18 months). An average of 987.5 g (range 505-1621 g) of breast and fatty tissue was removed. The average dermal thickness was 4.99 mm (range 3.5-6.8 mm). The most common skin type was Fitzpatrick type IV (33 patients). The average total scar score was 14 (range 8-25). The total scar score was not significantly associated with dermal thickness. The scar width in patients with a dermal thickness of <0.5 cm was narrower than that in patients with a dermal thickness of >=0.5 cm. Scar vascularity and noticeability were observed less often in patients with Fitzpatrick skin type III, regardless of scar width. CONCLUSION: The study findings show that increased dermal thickness is a risk factor for wide scar formation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25787788 TI - Mechanochemical regulations of RPA's binding to ssDNA. AB - Replication protein A (RPA) is a ubiquitous eukaryotic single-stranded DNA (ssDNA) binding protein that serves to protect ssDNA from degradation and annealing, and as a template for recruitment of many downstream factors in virtually all DNA transactions in cell. During many of these transactions, DNA is tethered and is likely subject to force. Previous studies of RPA's binding behavior on ssDNA were conducted in the absence of force; therefore the RPA-ssDNA conformations regulated by force remain unclear. Here, using a combination of atomic force microscopy imaging and mechanical manipulation of single ssDNA tethers, we show that force mediates a switch of the RPA bound ssDNA from amorphous aggregation to a much more regular extended conformation. Further, we found an interesting non-monotonic dependence of the binding affinity on monovalent salt concentration in the presence of force. In addition, we discovered that zinc in micromolar concentrations drives ssDNA to a unique, highly stiff and more compact state. These results provide new mechanochemical insights into the influences and the mechanisms of action of RPA on large single ssDNA. PMID- 25787789 TI - Optimized Analytical Procedures for the Untargeted Metabolomic Profiling of Human Urine and Plasma by Combining Hydrophilic Interaction (HILIC) and Reverse-Phase Liquid Chromatography (RPLC)-Mass Spectrometry. AB - Profiling of body fluids is crucial for monitoring and discovering metabolic markers of health and disease and for providing insights into human physiology. Since human urine and plasma each contain an extreme diversity of metabolites, a single liquid chromatographic system when coupled to mass spectrometry (MS) is not sufficient to achieve reasonable metabolome coverage. Hydrophilic interaction liquid chromatography (HILIC) offers complementary information to reverse-phase liquid chromatography (RPLC) by retaining polar metabolites. With the objective of finding the optimal combined chromatographic solution to profile urine and plasma, we systematically investigated the performance of five HILIC columns with different chemistries operated at three different pH (acidic, neutral, basic) and five C18-silica RPLC columns. The zwitterionic column ZIC-HILIC operated at neutral pH provided optimal performance on a large set of hydrophilic metabolites. The RPLC columns Hypersil GOLD and Zorbax SB aq were proven to be best suited for the metabolic profiling of urine and plasma, respectively. Importantly, the optimized HILIC-MS method showed excellent intrabatch peak area reproducibility (CV < 12%) and good long-term interbatch (40 days) peak area reproducibility (CV < 22%) that were similar to those of RPLC-MS procedures. Finally, combining the optimal HILIC- and RPLC-MS approaches greatly expanded metabolome coverage with 44% and 108% new metabolic features detected compared with RPLC-MS alone for urine and plasma, respectively. The proposed combined LC MS approaches improve the comprehensiveness of global metabolic profiling of body fluids and thus are valuable for monitoring and discovering metabolic changes associated with health and disease in clinical research studies. PMID- 25787790 TI - Genetic variation in caveolin-1 correlates with long-term pancreas transplant function. AB - Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long-term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin-1 gene (Cav1), previously shown to correlate with long-term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death-censored cumulative events were analyzed using Kaplan-Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long-term graft function (p = 0.331-0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long-term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16-2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03-2.73]) with long-term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long-term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results. PMID- 25787791 TI - Pulmonary arterial hypertension associated with congenital heart disease. Personal perspectives. AB - The management of patients with congenital heart disease (CHD) and pulmonary arterial hypertension (PAH) has changed dramatically with the development of targeted therapy with selective pulmonary vasodilators. The number of adult Japanese patients with PAH associated with CHD is increasing. It is important to develop evidence-based guidelines for the management of these patients, and to achieve this, a register of adult Japanese patients with PAH associated with CHD should be established. At the World Symposium in Nice, France, in 2013, the consensus was reached that patients with a pulmonary resistance of < 4 Wood Units (WU).m(2) have operable disease, and patients with a pulmonary resistance of > 8 WU.m(2) have inoperable disease. However, these criteria are conservative. Some patients with a pulmonary resistance of > 8 WU.m(2) and a good response to a pulmonary vasodilator test have operable disease and a favorable clinical course long after repair of CHD. The criteria determining operability in patients with PAH associated with CHD in the era of pulmonary vasodilators should be established using data obtained from patient registers and/or multicenter studies. The optimal management of Eisenmenger syndrome should also be established using data obtained from patient registers. Prospective studies should be conducted to determine the life expectancy of patients with Eisenmenger syndrome in the era of targeted therapy. A relatively mild increase in pulmonary resistance may result in failure of a Fontan circulation. The effects of pulmonary vasodilators on the long-term prognosis of patients who have undergone the Fontan operation are still unclear. PMID- 25787792 TI - Can pulmonary vasodilator therapy expand the operative indications for congenital heart disease? AB - The operability of congenital heart disease with left to right shunt depends on the severity of the pulmonary vascular disease induced by the increased pulmonary blood flow. Although some recommendations exist regarding operative indications according to pathological, hemodynamic, and epidemiological factors, the evidence underlying these recommendations is not conclusive. Recently, oral pulmonary vasodilator therapy has been reported to improve outcomes in patients with idiopathic pulmonary arterial hypertension, and this therapy also appears to be effective in patients with congenital heart disease and pulmonary arterial hypertension, including those with postoperative pulmonary hypertension and Eisenmenger syndrome. It is expected that the availability of novel pulmonary vasodilator therapy will expand the operative indications in patients with congenital heart disease with left to right shunt, but there is currently insufficient evidence to definitively determine this. A multicenter double-blind study should be conducted to further examine this issue. PMID- 25787793 TI - Pulmonary arterial hypertension associated with tetralogy of Fallot. AB - Pulmonary arterial hypertension (PAH) is a common postoperative complication in patients with congenital heart disease (CHD). Although the recent clinical classification of pulmonary hypertension divided PAH associated with CHD (PAH CHD) into several subclasses, the anatomical and hemodynamic features of postoperative PAH-CHD vary enormously. Therefore, it is still difficult to obtain clinical evidence supporting the indication of pulmonary vasodilators for PAH CHD. We often encounter patients with PAH occurring after surgical treatment of tetralogy of Fallot (TOF), especially patients with major aortopulmonary collateral arteries (MAPCAs). PAH might be caused by pulmonary agenesis, hypoplasia and/or thrombosis, inadequate closure of the ventricular septal defect, relief of the pulmonic stenosis, or an excessively large prior systemic to-pulmonary shunt. Moreover, patients with TOF and MAPCAs who are diagnosed as inoperable because of the presence of PAH show similar hemodynamic and clinical features to patients with Eisenmenger syndrome. The MAPCAs in these patients usually show hypoplastic and abnormal arborization. Based on our experience, we believe that PAH-targeted therapies are effective in some patients with PAH occurring after surgical treatment of TOF and MAPCAs, especially as an adjunct to percutaneous pulmonary angioplasty. To help classify patients with PAH associated with TOF, especially with MAPCAs, we propose several new subclassifications: "PAH due to hypoplastic pulmonary arterial beds", "PAH due to abnormal pulmonary arborization", or "segmental PAH associated with CHD." A multicenter registry of patients using a unified protocol is essential to explore the indications and efficacy of pulmonary vasodilators for postoperative PAH-CHD. PMID- 25787794 TI - Pulmonary arterial hypertension associated with bronchopulmonary dysplasia and congenital heart disease in preterm infants. A case report of a preterm infant with recurrent pulmonary hypertension after corrective cardiac surgery and review of the literature. AB - In preterm infants with congenital heart disease, concomitant bronchopulmonary dysplasia (BPD) is associated with relatively poor clinical outcomes because of the increased pulmonary vascular resistance and adverse effects of inflammation on the damaged lungs, even after surgery. We present herein a 1-year-old female who developed recurrent pulmonary arterial hypertension 6 months after closure of a ventricular septal defect. She was born at 26 weeks of gestation (birth weight, 470 g), and developed BPD requiring oxygen supplementation. Her systemic-to pulmonary blood flow ratio was 2.1 preoperatively and 1.0 postoperatively, pulmonary arterial pressure was 61/15 (mean 39) mmHg preoperatively and 41/17 (mean 24) mmHg postoperatively, and pulmonary vascular resistance was 4.2 mmHg/L.minute.m(2) preoperatively and 3.6 mmHg/L.minute.m(2) postoperatively. At 1 year of age, echocardiography showed an increase in her estimated right ventricular pressure, indicating worsening pulmonary hypertension. After 3 years of treatment with oxygen supplementation, prostacyclin, and bosentan, her pulmonary arterial pressure improved to the normal range. The pathophysiology of pulmonary arterial hypertension is heterogeneous in preterm infants with congenital heart disease and concomitant BPD. Careful management of these patients is warranted even after corrective cardiac surgery. PMID- 25787795 TI - Efficacy of pulmonary vasodilator therapy in patients with functionally single ventricle. AB - This study retrospectively evaluated the effectiveness of pulmonary vasodilator therapy with bosentan (n = 14) and/ or sildenafil (n = 23) in 34 patients with a functionally single ventricle. Vasodilator therapy was initiated before the Fontan procedure in 18 patients and after the procedure in 16 patients. The reasons for vasodilator treatment included high pulmonary artery pressure or pulmonary vascular resistance (n = 8), high central venous pressure after the Fontan or bidirectional Glenn procedure (n = 7), and ventilatory impairment (n = 8). In the 11 patients who underwent right heart catheterization before and after the initiation of therapy, the mean pulmonary artery pressure decreased significantly from 19.5 +/- 5.5 mmHg to 14.3 +/- 3.0 mmHg (P = 0.023) and the transpulmonary pressure gradient decreased significantly from 10.9 +/- 4.6 mmHg to 7.2 +/- 3.3 mmHg (P = 0.046). Of the 18 patients who started vasodilator therapy before the Fontan procedure, 10 survived surgery, 4 are awaiting surgery, 3 had not been evaluated for the Fontan procedure at the end of the study period, and 1 died of heart failure after discontinuing bosentan therapy. There were no deaths among the patients who started therapy after the Fontan procedure. Two of the 14 patients receiving bosentan discontinued treatment because of adverse effects (hepatic dysfunction and increased serum brain natriuretic peptide level). Bosentan or sildenafil therapy is usually safe and may contribute to reducing pulmonary vascular resistance in patients with a functionally single ventricle before and after a Fontan type operation. PMID- 25787796 TI - Case studies of patients successfully and unsuccessfully managed pre- and post Fontan procedure. AB - As a result of advances and modifications in surgical procedures and the development of drugs for pulmonary arterial hypertension, many patients who have undergone Fontan procedures are able to enjoy good quality of life, without pulmonary arterial hypertension and severe complications. In Shizuoka Children's Hospital, drugs for pulmonary arterial hypertension have long been given to Fontan candidates and patients with established Fontan circulation to maintain sufficient pulmonary blood flow and suppress pulmonary arterial hypertension. We present three typical cases that were treated with anti-pulmonary hypertensive drugs before or after Fontan procedure. The first case had asplenia syndrome, and a single ventricle with major aortopulmonary collateral arteries. Anti-pulmonary hypertensive therapy permitted a Fontan procedure and maintained a good long-term quality of life. The second case was a Down syndrome patient who had progressive cyanosis after a Fontan operation. Anti-pulmonary hypertensive therapy improved cyanosis. The third case suffered from protein-losing enteropathy, for which all procedures and medical therapies were ineffective. Fontan candidates and patients with Fontan circulation have varied anatomical backgrounds and pulmonary properties. We must identify the conditions that lead to successful Fontan procedure and Fontan circulation correction, as well as conditions that result in failed Fontan procedure and poorly-controlled Fontan circulation. PMID- 25787797 TI - Update on medical treatment of patients with eisenmenger syndrome. AB - Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) associated with congenital heart defects. ES greatly affects functional capacity, quality of life, and survival of patients. Clinical management of patients with ES has been dramatically changed and developed in a new therapeutic era of PAH, approximately a century after the first ES case described by Dr. Eisenmenger. Targeted drugs for PAH improve functional capacity and quality of life of patients with ES. In addition, these drugs may also provide a benefit for patients' survival. To achieve further development in medical treatment of patients with ES, they will need to be individualized according to functional classes, underlying cardiac defects, and underlying systemic diseases. PMID- 25787798 TI - Medical treatment for an adult patient with eisenmenger syndrome. A case report. AB - Previous studies examining the use of pulmonary arterial hypertension (PAH) drugs in patients with Eisenmenger syndrome (ES) have shown that it may have beneficial effects in some patients with ES; however, experience with additional cases is necessary to confirm its efficacy and appropriate clinical use. We herein report our experience of an adult patient with ES who benefitted from treatment with PAH drugs. A 32-year-old Japanese man with severe ES induced by a ventricular septal defect associated with Down syndrome began treatment with bosentan at 62.5 mg. Eleven months later, he was admitted for tadalafil (40 mg) add-on therapy because his 6-minute walking distance and brain natriuretic peptide (BNP) level had not improved and his hepatic enzyme levels had increased. However, marked hypotension developed, and the tadalafil dose was decreased. His BNP level subsequently increased, so the bosentan dose was increased to 125 mg. The bosentan was then abruptly stopped because of a low platelet count and high liver enzyme levels. Ambrisentan was then administered for these side effects, but because severe dyspnea developed, the bosentan was started again at 62.5 mg. This resulted in immediate clinical improvement. The patient was finally switched to ambrisentan (5 mg), which was well tolerated. The findings in this particular case show that although it should be used with caution, bosentan may be beneficial in select patients with ES. In addition, ambrisentan may be considered as first-line treatment in some patients as long as liver enzymes and platelets are carefully monitored. PMID- 25787799 TI - Mixed messages from the GMC on disciplinary processes. PMID- 25787800 TI - N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as beta-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation. AB - A novel series of N-(2-(piperazin-1-yl)phenyl)aryl carboxamide derivatives were simply synthesized by Ugi-multicomponent reaction as beta-secretase (BACE1) inhibitors. The BACE1 inhibitory activity of the synthesized compounds was examined using a Forester resonance energy transfer (FRET)-based assay. Among the tested compounds, the N-(5-bromo-2-(4-phenylpiperazine-1-yl)phenyl)thiophene carboxamide derivative 14 containing the N-cyclohexyl indole acetamide moiety showed superior BACE1 inhibition at 10 and 40 uM. The results of the molecular docking study indicated that compound 14 establishes favorable hydrogen bonding interactions with the catalytic amino acid residues Asp228 and Thr72 and could be well accommodated in the flap region and P2 and P'2 pockets of the BACE1 active site. PMID- 25787801 TI - Characterization of Russell bodies accumulating mutant antithrombin derived from the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) adjusts its size and architecture to adapt to change in the surrounding environment. Russell bodies (RBs) were originally described as dilated structures of the ER cisternae containing large amounts of mutant immunoglobulin. Similar structures are observed in a wide variety of mutant proteins accumulated in the ER. We previously prepared Chinese hamster ovary (CHO) cells in which the expression of mutant antithrombin (AT) (C95R) was controlled with a Tet-On system and showed that RBs can be conditionally formed. However the precise architecture and intracellular behavior of RBs have been as yet only poorly characterized. To characterize the properties of RB, we prepared the same system using a green fluorescent protein (GFP)-fused mutant and measured the dynamics and architecture of RBs. We observed the mobile nature of the molecule in the RB lumen and RBs were separated from the rest of the ER network by narrow tubes. Furthermore, we found that the RBs were not simply expanded ER membranes. The RB lumen is filled with misfolded proteins that are surrounded by ER membranes. In addition, RBs mostly maintain their structure during cell division, possess ribosomes on their membranes and synthesize AT(C95R)-GFP. Based on the characterization of the hydrodynamic radius of AT(C95R)-GFP and the effect of DP1, an ER-shaping protein, we propose that RBs are spontaneously formed as a result of the partitioning of the misfolded AT with the shaping protein. PMID- 25787802 TI - X-ray structure analysis reveals beta-turn mimicry by N-amino-imidazolidin-2 ones. AB - The conformation of the N-amino-imidazolidin-2-one (Aid) peptidomimetic was investigated using NMR spectroscopy and X-ray crystallography. In solution, the tetrapeptide model p-bromobenzoyl-Aid-l-Phe-N'-iso-propylamide (1) exhibited shielded and solvent exposed amide protons indicative of a turn conformation. In the crystal lattice of 1, four turn conformers were present in the unit cell differing primarily by the ring puckering of the Aid residue. Two pairs of beta turn conformers were observed each possessing an intramolecular ten-member hydrogen bond between the benzamide carbonyl and iso-propylamine NH moieties. The pairs had types II and II' beta-turn geometry that differed slightly about the phi and psi torsion angles. Moreover, the X-ray analysis of 1 has been compared with that of the related unsaturated N-amino-imidazolin-2-one (Nai) analogs indicating the influences of ring flattening and substituents on conformation. Insertion of the preorganized Aid structure into biologically active peptides has thus been shown to offer a potentially valuable means for exploring the importance of turn geometry for activity, particularly in drug discovery. PMID- 25787803 TI - Part 2: pressure ulcer assessment: implementation and revision of CALCULATE. AB - INTRODUCTION: Critically ill patients are a vulnerable group at very high risk of developing pressure ulcers, and the incidence varies within critical care. METHODS: A number of strategies were used to implement the pressure ulcer assessment tool CALCULATE across four adult critical care units. Strategies included, nursing leadership, the provision of definitions for each risk factor, information laid out on posters at each patient's bedside, changes to pre-printed nursing documentation and a 30-min focused training package. Two local audits were conducted to measure the number and types of risk factors occurring in patients with pressure ulcers, and to assess the frequency of assessments and gain feedback on the usability of the tool in practice. FINDINGS: Critical care acquired pressure ulcer incidence was 3.4%. The two most commonly occurring risk factors were impaired circulation (82%) and mechanical ventilation (75%). Patients had a mean score of 4, and 65% had 4 or more reported risk factors. Feedback on the usability of the tool was mainly positive. DISCUSSION: The tool CALCULATE was relatively straightforward to implement and was likely to be due to the design and the various change strategies used to implement the new approach. The seven point tool was revised to an eight point score based on nurses' clinical feedback. CONCLUSIONS: Research is required to further enhance and develop pressure ulcer assessment. Meanwhile CALCULATE offers an easy to use and appropriate tool to assist in the identification of patients at an elevated risk of pressure ulcer damage. IMPLICATIONS FOR PRACTICE: Careful choice of change management strategies are needed when implementing a new assessment tool. CALCULATE should be considered for use in critical care for pressure ulcer assessment, but used alongside nurses' clinical judgement and observations of skin. PMID- 25787804 TI - PetriJet Platform Technology: An Automated Platform for Culture Dish Handling and Monitoring of the Contents. AB - Due to the size of the required equipment, automated laboratory systems are often unavailable or impractical for use in small- and mid-sized laboratories. However, recent developments in automation engineering provide endless possibilities for incorporating benchtop devices. Here, the authors describe the development of a platform technology to handle sealed culture dishes. The programming is based on the Petri net method and implemented via Codesys V3.5 pbF. The authors developed a system of three independent electrical driven axes capable of handling sealed culture dishes. The device performs two difference processes. First, it automatically obtains an image of every processed culture dish. Second, a server based image analysis algorithm provides the user with several parameters of the cultivated sample on the culture dish. For demonstration purposes, the authors developed a continuous, systematic, nondestructive, and quantitative method for monitoring the growth of a hairy root culture. New results can be displayed with respect to the previous images. This system is highly accurate, and the results can be used to simulate the growth of biological cultures. The authors believe that the innovative features of this platform can be implemented, for example, in the food industry, clinical environments, and research laboratories. PMID- 25787805 TI - Paper-Based Systems for Point-of-Care Biosensing. AB - Paper-based systems have been widely investigated for developing point-of-care devices because of their simplicity, affordability, and ease of use. Recent advances have resulted in paper systems that have progressed beyond the historical "single-strip" format and allow for a larger range of functions. This review provides a summary of the advances that have been made to improve the utility of paper-based diagnostic tests for biosensing. Specifically, techniques for designing paper devices, including different geometries and chemical patterning to control fluid flow, are discussed. This review also examines novel approaches to improve paper-based assay sensitivities, such as sample preconcentration, signal amplification at the detection zone, and electrochemical methods. PMID- 25787806 TI - Gold Nanorods Bioconjugates for Intracellular Delivery and Cancer Cell Apoptosis. AB - The aim of this study was to identify an improved delivery scheme for intracellular delivery and anticancer therapy. Novel gold nanorods (GNRs) bioconjugates were prepared by using GNRs as nonviral vectors conjugated with thiol-modified antisense oligodeoxynucleotides (ASODNs). We then investigated the possibility of using GNRs as carriers for nucleus delivery of ASODNs genes by using confocal microscopy and cell transmission electron microscope imaging. Our results demonstrate that the GNRs-ASODNs entered into the cell nucleus and increased cell apoptosis. Therefore, the GNRs could hold great promise for biological delivery applications and gene therapy. PMID- 25787807 TI - Ataxia with oculomotor apraxia type 2: not always an easy diagnosis. PMID- 25787808 TI - Effect of simvastatin on L-DOPA-induced abnormal involuntary movements of hemiparkinsonian rats. AB - Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often results in debilitating involuntary movements known as L-DOPA-induced dyskinesia (LID), which is the main obstacle in PD. The abnormal involuntary movements (AIMs) are consistently involved with the activation of the Ras extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway. Previous research has also shown that blockade of ERK phosphorylation could reduce the induction of LID. Consequently, inhibitors of MAPK signaling cascade that block the aberrant supersensitive response of direct pathway striatal neurons could provide a novel therapeutic adjunct to L-DOPA in the treatment of PD. Statins, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity, and the subsequent phosphorylation of ERK1/2 (pERK1/2). Simvastatin, a representative of statins, could reduce L-DOPA-induced AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by preventing the L-DOPA/benserazide-induced increase in pERK1/2 levels in our study. The simvastatin-L-DOPA/benserazide-treated 6-OHDA animals displayed less severe rotational behavior and a dramatic reduction in AIM severity than the L DOPA/benserazide-treated ones. This lower AIM severity was related to a decrease in L-DOPA-induced increase in the following: (1) striatal pERK1/2 and (2) FosB levels. These results suggest that simvastatin could represent a treatment option for managing LID in PD. PMID- 25787809 TI - Transcranial sonography and the pocket smell test in the differential diagnosis between parkinson's disease and essential tremor. AB - The aim of this study was to determine the specificity and sensitivity of transcranial sonography (TCS) and the Pocket Smell Test (PST) in differing Parkinson's disease from essential tremor. The results were compared with the dopamin transporter scan (DaTSCAN) findings. Based on the DaTSCAN finding we formed a group of patients with essential tremor (51 patients) and a group with the Parkinson's disease (59 patients). The control group consisted of 26 healthy one. To evaluate the olfactory dysfunction the PST was used, whereas by TCS the substantia nigra hyperechogenicity was marked. The sensitivity and specificity of each diagnostic method was statistically calculated. In confirming Parkinson's disease the specificity of TCS was 88.2 % and the sensitivity 94.9 %. The specificity of PST was 80.4 % whereas the sensitivity was 74.6 %. TCS and PST should be performed to evaluate which patients need to be examined by DaTSCAN. PMID- 25787811 TI - Whose responsibility is orthopaedic and trauma nursing research? PMID- 25787810 TI - Injection of insulin amyloid fibrils in the hippocampus of male Wistar rats: report on memory impairment and formation of amyloid plaques. AB - Amyloid fibrils result from a particular type of protein aggregation, and have been linked with various disorders, including neurodegenerative ones. In the case of Alzheimer's disease, amyloid beta (abeta) fibrils are detected in patients' brain, in the amyloid plaques. These fibrils can be produced in vitro, and their injection into animals' brains generates an animal model of Alzheimer's disease. Based on the structural similarity of amyloid fibrils that are formed from different proteins, we hypothesized that injecting insulin amyloid fibrils into rats' brains could result in amyloid plaque formation. Fourteen male Wistar rats were divided into control and experimental groups (n = 7). The experimental group was bilaterally injected with insulin amyloid in the hippocampus. Seven days after injection, a shuttle box test was performed and the experimental group's memory was found to be impaired. Histological investigation of these rats' brain showed the formation of amyloid plaques in the hippocampus. A limited test has provided preliminary evidence for the stability of these plaques up to 35 days. Further complementary studies are required to fully validate the proposed procedure, which is simple and relatively low cost, and could be suggested as an alternative to models generated with abeta fibrils. PMID- 25787812 TI - Total knee replacement pre-operative education in a Singapore tertiary hospital: A best practice implementation project. AB - OBJECTIVES: To increase the competency of specialist outpatient clinic nurses in the provision of pre-operative total knee replacement (TKR) education, and ensure that all patients scheduled for elective TKR received the pre-operative education package. METHODS: The project was implemented in three phases. Phase 1 entailed a baseline audit that analysed 30 randomized TKR patients who received pre operative education. In Phase 2, the gaps and barriers in the project were discussed. Using best practice recommendations from the Joanna Briggs Institute, the project team leader collated and standardized the pre-operative education tools, which consisted of a pictorial booklet, a video and home care advice. A teaching plan guided the nurses to increase their understanding and improve practice using the education tools. The usefulness of education strategies and tools was discussed and these were improved over the proposed timeline. Phase 3 entailed a post-implementation audit to evaluate the provision of pre-operative education. RESULTS: Post implementation, nurses' competency in the provision of pre-operative TKR education increased from 18% to 91%. The number of patients who received the structured pre-operative education package increased from 27% to 50%. CONCLUSION: Overall, there was improvement in the provision of pre-operative TKR education to patients by clinic nurses using evidence-based best practice and a standardized education package. PMID- 25787813 TI - A case study from a nursing and occupational therapy perspective - Providing care for a patient with a traumatic brachial plexus injury. AB - This paper presents a case study that demonstrates how collaborative working between professionals enhanced the holistic care for a patient following a traumatic brachial plexus injury. The paper will describe the patient's journey of care from initial presentation, diagnosis and assessment, acute care provision, discharge & rehabilitation to ongoing supportive counselling. The care encompasses input from both a nursing and occupational therapy perspective. PMID- 25787814 TI - Improving the experience of hip fracture care: A multidisciplinary collaborative approach to implementing evidence-based, person-centred practice. AB - BACKGROUND: Hip fracture care is well supported by national guidelines and audit that provide evidence of safe interventions and an improved process. In the drive for organisational efficiency, complications have been reduced and length of stay shortened. Prioritising targets and performance alone can lead to poor multidisciplinary communication that potentially omits the psychosocial needs of older people recovering from hip fracture. AIM: To explore a multidisciplinary collaborative approach to implementing evidence-based, person-centred hip fracture care. DESIGN: Collaborative inquiry. METHODS: Sixteen clinical leaders (n = 16) from different disciplines, working with older people with hip fracture at different stages of the care pathway participated in eight two-hourly facilitated action meetings. Data collection included strengths and limitations of the present service, values clarification, clinical stories, review of case records and reflections on the stories of three older people and two carers. RESULTS: Hip fracture care was driven by service pressures, guidelines and audits. The care journey was divided into service delivery units. Professional groups worked independently resulting in poor communication. Time away from practice enabled collaboration and the sharing of different perspectives. CONCLUSIONS: Working together improved communication and enhanced understanding of the whole care experience. IMPLICATIONS FOR PRACTICE: Enabling teams to find evidence of safe, effective person-centred cultures requires facilitated time for reflective practice. PMID- 25787815 TI - Physical health problems experienced in the early postoperative recovery period following total knee replacement. AB - BACKGROUND: The length of stay in hospital following total knee replacement is markedly shortened due to fast-track programmes. Patients have to be responsible for their recovery at a very early stage. The aim of this study was to investigate the prevalence of physical health problems and the level of exercising in the early recovery period after discharge from hospital following total knee replacement. METHOD: A cross-sectional survey was conducted using a questionnaire. A total of 86 patients were included following first-time elective total knee replacement. Descriptive statistics were used. RESULTS: The majority of the patients experienced leg oedema (90.7%). Secondary to this were pain (81.4%), sleeping disorders (47.7%) problems with appetite (38.4%) and bowel function (34.9%) were the most frequently identified physical health problems. In total, 69.8% of the patients indicated that they did not exercise or only partly exercise as recommended, but without associated experience of pain. CONCLUSION: Patients experienced a wide range of physical health problems following total knee replacement and deviation from recommended self-training was identified. These findings are valuable for health professionals in regard to improve treatment as well as patient education and information. PMID- 25787816 TI - Anti-embolic stockings for the prevention of VTE in orthopaedic patients: A practice update. PMID- 25787817 TI - A day in the life of orthopaedic and trauma practitioners: Orthopaedic Nurse Practitioner - Hip Fracture. PMID- 25787821 TI - Circulating serum miRNAs as potential biomarkers for nephroblastoma. AB - BACKGROUND: Nephroblastoma (or Wilms tumor-WT) is the most common childhood kidney cancer. In Europe, nephroblastoma is treated with preoperative chemotherapy without histological confirmation by biopsy. Therefore, minimal invasive diagnostic markers confirming nephroblastoma diagnosis are highly warranted. PROCEDURE: In our study, we aim to identify circulating miRNAs with diagnostic potential for differentiating nephroblastoma from controls. We determined the level of 19 miRNAs in serum of 32 patients with nephroblastoma and 12 controls with quantitative real-time PCR. Three miRNAs were further tested in an independent validation set including sera of patients with renal tumors other than Wilms. RESULTS: In total, 14 miRNAs showed significantly higher abundance in serum of patients with nephroblastoma than in controls. The miRNAs with highest diagnostic potentials included miRs-130b-3p, -100-5p, and -143-3p with an AUC of 0.94, 0.90, and 0.89, respectively. A signature based on these three miRNAs to differentiated patients from controls with an accuracy of 84.58%, a sensitivity of 76.67%, and a specificity of 92.5%. Higher expression of miRs-100-5p and -130b 3p was confirmed in an independent validation set. The signature based on miRs 100-5p and -130b-3p differentiated patients with nephroblastoma from healthy controls with an accuracy, sensitivity, and specificity of 79.6%, 69.2%, and 90.0%, respectively. CONCLUSION: In summary, we provide first evidence that serum miR-100-5p and -130b-3p hold potential as biomarker for WT irrespective of the subtype and that expression level of these miRNA in serum is unaffected by differences in serum collection. PMID- 25787822 TI - Educational awareness of biotechnology issues among undergraduate students at the United Arab Emirates University. AB - Due to its valuable benefits and potential risks, there is a progressing debate among opponents and proponents of biotechnology in recent decades. Previous studies have shown that lack of knowledge about biotechnology remains the concern about genetically modified organisms/food (GMO/GMF). This study assessed levels of educational awareness perceptions and attitudes of United Arab Emirates University (UAEU) students towards biotechnology. An electronic survey including literacy, environmental, social, and economic domains associated with biotechnology was administered to obtain data from undergraduate students in different colleges of the university. Responses from students (n = 1,104) were gathered and statistically analyzed. Results indicated that educational awareness in biotechnology literacy and environmental domains were significantly different according to the enrolled college and the academic achievement of the student. In general, a poor overall performance of our students' understanding was concluded. Aware groups most likely accepted accurate biotechnology information delivered by reliable sources from internet or lectures; they grasped their knowledge from surrounding people as a secondary source. Since UAEU students have several concept misunderstandings of biotechnology and its ethics, our results suggest that awareness plays a crucial role in forming a "clear-cut" opinion about this technology. Because education can shape public attitudes toward biotechnology, priorities on university curricula and teaching strategies should be extensively given, and therefore, improve in respect to this topic. Ultimately, this promotes the students' perception in understanding the new technology. PMID- 25787823 TI - When cationic cell-penetrating peptides meet hydrocarbons to enhance in-cell cargo delivery. AB - Cell-penetrating peptides (CPPs) are short sequences often rich in cationic residues with the remarkable ability to cross cell membranes. In the past 20 years, CPPs have gained wide interest and have found numerous applications in the delivery of bioactive cargoes to the cytosol and even the nucleus of living cells. The covalent or non-covalent addition of hydrocarbon moieties to cationic CPPs alters the hydrophobicity/hydrophilicity balance in their sequence. Such perturbation dramatically influences their interaction with the cell membrane, might induce self-assembling properties and modifies their intracellular trafficking. In particular, the introduction of lipophilic moieties changes the subcellular distribution of CPPs and might result in a dramatically increase of the internalization yield of the co-transported cargoes. Herein, we offer an overview of different aspects of the recent findings concerning the properties of CPPs covalently or non-covalently associated to hydrocarbons. We will focus on the impact of the hydrocarbon moieties on the delivery of various cargoes, either covalently or non-covalently bound to the modified CPPs. We will also provide some key elements to rationalize the influence of the hydrocarbons moieties on the cellular uptake. Furthermore, the recent in vitro and in vivo successful applications of acylated CPPs will be summarized to provide a broad view of the versatility of these modified CPPs as small-molecules and oligonucleotides vectors. PMID- 25787825 TI - Investigation into the Effects of Boron on Liver Tissue Protein Carbonyl, MDA, and Glutathione Levels in Endotoxemia. AB - Endotoxin has been known to cause the formation and damage of free radical. The importance of boron for human life is increasing each passing day, and its consuming fields are continuing to expand due to the advances in science and technology. Therefore, in our study, we intended to investigate into the effects of boron on liver tissue oxidative events. Eighteen male Wistar albino rats were randomly separated into three equal groups in the experiments; control group, boron + endotoxin group, and endotoxin group. Dissolved in distilled water, boric acid (100 mg/kg) was administered to boron + endotoxin group via gavage procedure for 28 days. Only distilled water was administered to control and endotoxin groups via gavage procedure for 28 days. Then 4 mg/kg endotoxin (LPS; Escherichia coli 0111:B4) was intraperitoneally (ip) administered to boron + endotoxin and endotoxin groups on the 28th day. Sterile saline was injected into control group on the 28th day (ip). Malondialdehyde (MDA), which is the end product of lipid peroxidation in liver tissues, protein carbonyl compounds (PC), which are protein oxidization markers, and glutathione (GSH) levels were measured spectrophotometrically. The results were compared with Mann-Whitney U test. When boron + endotoxin group is compared with endotoxin group, PC levels of endotoxin group showed a significant increase. When GSH levels are compared, GSH level in boron + endotoxin group decreased according to endotoxin group. Variations among all groups in MDA levels were found to be statistically insignificant. We are of the opinion that endotoxin affects the proteins by forming free radicals, and boron may also cause the structural and/or functional changes in proteins in order to protect proteins from oxidization. PMID- 25787824 TI - Behavioral momentum and accumulation of mass in multiple schedules. AB - Behavioral momentum theory suggests that the relation between a discriminative stimulus situation and reinforcers obtained in that context (i.e., the Pavlovian stimulus-reinforcer relation) governs persistence of operant behavior. Within the theory, a mass-like aspect of behavior has been shown to be a power function of predisruption reinforcement rates. Previous investigations of resistance to change in multiple schedules, however, have been restricted to examining response persistence following protracted periods of stability in reinforcer rates within a discriminative situation. Thus, it is unclear how long a stimulus-reinforcer relation must be in effect prior to disruption in order to affect resistance to change. The present experiment examined resistance to change of pigeon's key pecking following baseline conditions where reinforcer rates that were correlated with discriminative-stimulus situations changed. Across conditions, one multiple schedule component arranged either relatively higher rates or lower rates of variable-interval food delivery, while the other component arranged the opposite rate. These schedules alternated between multiple-schedule components across blocks of sessions such that reinforcer rates in the components were held constant for 20, 5, 3, 2, or 1 session(s) between alternations. Resistance to extinction was higher in the component that most recently was associated with higher rates of food delivery in all conditions except when schedules alternated daily or every other day. These data suggest that resistance to change in multiple schedules is related to recently experienced reinforcer rates but only when multiple-schedule components are associated with specific reinforcer rates for several sessions. PMID- 25787826 TI - Comparison of Before and After Varicocelectomy Levels of Trace Elements, Nitric Oxide, Asymmetric Dimethylarginine and Malondialdehyde in the Seminal Plasma and Peripheral and Spermatic Veins. AB - Increased oxidative damage has been suggested to play an important role in the spermatogenesis and sperm function changes in patients with varicocele. However, changes in levels of nitric oxide (NO), asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), iron (Fe), zinc (Zn) and copper (Cu) in blood and seminal plasma, and semen quality, are unknown. The aim of this study was to investigate the NO, ADMA, Fe, Cu, Zn and MDA levels from seminal plasma and peripheral and spermatic vein blood samples of patients with varicocele before and after varicocelectomy. In this before and after comparative study, 29 consecutive patients attending a training hospital in Tekirdag, Turkey, were recruited. MDA and NO levels were determined by spectrophotometric methods. The levels of ADMA were determined by enzyme-linked immunosorbent assay method. Trace element level was determined by atomic absorption spectrophotometric method. The levels of MDA in the seminal plasma and peripheral and spermatic vein samples were observed to decrease significantly in the comparison of before and after phases of the study group (p = 0.022, p = 0.001 and p = 0.034, respectively). Also, the levels of NO in the seminal plasma and spermatic vein samples decreased significantly in the comparison of before and after phases of the study group (p = 0.025 and p = 0.001, respectively), while the levels of ADMA in seminal plasma and spermatic vein samples increased significantly in the comparison of before and after phases of the study group (p = 0.003 and p = 0.001, respectively). There were no significant differences in the levels of trace elements and sperm count (p > 0.05). Oxidative stress is significantly higher in the spermatic vein and seminal plasma samples of patients with varicocele before varicocelectomy. In conclusion, these events may be evaluated accordingly for the potentially beneficial treatment methods. PMID- 25787827 TI - The Circulating Levels of Selenium, Zinc, Midkine, Some Inflammatory Cytokines, and Angiogenic Factors in Mitral Chordae Tendineae Rupture. AB - Chordae tendineae rupture process is associated with increased production of inflammatory and angiogenesis mediators in connective tissues, which contributes to chronic inflammation and pathogenesis of degenerative chordae. A few trace elements are known to possess antioxidant, anti-inflammatory, and antiangiogenic properties. Therefore, the aim of this study was to determine whether zinc, selenium, midkine (MK), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor-A (VEGF-A), platelet-derived growth factor-BB (PDGF BB), and reduced glutathione (GSH) levels are associated with inflammation and angiogenesis processes in the context of a potential etiology causing aggravation of mitral regurgitation and/or ruptured chordae tendineae. Seventy-one subjects comprising 34 patients with mitral chordae tendineae rupture (MCTR) and 37 healthy controls diagnosed on the basis of their clinical profile and transthoracic echocardiography were included in this study. The levels of GSH, MK, selenium, and zinc were found to be lower in the patients group when compared to control group. There were no significant difference in plasma TNF-alpha, IL 1beta, IL-6, IL-8, VEGF-A, and PDGF-BB levels between two groups. There were positive significant correlations between MK and GSH, MK, and selenium levels in patients with MCTR. According to our data in which selenium, zinc, MK, and GSH decreased in MCTR patients, inflammatory response, oxidative stress, and trace element levels may contribute to etiopathogenesis of mitral regurgitation and/or ruptured chordae tendineae. PMID- 25787828 TI - Resilience in adults with cancer: development of a conceptual model. AB - OBJECTIVE: Resilience is a construct addressed in the psycho-oncology literature and is especially relevant to cancer survivorship. The purpose of this paper is to propose a model for resilience that is specific to adults diagnosed with cancer. METHODS: To establish the proposed model, a brief review of the various definitions of resilience and of the resilience literature in oncology is provided. RESULTS: The proposed model includes baseline attributes (personal and environmental) which impact how an individual responds to an adverse event, which in this paper is cancer-related. The survivor has an initial response that fits somewhere on the distress-resilience continuum; however, post-cancer experiences (and interventions) can modify the initial response through a process of recalibration. CONCLUSIONS: The literature reviewed indicates that resilience is a common response to cancer diagnosis or treatment. The proposed model supports the view of resilience as both an outcome and a dynamic process. Given the process of recalibration, a discussion is provided of interventions that might facilitate resilience in adults with cancer. PMID- 25787829 TI - Stage III pancreatic cancer and the role of irreversible electroporation. AB - About a third of patients with pancreatic cancer present with locally advanced disease that is not amenable to resection. Because these patients have localized disease, conventional ablative therapies (thermal ablation and cryoablation) have the potential to be beneficial, but their use is inherently limited in the pancreas. These limitations could be overcome by irreversible electroporation-a novel, non-thermal ablative method that is gaining popularity for the treatment of many soft tissue tumors, including those of the pancreas. This review summarizes the status of this technique in the treatment of locally advanced pancreatic cancer. Most of the evidence on efficacy and safety is based on non randomized prospective series, which show that irreversible electroporation may improve overall survival and pain control in locally advanced pancreatic cancer. As experience with this procedure increases, randomized controlled trials are needed to document its efficacy in locally advanced pancreatic cancer more precisely. PMID- 25787830 TI - Endoscopic findings and lesion distribution in amebic colitis. AB - A retrospective cohort study was conducted in 55 symptomatic patients with amebic colitis that visited at St. Luke's International Hospital and Mie University Hospital from 1994 through 2013. To diagnose amebic colitis, 40 patients underwent total colonoscopy within 1 week after hospital visiting and before receiving any treatment. The percentage of characteristic endoscopic findings of amebic colitis including discrete ulcers or erosions with white or yellow exudates were 0% in terminal ileum, 93% in cecum, 28% in ascending, 25% in transverse, 15% in descending, 20% in sigmoid colon and 45% in rectum. The rectal lesions in 55% of patients with amebic colitis were nonspecific. The trophozoite identification rate by direct smear of intestinal tract washings performed during colonoscopy was 88%. The protozoan identification rate was 70% in biopsy specimens taken from the periphery of the characteristic discrete ulcers. Total colonoscopy should be considered for the diagnosis of amebic colitis. PMID- 25787831 TI - Vestibular evaluation in children with otitis media with effusion. AB - BACKGROUND: Fifty per cent of children with serous otitis media may have some balance disturbances. OBJECTIVE: To evaluate vestibular function in children with otitis media with effusion. METHODS: The control group comprised 25 children with bilateral normal hearing and middle-ear function. The study group consisted of 30 children with bilateral otitis media with effusion; these were divided into 2 subgroups according to air-bone gap size. Measures included the Arabic Dizziness Handicap Inventory, an imbalance evaluation sheet for children, vestibular bedside tests for children, and air- and bone-conducted vestibular-evoked myogenic potential testing. RESULTS: Arabic Dizziness Handicap Inventory scores and some vestibular bedside test results were significantly abnormal, with normal video-nystagmography results, in children with otitis media with effusion. Air conducted vestibular-evoked myogenic potentials were recorded in 73 per cent of children with otitis media with effusion, with significantly delayed latencies. Bone-conducted vestibular-evoked myogenic potentials were successfully detected in 100 per cent of children with otitis media with effusion with similar results to the control group. CONCLUSION: The Arabic Dizziness Handicap Inventory and vestibular bedside tests are valuable tools for detecting vestibular impairment in children. Bone-conducted vestibular-evoked myogenic potentials are useful for vestibular system evaluation. PMID- 25787834 TI - Electrical device for patients with glioblastoma met with support, skepticism: some question the device's efficacy, others tout it as a new standard of care. PMID- 25787833 TI - Validation of High-Resolution Tractography Against In Vivo Tracing in the Macaque Visual Cortex. AB - Diffusion magnetic resonance imaging (MRI) allows for the noninvasive in vivo examination of anatomical connections in the human brain, which has an important role in understanding brain function. Validation of this technique is vital, but has proved difficult due to the lack of an adequate gold standard. In this work, the macaque visual system was used as a model as an extensive body of literature of in vivo and postmortem tracer studies has established a detailed understanding of the underlying connections. We performed probabilistic tractography on high angular resolution diffusion imaging data of 2 ex vivo, in vitro macaque brains. Comparisons were made between identified connections at different thresholds of probabilistic connection "strength," and with various tracking optimization strategies previously proposed in the literature, and known connections from the detailed visual system wiring map described by Felleman and Van Essen (1991; FVE91). On average, 74% of connections that were identified by FVE91 were reproduced by performing the most successfully optimized probabilistic diffusion MRI tractography. Further comparison with the results of a more recent tracer study ( Markov et al. 2012) suggests that the fidelity of tractography in estimating the presence or absence of interareal connections may be greater than this. PMID- 25787835 TI - Quality of life in patients with high-risk prostate cancer improves with shorter course of androgen deprivation therapy. PMID- 25787832 TI - Molecular and Electrophysiological Characterization of GABAergic Interneurons Expressing the Transcription Factor COUP-TFII in the Adult Human Temporal Cortex. AB - Transcription factors contribute to the differentiation of cortical neurons, orchestrate specific interneuronal circuits, and define synaptic relationships. We have investigated neurons expressing chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which plays a role in the migration of GABAergic neurons. Whole-cell, patch-clamp recording in vitro combined with colocalization of molecular cell markers in the adult cortex differentiates distinct interneurons. The majority of strongly COUP-TFII-expressing neurons were in layers I-III. Most calretinin (CR) and/or cholecystokinin- (CCK) and/or reelin positive interneurons were also COUP-TFII-positive. CR-, CCK-, or reelin-positive neurons formed 80%, 20%, or 17% of COUP-TFII-positive interneurons, respectively. About half of COUP-TFII-/CCK-positive interneurons were CR-positive, a quarter of them reelin-positive, but none expressed both. Interneurons positive for COUP TFII fired irregular, accommodating and adapting trains of action potentials (APs) and innervated mostly small dendritic shafts and rarely spines or somata. Paired recording showed that a calretinin-/COUP-TFII-positive interneuron elicited inhibitory postsynaptic potentials (IPSPs) in a reciprocally connected pyramidal cell. Calbindin, somatostatin, or parvalbumin-immunoreactive interneurons and most pyramidal cells express no immunohistochemically detectable COUP-TFII. In layers V and VI, some pyramidal cells expressed a low level of COUP TFII in the nucleus. In conclusion, COUP-TFII is expressed in a diverse subset of GABAergic interneurons predominantly innervating small dendritic shafts originating from both interneurons and pyramidal cells. PMID- 25787836 TI - Analysis shows CT lung cancer screening is cost effective. PMID- 25787839 TI - Tribute to Markku O. Rasanen. PMID- 25787838 TI - Divalent cations and molecular crowding buffers stabilize G-triplex at physiologically relevant temperatures. AB - G-triplexes are non-canonical DNA structures formed by G-rich sequences with three G-tracts. Putative G-triplex-forming sequences are expected to be more prevalent than putative G-quadruplex-forming sequences. However, the research on G-triplexes is rare. In this work, the effects of molecular crowding and several physiologically important metal ions on the formation and stability of G triplexes were examined using a combination of circular dichroism, thermodynamics, optical tweezers and calorimetry techniques. We determined that molecular crowding conditions and cations, such as Na(+), K(+), Mg(2+) and Ca(2+), promote the formation of G-triplexes and stabilize these structures. Of these four metal cations, Ca(2+) has the strongest stabilizing effect, followed by K(+), Mg(2+), and Na(+) in a decreasing order. The binding of K(+) to G triplexes is accompanied by exothermic heats, and the binding of Ca(2+) with G triplexes is characterized by endothermic heats. G-triplexes formed from two G triad layers are not stable at physiological temperatures; however, G-triplexes formed from three G-triads exhibit melting temperatures higher than 37 degrees C, especially under the molecular crowding conditions and in the presence of K(+) or Ca(2+). These observations imply that stable G-triplexes may be formed under physiological conditions. PMID- 25787840 TI - Autobiography of Markku O. Rasanen. PMID- 25787844 TI - Association between plasma leptin and adiponectin levels and diastolic function in the general population. AB - BACKGROUND: Total and visceral obesity are associated with subclinical diastolic dysfunction (DD) and heart failure. Adipose tissue is an endocrine organ able to secrete adipokines involved in several obesity-associated diseases. We aimed to evaluate the association between leptin and adiponectin levels and diastolic function. METHODS AND RESULTS: Within a population-based study (EPIPorto), 556 individuals were evaluated. DD was assessed by echocardiography, using tissue Doppler analysis (early diastolic E' velocity and E/E', the ratio between E wave velocity of transmitral flow and E' velocity), according to consensus recommendations. Patients with DD had significantly higher leptin, but similar adiponectin levels. Patients in the highest leptin tertile had lower E' velocity and an increased E/E' ratio (p < 0.01). The association between leptin and DD was sex-specific. After multivariate adjustment, women in the highest leptin tertile had an increased risk of DD (adjusted odds ratio: 3.06; 95% CI: 1.44 - 6.49). Adiponectin levels were not significantly associated with increased risk of DD in both men and women. CONCLUSIONS: Higher leptin levels were independently associated with DD, especially in women. Secretion of leptin can be involved in the association between obesity, DD and heart failure risk. Future studies will determine if the inhibition of leptin can improve diastolic function. PMID- 25787843 TI - Contribution of susceptibility variants at FCGR2A and 13q12 to the risk of relapse among Japanese patients with ulcerative colitis. AB - BACKGROUND: Recent genome-wide association studies have identified nearly 100 susceptibility genes for ulcerative colitis (UC). However, the contribution of susceptibility variants for UC to clinical outcome has scarcely been reported. The aim of this study was to investigate whether UC-associated genetic variants confer a risk of clinical relapse. METHODS: One hundred and nine consecutive Japanese subjects with quiescent UC were recruited. Four genetic variants of HLA DRB1*1502, rs6671847 at FCGR2A, rs17085007 at 13q12, and rs2108225 at SLC26A3 were genotyped by Invader assay. The clinical courses were followed after blood sampling, and the risk of relapse according to these genotypes was calculated by Cox proportional hazard model. RESULTS: During the mean follow-up period of 35 months (range 1-81 months), 49 of 109 subjects (45 %) relapsed. Carriers of the G allele of rs6671847 showed an increased risk of relapse compared with non carriers [adjusted hazard ratio (HR), 2.27; 95 % confidence interval (CI), 1.20 4.32; p = 0.01]. Patients with the CT or TT genotypes of rs17085007 also had an increased risk of relapse compared to subjects with the CC genotype (for CT: adjusted HR, 2.16; 95 % CI, 1.10-4.23; p = 0.03; for TT: adjusted HR, 3.25; 95 % CI, 1.18-8.95; p = 0.02). These two risk variants multiplied the risk of relapse by 2.74 times (95 % CI, 1.10-4.23; p = 0.01) in patients with one risk genotype and 5.40 times (95 % CI, 2.06-14.13; p = 0.0006) in patients with both risk genotypes. CONCLUSIONS: Genetic variants of rs6671847 at FCGR2A and rs17085007 at 13q12 conferred a risk of relapse in patients with UC. PMID- 25787845 TI - Subjective quality of life of those 65 years and older experiencing dementia. AB - BACKGROUND/OBJECTIVES: To describe how people experiencing dementia define quality of life and how this may be supported. DESIGN: Qualitative descriptive component of mixed methods cross-sectional study. SETTING: Western Canadian community (4-h weekly care minimum), supportive housing (24-h support/supervision), personal care homes (24-h nursing). PARTICIPANTS: One hundred and thirty-six persons aged 65+ experiencing dementia. MEASUREMENTS: Semi structured interview questions. Rating of meeting life's goals. RESULTS: Participants characterised quality of life as: freedom, independence, having basic needs met, physical health, engagement in meaningful activities and tranquility. A need for self-determination/choice was evidenced across all domains. Increased access to skilled nursing care, support for meaningful engagement with family and meeting life's goals were endorsed as adding most to quality of life; 43% reported meeting all life's major goals. CONCLUSION: People experiencing dementia may have better quality of life when choice/self determination is supported. Enhancements in care environment, independence, engagement and meeting of life's goals merit urgent attention. PMID- 25787847 TI - Immune thrombocytopenic purpura: new biological therapy of an old disease. AB - Immune Thrombocytopenic Purpura (ITP) is the most common autoimmune disorder that is caused by antibody- mediated destruction of thrombocytes and impaired megakaryocyte platelet production. ITP remains a diagnosis of exclusion. Recent pathophysiologic mechanisms and therapeutical approaches of ITP have emerged. Although steroids and intravenous immunglobulins (IVIg) have still been the main therapeutic strategies, a group of patients develop resistance to those eventually and there have been some biological treatment options such as rituximab especially in the last decade. In this review article, we have summarized the therapeutic options for patients with ITP and mainly focused on the timing and potential effects of biological agents. PMID- 25787846 TI - Environmental Justice and Community-Based Research in Texas Borderland Colonias. AB - OBJECTIVE: An innovative academic-community partnership studied daily decisions in communities of mostly Spanish-speaking, low-income residents of colonias in Hidalgo County, TX, about risk of exposure to fish contaminated by PCBs at an Environmental Protection Agency (EPA) Superfund site. DESIGN AND SAMPLE: The team used focus group interviews with colonia residents and content analysis to assess knowledge of risk related to the Superfund site, the Donna Reservoir and Canal System. RESULTS: (1) many lacked knowledge of the Superfund site contamination; (2) a few participants fished at the lake, knew people who did so, and consumed the catch, but most participants feared going there; (3) some participants remember receiving messages saying not to fish at the site, although they recalled nothing about contamination, but most participants knew of no such messages; (4) many use cell phones to get local information through personal networks and several Spanish-language news sources, but they have no consistent, culturally tailored local information source. CONCLUSIONS: The findings indicate the need for further efforts to design culturally tailored means of communication and messages to inform local communities widely about the dangers related to the Superfund site and thus decrease health disparities resulting from consuming fish from the site. PMID- 25787848 TI - Gender differences in salivary alpha-amylase and attentional bias towards negative facial expressions following acute stress induction. AB - This study investigated gender differences in two key processes involved in anxiety, arousal and attentional bias towards threat. Arousal was assessed using salivary alpha-amylase (sAA), a biomarker of noradrenergic arousal and attention bias using a dot-probe task. Twenty-nine women and 27 men completed the dot-probe task and provided saliva samples before and after a stress induction [cold pressor stress (CPS) test]. Women displayed a significant increase in arousal (sAA) following the stressor compared to men, who displayed a significant reduction in arousal. Reaction time data revealed a significant avoidance of threat in women at baseline, but a significant change to an attention bias towards threat following the stressor. Men did not significantly respond to the stressor in terms of attentional bias. These findings suggest that women are more reactive to a stressor than men, and display an initial avoidance response to threat, but an attentional bias towards threat following stress. PMID- 25787849 TI - Pathological findings of hemorrhagic bowel syndrome (HBS) in six dairy cattle cases. AB - Six adult dairy cows clinically diagnosed as hemorrhagic bowel syndrome (HBS) were the subjects of this study. The involved intestinal lesions were fixed in formalin and examined macroscopically and histopathologically. Pathological examinations revealed large intramural hematomas with necrotic foci, resulting in luminal obstruction. The mucosal layer in the lesions was detached from the intestinal wall, and there were no hemorrhagic changes in the lumen. The intramural hematomas were sometimes covered with histologically intact mucosal layer. These pathological findings were not consistent with those of "intraluminal blood clots" reported previously. Gram-positive and anti Clostridium antibody-positive short bacilli were found in hemorrhagic necrotic areas. However, the exact relationship between Clostridium spp. observed in the lesions and HBS remains unclear, because this bacterium is a normal inhabitant in cattle. PMID- 25787850 TI - A globotetraosylceramide (Gb4) receptor-based ELISA for quantitative detection of Shiga toxin 2e. AB - Currently, no simple assays are available for routine quantitative detection of Escherichia coli-produced Shiga toxin 2e (Stx2e) that causes porcine edema disease. Here, we present a novel quantitative detection method for Stx2e based on the measurement of Stx2e binding to the specific globotetraosylceramide (Gb4) receptor by ELISA (Gb4-ELISA). No cross-reactivity was found with the other Shiga toxins Stx1 and Stx2, indicating high specificity. When the recombinant Stx2e B subunit (Stx2eB) was used, the absorbance measured by Gb4-ELISA increased linearly with Stx2eB concentration in the range of 20-2,500 ng/ml. The Gb4-ELISA method can be easily performed, suggesting that it would be a useful diagnostic tool for porcine edema disease. PMID- 25787851 TI - Decline in admissions for childhood asthma, a 26-year period population-based study. AB - BACKGROUND: The prevalence of childhood asthma has increased, although the rate of hospitalization for asthma seems to decrease. In Norway, the rate of hospital admission for childhood asthma from 1984 to 2000 increased. The aim of this study was to assess further trends in hospital admissions for childhood asthma up to 2010. METHODS: A population-based study including children 1-13 yrs of age hospitalized for asthma during six periods from 1984/1985 to 2009/2010 in Rogaland, Norway, was performed. Medical records from 1536 admissions (1050 children) were studied; and gender, age, number of admissions, length of hospital stay, medications and symptoms were recorded. RESULTS: For all age groups, the rate of admissions per 10.000 increased from 20.1 in 1984/85 to 33.7 in 1989/90, but declined to 14.4 in 2009/2010. Rates were highest in boys (OR 1.87; 95% CI: 1.69, 2.09), younger age groups (OR 2.51; 2.38, 2.64) and decreased from 1984 to 2010 (OR 0.92; 0.88, 0.94). The rates of readmissions were higher than for primary admissions (OR 1.33; 1.19, 1.47). From 1984 to 2010, there was an increased use of inhaled corticosteroids prior to admission (6 to 51%) and started at discharge (7 to 37%), and systemic steroids given during admission (19 to 83%). CONCLUSION: There has been a substantial decline in the rate of hospital admissions for childhood asthma after 1989/1990, with major differences between age groups and genders. The decline could be due to improved care of children with asthma or a real reduction in asthma exacerbations. PMID- 25787852 TI - Simultaneous effects of surface spins: rarely large coercivity, high remanence magnetization and jumps in the hysteresis loops observed in CoFe2O4 nanoparticles. AB - Well-dispersed uniform cobalt ferrite nanoparticles were synthesized by thermal decomposition of a metal-organic salt in organic solvent with a high boiling point. Some of the nanoparticles were diluted in a SiO2 matrix and then the undiluted and diluted samples were characterized and their magnetic behavior explored. The undiluted and diluted samples exhibited maximum coercivity Hc of 23,817 and 15,056 Oe at 10 K, respectively, which are the highest values reported to date, and the corresponding ratios of remanence (Mr) to saturation (Ms) magnetization (Mr/Ms) were as high as 0.85 and 0.76, respectively. Interestingly, the magnetic properties of the samples changed at 200 K, which was observed in magnetic hysteresis M(H) loops and zero-field cooling curves as well as the temperature dependence of Hc, Mr/Ms, anisotropy, dipolar field, and the magnetic grain size. Below 200 K, both samples have large effective anisotropy, which arises from the surface spins, resulting in large Hc and Mr/Ms. Above 200 K, the effective anisotropy decreases because there is no contribution from surface spins, while the dipolar interaction increases, resulting in small Hc and Mr/Ms. Our results indicate that strong anisotropy and weak dipolar interaction tend to increase Hc and Mr/Ms, and also clarify that the jumps around H = 0 in M(H) loops can be attributed to the reorientation of surface spins. This work exposes the underlying mechanism in nanoscale magnetic systems, which should lead to improved magnetic performance. PMID- 25787853 TI - Perspectives on 2014 Nobel Prize. AB - In celebration of the 2014 Nobel Prize in Physiology or Medicine, this issue of Hippocampus includes a collection of commentaries from a broad range of perspectives on the significance of position coding neurons in the hippocampal region. From the perspective of this student of hippocampal physiology, it is argued that place cells and grid cells reflect the outcome of experiments that strongly select the information available and correspondingly observe singular "trigger features" of these neurons. Notably, however, in more naturalistic situations where multiple dimensions of information are available, hippocampal neurons have mixed selectivity wherein population-firing patterns reflect the organization of many features of experience. Thus, while discoveries on position coding were major breakthroughs in penetrating the hippocampal code, future studies exploring more complex behaviors hold the promise of revealing the full contribution of the hippocampal region to cognition and memory. PMID- 25787854 TI - Potential synergistic effects of human placental extract and minoxidil on hair growth-promoting activity in C57BL/6J mice. AB - BACKGROUND: Human placenta extract (HPE) has been used to alleviate tiredness and promote wound healing, and for its antiageing functions; however, it has not yet been studied for its effects on hair growth. In the present study, we evaluated the in vitro effect of HPE on hair growth by observing its actions on human dermal papilla cells (DPCs). AIM: To define how HPE promotes induction of anagen hair growth during the telogen phase, and to understand the synergistic molecular mechanisms of HPE and minoxidil (MXD) actions on hair growth. METHODS: We examined the effects of HPE and MXD on C57BL6/J mice using haematoxylin and eosin staining, quantitative histomorphometry, hair growth scoring, immunohistochemistry and immunofluorescence on the dorsal skins of C57BL/6J mice. RESULTS: We found that HPE synergistically augmented the effects of MXD, a promoter of hair growth. In particular, histomorphometric analysis data indicated that subcutaneous injection of HPE induced an earlier anagen phase and prolonged the anagen phase. It also stimulated increases in both the number and size of hair follicles in groups treated with HPE alone and HPE + MXD. CONCLUSIONS: From our data, we conclude that HPE increases beta-catenin and Wnt3a expression levels. Overall, our findings suggest that HPE in combination with MXD has hair growth-promoting activity and is a potential novel therapeutic treatment for alopecia or baldness in humans. PMID- 25787855 TI - [Drug prescriptions: Adherence and understanding in Madagascar]. AB - Frequently ignored or neglected, poor adherence is an important cause of treatment failure and a major public health problem. We assessed the factors involved in adherence in a hospital in Madagascar. This long-term study evaluated two groups of variables: patients' level of understanding of their disease and drug prescriptions, and the information on the prescription written by the doctor. We interviewed 93 in-patients (mean age: 50 years) and found that 16% were illiterate. Overall, 27% did not know the name of their illness, 34% were unaware of the treatment objectives, and 14% did not understand the drug prescription. On 20% of the prescriptions, the patients' name was not included, and the daily dose information and schedule was omitted from 16%. A day after receiving the prescription, only 64% had purchased the medication and only 53% of all patients had taken any. A correlation was observed between illiteracy, knowledge of the disease/treatment goals, and non-purchase of drugs. The poor quality of information contained in the prescriptions and patients' poor understanding of what they were supposed to do are obvious. Using pre-completed health forms and text messages might improve adherence. PMID- 25787856 TI - Human germline differentiation charts a new course. AB - Understanding the molecular events of reproduction requires a system to differentiate human pluripotent stem cells to germline cells (gametes) in vitro. Such a system is not only critical to unlock the secrets of germline development; it may also allow screening for environmental agents that affect gametogenesis. Two recent papers, one in this issue of TheEMBO Journal, have developed complementary approaches for generating human germline cells with unprecedented efficiency from pluripotent stem cells(Sugawa et al, 2015; Irie et al, 2015). This work illustrates the power and limitations of extrapolating molecular pathways for lineage differentiation from mice to humans and illuminates the importance of using human cell-based models to study reproductive health. PMID- 25787858 TI - Utility of electromyographic fatigue threshold during treadmill running. AB - INTRODUCTION: We investigated 2 different methods for determining muscle fatigue threshold by electromyography (EMG). METHODS: Thirteen subjects completed an incremental treadmill running protocol for EMG fatigue threshold (EMGFT ) determination based on the critical power concept (EMGFT 1) and the breakpoint in the linear relationship between EMG amplitude and exercise intensity (EMGFT 2). Then, both the EMGFT 1 and EMGFT 2 were tested in a continuous treadmill running protocol. EMG was recorded from the rectus femoris (RF), vastus lateralis (VL), biceps femoris (BF), and lateral gastrocnemius (LG) muscles. RESULTS: For BF, EMGFT 2 was higher than EMGFT 1, and EMGFT 1 for BF was lower than EMGFT 1 for LG. EMG of RF was higher at EMGFT 2 than at EMGFT 1, and LG EMG was lower at EMGFT 2. CONCLUSIONS: EMGFT can be determined during a single treadmill running test, and EMGFT 1 may be the most appropriate method to estimate the muscle fatigue threshold during running. PMID- 25787857 TI - Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells. AB - The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12 dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-gamma-secreting CD4(+) T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27 dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses. PMID- 25787859 TI - Design, Synthesis and Biological Evaluation of Imidazo[1,2-a]pyridine Derivatives as Novel DPP-4 Inhibitors. AB - A new series of DPP-4 inhibitors with imidazo[1,2-a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2-benzene ring and pyridine moieties of compound 5a led to the identification of compound 5d with 2, 4 dichlorophenyl group at the 2-position as a potent (IC50 = 0.13 MUm), selective (DPP-8/DPP-4 = 215 and DPP-9/DPP-4 = 192) and in vivo efficacious DPP-4 inhibitor. Further, molecular docking revealed that compound 5d could retain key binding features of DPP-4 with the pyridine moiety of imidazo[1,2-a]pyridine ring providing an additional pi-pi interaction with Phe357 of DPP-4. Compound 5d might be a promising lead for further development of novel DPP-4 inhibitor treating T2DM. PMID- 25787860 TI - Sexually transmitted infections in older adults - raising awareness for better screening and prevention strategies. PMID- 25787861 TI - [Obituary for prof. Dr. Rainer Tolle]. PMID- 25787862 TI - Nasal drug delivery. PMID- 25787863 TI - Current understanding of nasal morphology and physiology as a drug delivery target. AB - The nasal cavity is both a target for locally and systemically acting medications. An adequate treatment for rhinosinusitis continues to be an unmet need. With the recent approval of intranasal medications for the treatment of pain, the nasal cavity continues to be a viable route for rapid uptake into the systemic circulation. Despite the opportunities, there is still a void in the knowledge of how therapeutic entities interact with the nasal epithelium. In addition, new opportunities in mucosal immunity via nasal vaccination as well as the elusive nose to brain uptake continue to drive innovation. To facilitate understanding of the issues involved that facilitate drug delivery in the nose, a review of nasal morphology and physiology is presented. PMID- 25787864 TI - High efficiency intranasal drug delivery using Intravail(r) alkylsaccharide absorption enhancers. AB - A new class of alkylsaccharide transmucosal delivery enhancement agents are described that overcome the principal limitations preventing broad acceptance of intranasal administration for many potential applications in systemic drug delivery, namely, poor transmucosal absorption and damage to the nasal mucosa. This review will describe recent developments in use of these excipients in human clinical trials and preclinical studies along with their chemical and pharmacological properties and explore commercial implications of the use of these excipients in introduction of new intranasal formulations of peptidic and nonpeptidic drugs. PMID- 25787865 TI - CriticalSorbTM: enabling systemic delivery of macromolecules via the nasal route. AB - Systemic delivery of proteins via the nasal route has to date been limited by their poor absorption across the nasal mucosa, and the less than optimal tolerability of known permeation enhancers. We have recently developed a highly effective nasal delivery system (CriticalSorbTM) based on Solutol HS15. Extensive toxicology studies have shown CriticalSorbTM to be very well tolerated, non-toxic and non-irritant. Cell culture and ex vivo-isolated tissue studies have shown it to promote transport of molecules mainly via transcellular but also to some extent, via paracellular routes. Pharmacokinetic/pharmacodynamic studies in rats, rabbits, non-human primates and recently in man have demonstrated significantly enhanced systemic delivery of nasally administered proteins including insulin (~6 kDa) and human growth hormone (~22 kDa), and pharmacodynamics similar to those after subcutaneous injection. CriticalSorbTM therefore opens up the possibility of developing nasal spray formulations for macromolecules such as proteins. PMID- 25787866 TI - Microparticles based on chitosan/pectin polyelectrolyte complexes for nasal delivery of tacrine hydrochloride. AB - The aim of this study was the investigation of powder-based formulations for nasal administration of tacrine hydrochloride. The anti-Alzheimer drug was encapsulated in mucoadhesive microparticles based on chitosan/pectin polyelectrolyte complexes. Microparticles were prepared by means of two different technological approaches (direct spray-drying and spray-drying followed by lyophilization) and analysed in terms of size, morphology and physico-chemical characteristics. Moreover, water uptake and mucoadhesion ability were evaluated as well as drug release and permeation behaviour. The results suggest that lyophilization favours the formation of small particle aggregates with a size of 10 MUm, instead of single particles (size smaller than 5 MUm) such as direct spray-drying. Particles obtained with the two loading methods present different functional properties according to the different physical state of the loaded drug and its possible interaction with chitosan/pectin complex. Moreover, the presence of different amount of chitosan and pectin in the complex influences their ability to hydrate, interact with mucin and favour drug permeation. PMID- 25787867 TI - Nasal delivery of fentanyl. AB - Fentanyl, a potent opioid analgesic, is rapidly and efficiently absorbed from the nasal cavity, giving significant potential for nasally administered fentanyl to be used in pain management. Many reported clinical studies have used nasally administered IV solution, often as drops, which requires high volumes of solution to deliver an effective dose, resulting in insignificant runoff and drip which, in turn, compromises absorption and efficacy. More recently, products have been developed and commercialised with features intended to overcome these drawbacks, notably delivering the dose as a spray in a lower volume of solution and, for one of the products, incorporating an in situ gelling agent with the aim of both reducing runoff/drip and modifying the fentanyl absorption profile. The commercial fentanyl nasal spray products (PecFent/Lazanda and Instanyl) are currently licensed solely for the treatment of breakthrough pain in cancer patients; they have a number of advantages over oral transmucosal (buccal/sublingual) products used in the same indication, including faster onset of action and easier administration, especially in patients suffering from oral cavity disorders associated with cancer treatment. Given the nature of fentanyl, regulatory agencies will expect that appropriate safety features are incorporated into the primary and secondary packaging in products intended for use by patients in the home and may also impose risk management protocols to control the distribution and prescription of controlled substances. These demands notwithstanding, intranasal fentanyl offers much future promise, including for additional indications and paediatric use. PMID- 25787870 TI - Erratum to: Potential of Piperazinylalkylester Prodrugs of 6-Methoxy-2 Naphthylacetic Acid (6-MNA) for Percutaneous Drug Delivery. PMID- 25787868 TI - Clinical translation of RNAi-based treatments for respiratory diseases. AB - The ability to harness the RNA interference (RNAi) mechanism as a potential potent therapeutic has attracted great interest from academia and industry. Numerous preclinical and recent clinical trials have demonstrated the effectiveness of RNAi triggers such as synthetic small interfering RNA (siRNA). Chemical modification and delivery technologies can be utilized to avoid immune stimulation and improve the bioactivity and pharmacokinetics. Local application to the respiratory epithelia allows direct access to the site of respiratory pathogens that include influenza and respiratory syncytial virus (RSV). This review outlines the essential steps required for the clinical translation of RNAi based respiratory therapies including disease and RNA target selection, siRNA design, respiratory barriers, and delivery solutions. Attention is given to antiviral therapies and preclinical evaluation with focus on the current status of anti-RSV clinical trials. PMID- 25787869 TI - Development and Evaluation of Artesunate-Loaded Chitosan-Coated Lipid Nanocapsule as a Potential Drug Delivery System Against Breast Cancer. AB - Artesunate (ART)--a well-known hydrophobic anti-malarial agent was incorporated in a polymer-lipid hybrid nanocolloidal system for anti-cancer therapeutic. The lipid negatively charged nanoemulsion was formulated by modified hot homogenization method then covered with positively charged chitosan via electrostatic interaction to obtain chitosan-coated lipid nanocapsule (ART-CLN). Physical properties of the system were characterized in terms of size, charge, morphology, drug loading capacity, and physical state. In addition, anti-cancer activities were confirmed by conducting MTT assay for ART and ART-CLN on different cancer cell lines. Obtained ART-CLN after coating chitosan revealed positive charge (13.2 +/- 0.87 mV), small particle size (160.9 +/- 3.5 nm), and spherical shape. High drug entrapment efficiency (95.49 +/- 1.13%) and sustained release pattern were observed. Moreover, the good cellular uptake was recorded by flow cytometry as well as confocal image. Finally, ART-CLN exhibited stronger anti-cancer activity than free ART on breast cancer cell lines (MCF-7, MDA-MB 231). These results suggested that by loading ART into lipid core of polymer lipid hybrid carrier, the activity and physical stability of ART can be significantly increased for cancer chemotherapy. PMID- 25787871 TI - Highly Porous Gelatin Reinforced 3D Scaffolds for Articular Cartilage Regeneration. AB - 3D highly porous (93% total porosity) gelatin scaffolds were prepared according to a novel, simple method, which implies gelatin foaming, gelification, soaking into ethanol and successive freeze-drying. Reinforcement of the as-prepared scaffolds (GEL) was performed through immersion in aqueous solutions at different gelatin concentrations. Reinforcement solutions with and without genipin addition allowed to prepare two series of samples:cross-linked and uncross-linked samples, respectively. The amount of gelatin adsorbed onto the reinforced samples increases as a function of gelatin concentration in solution and provokes a drastic improvement of the compressive modulus and collapse strength up to values of about 30 and 4 MPa, respectively. The open and interconnected porosity, although slightly reduced, is still of the order of 80% in the samples reinforced with the highest concentration of gelatin. Water uptake ability evaluated after immersion in PBS for 20 s decreases with gelatin reinforcement. The presence of genipin in cross-linked samples reduces gelatin release and stabilizes the scaffolds in solution. Chondrocytes from human articular cartilage adhere, proliferate, and penetrate into the scaffolds. The evaluation of differentiation markers both on the supernatants of cell culture and by means of quantitative polymerase chain reaction (qPCR) indicates a dose-dependent promotion of cell differentiation. PMID- 25787872 TI - Evaluation of the cytotoxic and antitumour effects of the essential oil from Mentha x villosa and its main compound, rotundifolone. AB - OBJECTIVES: The aim of this study was to investigate the cytotoxic and antitumour effects of the essential oil from the leaves of Mentha x villosa (EOMV) and its main component (rotundifolone). METHODS: In-vitro cytotoxic activity of the EOMV and rotundifolone was determined on cultured tumour cells. In-vivo antitumour activity of the EOMV was assessed in sarcoma 180-bearing mice. KEY FINDINGS: The EOMV displayed cytotoxicity against human tumour cell lines, showing IC50 values in the range of 0.57-1.02 MUg/ml in the HCT-116 and SF-295 cell lines, respectively. Rotundifolone showed weak cytotoxicity against HCT-116, SF-295 and OVCAR-8 cell lines (IC50 > 25.00 MUg/ml). Tumour growth inhibition rates were 29.4-40.5% and 25.0-45.2% for the EOMV treatment by intraperitoneal (50-100 mg/kg/day) and oral (100-200 mg/kg/day) administration, respectively. The EOMV did not significantly affect body mass and macroscopy of the organs. CONCLUSIONS: The EOMV possesses significant antitumour activity with low systemic toxicity, possibly due to the synergistic action of its minor constituents. PMID- 25787874 TI - Sustained Reduction in Health Disparities Achieved through Targeted Quality Improvement: One-Year Follow-up on a Three-Year Intervention. AB - OBJECTIVE: To assess a quality improvement disparity reduction intervention and its sustainability. DATA SOURCES/STUDY SETTING: Electronic health records and Quality Index database of Clalit Health Services in Israel (2008-2012). STUDY DESIGN: Interrupted time-series with pre-, during, and postintervention disparities measurement between 55 target clinics (serving approximately 400,000 mostly low socioeconomic, minority populations) and all other (126) clinics. DATA COLLECTION/EXTRACTION METHODS: Data on a Quality Indicator Disparity Scale (QUIDS 7) of 7 indicators, and on a 61-indicator scale (QUIDS-61). PRINCIPAL FINDINGS: The gap between intervention and nonintervention clinics for QUIDS-7 decreased by 66.7 percent and by 70.4 percent for QUIDS-61. Disparity reduction continued (18.2 percent) during the follow-up period. CONCLUSIONS: Quality improvement can achieve significant reduction in disparities in a wide range of clinical domains, which can be sustained over time. PMID- 25787875 TI - Anti-laminin gamma1 pemphigoid associated with ulcerative colitis and psoriasis vulgaris showing autoantibodies to laminin gamma1, type XVII collagen and laminin 332. PMID- 25787876 TI - Misunderstanding the meaning of resilience. PMID- 25787873 TI - Carnitine in bacterial physiology and metabolism. AB - Carnitine is a quaternary amine compound found at high concentration in animal tissues, particularly muscle, and is most well studied for its contribution to fatty acid transport into mitochondria. In bacteria, carnitine is an important osmoprotectant, and can also enhance thermotolerance, cryotolerance and barotolerance. Carnitine can be transported into the cell or acquired from metabolic precursors, where it can serve directly as a compatible solute for stress protection or be metabolized through one of a few distinct pathways as a nutrient source. In this review, we summarize what is known about carnitine physiology and metabolism in bacteria. In particular, recent advances in the aerobic and anaerobic metabolic pathways as well as the use of carnitine as an electron acceptor have addressed some long-standing questions in the field. PMID- 25787877 TI - The Effects of Pre-Exercise Ginger Supplementation on Muscle Damage and Delayed Onset Muscle Soreness. AB - Ginger possesses analgesic and pharmacological properties mimicking non-steroidal antiinflammatory drugs. We aimed to determine if ginger supplementation is efficacious for attenuating muscle damage and delayed onset muscle soreness (DOMS) following high-intensity resistance exercise. Following a 5-day supplementation period of placebo or 4 g ginger (randomized groups), 20 non weight trained participants performed a high-intensity elbow flexor eccentric exercise protocol to induce muscle damage. Markers associated with muscle damage and DOMS were repeatedly measured before supplementation and for 4 days following the exercise protocol. Repeated measures analysis of variance revealed one repetition maximum lift decreased significantly 24 h post-exercise in both groups (p < 0.005), improved 48 h post-exercise only in the ginger group (p = 0.002), and improved at 72 (p = 0.021) and 96 h (p = 0.044) only in the placebo group. Blood creatine kinase significantly increased for both groups (p = 0.015) but continued to increase only in the ginger group 72 (p = 0.006) and 96 h (p = 0.027) post-exercise. Visual analog scale of pain was significantly elevated following eccentric exercise (p < 0.001) and was not influenced by ginger. In conclusion, 4 g of ginger supplementation may be used to accelerate recovery of muscle strength following intense exercise but does not influence indicators of muscle damage or DOMS. PMID- 25787878 TI - Ear manipulations reveal a critical period for survival and dendritic development at the single-cell level in Mauthner neurons. AB - Second-order sensory neurons are dependent on afferents from the sense organs during a critical period in development for their survival and differentiation. Past research has mostly focused on whole populations of neurons, hampering progress in understanding the mechanisms underlying these critical phases. To move toward a better understanding of the molecular and cellular basis of afferent-dependent neuronal development, we developed a new model to study the effects of ear removal on a single identifiable cell in the hindbrain of a frog, the Mauthner cell. Ear extirpation at various stages of Xenopus laevis development defines a critical period of progressively-reduced dependency of Mauthner cell survival/differentiation on the ear afferents. Furthermore, ear removal results in a progressively decreased reduction in the number of dendritic branches. Conversely, addition of an ear results in an increase in the number of dendritic branches. These results suggest that the duration of innervation and the number of inner ear afferents play a quantitative role in Mauthner cell survival/differentiation, including dendritic development. PMID- 25787879 TI - Dehydroglyasperin C suppresses TPA-induced cell transformation through direct inhibition of MKK4 and PI3K. AB - Bioactive natural compounds from plant-derived sources have received substantial interest due to their potential therapeutic and preventive effects toward various human diseases. Licorice (Glycyrrhiza), a frequently-used component in traditional oriental medicines, has been incorporated into recipes not only to enhance taste, but also to treat various conditions including inflammation, chronic fatigue syndrome, and even cancer. Dehydroglyasperin C (DGC) is a major isoflavone found in the root of licorice. In the present study, we investigated the cancer chemopreventive effect of DGC and the underlying molecular mechanisms involved, by analyzing its effects on 12-O-tetradecanoylphorbol-13-acetate (TPA) induced neoplastic cell transformation and cyclooxygenase (COX)-2 expression in JB6 P+ mouse epidermal cells. DGC treatment attenuated TPA-induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) transcriptional activation, two major regulators of TPA-induced cell transformation, and COX-2 expression. TPA-induced phosphorylation of p38, JNK1/2 and Akt was also suppressed by DGC. Kinase assay data revealed that DGC inhibited the kinase activity of MKK4 and PI3K and this outcome was due to direct physical binding with DGC. Notably, DGC bound directly to MKK4 and PI3K in an ATP-competitive manner. Taken together, these results suggest that DGC exhibits cancer chemopreventive potential via its inhibitory effect on TPA-induced neoplastic cell transformation and COX-2 modulation through regulation of the MKK4 and PI3K pathways. PMID- 25787880 TI - Relaxed specificity of prokaryotic DNA methyltransferases results in DNA site specific modification of RNA/DNA heteroduplexes. AB - RNA/DNA hybrid duplexes regularly occur in nature, for example in transcriptional R loops. Their susceptibility to modification by DNA-specific or RNA-specific enzymes is, thus, a biologically relevant question, which, in addition, has possible biotechnological implications. In this study, we investigated the activity of four isospecific DNA methyltransferases (M.EcoVIII, M.LlaCI, M.HindIII, M.BstZ1II) toward an RNA/DNA duplex carrying one 5'-AAGCUU-3'/3' TTCGAA-5' target sequence. The analyzed enzymes belong to the beta-group of adenine N6-methyltransferases and recognize the palindromic DNA sequence 5' AAGCTT-3'/3'-TTCGAA-5'. Under standard conditions, none of these isospecific enzymes could detectibly methylate the RNA/DNA duplex. However, the addition of agents that generally relax specificity, such as dimethyl sulfoxide (DMSO) and glycerol, resulted in substantial methylation of the RNA/DNA duplex by M.EcoVIII and M.LlaCI. Only the DNA strand of the RNA/DNA duplex was methylated. The same was not observed for M.HindIII or M.BstZ1II. This is, to our knowledge, the first report that demonstrates such activity by prokaryotic DNA methyltransferases. Possible applications of these findings in a laboratory practice are also discussed. PMID- 25787881 TI - Permeation of steryl ferulates through an in vitro intestinal barrier model. AB - SCOPE: Steryl ferulates (SFs) belong to the bioactive lipids contributing to the health promoting effects of whole grains. However, their intestinal absorption remains unclear. We investigated the permeation of individual SFs using an in vitro intestinal barrier model. METHODS AND RESULTS: An in vitro Caco-2 cell monolayer, mimicking the intestinal barrier, was used to evaluate the permeation of eight SFs from different sources. A method based on ultra-performance LC with high-resolution mass spectrometric detection was developed for their quantification. Although only a negligible amount (< 0.5%) permeated across the Caco-2 cell monolayer, some differences in the permeability coefficients were observed between individual SFs. Permeation mechanism was mainly passive diffusion. CONCLUSION: This work indicates that the permeation of SFs across the gut is very low. Therefore, cholesterol lowering and antioxidant activity-related health benefits of SFs most likely occur in the gut independently from absorption. PMID- 25787882 TI - Effective 1,5-stereocontrol in Pd(0)/InI promoted reactions of chiral N-Ts-4 vinylazetidin-2-ones with aldehydes. An efficient entry into nonracemic semi protected (3Z)-2,6-anti-enediols. AB - epsilon-Amido-allylindiums generated in situ from N-Ts-4-vinylazetidin-2-ones in the presence of 2 eq. of InI and catalytic amounts of Pd(PPh3)4 react with a number of aromatic and aliphatic aldehydes with effective remote 1,5 stereocontrol to afford (3Z)-2,6-anti-enediols as major products in good yields and with excellent diastereoselectivity. PMID- 25787883 TI - Low-Molecular-Weight Fucoidan Inhibits the Viability and Invasiveness and Triggers Apoptosis in IL-1beta-Treated Human Rheumatoid Arthritis Fibroblast Synoviocytes. AB - Fucoidan is a sulfated polysaccharide found mainly in various species of brown algae and brown seaweed. Here, we investigated the effects of low-molecular weight (LMW) fucoidan (4 kDa) on interleukin-1beta (IL-1beta)-stimulated rheumatoid arthritis fibroblast-like synoviocyte (RAFLS). 3-[4,5-Dimethylthiazol 2-yl]-2,5 diphenyl tetrazolium bromide assay and annexin V/propidium iodide assay were used to assess cell viability and apoptosis, respectively. Transwell assay was performed to evaluate cell invasion. Reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay analysis was done to measure gene expression and secretion. Nuclear factor-kappa B (NF-kappaB) DNA binding activity was determined by electrophoretic mobility shift assay. LMW fucoidan dose-dependently inhibited the viability and induced apoptosis of IL 1beta-treated RAFLS. Fucoidan attenuated IL-1beta-induced invasion of RAFLS and decreased the expression and secretion of metalloproteinase (MMP)-1, MMP-3, and MMP-9. Fucoidan suppressed NF-kappaB binding activity, p65 nuclear translocation, and IkappaB-alpha degradation in IL-1beta-stimulated RAFLS. Additionally, IL 1beta-induced phosphorylation of p38 but not ERK or JNK was significantly impaired by fucoidan treatment. LMW fucoidan reduces the viability, survival, and invasiveness of IL-1beta-treated RAFLS, which is associated with inhibition of NF kappaB and p38 activation. LMW fucoidan may have therapeutic potential in the treatment of rheumatoid arthritis. PMID- 25787884 TI - Probing immobilization mechanism of alpha-chymotrypsin onto carbon nanotube in organic media by molecular dynamics simulation. AB - The enzyme immobilization has been adopted to enhance the activity and stability of enzymes in non-aqueous enzymatic catalysis. However, the activation and stabilization mechanism has been poorly understood on experiments. Thus, we used molecular dynamics simulation to study the adsorption of alpha-chymotrypsin (alpha-ChT) on carbon nanotube (CNT) in aqueous solution and heptane media. The results indicate that alpha-ChT has stronger affinity with CNT in aqueous solution than in heptane media, as confirmed by more adsorption atoms, larger contact area and higher binding free energies. Although the immobilization causes significant structure deviations from the crystal one, no significant changes in secondary structure of the enzyme upon adsorption are observed in the two media. Different from aqueous solution, the stabilization effects on some local regions far from the surface of CNT were observed in heptane media, in particular for S1 pocket, which should contribute to the preservation of specificity reported by experiments. Also, CNT displays to some extent stabilization role in retaining the catalytic H-bond network of the active site in heptane media, which should be associated with the enhanced activity of enzymes. The observations from the work can provide valuable information for improving the catalytic properties of enzymes in non-aqueous media. PMID- 25787886 TI - Editorial. PMID- 25787887 TI - Preface. PMID- 25787885 TI - Direct and maternal n-3 long-chain polyunsaturated fatty acid supplementation improved triglyceridemia and glycemia through the regulation of hepatic and muscle sphingolipid synthesis in offspring hamsters fed a high-fat diet. AB - PURPOSE: We recently reported that direct and maternal supplementation with n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) alleviates the metabolic disturbances in adult hamster pups fed with a high-fat diet (HFD). In this study, we hypothesized that these results involved a perinatal modulating effect of sphingolipids by n-3 LC-PUFA. METHODS: We studied the effect of direct and maternal n-3 LC-PUFA supplementation on sphingolipid contents in liver and muscle, hepatic triglycerides (TG) secretion and glucose tolerance. Offspring male hamsters born from supplemented (Comega) or unsupplemented (C) mothers were subjected after weaning to a HFD during 16 weeks, without (Comega-HF or C-HF) or with direct supplementation with n-3 LC-PUFA (C-HFomega). RESULTS: Direct supplementation decreased sphingosine, sphinganine and ceramides in liver and decreased sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and ceramides in muscle in C-HFomega compared to C-HF (p < 0.05). Maternal supplementation decreased C20 ceramide and lactosylceramide in liver and sphinganine, S1P and lactosylceramide in muscle (p < 0.05). This supplementation tended to decrease glucosylceramide in liver (p < 0.06) and muscle (p < 0.07) in Comega-HF compared to C-HF. Direct supplementation increased glucose tolerance and decreased hepatic TG secretion and hepatic gene expression levels of diacylglycerol O acyltransferase 2 (DGAT2), sterol regulatory element-binding protein-1c (SREBP 1c), fatty acid synthase, stearoyl-CoA desaturase-1 (SCD1) and tumor necrosis factor alpha (TNFalpha). Maternal supplementation decreased basal glycemia and hepatic TG secretion. We observed a positive correlation between hepatic TG secretion and hepatic ceramide (p = 0.0059), and between basal glycemia and hepatic ceramide (p = 0.04) or muscle lactosylceramide contents (p = 0.001). CONCLUSION: We observed an improvement of lipids and glucose metabolism in hamster with n-3 LC-PUFA direct supplementation and a decrease in glycemia and hepatic TG secretion with maternal supplementation. These results are probably related to a decrease in both lipogenesis and sphingolipid contents in liver and muscle. PMID- 25787888 TI - Drug delivery and translation. PMID- 25787889 TI - A new approach for skin tumor treatment: from delivery system characterization to in vivo evaluation. AB - Topical therapy for skin cancer is considered ineffective, due to insufficient penetration of the anticancer drug into the tumor located in the deep layers of the skin. The aim of this work was to investigate a new system, Tumorep DS, tailored to deliver the anti-cancer actives into the tumor cells in the deep skin and to induce cell differentiation. Tumorep DS containing 5-fluorouracil (5-FU) anticancer drug and a sulfoxide derivative, as a differentiation agent, was characterized and tested for storage stability. The system was tested in cell lines, in vitro and in animal models. Experiments were carried out on five cell types: three tumorigenic (TE.354.T, ES-2, and Mel624), one precancerous (HaCaT), and a primary keratinocyte (human normal keratinocytes) cell culture. Treatment of keratinocytes with Tumorep DS resulted in reduction in the percent of keratin 14-positive cells, suggesting its ability to induce cell differentiation. Skin penetration was assessed in vitro in Franz diffusion cells and in vivo. The antitumor effect of the new system evaluated in two skin cancer animal models showed a significant repression of tumor development, which was significantly better statistically than a 5-FU commercial product. Tumorep DS was found to be safe to the skin when tested in vitro in the EpiDermTM skin irritation test and in animals. PMID- 25787890 TI - Liposomes as multicompartmental carriers for multidrug delivery in anticancer chemotherapy. AB - A new PEGylated liposomal formulation containing both gemcitabine (GEM) and paclitaxel (PTX) was investigated in order to realize an innovative multidrug carrier (MDC) to test on human cancer cells. The MDC in question was realized by the liposome extrusion method. Photocorrelation spectroscopy was used for the physicochemical characterization of the vesicular carriers. In vitro cytotoxicity was studied through MTT testing. The contemporary presence of the two antitumoral compounds induced no destabilization phenomena in the liposomal structure. The extrusion method provided vesicles with mean sizes of ~100 nm and a zeta potential of ~ -10 mV. The liposomal MDC showed a high drug loading capacity (~90% and ~80% for GEM and PTX, respectively) as well as a controlled release of the active compounds over a 24-h period. Cell viability testing on Michigan Cancer Foundation-7 human breast cancer cells evidenced the MDC as having a stronger cytotoxic effect with respect to the active compounds tested in free and liposomal formulations, both as single molecules and in association. Flow cytometry furnished evidence of the synergistic in vitro antitumoral action between the GEM and PTX co-encapsulated the liposomal MDC. This formulation may offer even more advantages in in vivo testing in terms of drug pharmacokinetic, biodistribution, and antitumoral efficacy for the treatment of breast cancer, as compared to past formulations. PMID- 25787891 TI - Looking over the fence-how travel medicine can benefit from tourism research. PMID- 25787892 TI - Treatment beliefs and preferences for psychological therapies for weight management. AB - OBJECTIVE: Treatment beliefs and preferences for psychological therapies were investigated in 80 overweight individuals trying to manage their weight. METHOD: Participants read 4 therapy descriptions: cognitive behavioral therapy (CBT), behavior therapy (BT), cognitive therapy (CT), and acceptance and commitment therapy (ACT). They ranked the treatments in order of preference, explained the reason for their preferred choice, and reported their beliefs about each approach. RESULTS: Individual CBT (43.42%) and BT (31.58%), delivered face-to face or technologically, were the most preferred treatment options, while ACT (17.12%) and CT (7.89%) were the least preferred. The main reasons cited among those who chose CBT and BT were perceived comprehensiveness and the practical nature of the approach, respectively. Treatment beliefs were strongly predicted by psychological need satisfaction as well as perceived ease and effort. CONCLUSIONS: Further research should ascertain the stability of treatment beliefs and the efficacy of modifying the treatment context to meet individual needs. PMID- 25787893 TI - Addressing Psychosocial Adversity Within the Patient-Centered Medical Home: Expert-Created Measurable Standards. AB - The Patient-Centered Medical Home (PCMH) may be improved by embedding identification and response for patients' experiences with psychosocial adversity, but how this might optimally occur in practice has not been well specified. We sought input from an expert panel to define feasible elements that could adapt the PCMH to adequately respond to patients' experiences with psychosocial adversity. From December 2012 through September 2013, we used a Delphi process to systematically obtain expert opinions and reach consensus. We invited 37 experts to participate in three successive and iterative rounds of questionnaires, with each round based on aggregated, de-identified data from the prior round. We first asked experts to generate elements to adapt the PCMH, using the National Committee for Quality Assurance (NCQA's) established six PCMH standards as the foundation. We then asked the experts to rate these elements on a 5-point Likert scale, and finally specify what they considered the most and least valuable elements. Eighteen of the 37 (49 %) invited experts responded to the first survey, and constituted our sample. Experts identified 35 elements that fell under the six NCQA standards. The top rated elements included using a screening tool to identify adversity; training providers to address psychosocial adversity; having a team member with mental health expertise; providing culturally-competent care; and having written patient information related to adversity and coping. This study derived key elements that may enhance the PCMH's ability to improve patient outcomes by purposefully identifying and responding to their psychosocial adversity. PMID- 25787894 TI - The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors. AB - The recent recognition that antibody-mediated rejection (ABMR) is the major cause of kidney transplant loss creates strong interest in its pathogenesis. We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set. In the Combined Set of 703 biopsies, 2603 transcripts were significantly changed (FDR < 0.05) in ABMR versus all other biopsies. In cultured cells, the transcripts strongly associated with ABMR were expressed in endothelial cells, e.g. cadherins CDH5 and CDH13; IFNG treated endothelial cells, e.g. phospholipase PLA1A and chemokine CXCL11; or NK cells, e.g. cytotoxicity molecules granulysin (GNLY) and FGFBP2. Other ABMR transcripts were expressed in normal kidney but not cell lines, either increased e.g. Duffy chemokine receptor (DARC) or decreased e.g. sclerostin (SOST). Pathway analysis of ABMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors; leukocyte-endothelial interactions; and NK signaling, including evidence for CD16a Fc receptor signaling elements shared with T cells. These data support a model of ABMR involving injury-repair in the microcirculation induced by cognate recognition involving antibody and CD16a, triggering IFNG release and antibody-dependent NK cell-mediated cytotoxicity. PMID- 25787895 TI - Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer. AB - Dendritic cell (DC)-based vaccines are a promising therapeutic modality for cancer. Results from recent trials and approval of the first DC vaccine by the U.S. Food and Drugs Administration for prostate cancer have paved the way for DC based vaccines. A total of 21 hormone refractory prostate cancer (HRPC) patients with a life expectancy >3 months were randomised into two groups. DC loaded with recombinant Prostate Specific Membrane Antigen (rPSMA) and recombinant Survivin (rSurvivin) peptides was administered as an subcutaneous (s.c.) injection (5*10(6) cells). Docetaxel (75 mg/m(2) intravenous (i.v.)) and prednisone (5 mg, bis in die (b.i.d.)) served as control. Clinical and immunological responses were evaluated. Primary endpoints were safety and feasibility; secondary endpoint was overall survival. Responses were evaluated on day 15, day 30, day 60, and day 90. DC vaccination was well tolerated with no signs of grade 2 toxicity. DC vaccination induced delayed-type hypersensitivity reactivity and an immune response in all patients. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) was 72.7% (8/11) versus 45.4 (5/11) in the docetaxel arm and immune related response criteria (irRC) was 54.5% (6/11) compared with 27.2% (3/11) in the control arm. The DC arm showed stable disease (SD) in 6 patients, progressive disease (PD) in 3 patients, and partial remission (PR) in two patients compared to SD in 5 patients, PD in 6 patients, and PR in none in the docetaxel arm. There was a cellular response, disease stabilization, no adverse events, and partial remission with the rPSMA and rSurvivin primed DC vaccine. PMID- 25787896 TI - Problem-solving Test: Analysis of the mechanism of action of an apoptosis inducing compound. PMID- 25787897 TI - High-resolution far-field ghost imaging via sparsity constraint. AB - Ghost imaging (GI) is a method to nonlocally image an object with a single-pixel detector. However, the speckle's transverse size at the object plane limits the system's imaging resolution for conventional GI linear reconstruction algorithm. By combining the sparsity constraint of imaging object with ghost imaging method, we demonstrate experimentally that ghost imaging via sparsity constraint (GISC) can dramatically enhance the imaging resolution even using the random measurements far below the Nyquist limit. The image reconstruction algorithm of GISC is based on compressive sensing. Factors affecting the reconstruction quality of high-resolution GISC, such as the receiving system's numerical aperture and the object's sparse representation basis, are also investigated experimentally. This high-resolution imaging technique will have great applications in the microscopy and remote-sensing areas. PMID- 25787898 TI - Molecular investigation of the interaction between ionic liquid type gemini surfactant and lysozyme: A spectroscopic and computational approach. AB - Herein, we are reporting the interaction of ionic liquid type gemini surfactant, 1,4-bis(3-dodecylimidazolium-1-yl) butane bromide ([C12-4-C12 im]Br2) with lysozyme by using Steady state fluorescence, UV-visible, Time resolved fluorescence, Fourier transform-infrared (FT-IR) spectroscopy techniques in combination with molecular modeling and docking method. The steady state fluorescence spectra suggested that the fluorescence of lysozyme was quenched by [C12-4-C12 im]Br2 through static quenching mechanism as confirmed by time resolved fluorescence spectroscopy. The binding constant for lysozyme-[C12-4-C12 im]Br2 interaction have been measured by UV-visible spectroscopy and found to be 2.541 * 10(5) M(-1). The FT-IR results show conformational changes in the secondary structure of lysozyme by the addition of [C12-4-C12 im]Br2. Moreover, the molecular docking study suggested that hydrogen bonding and hydrophobic interactions play a key role in the protein-surfactant binding. Additionally, the molecular dynamic simulation results revealed that the lysozyme-[C12-4-C12 im]Br2 complex reaches an equilibrium state at around 3 ns. PMID- 25787900 TI - Current radiologist workload and the shortages in Japan: how many full-time radiologists are required? AB - PURPOSE: To clarify the workload of certified radiologists and to estimate the current manpower shortages in Japan. METHODS: We conducted a questionnaire survey for accredited training institutions. The contents included the radiologist employment pattern (full vs. part time), the number of computed tomography (CT) and magnetic resonance imaging (MRI) examinations and their radiology reports, the number of radiation therapy planning sessions, and the time per week spent for each work activity. We also used the hospital survey reports of Japan's Ministry of Health, Labor, and Welfare in our analyses. RESULTS: The estimated numbers of CT and MRI interpretation reports and radiation treatment plans that one full-time radiologist could complete within 1 hospital day (8 h) were 19.9 and 1.22, respectively. To complete all CT and MRI reports, at least 2.09 times more full-time diagnostic radiologists are needed in Japan. For radiation therapy, at least 1.23 times more full-time radiation oncologists are necessary at large- and medium-scale hospitals, although the number of radiation oncologists needed in Japan is balanced to the current number. CONCLUSION: The number of full-time certified diagnostic radiologists for CT and MRI interpretation in Japan is insufficient. Centralized radiation therapy facilities may be more efficient for meeting the increasing demand. PMID- 25787901 TI - A detailed view on pacemaker lead parameters remotely transmitted after magnetic resonance. AB - BACKGROUND: The purpose of this study was to analyze potential influences of magnetic resonance (MR) on the course of automatically device-based assessed lead parameters remotely transmitted in patients who were implanted with MR conditional permanent pacemakers (PMs) and who had nondiagnostic brain and lumbar spine MR (1.5T) within the ProMRI single center pilot study. METHODS: The ProMRI study evaluated the feasibility of the Evia PMs with Safio S leads (Biotronik SE&Co KG, Berlin, Germany) in the MR environment. All patients were equipped with remote monitoring on the day of MR. Atrial (RA) und ventricular (RV) lead parameters (sensing, pacing capture threshold [PCT], pacing impedance) were automatically assessed and remotely transmitted on a daily or event-triggered basis for 3 months post MR. Remotely transmitted data were normalized for potential differences between at-daytime (in-office) and at-night-time (remotely) assessed parameters using the 1-month follow-up data for each patient. Confidence intervals of continuous data were calculated day-wise with one sample t-tests of post-MR/pre-MR differences, respectively. RESULTS: A total of 2,428 data sets (mean 80 +/- 20 per patient) were transmitted. Mean values for the different lead parameters were (RA/RV) 3.3 +/- 2.0/14.4 +/- 6.9 mV for sensing, 0.65 +/- 0.17/0.78 +/- 0.23 V/0.4 ms for PCT, and 516 +/- 60/607 +/- 47 Omega for pacing impedance. No significant differences were found compared with pre-MR measurements. No atrial PCT increases >=0.5 V compared with pre-MR were observed, and in only one patient the ventricular PCT increased by >=0.5 V from day 76 post MR, presumably based on new antiarrhythmic therapy with amiodarone. CONCLUSION: Our analyses of automatically assessed and remotely transmitted PM lead parameters after MR show that sensing amplitudes, PCTs, and pacing impedances are not affected in a clinically relevant way by MR. PMID- 25787902 TI - The Effect of Realtime Monitoring on Dose Exposure to Staff Within an Interventional Radiology Setting. AB - PURPOSE: The purpose of this study is to evaluate a new device providing real time monitoring on radiation exposure during fluoroscopy procedures intending to reduce radiation in an interventional radiology setting. MATERIALS AND METHODS: In one interventional suite, a new system providing a real-time radiation dose display and five individual wireless dosimeters were installed. The five dosimeters were worn by the attending, fellow, nurse, technician, and anesthesiologist for every procedure taking place in that suite. During the first 6-week interval the dose display was off (closed phase) and activated thereafter, for a 6-week learning phase (learning phase) and a 10-week open phase (open phase). During these phases, the staff dose and the individual dose for each procedure were recorded from the wireless dosimeter and correlated with the fluoroscopy time. Further subanalysis for dose exposure included diagnostic versus interventional as well as short (<10 min) versus long (>10 min) procedures. RESULTS: A total of 252 procedures were performed (n = 88 closed phase, n = 50 learning phase, n = 114 open phase). The overall mean staff dose per fluoroscopic minute was 42.79 versus 19.81 uSv/min (p < 0.05) comparing the closed and open phase. Thereby, anesthesiologists were the only individuals attaining a significant dose reduction during open phase 16.9 versus 8.86 uSv/min (p < 0.05). Furthermore, a significant reduction of total staff dose was observed for short 51 % and interventional procedures 45 % (p < 0.05, for both). CONCLUSION: A real-time qualitative display of radiation exposure may reduce team radiation dose. The process may take a few weeks during the learning phase but appears sustained, thereafter. PMID- 25787903 TI - Cone-Beam Computed Tomography (CBCT) Versus CT in Lung Ablation Procedure: Which is Faster? AB - AIM: To compare cone-beam CT (CBCT) versus computed tomography (CT) guidance in terms of time needed to target and place the radiofrequency ablation (RFA) electrode on lung tumours. MATERIALS AND METHODS: Patients at our institution who received CBCT- or CT-guided RFA for primary or metastatic lung tumours were retrospectively included. Time required to target and place the RFA electrode within the lesion was registered and compared across the two groups. Lesions were stratified into three groups according to their size (<10, 10-20, >20 mm). Occurrences of electrode repositioning, repositioning time, RFA complications, and local recurrence after RFA were also reported. RESULTS: Forty tumours (22 under CT, 18 under CBCT guidance) were treated in 27 patients (19 male, 8 female, median age 67.25 +/- 9.13 years). Thirty RFA sessions (16 under CBCT and 14 under CT guidance) were performed. Multivariable linear regression analysis showed that CBCT was faster than CT to target and place the electrode within the tumour independently from its size (beta = -9.45, t = -3.09, p = 0.004). Electrode repositioning was required in 10/22 (45.4 %) tumours under CT guidance and 5/18 (27.8 %) tumours under CBCT guidance. Pneumothoraces occurred in 6/14 (42.8 %) sessions under CT guidance and in 6/16 (37.5 %) sessions under CBCT guidance. Two recurrences were noted for tumours receiving CBCT-guided RFA (2/17, 11.7 %) and three after CT-guided RFA (3/19, 15.8 %). CONCLUSION: CBCT with live 3D needle guidance is a useful technique for percutaneous lung ablation. Despite lesion size, CBCT allows faster lung RFA than CT. PMID- 25787904 TI - Public policy response, aging in place, and big data platforms: Creating an effective collaborative system to cope with aging of the population. AB - The unprecedented rapid aging of the population is poised to become the next global public health challenge, as is apparent by the fact that 23.1% of the total global burden of disease is attributable to disorders in people aged 60 years and older. Aging of the population is the biggest driver of substantial increases in the prevalence of chronic conditions, and the prevalence of multi morbidity is much higher in older age groups. This places a large burden on countries' health and long-term care systems. Many behavioral changes and public policy responses to aging of the population have been implemented to cope with these challenges. A system of "aging in place" has been implemented in some high income countries in order to better provide coordinated and cost-effective health services for the elderly. This approach reduces institutional care while supporting home- or community-based care and other services. Advances in information and communications technology (ICT), assistive devices, medical diagnostics, and interventions offer many ways of more efficiently providing long term care as part of aging in place. The use of big data on a web services platform in an effective collaborative system should promote systematic data gathering to integrate clinical and public health information systems to provide support across the continuum of care. However, the use of big data in collaborative system is a double-edged sword, as it also bring challenges for information sharing, standardized data gathering, and the security of personal information, that warrant full attention. PMID- 25787905 TI - Food traceability systems in China: The current status of and future perspectives on food supply chain databases, legal support, and technological research and support for food safety regulation. AB - Over the past few decades, the field of food security has witnessed numerous problems and incidents that have garnered public attention. Given this serious situation, the food traceability system (FTS) has become part of the expanding food safety continuum to reduce the risk of food safety problems. This article reviews a great deal of the related literature and results from previous studies of FTS to corroborate this contention. This article describes the development and benefits of FTS in developed countries like the United States of America (USA), Japan, and some European countries. Problems with existing FTS in China are noted, including a lack of a complete database, inadequate laws and regulations, and lagging technological research into FTS. This article puts forward several suggestions for the future, including improvement of information websites, clarification of regulatory responsibilities, and promotion of technological research. PMID- 25787906 TI - The advantages of using traditional Chinese medicine as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer. AB - Recent studies indicate that Traditional Chinese medicine (TCM) can play an important role in the whole course of cancer treatment such as recovery stages of post-operative, radiotherapy or chemotherapy stages instead of only terminal stage of cancer. In this review, we have summarized current evidence for using TCM as adjuvant cancer treatment in different stages of cancer lesions. Some TCMs (e.g., TJ-41, Liu-jun-zi-tang, PHY906, Coumarin, and Aescine) are capable of improving the post-operative symptoms such as fatigue, pain, appetite, diarrhea, nausea, vomiting, and lymphedema. Some TCMs (e.g., Ginseng, Huang-Qi, BanZhiLian, TJ-48, Huachansu injection, Shenqi fuzheng injection, and Kanglaite injection) in combination with chemo- or radio-therapy are capable of enhancing the efficacy of and diminishing the side effects and complications caused by chemo- and radiotherapy. Taken together, they have great advantages in terms of suppressing tumor progression, relieving surgery complications, increasing the sensitivity of chemo- and radio- therapeutics, improving an organism's immune system function, and lessening the damage caused by surgery, chemo- or radio-therapeutics. They have significant effects on relieving breast cancer-related lymphedema, reducing cancer-related fatigue and pain, improving radiation pneumonitis and gastrointestinal side effects, protecting liver function, and even ameliorating bone marrow suppression. This review of those medicines should contribute to an understanding of Chinese herbal medicines as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer, by providing useful information for development of more effective anti-cancer drugs and making more patients "survival with cancer" for a long time. PMID- 25787907 TI - Perinatal outcomes of pregnancies complicated by preterm premature rupture of the membranes before 34 weeks of gestation in a tertiary center in China: A retrospective review. AB - Preterm premature rupture of the membranes (PPROM) remains the leading cause of preterm deliveries and neonatal mortality and morbidity. The current cohort study sought to retrospectively examine perinatal outcomes in cases of PPROM < 34 weeks' gestation that were managed conservatively from 2010 to 2012 and to identify risk factors for short-term neonatal outcomes. Subjects were 510 pregnancies consisting of 114 twin and 396 singleton pregnancies. Clinical chorioamnionitis occurred in 17.8% of the pregnancies. Neonatal mortality was 7.4%, the rate of major neonatal conditions was 40%, and the rate of NICU admission was 72.9%. The latency period exceeded 48 h in 62.5% of the pregnancies and 7 days in 24.3% of the pregnancies. Twin pregnancies had a shorter latency period than singleton pregnancies (median of 2 days versus 4 days, p < 0.001). Pregnancies complicated with early vaginal bleeding had a higher neonatal mortality (13.95% vs. 6.36%, p = 0.013) and morbidity (51.16% vs. 38.32%, p = 0.024), fewer weeks of gestation at PPROM (p = 0.029). Multivariate logistic regression analysis revealed that weeks of gestation at PPROM (OR: 0.953, 95% CI: 0.939-0.966, p < 0.001) and a latency period (OR: 0.948, 95%CI: 0.926-0.970, p < 0.001) were associated with neonatal mortality or morbidity. A twin pregnancy (OR: 0.319, 95% CI: 0.17-0.6, p < 0.001) and weeks of gestation at PPROM (OR: 0.737, 95% CI: 0.66-0.822, p < 0.001) were associated with the latency period. Gestational age at PPROM, a twin pregnancy, and the latency period are associated with neonatal mortality and morbidity. PMID- 25787908 TI - L-carnitine affects osteoblast differentiation in NIH3T3 fibroblasts by the IGF 1/PI3K/Akt signalling pathway. AB - Fibroblasts in soft tissues are one of the progenitors of ectopic calcification. Our previous experiment found that the serum concentrations of small metabolite L carnitine (LC) decreased in an ectopic calcification animal model, indicating LC is a potential calcification or mineralization inhibitor. In this study, we investigated the effect of LC on NIH3T3 fibroblast osteoblast differentiation, and explored its possible molecular mechanisms. Two concentrations of LC (10 MUM and 100 MUM) were added in Pi-induced NIH3T3 fibroblasts, cell proliferation was compared by MTT assays, osteoblast differentiation was evaluated by ALP activity, mineralized nodules formation, calcium deposition, and expressions of the osteogenic marker genes. Our results indicated that 10 MUM LC increased the proliferation of NIH3T3 cells, but 100 MUM LC slightly inhibited cell proliferation. 100 MUM LC inhibits NIH3T3 differentiation as evidenced by decreases in ALP activity, mineralized nodule formation, calcium deposition, and down-regulation of the osteogenic marker genes ALP, Runx2 and OCN, meanwhile 10 MUM of LC exerts an opposite effect that promotes NIH3T3 osteogenesis. Mechanistically, 100 MUM LC significantly inhibits IGF-1/PI3K/Akt signalling, while 10 MUM LC slightly activates this pathway. Our study suggests that a decease in LC level might contribute to the development of ectopic calcification in fibroblasts by affecting IGF-1/PI3K/Akt, and addition of LC may benefit patients with ectopic calcification. PMID- 25787909 TI - Susceptibility to proteases of anti-Tn-antigen MLS128 binding glycoproteins expressed in human colon cancer cells. AB - Anti-Tn antigen MLS128 monoclonal antibody was produced two decades ago by immunizing mice with "cancerous antigens" derived from LS180 colon cancer cells. Previous studies demonstrated that MLS128 bound to 110 kDa glycoprotein (GP) in colon cancer cells, thereby inhibiting cell growth. Extensive attempts have been made towards understanding the inhibitory action of MLS128 on colon cancer cell growth and solving the primary structure of 110 kDa GP. Since limited proteolysis of 110 kDa GP was observed in microdomain fractions that had been kept frozen for several years, susceptibility of 110 kDa GP to trypsin and other proteases as well as N-glycosidase F has been investigated. Furthermore, 110 kDa GP expression was examined in colon cancer cells independently cultured in Akiyama laboratory. In summary, 110 kDa GP contains N-glycans. It does not contain inter-disulfide bonds but appears to have intra-disulfides. It must contain multiple cleavage sites for trypsin and thermolysin since these proteases digested 110 kDa GP to MLS128-undetectable small fragments. It seems to contain cleavage sites for cathepsin D which could cause limited digestion. LS180 cells derived from Akiyama laboratory produced a limited proteolysis product-like 75 kDa GP. This study provides a structural basis for developing cancer diagnostics and therapeutics. PMID- 25787910 TI - Roles of the highly conserved amino acids in the globular head and stalk region of the Newcastle disease virus HN protein in the membrane fusion process. AB - Newcastle disease virus (NDV), an avain paramyxovirus, has been assigned to the genus Avulavirus within the family Paramyxoviridae. It causes Newcastle disease (ND) that is a highly contagious and fatal viral disease affecting poultry and most species of birds. The hemagglutinin-neuraminidase (HN) protein of NDV has multiple functions including mediating hemadsorption (HAD), neuraminidase (NA), and fusion promotion activities affecting the process of viral attachment, entry, replication and dissemination. Fusion ability of the NDV was highly correlated to its virulence. Mutations in the HN globular head and headless HN of NDV were constructed to determinate the impact of highly conserved amino acids in the globular head of paramyxovirus HN proteins and the roles of the stalk region of HN in the fusion process. It was found that the interaction between F and HN mutants E401A, G402A, G468A, V469A, Y526A, and T527A was equal to that in F and wt HN. The mutations of G402A, G468A, V469A, and T527A had various effects on cell fusion promotion, receptor binding ability, and NA activity, but the membrane merging rate was comparable to wt HN. The elimination of hemadsorption ability and NA activity of E401A and Y526A resulted in the loss of the fusion promotion function of HN. The conclusion was that receptor binding and NA had a common active site and E401 and Y526 amino acids were essential for virus attachment, entry, and dissemination. In addition, G468A mutation made different contributions to HAD and NA, which indicated that G468 was one of the potential key amino acids in switching the two functions between receptor binding and sialic acid destruction of HN. It was also proven that the headless HN of NDV could promote the fusion event mediated by F. Thus, it revealed a novel mechanism in F activation of NDV. PMID- 25787911 TI - Short- and long-term outcomes of hepatectomy with or without radiofrequency assist for the treatment of hepatocellular carcinomas: a retrospective comparative cohort study. AB - The objective of this study was to compare the short- and long-term outcomes of radiofrequency-assisted liver resection (RFLR) and conventional clamp-crushing liver resection (CCLR) and to evaluate the safety and efficiency of RFLR. Between January 2008 and December 2012, a total of 597 patients with hepatocellular carcinoma (HCC) who underwent curative hepatectomy were identified. A total of 272 patients underwent RFLR, and 325 patients received CCLR. The short- and long term outcomes were compared. The patients in the RFLR and CCLR groups showed similar baseline characteristics. The RFLR group showed less intraoperative blood loss (485.5 vs. 763.2 mL, p = 0.003), a lower transfusion requirement rate (19.1 vs. 31.7%, p <= 0.01), shorter surgery duration (211 vs. 296 min, p <= 0.01) and a lower vascular inflow occlusion rate (25.7 vs. 33.8%, p = 0.032). No significant postoperative changes in bilirubin or liver enzymes were observed in the two groups. The degree of postoperative complications and morbidity did not significantly differ between the two groups. There were no significant differences in the 1-, 2- and 3-year overall survival rates (73.8%, 58.5%, and 55.7% vs. 80.8%, 65.8%, and 56.2%, respectively) or disease-free rates (51.9%, 47.2%, and 46.0% vs. 54.5%, 44.9%, and 38.5%, respectively) between the RFLR and CCLR groups. These results suggested RFLR was a safe and efficient method for patients with HCC. RFLR was associated with decreased blood loss, fewer blood transfusions, shorter surgery times and less vascular inflow occlusion application. The RFLR group did not show increased liver injury or postoperative morbidity or mortality. PMID- 25787912 TI - Fatal cases of human infection with avian influenza A (H7N9) virus in Shanghai, China in 2013. AB - We retrospectively reviewed the medical records of 17 fatal H7N9 cases in Shanghai in 2013, analyzed clinical variables and described their clinical and epidemiologic characteristics. The median age was 73 years, and 82.4% had underlying medical conditions. The most frequent symptoms were fever (100%), followed by productive cough (47.1%) and dry cough (35.5%). Thirteen (76.5%) patients had dyspnea or respiratory distress, five (29.4%) had shock, and four (23.5%) had acute kidney injury. Seventeen (100.0%) patients had lymphopenia. Involvement of both lungs was found by chest radiography in 14 (82.4%) patients at presentation. Fifteen (88.2%) patients were hospitalized. The median times from illness onset to hospitalization and to diagnosis confirmation were both six days. Eleven (64.7%) patients were admitted to the intensive care unit. Sixteen (94.1%) patients were treated with oseltamivir. The median time from illness onset to oseltamivir treatment was six days. Among six patients for whom the duration of viral shedding was available, the median duration of viral shedding after oseltamivir treatment was 17 days. The median time from illness onset to death was 11 days. Refractory hypoxemia accounted for most deaths. The clinical and epidemiologic characteristics in the Shanghai fatal series of patients do not differ from other reports of H7N9 patients in China. This investigation reflects a delay in the diagnosis and antiviral treatment of H7N9 patients in the early stage of the epidemic in Shanghai. Late antiviral treatment and a long duration of viral shedding may be associated with a fatal outcome in these patients. PMID- 25787913 TI - Possible relationship between the heart rates and serum amyloid A in a hyperglycemic population. AB - Hyperglycemia predicts cardiovascular disease (CVD)-related outcomes. The resting heart rates (HRs) and serum amyloid A (SAA), an inflammatory marker, are respectively factors associated with CVD-related outcomes; however, little is known regarding the associations between these two factors. This study aimed to investigate the correlation between the HRs and SAA levels under hyperglycemic conditions. This study included 298 subjects (males, 44%; mean age, 61.1 years) without a history of CVD and/or hypertensive levels. Clinical data, including general laboratory measurements, HRs and SAA, were measured. The analyses were performed after dividing all of the subjects into two groups based on the blood glucose level (< or >= 6.1 mmol/L). There was a higher SAA level in the hyperglycemic group (n = 143; median [interquartile range] 6.1 [4.1-10.6] MUg/mL) than in the counterpart group (n = 155; 6.0 [3.5-8.5] MUg/mL; p < 0.01). There was a trend toward increased HRs in the hyperglycemic group (mean [standard deviation] 65.3 [11.2] bpm) compared to the counterpart group (63.2 [9.4] bpm; p = 0.08). In the hyperglycemic group, there was a significant positive correlation between the HRs and SAA levels (multiple variables-adjusted analysis: beta = 0.21, p = 0.02), while no correlation was found in the counterpart group (beta = 0.06, p = 0.50). In summary, a positive correlation between the HRs and SAA levels can present under hyperglycemic conditions. These findings may provide relevant insights into the CVD-related pathologies associated with hyperglycemia. Further studies are warranted. PMID- 25787914 TI - Next-generation sequencing reveals clinically actionable molecular markers in myeloid sarcoma. PMID- 25787916 TI - Lines on a posteroanterior chest radiograph. PMID- 25787915 TI - Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. AB - We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (?VGPR) in 504 newly diagnosed, transplant eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ?VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ?2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (?3 degrees ) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (?2 degrees ) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ?VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy. PMID- 25787917 TI - The Dimensionality of Spanish in Young Spanish-English Dual-Language Learners. AB - PURPOSE: This study examined the latent dimensionality of Spanish in young Spanish-English dual-language learners (DLLs). METHOD: Two hundred eighty-six children participated. In their prekindergarten year, children completed norm referenced and experimental language measures in Spanish requiring different levels of cognitive processing in both receptive and expressive language modalities. RESULTS: The best-fitting model suggested a bifactor solution with a single general language factor L plus two additional factors word knowledge and integrative language knowledge. The general trait L reflects the proportion of common item variance for all of the items, and the group traits of word knowledge and integrative language knowledge explain additional domain-specific variance for those item subsets. CONCLUSION: Results suggest that the Spanish language in preschool-age Spanish-English DLLs is not separable into content, form, and use, nor is it separable by higher- and lower-level language domains or processing demands. Instead it appears that a general language factor underlies oral language in Spanish in DLL preschoolers and that other factors account for additional variance over and above L. Findings are discussed in relation to a companion study of monolingual English-speaking prekindergarteners. PMID- 25787918 TI - A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. AB - Here we report on a child with Li-Fraumeni syndrome with a de novo TP53 mutation c.818G>A, who developed three malignancies at the age of 4 months, 4 and 5 years, respectively. We show that (i) in the choroid plexus carcinoma, the germline mutation was detected in a homozygous state due to copy-neutral LOH/uniparental disomy, (ii) in the secondary AML, a complex karyotype led to loss of the wild type TP53 allele, (iii) in the Wilms tumor, the somatic mutation c.814G>A led to compound heterozygosity. The findings show that the complete inactivation of TP53 by different mechanisms is an important step towards tumorigenesis. PMID- 25787919 TI - Proprioception in musculoskeletal rehabilitation. Part 2: Clinical assessment and intervention. AB - INTRODUCTION: Proprioception can be impaired in gradual-onset musculoskeletal pain disorders and following trauma. Understanding of the role of proprioception in sensorimotor dysfunction and methods for assessment and interventions is of vital importance in musculoskeletal rehabilitation. In Part 1 of this two-part Masterclass we presented a theory-based overview of the role of proprioception in sensorimotor control, causes and findings of altered proprioception in musculoskeletal conditions, and general principles of assessment and interventions. PURPOSE: The aim of this second part is to present specific methods for clinical assessment and interventions to improve proprioception in the spine and extremities. IMPLICATIONS: Clinical assessment of proprioception can be performed using goniometers, inclinometers, laser-pointers, and pressure sensors. Manual therapy, taping, and bracing can immediately enhance proprioception and should be used to prepare for exercise interventions. Various types of exercise (active joint repositioning, force sense, co-ordination, muscle performance, balance/unstable surface, plyometric, and vibration training) should be employed for long-term enhancement of proprioception. PMID- 25787920 TI - Part 1: Pressure ulcer assessment - the development of Critical Care Pressure Ulcer Assessment Tool made Easy (CALCULATE). AB - INTRODUCTION: Critically ill patients are at high risk of developing pressure ulcers resulting in serious untoward patient and health care system outcomes. Pressure ulcer prevention is therefore an important patient safety priority and establishing a structured approach to pressure ulcer risk assessment to identify patients at risk is a critical first step. METHODS: The literature was searched using three electronic databases from 2000 to 2011 to identify papers reporting on pressure ulcer risk factors and assessment in adult critical care. The review and appraisal of papers were conducted by two critical care nurses. Papers underwent detailed review if they met inclusion criteria where they identified pressure ulcer assessment scores, scales or risk factors and related to adult critical care patients FINDINGS: Seven papers were reviewed. No single assessment tool was sufficiently validated for critically ill patients and seven key critical care risk factors were identified. These risk factors were: mechanical ventilation, impaired circulation, dialysis, long surgery, low protein and too unstable to turn. TOOL DEVELOPMENT: The tool Critical Care Pressure Ulcer Assessment Tool made Easy (CALCULATE) was developed utilizing the risk factors from the literature and expert critical care nursing consensus decision-making. DISCUSSION: In the absence of current consensus, valid assessment scales and limited evidence for the most appropriate pressure ulcer assessment for critically ill patients, this assessment tool offers an easy, appropriate alternative for critically ill patients than existing tools primarily validated for acute care wards. CONCLUSIONS: 'CALCULATE' offers an important contribution towards the advancement and development of critical care pressure ulcer risk assessment. Future research is needed to further enhance and inform pressure ulcer risk assessment of the critically ill patients. IMPLICATIONS FOR PRACTICE: The identification of critical care risk factors may be an indicative method of assessing pressure ulcer risk in the critically ill patients. PMID- 25787921 TI - Patients' preference and informed consent. PMID- 25787922 TI - Reply to the letter to the editor 'patients' preference and informed consent' by Pumo et al. PMID- 25787923 TI - Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor 2 in patients with advanced solid tumors. AB - BACKGROUND: Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed. RESULTS: Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ~110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers. CONCLUSION: Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors. CLINICALTRIALSGOV: NCT00786383. PMID- 25787924 TI - Theoretical investigation on the chemistry of entrapment of the elusive aminoborane (H2 N=BH2 ) molecule. AB - Aminoborane (H2 N=BH2 ) is an elusive entity and is thought to be produced during dehydropolymerization of ammonia borane, a molecule of prime interest in the field of chemical hydrogen storage. The entrapment of H2 N=BH2 through hydroboration of exogenous cyclohexene has emerged as a routine technique to infer if free H2 N=BH2 is produced or not during metal-catalyzed ammonia borane dehydrogenation reactions. But to date, the underlying mechanism of this trapping reaction remains unexplored. Herein, by using DFT calculations, we have investigated the mechanism of trapping of H2 N=BH2 by cyclohexene. Contrary to conventional wisdom, our study revealed that the trapping of H2 N=BH2 does not occur through direct hydroboration of H2 N=BH2 on the double bond of cyclohexene. We found that autocatalysis by H2 N=BH2 is crucial for the entrapment of another H2 N=BH2 molecule by cyclohexene. Additionally, nucleophilic assistance from the solvent is also implicated for the entrapment reaction carried out in nucleophilic solvents. In THF, the rate-determining barrier for formation of the trapping product was predicted to be 16.7 kcal mol(-1) at M06 L(CPCM) level of theory. PMID- 25787925 TI - Activation of senescence-associated Dark-inducible (DIN) genes during infection contributes to enhanced susceptibility to plant viruses. AB - Virus infections in plants cause changes in host gene expression that are common to other environmental stresses. In this work, we found extensive overlap in the transcriptional responses between Arabidopsis thaliana plants infected with Tobacco rattle virus (TRV) and plants undergoing senescence. This is exemplified by the up-regulation during infection of several senescence-associated Dark inducible (DIN) genes, including AtDIN1 (Senescence 1, SEN1), AtDIN6 (Asparagine synthetase 1, AtASN1) and AtDIN11. DIN1, DIN6 and DIN11 homologues were also activated in Nicotiana benthamiana in response to TRV and Potato virus X (PVX) infection. Reduced TRV levels in RNA interference (RNAi) lines targeting AtDIN11 indicate that DIN11 is an important modulator of susceptibility to TRV in Arabidopsis. Furthermore, low accumulation of TRV in Arabidopsis protoplasts from RNAi lines suggests that AtDIN11 supports virus multiplication in this species. The effect of DIN6 on virus accumulation was negligible in Arabidopsis, perhaps as a result of gene or functional redundancy. However, TRV-induced silencing of NbASN, the DIN6 homologue in N. benthamiana, compromises TRV and PVX accumulation in systemically infected leaves. Interestingly, NbASN inactivation correlates with the appearance of morphological defects in infected leaves. We found that DIN6 and DIN11 regulate virus multiplication in a step prior to the activation of plant defence responses. We hypothesize on the possible roles of DIN6 and DIN11 during virus infection. PMID- 25787926 TI - Efficacy and safety of lomefloxacin on bacterial extraocular disease in the horse. AB - Lomefloxacin is a broad-spectrum fluoroquinolone antibiotic used for the treatment of bacterial extraocular disease. This study investigated the efficacy and safety of lomefloxacin eye drops for bacterial extraocular disease in horses. Lomefloxacin ophthalmic solution (0.3%) was instilled three times daily for 2-5 days in 65 horses diagnosed with bacterial extraocular disease based on clinical findings. Clinical observations and bacteriological examinations were performed at the start of treatment, 2 and 5 days after the start of treatment, and at the discontinuation or termination of treatment. Of the 65 horses, 64 were positive for bacteria, and 22 bacterial genera and 47 bacterial species were identified. The efficacy of lomefloxacin was evaluated in 63 horses; one horse with a negative culture and another with suspected bacterial contamination were excluded. Lomefloxacin was considered to be clinically effective in 54 horses. The major bacterial species identified were Staphylococcus aureus, Streptococcus equi subsp. zooepidemicus, Acinetobacter lwoffii, Staphylococcus xylosus, Staphylococcus vitulinus, Enterobacter agglomerans, Flavimonas oryzihabitans and Staphylococcus sciuri, with a cumulative disappearance rate of 80% or more at the termination of instillation. Excluding one horse that did not undergo a bacteriological examination, the remaining 62 horses were assessed for bacteriological outcome. Full or partial bacterial clearance was detected in 95% or more of the 62 horses. One of the 65 horses reported adverse events that had no causal relation with the eye drops. Our results showed that lomefloxacin is safe and effective for the treatment of bacterial extraocular disease in horses. PMID- 25787927 TI - Detecting endotoxin activity in bovine serum using an automated testing system. AB - The aim of the present study was to compare the ability of the commercially available portable test system (PTS(TM)) to detect endotoxin activity in bovine serum, with that of the traditional LAL-kinetic turbidimetric (KT) and chromogenic (KC) assays. Prior to testing, serum samples, which were obtained from endotoxin-challenged cattle, were diluted 1:20 in endotoxin-free water and heated to 80 degrees C for 10 min. The performance of the PTS(TM) was not significantly different from that of the traditional LAL-based assays. The results using PTS(TM) correlated with those using KT (r(2)=0.963, P<0.001) or KC assays (r(2)=0.982, P<0.001). Based on these findings, the PTS(TM) could be applied as a simplified system to assess endotoxin activity in bovine serum. PMID- 25787928 TI - First detection of adiaspiromycosis in the lungs of a deer. AB - Adiaspiromycosis is a pulmonary infection caused by the soil fungi, Emmonsia crescens and E. parva. It primarily affects small mammals and can range from an asymptomatic condition to fatal disseminated disease. We detected a granuloma containing fungal spherules, which were morphologically consistent with the adiaspores of E. crescens in the lungs of a female Hokkaido sika deer. This is the first reported case of adiaspiromycosis involving a cervid in the world. PMID- 25787929 TI - Plasma amino acid profiles at various reproductive stages in female rats. AB - We measured the plasma levels of amino acids at various reproductive stages in female rats, including the estrous cycle, pregnancy and lactation, and compared the resulting amino acid profiles using two- or three-dimensional figures. These figures revealed that the amino acid profiles of pregnant and lactating dams differed considerably from those during the estrous cycle or in male rats. The plasma levels of individual amino acids were almost the same between proestrus, estrus, metestrus and diestrus, and their profiles did not differ significantly. However, the amino acid profiles changed during pregnancy and lactation in dams. The plasma Ser level decreased significantly in mid and late pregnancy, whereas Tyr, Gly and His decreased significantly in the late and end stages of pregnancy, and Trp and Lys significantly decreased and increased at the end of pregnancy, respectively. Much larger changes in amino acid profiles were observed during lactation, when the levels of many amino acids increased significantly, and none showed a significant decrease. Plasma Pro, Ser and Gly levels increased continuously from day 1 until day 15 of lactation, whereas Asn and Met increased significantly from days 1 and 5 respectively until the end of lactation. These results suggest that the profiles of plasma amino acids show characteristic changes according to reproductive stage and that it may be necessary to consider such differences when performing amino acid-based diagnosis. PMID- 25787930 TI - Classification and management of low back pain: Is this the right direction? PMID- 25787931 TI - High frequency functional brain networks in neonates revealed by rapid acquisition resting state fMRI. AB - Understanding how spatially remote brain regions interact to form functional brain networks, and how these develop during the neonatal period, provides fundamental insights into normal brain development, and how mechanisms of brain disorder and recovery may function in the immature brain. A key imaging tool in characterising functional brain networks is examination of T2*-weighted fMRI signal during rest (resting state fMRI, rs-fMRI). The majority of rs-fMRI studies have concentrated on slow signal fluctuations occurring at <0.1 Hz, even though neuronal rhythms, and haemodynamic responses to these fluctuate more rapidly, and there is emerging evidence for crucial information about functional brain connectivity occurring more rapidly than these limits. The characterisation of higher frequency components has been limited by the sampling frequency achievable with standard T2* echoplanar imaging (EPI) sequences. We describe patterns of neonatal functional brain network connectivity derived using accelerated T2* weighted EPI MRI. We acquired whole brain rs-fMRI data, at subsecond sampling frequency, from preterm infants at term equivalent age and compared this to rs fMRI data acquired with standard EPI acquisition protocol. We provide the first evidence that rapid rs-fMRI acquisition in neonates, and adoption of an extended frequency range for analysis, allows identification of a substantial proportion of signal power residing above 0.2 Hz. We thereby describe changes in brain connectivity associated with increasing maturity which are not evident using standard rs-fMRI protocols. Development of optimised neonatal fMRI protocols, including use of high speed acquisition sequences, is crucial for understanding the physiology and pathophysiology of the developing brain. PMID- 25787933 TI - Transparent conductor-embedding nanocones for selective emitters: optical and electrical improvements of Si solar cells. AB - Periodical nanocone-arrays were employed in an emitter region for high efficient Si solar cells. Conventional wet-etching process was performed to form the nanocone-arrays for a large area, which spontaneously provides the graded doping features for a selective emitter. This enables to lower the electrical contact resistance and enhances the carrier collection due to the high electric field distribution through a nanocone. Optically, the convex-shaped nanocones efficiently reduce light-reflection and the incident light is effectively focused into Si via nanocone structure, resulting in an extremely improved the carrier collection performances. This nanocone-arrayed selective emitter simultaneously satisfies optical and electrical improvement. We report the record high efficiency of 16.3% for the periodically nanoscale patterned emitter Si solar cell. PMID- 25787934 TI - Drug coated microneedles for minimally-invasive treatment of oral carcinomas: development and in vitro evaluation. AB - Treatment of recurring oral cancers is challenging as common surgical approaches are not feasible for these patients. In addition, these patients do not respond well to systemic chemotherapy. Localized intratumoral injection of anti-cancer drugs is considered to be an attractive alternative treatment approach for these patients. However, conventional hypodermic injections result in poor distribution of the drug in the tumor and leakage of the drug from the injection site to systemic circulation, in addition to causing pain to the patient. The objective of this study was to develop coated microneedles as a novel device for direct and minimally invasive intratumoral delivery of anti-cancer drugs. Poly(lactic-co glycolic) acid (PLGA) nanoparticles encapsulating doxorubicin (DOX) were prepared and coated on inplane (1D) microneedles. Microscopic evaluation of 3D tissue phantoms and porcine cadaver buccal tissues that were treated with 1D microneedle arrays coated with DOX-PLGA nanoparticles demonstrated that DOX could diffuse both laterally and vertically in to the tissues and produced cellular cytotoxicity. Out of plane (2D) microneedle arrays measuring 1 cm x 1 cm with 57 microneedles coated with free DOX could produce uniform distribution of DOX in a porcine cadaver buccal tissue up to a depth greater than 3 mm. Hypodermic injection of different volumes in to a porcine buccal tissue confirmed significant leakage of the injected volume (about 25% of the injected 80 MUl). In summary, this study demonstrates that drug coated microneedles is an attractive microscale device that can uniformly and effectively deliver drugs to localized oral cancers. This microscale device has potential to impact the treatment of oral cancer patients. PMID- 25787932 TI - The Economic Costs of Type 2 Diabetes: A Global Systematic Review. AB - BACKGROUND: There has been a widely documented and recognized increase in diabetes prevalence, not only in high-income countries (HICs) but also in low- and middle-income countries (LMICs), over recent decades. The economic burden associated with diabetes, especially in LMICs, is less clear. OBJECTIVE: We provide a systematic review of the global evidence on the costs of type 2 diabetes. Our review seeks to update and considerably expand the previous major review of the costs of diabetes by capturing the evidence on overall, direct and indirect costs of type 2 diabetes worldwide that has been published since 2001. In addition, we include a body of economic evidence that has hitherto been distinct from the cost-of-illness (COI) work, i.e. studies on the labour market impact of diabetes. METHODS: We searched PubMed, EMBASE, EconLit and IBSS (without language restrictions) for studies assessing the economic burden of type 2 diabetes published from January 2001 to October 2014. Costs reported in the included studies were converted to international dollars ($) adjusted for 2011 values. Alongside the narrative synthesis and methodological review of the studies, we conduct an exploratory linear regression analysis, examining the factors behind the considerable heterogeneity in existing cost estimates between and within countries. RESULTS: We identified 86 COI and 23 labour market studies. COI studies varied considerably both in methods and in cost estimates, with most studies not using a control group, though the use of either regression analysis or matching has increased. Direct costs were generally found to be higher than indirect costs. Direct costs ranged from $242 for a study on out-of-pocket expenditures in Mexico to $11,917 for a study on the cost of diabetes in the USA, while indirect costs ranged from $45 for Pakistan to $16,914 for the Bahamas. In LMICs-in stark contrast to HICs-a substantial part of the cost burden was attributed to patients via out-of-pocket treatment costs. Our regression analysis revealed that direct diabetes costs are closely and positively associated with a country's gross domestic product (GDP) per capita, and that the USA stood out as having particularly high costs, even after controlling for GDP per capita. Studies on the labour market impact of diabetes were almost exclusively confined to HICs and found strong adverse effects, particularly for male employment chances. Many of these studies also took into account the possible endogeneity of diabetes, which was not the case for COI studies. CONCLUSIONS: The reviewed studies indicate a large economic burden of diabetes, most directly affecting patients in LMICs. The magnitude of the cost estimates differs considerably between and within countries, calling for the contextualization of the study results. Scope remains large for adding to the evidence base on labour market effects of diabetes in LMICs. Further, there is a need for future COI studies to incorporate more advanced statistical methods in their analysis to account for possible biases in the estimated costs. PMID- 25787935 TI - Prenatal exposure to the contaminant perfluorooctane sulfonate elevates lipid peroxidation during mouse fetal development but not in the pregnant dam. AB - Perfluorooctane sulfonate (PFOS), a member of the perfluorinated chemical family, has been convincingly demonstrated to affect lipid metabolism in animals and humans and readily crosses the placenta to exert its effects on the developing fetuses. While its exact mechanism is still not clear, PFOS exposure has long been suggested to exert its toxicity via oxidative stress and/or altered gene expression. Levels of PFOS and malondialdehyde in various organs and cell cultures have been widely determined as general indicators of non-specific lipid peroxidation after PFOS exposure. In this study, the oxidation of precise polyunsaturated fatty acids and their metabolites, derived from enzymatic and non enzymatic pathways was determined following PFOS exposure in both adult and maternal/fetal mice. CD-1 mice were exposed to 3 mg/kg body weight/day of PFOS in corn oil by oral gavage until late gestation (GD17). We demonstrated that lipid peroxidation was particularly and exclusively affected in fetuses exposed to PFOS, but this was not the case in the maternal mice, where limited effects were observed in the enzymatic oxidation pathway. In this study, we demonstrated that PFOS-induced lipid peroxidation might have a greater impact in free radical generation in fetuses than in dams and could be responsible for affecting fetal development. In addition, antioxidant enzymes, such as superoxide dismutase and catalase, appeared to maintain oxidative stress homeostasis partially in adult mice exposed to PFOS. Taken together, our results might elucidate the mechanism of how PFOS induces oxidative stress in vivo. PMID- 25787936 TI - Response to Letter to the Editor by Dr. Witsch et al. PMID- 25787937 TI - Distraction from emotional information reduces biased judgements. AB - Biases arising from emotional processes are some of the most robust behavioural effects in the social sciences. The goal of this investigation was to examine the extent to which the emotion regulation strategy of distraction could reduce biases in judgement known to result from emotional information. Study 1 explored lay views regarding whether distraction is an effective strategy to improve decision-making and revealed that participants did not endorse this strategy. Studies 2-5 focused on several established, robust biases that result from emotional information: loss aversion, desirability bias, risk aversion and optimistic bias. Participants were prompted to divert attention away from their feelings while making judgements, and in each study this distraction strategy resulted in reduced bias in judgement relative to control conditions. The findings provide evidence that distraction can improve choice across several situations that typically elicit robustly biased responses, even though participants are not aware of the effectiveness of this strategy. PMID- 25787938 TI - Identification, characterization and full-length sequence analysis of a novel dsRNA virus isolated from the arboreal ant Camponotus yamaokai. AB - A novel dsRNA virus was identified from the arboreal ant Camponotus yamaokai. The complete nucleotide sequence analysis of the virus revealed that the virus consisted of 5704 bp with two ORFs. ORF1 (3084 nt) encoded a putative capsid protein. ORF2 (1977 nt) encoded a viral RNA-dependent RNA polymerase (RdRp). ORF2 could be translated as a fusion with the ORF1 product by a - 1 frameshift in the overlapping ORF1. Phylogenetic analyses based on the RdRp revealed that the virus from C. yamaokai was most likely a novel totivirus, but it was not closely related to the previously known totiviruses in arthropods. Transmission electron microscopy revealed isometric virus particles of ~30 nm diameter in the cytoplasm, which was consistent with the characteristics of the family Totiviridae. The virus was detected by reverse transcription-PCR in all caste members and developmental stages of ants, including eggs, larvae, pupae, adult workers, alates (male and female) and queens. To our knowledge, this is the first report of a member of the family Totiviridae in a hymenopteran; the virus was designated Camponotus yamaokai virus. PMID- 25787939 TI - Serological survey of Seewis virus antibodies in patients suspected for hantavirus infection in Finland; a cross-reaction between Puumala virus antiserum with Seewis virus N protein? AB - Puumala virus (PUUV, carried by Myodes glareolus) co-circulates with Seewis virus (SWSV, carried by Sorex araneus) in Finland. While PUUV causes 1000-3000 nephropathia epidemica (NE) cases annually, the pathogenicity of SWSV to man is unknown. To study the prevalence of SWSV antibodies in hantavirus fever-like patients' sera, we used recombinant SWSV nucleocapsid (N) protein as the antigen in ELISA, immunofluorescence assay (IFA) and immunoblotting. While characterizing the recombinant SWSV N protein, we observed that a polyclonal rabbit antiserum against PUUV N protein cross-reacted with SWSV N protein and vice versa. We initially screened 486 (450 PUUV-seronegative and 36 PUUV-seropositive) samples sent to Helsinki University Hospital Laboratory for PUUV serodiagnosis during 2002 and 2007 in an SWSV N protein IgG ELISA. In total, 4.2 % (19/450) of the PUUV-seronegative samples were reactive in the SWSV N protein IgG ELISA and none of the tested samples [43 PUUV-seronegative (weakly reactive in the SWSV IgG ELISA) and 15 random] were reactive in the SWSV N protein IgM ELISA. None of the IgG reactions could be confirmed by IFA or immunoblotting. Furthermore, among the 36 PUUV-seropositive samples three were reactive in SWSV N protein IgG and ten in SWSV N protein IgM ELISA. One PUUV-seropositive sample reacted with SWSV N protein in IFA and four in immunoblotting. Finally, we applied competitive ELISA to confirm that the observed reactivity was due to cross-reactivity rather than a true SWSV response. In conclusion, no evidence of SWSV infection was found among the 486 samples studied; however, we did demonstrate that PUUV antiserum cross reacted with shrew-borne hantavirus N protein. PMID- 25787940 TI - Animal models play a vital role in translational aging research. PMID- 25787941 TI - A model of chronic hepatitis in mice expressing a truncated XRCC1 protein. PMID- 25787942 TI - Gut instinct: a diagnostic tool? AB - OBJECTIVES: It is generally accepted that with experience clinicians develop the ability to identify patients who present with malignancy prior to a formal diagnosis. This ability cannot be quantified, nor is it a plausible substitute for investigation. This study aimed to evaluate the association between instinct and head and neck cancer diagnosis. METHODS: A prospective study of patients requiring urgent diagnostic procedures for suspected cancer between August and December 2010 was performed. Risk factors, symptoms, signs and the clinician's impression were recorded. These were graded and subsequently correlated with histology findings. RESULTS: Twenty-seven patients, with a mean age of 62.2 years, underwent a diagnostic procedure. Thirty per cent of patients were referred under the two-week pathway and 18.5 per cent had a previous history of head and neck cancer. A diagnosis of cancer was made in 37 per cent of patients. There was a positive correlation between clinical suspicion and cancer diagnosis (Kendall's tau-b = 0.648749). CONCLUSION: This study highlights the importance of clinical suspicion in cancer diagnosis. Although clinical suspicion cannot be quantified, it should be regarded as an integral part of patient assessment. PMID- 25787943 TI - Odor-cued taste avoidance: a simple and robust test of mouse olfaction. AB - In odor-cued taste avoidance (OCTA), thirsty mice, offered either an odorized nonaversive fluid (S+) or an odorized aversive fluid (S-), quickly learn to use odor to avoid drinking the S-. Acquisition of both odor detection and odor discrimination tasks is very rapid with learning evidenced in most cases by either long response times or total avoidance on the second presentation of the S stimulus. OCTA is perhaps one of the simplest conditioning procedures for assessing olfaction in mice; it requires only a test box, drinkometer circuit, and thirsty mice accustomed to drinking in the apparatus. Its advantages over the most commonly used alternatives, habituation-dishabituation, and the mouse dig test, are discussed. PMID- 25787944 TI - Oxidative potential of particulate matter at a German motorway. AB - Ambient particulate matter (PM10) was sampled alongside a motorway in North-Rhine Westphalia, Germany, during a one-year period. In sum, 120 PM10 samples on quartz fibre filters, 60 samples at each side of the motorway, were taken during clear cross-wind direction situations, i.e. upwind (local background situation) and downwind (traffic influenced). To quantify the traffic-related oxidative potential (OP), or more precisely the hydroxyl radical (OH) generation potency, these samples were analysed to study their hydrogen peroxide dependent oxidant generation by Electron Paramagnetic Resonance (EPR) spectroscopy using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide. In addition the PM10 mass, the chemical composition and the NOx concentrations were determined. For PM10 mass and traffic tracers like Sb, Ba, elemental and organic carbon as well as for NOx, an additional contribution to the background concentration caused by the traffic was observed (factor: 1.3-6.0). The downwind measurements showed in 72% of cases higher OH generation potencies with an average factor of 1.4. Significant correlations to OH were detected for Fe (r > 0.58) and Cu (r > 0.57) for the upwind and overall (upwind + downwind, r > 0.44) dataset. At the downwind side these correlations were absent and are assumed to be covered by the interferences with additional soot particles leading to a quenching of OH. Accordingly, no significant overall correlation of the OH generation potency with the traffic intensity was detected. The suggested quenching effect was confirmed via standard diesel soot (SRM 2975) measurements using the EPR approach. In summary, the traffic related PM causes an intrinsic OH generation via Fenton-like reaction but obviously also leads to interferences and scavenging by traffic related carbonaceous compounds. In consequence, for future studies that would link the intrinsic OP and adverse health effects we suggest to analyse the relationship to EC/OC and to use in parallel also a further OP detection method. PMID- 25787945 TI - Bone loss of the superior adjacent vertebral body immediately posterior to the anterior flange of Bryan cervical disc. AB - BACKGROUND: No previous reports have mentioned bone loss of the superior adjacent vertebra immediately posterior to the anterior flange of Bryan cervical disc (Medtronic Sofamor Danek, Memphis, TN, USA), which plays a central role to prevent posterior migration of the device. The purpose of this study is to describe a new potential complication, bone loss immediately posterior to the anterior total disc replacement (TDR) flange on the superior adjacent vertebra following the Bryan cervical TDR and to discuss the possible mechanism. METHODS: The authors retrospectively reviewed 37 patients undergoing cervical TDR with the Bryan cervical disc. The clinical and radiological outcome data were collected at 1, 3, 6, 12, 24, and 36 months postoperatively, and at last follow-up, which ranged from 42 to 113 moths (average, 60.1 months). Clinical evaluation included the visual analog scale and neck disability index, and the radiographic evaluation included measurements of the functional spinal unit range of motion on flexion and extension and identification of radiographic changes such as bone loss. RESULTS: The Bryan TDR showed good mid-term clinical and radiological outcomes. Interestingly, however, bone loss was noted immediately posterior to the TDR flange on superior adjacent vertebra in 3 total patients; at 3 months (n = 2) and 6 months (n = 1). Although the bone loss was increased up to 6 months, this did not progress and no degradation of clinical and radiological outcomes occurred at last follow-up. CONCLUSIONS: Bone loss immediately posterior to the anterior TDR flange on the superior adjacent vertebra can occur in the early postoperative period due to possibly stress shielding effect. However, it did not result in clinical changes or increased rates of graft failure at last follow-up. A long-term follow-up study is mandatory to evaluate the long-term effects of the bone loss. PMID- 25787946 TI - [Gross hematuria in sickle cell disease at Tokoin teaching hospital in Lome (Togo)]. AB - The renal complications of sickle cell anemia are well known. Gross hematuria is one of these, although it is associated more often with the sickle cell trait than with the disease. Nonetheless, in Togo, where the frequency of S gene is 16%, hematuria is rarely report in people with this gene. We describe 3 cases of gross hematuria in patients with sickle cell disease: primary hematuria associated with sickle cell disease. We found no promoting factors in our patients. The course was short, and after 4 to 15 years, there have been no recurrences. PMID- 25787947 TI - Protective effect of mirtazapine and hesperidin on cyclophosphamide-induced oxidative damage and infertility in rat ovaries. AB - Cyclophosphamide (CP) causes infertility due to ovarian toxicity. The toxicity mechanism suggests oxidative stress. We assessed whether mirtazapine (MTZ) and hesperidin (HSP) could promote ovarian protection against damage due to CP chemotherapy. Female Wistar rats aged 14 weeks were used. Animals were divided into four groups: control vehicle group (n = 8); CP group (n = 8, rats received 150 mg/kg of CP, single intraperitoneal [i.p.] injection); CP + MTZ group (n = 8, rats received same dose of CP + 30 mg/kg of MTZ, orally, daily); and HSP + CP group (n = 8, rats received same dose of CP + 100 mg/kg of HSP, orally, daily). After eight days of medication, ovaries were removed and ovarian toxicity was assessed by counting follicles and corpora lutea. Nitric oxide (NO) and malondialdehyde (MDA) levels, myeloperoxidase (MPO), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities were estimated in ovarian tissue. NO level, MDA level, and MPO activity were increased (P < 0.001), while, GPx and SOD activities were lowered significantly (P < 0.001) in CP-treated group compared with control vehicle. In addition, ovulation, number of follicles, and ovarian weight were reduced by CP treatment. On the contrary, rats pretreated with MTZ and HSP showed significant decrease in NO, MDA levels, and MPO activity, while, activities of SOD and GPx were increased (P < 0.001). Oxidative stress induced by CP in the rat ovary causes infertility in the female rats. HSP and MTZ could reverse this effect and provide protection of fertility against CP-induced toxicity. PMID- 25787949 TI - Discriminating neural representations of physical and social pains: how multivariate statistics challenge the "shared representation" theory of pain. AB - Overlapping functional magnetic resonance imaging (fMRI) activity elicited by physical pain and social rejection has posited a common neural representation between the two experiences. However, Woo and colleagues (Nat Commun 5: 5380, 2014) recently used multivariate statistics to challenge the "shared representation" theory of pain. This study has implications in the way results from fMRI studies are interpreted and has the potential of broadening our understanding of different pain states and future development of personalized medicine. PMID- 25787948 TI - Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice. AB - Neurosteroids are formed de novo in the brain and can modulate both inhibitory and excitatory neurotransmission. Recent evidence suggests that the anxiolytic effects of neurosteroids are mediated by the amygdala, a key structure for emotional and cognitive behaviors. Tonic inhibitory signaling via extrasynaptic type A gamma-aminobutyric acid receptors (GABA(A)Rs) is known to be crucially involved in regulating network activity in various brain regions including subdivisions of the amygdala. Here we provide evidence for the existence of tonic GABAergic inhibition generated by the activation of delta-subunit-containing GABA(A)Rs in neurons of the lateral section of the mouse central amygdala (CeAl). Furthermore, we show that neurosteroids play an important role in the modulation of tonic GABAergic inhibition in the CeAl. Taken together, these findings provide new mechanistic insights into the effects of pharmacologically relevant neurosteroids in the amygdala and might be extrapolated to the regulation of anxiety. PMID- 25787950 TI - Human Na(v)1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. AB - Although species-specific differences in ion channel properties are well documented, little has been known about the properties of the human Nav1.8 channel, an important contributor to pain signaling. Here we show, using techniques that include voltage clamp, current clamp, and dynamic clamp in dorsal root ganglion (DRG) neurons, that human Na(v)1.8 channels display slower inactivation kinetics and produce larger persistent current and ramp current than previously reported in other species. DRG neurons expressing human Na(v)1.8 channels unexpectedly produce significantly longer-lasting action potentials, including action potentials with half-widths in some cells >10 ms, and increased firing frequency compared with the narrower and usually single action potentials generated by DRG neurons expressing rat Na(v)1.8 channels. We also show that native human DRG neurons recapitulate these properties of Na(v)1.8 current and the long-lasting action potentials. Together, our results demonstrate strikingly distinct properties of human Na(v)1.8, which contribute to the firing properties of human DRG neurons. PMID- 25787951 TI - Compensatory plasticity restores locomotion after chronic removal of descending projections. AB - Homeostatic plasticity is an important attribute of neurons and their networks, enabling functional recovery after perturbation. Furthermore, the directed nature of this plasticity may hold a key to the restoration of locomotion after spinal cord injury. Here we studied the recovery of crawling in the leech Hirudo verbana after descending cephalic fibers were surgically separated from crawl central pattern generators shown previously to be regulated by dopamine. We observed that immediately after nerve cord transection leeches were unable to crawl, but remarkably, after a day to weeks, animals began to show elements of crawling and intersegmental coordination. Over a similar time course, excessive swimming due to the loss of descending inhibition returned to control levels. Additionally, removal of the brain did not prevent crawl recovery, indicating that connectivity of severed descending neurons was not essential. After crawl recovery, a subset of animals received a second transection immediately below the anterior-most ganglion remaining. Similar to their initial transection, a loss of crawling with subsequent recovery was observed. These data, in recovered individuals, support the idea that compensatory plasticity directly below the site of injury is essential for the initiation and coordination of crawling. We maintain that the leech provides a valuable model to understand the neural mechanisms underlying locomotor recovery after injury because of its experimental accessibility, segmental organization, and dependence on higher-order control involved in the initiation, modulation, and coordination of locomotor behavior. PMID- 25787953 TI - Assessment of nonlinear interactions in event-related potentials elicited by stimuli presented at short interstimulus intervals using single-trial data. AB - The recording of brain event-related potentials (ERPs) is a widely used technique to investigate the neural basis of sensory perception and cognitive processing in humans. Due to the low magnitude of ERPs, averaging of several consecutive stimuli is typically employed to enhance the signal to noise ratio (SNR) before subsequent analysis. However, when the temporal interval between two consecutive stimuli is smaller than the latency of the main ERP peaks, i.e., when the stimuli are presented at a fast rate, overlaps between the corresponding ERPs may occur. These overlaps are usually dealt with by assuming that there is a simple additive superposition between the elicited ERPs and consequently performing algebraic waveform subtractions. Here, we test this assumption rigorously by providing a statistical framework that examines the presence of nonlinear additive effects between overlapping ERPs elicited by successive stimuli with short interstimulus intervals (ISIs). The results suggest that there are no nonlinear additive effects due to the time overlap per se but that, for the range of ISIs examined, the second ERP is modulated by the presence of the first stimulus irrespective of whether there is time overlap or not. In other words, two ERPs that overlap in time can still be written as an addition of two ERPs but with the second ERP being different from the first. This difference is also present in the case of nonoverlapping ERPs with short ISIs. The modulation effect elicited on the second ERP by the first stimulus is dependent on the ISI value. PMID- 25787952 TI - Dorsal premotor cortex: neural correlates of reach target decisions based on a color-location matching rule and conflicting sensory evidence. AB - We recorded single-neuron activity in dorsal premotor (PMd) and primary motor cortex (M1) of two monkeys in a reach-target selection task. The monkeys chose between two color-coded potential targets by determining which target's color matched the predominant color of a multicolored checkerboard-like Decision Cue (DC). Different DCs contained differing numbers of colored squares matching each target. The DCs provided evidence about the correct target ranging from unambiguous (one color only) to very ambiguous and conflicting (nearly equal number of squares of each color). Differences in choice behavior (reach response times and success rates as a function of DC ambiguity) of the monkeys suggested that each applied a different strategy for using the target-choice evidence in the DCs. Nevertheless, the appearance of the DCs evoked a transient coactivation of PMd neurons preferring both potential targets in both monkeys. Reach response time depended both on how long it took activity to increase in neurons that preferred the chosen target and on how long it took to suppress the activity of neurons that preferred the rejected target, in both correct-choice and error choice trials. These results indicate that PMd neurons in this task are not activated exclusively by a signal proportional to the net color bias of the DCs. They are instead initially modulated by the conflicting evidence supporting both response choices; final target selection may result from a competition between representations of the alternative choices. The results also indicate a temporal overlap between action selection and action initiation processes in PMd and M1. PMID- 25787954 TI - The influence of cochlear spectral processing on the timing and amplitude of the speech-evoked auditory brain stem response. AB - The speech-evoked auditory brain stem response (speech ABR) is widely considered to provide an index of the quality of neural temporal encoding in the central auditory pathway. The aim of the present study was to evaluate the extent to which the speech ABR is shaped by spectral processing in the cochlea. High-pass noise masking was used to record speech ABRs from delimited octave-wide frequency bands between 0.5 and 8 kHz in normal-hearing young adults. The latency of the frequency-delimited responses decreased from the lowest to the highest frequency band by up to 3.6 ms. The observed frequency-latency function was compatible with model predictions based on wave V of the click ABR. The frequency-delimited speech ABR amplitude was largest in the 2- to 4-kHz frequency band and decreased toward both higher and lower frequency bands despite the predominance of low frequency energy in the speech stimulus. We argue that the frequency dependence of speech ABR latency and amplitude results from the decrease in cochlear filter width with decreasing frequency. The results suggest that the amplitude and latency of the speech ABR may reflect interindividual differences in cochlear, as well as central, processing. The high-pass noise-masking technique provides a useful tool for differentiating between peripheral and central effects on the speech ABR. It can be used for further elucidating the neural basis of the perceptual speech deficits that have been associated with individual differences in speech ABR characteristics. PMID- 25787955 TI - Robust presynaptic serotonin 5-HT(1B) receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment. AB - The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT(1B)Rs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT(1B)Rs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT(1B)R agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT(1B)R-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT(1B)Rs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5 HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT(1B)R-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment. PMID- 25787956 TI - Short-term peripheral nerve stimulation ameliorates axonal dysfunction after spinal cord injury. AB - There is accumulating evidence that peripheral motor axons deteriorate following spinal cord injury (SCI). Secondary axonal dysfunction can exacerbate muscle atrophy, contribute to peripheral neuropathies and neuropathic pain, and lead to further functional impairment. In an attempt to ameliorate the adverse downstream effects that developed following SCI, we investigated the effects of a short-term peripheral nerve stimulation (PNS) program on motor axonal excitability in 22 SCI patients. Axonal excitability studies were undertaken in the median and common peroneal nerves (CPN) bilaterally before and after a 6-wk unilateral PNS program. PNS was delivered percutaneously over the median nerve at the wrist and CPN around the fibular head, and the compound muscle action potential (CMAP) from the abductor pollicis brevis and tibialis anterior was recorded. Stimulus intensity was above motor threshold, and pulses (450 MUs) were delivered at 100 Hz with a 2 s on/off cycle for 30 min 5 days/wk. SCI patients had consistently high thresholds with a reduced CMAP consistent with axonal loss; in some patients the peripheral nerves were completely inexcitable. Nerve excitability studies revealed profound changes in membrane potential, with a "fanned-in" appearance in threshold electrotonus, consistent with membrane depolarization, and significantly reduced superexcitability during the recovery cycle. These membrane dysfunctions were ameliorated after 6 wk of PNS, which produced a significant hyperpolarizing effect. The contralateral, nonstimulated nerves remained depolarized. Short-term PNS reversed axonal dysfunction following SCI, may provide an opportunity to prevent chronic changes in axonal and muscular function, and may improve rehabilitation outcomes. PMID- 25787957 TI - Intrinsic excitability of human motoneurons in biceps brachii versus triceps brachii. AB - The intrinsic excitability of spinal motoneurons is mediated in part by the presence of persistent inward currents (PICs), which amplify synaptic input and promote self-sustained firing. Studies using animal models have shown that PICs are greater in extensor motoneurons over flexor motoneurons, but this difference has not yet been demonstrated in humans. The primary objective of this study was to determine whether a similar difference exists in humans by recording from motor units in biceps and triceps brachii during isometric contractions. We compared firing rate profiles of pairs of motor units, in which the firing rate of the lower-threshold "control" unit was used as an indicator of common drive to the higher-threshold "test" unit. The estimated contribution of the PIC was calculated as the difference in firing rate of the control unit at recruitment versus derecruitment of the test unit, a value known as the delta-F (DeltaF). We found that DeltaF values were significantly higher in triceps brachii (5.4 +/- 0.9 imp/s) compared with biceps brachii (3.0 +/- 1.4 imp/s; P < 0.001). This difference was still present even after controlling for saturation in firing rate of the control unit, rate modulation of the control unit, and differences in recruitment time between test and control units, which are known to contribute to DeltaF variability. We conclude that human elbow flexor and extensor motor units exhibit differences in intrinsic excitability, contributing to different neural motor control strategies between muscle groups. PMID- 25787958 TI - TRPV1 expression level in isolectin B4-positive neurons contributes to mouse strain difference in cutaneous thermal nociceptive sensitivity. AB - Differential thermal nociception across inbred mouse strains has genetic determinants. Thermal nociception is largely attributed to the heat/capsaicin receptor transient receptor potential vanilloid 1 (TRPV1); however, the contribution of this channel to the genetics of thermal nociception has not been revealed. In this study we compared TRPV1 expression levels and electrophysiological properties in primary sensory neurons and thermal nociceptive behaviors between two (C57BL/6 and BALB/c) inbred mouse strains. Using immunofluorescence and patch-clamp physiology methods, we demonstrated that TRPV1 expression was significantly higher in isolectin B4 (IB4)-positive trigeminal sensory neurons of C57BL/6 relative to BALB/c; the expression in IB4 negative neurons was similar between the strains. Furthermore, using electrophysiological cell classification (current signature method), we showed differences between the two strains in capsaicin sensitivity in IB4-positive neuronal cell types 2 and 13, which were previously reported as skin nociceptors. Otherwise electrophysiological membrane properties of the classified cell types were similar in the two mouse strains. In publicly available nocifensive behavior data and our own behavior data from the using the two mouse strains, C57BL/6 exhibited higher sensitivity to heat stimulation than BALB/c, independent of sex and anatomical location of thermal testing (the tail, hind paw, and whisker pad). The TRPV1-selective antagonist JNJ-17203212 inhibited thermal nociception in both strains; however, removing IB4-positive trigeminal sensory neurons with IB4 conjugated saporin inhibited thermal nociception on the whisker pad in C57BL/6 but not in BALB/c. These results suggest that TRPV1 expression levels in IB4 positive type 2 and 13 neurons contributed to differential thermal nociception in skin of C57BL/6 compared with BALB/c. PMID- 25787959 TI - Adaptive shaping of cortical response selectivity in the vibrissa pathway. AB - One embodiment of context-dependent sensory processing is bottom-up adaptation, where persistent stimuli decrease neuronal firing rate over hundreds of milliseconds. Adaptation is not, however, simply the fatigue of the sensory pathway, but shapes the information flow and selectivity to stimulus features. Adaptation enhances spatial discriminability (distinguishing stimulus location) while degrading detectability (reporting presence of the stimulus), for both the ideal observer of the cortex and awake, behaving animals. However, how the dynamics of the adaptation shape the cortical response and this detection and discrimination tradeoff is unknown, as is to what degree this phenomenon occurs on a continuum as opposed to a switching of processing modes. Using voltage sensitive dye imaging in anesthetized rats to capture the temporal and spatial characteristics of the cortical response to tactile inputs, we showed that the suppression of the cortical response, in both magnitude and spatial spread, is continuously modulated by the increasing amount of energy in the adapting stimulus, which is nonuniquely determined by its frequency and velocity. Single trial ideal observer analysis demonstrated a tradeoff between detectability and spatial discriminability up to a moderate amount of adaptation, which corresponds to the frequency range in natural whisking. This was accompanied by a decrease in both detectability and discriminability with high-energy adaptation, which indicates a more complex coupling between detection and discrimination than a simple switching of modes. Taken together, the results suggest that adaptation operates on a continuum and modulates the tradeoff between detectability and discriminability that has implications for information processing in ethological contexts. PMID- 25787960 TI - Long-range intralaminar noise correlations in the barrel cortex. AB - Identifying the properties of correlations in the firing of neocortical neurons is central to our understanding of cortical information processing. It has been generally assumed, by virtue of the columnar organization of the neocortex, that the firing of neurons residing in a certain vertical domain is highly correlated. On the other hand, firing correlations between neurons steeply decline with horizontal distance. Technical difficulties in sampling neurons with sufficient spatial information have precluded the critical evaluation of these notions. We used 128-channel "silicon probes" to examine the spike-count noise correlations during spontaneous activity between multiple neurons with identified laminar position and over large horizontal distances in the anesthetized rat barrel cortex. Eigen decomposition of correlation coefficient matrices revealed that the laminar position of a neuron is a significant determinant of these correlations, such that the fluctuations of layer 5B/6 neurons are in opposite direction to those of layers 5A and 4. Moreover, we found that within each experiment, the distribution of horizontal, intralaminar spike-count correlation coefficients, up to a distance of ~1.5 mm, is practically identical to the distribution of vertical correlations. Taken together, these data reveal that the neuron's laminar position crucially affects its role in cortical processing. Moreover, our analyses reveal that this laminar effect extends over several functional columns. We propose that within the cortex the influence of the horizontal elements exists in a dynamic balance with the influence of the vertical domain and this balance is modulated with brain states to shape the network's behavior. PMID- 25787962 TI - Is the place cell a "supple" engram? AB - This short note, which honors Nobelists O'Keefe and the Mosers, asks how the patterning of inputs to a single place cell regulates its firing. Because the combination of inputs to a single CA1 place cell is very large, the generally accepted view is rejected that inputs to a place cell are relatively restricted, near identical repetition upon re-presentation of the environment. The alternative proposed here is that when any 100 excitatory inputs are fired activating a subset combination, which is a large number, selected from the 30,000 synapses, this leads to CA1 cell firing. The selection of the combination of inputs is a very large number it nonetheless leads to the conclusion that even though the same cell dutifully fires when the animal is in an identical location, the inputs that fire the place cell are nonetheless obligatorily non-identical. This CA1 input combinatorial proposal may help us understand the physiological underpinnings of the memory mechanism arising from supple synapses (Routtenberg (2013), Hippocampus 23:202-206). PMID- 25787963 TI - Large eddy simulation of wind-induced interunit dispersion around multistory buildings. AB - Previous studies regarding interunit dispersion used Reynolds-averaged Navier Stokes (RANS) models and thus obtained only mean dispersion routes and re-entry ratios. Given that the envelope flow around a building is highly fluctuating, mean values could be insufficient to describe interunit dispersion. This study investigates the wind-induced interunit dispersion around multistory buildings using the large eddy simulation (LES) method. This is the first time interunit dispersion has been investigated transiently using a LES model. The quality of the selected LES model is seriously assured through both experimental validation and sensitivity analyses. Two aspects are paid special attention: (i) comparison of dispersion routes with those provided by previous RANS simulations and (ii) comparison of timescales with those of natural ventilation and the survival times of pathogens. The LES results reveal larger dispersion scopes than the RANS results. Such larger scopes could be caused by the fluctuating and stochastic nature of envelope flows, which, however, is canceled out by the inherent Reynolds-averaged treatment of RANS models. The timescales of interunit dispersion are comparable with those of natural ventilation. They are much shorter than the survival time of most pathogens under ordinary physical environments, indicating that interunit dispersion is a valid route for disease transmission. PMID- 25787961 TI - Population coding in area V4 during rapid shape detections. AB - While previous studies have suggested that neuronal correlations are common in visual cortex over a range of timescales, the effect of correlations on rapid visually based decisions has received little attention. We trained Macaca mulatta to saccade to a peripherally presented shape embedded in dynamic noise as soon as the shape appeared. While the monkeys performed the task, we recorded from neuronal populations (5-29 cells) using a microelectrode array implanted in area V4, a visual area thought to be involved in form perception. While modest correlations were present between cells during visual stimulation, their magnitude did not change significantly subsequent to the appearance of a shape. We quantified the reliability and temporal precision with which neuronal populations signaled the appearance of the shape and predicted the animals' choices using mutual information analyses. To study the impact of correlations, we shuffled the activity from each cell across observations while retaining stimulus-dependent modulations in firing rate. We found that removing correlations by shuffling across trials minimally affected the reliability or timing with which pairs, or larger groups of cells, signaled the presence of a shape. To assess the downstream impact of correlations, we also studied how shuffling affected the ability of V4 populations to predict behavioral choices. Surprisingly, shuffling created a modest increase in the accuracy of such predictions, suggesting that the reliability of downstream neurons is slightly compromised by activity correlations. Our findings are consistent with neuronal correlations having a minimal effect on the reliability and timing of rapid perceptual decisions. PMID- 25787964 TI - Antimicrobial Photosensitizers: Drug Discovery Under the Spotlight. AB - Although photodynamic therapy (PDT) was discovered over a hundred years ago by its ability to destroy microorganisms, it has been developed mainly as a cancer therapy. In recent years, due to the inexorable rise in multi-antibiotic resistant strains of pathogens, PDT is being considered as a versatile antimicrobial approach to which microbial cells will not be able to develop resistance. The goal of this review is to survey the different classes of chemical compounds that have been tested as antimicrobial photosensitizers. Some of these compounds have been known for many years, while others have been rationally designed based on recently discovered structural principles. Tetrapyrrole-based compounds (some of which are approved as cancer therapies) that efficiently generate singlet oxygen are more efficient and broad-spectrum when they bear cationic charges, As the macrocycle structure moves from porphyrins to chlorins to phthalocyanines to bacteriochlorins the long wavelength absorption moves to the near-infrared where tissue penetration is better. Four main types of natural products have been tested: curcumin, riboflavin, hypericin and psoralens. Phenothiazinium dyes, such as methylene blue and toluidine blue, have been tested, and some are clinically approved. A variety of non phenothiazinium dyes with xanthene, triarylmethane and indocyanine structures have also been tested. New ring structures based on BODIPY, squaraine and fullerene cages can also mediate antimicrobial PDT. Finally the process of photocatalysis using titanium dioxide can also have medical uses. Designing new antimicrobial photosensitizers is likely to keep chemists engaged for a long time to come. PMID- 25787965 TI - Renaissance in Antibiotic Discovery: Some Novel Approaches for Finding Drugs to Treat Bad Bugs. AB - With the alarming resistance to currently used antibiotics, there is a serious worldwide threat to public health. Therefore, there is an urgent need to search for new antibiotics or new cellular targets which are essential for survival of the pathogens. However, during the past 50 years, only two new classes of antibiotics (oxazolidinone and lipopeptides) have reached the clinic. This suggests that the success rate in discovering new/novel antibiotics using conventional approaches is limited and that we must reconsider our antibiotic discovery approaches. While many new strategies are being pursued lately, this review primarily focuses only on a few of these novel/new approaches for antibiotic discovery. These include structure-based drug design (SBDD), the genomic approach, anti-virulence strategy, targeting nonmultiplying bacteria and the use of bacteriophages. In general, recent advancements in nuclear magnetic resonance, Xcrystallography, and genomic evolution have significant impact on antibacterial drug research. This review therefore aims to discuss recent strategies in searching new antibacterial agents making use of these technical novelties, their advantages, disadvantages and limitations. PMID- 25787971 TI - Polypoidal subepicardial lipoma of the right atrium. PMID- 25787966 TI - Sterol Biosynthesis Pathway as an Alternative for the Anti-Protozoan Parasite Chemotherapy. AB - Sterols play an essential role in the physiology of eukaryotic cells; they play a pivotal role in the normal structure and function of cell membranes and also act as precursors for the synthesis of several different molecules like steroid hormones. Trypanosomatids and fungi have an essential requirement of ergosterol and other 24-alkyl sterols, which are absent in mammalian cells, for their survival and growth. At least 20 metabolic steps are necessary to synthesize sterols as cholesterol and ergosterol with the involvement of different specific enzymes. Some enzymes have been studied in detail in order to find new inhibitors that are able to abolish the parasite growth in vitro; besides, they also promote the curative efficacy in murine models of infection, thus opening new possibilities to introduce new drugs for the treatment of leishmaniasis and Chagas' disease. Sterols biosynthesis inhibitors (SBIs) can potentially be used as a chemotherapeutic agent against trypanosomatids. Actually, there are several drugs that interfere with the SB pathway, and some of them are already in clinical trials, such as posaconazole, and a new pro-drug, the ravuconazole. Furthermore, new approaches are being used, such as the combination of drugs, to reduce the resistance and minimize toxic effects. In this review, we discuss the main steps of the SB pathway, showing each enzyme involved in the steps, as well as the antiproliferative, physiological, biochemical, and ultrastructural effects of the several known inhibitors. PMID- 25787972 TI - Cor triatriatum sinistrum presenting in adulthood. PMID- 25787973 TI - Mitral valve repair for rheumatic mitral regurgitation: Mid-term results. AB - AIM: This retrospective study was undertaken to evaluate the midterm results of mitral valve repair for rheumatic mitral regurgitation, in term of survival rate and late valve failure. METHODS: From January 2003 to January 2014, 97 patients underwent mitral valve repair in our hospital. Age ranged from 8 to 74 years, mean 24 +/- 1.4 years; 74 (76%) patients were female. Mean preoperative functional class was 2.47 +/- 0.07. Mean preoperative ejection fraction was 59.9% +/- 2%. The lesions were pure mitral regurgitation in 79 (81.4%) patients, predominant mitral regurgitation with stenosis in 9 (9.3%), and predominant mitral stenosis with regurgitation in 9 (9.3%). Seventy-one (73%) patients were in normal sinus rhythm. RESULTS: One patient died in the postoperative period, and 8 were lost during follow-up. Follow-up time ranged from 6 to 137 months, mean 58.8 +/- 4.2 months. There were 6 late deaths. Actuarial survival at 5 and 10 years was 95.5% and 89.2%, respectively. Twenty-seven (27.8%) patients had mitral regurgitation during follow-up, and 7 underwent reoperation with no hospital mortality. Freedom from reoperation at 5 and 10 years was 94.5% and 82.7%, respectively. Freedom from reoperation or progression of mitral regurgitation at 5 and 10 years was 70.4% and 61.8%, respectively. Freedom from all late events at 5 and 10 years was 68 % and 56.4%, respectively. CONCLUSIONS: Mitral valve repair for rheumatic mitral regurgitation is associated with a significant rate of valve failure and reoperation. However, it has a satisfactory survival rate and is a good alternative to valve replacement, especially for young patients, to avoid the life-long risks of a prosthetic valve. PMID- 25787975 TI - Cirsoid aneurysm: a clinicopathological reminder. PMID- 25787974 TI - Consequence of the tumor-associated conversion to cyclin D1b. AB - Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant. PMID- 25787976 TI - Clinicopathologic features of primary cutaneous melanoma: a single centre analysis of a Swiss regional population. AB - BACKGROUND: Melanoma is a common type of skin cancer with poor survival in advanced stages. Screening efforts aim to detect and tackle tumors at an early stage. However, regional population-based data at the time of initial diagnosis are sparse. OBJECTIVES: To analyse clinical and pathologic tumor characteristics in a Swiss population. MATERIALS AND METHODS: Melanoma samples diagnosed at a large Swiss academic department were evaluated for demographic, clinical and histopathologic data. RESULTS: We analysed a total of 254 melanoma samples. In situ tumors were more common in females than in males (70.6% vs. 29.4%; p = 0.0032). The acro-lentiginous subtype was more common in in situ compared to invasive tumors (14.7% vs. 5.5%; p = 0.0011). Invasive tumors showed a preference for male gender in patients beyond 60 years of age (p = 0.0080). The most frequent anatomic sites were the trunk in males and the legs in females. Regression was more common in males than in females (35.2% vs. 11.7%; p = 0.0001). Breslow's thickness correlated significantly with age but not with gender. Ulceration was common in tumors thicker than 2.01 mm (48.4%; p = 0.0001). Regression was frequently detected in melanomas thinner than 1.00 mm (29.3%; p = 0.0263). CONCLUSION: Screening efforts should target elderly patients. Skin examinations should include acral localisations and focus on the trunk in males and the lower extremities in females. Population-based analyses can help to fine tune melanoma screening in defined regional populations. PMID- 25787978 TI - [Systematics of injuries of the rotator cuff and biceps tendon]. AB - PERFORMANCE: Injuries of the rotator cuff and the biceps tendon demonstrate different patterns, which can be recognized clinically and radiologically. ACHIEVEMENTS: These patterns are impingement syndrome with additional trauma, isolated trauma of the rotator cuff and shoulder dislocation causing rotator cuff tears. Furthermore, it is clinically crucial to evaluate the extent of a rotator cuff injury. PRACTICAL RECOMMENDATION: Magnetic resonance imaging (MRI) is the modality of choice to differentiate these patterns. PMID- 25787977 TI - Lantibiotic resistance. AB - The dramatic rise in the incidence of antibiotic resistance demands that new therapeutic options will have to be developed. One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine containing peptides. It is interesting that low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Given that there are very few examples of naturally occurring lantibiotic resistance, attempts have been made to deliberately induce resistance phenotypes in order to investigate this phenomenon. Mechanisms that hinder the action of lantibiotics are often innate systems that react to the presence of any cationic peptides/proteins or ones which result from cell well damage, rather than being lantibiotic specific. Such resistance mechanisms often arise due to altered gene regulation following detection of antimicrobials/cell wall damage by sensory proteins at the membrane. This facilitates alterations to the cell wall or changes in the composition of the membrane. Other general forms of resistance include the formation of spores or biofilms, which are a common mechanistic response to many classes of antimicrobials. In rare cases, bacteria have been shown to possess specific antilantibiotic mechanisms. These are often species specific and include the nisin lytic protein nisinase and the phenomenon of immune mimicry. PMID- 25787980 TI - Cancer stem cells. PMID- 25787979 TI - Effects of supplementing rare earth element cerium on rumen fermentation, nutrient digestibility, nitrogen balance and plasma biochemical parameters in beef cattle. AB - The objectives of the trial were to investigate the effects of supplementing rare earth element (REE) cerium (Ce) on rumen fermentation, nutrient digestibility, methane (CH4 ) production, nitrogen (N) balance and plasma biochemical parameters in beef cattle. Four Simmental male cattle, aged at 14 months, with initial liveweight of 355 +/- 8 kg and fitted with permanent rumen cannulas, were used as experimental animals. The cattle were fed with a total mixed ration (TMR) composed of concentrate mixture and corn silage. Four levels of cerium chloride (CeCl3 .7H2 O, purity 99.9%), that is 0, 80, 160 and 240 mg CeCl3 /kg DM, were added to basal ration in a 4 * 4 Latin square design. Each experimental period lasted 15 days, of which the first 12 days were for pre-treatment and the last 3 days were for sampling. The results showed that supplementing CeCl3 at 160 or 240 mg/kg DM increased neutral detergent fibre (NDF) digestibility (p < 0.05) and tended to increased acid detergent fibre (ADF) digestibility (p = 0.083). Supplementing CeCl3 at 80, 160 or 240 mg/kg DM decreased the molar ratio of rumen acetate to propionate linearly (p < 0.05). Supplementing CeCl3 at 160 or 240 mg/kg DM decreased total N excretion, urinary N excretion and increased N retention (p < 0.05), increased excretion of total urinary purine derivatives (PD) (p < 0.05) and decreased CH4 /kg DMI (p < 0.05). In conclusion, supplementing CeCl3 at 160 or 240 mg/kg DM in the ration of beef cattle increased the digestibility of NDF, decreased the molar ratio of rumen acetate to propionate, increased N retention and microbial N flow and decreased CH4 /kg DMI. PMID- 25787982 TI - Identification and characterization of a novel scFv recognizing human and mouse CD133. AB - CD133, also known as Prominin-1, is expressed on stem cells present in many tissues and tumors. In this work, we have identified and characterized a single chain variable fragment (scFv) for the efficient and specific recognition of CD133. Phage display was used to develop the scFv from a previously reported anti CD133 hybridoma clone 7, which was capable of recognizing both glycosylated and non-glycosylated forms of human CD133. The scFv immunostained CD133(+) Caco-2 cells, but not CD133(-/low) U87 cells. Significantly, it immunostained CD133(-) cells transiently transfected with the mouse CD133 gene as well as CD133(+) mouse cells. Co-immunostaining studies in mouse bone marrow cells, using anti-CD133 scFv-FITC and anti-mouse CD133-PE (clone 13A4) commercial antibody, indicated that the epitopes recognized by these reagents partially overlap. Taken together, these results suggest that the scFv can recognize mouse CD133 protein in addition to recognizing human CD133. This new scFv is expected to be valuable both as a molecular diagnostic reagent for identifying CD133(+) cells and as a ligand for targeting therapeutics to CD133(+) tumor-initiating cells. PMID- 25787981 TI - Cell surface markers of cancer stem cells: diagnostic macromolecules and targets for drug delivery. AB - The recognition that the persistence of cancer stem cells (CSCs) in patients following chemotherapy can result in disease relapse underscores the necessity to develop therapeutics against those cells. CSCs display a unique repertoire of cell surface macromolecules, which have proven essential for their characterization and isolation. Additionally, CSC-specific cell surface macromolecules or markers provide targets for the development of specific agents to destroy them. In this review, we compiled those cell surface molecules that have been validated as CSC markers for many common blood and solid tumors. We describe the unique chemical and structural features of the most common cell surface markers, as well as recent efforts to deliver chemotherapeutic agents into CSCs by targeting those macromolecules. PMID- 25787984 TI - Immunotoxin targeting CD133(+) breast carcinoma cells. AB - CD133 expression enriches for tumor-initiating cells and is a negative prognostic factor in numerous cancers. We previously developed an immunotoxin against CD133 by fusing a gene fragment encoding the scFv portion of an anti-CD133 antibody to a gene fragment encoding deimmunized PE38KDEL. The resulting fusion protein, dCD133KDEL, demonstrated potent antitumor activity following intratumoral delivery into head neck cell carcinoma xenografts. However, the efficacy against other tumors and the tolerability of systemic administration remained unclear. The purpose of this study was to evaluate the tolerability and efficacy of dCD133KDEL in a systemic human breast carcinoma model. Time course viability studies showed that dCD133KDEL selectively inhibited MDA-MB-231 ductal breast carcinoma cells that contained a minority CD133(+) subpopulation, implicating CD133(+) cells as a source for self-renewal within this cell line. Furthermore, systemic administration of dCD133KDEL caused regression or inhibition of tumor growth in mice bearing an intrasplenic MDA-MB-231 tumor challenge as a model for metastatic disease. In the same model, combined therapy with dCD133KDEL and another immunotoxin designed to target the bulk tumor mass was the most effective therapy, supporting the idea that such combination therapies might better address tumor heterogeneity. dCD133KDEL shows promise as a therapeutic agent and as a biologic tool to study cancer stem cells. PMID- 25787985 TI - Experiences of Discrimination and HIV Risk Among Men Who Have Sex With Men in New York City. AB - The extent of gay-related discrimination in New York City (NYC) and the demographic and behavioral factors correlated with experiences of gay-related discrimination are not well understood. The Centers for Disease Control and Prevention-sponsored National HIV Behavioral Surveillance System, a cross sectional study, was conducted in NYC in 2011. Men who have sex with men were venue-sampled, interviewed, and offered HIV testing. Frequencies of types of gay related discrimination experienced in the past 12 months were calculated. Associations between types of discrimination and demographic and HIV risk variables were examined through the estimation of prevalence ratios (PRs) and 95% confidence intervals (CIs). More than half (53.2%) of all study participants reported having experienced any gay-related discrimination in the past 12 months; 45.0% reported that they had been called names or insulted; 23.6% reported receiving poorer services than other people in restaurants, stores, other businesses, or agencies; 22.0% reported being treated unfairly at work or school; 15.1% reported being physically attacked or injured; and 6.7% reported being denied or given lower quality health care. HIV-positive status (adjusted PR [aPR] = 2.9; 95% CI = 1.5, 5.6) and drug use in the past 12 months (aPR = 0.3; 95% CI = 0.1, 0.7) were independently associated with reports of having been denied or given lower quality health care. High rates of reported gay-related discrimination suggest that greater efforts are needed to reduce gay-related discrimination in affected communities. Future research is needed to better understand the extent of gay-related discrimination in NYC, particularly with regard to the relationship between HIV status and health care access. PMID- 25787986 TI - Low-Intensity Extracorporeal Shock Wave as a Novel Treatment for Erectile Dysfunction. AB - The paradigm of erectile dysfunction (ED) treatment was fundamentally altered following the introduction of oral phosphodiesterase type 5 inhibitors. Unfortunately, a significant number of men exhibit a suboptimal response and require additional management strategies. One of the novel, minimally invasive strategies being developed is low-intensity extracorporeal shock wave therapy. Used in the hope of delaying placement of an inflatable penile prosthesis, the final phase of ED treatment, low-intensity extracorporeal shock wave therapy is a unique application of an established technology that may hopefully one day expand the medical options for patients with ED. This commentary will highlight the physiology underlying this technique and summarize the most recent studies. PMID- 25787987 TI - A Community-Level Assessment of Barriers to Preventive Health Behaviors Among Culturally Diverse Men. AB - There are significant gender disparities in health outcomes and health care utilization in the United States, with men experiencing more of these disparities. It is critical to ascertain the interplay between societal conditions, health behaviors, and access to services and the impact of these factors on health outcomes and utilization of health care. The present study is part of a larger initiative titled, The Men's Health Study: Addressing Healthy Lifestyle Behaviors, which has two purposes-to annually assess the motivators of and barriers to health-promoting behaviors among culturally diverse men attending the Men's Health Forum (MHF) and to use this information to develop an intervention program that facilitates healthy lifestyle behaviors among men. The MHF is a community-driven initiative for medically underserved men in Tampa, Florida that offers free health screenings and wellness exhibitors in order to empower men to lead a healthy lifestyle. The purpose of this article is to identify barriers to engaging in health-smart behaviors (e.g., cancer screenings, physical activity) among culturally diverse men who participated in the MHF and to detect any demographic differences among these barriers. A total of 254 men participated in the study. Findings identify that age was the only demographic variable that had a statistically significant association with any of the cancer screening barriers. Some cancer-screening barriers appear to exist among all demographic groups since no statistical demographic differences were discovered. Income and education were significantly associated with barriers to engaging in health-smart behaviors. This may give researchers, health educators, and providers information needed to customize interventions to promote health and preventive health care among culturally diverse men. PMID- 25787983 TI - Tumor-initiating stem-like cells and drug resistance: carcinogenesis through Toll like receptors, environmental factors, and virus. AB - Neoplasms contain distinct subpopulations of cells known as tumor-initiating stem like cells (TICs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells normally proliferate through self-renewing divisions in which the two daughter cells differ markedly in their proliferative potential, with one displaying the differentiation phenotypes and another retaining self-renewing activity. Therefore, understanding the molecular mechanisms of hepatocarcinogenesis will be required for the eventual development of improved therapeutic modalities for treating hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) and hepatitis B virus is a major cause of HCC. Compelling epidemiologic evidence identifies obesity and alcohol as co-morbidity factors that can increase the risk of HCV patients for HCC, especially in alcoholics or obese patients. The mechanisms underlying liver oncogenesis, and how environmental factors contribute to this process, are not yet understood. The HCV-Toll-like receptor 4 (TLR4)-Nanog signaling network is established since alcohol/obesity-associated endotoxemia then activates TLR4 signaling, resulting in the induction of the stem cell marker Nanog expression and liver tumors. Liver TICs are highly sensitized to leptin and exposure of TICs to leptin increases the expression and activity of an intrinsic pluripotency associated transcriptional network comprised of signal transducer and activator of transcription 3, SOX2, OCT4, and Nanog. Stimulation of the pluripotency network may have significant implications for hepatocellular oncogenesis via genesis and maintenance of TICs. It is important to understand how HCV induces liver cancer through genesis of TICs so that better prevention and treatment can be found. This article reviews the oncogenic pathways to generate TICs. PMID- 25787988 TI - Men Who Have Sex With Men in Peru: Acceptability of Medication-Assisted Therapy for Treating Alcohol Use Disorders. AB - In Peru, the HIV epidemic is concentrated in men who have sex with men (MSM) and transgender women (TGW). Multiple studies correlate alcohol use disorders (AUDs) with risky sexual behaviors among Peruvian MSM. Qualitative research was used to inform a clinical trial on the acceptability of medication-assisted therapies to assist management of AUDs and improve antiretroviral therapy (ART) adherence among MSM/TGW in Peru. Three focus groups involving HIV-infected or HIV uninfected MSM/TGW ( n = 26) with AUDs (AUDIT >= 8) were transcribed, translated from Spanish into English, and analyzed using thematic content analysis. Despite having an AUD, participants considered themselves "social" drinkers, minimized their drinking behaviors, and differed about whether or not alcohol problems could be treated. Participants expressed skepticism about medication for treating AUDs. Three concepts emerged as necessary components of a treatment program for alcohol problems: cost, family support, and the potential to drink less alcohol without attaining total abstinence. This study reveals important areas of education to increase potential acceptability of a medication for treating AUDs among MSM/TGW. Given the social conditions and knowledge base of the participants, medication-assisted therapies using naltrexone may be a beneficial strategy for MSM with AUDs. PMID- 25787989 TI - Interventions to combat or prevent drug counterfeiting: a systematic review. AB - OBJECTIVE: Drug counterfeiting has serious public health and safety implications. The objective of this study was to systematically review the evidence on the effectiveness of interventions to combat or prevent drug counterfeiting. DATA SOURCES: We searched multiple electronic databases and the grey literature up to March 2014. Two reviewers completed, in duplicate and independently, the study selection, data abstraction and risk of bias assessment. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: We included randomised trials, non randomised studies, and case studies examining any intervention at the health system-level to combat or prevent drug counterfeiting. Outcomes of interest included changes in failure rates of tested drugs and changes in prevalence of counterfeit medicines. We excluded studies that focused exclusively on substandard, degraded or expired drugs, or that focused on medication errors. APPRAISAL AND SYNTHESIS: We assessed the risk of bias in each included study. We reported the results narratively and, where applicable, we conducted meta analyses. RESULTS: We included 21 studies representing 25 units of analysis. Overall, we found low quality evidence suggesting positive effects of drug registration (OR=0.23; 95% CI 0.08 to 0.67), and WHO-prequalification of drugs (OR=0.06; 95% CI 0.01 to 0.35) in reducing the prevalence of counterfeit and substandard drugs. Low quality evidence suggests that licensing of drug outlets is probably ineffective (OR=0.66; 95% CI 0.41 to 1.05). For multifaceted interventions (including a mix of regulations, training of inspectors, public private collaborations and legal actions), low quality evidence suggest they may be effective. The single RCT provided moderate quality evidence of no effect of 'two extra inspections' in improving drug quality. CONCLUSIONS: Policymakers and stakeholders would benefit from registration and WHO-prequalification of drugs and may also consider multifaceted interventions. Future effectiveness studies should address the methodological limitations of the available evidence. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014009269. PMID- 25787990 TI - Neurodevelopmental outcomes at 7 years' corrected age in preterm infants who were fed high-dose docosahexaenoic acid to term equivalent: a follow-up of a randomised controlled trial. AB - OBJECTIVE: To determine if improvements in cognitive outcome detected at 18 months' corrected age (CA) in infants born <33 weeks' gestation receiving a high docosahexaenoic acid (DHA) compared with standard-DHA diet were sustained in early childhood. DESIGN: Follow-up of a multicentre randomised controlled trial. Randomisation was stratified for sex, birth weight (<1250 vs >=1250 g) and hospital. SETTING: Five Australian tertiary hospitals from 2008 to 2013. PARTICIPANTS: 626 of the 657 participants randomised between 2001 and 2005 were eligible to participate. INTERVENTIONS: High-DHA (~1% total fatty acids) enteral feeds compared with standard-DHA (~0.3% total fatty acids) from age 2-4 days until term CA. PRIMARY OUTCOME: Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence (WASI) at 7 years CA. Prespecified subgroup analyses based on the randomisation strata (sex, birth weight) were conducted. RESULTS: 604 (92% of the 657 originally randomised) consented to participate (291 high-DHA, 313 standard DHA). To address missing data in the 604 consenting participants (22 for primary outcome), multiple imputation was performed. The Full Scale IQ was not significantly different between groups (high-DHA 98.3, SD 14.0, standard-DHA 98.5, SD 14.9; mean difference adjusted for sex, birthweight strata and hospital 0.3, 95% CI -2.9 to 2.2; p=0.79). There were no significant differences in any secondary outcomes. In prespecified subgroup analyses, there was a significant sex by treatment interaction on measures of parent-reported executive function and behaviour. Scores were within the normal range but girls receiving the high DHA diet scored significantly higher (poorer outcome) compared with girls receiving the standard-DHA diet. CONCLUSIONS: Supplementing the diets of preterm infants with a DHA dose of approximately 1% total fatty acids from days 2-4 until term CA showed no evidence of benefit at 7 years' CA. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12606000327583. PMID- 25787991 TI - Quantitative analysis of cadherin-11 and beta-catenin signalling during proliferation of rheumatoid arthritis-derived synovial fibroblast cells. AB - OBJECTIVES: Cadherin-11 (CDH11) is an adhesion molecule that anchors beta-catenin and is involved with various functions of synovial fibroblast cells (SFCs) during the development of rheumatoid arthritis (RA). However, the mechanism of CDH11 during RA-SFC proliferation is unclear. The aim of our study was to clarify the involvement of CDH11 and beta-catenin signalling during proliferation. METHODS: IL-1beta-induced and tumour necrosis factor-alpha (TNF-alpha)-induced cell proliferation, with CDH11 siRNAs, beta-catenin-specific siRNAs and a CDH11 neutralizing antibody, were assessed by 5-Bromo-2'-deoxy-uridine ELISA. KEY FINDINGS: Using CDH11 siRNAs, there were a 42% reduction in IL-1beta-induced proliferation and a 64% reduction in beta-catenin protein. When beta-catenin siRNAs were applied, there was a 63% reduction in IL-1beta-induced proliferation. The median effective concentration (EC50 ) values for IL-1beta-induced proliferation via CDH11-mediated beta-catenin-dependent, total beta-catenin dependent and beta-catenin-independent signalling were 0.0015, 0.016 and 0.18 ng/ml, respectively. Blocking CDH11 ligation with a CDH11-neutralizing antibody did not decrease IL-1beta-induced proliferation. CONCLUSIONS: CDH11-mediated beta catenin signalling was 42% involved in IL-1beta-induced proliferation and had the highest susceptibility to IL-1beta among the proliferative signallings analysed in this study. The mode of action for CDH11 during the cell proliferation was likely associated with a pool of beta-catenin protein. In contrast, CDH11 and beta-catenin were not involved in TNF-alpha-induced RA-SFC proliferation. PMID- 25787992 TI - Spatial pattern of spontaneous retinal waves instructs retinotopic map refinement more than activity frequency. AB - Spontaneous activity during early development is necessary for the formation of precise neural connections, but it remains uncertain whether activity plays an instructive or permissive role in brain wiring. In the visual system, retinal ganglion cell (RGC) projections to the brain form two prominent sensory maps, one reflecting eye of origin and the other retinotopic location. Recent studies provide compelling evidence supporting an instructive role for spontaneous retinal activity in the development of eye-specific projections, but evidence for a similarly instructive role in the development of retinotopy is more equivocal. Here, we report on experiments in which we knocked down the expression of beta2 containing nicotinic acetylcholine receptors (beta2-nAChRs) specifically in the retina through a Cre-loxP recombination strategy. Overall levels of spontaneous retinal activity in retina-specific beta2-nAChR mutant mice (Rx-beta2cKO), examined in vitro and in vivo, were reduced to a degree comparable to that observed in whole animal beta2-nAChR mouse mutants (beta2KO). However, many residual spontaneous waves in Rx-beta2cKO mice displayed local propagating features with strong correlations between nearby but not distant RGCs typical of waves observed in wild-type (WT) but not beta2KO mice. We further observed that eye-specific segregation was disrupted in Rx-beta2cKO mice, but retinotopy was spared in a competition-dependent manner. These results suggest that propagating patterns of spontaneous retinal waves are essential for normal development of the retinotopic map, even while overall activity levels are significantly reduced, and support an instructive role for spontaneous retinal activity in both eye specific segregation and retinotopic refinement. PMID- 25787993 TI - Isocitrate dehydrogenase mutations: new opportunities for translational research. AB - Over the last decade, comprehensive genome-wide sequencing studies have enabled us to find out unexpected genetic alterations of metabolism in cancer. An example is the identification of arginine missense mutations of isocitrate dehydrogenases 1 and -2 (IDH1/2) in glioma, acute myeloid leukemia (AML), chondrosarcomas, and cholangiocarcinoma. These alterations are closely associated with the production of a new stereospecific metabolite, (R)-2-hydroxyglutarate (R-2HG). A large number of follow-up studies have been performed to address the molecular mechanisms of IDH1/2 mutations underlying how these events contribute to malignant transformation. In the meanwhile, the development of selective mutant IDH1/2 chemical inhibitors is being actively pursued in the scientific community and pharmaceutical industry. The present review article briefly discusses the important findings that highlight the molecular mechanisms of IDH1/2 mutations in cancer and provides a current status for development of selective mutant IDH1/2 chemical inhibitors. PMID- 25787994 TI - Swapping of interaction partners with ATG5 for autophagosome maturation. AB - Autophagy is a tightly regulated lysosome-mediated catabolic process in eukaryotes that maintains cellular homeostasis. A distinguishable feature of autophagy is the formation of double-membrane structures, autophagosome, which envelopes the intracellular cargoes and finally degrades them by fusion with lysosomes. So far, many structures of Atg proteins working on the autophagosome formation have been reported, however those involved in autophagosome maturation, a fusion with lysosome, are relatively unknown. One of the molecules in autophagosome maturation, TECPR1, has been identified and recently, structural studies on both ATG5-TECPR1 and ATG5-ATG16L1 complexes revealed that TECPR1 and ATG16L1 share the same binding site on ATG5. These results, in combination with supporting biochemical and cellular biological data, provide an insight into a model for swapping ATG5 partners for autophagosome maturation. PMID- 25787995 TI - Plasma phospholipid fatty acids and fish-oil consumption in relation to osteoporotic fracture risk in older adults: the Age, Gene/Environment Susceptibility Study. AB - BACKGROUND: Polyunsaturated fatty acids (PUFAs) may play a role in fracture, but studies have been largely confined to estimates of dietary intake. OBJECTIVE: We aimed to examine associations between fatty acids measured in late life and fish oil consumption in early life, midlife, and late life with osteoporotic fracture risk. DESIGN: Osteoporotic fractures were determined from medical records over 5 9 y of follow-up in men and women aged 66-96 y. Data were analyzed from 1438 participants including 898 participants who were randomly selected from the Age, Gene/Environment Susceptibility Study, which is an observational study, and 540 participants with incident fracture. Plasma phospholipid fatty acids were assessed by using gas chromatography. Fish-oil consumption was assessed by using validated questionnaires as never (referent), less than daily, or daily. HRs and 95% CIs adjusted for age, education, height, weight, diabetes, physical activity, and medications were estimated by using Cox regression. RESULTS: In men, the highest tertile of PUFAs, n-3 (omega-3), and eicosapentaenoic acid were associated with decreased fracture risk [HRs (95% CIs): 0.60 (95% CI: 0.41, 0.89), 0.66 (0.45, 0.95), and 0.59 (0.41, 0.86), respectively]. In women, PUFAs tended to be inversely associated with fracture risk (P-trend = 0.06), but tertiles 2 and 3 were not independently associated with risk. Tertile 2 of n-6 and arachidonic acid was associated with fracture risk in women [HRs (95% CIs): 1.43 (1.10, 1.85) and 1.42 (1.09, 1.85), respectively]. Daily fish-oil consumption in late life was associated with lower fracture risk in men (HR: 0.64; 95% CI: 0.45, 0.91). Daily fish-oil consumption in midlife was associated with lower fracture risk in women (HR: 0.75; 95% CI: 0.58, 0.98). CONCLUSIONS: Greater PUFA concentrations may be associated with lower osteoporotic fracture risk in older adults, particularly in men. Critical time periods for n-3 fatty acid consumption may differ by sex. PMID- 25787997 TI - Effect of sodium and potassium supplementation on vascular and endothelial function: a randomized controlled trial. AB - BACKGROUND: It is known that increased potassium and reduced sodium intakes can improve postprandial endothelial function. However, the effect of increasing potassium in the presence of high sodium in the postprandial state is not known. OBJECTIVE: We aimed to determine the effect of high potassium and high sodium on postprandial endothelial function as assessed by using flow-mediated dilatation (FMD) and arterial compliance as assessed by using pulse wave velocity (PWV) and central augmentation index (AIx). DESIGN: Thirty-nine healthy, normotensive volunteers [21 women and 18 men; mean +/- SD age: 37 +/- 15 y; BMI (in kg/m(2)): 23.0 +/- 2.8] received a meal with 3 mmol K and 65 mmol Na (low-potassium, high sodium meal (LKHN)], a meal with 38 mmol K and 65 mmol Na [high-potassium, high sodium meal (HKHN)], and a control meal with 3 mmol K and 6 mmol Na (low potassium, low-sodium meal) on 3 separate occasions in a randomized crossover trial. Brachial artery FMD, carotid-femoral PWV, central AIx, and blood pressure (BP) were measured while participants were fasting and at 30, 60, 90, and 120 min after meals. RESULTS: Compared with the LKHN, the addition of potassium (HKHN) significantly attenuated the postmeal decrease in FMD (P-meal by time interaction < 0.05). FMD was significantly lower after the LKHN than after the HKHN at 30 min (P < 0.01). AIx decreased after all meals (P < 0.05). There were no significant differences in AIx, PWV, or BP between treatments over time. CONCLUSION: The addition of potassium to a high-sodium meal attenuates the sodium-induced postmeal reduction in endothelial function as assessed by FMD. This trial was registered at http://www.anzctr.org.au/ as ACTRN12613000772741. PMID- 25787996 TI - Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study. AB - BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes. OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes. DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes. RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47% lower risk of diabetes (95% CI: 23%, 63%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33% (95% CI: 6%, 53%; P-trend: 0.02) and 37% (95% CI: 11%, 55%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32% lower risk for fourth vs. first quartile; P-trend: 0.04). CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133. PMID- 25787998 TI - How effective are current dietary guidelines for cardiovascular disease prevention in healthy middle-aged and older men and women? A randomized controlled trial. AB - BACKGROUND: Controversy surrounds the effectiveness of dietary guidelines for cardiovascular disease (CVD) prevention in healthy middle-aged and older men and women. OBJECTIVE: The objective was to compare effects on vascular and lipid CVD risk factors of following the United Kingdom dietary guidelines with a traditional British diet (control). DESIGN: With the use of a parallel-designed randomized controlled trial in 165 healthy nonsmoking men and women (aged 40-70 y), we measured ambulatory blood pressure (BP) on 5 occasions, vascular function, and CVD risk factors at baseline and during 12 wk after random assignment to treatment. The primary outcomes were differences between treatments in daytime ambulatory systolic BP, flow-mediated dilation, and total cholesterol/HDL cholesterol. Secondary outcomes were differences between treatment in carotid-to femoral pulse wave velocity, high-sensitivity C-reactive protein, and a measure of insulin sensitivity (Revised Quantitative Insulin Sensitivity Check Index). RESULTS: Data were available on 162 participants, and adherence to the dietary advice was confirmed from dietary records and biomarkers of compliance. In the dietary guidelines group (n = 80) compared with control (n = 82), daytime systolic BP was 4.2 mm Hg (95% CI: 1.7, 6.6 mm Hg; P < 0.001) lower, the treatment effect on flow-mediated dilation [-0.62% (95% CI: -1.48%, 0.24%)] was not significant, the total cholesterol:HDL cholesterol ratio was 0.13 (95% CI: 0, 0.26; P = 0.044) lower, pulse wave velocity was 0.29 m/s (95% CI: 0.07, 0.52 m/s; P = 0.011) lower, high-sensitivity C-reactive protein was 36% (95% CI: 7%, 48%; P = 0.017) lower, the treatment effect on the Revised Quantitative Insulin Sensitivity Check Index [2% (95% CI: -2%, 5%)] was not significant, and body weight was 1.9 kg (95% CI: 1.3, 2.5 kg; P < 0.001) lower. Causal mediated effects analysis based on urinary sodium excretion indicated that sodium reduction explained 2.4 mm Hg (95% CI: 1.0, 3.9 mm Hg) of the fall in blood pressure. CONCLUSION: Selecting a diet consistent with current dietary guidelines lowers BP and lipids, which would be expected to reduce the risk of CVD by one-third in healthy middle-aged and older men and women. This study is registered at www.isrctn.com as 92382106. PMID- 25787999 TI - Teaching our children when to eat: how parental feeding practices inform the development of emotional eating--a longitudinal experimental design. AB - BACKGROUND: Emotional eating in children has been related to the consumption of energy-dense foods and obesity, but the development of emotional eating in young children is poorly understood. OBJECTIVES: We evaluated whether emotional eating can be induced in 5-7-y-old children in the laboratory and assessed whether parental use of overly controlling feeding practices at 3-5 y of age predicts a greater subsequent tendency for children to eat under conditions of mild stress at ages 5-7 y. DESIGN: Forty-one parent-child dyads were recruited to participate in this longitudinal study, which involved parents and children being observed consuming a standard lunch, completing questionnaire measures of parental feeding practices, participating in a research procedure to induce child emotion (or a control procedure), and observing children's consumption of snack foods. RESULTS: Children at ages 5-7 y who were exposed to a mild emotional stressor consumed significantly more calories from snack foods in the absence of hunger than did children in a control group. Parents who reported the use of more food as a reward and restriction of food for health reasons with their children at ages 3-5 y were more likely to have children who ate more under conditions of negative emotion at ages 5-7 y. CONCLUSIONS: Parents who overly control children's food intake may unintentionally teach children to rely on palatable foods to cope with negative emotions. Additional research is needed to evaluate the implications of these findings for children's food intake and weight outside of the laboratory setting. This trial was registered at clinicaltrials.gov as NCT01122290. PMID- 25788000 TI - Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta analysis of trials and observational studies. AB - BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism is a risk factor for neural tube defects. The T allele produces an enzyme with reduced folate-processing capacity, which has been associated with lower blood folate concentrations. OBJECTIVE: We assessed the association between MTHFR C677T genotypes and blood folate concentrations among healthy women aged 12-49 y. DESIGN: We conducted a systematic review of the literature published from January 1992 to March 2014 to identify trials and observational studies that reported serum, plasma, or red blood cell (RBC) folate concentrations and MTHFR C677T genotype. We conducted a meta-analysis for estimates of percentage differences in blood folate concentrations between genotypes. RESULTS: Forty studies met the inclusion criteria. Of the 6 studies that used the microbiologic assay (MA) to measure serum or plasma (S/P) and RBC folate concentrations, the percentage difference between genotypes showed a clear pattern of CC > CT > TT. The percentage difference was greatest for CC > TT [S/P: 13%; 95% credible interval (CrI): 7%, 18%; RBC: 16%; 95% CrI: 12%, 20%] followed by CC > CT (S/P: 7%; 95% CrI: 1%, 12%; RBC: 8%; 95% CrI: 4%, 12%) and CT > TT (S/P: 6%; 95% CrI: 1%, 11%; RBC: 9%; 95% CrI: 5%, 13%). S/P folate concentrations measured by using protein binding assays (PBAs) also showed this pattern but to a greater extent (e.g., CC > TT: 20%; 95% CrI: 17%, 22%). In contrast, RBC folate concentrations measured by using PBAs did not show the same pattern and are presented in the Supplemental Material only. CONCLUSIONS: Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677T genotypes. Lower blood folate concentrations associated with this polymorphism could have implications for a population-level risk of neural tube defects. PMID- 25788001 TI - Orange juice-derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: a randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease. AB - BACKGROUND: Epidemiologic data suggest inverse associations between citrus flavanone intake and cardiovascular disease (CVD) risk. However, insufficient randomized controlled trial data limit our understanding of the mechanisms by which flavanones and their metabolites potentially reduce cardiovascular risk factors. OBJECTIVE: We examined the effects of orange juice or a dose-matched hesperidin supplement on plasma concentrations of established and novel flavanone metabolites and their effects on cardiovascular risk biomarkers in men at moderate CVD risk. DESIGN: In an acute, randomized, placebo-controlled crossover trial, 16 fasted participants (aged 51-69 y) received orange juice or a hesperidin supplement (both providing 320 mg hesperidin) or control (all matched for sugar and vitamin C content). At baseline and 5 h postintake, endothelial function (primary outcome), blood pressure, arterial stiffness, cardiac autonomic function, platelet activation, and NADPH oxidase gene expression and plasma flavanone metabolites were assessed. Before each intervention, a diet low in flavonoids, nitrate/nitrite, alcohol, and caffeine was followed, and a standardized low-flavonoid evening meal was consumed. RESULTS: Orange juice intake significantly elevated mean +/- SEM plasma concentrations of 8 flavanone (1.75 +/- 0.35 MUmol/L, P < 0.0001) and 15 phenolic (13.27 +/- 2.22 MUmol/L, P < 0.0001) metabolites compared with control at 5 h postconsumption. Despite increased plasma flavanone and phenolic metabolite concentrations, cardiovascular risk biomarkers were unaltered. After hesperidin supplement intake, flavanone metabolites were not different from the control, suggesting altered absorption/metabolism compared with the orange juice matrix. CONCLUSIONS: After single-dose flavanone intake within orange juice, circulating flavanone and phenolic metabolites collectively reached a concentration of 15.20 +/- 2.15 MUmol/L, but no effects were observed on cardiovascular risk biomarkers. Longer duration randomized controlled trials are required to examine previous associations between higher flavanone intakes and improved cardiovascular health and to ascertain the relative importance of food matrix and flavanone-derived phenolic metabolites. This trial was registered at clinicaltrials.gov as NCT01530893. PMID- 25788002 TI - Assessing global dietary habits: a comparison of national estimates from the FAO and the Global Dietary Database. AB - BACKGROUND: Accurate data on dietary habits are crucial for understanding impacts on disease and informing policy priorities. Nation-specific food balance sheets from the United Nations FAO provided the only available global dietary estimates but with uncertain validity. OBJECTIVES: We investigated how FAO estimates compared with nationally representative, individual-based dietary surveys from the Global Dietary Database (GDD) and developed calibration equations to improve the validity of FAO data to estimate dietary intakes. DESIGN: FAO estimates were matched to GDD data for 113 countries across the following 9 major dietary metrics for 30 y of data (1980-2009): fruit, vegetables, beans and legumes, nuts and seeds, whole grains, red and processed meats, fish and seafood, milk, and total energy. Both absolute and percentage differences in FAO and GDD mean estimates were evaluated. Linear regression was used to evaluate whether FAO estimates predicted GDD dietary intakes and whether this prediction varied according to age, sex, region, and time. Calibration equations were developed to adjust FAO estimates to approximate national dietary surveys validated by using randomly split data sets. RESULTS: For most food groups, FAO estimates substantially overestimated individual-based dietary intakes by 74.5% (vegetables) and 270% (whole grains) while underestimating beans and legumes ( 50%) and nuts and seeds (-29%) (P < 0.05 for each). In multivariate regressions, these overestimations and underestimations for each dietary factor further varied by age, sex, region, and time (P < 0.001 for each). Split-data set calibration models, which accounted for country-level covariates and other sources of heterogeneity, effectively adjusted FAO estimates to approximate estimates from national survey data (r = 0.47-0.80) with small SEs of prediction (generally 1-5 g/d). CONCLUSIONS: For all food groups and total energy, FAO estimates substantially exceeded or underestimated individual-based national surveys of individual intakes with significant variation depending on age, sex, region, and time. Calibration models effectively adjusted the comprehensive, widely accessible FAO data to facilitate a more-accurate estimation of individual-level dietary intakes nationally and by age and sex. PMID- 25788003 TI - Noroviruses as a Cause of Diarrhea in Immunocompromised Pediatric Hematopoietic Stem Cell and Solid Organ Transplant Recipients. AB - Case reports describe significant norovirus gastroenteritis morbidity in immunocompromised patients. We evaluated norovirus pathogenesis in prospectively enrolled solid organ (SOT) and hematopoietic stem cell transplant (HSCT) patients with diarrhea who presented to Texas Children's Hospital and submitted stool for enteric testing. Noroviruses were detected by real-time reverse transcription polymerase chain reaction. Clinical outcomes of norovirus diarrhea and non norovirus diarrhea patients, matched by transplanted organ type, were compared. Norovirus infection was identified in 25 (22%) of 116 patients, more frequently than other enteropathogens. Fifty percent of norovirus patients experienced diarrhea lasting >=14 days, with median duration of 12.5 days (range 1-324 days); 29% developed diarrhea recurrence. Fifty-five percent of norovirus patients were hospitalized for diarrhea, with 27% requiring intensive care unit (ICU) admission. One HSCT recipient developed pneumatosis intestinalis. Three HSCT patients expired <=6 months of norovirus diarrhea onset. Compared to non norovirus diarrhea patients, norovirus patients experienced significantly more frequent ICU admission (27% vs. 0%, p = 0.02), greater serum creatinine rise (median 0.3 vs. 0.2 mg/dL, p = 0.01), and more weight loss (median 1.6 vs. 0.6 kg, p < 0.01). Noroviruses are an important cause of diarrhea in pediatric transplant patients and are associated with significant clinical complications. PMID- 25788004 TI - 5-diphenylacetamido-indirubin-3'-oxime as a novel mitochondria-targeting agent with anti-leukemic activities. AB - Current treatment for leukemia largely depends on chemotherapy. Despite the progress in treatment efficacy of chemotherapy, a poor outcome consequent upon chemoresistance against conventional anti-cancer drugs still remains to be solved. In this study, we report 5-diphenylacetamido-indirubin-3'-oxime (LDD398) as a novel mitochondria-targeting anti-leukemic agent, which is a derivative of indirubin used in traditional medicine. Treatment with LDD398 resulted in caspase activation, cell death, and growth arrest at G2/M phases in leukemia cells. Interestingly, LDD398 quickly collapsed mitochondrial membrane potential (MMP) within 1 h, accompanied by cytochrome c release into cytosol and severe depletion of cellular ATP. However, the LDD398-induced cellular events was significantly mitigated by blockage of mitochondrial permeability transition pore (MPTP) opening with chemical and genetic modifications, strongly supporting that LDD398 executes its anti-leukemic activity via an inappropriate opening of MPTP and a consequent depletion of ATP. The most meaningful finding was the prominent effectiveness of LDD398 on primary leukemia cells and also on malignant leukemia cells resistant to anticancer drugs. Our results demonstrate that, among a series of indirubin derivatives, LDD398 induces leukemia cell death via a different mode from indirubin or conventional chemotherapeutics, and can be employed as a potent anti-cancer agent in the treatment for newly diagnosed and relapsed leukemia. PMID- 25788005 TI - Computer Aided Semi-Automated Evaluation of HER2 Immunodetection--A Robust Solution for Supporting the Accuracy of Anti HER2 Therapy. AB - HER2-positive breast cancers usually benefit from anti-HER2 therapy, thus, HER2 evaluation became inevitable for patient selection. HER2-negative (IHC 0, 1+) and strong positive (IHC 3+) cases can easily be interpreted with immunohistochemistry, but equivocal (IHC 2+) cases require further analysis of HER2 gene amplification using in situ hybridization. Our study aimed to validate digital pathology and automated image analysis for unbiased evaluation of HER2 immunostains. We developed an image segmentation algorithm for analyzing HER2 immunostaining (4B5 clone) in tissue microarrays of breast cancers. Two pathologists assessed 309 microscopic regions of at least 100 tumor cells each- representing all HER2 positivity groups--according to international guidelines either semi-quantitatively or by using the MembraneQuant software. Scoring results were statistically correlated with each other and with FISH data, and almost perfect agreement was found (inter-method Cohen's kappa = 0.872, Spearman rho = 0.928). When clinical relevance (scoring disagreement that may define erroneous treatment selection) was examined high agreement was found (quadratic weighted kappa = 0.967). Image analysis classified cases with excellent correlation with visual evaluation, therefore, MembraneQuant software proved to be a reliable tool for assessing HER2 immunoreactions and supporting better targeting anti-HER2 therapy. As digital analysis of immunomorphological markers allows permanent archiving, standardization and accurate reviewing of results, it supports quality assurance initiatives in diagnostic pathology--especially of equivocal cases which are hard to interpret. PMID- 25788006 TI - Effects of experimental craniofacial pain on fine jaw motor control: a placebo controlled double-blinded study. AB - The aim of the experiment was to test the hypothesis that experimental pain in the masseter muscle or temporomandibular joint (TMJ) would perturb the oral fine motor control, reflected in bigger variability of bite force values and jaw muscle activity, during repeated splitting of food morsels. Twenty healthy volunteers participated in four sessions. An intervention was made by injection of either 0.2 ml of monosodium glutamate/isotonic saline (MSG/IS) (randomized) in either the masseter or TMJ (randomized). The participants were asked to hold and split a flat-faced placebo tablet with their anterior teeth, thirty times each at baseline, during intervention and post-intervention. Pain was measured using a 0 10 visual analog scale. The force applied by the teeth to "hold" and "split" the tablet along with the corresponding electromyographic (EMG) activity of the jaw muscles and subject-based reports on perception of pain was recorded. The data analysis included a three-way analysis of variance model. The peak pain intensity was significantly higher during the painful MSG injections in the TMJ (6.1 +/- 0.4) than the injections in masseter muscle (5.5 +/- 0.5) (P = 0.037). Variability of hold force was significantly smaller during the MSG injection than IS injection in the masseter (P = 0.024). However, there was no significant effect of intervention on the variability of split force during the masseter injections (P = 0.769) and variability of hold and split force during the TMJ injections (P = 0.481, P = 0.545). The variability of the EMG activity of the jaw muscles did not show significant effects of intervention. Subject-based reports revealed that pain did not interfere in the ability to hold the tablet in 57.9 and 78.9 %, and the ability to split the tablet in 78.9 and 68.4 %, of the participants, respectively, during painful masseter and TMJ injections. Hence, experimental pain in the masseter muscle or TMJ did not have any robust effect in terms of bigger variability of bite force and jaw muscle activity, during repeated splitting of food morsels. PMID- 25788007 TI - Effect of skin-transmitted vibration enhancement on vibrotactile perception. AB - Vibration on skin elicited by the mechanical interaction of touch between the skin and an object propagates to skin far from the point of contact. This paper investigates the effect of skin-transmitted vibration on vibrotactile perception. To enhance the transmission of high-frequency vibration on the skin, stiff tape was attached to the skin so that the tape covered the bottom surface of the index finger from the periphery of the distal interphalangeal joint to the metacarpophalangeal joint. Two psychophysical experiments with high-frequency vibrotactile stimuli of 250 Hz were conducted. In the psychophysical experiments, discrimination and detection thresholds were estimated and compared between conditions of the presence or the absence of the tape (normal bare finger). A method of limits was applied for the detection threshold estimation, and the discrimination task using a reference stimulus and six test stimuli with different amplitudes was applied for the discrimination threshold estimation. The stimulation was given to bare fingertips of participants. Result showed that the detection threshold was enhanced by attaching the tape, and the discrimination threshold enhancement by attaching the tape was confirmed for participants who have relatively large discrimination threshold under normal bare finger. Then, skin-transmitted vibration was measured with an accelerometer with the psychophysical experiments. Result showed that the skin-transmitted vibration when the tape was attached to the skin was larger than that when normal bare skin. There is a correlation between the increase in skin-transmitted vibration and the enhancement of the discrimination threshold. PMID- 25788008 TI - Factors underlying age-related changes in discrete aiming. AB - Age has a clear impact on one's ability to make accurate goal-directed aiming movements. Older adults seem to plan slower and shorter-ranged initial pulses towards the target, and rely more on sensory feedback to ensure endpoint accuracy. Despite the fact that these age-related changes in manual aiming have been observed consistently, the underlying mechanism remains speculative. In an attempt to isolate four commonly suggested underlying factors, young and older adults were instructed to make discrete aiming movements under varying speed and accuracy constraints. Results showed that older adults were physically able to produce fast primary submovements and that they demonstrated similar movement programming capacities as young adults. On the other hand, considerable evidence was found supporting a decreased visual feedback-processing efficiency and the implementation of a play-it-safe strategy in older age. In conclusion, a combination of the latter two factors seems to underlie the age-related changes in manual aiming behaviour. PMID- 25788009 TI - Audiovisual integration in near and far space: effects of changes in distance and stimulus effectiveness. AB - A factor that is often not considered in multisensory research is the distance from which information is presented. Interestingly, various studies have shown that the distance at which information is presented can modulate the strength of multisensory interactions. In addition, our everyday multisensory experience in near and far space is rather asymmetrical in terms of retinal image size and stimulus intensity. This asymmetry is the result of the relation between the stimulus-observer distance and its retinal image size and intensity: an object that is further away is generally smaller on the retina as compared to the same object when it is presented nearer. Similarly, auditory intensity decreases as the distance from the observer increases. We investigated how each of these factors alone, and their combination, affected audiovisual integration. Unimodal and bimodal stimuli were presented in near and far space, with and without controlling for distance-dependent changes in retinal image size and intensity. Audiovisual integration was enhanced for stimuli that were presented in far space as compared to near space, but only when the stimuli were not corrected for visual angle and intensity. The same decrease in intensity and retinal size in near space did not enhance audiovisual integration, indicating that these results cannot be explained by changes in stimulus efficacy or an increase in distance alone, but rather by an interaction between these factors. The results are discussed in the context of multisensory experience and spatial uncertainty, and underline the importance of studying multisensory integration in the depth space. PMID- 25788010 TI - Anaesthesia changes perceived finger width but not finger length. AB - The brain needs information about the size of the body to control our interactions with the environment. No receptor signals this information directly; the brain must determine body size from multiple sensory inputs and then store this information. This process is poorly understood, but somatosensory information is thought to play a role. In particular, anaesthetising a body part has been reported to make it feel bigger. Here, we report the first study to measure whether changes in body size following anaesthesia are uniform across dimensions (e.g. width and length). We blocked the digital nerves of ten human subjects with a clinical dose of local anaesthetic (1 % lignocaine) and again in separate sessions with a weaker dose (0.25 % lignocaine) and a saline control. Subjects reported the perceived size of their index finger by selecting templates from a set that varied in size and aspect ratio. We also measured changes in sensory signals that might contribute to the anaesthetic-induced changes using quantitative sensory testing. Subjects perceived their finger to be up to 32 % wider during anaesthesia when compared to during a saline control condition. However, changes in perceived length of the finger were much smaller (<5 %). Previous studies have shown a change in perceived body size with anaesthesia, but have assumed that the aspect ratio is preserved. Our data show that this is not the case. We suggest that nonuniform changes in perceived body size might be due to the brain increasing the body's perimeter to protect it from further injury. PMID- 25788011 TI - The amplitude of interlimb cutaneous reflexes in the leg is influenced by fingertip touch and vision during treadmill locomotion. AB - Light touch at the fingertip has been shown to influence postural control during standing and walking. Interlimb cutaneous reflexes have been proposed to provide a neural link between the upper and lower limbs to assist in interlimb coordination during activities such as walking. In this study, we tested the hypothesis that cutaneous sensory pathways linking the arm and leg will be facilitated if subjects use light touch to assist with postural control during treadmill walking. To test this, interlimb cutaneous reflexes from the median nerve, serving the skin contact region, and radial nerve, serving an irrelevant sensory territory, were tested in the legs of subjects walking on treadmill in an unstable environment. Interlimb cutaneous reflexes were tested while subjects (a) touched or (b) did not touch a stable contact with their fingertip, and while the eyes were either (c) open or (d) closed. Reflexes arising from both nerves were facilitated when vision was removed that was then ameliorated when touch was provided. These changes in reflex amplitude during the eyes closed conditions were mirrored by changes in background muscle activity. We suggest that this facilitation of interlimb reflexes from both nerves arises from a generalized increase in excitability related to the postural anxiety of walking on a treadmill with the eyes closed, which is then restored by the provision of light touch. However, the influence of touch when the eyes were open differed depending upon the nerve stimulated. Radial nerve reflexes in the legs were suppressed when touch was provided, mirroring a suppression in the background muscle activity. In contrast, median nerve reflexes in the leg were larger when touch was provided with the eyes open, despite a suppression of background muscle activity. This nerve-specific effect of touch on the amplitude of the interlimb cutaneous reflexes suggests that touch sensory information from the median nerve was facilitated when that input was functionally relevant. PMID- 25788012 TI - Timing and specificity of early changes in motor excitability during movement observation. AB - Motor resonance is typically considered a modulation of motor activity during action observation, which mirrors the pattern of muscle activation occurring during execution of the observed action. There is preliminary evidence that motor activity accompanying action observation comprises two stages: an initial non specific modulation, followed by a later change in excitability that is specific to the muscles involved in the action. We built on this previous work, with the aims of (1) clarifying the time-course of muscle specificity during action observation and (2) establishing whether modulation at each time point reflects significant changes (facilitation or suppression) from baseline. Motor-evoked potentials were elicited in two muscles-the first dorsal interosseous (FDI) and abductor digiti minimi (ADM)-while participants watched stimuli showing index or little finger abduction. Our results provide partial support for previous findings of muscle-specific modulation after, but not before, 200 ms. Interestingly, however, this was shown only by facilitation of the FDI during index finger observation; there was no significant facilitation of the ADM when little finger movement was observed. Furthermore, we found no facilitation of corticospinal excitability (specific or non-specific) at time points earlier than 200 ms (100-150 ms). We discuss these results in the context of previous work showing a non-specific increase in excitability at 90 ms during action observation. Together, these findings suggest a fast and short-lived facilitation of corticospinal excitability that occurs at around 60-90 ms and ends by 100-150 ms. PMID- 25788014 TI - A single quantum dot-based biosensor for telomerase assay. AB - Telomerase is a promising biomarker and a therapeutic target due to its extensive expression in human tumors such as lung cancer and breast cancer. Here, we develop a single quantum dot (QD)-based biosensor for the sensitive detection of telomerase activity. This single QD-based biosensor has significant advantages of simplicity and high sensitivity, and it can be applied for the discrimination of tumor cells from normal cells as well as the screening of anticancer drugs. PMID- 25788013 TI - Orientin improves depression-like behavior and BDNF in chronic stressed mice. AB - SCOPE: Oxidative stress is involved in chronic stress-induced depression and the disruption of neurotransmission and neuroplasticity. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential antidepressant effects of orientin against chronic stress and its underlying mechanisms. METHODS AND RESULTS: The chronic unpredictable mild stress (CUMS) model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 2 weeks of the CUMS protocol, the mice were treated with orientin (20 mg/kg and 40 mg/kg, oral gavage) for 3 weeks. Administration of orientin significantly alleviated the CUMS-induced depression-like behavior, including sucrose preference reduction, locomotor activity decline, and hypomotility. Orientin treatment attenuated the oxidative stress markers and increased the concentrations of serotonin and norepinephrine in the hippocampus and prefrontal cortex of CUMS mice. Orientin treatment also increased the brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) of CUMS mice. CONCLUSION: Orientin exerts antidepressant-like effects on CUMS mice, specifically by improving central oxidative stress, neurotransmission, and neuroplasticity. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic stress-induced depression. PMID- 25788015 TI - Reservations about the conclusions of the interdivisional (APA Divisions 12 & 29) task force on evidence-based therapy relationships: what do we know, what don't we know? AB - We offer a critical and constructive appraisal of the conclusions provided by the Interdivisional (American Psychological Association [APA] Divisions 12 & 29) Task Force on Evidence-Based Therapy Relationships. We highlight problems in overlapping terminology and definitions, as well as problems in the conduct of its meta-analyses (i.e., duplication of studies between reviews, inappropriate study inclusion, and use of measures of specific constructs for the calculation of effects for multiple relationship elements). On this basis, we express reservation about the conclusions offered by the APA Task Force. This special issue explores whether there are other therapeutic relationship elements that warrant consideration and further study. We were particularly interested in those elements that showed promise based on empirical or theoretical grounds, and in each article, we asked for an account of how the case formulation would guide the methods of adaptation for each individual client, and how the element would contribute to clinically relevant changes. PMID- 25788016 TI - Relative contributions of emphysema and airway remodelling to airflow limitation in COPD: Consistent results from two cohorts. AB - BACKGROUND AND OBJECTIVE: The relative contributions of emphysema and airway remodelling to airflow limitation remain unclear in chronic obstructive pulmonary disease (COPD). We aimed to evaluate the relative contributions of emphysema and airway wall thickness measured by quantitative computed tomography (CT) to the prediction of airflow limitation in two separate COPD cohorts. METHODS: Pulmonary function tests and whole-lung CT were performed in 250 male smokers with COPD, including 167 from University Medical Center at Ho Chi Minh City, Vietnam, and 83 from Shiga University of Medical Science Hospital, Japan. The same CT analysis software was used to measure the percentage of low attenuation volume (%LAV) at the threshold of -950 Hounsfield units and the square root of wall area of a hypothetical airway with an internal perimeter of 10 mm (Pi10). The standardized coefficients in multiple linear regressions were used to evaluate the relative contributions of %LAV and Pi10 to predictions of FEV1 /FVC and FEV1 % predicted. RESULTS: Both %LAV and Pi10 independently predicted either forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC) or FEV1 % predicted (P <= 0.001 for all standardized coefficients). However, the absolute values of the standardized coefficients were 2-3 times higher for %LAV than for Pi10 in all prediction models. The results were consistent in the two COPD cohorts. CONCLUSIONS: %LAV predicts both FEV1 /FVC and FEV1 better than Pi10 in patients with COPD. Thus, emphysema may make a greater contribution to airflow limitation than airway remodelling in COPD. PMID- 25788017 TI - Enhanced production of branched-chain fatty acids by replacing beta-ketoacyl (acyl-carrier-protein) synthase III (FabH). AB - Branched-chain fatty acids (BCFAs) are important precursors for the production of advanced biofuels with improved cold-flow properties. Previous efforts in engineering type II fatty acid synthase (FAS) for BCFA production suffered from low titers and/or the co-production of a large amount of straight-chain fatty acids (SCFAs), making it nearly impossible for further conversion of BCFAs to branched biofuels. Synthesis of both SCFAs and BCFAs requires FabH, the only beta ketoacyl-(acyl-carrier-protein) synthase in Escherichia coli that catalyzes the initial condensation reaction between malonyl-ACP and a short-chain acyl-CoA. In this study, we demonstrated that replacement of the acetyl-CoA-specific E. coli FabH with a branched-chain-acyl-CoA-specific FabH directed the flux to the synthesis of BCFAs, resulting in a significant enhancement in BCFA titer compared to a strain containing both acetyl-CoA- and branched-chain-acyl-CoA-specific FabHs. We further demonstrated that the composition of BCFAs can be tuned by engineering the upstream pathway to control the supply of different branched chain acyl-CoAs, leading to the production either even-chain-iso-, odd-chain-iso , or odd-chain-anteiso-BCFAs separately. Overall, the top-performing strain from this study produced BCFAs at 126 mg/L, comprising 52% of the total free fatty acids. PMID- 25788019 TI - Self-generated local heating induced nanojoining for room temperature pressureless flexible electronic packaging. AB - Metallic bonding at an interface is determined by the application of heat and/or pressure. The means by which these are applied are the most critical for joining nanoscale structures. The present study considers the feasibility of room temperature pressureless joining of copper wires using water-based silver nanowire paste. A novel mechanism of self-generated local heating within the silver nanowire paste and copper substrate system promotes the joining of silver to-silver and silver-to-copper without any external energy input. The localized heat energy was delivered in-situ to the interfaces to promote atomic diffusion and metallic bond formation with the bulk component temperature stays near room temperature. This local heating effect has been detected experimentally and confirmed by calculation. The joints formed at room-temperature without pressure achieve a tensile strength of 5.7 MPa and exhibit ultra-low resistivity in the range of 101.3 nOhm . m. The good conductivity of the joint is attributed to the removal of organic compounds in the paste and metallic bonding of silver-to copper and silver-to-silver. The water-based silver nanowire paste filler material is successfully applied to various flexible substrates for room temperature bonding. The use of chemically generated local heating may become a potential method for energy in-situ delivery at micro/nanoscale. PMID- 25788018 TI - School based education programme to reduce salt intake in children and their families (School-EduSalt): cluster randomised controlled trial. AB - OBJECTIVE: To determine whether an education programme targeted at schoolchildren could lower salt intake in children and their families. DESIGN: Cluster randomised controlled trial, with schools randomly assigned to either the intervention or control group. SETTING: 28 primary schools in urban Changzhi, northern China. PARTICIPANTS: 279 children in grade 5 of primary school, with mean age of 10.1; 553 adult family members (mean age 43.8). INTERVENTION: Children in the intervention group were educated on the harmful effects of salt and how to reduce salt intake within the schools' usual health education lessons. Children then delivered the salt reduction message to their families. The intervention lasted for one school term (about 3.5 months). MAIN OUTCOME MEASURES: The primary outcome was the difference between the groups in the change in salt intake (as measured by 24 hour urinary sodium excretion) from baseline to the end of the trial. The secondary outcome was the difference between the two groups in the change in blood pressure. RESULTS: At baseline, the mean salt intake in children was 7.3 (SE 0.3) g/day in the intervention group and 6.8 (SE 0.3) g/day in the control group. In adult family members the salt intakes were 12.6 (SE 0.4) and 11.3 (SE 0.4) g/day, respectively. During the study there was a reduction in salt intake in the intervention group, whereas in the control group salt intake increased. The mean effect on salt intake for intervention versus control group was -1.9 g/day (95% confidence interval -2.6 to -1.3 g/day; P<0.001) in children and -2.9 g/day (-3.7 to -2.2 g/day; P<0.001) in adults. The mean effect on systolic blood pressure was -0.8 mm Hg (-3.0 to 1.5 mm Hg; P=0.51) in children and -2.3 mm Hg (-4.5 to -0.04 mm Hg; P<0.05) in adults. CONCLUSIONS: An education programme delivered to primary school children as part of the usual curriculum is effective in lowering salt intake in children and their families. This offers a novel and important approach to reducing salt intake in a population in which most of the salt in the diet is added by consumers.Trial registration ClinicalTrials.gov NCT01821144. . PMID- 25788020 TI - Hemispheric asymmetry in cerebrovascular reactivity of the human primary motor cortex: an in vivo study at 7 T. AB - Current functional MRI (fMRI) approaches assess underlying neuronal activity through monitoring the related local variations in cerebral blood oxygenation, blood volume and blood flow. This vascular response is likely to vary across brain regions and across individuals, depending on the composition of the local vascular bed and on the vascular capacity to dilate. The most widely used technique uses the blood oxygen level dependent (BOLD) fMRI signal, which arises from a complex combination of all of these factors. The model of handedness provides a case where one brain region (dominant motor cortex) is known to have a stronger BOLD response over another (non-dominant motor cortex) during hand motor task performance. We predict that this is accompanied by a higher vascular reactivity in the dominant motor cortex, when compared with the non-dominant motor cortex. Precise measurement of end-tidal CO2 and a novel sinusoidal CO2 respiratory challenge were combined with the high sensitivity and finer spatial resolution available for fMRI at 7 T to measure BOLD cerebrovascular reactivity (CVR) in eight healthy male participants. BOLD CVR was compared between the left (dominant) and right (non-dominant) primary motor cortices of right-handed adults. Hemispheric asymmetry in vascular reactivity was predicted and observed in the primary motor cortex (left CVR = 0.60 +/- 0.15%/mm Hg; right CVR = 0.47 +/ 0.08%/mm Hg; left CVR > right CVR, P = 0.04), the first reported evidence of such a vascular difference. These findings demonstrate a cerebral vascular asymmetry between the left and right primary motor cortex. The origin of this asymmetry largely arises from the contribution of large draining veins. This work has implications for future motor laterality studies that use BOLD, and it is also suggestive of a vascular plasticity in the human primary motor cortex. PMID- 25788021 TI - Drug-resistant parietal epilepsy: polymorphic ictal semiology does not preclude good post-surgical outcome. AB - We investigated the anatomo-electro-clinical features and clinical outcome of surgical resections strictly confined to the parietal lobe in 40 consecutive patients who received surgery for pharmacoresistant seizures. The population was subcategorized into a paediatric (11 subjects; mean age at surgery: 7.2+/-3.7 years) and an adult group (29 patients; mean age at surgery: 30+/-10.8 years). The paediatric group more frequently exhibited personal antecedents, neurological impairment, high seizure frequency, and dysplastic lesions. Nonetheless, compared with adults, children had better outcome and more frequently reached definitive drug discontinuation after surgery. After a mean follow-up of 9.4 years (range: 3.1-16.7), 30 subjects (75%) were classified as Engel Class I. The presence of multiple types of aura in the same patient, as well as a high incidence of secondary generalization, represented a characteristic feature of parietal seizures and did not correlate negatively with surgical outcome. A total resection of the epileptogenic zone and a localizing/regional interictal EEG were statistically significant predictive factors of outcome. Intracerebral investigation, performed in 55% of cases, contributed to complete tailored resections of the epileptogenic area and determination of prognosis. Frequent subjective manifestations of parietal lobe seizures, such as vertiginous, cephalic and visual-moving sensations, underscore their potential misdiagnosis as non-epileptic events. PMID- 25788022 TI - Melatonin enhances the occurrence of autophagy induced by oxidative stress in Arabidopsis seedlings. AB - The beneficial effect that melatonin has against mitochondrial dysfunctioning seems to be linked to mitophagy. Roles for melatonin have been demonstrated in promoting health and preventing disease, as well as activating the process of autophagy in general. However, no reports have been made about how the application of melatonin regulates that process when plants are exposed to oxidative stress. We investigated the influence of different concentrations of melatonin (0.0, 0.5, 5.0, 10.0, or 50.0 MUm) on autophagy under methyl viologen (MV)-induced oxidative stress. Arabidopsis seedlings that were pretreated with 5 or 10 MUm melatonin underwent relatively strong induction of autophagy, as evidenced by the number of monodansylcadaverine (MDC)-stained autophagosomes in root samples. Pretreatment with 10 MUm melatonin also alleviated MV-induced photo oxidation damage and significantly reduced the accumulation of oxidized proteins. Those responses might have been due to the strong upregulation of genes that involved in AtATG8-PE conjugation pathway, which enhanced the capacity for autophagy. Histochemical staining revealed that both O2-. and H2 O2 were highly accumulated upon MV exposure, although the response did not differ significantly between control and melatonin-pretreated seedlings. By contrast, exogenous melatonin upregulated the expression of two genes for H2 O2 -scavenging enzymes, that is, AtAPX1 and AtCATs. The activation of autophagy by melatonin without an alteration in ROS production may be part of a survival mechanism that is enhanced by melatonin after cellular damage. Therefore, it represents a second level of defense to remove damaged proteins when antioxidant activities are compromised. PMID- 25788023 TI - Information needs of female Italian breast cancer patients during their first oncological consultation. AB - PURPOSE: Questions asked by patients during consultations reflect their most immediate information needs. The aim of this study is to observe the frequency and type of questions asked by Italian breast cancer patients and to explore associated factors. METHODS: Breast cancer patients at their first meeting with the oncologist were asked to complete five questionnaires (STAI-X1, PHQ-9, GHQ 12, CPS and DSES) before the consultation and three other questionnaires (PEI, SDM-Q, SWD) after. Consultations were audio taped and subsequently analyzed for the content and number of questions to identify patients' information requests. RESULTS: Patients asked an average of 18 questions, mainly about illness management: patients who were prescribed chemo-therapy asked more questions (t = 3.17, dof = 23.45, p < 0.01). Other factors related to a greater number of questions were younger age (r = -0.24, p = 0.05), being employed (t-test = 0.32; p = 0.04), and longer consultation length (r = 0.47, p < 0.01). CONCLUSION: Italian breast cancer patients asked on average more questions than in other countries. Knowledge of the factors associated with information needs can contribute to achieve a major involvement and consequently a better quality of patient-centered care. PMID- 25788025 TI - Winter warming as an important co-driver for Betula nana growth in western Greenland during the past century. AB - Growing season conditions are widely recognized as the main driver for tundra shrub radial growth, but the effects of winter warming and snow remain an open question. Here, we present a more than 100 years long Betula nana ring-width chronology from Disko Island in western Greenland that demonstrates a highly significant and positive growth response to both summer and winter air temperatures during the past century. The importance of winter temperatures for Betula nana growth is especially pronounced during the periods from 1910-1930 to 1990-2011 that were dominated by significant winter warming. To explain the strong winter importance on growth, we assessed the importance of different environmental factors using site-specific measurements from 1991 to 2011 of soil temperatures, sea ice coverage, precipitation and snow depths. The results show a strong positive growth response to the amount of thawing and growing degree-days as well as to winter and spring soil temperatures. In addition to these direct effects, a strong negative growth response to sea ice extent was identified, indicating a possible link between local sea ice conditions, local climate variations and Betula nana growth rates. Data also reveal a clear shift within the last 20 years from a period with thick snow depths (1991-1996) and a positive effect on Betula nana radial growth, to a period (1997-2011) with generally very shallow snow depths and no significant growth response towards snow. During this period, winter and spring soil temperatures have increased significantly suggesting that the most recent increase in Betula nana radial growth is primarily triggered by warmer winter and spring air temperatures causing earlier snowmelt that allows the soils to drain and warm quicker. The presented results may help to explain the recently observed 'greening of the Arctic' which may further accelerate in future years due to both direct and indirect effects of winter warming. PMID- 25788024 TI - Generation of reactive oxygen species in thylakoids from senescing flag leaves of the barley varieties Lomerit and Carina. AB - MAIN CONCLUSION: During senescence, production of reactive oxygen species increased in thylakoids. In two barley varieties, no difference in superoxide production was observed while singlet oxygen production increased only in one variety. During senescence, chlorophyll content decreased and photosynthetic electron transport was inhibited as shown for flag leaves collected from barley varieties Lomerit and Carina grown in the field. Spin trapping electron paramagnetic resonance (EPR) was used to investigate the production of reactive oxygen species in thylakoid membranes during senescence. EPR measurements were performed with specific spin traps to discriminate between singlet oxygen on one hand and reactive oxygen intermediates on the other hand. The results show that the generation of reactive oxygen intermediates increases in both varieties during senescence. Singlet oxygen increased only in the variety cv. Lomerit while it remained constant at a low level in the variety cv. Carina. Measurements in the presence of inhibitors of photosystem II and of the cytochrome b6f complex revealed that in senescing leaves reduction of oxygen at the acceptor side of photosystem I was the major, but not the only source of superoxide anions. This study shows that during senescence the production of individual reactive oxygen species varies in different barley varieties. PMID- 25788026 TI - Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats. AB - AIMS: To test if urodynamic effects from systemic Fatty Acid Amide Hydrolase (FAAH) inhibition involve sacral spinal cannabinoid type 1 (CB1) or type 2 (CB2) receptors. METHODS: Male rats with or without partial urethral obstruction were used for cystometry or immunohistochemistry. Urodynamic effects of intravenous (IV) 0.3 mg/kg Oleoyl Ethyl Amide (OEtA; FAAH inhibitor), and intrathecal (IT) 5 MUg rimonabant (CB1 antagonist) or 5 MUg SR144528 (CB2 antagonist) were studied in awake rats. RESULTS: After administration of rimonabant or SR144528, non obstructed rats with normal bladder function developed bladder overactivity (BO), which was counteracted by OEtA. OEtA also counteracted BO in obstructed rats. SR144528 did not affect bladder function in obstructed rats but counteracted the urodynamic effects of OEtA. Surprisingly, rimonabant (and AM251, another CB1 antagonist) reduced BO in obstructed rats, whereafter OEtA produced no additional urodynamic effects. CB1 expression increased in the sacral spinal cord of obstructed rats whereas no changes were observed for CB2 or FAAH. CONCLUSIONS: Urodynamic effects of systemic FAAH inhibition involve activities at spinal neuronal CB1 and CB2 receptors in normal and obstructed rats. Endogenous spinal CB receptor ligands seem to regulate normal micturition and BO. Altered spinal CB receptor functions may be involved in the pathogenesis of obstruction-induced BO. Neurourol. Urodynam. 35:464-470, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25788027 TI - Nutraceuticals and Blood Pressure Control: Results from Clinical Trials and Meta Analyses. AB - Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets, a large number of studies has investigated the possible BP lowering effect of different dietary supplements and nutraceuticals, the most part of them being antioxidant agents with a high tolerability and safety profile. In particular relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of the above discussed products. Moreover further clinical research is advisable to identify between the available active nutraceuticals those with the best cost effectiveness and risk-benefit ratio for a large use in general population with low-added cardiovascular risk related to uncomplicated hypertension. PMID- 25788028 TI - Towards reconstitution of membrane fusion mediated by SNAREs and other synaptic proteins. AB - Proteoliposomes have been widely used for in vitro studies of membrane fusion mediated by synaptic proteins. Initially, such studies were made with large unsynchronized ensembles of vesicles. Such ensemble assays limited the insights into the SNARE-mediated fusion mechanism that could be obtained from them. Single particle microscopy experiments can alleviate many of these limitations but they pose significant technical challenges. Here we summarize various approaches that have enabled studies of fusion mediated by SNAREs and other synaptic proteins at a single-particle level. Currently available methods are described and their advantages and limitations are discussed. PMID- 25788029 TI - Transcriptional 'memory' of a stress: transient chromatin and memory (epigenetic) marks at stress-response genes. AB - Drought, salinity, extreme temperature variations, pathogen and herbivory attacks are recurring environmental stresses experienced by plants throughout their life. To survive repeated stresses, plants provide responses that may be different from their response during the first encounter with the stress. A different response to a similar stress represents the concept of 'stress memory'. A coordinated reaction at the organismal, cellular and gene/genome levels is thought to increase survival chances by improving the plant's tolerance/avoidance abilities. Ultimately, stress memory may provide a mechanism for acclimation and adaptation. At the molecular level, the concept of stress memory indicates that the mechanisms responsible for memory-type transcription during repeated stresses are not based on repetitive activation of the same response pathways activated by the first stress. Some recent advances in the search for transcription 'memory factors' are discussed with an emphasis on super-induced dehydration stress memory response genes in Arabidopsis. PMID- 25788030 TI - Methods of reconstruction after esophagectomy on long-term health-related quality of life: a prospective, randomized study of 5-year follow-up. AB - The health-related quality of life (HRQL) is generally accepted as an important parameter for patients undergoing oncologic surgery. We conducted this prospective, randomized study to compare the effect of narrow gastric tube (NGT) reconstruction and whole-stomach (WS) reconstruction on the long-term HRQL in patients after esophagectomy. One hundred and four patients undergoing esophagectomy were enrolled in our study from 2007 to 2008, with 52 in NGT group and 52 in WS group. A questionnaire with reference to the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-OES18 was used to assess the HRQL at 3 weeks, 6 months, 1, 2, 3, 4, and 5 years after esophagectomy. Data collection and follow-up were performed regularly. No significant difference was found between NGT group and WS group in the patients' baseline characteristics. Patients in NGT group had decreased risk of postoperative reflux esophagitis by comparison with those in WS group. The 5-year cumulative survival rate was 42 % (NGT) and 27 % (WS), respectively. Compared with WS group, a significant increased survival rate (P = 0.027) was found in NGT group. Additionally, patients had lower dysphagia scores (better) in NGT group than those in WS group at 5 years after esophagectomy (P < 0.05). However, the scores of the other scales did not show statistical difference at 5-year follow-up. NGT is a better option for the reconstruction after esophagectomy because of decreased risk of postoperative complication, increased survival rate, and better HRQL, and NGT should be preferred to be recommended for patients undergoing esophagectomy. PMID- 25788031 TI - The more we use, the more we lose. PMID- 25788032 TI - Galectin-3 knockdown increases gefitinib sensitivity to the inhibition of EGFR endocytosis in gefitinib-insensitive esophageal squamous cancer cells. AB - Esophageal cancer (EC) is one of the most aggressive malignancies with a distinctly high incidence and mortality rate. Esophageal squamous cell carcinoma (ESCC) is the major histologic subtype of EC, with 40-70 % of tumors overexpressing the epidermal growth factor receptor (EGFR). Blockade of EGFR signal transduction may be a promising and effective strategy for EC therapy. However, the therapeutic efficacy of EGFR-tyrosine kinase inhibitors is clinically limited because of drug resistance. Galectin-3, a member of the animal lectin family, has been associated with a variety of biological functions and the progression of multiple tumors, including ESCC. In this study, we investigated the role of galectin-3 involved in potential gefitinib-resistance mechanisms in EGFR-positive ESCC cell lines. The results revealed that gefitinib treatment induced different inhibitory effects on cell viability, cell cycle progression and cell invasion in gefitinib-sensitive KYSE-450 and gefitinib-insensitive TE-8 cells with different levels of galectin-3 expression. Interestingly, we further found that EGF-induced EGFR endocytosis and EGFR signaling were different between gefitinib-sensitive and gefitinib-insensitive ESCC cell lines. Galectin-3 inhibition in combination with gefitinib treatment induced greater inhibitory effects on cell viability, cell cycle progression and cell invasion in gefitinib insensitive TE-8 cells. Moreover, galectin-3 inhibition increased the gefitinib sensitivity of TE-8 cells in terms of EGFR endocytosis in vitro and anti-tumor effects in vivo. Taken together, galectin-3 knockdown increased gefitinib sensitivity through the inhibition of EGFR endocytosis in gefitinib-insensitive ESCC cells and galectin-3 may be a rational therapeutic target in ESCC with gefitinib resistance. PMID- 25788033 TI - Evaluation of Clavien-Dindo classification in patients undergoing total gastrectomy for gastric cancer. AB - The Clavien-Dindo classification for postoperative complications has been established as a standardized system and applied in many fields of surgery. The aim of our study was to assess the complications after total gastrectomy using the Clavien-Dindo classification and identify risk factors related to them. Four hundred and fifteen patients who underwent total gastrectomy for gastric cancer between April 2009 and September 2014 were enrolled in this study. Postoperative complications were graded, and possible risk factors related to complications were analyzed. The overall complication rate was 13.3 %, with the severe complications classified as grade III or above accounting for 3.1 %. Age of 65 years old or more, higher TNM staging, and open surgery were identified as independent risk factors for overall complications. Age of 65 years old or more, ASA score of 3 or more, multiorgan resection, and retrieved lymph nodes of 30 or more were identified as independent risk factors for severe complications. The Clavien-Dindo system has a broad applicability and facilitates the assessment on the incidence and severity of complications. Large-scaled, prospective clinical trials using the classification are necessary to evaluate the postoperative complications of total gastrectomy for gastric cancer. PMID- 25788034 TI - Cost-effectiveness analysis of gemcitabine, S-1 and gemcitabine plus S-1 for treatment of advanced pancreatic cancer based on GEST study. AB - Gemcitabine (GEM) alone, S-1 alone and gemcitabine plus S-1 (GS) have shown a marginal clinical benefit for the treatment of advanced pancreatic cancer. However, there is no clearly defined optimal cost-effectiveness treatment. The objective of this study was to assess the cost-effectiveness of GEM alone, S-1 alone and GS for the treatment of advanced pancreatic cancer based on GEST study for public payers. A decision model compared GEM alone, S-1 alone and GS. Primary base case data were identified using the GEST study and the literatures. Costs were estimated from West China Hospital, Sichuan University, China, and incremental cost-effectiveness ratios (ICERs) were calculated. Survival benefits were reported in quality-adjusted life-months (QALMs). Sensitive analyses were performed by varying potentially modifiable parameters of the model. The base case analysis showed that the GEM cost $21,912 and yielded survival of 6.93 QALMs, S-1 cost $19,371 and yielded survival of 7.90 QALMs and GS cost $22,943 and yielded survival of 7.46 QALMs in the entire treatment. The one-way sensitivity analyses showed that the ICER of S-1 was driven mostly by the S-1 group utility score of stable state compared with GEM, and the GEM group utility score of progressed state played a key role on the ICER of GS compared with GEM. S-1 represents an attractive cost-effective treatment for advanced pancreatic cancer, given the favorable cost per QALM and improvement in clinical efficacy, especially the limited available treatment options. PMID- 25788036 TI - Spatial constancy of attention across eye movements is mediated by the presence of visual objects. AB - Recent studies have shown that attentional facilitation lingers at the retinotopic coordinates of a previously attended position after an eye movement. These results are intriguing, because the retinotopic location becomes behaviorally irrelevant once the eyes have moved. Critically, in these studies participants were asked to maintain attention on a blank location of the screen. In the present study, we examined whether the continuing presence of a visual object at the cued location could affect the allocation of attention across eye movements. We used a trans-saccadic cueing paradigm in which the relevant positions could be defined or not by visual objects (simple square outlines). We find an attentional benefit at the spatiotopic location of the cue only when the object (the placeholder) has been continuously present at that location. We conclude that the presence of an object at the attended location is a critical factor for the maintenance of spatial constancy of attention across eye movements, a finding that helps to reconcile previous conflicting results. PMID- 25788035 TI - Searching for the right word: Hybrid visual and memory search for words. AB - In "hybrid search" (Wolfe Psychological Science, 23(7), 698-703, 2012), observers search through visual space for any of multiple targets held in memory. With photorealistic objects as the stimuli, response times (RTs) increase linearly with the visual set size and logarithmically with the memory set size, even when over 100 items are committed to memory. It is well-established that pictures of objects are particularly easy to memorize (Brady, Konkle, Alvarez, & Oliva Proceedings of the National Academy of Sciences, 105, 14325-14329, 2008). Would hybrid-search performance be similar if the targets were words or phrases, in which word order can be important, so that the processes of memorization might be different? In Experiment 1, observers memorized 2, 4, 8, or 16 words in four different blocks. After passing a memory test, confirming their memorization of the list, the observers searched for these words in visual displays containing two to 16 words. Replicating Wolfe (Psychological Science, 23(7), 698-703, 2012), the RTs increased linearly with the visual set size and logarithmically with the length of the word list. The word lists of Experiment 1 were random. In Experiment 2, words were drawn from phrases that observers reported knowing by heart (e.g., "London Bridge is falling down"). Observers were asked to provide four phrases, ranging in length from two words to no less than 20 words (range 21 86). All words longer than two characters from the phrase, constituted the target list. Distractor words were matched for length and frequency. Even with these strongly ordered lists, the results again replicated the curvilinear function of memory set size seen in hybrid search. One might expect to find serial position effects, perhaps reducing the RTs for the first (primacy) and/or the last (recency) members of a list (Atkinson & Shiffrin, 1968; Murdock Journal of Experimental Psychology, 64, 482-488, 1962). Surprisingly, we showed no reliable effects of word order. Thus, in "London Bridge is falling down," "London" and "down" were found no faster than "falling." PMID- 25788037 TI - Numerosity adaptation along the Y-Axis affects numerosity perception along the X Axis: does numerosity adaptation activate MNLs? AB - The current study characterized the spatial selectivity of numerosity adaptation. In Experiment 1, adaptors were arranged vertically with 8 dots at the top of the visual field and 400 dots at the bottom, and participants' perceived magnitude in the left field decreased compared to that in the right, as revealed in the numerosity comparing task after adaptation. In contrast, the perceived magnitude in the right field decreased compared to that in the left with inversed adaptors (400 dots at top, 8 at bottom). In Experiment 2, adaptors were presented horizontally, and they showed no significant effect on numerosity perception, which was tested vertically. This study demonstrated that numerosity adaptation along the vertical orientation could affect numerosity perception along the horizontal orientation, and the latter was affected by the former according to a rule of associating "top" with "right" and "bottom" with "left." The spatial selectivity of numerosity adaptation showed distinguishing features that should function to abstract spatial relationships rather than create purely retinotopic mapping. We proposed that numerosity adaptation is based on spatial-numerical associated codes. Vertical adaptors could activate both the vertical and horizontal Mental Number Lines (MNLs) and involve an interaction between these types of MNLs. According to behavioral data, horizontal adaptors showed no significant influence on perception along the vertical orientation, which might be due to the higher threshold required to activate the vertical MNL. PMID- 25788038 TI - Slow change deafness. AB - In four experiments, we demonstrated a new phenomenon called "slow-change deafness." In Experiment 1 we presented listeners with continuous speech that changed three semitones in pitch over time, and we found that nearly 50 % failed to notice the change. Experiments 2 and 3 replicated the finding, demonstrated that the changes in the stimuli were well above threshold, and showed that when listeners were alerted to the possibility of a change, detection rates improved dramatically. Experiment 4 showed that increasing the magnitude of the change that occurred in the stimulus decreased the rate of change deafness. Our results are consistent with previous work that had shown that cueing listeners to potential auditory changes can significantly reduce change deafness. These findings support an account of change deafness that is dependent on both the magnitude of a stimulus change and listener expectations. PMID- 25788039 TI - Cost-effectiveness of adding ezetimibe to atorvastatin vs switching to rosuvastatin therapy in Portugal. AB - BACKGROUND: Statin monotherapy is the mainstay of low-density lipoprotein cholesterol (LDL-C) management for high cardiovascular risk patients in Portugal; however, several therapeutic options are available and predicted to have different clinical and economic impacts. The aim of this study was to evaluate the cost-effectiveness of adding ezetimibe 10 mg (EZ10) to atorvastatin 10 or 20 mg (A10/20) vs switching to rosuvastatin 10 or 20 mg (R10/20) in Portuguese patients with coronary heart disease (CHD) and/or diabetes who are currently above the LDL-C goal. METHODS: A Markov model was used to describe CHD disease progression and the lifetime costs and utilities associated with each disease state were used to estimate the gains in life-years and quality-adjusted life years (QALYs), as well as the incremental cost-effectiveness ratio (ICER), of the two treatment regimens. Model inputs, such as age, gender, and prevalence of cardiovascular risk factors of the dyslipidemic Portuguese patients were obtained from the Portuguese cohort of the Dyslipidemia International Study (DYSIS). The efficacy of each treatment regimen, the cost of drugs and of treating CHD events, and the utilities for each disease state were derived from published sources. RESULTS: The estimated lifetime discounted number of QALYs gained by patients treated with A10/20 was 8.70, while in those switching to R10/20 it was 8.81 and in those adding EZ10 it was 8.93. Discounted total health costs were estimated to be ?11,131 for A10/20, but ?14,511 and ?16,571 for R10/20 and A10/20 + EZ10, respectively. The ICER of adding ezetimibe vs switching to rosuvastatin was ?16,465/QALY. Based on the Portuguese cost-effectiveness willingness-to-pay threshold of ?30,000/QALY, adding ezetimibe vs switching to rosuvastatin would be a cost-effective use of resources in Portugal. Sensitivity analyses in patients with differing clinical histories (CHD or diabetes or both) yielded similar values, with no ICER over ?30,000/QALY. CONCLUSIONS: From the perspective of the National Health Service, prescribing ezetimibe to high cardiovascular risk patients being treated with atorvastatin vs switching them to rosuvastatin is projected to be a cost-effective use of resources in Portugal. PMID- 25788040 TI - Long-Term Results of Cardiac Resynchronization Therapy: A Comparison between CRT Pacemakers versus Primary Prophylactic CRT-Defibrillators. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) with or without a defibrillator has a positive effect on mortality and morbidity for patients with heart failure. However, comparisons between CRT-defibrillators (CRT-D) and CRT pacemakers (CRT-P) are relatively scarce outside the clinical trial setting. This study aimed to assess baseline characteristics in relation to long-term prognosis in patients treated with CRT, and to investigate the potential benefit of CRT-D versus CRT-P. METHODS: Data were retrospectively collected from the medical records of all consecutive patients treated with CRT-P or primary prophylactic CRT-D at a large tertiary care center between 1999 and 2012. Predictors of mortality were investigated, and time-dependent analysis was performed with all cause mortality as the primary end point. RESULTS: A total of 705 patients were included (69.6 +/- 10 years, 78% New York Heart Association classes III-IV, left ventricular ejection fraction median 25%, 16% female, 36% CRT-D). The patients were followed for a median of 59 months. Annual mortality differed between CRT-D primary prophylactic and CRT-P groups (5.3% and 11.8%, respectively), but when adjusted for covariates, CRT-D treatment (compared to CRT-P) was not associated with better long-term survival. Independent predictors of survival were: age, use of loop diuretics, hemoglobin levels, and use of renin angiotensin aldosterone system blockers. CONCLUSIONS: In CRT treatment outside of the clinical trial setting, CRT-D treatment was not an independent predictor of long-term survival. Future research should focus on correct selection of the patients who receive enough benefit of an added defibrillator to justify CRT-D implantation instead of CRT-P treatment only. PMID- 25788041 TI - Observing Interactions between Children and Adolescents and their Parents: The Effects of Anxiety Disorder and Age. AB - Parental behaviors, most notably overcontrol, lack of warmth and expressed anxiety, have been implicated in models of the development and maintenance of anxiety disorders in children and young people. Theories of normative development have proposed that different parental responses are required to support emotional development in childhood and adolescence, yet age has not typically been taken into account in studies of parenting and anxiety disorders. In order to identify whether associations between anxiety disorder status and parenting differ in children and adolescents, we compared observed behaviors of parents of children (7-10 years) and adolescents (13-16 years) with and without anxiety disorders (n = 120), while they undertook a series of mildly anxiety-provoking tasks. Parents of adolescents showed significantly lower levels of expressed anxiety, intrusiveness and warm engagement than parents of children. Furthermore, offspring age moderated the association between anxiety disorder status and parenting behaviors. Specifically, parents of adolescents with anxiety disorders showed higher intrusiveness and lower warm engagement than parents of non-anxious adolescents. A similar relationship between these parenting behaviors and anxiety disorder status was not observed among parents of children. The findings suggest that theoretical accounts of the role of parental behaviors in anxiety disorders in children and adolescents should distinguish between these different developmental periods. Further experimental research to establish causality, however, would be required before committing additional resources to targeting parenting factors within treatment. PMID- 25788042 TI - Beyond Symptom Counts for Diagnosing Oppositional Defiant Disorder and Conduct Disorder? AB - Conduct Disorder (CD) and Oppositional Defiant Disorder (ODD) are among the most commonly diagnosed childhood behavioral health disorders. Although there is substantial evidence of heterogeneity of symptom presentations, DSM diagnoses of CD and ODD are formally diagnosed on the basis of symptom counts without regard to individual symptom patterns. We used unidimensional item response theory (IRT) two-parameter logistic (2PL) models to examine item parameters for the individual symptoms of CD and ODD using data on 6,491 adolescents (ages 13-17) from the National Comorbidity Study: Adolescent Supplement (NCS-A). For each disorder, the symptoms differed in terms of severity and discrimination parameters. As a result, some adolescents who were above DSM diagnostic thresholds for disruptive behavior disorders exhibited lower levels of the underlying construct than others below the thresholds, based on their unique symptom profile. In terms of incremental benefit, our results suggested an advantage of latent trait scores for CD but not ODD. PMID- 25788044 TI - Radioguided localization of neuroblastomas in laparoscopic surgery using (123)I- radiolabeled metaiodobenzylguanidine. AB - Minimally invasive surgery has become widely recognized and is commonly used for the diagnosis and treatment of neuroblastoma. However, in post-chemotherapy status or during reoperations, it is occasionally difficult to precisely locate small neuroblastoma lesions, and this becomes prominent in endoscopic surgeries, in which tactile sense is essentially lost. Herein, we report our preliminary experience in two abdominal neuroblastoma cases undergoing laparoscopic tumor resection with aid of intraoperative (123)I- metaiodobenzylguanidine (MIBG) radioguidance using a specifically designed gamma-probe. The procedure enables easier localization of viable neuroblastoma tissue, provided that the tumor shows moderate to high MIBG uptake. PMID- 25788043 TI - Cool Decision-Making in Adolescents with Behavior Disorder and/or Mild-to Borderline Intellectual Disability. AB - Adolescents with Behavior Disorders (BD), Mild-to-Borderline Intellectual Disability (MBID), and with both BD and MBID (BD + MBID) are known to take more risks than normal controls. To examine the processes underlying this increased risk-taking, the present study investigated cool decision-making strategies in 479 adolescents (12-18 years, 55.9 % male) from these four groups. Cool decision making was assessed with the paper-and-pencil Gambling Machine Task. This task, in combination with advanced latent group analysis, allows for an assessment of decision strategies. Results indicated that adolescents with BD and controls were almost equivalent in their decision-making strategies, whereas adolescents with MBID and adolescents with BD + MBID were characterized by suboptimal decision making strategies, with only minor differences between these two clinical groups. These findings may have important clinical implications, as they suggest that risk taking in adolescents with MBID and in adolescents with BD + MBID can be (partly) attributed to the strategies that these adolescents use to make their decisions. Interventions may therefore focus on an improvement of these strategies. PMID- 25788045 TI - Impact of serum ferritin level on hepatocarcinogenesis in chronic hepatitis C patients. AB - AIM: To elucidate the impact of the serum ferritin level, a surrogate indicator of hepatic iron accumulation, on hepatocarcinogenesis in chronic hepatitis C patients. METHODS: Serum ferritin was measured in 487 chronic hepatitis C patients without history of hepatocellular carcinoma (HCC) after excluding patients in phlebotomy, those with overt chronic gastrointestinal bleeding and those who achieved sustained virological response before enrollment. Patients were divided into four groups (G1-G4) by quartile points of serum ferritin, with sexes separated. RESULTS: The serum ferritin level was positively correlated with total bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), gamma-glutamyltransferase, hemoglobin and AFP, and inversely correlated with prothrombin activity in both sexes. A significant difference in HCC incidence was observed only in male patients; the incidence was higher in G1 (<=80 ng/mL, n = 54) and G4 (>=323 ng/mL, n = 54) compared with that of G2 (81-160 ng/mL, n = 54) and G3 (161-322 ng/mL, n = 52). The spline curve indicating the relationship between the hazard ratio and serum ferritin level took the form of a J-shape for male patients. In multivariate analysis, G1 and G4 showed higher incidence of HCC among men with a hazard ratio of 2.19 (95% confidence interval, 1.02-4.70; P = 0.045) compared with G2 and G3, together with older age, lower serum albumin and ALT above the normal upper limit. CONCLUSION: The serum ferritin level is an independent risk factor for HCC development in male patients with chronic hepatitis C when the level is extremely high or low. PMID- 25788047 TI - Anti-tumor effects and cellular mechanisms of resveratrol. AB - Resveratrol (3, 5, 4'-trihydroxystilbene) is a phytoalexin contained in a variety of plants, such as grapes, berries and especially in the dried roots of Polygonum cuspidatum Sieb. et Zucc. It has been shown to exhibit anti-oxidative and anti inflammation activity, and to reverse the effects of aging. Its ability to suppress cell proliferation, induce apoptosis and suppress the metastasis and invasion in a number of cell lines has prompted a large interest from people for its use as an anti-tumor component. In this review, evidence of resveratrol's anti-tumor effects and molecular mechanisms are recapitulated. First, we present the anti-apoptosis, anti-invasion/metastasis and anti-inflammation effect of resveratrol; second, the main signaling pathways involved in these activities are described and summarized with the studies of different tumors involved. Resveratrol not only induces apoptosis of tumor cells through intrinsic/extrinsic pathways and cell cycle arrest, but also inhibits the invasion and metastasis abilities of tumors via modulating collagen degradation-related molecular targets. Altogether, the present findings suggest the anti-tumor potential of resveratrol against various types of cancers. PMID- 25788048 TI - Oligonol, a low-molecular-weight polyphenol derived from lychee fruit, attenuates gluco-lipotoxicity-mediated renal disorder in type 2 diabetic db/db mice. AB - Oligonol is a phenolic product derived from lychee fruit extract containing catechin-type monomers and oligomers of proanthocyanidins, produced by a manufacturing process which converts polyphenol polymers into oligomers. These proanthocyanidins have been reported to exhibit beneficial bioactivities in many studies, and so oligonol, a rich source of polyphenol, is expected to show favorable effects on various chronic diseases. This article summarizes recent work whether oligonol has an ameliorative effect on diabetic indices and renal disorders associated with gluco-lipotoxicity-mediated oxidative stress, inflammation, and apoptosis in db/db mice with diabetes. Oligonol was able to improve diabetic indices, prevent the development of diabetic renal disease, and preserve renal cells and the renal morphological structure via the attenuation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced oxidative stress, inhibition of advanced glycation endproduct (AGE) generation, and prevention of apoptosis-induced cell death in db/db mice, being independent of changes in the body weight or serum glucose levels. The present study provides important evidence that oligonol exhibits a pleiotropic effect, representing renoprotective effects against the development of diabetic complications in type 2 diabetic db/db mice. PMID- 25788049 TI - Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). AB - Ginseng, Panax ginseng (C. A. Mey.), is a well-known Chinese traditional medicine in the Far East and has gained popularity in the West during the last decade. There is extensive literature on the chemical constituents and bioactivities of ginseng. In this paper we compiled the chemical constituents isolated and detected from ginseng including polysaccharides, ginsenosides, peptides, polyacetylenic alcohols, fatty acids, etc. Meanwhile we summarized the biological activities of ginseng, which have been reported over the past few decades, including: anti-aging activity, anti-diabetic activity, immunoregulatory activity, anti-cancer activity, neuroregulation activity, wound and ulcer healing activity, etc. Nevertheless, further studies to exploit other kinds of constituents and new biological activities of ginseng are still necessary to facilitate research and development in the future. PMID- 25788050 TI - Tauroursodeoxycholic acid attenuates inorganic phosphate-induced osteoblastic differentiation and mineralization in NIH3T3 fibroblasts by inhibiting the ER stress response PERK-eIF2alpha-ATF4 pathway. AB - Ectopic ossification occurs in a wide range of common and genetic diseases, but its molecular mechanisms and effective therapeutic targets remain to be clarified. The aim of the study is to investigate whether endoplasmic reticulum (ER) stress is involved in ectopic ossification and ER stress inhibitor tauroursodeoxycholic acid (TUDCA) has potential to treat the pathological conditions. In this study, inorganic phosphate (Pi)-induced NIH3T3 fibroblasts induced osteogenesis and mineralization was used as an in vitro model for ectopic ossification. Various concentrations of TUDCA (0.1, 1, 5, 10 MUM) were added during osteogenic induction. Osteoblast differentiation and minerlization were determined by RT-qPCR, alkaline phosphatase (ALP) activity assay, Alizarin Red-S (AR-S) staining, and calcium deposition. ER stress signalling components were detected by Western-blot analysis. We found ER stress was activated by inorganic phosphate in NIH3T3 cells. During osteogenic induction, TUDCA inhibited NIH3T3 cells ALP activity and mineral nodule formation. In addition, TUDCA caused decreased expression of osteoblastic markers Runx2, Col1a1, ALP, OCN. Mechanistically, TUDCA inhibited the ER stress response PERK-eIF2alpha-ATF4 pathway during osteogenesis. In conclusion, TUDCA could inhibit fibroblasts mineralization via supressing the ER stress response PERK-eIF2alpha-ATF4 pathway, and has potential pharmacologic and therapeutic applications for treating ectopic ossification associated diseases. PMID- 25788051 TI - Enhanced anticancer activity of 5-FU in combination with Bestatin: Evidence in human tumor-derived cell lines and an H22 tumor-bearing mouse. AB - The clinical use of 5-fluorouracil (5-FU) is increasingly limited by low response rates, adverse reactions, and toxicity. A drug combination offers a new strategy for appropriate use of 5-FU. Bestatin, an aminopeptidase N (APN) inhibitor, has been used as an adjuvant chemotherapy drug because of its actions to suppress tumorigenesis and invasion. The current study evaluated the anticancer efficacy of 5-FU plus Bestatin at the cellular and animal level. The combination killed more colonic cancer, hepatic carcinoma, and ovarian cancer cells and fewer nonmalignant human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells than 5-FU or Bestatin alone. Moreover, 41.58% of ES-2 and 20.86% of PLC/PRF/5 cell apoptosis was caused by the combination of the two, while 5-FU caused apoptosis of 20.86% of ES-2 cells and 8.85% of PLC/PRF/5 cells. The cell cycle was arrested in the S and G0/G1 phases when a combination of the two was used. In an experiment involving mice bearing tumors, a combination of the two had a rate of tumor inhibition of 61.98%, while 5-FU alone had a rate of tumor inhibition of just 49.17%. In addition, the combination of the two was safer than either drug alone and did not cause weight loss or death. In conclusion, combining 5-FU and Bestatin could enhance the anticancer activity of 5-FU and decrease its cytotoxicity. These results suggest that 5-FU plus Bestatin has greater efficacy as a tumor therapy. PMID- 25788052 TI - Anti-metastatic action of anacardic acid targets VEGF-induced signalling pathways in epithelial to mesenchymal transition. AB - Anacardic acid is a major constituent of nutshell of cashew. In this study, we have isolated it from the leaves of Anacardium Occidentale L. using polarity based fractionation and confirmed the structure using GC-MS, NMR and FT-IR. The main focus of this study is to harness the molecular mechanism of anti-metastatic action of anacardic acid (A1). We have used MCF-7, a weak metastatic and U-87, a highly metastatic, breast and glioma cell lines respectively, for our study. We have shown that VEGF increases migration and invasion activities of MCF-7 cells, upon overexpression of Twist and Snail genes. It is observed from the current study that exposure of MCF-7 cells to A1 resulted in upregulation of epithelial marker E-cadherin with a concomitant decrease in the expression of mesenchymal markers Twist and Snail gene expression besides exhibiting a strong anti migratory and anti-invasive activity. In metastatic U-87 glioma cells, treatment with A1 decreased the phosphorylation of MAP kinases, inhibited the translocation of Sp1 and down regulated VEGF and Flt-1 gene expression. Overall, the current findings demonstrate for the first time that anacardic acid functions as a potent EMT inhibitor by targeting VEGF signaling pathway, providing a novel template for drug discovery. PMID- 25788053 TI - Construction of recombinant adenoviral vector carrying cyclinA2 gene. AB - Cell cycle related molecules in mammalian cochleae could provide a new avenue to restore hearing loss caused by a variety of genetic and environmental insults. CyclinA2 is one of the most important regulators of cell cycle, but its role in the mammalian cochlea is still unknown. So, it is necessary to construct an adenovirus vector carrying cyclinA2 gene for clarifying its function in the cochlea. In this study, the cyclinA2 genes were cloned into the shuttle plasmid pDC316-mCMV-EGFP to construct pDC316-CyclinA2-mCMV-EGFP, which was co-transfected with the rescue plasmid pBHGlox?E1,3Cre into 293 cells to obtain the recombinant adenovirus Ad.CyclinA2-EGFP. Then, the plasmid pDC316-CyclinA2-mCMV-EGFP and recombinant adenovirus Ad.CyclinA2-EGFP were identified by restriction enzymes and reverse transcription-polymerase chain reaction (RT-PCR). The recombinant adenovirus vector was purified by CsCl banding, and was titrated. Finally, the recombinant adenovirus vector carrying cyclinA2 gene was constructed and confirmed by restriction enzyme analysis and RT-PCR. The titer of the recombinant adenovirus vectors reached 2.5 * 10(-11) v.p/mL. Thus, we had successfully established the Ad.CyclinA2-EGFP vector, and it could express efficiently in various cells of cochlea. This study established the foundation for the further research of cyclinA2 gene's function in the cochlea. PMID- 25788054 TI - Circadian rhythm of serum 25 (OH) vitamin D, calcium and phosphorus levels in the treatment and management of type-2 diabetic patients. AB - The circadian time structure of serum 25 (OH) vitamin D (25-OHD), calcium (Ca) and phosphorus (P) may prove to be helpful in prevention, efficacy and management of diabetes mellitus. Ten newly diagnosed patients with type-2 diabetes mellitus (6 men and 4 women), 30-65 years of age, and 10 age-matched clinically healthy volunteers (7 men and 3 women) were synchronized for one week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was served around 08:00, lunch around 13:30 and dinner around 20:00. Drugs/nutraceuticals known to affect the vitamin D-calcium metabolism and status were not taken. Blood samples were collected at 6-h intervals for 24 h under standardized, 24-h synchronized conditions. Serum 25-OHD, Ca, P, Ca-P product and Ca-P ratio were determined. A marked circadian variation was demonstrated for 25-OHD in healthy volunteers (p = 0.030) and of borderline statistical significance in the diabetic patients (p = 0.083) by population-mean cosinor analysis. Similarly, healthy volunteers showed borderline significance for serum Ca, P and Ca-P ratio. The circadian acrophase of Ca occurred later in the patients as compared to healthy controls. Mapping the circadian rhythm (an important component of the broader time structure or chronome, which includes a.o., trends with age and extra circadian components) of vitamin D and calcium is needed for exploring their role as markers in the treatment and management of diabetic patients. PMID- 25788055 TI - Combination chemotherapy with S-1 and docetaxel for cutaneous angiosarcoma resistant to paclitaxel. AB - The prognosis of cutaneous angiosarcoma is very poor compared with that of other skin malignancies. The main reason for this is the limited regimens of chemotherapy available for angiosarcoma, because it is resistant to most common chemotherapeutic agents. Therefore, there is an urgent need to identify new treatment options. Recently, S-1 and docetaxel therapy was reported to be effective for advanced gastric cancer and metastatic extramammary Paget's disease. Therefore, we treated paclitaxel-resistant angiosarcoma patient with S 1/docetaxel chemotherapy. The progression-free survival was 5.0 months although grade 3 adverse events such as diarrhea and neutropenia developed. Our data need to be confirmed in a large number of patients, but S-1/docetaxel chemotherapy as an additional regimen seems to be an effective treatment option for paclitaxel resistant angiosarcoma. PMID- 25788056 TI - Hollow humour. PMID- 25788057 TI - A clean, green science machine. PMID- 25788058 TI - Strike a chord. PMID- 25788059 TI - Share the risks of Ebola vaccine development. PMID- 25788072 TI - Marijuana gears up for production high in US labs. PMID- 25788073 TI - Crunch time for Canada's role in mega-telescope. PMID- 25788074 TI - Ethics of embryo editing divides scientists. PMID- 25788075 TI - Irish government under fire for turning its back on basic research. PMID- 25788076 TI - Five Solar System sights NASA should visit. PMID- 25788077 TI - The myopia boom. PMID- 25788078 TI - Fisheries: eyes on the ocean. PMID- 25788079 TI - Agriculture: increase water harvesting in Africa. PMID- 25788080 TI - Leadership: ten tips for choosing an academic chair. PMID- 25788086 TI - Neutron facility: European Spallation Source is on track. PMID- 25788085 TI - Microscopy: access to the bigger picture in histology. PMID- 25788088 TI - Graphics: scrap rainbow colour scales. PMID- 25788089 TI - Intersex: concept of multiple sexes is not new. PMID- 25788090 TI - Urban observatories: city data can inform decision theory. PMID- 25788091 TI - Charles H. Townes (1915-2015). PMID- 25788092 TI - Biogeochemistry: signs of saturation in the tropical carbon sink. PMID- 25788093 TI - Renewable energy: better luminescent solar panels in prospect. PMID- 25788094 TI - Neuroscience: spotlight on deep-brain stimulation. PMID- 25788096 TI - Highly efficient star formation in NGC 5253 possibly from stream-fed accretion. AB - Gas clouds in present-day galaxies are inefficient at forming stars. Low star formation efficiency is a critical parameter in galaxy evolution: it is why stars are still forming nearly 14 billion years after the Big Bang and why star clusters generally do not survive their births, instead dispersing to form galactic disks or bulges. Yet the existence of ancient massive bound star clusters (globular clusters) in the Milky Way suggests that efficiencies were higher when they formed ten billion years ago. A local dwarf galaxy, NGC 5253, has a young star cluster that provides an example of highly efficient star formation. Here we report the detection of the J = 3->2 rotational transition of CO at the location of the massive cluster. The gas cloud is hot, dense, quiescent and extremely dusty. Its gas-to-dust ratio is lower than the Galactic value, which we attribute to dust enrichment by the embedded star cluster. Its star formation efficiency exceeds 50 per cent, tenfold that of clouds in the Milky Way. We suggest that high efficiency results from the force-feeding of star formation by a streamer of gas falling into the galaxy. PMID- 25788095 TI - The fine-scale genetic structure of the British population. AB - Fine-scale genetic variation between human populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population. PMID- 25788099 TI - Osteomalacia induced by a phosphaturic mesenchymal tumor secreting fibroblast growth factor 23. PMID- 25788100 TI - Effective connectivity of brain regions related to visual word recognition: An fMRI study of Chinese reading. AB - Past neuroimaging studies have focused on identifying specialized functional brain systems for processing different components of reading, such as orthography, phonology, and semantics. More recently, a few experiments have been performed to look into the integration and interaction of distributed neural systems for visual word recognition, suggesting that lexical processing in alphabetic languages involves both ventral and dorsal neural pathways originating from the visual cortex. In the present functional magnetic resonance imaging study, we tested the multiple pathways model with Chinese character stimuli and examined how the neural systems interacted in reading Chinese. Using dynamic causal modeling, we demonstrated that visual word recognition in Chinese engages the ventral pathway from the visual cortex to the left ventral occipitotemporal cortex, but not the dorsal pathway from the visual cortex to the left parietal region. The ventral pathway, however, is linked to the superior parietal lobule and the left middle frontal gyrus (MFG) so that a dynamic neural network is formed, with information flowing from the visual cortex to the left ventral occipitotemporal cortex to the parietal lobule and then to the left MFG. The findings suggest that cortical dynamics is constrained by the differences in how visual orthographic symbols in writing systems are linked to spoken language. PMID- 25788101 TI - Chemical Speciation and Bond Lengths of Organic Solutes by Core-Level Spectroscopy: pH and Solvent Influence on p-Aminobenzoic Acid. AB - Through X-ray absorption and emission spectroscopies, the chemical, electronic and structural properties of organic species in solution can be observed. Near edge X-ray absorption fine structure (NEXAFS) and resonant inelastic X-ray scattering (RIXS) measurements at the nitrogen K-edge of para-aminobenzoic acid reveal both pH- and solvent-dependent variations in the ionisation potential (IP), 1s->pi* resonances and HOMO-LUMO gap. These changes unequivocally identify the chemical species (neutral, cationic or anionic) present in solution. It is shown how this incisive chemical state sensitivity is further enhanced by the possibility of quantitative bond length determination, based on the analysis of chemical shifts in IPs and sigma* shape resonances in the NEXAFS spectra. This provides experimental access to detecting even minor variations in the molecular structure of solutes in solution, thereby providing an avenue to examining computational predictions of solute properties and solute-solvent interactions. PMID- 25788102 TI - Predicting Inter-session Performance of SMR-Based Brain-Computer Interface Using the Spectral Entropy of Resting-State EEG. AB - Currently most subjects can control the sensorimotor rhythm-based brain-computer interface (SMR-BCI) successfully after several training procedures. However, 15 30% of subjects cannot achieve SMR-BCI control even after long-term training, and they are termed as "BCI inefficiency". This study focuses on the investigation of reliable SMR-BCI performance predictor. 40 subjects participated in the first experimental session and 26 of them returned in the second session, each session consists of an eyes closed/open resting-state EEG recording run and four EEG recording runs with hand motor imagery. We found spectral entropy derived from eyes closed resting-state EEG of channel C3 has a high correlation with SMR-BCI performance (r = 0.65). Thus, we proposed to use it as a biomarker to predict individual SMR-BCI performance. Receiver operating characteristics analysis and leave-one-out cross-validation demonstrated that the spectral entropy predictor provide outstanding classification capability for high and low aptitude BCI users. To our knowledge, there has been no discussion about the reliability of inter-session prediction in previous studies. We further evaluated the inter session prediction performance of the spectral entropy predictor, and the results showed that the average classification accuracy of inter-session prediction up to 89%. The proposed predictor is convenient to obtain because it derived from single channel resting-state EEG, it could be used to identify potential SMR-BCI inefficiency subjects from novel users. But there are still limitations because Kubler et al. have shown that some BCI users may need eight or more sessions before they develop classifiable SMR activity. PMID- 25788097 TI - Long-term decline of the Amazon carbon sink. AB - Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades, with a substantial fraction of this sink probably located in the tropics, particularly in the Amazon. Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long term decreasing trend of carbon accumulation. Rates of net increase in above ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity. The observed decline of the Amazon sink diverges markedly from the recent increase in terrestrial carbon uptake at the global scale, and is contrary to expectations based on models. PMID- 25788103 TI - Developing register-based measures for assessment of working time patterns for epidemiologic studies. AB - OBJECTIVES: Epidemiological studies suggest that long working hours and shift work may increase the risk of chronic diseases, but the "toxic" elements remain unclear due to crude assessment of working time patterns based on self-reports. In this methodological paper, we present and evaluate objective register-based algorithms for assessment of working time patterns and validate a method to retrieve standard payroll data on working hours from the employer electronic records. METHODS: Detailed working hour records from employers' registers were obtained for 12 391 nurses and physicians, a total 14.5 million separate work shifts from 2008-2013. We examined the quality and validity of the obtained register data and designed 29 algorithms characterizing four potentially health relevant working time patterns: (i) length of the working hours; (ii) time of the day; (iii) shift intensity; and (iv) social aspects of the working hours. RESULTS: The collection of the company-based register data was feasible and the retrieved data matched with the originally published shift plans. The transferred working time records included <0.01% missing data. Two percent were duplicates that could be easily removed. The 29 variables of working time patterns, generated for each year, were stable across the follow-up (year-to-year correlation coefficients from r=0.7-0.9 for 23 variables), their distributions were as expected, and correlations of the variables within the four main dimensions of working hours were plausible. CONCLUSION: The developed method and algorithms allow a detailed characterization of four main dimensions of working time patterns potentially relevant for health. We recommend this method for future large-scale epidemiological studies. PMID- 25788104 TI - A Ti(4+)-immobilized phosphate polymer-patterned silicon substrate for on-plate selective enrichment and self-desalting of phosphopeptides. AB - A circular hydrophobic-hydrophilic-Ti(4+) immobilized phosphate polymer is patterned on a silicon wafer. Such a wafer is used as a novel sample support to allow fast selective enrichment, wash-free self-desalting and mass spectroscopy (MS) analysis of phosphopeptides, thanks to the high Ti(4+) loading amount, pure phosphate polymer-Ti(4+) interface, and strong hydrophobic-hydrophilic attraction pattern. The detection sensitivity was enhanced 300 folds compared with what was obtained using the common MALDI plate. Remarkable selectivity for phosphopeptides can be achieved at a molar ratio as low as 1 : 500 of phosphopeptides (casein digest)/nonphosphopeptides (BSA). High-quality mass spectra can be obtained even in the presence of NaCl (1 M), NH4HCO3 (100 mM), or urea (1 M). These microspots were also used to selectively capture phosphopeptides from milk and human serum, which further demonstrated that they were capable of identifying low-abundance phosphopeptides from real complex samples. They provide a low detection limit (3 fmol MUL(-1)), small sample size, and excellent enrichment and desalting efficiency. Such a method significantly simplifies the analytical procedures, reduces possible sample loss, and is relatively low cost. Therefore, this on plate patterned technique is very promising in the high-throughput phosphoproteomic research, especially for the detection of tiny amounts of samples. PMID- 25788105 TI - Best practices for ECG screening in children. AB - Screening for conditions associated with sudden cardiac arrest in the United States (US) is aimed at high school athletes in most states and utilizes a preparticipation history and physical form that is not standardized across the US. In Italy, data have shown that their incidence of sudden cardiac arrest has decreased significantly after implementation of an electrocardiographic-based screening program including history and physical exam. The American Heart Association recommendations do not include an electrocardiogram. A recent AHA statement has suggested that those screening athletes should consider all children of similar ages in the selected venue, but still should not include an electrocardiogram. A number of models of screening are presented along with a best practice recommendation for further evaluation and study. PMID- 25788106 TI - Navigating the human hippocampus without a GPS. AB - The award of the Nobel Prize to Professors John O'Keefe, May-Britt Moser, and Edvard Moser brings global recognition to one of the most significant success stories in modern neuroscience. Here, we consider how their findings, along with related studies of spatial cognition in rodents, have informed our understanding of the human hippocampus. Rather than identifying a "GPS" in the brain, we emphasize that these researchers helped to establish a fundamental role for cortico-hippocampal networks in the guidance of behavior based on a representation of the current place, time, and situation. We conclude by highlighting the major questions that remain to be addressed in future research. PMID- 25788107 TI - Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018. AB - Although the putative pharmacological targets of synthetic cannabinoids (SCBs) abused in "K2" and "Spice" are similar to Delta(9) -tetrahydrocannabinol (Delta(9) -THC), it remains unclear why SCB toxicity is similar yet different from marijuana. There are obvious potency and efficacy differences, but also important metabolic differences that help explain the unique adverse reactions associated with SCBs. This brief review discusses the limited research on the metabolism of the SCB JWH-018 and contrasts that with the metabolism of Delta(9) THC. PMID- 25788108 TI - Plant resistance reduces the strength of consumptive and non-consumptive effects of predators on aphids. AB - 1. The impact of predators on prey has traditionally been attributed to the act of consumption. Prey responses to the presence of the predator (non-consumptive effects), however, can be as important as predation itself. While plant defences are known to influence predator-prey interactions, their relative effects on consumptive vs. non-consumptive effects are not well understood. 2. We evaluated the consequences of plant resistance and predators (Hippodamia convergens) on the mass, number of nymphs, population growth, density and dispersal of aphids (Macrosiphum euphorbiae). We tested for the effects of plant resistance on non consumptive and consumptive effects of predators on aphid performance and dispersal using a combination of path analysis and experimental manipulation of predation risk. 3. We manipulated plant resistance using genetically modified lines of tomato (Solanum lycopersicum) that vary incrementally in the expression of the jasmonate pathway, which mediates induced resistance to insects and manipulated aphid exposure to lethal and risk predators. Predation risk predators had mandibles impaired to prevent killing. 4. Plant resistance reduced predation rate (consumptive effect) on high resistance plants. As a consequence, predators had no impact on the number of nymphs, aphid density or population growth on high resistance plants, whereas on low resistance plants, predators reduced aphid density by 35% and population growth by 86%. Path analysis and direct manipulation of predation risk showed that predation risk rather than predation rate promoted aphid dispersal and varied with host plant resistance. Aphid dispersal in response to predation risk was greater on low compared to high resistance plants. The predation risk experiment also showed that the number of aphid nymphs increased in the presence of risk predators but did not translate into increased population growth. 5. In conclusion, the consumptive and non consumptive components of predators affect different aspects of prey demography, acting together to shape prey population dynamics. While predation risk accounts for most of the total effect of the predator on aphid dispersal and number of nymphs, the suppressive effect of predators on aphid population occurred largely through consumption. These effects are strongly influenced by plant resistance levels, suggesting that they are context dependent. PMID- 25788109 TI - Novel antigen delivery technologies: a review. AB - Over the past few years, new insights into immunobiology and delivery systems have allowed the development of better vaccines and for a wider range of diseases. Currently available vaccines represent outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide. Conventional vaccines have been based on live attenuated, or killed, viruses or bacteria, or recombinant proteins from these organisms. The design of live attenuated vaccines depended to some extent on serendipity and resulted in low success rates. Both live attenuated and killed vaccines require handling of live pathogens and are associated with safety problems. Despite the success of vaccines, there is a clear need for novel antigen delivery technologies to improve vaccine efficacy and safety. Antigen stability, safety, and immunogenicity are the key hurdles in development of novel antigen delivery technologies. Nowadays, various novel drug delivery systems are becoming one of the fastest growing sectors in the pharmaceutical and biotechnological industries. Delivery of vaccines via oral, intranasal, transcutaneous, and intradermal routes will decrease the risk of needle-borne diseases and may eliminate the need for trained personnel and sterile equipment. Currently, various techniques involving DNA vaccines, adjuvants, nanoparticles, liposome, microneedle, and NanoMAP technology are being developed and evaluated. This review focuses on the current development of some novel vaccine delivery systems and will explore the non-parenteral routes of vaccine administrations. PMID- 25788110 TI - Validation of the reconstituted high-density lipoprotein (rHDL) drug delivery platform using dilauryl fluorescein (DLF). AB - Dilauryl fluorescein (DLF) is a lipid soluble molecule that becomes fluorescent when lauric acid is removed by hydrolysis The purpose of these studies was to evaluate DLF as a potential probe for the function of reconstituted high-density lipoproteins (rHDL) as hydrophobic drug transport vehicles. The DLF containing rHDL nanoparticles were characterized regarding their physical/chemical properties, including molecular diameter, molecular weight, chemical composition, and buoyant density. We investigated the uptake of DLF from rHDL in cells that overexpress the scavenger receptor (SR-B1), known to facilitate the selective cellular uptake of cholesteryl esters from HDL. These studies show that DLF can be incorporated into rHDL and redistributed in the plasma compartment. In addition, these studies demonstrated an enhanced uptake and hydrolysis of DLF from rHDL by cells that overexpress the SR-B1 receptor, suggesting the involvement of a receptor mediated mechanism. The incorporation of DLF into the rHDL nanoparticles appear to protect against hydrolysis in the systemic circulation based on the lower rate of rHDL/DLF hydrolysis compared with the free DLF during incubation with human plasma. DLF may thus be used as a probe to track the movement and metabolism of HDL core constituents, including cancer chemotherapeutic agents. PMID- 25788111 TI - The use of bone cement for the localized, controlled release of the antibiotics vancomycin, linezolid, or fusidic acid: effect of additives on drug release rates and mechanical strength. AB - Bone cement containing antibiotics is commonly used to treat orthopedic related infections. However, effective treatment (especially of resistant bacteria, methacillin-resistant Staphylococcus aureus (MRSA)) is compromised by very low levels of drug release so that typically less than 10% of loaded drug is released over a 6-week period. The objective of this study was to investigate the effect of incorporation of water soluble excipients (polyethylene glycol, sodium chloride, or dextran) into antibiotic-loaded cement on mechanical strength and drug release properties. Poly(methyl methylacrylate) cement implants containing various amounts of drug (vancomycin, linezolid or fusidic acid (all MRSA active)) and excipients were cast in the form of beads or films and characterized using differential scanning calorimetry. Mechanical strength as assessed by Young's modulus was determined by thermo-mechanical analysis. Drug release was measured by incubation in phosphate buffered saline with analysis by HPLC methods. The inclusion of sodium chloride up to 20% w/w caused only minor reductions in Young's modulus. Vancomycin and linezolid released very slowly from unmodified bone cement beads (less than 3% released by 4 weeks) whereas fusidic acid released more quickly (approximately 8% released by 4 weeks). The inclusion of sodium chloride or dextran in bone cement resulted in major increases in the release rate of vancomycin, linezolid and fusidic acid. These studies support the inclusion of sodium chloride and dextran in bone cement to increase the release rate of vancomycin, linezolid, or fusidic acid without compromising the mechanical strength of the composite material. PMID- 25788112 TI - Design and evaluation of matrix base with sigmoidal release profile for colon specific delivery using a combination of Eudragit and non-ionic cellulose ether polymers. AB - A pH- and time-controlled drug delivery system with sigmoidal release profile was developed using Eudragit (L100 or S100) in combination with hydroxy ethyl cellulose (HEC) or hydroxy propyl cellulose (HPC) for sigmoidal release of indomethacin in the potential treatment of colon cancer. The effect of varying proportions of polymer type on sigmoidal release was evaluated. The prepared tablets were also characterized for physical characteristics, in vitro drug release, release kinetics, and stability on storage. The gastrointestinal transit of formulations was also investigated in human subjects. Results from in vitro release studies indicated that due to the presence of pH-responsive polymers, a pH- and time-dependent release pattern was observed, which was characterized by negligible drug release in first 4-6 h followed by controlled release for 14-16 h in alkaline pH. In vivo studies indicated that HPC-based formulations had satisfactory matrix strength to withstand gastric and colonic transit, while HEC based tablets disintegrated during transit through the small intestine. All the formulations were stable on storage. It was concluded that such a matrix design has good potential for drug delivery to colon with controlled release. PMID- 25788114 TI - Sustained release ocular inserts of brimonidine tartrate for better treatment in open-angle glaucoma. AB - Pathology of eye, especially in the case of glaucoma, requires optimal therapeutically effective concentration of the drug in the ocular tissues for prolonged period of time with decreased dosing frequency and improved patient compliance. In the present study, brimonidine tartrate (BRT) ocular inserts were designed based on hydrophilic and/or inert/zwitterionic polymer matrix to design mucoadhesive and extended release ocular inserts. Designed inserts were evaluated for their physicochemical properties such as crushing strength/hardness, friability, drug content and mucoadhesion, and erosion and in vitro drug release characteristics. The selected optimised formulations were compared with marketed preparation for in vivo ocular irritation in healthy rabbits and for in vivo pharmacodynamic efficacy on alpha-chymotrypsin-induced glaucomatous rabbits. The developed formulations showed good physicochemical properties and mucoadhesive strength, and a good correlation was seen between rate of erosion or swelling with drug release rate in case of formulations with higher proportion of polyethylene oxide (PEO). Modulation of drug release was achieved by incorporating Eudragit in PEO matrix. Addition of Eudragit resulted in shifting of drug release mechanism from erosion-controlled to diffusion-controlled mechanism. In vivo ocular irritation studies confirmed the absence of any irritation upon administration in rabbits. Intraocular pressure (IOP) measurement studies showed an improved IOP-lowering ability of ocular insert of BRT in comparison to eye drops. PMID- 25788113 TI - Nanofibrous scaffold with incorporated protein gradient for directing neurite outgrowth. AB - Concentration gradient of diffusible bioactive chemicals assumes many important roles in regulating cellular behavior. Among the many factors influencing functional recovery after nerve injury, such as topographical and biochemical signals, concentration gradients of neurotrophic factors provide chemotactic cues for neurite outgrowth and targeted renervation. In this study, a concentration gradient of nerve growth factor (NGF, 0-250 MUg/ml) was incorporated throughout the thickness of poly(epsilon-caprolactone)-poly(ethylene glycol) coaxial electrospun nanofibrous scaffolds (~700 MUm thick with ~800 nm average fiber diameter). The existence of the protein gradient upon protein release was demonstrated using a customized under-agarose-PC12 neurite outgrowth assay. When exposed to scaffolds endowed with NGF concentration gradient (NGF-CG), a significant difference in the percentage of cells bearing neurite outgrowth was observed (7.1 +/- 1.9% vs. 0.8 +/- 0.3% for cells exposed to high vs. low concentration surface, respectively; p < 0.05). In contrast, no significant difference was observed when cells were exposed to scaffolds that encapsulated a fixed concentration of NGF. Direct culture of PC12 cells on the substrates demonstrated the cytocompatibility and the effect of diffusible NGF gradient on neurite outgrowth. A significant difference in the percentage of cells with neurite extensions was observed when PC12 cells were seeded on NGF-CG scaffolds (21.2 +/- 3.6% vs. 10.4 +/- 1.3% on high vs. low concentration surface, respectively; p < 0.05). Furthermore, Z-stack confocal microscopy tracking of neurite extensions revealed the chemotatic guidance effect of NGF concentration gradient. Directed and enhanced neurite penetration into the scaffolds towards increasing NGF concentration was observed. In vitro release study indicated that the encapsulated NGF was released in a sustained manner for at least 30 days (80.4 +/- 3.6% released). Taken together, this study demonstrates the feasibility of incorporating concentration gradient of diffusible bioactive chemicals in nanofibrous scaffolds via the coaxial electrospinning technique. PMID- 25788115 TI - Preclinical evaluation of UC781 microbicide vaginal drug delivery. AB - UC781 is a potent nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide to prevent transmission of HIV-1 both vaginally and rectally. This study was designed to investigate the in vitro drug release, in vitro permeability/safety, and in vivo pharmacokinetics in rabbits of a vaginal gel prepared with micronized or nonmicronized UC781 (UC781m and UC781nm, respectively). Gels prepared with UC781m had greater in vitro release rates (Franz cells) and permeability/tissue-associated UC781 concentrations than gels prepared with UC781nm (EpiVaginal tissues). Both gels were well tolerated under in vitro conditions compared with controls using EpiVaginal tissues. Following intravaginal administration of both gels to rabbits, tissue concentrations typically ranged from 1,000 to over 10,000 ng/g regardless of dosing regimen (single dose or 7 days once daily dosing) and sampling times (2 and 24 h post-dose). Tissue-associated concentrations were highly variable, and no statistically significant differences were found between test conditions. Plasma levels were generally low after vaginal administration: following a single dose, the concentrations were between 0.5 and 1.0 ng/mL. After 7 days repeated once daily dosing, UC781 concentrations were slightly higher ranging from below 1.0 to about 2 ng/mL, although none of the differences were statistically significant. Based on these results, gels prepared with either form of UC781 led to tissue concentrations well in excess of UC781's EC50 under in vitro conditions (~3 ng/mL). PMID- 25788116 TI - The unusual presence of Streptococcus gallolyticus within neutrophils in a patient with endocarditis and brain abscesses. PMID- 25788117 TI - Inhibitory deterioration may contribute to hallucinations in Alzheimer's disease. AB - INTRODUCTION: Although delusions and hallucinations are relatively common symptoms in individuals with Alzheimer's disease (AD), very little is known regarding underlying mechanisms. We examined whether these manifestations could be underpinned by psychological distress and executive impairments. METHODS: Thirty-one participants with probable mild AD and 33 healthy older adults were administered a neuropsychological and clinical battery assessing delusions, hallucinations, anxiety, depression, episodic memory and executive functions (shifting, updating and inhibition). RESULTS: Prevalence of delusions and hallucinations were significantly higher in AD participants compared to control participants. Further, hallucinations in AD participants were significantly correlated with poor inhibition, with the latter uniquely predicting the former, as compared to other variables. In addition, hallucinations in AD participants were associated with depression, a relationship that was further mediated by inhibition. CONCLUSION: Hallucinations in individuals with AD seem to be related to difficulties suppressing irrelevant thoughts, resulting in these irrelevant thoughts becoming confused with ongoing reality. PMID- 25788118 TI - Factors controlling volatile organic compounds in dwellings in Melbourne, Australia. AB - This study characterized indoor volatile organic compounds (VOCs) and investigated the effects of the dwelling characteristics, building materials, occupant activities, and environmental conditions on indoor VOC concentrations in 40 dwellings located in Melbourne, Australia, in 2008 and 2009. A total of 97 VOCs were identified. Nine VOCs, n-butane, 2-methylbutane, toluene, formaldehyde, acetaldehyde, d-limonene, ethanol, 2-propanol, and acetic acid, accounted for 68% of the sum of all VOCs. The median indoor concentrations of all VOCs were greater than those measured outdoors. The occupant density was positively associated with indoor VOC concentrations via occupant activities, including respiration and combustion. Terpenes were associated with the use of household cleaning and laundry products. A petroleum-like indoor VOC signature of alkanes and aromatics was associated with the proximity of major roads. The indoor VOC concentrations were negatively correlated (P < 0.05) with ventilation. Levels of VOCs in these Australian dwellings were lower than those from previous studies in North America and Europe, probably due to a combination of an ongoing temporal decrease in indoor VOC concentrations and the leakier nature of Australian dwellings. PMID- 25788119 TI - Effect of Billroth II or Roux-en-Y Reconstruction for the Gastrojejunostomy After Pancreaticoduodenectomy: Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND AND OBJECTIVES: This study aimed to compare Billroth II with Roux-en-Y reconstruction after pancreaticoduodenectomy (PD). METHODS: A literature search was carried out to identify all randomized controlled trials (RCTs) comparing postoperative complications of Billroth II versus Roux-en-Y reconstruction following PD published from 1 January 1990 to 31 August 2014. Pooled risk ratios (RRs) with 95 % confidence intervals (CIs) were calculated using fixed effects or random effects models RESULTS: In total, three RCTs with 470 patients were included. Using International Study Group of Pancreatic Surgery (ISGPS) definitions, incidences of delayed gastric emptying (DGE) [grades B and C (3.9 versus 12.9 %; RR 0.30, 95 % CI 0.11-0.79; P = 0.01), DGE grade C (0.7 versus 9.6 %; RR 0.11, 95 % CI 0.02-0.61; P = 0.01)] were significantly lower in the Billroth II group than in the Roux-en-Y group, as was the length of hospital stay (weighted mean difference -4.72, 95 % CI -8.91, -0.53; P = 0.03). CONCLUSIONS: Meta-analysis revealed that the incidence of DGE (grades B and C) after PD can be decreased by using Billroth II rather than Roux-en-Y reconstruction. PMID- 25788120 TI - Laparoscopic Repair of Paraesophageal Hernias with a Falciform Ligament Buttress. AB - BACKGROUND: Buttressing the crura in paraesophageal hernia (PEH) repairs with synthetic mesh may be associated with erosions and dysphagia, while biologic buttresses are expensive and do not decrease long-term recurrence rates. This study documents outcomes following laparoscopic PEH repairs using the falciform ligament as a buttress. METHODS: This is a prospective study of laparoscopic PEH repairs with a falciform ligament buttress. Preoperatively and at 6 months follow up, medications, radiologic studies and symptom scores were recorded. Patients included had a hiatal defect greater than 5 cm, while recurrent PEH or prior gastric surgery patients were excluded. RESULTS: Thirty-four patients were included with a mean age of 61 years, and 33 patients completed postoperative evaluation with a mean follow-up of 7.1 months. The mean symptom severity decreased from 11.24 +/- 1.71 to 3.24 +/- 0.84, mean symptom frequency decreased from 11.62 +/- 1.70 to 3.45 +/- 0.85, and mean total symptom score decreased from 22.85 +/- 3.40 to 6.69 +/- 1.69 (p < 0.0001). Three patients had recurrences on the upper gastrointestinal (UGI) series. Only one required reoperation. CONCLUSIONS: Laparoscopic PEH repair with a falciform ligament buttress is a viable option. Ongoing follow-up will demonstrate the utility of this approach to decrease morbidity and recurrence rates for paraesophageal hernia repairs. PMID- 25788121 TI - SNP genotyping using TaqMan technology: the CYP2D6*17 assay conundrum. AB - CYP2D6 contributes to the metabolism of many clinically used drugs and is increasingly tested to individualize drug therapy. The CYP2D6 gene is challenging to genotype due to the highly complex nature of its gene locus. TaqMan technology is widely used in the clinical and research settings for genotype analysis due to assay reliability, low cost, and the availability of commercially available assays. The assay identifying 1023C>T (rs28371706) defining a reduced function (CYP2D6*17) and several nonfunctional alleles, produced a small number of unexpected diplotype calls in three independent sets of samples, i.e. calls suggested the presence of a CYP2D6*4 subvariant containing 1023C>T. Gene resequencing did not reveal any unknown SNPs in the primer or probe binding sites in any of the samples, but all affected samples featured a trio of SNPs on their CYP2D6*4 allele between one of the PCR primer and probe binding sites. While the phenomenon was ultimately overcome by an alternate assay utilizing a PCR primer excluding the SNP trio, the mechanism causing this phenomenon remains elusive. This rare and unexpected event underscores the importance of assay validation in samples representing a variety of genotypes, but also vigilance of assay performance in highly polymorphic genes such as CYP2D6. PMID- 25788122 TI - Adolescents' Social Network Site Use, Peer Appearance-Related Feedback, and Body Dissatisfaction: Testing a Mediation Model. AB - Previous correlational research indicates that adolescent girls who use social network sites more frequently are more dissatisfied with their bodies. However, we know little about the causal direction of this relationship, the mechanisms underlying this relationship, and whether this relationship also occurs among boys to the same extent. The present two-wave panel study (18 month time lag) among 604 Dutch adolescents (aged 11-18; 50.7% female; 97.7% native Dutch) aimed to fill these gaps in knowledge. Structural equation modeling showed that social network site use predicted increased body dissatisfaction and increased peer influence on body image in the form of receiving peer appearance-related feedback. Peer appearance-related feedback did not predict body dissatisfaction and thus did not mediate the effect of social network site use on body dissatisfaction. Gender did not moderate the findings. Hence, social network sites can play an adverse role in the body image of both adolescent boys and girls. PMID- 25788123 TI - Increased Pre- and Early-Adolescent Stress in Youth with a Family History of Substance Use Disorder and Early Substance Use Initiation. AB - Individuals with a family history of substance use disorders (Family History Positive) are more likely to have early-onset substance use (i.e., prior to age 15), which may contribute to their higher rates of substance use disorders. One factor that may differentiate Family History Positive youth who engage in early onset substance use from other Family History Positive youth is exposure to stressors. The aim of this study was to quantify how exposure to stressors from age 11-15 varies as a function of family history of substance use disorders and early-onset substance use. Self-reported stressors were prospectively compared in a sample of predominately (78.9%) Hispanic youth that included 68 Family History Positive youth (50% female) who initiated substance use by age 15 and demographically matched non-users with (n = 136; 52.9% female) and without (n = 75; 54.7% female) family histories of substance use disorders. Stressors were assessed at 6-month intervals for up to 4 years. Both the severity of stressors and the degree to which stressors were caused by an individual's own behavior were evaluated. All three groups differed from one another in overall exposure to stressors and rates of increase in stressors over time, with Family History Positive youth who engaged in early-onset substance use reporting the greatest exposure to stressors. Group differences were more pronounced for stressors caused by the participants' behavior. Family History Positive users had higher cumulative severity of stressors of this type, both overall and across time. These results indicate greater exposure to stressors among Family History Positive youth with early-onset substance use, and suggest that higher rates of behavior-dependent stressors may be particularly related to early-onset use. PMID- 25788124 TI - Risk and protective factors for sexual and dating violence victimization: a longitudinal, prospective study of Latino and African American adolescents. AB - Teen dating violence and sexual victimization are serious public health concerns. Although research has highlighted the correlates and consequences of such abuse, little is known about early antecedents. The current study sought to identify the risk and protective factors evident in early adolescence that are associated with sexual and dating violence victimization in late adolescence. The sample involved 236 (52% female) low-income Latino (69%) and African American (31%) youth, their older sisters, and their mothers who were studied when youth were, on average, ages 13 and 18 years. The results indicated that early indicators of a risky lifestyle (e.g., getting drunk, having sex) and having deviant friends and siblings were associated with a higher likelihood of subsequent victimization. Mothers' early strictness, monitoring, and conservative sexual attitudes predicted a lower likelihood of subsequent assault and served as significant buffers given specific risks, particularly for girls and Latinos. The findings suggest that behavior and social network patterns established relatively early in life increase one's vulnerability to victimization later in life, as well as point to aspects of parenting that serve a protective function against such outcomes. PMID- 25788125 TI - A comparative histopathological study of vocal fold polyps in smokers versus non smokers. AB - BACKGROUND: A large proportion of patients with vocal fold polyps are cigarette smokers. However, prior to this report no comparative study of polyp histopathology in smokers versus non-smokers had been performed. METHODS: A prospective histopathological study of vocal fold polyps excised from 29 patients was undertaken. This comprised a comparative analysis of polyp histopathology in smokers versus non-smokers and a review of the pertinent literature. RESULTS: Vocal fold polyps were larger in smokers than in non-smokers. Histopathological features significantly associated with the polyps of smokers versus those of non smokers were increased keratinisation, dysplasia, a basement membrane thinning and hyaline degeneration. CONCLUSION: Cigarette smoke has an injurious effect on vocal fold polyp epithelium and leads to increased hyaline degeneration in polyps. PMID- 25788126 TI - Redox-sensitive mechanisms underlying vascular dysfunction in heart failure. AB - Regardless of the progress in therapeutic drugs and devices to treat heart failure (HF) during the last few years, the clinical outcome of this disease remains deleterious. Impaired left ventricular function leads to neurohumoral activation, altered local shear forces, and hypoxia, which might give rise to inflammatory processes within the vasculature. Among those, the imbalance of the redox equilibrium toward increased concentrations of reactive oxygen species (ROS) is particularly important, as it affects the integrity of vascular function. Apart from injured or dysfunctional cardiomyocytes, vascular dysfunction has been demonstrated to play a crucial role in the development and progression of HF, which makes it an interesting target for new HF therapies. The mechanisms that initiate vascular dysfunction in HF pathogenesis and the processes leading to oxidative stress are not yet fully elucidated. However, oxidative stress promotes a variety of redox-sensitive mechanisms contributing to vascular dysfunction in HF. Here, we will summarize the sources of ROS in the vasculature, elucidate the impact of oxidative stress on functional and structural vascular remodeling, and consider the link to vascular dysfunction. Furthermore, we will point out the importance of vascular dysfunction in HF and discuss therapeutic options. PMID- 25788127 TI - Rational drug design applied to myeloperoxidase inhibition. AB - Rational drug design is a general approach using protein-structure technique in which the discovery of a ligand can be driven either by chance, screening, or rational theory. Myeloperoxidase (MPO) was rapidly identified as a therapeutical target because of its involvement in chronic inflammatory syndromes. In this context, the research of MPO inhibitors was intensified and development of new chemical entities was rationally driven by the research of ligands that enter into the MPO catalytic pocket. Actually, as soon as crystallography data of MPO have become available and its structure was virtually designed, the rational drug design has been applied to this peroxidase. Pharmaceutical industries and academic laboratories apply rational drug design on MPO by either optimizing known inhibitors or searching new molecules by high-throughput virtual screening. By these ways, they were able to find efficient MPO inhibitors and understand their interactions with the enzyme. During this quest of MPO inhibition, it appears that Glu268 is a crucial residue in order to optimize ligand-target interaction. This amino acid should be carefully considered by medicinal chemist when they design inhibitors interfering with MPO activity. PMID- 25788128 TI - Prediction of the crystal packing of di-tetrazine-tetroxide (DTTO) energetic material. AB - Previous calculations suggested that di-tetrazine-tetroxide (DTTO), aka tetrazino tetrazine-tetraoxide, might have a particularly large density (2.3 g/cm(3) ) and high energy release (8.8 kJ/kg), but it has not yet been synthesized successfully. We report here density functional theory (DFT) (M06, B3LYP, and PBE ulg) on 20 possible isomers of DTTO. For the two most stable isomers, c1 and c2 we predict the best packings (i.e., polymorphs) among the 10 most common space groups for organic molecular crystal using the Universal force field and Dreiding force field with Monte Carlo sampling. This was followed by DFT calculations at the PBE-ulg level to optimize the crystal packing. We conclude that the c1 isomer has the P21 21 21 space group with a density of 1.96 g/cm(3) , while the c2 isomer has the Pbca space group with a density of 1.98 g/cm(3) . These densities are among the highest of current energetic materials, RDX (1.81 g/cm(3) ) and CL20 (2.01 g/cm(3) ). We observe that the stability of the polymorphs increases with the density while the planarity decreases. (c) 2015 Wiley Periodicals, Inc. PMID- 25788129 TI - Overcoming the stratum corneum barrier: a nano approach. PMID- 25788130 TI - Glyceryl monooleate-coated bioadhesive hollow microspheres of riboflavin for improved gastroretentivity: optimization and pharmacokinetics. AB - The bioadhesive hollow microspheres of riboflavin were developed as a site specific gastroretentive system to prolong the residence time of drug in the stomach and, consequently, to enhance the bioavailability. Hollow microspheres (M1-M9) prepared by the emulsion solvent diffusion method using ethyl cellulose and Eudragit E100 as shell-forming polymers were designed using 3(2) full factorial design. The optimized formulation (M5) with 93.23 +/- 0.6 % entrapment efficiency and 75.39 +/- 3.4 % cumulative drug release at 8 h was subjected to coating with a bioadhesive layer of glyceryl monooleate (GMO) to obtain BM5. It exhibited excellent in vitro buoyancy for 12 h (100 %), in vitro bioadhesion (88.33 +/- 2.35 %), and presented micromeritic properties amenable to processing steps. Scanning electron microscopy depicted a spherical shape and hollow cavity of microspheres and evidenced smooth surface coating of GMO. The compatibility of drug and excipients and the absence of interaction were determined using differential scanning calorimetry and diffuse reflectance spectroscopy, respectively. The in vitro release from BM5 (novel release apparatus) demonstrated that drug release was not hindered by the bioadhesive coating layer of GMO. The pharmacokinetic study provided convincing evidence for the increased absorption of riboflavin and bioavailability (Fr = 178.47 %) from bioadhesive hollow microspheres. Conclusively, the study demonstrated the superiority of the synergistic approach of floating and bioadhesive system over either floating or bioadhesive system for the prolongation of gastric residence time of riboflavin to improve its absorption. PMID- 25788131 TI - Liposomally encapsulated CDC20 siRNA inhibits both solid melanoma tumor growth and spontaneous growth of intravenously injected melanoma cells on mouse lung. AB - Cell division cycle homologue 20 (CDC20), a key cell cycle regulator required for the completion of mitosis in organisms from yeast to human, is highly expressed in several carcinomas. Recent studies have shown that specific knockdown of CDC20 expression is capable of significantly inhibiting the growth of human pancreatic carcinoma cells. However, preclinical studies aimed at demonstrating the therapeutic potential of CDC20 siRNA in combating tumor growth has not yet been reported. Herein, in a syngeneic C57BL/6J mouse tumor model, we show that intraperitoneal administration of a 19-bp synthetic CDC20 siRNA encapsulated within liposomes of guanidinylated cationic amphiphile with stearyl tails inhibits solid melanoma (B16F10) tumor growth. In addition, using a spontaneous lung metastasis model in C57BL/6J mice, we show that intravenous administration of the same liposomally encapsulated 19-bp synthetic CDC20 siRNA inhibits B16F10 melanoma growth on mouse lung. Liposomally bound CDC20 siRNA was found to be efficient in silencing the expression of CDC20 in B16F10 cells at both protein and mRNA levels. Findings in the flow cytometric studies confirmed the presence of significantly enhanced populations of G2/M phase in cells treated with liposomally bound CDC20 siRNA. To the best of our knowledge, the present findings demonstrate, for the first time, systemic use of CDC20 siRNA in inhibiting mouse tumor growth. PMID- 25788132 TI - Fabrication of cyclodextrin-templated mesoporous silica for improved dissolution of carbamazepine. AB - In the present paper, preparation of mesoporous silica using hydroxy propyl-beta cyclodextrin as a template and its use in solubility enhancement of carbamazepine (CBZ) is reported. The produced mesoporous silica (MS) displayed a large surface area 480.37 m(2)/g and pore volume 0.8041 cm(3)/g. CBZ was loaded on MS and then compressed into a tablet. Dissolution kinetics studies revealed rapid release profiles in comparison to neat crystalline CBZ. Solid-state characterization was done using IR, DSC, PXRD, SEM and TEM, and nitrogen sorption studies. CBZ was found to be in non-crystalline state due to geometric confinement in the nanopore. PMID- 25788133 TI - Pharmacokinetic evaluation of three oral formulations of docetaxel boosted with ritonavir: two single-drug formulations vs. a fixed-dose combination tablet. AB - The ability to deliver the potent anti-cancer agent docetaxel via the oral route may enable the development of promising new treatment regimens with reduced toxicity, increased efficacy, and increased patient convenience. Recently, we were able to overcome the low oral bioavailability of docetaxel by concomitant administration of the pharmacokinetic booster ritonavir and the design of an oral solid dispersion formulation of docetaxel (ModraDoc001 10-mg capsule). Further research lead to the development of a docetaxel tablet (ModraDoc003 10-mg tablet) and a fixed-dose combination (FDC) tablet of docetaxel and ritonavir (ModraDoc004 10/50-mg tablet). In this clinical proof-of-concept study the exposure to docetaxel and ritonavir was compared between the single agent formulations and the FDC tablet. Six evaluable patients received 40 mg docetaxel and 200 mg of ritonavir once a week according to a cross-over design. No significant differences were found in the exposure to docetaxel and ritonavir between the single agent formulations and the FDC tablet. There was, however, a tendency towards a higher exposure to docetaxel after the administration of the FDC tablet, which could be an effect of the simultaneous release of docetaxel and ritonavir in the gastrointestinal tract. The FDC tablet of docetaxel and ritonavir is a pharmaceutically and clinically feasibly option in the development of patient convenient oral anti-cancer therapy with docetaxel. PMID- 25788134 TI - Development of carbamazepine transnasal microemulsion for treatment of epilepsy. AB - Carbamazepine is widely preferred therapy for the treatment of epilepsy. However, oral therapy results in slower brain uptake and systemic side effects. Intranasal route can achieve faster brain uptake, but poor aqueous solubility of carbamazepine is the main obstacle for administration by nasal route. The purpose of this study was to prepare and evaluate intranasal oil in water microemulsion of carbamazepine to improve its solubility and enhance the brain uptake. Intranasal microemulsion of carbamazepine was prepared by water titration method using oleic acid as oil, Tween 80 as surfactant and Transcutol(r) as cosurfactant. Microemulsions were evaluated for various physical parameters including globule size, viscosity, pH and conductivity. Toxicity study of microemulsion was carried out by employing sheep nasal mucosa. The microemulsion was also evaluated by maximal electric shock, and the brain uptake study was done using HPLC method. The microemulsion was stable and transparent with average globule size of 21.03 nm and did not show any toxic symptoms. It showed reduction in the hind limb extension phase and faster recovery from seizures in comparison to oral microemulsion and nasal solution. Higher brain/plasma ratio was obtained with nasal microemulsion in comparison to ratio obtained after intraperitoneal injection of carbamazepine solution. PMID- 25788136 TI - Towards scale-up and regulatory shelf-stability testing of curcumin encapsulated polyester nanoparticles. AB - This study reports scale-up and shelf-stability of curcumin encapsulated poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles. The curcumin encapsulated PLGA nanoparticles were prepared by emulsification solvent evaporation/diffusion, and large quantities were made by varying the homogenisation time (5, 15 and 30 min). The particle size decreased as the homogenisation duration increased from 5 to 30 min, and the particles were spherical as confirmed by atomic force microscopy. For the large-scale preparations, the mean particles size was found to be 288.7 +/- 3.4 (polydispersity index 0.15 +/- 0.01) with curcumin entrapment 52.5 +/- 4.3 %, which were comparable to the lab-scale preparations. The curcumin encapsulated nanoparticles were freeze-dried using sucrose (5 %, w/v) as a cryoprotectant. The freeze-dried nanoparticles were subjected to 6-month stability study as per the International Conference on Harmonisation guideline at room temperature and refrigerated storage conditions. Intermediate sampling was done (monthly), and the nanoparticles were thoroughly characterised for particle size, entrapment efficiency, surface morphology and crystallinity, which were compared to fresh preparations. The curcumin encapsulated PLGA nanoparticles were found to be stable at refrigerated as well as room temperature storage test conditions indicated by their particle characteristics. X-ray diffraction results confirm amorphous nature of curcumin on nano-encapsulation that stays intact after freeze drying and 6-month stability testing. Together these data offer possibility of producing large quantities of polymer nanoparticles that are suitable for room as well as refrigerated storage conditions opening up possibilities to conduct repeated dosings in a chronic setting or regulatory toxicology studies of such nanomedicines. PMID- 25788135 TI - Transdermal delivery of cyclodextrin-solubilized curcumin. AB - The purpose of the present investigation was to explore the effect of cyclodextrin (CD) as permeation enhancer through rat skin in the form of a valuable and stable transdermal drug delivery system by exploiting its favorable properties. Phase-solubility studies demonstrated that the CD:drug ratio 1:2 was employed in complexation. Solid-state characterizations of complexes was performed by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared, nuclear magnetic resonance spectrophotometry analysis, and scanning electron micrograph. The HP-beta-CD by virtue of its greater stability than the pure curcumin (CMN), allowed greater transdermal flux of CMN indicative of enhanced permeation via CMN-2-hydroxy propyl beta cyclodextrins (HP-beta-CD). Permeability studies of drug, complex, and with various penetration enhancers (PEs), were performed through rat skin, highlighted a favorable effect of CDs on drug permeation rate, due to its solubilizing action; in contrast with unpredictably poor skin permeation of pure drug. The complexes were found to cause relatively less irritation as compared to the pure drug and drug with PEs in skin irritation studies. The anti-inflammatory activity using paw odema model showed that the formulations of CMNCur-HP-beta-CD complex exhibited significant (p < 0.001) decrease in paw edema volume than its pure CMN gel demonstrating enhanced biological activity. PMID- 25788137 TI - Quantitative Proteomic Analysis of Peripheral Blood Mononuclear Cells in Ankylosing Spondylitis by iTRAQ. AB - This study was designed to identify and quantify the different proteins expression levels in ankylosing spondylitis (AS) and to explore the pathogenesis of AS. We performed isobaric tags for relative and absolute quantitation (iTRAQ) coupled with multiple chromatographic fractionation and tandem mass spectrometry to detect the proteins profiling in peripheral blood mononuclear cells (PBMCs) from AS patients and healthy controls. Mascot software and the International Protein Index and the Gene Ontology (GO) database were used to conduct the bioinformatics analysis. The differentially expressed proteins were validated by enzyme-linked immunosorbent assay (ELISA). A total of 1,232 proteins were identified by iTRAQ, of which 183 showed differential expression and 18 differentially expressed proteins were acute phase reactants. Upon mapping of the differentially expressed proteins to GO database, we found four differentially expressed proteins involved in the biological process of cell killing, including up-regulated cathepsin G (CTSG), neutrophil defensin3 (DEFA3), protein tyrosine phosphatase receptor type C (PTPRC), and down-regulated peroxiredoxin 1(PRDX1),which were consistent with the verified results of ELISA. Our proteomic analyses suggested that the proteins involved in the biological process of cell killing might play an important role in the pathogenesis of AS. PMID- 25788138 TI - Prox1 identifies proliferating neuroblasts and nascent neurons during neurogenesis in sympathetic ganglia. AB - Neurogenesis in embryonic sympathetic ganglia involves neuroblasts that resume proliferation following neuronal differentiation. As cell cycle exit is not associated with neuronal differentiation, the identity of proliferating neuroblasts is incompletely understood. Here, we use sympathetic ganglia of chick embryos to define the timing of neurogenesis and neuroblast identity focusing on the expression and function of the transcription factor Prox1. We show that a large fraction of neuroblasts has initially withdrawn from the cell cycle at embryonic day 3 (E3), which is reflected by a high proportion of p27(+)/Islet1(+) neuroblasts (63%) and low numbers of EdU(+)/Islet1(+) cells (12%). The proportion of proliferating Islet1(+) neuroblasts, identified by EdU pulse labeling and by the absence of the postmitotic marker p27 increases to reach maximal levels at E5, when virtually all neuroblasts are in the cell cycle (95%). Subsequently, the proportion of EdU-labeled and p27(-) neuroblasts is reduced to reach low levels at E11. Interestingly, the expression of the transcription factor Prox1 is restricted to the neuronal lineage, that is, Sox10(+)/Phox2b(+) neuron progenitors, proliferating p27(-)/Islet1(+) neuroblasts and nascent neurons but is rapidly lost in postmitotic neurons. In vitro and in vivo knockdown and overexpression experiments demonstrate effects of Prox1 in the support of neuroblast proliferation and survival. Taken together, these results define the neurogenesis period in the chick paravertebral sympathetic ganglia including an initial cell cycle withdrawal and identify Prox1 as a marker and regulator of proliferating sympathetic neuroblasts. PMID- 25788139 TI - Cost of management of nonvalvular atrial fibrillation in Brazzaville (Congo): preliminary findings. AB - The frequency of nonvalvular atrial fibrillation is increasing in sub-Saharan Africa, particularly as a consequence of population aging and the high prevalence of hypertension. The aim of this descriptive study was to determine the cost of management of this disease in the cardiology department at University Hospital of Brazzaville. The study included 50 patients aged 67.3 +/- 12.8 years (range: 34 to 88 years). Among them, 21 (42%) were unemployed, and 49 (98%) had no health insurance. Their average monthly salary was 152.8 +/- 149 ? (range: 0 to 686 ?). The mean total cost of care was 442.4 +/- 109.8 ? (range: 146.6 to 646.2 ?). The average monthly salary was higher than the average cost of drugs (P <0.0001), or of additional tests (P <0.0001), or of hospital hospitality (P <0.0001). But the overall cost of care was substantially higher than the patients' mean salary (p <0.0001). This study illustrates the increasing healthcare costs related to the growing burden of cardiovascular disease in sub-Saharan Africa. PMID- 25788140 TI - Recurrent angular cheilitis in a patient with mucocutaneous pemphigus vulgaris. PMID- 25788141 TI - The investigation of interspecies diversity of erythrocyte aggregation properties by two different photometric methods in four animal species. AB - Among the haemorheological parameters, red blood cell (RBC) aggregation shows the largest interspecies diversity, and often controversial data can be found in the literature, besides the methodology-dependent issues. In this present investigation, we compared four experimental/laboratory animal species' RBC aggregation by two different photometric methods for better revealing the differences. Blood samples (K3-EDTA, 1.5 mg/ml) were taken from female animals: 16 inbred mice (Mus musculus, cardiac puncture), 15 outbred rats (Rattus norvegicus, caudal caval vein puncture), 15 beagle dogs (Canis canis, cephalic vein) and 23 juvenile pigs (Sus scrofa domesticus, medial saphenous vein). Haematological parameters (microcell counter) and RBC aggregation (light transmission and syllectometry-laser backscatter methods) were determined within 2 h after sampling. Describing the first 5-10 s of the aggregation process, additional parameters were calculated out of the syllectometric raw data. Standardized difference was calculated to determine the sensitivity of the two devices. Parameters describing the extent and magnitude of red blood cell aggregation showed the lowest values in the rat and the highest in the pig and canine blood. In turn, parameters describing the kinetics of aggregation showed the lowest values in the mouse and the highest in the rat. The standardized difference values for the laser backscattering method were 2-4 times larger vs. the light transmission one. The magnitude of the differences was not consequent in the aggregation parameters. These comparative results show that the laser backscattering method can detect the RBC aggregation differences between the investigated species more sensitively than the light transmission method. PMID- 25788142 TI - Ocular biomarkers of Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disease characterised clinically by a progressive decline in executive functions, memory and cognition. Classic neuropathological hallmarks of AD include intracellular hyper phosphorylated tau protein which forms neurofibrillary tangles (NFT), and extracellular deposits of amyloid beta (Abeta) protein, the primary constituent of senile plaques (SP). The gradual process of pathogenic amyloid accumulation is thought to occur 10-20 years prior to symptomatic manifestation. Advance detection of these deposits therefore offers a highly promising avenue for prodromal AD diagnosis. Currently, the most sophisticated method of 'probable AD' diagnosis is via neuroimaging or cerebral spinal fluid (CSF) biomarker analysis. Whilst these methods have reported a high degree of diagnostic specificity and accuracy, they fall significantly short in terms of practicality; they are often highly invasive, expensive or unsuitable for large-scale population screening. In recent years, ocular screening has received substantial attention from the scientific community due to its potential for non-invasive and inexpensive central nervous system (CNS) imaging. In this appraisal we build upon our previous reviews detailing ocular structural and functional changes in AD (Retinal manifestations of Alzheimer's disease, Alzheimer's disease and Retinal Neurodegeneration) and consider their use as biomarkers. In addition, we present an overview of current advances in the use of fluorescent reporters to detect AD pathology through non-invasive retinal imaging. PMID- 25788143 TI - Pharmacophore Modeling, 3D-QSAR and Molecular Docking of Furanochalcones as Inhibitors of Monoamine Oxidase-B. AB - Monoamine oxidase B inhibitors are of particular importance in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported furan based MAO-B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated with the five-point hypotheses of ADHRR: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H) and two aromatic rings (R1 & R2). On the basis of generated model, a statistically valid 3D-QSAR with good predictability was developed. Molecular docking of lead compound showed binding energy of -8.66 kcal/mol with a predicted inhibition constant of 0.448 MUM towards MAO-B. PMID- 25788144 TI - Impact of diet on incisor growth and attrition and the development of dental disease in pet rabbits. AB - OBJECTIVES: To assess the impact of four rabbit diets (hay only; extruded diet with hay; muesli with hay; muesli only) on length and curvature of cheek teeth and eruption and attrition rates of incisors. MATERIALS AND METHODS: Thirty-two Dutch rabbits, randomly divided into four diet groups, had length and saggital plane curvature of the first cheek teeth measured radiographically at 1, 9 and 17 months. Eruption/attrition of the left upper incisor was directly measured at weeks 30, 32 and 35. RESULTS: Eruption rates matched attrition rates in all groups, but were higher in the hay only group than in both groups fed muesli. By month 9, a greater degree of tooth curvature was present in rabbits fed muesli only than in those fed hay only and extruded diet with hay. After 17 months, rabbits fed muesli only and muesli with hay had longer lower first cheek teeth and larger interdental spaces between the first two molars than rabbits fed extruded diet and hay and hay only. Three rabbits fed muesli only developed evidence of dental disease. CLINICAL SIGNIFICANCE: Presence of increased tooth length, curvature and interdental spaces indicated early dental pathology in rabbits fed muesli. Muesli diets cannot be recommended for pet rabbits. PMID- 25788146 TI - New examples of antibody-based assay interferences. PMID- 25788145 TI - A murine model for the development of melanocytic nevi and their progression to melanoma. AB - Acquired melanocytic nevi are commonly found in sun exposed and unexposed human skin, but the potential for their transformation into invasive melanoma is not clear. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Nevi develop due to DNA damage initiated by dimethylbenz(a) anthracene (DMBA) followed by chronic promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Dysplastic pigmented skin lesions appeared in 7-9 wk with 100% penetrance. Nests of melanocytic cells appeared in a subset of skin draining lymph nodes (dLN) by 25 wk, but not in age matched controls. Immunohistochemistry, real-time PCR, and flow cytometric analyses confirmed their melanocytic origin. Transformed cells were present in a subset of nevi and dLNs, which exhibited anchorage-independent growth, tumor development, and metastasis in nude mice. Approximately 50% of the cell lines contained H-Ras mutations and lost tumor suppressor p16(Ink4a) expression. While most studies of melanoma focus on tumor progression in transgenic mouse models where the mutations are present from birth, our model permits investigation of acquired mutations at the earliest stages of nevus initiation and promotion of nevus cell transformation. This robust nevus/melanoma model may prove useful for identifying genetic loci associated with nevus formation, novel oncogenic pathways, tumor targets for immune-prevention, screening therapeutics, and elucidating mechanisms of immune surveillance and immune evasion. PMID- 25788147 TI - Guidelines for the isolation and characterization of murine vascular smooth muscle cells. A report from the International Society of Cardiovascular Translational Research. AB - Vascular smooth muscle cells (VSMCs) play important roles in cardiovascular disorders and biology. Outlined in this paper is a step-by-step procedure for isolating aortic VSMCs from adult C57BL6J male mice by enzymatic digestion of the aorta using collagenase. The plating, culturing, and subculturing of the isolated cells are discussed in detail along with techniques to characterize VSMC phenotype by gene expression and immunofluorescence. Traction force microscopy was used to characterize contractility of single subcultured VSMCs at baseline. PMID- 25788148 TI - Efficient In Vitro Electropermeabilization of Reconstructed Human Dermal Tissue. AB - DNA electrotransfer is a successful technic for gene delivery. However, its use in clinical applications is limited since little is known about the mechanisms governing DNA electrotransfer in the complex environment occurring in a tissue. The objectives of this work were to investigate the role of the extracellular matrix (ECM) in that process. Tumor ECM composition was shown to modulate in vivo gene electrotransfer efficiency. In order to assess the effects of ECM composition and organization, as well as intercellular junctions and communication, in normal tissue response to electric pulses, we developed an innovative three-dimensional (3D) reconstructed human connective tissue model. 3D human dermal tissue was reconstructed in vitro by a tissue engineering approach and was representative of in vivo cell organization since cell-cell contacts were present as well as complex ECM. This human cell model presented multiple layers of primary dermal fibroblasts embedded in a native, collagen-rich ECM. This dermal tissue could become a useful tool to study skin DNA electrotransfer mechanisms. As proof of the concept, we show here that the cells within this standardized 3D tissue can be efficiently electropermeabilized by milliseconds electric pulses. We believe that a better comprehension of gene electrotransfer in such a model tissue would help improve electrogene therapy approaches such as the systemic delivery of therapeutic proteins and DNA vaccination. PMID- 25788150 TI - Selective electrocatalytic hydrogenation using palladium nanoparticles electrochemically formed in layer-by-layer multilayer films. AB - Sequential adsorption of PdCl4(2-) within weak polyelectrolyte layer-by-layer (LbL) self-assembled multilayer films with further electrochemical reduction to yield Pd(0) nanoparticles (Pd-NPs) has been demonstrated. The electrocatalytic hydrogenation (ECH) of model molecules such as acetophenone and benzophenone on Pd-NPs of different sizes (6 to 35 nm) and bulk Pd crystal surface in hydroalcoholic acid solution has been investigated. Distribution of reaction products (secondary alcohols and alkanes) and faradaic yield was systematically investigated. While the polyelectrolyte multilayers act as nanoreactors by confining PdCl4(2-) ions and preventing the formation of large crystals, their presence also alters the hydrogenation reaction and therefore heat treated surfaces showed only the effect of nanocrystal size on the reaction selectivity and faradaic yield. PMID- 25788149 TI - Elevated levels of adaption in Helicobacter pylori genomes from Japan; a link to higher incidences of gastric cancer? AB - Helicobacter pylori is a bacterium that lives in the human stomach and is a major risk factor for gastric cancer and ulcers. H.pylori is host dependent and has been carried with human populations around the world after their departure from Africa. We wished to investigate how H.pylori has coevolved with its host during that time, focusing on strains from Japanese and European populations, given that gastric cancer incidence is high in Japanese populations, while low in European. A positive selection analysis of eight H.pylori genomes was conducted, using maximum likelihood based pairwise comparisons in order to maximize the number of strain-specific genes included in the study. Using the genic Ka/Ks ratio, comparisons of four Japanese H.pylori genomes suggests 25-34 genes under positive selection, while four European H.pylori genomes suggests 16-21 genes; few of the genes identified were in common between lineages. Of the identified genes which were annotated, 38% possessed homologs associated with pathogenicity and / or host adaptation, consistent with their involvement in a coevolutionary 'arms race' with the host. Given the efficacy of identifying host interaction factors de novo, in the absence of functionally annotated homologs our evolutionary approach may have value in identifying novel genes which H.pylori employs to interact with the human gut environment. In addition, the larger number of genes inferred as being under positive selection in Japanese strains compared to European implies a stronger overall adaptive pressure, potentially resulting from an elevated immune response which may be linked to increased inflammation, an initial stage in the development of gastric cancer. PMID- 25788151 TI - Dose-dependent induction of signaling pathways by the flavonoid quercetin in human primary hepatocytes: A transcriptomic study. AB - SCOPE: Quercetin is widespread in plant kingdom and consumed regularly with human diet (16 mg/day). Due to reported positive effects on health, quercetin supplements with recommended doses up to 2 g/day are offered. However, molecular effects of such high doses on human liver have not been assessed yet. Therefore, molecular effects on human hepatocytes were analyzed to help assessing the risk of quercetin supplementation. METHODS AND RESULTS: Molecular effects of three different quercetin concentrations on gene expression in human hepatocytes were investigated by microarray analysis. Possible new signaling pathways were investigated using reporter gene assays. Quercetin concentrations representing the normal intake showed weak effects on mRNA expression in liver cells. In contrast, supplemental doses affect immune response and p53 signaling and might be associated with cancer. Additionally, quercetin showed inhibition of transcriptional activation and mRNA-expression of HNF4alpha and its target genes. Inhibitory effects were also found for FXR, LXRalpha, and PXR. CONCLUSION: Normal intake of quercetin seems to play a minor regulatory role, while supplement doses may have great effects on gene expression in hepatocytes. However, since it is not clarified whether such high doses of quercetin exert positive or negative effects, a careful handling of quercetin supplements is advised. PMID- 25788152 TI - The analyst's authenticity: "if you see something, say something". AB - The history of authenticity in psychoanalysis is as old as analysis itself, but the analyst's authenticity in particular has become an increasingly important area of focus in recent decades. This article traces the development of conceptions of analytic authenticity and proposes that the analyst's spontaneous verbalization of his or her unformulated experience in session can be a potent force in the course of an analysis. We acknowledge that although analytic authenticity can be a challenging ideal for the analyst to strive for, it contains the power to transform the experience of the patient and the analyst, as well as the meaning of their work together. Whether it comes in the form of an insight-oriented comment or a simple acknowledgment of things as they seem to be, a therapist's willingness to speak aloud something that has lost its language is a powerful clinical phenomenon that transcends theoretical orientation and modality. PMID- 25788153 TI - Metabolic control of respiratory levels in coenzyme Q biosynthesis-deficient Escherichia coli strains leading to fine-tune aerobic lactate fermentation. AB - A novel strategy to finely control the electron transfer chain (ETC) activity of Escherichia coli was established. In this study, the fine-tuning of the ubiquinone biosynthesis pathway was applied to further controlling ETC function in coenzyme Q8 biosynthesis-deficient E. coli strains, HW108 and HW109, which contain mutations in ubiE and ubiG, respectively. A competing pathway on the intermediate substrates of the Q8 synthesis pathway, catalyzed by diphosphate:4 hydroxybenzoate geranyltransferase (PGT-1) of Lithospermum erythrorhizon, was introduced into these mutant strains. A nearly theoretical yield of lactate production can be achieved under fully aerobic conditions via an in vivo, genetically fine-tunable means to further control the activity of the ETC of the Q8 biosynthesis-deficient E. coli strains. PMID- 25788154 TI - Claudin clusters as determinants of epithelial barrier function. AB - Claudins are tetraspan tight junction proteins which have been attributed to primarily determine epithelial barrier function in a wide variety of different organs and tissues. Among this protein family with currently 27 members, single claudins contribute in an organ- and tissue-specific manner to defined properties such as cation-, anion- or water-selective pore functions, sealing functions or ambiguous functions. As the size of tight junction strand particles visualized by freeze-fracture electron microscopy have a diameter of approximately 10 nm, multimeric assembly of tight junction proteins appears to be a basic principle for barrier formation. Moreover, expression patterns of different tissues showed that single claudins appear to specifically co-localize with other claudins, which indicates a cluster formation within tight junction strand particles with a fixed stoichiometry. This review provides a critical view on the current understanding of tight junction protein co-localization within strands. We analyze how tissue specific differences of claudin functions could be dependent on their specific partners for barrier formation. Furthermore, a model of claudin clusters as structural and functional units within tight junction strands is provided. PMID- 25788155 TI - Correction of B1-inhomogeneities for relaxation-compensated CEST imaging at 7 T. AB - Chemical exchange saturation transfer (CEST) imaging of endogenous agents in vivo is influenced by direct water proton saturation (spillover) and semi-solid macromolecular magnetization transfer (MT). Lorentzian fit isolation and application of the inverse metric yields the pure CEST contrast AREX, which is less affected by these processes, but still depends on the measurement technique, in particular on the irradiation amplitude B1 of the saturation pulses. This study focuses on two well-known CEST effects in the slow exchange regime originating from amide and aliphatic protons resonating at 3.5 ppm or -3.5 ppm from water protons, respectively. A B1-correction of CEST contrasts is crucial for the evaluation of data obtained in clinical studies at high field strengths with strong B1-inhomogeneities. Herein two approaches for B1-inhomogeneity correction, based on either CEST contrasts or Z-spectra, are investigated. Both rely on multiple acquisitions with different B1-values. One volunteer was examined with eight different B1-values to optimize the saturation field strength and the correction algorithm. Histogram evaluation allowed quantification of the quality of the B1-correction. Finally, the correction was applied to CEST images of a patient with oligodendroglioma WHO grade 2, and showed improvement of the image quality compared with the non-corrected CEST images, especially in the tumor region. PMID- 25788156 TI - Deciphering deterioration mechanisms of complex diseases based on the construction of dynamic networks and systems analysis. AB - The early diagnosis and investigation of the pathogenic mechanisms of complex diseases are the most challenging problems in the fields of biology and medicine. Network-based systems biology is an important technique for the study of complex diseases. The present study constructed dynamic protein-protein interaction (PPI) networks to identify dynamical network biomarkers (DNBs) and analyze the underlying mechanisms of complex diseases from a systems level. We developed a model-based framework for the construction of a series of time-sequenced networks by integrating high-throughput gene expression data into PPI data. By combining the dynamic networks and molecular modules, we identified significant DNBs for four complex diseases, including influenza caused by either H3N2 or H1N1, acute lung injury and type 2 diabetes mellitus, which can serve as warning signals for disease deterioration. Function and pathway analyses revealed that the identified DNBs were significantly enriched during key events in early disease development. Correlation and information flow analyses revealed that DNBs effectively discriminated between different disease processes and that dysfunctional regulation and disproportional information flow may contribute to the increased disease severity. This study provides a general paradigm for revealing the deterioration mechanisms of complex diseases and offers new insights into their early diagnoses. PMID- 25788157 TI - Treatment resistant or resistant to treatment? Antipsychotic plasma levels in patients with poorly controlled psychotic symptoms. AB - A large proportion of individuals with schizophrenia show an inadequate response to treatment with antipsychotics. It can be unclear whether this is secondary to subtherapeutic antipsychotic plasma levels or to medication ineffectiveness. The purpose of the present study was to determine the extent of subtherapeutic antipsychotic plasma levels in a group of patients clinically identified as treatment-resistant. In addition we investigated the frequency of antipsychotic plasma level monitoring in standard clinical practice. Antipsychotic plasma levels were measured in 36 patients identified as having treatment-resistant schizophrenia by their treating clinicians. Sixteen (44%) patients showed either undetectable (19%) or subtherapeutic levels (25%), and 20 (56%) patients had levels in the therapeutic range. Subtherapeutic plasma levels were significantly associated with black ethnicity, shorter duration of current treatment and antipsychotics other than olanzapine and amisulpride. Antipsychotic plasma levels had been measured in only one patient in the year prior to our study. We found over one-third of patients identified as treatment-resistant have subtherapeutic antipsychotic levels. This indicates that they may be under-treated rather than treatment-resistant, and thus should receive different management. Currently the measurement of antipsychotic levels may be under-utilised. PMID- 25788158 TI - Facile synthesis of iron oxides/reduced graphene oxide composites: application for electromagnetic wave absorption at high temperature. AB - Iron oxides/reduced graphene oxide composites were synthesized by facile thermochemical reactions of graphite oxide and FeSO4 . 7H2O. By adjusting reaction temperature, alpha-Fe2O3/reduced graphene oxide and Fe3O4/reduced graphene oxide composites can be obtained conveniently. Graphene oxide and reduced graphene oxide sheets were demonstrated to regulate the phase transition from alpha-Fe2O3 to Fe3O4 via gamma-Fe2O3, which was reported for the first time. The hydroxyl groups attached on the graphene oxide sheets and H2 gas generated during the annealing of graphene oxide are believed to play an important role during these phase transformations. These samples showed good electromagnetic wave absorption performance due to their electromagnetic complementary effect. These samples possess much better electromagnetic wave absorption properties than the mixture of separately prepared Fe3O4 with rGO, suggesting the crucial role of synthetic method in determining the product properties. Also, these samples perform much better than commercial absorbers. Most importantly, the great stability of these composites is highly advantageous for applications as electromagnetic wave absorption materials at high temperatures. PMID- 25788161 TI - A localised threat to an excellent antimalarial drug. PMID- 25788163 TI - Oseltamivir reduces clinical illness in households in Bangladesh. PMID- 25788165 TI - The Association of Prehypertension With Meals Eaten Away From Home in Young Adults in Singapore. AB - BACKGROUND: Elevated blood pressure (BP) during early life years is associated with future risk of hypertension and cardiovascular morbidity and mortality. This study aimed to determine the prevalence and lifestyle factors associated with prehypertension (systolic BP (SBP) 120-139 mm Hg and/or diastolic BP (DBP) 80-89 mm Hg) or hypertension (SBP >= 140 mm Hg and/or DBP >= 90 mm Hg or on antihypertensive medications) among young adults at a Singapore university. METHODS: A cross-sectional survey of 501 university-going young adults aged 18-40 years in Singapore was conducted using convenience sampling. Data on BP, body mass index (BMI), and lifestyle factors (meals eaten away from home/week, physical activity) was collected, and their association with prehypertension or hypertension was determined. RESULTS: Prehypertension was found in 27.4% (95% confidence interval (95% CI) = 24-32) of the population: 49% (44-58) in men and 9% (6-13) in women (P < 0.001). 2.2% (1.2-3.9) had hypertension. In a multivariable model, those with prehypertension or hypertension tended to eat more meals away from home per week (per meal/week odds ratio (OR) = 1.05, 95% CI = 1.01-1.09), have higher BMI (per kg/m2 OR = 1.15, 95% CI = 1.02-1.30), and low physical activity (low vs. moderate/high activity OR = 2.14, 95% CI = 1.20-3.82). Other associates were male gender (OR = 7.01, 95% CI = 3.97-12.4) and older age (per year OR = 1.06, 95% CI = 1.01-1.11). CONCLUSION: Prehypertension may be common among university-going young adults in Singapore and is associated with potentially preventable lifestyle factors. Our findings call for large-scale population-based studies, including lifestyle modification trials for prevention of hypertension among young adults in Singapore. PMID- 25788164 TI - Effects of oseltamivir treatment of index patients with influenza on secondary household illness in an urban setting in Bangladesh: secondary analysis of a randomised, placebo-controlled trial. AB - BACKGROUND: Antiviral drugs are a proposed medical intervention to reduce household transmission of influenza viruses. In a previously described randomised, placebo-controlled trial in Dhaka, Bangladesh, we showed that oseltamivir treatment of index patients was able to reduce influenza symptom duration and virus shedding. In a further analysis that is part of the same study, we aimed to assess efficacy of oseltamivir to reduce secondary household illnesses in the same cohort. METHODS: In this double-blind oseltamivir efficacy trial, we identified index patients aged older than 1 year through surveillance of households in Dhaka, Bangladesh. We randomly allocated eligible patients (1:1) to receive oseltamivir or placebo twice-daily for 5 days, and we stratified them by enrolment 48 h versus 48-120 h since illness onset. Participants provided nasal wash specimens at enrolment and 2, 4, and 7 days after enrolment and were visited daily by a research assistant to record symptoms, both in index patients and in household members. For this part of the study, household members were asked to give respiratory specimens for influenza PCR testing. Our primary outcomes were household secondary illness and PCR-confirmed influenza virus infection, assessed in household members of all randomly allocated index patients. This trial is registered with ClinicalTrials.gov, number NCT00707941. FINDINGS: From May 11, 2008, to Dec 31, 2010, we enrolled 1190 index patients with 4694 household members. 592 patients were allocated to placebo (2292 household members) and 598 to oseltamivir (2402 household members). Household secondary illness was lower in the oseltamivir group (196 [8%] influenza cases) than in the placebo group (233 [10%]; odds ratio [OR] 0.77, 95% CI 0.60-0.98, p=0.031). PCR-confirmed influenza virus infection did not differ between the placebo (103 [5%]) and oseltamivir groups (92 [4%]; 0.84, 0.59-1.19, p=0.319); however, only 243 (57%) of ill household members gave a specimen for analysis. INTERPRETATION: In a crowded, low income setting, oseltamivir treatment of index patients resulted in a small reduction of secondary influenza in their households. Even this slight reduction, in the setting of widespread antiviral use during a community influenza outbreak, might result in reductions in overall disease burden. FUNDING: Centers for Disease Control and Prevention (in an agreement with the International Centre for Diarrhoeal Disease Research, Bangladesh). PMID- 25788166 TI - Significance of p53 expression in background endometrium in endometrial carcinoma. AB - The p53 signature (p53S) has been proposed to be a marker of the earliest phase of development of endometrial serous carcinoma. We examined the presence of p53S in the background endometrium in cases of endometrial carcinoma. From a series of 351 endometrial carcinomas, 225 (64.1 %) lesions, for which slides of the adjacent noncancerous endometrium were available for review, were included. Expression of estrogen receptor (ER)-alpha, Ki-67, and p53 in the adjacent endometrium was studied by immunohistochemistry. The p53S was defined as the presence of morphologically benign endometrial epithelial cells with moderate to strong intensity of p53 immunostaining. Of the 225 noncancerous endometrium samples, 34 consisted of hyperplastic and 191 of non-hyperplastic endometrium. A p53S was found in 22 cases (mean age 64.2 years), 2 in hyperplastic, and 20 in non-hyperplastic background endometrium. All p53S-positive cases also expressed ER-alpha; their median Ki-67 labeling index (LI) was 4.0 % (range 0.0 to 21.0 %). The two cases with hyperplastic p53S-positive background endometrium were in association with a grade 1 endometrioid tumor in a premenopausal woman with Lynch syndrome. Of the 152 cases of endometrioid adenocarcinomas with non-hyperplastic endometrium, 12 (8 %) were p53S positive, none of which associated with EIC. Of the 21 cases of serous carcinoma, five (24 %) were p53S positive, 4 of which (19 %) associated with EIC while in 5 others (24 %) EIC was found without p53S. Of three clear cell adenocarcinomas, none were p53S positive while two contained EIC without p53S. Of 15 carcinosarcomas, 3 (20 %) were p53S positive, all of which with EIC while 6 others (40 %) were associated with EIC but without p53S. Of the 8 non-endometrioid tumors with p53S, 7 (88 %) were associated with EIC. p53S is thought to be associated with precancerous lesions of non-endometrioid tumors, including carcinosarcomas. PMID- 25788167 TI - Intraoperative mechanical ventilation strategies for obese patients: a systematic review and network meta-analysis. AB - Several intraoperative ventilation strategies are available for obese patients. However, the same ventilation interventions have exhibited different effects on PaO2 /FIO2 concerning obese patients in different trials, and the issue remains controversial. Therefore, we conducted a network meta-analysis to identify the optimal mechanical ventilation strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Embase, MEDLINE, CINAHL and Web of Science for studies published up to June 2014, and the PaO2 /FIO2 in obese patients given different mechanical ventilation strategies was assessed. We assessed the studies for eligibility and extracted data and then pooled the data and used a Bayesian fixed-effect model to combine direct comparisons with indirect evidence. Eligible studies evaluated different ventilation strategies for obese patients and reported the intraoperative PaO2 /FIO2 ratio, atelectasis and pulmonary compliance. Thirteen randomized controlled trials were included for network meta-analysis, including 476 patients who received 1 of 12 ventilation strategies. Volume-controlled ventilation with higher PEEP plus single recruitment manoeuvres (VCV + higher PEEP + single RM) was associated with the highest PaO2 /FiO2 ratio, improving intraoperative pulmonary compliance and reducing the incidence of intraoperative atelectasis. PMID- 25788168 TI - Combined effect of a nanoemulsion of D-limonene and nisin on Listeria monocytogenes growth and viability in culture media and foods. AB - The present work evaluated the antibacterial effect of nanoemulsions from natural compounds d-limonene and nisin against Listeria monocytogenes in tryptic soy broth growth medium, chicken broth, and vegetable cream. Experiments were performed by means of optical density growth curves and studies of viability in culture media and foods. Stability of nanoemulsions was evaluated by a Mastersizer 2000 equipment. Results showed greater effectiveness when applying D limonene in form of nanoemulsion than when applying it directly, and when using both compounds together, both directly and in the form of nanoemulsion. Concentration of L. monocytogenes decreased at least in three log cycles in all the culture media and foods used within the first 90 min after the addition of the natural antimicrobials combined in form of nanoemulsion. Moreover, the growth of L. monocytogenes was inhibited with the combination of antimicrobials in the four weeks that the experiment lasted. Nanoemulsion technology would solve present problems of solubility and stability of oily antimicrobials in the food industry. PMID- 25788162 TI - The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. AB - BACKGROUND: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. METHODS: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. FINDINGS: We included 61 studies done between January, 1998, and December, 2012, and included 14,327 patients in our analyses. The PCR adjusted therapeutic efficacy was 97.6% (95% CI 97.4-97.9) at day 28 and 96.0% (95.6-96.5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0.92, 95% CI 0.86-0.99 for every 1 mg/kg increase in daily artemether dose; p=0.024), but not on day 2 (p=0.69) or day 3 (0.087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91.7%, 95% CI 86.5-96.9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94.3%, 95% CI 92.3-96.3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0.92, 95% CI 0.85-0.99; p=0.037 for every 1 mg/kg increase in total artemether dose). INTERPRETATION: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. FUNDING: Bill & Melinda Gates Foundation. PMID- 25788169 TI - Effects of emulsion gels containing bioactive compounds on sensorial, technological, and structural properties of frankfurters. AB - Emulsion gels prepared with olive oil, chia, and cold gelling agents (transglutaminase, alginate, or gelatin) were used as fat replacers in reduced fat frankfurter formulation. Nutritional advantages, sensory analysis, technological properties, and microbiological populations of frankfurters were evaluated along with their lipid structural characteristics over chilled storage. Frankfurters with emulsion gels showed significant improvements in fat content (lower saturated fatty acid, higher mono- and polyunsaturated fatty acid contents) and had good fat and water-binding properties. The presence of an emulsion gel reduced lightness and redness, but increased yellowness. Textural behavior of samples was significantly affected by the presence of emulsion gels and by storage. Sensory properties were not affected by the incorporation of emulsion gels, and all frankfurters were judged acceptable. Attenuated total reflectance-Fourier transform infrared spectroscopy results showed that samples with emulsion gels involve more lipid-protein interactions. Frankfurters with emulsion gels showed good stability to oxidation during storage and contained lower levels of microorganism than reduced-fat control at 85 days. PMID- 25788170 TI - Undergraduates' perceptions of the value of practical inhalation sedation experience in a UK dental school. AB - AIM: This was to establish the level and reported value of paediatric IHS experience from the perspective of final year undergraduates and to evaluate whether those students with more experience expressed feeling better-prepared for future practice and more likely to undertake further postgraduate education in IHS. METHODS: All final year students were invited to complete an anonymous questionnaire designed to elicit undergraduate perceptions of IHS using visual analogue scales and free-text questions. RESULTS: A response rate of 77 % was achieved. Results revealed that only 21 % of participants reported acting as operator sedationist in ten or more IHS cases. Thus, the majority of undergraduates' did not meet the recommended quantity of practical IHS experiences, as outlined by the British Dental Sedation Teachers Group. In general, students felt on the value of IHS in the management of anxious children and expressed a desire to undertake further postgraduate education in conscious sedation. However, those students with more experience of practical IHS expressed feeling better able to describe the IHS experience with patients and parents, and were more satisfied with the quality of teaching. Furthermore free-text comments revealed that, regardless of experience, students wished to gain more experience of the practical administration of IHS. CONCLUSION: There is a need to increase the provision of IHS training within an undergraduate curriculum, in addition to improving the accessibility of postgraduate sedation courses. PMID- 25788171 TI - Prevalence, pattern and severity of molar incisor hypomineralisation in 8- to 10 year-old school children in Ile-Ife, Nigeria. AB - AIM: This study aimed to determine the prevalence, pattern and severity of MIH in school children resident in a suburban population in Nigeria. METHODS: This was a cross-sectional study involving pupils aged 8-10 years resident in suburban Nigeria. Details of each pupil's socio-demographic variables were collected. Intra-oral examination was conducted to determine the presence of MIH, the affected tooth and the severity of the lesion. The association between the prevalence of MIH and socio-demographic variables of each child was determined. The predictors of MIH were also determined using a binomial regression analysis. RESULT: Eighty-three of the 469 children examined (17.7 %) had MIH. There was no significant association between sex (p = 0.58), socio-economic status (p = 0.09), age (p = 0.26) and MIH. There was also no significant difference in the number of teeth affected by MIH in the maxilla and mandible, and on the right and left side of the face. The most commonly affected teeth were the left mandibular molars. The occlusal surfaces of the first molars were mostly affected by MIH and the severity of MIH on the teeth examined varied from mild (80.8 %), moderate (14.0 %) to severe (5.2 %). CONCLUSION: The prevalence of MIH in this study population is consistent with previous reports. The non-association between sex and MIH prevalence, the varied severity of the lesion and association between MIH affectation of the first permanent molars and central incisors give more weight to the possible role of environmental factors in the aetiology of the lesion. The non-association between MIH and socio-economic status may serve as a distinctive feature of MIH and chronological enamel hypoplasia. PMID- 25788172 TI - Clinical and radiographic evaluation of Portland cement added to radiopacifying agents in primary molar pulpotomies. AB - AIM: This was to evaluate the clinical and radiographic outcomes of Portland cement (PC) added to radiopacifying agents in primary molar pulpotomies. METHODS: Thirty primary mandibular molars of children aged between 5 and 9 years were randomly assigned to the following groups: PC; PC with iodoform (PC + CHI(3)); PC with zirconium oxide (PC + ZrO(2)) and treated by pulpotomy technique. Clinical and radiographic follow-up assessments were performed at 6, 12 and 24 months. Statistical analysis was performed by Fisher's exact test (P < 0.05). RESULTS: The clinical and radiographic evaluations showed 100 % success rates, and the results showed no statistically significant difference between groups. CONCLUSIONS: According to this study, PC added to radiopacifying agents exhibited satisfactory clinical and radiographic results in primary molar pulpotomies. PMID- 25788173 TI - Clinical success and longevity of band and loop compared to crown and loop space maintainers. AB - AIM: To prospectively evaluate the success and survival rates of band and loop (B&L) compared to crown and loop (C&L) space maintainers. METHODS: Thirty-six children were divided into two groups (18 B&Ls and 18 C&Ls) matched for gender, age and the extracted tooth. For the study group, all clinical procedures were performed by the same paediatric dentist. Regular follow-up appointments were scheduled at 4-6 months. Comparisons in survival time and variables which might have affected the mean survival time were tested using Log rank and Chi-square tests. RESULTS: A total of 16 girls and 20 boys (3.4-6.3 years old) were included. The overall failure rate was 53 %. For B&Ls, the failure rate was 83 % compared to 22 % for C&Ls. The main reason for failure of B&Ls was decementation (87 %), while for C&Ls, it was solder breakage (75 %). The mean survival time for B&Ls was 18.8 months, and for C&L, it was 40.4 months (p < 0.001). CONCLUSIONS: The failure rate and mean survival time for C&Ls were clinically and statistically significantly better than those for B&Ls. Depending on the clinical presentation of the abutment tooth and the intended life expectancy of the space maintainer among other factors, it is recommended that, where a space maintainer is indicated in the primary dentition, preference is given to C&L over B&L space maintainers. PMID- 25788174 TI - We don't need an "evidence base" for a smoking ban in outdoor spaces. PMID- 25788175 TI - A molecular mechanism that confines the activity pattern of miR165 in Arabidopsis leaf primordia. AB - In Arabidopsis leaf primordia, the expression of HD-Zip III, which promotes tissue differentiation on the adaxial side of the leaf primordia, is repressed by miRNA165/166 (miR165/166). Small RNAs, including miRNAs, can move from cell to cell. In this study, HD-Zip III expression was strikingly repressed by miR165/166 in the epidermis and parenchyma cells on the abaxial side of the leaf primordia compared with those on the adaxial side. We also found that the MIR165A locus, which was expressed in the abaxial epidermis, was sufficient to establish the rigid repression pattern of HD-Zip III expression in the leaf primordia. Ectopic expression analyses of MIR165A showed that the abaxial-biased miR165 activity in the leaf primordia was formed neither by a polarized distribution of factors affecting miR165 activity nor by a physical boundary inhibiting the cell-to-cell movement of miRNA between the adaxial and abaxial sides. We revealed that cis acting factors, including the promoter, backbone, and mature miRNA sequence of MIR165A, are necessary for the abaxial-biased activity of miR165 in the leaf primordia. We also found that the abaxial-determining genes YABBYs are trans acting factors that are necessary for the miR165 activity pattern, resulting in the rigid determination of the adaxial-abaxial boundary in leaf primordia. Thus, we proposed a molecular mechanism in which the abaxial-biased patterning of miR165 activity is confined. PMID- 25788176 TI - Contextual control of conditioning is not affected by extinction in a behavioral task with humans. AB - The Attentional Theory of Context Processing (ATCP) states that extinction will arouse attention to contexts resulting in learning becoming contextually controlled. Participants learned to suppress responding to colored sensors in a video-game task where contexts were provided by different gameplay backgrounds. Four experiments assessed the contextual control of simple excitatory learning acquired to a test stimulus (T) after (Exp. 1) or during (Exp. 2-4) extinction of another stimulus (X). Experiment 1 produced no evidence of contextual control of T, though renewal to X was present both at the time T was trained and tested. In Experiment 2 no contextual control of T was evident when X underwent extensive conditioning and extinction. In Experiment 3 no contextual control of T was evident after extensive conditioning and extinction of X, and renewal to X was present. In Experiment 4 contextual control was evident to T, but it neither depended upon nor was enhanced by extinction of X. The results presented here appear to limit the generality of ATCP. PMID- 25788177 TI - Interacting effects of selected trace and toxic metals on thyroid function. AB - Interacting effects of blood levels of manganese (Mn), selenium, cadmium (Cd), lead (Pb), and mercury, and serum levels of iron (Fe), zinc (Zn), and copper (Cu) on thyroid function in general US population were evaluated. Data from the National Health and Nutrition Examination Survey for 2011-2012 were used for this evaluation. The variables used to evaluate thyroid function were as follows: thyroid-stimulating hormone, free and total triiodothyronine (FT3, TT3), free and total thyroxine (FT4, TT4), and thyroglobulin (Tg). Levels of FT4 were positively associated with the levels of copper and negatively associated with the levels of Fe for males only. Elevated levels of Mn and Fe were associated with increased levels of FT3 for both males and females. TT4 had a positive association with the levels of Cu and a negative association with the levels of Fe for both males and females. PMID- 25788178 TI - Perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging predict outcomes of hepatocellular carcinoma receiving radiotherapy with or without thalidomide. AB - BACKGROUND: To correlate between signal parameters using dynamic contrast enhanced magnetic resonance imaging (DCEMRI) and outcomes of hepatocellular carcinoma (HCC) receiving radiotherapy with or without concomitant thalidomide. METHODS: DCEMRI was performed in advanced HCC patients undergoing radiotherapy with or without concomitant thalidomide. Initial first-pass enhancement slopes (slope) and peak enhancement ratios (peak) were measured over an operator-defined region of interest over tumor and non-tumor liver parenchyma. The perfusion parameters were correlated with clinical outcomes. The study was registered with ClinicalTrials.gov. (identifier NCT00155272). RESULTS: Forty-three patients were evaluable. There were 18 partial responses (PRs), 5 minimal responses (MRs), 17 stable diseases (SDs), and 3 progressive diseases (PDs). Baseline perfusion parameters as well as slope at 14 days of radiotherapy were higher in patients with PR or MR compared to SD or PD (0.81 +/- 0.29 vs. 0.49 +/- 0.34, p < 0.01; 0.39 +/- 0.15 vs. 0.28 +/- 0.16, p = 0.02; 0.97 +/- 0.38 vs. 0.46 +/- 0.26, p < 0.01; respectively). Multivariate analysis revealed perfusion parameters over liver parenchyma, but not over tumor, and independently predicted progression free and overall survival (182 +/- 33 vs. 105 +/- 26 days, p = 0.01; 397 +/- 111 vs. 233 +/- 19 days, p = 0.001 respectively). For 22 patients receiving concomitant thalidomide, the perfusion parameters were not significantly different from those receiving radiotherapy alone. CONCLUSIONS: Signal parameters of DCEMRI over tumor and liver parenchyma correlated with tumor response and survival, respectively, in HCC patients receiving radiotherapy. PMID- 25788179 TI - Characteristics and outcome of autoimmune liver disease in Asian children. AB - BACKGROUND: Little is known about autoimmune liver disease (AILD) in Asian children. We studied the clinical features and predictors of outcome in childhood AILD in an Asian population. METHODS: Retrospective review of AILD [autoimmune hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC)] seen at two pediatric liver units in Malaysia. RESULTS: At presentation, 17 (56%) of the 32 children [19 females, 59%; median (range) age 7.7 (1.8-15.5) years] with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9) had liver cirrhosis. At final review [median (range) duration of follow up 4.8 (0.4-12) years], 24 patients (75%) survived with a native liver. Twenty one (66%) were in remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on prednisolone and/or azathioprine, one on cyclosporine and another on mycophenolate mofetil. Three (AIH1 = 3) were in partial remission. Of the two who underwent liver transplantation (LT; 6.5%; both ASC), one died of primary graft failure after LT. Six patients (19%) died without LT (acute liver failure, n = 1; end-stage liver disease, n = 5). The overall survival rate (native liver and survival post-LT) was 78%. A delay in seeking treatment adversely affected the final outcome [survival with native liver vs. LT or death (duration between onset of disease and treatment; median +/- standard error) = 2.5 +/- 2.9 months vs. 24.0 +/- 13.3 months; p = 0.012]. CONCLUSIONS: Although remission was achieved in the majority of patients with prednisolone and/or azathioprine therapy, delay in seeking diagnosis and treatment adversely affects the outcome of childhood AILD in Malaysia. PMID- 25788180 TI - Anti-viral therapy in hepatitis B virus reactivation with acute-on-chronic liver failure. AB - Hepatitis B virus (HBV) reactivation with hepatic decompensation leading to acute on chronic liver failure is not uncommon. It is associated with high mortality of up to 30-70%. Prognostic factors for mortality include high bilirubin level, more prolonged prothrombin time, low platelet count and presence of pre-existing cirrhosis. Several studies addressing the efficacy of different anti-viral therapies, namely lamivudine, entecavir and tenofovir, have been performed. Although the results were not highly consistent, it appeared that use of anti viral agents was associated with decreasing chance of mortality, subsequent HBV reactivation, disease progression, and with excellent viral suppression. The beneficial effects were most prominently observed in patients with MELD score 20 30. However, even with anti-viral therapy, patients may still have irreversible liver decompensation requiring liver transplantation if other adverse parameters. including pre-existing cirrhosis, bilirubin >20 mg/dL (340 umol/L), prothrombin time <40%, platelet count <120 * 10(9)/L. were present. Mortality rate in patients with MELD score >30 was >92% even with prompt anti-viral treatment. Liver transplantation should be considered urgently. PMID- 25788181 TI - beta-Blocker therapy ameliorates hypersplenism due to portal hypertension in children. AB - BACKGROUND/PURPOSE: Thrombocytopenia due to hypersplenism precludes percutaneous liver biopsy in many cases of chronic liver disease (CLD). The aim of this study was to assess the efficacy of propranolol in correcting platelet counts (>100,000/mm(3)) to ensure percutaneous liver biopsy in children with CLD. METHODS: From January 2005 to December 2012, 51 consecutive children (mean age 11.5 +/- 3.0 years, 34 boys) with CLD who needed liver biopsy but could not be done due to hypersplenism-related thrombocytopenia (platelets <100,000/mm(3) and/or total leukocyte counts <4,000/mm(3) with splenomegaly) were recruited and given a 4-week trial of long-acting propranolol (1.5-2 mg/kg/day). Hemodynamic parameters and splenic artery hemodynamics by Doppler ultrasound were recorded before and after the propranolol trial. Response to therapy was defined as improvement of platelet counts to >=10(5)/mm(3). RESULTS: Thirty-two (62.7%) children responded to propranolol therapy and their mean platelet counts increased from 57.5 +/- 13.0 * 10(3) to 140.7 +/- 43.3 * 10(3)/mm(3), p = 0.0001. Liver biopsy could be done in 29. While comparing responders with non-responders, baseline spleen size (7.4 +/- 3.3 vs. 12.7 +/- 4.5 cm, p = 0.0001) and platelet counts (57.5 +/- 13.0 * 10(3) vs. 39.5 +/- 14.5 * 10(3), p = 0.0001) were found to be significant. ROC curve suggested a cut-off value of <=8.5 cm of spleen and >=53,000 platelets as predictors of response. With propranolol, mean arterial pressure and spleen size reduced (p < 0.05) and splenic artery resistance increased significantly (p = 0.005) in responders. CONCLUSIONS: Propranolol corrects thrombocytopenia and makes liver biopsy possible in almost two-thirds of cases by reducing splenic sequestration through splenic artery vasoconstriction. The baseline spleen size and platelet counts determine the effectiveness of therapy. A trial of beta-blocker is worth carrying out in cases where liver biopsy is contraindicated due to hypersplenism-related thrombocytopenia. PMID- 25788183 TI - Criteria for liver transplantation in ACLF and outcome. AB - Liver transplantation (LT) remains the only curative treatment for patients with failed medical treatment for acute-on-chronic liver failure (ACLF). However, the selection criteria for LT in ACLF is ill-defined. Given the scarcity of deceased organs and the inherent risk of living donor hepatectomy, it is mandatory to identify unfavourable prognostic factors for survival in ACLF in order to establish an objective and fair selection criteria for LT, and more importantly to ensure a satisfactory post-transplant outcome. The aim of this article was to review the current evidence on the validity of the existing prognostic models and to evaluate the survival outcomes after LT for ACLF. PMID- 25788182 TI - Analysis of adult 20-year survivors after liver transplantation. AB - BACKGROUND: Liver transplantation (LT) is the treatment of choice for chronic and acute liver failure; however, the status of long-term survivors and allograft function is not well known. AIM: To evaluate the clinical outcome and allograft function of survivors 20 years post-LT, cause of death during the same period and risk factors of mortality. METHODS: A retrospective study was conducted from prospective, longitudinal data collected at a single center of adult LT recipients surviving 20 years. A comparative sub-analysis was made with patients who were not alive 20 years post-transplantation to identify the causes of death and risk factors of mortality. RESULTS: Between 1988 and 1994, 132 patients received 151 deceased-donors LT and 28 (21%) survived more than 20 years. Regarding liver function in this group, medians of AST, ALT and total bilirubin at 20 years post-LT were 33 IU/L (13-135 IU/L), 27 (11-152 IU/L) and 0.6 mg/dL (0.3-1.1 mg/dL). Renal dysfunction was observed in 40% of patients and median eGFR among 20-year survivors was 64 mL/min/1.73 m(2) (6-144 mL/min/1.73 m(2)). Sixty-one percent of 20-year survivors had arterial hypertension, 43% dyslipidemia, 25% de novo tumors and 21% diabetes mellitus. Infections were the main cause of death during the 1st year post-transplant (32%) and between the 1st and 5th year post-transplant (25%). After 5th year from transplant, hepatitis C recurrence (22%) became the first cause of death. Factors having an impact on long-term patient survival were HCC indication (p = 0.049), pre-transplant renal dysfunction (p = 0.043) and long warm ischemia time (p = 0.016); furthermore, post-transplant factors were diabetes mellitus (p = 0.001) and liver dysfunction (p = 0.05) at 1 year. CONCLUSION: Our results showed the effect of immunosuppression used during decades on long-term outcome in our LT patients in terms of morbidity (arterial hypertension, diabetes mellitus, dyslipidemia and renal dysfunction) and mortality (infections and hepatitis C recurrence). PMID- 25788184 TI - Potential of Gd-EOB-DTPA-enhanced MR imaging for evaluation of bile duct ligation induced liver injury in rabbits. AB - OBJECTIVES: The aim of this study was to evaluate the potential of gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI for assessment of bile duct ligation (BDL)-induced chelostatic liver injury in an animal model by T1 relaxation time measurements and first-pass perfusion analyses. MATERIALS AND METHODS: Twenty-four rabbits were classified into three groups as follows: control group (N group), n = 8; BDL group studied on the 5th postoperative day (BDL-5d group), n = 8; BDL group studied on the 14th postoperative day (BDL-14d group), n = 8. A dual flip angle three-dimensional gradient echo sequence with volumetric interpolated breath-hold examination was performed before and at 20 min [hepatobiliary phase (HBP)] after Gd-EOB-DTPA administration. Besides, early dynamic contrast-enhanced MRI was performed for 4.32 min with a temporal resolution of 2.2 s. T1 relaxation times of liver parenchyma were measured and perfusion parameters were calculated. RESULTS: Dilatation of intra-hepatic bile duct was found only in the BDL-14d group. HBP T1 relaxation times of the BDL-5d and BDL-14d groups were significantly prolonged (p < 0.001) and the enhancement slope percentage of BDL 5d and BDL-14d groups were significantly lowered in comparison with that of the N group (p < 0.001). There were no differences between the BDL-5d group and the BDL 14d group for HBP T1 relaxation times and the enhancement slope percentage (p > 0.05). Area under the receiver operating characteristic curve of HBP T1 relaxation time and the enhancement slope percentage for the selection of chelostatic liver were 0.98 and 0.92 for the BDL-5d group, and 0.96 and 0.98 for the BDL-14d group, respectively. CONCLUSIONS: HBP T1 relaxation time measurement in combination with first-pass enhancement slope percentage withhold promise to assess extrahepatic chelostatic liver injury. PMID- 25788185 TI - A novel 2-step approach combining the NAFLD fibrosis score and liver stiffness measurement for predicting advanced fibrosis. AB - BACKGROUND: The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is indeterminate in a proportion of NAFLD patients. Combining the NFS with liver stiffness measurement (LSM) may improve prediction of advanced fibrosis. We aim to evaluate the NFS and LSM in predicting advanced fibrosis in NAFLD patients. METHODS: The NFS was calculated and LSM obtained for consecutive adult NAFLD patients scheduled for liver biopsy. The accuracy of predicting advanced fibrosis using either modality and in combination were assessed. An algorithm combining the NFS and LSM was developed from a training cohort and subsequently tested in a validation cohort. RESULTS: There were 101 and 46 patients in the training and validation cohort, respectively. In the training cohort, the percentages of misclassifications using the NFS alone, LSM alone, LSM alone (with grey zone), both tests for all patients and a 2-step approach using LSM only for patients with indeterminate and high NFS were 5.0, 28.7, 2.0, 2.0 and 4.0 %, respectively. The percentages of patients requiring liver biopsy were 30.7, 0, 36.6, 36.6 and 18.8 %, respectively. In the validation cohort, the percentages of misclassifications were 8.7, 28.3, 2.2, 2.2 and 8.7 %, respectively. The percentages of patients requiring liver biopsy were 28.3, 0, 41.3, 43.5 and 19.6 %, respectively. CONCLUSIONS: The novel 2-step approach further reduced the number of patients requiring a liver biopsy whilst maintaining the accuracy to predict advanced fibrosis. The combination of NFS and LSM for all patients provided no apparent advantage over using either of the tests alone. PMID- 25788187 TI - A novel cell-free strategy for promoting mouse liver regeneration: utilization of a conditioned medium from adipose-derived stem cells. AB - BACKGROUND: Although stem cells have beneficial effects, their clinical application faces many issues, including high cost and safety. Because stem cell plasty is largely based on their paracrine activity, this study aimed to test the hypothesis that utilization of the stem-cell secretome instead of actual cells would not only overcome these limitations, but also have similar effects as stem cell-based therapy. METHODS: Partial hepatectomized mice were divided into four groups according to the material administered via the tail vein: normal saline (saline group); 1.0 * 10(6) human adipose tissue-derived stem cells (ASCs) in 0.1 mL saline (ASC group); 25-fold concentrated conditioned medium from ASCs (ASC secretome group); and concentrated medium (media group). Specimens were obtained postoperatively. Liver regeneration was estimated by bromodeoxyuridine incorporation, Lgr5 RT-PCR, proliferating cell nuclear antigen western blot, and liver weights, and liver function was estimated by albumin immunohistochemistry and liver function tests. RESULTS: The liver regenerative capacities of the ASC and ASC-secretome groups were not statistically different from each other, but were higher than their respective control groups. Moreover, the ASC and ASC secretome groups promoted the phosphorylation of Akt, STAT3, and Erk1/2, and expressed higher levels of mouse albumin in immunohistochemistry. CONCLUSION: ASCs and ASC-secretome infusions to the partially hepatectomized mice produced similar outcomes in terms of liver regeneration and mouse albumin expression. Therefore, cell-free therapy, which is based on the paracrine properties of stem cells, is expected to overcome the limitations of cell-based methods and to provide a novel treatment for liver diseases. PMID- 25788186 TI - High rate of core promoter and precore mutations in patients with chronic hepatitis B. AB - BACKGROUND: The prevalence of precore (PC) and core promoter (CP) mutations in patients with chronic hepatitis B virus (HBV) infection (CHB) and their impact on liver disease is incompletely defined in the United States. METHODS: A retrospective chart review using a cross-sectional approach of 1,186 CHB patients was conducted. RESULTS: Of 926 patients tested for HBV e antigen (HBeAg), 37% were HBeAg+. Of 194 patients tested for mutations, 80% had PC or CP mutations or both; 89% of HBeAg-negative and 56% of HBeAg+ patients had PC or CP mutations or both (p < 0.001). The mean log10 ALT was significantly lower in patients with both mutations compared to patients without mutations. The mean log10 HBV DNA was significantly lower in patients with only PC mutations (4.82) compared to patients without mutations (5.71, p = 0.019). With the study population divided into four subgroups based on ALT level at time of diagnosis, cirrhosis incidence was significantly higher in patients with ALT 1-2 * ULN and ALT > 2 * ULN compared to patients with ALT <= 0.5 * ULN. CONCLUSIONS: Our finding that PC and CP mutations may be associated with milder liver disease in some patients could serve as the basis for longitudinal studies to help delineate treatment need and duration in patients with these mutations. If confirmed, the finding of an association between ALT 1-2 * ULN and increased incidence of cirrhosis could call into question guidelines which only recommend treatment with ALT > 2 * ULN. PMID- 25788188 TI - Long-term use of methotrexate does not result in hepatitis B reactivation in rheumatologic patients. AB - BACKGROUND AND OBJECTIVE: Hepatitis B virus (HBV) infection is still prevalent in Asia, including Thailand. HBV can archive in hepatocytes for life and can reactivate after immunosuppression and chemotherapy administration. Use of immunosuppressive agents is recommended in many rheumatologic diseases and reactivation of HBV can occur. Data regarding the effect of methotrexate (MTX) on HBV reactivation is scanty. MTX is a well known cause of hepatic fibrosis but its effect on HBV reactivation is not clearly understood. There is no specific recommendation for HBV prophylaxis for patients using MTX. This study aimed to determine the prevalence of HBV seromarkers in rheumatologic patients who were treated with long-term MTX and to evaluate the hepatitis outcome in the patients with positive HBV markers. METHODS: This was a cross-sectional study at the Rheumatology Clinic, Siriraj Hospital, Bangkok, Thailand. Patients aged 15 years or older treated with MTX more than 24 weeks were invited in the study. Review of medical history, MTX prescription and dosage during the last 52 weeks, blood tests for liver function tests, HBV serology, and HBV DNA viral load were performed. The exclusion criteria included patients who were treated with biological DMARDs, drugs active against HBV, known co-infection with HCV or HIV and previous diagnosis of cirrhosis from any causes or presence of hepatocellular carcinoma. RESULTS: A total of 173 patients were enrolled (153 females, 20 males, mean age of 52.6 +/- 13.6 years). The majority of patients were diagnosed with rheumatoid arthritis (67.0%), SLE (13.9%), spondyloarthopathies (8.7%) and others (10.4%). Thirty percent of them (55/173) had no previous data for HBV seromarkers. Among 118 patients who had baseline data, only one patient (0.8%) had HBsAg positive. Average duration of treatment was 9.9 years and MTX dose prescribed was 571.6 +/- 240.4 mg during the last 52 weeks. Out of 173 patients, only two had clinically significant hepatitis (1.16%) and one was HBsAg positive (0.58%). Ninety-six patients (55.5%) were negative for all HBV seromarkers, 67/173 (38.7%) positive for anti-HBs antibody and 65/173 (37.6%) positive for anti-HBc IgG. Only one in 65 patients (1.5%) who had any positive HBV seromarkers had HBV DNA detectable. CONCLUSION: Prevalence of HBsAg positive rheumatologic patients treated with MTX in Thailand was only 0.58%, which was lower than the general Thai population. About one-third of the patients had exposure to HBV as demonstrated by presence of anti-HBc IgG (37.6%), but none of them had hepatitis B reactivation during 9.9 years of MTX treatment. Moreover, one case with HBsAg positive had been receiving MTX without HBV prophylaxis for 5 years but had no evidence of HBV flare and evidence of fibrosis. From our study, long-term MTX in patients exposed to HBV was safe and not associated with hepatitis flare. However, more study is needed as to whether HBV prophylaxis is required. PMID- 25788189 TI - Can hypersplenism secondary to portal hypertension be treated by non-selective beta blockers? PMID- 25788190 TI - Autoimmune liver disease in Asian children. PMID- 25788191 TI - Liver transplantation in acute-on-chronic liver failure: lessons learnt from acute liver failure setting. AB - Acute-on-chronic liver failure is a clinical entity with high risk of mortality. These patients can have severe liver dysfunction complicated with multiple organ failure. Liver transplantation is the definitive treatment for these patients. Literature regarding management of acute liver failure with special emphasis on liver transplantation was reviewed. Lessons learnt from the management of patients with acute liver failure which could be extrapolated to the management of patients with acute-on-chronic liver failure are discussed. Significant improvement in outcomes of acute liver failure has been reported across the world. Several aspects in transplantation for acute liver failure were found to be relevant to the management of acute-on-chronic liver failure. These include defining criteria to identify patients needing early liver transplantation, prioritizing patients with acute liver failure on the waiting list, defining when to abandon transplantation in acute liver failure, emphasis on graft quality and the need for a multi-disciplinary approach to manage multiple organ dysfunction. Useful lessons can be learnt from the progress made in the management of acute liver failure and these can be extrapolated to the management of patients with acute-on-chronic liver failure. PMID- 25788192 TI - Sulforaphane reduces apoptosis and oncosis along with protecting liver injury induced ischemic reperfusion by activating the Nrf2/ARE pathway. AB - PURPOSE: The purpose of this study was to determine the effect of sulforaphane (SFN) on hepatic ischemia reperfusion injury (HIRI) and to explore the underlying mechanisms. METHODS: The rat model of HIRI was established. Thirty-two rats were randomly divided into sham (A), SFN (B), HIRI (C), and SFN + HIRI (D) groups. Animals in the HIRI and Sham groups were treated with equal volumes of the vehicle of SPF. Liver functions were evaluated by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples were collected for histological examination and determination of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) levels. Mitochondrial Na(+)-K(+)-ATPase and Ca(2+)-ATPase were measured by colorimetry. Expression levels of NQO1, Nrf2, and HO-1 in liver tissue were detected by western blot analysis. Additionally, oncosis and apoptosis were detected by Annexin V-FITC/PI immunofluorescent flow cytometry analysis. RESULTS: The HIRI group showed a significant increase in serum levels of liver enzymes (ALT, AST) associated with histopathological damage in the liver. Pre-treatment with SFN could reduce the levels of MDA and MPO in liver tissue and improve the activities of SOD, GSH, GSH-Px, and mitochondrial Na(+)-K(+)-ATPase and Ca(2+)-ATPase in liver tissue. Moreover, SFN could still increase the expression of NQO1, Nrf2, and HO-1 in liver tissue and decrease the oncosis and apoptosis of liver cells. CONCLUSIONS: Pre-treatment with SFN could attenuate HIRI via the activation of Nrf2/ARE signaling pathways, ameliorate oxidative stress, and maintain the normal activities of Na(+)-K(+)-ATPase and Ca(2+)-ATPase, thus reducing the occurrence of cell oncosis and apoptosis. Therefore, SFN can be considered a potential candidate as an anti-ischemic medication to minimize HIRI. PMID- 25788193 TI - New discriminant score to predict the fibrotic stage of non-alcoholic steatohepatitis in Japan. AB - BACKGROUND AND AIM: Currently, non-alcoholic steatohepatitis (NASH) can only be diagnosed histopathologically. Our objective was to establish a new scoring system for the fibrotic stage of NASH. METHODS: We enrolled 139 patients with histologically proven NASH and divided them into two groups to construct (n = 90) and validate (n = 49) a fibrotic score for NASH (FSN). We used 17 variables and their natural logarithmic transformations in the multivariate analysis. To assess the accuracy of the FSN in determining NASH advanced fibrosis (stages 3-4), we compared various fibrotic scores for NASH. RESULTS: In the construct group, multivariate regression analysis ultimately obtained the following function: z = 1.022 * ln (type IV collagen 7S) (ng/mL) - 0.00680 * (platelet count) (*10(9)/L) + 1.925 * ln (AST) (IU/L) - 1.239 * ln (ALT) (IU/L) + 0.249. Median values of the FSN for stages 1, 2, 3 and 4 were 1.87, 2.14, 3.26 and 3.89, respectively. The multiple regression coefficient and coefficient of determination were 0.70 and 0.46, respectively. In the validation group, the median value was 2.00, 2.83, 3.08 and 4.37 in each stage. With regard to the utility of the FSN for predicting advanced fibrosis of NASH (stage >=3), the area under the receiver operating characteristic curves (AUROC), 0.909 (95% CI 0.847-0.970, p < 0.001), was higher than that for the other fibrotic scores (APRI, NAFLD fibrosis score, FIB-4 index, BARD score, NIKEI) in the construct group. CONCLUSIONS: This simple scoring system accurately predicts fibrotic stage and discriminates patients with advanced fibrosis of NASH. PMID- 25788194 TI - Sofosbuvir for treatment of chronic hepatitis C. AB - Chronic hepatitis C is a leading cause of liver-related morbidity and mortality worldwide. If untreated, chronic hepatitis C can progress to advanced liver fibrosis, cirrhosis, liver failure, hepatocellular carcinoma and death. Until recently, treatment of hepatitis C predominantly constituted an immunomodulatory agent, peg-interferon-alfa and ribavirin. In 2011, the first class of directly acting antiviral agents, HCV NS3/4A serine protease inhibitors, was added to peg interferon-alfa and ribavirin with increased efficacy. In the past year, an NS5B inhibitor, sofosbuvir, has emerged as a potent agent with pangenotypic efficacy, resulting in the first interferon-free regimen for the treatment of hepatitis C. This review summarizes the data that resulted in regulatory approval of sofosbuvir and highlights the future of hepatitis C therapy with sofosbuvir as the backbone of a highly effective antiviral regimen. PMID- 25788195 TI - Association between retinal artery lesions and nonalcoholic fatty liver disease. AB - OBJECTIVE: Retinal artery lesions have been reported to be a risk marker of morbidity and mortality for cardiovascular and cerebrovascular diseases in various study populations. Nonalcoholic fatty liver disease (NAFLD) is also a risk factor for cardiovascular disease. However, the relationship between retinal artery lesions and NAFLD is less certain. METHODS: Data were obtained from 2,454 patients who attended their annual health examination (2,143 males and 311 females, aged 62.34 +/- 10.03 years). NAFLD was diagnosed by hepatic ultrasonography. Retinal artery lesions were diagnosed according to the criteria. Total plasma cholesterol, plasma triglyceride and fasting glucose levels were determined by using a multichannel analyzer; the body mass index, systolic blood pressure, diastolic blood pressure, incidence of hypertension and coronary artery disease were measured or analyzed by statistical analysis. RESULTS: Patients with NAFLD had older age and higher values of BMI, systolic blood pressure, diastolic blood pressure, fasting glucose, total cholesterol and triglycerides and had a higher incidence of hypertension, coronary artery disease and retinal artery lesions (p < 0.01). Retinal artery lesions were taken as a dependent variable, and age, gender, BMI, systolic blood pressure, diastolic blood pressure, fasting glucose, total cholesterol and triglyceride levels, and NAFLD were taken as covariates. We found that age >=65 years (p < 0.01, OR 1.968), being male (p < 0.01, OR 1.668), BMI >= 25 (p < 0.01, OR 0.743), SBP >= 140 mmHg (p < 0.01, OR 1.368) and NAFLD (p < 0.01, OR 2.378) were significantly associated with a risk of retinal artery lesions by binary logistic regression analysis. CONCLUSIONS: Patients with NAFLD were older and had higher values for BMI, systolic blood pressure, diastolic blood pressure, fasting glucose, total cholesterol and triglycerides, and higher incidence of hypertension, coronary artery disease and retinal artery lesions. NAFLD is a risk factor for retinal artery lesions. PMID- 25788196 TI - Recent advances in hemochromatosis: a 2015 update : a summary of proceedings of the 2014 conference held under the auspices of Hemochromatosis Australia. AB - This review focuses on iron metabolism, the genetics of hemochromatosis, current treatment protocols and various screening methods. Even though the most common form of hereditary hemochromatosis, C282Y gene mutations in the HFE gene, has been extensively studied, novel mutations in both HFE and non-HFE genes have been implicated in this disease. These have important implications for the Asia Pacific region. In overload, deposition of iron in various body tissues leads to toxic damage. Patients commonly present with non-specific symptoms of malaise and lethargy. Biochemical, imaging and genetic testing can be carried out to confirm diagnosis. Venesection forms the mainstay of treatment and at present cascade screening of affected families is recommended over population-level screening. PMID- 25788197 TI - Preemptive adefovir versus lamivudine for prevention of hepatitis B reactivation in chronic hepatitis B patients undergoing chemotherapy. AB - BACKGROUND: This proof-of-concept study compared lamivudine (LAM) with a newer antiviral agent, adefovir dipivoxil (ADF), in preventing hepatitis B virus (HBV) reactivation in chronic HBV patients undergoing chemotherapy. METHODS: Hepatitis B surface antigen (HBsAg) positive patients intended to undergo chemotherapy were randomized to receive either LAM 100 mg daily or ADF 10 mg daily. Anti-viral therapy was started 1 week prior to chemotherapy and until 6 months after completing chemotherapy. The primary outcome was HBV reactivation rate. All patients with viral breakthrough were screened for resistance mutations by direct sequencing. RESULTS: Seventy treatment-naive patients were consecutively randomized 1:1 to LAM or ADF. The median baseline HBV DNA levels were similar (LAM 3.36 vs. ADF 3.17 log10 copies/mL, p = 0.860). The median duration was 8.3 months on LAM and 10.6 months on ADF (p = 0.220). HBV reactivation was observed in 13/35 (37.1%) on LAM compared with 10/35 (28.6%) on ADF (p = 0.611). The median time to HBV reactivation was 4.6 and 8.1 months, on LAM and ADF respectively. Among these 13 patients, 8/13 (61.5%) on LAM had developed drug resistance mutations but none on ADF had developed drug resistance mutations to ADF (p = 0.003). Both drugs were well tolerated and no severe drug-related toxicities were reported. CONCLUSION: In this randomized clinical study, adefovir and lamivudine demonstrated similar efficacy in preventing hepatitis B reactivation in HBsAg-positive patients undergoing chemotherapy. In patients whose hepatitis B reactivated, adefovir was associated with a lower resistance profile. PMID- 25788199 TI - Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years. AB - BACKGROUND: Phase 3 clinical studies have shown that long-term treatment with tenofovir disoproxil fumarate (TDF) can suppress hepatitis B viral load and promote significant fibrosis regression and cirrhosis reversal in a majority of treated chronic hepatitis B (CHB) patients. This retrospective analysis investigated the impact of baseline cirrhosis status on virologic, serologic, and histologic outcomes in patients treated with TDF. METHODS: Patients enrolled in studies GS-US-174-0102 and GS-US-174-0103 who had baseline liver biopsy-diagnosed cirrhosis and entered the open-label phase of the studies were included in the virologic and serologic analyses. Patients (both HBeAg positive and negative) with paired liver biopsies at baseline and 5 years (N = 348) were included in a histologic analysis. RESULTS: After 5 years on study, comparing patients with and without baseline cirrhosis, respectively: 99.2 and 98.0% achieved virologic response (hepatitis B viral load < 69 IU/ml) (p = 0.686); 79.7 and 81.9% had normal serum levels of alanine aminotransferase (p = 0.586); 4.0 and 1.2% developed hepatocellular carcinoma (p = 0.044). In HBeAg-positive patients with and without baseline cirrhosis, HBsAg loss occurred in 14.4 and 8.3% of patients, respectively (p = 0.188). One HBeAg-negative patient had HBsAg loss. CONCLUSIONS: This represents the largest analyses to date of CHB patients with sequential liver biopsies demonstrating that treatment with TDF for up to 5 years is associated with favorable virologic, serologic, and histologic outcomes, regardless of baseline cirrhosis status. Notably, histologic improvement was observed in the majority of cirrhotic and noncirrhotic patients. PMID- 25788198 TI - New cellular and molecular targets for the treatment of portal hypertension. AB - Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease. PMID- 25788200 TI - Obstructive sleep apnea is an important predictor of hepatic fibrosis in patients with nonalcoholic fatty liver disease in a tertiary care center. AB - BACKGROUND: The association of obstructive sleep apnea (OSA) with nonalcoholic fatty liver disease (NAFLD) has only been studied in selected subgroups such as the morbidly obese. We aimed to determine the prevalence and effect of OSA on NAFLD and vice versa in unselected patients attending the outpatient department. METHODS: OSA was diagnosed by polysomnography, done in patients having symptoms of OSA, in patients with NAFLD attending the liver clinic. Polysomnography-proven patients with OSA attending the chest clinic were evaluated for NAFLD by ultrasonography. Anthropometry, liver function tests, metabolic syndrome evaluation and transient elastography were performed in all patients. RESULTS: Three (3%; 95% CI 1.03-8.45%) out of 100 patients with NAFLD (mean age 41 +/- 11 years) had symptomatic OSA. Of 23 patients with OSA (mean age 46 +/- 12 years,), 3 (13%) had mild, 5 (22%) moderate and 15 (65%) severe OSA. Twenty-one (91.3%; 95% CI 73.2-97.6%) patients with OSA had NAFLD, while raised hepatic transaminase levels were seen in seven (30.4%; 95% CI 15.6-50.9%). Body mass index (OR 1.21, 95% CI 1.02-1.44) and male gender (OR 4.79, 95% CI 1.12-20.48) were significant independent predictors of OSA in NAFLD. The apnea-hypopnea index (OR 1.084, 95% CI 1.002-1.172), a marker of OSA severity, was the only significant independent predictor of significant fibrosis in patients with NAFLD. CONCLUSIONS: Prevalence of symptomatic OSA in patients with NAFLD is low and is predicted by male gender and obesity. Prevalence of NAFLD in patients with OSA is very high. Significant hepatic fibrosis in patients with NAFLD is predicted by OSA independent of obesity and metabolic syndrome. PMID- 25788202 TI - Value of dynamic contrast enhanced MRI in predicting outcomes of HCC receiving radiotherapy. PMID- 25788201 TI - Adipocytokines and liver fibrosis stages in patients with chronic hepatitis B virus infection. AB - BACKGROUND: Adipocytokines play an important role in lipid metabolism and liver disease progression. However, the interactions between hepatitis B virus (HBV) infection and adipocytokines remain largely unknown. AIMS: To investigate the association of HBV infection with adipocytokines in HBV-infected and noninfected subjects. In addition, the impact of adipocytokines on serum HBV DNA, HBsAg levels and liver fibrosis stage was also examined. METHODS: A case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 187 patients with chronic HBV infection, and the control group consisted of 184 age-, gender- and body mass index-matched subjects without HBV infection. Fasting blood glucose, lipid profiles, adiponectin, leptin and visfatin levels were compared between the two groups. APRI and FIB-4 were calculated to estimate the severity of liver fibrosis. RESULTS: Most of the enrolled subjects had lower ALT levels [228 (57.7%) ALT < ULN] and milder hepatic fibrosis [381 (96.5%) APRI < 0.7; 307 (77.7%) FIB4 < 1.45]. The HBV group had significantly higher serum adiponectin and visfatin but lower leptin levels than the control group. This difference remained significant after adjustment for age, sex, BMI and ALT levels (p < 0.05). Serum adiponectin, leptin and visfatin levels were significantly associated with serum HBsAg and HBV DNA levels (p < 0.05). In addition, a higher serum adiponectin level was associated with advanced liver fibrosis in elder male HBeAg-negative patients. CONCLUSIONS: Patients with chronic HBV infection have significantly higher serum adiponectin and visfatin but lower leptin levels than healthy controls. Serum adipocytokine levels independently correlate with HBV viremia, HBsAg levels and liver fibrosis stages. PMID- 25788203 TI - Influence of IFNL3.rs12979860 and IFNL4.ss469415590 polymorphism on clearance of hepatitis C virus infection among Egyptians. AB - BACKGROUND/PURPOSE: Single-nucleotide polymorphisms (SNPs) around the interferon lambda 3 (IFNL3; also known as interleukin 28B; IL28B) gene are associated with spontaneous hepatitis C virus (HCV) clearance. Interferon lambda 4 (IFNL4).ss469415590, in linkage disequilibrium (LD) with IFNL3.rs12979860 among the Caucasian population, has recently been identified as a potential functional variant. Our objective was to assess the LD between IFNL3.rs12979860 and IFNL4.ss469415590 and to compare their effect on the outcome of HCV infection among Egyptians, mainly infected with HCV genotype 4. METHODS: One-hundred and eighty-five Egyptian HCV patients (77 spontaneous resolvers and 108 chronic subjects), and 122 healthy controls were genotyped for both IL28B.rs12979860 and IFNL4.ss469415590. Logistic regression models including factors with univariate association with the outcome of infection were calculated for each genetic marker. The LD was also calculated for the 122 healthy controls. RESULTS: The CC genotype of IFNL3.rs12979860 was more frequent among individuals with HCV spontaneous resolution than among those with chronic infection (57 vs. 27%; adjusted OR 3.84; 95% CI 2.02-7.30; p < 0.0001). Also, the TT/TT genotype of IFNL4.ss469415590 was more frequent among individuals with spontaneous resolution (49 vs. 20%; adjusted OR 4.17; 95% CI 2.12-8.19; p < 0.0001). Both markers were in LD (D' = 0.96; r (2) = 0.84). CONCLUSION: The IFNL3.rs12979860 and IFNL4.ss469415590 variants have comparable effects on spontaneous resolution of HCV among Egyptians, for whom both markers are closely linked. PMID- 25788204 TI - Natural history of large regenerative nodules and dysplastic nodules in liver cirrhosis: 28-year follow-up study. AB - BACKGROUND AND AIMS: Some follow-up studies of large regenerative nodules (LRNs) and dysplastic nodules (DNs) were reported previously. However, the pre-malignant potentiality of LRNs has remained controversial up to now. No LRNs showed malignant transformation in our previous study. We aimed to evaluate the pre malignant potentiality of LRNs and DNs with a greater number of cases and longer follow-up periods. METHODS: From 1982 to 2005, 1,500 consecutive nodular lesions up to 2 cm in diameter were subjected to US guided thin-needle biopsy in cirrhotic patients at Chiba University Hospital. Of these lesions, 68 LRNs in 60 cases and 20 DNs in 22 cases were followed up for more than 6 months without any anti-cancer therapy. The last US examination was in 2010. The total study period was 28 years. We analyzed the histological findings and the clinical data of all cases retrospectively. The outcome of the lesions was examined. RESULTS: The mean follow-up period was 38.9 (16-119) months in LRNs and 31.9 (6-101 months) in DNs. Rate of nodule enlargement was higher in DNs (8/24 nodules, 33%) than LRNs (11/68 nodules, 16 %), (p = 0.0743, not significant). Rate of malignant transformation was also higher in DNs (10/24 nodules, 42%) than LRNs (9/68 nodules, 13%), (p = 0.0040, significant). The rate of disappearance in images was similar between LRNs and DNs. CONCLUSIONS: We should recognize LRN as low risk pre-malignant lesions whereas DNs as high risk lesions. PMID- 25788205 TI - The role of interstitial Cajal-like cells in the formation of cholesterol stones in guinea pig gallbladder. AB - OBJECTIVES: To investigate the effect of interstitial Cajal-like cells (ICLCs) on contraction of gallbladder muscle strips; and to analyze the changes of ICLCs during cholesterol gallstone formation in guinea pig. METHODS: The cholesterol gallstone animal model was made by feeding guinea pig with high cholesterol diet (HCD). In vitro isolated gallbladder muscle strips were prepared. Gallbladder motility was assessed by the contraction frequency and amplitude of slow wave in response to CCK-8. The alteration in ICLC density was estimated by using immunohistochemistry. The expression of c-kit and stem cell factor (SCF) were determined. RESULTS AND CONCLUSIONS: The amplitude and frequency of slow wave was significantly lower in gallbladder muscle strips with the impaired ICLCs. And it is correlated with the decreased contractile response to CCK-8. In HCD guinea pig, the ICLC density and bile flow in response to CCK-8 were remarkably decreased. The results indicated that gallbladder ICLCs can create slow wave potential, and also get involved in the regulation of CCK-8 induced gallbladder smooth muscle motility. In the process of cholesterol gallstone formation, ICLC density clearly decreased. This further impaired gallbladder motility. The decrease in ICLC density may result from decreased expression of c-kit and SCF during cholesterol gallstone formation. PMID- 25788207 TI - [Congratulations, dear Dr. Israel!]. PMID- 25788206 TI - Two are better than one: noninvasive assessment of liver fibrosis in nonalcoholic fatty liver disease. PMID- 25788209 TI - Dr. Francesco Moscato appointed as co-editor representing the International Society for Rotary Blood Pumps. PMID- 25788208 TI - Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia. AB - High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6 mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression. PMID- 25788210 TI - Nuclear powered devices: is it time to revisit the use of nuclear energy? PMID- 25788211 TI - Artificial organs 2014: a year in review. AB - In this Editor's Review, articles published in 2014 are organized by category and briefly summarized. We aim to provide a brief reflection of the currently available worldwide knowledge that is intended to advance and better human life while providing insight for continued application of technologies and methods of organ Replacement, Recovery, and Regeneration. As the official journal of the International Federation for Artificial Organs, the International Faculty for Artificial Organs, the International Society for Rotary Blood Pumps, the International Society for Pediatric Mechanical Cardiopulmonary Support, and the Vienna International Workshop on Functional Electrical Stimulation, Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery, and Regeneration from all over the world. We take this time also to express our gratitude to our authors for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers, the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons, for their expert attention and support in the production and marketing of Artificial Organs. We look forward to reporting further advances in the coming years. PMID- 25788212 TI - Left thoracotomy and descending aortic anastomosis for HeartWare implantation after previous coronary artery bypass graft and left ventriculotomy. PMID- 25788213 TI - Utilizing right ventricular assist device with extracorporeal membrane oxygenator for management of diffuse alveolar damage after orthotopic heart transplant. PMID- 25788215 TI - French Validation of the Multidimensional Attitude Scale Toward Persons with Disabilities (MAS): The Case of Attitudes Toward Autism and Their Moderating Factors. AB - This research investigates the renewed interest in autism, the stigmatization of persons with autism and the need to better measure such stigmatization. Two studies were thus conducted on 101 and 104 participants in order to validate the French version of the Multidimensional Attitude Scale toward persons with disabilities, and examine the moderating effects of age, gender and contact on such attitudes. Both the exploratory and confirmatory factor analyses yielded a four-dimensional scale, indicating that the observed data fit with the theoretical model and that the sub-scale show an acceptable internal consistency. Results on moderating effect were less clear cut. The discussion deals with the measurement of attitudes toward people with autism as well as the role of social contact. PMID- 25788216 TI - Curing sickle cell disease: Mission accomplished? PMID- 25788217 TI - Cytoreductive surgery and HIPEC in treatment of colorectal peritoneal carcinomatosis: experiment or standard care? A survey among oncologic surgeons and medical oncologists. AB - BACKGROUND: Controversy still exists regarding the position of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis of colorectal carcinoma. The goal of the current study was to evaluate the opinions about this treatment among Dutch oncologic surgeons and medical oncologists. METHODS: An online survey was sent to all known Dutch oncologic surgeons (n = 459) and medical oncologists (n = 363) representing the respective departments of 84 hospitals. A comparison was made between surgeons and oncologists. RESULTS: 185 eligible responses were received from 71 hospitals, resulting in a response rate of 23 % for individuals and a response rate of 85 % for hospitals. Overall, 65 % of respondents regarded CRS+HIPEC as effective with sufficient evidence, 29 % responded that CRS+HIPEC is probably effective without sufficient evidence, and 7 % of respondents regards HIPEC as probably ineffective. Medical oncologists were less convinced of the effectiveness of CRS+HIPEC than surgeons (P = 0.006). Of all the respondents, 68 % indicated that they regard CRS+HIPEC as a standard treatment for patients with peritoneal dissemination of colorectal carcinoma (77 % of surgeons vs 54 % of oncologists, P = 0.001). Additionally, 68 % of respondents regard CRS+HIPEC as potentially curative (77 % of surgeons vs 54 % of oncologists, P = 0.001). CONCLUSIONS: Approximately 30 % of physicians who treat colorectal carcinoma do not regard CRS+HIPEC as standard care. Surgeons appear to be significantly more in favor of this treatment than medical oncologists. This study shows that efforts should be made to improve knowledge and increase acceptance of CRS and HIPEC in colorectal cancer treatment among medical oncologists and surgeons. PMID- 25788218 TI - Role of bevacizumab in neoadjuvant chemotherapy and its influence on microvessel density in rectal cancer. AB - BACKGROUND: The role of bevacizumab (Bev) in neoadjuvant chemotherapy (NAC) without radiotherapy for rectal cancer has not been fully discussed. The purpose of this study is to assess the clinicopathological benefit of Bev in NAC for rectal cancer and to investigate its influence on microvessel status in cancerous tissue. METHODS: Data on 47 patients with rectal cancer, who received NAC with or without Bev between August 2008 and November 2012, were analyzed retrospectively. The objective response was evaluated using the maximum tumor diameter. Tumor regression grade 3/4 was classified as a pathological response. RESULTS: Thirty one patients (66 %) received NAC that included Bev and the other 16 patients were treated without Bev. The objective response rate was significantly higher in the Bev group than in the non-Bev group (64.5 vs. 25.0 %, p = 0.015). The rate of pathological response was much higher in the Bev group (41.9 %) than in the non Bev group (12.5 %), but did not reach significant difference (p = 0.052). Microvessel density (MVD) in the resected cancerous tissue was significantly lower in the Bev group than in the non-Bev group. CONCLUSIONS: We have confirmed that objective and pathological responses were better in patients treated with NAC that included Bev than in those who received NAC without Bev. Additionally, MVD in tumor tissues was inhibited in the patients treated with Bev. To investigate the impact of Bev in NAC on long-term survival, further follow-up is required. PMID- 25788219 TI - MicroRNA expression in hepatocellular carcinoma after the eradication of chronic hepatitis virus C infection using interferon therapy. AB - AIM: Hepatocellular carcinoma (HCC) develops in up to 5% of patients after the successful treatment of chronic hepatitis C virus (HCV) infection using interferon therapy. The aim of this study was to characterize miRNA expression in liver tissues from patients who achieved a sustained viral response (SVR). METHODS: Seventy-one patients with resected HCC were enrolled into the present study: 61 HCC from patients with continuously infected HCV (HCV-HCC) and 10 from patients who had achieved SVR (SVR-HCC). We also included non-tumor tissues (SVR NT) from four patients with SVR-HCC, and liver tissue (SVR-CH) from four SVR patients without HCC. Total RNA was extracted from liver samples. The miRNA expression patterns were analyzed using microarrays. In addition, target gene expression was quantified after miRNA overexpression in HEK293 cells. RESULTS: We could discriminate between SVR-HCC and HCV-HCC with 75.36% accuracy using the expression pattern of six specific miRNA. The expression levels of 37 miRNA were significantly lower in HCV-HCC than in SVR-HCC, whereas the expression of 25 miRNA was significantly higher in HCV-HCC than SVR-HCC (P < 1.0E-05). The expression of thrombospondin 1 was regulated in an opposing manner by miR-30a-3p in SVR-HCC and HCV-HCC. In non-tumor tissues, the expression pattern of seven miRNA could distinguish between SVR-CH and SVR-NT with 87.50% accuracy. CONCLUSION: Comprehensive miRNA expression analyses could not only differentiate between SVR-HCC and HCV-HCC but also forecast hepatocarcinogenesis after achieving SVR. PMID- 25788220 TI - The safety and prognostic factors for mortality in extremely elderly patients undergoing an emergency operation. AB - PURPOSE: As the number of elderly people has increased, the number of elderly patients who need emergency operations has also increased. Although there are many models to evaluate the risk of surgery in elderly patients, they all are associated with limitations. We herein evaluated the prognostic factors for surgical mortality in elderly patients more than 80 years old who needed emergency operations. METHODS: A total of 171 patients more than 80 years old underwent emergency operations from January 2001 to December 2012. Among them, 79 patients with acute cholecystitis, panperitonitis and intestinal obstruction with strangulation, which included mortality cases, were included. We retrospectively reviewed the medical records of the patients and analyzed the prognostic factors for surgical mortality. RESULTS: Forty-eight patients had a co-morbidity. Thirty one patients initially had systemic inflammatory response syndrome. There were 27 surgical mortality cases. A univariate analysis revealed that panperitonitis, a positive blood culture and the level of albumin were significant prognostic factors predicting a worse prognosis. However, a multivariate analysis revealed that a serum albumin level more than 3.5 g/dL was the only significant prognostic factor (p = 0.037). CONCLUSION: Surgeons cannot fully evaluate the risk of emergency operation cases. However, our data indicate that if patients do not show hypoalbuminemia, the surgeon may be able to perform an emergency operation without a high risk of surgical mortality. PMID- 25788221 TI - Clinical observation of panniculitis in two patients with BRAF-mutated metastatic melanoma treated with a combination of a BRAF inhibitor and a MEK inhibitor. AB - BACKGROUND: Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy. PATIENTS AND METHODS: Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials. Ten and 150 days after treatment start respectively, the patients developed painful nodules on the legs. In addition, one patient developed symmetrical articulation pain and intermittent fever episodes. RESULTS: Based on the clinical and histological presentation, erythema nodosum-like panniculitis was diagnosed in both cases. No other aetiology could be found. After receiving topical or oral steroid treatment and anti-inflammatory analgesics, the painful nodular lesions disappeared several weeks later. In one case, a rebound of the painful nodules was observed when the combination treatment (dabrafenib and trametinib) was resumed after a 1-week unscheduled treatment interruption. CONCLUSIONS: Panniculitis has previously been described in association with BRAF inhibitor treatment, but not MEK inhibitor treatment. Combination treatment is usually associated with a lower incidence of cutaneous adverse events (AEs), as compared to monotherapy. Panniculitis was observed in two patients during combined BRAF and MEK inhibitor treatment. These cases illustrate the need for further research in a larger patient population to identify a possible link between combined BRAF and MEK inhibitor treatment and the incidence of panniculitis. PMID- 25788222 TI - Similar striatal D2/D3 dopamine receptor availability in adults with Tourette syndrome compared with healthy controls: A [(11) C]-(+)-PHNO and [(11) C]raclopride positron emission tomography imaging study. AB - Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. We investigated striatal D2/3 dopamine receptors in TS using the radioligands [(11) C]raclopride and [(11) C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [(11) C]raclopride and [(11) C]-(+)-PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BPND ) between TS and HC participants. Analysis of variance was performed to investigate main effect of radioligand. In addition, BPND values were extracted for ventral, motor, and associative striatum. Finally, we examined the relationship between BPND measures and symptom severity in TS participants. Main effects analyses showed that [(11) C]-(+)-PHNO BPND was higher in ventral striatum, whereas [(11) C]raclopride BPND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [(11) C]-(+)-PHNO and [(11) C]raclopride BPND in the three striatal subregions. Moreover, there was no significant correlation between BPND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [(11) C]-(+)-PHNO localized preferentially to ventral striatal, D3 receptor-rich regions, in contrast to [(11) C]raclopride, which localized preferentially in the dorsal striatum. PMID- 25788223 TI - Synthesis, characterisation and reactivity of copper(I) amide complexes and studies on their role in the modified Ullmann amination reaction. AB - A series of copper(I) alkylamide complexes have been synthesised; copper(I) dicyclohexylamide (1), copper(I) 2,2,6,6-tetramethylpiperidide (2), copper(I) pyrrolidide (3), copper(I) piperidide (4), and copper(I) benzylamide (5). Their solid-state structures and structures in [D6 ]benzene solution are characterised, with the aggregation state in solution determined by a combination of DOSY NMR spectroscopy and DFT calculations. Complexes 1, 2 and 4 are shown to exist as tetramers in the solid state by X-ray crystallography. In [D6 ]benzene solution, complexes 1, 2 and 5 were found by using (1) H DOSY NMR to exist in rapid equilibrium between aggregates with average aggregation numbers of 2.5, 2.4 and 3.3, respectively, at 0.05 M concentration. Conversely, distinct trimeric, tetrameric and pentameric forms of 3 and 4 were distinguishable by one dimensional (1) H and (1) H DOSY NMR spectroscopy. Complexes 3-5 are found to react stoichiometrically with iodobenzene, in the presence or absence of 1,10 phenanthroline as an ancillary ligand, to give arylamine products indicative of their role as potential intermediates in the modified Ullmann reaction. The role of phenanthroline has also been explored both in the stoichiometric reaction and in the catalytic Ullmann protocol. PMID- 25788224 TI - Cardiac Autoantibody Levels Predict Recurrence Following Cryoballoon-Based Pulmonary Vein Isolation in Paroxysmal Atrial Fibrillation Patients. AB - INTRODUCTION: Recent evidence has suggested that autoantibodies may play an important role in the development of atrial fibrillation (AF). The predictive value of preprocedural autoantibodies against beta-1 adrenergic receptor (anti beta1-R) and M2-muscarinic acetylcholine receptor (anti-M2-R) for AF recurrence following cryoballoon-based pulmonary vein isolation (PVI) is still unclear. We aimed to determine the predictive value of preprocedural anti-beta1-R and anti-M2 R levels for AF recurrence. METHODS: Eighty patients (mean age 54.25 +/- 7.70 years; 40% female) with paroxysmal AF and preserved left ventricular function who underwent cryoballoon-based PVI were included in the study. Preprocedural anti-M2 R and anti-beta1-R levels were measured with ELISA. RESULTS: At 1-year follow-up after ablation, late AF recurrence was observed in 17 (21.25%) patients. In the Cox regression model, including number of antiarrhythmic drugs, early AF recurrence, anti-beta1-R levels >159.88 ng/mL, anti-M2-R levels >277.65 ng/mL, AF duration, and left atrial volume index, only anti-beta1-R levels >159.88 ng/mL (HR: 4.281, P = 0.039) and anti-M2-R levels >277.65 ng/mL (HR: 4.313, P = 0.030) were found to be independent predictors of late AF recurrence. Anti-beta1-R level >159.88 ng/mL was shown to predict late AF recurrence with a sensitivity of 70.59% and specificity of 90.48%. A cut-off value of 277.65 ng/mL for anti-M2-R level predicted AF recurrence with a sensitivity of 70.59% and specificity of 95.24%. CONCLUSION: Preprocedural serum anti-beta1-R and anti-M2-R levels are independent predictors of late AF recurrence following cryoballoon-based PVI in paroxysmal AF patients. Detection of preprocedural anti-beta1-R and anti-M2-R levels may serve as a novel method for determination of paroxysmal AF patients who may not benefit from cryoballoon-based PVI. PMID- 25788225 TI - Diagnostic accuracy of sentinel node identification is maintained with the addition of local lidocaine and subareolar radioactive colloid injection. AB - Preoperative sentinel node localization (SNL) using a subareolar injection of radiotracer technetium-99m-sulfur colloid (Tc(99m)SC) is associated with significant pain. Lidocaine use during SNL is not widely adopted partly due to a concern that it can obscure sentinel node identification and reduce its diagnostic accuracy. We prospectively identified women with a biopsy-proven infiltrating breast cancer who were awaiting a SNL. The women completed the McGill pain questionnaire, Visual Analog Scale, and Wong-Baker FACES Pain Rating Scale prior to and following SNL. We identified a retrospective cohort of women with similar demographic and tumor characteristics who did not receive lidocaine before SNL. We compared sentinel lymph node identification rates in the two cohorts. We used Wilcoxon rank sum tests to compare continuous measures and Fisher's exact test for categorical measures. Between January 2011 to July 2012, 110 women consented, and 105 were eligible for and received lidocaine prior to Tc(99m)SC injection. The post-lidocaine identification rate of SNL was 95 % with Tc(99m)SC, and 100 % with the addition of intraoperative methylene blue dye/saline. Pain range prior to and following the SNL was unchanged (P = 0.703). We identified 187 women from 2005 to 2009 who did not receive lidocaine during preoperative SNL. There was no significant difference in the success rate of SNL, with or without lidocaine (P = 0.194). The administration of lidocaine during SNL prevents pain related to isotope injection while maintaining the success rate. We have changed our practice at our center to incorporate the use of lidocaine during all SNL. PMID- 25788227 TI - Cancer risks in Jewish male BRCA1 and BRCA2 mutation carriers. AB - Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 (n = 150) or a BRCA2 (n = 88) mutation or both (n = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 +/- 4.1 years (1064 person/years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83-4.29)] and breast cancer [16.44 (95 % CI 9.65-26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4-0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure. PMID- 25788226 TI - Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells. AB - Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, occurs in younger women and is associated with poor prognosis. Gain-of-function mutations in TP53 are a frequent occurrence in TNBC and have been demonstrated to repress apoptosis and up-regulate cell cycle progression. Even though TNBC responds to initial chemotherapy, resistance to chemotherapy develops and is a major clinical problem. Tumor recurrence eventually occurs and most patients die from their disease. An urgent need exists to identify molecular-targeted therapies that can enhance chemotherapy response. In the present study, we report that targeting PELP1, an oncogenic co-regulator molecule, could enhance the chemotherapeutic response of TNBC through the inhibition of cell cycle progression and activation of apoptosis. We demonstrate that PELP1 interacts with MTp53, regulates its recruitment, and alters epigenetic marks at the target gene promoters. PELP1 knockdown reduced MTp53 target gene expression, resulting in decreased cell survival and increased apoptosis upon genotoxic stress. Mechanistic studies revealed that PELP1 depletion contributes to increased stability of E2F1, a transcription factor that regulates both cell cycle and apoptosis in a context-dependent manner. Further, PELP1 regulates E2F1 stability in a KDM1A-dependent manner, and PELP1 phosphorylation at the S1033 residue plays an important role in mediating its oncogenic functions in TNBC cells. Accordingly, depletion of PELP1 increased the expression of E2F1 target genes and reduced TNBC cell survival in response to genotoxic agents. PELP1 phosphorylation was significantly greater in the TNBC tumors than in the other subtypes of breast cancer and in the normal tissues. These findings suggest that PELP1 is an important molecular target in TNBC, and that PELP1-targeted therapies may enhance response to chemotherapies. PMID- 25788228 TI - Water proton NMR-a sensitive probe for solute association. AB - It is found that the transverse relaxation rate R2 of the water protons can be used to quantify protein aggregation and surfactant micellization in water. The simplicity and high intensity of the water proton signal enables non-invasive chemical analysis not readily achievable through solute proton signals, such as inspecting finished biologic products. PMID- 25788229 TI - Place fields and the cognitive map. AB - The discovery of place cells by John O'Keefe in the early 1970s was a breakthrough not just for systems neuroscience, but also for psychology: place fields provided a clear neural substrate for the notion of a cognitive map, a construct devised to explain rat learning and spatial cognition. However, is the robust location-related firing of place cells still best conceptualised as a cognitive map? In this commentary, we reassess this view of hippocampus function in light of subsequent findings on place cells. We argue that as place fields encode local space, and as they are modulated by ongoing behavior, the representation they provide may be more cognitive than map-like. PMID- 25788232 TI - The theory and practice of imaging outcomes research. PMID- 25788231 TI - 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. AB - BACKGROUND: Based on the early results of the Placement of Aortic Transcatheter Valves (PARTNER) trial, transcatheter aortic valve replacement (TAVR) is an accepted treatment for patients with severe aortic stenosis who are not suitable for surgery. However, little information is available about the late clinical outcomes in such patients. METHODS: We did this randomised controlled trial at 21 experienced valve centres in Canada, Germany, and the USA. We enrolled patients with severe symptomatic inoperable aortic stenosis and randomly assigned (1:1) them to transfemoral TAVR or to standard treatment, which often included balloon aortic valvuloplasty. Patients and their treating physicians were not masked to treatment allocation. The randomisation was done centrally, and sites learned of the assignment only after a patient had been screened, consented, and entered into the database. The primary outcome of the trial was all-cause mortality at 1 year in the intention-to-treat population, here we present the prespecified findings after 5 years. This study is registered with ClinicalTrials.gov, number NCT00530894. FINDINGS: We screened 3015 patients, of whom 358 were enrolled (mean age 83 years, Society of Thoracic Surgeons Predicted Risk of Mortality 11.7%, 54% female). 179 were assigned to TAVR treatment and 179 were assigned to standard treatment. 20 patients crossed over from the standard treatment group and ten withdrew from study, leaving only six patients at 5 years, of whom five had aortic valve replacement treatment outside of the study. The risk of all-cause mortality at 5 years was 71.8% in the TAVR group versus 93.6% in the standard treatment group (hazard ratio 0.50, 95% CI 0.39-0.65; p<0.0001). At 5 years, 42 (86%) of 49 survivors in the TAVR group had New York Heart Association class 1 or 2 symptoms compared with three (60%) of five in the standard treatment group. Echocardiography after TAVR showed durable haemodynamic benefit (aortic valve area 1.52 cm(2) at 5 years, mean gradient 10.6 mm Hg at 5 years), with no evidence of structural valve deterioration. INTERPRETATION: TAVR is more beneficial than standard treatment for treatment of inoperable aortic stenosis. TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement to improve their survival and functional status. Appropriate selection of patients will help to maximise the benefit of TAVR and reduce mortality from severe comorbidities. FUNDING: Edwards Lifesciences. PMID- 25788233 TI - PARTNERs in the future of surgical aortic valve replacement. PMID- 25788230 TI - CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. AB - BACKGROUND: The benefit of CT coronary angiography (CTCA) in patients presenting with stable chest pain has not been systematically studied. We aimed to assess the effect of CTCA on the diagnosis, management, and outcome of patients referred to the cardiology clinic with suspected angina due to coronary heart disease. METHODS: In this prospective open-label, parallel-group, multicentre trial, we recruited patients aged 18-75 years referred for the assessment of suspected angina due to coronary heart disease from 12 cardiology chest pain clinics across Scotland. We randomly assigned (1:1) participants to standard care plus CTCA or standard care alone. Randomisation was done with a web-based service to ensure allocation concealment. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6 weeks. All analyses were intention to treat, and patients were analysed in the group they were allocated to, irrespective of compliance with scanning. This study is registered with ClinicalTrials.gov, number NCT01149590. FINDINGS: Between Nov 18, 2010, and Sept 24, 2014, we randomly assigned 4146 (42%) of 9849 patients who had been referred for assessment of suspected angina due to coronary heart disease. 47% of participants had a baseline clinic diagnosis of coronary heart disease and 36% had angina due to coronary heart disease. At 6 weeks, CTCA reclassified the diagnosis of coronary heart disease in 558 (27%) patients and the diagnosis of angina due to coronary heart disease in 481 (23%) patients (standard care 22 [1%] and 23 [1%]; p<0.0001). Although both the certainty (relative risk [RR] 2.56, 95% CI 2.33-2.79; p<0.0001) and frequency of coronary heart disease increased (1.09, 1.02-1.17; p=0.0172), the certainty increased (1.79, 1.62-1.96; p<0.0001) and frequency seemed to decrease (0.93, 0.85-1.02; p=0.1289) for the diagnosis of angina due to coronary heart disease. This changed planned investigations (15% vs 1%; p<0.0001) and treatments (23% vs 5%; p<0.0001) but did not affect 6-week symptom severity or subsequent admittances to hospital for chest pain. After 1.7 years, CTCA was associated with a 38% reduction in fatal and non-fatal myocardial infarction (26 vs 42, HR 0.62, 95% CI 0.38-1.01; p=0.0527), but this was not significant. INTERPRETATION: In patients with suspected angina due to coronary heart disease, CTCA clarifies the diagnosis, enables targeting of interventions, and might reduce the future risk of myocardial infarction. FUNDING: The Chief Scientist Office of the Scottish Government Health and Social Care Directorates funded the trial with supplementary awards from Edinburgh and Lothian's Health Foundation Trust and the Heart Diseases Research Fund. PMID- 25788235 TI - In vivo imaging of the cannabinoid CB1 receptor with positron emission tomography. AB - Positron emission tomography (PET) can visualize and quantify receptors and other targets in the living human brain, and recent progress in radioligand development has enabled measurement of cannabinoid type-1 (CB1 ) receptors. Cannabinoid CB1 receptors have been implicated in multiple human diseases, such as obesity, mood disorders, and addiction. First in vivo human studies have shown distinctive spatial and temporal alterations in cannabinoid CB1 receptor binding in addictive disorders. PMID- 25788234 TI - 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. AB - BACKGROUND: The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that mortality at 1 year, 2 years, and 3 years is much the same with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) for high-risk patients with aortic stenosis. We report here the 5-year outcomes. METHODS: We did this randomised controlled trial at 25 hospitals, in Canada (two), Germany (one), and the USA (23). We used a computer generated randomisation sequence to randomly assign high-risk patients with severe aortic stenosis to either SAVR or TAVR with a balloon-expandable bovine pericardial tissue valve by either a transfemoral or transapical approach. Patients and their treating physicians were not masked to treatment allocation. The primary outcome of the trial was all-cause mortality in the intention-to treat population at 1 year, we present here predefined outcomes at 5 years. The study is registered with ClinicalTrials.gov, number NCT00530894. FINDINGS: We screened 3105 patients, of whom 699 were enrolled (348 assigned to TAVR, 351 assigned to SAVR). Overall mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 11.7%. At 5 years, risk of death was 67.8% in the TAVR group compared with 62.4% in the SAVR group (hazard ratio 1.04, 95% CI 0.86-1.24; p=0.76). We recorded no structural valve deterioration requiring surgical valve replacement in either group. Moderate or severe aortic regurgitation occurred in 40 (14%) of 280 patients in the TAVR group and two (1%) of 228 in the SAVR group (p<0.0001), and was associated with increased 5-year risk of mortality in the TAVR group (72.4% for moderate or severe aortic regurgitation vs 56.6% for those with mild aortic regurgitation or less; p=0.003). INTERPRETATION: Our findings show that TAVR as an alternative to surgery for patients with high surgical risk results in similar clinical outcomes. FUNDING: Edwards Lifesciences. PMID- 25788236 TI - Global patterns and predictors of fish species richness in estuaries. AB - 1. Knowledge of global patterns of biodiversity and regulating variables is indispensable to develop predictive models. 2. The present study used predictive modelling approaches to investigate hypotheses that explain the variation in fish species richness between estuaries over a worldwide spatial extent. Ultimately, such models will allow assessment of future changes in ecosystem structure and function as a result of environmental changes. 3. A comprehensive worldwide data base was compiled of the fish assemblage composition and environmental characteristics of estuaries. Generalized Linear Models were used to quantify how variation in species richness among estuaries is related to historical events, energy dynamics and ecosystem characteristics, while controlling for sampling effects. 4. At the global extent, species richness differed among marine biogeographic realms and continents and increased with mean sea surface temperature, terrestrial net primary productivity and the stability of connectivity with a marine ecosystem (open vs. temporarily open estuaries). At a smaller extent (within a marine biogeographic realm or continent), other characteristics were also important in predicting variation in species richness, with species richness increasing with estuary area and continental shelf width. 5. The results suggest that species richness in an estuary is defined by predictors that are spatially hierarchical. Over the largest spatial extents, species richness is influenced by the broader distributions and habitat use patterns of marine and freshwater species that can colonize estuaries, which are in turn governed by history contingency, energy dynamics and productivity variables. Species richness is also influenced by more regional and local parameters that can further affect the process of community colonization in an estuary including the connectivity of the estuary with the adjacent marine habitat, and, over smaller spatial extents, the size of these habitats. In summary, patterns of species richness in estuaries across large spatial extents seem to reflect from global to local processes acting on community colonization. The importance of considering spatial extent, sampling effects and of combining history and contemporary environmental characteristics when exploring biodiversity is highlighted. PMID- 25788237 TI - Emotions, affects and the production of social life. AB - While many aspects of social life possess an emotional component, sociology needs to explore explicitly the part emotions play in producing the social world and human history. This paper turns away from individualistic and anthropocentric emphases upon the experience of feelings and emotions, attending instead to an exploration of flows of 'affect' (meaning simply a capacity to affect or be affected) between bodies, things, social institutions and abstractions. It establishes a materialist sociology of affects that acknowledges emotions as a part, but only a part, of a more generalized affective flow that produces bodies and the social world. From this perspective, emotions are not a peculiarly remarkable outcome of the confluence of biology and culture, but part of a continuum of affectivity that links human bodies to their physical and social environment. This enhances sociological understanding of the part emotions play in shaping actions and capacities in many settings of sociological concern. PMID- 25788238 TI - Advances in vaginal drug delivery. PMID- 25788239 TI - Intravaginal rings: controlled release systems for contraception and prevention of transmission of sexually transmitted infections. AB - Intravaginal rings (IVRs) are a dosage form used to locally or systemically deliver drugs in the vagina. They are capable of releasing one or more drugs over an extended period of time (from several weeks to a year or longer). Contraceptive IVRs are currently gaining popularity due to the success of the contraceptive product NuvaRing(r). Delivery of contraceptives from IVRs should promote compliance/adherence, and they also provide effective cycle control and symptom relief (menorrhagia, dysmenorrheal, and polycystic ovarian syndrome). Vaginal delivery of proteins from IVRs was first explored in an attempt to deliver IgG2a antibody intravaginally to neutralize herpes simplex virus 2. More recently, IVRs capable of releasing antibodies and recombinant proteins potentially along with low molecular weight microbicides are under investigation for prevention of HIV-1 transmission. Vaginal delivery of microbicides has been studied with several drugs most notably the non-nucleoside reverse transcriptase inhibitor dapivirine. Another drug capable of blocking transmission of HIV-1 when released from IVRs is tenofovir. Finally, combinations of drugs with different indications (i.e., multipurpose prevention technologies) are actively being pursued. PMID- 25788240 TI - Treatment of blood flow abnormality using mucosal delivery of nitric oxide. AB - This review focuses on clinical application of intravaginal formulations containing nitric oxide (NO). Poly(D,L-lactic acid-co-glycolic acid)-based microparticles or nanoparticles encapsulated with nitric oxide prodrugs, such as diethylenetriamine diazeniumdiolate and S-nitrosoglutathione, have been developed for the treatment of blood flow abnormality in various diseases including diabetes. Advanced nanotechnology allows for production of novel formulations with the capability of long-term protection, preserving the integrity of the NO donors, and delivering NO in a controlled and sustained release manner at the mucosal sites. The gene expressions of MAPK and PKC in the vaginal mucosa upon exposure to microparticles were evaluated for the mechanistic study involved with blood flow changes. The blood flow changes and protein expression of the vaginal mucosa upon exposure to intravaginal formulations containing NO donors supported that NO therapy would be suitable for the treatment of blood flow abnormality. This review subsequently would help to establish a scientific foundation for clinical trials of intravaginal NO delivery systems in humans. PMID- 25788241 TI - Engineering a degradable polyurethane intravaginal ring for sustained delivery of dapivirine. AB - We describe the engineering of a degradable intravaginal ring (IVR) for the delivery of the potent HIV-1 reverse transcriptase inhibitor dapivirine. The degradable polymer used in fabricating the device incorporated poly(caprolactone) ester blocks in a poly(tetramethylene ether) glycol ABA type polyurethane backbone. The polymer was designed to maintain its structure for 1 month during usage and then degrade in the environment post-disposal. In vitro release of dapivirine showed zero-order kinetics for up to 1 month and significant levels of drug release into engineered vaginal tissue. The mechanical properties of the degradable IVR were comparable to those of a widely used contraceptive intravaginal ring upon exposure to simulated vaginal conditions. Incubation under simulated vaginal conditions for a month caused minimal degradation with minimal effect on the mechanical properties of the ring and polymer. The cytotoxicity evaluation of the drug-loaded IVRs against Vk2/E6E7 human vaginal epithelial cells, Lactobacillus jensenii, and engineered vaginal tissue constructs showed the degradable polyurethane to be non-toxic. In vitro evaluation of inflammatory potential monitored through the levels of inflammatory cytokines IL-8, IL-1alpha, IL-6, IL-1beta, and MIP-3alpha when engineered EpiVaginalTM tissue was incubated with the polyurethanes suggested that the degradable polyurethane was comparable to commercial medical grade polyurethane. These results are encouraging for further development of this degradable IVR for topical vaginal delivery of microbicides. PMID- 25788242 TI - Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices. AB - UC781 is a potent and poorly water-soluble nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide for preventing sexual transmission of HIV-1. This study was designed to evaluate the in vivo release and pharmacokinetics of UC781 delivered from matrix-type intravaginal ring segments in rabbits. Three polymer matrices (polyurethane, ethylene vinyl acetate copolymer, and silicone elastomer) and two drug loadings (5 and 15 mg/segment) were evaluated in at least one of two independent studies for up to 28 days in vivo. Inter-study comparison of in vivo release, vaginal tissue, and plasma concentrations for similar formulations demonstrated good reproducibility of the animal model. Mean estimates for a 28-day in vivo release ranged from 0.35 to 3.17 mg UC781 per segment. Mean proximal vaginal tissue levels (adjacent to the IVR segment) were 8-410 ng/g and did not change significantly with time for most formulations. Distal vaginal tissue levels of UC781 were 6- to 49-fold lower than proximal tissue levels. Mean UC781 plasma levels were low for all formulations, at 0.09-0.58 ng/mL. All formulations resulted in similar UC781 concentrations in vaginal tissue and plasma, except the low loading polyurethane group which provided significantly lower levels. Loading dependent release and pharmacokinetics were only clearly observed for the polyurethane matrix. Based on these results, intravaginal ring segments loaded with UC781 led to vaginal tissue concentrations ranging from below to approximately two orders of magnitude higher than UC781's EC50 under in vitro conditions (2.8 ng/mL), with little influence by polymer matrix or UC781 loading. Moreover, these findings support the use of rabbit vaginal pharmacokinetic studies in preclinical testing of microbicide intravaginal rings. PMID- 25788243 TI - Ethylene vinyl acetate intravaginal rings for the simultaneous delivery of the antiretroviral UC781 and contraceptive levonorgestrel. AB - Ethylene vinyl acetate intravaginal rings (IVRs) were prepared by hot-melt compounding and injection moulding. The IVRs contained various levels of the antiretroviral drug UC781 and the contraceptive hormone levonorgestrel. The IVRs were assayed for drug content and related substances, characterized for physical properties, in vitro drug-elution kinetics, photostress stability, and 3-month accelerated storage stability under ICH conditions. UC781 degrades on exposure to light and during thermal processing. UC22 is the major degradant of UC781. Drug release rates were proportional to drug loading, independent of the other drug in combination with IVRs, and were stable for 3 M at 40 degrees C/75% RH despite changes in the appearance of the IVRs which is tentatively ascribed to crystallization of UC781 at or near the surface of the IVRs. The behavior of UC781 poses a substantial barrier to the commercial development of these IVRs. PMID- 25788244 TI - Characterization of coal tattoos by Raman spectroscopy. PMID- 25788245 TI - The First Step is the Hardest: Overcoming Barriers to Primary Care. PMID- 25788246 TI - Outcome of a grocery voucher incentive scheme for low-income tuberculosis patients on directly observed therapy in Singapore. AB - INTRODUCTION: The 'DOT & Shop' scheme is sponsored by SATA CommHealth, a local non-governmental organisation. It was launched in July 2009, in collaboration with Singapore's Tuberculosis Control Unit (TBCU). Under this scheme, grocery vouchers are disbursed to low-income patients with tuberculosis (TB) at each clinic visit if they have been adherent to directly observed therapy (DOT). This study aimed to determine the effect of this incentive scheme on treatment completion rates and to report the characteristics of patients who were non adherent to the scheme. METHODS: This descriptive study used data from the TBCU medical social worker database and the National TB Registry. RESULTS: From July 2009 to December 2012, a total of 883 TB patients were enrolled in the scheme. The overall treatment completion rates of the patients before (July 2006-June 2009) and after (July 2009-December 2012) the implementation of the scheme improved from 85.3% to 87.2% (p = 0.02). Patients under this scheme had a higher treatment completion rate (90.0%) than those not under this scheme (86.4%) (p < 0.01). It was found that the non-adherent patients were more likely to be of Malay ethnicity, younger and unemployed. CONCLUSION: We demonstrate the salutary effect of a non-governmental organisation-funded grocery voucher incentive scheme for low-income TB patients on DOT in Singapore. PMID- 25788247 TI - Development of 10 microsatellite markers from Pantala flavescens and their applicability in studying genetics diversity. AB - Pantala flavescens (Fabricius 1798) is one of the most common species among migration dragonflies. It is often encountered in large swarms during migration or directed dispersal flights. For a better understanding of its gene flow, genetic structure and migration patterns throughout the world, 10 polymorphic microsatellite markers were isolated in this study. We respectively collected 32 P. flavescens from three places (Hunan, Liaoning and Heilongjiang) and 20 P. flavescens from Beijing. Partial genomic libraries containing microsatellite sequences were constructed with magnetic-bead enrichment method. By screening, sequence analysis, PCR amplification and so on, ten 10 polymorphic microsatellite markers were isolated. In order to assess their applicability, genetic diversity of these novel markers was tested in 96 individuals from three populations in China (Hunan, Liaoning and Heilongjiang). These markers were highly polymorphic, with 3-12 alleles per markers. The observed (Ho) and expected (He) heterozygosities ranged 0.321-0.667 and from 0.531 to 0.948 respectively. The genetic difference between Hunan and Liaoning is 0.429, while the genetic difference between Liaoning and Heilongjiang is 0.0508. These microsatellite markers for P. flavescens were developed for the first time, and will be a powerful tool for studying population genetic diversity and dispersal behavior of P. flavescens in China and worldwide. PMID- 25788248 TI - Single cell visualization of transcription kinetics variance of highly mobile identical genes using 3D nanoimaging. AB - Multi-cell biochemical assays and single cell fluorescence measurements revealed that the elongation rate of Polymerase II (PolII) in eukaryotes varies largely across different cell types and genes. However, there is not yet a consensus whether intrinsic factors such as the position, local mobility or the engagement by an active molecular mechanism of a genetic locus could be the determinants of the observed heterogeneity. Here by employing high-speed 3D fluorescence nanoimaging techniques we resolve and track at the single cell level multiple, distinct regions of mRNA synthesis within the model system of a large transgene array. We demonstrate that these regions are active transcription sites that release mRNA molecules in the nucleoplasm. Using fluctuation spectroscopy and the phasor analysis approach we were able to extract the local PolII elongation rate at each site as a function of time. We measured a four-fold variation in the average elongation between identical copies of the same gene measured simultaneously within the same cell, demonstrating a correlation between local transcription kinetics and the movement of the transcription site. Together these observations demonstrate that local factors, such as chromatin local mobility and the microenvironment of the transcription site, are an important source of transcription kinetics variability. PMID- 25788249 TI - Factors associated with delays in head and neck cancer treatment: case-control study. AB - BACKGROUND: Delays in head and neck cancer treatment lead to increased mortality, more extensive treatment and patient anxiety. We aim to treat all patients with cancer within 62 days of receipt of a referral. An analysis was conducted of those patients whose treatment had been delayed in order to identify factors associated with treatment delay. METHODS: In this retrospective case-control study, 50 patients whose treatment was delayed were identified and compared with 50 patients whose treatment was not delayed. Individual factors assessed included patient age, co-morbidity, tumour location and stage, the treatment agreed, the hospitals to which the patients were referred, and the clinicians they saw. RESULTS: There was a significant association between referral to a non-head and neck cancer centre, or review by a non-head and neck multidisciplinary team member, and treatment delay. CONCLUSION: In the context of centralisation of head and neck cancer services, it is important to consider delays that may be associated with a 'hub and spoke' model of service provision. PMID- 25788250 TI - An anisotropic coarse-grained model based on Gay-Berne and electric multipole potentials and its application to simulate a DMPC bilayer in an implicit solvent model. AB - In this work, we aim at optimizing the performance of the anisotropic GBEMP model, which adopts a framework by combining a Gay-Berne (GB) anisotropic potential with an electric multipole (EMP) potential, in simulating a DMPC lipid bilayer in an implicit solvent model. First, the Gay-Berne parameters were initially obtained by fitting to atomistic profiles of van der Waals interactions between homodimers of molecular fragments while EMP parameters was directly derived from the expansion of point multipoles at predefined EMP sites. Second, the GB and EMP parameters for DMPC molecule were carefully optimized to be comparable to AMBER atomistic model in the calculations of the dipole moments of DMPC monomers adopting different conformations as well as the nonbonded interactions between two DMPC molecules adopting different conformations and separated at various distances. Finally, the GB parameters for DMPC were slightly adjusted in simulating a 72 DMPC bilayer system so that our GBEMP model would be able to reproduce a few important structural properties, namely, thickness (DHH), area per lipid ( AL) and volume per lipid ( VL). Meanwhile, the atomistic and experimental results for electron density profiles and order parameters were reproduced reasonably well by the GBEMP model, demonstrating the promising feature of GBEMP model in modeling lipid systems. Finally, we have shown that current GBEMP model is more efficient by a factor of about 25 than AMBER atomistic point charge model. PMID- 25788251 TI - Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014. AB - Enterovirus D68 (EV-D68), phylogenetic clade B was identified in nasopharyngeal specimens of two cases of severe acute flaccid myelitis. The cases were six and five years-old and occurred in September and November 2014. EV-D68 is increasingly associated with acute flaccid myelitis in children, most cases being reported in the United States. Awareness of this possible neurological complication of enterovirus D68 infection is needed. PMID- 25788252 TI - Self-sampling for community respiratory illness: a new tool for national virological surveillance. AB - This report aims to evaluate the usefulness of self-sampling as an approach for future national surveillance of emerging respiratory infections by comparing virological data from two parallel surveillance schemes in England. Nasal swabs were obtained via self-administered sampling from consenting adults (>= 16 years old) with influenza symptoms who had contacted the National Pandemic Flu Service (NPFS) health line during the 2009 influenza pandemic. Equivalent samples submitted by sentinel general practitioners participating in the national influenza surveillance scheme run jointly by the Royal College of General Practitioners (RCGP) and Health Protection Agency were also obtained. When comparable samples were analysed there was no significant difference in results obtained from self-sampling and clinician-led sampling schemes. These results demonstrate that self-sampling can be applied in a responsive and flexible manner, to supplement sentinel clinician-based sampling, to achieve a wide spread and geographically representative way of assessing community transmission of a known organism. PMID- 25788253 TI - Household transmissibility of avian influenza A (H7N9) virus, China, February to May 2013 and October 2013 to March 2014. AB - To study human-to-human transmissibility of the avian influenza A (H7N9) virus in China, household contact information was collected for 125 index cases during the spring wave (February to May 2013), and for 187 index cases during the winter wave (October 2013 to March 2014). Using a statistical model, we found evidence for human-to-human transmission, but such transmission is not sustainable. Under plausible assumptions about the natural history of disease and the relative transmission frequencies in settings other than household, we estimate the household secondary attack rate (SAR) among humans to be 1.4% (95% CI: 0.8 to 2.3), and the basic reproductive number R0 to be 0.08 (95% CI: 0.05 to 0.13). The estimates range from 1.3% to 2.2% for SAR and from 0.07 to 0.12 for R0 with reasonable changes in the assumptions. There was no significant change in the human-to-human transmissibility of the virus between the two waves, although a minor increase was observed in the winter wave. No sex or age difference in the risk of infection from a human source was found. Human-to-human transmissibility of H7N9 continues to be limited, but it needs to be closely monitored for potential increase via genetic reassortment or mutation. PMID- 25788254 TI - Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012. AB - We describe an Australia-wide Clostridium difficile outbreak in 2011 and 2012 involving the previously uncommon ribotype 244. In Western Australia, 14 of 25 cases were community-associated, 11 were detected in patients younger than 65 years, 14 presented to emergency/outpatient departments, and 14 to non tertiary/community hospitals. Using whole genome sequencing, we confirm ribotype 244 is from the same C. difficile clade as the epidemic ribotype 027. Like ribotype 027, it produces toxins A, B, and binary toxin, however it is fluoroquinolone-susceptible and thousands of single nucleotide variants distinct from ribotype 027. Fifteen outbreak isolates from across Australia were sequenced. Despite their geographic separation, all were genetically highly related without evidence of geographic clustering, consistent with a point source, for example affecting the national food chain. Comparison with reference laboratory strains revealed the outbreak clone shared a common ancestor with isolates from the United States and United Kingdom (UK). A strain obtained in the UK was phylogenetically related to our outbreak. Follow-up of that case revealed the patient had recently returned from Australia. Our data demonstrate new C. difficile strains are an on-going threat, with potential for rapid spread. Active surveillance is needed to identify and control emerging lineages. PMID- 25788255 TI - Impact of 10- and 13-valent pneumococcal conjugate vaccines on incidence of invasive pneumococcal disease in children aged under 16 years in Germany, 2009 to 2012. AB - We assessed the impact of 10-valent and 13-valent pneumococcal vaccines (PCV10 and PCV13), which were introduced in Germany in 2009, on the incidence of meningitis and non-meningitis invasive pneumococcal disease (IPD) in children aged under 16 years in a population previously vaccinated with a seven-valent vaccine (PCV7). Surveillance of IPD (isolation of Streptococcus pneumonia from a normally sterile body site) is based on data from two independent reporting sources: hospitals and laboratories. IPD incidence was estimated by capture recapture analysis. Incidence rate ratios (IRRs) were calculated for 2009 and 2012, thus comparing pre- and post-PCV10 and PCV13 data. IPD incidence caused by serotypes included in PCV13 decreased in all age and diagnosis groups. A rise in non-vaccine serotype incidence was seen only in children aged under two years. The overall impact varied by age group and infection site: for meningitis IPD in children aged under 2, 2-4 and 5-15 years, incidence changed by 3% (95% CI: -31 to 52), -60% (95% CI: -81 to -17) and -9% (95% CI: -46 to 53), respectively. A more pronounced incidence reduction was observed for non-meningitis IPD: -30% (95% CI: -46 to -7), -39% (95% CI: -54 to -20) and -83% (95% CI: -89 to -73) in children aged under 2, 2-4 and 5-15 years, respectively. A higher tropism of the additional serotypes for non-meningitis IPD may be a potential explanation. The heterogeneous findings emphasise the need for rigorous surveillance PMID- 25788256 TI - WHO publishes first guidelines for hepatitis B treatment. PMID- 25788258 TI - Designing a CTSA-Based Social Network Intervention to Foster Cross-Disciplinary Team Science. AB - This paper explores the application of network intervention strategies to the problem of assembling cross-disciplinary scientific teams in academic institutions. In a project supported by the University of Florida (UF) Clinical and Translational Science Institute, we used VIVO, a semantic-web research networking system, to extract the social network of scientific collaborations on publications and awarded grants across all UF colleges and departments. Drawing on the notion of network interventions, we designed an alteration program to add specific edges to the collaboration network, that is, to create specific collaborations between previously unconnected investigators. The missing collaborative links were identified by a number of network criteria to enhance desirable structural properties of individual positions or the network as a whole. We subsequently implemented an online survey (N = 103) that introduced the potential collaborators to each other through their VIVO profiles, and investigated their attitudes toward starting a project together. We discuss the design of the intervention program, the network criteria adopted, and preliminary survey results. The results provide insight into the feasibility of intervention programs on scientific collaboration networks, as well as suggestions on the implementation of such programs to assemble cross-disciplinary scientific teams in CTSA institutions. PMID- 25788259 TI - A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties. AB - The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft model by both inducing tumour cell apoptosis and inhibiting tumour angiogenesis. Thus, this selective ATP competitive SK inhibitor provides a promising candidate for potential development as an anti-cancer therapy, and also, due to its different mode of inhibition to other known SK inhibitors, both validates the SKs as targets for anti-cancer therapy, and represents an important experimental tool to study these enzymes. PMID- 25788260 TI - Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. AB - INTRODUCTION: To explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT). PATIENTS AND METHODS: Enrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS. RESULTS: Fifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 +/- 0.72%) at 30 Gy, which was significantly higher than that 1.34 +/- 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively. CONCLUSION: The BBB permeability of gefitinib increased in accordance with escalated dose of WBRT. PMID- 25788261 TI - Stratifying risk of recurrence in stage II colorectal cancer using deregulated stromal and epithelial microRNAs. AB - MicroRNAs (miRNAs) enable colonic epithelial cells to acquire malignant characteristics and metastatic capabilities. Recently, cancer relevant miRNAs deregulated during disease progression have also been identified in tumor associated stroma.By combining laser-microdissection (LMD) with high-throughput screening and high-sensitivity quantitation techniques, miRNA expression in colorectal cancer (CRC) specimens and paired normal colonic tissue was independently characterized in stromal and epithelial tissue compartments. Notably, deregulation of the key oncogene miR-21 was identified exclusively as a stromal phenomenon and miR-106a, an epithelial phenomenon in the malignant state.MiRNAs identified in this study successfully distinguished CRC from normal tissue and metastatic from non-metastatic tumor specimens. Furthermore, in a separate cohort of 50 consecutive patients with CRC, stromal miR-21 and miR-556 and epithelial miR-106a expression predicted short disease free survival (DFS) and overall survival (OS) in stage II disease: miR-21 (DFS: HR = 2.68, p = 0.015; OS: HR = 2.47, p = 0.029); miR-556 (DFS: HR = 2.60, p = 0.018); miR-106a (DFS: HR = 2.91, p = 0.008; OS: HR = 2.25, p = 0.049); combined (All High vs. All Low. DFS: HR = 5.83, p = 0.002; OS: HR = 4.13, p = 0.007).These data support the notion that stromal as well as epithelial miRNAs play important roles during disease progression, and that mapping patterns of deregulated gene expression to the appropriate tumor strata may be a valuable aid to therapeutic decision making in CRC. PMID- 25788263 TI - Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers. AB - The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers. PMID- 25788262 TI - Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1. AB - Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1-3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU 145, 22Rv1, and C4-2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAPE treatment significantly reduced protein abundance of Skp2, Cdk2, Cdk4, Cdk7, Rb, phospho-Rb S807/811, cyclin A, cyclin D1, cyclin H, E2F1, c Myc, SGK, phospho-p70S6kinase T421/S424, phospho-mTOR Ser2481, phospho-GSK3alpha Ser21, but induced p21Cip1, p27Kip1, ATF4, cyclin E, p53, TRIB3, phospho-p53 (Ser6, Ser33, Ser46, Ser392), phospho-p38 MAPK Thr180/Tyr182, Chk1, Chk2, phospho ATM S1981, phospho-ATR S428, and phospho-p90RSK Ser380. CAPE treatment decreased Skp2 and Akt1 protein expression in LNCaP 104-R1 tumors as compared to control group. Overexpression of Skp2, or siRNA knockdown of p21Cip1, p27Kip1, or p53 blocked suppressive effect of CAPE treatment. Co-treatment of CAPE with PI3K inhibitor LY294002 or Bcl-2 inhibitor ABT737 showed synergistic suppressive effects. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21Cip1, and p27Kip1. PMID- 25788264 TI - Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder in which chemotherapy resistance and refractory relapses occur, with a poorer prognostic outcome.Constitutively active PI3K/Akt/mTOR pathway is a common feature of T-ALL upregulating cell proliferation, survival and drug resistance. This pathway is currently under clinical trials with small molecules inhibitors (SMI).To verify whether a multi-inhibition treatment against Akt protein could enhance the efficacy of individual drug administration and overcome drug resistance as well as to obtain a decrease in single drug concentration, we tested on T-ALL cell lines the effects of combined treatments with three Akt inhibitors with different mode of action, GSK690693, MK-2206 and Perifosine.In cells with hyperactivated Akt, combined administration of the drugs displayed a significant synergistic and cytotoxic effect and affected PI3K/Akt/mTOR pathway at much lower concentration than single drug use. Highest synergistic effect for full inhibition of Akt was also related to the timing of every drug administration. Furthermore the triple treatment had greater efficacy in inducing cell cycle arrest in G0/G1 phase and both apoptosis and autophagy.Targeting Akt as a key protein of PI3K/Akt/mTOR pathway with multiple drugs might represent a new and promising pharmacological strategy for treatment of T-ALL patients. PMID- 25788265 TI - Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma. AB - Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389-2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214-2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim. PMID- 25788266 TI - H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription. AB - Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERalpha binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERalpha-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERalpha-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers. PMID- 25788267 TI - Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS 3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel. AB - Persistent phosphorylation of signal transducers and activators of transcription 3 (STAT3) is frequently observed in tumor cells. We found that brassinin (BSN) suppressed both constitutive and IL-6-inducible STAT3 activation in lung cancer cells. Moreover, BSN induced PIAS-3 protein and mRNA, whereas the expression of SOCS-3 was reduced. Knockdown of PIAS-3 by small interfering RNA prevented inhibition of STAT3 and cytotoxicity by BSN. Overexpression of SOCS-3 in BSN treated cells increased STAT3 phosphorylation and cell viability. BSN down regulated STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced apoptosis. Most importantly, when administered intraperitoneally, combination of BSN and paclitaxel significantly decreased the tumor development in a xenograft lung cancer mouse model associated with down-modulation of phospho STAT3, Ki-67 and CD31. We suggest that BSN inhibits STAT3 signaling through modulation of PIAS-3 and SOCS-3, thereby attenuating tumor growth and increasing sensitivity to paclitaxel. PMID- 25788268 TI - Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP. AB - Hepatocellular carcinomas (HCC) are highly malignant and aggressive tumors lack of effective therapeutic drugs. Piperlongumine (PL), a natural product isolated from longer pepper plants, is recently identified as a potent cytotoxic compound highly selective to cancer cells. Here, we reported that PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway. PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 uM while PL at much lower concentrations only suppressed HCC cell migration/invasion. PL selectively elevated reactive oxygen species (ROS) in HCC cells, which activated or up-regulated downstream PERK/Ire 1alpha/Grp78, p38/JNK/Erk and CHOP subsequently. Administration of antioxidants completely abolished PL's effects on cell death and migration/invasion. However, pharmacological inhibition of ER stress-responses or MAPKs signaling pathways with corresponding specific inhibitors only reversed PL's effect on cell migration/invasion but not on cell death. Consistently, knocking-down of CHOP by RNA interference only reversed PL-suppressed HCC cell migration. Finally, PL significantly suppressed HCC development and activated the ER-MAPKs-CHOP signaling pathway in HCC xenografts in vivo. Taken together, PL selectively killed HCC cells and preferentially inhibited HCC cell migration/invasion via ROS ER-MAPKs-CHOP axis, suggesting a novel therapeutic strategy for the highly malignant and aggressive HCC clinically. PMID- 25788269 TI - Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B cell lymphomas and propels malignant B-cell growth. AB - Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of alpha catalytic and beta regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2 inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2alpha immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-kappaB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL. PMID- 25788270 TI - Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation. AB - Granzyme M is a serine protease known to be often expressed by natural killer cells and induce target cells apoptosis in combination with perforin. However, we detected granzyme M expression in murine and human cancer cell lines and human tumor samples in our study. Granzyme M increased chemoresistance, colony formation, cytokine secretion and invasiveness in vitro. Most importantly, granzyme M facilitated tumor growth and metastasis in vivo. Granzyme M induced the epithelial-mesenchymal transition (EMT) in cancer cells associated with STAT3 activation. Our study revealed the role of granzyme M expressed by tumor in chemoresistance, invasion, metastasis and EMT. PMID- 25788271 TI - CD133+ ovarian cancer stem-like cells promote non-stem cancer cell metastasis via CCL5 induced epithelial-mesenchymal transition. AB - Cancer stem cells (CSCs, also called cancer stem-like cells, CSLCs) can function as "seed cells" for tumor recurrence and metastasis. Here, we report that, in the presence of CD133+ ovarian CSLCs, CD133- non-CSLCs can undergo an epithelial mesenchymal transition (EMT)-like process and display enhanced metastatic capacity in vitro and in vivo. Highly elevated expression of chemokine (C-C motif) ligand 5 (CCL5) and its receptors chemokine (C-C motif) receptor (CCR) 1/3/5 are observed in clinical and murine metastatic tumor tissues from epithelial ovarian carcinomas. Mechanistically, paracrine CCL5 from ovarian CSLCs activates the NF-kappaB signaling pathway in ovarian non-CSLCs via binding CCR1/3/5, thereby inducing EMT and tumor invasion. Taken together, our results redefine the metastatic potential of non-stem cancer cells and provide evidence that targeting the CCL5:CCR1/3/5-NF-kappaB pathway could be an effective strategy to prevent ovarian cancer metastasis. PMID- 25788272 TI - DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling. AB - Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival. PMID- 25788273 TI - Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer. AB - Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/beta-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/beta-catenin signaling that also has undefined beta-catenin independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer. PMID- 25788274 TI - Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen. AB - Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization. PMID- 25788275 TI - MAP17 (PDZKIP1) as a novel prognostic biomarker for laryngeal cancer. AB - Larynx cancer organ preservation treatments with chemo and radiotherapy have substantially improved laryngoesophageal dysfunction-free survival. However, both of them lead to a high incidence of acute and chronic toxicities and a significant number of patients relapse. To date, there is no evidence available to establish the group of patients that may benefit from preservation approaches and clinical criteria such as primary tumor extension or pretreatment tracheotomy are not validated. MAP17 is a small non-glycosylated membrane protein overexpressed in carcinomas. The tumoral behavior induced by MAP17 is associated with reactive oxygen species production in which SGLT1 seems involved. In this study we found that the levels of MAP17 were related to clinical findings and survival in a cohort of 58 patients with larynx cancer. MAP17 expression is associated with overall survival (p<0.001) and laryngoesophageal dysfunction-free survival (p=0.002). Locoregional control in patients with high MAP17 showed better outcomes than those with low MAP17 (p=0.016). Besides, a positive correlation was observed between MAP17 expression and SGLT (p=0.022) and the combination of high levels of MAP17/SGLT also led to an increased overall survival (p=0,028). These findings suggest that MAP17, alone or in combination with SGLT1, may become a novel predictive biomarker for laryngeal carcinoma. PMID- 25788276 TI - The anti-tumor effect is enhanced by simultaneously targeting VEGF and PROK1 in colorectal cancer. AB - Hematogenous metastasis, mainly hepatic metastasis, is a frequent metastatic mode in colorectal cancer involving angiogenic growth factors. Two angiogenic growth factors, in particular, Vascular endothelial growth factor (VEGF) and Prokineticin1(PROK1), are considered to have an important role in hematogenous metastasis of colorectal cancer. Accordingly, we report our findings on the importance of the anti-tumor efffect by inhibiting these two factors in human colorectal cancer.When the culture fluid of Colorectal cancer cell lines(DLD-1, HCT116, and LoVo) with high levels of VEGF/PROK1 expression was injected subcutaneously into mice, the culture fluid increased subcutaneous angiogenesis. But when both anti-PROK1 and anti-VEGF antibodies were present in the culture fluid, the length and size of the blood vessels were reduced compared with those seen in the fluid-only, anti-PROK1, and anti-VEGF controls. Also, tumor masses were produced in mice by subcutaneously embedding colorectal cancer cells with high levels VEGF/PROK1 expression. When both anti-PROK1 and anti-VEGF antibodies were simultaneously applied, tumor formation and peritumoral angiogenesis were strongly suppressed, compared with when either anti-PROK1 antibody or anti-VEGF antibody was applied alone.Simultaneous targeting of both angiogenic growth factors (VEGF/PROK1) may prove more useful in colorectal cancer. PMID- 25788278 TI - Nano/bio interface:impact on drug delivery applications. PMID- 25788279 TI - Nanoscience and nanotechnology in the twenty-first century. PMID- 25788277 TI - HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients. AB - Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID- 25788280 TI - Contributory roles of innate properties of cetyl alcohol/gelucire nanoparticles to antioxidant and anti-inflammation activities of quercetin. AB - The protective effects of synthetic lung surfactant Exosurf(r) (containing cetyl alcohol) against endotoxin-induced inflammation have been demonstrated in the literature. Thus, it is envisioned that nanoparticles loaded with quercetin (Q NPs) prepared with binary mixtures of cetyl alcohol (CA) and Gelucire 44/14(r) (gelucire) as matrix materials will be capable of overcoming some of the protracted challenges confronting clinical application of quercetin and possess innate protective activity against inflammatory responses, which could be synergistic with quercetin. The NPs were stable in simulated biological media while retaining their particle size and spherical morphology. Further analysis by gel permeation chromatography, spectroscopic analysis (ultraviolet-visible, fluorescence, and Fourier transform infrared spectroscopy) indicated entrapment of quercetin in NPs. Q-NPs effectively enhanced xanthine oxidase inhibitory and free radical scavenging effect of quercetin. Furthermore, Q-NPs showed marked reduction (compared to quercetin alone) in production of nitric oxide and cytokine (interleukin-6 and tumor necrosis factor alpha) from lipopolysaccharide activated macrophages. Superiority of Q-NPs over quercetin alone was confirmed from in vivo anti-inflammatory efficacy studies in BALB/c mice. Data from additional studies with blank NPs (without quercetin) showed that the NPs reported herein most likely possessed intrinsic protective properties against LPS induced inflammation. Although further mechanistic studies are warranted, the overall work depicted a novel approach of possible exploiting innate protective properties of NPs in quercetin delivery for treating oxidative stress and inflammation. PMID- 25788281 TI - Self-assembling peptide scaffolds as innovative platforms for drug and cell delivery systems in cardiac regeneration. AB - Today, the use of biomaterials in many biomedical platforms is becoming increasingly popular due to their high diversity, infinite mimicking capacity, and emerging functions. Applications currently cover diverse areas in biomedicine including systems for cell isolation, expansion and maintenance, platforms for drug and cell delivery, scaffolds for tissue engineering, tissue regeneration and repair, cancer therapy, etc. Biomaterials in general can be: (1) natural in origin such as many proteins from the extracellular matrix, natural polysaccharides or scaffolds presented in a blood clot or (2) synthetic, including polymers, ceramics, or peptides. In this review, we focus on the use of self-assembling peptide scaffolds as an innovative and reliable strategy to obtain platforms for cell and drug delivery to injured or diseased tissues and organs. This type of material is molecular by design and it develops spontaneously into nanofiber scaffolds with multiple uses. In particular, examples are given for applications in the area of cardiac repair and regeneration. PMID- 25788282 TI - Cyclodextrin-based targeting strategies for tumor treatment. AB - The efficacy and applicability of anticancer drugs are greatly restricted by severe systemic toxicities and drug resistance. Targeting drug delivery strategies have been developed to prevent the shortcomings of chemotherapy. Among various approaches to specifically target drug-loaded carrier systems to the required pathological sites, ligand-attached cyclodextrin-based targeting complexes are a promising drug delivery system, which is achieved mainly through specific molecular interactions between the drugs and cell surface receptors. The principal targeting tactics include conjugation of cyclodextrin with targeting moieties or encapsulation drugs in cyclodextrins. The cyclodextrin-based supramolecules, polymers, or nanoparticles bearing bioactive substances such as folate, estrogens, carbohydrates, peptides, etc. have been reviewed. PMID- 25788284 TI - Transient ipsilateral retinal ganglion cell projections to the brain: Extent, targeting, and disappearance. AB - During development of the mammalian eye, the first retinal ganglion cells (RGCs) that extend to the brain are located in the dorsocentral (DC) retina. These RGCs extend to either ipsilateral or contralateral targets, but the ipsilateral projections do not survive into postnatal periods. The function and means of disappearance of the transient ipsilateral projection are not known. We have followed the course of this transient early ipsilateral cohort of RGCs, paying attention to how far they extend, whether they enter targets and if so, which ones, and the time course of their disappearance. The DC ipsilateral RGC axons were traced using DiI labeling at E13.5 and E15.5 to compare the proportion of ipsi- versus contralateral projections during the first period of growth. In utero electroporation of E12.5 retina with GFP constructs was used to label axons that could be visualized at succeeding time points into postnatal ages. Our results show that the earliest ipsilateral axons grow along the cellular border of the brain, and are segregated from the laterally positioned contralateral axons from the same retinal origin. In agreement with previous reports, although many early RGCs extend ipsilaterally, after E16 their number rapidly declines. Nonetheless, some ipsilateral axons from the DC retina enter the superior colliculus and arborize minimally, but very few enter the dorsal lateral geniculate nucleus and those that do extend only short branches. While the mechanism of selective axonal disappearance remains elusive, these data give further insight into establishment of the visual pathways. PMID- 25788285 TI - Association of ApaI and BsmI polymorphisms with vitiligo risk: a meta-analysis. AB - BACKGROUND: It has been reported that polymorphisms of the vitamin D receptor gene (VDR) such as ApaI or BsmI may affect the risk of vitiligo. However, the results have been inconsistent. AIM: To evaluate the association between two common polymorphisms (ApaI and BsmI) in the VDR gene and the susceptibility to vitiligo. METHODS: The PubMed, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases were searched, and OR with 95% CI was calculated. The strength of association and vitiligo risk was assessed under five genetic models: allele, dominant, recessive, homozygous and heterozygous. RESULTS: Six relevant studies were identified, including five studies that assessed the ApaI polymorphism and four the BsmI polymorphism (some overlapped). The meta-analysis results indicated that either the ApaI or the BsmI gene polymorphism may increase the risk of vitiligo in East Asian populations (aa + Aa vs. AA: OR = 1.40, 95% CI 1.01-1.96, P < 0.05; bb vs. Bb + BB: OR = 1.32, 95% CI 1.09-1.59, P < 0.01). No publication bias was detected in this meta-analysis. CONCLUSION: The current meta analysis suggests that the ApaI a allele or BsmI bb genotype are associated with the risk of vitiligo in East Asian populations. Thus, these polymorphisms could be potential biomarkers for early detection of vitiligo. PMID- 25788286 TI - Drosophila Cappuccino alleles provide insight into formin mechanism and role in oogenesis. AB - During Drosophila development, the formin actin nucleator Cappuccino (Capu) helps build a cytoplasmic actin mesh throughout the oocyte. Loss of Capu leads to female sterility, presumably because polarity determinants fail to localize properly in the absence of the mesh. To gain deeper insight into how Capu builds this actin mesh, we systematically characterized seven capu alleles, which have missense mutations in Capu's formin homology 2 (FH2) domain. We report that all seven alleles have deleterious effects on fly fertility and the actin mesh in vivo but have strikingly different effects on Capu's biochemical activity in vitro. Using a combination of bulk and single- filament actin-assembly assays, we find that the alleles differentially affect Capu's ability to nucleate and processively elongate actin filaments. We also identify a unique "loop" in the lasso region of Capu's FH2 domain. Removing this loop enhances Capu's nucleation, elongation, and F-actin-bundling activities in vitro. Together our results on the loop and the seven missense mutations provides mechanistic insight into formin function in general and Capu's role in the Drosophila oocyte in particular. PMID- 25788287 TI - Polarized activities of AMPK and BRSK in primary hippocampal neurons. AB - 5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master metabolic regulator that has been shown to inhibit the establishment of neuronal polarity/axogenesis under energy stress conditions, whereas brain-specific kinase (BRSK) promotes the establishment of axon-dendrite polarity and synaptic development. However, little information exists regarding the localized activity and regulation of these kinases in developing neurons. In this study, using a fluorescence resonance energy transfer (FRET)-based activity reporter that responds to both AMPK and BRSK, we found that BRSK activity is elevated in the distal region of axons in polarized hippocampal neurons before any stimulation and does not respond to either Ca(2+) or 2-deoxyglucose (2-DG) stimulation. In contrast, AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon. Our study shows that the activities of both AMPK and BRSK are polarized in developing hippocampal neurons, with high levels in the distal region of extended axons. PMID- 25788289 TI - MiR-34a regulates blood-tumor barrier function by targeting protein kinase Cepsilon. AB - MicroRNA-34a (miR-34a) functions to regulate protein expression at the posttranscriptional level by binding the 3' UTR of target genes and regulates functions of vascular endothelial cells. However, the role of miR-34a in regulating blood-tumor barrier (BTB) permeability remains unknown. In this study, we show that miR-34a overexpression leads to significantly increased permeability of BTB, whereas miR-34a silencing reduces the permeability of the BTB. In addition, miR-34a overexpression significantly down-regulates the expression and distribution of tight junction-related proteins in glioma endothelial cells (GECs), paralleled by protein kinase Cepsilon (PKCepsilon) reduction. Moreover, luciferase reporter gene analysis shows that PKCepsilon is the target gene of miR 34a. We also show that cotransfection of miR-34a and PKCepsilon inversely coregulates BTB permeability and protein expression levels of tight junction related proteins. Pretreatment of psiepsilonRACK, a PKCepsilon-specific activator, decreases BTB permeability in miR-34a-overexpressed GECs and up regulates expression levels of tight junction proteins. In contrast, pretreatment of epsilonV1-2, a specific PKCepsilon inhibitor, gives opposite results. Collectively, our findings indicate that miR-34a regulates BTB function by targeting PKCepsilon; after phosphorylation, PKCepsilon is activated and contributes to regulation of the expression of tight junction-related proteins, ultimately altering BTB permeability. PMID- 25788291 TI - Nurse staffing matters: now what? PMID- 25788288 TI - The AP2 clathrin adaptor protein complex regulates the abundance of GLR-1 glutamate receptors in the ventral nerve cord of Caenorhabditis elegans. AB - Regulation of glutamate receptor (GluR) abundance at synapses by clathrin mediated endocytosis can control synaptic strength and plasticity. We take advantage of viable, null mutations in subunits of the clathrin adaptor protein 2 (AP2) complex in Caenorhabditis elegans to characterize the in vivo role of AP2 in GluR trafficking. In contrast to our predictions for an endocytic adaptor, we found that levels of the GluR GLR-1 are decreased at synapses in the ventral nerve cord (VNC) of animals with mutations in the AP2 subunits APM-2/MU2, APA 2/alpha, or APS-2/sigma2. Rescue experiments indicate that APM-2/MU2 functions in glr-1-expressing interneurons and the mature nervous system to promote GLR-1 levels in the VNC. Genetic analyses suggest that APM-2/MU2 acts upstream of GLR-1 endocytosis in the VNC. Consistent with this, GLR-1 accumulates in cell bodies of apm-2 mutants. However, GLR-1 does not appear to accumulate at the plasma membrane of the cell body as expected, but instead accumulates in intracellular compartments including Syntaxin-13- and RAB-14-labeled endosomes. This study reveals a novel role for the AP2 clathrin adaptor in promoting the abundance of GluRs at synapses in vivo, and implicates AP2 in the regulation of GluR trafficking at an early step in the secretory pathway. PMID- 25788292 TI - The future of measuring patient safety: prospective clinical surveillance. PMID- 25788293 TI - 'The problem with...': a new series on problematic improvements and problematic problems in healthcare quality and patient safety. PMID- 25788290 TI - SINC, a type III secreted protein of Chlamydia psittaci, targets the inner nuclear membrane of infected cells and uninfected neighbors. AB - SINC, a new type III secreted protein of the avian and human pathogen Chlamydia psittaci, uniquely targets the nuclear envelope of C. psittaci-infected cells and uninfected neighboring cells. Digitonin-permeabilization studies of SINC-GFP transfected HeLa cells indicate that SINC targets the inner nuclear membrane. SINC localization at the nuclear envelope was blocked by importazole, confirming SINC import into the nucleus. Candidate partners were identified by proximity to biotin ligase-fused SINC in HEK293 cells and mass spectrometry (BioID). This strategy identified 22 candidates with high confidence, including the nucleoporin ELYS, lamin B1, and four proteins (emerin, MAN1, LAP1, and LBR) of the inner nuclear membrane, suggesting that SINC interacts with host proteins that control nuclear structure, signaling, chromatin organization, and gene silencing. GFP SINC association with the native LEM-domain protein emerin, a conserved component of nuclear "lamina" structure, or with a complex containing emerin was confirmed by GFP pull down. Our findings identify SINC as a novel bacterial protein that targets the nuclear envelope with the capability of globally altering nuclear envelope functions in the infected host cell and neighboring uninfected cells. These properties may contribute to the aggressive virulence of C. psittaci. PMID- 25788294 TI - The effect of including genomic relationships in the estimation of genetic parameters of functional traits in pigs. AB - The term functionality in animal breeding is used for traits that increase the efficiency of production by lowering the input cost, such as animal health and leg weakness related to longevity. The main objective of the study was to investigate the impact of genomic information, in a multivariate variance component analysis, on some of these traits. In addition, the effect of the inclusion was studied by testing the model's prediction ability based on best linear unbiased estimates for fixed and random effects. The material in this study consists of phenotypes from 76,683 animals, of which 4933 animals are genotyped. The heritabilities for front leg conformation, stayability, osteochondrosis and arched back, estimated using the traditional pedigree, were found to be between 0.12 and 0.29. When using the combined genomic and pedigree relationship matrix, the heritabilities were between 0.14 and 0.36. The results show that the combined relationship matrix can be used for the estimation of (co)variance components, and that the predictive ability of the model in this study marginally increases with the inclusion of genomic information. PMID- 25788295 TI - Slow potentials encode intercellular coupling and insulin demand in pancreatic beta cells. AB - AIMS/HYPOTHESIS: Ion fluxes constitute a major integrative signal in beta cells that leads to insulin secretion and regulation of gene expression. Understanding these electrical signals is important for deciphering the endogenous algorithms used by islets to attain homeostasis and for the design of new sensors for monitoring beta cell function. METHODS: Mouse and human islets were cultured on multielectrode arrays (MEAs) for 3-13 days. Extracellular electrical activities received on each electrode were continuously amplified and recorded for offline characterisation. RESULTS: Differential band-pass filtering of MEA recordings of mouse islets showed two extracellular voltage waveforms: action potentials (lasting 40-60 ms) and very robust slow potentials (SPs, lasting 800-1,500 ms), the latter of which have not been described previously. The frequency of SPs directly correlated with glucose concentration, peaked at 10 mmol/l glucose and was further augmented by picomolar concentrations of glucagon-like peptide-1. SPs required the closure of ATP-dependent potassium channels as they were induced by glucose or glibenclamide but were not elicited by KCl-induced depolarisation. Pharmacological tools and the use of beta cell specific knockout mice showed that SPs reflected cell coupling via connexin 36. Moreover, increasing and decreasing glucose ramps showed hysteresis with reduced glucose sensitivity during the decreasing phase. SPs were also observed in human islets and could be continuously recorded over 24 h. CONCLUSIONS/INTERPRETATION: This novel electrical signature reflects the syncytial function of the islets and is specific to beta cells. Moreover, the observed hysteresis provides evidence for an endogenous algorithm naturally present in islets to protect against hypoglycaemia. PMID- 25788296 TI - Clinicopathologic features of chronic nonspecific multiple ulcers of the small intestine. AB - Chronic nonspecific multiple ulcers of the small intestine is a rare but distinct clinical condition, characterized by multiple small intestinal ulcers of nonspecific histology and chronic, persistent gastrointestinal bleeding without nonsteroidal anti-inflammatory drug use. However, because of the term "nonspecific" in its nomenclature, some gastroenterologists have misinterpreted the disease as the condition with small intestinal ulcers caused by undetermined etiologies without considering clinical features. Such misinterpretation has led to the heterogeneity of clinicopathologic features of the disease, as well as to ambiguity regarding a possible genetic contribution. It thus seems necessary to recognize the clinical entity of the disease precisely to avoid misinterpretation. In this review, we describe the clinicopathologic features, differential diagnosis, and the possibility of a genetic contribution to the disease. PMID- 25788297 TI - Scripted secure base knowledge and its relation to perceived social acceptance and competence in early middle childhood. AB - Attachment theory regards experiences with caregivers as the affective ground for the development of early images of self, possibly embedded in scripted secure base knowledge as a rudimentary representation of early caregiver-child attachment relationships. However, the possible link between implicit representations of secure base availability - and the image of self in these representations - and explicit evaluations of self, is still unclear. The present study assessed whether implicit knowledge of secure-base interactions with caregivers is related to self-reported self-esteem in early middle childhood (N = 97 second-grade children). Results revealed that children with rich knowledge of secure base interactions perceived themselves not only as more accepted and appreciated by their peers and mothers but also as more cognitively competent, beyond actual differences in cognitive competence. Yet, given the limited strength of this link, the role of contextual factors beyond attachment ought to be considered in the assessment of self-perception in early middle childhood. PMID- 25788298 TI - Scalable liquid shear-driven fabrication of polymer nanofibers. AB - A simple process for batch or continuous formation of polymer nanofibers and other nanomaterials in the bulk of a sheared fluid medium is introduced. The process may be of high value to commercial nanotechnology, as it can be easily scaled up to the fabrication of staple nanofibers at rates that may exceed tens of kilograms per hour. PMID- 25788299 TI - Microbiological culture methods for pediatric musculoskeletal infection: a guideline for optimal use. AB - BACKGROUND: Culture results affect the diagnosis and treatment of children with musculoskeletal infection. To our knowledge, no previous large-scale study has assessed the relative value of culture methods employed during the evaluation of these conditions. The purpose of this study was to identify an optimal culture strategy for pediatric musculoskeletal infection. METHODS: Children with musculoskeletal infection were retrospectively studied to assess culture results from the infection site or blood; culture type, including aerobic, anaerobic, fungal, and acid-fast bacteria (AFB); antibiotic exposure history; and clinical history of children with positive culture results. RESULTS: We studied 869 children, including 353 with osteomyelitis, 199 with septic arthritis, forty-two with pyomyositis, and 275 with abscess. The 4537 cultures processed included 1303 aerobic, 903 anaerobic, 340 fungal, 289 AFB, and 1702 blood. Of 3004 specimens sent during initial work-up, positive results occurred in 677 of 1049 aerobic cultures (64.5%), 140 of 763 blood cultures (18.3%), eighteen of 722 anaerobic cultures (2.5%), five of 251 fungal cultures (2.0%), and two of 219 AFB cultures (0.9%). Staphylococcus aureus was the most common pathogen isolated, from 428 (50.7%) of 844 children for whom blood or infection-site culture material was sent (methicillin-resistant S. aureus, 252; and oxacillin-sensitive S. aureus, 176). Cultures were negative in 206 (29.0%) of the 710 children for whom culture material from the site of infection was sent. Children with true-positive anaerobic, fungal, or AFB cultures had a history of immunocompromise, penetrating inoculation, or failed primary treatment. Antibiotic exposure prior to culture sample acquisition did not interfere with aerobic culture results from the site of infection. CONCLUSIONS: Our findings suggest that anaerobic, fungal, and AFB cultures should not be routinely performed during the initial evaluation of children with hematogenous musculoskeletal infection. These cultures should be performed for children with immunocompromise, clinical suspicion of penetrating inoculation, or failed primary treatment. PMID- 25788300 TI - Factors associated with infection following anterior cruciate ligament reconstruction. AB - BACKGROUND: Although rare, infection can be devastating after anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to test the association between infection after ACL reconstruction and potential risk factors such as age, body mass index (BMI), smoking, diabetes, and graft choice. METHODS: We reviewed the Multicenter Orthopaedic Outcomes Network (MOON) cohort from 2002 to 2005 to identify patients with a postoperative infection. The age, BMI, smoking status, history of diabetes, and graft choice were recorded for each patient. A multivariable regression analysis was constructed to examine which baseline risk factors were independently associated with postoperative infection after ACL reconstruction requiring surgical intervention. RESULTS: There were 2198 eligible patients in the cohort, with seventeen (0.8%) reporting a postoperative infection. Diabetes was found to be a significant risk factor for infection (odds ratio [OR] = 18.8; 95% confidence interval [CI] = 3.8 to 94.0; p < 0.001). Compared with bone-tendon-bone autograft, both hamstring autograft and other grafts (e.g., the majority of allografts, with some that were both autograft and allograft) also increased the risk of infection (OR = 4.6 [95% CI = 1.2 to 17.9; p = 0.026] for hamstrings and 4.3 [95% CI = 1.0 to 18.1; p = 0.047] for other grafts). Although the OR for infection in smokers was 2.5, this finding did not reach significance. CONCLUSIONS: Patients with diabetes undergoing ACL reconstruction have a significantly elevated risk of postoperative infection (18.8-times higher odds) compared with that for patients without diabetes. Use of bone-tendon-bone autograft is associated with a lower risk of infection after ACL reconstruction. PMID- 25788301 TI - General compared with spinal anesthesia for total hip arthroplasty. AB - BACKGROUND: Total hip arthroplasty may be performed under general or spinal anesthesia. The purpose of the current study was to compare perioperative outcomes between anesthetic types for patients undergoing primary elective total hip arthroplasty. METHODS: Patients who had undergone primary elective total hip arthroplasty from 2010 to 2012 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Operating room times, length of stay, thirty-day adverse events, and readmission were compared between patients who had received general anesthesia and those who had received spinal anesthesia. Propensity-adjusted multivariate analysis was used to control for selection bias and baseline patient characteristics. RESULTS: A total of 20,936 patients who had undergone total hip arthroplasty met inclusion criteria for this study. Of these, 12,752 patients (60.9%) had received general anesthesia and 8184 patients (39.1%) had received spinal anesthesia. On propensity-adjusted multivariate analyses, general anesthesia for total hip arthroplasty was associated with increased operative time (+12 minutes [95% confidence interval, +11 to +13 minutes]; p < 0.001) and postoperative room time (+5 minutes [95% confidence interval, +4 to +6 minutes]; p < 0.001). General anesthesia was also associated with the occurrence of any adverse event (odds ratio, 1.31 [95% confidence interval, 1.23 to 1.41]; p < 0.001), prolonged postoperative ventilator use (odds ratio, 5.81 [95% confidence interval, 1.35 to 25.06]; p = 0.018), unplanned intubation (odds ratio, 2.17 [95% confidence interval, 1.11 to 4.29]; p = 0.024), stroke (odds ratio, 2.51 [95% confidence interval, 1.02 to 6.20]; p = 0.046), cardiac arrest (odds ratio, 5.04 [95% confidence interval, 1.15 to 22.07]; p = 0.032), any minor adverse event (odds ratio, 1.35 [95% confidence interval, 1.25 to 1.45]; p = 0.001), and blood transfusion (odds ratio, 1.34 [95% confidence interval, 1.25 to 1.45]; p < 0.001). General anesthesia was not associated with any difference in preoperative room time, postoperative length of stay, or readmission. CONCLUSIONS: General anesthesia was associated with an increased rate of adverse events and mildly increased operating room times. PMID- 25788302 TI - Long-term follow-up after latissimus dorsi transfer for irreparable posterosuperior rotator cuff tears. AB - BACKGROUND: Irreparable posterosuperior rotator cuff tears are treated in several ways. Transfer of the latissimus dorsi is an alternative with acceptable mid-term results, but long-term results have rarely been published. METHODS: The cases of 108 consecutive patients with 115 shoulders treated with latissimus dorsi transfer between 2000 and 2005 were reviewed clinically and radiographically. Ninety-three shoulders in eighty-six patients were included in the follow-up analysis. The mean duration of follow-up was 9.3 years (range, 6.6 to 11.7 years), and the mean age at the operation was fifty-six years (range, forty to seventy-two years). Outcome measures included the Constant-Murley score (Constant score), American Shoulder and Elbow Surgeons (ASES) index, and visual analog scale (VAS) for pain. The progress of cuff tear arthropathy was determined with radiographic evaluation according to the system described by Hamada et al. RESULTS: The mean relative Constant score improved from 44% preoperatively to 71% at the time of follow-up (p < 0.0001, effect size = 0.6), excluding the clinical failures. Similarly, the mean ASES index improved from 30 to 70 (p < 0.0001, effect size = 0.7), and the mean VAS score decreased from 7.8 to 2.4 (p < 0.0001, effect size = 0.8). A pain-free outcome was reported in only eighteen shoulders (19%). Active shoulder movement improved significantly (p < 0.05). The mean Hamada radiographic grade of cuff tear arthropathy increased from 1.7 (range, 0 to 2) preoperatively to 2.2 (range, 1 to 5) (p < 0.0001, effect size = 0.2). The rate of clinical failure of latissimus dorsi transfer was 10%, and the rate of shoulder prosthetic replacement after latissimus dorsi transfer was 4%. CONCLUSIONS: Pain relief and improvement of shoulder function were maintained a mean of 9.3 years after latissimus dorsi transfer for irreparable posterosuperior cuff defects. The younger the patient, the better the outcome. PMID- 25788303 TI - Symptomatic venous thromboembolism following fractures distal to the knee: a nationwide Danish cohort study. AB - BACKGROUND: Our aims were to determine the incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) that required inpatient or outpatient treatment, and to identify specific risk factors associated with DVT/PE in patients who had undergone surgery for a fracture distal to the knee. METHODS: Using individual linkage of nationwide registries, we included all Danish patients who had undergone surgery for a fracture distal to the knee between 1999 and 2011. Patients were followed for 180 days from discharge. Event rates of DVT/PE were calculated, and significant risk factors were identified with use of multivariable Cox regression analyses. Routine postdischarge antithrombotic chemoprophylaxis was not given to these patients. RESULTS: The study included 57,619 patients, 594 of whom had a venous thromboembolic event during the follow-up period. Thirty-nine (6.6%) of the 594 events were death due to PE. The overall event rate during the 180-day study period was 1.0%. The incidence rate was 7.28 events per 100 person-years before discharge, decreasing to a stable level below one event per 100 person-years in week 13 to 14 after discharge. Use of oral contraception by patients eighteen to fifty years of age (hazard ratio [HR] = 5.23, 95% confidence level [CI] = 3.35 to 8.18), previous DVT (HR = 6.27, 95% CI = 4.18 to 9.40), previous PE (HR = 5.45, 95% CI = 3.05 to 9.74), coagulopathy (HR = 2.47, 95% CI = 1.07 to 5.72), and peripheral artery disease (HR = 2.34, 95% CI = 1.20 to 4.56) were the factors associated with the highest risk of postoperative DVT/PE. Also, increasing age, increasing body mass index, cancer, and treatment with nonsteroidal anti-inflammatory drugs were associated with a significantly increased risk of DVT/PE. CONCLUSIONS: The incidence of DVT/PE was low following surgery for fractures distal to the knee; however, the risk was increased in the presence of a number of risk factors. This study suggests that specific groups of patients undergoing surgery for a fracture distal to the knee might benefit from postdischarge antithrombotic treatment. PMID- 25788304 TI - Inflammatory cytokine response following acute tibial plateau fracture. AB - BACKGROUND: The objective of the present study was to evaluate human synovial fluid for inflammatory cytokine concentrations following acute tibial plateau fracture. Our hypothesis was that there would be an elevated inflammatory response following intra-articular fracture, and that the inflammatory response would be greater after high-energy compared with low-energy injuries. METHODS: Between December 2011 and June 2013, we prospectively enrolled forty-five patients with an acute tibial plateau fracture. Synovial fluid aspirations were performed on the injured and uninjured knees. Twenty patients who required an external fixator followed by delayed fixation underwent aspiration at both surgical procedures. The concentrations of interferon-gamma (IFN-gamma), interleukin-1 beta (IL-1beta), interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1beta) were quantified with use of multiplex assays. RESULTS: The forty-five patients had an average age of forty-two years (range, twenty to sixty years). There were twenty-four low-energy and twenty-one high-energy tibial plateau injuries. There was a significant difference between injured and uninjured knees (p < 0.001) with regard to concentrations of IL 1beta, IL-6, IL-8, IL-10, IL-1RA, and MCP-1. There was not a detectable difference in synovial fluid cytokine concentrations between high and low-energy injuries. The concentrations of IL-10 (p < 0.001), IL-1RA (p = 0.002), IL-6 (p < 0.001), IL-8 (p < 0.001), and MCP-1 (p = 0.002) were significantly greater in the injured knee than in the uninjured knee at the second aspiration, at a mean of 9.5 days (range, three to twenty-one days) after the initial injury. CONCLUSIONS: There was a significant local inflammatory response following acute tibial plateau fracture. There was not a detectable difference in inflammatory cytokine concentration between high and low-energy injuries. Synovial fluid concentrations of IL-10, IL-8, IL-6, IL-1RA, and MCP-1 remained elevated at the second aspiration. PMID- 25788305 TI - Evaluation of articular cartilage progenitor cells for the repair of articular defects in an equine model. AB - BACKGROUND: We sought to determine the effectiveness of chondroprogenitor cells derived from autologous and allogenic articular cartilage for the repair of cartilage defects in an equine model. METHODS: Cartilage defects (15 mm) were created on the medial trochlear ridge of the femur. The following experimental treatments were compared with empty-defect controls: fibrin only, autologous chondroprogenitor cells plus fibrin, and allogenic chondroprogenitor cells plus fibrin (n = 4 or 12 per treatment). Horses underwent strenuous exercise throughout the twelve-month study, and evaluations included lameness (pain) and arthroscopic, radiographic, gross, histologic, and immunohistochemical analyses. RESULTS: Arthroscopy and microscopy indicated that defects in the autologous cell group had significantly better repair tissue compared with defects in the fibrin only and control groups. Repair tissue quality in the allogenic cell group was not superior to that in the fibrin-only group with the exception of the percentage of type-II collagen, which was greater. Radiographic changes in the allogenic cell group were poorer on average than those in the autologous cell group. Autologous cells significantly reduced central osteophyte formation compared with fibrin alone. CONCLUSIONS: On the basis of the arthroscopic, radiographic, and histologic scores, autologous cells in fibrin yielded better results than the other treatments; allogenic cells cannot be recommended at this time. PMID- 25788306 TI - Pediatric distal humeral fractures and complications of treatment in Finland: a review of compensation claims from 1990 through 2010. AB - BACKGROUND: The distal part of the humerus is the second most common fracture location in children. Complications are more common than with other pediatric fractures and are mostly related to inappropriate diagnosis and treatment. METHODS: On the basis of data from 1990 through 2010 in the national registry of inpatient care treatment in Finland, we calculated the number of children less than seventeen years of age who were treated under anesthesia for a distal humeral fracture (reduction with or without internal fixation) and the number of treatment institutions. We analyzed compensation claims concerning the treatment of these fractures that were received by the Patient Insurance Centre. The risk of a complication of treatment and the number of avoidable complications of treatment were assessed. RESULTS: A total of 7909 children underwent a procedure under anesthesia to treat a distal humeral fracture. Claims were filed for 117 patients (118 fractures, including seventy-four supracondylar, nineteen epicondylar, nineteen condylar, and six T-type), and compensation was granted for eighty-three (71%) of the patients. Deformity (forty-nine), delayed treatment (twenty), nerve injury (seventeen), and infection (seven) were the most common reasons for compensation. On reevaluation of the claims, ninety patients were assessed as having had complications of treatment. In our opinion, complications could have been avoided for eighty-six (96%) of these patients. CONCLUSIONS: We believe that improving the quality of primary assessment and operative technique would decrease the number of complications in the treatment of pediatric distal humeral fractures. Centralizing operative treatment to tertiary hospitals should be considered. PMID- 25788307 TI - Long-term results and outcome predictors in one-stage hip reconstruction in children with cerebral palsy. AB - BACKGROUND: One-stage hip reconstruction is the gold standard for treatment of hip displacement in children with cerebral palsy. The aims of this study were (1) to report the subjective clinical, objective clinical, and radiographic outcomes; and (2) to investigate outcome predictors, including the influence of the following risk factors: femoral head shape, migration percentage, direction of migration, and age at surgery. METHODS: We reviewed 168 hip reconstructions (eighty-two right, eighty-six left) in 121 patients (101 male, twenty female) at a mean follow-up of 7.3 +/- 4.6 years (range, four to eighteen years). Surgical outcomes were assessed on the basis of the pain intensity and frequency (measured on 10-point visual analog scales) as well as GMFCS (Gross Motor Function Classification System) and MCPHCS (Melbourne Cerebral Palsy Hip Classification System) scores and postoperative migration percentage. The effects of femoral head shape, preoperative migration percentage, direction of migration, and age at surgery on surgical outcome were assessed by multivariate regression adjusting for potential confounders including sex, triradiate cartilage status, type of cerebral palsy, and surgical technique. RESULTS: Pain intensity and frequency were reduced significantly. Preoperative femoral head shape had no significant effect on the changes in pain, MCPHCS grade, and GMFCS level. The preoperative migration percentage was the most influential risk factor with respect to postoperative outcome. Age at surgery had no effect on the changes in pain score and GMFCS level. The overall surgical complication rate was 10.5%. CONCLUSIONS: Our data on 168 hip reconstructions at a mean follow-up of seven years showed significant and clinically meaningful improvements in pain intensity and frequency as well as in clinical scores and hip coverage. Analysis of potential risk factors showed only the preoperative migration percentage to have a relevant influence on outcomes. PMID- 25788308 TI - Smaller body size increases the percentage of blood volume lost during posterior spinal arthrodesis. AB - BACKGROUND: Our goal was to analyze the relationship between patient size and the proportion of blood volume lost during spinal arthrodesis in patients with a diagnosis of adolescent idiopathic scoliosis, Scheuermann kyphosis, or cerebral palsy. We hypothesized that smaller patients (those with less blood volume) lose a greater proportion of circulating total blood volume during surgery. METHODS: We reviewed a large, multicenter database, identifying patients with adolescent idiopathic scoliosis (1832), Scheuermann kyphosis (106), or cerebral palsy (196) who had undergone posterior spinal arthrodesis for spinal deformity. Blood volume (estimated from body weight) was used as a measure of patient size. Our primary outcome was the proportion of total circulating blood volume lost (intraoperative blood loss/blood volume, expressed as a percentage). RESULTS: On multivariate analysis, there was a negative relationship between intraoperative blood loss/blood volume and blood volume in patients with adolescent idiopathic scoliosis (coefficient, -5.8; p < 0.001), Scheuermann kyphosis (coefficient, 2.5; p < 0.001), or cerebral palsy (coefficient, -20.3; p < 0.001), indicating that, despite adjustment for all other factors, smaller patients lost a greater proportion of their blood volume. In patients with adolescent idiopathic scoliosis or Scheuermann kyphosis, multivariate analysis showed that intraoperative blood loss/blood volume also increased significantly when the patient was male and with a greater number of levels fused. CONCLUSIONS: There is an inverse relationship between the proportion of blood volume lost during deformity correction surgery and size in patients with adolescent idiopathic scoliosis, cerebral palsy, or Scheuermann kyphosis. PMID- 25788309 TI - Investigating the relationship between ankle arthrodesis and adjacent-joint arthritis in the hindfoot: a systematic review. AB - BACKGROUND: Ankle arthrodesis traditionally has been regarded as the treatment of choice for many patients with end-stage ankle arthritis. However, a major reported risk of ankle arthrodesis is adjacent-joint degeneration. There are conflicting views in the literature as to the causative link between ankle arthrodesis and progression to adjacent-joint arthritis. Recent studies have challenged the causative link between arthrodesis and adjacent-joint arthritis, purporting that preexisting adjacent-joint arthritis is present in many patients. The aim of the present study was to systematically review the available literature to determine if there is sufficient evidence to support either hypothesis. METHODS: A literature search of the EMBASE and PubMed/MEDLINE databases (1974 to present) was performed. A total of twenty-four studies were included for review. The studies were reviewed, and the relevant information was extracted, including research methodology, postoperative outcomes in the adjacent joints of the foot, and whether pre-arthrodesis radiographs and medical records were available for analysis. RESULTS: The twenty-four manuscripts included eighteen clinical studies, five biomechanical studies, and one gait-analysis study. The majority of biomechanical studies showed altered biomechanics in the fused ankle; however, there was no clear consensus as to whether these findings were causes of adjacent-joint arthritis. In studies assessing clinical outcomes, the reported prevalence of subtalar joint arthritis ranged from 24% to 100% and the prevalence of talonavicular and calcaneocuboid arthritis ranged from 18% to 77%. Correlation between imaging findings of arthritis in adjacent joints and patient symptoms was not established in a number of the clinical studies reviewed. CONCLUSIONS: There is no true consensus in the literature as to the effects of ankle arthrodesis on biomechanics or whether ankle arthrodesis leads to adjacent-joint arthritis. Similarly, a correlation between postoperative imaging findings and clinical presentation in this cohort of patients has not been conclusively demonstrated. PMID- 25788310 TI - What's new in hand surgery. PMID- 25788311 TI - Surgical treatment of cavus foot in Charcot-Marie-tooth disease: a review of twenty-four cases: AAOS exhibit selection. AB - Charcot-Marie-Tooth disease is the single most common diagnosis associated with cavus foot. The imbalance involving intrinsic and extrinsic muscles has been suggested as the main pathogenetic cause of cavus foot in this disease. The goal of surgical treatment is to correct the deformity to obtain a plantigrade foot. In the presence of a flexible deformity and the absence of degenerative arthritis, preserving as much as possible of the overall range of motion of the foot and ankle is advisable. Twenty-four cavus feet in twelve patients with Charcot-Marie-Tooth disease were included in the study. Clinical evaluation was summarized with the Maryland Foot Score. Radiographic evaluation assessed calcaneal pitch, Meary angle, Hibb angle, and absence of degenerative joint changes. Only patients who had a flexible deformity, with varus of the heel reducible in the Coleman-Andreasi test, and did not have degenerative joint arthritis were included in this study. Surgical treatment consisted in plantar fasciotomy, midtarsal osteotomy, extensor hallucis longus tendon transfer to the first metatarsal (Jones procedure), and dorsiflexion osteotomy of the first metatarsal. Mean follow-up was six years (range, two to thirteen years). The mean Maryland Foot Score was 72 preoperatively and 86 postoperatively. The postoperative result was rated as excellent in twelve feet (50%), good in ten (42%), and fair in two (8%). Mean calcaneal pitch was 34 degrees preoperatively and 24 degrees at the time of the latest follow-up, the mean Hibb angle was 121 degrees preoperatively and 136 degrees postoperatively, and the mean Meary angle was 25 degrees preoperatively and 2 degrees postoperatively. Plantar fasciotomy, midtarsal osteotomy, the Jones procedure, and dorsiflexion osteotomy of the first metatarsal yielded adequate correction of flexible cavus feet in patients with Charcot-Marie-Tooth disease in the absence of fixed hindfoot deformity. The fact that the improvement in the outcome score was only modest may be attributable to the lack of motor balance. PMID- 25788312 TI - Estimating the global incidence of femoral fracture from road traffic collisions: a literature review. AB - BACKGROUND: Worldwide, road injuries cause over 1.3 million deaths and many more disabilities annually, disproportionately affecting the young and the poor. Approximately one in ten road injuries involves a femoral shaft fracture that is most effectively treated with surgery. Current femoral shaft fracture incidence according to country and age group is unknown and difficult to measure directly but is critical to designing and evaluating interventions. METHODS: We modeled femoral shaft fracture incidence from road traffic collisions with use of World Bank, World Health Organization, and Global Burden of Disease Study data for 176 countries and five age groups. We used road traffic death rates, ratios of road traffic deaths to injuries, and proportions of road traffic injuries that were femoral shaft fractures to calculate the fracture incidence. RESULTS: The worldwide annual femoral shaft fracture incidence from road traffic collisions was between 1.0 and 2.9 million. Incidence rates were significantly higher in low and middle income countries compared with high income countries. Overall, low and middle income countries had a mean femoral shaft fracture incidence between 15.7 and 45.5 per 100,000 people per year, with a rate ratio of 2.08 (95% confidence interval, 2.02 to 2.13; p < 0.001) relative to high income countries. CONCLUSIONS: Our results demonstrate a substantial worldwide burden and disparities in femoral shaft fracture incidence between low to middle income and high income countries, and the young are disproportionately affected, underscoring the potential impact of improved access to treatment. We believe that the methodology of this study can be applied to estimate the burden of other diseases, allowing for better direction of global health efforts. PMID- 25788313 TI - To culture or not to culture: commentary on an article by Jarren Section, MS, et al.: "Microbiological culture methods for pediatric musculoskeletal infection. a guideline for optimal use". PMID- 25788314 TI - Knee trauma and posttraumatic osteoarthritis-more science needed: commentary on an article by Justin M. Haller, MD, et al.: "Inflammatory cytokine response following acute tibial plateau fracture". PMID- 25788315 TI - Elbow fractures in children remain a challenge: commentary on an article by Noora Vallila, MD, et al.: "Pediatric distal humeral fractures and complications of treatment in Finland. A review of compensation claims from 1990 through 2010". PMID- 25788316 TI - Quantitative volumetric analysis of head and neck venous and lymphatic malformations to assess response to percutaneous sclerotherapy. AB - BACKGROUND: Venous and lymphatic malformations of the head and neck can be successfully treated with percutaneous sclerotherapy. PURPOSE: To examine the utility of three-dimensional volumetric analysis to assess these lesions and their response to therapy. MATERIAL AND METHODS: Prospectively maintained procedure records were retrospectively reviewed to identify all patients with vascular malformations who underwent percutaneous sclerotherapy. Clinical data were used to classify lesions by apparent size and degree of visible physical asymmetry due to the lesions. Lesion volume was calculated using magnetic resonance images. Cohen's weighted kappa coefficients were calculated to assess both intra- and inter-rater agreement. Pearson coefficients were calculated to identify correlation between clinical and volumetric measures, both at initial diagnosis and following treatment. RESULTS: Thirty-seven patients with head and neck venous or lymphatic malformations underwent 55 treatment sessions. Cohen's weighted kappa coefficients were 0.84 and 0.77 for intra- and inter-rater agreement, respectively. Clinical size did not significantly correlate with measured volume at diagnosis (rho = 0.08, P = 0.57). For lymphatic malformations, total lesion volume correlated with volume of macrocystic components (rho = 0.47, P < 0.01). Total volume reduction significantly correlated with clinical response grade (rho = 0.46, P = 0.02). For lymphatic malformations, reduction of volume of the macrocystic component significantly correlated with clinical response grade (rho = 0.44, P = 0.03). CONCLUSION: Changes in calculated volume corresponded to clinical measures of treatment response. Variability of qualitative approaches to lesion analysis may have led to the lack of correlation between initial size of a lesion based on clinical measures and calculated volume. Future research should include quantitative metrics to augment qualitative clinical results. PMID- 25788317 TI - Water soluble polyhydroxyalkanoates: future materials for therapeutic applications. AB - Polyhydroxyalkanoates (PHAs) are excellent candidate biomaterials due to their exceptional biodegradability and biocompatibility. However, PHAs need to have tunable hydrophilicity, chemical functionalities, and appropriate hydrolytic stability to expand their therapeutic applications towards more advanced areas. In this Tutorial Review, we present the most recent progress in the synthetic strategies of PHA-based water soluble polymers, including the functionalisation of PHAs with polar functional groups and the block/graft copolymerization of PHAs with hydrophilic components in various polymeric architectures. These chemically modified water soluble PHAs have significant impact on materials engineering and show great value in the fulfilment of smart biomaterials in emerging areas. The applications of water soluble PHAs in controlled drug release, cancer therapy, DNA/siRNA delivery and tissue engineering in new aspects are discussed. In addition, water soluble PHA monomer production will be briefly introduced, with emphasis on its bio-significance in medical physiology and the therapeutic effect in the treatment of diseases. PMID- 25788318 TI - Case formulation and the therapeutic relationship: the role of therapist self reflection and self-revelation. AB - This article examines the role of the therapist's self-reflection and self revelation in case formulation. We believe that a collaboratively constructed case formulation must always be considered in the context of an evolving therapeutic relationship. Further, self-reflection and self-revelation on the part of the therapist are critical for a more elaborate and nuanced case formulation and for understanding the patient. This highlights the importance of attunement to the here and now and the evolving therapeutic relationship. From this attunement, the therapist's self-reflection and self-revelation can emerge further, which can lead to the patient's personal growth and increased self-other awareness. To illustrate our point, we present an integrative, relational model in the case of a patient who has been in treatment. PMID- 25788319 TI - Customization of Protein Single Nanowires for Optical Biosensing. AB - An all-protein single-nanowire optical biosensor is constructed by a facile and general femtosecond laser direct writing approach with nanoscale structural customization. As-formed protein single nanowires show excellent optical properties (fine waveguiding performance and bio-applicable transmission windows), and are utilized as evanescent optical nanobiosensors for label-free biotin detection. PMID- 25788320 TI - Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. AB - BACKGROUND: Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO. METHODS: We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO. RESULTS: Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77). CONCLUSION: In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect. PMID- 25788322 TI - Conception, Pregnancy, and Lactation Despite Chronic Intestinal Failure Requiring Home Parenteral Nutrition. AB - BACKGROUND: Short-term parenteral nutrition is commonly accepted to be safe in pregnancy, but knowledge about the management of pregnancy during long-term home parenteral nutrition (HPN) is sparse. METHODS AND RESULTS: A systematic literature review revealed that the published experience is limited to 15 pregnancies with parenteral nutrition from preconception to delivery and beyond. Maternal morbidity was surprisingly low, and fetal outcome was good; however, micronutrient deficiencies may have contributed to fetal anomalies. Herein, we additionally report the case of a 26-year-old Caucasian woman with long-term HPN dependence secondary to short bowel syndrome caused by recurrent thromboembolic mesenteric infarctions who delivered a healthy fetus at 37 weeks of gestation. Individual macronutrient support and adequate micronutrient supplementation ensured normal maternal weight gain and fetal development. Based on the individual maternal risk of recurrent thrombosis, anticoagulant treatment was carefully titrated throughout pregnancy. Furthermore, loss of abdominal domain with a rigid maternal abdominal wall secondary to short bowel syndrome and multiple laparotomies resulted in food intolerance during the third trimester. Still, with multidisciplinary efforts, both mother and the breast-fed infant were in good health at 12 months after delivery. CONCLUSIONS: Taking the reported literature into consideration, we conclude that under the premise of optimal medical care, the risk:benefit ratio for pregnancy of HPN-dependent women seems to be justifiable. To minimize the risks, we recommend preconception counseling and early referral to a tertiary center offering both a high-risk pregnancy unit and a nutrition service. In particular, maternal micronutrient levels should be monitored. PMID- 25788321 TI - Targeting the canonical Wnt/beta-catenin pathway in hematological malignancies. AB - The canonical Wnt/beta-catenin pathway plays an important role in different developmental processes through the regulation of stem cell functions. In the activation of the canonical Wnt/beta-catenin pathway, beta-catenin protein is imported into the nucleus and activates transcription of target genes including cyclin D1 and c-myc. Aberrant activation of the Wnt/beta-catenin pathway contributes to carcinogenesis and malignant behaviors, and Wnt signaling is essential for the maintenance of cancer stem cells. The canonical Wnt/beta catenin pathway has been investigated extensively as a target in cancer treatment and several specific inhibitors of this signaling pathway have been identified through high-throughput screening. In this review, the significance of the canonical Wnt/beta-catenin pathway in hematological carcinogenesis and screening methods for specific inhibitors are discussed. PMID- 25788323 TI - Integration of acupuncture into conventional medicine from health professionals' perspective: A thematic synthesis of qualitative studies. AB - Acupuncture is a prominent Complementary Medicine. Although health professionals' conceptions of acupuncture may affect its utilisation and integration within conventional medicine, these aspects have not been well studied. The aim of this review was to analyse the integration of acupuncture into conventional medicine from the perspective of health professionals. We conducted a systematic review and a thematic synthesis of qualitative studies that analysed the integration of acupuncture into conventional medicine grounded in participants' perspectives. A systematic search was undertaken in PubMed, Web of Science, the Cochrane Library Plus, Scopus and CINAHL. This review included 18 articles: 6 analysed the viewpoint of physicians, 3 of nurses and 9 comprised different health-related professionals. Most of these studies included healthcare professionals practising acupuncture and took place in sites where the relation between acupuncture and biomedicine is favourable. The most used research techniques were convenience sampling, semi-structured interviews and interpretative approach. The holistic approach of acupuncture and its lack of adverse effects were highlighted by the analysed studies. This led to health professionals encouraging its integration into conventional medicine. The main obstacles perceived for the integration were lack of knowledge and institutional support. In general, acupuncture has been adapted to the biomedical model (often practised in an unsystematic and individual manner), and it is conceived as a supplement of Western medicine. 'Working together' and overcoming the biomedical model are recognised by the participants as key conditions for successful integration of acupuncture. PMID- 25788324 TI - Author's reply to Reynolds. PMID- 25788325 TI - Evaluation of a two-stage framework for prediction using big genomic data. AB - We are in the era of abundant 'big' or 'high-dimensional' data. These data afford us the opportunity to discover predictors of an event of interest, and to estimate occurrence of the event based on values of these predictors. For example, 'genome-wide association studies' examine millions of single-nucleotide polymorphisms (SNPs), along with disease status. We can learn SNPs that affect disease status from these data sets, and use the knowledge learned to predict disease likelihood. Owing to the large number of features, it is difficult for many prediction methods to use all the features directly. The ReliefF algorithm ranks a set of features in terms of how well they predict a target. It can be used to identify good predictors, which can then be provided to a prediction method. We compared the performance of eight prediction methods when predicting binary outcomes using high-dimensional discrete data sets. We performed two-stage prediction, where ReliefF is used in the first stage to identify good predictors. Bayesian network (BN)-based methods performed best overall. Furthermore, ReliefF did not improve their performance. The BN-based methods use the Bayesian Dirichlet Equivalent Uniform score to evaluate candidate models, and use BN inference algorithms to perform prediction. This score and these algorithms were developed for discrete variables. This perhaps explains why they perform better in this domain. Many prediction methods are available, and researchers have little reason for choosing one over the other in the domain of binary prediction using high-dimensional data sets. Our results indicate that the best choices overall are BN-based methods. PMID- 25788326 TI - A comparative study of RNA-seq analysis strategies. AB - Three principal approaches have been proposed for inferring the set of transcripts expressed in RNA samples using RNA-seq. The simplest approach uses curated annotations, which assumes the transcripts in a sample are a subset of the transcripts listed in a curated database. A more ambitious method involves aligning reads to a reference genome and using the alignments to infer the transcript structures, possibly with the aid of a curated transcript database. The most challenging approach is to assemble reads into putative transcripts de novo without the aid of reference data. We have systematically assessed the properties of these three approaches through a simulation study. We have found that the sensitivity of computational transcript set estimation is severely limited. Computational approaches (both genome-guided and de novo assembly) produce a large number of artefacts, which are assigned large expression estimates and absorb a substantial proportion of the signal when performing expression analysis. The approach using curated annotations shows good expression correlation even when the annotations are incomplete. Furthermore, any incorrect transcripts present in a curated set do not absorb much signal, so it is preferable to have a curation set with high sensitivity than high precision. Software to simulate transcript sets, expression values and sequence reads under a wider range of parameter values and to compare sensitivity, precision and signal-to-noise ratios of different methods is freely available online (https://github.com/boboppie/RSSS) and can be expanded by interested parties to include methods other than the exemplars presented in this article. PMID- 25788327 TI - A continuous peptide epitope reacting with pandemic influenza AH1N1 predicted by bioinformatic approaches. AB - Computational identification of potential epitopes with an immunogenic capacity challenges immunological research. Several methods show considerable success, and together with experimental studies, the efficiency of the algorithms to identify potential peptides with biological activity has improved. Herein, an epitope was designed by combining bioinformatics, docking, and molecular dynamics simulations. The hemagglutinin protein of the H1N1 influenza pandemic strain served as a template, owing to the interest of obtaining a scheme of immunization. Afterward, we performed enzyme-linked immunosorbent assay (ELISA) using the epitope to analyze if any antibodies in human sera before and after the influenza outbreak in 2009 recognize this peptide. Also, a plaque reduction neutralization test induced by virus-neutralizing antibodies and the IgG determination showed the biological activity of this computationally designed peptide. The results of the ELISAs demonstrated that the serum of both prepandemic and pandemic recognized the epitope. Moreover, the plaque reduction neutralization test evidenced the capacity of the designed peptide to neutralize influenza virus in Madin-Darby canine cells. PMID- 25788328 TI - Reduction of invasive bacteria in ethanol fermentations using bacteriophages. AB - Invasive Lactobacillus bacteria inhibit ethanol fermentations and reduce final product yields. Due to the emergence of antibiotic resistant strains of Lactobacillus spp., alternative disinfection strategies are needed for ethanol fermentations. The feasibility of using the bacteriophage (phage) 8014-B2 to control Lactobacillus plantarum in ethanol fermentations by Saccharomyces cerevisiae was investigated. In 48 h media-based shake flask fermentations, phages achieved greater than 3-log inactivation of L. plantarum, protected final ethanol yields, and maintained yeast viability. The phage-based bacterial disinfection rates depended on both the initial phage and bacterial concentrations. Furthermore, a simple set of kinetic equations was used to model the yeast, bacteria, phage, reducing sugars, and ethanol concentrations over the course of 48 h, and the various kinetic parameters were determined. Taken together, these results demonstrate the applicability of phages to reduce L. plantarum contamination and to protect final product yields in media-based fermentations. PMID- 25788330 TI - Compact multilayer film structure for angle insensitive color filtering. AB - Here we report a compact multilayer film structure for angle robust color filtering, which is verified by theoretical calculations and experiment results. The introduction of the amorphous silicon in the proposed unsymmetrical resonant cavity greatly reduces the angular sensitivity of the filters, which is confirmed by the analysis of the phase shift within the structure. The temperature of the substrate during the deposition is expressly investigated to obtain the best optical performance with high peak reflectance and good angle insensitive color filtering by compromising the refractive index of dielectric layer and the surface roughness of the multilayer film. And the outlayer of the structure, worked as the anti-reflection layer, have an enormous impact on the filtering performance. This method, described in this paper, can have enormous potential for diverse applications in display, colorful decoration, anti-counterfeiting and so forth. PMID- 25788329 TI - Understanding the effect of alternative splicing in the folding and function of the second PDZ from protein tyrosine phosphatase-BL. AB - PDZ domains are the most prominent biological structural domains involved in protein-protein interactions in the human cell. The second PDZ domain of the protein tyrosine phosphatase BL (PDZ2) interacts and binds the C-termini of the tumour suppressor protein APC and of the LIM domain-containing protein RIL. One isoform of PDZ2 (PDZ2as) involves an alternative spliced form that exhibits an insertion of 5 residues in a loop. PDZ2as abrogates binding to its partners, even if the insertion is directly located in its binding pocket. Here, we investigate the folding and function of PDZ2as, in comparison to the previously characterized PDZ2 domain. Data reveal that, whilst the thermodynamic stability of PDZ2as appears as nearly identical to that of PDZ2, the insertion of 5 amino acids induces formation of some weak transient non-native interactions in the folding transition state, as mirrored by a concomitant increase of both the folding and unfolding rate constants. From a functional perspective, we show that the decrease in affinity is caused by a pronounced decrease of the association rate constants (by nearly ten fold), with no effect on the microscopic dissociation rate constants. The results are briefly discussed in the context of previous work on PDZ domains. PMID- 25788331 TI - Does a true knowledge of dental crowding affect orthodontic treatment decisions? AB - OBJECTIVES: To assess whether a true knowledge of crowding alters treatment decisions compared with estimates of crowding. MATERIALS AND METHODS: Thirty-six orthodontists were asked to estimate crowding using visualization on eight mandibular arch study models and to indicate possible extraction choices. For each model, the intermolar widths, intercanine widths, and clinical scenarios were identical, but the true crowding varied from 0.2 to 8.4mm as to a lesser extent did the curve of Spee. Eleven orthodontists repeated the visualization exercise after 2 weeks to assess reliability. All 36 of the orthodontists were asked to repeat the treatment planning exercise on the same models, but this time was provided with the true amount of crowding in each case. RESULTS: When the 36 orthodontists used direct visualization of the models to assess crowding, the range of their estimates of crowding increased as the crowding increased. As might be expected, they also tended to move towards extraction treatments as the crowding increased (P = 0.013, odds ratio = 3). Although the reliability of the repeat estimates of crowding were moderate, the mean estimates were greater than the true crowding for each model. When orthodontists were presented with the true amount of crowding, rather than their estimate of crowding, it had a significant effect on the decision to extract, with fewer orthodontists recommending extractions. LIMITATIONS: The principal limitation of this study is that it was a laboratory-based study and utilized just the mandibular arch model for estimation and treatment planning. CONCLUSIONS: Direct visualization may overestimate the amount of crowding present. When the true amount of crowding is known, it can lead to more consistent treatment planning, with the decision to extract fewer teeth in the borderline cases. A formal space analysis is likely to assist with treatment planning. PMID- 25788332 TI - Demographic characteristics of systematic reviews, meta-analyses, and randomized controlled trials in orthodontic journals with impact factor. AB - INTRODUCTION: The aim of this study was to explore demographic characteristics of systematic reviews (SRs), meta-analyses (MAs), and randomized controlled trials (RCTs) published in orthodontic journals with an impact factor (IF). MATERIALS AND METHODS: An electronic search was developed and implemented to identify all the SRs, MAs, and RCTs published in the seven orthodontic journals with an IF. No restrictions were applied regarding language, publication date, or publication status. The initial search generated 1147 articles, which were reviewed by three authors in order to determine if they met the inclusion criteria. Five hundred and fifty-seven articles were included in the final analysis. Type of article, name of journal, year of publication, number of authors, country of origin, and primary affiliation were recorded. Associations between those parameters were tested with the Pearson chi-square test for independence at the 0.05 level of significance. RESULTS: The majority (72%) of this kind of articles published in the orthodontic literature were RCTs, followed by SRs (20.1%) and MAs (7.9%). Approximately 77.2% of all RCTs, SRs, and MAs were published between 2004 and 2013, and 72.9% came from orthodontic departments. More than 80% of all articles were collaborative efforts between three or more authors. Contributions from Asia, South and Central America significantly increased during last decade, while contributions from North America decreased by almost 30%. CONCLUSIONS: Most RCTs, MAs, and SRs have been published between 2004 and 2013, indicating a significant improvement of the orthodontic literature during the last decade. Asia, South and Central America have significantly increased their contributions to the high evidence orthodontic literature since 2004. PMID- 25788333 TI - Effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures. AB - BACKGROUND/OBJECTIVE: To investigate the effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures. MATERIALS/METHODS: Five thermoplastic materials, polyethylene terephthalate glycol (Duran(r), Scheu Dental), polypropylene (Hardcast(r), Scheu Dental), and polyurethane (SMP MM(r), SMP Technologies) with three different glass transition temperatures (T g) were selected. The T g and crystal structure were assessed using differential scanning calorimetry and X-ray diffraction. The deterioration of mechanical properties by thermal cycling and the orthodontic forces during stepwise temperature changes were investigated using nanoindentation testing and custom-made force-measuring system. The mechanical properties were also evaluated by three-point bending tests; shape recovery with heating was then investigated. RESULTS: The mechanical properties for each material were decreased significantly by 2500 cycles and great decrease was observed for Hardcast (crystal plastic) with higher T g (155.5 degrees C) and PU 1 (crystalline or semi-crystalline plastic) with lower T g (29.6 degrees C). The Duran, PU 2, and PU 3 with intermediate T g (75.3 degrees C for Duran, 56.5 degrees C for PU 2, and 80.7 degrees C for PU 3) showed relatively stable mechanical properties with thermal cycling. The polyurethane polymers showed perfect shape memory effect within the range of intraoral temperature changes. The orthodontic force produced by thermoplastic appliances decreased with the stepwise temperature change for all materials. CONCLUSIONS/IMPLICATIONS: Orthodontic forces delivered by thermoplastic appliances may influence by the T g of the materials, but not the crystal structure. Polyurethane is attractive thermoplastic materials due to their unique shape memory phenomenon, but stress relaxation with temperature changes is expected. PMID- 25788334 TI - A synthetic erectile optogenetic stimulator enabling blue-light-inducible penile erection. AB - Precise spatiotemporal control of physiological processes by optogenetic devices inspired by synthetic biology may provide novel treatment opportunities for gene- and cell-based therapies. An erectile optogenetic stimulator (EROS), a synthetic designer guanylate cyclase producing a blue-light-inducible surge of the second messenger cyclic guanosine monophosphate (cGMP) in mammalian cells, enabled blue light-dependent penile erection associated with occasional ejaculation after illumination of EROS-transfected corpus cavernosum in male rats. Photostimulated short-circuiting of complex psychological, neural, vascular, and endocrine factors to stimulate penile erection in the absence of sexual arousal may foster novel advances in the treatment of erectile dysfunction. PMID- 25788335 TI - Attitude of an Egyptian Sample of Medical Students Toward Psychiatry in Comparison to Previous Studies Using the Attitudes Towards Psychiatry (ATP-30) Questionnaire. AB - OBJECTIVE: This study aims to determine the attitude of medical students toward psychiatry at the College of Medicine, Menoufia University, Egypt, and to compare it with previous similar studies in other countries. METHODS: Four hundred medical students, randomly selected from four different years, completed the Attitudes Towards Psychiatry (ATP-30) in a cross-sectional study. RESULTS: The mean ATP score was 99.31; 76.3% of the students had favorable attitudes toward psychiatry and 29.5% considered psychiatry as a potential career choice. CONCLUSIONS: A generally positive attitude toward psychiatry was found among medical students in Menoufia University. Consistent with this positive attitude was the relatively high percentage of students who considered psychiatry as a potential career. PMID- 25788336 TI - Impact of assaults on recruitment into psychiatry. PMID- 25788337 TI - Improving Training and Systems of Care in Child and Adolescent Consultation Liaison Psychiatry Through Patient-Centered Graduate Medical Education: One Institution's Approach. PMID- 25788338 TI - Laser lithotripsy of salivary stones: Correlation with physical and radiological parameters. AB - BACKGROUND AND OBJECTIVES: Sialolithiasis is a common disease of the major salivary glands. Owing to the variety of conservative and minimally invasive techniques, it is now possible to treat most cases of sialolithiasis without removal of the affected salivary gland. One treatment option is the endoscopic removal of the calculi. In cases of larger concretions, intraductal disintegration using laser-induced shock waves can be appropriate to allow endoscopic removal. In the present study, we investigated whether physical and radiological parameters of salivary stones can effectively predict the applicability of laser lithotripsy. Furthermore, we determined to what extent the applied laser energy resulted in tissue damage. STUDY DESIGN/MATERIALS AND METHODS: In addition to basic parameters like size and density, we analysed 47 salivary stones using fluorescence spectroscopy, infrared spectroscopy, Raman spectroscopy, and dual-energy computed tomography. Subsequent fragmentation of all stones was performed with a Ho:YAG laser in a near-contact manner. Fragmentation rates were calculated and correlated with the previously measured physical and radiological parameters. Finally, to test for tissue damage, we performed HE-histology of salivary duct mucosa treated with the same laser energy used for stone fragmentation. RESULTS: Blue light excitation induced either green or red fluorescence emission. Dual-energy CT resulted in evidence of calcium containing material. Infrared spectroscopy and Raman spectroscopy, both identified carbonate apatite as the main component of salivary stones. Disintegration into pieces smaller than 2 mm was possible in all cases. Fragmentation rates depended on the energy per pulse applied but not on any of the analysed physical and radiological parameters. In contrast to lithotripsy with 500 mJ per pulse, which was associated with no tissue damage, lithotripsy with 1,000 mJ per pulse resulted in damage of salivary duct mucosa. This suggests that the optimal laser energy for stone fragmentation is between 500 and 1,000 mJ per pulse. CONCLUSION: Laser lithotripsy using Ho:YAG laser is a highly efficient treatment, at least in vitro. All salivary stones could be disintegrated irrespective of their physical and radiological composition. PMID- 25788339 TI - Time to competency, reliability of flexible transnasal laryngoscopy by training level: a pilot study. AB - OBJECTIVE: To determine the progression of flexible transnasal laryngoscopy reliability and competency in otolaryngology residency training. STUDY DESIGN: Prospective case control study. SETTING: Academic otolaryngology department. SUBJECTS: Medical students, otolaryngology residents, and otolaryngology attending physicians. METHODS: Fourteen otolaryngology residents from PGY-1 to PGY-5 and 3 attending otolaryngologists viewed 25 selected and digitally recorded flexible transnasal laryngoscopies. The evaluators were asked to rate 13 items relating to abnormalities in the oropharynx, hypopharynx, larynx, and subglottis. The level of concern and level of comfort with the diagnosis were assessed. Intraclass correlations were calculated for each topic and by level of training to determine reliability within each class and compare competency versus attending interpretations. RESULTS: Intraclass correlation of residents compared to attending physicians demonstrated significant improvements by year for left and right vocal fold immobility, subglottic stenosis, laryngeal mass, left and right vocal cord abnormalities, and level of concern. Additionally, pooled vocal cord mobility and pooled results in categories with good attending reliability demonstrated stepwise improvement as well. For these categories, resident reliability was found to be statistically similar to attending physicians in all categories by PGY-3. There were no trends for base of tongue abnormalities, pharyngeal abnormalities, and pharyngeal and hypopharyngeal masses. CONCLUSIONS: Resident competency for flexible transnasal laryngoscopy progresses during residency to reliability with attending otolaryngologists by the PGY-3 year over key facets of the examination. PMID- 25788340 TI - Coffee consumption and bladder cancer are linked, analysis shows. PMID- 25788341 TI - Multisite Near Infrared Spectroscopy During Cardiopulmonary Bypass in Pediatric Patients. AB - Multisite near infrared spectroscopy (NIRS) monitoring during pediatric cardiopulmonary bypass (CPB) has not been extensively validated. Although it might be rational to explore regional tissue saturation at different body sites (namely brain, kidney, upper body, lower body), conflicting results are currently provided by experience in children. The aim of our study was to evaluate absolute values of multisite NIRS saturation during CPB in a cohort of infants undergoing pediatric cardiac surgery to describe average differences between cerebral, renal, upper body (arm), and lower body (thigh) regional saturation. Furthermore, the correlation between cerebral NIRS and cardiac index (CI) at CPB weaning was evaluated. Twenty-five infants were enrolled: their median weight, age, and body surface area were 3.9 (3.3-6) kg, 111 (47-203) days, and 0.24 (0.22-0.33) m(2) , respectively. Median Aristotle score was 8 (6-10), and vasoactive inotropic score at CPB weaning was 16 (14-25). A total of 17 430 data points were recorded by each sensor: two-way ANOVA showed that time (P < 0.0001) and site (P = 0.0001) significantly affected variations of NIRS values: however, if cerebral NIRS values are excluded, sensor site is no more significant (P = 0.184 in the no circulatory arrest [noCA] group and P = 0.42 in the circulatory arrest [CA] group). Analysis of NIRS saturation changes over time showed that, at all sites, average NIRS values increased after CPB start, even if the increase of cerebral saturation was less intense than other sites (P < 0.0001). Detailed analysis of interaction between site of NIRS measurement and time point showed that cerebral NIRS (ranging from 65 to 75%) was always significantly lower than that of other channels (P < 0.0001) that tended to be in the range of oversaturation (80-90%), especially during the CPB phase. Average cerebral NIRS values of patients who did not undergo circulatory arrest (CA) during CPB, 10 min after CPB weaning, were associated with average CI values with a significant correlation (r = 0.7, P = 0.003). In conclusion, during CPB, cerebral NIRS values are expected to remain constantly lower than somatic sensors, which instead tend to show similar elevated saturations, regardless of their position. Based on these results, positioning of noncerebral NIRS sensors during CPB without CA may be questioned. PMID- 25788342 TI - Percutaneous coronary interventions in the diabetic patient: where do we stand? PMID- 25788343 TI - Coronary artery fenestration guided by optical coherence tomograhy before stenting: new interventional option in rescue management of compressive spontaneous intramural hematoma. PMID- 25788344 TI - Nanomedicine-prospects and challenges. PMID- 25788345 TI - Many faces of nanomedicine. PMID- 25788346 TI - Fabrication of isradipine nanosuspension by anti-solvent microprecipitation-high pressure homogenization method for enhancing dissolution rate and oral bioavailability. AB - The aim of this study was to develop a nanosuspension of a highly hydrophobic drug, isradipine (ISR) by combination of anti-solvent microprecipitation and high pressure homogenization to achieve the superior in vitro dissolution and in vivo pharmacokinetic profile. The nanosuspension was formulated using combination of stabilizers as vitamin E TPGS and sodium lauryl sulfate. The developed nanosuspension was characterized for particle size, shape, and zeta potential. The particle size of the developed ISR nanosuspension was observed to be approximately 538 nm (by laser diffraction) and 469 nm (by photon correlation spectroscopy) with -33.3 mV zeta potential. Scanning electron microscopy study revealed the good correlation with particle size measured by photon correlation spectroscopy and laser diffraction. The X-ray diffraction and differential scanning calorimetry showed that ISR was present as an amorphous state in the lyophilized form of nanosuspension. In vitro dissolution and saturation solubility study showed the dissolution rate of nanosuspensions (98.60 %) and saturation solubility (98.76 MUg/ml) compared with the coarse drug (11.53 % and 14.1 MUg/ml, respectively) had been significantly enhanced. The pharmacokinetic study showed that the nanosuspension exhibits increased in AUC0-48 by 2.0-fold compared to coarse suspension. Further, there was increased in C max and decreased in t max of ISR nanosuspension compared to coarse suspension of ISR. These studies proved that particle size reduction can influence ISR absorption in gastrointestinal tract and thus nanosuspension technology is responsible for enhancing oral bioavailability in rats. PMID- 25788347 TI - Development, characterisation and evaluation of supersaturated triglyceride free drug delivery (s-TFDDS) of lornoxicam. AB - The present work was aimed at formulating a supersaturated triglyceride free drug delivery system (s-TFDDS) of lornoxicam and evaluating its in vitro and in vivo potential. s-TFDDS contain the drug above its saturation solubility and consists of a hydrophilic surfactant, a hydrophobic surfactant, solubiliser and pH modifier. D-optimal mixture experimental design was applied to optimise s-TFDDS. Three formulation variables, X 1 (Tween 20(r)), the surfactant X 2 (Capryl PGMC(r)) and X 3 (Transcutol P), were included in the design. The systems were assessed for light transmittance and solubility of lornoxicam. The values of optimised formulation components (X 1, X 2 and X 3) were 60.0, 10.0 and 30.0 %, respectively. The combination of components was optimised for maximum solubilisation capacity of lornoxicam by combined effect of pH and temperature. The optimised liquid preconcentrate was evaluated for particle size (small-angle neutron scattering study), robustness to precipitation, effect of polymer on precipitation inhibition and by in vitro dissolution. The liquid preconcentrate was adsorbed on solid carrier (Neusilin US2, Sylysia 320) and characterised by in vitro dissolution, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy study. An increase in dissolution (DE15min, 100 %) in simulated gastric fluid at pH 1.2 was achieved without precipitation of lornoxicam. Spectral characterisation reveals no sign of lornoxicam precipitation on solid carriers. Comparative pharmacodynamic evaluation was investigated in terms of anti-inflammatory efficacy using a rat paw oedema model in rats. The s TFDDS formulation showed the maximum percent inhibition of oedema as compared with plain and micronised lornoxicam. PMID- 25788348 TI - Preparation and characterization of solid lipid nanoparticle-based nasal spray of budesonide. AB - The present research work was aimed at developing solid lipid nanoparticle (SLN) based formulation of budesonide (BDS) for nasal delivery. Melt emulsification method was chosen for fabrication of BDS-SLN using ultrasound dispersion and hot high-pressure homogenization techniques. The Compritol888 ATO was chosen as the lipid component for SLN formulation due to highest solubility for BDS. Different surfactants were screened and it was found that combination of Tween 80 and plurol oleique has shown desired particle size with improved stability and entrapment efficiency. The optimized SLN composition had a particle size of 185.2 nm with polydispersibility index of 0.387. Entrapment efficiency of the SLN composition was observed to be 61 %. Further, the optimized SLN dispersion was formulated into nasal spray. In vitro permeation study was carried out using Ovis aries (Indian sheep) nasal mucosa and it was observed that the permeability of BDS nasal spray of SLN was increased significantly by 3.4-fold as compared to the plain BDS and 1.8-fold as compared to the marketed nasal formulation. Thus, SLN based nasal drug delivery was observed to be a promising approach for improving the bioavailability of hydrophobic drugs. PMID- 25788349 TI - Pyrimethamine nanosuspension with improved bioavailability: in vivo pharmacokinetic studies. AB - Pyrimethamine is a standard antiprotozoal drug recommended for prophylaxis and treatment of malarial infections. Limited bioavailability, slow onset of action, and life-threatening side effects restrict its use. Hence, in the present study, pyrimethamine nanosuspension was prepared with the objective to improve its dissolution rate and pharmacokinetic profile. Stable pyrimethamine nanosuspension with submicron particle size was prepared by nanoprecipitation and high-pressure homogenization techniques. Nanosizing and stabilizers modified the surface characteristics of drug particles resulting in considerable increase in the dissolution rate. The in vivo pharmacokinetic studies of the prepared nanosuspension were carried out and compared with plain pyrimethamine suspension and marketed pyrimethamine suspension. The in vivo pharmacokinetic profiling of pyrimethamine nanosuspension in rats showed higher AUC0-24 h and C max compared to the plain and marketed pyrimethamine suspensions. In contrast to its plain and marketed formulation, pyrimethamine nanosuspension showed rapid onset of action (T max 0.5 h vs. 2 h). Also, the low volume of distribution and reduced elimination half-life of the developed nanosuspension can lead to reduced side effects. Thus, improved in vitro-in vivo kinetics indicated that nanosuspension proved to be a suitable strategy for elevating the therapeutic profile of pyrimethamine. PMID- 25788350 TI - Genotoxicity evaluation of asymmetric lipid polymer hybrid nanoparticles of doxycycline hydrochloride following intravenous administration. AB - Nanoparticles, being small (<1,000 nm) in size, provide high surface area-to volume ratio as compared with the bulk materials which increase the concern about their potential toxicities. The present investigation was undertaken to evaluate the genotoxic potential of asymmetric lipid polymer hybrid nanoparticles of doxycycline hydrochloride (DH lipomer) following intravenous route. DH lipomer was prepared by modified nano-precipitation method as reported earlier. Doxycyline loading was found to be 20 +/- 2.5 %. Average particle size of DH lipomer and blank lipomer was 512 +/- 8 and 520 +/- 6 nm, respectively. Micronucleus (MN) assay was performed in adult healthy Swiss mice whereas chromosomal aberration (CA) test and comet assay were performed in healthy Holtzman rats following intravenous administration. Animals were divided into two sets, male and female, each set comprising of six groups (n = 5/group), viz., three test groups, blank lipomer (BL), vehicle control (VC), and positive control. Groups treated with 1.5 mg/kg BW DH lipomer did not show micronuclei formation in bone marrow cell, DNA damage, and CA, respectively, as compared with VC, suggesting no genotoxicity. On the other hand 3 and 6 mg/kg BW revealed significant (P > 0.001) increase in micronuclei formation, DNA damage, and chromosomal aberrations. Furthermore, BL (6 mg/kg BW) did not reveal genotoxic response in any of the tests, suggesting lipomer components as non-genotoxic. No sex-dependent variation in genotoxicity was observed. This study therefore suggests the potential safety of the proposed dose of DH lipomer at 1 mg/kg BW. An interesting highlight of the study is safety of lipomer matrix which could be exploited for other biomedical application. PMID- 25788351 TI - Optimized lysis buffer reagents for solubilization and preservation of proteins from cells and tissues. AB - Reagents that facilitate solubilization of cells and tissues while preserving the biological activity of their constituents play a major role in various applications including drug delivery. Such reagents are necessary for the accurate determination of cellular and tissue concentrations of proteins, peptides, and nucleic acids, and to measure therapeutic efficacy of drug delivery technologies. Surfactant-based reagents are commonly used for this purpose; however, their utility is marred either by limited ability to solubilize or tendency to denature the proteins during solubilization. Here, we report on the screening and identification of combinations of nonionic and zwitterionic surfactants that possess excellent ability to solubilize mechanically strong and elastic tissues such as skin, while preserving its protein constituents. The leading combination, comprising an equi-mass mixture of 3-(N,N-dimethyl myristyl ammonio) propanesulfonate (TPS, CAS number:14933-09-6) and polyoxyethylene(10) cetyl ether (Brij(r) C10, CAS number: 9004-95-9) with a total surfactant concentration 0.5 % w/v, solubilized keratinocytes and preserved the activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme in its extracts at room temperature for 7 days. The ability of this mixture to preserve GAPDH activity far exceeded that of a commonly used reagent, Triton-X100. The same mixture also helped solubilize mouse skin to extract proteins and maintain detectable activity of GAPDH in the extract for 1 day. Several other mixtures of nonionic and zwitterionic surfactants were studied. These mixtures provide new reagents for solubilization of cells and tissues for research as well as technological applications. PMID- 25788352 TI - Nanomedicine for gene therapy. AB - Viruses are promising vehicles that result in high gene expression level, but issues of safety and virulent nature prevented its extensive use. Therefore, nonviral approach was investigated with the intervention of nanomedicine. The science of nanomedicine offered an excellent platform for therapeutic delivery as they provide options to include functionalities and engineer the system. As the term 'nano' refers to the generation of a very small dimension structure, their unique physicochemical characteristics with increased surface area/volume ratio made them potential vectors to perform gene therapy. Various forms of nanoparticles are continued to be synthesised, and this review discusses the immediate barriers that nanoparticles have to encounter both during systemic movement in the body and intracellular trafficking to deliver the genes at the site of action. PMID- 25788354 TI - Liposomes as nanocarriers for anti-HIV therapy. AB - Globally, in the last three decades of medical research, the use of liposomes as carrier for anti-HIV/AIDS drugs is gaining prominence. These potential anti-HIV nanocarriers are concentric lipid bilayers which can be fabricated to protect molecules and to target the drugs to specific sites, which is the reason behind their popularity in the antiretroviral drug delivery. The development of an effective drug delivery system such as liposomes presents an opportunity to circumvent the many challenges associated with antiretroviral drug therapy. The physiochemical properties of liposomes such as size, charge, and lipid composition significantly affect the liposomal efficiency. These nanocarriers offer advantages such as drug loading both in aqueous region and within the bilayer of the vesicles, act as solubilizing agents, protect drug from degradation in the body, allow modification of the pharmacokinetic and tissue distribution patterns of the drug, provide drug targeting, and have low immunogenicity, biocompatibility, and cell specificity. Different types of liposome-based delivery systems, such as cationic, anionic, sterically stabilized, and immunoliposomes, have been studied for the anti-HIV/AIDS drug delivery. Liposomes, however, face challenges with regard to their use in antiretroviral drug delivery such as limited hydrophilic drug-loading capacity, issues related to physical and biologic stability, poor scale-up, cost, short shelf life, and toxicity. Numerous patented strategies have been granted in the USA and around the world related to these anti-HIV nanocarriers. In the present article, we have discussed the general physiological aspects of the HIV infection, relevance of the nanocarrier, liposomes, in the treatment of this disease and some recently awarded US patents and patent applications of these liposomal delivery systems for anti-HIV drugs. PMID- 25788356 TI - Catheterization & cardiovascular intervention: China special edition, editor's comments. PMID- 25788355 TI - Multifunctional nanomedicines: potentials and prospects. AB - Nanotechnology is considered to be significant innovative revolution that have found wide spectrum of applications in the fields ranging from medicine, diagnostics, electronics, and communications. Currently used pharmaceutical nanocarriers, such as dendrimers, micelles, nanoparticles, polymeric nanoparticles, microspheres, and many of the nanocarriers particularly in the area of drug delivery, offer a wide variety of useful properties, such as longevity in the blood allowing for their accumulation in pathological areas particularly those with compromised vasculature; specific targeting to certain disease sites; enhanced intracellular penetration of nanomaterial with contrast properties allowing for the direct visualization of carrier in vivo, and stimuli sensitivity allowing for triggered drug release from the carriers under certain physiological conditions. Some of the pharmaceutical carriers have already made their way into clinic, while others are still under preclinical development. Moreover, the engineering of multifunctional nanocarriers with several useful properties can significantly enhance the efficacy of many therapeutic and diagnostic protocols. These novel materials operate at the nanoscale range and provide new and powerful cutting edge tools for imaging, diagnosis, and therapy. This review considers current standing and possible future directions in the emerging area of multifunctional nanocarriers with primary attention on the combination of such properties as longevity, targetability, intracellular penetration, and contrast loading. PMID- 25788358 TI - Activity of N-coordinated multi-metal-atom active site structures for Pt-free oxygen reduction reaction catalysis: role of *OH ligands. AB - We report calculated oxygen reduction reaction energy pathways on multi-metal atom structures that have previously been shown to be thermodynamically favorable. We predict that such sites have the ability to spontaneously cleave the O2 bond and then will proceed to over-bind reaction intermediates. In particular, the *OH bound state has lower energy than the final 2 H2O state at positive potentials. Contrary to traditional surface catalysts, this *OH binding does not poison the multi-metal-atom site but acts as a modifying ligand that will spontaneously form in aqueous environments leading to new active sites that have higher catalytic activities. These *OH bound structures have the highest calculated activity to date. PMID- 25788353 TI - Inorganic nanovectors for nucleic acid delivery. AB - Nucleic acids show immense potential to treat cancer, acquired immune deficiency syndrome, neurological diseases and other incurable human diseases. Upon systemic administration, they encounter a series of barriers and hence barely reach the site of action, the cell. Intracellular delivery of nucleic acids is facilitated by nanovectors, both viral and non-viral. A major advantage of non-viral vectors over viral vectors is safety. Nanovectors evaluated specifically for nucleic acid delivery include polyplexes, lipoplexes and other cationic carrier-based vectors. However, more recently there is an increased interest in inorganic nanovectors for nucleic acid delivery. Nevertheless, there is no comprehensive review on the subject. The present review would cover in detail specific properties and types of inorganic nanovectors, their preparation techniques and various biomedical applications as therapeutics, diagnostics and theranostics. Future prospects are also suggested. PMID- 25788357 TI - Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death. AB - The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATG(Met85)), denoted here as Met(85)-TDP-35. Met(85)-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and aggregation. Furthermore, Met(85)-TDP-35 sequestered full-length TDP-43 from the nucleus to form cytoplasmic aggregates. Expression of Met(85)-TDP-35 in primary motor neurons resulted in the formation of Met(85)-TDP-35-positive cytoplasmic aggregates and motor neuron death. A neo-epitope antibody specific for Met(85) TDP-35 labeled the 35-kDa lower molecular weight species on immunoblots of urea soluble extracts from ALS-FTLD disease-affected tissues and co-labeled TDP-43 positive inclusions in ALS spinal cord sections, confirming the physiological relevance of this species. These results show that the 35-kDa low molecular weight species in ALS-FTLD can be generated from an abnormal splicing event and use of a downstream initiation codon and may represent a mechanism by which TDP 43 elicits its pathogenicity. PMID- 25788359 TI - Embryonic early-cleavage rate is decreased with aging in GnRH agonist but not inantagonist protocols. AB - PURPOSE: The aim of this study was to evaluate the correlation between embryonic early-cleavage status and the age of patients receiving either a GnRH agonist long protocol or a GnRH antagonist protocol. METHODS: This retrospective study included 534 patients undergoing a fresh cycle of oocyte retrieval and day-3 embryo transfer. Of the 534 patients treated, 331 received a GnRH agonist long stimulation protocol (GnRH agonist group) for ovarian stimulation and 203 patients received a GnRH antagonist protocol (GnRH antagonist group). RESULTS: By logistic regression analysis, the rate of embryonic early-cleavage was significantly decreased with increasing age of women in the agonist (P < 0.001) but not in antagonist groups (P = 0.61). Based on the results of this study, maternal age is a critical factor for embryonic early-cleavage in agonist protocol but not in antagonist protocol. The results also showed that early cleavage embryos were of better quality and resulted in a higher pregnancy rate than late-cleavage embryos in the GnRH agonist group. However, embryo quality and pregnancy rate was not significantly different between early and late cleavage embryos in the GnRH antagonist group. CONCLUSIONS: We conclude that embryonic early-cleavage status is negatively correlated with aging in women receiving GnRH agonist long down-regulation but not in GnRH antagonist protocols. We also conclude that early cleavage of the zygote is not a reliable predictor for pregnancy potential using the GnRH antagonist protocol. PMID- 25788360 TI - Factors associated with general self-efficacy and resilience among youth heads of households in Kenya. AB - This study assesses resilience and general self-efficacy among Kenyan orphans and vulnerable children (n = 1060) active in a community-based program combining economic household strengthening with psychosocial support. Quantile regression analyses modeled associations between the 25th, 50th, and 75th percentiles of resilience and general self-efficacy and multiple covariates. Program participation positively predicted increased general self-efficacy at all levels. Program participation predicted increased resilience at the 25th percentile but decreased resilience at the 75th percentile. Other significant predictors included economic, educational, sexual behavior and other demographic factors. This study suggests support for an integrated approach to economic and psychosocial empowerment. PMID- 25788361 TI - Cardiovascular Changes After Gastric Bypass Surgery: Involvement of Increased Secretions of Glucagon-Like Peptide-1 and Brain Natriuretic Peptide. AB - BACKGROUND: Obesity induces cardiovascular alterations, including cardiac hypertrophy, impaired relaxation, and heart rate variability (HRV), which are associated with increased mortality. Gastric bypass surgery (GBP) reduces cardiovascular mortality, but the mechanisms involved are not clearly established. To date, the implication of postsurgical hormonal changes has not been tested. Our aim was to study the relationships between the evolution of cardiovascular functions after GBP and changes in metabolic and hormonal parameters, including glucagon-like peptide-1 (GLP-1) and brain natriuretic peptide (N-terminal pro-brain natriuretic peptide (NT-proBNP)). METHODS: Echocardiographic parameters, 24-h rhythmic Holter recording, plasma concentrations of GLP-1 before and after a test meal, and fasting NT-proBNP were assessed in 34 patients (M/F 2/32, age 36 +/- 11 years, BMI 46 +/- 6 kg/m(2)), before and 1 year after GBP. RESULTS: After GBP, excess weight loss was 79 +/- 20%. Blood pressure (BP), heart rate, and left ventricular mass decreased, while HRV and diastolic function (E/A ratio) improved. Plasma concentrations of NT proBNP and postprandial (PP) GLP-1 increased. Changes in cardiovascular parameters were related to BMI and insulin sensitivity. Furthermore, the decrease in BP was independently associated with the increase of PP GLP-1 level and HRV was positively associated with NT-proBNP concentration after surgery. CONCLUSIONS: The increase in endogenous GLP-1 observed after GBP was associated with decreased BP but not with improvement of other cardiovascular parameters, whereas the increase in NT-proBNP, within the physiological range, was associated with improved HRV. PMID- 25788362 TI - Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma. AB - Small interfering RNAs (siRNAs) are small RNA molecules that have a potent, sequence-specific gene silencing effect and therefore show promise for therapeutic use as molecular-targeted drugs for the treatment of various genetic diseases, including cancer. The aim of the present study was to evaluate whether Argonaute2 (Ago2) is a therapeutically effective target for siRNA-based cancer therapy. Ago2 is the key protein in mammalian RNAi and is also known as the only member of the Ago family that mediates the microRNA (miRNA)-dependent cleavage of targeted mRNAs. It is assumed that these unique properties of the Ago2 protein can play a central role in the regulation of the miRNA pathway and subsequent translational inhibition of miRNA-targeted mRNAs, including cell survival and cancer progression. To assess its therapeutic effect, siRNA against Ago2 (Ago2 siRNA) was transfected into HT1080 human fibrosarcoma cells, which are malignant cancer cells. Ago2 gene silencing resulted in the inhibition of cell growth and the induction of apoptosis and G0/G1 arrest in the cell cycle. In addition, Ago2 knockdown induced morphological changes and actin stress fiber formation in the cells. The results of a microarray study showed that Ago2 suppression stimulated several crucial genes related to apoptosis, the cell cycle, immune response, cell adhesion, metabolism, etc. Repeated intratumoral injection of Ago2-siRNA/cationic liposome complex induced tumor growth suppression in an HT1080 xenograft model. These results suggest that the suppression of the Ago2 gene may be useful for the inhibition of cancer progression and that Ago2 may be a desirable target for siRNA-based cancer therapy. PMID- 25788363 TI - Electrostatic droplets assisted synthesis of alginate microcapsules. AB - This paper demonstrates a proof-of-concept approach for encapsulating the insulin and Fe3O4 nanoparticles into size-controllable alginate microcapsules utilizing the electrostatic droplets (ESD) technique. We have established that the combination of ESD and external gelation is quite effective in producing uniform sized polymer particles. In addition, using the external gelation technique, the droplets containing a sodium-alginate were gelled in situ by immersion in Ca(2+), Ba(2+), or Cu(2+) ions for a few minutes. The results show that different-type divalent cations caused various surface features to appear on the microcapsules (e.g., cracking, orange peel, pitting, splitting, wrinkling, etc.). The particle size can be adjusted from a few micrometers to ca. 1,000 MUm by electrostatic force. The microcapsules can be made magnetic by incorporating a super paramagnetic nanomaterial (e.g., Fe3O4 nanoparticles) during the preparation. The composite magnetic microcapsules are potential candidates for a magnetic responsive drug delivery system. In addition, our results show that the encapsulation and in vitro release of a model drug, insulin, can enhance the effect of the controlled release. These microcapsules are addressable by an external magnetic field and are capable of loading a model drug and releasing it in a highly differential drug release profile. We have demonstrated that the appropriate magnetic field intensity for different release patterns is predictable, which enables a better application of microcapsules as a smart drug carrier. PMID- 25788364 TI - Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin. AB - The development of alternative routes to the conventional subcutaneous administration of insulin is expected to provide an important advance in the management of diabetes. The aim of this work was to produce and characterize chitosan-coated Witepsol 85E solid lipid nanoparticles (SLN) containing insulin, and to evaluate the potential of these colloidal carriers for oral administration. SLN were prepared by a modified solvent emulsification evaporation method based on a water/oil/water double emulsion followed by chitosan adsorption to SLN surface. Optimized chitosan-coated SLN presented a mean particle size around 450 nm and were positively charged, indicating synergic properties for intestinal absorption. Higher extent of insulin permeation was observed for SLN and chitosan-coated SLN in a Caco-2 cell monolayer model. When comparing both SLN formulations, chitosan coating was shown to provide higher insulin permeation. Also, similar effects were also observed using a Caco-2/HT29 monolayer model, which more closely resemble the intestinal membrane, thus indicating that the mucoadhesive properties and permeation enhancement effect of chitosan may contribute significantly to the enhanced insulin permeation. After oral administration of insulin-loaded SLN to diabetic rats, a considerable hypoglycemic effect was observed for 24 h, which was more pronounced when chitosan-coated SLN were used, resulting in relative pharmacological bioavailabilities of 8% and 17% for uncoated and chitosan-coated SLN, respectively. Also, fluorescently labeled insulin was located on the intestinal walls and internalized into enterocytes after administration in chitosan-coated SLN, thus revealing the effectiveness of this nanocarrier in promoting the intestinal absorption of insulin. In conclusion, the use of chitosan-coated SLN may provide an interesting platform for the development of oral insulin formulations to be used in the management of diabetes. PMID- 25788365 TI - Preparation and characterization of niosomal gel for iontophoresis mediated transdermal delivery of isosorbide dinitrate. AB - The purpose of the present study was to improve the bioavailability of isosorbide dinitrate (ISDN) through transdermal route by using cationic niosomal gel as a carrier with anodic iontophoresis. ISDN-loaded cationic niosomes prepared by thin film hydration technique had an average diameter of 262 +/- 6.92 nm, polydispersity index of 0.217 +/- 0.02, zeta potential of +25.4 +/- 0.12, and entrapment efficiency of 68.16 +/- 1.14%. The prepared niosomes were incorporated in minimum quantity of carbopol gel which exhibited thixotropic behavior suitable for transdermal application. While free drug was found to degrade upon application of current, interestingly, it was a found that niosomes offered protection to ISDN from degradation during the iontophoresis. The in vitro permeation studies with different current densities showed increase in transdermal flux and decrease in lag time by 11.15- and 2.42-fold (0.5 mA/cm(2)), 12.66- and 2.58-fold (1.0 mA/cm(2)), and 14.46- and 3.75-fold (1.5 mA/cm(2)), respectively, as compared to passive diffusion of free drug. The study confirms the synergistic effect of niosomes and iontophoresis in improving the transdermal permeation profile of ISDN. The enhanced permeation by iontophoresis was investigated by scanning electron microscopy and it was observed that "latent shunt" around the hair follicles became activated and their pore size also increased upon increasing the current densities. Finally, in vivo skin permeation studies demonstrated 2.47 times increased in transdermal bioavailability of ISDN using niosomes in comparison to free drug. The study confirmed that both niosomes and iontophoresis enhance transdermal permeation by two different mechanisms and combination of both has synergistic effect that resulted in higher transdermal flux of ISDN. PMID- 25788366 TI - Comparative oral bioavailability advantage from curcumin formulations. AB - The aim of the present study was to study the oral bioavailability of seven different formulations of curcumin (CRM). CRM formulations viz. aqueous suspension, micronized suspension, nanosuspension, amorphous solid dispersion, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) inclusion complex, combination with piperine, and spray-dried CRM-milk composite were compared for oral bioavailability in male Sprague-Dawley rats at a CRM dose of 250 mg/kg body weight using a validated high-performance liquid chromatography method. Aqueous suspension provided a C max and AUC(0 - t) of 28.9 ng/ml and 26.9 ng h/ml, respectively. In comparison, statistically significant increase in the oral bioavailability was obtained with the nanosuspension, HP-beta-CD inclusion complex, and amorphous solid dispersion with 251%, 567%, and 446% increase in terms of AUC(0 - t) and 405%, 415%, and 270% in terms of C max. However, no significant increase in AUC(0 - t) and C max was observed with piperine and micronized suspension. The milk composite reduced the oral bioavailability of CRM (10% and 37% in terms of AUC(0 - t) and C max). A statistically significant increase in the T max was observed with piperine and in HP-beta-CD complex, while the T max was reduced for nanosuspension. The results provide interesting insights into the role of solubility enhancement and metabolism inhibition, for improving the oral bioavailability of CRM. PMID- 25788367 TI - Curcumin implants for continuous systemic delivery: safety and biocompatibility. AB - Curcumin, an anti-oxidant, anti-inflammatory, and anti-neoplastic agent, exhibited limited oral efficacy due to its poor bioavailability. To overcome this limitation, polymeric implants for continuous systemic delivery of curcumin were developed and tested for their safety and biocompatibility. Two 2-cm polycaprolactone implants containing polyethylene glycol and 20% (w/w) curcumin were grafted subcutaneously at the back of the Augustus Copenhagen Irish rats. Rats were euthanized and blood was analyzed for various hematological parameters; biochemical markers of liver/kidney function and local tissues were analyzed for local inflammatory reactions. Curcumin implants exhibited biphasic release kinetics with ~3.6 + 0.8, 5.8 +/- 1.1, 13.1 +/- 2.1, 21.8 +/- 0.3, 38.1 +/- 0.6, and 47.2 +/- 1.6 mg cumulative curcumin being released from both the implants after 1, 4, 12, 25, and 90 days. No significant differences in various hematological parameters (like white blood cells, red blood cells, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), liver enzymes (like aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, amylase, or lipase), or biochemical parameters of kidney function (like blood urea nitrogen, creatinine, Ca(2+), Na(+), and Cl(-) levels) were observed at any of these time points. However, a significant increase in serum phosphorus levels was observed at all the time points in sham implants as well as in curcumin diet and implant groups. Local implantation site showed foreign body granulomatous reaction with influx of histiocytes and occasional multi-nucleated giant cells with sham implants and was minimal around the curcumin implants. These polymeric implants were found to have little or no systemic toxicity with an acute reaction at local site which was reduced significantly by curcumin implants. PMID- 25788368 TI - A miniature, single use, skin-adhered, low-voltage, electroosmotic pumping-based subcutaneous infusion system. AB - A programmable, skin-attached, 36 * 30 * 8 mm system for subcutaneous infusion of 1.2 mL of a drug solution is described. The system is intended to be replaced daily. It comprises a 20 * 14 * 8 mm electronic controller and power source, an 8 mm diameter 2 mm thick electroosmotic pump, a two-compartment reservoir for a pumped water and a drug solution, an adhesive tape for attachment to the skin, and a 6 mm long 27 gauge needle. Its removable electronic controller programs the dose rate and dose and is re-used. The electroosmotic pump consists of a porous ceramic membrane sandwiched between a pair of Ag/Ag2O plated carbon paper electrodes. It operates below 1.23 V, the thermodynamic threshold for water electrolysis without gassing. The flow rate can be adjusted between 4 and 30 MUL min(-1) by setting either by the voltage (0.2-0.8 V) or the current (30-200 MUA). For average flow rates below 4 MUL min(-1), the pump is turned on and off intermittently. For example, a flow rate of 160 MUL day(-1), i.e., 0.13 MUL min( 1) for basal insulin infusion in type 1 diabetes management, is obtained when 10 s pulses of 75 MUA is applied every 15 min. High flow rates of 10-30 MUL min(-1), required for prandial insulin administration, are obtained when the pump operates at 50-200 MUA. To prevent fouling by the drug, only pure water passes the pump; the water pushes a drop of oil, which, in turn, pushes the drug solution. PMID- 25788369 TI - Variability of laboratory parameters is associated with frailty markers and predicts non-cardiac mortality in hemodialysis patients. AB - BACKGROUND: The levels of many laboratory parameters are associated with the outcomes of dialysis patients, but the significance of their variability has not been well studied. METHODS: A total of 384 patients receiving stable hemodialysis treatment during 2002 were followed up for mortality until the end of 2013. The within-patient coefficients of variation (CV) were calculated for 13 laboratory parameters from 1 year of data. We defined variability as CV and analyzed the survival of the patients according to the baseline CV values of each parameter by proportional hazard modeling. RESULTS: During the 11-year observation period, 125 patients died. Higher CV levels for eight parameters, namely, blood urea nitrogen (BUN), sodium, hemoglobin, creatinine, total protein, albumin, potassium and phosphate, were significantly associated with all-cause mortality. The adjusted hazard ratios for a high BUN-CV (>15 %) and a high Na-CV (>1.3 %) against a lower CV were 1.92 (95 % CI 1.31-2.81) and 1.95 (1.36-2.80), respectively. The increased mortality risk associated with each variability was attributed to excess non-cardiac deaths. The CV values of most parameters were correlated with each other and often exhibited negative associations with age, diabetes, and mobility as well as the levels of hemoglobin, albumin, creatinine, Na, the protein catabolic rate, and the creatinine generation rate. Therefore, a high variability was generally associated with frailty-related adverse prognostic factors. CONCLUSIONS: The variability of several blood parameters had a significant impact on all-cause and non-cardiac mortality. The levels of the variabilities were most likely related to poor physical conditions of the patients. PMID- 25788370 TI - Mechanical stretch-induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection. AB - Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimuli, endoplasmic reticulum (ER) stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to TAAD. Therefore, we studied the role of ER stress in TAAD formation. A lysyl oxidase inhibitor, 3-aminopropionitrile fumarate (BAPN), was administrated to induce TAAD formation in mice, which showed significant SMC loss (alpha-SMA level). Excessive apoptosis (TUNEL staining) and ER stress (ATF4 and CHOP), along with inflammation, were present in TAAD samples from both mouse and human. Transcriptional profiling of SMCs after mechanical stress demonstrated the expression of genes for ER stress and inflammation. To explore the causal role of ER stress in initiating degenerative signalling events and TAAD, we treated wild-type (CHOP(+/+)) or CHOP(-/-) mice with BAPN and found that CHOP deficiency protected against TAAD formation and rupture, as well as reduction in alpha-SMA level. Both SMC apoptosis and inflammation were significantly reduced in CHOP(-/-) mice. Moreover, SMCs isolated from CHOP(-/-) mice were resistant to mechanical stress-induced apoptosis. Taken together, our results demonstrated that mechanical stress-induced ER stress promotes SMCs apoptosis, inflammation and degeneration, providing insight into TAAD formation and progression. PMID- 25788371 TI - Time to update radiological criteria for non-invasive diagnosis of hepatocellular carcinoma. PMID- 25788372 TI - Use of BAR score as predictor of short and long-term survival of liver transplantation patients. PMID- 25788373 TI - Is hepatitis C subtyping still relevant in the era of direct-acting antiviral therapy? PMID- 25788374 TI - How to achieve immune control in chronic hepatitis B? AB - Chronic hepatitis B infection remains a major global health problem despite the existence of an effective vaccine. The current treatment options are either nucleos(t)ide analog therapy, which inhibits viral replication, or peginterferon alpha, which has mainly immunomodulatory effects. However, treatment-induced HBeAg seroconversion with suppressed viral replication is mostly not sustainable, and loss of HBsAg is a rarely achieved endpoint. In addition, the hepatitis B virus persists in hepatocytes even after HBsAg clearance as covalently closed circular DNA is not eliminated from the hepatocytes. Because the course of chronic hepatitis B is determined by an ongoing interaction between the virus and the host immune system, immunomodulation may be the most logical approach in attempting to accomplish control or even cure of chronic hepatitis B. In the last years, methods for measuring the degree of immune control have been a major area of interest, with an important role for monitoring of HBsAg levels. In addition, new immunomodulatory agents are being developed and tested, providing promising options for future treatment. PMID- 25788375 TI - Immunologic, hemodynamic, and adrenal incompetence in cirrhosis: impact on renal dysfunction. AB - Acute kidney injury (AKI) is one of the most severe complications of cirrhosis and is associated with significant morbidity and mortality. Liver fibrosis and liver insufficiency, portal hypertension, systemic vasodilation, and a subsequent hyperdynamic circulation undermine the renal and cardiac function, making cirrhotic patients more susceptible to hemodynamic incidents. In addition, the immune system is impaired in cirrhosis, leading to an exaggerated production of vasoactive mediators, and the adrenal cortisol response is insufficient, which causes further impairment of the vascular tonus, cardiac output, and renal perfusion. Consequently, the cardiovascular and renal dysfunction is aggravated, resulting in a hepatorenal syndrome (HRS). HRS is seen exclusively in patients with liver disease and has been considered an entirely functional prerenal dysfunction, rather than a structural dysfunction, but is not responsive to volume expansion. Recent research indicates that development of hepatic nephropathy represents a continuous spectrum of functional and structural dysfunction and may be precipitated by the inherent immunologic, adrenal, and hemodynamic incompetence in cirrhosis. New research explores several new markers of renal dysfunction that may replace serum creatinine in the future and give new insight on the hepatic nephropathy. Our understanding of the pathophysiological mechanisms causing the immunologic, adrenal, and hemodynamic incompetence, and the impact on renal dysfunction, has improved in recent years, and in this review we aim to highlight recent achievements in this field. PMID- 25788376 TI - Novel insights in preventing Gram-negative bacterial infection in cirrhotic patients: review on the effects of GM-CSF in maintaining homeostasis of the immune system. AB - Cirrhotic patients with dysfunctional and/or low numbers of leukocytes are often infected with bacteria, especially Gram-negative bacteria, which is characterized by producing lipopolysaccharide (LPS). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that influences the production, maturation, function, and survival of various immune cells. In this paper, we reviewed not only Toll-like receptors 4 (TLR4) signaling pathway and its immunological effect, but also the specific stimulating function and autocrine performance of GM-CSF on hematopoietic cells, as well as the recent discovery of innate response activator-B cells in protection against microbial sepsis and the direct LPS-TLR4 signaling on hematopoiesis. Thus we concluded that GM-CSF might play important roles in preventing Gram-negative bacterial infections in cirrhotic patients through maintaining immune system functions and homeostasis. PMID- 25788377 TI - Clinical significance of circulating miR-122 in patients with dual chronic hepatitis B and C virus infection. AB - BACKGROUND: The clinical significance of serum microRNA-122 (miR-122) has been shown in viral hepatitis B and C, respectively. Specifically, miR-122 stimulates hepatitis C virus (HCV) replication but suppresses hepatitis B virus (HBV) replication. The profile and clinical significance of serum miR-122 in patients with dual chronic hepatitis B and C would be an interesting and important clinical issue. METHODS: A total of 76 patients with HBV/HCV dual infection, 105 with HCV monoinfection and 39 with HBV monoinfection were enrolled. All patients received peginterferon alfa-2a (PEG-IFN)-based treatment. Serum miR-122 levels were quantified by using a sensitive hybridization-based assay. RESULTS: At baseline, the serum miR-122 level was lower in HCV-monoinfected patients than in HBV-monoinfected patients, whereas HBV coinfection increased the expression of miR-122. In multivariate analysis, the serum miR-122 level was positively correlated with the serum HBsAg level in patients with HBV/HCV dual infection and those with HBV monoinfection. In dually infected patients who received PEG-IFN based treatment, a high baseline miR-122 level was positively correlated with a greater reduction of the posttreatment serum HBsAg level. CONCLUSION: In summary, the serum miR-122 level is highly correlated with the HBsAg level in HBV/HCV dually infected patients and may serve as a biomarker to predict posttreatment HBsAg decline. PMID- 25788378 TI - Reimbursement policies in the Asia-Pacific for chronic hepatitis B. AB - BACKGROUND: There is considerable variation in reimbursement policies in Asian countries and this is likely to have an impact on treatment practice for chronic hepatitis B (CHB). Consequently a survey of leading hepatologists was performed to evaluate such policies and their impact on management of CHB in the Asia Pacific region. METHODS: A questionnaire was sent to key hepatologists in Asia Pacific for information on CHB reimbursement policy-its nature, coverage, funding source, duration, review strategy and impact on Asia Pacific Association for the Study of the Liver (APASL) CHB guidelines. The results were analysed and described. RESULTS: Leading hepatologists from 16 Asia Pacific countries responded. Almost all of the countries have reimbursement policies but eligibility varied from only a limited group (e.g. civil servants only) to universal access. In most instances reimbursement was from the central government (except China, Pakistan and Hong Kong). Reimbursement policies were usually created by Ministry of Health committees, who received input from medical professionals, although they may not be aware of the APASL guidelines. Policies were limited by available resources, funds and prioritization. Where there was a regular review this occurred between 1 and 5 years. The quantum of reimbursement varied from 50% in Singapore to 100% in the majority of other countries. The criteria for treatment reimbursement were based on doctor's opinion alone (Bangladesh, India, Pakistan, Philippines, Singapore and Vietnam) or specific clinical/laboratory criteria in the rest of the countries. In general, most countries offered unlimited duration for reimbursement except Taiwan, Indonesia and Pakistan. Monitoring tests for treatment response were reimbursed in all countries other than Vietnam. Viral resistance was diagnosed by viral or biochemical breakthrough, and viral resistance testing was uncommon. The main rescue therapy was adefovir. CONCLUSION: Reimbursement policies differed from country to country, the quantum and the proportion of patients who received reimbursement also varied significantly. Asia Pacific countries were able to follow APASL guidelines with variable success based on their reimbursement policies. PMID- 25788379 TI - HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome. AB - AIM: To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA). PATIENTS AND METHODS: A total of 1,233 naive patients with HCV genotype-1 infection, 159 (13%) with subtype 1a and 1,074 (87%) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma glutamiltranspeptidase (gammaGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype. RESULTS: At multivariate analysis, baseline characteristics differentiating patients with HCV 1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37% of patients with subtype 1b and 45% of those with subtype 1a, a nonsignificant difference of 8% (p = 0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98-16.83), RVR (OR 4.18, CI 1.66 10.55), female gender (OR 2.83, CI 1.83-6.78), and HCVRNA (OR 0.55, CI 0.32 0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32-9.73), IL28B CC (OR 3.32, CI 2.15-4.58), gammaGT (OR 1.59, CI 0.14 2.22), HCVRNA (OR 0.61, CI 0.47-0.79), and age (OR 0.01, CI 0.02-0.42). CONCLUSION: In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response. PMID- 25788380 TI - A comparative study of patients' knowledge about hepatitis C in the United States and in urban and rural China. AB - BACKGROUND: Hepatitis C (HCV) is the predominant cause of chronic liver disease in the USA and is increasingly recognized as a common cause of liver disease in China. Studies of HCV patients in the US found major gaps in knowledge but little is known about HCV knowledge among patients in China. METHODS: We conducted a survey in three cohorts of HCV patients in Ann Arbor, MI, US, and in Beijing and Hebei, China, between April and November 2012 to compare patient knowledge about HCV in the US and in urban and rural China. RESULTS: A total of 525 patients (US 186; Beijing 186; Hebei 153) were enrolled. Mean ages of the three cohorts ranged from 52-56 years; 63% of US and 47% of Chinese patients were males; 63% of US and 39% of Beijing patients had college or postgraduate education compared to 0.7% in Hebei. More than half of the US and Beijing patients but only 13% of Hebei patients had received HCV treatment. The average HCV knowledge score out of a total of 16 in the US, Beijing, and Hebei was 12.7, 11.7, and 6.4, respectively (p < 0.001). Study site, education, gender, and prior HCV treatment were independent predictors of HCV knowledge. CONCLUSIONS: Knowledge about HCV in the US and Beijing patients was similar and significantly better than in Hebei patients. Our data show that efforts to improve HCV knowledge are necessary for all three cohorts and should be tailored to the education level and health literacy of the patients. PMID- 25788381 TI - Prognostic effect of response to interferon therapy after laparoscopic splenectomy among patients with marked thrombocytopenia and hepatitis C virus related cirrhosis. AB - BACKGROUND/PURPOSE: Laparoscopic splenectomy enables patients with marked thrombocytopenia and hepatitis C virus (HCV)-related cirrhosis to receive sufficient interferon-based therapy. The purpose of this study was to evaluate whether the response to interferon after laparoscopic splenectomy contributes to the survival of cirrhotic patients with marked thrombocytopenia. METHODS: Eighty seven patients with marked thrombocytopenia and HCV-related cirrhosis who met the inclusion criteria were enrolled. Of the 87 patients, 65 underwent laparoscopic splenectomy for IFN therapy, and 22 patients declined laparoscopic splenectomy and IFN therapy. Finally, 61 patients received IFN therapy after splenectomy, and 26 patients did not receive IFN therapy. RESULTS: The numbers of patients in the sustained virological response (SVR) group, the transient response (TR) group, the no response (NR) group, and the no interferon (IFN) group were 25, 12, 24, and 26, respectively. Seven-year survival in the SVR group, the TR group, NR group, and the no IFN group was 86, 76, 44, and 42%, respectively. When the response group was defined as the SVR or TR group, survival was significantly higher for the response group than for the other groups. However, there was no significant difference between survival in the NR and no IFN groups. On multivariate analysis, independent factors related to survival were the response to interferon, the presence of esophageal varices, and a history of treatment for hepatocellular carcinoma. CONCLUSION: A good response to interferon after splenectomy was associated with a favorable prognosis. Therefore, prediction of the efficacy of IFN therapy is crucial before splenectomy. PMID- 25788382 TI - High sustained virological response to pegylated interferon and ribavirin for recurrent genotype 3 hepatitis C infection post-liver transplantation. AB - INTRODUCTION: Treatment outcomes of recurrent HCV genotype 3 (GT-3) after liver transplantation (LT) are ill-defined. AIMS: To determine efficacy, predictors, and long-term survival after treatment of recurrent HCV GT-3 infection, post-LT, with a combination of pegylated interferon (PEG) and ribavirin (RBV). METHODS: We studied all LT recipients (LTR) in our program treated with PEG and RBV for recurrent HCV GT-3 between Jan 1st 2002 and Dec 31st 2013. Antiviral therapy (AVT) was started if histology showed recurrent HCV with >= stage 2 fibrosis. Treatment was intended for 24 or 36 weeks, depending on early virologic response, and/or 24 weeks consolidation. Primary endpoint was sustained virological response (SVR). We also studied predictors of SVR and long-term patient survival. RESULTS: Among 492 LT for HCV-related cirrhosis and/or hepatocellular carcinoma performed during the study period, 110 (22%) had HCV GT-3 infection. Fifty-two (10.5%) HCV GT-3 patients had indications for AVT. Six were unable to complete the AVT, three because of clinical decompensation and one each because of metastatic disease involving the brain, lung cancer, and ductopenic rejection. Forty-seven (90%) patients achieved early virological response (EVR) and 37 (71%) achieved SVR. Predictors of SVR were EVR (p < 0.001), stage <= 3 fibrosis (p = 0.008), and 36 weeks treatment duration (p < 0.001). Less advanced fibrosis <= 3 was independent predictor of SVR (OR 0.18, 95% CI 0.05-0.67). SVR patients had actuarial (Kaplan-Meier) 1, 3, and 10 year post-treatment survival of 100, 100, and 95%, compared with 87, 78, and 20% for non-SVR patients (p < 0.001, log rank test). CONCLUSION: Efficacy of AVT for recurrent HCV GT-3 post-LT is high, and comparable with that for non-transplant patients. Less advanced fibrosis is an independent predictor of SVR. SVR improves long-term survival. PMID- 25788383 TI - Non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI as a predictor of outcomes for early-stage HCC. AB - BACKGROUND/PURPOSE: In patients with hepatocellular carcinoma (HCC), gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) often identifies non-hypervascular hypointense hepatic nodules during the hepatobiliary phase, but their prognostic significance is unclear. We conducted a prospective observational study to investigate the impact of non-hypervascular hypointense hepatic nodules detected by Gd-EOB-DTPA-enhanced MRI on the outcome of patients with early-stage HCC. METHODS: Post-treatment recurrence and survival rates were analyzed in 138 patients with non-recurrent, early-stage HCC [Barcelona Clinic Liver Cancer (BCLC) stage 0 or A] and Child Pugh A liver function according to the presence of non-hypervascular hypointense nodules on pretreatment Gd-EOB-DTPA-enhanced MRI. RESULTS: Non-hypervascular hypointense hepatic nodules were detected in 51 (37.0%) patients with early-stage HCC on pretreatment Gd-EOB-DTPA-enhanced MRI. Recurrence rates were significantly higher in patients with non-hypervascular hypointense nodules (p < 0.0001). Based on a multivariate analysis, the presence of non-hypervascular hypointense hepatic nodules on Gd-EOB-DTPA-enhanced MRI was independently associated with an increased recurrence rate, independent of tumor progression or treatment (p = 0.0005). The survival rate was significantly lower in patients with non hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI (p = 0.0108). CONCLUSIONS: In patients with early-stage typical HCC (BCLC 0 or A), the presence of concurrent non-hypervascular hypointense hepatic nodules in the hepatobiliary phase of pretreatment Gd-EOB-DTPA-enhanced MRI is an indicator of higher likelihood of recurrence after treatment and may be a marker for unfavorable outcome. PMID- 25788384 TI - Efficacy of hepatic arterial infusion chemotherapy in combination with irradiation for advanced hepatocellular carcinoma with portal vein invasion. AB - BACKGROUND: The presence of portal vein tumor thrombosis (PVTT) is a poor prognostic factor for patients with hepatocellular carcinomas (HCC). The purpose of this study was to determine the treatment effect of irradiation in combination with hepatic arterial infusion chemotherapy (HAIC) for these patients. METHODS: We retrospectively examined the outcome of 67 HCC patients with PVTT of the main trunk or first branch who received HAIC alone or with concurrent irradiation for PVTT (CCRT). RESULTS: Thirty-four patients received HAIC, and 33 patients received CCRT. The time to progression (TTP) of PVTT in the CCRT group was significantly longer than in the HAIC group (p < 0.01), and the TTP of intrahepatic nodules in the CCRT group tended to be longer than in the HAIC group (p = 0.06). The objective response rates of intrahepatic nodules (52 vs. 18%, p < 0.01) and PVTT (45 vs. 18%, p = 0.01) were both significantly higher in the CCRT group than in the HAIC group, respectively. No significant difference in overall survival was found between the two groups (p = 0.14); however, the median survival time in the CCRT group was longer than that in the HAIC group (12.4 vs. 5.7 months, respectively). CONCLUSIONS: CCRT might be a promising treatment for advanced-stage HCC with PVTT. CCRT prolonged the TTP of intrahepatic nodules and PVTT, and it improved the objective response rate of intrahepatic nodules and PVTT. PMID- 25788385 TI - Application of the BAR score as a predictor of short- and long-term survival in liver transplantation patients. AB - BACKGROUND: The balance of risk (BAR) is a prediction system after liver transplantation. METHODS: To assess the BAR system, a retrospective observational study was performed in 402 patients who had transplant surgery between 1997 and 2012. The BAR score was computed for each patient. Receiver operating characteristic curve analysis with the Hosmer-Lemeshow test was used to calculate sensitivity, specificity, and model calibration. The cutoff value with the best Youden index was selected. Statistical analysis employed the Kaplan-Meier method (log-rank test) for survival, the Mann-Whitney test for group comparison, and multiple logistic regression analysis. RESULTS: 3-month survival was 46% for BAR >= 11 and 77% for BAR <11 (p = 0.001); 12-month survival was 44% for BAR >= 11 and 69% for BAR <11 (p = 0.001). Factors of survival <3 months were BAR >= 11 [odds ratio (OR) 3.08; 95% confidence interval (CI) 1.75-5.42; p = 0.001] and intrasurgical use of packed red blood cells (RBC) above 6 units (OR 4.49; 95% CI 2.73-7.39; p = 0.001). For survival <12 months, factors were BAR >= 11 (OR 2.94; 95% CI 1.67-5.16; p = 0.001) and RBC >6 units (OR 2.99; 95% CI 1.92-4.64; p = 0.001). CONCLUSIONS: Our study contributes to the incorporation of the BAR system into Brazilian transplantation centers. PMID- 25788386 TI - Efficacy of vasopressin/terlipressin and somatostatin/octreotide for the prevention of early variceal rebleeding after the initial control of bleeding: a systematic review and meta-analysis. AB - PURPOSE: Our purpose was to conduct a meta-analysis to compare the effectiveness of vasopressin/terlipressin and somatostatin/octreotide on variceal re-bleeding within and after 5 days of initial control bleeding. METHODS: A search was conducted of PubMed, the Cochrane database, and Google Scholar until June 31, 2014 using combinations of the search terms: esophageal varices, variceal re bleeding, recurrent variceal hemorrhage, early re-bleeding, vasopressin, somatostatin, terlipressin, octreotide. Inclusion criteria were: (1) randomized controlled trials, (2) patients with esophageal or esophageal and gastric varices confirmed by endoscopy, (3) re-bleeding control was evaluated, (4) treatment with somatostatin/vasopressin. Outcome measures were the re-bleeding rates within 5 days (<= 5 days) or after 5 days (>5 days) after initial treatment. RESULTS: Six studies were included in the analysis. Five studies had complete data of re bleeding rate within 5 days after initial treatment, and the combined odds ratio (OR) of 0.87 [95% confidence interval (CI) 0.51, 1.50] indicated that there was no difference in the re-bleeding rate between patients treated with vasopressin/terlipressin or somatostatin/octreotide. Two studies had complete data of the re-bleeding rate 5 days after initial treatment, and the combined OR of 1.12 (95% CI 0.64, 1.95) indicated there was no difference in the re-bleeding rate between patients who were treated with vasopressin/terlipressin or somatostatin/octreotide. CONCLUSION: There is no difference between vasopressin/terlipressin and somatostatin/octreotide in prevention of re-bleeding after the initial treatment of bleeding esophageal varices. PMID- 25788387 TI - Insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) contributes to liver inflammation and fibrosis via activation of the ERK1/2 pathway. AB - BACKGROUND AND AIM: Previously, we suggested that IGFBPrP1 played a major role in hepatic stellate cell (HSC) activation, yet the molecular mechanism of IGFBPrP1 in hepatic fibrosis is unclear. The ERK pathway is involved in activation of HSCs. This study investigated the involvement of the ERK1/2 pathway in IGFBPrP1 induced liver inflammation and fibrosis. METHODS: An adenoviral vector encoding IGFBPrP1 (AdIGFBPrP1) was constructed. Rats received AdIGFBPrP1 or CAd (vector control) via their tail vein injection. One hour prior to adenoviral injections, rats were intraperitoneally administrated with 10 mg/kg U0126 (a specific MEK/ERK1/2 inhibitor) or DMSO (vehicle control). At weeks 2 or 4 post-gene transduction, serum samples were obtained and the levels of liver enzymes and hydroxyproline were determined. Liver tissue were histologically evaluated for inflammation and fibrosis. The expression of alpha-SMA and ECM were evaluated by qRT-PCR and western blotting. RESULTS: After transduction, IGFBPrP1 expression significantly increased in livers and transduced cells. MEK/ERK1/2 inhibition administration of AdIGFBPrP1-treated rats and cells significantly blocked AdIGFBPrP1-induced activation of ERK1/2. U0126 significantly down-regulated the number of F4/80-positive cells and CD3-positive cells (markers of liver inflammation), the expression of alpha-SMA and the concentration of ECM components in vivo. In addition, alpha-SMA and TGF-beta1 levels in AdIGFBPrP1 HSCs were markedly inhibited by a MEK/ERK1/2 inhibitor, indicating that HSC activation was inhibited. CONCLUSION: These findings suggest that IGFBPrP1 acts as an initiator of liver fibrosis by inducing inflammation, HSC activation and ECM deposition through the ERK1/2 pathway. PMID- 25788388 TI - Intraarterial 5-fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma. AB - PURPOSE: The prognosis in advanced biliary carcinoma has remained poor. The purpose of this study was to investigate the efficacy of intraarterial 5 fluorouracil and interferon therapy against unresectable biliary carcinoma. METHODS: Patients with unresectable biliary carcinoma with performance status 0 or 1 were enrolled between January 2002 and September 2012. They received pegylated interferon-alpha 2a and intraarterial 5-FU every 4 weeks. The therapy was either terminated at the end of the first cycle for the patients with progressive disease or continued for at least three cycles. Patients' characteristics (physical, laboratory and radiographic) at the time of starting intraarterial 5-FU therapy were investigated. The relationship between the patients' characteristics and outcome, i.e., survival time and radiographic therapeutic evaluation of patients, was statistically analyzed. RESULTS: Tumor sites were the intrahepatic bile ducts in 23 patients and gallbladder in 2 patients. Previous treatment had been administered in ten patients. The overall response rate was 24% (6 partial responses in 25 patients). Stable disease was observed in 13 patients. The median overall survival was 358 days. Among the six partial responses, three patients received surgery, and one patient received radiofrequency ablation because clinical downstaging was obtained. The treatment was well tolerated. The survival analyses revealed that two factors (serum albumin >= 3.5 and hypovascular tumor) were significantly associated with overall survival. CONCLUSIONS: Combination therapy with 5-FU and interferon-alpha was safe and may improve the prognosis of advanced biliary carcinomas. PMID- 25788390 TI - A universal method for the preparation of functional ITO electrodes with ultrahigh stability. AB - A universal method for electrodeposition of various materials onto an indium tin oxide (ITO) coated substrate with high mechanical stability, which solves one of the most important problems concerning the modified ITO electrodes in practical applications, is presented. PMID- 25788389 TI - FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, protects sinusoid endothelial cells from radiation injury in vitro. AB - PURPOSE: To determine whether FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, would protect sinusoid endothelial cells (SECs) from radiation injury in vitro. MATERIALS AND METHODS: The effect of FTY720 on the viability of irradiated human liver SECs were examined by MTT assay or FACS analysis. The effect of FTY720 on the survival of hepatocellular carcinoma cell line, HepG2 and McA-RH7777, were determined by clonogenic assays. The activation of Akt pathway was tested by western bolt. RESULTS: FTY720 increases the survival of irradiated SECs; in contrast, it does not appear to be radioprotective of tumor cells. Furthermore, the activation of Akt pathway was confirmed in the protective effect of FTY720 on SECs. CONCLUSION: These results suggest that FTY720 will be a potential therapeutic protector for the SEC apoptosis during RILD. PMID- 25788392 TI - Observation of large positive magneto-resistance in bubble decorated graphene oxide films derived from shellac biopolymer: a new carbon source and facile method for morphology-controlled properties. AB - We report a large positive magneto-resistance (MR) in bubble decorated graphene oxide films that are derived from shellac biopolymer as a carbon source. These films were produced on a quartz substrate by heating the biopolymer coated substrate at 900 degrees C in an argon atmosphere. The characterization data of the films using Raman, X-ray photoelectron spectroscopy, field emission scanning electron microscopy and transmission electron microscopy reveal that shellac can be used as a new carbon source to produce transparent bubble decorated graphene oxide films. The magneto-resistance results show a 130% change in the resistance of the films at 3 K under a perpendicular magnetic field of 15 T, and the value decreases exponentially up to 50 K. The observed MR properties of the bubble decorated graphene oxide films are explained using a weak anti-localization and quantum interference model in the low magnetic field region, while the Lorentz force accounts for the MR properties well in the high magnetic field region. PMID- 25788391 TI - The gender gap in mental health service use. AB - PURPOSE: This study examines why men engage less in mental health service use, by studying how gender is performed in interactions, following the doing gender perspective. We hypothesize that seeking help for mental illness may constitute a gendered role conflict among men since help seeking is associated with femininity. Therefore, we expect that men will recommend reliance on self-care options to other men, and in cases in which professional treatment is recommended, they will prefer medication to psychotherapy. We also expect that men will report greater stigmatizing attitudes. METHODS: The survey Stigma in a Global Context-Belgian Mental Health Study (2009) conducted interviews of a representative sample of the Belgian general population (N = 743). The vignette technique, depicting depressive and schizophrenic symptoms, was used. Multiple linear and logistic models were estimated in SPSS. RESULTS: In male vignettes, self-care is more likely to be recommended, both by male and female respondents. Men are less likely to acknowledge the helpfulness of psychotherapy and women rate psychotherapy as less helpful when judging a man compared to a woman. Men rate tranquilizers as more helpful for other males than that women do for other females. Furthermore, male respondents seem to ascribe more shame and blame to the situation. CONCLUSIONS: The gender gap in mental health service use is due not only to men and their negative attitudes toward help seeking, but also to structured social norms that are reconstructed in interactions. Women also contribute to the maintenance of masculinity norms. PMID- 25788393 TI - Large-area assembly of densely aligned single-walled carbon nanotubes using solution shearing and their application to field-effect transistors. AB - Dense alignment of single-walled carbon nanotubes over a large area is demonstrated using a novel solution-shearing technique. A density of 150-200 single-walled carbon nanotubes per micro-meter is achieved with a current density of 10.08 MUA MUm(-1) at VDS = -1 V. The on-current density is improved by a factor of 45 over that of random-network single-walled carbon nanotubes. PMID- 25788394 TI - Cannabinoids in late-onset Alzheimer's disease. AB - Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia. PMID- 25788395 TI - Stepwise adaptation of murine cytomegalovirus to cells of a foreign host for identification of host range determinants. AB - Ever since their first isolation 60 years ago, cytomegaloviruses have been recognized as being highly species specific. They replicate only in cells of their own or a closely related host species, while cells of phylogenetically more distant hosts are usually not permissive for viral replication. For instance, human cytomegalovirus replicates in human and chimpanzee fibroblasts but not in rodent cells, and murine cytomegalovirus (MCMV) replicates in cells of mice and rats but not in primate cells. However, the viral and cellular factors determining the narrow host range of cytomegaloviruses have remained largely unknown. We show that MCMV can be adapted stepwise to replicate in cultured human retinal pigment epithelial (RPE-1) cells and human fibroblasts. The human RPE-1 cells used for the initial adaptation step showed a pronounced contact inhibition and produced very low level of interferon-beta transcripts upon cytomegalovirus infection, suggesting that these cells provide a particularly favorable environment for adaptation. By whole genome sequencing of the 230 kbp viral genomes of several adapted mutants, a limited number of mutations were detected. Comparison of several human cell-adapted MCMV clones and introduction of specific mutations into the wild-type MCMV genome by site-directed mutagenesis allows for the identification of viral host range determinants and provides the basis for elucidating the molecular basis of the cytomegalovirus host species specificity. PMID- 25788397 TI - Laser treatment of solar lentigines on dorsum of hands: QS Ruby laser versus ablative CO2 fractional laser - a randomized controlled trial. AB - BACKGROUND: Lentigines solares (LS) on the dorsum of hands are often esthetically disturbing. Q-switched ruby laser treatment is highly effective in the treatment of these lesions. Ablative fractional photothermolysis may be a suitable alternative. We compared the Q-switched ruby laser with ablative CO2 fractional photothermolysis for the treatment of solar lentigines. OBJECTIVE: To evaluate the efficacy and side-effects of 694nm Q-switched ruby laser (Sinon) with the ablative 10,600nm CO2 fractional laser (Quantel Excel O2) in an intra-individual side-to-side comparison in the treatment of LS on the dorsum of hands. MATERIAL AND METHODS: Eleven patients were included in the study. The hands of each patient were randomized for treatment with the two laser systems. Three treatment sessions were scheduled at weeks 0, 4 and 8. Evaluations by patients, treating physician and blinded experts were scheduled at weeks 0, 4, 8, 16 and 24. RESULTS: The Q-switched ruby laser was significantly more efficacious than the ablative CO2 fractional laser for removing LS on the dorsum of hands (p = 0.01). CONCLUSION: In this first study on this topic, the Q-switched ruby laser was superior to the ablative CO2 fractional laser in the treatment of lentigines solares on the dorsum of hands. PMID- 25788398 TI - Collapse and coexistence for a molecular braid with an attractive interaction component subject to mechanical forces. AB - Dual mechanical braiding experiments provide a useful tool with which to investigate the nature of interactions between rod-like molecules, for instance actin and DNA. In conditions close to molecular condensation, one would expect an appearance of a local minimum in the interaction potential between the two molecules. We investigate this situation, introducing an attractive component into the interaction potential, using a model developed for describing such experiments. We consider both attractive interactions that do not depend on molecular structure and those which depend on a DNA-like helix structure. In braiding experiments, an attractive term may lead to certain effects. A local minimum may cause molecules to collapse from a loosely braided configuration into a tight one, occurring at a critical value of the moment applied about the axis of the braid. For a fixed number of braid pitches, this may lead to coexistence between the two braiding states, tight and loose. Coexistence implies certain proportions of the braid are in each state, their relative size depending on the number of braid pitches. This manifests itself as a linear dependence in numerically calculated quantities as functions of the number of braid pitches. Also, in the collapsed state, the braid radius stays roughly constant. Furthermore, if the attractive interaction is helix dependent, the left-right handed braid symmetry is broken. For a DNA like charge distribution, using the Kornyshev-Leikin interaction model, our results suggest that significant braid collapse and coexistence only occurs for left handed braids. Regardless of the interaction model, the study highlights the possible qualitative physics of braid collapse and coexistence; and the role helix specific forces might play, if important. The model could be used to connect other microscopic theories of interaction with braiding experiments. PMID- 25788396 TI - Sepsis and cytomegalovirus: foes or conspirators? AB - Cytomegalovirus (CMV) reactivation in non-immune-suppressed critically ill patients is an area of increasing interest. CMV has long been appreciated as a pathogen in immunocompromised hosts. CMV reactivates in approximately one-third of latently infected non-immune-suppressed hosts during critical illness; however, its role as a pathogen in these patients remains unclear. CMV reactivation has been linked to bacterial sepsis and likely results from inflammation, transient immune compromise, and viral epigenetic changes. While CMV may improve immune response to some bacterial infections, other data suggest that CMV induces exaggerated responses to severe infections that may be harmful to latently infected hosts. These results also suggest that previous infection history may explain significant differences seen between human septic responses and murine models of sepsis. While critically ill human hosts clearly have worse outcomes associated with CMV reactivation, determining causality remains an area of investigation, with randomized control trials currently being performed. Here we review the current literature and highlight areas for future investigation. PMID- 25788399 TI - Genetic variability of the stable fly assessed on a global scale using amplified fragment length polymorphism. AB - The stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), is a blood-feeding, economically important pest of animals and humans worldwide. Improved management strategies are essential and their development would benefit from studies on genetic diversity of stable flies. Especially if done on a global scale, such research could generate information necessary for the development and application of more efficient control methods. Herein we report on a genetic study of stable flies using amplified fragment length polymorphism, with samples of 10-40 individuals acquired from a total of 25 locations in the Nearctic, Neotropic, Palearctic, Afrotropic and Australasian biogeographical regions. We hypothesized that genetic differentiation would exist across geographical barriers. Although FST (0.33) was moderately high, the GST (0.05; representing genetic diversity between individuals) was very low; Nm values (representing gene flow) were high (9.36). The mismatch distribution and tests of neutrality suggested population expansion, with no genetic differentiation between locations. The analysis of molecular variance (AMOVA) results showed the majority of genetic diversity was within groups. The mantel test showed no correlation between geographic and genetic distance; this strongly supports the AMOVA results. These results suggest that stable flies did not show genetic differentiation but are panmictic, with no evidence of isolation by distance or across geographical barriers. PMID- 25788400 TI - Hierarchical Conducting Polymer@Clay Core-Shell Arrays for Flexible All-Solid State Supercapacitor Devices. AB - A sophisticated hierarchical nanoarray consisting of a conducting polymer (polypyrrole, PPy) core and layered double hydroxide (LDH) shell are synthesized via a facile two-step electrosynthesis method. The obtained PPy@LDH-based flexible all-solid-state supercapacitor meets the requirements of both high energy/power output and long-term endurance, which can be potentially used in highly-efficient and stable energy storage. PMID- 25788401 TI - Prognostic implications of stress modality on mortality risk and cause of death in patients undergoing office-based SPECT myocardial perfusion imaging. AB - BACKGROUND: Patients requiring vasodilator single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) have a higher mortality risk than those selected for exercise or vasodilator with low-level exercise SPECT MPI. However, it is unknown whether the increased mortality is driven by cardiac deaths alone or cardiac and non-cardiac deaths. METHODS: In a prospective cohort of 1,511 consecutive patients referred for SPECT-MPI, patients were classified according to stress test modality: exercise, adenosine with low-level exercise (AdenoEx), and adenosine. Subjects were followed for events of all-cause mortality and cause of death. Survival analyses using multivariate Cox regression and propensity score matching methods were performed. RESULTS: During a follow-up of 4.9 +/- 0.9 years, a total of 68 (4.5%) deaths occurred: 50 non-cardiac and 18 cardiac. The adenosine group had the highest annual mortality (all-cause 3.65%, non-cardiac 2.36%, cardiac 1.29%), while exercise stress had the lowest mortality (all-cause 0.42%, non-cardiac 0.37%, cardiac 0.05%) and AdenoEx had an intermediate mortality (all-cause 1.3%, non-cardiac 0.91%, cardiac 0.39%); all P values <0.001. The majority of non-cardiac deaths were attributed to cancer. Using exercise stress as a reference standard, multivariable Cox regression analyses demonstrated that adenosine stress was independently predictive of all cause mortality [HR 3.23 (CI 1.77-5.88); P < 0.001], non-cardiac death [HR 2.67 (CI 1.34-5.31); P = 0.005], and cardiac death [HR 6.30 (CI 1.55-25.56); P = 0.010] after adjusting for univariate predictors of mortality. These findings were consistent in the subgroups of patients with normal and abnormal MPI. AdenoEx was predictive of all-cause, non-cardiac, and cardiac deaths in univariate analysis, but it was not predictive by multivariate analysis. Propensity score matched cohort analysis showed that the adenosine stress group had the highest all-cause (P < 0.001), non-cardiac (P = 0.013), and cardiac deaths (P < 0.001), while the exercise stress group had the lowest mortality of any cause. CONCLUSIONS: The inability to perform any level of exercise during a SPECT-MPI stress is associated with high mortality risk, which is derived from both cardiac and non-cardiac deaths. PMID- 25788402 TI - High performances of (18)F-fluorodeoxyglucose PET-CT in cardiac implantable device infections: A study of 40 patients. AB - BACKGROUND: Cardiovascular implantable electronic devices (CIED) infections are life-threatening complications. The diagnosis can be difficult to establish. Our purpose is to evaluate the diagnostic value of (18)F-FDG PET. METHODS: Forty patients who received work-up for suspected CIED infection were retrospectively included (group 1) and compared with 40 controls (group 2); CIED patients were referred for oncologic PET. PET-CT data were blindly assessed. Interpretation was based on visual analysis of both attenuation-corrected and non-corrected images and a semi-quantitative analysis was performed. The gold standard was bacteriological data of explanted devices or clinical follow-up for at least 1 year. RESULTS: Infection was present in 18 out of 40 patients of group 1. Sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 83%, 95%, 94%, and 88%, respectively. Accuracy was 90%. PET CT revealed the presence of additional pathological hypermetabolic foci in 28% of cases. PET-CT was negative at implanted devices in all patients of group 2. CONCLUSION: (18)F-FDG PET-CT is helpful in the work-up of suspected CIED infections. It is a potential tool to make the accurate diagnosis of CIED infection and to assess the extent of infection. The promising results in this indication need to be validated in a prospective multicenter study. PMID- 25788404 TI - Building terpene production platforms in yeast. AB - Plants and microbes commonly make terpenes and terpenoids in small amounts and as complex mixtures, and their chemical synthesis is often costly and inefficient. Hence, there are many efforts to create robust and efficient biological production platforms for this interesting class of molecules. In this study, our effort was directed towards building a yeast production platform using an unbiased genetic selection approach. Yeast strain BY4741 was subjected to EMS mutagenesis, followed by selection for growth in the presence of nystatin, squalestatin, and exogenous cholesterol. This unbiased screen selected for mutant yeast lines having a dispensable mevalonate pathway and containing uncharacterized SUE (sterol uptake enhancement) mutations supporting aerobic uptake of exogenous sterol. These mutants were next screened for high level accumulation of farnesol (FOH), an indicator for high level accumulation of the key intermediate FPP, farnesyl diphosphate. To further improve the FPP pool in these mutants, insertional mutations into the ERG9 gene (coding for squalene synthase) were introduced into those lines capable of accumulating >=50 mg farnesol/L. This generated another series of lines that accumulated farnesol levels over 70 mg/L in small-scale shake cultures. To evaluate the utility of these lines as a general production platform for specific terpenes, select SUE/erg9 lines were transformed with a vector harboring the Hyoscyamus muticus premnaspirodiene synthase (HPS) gene encoding for a sesquiterpene synthase. The new yeast line ZX178-08 accumulated the highest level of premnaspirodiene, up to 116 mg/L, with FOH levels of 23.6 mg/L. In comparison, the parental line BY4741 accumulated 10 times less premnaspirodiene, 10.94 mg/L, with no farnesol detectable. Co-expression of the HPS gene with an amino-terminal truncated, catalytic form of the hamster HMGR gene, tHMGR, increased premnaspirodiene accumulation to 170.23 +/- 30.44 mg/L, almost a 50% increase. Further utility of this yeast line was demonstrated for triterpene production. When engineered for the production of a non-native triterpene, Zx178-08 accumulated upwards of 60 mg/L of botryococcene. To engineer more native triterpene accumulation, additional insertion mutants into the ERG1 gene (coding for squalene epoxidase) were evaluated. Insertion of a simple selection marker followed by over expression of a heterologous squalene synthase gene resulted in greater than 85 mg/L of squalene. However, when the ERG1 insertional mutant included chromosomal insertion of a truncated, heterologous HMGR gene, squalene production was more than tripled to 270 mg/L. These results are discussed in comparison to other recently developed terpene production platforms. PMID- 25788403 TI - Quantitative iodine-123-metaiodobenzylguanidine (MIBG) SPECT imaging in heart failure with left ventricular systolic dysfunction: Development and validation of automated procedures in conjunction with technetium-99m tetrofosmin myocardial perfusion SPECT. AB - BACKGROUND: The purpose of this study was to develop and validate new approaches to quantitative MIBG myocardial SPECT imaging in heart failure (HF) subjects. METHODS AND RESULTS: Quantitative MIBG myocardial SPECT analysis methods, alone and in conjunction with 99mTc-tetrofosmin perfusion SPECT, were adapted from previously validated techniques for the analysis of SPECT and PET perfusion imaging. To account for underestimation of MIBG defect severity in subjects with global reduction in uptake, a mixed reference database based on planar heart/mediastinum (H/M) ratio categories was used. Extent and severity of voxel based defects and number of myocardial segments with significant dysinnervation (derived score >=2) were determined. MIBG/99mTc-tetrofosmin mismatch was quantified using regions with preserved innervation as the reference for scaling 99mTc-tetrofosmin voxel maps. Quantification techniques were tested on studies of 619 ischemic (I) and 319 non-ischemic (NI) HF subjects. Using all analytical techniques, IHF subjects had significantly greater and more severe MIBG SPECT abnormalities compared with NIHF subjects. Innervation/perfusion mismatches were also larger in IHF subjects. Findings were consistent between voxel- and myocardial-segment-based quantitation methods. CONCLUSIONS: Multiple objective methods for quantitation of MIBG SPECT imaging studies provided internally consistent results for distinguishing the different patterns of uptake between IHF and NIHF subjects. PMID- 25788405 TI - Exploration of the protein requirement during weight loss in obese older adults. AB - RATIONALE: Currently there is no consensus on protein requirements for obese older adults during weight loss. Here we explore the potential use of a new method for assessment of protein requirements based on changes in appendicular muscle mass during weight loss. METHODS: 60 obese older adults were subjected to 13 wk weight loss program, including hypocaloric diet and resistance training. Assessment of appendicular muscle mass was performed by DXA at baseline and after 13 wk challenge period, and the difference calculated as muscle mass change. Protein intake (g/kg body weight and g/kg fat free mass (FFM)) at 13wks was used as marker of protein intake during 13 wk period. 30 subjects received 10 times weekly 20 g protein supplement throughout the 13 week hypocaloric phase which is included in the calculation of total protein intake. Receiver operating characteristic (ROC) curve analysis was used to explore the optimal cutoff point for protein intake (g/kg) versus increase in appendicular muscle mass of more than 250 g over 13 wks (y/n). Subsequently, logistic regression analysis was performed for protein intake cutoff and muscle mass accretion, adjusted for sex, age, baseline BMI, and training compliance. RESULTS: ROC curve analysis provided a protein intake level per day of 1.2 g/kg bw and 1.9 g/kg FFM as cutoff point. Presence of muscle mass accretion during 13 wk challenge period was significantly higher with protein intake higher than 1.2 g/kg bw (OR 5.4, 95%CI 1.4-20.6, p = 0.013) or higher than 1.9 g/kg FFM (OR 8.1, 95%CI 2.1-31.9, p = 0.003). Subjects with a protein intake higher than 1.2 g/kg had significantly more often muscle mass accretion, compared to subjects with less protein intake (10/14 (72%) vs 15/46 (33%), p = 0.010). For 1.9 g/kg FFM this was 70% vs 28% (p = 0.002). CONCLUSION: This exploratory study provided a level of at least 1.2 g/kg body weight or 1.9 g/kg fat free mass as optimal daily protein intake for obese older adults under these challenged conditions of weight loss, based on muscle mass accretion during the challenge. TRIAL REGISTRATION: Dutch Trial Register under number NTR2751. PMID- 25788406 TI - Surgical treatment of varicose veins and venous malformations in Klippel Trenaunay syndrome. AB - BACKGROUND: Klippel-Trenaunay syndrome (KTS) is a mixed mesenchymal malformation characterised by varicose veins, venous and capillary malformations, and hypertrophy of soft tissue and bone. The purpose of this study was to evaluate the surgical outcomes in KTS patients to provide standards for comparison with endovenous therapy. METHODS: The clinical data of consecutive patient with KTS who underwent open venous surgical treatment between January 1987 and December 2008 were reviewed. Demographics, clinical presentation, operative data, and clinical outcomes were recorded. Follow-up information was obtained from the medical records, mailed questionnaires and phone calls. Descriptive statistics, the Kaplan-Meier method and Log-rank statistics were used where appropriate. RESULTS: Twenty-seven females and 22 males, (mean age 26.5 years, range 7.7-55.8) were included in this study. All had varicose veins, 36 (73%) had limb hypertrophy, and 33 (67%) had capillary malformations, with two of three clinical features present in all. The most frequent symptom was pain (N = 43, 88%). Forty nine patients underwent operations on 53 limbs. Stripping of the GSV, small and accessory saphenous and lateral embryonic veins was performed in 17 (32%), 10 (19%), 9 (17%), and 15 (28%) limbs, respectively. Two patients developed deep vein thrombosis, one had pulmonary embolism (PE), and one patient had peroneal nerve palsy. Freedom from disabling pain at 1, 3 and 5 years was 95%, 77% and 59%, respectively, and freedom from secondary procedures was 78% at 3 years, and 74% at 5 years. At the last follow-up visit, the venous clinical severity score had decreased from 9.48 +/- 3.27 to 6.07 +/- 3.20 (P < 0.001). CONCLUSIONS: In selected symptomatic patients with KT syndrome, open surgical treatment is safe and durable. Three-fourths of the patients remain free of disabling pain at five years, but secondary procedures are required in one-fourth of the patients. These data can serve as standards for comparison of endovenous therapy for KT syndrome. PMID- 25788407 TI - Leishmaniasis, lupus nephritis and immunosuppressive therapy. PMID- 25788408 TI - New drug combination may shorten tuberculosis treatment, study says. PMID- 25788410 TI - Impact of the Nature of the Organic Spacer on the Crystallization Kinetics of UiO 66(Zr)-Type MOFs. AB - The influence of the constitutive dicarboxylate linkers (size, functional group) over the crystallization kinetics of a series of porous Zr metal-organic frameworks with the UiO-66 topology has been investigated by in situ time resolved energy dispersive X-ray diffraction (EDXRD). Both large aromatic spacers (2,6-naphthalene-, 4,4'-biphenyl- and 3,3'-dichloro-4,4'-azobenzene dicarboxylates) and a series of X-functionalized terephthalates (X=NH2 , NO2 , Br, CH3 ) were investigated in dimethylformamide (DMF) at different temperatures and compared with the parent UiO-66. Using different crystallization models, rate constants and further kinetic parameters (such as activation energy) have been extracted. Finally, the impact of the replacement of the toxic DMF by water on the crystallization kinetics was studied through the synthesis of the functionalized UiO-66-NO2 solid. PMID- 25788411 TI - Long-Term Results of Balloon Valvuloplasty as Primary Treatment for Congenital Aortic Valve Stenosis: a 20-Year Review. AB - In the presence of new surgical techniques, the treatment of congenital valvular aortic stenosis is under debate. We reviewed the results and late outcomes of all 93 patients aged 1 day to 18 years, treated with balloon valvuloplasty (BAV) as first-line therapy for congenital aortic valve stenosis in our center from January 1991 to May 2012. Mean age at procedure time was 2.4 years; 37 patients underwent BAV at age <=30 days (neonates), 29 patients at age >=1 month and <1 year (infants), and 27 patients were older than 1 year (children). The invasive BAV peak-to-peak aortic valve gradient (mean 59 +/- 22 mmHg) was immediately reduced (mean 24 +/- 12 mmHg). The observed diminution of gradient was similar for each age group. Four patients had significant post-BAV AI. Mean follow-up after BAV was 11.4 +/- 7 years. The last echo peak aortic gradient was 37 +/- 18 mmHg and mean gradient was 23 +/- 10 mmHg, and two patients had significant AI. Actuarial survival for the whole cohort was 88.2 and 72.9 % for the neonates. All infants, except one, and all children survived. Sixty-six percent of patients were free from surgery, and 58 % were free from any reintervention, with no difference according to age. Freedom from surgery after BAV at 5, 10, and 20 years, respectively, was 82, 72, and 66 %. Our study confirms that BAV as primary treatment for congenital AS is an efficient and low-risk procedure in infants and children. In neonates, the prognosis is more severe and clearly related to "borderline LV." PMID- 25788409 TI - Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling. AB - RATIONALE: Vascular smooth muscle cell (SMC) phenotypic modulation and vascular remodeling contribute to the development of several vascular disorders such as restenosis after angioplasty, transplant vasculopathy, and atherosclerosis. The mechanisms underlying these processes, however, remain largely unknown. OBJECTIVE: The objective of this study is to determine the role of dedicator of cytokinesis 2 (DOCK2) in SMC phenotypic modulation and vascular remodeling. METHODS AND RESULTS: Platelet-derived growth factor-BB induced DOCK2 expression while modulating SMC phenotype. DOCK2 deficiency diminishes platelet-derived growth factor-BB or serum-induced downregulation of SMC markers. Conversely, DOCK2 overexpression inhibits SMC marker expression in primary cultured SMC. Mechanistically, DOCK2 inhibits myocardin expression, blocks serum response factor nuclear location, attenuates myocardin binding to serum response factor, and thus attenuates myocardin-induced smooth muscle marker promoter activity. Moreover, DOCK2 and Kruppel-like factor 4 cooperatively inhibit myocardin-serum response factor interaction. In a rat carotid artery balloon-injury model, DOCK2 is induced in media layer SMC initially and neointima SMC subsequently after vascular injury. Knockdown of DOCK2 dramatically inhibits the neointima formation by 60%. Most importantly, knockout of DOCK2 in mice markedly blocks ligation induced intimal hyperplasia while restoring SMC contractile protein expression. CONCLUSIONS: Our studies identified DOCK2 as a novel regulator for SMC phenotypic modulation and vascular lesion formation after vascular injury. Therefore, targeting DOCK2 may be a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases. PMID- 25788412 TI - Fast maximum likelihood estimation using continuous-time neural point process models. AB - A recent report estimates that the number of simultaneously recorded neurons is growing exponentially. A commonly employed statistical paradigm using discrete time point process models of neural activity involves the computation of a maximum-likelihood estimate. The time to computate this estimate, per neuron, is proportional to the number of bins in a finely spaced discretization of time. By using continuous-time models of neural activity and the optimally efficient Gaussian quadrature, memory requirements and computation times are dramatically decreased in the commonly encountered situation where the number of parameters p is much less than the number of time-bins n. In this regime, with q equal to the quadrature order, memory requirements are decreased from O(np) to O(qp), and the number of floating-point operations are decreased from O(np(2)) to O(qp(2)). Accuracy of the proposed estimates is assessed based upon physiological consideration, error bounds, and mathematical results describing the relation between numerical integration error and numerical error affecting both parameter estimates and the observed Fisher information. A check is provided which is used to adapt the order of numerical integration. The procedure is verified in simulation and for hippocampal recordings. It is found that in 95 % of hippocampal recordings a q of 60 yields numerical error negligible with respect to parameter estimate standard error. Statistical inference using the proposed methodology is a fast and convenient alternative to statistical inference performed using a discrete-time point process model of neural activity. It enables the employment of the statistical methodology available with discrete time inference, but is faster, uses less memory, and avoids any error due to discretization. PMID- 25788413 TI - Past, present, and future in hippocampal formation and memory research. AB - Over 100 years of research on the hippocampal formation has led us understand the consequences of lesions in humans, the functional networks, anatomical pathways, neuronal types and their local circuitry, receptors, molecules, intracellular cascades, and some of the physiological mechanisms underlying long-term spatial and episodic memory. In addition, complex computational models allow us to formulate sophisticated hypotheses; many of them testable with techniques recently developed unthinkable in the past. Although the neurobiology of the cognitive map is starting to be revealed today, we still face a future with many unresolved questions. The aim of this commentary is twofold. First is to point out some of the critical findings in hippocampal formation research and new challenges. Second, to briefly summarize what the anatomy of memory can tell us about how highly processed sensory information from distant cortical areas communicate with different subareas of the entorhinal cortex, dentate gyrus, and hippocampal subfields to integrate and consolidate unique episodic memory traces. PMID- 25788414 TI - Surgical implantation of STN-DBS leads using intraoperative MRI guidance: technique, accuracy, and clinical benefit at 1-year follow-up. AB - BACKGROUND: Improvement of surgical accuracy during DBS-lead implantation has been described recently, leading to "frameless" or "MRI-verified" techniques. However, combining a high-quality definition of the STN using intraoperative 1.5 MRI with the possibility to reduce errors due to co-registration and to monitor lead progression during surgical insertion while checking the absence of surgical complication is an appealing method. We report here surgical methodology, safety, application accuracy, and clinical benefit of STN-lead implantation under MRI guidance. METHODS: Two patients with a severe PD state were treated by bilateral STN-DBS. Leads were implanted under general anesthesia using intraoperative MRI guidance (ClearPoint system). Lead implantation accuracy was measured on T1 axial images at the level of the target. Clinical improvement was measured on the pre- and post-UPDRS 3 scale at 1-year follow-up. RESULTS: Surgery was safe and uneventful in both cases. Radial error was 0.36 (right) and 0.86 mm (left) in case 1, and 0.41 (right) and 0.14 mm (left) in case 2. No edema or hemorrhage were noticed. CONCLUSIONS: Intraoperative MRI guidance allows DBS lead implantation with high accuracy and with great clinical efficacy. A larger cohort of patients is needed to confirm these initial results. PMID- 25788416 TI - Normative data for Italian Deese/Roediger-McDermott lists. AB - The present study provides norms for Deese/Roediger-McDermott (DRM) lists that were used to create false memories in native speakers of Italian. The word lists reported in this article are based on the DRM lists that have been used extensively to examine illusory memories in English speakers (Deese in Journal of Experimental Psychology, 58, 17-22, 1959; Roediger & McDermott in Journal of Experimental Psychology: Learning, Memory, & Cognition, 21, 803-814, 1995). We translated the 24 critical lures from 24 English DRM lists and created semantically associated Italian word lists that were then normed with native Italian speakers. Overall, the participants recalled 63% of the list items and 22% of the critical lures with the word lists developed. In addition, 56% of the list items and 82% of the critical lures were recognized by the participants. The present study provides a set of Italian lists that can be used by researchers interested in evaluating false memories in Italian-speaking participants. PMID- 25788415 TI - Activated k-ras, but not h-ras or N-ras, regulates brain neural stem cell proliferation in a raf/rb-dependent manner. AB - Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since some neurodevelopmental brain disorders (Costello syndrome and Noonan syndrome) are caused by germline activating mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional-activated Ras molecule-expressing genetically engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N Ras, expression increases brain NSC growth in a Raf-dependent, but Mek independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate through a noncanonical mechanism. PMID- 25788418 TI - Formulation of ionic-liquid electrolyte to expand the voltage window of supercapacitors. AB - An effective method to expand the operating potential window (OPW) of electrochemical capacitors based on formulating the ionic-liquid (IL) electrolytes is reported. Using model electrochemical cells based on two identical onion-like carbon (OLC) electrodes and two different IL electrolytes and their mixtures, it was shown that the asymmetric behavior of the electrolyte cation and anion toward the two electrodes limits the OPW of the cell and therefore its energy density. Also, a general solution to this problem is proposed by formulating the IL electrolyte mixtures to balance the capacitance of electrodes in a symmetric supercapacitor. PMID- 25788417 TI - Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health. AB - There is currently no biochemical test for detection of early-stage osteoarthritis (eOA). Tests for early-stage rheumatoid arthritis (eRA) such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies require refinement to improve clinical utility. We developed robust mass spectrometric methods to quantify citrullinated protein (CP) and free hydroxyproline in body fluids. We detected CP in the plasma of healthy subjects and surprisingly found that CP was increased in both patients with eOA and eRA whereas anti-CCP antibodies were predominantly present in eRA. A 4-class diagnostic algorithm combining plasma/serum CP, anti-CCP antibody and hydroxyproline applied to a cohort gave specific and sensitive detection and discrimination of eOA, eRA, other non-RA inflammatory joint diseases and good skeletal health. This provides a first-in-class plasma/serum-based biochemical assay for diagnosis and type discrimination of early-stage arthritis to facilitate improved treatment and patient outcomes, exploiting citrullinated protein and related differential autoimmunity. PMID- 25788419 TI - Comprehensive Two-dimensional Gas Chromatography Time-of-flight Mass Spectrometry to Assess the Presence of alpha,alpha-Trehalose and Other Disaccharides in Apple and Peach. AB - INTRODUCTION: Carbohydrates are important constituents in fruits. Among the carbohydrates, disaccharides have rarely been studied in apple and peach. Indeed, the abiotic stress biomarker and preservation agent alpha,alpha-trehalose is a disaccharide. OBJECTIVES: To establish a comprehensive method based on two dimensional gas chromatography combined with time-of-flight MS detection (GC * GC ToF/MS) to analyse the disaccharide composition of apple and peach. METHODS: The sample preparation was based on aqueous-methanolic extraction of the analytes, followed by oxime formation and trimethylsilylation of the disaccharides. First, three columns were tested with standards on the one-dimensional system. Next, to perform the sample analysis using GC * GC-MS (which offers significant advantages over conventional GC because it allows higher separation efficiencies), various column configurations were assessed on the two-dimensional system to obtain enhanced separation and low detection limits. The column sets tested included non polar/semi-polar, semi-polar/polar and polar/non-polar. RESULTS: Using the method that proved to be more efficient, namely the method developed with the semi polar/non-polar configuration, ten disaccharides were identified, based on analytical standards, retention index and mass spectra. These compounds were quantified in several varieties of apple and peach fruit using the developed GC * GC method and linear curve calibration, resulting in substantial differences among the fruits. However, cultivars within the fruits exhibited no significant differences. CONCLUSION: The proposed method allowed for the identification and quantification of several disaccharides in apple and peach, including the biomarker alpha,alpha-trehalose. PMID- 25788420 TI - Neurodegenerative diseases: challenges. PMID- 25788421 TI - Drug delivery to the testis: current status and potential pathways for the development of novel therapeutics. AB - Nanotechnology has been increasingly utilized for the targeting and delivery of novel therapeutic agents to different tissues and cell types. The current therapeutic options for testicular disorders fall short in many instances due to difficulty traversing the blood-testis barrier, systemic toxicities, and complicated dosing regiments. For testicular tissue, potential targeting can be obtained either via anatomic methods or specific ligands such as luteinizing hormone or follicle-stimulating hormone analogs. Potential novel therapeutic agents include DNA, RNA, cytokines, peptide receptor antagonists, peptide receptor agonists, hormones, and enzymes. Nanotherapeutic treatment of testicular cancer, infertility, testicular torsion, orchalgia, hypogonadism, testicular infections, and cryptorchidism within the framework of potential target cells are an emerging area of research. While there are many potential applications of nanotechnology in drug delivery to the testis, this remains a relatively unexplored field. This review highlights the current status as well as potential future of nanotechnology in the development of novel therapeutics for testicular disorders. PMID- 25788422 TI - Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. AB - Efforts to develop neurotrophic factors to restore function and protect dying neurons in chronic neurodegenerative diseases like Alzheimer's (AD) and Parkinson's (PD) have been attempted for decades. Despite abundant data establishing nonclinical proof-of-concept, significant delivery issues have precluded the successful translation of this concept to the clinic. The development of AAV2 viral vectors to deliver therapeutic genes has emerged as a safe and effective means to achieve sustained, long-term, targeted, bioactive protein expression. Thus, it potentially offers a practical means to solve those long-standing delivery/translational issues associated with neurotrophic factors. Data are presented for two AAV2 viral vector constructs expressing one of two different neurotrophic factors: nerve growth factor (NGF) and neurturin (NRTN). One (AAV2-NGF; aka CERE-110) is being developed as a treatment to improve the function and delay further degeneration of cholinergic neurons in the nucleus basalis of Meynert, the degeneration of which has been linked to cognitive deficits in AD. The other (AAV2-NRTN; aka CERE-120) is similarly being developed to treat the degenerating nigrostriatal dopamine neurons and major motor deficits in PD. The data presented here demonstrate: (1) 2-year, targeted, bioactive protein in monkeys, (2) persistent, bioactive-protein throughout the life-span of the rat, and (3) accurately targeted bioactive-protein in aged rats, with (4) no safety issues or antibodies to the protein detected. They also provide empirical guidance to establish parameters for human dosing and collectively support the idea that gene transfer may overcome key delivery obstacles that have precluded successful translation of neurotrophic factors to the clinic. More specifically, they also enabled the AAV-NGF and AAV-NRTN programs to advance into ongoing multi center, double-blind clinical trials in AD and PD patients. PMID- 25788423 TI - Enhanced dermal delivery of acyclovir using solid lipid nanoparticles. AB - The present investigation was enthused by the possibility to develop solid lipid nanoparticles (SLNs) of hydrophilic drug acyclovir (ACV) and evaluate their potential as the carrier for dermal delivery. ACV-loaded SLNs (ACV-SLNs) were prepared by the optimized double emulsion process using Compritol 888 ATO as solid lipid. The prepared SLNs were smooth and spherical in shape with average diameter, polydispersity index, and entrapment efficiency of 262 +/- 13 nm, 0.280 +/- 0.01, and 40.08 +/- 4.39% at 10% (w/w) theoretical drug loading with respect to Compritol 888 ATO content. Differential scanning calorimetry and powder X-ray diffraction pattern revealed that ACV was present in the amorphous state inside the SLNs. In vitro skin permeation studies on human cadaver and Sprague-Dawley rat skin revealed 17.65 and 15.17 times higher accumulation of ACV-SLNs in the dermal tissues in comparison to commercially available ACV cream after 24 h. Mechanism of topical permeation and dermal distribution was studied qualitatively using confocal laser scanning microscopy. While free dye (calcein) failed to penetrate skin barrier, the same encapsulated in SLNs penetrated deeply into the dermal tissue suggesting that pilosebaceous route was followed by SLNs for skin penetration. Histological examination and transdermal epidermal water loss measurement suggested that no major morphological changes occurred on rat skin surface due to the application of SLNs. Overall, it was concluded that ACV-loaded SLNs might be beneficial in improving dermal delivery of antiviral agent(s) for the treatment of topical herpes simplex infection. PMID- 25788424 TI - Circulating peptidome to indicate the tumor-resident proteolysis. AB - Tumor-resident proteases (TRPs) are regarded as informative biomarkers for staging cancer progression and evaluating therapeutic efficacy. Currently in the clinic, measurement of TRP is dependent on invasive biopsies, limiting their usefulness as monitoring tools. Here we identified circulating peptides naturally produced by TRPs, and evaluated their potential to monitor the efficacy of anti tumor treatments. We established a mouse model for ovarian cancer development and treatment by orthotopic implantation of the human drug-resistant ovarian cancer cell line HeyA8-MDR, followed by porous silicon particle- or multistage vector (MSV) - enabled EphA2 siRNA therapy. Immunohistochemistry staining of tumor tissue revealed decreased expression of matrix metallopeptidase 9 (MMP-9) in mice exhibiting positive responses to MSV-EphA2 siRNA treatment. We demonstrated, via an ex vivo proteolysis assay, that C3f peptides can act as substrates of MMP-9, which cleaves C3f at L1311-L1312 into two peptides (SSATTFRL and LWENGNLLR). Importantly, we showed that these two C3f-derived fragments detected in serum were primarily generated by tumor-resident, but not blood-circulating, MMP-9. Our results suggested that the presence of the circulating fragments specially derived from the localized cleavage in tumor microenvironment can be used to evaluate therapeutic efficacy of anti-cancer treatment, assessed through a relatively noninvasive and user-friendly proteomics approach. PMID- 25788425 TI - Inflammation and prostate cancer: friends or foe? AB - INTRODUCTION: Prostate cancer is the most common non-cutaneous malignancy diagnosed in men. Moving from histological observations since a long time, it has been recognized that innate and adaptive immunity actively participates in the pathogenesis, surveillance, and progression of prostate cancer. MATERIALS AND METHODS: A PubMed and Web of Science databases search was performed for studies providing evidence on the roles of the innate and adaptive immunity during the development and progression of prostate cancer. CONCLUSIONS: There are growing evidences that chronic inflammation is involved in the regulation of cellular events in prostate carcinogenesis, including disruption of the immune response and regulation of the tumor microenvironment. This review discusses the role played by the innate and adaptive immune system in the local progression of prostate cancer, and the prognostic information that we can currently understand and exploit. PMID- 25788426 TI - The experimental model of nephrotic syndrome induced by Doxorubicin in rodents: an update. AB - Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, generalized edema, and hyperlipidemia. It begins by changes in the glomerular filtration barrier, with increased permeability to plasma proteins. It affects all age groups and can progress to end-stage renal disease. NS pathophysiology is still unknown. However, the critical role of the immune system is well recognized. Animal models are useful tools for the investigation of NS. Among different experimental models proposed in the literature, disease induced by Doxorubicin has been considered helpful to the purpose of many studies. The aim of this review article is to describe the animal model of NS induced by the injection of Doxorubicin in rodents, with emphasis on action of the drug, potential mechanisms of renal injury, as well biochemical, histological, and corporal changes obtained with this model. PMID- 25788428 TI - The association between childhood maltreatment, mental health problems, and aggression in justice-involved boys. AB - The link between childhood maltreatment and adolescent aggression is well documented; yet, studies examining potential mechanisms that explain this association are limited. In the present study, we tested the association between childhood maltreatment and adolescent aggression in boys in juvenile justice facilities (N = 767) and examined the contribution of mental health problems to this relationship. Data on childhood maltreatment, mental health problems, and aggression were collected by means of self-report measures and structural equation models were used to test mediation models. We found that mental health problems mediated the link between maltreatment and aggression. Results demonstrated different pathways depending on the type of aggression examined. The association between childhood maltreatment and reactive aggression was fully mediated by a variety of mental health problems and for proactive aggression the association was partially mediated by mental health problems. We also found that reactive and proactive aggression partially mediated the association between maltreatment and mental health problems. These findings suggest that a transactional model may best explain the negative effects of childhood trauma on mental health problems and (in particular reactive) aggression. In addition, our findings add to the existing evidence that reactive and proactive aggression have different etiological pathways. PMID- 25788429 TI - Highly stretchable and self-deformable alternating current electroluminescent devices. PMID- 25788427 TI - MicroRNAs in the axon locally mediate the effects of chondroitin sulfate proteoglycans and cGMP on axonal growth. AB - Axonal miRNAs locally regulate axonal growth by modulating local protein composition. Whether localized miRNAs in the axon mediate the inhibitory effect of Chondroitin sulfate proteoglycans (CSPGs) on the axon remains unknown. We showed that in cultured cortical neurons, axonal application of CSPGs inhibited axonal growth and altered axonal miRNA profiles, whereas elevation of axonal cyclic guanosine monophosphate (cGMP) levels by axonal application of sildenafil reversed the effect of CSPGs on inhibition of axonal growth and on miRNA profiles. Specifically, CSPGs elevated and reduced axonal levels of miR-29c and integrin beta1 (ITGB1) proteins, respectively, while elevation of cGMP levels overcame these CSPG effects. Gain-of- and loss-of-function experiments demonstrated that miR-29c in the distal axon mediates axonal growth downstream of CSPGs and cGMP by regulating axonal protein levels of ITGB1, FAK, and RhoA. Together, our data demonstrate that axonal miRNAs play an important role in mediating the inhibitory action of CSPGs on axonal growth and that miR-29c at least partially mediates this process. PMID- 25788430 TI - Abstracts of the 24th Annual Conference of APASL, March 12-15, 2015, Istanbul, Turkey. PMID- 25788431 TI - AML versus ICU: outcome of septic AML patients in an intensive care setting. AB - PURPOSE: Intensive therapy regimens in patients with acute myeloid leukemia (AML) frequently result in sepsis and septic shock. In this study, we investigated the prognostic outcome of AML patients requiring intensive care treatment due to severe sepsis or septic shock. DESIGN: We present a retrospective cohort study in a medical intensive care unit (ICU) of a university hospital that serves as a tertiary care center. MATERIALS AND METHODS: Here we present data from 44 AML patients of our ICU with 29 requiring invasive mechanical ventilation due to sepsis and compared multiple clinical and laboratory parameters of ICU survivors and non-survivors. RESULTS: Mean age was 59.5 years, the overall mortality rate was 41% (18/44), and the mortality rate among patients who received mechanical ventilation was 55% (16/29). The mortality rate among younger patients (aged 60 years or less) was 17% (3/18), while 58% of the older patients died (15/26). The mortality rate among younger patients who received mechanical ventilation was 23% (3/13) compared with 81% (13/16) of the older patients. The mean invasive ventilation time was 415 h in non-survivors compared with 667 h in survivors. No differences could be identified between survivors and non-survivors, concerning multiple laboratory parameters or AML prognostic and therapeutic parameters; our analysis, however, confirmed a statistically significant difference in the patients' age. CONCLUSIONS: In previous studies, age was one of the most important prognostic factors in AML patients receiving mechanical ventilation due to severe sepsis or septic shock. In spite of improvements in diagnostic and treatment over the last couple of years, our study indicates that this fact still is true. However, the overall outcome has improved over the years due to improvements in intensive care medicine. PMID- 25788432 TI - Meaningful activity for persons with dementia: family caregiver perspectives. AB - Dementia threatens the capacity to engage in activity, suggesting meaningful activity may be helpful for persons with dementia (PWDs). This study explores the concept of meaningful activity, as defined by caregivers of PWDs. Family caregivers of PWDs, who provide 3 hours of care over 3 days/week, were interviewed after 6 months of cholinesterase inhibitors (ChEIs) therapy. Caregiver responses (N = 906) to the open-ended question What do you believe getting involved in activities outside the home means for someone with dementia are assessed. The themes are analyzed in terms of content, frequency, co occurrence, and dementia severity. Caregivers emphasize the benefits of social connectedness, physical health, and mental stimulation. Activity is also viewed as respite, difficult, and has no meaning for care recipient. The implications of activity for self- and social-identity in PWD and caregiver are discussed. The benefits of activity varied by stage of disease. This knowledge indicates areas for improved activity provision and health care support. PMID- 25788433 TI - Influence of asafoetida on prevention and treatment of memory impairment induced by d-galactose and NaNO2 in mice. AB - In Iranian traditional medicine, asafoetida is introduced as a valuable remedy for nervous disorders. Dementia was induced by injection of d-galactose and NaNO2 for 60 consecutive days. Animals were divided into normal control (NC), dementia control (DC), dementia prophylactic (DP), and dementia treated (DT). The learning and memory functions were examined by 1-way active and passive avoidance tests, using a shuttle box device. Avoidance response in training tests and 1 and 3 weeks later was significantly increased in NC, DP, and DT groups compared to the DC group. Step through latency in all groups was significantly greater than the DC group. Total time spent in light room, which shows the memory retention ability, in DP, NC, and DT was significantly greater than the DC group. Our findings indicate that asafoetida could prevent and treat amnesia. These beneficial effects maybe related to some constituent's effectiveness such as ferulic acid and umbelliferone. PMID- 25788434 TI - Verbal memory and brain aging: an exploratory analysis of the role of error responses in the Framingham Study. AB - OBJECTIVE: Analysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements. METHODS: The LM immediate (LM-I) and LM delay (LM-D) free recall correct responses and related and unrelated errors were scored. Principal components analysis yielded a 3-factor solution: LM-I and LM-D correct responses, LM-I and LM-D-unrelated errors, and LM-I/-D-related errors. The MRI total cerebral brain volume, frontal brain volume, temporal horn volume (THV), and white matter hyperintensities volume (WMHIV) were obtained. RESULTS: Increasing THV (suggesting greater regional atrophy) was associated with lower scores on the LM-correct responses factor. Extensive WMHIV was associated with higher scores on the LM-related errors factor. CONCLUSION: These results suggest that LM-correct responses could relate to emerging brain alterations. Longitudinal research might enhance the sensitivity of this test to identify preclinical impairment and persons at risk of mild cognitive impairment and dementia. PMID- 25788436 TI - Direct imaging of long-range concentration fluctuations in a ternary mixture. AB - We used a direct imaging technique to investigate concentration fluctuations enhanced by thermal fluctuations in a ternary mixture of methanol (Me), cyclohexane (C), and partially deuterated cyclohexane (C*) within 1mK above its consolute critical point. The experimental setup used a low-coherence white-light source and a red filter to visualize fluctuation images. The red-filtered images were analyzed off-line using a differential dynamic microscopy algorithm that allowed us to determine the correlation time, tau, of concentration fluctuations. From tau, we determined the mutual mass diffusion coefficient, D, very near and above the critical point of Me-CC* mixtures. We also numerically estimated both the background and critical contributions to D and compared the results against our experimental values determined from tau. We found that the experimental value of D is close to the prediction based on Stokes-Einstein diffusion law with Kawasaki's correction. PMID- 25788435 TI - Cannabinoid abuse and addiction: Clinical and preclinical findings. AB - Cannabinoid abuse disorders represent a widespread public health issue, but there are no approved medications for their treatment. This review describes efforts to understand the mechanisms of cannabinoid abuse and its adverse effects, to identify molecular targets for pharmacotherapy, and to evaluate potential treatments in human volunteers and animal models of cannabinoid reward, withdrawal, and relapse. PMID- 25788437 TI - The Interventional Heart Failure Initiative: a mission statement for the next generation of invasive cardiologists. PMID- 25788438 TI - Obesity and coronary artery calcification: Can it explain the obesity-paradox? AB - The inverse relationship between obesity and adverse cardiovascular outcomes has been coined the 'obesity-paradox'. We sought to determine the relationship between measures of obesity [body mass index (BMI), body surface area (BSA) and body fat percentage (BF%)] and coronary artery calcification (CAC). We retrospectively analyzed patients who underwent CAC using the Agatston score. Baseline demographics were collected and BMI, BSA and BF% were calculated. A two stage regression modeling approach was used to evaluate the association between BMI, BSA, BF% and Agatston score. Of the 6661 patients [mean age = 57.1 +/- 10.8 years, men = 54.3%, median Agatston score = 14 (0, 163)], 0.1% were underweight, 21.3% had normal BMI, 39.1% were overweight and 39.4% were obese. The mean BMI, BSA and BF% were 29.6 +/- 6.1 kg/m(2), 1.97 +/- 0.25 m(2) and 37 +/- 10 %, respectively. There was an independent association between the presence of CAC and BMI (5 kg/m(2) increments) (OR 1.05, CI 1.00-1.11, P = 0.038) and BF% (OR 2.38, CI 1.05-5.41, P = 0.038). Neither BMI categories nor large BSA independently predicted the presence of CAC. BF% predicted the extent of CAC in men but not in women, and higher BF% was associated with higher category of CAC severity in men only. BMI and BF% were independent predictors of the presence of CAC. BF% was associated with the extent of CAC and higher BF% was associated with higher category of CAC severity in men only. These results suggest that further study is needed to better understand the obesity-paradox. PMID- 25788439 TI - Sensitive cardiac troponins and N-terminal pro-B-type natriuretic peptide in stable coronary artery disease: correlation with left ventricular function as assessed by myocardial strain. AB - N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponins (cTns) measured with sensitive assays provide strong prognostic information in patients with stable coronary artery disease. However, the relationship between these biomarkers and myocardial contractile function, as well as infarct size, in this patient group, remains to be defined. The study population consisted of 160 patients referred to a follow-up echocardiography scheduled 1 year after coronary revascularization. Concentrations of NT-proBNP, high-sensitive cTnT (hs-cTnT) and sensitive cTnI assays were assessed. Left ventricular function was measured as global peak systolic longitudinal strain by speckle tracking echocardiography and infarct size was assessed by late-enhancement MRI. NT-proBNP and sensitive cTnI levels were significantly associated with left ventricular function by peak systolic strain (R-values 0.243 and 0.228, p = 0.002 and 0.004) as well as infarct size (R-values 0.343 and 0.366, p = 0.014 and p = 0.008). In contrast, hs cTnT did not correlate with left ventricular function (R = 0.095, p = 0.231) and only marginally with infarct size (R = 0.237, p = 0.094). NT-proBNP and sensitive cTnI levels correlate with left ventricular function and infarct size in patients with stable coronary artery disease after revascularization. As opposed to hs cTnT, NT-proBNP and cTnI seem to be indicators of incipient myocardial dysfunction and the extent of myocardial necrosis. PMID- 25788441 TI - Building with Balint: A conference that connected generations. AB - The American Balint Society held its First National Meeting in Estes Park Colorado in July 2014. The meeting brought together multiple generations of physicians and behavioral scientists interested in promoting Balint work in the United States. This article will provide an overview of the Balint method and its importance in medicine, a brief history of the American Balint Society, and the various elements of the First National Meeting. PMID- 25788440 TI - Porous three-dimensional carbon nanotube scaffolds for tissue engineering. AB - Assembly of carbon nanomaterials into three-dimensional (3D) architectures is necessary to harness their unique physiochemical properties for tissue engineering and regenerative medicine applications. Herein, we report the fabrication and comprehensive cytocompatibility assessment of 3D chemically crosslinked macrosized (5-8 mm height and 4-6 mm diameter) porous carbon nanotube (CNT) scaffolds. Scaffolds prepared via radical initiated thermal crosslinking of single- or multiwalled CNTs (SWCNTs and MWCNTs) possess high porosity (>80%), and nano-, micro-, and macroscale interconnected pores. MC3T3 preosteoblast cells on MWCNT and SWCNT scaffolds showed good cell viability comparable to poly(lactic-co glycolic) acid (PLGA) scaffolds after 5 days. Confocal live cell and immunofluorescence imaging showed that MC3T3 cells were metabolically active and could attach, proliferate, and infiltrate MWCNT and SWCNT scaffolds. SEM imaging corroborated cell attachment and spreading and suggested that cell morphology is governed by scaffold surface roughness. MC3T3 cells were elongated on scaffolds with high surface roughness (MWCNTs) and rounded on scaffolds with low surface roughness (SWCNTs). The surface roughness of scaffolds may be exploited to control cellular morphology and, in turn, govern cell fate. These results indicate that crosslinked MWCNTs and SWCNTs scaffolds are cytocompatible, and open avenues toward development of multifunctional all-carbon scaffolds for tissue engineering applications. PMID- 25788442 TI - Molecular characterization and diversity analysis of bacterial communities associated with Dialeurolonga malleswaramensis (Hemiptera: Aleyrodidae) adults using 16S rDNA amplicon pyrosequencing and FISH. AB - Dialeurolonga malleswaramensis Sundararaj (Hemiptera: Aleyrodidae) is a phytophagous sap sucking insect. It infests Polyalthia longifolia, an important avenue tree of India, effective in alleviating noise pollution and having immense medicinal importance. Samples of this insect were collected from Polyalthia longifolia. The cytochrome c oxidase subunit I gene (mtCO1) helped in the molecular characterization of the insect. This study reports the bacterial diversity in D. malleswaramensis adults by high throughput 16S rDNA amplicon pyrosequencing. The major genera identified were Portiera and Arsenophonus. Other bacterial genera detected were uncultured alpha proteobacterium, Sphingopyxis and Methylobacterium. We also employed fluorescence in situ hybridization (FISH) in whole mount samples to confirm the presence of dominant endosymbionts Portiera and Arsenophonus to the bacteriocyte of D. malleswaramensis. This study concludes that combining techniques like 16S rDNA amplicon pyrosequencing and FISH reveal both dominant and rare bacteria. The data also predict the evolutionary position of this pest with respect to other whitefly species using a mitochondrial marker. PMID- 25788443 TI - Particle sizing by dynamic light scattering: non-linear cumulant analysis. AB - We revisit the method of cumulants for analysing dynamic light scattering data in particle sizing applications. Here the data, in the form of the time correlation function of scattered light, is written as a series involving the first few cumulants (or moments) of the distribution of particle diffusion constants. Frisken (2001 Appl. Opt. 40 4087) has pointed out that, despite greater computational complexity, a non-linear, iterative, analysis of the data has advantages over the linear least-squares analysis used originally. In order to explore further the potential and limitations of cumulant methods we analyse, by both linear and non-linear methods, computer-generated data with realistic 'noise', where the parameters of the distribution can be set explicitly. We find that, with modern computers, non-linear analysis is straightforward and robust. The mean and variance of the distribution of diffusion constants can be obtained quite accurately for distributions of width (standard deviation/mean) up to about 0.6, but there appears to be little prospect of obtaining meaningful higher moments. PMID- 25788444 TI - Nagashima-type palmoplantar keratosis caused by compound heterozygous mutations in SERPINB7. PMID- 25788446 TI - Commentary: Childhood parental loss and adulthood health: discussing the role of parental cause of death, child's age at death and historical context. PMID- 25788448 TI - A Flow-Cytometry-Based Approach to Facilitate Quantification, Size Estimation and Characterization of Sub-visible Particles in Protein Solutions. AB - PURPOSE: Sub-visible particles were shown to facilitate unwanted immunogenicity of protein therapeutics. To understand the root cause of this phenomenon, a comprehensive analysis of these particles is required. We aimed at establishing a flow-cytometry-based technology to analyze the amount, size distribution and nature of sub-visible particles in protein solutions. METHODS: We adjusted the settings of a BD FACS Canto II by tuning the forward scatter and the side scatter detectors and by using size calibration beads to facilitate the analysis of particles with sizes below 1 MUM. We applied a combination of Bis-ANS (4,4' dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt) and DCVJ (9-(2,2 dicyanovinyl)julolidine) to identify specific characteristics of sub-visible particles. RESULTS: The FACS technology allows the analysis of particles between 0.75 and 10 MUm in size, requiring relatively small sample volumes. Protein containing particles can be distinguished from non-protein particles and cross beta-sheet structures contained in protein particles can be identified. CONCLUSIONS: The FACS technology provides robust and reproducible results with respect to number, size distribution and specific characteristics of sub-visible particles between 0.75 and 10 MUm in size. Our data for number and size distribution of particles is in good agreement with results obtained with the state-of-the-art technology micro-flow imaging. PMID- 25788449 TI - The Effect of Active Pharmaceutical Ingredients on Aerosol Electrostatic Charges from Pressurized Metered Dose Inhalers. AB - PURPOSE: This study investigated the effect of different active pharmaceutical ingredients (API) on aerosol electrostatic charges and aerosol performances for pressurized metered dose inhalers (pMDIs), using both insulating and conducting actuators. METHODS: Five solution-based pMDIs containing different API ingredients including: beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FS), salbutamol base (SB) and ipratropium bromide (IPBr) were prepared using pressure filling technique. Actuator blocks made from nylon, polytetrafluoroethylene (PTFE) and aluminium were manufactured with 0.3 mm nominal orifice diameter and cone nozzle shape. Aerosol electrostatics for each pMDI formulation and actuator were evaluated using the electrical low-pressure impactor (ELPI) and drug depositions were analysed using high performance liquid chromatography (HPLC). RESULTS: All three actuator materials showed the same net charge trend across the five active drug ingredients, with BDP, BUD and FS showing positive net charges for both nylon and PTFE actuators, respectively. While SB and IPBr had significantly negative net charges across the three different actuators, which correlates to the ionic functional groups present on the drug molecule structures. CONCLUSIONS: The API present in a pMDI has a dominant effect on the electrostatic properties of the formulation, overcoming the charge effect arising from the actuator materials. Results have shown that the electrostatic charges for a solution-based pMDI could be related to the interactions of the chemical ingredients and change in the work function for the overall formulation. PMID- 25788450 TI - Genomic Analyses Reveal Potential Independent Adaptation to High Altitude in Tibetan Chickens. AB - Much like other indigenous domesticated animals, Tibetan chickens living at high altitudes (2,200-4,100 m) show specific physiological adaptations to the extreme environmental conditions of the Tibetan Plateau, but the genetic bases of these adaptations are not well characterized. Here, we assembled a de novo genome of a Tibetan chicken and resequenced whole genomes of 32 additional chickens, including Tibetan chickens, village chickens, game fowl, and Red Junglefowl, and found that the Tibetan chickens could broadly be placed into two groups. Further analyses revealed that several candidate genes in the calcium-signaling pathway are possibly involved in adaptation to the hypoxia experienced by these chickens, as these genes appear to have experienced directional selection in the two Tibetan chicken populations, suggesting a potential genetic mechanism underlying high altitude adaptation in Tibetan chickens. The candidate selected genes identified in this study, and their variants, may be useful targets for clarifying our understanding of the domestication of chickens in Tibet, and might be useful in current breeding efforts to develop improved breeds for the highlands. PMID- 25788447 TI - Solvent-free melting techniques for the preparation of lipid-based solid oral formulations. AB - Lipid excipients are applied for numerous purposes such as taste masking, controlled release, improvement of swallowability and moisture protection. Several melting techniques have evolved in the last decades. Common examples are melt coating, melt granulation and melt extrusion. The required equipment ranges from ordinary glass beakers for lab scale up to large machines such as fluid bed coaters, spray dryers or extruders. This allows for upscaling to pilot or production scale. Solvent free melt processing provides a cost-effective, time saving and eco-friendly method for the food and pharmaceutical industries. This review intends to give a critical overview of the published literature on experiences, formulations and challenges and to show possibilities for future developments in this promising field. Moreover, it should serve as a guide for selecting the best excipients and manufacturing techniques for the development of a product with specific properties using solvent free melt processing. PMID- 25788451 TI - Negatively charged metallacarborane redox couples with both members stable to air. AB - The metallacarborane [3,3'-Co(1,2-closo-C2B9H11)2](-) has been synthesized. This species allows the formation of redox couples in which both partners are negatively charged. The E1/2 potential can be tuned by adjusting the nature and number of substituents on B and C. The octaiodinated species [3,3'-Co(1,2-closo C2B9H7I4)2](-) is the most favorable, as it is isolatable and stable in air. A DFT study on stability and redox potentials of complexes has been performed. PMID- 25788452 TI - The groin: an unusual location of endometriosis-a multi-institutional clinicopathological study. PMID- 25788453 TI - Sarcoma of the breast and chest wall after radiation treatment for bilateral breast carcinoma. PMID- 25788454 TI - From the GPS to HM: Place cells, grid cells, and memory. AB - A longstanding debate in hippocampus research has revolved around how to reconcile spatial mapping functions of the hippocampus with the global amnesia produced by hippocampal damage in humans. Is the hippocampus primarily a cognitive map used to support spatial learning, or does it support more general types of learning necessary for declarative memory? In recent years, a general consensus has emerged that the hippocampus receives both spatial and nonspatial inputs from the entorhinal cortex. The hippocampus creates representations of experience in a particular spatial and temporal context. This process allows the individual components of experience to be stored in such a way that they can be retrieved together as a conscious recollection. PMID- 25788455 TI - Bi-thalamic infarction due to a suprasellar germinoma. PMID- 25788456 TI - Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Pulmonary Infection Caused by Pseudomonas aeruginosa via Inhibiting Overproduction of Prostaglandin E2. AB - RATIONALE: New strategies for treating Pseudomonas aeruginosa pulmonary infection are urgently needed. Adipose tissue-derived mesenchymal stem cells (ASCs) may have a potential therapeutic role in P. aeruginosa-induced pulmonary infection. METHODS: The therapeutic and mechanistic effects of ASCs on P. aeruginosa pulmonary infection were evaluated in a murine model of P. aeruginosa pneumonia. RESULTS: ASCs exhibited protective effects against P. aeruginosa pulmonary infection, evidenced by reduced bacterial burdens, inhibition of alveolar neutrophil accumulation, decreased levels of myeloperoxidase, macrophage inflammatory protein-2 and total proteins in broncho-alveolar lavage fluid (BALF), and attenuated severity of lung injury. ASCs had no effects on BALF and serum levels of keratinocyte growth factor or Ang-1. ASCs had no effects on the levels of insulin growth factor 1 (IGF-1) in BALF, but increased IGF-1 levels in serum. ASCs inhibited the overproduction of prostaglandin E2 (PGE2 ) by decreasing the expression of cyclooxygenase-2 (COX2) and enhancing the expression of 15-PGDH. In addition, the addition of exogenous PGE2 with ASCs abolished many of the protective effects of ASCs, and administrating PGE2 alone exacerbated lung infection. By inhibiting production of PGE2 , ASCs improved phagocytosis and the bactericidal properties of macrophages. Furthermore suppressing PGE2 signaling by COX2 inhibition or EP2 inhibition exhibited protective effects against pulmonary infection as well. CONCLUSIONS: In a murine model of P. aeruginosa pneumonia, ASCs exhibited protective effects by inhibiting production of PGE2 , which subsequently improved phagocytosis and the bactericidal properties of macrophages. ASCs may provide a new strategy for managing pulmonary infection caused by P. aeruginosa. PMID- 25788457 TI - The role of activated cytotoxic T cells in etiopathogenesis of periodontal disease: does it harm or does it heal? AB - The objective of this study was to determine the phenotypic profile of blood mononuclear cells, specifically CD8(+)/CD28(+) cells, in patients with generalized aggressive periodontitis (GAgP) and chronic periodontitis (CP) in peripheral blood and in blood obtained from periodontal defect site which might contribute to tissue damage. 13 GAgP, 11 chronic periodontitis (CP) and 5 healthy controls (H) were included in the study. Plaque index (PI), bleeding on probing (BoP), periodontal probing depth (PPD) and clinical attachment level (CAL) were recorded. Blood from the base of periodontal defect site and peripheral blood from the antecubital vein were obtained. Relative counts of CD45(+), CD3(+), CD4(+), CD8(+)/CD28(+), CD8(+)/CD28(-), CD19(+), CD16(+)/CD56(+)/CD3, CD3(+)/CD16(+)/CD56(+) receptors were determined with two color flow cytometry using monoclonal antibodies. BoP, PPD and CAL were significantly higher in both periodontitis groups than healthy controls (p <0.05). Activated cytotoxic T cells, CD8(+)/CD28(+) cells, were significantly elevated in GAgP and CP groups compared to HC both in blood obtained from defect site and blood obtained from systemic circulation (p <0.05). GAgP and CP patients have an increased levels of activated cytotoxic T cells as a result of inflammation which may cause severe tissue damage that lead to severe and rapid loss of periodontal tissues. PMID- 25788458 TI - Coronary artery bypass grafting in patients 50 years or younger: a Swedish nationwide cohort study. AB - BACKGROUND: There are limited data regarding long-term results after coronary artery bypass grafting (CABG) in young adults. We performed a nationwide population-based cohort study to analyze long-term survival, major adverse cardiovascular events, and factors associated with elevated risk in young adults undergoing CABG. METHODS AND RESULTS: We included all adult patients <=50 years of age who underwent primary isolated CABG in Sweden between 1997 and 2013 from the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) register. Patient data were linked from national Swedish health data registers to create a study database. We identified 4086 young adults with a mean age of 46 years and 18% women. During a median follow-up time of 10.9 years (interquartile range, 6.4 14.1) 490 (12%) patients died. Survival at 5, 10, and 15 years was 96% (95% CI, 95-96), 90% (95% CI, 89-91), and 82% (95%CI, 80-83), respectively, which was significantly better in comparison with patients aged 51 to 70 years and >70 years who underwent CABG during the same period. The cumulative incidence of death or a major adverse cardiovascular event during 17 years after CABG was mainly driven by myocardial infarction or the need for repeat revascularization. The most important risk factors for all-cause mortality were chronic kidney disease, reduced left ventricular ejection fraction, peripheral vascular disease, or chronic obstructive pulmonary disease. CONCLUSIONS: Long-term survival and freedom from major cardiovascular events after CABG was better in young adults than in older patients. Factors significantly associated with an elevated long term risk of death or adverse outcome were similar to well-known risk factors for older age groups following CABG. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02276950. PMID- 25788464 TI - Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy. AB - Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally activated prodrug strategy. PMID- 25788465 TI - Cytopathology of pulmonary adenocarcinoma with a single histological pattern using the proposed International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification. AB - BACKGROUND: Guidelines for histological subtyping in patients with surgically resected lung adenocarcinoma (ADC) were recently proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. The objective of the current study was to investigate the cytomorphology of these subtypes of ADC in cases with matched histology specimens demonstrating a single pure subtype. METHODS: The authors reviewed their database for patients with histological diagnoses of primary lung ADC with a single histological pattern observed on surgical resection and investigated the cytological findings in 18 matched cytology specimens to eliminate sampling issues in cases of mixed ADC. RESULTS: Resections were classified as acinar (7 specimens), solid (6 specimens), lepidic (2 specimens), mucinous (2 specimens), and papillary (1 specimen). Cytology specimens demonstrating a solid pattern had a predominance of 3-dimensional clusters (5 of 6 vs 0 of 12 specimens) (P = .0007, Fisher exact test), necrotic background (3 of 6 vs 0 of 12 specimens) (P = .02), pleomorphic nuclei (6 of 6 vs 1 of 12 specimens) (P = .0004), irregular nuclear contours (6 of 6 vs 3 of 12 specimens) (P = .009), and nuclear enlargement (5 of 6 vs 2 of 12 specimens) (P = .01) compared with the nonsolid patterns. Nuclear pseudoinclusions were present only in nonsolid patterns (5 of 12 specimens), although this finding was not statistically significant (P = .05) CONCLUSIONS: Cytological features of lung ADC subtypes proposed by the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification overlap. However, architectural and nuclear features may be helpful, particularly in distinguishing the prognostically adverse solid pattern from other patterns. PMID- 25788466 TI - Novel 1,4-substituted-1,2,3-triazoles as antitubercular agents. AB - Tuberculosis (TB) remains a pressing unmet medical need, particularly with the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. Here, a series of 1,4-substituted-1,2,3-triazoles have been synthesized and evaluated as potential antitubercular agents. These compounds were assembled via click chemistry in high crude purity and in moderate to high yield. Of the compounds tested, 12 compounds showed promising antitubercular activity with six possessing minimum inhibitory concentration (MIC) values <10 MUg mL(-1) , and total selectivity for Mycobacterium tuberculosis (Mtb) growth inhibition. A second set of 21 compounds bearing variations on ring C were synthesized and evaluated. This second library gave an additional six compounds displaying MIC values <=10 MUg mL(-1) and total selectivity for Mtb growth inhibition. These compounds serve as an excellent starting point for further development of antitubercular therapies. PMID- 25788467 TI - Analytical solution of electronic transport through a benzene molecule using lattice Green's functions. AB - Using a Green's function formalism we derive analytical expressions for electronic transmittance through a benzene ring. To motivate the approach we first solve the resonant level system and then extend the method to the benzene case. These results can be used to validate numerical methods. PMID- 25788468 TI - Tunneling conductivity in anisotropic nanofiber composites: a percolation-based model. AB - The critical path approximation ('CPA') is integrated with a lattice-based approach to percolation to provide a model for conductivity in nanofiber-based composites. Our treatment incorporates a recent estimate for the anisotropy in tunneling-based conductance as a function of the relative angle between the axes of elongated nanoparticles. The conductivity is examined as a function of the volume fraction, degree of clustering, and of the mean value and standard deviation of the orientational order parameter. Results from our calculations suggest that the conductivity can depend strongly upon the standard deviation in the orientational order parameter even when all the other variables (including the mean value of the order parameter ) are held invariant. PMID- 25788469 TI - Achieving high acceptability of HIV testing in a population-based survey among immigrants in Finland. AB - AIMS: The aim of this study was to assess the acceptability of human immunodeficiency virus (HIV) testing among migrants in Finland and the factors contributing to non-acceptance. METHODS: The Finnish Migrant Health and Wellbeing Study 'Maamu' was the first national population-based Health Interview and Examination Survey (HIS/HES) among migrants in Finland. A total of 386 Kurdish, Russian and Somali immigrants in Helsinki participated in the study. RESULTS: Despite the participants' different sociodemographic backgrounds, a high rate of test acceptability (92%, 95% CI 90-95) was achieved. HIV test acceptance was associated with pretest counselling, ability to understand spoken Finnish or Swedish and employment status. No participants tested positive for HIV. CONCLUSIONS: The results imply that a universal HIV testing strategy is well accepted in a low-HIV prevalence immigrant population and can be included in a general health examination in immigrant population-based surveys. PMID- 25788471 TI - Intimate partner violence among women in Spain: the impact of regional-level male unemployment and income inequality. AB - BACKGROUND: Intimate partner violence (IPV) against women is a complex worldwide public health problem. There is scarce research on the independent effect on IPV exerted by structural factors such as labour and economic policies, economic inequalities and gender inequality. OBJECTIVE: To analyse the association, in Spain, between contextual variables of regional unemployment and income inequality and individual women's likelihood of IPV, independently of the women's characteristics. METHOD: We conducted multilevel logistic regression to analyse cross-sectional data from the 2011 Spanish Macrosurvey of Gender-based Violence which included 7898 adult women. The first level of analyses was the individual women' characteristics and the second level was the region of residence. RESULTS: Of the survey participants, 12.2% reported lifetime IPV. The region of residence accounted for 3.5% of the total variability in IPV prevalence. We determined a direct association between regional male long-term unemployment and IPV likelihood (P = 0.007) and between the Gini Index for the regional income inequality and IPV likelihood (P < 0.001). Women residing in a region with higher gender-based income discrimination are at a lower likelihood of IPV than those residing in a region with low gender-based income discrimination (odds ratio = 0.64, 95% confidence intervals: 0.55-0.75). CONCLUSIONS: Growing regional unemployment rates and income inequalities increase women's likelihood of IPV. In times of economic downturn, like the current one in Spain, this association may translate into an increase in women's vulnerability to IPV. PMID- 25788470 TI - Still childless at the age of 32: An investigation of predictors in 22-year-old women and men. AB - AIM: The aim of this study was to investigate if family background and attitudes in early adulthood contribute to postponement of parenthood. Postponement of parenthood is associated with increased need for artificial reproductive techniques, increased risk for adverse pregnancy outcomes and reduced fertility rates. METHODS: This was a cohort study including 1000 women and men aged 22 years from the Swedish Young Adult Panel Study. Questionnaire data were linked to information from the Swedish Total Population Register 10 years later. Logistic regression analyses were conducted. RESULTS: Background factors associated with being childless were: being second-generation Polish or Turkish (odds ratio [OR] 1.5; 95% confidence intervals [CI] 1.2-2.0), growing up in a large city (OR 1.5; 95% CI 1.1-2.0), well-educated mother (OR 1.5; 95% CI 1.1-1.9) or father (OR 1.4; 95% CI 1.1-1.9), no siblings (OR 1.9; 95% CI 1.1-3.2), living in parental home (OR 2.2; 95% CI 1.6-3.1), less than good assessment of own mother (OR 1.8; 95% CI 1.2-2.7) or father (OR 1.4; 95% CI 1.0-1.9) as a parent, and less than satisfactory relationship with own mother (OR 1.5; 95% CI 1.1-2.1). Attitudes associated with being childless were: not enjoying children (OR 2.7; 95% CI 2.0 3.6), finding that one could be satisfied in life without being a good parent (OR 2.3; 95% CI 1.7-3.0) and not assuming that one will have children in the future (OR 2.9; 95% CI 2.1-3.9). CONCLUSIONS: The findings suggest that postponement of parenthood to the age of 32 could partly be explained by family background and negative or ambivalent attitudes to children and parenthood in early adulthood. PMID- 25788472 TI - Pregestational excess weight, maternal obstetric complications and mode of delivery in the Rhea cohort in Crete. AB - BACKGROUND: There has been a significant increase in overweight and obesity worldwide reaching global epidemic, with dramatic increase also among women of reproductive age or entering pregnancy. Aims of the study were to estimate the prevalence of maternal pregestational overweight and obesity and their association with and contribution to maternal obstetric complications and mode of delivery. METHODS: One thousand two hundred eighty-six women with singleton pregnancies were followed-up prospectively from early pregnancy to delivery in Crete. RESULTS: The prevalence of pre-pregnancy overweight and obesity were 20 and 11.5%, respectively. After adjusting for potential confounders, overweight and/or obesity were associated with an increased risk for caesarean deliveries [RR(overweight_vs._normal) BMI = 1.21, 95% CI (1.06, 1.38), RR(obese_vs._normal) BMI = 1.21, 95% CI (1.02, 1.42)], gestational diabetes mellitus [RR(obese_vs._normal) BMI = 2.11, 95% CI (1.28, 3.47)] and high blood pressure [RR(severy.obese_vs._normal) BMI = 3.32, 95% CI (1.36, 8.06)] any time in pregnancy. Pre-pregnancy excess weight has potentially contributed to 21% of planned caesarean deliveries in primiparae (almost 45% of such cases among overweight/obese primiparea were potentially attributed to pregestational excess weight). One-third of gestational hypertension and gestational diabetes cases among overweight/obese mothers could be attributed to pregestational excess weight, although results did not reach statistical significance. CONCLUSIONS: Pregestational overweight and obesity continued to increase even more in recent years. Findings further support that maternal excess weight has a significant effect on and contribution to multiple maternal obstetric complications and the mode of delivery, underlining the necessity of obesity prevention, health policy strategies and health care that can result in significant individual and societal benefits. PMID- 25788473 TI - Fast-food outlets and grocery stores near school and adolescents' eating habits and overweight in Finland. AB - BACKGROUND: Environmental factors may affect adolescents' eating habits and thereby body weight. However, the contribution of school neighbourhood environment is poorly understood. This study examined the association between proximity of a fast-food outlet or grocery store to school and adolescents' eating habits and overweight. METHODS: Participants were 23 182 adolescents (mean age 15 years) who responded to a classroom survey in 181 lower secondary schools in Finland (2008-09). School location was linked to data on distance from school to the nearest fast-food outlet or grocery store (<=100 m, 101-500 m, >500 m) using global positioning system-coordinate databases. Outcomes were irregular eating habits (skipping breakfast, skipping free school lunch, skipping free school-provided snacks and not having family dinners), the accumulation of these habits and overweight, including obesity (body mass index >= 25 kg/m(2)). RESULTS: Thirteen percentage of the participants were overweight. Having a fast food outlet or grocery store near school was associated with skipping often breakfast and free school lunch, and the accumulation of irregular eating habits. The proximity of a fast-food outlet or grocery store was associated with a 1.25 fold (95% confidence interval 1.03-1.52) risk of overweight among adolescent with a low socioeconomic status but not among those with higher socioeconomic status. This association was partly (12%) explained by the accumulation of irregular eating habits. CONCLUSIONS: Among adolescents from low socioeconomic background, the presence of fast-food retailers near schools is associated with accumulation of irregular eating habits and greater overweight. These findings suggest that obesogenic school neighbourhoods may contribute to social inequalities in overweight. PMID- 25788474 TI - A regional analysis of outpatient antibiotic prescribing in Germany in 2010. AB - The aim of this study was to investigate whether the previously reported regional variation in outpatient antimicrobial use density in Germany has persisted or changed over time and has been similar for both children and adults. Antibiotic [at least 1 Anatomical Therapeutic Chemical (ATC) Code 'J01' drug] prescription prevalence data for the year 2010 were analysed for 17 regions. The overall age standardized antibiotic prescription prevalence ranged between 25.0 and 36.6% in the different regions. Regional prescription patterns for children differed from those seen in adults. Age-specific differences in antibiotic prescription prevalence need to be considered when comparing antibiotic consumption between regions. PMID- 25788475 TI - Growing up in Glasgow: the social context of adolescence. AB - The adolescent population of Glasgow, the city with the highest mortality in the UK, has a higher prevalence of risk behaviours than elsewhere in Scotland. Previous research has highlighted the importance of social context in interpreting such differences. Contextual variables from the 2010 Health Behaviour in School-aged Children Scotland survey were analysed. Glaswegian adolescents were more likely to live in low socioeconomic status, single-parent or step-families, or with neither parent in employment, less likely to share family meals, more likely to buy lunch outside school, and spend time with friends after school and in the evenings. They also had a poorer perception of their local neighbourhood. Family affluence only partially explained these differences. PMID- 25788476 TI - Endostatin has ATPase activity, which mediates its antiangiogenic and antitumor activities. AB - Endostatin is an endogenous angiogenesis inhibitor with broad-spectrum antitumor activities. Although the molecular mechanisms of endostatin have been extensively explored, the intrinsic biochemical characteristics of endostatin are not completely understood. Here, we revealed for the first time that endostatin embedded novel ATPase activity. Moreover, mutagenesis study showed that the ATPase activity of endostatin mutants positively correlated with effects on endothelial cell activities and tumor growth. E-M, an endostatin mutant with higher ATPase activity than that of wild-type (WT) endostatin, significantly increased endostatin-mediated inhibitory effects on endothelial cell proliferation, migration, tube formation, and adhesion. In vivo study showed that E-M displayed enhanced antitumor effects compared with WT. On the other hand, K96A, K96R, and E176A, endostatin mutants with lower ATPase activities than that of WT, showed reduced or comparable effects on targeting both in vitro endothelial cell activities and in vivo tumor angiogenesis and tumor growth. Furthermore, endostatin and its mutants exhibited distinct abilities in regulations of gene expression (Id1, Id3), cell signaling (Erk, p38, and Src phosphorylation), and intracellular ATP levels. Collectively, our study demonstrates that endostatin has novel ATPase activity, which mediates its antiangiogenic and antitumor activities, suggesting that construction of endostatin analogues with high ATPase activity may provide a new direction for the development of more potent antiangiogenic drugs. PMID- 25788477 TI - Addressing Disparities in Stroke Prevention for Atrial Fibrillation: Educational Opportunities. AB - Disparities in atrial fibrillation (AF)-related stroke and mortality persist, especially racial disparities, within the US "Stroke Belt." This study identified barriers to optimal stroke prevention to develop a framework for clinician education. A comprehensive educational needs assessment was developed focusing on clinicians within the Stroke Belt. The mixed qualitative-quantitative approach included regional surveys and one-on-one clinician interviews. Identified contributors to disparities included implicit racial biases, lack of awareness of racial disparities in AF stroke risk, and lack of effective multicultural awareness and training. Additional barriers affecting disparities included patient medical mistrust and clinician-patient communication challenges. General barriers included lack of consistency in assessing stroke and anticoagulant related bleeding risk, underuse of standardized risk assessment tools, discomfort with novel anticoagulants, and patient education deficiencies. Effective cultural competency training is one strategy to reduce disparities in AF-related stroke and mortality by improving implicit clinician bias, addressing medical mistrust, and improving clinician-patient communication. PMID- 25788478 TI - Population-Level Quality Measures for Behavioral Screening and Intervention. AB - Delivered routinely in general health care settings, smoking, alcohol, depression, and obesity screening and intervention (behavioral screening and intervention [BSI]) could substantially improve population health and reduce health care costs. Yet BSI is seldom delivered in an evidence-based manner. This article assesses the adequacy of quality measures for BSI. Online searches of the National Quality Forum's Quality Positioning System and the National Clearinghouse for Quality Measures databases were conducted using the keywords smoking, tobacco, alcohol, depression, and obesity The types and focuses of each measure were classified, and differences between the metrics and evidence-based practice were identified. Most measures indicate whether BSI components are delivered, not how well. Clinicians can perform well on most metrics without delivering evidence-based services. More rigorous quality measures are needed. A new kind of measure is proposed, whereby separate terms representing the reach and effectiveness of key BSI components are multiplied to produce a single indicator of population-level impact for each behavioral topic. PMID- 25788479 TI - Improvement in catheter-associated urinary tract infection in surgery patients: results of a quality improvement program. PMID- 25788480 TI - Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts. AB - Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD precursor nicotinamide riboside (NR) ameliorates energetic derangement and symptoms in mouse models of mitochondrial disorders. Whether these pharmacological approaches also improve bioenergetics of human cells harboring mitochondrial defects is unknown. It is also unclear whether the same signaling cascade is prompted by PARP-1 inhibitors and NR supplementation to improve mitochondrial homeostasis. Here, we show that human fibroblasts mutant for the NADH dehydrogenase (ubiquinone) Fe-S protein 1 (NDUFS1) subunit of respiratory complex I have similar ATP, NAD, and mitochondrial content compared with control cells, but show reduced mitochondrial membrane potential. Interestingly, mutant cells also show increased transcript levels of mitochondrial DNA but not nuclear DNA respiratory complex subunits, suggesting activation of a compensatory response. At variance with prior work in mice, however, NR supplementation, but not PARP-1 inhibition, increased intracellular NAD content in NDUFS1 mutant human fibroblasts. Conversely, PARP-1 inhibitors, but not NR supplementation, increased transcription of mitochondrial transcription factor A and mitochondrial DNA encoded respiratory complexes constitutively induced in mutant cells. Still, both NR and PARP-1 inhibitors restored mitochondrial membrane potential and increased organelle content as well as oxidative activity of NDUFS1-deficient fibroblasts. Overall, data provide the first evidence that in human cells harboring a mitochondrial respiratory defect exposure to NR or PARP-1, inhibitors activate different signaling pathways that are not invariantly prompted by NAD increases, but equally able to improve energetic derangement. PMID- 25788482 TI - Bayesian and frequentist approaches to assessing reliability and precision of health-care provider quality measures. AB - Our purpose was to compare frequentist, empirical Bayes, and Bayesian hierarchical model approaches to estimating reliability of health care quality measures, including construction of credible intervals to quantify uncertainty in reliability estimates, using data on inpatient fall rates on hospital nursing units. Precision of reliability estimates and Bayesian approaches to estimating reliability are not well studied. We analyzed falls data from 2372 medical units; the rate of unassisted falls per 1000 inpatient days was the measure of interest. The Bayesian methods "shrunk" the observed fall rates and frequentist reliability estimates toward their posterior means. We examined the association between reliability and precision in fall rate rankings by plotting the length of a 90% credible interval for each unit's percentile rank against the unit's estimated reliability. Precision of rank estimates tended to increase as reliability increased but was limited even at higher reliability levels: Among units with reliability >0.8, only 5.5% had credible interval length <20; among units with reliability >0.9, only 31.9% had credible interval length <20. Thus, a high reliability estimate may not be sufficient to ensure precise differentiation among providers. Bayesian approaches allow for assessment of this precision. PMID- 25788483 TI - Morphological features of retinal development in premature Chinese infants observed by computer-assisted indirect ophthalmoscope imaging. AB - OBJECTIVE: To investigate retinal maturation in premature infants (gestation age <37 weeks). using computer-assisted indirect ophthalmoscope imaging. METHODS: Premature infants at postmenstrual age 33-46 weeks, who underwent fundus examinations using computer-aided indirect ophthalmoscopy, were stratified into seven postmenstrual-age groups. Images of macular morphology, peripheral retinal vascularization and fundus pigmentation were compared. RESULTS: The study included 268 infants in the following postmenstrual-age groups: 33-34 weeks (n = 19), 35-36 weeks (n = 37), 37-38 weeks (n = 49), 39-40 weeks (n = 55), 41-42 weeks (n = 49), 43-44 weeks (n = 34), and 45-46 weeks (n = 25). The macula matured with increasing postmenstrual age. A mature macula was observed in 92% of infants at 45-46 weeks. Complete vascularization was achieved at 41-42 weeks in the nasal retina and at 43-44 weeks in the temporal retina. The number of retinas with normal pigmentation increased with postmenstrual age (rising to 84% of infants at postmenstrual age 45-46 weeks). CONCLUSIONS: Following premature birth, macular morphology, retinal vascularization and retinal pigmentation continue to develop. This study provides reference images of normal retinal development in premature infants. PMID- 25788484 TI - Symptomatology of irritable bowel syndrome and inflammatory bowel disease during the menstrual cycle. AB - Gender-related physiological variations in gastrointestinal (GI) symptomatology have been observed in women of reproductive age. Many women experience cyclical changes in GI symptomatology during their menstrual cycle, particularly alteration in their bowel habits. Physiological studies of healthy women during the menstrual cycle showed a prolonged GI transit time during the luteal phase, either in the oro-cecum route or in the colon. Worsened GI symptoms, such as abdominal pain, bloating or diarrhea are observed in patients with irritable bowel syndrome (IBS) during menses. This may be due to elevated prostaglandin levels during menses, with an enhanced perception of viscera-somatic stimuli resulting in nausea, abdominal distension and pain. Also patients with IBS or IBD demonstrate a cyclical pattern more closely related to their bowel habits than healthy controls. Women with inflammatory bowel disease (IBD) also have exacerbated symptoms during menses; however, it is unclear whether this relates to physiological variation or disease exacerbation in IBS or IBD. Studies examining the association of the menstrual cycle and GI symptomatology in patients with IBS or IBD, have not yet clarified the underlying mechanisms. Moreover medications-such as non-steroidal anti-inflammatory drugs and oral contraceptive pills used for dysmenorrhea and menstrual migraine in those patients have not well been controlled for in the previous studies, which can contribute to further bias. Understanding changes in GI symptomatology during the menstrual cycle may help to determine the true extent of disease exacerbation and proper management strategy. PMID- 25788485 TI - Plasmodium infection brings forward mosquito oviposition. AB - Invertebrate hosts often bring forward their reproductive effort in response to a parasitic infection. This is widely interpreted as a host-driven response aimed at compensating for the expected losses in future fitness as a result of parasitism. Here we report that mosquitoes bring forward their oviposition schedule when they are infected with Plasmodium, a parasite known to severely curtail mosquito fecundity. This response could aim at compensating for a negative time-dependent effect of the parasite on mosquito fitness, as infected mosquitoes seem to display a strong and progressive decrease in the quality of the eggs they lay. In addition, we show that this shift in oviposition date is dependent on mosquito strain: a comparison of several isogenic mosquitoes strains, one insecticide-susceptible and two insecticide-resistant ones, reveals that only the former shift their oviposition strategy when infected. This pattern suggests the existence of a costly host-driven response to parasitism, as insecticide-resistant mosquitoes have been shown to be in generally poorer condition. PMID- 25788486 TI - Transgenerational effects of sexual interactions and sexual conflict: non-sires boost the fecundity of females in the following generation. AB - The consequences of sexual interactions extend beyond the simple production of offspring. These interactions typically entail direct effects on female fitness, but may also impact the life histories of later generations. Evaluating the cross generational effects of sexual interactions provides insights into the dynamics of sexual selection and conflict. Such studies can elucidate whether offspring fitness optima diverge across sexes upon heightened levels of sexual interaction among parents. Here, we found that, in Drosophila melanogaster, components of reproductive success in females, but not males, were contingent on the nature of sexual interactions experienced by their mothers. In particular, maternal sexual interactions with non-sires enhanced female fecundity in the following generation. This highlights the importance of non-sire influences of sexual interactions on the expression of offspring life histories. PMID- 25788487 TI - Salivary oxytocin increases concurrently with testosterone and time away from home among returning Tsimane' hunters. AB - Oxytocin, testosterone and cortisol can have opposing effects on social behaviour, yet few studies have examined their interactions. We measured changes in salivary oxytocin, testosterone and cortisol among Tsimane' men returning home after hunting, an ancient context of male status competition, parental investment and cooperation. Contra normal diurnal rhythm, oxytocin increased relative to baseline and this increase was positively associated with duration of the hunt and change in testosterone, but not cortisol, social context, hunting outcome or physical activity. The concurrent increase in endogenous peripheral oxytocin and testosterone is unexpected given their opposing independent effects on social cognition and behaviour, and has not been observed before. We discuss the potential significance of these effects for the biology of pair-bonding, parenting and social foraging in humans and other species. PMID- 25788488 TI - Near-infrared light increases ATP, extends lifespan and improves mobility in aged Drosophila melanogaster. AB - Ageing is an irreversible cellular decline partly driven by failing mitochondrial integrity. Mitochondria accumulate DNA mutations and reduce ATP production necessary for cellular metabolism. This is associated with inflammation. Near infrared exposure increases retinal ATP in old mice via cytochrome c oxidase absorption and reduces inflammation. Here, we expose fruitflies daily to 670 nm radiation, revealing elevated ATP and reduced inflammation with age. Critically, there was a significant increase in average lifespan: 100-175% more flies survived into old age following 670 nm exposure and these had significantly improved mobility. This may be a simple route to extending lifespan and improving function in old age. PMID- 25788489 TI - Relationship between amino acid changes in mitochondrial ATP6 and life-history variation in anguillid eels. AB - Mitochondrial genes are part of the oxidative phosphorylation pathway and important for energy production. Although evidence for positive selection at the mitochondrial level exists, few studies have investigated the link between amino acid changes and phenotype. Here we test the hypothesis that differences in two life-history related traits, migratory distance between spawning and foraging areas and larval phase duration, are associated with divergent selection within the mitochondrial ATP6 gene in anguillid eels. We compare amino acid changes among 18 species with the sequence of the putative ancestral species, believed to have shown short migratory distance and larval phase duration. We find positive correlations between both life-history related traits and (i) the number of amino acid changes and (ii) the strength of the combined physico-chemical and structural changes at positions previously identified as candidates for positive selection. This supports a link between genotype and phenotype driven by positive selection at ATP6. PMID- 25788490 TI - Partial migration: growth varies between resident and migratory fish. AB - Partial migration occurs in many taxa and ecosystems and may confer survival benefits. Here, we use otolith chemistry data to determine whether fish from a large estuarine system were resident or migratory, and then examine whether contingents display differences in modelled growth based on changes in width of otolith growth increments. Sixty-three per cent of fish were resident based on Ba : Ca of otoliths, with the remainder categorized as migratory, with both contingents distributed across most age/size classes and both sexes, suggesting population-level bet hedging. Migrant fish were in slightly better condition than resident fish based on Fulton's K condition index. Migration type (resident versus migratory) was 56 times more likely to explain variation in growth than a model just incorporating year- and age-related growth trends. While average growth only varied slightly between resident and migratory fish, year-to-year variation was significant. Such dynamism in growth rates likely drives persistence of both life-history types. The complex relationships in growth between contingents suggest that management of species exhibiting partial migration is challenging, especially in a world subject to a changing climate. PMID- 25788491 TI - Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. AB - PURPOSE: Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. Drugs blocking PD-L1 or its receptor have shown unprecedented activity in melanoma, and our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in metastatic melanomas. EXPERIMENTAL DESIGN: We used a tissue microarray (TMA) consisting of two cores from 95 metastatic melanomas characterized for clinical stage, outcome, and anatomic site of disease. We assessed PD-L1 expression and tumor-infiltrating lymphocyte (TIL) content (total T cells and CD4/CD8 subsets) by quantitative immunofluorescence. RESULTS: High PD-L1 expression was associated with improved survival (P = 0.02) and higher T-cell content (P = 0.0005). Higher T-cell content (total and CD8 cells) was independently associated with improved overall survival; PD-L1 expression was not independently prognostic. High TIL content in extracerebral metastases was associated with increased time to developing brain metastases (P = 0.03). Cerebral and dermal metastases had slightly lower PD-L1 expression than other sites, not statistically significant. Cerebral metastases had less T cells (P = 0.01). CONCLUSIONS: T-cell-infiltrated melanomas, particularly those with high CD8 T-cell content, are more likely to be associated with PD-L1 expression in tumor cells, an improved prognosis, and increased time to development of brain metastases. Studies of T-cell content and subsets should be incorporated into trials of PD-1/PD-L1 inhibitors to determine their predictive value. Furthermore, additional studies of anatomic sites with less PD-L1 expression and T-cell infiltrate are needed to determine if discordant responses to PD-1/PD-L1 inhibitors are seen at those sites. PMID- 25788492 TI - A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma. AB - PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including >= 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. RESULTS: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. CONCLUSIONS: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. PMID- 25788495 TI - Night-to-Night Variability of Sleep in Children With ADHD and Typically Developing Controls. AB - OBJECTIVE: Research results on the nature of sleep problems in children with ADHD are highly inconsistent. It is frequently reported that children with ADHD show more night-to-night variability in sleep than their typically developing (TD) peers, but this finding is also inconsistent. Lack of methodological control may account for these inconsistent findings. The current study examined the night-to night variability of sleep between TD children and children with ADHD who were rigorously diagnosed, medication naive, and free from comorbid mental health disorders. METHOD: Sleep parameters were analyzed for night-to-night variability across 4 weekday nights using actigraphy in 50 children with ADHD and 50 age- and sex-matched TD children. RESULTS: There was a significant night-to-night variability for only sleep duration, but this was similar in both groups. CONCLUSION: These findings suggest that sleep problems in children with ADHD are not due to greater variability in sleep parameters relative to their TD peers. PMID- 25788494 TI - Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma. AB - PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL). EXPERIMENTAL DESIGN: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients. RESULTS: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL. CONCLUSIONS: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO. PMID- 25788493 TI - Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. AB - PURPOSE: Serum PSA (sPSA) testing has led to the identification of patients with indolent prostate cancer, and inevitably overtreatment has become a concern. Progensa PCA3 urine testing was shown to improve the diagnosis of prostate cancer, but its diagnostic value for aggressive prostate cancer is limited. Therefore, urinary biomarkers that can be used for prediction of Gleason score >=7 prostate cancer in biopsies are urgently needed. EXPERIMENTAL DESIGN: Using gene expression profiling data, 39 prostate cancer biomarkers were identified. After quantitative PCR analysis on tissue specimens and urinary sediments, eight promising biomarkers for the urinary detection of prostate cancer were selected (ONECUT2, HOXC4, HOXC6, DLX1, TDRD1, NKAIN1, MS4A8B, PPFIA2). The hypothesis that biomarker combinations improve the diagnostic value for aggressive prostate cancer was tested on 358 urinary sediments of an intention-to-treat cohort. RESULTS: A urinary three-gene panel (HOXC6, TDRD1, and DLX1) had higher accuracy [area under the curve (AUC), 0.77; 95% confidence interval (CI), 0.71-0.83] to predict Gleason score >=7 prostate cancer in biopsies compared with Progensa PCA3 (AUC, 0.68; 95% CI, 0.62-0.75) or sPSA (AUC, 0.72; 95% CI, 0.65-0.78). Combining the three-gene panel with sPSA further improved the predictive accuracy (AUC, 0.81; 95% CI, 0.75-0.86). The accuracy of the three-gene predictive model was maintained in subgroups with low sPSA concentrations. CONCLUSIONS: The urinary three-gene panel (HOXC6, TDRD1, and DLX1) represents a promising tool to identify patients with aggressive prostate cancer, also in those with low sPSA values. The combination of the urinary three-gene panel with sPSA bears great potential for the early diagnosis of patients with clinically significant prostate cancer. PMID- 25788496 TI - On the nosology of formal thought disorder. PMID- 25788497 TI - Amisulpride monotherapy may be a choice of maintenance treatment for patients with both bipolar I disorder and metabolic syndrome. PMID- 25788498 TI - Successful use of olfactory hallucinations as early warning sign in a patient with bipolar disorder. PMID- 25788499 TI - Decreased regional activity and network homogeneity of the fronto-limbic network at rest in drug-naive major depressive disorder. AB - OBJECTIVE: The fronto-limbic network is implicated in the neurobiology of major depressive disorder. However, no studies are designed to assess directly the abnormalities of regional activity and network homogeneity of this network in major depressive disorder. METHODS: A total of 44 drug-naive major depressive disorder patients and 44 healthy controls participated in the study, and resting state functional magnetic resonance imaging data were obtained. The fractional amplitude of low-frequency fluctuations and network homogeneity methods were employed to analyze the data. RESULTS: Compared with the controls, the patients exhibited reduced fractional amplitude of low-frequency fluctuations in the right middle frontal gyrus (orbital part) and decreased network homogeneity in the left middle frontal gyrus. There was no correlation between abnormal fractional amplitude of low-frequency fluctuations/network homogeneity and clinical variables. CONCLUSIONS: Our findings suggest that decreased regional activity and network homogeneity in the frontal cortex may be the key impairment of the fronto limbic network in major depressive disorder, and thus highlight the importance of the fronto-limbic network in the neurobiology of major depressive disorder. PMID- 25788500 TI - Ceftazidime with beta-lactamase inhibitor approved for complicated infections. PMID- 25788501 TI - Prepare now for USP standard on handling hazardous drugs. PMID- 25788502 TI - CMS explains Medicare payment for chronic care management services. PMID- 25788503 TI - Effective drug therapy for Alzheimer's disease remains elusive. PMID- 25788504 TI - Dietary suggestions for migraine prevention. PMID- 25788505 TI - Support for "second victims". PMID- 25788506 TI - Comparative efficacy and safety of insulin analogs in hospitalized adults. AB - PURPOSE: The comparative efficacy, safety, and cost-effectiveness of rapid and long-acting insulin analogs compared with regular or neutral protamine Hagedorn nonanalog insulins or with oral antidiabetic agents in hospitalized adults were evaluated. METHODS: A literature search was conducted to identify studies that compared the effects of rapid-acting, long-acting, or mixed insulin analogs with short- or intermediate-acting insulin or any other oral antidiabetic medication. RESULTS: Twenty-three primary studies were included in the review. Rapid-acting analogs and basal-bolus analog regimens were found to reduce the duration of hospital stay by approximately one day compared with regular insulin and basal bolus nonanalog regimens. One large cohort study found an adjusted 48% relative risk reduction in mortality with rapid-acting analogs versus regular insulin in a heterogeneous hospitalized hyperglycemic population. A randomized controlled trial found a significant reduction in postoperative complications with basal bolus analogs compared with basal-bolus nonanalog insulin. When compared with regular sliding-scale insulin (SSI), fixed-dose insulin glargine with or without insulin glulisine was found to reduce the blood glucose concentration in patients with type 2 diabetes and reduce postoperative complications in surgical patients with diabetes. The quality of evidence was primarily very low or low for most outcomes. CONCLUSION: A systematic literature review revealed a very low or low quality of evidence, suggesting that, compared with nonanalog regimens, rapid acting insulin analogs reduce the duration of hospital stay and mortality rates and that basal- bolus analog regimens may reduce the duration of hospital stay and postoperative complications. There is also a low quality of evidence to suggest that a fixed-dose analog regimen of insulin glargine with or without insulin glulisine is more effective than regular SSI for reducing blood glucose concentrations and postoperative complications. PMID- 25788507 TI - Recurrence of prostate cancer in patients receiving testosterone supplementation for hypogonadism. AB - PURPOSE: The relationship between recurrent prostate cancer risk and testosterone replacement therapy (TRT) for hypogonadal men is explored. SUMMARY: The medical literature was searched to identify articles evaluating the use of TRT in symptomatic hypogonadal men with a history of prostate cancer. Eight English language articles investigating TRT use in hypogonadal men with a history of prostate cancer were analyzed. For evaluative purposes, the normal ranges used for prostate-specific antigen (PSA) and total testosterone levels were less than 4.0 ng/mL and 300-1000 ng/dL, respectively. Most trials were small and involved patients with localized prostate cancer treated with radical prostatectomy or radiotherapy, though patients with metastatic disease or a Gleason score of >=8 were included in a few studies. TRT was administered in a variety of dosages and dosage forms for up to nine years to manage hypogonadal symptoms. Testosterone concentrations increased, as expected, after TRT, but serum PSA levels remained below 0.1 ng/mL in the majority of patients. PSA levels were found to increase in select patients with high-risk and metastatic disease, but these elevations were not accompanied by disease progression. These studies have suggested a potential benefit for TRT use in select symptomatic hypogonadal men with a history of prostate cancer. Data were limited, however, by the retrospective nature of most studies, the lack of control groups, small sample sizes, and short follow-up periods. CONCLUSION: There is insufficient evidence to withhold TRT in certain populations of men with a history of prostate cancer. PMID- 25788508 TI - Development of recommendations for dosing of commonly prescribed medications in critically ill obese children. AB - PURPOSE: The development and use of a decision support tool to help formulate recommendations for dosing of commonly prescribed medications in critically ill obese children are described. METHODS: Medications prescribed in 2010 to critically ill infants and children (younger than 18 years) were identified from the Pediatric Health Information System. The most commonly prescribed and therapeutically monitored medications were extracted. Supportive evidence for obesity dosing was identified through a standardized computerized search involving medical subject heading terminology and age filters using PubMed and Ovid. A usefulness scoring system was developed to rate the strength and applicability of the literature to critically ill obese children. A decision supporttool was then created to aid in the formulation of a dosing weight for each medication based on the usefulness score, published pharmacokinetic properties, clinical studies available in the primary literature, and consideration of clinical consequences of underdosing or overdosing. RESULTS: A total of 113 medications were evaluated, and 122 discrete citations, supporting 66 medications, were reviewed. Seventy-two percent of citations had general obesity dosing information, and 13% had pediatric-specific information. The overall mean usefulness score was 5.1+/-4.7 (median, 7). The decision support tool was incorporated to make final dosing weight recommendations for obese children. Ultimately, total body weight was recommended for 52 medications, adjusted weight for 43 medications, and ideal body weight for 18 medications. CONCLUSION: The inadequacy of obesity dosing information for most medications commonly ordered for children admitted to a pediatric intensive care unit led to the development of a decision support tool to aid in formulating dosing recommendations. PMID- 25788509 TI - Comparison of warfarin time in the therapeutic range at a pharmacist-run anticoagulation clinic and the RE-LY trial. AB - PURPOSE: An audit was conducted to determine if the benefits of dabigatran treatment, as demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, are applicable to patients with nonvalvular atrial fibrillation managed by a pharmacist-run anticoagulation clinic (PAC). METHODS: The records of warfarin-treated patients managed by a PAC program over a three-year period were screened to identify patients with diagnosed nonvalvular atrial fibrillation and a goal International Normalized Ratio (INR) of 2-3; the case selection criteria were similar to those used in the RE-LY trial. Abstracted data included dates and results of INR monitoring and information needed to calculate CHADS2 (Congestive Heart Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) scores. Warfarin time in the therapeutic range (TTR) was the primary endpoint. A pairwise comparison of TTR distributions in subsets of patients grouped by CHADS2 score was performed to test the hypothesis that any two groups had identical distributions. RESULTS: Data on 314 PAC patients, including 9772 INR values, were analyzed. The mean+/-S.D. TTR was 62.4%+/-24.5% (median, 66.7%), which was similar to the mean TTR reported in the RE-LY trial (p=0.092). The distribution of TTR values in the PAC population differed significantly in patients with a CHADS2 score of 2 versus a score of 3 (p=0.0333 for Kuiper test), but no other significant differences were noted. CONCLUSION: TTR values among PAC-managed patients with nonvalvular atrial fibrillation were comparable to those reported in the RE-LY trial. PMID- 25788510 TI - Implementation of a "second victim" program in a pediatric hospital. AB - PURPOSE: A formal support program for pharmacy employees involved in adverse drug events, patient-related injuries, and other traumatic work experiences is described. SUMMARY: Healthcare workers are sometimes referred to as the "second victims" of patient care mishaps due to the anxiety, loss of confidence, and career uncertainty they may experience. After a survey indicating that about 30% of its staff had been involved in a second-victim event, the Nationwide Children's Hospital (NCH) pharmacy department implemented a peer-based support initiative (the YOU Matter program) based on an established three-tiered intervention model. All staff members are trained to identify second victims. The core of the program is a team of trained peer supporters who serve as first responders; if additional support is required, referrals to behavioral health, social work, and employee assistance personnel are made as appropriate. Staff members involved in troubling work-related events can seek support via a Web based portal for event reporting and discussion. Since the launch of the NCH second victim program, the team of trained peer supporters has been expanded from 13 to over 120. In a postimplementation survey, 85% of the NCH pharmacy department staff indicated that the YOU Matter program has been beneficial. CONCLUSION: The majority of the NCH pharmacy staff reported that the department benefited from implementation of the second victim program. A survey conducted five months after implementation of the program revealed that 3 respondents had personally used the program and 11 had referred a coworker to a peer supporter. PMID- 25788512 TI - ASHP guidelines on the pharmacist's role in providing drug information. PMID- 25788511 TI - Expansion of clinical pharmacy through increased use of outpatient pharmacists for anticoagulation services. AB - PURPOSE: The expansion of clinical pharmacy services through increased use of outpatient pharmacists for anticoagulation services is described. SUMMARY: Due to the high demand for clinical pharmacist services by patients and medical staff at Harris Health System in Houston, Texas, and the strict budgetary restrictions to improve the quality of care through cost-neutral services, a new telephone anticoagulation monitoring service, provided by clinical pharmacists, was established at four of the busiest anticoagulation ambulatory care centers within the system. One clinical staff pharmacist was trained in each of the four clinics by a clinical pharmacy specialist. Each pharmacist received roughly two weeks of training to provide this service. Implementation of the new anticoagulation monitoring service occurred on April 1, 2013. Data collected between October 2011 and April 2014 revealed significantly more visits per month for the clinical pharmacy service after the implementation of the telephone anticoagulation monitoring service (p=0.011). Redistribution of workflow resulted in a 16% increase in clinical pharmacy patient volume at the ambulatory care clinics (p=0.011). The percentage of International Normalized Ratio values in the therapeutic range, the proportion of hospitalizations due to thromboembolic or bleeding events, work hours per prescription volume, project completion rates, and the number of students precepted did not significantly differ between groups. CONCLUSION: The implementation of a clinical pharmacy telephone service for patients receiving anticoagulation at an outpatient center resulted in increased patient clinic visits without adversely affecting patient outcomes or increasing personnel or costs. PMID- 25788513 TI - ASHP statement on the pharmacist's role in clinical pharmacogenomics. PMID- 25788517 TI - Impact of video technology on efficiency of pharmacist-provided anticoagulation counseling and patient comprehension. AB - BACKGROUND: Discharge anticoagulation counseling is important for ensuring patient comprehension and optimizing clinical outcomes. As pharmacy resources become increasingly limited, the impact of informational videos on the counseling process becomes more relevant. OBJECTIVE: To evaluate differences in pharmacist time spent counseling and patient comprehension (measured by the Oral Anticoagulation Knowledge [OAK] test) between informational videos and traditional face-to-face (oral) counseling. METHODS: This prospective, open, parallel-group study at an academic medical center randomized 40 individuals-17 warfarin-naive ("New Start") and 23 with prior warfarin use ("Restart")-to receive warfarin discharge education by video or face-to-face counseling. "Teach back" questions were used in both groups. RESULTS: Although overall pharmacist time was reduced in the video counseling group (P < 0.001), an interaction between prior warfarin use and counseling method (P = 0.012) suggests the difference between counseling methods was smaller in New Start participants. Following adjustment, mean total time was reduced 8.71 (95% CI = 5.15-12.26) minutes (adjusted P < 0.001) in Restart participants and 2.31 (-2.19 to 6.81) minutes (adjusted P = 0.472) in New Start participants receiving video counseling. Postcounseling OAK test scores did not differ. Age, gender, socioeconomic status, and years of education were not predictive of total time or OAK test score. CONCLUSION: Use of informational videos coupled with teach-back questions significantly reduced pharmacist time spent on anticoagulation counseling without compromising short-term patient comprehension, primarily in patients with prior warfarin use. Study results demonstrate that video technology provides an efficient method of anticoagulation counseling while achieving similar comprehension. PMID- 25788516 TI - Substandard/counterfeit antimicrobial drugs. AB - Substandard/counterfeit antimicrobial drugs are a growing global problem. The most common substandard/counterfeit antimicrobials include beta-lactams (among antibiotics) and chloroquine and artemisin derivatives (among antimalarials). The most common type of substandard/counterfeit antimicrobial drugs have a reduced amount of the active drug, and the majority of them are manufactured in Southeast Asia and Africa. Counterfeit antimicrobial drugs may cause increased mortality and morbidity and pose a danger to patients. Here we review the literature with regard to the issue of substandard/counterfeit antimicrobials and describe the prevalence of this problem, the different types of substandard/counterfeit antimicrobial drugs, and the consequences for the individuals and global public health. Local, national, and international initiatives are required to combat this very important public health issue. PMID- 25788518 TI - Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. AB - Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DA-dependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. PMID- 25788515 TI - Actinomyces and related organisms in human infections. AB - Actinomyces israelii has long been recognized as a causative agent of actinomycosis. During the past 3 decades, a large number of novel Actinomyces species have been described. Their detection and identification in clinical microbiology laboratories and recognition as pathogens in clinical settings can be challenging. With the introduction of advanced molecular methods, knowledge about their clinical relevance is gradually increasing, and the spectrum of diseases associated with Actinomyces and Actinomyces-like organisms is widening accordingly; for example, Actinomyces meyeri, Actinomyces neuii, and Actinomyces turicensis as well as Actinotignum (formerly Actinobaculum) schaalii are emerging as important causes of specific infections at various body sites. In the present review, we have gathered this information to provide a comprehensive and microbiologically consistent overview of the significance of Actinomyces and some closely related taxa in human infections. PMID- 25788519 TI - Analyses of disease-related GNPTAB mutations define a novel GlcNAc-1 phosphotransferase interaction domain and an alternative site-1 protease cleavage site. AB - Mucolipidosis II (MLII) and III alpha/beta are autosomal-recessive diseases of childhood caused by mutations in GNPTAB encoding the alpha/beta-subunit precursor protein of the GlcNAc-1-phosphotransferase complex. This enzyme modifies lysosomal hydrolases with mannose 6-phosphate targeting signals. Upon arrival in the Golgi apparatus, the newly synthesized alpha/beta-subunit precursor is catalytically activated by site-1 protease (S1P). Here we performed comprehensive expression studies of GNPTAB mutations, including two novel mutations T644M and T1223del, identified in Brazilian MLII/MLIII alpha/beta patients. We show that the frameshift E757KfsX1 and the non-sense R587X mutations result in the retention of enzymatically inactive truncated precursor proteins in the endoplasmic reticulum (ER) due to loss of cytosolic ER exit motifs consistent with a severe clinical phenotype in homozygosity. The luminal missense mutations, C505Y, G575R and T644M, partially impaired ER exit and proteolytic activation in accordance with less severe MLIII alpha/beta disease symptoms. Analogous to the previously characterized S399F mutant, we found that the missense mutation I403T led to retention in the ER and loss of catalytic activity. Substitution of further conserved residues in stealth domain 2 (I346 and W357) revealed similar biochemical properties and allowed us to define a putative binding site for accessory proteins required for ER exit of alpha/beta-subunit precursors. Interestingly, the analysis of the Y937_M972del mutant revealed partial Golgi localization and formation of abnormal inactive beta-subunits generated by S1P which correlate with a clinical MLII phenotype. Expression analyses of mutations identified in patients underline genotype-phenotype correlations in MLII/MLIII alpha/beta and provide novel insights into structural requirements of proper GlcNAc-1-phosphotransferase activity. PMID- 25788520 TI - FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK POU1F1 pathway in breast tumorigenesis. AB - The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR. Our results show that expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy. This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer. PMID- 25788521 TI - Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. AB - To assess a potential diagnostic and therapeutic biomarker for age-related macular degeneration (AMD), we sequenced the complement factor I gene (CFI) in 2266 individuals with AMD and 1400 without, identifying 231 individuals with rare genetic variants. We evaluated the functional impact by measuring circulating serum factor I (FI) protein levels in individuals with and without rare CFI variants. The burden of very rare (frequency <1/1000) variants in CFI was strongly associated with disease (P = 1.1 * 10(-8)). In addition, we examined eight coding variants with counts >=5 and saw evidence for association with AMD in three variants. Individuals with advanced AMD carrying a rare CFI variant had lower mean FI compared with non-AMD subjects carrying a variant (P < 0.001). Further new evidence that FI levels drive AMD risk comes from analyses showing individuals with a CFI rare variant and low FI were more likely to have advanced AMD (P = 5.6 * 10(-5)). Controlling for covariates, low FI increased the risk of advanced AMD among those with a variant compared with individuals without advanced AMD with a rare CFI variant (OR 13.6, P = 1.6 * 10(-4)), and also compared with control individuals without a rare CFI variant (OR 19.0, P = 1.1 * 10(-5)). Thus, low FI levels are strongly associated with rare CFI variants and AMD. Enhancing FI activity may be therapeutic and measuring FI provides a screening tool for identifying patients who are most likely to benefit from complement inhibitory therapy. PMID- 25788522 TI - Obesity, starch digestion and amylase: association between copy number variants at human salivary (AMY1) and pancreatic (AMY2) amylase genes. AB - The human salivary amylase genes display extensive copy number variation (CNV), and recent work has implicated this variation in adaptation to starch-rich diets, and in association with body mass index. In this work, we use paralogue ratio tests, microsatellite analysis, read depth and fibre-FISH to demonstrate that human amylase CNV is not a smooth continuum, but is instead partitioned into distinct haplotype classes. There is a fundamental structural distinction between haplotypes containing odd or even numbers of AMY1 gene units, in turn coupled to CNV in pancreatic amylase genes AMY2A and AMY2B. Most haplotypes have one copy each of AMY2A and AMY2B and contain an odd number of copies of AMY1; consequently, most individuals have an even total number of AMY1. In contrast, haplotypes carrying an even number of AMY1 genes have rearrangements leading to CNVs of AMY2A/AMY2B. Read-depth and experimental data show that different populations harbour different proportions of these basic haplotype classes. In Europeans, the copy numbers of AMY1 and AMY2A are correlated, so that phenotypic associations caused by variation in pancreatic amylase copy number could be detected indirectly as weak association with AMY1 copy number. We show that the quantitative polymerase chain reaction (qPCR) assay previously applied to the high-throughput measurement of AMY1 copy number is less accurate than the measures we use and that qPCR data in other studies have been further compromised by systematic miscalibration. Our results uncover new patterns in human amylase variation and imply a potential role for AMY2 CNV in functional associations. PMID- 25788523 TI - APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans. AB - APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naive South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa. PMID- 25788524 TI - Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression. AB - Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca(2+) signals mediated by store operated Ca(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca(2+) channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store-operated Ca(2+) channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release-activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2 aminoethyl diphenylborinate significantly augmented angiotensin II-induced fibronectin protein expression, whereas thapsigargin abrogated high glucose- and TGF-beta1-stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno-associated virus-encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store-operated Ca(2+) channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes. PMID- 25788525 TI - Zinc-alpha2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart. AB - Zinc-alpha2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-beta signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-beta signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease. PMID- 25788526 TI - Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation. AB - A subset of familial and sporadic clear cell renal cell carcinomas (ccRCCs) is believed to develop from cystic precursor lesions. Loss of function of the von Hippel-Lindau tumor suppressor gene (VHL) predisposes renal epithelial cells to loss of the primary cilium in response to specific signals. Because the primary cilium suppresses renal cyst formation, loss of the cilium may be an initiating event in the formation of ccRCC. To test this hypothesis, we analyzed the consequences of inducible renal epithelium-specific deletion of Vhl together with ablation of the primary cilium via deletion of the kinesin family member 3A (Kif3a) gene. We developed a microcomputed tomography-based imaging approach to allow quantitative longitudinal monitoring of cystic burden, revealing that combined loss of Vhl and Kif3a shortened the latency of cyst initiation, increased the number of cysts per kidney, and increased the total cystic burden. In contrast with findings in other cystic models, cysts in Kif3a mutant mice did not display accumulation of hypoxia-inducible factor 1-alpha (HIF1alpha), and deletion of both Hif1a and Kif3a did not affect cyst development or progression. Vhl/Kif3a double mutation also increased the frequency of cysts that displayed multilayered epithelial growth, which correlated with an increased frequency of misoriented cystic epithelial cell divisions. These results argue against the involvement of HIF1alpha in promoting renal cyst growth and suggest that the formation of simple and atypical renal cysts that resemble ccRCC precursor lesions is greatly accelerated by the combined loss of Vhl and the primary cilium. PMID- 25788527 TI - Uric Acid and Cardiovascular Events: A Mendelian Randomization Study. AB - Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death. PMID- 25788528 TI - Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis. AB - Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidin-induced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion-induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin -: deficient mice demonstrated increased susceptibility to ischemia reperfusion injury compared with wild-type mice. Reconstituting hepcidin deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemia-reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI. PMID- 25788529 TI - Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA Associated Vasculitis. AB - ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease. PMID- 25788530 TI - Recipient Myd88 Deficiency Promotes Spontaneous Resolution of Kidney Allograft Rejection. AB - The myeloid differentiation protein 88 (MyD88) adapter protein is an important mediator of kidney allograft rejection, yet the precise role of MyD88 signaling in directing the host immune response toward the development of kidney allograft rejection remains unclear. Using a stringent mouse model of allogeneic kidney transplantation, we demonstrated that acute allograft rejection occurred equally in MyD88-sufficient (wild-type [WT]) and MyD88(-/-) recipients. However, MyD88 deficiency resulted in spontaneous diminution of graft infiltrating effector cells, including CD11b(-)Gr-1(+) cells and activated CD8 T cells, as well as subsequent restoration of near-normal renal graft function, leading to long-term kidney allograft acceptance. Compared with T cells from WT recipients, T cells from MyD88(-/-) recipients failed to mount a robust recall response upon donor antigen restimulation in mixed lymphocyte cultures ex vivo. Notably, exogenous IL 6 restored the proliferation rate of T cells, particularly CD8 T cells, from MyD88(-/-) recipients to the proliferation rate of cells from WT recipients. Furthermore, MyD88(-/-) T cells exhibited diminished expression of chemokine receptors, specifically CCR4 and CXCR3, and the impaired ability to accumulate in the kidney allografts despite an otherwise MyD88-sufficient environment. These results provide a mechanism linking the lack of intrinsic MyD88 signaling in T cells to the effective control of the rejection response that results in spontaneous resolution of acute rejection and long-term graft protection. PMID- 25788531 TI - Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia. AB - Renal ischemia and reperfusion injury causes loss of renal epithelial cell polarity and perturbations in tubular solute and fluid transport. Na(+),K(+) ATPase, which is normally found at the basolateral plasma membrane of renal epithelial cells, is internalized and accumulates in intracellular compartments after renal ischemic injury. We previously reported that the subcellular distribution of Na(+),K(+)-ATPase is modulated by direct binding to Akt substrate of 160 kD (AS160), a Rab GTPase-activating protein that regulates the trafficking of glucose transporter 4 in response to insulin and muscle contraction. Here, we investigated the effect of AS160 on Na(+),K(+)-ATPase trafficking in response to energy depletion. We found that AS160 is required for the intracellular accumulation of Na(+),K(+)-ATPase that occurs in response to energy depletion in cultured epithelial cells. Energy depletion led to dephosphorylation of AS160 at S588, which was required for the energy depletion-induced accumulation of Na,K ATPase in intracellular compartments. In AS160-knockout mice, the effects of renal ischemia on the distribution of Na(+),K(+)-ATPase were substantially reduced in the epithelial cells of distal segments of the renal tubules. These data demonstrate that AS160 has a direct role in linking the trafficking of Na(+),K(+)-ATPase to the energy state of renal epithelial cells. PMID- 25788514 TI - The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. AB - The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps. PMID- 25788532 TI - EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy. AB - Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF-beta1 and NF-kappaB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF-beta1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body. PMID- 25788533 TI - A Role for Tubular Necroptosis in Cisplatin-Induced AKI. AB - Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway-receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)-by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice. Similar results were obtained in cultured proximal tubular cells. Furthermore, necroptosis of cultured cells could be induced by cisplatin or by a combination of cytokines (TNF-alpha, TNF-related weak inducer of apoptosis, and IFN-gamma) that were upregulated in proximal tubules of cisplatin-treated mice. However, cisplatin induced an increase in RIP1 and RIP3 expression in cultured tubular cells in the absence of cytokine release. Correspondingly, overexpression of RIP1 or RIP3 enhanced cisplatin-induced necroptosis in vitro. Notably, inflammatory cytokine upregulation in cisplatin-treated mice was partially diminished in RIP3- or MLKL-deficient mice, suggesting a positive feedback loop involving these genes and inflammatory cytokines that promotes necroptosis progression. Thus, our data demonstrate that necroptosis is a major mechanism of proximal tubular cell death in cisplatin-induced nephrotoxic AKI. PMID- 25788534 TI - A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion. AB - Grainyhead transcription factors control epithelial barriers, tissue morphogenesis, and differentiation, but their role in the kidney is poorly understood. Here, we report that nephric duct, ureteric bud, and collecting duct epithelia express high levels of grainyhead-like homolog 2 (Grhl2) and that nephric duct lumen expansion is defective in Grhl2-deficient mice. In collecting duct epithelial cells, Grhl2 inactivation impaired epithelial barrier formation and inhibited lumen expansion. Molecular analyses showed that GRHL2 acts as a transcriptional activator and strongly associates with histone H3 lysine 4 trimethylation. Integrating genome-wide GRHL2 binding as well as H3 lysine 4 trimethylation chromatin immunoprecipitation sequencing and gene expression data allowed us to derive a high-confidence GRHL2 target set. GRHL2 transactivated a group of genes including Ovol2, encoding the ovo-like 2 zinc finger transcription factor, as well as E-cadherin, claudin 4 (Cldn4), and the small GTPase Rab25. Ovol2 induction alone was sufficient to bypass the requirement of Grhl2 for E cadherin, Cldn4, and Rab25 expression. Re-expression of either Ovol2 or a combination of Cldn4 and Rab25 was sufficient to rescue lumen expansion and barrier formation in Grhl2-deficient collecting duct cells. Hence, we identified a Grhl2/Ovol2 network controlling Cldn4 and Rab25 expression that facilitates lumen expansion and barrier formation in subtypes of renal epithelia. PMID- 25788535 TI - Visualization of Calcium Dynamics in Kidney Proximal Tubules. AB - Intrarenal changes in cytoplasmic calcium levels have a key role in determining pathologic and pharmacologic responses in major kidney diseases. However, cell specific delivery of calcium-sensitive probes in vivo remains problematic. We generated a transgenic rat stably expressing the green fluorescent protein calmodulin-based genetically encoded calcium indicator (GCaMP2) predominantly in the kidney proximal tubules. The transposon-based method used allowed the generation of homozygous transgenic rats containing one copy of the transgene per allele with a defined insertion pattern, without genetic or phenotypic alterations. We applied in vitro confocal and in vivo two-photon microscopy to examine basal calcium levels and ligand- and drug-induced alterations in these levels in proximal tubular epithelial cells. Notably, renal ischemia induced a transient increase in cellular calcium, and reperfusion resulted in a secondary calcium load, which was significantly decreased by systemic administration of specific blockers of the angiotensin receptor and the Na-Ca exchanger. The parallel examination of in vivo cellular calcium dynamics and renal circulation by fluorescent probes opens new possibilities for physiologic and pharmacologic investigations. PMID- 25788537 TI - Measuring and modelling the reflectance spectra of male Swinhoe's pheasant feather barbules. AB - A range of iridescent colour appearances are presented by male Swinhoe's pheasants' (Lophura swinhoii) mantle feathers. Two distinct regions of the open pennaceous portion of its feathers display particularly conspicuous angle dependent reflection. A bright blue band appears in one region at normal incidence that spatially shifts to another at higher illumination angles. The two dimensional photonic crystal-like nanostructures inside the barbules of these two regions are similar. However, this study found that the spatial variation in their colour appearance results from a continuously changing orientation of barbules with respect to the alignment of their associated barb. A multi-layered rigorous coupled-wave analysis approach was used to model the reflections from the identified intra-barbule structures. Well-matched simulated and measured reflectance spectra, at both normal and oblique incidence, support our elucidation of the origin of the bird's distinctive feather colour appearance. PMID- 25788536 TI - Placental Growth Factor as a Predictor of Cardiovascular Events in Patients with CKD from the NARA-CKD Study. AB - Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA CKD) study between April 1, 2004, and December 31, 2011. During a median follow up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile (>=19.6 pg/ml) and the lowest eGFR tertile (<30 ml/min per 1.73 m(2)). The association between PlGF and mortality or cardiovascular events was not attenuated when participants were stratified by age, sex, traditional risk factors, and eGFR. These data suggest elevated PlGF is an independent risk factor for all-cause mortality and cardiovascular events in patients with CKD. PMID- 25788538 TI - Knowing one's place: a free-energy approach to pattern regulation. AB - Understanding how organisms establish their form during embryogenesis and regeneration represents a major knowledge gap in biological pattern formation. It has been recently suggested that morphogenesis could be understood in terms of cellular information processing and the ability of cell groups to model shape. Here, we offer a proof of principle that self-assembly is an emergent property of cells that share a common (genetic and epigenetic) model of organismal form. This behaviour is formulated in terms of variational free-energy minimization-of the sort that has been used to explain action and perception in neuroscience. In brief, casting the minimization of thermodynamic free energy in terms of variational free energy allows one to interpret (the dynamics of) a system as inferring the causes of its inputs-and acting to resolve uncertainty about those causes. This novel perspective on the coordination of migration and differentiation of cells suggests an interpretation of genetic codes as parametrizing a generative model-predicting the signals sensed by cells in the target morphology-and epigenetic processes as the subsequent inversion of that model. This theoretical formulation may complement bottom-up strategies-that currently focus on molecular pathways-with (constructivist) top-down approaches that have proved themselves in neuroscience and cybernetics. PMID- 25788539 TI - Power reduction and the radial limit of stall delay in revolving wings of different aspect ratio. AB - Airplanes and helicopters use high aspect ratio wings to reduce the power required to fly, but must operate at low angle of attack to prevent flow separation and stall. Animals capable of slow sustained flight, such as hummingbirds, have low aspect ratio wings and flap their wings at high angle of attack without stalling. Instead, they generate an attached vortex along the leading edge of the wing that elevates lift. Previous studies have demonstrated that this vortex and high lift can be reproduced by revolving the animal wing at the same angle of attack. How do flapping and revolving animal wings delay stall and reduce power? It has been hypothesized that stall delay derives from having a short radial distance between the shoulder joint and wing tip, measured in chord lengths. This non-dimensional measure of wing length represents the relative magnitude of inertial forces versus rotational accelerations operating in the boundary layer of revolving and flapping wings. Here we show for a suite of aspect ratios, which represent both animal and aircraft wings, that the attachment of the leading edge vortex on a revolving wing is determined by wing aspect ratio, defined with respect to the centre of revolution. At high angle of attack, the vortex remains attached when the local radius is shorter than four chord lengths and separates outboard on higher aspect ratio wings. This radial stall limit explains why revolving high aspect ratio wings (of helicopters) require less power compared with low aspect ratio wings (of hummingbirds) at low angle of attack and vice versa at high angle of attack. PMID- 25788540 TI - Fine resolution mapping of population age-structures for health and development applications. AB - The age-group composition of populations varies considerably across the world, and obtaining accurate, spatially detailed estimates of numbers of children under 5 years is important in designing vaccination strategies, educational planning or maternal healthcare delivery. Traditionally, such estimates are derived from population censuses, but these can often be unreliable, outdated and of coarse resolution for resource-poor settings. Focusing on Nigeria, we use nationally representative household surveys and their cluster locations to predict the proportion of the under-five population in 1 * 1 km using a Bayesian hierarchical spatio-temporal model. Results showed that land cover, travel time to major settlements, night-time lights and vegetation index were good predictors and that accounting for fine-scale variation, rather than assuming a uniform proportion of under 5 year olds can result in significant differences in health metrics. The largest gaps in estimated bednet and vaccination coverage were in Kano, Katsina and Jigawa. Geolocated household surveys are a valuable resource for providing detailed, contemporary and regularly updated population age-structure data in the absence of recent census data. By combining these with covariate layers, age structure maps of unprecedented detail can be produced to guide the targeting of interventions in resource-poor settings. PMID- 25788541 TI - Constitutive modelling of arteries considering fibre recruitment and three dimensional fibre distribution. AB - Structurally motivated material models may provide increased insights into the underlying mechanics and physics of arteries under physiological loading conditions. We propose a multiscale model for arterial tissue capturing three different scales (i) a single collagen fibre; (ii) bundle of collagen fibres; and (iii) collagen network within the tissue. The waviness of collagen fibres is introduced by a probability density function for the recruitment stretch at which the fibre starts to bear load. The three-dimensional distribution of the collagen fibres is described by an orientation distribution function using the bivariate von Mises distribution, and fitted to experimental data. The strain energy for the tissue is decomposed additively into a part related to the matrix material and a part for the collagen fibres. Volume fractions account for the matrix/fibre constituents. The proposed model only uses two parameters namely a shear modulus of the matrix material and a (stiffness) parameter related to a single collagen fibre. A fit of the multiscale model to representative experimental data obtained from the individual layers of a human thoracic aorta shows that the proposed model is able to adequately capture the nonlinear and anisotropic behaviour of the aortic layers. PMID- 25788543 TI - Refinement of whole-genome multilocus sequence typing analysis by addressing gene paralogy. AB - We developed a user-friendly program, Genome Profiler (GeP), to refine whole genome multilocus sequence typing analysis by addressing gene paralogy with conserved gene neighborhoods. In comparison to similar programs, GeP produced overall the best results in terms of accuracy and is thus a useful alternative to resolve relationships of bacterial isolates. PMID- 25788542 TI - Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation. PMID- 25788544 TI - Has CXCL13 an added value in diagnosis of neurosyphilis? AB - In patients with syphilis, central nervous system (CNS) involvement is often difficult to determine. In patients who also are infected with human immunodeficiency virus (HIV), this is even more challenging, as cerebrospinal fluid (CSF) pleocytosis can be attributed to HIV, syphilis, or both. Hence, this study investigated (i) CSF chemokine (C-X-C motif) ligand 13 (CXCL13) as a potential marker to diagnose neurosyphilis in HIV-infected individuals and (ii) the added value of CSF CXCL13 to conventional CSF biomarkers, such as the rapid plasma reagin test (RPR), in diagnosing neurosyphilis. We included 103 syphilis patients from two centers in The Netherlands: 47 non-HIV-infected patients and 56 HIV-infected patients. A positive CSF-RPR was regarded as the gold standard for neurosyphilis. CSF CXCL13 levels were significantly higher in neurosyphilis patients when neurosyphilis was diagnosed by CSF-RPR (P = 0.0002) than in the syphilis control group. The sensitivity and specificity of CSF CXCL13 (cutoff of 76.3 pg/ml) to diagnose neurosyphilis by using positive CSF-RPR as the gold standard were 50% and 90%, respectively. CSF CXCL13 had an added value to CSF-RPR positivity in 70% of HIV-positive patients and in 33% of HIV-negative patients. Our data show that CSF CXCL13 might be a potential additional marker in neurosyphilis when other markers are not conclusive. The added value of CSF CXCL13 measurement to the current neurosyphilis gold standard appears to benefit HIV-positive patients more than HIV-negative patients. PMID- 25788545 TI - Borrelia burgdorferi not confirmed in human-biting Amblyomma americanum ticks from the southeastern United States. AB - The predominant human-biting tick throughout the southeastern United States is Amblyomma americanum. Its ability to transmit pathogens causing Lyme disease-like illnesses is a subject of ongoing controversy. Results of previous testing by the Department of Defense Human Tick Test Kit Program and other laboratories indicated that it is highly unlikely that A. americanum transmits any pathogen that causes Lyme disease. In contrast, a recent publication by Clark and colleagues (K. L. Clark, B. Leydet, and S. Hartman, Int. J. Med. Sci. 10:915-931, 2013) reported detection of Lyme group Borrelia in A. americanum using a nested flagellin-gene PCR. We evaluated this assay by using it and other assays to test 1,097 A. americanum ticks collected from humans. Using the Clark assay, in most samples we observed nonspecific amplification and nonrepeatability of results on subsequent testing of samples. Lack of reaction specificity and repeatability is consistent with mispriming, likely due to high primer concentrations and low annealing temperatures in this protocol. In six suspect-positive samples, Borrelia lonestari was identified by sequencing of an independent gene region; this is not a Lyme group spirochete and is not considered zoonotic. B. burgdorferi was weakly amplified from one pool using some assays, but not others, and attempts to sequence the amplicon of this pool failed, as did attempts to amplify and sequence B. burgdorferi from the five individual samples comprising this pool. Therefore, B. burgdorferi was not confirmed in any sample. Our results do not support the hypothesis that A. americanum ticks are a vector for Lyme group Borrelia infections. PMID- 25788546 TI - Pan-Serotype Diagnostic for Foot-and-Mouth Disease Using the Consensus Antigen of Nonstructural Protein 3B. AB - An amino acid consensus sequence for the seven serotypes of foot-and-mouth disease virus (FMDV) nonstructural protein 3B, including all three contiguous repeats, and its use in the development of a pan-serotype diagnostic test for all seven FMDV serotypes are described. The amino acid consensus sequence of the 3B protein was determined from a multiple-sequence alignment of 125 sequences of 3B. The consensus 3B (c3B) protein was expressed as a soluble recombinant fusion protein with maltose-binding protein (MBP) using a bacterial expression system and was affinity purified using amylose resin. The MBP-c3B protein was used as the antigen in the development of a competition enzyme-linked immunosorbent assay (cELISA) for detection of anti-3B antibodies in bovine sera. The comparative diagnostic sensitivity and specificity at 47% inhibition were estimated to be 87.22% and 93.15%, respectively. Reactivity of c3B with bovine sera representing the seven FMDV serotypes demonstrated the pan-serotype diagnostic capability of this bioreagent. The consensus antigen and competition ELISA are described here as candidates for a pan-serotype diagnostic test for FMDV infection. PMID- 25788547 TI - Use of amplification refractory mutation system PCR assay as a simple and effective tool to detect HIV-1 drug resistance mutations. AB - Access to genotyping assays to determine successful antiretroviral treatment (ART) is limited in resource-constrained settings by high cost, suggesting the need for a cost-effective and simplified method to identify HIV-1 drug resistance (HIVDR) mutations. In this study, an amplification refractory mutation system (ARMS)-PCR assay was developed and used to investigate the most frequent HIVDR mutations affecting first-line ART in settings where WHO ART guidelines are applied. Seventy-five HIV-positive (HIV(+)) samples from Cameroon were used to assess the performance of this assay. Sequencing of HIV-1 reverse transcriptase was simultaneously performed for comparison, and discordant samples were tested with a Trugene HIV-1 genotyping kit. The ARMS-PCR assay was able to detect M184V, T215Y/F, K103N, and Y181C mutations with sensitivities of 96.8%, 85.7%, 91.3%, and 70%, respectively, and specificities of 90.6%, 95%, 100%, 96.9%, respectively, compared with data on sequencing. The results indicated the highest positive predictive value for K103N (100%) and the highest negative predictive value for M184V (97.5%). ARMS-PCR's limits of detection for mutations M184V, T215Y/F, K103N, and Y181C were <75 copies/ml, 143 copies/ml, 143 copies/ml, and 836 copies/ml, respectively. ARMS-PCR efficiently identified mutations in individuals harboring different HIV-1 clades (CRF02_AG and non-CRF02_AG). In addition, this approach was more cost-effective than other genotyping assays. The high throughput, the cost-effectiveness, and the simplicity of the ARMS-PCR assay make it a suitable tool to monitor HIVDR patterns in resource-constrained settings with broad HIV-1 genetic diversity. PMID- 25788548 TI - Universal Primers for Detection and Sequencing of Hepatitis B Virus Genomes across Genotypes A to G. AB - Hepatitis B virus (HBV) has been divided into 10 genotypes, A to J, based on an 8% nucleotide sequence divergence between genotypes. The conventional practice of using a single set of primers to amplify a near-complete HBV genome is hampered by its low analytical sensitivity. The current practice of using overlapping conserved primer sets to amplify a complete HBV genome in a clinical sample is limited by the lack of pan-primers to detect all HBV genotypes. In this study, we designed six highly conserved, overlapping primer sets to cover the complete HBV genome. We based our design on the sequences of 5,154 HBV genomes of genotypes A to I downloaded from the GenBank nucleotide database. These primer sets were tested on 126 plasma samples from Malaysia, containing genotypes A to D and with viral loads ranging from 20 to >79,780,000 IU/ml. The overall success rates for PCR amplification and sequencing were >96% and >94%, respectively. Similarly, there was 100% amplification and sequencing success when the primer sets were tested on an HBV reference panel of genotypes A to G. Thus, we have established primer sets that gave a high analytical sensitivity for PCR-based detection of HBV and a high rate of sequencing success for HBV genomes in most of the viral genotypes, if not all, without prior known sequence data for the particular genotype/genome. PMID- 25788549 TI - Comparison of the Vidas C. difficile GDH Automated Enzyme-Linked Fluorescence Immunoassay (ELFA) with Another Commercial Enzyme Immunoassay (EIA) (Quik Chek 60), Two Selective Media, and a PCR Assay for gluD for Detection of Clostridium difficile in Fecal Samples. AB - Prevention and management of Clostridium difficile infection (CDI) can be improved by rapid and reliable diagnostics. The Vidas C. difficile glutamate dehydrogenase assay had performance comparable to that of the Quik Chek-60 assay (overall agreement, 95%) and a sensitivity of >93%; thus, it is suitable as the first test in two-stage algorithms for a CDI diagnosis. PMID- 25788550 TI - Simultaneous Identification of Multiple beta-Lactamases in Acinetobacter baumannii in Relation to Carbapenem and Ceftazidime Resistance, Using Liquid Chromatography-Tandem Mass Spectrometry. AB - Shotgun proteomics using liquid chromatography-tandem mass spectrometry (LC MS/MS) was applied to detect beta-lactamases in clinical Acinetobacter baumannii isolates. The correlation of the detection of beta-lactamase proteins (rather than PCR detection of the corresponding genes) with the resistance phenotypes demonstrated an added value for LC-MS/MS in antimicrobial susceptibility testing. PMID- 25788551 TI - Comparison of the AmpliVue, BD Max System, and illumigene Molecular Assays for Detection of Group B Streptococcus in Antenatal Screening Specimens. AB - The performances of the AmpliVue, BD Max, and illumigene group B Streptococcus (GBS) nucleic acid amplification tests (NAATs) were compared to that of enriched culture for detection of GBS in antenatal screening specimens. Two hundred specimens were tested simultaneously with the NAATs, following 18 to 24 h of Lim broth enrichment; 15% of specimens were culture positive for GBS, whereas 31.5% were positive by at least one NAAT. All three NAATs were more sensitive (sensitivity, 90.9 to 100%) than culture (sensitivity, 53.6%). PMID- 25788552 TI - Treponemes detected in digital dermatitis lesions in Brazilian dairy cattle and possible host reservoirs of infection. AB - The main pathogenic treponemes causing bovine digital dermatitis were identified from 17 infected herds in southern Brazil for the first time in this study using PCR. We did not find a relationship between treponeme phylogroup composition and clinical classification. Treponema phagedenis was present in all lesions. Rumen fluid was implicated as a reservoir location for these pathogens. PMID- 25788553 TI - The diatom-derived aldehyde decadienal affects life cycle transition in the ascidian Ciona intestinalis through nitric oxide/ERK signalling. AB - Polyunsaturated aldehydes (PUAs) are fatty-acid-derived metabolites produced by some microalgae, including different diatom species. PUAs are mainly produced as a wound-activated defence mechanism against microalgal predators or released from senescent cells at the end of a bloom. PUAs, including 2,4-trans-decadienal (DD), induce deleterious effects on embryonic and larval development of several planktonic and benthic organisms. Here, we report on the effects of DD on larval development and metamorphosis of the ascidian Ciona intestinalis. Ciona larval development is regulated by the cross-talking of different molecular events, including nitric oxide (NO) production, ERK activation and caspase 3-dependent apoptosis. We report that treatment with DD at the competence larval stage results in a delay in metamorphosis. DD affects redox balance by reducing total glutathione and NO levels. By biochemical and quantitative gene expression analysis, we identify the NO-signalling network affected by DD, including the upregulation of ERK phosphatase mkp1 and consequent reduction of ERK phosphorylation, with final changes in the expression of downstream ERK target genes. Overall, these results give new insights into the molecular pathways induced in marine organisms after exposure to PUAs during larval development, demonstrating that this aldehyde affects key checkpoints of larval transition from the vegetative to the reproductive life stage. PMID- 25788554 TI - Recurrence of reversible cerebral vasoconstriction syndrome: a long-term follow up study. AB - OBJECTIVE: We aimed to investigate whether reversible cerebral vasoconstriction syndrome (RCVS) could recur and to identify the potential predictors of recurrence in a large cohort of patients. METHODS: This study followed a cohort of 210 patients with RCVS in a hospital-based headache center from 2000 to 2012. All patients were regularly followed up by telephone after remission for RCVS and were particularly asked to return to our hospital immediately if they developed new acute, severe (i.e., thunderclap-like) headaches. Sequential neuroimaging studies were used to determine whether the patients had recurrent RCVS. RESULTS: One hundred sixty-eight patients were successfully followed. The response rate was 80.8%, and the mean follow-up period was 37.5 +/- 24.4 (range 6-131) months. Eighteen patients (10.7%) returned to our hospital because of new thunderclap like headaches, and 9 (5.4% of the total 168, and 50% of 18) were confirmed to have recurrent RCVS that occurred a mean 40.9 +/- 27.2 (median 35, range 6-87) months after the initial bout. The incidence rate was 1.71 per 100 person-years (95% confidence interval 1.68-1.75). Having sexual activities as a trigger for thunderclap headaches (hazard ratio = 5.68, 95% confidence interval 1.11-29.15, p = 0.038) was an independent predictor of recurrent RCVS. None of the patients with recurrent RCVS developed cerebrovascular complications. CONCLUSIONS: Recurrent RCVS should be considered when patients with RCVS develop new thunderclap-like headaches. Having sexual activities as a trigger for RCVS is a potential predictor of recurrent RCVS. PMID- 25788555 TI - Predicting the risk of mild cognitive impairment in the Mayo Clinic Study of Aging. AB - OBJECTIVE: We sought to develop risk scores for the progression from cognitively normal (CN) to mild cognitive impairment (MCI). METHODS: We recruited into a longitudinal cohort study a randomly selected, population-based sample of Olmsted County, MN, residents, aged 70 to 89 years on October 1, 2004. At baseline and subsequent visits, participants were evaluated for demographic, clinical, and neuropsychological measures, and were classified as CN, MCI, or dementia. Using baseline demographic and clinical variables in proportional hazards models, we derived scores that predicted the risk of progressing from CN to MCI. We evaluated the ability of these risk scores to classify participants for MCI risk. RESULTS: Of 1,449 CN participants, 401 (27.7%) developed MCI. A basic model had a C statistic of 0.60 (0.58 for women, 0.62 for men); an augmented model resulted in a C statistic of 0.70 (0.69 for women, 0.71 for men). Both men and women in the highest vs lowest sex-specific quartiles of the augmented model's risk scores had an approximately 7-fold higher risk of developing MCI. Adding APOE epsilon4 carrier status improved the model (p = 0.002). CONCLUSIONS: We have developed MCI risk scores using variables easily assessable in the clinical setting and that may be useful in routine patient care. Because of variability among populations, validation in independent samples is required. These models may be useful in identifying patients who might benefit from more expensive or invasive diagnostic testing, and can inform clinical trial design. Inclusion of biomarkers or other risk factors may further enhance the models. PMID- 25788556 TI - Risk of mild cognitive impairment: The Olmsted County MCI Risk Score. PMID- 25788558 TI - Comment: reversible cerebral vasoconstriction syndrome can hit twice. PMID- 25788557 TI - Functional brain network modularity predicts response to cognitive training after brain injury. AB - OBJECTIVE: We tested the value of measuring modularity, a graph theory metric indexing the relative extent of integration and segregation of distributed functional brain networks, for predicting individual differences in response to cognitive training in patients with brain injury. METHODS: Patients with acquired brain injury (n = 11) participated in 5 weeks of cognitive training and a comparison condition (brief education) in a crossover intervention study design. We quantified the measure of functional brain network organization, modularity, from functional connectivity networks during a state of tonic attention regulation measured during fMRI scanning before the intervention conditions. We examined the relationship of baseline modularity with pre- to posttraining changes in neuropsychological measures of attention and executive control. RESULTS: The modularity of brain network organization at baseline predicted improvement in attention and executive function after cognitive training, but not after the comparison intervention. Individuals with higher baseline modularity exhibited greater improvements with cognitive training, suggesting that a more modular baseline network state may contribute to greater adaptation in response to cognitive training. CONCLUSIONS: Brain network properties such as modularity provide valuable information for understanding mechanisms that influence rehabilitation of cognitive function after brain injury, and may contribute to the discovery of clinically relevant biomarkers that could guide rehabilitation efforts. PMID- 25788559 TI - Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study. AB - OBJECTIVE: To determine whether a structured and quantitative assessment of differential olfactory performance-recognized between a blast-injured traumatic brain injury (TBI) group and a demographically comparable blast-injured control group-can serve as a reliable antecedent marker for preclinical detection of intracranial neurotrauma. METHODS: We prospectively and consecutively enrolled 231 polytrauma inpatients, acutely injured from explosions during combat operations in either Afghanistan or Iraq and requiring immediate stateside evacuation and sequential admission to our tertiary care medical center over a 21/2-year period. This study correlates olfactometric scores with both contemporaneous neuroimaging findings as well as the clinical diagnosis of TBI, tabulates population-specific incidence data, and investigates return of olfactory function. RESULTS: Olfactometric score predicted abnormal neuroimaging significantly better than chance alone (area under the curve = 0.78, 95% confidence interval [CI] 0.70-0.87). Normosmia was present in all troops with mild TBI (i.e., concussion) and all control subjects. Troops with radiographic evidence of frontal lobe injuries were 3 times more likely to have olfactory impairment than troops with injuries to other brain regions (relative risk 3.0, 95% CI 0.98-9.14). Normalization of scores occurred in all anosmic troops available for follow-up testing. CONCLUSION: Quantitative identification olfactometry has limited sensitivity but high specificity as a marker for detecting acute structural neuropathology from trauma. When considering whether to order advanced neuroimaging, a functional disturbance with central olfactory impairment should be regarded as an important tool to inform the decision process. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that central olfactory dysfunction identifies patients with TBI who have intracranial radiographic abnormalities with a sensitivity of 35% (95% CI 20.6%-51.7%) and specificity of 100% (95% CI 97.7%-100.0%). PMID- 25788560 TI - Discrepancy between stimulus response and tolerance of pain in Alzheimer disease. AB - BACKGROUND: Affective-motivational and sensory-discriminative aspects of pain were investigated in patients with mild to moderate Alzheimer disease (AD) and healthy elderly controls using the cold pressor test tolerance and repetitive stimuli of warmth and heat stimuli, evaluating the stimulus-response function. METHODS: A case-control design was applied examining 33 patients with mild to moderate AD dementia and 32 healthy controls with the cold pressor test (4 degrees C). Warmth detection threshold (WDT) and heat pain threshold (HPT) were assessed using 5 stimulations. A stimulus-response function was estimated using 4 incrementally increasing suprathreshold heat stimuli. RESULTS: Cold pressor tolerance was lower in patients with AD dementia than in controls (p = 0.027). There were no significant differences between groups regarding WDT and HPT. Significant successive increases in HPT assessments indicated habituation (p < 0.0001), which was similar in the 2 groups (p = 0.85). A mixed model for repeated measures demonstrated that pain rating of suprathreshold stimuli depended on HPT (p = 0.0004) and stimulus intensity (p < 0.0001). Patients with AD dementia had significantly lower increases in pain ratings than controls during suprathreshold stimulation (p = 0.0072). CONCLUSION: Our results indicate that AD dementia is not associated with a propensity toward development of sensitization or a lack of habituation, suggesting preservation of sensory-discriminative aspects of pain perception. The results further suggest that the attenuated cold pressor pain tolerance may relate to impairment of coping abilities. Paradoxically, we found an attenuated stimulus-response function, compared to controls, suggesting that AD dementia interferes with pain ratings over time, most likely due to memory impairment. PMID- 25788561 TI - Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation. AB - OBJECTIVES: We present a family with a mitochondrial DNA 3243A>G mutation resulting in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes (MELAS), of which some members have hearing loss in which a novel mutation in the P2RX2 gene was identified. METHODS: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic causes of hearing loss. RESULTS: A novel mutation in the P2RX2 gene that corresponded to c.601G>A (p.Asp201Tyr) was identified. Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing. CONCLUSION: This is the first case report of a diagnosis of hearing loss caused by P2RX2 mutation in patients with MELAS. A potential explanation is that a decrease in adenosine triphosphate (ATP) production due to MELAS with a mitochondrial 3243A>G mutation might suppress activation of P2X2 receptors. We also suggest that hearing loss caused by the P2RX2 mutation might be influenced by the decrease in ATP production due to MELAS. PMID- 25788562 TI - Novel mutations in LRTOMT associated with moderate progressive hearing loss in autosomal recessive inheritance. AB - OBJECTIVE: We present a patient who was identified with novel mutations in the LRTOMT gene and describe the clinical features of the phenotype including serial audiological findings. METHODS: One hundred six Japanese patients with mild to moderate sensorineural hearing loss from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic cause of hearing loss. RESULTS: Compound heterozygotes with a novel frame-shift mutation and a missense mutation were identified in the LRTOMT gene. The mutated residues were segregated in both alleles of LRTOMT, present within the LRTOMT2 protein coding region. The patient had moderate sloping hearing loss at high frequencies, which progressed at 1000 Hz and higher frequencies over a period of 6 years. CONCLUSION: Hearing loss caused by mutations in the LRTOMT gene is extremely rare. This is the first case report of a compound heterozygous mutation in a nonconsanguineous family. PMID- 25788563 TI - Deafness gene variations in a 1120 nonsyndromic hearing loss cohort: molecular epidemiology and deafness mutation spectrum of patients in Japan. AB - OBJECTIVES: To elucidate the molecular epidemiology of hearing loss in a large number of Japanese patients analyzed using massively parallel DNA sequencing (MPS) of target genes. METHODS: We performed MPS of target genes using the Ion PGM system with the Ion AmpliSeq and HiSeq 2000 systems using SureSelect in 1389 samples (1120 nonsyndromic hearing loss cases and 269 normal hearing controls). We filtered the variants identified using allele frequencies in a large number of controls and 12 predication program scores. RESULTS: We identified 8376 kinds of variants in the 1389 samples, and 409 835 total variants were detected. After filtering the variants, we selected 2631 kinds of candidate variants. The number of GJB2 mutations was exceptionally high among these variants, followed by those in CDH23, SLC26A4, MYO15A, COL11A2, MYO7A, and OTOF. CONCLUSIONS: We performed a large number of MPS analyses and clarified the genetic background of Japanese patients with hearing loss. This data set will be a powerful tool to discover rare causative gene mutations in highly heterogeneous monogenic diseases and reveal the genetic epidemiology of deafness. PMID- 25788564 TI - Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss. AB - OBJECTIVES: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. METHODS: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. RESULTS: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. CONCLUSION: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction. PMID- 25788566 TI - Functional evaluation of genetic variants associated with endometriosis near GREB1. AB - STUDY QUESTION: Do DNA variants in the growth regulation by estrogen in breast cancer 1 (GREB1) region regulate endometrial GREB1 expression and increase the risk of developing endometriosis in women? SUMMARY ANSWER: We identified new single nucleotide polymorphisms (SNPs) with strong association with endometriosis at the GREB1 locus although we did not detect altered GREB1 expression in endometriosis patients with defined genotypes. WHAT IS ALREADY KNOWN: Genome-wide association studies have identified the GREB1 region on chromosome 2p25.1 for increasing endometriosis risk. The differential expression of GREB1 has also been reported by others in association with endometriosis disease phenotype. STUDY DESIGN, SIZE, DURATION: Fine mapping studies comprehensively evaluated SNPs within the GREB1 region in a large-scale data set (>2500 cases and >4000 controls). Publicly available bioinformatics tools were employed to functionally annotate SNPs showing the strongest association signal with endometriosis risk. Endometrial GREB1 mRNA and protein expression was studied with respect to phases of the menstrual cycle (n = 2-45 per cycle stage) and expression quantitative trait loci (eQTL) analysis for significant SNPs were undertaken for GREB1 [mRNA (n = 94) and protein (n = 44) in endometrium]. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants in this study are females who provided blood and/or endometrial tissue samples in a hospital setting. The key SNPs were genotyped using Sequenom MassARRAY. The functional roles and regulatory annotations for identified SNPs are predicted by various publicly available bioinformatics tools. Endometrial GREB1 expression work employed qRT-PCR, western blotting and immunohistochemistry studies. MAIN RESULTS AND THE ROLE OF CHANCE: Fine mapping results identified a number of SNPs showing stronger association (0.004 < P < 0.032) with endometriosis risk than the original GWAS SNP (rs13394619) (P = 0.034). Some of these SNPs were predicted to have functional roles, for example, interaction with transcription factor motifs. The haplotype (a combination of alleles) formed by the risk alleles from two common SNPs showed significant association (P = 0.026) with endometriosis and epistasis analysis showed no evidence for interaction between the two SNPs, suggesting an additive effect of SNPs on endometriosis risk. In normal human endometrium, GREB1 protein expression was altered depending on the cycle stage (significantly different in late proliferative versus late secretory, P < 0.05) and cell type (glandular epithelium, not stromal cells). However, GREB1 expression in endometriosis cases versus controls and eQTL analyses did not reveal any significant changes. LIMITATIONS, REASONS FOR CAUTION: In silico prediction tools are generally based on cell lines different to our tissue and disease of interest. Functional annotations drawn from these analyses should be considered with this limitation in mind. We identified cell-specific and hormone-specific changes in GREB1 protein expression. The lack of a significant difference observed following our GREB1 expression studies may be the result of moderate power on mixed cell populations in the endometrial tissue samples. WIDER IMPLICATIONS OF THE FINDINGS: This study further implicates the GREB1 region on chromosome 2p25.1 and the GREB1 gene with involvement in endometriosis risk. More detailed functional studies are required to determine the role of the novel GREB1 transcripts in endometriosis pathophysiology. STUDY FUNDING/COMPETING INTERESTS: Funding for this work was provided by NHMRC Project Grants APP1012245, APP1026033, APP1049472 and APP1046880. There are no competing interests. PMID- 25788565 TI - The comprehensiveness of the ESHRE/ESGE classification of female genital tract congenital anomalies: a systematic review of cases not classified by the AFS system. AB - STUDY QUESTION: How comprehensive is the recently published European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) classification system of female genital anomalies? SUMMARY ANSWER: The ESHRE/ESGE classification provides a comprehensive description and categorization of almost all of the currently known anomalies that could not be classified properly with the American Fertility Society (AFS) system. WHAT IS KNOWN ALREADY: Until now, the more accepted classification system, namely that of the AFS, is associated with serious limitations in effective categorization of female genital anomalies. Many cases published in the literature could not be properly classified using the AFS system, yet a clear and accurate classification is a prerequisite for treatment. STUDY DESIGN, SIZE AND DURATION: The CONUTA (CONgenital UTerine Anomalies) ESHRE/ESGE group conducted a systematic review of the literature to examine if those types of anomalies that could not be properly classified with the AFS system could be effectively classified with the use of the new ESHRE/ESGE system. An electronic literature search through Medline, Embase and Cochrane library was carried out from January 1988 to January 2014. Three participants independently screened, selected articles of potential interest and finally extracted data from all the included studies. Any disagreement was discussed and resolved after consultation with a fourth reviewer and the results were assessed independently and approved by all members of the CONUTA group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the 143 articles assessed in detail, 120 were finally selected reporting 140 cases that could not properly fit into a specific class of the AFS system. Those 140 cases were clustered in 39 different types of anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: The congenital anomaly involved a single organ in 12 (30.8%) out of the 39 types of anomalies, while multiple organs and/or segments of Mullerian ducts (complex anomaly) were involved in 27 (69.2%) types. Uterus was the organ most frequently involved (30/39: 76.9%), followed by cervix (26/39: 66.7%) and vagina (23/39: 59%). In all 39 types, the ESHRE/ESGE classification system provided a comprehensive description of each single or complex anomaly. A precise categorization was reached in 38 out of 39 types studied. Only one case of a bizarre uterine anomaly, with no clear embryological defect, could not be categorized and thus was placed in Class 6 (un-classified) of the ESHRE/ESGE system. LIMITATIONS, REASONS FOR CAUTION: The review of the literature was thorough but we cannot rule out the possibility that other defects exist which will also require testing in the new ESHRE/ESGE system. These anomalies, however, must be rare. WIDER IMPLICATIONS OF THE FINDINGS: The comprehensiveness of the ESHRE/ESGE classification adds objective scientific validity to its use. This may, therefore, promote its further dissemination and acceptance, which will have a positive outcome in clinical care and research. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 25788567 TI - Caffeine and caffeinated beverage consumption and risk of spontaneous abortion. AB - STUDY QUESTION: Is caffeine and caffeinated beverage consumption associated with the risk of spontaneous abortion (SAB)? SUMMARY ANSWER: While preconceptional caffeine consumption was not materially associated with an increased risk of SAB, consumption during early pregnancy was associated with a small increased risk of SAB, although the relation was not linear. WHAT IS KNOWN ALREADY: Caffeine has been hypothesized as a risk factor for SAB since the 1980s; however, results from previous studies have been conflicting. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 5132 Danish women planning pregnancy and enrolled from 2007 to 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women who conceived after entry into the Snart-Gravid cohort and who were aged 18-40, in a stable relationship with a male partner, and did not use fertility treatments to conceive. Women reported their daily caffeine and caffeinated beverage consumption on questionnaires before conception and during early pregnancy. All exposure measurements were prospective with respect to outcome ascertainment. We estimated hazard ratios (HRs) of SAB for categories of caffeine consumption in milligrams (mg) per day and the corresponding 95% confidence intervals (CIs) using Cox proportional hazards regression models with gestational weeks as the time scale. MAIN RESULTS AND THE ROLE OF CHANCE: There were 732 women (14.3%) who were identified as having a SAB. In the preconceptional period, caffeine consumption was not materially associated with SAB risk (HR comparing >=300 with <100 mg/day: 1.09; 95% CI: 0.89, 1.33). In early pregnancy, the HRs for 100-199, 200-299 and >=300 mg/day of caffeine consumption were 1.62 (95% CI: 1.19, 2.22), 1.48 (95% CI: 1.03, 2.13) and 1.23 (95% CI: 0.61, 2.46), respectively, compared with that for <100 mg/day. LIMITATIONS, REASONS FOR CAUTION: The observed results may be affected by non differential exposure misclassification, reverse causation and residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date of prospectively measured, preconception caffeine consumption and risk of SAB. We were able to reduce the likelihood of differential left truncation bias and recall bias present in other analyses. STUDY FUNDING/COMPETING INTERESTS: Snart-Gravid was funded by the NICHD (R21-050264). Dr. Hahn's work was funded in part by the BU Reproductive, Perinatal, and Pediatric Epidemiology Training Grant NIH #T32HD052458. There are no competing interests. PMID- 25788568 TI - Total motile sperm count: a better indicator for the severity of male factor infertility than the WHO sperm classification system. AB - STUDY QUESTION: Does the prewash total motile sperm count (TMSC) have a better predictive value for spontaneous ongoing pregnancy (SOP) than the World Health Organization (WHO) classification system? SUMMARY ANSWER: The prewash TMSC shows a better correlation with the spontaneous ongoing pregnancy rate (SOPR) than the WHO 2010 classification system. WHAT IS KNOWN ALREADY: According to the WHO classification system, an abnormal semen analysis can be diagnosed as oligozoospermia, astenozoospermia, teratozoospermia or combinations of these and azoospermia. This classification is based on the fifth percentile cut-off values of a cohort of 1953 men with proven fertility. Although this classification suggests accuracy, the relevance for the prognosis of an infertile couple and the choice of treatment is questionable. The TMSC is obtained by multiplying the sample volume by the density and the percentage of A and B motility spermatozoa. STUDY DESIGN, SIZE, DURATION: We analyzed data from a longitudinal cohort study among unselected infertile couples who were referred to three Dutch hospitals between January 2002 and December 2006. Of the total cohort of 2476 infertile couples, only the couples with either male infertility as a single diagnosis or unexplained infertility were included (n = 1177) with a follow-up period of 3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all couples a semen analysis was performed. Based on the best semen analysis if more tests were performed, couples were grouped according to the WHO classification system and the TMSC range, as described in the Dutch national guidelines for male infertility. The primary outcome measure was the SOPR, which occurred before, during or after treatments, including expectant management, intrauterine insemination, in vitro fertilization or intracytoplasmic sperm injection. After adjustment for the confounding factors (female and male age, duration and type of infertility and result of the postcoital test) the odd ratios (ORs) for risk of SOP for each WHO and TMSC group were calculated. The couples with unexplained infertility were used as reference. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 514 couples did and 663 couples did not achieve a SOP. All WHO groups have a lower SOPR compared with the unexplained group (ORs varying from 0.136 to 0.397). Comparing the couples within the abnormal WHO groups, there are no significant differences in SOPR, except when oligoasthenoteratozoospermia is compared with asthenozoospermia [OR 0.501 (95% CI 0.311-0.809)] and teratozoospermia [OR 0.499 (95% CI: 0.252-0.988)], and oligoasthenozoospermia is compared with asthenozoospermia [OR 0.572 (95% CI: 0.373-0.877)]. All TMSC groups have a significantly lower SOPR compared with the unexplained group (ORs varying from 0.171 to 0.461). Couples with a TMSC of <1 * 10(6) and 1-5 * 10(6) have significantly lower SOPR compared with couples with a TMSC of 5-10 * 10(6) [respectively, OR 0.371 (95% CI: 0.215-0.64) and OR 0.505 (95% CI: 0.307-0.832)]. LIMITATIONS, REASON FOR CAUTION: To include all SOPs during the follow-up period of 3 years, couples were not censured at the start of treatment. WIDER IMPLICATIONS OF THE FINDINGS: Roughly, three prognostic groups can be discerned: couples with a TMSC <5, couples with a TMSC between 5 and 20 and couples with a TMSC of more than 20 * 10(6) spermatozoa. We suggest using TMSC as the method of choice to express severity of male infertility. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 25788570 TI - Working alliances not loggerheads: understanding and addressing dissonance between families and treating teams in older people's mental health. AB - OBJECTIVES: To identify and describe common sources of dissonance which arise for treating teams in older person's mental health and the strategies for addressing them. METHODS: A literature review was conducted with the terms: 'family conflict and treatment team', 'family therapy and old age' and 'family caregiver'. RESULTS: We discuss the importance of an alliance with families regarding older people's mental health, and the contribution of engagement, attachment and family dynamics to dissonance. We offer strategies to prevent and address dissonance. CONCLUSIONS: To prevent and manage dissonance, its causes need to be identified and understood. Routinely 'thinking family' first, then 'knowing' and 'hearing' the family are crucial steps to enhancing communication with families. PMID- 25788569 TI - Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial. AB - STUDY QUESTION: Can controlled ovarian stimulation with low-dose human menopausal gonadotrophin (hMG) improve the clinical pregnancy rate when compared with ovarian stimulation with clomiphene citrate (CC) in an intrauterine insemination (IUI) programme for subfertile couples? SUMMARY ANSWER: Ovarian stimulation with low-dose hMG is superior to CC in IUI cycles with respect to clinical pregnancy rate. WHAT IS KNOWN ALREADY: IUI after ovarian stimulation is an effective treatment for mild male subfertility, unexplained subfertility and minimal-mild endometriosis, but it is unclear which medication for ovarian stimulation is more effective. STUDY DESIGN, SIZE, DURATION: A total of 330 women scheduled for IUI during 657 cycles (September 2004-December 2011) were enrolled in an open-label randomized clinical trial to ovarian stimulation with low-dose hMG subcutaneous (n = 334, 37.5-75 IU per day) or CC per oral (n = 323, 50 mg/day from Day 3-7). Assuming a difference of 10% in 'clinical pregnancy with positive fetal heart beat', we needed 219 cycles per group (alpha-error 0.05, power 0.80). PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied subfertile couples with mild male subfertility, unexplained subfertility or minimal-mild endometriosis. Further inclusion criteria were failure to conceive for >=12 months, female age <=42 years, at least one patent Fallopian tube and a total motility count (TMC) >=5.0 million spermatozoa after capacitation. The primary end-point was clinical pregnancy. Analysis was by intention to treat and controlled for the presence of multiple measures, as one couple could have more randomizations in multiple cycles. Linear mixed models were used for continuous measures. For binary outcomes we estimated the relative risk using a Poisson model with log link and using generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE: When compared with ovarian stimulation with CC, hMG stimulation was characterized by a higher clinical pregnancy rate (hMG 48/334 (14.4%) versus CC 29/323 (9.0%), relative risk (RR) 1.6 (95% confidence interval (CI) 1.1-2.4)), higher live birth rate (hMG 46/334 (13.8%) versus CC 28/323 (8.7%), RR 1.6 (95% CI 1.0-2.4)), low and comparable multiple live birth rate (hMG 3/46 (6.5%) versus CC 1/28 (3.6%), P > 0.99), lower number of preovulatory follicles (hMG 1.2 versus CC 1.5, P < 0.001), increased endometrial thickness (hMG 8.5 mm versus CC 7.5 mm, P < 0.001), and a lower cancellation rate per started cycle (hMG 15/322 (4.7%) versus CC 46/298 (15.4%), P < 0.001). LIMITATIONS, REASONS FOR CAUTION: We randomized patients at a cycle level, and not at a strategy over multiple cycles. WIDER IMPLICATIONS OF THE FINDINGS: This study showed better reproductive outcome after ovarian stimulation with low-dose gonadotrophins. A health economic analysis of our data is planned to test the hypothesis that ovarian stimulation with low-dose hMG combined with IUI is associated with increased cost-effectiveness when compared with ovarian stimulation with CC. STUDY FUNDING/ COMPETING INTERESTS: T.M.D. and K.P. were supported by the Clinical Research Foundation of UZ Leuven, Belgium. This study was also supported by the Ferring company (Copenhagen, Denmark) which provide free medication (Menopur) required for the group of patients who were randomized in the hMG COS group. The Ferring company was not involved in the study design, data analysis, writing and submission of the paper. TRIAL REGISTRATION NUMBER: NCT01569945 (ClinicalTrials.gov). PMID- 25788571 TI - Adrenal fasciculata cells express T-type and rapidly and slowly activating L-type Ca2+ channels that regulate cortisol secretion. AB - In whole cell patch-clamp recordings, we characterized the L-type Ca(2+) currents in bovine adrenal zona fasciculata (AZF) cells and explored their role, along with the role of T-type channels, in ACTH- and angiotensin II (ANG II)-stimulated cortisol secretion. Two distinct dihydropyridine-sensitive L-type currents were identified, both of which were activated at relatively hyperpolarized potentials. One activated with rapid kinetics and, in conjunction with Northern blotting and PCR, was determined to be Cav1.3. The other, expressed in approximately one-half of AZF cells, activated with extremely slow voltage-dependent kinetics and combined properties not previously reported for an L-type Ca(2+) channel. The T type Ca(2+) channel antagonist 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4 ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2) inhibited Cav3.2 current in these cells, as well as ACTH- and ANG II-stimulated cortisol secretion, at concentrations that did not affect L-type currents. In contrast, nifedipine specifically inhibited L-type currents and cortisol secretion, but less effectively than TTA-P2. Diphenylbutylpiperidine Ca(2+) antagonists, including pimozide, penfluridol, and fluspirilene, and the dihydropyridine niguldipine blocked Cav3.2 and L-type currents and inhibited ACTH-stimulated cortisol secretion with similar potency. This study shows that bovine AZF cells express three Ca(2+) channels, the voltage-dependent gating and kinetics of which could orchestrate complex mechanisms linking peptide hormone receptors to cortisol secretion through action potentials or sustained depolarization. The function of the novel, slowly activating L-type channel is of particular interest in this respect. Regardless, the well-correlated selective inhibition of T- and L type currents and ACTH- and ANG II-stimulated cortisol secretion by TTA-P2 and nifedipine establish the critical importance of these channels in AZF cell physiology. PMID- 25788572 TI - JunD enhances miR-29b levels transcriptionally and posttranscriptionally to inhibit proliferation of intestinal epithelial cells. AB - Through its actions as component of the activating protein-1 (AP-1) transcription factor, JunD potently represses cell proliferation. Here we report a novel function of JunD in the regulation of microRNA expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically increased the expression of primary and mature forms of miR-29b, whereas JunD silencing inhibited miR-29b expression. JunD directly interacted with the miR-29b1 promoter via AP-1-binding sites, whereas mutation of AP-1 sites from the miR-29b1 promoter prevented JunD-mediated transcriptional activation of the miR-29b1 gene. JunD also enhanced formation of the Drosha microprocessor complex, thus further promoting miR-29b biogenesis. Cellular polyamines were found to regulate miR-29b expression by altering JunD abundance, since the increase in miR-29b expression levels in polyamine-deficient cells was abolished by JunD silencing. In addition, miR-29b silencing prevented JunD-induced repression of IEC proliferation. Our findings indicate that JunD activates miR-29b by enhancing its transcription and processing, which contribute to the inhibitory effect of JunD on IEC growth and maintenance of gut epithelium homeostasis. PMID- 25788573 TI - Revisiting the NaCl cotransporter regulation by with-no-lysine kinases. AB - The renal thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC. Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase complex. Extensive research has shown that WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and that WNKs modulate the activity of NCC by means of intermediary Ste20-type kinases known as SPAK or OSR1. The understanding of the effect of WNKs on NCC is a complex issue, but recent evidence discussed in this review suggests that we could be reaching the end of the dark ages regarding this matter. PMID- 25788574 TI - A physical sciences network characterization of circulating tumor cell aggregate transport. AB - Circulating tumor cells (CTC) have been implicated in the hematogenous spread of cancer. To investigate the fluid phase of cancer from a physical sciences perspective, the multi-institutional Physical Sciences-Oncology Center (PS-OC) Network performed multidisciplinary biophysical studies of single CTC and CTC aggregates from a patient with breast cancer. CTCs, ranging from single cells to aggregates comprised of 2-5 cells, were isolated using the high-definition CTC assay and biophysically profiled using quantitative phase microscopy. Single CTCs and aggregates were then modeled in an in vitro system comprised of multiple breast cancer cell lines and microfluidic devices used to model E-selectin mediated rolling in the vasculature. Using a numerical model coupling elastic collisions between red blood cells and CTCs, the dependence of CTC vascular margination on single CTCs and CTC aggregate morphology and stiffness was interrogated. These results provide a multifaceted characterization of single CTC and CTC aggregate dynamics in the vasculature and illustrate a framework to integrate clinical, biophysical, and mathematical approaches to enhance our understanding of the fluid phase of cancer. PMID- 25788575 TI - Macrophage deficiency in osteopetrotic (op/op) mice inhibits activation of satellite cells and prevents hypertrophy in single soleus fibers. AB - Effects of macrophage on the responses of soleus fiber size to hind limb unloading and reloading were studied in osteopetrotic homozygous (op/op) mice with inactivated mutation of macrophage colony-stimulating factor (M-CSF) gene and in wild-type (+/+) and heterozygous (+/op) mice. The basal levels of mitotically active and quiescent satellite cell (-46 and -39% vs. +/+, and -40 and -30% vs. +/op) and myonuclear number (-29% vs. +/+ and -28% vs. +/op) in fibers of op/op mice were significantly less than controls. Fiber length and sarcomere number in op/op were also less than +/+ (-22%) and +/op (-21%) mice. Similar trend was noted in fiber cross-sectional area (CSA, -15% vs. +/+, P = 0.06, and -14% vs. +/op, P = 0.07). The sizes of myonuclear domain, cytoplasmic volume per myonucleus, were identical in all types of mice. The CSA, length, and the whole number of sarcomeres, myonuclei, and mitotically active and quiescent satellite cells, as well as myonuclear domain, in single muscle fibers were decreased after 10 days of unloading in all types of mice, although all of these parameters in +/+ and +/op mice were increased toward the control values after 10 days of reloading. However, none of these levels in op/op mice were recovered. Data suggest that M-CSF and/or macrophages are important to activate satellite cells, which cause increase of myonuclear number during fiber hypertrophy. However, it is unclear why their responses to general growth and reloading after unloading are different. PMID- 25788576 TI - Close spatio-association of the transient receptor potential canonical 4 (TRPC4) channel with Galphai in TRPC4 activation process. AB - TPRC channels are Ca(2+)-permeable, nonselective cation channels that are activated by a wide variety of stimuli, including G protein-coupled receptors (GPCRs). TRPC4 is commonly assumed to be activated by Gq/phospholipase C-coupled receptors. However, the other molecular mechanisms by which Galpha proteins regulate TRPC4 remain unclear. Here, we found that Galphai2 regulates TRPC4 activation by direct binding. To investigate this mechanism, we used whole patch clamp and fluorescence resonance energy transfer (FRET). We tagged an isoform of mTRPC4 and G protein with CFP and YFP, respectively, and transiently transfected cells with the FRET pair. The FRET efficiency between TRPC4beta-CFP and the constitutively active mutant form of Galphai2 was nearly 15% and was greater than that observed with wild-type Galphai2 (nearly 5%). Gbetagamma and the TRPC4 channel showed a FRET efficiency lower than 6%. In HEK293 cells transfected with the M2 muscarinic receptor, the application of carbachol increased the FRET efficiency between TRPC4beta-CFP and Galphai2(WT)-YFP from 4.7 +/- 0.4% (n = 7) to 12.6 +/- 1.4% (n = 7). We also found that the TRPC4 channel directly interacts with Galphai2, but not with Galphaq, when the channel is open. We analyzed the calcium levels in HEK293 cells expressing the channels and Galphai2 or Galphaq using the calcium indicator YC6.1 (Yellow Cameleon 6.1). In response to the muscarinic agonist carbachol, M2-, Galphai2-, and TRPC4-expressing cells showed a prolonged Ca(2+) influx compared with cells expressing only M2. Together, these data suggest that Galphai2 activates the TRPC4 channel by direct binding, which then induces Ca(2+) entry. PMID- 25788578 TI - Pseudoaneurysm of a branch of left internal mammary artery: a late and potentially fatal complication after redo-sternotomy. AB - Post-sternotomy pseudoaneurysms of the internal mammary arteries (IMAs) and their branches are rare and often present with rupture-associated haemothorax and haemodynamic instability. In those cases, urgent surgical correction or embolization can be the treatment of choice. Traumatic chest injuries might lead to IMA branch injury as well; after cardiac surgery, injuries to these branches during sternal closure can be an extremely rare cause of pseudoaneurysm. We describe the case of a 78-year old lady with a left IMA branch pseudoaneurysm, arising from left sternal edge a few weeks after redo-sternotomy for mitral valve surgery. We also describe its non-surgical successful repair. PMID- 25788577 TI - Functional plasticity of the N-methyl-d-aspartate receptor in differentiating human erythroid precursor cells. AB - Calcium signaling is essential to support erythroid proliferation and differentiation. Precise control of the intracellular Ca(2+) levels in erythroid precursor cells (EPCs) is afforded by coordinated expression and function of several cation channels, including the recently identified N-methyl-d-aspartate receptor (NMDAR). Here, we characterized the changes in Ca(2+) uptake and electric currents mediated by the NMDARs occurring during EPC differentiation using flow cytometry and patch clamp. During erythropoietic maturation, subunit composition and properties of the receptor changed; in proerythroblasts and basophilic erythroblasts, fast deactivating currents with high amplitudes were mediated by the GluN2A subunit-dominated receptors, while at the polychromatic and orthochromatic erythroblast stages, the GluN2C subunit was getting more abundant, overriding the expression of GluN2A. At these stages, the currents mediated by the NMDARs carried the features characteristic of the GluN2C containing receptors, such as prolonged decay time and lower conductance. Kinetics of this switch in NMDAR properties and abundance varied markedly from donor to donor. Despite this variability, NMDARs were essential for survival of EPCs in any subject tested. Our findings indicate that NMDARs have a dual role during erythropoiesis, supporting survival of polychromatic erythroblasts and contributing to the Ca(2+) homeostasis from the orthochromatic erythroblast stage to circulating red blood cells. PMID- 25788579 TI - The sequelae of misinterpretating surgical outcome data. PMID- 25788580 TI - Malnutrition prevalence and nutrition barriers in children under 5 years: a mixed methods study in Madagascar. AB - BACKGROUND: Limited data exist on malnutrition prevalence in Madagascar. We aimed to assess the point prevalence of childhood malnutrition in the Anivorano region, and to explore mothers' perceptions of barriers to proper nutrition. METHODS: In a mixed methods study we measured height and weight for 313 children, aged 6 months to 5 years during summer 2011 using a recumbent measuring board and calibrated scale, and simultaneously conducted semi-structured interviews with 60 mothers of malnourished (n=19) and healthy (n=41) children. Multivitamins and high-energy supplemental food were provided to malnourished children. Mothers were trained how to prepare high-energy supplemental food. RESULTS: Prevalence of wasting defined by low weight-for-height was 10.3% (31/301); stunting or low height-for-age was 36.2% (109/301). The majority of families interviewed cultivated their own rice and other crops. Major themes regarding barriers to proper nutrition included inadequate purchasing power and access issues, low health literacy and misconceptions regarding proper nutrition and malnutrition, and insufficient variety of crops produced. CONCLUSIONS: Malnutrition rates are alarming. Health and nutritional education to improve health literacy and address misconceptions, and improvement in social services, are warranted. A multilateral approach with involvement of health and social service agencies and non governmental organizations to plan effective preventative strategies, along with broader national and transnational strategies are instrumental to address the fundamental causes of lack of access to proper nutrition. PMID- 25788581 TI - Sex, Adiposity, and Hypertension Status Modify the Inverse Effect of Marine Food Intake on Blood Pressure in Alaska Native (Yup'ik) People. AB - BACKGROUND: Alaska Native people currently have a higher prevalence of hypertension than do nonnative Alaskans, although in the 1950s hypertension was rare among Alaska Native people. A novel biomarker of marine foods, the nitrogen isotope ratio (delta15N) in RBCs was shown to be negatively associated with systolic and diastolic blood pressure. Few studies have examined how individual characteristics modify the association of marine food intake with blood pressure. OBJECTIVE: This exploratory analysis examined whether sex, adiposity, and hypertension modify the inverse association between marine food intake and blood pressure. METHODS: We used covariate-adjusted linear models to describe the association between delta15N and blood pressure in 873 adult Alaska Native (Yup'ik) people who resided in 8 communities in southwest Alaska. We separately stratified by sex, body mass index (BMI) group, abdominal obesity, and hypertension status and assessed the interaction between delta15N and participant characteristics on blood pressure via likelihood ratio tests. RESULTS: The association between delta15N and systolic blood pressure was modified by sex, BMI status, and abdominal obesity, with the inverse association observed only in the male (beta = -1.5; 95% CI: -2.4, -0.6 : , nonobese BMI (beta = -1.7; 95% CI: 2.5, -1.0), and non-abdominally obese (beta = -1.6; 95% CI: -2.4, -0.9) strata (all P-interaction < 0.0001). A reduction in diastolic blood pressure associated with delta15N was observed in the nonobese BMI (beta = -1.1; 95% CI: -1.7, -0.5) and non-abdominally obese (beta = -1.1; 95% CI: -1.7, -0.5) strata, although only the interaction between BMI group and delta15N with diastolic blood pressure was significant. The inverse association between delta15N and both systolic and diastolic blood pressure was observed in nonhypertensive individuals, although the comparison had limited power. The results were consistent with those identified by using combined RBC concentrations of eicosapentaenoic acid and docosahexaenoic acid as the biomarker of marine food intake, although the associations identified by using delta15N were larger. CONCLUSIONS: Obesity status modified the inverse association between marine food intake and both systolic and diastolic blood pressure in adult Alaska Native (Yup'ik) people. The inverse association between delta15N and systolic blood pressure was also modified by sex. PMID- 25788583 TI - Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain. AB - BACKGROUND: Iron accumulation in the central nervous system (CNS) is a common feature of many neurodegenerative diseases. Multicopper ferroxidases (MCFs) play an important role in cellular iron metabolism. However, the role of MCFs in the CNS in health and disease remains poorly characterized. OBJECTIVE: The aim was to study the role of hephaestin (HEPH) and ceruloplasmin (CP) in CNS iron metabolism and homeostasis. METHODS: Iron concentrations and L-ferritin protein levels of selected brain regions were determined in global hephaestin knockout (Heph KO), global ceruloplasmin knockout (Cp KO), and wild-type (WT) male mice at 6-7 mo of age. Gene expression of divalent metal transporter 1 (Dmt1), ferroportin 1 (Fpn1), Heph, Cp, and transferrin receptor 1 (Tfrc) and HEPH protein level was quantitated in the same brain regions. RESULTS: Iron and L-ferritin protein levels were significantly increased in Heph KO mouse brain cortex (iron: 30%, P < 0.05; L-ferritin: 200%, P < 0.05), hippocampus (iron: 80%, P < 0.05; L-ferritin: 300%, P < 0.05), brainstem (iron: 20%, P < 0.05; L-ferritin: 150%, P < 0.05), and cerebellum (iron: 20%, P < 0.05; L-ferritin: 100%, P < 0.05) regions than in WT and Cp KO mouse brain regions at 6 mo of age. Expression of the Heph gene was significantly increased in the Cp KO mouse cortex (100%; P < 0.01), hippocampus (350%; P < 0.001), brainstem (30%; P < 0.01), and cerebellum (150%; P < 0.001) than in WT controls, and Cp gene expression was significantly decreased in the Heph KO mouse hippocampus (20%; P < 0.05) than in WT control mice at 6 mo of age. CONCLUSIONS: Ablation of HEPH or CP results in disordered brain iron homeostasis in mice. Heph KO may provide a novel model for neurodegenerative disorders. PMID- 25788582 TI - Fish Oil Contaminated with Persistent Organic Pollutants Reduces Antioxidant Capacity and Induces Oxidative Stress without Affecting Its Capacity to Lower Lipid Concentrations and Systemic Inflammation in Rats. AB - BACKGROUND: Numerous studies have investigated the benefits of fish, fish oil, and omega-3 (n-3) polyunsaturated fatty acids against cardiovascular diseases. However, concern surrounding contamination with persistent organic pollutants (POPs) prompts caution in the recommendation to consume fish and fish oil. OBJECTIVE: The present study compared the effects of fish oil contaminated with polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs) on serum lipid profiles, inflammation, and oxidative stress. METHODS: Twenty eight-day-old male Sprague-Dawley rats (n = 30) consumed diets of unmodified fish oil (FO) consisting of 15% fat by weight, persistent organic pollutant-contaminated fish oil (POP FO) (PCBs at 2.40 MUg/g; OCs at 3.80 MUg/g FO), or corn oil (control; CO) for 9 wk. Lipid profiles and C-reactive protein concentrations were assessed. Hepatic gene expression related to lipid metabolism was determined by real time quantitative polymerase chain reaction analysis. RESULTS: After 9 wk of feeding, accumulation of PCBs and OCs in the fat tissue of the POP FO group compared with the other 2 groups was confirmed (P < 0.01). Both fish oil groups showed greater HDL cholesterol (FO 53 +/- 5.3 and POP FO 55 +/- 7.7 vs. CO 34 +/- 2.3 mg/dL), but lower triglycerides (24 +/- 2.8 and 22 +/- 3.0 vs. 43 +/- 5.6 mg/dL), LDL cholesterol (38 +/- 14 and 34 +/- 9.2 vs. 67 +/- 4.4 mg/dL), and C-reactive protein (113 +/- 20 and 120 +/- 26 vs. 189 +/- 22 MUg/dL) compared with the CO group (P < 0.05). Gene expression of fatty acid synthase in both fish oil groups was also less than in the CO group (P < 0.05). However, the POP FO group showed greater lipid peroxidation (5.1 +/- 0.7 vs. 2.9 +/- 0.9 and 2.6 +/- 0.6 MUM) and less antioxidant capacity (0.08 +/- 0.06 vs. 0.5 +/- 0.1 and 0.4 +/- 0.1 mM) than the CO and FO groups (P < 0.05). CONCLUSIONS: These findings indicate that, despite exhibiting benefits on serum lipid concentrations and inflammation, contamination with PCBs and OCs showed significant negative effects on oxidative stress and antioxidant capacity in rats. Future studies should investigate the effects of different contaminant doses and the possibility of a dose-dependent response, a lengthened feeding time, and interactions between contaminant mixtures and oils of varying composition to advise on dietary consumption of fish and fish oil. PMID- 25788584 TI - 25-Hydroxycholecalciferol Enhances Male Broiler Breast Meat Yield through the mTOR Pathway. AB - BACKGROUND: In recent years, there has been a growing body of evidence indicating that replacing cholecalciferol (vitamin D3) with 25-hydroxycholecalciferol [25(OH)D3] through dietary supplementation enhances breast meat yield in broiler chickens. However, the underlying molecular mechanisms are still unknown. OBJECTIVE: We investigated the effect of 25(OH)D3 on male broiler growth performance (body weight, feed intake, feed conversion ratio, and breast meat yield), muscle protein synthesis, and the potential underlying molecular mechanisms. METHODS: Male Cobb 500 broiler chickens were divided into 4 body weight-matched groups and received a control diet with normal cholecalciferol (2760 IU/kg feed) for 42 d, a diet with high concentrations of cholecalciferol (5520 IU/kg feed) for 42 d, or a diet with 25(OH)D3 (5520 IU/kg feed) for 42 d (HyD-42). A fourth group consumed the HyD-42 for 21 d and then control feed for 21 d (HyD-21) (n = 360 birds, 12 replicates/treatment). Food and clean water were available for ad libitum consumption. At the end of the 42-d experiment, protein turnover was measured by phenylalanine flooding dose. Breast muscle tissues were collected and protein synthesis-related gene and protein expression were measured by real time polymerase chain reaction and Western blot, respectively. Functional studies were performed in vitro with the use of a quail myoblast (QM7) cell line. QM7 cells were treated with 2 doses (1 nM and 10 nM) of cholecalciferol or 25(OH)D3 alone or in combination with 100 nM rapamycin, and cell proliferation was determined by cell proliferation assay. Protein synthesis-related gene and protein expression were also determined. RESULTS: The HyD-42 increased 25(OH)D3 circulating concentrations by 126% (P < 0.05), enhanced breast meat yield (P < 0.05), and increased the fractional rate of protein synthesis by 3-fold (P < 0.05) compared with the control diet. Molecular analyses revealed that breast muscle from chickens consuming the HyD-42 expressed significantly higher concentrations of vitamin D receptor (VDR), phospho mechanistic target of rapamycin(Ser2481), phospho ribosomal P70 S6 kinase (RPS6K)(Thr421/Ser424), and antigen Ki-67 (Ki67) compared with the other groups. In line with the in vivo data, in vitro functional studies showed that cells treated with 25(OH)D3 for 24 h had increased VDR expression, and activated the mechanistic target of rapamycin (mTOR)/S6 kinase (S6K) pathway, enhanced Ki67 protein concentrations, and induced QM7 cell proliferation compared with untreated or cholecalciferol-treated cells. Blocking the mTOR pathway with rapamycin reversed these effects. CONCLUSION: Taken together, our findings provide evidence that the effects of 25(OH)D3 on male broiler breast muscle are likely mediated through the mTOR-S6K pathway. PMID- 25788586 TI - Lymph formation, composition and circulation: a proteomics perspective. AB - During the last 20 years a deeper understanding of the lymphatic circulatory system, lymph formation and composition has emerged. This review will examine the current knowledge on the organization of the lymphatic vascular tree, the formation of lymph from the extracellular fluid, lymph circulation and the lymph proteomic composition during physiological and pathological conditions. Formation of the lymph fluid is dependent on pressure gradients in the capillary beds and the composition of the endothelial cell glycocalyx, which acts as a molecular sieve. Fluid propulsion toward the draining node is dependent on the intrinsic pumping mechanism of the lymphangions and their unidirectional valves. The lymph 'omics' composition is dependent on the ultrafiltration of plasma proteins as well as proteins and molecules derived from the metabolic and catabolic activities of each parenchymal organ from which the lymph drains. Altogether, these new insights have brought about a new awareness of the importance of the lymphatic system in human physiology and pathology. PMID- 25788585 TI - Childhood energy intake is associated with nonalcoholic fatty liver disease in adolescents. AB - BACKGROUND: Greater adiposity is an important risk factor for nonalcoholic fatty liver disease (NAFLD). Thus, it is likely that dietary intake is involved in the development of the disease. Prospective studies assessing the relation between childhood dietary intake and risk of NAFLD are lacking. OBJECTIVE: This study was designed to explore associations between energy, carbohydrate, sugar, starch, protein, monounsaturated fat, polyunsaturated fat, saturated fat, and total fat intake by youth at ages 3, 7, and 13 y and subsequent (mean age: 17.8 y) ultrasound scan (USS)-measured liver fat and stiffness and serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase. We assessed whether observed associations were mediated through fat mass at the time of outcome assessment. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Trajectories of energy and macronutrient intake from ages 3-13 y were obtained with linear-spline multilevel models. Linear and logistic regression models examined whether energy intake and absolute and energy adjusted macronutrient intake at ages 3, 7, and 13 y were associated with liver outcomes. RESULTS: Energy intake at all ages was positively associated with liver outcomes; for example, the odds of having a USS-measured liver fat per 100 kcal increase in energy intake at age 3 y were 1.79 (95% CI: 1.14, 2.79). Associations between absolute macronutrient intake and liver outcomes were inconsistent and attenuated to the null after adjustment for total energy intake. The majority of associations attenuated to the null after adjustment for fat mass at the time liver outcomes were assessed. CONCLUSION: Higher childhood and early adolescent energy intake is associated with greater NAFLD risk, and the macronutrients from which energy intake is derived are less important. These associations appear to be mediated, at least in part, by fat mass at the time of outcome assessment. PMID- 25788587 TI - East Meets West-A Novel Steerable Grasper to Facilitate Gastric Endoscopic Submucosal Dissection (ESD): Randomized Comparative Study in a Porcine Model. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is challenging because of the limited ability of conventional endoscopic tools to achieve adequate traction. We have recently used a novel steerable grasper (SG; ANUBIS grasper, Karl Storz, Tuttlingen, Germany) with intuitive manipulating handles to lift up the mucosa. The aim of this study is to evaluate the efficacy of the assistance of the SG in a porcine acute model. MATERIALS AND METHODS: A total of 36 gastric ESDs were performed in 12 swine (3 ESDs/pig), at the antrum, greater curvature of the gastric body, and cardia. Pigs were randomly assigned to the SG group (n = 6) or to the control group (n = 6). ESD steps included the following: scoring the area, submucosal injection, and precut and submucosal dissection with or without SG assistance. Outcomes measured were as follows: dissection time, dissection speed, size of specimen, completeness of dissection (all marks included in the specimen), en bloc dissection, and complications. RESULTS: Overall mean dissection time was 18.6 +/- 7.56 versus 29 +/- 18.14 minutes (P = .032), and mean dissection speed was 94.74 +/- 39.74 mm(2)/min versus 65.41 +/- 39.5 mm(2)/min (P = .033) in the SG and control groups, respectively. Mean size of the specimen was 1451.4 +/- 549.2 mm(2) in the SG group and 1615.3 +/- 605.9 in the control group. Complete and en bloc dissections were achieved in all cases. One deep muscular injury occurred in the control group (gastric body). CONCLUSION: The ANUBIS grasper is a user-friendly, effective, and safe tool to achieve adequate traction and exposure of the ESD plane in the pig model. PMID- 25788588 TI - Corrigendum (e-only). AB - Hori T, Ogura Y, Yagi S, et al. How Do Transplant Surgeons Accomplish Optimal Portal Venous Flow During Living-Donor Liver Transplantation? Noninvasive Measurement of Indocyanine Green Elimination Rate. Surg Innov. 2014;21:43-51. In the version of this article initially published, the affiliation of author Mohammed Saied Hedaya was incorrectly listed as Kyoto University Hospital, Kyoto, Japan. His correct affiliation is Theodore Bilharz Research Institute, Cairo, Egypt. PMID- 25788589 TI - Assessing Needs and Feasibility of Diabetes Self-management Coaching at Faith Based Organizations for Indo-Guyanese Immigrants. AB - PURPOSE: The purpose of this study is to explore barriers and needs related to diabetes care and the feasibility of diabetes self-management (DSM) "coaching" at faith-based organizations (FBOs) for the Indo-Guyanese community in Schenectady, New York. METHODS: Participants were recruited though flyers and mass mailings, and in-depth interviews were conducted at their homes by a team of culturally matched interviewers using a semi-structured questionnaire. Characteristics of participants were compared with existing population-based data to confirm their representativeness. Responses were transcribed, coded, and summarized, and findings are presented along with selective quotations. Key dimensions of feasibility were scored and charted for visualization. RESULTS: Findings revealed barriers regarding diet-related knowledge and skills, access to structured DSM education, hyperglycemia control, and environmental support for physical activity. Participants responded positively to receiving free DSM coaching at their FBOs. All participants preferred a qualified health care professional such as certified diabetes educator as their coach and wanted coaching in all aspects of DSM; however, food preparation/diet was the most frequently requested specific topic. Participants uniformly disliked contact with the coach through e-mails and text messages but liked receiving periodic telephone calls at home by the coach. Overall, DSM coaching at FBOs rated high on the key dimensions of feasibility, namely, affordability, accessibility, acceptability, cultural relevance, and safety. CONCLUSIONS: This study sheds light on the feasibility of an FBO-based DSM intervention for the Indo-Guyanese. It offers insights into developing culturally appropriate DSM intervention format and strategy. PMID- 25788590 TI - Sensory adaptation for timing perception. AB - Recent sensory experience modifies subjective timing perception. For example, when visual events repeatedly lead auditory events, such as when the sound and video tracks of a movie are out of sync, subsequent vision-leads-audio presentations are reported as more simultaneous. This phenomenon could provide insights into the fundamental problem of how timing is represented in the brain, but the underlying mechanisms are poorly understood. Here, we show that the effect of recent experience on timing perception is not just subjective; recent sensory experience also modifies relative timing discrimination. This result indicates that recent sensory history alters the encoding of relative timing in sensory areas, excluding explanations of the subjective phenomenon based only on decision-level changes. The pattern of changes in timing discrimination suggests the existence of two sensory components, similar to those previously reported for visual spatial attributes: a lateral shift in the nonlinear transducer that maps relative timing into perceptual relative timing and an increase in transducer slope around the exposed timing. The existence of these components would suggest that previous explanations of how recent experience may change the sensory encoding of timing, such as changes in sensory latencies or simple implementations of neural population codes, cannot account for the effect of sensory adaptation on timing perception. PMID- 25788591 TI - Composition of symbiotic bacteria predicts survival in Panamanian golden frogs infected with a lethal fungus. AB - Symbiotic microbes can dramatically impact host health and fitness, and recent research in a diversity of systems suggests that different symbiont community structures may result in distinct outcomes for the host. In amphibians, some symbiotic skin bacteria produce metabolites that inhibit the growth of Batrachochytrium dendrobatidis (Bd), a cutaneous fungal pathogen that has caused many amphibian population declines and extinctions. Treatment with beneficial bacteria (probiotics) prevents Bd infection in some amphibian species and creates optimism for conservation of species that are highly susceptible to chytridiomycosis, the disease caused by Bd. In a laboratory experiment, we used Bd-inhibitory bacteria from Bd-tolerant Panamanian amphibians in a probiotic development trial with Panamanian golden frogs, Atelopus zeteki, a species currently surviving only in captive assurance colonies. Approximately 30% of infected golden frogs survived Bd exposure by either clearing infection or maintaining low Bd loads, but this was not associated with probiotic treatment. Survival was instead related to initial composition of the skin bacterial community and metabolites present on the skin. These results suggest a strong link between the structure of these symbiotic microbial communities and amphibian host health in the face of Bd exposure and also suggest a new approach for developing amphibian probiotics. PMID- 25788592 TI - Enemies and turncoats: bovine tuberculosis exposes pathogenic potential of Rift Valley fever virus in a common host, African buffalo (Syncerus caffer). AB - The ubiquity and importance of parasite co-infections in populations of free living animals is beginning to be recognized, but few studies have demonstrated differential fitness effects of single infection versus co-infection in free living populations. We investigated interactions between the emerging bacterial disease bovine tuberculosis (BTB) and the previously existing viral disease Rift Valley fever (RVF) in a competent reservoir host, African buffalo, combining data from a natural outbreak of RVF in captive buffalo at a buffalo breeding facility in 2008 with data collected from a neighbouring free-living herd of African buffalo in Kruger National Park. RVF infection was twice as likely in individual BTB+ buffalo as in BTB- buffalo, which, according to a mathematical model, may increase RVF outbreak size at the population level. In addition, co-infection was associated with a far higher rate of fetal abortion than other infection states. Immune interactions between BTB and RVF may underlie both of these interactions, since animals with BTB had decreased innate immunity and increased pro inflammatory immune responses. This study is one of the first to demonstrate how the consequences of emerging infections extend beyond direct effects on host health, potentially altering the dynamics and fitness effects of infectious diseases that had previously existed in the ecosystem on free-ranging wildlife populations. PMID- 25788593 TI - Repeatability of adaptation in experimental populations of different sizes. AB - The degree to which evolutionary trajectories and outcomes are repeatable across independent populations depends on the relative contribution of selection, chance and history. Population size has been shown theoretically and empirically to affect the amount of variation that arises among independent populations adapting to the same environment. Here, we measure the contribution of selection, chance and history in different-sized experimental populations of the unicellular alga Chlamydomonas reinhardtii adapting to a high salt environment to determine which component of evolution is affected by population size. We find that adaptation to salt is repeatable at the fitness level in medium (Ne = 5 * 10(4)) and large (Ne = 4 * 10(5)) populations because of the large contribution of selection. Adaptation is not repeatable in small (Ne = 5 * 10(3)) populations because of large constraints from history. The threshold between stochastic and deterministic evolution in this case is therefore between effective population sizes of 10(3) and 10(4). Our results indicate that diversity across populations is more likely to be maintained if they are small. Experimental outcomes in large populations are likely to be robust and can inform our predictions about outcomes in similar situations. PMID- 25788594 TI - Rapidly increasing methyl mercury in endangered ivory gull (Pagophila eburnea) feathers over a 130 year record. AB - Mercury (Hg) is increasing in marine food webs, especially at high latitudes. The bioaccumulation and biomagnification of methyl mercury (MeHg) has serious effects on wildlife, and is most evident in apex predators. The MeHg body burden in birds is the balance of ingestion and excretion, and MeHg in feathers is an effective indicator of overall MeHg burden. Ivory gulls (Pagophila eburnea), which consume ice-associated prey and scavenge marine mammal carcasses, have the highest egg Hg concentrations of any Arctic bird, and the species has declined by more than 80% since the 1980s in Canada. We used feathers from museum specimens from the Canadian Arctic and western Greenland to assess whether exposure to MeHg by ivory gulls increased from 1877 to 2007. Based on constant feather stable-isotope (delta(13)C, delta(15)N) values, there was no significant change in ivory gulls' diet over this period, but feather MeHg concentrations increased 45* (from 0.09 to 4.11 ug g(-1) in adults). This dramatic change in the absence of a dietary shift is clear evidence of the impact of anthropogenic Hg on this high-latitude threatened species. Bioavailable Hg is expected to increase in the Arctic, raising concern for continued population declines in high-latitude species that are far from sources of environmental contaminants. PMID- 25788595 TI - Sex differences in lizard escape decisions vary with latitude, but not sexual dimorphism. AB - Sexual selection is a powerful evolutionary mechanism that has shaped the physiology, behaviour and morphology of the sexes to the extent that it can reduce viability while promoting traits that enhance reproductive success. Predation is one of the underlying mechanisms accounting for viability costs of sexual displays. Therefore, we should expect that individuals of the two sexes adjust their anti-predator behaviour in response to changes in predation risk. We conducted a meta-analysis of 28 studies (42 species) of sex differences in risk taking behaviour in lizards and tested whether these differences could be explained by sexual dichromatism, by sexual size dimorphism or by latitude. Latitude was the best predictor of the interspecific heterogeneity in sex specific behaviour. Males did not change their escape behaviour with latitude, whereas females had increasingly reduced wariness at higher latitudes. We hypothesize that this sex difference in risk-taking behaviour is linked to sex specific environmental constraints that more strongly affect the reproductive effort of females than males. This novel latitudinal effect on sex-specific anti predator behaviour has important implications for responses to climate change and for the relative roles of natural and sexual selection in different species. PMID- 25788596 TI - A fish that uses its hydrodynamic tongue to feed on land. AB - To capture and swallow food on land, a sticky tongue supported by the hyoid and gill arch skeleton has evolved in land vertebrates from aquatic ancestors that used mouth-cavity-expanding actions of the hyoid to suck food into the mouth. However, the evolutionary pathway bridging this drastic shift in feeding mechanism and associated hyoid motions remains unknown. Modern fish that feed on land may help to unravel the physical constraints and biomechanical solutions that led to terrestrialization of fish-feeding systems. Here, we show that the mudskipper emerges onto land with its mouth cavity filled with water, which it uses as a protruding and retracting 'hydrodynamic tongue' during the initial capture and subsequent intra-oral transport of food. Our analyses link this hydrodynamic action of the intra-oral water to a sequence of compressive and expansive cranial motions that diverge from the general pattern known for suction feeding in fishes. However, the hyoid motion pattern showed a remarkable resemblance to newts during tongue prehension. Consequently, although alternative scenarios cannot be excluded, hydrodynamic tongue usage may be a transitional step onto which the evolution of adhesive mucosa and intrinsic lingual muscles can be added to gain further independence from water for terrestrial foraging. PMID- 25788597 TI - The fossil record and macroevolutionary history of the beetles. AB - Coleoptera (beetles) is the most species-rich metazoan order, with approximately 380 000 species. To understand how they came to be such a diverse group, we compile a database of global fossil beetle occurrences to study their macroevolutionary history. Our database includes 5553 beetle occurrences from 221 fossil localities. Amber and lacustrine deposits preserve most of the beetle diversity and abundance. All four extant suborders are found in the fossil record, with 69% of all beetle families and 63% of extant beetle families preserved. Considerable focus has been placed on beetle diversification overall, however, for much of their evolutionary history it is the clade Polyphaga that is most responsible for their taxonomic richness. Polyphaga had an increase in diversification rate in the Early Cretaceous, but instead of being due to the radiation of the angiosperms, this was probably due to the first occurrences of beetle-bearing amber deposits in the record. Perhaps, most significant is that polyphagan beetles had a family-level extinction rate of zero for most of their evolutionary history, including across the Cretaceous-Palaeogene boundary. Therefore, focusing on the factors that have inhibited beetle extinction, as opposed to solely studying mechanisms that may promote speciation, should be examined as important determinants of their great diversity today. PMID- 25788598 TI - Marsh rabbit mortalities tie pythons to the precipitous decline of mammals in the Everglades. AB - To address the ongoing debate over the impact of invasive species on native terrestrial wildlife, we conducted a large-scale experiment to test the hypothesis that invasive Burmese pythons (Python molurus bivittatus) were a cause of the precipitous decline of mammals in Everglades National Park (ENP). Evidence linking pythons to mammal declines has been indirect and there are reasons to question whether pythons, or any predator, could have caused the precipitous declines seen across a range of mammalian functional groups. Experimentally manipulating marsh rabbits, we found that pythons accounted for 77% of rabbit mortalities within 11 months of their translocation to ENP and that python predation appeared to preclude the persistence of rabbit populations in ENP. On control sites, outside of the park, no rabbits were killed by pythons and 71% of attributable marsh rabbit mortalities were classified as mammal predations. Burmese pythons pose a serious threat to the faunal communities and ecological functioning of the Greater Everglades Ecosystem, which will probably spread as python populations expand their range. PMID- 25788599 TI - Evolutionary responses to environmental change: trophic interactions affect adaptation and persistence. AB - According to recent reviews, the question of how trophic interactions may affect evolutionary responses to climate change remains unanswered. In this modelling study, we explore the evolutionary dynamics of thermal and plant-herbivore interaction traits in a warming environment. We find the herbivore usually reduces adaptation speed and persistence time of the plant by reducing biomass. However, if the plant interaction trait and thermal trait are correlated, herbivores can create different coevolutionary attractors. One attractor has a warmer plant thermal optimum, and the other a colder one compared with the environment. A warmer plant thermal strategy is given a head start under warming, the only case where herbivores can increase plant persistence under warming. Persistence time of the plant under warming is maximal at small or large thermal niche width. This study shows that considering trophic interactions is necessary and feasible for understanding how ecosystems respond to climate change. PMID- 25788600 TI - Effects of geographical heterogeneity in species interactions on the evolution of venom genes. AB - Geographical heterogeneity in the composition of biotic interactions can create a mosaic of selection regimes that may drive the differentiation of phenotypes that operate at the interface of these interactions. Nonetheless, little is known about effects of these geographical mosaics on the evolution of genes encoding traits associated with species interactions. Predatory marine snails of the family Conidae use venom, a cocktail of conotoxins, to capture prey. We characterized patterns of geographical variation at five conotoxin genes of a vermivorous species, Conus ebraeus, at Hawaii, Guam and American Samoa, and evaluated how these patterns of variation are associated with geographical heterogeneity in prey utilization. All populations show distinct patterns of prey utilization. Three 'highly polymorphic' conotoxin genes showed significant geographical differences in allelic frequency, and appear to be affected by different modes of selection among populations. Two genes exhibited low levels of diversity and a general lack of differentiation among populations. Levels of diversity of 'highly polymorphic' genes exhibit a positive relationship with dietary breadth. The different patterns of evolution exhibited by conotoxin genes suggest that these genes play different roles in prey capture, and that some genes are more greatly affected by differences in predator-prey interactions than others. Moreover, differences in dietary breadth appear to have a greater influence on the differentiation of venoms than differences in the species of prey. PMID- 25788602 TI - Cascading effects of induced terrestrial plant defences on aquatic and terrestrial ecosystem function. AB - Herbivores induce plants to undergo diverse processes that minimize costs to the plant, such as producing defences to deter herbivory or reallocating limited resources to inaccessible portions of the plant. Yet most plant tissue is consumed by decomposers, not herbivores, and these defensive processes aimed to deter herbivores may alter plant tissue even after detachment from the plant. All consumers value nutrients, but plants also require these nutrients for primary functions and defensive processes. We experimentally simulated herbivory with and without nutrient additions on red alder (Alnus rubra), which supplies the majority of leaf litter for many rivers in western North America. Simulated herbivory induced a defence response with cascading effects: terrestrial herbivores and aquatic decomposers fed less on leaves from stressed trees. This effect was context dependent: leaves from fertilized-only trees decomposed most rapidly while leaves from fertilized trees receiving the herbivory treatment decomposed least, suggesting plants funnelled a nutritionally valuable resource into enhanced defence. One component of the defence response was a decrease in leaf nitrogen leading to elevated carbon : nitrogen. Aquatic decomposers prefer leaves naturally low in C : N and this altered nutrient profile largely explains the lower rate of aquatic decomposition. Furthermore, terrestrial soil decomposers were unaffected by either treatment but did show a preference for local and nitrogen-rich leaves. Our study illustrates the ecological implications of terrestrial herbivory and these findings demonstrate that the effects of selection caused by terrestrial herbivory in one ecosystem can indirectly shape the structure of other ecosystems through ecological fluxes across boundaries. PMID- 25788603 TI - Fate and nature of the onychophoran mouth-anus furrow and its contribution to the blastopore. AB - The ancestral states of bilaterian development, and which living groups have conserved them the most, has been a controversial topic in biology for well over a hundred years. In recent years, the idea that gastrulation primitively proceeded via the formation of a slit-like blastopore that then evolved into either protostomy or deuterostomy has gained renewed attention and some molecular developmental support. One of the key pieces of evidence for this 'amphistomy' theory comes from the onychophorans, which form a clear ventral groove during gastrulation. The interpretation of this structure has, however, proved problematic. Based on expression patterns of forkhead (fkh), caudal (cad), brachyury (bra) and wingless (wg/Wnt1), we show that this groove does not correspond to the blastopore, even though both the mouth and anus later develop from it. Rather, the posterior pit appears to be the blastopore; the posterior of the groove later fuses with it to form the definitive anus. Onychophoran development therefore represents a case of 'concealed' deuterostomy. The new data from the onychophorans thus remove one of the key pieces of evidence for the amphistomy theory. Rather, in line with other recent results, it suggests that ancestral bilaterian development was deuterostomic. PMID- 25788601 TI - Regulation of dopamine system responsivity and its adaptive and pathological response to stress. AB - Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood. The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system. This review explores the current knowledge of afferent modulation of the stress/DA circuitry, and presents recent data focusing on the effect of stress on the DA system and its relevance to psychiatric disorders. PMID- 25788605 TI - Editor's Letter. PMID- 25788604 TI - Making teeth to order: conserved genes reveal an ancient molecular pattern in paddlefish (Actinopterygii). AB - Ray-finned fishes (Actinopterygii) are the dominant vertebrate group today (+30 000 species, predominantly teleosts), with great morphological diversity, including their dentitions. How dental morphological variation evolved is best addressed by considering a range of taxa across actinopterygian phylogeny; here we examine the dentition of Polyodon spathula (American paddlefish), assigned to the basal group Acipenseriformes. Although teeth are present and functional in young individuals of Polyodon, they are completely absent in adults. Our current understanding of developmental genes operating in the dentition is primarily restricted to teleosts; we show that shh and bmp4, as highly conserved epithelial and mesenchymal genes for gnathostome tooth development, are similarly expressed at Polyodon tooth loci, thus extending this conserved developmental pattern within the Actinopterygii. These genes map spatio-temporal tooth initiation in Polyodon larvae and provide new data in both oral and pharyngeal tooth sites. Variation in cellular intensity of shh maps timing of tooth morphogenesis, revealing a second odontogenic wave as alternate sites within tooth rows, a dental pattern also present in more derived actinopterygians. Developmental timing for each tooth field in Polyodon follows a gradient, from rostral to caudal and ventral to dorsal, repeated during subsequent loss of teeth. The transitory Polyodon dentition is modified by cessation of tooth addition and loss. As such, Polyodon represents a basal actinopterygian model for the evolution of developmental novelty: initial conservation, followed by tooth loss, accommodating the adult trophic modification to filter-feeding. PMID- 25788606 TI - HIV/AIDS Research in Correctional Settings: A Difficult Task Made Even Harder? AB - Housing a large number of individuals living with or at risk for HIV/AIDS, correctional settings have considerable potential for epidemiological, prevention, and treatment research. However, federal regulations and institutional challenges have limited the extent and types of such research with prisoners. This study examines the degree to which HIV/AIDS correctional researchers report greater challenges than do their noncorrectional counterparts. Results indicate that correctional researchers reported significantly more frequent challenges than those in noncorrectional settings, even after controlling for experience, with the dominant difference related to challenges due to the research setting. These findings add empirical data and support previous research in the field; however, additional research should include correctional staff and incarcerated individuals, and explore whether these differences extend to other research topics. PMID- 25788609 TI - After the Fact: A Brief Educational Program on HIV Postexposure Prophylaxis for Female Detainees in a Local Jail. AB - Women who have been in jail are at increased risk of acquiring HIV when they are in the community. Nonoccupational postexposure prophylaxis (nPEP) reduces HIV transmission following high-risk behaviors and is an effective HIV prevention strategy. The authors designed a 15-minute interactive educational program to increase inmates' knowledge of nPEP. Before the program, participants self reported high HIV risk yet low risk perception and lack of nPEP awareness. After the program, nPEP knowledge scores increased by 40% regardless of demographic or HIV-risk characteristics. This study demonstrates that a brief, easy-to-deliver educational intervention can be carried out in a jail, is effective at raising awareness of both HIV risk and nPEP, and may be useful for others seeking to increase use of this prevention strategy for high-risk women during incarceration. PMID- 25788607 TI - HIV Knowledge Among a Longitudinal Cohort of Juvenile Detainees in an Urban Setting. AB - The authors investigated HIV knowledge change among a cohort of juvenile detainees. Participants completed an HIV knowledge survey at baseline and up to 4 more times over 6 years. The authors calculated knowledge scores; the time serial trend of scores was modeled using generalized estimating equations. A baseline survey was completed by 798 participants, ages 14 to 18 years; mean HIV knowledge scores ranged from 11.4 to 14.1 (maximum score = 18). Males had significantly lower HIV knowledge scores than females at baseline only. Over time, Hispanic participants had significantly lower scores than non-Hispanic Black and non Hispanic White participants. Overall, HIV knowledge increased but was still suboptimal 5 years after baseline. These findings suggest the need to develop and strengthen HIV prevention education programs in youth detention settings. PMID- 25788608 TI - Prevalence and Predictors of Mental/Emotional Distress Among HIV+ Jail Detainees at Enrollment in an Observational Study. AB - This study evaluates the prevalence of mental/emotional distress and its specific correlates among people living with HIV/AIDS (PLWHA) in 20 jail systems across the United States. Of the 878 PLWHA jail detainees, 52% had high levels of mental/emotional distress, defined by the composite Addiction Severity Index score. High mental/emotional distress was found to be associated with the inmate living in a city with lower income inequality, lower health ranking, and higher degree of danger. Proximate variables included being female, bisexual orientation, poorer physical health, and increased severity of substance abuse. Inmates in jails with accredited health services and those satisfied with family support had lower mental/emotional distress scores. These findings indicate the need for expanded mental health assessment of PLWHAs entering jail. PMID- 25788610 TI - Epidemiological Criminology: Contextualization of HIV/AIDS Health Care for Female Inmates. AB - Worldwide, women are increasingly being incarcerated. One unintended consequence is the increase in unhealthy female offenders. Among the more serious health concerns are HIV and AIDS. Challenges associated with caring for women with HIV/AIDS impacts not only disease management and infection control within correctional facilities but also the prisoners' home communities where they will need health care, drug and alcohol rehabilitation, housing assistance, and employment opportunities. No bridging theory has been presented that links prison and community health concerns with criminal justice policy. This article not only presents recommendations for effective HIV/AIDS policy but also suggests epidemiological criminology as a means of explicit merging of health with justice issues and consequently provides a bridging framework. PMID- 25788611 TI - Improvements in Correctional HIV Services: A Case Study in Delaware. AB - This article describes the experience and outcomes of the National Institute on Drug Abuse-funded Criminal Justice Drug Abuse Treatment Studies HIV Services and Treatment Implementation in Corrections protocol in the state of Delaware. The protocol was designed to test the effectiveness of a change team model in improving HIV services in correctional settings. In Delaware, a team was created with representatives from correctional and community agencies to work on improving linkage to HIV care for individuals released from incarceration. The team made improvements in the entire HIV service continuum: linkage to HIV care, HIV education, and HIV testing. The experiences in Delaware and the findings from this study suggest that the use of a change team model is a viable method for making organizational change in correctional settings. PMID- 25788612 TI - HIV Subspecialty Care in Correctional Facilities Using Telemedicine. AB - In the United States, prisons and jails contain a population at high risk for HIV infection with a relatively large proportion known to be HIV positive. However, many incarcerated persons lack access to subspecialty HIV care due to barriers of geography and travel. Telemedicine clinics can remove these barriers, increasing access to expert, multidisciplinary care. With telemedicine, correctional facilities can provide up-to-date, evidence-based HIV management, which may lead to improved compliance, greater virologic suppression, improved CD4 T-cell counts, fewer adverse drug interactions, and decreased transmission in the community. While HIV care in prisons is an example of harnessing this technology, telemedicine can be used for the diagnosis and management of multiple acute and chronic diseases for underserved populations. PMID- 25788613 TI - Position statement: optimizing insurance coverage for detainees and inmates postrelease. PMID- 25788614 TI - Position Statement: STD Testing for Adolescents and Adults Upon Admission to Correctional Facilities. PMID- 25788617 TI - Erratum. AB - Piccolino, A. L., & Solberg, K. B. (2014). The Impact of Traumatic Brain Injury on Prison Health Services and Offender Management. Journal of Correctional Health Care, 20(3), 203-212. Original DOI: 10.1177/1078345814530871. PMID- 25788618 TI - Evaluation of a real-time display for skin dose map in cardiac catheterisation procedures. AB - The purpose of this work was to validate a prototype designed to display skin dose maps in real time for clinicians that perform interventional cardiology procedures. Measurements using copper absorbers and three kinds of dosemeters (solid-state, radiochromic film and optically stimulated luminescence) were performed in a catheterisation laboratory. Some clinical results are also discussed. The system provides patient skin doses with acceptable accuracy, taking into account couch shifts, wedge compensation filters and collimation. The greatest source of uncertainty is that resulting from patient shape modelling. From a set of 374 patients recorded, it can be concluded that the peak skin dose (PSD) for patients with the same cumulative air kerma at the patient entrance reference point can be rather different. This real-time skin dose calculator has resulted easier to manage for measuring patient PSDs than other methods based on films or CR plates. As well as an improvement for patient safety, it could prove a useful training tool for clinicians. PMID- 25788619 TI - Intra- and inter-observer variability in ultrasonographical measurements of the uterus and ovaries in healthy, non-pregnant queens. AB - OBJECTIVES: We aimed to (1) evaluate how frequently the uterus and ovaries of healthy, non-pregnant queens are visible; (2) describe their appearance; (3) take their measurements; and (4) determine intra- and inter-observer variabilities in their measurements. We hypothesised that, using a high-frequency linear probe, the uterus and ovaries could be ultrasonographically visualised during any period of the sexual cycle and with any level of operator expertise. METHODS: Eight queens were enrolled in the study and the ultrasonographical appearance of their uterus and ovaries assessed with a high-frequency linear probe of 15-19 MHz. The diameter of the uterine horns, body and cervix in transverse and longitudinal sections, and the length of the ovaries were recorded. Three observers of different expertise level participated in the study, and the differences between the separate measurements made per queen were evaluated. RESULTS: The ovaries and the entire uterus were visualised in every queen. The ovaries were ovoid structures with submillimetric follicles during anoestrus and additional larger follicles depending on the stage of the cycle. An ovarian pattern suggesting cortex and medulla was observed in half the cases. In the uterus, the serosa was a thin hyperechoic outer rim, and layering was observed in half the cases. The cervix was difficult to identify. The intra- and inter-observer variabilities in the uterine horns and the ovaries were minimal (coefficient of variation [CV] 1.4 4.1%) compared with the differences within the queens (CV 10.9-43.4%). The longitudinal and transverse measurements of the horns and the uterine body were the same. CONCLUSIONS AND RELEVANCE: The ovaries and uterine horns in queens are accessible ultrasonographically at any stage of their cycle, and can be measured with low intra- and inter-observer variabilities. PMID- 25788620 TI - SiPAN: simultaneous prediction and alignment of protein-protein interaction networks. AB - MOTIVATION: Network prediction as applied to protein-protein interaction (PPI) networks has received considerable attention within the last decade. Because of the limitations of experimental techniques for interaction detection and network construction, several computational methods for PPI network reconstruction and growth have been suggested. Such methods usually limit the scope of study to a single network, employing data based on genomic context, structure, domain, sequence information or existing network topology. Incorporating multiple species network data for network reconstruction and growth entails the design of novel models encompassing both network reconstruction and network alignment, since the goal of network alignment is to provide functionally orthologous proteins from multiple networks and such orthology information can be used in guiding interolog transfers. However, such an approach raises the classical chicken or egg problem; alignment methods assume error-free networks, whereas network prediction via orthology works affectively if the functionally orthologous proteins are determined with high precision. Thus to resolve this intertwinement, we propose a framework to handle both problems simultaneously, that of SImultaneous Prediction and Alignment of Networks (SiPAN). RESULTS: We present an algorithm that solves the SiPAN problem in accordance with its simultaneous nature. Bearing the same name as the defined problem itself, the SiPAN algorithm employs state-of-the-art alignment and topology-based interaction confidence construction algorithms, which are used as benchmark methods for comparison purposes as well. To demonstrate the effectiveness of the proposed network reconstruction via SiPAN, we consider two scenarios; one that preserves the network sizes and the other where the network sizes are increased. Through extensive tests on real-world biological data, we show that the network qualities of SiPAN reconstructions are as good as those of original networks and in some cases SiPAN networks are even better, especially for the former scenario. An alternative state-of-the-art network reconstruction algorithm random walk with resistance produces networks considerably worse than the original networks and those reproduced via SiPAN in both cases. AVAILABILITY AND IMPLEMENTATION: Freely available at http://webprs.khas.edu.tr/~cesim/SiPAN.tar.gz. PMID- 25788621 TI - 4DGenome: a comprehensive database of chromatin interactions. AB - MOTIVATION: The 3D structure of the genome plays a critical role in regulating gene expression. Recent progress in mapping technologies for chromatin interactions has led to a rapid increase in this kind of interaction data. This trend will continue as research in this burgeoning field intensifies. RESULTS: We describe the 4DGenome database that stores chromatin interaction data compiled through comprehensive literature curation. The database currently covers both low and high-throughput assays, including 3C, 4C-Seq, 5C, Hi-C, ChIA-PET and Capture C. To complement the set of interactions detected by experimental assays, we also include interactions predicted by a recently developed computational method with demonstrated high accuracy. The database currently contains ~8 million records, covering 102 cell/tissue types in five organisms. Records in the database are described using a standardized file format, facilitating data exchange. The vast major of the interactions were assigned a confidence score. Using the web interface, users can query and download database records via a number of annotation dimensions. Query results can be visualized along with other genomics datasets via links to the UCSC genome browser. We anticipate that 4DGenome will be a valuable resource for investigating the spatial structure-and-function relationship of genomes. PMID- 25788622 TI - A novel motif-discovery algorithm to identify co-regulatory motifs in large transcription factor and microRNA co-regulatory networks in human. AB - MOTIVATION: Interplays between transcription factors (TFs) and microRNAs (miRNAs) in gene regulation are implicated in various physiological processes. It is thus important to identify biologically meaningful network motifs involving both types of regulators to understand the key co-regulatory mechanisms underlying the cellular identity and function. However, existing motif finders do not scale well for large networks and are not designed specifically for co-regulatory networks. RESULTS: In this study, we propose a novel algorithm CoMoFinder to accurately and efficiently identify composite network motifs in genome-scale co-regulatory networks. We define composite network motifs as network patterns involving at least one TF, one miRNA and one target gene that are statistically significant than expected. Using two published disease-related co-regulatory networks, we show that CoMoFinder outperforms existing methods in both accuracy and robustness. We then applied CoMoFinder to human TF-miRNA co-regulatory network derived from The Encyclopedia of DNA Elements project and identified 44 recurring composite network motifs of size 4. The functional analysis revealed that genes involved in the 44 motifs are enriched for significantly higher number of biological processes or pathways comparing with non-motifs. We further analyzed the identified composite bi-fan motif and showed that gene pairs involved in this motif structure tend to physically interact and are functionally more similar to each other than expected. AVAILABILITY AND IMPLEMENTATION: CoMoFinder is implemented in Java and available for download at http://www.cs.utoronto.ca/~yueli/como.html. PMID- 25788623 TI - Two-group comparisons of zero-inflated intensity values: the choice of test statistic matters. AB - MOTIVATION: A special characteristic of data from molecular biology is the frequent occurrence of zero intensity values which can arise either by true absence of a compound or by a signal that is below a technical limit of detection. RESULTS: While so-called two-part tests compare mixture distributions between groups, one-part tests treat the zero-inflated distributions as left censored. The left-inflated mixture model combines these two approaches. Both types of distributional assumptions and combinations of both are considered in a simulation study to compare power and estimation of log fold change. We discuss issues of application using an example from peptidomics.The considered tests generally perform best in scenarios satisfying their respective distributional assumptions. In the absence of distributional assumptions, the two-part Wilcoxon test or the empirical likelihood ratio test is recommended. Assuming a log-normal subdistribution the left-inflated mixture model provides estimates for the proportions of the two considered types of zero intensities. AVAILABILITY: R code is available at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/ PMID- 25788624 TI - Crossfinder-assisted mapping of protein crosslinks formed by site-specifically incorporated crosslinkers. AB - Protein crosslinking has been used for decades to derive structural information about proteins and protein complexes. Only recently, however, it became possible to map the amino acids involved in the crosslinks with the advent of high resolution mass spectrometry (MS). Here, we present Crossfinder, which automates the search for crosslinks formed by site-specifically incorporated crosslinking amino acids in LC-MS-MS data. AVAILABILITY AND IMPLEMENTATION: An executable version of Crossfinder for Windows machines (64-bit) is freely available to non commercial users. It is bundled with a manual and example data. PMID- 25788625 TI - Efficient visualization of high-throughput targeted proteomics experiments: TAPIR. AB - MOTIVATION: Targeted mass spectrometry comprises a set of powerful methods to obtain accurate and consistent protein quantification in complex samples. To fully exploit these techniques, a cross-platform and open-source software stack based on standardized data exchange formats is required. RESULTS: We present TAPIR, a fast and efficient Python visualization software for chromatograms and peaks identified in targeted proteomics experiments. The input formats are open, community-driven standardized data formats (mzML for raw data storage and TraML encoding the hierarchical relationships between transitions, peptides and proteins). TAPIR is scalable to proteome-wide targeted proteomics studies (as enabled by SWATH-MS), allowing researchers to visualize high-throughput datasets. The framework integrates well with existing automated analysis pipelines and can be extended beyond targeted proteomics to other types of analyses. AVAILABILITY AND IMPLEMENTATION: TAPIR is available for all computing platforms under the 3 clause BSD license at https://github.com/msproteomicstools/msproteomicstools. PMID- 25788626 TI - Family genome browser: visualizing genomes with pedigree information. AB - MOTIVATION: Families with inherited diseases are widely used in Mendelian/complex disease studies. Owing to the advances in high-throughput sequencing technologies, family genome sequencing becomes more and more prevalent. Visualizing family genomes can greatly facilitate human genetics studies and personalized medicine. However, due to the complex genetic relationships and high similarities among genomes of consanguineous family members, family genomes are difficult to be visualized in traditional genome visualization framework. How to visualize the family genome variants and their functions with integrated pedigree information remains a critical challenge. RESULTS: We developed the Family Genome Browser (FGB) to provide comprehensive analysis and visualization for family genomes. The FGB can visualize family genomes in both individual level and variant level effectively, through integrating genome data with pedigree information. Family genome analysis, including determination of parental origin of the variants, detection of de novo mutations, identification of potential recombination events and identical-by-decent segments, etc., can be performed flexibly. Diverse annotations for the family genome variants, such as dbSNP memberships, linkage disequilibriums, genes, variant effects, potential phenotypes, etc., are illustrated as well. Moreover, the FGB can automatically search de novo mutations and compound heterozygous variants for a selected individual, and guide investigators to find high-risk genes with flexible navigation options. These features enable users to investigate and understand family genomes intuitively and systematically. AVAILABILITY AND IMPLEMENTATION: The FGB is available at http://mlg.hit.edu.cn/FGB/. PMID- 25788627 TI - Multiscale reaction-diffusion simulations with Smoldyn. AB - Smoldyn is a software package for stochastic modelling of spatial biochemical networks and intracellular systems. It was originally developed with an accurate off-lattice particle-based model at its core. This has recently been enhanced with the addition of a computationally efficient on-lattice model, which can be run stand-alone or coupled together for multiscale simulations using both models in regions where they are most required, increasing the applicability of Smoldyn to larger molecule numbers and spatial domains. Simulations can switch between models with only small additions to their configuration file, enabling users with existing Smoldyn configuration files to run the new on-lattice model with any reaction, species or surface descriptions they might already have. AVAILABILITY AND IMPLEMENTATION: Source code and binaries freely available for download at www.smoldyn.org, implemented in C/C++ and supported on Linux, Mac OSX and MS Windows. PMID- 25788628 TI - Test set bias affects reproducibility of gene signatures. AB - MOTIVATION: Prior to applying genomic predictors to clinical samples, the genomic data must be properly normalized to ensure that the test set data are comparable to the data upon which the predictor was trained. The most effective normalization methods depend on data from multiple patients. From a biomedical perspective, this implies that predictions for a single patient may change depending on which other patient samples they are normalized with. This test set bias will occur when any cross-sample normalization is used before clinical prediction. RESULTS: We demonstrate that results from existing gene signatures which rely on normalizing test data may be irreproducible when the patient population changes composition or size using a set of curated, publicly available breast cancer microarray experiments. As an alternative, we examine the use of gene signatures that rely on ranks from the data and show why signatures using rank-based features can avoid test set bias while maintaining highly accurate classification, even across platforms. AVAILABILITY AND IMPLEMENTATION: The code, data and instructions necessary to reproduce our entire analysis is available at https://github.com/prpatil/testsetbias. PMID- 25788629 TI - The Overton in Meyer-Overton: a biographical sketch commemorating the 150th anniversary of Charles Ernest Overton's birth. PMID- 25788630 TI - Anaesthetic management for laparoscopic bilateral adrenalectomy in MEN2A (Multiple endocrine neoplasia) followed by subsequent total thyroidectomy and radical neck dissection. PMID- 25788631 TI - Elevated serum concentrations of erythropoietin after xenon anaesthesia in cardiac surgery: secondary analysis of a randomized controlled trial. PMID- 25788632 TI - Usefulness of ultrasound in percutaneous tracheotomy. PMID- 25788633 TI - Chlorhexidine allergy: sources of exposure in the health-care setting. PMID- 25788634 TI - Do not resuscitate and the intensive care unit: time to talk. PMID- 25788635 TI - Difficult decisions. PMID- 25788636 TI - Need for development of face-to-face orotracheal intubation using direct (Macintosh) laryngoscopy. PMID- 25788637 TI - Robotic assistance with needle guidance. PMID- 25788638 TI - Perioperative management of severe anorexia nervosa. PMID- 25788639 TI - Are the obese difficult to intubate? PMID- 25788646 TI - Glutaredoxin 1 (Grx1) Protects Human Retinal Pigment Epithelial Cells From Oxidative Damage by Preventing AKT Glutathionylation. AB - PURPOSE: Glutaredoxin 1 (Grx1) belongs to the oxidoreductase family and is a component of the endogenous antioxidant defense system. However, its physiological function remains largely unknown. In this study, we investigated whether and how Grx1 overexpression protects the retinal pigment epithelial (RPE) cells against H2O2-induced apoptosis. METHODS: Human retinal pigment epithelial (ARPE-19) cells were transfected with either a Grx1-containing plasmid or an empty vector. Primary human RPE cells were transfected with Grx1 small interfering RNA (siRNA) or scrambled siRNA. Cell viability was measured with the WST8 assay. Apoptosis was quantitatively measured by annexin V/propidium iodide (PI) double staining. The level of protein glutathionylation (PSSG) was measured by immunoblotting using anti-PSSG antibody. Protein kinase B (AKT) activation was examined by Western blot. Protein kinase B glutathionylation was detected by immunoprecipitation followed by immunoblotting with anti-PSSG antibody. RESULTS: Glutaredoxin 1 overexpression protected ARPE-19 cells from H2O2-induced cell viability loss. Conversely, Grx1 gene knockdown sensitized primary human RPE cells to H2O2. Assessment of apoptosis indicated that cells transfected with the Grx1-containing plasmid were more resistant to H2O2 with fewer cells undergoing apoptosis as compared to empty vector-transfected cells. Hydrogen peroxide induced PSSG accumulation was also attenuated by Grx1 enrichment. Furthermore, Grx1 overexpression prevented H2O2-induced AKT glutathionylation, resulting in a sustained phospho-AKT elevation in RPE cells. CONCLUSIONS: Glutaredoxin 1 can protect RPE cells against oxidative stress-induced apoptosis. The mechanism of this protection is associated with its ability to stimulate the phosphorylation of AKT by preventing AKT glutathionylation. Considering Grx1's protective abilities in RPE cells, Grx1 could be a potential pharmacological target for retinal degenerative diseases. PMID- 25788647 TI - Lamina cribrosa configuration in tilted optic discs with different tilt axes: a new hypothesis regarding optic disc tilt and torsion. AB - PURPOSE: To determine the configuration of the anterior lamina cribrosa (LC) surface in eyes with different tilt axes. METHODS: A total of 114 eyes (66 glaucomatous eyes and 48 healthy eyes) with tilted optic discs (ovality index > 1.3) were divided into vertical- and horizontal-tilt groups according to their optic disc tilt axis. Serial horizontal B-scan images of the ONH were obtained from each eye using enhanced-depth imaging spectral-domain optical coherence tomography. After three-dimensional reconstruction of the images, the anterior LC surface depth (LCD) was measured in each of the oblique scans containing the long disc axis and in the seven horizontal B-scans that divided the anterior LC surface vertically into eight parts. RESULTS: The configuration of the anterior LC surface along the long disc axis differed markedly between groups. The vertical-tilt group had a larger LCD at superior locations than at inferior locations, while the pattern was the opposite in the horizontal-tilt group. The RNFL thinning in glaucomatous eyes was most prominent at both the superotemporal and inferotemporal sectors in the vertical-tilt group, while it was predominated at the inferotemporal sector in the horizontal-tilt group. CONCLUSIONS: The configuration of the anterior LC surface in eyes with differed optic disc tilt axis suggested that the horizontally-tilted optic discs may not be resulted from the optic disc rotation, but from the optic disc tilt centered on the oblique axis. The preferential location of RNFL thinning could be explained by the LCD profile differing according to the tilt axis. PMID- 25788648 TI - Changes in Choroidal Thickness After Panretinal Photocoagulation for Diabetic Retinopathy: A 12-Week Longitudinal Study. AB - PURPOSE: To investigate the longitudinal changes in choroidal thickness of the eyes of diabetic retinopathy patients during 12 weeks after panretinal photocoagulation (PRP). METHODS: This prospective, comparative study included 46 eyes undergoing four-session PRP. At baseline and 1, 4, 8, and 12 weeks after completion of the PRP treatments, subfoveal choroidal thickness (SFCT) was measured by using enhanced depth imaging optical coherence tomography. Also measured were central macular thickness (CMT) and best-corrected visual acuity (BCVA). RESULTS: The mean SFCT at baseline was 309 +/- 77 MUm, changing to 323 +/ 78 MUm, 315 +/- 75 MUm, 299 +/- 68 MUm, and 289 +/- 71 MUm at 1, 4, 8, and 12 weeks, respectively. This constituted a statistically significant increase at 1 week and a significant decrease at 12 weeks. The mean baseline CMT was 294 +/- 92 MUm, which increased significantly 1 week after PRP to 344 +/- 123 MUm, remaining higher at 4 weeks (340 +/- 117 MUm) and 8 weeks (318 +/- 100 MUm), but subsiding to baseline at 12 weeks (311 +/- 96 MUm). The mean BCVA at baseline and the last visit were 0.63 +/- 0.28 logMAR and 0.53 +/- 0.42 logMAR, respectively. There was no significant difference in BCVA between eyes with and without central-involved diabetic macular edema at all time points. Compared with the baseline, the mean BCVA dropped at 1 week and 4 weeks but recovered by 12 weeks. CONCLUSIONS: Choroidal thickness decreased 12 weeks after PRP, suggesting that PRP may reduce choroidal vascular permeability or cause atrophy of choroidal vessels over a 12 week period. PMID- 25788649 TI - In Vivo Imaging of Subretinal Bleb-Induced Outer Retinal Degeneration in the Rabbit. AB - PURPOSE: To analyze the morphologic effects of subretinal blebs in rabbits using real-time imaging by spectral-domain optical coherence tomography (SD-OCT), infrared-confocal scanning laser ophthalmoscopy (IR-cSLO), and blue-light fundus autofluorescence (BAF). METHODS: Subretinal blebs of PBS or balanced salt solution (BSS) were induced in albino or pigmented rabbits using a transvitreal pars plana technique. Spectral-domain optical coherence tomography, IR-cSLO, and BAF were done at multiple intervals for up to 12 weeks after subretinal bleb injection. The morphologic effects were compared with histologic analysis on hematoxylin-eosin-stained sections of the neurosensory retina and on flat-mounts of phalloidin-labeled RPE. RESULTS: Scans of SD-OCT of the normal rabbit posterior segment revealed 11 bands including six layers of the photoreceptors. Subretinal blebs of PBS or BSS caused acute swelling of the neurosensory retina followed by gradual atrophy. Outer retinal thickness was significantly reduced with pronounced degeneration of all the photoreceptor OCT layers. En face IR-cSLO showed a hyperreflective area corresponding to the progressive photoreceptor degeneration, whereas BAF revealed both hyper- and hypofluorescent changes in the RPE layer. The in vivo results were confirmed by histology and on subretinal flatmounts demonstrating extensive photoreceptor loss and disruption of the RPE mosaic. CONCLUSIONS: Subretinal blebs induce pronounced photoreceptor degeneration and RPE changes in the rabbit as demonstrated by in vivo imaging using SD-OCT, IR-cSLO, and BAF. PMID- 25788650 TI - IOP-Lowering Effect of ONO-9054, A Novel Dual Agonist of Prostanoid EP3 and FP Receptors, in Monkeys. AB - PURPOSE: The purpose of this study was to determine whether a better IOP reduction can be observed in conscious, normotensive monkeys treated with ONO 9054, a novel dual EP3 and FP receptor agonist, compared with prostaglandin F2alpha analogs. METHODS: The binding affinities and agonistic activities of ONO AG-367, a carboxylic acid of ONO-9054, to prostanoid receptors were assessed. The IOP-lowering effect of ONO-9054 in monkeys was analyzed after a single (0.3, 3, or 30 MUg/mL) or 7-day repeated (30 MUg/mL, every day) topical ocular administration. Ophthalmologic and histopathologic evaluations of the eye were performed after 4-week ocular administration of ONO-9054 (30 MUg/mL, twice a day) in monkeys. RESULTS: The ONO-AG-367 exhibited high affinity for both EP3 and FP receptors and potent agonist activity, with EC50 values of 28.6 nM for the EP3 receptor and 22.3 nM for the FP receptor. Single and repeated topical ocular administration of ONO-9054 caused IOP reductions in normotensive monkeys. The maximum IOP reductions on day 7 observed with ONO-9054 (7.3 +/- 0.8 mm Hg) were significantly greater than those observed with latanoprost (50 MUg/mL, 4.9 +/- 0.4 mm Hg) or travoprost (40 MUg/mL, 5.1 +/- 0.6 mm Hg). In ophthalmologic and histopathologic evaluations, slight and transient mydriasis was occasionally observed and no histopathologic lesions attributable to ONO-9054 were noted. CONCLUSIONS: A more profound and longer-lasting reduction in IOP in normotensive monkeys can be observed with ONO-9054, which simultaneously stimulates both EP3 and FP receptors, compared with prostaglandin analogs. PMID- 25788651 TI - Risk Factors for Age-Related Macular Degeneration in an Elderly Japanese Population: The Hatoyama Study. AB - PURPOSE: To estimate the risk factors of AMD in an elderly Japanese population from a suburban area north of metropolitan Tokyo. METHODS: The Hatoyama Cohort Study was launched in 2010, and 742 persons participated in the baseline study. Among these participants, 596 persons who attended the 2-year follow-up examinations in 2012 were evaluated, and the presence of early and late AMD was determined via grading of their fundus photographs. Based on the cohorts' data, logistic regression analyses were performed to identify the risk factors for AMD. The possible risk factors that we examined were age, sex, medical history of systemic disorders, smoking, inflammatory markers at baseline, and the complement factor H (CFH) I62V and age-related maculopathy susceptibility 2 (ARMS2) A69S variants. RESULTS: We assessed 480 participants (40.0% women) who had gradable fundus photographs. The prevalence of early AMD was 37.9% and the prevalence of late AMD was 0.6%. Mantel-Haenszel analysis revealed that the CFH I62V and ARMS2 A69S variants were significantly associated with the prevalence of AMD (P = 0.029 and 0.025, respectively). CONCLUSIONS: The CFH I62V and ARMS2 A69S variants were significantly associated with the prevalence of AMD. (www.umin.ac.jp/ctr number, UMIN000014520.). PMID- 25788652 TI - Prevalence of antiseptic-resistance genes in staphylococci isolated from orthokeratology lens and spectacle wearers in Hong Kong. AB - PURPOSE: To compare isolation of staphylococci from periorbital tissues and accessories of orthokeratology (ortho-k) lens and spectacle wearers and investigate prevalence of antiseptic-resistance (QAC) genes. To determine minimum inhibitory concentrations (MIC) of antiseptics and antibiotic susceptibility of isolates. METHODS: Staphylococci were isolated from eyelids, eyelashes, and conjunctival sacs of 23 ortho-k lens wearers and 20 spectacle wearers. Samples were also collected from ortho-k lenses, lens cases, and spectacle frames. Isolations of Staphylococcus aureus were compared between ortho-k subjects and controls for all samples and for coagulase-negative staphylococci (CNS) from conjunctival sacs. QAC genes were amplified in 110 S. aureus and 59 CNS isolates and prevalence compared in isolates from ortho-k lens and spectacle wearers. Associations were assessed between presence of QAC genes and antibiotic and antiseptic susceptibility. RESULTS: Although isolation of S. aureus did not differ significantly in periorbital samples from ortho-k and control subjects, QAC genes were significantly more common in both S. aureus and CNS from ortho-k subjects (odds ratio 4.4 and 10.74, respectively). Overall, qacA/B was the predominant gene detected, being present in 26.5% CNS and 11% S. aureus. smr and qacH were present in 12% of CNS, but were less common in S. aureus. QAC gene positive isolates had higher MICs to benzalkonium chloride and chlorhexidine digluconate. CONCLUSIONS: Our results suggest that long-term use of multipurpose solutions containing quaternary ammonium compounds may select for carriage of organisms harboring QAC genes. As these genes are associated with antibiotic resistance, their increased prevalence in isolates from contact lens wearers is a concern. PMID- 25788654 TI - Effect of Amblyopia Treatment on Macular Thickness in Eyes With Myopic Anisometropic Amblyopia. AB - PURPOSE: To determine whether abnormal macular thickness in myopic anisometropic amblyopia differed after amblyopia treatment. Furthermore, to investigate whether effect of treatment on macular thickness was associated with subject age or improvement in stereoacuity. METHODS: Seventeen children (mean age: 9.0 [+/-3.0] years, ranging from 5.7-13.9 years) with myopic anisometropic amblyopia (visual acuity [VA] in amblyopic eyes: 20/80-20/400) were recruited and treated with 16 week refractive correction, followed by an additional 16-week refractive correction and patching. Macular thickness, best-corrected VA, and stereoacuity were measured both before and after amblyopia treatment. Factorial repeated measures analysis of variance was performed to determine whether macular thickness in amblyopic eyes changed after amblyopia treatment. RESULTS: Mean baseline VA in the amblyopic eye was 1.0 +/- 0.3 logMAR and improved to 0.7 +/- 0.3 after amblyopia treatment (P < 0.0001). The interaction between eye and amblyopia treatment was statistically significant for average foveal thickness (P = 0.040). There was no treatment effect on fellow eyes (P = 0.245); however, the average foveal thickness in the amblyopic eye was significantly reduced after amblyopia treatment (P = 0.049). No statistically significant interactions were found for the other macular thickness parameters (P > 0.05). CONCLUSIONS: Abnormal central macula associated with myopic anisometropic amblyopia tended to be thinner following amblyopia treatment with no significant changes in peripheral macular thickness. PMID- 25788655 TI - Evaluation of a Portable Collision Warning Device for Patients With Peripheral Vision Loss in an Obstacle Course. AB - PURPOSE: A pocket-sized collision warning device equipped with a video camera was developed to predict impending collisions based on time to collision rather than proximity. A study was conducted in a high-density obstacle course to evaluate the effect of the device on collision avoidance in people with peripheral field loss (PFL). METHODS: The 41-meter-long loop-shaped obstacle course consisted of 46 stationary obstacles from floor to head level and oncoming pedestrians. Twenty five patients with tunnel vision (n = 13) or hemianopia (n = 12) completed four consecutive loops with and without the device, while not using any other habitual mobility aid. Walking direction and device usage order were counterbalanced. Number of collisions and preferred percentage of walking speed (PPWS) were compared within subjects. RESULTS: Collisions were reduced significantly by approximately 37% (P < 0.001) with the device (floor-level obstacles were excluded because the device was not designed for them). No patient had more collisions when using the device. Although the PPWS were also reduced with the device from 52% to 49% (P = 0.053), this did not account for the lower number of collisions, as the changes in collisions and PPWS were not correlated (P = 0.516). CONCLUSIONS: The device may help patients with a wide range of PFL avoid collisions with high-level obstacles while barely affecting their walking speed. PMID- 25788653 TI - High-Fat Diet-Induced Retinal Dysfunction. AB - PURPOSE: The purpose of this study was to investigate the impact of obesity induced prediabetes/early diabetes on the retina to provide new evidence on the pathogenesis of type 2 diabetes-associated diabetic retinopathy (DR). METHODS: A high-fat diet (HFD)-induced obesity mouse model (male C57BL/6J) was used in this study. At the end of the 12-week HFD feeding regimen, mice were evaluated for glucose and insulin tolerance, and retinal light responses were recorded by electroretinogram (ERG). Western immunoblot and immunohistochemical staining were used to determine changes in elements regulating calcium homeostasis between HFD and control retinas, as well as unstained human retinal sections from DR patients and age-appropriate controls. RESULTS: Compared to the control, the scotopic and photopic ERGs from HFD mice were decreased. There were significant decreases in molecules related to cell signaling, calcium homeostasis, and glucose metabolism from HFD retinas, including phosphorylated protein kinase B (pAKT), glucose transporter 4, L-type voltage-gated calcium channel (L-VGCC), and plasma membrane calcium ATPase (PMCA). Similar changes for pAKT, PMCA, and L-VGCC were also observed in human retinal sections from DR patients. CONCLUSIONS: Obesity-induced hyperglycemic and prediabetic/early diabetic conditions caused detrimental impacts on retinal light sensitivities and health. The decrease of the ERG components in early diabetes reflects the decreased neuronal activity of retinal light responses, which may be caused by a decrease in neuronal calcium signaling. Since PI3K-AKT is important in regulating calcium homeostasis and neural survival, maintaining proper PI3K-AKT signaling in early diabetes or at the prediabetic stage might be a new strategy for DR prevention. PMID- 25788656 TI - Repeatability of Nidek MP-1 Fixation Measurements in Patients With Bilateral Central Field Loss. AB - PURPOSE: Visual performance in patients with bilateral central field loss is related to fixation stability. This study evaluated the repeatability of visual fixation parameters in patients with bilateral central field loss, measured with the MP-1 microperimeter for fixation durations on the order of 15 to 30 seconds. METHODS: Bivariate contour ellipse area (BCEA), and the eccentricity and meridian of the preferred retinal locus (PRL) were determined in 56 eyes of 56 patients, sampled at two investigational sites. Repeatability and agreement were assessed by estimating 95% limits of agreement for each parameter from two fixation examinations conducted on the same day. RESULTS: The 95% confidence intervals (CI) for log BCEA and for PRL eccentricity and meridian were +/-0.67 log deg2, +/ 2.0 degrees , and +/-65.9 degrees , respectively. Each CI decreased substantially if a small number of outlying data points were excluded. For all parameters, the mean difference between the two fixation examinations was close to zero. CONCLUSIONS: For most patients with bilateral central field loss, the repeatability of estimated BCEA and PRL eccentricity and meridian is good. When repeated estimates of fixation parameters do not agree, the absence of a well developed PRL or the use of multiple PRLs may be suspected. PMID- 25788657 TI - Fibrinogen plasma concentration before delivery is not associated with postpartum haemorrhage: a prospective observational study. AB - BACKGROUND: Low plasma fibrinogen concentration has been linked to postpartum haemorrhage. The primary aim of this study was to assess whether fibrinogen concentration at admission before labour is associated with severe postpartum haemorrhage. Secondary aims were to describe fibrinogen concentration before and after labour and to identify predictors for severe postpartum haemorrhage. METHODS: 1951 healthy women were included in a prospective observational study. Fibrinogen concentration was determined at admission to the labour ward and in a subgroup of women (n=80) also after the placenta was delivered. Bleeding volume postpartum was estimated by weighing surgical sponges and pads and by measuring collected blood. Predictors for severe postpartum haemorrhage (>1000 ml) were identified with bivariate and multivariate regression analyses. RESULTS: Mean fibrinogen concentration was 5.3 (SD 0.8) g litre(-) (1). Median estimated blood loss was 450 (range 70-4400) ml and 250 (12.8%) women bled >1000 ml. Fibrinogen concentration was not correlated with postpartum haemorrhage in the entire cohort (r(s)=0.003, P=0.90) or in any subgroup. Fibrinogen concentration was not associated with bleeding >1000 ml (odds ratio 1.01 (CI 95% 0.85-1.19), P=0.93) and did not differ significantly before and after delivery. Oxytocin stimulation, instrumental delivery, Caesarean section and exploration of uterus were identified as independent predictors of haemorrhage >1000 ml. CONCLUSIONS: Fibrinogen plasma concentration at admission before labour does not predict severe postpartum haemorrhage in a general obstetric population. Fibrinogen concentration does not decrease significantly during normal labour. Excessive postpartum bleeding is mainly as a result of obstetric complications. PMID- 25788658 TI - Tailoring therapy to hidden primary tumors. PMID- 25788659 TI - Parsing pancreatic cancer. PMID- 25788660 TI - Generation of fully pluripotent female murine-induced pluripotent stem cells. AB - The high quality of induced pluripotent stem cells (iPSCs) has been determined to be high-grade chimeras that are competent for germline transmission, and viable mice can be generated through tetraploid complementation. Most of the high quality iPSCs described to date have been male. Female iPSCs, especially fully pluripotent female iPSCs, are also essential for clinical applications and scientific research. Here, we show, for the first time, that a gender-mixed induction strategy could lead to a skewed sex ratio of iPSCs. After reprogramming, 50%, 70%, and 90% female initiating mouse embryonic fibroblasts at different male ratios resulted in 14.1 +/- 6.8% (P < 0.05), 31.8 +/- 5.4% (P < 0.05), and 80.1 +/- 2.8% (P < 0.05) female iPSCs, respectively. Furthermore, these female iPSCs had pluripotent properties typical of embryonic stem cells. Importantly, these fully pluripotent female iPSCs could generate viable mice by tetraploid complementation. These findings indicate that high-quality female iPSCs could be derived effectively, and suggest that clinical application of female iPSCs is feasible. PMID- 25788661 TI - RBBP4 regulates histone deacetylation and bipolar spindle assembly during oocyte maturation in the mouse. AB - During meiosis I (MI) in oocytes, the maturation-associated decrease of histone acetylation is critical for normal meiotic progression and accurate chromosome segregation. RBBP4 is a component of several different histone deacetylase containing chromatin-remodeling complexes, but RBBP4's role in regulating MI is not known. Depleting RBBP4 in mouse oocytes resulted in multipolar spindles at metaphase (Met) I with subsequent perturbed meiotic progression and increased incidence of abnormal spindles, chromosome misalignment, and aneuploidy at Met II. We attribute these defects to improper deacetylation of histones because histones H3K4, H4K8, H4K12, and H4K16 were hyperacetylated in RBBP4-depleted oocytes. Importantly, we show that RBBP4-mediated histone deacetylation is essential for regulating bipolar spindle assembly, at least partially, through promoting Aurora kinase (AURK) C function. To our knowledge, these results are the first to identify RBBP4 as a regulator of histone deacetylation during oocyte maturation, and they provide evidence that deacetylation is required for bipolar spindle assembly through AURKC. PMID- 25788662 TI - Actin depolymerization is associated with meiotic acceleration in cycloheximide treated ovine oocytes. AB - Oocytes treated with the protein synthesis inhibitor cycloheximide (CHX) arrest at the germinal vesicle (GV) stage and undergo accelerated GV breakdown (GVBD) after CHX is removed. However, little is known about the underlying mechanism of accelerated meiotic maturation. Here, we investigated this mechanism and found that oocytes released from CHX arrest have higher amounts of cyclin B1 (CCNB1) and phosphorylated mitogen-activated protein kinase (pMAPK) proteins. Increased levels of these factors were not associated with mRNA polyadenylation or increased transcription rates of CCNB1 and MOS (Moloney murine sarcoma viral oncogene homolog) during CHX arrest. We found that treatment of CHX-arrested oocytes with the actin filament-stabilizing agent Jasplakinolide (Jasp) delayed GVBD following release from CHX arrest and that this was correlated with reduced maturation-promoting factor (MPF) activity. These results suggest that CCNB1 mRNAs released from actin filaments during CHX arrest increase CCNB1 transcripts available for translation after release from CHX arrest, leading to the precocious activation of MPF and accelerated meiotic progression. PMID- 25788663 TI - Integrin beta 8 (ITGB8) regulates embryo implantation potentially via controlling the activity of TGF-B1 in mice. AB - Integrins (ITGs) are mediators of cell-cell and cell-matrix interactions, which are also associated with embryo implantation processes by controlling the interaction of blastocyst with endometrium. During early pregnancy, ITGbeta8 (ITGB8) has been shown to interact with latent transforming growth factor (TGF) beta 1 (TGFB1) at the fetomaternal interface. However, the precise role of ITGB8 in the uterus and its association with embryo implantation has not been elucidated. Therefore, we attempted to ascertain the role of ITGB8 during the window of embryo implantation process by inhibiting its function or protein expression. Uterine plasma membrane-anchored ITGB8 was augmented at peri implantation and postimplantation stages. A similar pattern of mRNA expression was also found during the embryo implantation period. An immunolocalization study revealed the presence of ITGB8 on luminal epithelial cells along with mild expression on the stromal cells throughout the implantation period studied; however, an intense fluorescence was noted only during the peri- and postimplantation stages. Bioneutralization and mRNA silencing of the uterine Itgb8 at preimplantation stage reduced the rate/frequency of embryo implantation and subsequent pregnancy, suggesting its indispensable role during the embryo implantation period. ITGB8 can also regulate the liberation of active TGFB1 from its latent complex, which, in turn, acts on SMAD2/3 phosphorylation (activation) in the uterus during embryo implantation. This indicates involvement of ITGB8 in the embryo implantation process through regulation of activation of TGFB1. PMID- 25788664 TI - A novel class of interstitial cells in the mouse and monkey female reproductive tracts. AB - Growing evidence suggests important roles for specialized platelet-derived growth factor receptor alpha-positive (PDGFRalpha(+)) cells in regulating the behaviors of visceral smooth muscle organs. Examination of the female reproductive tracts of mice and monkeys showed that PDGFRalpha(+) cells form extensive networks in ovary, oviduct, and uterus. PDGFRalpha(+) cells were located in discrete locations within these organs, and their distribution and density were similar in rodents and primates. PDGFRalpha(+) cells were distinct from smooth muscle cells and interstitial cells of Cajal (ICC). This was demonstrated with immunohistochemical techniques and by performing molecular expression studies on PDGFRalpha(+) cells from mice with enhanced green fluorescent protein driven off of the endogenous promoter for Pdgfralpha. Significant differences in gene expression were found in PDGFRalpha(+) cells from ovary, oviduct, and uterus. Differences in gene expression were also detected in cells from different tissue regions within the same organ (e.g., uterine myometrium vs. endometrium). PDGFRalpha(+) cells are unlikely to provide pacemaker activity because they lack significant expression of key pacemaker genes found in ICC (Kit and Ano1). Gja1 encoding connexin 43 was expressed at relatively high levels in PDGFRalpha(+) cells (except in the ovary), suggesting these cells can form gap junctions to one another and neighboring smooth muscle cells. PDGFRalpha(+) cells also expressed the early response transcription factor and proto-oncogene Fos, particularly in the ovary. These data demonstrate extensive distribution of PDGFRalpha(+) cells throughout the female reproductive tract. These cells are a heterogeneous population of cells that are likely to contribute to different aspects of physiological regulation in the various anatomical niches they occupy. PMID- 25788665 TI - The Role of Placental 11-Beta Hydroxysteroid Dehydrogenase Type 1 and Type 2 Methylation on Gene Expression and Infant Birth Weight. AB - Maternal stress has been linked to infant birth weight outcomes, which itself may be associated with health later in life. The placenta acts as a master regulator for the fetal environment, mediating intrauterine exposures to stress through the activity of genes regulating glucocorticoids, including the 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1 and 2 genes, and so we hypothesized that variation in these genes will be associated with infant birth weight. We investigated DNA methylation levels at six sites across the two genes, as well as mRNA expression for each, and the relationship to infant birth weight. Logistic regressions correcting for potential confounding factors revealed a significant association between methylation at a single CpG site within HSD11B1 and being born large for gestational age. In addition, our analysis identified correlations between methylation and gene expression, including sex-specific transcriptional regulation of HSD11B2. Our work is one of the first comprehensive views of DNA methylation and expression in the placenta for both HSD11B types 1 and 2, linking epigenetic alterations with the regulation of fetal stress and birth weight outcomes. PMID- 25788667 TI - Dissemination does not equal public engagement. PMID- 25788666 TI - Syphilitic uveitis and optic neuritis in Sydney, Australia. AB - AIMS: To describe ocular syphilis presentations to a tertiary referral eye hospital over a 5-year period and to document HIV coinfection frequency. METHODS: A retrospective chart review was conducted of consecutive ocular syphilis presentations to Sydney Eye Hospital from 2007 to 2012. Inclusion criteria were positive syphilis serology, ocular inflammation on clinical examination and appropriate syphilis treatment. Outcome measures were clinical features at presentation and best-corrected visual acuity (BCVA) at interval follow-up. RESULTS: Thirty-seven eyes of 25 patients were included in the series. Patients were predominantly male (92.0%, p<0.05) with mean age 43.7+/-14.0 years. Eight (32.0%) patients had confirmed HIV coinfection, three newly diagnosed with HIV. Twelve (32.4%) eyes demonstrated anterior segment involvement with anterior uveitis. Twenty-five (67.6%) eyes demonstrated posterior segment involvement, including panuveitis, acute syphilitic posterior placoid chorioretinitis, retinitis, necrotising retinitis, punctate retinitis and optic neuritis. There was a significant improvement in BCVA for involved eyes (p<0.05) at 1 month and 2 3 months follow-up. CONCLUSIONS: The clinical findings of 37 eyes with ocular syphilis demonstrated a broad spectrum of clinical manifestations. Rates of HIV coinfection were high, with patients exhibiting both anterior and posterior segment inflammation. Visual outcome improved following syphilis treatment. PMID- 25788668 TI - Neural and behavioral correlates of extended training during sleep deprivation in humans: evidence for local, task-specific effects. AB - Recent work has demonstrated that behavioral manipulations targeting specific cortical areas during prolonged wakefulness lead to a region-specific homeostatic increase in theta activity (5-9 Hz), suggesting that theta waves could represent transient neuronal OFF periods (local sleep). In awake rats, the occurrence of an OFF period in a brain area relevant for behavior results in performance errors. Here we investigated the potential relationship between local sleep events and negative behavioral outcomes in humans. Volunteers participated in two prolonged wakefulness experiments (24 h), each including 12 h of practice with either a driving simulation (DS) game or a battery of tasks based on executive functions (EFs). Multiple high-density EEG recordings were obtained during each experiment, both in quiet rest conditions and during execution of two behavioral tests, a response inhibition test and a motor test, aimed at assessing changes in impulse control and visuomotor performance, respectively. In addition, fMRI examinations obtained at 12 h intervals were used to investigate changes in inter-regional connectivity. The EF experiment was associated with a reduced efficiency in impulse control, whereas DS led to a relative impairment in visuomotor control. A specific spatial and temporal correlation was observed between EEG theta waves occurring in task-related areas and deterioration of behavioral performance. The fMRI connectivity analysis indicated that performance impairment might partially depend on a breakdown in connectivity determined by a "network overload." Present results demonstrate the existence of an association between theta waves during wakefulness and performance errors and may contribute explaining behavioral impairments under conditions of sleep deprivation/restriction. PMID- 25788670 TI - The olfactory tubercle encodes odor valence in behaving mice. AB - Sensory information acquires meaning to adaptively guide behaviors. Despite odors mediating a number of vital behaviors, the components of the olfactory system responsible for assigning meaning to odors remain unclear. The olfactory tubercle (OT), a ventral striatum structure that receives monosynaptic input from the olfactory bulb, is uniquely positioned to transform odor information into behaviorally relevant neural codes. No information is available, however, on the coding of odors among OT neurons in behaving animals. In recordings from mice engaged in an odor discrimination task, we report that the firing rate of OT neurons robustly and flexibly encodes the valence of conditioned odors over identity, with rewarded odors evoking greater firing rates. This coding of rewarded odors occurs before behavioral decisions and represents subsequent behavioral responses. We predict that the OT is an essential region whereby odor valence is encoded in the mammalian brain to guide goal-directed behaviors. PMID- 25788669 TI - Temporal dynamics of L5 dendrites in medial prefrontal cortex regulate integration versus coincidence detection of afferent inputs. AB - Distinct brain regions are highly interconnected via long-range projections. How this inter-regional communication occurs depends not only upon which subsets of postsynaptic neurons receive input, but also, and equally importantly, upon what cellular subcompartments the projections target. Neocortical pyramidal neurons receive input onto their apical dendrites. However, physiological characterization of these inputs thus far has been exclusively somatocentric, leaving how the dendrites respond to spatial and temporal patterns of input unexplored. Here we used a combination of optogenetics with multisite electrode recordings to simultaneously measure dendritic and somatic responses to afferent fiber activation in two different populations of layer 5 (L5) pyramidal neurons in the rat medial prefrontal cortex (mPFC). We found that commissural inputs evoked monosynaptic responses in both intratelencephalic (IT) and pyramidal tract (PT) dendrites, whereas monosynaptic hippocampal input primarily targeted IT, but not PT, dendrites. To understand the role of dendritic integration in the processing of long-range inputs, we used dynamic clamp to simulate synaptic currents in the dendrites. IT dendrites functioned as temporal integrators that were particularly responsive to dendritic inputs within the gamma frequency range (40-140 Hz). In contrast, PT dendrites acted as coincidence detectors by responding to spatially distributed signals within a narrow time window. Thus, the PFC extracts information from different brain regions through the combination of selective dendritic targeting and the distinct dendritic physiological properties of L5 pyramidal dendrites. PMID- 25788671 TI - Regional and stage-specific effects of prospectively purified vascular cells on the adult V-SVZ neural stem cell lineage. AB - Adult neural stem cells reside in specialized niches. In the ventricular subventricular zone (V-SVZ), quiescent neural stem cells (qNSCs) become activated (aNSCs), and generate transit amplifying cells (TACs), which give rise to neuroblasts that migrate to the olfactory bulb. The vasculature is an important component of the adult neural stem cell niche, but whether vascular cells in neurogenic areas are intrinsically different from those elsewhere in the brain is unknown. Moreover, the contribution of pericytes to the neural stem cell niche has not been defined. Here, we describe a rapid FACS purification strategy to simultaneously isolate primary endothelial cells and pericytes from brain microregions of nontransgenic mice using CD31 and CD13 as surface markers. We compared the effect of purified vascular cells from a neurogenic (V-SVZ) and non neurogenic brain region (cortex) on the V-SVZ stem cell lineage in vitro. Endothelial and pericyte diffusible signals from both regions differentially promote the proliferation and neuronal differentiation of qNSCs, aNSCs, and TACs. Unexpectedly, diffusible cortical signals had the most potent effects on V-SVZ proliferation and neurogenesis, highlighting the intrinsic capacity of non neurogenic vasculature to support stem cell behavior. Finally, we identify PlGF-2 as an endothelial-derived mitogen that promotes V-SVZ cell proliferation. This purification strategy provides a platform to define the functional and molecular contribution of vascular cells to stem cell niches and other brain regions under different physiological and pathological states. PMID- 25788672 TI - Serotonergic regulation of excitability of principal cells of the dorsal cochlear nucleus. AB - The dorsal cochlear nucleus (DCN) is one of the first stations within the central auditory pathway where the basic computations underlying sound localization are initiated and heightened activity in the DCN may underlie central tinnitus. The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), is associated with many distinct behavioral or cognitive states, and serotonergic fibers are concentrated in the DCN. However, it remains unclear what is the function of this dense input. Using a combination of in vitro electrophysiology and optogenetics in mouse brain slices, we found that 5-HT directly enhances the excitability of fusiform principal cells via activation of two distinct 5-HT receptor subfamilies, 5 HT2A/2CR (5-HT2A/2C receptor) and 5-HT7R (5-HT7 receptor). This excitatory effect results from an augmentation of hyperpolarization-activated cyclic nucleotide gated channels (Ih or HCN channels). The serotonergic regulation of excitability is G-protein-dependent and involves cAMP and Src kinase signaling pathways. Moreover, optogenetic activation of serotonergic axon terminals increased excitability of fusiform cells. Our findings reveal that 5-HT exerts a potent influence on fusiform cells by altering their intrinsic properties, which may enhance the sensitivity of the DCN to sensory input. PMID- 25788673 TI - Selective activation of microglia facilitates synaptic strength. AB - Synaptic plasticity is thought to be initiated by neurons only, with the prevailing view assigning glial cells mere specify supportive functions for synaptic transmission and plasticity. We now demonstrate that glial cells can control synaptic strength independent of neuronal activity. Here we show that selective activation of microglia in the rat is sufficient to rapidly facilitate synaptic strength between primary afferent C-fibers and lamina I neurons, the first synaptic relay in the nociceptive pathway. Specifically, the activation of the CX3CR1 receptor by fractalkine induces the release of interleukin-1beta from microglia, which modulates NMDA signaling in postsynaptic neurons, leading to the release of an eicosanoid messenger, which ultimately enhances presynaptic neurotransmitter release. In contrast to the conventional view, this form of plasticity does not require enhanced neuronal activity to trigger the events leading to synaptic facilitation. Augmentation of synaptic strength in nociceptive pathways represents a cellular model of pain amplification. The present data thus suggest that, under chronic pain states, CX3CR1-mediated activation of microglia drives the facilitation of excitatory synaptic transmission in the dorsal horn, which contributes to pain hypersensitivity in chronic pain states. PMID- 25788675 TI - Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. AB - Conditioned taste aversion (CTA) is a phenomenon in which an individual forms an association between a novel tastant and toxin-induced gastrointestinal malaise. Previous studies showed that the parabrachial nucleus (PBN) contains neurons that are necessary for the acquisition of CTA, but the specific neuronal populations involved are unknown. Previously, we identified calcitonin gene-related peptide (CGRP)-expressing neurons in the external lateral subdivision of the PBN (PBel) as being sufficient to suppress appetite and necessary for the anorexigenic effects of appetite-suppressing substances including lithium chloride (LiCl), a compound often used to induce CTA. Here, we test the hypothesis that PBel CGRP neurons are sufficient and necessary for CTA acquisition in mice. We show that optogenetic activation of these neurons is sufficient to induce CTA in the absence of anorexigenic substances, whereas genetically induced silencing of these neurons attenuates acquisition of CTA upon exposure to LiCl. Together, these results demonstrate that PBel CGRP neurons mediate a gastrointestinal distress signal required to establish CTA. PMID- 25788674 TI - Peroxisome proliferator-activated receptor gamma controls ingestive behavior, agouti-related protein, and neuropeptide Y mRNA in the arcuate hypothalamus. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARgamma agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARgamma in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPARgamma antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARgamma mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad libitum fed animals; (4) whether intraperitoneally administered PPARgamma antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPARgamma modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPARgamma exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPARgamma activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARgamma-dependent process that controls ingestive behaviors. PMID- 25788676 TI - Mutations in the microtubule-associated protein 1A (Map1a) gene cause Purkinje cell degeneration. AB - The structural microtubule-associated proteins (MAPs) are critical for the organization of neuronal microtubules (MTs). Microtubule-associated protein 1A (MAP1A) is one of the most abundantly expressed MAPs in the mammalian brain. However, its in vivo function remains largely unknown. Here we describe a spontaneous mouse mutation, nm2719, which causes tremors, ataxia, and loss of cerebellar Purkinje neurons in aged homozygous mice. The nm2719 mutation disrupts the Map1a gene. We show that targeted deletion of mouse Map1a gene leads to similar neurodegenerative defects. Before neuron death, Map1a mutant Purkinje cells exhibited abnormal focal swellings of dendritic shafts and disruptions in axon initial segment (AIS) morphology. Furthermore, the MT network was reduced in the somatodendritic and AIS compartments, and both the heavy and light chains of MAP1B, another brain-enriched MAP, was aberrantly distributed in the soma and dendrites of mutant Purkinje cells. MAP1A has been reported to bind to the membrane-associated guanylate kinase (MAGUK) scaffolding proteins, as well as to MTs. Indeed, PSD-93, the MAGUK specifically enriched in Purkinje cells, was reduced in Map1a(-/-) Purkinje cells. These results demonstrate that MAP1A functions to maintain both the neuronal MT network and the level of PSD-93 in neurons of the mammalian brain. PMID- 25788677 TI - Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity. AB - Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date. PMID- 25788678 TI - Nociceptor beta II, delta, and epsilon isoforms of PKC differentially mediate paclitaxel-induced spontaneous and evoked pain. AB - As one of the most effective and frequently used chemotherapeutic agents, paclitaxel produces peripheral neuropathy (paclitaxel-induced peripheral neuropathy or PIPN) that negatively affects chemotherapy and persists after cancer therapy. The mechanisms underlying this dose-limiting side effect remain to be fully elucidated. This study aimed to investigate the role of nociceptor protein kinase C (PKC) isoforms in PIPN. Employing multiple complementary approaches, we have identified a subset of PKC isoforms, namely betaII, delta, and epsilon, were activated by paclitaxel in the isolated primary afferent sensory neurons. Persistent activation of PKCbetaII, PKCdelta, and PKCepsilon was also observed in the dorsal root ganglion neurons after chronic treatment with paclitaxel in a mouse model of PIPN. Isoform-selective inhibitors of PKCbetaII, PKCdelta, and PKCepsilon given intrathecally dose-dependently attenuated paclitaxel-induced mechanical allodynia and heat hyperalgesia. Surprisingly, spinal inhibition of PKCbetaII and PKCdelta, but not PKCepsilon, blocked the spontaneous pain induced by paclitaxel. These data suggest that a subset of nociceptor PKC isoforms differentially contribute to spontaneous and evoked pain in PIPN, although it is not clear whether PKCepsilon in other regions regulates spontaneous pain in PIPN. The findings can potentially offer new selective targets for pharmacological intervention of PIPN. PMID- 25788679 TI - Cascades and cognitive state: focused attention incurs subcritical dynamics. AB - The analysis of neuronal avalanches supports the hypothesis that the human cortex operates with critical neural dynamics. Here, we investigate the relationship between cascades of activity in electroencephalogram data, cognitive state, and reaction time in humans using a multimodal approach. We recruited 18 healthy volunteers for the acquisition of simultaneous electroencephalogram and functional magnetic resonance imaging during both rest and during a visuomotor cognitive task. We compared distributions of electroencephalogram-derived cascades to reference power laws for task and rest conditions. We then explored the large-scale spatial correspondence of these cascades in the simultaneously acquired functional magnetic resonance imaging data. Furthermore, we investigated whether individual variability in reaction times is associated with the amount of deviation from power law form. We found that while resting state cascades are associated with approximate power law form, the task state is associated with subcritical dynamics. Furthermore, we found that electroencephalogram cascades are related to blood oxygen level-dependent activation, predominantly in sensorimotor brain regions. Finally, we found that decreased reaction times during the task condition are associated with increased proximity to power law form of cascade distributions. These findings suggest that the resting state is associated with near-critical dynamics, in which a high dynamic range and a large repertoire of brain states may be advantageous. In contrast, a focused cognitive task induces subcritical dynamics, which is associated with a lower dynamic range, which in turn may reduce elements of interference affecting task performance. PMID- 25788680 TI - beta oscillations are linked to the initiation of sensory-cued movement sequences and the internal guidance of regular tapping in the monkey. AB - beta oscillations in the basal ganglia have been associated with interval timing. We recorded the putaminal local field potentials (LFPs) from monkeys performing a synchronization-continuation task (SCT) and a serial reaction-time task (RTT), where the animals produced regularly and irregularly paced tapping sequences, respectively. We compared the activation profile of beta oscillations between tasks and found transient bursts of beta activity in both the RTT and SCT. During the RTT, beta power was higher at the beginning of the task, especially when LFPs were aligned to the stimuli. During the SCT, beta was higher during the internally driven continuation phase, especially for tap-aligned LFPs. Interestingly, a set of LFPs showed an initial burst of beta at the beginning of the SCT, similar to the RTT, followed by a decrease in beta oscillations during the synchronization phase, to finally rebound during the continuation phase. The rebound during the continuation phase of the SCT suggests that the corticostriatal circuit is involved in the control of internally driven motor sequences. In turn, the transient bursts of beta activity at the beginning of both tasks suggest that the basal ganglia produce a general initiation signal that engages the motor system in different sequential behaviors. PMID- 25788682 TI - Emergence of complex wave patterns in primate cerebral cortex. AB - Slow brain rhythms are attributed to near-simultaneous (synchronous) changes in activity in neuron populations in the brain. Because they are slow and widespread, synchronous rhythms have not been considered crucial for information processing in the waking state. Here we adapted methods from turbulence physics to analyze delta-band (1-4 Hz) rhythms in local field potential (LFP) activity, in multielectrode recordings from cerebral cortex in anesthetized marmoset monkeys. We found that synchrony contributes only a small fraction (less than one fourth) to the local spatiotemporal structure of delta-band signals. Rather, delta-band activity is dominated by propagating plane waves and spatiotemporal structures, which we call complex waves. Complex waves are manifest at submillimeter spatial scales, and millisecond-range temporal scales. We show that complex waves can be characterized by their relation to phase singularities within local nerve cell networks. We validate the biological relevance of complex waves by showing that nerve cell spike rates are higher in presence of complex waves than in the presence of synchrony and that there are nonrandom patterns of evolution from one type of complex wave to another. We conclude that slow brain rhythms predominantly indicate spatiotemporally organized activity in local nerve cell circuits, not synchronous activity within and across brain regions. PMID- 25788681 TI - Long-latency reductions in gamma power predict hemodynamic changes that underlie the negative BOLD signal. AB - Studies that use prolonged periods of sensory stimulation report associations between regional reductions in neural activity and negative blood oxygenation level-dependent (BOLD) signaling. However, the neural generators of the negative BOLD response remain to be characterized. Here, we use single-impulse electrical stimulation of the whisker pad in the anesthetized rat to identify components of the neural response that are related to "negative" hemodynamic changes in the brain. Laminar multiunit activity and local field potential recordings of neural activity were performed concurrently with two-dimensional optical imaging spectroscopy measuring hemodynamic changes. Repeated measurements over multiple stimulation trials revealed significant variations in neural responses across session and animal datasets. Within this variation, we found robust long-latency decreases (300 and 2000 ms after stimulus presentation) in gamma-band power (30 80 Hz) in the middle-superficial cortical layers in regions surrounding the activated whisker barrel cortex. This reduction in gamma frequency activity was associated with corresponding decreases in the hemodynamic responses that drive the negative BOLD signal. These findings suggest a close relationship between BOLD responses and neural events that operate over time scales that outlast the initiating sensory stimulus, and provide important insights into the neurophysiological basis of negative neuroimaging signals. PMID- 25788683 TI - Anatomical identification of extracellularly recorded cells in large-scale multielectrode recordings. AB - This study combines for the first time two major approaches to understanding the function and structure of neural circuits: large-scale multielectrode recordings, and confocal imaging of labeled neurons. To achieve this end, we develop a novel approach to the central problem of anatomically identifying recorded cells, based on the electrical image: the spatiotemporal pattern of voltage deflections induced by spikes on a large-scale, high-density multielectrode array. Recordings were performed from identified ganglion cell types in the macaque retina. Anatomical images of cells in the same preparation were obtained using virally transfected fluorescent labeling or by immunolabeling after fixation. The electrical image was then used to locate recorded cell somas, axon initial segments, and axon trajectories, and these signatures were used to identify recorded cells. Comparison of anatomical and physiological measurements permitted visualization and physiological characterization of numerically dominant ganglion cell types with high efficiency in a single preparation. PMID- 25788684 TI - Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic function and plasticity and plays important roles in neuronal development, survival, and brain disorders. Despite such diverse and important roles, how BDNF, or more generally speaking, neurotrophins affect synapses, particularly nerve terminals, remains unclear. By measuring calcium currents and membrane capacitance during depolarization at a large mammalian central nerve terminal, the rat calyx of Held, we report for the first time that BDNF slows down calcium channel activation, including P/Q-type channels, and inhibits exocytosis induced by brief depolarization or single action potentials, inhibits slow and rapid endocytosis, and inhibits vesicle mobilization to the readily releasable pool. These presynaptic mechanisms may contribute to the important roles of BDNF in regulating synapses and neuronal circuits and suggest that regulation of presynaptic calcium channels, exocytosis, and endocytosis are potential mechanisms by which neurotrophins achieve diverse neuronal functions. PMID- 25788685 TI - The spiral staircase: tonotopic microstructure and cochlear tuning. AB - Although usually assumed to be smooth and continuous, mammalian cochlear frequency-position maps are predicted to manifest a staircase-like structure comprising plateaus of nearly constant characteristic frequency separated by abrupt discontinuities. The height and width of the stair steps are determined by parameters of cochlear frequency tuning and vary with location in the cochlea. The step height is approximately equal to the bandwidth of the auditory filter (critical band), and the step width matches that of the spatial excitation pattern produced by a low-level pure tone. Stepwise tonotopy is an emergent property arising from wave reflection and interference within the cochlea, the same mechanisms responsible for the microstructure of the hearing threshold. Possible relationships between the microstructure of the cochlear map and the tiered tonotopy observed in the inferior colliculus are explored. PMID- 25788686 TI - Analogous synaptic plasticity profiles emerge from disparate channel combinations. AB - An open question within the Bienenstock-Cooper-Munro theory for synaptic modification concerns the specific mechanism that is responsible for regulating the sliding modification threshold (SMT). In this conductance-based modeling study on hippocampal pyramidal neurons, we quantitatively assessed the impact of seven ion channels (R- and T-type calcium, fast sodium, delayed rectifier, A type, and small-conductance calcium-activated (SK) potassium and HCN) and two receptors (AMPAR and NMDAR) on a calcium-dependent Bienenstock-Cooper-Munro-like plasticity rule. Our analysis with R- and T-type calcium channels revealed that differences in their activation-inactivation profiles resulted in differential impacts on how they altered the SMT. Further, we found that the impact of SK channels on the SMT critically depended on the voltage dependence and kinetics of the calcium sources with which they interacted. Next, we considered interactions among all the seven channels and the two receptors through global sensitivity analysis on 11 model parameters. We constructed 20,000 models through uniform randomization of these parameters and found 360 valid models based on experimental constraints on their plasticity profiles. Analyzing these 360 models, we found that similar plasticity profiles could emerge with several nonunique parametric combinations and that parameters exhibited weak pairwise correlations. Finally, we used seven sets of virtual knock-outs on these 360 models and found that the impact of different channels on the SMT was variable and differential. These results suggest that there are several nonunique routes to regulate the SMT, and call for a systematic analysis of the variability and state dependence of the mechanisms underlying metaplasticity during behavior and pathology. PMID- 25788687 TI - Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function. AB - Angelman syndrome (AS) is a neurogenetic disorder caused by deficiency of maternally expressed ubiquitin-protein ligase E3A (UBE3A), an E3 ligase that targets specific proteins for proteasomal degradation. Although motor function impairment occurs in all patients with AS, very little research has been done to understand and treat it. The present study focuses on Ube3A deficiency-induced alterations in signaling through the mechanistic target of rapamycin (mTOR) pathway in the cerebellum of the AS mouse model and on potential therapeutic applications of rapamycin. Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in AS mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased. Correspondingly, levels of phosphorylated/active mTOR were increased. Phosphorylation of the mTORC1 substrates S6 kinase 1 (S6K1) and S6 was elevated, whereas that of the mTORC2 substrates AKT and N-myc downstream regulated 1 was decreased, suggesting enhanced mTORC1 but inhibited mTORC2 signaling. Semi chronic treatment of AS mice with rapamycin not only improved their motor performance but also normalized mTORC1 and mTORC2 signaling. Furthermore, inhibitory phosphorylation of rictor, a key regulatory/structural subunit of the mTORC2 complex, was increased in AS mice and decreased after rapamycin treatment. These results indicate that Ube3A deficiency leads to overactivation of the mTORC1-S6K1 pathway, which in turn inhibits rictor, resulting in decreased mTORC2 signaling in Purkinje neurons of AS mice. Finally, rapamycin treatment also improved dendritic spine morphology in AS mice, through inhibiting mTORC1 and possibly enhancing mTORC2-mediated regulation of synaptic cytoskeletal elements. Collectively, our results indicate that the imbalance between mTORC1 and mTORC2 activity may contribute to synaptic pathology and motor impairment in AS. PMID- 25788688 TI - Motor cortex maturation is associated with reductions in recurrent connectivity among functional subpopulations and increases in intrinsic excitability. AB - Behavior is derived from the configuration of synaptic connectivity among functionally diverse neurons. Fine motor behavior is absent at birth in most mammals but gradually emerges during subsequent postnatal corticospinal system maturation; the nature of circuit development and reorganization during this period has been largely unexplored. We investigated connectivity and synaptic signaling among functionally distinct corticospinal populations in Fischer 344 rats from postnatal day 18 through 75 using retrograde tracer injections into specific spinal cord segments associated with distinct aspects of forelimb function. Primary motor cortex slices were prepared enabling simultaneous patch clamp recordings of up to four labeled corticospinal neurons and testing of 3489 potential synaptic connections. We find that, in immature animals, local connectivity is biased toward corticospinal neurons projecting to the same spinal cord segment; this within-population connectivity significantly decreases through maturation until connection frequency is similar between neurons projecting to the same (within-population) or different (across-population) spinal segments. Concomitantly, postnatal maturation is associated with a significant reduction in synaptic efficacy over time and an increase in intrinsic neuronal excitability, altering how excitation is effectively transmitted across recurrent corticospinal networks. Collectively, the postnatal emergence of fine motor control is associated with a relative broadening of connectivity between functionally diverse cortical motor neurons and changes in synaptic properties that could enable the emergence of smaller independent networks, enabling fine motor movement. These changes in synaptic patterning and physiological function provide a basis for the increased capabilities of the mature versus developing brain. PMID- 25788689 TI - Secreted frizzled related proteins modulate pathfinding and fasciculation of mouse retina ganglion cell axons by direct and indirect mechanisms. AB - Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye-brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in which RGC axons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N cadherin, two ADAM10 substrates previously implicated in axon guidance. We thus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues. PMID- 25788690 TI - Single granule cells excite Golgi cells and evoke feedback inhibition in the cochlear nucleus. AB - In cerebellum-like circuits, synapses from thousands of granule cells converge onto principal cells. This fact, combined with theoretical considerations, has led to the concept that granule cells encode afferent input as a population and that spiking in individual granule cells is relatively unimportant. However, granule cells also provide excitatory input to Golgi cells, each of which provide inhibition to hundreds of granule cells. We investigated whether spiking in individual granule cells could recruit Golgi cells and thereby trigger widespread inhibition in slices of mouse cochlear nucleus. Using paired whole-cell patch clamp recordings, trains of action potentials at 100 Hz in single granule cells was sufficient to evoke spikes in Golgi cells in ~40% of paired granule-to-Golgi cell recordings. High-frequency spiking in single granule cells evoked IPSCs in ~5% of neighboring granule cells, indicating that bursts of activity in single granule cells can recruit feedback inhibition from Golgi cells. Moreover, IPSPs mediated by single Golgi cell action potentials paused granule cell firing, suggesting that inhibitory events recruited by activity in single granule cells were able to control granule cell firing. These results suggest a previously unappreciated relationship between population coding and bursting in single granule cells by which spiking in a small number of granule cells may have an impact on the activity of a much larger number of granule cells. PMID- 25788692 TI - Proximodistal structure of theta coordination in the dorsal hippocampus of epileptic rats. AB - Coherent neuronal activity in the hippocampal-entorhinal circuit is a critical mechanism for episodic memory function, which is typically impaired in temporal lobe epilepsy. To better understand how this mechanism is implemented and degraded in this condition, we used normal and epileptic rats to examine theta activity accompanying active exploration. Assisted by multisite recordings of local field potentials (LFPs) and layer-specific profiling of input pathways, we provide detailed quantification of the proximodistal coherence of theta activity in the dorsal hippocampus of these animals. Normal rats showed stronger coordination between the temporoammonic and perforant entorhinal inputs (measured from lamina-specific current source density signals) at proximal locations, i.e., closer to CA3; while epileptic rats exhibited stronger interactions at distal locations, i.e., closer to subiculum. This opposing trend in epileptic rats was associated with the reorganization of the temporoammonic and perforant pathways that accompany hippocampal sclerosis, the pathological hallmark of this disease. In addition to this connectivity constraint, we discovered that the appropriate timing between entorhinal inputs arriving over several theta cycles at the proximal and distal ends of the dorsal hippocampus was impaired in epileptic rats. Computational reconstruction of LFP signals predicted that restoring timing variability has a major impact on repairing theta coherence. This manipulation, when tested pharmacologically via systemic administration of group III mGluR antagonists, successfully re-established theta coordination of LFPs in epileptic rats. Thus, proximodistal organization of entorhinal inputs is instrumental in temporal lobe physiology and a candidate mechanism to study cognitive comorbidities of temporal lobe epilepsy. PMID- 25788691 TI - A trade-off between somatosensory and auditory related brain activity during object naming but not reading. AB - The parietal operculum, particularly the cytoarchitectonic area OP1 of the secondary somatosensory area (SII), is involved in somatosensory feedback. Using fMRI with 58 human subjects, we investigated task-dependent differences in SII/OP1 activity during three familiar speech production tasks: object naming, reading and repeatedly saying "1-2-3." Bilateral SII/OP1 was significantly suppressed (relative to rest) during object naming, to a lesser extent when repeatedly saying "1-2-3" and not at all during reading. These results cannot be explained by task difficulty but the contrasting difference between naming and reading illustrates how the demands on somatosensory activity change with task, even when motor output (i.e., production of object names) is matched. To investigate what determined SII/OP1 deactivation during object naming, we searched the whole brain for areas where activity increased as that in SII/OP1 decreased. This across subject covariance analysis revealed a region in the right superior temporal sulcus (STS) that lies within the auditory cortex, and is activated by auditory feedback during speech production. The tradeoff between activity in SII/OP1 and STS was not observed during reading, which showed significantly more activation than naming in both SII/OP1 and STS bilaterally. These findings suggest that, although object naming is more error prone than reading, subjects can afford to rely more or less on somatosensory or auditory feedback during naming. In contrast, fast and efficient error-free reading places more consistent demands on both types of feedback, perhaps because of the potential for increased competition between lexical and sublexical codes at the articulatory level. PMID- 25788693 TI - Importance of Reelin C-terminal region in the development and maintenance of the postnatal cerebral cortex and its regulation by specific proteolysis. AB - During brain development, Reelin exerts a variety of effects in a context dependent manner, whereas its underlying molecular mechanisms remain poorly understood. We previously showed that the C-terminal region (CTR) of Reelin is required for efficient induction of phosphorylation of Dab1, an essential adaptor protein for canonical Reelin signaling. However, the physiological significance of the Reelin CTR in vivo remains unexplored. To dissect out Reelin functions, we made a knock-in (KI) mouse in which the Reelin CTR is deleted. The amount of Dab1, an indication of canonical Reelin signaling strength, is increased in the KI mouse, indicating that the CTR is necessary for efficient induction of Dab1 phosphorylation in vivo. Formation of layer structures during embryonic development is normal in the KI mouse. Intriguingly, the marginal zone (MZ) of the cerebral cortex becomes narrower at postnatal stages because upper-layer neurons invade the MZ and their apical dendrites are misoriented and poorly branched. Furthermore, Reelin undergoes proteolytic cleavage by proprotein convertases at a site located 6 residues from the C terminus, and it was suggested that this cleavage abrogates the Reelin binding to the neuronal cell membrane. Results from ectopic expression of mutant Reelin proteins in utero suggest that the dendrite development and maintenance of the MZ require Reelin protein with an intact CTR. These results provide a novel model regarding Reelin functions involving its CTR, which is not required for neuronal migration during embryonic stages but is required for the development and maintenance of the MZ in the postnatal cerebral cortex. PMID- 25788694 TI - A chemical genetics approach for the functional assessment of novel cancer genes. AB - Assessing the functional significance of novel putative oncogenes remains a significant challenge given the limitations of current loss-of-function tools. Here, we describe a method that employs TALEN or CRISPR/Cas9-mediated knock-in of inducible degron tags (Degron-KI) that provides a versatile approach for the functional characterization of novel cancer genes and addresses many of the shortcomings of current tools. The Degron-KI system allows for highly specific, inducible, and allele-targeted inhibition of endogenous protein function, and the ability to titrate protein depletion with this system is able to better mimic pharmacologic inhibition compared with RNAi or genetic knockout approaches. The Degron-KI system was able to faithfully recapitulate the effects of pharmacologic EZH2 and PI3Kalpha inhibitors in cancer cell lines. The application of this system to the study of a poorly understood putative oncogene, SF3B1, provided the first causal link between SF3B1 hotspot mutations and splicing alterations. Surprisingly, we found that SF3B1-mutant cells are not dependent upon the mutated allele for in vitro growth, but instead depend upon the function of the remaining wild-type alleles. Collectively, these results demonstrate the broad utility of the Degron-KI system for the functional characterization of cancer genes. PMID- 25788695 TI - 26th Pezcoller symposium: cancers driven by hormones. AB - This symposium was held in Trento, Italy, on June 19-21, 2014, and was focused on advances in biology, physiology, and pathology of neoplasms affected by hormones, especially breast and prostate cancers. The stem cell function, the genetic and epigenetic interactions with hormones, the mechanisms of estrogen receptor transcription, biochemical markers and therapeutic targets in breast cancer, promotion of breast cancer carcinogenesis by progesterone, the basis for prostate cancer progression and the relevance of DNA repair processes, androgen receptor programming during prostate carcinogenesis, the metabolic stress role in tumor survival, and the diagnostic use of imaging in prostate cancer were discussed. PMID- 25788696 TI - Cell membrane fluid-mosaic structure and cancer metastasis. AB - Cancer cells are surrounded by a fluid-mosaic membrane that provides a highly dynamic structural barrier with the microenvironment, communication filter and transport, receptor and enzyme platform. This structure forms because of the physical properties of its constituents, which can move laterally and selectively within the membrane plane and associate with similar or different constituents, forming specific, functional domains. Over the years, data have accumulated on the amounts, structures, and mobilities of membrane constituents after transformation and during progression and metastasis. More recent information has shown the importance of specialized membrane domains, such as lipid rafts, protein-lipid complexes, receptor complexes, invadopodia, and other cellular structures in the malignant process. In describing the macrostructure and dynamics of plasma membranes, membrane-associated cytoskeletal structures and extracellular matrix are also important, constraining the motion of membrane components and acting as traction points for cell motility. These associations may be altered in malignant cells, and probably also in surrounding normal cells, promoting invasion and metastatic colonization. In addition, components can be released from cells as secretory molecules, enzymes, receptors, large macromolecular complexes, membrane vesicles, and exosomes that can modify the microenvironment, provide specific cross-talk, and facilitate invasion, survival, and growth of malignant cells. PMID- 25788697 TI - Biased assembly of the nuclear pore complex is required for somatic and germline nuclear differentiation in Tetrahymena. AB - Ciliates have two functionally distinct nuclei, a somatic macronucleus (MAC) and a germline micronucleus (MIC) that develop from daughter nuclei of the last postzygotic division (PZD) during the sexual process of conjugation. Understanding this nuclear dimorphism is a central issue in ciliate biology. We show, by live-cell imaging of Tetrahymena, that biased assembly of the nuclear pore complex (NPC) occurs immediately after the last PZD, which generates anterior-posterior polarized nuclei: MAC-specific NPCs assemble in anterior presumptive MACs but not in posterior presumptive MICs. MAC-specific NPC assembly in the anterior nuclei occurs much earlier than transport of Twi1p, which is required for MAC genome rearrangement. Correlative light-electron microscopy shows that addition of new nuclear envelope (NE) precursors occurs through the formation of domains of redundant NE, where the outer double membrane contains the newly assembled NPCs. Nocodazole inhibition of the second PZD results in assembly of MAC-specific NPCs in the division-failed zygotic nuclei, leading to failure of MIC differentiation. Our findings demonstrate that NPC type switching has a crucial role in the establishment of nuclear differentiation in ciliates. PMID- 25788698 TI - Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. AB - A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS. PMID- 25788699 TI - The evolution of compositionally and functionally distinct actin filaments. AB - The actin filament is astonishingly well conserved across a diverse set of eukaryotic species. It has essentially remained unchanged in the billion years that separate yeast, Arabidopsis and man. In contrast, bacterial actin-like proteins have diverged to the extreme, and many of them are not readily identified from sequence-based homology searches. Here, we present phylogenetic analyses that point to an evolutionary drive to diversify actin filament composition across kingdoms. Bacteria use a one-filament-one-function system to create distinct filament systems within a single cell. In contrast, eukaryotic actin is a universal force provider in a wide range of processes. In plants, there has been an expansion of the number of closely related actin genes, whereas in fungi and metazoa diversification in tropomyosins has increased the compositional variety in actin filament systems. Both mechanisms dictate the subset of actin-binding proteins that interact with each filament type, leading to specialization in function. In this Hypothesis, we thus propose that different mechanisms were selected in bacteria, plants and metazoa, which achieved actin filament compositional variation leading to the expansion of their functional diversity. PMID- 25788700 TI - Structural and functional characterization of a specific antidote for ticagrelor. AB - Ticagrelor is a direct-acting reversibly binding P2Y12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y12. Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 5'-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures. PMID- 25788701 TI - NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT. AB - In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft versus-host disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8(+) T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8(+) T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCT-recipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8(+) T cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8(+) T cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8(+) T cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate GVHD from GVT effects. PMID- 25788702 TI - Autophagy is required for stem cell mobilization by G-CSF. AB - Granulocyte colony-stimulating factor (G-CSF) is widely used clinically to prevent neutropenia after cytotoxic chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Autophagy, a process of cytoplasmic component recycling, maintains cellular homeostasis and protects the cell during periods of metabolic stress or nutrient deprivation. We have observed that G-CSF activates autophagy in neutrophils and HSCs from both mouse and human donors. Furthermore, G-CSF-induced neutrophil and HSC mobilization is impaired in the absence of autophagy. In contrast, autophagy is dispensable for direct HSC mobilization in response to the CXCR4 antagonist AMD3100. Altogether, these data demonstrate an important role for G-CSF in invoking autophagy within hematopoietic and myeloid cells and suggest that this pathway is critical for ensuring cell survival in response to clinically relevant cytokine-induced stress. These findings have direct relevance to HSC transplantation and the increasing clinical use of agents that modulate autophagy. PMID- 25788704 TI - The biomechanics of walking shape the use of visual information during locomotion over complex terrain. AB - The aim of this study was to examine how visual information is used to control stepping during locomotion over terrain that demands precision in the placement of the feet. More specifically, we sought to determine the point in the gait cycle at which visual information about a target is no longer needed to guide accurate foot placement. Subjects walked along a path while stepping as accurately as possible on a series of small, irregularly spaced target footholds. In various conditions, each of the targets became invisible either during the step to the target or during the step to the previous target. We found that making targets invisible after toe off of the step to the target had little to no effect on stepping accuracy. However, when targets disappeared during the step to the previous target, foot placement became less accurate and more variable. The findings suggest that visual information about a target is used prior to initiation of the step to that target but is not needed to continuously guide the foot throughout the swing phase. We propose that this style of control is rooted in the biomechanics of walking, which facilitates an energetically efficient strategy in which visual information is primarily used to initialize the mechanical state of the body leading into a ballistic movement toward the target foothold. Taken together with previous studies, the findings suggest the availability of visual information about the terrain near a particular step is most essential during the latter half of the preceding step, which constitutes a critical control phase in the bipedal gait cycle. PMID- 25788705 TI - Temporal crowding and its interplay with spatial crowding. AB - Spatial crowding refers to impaired target identification when the target is surrounded by other stimuli in space temporal crowding refers to impaired target identification when the target is surrounded by other stimuli in time previously, when spatial and temporal crowding were measured in the fovea they were interrelated with amblyopic observers but almost absent with normal observers bonneh, sagi, & polat, 2007. In the current study we examined whether reliable temporal crowding can be found for normal observers with peripheral presentation 9 degrees of eccentricity, and whether similar relations between temporal and spatial crowding will emerge to that end, we presented a sequence of three displays separated by a varying interstimulus interval (ISI). Each display included either one letter : experiments 1a ,: 1b ,: 1c or three letters separated by a varying interletter spacing: Experiments 2a ,: 2b). One of these displays included an oriented T. Observers indicated the T's orientation. As expected, we found spatial crowding: accuracy improved as the interletter spacing increased. Critically, we also found temporal crowding: in all experiments accuracy increased as the ISI increased, even when only stimulus-onset asynchronies (SOAs) larger than 150 ms were included, ensuring this effect does not reflect mere ordinary masking. Thus, with peripheral presentation, temporal crowding also emerged for normal observers. However, only a weak interaction between temporal and spatial crowding was found. PMID- 25788703 TI - IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice. AB - Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb(-/-) mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb(-/-) HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs. Although they had normal-to-elevated viability and no significant homing defects, Itpkb(-/-) HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb(-/-) mice lost hematopoietic stem and progenitor cells and died with severe anemia. WT HSC normally repopulated Itpkb(-/-) hosts, indicating an HSC-intrinsic Itpkb requirement. Itpkb(-/-) HSC showed reduced colony-forming activity and increased stem-cell-factor activation of the phosphoinositide-3-kinase (PI3K) effectors Akt/mammalian/mechanistic target of rapamycin (mTOR). This was reversed by treatment with the Itpkb product and PI3K/Akt antagonist IP4. Transcriptome changes and biochemistry support mTOR hyperactivity in Itpkb(-/-) HSC. Treatment with the mTOR-inhibitor rapamycin reversed the excessive mTOR signaling and hyperproliferation of Itpkb(-/-) HSC without rescuing colony forming activity. Thus, we propose that Itpkb ensures HSC quiescence and function through limiting cytokine-induced PI3K/mTOR signaling and other mechanisms. PMID- 25788706 TI - Acute onset incomitant image disparity modifies saccadic and vergence eye movements. AB - New-onset impairment of ocular motility will cause incomitant strabismus, i.e., a gaze-dependent ocular misalignment. This ocular misalignment will cause retinal disparity, that is, a deviation of the spatial position of an image on the retina of both eyes, which is a trigger for a vergence eye movement that results in ocular realignment. If the vergence movement fails, the eyes remain misaligned, resulting in double vision. Adaptive processes to such incomitant vergence stimuli are poorly understood. In this study, we have investigated the physiological oculomotor response of saccadic and vergence eye movements in healthy individuals after shifting gaze from a viewing position without image disparity into a field of view with increased image disparity, thus in conditions mimicking incomitance. Repetitive saccadic eye movements into a visual field with increased stimulus disparity lead to a rapid modification of the oculomotor response: (a) Saccades showed immediate disconjugacy (p < 0.001) resulting in decreased retinal image disparity at the end of a saccade. (b) Vergence kinetics improved over time (p < 0.001). This modified oculomotor response enables a more prompt restoration of ocular alignment in new-onset incomitance. PMID- 25788708 TI - Using a Virtual Environment to Study Pedestrian Behaviors: How Does Time Pressure Affect Children's and Adults' Street Crossing Behaviors? AB - OBJECTIVE: The aim of this study was to examine how crossing under time pressure influences the pedestrian behaviors of children and adults. METHODS: Using a highly immersive virtual reality system interfaced with a 3D movement measurement system, various indices of children's and adults' crossing behaviors were measured under time-pressure and no time-pressure conditions. RESULTS: Pedestrians engaged in riskier crossing behaviors on time-pressure trials as indicated by appraising traffic for a shorter period before initiating their crossing, selecting shorter more hazardous temporal gaps to cross into, and having the car come closer to them (less time to spare). There were no age or sex differences in how time pressure affected crossing behaviors. CONCLUSIONS: The current findings indicate that, at all ages, pedestrians experience greater exposure to traffic dangers when they cross under time pressure. PMID- 25788709 TI - Depressive Symptoms, Ethnic Identity, and Health-Related Quality of Life in Obese Youth. AB - OBJECTIVE: Examine relations between depressive symptoms, ethnic identity, and health-related quality of life (HRQOL) in overweight or obese (OV/OB) children. METHODS: A total of 166 OV/OB 8- to 17-year-olds (M = 12.94 years; 86.7% obese; 50.6% racial/ethnic minority) attending an outpatient pediatric obesity medical clinic participated. Children completed the Children's Depression Inventory-Short Form, Multigroup Ethnic Identity Measure (MEIM), and Pediatric Quality of Life Inventory. RESULTS: Increased depressive symptoms significantly predicted reduced total, physical, and psychosocial HRQOL. For minority OV/OB youth only, MEIM Affirmation/Belonging moderated depressive symptoms and total HRQOL (effect = 2.59, t = -2.24, p = .027; R(2) overall model = 0.315) and depressive symptoms and psychosocial HRQOL (effect = -3.01, t = -2.47, p = .015; R(2) overall model = 0.331). CONCLUSIONS: Depressive symptoms are negatively associated with HRQOL. In minority OV/OB youth, high ethnic identity may be protective when depressive symptoms are minimal. Ethnic identity and other cultural factors are important to consider in psychosocial treatments for pediatric obesity. PMID- 25788707 TI - Effect of stimulus size and luminance on the rod-, cone-, and melanopsin-mediated pupillary light reflex. AB - This study determined if the pupillary light reflex (PLR) driven by brief stimulus presentations can be accounted for by the product of stimulus luminance and area (i.e., corneal flux density, CFD) under conditions biased toward the rod, cone, and melanopsin pathways. Five visually normal subjects participated in the study. Stimuli consisted of 1-s short- and long-wavelength flashes that spanned a large range of luminance and angular subtense. The stimuli were presented in the central visual field in the dark (rod and melanopsin conditions) and against a rod-suppressing short-wavelength background (cone condition). Rod- and cone-mediated PLRs were measured at the maximum constriction after stimulus onset whereas the melanopsin-mediated PLR was measured 5-7 s after stimulus offset. The rod- and melanopsin-mediated PLRs were well accounted for by CFD, such that doubling the stimulus luminance had the same effect on the PLR as doubling the stimulus area. Melanopsin-mediated PLRs were elicited only by short wavelength, large (>16 degrees ) stimuli with luminance greater than 10 cd/m(2), but when present, the melanopsin-mediated PLR was well accounted for by CFD. In contrast, CFD could not account for the cone-mediated PLR because the PLR was approximately independent of stimulus size but strongly dependent on stimulus luminance. These findings highlight important differences in how stimulus luminance and size combine to govern the PLR elicited by brief flashes under rod , cone-, and melanopsin-mediated conditions. PMID- 25788710 TI - Arsenic, reactive oxygen, and endothelial dysfunction. AB - Human exposure to drinking water contaminated with arsenic is a serious global health concern and predisposes to cardiovascular disease states, such as hypertension, atherosclerosis, and microvascular disease. The most sensitive target of arsenic toxicity in the vasculature is the endothelium, and incubation of these cells with low concentrations of arsenite, a naturally occurring and highly toxic inorganic form of arsenic, rapidly induces reactive oxygen species (ROS) formation via activation of a specific NADPH oxidase (Nox2). Arsenite also induces ROS accumulation in vascular smooth muscle cells, but this is relatively delayed because, depending on the vessel from which they originate, these cells often lack Nox2 and/or its essential regulatory cytosolic subunits. The net effect of such activity is attenuation of endothelium-dependent conduit artery dilation via superoxide anion-mediated scavenging of nitric oxide (NO) and inhibition and downregulation of endothelial NO synthase, events that are temporally matched to the accumulation of oxidants across the vessel wall. By contrast, ROS induced by the more toxic organic trivalent arsenic metabolites (monomethylarsonous and dimethylarsinous acids) may originate from sources other than Nox2. As such, the mechanisms through which vascular oxidative stress develops in vivo under continuous exposure to all three of these potent arsenicals are unknown. This review is a comprehensive analysis of the mechanisms that mediate arsenic effects associated with Nox2 activation, ROS activity, and endothelial dysfunction, and also considers future avenues of research into what is a relatively poorly understood topic with major implications for human health. PMID- 25788711 TI - Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency. AB - Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that SRI-9804 [N-(diphenylmethyl)-2-phenyl-4 quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [(125)I]RTI-55 ([(125)I]3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester) binding and [(3)H]dopamine ([(3)H]DA) uptake, slow the dissociation rate of [(125)I]RTI-55 from the DAT, and allosterically modulate d-amphetamine induced, DAT-mediated DA release. We synthesized and evaluated the activity of >500 analogs of these ligands and report here on 36 selected compounds. Using synaptosomes prepared from rat caudate, we conducted [(3)H]DA uptake inhibition assays, DAT binding assays with [(3)H]WIN35428 ([(3)H]2beta-carbomethoxy-3beta-(4 fluorophenyl)tropane), and DAT-mediated release assays with either [(3)H]MPP(+) ([(3)H]1-methyl-4-phenylpyridinium) or [(3)H]DA. We observed three groups of [(3)H]DA uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) full efficacy agents with a two-site fit, and 3) partial-efficacy agents with a one site fit-the focus of further studies. These agents partially inhibited DA, serotonin, and norepinephrine uptake, yet were much less potent at inhibiting [(3)H]WIN35428 binding to the DAT. For example, SRI-29574 [N-(2,2-diphenylethyl) 2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine] partially inhibited DAT uptake, with an IC50 = 2.3 +/- 0.4 nM, without affecting binding to the DAT. These agents did not alter DAT-mediated release of [(3)H]MPP(+) in the absence or presence of 100 nM d-amphetamine. SRI-29574 had no significant effect on the d-amphetamine EC50 or Emax value for DAT-mediated release of [(3)H]MPP(+). These studies demonstrate the existence of potent DAT ligands that partially block [(3)H]DA uptake, without affecting DAT binding or d-amphetamine-induced [(3)H]MPP(+) release. These compounds may prove to be useful probes of biogenic amine transporter function as well as novel therapeutics. PMID- 25788712 TI - Inhibition of extracellular cyclophilins with cyclosporine analog and development of atherosclerosis in apolipoprotein E-deficient mice. AB - Cyclophilins exert both intracellular and extracellular activities related to immune responses and inflammation, which have been implicated in pathogenesis of atherosclerosis. Pan-inhibition of cyclophilins has both pro- and antiatherosclerotic properties, but specific contributions of extracellular and intracellular cyclophilins to these effects have not been characterized. Here, using selective inhibitor of extracellular cyclophilins, we investigated the role of these molecules in atherosclerosis. Apolipoprotein E-null mice fed a high-fat diet received intraperitoneal injections every second day of either vehicle or two analogs of cyclosporine A (CsA): [Melle](4)-CsA (NIM811), a nonimmunosupressive cell-permeable inhibitor of both intracellular and extracellular cyclophilins; and [(4R)-4-[(6-carboxy-1H-benzo[d]imidazol-2-yl) methyl]-4-methyl-l-threonine](1)-CsA (MM284), cell-impermeable analog only inhibiting extracellular cyclophilins. Development of atherosclerosis and composition of plaques in aorta and innominate artery were studied. Both analogs increased abundance and cross-sectional size of the atherosclerotic plaques in aorta but did not affect development of atherosclerosis in innominate artery. Neither compound affected abundance of macrophages and amount of vascular cell adhesion molecule-1 or nitrotyrosine in the plaques of both arteries. Both compounds reduced the amount of collagen in innominate artery without affecting abundance of collagen in aortic sinus. MM284, but not NIM811, significantly reduced plasma concentration of tumor necrosis factor-alpha (TNFalpha); neither compound affected plasma concentrations of interleukin (IL)-6, IL-10 or monocyte chemoattractant protein-1. Ratio between different populations of immune cells in blood or isolated from lymph nodes and spleen as well as plasma lipoprotein profile were unaffected by both compounds. In conclusion, selective inhibition of extracellular cyclophilins reduced TNFalpha levels in plasma but increased atherosclerosis. PMID- 25788714 TI - Some factors affecting rubella seronegative prevalence among pregnant women in a North West England region between April 2011 and March 2013. AB - BACKGROUND: Rubella is usually a mild viral illness, but during pregnancy, it can have potentially devastating effects causing fetal losses and severe congenital malformations (congenital rubella syndrome). Rubella is now rare in most developed countries following a successful vaccination programme. We aimed to investigate differences in epidemiological profile of pregnant women screened antenatally in Liverpool to identify risk factors for rubella immunity. METHODS: All samples were tested with the Elecsys Rubella IgG immunoassay kit. A result <10 IU/ml was considered to be seronegative. RESULTS: The seronegativity prevalence among pregnant women in Liverpool (6.3%) is higher than average value for the North West region (3.7%). The seronegative rates varied with age (15.4% for <15 years, 18.7% for 15-20 years, compared with 2% for 30-35 years). The areas with the highest seronegative rates correspond with areas of Liverpool with high pockets of socioeconomic deprivation. CONCLUSION: The highest proportion of seronegative women were among the youngest age groups. Local areas with highest level of deprivation should be given priority and additional resources to develop targeted programmes and pathways to implement appropriate interventions such as MMR catch-up programmes and put in place arrangements for offering MMR vaccination in maternity units. PMID- 25788713 TI - Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse. AB - Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse. PMID- 25788715 TI - Photo quiz: Diarrhea and fever in a child returning from Africa. Answer to photo quiz: Enteric fever. PMID- 25788716 TI - Correction for Milillo et al., Rapid and simultaneous detection of blaKPC and blaNDM by use of multiplex real-time PCR. PMID- 25788719 TI - Commentary on "Are fluoride levels in drinking water associated with hypothyroidism prevalence in England? A large observational study of GP practice data and fluoride levels in drinking water". PMID- 25788720 TI - Smoking, sex, risk factors and abdominal aortic aneurysm: is it all down to testosterone? PMID- 25788721 TI - Hydrodynamic sensing and behavior by oyster larvae in turbulence and waves. AB - Hydrodynamic signals from turbulence and waves may provide marine invertebrate larvae with behavioral cues that affect the pathways and energetic costs of larval delivery to adult habitats. Oysters (Crassostrea virginica) live in sheltered estuaries with strong turbulence and small waves, but their larvae can be transported into coastal waters with large waves. These contrasting environments have different ranges of hydrodynamic signals, because turbulence generally produces higher spatial velocity gradients, whereas waves can produce higher temporal velocity gradients. To understand how physical processes affect oyster larval behavior, transport and energetics, we exposed larvae to different combinations of turbulence and waves in flow tanks with (1) wavy turbulence, (2) a seiche and (3) rectilinear accelerations. We quantified behavioral responses of individual larvae to local instantaneous flows using two-phase, infrared particle image velocimetry. Both high dissipation rates and high wave-generated accelerations induced most larvae to swim faster upward. High dissipation rates also induced some rapid, active dives, whereas high accelerations induced only weak active dives. In both turbulence and waves, faster swimming and active diving were achieved through an increase in propulsive force and power output that would carry a high energetic cost. Swimming costs could be offset if larvae reaching surface waters had a higher probability of being transported shoreward by Stokes drift, whereas diving costs could be offset by enhanced settlement or predator avoidance. These complex behaviors suggest that larvae integrate multiple hydrodynamic signals to manage dispersal tradeoffs, spending more energy to raise the probability of successful transport to suitable locations. PMID- 25788722 TI - The descent of ant: field-measured performance of gliding ants. AB - Gliding ants avoid predatory attacks and potentially mortal consequences of dislodgement from rainforest canopy substrates by directing their aerial descent towards nearby tree trunks. The ecologically relevant measure of performance for gliding ants is the ratio of net horizontal to vertical distance traveled over the course of a gliding trajectory, or glide index. To study variation in glide index, we measured three-dimensional trajectories of Cephalotes atratus ants gliding in natural rainforest habitats. We determined that righting phase duration, glide angle, and path directness all significantly influence variation in glide index. Unsuccessful landing attempts result in the ant bouncing off its target and being forced to make a second landing attempt. Our results indicate that ants are not passive gliders and that they exert active control over the aerodynamic forces they experience during their descent, despite their apparent lack of specialized control surfaces. PMID- 25788723 TI - Conrad Waddington and the origin of epigenetics. AB - Denis Noble discusses Conrad Waddington's classic paper, "The genetic assimilation of the bithorax phenotype", published in Evolution in 1956. PMID- 25788724 TI - Insect navigation: do ants live in the now? AB - Visual navigation is a critical behaviour for many animals, and it has been particularly well studied in ants. Decades of ant navigation research have uncovered many ways in which efficient navigation can be implemented in small brains. For example, ants show us how visual information can drive navigation via procedural rather than map-like instructions. Two recent behavioural observations highlight interesting adaptive ways in which ants implement visual guidance. Firstly, it has been shown that the systematic nest searches of ants can be biased by recent experience of familiar scenes. Secondly, ants have been observed to show temporary periods of confusion when asked to repeat a route segment, even if that route segment is very familiar. Taken together, these results indicate that the navigational decisions of ants take into account their recent experiences as well as the currently perceived environment. PMID- 25788725 TI - Species-specific loss of sexual dimorphism in vocal effectors accompanies vocal simplification in African clawed frogs (Xenopus). AB - Phylogenetic studies can reveal patterns of evolutionary change, including the gain or loss of elaborate courtship traits in males. Male African clawed frogs generally produce complex and rapid courtship vocalizations, whereas female calls are simple and slow. In a few species, however, male vocalizations are also simple and slow, suggesting loss of male-typical traits. Here, we explore features of the male vocal organ that could contribute to loss in two species with simple, slow male calls. In Xenopus boumbaensis, laryngeal morphology is more robust in males than in females. Larynges are larger, have a more complex cartilaginous morphology and contain more muscle fibers. Laryngeal muscle fibers are exclusively fast-twitch in males but are both fast- and slow-twitch in females. The laryngeal electromyogram, a measure of neuromuscular synaptic strength, shows greater potentiation in males than in females. Male-specific physiological features are shared with X. laevis, as well as with a species of the sister clade, Silurana tropicalis, and thus are likely ancestral. In X. borealis, certain aspects of laryngeal morphology and physiology are sexually monomorphic rather than dimorphic. In both sexes, laryngeal muscle fibers are of mixed-twitch type, which limits the production of muscle contractions at rapid intervals. Muscle activity potentiation and discrete tension transients resemble female rather than male X. boumbaensis. The de-masculinization of these laryngeal features suggests an alteration in sensitivity to the gonadal hormones that are known to control the sexual differentiation of the larynx in other Xenopus and Silurana species. PMID- 25788726 TI - Six degree-of-freedom analysis of hip, knee, ankle and foot provides updated understanding of biomechanical work during human walking. AB - Measuring biomechanical work performed by humans and other animals is critical for understanding muscle-tendon function, joint-specific contributions and energy saving mechanisms during locomotion. Inverse dynamics is often employed to estimate joint-level contributions, and deformable body estimates can be used to study work performed by the foot. We recently discovered that these commonly used experimental estimates fail to explain whole-body energy changes observed during human walking. By re-analyzing previously published data, we found that about 25% (8 J) of total positive energy changes of/about the body's center-of-mass and >30% of the energy changes during the Push-off phase of walking were not explained by conventional joint- and segment-level work estimates, exposing a gap in our fundamental understanding of work production during gait. Here, we present a novel Energy-Accounting analysis that integrates various empirical measures of work and energy to elucidate the source of unexplained biomechanical work. We discovered that by extending conventional 3 degree-of-freedom (DOF) inverse dynamics (estimating rotational work about joints) to 6DOF (rotational and translational) analysis of the hip, knee, ankle and foot, we could fully explain the missing positive work. This revealed that Push-off work performed about the hip may be >50% greater than conventionally estimated (9.3 versus 6.0 J, P=0.0002, at 1.4 m s(-1)). Our findings demonstrate that 6DOF analysis (of hip knee-ankle-foot) better captures energy changes of the body than more conventional 3DOF estimates. These findings refine our fundamental understanding of how work is distributed within the body, which has implications for assistive technology, biomechanical simulations and potentially clinical treatment. PMID- 25788727 TI - Acoustic models of orangutan hand-assisted alarm calls. AB - Orangutans produce alarm calls called kiss-squeaks, which they sometimes modify by putting a hand in front of their mouth. Through theoretical models and observational evidence, we show that using the hand when making a kiss-squeak alters the acoustics of the production in such a way that more formants per kilohertz are produced. Our theoretical models suggest that cylindrical wave propagation is created with the use of the hand and face as they act as a cylindrical extension of the lips. The use of cylindrical wave propagation in animal calls appears to be extremely rare, but is an effective way to lengthen the acoustic system; it causes the number of resonances per kilohertz to increase. This increase is associated with larger animals, and thus using the hand in kiss-squeak production may be effective in exaggerating the size of the producer. Using the hand appears to be a culturally learned behavior, and therefore orangutans may be able to associate the acoustic effect of using the hand with potentially more effective deterrence of predators. PMID- 25788728 TI - Pregnancy limits lung function during exercise and depresses metabolic rate in the skink Tiliqua nigrolutea. AB - High gestational loads have been associated with a range of ecological costs, such as decreased locomotor ability; however, the physiological mechanisms that underpin these changes are poorly understood. In this study, breathing patterns, metabolic rates, lung volume and lung diffusing capacity were measured at rest and during exercise in the pregnant skink Tiliqua nigrolutea. Breathing patterns were largely unaffected by gestation; however, decreases in metabolic rate (rate of oxygen consumption) in the late stages of pregnancy induced a relative hyperventilation. The reductions in metabolic rate during late pregnancy prevent the calculation of the maintenance cost of pregnancy based on post-partum and neonatal metabolic rates. Despite the high relative litter mass of 38.9+/-5.3%, lung diffusing capacity was maintained during all stages of pregnancy, suggesting that alterations in diffusion at the alveolar capillary membrane were not responsible for the relative hyperventilation. Lung volume was increased during pregnancy compared with non-pregnant females, but lung volume was significantly lower during pregnancy compared with post-partum lung volume. Pregnant females were unable to produce the same metabolic and ventilatory changes induced by exercise in non-pregnant females. This lack of ability to respond to increased respiratory drive during exercise may underpin the locomotor impairment measured during gestation in previous studies. PMID- 25788729 TI - Learning context modulates aversive taste strength in honey bees. AB - The capacity of honey bees (Apis mellifera) to detect bitter substances is controversial because they ingest without reluctance different kinds of bitter solutions in the laboratory, whereas free-flying bees avoid them in visual discrimination tasks. Here, we asked whether the gustatory perception of bees changes with the behavioral context so that tastes that are less effective as negative reinforcements in a given context become more effective in a different context. We trained bees to discriminate an odorant paired with 1 mol l(-1) sucrose solution from another odorant paired with either distilled water, 3 mol l(-1) NaCl or 60 mmol l(-1) quinine. Training was either Pavlovian [olfactory conditioning of the proboscis extension reflex (PER) in harnessed bees], or mainly operant (olfactory conditioning of free-walking bees in a Y-maze). PER trained and maze-trained bees were subsequently tested both in their original context and in the alternative context. Whereas PER-trained bees transferred their choice to the Y-maze situation, Y-maze-trained bees did not respond with a PER to odors when subsequently harnessed. In both conditioning protocols, NaCl and distilled water were the strongest and the weakest aversive reinforcement, respectively. A significant variation was found for quinine, which had an intermediate aversive effect in PER conditioning but a more powerful effect in the Y-maze, similar to that of NaCl. These results thus show that the aversive strength of quinine varies with the learning context, and reveal the plasticity of the bee's gustatory system. We discuss the experimental constraints of both learning contexts and focus on stress as a key modulator of taste in the honey bee. Further explorations of bee taste are proposed to understand the physiology of taste modulation in bees. PMID- 25788730 TI - Exploiting heterogeneous environments: does photosynthetic acclimation optimize carbon gain in fluctuating light? AB - Plants have evolved complex mechanisms to balance the efficient use of absorbed light energy in photosynthesis with the capacity to use that energy in assimilation, so avoiding potential damage from excess light. This is particularly important under natural light, which can vary according to weather, solar movement and canopy movement. Photosynthetic acclimation is the means by which plants alter their leaf composition and structure over time to enhance photosynthetic efficiency and productivity. However there is no empirical or theoretical basis for understanding how leaves track historic light levels to determine acclimation status, or whether they do this accurately. We hypothesized that in fluctuating light (varying in both intensity and frequency), the light response characteristics of a leaf should adjust (dynamically acclimate) to maximize daily carbon gain. Using a framework of mathematical modelling based on light-response curves, we have analysed carbon-gain dynamics under various light patterns. The objective was to develop new tools to quantify the precision with which photosynthesis acclimates according to the environment in which plants exist and to test this tool on existing data. We found an inverse relationship between the optimal maximum photosynthetic capacity and the frequency of low to high light transitions. Using experimental data from the literature we were able to show that the observed patterns for acclimation were consistent with a strategy towards maximizing daily carbon gain. Refinement of the model will further determine the precision of acclimation. PMID- 25788732 TI - Interplay between reactive oxygen species and hormones in the control of plant development and stress tolerance. AB - As a consequence of a sessile lifestyle, plants are continuously exposed to changing environmental conditions and often life-threatening stresses caused by exposure to excessive light, extremes of temperature, limiting nutrient or water availability, and pathogen/insect attack. The flexible coordination of plant growth and development is necessary to optimize vigour and fitness in a changing environment through rapid and appropriate responses to such stresses. The concept that reactive oxygen species (ROS) are versatile signalling molecules in plants that contribute to stress acclimation is well established. This review provides an overview of our current knowledge of how ROS production and signalling are integrated with the action of auxin, brassinosteroids, gibberellins, abscisic acid, ethylene, strigolactones, salicylic acid, and jasmonic acid in the coordinate regulation of plant growth and stress tolerance. We consider the local and systemic crosstalk between ROS and hormonal signalling pathways and identify multiple points of reciprocal control, as well as providing insights into the integration nodes that involve Ca(2+)-dependent processes and mitogen-activated protein kinase phosphorylation cascades. PMID- 25788731 TI - Hijacking of the jasmonate pathway by the mycotoxin fumonisin B1 (FB1) to initiate programmed cell death in Arabidopsis is modulated by RGLG3 and RGLG4. AB - The mycotoxin fumonisin B1 (FB1) is a strong inducer of programmed cell death (PCD) in plants, but its underlying mechanism remains unclear. Here, we describe two ubiquitin ligases, RING DOMAIN LIGASE3 (RGLG3) and RGLG4, which control FB1 triggered PCD by modulating the jasmonate (JA) signalling pathway in Arabidopsis thaliana. RGLG3 and RGLG4 transcription was sensitive to FB1. Arabidopsis FB1 sensitivity was suppressed by loss of function of RGLG3 and RGLG4 and was increased by their overexpression. Thus RGLG3 and RGLG4 have coordinated and positive roles in FB1-elicited PCD. Mutated JA perception by coi1 disrupted the RGLG3- and RGLG4-related response to FB1 and interfered with their roles in cell death. Although FB1 induced JA-responsive defence genes, it repressed growth related, as well as JA biosynthesis-related, genes. Consistently, FB1 application reduced JA content in wild-type plants. Furthermore, exogenously applied salicylic acid additively suppressed JA signalling with FB1 treatment, suggesting that FB1-induced salicylic acid inhibits the JA pathway during this process. All of these effects were attenuated in rglg3 rglg4 plants. Altogether, these data suggest that the JA pathway is hijacked by the toxin FB1 to elicit PCD, which is coordinated by Arabidopsis RGLG3 and RGLG4. PMID- 25788733 TI - Winter cold-tolerance thresholds in field-grown Miscanthus hybrid rhizomes. AB - The cold tolerance of winter-dormant rhizomes was evaluated in diploid, allotriploid, and allotetraploid hybrids of Miscanthus sinensis and Miscanthus sacchariflorus grown in a field setting. Two artificial freezing protocols were tested: one lowered the temperature continuously by 1 degrees C h(-1) to the treatment temperature and another lowered the temperature in stages of 24h each to the treatment temperature. Electrolyte leakage and rhizome sprouting assays after the cold treatment assessed plant and tissue viability. Results from the continuous-cooling trial showed that Miscanthus rhizomes from all genotypes tolerated temperatures as low as -6.5 degrees C; however, the slower, staged cooling procedure enabled rhizomes from two diploid lines to survive temperatures as low as -14 degrees C. Allopolyploid genotypes showed no change in the lethal temperature threshold between the continuous and staged-cooling procedure, indicating that they have little ability to acclimate to subzero temperatures. The results demonstrated that rhizomes from diploid Miscanthus lines have superior cold tolerance that could be exploited to improve performance in more productive polyploid lines. With expected levels of soil insulation, low winter air temperatures should not harm rhizomes of tolerant diploid genotypes of Miscanthus in temperate to sub-boreal climates (up to 60 degrees N); however, the observed winter cold in sub-boreal climates could harm rhizomes of existing polyploid varieties of Miscanthus and thus reduce stand performance. PMID- 25788734 TI - Plant-mediated gene silencing restricts growth of the potato late blight pathogen Phytophthora infestans. AB - Phytophthora infestans is an oomycete that causes severe damage to potato, and is well known for its ability to evolve rapidly in order to overcome resistant potato varieties. An RNA silencing strategy was evaluated here to clarify if small interfering RNA homologous to selected genes in P. infestans could be targeted from the plant host to reduce the magnitude of the infection. As a proof of-concept, a hairpin RNA (hp-RNA) construct using the GFP marker gene was designed and introduced in potato. At 72 hpi, a 55-fold reduction of the signal intensity of a corresponding GFP expressing P. infestans strain on leaf samples of transgenic plants, compared with wild-type potato, was detected. This suggests that an RNA interference construct in the potato host could be processed and target a transcript of the pathogen. Three genes important in the infection process of P. infestans, PiGPB1, PiCESA2, and PiPEC, together with PiGAPDH taking part in basic cell maintenance were subsequently tested using an analogous transgenic strategy. Out of these gene candidates, the hp-PiGPB1 targeting the G protein beta-subunit (PiGPB1) important for pathogenicity resulted in most restricted disease progress. Further, Illumina sequencing of inoculated transgenic potato leaves revealed sRNAs of 24/25 nt size homologous to the PiGPB1 gene in the transgenic plants indicating post-transcriptional silencing of the target gene. The work demonstrates that a host-induced gene-silencing approach is functional against P. infestans but is highly dependent on target gene for a successful outcome. This finding broadens the arsenal of control strategies to this important plant disease. PMID- 25788735 TI - Dissecting the contribution of microtubule behaviour in adventitious root induction. AB - Induction of adventitious roots (ARs) in recalcitrant plants often culminates in cell division and callus formation rather than root differentiation. Evidence is provided here to suggest that microtubules (MTs) play a role in the shift from cell division to cell differentiation during AR induction. First, it was found that fewer ARs form in the temperature-sensitive mutant mor1-1, in which the MT associated protein MOR1 is mutated, and in bot1-1, in which the MT-severing protein katanin is mutated. In the two latter mutants, MT dynamics and form are perturbed. By contrast, the number of ARs increased in RIC1-OX3 plants, in which MT bundling is enhanced and katanin is activated. In addition, any1 plants in which cell walls are perturbed made more ARs than wild-type plants. MT perturbations during AR induction in mor1-1 or in wild-type hypocotyls treated with oryzalin led to the formation of amorphous clusters of cells reminiscent of callus. In these cells a specific pattern of polarized light retardation by the cell walls was lost. PIN1 polarization and auxin maxima were hampered and differentiation of the epidermis was inhibited. It is concluded that a fine-tuned crosstalk between MTs, cell walls, and auxin transport is required for proper AR induction. PMID- 25788737 TI - Global gene expression profiling of two switchgrass cultivars following inoculation with Burkholderia phytofirmans strain PsJN. AB - Improvement and year-to-year stabilization of biomass yields are primary objectives for the development of a low-input switchgrass feedstock production system using microbial endophytes. An earlier investigation of the effect of Burkholderia phytofirmans strain PsJN on switchgrass germplasm demonstrated differential responses between genotypes. PsJN inoculation of cv. Alamo (lowland ecotype) increased the plant root system, shoot length, and biomass yields, whereas it had no beneficial effect on cv. Cave-in-Rock (upland ecotype). To understand the gene networks governing plant growth promotion responses triggered by PsJN, the gene expression profiles were analysed in these two hosts, following seedling inoculation. The Affymetrix platform switchgrass expressed sequence tag (EST) microarray chip representing 122 972 probe sets, developed by the DOE BioEnergy Science Center, was employed to assess transcript abundance at 0.5, 2, 4, and 8 DAI (days after PsJN inoculation). Approximately 20 000 switchgrass probe sets showed significant responses in either cultivar. Switchgrass identifiers were used to map 19 421 genes in MapMan software. There were apparent differences in gene expression profiling between responsive and non-responsive cultivars after PsJN inoculation. Overall, there were 14 984 and 9691 genes affected by PsJN inoculation in Alamo and Cave-in-Rock, respectively. Of these, 394 are annotated as pathogenesis-related genes. In the responsive cv. Alamo, 68 pathogenesis-related genes were affected, compared with only 10 in the non responsive cv. Cave-in-Rock. At the very early stage at 0.5 DAI, both cultivars exhibited similar recognition and defence responses, such as genes in signalling and proteolysis, after which the defence reaction in the responsive cv. Alamo became weaker while it was sustained in non-responsive cv. Cave-in-Rock. PMID- 25788738 TI - Anaesthesia provider's perception of law: Focus on preventive measures. AB - Anaesthesiology is a speciality that delivers most prompt and positive results in medical field. This naturally leads to high expectations among the general public. In the past, patients used to subject themselves to surgery after signing a simple willingness form. But in the present scenario, if any catastrophe occurs, it grabs news headlines, negligence is suspected by laymen in such cases, and these cases land up in a court of law. In the courts, decisions are left to judiciary, which can be potentially influenced by the opinon of general public. This leaves a lot of subjectivity in these decisions. There has been a rising trend in medical negligence cases registered in consumer courts after the decision of the Supreme Court, that the services provided by an anaesthesiologist come under the word "service" of Consumer Protection Act (1986). So the apprehension amongst the anaesthesiologists regarding the legal issues is rising. This article underlines the standard of care, protocols by which anaesthesiologists should abide to avoid legal consequences. Doctors should have legal awareness so that they can defend their cases in courts properly. There is a need to maintain healthy doctor-patient relationship, good record keeping, and to provide a reasonable standard of care. Doctors should keep abreast with the latest development in the medical field. PMID- 25788739 TI - Comparison of equi-minimum alveolar concentration of sevoflurane and isoflurane on bispectral index values during both wash in and wash out phases: A prospective randomised study. AB - BACKGROUND AND AIMS: At equal minimum alveolar concentration (MAC), volatile agents may produce different bispectral index (BIS) values especially at low BIS levels when the effect is volatile agent specific. The present study was performed to compare the BIS values produced by sevoflurane and isoflurane at equal MAC and thereby assessing which is a better hypnotic agent. METHODS: Sixty American Society of Anaesthesiologists I and II patients undergoing elective mastoidectomy were divided into groups receiving either isoflurane or sevoflurane, and at equi-MAC. BIS value was measured during both wash in and wash out phase, keeping other parameters same. Statistical analysis was performed using the Friedman two-way analysis and Mann-Whitney U-test. A P < 0.05 was considered significant. RESULTS: BIS value was significantly lower with sevoflurane at all MAC values as compared to isoflurane, except in the beginning and at MAC awake. However, both the drugs proved to be cardiostable. CONCLUSION: At equi-MAC sevoflurane produces lower BIS values during wash in as well as wash out phase as compared to isoflurane, reflecting probably an agent specific effect and a deficiency in BIS algorithm for certain agents and their interplay. PMID- 25788736 TI - Functions for rice RFL in vegetative axillary meristem specification and outgrowth. AB - Axillary meristems (AMs) are secondary shoot meristems whose outgrowth determines plant architecture. In rice, AMs form tillers, and tillering mutants reveal an interplay between transcription factors and the phytohormones auxin and strigolactone as some factors that underpin this developmental process. Previous studies showed that knockdown of the transcription factor gene RFL reduced tillering and caused a very large decrease in panicle branching. Here, the relationship between RFL, AM initiation, and outgrowth was examined. We show that RFL promotes AM specification through its effects on LAX1 and CUC genes, as their expression was modulated on RFL knockdown, on induction of RFL:GR fusion protein, and by a repressive RFL-EAR fusion protein. Further, we report reduced expression of auxin transporter genes OsPIN1 and OsPIN3 in the culm of RFL knockdown transgenic plants. Additionally, subtle change in the spatial pattern of IR4 DR5:GFP auxin reporter was observed, which hints at compromised auxin transport on RFL knockdown. The relationship between RFL, strigolactone signalling, and bud outgrowth was studied by transcript analyses and by the tillering phenotype of transgenic plants knocked down for both RFL and D3. These data suggest indirect RFL-strigolactone links that may affect tillering. Further, we show expression modulation of the auxin transporter gene OsPIN3 upon RFL:GR protein induction and by the repressive RFL-EAR protein. These modified forms of RFL had only indirect effects on OsPIN1. Together, we have found that RFL regulates the LAX1 and CUC genes during AM specification, and positively influences the outgrowth of AMs though its effects on auxin transport. PMID- 25788740 TI - Use of Microcuff((r)) endotracheal tubes in paediatric laparoscopic surgeries. AB - BACKGROUND AND AIMS: Traditionally, uncuffed endotracheal tubes have been used in children. Cuffed tubes may be useful in special situations like laparoscopy. Microcuff((r)) endotracheal tube is a specifically designed cuffed endotracheal tube for the paediatric airway. We studied the appropriateness of Microcuff((r)) tube size selection, efficacy of ventilation, and complications, in children undergoing laparoscopy. METHODS: In a prospective, observational study, 100 children undergoing elective laparoscopy were intubated with Microcuff((r)) tube as per recommended size. We studied appropriateness of size selection, sealing pressure, ability to ventilate with low flow, quality of capnography and post extubation laryngospasm or stridor. RESULTS: Mean age of the patients was 5.44 years (range 8 months 5 days-9 years 11 months). There was no resistance for tube passage during intubation in any patient. Leak on intermittent positive pressure ventilation at airway pressure <=20 cm H2O was present in all patients. Mean sealing pressure was 11.72 (1.9 standard deviation [SD]) cm H2 O. With the creation of pnemoperitoneum, mean intracuff pressure increased to 12.48 (3.12 SD) cm H2 O. With head low positioning, mean cuff pressure recorded was 13.32 (2.92 SD). Ventilation at low flow (mean flow 1 L/min), plateau-type capnography was noted in all patients. Mean duration of intubation was 83.50 min. Coughing at extubation occurred in 6 patients. Partial laryngospasm occurred in 4 patients, which responded to continuous positive airway pressure via face mask. Severe laryngospasm or stridor was not seen in any patient. CONCLUSION: Microcuff((r)) tubes can be safely used in children if size selection recommendations are followed and cuff pressure is strictly monitored. Advantages are better airway seal and effective ventilation, permitting use of low flows. PMID- 25788741 TI - Effect of perineural dexmedetomidine on the quality of supraclavicular brachial plexus block with 0.5% ropivacaine and its interaction with general anaesthesia. AB - BACKGROUND AND AIMS: The effect of perineural dexmedetomidine on the time to onset, quality and duration of motor block with ropivacaine has been equivocal and its interaction with general anaesthesia (GA) has not been reported. We assessed the influence of dexmedetomidine added to 0.5% ropivacaine on the characteristics of supraclavicular brachial plexus block and its interaction with GA. METHODS: In a randomised, double blind study, 36 patients scheduled for orthopaedic surgery on the upper limb under supraclavicular block and GA were divided into either R group (35 ml of 0.5% ropivacaine with 0.5 ml of normal saline [n - 18]) or RD group (35 mL of 0.5% ropivacaine with 50 MUg dexmedetomidine [n - 18]). The onset time and duration of motor and sensory blockade were noted. The requirement of general anaesthetics was recorded. RESULTS: Both the groups were comparable in demographic characteristics. The time of onset of sensory block was not significantly different. The proportion of patients who achieved complete motor blockade was more in the RD group. The onset of motor block was earlier in group RD than group R (P < 0.05). The durations of analgesia, sensory and motor blockade were significantly prolonged in group RD (P < 0.00). The requirement of entropy guided anaesthetic agents was not different in both groups. CONCLUSIONS: The addition of dexmedetomidine to 0.5% ropivacaine improved the time of onset, quality and duration of supraclavicular brachial plexus block but did not decrease the requirement of anaesthetic agents during GA. PMID- 25788742 TI - Cuff leak test and laryngeal survey for predicting post-extubation stridor. AB - BACKGROUND AND AIMS: Evidence for the predictive value of the cuff leak test (CLT) for post-extubation stridor (PES) is conflicting. We evaluated the association and accuracy of CLT alone or combined with other laryngeal parameters with PES. METHODS: Fifty-one mechanically ventilated adult patients in a medical surgical intensive care unit were tested prior to extubation using; CLT, laryngeal ultrasound and indirect laryngoscopy. Biometric, laryngeal and endotracheal tube (ETT) parameters were recorded. RESULTS: PES incidence was 4%. CLT demonstrated 'no leak' in 20% of patients. Laryngeal oedema was present in 10% of the patients on indirect laryngoscopy, and 71% of the patients had a Grades 1-3 indirect laryngoscopic view. Mean air column width on laryngeal ultrasound was 0.66 +/- 0.15 cm (cuff deflated), mean ratio of ETT to laryngeal diameter was 0.48 +/- 0.07, and the calculated CLT and laryngeal survey composite was 0.86 +/- 1.25 (range 0-5). CLT and the CLT and Laryngeal survey composite measure were not associated with or predict PES. Age, sex, peri-extubation steroid use, intubation duration and body mass index were not associated with PES. CONCLUSION: Even including ultrasonographic and indirect laryngoscopic examination of the airway, no single aspect of the CLT or combination with laryngeal parameters accurately predicts PES. PMID- 25788743 TI - Survey of anaesthesiologists' reactions to implementation of laws related to anaesthesia practice. AB - BACKGROUND AND AIMS: The anaesthesiologists' understanding and knowledge of law has an important bearing on issues, related to anaesthesia practice. Lack of such knowledge could also lead to misperceptions affecting both patient care and professional practices. The aim of the study was to find out exact nature of apprehension of the anaesthesia providers towards the implementation of the law related to anaesthesia practice. METHODS: A prospective survey of 875 anaesthesia specialists was conducted during informal meetings personally by the investigator and the responses to a standard set of queries were noted. Also included were the remarks and suggestions related to each query. Three different set of practitioners depending on the place of work (teaching hospital, corporate hospital and small establishments) were queried. RESULTS: The opinions of all three groups of anaesthesiologists did not differ materially. The opinions and views were similar in many aspects and controversy existed in few areas. Major confusion was about how much information should be provided to patients before anaesthesia to obtain informed consent. Opinions were offered for prevention of litigations and how to face litigations but there was the lack of clarity on these issues. CONCLUSIONS: The anaesthesiologists are invariably confused about how exactly they should prevent litigations or respond to them. The majority expressed need for intervention by Indian Society of Anaesthesiologists (ISA) to prepare protocols and set up medico-legal cells. PMID- 25788744 TI - Awareness about scope of anaesthesiology, attitudes towards the speciality and stress levels amongst postgraduate students in anaesthesiology: A cross-sectional study. AB - Trends in selection of a career in medicine vary from country to country. To plan future recruitment strategies and to balance distribution of physicians among medical specialties, each country needs to examine these reasons as part of educational research. The aim of this study was to explore the Anaesthesiology postgraduate students' knowledge about anaesthesia as a speciality, their attitude towards anaesthesia as a career choice, stress levels during the period of postgraduation, views regarding Diploma in Anaesthesiology and undergraduate exposure to the subject. Eight hundred pretested questionnaires were provided to the anaesthesia postgraduate students attending various national level conferences in India. The collected data were statistically analysed using SPSS version 20. Only 31.6% of the students were aware of scope of anaesthesiology and 42.3% of students joined the speciality out of the interest to learn the subject, whereas 55.7% joined for other reasons, including non-availability of other specialties during medical postgraduate counselling. About 70% of students were stressed out during postgraduation, 31.6% found difficulty in accommodating the demands of challenging job and 3.8% went into depression. Majority of anaesthesiology postgraduate students were unaware of the scope of Anaesthesiology at the time of medical postgraduate counselling; only two-fifth of the students joined the speciality out of interest to learn the subject and most of them felt stressed out during the period of postgraduation. Majority of the students were of the opinion that Diploma in Anaesthesia was not a viable career option and should be scrapped. PMID- 25788745 TI - Ultrasound-guided rectus sheath catheters: A feasible and effective, opioid sparing, post-operative pain management technique: A case series. AB - Epidural analgesia, though the gold standard of post-operative pain management for laparotomies, is associated with limitations and is contraindicated in many patients. Opioid-based pain management, which is an alternative to epidural, has been implicated in post-operative nausea, vomiting, and ileus. We report successful management of post operative pain with ultrasound guided rectus sheath (RS) catheters. RS block is a promising alternative in scenarios were epidural is contraindicated, has failed or in case of unexpected change in the surgical plan. PMID- 25788746 TI - Anaesthetic considerations in an infant with Beckwith-Weidemann syndrome and hepatoblastoma for partial hepatectomy. PMID- 25788747 TI - Seizures following accidental intravascular injection of ropivacaine through epidural catheter. PMID- 25788748 TI - Anaesthesia and Ascaris pneumonia (Loeffler's syndrome). PMID- 25788749 TI - Spontaneous pneumothorax in the immediate post-operative hour in a primigravida following emergency caesarean section under spinal anaesthesia. PMID- 25788750 TI - Foregut reduplication cyst: Anaesthetic implications of the rare anomaly. PMID- 25788751 TI - Converting a nasoendotracheal tube to orotracheal, following fibreoptic intubation under general anaesthesia in a paediatric patient with complete cleft palate. PMID- 25788752 TI - i-gel insertion with modified jaw thrust technique. PMID- 25788753 TI - No rent is small for migration of epidural catheter into sub-arachnoid space. PMID- 25788754 TI - Povidone-iodine toxicity in a child posted for laparoscopic removal of hepatic and renal hydatid cysts. PMID- 25788755 TI - Anaesthesia for repair of anomalous origin of left coronary artery from pulmonary artery. PMID- 25788756 TI - Off pump coronary artery bypass grafting in a patient with cerebrovascular disease. PMID- 25788757 TI - Neighborhood Disadvantage, Preconception Health Behaviors and Infant Birthweight: A Preliminary Study. AB - Prior studies have shown that neighborhood disadvantage and disorder are associated with birth outcomes. This study examined preconception diet and physical activity level, as well as body mass index, as mediators of the association between neighborhood conditions and birthweight. Secondary data analyses were conducted using data from the National Longitudinal Study of Adolescent Health (Add Health). The final analytic sample consisted of 523 adolescent and young adult mothers giving singleton live births between 1997 and 1998. In contrast to previous research, we found that neighborhood characteristics were unrelated to birthweight. Consistent with prior studies, compared to those who were White, on average, Blacks had birthweights that were 163.25 grams lighter. In addition, compared to mothers who were married or living with a partner, mothers who did not have a partner at the time of birth, on average, had offspring that were 127.20 grams lighter. No evidence was found for the mediation hypotheses as there were no associations between neighborhood characteristics and preconception diet or physical activity or between these behavioral variables and birthweight. To the authors' knowledge, this is the first study examining diet and physical activity as possible behavioral pathways between the neighborhood context and birthweight. PMID- 25788759 TI - Comment on "Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio: novel markers for diagnosis and prognosis in patients with idiopathic sudden sensorineural hearing loss". PMID- 25788758 TI - The -844 G>A PAI-1 polymorphism is associated with acute coronary syndrome in Mexican population. AB - BACKGROUND: Acute coronary syndrome (ACS) has an important impact in public health with high morbidity and mortality. Prothrombotic and proinflammatory states are involved in the pathogenesis of the disease. Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of the fibrinolysis and also is part of immune response. The -844 G>A gene polymorphism is related to increased PAI-1 protein levels. The aim of the study is to evaluate the association of -844 G>A PAI-1 polymorphism with ACS. METHODS: A total of 646 individuals were recruited from Western Mexico: 350 unrelated healthy subjects and 296 patients with diagnosis of ACS. RESULTS: The most important risk factor in our population was hypertension, followed by smoking. The genetic distribution showed an association of the A allele (OR = 1.27, P = 0.04) and AA genotype (OR = 1.86, P = 0.02) with ACS. The recessive model displayed similar results (OR = 1.76, P = 0.02). As additional finding, we observed significant differences in the genetic distribution of ACS dyslipidemic patients (OR = 1.99, P = 0.04). The A allele and AA genotype of -844 polymorphism of PAI-1 gene are risk factors for ACS. The AA genotype might be associated with the development of dyslipidemia in ACS patients. PMID- 25788760 TI - The impact of changed strategies for patients with cholangiocarcinoma in this millenium. AB - Background. Cholangiocarcinoma is a cancer with a poor prognosis. In this millennium there are new diagnostic and therapeutic strategies for these patients. Aim. The aim of this study was to find if these changes influenced survival of individuals with proximal cholangiocarcinoma. Material. 627 individuals with a diagnosis of cholangiocarcinoma (not including distal common duct cancer) during the period from 2000 to 2011 were registered in Sweden's Western Region. The material was divided into three consecutive time periods. Results. The overall survival curves for individuals with cholangiocarcinoma improved over the three time periods (n = 627) (P = 0.0013). Median survival increased from 2.6 months in the first period (2000-2003) to 3.6 months in the final four years (2008-2011). Patients with perihilar cholangiocarcinoma (PHC) had longer median survival than those with intrahepatic cholangiocarcinoma (IHC): 6.8 versus 3.2 months (P = 0.0003). An improvement in the survival curves over time was seen for those with IHC (P = 0.034) but not for patients with PHC (P = 0.38). Nine percent of the patients with IHC had potential curative surgical therapy. The three-year survival rate after liver resection for patients with IHC was 35% and 60% after liver transplantation. Among patients with PHC, 15.3% had potential curative bile duct resection with a concomitant liver resection and 6.1% bile duct resection alone. The three-year survival rate for these two groups was 32% and 20%, respectively. Conclusion. Overall survival for individuals with PHC was better than for those with IHC. Over time survival in IHC patients improved but not in those with PHC. PMID- 25788761 TI - Presence of fatty liver and the relationship between alcohol consumption and markers of inflammation. AB - Background and Aims. Local and systemic inflammation represent a major feature of atherosclerotic cardiovascular disease (CVD) and are also linked to nonalcoholic fatty liver disease (NAFLD). Studies indicate that NAFLD might be a risk factor for CVD whereas low-to-moderate alcohol consumption is associated with lower cardiovascular morbidity and mortality compared to abstainers and heavy drinkers. We hypothesize that FLD interacts with the effect of alcohol intake on markers of inflammation, and thus potentially on cardiovascular risk. Methods and Results. We evaluated alcohol consumption, markers of inflammation and sonographic criteria of FLD in 515 subjects, representing a subsample of a cross-sectional population based study (Echinococcus multilocularis and Internal Diseases in Leutkirch (EMIL) Study). Presence of FLD was markedly reduced in subjects drinking 0-20 g alcohol/d (19%), compared to nondrinkers (35%) and heavy drinkers (34-44.9%). Serum concentrations of inflammatory markers were substantially higher in subjects with FLD. However, presence of FLD showed no effect on the association between alcohol consumption and inflammatory biomarkers. Conclusions. Based on data from a population-based sample, there is no evidence for a link between FLD, alcohol consumption, and inflammatory cardiovascular risk markers. However, larger prospective studies are needed to confirm this. PMID- 25788763 TI - Altered viral replication and cell responses by inserting microRNA recognition element into PB1 in pandemic influenza A virus (H1N1) 2009. AB - Objective. MicroRNAs (miRNAs) are endogenous noncoding RNAs that spatiotemporally modulate mRNAs in a posttranscriptional manner. Engineering mutant viruses by inserting cell-specific miRNA recognition element (MRE) into viral genome may alter viral infectivity and host responses in vital tissues and organs infected with pandemic influenza A virus (H1N1) 2009 (H1N1pdm). Methods. In this study, we employed reverse genetics approach to generate a recombinant H1N1pdm with a cell specific miRNA target sequence inserted into its PB1 genomic segment to investigate whether miRNAs are able to suppress H1N1pdm replication. We inserted an MRE of microRNA-let-7b (miR-let-7b) into the open reading frame of PB1 to test the feasibility of creating a cell-restricted H1N1pdm virus since let-7b is abundant in human bronchial epithelial cells. Results. miR-let-7b is rich in human bronchial epithelial cells (HBE). Incorporation of the miR-let-7b-MRE confers upon the recombinant H1N1pdm virus susceptibility to miR-let-7b targeting, suggesting that the H1N1pdm and influenza A viruses can be engineered to exert the desired replication restrictive effect and decrease infectivity in vital tissues and organs. Conclusions. This approach provides an additional layer of biosafety and thus has great potential for the application in the rational development of safer and more effective influenza viral vaccines. PMID- 25788764 TI - Responsibility and accountability. PMID- 25788762 TI - Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease. AB - The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1beta. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease. PMID- 25788765 TI - Vistas for the future. PMID- 25788766 TI - Postoperative pain management in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) is a health care problem with increasing prevalence worldwide. Pain management represents one of the challenges in providing perioperative care for this group of patients. Physicians from different specialties may be involved in pain management of CKD patients, especially in advanced stages. It is important to understand the clinical staging of kidney function in CKD patients as the pharmacotherapeutic pain management strategies change as kidney function becomes progressively impaired. Special emphasis should be placed on dose adjustment of certain analgesics as well as prevention of further deterioration of renal function that could be induced by certain classes of analgesics. Chronic pain is a common finding in CKD patients which may be caused by the primary disease that led to kidney damage or can be a direct result of CKD and hemodialysis. The presence of chronic pain in some of the CKD patients makes postoperative pain management in these patients more challenging. This review focuses on the plans and challenges of postoperative pain management for patient at different stages of CKD undergoing surgical intervention to provide optimum pain control for this patient population. Further clinical studies are required to address the optimal medication regimen for postoperative pain management in the different stages of CKD. PMID- 25788768 TI - Retroperitoneal versus transperitoneal approach for nephrectomy in children: Anesthetic implications. PMID- 25788767 TI - Technological advances in perioperative monitoring: Current concepts and clinical perspectives. AB - Minimal mandatory monitoring in the perioperative period recommended by Association of Anesthetists of Great Britain and Ireland and American Society of Anesthesiologists are universally acknowledged and has become an integral part of the anesthesia practice. The technologies in perioperative monitoring have advanced, and the availability and clinical applications have multiplied exponentially. Newer monitoring techniques include depth of anesthesia monitoring, goal-directed fluid therapy, transesophageal echocardiography, advanced neurological monitoring, improved alarm system and technological advancement in objective pain assessment. Various factors that need to be considered with the use of improved monitoring techniques are their validation data, patient outcome, safety profile, cost-effectiveness, awareness of the possible adverse events, knowledge of technical principle and ability of the convenient routine handling. In this review, we will discuss the new monitoring techniques in anesthesia, their advantages, deficiencies, limitations, their comparison to the conventional methods and their effect on patient outcome, if any. PMID- 25788769 TI - Monitored anesthesia care: An overview. PMID- 25788770 TI - Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study. AB - BACKGROUND & AIMS: Postoperative cognitive dysfunction (POCD) is a decline in cognitive function that occurs after surgery. The purpose of this study was to estimate the incidence and identify potential risk factors of POCD in older adults undergoing major noncardiac surgery. MATERIALS AND METHODS: A total of 69 patients aged 65 years or older undergoing major noncardiac surgery were enrolled. Patients' cognitive function was assessed before and 3 months after surgery using a computerized neurocognitive battery. A nonsurgical control group of 54 older adults was recruited to adjust for learning effects from repeated administration of neurocognitive tests. Data about potential risk factors for POCD were collected before, during, and after surgery, including patient, medication, and surgery factors. The incidence of POCD was calculated using the Z score method. A multivariable logistic regression model was used to identify risk factors for POCD. RESULTS: POCD was present in eleven patients (15.9%, 95% confidence interval [CI] = 7.3-24.6) 3 months after major noncardiac surgery. Carrying the apolipoprotein E4 (APOE4) genotype (odds ratio [OR] = 4.74, 95% CI = 1.09-22.19), using one or more highly anticholinergic or sedative-hypnotic drugs at home prior to surgery (OR = 5.64, 95% CI = 1.35-30.22), and receiving sevoflurane for anesthesia (OR = 6.43, 95% CI = 1.49-34.66) were associated with the development of POCD. CONCLUSIONS: POCD was observed in 15.9% of older adults after major noncardiac surgery. Risk factors for POCD in these patients were carrying the APOE4 genotype, using one or more highly anticholinergic or sedative hypnotic drugs prior to surgery, and receiving sevoflurane for anesthesia. PMID- 25788772 TI - Can cystatin C become an easy and reliable tool for anesthesiologists to calculate glomerular filtration rate? AB - BACKGROUND AND AIMS: The aim was to evaluate the role of cystatin C as a noninvasive and easy marker of glomerular filtration rate (GFR) estimation in voluntary kidney donors. MATERIALS AND METHODS: We retrospectively evaluated 40 voluntary kidney donors. They underwent complete biochemical and nuclear tests as a part of transplant workup. Serum cystatin C, serum creatinine, and Tc-99m diethylene-triamine-penta-acetic acid (DTPA) were used in our study. We calculated GFR using the chronic kidney disease epidemiology collaboration (CKD EPI) formula based on creatinine only (GFR-CKD-EPI-creat), CKD-EPI formula using creatinine and cystatin C (GFR-CKD-EPI-cyst-creat), and modification of diet in renal disease (MDRD) and CKD-EPI cystatin C equation (2012) (GFR-cyst). Data was evaluated using the SPSS software (version 11.5). The correlation analysis and analysis of variance was used for statistical computation. Agreement was determined using analyze-it version 2.30 for MS-Excel 12+. RESULTS: The mean age of the donors in our study was 49.83 +/- 13.06. The mean cystatin C in females was 0.72 +/- 0.12, the mean cystain C in males was 0.87 +/- 0.23. On correlating GFR-cyst with GFR-DTPA the Pearson correlation coefficient (rho) was found to be 0.388 this correlation was significant with P < 0.05. While comparing with DTPA the correlation coefficient of GFR-CKD-EPI-creat group was 0.587 which was significant with P < 0.01. The correlation coefficient of GFR-CKD-EPI-cyst-creat group compared with GFR-DTPA group was 0.543 which was also significant at P < 0.001. GFR-CKD-EPI-creat gave the highest correlation with DTPA in our study. The correlation coefficient of GFR-MDRD group with DTPA group was 0.576 this correlation was also significant with P < 0.01. The results obtained were further statistically analyzed by Bland-Altman analysis the percentage error for GFR-DTPA versus GFR-cyst-creat is 29.72%; for GFR-DTPA versus GFR-EPI-creat is 30.73%; or GFR-DTPA versus MDRD is 31.63% and for GFR-DTPA versus GFR-cyst is 34.37%. CONCLUSION: Cystatin C is a good endogenous marker for calculating GFR as it correlates very well with DTPA and CKD-EPI equation based GFR. PMID- 25788771 TI - A comparative study between oral melatonin and oral midazolam on preoperative anxiety, cognitive, and psychomotor functions. AB - BACKGROUND & AIMS: Melatonin, a naturally occurring hormone in the human body, has been reported to cause preoperative anxiolysis and sedation without impairing orientation. The aim of the following study was to evaluate and to compare the effects of oral melatonin and oral midazolam on preoperative anxiety, sedation, psychomotor, and cognitive function. MATERIALS AND METHODS: A study conducted on 120 patients aged 16-55 years, of American Society of Anesthesiologists Grade 1 and 2 posted for elective surgery, with each group of melatonin, midazolam, and placebo comprising 40 patients. Patients were given either 0.4 mg/kg oral melatonin or 0.2 mg/kg oral midazolam or a placebo 60-90 min before induction. Preoperative anxiety was studied before and 60-90 min after giving medications using visual analog scale (VAS) anxiety score, orientation score, and sedation score. Psychomotor and cognitive functions were studied using the digit symbol substitution test (DSST) and trail making test (TMT) tests. Data were analyzed using Chi-square test or Kruskal-Wallis analysis of variance and the value of P < 0.05 was considered as statistically significant. RESULTS: Changes in VAS anxiety scores were significant when melatonin was compared with placebo (P = 0.0124) and when midazolam was compared with placebo (P = 0.0003). When melatonin was compared with midazolam, no significant difference (P = 0.49) in VAS anxiety scores was observed. Intergroup comparison of sedation scores showed melatonin (P = 0.0258) and midazolam (P = 0.0000) to be statistically significant when compared with placebo. No changes in orientation scores occurred in melatonin and placebo group. Change in DSST scores and TMT scores were seen to be significant only in midazolam group. CONCLUSION: Oral melatonin 0.4 mg/kg provides adequate anxiolysis comparable to that of oral midazolam. Unlike midazolam, oral melatonin 0.4 mg/kg does not impair the general cognitive and psychomotor function especially cognitive aspects such as working memory, memory retrieval, sustained attention, and flexibility of thinking. PMID- 25788773 TI - Do they hear what we speak? Assessing the effectiveness of communication to families of critically ill neurosurgical patients. AB - BACKGROUND AND AIMS: Clinician-family communication must be effective for medical decision making in any Intensive Care Unit (ICU) setting. We performed a prospective study to assess the effectiveness of communication to families of critically ill neurosurgical patients based on the two criteria of comprehension and satisfaction. MATERIALS AND METHODS: The study was conducted on 75 patients in a 15 bedded neurosurgical ICU. An independent investigator assessed the comprehension and satisfaction of families between the 3(rd) and the 5(th) day of admission in ICU. Comprehension was tested using three components, that is, comprehension of diagnosis, prognosis and treatment. The satisfaction was measured using a modified version of the Critical Care Family Needs Inventory (CCFNI) (score of 56-extreme dissatisfaction and 14-extreme satisfaction). RESULTS: Poor comprehension was noted in 52 representatives (71.2%). The mean satisfaction score as measured by the CCFNI score was 28. Factors associated with poor comprehension included increasing age of patient representative (P = 0.024), higher simplified acute physiology score (P = 0.26), nonoperated patients (P = 0.0087) and clinician estimation of poor prognosis (P = 0.01). Operated patients had significantly better satisfaction score (P = 0.04). CONCLUSION: Families of patients were reasonably satisfied, but had poor comprehension levels of the patient's illness. The severity of the patient's illness, poor prognosis as estimated by the physician and nonoperated patients were independent predictors of poor comprehension. Extra effort to communicate with patient representatives at risk of poor comprehension and provision of a family information leaflet could possibly remedy this situation. PMID- 25788774 TI - Comparison between intravenous paracetamol and fentanyl for intraoperative and postoperative pain relief in dilatation and evacuation: Prospective, randomized interventional trial. AB - BACKGROUND AND AIMS: Dilatation and Evacuation procedure involves pain, for which pain control measures need to be undertaken. The purpose of this study was to compare paracetamol with fentanyl for pain relief in dilatation and curettage procedures. MATERIALS AND METHODS: Sixty female patients were randomly included during the period from March 1, 2012 to February 28, 2013. All patients had received oral midazolam 7.5 mg as a premedication 30 min before procedure in the ward. Group P had received intravenous (IV) paracetamol 15 mg/kg in the waiting area of the operating room 15 min before starting the procedure. Group F had received IV fentanyl 2 ug/kg/min at induction of anesthesia. Pain scores on a numerical rating scale at 5, 15, and 30 min intervals after surgery were recorded. RESULTS: Mild pain was commonly observed in both groups, an insignificant difference between groups. CONCLUSION: The study demonstrates the usefulness of IV paracetamol which may be as effective as fentanyl in dilation and curettage procedures. PMID- 25788776 TI - The analgesic efficacy of ultrasound-guided transversus abdominis plane block with mid-axillary approach after gynecologic laparoscopic surgery: A randomized controlled trial. AB - BACKGROUND AND AIMS: The transversus abdominis plane (TAP) block is widely used in clinical practice as a part of the multimodal analgesic regimen after abdominal surgery. The analgesic efficacy of ultrasound (US)-guided TAP block with the mid-axillary approach was investigated in patients undergoing laparoscopic gynecologic surgery in a randomized controlled clinical trial. MATERIALS AND METHODS: Adult patients (n = 119) undergoing laparoscopic gynecologic surgery were randomized to undergo either TAP block with ropivacaine (Group A, n = 60) or that with saline (Group B, n = 59), in a blinded manner. Following general anesthesia, TAP block was performed bilaterally by infusion of either 20-mL 0.375% ropivacaine/one side in Group A or 20-mL saline/one side in Group B, under US guidance with a mid-axillary approach. Patient-controlled analgesia (PCA) was performed postoperatively with tramadol. The analgesic effect was postoperatively evaluated using a four-grade pain score and the prince Henry pain scale (PHS) at 0, 6, 12, and 24 h. Postoperative tramadol PCA consumption and vomiting/nausea were recorded. Statistical analyses were performed using the Mann-Whitney U-test or Fisher's exact probability test. A P < 0.05 was considered significant. RESULTS: There was no statistically significant difference in background characteristics. The dose of remifentanil was significantly higher in Group B (P = 0.01). The pain score (P = 0.02) and PHS (P = 0.01) were significantly lower in Group A at 0 h. Tramadol PCA consumption in the period of 0-6 h (P = 0.01) and postoperative nausea (P = 0.04) were significantly less in Group A. CONCLUSION: Postoperative pain/nausea and PCA consumption were significantly lower in patients with TAP block in the early postoperative stage. TAP block with a mid-axillary approach holds considerable promise as a part of a balanced postoperative analgesic regimen following laparoscopic gynecologic surgery. PMID- 25788775 TI - Regional anesthesia practice in Greece: A census report. AB - BACKGROUND AND AIMS: Regional anesthesia (RA) techniques (central neuraxial and peripheral nerve blocks [CNBs and PNBs]) are well-established anesthesia/analgesia modalities. However, information on their nationwide use is sparse. The aim of the survey was to assess the utility of RA techniques in Greece, during 2011. MATERIALS AND METHODS: A nationwide, cross-sectional descriptive survey was conducted (March to June, 2012), using a structured questionnaire that was sent to 128 Greek Anesthesia Departments. RESULTS: Sixty six completed questionnaires (response rate 51.56%) were analyzed. The data corresponded to 187,703 operations and represented all hospital categories and geographical regions of Greece. On the whole, RA was used in 45.5% of performed surgical procedures (85,386/187,703). Spinal anesthesia was the technique of choice (51.9% of all RA techniques), mostly preferred in orthopedics (44.8%). Epidural anesthesia/analgesia (application rate of 23.2%), was mostly used in obstetrics and gynecology (50.4%). Combined spinal-epidural and PNBs were less commonly instituted (11.24% and 13.64% of all RA techniques, respectively). Most PNBs (78.5%) were performed with a neurostimulator, while elicitation of paresthesia was used in 16% of the cases. Conversely, ultrasound guidance was quite limited (5%). The vast majority of consultant anesthesologists (94.49%) were familiar with CNBs, whereas only 46.4% were familiar with PNBs. The main reported limitations to RA application were lack of equipment (58.23%) and inadequate education/training (49.29%). CONCLUSION: Regional modalities were routinely used by Greek anesthesiologists during 2011. Neuraxial blocks, especially spinal anesthesia, were preferred over PNBs. The underutilization of certain RA techniques was attributed to lack of equipment and inadequate training. PMID- 25788777 TI - Dose-dependent effect of intrathecal dexmedetomidine on isobaric ropivacaine in spinal anesthesia for abdominal hysterectomy: Effect on block characteristics and hemodynamics. AB - BACKGROUND AND AIMS: Effect of intrathecal dexmedetomidine as an adjuvant to isobaric ropivacaine in spinal anesthesia for abdominal hysterectomy is not much investigated. The objective was to assess the dose dependent effect of dexmedetomidine (3 mcg vs 5 mcg) as an adjunct to isobaric ropivacaine in spinal anesthesia. MATERIALS AND METHODS: Forty selected female patients were randomized to receive intrathecal 0.5% isobaric ropivacaine (15 mg) with dexmedetomidine 3 mcg (Group D3) or 5 mcg (Group D5) in spinal anesthesia for abdominal hysterectomy. Block characteristics, hemodynamic changes, postoperative analgesia, and adverse effects were compared. RESULTS: Both groups were comparable regarding sensory-motor block characteristics and postoperative analgesia (P > 0.05). Four (10%) patients of Group D5 and 5 (12.5%) of Group D3 could not achieve desired T6 sensory level and Bromage score of 3(complete motor block) hence were converted to general anesthesia at the outset. Nine (22.5%) patients each in both groups required ketamine supplementation (0.5 mg/kg) for intraoperative pain at the time of uterine manipulation. Incidence of hypotension was comparable (55.56% in Group D5 and 37.14% in Group D3, P = 0.11), but this occurred significantly earlier in Group D5, P < 0.001. Sedation was also significantly more in Group D5 as compared with Group D3, P < 0.01. CONCLUSION: We conclude that spinal anesthesia with isobaric ropivacaine (15 mg) with dexmedetomidine (3 mcg or 5 mcg) did not show much promise for abdominal hysterectomy as one third cases required analgesic supplementation. Both doses of dexmedetomidine produced a similar effect on block characteristic and postoperative analgesia; however, a dose of 5 mcg dose was associated with more hypotension and sedation. PMID- 25788778 TI - Development and implementation of a dedicated postoperative evaluation service to improve compliance of postoperative visits. AB - BACKGROUND AND AIMS: Postoperative patient evaluation is an integral component of perioperative care. An audit of our anesthesia department's records demonstrated a compliance rate of <50%. We postulated that the development of clinical anesthesia service dedicated to performing such evaluations would improve compliance significantly. MATERIALS AND METHODS: This retrospective study examined postoperative follow-up completion rate at a large academic center. Data were collected from 58,000 anesthetics during three periods, between each of which an intervention was introduced. The first period examined completion rate when postoperative evaluations were left to the team performing the anesthetic. During the second period, this task was delegated to groups of anesthesiologists based on surgical subspecialty; these smaller groups utilized rotating residents. The third period examined completion rate after implementation of a postoperative evaluation service. All periods utilized the department's electronics database to identify operative patients. The number of adverse anesthesia events reported was also recorded. RESULTS: A significant difference in the proportions of compliance with postoperative evaluations among all three periods was detected. Compliance was 47% during period one and improved to 66% during period two. During period three, which employed a postoperative evaluation service, compliance was 83%. The number of adverse events reported per month increased significantly following the first study period from 95 reported monthly events to 215 and 201 in the second and third periods, respectively. CONCLUSION: By creating a dedicated postoperative evaluation service using available technology, we improved postoperative evaluation completion rate from 47% to 83%, and demonstrated a significant increase in the number of adverse events reported. Based on this, we support the deployment of a dedicated service as a quality improvement initiative. PMID- 25788779 TI - Cons and pros of female anesthesiologists: Academic versus nonacademic. AB - BACKGROUND AND AIMS: We hypothesized that "Feminization" of medicine has an impact on the choice of anesthesiology as a specialty. However anesthesiology is still not a more popular choice among women in medicine. We aimed to evaluate the implications of anesthesiology as a profession on personal and family life of women anesthesiologists; the differences between academic and nonacademic women anesthesiologists with respect to these effects and the effect of women anesthesiologists on the profession. MATERIALS AND METHODS: This study surveyed a total of 46 woman anesthesiologists; both academic and nonacademic institutions in our country between January and May 2013. A convenient sampling method was used. A constructed self-reported questionnaire was developed to explore the 29 items of woman-anesthesiology-related implications (family, personal, and job), in the form of close-ended questions. RESULTS: Negative implications of anesthesiology on personal and family life of woman were common. With the exception of financial limitation, academic group was significantly more affected. Increased surgeons conflict (98%), poor surgeon acceptance (87%), poor patient acceptance and recurrent change of work schedule (80% each) were the most common perceived negative impacts of women in the field of anesthesiology. Some positive implications were perceived as independent, positive social interaction, empowerment, soothing work environment, emotional reaction to patient complaint, and increased perfectionism (nearly 94%, 98%, 87%, 91%, 89%, and 76%, respectively). CONCLUSION: Serious implications exist for the personality and family life of women who chose anesthesiology as a specialty and career, and most of these implications were significantly more prevalent among women with an academic career. Furthermore, anesthesiology as a profession was significantly affected by women joining the department. PMID- 25788780 TI - Role of dexmedetomidine in early extubation of the intensive care unit patients. AB - BACKGROUND AND AIMS: Patients on ventilatory support in intensive care unit (ICU) require sedation and analgesia to facilitate mechanical ventilation and endotracheal tube tolerance. The selection of the agent should be such that it does not interfere with the early extubation of the patients. We compared the efficacy of dexmedetomidine with midazolam to facilitate extubation of patients from mechanical ventilation in terms of the sedative properties, cardiovascular responses, ventilation, and extubation characteristics and safety profile. MATERIALS AND METHODS: A total of 40 adult, mechanically ventilated patients of either sex, aged 18-60 years, meeting the standard criteria for weaning, randomized into 2 groups of 20 patients each, received intravenous infusion of dexmedetomidine (0.2-0.7 mcg/kg/h) or midazolam (0.04-0.2 mg/kg/h) as needed for Ramsay sedation scale 2-4. Extubation following standard extubation protocol was done. Time for extubation and vital parameters were regularly recorded. RESULTS: The time to extubation in the dexmedetomidine group was significantly lower than in the midazolam group. Heart rate and blood pressure was significantly lower in dexmedetomidine group than the midazolam group at most of the times. CONCLUSIONS: Dexmedetomidine has clinically relevant benefits compared with midazolam in facilitating extubation due to its shorter time to extubation, more hemodynamic stability, easy arousability, and lack of respiratory depression. PMID- 25788781 TI - Incidence and risk factors for oxygen desaturation during recovery from modified electroconvulsive therapy: A prospective observational study. AB - BACKGROUND AND AIMS: Electroconvulsive therapy (ECT) is an established modality of treatment for severe psychiatric illnesses. Among the various complications associated with ECT, oxygen desaturation is often under reported. None of the previous studies has evaluated the predictive factors for oxygen desaturation during ECT. The objective of this study was to evaluate the incidence of oxygen desaturation during recovery from anesthesia for modified ECT and evaluate its risk factors in a large sample. MATERIALS AND METHODS: All patients aged above 15 years who were prescribed a modified ECT for their psychiatric illness over 1 year were prospectively included in this observational study. The association between age, body mass index (BMI), doses of thiopentone and suxamethonium, stimulus current, ECT session number, pre- and post-ECT heart rate and mean arterial pressure, seizure duration, and pre- and post ECT oxygen saturation, was systematically studied. RESULTS: The incidence of oxygen desaturation was 29% (93/316 patients). Seizure duration and BMI were found to be significantly correlated with post ECT desaturation. CONCLUSION: In this prospective observational study, the incidence of oxygen desaturation during recovery from anesthesia for ECT was high. The study identified obesity and duration of seizure as the independent predictors of this complication. This knowledge is likely to help in identifying and optimizing such patients before subsequent ECT sessions. PMID- 25788782 TI - Efficacy of caudal fentanyl and ketamine on post-operative pain and neuroendocrine stress response in children undergoing infraumbilical and perineal surgery: A pilot study. AB - BACKGROUND AND AIMS: It is well-known that neuroendocrine stress response (NESR) occurs in children and it can be modified by caudal block. However, there is paucity of literature comparing caudal fentanyl and ketamine on NESR. The present study was aimed to compare the analgesic efficacy of these caudal adjuvants and their effect on (NESR) in children undergoing infraumbilical and perineal surgery. MATERIALS AND METHODS: A total of 60 children undergoing infraumbilical surgery were included in this randomized, double-blind study. Three groups of 20 each were assigned to receive caudal block with bupivacaine 0.25% 1 ml/kg along with either 0.9% normal saline (Group I) 1 MUg/kg fentanyl (Group II) or 0.5 mg/kg ketamine (Group III). Modified visual analogue scale (VAS) was used for assessment of post-operative pain, and stress response was assessed by blood glucose, serum cortisol and insulin levels at various time intervals. RESULTS: VAS scores were significantly lower in the ketamine group at all-time intervals upto 4 h (P < 0.05). Patients in ketamine group required rescue analgesia significantly later (8.23 h) when compared to fentanyl (5.95 h) and bupivacaine group (4.10 h). Caudal block led to significant decrease in cortisol and insulin levels within the groups however this significance was not achieved between groups. CONCLUSION: Caudal ketamine in a dose of 0.5 mg/kg provides prolonged analgesia when compared to fentanyl 1 MUg/kg. Blunting of the NESR was observed in all the groups though the indicators of the response were lowest with ketamine. PMID- 25788783 TI - Attenuation of hemodynamic response to laryngoscopy and orotracheal intubation using intravenous clonidine. AB - BACKGROUND AND AIMS: Alpha-2 agonists are being increasingly used as adjuncts in general anesthesia and the present study was carried out to study the effect of clonidine as an adjuvant to low dose fentanyl in attenuating the hemodynamic response to laryngoscopy and orotracheal intubation. MATERIALS AND METHODS: Ninety female patients belonging to American Society of Anesthesiologists (ASA) physical status I, II, and III in age group 25-65 years, body mass index (BMI) 21 26 kg/m(2), and diagnosed as carcinoma breast scheduled for breast surgery were included in this Prospective, randomized, placebo-controlled study. One-way analysis of variance (ANOVA), paired t-test, and chi-square test was applied where deemed appropriate. P-value at or below the level of 0.05 was considered as statistically significant. RESULTS: Intravenous (IV) clonidine 1.0 MUg kg(-1) and clonidine 2.0 MUg kg(-1) significantly attenuated the hyperdynamic response to laryngoscopy and intubation. Clonidine 2.0 MUg kg(-1) was associated with adverse effects like hypotension at the time of induction and postoperative sedation which was not observed with clonidine 1.0 MUg kg(-1). CONCLUSIONS: A single intravenous low dose clonidine (1.0 MUg kg(-1)) when combined with low dose fentanyl (2 MUg kg(-1)) is a practical, pharmacological and safe method with minimal side effects to attenuate the hyperdynamic response to laryngoscopy and intubation. PMID- 25788784 TI - Pediatric retroperitoneoscopic nephrectomy: An initial experience of 15 cases. AB - Retroperitoneoscopic approach of nephrectomy in pediatric patients is a debatable issue from surgical point of view. Experience of anesthetic management of 15 such patients from a tertiary care teaching hospital has been described here. We found that capno-retroperitoneum increases end-tidal carbon-di-oxide, but normocapnea was achieved in the most of the patients. No significant hemodynamic changes were noted in any patients. However, subcutaneous emphysema was common, but self limiting without any serious consequence. Postoperative pain after this procedure is usually manageable by nonopioid analgesics. PMID- 25788785 TI - Cesarean section under epidural anesthesia in a documented case of ruptured aneurysm of the sinus of valsalva. AB - Ruptured aneurysm of sinus of Valsalva (RSOV) occurring in pregnancy is a rare cardiac anomaly and it may be either congenital or acquired. Congenital sinus of Valsalva aneurysms are commonly associated with other structural defects such as ventricular septal defect (50-55%), aortic regurgitation (AR) (25-35%), bicuspid aortic valve (10-15%) and Marfan's syndrome (10%). RSOV in pregnancy accentuates the hemodynamic stress on maternal cardiovascular system and pose a significant challenge from obstetric anesthesia point of view. We report a case of 35-year old documented patient of RSOV with mild AR presenting completely asymptomatic at 37 weeks 4 days of gestation. A successful elective lower segment cesarean section was conducted under epidural anesthesia. PMID- 25788786 TI - Unanticipated cannot intubate situation due to difficult mouth opening. AB - We report a case of unanticipated difficult endotracheal intubation secondary to an abrupt onset of difficulty in opening the mouth in an anesthetized adult. A female aged 76 years with American Society of Anesthetists risk Class IV E with an apparently normal preoperative temporomandibular joint was scheduled for emergency laparotomy. Following rapid sequence induction, and muscle relaxation with rocuronium, the anesthesiologist noticed lock-jaw when intubation was attempted. She was ventilated with nasopharyngeal airway, but was progressively desaturating. An emergency tracheostomy was performed. Unfortunately, she sustained cardiac arrest and could not be revived. The complication of the lock jaw is a nightmare to airway management, especially in an unprepared situation. PMID- 25788787 TI - Common gas outlet error leading to severe hypoxia and general anesthesia during cesarean section under spinal anesthesia. PMID- 25788788 TI - Neuro-anesthesia handover checklist. PMID- 25788789 TI - The wonderful world of medical apps. PMID- 25788790 TI - In-plane interscalene block: A word of caution. PMID- 25788791 TI - Ultrasound guided quadratus lumborum block or posterior transversus abdominis plane block catheter infusion as a postoperative analgesic technique for abdominal surgery. PMID- 25788792 TI - An unusual cause of electrocardiogram interference in the operation theater. PMID- 25788793 TI - Cutaneous fluid leakage after epidural catheter removal. PMID- 25788794 TI - The A.P. Advance video laryngoscope as a rescue airway device in an unpredicted difficult airway. PMID- 25788795 TI - Virtual reality applications in mental health: Challenges and perspectives. PMID- 25788796 TI - Mental health of survivors of 1984 Bhopal disaster: A continuing challenge. AB - Bhopal disaster is an important milestone in Indian Industrial Psychiatry. The disaster was not only the biggest industrial disaster but also one in which complex forces have joined hands to demy the mental health needs of the population. Though the biggest general population epidemiological study over 5 years was carried out to understand the mental health impact of the disaster, the findings of this study did not get reflected in mental health care for the population. Furthermore, the needed longitudinal studies and evaluation of the interventions were not undertaken. There was no sharing of information with the survivors about the impact of the disaster on their health and well-being and sharing of skills for self-care. A result of these factors is the extreme degree of dissatisfaction in the population. Looking back, it would have met the needs of the Bhopal population, if the mental health services were community based and reaching the population, rather than the clinic-based approaches, there was a wide range of services, especially rehabilitation, continuous research into the changing mental health needs of the population and the effectiveness of interventions and most importantly, there was a continuous dialogue with the population and sharing of information with the general population. These are the tasks for the immediate future to reorganize the focus of mental health initiatives in Bhopal. Many lessons can be learnt from the Bhopal disaster and the continuing tragedy for the population. PMID- 25788797 TI - Psychological interventions in pervasive developmental disorder: An overview. AB - Pervasive developmental disorders (PDDs) are characterized by several impairments in the domains of social communication, social interaction and expression of social attachment, and other aspects of development like symbolic play. As the role of drugs in treating these impairments is extremely limited, a variety of psychological interventions have been developed to deal with them. Some of these have strong empirical support, while others are relatively new and hence controversial. Though it may prove to be a daunting task to begin with, the final reward of being able to improve the life of a child with PDD is enormous and hugely satisfying. Therefore, knowledge of these psychological interventions is important for a mental health professional, in order to be effective in the profession. Present paper presents an overview of these techniques in the management of PDD. PMID- 25788798 TI - Psychiatric morbidity in elderly patients attending OPD of tertiary care centre in western region of Nepal. AB - CONTEXT: Aging of population is currently a global phenomenon. At least one in 5 people over the age of 65 years will suffer from a mental disorder by 2030. Study of psychiatric morbidities in this age group is essential to prepare for upcoming challenges. AIMS: To find out the prevalence of different psychiatric morbidities in elderly population and to find out if there are any age and gender specific differences. SETTINGS AND DESIGN: Retrospective review; Psychiatric outpatient department of Manipal Teaching Hospital, Pokhara, Nepal. MATERIALS AND METHODS: Data for patients >= 65 years of age attending the psychiatric outpatient department of Manipal Teaching Hospital, Pokhara, Nepal, from 1(st) January 2012 to 15(th) January 2013 were collected retrospectively in a predesigned proforma. STATISTICAL ANALYSIS USED: Risk of having different psychiatric disorders was estimated using odds ratio. RESULTS: The mean age of 120 patients included in this study was 69.67 (SD = 5.94) years. Depressive disorder (26.7%) was the most common diagnosis. There was no statistically significant difference in psychiatric disorders in >75 years compared with <=75 years except for dementia [odd ratio (OR) (<=75 years/>75 years)=0.055, 95% confidence interval (CI)=0.016; 0.194]. Alcohol dependence syndrome [OR (male/female)=7.826, 95% CI = 1.699;36.705] and dementia [OR (male/female)=3.394, 95% CI = 1.015;11.350] was more common in males. CONCLUSIONS: Depressive disorder was the most common psychiatric morbidity among the elderly patients. The odds suffering from dementia increased with increasing age. The odds of having alcohol related problems and dementia were more in males compared with females. PMID- 25788799 TI - Inclination to speeding and its correlates among two-wheeler riding Indian youth. AB - CONTEXT: Concerns about road safety have been increasingly associated with two wheeler riding and especially with young commuters in India. AIMS: The study was designed to explore inclination to speeding and to profile the driving behaviors in two-wheeler riding young men and women who reported a tendency to ride faster than their peers. DESIGN: A cross-sectional survey design was used. MATERIALS AND METHODS: On the basis of three focus group discussions and review of literature, a survey was prepared to tap domains such as affect states associated with riding/speeding, factors contributing to speeding, inclination for competing, perceived speed and safety, etc. The study sample comprised of 961 two-wheeler riding college-going young men and women in Bangalore. STATISTICAL ANALYSIS: Descriptive and inferential statistical procedures were used including Chi square, Spearman's rank correlation, and independent sample t-test. RESULTS: The sample was divided into two subgroups on the basis of self-report of greater speeding than one's peers. A subgroup of 349 participants endorsed the item regarding inclination to ride faster than one's peers, whereas, the remaining 612 participants did not endorse it. The profiles of these two subgroups were obtained in terms of sociodemographic variables, riding behaviors, and associated domains. Significant differences between the subgroups emerged on domains such as motives for riding fast, tendency for competing, perceived safety and frequency of minor accidents while riding. CONCLUSIONS: Several correlates of the tendency to speeding among young two-wheeler riders emerged that have implications for enhancing safe riding. PMID- 25788800 TI - Cross-sectional study of self-reported ADHD symptoms and psychological comorbidity among college students in Chandigarh, India. AB - BACKGROUND: Existence of attention deficit hyperactivity disorder (ADHD) in adults is scantily researched in India. There is dearth of information on prevalence of ADHD in college students worldwide. Further, fewer studies in the past have evaluated the impact of ADHD on the psychological well-being of college students. AIMS: To study the prevalence of ADHD among college students and psychological problems related to ADHD. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: A total of 237 students were recruited from various medical, engineering, and commerce and arts colleges of Chandigarh, India. They were administered the Adult ADHD Self Report Scale v1.1(ASRS) and the Wender Utah Rating Scale (WURS) to diagnose adult ADHD. To assess comorbidities; General Health Questionnaire-12 (GHQ); Zung Depression Rating Scale (ZDRS); Rosenberg's Self-Esteem Scale (RSES);and questions on emotional stability, social problems, and substance use (alcohol, tobacco, and cannabis) were administered on all participants. RESULTS: A total of 13 students (5.48%) fulfilled the criteria for adult ADHD. These students experienced significantly higher emotional instability and low self-esteem than those without ADHD (N = 224). The occurrence of psychological problems, depression, social problems, and substance abuse was comparable in students with and without ADHD. CONCLUSIONS: ADHD is prevalent among the college students studying in the most competitive institutes as well. Students with ADHD experience higher emotional instability and poor self-esteem than others. It has little effect on their psychological well-being and social adjustment. Prompt detection and management of ADHD in college students may help them deal with these problems effectively. PMID- 25788801 TI - Psychological profile of women with infertility: A comparative study. AB - BACKGROUND: An endeavour to probe into the psychological profile of infertile women in a comparative stance with the fertile women is not very common. This study is an attempt to explore the possible non-apparent personality factors which contribute to the unexplained pain of infertility. METHODS: The main objectives of the present study were (a) to examine whether infertile women are different from fertile women in terms of selected psychological variables- narcissistic components, dimensions of attachment style and uses of defensive manoeuvres; and (b) whether the primary infertile women (n=18) are different from the secondary infertile women (n=12) with respect to those variables. A total of 60 individuals (30 infertile women and 30 matched fertile women) were assessed through Attachment Style Questionnaire (ASQ), Narcissistic Personality Inventory (NPI) and Defense Style Questionnaire (DSQ-40). General Health Questionnaire (GHQ) was administered on to the fertile women to rule out the psychiatric morbidity. RESULTS: Findings revealed that infertile women group differed from fertile women group with respect to narcissism, dimensions of attachment style and uses of defense mechanism. The primary infertile group also showed marked difference from the secondary infertile group with respect to those variables. CONCLUSIONS: This study endeavours to enrich the knowledge regarding the personality dynamics of infertile women to design psychotherapeutic programme to aid their well-being, help them to cherish the flavour of parenthood and improve their quality of life. PMID- 25788802 TI - Oxidative stress and psychological functioning among medical students. AB - BACKGROUND: Oxidative stress has gained attention recently in behavioral medicine and has been reported to be associated with various psychological disturbances and their prognoses. OBJECTIVES: Study aims to evaluate the oxidative stress (malonylaldehyde (MDA) levels) and its relation with psychological factors (dimensions of personality, levels of anxiety, stress, and depression) among medical/paramedical students of 1(st) and 3(rd) year). MATERIALS AND METHODS: A total of 150 students; 75 from 1(st) year (2010-2011) and75 from 3(rd) year (2009 2010); of medical and paramedical background were assessed on level of MDA (oxidative stress) and personality variables, that is, level of anxiety, stress, and depression. These psychological variables were correlated with the level of their oxidative stress. RESULTS: Findings revealed that both groups are influenced by oxidative stress and their psychological variables are also compatible in order to confirm their vulnerabilities to stress. CONCLUSIONS: Stress in 3(rd) year students was significantly higher and it was noted that it adversely affects the psychological parameters. Hence, special attention on mental health aspect in these students may be given. PMID- 25788803 TI - A study of sociodemographic clinical and glycemic control factors associated with co-morbid depression in type 2 diabetes mellitus. AB - CONTEXT: Diabetes affects 9.2% of adults in India. About 8-16% of its population also suffer from depression. Both diseases pose a serious health challenge at individual and system level. The prevalence of depression in diabetes is much higher than in the general population. Undiagnosed and untreated depression puts people at higher morbidity and mortality risk. AIM: To study the prevalence of depression in diabetes and to identify associated risk factors. SETTINGS AND DESIGN: Case control study carried out in an outpatient setting of a tertiary hospital in central India. MATERIALS AND METHODS: One hundred and nine type 2 diabetes patients and 91 healthy controls formed the subjects of the study. Sociodemographic data were obtained on seven parameters. Comprehensive clinical data were obtained by means of standard procedures. Blood sugar levels and glycosylated hemoglobin levels were measured to assess glycemic control. Data of diabetic patients and controls as well as that of depressed and nondepressed diabetics were subjected to statistical analysis. RESULTS: About 42.2% of diabetes patients and only 4.39% of controls had depression. About 19% of diabetics had peripheral neuropathy but had much higher neuropathic symptoms. Depression was not related to any sociodemographic or clinical factors but was strongly associated with poor glycemic control. CONCLUSION: Depression is highly prevalent in diabetes. Physical symptoms mask depression. Special attention needs to be paid to diagnose depression in diabetes and treat it appropriately along with effective glycemic control. Diabetes patients need to be treated collaboratively by physicians and psychiatrists. PMID- 25788805 TI - Psychological aspects of peacekeeping operations. AB - Peacekeeping operations are but one aspect of the systems of peace that have evolved over the past seven decades in a world that is riven with violence of all kinds. With the end of cold war in the late eighties of the last century we have come to see much intrastate violence, in addition to usual interstate hostilities and war, arising out of religious, political, ethnic and economic differences between people. In the changed scenario peacekeeping operations have become complex politico-military-humanitarian efforts. A soldier, trained for conventional military operations, is obliged to participate in the unconventional operations of waging peace in alien lands often in volatile and violent situations and in the process he stands to get exposed to widely variable demands for adjustment that have the potential to bring to the fore many maladaptive responses. Peacekeeping operations also have the potential to offer opportunities for growth and resilience. India is a major player in peacekeeping activities for well over sixty years all over the world. It is necessary for the commanders and mental health professionals to understand the multifarious factors that impinge on the peacekeeping soldier's mind and the emerging patterns of responses thereof for effective management trained manpower and fulfillment of mission objectives. PMID- 25788804 TI - Study of attitude of interns toward psychiatry: A survey of a tertiary level hospital in Ahmedabad. AB - BACKGROUND: Worldwide, multiple studies demonstrate a negative attitude of interns toward psychiatry. Scenario in Gujarat state has never been looked upon. The objective of this study is to identify the situation in this region by studying the attitude of interns toward various areas of psychiatry and to study the gender differences if any. MATERIALS AND METHODS: For study, all 122 interns who attended psychiatry posting for the 1st time in their internship, over a period of 8 months were approached amongst which 100 (56 males and 44 females) consented to be a part. Attitude was measured with 30 items attitude toward psychiatry (ATP 30) questionnaire on the 1st day of their posting. The data thus collected were analyzed by SPSS version 20. RESULT: The results showed a neutral to the negative attitude in major areas of psychiatry. Most neutral responses were seen regarding contribution of psychiatric hospitals in the treatment, regarding psychiatric patients considered to be interesting and psychiatry enabling people to have rewarding relationships. Negative attitude toward areas on scientific information in psychiatry and psychotherapy's validity were obtained. While attitude was positive in areas of psychiatric knowledge and teaching, but female interns were lagging behind their male counterparts. Psychiatric treatment lessens worries and psychiatric illness should be considered at par with other medical illnesses, were most common positively viewed attitude. CONCLUSION: Interns overall shared a neutral to negative ATP. Adequate rectification is required in existing medical curriculum, and more exposure to the subject is essential to improve the attitude of interns toward mental health. PMID- 25788806 TI - Management challenges in a case of gender identity disorder. AB - Gender identity disorder (GID) is a complex disorder and can be defined as a group of disorders whose common feature is a strong and persistent preference for living as a person of the other sex. It is associated with significant impairment in social, occupational, interpersonal, and other areas of functioning. We describe the case of an adolescent, biologically male who was brought to our outpatient department primarily with symptoms of adjustment disorder with GID and the management provided. The role of a psychiatrist in the management, ethical and legal issues involved is also discussed. PMID- 25788807 TI - Seasonal obsessive-compulsive disorder. AB - A case of obsessive-compulsive disorder (OCD) with seasonal variation in symptoms of 10-years duration is reported because of its rarity. The phenomenology of the observed disorder was obsessions related to dirt and contamination resulting in washing compulsions with onset in October and complete resolution in April-May every year. The patient responded to phototherapy along with exposure and response prevention therapy and pharmacotherapy. PMID- 25788808 TI - Catatonia versus neuroleptic malignant syndrome: the diagnostic dilemma and treatment. AB - Catatonia is a syndrome, comprised of symptoms such as motor immobility, excessive motor activity, extreme negativism, and stereotyped movements. Neuroleptic is able to induce catatonia like symptoms, that is, the neuroleptic malignant syndrome (NMS). In NMS, patients typically show symptoms such as an altered mental state, muscle rigidity, tremor, tachycardia, hyperpyrexia, leukocytosis, and elevated serum creatine phosphorous kinase. Several researchers have reported studies on catatonia and the association between catatonia and NMS, but none were from this part of the eastern India. In our case, we observed overlapping symptoms of catatonia and NMS; we wish to present a case of this diagnostic dilemma in a patient with catatonia, where a detailed history, investigation, and symptom management added as a great contribution to the patient's rapid improvement. PMID- 25788809 TI - The efficacy of electroencephalogram neurofeedback training in cognition, anxiety, and depression in alcohol dependence syndrome: A case study. AB - Electroencephalogram (EEG) neurofeedback's efficacy in reducing the symptoms of patients with alcohol dependence syndrome is well-documented in previous literature. Here, a case is being described who presented with alcohol dependence syndrome was given EEG neurofeedback training. After 10 sessions of EEG neurofeedback training program, a significant reduction was found in the cognitive deficits, anxiety, and depression of the patient. Furthermore, noticeable improvement was found in his memory and neurological functioning. He also showed a significant reduction in his alcohol intake on follow-up. PMID- 25788810 TI - Delusion of dhat: The quandary of the form-content dichotomy! PMID- 25788811 TI - Bioethics, neurosurgery, and integral healing. PMID- 25788812 TI - Retro-odontoid mass: An evidence of craniovertebral instability. PMID- 25788813 TI - Awake craniotomies for aneurysms, arteriovenous malformations, skull base tumors, high flow bypass, and brain stem lesions. PMID- 25788814 TI - C2 ganglion resection for lateral mass fixation techniques. PMID- 25788815 TI - Additional merit of coronal STIR imaging for MR imaging of lumbar spine. AB - INTRODUCTION: Back pain is a common clinical problem and is the frequent complaint for referral of lumbar spine magnetic resonance imaging (MRI). Coronal short tau inversion recovery sequence (STIR) can provide diagnostically significant information in small percentage of patients. MATERIALS AND METHODS: MRI examinations of a total of 350 patients were retrospectively included in the study. MR sequences were evaluated in two settings. One radiologist evaluated sagittal and axial images only, while another radiologist evaluated all sequences, including coronal STIR sequence. After recording the diagnoses, we compared the MRI findings in two subsets of patients to evaluate additional merit of coronal STIR imaging. RESULTS: With addition of coronal STIR imaging, significant findings were observed in 24 subjects (6.8%). Twenty-one of these subjects were considered to be normal on other sequences and in three subjects diagnosis was changed with the addition of coronal STIR. Additional diagnoses on STIR included sacroiliitis, sacroiliac joint degenerative disease, sacral stress/insufficiency fracture/Looser's zones, muscular sprain and atypical appendicitis. CONCLUSION: Coronal STIR imaging can provide additional diagnoses in a small percentage of patients presenting for lumbar spine MRI for back pain. Therefore, it should be included in the routine protocol for MR imaging of lumbar spine. PMID- 25788816 TI - Upper cervical injuries: Clinical results using a new treatment algorithm. AB - INTRODUCTION: Upper cervical injuries (UCI) have a wide range of radiological and clinical presentation due to the unique complex bony, ligamentous and vascular anatomy. We recently proposed a rational approach in an attempt to unify prior classification system and guide treatment. In this paper, we evaluate the clinical results of our algorithm for UCI treatment. MATERIALS AND METHODS: A prospective cohort series of patients with UCI was performed. The primary outcome was the AIS. Surgical treatment was proposed based on our protocol: Ligamentous injuries (abnormal misalignment, facet perched or locked, increase atlanto-dens interval) were treated surgically. Bone fractures without ligamentous injuries were treated with a rigid cervical orthosis, with exception of fractures in the dens base with risk factors for non-union. RESULTS: Twenty-three patients treated initially conservatively had some follow-up (mean of 171 days, range from 60 to 436 days). All of them were neurologically intact. None of the patients developed a new neurological deficit. Fifteen patients were initially surgically treated (mean of 140 days of follow-up, ranging from 60 to 270 days). In the surgical group, preoperatively, 11 (73.3%) patients were AIS E, 2 (13.3%) AIS C and 2 (13.3%) AIS D. At the final follow-up, the American Spine Injury Association (ASIA) score was: 13 (86.6%) AIS E and 2 (13.3%) AIS D. None of the patients had neurological worsening during the follow-up. CONCLUSIONS: This prospective cohort suggested that our UCI treatment algorithm can be safely used. Further prospective studies with longer follow-up are necessary to further establish its clinical validity and safety. PMID- 25788817 TI - Primary bone tumors of the spine revisited: A 10-year single-center experience of the management and outcome in a neurosurgical department. AB - OBJECTIVE: To report a large clinical series of primary bone tumors of the spine (PBTS) and review the current concepts of management. MATERIALS AND METHODS: We retrospectively analyzed a clinical series of PBTS treated over the last decade (2004-2014) in the spine unit of a large European tertiary care center. Every PBTS was identified from an electronic medical-record system. Analysis comprised medical records and clinical imaging. Overall survival and outcome was measured using the Glasgow Outcome Scale (GOS) at six weeks, six months and one year postoperatively. Surgical management and adjuvant/neoadjuvant strategies were analyzed. A thorough review of the current literature was performed. RESULTS: A total of 79 patients were included. Of these, 44 (55.7%) were male. The age ranged from 9 to 90 years (mean 55), and most patients were adults (93.6%). Local pain was the most common symptom and was present in 91.1% of the patients. The majority of the tumors occurred in the thoracic spine (52 patients, 65.8%). Overall 86% (68 patients) of PBTS were classified as malignant and at the time of diagnosis, 7 patients (8.9%) presented with non-spinal metastasis. The most common histologic types were hematopoietic tumors (72.2%), followed by chondrogenic ones (12.7%). Within hematopoietic tumors, plasmacytoma was the most frequent type (49 patients, 62%). In 12 patients (15.2%) recurrences were seen during the follow-up period. Overall mean survival of benign PBTS was 100%, malignant non-hematopoietic PBTS 50% and, malignant hematopoietic PBTS 84% at one year, respectively. At six weeks and one year after the initial surgery, 79% and 54% of the patients presented a GOS >3, respectively. CONCLUSION: PBTS were almost exclusively seen in adults. Malignant tumors were markedly more frequent than benign tumors, with hematopoietic tumors being the most common type. For PBTS, early surgery is important in order to restore spinal stability and decompress the spinal cord. This allows pain reduction and prevention of neurological deficits. PMID- 25788818 TI - Radiological anatomy of the C7 vertebra: Clinical implications in spine surgery. AB - CONTEXT: This study was designed to understand and define the special radio anatomic morphometry of C7 vertebra by using multidetector computed tomography (MDCT). AIMS: The major aim of the study was to detect the gender- and side related morphometric differences of C7 vertebra among subjects. SETTING AND DESIGN: Our radiology unit database scanned for MDCT sections of the C7 vertebra. MATERIALS AND METHODS: A total of 214 patients (134 men, 80 women) were selected. A detailed morphometric evaluation of C7 was done. STATISTICAL ANALYSIS USED: T test, ANOVA. Lamina length (P < 0.001), pedicle length (P < 0.001), outer cortical (P = 0.01) and inner cancellous pedicle (P < 0.001) width, pedicle angle to sagittal plane (P < 0.001) values were statistically significantly different on the right versus left side. When the results were stratified by gender, lamina length, inner cancellous lamina height, pedicle length, inner cancellous pedicle height, outer cortical pedicle width, lateral mass anteroposterior length, anteroposterior length of C7 corpus, height of C7 corpus (P < 0.001), C6-7 (P = 0.013) and C7-T1disc height (P = 0.04), transverse foramina perpendicular width at C7 (P = 0.046) values were found to be statistically significantly different. Vertebral artery most commonly enters into the transverse foramina at C6 level. CONCLUSIONS: Gender and side differences are important factors for preoperative planning and showed significant differences among subjects. MDCT is a practical option for investigating the exact anatomical features of osseous structures. PMID- 25788819 TI - A comparison of two techniques: Open and percutaneous biopsies of thoracolumbar vertebral body lesions. AB - AIM: The purpose of this article is to compare the similarity of initial radiological diagnosis and pathological diagnosis between thoracal and lumbar vertebral bodies and the adequacy and the reliability of open and percutaneous biopsies performed via transpedicular approach in the lesions located in vertebral bodies. MATERIALS AND METHODS: Thirty-three patients who had undergone transpedicular biopsy for vertebral body lesions were retrospectively evaluated. Seventeen patients were diagnosed by percutaneous transpedicular biopsy (11 in the lumbar vertebrae, 6 in the thoracal vertebrae). Sixteen patients were diagnosed by open transpedicular biopsy (9 in the lumbar vertebrae, 7 in the thoracal vertebrae). RESULTS: The similarity ratio between the initial radiological diagnosis and the final pathological diagnosis was 71.4% in the open biopsy and was 69.2% in the percutaneous biopsy (P > 0.05). The similarity ratio between the initial radiological diagnosis and the final pathological diagnosis was 66.7% in the lumbar region and was 77.8% in the thoracal region (P > 0.05). For percutaneous biopsy group, the similarity ratio was 72.7% in the lumbar region and was 66.7% in the thoracal region (P > 0.05). For open biopsy group, the similarity ratio was 62.5% in the lumbar region and 83.3% in the thoracal region (P > 0.05). No complication was observed. CONCLUSION: Specimen adequacy of open biopsy was higher than percutaneous biopsy. Particularly, the open thoracal biopsy has provided the highest similarity ratio between the initial radiological diagnosis and the final pathological diagnosis. PMID- 25788820 TI - Atlantoaxial dislocation in a patient with nonsyndromic symmetrical dwarfism: Report of a rare case. AB - Congenital anomalies of the craniovertebral junction (CVJ) are complex developmental defects. We describe a patient with atlantoaxial dislocation (AAD) and short stature whose morphopathologydid not fit into any of the previously described syndromic constellations. The patient underwent a reduction of the AAD followed by fixation with C1-C2 transarticular screws. Although numerous syndromes have been linked to both dwarfism and craniovertebral junction anomalies, this patient did not fit into any of these patterns. It is possible that this may be one of the many as yet unrecognized patterns of congenital anomalies. PMID- 25788821 TI - Surgical treatment of cervical unilateral locked facet in a 9-year-old boy: A case report. AB - Most of the cervical spine injuries in the pediatric population are typically seen in the upper cervical region. Unilateral cervical facet dislocation (UFD) in subaxial region is a rare injury in pediatric population. In this paper, a rare case of delayed locked UFD in a 9-year-old boy with rare injury mechanism treated surgically is reported. Clinical and radiological findings were described. The patient with C6-7 UFD without neurologic deficit was underwent open reduction and internal fixation via anterior and posterior combined approaches. Significant improvement of pain and free motion in cervical spine was obtained. There was no complication during the follow up. Only three case reports presented about the lower cervical spine injury with UFD under the age of 10 were found in the literature. PMID- 25788823 TI - Pilot Clinical Studies of Long Duration, Low Intensity Therapeutic Ultrasound for Osteoarthritis. AB - Osteoarthritis is one of the leading causes of disability in the aging population. Long duration, low intensity therapeutic ultrasound has had promising impact in animal models to slow the progression of the disease and provide joint relief. Two pilot studies were conducted using a novel, wearable platform for delivering ultrasound to evaluate the potential clinical benefits of ultrasound therapy on knee osteoarthritis. There was a pain reduction effect from using ultrasound, as high as fifty two percent in one study. As well, initial data demonstrates that mobility may be increased for patients experiencing mild to moderate arthritis of the knee. PMID- 25788822 TI - Pelvic surgical site infections in gynecologic surgery. AB - The development of surgical site infection (SSI) remains the most common complication of gynecologic surgical procedures and results in significant patient morbidity. Gynecologic procedures pose a unique challenge in that potential pathogenic microorganisms from the skin or vagina and endocervix may migrate to operative sites and can result in vaginal cuff cellulitis, pelvic cellulitis, and pelvic abscesses. Multiple host and surgical risk factors have been identified as risks that increase infectious sequelae after pelvic surgery. This paper will review these risk factors as many are modifiable and care should be taken to address such factors in order to decrease the chance of infection. We will also review the definitions, microbiology, pathogenesis, diagnosis, and management of pelvic SSIs after gynecologic surgery. PMID- 25788824 TI - Laparoscopic ovarian surgery in children and adolescents. AB - BACKGROUND AND OBJECTIVES: Although laparoscopy is widely used in gynecologic surgery in adults, few studies have been undertaken to examine its use in young and adolescent patients. This study was conducted to investigate the safety and feasibility of laparoscopic surgery for the treatment of benign ovarian disease in children and adolescents. METHODS: A retrospective chart review was conducted on 106 patients (age, <20 years) who underwent laparoscopic surgery at Kangnam Sacred Heart Hospital from 2006 through 2012. RESULTS: The mean patient age was 17.1 years, and the youngest one was 8. Pathologic analyses revealed that 32 (30.2%) patients had dermoid cyst, 30 (28.3%) had simple cyst, and 15 (14.2%) had endometrioma. Conservative procedures, such as cystectomy (48.1%), aspiration (5.7%), fulguration (4.7%), and detorsion (3.8%), were performed in 65.1% of all cases. A subanalysis revealed that the surgical outcomes of children (age, <=15 years), including operative time, estimated blood loss, postoperative hemoglobin decrease, and postoperative length of hospital stay, were comparable to those of adolescents (age, 16-19 years), despite significant differences in mean height between the 2 groups (156.1 +/- 10.71 cm in children vs. 162.1 +/- 5.14 cm in adolescents; P < .0001). (The age break between the study groups was set at 15 years, because most girls reach their adult height between the ages of 15 and 16 years.) No intra- or perioperative complications were noted. In a comparison study of surgical outcomes in 433 women (age, 20-50 years) and the 106 young and adolescent girls in our sample (age, <20 years), those in our patients were not inferior. CONCLUSION: In children and adolescents, laparoscopic surgery can be successfully performed with conventional instruments designed for use in adults. PMID- 25788826 TI - Variations in the Home Literacy Environment of Preschool Children: A Cluster Analytic Approach. AB - Home literacy surveys were collected from the primary caregiver of 1,044 2- to 5 year-old children (M = 49.32 months, SD = 9.36) representing a wide range of socioeconomic backgrounds and types of early educational programs or child care. The caregivers completed survey questions on family background and home literacy activities and materials. Hierarchical cluster analyses performed on three randomly constituted subsamples and on the total sample revealed that a three cluster solution best fit the data. Clusters differed on frequency of shared reading and literacy teaching activities with clusters representing caregivers either low or high on all behaviors or low on shared reading behaviors but high on literacy teaching behaviors. Cluster membership was significantly related to socioeconomic status, family living circumstances, caregiver stress, and caregiver reading ability. Results support a model of home literacy behavior informed not only by knowledge and resources but also by parental beliefs and deliberate choices. PMID- 25788825 TI - Feasibility and safety of outpatient total laparoscopic hysterectomy. AB - BACKGROUND AND OBJECTIVE: Ambulatory total laparoscopic hysterectomy (TLH) could lead to significant cost savings, but some fear the effects of what could be premature postsurgical discharge. We sought to estimate the feasibility and safety of TLH as an outpatient procedure for benign gynecologic conditions. METHODS: We report a prospective, consecutive case series of 128 outpatient TLHs performed for benign gynecologic conditions in a tertiary care center. RESULTS: Of the 295 women scheduled for a TLH, 151 (51%) were attempted as an outpatient procedure. A total of 128 women (85%) were actually discharged home the day of their surgery. The most common reasons for admission the same day were urinary retention (19%) and nausea (15%). Indications for hysterectomy were mainly leiomyomas (62%), menorrhagia (24%), and pelvic pain (9%). Endometriosis and adhesions were found in 23% and 25% of the cases, respectively. Mean estimated blood loss was 56 mL and mean uterus weight was 215 g, with the heaviest uterus weighing 841 g. Unplanned consultation and readmission were infrequent, occurring in 3.1% and 0.8% of cases, respectively, in the first 72 hours. At 3 months, unplanned consultation, complication, and readmission had occurred in a similar proportion of inpatient and outpatient TLHs (17.2%, 12.5%, and 4.7% versus 18.1%, 12.7%, and 5.4%, respectively). In a logistic regression model, uterus weight, presence of adhesions or endometriosis, and duration of the operation were not associated with adverse outcomes. CONCLUSION: Same-day discharge is a feasible and safe option for carefully selected patients who undergo an uncomplicated TLH, even in the presence of leiomyomas, severe adhesions, or endometriosis. PMID- 25788828 TI - Web tool for estimating the cancer hazard rates in aging. AB - A computational approach for estimating the overall, population, and individual cancer hazard rates was developed. The population rates characterize a risk of getting cancer of a specific site/type, occurring within an age-specific group of individuals from a specified population during a distinct time period. The individual rates characterize an analogous risk but only for the individuals susceptible to cancer. The approach uses a novel regularization and anchoring technique to solve an identifiability problem that occurs while determining the age, period, and cohort (APC) effects. These effects are used to estimate the overall rate, and to estimate the population and individual cancer hazard rates. To estimate the APC effects, as well as the population and individual rates, a new web-based computing tool, called the CancerHazard@Age, was developed. The tool uses data on the past and current history of cancer incidences collected during a long time period from the surveillance databases. The utility of the tool was demonstrated using data on the female lung cancers diagnosed during 1975 2009 in nine geographic areas within the USA. The developed tool can be applied equally well to process data on other cancer sites. The data obtained by this tool can be used to develop novel carcinogenic models and strategies for cancer prevention and treatment, as well as to project future cancer burden. PMID- 25788827 TI - Extensive genomic variability of knops blood group polymorphisms is associated with sickle cell disease in Africa. AB - Sickle cell disease (SCD) is a multisystem disorder characterized by chronic hemolytic anemia, vaso-occlusive crises, and marked variability in disease severity. Patients require transfusions to manage disease complications, with complements, directed by complement regulatory genes (CR1) and its polymorphisms, implicated in the development of alloantibodies. We hypothesize that CR1 polymorphisms affect complement regulation and function, leading to adverse outcome in SCD. To this end, we determined the genomic diversity of complement regulatory genes by examining single nucleotide polymorphisms associated with Knops blood group antigens. Genomic DNA samples from 130 SCD cases and 356 control Africans, 331 SCD cases and 497 control African Americans, and 254 Caucasians were obtained and analyzed, utilizing a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay. Analyzing for ethnic diversity, we found significant differences in the genotypic and allelic frequencies of Sl1/Sl2 (rs17047661) and McCa/b (rs17047660) polymorphisms between Africans, African Americans, and Caucasians (P < 0.05). The homozygote mutant variants had significantly higher frequencies in Africans and African Americans but were insignificant in Caucasians (80.2% and 59.6% vs 5.9% for Sl1/2; and 36% and 24% vs 1.8% for McCa/b). With SCD, we did not detect any difference among cases and controls either in Africa or in the United States. However, we found significant difference in genotypic (P < 0.0001) and allelic frequencies (P < 0.0001) of Sl1/Sl2 (rs17047661) and McCa/b (rs17047660) polymorphisms between SCD groups from Africa and the United States. There was no difference in haplotype frequencies of these polymorphisms among or between groups. The higher frequency of CR1 homozygote mutant variants in Africa but not United States indicates a potential pathogenic role, possibly associated with complicated disease pathophysiology in the former and potentially protective in the latter. The difference between sickle cell groups suggests potential genetic drift or founder effect imposed on the disease in the United States, but not in Africa, and a possible confirmation of the ancestral susceptibility hypothesis. The lower haplotype frequencies among sickle cell and control populations in the United States may be due to the admixture and the dilution of African genetic ancestry in the African American population. PMID- 25788829 TI - Identification of medium-sized copy number alterations in whole-genome sequencing. AB - The genome-wide discoveries such as detection of copy number alterations (CNA) from high-throughput whole-genome sequencing data enabled new developments in personalized medicine. The CNAs have been reported to be associated with various diseases and cancers including acute myeloid leukemia. However, there are multiple challenges to the use of current CNA detection tools that lead to high false-positive rates and thus impede widespread use of such tools in cancer research. In this paper, we discuss these issues and propose possible solutions. First, since the entire genome cannot be mapped due to some regions lacking sequence uniqueness, current methods cannot be appropriately adjusted to handle these regions in the analyses. Thus, detection of medium-sized CNAs is also being directly affected by these mappability problems. The requirement for matching control samples is also an important limitation because acquiring matching controls might not be possible or might not be cost efficient. Here we present an approach that addresses these issues and detects medium-sized CNAs in cancer genomes by (1) masking unmappable regions during the initial CNA detection phase, (2) using pool of a few normal samples as control, and (3) employing median filtering to adjust CNA ratios to its surrounding coverage and eliminate false positives. PMID- 25788830 TI - 7-NI and ODQ Disturbs Memory in the Elevated Plus Maze, Morris Water Maze, and Radial Arm Maze Tests in Mice. AB - Nitric oxide (NO) is an atypical neurotransmitter that causes changes in cognition. Nitric oxide synthase (NOS) and guanylate cyclase (GC) inhibitors have been shown to exert some effects on cognition in previous studies; however, the findings have been controversial. This study was aimed at understanding the effects of an NOS inhibitor, 7-nitroindazole (7-NI), and a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on spatial memory in modified elevated plus maze (mEPM), Morris water maze (MWM), and radial arm maze (RAM) tests. Male Balb-c mice were treated via intraperitoneal injections with 7-NI (15 mg/kg), ODQ (3, 10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline. ODQ (3 mg/kg) and 7-NI (15 mg/kg) significantly increased the second-day latency in the mEPM test. 7-NI (15 mg/kg) and ODQ (10 mg/kg) significantly increased the escape latency in second, third, and fourth sessions, decreased the time spent in the escape platform's quadrant, and increased the mean distance to the platform in the probe trial of the MWM test. ODQ (3, 10 mg/kg) and 7-NI (15 mg/kg) significantly increased the number of errors, whereas only 7-NI increased the latency in the RAM test. The administration of L-arginine (100 mg/kg) prior to 7-NI inverted the effects of 7 NI, which supports the role of NO on cognition. Our study shows that the NO/cGMP/GS pathway can regulate spatial memory in mice. PMID- 25788831 TI - A systems biology approach reveals the dose- and time-dependent effect of primary human airway epithelium tissue culture after exposure to cigarette smoke in vitro. AB - To establish a relevant in vitro model for systems toxicology-based mechanistic assessment of environmental stressors such as cigarette smoke (CS), we exposed human organotypic bronchial epithelial tissue cultures at the air liquid interface (ALI) to various CS doses. Previously, we compared in vitro gene expression changes with published human airway epithelia in vivo data to assess their similarities. Here, we present a follow-up evaluation of these in vitro transcriptomics data, using complementary computational approaches and an integrated mRNA-microRNA (miRNA) analysis. The main cellular pathways perturbed by CS exposure were related to stress responses (oxidative stress and xenobiotic metabolism), inflammation (inhibition of nuclear factor-kappaB and the interferon gamma-dependent pathway), and proliferation/differentiation. Within post-exposure periods up to 48 hours, a transient kinetic response was observed at lower CS doses, whereas higher doses resulted in more sustained responses. In conclusion, this systems toxicology approach has potential for product testing according to "21st Century Toxicology". PMID- 25788832 TI - "Chasing the high" - experiences of ethylphenidate as described on international internet forums. AB - Ethylphenidate is a novel psychoactive substance with undocumented effects, risks, and motivation for use. In this study, we investigated the experience of ethylphenidate by analyzing self-reports published on Internet forums, which revealed seven overarching themes: (1) compulsive redosing and addiction; (2) impacts on the mental state; (3) bodily agitation; (4) increased sociableness; (5) administration; (6) diverse evaluations based on intention; and (7) safety and precaution. Ethylphenidate appeared as a potent psychostimulant with an imminent abuse potential. It was mainly used for recreational purposes. The effects included not only pleasurable stimulation, euphoria, and cognitive enhancement but also indecisiveness, anxiety, and cognitive fragmentation. The users reported an increase in body temperature, heart rate, and blood pressure, but they also experienced profuse sweating and muscle tension. Ethylphenidate acted as a social lubricant, enhancing intimacy, communication, and social skills. Two opposing user mentalities were uncovered: (1) pleasure seeking and risk neglecting, and (2) safety-first orientation. This information could be of importance to legislators, public health personnel, and prevention strategists. PMID- 25788833 TI - Disease vectors. PMID- 25788834 TI - Conversion Percentage of Tryptophan to Nicotinamide is Higher in Rice Protein Diet than in Wheat Protein Diet in Rats. AB - We reported previously that the pellagragenic property of corn protein is not only low l-tryptophan concentration but also the lower conversion percentage of l tryptophan to nicotinamide; the amino acid composition greatly affected the conversion percentage. The amino acid value of wheat protein is lower than that of rice protein. In the present study, we compare the conversion percentages of l tryptophan to nicotinamide between wheat protein and rice protein diets in growing rats. The body weight gain for 28 days in rats fed with a 10% amino acid mixture diet with wheat protein was lower than that of rats fed with a 10% amino acid diet with rice protein (68.1 +/- 1.6 g vs 108.4 +/- 1.9 g; P < 0.05). The conversion percentage of l-tryptophan to nicotinamide was also lower for the wheat protein diet compared with the rice protein diet (1.44 +/- 0.036% vs 2.84 +/- 0.19%; P < 0.05). The addition of limiting amino acids (l-isoleucine, l lysine, l-tryptophan, l-methionine, l-threonine) to the wheat protein diet improved growth and the conversion percentage. In conclusion, our result supports the thinking that the composition of amino acids affects the conversion ratio of l-tryptophan to nicotinamide. PMID- 25788835 TI - Histological features of layers and sublayers in cortical visual areas V1 and V2 of chimpanzees, macaque monkeys, and humans. AB - The layers and sublayers of primary visual cortex, or V1, in primates are easily distinguishable compared to those in other cortical areas, and are especially distinct in anthropoid primates - monkeys, apes, and humans - where they also vary in histological appearance. This variation in primate-specific specialization has led to a longstanding confusion over the identity of layer 4 and its proposed sublayers in V1. As the application of different histological markers relate to the issue of defining and identifying layers and sublayers, we applied four traditional and four more recent histological markers to brain sections of V1 and adjoining secondary visual cortex (V2) in macaque monkeys, chimpanzees, and humans in order to compare identifiable layers and sublayers in both cortical areas across these species. The use of Nissl, neuronal nuclear antigen (NeuN), Gallyas myelin, cytochrome oxidase (CO), acetylcholinesterase (AChE), nonphosphorylated neurofilament H (SMI-32), parvalbumin (PV), and vesicular glutamate transporter 2 (VGLUT2) preparations support the conclusion that the most popular scheme of V1 lamination, that of Brodmann, misidentifies sublayers of layer 3 (3Bbeta and 3C) as sublayers of layer 4 (4A and 4B), and that the specialized sublayer of layer 3 in monkeys, 3Bbeta, is not present in humans. These differences in interpretation are important as they relate to the proposed functions of layer 4 in primate species, where layer 4 of V1 is a layer that receives and processes information from the visual thalamus, and layer 3 is a layer that transforms and distributes information to other cortical areas. PMID- 25788836 TI - Lumbar sympathicolysis in patients with severe peripheral artery disease: hemodynamics of the lower limbs determined by near-infrared spectroscopy, color coded duplex sonography, and temperature measurement. AB - The objective was to investigate the effects of CT-guided lumbar sympathicolysis on somatic regional oxygen saturation, arterial flow velocity, and skin temperature of the lower limbs in patients with advanced peripheral artery disease (PAD). CT-guided lumbar sympathicolysis was additionally performed after successful revascularization therapy in 61 patients with PAD in categories 5 and 6 according to Rutherford. Somatic regional oxygen saturation in the distal lower limbs was determined semiquantitatively with a near-infrared spectroscopy (NIRS) system. Before and after intervention, peak flow and end-diastolic flow velocity in the dorsalis pedis artery were determined by means of color-coded duplex sonography, and the skin temperature of the feet was measured with an infrared thermometer. After CT-guided lumbar sympathicolysis, somatic regional oxygen saturation, peak flow, end-diastolic flow velocity, and skin temperature in the lower limbs increased significantly. PMID- 25788837 TI - Left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy - a cardiac magnetic resonance imaging study. AB - BACKGROUND: Few studies evaluated left ventricular (LV) involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The aim of this study is to determine the frequency, clinical presentation, and pattern of LV involvement in ARVD/C (LV-ARVD/C). METHODS: We retrospectively evaluated the cardiac magnetic resonance (CMR) in 202 patients referred between 2008 and 2012 to our institution, and we determined the presence or the absence of CMR criteria in the revised task force criteria 2010 for the diagnosis of ARVD/C. A total of 21 patients were diagnosed with ARVD/C according to the revised task force criteria 2010. All included patients had no previous history of myocarditis, acute coronary syndrome, or any other cardiac disease that could interfere with the interpretations of structural abnormalities. The LV involvement in ARVD/C was defined by the presence of one or more of the following criteria: LV end diastolic volume (LVEDV; >95 mL/m(2)), LV ejection fraction (LVEF; <55%), LV late enhancement of gadolinium (LVLE) in a non-ischemic pattern, and LV wall motion abnormalities (WMAs). In the follow-up for the occurrence of cardiac death, ventricular tachycardia (VT) was obtained at a mean of 31 +/- 20.6 months. RESULTS: A total of 21 patients had ARVD/C. The median age was 48 (33-63) years. In all, 11 patients (52.4%) had LV-ARVD/C. The demographic characteristics of patients with or without LV were similar. There was a higher frequency of left bundle-branch block (LBBB) VT morphology in ARVD/C (P = 0.04). In CMR, regional WMAs of right ventricle (RV) and RV ejection fraction (RVEF; <45%) were strongly correlated with LV-WMAs (r = 0.72, P = 0.02, r = 0.75, P = 0.02, respectively). RV late enhancement of gadolinium (RVLE) was associated with LV-WMs and LVLE (r = 0.7, P = 0.03; r = 0.8, P = 0.006). LVLE was associated with LV-WMAs, LVEF, and LVEDV (r = 0.9, P = 0.001; r = 0.8, P = 0.001; r = 0.8, P = 0.01). CONCLUSION: LV involvement in ARVD/C is common and frequently associated with moderate to severe right ventricular (RV) abnormalities. The impact of LV involvement in ARVD/C on the prognosis needs further investigations. PMID- 25788839 TI - Normal Growth of Healthy Infants Born from HIV+ Mothers Fed a Reduced Protein Infant Formula Containing the Prebiotics Galacto-Oligosaccharides and Fructo Oligosaccharides: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of the current study was to evaluate the safety of a new reduced protein (2.1 g/100 kcal) infant formula containing 4 g/L of 90% galacto oligosaccharides (GOS) and 10% fructo-oligosaccharides (FOS). METHODS: Healthy term infants from Brazil were enrolled. Those born to human immunodeficiency virus (HIV)-positive mothers were randomized to a test (n = 65) or control (n = 63) formula group. Infants born to HIV-negative mothers were either exclusively breast-fed (n = 79) or received a mixed diet (breast milk and test formula, n = 65). Between 2 weeks and 4 months of age, infants were exclusively fed according to their assigned group. Anthropometric measurements were taken at baseline, 1, 2, 3, 4, 6, 8, 10, and 12 months. Digestive tolerance was evaluated during the first 4 months. The primary outcome was mean daily weight gain between 2 weeks and 4 months in the test formula and breast-fed groups. RESULTS: Data from all infants (N = 272) were used in the intention-to-treat (ITT) analysis and data from 230 infants were used in the per-protocol (PP) analysis. The difference in mean daily weight gain between 2 weeks and 4 months in the test formula and breast-fed groups was 1.257 g/day (one-sided 95% confidence interval [CI]: -0.705 to inf, P < 0.001) in the PP analysis, showing that the lower bound of the 95% CI was above the -3.0 g/day non-inferiority margin. Results were similar in the ITT analysis. Symptoms of digestive tolerance and frequency of adverse events were similar in the two groups. CONCLUSIONS: The formula containing 2.1 g/100 kcal protein and GOS and FOS was safe and tolerated well. PMID- 25788840 TI - COMET, TUNEL, and TEM analysis of an infertile male with short tail sperm. AB - Male infertility is correlated with sperm morphology and sperm DNA damage, which are completely different from that of fertile individuals. An accurate sperm DNA damage analysis and ultrastructural examination of the ejaculate provide important support in the clinical evaluation. It is supposed that in the near future, the fertilization rate, pregnancy rate, and miscarriages could be predicted using the combination of these types of tests in assisted reproductive technologies (ARTs). For this purpose, we report a very rare case of an infertile man having short tail sperm. The infertile man and his wife underwent in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). During this process, we examined the ultrastructure of the ejaculated sperm with transmission electron microscopy (TEM) and calculated the sperm DNA damage with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and COMET assays. Then, we evaluated the association between sperm DNA damage and embryo quality. PMID- 25788841 TI - Impact of current video game playing on robotic simulation skills among medical students. AB - OBJECTIVE: To evaluate the impact of current and prior video game playing on initial robotic simulation skill acquisition. MATERIAL AND METHODS: This cross sectional descriptive study (Canadian Task Force Classification II-1) was conducted at a medical university training center. The study subjects were medical students who currently played video games (Group I) and those who had not played video games in the last 2 years (Group II). The robotic skills of both groups were assessed using simulation. RESULTS: Twenty-two students enrolled in this study; however, only 21 completed it. The median age of the participants was 23 (22-24) years and 24 (23-26) years in Groups I and II, respectively. Among the participants, 15 (71.4%) were male and 6 (28.5%) were female, and 90.4% of the students started playing video games in primary school. When the 2 groups were compared according to the completion time of each exercise, Group I finished more quickly than Group II in the Peg Board-1 exercise (p>0.05), whereas Group II had better results in 3 exercises including Pick and Place, Ring and Rail, and Thread the Rings-1. However, none of the differences were found to be statistically significant (p>.05), and according to the overall scores based on the time to complete exercises, economy of motion, instrument collision, use of excessive instrument force, instruments out of view, and master workspace range, the scores were not statistically different between Groups I and II (p>.05). CONCLUSION: According to the basic robotic simulation exercise results, there was no difference between medical students who used to play video games and those who still played video games. Studies evaluating baseline visuospatial skills with larger sample sizes are needed. PMID- 25788838 TI - Osteoporosis in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a lifestyle-related chronic inflammatory pulmonary disease associated with significant morbidity and mortality worldwide. COPD is associated with various comorbidities found in all stages of COPD. The comorbidities have significant impact in terms of morbidity, mortality, and economic burden in COPD. Management of comorbidities should be incorporated into the comprehensive management of COPD as this will also have an effect on the outcome in COPD patients. Various comorbidities reported in COPD include cardiovascular disease, skeletal muscle dysfunction, anemia, metabolic syndrome, and osteoporosis. Osteoporosis is a significant comorbidity in COPD patients. Various risk factors, such as tobacco smoking, systemic inflammation, vitamin D deficiency, and the use of oral or inhaled corticosteroids (ICSs) are responsible for its occurrence in patients with COPD. This review will focus on the prevalence, pathogenesis, risk factors, diagnosis, and treatment of osteoporosis in COPD patients. PMID- 25788842 TI - Predicting pregnancy in women undergoing in-vitro fertilization with basal serum follicle stimulating hormone levels between 10.0 and 11.9 IU/L. AB - OBJECTIVE: To evaluate the results of the in vitro fertilization (IVF) cycle outcomes in women whose borderline basal follicle stimulating hormone (FSH) levels were between 10.0 and 11.9 IU/L and to analyze the predictors of pregnancy in this population. MATERIAL AND METHODS: A prospective cohort study was performed at an academic teaching hospital; participants were infertile couples in which the women were undergoing IVF treatment and had borderline basal highest FSH levels between 10.0 and 11.9 IU/L. Statistical modeling was performed to determine risk factors for pregnancy and clinical pregnancy. RESULTS: A clinical pregnancy rate of 26.5% per cycle and 35% per patient was found in the study population. Among all subjects and non-intracytoplasmic sperm injection (ICSI) subjects, younger age, higher gravidity, higher number of mature follicles on day of Human Chorionic gonadotrophin (hCG) triggering, higher number of oocytes retrieved, and number of embryos produced were significant discriminators between individuals who conceived and those who did not. However, only the number of embryos predicted those who had a clinical pregnancy when compared with those who did not. Higher gravidity, and basal estradiol (E2) levels, and lower maximum basal FSH levels predicted clinical pregnancy in non-ICSI patients. Among ICSI patients, the only predictor of pregnancy was a thicker endometrium. A trend towards higher pregnancy rates was noted in ICSI patients. CONCLUSION: We showed that pregnancy rates per cycle and per patient in this population were not significantly different than those in patients with a basal FSH level below 10.0 IU/L. Preliminary evidence suggests that ICSI is the fertilization method of choice in these patients. PMID- 25788843 TI - Autonomic control of cardiovascular system in pre- and postmenopausal women: a cross-sectional study. AB - OBJECTIVE: The aim of this cross-sectional study was to assess the features of autonomic control of the cardiovascular system in pre- and postmenopausal women. MATERIAL AND METHODS: We studied 185 postmenopausal women aged 59.3+/-8.5 years (mean+/-SD) and 104 premenopausal women aged 45.1+/-5.8 years. Standard indices of heart rate variability (HRV) (mean heart rate, coefficient of variation, standard deviation of the NN interval (the time elapsing between two consecutive R waves in the electrocardiogram with normal sinus rhythm) (SDNN), square root of the mean squared differences of successive NN intervals (RMSSD), proportion derived by dividing RR50, the number of interval differences of successive NN intervals greater than 50 ms, by the total number of NN intervals (PNN50), and power of low frequency (LF) and high frequency (HF) bands in absolute values and percentages of total spectral power) and index S of synchronization between the 0.1-Hz rhythms in heart rate and photoplethysmogram were compared between these two groups at rest. We assessed the following sex hormones: estradiol, follicle stimulating hormone, dehydroepiandrosterone sulfate, and testosterone. RESULTS: Mean heart rate and power of LF and HF bands were significantly different (p<0.05) in pre- and postmenopausal women. The autonomic indices were similar in women with natural and surgical menopause. Some indices (coefficient of variation, SDNN, RMSSD, PNN50, and power of LF and HF bands) showed weak correlation with menopause time in women with natural menopause. In women with surgical menopause, a moderate statistically significant correlation was observed only between menopause time and S index (r=-0.41, p=0.039). In premenopausal women, only testosterone correlated weakly with coefficient of variation, SDNN, PNN50, RMSSD, and power of HF band. In postmenopausal women, no correlations were found. We did not find any significant relationship between autonomic indices and hot flashes, assessed by hot flash diary. CONCLUSION: We did not find a clinically important relationship between cardiovascular autonomic control and menopausal status in women. PMID- 25788844 TI - Determination of risk factors and perinatal outcomes of singleton pregnancies complicated by isolated single umbilical artery in Turkish population. AB - OBJECTIVE: To address the possible risk factors, eventual pregnancy outcomes, and probable troubles in follow-ups of pregnancies complicated by an isolated single umbilical artery and to provide data on Turkish cases in such an aspect that ethnic divergences may have influence. MATERIAL AND METHODS: A total of 16568 singleton pregnancies that were delivered between May 2006 and May 2013 were retrospectively screened. Ninety-three fetuses were found to have an isolated single umbilical artery. One-hundred pregnancies that did not show any structural or chromosomal abnormalities were randomly selected from the rest of the cases to establish the control group. IBM SPSS Statistics 20.0 software was utilized for statistical analysis. Non-parametric data were analyzed with Mann-Whitney U test and were presented as means+/-standard deviations. P values less than 0.05 were statistically significant. For the adjustment of confounding factors, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by multiple logistic regression analysis. RESULTS: The incidence of small for gestational age (SGA) fetuses and hypertensive disorders in pregnancy was found to be significantly higher in cases with an isolated single umbilical artery (p<0.001 and p=0.022, respectively). Maternal smoking was found to be independently associated with the occurrence of an isolated single umbilical artery (OR: 3.556; 95% CI: 1.104 11.45). The risk of preterm birth was not higher in the study group (OR: 0.538; 95% CI: 0.576-2.873). The incidence of cases who underwent cesarean delivery because of non-reassuring fetal heart trace was similar in the study and control groups (p=0.499). CONCLUSION: Attention should be paid to the development of hypertensive disorders in cases with a diagnosis of an isolated single umbilical artery, and parents should be counseled properly, including the information on increased risk of SGA. Strict follow-up of pregnancies complicated with an isolated single umbilical artery in terms of preterm birth seems unfeasible except in cases with accompanying risk factors for preterm labor. PMID- 25788845 TI - Gestational diabetes mellitus screening and outcomes. AB - OBJECTIVE: To verify the usefulness of the World Health Organization criteria for the diagnosis of gestational diabetes mellitus in pregnant women and its effectiveness in the prevention of maternal and neonatal adverse results in women younger than 35 years without apparent risk factors for gestational diabetes mellitus. MATERIAL AND METHODS: This is a retrospective study based on population involving 1360 pregnant women who delivered and who were followed-up in a university hospital in Istanbul. All women underwent the 75-g oral glucose tolerance test screening, usually in between the 24(th)-28(th) weeks of pregnancy. In all cases, the identification of gestational diabetes mellitus was determined in accordance with the World Health Organization criteria. RESULTS: Approximately 28% of the pregnant women aged younger than 35 years with no risk factors for gestational diabetes mellitus were diagnosed with the oral glucose tolerance test in this study. In the gestational diabetes mellitus group, the primary cesarean section rate was importantly higher than that in the non gestational diabetes mellitus group. Preterm delivery was also associated with gestational diabetes mellitus. The diagnosis of gestational diabetes mellitus was strongly associated with admittance to the neonatal intensive care unit. Neonatal respiratory problems didn't showed any significant deviation between the groups. There was a moderate association between gestational diabetes mellitus and metabolic complications. CONCLUSION: Pregnant women with no obvious risk factors were diagnosed with gestational diabetes mellitus using the World Health Organization criteria. The treatment of these women potentially reduced their risk of adverse maternal and neonatal hyperglycemia-related events, such as cesarean section, polyhydramnios, preterm delivery, admission to neonatal intensive care unit, large for gestational age, and higher neonatal weight. PMID- 25788846 TI - Single-incision-two port laparoscopic tubal ligation: A cost comparison and technique description. AB - OBJECTIVE: Laparoscopic surgery is the principal minimally invasive technique that is used for the treatment of gynecologic pathologies. The single-incision laparoscopic surgery (SILS) is another innovation in minimally invasive medicine. The cost of the procedure correlates with the fundamental materials used to access the abdominal cavity and utilize trocars. MATERIAL AND METHODS: We applied the single-incision tubal ligation procedure to three patients. A 15-20-mm vertical incision was made in the umbilicus. Two trocars were inserted through the same incision at different fascial regions after insufflation of the abdomen. A 5-mm bipolar cautery was introduced through the accessory trocar, and the mid portion of the tubes was coagulated and cut bilaterally. RESULTS: The postoperative periods of the three patients were uneventful. All patients were discharged on the day of surgery. No major or minor complications occurred. CONCLUSION: The cost for the abdominal access will drop about 82%. When we consider the low pricing for the tubal ligation procedure, the single-incision technique will be more applicable by this method. Moreover, patients will have the advantages of single-incision laparoscopic surgery with low cost. PMID- 25788847 TI - Juvenile granulosa cell ovarian tumor: clinicopathological evaluation of ten patients. AB - OBJECTIVE: We aimed to analyze the clinical characteristics and management of ten patients who were diagnosed with juvenile granulosa cell ovarian tumor (JGCOT). MATERIAL AND METHODS: The records of 10 patients diagnosed with JGCOT between April 1995 and January 2014 in the Gynecological Oncology Clinic of our institution were retrospectively evaluated. RESULTS: The median age of the patients was 21.5 years (range; 13-36). Nine patients had stage IA disease and one had stage IC disease according to the International Federation of Gynecology and Obstetrics (FIGO) criteria. Five patients underwent pelvic and para-aortic lymph node dissection. None of them had lymph node involvement. All but two patients underwent unilateral salpingo-oophorectomy. One of the other two patients had cystectomy and the other had total abdominal hysterectomy and bilateral salpingo-oophorectomy. Three patients had adjuvant therapy after surgery. Two of these patients took chemotherapy and the other took radiotherapy. Four of the five patients who desired pregnancy achieved five term pregnancies. The median follow-up time of the patients was 58 months (range; 3-113). No recurrence was observed in the follow up period. CONCLUSION: JGCOT generally occurs during childhood. The primary management of JGCOT is through surgery. The role of adjuvant therapy is controversial. Because survival is long at early stages and most of the patients are young, fertility sparing surgery could be safely suggested to these patients. PMID- 25788848 TI - Gonadotropin-releasing hormone agonist triggering is effective, even at a low dose, for final oocyte maturation in ART cycles: Case series. AB - OBJECTIVE: To investigate the efficacy of low-dose gonadotropin-releasing hormone (GnRH) agonist for final oocyte maturation in females undergoing assisted reproductive treatment (ART) cycles. MATERIAL AND METHODS: Nine females undergoing ovarian stimulation in a GnRH antagonist protocol who received triptorelin 0.1 mg to trigger final oocyte maturation were included. Treatment outcomes of these patients were compared with those of controls, matched for age and oocyte number (n=14), who received 0.2 mg triptorelin at the same time. The luteal phase was supported with vaginal micronized progesterone and oral estradiol hemihydrate 2 mg twice daily. RESULTS: The mean (+/-) numbers of retrieved, metaphase II, and fertilized oocytes were 15.66+/-7.82, 14+/-7.28, and 10.11+/-5.86, respectively. The implantation and clinical pregnancy rates were 46.1% and 71.4%, respectively. Of the pregnancies, 2 were live births, 1 was a preterm birth (twins), 2 are on-going, and 2 ended as miscarriages. No case of OHSS was encountered. On comparison of the results of these patients (fresh cycles; n=7) with those of matched controls, there were no significant differences in terms of retrieved mature oocytes, implantation rates, or clinical pregnancy rates (p>0.05). CONCLUSION: These findings suggest that low-dose GnRH agonist triggering has similar efficacy as standard doses in terms of retrieved mature oocytes and clinical pregnancy rates in in vitro fertilization cycles. PMID- 25788849 TI - Efficacy of a real time optoelectronic device (TruScreenTM) in detecting cervical intraepithelial pathologies: a prospective observational study. AB - OBJECTIVE: To assess the effect of TruScreenTM (an objective optoelectronic cervical screening device) in improving the sensitivity of cervical screening programs either alone or in combination with Papanicolaou (PAP) smear or human papilloma virus (HPV) DNA screening. MATERIAL AND METHODS: Our study was performed in 285 patients with abnormal Pap test results. TruScreenTM and HPV screening methods were performed in all participants. Consistency and differences between the tests were compared with cervical biopsy results. RESULTS: TruScreenTM was found to be an approach method in the determination of cervical pathologies (ROC curve area underlined=0.606) and with an 89.5% negative predictive value. HPV screening remains a counterpart to TruScreenTM with a 0.620 area underlined in the ROC curve and an 83% negative predictive value. CONCLUSION: As determined in our study, TruScreenTM with a sensitivity of 86.1% can be used as a screening test with instant and not professional dependent results for cervical cancer screening. Avoiding from subjectivity in interpretation of Pap smears and requirement for pathologists, TruScreenTM can be a used for cervical cancer screening especially in countries with a low socio economic status. The combination of TruScreenTM and HPV screening was not able to demonstrate a significant rise of effectiveness in screening. PMID- 25788850 TI - Might uterus transplantation be an option for uterine factor infertility? AB - Current data on uterus allotransplantation research has been reviewed and summarized. Over the past 15 years, progress in uterus transplantation research has increased dramatically. As a consequence, the first pregnancy and delivery following uterus allotransplantation in rats have been reported. The technique has been better defined. Although clinical pregnancy and delivery following uterus allotransplantation has been reported in humans, there are still many questions to be answered before clinical application. Gestational surrogacy still remains an important option for being a genetic parent in selected cases with uterine factor infertility. PMID- 25788851 TI - Multiple sclerosis; a disease of reproductive-aged women and the dilemma involving contraceptive methods. AB - Multiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation in the central nerves system. Because the disease predominantly affects women of reproductive ages, having knowledge about contraception options for MS patients can make clinicians provide better counseling. Although most contraceptive methods are generally accepted as safe and effective in MS patients, recent studies have raised questions about their potential adverse effects on the disease. The use of contraceptive methods to avoid unintended pregnancies is crucial in MS patients, particularly during the relapse phase of the disease or the time when the disease is not completely under control. This review investigates the contraception options and their effects on female MS patients. Providing appropriate contraception options to multiple sclerosis patients will be one of the most challenging issues for clinicians to deal with. Recent studies have raised questions that the use of hormonal contraceptives may at least partly contribute to the rise in incidence of MS in women. This review investigates the contraception options and their effects on female MS patients. PMID- 25788852 TI - Osseous metaplasia of the cervix: A rare transformation. AB - Although numerous cases of endometrial osseous metaplasia appear in the literature, only 6 cases of osseous metaplasia of the cervix have been reported since 1982. A 30 years old nulligravida women was referred to our colposcopy clinic with cervical mass. General, gynecologic and colposcopic assessments were done. The patient had an excision biopsy. Diagnosis of cervical osseous metaplasia was confirmed on histologic examination. The cervical epithelium has the potency to differentiate to multiple types of epithelium including osseous epithelium. PMID- 25788853 TI - What is your diagnosis? PMID- 25788854 TI - Bleeding and fetal Doppler parameter. PMID- 25788855 TI - Required propofol dose for anesthesia and time to emerge are affected by the use of antiepileptics: prospective cohort study. AB - BACKGROUND: We investigated the impact of the type of neurological disorder on the required propofol dose for anesthesia and the time to emerge from anesthesia during dental treatment in patients with autism (AU), cerebral palsy (CP), and intellectual disability (ID), some of whom also had epilepsy. METHODS: We studied 224 patients with a neurological disorder who underwent dental treatment under intravenous general anesthesia. Patients were categorized according to neurological disorder (AU, CP, and ID; and with or without an antiepileptic). The propofol dose required for anesthesia, time to emerge, and modeled propofol blood concentration at emergence were evaluated. RESULTS: In patients not given an antiepileptic, we found no significant differences in the propofol dose, modeled propofol blood concentration at emergence, or time to emerge among patients with AU, CP, and ID (P > 0.05). When using an antiepileptic, the dose of propofol (5.7 +/- 1.51 mg/kg/h) was significantly lower than without an antiepileptic (6.8 +/- 1.27 mg/kg/h) (P < 0.0001). The modeled propofol blood concentration at emergence in patients given an antiepileptic (0.5 +/- 0.03 MUg/ml) was significantly lower than without an antiepileptic (0.7 +/- 0.02 MUg/ml) (P < 0.0001). The time to emerge in patients given an antiepileptic (29.5 +/- 12.5 min) was significantly longer than without an antiepileptic (21.6 min +/- 10.0 min) (P < 0.0001). CONCLUSION: The propofol dose required for anesthesia and the time to emerge from anesthesia are not affected by the type of neurological disorder, but are affected by antiepileptic use. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN000014179), Date of registration 4 June 2014. PMID- 25788856 TI - Relationship between abnormal osteoblasts and cellular immunity in multiple myeloma. AB - Bone destruction and abnormal immunity always occur in patients with multiple myeloma (MM), which manifested by impaired osteoblasts and immune system. In this study, we investigated the quantity and function of osteoblasts by co-culture, the status of cellular immunity by flow cytometry, and the relationship between them in MM patients. The results showed that the numbers and function of osteoblasts in MM patients were lower than those in normal controls. Bortezomib could increase the numbers, calcium depositions and the expression of Bone morphogenetic protein-2 (BMP-2) mRNA of osteoblasts from MM patients in vitro. The status of cellular immunity in MM patients was abnormal, including decreased ratio of CD4(+)/CD8(+), DC1/DC2 and Th1/Th2, and increased ratio of regulatory T cells. The ratio of CD4(+)/CD8(+)(r = 0.685) and CD4(+)CD25(+)/CD3(+)T(r = 0.568) were positively correlated with the quantity of osteoblasts (both P < 0.05). The serum interleukin-7(IL-7) level of MM patients was higher than that of normal controls (2.07 +/- 0.71 vs. 1.62 +/- 0.15 ng/L, P < 0.05), and was negatively correlated with the quantity of osteoblasts (r = -0.682, P < 0.01). Our data indicated that the proliferation and osteogenic potential of osteoblasts in MM patients were decreased which could be recovered by bortezomib in vitro. The down regulation of cellular immunity was correlated with the quantity of osteoblasts. PMID- 25788857 TI - The RelB alternative NF-kappaB subunit promotes autophagy in 22Rv1 prostate cancer cells in vitro and affects mouse xenograft tumor growth in vivo. AB - BACKGROUND: The involvement of NF-kappaB signaling in prostate cancer (PCa) has largely been established through the study of the classical p65 subunit. Nuclear localization of p65 in PCa patient tissues has been shown to correlate with biochemical recurrence, while in vitro studies have demonstrated that the classical NF-kappaB signaling pathway promotes PCa progression and metastatic potential. More recently, the nuclear location of RelB, a member of the alternative NF-kappaB signaling, has also been shown to correlate with the Gleason score. The current study aims to clarify the role of alternative NF kappaB in PCa cells by exploring, in vitro and in vivo, the effects of RelB overexpression on PCa biology. METHODS: Using a lentivirus-expression system, we constitutively overexpressed RelB or control GFP into 22Rv1 cells and monitored alternative transcriptional NF-kappaB activity. In vivo, tumor growth was assessed after the injection of 22Rv1-derived cells into SCID mice. In vitro, the impact of RelB on 22Rv1 cell proliferation was evaluated in monolayer culture. The anchorage-independent cell growth of derived-22Rv1 cells was assessed by soft agar assay. Apoptosis and autophagy were evaluated by Western blot analysis in 22Rv1-derived cells cultured in suspension using poly-HEMA pre-coated dishes. RESULTS: The overexpression of RelB in 22Rv1 cells induced the constitutive activation of the alternative NF-kappaB pathway. In vivo, RelB expression caused a lag in the initiation of 22Rv1-induced tumors in SCID mice. In vitro, RelB stimulated the proliferation of 22Rv1 cells and reduced their ability to grow in soft agar. These observations may be reconciled by our findings that, when cultured in suspension on poly-HEMA pre-coated dishes, 22Rv1 cells expressing RelB were more susceptible to cell death, and more specifically to autophagy controlled death. CONCLUSIONS: This study highlights a role of the alternative NF kappaB pathway in proliferation and the controlled autophagy. Thus, the interplay of these properties may contribute to tumor survival in stress conditions while promoting PCa cells growth contributing to the overall tumorigenicity of these cells. PMID- 25788859 TI - Myricetin enhance chemosensitivity of 5-fluorouracil on esophageal carcinoma in vitro and in vivo. AB - BACKGROUND: Flavonoids are structurally heterogeneous, polyphenolic compounds present in high concentrations in fruits, vegetables, and other plant-derived foods. Currently, there is growing interest in the therapeutic applications of bioflavonoids for the treatment and prevention of diseases in humans. Myricetin is a naturally occurring flavonoid that is commonly found in tea, berries, fruits, vegetables, and medicinal herbs. Previous studies have shown that myricetin has antioxidant, anti-inflammatory and potent anticancer effects. It was interesting to investigate whether myricetin has the cooperative inhibitory effect combined with 5-fluorouracil on esophageal cancer cells. METHODS: EC9706 cells were treated with 5-fluorouracil combination with or without myricetin. Colony formation assays, CCK-8 assay and flow cytometry were used to evaluate the chemosensitization activity of myricetin combine with 5-fluorouracil on the cell growth and viability, cell proliferation and apoptosis in vitro. Western blot was engaged to detect changes of Survivin, Cyclin D, Bcl-2, Caspase-3 and P53 protein expression level, which were associated with cells proliferation and apoptosis. Nude mouse tumor xenograft model was built to assessed chemosensitization effect of myricetin combine with 5-fluorouracil in vivo. RESULTS: Compared with the 5 fluorouracil group without myricetin treatment, the groups treated with 5 fluorouracil combine with myricetin showed significantly suppressed cell survival fraction and proliferation, increased the cell apoptosis. Decreased Survivin, Cyclin D, Bcl-2, and increased Caspase-3, P53 expression level were aslo confirmed by western blot in 5-fluorouracil combine with myricetin groups in vitro. And in vivo assay, growth speed of tumor xenografts was significantly decreased in the mice treated with 5-fluorouracil + myricetin combiantion group. CONCLUSIONS: The study demonstrated both in vitro and in vivo evidence that combination of myricetin with 5-fluorouracil chemotherapy can enhance tumor chemosensitivity of esophageal cancer EC9706 cells, and myricetin could be a potential chemosensitizer for esophageal cancer therapy. PMID- 25788858 TI - Hep88 mAb-initiated paraptosis-like PCD pathway in hepatocellular carcinoma cell line through the binding of mortalin (HSPA9) and alpha-enolase. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent hepatic cancer worldwide. Currently, a targeted therapy via monoclonal antibodies (mAbs) specific to tumor-associated antigen is undergoing continual development in HCC treatment. METHODS: In this regard, after establishing and consequently exploring Hep88 mAb's tumoricidal effect on hepatocellular carcinoma cell line (HepG2 cell line), the Hep88 mAb's specific antigens from both membrane and cytoplasmic fractions of HepG2 cell line were identified by 2-D gel electrophoresis and western blot analysis. After in-gel digestion and subsequent analysis by liquid chromatography-mass spectrometry (LC-MS), mortalin (HSPA9) and alpha-enolase were identified. The recombinant proteins specific to Hep88 mAb were cloned and expressed in E. coli BL21(DE3). Moreover, alteration of HepG2 and Chang liver cell line after being induced by Hep88 mAb for 1-3 days was investigated using a transmission electron microscope. RESULTS: The result demonstrated that Hep88 mAb can bind to the recombinant mortalin (HSPA9) and alpha-enolase. In addition, the gradual appearing of mitochondria vacuolization and endoplasmic reticulum dilatation were observed. Those characteristics might be explained by the paraptosis-like program cell death (PCD), which is induced by the binding of Hep88 mAb to mortalin (HSPA9). Mortalin depletion resulting from the formation of Hep88 mAb-mortalin (HSPA9) complex might initiate transcription-independence of p53-mediated apoptosis. Additionally, Hep88mAb-alpha-enolase complex might initiate HepG2 cells energy exhaustion by glycolysis pathway obstruction. CONCLUSION: These fascinating results imply that Hep88 mAb might be a promising tool for the development of an effective treatment of HCC in the next decade. PMID- 25788860 TI - K-D:rib dampens Hs 578T cancer cell chemoinvasion and proliferation. AB - BACKGROUND: Cancer cells, even in the presence of available oxygen, have a glycolysis enhancement. The "aerobic glycolysis" is known as the Warburg effect and it is considered one of the fundamental hallmarks of metabolic alteration during malignant transformation. A feature of many tumors is also a change into ions equilibrium, with particular reference to K(+) intracellular concentration. Another hallmark in cancer is the reprogrammed chemotaxis pathways in favour of tumor cell dissemination. RESULTS: The doubling population time of 5 mM K:D-rib treated Hs 578T (HTB-126 (r) ATCC) cell line is reduce by 30% respect to the control. During the chemotactic invasion assay, the relative number of motile and invasive cells, counted inside the FBS-AGAR spot, shows a decrease with the maintenance of the treatment reaching the 25% after nine days. Hs 578Bst (HTB-125 (r) ATCC) non-tumor cell line treated for nineteen days with 5 mM K:D-rib was split twice as well as the control. No morphological change was visible in the treated respect to untreated cells. CONCLUSIONS: We demonstrate that the synergic action of potassium bicarbonate and D-ribose has effect on Hs 578T cancer cell line proliferation reducing the cell cycle time. At 5 mM concentration, K:D-rib is able to modify the tumorigenic potential of human breast cancer cell line Hs 578T, interfering in vitro with the capability of Hs 578 T cell line to migrate under chemotactic stimuli. Despite this, K:D-rib solution, does not exhibit any appreciable toxicity as confirmed by the proliferation assay accomplished on Hs 578Bst cell line. PMID- 25788861 TI - Analysis of the functional repertoire of a mutant form of survivin, K129E, which has been linked to lung cancer. AB - BACKGROUND: Survivin is a protein that is normally present only in G2 and M phases in somatic cells, however, in cancer cells, it is expressed throughout the cell cycle. A prosurvival factor, survivin is both an inhibitor of apoptosis and an essential mitotic protein, thus it has attracted much attention as a target for new oncotherapies. Despite its prevalence in cancer, reports of survivin mutations have mostly been restricted to loci within its promoter, which increase the abundance of the protein. To date the only published mutation within the coding sequence is an adenine > guanine substitution in exon 4. This polymorphism, which was found in a cohort of Korean lung cancer patients, causes a lysine > glutamic acid mutation (K129E) in the protein. However, whether it plays a causative role in cancer has not been addressed. METHODS: Using site directed mutagenesis we recapitulate K129E expression in cultured human cells and assess its anti-apoptotic and mitotic activities. RESULTS: K129E retains its anti apoptotic activity, but causes errors in mitosis and cytokinesis, which may be linked to its reduced affinity for borealin. CONCLUSION: K129E expression can induce genomic instability by introducing mitotic aberrations, thus it may play a causative role in cancer. PMID- 25788862 TI - HOXA11 gene is hypermethylation and aberrant expression in gastric cancer. AB - BACKGROUND: Aberrant DNA methylation is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor genes and other genes in diverse human cancers. Gastric carcinoma is one of the tumors with a high frequency of aberrant methylation in promoter region. Hence we investigated the promoter methylation status and expression level of HOXA11 gene which may involve in GC development. METHODS: Thirty-two surgical excised gastric cancer specimens, twelve paired adjacent non-cancerous specimens and seven normal gastric mucosas were examined. The methylation status and expression level of HOXA11 gene were determined by bisulfite sequencing polymerase chain reaction (BSP), real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) respectively. HOXA11 expression was knocked-down with siRNA to mimic HOXA11 gene hypermethylation and ability of cell proliferation and migration was determinate. In addition, we analyzed and correlated the findings with clinicopathological features. RESULTS: The methylation level of HOXA11 gene in gastric cancer tissues and adjacent non-cancerous tissues were higher than those in normal gastric mucosa (P < 0.05). The methylation level was higher in TNM III and IV patients of GC than those in TNM I and II patients (P < 0.05). The expression of HOXA11 mRNA and protein decreased in normal gastric mucosa, peri cancer tissue and GC (P < 0.05). HOXA11 expression was inversely correlated with DNA methylation (P < 0.05). Knocked-down of HOXA11 expression with siRNA in BGC 823 cells enhanced cell proliferation compared with control, but no significant different was observed in migration ability. CONCLUSION: Hypermethylation and decreased expression of HOXA11 gene may be involved in the carcinogenesis and development of GC and may provide useful information for the prediction of the malignant behaviors of GC. And the expression of HOXA11 is impaired by DNA methylation. However, repression of HOXA11 expression promoted BGC-823 cell proliferation. PMID- 25788863 TI - The stimulatory activity of plasma in patients with advanced non-small cell lung cancer requires TLR-stimulating nucleic acid immunoglobulin complexes and discriminates responsiveness to chemotherapy. AB - BACKGROUND: Therapeutic options for patients with non-small cell lung cancer (NSCLC) are often restricted to systemic chemotherapy. However, the molecular and cellular processes during chemotherapy of advanced NSCLC patients still remain unclear. Here we investigated the stimulatory activity of plasma in advanced NSCLC patients and its correlation with chemotherapy. METHODS: Whole blood samples from advanced NSCLC patients were collected before the first, second, and third cycle of chemotherapy. Plasma was isolated following centrifugation of whole blood. PBMCs were isolated from whole-blood specimens by Ficoll-Hypaque density gradient centrifugation. Immune complexes (ICs) were isolated from NSCLC plasma using the IgG Purification Kit. qRT-PCR was used to detect a broad array of cytokines and chemokines. RESULTS: The plasma in advanced NSCLC patients was endowed with stimulatory activity and capable of inducing proinflammatory cytokines. Both nucleic acids and immunoglobulin components were required for the stimulatory activity of NSCLC plasma. In consistent, TLR8 and TLR9 conferred the stimulatory activity of plasma in NSCLC patients. Of note, we revealed the decreased stimulatory activity of plasma in patients who responded to chemotherapy. CONCLUSIONS: Our findings demonstrated that the plasma of advanced NSCLC patients required TLR-stimulating nucleic acid immunoglobulin complexes and could discriminate the responsiveness to chemotherapy, which might provide a novel mechanism by which the proinflammatory immune response was induced and a potential new biomarker for evaluating responsiveness to chemotherapy in NSCLC patients. PMID- 25788864 TI - Serum microRNA-205 as a novel biomarker for cervical cancer patients. AB - OBJECTIVE: Serum microRNAs (miRNAs) are a novel class of diagnostic and prognostic biomarkers for numerous cancers. However, the level and clinical relevance of circulating miR-205 transcripts in human serum of cervical cancer patients are unclear. The purpose of this study was to determine serum miR-205 levels in cervical cancer patients and explore its association with clinicopathological factors and prognosis. METHODS: Serum miR-205 expression was investigated in 60 cervical cancer patients and 60 healthy normal controls by using real-time PCR. Correlations between miR-205 expression and the clinicopathological features and prognosis of cervical cancer patients were then evaluated. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of serum miR-205. RESULTS: Serum miR-205 was significantly upregulated in cervical cancer patients compared with healthy donors (p < 0.01), and a high level of miR-205 expression was correlated with poor tumor differentiation (p = 0.009), lymph node metastasis (p = 0.015) and increased tumor stage (p = 0.001). The serum miR-205 level was capable of separating advanced stage from early stage metastatic cervical cancer from non metastatic samples and poorly differentiated tumors from differentiated tumors with an area under the curve values of 0.74, 0.694 and 0.717, respectively. The expression of miR-205 was also higher in the cervical cancer tissues compared with the para-carcinoma tissues. In addition, Kaplan-Meier survival analysis showed that cervical cancer patients with high miR-205 expression tended to have shorter overall survival. In multivariate Cox regression analysis, miR-205 was identified as an independent prognostic marker. CONCLUSIONS: Serum miR-205, which is upregulated in cervical cancer, represents a predictive biomarker for the prognosis of cervical cancer patients. PMID- 25788865 TI - Astrocytoma-associated antigens - IL13Ralpha2, Fra-1, and EphA2 as potential markers to monitor the status of tumour-derived cell cultures in vitro. AB - BACKGROUND: The molecular heterogeneity of high-grade astrocytomas underlies the difficulties in the development of representative and valuable in vitro experimental models for their studies. The purpose of our study was to estimate the value of astrocytoma-associated antigens (AAAs) - IL13Ralpha2, Fra-1, EphA2 - and the most common molecular aberrations typical for astrocytomas as potential markers to screen the status of tumour-derived cell cultures in vitro. METHODS: The tumour-derived cell cultures were established from high-grade astrocytomas. The expression analyses of the tested genes were performed via semi-quantitative real-time PCR and subsequently verified by immunohistochemical and immunocytochemical technique. The analyses of molecular aberrations at DNA level included gene dosage status evaluation based on real-time PCR, sequencing analysis, and loss of heterozygosity (LOH) assay. RESULTS: The expression analyses based on semi-quantitative real-time PCR showed that in the final stage of culture the expression level of all tested AAAs was significantly higher or at least comparable to that of primary tumours; however, two expression patterns were observed during cell culture establishment. Analysis at the single cell level via immunocytochemistry also demonstrated an increase of the level of tested proteins and/or selection of tumour cell populations strongly positive for AAAs vs. other cell types including admixed non-tumoural cells. Confrontation of AAA expression data with the results of molecular analyses at DNA level seems to support the latter, revealing that the expression pattern of astrocytoma associated antigens in tumour-derived cells in subsequent stages of culture is convergent with changes in the molecular profile of examined cell populations. CONCLUSIONS: The consistency of the obtained results seems to support the use of the selected AAAs, in particular IL13Ralpha2 and Fra-1, as tools facilitating the establishment of tumour-derived cultures. However, the intratumoural heterogeneity of high-grade astrocytomas may require further detailed characterisation of the molecular profile of a tumour in order to evaluate the value of the experimental model in relation to the individual context of particular studies. PMID- 25788867 TI - Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers: Retraction. AB - [This retracts the article on p. 1 in vol. 10, PMID: 21297921.]. PMID- 25788866 TI - Cancer review: Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is the most common biliary tract malignancy. CCA is classified as intrahepatic, perihilar or distal extrahepatic; the individual subtypes differ in their biologic behavior, clinical presentation, and management. Throughout the last decades, CCA incidence rates had significantly increased. In addition to known established risk factors, novel possible risk factors (i.e. obesity, hepatitis C virus) have been identified that are of high importance in developed countries where CCA prevalence rates have been low. CCA tends to develop on the background of inflammation and cholestasis. In recent years, our understanding of the molecular mechanisms of cholangiocarcinogenesis has increased, thereby, providing the basis for molecularly targeted therapies. In its diagnostic evaluation, imaging techniques have improved, and the role of complementary techniques has been defined. There is a need for improved CCA biomarkers as currently used ones are suboptimal. Multiple staging systems have been developed, but none of these is optimal. The prognosis of CCA is considered dismal. However, treatment options have improved throughout the last two decades for carefully selected subgroups of CCA patients. Perihilar CCA can now be treated with orthotopic liver transplantation with neoadjuvant chemoradiation achieving 5-year survival rates of 68%. Classically considered chemotherapy resistant, the ABC-02 trial has shown the therapeutic benefit of combination therapy with gemcitabine and cisplatin. The benefits of adjuvant treatments for resectable CCA, local ablative therapies and molecularly targeted therapies still need to be defined. In this article, we will provide the reader with an overview over CCA, and discuss the latest developments and controversies. PMID- 25788868 TI - Remarkable regression of massive deep vein thrombosis in response to intensive oral rivaroxaban treatment. AB - Deep vein thrombosis (DVT) is a common disease and is associated with pulmonary embolism (PE). Proximal iliofemoral DVT may lead to severe PE and chronic venous insufficiency. The standard therapy for DVT is anticoagulant therapy using heparin and a vitamin K antagonist, but a recent clinical study showed that rivaroxaban, an oral Xa inhibitor, was comparable to standard therapy and had less bleeding complications. Intensive high-dose anticoagulation is recommended during the initial 3 weeks of DVT treatment. The present report describes a case of a 77-year-old male showing a remarkable regression of DVT in response to rivaroxaban treatment within the initial 3 weeks of therapy and who did not experience any adverse events. His DVT was massive and was accompanied by proximal iliofemoral vein thrombus and iliac vein compression syndrome. Rivaroxaban, especially in intensive high-dose treatment, might be a safe and effective therapeutic choice for massive DVT. PMID- 25788869 TI - Multiple biomarker models for improved risk estimation of specific cardiovascular diseases related to metabolic syndrome: a cross-sectional study. AB - BACKGROUND: Metabolic syndrome (MetS) is the co-occurrence of several conditions that increase risk of chronic disease and mortality. Multivariate models for calculating risk of MetS-related diseases based on combinations of biomarkers are promising for future risk estimation if based on large population samples. Given biomarkers' nonspecificity and commonality in predicting diseases, we hypothesized that unique combinations of the same clinical diagnostic criteria can be used in different multivariate models to develop more accurate individual and cumulative risk estimates for specific MetS-related diseases. METHODS: We utilized adult biomarker and cardiovascular disease (CVD) data from the National Health and Nutrition Examination Survey as part of a cross-sectional analysis. Serum C-reactive protein (CRP), glycohemoglobin, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, fasting glucose, and apolipoprotein-B were modeled. CVDs included congestive heart failure, coronary heart disease, angina, myocardial infarction, and stroke. Decile analysis for disease prevalence in each biomarker group and multivariate logistic regression for estimation of odds ratios were employed to measure the joint association between multiple biomarkers and CVD diagnoses. RESULTS: Of the biomarkers considered, glycohemoglobin, triglycerides, and CRP were consistently associated with the CVD outcomes of interest in decile analysis and were selected for the final models. Associations were overestimated when using single-marker models in comparison with full models; individual odds ratios decreased an average of 16.4% from the single-biomarker models to the joint association models for CRP, 6.6% for triglycerides, and 1.4% for glycohemoglobin. However, joint associations were stronger than any single-marker estimate. Additionally, reduced models produced unique combinations of biomarkers for specific CVD outcomes. CONCLUSION: The reduced joint association modeling results suggest that unique combinations of biomarkers with their related measure of association can be used to produce more accurate cumulative risk estimates for each CVD. Additionally, our results indicate that the use of multiple biomarkers in a single multivariate model may provide increased accuracy of individual biomarker association estimates by controlling for statistical artifacts and spurious relationships due to co-biomarker confounding. PMID- 25788870 TI - Cutaneous Leishmaniasis: Current Treatment Practices in the USA for Returning Travelers. AB - Leishmaniasis, a protozoal infection transmitted by sandfly bite, produces a clinical spectrum of disease ranging from asymptomatic infection to ulcerative skin and mucosal lesions to visceral involvement. Leishmaniasis is endemic in regions of Africa, the Middle East, south Asia, southern Europe, northern South America, and Central America. There has been an increase in imported leishmaniasis into developed, non-endemic countries due to increasing global travel. While pentavalent antimonials have been the mainstay of antileishmanial treatment for decades, newer therapeutic options have become available for all forms of infection, including liposomal amphotericin B, miltefosine, fluconazole, and ketoconazole. For the returning traveler with cutaneous leishmaniasis in the USA, treatment approaches are determined based on infecting species, initial presentation, extent and progression of disease, the advantages and drawbacks of available parenteral and oral drugs, and clinician-consultant experience. PMID- 25788871 TI - Improved Generalized Born Solvent Model Parameters for Protein Simulations. AB - The generalized Born (GB) model is one of the fastest implicit solvent models and it has become widely adopted for Molecular Dynamics (MD) simulations. This speed comes with tradeoffs, and many reports in the literature have pointed out weaknesses with GB models. Because the quality of a GB model is heavily affected by empirical parameters used in calculating solvation energy, in this work we have refit these parameters for GB-Neck, a recently developed GB model, in order to improve the accuracy of both the solvation energy and effective radii calculations. The data sets used for fitting are significantly larger than those used in the past. Comparing to other pairwise GB models like GB-OBC and the original GB-Neck, the new GB model (GB-Neck2) has better agreement to Poisson Boltzmann (PB) in terms of reproducing solvation energies for a variety of systems ranging from peptides to proteins. Secondary structure preferences are also in much better agreement with those obtained from explicit solvent MD simulations. We also obtain near-quantitative reproduction of experimental structure and thermal stability profiles for several model peptides with varying secondary structure motifs. Extension to non-protein systems will be explored in the future. PMID- 25788872 TI - Non-cell autonomous and non-catalytic activities of ATX in the developing brain. AB - The intricate formation of the cerebral cortex requires a well-coordinated series of events, which are regulated at the level of cell-autonomous and non-cell autonomous mechanisms. Whereas cell-autonomous mechanisms that regulate cortical development are well-studied, the non-cell autonomous mechanisms remain poorly understood. A non-biased screen allowed us to identify Autotaxin (ATX) as a non cell autonomous regulator of neural stem cells. ATX (also known as ENPP2) is best known to catalyze lysophosphatidic acid (LPA) production. Our results demonstrate that ATX affects the localization and adhesion of neuronal progenitors in a cell autonomous and non-cell autonomous manner, and strikingly, this activity is independent from its catalytic activity in producing LPA. PMID- 25788873 TI - Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases. AB - Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer's and prion diseases) or motor deficits (Parkinson's and related diseases). PMID- 25788875 TI - Understanding the rules of the road: proteomic approaches to interrogate the blood brain barrier. AB - The blood brain barrier (BBB) is often regarded as a passive barrier that protects brain parenchyma from toxic substances, circulating leukocytes, while allowing the passage of selected molecules. Recently, a combination of molecular profiling techniques have characterized the constituents of the BBB based on in vitro models using isolated endothelial cells and ex vivo models analyzing isolated blood vessels. Characterization of gene expression profiles that are specific to the endothelium of brain blood vessels, and the identification of proteins, cells and multi-cellular structure that comprise the BBB have led to a emerging consensus that the BBB is not, in and of itself, a simple barrier of specialized endothelial cells. Instead, regulation of transcytosis, permeability, and drug translocation into the central nervous system is now viewed as a collection of neurovascular units (NVUs) that, together, give the BBB its unique biological properties. We will review recent technology advancing the understanding of the molecular basis of the BBB with a focus on proteomic approaches. PMID- 25788874 TI - Methamphetamine effects on blood-brain barrier structure and function. AB - Methamphetamine (Meth) is a widely abuse psychostimulant. Traditionally, studies have focused on the neurotoxic effects of Meth on monoaminergic neurotransmitter terminals. Recently, both in vitro and in vivo studies have investigated the effects of Meth on the BBB and found that Meth produces a decrease in BBB structural proteins and an increase in BBB permeability to various molecules. Moreover, preclinical studies are validated by clinical studies in which human Meth users have increased concentrations of toxins in the brain. Therefore, this review will focus on the structural and functional disruption of the BBB caused by Meth and the mechanisms that contribute to Meth-induced BBB disruption. The review will reveal that the mechanisms by which Meth damages dopamine and serotonin terminals are similar to the mechanisms by which the blood-brain barrier (BBB) is damaged. Furthermore, this review will cover the factors that are known to potentiate the effects of Meth (McCann et al., 1998) on the BBB, such as stress and HIV, both of which are co-morbid conditions associated with Meth abuse. Overall, the goal of this review is to demonstrate that the scope of damage produced by Meth goes beyond damage to monoaminergic neurotransmitter systems to include BBB disruption as well as provide a rationale for investigating therapeutics to treat Meth-induced BBB disruption. Since a breach of the BBB can have a multitude of consequences, therapies directed toward the treatment of BBB disruption may help to ameliorate the long-term neurodegeneration and cognitive deficits produced by Meth and possibly even Meth addiction. PMID- 25788876 TI - cGMP in mouse rods: the spatiotemporal dynamics underlying single photon responses. AB - Vertebrate vision begins when retinal photoreceptors transduce photons into electrical signals that are then relayed to other neurons in the eye, and ultimately to the brain. In rod photoreceptors, transduction of single photons is achieved by a well-understood G-protein cascade that modulates cGMP levels, and in turn, cGMP-sensitive inward current. The spatial extent and depth of the decline in cGMP during the single photon response (SPR) have been major issues in phototransduction research since the discovery that single photons elicit substantial and reproducible changes in membrane current. The spatial profile of cGMP decline during the SPR affects signal gain, and thus may contribute to reduction of trial-to-trial fluctuations in the SPR. Here we summarize the general principles of rod phototransduction, emphasizing recent advances in resolving the spatiotemporal dynamics of cGMP during the SPR. PMID- 25788878 TI - Photopic and scotopic spatiotemporal tuning of adult zebrafish vision. AB - Sensitivity to spatial and temporal patterns is a fundamental aspect of vision. Herein, we investigated this sensitivity in adult zebrafish for a wide range of spatial (0.014 to 0.511 cycles/degree [c/d]) and temporal frequencies (0.025 to 6 cycles/s) to better understand their visual system. Measurements were performed at photopic (1.8 log cd m(-2)) and scotopic (-4.5 log cd m(-2)) light levels to assess the optokinetic response (OKR). The resulting spatiotemporal contrast sensitivity (CS) functions revealed that the OKR of zebrafish is tuned to spatial frequency and speed but not to temporal frequencies. Thereby, optimal test parameters for CS measurements were identified. At photopic light levels, a spatial frequency of 0.116 +/- 0.01 c/d (mean +/- SD) and a grating speed of 8.42 +/- 2.15 degrees/second (d/s) was ideal; at scotopic light levels, these values were 0.110 +/- 0.02 c/d and 5.45 +/- 1.31 d/s, respectively. This study allows to better characterize zebrafish mutants with altered vision and to distinguish between defects of rod and cone photoreceptors as measurements were performed under different light conditions. PMID- 25788877 TI - Life-time expression of the proteins peroxiredoxin, beta-synuclein, PARK7/DJ-1, and stathmin in the primary visual and primary somatosensory cortices in rats. AB - Four distinct proteins are regulated in the aging neuroretina and may be regulated in the cerebral cortex, too: peroxiredoxin, beta-synuclein, PARK[Parkinson disease(autosomal recessive, early onset)]7/DJ-1, and Stathmin. Thus, we performed a comparative analysis of these proteins in the the primary somatosensory cortex (S1) and primary visual cortex (V1) in rats, in order to detect putative common development-, maturation- and age-related changes. The expressions of peroxiredoxin, beta-synuclein, PARK[Parkinson disease (autosomal recessive, early onset)]7/DJ-1, and Stathmin were compared in the newborn, juvenile, adult, and aged S1 and V1. Western blot (WB), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and immunohistochemistry (IHC) analyses were employed to determine whether the changes identified by proteomics were verifiable at the cellular and molecular levels. All of the proteins were detected in both of the investigated cortical areas. Changes in the expressions of the four proteins were found throughout the life-time of the rats. Peroxiredoxin expression remained unchanged over life-time. Beta-Synuclein expression was massively increased up to the adult stage of life in both the S1 and V1. PARK[Parkinson disease (autosomal recessive, early onset)]7/DJ-1 exhibited a massive up-regulation in both the S1 and V1 at all ages. Stathmin expression was massively down regulated after the neonatal period in both the S1 and V1. The detected protein alterations were analogous to their retinal profiles. This study is the first to provide evidence that peroxiredoxin, beta synuclein, PARK[Parkinson disease (autosomal recessive, early onset)]7/DJ-1, and Stathmin are associated with postnatal maturation and aging in both the S1 and V1 of rats. These changes may indicate their involvement in key functional pathways and may account for the onset or progression of age-related pathologies. PMID- 25788879 TI - Control of fluid intake by estrogens in the female rat: role of the hypothalamus. AB - Body fluid homeostasis is maintained by a complex network of central and peripheral systems that regulate blood pressure, fluid and electrolyte excretion, and fluid intake. The behavioral components, which include well regulated water and saline intake, are influenced by a number of hormones and neuropeptides. Since the early 1970s, it has been known that the ovarian estrogens play an important role in regulating fluid intake in females by decreasing water and saline intake under a variety of hypovolemic conditions. Behavioral, electrophysiological, gene and protein expression studies have identified nuclei in the hypothalamus, along with nearby forebrain structures such as the subfornical organ (SFO), as sites of action involved in mediating these effects of estrogens and, importantly, all of these brain areas are rich with estrogen receptors (ERs). This review will discuss the multiple ER subtypes, found both in the cell nucleus and associated with the plasma membrane, that provide diversity in the mechanism through which estrogens can induce behavioral changes in fluid intake. We then focus on the relevant brain structures, hypothesized circuits, and various peptides, such as angiotensin, oxytocin, and vasopressin, implicated in the anti-dipsogenic and anti-natriorexigenic actions of the estrogens. PMID- 25788880 TI - Dorsal periaqueductal gray simultaneously modulates ventral subiculum induced plasticity in the basolateral amygdala and the nucleus accumbens. AB - The ventral subiculum of the hippocampus projects both to the basolateral amygdala (BLA), which is typically, associated with a response to aversive stimuli, as well as to the nucleus accumbens (NAcc), which is typically associated with a response to appetitive stimuli. Traditionally, studies of the responses to emotional events focus on either negative or positive affect-related processes, however, emotional experiences often affect both. The ability of high level processing brain regions (e.g., medial prefrontal cortex) to modulate the balance between negative and positive affect-related regions was examined extensively. In contrast, the ability of low-level processing areas (e.g., periaqueductal gray-PAG) to do so, has not been sufficiently studied. To address whether midbrain structures have the ability to modulate limbic regions, we first examined the ventral subiculum stimulation's (vSub) ability to induce plasticity in the BLA and NAcc simultaneously in rats. Further, dorsal PAG (dPAG) priming ability to differentially modulate vSub stimulation induced plasticity in the BLA and the NAcc was subsequently examined. vSub stimulation resulted in plasticity in both the BLA and the NAcc simultaneously. Moreover, depending on stimulus intensity, differential dPAG priming effects on LTP in these two regions were observed. The results demonstrate that negative and positive affect-related processes may be simultaneously modulated. Furthermore, under some conditions lower-level processing areas, such as the dPAG, may differentially modulate plasticity in these regions and thus affect the long-term emotional outcome of the experience. PMID- 25788882 TI - Detailed behavioral assessment promotes accurate diagnosis in patients with disorders of consciousness. AB - INTRODUCTION: Assessing the awareness level in patients with disorders of consciousness (DOC) is made on the basis of exhibited behaviors. However, since motor signs of awareness (i.e., non-reflex motor responses) can be very subtle, differentiating the vegetative from minimally conscious states (which is in itself not clear-cut) is often challenging. Even the careful clinician relying on standardized scales may arrive at a wrong diagnosis. AIM: To report our experience in tackling this problem by using two in-house use assessment procedures developed at Reuth Rehabilitation Hospital, and demonstrate their clinical significance by reviewing two cases. METHODS: (1) Reuth DOC Response Assessment (RDOC-RA) -administered in addition to the standardized tools, and emphasizes the importance of assessing a wide range of motor responses. In our experience, in some patients the only evidence for awareness may be a private specific movement that is not assessed by standard assessment tools. (2) Reuth DOC Periodic Intervention Model (RDOC-PIM) - current literature regarding assessment and diagnosis in DOC refers mostly to the acute phase of up to 1 year post injury. However, we have found major changes in responsiveness occurring 1 year or more post-injury in many patients. Therefore, we conduct periodic assessments at predetermined times points to ensure patients are not misdiagnosed or neurological changes overlooked. RESULTS: In the first case the RDOC-RA promoted a more accurate diagnosis than that based on standardized scales alone. The second case shows how the RDOC-PIM allowed us to recognize late recovery and promoted reinstatement of treatment with good results. CONCLUSION: Adding a detailed periodic assessment of DOC patients to existing scales can yield critical information, promoting better diagnosis, treatment, and clinical outcomes. We discuss the implications of this observation for the future development and validation of assessment tools in DOC patients. PMID- 25788881 TI - Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3. AB - Brain glycogen synthase kinase-3 (GSK3) is hyperactive in several neurological conditions that involve impairments in both cognition and neurogenesis. This raises the hypotheses that hyperactive GSK3 may directly contribute to impaired cognition, and that this may be related to deficiencies in neural precursor cells (NPC). To study the effects of hyperactive GSK3 in the absence of disease influences, we compared adult hippocampal NPC proliferation and performance in three cognitive tasks in male and female wild-type (WT) mice and GSK3 knockin mice, which express constitutively active GSK3. NPC proliferation was ~40% deficient in both male and female GSK3 knockin mice compared with WT mice. Environmental enrichment (EE) increased NPC proliferation in male, but not female, GSK3 knockin mice and WT mice. Male and female GSK3 knockin mice exhibited impairments in novel object recognition, temporal order memory, and coordinate spatial processing compared with gender-matched WT mice. EE restored impaired novel object recognition and temporal ordering in both sexes of GSK3 knockin mice, indicating that this repair was not dependent on NPC proliferation, which was not increased by EE in female GSK3 knockin mice. Acute 1 h pretreatment with the GSK3 inhibitor TDZD-8 also improved novel object recognition and temporal ordering in male and female GSK3 knockin mice. These findings demonstrate that hyperactive GSK3 is sufficient to impair adult hippocampal NPC proliferation and to impair performance in three cognitive tasks in both male and female mice, but these changes in NPC proliferation do not directly regulate novel object recognition and temporal ordering tasks. PMID- 25788883 TI - Amygdala responses to unpleasant pictures are influenced by task demands and positive affect trait. AB - The role of attention in emotional processing is still the subject of debate. Recent studies have found that high positive affect in approach motivation narrows attention. Furthermore, the positive affect trait has been suggested as an important component for determining human variability in threat reactivity. We employed functional magnetic resonance imaging to investigate whether different states of attention control would modulate amygdala responses to highly unpleasant pictures relative to neutral and whether this modulation would be influenced by the positive affect trait. Participants (n = 22, 12 male) were scanned while viewing neutral (people) or unpleasant pictures (mutilated bodies) flanked by two peripheral bars. They were instructed to (a) judge the picture content as unpleasant or neutral or (b) to judge the difference in orientation between the bars in an easy condition (0 or 90(?) orientation difference) or (c) in a hard condition (0 or 6(?) orientation difference). Whole brain analysis revealed a task main effect of brain areas related to the experimental manipulation of attentional control, including the amygdala, dorsolateral prefrontal cortex, and posterior parietal cortex. Region of interest analysis showed an inverse correlation (r = -0.51, p < 0.01) between left amygdala activation and positive affect level when participants viewed unpleasant stimuli and judged bar orientation in the easy condition. This result suggests that subjects with high positive affect exhibit lower amygdala reactivity to distracting unpleasant pictures. In conclusion, the current study suggests that positive affect modulates attention effect on unpleasant pictures, therefore attenuating emotional responses. PMID- 25788884 TI - Self-regulation therapy increases frontal gray matter in children with fetal alcohol spectrum disorder: evaluation by voxel-based morphometry. AB - Children with fetal alcohol spectrum disorder show executive function (EF) deficits, particularly in self-regulation skills, and abnormalities in brain regions critical for these skills. None of the validated EF interventions for these children has been evaluated with regards to impacts on brain structure. Twenty-nine children with FASD were assigned to either an immediate-treatment (TX) or delayed-treatment control (DTC) group (DTC). Nineteen typically developing children served as healthy controls (CT). All received a structural MRI scan and baseline neuropsychological testing, following which the TX group underwent 12 weekly 1.5-h sessions of the Alert Program for Self-Regulation((r)). After treatment or a period of ~14 weeks, all received a repeat scan and post intervention testing. Whole-brain and region-of-interest analyses using voxel based morphometry evaluated group differences and changes over time in gray matter (GM). Exploratory analyses revealed significant group changes: (1) At baseline, combined TX and DTC groups demonstrated global GM reductions compared with the CT group. (2) Region-of-interest analysis using a frontal mask, comparing post-intervention to pre-intervention results, showed significantly increased GM in the left middle frontal gyrus (BA10), right frontal pole (BA11), and right anterior cingulate (BA32) in the TX group. Similar results were not found in the DTC or CT groups. (3) At post-intervention, both TX and CT groups showed larger GM volumes than the DTC group in the left superior frontal gyrus (BA9), which was smaller in the FASD group at baseline. These results suggested that Alert led to improvements in post-intervention testing of self-regulation skills and typical brain development in treated children. PMID- 25788885 TI - Phase diagram of spiking neural networks. AB - In computer simulations of spiking neural networks, often it is assumed that every two neurons of the network are connected by a probability of 2%, 20% of neurons are inhibitory and 80% are excitatory. These common values are based on experiments, observations, and trials and errors, but here, I take a different perspective, inspired by evolution, I systematically simulate many networks, each with a different set of parameters, and then I try to figure out what makes the common values desirable. I stimulate networks with pulses and then measure their: dynamic range, dominant frequency of population activities, total duration of activities, maximum rate of population and the occurrence time of maximum rate. The results are organized in phase diagram. This phase diagram gives an insight into the space of parameters - excitatory to inhibitory ratio, sparseness of connections and synaptic weights. This phase diagram can be used to decide the parameters of a model. The phase diagrams show that networks which are configured according to the common values, have a good dynamic range in response to an impulse and their dynamic range is robust in respect to synaptic weights, and for some synaptic weights they oscillates in alpha or beta frequencies, independent of external stimuli. PMID- 25788886 TI - Good and bad sides of TGFbeta-signaling in myocardial infarction. AB - Myocardial infarction is a prevailing cause of death in industrial countries. In spite of the good opportunities we have nowadays in interventional cardiology to reopen the clotted coronary arteries for reperfusion of ischemic areas, post infarct remodeling emerges and contributes to unfavorable structural conversion processes in the myocardium, finally resulting in heart failure. The growth factor TGFbeta is upregulated during these processes. In this review, an overview on the functional role of TGFbeta signaling in the process of cardiac remodeling is given, as it can influence apoptosis, fibrosis and hypertrophy thereby predominantly aggravating ischemia/reperfusion injury. PMID- 25788887 TI - From War to Classroom: PTSD and Depression in Formerly Abducted Youth in Uganda. AB - BACKGROUND: Trained local screeners assessed the mental-health status of male and female students in Northern Ugandan schools. The study aimed to disclose potential differences in mental health-related impairment in two groups, former child soldiers (n = 354) and other war-affected youth (n = 489), as well as to separate factors predicting mental suffering in learners. METHODS: Participants were randomly selected. We used the Post-Traumatic Diagnostic Scale to assess symptoms of post-traumatic stress disorder (PTSD) and for potential depression the respective section of the Hopkins Symptom Checklist with a locally validated cut-off. RESULTS: Almost all respondents had been displaced at least once in their life. 30% of girls and 50% of the boys in the study reported past abduction history. Trauma exposure was notably higher in the group of abductees. In former child soldiers, a PTSD rate of 32% was remarkably higher than that for non abductees (12%). Especially in girls rates of potential depression were double those in the group of former abductees (17%) than in the group of non-abductees (8%). In all groups, trauma exposure increased the risk of developing PTSD. A path-analytic model for developing PTSD and potential depression revealed both previous trauma exposure as well as duration of abduction to have significant influences on trauma-related mental suffering. Findings also suggest that in Northern Ugandan schools trauma spectrum disorders are common among war-affected learners. CONCLUSIONS: Therefore, it is suggested the school context should be used to provide mental-health support structures within the education system for war-affected youth at likely risk of developing war-related mental distress. PMID- 25788888 TI - Stages in the psychological resolution of schizophrenia. AB - From the work of Dr. Michael Robbins in Massachusetts, USA, it is known that nine schizophrenic patients out of a series of 18, and a further schizophrenic patient, treated by him achieved positive outcomes using psychoanalytic methodology. Four of these had strikingly successful outcomes, for example completing their treatment without a need for further medication, and also becoming happily married or graduating at university. This paper aims to illustrate the stages identified by him through which this can be accomplished. Dr. Robbins' Stages of Psychological Therapy of Schizophrenia are compared with Dr. Steggles' detailed case study of a patient's recovery from schizoaffective disorder. These two data sources are juxtaposed and compared. Dr. Robbins' therapeutic stages are found to parallel exactly Dr. Steggles' findings from her case study, which she summarized as her psychodynamic pentapointed cognitive construct (PPCC) model of her schizoaffective patient's experience. Psychological therapy of schizophrenia is still in its early stages of development. However, Dr. Robbins' psychoanalytic psychotherapeutic technique has given rise to positive outcomes in 10 of the 19 patients he treated, that is, his series of 18 patients together with a further patient; these 19 patients he gave full psychological treatment, i.e., usually four sessions per week. The Stages he identifies in his therapeutic process match perfectly the stages Dr. Steggles identified in her own patient's healing mind. Not all schizophrenic patients are likely to be able to benefit from this psychological therapy. Females seem to be better able than males to respond to the treatment, and motivation is necessary for a successful outcome. It is not known how to identify precisely those patients who will be successful. But those patients who do benefit may counterbalance by their economic activity the healthcare costs of those who do not recover, as well as achieving benefit from their human suffering. Many of the other groups of patients suffering from schizophrenia can be helped by engaging with a clinician for social skills or family therapy, and where appropriate this should always be done. PMID- 25788889 TI - A brief review of exercise, bipolar disorder, and mechanistic pathways. AB - Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology. PMID- 25788890 TI - Spontaneous strategy use in children with autism spectrum disorder: the roles of metamemory and language skills. AB - Metamemory, or beliefs about one's own memory capabilities, knowing what you know, and knowing what you don't know, has frequently been linked to the spontaneous use of rehearsal strategies in typically developing children. However, limited research has investigated mnemonic strategy use, metamemory, or the relationship between these two cognitive processes in children with autism spectrum disorders (ASDs). The current study examined the relative strength of metamemory knowledge and language skills as predictors of rehearsal use and memory performance in individuals with ASD. Twenty-one children with ASD and 21 children in a combined comparison group were matched on chronological and verbal mental age. Over two sessions, participants completed a serial recall task, a language measure, and a metamemory questionnaire. Children were classified as rehearsers/non-rehearsers based on behavioral observations and/or verbal reports of strategy use. As expected from previous research, the comparison group had a significantly higher proportion of rehearsers than the ASD group. However, spontaneous rehearsers performed significantly better on the serial recall task than non-rehearsers, regardless of group membership. Children in the comparison group had a higher mean total score on the metamemory questionnaire than the ASD group. However, when examined by rehearsal use, participants classified as rehearsers, regardless of diagnostic group, scored significantly higher on the metamemory questionnaire than non-rehearsers. Finally, across groups, hierarchical regression analyses identified both metamemory and language proficiency as significant predictors of rehearsal strategy use. The fact that the predictors showed the same relationship across the comparison group and the ASD group implies that metamemory and language proficiency, while separate entities, are both fundamental underlying skills contributing to the emergence of rehearsal strategies, and that the results are likely generalizable to other populations with developmental challenges. PMID- 25788891 TI - A case of posterior reversible encephalopathy syndrome associated with gilenya((r)) (fingolimod) treatment for multiple sclerosis. AB - We describe posterior reversible encephalopathy syndrome (PRES) in a woman with multiple sclerosis treated with Gilenya((r)) (Fingolimod). The first symptoms appeared after 21 months of fingolimod treatment. She experienced headache, altered mental status, cognitive deficits, seizures, and visual disturbances. Not at any time during the course of the disease could any signs of infection or rheumatic disorder be detected. Test for anti-neuronal antibodies was also negative. Her blood pressure was normal. MRI showed widespread cortical and subcortical changes with some mass-effect in the temporo-occipital-parietal lobes in the left hemisphere. Contrast enhancement was seen in the leptomeninges and, in addition, there were no areas with restricted diffusion and no signs of hemorrhage. Her condition deteriorated until fingolimod was discontinued. Slowly her condition improved and after 8 months, the only symptoms that remained were two small, non-corresponding, right inferior scotomas. We believe that all symptoms, the clinical course, and the MRI findings in this case can all be explained by considering PRES, a probably rare, but serious, side effect of fingolimod treatment. PMID- 25788892 TI - Concurrence of multiple sclerosis and brain tumors. PMID- 25788893 TI - Mechanisms mediating environmental chemical-induced endocrine disruption in the adrenal gland. AB - Humans are continuously exposed to hundreds of man-made chemicals that pollute the environment in addition to multiple therapeutic drug treatments administered throughout life. Some of these chemicals, known as endocrine disruptors (EDs), mimic endogenous signals, thereby altering gene expression, influencing development, and promoting disease. Although EDs are eventually removed from the market or replaced with safer alternatives, new evidence suggests that early-life exposure leaves a fingerprint on the epigenome, which may increase the risk of disease later in life. Epigenetic changes occurring in early life in response to environmental toxicants have been shown to affect behavior, increase cancer risk, and modify the physiology of the cardiovascular system. Thus, exposure to an ED or combination of EDs may represent a first hit to the epigenome. Only limited information is available regarding the effect of ED exposure on adrenal function. The adrenal gland controls the stress response, blood pressure, and electrolyte homeostasis. This endocrine organ therefore has an important role in physiology and is a sensitive target of EDs. We review herein the effect of ED exposure on the adrenal gland with particular focus on in utero exposure to the plasticizer di(2-ethylehyl) phthalate. We discuss the challenges associated with identifying the mechanism mediating the epigenetic origins of disease and availability of biomarkers that may identify individual or population risks. PMID- 25788894 TI - IL28B gene polymorphisms in mono- and HIV-coinfected chronic hepatitis C patients. AB - INTRODUCTION: Single-nucleotide polymorphisms (SNPs) associated with hepatitis C virus (HCV) clearance were identified near the IL28B gene. Coinfection by the human immunodeficiency virus (HIV) influences the course of HCV contributing to liver damage. Nevertheless, little is known about the relationship between these SNPs and HCV/HIV coinfection. Our aim was to estimate the frequencies of the allelic and genotypic variants of the IL28B polymorphisms rs12979860 (C/T) and rs8099917 (T/G) and their possible association with the establishment of HCV infection. METHODOLOGY: A total of 199 non-infected controls and 230 patients with chronic hepatitis C, including 53 coinfected with HIV, participated in the study. Genotyping consisted of polymerase chain reaction and subsequent analysis of the restriction patterns resulting from exposure to endonucleases. RESULTS: Among the controls with established results, 47.4% (90/190) exhibited the rs12979860 CC genotype, 43.7 CT, and 8.9% TT, whereas 29.1% (66/227), 51.5%, and 19.4% of the patients exhibited the CC, CT, and TT genotypes, respectively. With respect to rs8099917, 66.8% (133/199) of the controls exhibited the TT genotype, 31.2% TG, and 2.0% GG, whereas 56.1% (129/230), 40.9%, and 3.0% of the patients exhibited the TT, TG, and GG genotypes, respectively. CONCLUSION: The frequencies of the rs12979860 C allele and CC genotype and of the rs8099917 T allele and TT genotype were significantly higher among controls compared with patients, thus confirming the suggested protective effect against HCV infection. No significant difference was observed in the genotype and allelic distributions between the mono- and coinfected patients. PMID- 25788895 TI - Viruses and bacteria in floodplain lakes along a major Amazon tributary respond to distance to the Amazon River. AB - In response to the massive volume of water along the Amazon River, the Amazon tributaries have their water backed up by 100s of kilometers upstream their mouth. This backwater effect is part of the complex hydrodynamics of Amazonian surface waters, which in turn drives the variation in concentrations of organic matter and nutrients, and also regulates planktonic communities such as viruses and bacteria. Viruses and bacteria are commonly tightly coupled to each other, and their ecological role in aquatic food webs has been increasingly recognized. Here, we surveyed viral and bacterial abundances (BAs) in 26 floodplain lakes along the Trombetas River, the largest clear-water tributary of the Amazon River's north margin. We correlated viral and BAs with temperature, pH, dissolved inorganic carbon, dissolved organic carbon (DOC), phosphorus, nitrogen, turbidity, water transparency, partial pressure of carbon dioxide (pCO2), phytoplankton abundance, and distance from the lake mouth until the confluence of the Trombetas with the Amazon River. We hypothesized that both bacterial and viral abundances (VAs) would change along a latitudinal gradient, as the backwater effect becomes more intense with increased proximity to the Amazon River; different flood duration and intensity among lakes and waters with contrasting sources would cause spatial variation. Our measurements were performed during the low water period, when floodplain lakes are in their most lake-like conditions. Viral and BAs, DOC, pCO2, and water transparency increased as distance to the Amazon River increased. Most viruses were bacteriophages, as viruses were strongly linked to bacteria, but not to phytoplankton. We suggest that BAs increase in response to DOC quantity and possibly quality, consequently leading to increased VAs. Our results highlight that hydrodynamics plays a key role in the regulation of planktonic viral and bacterial communities in Amazonian floodplain lakes. PMID- 25788896 TI - In vitro Production of IL-6 and IFN-gamma is Influenced by Dietary Variables and Predicts Upper Respiratory Tract Infection Incidence and Severity Respectively in Young Adults. AB - Assessment of immune responses in healthy adults following dietary or lifestyle interventions is challenging due to significant inter-individual variability. Thus, gaining a better understanding of host factors that contribute to the heterogeneity in immunity is necessary. To address this question, healthy adults [n = 36, 18-40 years old, body mass index (BMI) 20-35 kg/m(2)] were recruited. Dietary intake was obtained via 3-day dietary recall records, physical activity level was evaluated using the International Physical Activity Questionnaire, and peripheral blood mononuclear cells were isolated from peripheral blood. Expression of activation markers on unstimulated immune subsets was assessed by flow cytometry. T-cell proliferation and cytokine secretion was assessed following in vitro stimulation with anti-CD3 or lipopolysaccharide. Furthermore, the incidence and severity of cold or flu symptoms were obtained from self reported upper respiratory tract infection (URTI) questionnaires. The relationship between activation marker expression on T cells and T-cell effector functions; and in vitro cytokine secretion and URTI was determined by linear or logistic regression. CD69 and CD25 expression on unstimulated T cells was significantly associated with T-cell proliferation and interleukin-2 secretion. Incidence and severity of cold or flu symptoms was significantly associated with in vitro interleukin-6 and interferon-gamma secretion, respectively. Furthermore, host factors (e.g., age, BMI, physical activity, and diet) contributed significantly to the relationship between activation marker expression and T-cell effector function, and cytokine secretion and cold and flu status. In conclusion, these results suggest that lifestyle and dietary factors are important variables that contribute to immune responses and should be included in human clinical trials that assess immune endpoints. PMID- 25788897 TI - Mycobacterium avium ss. paratuberculosis Zoonosis - The Hundred Year War - Beyond Crohn's Disease. AB - The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohn's disease has been debated for more than a century. The controversy is due to the fact that Crohn's disease is so similar to a disease of MAP-infected ruminant animals, Johne's disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohn's specimens as well as dedicated specialty labs successful in culturing MAP from Crohn's patients have provided strong argument for MAP's role in Crohn's disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between protein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders. PMID- 25788898 TI - NKG2D Ligands in Tumor Immunity: Two Sides of a Coin. AB - The activating/co-stimulatory receptor NKG2D (natural-killer group 2, member D) is expressed on the surface of all human NK, NKT, CD8(+) T, and subsets of gammadelta(+) T cells. The significance of NKG2D function in tumor immunity has been well demonstrated in experimental animal models. However, the role of human NKG2D ligands in regulating tumor immunity and cancer prognosis had been controversial in the literature. In this review, we summarize the latest advancement, discuss the controversies, and present evidence that membrane-bound and soluble NKG2D ligands oppositely regulate tumor immunity. We also discuss new perspectives of targeting NKG2D ligands for cancer immunotherapy. PMID- 25788899 TI - Effect of quorum sensing signals produced by seaweed-associated bacteria on carpospore liberation from Gracilaria dura. AB - Epiphytic and endophytic bacteria associated with green macroalgae Ulva (U. fasciata and U. lactuca) and red macroalgae Gracilaria (G. corticata and G. dura) have been identified from three different seasons to evaluate the effect of quorum sensing (QS) molecules on carpospores liberation from Gracilaria dura. The bacterial isolates belonging to the orders Bacillales, Pseudomonadales, Alteromonadales, and Vibrionales were present in all seasons, whereas Actinomycetales and Enterobacteriales were confined to pre-monsoon and post monsoon seasons, respectively. Among all the Gram-negative bacteria, seven isolates were found to produce different types of N-acyl homoserine lactones (AHLs). Interestingly, Shewanella algae produced five types of AHL: C4-HSL, HC4 HSL, C6-HSL, 3-oxo-C6-HSL, and 3-oxo-C12-HSL. Subsequently, the AHLs producing bacterial isolates were screened for carpospore liberation from G. dura and these isolates were found to positively induce carpospore liberation over the control. Also, observed that carpospore liberation increased significantly in C4- and C6 HSL treated cystocarps. Sodium dodecyl sulfate and native polyacrylamide gel electrophoresis of the total protein of the C4- and C6-HSL treated cystocarps showed two specific peptide bands of different molecular weights (50 kDa and 60 kDa) as compared to the control, confirming their indirect effect on carpospore liberation. PMID- 25788900 TI - A genomic comparison of two termites with different social complexity. AB - The termites evolved eusociality and complex societies before the ants, but have been studied much less. The recent publication of the first two termite genomes provides a unique comparative opportunity, particularly because the sequenced termites represent opposite ends of the social complexity spectrum. Zootermopsis nevadensis has simple colonies with totipotent workers that can develop into all castes (dispersing reproductives, nest-inheriting replacement reproductives, and soldiers). In contrast, the fungus-growing termite Macrotermes natalensis belongs to the higher termites and has very large and complex societies with morphologically distinct castes that are life-time sterile. Here we compare key characteristics of genomic architecture, focusing on genes involved in communication, immune defenses, mating biology and symbiosis that were likely important in termite social evolution. We discuss these in relation to what is known about these genes in the ants and outline hypothesis for further testing. PMID- 25788901 TI - Epigenetics and animal virus infections. PMID- 25788902 TI - Microsatellite genotyping of medieval cattle from central Italy suggests an old origin of Chianina and Romagnola cattle. AB - Analysis of DNA from archeological remains is a valuable tool to interpret the history of ancient animal populations. So far most studies of ancient DNA target mitochondrial DNA (mtDNA), which reveals maternal lineages, but only partially the relationships of current breeds and ancient populations. In this study we explore the feasibility of nuclear DNA analysis. DNA was extracted from 1000 years old cattle bone collected from Ferento, an archeological site in central Italy. Amplification of 15 microsatellite FAO-recommended markers with PCR products yielded genotypes for four markers. Expected heterozygosity was comparable with values of modern breeds, but observed heterozygosity was underestimated due to allelic loss. Genetic distances suggested a position intermediate between (1) Anatolian, Balkan, Sicilian and South-Italian cattle and (2) the Iberian, North-European and Central-European cattle, but also a clear relationship with two central-Italian breeds, Chianina and Romagnola. This suggests that these breeds are derived from medieval cattle living in the same area. Our results illustrate the potential of ancient DNA for reconstructing the history of local cattle husbandry. PMID- 25788904 TI - Letter from the Editors-in-Chief. PMID- 25788905 TI - Fat cell-secreted adiponectin mediates physical exercise-induced hippocampal neurogenesis: an alternative anti-depressive treatment? AB - Psychological depression is drawing accumulating attention nowadays, due to the skyrocketing incidence worldwide and the enormous burdens it incurs. Physical exercise has been long recognized for its therapeutic effects on depressive disorders, although knowledge of the underlying mechanisms remains limited. Suppressed hippocampal neurogenesis in adult brains has been regarded, at least partly, contributive to depression, whereas physical exercise that restores neurogenesis accordingly exerts the anti-depressive action. Several recent publications have suggested the potential role of adiponectin, a protein hormone secreted by peripheral mature adipocytes, in mediating physical exercise triggered enhancement of hippocampal neurogenesis and alleviation of depression. Here, we briefly review these novel findings and discuss the possibility of counteracting depression by modulating adiponectin signaling in the hippocampus with interventions including physical exercise and administration of pharmacological agents. PMID- 25788903 TI - Network-based analysis of the sphingolipid metabolism in hypertension. AB - Common diseases like essential hypertension or diabetes mellitus are complex as they are polygenic in nature, such that each genetic variation only has a small influence on the disease. Genes operates in integrated networks providing the blue-print for all biological processes and conditional of the complex genotype determines the state and dynamics of any trait, which may be modified to various extent by non-genetic factors. Thus, diseases are heterogenous ensembles of conditions with a common endpoint. Numerous studies have been performed to define genes of importance for a trait or disease, but only a few genes with small effect have been identified. The major reasons for this modest progress is the unresolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition. Here, a two-step procedure is presented in which physiological heterogeneity is disentangled and genetic effects are analyzed by variance decomposition of genetic interactions and by an information theoretical approach including 162 single nucleotide polymorphisms (SNP) in 84 genes in the sphingolipid metabolism and related networks in blood pressure regulation. As expected, almost no genetic main effects were detected. In contrast, two-gene interactions established the entire sphingolipid metabolic and related genetic network to be highly involved in the regulation of blood pressure. The pattern of interaction clearly revealed that epistasis does not necessarily reflects the topology of the metabolic pathways i.e., the flow of metabolites. Rather, the enzymes and proteins are integrated in complex cellular substructures where communication flows between the components of the networks, which may be composite in structure. The heritabilities for diastolic and systolic blood pressure were estimated to be 0.63 and 0.01, which may in fact be the maximum heritabilities of these traits. This procedure provide a platform for studying and capturing the genetic networks of any polygenic trait, condition, or disease. PMID- 25788906 TI - Induced pluripotent stem cell-derived neural stem cell therapies for spinal cord injury. AB - The greatest challenge to successful treatment of spinal cord injury is the limited regenerative capacity of the central nervous system and its inability to replace lost neurons and severed axons following injury. Neural stem cell grafts derived from fetal central nervous system tissue or embryonic stem cells have shown therapeutic promise by differentiation into neurons and glia that have the potential to form functional neuronal relays across injured spinal cord segments. However, implementation of fetal-derived or embryonic stem cell-derived neural stem cell therapies for patients with spinal cord injury raises ethical concerns. Induced pluripotent stem cells can be generated from adult somatic cells and differentiated into neural stem cells suitable for therapeutic use, thereby providing an ethical source of implantable cells that can be made in an autologous fashion to avoid problems of immune rejection. This review discusses the therapeutic potential of human induced pluripotent stem cell-derived neural stem cell transplantation for treatment of spinal cord injury, as well as addressing potential mechanisms, future perspectives and challenges. PMID- 25788908 TI - Clinical strategies to enhance nerve regeneration. PMID- 25788907 TI - Synthetic neurosteroids on brain protection. AB - Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids administration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute promising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3alpha hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions. PMID- 25788909 TI - "Bad regenerators" die after spinal cord injury: insights from lampreys. PMID- 25788910 TI - Prediabetes and type 2 diabetes implication in central proliferation and neurogenesis. PMID- 25788911 TI - Can cinnamon bring aroma in Parkinson's disease treatment? PMID- 25788912 TI - Acupuncture: a potent therapeutic tool for inducing adult neurogenesis. PMID- 25788913 TI - Acute carbon monoxide poisoning and delayed neurological sequelae: a potential neuroprotection bundle therapy. PMID- 25788914 TI - The human retinal stem niches could overlap a vascular anatomical pattern. PMID- 25788915 TI - A substrate scaffold for assessment of nerve regeneration and neurodegenerative diseases. PMID- 25788916 TI - Acetylcholinesterase inhibitor modifications: a promising strategy to delay the progression of Alzheimer's disease. PMID- 25788917 TI - LOTUS, a potent blocker of Nogo receptor-1 causing inhibition of axonal growth. PMID- 25788918 TI - Multiple facets of poly(ADP-ribose) polymerase-1 in neurological diseases. PMID- 25788919 TI - Neural regeneration after peripheral nerve injury repair is a system remodelling process of interaction between nerves and terminal effector. PMID- 25788920 TI - Sleeve bridging of the rhesus monkey ulnar nerve with muscular branches of the pronator teres: multiple amplification of axonal regeneration. AB - Multiple-bud regeneration, i.e., multiple amplification, has been shown to exist in peripheral nerve regeneration. Multiple buds grow towards the distal nerve stump during proximal nerve fiber regeneration. Our previous studies have verified the limit and validity of multiple amplification of peripheral nerve regeneration using small gap sleeve bridging of small donor nerves to repair large receptor nerves in rodents. The present study sought to observe multiple amplification of myelinated nerve fiber regeneration in the primate peripheral nerve. Rhesus monkey models of distal ulnar nerve defects were established and repaired using muscular branches of the right forearm pronator teres. Proximal muscular branches of the pronator teres were sutured into the distal ulnar nerve using the small gap sleeve bridging method. At 6 months after suture, two-finger flexion and mild wrist flexion were restored in the ulnar-sided injured limbs of rhesus monkey. Neurophysiological examination showed that motor nerve conduction velocity reached 22.63 +/- 6.34 m/s on the affected side of rhesus monkey. Osmium tetroxide staining demonstrated that the number of myelinated nerve fibers was 1,657 +/- 652 in the branches of pronator teres of donor, and 2,661 +/- 843 in the repaired ulnar nerve. The rate of multiple amplification of regenerating myelinated nerve fibers was 1.61. These data showed that when muscular branches of the pronator teres were used to repair ulnar nerve in primates, effective regeneration was observed in regenerating nerve fibers, and functions of the injured ulnar nerve were restored to a certain extent. Moreover, multiple amplification was subsequently detected in ulnar nerve axons. PMID- 25788921 TI - Large animal models of human cauda equina injury and repair: evaluation of a novel goat model. AB - Previous animal studies of cauda equina injury have primarily used rat models, which display significant differences from humans. Furthermore, most studies have focused on electrophysiological examination. To better mimic the outcome after surgical repair of cauda equina injury, a novel animal model was established in the goat. Electrophysiological, histological and magnetic resonance imaging methods were used to evaluate the morphological and functional outcome after cauda equina injury and end-to-end suture. Our results demonstrate successful establishment of the goat experimental model of cauda equina injury. This novel model can provide detailed information on the nerve regenerative process following surgical repair of cauda equina injury. PMID- 25788922 TI - Expression pattern of neuregulin-1 type III during the development of the peripheral nervous system. AB - Neuregulin-1 type III is a key regulator in Schwann cell proliferation, committing to a myelinating fate and regulating myelin sheath thickness. However, the expression pattern of neuregulin-1 type III in the peripheral nervous system during developmental periods (such as the premyelinating stage, myelinating stage and postmyelinating stage) has rarely been studied. In this study, dorsal root ganglia were isolated from rats between postnatal day 1 and postnatal day 56. The expression pattern of neuregulin-1 type III in dorsal root ganglia neurons at various developmental stages were compared by quantitative real-time polymerase chain reaction, western blot assay and immunofluorescent staining. The expression of neuregulin-1 type III mRNA reached its peak at postnatal day 3 and then stabilized at a relative high expression level from postnatal day 3 to postnatal day 56. The expression of neuregulin-1 type III protein increased gradually from postnatal day 1, reached a peak at postnatal day 28, and then decreased at postnatal day 56. Immunofluorescent staining results showed a similar tendency to western blot assay results. Experimental findings indicate that the expression of neuregulin-1 type III in rat dorsal root ganglion was increased during the premyelinating (from postnatal day 2 to postnatal day 5) and myelinating stage (from postnatal day 5 to postnatal day 10), but remained at a high level in the postmyelinating stage (after postnatal day 10). PMID- 25788924 TI - Use of nerve elongator to repair short-distance peripheral nerve defects: a prospective randomized study. AB - Repair techniques for short-distance peripheral nerve defects, including adjacent joint flexion to reduce the distance between the nerve stump defects, "nerve splint" suturing, and nerve sleeve connection, have some disadvantages. Therefore, we designed a repair technique involving intraoperative tension-free application of a nerve elongator and obtained good outcomes in the repair of short-distance peripheral nerve defects in a previous animal study. The present study compared the clinical outcomes between the use of this nerve elongator and performance of the conventional method in the repair of short-distance transection injuries in human elbows. The 3-, 6-, and 12-month postoperative follow-up results demonstrated that early neurological function recovery was better in the nerve elongation group than in the conventional group, but no significant difference in long-term neurological function recovery was detected between the two groups. In the nerve elongation group, the nerves were sutured without tension, and the duration of postoperative immobilization of the elbow was decreased. Elbow function rehabilitation was significantly better in the nerve elongation group than in the control group. Moreover, there were no security risks. The results of this study confirm that the use of this nerve elongator for repair of short-distance peripheral nerve defects is safe and effective. PMID- 25788923 TI - Biological conduit small gap sleeve bridging method for peripheral nerve injury: regeneration law of nerve fibers in the conduit. AB - The clinical effects of 2-mm small gap sleeve bridging of the biological conduit to repair peripheral nerve injury are better than in the traditional epineurium suture, so it is possible to replace the epineurium suture in the treatment of peripheral nerve injury. This study sought to identify the regeneration law of nerve fibers in the biological conduit. A nerve regeneration chamber was constructed in models of sciatic nerve injury using 2-mm small gap sleeve bridging of a biodegradable biological conduit. The results showed that the biological conduit had good histocompatibility. Tissue and cell apoptosis in the conduit apparently lessened, and regenerating nerve fibers were common. The degeneration regeneration law of Schwann cells and axons in the conduit was quite different from that in traditional epineurium suture. During the prime period for nerve fiber regeneration (2-8 weeks), the number of Schwann cells and nerve fibers was higher in both proximal and distal ends, and the effects of the small gap sleeve bridging method were better than those of the traditional epineurium suture. The above results provide an objective and reliable theoretical basis for the clinical application of the biological conduit small gap sleeve bridging method to repair peripheral nerve injury. PMID- 25788925 TI - Local administration of icariin contributes to peripheral nerve regeneration and functional recovery. AB - Our previous study showed that systemic administration of the traditional Chinese medicine Epimedium extract promotes peripheral nerve regeneration. Here, we sought to explore the therapeutic effects of local administration of icariin, a major component of Epimedium extract, on peripheral nerve regeneration. A poly(lactic-co-glycolic acid) biological conduit sleeve was used to bridge a 5 mm right sciatic nerve defect in rats, and physiological saline, nerve growth factor, icariin suspension, or nerve growth factor-releasing microsphere suspension was injected into the defect. Twelve weeks later, sciatic nerve conduction velocity and the number of myelinated fibers were notably greater in the rats treated with icariin suspension or nerve growth factor-releasing microspheres than those that had received nerve growth factor or physiological saline. The effects of icariin suspension were similar to those of nerve growth factor-releasing microspheres. These data suggest that icariin acts as a nerve growth factor-releasing agent, and indicate that local application of icariin after spinal injury can promote peripheral nerve regeneration. PMID- 25788926 TI - Electrical stimulation does not enhance nerve regeneration if delayed after sciatic nerve injury: the role of fibrosis. AB - Electrical stimulation has been shown to accelerate and enhance nerve regeneration in sensory and motor neurons after injury, but there is little evidence that focuses on the varying degrees of fibrosis in the delayed repair of peripheral nerve tissue. In this study, a rat model of sciatic nerve transection injury was repaired with a biodegradable conduit at 1 day, 1 week, 1 month and 2 months after injury, when the rats were divided into two subgroups. In the experimental group, rats were treated with electrical stimuli of frequency of 20 Hz, pulse width 100 ms and direct current voltage of 3 V; while rats in the control group received no electrical stimulation after the conduit operation. Histological results showed that stained collagen fibers comprised less than 20% of the total operated area in the two groups after delayed repair at both 1 day and 1 week but after longer delays, the collagen fiber area increased with the time after injury. Immunohistochemical staining revealed that the expression level of transforming growth factor beta (an indicator of tissue fibrosis) decreased at both 1 day and 1 week after delayed repair but increased at both 1 and 2 months after delayed repair. These findings indicate that if the biodegradable conduit repair combined with electrical stimulation is delayed, it results in a poor outcome following sciatic nerve injury. One month after injury, tissue degeneration and distal fibrosis are apparent and are probably the main reason why electrical stimulation fails to promote nerve regeneration after delayed repair. PMID- 25788927 TI - One-stage human acellular nerve allograft reconstruction for digital nerve defects. AB - Human acellular nerve allografts have a wide range of donor origin and can effectively avoid nerve injury in the donor area. Very little is known about one stage reconstruction of digital nerve defects. The present study observed the feasibility and effectiveness of human acellular nerve allograft in the reconstruction of < 5-cm digital nerve defects within 6 hours after injury. A total of 15 cases of nerve injury, combined with nerve defects in 18 digits from the Department of Emergency were enrolled in this study. After debridement, digital nerves were reconstructed using human acellular nerve allografts. The patients were followed up for 6-24 months after reconstruction. Mackinnon-Dellon static two-point discrimination results showed excellent and good rates of 89%. Semmes-Weinstein monofilament test demonstrated that light touch was normal, with an obvious improvement rate of 78%. These findings confirmed that human acellular nerve allograft for one-stage reconstruction of digital nerve defect after hand injury is feasible, which provides a novel trend for peripheral nerve reconstruction. PMID- 25788928 TI - Natural history of sensory nerve recovery after cutaneous nerve injury following foot and ankle surgery. AB - Cutaneous nerve injury is the most common complication following foot and ankle surgery. However, clinical studies including long-term follow-up data after cutaneous nerve injury of the foot and ankle are lacking. In the current retrospective study, we analyzed the clinical data of 279 patients who underwent foot and ankle surgery. Subjects who suffered from apparent paresthesia in the cutaneous sensory nerve area after surgery were included in the study. Patients received oral vitamin B12 and methylcobalamin. We examined final follow-up data of 17 patients, including seven with sural nerve injury, five with superficial peroneal nerve injury, and five with plantar medial cutaneous nerve injury. We assessed nerve sensory function using the Medical Research Council Scale. Follow up immediately, at 6 weeks, 3, 6 and 9 months, and 1 year after surgery demonstrated that sensory function was gradually restored in most patients within 6 months. However, recovery was slow at 9 months. There was no significant difference in sensory function between 9 months and 1 year after surgery. Painful neuromas occurred in four patients at 9 months to 1 year. The results demonstrated that the recovery of sensory function in patients with various cutaneous nerve injuries after foot and ankle surgery required at least 6 months. PMID- 25788929 TI - Biodegradable chitin conduit tubulation combined with bone marrow mesenchymal stem cell transplantation for treatment of spinal cord injury by reducing glial scar and cavity formation. AB - We examined the restorative effect of modified biodegradable chitin conduits in combination with bone marrow mesenchymal stem cell transplantation after right spinal cord hemisection injury. Immunohistochemical staining revealed that biological conduit sleeve bridging reduced glial scar formation and spinal muscular atrophy after spinal cord hemisection. Bone marrow mesenchymal stem cells survived and proliferated after transplantation in vivo, and differentiated into cells double-positive for S100 (Schwann cell marker) and glial fibrillary acidic protein (glial cell marker) at 8 weeks. Retrograde tracing showed that more nerve fibers had grown through the injured spinal cord at 14 weeks after combination therapy than either treatment alone. Our findings indicate that a biological conduit combined with bone marrow mesenchymal stem cell transplantation effectively prevented scar formation and provided a favorable local microenvironment for the proliferation, migration and differentiation of bone marrow mesenchymal stem cells in the spinal cord, thus promoting restoration following spinal cord hemisection injury. PMID- 25788930 TI - Nerve biopsy findings contribute to diagnosis of multiple mononeuropathy: 78% of findings support clinical diagnosis. AB - Multiple mononeuropathy is an unusual form of peripheral neuropathy involving two or more nerve trunks. It is a syndrome with many different causes. We reviewed the clinical, electrophysiological and nerve biopsy findings of 14 patients who suffered from multiple mononeuropathy in our clinic between January 2009 and June 2013. Patients were diagnosed with vasculitic neuropathy (n = 6), perineuritis (n = 2), chronic inflammatory demyelinating polyradiculoneuropathy (n = 2) or Lewis Sumner syndrome (n = 1) on the basis of clinical features, laboratory data, electrophysiological investigations and nerve biopsies. Two patients who were clinically diagnosed with vasculitic neuropathy and one patient who was clinically diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy were not confirmed by nerve biopsy. Nerve biopsies confirmed clinical diagnosis in 78.6% of the patients (11/14). Nerve biopsy pathological diagnosis is crucial to the etiological diagnosis of multiple mononeuropathy. PMID- 25788931 TI - Dorsal root ganglion neurons promote proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. AB - Preliminary animal experiments have confirmed that sensory nerve fibers promote osteoblast differentiation, but motor nerve fibers have no promotion effect. Whether sensory neurons promote the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells remains unclear. No results at the cellular level have been reported. In this study, dorsal root ganglion neurons (sensory neurons) from Sprague-Dawley fetal rats were co-cultured with bone marrow mesenchymal stem cells transfected with green fluorescent protein 3 weeks after osteogenic differentiation in vitro, while osteoblasts derived from bone marrow mesenchymal stem cells served as the control group. The rat dorsal root ganglion neurons promoted the proliferation of bone marrow mesenchymal stem cell-derived osteoblasts at 3 and 5 days of co-culture, as observed by fluorescence microscopy. The levels of mRNAs for osteogenic differentiation-related factors (including alkaline phosphatase, osteocalcin, osteopontin and bone morphogenetic protein 2) in the co-culture group were higher than those in the control group, as detected by real-time quantitative PCR. Our findings indicate that dorsal root ganglion neurons promote the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells, which provides a theoretical basis for in vitro experiments aimed at constructing tissue-engineered bone. PMID- 25788932 TI - Bacterial melanin promotes recovery after sciatic nerve injury in rats. AB - Bacterial melanin, obtained from the mutant strain of Bacillus Thuringiensis, has been shown to promote recovery after central nervous system injury. It is hypothesized, in this study, that bacterial melanin can promote structural and functional recovery after peripheral nerve injury. Rats subjected to sciatic nerve transection were intramuscularly administered bacterial melanin. The sciatic nerve transected rats that did not receive intramuscular administration of bacterial melanin served as controls. Behavior tests showed that compared to control rats, the time taken for instrumental conditioned reflex recovery was significantly shorter and the ability to keep the balance on the rotating bar was significantly better in bacterial melanin-treated rats. Histomorphological tests showed that bacterial melanin promoted axon regeneration after sciatic nerve injury. These findings suggest that bacterial melanin exhibits neuroprotective effects on injured sciatic nerve, contributes to limb motor function recovery, and therefore can be used for rehabilitation treatment of peripheral nerve injury. PMID- 25788933 TI - Improvement in acupoint selection for acupuncture of nerves surrounding the injury site: electro-acupuncture with Governor vessel with local meridian acupoints. AB - Peripheral nerve injury not only affects the site of the injury, but can also induce neuronal apoptosis at the spinal cord. However, many acupuncture clinicians still focus only on the injury site, selecting acupoints entirely along the injured nerve trunk and neglecting other regions; this may delay onset of treatment efficacy and rehabilitation. Therefore, in the present study, we compared the clinical efficacy of acupuncture at Governor vessel and local meridian acupoints combined (GV/LM group) with acupuncture at local meridian acupoints alone (LM group) in the treatment of patients with peripheral nerve injury. In the GV/LM group (n = 15), in addition to meridian acupoints at the injury site, the following acupoints on the Governor vessel were stimulated: Baihui (GV20), Fengfu (GV16), Dazhui (GV14), and Shenzhu (GV12), selected to treat nerve injury of the upper limb, and Jizhong (GV6), Mingmen (GV4), Yaoyangguan (GV3), and Yaoshu (GV2) to treat nerve injury of the lower limb. In the LM group (n = 15), only meridian acupoints along the injured nerve were selected. Both groups had electroacupuncture treatment for 30 minutes, once a day, 5 times per week, for 6 weeks. Two cases dropped out of the LM group. A good or excellent clinical response was obtained in 80% of the patients in the GV/LM group and 38.5% of the LM group. In a second study, an additional 20 patients underwent acupuncture with the same prescription as the GV/LM group. Electomyographic nerve conduction tests were performed before and after acupuncture to explore the mechanism of action of the treatment. An effective response was observed in 80.0% of the patients, with greater motor nerve conduction velocity and amplitude after treatment, indicating that electroacupuncture on specific Governor vessel acupoints promotes functional motor nerve repair after peripheral nerve injury. In addition, electromyography was performed before, during and after electroacupuncture in one patient with radial nerve injury. After a single session, the patient's motor nerve conduction velocity increased by 23.2%, indicating that electroacupuncture at Governor vessel acupoints has an immediate therapeutic effect on peripheral nerve injury. Our results indicate that Governor vessel and local meridian acupoints used simultaneously promote functional repair after peripheral nerve injury. The mechanism of action may arise from an improvement of the local microenvironment in injured nervous tissue, as well as immediate effects of Governor vessel and local meridian acupoint stimulation to ensure the continuity between the peripheral and central nervous systems. PMID- 25788934 TI - Allograft pretreatment for the repair of sciatic nerve defects: green tea polyphenols versus radiation. AB - Pretreatment of nerve allografts by exposure to irradiation or green tea polyphenols can eliminate neuroimmunogenicity, inhibit early immunological rejection, encourage nerve regeneration and functional recovery, improve tissue preservation, and minimize postoperative infection. In the present study, we investigate which intervention achieves better results. We produced a 1.0 cm sciatic nerve defect in rats, and divided the rats into four treatment groups: autograft, fresh nerve allograft, green tea polyphenol-pretreated (1 mg/mL, 4 degrees C) nerve allograft, and irradiation-pretreated nerve allograft (26.39 Gy/min for 12 hours; total 19 kGy). The animals were observed, and sciatic nerve electrophysiology, histology, and transmission electron microscopy were carried out at 6 and 12 weeks after grafting. The circumference and structure of the transplanted nerve in rats that received autografts or green tea polyphenol pretreated nerve allografts were similar to those of the host sciatic nerve. Compared with the groups that received fresh or irradiation-pretreated nerve allografts, motor nerve conduction velocity in the autograft and fresh nerve allograft groups was greater, more neurites grew into the allografts, Schwann cell proliferation was evident, and a large number of new blood vessels was observed; in addition, massive myelinated nerve fibers formed, and abundant microfilaments and microtubules were present in the axoplasm. Our findings indicate that nerve allografts pretreated by green tea polyphenols are equivalent to transplanting autologous nerves in the repair of sciatic nerve defects, and promote nerve regeneration. Pretreatment using green tea polyphenols is better than pretreatment with irradiation. PMID- 25788935 TI - Applied anatomical study of the vascularized ulnar nerve and its blood supply for cubital tunnel syndrome at the elbow region. AB - Cubital tunnel syndrome is often accompanied by paresthesia in ulnar nerve sites and hand muscle atrophy. When muscle weakness occurs, or after failure of more conservative treatments, anterior transposition is used. In the present study, the ulnar nerve and its blood vessels were examined in the elbows of 18 adult cadavers, and the external diameter of the nutrient vessels of the ulnar nerve at the point of origin, the distances between the origin of the vessels and the medial epicondyle of the humerus, and the length of the vessels accompanying the ulnar nerve in the superior ulnar collateral artery, the inferior ulnar collateral artery, and the posterior ulnar recurrent artery were measured. Anterior transposition of the vascularized ulnar nerve was performed to treat cubital tunnel syndrome. The most appropriate distance that the vascularized ulnar nerve can be moved to the subcutaneous tissue under tension-free conditions was 1.8 +/- 0.6 cm (1.1-2.5 cm), which can be used as a reference value during the treatment of cubital tunnel syndrome with anterior transposition of the vascularized ulnar nerve. PMID- 25788936 TI - Neuroprotective effects of daidzein on focal cerebral ischemia injury in rats. AB - Daidzein, a plant extract, has antioxidant activity. It is hypothesized, in this study, that daidzein exhibits neuroprotective effects on cerebral ischemia. Rat models of middle cerebral artery occlusion were intraperitoneally administered daidzein. Biochemical and immunohistochemical tests showed that superoxide dismutase and nuclear respiratory factor 1 expression levels in the brain tissue decreased after ischemia and they increased obviously after daidzein administration; malondialdehyde level and apoptosis-related cysteine peptidase caspase-3 and caspase-9 immunoreactivity in the brain tissue increased after ischemia and they decreased obviously after daidzein administration. Hematoxylin eosin staining and luxol fast blue staining results showed that intraperitoneal administration of daidzein markedly alleviated neuronal damage in the ischemic brain tissue. These findings suggest that daidzein exhibits neuroprotective effects on ischemic brain tissue by decreasing oxygen free radical production, which validates the aforementioned hypothesis. PMID- 25788937 TI - The pathways by which mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury. AB - Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing caspase-3 expression. It is hypothesized that mild hypothermia exhibits neuroprotective effects on neurons exposed to ischemia/reperfusion condition produced by oxygen-glucose deprivation. Mild hypothermia significantly reduced the number of apoptotic neurons, decreased the expression of pro-apoptotic protein Bax and increased mitochondrial membrane potential, with the peak of anti-apoptotic effect appearing between 6 and 12 hours after the injury. These findings indicate that mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury by protecting the mitochondria and that the effective time window is 6-12 hours after ischemia/reperfusion injury. PMID- 25788938 TI - Therapeutic effects of different durations of acupuncture on rats with middle cerebral artery occlusion. AB - Acupuncture is regarded as an effective therapy for cerebral ischemia. Different acupuncture manipulations and durations may result in different therapeutic effects. In the present study, the Neiguan (PC6) acupoint of rats with occluded middle cerebral arteries was needled at a fixed frequency (3 Hz) with different durations, i.e., 5, 60 and 180 seconds under a twisting-rotating acupuncture method. Results showed that different durations of acupuncture had different therapeutic effects, with 60 seconds yielding a better therapeutic effect than the other two groups. This duration of treatment demonstrated rapid cerebral blood flow, encouraging recovery of neurological function, and small cerebral infarct volume. Experimental findings indicated that under 3 Hz frequency, the treatment of needling Neiguan for 60 seconds is effective for ischemic stroke. PMID- 25788939 TI - Hypersensitivity of vascular alpha-adrenoceptor responsiveness: a possible inducer of pain in neuropathic states. PMID- 25788940 TI - Hepatitis B virus-related glomerulonephritis: not a predominant cause of proteinuria in korean patients with chronic hepatitis B. AB - Background/Aims. Hepatitis B virus (HBV) can form immune complexes which may result in various types of glomerulonephritis (GN). However, proteinuria can occur because of other kidney diseases besides HBV-related GN (HBV-GN). The aim of this study is to elucidate the causes of proteinuria and report on the clinical outcomes of HBV-GN. Methods. We reviewed the medical records of patients positive for serum hepatitis B surface antigen who underwent renal biopsies due to proteinuria at a tertiary medical center in Korea. Results. A total of 55 patients were included. HBV-GN was diagnosed in 20 (36.4%) of the patients by confirming the presence of immune complexes (12 of 13 membranoproliferative glomerulonephritis, 7 of 8 membranous glomerulonephritis, and 1 of 13 immunoglobulin A nephropathy). Twenty-one patients had other types of GN. A total of 13 (65%) HBV-GN patients were treated with antiviral agents for a median of 11 months. However, the degrees of proteinuria were not significantly reduced in the antiviral intervention group when compared to the control group. Conclusions. Proteinuria can be caused by various glomerular diseases and HBV-GN accounts for one-third of total GN cases. Well-designed prospective study is needed to assess whether antiviral therapy against HBV infection may improve the prognosis of HBV GN. PMID- 25788941 TI - Risk factors and medico-economic effect of pancreatic fistula after pancreaticoduodenectomy. AB - The study aimed to uncover the risk factors for the new defined pancreatic fistula (PF) and clinical related PF (CR-PF) after pancreaticoduodenectomy (PD) surgery and to evaluate the medico-economic effect of patients. A total of 412 patients were classified into two groups according to different criteria, PF and NOPF according to PF occurrence: CR-PF (grades B and C) and NOCR-PF (grade A) based on PF severity. A total of 28 factors were evaluated by univariate and multivariate logistic regression test. Hospital charges and stays of these patients were assessed. The results showed that more hospital stages and charges are needed for patients in PF and CR-PF groups than in NOPF and NOCR-PF groups (P < 0.05). The excessive drinking, soft remnant pancreas, preoperative albumin, and intraoperative blood transfusion are risk factors affecting both PF and CR-PF incidence. More professional surgeons can effectively reduce the PF and CR-PF incidence. Patients with PF and CR-PF need more hospital costs and stages than that in NOPF and NOCR-PF groups. It is critical that surgeons know the risk factors related to PF and CR-PF so as to take corresponding therapeutic regimens for each patient. PMID- 25788942 TI - Antithyroid antibodies and thyroid function in pediatric patients with celiac disease. AB - Objective. Aim of the study was to determine the prevalence of autoimmune thyroid disease, persistence of antithyroid antibodies, effect of gluten-free diet, and long-term outcome of thyroid function in pediatric patients with celiac disease (CD). Methods. 67 patients with CD aged from 1 year to 16 years were screened for thyroid antithyroperoxidase, antithyroglobulin and anti-TSH receptor antibodies, serum free triiodothyronine, free thyroxine, and thyroid-stimulating hormone (TSH) at diagnosis and during follow-up. Results. None of the patients had antithyroid antibodies at diagnosis. Antithyroid antibodies became positive in 16.4% of the patients (11/67) 2 to 3 years after the diagnosis of CD. Clinical hypothyroidism was observed only in 3 of 11 CD patients with positive antithyroid antibodies (27.2%). The antithyroid antibodies positive and negative patients did not differ significantly according to compliance to GFD (P > 0.05). A statistically significant difference was observed only in age, in which the patients with positive antithyroid antibodies were younger than the patients with negative antithyroid antibodies (P = 0.004). None of the patients had any change in their thyroid function and antibody profile during their follow-up. Conclusion. Antithyroid antibodies were detected in younger pediatric patients with CD and the prevalence of antithyroid antibodies did not correlate with the duration of gluten intake. PMID- 25788943 TI - Relationship between Body Mass Index and Tooth Decay in a Population of 3-6-Year Old Children in Iran. AB - The aim of the present study was to evaluate the relationship between BMI and tooth decay in a population of Iranian children. In this cross-sectional descriptive/analytical study, 1482 children were selected from kindergartens and preschool centers in Kerman, Iran. The children underwent examination of deciduous teeth (using the dmft index) after determination of height and weight for calculation of BMI. The relationship between BMI (after adjustment for age) and dmft was determined using Poisson's regression model. The mean of dmft in children with normal BMI was 1.5-fold that in subjects with extra body weight. Age had a significant effect on dmft. In addition, dmft was higher in boys compared to girls. The results of the present study showed that caries rate in the deciduous teeth of 3-6-year-old children decreases with an increase in body weight. PMID- 25788944 TI - Isolation, Characterization, and RP-HPLC Estimation of P-Coumaric Acid from Methanolic Extract of Durva Grass (Cynodon dactylon Linn.) (Pers.). AB - P-coumaric acid is a nonflavonoid phenolic acid and is a major constituent of the species Cynodon dactylon Linn. (Pers.). In this study isolation of P-coumaric acid was achieved by preparative TLC and the compound thus isolated was characterised by UV, mass, and H(1) NMR spectral analysis. An isocratic RP-HPLC method was developed for the estimation of P-coumaric acid from methanolic extracts of durva grass. The chromatographic separations were achieved by RP-C18 column (250 mm * 4.6 mm, 5 MU), Shimadzu LC-20AT Prominence liquid chromatograph, and a mobile phase composed of water : methanol : glacial acetic acid (65 : 34 : 1 v/v). The flow rate was 1.0 mL/min and the analyses of column effluents were performed using UV-visible detector at 310 nm. Retention time of P-coumaric acid was found to be 6.617 min. This method has obeyed linearity over the concentration range of 2-10 MUg/mL and the regression coefficient obtained from linearity plot for P-coumaric acid was found to be 0.999. RP-HPLC method was validated in pursuance of ICH guidelines. PMID- 25788945 TI - Nightmare-induced atypical midventricular tako-tsubo cardiomyopathy. AB - Tako-Tsubo cardiomyopathy (TTC) is a reversible cardiomyopathy characterized by acute left ventricular segmental dysfunction, whose clinical presentation resembles that of acute myocardial infarction. The syndrome often follows a psychophysical stressful event and is characterized by echocardiographic evidence of akinesia of the left ventricular mid-apical segments. Atypical echocardiographic patterns of TTC have recently been described, often triggered by emotional stressors, rather than physical. In this report, we describe a case of atypical TTC triggered by an unusual stressor (recurrent nightmare) in a 45 year-old woman, with peculiar clinical presentation and evolution characterized by persistent loss of consciousness, neurological deterioration, absence of typical symptoms of TTC, and features suggestive of a hysterical crisis. PMID- 25788946 TI - How to Be 80 Year Old and Have a VO2max of a 35 Year Old. AB - Background. To discuss the cardiovascular and pulmonary physiology and common risk factors of an 80-year-old man with a world record maximal oxygen uptake of 50 mL.kg(-1).min(-1). Methods. CASE REPORT: Results. His maximal oxygen uptake of 3.31 L.min(-1), maximal heart rate of 175 beats.min(-1), and maximal oxygen pulse of 19 mL.beats(-1) are high. He is lean (66.6 kg) and muscular (49% skeletal muscle mass). His echo parameters of mitral flow (left ventricular filling, E = 82 cm.s(-1) and E/A = 1.2) were normal for 40- to 60-year-old men. Systolic and diastolic function increased adequately during exercise, with no increase in left ventricular filling pressure. He has excellent pulmonary function (FVC = 4.31 L, FEV1 = 3.41, FEV1/FVC = 0.79, and DLCO = 12.0 Si(1)) and normal FMD and blood volumes (5.8 L). He has a high level of daily activity (10,900 steps.day(-1) and 2:51 hours.day(-1) of physical activity) and a lifelong history of physical activity. Conclusion. The man is in excellent cardiopulmonary fitness and is highly physically active. His cardiac and pulmonary functions are above expectations for his age, and his VO2max is comparable to that of an inactive 25 year-old and of a normal, active 35-year-old Norwegian man. PMID- 25788947 TI - A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier. AB - Cerebral palsy is a nonprogressive heterogeneous group of neurological disorders with a growing rate of prevalence. Recently, cellular therapy is emerging as a potential novel treatment strategy for cerebral palsy. The various mechanisms by which cellular therapy works include neuroprotection, immunomodulation, neurorestoration, and neurogenesis. We conducted an open label, nonrandomized study on 40 cases of cerebral palsy with an aim of evaluating the benefit of cellular therapy in combination with rehabilitation. These cases were administered autologous bone marrow mononuclear cells intrathecally. The follow up was carried out at 1 week, 3 months, and 6 months after the intervention. Adverse events of the treatment were also monitored in this duration. Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. The results of this study demonstrate that cellular therapy may accelerate the development, reduce disability, and improve the quality of life of patients with cerebral palsy. PMID- 25788948 TI - Effects of Transient Hypoxia versus Prolonged Hypoxia on Satellite Cell Proliferation and Differentiation In Vivo. AB - The microenvironment of the injury site can have profound effects on wound healing. Muscle injury results in ischemia leading to short-term local hypoxia, but there are conflicting reports on the role of hypoxia on the myogenic program in vivo and in vitro. In our rat model of mitochondrial restoration (MR), temporary upregulation of mitochondrial activity by a cocktail of organelle encoded RNAs results in satellite cell proliferation and initiation of myogenesis. We now report that MR leads to a transient hypoxic response in situ. Inhibition of hypoxia by lowering mitochondrial O2 consumption, either by respiratory electron transport inhibitors, or by NO-mediated inhibition of O2 binding to cytochrome c oxidase, resulted in exacerbation of inflammation. Lentivirus-mediated knockdown of hypoxia-inducible factor 1alpha (HIF1alpha) or of Notch signaling components had a similar effect, and pharmacologic inhibition of HIF or Notch reduced the number of proliferating Pax7(+) cells. In contrast, a prolonged hypoxic response induced either by uncoupling of respiration from oxidative phosphorylation or through HIF stabilization by dimethyloxalylglycine (DMOG) had an immediate anti-inflammatory effect. Although significant satellite cell proliferation occurred in presence of DMOG, expression of differentiation markers was affected. These results emphasize the importance of transient hypoxia as opposed to prolonged hypoxia for myogenesis. PMID- 25788949 TI - Efficacy and safety of ragweed sublingual immunotherapy in Canadian patients with allergic rhinoconjunctivitis. AB - BACKGROUND: Currently accepted therapies for ragweed allergy in North America consist of pharmacotherapy and subcutaneous allergen immunotherapy injections to treat symptoms. Allergen immunotherapy not only reduces symptoms and the need for pharmacotherapy but has also been shown to have disease-modifying potential. Recently, ragweed immunotherapy administered via sublingual allergen tablet has been approved in North America for treatment of allergic rhinitis with and without conjunctivitis. METHODS: This was an analysis of pooled data for a prespecified subgroup of Canadian subjects from two multicentre, randomized, double-blind placebo-controlled trials of ragweed sublingual tablet (SLIT-T; 6 and 12 Amb a 1-U of Ambrosia artemisiifolia) in patients aged >=18y, with ragweed induced allergic rhinoconjunctivitis (AR/C) with or without asthma. Randomized subjects used once-daily ragweed SLIT-T or placebo for at least 12 weeks before the ragweed season and for up to 52 weeks post-randomization. The primary efficacy endpoint was the total combined score (TCS) based on the sum of AR/C daily symptom score (DSS) and daily medication score (DMS) averaged over the peak season. Treatment effects on TCS, DSS, and DMS in the entire season were also assessed. Adverse events (AEs) were monitored to assess safety. RESULTS: 337 Canadian subjects were randomized in the two trials. During the peak season, ragweed SLIT-T 6 and 12 Amb a 1-U significantly reduced TCS by 26% (difference, 2.46 score point; p = .0009) and 40% (difference, -3.75 score point; p < .0001), respectively. In the overall population (N = 961), TCS reductions with 6 and 12 Amb a 1-U were 20% and 23%, respectively (both p < .001). Clinically meaningful reductions in entire-season TCS in Canadians were similar to those during peak ragweed season. Dose-dependent reduction of DSS and DMS was also observed for ragweed SLIT-T 6 and 12 Amb a 1-U during the peak season and the entire season. Ragweed SLIT-T was well tolerated in Canadian subjects and the overall population. Adverse events were generally mild to moderate and transient, occurring early in treatment; no systemic allergic reaction/anaphylaxis was noted. CONCLUSION: Ragweed SLIT-T is an effective form of immunotherapy that provides symptomatic efficacy of AR/C with a favorable risk profile in Canadian and overall populations. TRIAL REGISTRATION: Clinicaltrials.gov identifiers NCT00783198 and NCT00770315. PMID- 25788950 TI - IgE-Mediated allergy to wheat in a child with celiac disease - a case report. AB - INTRODUCTION: Celiac disease and immediate type hypersensitivity to wheat are immune responses with different pathogenic mechanisms. Both diseases are well known entities but their coexistence in the same patient is rarely reported. This is a unique case presentation of a patient with celiac disease who developed concomitant IgE-mediated wheat allergy and presented with immediate symptoms in two body systems. CASE PRESENTATION: We report the case of a girl with celiac disease who subsequently developed IgE-mediated hypersensitivity to wheat. The patient is a Caucasian female who was diagnosed with celiac disease at 18 months of age after presenting with recurrent vomiting and failure to thrive. Her anti tTG antibody level was greater than 200 E.U. and biopsy results from endoscopy were consistent with celiac disease. Specific IgE antibody to wheat was negative at 2 years of age. Around seven years of age, she developed immediate symptoms of urticaria, cough and shortness of breath with accidental exposures to wheat. Specific IgE antibody testing was repeated and positive to wheat (42.5 kU/L), as well as rye (33.9 kU/L), barley (53.4 kU/L) and oat (11.3 kU/L). At 9 years of age, skin prick testing was positive to wheat, barley and rye but negative to oat. The patient has subsequently tolerated an open oral food challenge to oat. She continues to avoid wheat, rye and barley and carries an epinephrine autoinjector at all times. CONCLUSION: To our knowledge, this is the first report of a patient with celiac disease and concomitant IgE-mediated allergy to wheat presenting with immediate symptoms in two body systems. Although the pathophysiology of these diseases is different, this case demonstrates that they are not exclusive of one another. In patients who develop unexplained symptoms consistent with IgE-mediated allergy, an allergy assessment should be considered. PMID- 25788951 TI - Two year effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies. AB - BACKGROUND: Food allergy (FA) can have serious psychosocial and economic repercussions on food-allergic children and their caregivers and be associated with negative effects on their quality of life. Food allergen immunotherapy (IT) is a promising experimental therapy but can be linked to anxiety. This study investigated the effects of IT on FA-specific health-related quality of life (HRQL) over a 24 month-follow-up in caregivers of children with single and multiple food allergies. We hypothesized that characteristics such as age, asthma at baseline and respiratory allergic reactions during therapy were key characteristics that influenced HRQL scores. METHODS: A validated Food Allergy Quality of Life - Parental Burden Questionnaire (FAQL-PB) was used to assess HRQL. It was randomly distributed to and filled out by caregivers of 57 food allergic children enrolled in clinical trials of IT. The same parent answered the FABQL-PB questionnaire at baseline and for 6-month, 12- month, 18- month, and 24 month time points on IT. RESULTS: Caregiver HRQL improved significantly (change < - 0.5, p <0.0001) at each follow-up time point compared to baseline. The percentages of caregivers with improvement in HRQL progressively increased (92% at 24 month-follow-up time point compared to baseline). HRQL improved more in caregivers of participants older than 10 years or desensitized to more than 4 food allergens than those who were not (p <0.0001). Caregivers of participants with pre-existing asthma or dose-related respiratory allergic reactions had less improvement in HRQL than those who did not (p <0.01). CONCLUSION: IT lead to improvement in caregiver HRQL. Certain characteristics were associated with greater improvements in caregiver HRQL. PMID- 25788952 TI - The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: a review and statistical analysis. AB - Physical activity increases oxidative stress and therefore the antioxidant effects of vitamin C administration might become evident in people undertaking vigorous exercise. Vitamin C is involved in the metabolism of histamine, prostaglandins, and cysteinyl leukotrienes, all of which appear to be mediators in the pathogenesis of exercise-induced bronchoconstriction (EIB). Three studies assessing the effect of vitamin C on patients with EIB were subjected to a meta analysis and revealed that vitamin C reduced postexercise FEV1 decline by 48% (95% CI: 33% to 64%). The correlation between postexercise FEV1 decline and respiratory symptoms associated with exercise is poor, yet symptoms are the most relevant to patients. Five other studies examined subjects who were under short term, heavy physical stress and revealed that vitamin C reduced the incidence of respiratory symptoms by 52% (95% CI: 36% to 65%). Another trial reported that vitamin C halved the duration of the respiratory symptoms in male adolescent competitive swimmers. Although FEV1 is the standard outcome for assessing EIB, other outcomes may provide additional information. In particular, the mean postexercise decline of FEF50 is twice the decline of FEV1. Schachter and Schlesinger (1982) reported the effect of vitamin C on exercise-induced FEF60 levels in 12 patients suffering from EIB and their data are analyzed in this paper. The postexercise FEF60 decline was greater than 60% for five participants and such a dramatic decline indicates that the absolute postexercise FEF60 level becomes an important outcome in its own right. Vitamin C increased postexercise FEF60 levels by 50% to 150% in those five participants, but had no significant effect in the other seven participants. Thus, future research on the effects of vitamin C on EIB should not be restricted to measuring only FEV1. Vitamin C is inexpensive and safe, and further study on those people who have EIB or respiratory symptoms associated with exercise is warranted. PMID- 25788953 TI - Oxidative stress response in patients infected by diverse hepatitis C virus genotypes. AB - BACKGROUND: The molecular mechanism of hepatitis C-virus (HCV) genome-specific pathogenesis remains unclear. Oxidative stress is an important pathophysiological mechanism in chronic HCV infection, but its relation to HCV genotypes has not been thoroughly examined. OBJECTIVES: In the present case-control study, the effect of diverse HCV genotypes on oxidative status changes was investigated. PATIENTS AND METHODS: From 310 patients examined by enzyme immunoassay and PCR, 160 patients with positive results for HCV with previously determined genotypes were chosen. For the control group, 160 first time blood donors referred to the Regional Blood Transfusion organization of the West Azerbaijan province, northwestern Iran were selected. Oxidative stress markers such as total antioxidant status (TAS), serum levels of reduced (GSH) and oxidized (GSSG) glutathione, Gamma-glutamyl transferase (GGT) and malondialdehyde (MDA) were evaluated in patients infected with diverse HCV genotypes and those in the control group. RESULTS: In the patient and control groups, the mean +/- SE of TAS, GSH, GSSG, GGT and MDA were 1.04 +/- 0.35 vs. 2.68 +/- 0.77, 1.25 +/- 0.37 vs. 3.12 +/- 0.58, 0.20 +/- 0.05 vs. 0.08 +/- 0.04, 26.82 +/- 5.62 vs 8.28 +/- 2.03 and 2.56 +/- 0.60 vs. 0.93 +/- 0.34. All markers had statistical difference between the two groups (P <0.05). Obvious differences were found in oxidant/antioxidant balance among diverse HCV genotypes with an ascending trend in antioxidant levels among patients infected with genotypes 1a/b, 4, 2a/c, 2b, 3a and healthy controls and a vice versa trend in measures of oxidative markers except for malondialdehyde with a variable pattern. CONCLUSIONS: More serious disease in HCV genetic subtype 1a/1b might be associated with more severe oxidative stress. Milder damage in subtypes 4, 2a/c, 2b and 3a could be related to lower oxidative response, respectively. A combination of antiviral and antioxidative therapies may enhance the overall response rate of patients with HCV infection, especially with more destructive genotypes. PMID- 25788954 TI - Hepatoprotective effect of 17beta-estradiol as antioxidant modulators against stress damage. AB - BACKGROUND: Liver is one of the most important organs affected by exercise. According to the literature a few study to date has investigated the effects of estrogen supplementation on exercise-induced oxidative stress in liver tissue of rats. OBJECTIVES: We aimed to investigate the effects of estrogen supplementation on oxidative stress markers in liver tissue of exercised rats. MATERIALS AND METHODS: Male rats (n = 35) were divided as estrogen supplemented (n = 18) and non-supplemented groups (n = 17); these groups were further divided as rest and eccentric exercised groups. Eccentric exercise groups were further divided as rats killed after 1 hour and 48 hours of eccentric exercise. Estrogen (10 mg/kg) was administered subcutaneously for 30 days. Eccentric exercise was applied as treadmill run (15 degrees downhill, 20 m/min) consisting of periods of "5 min" run and 2 min rest repeated 18 times. The rat liver was examined biochemically and histologically. Activities of GST, GSH-Px, CAT, SOD and MDA concentration were also measured spectrophotometrically. RESULTS: Some disruptions were detected in experimental groups compared with the control group. Additionally, exercise training caused an increase in SOD and decrease in GSH-Px activities in some experimental groups. SOD activities increased significantly in group 3 (Estrogen (-), eccentric exercise (+) killed (after 1 h), compared with group 5 (Estrogen (-), eccentric exercise (+) killed (after 48 h). On the other hand, GSH Px activities were also significantly decreased in groups 3, 4 and 5 compared with the control group. Leukocyte infiltration in liver increased after 48 hours compared with after 1 hour and estrogen supplementation was not able to prevent this infiltration. CONCLUSIONS: Estrogen seemed to be not very effective to prevent eccentric exercise-induced liver damage. PMID- 25788955 TI - Serum NX-DCP as a New Noninvasive Model to Predict Significant Liver Fibrosis in Chronic Hepatitis C. AB - BACKGROUND: Finding a noninvasive method to predict liver fibrosis using inexpensive and easy-to-use markers is important. OBJECTIVES: We aimed to clarify whether NX-des-gamma-carboxyprothrombin (NX-DCP) could become a new noninvasive model to predict liver fibrosis in hepatitis C virus (HCV) related liver disease. PATIENTS AND METHODS: We performed a prospective cohort study on a consecutive group of 101 patients who underwent liver biopsy for HCV-related liver disease at Kobe University Hospital. Laboratory measurements were performed on the same day as the biopsy. Factors associated with significant fibrosis (F3-4) were assessed by multivariate analyses. A comparison of predictive ability between multivariate factors and abovementioned noninvasive models was also performed. RESULTS: Increase in serum NX-DCP was significantly related to increase in fibrosis stage (P = 0.006). Moreover, NX-DCP was a multivariate factor associated with the presence of significant fibrosis F 3-4 (median 21 of F0-2 group vs. median 22 of F3-4 group with P = 0.002). The AUC of NX-DCP showed no significant differences compared with those of the AST-to-platelet ratio index (APRI), modified-APRI, the Goteborg University Cirrhosis Index (GUCI), the Lok index, the Hui score, cirrhosis discriminating score (CDS) and the Pohl score (P > 0.05). CONCLUSIONS: NX-DCP correlated positively with fibrosis stage and could discriminate well between HCV-related patients with or without significant fibrosis. Moreover, NX DCP had a similar predictive ability to the abovementioned models, and thereby could be a new noninvasive prediction tool for fibrosis. PMID- 25788956 TI - Association of Mutations in the Basal Core Promoter and Pre-core Regions of the Hepatitis B Viral Genome and Longitudinal Changes in HBV Level in HBeAg Negative Individuals: Results From a Cohort Study in Northern Iran. AB - BACKGROUND: Although certain HBV mutations are known to affect the expression of Hepatitis e antigen, their association with HBV viral level or clinical outcomes is less clear. OBJECTIVES: We evaluated associations between different mutations in the Basal Core promoter (BCP) and Pre-core (PC) regions of HBV genome and subsequent changes in HBV viral DNA level over seven years in a population of untreated HBeAg negative chronic hepatitis B (CHB) participants in Northeast of Iran. MATERIALS AND METHODS: Participants in the current study were drawn from the Golestan Hepatitis B Cohort Study (GHBCS), a cohort of approximately 2590 HBsAg positive subjects (living in Gonbad city) embedded in the Golestan Cohort Study (GCS). At baseline, HBsAg was measured in all participants and revealed 2590 HBsAg positive cases. We randomly selected 304 participants who their blood sample were taken at both baseline and seven years later in follow-up and had not been treated for HBV during this time. HBV viral load were assessed at baseline and at year 7. The BCP and PC regions of the HBV DNA, at baseline, were amplified via hemi-nested PCR and sequenced by cycle sequencing. At year 7, liver stiffness was assessed by fibroscan; also, other parameters of liver disease were assessed following standard clinical protocols. Associations were assessed via tabulation, chi-square, t-tests and logistic regression. P values < 0.05 were considered statistically significant and all tests were two-sided. RESULTS: Among 304 HBsAg positive participants, 99 had detectable HBV DNA at study baseline. Of these, 61.6% had PC mutations (48.5% A1896 and 25.2% G1899). In contrast to other mutations, A1896 was associated with a higher proportion of detectable HBV DNA at year 7 (39.6%) compared to patients with the wild type (13.7%) (OR: 4.36, CI95% = 1.63-11.70; P Value = 0.002). Although participants with the A1896 mutation had higher year-7 HBV viral load than participants with G1896 (2.30 +/- 1.66 IU/mL vs. 1.76 +/- 1 IU/mL among patients with detectable HBV; P value = 0.052), no association was observed with either serum level ALT or liver stiffness. Interestingly, mutations in the basal core promoter (BCP) region had no significant effect on virus DNA detection. CONCLUSIONS: In this population with chronic HBeAg negative hepatitis B, an association was observed between the G1896A mutation in the Pre-core region of HBV and subsequent level of HBV DNA seven years later, which indicated that mutations in this region of HBV genome may contribute to disease progression in these patients and play an important role in HBV natural course of disease. PMID- 25788957 TI - The prevalence of hepatitis C virus infection and its related risk factors among the rural population of fars province, southern iran. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a major blood-borne infection with silent epidemic, major global public health problem and diverse prevalence worldwide. OBJECTIVES: This study aimed to evaluate the prevalence of HCV infection and related risk factors in the general population of two villages, Farmashkan and Akbarabad, of the Kavar City in Fars Province, Iran. PATIENTS AND METHODS: A 34-month cross-sectional study was performed on all people of the villages aged >= 7 years from July 2007 to April 2010. Demographic information and history of HCV-related risk factors were extracted from their medical records. For each participant, the serum anti-HCV IgG was assessed by the commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: A total of 6095 participants (36.4% male and 65.6% female) with the mean age of 92 (7-95) and mean +/- SD of 34.6 +/- 17.3 years were included in this study. Fifteen persons (0.24%) were detected as HCV-positive and the highest prevalence was seen in age <= 12 years old (1%). A significant association was only detected between blood transfusion and HCV infection; therefore, those persons with history of blood transfusion had 15-fold higher risk for HCV seropositivity (odds ratio 15.54, 95% CI = 4.89-49.41). CONCLUSIONS: Our reported rate of HCV seropositivity is similar to the previous Iranian reports. However, future evaluations should be focused on the Polymerase Chain Reaction method for the detection of HCV and determining and evaluating of other related risk factors. Moreover, more attention should be paid to blood donors as a reservoir population of HCV. PMID- 25788958 TI - The effect of berberis vulgaris extract on transaminase activities in non alcoholic Fatty liver disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder in western countries and an important cause of liver cirrhosis, as well as liver failure. Up to now, 20-40% of the individuals suffer from this disorder and its prevalence is estimated around 5-30% in Asia. The NAFLD is one of the most prevalent causes for increases in liver enzymes and has a close relationship with obesity, dyslipidemia, hypertension, and type II diabetes. However, no definite treatment has been identified for it yet. OBJECTIVES: The present study aimed to investigate the effect of berberis vulgaris extract in inducing changes in liver enzymes levels. PATIENTS AND METHODS: The present clinical trial was conducted on 80 patients, including 32 males (40%) and 48 females (60%), who were randomly assigned into two groups of case and control. All the patients had ultrasound evidence of lipid accumulation in the liver and increases in liver enzymes. The case group received two capsules (750 mg) containing berberis vulgaris extract every day for 3 months, while the control group was treated with placebo. The weight, liver transaminases levels and lipid profiles of the two groups were assessed before, during, and after the study. RESULTS: In the case group, the mean serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) decreased from 49 to 27.48 and 48.22 to 29.8 u/L, respectively, which was statistically significant compared to the control group (P < 0.001, P < 0.001). In the control group, the mean of ALT and AST decreased from 50.4 to 46.8 and 45.7 to 44.9 u/L, respectively. The difference was not statistically significant. In addition, a significant decrease was observed in weight, triglycerides, and cholesterol, while no significant change was found in fasting blood sugar, high-density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL). CONCLUSIONS: Considering the significant decrease in the liver enzymes, triglycerides and cholesterol after using berberis vulgaris extract, further studies with larger sample sizes will identify the accurate dose as well as duration of consumption for this extract, to recommend in the treatment of patients with NAFLD. PMID- 25788959 TI - Telaprevir experience from Turkey. AB - BACKGROUND: In patients with chronic hepatitis C, triple drug regimens containing a protease inhibitor, peginterferon and ribavirin were found to significantly increase sustained virologic response rates compared to dual drug regimen containing pegylated interferon and ribavirin, especially in genotype 1. OBJECTIVES: In Turkey, telaprevir has been used since March 2013. We aimed to evaluate results of patients with chronic hepatitis C treated with telaprevir, peginterferon and ribavirin. PATIENTS AND METHODS: We evaluated 28 patients with genotype 1 chronic hepatitis C infection treated with triple drug regimen containing telaprevir, in three medical centers in Turkey, retrospectively. Demographic data of patients, treatment indications, adverse events and outcomes were recorded. RESULTS: Of 28 patients intended to treat, 25 (89.2%) patients completed the treatment. Overall, 21 (82.1%) patients had relapse and five patients were non-responder. Regarding the treatment outcomes of Telaprevir based regimen, 20/26 patients achieved sustained virological response. Pruritus, rash, dysgeusia, anorectal discomfort and anemia were main adverse effects. Blood transfusion and ribavirin dose reduction required for 7 and 11 patients, respectively. Due to several adverse effects, 10 patients were hospitalized. CONCLUSIONS: Although more frequent and severe adverse effects, telaprevir has been promising for patients with treatment-experienced hepatitis C. PMID- 25788960 TI - When modern technology meets ancient traditional chinese medicine. PMID- 25788961 TI - Echinacoside Protects against 6-Hydroxydopamine-Induced Mitochondrial Dysfunction and Inflammatory Responses in PC12 Cells via Reducing ROS Production. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons at the substantia nigra. Mitochondrial dysfunction and inflammatory responses are involved in the mechanism of cell damage in PD. 6-Hydroxydopamine (6-OHDA), a dopamine analog, specifically damages dopaminergic neurons. Echinacoside (ECH) is a phenylethanoid glycoside isolated from the stems of Cistanche salsa, showing a variety of neuroprotective effects in previous studies. The present study was to investigate its effect against 6-OHDA-induced neurotoxicity and possible mechanisms in PC12 cells. The results showed that 6-OHDA reduced cell viability, decreased oxidation reduction activity, decreased mitochondrial membrane potential, and induced mitochondria-mediated apoptosis compared with untreated PC12 cells. However, echinacoside treatment significantly attenuated these changes induced by 6-OHDA. In addition, echinacoside also could significantly alleviate the inflammatory responses induced by 6-OHDA. Further research showed that echinacoside could reduce 6-OHDA-induced ROS production in PC12 cells. These results suggest that the underlying mechanism of echinacoside against 6-OHDA-induced neurotoxicity may be involve in attenuating mitochondrial dysfunction and inflammatory responses by reducing ROS production. PMID- 25788962 TI - Renoprotective Effects of Vitex megapotamica (Spreng.) Moldenke in C57BL/6 LDLr Null Mice Undergoing High Fat Diet. AB - Although Vitex megapotamica (Spreng.) Moldenke is used in Brazilian folk medicine as hypolipidemic drug no study has been conducted to evaluate the effects of this species in an experimental model of atherosclerosis. So, the aim of this study was to evaluate the possible renoprotective activity of methanolic extract obtained from Vitex megapotamica (MEVM) using C57BL/6 LDLr-null mice submitted to high fat diet (HFD). MEVM was orally administered at doses of 30, 100, and 300 mg/kg, for three weeks, starting from the 2nd week of HFD. Systolic blood pressure (SBP) and diuretic activity were measured weekly. At the end of experiments the serum lipids, atherogenic index serum (AIS), oxidative stress, and markers of renal function were determined. HFD induced a significant increase in the systolic blood pressure, dyslipidemia, increase in AIS, and lipid peroxidation accompanied by an important reduction in renal function. Treatment with MEVM was able to prevent increase in SBP, total cholesterol, triglycerides, AIS, urea, and creatinine levels in LDLr-null mice. These effects were accompanied by a significant reduction in oxidative stress and renal injury. The data reported here support the potential of Vitex megapotamica as candidate to be an herbal medicine used in cardiovascular or renal diseases. PMID- 25788963 TI - Fourier-domain optical coherence tomography for monitoring the lower tear meniscus in dry eye after acupuncture treatment. AB - Dry eye is highly prevalent and has a significant impact on quality of life. Acupuncture was found to be effective to treat dry eye. However, little was known about the effect of acupuncture on different subtypes of dry eye. The objective of this study was to investigate the applicability of tear meniscus assessment by Fourier-domain optical coherence tomography in the evaluation of acupuncture treatment response in dry eye patients and to explore the effect of acupuncture on different subtypes of dry eye compared with artificial tear treatment. A total of 108 dry eye patients were randomized into acupuncture or artificial tear group. Each group was divided into three subgroups including lipid tear deficiency (LTD), Sjogren syndrome dry eye (SSDE), and non-Sjogren syndrome dry eye (Non-SSDE) for data analysis. After 4-week treatment, the low tear meniscus parameters including tear meniscus height (TMH), tear meniscus depth (TMD), and tear meniscus area (TMA) in the acupuncture group increased significantly for the LTD and Non-SSDE subgroups compared with both the baseline and the control groups (all P values < 0.05), but not for the SSDE. Acupuncture provided a measurable improvement of the tear meniscus dimensions for the Non-SSDE and LTD patients, but not for the SSDE patients. PMID- 25788964 TI - The effect of tou nong san on transplanted tumor growth in nude mice. AB - Tou Nong San (TNS) is a traditional Chinese medicinal decoction used to treat sores and carbuncles. It contains four herbal drugs and one animal medicine: Radix Astragaliseu Seu Hedysari, Angelica sinensis, Ligustici Chuanxiong, Spina Gleditsiae, and stir-baked Squama Manis. Previous studies have shown that it has anticancer effects. This report validates in vivo antitumor properties of TNS. The compounds contained in TNSE were confirmed by liquid chromatographmass spectrometer (LC-MS) analysis. The in vivo antitumor activity of TNS extract (TNSE) was tested by feeding it to athymic mice harboring a human colonic tumor subcutaneous xenograft. Toxicity was monitored by recording behavior and weight parameters. Seven compounds were detected in TNSE by LC-MS. TNSE was fed to athymic mice for 2 weeks. No adverse reactions were reported. Compared to the control group, administration of TNSE to tumor bearing mice significantly reduced both tumor weight and volume. The expressions of p-PI3K, p-AKT, p-mTOR, p p70s6k1, VEGF, and CD31 were significantly reduced, the expression levels of cleaved Caspase-9 and cleaved Caspase-3 were significantly increased in the TNSE groups compared to the control group as determined by western blot and immunohistochemistry. TNSE produced anticolonic cancer effects and the underlying mechanisms involved inhibition of the PI3K/AKT signal transduction pathway, inhibition of angiogenesis, and promotion of apoptotic proteins. PMID- 25788965 TI - Can Herbal Medicine Cause Hematoma Enlargement of Hypertensive Intracerebral Hemorrhage within 24 hrs Time Window? A Retrospective Study of 256 Cases from a Single Center in China. AB - A retrospective review was performed of consecutive patients presenting with HICH within 24 hours of ictus presenting between March 2008 and March 2013 who were diagnosed as having HICH by CT scan. Of the 256 patients who matched study inclusion standard, 43 patients hematoma was enlarged (16.8%). The number of the patients who did not take PBC or RBC herbal medicine, took the PBC herbal medicine, and took RBS herbal medicine was 19 (44.2%), 2 (4.7%), and 22 (51.2%) in hematoma enlargement group and 78 (36.6%), 26 (12.2%), and 109 (51.2%) in nonhematoma enlargement group, individually. There was no significant difference between two groups (P = 0.671). PBC and RBS herbal medicine did not increase the incidence of hematoma expansion of ICH within 24 hours after onset of symptom. PMID- 25788966 TI - The inhibitory effect of kakkonto, Japanese traditional (kampo) medicine, on brain penetration of oseltamivir carboxylate in mice with reduced blood-brain barrier function. AB - Oseltamivir phosphate (OP) is used to treat influenza virus infections. However, its use may result in central nervous system (CNS) adverse effects. In Japan, OP is used with Kampo formulations to improve clinical effectiveness. We evaluated the potential for using Kampo formulations to reduce CNS adverse effects by quantifying the CNS distribution of oseltamivir and its active metabolite oseltamivir carboxylate (OC) when administered with maoto and kakkonto. We administered lipopolysaccharide (LPS) by intraperitoneal injection to C57BL/6 mice to reduce blood-brain barrier function. Saline, maoto, and kakkonto were administered orally at the same time as LPS. OP was orally administered 4 hours after the last LPS injection and the migration of oseltamivir and OC was examined. Additionally, we examined the brain distribution of OC following intravenous administration. Changes in OC concentrations in the brain suggest that, in comparison to LPS-treated control mice, both Kampo formulations increased plasma levels of OC, thereby enhancing its therapeutic effect. Additionally, our findings suggest kakkonto may not only improve the therapeutic effect of oseltamivir but also reduce the risk of CNS-based adverse effects. Considering these findings, it should be noted that administration of kakkonto during periods of inflammation has led to increased OAT3 expression. PMID- 25788967 TI - Influence of quinacrine and chloroquine on the in vitro 3'-azido-3' deoxythymidine antiretroviral effect. AB - BACKGROUND: Antimalarials quinacrine (Qc) and chloroquine (Cq) intercalate DNA, potentiate the activity of other drugs and have lysosomotropic, anti-inflammatory and antiviral activities that could increase the effect of the 3'-azido-3' deoxythymidine (AZT) antiretroviral agent. The aim of the current study was to evaluate if Qc and Cq could improve the in vitro effect of the antiretroviral AZT agent. FINDINGS: Inhibition of viral replication in human immunodeficiency virus (HIV)SF33-infected peripheral blood mononuclear cells treated with Qc or Cq, alone or combined with a low dose of AZT was measured. Viral replication increased with Qc and decreased with high doses of Cq. The increase of replication caused by Qc was reversed by AZT. Neither Qc nor Cq significantly changed the antiviral activity of AZT. CONCLUSION: Cq does not potentiate the effect of AZT, but it is effective by itself at high doses. The rise of HIV replication by Qc could be deleterious in HIV endemic regions, where it is used as antimalarial. The mechanisms associated to this phenomenon must be identified. PMID- 25788968 TI - Responsive organogels formed by supramolecular self assembly of PEG-block-allyl functionalized racemic polypeptides into beta-sheet-driven polymeric ribbons. AB - A chemically reactive hybrid diblock polypeptide gelator poly(ethylene glycol) block-poly(dl-allylglycine) (PEG-b-PDLAG) is an exceptional material, due to the characteristics of thermo-reversible organogel formation driven by the combination of a hydrophilic polymer chain linked to a racemic oligomeric homopeptide segment in a range of organic solvents. One-dimensional stacking of the block copolymers is demonstrated by ATR-FTIR spectroscopy, wide-angle X-ray scattering to be driven by the supramolecular assembly of beta-sheets in peptide blocks to afford well-defined fiber-like structures, resulting in gelation. These supramolecular interactions are sufficiently strong to achieve ultra low critical gelation concentrations (ca. 0.1 wt%) in N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and methanol. The critical gel transition temperature was directly proportional to the polymer concentration, so that at low concentrations, thermoreversibility of gelation was observed. Dynamic mechanical analysis studies were employed to determine the organogel mechanical properties, having storage moduli of ca. 15.1 kPa at room temperature. PMID- 25788969 TI - The development and trial of a medication discontinuation program in the department of forensic psychiatry. AB - BACKGROUND: When treating mentally ill criminal offenders, improving medication adherence is essential to achieving goals, such as long-term stabilization of symptoms and the prevention of recidivism. Most subjects who are treated under the Medical Treatment and Supervision Act have schizophrenia, which is considered a particularly difficult disorder for which to improve medication adherence. For such patients, we developed a Medication Discontinuation Program (MDP) that aims to improve medication adherence by discontinuing antipsychotic drugs and monitoring changes in psychiatric symptoms. We examined whether there was any utility for the MDP on a trial basis as well as whether it would be worthwhile to introduce the MDP to psychiatric programs. METHODS: We conducted the MDP with an intervention group (n = 7) and compared Drug Attitude Inventory-30 (DAI-30) scores before and after implementation of the MDP. We also categorized 30 questions of the DAI-30 into three subscales: "awareness of the need for medication", "awareness of the effects of psychiatric drugs", and "impression of medication", and examined factors affecting improvement in medication adherence. RESULTS: The total DAI-30 score significantly increased after completion of the MDP (P = 0.002). Significant elevations after completion of the MDP were also observed in the scores for three subscales of the DAI-30. CONCLUSIONS: Our study suggests that the MDP has a possibility of improving medication adherence, and this program might have multidirectional and stimulatory effects on each factor related to the improvement of medication adherence. PMID- 25788970 TI - "Be positive as well as realistic": a qualitative description analysis of information gaps experienced by breastfeeding mothers. AB - BACKGROUND: Early breastfeeding cessation is common in many regions of the world despite high breastfeeding initiation rates and strong evidence of the health benefits to both mother and infant. This research investigated mothers' perceived breastfeeding information needs in order to increase our understanding of this phenomenon. METHODS: Surveys were distributed by public health nurses in a health region in Western Canada to mothers who had initiated breastfeeding and whose infants were six to eleven months old to learn more about their infant feeding experiences during the birth to six month period. Two open-ended survey questions asked: (1) What support or advice did you receive that helped you with feeding your baby?" and (2) "What support or information on feeding your baby would you have found helpful but did not receive?" A total of 191 eligible mothers submitted a survey (response rate 35%) between January and October 2012. Qualitative description was used in analyzing the responses of the women who provided comments for the open-ended questions. RESULTS: While many mothers felt their information needs were met, others outlined important content areas where more information and guidance was desired. These areas included milk supply management, frequency/duration of feeds, proper latch and feeding positions, nipple care, expression/pumping, other nutrition sources, and realistic information regarding common breastfeeding concerns. CONCLUSIONS: The results suggest that several of the information gaps highlighted by respondents in this study closely align with commonly cited reasons for breastfeeding cessation including perceived insufficient milk supply, latching difficulties and nipple discomfort. The findings emphasize the need for lactation support with systematic measures to ensure breastfeeding mothers are universally provided with information on these key content areas. Lactation supports should reinforce critical information and seek feedback to ascertain that mothers have clearly understood the information provided. Ensuring mothers receive and understand key breastfeeding information is a modifiable factor in efforts to increase breastfeeding duration rates. PMID- 25788971 TI - Ion Torrent sequencing as a tool for mutation discovery in the flax (Linum usitatissimum L.) genome. AB - BACKGROUND: Detection of induced mutations is valuable for inferring gene function and for developing novel germplasm for crop improvement. Many reverse genetics approaches have been developed to identify mutations in genes of interest within a mutagenized population, including some approaches that rely on next-generation sequencing (e.g. exome capture, whole genome resequencing). As an alternative to these genome or exome-scale methods, we sought to develop a scalable and efficient method for detection of induced mutations that could be applied to a small number of target genes, using Ion Torrent technology. We developed this method in flax (Linum usitatissimum), to demonstrate its utility in a crop species. RESULTS: We used an amplicon-based approach in which DNA samples from an ethyl methanesulfonate (EMS)-mutagenized population were pooled and used as template in PCR reactions to amplify a region of each gene of interest. Barcodes were incorporated during PCR, and the pooled amplicons were sequenced using an Ion Torrent PGM. A pilot experiment with known SNPs showed that they could be detected at a frequency > 0.3% within the pools. We then selected eight genes for which we wanted to discover novel mutations, and applied our approach to screen 768 individuals from the EMS population, using either the Ion 314 or Ion 316 chips. Out of 29 potential mutations identified after processing the NGS reads, 16 mutations were confirmed using Sanger sequencing. CONCLUSIONS: The methodology presented here demonstrates the utility of Ion Torrent technology in detecting mutation variants in specific genome regions for large populations of a species such as flax. The methodology could be scaled-up to test >100 genes using the higher capacity chips now available from Ion Torrent. PMID- 25788974 TI - A simple data-adaptive probabilistic variant calling model. AB - BACKGROUND: Several sources of noise obfuscate the identification of single nucleotide variation (SNV) in next generation sequencing data. For instance, errors may be introduced during library construction and sequencing steps. In addition, the reference genome and the algorithms used for the alignment of the reads are further critical factors determining the efficacy of variant calling methods. It is crucial to account for these factors in individual sequencing experiments. RESULTS: We introduce a simple data-adaptive model for variant calling. This model automatically adjusts to specific factors such as alignment errors. To achieve this, several characteristics are sampled from sites with low mismatch rates, and these are used to estimate empirical log-likelihoods. The likelihoods are then combined to a score that typically gives rise to a mixture distribution. From this we determine a decision threshold to separate potentially variant sites from the noisy background. CONCLUSIONS: In simulations we show that our simple model is competitive with frequently used much more complex SNV calling algorithms in terms of sensitivity and specificity. It performs specifically well in cases with low allele frequencies. The application to next generation sequencing data reveals stark differences of the score distributions indicating a strong influence of data specific sources of noise. The proposed model is specifically designed to adjust to these differences. PMID- 25788973 TI - PET-specific parameters and radiotracers in theoretical tumour modelling. AB - The innovation of computational techniques serves as an important step toward optimized, patient-specific management of cancer. In particular, in silico simulation of tumour growth and treatment response may eventually yield accurate information on disease progression, enhance the quality of cancer treatment, and explain why certain therapies are effective where others are not. In silico modelling is demonstrated to considerably benefit from information obtainable with PET and PET/CT. In particular, models have successfully integrated tumour glucose metabolism, cell proliferation, and cell oxygenation from multiple tracers in order to simulate tumour behaviour. With the development of novel radiotracers to image additional tumour phenomena, such as pH and gene expression, the value of PET and PET/CT data for use in tumour models will continue to grow. In this work, the use of PET and PET/CT information in in silico tumour models is reviewed. The various parameters that can be obtained using PET and PET/CT are detailed, as well as the radiotracers that may be used for this purpose, their utility, and limitations. The biophysical measures used to quantify PET and PET/CT data are also described. Finally, a list of in silico models that incorporate PET and/or PET/CT data is provided and reviewed. PMID- 25788972 TI - Multimodality functional imaging in radiation therapy planning: relationships between dynamic contrast-enhanced MRI, diffusion-weighted MRI, and 18F-FDG PET. AB - OBJECTIVES: Biologically guided radiotherapy needs an understanding of how different functional imaging techniques interact and link together. We analyse three functional imaging techniques that can be useful tools for achieving this objective. MATERIALS AND METHODS: The three different imaging modalities from one selected patient are ADC maps, DCE-MRI, and 18F-FDG PET/CT, because they are widely used and give a great amount of complementary information. We show the relationship between these three datasets and evaluate them as markers for tumour response or hypoxia marker. Thus, vascularization measured using DCE-MRI parameters can determine tumour hypoxia, and ADC maps can be used for evaluating tumour response. RESULTS: ADC and DCE-MRI include information from 18F-FDG, as glucose metabolism is associated with hypoxia and tumour cell density, although 18F-FDG includes more information about the malignancy of the tumour. The main disadvantage of ADC maps is the distortion, and we used only low distorted regions, and extracellular volume calculated from DCE-MRI can be considered equivalent to ADC in well-vascularized areas. CONCLUSION: A dataset for achieving the biologically guided radiotherapy must include a tumour density study and a hypoxia marker. This information can be achieved using only MRI data or only PET/CT studies or mixing both datasets. PMID- 25788975 TI - Self-care strategies for emotional distress among young adults in Catalonia: a qualitative study. AB - BACKGROUND: Emotional distress is common in adolescence, and self-care strategies are frequently preferred to address it. The aim of this article is to analyze the self-care strategies among adolescents and young people diagnosed with depression or with self-perceived depressive distress in Catalonia using a qualitative design. METHODS: We analyzed the self-care strategies of 105 young people (17-21 years of age) in Catalonia who had participated in a national survey on adolescents. The sample was divided into thirds, with 37 who had a previous diagnosis of depression, 33 who had self-perceived emotional distress, and 35 controls. The participants' narratives on self-care strategies for emotional distress were elicited through in-depth semi-structured interviews. The data were managed using ATLAS-Ti 6.5 software18. We applied hermeneutic theory and the ethnographic method to analyze the interviews. RESULTS: The ten self-care strategies identified in the analysis were grouped into four areas covering the various pathways the young people followed according to whether they had a diagnosis of depression or their depressive distress was self-perceived. The young people feel responsible for their emotional distress and consider that they are capable of resolving it through their own resources. Their strategies ranged from their individuality to sociability expressed through their relationships with others, membership of groups or other self-care strategies (relaxation, meditation, naturopathy, etc.). CONCLUSIONS: The study results highlight the importance of sensitivity in considering young people's self-care strategies as another option in the care of emotional distress. PMID- 25788977 TI - A combined cell-consortium approach for lignocellulose degradation by specialized Lactobacillus plantarum cells. AB - BACKGROUND: Lactobacillus plantarum is an attractive candidate for metabolic engineering towards bioprocessing of lignocellulosic biomass to ethanol or polylactic acid, as its natural characteristics include high ethanol and acid tolerance and the ability to metabolize the two major polysaccharide constituents of lignocellulolytic biomass (pentoses and hexoses). We recently engineered L. plantarum via separate introduction of a potent cellulase and xylanase, thereby creating two different L. plantarum strains. We used these strains as a combined cell-consortium for synergistic degradation of cellulosic biomass. RESULTS: To optimize enzymatic degradation, we applied the cell-consortium approach to assess the significance of enzyme localization by comparing three enzymatic paradigms prevalent in nature: (i) a secreted enzymes system, (ii) enzymes anchored to the bacterial cell surface and (iii) enzymes integrated into cellulosome complexes. The construction of the three paradigmatic systems involved the division of the production and organization of the enzymes and scaffold proteins into different strains of L. plantarum. The spatial differentiation of the components of the enzymatic systems alleviated the load on the cell machinery of the different bacterial strains. Active designer cellulosomes containing a xylanase and a cellulase were thus assembled on L. plantarum cells by co-culturing three distinct engineered strains of the bacterium: two helper strains for enzyme secretion and one producing only the anchored scaffoldin. Alternatively, the two enzymes were anchored separately to the cell wall. The secreted enzyme consortium appeared to have a slight advantage over the designer cellulosome system in degrading the hypochlorite pretreated wheat straw substrate, and both exhibited significantly higher levels of activity compared to the anchored enzyme consortium. However, the secreted enzymes appeared to be less stable than the enzymes integrated into designer cellulosomes, suggesting an advantage of the latter over longer time periods. CONCLUSIONS: By developing the potential of L. plantarum to express lignocellulolytic enzymes and to control their functional combination and stoichiometry on the cell wall, this study provides a step forward towards optimal biomass bioprocessing and soluble fermentable sugar production. Future expansion of the preferred secreted-enzyme and designer cellulosome systems to include additional types of enzymes will promote enhanced deconstruction of cellulosic feedstocks. PMID- 25788978 TI - Bioethanol from poplar: a commercially viable alternative to fossil fuel in the European Union. AB - BACKGROUND: The European Union has made it a strategic objective to develop its biofuels market in order to minimize greenhouse gas (GHG) emissions, to help mitigate climate change and to address energy insecurity within the transport sector. Despite targets set at national and supranational levels, lignocellulosic bioethanol production has yet to be widely commercialized in the European Union. Here, we use techno-economic modeling to compare the price of bioethanol produced from short rotation coppice (SRC) poplar feedstocks under two leading processing technologies in five European countries. RESULTS: Our evaluation shows that the type of processing technology and varying national costs between countries results in a wide range of bioethanol production prices (?0.275 to 0.727/l). The lowest production prices for bioethanol were found in countries that had cheap feedstock costs and high prices for renewable electricity. Taxes and other costs had a significant influence on fuel prices at the petrol station, and therefore the presence and amount of government support for bioethanol was a major factor determining the competitiveness of bioethanol with conventional fuel. In a forward-looking scenario, genetically engineering poplar with a reduced lignin content showed potential to enhance the competitiveness of bioethanol with conventional fuel by reducing overall costs by approximately 41% in four out of the five countries modeled. However, the possible wider phenotypic traits of advanced poplars needs to be fully investigated to ensure that these do not unintentionally negate the cost savings indicated. CONCLUSIONS: Through these evaluations, we highlight the key bottlenecks within the bioethanol supply chain from the standpoint of various stakeholders. For producers, technologies that are best suited to the specific feedstock composition and national policies should be optimized. For policymakers, support schemes that benefit emerging bioethanol producers and allow renewable fuel to be economically competitive with petrol should be established. Finally, for researchers, better control over plant genetic engineering and advanced breeding and its consequential economic impact would bring valuable contributions towards developing an economically sustainable bioethanol market within the European Union. PMID- 25788976 TI - Improved production of a recombinant Rhizomucor miehei lipase expressed in Pichia pastoris and its application for conversion of microalgae oil to biodiesel. AB - BACKGROUND: We previously cloned a 1,3-specific lipase gene from the fungus Rhizomucor miehei and expressed it in methylotrophic yeast Pichia pastoris strain GS115. The enzyme produced (termed RML) was able to catalyze methanolysis of soybean oil and showed strong position specificity. However, the enzyme activity and amount of enzyme produced were not adequate for industrial application. Our goal in the present study was to improve the enzyme properties of RML in order to apply it for the conversion of microalgae oil to biofuel. RESULTS: Several new expression plasmids were constructed by adding the propeptide of the target gene, optimizing the signal peptide, and varying the number of target gene copies. Each plasmid was transformed separately into P. pastoris strain X-33. Screening by flask culture showed maximal (21.4-fold increased) enzyme activity for the recombinant strain with two copies of the target gene; the enzyme was termed Lipase GH2. The expressed protein with the propeptide (pRML) was a stable glycosylated protein, because of glycosylation sites in the propeptide. Quantitative real-time RT-PCR analysis revealed two major reasons for the increase in enzyme activity: (1) the modified recombinant expression system gave an increased transcription level of the target gene (rml), and (2) the enzyme was suitable for expression in host cells without causing endoplasmic reticulum (ER) stress. The modified enzyme had improved thermostability and methanol or ethanol tolerance, and was applicable directly as free lipase (fermentation supernatant) in the catalytic esterification and transesterification reaction. After reaction for 24 hours at 30 degrees C, the conversion rate of microalgae oil to biofuel was above 90%. CONCLUSIONS: Our experimental results show that signal peptide optimization in the expression plasmid, addition of the gene propeptide, and proper gene dosage significantly increased RML expression level and enhanced the enzymatic properties. The target enzyme was the major component of fermentation supernatant and was stable for over six months at 4 degrees C. The modified free lipase is potentially applicable for industrial-scale conversion of microalgae oil to biodiesel. PMID- 25788979 TI - Engineering a fungal peroxidase that degrades lignin at very acidic pH. AB - BACKGROUND: Ligninolytic peroxidases are divided into three families: manganese peroxidases (MnPs), lignin peroxidases (LiPs), and versatile peroxidases (VPs). The latter two are able to degrade intact lignins, as shown using nonphenolic lignin model compounds, with VP oxidizing the widest range of recalcitrant substrates. One of the main limiting issues for the use of these two enzymes in lignocellulose biorefineries (for delignification and production of cellulose based products or modification of industrial lignins to added-value products) is their progressive inactivation under acidic pH conditions, where they exhibit the highest oxidative activities. RESULTS: In the screening of peroxidases from basidiomycete genomes, one MnP from Ceriporiopsis subvermispora was found to have a remarkable acidic stability. The crystal structure of this enzyme recently became available and, after comparison with Pleurotus ostreatus VP and Phanerochaete chrysosporium LiP structures, it was used as a robust scaffold to engineer a stable VP by introducing an exposed catalytic tryptophan, with different protein environments. The variants obtained largely maintain the acidic stability and strong Mn(2+)-oxidizing activity of the parent enzyme, and the ability to oxidize veratryl alcohol and Reactive Black 5 (two simple VP substrates) was introduced. The engineered peroxidases present more acidic optimal pH than the best VP from P. ostreatus, enabling higher catalytic efficiency oxidizing lignins, by lowering the reaction pH, as shown using a nonphenolic model dimer. CONCLUSIONS: A peroxidase that degrades lignin at very acidic pH could be obtained by engineering an exposed catalytic site, able to oxidize the bulky and recalcitrant lignin polymers, in a different peroxidase type selected because of its high stability at acidic pH. The potential of this type of engineered peroxidases as industrial biocatalysts in lignocellulose biorefineries is strongly enhanced by the possibility to perform the delignification (or lignin modification) reactions under extremely acidic pH conditions (below pH 2), resulting in enhanced oxidative power of the enzymes. PMID- 25788980 TI - A novel thermostable xylanase GH10 from Malbranchea pulchella expressed in Aspergillus nidulans with potential applications in biotechnology. AB - BACKGROUND: The search for novel thermostable xylanases for industrial use has intensified in recent years, and thermophilic fungi are a promising source of useful enzymes. The present work reports the heterologous expression and biochemical characterization of a novel thermostable xylanase (GH10) from the thermophilic fungus Malbranchea pulchella, the influence of glycosylation on its stability, and a potential application in sugarcane bagasse hydrolysis. RESULTS: Xylanase MpXyn10A was overexpressed in Aspergillus nidulans and was active against birchwood xylan, presenting an optimum activity at pH 5.8 and 80 degrees C. MpXyn10A was 16% glycosylated and thermostable, preserving 85% activity after 24 hours at 65 degrees C, and deglycosylation did not affect thermostability. Circular dichroism confirmed the high alpha-helical content consistent with the canonical GH10 family (beta/alpha)8 barrel fold observed in molecular modeling. Primary structure analysis revealed the existence of eight cysteine residues which could be involved in four disulfide bonds, and this could explain the high thermostability of this enzyme even in the deglycosylated form. MpXyn10A showed promising results in biomass degradation, increasing the amount of reducing sugars in bagasse in natura and in three pretreated sugarcane bagasses. CONCLUSIONS: MpXyn10A was successfully secreted in Aspergillus nidulans, and a potential use for sugarcane bagasse biomass degradation was demonstrated. PMID- 25788981 TI - Towards a deeper understanding of structural biomass recalcitrance using phase contrast tomography. AB - BACKGROUND: The development of technological routes to convert lignocellulosic biomass to liquid fuels requires an in-depth understanding of the cell wall architecture of substrates. Essential pretreatment processes are conducted to reduce biomass recalcitrance and usually increase the reactive surface area. Quantitative three-dimensional information about both bulk and surface structural features of substrates needs to be obtained to expand our knowledge of substrates. In this work, phase-contrast tomography (PCT) was used to gather information about the structure of a model lignocellulosic biomass (piassava fibers). RESULTS: The three-dimensional cellular organization of piassava fibers was characterized by PCT using synchrotron radiation. This technique enabled important physical features that describe the substrate piassava fibers to be visualized and quantified. The external surface area of a fiber and internal surface area of the pores in a fiber could be determined separately. More than 96% of the overall surface area available to enzymes was in the bulk substrate. The pore surface area and length exhibited a positive linear relationship, where the slope of this relationship depended on the plant tissue. CONCLUSIONS: We demonstrated that PCT is a powerful tool for the three-dimensional characterization of the cell wall features related to biomass recalcitrance. Original and relevant quantitative information about the structural features of the analyzed material were obtained. The data obtained by PCT can be used to improve processing routes to efficiently convert biomass feedstock into sugars. PMID- 25788982 TI - The use of fluorescent Nile red and BODIPY for lipid measurement in microalgae. AB - Microalgae are currently emerging as one of the most promising alternative sources for the next generation of food, feed, cosmetics and renewable energy in the form of biofuel. Microalgae constitute a diverse group of microorganisms with advantages like fast and efficient growth. In addition, they do not compete for arable land and offer very high lipid yield potential. Major challenges for the development of this resource are to select lipid-rich strains using high throughput staining for neutral lipid content in microalgae species. For this purpose, the fluorescent dyes most commonly used to quantify lipids are Nile red and BODIPY 505/515. Their fluorescent staining for lipids offers a rapid and inexpensive analysis tool to measure neutral lipid content, avoiding time consuming and costly gravimetric analysis. This review collates and presents recent advances in algal lipid staining and focuses on Nile red and BODIPY 505/515 staining characteristics. The available literature addresses the limitations of fluorescent dyes under certain conditions, such as spectral properties, dye concentrations, cell concentrations, temperature and incubation duration. Moreover, the overall conclusion of the present review study gives limitations on the use of fluorochrome for screening of lipid-rich microalgae species and suggests improved protocols for staining recalcitrant microalgae and recommendations for the staining quantification. PMID- 25788983 TI - CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells. AB - BACKGROUND: The histone H3 variant CENP-A is normally tightly regulated to ensure only one centromere exists per chromosome. Native CENP-A is often found overexpressed in human cancer cells and a range of human tumors. Consequently, CENP-A misregulation is thought to contribute to genome instability in human cancers. However, the consequences of such overexpression have not been directly elucidated in human cancer cells. RESULTS: To investigate native CENP-A overexpression, we sought to uncover CENP-A-associated defects in human cells. We confirm that CENP-A is innately overexpressed in several colorectal cancer cell lines. In such cells, we report that a subset of structurally distinct CENP-A containing nucleosomes associate with canonical histone H3, and with the transcription-coupled chaperones ATRX and DAXX. Furthermore, such hybrid CENP-A nucleosomes localize to DNase I hypersensitive and transcription factor binding sites, including at promoters of genes across the human genome. A distinct class of CENP-A hotspots also accumulates at subtelomeric chromosomal locations, including at the 8q24/Myc region long-associated with genomic instability. We show this 8q24 accumulation of CENP-A can also be seen in early stage primary colorectal tumors. CONCLUSIONS: Our data demonstrate that excess CENP-A accumulates at noncentromeric locations in the human cancer genome. These findings suggest that ectopic CENP-A nucleosomes could alter the state of the chromatin fiber, potentially impacting gene regulation and chromosome fragility. PMID- 25788984 TI - Constitutive heterochromatin formation and transcription in mammals. AB - Constitutive heterochromatin, mainly formed at the gene-poor regions of pericentromeres, is believed to ensure a condensed and transcriptionally inert chromatin conformation. Pericentromeres consist of repetitive tandem satellite repeats and are crucial chromosomal elements that are responsible for accurate chromosome segregation in mitosis. The repeat sequences are not conserved and can greatly vary between different organisms, suggesting that pericentromeric functions might be controlled epigenetically. In this review, we will discuss how constitutive heterochromatin is formed and maintained at pericentromeres in order to ensure their integrity. We will describe the biogenesis and the function of main epigenetic pathways that are involved and how they are interconnected. Interestingly, recent findings suggest that alternative pathways could substitute for well-established pathways when disrupted, suggesting that constitutive heterochromatin harbors much more plasticity than previously assumed. In addition, despite of the heterochromatic nature of pericentromeres, there is increasing evidence for active and regulated transcription at these loci, in a multitude of organisms and under various biological contexts. Thus, in the second part of this review, we will address this relatively new aspect and discuss putative functions of pericentromeric expression. PMID- 25788986 TI - Effective radiation dose of a MSCT, two CBCT and one conventional radiography device in the ankle region. AB - BACKGROUND: The aim of this study was to assess and compare the effective doses (ICRP 103) in the ankle region of X-ray imaging resulting from a multi slice computed tomography (MSCT) device, two cone beam CT (CBCT) devices and one conventional x-ray device. METHODS: Organ dose measurements were performed using 20 metal oxide field effect transistor (MOSFET) dosimeters that were placed in a custom made anthropomorphic RANDO ankle phantom. The following scanners were assessed in this study: Siemens Sensation Open 24-slice MSCT-scanner (120 kVp, 54 mAs), NewTom 5G CBCT scanner (110 kVp, 2.3 - 59 mAs), Planmed Verity CBCT-scanner (90 kVp, 48 mAs), Shimadzu FH-21 HR direct radiography equipment (AP + LAT), (57 kVp, 16 mAs). RESULTS: Measurements of the MSCT device resulted in 21.4 MUSv effective dose. The effective doses of CBCTs were between 1.9 MUSv and 14.3 MUSv for NewTom 5G and 6.0 MUSv for Planmed Verity. Effective doses for the Shimadzu FH-21 HR conventional radiography were 1.0 MUSv (LAT) and 0.5 MUSv (AP), respectively. CONCLUSIONS: Compared with a conventional 2D radiographic device, this study showed a 14-fold effective dose for standard MSCT and 1.3 -10 fold effective dose for standard CBCT protocols. CBCT devices offers a 3D view of ankle imaging and exhibited lower effective doses compared with MSCT. PMID- 25788985 TI - Genome-wide assays that identify and quantify modified cytosines in human disease studies. AB - The number of different assays that has been published to study DNA methylation is extensive, complemented by recently described assays that test modifications of cytosine other than the most abundant 5-methylcytosine (5mC) variant. In this review, we describe the considerations involved in choosing how to study 5mC throughout the genome, with an emphasis on the common application of testing for epigenetic dysregulation in human disease. While microarray studies of 5mC continue to be commonly used, these lack the additional qualitative information from sequencing-based approaches that is increasingly recognized to be valuable. When we test the representation of functional elements in the human genome by several current assay types, we find that no survey approach interrogates anything more than a small minority of the nonpromoter cis-regulatory sites where DNA methylation variability is now appreciated to influence gene expression and to be associated with human disease. However, whole-genome bisulphite sequencing (WGBS) adds a substantial representation of loci at which DNA methylation changes are unlikely to be occurring with transcriptional consequences. Our assessment is that the most effective approach to DNA methylation studies in human diseases is to use targeted bisulphite sequencing of the cis-regulatory loci in a cell type of interest, using a capture-based or comparable system, and that no single design of a survey approach will be suitable for all cell types. PMID- 25788987 TI - High prevalence of diabetes and intermediate hyperglycemia - The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: The global burden of diabetes mellitus and other chronic diseases is high, and 80% of those with diabetes now live in low and middle income countries. Yet, little information is available regarding prevalence of diabetes and intermediate hyperglycemia in these countries, especially when a full range of diagnostic tests is employed. The purpose of this study is to provide a full accounting of these prevalences in a large, free-living Brazilian population. METHODS: We report baseline data (2008-2010) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a cohort study of 15,105 civil servants aged 35-74 years. Diabetes mellitus was ascertained by self-report of diagnosis, medication use, fasting glucose, an oral glucose tolerance test, and/or glycated hemoglobin. Cut-offs for diabetes and intermediate hyperglycemia followed the recommendations of the World Health Organization and the American Diabetes Association. Adjusted prevalences were estimated through logistic regression. FINDINGS: With this full accounting, 19.7% (19.0%-20.3%) had diabetes mellitus, 50.4% being previously undiagnosed. Frequencies of intermediate hyperglycemia according to various criteria ranged from 16.1% to 52.6%. Diabetes or intermediate hyperglycemia was present in 79.1% of participants when using the most comprehensive definitions. The burden was greatest in the elderly, the obese, non-whites, and those with less formal education (p < 0.001). INTERPRETATION: That four of every five free-living individuals aged 35-74 years working in selected public institutions in six Brazilian state capitals presented either diabetes or intermediate hyperglycemia highlights the advanced stage of the obesity - diabetes epidemic in urban Brazil and indicates the need for urgent action. PMID- 25788988 TI - Dementia trials and dementia tribulations: methodological and analytical challenges in dementia research. AB - Dementia is a substantial and increasing public health concern. Despite decades of research, a cure or effective preventative treatment for dementia remains elusive. We offer critical review of contemporary dementia research and discuss potential reasons why progress in the field has not been as rapid as in other disciplines. We adopt a broad approach in keeping with the broad nature of the topic. We cover the difficulties inherent in studying dementia from 'bench' to 'bedside' to 'population'. We make particular reference to issues of operationalisation of the dementia syndrome and our evolving understanding of dementia as a research 'outcome'. We discuss contemporary 'hot topics' in dementia research methodology focussing on dementia models, pre-dementia states and biomarkers. Recognising the importance of prospective epidemiological cohorts and large-scale clinical trials we pay particular attention to these approaches and the challenges of generating results that have 'real world' external validity. Based on our thoughts we end with suggestions for future dementia research. Our review is designed to be critical but not unnecessarily negative. There is reason for cautious optimism in dementia research. The recent G8 summit on dementia and subsequent establishment of the World Dementia Council are examples of initiatives that reflect societal and political will to increase research efforts in dementia. PMID- 25788989 TI - Molecular mechanisms of tamoxifen-associated endometrial cancer (Review). AB - Tamoxifen has been prescribed to millions of females for breast cancer prevention or treatment. However, tamoxifen is known to significantly enhance the risk of developing endometrial lesions, including hyperplasia, polyps, carcinomas, and sarcoma. Notably, tamoxifen-associated endometrial cancer often has a poor clinical outcome. Understanding the molecular mechanism of tamoxifen-induced endometrial cancer is essential for developing strategies that minimize tamoxifen's effects on the endometrium without jeopardizing its breast cancer treatment effects. However, this understanding remains limited. Tamoxifen appears to mediate its effect on endometrial cells through estrogenic and non-genomic pathways, rather than introducing a genomic alteration as a carcinogen. Although tamoxifen functions as an agonist and promotes cell proliferation in endometrial cancer, it also displays antagonist activity towards some estrogen targets. Alterations in estrogen receptor-alpha and its isoforms, as well as the membrane associated estrogen receptor G protein-coupled receptor 30, have been observed with tamoxifen-exposed endometrial cells, and likely mediate the effects of tamoxifen on endometrial cancer cell proliferation and invasion. In addition, gene profile studies of short-term exposure to tamoxifen indicate that the majority of tamoxifen targets are tamoxifen-specific. However, the tamoxifen regulated gene targets that are involved in mediating the effects of long-term exposure to tamoxifen are not yet fully understood. Recent progress has indicated a potential role of unfolded protein response and mammalian target of rapamycin signaling in tamoxifen-associated endometrial cancer. In the future, studies focusing on long-term effects of tamoxifen exposure are required to understand the molecular mechanisms of tamoxifen-associated endometrial cancer. PMID- 25788990 TI - Biomarkers for gastric cancer: Progression in early diagnosis and prognosis (Review). AB - Gastric cancer is one of leading causes of cancer-related mortality worldwide and is a notable disease due to its heterogeneity. Recently, numerous studies have investigated the molecular basis of gastric cancer, involving the alteration of pathogenesis, and invasion and metastasis. With the development of modern technologies, various novel biomarkers had been identified that appear to possess diagnostic and prognostic value; therefore, the present review describes our current knowledge of biomarkers for the early diagnosis and prognosis of gastric cancer. Classic biomarkers for gastric cancer diagnosis include carcinoembryonic antigen and cancer antigen 19-9, while microRNA and DNA hypomethylation are proposed as novel biomarkers. Excluding classical biomarkers, biomarkers for determining the progression and prognosis of gastric cancer focus on targeting microRNAs, epigenetic alterations and genetic polymorphisms. PMID- 25788991 TI - Depression in cancer patients: Pathogenesis, implications and treatment (Review). AB - Depression is a common comorbidity in cancer cases, affecting >10% of patients. A cancer diagnosis is life-changing, and is a source of considerable psychological and emotional stress. Non-pathological sadness may be a normal response to a cancer diagnosis, however, stress beyond the coping mechanisms of patients may result in major depressive disorder. The current review, in addition to the obvious psychosocial elements of depression, explores its biological mechanisms, including tissue damage, inflammatory mediators and the chronic stress response, and how these immune and endocrine pathways may underlie depression in cancer. Possible iatrogenic causes of depression in cancer are also explored. There is a strong need to identify and treat depression in cancer patients in order to increase quality of life and reduce mortality. The most popular clinical and potential future biochemical screening tools for depression in cancer are briefly discussed. The interventions used will vary for every patient, but may include psychosocial therapies or pharmacotherapy; however, a paucity of research on the most effective management of depression in cancer means the optimal combination of therapies is unknown. Selection of antidepressants should be carefully considered, given the common side effects of chemotherapy (such as nausea), and the necessity to avoid serious interactions, including reducing the effectiveness of chemotherapeutic drugs. The possible link between the chronic stress response, which may predispose patients to depression, and the risk of mortality from cancer is also explored. The complex interactions between the endocrine, nervous and immune systems, which continue to be elucidated, may offer the opportunity for the development of more rapid and efficacious treatments for depression in cancer in the future. PMID- 25788992 TI - Animal models for bladder cancer: The model establishment and evaluation (Review). AB - Bladder cancer is the most common type of tumor in the urogenital system. Approximately 75% of patients with bladder cancer present with non-muscle invasive cancer, which is generally treated by transurethral resection and intravesical chemotherapy. In spite of different therapeutic options, there remains a very variable risk of recurrence and progression. Novel therapeutic methods of treating bladder cancer are urgently required. The exploration and preclinical evaluation of new treatments requires an animal tumor model that mimics the human counterpart. Animal models are key in bladder cancer research and provide a bridge to the clinic. Various animal bladder cancer models have been described to date, but the tumor take rate is reported to be 30-100%. Establishment of reliable, simple, practicable and reproducible animal models remains an ongoing challenge. The present review summarizes the latest developments with regard to the establishment of animal models and tumor evaluation. PMID- 25788993 TI - Spontaneous complete necrosis of hepatocellular carcinoma: A case report and review of the literature. AB - The present study reports the case of a 68-year-old male patient who presented to Tokyo Rosai Hospital for the treatment of alcoholic liver disease. A high density was observed in liver segment S2, while a tumor, 30 mm in size, exhibiting a low density was observed in the delayed phase upon contrast-enhanced computed tomography (CT), which was performed prior to admission. The tumor appeared slightly poorly defined upon abdominal ultrasound and was observed as a 30 mm low echoic nodule that was internally heterogeneous. A 5-mm thick contrast enhancement effect was observed in the tumor border in the vascular phase on Sonazoid contrast-enhanced ultrasonography, while a defect in the entire tumor was observed in the post-vascular phase. Dysphagia had commenced three months prior to presentation and a weight loss of ~3 kg was observed. Therefore, the patient was admitted to Tokyo Rosai Hospital due to the presence of a hepatic tumor, and to undergo a close inspection of the cause of the tumor. Upon close inspection, it was determined that the weight loss and aphagia were caused by progressive bulbar paralysis. A contrast-enhanced CT was performed on post admission day 29 as a follow-up regarding the hepatic tumor. As a result, although no change in the tumor size was observed, the contrast enhancement in the tumor borderline had disappeared. Necrosis of the tumor was considered. However, as viable persistence of the malignant tumor could not be excluded, a hepatic left lobe excision was performed. The patient was diagnosed with hepatocellular carcinoma (HCC) based on the morphology of the cellular necrosis. In addition, occlusion due to thrombus was observed within the blood vessels passing inside the fibrous capsule. It was hypothesized that the formation of a thick fibrous capsule and occlusion due to thrombus in the feeding vessel were possibly involved as the cause of complete spontaneous necrosis. Written informed consent was obtained from the patient. PMID- 25788994 TI - Poorly differentiated cecal adenocarcinoma showing prominent rhabdoid feature combined with appendiceal mucinous cystadenoma: A case report and review of the literature. AB - Extrarenal rhabdoid tumors (ERRTs) are extremely rare neoplasms; of these, colorectal ERRTs are the most rare, and only nine cases have been previously described in the English language literature. The current study reports the pathological features of a case of poorly differentiated cecal adenocarcinoma with prominent rhabdoid feature, which was combined with mucinous cystadenoma of the appendix in a 73-year-old male, and additionally reviews the previously reported cases. Microscopically, the majority of tumor cells were non-cohesive or loosely cohesive, with a polygonal morphology and prominent rhabdoid feature, showing eccentric vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) and vimentin, but negative for CK20, CK7, desmin and smooth muscle actin. This indicated a diagnosis of poorly differentiated adenocarcinoma with prominent rhabdoid features, combined with appendiceal mucinous cystadenoma. At two months following surgery the patient succumbed to peritoneal seeding and metastasis of liver and bone The emergence of the rhabdoid phenotype is invariably associated with an aggressive and almost always fatal clinical course. The present case is the 10th example of such a tumor in the colon, and to the best of our knowledge, this is the first case of colonic rhabdoid tumor coinciding with appendiceal benign mucinous neoplasm. PMID- 25788995 TI - Role of Numb expression and nuclear translocation in endometrial cancer. AB - The cell fate determinant Numb orchestrates numerous cell physiological and pathological processes and previous evidence has indicated that Numb expression is associated with tumorigenesis. The present study investigated the potential role of Numb in endometrial cancer (EC). Numb expression was compared between the normal endometrium and EC tissue by immunohistochemistry, and the protein levels were assessed by western blotting and confocal microscopy in the human endometrial HEC-1B cancer cell line and normal epithelial cells. The intracellular localization of Numb in HEC-1B cells was examined by immunofluorescence. Numb was found to be expressed at higher levels in endometrial cancer compared with the normal endometrium. Although Numb localizes to the cytoplasm and plasma membrane in the normal epithelium, the present study found that Numb accumulated in the nucleus of HEC-1B cells. The present data reveals the upregulation of Numb expression in EC tissues and indicates that Numb plays a role in the occurrence of EC, which may be mediated by its translocation into the nucleus. The role of Numb in cancer development requires additional investigation. PMID- 25788996 TI - Response to erlotinib in a patient with lung adenocarcinoma harbouring the EML4 ALK translocation: A case report. AB - Lung cancer is the leading cause of cancer-associated mortality worldwide, and the mainstay of treatment remains to be personalised therapy. Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have been reported to exert a significant impact in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harbouring mutations in the EGFR gene. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4 ALK) gene translocation has been described in a subset of patients with NSCLC and possesses potent oncogenic activity. This translocation represents one of the most novel molecular targets in the treatment of NSCLC. Patients who harbour the EML4-ALK rearrangement possess lung tumours that lack EGFR or K-ras mutations. The present study reports the case of a patient possessing the EML4-ALK rearrangement that was initially treated with erlotinib and achieved a lasting clinical response. To the best of our knowledge, the current study is the first report of a clinical response to EGFR-TKI in a patient with lung adenocarcinoma harbouring the EML4-ALK fusion gene, but no EGFR mutations. However, as the disease progressed, the ALK gene status of the tumour was investigated, and based upon a positive result, the patient was treated with crizotinib and achieved a complete response. In conclusion, the present study suggests that the EML4-ALK rearrangement is not always associated with resistance to EGFR-TKIs. Further studies are required to clarify the biological features of these tumours and to investigate the mechanisms underlying the primary resistance to EGFR-TKIs when the EML4-ALK rearrangement is present. PMID- 25788997 TI - Multiple cutaneous and intestinal metastases in lung cancer: A case report. AB - Lung cancer is a common malignant neoplasm that is prone to distant metastasis. However, the incidence of multiple cutaneous and intestinal metastases is rare. The present study describes the case of a 62-year-old female who was admitted to The Affiliated Hospital of Shandong Academy of Medical Sciences in August 2013 with multiple cutaneous lumps. Contrast-enhanced computed tomography showed nodules and masses in the right lung, and multiple enlarged lymph nodes in the mediastinum and right hilum. Biopsies of the lumps in the right lung and skin revealed moderately-differentiated adenocarcinoma, which were considered to be cutaneous metastases of lung cancer. The patient subsequently experienced symptoms of rectal irritation. A digital rectal examination and colonoscopy were performed, and the consequent pathological biopsy identified moderately differentiated adenocarcinoma. After analyzing the results of previous pathological examinations and immunohistochemistry, it may be suggested that intestinal metastasis had developed. This case highlights the fact that a comprehensive analysis and examination should be performed for suspected cutaneous and intestinal lesions, during which, a pathological biopsy is of great importance in order to form the correct diagnosis for timely treatment. PMID- 25788998 TI - Treatment of a recurrent pulmonary artery leiomyosarcoma with a combination of surgery, chemotherapy, and radiotherapy: A case report and literature review. AB - Pulmonary artery (PA) leiomyosarcoma (PAL) is a rare but extremely malignant tumor of the cardiovascular system, which is often misdiagnosed as pulmonary thromboembolism. Although the early detection and surgical resection improves patient survival, the benefits of adjuvant therapy are not well understood. The current study presents the case of a patient with primary PAL who underwent surgical resection along with three courses of chemotherapy. Despite these interventions, the patient experienced recurrence of the PAL within four months following treatment. The patient received localized radiotherapy and subsequently achieved a stable disease state. This case indicates that radiotherapy may offer a benefit to PAL patients, particularly those who do not respond to chemotherapy. PMID- 25788999 TI - Cytokine-induced killer cells co-cultured with dendritic cells loaded with the protein lysate produced by radiofrequency ablation induce a specific antitumor response. AB - Radiofrequency ablation (RFA) causes coagulative necrosis of tumor tissue and the production of local tumor protein debris. These fragments of tumor protein debris contain a large number of various antigens, which can stimulate a specific cellular immune response. In the present study, dendritic cells (DCs) were loaded with tumor protein lysate antigens that were produced in situ by RFA, and were used to treat murine colon carcinoma in combination with cytokine-induced killer (CIK) cells. Subsequent to the treatment of murine colon carcinoma by RFA, the in situ supernatant of tumor lysis was collected and the DCs were loaded with the lysate antigen to generate Ag-DCs. CIK cells induced from the spleen cells of mice were co-cultured with Ag-DCs to generate Ag-DC-CIK cells. The results revealed that the Ag-DC-CIK cells exhibited strong antitumor activity in vitro and in vivo. The morphology and immunophenotypes of these cells were determined using microscopy and flow cytometry, respectively. The cytotoxic activity of Ag DC-CIK cells was determined using a CCK-8 assay. To establish a mouse model, mice were randomized into Ag-DC-CIK, DC-CIK, CIK and PBS control groups and monitored for tumor growth and survival time. ANOVA was used to compare the trends in the three groups for implanted tumor volumes. The log-rank test was used to compare the survival time. The present findings indicated that DCs loaded with the protein lysate antigens of tumors, produced in situ by RFA, combined with CIK cells may be a novel strategy for cancer treatment. PMID- 25789000 TI - Complete response to comprehensive treatment of a primary hepatic diffuse large B cell lymphoma: A case report. AB - Primary hepatic lymphoma (PHL) is an uncommon lymphoid tumor with varied clinical features and treatment outcome. In the present study, the case of a 56-year-old patient with PHL and no clinical presentation was reported. During a routine physical examination, multiple hypodense nodules were incidentally detected in right lobes of the liver and hepatic portal in an abdominal computed tomography scan. A liver biopsy revealed the presence of a non-Hodgkin's lymphoma diffuse large B cell type that was CD20-positive, followed by the diagnosis of a PHL. The patient was treated with R-CHOP, radiotherapy and R-Hyper-CVAD/R-HD MTX-ara-C, and complete remission was achieved. PMID- 25789001 TI - miR-218 inhibits the migration and invasion of glioma U87 cells through the Slit2 Robo1 pathway. AB - Malignant gliomas are the most common primary brain tumors in adults and are associated with the highest mortality rate. Glioma invasion is one of the most notable causes of the poor prognosis of this cancer. Preventing the invasive behavior of malignant glioma cells by altering effector molecules can significantly improve the prognosis of a patient. microRNAs (miRNAs) are small noncoding RNAs, ~22 nucleotides in length, that are able to function as oncogenes or tumor suppressors in human cancer. In the present study, the expression level of miRNA 218 (miR-218) was found to be markedly downregulated in glioma cell lines and human primary glioma tissues. miR-218 upregulation was found to dramatically reduce the migratory speed and invasive ability of glioma cells. Furthermore, it was demonstrated that ectopic expression of miR-218 in glioma cells resulted in the downregulation of roundabout, axon guidance receptor, homolog 1 (Robo1), upregulation of Slit homolog 2 (Slit2) and the expression of associated proteins following Robo1 knockdown by small interfering RNA. In addition, it was demonstrated that miR-218 inactivated the Slit2-Robo1 pathway through downregulating Robo1 expression by directly targeting the 3'-untranslated region (3'-UTR) of Robo1. The present results indicate that miR-218 plays important roles in preventing the invasiveness of glioma cells, and reveals a novel mechanism of miRNA-mediated direct suppression of the Slit2-Robo1 pathway in glioma. PMID- 25789002 TI - UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer. AB - Human telomerase reverse transcriptase (hTERT) is a critical factor in unlimited cell proliferation and immortalization, with numerous studies demonstrating that high expression of hTERT is a poor prognostic factor in various types of cancer. Ubiquitin-conjugating enzyme E2D 3 (UBE2D3) is a member of the E2 family, and participates in the ubiquitin proteasome pathway to regulate basic cellular activities, such as cell cycle control, the DNA damage response, apoptosis, and tumorigenesis. Our previous study initially determined that downregulation of UBE2D3 expression increases hTERT expression and cell proliferation, however, the association between the expression of these two proteins and their functions in cancer tissues remains unknown. Therefore, the protein expression levels of hTERT and UBE2D3 were evaluated in 150 esophageal cancer and 30 adjacent healthy tissue samples by performing immunohistochemical analysis. Concurrently, the clinicopathological data of the enrolled patients were obtained to allow correlation analysis. It was identified that the expression of hTERT in the esophageal cancer tissues was significantly higher compared with that of the adjacent tissues (P=0.015), however, the expression of UBE2D3 was significantly lower in esophageal cancer tissues than the adjacent tissues (P=0.001). Additionally, the study demonstrated that hTERT was significantly upregulated in poorly-differentiated, advanced tumor-node-metastasis (TNM) stage cancer tissues (P<0.05 for all), however, UBE2D3 expression was downregulated in poorly differentiated, lymph node invaded cancer tissues and recurrent cases. It was also identified that traditional factors, including tumor location, T stage, lymph node status, TNM stage, and molecular factors of hTERT and UBE2D3, were significantly associated with overall survival time (P<0.05 for all). Furthermore, UBE2D3, lymph node status and tumor location were independent prognostic factors for esophageal cancer in multivariate analysis. Most notably, hTERT and UBE2D3 expression were negatively correlated with each other. In conclusion, the findings of the present study indicated that hTERT and UBE2D3 proteins appear to be involved in the development of esophageal cancer, that UBE2D3 may a positive prognostic factor for esophageal cancer, and that UBE2D3 and hTERT expression levels are inversely correlated. PMID- 25789003 TI - Primary pulmonary lymphoma mimicking a refractory lung abscess: A case report. AB - The current study presents a case of primary pulmonary lymphoma (PPL) mimicking refractory lung abscess that was diagnosed at autopsy. An 80-year-old male with clinically inapparent aspiration presented with a large cavitated mass and pleural effusion. A lung abscess and empyema was diagnosed, therefore, antibiotics were administered and the pleural effusion was drained. Various examinations, including a biopsy, yielded no specific diagnosis. The lesion was considered inoperable due to the poor general condition of the patient. Subsequently, the mass that had been diagnosed as a refractory lung abscess became enlarged and a repeat biopsy resulted in a diagnosis of diffuse large B cell lymphoma. The patient succumbed to sudden respiratory failure, and the final diagnosis of PPL was confirmed at autopsy. PPL is a rare disease that accounts for 0.45% of all pulmonary malignant tumors and is difficult to diagnose in inoperable cases. Therefore, patients with PPL who do not undergo surgery can be misdiagnosed and consequently treated inappropriately. PPL should therefore be considered in the differential diagnosis of a refractory lung abscess. PMID- 25789004 TI - Imaging features of glucagonoma syndrome: A case report and review of the literature. AB - Glucagonoma syndrome appears as an extremely rare neuroendocrine tumour, with few studies ever having detailed its imaging manifestations. In particular, the magnetic resonance imaging (MRI) features of the lesion have not yet been reported. The present study describes a 54-year-old male who presented with uncontrollable skin erythema and weight loss that had been apparent for two years, and diabetes mellitus that had been apparent for five years. The glucagon level was 180 pg/ml. The plain abdominal computed tomography (CT) scan revealed a solid tumour in the neck of the pancreas, which was slightly reinforced during the arterial phase of the enhanced CT scan. Upon MRI, the lesion exhibited a low signal on T1-weighted imaging, and a slightly high signal on T2-weighted and half Fourier acquisition single-shot turbo spin echo sequence imaging, which measured ~4.5*3.0*3.0 cm in size. Upon diffusion-weighted imaging, the lesion demonstrated heterogeneous hyperintensity, which was mildly enhanced during the arterial phase and washed out during the portal venous phase of gadopentetate dimeglumine enhanced MRI. 18F-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT identified a mild uptake of 18F-FDG by the lesion. The patient was diagnosed with glucagonoma syndrome, and a distal pancreatectomy and splenectomy were subsequently performed. Microscopy revealed that the tumour cells exhibited nest- and belt-like arrangements. The immunohistochemical staining identified positive reactions for glucagon, synaptophysin and chromogranin A, which are consistent with a diagnosis of glucagonoma. Following surgery, the symptoms disappeared and the glucagon level returned to normal. In conclusion, imaging examinations are useful for determining the location and size of a glucagonoma. In particular, MRI is able to identify the distinctive morphological features of the lesion. Immunohistochemical staining provides diagnostic evidence based upon the neuroendocrine features. PMID- 25789005 TI - Importance of luminal membrane mesothelin expression in intraductal papillary mucinous neoplasms. AB - The present study demonstrated that luminal membrane mesothelin expression is a reliable prognostic factor in gastric cancer. Intraductal papillary mucinous neoplasms (IPMNs) often exhibit a spectrum of dysplasia, ranging between adenoma and carcinoma. Therefore, an immunohistochemical analysis of mesothelin expression in IPMN was performed in the present study, focusing on the localization of mesothelin. IPMNs were classified into two groups, IPMNs associated with invasive carcinoma and low-high (L-H) grade dysplasias. The tumors were classified as mesothelin-positive or -negative and in the mesothelin positive cases, the localization of mesothelin was evaluated as luminal membrane- or cytoplasmic-positive. Among the 37 IPMNs, mesothelin expression was observed in 21 samples (56.8%), including 46.2% (12 out of 26) of the L-H dysplasia and 81.8% (9 out of 11) of the invasive carcinoma samples (P=0.071). Luminal membrane localization was observed in 10 samples (27%), including 15.4% (4/26) of the L-H dysplasia samples and 54.5% (6 out of 11) of the invasive carcinoma samples (P=0.022). Six patients experienced post-operative recurrence, with five of the recurrent tumors exhibiting mesothelin expression and all six exhibiting luminal membrane localization. It was concluded that immunohistochemical examinations for mesothelin expression and localization are clinically useful for prognostic assessments and decision making regarding further treatment subsequent to surgical procedures in patients with IPMN. PMID- 25789006 TI - Huaier aqueous extract induces apoptosis of human fibrosarcoma HT1080 cells through the mitochondrial pathway. AB - In recent years, aqueous extract of Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine, has been frequently used in China for complementary cancer therapy. However, the mechanisms underlying its anticancer effects have yet to be elucidated. The present study aimed to evaluate the ability of Huaier extract to inhibit proliferation, promote apoptosis and suppress mobility in the fibrosarcoma HT1080 cell line in vitro. The cells were treated with gradient doses of Huaier extract at concentrations of 0, 4, 8 or 16 mg/ml for 24, 48 or 72 h. The cell viability and motility were measured in vitro using MTT, invasive, migration and scratch assays. The distribution of the cell cycle and the extent of cellular apoptosis were analyzed by flow cytometry. The apoptotic pathways were detected using a mitochondrial membrane potential transition assay and western blotting. The results revealed that the cellular viability decreased significantly with increasing concentrations of Huaier extract. In addition, cell invasiveness and migration were also suppressed significantly. It was demonstrated that Huaier extract induced G2 cell-cycle arrest and cellular apoptosis in a time- and dose-dependent manner. The decreased mitochondrial membrane potential, the downregulation of B-cell lymphoma 2 and pro-caspase-3, and upregulation of Bcl-2-associated X protein, cleaved caspase-9 and caspase-3 suggested that Huaier extract induced the apoptosis of HT1080 cells through the mitochondrial pathway. The results of the present study indicate that Huaier extract is a potential complementary agent for the treatment of fibrosarcoma. PMID- 25789007 TI - Surgical resection of cerebellar hemangioblastoma with enhanced wall thickness: A report of two cases. AB - Hemangioblastomas are tumors of the central nervous system, and the cerebellum is the most common site of occurrence. Cerebellar hemangioblastoma with enhanced wall thickness is rare and often misdiagnosed preoperatively. At present, no unified radiological classification system based on magnetic resonance imaging (MRI) findings exists for cerebellar hemangioblastoma, and this tumor type can be solid or cystic mass, according to the MRI findings. The most common presentation of cerebellar hemangioblastoma observed radiologically is a large sac with small nodules, where the wall of the large cyst is not enhanced. A tumor with enhanced large cysts and tumor nodules is extremely rare. The most effective treatment is complete resection of the cyst and the solid growth. The present case reports the successful treatment of two cases of cerebellar hemangioblastoma with enhanced wall thickness, including the MRI findings for the differential diagnoses and the surgical experiences. PMID- 25789008 TI - Abnormal expression of the Notch and Wnt/beta-catenin signaling pathways in stem like ALDHhiCD44+ cells correlates highly with Ki-67 expression in breast cancer. AB - Previous studies have reported that breast cancer stem cells may be closely associated with tumor metastasis, recurrence, and even the failure of chemotherapy and radiotherapy. The aim of the present study was to investigate whether important cell signaling pathways associated with drug resistance are activated in stem-like acetaldehyde dehydrogenase (ALDH)hi cluster of differentiation (CD)44+ cells, and to analyze the association between ALDHhiCD44+ cells and specific pathological features. ALDHhiCD44+ cells and non-stem-like ALDHlowCD44+ cells were separated from MDA-MB-231 cells by fluorescence-activated cell sorting, and the mRNA expression levels of Notch1 and beta-catenin were estimated by performing quantitative polymerase chain reaction in the stem-like and non-stem-like cells. Line correlation analysis was used to evaluate the correlation between an immunohistochemical panel of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67, and ALDHhiCD44+ cells from patients with invasive breast carcinoma. The mRNA levels of Notch1 and beta-catenin were significantly higher in the ALDHhiCD44+ cells compared with those in the ALDHlowCD44+ cells (P<0.05); furthermore, the present study determined a high correlation (P<0.05) between the ALDHhiCD44+ cells and Ki-67 expression (P=0.007), but no correlation (P>=0.05) with ER (P=0.065), PR (P=0.107) and HER2 (P=0.050). Overall, these data clearly indicate that ALDHhiCD44+ cells may serve as novel diagnostic and prognostic factors in breast cancer. PMID- 25789009 TI - Stereotactic aspiration combined with gamma knife radiosurgery for the treatment of cystic brainstem metastasis originating from lung adenosquamous carcinoma: A case report. AB - Brainstem metastases have a poor prognosis and are difficult to manage. The present study describes the first case of histopathologically-confirmed brainstem metastasis originating from lung adenosquamous carcinoma, and discusses the outcomes of treatment by stereotactic aspiration combined with gamma knife radiosurgery (GKRS). A 59-year-old female presented with a cystic mass (15*12*13 mm; volume, 1.3 cm3) located in the pons, two years following surgical treatment for adenosquamous carcinoma of the lung. The patient received initial GKRS for the lesion in the pons with a total dose of 54.0 Gy, however, the volume of the mass subsequently increased to 3.9 cm3 over a period of three months. Computed tomography-guided stereotactic biopsy and aspiration of the intratumoral cyst were performed, yielding 2.0 cm3 of yellow-white fluid. Histology confirmed the diagnosis of adenosquamous carcinoma. Aspiration provided immediate symptomatic relief, and was followed one week later by repeat GKRS with a dose of 12.0 Gy. The patient survived for 12 months following the repeat GKRS; however, later succumbed to the disease after lapsing into a two-week coma. The findings of this case suggest that stereotactic aspiration of cysts may improve the effects of GKRS for the treatment of cystic brainstem metastasis; the decrease in tumor volume allowed a higher radiation dose to be administered with a lower risk of radiation-induced side effects. Therefore, stereotactic aspiration combined with GKRS may be an effective treatment for brainstem metastasis originating from adenosquamous carcinoma. PMID- 25789010 TI - Ectopic expression of the WWOX gene suppresses stemness of human ovarian cancer stem cells. AB - The present study aimed to investigate the effects of the WW domain-containing oxidoreductase (WWOX) gene on the stem cell properties of human ovarian cancer stem cells. A eukaryotic expression vector containing the WWOX gene was transfected into human ovarian cancer stem cells and Western blotting was used to assess the expression of WWOX protein in the transfected cells compared with the control cells (untransfected cells and cells transfected with the empty vector). The self-renewal abilities of these three types of stem cells was also assessed in vitro. To monitor changes in their differentiation potential, cells were cultured in medium supplemented with serum, and the expression of specific stem cell markers was determined. Drug-sensitivity tests were used to measure the sensitivity of the stem cells to cisplatin, doxorubicin, and mitoxantrone. The cells were also transplanted into non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice to determine the changes in their tumorigenicity in vivo. Cells transfected with the WWOX-expressing plasmid stably expressed WWOX protein, while no WWOX protein was detected in control cells. Compared with the two types of control cells, WWOX-expressing stem cells manifested significantly reduced self-renewal ability. Compared with control cells, the expression levels of stem cell markers, including CD133, CD117, ATP-binding cassette sub-family G member 2, Nanog, octamer-binding transcription factor 4 and breast cancer resistance protein, were significantly lower in WWOX-expressing cells, while the level of the differentiation marker E-cadherin was significantly higher in WWOX expressing cells. Furthermore, WWOX-expressing cells were more sensitive to treatment with cisplatin, doxorubicin and mitoxantrone. In NOD/SCID mice, the tumorigenicity of WWOX-expressing cells was significantly lower compared with that of control cells. The results indicate that the tumor suppressor WWOX suppresses stem cell properties in cancer stem cells, including self-renewal ability, differentiation potential, in vivo tumorigenic capability, high-level expression of stem cell genes and multidrug resistance. PMID- 25789011 TI - Effects of targeted phosphorylation site mutations in the DNA-PKcs phosphorylation domain on low and high LET radiation sensitivity. AB - The present study investigated the effect of targeted mutations in the DNA dependent protein kinase catalytic subunit and phosphorylation domains on the survival of cells in response to different qualities of ionizing radiation. Mutated Chinese hamster ovary V3 cells were exposed to 500 MeV/nucleon initial energy and 200 keV/MUm monoenergetic Fe ions; 290 MeV/nucleon initial energy and average 50 keV/MUm spread-out Bragg peak C ions; 70 MeV/nucleon initial energy and 1 keV/MUm monoenergetic protons; and 0.663 MeV initial energy and 0.3 keV/MUm Cs137 gamma radiation. The results demonstrated that sensitivity to high linear energy transfer radiation is increased when both S2056 and T2609 clusters each contain a point mutation or multiple mutations are present in either cluster, whereas the phosphoinositide 3 kinase cluster only requires a single mutation to induce the sensitized phenotype of V3 cells. Additionally, the present study demonstrated that sensitivity to DNA cross-linking damage by cisplatin only requires a single mutation in one of the three clusters and that additional point mutations do not increase cell sensitivity. PMID- 25789012 TI - Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma and Child-Pugh A or B cirrhosis. AB - Sorafenib confers a survival benefit for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) A liver cirrhosis. At present, limited data exists with regard to the safety and efficacy of sorafenib in treating CP-B HCC patients. The present study describes the use of sorafenib in patients with HCC and CP-A or -B cirrhosis. Clinical data was obtained from patients with HCC who were treated with sorafenib at the Department of Clinical and Experimental Medicine, Second University of Naples (Naples, Italy) and were analyzed retrospectively in terms of tumor response, tolerance and survival. The treatment outcomes were analyzed according to the respective CP status. The adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 3.0, and the tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.2. In total, 26 patients received sorafenib at 400 mg twice daily. The median age was 69 years (range, 58-81 years) and the ratio of males to females was 18:8. Overall, 15 patients were infected with the hepatitis C virus (HCV), eight with HBV and three were co-infected with HCV/HBV. In total, 20 (77%) patients presented with an underlying CP-A (CP-A5 and CP-A6) cirrhosis and six (23%) with CP-B (CP-B7). Previous treatments included surgery (n=4), transarterial chemoembolization (n=5) and percutaneous ethanol injection or radiofrequency interstitial thermal ablation (n=12). A partial response was observed in three patients (12%), a stable disease lasting at least 12 weeks in 13 patients (50%) and a progression of disease in 10 patients (38%). The median overall survival (OS) time was 7.4 months [95% confidence interval (CI), 3.2-11.6) and the median progression-free survival (PFS) time was 3.7 months (95% CI, 1.9-5.5). The median OS and PFS times differed between patients with CP-A and CP-B, with a trend (P=0.06) toward a worse outcome in those with CP B, although this was not statistically significant. The CP-A and CP-B groups experienced a similar incidence in the majority of AEs. A reduction in dose was required in 59% of the patients. The CP-A5, CP-A6 and CP-B7 patients tolerated sorafenib similarly, and derived comparable clinical and survival benefits. PMID- 25789013 TI - Interstitial pneumonia induced by sorafenib in a patient with hepatocellular carcinoma: An autopsy case report. AB - Sorafenib is a multikinase inhibitor currently approved in Japan for the treatment of unresectable hepatocellular carcinoma. Interstitial pneumonia induced by sorafenib may have a fatal outcome, and therefore, has recently been the focus of many studies. The current report presents an autopsy case of diffuse alveolar damage (DAD) that occurred in a 59-year-old male, who had been treated with sorafenib. The patient had been given sorafenib for six months and had exhibited no respiratory symptoms during this time. However, 19 days after sorafenib treatment was resumed, acute interstitial pneumonia developed. In previously reported cases, the first symptoms of pulmonary toxicity appeared following a limited treatment duration with sorafenib; this was in contrast to the patient in the current study, who developed the first symptoms after eight months. We therefore conclude that physicians must be aware of interstitial pneumonia as a potential pulmonary toxicity associated with sorafenib treatment when treatment with sorafenib is resumed, even after prolonged use. In addition, to best of our knowledge, this is the first case of a postmortem examination reported in patient with interstitial pneumonia induced by sorafenib treatment. PMID- 25789014 TI - Periosteal chondroma of the femur: A case report and review of the literature. AB - Periosteal chondroma is a rare benign cartilage tumor located on the cortical bone, which may be mistaken clinically and histologically for other and more common tumors in this location. The current study reports the case of periosteal chondroma located in the distal femur of a 14-year-old female. A non-tender swelling, 5*4 cm in diameter, was identified on computed tomography, a radiological study of which revealed an overhanging edge and a radiolucent shadow with stippled calcification in radiographs and a lobular heterogeneous mass in magnetic resonance imaging. Cytological examination of the excision biopsy revealed cellular pleomorphism and binucleate cells. The patient underwent en bloc resection of the tumor and covering periosteum, and the histological diagnosis was subsequently determined to be periosteal chondroma. The present study also reviews nine previously reported cases of periosteal chondroma in the femur, with a discussion of the demographic characteristics, imaging features, differential diagnosis and treatment of bone tumors in this location. This study aims to inform clincians that periosteal chondromas may occur in the distal femur although osteochondromas are more common and to discuss making a differential diagnosis between periosteal chondroma and other bone tumors. PMID- 25789015 TI - Metastatic colon cancer cell populations contain more cancer stem-like cells with a higher susceptibility to natural killer cell-mediated lysis compared with primary colon cancer cells. AB - In the present study, the soft agar clonogenicity and the susceptibility of clonogenic cancer cells to natural killer (NK) cells were compared between primary colon cancer cells (KM12C) and metastatic colon cancer cells (KM12L4a and KM12SM) to determine whether the metastatic cancer cells consisted of more cancer stem-like cells and were resistant to NK cell-mediated lysis. The majority of colon cancer cells were positive for putative cancer stem cell markers, including CD44, CD133 and EpCAM, with the exception of KM12C cells, of which only ~55% were positive for CD133. In addition, the expression levels of sex determining region Y-box 2, Nanog and octamer-binding transcription factor 4, which are essential for maintaining self-renewal, were higher in KM12L4a and KM12SM compared with that in KM12C cells. Consistently, an increased clonogenicity of KM12L4a and KM12SM compared with KM12C cells in soft agar was observed. The expression levels of NKG2D ligands, including major histocompatibility complex class I polypeptide related sequence A/B and UL16 binding protein 2, and of death receptor 5 were significantly higher in KM12L4a and KM12SM than in KM12C cells. Furthermore, the results indicated an increased susceptibility of KM12L4a and KM12SM to NK cell mediated cytotoxicity in comparison with KM12C cells. These results indicated that metastatic colon cancer cell populations may consist of more cancer stem like cells, and have greater susceptibility to NK cell-mediated lysis compared with that of primary colon cancers. PMID- 25789016 TI - Isolated primary intracranial myeloid sarcoma with neuromeningeal infiltration: A case report. AB - Myeloid sarcoma is a rare extramedullary malignant tumor, which is often accompanied by the development of systemic myeloid disease at various sites. The involvement of the central nervous system is uncommon and spinal cord compression is particularly rare. In November 2012, a 27-year-old male presented with a paroxysmal headache, accompanied by nausea and vomiting, which had persisted for one year, and eyesight deterioration that had been apparent for five months. Magnetic resonance imaging (MRI) indicated a space-occupying disorder, a craniotomy to resect the brain tumor was undertaken, the pathological diagnosis of which was myeloid sarcoma. Two months after receiving 40 Gy of radiotherapy, the patient experienced numbness of the right thigh. MRI of the lumbar spinal canal revealed a mass involved both inside and outside the lumbar spinal canal. Pathological examination of the mass following resection also indicated myeloid sarcoma. Immunohistochemical analysis was positive for the ETO fusion gene in the bone marrow. Following six cycles of chemotherapy treatment, the patient achieved complete remission. At present, the patient is stable and is attending follow-up examinations regularly. PMID- 25789017 TI - Epidemiology of brain tumors in children aged two and under: A 10-year single institute study. AB - The aim of present study was to evaluate the incidence, clinical symptoms, pathological characteristics, surgical treatment strategies and prognosis of brain tumors in children aged two and under. The current study obtained data regarding 32 consecutive infants and young children aged two years and under, who were treated for brain tumors in the Children's Hospital of Fudan University (Shanghai, China) between 2003 and 2013. The types of tumor, clinical manifestations, location, histological features, applied treatment strategies and outcomes were retrospectively evaluated. The male to female ratio was 1.13:1, and among a total of 32 tumors, 14 (43.8%) were suptratentorial and 18 (56.3%) were infratentorial. Intracranial hypertension was the most common onset symptom, and astrocytoma was the most common tumor type (10 cases; 31.3%), followed by ependymoma (nine cases; 28.1%) and medulloblastoma (six cases; 18.8%). Surgical tumor resection was performed in 20 patients (62.5%), who experienced a mean post operative survival time of 67.6 months. By contrast, conservative treatment with medications was administered in 12 patients (37.5%), with a mean survival time of 25.3 months. Furthermore, four patients underwent conservative therapy combined with ventriculoperitoneal shunting to relieve intracranial pressure arising from cerebrospinal fluid accumulation, resulting in a mean survival time of 10.5 months. In conclusion, the present study indicates that surgical tumor resection may improve the overall prognosis of infants and young children aged two years and under who presented with brain tumors. In addition, ventriculoperitoneal shunts may facilitate pre- and post-operative improvement in clinical symptoms by relieving intracranial pressure; however, the shunts do not appear to increase long-term survival. Furthermore, high surgical risk is an important prognostic factor in this pediatric patient population. PMID- 25789018 TI - Analysis of ERCC1 and ERCC2 gene variants in osteosarcoma, colorectal and breast cancer. AB - The Asn118Asn (rs11615) variant in the ERCC1 gene, and the Lys751Gln (rs13181) and Asp312Asn (rs1799793) variants in the ERCC2 gene have been associated with the development of varied types of cancer. The aim of the present study was to test for any association between the ERCC1 and ERCC2 gene variants and three different types of cancer in Mexican-mestizo patients. Patients and their respective controls were formed into three groups: The osteosarcoma group, with 28 patients and 97 controls; the colorectal group, with 108 patients and 119 controls; and the breast cancer group, with 71 patients and 74 controls. Genotyping was performed using TaqMan probes and quantitative polymerase chain reaction. Allele and genotype frequencies were compared using a chi2 test. Only one SNP (rs1799793) was found to be associated with breast cancer. This is the first study analyzing the SNPs in ERCC1 and ERCC2 genes and the susceptibility to cancer in Mexican-mestizo patients with osteosarcoma, and colorectal and breast cancer. PMID- 25789019 TI - Differences between the clinical and histopathological tumor stages in breast cancer diagnosed using vacuum-assisted breast biopsy. AB - The present study aimed to determine the difference between the clinical tumor stage (T stage) based on pre-operative ultrasound and the histopathological T stage subsequent to surgery in vacuum-assisted breast biopsy (VABB)-diagnosed breast cancer. Tumor sizes measured ultrasonography (USG) and histologically were retrospectively calculated and analyzed using paired t-tests in 209 patients diagnosed with breast cancer using VABB. The patients were classified into two groups, consisting of breast imaging reporting and data system (BI-RADS) category 4a or below, who underwent complete resection by VABB, and BI-RADS category 4b or above, who underwent incisional biopsy by VABB. The histopathological tumor size was found to be smaller compared with the USG-determined size in 92.3% of pT1a, 75.5% of pT1b, 44.2% of pT1c, 47.7% of pT2 and 0% of pT3 cases. Furthermore, the histopathological tumor size was smaller compared with the USG-determined size in 62.8% of cases classified as BI-RADS category 3-4a and in 53.7% of cases classified as BI-RADS category 4b-5. The smaller the primary tumor at the time of diagnosis by VABB, the higher the likelihood of pathological underestimation on post-operative histopathological assessment compared to pre-operative USG. PMID- 25789021 TI - Reduced expression of erythropoietin-producing hepatocyte B6 receptor tyrosine kinase in prostate cancer. AB - Loss of erythropoietin-producing hepatocyte (Eph) B6 gene expression is associated with poor prognosis in neuroblastoma, melanoma and other tumors. The present study evaluated the expression of EphB6 receptor tyrosine kinase in normal and prostate cancer tissue using immunohistochemistry. The association between EphB6 expression, clinicopathological findings, proliferating-cell nuclear antigen (PCNA; another prognostic marker) and progression of prostate cancer was analyzed. Tissue microarray samples of normal prostatic tissue and prostate cancer tissue from 46 patients treated with radical prostatectomy for prostate cancer were included in this study. Polyclonal anti-EphB6 and monoclonal anti-PCNA antibodies were used to assess EphB6 and PCNA expression by immunohistochemistry. EphB6 was expressed in normal and prostate cancer tissue; however, its expression was significantly reduced in prostate cancer tissue compared with normal prostatic tissue (P<0.0001), in high volume (>=4 cm3) cancer compared with low volume (<4 cm3; P=0.015), and in pT3 stage compared with pT2 stage of the disease (P=0.0007). No correlation was observed between the expression of EphB6 and PCNA. Short biochemical progression-free survival was associated with low EphB6 protein expression (P=0.157). This study revealed that EphB6 may have a tumor suppressor effect in prostate cancer, at least during early stages of this disease. This provides new insight into the potential utility of EphB6 receptor as a diagnostic/prognostic marker for prostate cancer. PMID- 25789020 TI - Mosquito coil exposure associated with small cell lung cancer: A report of three cases. AB - Mosquito coils, which are commonly used as residential insecticides in Asia, contain different concentrations of octachlorodipropyl ether (S-2) as a synergist or an active ingredient. As bis(chloromethyl) ether (BCME) is an extremely potent lung carcinogen that can be produced by the thermolytic degradation of S-2, contact with mosquito coils is likely to expose individuals to a certain level of BCME, and therefore increase the risk of lung cancer. However, the significance of exposure is uncertain, as clinical and epidemiological studies concerning mosquito coil users and workers are lacking. The present study describes three cases of small cell lung cancer treated at the Shanghai Pulmonary Hospital that were likely to be the result of exposure to mosquito coils. All patients had worked in the mosquito coil manufacturing industry, with an mean occupational duration of 9.1 years, and presented with similar respiratory symptoms, such as cough and dyspnea. Upon diagnosis, no metastasis to other organs was identified in any of the cases. Subsequently, the three patients were treated with chemotherapy as well as radiotherapy in one case, however, all patients succumbed to the disease, with a mean overall survival time of 10.7 months. We conclude that contact with mosquito coils is likely to expose individuals to a level of S 2 that may increase the risk of SCLC. PMID- 25789022 TI - Intrapulmonary myelolipoma and its computed tomography features: A case report and literature review. AB - Intrapulmonary myelolipoma is a rare, benign tumor composed of mature adipose tissue and normal hematopoietic cells. To the best of our knowledge, 10 cases of intrapulmonary myelolipoma, including the present case, have been reported to date, and the majority have focused on the pathological diagnosis of the disease. The radiological features of intrapulmonary myelolipoma have not been studied. Therefore, the present study reports a case of primary myelolipoma in the lung, and examines its computed tomography features and pathology. Furthermore, other potential diagnoses are discussed in the context of the relevant literature. The present report describes the case of a 57-year-old female who experienced chills, but no coughing or expectoration, with an intermittent fever of 38.6 degrees C that had been apparent for 13 days. Chest CT scan revealed a benign nodule and bronchiectasis in the lower lobe of the right lung. The patient then underwent a lobectomy of the lower right lung by thoracoscopy. The histological analysis of the excised specimen identifid a myelolipoma consisting of mature adipose tissue and hematopoietic cells. There was no recurrence after 513 days of follow-up, as shown by CT. PMID- 25789023 TI - Clinical significance of KAI1/CD82 protein expression in nasopharyngeal carcinoma. AB - The aim of this study was to investigate KAI1/CD82 protein expression in human nasopharyngeal carcinoma (NPC) cell lines and human NPC tissues. Immunohistochemistry and western blot analysis were used to detect the localization and expression levels of the KAI1/CD82 protein in five human NPC cell lines. Immunohistochemistry was also conducted to detect the expression of the KAI1/CD82 protein in 70 NPC tissues and 30 non-neoplastic nasopharyngeal tissues. The levels of KAI1/CD82 protein expression were found to decrease as the metastatic potential of cells increased. The expression rate of KAI1/CD82 protein in the NPC tissues (44.3%) was significantly lower than that in the non neoplastic nasopharyngeal tissues (70.0%) (P<0.05). KAI1/CD82 protein expression in the NPC tissues was not associated with clinical parameters, including gender, age, histological type and T stage, and the positive expression of KAI1/CD82 decreased with increased N staging. The level of KAI1/CD82 protein expression was increased in different human NPC cell lines. The KAI1/CD82 gene was highly expressed in cells with low metastatic potential, while low expression was observed in cells with a high metastatic potential. In addition, the KAI1/CD82 gene was expressed at low levels in nasopharyngeal carcinoma tissues, while high expression was identified in non-neoplastic nasopharyngeal tissues, and was associated with lymph node metastasis. These results indicated that the KAI1/CD82 gene may be involved in the occurrence, development and metastasis of nasopharyngeal carcinoma. PMID- 25789024 TI - Diagnosis and treatment of penile verrucous carcinoma. AB - Penile verrucous carcinoma is an extremely rare disease that, at present, has not been well characterized. The etiology, diagnosis and treatment of this carcinoma remain poorly understood, particularly in the Chinese population. The aim of the present study was to discuss the methods of diagnosis and treatment of penile verrucous carcinoma in the Chinese population. The clinical and pathological data of 10 patients with penile verrucous carcinoma were analyzed alongside a literature review. All the tumors were exophytic papillary lesions, ranging between 0.4 and 4 cm in diameter and all 10 patients underwent partial penectomy with tumor-negative surgical margins. None of the 10 patients underwent ilioinguinal lymphadenectomy. All patients were regularly followed up for 0.7-9 years, which revealed that no patients developed recurrence, and only one case resulted in mortality due to unassociated causes. It was found that penile verrucous carcinoma is a well-differentiated disease with low malignant potential and locally aggressive features, which seldom metastasizes to regional lymph nodes or distant regions. However, misdiagnosis may occur due to an incorrect biopsy. Favorable outcomes can be achieved by surgery, even without any adjuvant therapy, but patients should be carefully followed up. PMID- 25789025 TI - Identification of differentially-expressed genes by DNA methylation in cervical cancer. AB - To identify novel cervical cancer-related genes that are regulated by DNA methylation, integrated analyses of genome-wide DNA methylation and RNA expression profiles were performed using the normal and tumor regions of tissues from four patients; two with cervical cancer and two with pre-invasive cancer. The present study identified 19 novel cervical cancer-related genes showing differential RNA expression by DNA methylation. A number of the identified genes were novel cervical cancer-related genes and their differential expression was confirmed in a publicly available database. Among the candidate genes, the epigenetic regulation and expression of three genes, CAMK2N1, ALDH1A3 and PPP1R3C, was validated in HeLa cells treated with a demethylating reagent using methylation-specific polymerase chain reaction (PCR) and quantitative PCR, respectively. From these results, the expression of the CAMK2N1, ALDH1A3 and PPP1R3C genes are were shown to be suppressed in cervical cancers by DNA methylation. These genes may be involved in the progression or initiation of cervical cancer. PMID- 25789026 TI - Expression of hypoxic markers and their prognostic significance in soft tissue sarcoma. AB - Tumor hypoxia is significant in promoting tumor progression and resistance to therapy, and hypoxia-inducible factor 1alpha (HIF-1alpha) is essential in the adaptive response of cells to hypoxia. The aim of the present study was to investigate the expression of hypoxic markers and evaluate their prognostic significance in soft tissue sarcoma (STS). A retrospective analysis of 55 patients with STS from Pusan National University Hospital (Busan, Korea) between 1998 and 2007 was conducted, using immunohistochemistry to analyze the expression of HIF-1alpha, carbonic anhydrase 9 (CA9), glucose transporter-1 (GLUT1) and vascular endothelial growth factor (VEGF). The association between the overexpression of these markers and clinicopathological characteristics, including the overall survival (OS) and progression-free survival (PFS) in cases of STS, were investigated. Overexpression of HIF-1alpha, CA9, GLUT1 and VEGF was shown in 54.5, 32.7, 52.7 and 25.5% of tumors, respectively, and all exhibited a significant association with high French Federation of Cancer Centers (FNCLCC) grade and high American Joint Committee on Cancer (AJCC) stage. Overexpression of HIF-1alpha and CA9 was associated with a shorter OS and a shorter PFS. On multivariate analysis, AJCC stage and HIF-1alpha overexpression had independent prognostic significance. In the group receiving chemotherapy (n=27), HIF-1alpha overexpression was independently associated with a decreased OS. These results indicate that overexpression of HIF-1alpha and CA9 is associated with poor prognosis, and that HIF-1alpha overexpression is an independent unfavorable prognostic factor in STS. PMID- 25789027 TI - Clinical significance of pAkt and pErk1/2 expression in early-stage breast cancer patients treated with anthracycline-based adjuvant chemotherapy. AB - The expression of phosphorylated Akt (pAkt) and phosphorylated extracellular regulated kinase 1/2 (pErk1/2) proteins may result in breast cancer progression and drug resistance in vitro, however, compelling evidence regarding the clinical significance of pAkt and pErk1/2 in early-stage breast cancer is currently lacking. Thus, the aim of the present study was to determine the prognostic value of pAkt and pErk1/2 expression in early-stage breast cancer patients treated with anthracycline-based adjuvant chemotherapy. Tumor specimens were obtained from 256 patients with early-stage breast cancer who had been treated with anthracycline based adjuvant chemotherapy, and pAkt and pErk1/2 protein expression was immunohistochemically determined. The interactions between pAkt, pErk1/2 and clinical characteristics were assessed by performing chi2 tests, and survival functions were estimated using the Kaplan-Meier method. It was identified that pAkt and pErk1/2 were expressed in 38.7 and 33.6% of patients, respectively, and that pAkt protein expression was correlated with pErk1/2 protein expression (P<0.001). In addition, after a median follow-up period of 52.5 months, the patients with pAkt- and pErk1/2-negative tumors experienced a significantly longer disease-free survival (DFS) time compared with pAkt- or pErk1/2-positive patients (P=0.028). pErk1/2 expression was associated with the decreased DFS time of the patients (P=0.049), and pAkt and pErk1/2 expression were associated with the decreased DFS time in human epidermal growth factor receptor (HER2)-positive patients (P=0.002). pErk1/2 expression was associated with chemotherapy resistance (P=0.016). Thus, the coexpression of pAkt and pErk1/2 was an independent factor for a poor prognosis in early-stage and HER2-positive breast cancer patients. By contrast, pErk1/2 expression alone may be a poor predictor for determining the efficacy of anthracycline-based chemotherapy. PMID- 25789028 TI - Response to nab-paclitaxel and nedaplatin in a heavily-metastatic thymic carcinoma: A case report. AB - Metastatic thymic carcinoma is an aggressive cancer that usually responds poorly to multimodal therapies. Although surgical resection is the preferred treatment for patients with advanced or metastatic disease, the clinical prognosis is typically poor. The present study describes a 63-year-old patient with thymic carcinoma who underwent a range of antitumor treatments, including surgical resection, post-operative radiotherapy and post-operative chemotherapy with several drugs, but ultimately responded to treatment with nab-paclitaxel (nab-P) and nedaplatin. Subsequent to six cycles of nab-P and nedaplatin, the lung and peritoneal metastases decreased in size and the pleural effusion was reduced. To the best of our knowledge, this is the first study to describe the response of an advanced thymic carcinoma to nab-P chemotherapy. PMID- 25789029 TI - A preliminary study of the effect of curcumin on the expression of p53 protein in a human multiple myeloma cell line. AB - Curcumin is an inexpensive, natural plant ingredient with protease inhibitor effects. The present study aimed to analyze the inhibitory effects of curcumin on the multiple myeloma (MM) RPMI 8226 cell line, and examine the underlying mechanism that promotes the apoptosis of RPMI 8226 cells. A growth curve was constructed in order to observe the relative growth velocity, and MTT was used to analyze the effect of different concentrations of curcumin on inhibiting the proliferation of the RPMI 8226 cells. The mRNA expression of the p53, Bax and MDM2 genes was detected using quantitative polymerase chain reaction. The expression of p53 protein in the MM RPMI 8226 cells following treatment with curcumin was detected by western blotting and ELISA. Curcumin inhibited the proliferation of the MM RPMI 8226 cells in a dose- and time-dependent manner. In the MM RPMI 8226 cells treated with curcumin, the expression of the p53 and Bax genes was upregulated, while the expression of the MDM2 gene was downregulated. p53 protein expression was higher in the curcumin experimental group compared with the control group. Subsequent to treatment with curcumin, the growth of the MM RPMI 8226 cell line was inhibited in a concentration- and time-dependent manner. In the MM RPMI 8226 cells treated with curcumin, p53 protein levels were upregulated, which suggested that curcumin may promote the apoptosis of MM cells by upregulating p53 protein expression. PMID- 25789030 TI - Long-term survival of a patient with scalp angiosarcoma and multiple metastases treated using combination therapy: A case report. AB - Angiosarcoma is a rare and deadly malignancy originating from the vascular endothelial cells. Surgery is the most effective method to cure this disease, but for metastatic angiosarcoma, a chemotherapy-based treatment is the main therapeutic choice. However, there is currently no standard chemotherapy regimen. The current study reports the case of a 66-year-old male with post-operative scalp angiosarcoma recurrence and multiple metastases. The patient obtained a complete response to first-line combination chemotherapy consisting of cyclophosphamide, epirubicin, vincristine and dacarbazine, with a progression free survival time of eight months. After benefitting from subsequent comprehensive treatment including, cyclophosphamide, epirubicin, vincristine, dacarbazine, docetaxel, cisplatin, gemcitabine and radiotherapy and anti angiogenic therapy, the patient obtained an overall survival time of 38 months following initial diagnosis. PMID- 25789031 TI - Lipid-rich carcinoma of the breast: A report of two cases and a literature review. AB - Lipid-rich carcinoma of the breast is extremely rare with no standard guidelines for treatment with poor patient prognosis. In the present study, the clinical features, imaging results, pathology, immunohistochemistry, treatment and prognoses of two patients with lipid-rich carcinoma of the breast were analyzed. Two patients were admitted to the Yantai Yuhuangding Hospital Affiliated to the Medical College of Qingdao University (Yantai, Shandong, China) for examination of a palpable mass in the breast. Enlarged lymph nodes were found in the axilla of each patient. The results of mammography and echography imaging suggested the presence of malignancy. A modified radical mastectomy was performed in each patient, and pathological examination revealed atypical large vacuolated cells arranged in clusters and confirmed lipid-rich carcinoma and lymph node metastases. The tumor tissue of patient one was immunohistochemically positive for estrogen receptor (ER), p53, p120 and E-cadherin, and negative for progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2), with a Ki-67 labeling index of 50%. The tumor tissue of patient two was immunohistochemically positive for p53, and negative for ER, PR, HER-2 and cytokeratin 5/6, with a Ki-67 labeling index of 30%. Post-surgery, patient one was administered chemotherapy for six cycles, radiotherapy and endocrine therapy in the form of anastrozole. Patient two was administered three cycles of chemotherapy without radiotherapy. Subsequent to being followed up for 25 months and 13 months, respectively, there was no evidence of recurrence or distant metastasis in patient one or two, respectively. PMID- 25789032 TI - Multiple liver metastases of pancreatic solid pseudopapillary tumor treated with resection following chemotherapy and transcatheter arterial embolization: A case report. AB - A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and multiple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and alpha-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. PMID- 25789033 TI - Coexistence of benign struma ovarii, pseudo-Meigs' syndrome and elevated serum CA 125: Case report and review of the literature. AB - Struma ovarii is an uncommon ovarian teratoma comprised predominantly of mature thyroid tissue. The combination of pseudo-Meigs' syndrome, and elevation of CA 125 to the struma ovarii is a rare condition that can mimic ovarian malignancy. We reported a case of benign struma ovarii, presenting with the clinical features of advanced ovarian carcinoma: complex pelvic mass, gross ascites, bilateral pleural effusion and markedly elevated serum CA 125 levels. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Ascites and pleural effusion were not evident and the CA 125 levels returned to normal following surgical excision. A systematic review of reported cases of coexistent benign struma ovarii, pseudo-Meigs' syndrome and elevated serum CA 125 was performed. Struma ovarii accompanied by pseudo-Meigs' syndrome and elevated serum CA 125 should be considered in the differential diagnosis of ovarian epithelial cancer. PMID- 25789034 TI - Ectopic meningioma in the bilateral nasal olfactory cleft: A case report and literature review. AB - Certain nasal neoplasms, such as ectopic menigioma, present as nasal polyps, together with similar symptoms. The present study reports the diagnosis and treatment of ectopic meningioma in the bilateral nasal olfactory cleft in order to improve the diagnosis and treatment of ectopic meningioma in the nasal cavity. By retrospectively analyzing the clinical data and reviewing the associated literature, a detailed introduction to the clinical manifestation, diagnosis and treatment of ectopic meningioma of the nasal cavity was ascertained. The tumor was removed from the sinus by functional endoscopy surgery. Regular follow-up appointments were scheduled every three months, with no evidence of recurrence to date. The olfactory recovery and nasal ventilation were normal subsequent to surgery. Meningiomas are infrequently occurring tumors with unpredictable clinical behavior. A clear understanding of the etiology and appropriate diagnostic and management principles may aid in overcoming the challenges of treating primary extracranial meningiomas. PMID- 25789035 TI - Symptom relief effect of palliative high dose rate intracavitary radiotherapy for advanced esophageal cancer with dysphagia. AB - Intracavitary radiotherapy (ICRT) for the palliative treatment of advanced esophageal cancer with dysphagia is currently performed at the University of Tokyo Hospital (Tokyo, Japan). In the present study, 24 patients exhibiting advanced esophageal cancer with dysphagia received palliative ICRT. ICRT, which was delivered 5 mm below the esophageal mucous membrane, with the exception of one case, was administered at a dose of 6 Gy/fraction. Specific patients additionally underwent definitive or palliative external beam radiation therapy for esophageal cancer a minimum of three months prior to ICRT. The effect of treatment on symptom alleviation was examined by comparing the dysphagia score prior to and following ICRT, with the patients' medical records and a questionnaire used to calculate a dysphagia score ranging from zero (no dysphagia) to four (total dysphagia). In consideration of the individual efficacy of the treatment, the maximum number of repeated ICRT fractions was four (median, 1.7 times). A trend in the improvement of the symptom of dysphagia was observed in response to esophageal ICRT, with the average dysphagia score markedly decreasing from 2.54 to 1.65, however, the difference was not significant (P=0.083). Furthermore, pain was the most frequent side-effect of the esophageal ICRT and no patients exhibited severe complications. Thus, esophageal ICRT at a dose of 6 Gy/fraction may present an effective strategy for relieving the symptom of dysphagia in cases of advanced esophageal cancer. PMID- 25789036 TI - Invasive cribriform carcinoma of the breast: A report of nine cases and a review of the literature. AB - Nine cases of infiltrating cribriform carcinoma (ICC) of the breast are reported and the clinicopathological features, particularly the imaging findings, are analyzed in the present study. Sonograms revealed that all masses exhibited a hypoechoic internal echo texture (9/9) and that a number of masses presented with an irregular shape (8/9), obscure boundary (5/9), partially microlobulated (5/9) or well-circumscribed (4/9) margins, and an inhomogeneous echo (8/9). Mammographic imaging revealed increased radiological density masses (6/8), and sand-like calcification was not observed in all patients. In two patients, the tumors were mammographically occult. Magnetic resonance imaging performed on one patient revealed a slightly high signal intensity on fat-saturated T1- and T2 weighted images. Following contrast enhancement, a homogeneous early enhancement was revealed with a quick ascent and quick descent time-density curve. Immunohistochemistry revealed that all ICCs expressed estrogen receptor and progesterone receptor, but that none were positive for human epidermal growth factor receptor 2. The Ki-67 labeling index was 3.75% (range, 2-5%) in the tumor tissue. Four patients were treated with mastectomy and the others with breast conserving surgery. Six clinically node-negative patients underwent sentinel lymph node biopsy; three then received axillary lymph node dissection. Following surgery, three patients received adjuvant chemotherapy, radiotherapy and hormonal therapy, respectively. With a median follow-up time of 38 months (range, 4-70 months), one patient developed local recurrence following breast-conserving surgery; axillary lymph nodes and distant metastases were not observed. This study confirms that this type of carcinoma has unique biological characteristics and a favorable prognosis, but that it remains possible to experience local recurrence. PMID- 25789037 TI - Chemoresistance is associated with Beclin-1 and PTEN expression in epithelial ovarian cancers. AB - The aim of the present study was to investigate the protein expression of the autophagy-related genes, BECN1 and PTEN, and the association with drug resistance in epithelial ovarian cancers. In total, 40 patients with pathologically diagnosed epithelial ovarian cancer were divided into a chemotherapy-sensitive group (n=20) and a chemotherapy-resistant group (n=20), according to the results of the pre- or post-operative normative chemotherapy and the post-operative follow-up. The protein expression of the phosphatase and tensin homolog (PTEN) and the BECN1 gene product, Beclin-1, was analyzed using immunohistochemistry in the 40 patients with ovarian carcinoma. The positive rate of Beclin-1 expression was significantly lower in the resistant group (35.0%) compared with the sensitive group (50.0%). The positive rate of PTEN expression was also significantly lower in the resistant group (30.0%) compared with the sensitive group (65.0%). Furthermore, the differences in the expression rates were revealed to be significant (P<0.05). The expression of Beclin-1 was identified to be positively correlated with the expression of PTEN (rs=0.816; P<0.0001). The low expression of the Beclin-1 and PTEN proteins in the ovarian cancer tissues was revealed to be closely associated with drug resistance. Therefore, Beclin-1 may interact with PTEN to participate in the mechanism of drug resistance and the changes in macrophage activity observed in cases of drug-resistant ovarian cancer. PMID- 25789038 TI - Extramedullary plasmacytoma of the cricoid cartilage progressing to multiple myeloma: A case report. AB - Extramedullary plasmacytoma (EMP) is an uncommon tumor of the plasma cells, and EMP of the cricoid cartilage is extremely rare The present study reports the rare case of a 43-year-old male complaining of hoarseness and dyspnea for over a year. Computed tomography imaging of the neck revealed an occupying lesion in the cricoid cartilage, and a diagnosis of EMP was subsequently confirmed by histopathological evaluation. The patient underwent surgery, but refused radiotherapy against medical advice. One year later, the patient was diagnosed with a recurrence of EMP via pathological examination and underwent a second surgery, however, radiotherapy was refused. After a further two years and four months, the patient presented with lumps in the neck, and was subsequently diagnosed with multiple myeloma. The patient received systematic chemotherapy in the hematology department; the patient's general condition stabilized, and no further anemia, bone pain, infection or other discomfort was experienced. Solitary plasmacytoma of the cricoid cartilage is a rare lesion and compliance with radiotherapy following surgery may provide significant benefit in the treatment of this disease. PMID- 25789039 TI - Primary pulmonary lymphoepithelioma-like carcinoma initially diagnosed as squamous metaplasia: A case report and literature review. AB - A mass was detected in the middle lobe of the right lung of a 58-year-old female. The patient did not present any symptoms and was a nonsmoker. Diagnostic evaluation revealed squamous metaplasia in the middle lobe of the right lung. During surgery, a tumor was identified, which was diagnosed as a lymphoepithelioma-like carcinoma (LELC). LELCs have been mainly reported in the Asian population and are associated with the Epstein-Barr virus (EBVs), while they are not associated with smoking. Squamous metaplasia, which is the basis of squamous cell carcinoma, differs from LELC in the therapeutic methods used and the prognostic evaluation. Squamous metaplasia requires regular follow-up in out patient clinics, while pulmonary LELC is treated by surgery and chemotherapy. Therefore, distinguishing between LELCs and other nonmalignant or premalignant conditions is essential. PMID- 25789040 TI - Cancer and embryo expression protein 65 promotes cancer cell growth and metastasis. AB - Cancer and embryo expression protein 65 (CEP65) is a centrosomal protein that is expressed at relatively high levels in embryonic tissue and different cancerous tissues, but its role in tumorigenesis remains unknown. In the present study, CEP65 was stably expressed in AGS gastric cancer cells. CEP65 was found to promote cell growth in the MTT assay and to enhance cell migration and invasion in Transwell chamber assays. To validate results from the in vitro experiments, CEP65 was stably expressed in BICR-H1 breast cancer cells through adenovirus mediated transduction. By inoculating BICR-H1 cells on chick chorioallantoic membrane (CAM), it was found that CEP65 promotes cell growth on the CAM and increases cell metastasis to the lungs of the chicken. By utilizing a xenograft severe combined immunodeficiency mouse model, CEP65 was also found to accelerate BICR-H1 cell growth and metastasis to the lungs. Furthermore, it was shown that CEP65 increases matrix metalloproteinase (MMP)2 activity in zymographic assays, however, microarray screening and reverse transcription polymerase chain reaction validation revealed that CEP65 had no effect on the expression levels of MMP2 or MMP9, but decreased the expression levels of metastasis-associated genes, TIMP2, RAP and VTN. Taken together, the results of the present study demonstrated the oncogenic function of CEP65 in promoting cancer cell growth and metastasis. PMID- 25789041 TI - Unicentric mesenteric Castleman's disease with littoral cell angioma, anemia, growth retardation and amenorrhea: A case report. AB - Castleman's disease (CD) is a rare lymphoproliferative disorder of unknown origin, and littoral cell angioma (LCA) is a rare vascular tumor of the spleen with an unknown etiology. The current study reports the case of a 28-year-old female who presented with anemia, growth retardation and amenorrhea. Physical examination revealed a mass in the mesentery, splenomegaly with multiple small nodules, hepatomegaly and an infantile uterus. Histopathological analysis of the resected mass and spleen confirmed the diagnosis of hyaline-vascular CD and LCA. The patient's anemia resolved, and menstruation and breast development also commenced following surgery. To the best of our knowledge, this is the first report of CD accompanied by littoral cell angioma, anemia, growth retardation and amenorrhea. PMID- 25789042 TI - Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients. AB - Cowden syndrome (CS) is an autosomal dominant disorder characterized by multiple hamartomas in the breast, thyroid and endometrium, with a prevalence of 1 per 250,000. Females with CS have a 21-28% lifetime risk of developing uterine cancer. Germline mutations in the phosphatase and tensin homolog (PTEN) gene, a tumor suppressor gene, are responsible for 30-80% of CS cases. PTEN is a nine exon gene, located on chromosome 10q23.3, which encodes the 403 amino acid PTEN protein. It negatively regulates the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway, affecting various cellular processes and signaling pathways. The present study examined whether PTEN mutations are present in CS-like families with uterine cancer (UC). UC patients underwent surgery at Karolinska University Hospital, Stockholm, Sweden (2008-2012). Pedigrees were analyzed and 54 unrelated CS-like families were identified. CS-like families were defined as having at least one occurrence of uterine cancer and one of breast cancer, as well as at least one additional Cowden-associated tumor (uterine, breast, thyroid, colon or kidney cancer) in the same individual or in first degree relatives. Genomic DNA was amplified using polymerase chain reaction, and DNA sequencing analysis of all nine exons of the PTEN gene was conducted. No germline PTEN mutations or polymorphisms were identified. Germline PTEN mutations are rare in CS-like families with uterine cancer, therefore, genetic screening must be restricted to patients that meet the strict National Comprehensive Cancer Network criteria. Gynecologists must be aware of the CS criteria and identify potential cases of CS in females where uterine cancer is the sentinel cancer. PMID- 25789043 TI - Myoid hamartoma of the breast with focal chondromyoxid metaplasia and pseudoangiomatous stromal hyperplasia: A case report. AB - Hamartomas of the breast, also known as fibroadenolipomas, lipofibroadenomas or adenolipomas, are benign lesions. Hamartomas account for between 0.04 and 1.15% of all benign breast tumors in females. Myoid hamartoma of the breast (MHB) is extremely rare. The present study describes a case of MHB in a 44-year-old female. Screening mammography revealed a lobulated partial indistinct isodense mass measuring ~3.8 cm in the upper outer quadrant of the left breast. Sonographic examinations revealed a 2-3-cm mass in the left breast, which was fairly well circumbscribed and demonstrated complex scattered echogenic areas and isoechoic tissue. A core needle biopsy demonstrated fibrocystic changes, with small focal ductule aggregations. As malignancy could not be excluded, a partial mastectomy was performed using a circumareolar incision. The mass was histopathologically diagnosed as MHB with focal chondromyoxid metaplasia and pseudoangiomatous stromal hyperplasia. The histological diagnosis was based upon the findings of the well-circumscribed tumor, which was composed of entrapped mammary ducts, fat cells and myoid stromal components, with focal chondromyxoid metaplasia and pseudoangiomatous stromal hyperplasia. The tumor cells exhibited diffuse cluster of differentiation 34-positive immunoreactivity, which was consistent with a diagnosis of pseudoangiomatous stromal hyperplasia. PMID- 25789044 TI - Expression of the gamma-phosphorylated histone H2AX in gastric carcinoma and gastric precancerous lesions. AB - The histone gammaH2AX is a marker of activated DNA damage that is overexpressed in various cancers and corresponding precursor lesions, indicating that gammaH2AX is a component in oncogenic transformation. The present study aimed to determine whether the immunohistochemical expression of gammaH2AX is involved in the progression between superficial gastritis (n=20), atrophic gastritis (n=24) and gastric carcinoma (n=79). There was no increase in gammaH2AX expression between superficial and atrophic gastritis, but there was a significant increase in gammaH2AX expression between these two conditions and gastric carcinoma (chi2=68.712; P<0.001). The expression of gammaH2AX in moderately-differentiated gastric adenocarcinoma (n=49) was evidently higher compared with poorly differentiated gastric adenocarcinoma (n=26; chi2=14.241; P<0.01). Staining for gammaH2AX did not reveal a significant association between the expression of the histone and patient age, depth of invasion, lymph node metastasis or the tumor node-metastasis stage of the gastric carcinoma. Overall, the present study demonstrated that enhanced gammaH2AX expression may be closely associated with gastric carcinoma, but is less likely to be involved in the genesis of gastric carcinoma. PMID- 25789045 TI - Diagnosis and treatment of primary central nervous system lymphoma: A report of nine cases and literature review. AB - Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant tumor type of the nervous system and is associated with poor prognosis. To investigate the efficacy of current treatment strategies for PCNSL, the present study retrospectively analyzed the clinical and pathological features, imaging results, clinical management, and prognoses of nine patients with PCNSL. Postoperative pathological examination confirmed a diagnosis of lymphoma in all the patients and the adopted treatment regimens were as follows: Stereotactic biopsy in combination with methylprednisolone (MP) and methotrexate (MTX) and/or radiotherapy; craniotomy in combination with dexamethasone or MP and/or radiotherapy; and neuroendoscopic surgery in combination with MP and MTX. The follow-up period was 5-27 months with an average duration of 10.1 months. After the initial three months of follow-up, the clinical symptoms of all the patients were significantly improved, with the tumor disappearing in seven patients and evidently reducing in size in two patients. However, six patients exhibited tumor recurrence, three of whom eventually succumbed to the disease during the follow up period. Currently, comprehensive treatment strategies based on a combination of stereotactic biopsy, chemotherapy and radiotherapy are recommended for the treatment of PCNSL. However, the effectiveness of these treatments remains unsatisfactory. Thus, future studies are required to investigate methods for improving the efficacy of PCNSL treatment strategies. PMID- 25789046 TI - Indirect computed tomography lymphography identifies lymph node metastasis in rabbit pyriform sinus VX2 carcinoma. AB - Indirect computed tomography lymphography (CT-LG) could be used to determine the regional spread of cancer and assess lymphatic function by the interstitial delivery of diagnostic agents. Few studies have been reported on its use in pyriform sinus carcinoma. The aim of the present study was to establish the rabbit VX2 tumor as a model for pyriform sinus carcinoma and to observe its neck lymph node metastasis by indirect CT-LG. VX2 tumor tissue suspension was transplanted into the pyriform sinus submucosa of 15 rabbits under direct laryngoscope. Rabbits were randomly placed into one of three groups, each comprised of five rabbits. Observation of the tumor growth and neck lymph node metastases were taken on days 14 (group 1), 21 (group 2) and 28 (group 3) following transplantation using the method of indirect CT-LG. VX2 tumors were transplanted successfully in all rabbits. Deep cervical lymph nodes were enhanced clearly in indirect CT-LG. The contrast agent filling defected appeared on the metastasis nodes while the lymph node without metastasis was smooth. The metastasis rates of deep cervical lymph nodes were 100% in all three groups on CT LG. The CT attenuation value of CT-LG reached peak values of 400 and 600 Hu at 1 and 3 min after the injection, which then decreased gradually. In this study, CT LG could demonstrate the internal architecture of lymph nodes and their lymphatic vessels, and therefore may have the advantages of radiological methods such as B ultrasound, CT, magnetic resonance imaging and positron emission tomography. PMID- 25789047 TI - Promoter methylation and expression changes of BRCA1 in cancerous tissues of patients with sporadic breast cancer. AB - BRCA1 is a susceptibility gene that has a genetic predisposition for breast cancer. BRCA1 gene mutation is closely associated with familial hereditary breast cancer, but the BRCA1 gene mutation is rarely found in sporadic breast cancer. According to previous studies, decreased expression of BRCA1 was detected in certain types of sporadic breast cancer. Aberrant methylation of DNA promoter CpG islands is one of the mechanisms by which tumor suppressor gene expression and function is lost. The aim of the present study was to investigate BRCA1 gene expression, methylation status and clinical significance in sporadic types of breast cancer. Quantitative polymerase chain reaction (PCR) and bisulfite sequencing PCR were respectively used to detect expression differences of BRCA1 mRNA and BRCA1 methylation in the 49 cancerous and paired non-cancerous samples from patients with breast cancer. The associations of BRCA1 expression and methylation status with the clinicopathologic characteristics were analysed. BRCA1 mRNA expression levels in the 49 breast cancer tissues were lower than those in the paired non-cancerous tissues. There was a significant statistical difference (P=0.001). BRCA1 mRNA expression was not associated with the main clinicopathologic characteristics. Frequency of the BRCA1 promoter methylation in the breast cancerous tissues was significantly higher than that in the non cancerous tissues (P=0.007); BRCA1 gene methylation status was negatively correlated with mRNA expression (P=0.029); and BRCA1 methylation exhibited no association with all clinicopathological features. DNA promoter hypermethylation may be the potential mechanism accounting for BRCA1 expression silence in part of sporadic types of breast cancer. Some patients with hypermethylated BRCA1 may display favorable clinicopathological status. PMID- 25789048 TI - Bone metastasis of a gastrointestinal stromal tumor: A report of two cases. AB - Gastrointestinal stromal tumors (GISTs) are the most frequently diagnosed mesenchymal tumors of the GI tract. GISTs usually arise from the stomach, followed by the small intestine, rectum and other locations in the GI tract. The most common metastatic sites are the liver and peritoneum, whereas GISTs rarely metastasize to the bone. Although a small number of previous studies have described bone metastases originating from GISTs, the true prevalence is yet to be elucidated. The present study describes two cases of bone metastasis in patients with GISTs and reviews the relevant literature. Case one was of a 78 year-old male who presented with bone metastasis to the femoral neck five years after the resection of a GIST. The metastasis was completely resected and the patient remains alive nine years after the initial diagnosis of the GIST. Case 2 was of a 41-year-old male who presented with bone metastases to the ribs following resection of GISTs seven and 17 years earlier. The metastases were completely resected and the patient remains alive 17 years after the initial diagnosis. In total, only 10 cases of GISTs with metastases to the bone have been reported in the English literature. The possibility of bone metastases originating from a GIST should be considered during clinical follow-up, particularly in the presence of liver metastases. If feasible, bone metastases should be completely surgically excised. PMID- 25789049 TI - Primary central nervous system lymphoma mimicking recurrent depressive disorder: A case report. AB - Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma, which is limited to the central nervous system. Few studies are available reporting psychiatric symptoms as the initial and dominant presentation of PCNSL. The current study reports the case of a PCNSL patient with a history of major depressive disorder and coexisting rheumatoid arthritis (treated with methotrexate), who initially presented with recurrent depressive disorder that showed no response to antidepressant drug therapy. Magnetic resonance imaging revealed multiple mass lesions in the brain, and pathological examination of the biopsy confirmed the diagnosis of diffuse large B cell lymphoma of the central nervous system. The present case demonstrated that PCNSL may affect mood in the early stages of the disease and thus, clinicians must be aware of this manifestation in patients with depressive disorder co-existing with immunosuppressive conditions, as early detection and appropriate treatment are important prognostic factors for PCNSL. PMID- 25789050 TI - Clinical experience with nanoparticle albumin-bound paclitaxel, a novel taxane anticancer agent, and management of adverse events in females with breast cancer. AB - Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is currently approved in Japan for treatment of breast cancer. However, apart from phase I clinical trials, data regarding Japanese patients are scant. In the present study, the efficacy and safety of nab-paclitaxel therapy were retrospectively analyzed in 22 patients with advanced or metastatic breast cancer who were treated at the National Hospital Organization Shikoku Cancer Center between November 2010 and June 2012. The nab-paclitaxel was administered once every three weeks. The median age of the patients was 59 years. The tumors were estrogen-receptor positive and/or progesterone-receptor positive in 63.6% patients. None of the patients had HER2-positive breast cancer. The median number of treatment cycles was six (range, two to 12). Six patients exhibited a partial response; the response rate was 27.3% and the clinical benefit rate was 31.8%. The response rate and clinical benefit rate were higher in patients who received nab-paclitaxel as first- or second-line treatment. The median time to treatment failure was 127 days (range, 27-257). Major adverse events were peripheral neuropathy (59%; Grade 3, 9%), myalgia (59%), rash (45%), and nausea and vomiting (50%). The results suggest that nab-paclitaxel is a well-tolerated and clinically useful anticancer preparation. PMID- 25789051 TI - Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma. AB - The development of chemoresistance in patients represents a major challenge in cancer treatment. Lactate dehydrogenase-A (LDHA) is one of the principle isoforms of LDH that is expressed in breast tissue, controlling the conversion of pyruvate to lactate and also playing a significant role in the metabolism of glucose. The aim of this study was to identify whether LDHA was involved in oral cancer cell resistance to Taxol and whether the downregulation of LDHA, as a result of cisplatin treatment, may overcome Taxol resistance in human oral squamous cells. The OECM-1 oral epidermal carcinoma cell line was used, which has been widely used as a model of oral cancer in previous studies. The role of LDHA in Taxol and cisplatin resistance were investigated and the synergistic cytotoxicity of cisplatin and/or Taxol in oral squamous cells was analyzed. Cell viability was analyzed by MTT assay, LDHA expression was analyzed by western blot analysis and siRNA tranfection was performed to knock down LDHA expression. The present study results showed that decreased levels of LDHA were responsible for the resistance of oral cancer cells to cisplatin (CDDP). CDDP treatments downregulated LDHA expression, and lower levels of LDHA were detected in the CDDP-resistant oral cancer cells compared with the CDDP-sensitive cells. By contrast, the Taxol resistant cancer cells showed elevated LDHA expression levels. In addition, small interfering RNA-knockdown of LDHA sensitized the cells to Taxol, but desensitized them to CDDP treatment, while exogenous expression of LDHA sensitized the cells to CDDP, but desensitized them to Taxol. The present study also revealed the synergistic cytotoxicity of CDDP and Taxol for killing oral cancer cells through the inhibition of LDHA. This study highlights LDHA as a novel therapeutic target for overcoming Taxol resistance in oral cancer patients using the combined treatments of Taxol and CDDP. PMID- 25789052 TI - B7-H1 enhances proliferation ability of gastric cancer stem-like cells as a receptor. AB - Cancer stem-like cells (CSCs) are a rare tumorigenic population with the ability to self-renew in numerous cancer types. Their existence is considered a pivotal contributor to tumor recurrence. B7-H1 is a ligand of inhibitory inducible co stimulator (ICOS) that is broadly expressed on various human cancers. ICOS acts as a ligand of programmed death-1 (PD-1) on T cells, induces the immune escape of cancer cells and also acts as a receptor mediating anti-apoptotic effects on cancer cells. However, the expression and function of B7-H1 on CSCs is not yet clear. In the present study, gastric cancer samples were collected and the B7-H1 expression in gastric cancer CSCs was detected. Ki67, a proliferation marker, was found to be expressed at a higher rate in B7-H1+ CSCs compared with the B7-H1- counterparts. SGC-7901 cells, a gastric cancer cell line, were cultured in serum free medium to form sphere cells that possessed stem cell characteristics and could express B7-H1 with the stimulation of interferon-gamma. The proliferative ability of sphere cells was enhanced following B7-H1 activation with recombinant PD-1 in vivo and in vitro. This effect could be eliminated by neutralizing B7-H1. Overall, B7-H1 can act as a stimulating receptor for CSCs, and induce CSC proliferation. Blocking B7-H1 on CSCs may possess therapeutic potential for treating gastric cancer. PMID- 25789054 TI - Osteopontin-c mediates the upregulation of androgen responsive genes in LNCaP cells through PI3K/Akt and androgen receptor signaling. AB - Androgen receptor (AR) signaling is a key pathway modulating prostate cancer (PCa) progression. Several steps in this pathway have been investigated in order to propose novel treatment strategies for advanced PCa. Total osteopontin (OPN) has been described as a biomarker for PCa, in addition to its role in activating the progression of this tumor. Based on the known effects of the OPNc splice variant on PCa progression, the present study investigated whether this isoform can also modulate AR signaling. In order to test this, an in vitro model was used in which LNCaP cells were cultured in the presence of conditioned medium (CM) secreted by PCa cells overexpressing OPNc (OPNc-CM). The activation of AR signaling was evaluated by measuring the expression levels of AR-responsive genes (ARGs) using quantitative polymerase chain reaction and specific oligonucleotides. The data demonstrated that all nine tested ARGs (Fgf8, TMPRSS2, Greb1, Cdk2, Ndrg1, Cdk1, Pmepa1, Psa and Ar) are significantly upregulated in response to OPNc-CM compared with LNCaP cells cultured in CM secreted by control cells transfected with empty expression vector. The specific involvement of OPNc was demonstrated by depleting OPNc from OPNc-CM using an anti-OPNc neutralizing antibody. In addition, by using a phosphoinositide 3-kinase (PI3K)-specific inhibitor and AR antagonists, such as flutamide and bicalutamide, it was also observed that upregulation of ARGs in response to OPNc-CM involves PI3K signaling and depends on the AR. In conclusion, these data indicated that OPNc is able to activate AR signaling through the PI3K pathway and the AR. These data further corroborate our previous data, revealing the OPNc splice variant to be a key molecule that is able to modulate key signaling pathways involved in PCa progression. PMID- 25789053 TI - Directional migration of adult hematopoeitic progenitors to C6 glioma in vitro. AB - Multiform glioblastoma is the most common primary, highly invasive, malignant tumor of the central nervous system, with an extremely poor prognosis. The median survival of patients following surgical resection, radiation therapy and chemotherapy does not exceed 12-15 months and thus, novel approaches for the treatment of the disease are required. The phenomenon of the directed migration of stem cells in tumor tissue presents a novel approach for the development of technologies that facilitate the targeted delivery of drugs and other therapeutic agents to the tumor foci. Hematopoietic cluster of differentiation (CD)34+/CD133+ stem cells possess significant reparative potential and are inert with respect to normal neural tissue. The aim of the present study was to investigate the substantiation ability of adult hematopoietic progenitors to the directed migration of glioma cells. A C6 glioma cell line, a culture of hematopoietic CD34+/CD133+ stem cells and primary cultures of rat astrocytes and fibroblasts were used. The cells were co-cultured for five days. The results revealed the formation of cell shaft hematopoietic stem cells on the perimeter of the culture inserts containing the glioma culture. However, this was not observed in the wells with fibroblast and astrocyte cultures. The results indicated that hematopoietic stem cells exhibit a high potential for the directional migration of C6 glioma cells, which allows them to be considered as a promising cell line for the development of novel anticancer biomedical technologies and increases our understanding with regard to previously unclear aspects of glial tumor carcinogenesis. PMID- 25789055 TI - Immunization with mutant HPV16 E7 protein inhibits the growth of TC-1 cells in tumor-bearing mice. AB - Two human papillomavirus (HPV) 16 oncogenic proteins, E6 and E7, are co-expressed in the majority of HPV16-induced cervical cancer cells. Thus, the E6 and E7 proteins are good targets for developing therapeutic vaccines for cervical cancer. In the present study, immunization with the mutant non-transforming HPV16 E7 (mE7) protein was demonstrated to inhibit the growth of TC-1 cells in the TC-1 mouse model. The HPV16 mE7 gene was amplified by splicing overlap extension polymerase chain reaction using pET-28a(+)-E7 as a template, and the gene was cloned into pET-28a(+) to form pET-28a(+)-mE7. Compared with the E7 protein, mE7 lacks amino acid residues 94-98, and at residue 24, there is a Cys to Gly substitution. pET-28a(+)-mE7 was then introduced into Escherichia coli Rosetta. The expression of mE7 was induced by isopropyl beta-D-1-thiogalactopyranoside. The mE7 protein was purified using Ni-NTA agarose and detected by SDS-PAGE and western blot analysis. In the tumor prevention model, no tumor was detected in the mice vaccinated with the mE7 protein. After 40 days, the tumor-free mice and control mice were challenged with 2*105 TC-1 cells. All control mice developed tumors six days later, but mE7 immunized mice were tumor free until 90 days. In the tumor therapy model, the TC-1 cells were initially injected subcutaneously, and the mice were subsequently vaccinated. Vaccination against the mE7 protein may significantly inhibit TC-1 cell growth compared to the control. These results demonstrated that immunization with the HPV16 mE7 protein elicited a long-term protective immunity against TC-1 tumor growth and generated a significant inhibition of TC-1 growth in a TC-1 mouse model. PMID- 25789056 TI - Osteoid osteoma of the rib: A report of two cases. AB - Osteoid osteoma is type of benign bone tumor, characterized by a well-demarcated core with a typical size of <1 cm and by a distinctive surrounding zone of reactive bone formation. The tumor can occur anywhere in the cortex or medulla of the skeleton. However, the lesion usually affects the long bones of the lower extremities. The present study describes two cases of osteoid osteomas located in the rib. PMID- 25789057 TI - Role of ribophorin II in the response to anticancer drugs in gastric cancer cell lines. AB - The identification of prognostic markers and establishing their value as therapeutic targets improves therapeutic efficacy against human cancers. Ribophorin II (RPN2) has been demonstrated to be a prognostic marker of human cancer, including breast and pancreatic cancers. The present study aimed to evaluate RPN2 expression in gastric cancer and to examine the possible correlation between RPN2 expression and the response of cells to clinical anticancer drugs, which has received little research attention at present. The gastric cancer AGS, TMC-1, SNU-1, TMK-1, SCM-1, MKN-45 and KATO III cell lines were used as a model to elucidate the role of RPN2 in the response of cells to six common chemotherapeutic agents, comprising oxaliplatin, irinotecan, doxorubicin, docetaxel, cisplatin and 5-fluorouricil. The functional role of RPN2 was assessed by silencing RPN2 using small interfering RNA (siRNA), and the cytotoxicity was determined by an MTS assay and analysis of apoptosis. Molecular events were evaluated by western blotting. All the anticancer drugs were found to exert a concentration-dependent decrease on the cell survival rate of each of the cell lines tested, although the RPN2 levels in the various cell lines were not directly correlated with responsiveness to clinical anticancer drugs, based on the calculated IC50 values. siRNA-mediated RPN2 downregulation enhanced cisplatin induced apoptosis in AGS cells, but did not markedly decrease the cell survival rates of these cells in response to the tested drugs. Furthermore, RPN2 silencing in MKN-45 cells resulted in no additional increase in the cisplatin-induced apoptosis and survival rates. It was also found that RPN2 depletion increased anticancer drug-mediated cytotoxicity in gastric cancer cell lines. However, the predictive value of RPN2 expression in cancer therapy is questionable in gastric cancer models. PMID- 25789058 TI - Renal cell carcinoma growing into the renal pelvis and mimicking transitional cell carcinoma: A case report and literature review. AB - Renal cell carcinoma (RCC) originated from parenchyma and the majority of malignancies originating in the renal pelvis are transitional cell carcinoma (TCC). In the present study, a rare case of RCC growing into the renal pelvis and mimicking TCC in medical imaging is reported. The preoperative differentiation between RCC and TCC is important in order to identify the type of surgical treatment required: Nephrectomy or ureteronephrectomy. The role of ureteroscopy and biopsy is emphasized in the accurate preoperative diagnosis of a renal pelvic mass. Thus, the present study provided fundamental evidence for the pathogenesis of RCC with pelvic extension and challenged the present tumor node metastasis staging system of RCC. PMID- 25789059 TI - Organ dysfunction in critically ill cancer patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. AB - The aim of the present study was to observe the incidence of organ dysfunction and the intensive care unit (ICU) outcomes of critically ill cancer patients during the cytoreductive surgery with hyperthermic intraperitoneal chemotherapy post-operative period. The present study included 25 critically ill cancer patients admitted to the ICU of the National Cancer Institute (Mexico City, Mexico) between January 2007 and February 2013. The incidence of organ dysfunction was 68% and patients exhibiting <=1 organ system dysfunction during ICU admittance remained in hospital for a significantly shorter period compared with patients who exhibited >=2 organ system dysfunctions (12.4+/-10.7 vs. 24.1+/ 12.8 days; P=0.025). Therefore, the present study demonstrated that a high incidence of organ dysfunction was associated with a longer ICU hospital stay. PMID- 25789060 TI - Imaging observations of pulmonary inflammatory myofibroblastic tumors in patients over 40 years old. AB - Pulmonary inflammatory myofibroblastic tumors (PIMTs) are extremely rare in adults. If occurring in patients >40 years old, PIMT should be rapidly distinguished from lung cancer. The present study aimed to characterize the imaging features of PIMT in patients >40 years old in order to improve the diagnosis of PIMT. The imaging data of 10 patients with PIMT were reviewed retrospectively. Of the patients, eight underwent computed tomography (CT), two underwent positron emission tomography (PET)/CT and four underwent single-photon emission computed tomography (SPECT). Unenhanced CT revealed 10 lesions with a maximum diameter ranging between 5 and 57 mm located in the lower (n=6) or upper (n=4) lobe, in a peripheral (n=9) or central (n=1) region, and that were well- (n=4) or ill-defined (n=6), and round to oval (n=5) or irregular (n=5) in shape. Calcification (n=3), necrosis (n=6), cavity (n=4), air bronchogram (n=6) and obstructive pneumonia (n=1) were also observed in the patients. Contrast-enhanced CT revealed six lesions with moderate to high contrast enhancement in the arterial and venous phases, including four lesions with delayed enhancement. PET/CT identified two lesions with increased tracer uptake that were homogeneous and heterogeneous and each exhibited a maximal standard uptake value (SUVmax) of 6.0 and 5.4, respectively. The delayed PET/CT revealed foci that each exhibited an increased SUVmax of 6.9 and 5.9, respectively. SPECT demonstrated no definitive bone metastases, but did reveal atypical hypertrophic pulmonary osteoarthropathy in one patient. The combined imaging methods may lead to a more precise evaluation of PIMT in patients >40 years old. PMID- 25789061 TI - Efficacy of temozolomide and bevacizumab for the treatment of leptomeningeal dissemination of recurrent glioblastoma: A case report. AB - The prognosis of leptomeningeal dissemination of recurrent glioblastoma is poor, and chemotherapy results in minimal palliative efficacy. Temozolomide (TMZ) is an established therapy for patients with malignant glioma and the standard of care in parenchymal gliomas; however, few reports have been published with regard to its use for the treatment of leptomeningeal dissemination. Only one report has indicated the radiographic response of leptomeningeal dissemination to a TMZ rechallenge, suggesting a potential causative effect. While bevacizumab is an effective therapy for recurrent glioblastoma, its effect on leptomeningeal dissemination of recurrent glioblastoma remains unclear. The present study reports a case of leptomeningeal dissemination of recurrent glioblastoma in which transient neurological and radiological improvement was observed following chemotherapy with TMZ and bevacizumab. However, five months after the diagnosis of leptomeningeal dissemination the patient succumbed to the disease. PMID- 25789062 TI - Laser CO2 treatment for vulvar lymphedema secondary to gynecological cancer therapy: A report of two cases and review of the literature. AB - Vulvar lymphedema is an uncommon and disabling side-effect of pelvic lymphadenectomy and pelvic radiotherapeutic treatment for invasive genital cancer. Lymphorrhea, a complication of lymphedema, may be extremely distressing for patients due to the requirement to wear sanitary towels and as the pain and loss of elasticity of the vulvar skin and mucosa can cause discomfort during coitus. Surgical treatments of lymphorrhea and vulvar lymphedema secondary to gynecological cancer treatments remain controversial and are not currently considered to be the standard therapy. The present study reports two cases of vulvar lymphedema complicated by vulvar lymphorrhea in females who had undergone treatment for cervical and endometrial cancer, respectively; a review of the literature is also included. In the two present cases, vulvar lymphedemas were refractory to standard treatments, including decongestive therapy, manual lymph drainage, elastic bandaging, low-stretch bandaging, exercises and skin care. Laser CO2 excision and vaporization of the whole skin and mucosal tissue of the vulva was successfully performed to treat the lymphorrhea and improve quality of life. Thus, the present two cases indicated that laser CO2 surgery may present an additional therapy for the treatment of genital lymphedema that is refractory to other treatments. PMID- 25789063 TI - Insufficient radiofrequency ablation promotes human hepatoma SMMC7721 cell proliferation by stimulating vascular endothelial growth factor overexpression. AB - The aims of the current study were to investigate the influence of insufficient radiofrequency ablation (RFA) on the cell proliferation of the human hepatocellular carcinoma (HCC) cells, SMMC7721, and to elucidate the underlying mechanism. SMMC7721 cells were subjected to a 47 degrees C treatment regimen to simulate insufficient RFA, in the presence or absence of KN93 [a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII)], PD98059 [a specific inhibitor of extracellular signal-regulated kinase (ERK)], or axitinib (a specific inhibitor of vascular endothelial growth factor (VEGF) receptor]. Cell proliferation was determined using a thiazolyl terazolium assay (MTT). The levels of CaMKII, phospho-CaMKII, ERK, phospho-ERK and VEGF were observed by western blot analysis. The results demonstrated that the 47 degrees C treatment regimen: i) Triggered upregulation of VEGF expression in the SMMC7721 cells, which was reduced by CaMKII or ERK inhibition; ii) induced ERK activation was prevented by KN93; and iii) promoted SMMC7721 cell proliferation, which was greatly inhibited by axitinib, KN93 and PD98059. In conclusion, the results indicated that insufficient RFA promotes SMMC7721 cell proliferation by activating CaMKII/ERK-dependent VEGF overexpression. PMID- 25789064 TI - Bilateral synchronous adrenal metastases of renal cell carcinoma: A case report and review of the literature. AB - Renal cell carcinomas (RCCs) metastasize to the adrenal glands via various mechanisms, including lymphatic vessel arterial embolism and retrograde venous embolism. The rate of ipsilateral metastasis is 3-5% and the rate of contralateral metastasis is ~0.7%, however, synchronous bilateral adrenal metastases are extremely rare. Therefore, the optimal diagnosis and treatment strategy for this condition is yet to be thoroughly defined. In the present study, a 50-year-old male patient presented with right flank pain. Ultrasonography (US) revealed a right renal mass and bilateral adrenal metastases, and a computerized tomography (CT) scan determined the size of the lesions: An 86*83*66-mm mass in the lower pole of the right kidney, an 18*12*10 mm mass in the right adrenal gland, and a 69*51*53-mm mass in the left adrenal gland with central necrosis and peripheral contrast uptake. A US-guided biopsy was performed which determined a diagnosis of right RCC and bilateral synchronous adrenal metastasis. Immunohistochemical examination of the biopsy revealed clear cell carcinoma (Fuhrman grade, III). Consequently, right radical nephrectomy, right partial adrenalectomy (with frozen section examination) and left adrenalectomy were planned. The bilateral synchronous adrenal metastases posed a challenge in the diagnosis and treatment of the disease, as there is no standard approach in the literature for the treatment of such patients. However, metastasectomy was selected, as it appears to be the most effective treatment strategy for increasing the rate of cancer-specific survival. As an adrenal mass was present in the current patient, a hormonal examination was recommended and an adrenal-preserving minimally invasive surgical procedure using frozen section examination during surgery was particularly important to prevent the patient from developing adrenal insufficiency. PMID- 25789065 TI - Impact of comorbidity on lung cancer mortality - a report from the Liverpool Lung Project. AB - The aim of the present study was to apply the Charlson comorbidity index (CCI) to evaluate the impact of comorbidity on lung cancer mortality in individuals not exhibiting lung cancer at the commencement of follow-up. Data from 9,579 participants without lung cancer were extracted from the Liverpool Lung Project between 1999 and 2010 and linked to the Hospital Episode Statistics database. The occurrence of comorbidities was assessed one year prior to the individual inclusion date. CCI scores were computed and Cox regression analysis was used to evaluate the association between comorbidity and lung cancer mortality using a competitive risk approach. During a median follow-up of 11 years, 1,320/9,579 (13.7%) individuals developed lung cancer, of which 886 (67.1%) succumbed to lung cancer and 875 of the 9,579 individuals (9.1%) succumbed due to other causes. The severity of comorbidity was associated with higher lung cancer-specific mortality; low to moderate comorbidity exhibited a hazard ratio (HR) of 2.86 [95% confidence interval (CI), 1.17-7.02] and severe comorbidity exhibited an HR of 5.16 (95% CI, 2.07-12.89). Furthermore, the CCI score determined that the severity of comorbidity increased the risk of lung cancer-specific mortality. Thus, CCI score is a good predictor of lung cancer-specific mortality and the use of comorbidity burdens in the clinical management of lung cancer is recommended. PMID- 25789066 TI - A let-7b binding site SNP in the 3'-UTR of the Bcl-xL gene enhances resistance to 5-fluorouracil and doxorubicin in breast cancer cells. AB - The development of acquired resistance to chemotherapy is a major obstacle in the successful treatment of cancer. In breast cancer cells, B-cell lymphoma-extra large (Bcl-xL) is involved in the development of resistance to various chemotherapeutic agents; therefore, preliminary biological prediction was performed to identify a putative binding site for let-7b in the 3'-untranslated region (UTR) of the Bcl-xL gene and a single nucleotide polymorphism (SNP) within this binding region. The present study investigated the association between the SNP rs3208684 A>C and chemotherapeutic agent resistance in breast cancer cells. The data indicated that let-7b negatively regulates the expression of Bcl-xL and appears to sensitize MCF-7 cells to the chemotherapeutic agents 5-fluorouracil (5 FU) and doxorubicin. Furthermore, the SNP rs3208684 A>C was demonstrated to enhance Bcl-xL protein expression by disrupting the binding of let-7b to the 3' UTR of Bcl-xL and, in MCF-7 cells, overexpression of let-7b in the presence of a mutant Bcl-xL 3'-UTR (C allele) significantly increased 5-FU and doxorubicin resistance. Thus, the results of the present study demonstrate that the SNP rs3208684 A>C may upregulate Bcl-xL protein expression and enhance the resistance of the MCF-7 cells to 5-FU and doxorubicin by decreasing the binding of let-7b to the 3'-UTR of Bcl-xL. PMID- 25789067 TI - Null genotypes of glutathione S-transferase MU1 and glutathione S-transferase theta1 are associated with osteosarcoma risk: A meta-analysis. AB - Glutathione S-transferase (GST) genetic polymorphisms has been reported to be associated with osteosarcoma; however, the results of previous studies are conflicting. Thus, in the present study, a meta-analysis was conducted to investigate the effects of GSTM1 and GSTT1 polymorphisms on osteosarcoma risk. A literature search was performed in the PubMed, Cochrane Library and China National Knowledge Infrastructure databases to identify case-control studies published prior to March 2014. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In addition, Begg's test was used to measure publication bias. Sensitivity analysis were performed to ensure the accuracy of the results. The meta-analysis results demonstrated no significant association between the null genotype of GSTM1 and osteosarcoma risk (OR=0.83; 95% CI, 0.37-1.85). By contrast, the results revealed a significant association for the comparison of null vs. non-null genotypes of GSTT1 (OR=1.54; 95% CI, 1.09-2.19). In conclusion, the GSTT1 null genotype may be associated with an increased risk of developing osteosarcoma. Further studies with larger sample sizes and well-designed methodologies are required to verify these conclusions. PMID- 25789068 TI - Magnetic resonance cholangiopancreatography: Comparison of two- and three dimensional sequences for the assessment of pancreatic cystic lesions. AB - The present study aimed to compare two-dimensional (2D) and three-dimensional (3D) magnetic resonance cholangiopancreatography (MRCP) for the assessment of pancreatic cystic lesions. Between February 2009 and December 2011, 35 patients that had been diagnosed with pancreatic cystic lesions, which was confirmed by surgery and pathology, underwent pre-operative 2D or 3D MRCP for pre-operative evaluation. In the present study, the quality of these 2D and 3D MRCP images, the visualization of the features of the cystic lesions, visualization of the pancreatic main duct and prediction of ductal communication with the cystic lesions were evaluated and compared using statistical software. The 3D MRCP images were determined to be of higher quality compared with the 2D MRCP images. The features of the cystic lesions were visualized better on 3D MRCP compared with 2D MRCP. The same capability for the visualization of the segment of the pancreatic main duct was exhibited by 3D and 2D MRCP. There was no significant difference between the area under the receiver operating characteristic curve values of 2D and 3D MRCP, which assessed the prediction of communication between cystic lesions and the pancreatic main duct. It was concluded that, compared with 2D MRCP, 3D MRCP provides an improved assessment of pancreatic cystic lesions, but does not exhibit an improved capability for the visualization of the pancreatic main duct or for the prediction of communication between cystic lesions and the pancreatic main duct. PMID- 25789069 TI - Efficacy of TCH/TEC neoadjuvant chemotherapy for the treatment of HER-2 overexpressing breast cancer. AB - The aim of the present study was to observe the efficacy of neoadjuvant trastuzumab combined with docetaxel and carboplatin (TCH), and docetaxel, epirubicin and cyclophosphamide (TEC) chemotherapy in human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer. The total cohort of 64 cases of HER-2-overexpressing breast cancer patients was divided into two groups according to their treatment preferences: The TCH group, consisting of 39 patients, and the TEC group, consisting of 25 patients. The neoadjuvant chemotherapy was continued for six cycles prior to comparison of the treatment efficacy. The TCG and TEC groups exhibited an overall response rate of 94.9 and 72.0% (37/39 and 18/25 cases; P<0.05), respectively, and a pathological complete response (pCR; defined as the presence of no invasive or in situ residual tumors in the breast) rate of 69.2 and 32.0% (27/39 and 8/25 cases; P<0.05), respectively. Furthermore, no significant differences were identified between the two groups of patients in terms of adverse reactions, such as cardiac dysfunction, bone marrow suppression and liver function impairment. In the present study, the treatment of HER-2-overexpressing breast cancer patients with TCH neoadjuvant chemotherapy demonstrated more favorable efficacy and a higher pCR rate when compared with the TEC-treated group. PMID- 25789070 TI - Clinical implications of insulin-like growth factor II mRNA-binding protein 3 expression in non-small cell lung carcinoma. AB - In order to examine the role of insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression for the prognostic evaluation of non-small cell lung carcinoma (NSCLC), a total of 186 breast cancer patients, with adjacent non-tumor lung tissues, were selected for immunohistochemical staining of IMP3 protein. The NSCLC tissues and paired adjacent non-tumor tissues of six patients were quantified using reverse transcription quantitative polymerase chain reaction. The correlations between IMP3 overexpression and the clinical features of NSCLC were evaluated using the chi2 test and Fisher's exact test. The survival rate was calculated using the Kaplan-Meier method, and the association between prognostic factors and patient survival was also analyzed by Cox's proportional hazards models. The results showed that IMP3 protein exhibited a mainly cytoplasmic staining pattern in the NSCLC tissues. The positive rate of IMP3 protein expression was 74.7% (139/186) in the NSCLC tissues and was significantly higher than the rate of 19.9% (37/186) in the adjacent non-tumor tissues. The expression rate of the NQO1 protein was correlated with a large tumor size, poor differentiation, lymph node metastasis, late clinical stage, and disease-free and overall survival rates in the NSCLC patients. In the early- and late-stage NSCLC groups, the disease-free and overall survival rates of the patients with IMP3 expression were significantly lower than those of the patients without IMP3 expression. Further analysis using Cox's proportional hazard regression model revealed that IMP3 expression was a significant independent hazard factor for the overall survival rate of patients with NSCLC. In conclusion, the present study found that IMP3 plays a significant role in the progression of NSCLC, and that it may potentially be used as an independent biomarker for prognostic evaluation of the cancer. PMID- 25789071 TI - Primitive neuroectodermal tumor in the spinal canal: A case report. AB - Primitive neuroectodermal tumors (PNETs) are rare tumors of uncertain histogenesis that occur predominantly in children and young adults. The current study reports a case of PNET in a 60-year-old female, which presented clinically as an intraspinal tumor, causing symptoms of lower back pain, numbness and pain in the right lower extremity. The patient underwent tumorectomy. Following primary therapy, the symptoms of spinal cord compression were relieved. The patient underwent several courses of radiotherapy following surgery but refused to continue with chemotherapy. After a further four months, the tumors recurred and the patient succumbed to the disease. PMID- 25789072 TI - Primary renal angiosarcoma with progressive clinical course despite surgical and adjuvant treatment: A case report. AB - Angiosarcoma is an extremely rare, high-grade malignancy, which accounts for <2% of all soft-tissue sarcomas. Cases of primary renal angiosarcoma represent 1% of these. Angiosarcomas involving the kidney usually originate from metastatic skin lesions or primary visceral lesions and most often occur in the sixth and seventh decades of life. The present study describes a case of primary renal angiosarcoma that presented as a large right-sided renal mass with symptoms of flank pain. Despite surgical removal of the tumor, recurrent disease with associated lung metastases was identified at the surgical site following adjuvant chemotherapy. The patient succumbed to the disease 13 months after the diagnosis. PMID- 25789073 TI - Enhancing effects of indirubin on the arsenic disulfide-induced apoptosis of human diffuse large B-cell lymphoma cells. AB - The aim of the present study was to investigate the indirubin-enhanced effects of arsenic disulfide (As2S2) on the proliferation and apoptosis of diffuse large B cell lymphoma (DLBCL) cells in order to identify an optimum combination therapy. The human DLBCL cells, LY1 and LY8, were treated with different concentrations of indirubin for 24, 48 and 72 h. Next, the cells were treated with 10 MUM As2S2 or a combination of 10 MUM As2S2 and 20 MUM indirubin for 48 h. Cell proliferation inhibition was detected using cell counting kit-8 and cell apoptosis was determined using flow cytometry. The expression levels of Bcl-2, Bcl-2-associated X protein (Bax) and caspase-3 were analyzed by quantitative polymerase chain reaction (qPCR) and western blotting. The DLBCL cell viability exhibited no significant changes at 24, 48 or 72 h with increasing indirubin concentration. In addition, the apoptotic rates of the LY1 and LY8 cells demonstrated no noticeable effects at 48 h with increasing indirubin concentration. Following treatment with the combination of indirubin and As2S2, the inhibitory and apoptotic rates of the cells were notably increased compared with those of the As2S2-treated group. The qPCR results revealed that indirubin alone had no enhancing effect upon the Bax/Bcl-2 mRNA expression ratio and caspase-3 mRNA expression. Western blot analysis revealed that indirubin alone had an enhancing effect upon the Bax/Bcl-2 protein ratio and procaspase-3 protein expression. In addition, the results demonstrated that the 21-KDa Bax protein was proteolytically cleaved into an 18 KDa Bax in the DLBCL cells treated with the combination of indirubin and As2S2. Indirubin alone did not inhibit proliferation or induce the apoptosis of the LY1 and LY8 cells. However, the combination of indirubin and As2S2 yielded enhancing effects. Therefore, the results of the present study demonstrated that with regard to antitumor activities, As2S2 served as the principal drug, whereas indirubin served as the adjuvant drug. The enhancing effect was due, in part, to the induction of the mitochondrial apoptotic pathway, which involves the cleavage of Bax. PMID- 25789074 TI - Glutathione S-transferase theta1 polymorphism contributes to lung cancer susceptibility: A meta-analysis of 26 case-control studies. AB - The GSTT1 gene encodes a key enzyme involved in the metabolism of xenobiotics and its polymorphisms have been associated with individual susceptibility to various malignancies. Numerous molecular epidemiological studies have been performed to investigate the association between GSTT1 gene polymorphisms and lung cancer susceptibility; however, the results of previous studies were inconsistent. Therefore, the aim of the present study was to conduct a meta-analysis in order to derive a more precise estimation of the association in the East Asian populations. The meta-analysis included 7,415 lung cancer cases and 6,084 controls from 26 published studies in East Asia, which were selected from the PubMed and China National Knowledge Infrastructure databases, up to March 20, 2014. Using crude odds ratios (ORs) with 95% confidence intervals (CIs), a statistically significant association was identified between the GSTT1 null genotype and lung cancer in the East Asian populations (OR=1.17; 95% CI, 1.09 1.25; Pheterogeneity=0.003). Furthermore, subgroup analyses revealed that the lung cancer risk in smokers carrying the GSTT1 null genotype was significantly increased compared with non-smokers (OR=1.71; 95% CI, 1.04-2.81; Pheterogeneity=0.002). Thus, the GSTT1 null genotype may increase the risk of lung cancer among the East Asian populations. PMID- 25789075 TI - Myelodysplastic syndrome with neutrophilic panniculitis: A report of two cases and a literature review. AB - Myelodysplastic syndrome (MDS) associated with neutrophilic panniculitis (NP) is rare. To the best of our knowledge, there are only five previously reported cases of MDS associated with NP, consisting of four adults and a young male. The present study reviews the literature of the previously reported cases and presents two case reports of adult male patients who were initially diagnosed as MDS. The two patients presented with a sudden onset of fever without infection and erythematous indurated papules. The patients were diagnosed with NP by skin biopsy and their symptoms disappeared completely following treatment with systemic corticosteroids. NP may be an independent high-risk factor for MDS. However, due to the rarity of such cases, the exact pathogenesis of NP associated with MDS requires further investigation. PMID- 25789076 TI - Dasatinib as the salvage therapy for chronic myeloid leukemia with blast crisis and central nervous system involvement: A case report. AB - BCR-ABL tyrosine-kinase inhibitors are the first-line therapy for the majority of patients with chronic myelogenous leukemia (CML). Up to 20% of patients who have imatinib-treated CML in blast crisis (BC) experience a relapse in the central nervous system (CNS) due to the poor penetration of the drug by the blood-brain barrier. The present case reports a successful experience of using dasatinib based combination therapy to treat a 22-year-old female who presented with initial symptoms of intermittent fever and easy bruising under the diagnosis of CML in BC. Although the patient eventually succumbed to profound sepsis, the CNS involvement was treated successfully using dasatinib-based combination therapy (cranial radiation and de-escalated intrathecal chemotherapy). This case demonstrates that dasatinib may be a viable option for those who are not medically fit for or are otherwise unwilling to receive high-dose chemotherapy. It appears that dose intensity is essential for optimal efficacy and should be maintained at 150 mg daily as far as possible. PMID- 25789077 TI - Hedyotis diffusa Willd. extract suppresses proliferation and induces apoptosis via IL-6-inducible STAT3 pathway inactivation in human colorectal cancer cells. AB - Recent studies have indicated that the inflammatory microenvironment plays a significant role in colorectal cancer (CRC). The interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway mediates the proliferative and anti-apoptotic activities required for oncogenesis under inflammatory conditions; thus, suppressing tumor growth by targeting the IL 6/STAT3 pathway is a promising therapeutic strategy for CRC. Our previous study reported that the ethanol extract obtained from Hedyotis diffusa Willd. (EEHDW) can induce apoptosis, and inhibit the proliferation of colon cancer cells and tumor angiogenesis by modulating various signaling pathways; however, less is known regarding the activity of EEHDW in a cancer-promoting inflammatory environment. Therefore, the present study investigated whether EEHDW inhibits the growth of the CRC HT-29 cell line via the IL-6/STAT3 signaling pathway. Pretreatment of HT-29 cells with IL-6 led to an increase in cell viability, colony formation and phosphorylated STAT3 (p-STAT3) expression. Treatment of these cells with EEHDW prior to IL-6 stimulation resulted in a significant reduction in the IL-6-induced phosphorylation of STAT3. In addition, EEHDW treatment significantly reduced the mRNA expression levels of cyclin D1, cyclin dependent kinase 4 and B-cell lymphoma-2 (Bcl-2), and upregulated the expression levels of Bcl-2-associated X protein (P<0.05), which are important target genes of the IL-6/STAT3 pathway. These findings strongly indicated that EEHDW suppresses tumor cell growth and induces the apoptosis of human CRC cells via inactivation of the IL-6/STAT3 signaling pathway. PMID- 25789078 TI - MicroRNA-125b suppresses the migration and invasion of hepatocellular carcinoma cells by targeting transcriptional coactivator with PDZ-binding motif. AB - MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that serve an important function in carcinogenesis and tumor progression. The present study investigated the roles and mechanisms of miRNA-125b (miR-125b) in human hepatocellular carcinoma (HCC). miR-125b was significantly downregulated in the examined HCC tissues and cell lines. Overexpression of miR-125b reduced HCC cell migration and invasion. By contrast, inhibition of miR-125b expression significantly accelerated HCC cell migration and invasion. In addition, the present study identified transcriptional coactivator with PDZ-binding motif (TAZ) as a functional downstream target of miR-125b. Furthermore, overexpression of TAZ impaired miR-125b-induced inhibition of invasion in HCC cells. The current study demonstrated that miR-125b may be involved in the tumorigenesis of HCC at least in part by the suppression of TAZ. PMID- 25789079 TI - The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth. AB - BACKGROUND: Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children. RESULTS: Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality. CONCLUSIONS: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature. PMID- 25789080 TI - The role of microRNA-1246 in the regulation of B cell activation and the pathogenesis of systemic lupus erythematosus. AB - BACKGROUND: The pathogenesis of systemic lupus erythematosus (SLE) has not yet been completely elucidated. One of the hallmarks of SLE is the production of autoantibodies by uncontrolled over-activated B cells. Early B cell factor 1 (EBF1) contributes to the development, activation, and proliferation of B cells through activation of the AKT signaling pathway. Accumulating evidence has demonstrated that several microRNAs (miRNAs) contribute to the pathogenesis of autoimmune diseases through the regulation of B cells in SLE. We aim to investigate the expression patterns of miR-1246 in B cells and its contribution to pathogenesis of SLE. RESULTS: Our results showed that the expression of miR 1246 was significantly decreased in B cells from SLE patients. We verified that miR-1246 specifically targeted the EBF1 messenger RNA (mRNA) by interacting with its 3'-untranslated region (3'-UTR) and regulated the expression of EBF1. Transfection of miR-1246 inhibitors into healthy B cells upregulated the expression of EBF1, enhanced B cell function, and increased the production of B cell surface co-stimulatory molecules CD40, CD80, and CD86. We also observed that abnormal activation of the AKT signaling pathway was associated with decreased P53 expression, leading to the downregulation of the miR-1246 expression; and upregulation of the miR-1246 expression reversed the responsiveness of B cells by inhibiting EBF1 expression. CONCLUSIONS: Activated B cells in lupus could decrease the expression of miR-1246 through the AKT-P53 signaling pathway, which in turn enhances the expression of EBF1, thereby promoting further activation of B cells. Conversely, upregulation of miR-1246 could interrupt this amplification pathway. Our findings thus provide a theoretical framework towards the research of novel biological targets in SLE treatment. PMID- 25789081 TI - Dry olive leaf extract counteracts L-thyroxine-induced genotoxicity in human peripheral blood leukocytes in vitro. AB - The thyroid hormones change the rate of basal metabolism, modulating the consumption of oxygen and causing production of reactive oxygen species, which leads to the development of oxidative stress and DNA strand breaks. Olive (Olea europaea L.) leaf contains many potentially bioactive compounds, making it one of the most potent natural antioxidants. The objective of this study was to evaluate the genotoxicity of L-thyroxine and to investigate antioxidative and antigenotoxic potential of the standardized oleuropein-rich dry olive leaf extract (DOLE) against hydrogen peroxide and L-thyroxine-induced DNA damage in human peripheral blood leukocytes by using the comet assay. Various concentrations of the extract were tested with both DNA damage inducers, under two different experimental conditions, pretreatment and posttreatment. Results indicate that L-thyroxine exhibited genotoxic effect and that DOLE displayed protective effect against thyroxine-induced genotoxicity. The number of cells with DNA damage, was significantly reduced, in both pretreated and posttreated samples (P < 0.05). Comparing the beneficial effect of all tested concentrations of DOLE, in both experimental protocols, it appears that extract was more effective in reducing DNA damage in the pretreatment, exhibiting protective role against L-thyroxine effect. This feature of DOLE can be explained by its capacity to act as potent free radical scavenger. PMID- 25789084 TI - ODF RECONSTRUCTION IN Q-BALL IMAGING WITH SOLID ANGLE CONSIDERATION. AB - Q-ball imaging (QBI) is a high angular resolution diffusion imaging (HARDI) technique which has been proven very successful in resolving multiple intravoxel fiber orientations in MR images. The standard computation of the orientation distribution function (ODF, the probability of diffusion in a given direction) from q-ball uses linear radial projection, neglecting the change in the volume element along the ray, thereby resulting in distributions different from the true ODFs. For instance, they are not normalized or as sharp as expected, and generally require post-processing, such as sharpening or spherical deconvolution. In this paper, we consider the mathematically correct definition of the ODF and derive a closed-form expression for it in QBI. The derived ODF is dimensionless and normalized, and can be efficiently computed from q-ball acquisition protocols. We describe our proposed method and demonstrate its significantly improved performance on artificial data and real HARDI volumes. PMID- 25789082 TI - Coenzyme Q10 inhibits the aging of mesenchymal stem cells induced by D-galactose through Akt/mTOR signaling. AB - Increasing evidences indicate that reactive oxygen species are the main factor promoting stem cell aging. Recent studies have demonstrated that coenzyme Q10 (CoQ10) plays a positive role in organ and cellular aging. However, the potential for CoQ10 to protect stem cell aging has not been fully evaluated, and the mechanisms of cell senescence inhibited by CoQ10 are still poorly understood. Our previous study had indicated that D-galactose (D-gal) can remarkably induce mesenchymal stem cell (MSC) aging through promoting intracellular ROS generation. In this study, we showed that CoQ10 could significantly inhibit MSC aging induced by D-gal. Moreover, in the CoQ10 group, the expression of p-Akt and p-mTOR was clearly reduced compared with that in the D-gal group. However, after Akt activating by CA-Akt plasmid, the senescence-cell number in the CoQ10 group was significantly higher than that in the control group. These results indicated that CoQ10 could inhibit D-gal-induced MSC aging through the Akt/mTOR signaling. PMID- 25789083 TI - Physical exercise and redox balance in type 2 diabetics: effects of moderate training on biomarkers of oxidative stress and DNA damage evaluated through comet assay. AB - OBJECTIVE: Hyperglycemia leads to increased production of reactive oxygen species (ROS) in type 2 diabetes, which reduces cellular antioxidant defenses and induces DNA lesions. The aim of this study was to investigate the effects on redox homeostasis and DNA oxidative damage of exercise training in patients with type 2 diabetes compared with nondiabetic individuals. METHODS AND RESULTS: 12 sedentary type 2 diabetic males (62.1 +/- 4.3 yrs) and 12 sedentary healthy males (61.7 +/- 3.9 yrs) were exposed to 4-month moderate training, 3 times per week, to evaluate the effect on plasma biomarkers of oxidative stress malondialdehyde and antioxidant status (GSSG, GSH/GSSG, and ascorbic acid) as well as basal and H2O2 induced DNA damage trough alkaline comet assay in peripheral blood lymphocytes. After training, glutathione and ascorbic acid levels increased in both groups, but only in diabetics the malondialdehyde as well as the DNA damage decreased. CONCLUSION: Our study demonstrates for the first time that moderate exercise training is not only effective in improving the redox homeostasis, through an increase of the endogenous antioxidant defences in healthy as well as in diabetic patients, but also, specifically in diabetic patients, effective in lowering the susceptibility to oxidative DNA damage and the lipid peroxidation levels. PMID- 25789085 TI - Laparoscopic liver resection: Toward a truly minimally invasive approach. AB - In the surgical treatment of hepatocellular carcinoma and colorectal liver metastasis, it is important to preserve sufficient liver volume after resection in order to avoid post-hepatectomy liver sufficiency and to increase the feasibility of repeated hepatectomy in case of intrahepatic recurrence. Parenchyma-sparing approach, which minimizes the extent of resection while obtaining sufficient surgical margins, has been developed in open hepatectomy. Although this approach can possibly have positive impacts on morbidity and mortality, it is not popular in laparoscopic approach because parenchyma-sparing resection is technically demanding especially by laparoscopy due to its intricate curved transection planes. "Small incision, big resection" is the words to caution laparoscopic surgeons against an easygoing trend to seek for a superficial minimal-invasiveness rather than substantial patient-benefits. Minimal parenchyma excision is often more important than minimal incision. Recently, several reports have shown that technical evolution and accumulation of experience allow surgeons to overcome the hurdle in laparoscopic parenchyma sparing resection of difficult-to-access liver lesions in posterosuperior segments, paracaval portion, and central liver. Laparoscopic surgeons should now seek for the possibility of laparoscopic parenchyma-sparing hepatectomy as open approach can, which we believe is beneficial for patients rather than just a small incision and lead laparoscopic hepatectomy toward a truly minimally invasive approach. PMID- 25789086 TI - Intentional ingestions of foreign objects among prisoners: A review. AB - The intentional ingestion of foreign objects (IIFO) is described more commonly in prison populations than in the general population, with an estimated annual incidence of 1 in 1900 inmates in our state correctional facilities. Incidents often involve ingestion of small metal objects (e.g., paperclips, razor blades) or other commonly available items like pens or eating utensils. Despite ingestion of relatively sharp objects, most episodes can be clinically managed with either observation or endoscopy. Surgery should be reserved for those with signs or symptoms of gastrointestinal perforation or obstruction. For those with a history of IIFO, efforts should focus on prevention of recurrence as subsequent episodes are associated with higher morbidity, significant healthcare and security costs. The pattern of IIFO is often repetitive, with escalation both in frequency of ingestions and in number of items ingested. Little is known about successful prevention strategies, but efforts to monitor patients and provide psychiatric care are potential best-practice strategies. This article aims to provide state of-the art review on the topic, followed by a set of basic recommendations. PMID- 25789087 TI - Therapeutic upper gastrointestinal tract endoscopy in Paediatric Gastroenterology. AB - Since the first report of use of endoscopy in children in the 1970s, there has seen an exponential growth in published experience and innovation in the field. In this review article we focus on modern age therapeutic endoscopy practice, explaining use of traditional as well as new and innovative techniques, for diagnosis and treatment of diseases in the paediatric upper gastrointestinal tract. PMID- 25789088 TI - Endoscopic management for congenital esophageal stenosis: A systematic review. AB - Congenital esophageal stenosis (CES) is an extremely rare malformation, and standard treatment have not been completely established. By years of clinical research, evidence has been accumulated. We conducted systematic review to assess outcomes of the treatment for CES, especially the role of endoscopic modalities. A total of 144 literatures were screened and reviewed. CES was categorized in fibromuscular thickening, tracheobronchial remnants (TBR) and membranous web, and the frequency was 54%, 30% and 16%, respectively. Therapeutic option includes surgery and dilatation, and surgery tends to be reserved for ineffective dilatation. An essential point is that dilatation for TBR type of CES has low success rate and high rate of perforation. TBR can be distinguished by using endoscopic ultrasonography (EUS). Overall success rate of dilatation for CES with or without case selection by using EUS was 90% and 29%, respectively. Overall rate of perforation with or without case selection was 7% and 24%, respectively. By case selection using EUS, high success rate with low rate of perforation could be achieved. In conclusion, endoscopic dilatation has been established as a primary therapy for CES except TBR type. Repetitive dilatation with gradual step up might be one of safe ways to minimize the risk of perforation. PMID- 25789089 TI - Endoscopic treatment for gastrointestinal stromal tumor: Advantages and hurdles. AB - One of the most prominent characteristics of gastrointestinal stromal tumors (GISTs) is their unpredictable and variable behavior. GISTs are not classified as "benign" or "malignant" but are rather stratified by their associated clinical risk of malignancy as determined by tumor size, location, and number of mitoses identified during surgical histology. The difficulty in assessing the malignant potential and prognoses of GISTs as well as the increasing incidence of "incidental GISTs" presents challenges to gastroenterologists. Recently, endoscopic enucleation has been actively performed as both a diagnostic and therapeutic intervention for GISTs. Endoscopic enucleation has several advantages, including keeping the stomach intact after the removal of GISTs, a relatively short hospital stay, a conscious sedation procedure, relatively low cost, and fewer human resources required compared with surgery. However, a low complete resection rate and the risk of perforation could reduce the overall advantages of this procedure. Endoscopic full-thickness resection appears to achieve a very high R0 resection rate. However, this technique absolutely requires a very skilled operator. Moreover, there is a risk of peritoneal seeding due to large active perforation. Laparoscopy endoscopy collaborations have been applied for more stable and pathologically acceptable management. These collaborative procedures have produced excellent outcomes. Many procedures have been developed and attempted because they were technically possible. However, we should first consider the theoretical basis for each technique. Until the efficacy and safety of sole endoscopic access are proved, the laparoscopy endoscopy collaborative procedure appears to be an appropriate method for minimally destructive GIST surgery. PMID- 25789090 TI - Techniques and efficacy of flexible endoscopic therapy of Zenker's diverticulum. AB - Zenker's diverticulum (ZD) is an abnormal hypopharyngeal pouch often presenting with dysphagia. Treatment is often sought with invasive surgical management of the diverticulum being the only mode of definitive therapy. Primarily done by an open transcervical approach in the past, nowadays treatment is usually provided by otolaryngologists using a less invasive trans-oral technique with a rigid endoscope. When first described, this method grew into acceptance quickly due to its similar efficacy and vastly improved safety profile compared to the open transcervical approach. However, the main limitation with this approach is that it may not be suitable for all patients. Nonetheless, progress in the field of natural orifice endoscopic surgery over the last 10-20 years has led to the increase in utilization of the flexible endoscope in the treatment of ZD. Primarily performed by interventional gastroenterologists, this approach overcomes the prior limitation of its surgical counterpart and allows adequate visualization of the diverticulum independent of the patient's body habitus. Additionally, it may be performed without the use of general anesthesia and in an outpatient setting, thus further increasing the utility of this modality, especially in elderly patients with other comorbidities. Today, results in more than 600 patients have been described in various published case series using different techniques and devices demonstrating a high percentage of clinical symptom resolution with low rates of adverse events. In this article, we present our experience with flexible endoscopic therapy of Zenker's diverticulum and highlight the endoscopic technique, outcomes and adverse events related to this minimally invasive modality. PMID- 25789091 TI - Endosonography in the diagnosis and management of pancreatic cysts. AB - Rapid advances in radiologic technology and increased cross-sectional imaging have led to a sharp rise in incidental discoveries of pancreatic cystic lesions. These cystic lesions include non-neoplastic cysts with no risk of malignancy, neoplastic non-mucinous serous cystadenomas with little or no risk of malignancy, as well as neoplastic mucinous cysts and solid pseudopapillary neoplasms both with varying risk of malignancy. Accurate diagnosis is imperative as management is guided by symptoms and risk of malignancy. Endoscopic ultrasound (EUS) allows high resolution evaluation of cyst morphology and precise guidance for fine needle aspiration (FNA) of cyst fluid for cytological, chemical and molecular analysis. Initially, clinical evaluation and radiologic imaging, preferably with magnetic resonance imaging of the pancreas and magnetic resonance cholangiopancreatography, are performed. In asymptomatic patients where diagnosis is unclear and malignant risk is indeterminate, EUS-FNA should be used to confirm the presence or absence of high-risk features, differentiate mucinous from non mucinous lesions, and diagnose malignancy. After analyzing the cyst fluid for viscosity, cyst fluid carcinoembryonic antigen, amylase, and cyst wall cytology should be obtained. DNA analysis may add useful information in diagnosing mucinous cysts when the previous studies are indeterminate. New molecular biomarkers are being investigated to improve diagnostic capabilities and management decisions in these challenging cystic lesions. Current guidelines recommend surgical pancreatic resection as the standard of care for symptomatic cysts and those with high-risk features associated with malignancy. EUS-guided cyst ablation is a promising minimally invasive, relatively low-risk alternative to both surgery and surveillance. PMID- 25789092 TI - Advanced endoscopic imaging to improve adenoma detection. AB - Advanced endoscopic imaging is revolutionizing our way on how to diagnose and treat colorectal lesions. Within recent years a variety of modern endoscopic imaging techniques was introduced to improve adenoma detection rates. Those include high-definition imaging, dye-less chromoendoscopy techniques and novel, highly flexible endoscopes, some of them equipped with balloons or multiple lenses in order to improve adenoma detection rates. In this review we will focus on the newest developments in the field of colonoscopic imaging to improve adenoma detection rates. Described techniques include high-definition imaging, optical chromoendoscopy techniques, virtual chromoendoscopy techniques, the Third Eye Retroscope and other retroviewing devices, the G-EYE endoscope and the Full Spectrum Endoscopy-system. PMID- 25789093 TI - New endoscopic imaging techniques in surveillance of inflammatory bowel disease. AB - Endoscopy plays a crucial role in the management of inflammatory bowel disease (IBD). Advances imaging techniques allow visualization of mucosal details, tissue characteristics and cellular alteration. In particular chromoendoscopy, magnification endoscopy, confocal laser endomicroscopy and endocytoscopy seem to have the possibility to radically modify the approach to surveillance and decision making. Dye-based chromoendoscopy (DBC) and magnification chromoendoscopy improve detection of dysplasia, and evaluation of inflammatory activity and extension of ulcerative colitis and are thus considered the standard of care. Dye-less chromoendoscopy could probably replace conventional DBC for surveillance. Narrow band imaging and i-scan have shown to improve activity and extent assessment in comparison to white-light endoscopy. Confocal laser endomicroscopy (CLE) can detect more dysplastic lesions in surveillance colonoscopy and predict neoplastic and inflammatory changes with high accuracy compared to histology. This technology is best used in conjunction with chromoendoscopy, narrow-band imaging, or autofluorescence because of its minute scanning area. This combination is useful for appropriate tissue classification of mucosal lesions already detected by standard or optically enhanced endoscopy. The best combination for IBD surveillance appear to be chromoendoscopy for identification of areas of suspicion, with further examination with CLE to detect intraepithelial neoplasia. However cost, availability, and experience are still an issue. PMID- 25789094 TI - Peroral endoscopic myotomy: Time to change our opinion regarding the treatment of achalasia? AB - Peroral endoscopic myotomy (POEM) is a new endoscopic treatment for achalasia. Compared to the classical surgical myotomy, POEM brings at least the advantage of minimal invasiveness. The data provided until now suggest that POEM offers excellent short-term symptom resolution, with improvement of dysphagia in more than 90% of treated patients, with encouraging manometric outcomes and low incidence of postprocedural gastroesophageal reflux. The effectiveness of this novel therapy requires long-term follow-up and comparative studies with other treatment modalities for achalasia. This technique requires experts in interventional endoscopy, with a learning curve requiring more than 20 cases, including training on animal and cadaver models, and with a need for structured proctoring during the first cases. This review aims to summarize the data on the technique, outcomes, safety and learning curve of this new endoscopic treatment of achalasia. PMID- 25789095 TI - Examining the whole bowel, double balloon enteroscopy: Indications, diagnostic yield and complications. AB - Double balloon enteroscopy (DBE) is an advanced type of endoscopic procedure which brings the advantage of reaching the whole small bowel using anterograde or the retrograde route. This procedure is both diagnostic and interventional for a variety of small intestinal diseases, such as vascular lesions, tumors, polyps and involvement of inflammatory bowel diseases. Main indication is the diagnosis and treatment of mid-gastrointestinal bleeding according to the recent published data all over the world. The complication rates seem to be higher than conventional procedures but growing experience is lowering them and improving the procedure to be safe and well tolerated. This review is about the technique, indications, diagnostic importance and complications of DBE according to the literature growing since 2001. PMID- 25789096 TI - Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of kidney lesions: A review. AB - Traditionally, treatment of renal lesions is indicated based only on imaging features. Although controversy exists about tissue sampling from small renal masses, renal biopsy is indicated in some cases. In this review, we discuss the rationale for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and summarize the recent advances in this field, providing recommendations for the practicing clinician. The use of EUS-FNA appears to be a safe and feasible means of confirming or excluding malignancy. EUS allows assessment and biopsy of masses or lesions within both kidneys and related complications are rare. The main advantages of EUS-FNA are that it can be done as an outpatient procedure, with good results, minimal morbidity and a short hospital stay. Nevertheless, EUS-FNA of renal masses should be indicated only in selected cases, in which there is potential to decrease unnecessary treatment of small renal masses and to best select tumors for active surveillance and minimally invasive ablative therapies. Additionally, some renal lesions may be ineligible for EUS-guided biopsy because of anatomical limitations. EUS-FNA renal biopsy will probably be best applied to central anterior renal masses, while tumors on the posterior aspect of the kidney, percutaneous access will probably be superior. PMID- 25789097 TI - Head mass in chronic pancreatitis: Inflammatory or malignant. AB - Chronic pancreatitis increases the risk of developing pancreatic cancer. This often presents as a mass lesion in the head of pancreas. Mass lesion in the head of pancreas can also occur secondary to an inflammatory lesion. Recognising this is crucial to avoid unnecessary surgery. This is sometimes difficult as there is an overlap in clinical presentation and conventional computed tomography (CT) abdomen findings in inflammatory and malignant mass. Advances in imaging technologies like endoscopic ultrasound in conjunction with techniques like fine needle aspiration, contrast enhancement and elastography as well as multidetector row CT, magnetic resonance imaging and positron emission tomography scanning have been shown to help in distinguishing inflammatory and malignant mass. Research is ongoing to develop molecular techniques to help characterise focal pancreatic mass lesions. This paper reviews the current status of imaging and molecular techniques in differentiating a benign mass lesion in chronic pancreatitis and from malignancy. PMID- 25789098 TI - Collagenous gastritis: Review. AB - Collagenous gastritis is a rare disease characterized by the subepithelial deposition of collagen bands thicker than 10 MUm and the infiltration of inflammatory mononuclear cells in the lamina propria. Collagenous colitis and collagenous sprue have similar histological characteristics to collagenous gastritis and are thought to be part of the same disease entity. However, while collagenous colitis has become more common in the field of gastroenterology, presenting with clinical symptoms of chronic diarrhea in older patients, collagenous gastritis is rare. Since the disease was first reported in 1989, only 60 cases have been documented in the English literature. No safe and effective treatments have been identified from randomized, controlled trials. Therefore, better understanding of the disease and the reporting of more cases will help to establish diagnostic criteria and to develop therapeutic strategies. Therefore, here we review the clinical characteristics, endoscopic and histological findings, treatment, and clinical outcomes from case reports and case series published to date, and provide a summary of the latest information on the disease. This information will contribute to improved knowledge of collagenous gastritis so physicians can recognize and correctly diagnose the disease, and will help to develop a standard therapeutic strategy for future clinical trials. PMID- 25789099 TI - Endoscopic treatment of difficult extrahepatic bile duct stones, EPBD or EST: An anatomic view. AB - Large bile duct stone (> 10 mm) or multiple stones (>= 3) are challenging for endoscopists. Endoscopic sphincterotomy (EST) is a routine therapeutic endoscopic retrograde cholangiopancreatography (ERCP) procedure usually used. It is safe and effective, but severe perforation or massive bleeding are the main causes of mortality. Because of the permanent destroy of Oddi sphincter, the use of EST is still controversial. Endoscopic papillary balloon dilation (EPBD) gives another way to open the sphincter. Less incidence of bleeding, perforation and partly preserving the Oddi sphincter's function are the main advantages. But high incidence of post-ERCP pancreatitis becomes a predominant problem. According to the anatomical feature of Oddi sphincter, limited EST + EPBD seems a more reasonable procedure. Compared to the former two procedures, it makes the stone extraction process much easier with lower incidences of short-term and long-term complications. PMID- 25789100 TI - Rotational assisted endoscopic retrograde cholangiopancreatography in patients with reconstructive gastrointestinal surgical anatomy. AB - AIM: To evaluate the success rates of performing therapy utilizing a rotational assisted enteroscopy device in endoscopic retrograde cholangiopancreatography (ERCP) in surgically altered anatomy patients. METHODS: Between June 1, 2009 and November 8, 2012, we performed 42 ERCPs with the use of rotational enteroscopy for patients with altered anatomy (39 with gastric bypass Roux-en-Y, 2 with Billroth II gastrectomy, and 1 with hepaticojejunostomy associated with liver transplant). The indications for ERCP were: choledocholithiasis: 13 of 42 (30.9%), biliary obstruction suggested on imaging: 20 of 42 (47.6%), suspected sphincter of Oddi dysfunction: 4 of 42 (9.5%), abnormal liver enzymes: 1 of 42 (2.4%), ascending cholangitis: 2 of 42 (4.8%), and bile leak: 2 of 42 (4.8%). All procedures were completed with the Olympus SIF-Q180 enteroscope and the Endo-Ease Discovery SB overtube produced by Spirus Medical. RESULTS: Successful visualization of the major ampulla was accomplished in 32 of 42 procedures (76.2%). Cannulation of the bile duct was successful in 26 of 32 procedures reaching the major ampulla (81.3%). Successful therapeutic intervention was completed in 24 of 26 procedures in which the bile duct was cannulated (92.3%). The overall intention to treat success rate was 64.3%. In terms of cannulation success, the intention to treat success rate was 61.5%. Ten out of forty two patients (23.8%) required admission to the hospital after procedure for abdominal pain and nausea, and 3 of those 10 patients (7.1%) had a diagnosis of post-ERCP pancreatitis. The average hospital stay was 3 d. CONCLUSION: It is reasonable to consider an attempt at rotational assisted ERCP prior to a surgical intervention to alleviate biliary complications in patients with altered surgical anatomy. PMID- 25789101 TI - Endoscopic ultrasound-guided biliary intervention in patients with surgically altered anatomy. AB - AIM: To evaluate the efficacy of endoscopic ultrasound guided biliary drainage (EUS-BD) in patients with surgically altered anatomies. METHODS: We performed a search of the MEDLINE database for studies published between 2001 to July 2014 reporting on EUS-BD in patients with surgically altered anatomy using the terms "EUS drainage" and "altered anatomy". All relevant articles were accessed in full text. A manual search of the reference lists of relevant retrieved articles was also performed. Only full-text English papers were included. Data regarding age, gender, diagnosis, method of EUS-BD and intervention, type of altered anatomy, technical success, clinical success, and complications were extracted and collected. Anatomic alterations were categorized as: group 1, Billroth I; group 2, Billroth II; group 4, Roux-en-Y with gastric bypass; and group 3, all other types. RESULTS: Twenty three articles identified in the literature search, three reports were from the same group with different numbers of cases. In total, 101 cases of EUS-BD in patients with altered anatomy were identified. Twenty-seven cases had no information and were excluded. Seventy four cases were included for analysis. Data of EUS-BD in patients categorized as group 1, 2 and 4 were limited with 2, 3 and 6 cases with EUS-BD done respectively. Thirty four cases with EUS BD were reported in group 3. The pooled technical success, clinical success, and complication rates of all reports with available data were 89.18%, 91.07% and 17.5%, respectively. The results are similar to the reported outcomes of EUS-BD in general, however, with limited data of EUS-BD in patients with altered anatomy rendered it difficult to draw a firm conclusion. CONCLUSION: EUS-BD may be an option for patients with altered anatomy after a failed endoscopic-retrograde cholangiography in centers with expertise in EUS-BD procedures in a research setting. PMID- 25789102 TI - Esophageal papilloma: Flexible endoscopic ablation by radiofrequency. AB - Squamous papilloma of the esophagus is a rare benign lesion of the esophagus. Radiofrequency ablation is an established endoscopic technique for the eradication of Barrett esophagus. No cases of endoscopic ablation of esophageal papilloma by radiofrequency ablation (RFA) have been reported. We report a case of esophageal papilloma successfully treated with a single session of radiofrequency ablation. Endoscopic ablation of the lesion was achieved by radiofrequency using a new catheter inserted through the working channel of endoscope. The esophageal ablated tissue was removed by a specifically designed cup. Complete ablation was confirmed at 3 mo by endoscopy with biopsies. This case supports feasibility and safety of as a new potential indication for Barrx(TM) RFA in patients with esophageal papilloma. PMID- 25789103 TI - mTOR: Driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus. AB - The World Health Organization estimates that diabetes mellitus (DM) will become the seventh leading cause of death during the next two decades. DM affects approximately 350 million individuals worldwide and additional millions that remain undiagnosed are estimated to suffer from the complications of DM. Although the complications of DM can be seen throughout the body, the nervous, cardiac, and vascular systems can be significantly affected and lead to disorders that include cognitive loss, stroke, atherosclerosis, cardiac failure, and endothelial stem cell impairment. At the cellular level, oxidative stress is a significant determinant of cell fate during DM and leads to endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, and autophagy. Multiple strategies are being developed to combat the complications of DM, but it is the mechanistic target of rapamycin (mTOR) that is gaining interest in drug development circles especially for protective therapies that involve cytokines and growth factors such as erythropoietin. The pathways of mTOR linked to mTOR complex 1, mTOR complex 2, AMP activated protein kinase, and the hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) complex can ultimately influence neuronal, cardiac, and vascular cell survival during oxidant stress in DM through a fine interplay between apoptosis and autophagy. Further understanding of these mTOR regulated pathways should foster novel strategies for the complications of DM that impact millions of individuals with death and disability. PMID- 25789104 TI - Technology and diabetes self-management: An integrative review. AB - Technology can be used to supplement healthcare provider diabetes care by providing both educational and motivational support. Education can be provided using technology allowing patients to learn new practices and routines related to diabetes management. Technology can support daily diabetes self-management activities including blood glucose monitoring, exercising, healthy eating, taking medication, monitoring for complications, and problem-solving. This article describes an integrative review conducted to evaluate the types of technology being used to facilitate diabetes self-management and the effect of that technology on self-management and diabetes outcomes for adults living with type 2 diabetes mellitus. A literature review was conducted by searching Medline, PubMed, and Psych INFO databases using the search terms: diabetes self management, technology, type 2 diabetes, smartphones, cell phones, and diabetes mellitus covering the years from 2008-2013. Articles relying on secondary data (editorials, systematic reviews) and articles describing study protocol only were excluded. Fourteen studies including qualitative, quasi-experimental, and randomized controlled trial designs were identified and included in the review. The review found that technological interventions had positive impacts on diabetes outcomes including improvements in hemoglobin A1C levels, diabetes self management behaviors, and diabetes self-efficacy. Results indicate that technological interventions can benefit people living with diabetes when used in conjunction with diabetes care delivered by healthcare providers. PMID- 25789105 TI - Type 2 diabetes after gestational diabetes: The influence of changing diagnostic criteria. AB - A previous diagnosis of gestational diabetes (GDM) carries a lifetime risk of progression to type 2 diabetes of up to 60%. Identification of those women at higher risk of progression to diabetes allows the timely introduction of measures to delay or prevent diabetes onset. However, there is a large degree of variability in the literature with regard to the proportion of women with a history of GDM who go on to develop diabetes. Heterogeneity between cohorts with regard to diagnostic criteria used, duration of follow-up, and the characteristics of the study population limit the ability to make meaningful comparisons across studies. As the new International Association for Diabetes in Pregnancy Study Group criteria are increasingly adopted worldwide, the prevalence of GDM is set to increase by two-to three-fold. Here, we review the literature to examine the evolution of diagnostic criteria for GDM, the implications of changing criteria on the proportion of women with previous GDM progressing to diabetes, and how the use of different diagnostic criteria may influence the development of appropriate follow-up strategies. PMID- 25789106 TI - Diabetic cardiac autonomic neuropathy: Do we have any treatment perspectives? AB - Cardiac autonomic neuropathy (CAN) is a serious and common complication of diabetes mellitus (DM). Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of CAN has not been fully appreciated. CAN among DM patients is characterized review the latest evidence and own data regarding the treatment and the treatment perspectives for diabetic CAN. Lifestyle modification, intensive glycemic control might prevent development or progression of CAN. Pathogenetic treatment of CAN includes: balanced diet and physical activity; optimization of glycemic control; treatment of dyslipoproteinemia; correction of metabolic abnormalities in myocardium; prevention and treatment of thrombosis; use of aldose reductase inhibitors; dihomo-gamma-linolenic acid (DGLA), acetyl-L-carnitine, antioxidants, first of all alpha-lipoic acid (alpha LA), use of long-chain omega-3 and omega-6 polyunsaturated fatty acids (omega-3 and omega-6 PUFAs), vasodilators, fat-soluble vitamin B1, aminoguanidine; substitutive therapy of growth factors, in severe cases-treatment of orthostatic hypotension. The promising methods include research and use of tools that increase blood flow through the vasa vasorum, including prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na(+), K(+)-ATPase (phosphodiesterase inhibitor), alpha-LA, DGLA, omega-3 PUFAs, and the simultaneous prescription of alpha-LA, omega-3 PUFA and DGLA. PMID- 25789107 TI - Short and long term neuro-behavioral alterations in type 1 diabetes mellitus pediatric population. AB - Type 1 diabetes mellitus (T1DM) is one of the most prevalent chronic conditions affecting individuals under the age of 18 years, with increasing incidence worldwide, especially among very young age groups, younger than 5. There is still no cure for the disease, and therapeutic goals and guidelines are a challenge. Currently, despite T1DM intensive management and technological interventions in therapy, the majority of pediatric patients do not achieve glycemic control goals. This leads to a potential prognosis of long term diabetic complications, nephrological, cardiac, ophthalmological and neurological. Unfortunately, the neurological manifestations, including neurocognitive and behavioral complications, may present soon after disease onset, during childhood and adolescence. These manifestations may be prominent, but at times subtle, thus they are often not reported by patients or physicians as related to the diabetes. Furthermore, the metabolic mechanism for such manifestations has been inconsistent and difficult to interpret in practical clinical care, as reported in several reviews on the topic of brain and T1DM. However, new technological methods for brain assessment, as well as the introduction of continuous glucose monitoring, provide new insights and information regarding brain related manifestations and glycemic variability and control parameters, which may impact the clinical care of children and youth with T1DM. This paper provides a comprehensive review of the most recently reported behavioral, cognitive domains, sleep related, electrophysiological, and structural alterations in children and adolescences from a novel point of view. The review focuses on reported impairments based on duration of T1DM, its timeline, and modifiable disease related risk parameters. These findings are not without controversy, and limitations of data are presented in addition to recommendations for future research direction. PMID- 25789108 TI - Role of phytoestrogens in prevention and management of type 2 diabetes. AB - Type 2 diabetes (T2D) has become a major public health threat across the globe. It has been widely acknowledged that diet plays an important role in the development and management of T2D. Phytoestrogens are polyphenols that are structurally similar to endogenous estrogen and have weak estrogenic properties. Emerging evidence from pre-clinical models has suggested that phytoestrogens may have anti-diabetic function via both estrogen-dependent and estrogen-independent pathways. In the current review, we have summarized the evidence linking two major types of phytoestrogens, isoflavones and lignans, and T2D from epidemiological studies and clinical trials. The cross-sectional and prospective cohort studies have reported inconsistent results, which may due to the large variations in different populations and measurement errors in dietary intakes. Long-term intervention studies using isoflavone supplements have reported potential beneficial effects on glycemic parameters in postmenopausal women, while results from short-term small-size clinical trials are conflicting. Taken together, the current evidence from different study designs is complex and inconsistent. Although the widespread use of phytoestrogens could not be recommended yet, habitual consumption of phytoestrogens, particularly their intact food sources like soy and whole flaxseed, could be considered as a component of overall healthy dietary pattern for prevention and management of T2D. PMID- 25789109 TI - Changing trends in management of gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) is on the rise globally. In view of the increasing prevalence of GDM and fetal and neonatal complications associated with it, there is a splurge of research in this field and management of GDM is undergoing a sea change. Trends are changing in prevention, screening, diagnosis, treatment and future follow up. There is emerging evidence regarding use of moderate exercise, probiotics and vitamin D in the prevention of GDM. Regarding treatment, newer insulin analogs like aspart, lispro and detemir are associated with better glycemic control than older insulins. Continuous glucose monitoring systems and continuous subcutaneous insulin systems may play a role in those who require higher doses of insulin for sugar control. Evidence exists that favors metformin as a safer alternative to insulin in view of good glycemic control and better perinatal outcomes. As the risk of developing GDM in subsequent pregnancies and also the risk of overt diabetes in later life is high, regular assessment of these women is required in future. Lifestyle interventions or metformin should be offered to women with a history of GDM who develop pre diabetes. Further studies are required in the field of prevention of GDM for optimizing obstetric outcome. PMID- 25789110 TI - Prediabetes diagnosis and treatment: A review. AB - Prediabetes is an intermediate state of hyperglycemia with glycemic parameters above normal but below the diabetes threshold. While, the diagnostic criteria of prediabetes are not uniform across various international professional organizations, it remains a state of high risk for developing diabetes with yearly conversion rate of 5%-10%. Observational evidence suggests as association between prediabetes and complications of diabetes such early nephropathy, small fiber neuropathy, early retinopathy and risk of macrovascular disease. Several studies have shown efficacy of lifestyle interventions with regards to diabetes prevention with a relative risk reduction of 40%-70% in adults with prediabetes. While there is increasing evidence to prove the efficacy of pharmacotherapy in prevention of diabetes in adults with prediabetes, pharmaceutical treatment options other than metformin are associated with adverse effects that limit their use for prediabetes. There are no reports of systematic evaluation of health outcomes related to prediabetes in children. The effects of pharmacotherapy of prediabetes on growth and pubertal development in children remains unknown. Secondary intervention with pharmacotherapy with metformin is advocated for high risk individuals but criteria for such consideration benefit of early intervention, long term cost effectiveness of such interventions and the end point of therapy remain unclear. Pharmacotherapy must be used with caution in children with prediabetes. Prediabetes is a condition defined as having blood glucose levels above normal but below the defined threshold of diabetes. It is considered to be an at risk state, with high chances of developing diabetes. While, prediabetes is commonly an asymptomatic condition, there is always presence of prediabetes before the onset of diabetes. The elevation of blood sugar is a continuum and hence prediabetes can not be considered an entirely benign condition. This aim of this review is to describe the challenges associated with diagnosis of prediabetes, the possible adverse medical outcomes associated with prediabetes and the treatment options and rationale for their use in context of prediabetes. PMID- 25789111 TI - Economic development and diabetes prevalence in MENA countries: Egypt and Saudi Arabia comparison. AB - Diabetes is increasing in epidemic proportions globally, exhibiting the most striking increase in third world countries with emerging economies. This phenomena is particularly evident in the Middle East and North Africa (MENA) region, which has the highest prevalence of diabetes in adults. The most concerning indirect cost of diabetes is the missed work by the adult population coupled with the economic burden of loss of productivity. The major drivers of this epidemic are the demographic changes with increased life expectancy and lifestyle changes due to rapid urbanization and industrialization. Our focus is to compare MENA region countries, particularly Egypt and Saudi Arabia, in terms of their economic development, labor force diversity and the prevalence of diabetes. PMID- 25789112 TI - Current knowledge on diabetic retinopathy from human donor tissues. AB - According to the American Diabetes Association, diabetes was the seventh leading cause of death, and diabetic retinopathy the leading cause of blindness in working age adults in the United States in 2010. Diabetes is characterized by hyperglycemia associated with either hypoinsulinemia or insulin resistance, and over time, this chronic metabolic condition may lead to various complications including kidney failure, heart attacks, and retinal degeneration. In order to better understand the molecular basis of this disease and its complications, animal models have been the primary approach used to investigate the effects of diabetes on various tissues or cell types of the body, including the retina. However, inherent to these animal models are critical limitations that make the insight gained from these models challenging to apply to the human pathology. These difficulties in translating the knowledge obtained from animal studies have led a growing number of research groups to explore the diabetes complications, especially diabetic retinopathy, on tissues from human donors. This review summarizes the data collected from diabetic patients at various stages of diabetic retinopathy and classifies the data based upon their relevance to the main aspects of diabetic retinopathy: retinal vasculature dysfunction, inflammation, and neurodegeneration. This review discusses the importance of those studies to discriminate and establish the relevance of the findings obtained from animal models but also the limitations of such approaches. PMID- 25789113 TI - Hepatic glycogenosis: An underdiagnosed complication of diabetes mellitus? AB - Hepatic glycogenosis (HG) is characterized by excessive glycogen accumulation in hepatocytes and represents a hepatic complication of diabetes that particularly occurs in patients with longstanding poorly controlled type 1 diabetes (T1D). HG has been reported to be a very rare disease, although it is believed to be extremely underdiagnosed because it is not possible to distinguish it from non alcoholic fatty liver disease (NAFLD) unless a liver biopsy is performed. In contrast to HG, NAFLD is characterized by liver fat accumulation and is the more likely diagnosis for patients with type 2 diabetes and metabolic syndrome. The pathogenesis of HG involves the concomitant presence of insulin and excess glucose, which increases glycogen storage in the liver. HG is characterized by a transient elevation in liver transaminases and hepatomegaly. Differentiating between these two conditions is of the utmost importance because HG is a benign disease that is potentially reversible by improving glycemic control, whereas NAFLD can progress to cirrhosis. Therefore, HG should be suspected when liver dysfunction occurs in patients with poorly controlled T1D. The aim of this article is to review the epidemiology, clinical characteristics, pathogenesis and histology of HG. PMID- 25789114 TI - Role of oxidative stress in endothelial insulin resistance. AB - The International Diabetes Federation estimates that 316 million people are currently affected by impaired glucose tolerance (IGT). Most importantly, recent forecasts anticipate a dramatic IGT increase with more that 470 million people affected by the year 2035. Impaired insulin sensitivity is major feature of obesity and diabetes and is strongly linked with adverse cardiometabolic phenotypes. However, the etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be deciphered. Although insulin resistance has been attributed to inflammatory programs starting in adipose tissue, emerging evidence indicates that endothelial dysfunction may represent the upstream event preceding peripheral impairment of insulin sensitivity. Indeed, suppression of reactive oxygen species-dependent pathways in the endothelium has shown to restore insulin delivery to peripheral organs by preserving nitric oxide (NO) availability. Here we describe emerging theories concerning endothelial insulin resistance, with particular emphasis on the role oxidative stress. Complex molecular circuits including endothelial nitric oxide synthase, prostacyclin synthase, mitochondrial adaptor p66(Shc), nicotinamide adenine dinucleotide phosphate-oxidase oxidase and nuclear factor kappa-B are discussed. Moreover, the review provides insights on the effectiveness of available compounds (i.e., ruboxistaurin, sildenafil, endothelin receptor antagonists, NO donors) in restoring endothelial insulin signalling. Taken together, these aspects may significantly contribute to design novel therapeutic approaches to restore glucose homeostasis in patients with obesity and diabetes. PMID- 25789115 TI - Antioxidant role of zinc in diabetes mellitus. AB - Chronic hyperglycemia statue noticed in diabetes mellitus favors the manifestation of oxidative stress by increasing the production of reactive oxygen species and/or by reducing the antioxidant defense system activity. Zinc plays an important role in antioxidant defense in type 2 diabetic patients by notably acting as a cofactor of the superoxide dismutase enzyme, by modulating the glutathione metabolism and metallothionein expression, by competing with iron and copper in the cell membrane and by inhibiting nicotinamide adenine dinucleotide phosphate-oxidase enzyme. Zinc also improves the oxidative stress in these patients by reducing chronic hyperglycemia. It indeed promotes phosphorylation of insulin receptors by enhancing transport of glucose into cells. However, several studies reveal changes in zinc metabolism in individuals with type 2 diabetes mellitus and controversies remain regarding the effect of zinc supplementation in the improvement of oxidative stress in these patients. Faced with the serious challenge of the metabolic disorders related to oxidative stress in diabetes along with the importance of antioxidant nutrients in the control of this disease, new studies may contribute to improve our understanding of the role played by zinc against oxidative stress and its connection with type 2 diabetes mellitus prognosis. This could serve as a prelude to the development of prevention strategies and treatment of disorders associated with this chronic disease. PMID- 25789117 TI - Impact of glucose level on morbidity and mortality in elderly with diabetes and pre-diabetes. AB - The prevalence of type 2 diabetes mellitus (DM) increases with age and reaches 25% in those older than age 65 years. Pre-diabetes status is also very common in the elderly, and is present in about half of those age 75 years and older. Many physicians care for elderly patients with diabetes and pre-diabetes, dealing with the challenge of controlling glucose levels and improving health with minimal adverse events. Over the last decade, research on diabetes among the elderly population has proliferated, adding new information on this topic. This review summarizes the updated medical literature on diabetes and pre-diabetes in the elderly, including the significance of pre-diabetic conditions, new-onset DM in the elderly and long-standing DM. The role of therapeutic intervention and the level of glycemic control for this population are discussed in particular. PMID- 25789116 TI - Effects of maternal diabetes on trophoblast cells. AB - Diabetes mellitus (DM) is a health condition characterized by hyperglycemia over a prolonged period. There are three main types of DM: DM type 1 (DM1), DM2 and gestational DM (GDM). Maternal diabetes, which includes the occurrence of DM1 and DM2 during pregnancy or GDM, increases the occurrence of gesttional complications and adverse fetal outcomes. The hyperglycemic intrauterine environment affects not only the fetus but also the placental development and function in humans and experimental rodents. The underlying mechanisms are still unclear, but some evidence indicates alterations in trophoblast proliferation, apoptosis and cell cycle control in diabetes. A proper coordination of trophoblast proliferation, differentiation and invasion is required for placental development. Initially, increased expression of proliferative markers in junctional and labyrinth zones of rat placentas and villous cytotrophoblast, syncytiotrophoblast, stromal cells and fetal endothelial cells in human placentas is reported among diabetics. Moreover, reduced apoptotic index and expression of some apoptotic genes are described in placentas of GDM women. In addition, cell cycle regulators including cyclins and cyclin-dependent kinase inhibitors seem to be affected by the hyperglycemic environment. More studies are necessary to check the balance between proliferation, apoptosis and differentiation in trophoblast cells during maternal diabetes. PMID- 25789118 TI - Statin use and risk of diabetes mellitus. AB - The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used in the primary and secondary prevention of cardiovascular diseases to lower serum cholesterol levels. As type 2 diabetes mellitus is accompanied by dyslipidemia, statins have a major role in preventing the long term complications in diabetes and are recommended for diabetics with normal low density lipoprotein levels as well. In 2012, United States Food and Drug Administration released changes to statin safety label to include that statins have been found to increase glycosylated haemoglobin and fasting serum glucose levels. Many studies done on patients with cardiovascular risk factors have shown that statins have diabetogenic potential and the effect varies as per the dosage and type used. The various mechanisms for this effect have been proposed and one of them is downregulation of glucose transporters by the statins. The recommendations by the investigators are that though statins can have diabetogenic risk, they have more long term benefits which can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increase, the statins should be used cautiously. Other than a subset of population with risk for diabetes; statins still have long term survival benefits in most of the patients. PMID- 25789119 TI - Association of gene variants with susceptibility to type 2 diabetes among Omanis. AB - AIM: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis. METHODS: Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of >= 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012. RESULTS: Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 * 10(-6), OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype variation % between diabetics and controls was found at KCNJ11 (2.07%) and TCF7L2 (1.62%). This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk. However, T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the Waist-to-Hip ratio (n = 532, P = 1.9 *10(-7), OR = 2.4), [among males (n = 234, P = 1.2 * 10(-4), OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)]. CONCLUSION: Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs. PMID- 25789120 TI - The cutaneous bacterial microflora of the bodybuilders using anabolic-androgenic steroids. AB - BACKGROUND: Anabolic-androgenic steroids (AAS) abuse by the athletes has dramatically increased during the recent decades. These substances might increase the skin lipids and enhance the cutaneous microbial proliferation. OBJECTIVES: The current study aimed to investigate the potential side effects of AAS on the bacterial microflora colonization of the bodybuilders' skin. PATIENTS AND METHODS: The skin samples of 94 male bodybuilders (71 AAS users, 23 non-AAS users) and 46 subjects of the control group, with similar gender and age, were cultured and incubated in both aerobic condition to isolate Staphylococcus aureus and anaerobic condition for Propionibacterium acnes. The isolated bacteria were identified by standard microbiological techniques. RESULTS: The skin lesions were more frequent in the body builders than the controls. Moreover, statistically significant differences were also observed in skin lesions among the AAS users and the non-AAS user athletes. The prevalence of S. aureus and P. acnes in the athletes was higher than that of the control group. In addition, there was a significant difference in distribution of P. acnes between the bodybuilders who used AAS and those who did not. CONCLUSIONS: A higher number of bacterial flora was found in the bodybuilders particularly those using AAS in comparison to the controls, which might be due to the influence of these AAS on the skin microflora and transmission of the bacteria through the direct contact of the naked skin with the exercise instruments. PMID- 25789121 TI - Plasmid mediated antibiotic resistance in isolated bacteria from burned patients. AB - BACKGROUND: Nowadays, the treatment of burned patients is difficult because of the high frequency of infection with antibiotic resistance bacteria. OBJECTIVES: This study was conducted to evaluate the level of antibiotic resistance in Gram negative bacteria and its relation with the existence of plasmid. MATERIALS AND METHODS: The samples were collected from two hundred twenty hospitalized burned patients in Isfahan burn hospital during a three-month period (March 2012 to June 2012). The samples were isolated and the Gram-negative bacteria were identified using phenotypic method and API 20E System. Antibiotic susceptibility and plasmid profile were determined by standard Agar disc diffusion and plasmid spin column extraction methods. RESULTS: Totally 117 Gram-negative bacteria were isolated, the most common were Pseudomonas aerugionsa (37.6%), P. fluorescens (25.6%), Acinetobacter baumanii (20/5%) and Klebsiella pneumoniae (7.6%), respectively. The isolates showed high frequency of antibiotic resistance against ceftazidime and co-amoxiclave (100%) and low frequency of antibiotic resistance against amikacin with (70%).The results indicated that 60% of the isolates harboured plasmid. On the other hand, the patients infected with A. baumanii and P. aeruginosa were cured (with 60% frequency) whereas, those infected with P. fluorescens were not cured. Hence, probably antibiotic resistance markers of A. baumanii and P. aeruginosa are plasmid mediated; however, P. fluorescens is chromosomally mediated. CONCLUSIONS: Based on our findings, P. aerugionsa is a major causative agent of wound infections and amikacin could be considered as a more effective antibiotic for treatment of the burned patients. PMID- 25789122 TI - Overexpression and Enzymatic Assessment of Antigenic Fragments of Hyaluronidase Recombinant Protein From Streptococcus pyogenes. AB - BACKGROUND: Hyaluronidase catalyzes the hydrolysis of hyaluronan polymers to N acetyl-D-glucosamine and D-glucuronic acid. This enzyme is a dimer of identical subunits. Hyaluronidase has different pharmaceutical and medical applications. Previously, we produced a recombinant hyaluronidase antigenic fragment of Streptococcus pyogenes. OBJECTIVES: This study aimed to improve the protein production and purity of hyaluronidase recombinant protein from S. pyogenes. In addition, the enzymatic activity of this protein was investigated. MATERIALS AND METHODS: The expression of hyaluronidase antigenic fragments was optimized using IPTG concentration, time of induction, temperature, culture, and absorbance of 0.6-0.8-1 at 600 nm. Afterwards, the expressed proteins were purified and the enzymatic activity was assessed by turbid metric method. RESULTS: Data indicated that maximum protein is produced in OD = 0.8, 0.5 mM Isopropyl beta-D-1 thiogalactopyranoside (IPTG), 37oC, NB 1.5x, without glucose, incubated for overnight. The enzymatic activity of the recombinant protein was similar to the commercial form of hyaluronidase. CONCLUSIONS: The results showed that an antigenic fragment of the recombinant hyaluronidase protein from S. pyogenes has a considerable enzymatic activity. It can be suggested to use it for medical purposes. In addition, applications of bioinformatics software would facilitate the production of a smaller protein with same antigenic properties and enzymatic activity. PMID- 25789123 TI - Frequency of PER, VEB, SHV, TEM and CTX-M Genes in Resistant Strains of Pseudomonas aeruginosa Producing Extended Spectrum beta-Lactamases. AB - BACKGROUND: Pseudomonas aeruginosa is the most common pathogen causing nosocomial infections. Resistance of P. aeruginosa strains to broad-spectrum cephalosporins may be mediated by extended-spectrum beta-lactamases (ESBLs). OBJECTIVES: We intended to investigate the prevalence of ESBLs and antimicrobial susceptibilities of P. aeruginosa isolated from patients in Zahedan, Iran. MATERIALS AND METHODS: In this cross-sectional study, during 2012-2013, 116 P. aeruginosa isolates were collected from a teaching hospital in Zahedan, Iran. Susceptibility to eight antimicrobial agents was carried out by disk diffusion method. The ESBL producing strains were detected by combination disk test (CDT). ESBL positive isolates as well as other isolates showing minimum inhibitory concentrations (MICs) >= 4 MUg/mL for ceftazidime, cefotaxime, ceftriaxone and aztreonam, were screened for the presence of the genes encoding blaTEM, blaSHV, blaPER-1 and blaVEB-1, by polymerase chain reaction (PCR). RESULTS: Ciprofloxacin and piperacillin were the most efficient antipseudomonal agents. The results disclosed that 19 (16.37%) of the isolates were multidrug resistant and 8 (6.89%) were ESBL-positive. Of the 116 isolates, 30 (25.86%) were resistant to at least one of the antibiotics ceftazidime, ceftriaxone, cefotaxime or aztreonam and among these 30 (100%), 4 (13.3%), 2 (6.6%) and 2 (6.6%), amplified blaTEM, blaVEB 1, blaPER-1 and blaSHV, respectively. From the 30 TEM-positive isolates, 22 were ESBL-negative. Sequencing of the ESBL genes verified the accuracy of the PCR products. CONCLUSIONS: According to our results, blaTEM-116 was the most frequent isolated ESBL gene among the P. aeruginosa strains isolated from patients. PMID- 25789124 TI - Evaluation of hepatitis B surface antibody and specific gamma interferon response in health care workers after vaccination. AB - BACKGROUND: Health care workers are at high risk of acquiring hepatitis B virus (HBV) infection through occupational exposure to blood or body fluids. Thus, the assessment of anti-HBs status after immunization is very important. OBJECTIVES: This study aimed to evaluate the measurement of HBsAb titer and specific gamma interferon response among the vaccinated health care workers in Golestan Hospital, Ahvaz, Iran. PATIENTS AND METHODS: The blood samples of 39 health care workers, including 13 general surgeons, 10 anesthesiologists, 5 neurosurgeons, 3 general physicians, 1 orthopedist, 2 urologist and 5 nurses were collected during June 2013. All the participants had received HBV vaccine. They had received last vaccine dose from 2 months to 14 years ago. Their sera were tested for anti hepatitis B antibody and HBc-IgG by the ELISA. Also, the evaluation of specific interferon gamma response against HBsAg was carried out using ELISA test. The age of health care workers were between 24 and 58 years with the mean age of 34.3 +/- 7.4 y. RESULTS: Out of 39 sera, 22 (56.41%) had HBsAb titer above 100 IU/mL, 17 (43.6%) had titer below 100 IU/mL, 27 (69.2%) had positive specific HBsAg interferon gamma, 8 (20.5%) cases had positive antibody response above 100IU, but negative for specific interferon gamma and 3 (7.6%) cases were positive for HBc IgG. CONCLUSIONS: Overall, 87.2% of the health care workers had immunity against HBV infection, which showed remarkable immunity response following HBV vaccination. Booster dose of HBV vaccine is recommended for those whose immunity are below 100 IU/mL. PMID- 25789125 TI - Antibiogram of Stenotrophomonas maltophilia Isolated From Nkonkobe Municipality, Eastern Cape Province, South Africa. AB - BACKGROUND: Assessment of resistance genes is imperative, as they become disseminated to bacterial flora in plants and to the indigenous bacterial community, and thus ultimately contributes to the clinical problems of antibiotic resistant pathogens. OBJECTIVES: The research was to assess the antibiotic characteristics and incidence of sul3 genes of Stenotrophomonas maltophilia isolates recovered from rhizospheres plant in Nkonkobe Municipality. MATERIALS AND METHODS: Identification and assessment of resistance genes (sul2 and sul3 genes) were carried out using polymerase chain reaction (PCR). Analytical profile index (API) was used for biochemical characterization for identification before the PCR. Antibiotic susceptibility test was carried out using the approved guidelines and standards of Clinical Laboratory Standard Institute (CLSI). RESULTS: A total of 125 isolates were identified, composed of 120 (96%) from grass root rhizosphere and 5 (4%) from soil butternut root rhizosphere. In vitro antibiotic susceptibility tests showed varying resistances to meropenem (8.9%), cefuroxime (95.6 %), ampicillin-sulbactam (53.9%), ceftazidime (10.7%), cefepime (29.3 %), minocycline (2.2%), kanamycin (56.9%), ofloxacin (2.9%), levofloxacin (1.3%), moxifloxacin (2.8%), ciprofloxacin (24.3%), gatifloxacin (1.3%), polymyxin B (2.9 %), cotrimoxazole (26.1%), trimethoprim (98.6%) and aztreonam (58%). The isolates were susceptible to the fluoroquinolones (74.3-94.7%), polymycin (97.1%) and meropenem (88.1%). The newest sulphonamide resistance gene, sul3, was detected among the trimethoprim-sulfamethoxazole (cotrimoxazole) resistant isolates, while the most frequent sulphonamide-resistant gene in animal source isolates, sul2, was not. CONCLUSIONS: The commensal S. maltophilia isolates in the Nkonkobe Municipality environment harbored the resistant gene sul3 as clinical counterparts, especially from the perspective of reservoirs of antibiotic resistance determinants. PMID- 25789126 TI - Molecular Genotyping of Shigella sonnei Strains Isolated From Children With Bloody Diarrhea Using Pulsed Field Gel Electrophoresis on the Total Genome and PCR-RFLP of IpaH and IpaBCD Genes. AB - BACKGROUND: Identification, understanding of antibiotic sensitivity patterns and molecular characterization of genetic elements of Shigella species are important because of both epidemiological and clinical indications in developing countries. OBJECTIVES: The aim of this study was to analyze molecular epidemiology of Shigella isolates recovered from children with diarrhea in Shiraz (Southern Iran), using IpaH and IpaBCD PCR-restriction fragment length polymorphism (RFLP), and to determine pulsed field gel electrophoresis (PFGE) patterns of total DNA of the S. sonnei isolates to find the clonality among these strains. PATIENTS AND METHODS: A total of 82 clinical strains of Shigella spp., S. sonnei (n = 61), S. flexneri (n = 16), Shigella boydii (n = 3) and S. dysenteriae (n = 2) isolated from the stool samples of 719 patients, aged two months to 14 years, with positive occult blood (OB) test were characterized based on their IpaH and IpaBCD genes PCR-RFLP patterns. Genomic DNAs of S. sonnei strains were analyzed by PFGE. RESULTS: All Shigella isolates were positive for both invasive genes and showed homogeneous profiles for such genes except for two S. sonnei strains, which had IpaH bands with different sizes and PCR-RFLP profiles. Forty palsotypes were determined among the 41 S. sonnei strains. Sample patterns were divided into two groups based on the drawn dendrogram with a similarity range of 70% to 100%. CONCLUSIONS: The results revealed that the strains under study could be epidemically related. It seems that an alternative subtyping method is needed to study the relationship among clinical S. sonnei strains and their transmission. Here, we reported for the first time, two strains of S. sonnei with a different PCR-RFLP pattern for IpaH gene. PMID- 25789127 TI - Association between toxin-antitoxin systems and biofilm formation. AB - BACKGROUND: Toxin-antitoxin (TA) systems are found on the chromosomes and plasmids of many Bacteria such as Escherichia coli. The roles of TA systems in bacteria are enigmatic. Multiple biological functions of TA systems are proposed including growth modulation, persistence, and biofilm formation. Biofilms of E. coli are cause of urinary tract infections, as well as bacteraemia. OBJECTIVES: The current study aimed to find the association between biofilm formation and toxin-antitoxin systems in clinical isolates of E. coli. MATERIALS AND METHODS: A total of 150 E. coli isolates were evaluated for biofilm formation by Congo red agar medium (CRA) and microtiter plate assay and the presence of different TA systems including MazEF, RelBE, hipBA, ccdAB and MqsRA. RESULTS: The results of the analysis revealed that 107 E. coli isolates were potent for biofilm formation by CRA. The findings by microtiter plates showed that 102 E. coli isolates were biofilm producers. The results indicated that 80%, 85%, 70%, 91% and 82% of the isolates possessed MazEF, RelBE, hipBA, ccdAB and MqsRA TA loci, respectively. CONCLUSIONS: The analysis recommended that TA genes are prevalent in clinical isolates of E. coli strains. The analysis revealed that hipBA TA system is associated with biofilm formation. PMID- 25789128 TI - Detection of helicobacter pylori in bronchoalveolar lavage of patients with chronic obstructive pulmonary disease by real time polymerase chain reaction. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the most important causes of disability and mortality in the world. Although cigarette smoking and environmental pollutants have been recognized as the major causes of COPD, the role of infection in the pathogenesis and progression of COPD has also been reported. OBJECTIVES: The aim of the present study was to find the relationship between Helicobacter Pylori infection and COPD through anti H. pylori IgG serology, real time PCR of bronchoalveolar lavage and trans bronchial biopsy urease tests. PATIENTS AND METHODS: This descriptive cross-sectional study was carried out on 60 adults with COPD. After obtaining the patient's history, physical examination, spirometry and confirmation of COPD diagnosis by pulmonologist, subjects were selected through convenience sampling. In order to determine the severity and prognosis of disease, the global initiative for chronic obstructive lung disease (GOLD) criteria and BODE index were used. Subjects underwent bronchoscopy for obtaining bronchoalveolar lavage (BAL) samples and biopsy was performed. Biopsy and BAL samples were investigated respectively by urease test and real time PCR. Moreover, patients' serum samples were serologically studied for detection of anti H. pylori IgG. RESULTS: Mean age of the participants was 60.65 +/- 9.15 years, and 25% were female and 75% were male. The prevalence rate of H. pylori in COPD patients was 10% according to real time PCR, 88.3% according to the serology test and 0% based on the urease test. According to the results of PCR and considering the severity of disease based on the GOLD criteria, from those with a positive PCR, one patient (16.6%) had very severe obstruction, three (50%) had severe obstruction and two patients (33.3%) had moderate obstruction. The relationship between H. pylori presence (based on PCR) and disease severity and prognosis was not statistically significant. CONCLUSIONS: These findings can justify the hypothesis of direct injury and chronic inflammation via inhalation and aspiration resulting in H. pylori colonization. In fact, it is thought that H. Pylori infection, beside the host genetic vulnerability and other environmental risk factors might make the patient susceptible to COPD or lead to COPD worsening. Although we found H. pylori infection in some patients with COPD, the results of this study, could not explain the pathogenic mechanisms of COPD. PMID- 25789129 TI - Detection of medically important Candida species by absolute quantitation real time polymerase chain reaction. AB - BACKGROUND: The number of invasive candidiasis cases has risen especially with an increase in the number of immunosuppressed and immunocom promised patients. The early detection of Candida species which is specific and sensitive is important in determining the correct administration of antifungal drugs to patients. OBJECTIVES: This study aims to develop a method for the detection, identification and quantitation of medically important Candida species through quantitative polymerase chain reaction (qPCR). MATERIALS AND METHODS: The isocitrate lyase (ICL) gene which is not found in mammals was chosen as the target gene of real time PCR. Absolute quantitation of the gene copy number was achieved by constructing the plasmid containing the ICL gene which is used to generate standard curve. Twenty fungal species, two bacterial species and human DNA were tested to check the specificity of the detection method. RESULTS: All eight Candida species were successfully detected, identified and quantitated based on the ICL gene. A seven-log range of the gene copy number and a minimum detection limit of 10(3) copies were achieved. CONCLUSIONS: A one-tube absolute quantification real-time PCR that differentiates medically important Candida species via individual unique melting temperature was achieved. Analytical sensitivity and specificity were not compromised. PMID- 25789130 TI - Gallbladder hydrops due to viral hepatitis a infection: a case report. AB - INTRODUCTION: Acute Hepatitis A Virus (HAV) infection is common in the developing countries among children, but hydrops of gallbladder due to hepatitis A infection is an uncommon presentation. CASE PRESENTATION: A five-year-old boy was admitted in Namazi Hospital, Shiraz, Iran due to jaundice and severe abdominal pain for 10 days. Physical examination revealed a mass in the right upper quadrant with severe tenderness. Liver function tests were abnormal while other laboratory data such as blood urea nitrogen, serum creatinine, sodium, and potassium were within the normal range. Blood and urine cultures were negative. Abdominal ultrasonography showed that the gallbladder was very much distended and its fundus was near the iliac crest. Hydrops of the gallbladder was diagnosed. HAV IgM titer was high. After five days, without any specific treatment, his symptoms improved and he was discharged with good condition. CONCLUSIONS: Acute acalculous gallbladder disease is a rare complication of HAV infection which should be suspected in any child with right upper quadrant abdominal pain, tenderness, and mass which can lead to surgical emergency in rare conditions. PMID- 25789131 TI - Molecular Diagnosis of Toxoplasma gondii in Aborted Women. PMID- 25789132 TI - Nucleic Acid-based approaches for detection of viral hepatitis. AB - CONTEXT: To determining suitable nucleic acid diagnostics for individual viral hepatitis agent, an extensive search using related keywords was done in major medical library and data were collected, categorized, and summarized in different sections. RESULTS: Various types of molecular biology tools can be used to detect and quantify viral genomic elements and analyze the sequences. These molecular assays are proper technologies for rapidly detecting viral agents with high accuracy, high sensitivity, and high specificity. Nonetheless, the application of each diagnostic method is completely dependent on viral agent. CONCLUSIONS: Despite rapidity, automation, accuracy, cost-effectiveness, high sensitivity, and high specificity of molecular techniques, each type of molecular technology has its own advantages and disadvantages. PMID- 25789133 TI - Necrotic Response to Low Pathogenic H9N2 Influenza Virus in Chicken Hepatoma Cells. AB - BACKGROUND: Limited knowledge about the molecular mechanism of avian influenza H9N2 virus pathogenicity in birds as well as human hosts has limited the development of effective control against the disease. To overcome this issue detailed understanding of the infectious characteristics of the virus in host cells should be obtained. OBJECTIVES: In this study we examined the replication kinetics of H9N2 virus in a chicken hepatoma cell line to obtain insight into the pathogenesis of H9N2 viruses. MATERIALS AND METHODS: The kinetic replication of H9N2 influenza virus in chicken hepatoma and fibroblastic cells was studied in the presence and absence of supplemental trypsin. High viral titers observed in liver cells in a short time correlated with the degree of cytopathic effects. To determine whether the ultimate outcome of infection results in programmed cell death, the infected cells were observed by the cell viability assay, DNA fragmentation, caspase cascade activation, and quantified lactate dehydrogenase release. RESULTS: The degree of viability was significantly reduced in infected hepatoma cells. Observations of caspase activation and cell DNA laddering in infected cells were not indicative of apoptosis. The infected hepatoma cells released lactate dehydrogenase, which is consistent with cell death by necrosis. CONCLUSIONS: Taken together, these data reveal that cellular protease of chicken liver cells allows the replication of high yields of H9N2 virus in the absence of trypsin and also cell death in the infected cells is due to necrosis. PMID- 25789134 TI - Molecular Detection of Class-D OXA Carbapenemase Genes in Biofilm and Non-Biofilm Forming Clinical Isolates of Acinetobacter baumannii. AB - BACKGROUND: Emergence and spread of carbapenemase (bla OXA) genes in multidrug resistant Acinetobacter baumannii (MDR-AB) forming biofilm complicated treatment of the patients infected with this microorganism particularly in intensive care units (ICUs). OBJECTIVES: The current study aimed to determine the prevalence of molecular class-D OXA carbapenemase in biofilm and non-biofilm forming strains of MDR-AB. MATERIALS AND METHODS: A total of 65 strains of MDR-AB were isolated from the patients hospitalized in the ICU of two hospitals in Kerman, Iran. The isolates were identified by conventional microbiological tests as well as API 20NE assay. Antibiotic susceptibility was carried out by disk diffusion method; minimum inhibitory concentration (MIC) of carbapenems was measured by E-test. The presence of bla OXA genes among the isolates were studied by duplex-polymerase chain reaction and application of appropriate primers. Biofilm formation was detected by microtiter plate method. RESULTS: The isolates were highly resistant to ciprofloxacin, levofloxacin, piperacillin, nalidixic acid and third generation cephalosporins such as tigecycline (7%; n = 5) and colistin (13%; n = 8). Among the isolates, 77% (n = 50) exhibited high MIC (265MUg/mL) for imipenem. Both the bla OXA-51 and bla OXA-23 like genes coexisted in all the isolates; while, bla OXA-24/40 like gene was only detected in 29 imipenem-resistant strains (P <= 0.05). The bla OXA-58 like gene was not detected among the isolated strains. Quantification of biofilm introduced 23 isolates (including bla OXA-24/40 strains) with efficient attachment to microtiter plate; while, those isolates without bla OXA-24/40, or imipenem-sensitive strains formed weak or no biofilm. CONCLUSIONS: Coexistence of the bla OXA-51, bla OXA-23 and bla OXA-24/40 like genes, along with formation of strong biofilm, in MDR-AB strains particularly with indiscriminate use of imipenem, complicated treatment of the patients infected with these bacteria in the hospitals understudy. PMID- 25789135 TI - Aflatoxin B1 Degradation by Metabolites of Phoma glomerata PG41 Isolated From Natural Substrate Colonized by Aflatoxigenic Aspergillus flavus. AB - BACKGROUND: Aflatoxin B1 (AFB1), produced by Aspergillus flavus, is one of the most life threatening food contaminants causing significant economic losses worldwide. Biological AFB1 degradation by microorganisms, or preferably microbial enzymes, is considered as one of the most promising approaches. OBJECTIVES: The current work aimed to study the AFB1-degrading metabolites, produced by Phoma glomerata PG41, sharing a natural substrate with aflatoxigenic A. flavus, and the preliminary determination of the nature of these metabolites. MATERIALS AND METHODS: The AFB1-degrading potential of PG41 metabolites was determined by a quantitative high performance liquid chromatography (HPLC) of residual AFB1 after 72 hours incubation at 27oC. The effects of pH, heat, and protease treatment on the AFB1-destroying activity of extracellular metabolites were examined. RESULTS: The AFB1-degrading activity of protein-enriched fractions, isolated from culture liquid filtrate and cell-free extract, is associated with high-molecular-weight components, is time- and pH-dependent, thermolabile, and is significantly reduced by proteinase K treatment. The AFB1 degradation efficiency of these fractions reaches 78% and 66%, respectively. CONCLUSIONS: Phoma glomerata PG41 strain sharing natural substrate with toxigenic A. flavus secretes metabolites possessing a significant aflatoxin-degrading activity. The activity is associated mainly with a protein-enriched high-molecular-weight fraction of extracellular metabolites and appears to be of enzymatic origin. PMID- 25789137 TI - Endothelial Function in Patients with Migraine without Aura during the Interictal Period. AB - BACKGROUND: In most of the studies, the association of vascular events is limited to migraine with aura or it is stronger in this group, whereas the link between migraine without aura (MO) and vascular events remained uncertain. Therefore, we decided to evaluate endothelial function by chemical and functional markers of endothelium in MO and compare with normal population. METHODS: In this study, 39 patients and 25 healthy subjects were enrolled and flow-mediated dilatation (FMD), C-reactive protein (CRP), nitrite and nitrate were measured in these two groups. RESULTS: The mean of FMD in healthy people was higher than the migraine patients (mean difference - 7.67%; 95% confidence interval [CI] -9.90--5.44). The means of nitrite concentration in migraineurs was significantly lower than healthy subjects (mean difference - 2.0 MUmol/L; 95% CI - 3.45--0.54). But the CRP concentrations in both groups were not significantly different (mean difference 0.42 pmol/L; 95% CI - 0.13-0.98). CONCLUSIONS: This study can show the endothelial dysfunction in migraineurs without aura and suggest that MO could also be a risk for cardiovascular disease. PMID- 25789136 TI - Seasonality and Physician-related Factors Associated with Antibiotic Prescribing: A Cross-sectional Study in Isfahan, Iran. AB - BACKGROUND: Irrational antibiotic prescribing as a global health problem has a major influence on medical care quality and healthcare expenditure. This study was aimed to determine the pattern of antibiotic use and to assess the seasonality and physician-related factors associated with variability in antibiotic prescribing in Isfahan province of Iran. METHODS: This cross-sectional survey was conducted on all prescriptions issued by general physicians from rural and urban areas in 2011. Associations between season of prescribing and physician related variables including gender, practice location and time since graduation with antibiotic prescriptions and also the pattern of antibiotic prescribing were assessed using Chi-square tests and multiple logistic regression models. RESULTS: Of the 7439709 prescriptions issued by 3772 general practitioners, 51% contained at least one antibiotic. Penicillins were the most frequently prescribed antibiotics, followed by cephalosporins and macrolides. Over-prescription of penicillins was associated with female gender (odds ratio [OR], 2.61; 95% confidence interval [CI] 2.13-3.19) and with moderate duration of time in practice (10-20 years) (OR, 1.42; 95% CI 1.14-1.76). Higher rates of cephalosporins prescription were observed in urban areas than rural areas and by male physicians. Seasonal peak was detected for penicillins and cephalosporins prescriptions in autumn. CONCLUSIONS: These findings showed the widespread use of antibiotics by general practitioners that was associated with the physicians' gender, time since graduation and practice location and also season of prescribing. More researches are needed on other factors related to the overprescribing of antibiotics and they could be used to project educational programs for improvement of antibiotic prescribing quality in our country. PMID- 25789138 TI - Reliability and validity of the modifiable activity questionnaire for an Iranian urban adolescent population. AB - BACKGROUND: The purpose of this study was to evaluate the validity and reliability on the Persian translation of the Modifiable Activity Questionnaire (MAQ) in a sample of Tehranian adolescents. METHODS: Of a total of 52 subjects, a sub-sample of 40 participations (55.0% boys) was used to assess the reliability and the validity of the physical activity questionnaire. The reliability of the two MAQs was calculated by intraclass correlation coefficients, and validation was evaluated using Pearson correlation coefficients to compare data between mean of the two MAQs and mean of four physical activity records. RESULTS: Intraclass correlation coefficient was calculated to assess the reliability between two MAQs and the results of leisure time physical activity over the past year were 0.97. Pearson correlation coefficients between mean of two MAQs and mean of four physical activity records were 0.49 (P < 0.001), for leisure time physical activities. CONCLUSIONS: High reliability and relatively moderate validity were found for the Persian translation of the MAQ in a Tehranian adolescent population. Further studies with large sample size are suggested to assess the validity more precisely. PMID- 25789139 TI - Formulating Evidence-based Public Health Policies: A Guide to Policy Makers. PMID- 25789140 TI - Is waist circumference a better predictor of diabetes than body mass index or waist-to-height ratio in Iranian adults? AB - BACKGROUND: Several measures of adiposity have been used for predicting diabetes. The results of studies regarding superiority of waist circumference (WC) to body mass index (BMI) are inconsistent. This study designed to compare the ability of different anthropometric measures in predicting diabetes and to determine their optimal cut-off values. METHODS: A population-based cross-sectional study was conducted with 1,000 representative sample among adults aged 20-80 years in Babol, the Northern Iran. The demographic data were collected in a household survey, and the anthropometric measures of weight, height, waist, and hip circumference were measured with a standard method. Fasting blood sugar (FBS) >=126 mg/dl was considered as diabetes. receiver operating characteristic analysis was used to estimate the predictive ability of different anthropometric indexes and their optimal cut-off values for high FBS. RESULTS: The overall prevalence rate of diabetes was 14.0% (14.4% in men vs. 13.5% in women, P = 0.65). The prevalence rate was significantly higher in older age (>60 years), low educated and obese (P = 0.001). The mean of BMI, WC, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were significantly higher among diabetic in both sexes (P = 0.001). Among men, WC (area under the ROC curve [AUC] =0.64) and WHtR (AUC = 0.63) have slightly higher accuracy index compared with BMI (AUC = 0.62) or WHR (AUC = 0.60). In contrast, among women, WHtR (AUC = 0.69) and WC (AUC = 0.68) yielded slightly better predictive than BMI (AUC = 0.67). The optimal cut off values obtained for BMI and WHtR were similar between two sexes (BMI = 24.95 kg/m(2) for men and BMI = 25.2 kg/m(2) for women, WHtR = 0.51 for both sexes) whereas the optimal cut-off value for WC was higher in men than women (98.5 cm men vs. 89.5 cm women). CONCLUSIONS: Overall WC and WHtR exhibited a slightly better discriminate performance than BMI for diabetes in both sexes, particularly in women. PMID- 25789141 TI - Frequency of Aggressive Behaviors in a Nationally Representative Sample of Iranian Children and Adolescents: The CASPIAN-IV Study. AB - BACKGROUND: This study aims to explore the frequency of aggressive behaviors among a nationally representative sample of Iranian children and adolescents. METHODS: This nationwide study was performed on a multi-stage sample of 6-18 years students, living in 30 provinces in Iran. Students were asked to confidentially report the frequency of aggressive behaviors including physical fighting, bullying and being bullied in the previous 12 months, using the questionnaire of the World Health Organization Global School Health Survey. RESULTS: In this cross-sectional study, 13,486 students completed the study (90.6% participation rate); they consisted of 49.2% girls and 75.6% urban residents. The mean age of participants was 12.47 years (95% confidence interval: 12.29, 12.65). In total, physical fight was more prevalent among boys than girls (48% vs. 31%, P < 0.001). Higher rates of involvement in two other behaviors namely being bullied and bulling to other classmates had a higher frequency among boys compared to girls (29% vs. 25%, P < 0.001 for being bullied) and (20% vs. 14%, P < 0.001 for bulling to others). Physical fighting was more prevalent among rural residents (40% vs. 39%, respectively, P = 0.61), while being bullied was more common among urban students (27% vs. 26%, respectively, P = 0.69). CONCLUSIONS: Although in this study the frequency of aggressive behaviors was lower than many other populations, still these findings emphasize on the importance of designing preventive interventions that target the students, especially in early adolescence, and to increase their awareness toward aggressive behaviors. Implications for future research and aggression prevention programming are recommended. PMID- 25789142 TI - Comment on: Prevention of Renal Damage by Treating Hyperuricemia. PMID- 25789143 TI - Protective effect of hydroalcoholic extract of tribulus terrestris on Cisplatin induced renal tissue damage in male mice. AB - BACKGROUND: According beneficial effects of Tribulus terrestris (TT) extract on tissue damage, the present study investigated the influence of hydroalcoholic extract of TT plant on cisplatin (CIS) (EBEWE Pharma, Unterach, Austria) induced renal tissue damage in male mice. METHODS: Thirty mice were divided into five groups (n = 6). The first group (control) was treated with normal saline (0.9% NaCl) and experimental groups with CIS (E1), CIS + 100 mg/kg extract of TT (E2), CIS + 300 mg/kg extract of TT (E3), CIS + 500 mg/kg extract of TT (E4) intraperitoneally. The kidneys were removed after 4 days of injections, and histological evaluations were performed. RESULTS: The data were analyzed using one-way analysis of variance followed by Tukey's post-hoc test, paired-sample t test, Kruskal-Wallis and Mann-Whitney tests. In the CIS treated group, the whole kidney tissue showed an increased dilatation of Bowman's capsule, medullar congestion, and dilatation of collecting tubules and a decreased in the body weight and kidney weight. These parameters reached to the normal range after administration of fruit extracts of TT for 4 days. CONCLUSIONS: The results suggested that the oral administration of TT fruit extract at dose 100, 300 and 500 mg/kg body weight provided protection against the CIS induced toxicity in the mice. PMID- 25789144 TI - Promoting Physical Activity Participation among Adolescents: The Barriers and the Suggestions. AB - BACKGROUND: Physical activity is a complex behavior. To designing the effective intervention, qualitative researches may be allowed for greater understanding of the reasons behind the adolescences' physical activity-related behaviors'. METHODS: Using the grounded theory approach, including semi-structured focus group discussions (FGDs) and in-depth interviews, we conducted a quantitative study to elicit the adolescents and key informants' opinion regarding the satiation, needs, social and environmental barriers of adolescents' physical activity. For FGDs, participants were selected from volunteered adolescent (aged 10-19 years) of the populated western part of Tehran, which was selected as a research field. Key informants were invited from the health professionals and experts in the field of adolescents' health. RESULTS: According to findings, although the majority of participants agreed on the important role of physical activity, the lack of essential motivation and the pressure of educational assignments remove it from the daily program priorities. Lack of a safe environment for girls' physical activity and high cost of professional sports were two first mentioned barriers. It was also suggested that future interventions should focus on improving more parents' engagement and their direct participation in physical activities with their adolescents. CONCLUSIONS: We proposed the participatory strategies for adolescent's physical activity promotion. Through which target groups participation during the designing, development, and implementation of health programs led to more effective interventions. PMID- 25789145 TI - The Percentage of Error of Different Weight Estimation Methods toward Actual Weight in Children Admitted to 17 Shahrivar Hospital. AB - BACKGROUND: In pediatric resuscitation, it is necessary to distinguish the weight in order to provide proper doses of drugs, equipment selection, and ventilator settings, therefore, access to a simple, unbiased, and accurate formula can decrease mistakes. The aim of this study is to determine the percentage of error (PE) of different weight estimation methods toward actual weight in children admitted to 17 Shahrivar Hospital. METHODS: This is a descriptive cross-sectional study conducted on 1-10 years children admitted in the pediatric clinic of 17 Shahrivar Hospital in Rasht. Data were collected by a checklist, including age, sex, height and mid-arm circumference (MAC). Investigators compared estimated weight by ten different methods with the actual weight. Finally, clinicians measured the PE and data were analyzed in SPSS software version.18. RESULTS: About 50.9% of participants were male. The mean age was 4.59 +/- 3.35 years and the mean weight was 17.4 +/- 5.69 (6.5-45) kg. Results showed no significant difference between the estimated weight and the actual one based on visual expert estimation and advanced pediatric life support (APLS) method. Visual estimation (0.017%) and MAC (25.48%) noted the lowest and highest PE, respectively. CONCLUSIONS: Results indicated a significant difference between the estimated weight and the actual one based on visual expert's estimation and APLS method. As, these methods were easy, rapid and accurate for body weight estimation in emergencies and may be more accurate than parent's estimation, it seems that it could be helpful for prescribing medication dosage and equipment sizes. PMID- 25789146 TI - Current status of the clinical epidemiology of myocardial infarction in men and women: a national cross-sectional study in iran. AB - BACKGROUND: Cardiovascular disease is the main reason for mortality in men and women. Clinical epidemiology of myocardial infarction (MI) in men and women has not been yet studied in Iran, one of the largest Middle East countries in South Western Asia. This study was conducted to determine the clinical epidemiology of MI in men and women in Iran. METHODS: This hospital-based, cross-sectional study used the data of 20,750 MI patients in Iran in 2012 (the codes I22, I21, I24, and I25.2). Univariate comparisons used Chi-square test for categorical variables and t-test for continuous variables. P < 0.05 was considered as significant. RESULTS: Totally, 20,750 MI patients (15,033 men and 5,717 women) with age range of 13-106 (mean; 61.2 +/- 13.4) years were enrolled. Only 9 (0.04%) patients (8 men and 1 woman) were <=18 years (mean age: 14.8 +/- 1.9), out of whom only two men were diabetic. 22.2% (18% men and 33.4% women) of the patients had diabetes, 26.2% (28.5% men and 20.1% women) were smoker and 35.5% (28.6% men and 53.7% women) had hypertension. ST-segment elevation MI incidence was 2.8 times higher in men than women. Left bundle branch block was significantly more prevalent in men than women. Men used percutaneous coronary intervention more frequently than women did. No difference in coronary artery bypass graft was noted between men and women. Mortality incidence was approximately twice higher in men than women. The prevalence of chest pain was higher in women than men. CONCLUSIONS: The MI incidence pattern, mortality from MI, and risk factors prevalence are significantly different between men and women in Iran. More emphasis on these issues in training people and healthcare professionals seems to contribute partially to patients' timely referring to health care centers and preventing MI associated mortalities. PMID- 25789147 TI - Is Serum Prostate-specific Antigen a Diagnostic Marker for Benign and Malignant Breast Tumors in Women? AB - BACKGROUND: Breast cancer is the most common cancer in women. Prostate-specific antigen (PSA) is a marker of prostate gland malignancy, which has been considered in cases with breast cancer in recent years. The goal of this study was to determine total and free PSA levels in cases with malignant and benign breast lesions. METHODS: In this case-control study, ninety women with histological proved malignant breast masses and 90 with benign breast masses were enrolled. Total and free PSA levels along with Histological grade and conditions of vascular and perinural invasion, status of hormonal tumor receptors, immune-histo chemistry markers recorded for all cases. Total and free PSA levels were assessed after treatment in cases with malignant masses. RESULTS: Total and free PSA levels were significantly higher in cases with malignant masses. The best cut-off point for total PSA to differentiate benign and malignant masses was 0.31 with sensitivity and specificity of 100%, 100% (area under the curve [AUC] =1, P < 0.001) and the best cut-off point for free PSA to differentiate benign and malignant masses was 0.19 with sensitivity and specificity of 100% and 100% (AUC = 1, P < 0.001). After treatment, mean free PSA level was significantly lower than free PSA before treatment (0.23 +/- 0.1 vs. 0.3 +/- 0.08, P < 0.001). CONCLUSIONS: Serum PSA level could be applied for differentiating benign and malignant breast masses. PMID- 25789148 TI - Commentary on prevention a possible drug-drug interaction: is concurrent administration of orlistat and pioglitazone increase the risk of durg-induced hepatotoxicity? AB - BACKGROUND: Drug-drug interactions (DDIs) are an emerging threat to public health and are difficult to detect. To prevent DDIs and their burden, the possible DDIs should be kept in mind. We know that the obesity predisposes to the development of insulin resistance and type 2 diabetes. Therefore, combinational uses of antiobesity drugs and glucose-lowering drugs are very common. As the hepatotoxicity of both pioglitazone (an antidiabetic drug) and orlistat (an antiobesity drug) has been shown in some cases, the aim of this study was to evaluate the interaction of pioglitazone and orlistat in human hepatocellular cell line human hepatocellular carcinoma (HepG2) cells to determine their effect on liver toxicity. METHODS: Human hepatocellular carcinoma cells were treated with 25 MUM Pioglitazon (Pio), 20 MUM Orlistat (Orl) pioglitazone, orlistat or combination of them. The MTT assay was used to assess cell viability. RESULTS: Pioglitazone and orlistat combination caused a loss of HepG2 cell viability. While pioglitazone (25 MUM) and orliatat (20 MUM) alone decreased the cell viability around 91% and 85% respectively (notsignificant, P > 0.05), the combination of these two drugs reduced the amount of viable cells to 55% which was significant when compared with each drug alone (P < 0.001). CONCLUSIONS: Revealing the significant loss of viability of HepG2 cells in the combination use of pioglitazone and orlistat indicates these two drugs should not be administered at the same time to prevent their hepatotoxic effects especially in patients with liver dysfunction. PMID- 25789150 TI - The Attitude of Physicians toward the Use of Patient Decision Aids in Iran as a Developing Country. AB - BACKGROUND: The patient decision aids (PDAs), which can facilitate the decision making process when choosing the optimal method of treatment, are a challenge to patients. This study tried to determine the attitude of physicians on the barriers of using PDAs in the way of prioritizing and proposing solutions to them. METHODS: This study was a cross-sectional research carried out on 150 clinical faculty members of research centers and scientific associations affiliated with Tehran University of Medical Sciences. The participants were chosen using the convenience sampling method. The attitude of physicians toward the application of PDAs was interviewed using a self-made questionnaire composed of 23 questions. The association between physicians' attitude to the use of PDAs and their characteristics was examined using the t-test, analysis of variance, and correlation test. RESULTS: The mean score of physicians' attitude was 76.2 (standard deviation =11.9) and the range was 33-107. There was a significant and direct association between the attitude toward the use of PDA and the respondents' age (r = 0.237, P = 0.007), years of experience (r = 0.205, P = 0.02), being male (P = 0.04), and working in the private sector (P = 0.009). The attitude score of instructors was significantly lower than that of professors (P = 0.02). CONCLUSIONS: The general attitude of physicians toward the use of PDAs was positive. However, apparently as a result of problems mentioned in this study for the developing countries such as Iran, it is much easier to employ these tools in centers run by the private sector. Usage of such tools in public centers necessitates systemic infrastructure as well as credits and budgets required for the training of patients and physicians. PMID- 25789149 TI - The Relationship between Perchlorate in Drinking Water and Cord Blood Thyroid Hormones: First Experience from Iran. AB - BACKGROUND: Considering the controversial information regarding the effects of perchlorate on thyroid function of high risk population as neonates, and given the high prevalence rate of thyroid disorders specially congenital hypothyroidism in our region, this study aims to investigate for the first time in Iran, the relationship between drinking groundwater perchlorate and cord blood thyroid hormones level in an industrial region. METHODS: In this cross-sectional study, drinking groundwater perchlorate level of rural areas of Zarinshahr, Isfahan was measured. Simultaneously, cord blood level of thyroid hormones of neonates born in the studied region was measured. Thyroid function test of neonates in regions with low and high perchlorate level were compared. RESULTS: In this study, 25 tap water samples were obtained for perchlorate measurement. Level of cord blood thyroid stimulating hormone (TSH), T4 and T3 of 25 neonates were measured. Mean (standard deviation) of perchlorate, TSH, T4 and T3 was 3.59 (5.10) MUg/l, 7.81 (4.14) mIU/m, 6.06 (0.85) mg/dl, and 63.46 (17.53) mg/dl, respectively. Mean levels of thyroid function tests were not different in low (<5 MUg/l) and high level of drinking ground water perchlorate (P > 0.05). CONCLUSIONS: Perchlorate did not appear to be related to thyroid function of neonates in the studied industrial region. It seems that iodine status of the regions, as well as other environmental contaminants and genetic background, could impact on its relation with thyroid function of neonates. PMID- 25789151 TI - Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders. AB - BACKGROUND: Many studies have demonstrated a robust statistical overlap between genes whose transcripts are reported as Fragile X Mental Retardation Protein (Fmrp)-binding targets and genes implicated in various psychiatric disorders, including autism. However, it is not clear how to interpret this overlap as the Fmrp protein itself is not considered to be central to all instances of these conditions. FINDINGS: We tested whether Fmrp binding may be a proxy for some other features of these transcripts. Reviewing recent literature on the cross linking and immunoprecipitation (CLIP)-derived targets of Fmrp in the brain, and the literature on identifying genes thought to mediate autism and other psychiatric disorders, reveals that both appear to be disproportionately made up of highly brain-expressed genes. This suggests a parsimonious explanation-that the overlap between Fmrp targets and neuropsychiatric candidate genes might be secondary to simple features such as transcript length and robust expression in the brain. Indeed, reanalyzing Fmrp high-throughput sequencing of RNAs isolated by CLIP (HITS-CLIP) data suggests that approximately 60% of CLIP tag depth can be predicted by gene expression, coding sequence length, and transcript length. Furthermore, there is a statistically significant overlap between autism candidate genes and random samples of long, highly brain-expressed genes, whether they are Fmrp targets or not. CONCLUSIONS: Comparison of known Fmrp-binding targets to candidate gene lists should be informed by both of these features. PMID- 25789152 TI - Database citation in supplementary data linked to Europe PubMed Central full text biomedical articles. AB - BACKGROUND: In this study, we present an analysis of data citation practices in full text research articles and their corresponding supplementary data files, made available in the Open Access set of articles from Europe PubMed Central. Our aim is to investigate whether supplementary data files should be considered as a source of information for integrating the literature with biomolecular databases. RESULTS: Using text-mining methods to identify and extract a variety of core biological database accession numbers, we found that the supplemental data files contain many more database citations than the body of the article, and that those citations often take the form of a relatively small number of articles citing large collections of accession numbers in text-based files. Moreover, citation of value-added databases derived from submission databases (such as Pfam, UniProt or Ensembl) is common, demonstrating the reuse of these resources as datasets in themselves. All the database accession numbers extracted from the supplementary data are publicly accessible from http://dx.doi.org/10.5281/zenodo.11771. CONCLUSIONS: Our study suggests that supplementary data should be considered when linking articles with data, in curation pipelines, and in information retrieval tasks in order to make full use of the entire research article. These observations highlight the need to improve the management of supplemental data in general, in order to make this information more discoverable and useful. PMID- 25789153 TI - Supporting the annotation of chronic obstructive pulmonary disease (COPD) phenotypes with text mining workflows. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a life-threatening lung disorder whose recent prevalence has led to an increasing burden on public healthcare. Phenotypic information in electronic clinical records is essential in providing suitable personalised treatment to patients with COPD. However, as phenotypes are often "hidden" within free text in clinical records, clinicians could benefit from text mining systems that facilitate their prompt recognition. This paper reports on a semi-automatic methodology for producing a corpus that can ultimately support the development of text mining tools that, in turn, will expedite the process of identifying groups of COPD patients. METHODS: A corpus of 30 full-text papers was formed based on selection criteria informed by the expertise of COPD specialists. We developed an annotation scheme that is aimed at producing fine-grained, expressive and computable COPD annotations without burdening our curators with a highly complicated task. This was implemented in the Argo platform by means of a semi-automatic annotation workflow that integrates several text mining tools, including a graphical user interface for marking up documents. RESULTS: When evaluated using gold standard (i.e., manually validated) annotations, the semi-automatic workflow was shown to obtain a micro averaged F-score of 45.70% (with relaxed matching). Utilising the gold standard data to train new concept recognisers, we demonstrated that our corpus, although still a work in progress, can foster the development of significantly better performing COPD phenotype extractors. CONCLUSIONS: We describe in this work the means by which we aim to eventually support the process of COPD phenotype curation, i.e., by the application of various text mining tools integrated into an annotation workflow. Although the corpus being described is still under development, our results thus far are encouraging and show great potential in stimulating the development of further automatic COPD phenotype extractors. PMID- 25789154 TI - NBD delivery improves the disease phenotype of the golden retriever model of Duchenne muscular dystrophy. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and afflicts skeletal and cardiac muscles. Previous studies showed that DMD is associated with constitutive activation of NF-kappaB, and in dystrophin-deficient mdx and utrophin/dystrophin (utrn (-/-) ;mdx) double knock out (dko) mouse models, inhibition of NF-kappaB with the Nemo Binding Domain (NBD) peptide led to significant improvements in both diaphragm and cardiac muscle function. METHODS: A trial in golden retriever muscular dystrophy (GRMD) canine model of DMD was initiated with four primary outcomes: skeletal muscle function, MRI of pelvic limb muscles, histopathologic features of skeletal muscles, and safety. GRMD and wild type dogs at 2 months of age were treated for 4 months with NBD by intravenous infusions. Results were compared with those collected from untreated GRMD and wild type dogs through a separate, natural history study. RESULTS: Results showed that intravenous delivery of NBD in GRMD dogs led to a recovery of pelvic limb muscle force and improvement of histopathologic lesions. In addition, NBD-treated GRMD dogs had normalized postural changes and a trend towards lower tissue injury on magnetic resonance imaging. Despite this phenotypic improvement, NBD administration over time led to infusion reactions and an immune response in both treated GRMD and wild type dogs. CONCLUSIONS: This GRMD trial was beneficial both in providing evidence that NBD is efficacious in a large animal DMD model and in identifying potential safety concerns that will be informative moving forward with human trials. PMID- 25789155 TI - DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy. AB - BACKGROUND: The most common form of facioscapulohumeral muscular dystrophy (FSHD) is caused by a genetic contraction of the polymorphic D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q. In some studies, genes centromeric to the D4Z4 repeat array have been reported to be over-expressed in FSHD, including FRG1 and FRG2, presumably due to decreased long-distance repression by the shorter array through a mechanism similar to position-effect variegation. Differential regulation of FRG1 in FSHD has never been unequivocally proven, however, FRG2 has been reproducibly shown to be induced in primary FSHD derived muscle cells when differentiated in vitro. The molecular function of FRG2 and a possible contribution to FSHD pathology remain unclear. Recent evidence has identified the mis-expression of DUX4, located within the D4Z4 repeat unit, in skeletal muscle as the cause of FSHD. DUX4 is a double homeobox transcription factor that has been shown to be toxic when expressed in muscle cells. METHODS: We used a combination of expression analysis by qRT/PCR and RNA sequencing to determine the transcriptional activation of FRG2 and DUX4. We examined this in both differentiating control and FSHD derived muscle cell cultures or DUX4 transduced control cell lines. Next, we used ChIP-seq analysis and luciferase reporter assays to determine the potential DUX4 transactivation effect on the FRG2 promoter. RESULTS: We show that DUX4 directly activates the expression of FRG2. Increased expression of FRG2 was observed following expression of DUX4 in myoblasts and fibroblasts derived from control individuals. Moreover, we identified DUX4 binding sites at the FRG2 promoter by chromatin immunoprecipitation followed by deep sequencing and confirmed the direct regulation of DUX4 on the FRG2 promoter by luciferase reporter assays. Activation of luciferase was dependent on both DUX4 expression and the presence of the DUX4 DNA binding motifs in the FRG2 promoter. CONCLUSION: We show that the FSHD specific upregulation of FRG2 is a direct consequence of the activity of DUX4 protein rather than representing a regional de-repression secondary to fewer D4Z4 repeats. PMID- 25789156 TI - Myocyte enhancer factor 2C function in skeletal muscle is required for normal growth and glucose metabolism in mice. AB - BACKGROUND: Skeletal muscle is the most abundant tissue in the body and is a major source of total energy expenditure in mammals. Skeletal muscle consists of fast and slow fiber types, which differ in their energy usage, contractile speed, and force generation. Although skeletal muscle plays a major role in whole body metabolism, the transcription factors controlling metabolic function in muscle remain incompletely understood. Members of the myocyte enhancer factor 2 (MEF2) family of transcription factors play crucial roles in skeletal muscle development and function. MEF2C is expressed in skeletal muscle during development and postnatally and is known to play roles in sarcomeric gene expression, fiber type control, and regulation of metabolic genes. METHODS: We generated mice lacking Mef2c exclusively in skeletal muscle using a conditional knockout approach and conducted a detailed phenotypic analysis. RESULTS: Mice lacking Mef2c in skeletal muscle on an outbred background are viable and grow to adulthood, but they are significantly smaller in overall body size compared to control mice and have significantly fewer slow fibers. When exercised in a voluntary wheel running assay, Mef2c skeletal muscle knockout mice aberrantly accumulate glycogen in their muscle, suggesting an impairment in normal glucose homeostasis. Consistent with this notion, Mef2c skeletal muscle knockout mice exhibit accelerated blood glucose clearance compared to control mice. CONCLUSIONS: These findings demonstrate that MEF2C function in skeletal muscle is important for metabolic homeostasis and control of overall body size. PMID- 25789157 TI - Mediation of exogenous hydrogen sulfide in recovery of ischemic post-conditioning induced cardioprotection via down-regulating oxidative stress and up-regulating PI3K/Akt/GSK-3beta pathway in isolated aging rat hearts. AB - The physiological and pathological roles of hydrogen sulfide (H2S) in the regulation of cardiovascular functions have been recognized. Cystathionine gamma lyase (CSE) is a major H2S-producing enzyme in cardiovascular system. Ischemic post-conditioning (PC) provides cadioprotection in young hearts but lost in the aging hearts. The involvement of H2S in the recovery of PC-induced cardioprotection in the aging hearts is unclear. In the present study, we demonstrated that ischemia/reperfusion (I/R) decreased H2S production rate and CSE expression, aggravated cardiomyocytes damage, apoptosis and myocardial infarct size, reduced cardiac function, increased the levels of Bcl-2, caspase-3 and caspase-9 mRNA, enhanced oxidative stress in isolated young and aging rat hearts. I/R also increased the release of cytochrome c and down-regulated the phosphorylation of PI3K, Akt and GSK-3beta in the aging rat hearts. We further found that PC increased H2S production rate and CSE expressions, and protected young hearts from I/R-induced cardiomyocytes damage, all of which were disappeared in the aging hearts. Supply of NaHS not only increased PC-induced cardioprotection in the young hearts, but also lightened I/R induced-myocardial damage and significantly recovered the cardioprotective role of PC against I/R induced myocardial damage in the aging hearts. LY294002 (a PI3K inhibitor) abolished but N-acetyl-cysteine (NAC, an inhibitor of reactive oxygen species, ROS) further enhanced the protective role of H2S against I/R induced myocardial damage in the aging hearts. In conclusion, these results demonstrate that exogenous H2S recovers PC-induced cardioprotection via inhibition of oxidative stress and up-regulation of PI3K-Akt-GSK-3beta pathway in the aging rat hearts. These findings suggested that H2S might be a novel target for the treatment of aging cardiovascular diseases. PMID- 25789158 TI - Combined influence of basal media and fibroblast growth factor on the expansion and differentiation capabilities of adipose-derived stem cells. AB - BACKGROUND: Interest in adipose-derived stem cells (ASCs) has increased in recent years due to their multi-linage differentiation capabilities. While much work has been done to optimize the differentiation media, few studies have focused on examining the influence of different expansion media on cell behavior. In this study, three basal media (low glucose Dulbecco's modified Eagle's medium (DMEM), high glucose DMEM and DMEM-F12) supplemented with or without fibroblast growth factor 2 (FGF) were examined to assess their suitability for expanding ASCs. FINDINGS: Flow cytometry, colony-forming unit assays (CFU-Fs) and differentiation assays were utilized to study cell behavior. High glucose media CFU-Fs produced fewest colonies while the addition of FGF increased colony size. By passage 2, the majority of cells were positive for CD44, 45, 73, 90 and 105 and negative for CD14, 31 and 45, indicating a mesenchymal phenotype. A sub-population of CD34 positive cells was present among passage 2 cells; however, by passage 4 the cells were negative for CD34. FGF has a negative effective on passage 4 ASC adipogenesis and high glucose media plus FGF-enhanced osteogenic capacity of passage 4 ASCs. FGF supplemented basal media were most suitable for chondrogenesis. High glucose media plus FGF appeared to be the most beneficial for priming ASCs to induce a keratocyte phenotype. CONCLUSIONS: These findings demonstrate the reciprocal effect FGF and basal media have on ASCs. This research has implications for those interested regenerating bone, cartilage, cornea or adipose tissues. PMID- 25789159 TI - Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging. AB - The correlation of physiological sensitivity to insulin ( vis-a-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice. PMID- 25789160 TI - Association between obesity and depression in patients with diabetes mellitus type 2; a study protocol. AB - BACKGROUND: Diabetes mellitus and depression are highly prevalent conditions throughout the world and have significant impact on health outcomes. It has been estimated that diabetes mellitus type 2 affects about 246 million people in the world; nevertheless, incidence varies among countries. There is evidence that depression is associated with a poor metabolic control in patients with type 2 diabetes mellitus that present other health problems (such as hypertension and obesity). The aim of this study protocol is to determine if obesity increases the risk for depression in patient with diabetes type 2. METHODS: The analysis will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).The studies suitable for inclusion will be assessed by the Newcastle-Ottawa Scale (NOS) to determine their methodological quality. To identify the studies of interest, we will search on PubMed and EBSCO databases. We will use the following keyword combinations: "Diabetes Mellitus type 2 AND obesity AND depression", "depression AND Diabetes Mellitus type 2", "Diabetes Mellitus type 2 AND body mass index cross sectional study", "depression AND obesity cross-sectional study". Causes for exclusion will be publications that studied patients diagnosed with diabetes mellitus type 1; articles that focused on the treatment and complications of diabetes mellitus type 2; publications that have studied other clinical or psychiatric conditions (for instance, seizure disorder or history of schizophrenia, bipolar disorder, psychotic symptoms or dementia). CONCLUSION: The results of this study will form the basis for a better understanding of the association between obesity and depression in patients with diabetes mellitus type 2, and will allow development of prediction tools and better interventions. It is evident that several modifiable and non-modifiable risk factors play an important role in the pathogenesis of diabetes among population. Currently, evidence for the deleterious effects of diabetes mellitus type 2 are based on cross-sectional or other observational designs. Therefore, this study will have important implications for future research and public health guidance. PMID- 25789161 TI - Every scientist is a memory researcher: Suggestions for making research more memorable. AB - Independent of the actual results, some scientific articles are more memorable than others. As anyone who has written an article collaboratively knows, there are numerous ways a manuscript can be written to convey the same general ideas. To aid with this, many scientific writing books and editorials provide advice, often anecdotal, on how to make articles more memorable. Here I ground these suggestions with empirical support from memory research. Specifically, I suggest that researchers consider how to emphasize their work's novelty, strive to describe their work using concrete, easy-to-understand terms, and use caution when attempting to evoke an emotional response in the reader. I also discuss considerations in title selections and conference presentations. PMID- 25789162 TI - Guiding Ebola patients to suitable health facilities: an SMS-based approach. AB - Access to appropriate health services is a fundamental problem in developing countries, where patients do not have access to information and to the nearest health service facility. We propose building a recommendation system based on simple SMS text messaging to help Ebola patients readily find the closest health service with available and appropriate resources. The system will map people's reported symptoms to likely Ebola case definitions and suitable health service locations. In addition to providing a valuable individual service to people with curable diseases, the proposed system will also predict population-level disease spread risk for infectious diseases using crowd-sourced symptoms from the population. Health workers will be able to better plan and anticipate responses to the current Ebola outbreak in West Africa. Patients will have improved access to appropriate health care. This system could also be applied in other resource poor or rich settings. PMID- 25789163 TI - FDA approved drugs as potential Ebola treatments. AB - In the search for treatments for the Ebola Virus, multiple screens of FDA drugs have led to the identification of several with promising in vitro activity. These compounds were not originally developed as antivirals and some have been further tested in mouse in vivo models. We put forward the opinion that some of these drugs could be evaluated further and move into the clinic as they are already FDA approved and in many cases readily available. This may be important if there is a further outbreak in future and no other therapeutic is available. PMID- 25789164 TI - Using optical mapping data for the improvement of vertebrate genome assemblies. AB - Optical mapping is a technology that gathers long-range information on genome sequences similar to ordered restriction digest maps. Because it is not subject to cloning, amplification, hybridisation or sequencing bias, it is ideally suited to the improvement of fragmented genome assemblies that can no longer be improved by classical methods. In addition, its low cost and rapid turnaround make it equally useful during the scaffolding process of de novo assembly from high throughput sequencing reads. We describe how optical mapping has been used in practice to produce high quality vertebrate genome assemblies. In particular, we detail the efforts undertaken by the Genome Reference Consortium (GRC), which maintains the reference genomes for human, mouse, zebrafish and chicken, and uses different optical mapping platforms for genome curation. PMID- 25789165 TI - Paediatric leukaemia DNA methylation profiling using MBD enrichment and SOLiD sequencing on archival bone marrow smears. AB - BACKGROUND: Acute Lymphoblastic Leukaemia (ALL) is the most common cancer in children. Over the past four decades, research has advanced the treatment of this cancer from a less than 60% chance of survival to over 85% today. The causal molecular mechanisms remain unclear. Here, we performed sequencing-based genomic DNA methylation profiling of eight paediatric ALL patients using archived bone marrow smear microscope slides. FINDINGS: SOLiDTM sequencing data was collected from Methyl-Binding Domain (MBD) enriched fractions of genomic DNA. The primary tumour and remission bone marrow sample was analysed from eight patients. Four patients relapsed and the relapsed tumour was analysed. Input and MBD-enriched DNA from each sample was sequenced, aligned to the hg19 reference genome and analysed for enrichment peaks using MACS (Model-based Analysis for ChIP-Seq) and HOMER (Hypergeometric Optimization of Motif EnRichment). In total, 3.67 gigabases (Gb) were sequenced, 2.74 Gb were aligned to the reference genome (average 74.66% alignment efficiency). This dataset enables the interrogation of differential DNA methylation associated with paediatric ALL. Preliminary results reveal concordant regions of enrichment indicative of a DNA methylation signature. CONCLUSION: Our dataset represents one of the first SOLiDTMMBD-Seq studies performed on paediatric ALL and is the first to utilise archival bone marrow smears. Differential DNA methylation between cancer and equivalent disease-free tissue can be identified and correlated with existing and published genomic studies. Given the rarity of paediatric haematopoietic malignancies, relative to adult counterparts, our demonstration of the utility of archived bone marrow smear samples to high-throughput methylation sequencing approaches offers tremendous potential to explore the role of DNA methylation in the aetiology of cancer. PMID- 25789166 TI - Nephrin - a biomarker of early glomerular injury. AB - Nephrin is a 180 KD trans-membrane protein expressed in glomerular podocytes. It was first identified in children with congenital nephrotic syndrome of the Finnish type (NPHS1). Nephrin forms an integral part of podocytes, which-together with endothelial cells and the basement-form the glomerular filtration barrier. Podocytopathies result in the detection of nephrin in the urine. We reviewed the literature to determine if urine nephrin measurements could become useful as a biomarker to detect early podocyte injury. Our search identified a total of 19 studies that have been published to date. The most common clinical conditions for which urine nephrin analyses were carried out included diabetic nephropathy, glomerulonephritis and pre-eclampsia. Nephrin measurement was carried out using commercially available ELISA kits, the messenger ribonucleic acid real-time polymerase chain Reaction, or electrophoresis. Nephrinuria showed positive correlation with proteinuria and severity of podocyte injury. In two studies, the level of nephrinuria declined in conjunction with clinical improvement in the patient following immunosuppressive treatment. Currently, there is no published data on the value of measuring urinary nephrin in pediatric patients. PMID- 25789167 TI - Spatiality, seasonality and ecological risks of heavy metals in the vicinity of a degenerate municipal central dumpsite in Enugu, Nigeria. AB - BACKGROUND: Improper waste disposal is responsible for the contamination of both surface and ground water resources. Heavy metals leached from improperly disposed solid waste constitute grave environmental and health hazards because of their toxic and persistent nature. There are thousands of open dumps in Nigeria one of which is the Enugu State Waste Management Authority dumpsite. METHOD: Forty sampling nodes were systematically established around the Enugu State waste Management Authority central dumpsite located at Ugwuaji, Enugu State, Nigeria. Ten heavy metals (arsenic, cadmium, cobalt, copper, chromium, iron, lead, manganese, nickel and zinc) were sampled at different depths of each node in both rainy and dry seasons. RESULT: Iron and lead were the predominant metals in the vicinity of the waste dump with average values of 132.10 mg/kg and 117.52 mg/kg respectively. The order of abundance of the ten heavy metals monitored is Pb > Fe > As > Zn > Cu > Co > Ni > Cd > Cr > Mn. Generally, there was significant correlation (0.25 to 0.74) among all the metals except between cobalt and manganese in the rainy season. In the dry season, all the metals were significantly correlated (0.29 to 0.813) except for copper and lead, copper and arsenic, zinc and arsenic, and cobalt and manganese. The concentrations of most of the heavy metals approached a constant level at a depth of 1 m. On the other hand, the concentrations of arsenic, cobalt and iron continued to decrease even at a depth of 2 m. The pollution loading index values for the soil are 1.706 for rainy season and 2.54 for dry season. CONCLUSION: The high pollution loading index represents a significant level of deterioration. It can be concluded that the dumpsite constitute a serious environmental and health hazard. PMID- 25789168 TI - Work productivity and neuropsychological function in persons with skull base tumors. AB - BACKGROUND: Skull base tumors comprise many common benign brain tumors. Treatment has advanced, allowing many survivors to return to work. However, literature is limited about the neuropsychological status of these patients prior to treatment. Literature pertaining to the relationship between neuropsychological functioning and occupational ability prior to surgical intervention is even more limited. The purpose of this analysis was to evaluate the impact of neuropsychological function on work productivity in persons with skull base tumors prior to resection. METHODS: Neuropsychological function and work productivity were assessed in adults newly diagnosed with skull base tumors (n = 45) prior to surgical intervention. Univariate analyses identified potential predictors of work limitations; variables with P < .10 were analyzed using multivariate regression analyses controlled for age, sex, tumor type, and education. RESULTS: Poorer mental attention and flexibility (MF) and higher depressive symptoms (DS) were significantly associated with poor time management at work (MF: beta = 0.59, P = .01; DS: beta = 3.42, P < .01; R2 = 0.54). Difficulty meeting physical work demands was significantly associated with poorer visuospatial ability (VA) and higher depressive symptoms (VA: beta = -3.30, P = .05; DS: beta = 2.29, P < .01; R2 = 0.29). Lower learning and memory scores (LM) and higher depressive symptoms were significantly associated with difficulty meeting mental interpersonal work demands (LM: beta = -3.39, P = .04; DS: beta = 3.25, P < .01; R2 = 0.47) and overall health-related loss of work productivity (LM: beta = 0.72, P = .05; DS: beta = 0.659, P < .001; R2 = 0.43). CONCLUSION: Domains of neuropsychological function that predicted work productivity were identified. Future research should examine neuropsychological function, depressive symptoms, and work productivity across the care trajectory from diagnosis through long-term survivorship. PMID- 25789169 TI - The Prevalence of Age-Related Eye Diseases and Cataract Surgery among Older Adults in the City of Lodz, Poland. AB - Purpose. To determine the prevalence of age-related eye diseases and cataract surgery among older adults in the city of Lodz, in central Poland. Material and Methods. The study design was cross-sectional and observational study. A total of 1107 women and men of predominantly Caucasian origin were successfully enumerated and recruited for the study. All selected subjects were interviewed and underwent detailed ophthalmic examinations. Results. Overall 8.04% (95% CI 6.44-9.64) subjects had cataract surgery in either eye. After excluding subjects with bilateral cataract surgery, the prevalence of cataract was 12.10% (95% CI 10.18 14.03). AMD was found in 4.33% (95% CI 3.14-5.54 ) of all subjects. Of them 3.25% (95% CI 2.21-4.30 ) had early AMD and 1.08% (95% CI 0.47-1.69) had late AMD. Various types of glaucoma were diagnosed in 5.51% (95% CI 4.17-6.85) of subjects and 2.62% (95% CI 1.68-3.56) had OHT. The prevalence rates of DR and myopic macular degeneration were 1.72% (95% CI 0.95-2.48) and 0.45% (95% CI 0.06-0.85), respectively. All multiple logistic regression models were only significantly associated with older age. The highest rate of visual impairment was observed among subjects with retinal diseases. Conclusions. The study revealed high prevalence of age-related eye diseases in this older population. PMID- 25789170 TI - Young adults, technology, and weight loss: a focus group study. AB - Overweight and obesity are a major concern in young adults. Technology has been integrated into many weight loss interventions; however little is known about the use of this technology in young adults. The purpose of this study was to explore through focus group sessions the opinions of young adults on the use of technology for weight loss. A total of 17 young adults, between 18 and 25 years of age, participated in three focus group sessions. Major results indicated that young adults have very little knowledge on the use of Smartphone technology for weight loss but would like to use this type of technology to help them lose weight. Results also indicated that young adults struggle to make healthy food choices and have priorities that outweigh exercise and they need support and guidance to make better decisions. In conclusion, young adults would be open to using Smartphone technology for weight loss but also need feedback and guidance to help make healthy decisions. PMID- 25789172 TI - Prevalence of Depression among Type 2 Diabetic Outpatients in Black Lion General Specialized Hospital, Addis Ababa, Ethiopia. AB - Background. The emotional consequences of diabetes have been scrutinized by a number of investigative teams and there are varying reports about the association of depression with type 2 diabetes mellitus. However, there is limited data about this in Ethiopia. Therefore, the purpose of this study was to assess the prevalence of comorbid depression among type 2 diabetic outpatients. Methods and Materials. Institution based cross-sectional study design was conducted on a random sample of 276 type 2 diabetic outpatients from Black Lion General Specialized Hospital. Systematic random sampling technique was used to get these individual patients from 920 type 2 diabetic outpatients who have an appointment during the data collection period. Patients' depression status was measured using Patient Health Questionnaire 9 (PHQ 9). Result. Totally 264 type 2 diabetic outpatients were interviewed with a response rate of 95.6%. The prevalence of depression among type 2 diabetic outpatients was 13%. Based on PHQ 9 score, 28.4% (75) fulfilled the criteria for mild depression, 12.1% (32) for moderate depression, 2.7% (7) for moderately severe depression, and 1.5% (4) for severe depression. But 45.8% (121) of patients had no clinically significant depression. Conclusion. This study demonstrated that depression is a common comorbid health problem in type 2 diabetic outpatients with a prevalence rate of 13%. PMID- 25789171 TI - Ascertainment and verification of end-stage renal disease and end-stage liver disease in the north american AIDS cohort collaboration on research and design. AB - The burden of HIV disease has shifted from traditional AIDS-defining illnesses to serious non-AIDS-defining comorbid conditions. Research aimed at improving HIV related comorbid disease outcomes requires well-defined, verified clinical endpoints. We developed methods to ascertain and verify end-stage renal disease (ESRD) and end-stage liver disease (ESLD) and validated screening algorithms within the largest HIV cohort collaboration in North America (NA-ACCORD). Individuals who screened positive among all participants in twelve cohorts enrolled between January 1996 and December 2009 underwent medical record review to verify incident ESRD or ESLD using standardized protocols. We randomly sampled 6% of contributing cohorts to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ESLD and ESRD screening algorithms in a validation subcohort. Among 43,433 patients screened for ESRD, 822 screened positive of which 620 met clinical criteria for ESRD. The algorithm had 100% sensitivity, 99% specificity, 82% PPV, and 100% NPV for ESRD. Among 41,463 patients screened for ESLD, 2,024 screened positive of which 645 met diagnostic criteria for ESLD. The algorithm had 100% sensitivity, 95% specificity, 27% PPV, and 100% NPV for ESLD. Our methods proved robust for ascertainment of ESRD and ESLD in persons infected with HIV. PMID- 25789173 TI - Higher mobility scores in patients with cystic fibrosis are associated with better lung function. AB - OBJECTIVE: The purpose of this study was to determine whether mobility and physical activity were associated with lung function in adults with cystic fibrosis (CF). DESIGN: This was a prospective cohort observational study in an urban, academic, specialized care center. Participants were ambulatory, nonhospitalized adults with CF. MAIN OUTCOME MEASURES: Mobility was assessed monthly by the Life-Space Assessment (LSA) questionnaire and quarterly by pedometer. Lung function was assessed by spirometry. RESULTS: Twenty-seven subjects participated. Subjects recorded mean pedometer steps of 20,213 +/- 11,331 over three days and FEV1% predicted of 77.48% +/- 22.60% over one year. The LSA score at enrollment was correlated with initial pedometer steps (r = 0.42 and P = 0.03), and mean LSA score over one year was correlated with mean number of steps (r = 0.51 and P = 0.007). LSA mobility and pedometer scores were correlated with FEV1% predicted at enrollment and throughout the study. CONCLUSIONS: Mobility and physical activity measured by LSA questionnaire and pedometer are positively associated with lung function in adults with CF. This study confirms the importance of mobility and physical activity and supports the utility of a simple office-based questionnaire as a measure of mobility in adults with CF. PMID- 25789176 TI - Formulation and evaluation of optimized oxybenzone microsponge gel for topical delivery. AB - Background. Oxybenzone, a broad spectrum sunscreen agent widely used in the form of lotion and cream, has been reported to cause skin irritation, dermatitis, and systemic absorption. Aim. The objective of the present study was to formulate oxybenzone loaded microsponge gel for enhanced sun protection factor with reduced toxicity. Material and Method. Microsponge for topical delivery of oxybenzone was successfully prepared by quasiemulsion solvent diffusion method. The effects of ethyl cellulose and dichloromethane were optimized by the 3(2) factorial design. The optimized microsponges were dispersed into the hydrogel and further evaluated. Results. The microsponges were spherical with pore size in the range of 0.10-0.22 um. The optimized formulation possesses the particle size and entrapment efficiency of 72 +/- 0.77 um and 96.9 +/- 0.52%, respectively. The microsponge gel showed the controlled release and was nonirritant to the rat skin. In creep recovery test it had shown highest recovery indicating elasticity. The controlled release of oxybenzone from microsponge and barrier effect of gel result in prolonged retention of oxybenzone with reduced permeation activity. Conclusion. Evaluation study revealed remarkable and enhanced topical retention of oxybenzone for prolonged period of time. It also showed the enhanced sun protection factor compared to the marketed preparation with reduced irritation and toxicity. PMID- 25789174 TI - 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling. AB - Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS), indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR) components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans. PMID- 25789175 TI - Bp-13 PLA2: Purification and Neuromuscular Activity of a New Asp49 Toxin Isolated from Bothrops pauloensis Snake Venom. AB - A new PLA2 (Bp-13) was purified from Bothrops pauloensis snake venom after a single chromatographic step of RP-HPLC on MU-Bondapak C-18. Amino acid analysis showed a high content of hydrophobic and basic amino acids and 14 half-cysteine residues. The N-terminal sequence showed a high degree of homology with basic Asp49 PLA2 myotoxins from other Bothrops venoms. Bp-13 showed allosteric enzymatic behavior and maximal activity at pH 8.1, 36 degrees -45 degrees C. Full Bp-13 PLA2 activity required Ca(2+); its PLA2 activity was inhibited by Mg(2+), Mn(2+), Sr(2+), and Cd(2+) in the presence and absence of 1 mM Ca(2+). In the mouse phrenic nerve-diaphragm (PND) preparation, the time for 50% paralysis was concentration-dependent (P < 0.05). Both the replacement of Ca(2+) by Sr(2+) and temperature lowering (24 degrees C) inhibited the Bp-13 PLA2-induced twitch tension blockade. Bp-13 PLA2 inhibited the contractile response to direct electrical stimulation in curarized mouse PND preparation corroborating its contracture effect. In biventer cervicis preparations, Bp-13 induced irreversible twitch-tension blockade and the KCl evoked contracture was partially, but significantly, inhibited (P > 0.05). The main effect of this new Asp49 PLA2 of Bothrops pauloensis venom is on muscle fiber sarcolemma, with avian preparation being less responsive than rodent preparation. The study enhances biochemical and pharmacological characterization of B. pauloensis venom. PMID- 25789177 TI - Hunting increases phosphorylation of calcium/calmodulin-dependent protein kinase type II in adult barn owls. AB - Juvenile barn owls readily adapt to prismatic spectacles, whereas adult owls living under standard aviary conditions do not. We previously demonstrated that phosphorylation of the cyclic-AMP response element-binding protein (CREB) provides a readout of the instructive signals that guide plasticity in juveniles. Here we investigated phosphorylation of calcium/calmodulin-dependent protein kinase II (pCaMKII) in both juveniles and adults. In contrast to CREB, we found no differences in pCaMKII expression between prism-wearing and control juveniles within the external nucleus of the inferior colliculus (ICX), the major site of plasticity. For prism-wearing adults that hunted live mice and are capable of adaptation, expression of pCaMKII was increased relative to prism-wearing adults that fed passively on dead mice and are not capable of adaptation. This effect did not bear the hallmarks of instructive information: it was not localized to rostral ICX and did not exhibit a patchy distribution reflecting discrete bimodal stimuli. These data are consistent with a role for CaMKII as a permissive rather than an instructive factor. In addition, the paucity of pCaMKII expression in passively fed adults suggests that the permissive default setting is "off" in adults. PMID- 25789178 TI - Etanercept-induced pityriasis lichenoides chronica in a patient with rheumatoid arthritis. AB - We present a 74-year-old female patient who developed a pityriasis lichenoides chronica (PLC) during etanercept therapy. This association is not described in the literature and might be considered in the spectrum of cutaneous adverse reactions of etanercept. PMID- 25789179 TI - A case of recalcitrant plantar warts associated with statin use. AB - Background. Plantar warts are a common presenting skin complaint caused by the human papillomavirus. 1st line therapies include cryotherapy and topical salicylic acid. Where there is resistance to these treatments, consideration is made for 2nd line therapies, including intralesional bleomycin, imiquimod, 5 fluorouracil, and photodynamic therapy. We present a case of bilateral persistent plantar warts, resistant to treatment with repeated cryotherapy and topical salicylic acid over a 6-year period. Following a patient initiated decision to discontinue their statin medication, we observed rapid clearance of plantar warts without change to standard therapy or their environment. This case correlates with emerging literature demonstrating a link between statin medication and proliferation of HPV through increased levels of FOXP3+ regulatory T cells. PMID- 25789180 TI - Mixed Cutaneous Infection Caused by Mycobacterium szulgai and Mycobacterium intermedium in a Healthy Adult Female: A Rare Case Report. AB - Nontuberculous mycobacteria (NTMs) are ubiquitous and are being increasingly reported as human opportunistic infection. Cutaneous infection caused by mixed NTM is extremely rare. We encountered the case of a 46-year-old female, who presented with multiple discharging sinuses over the lower anterior abdominal wall (over a previous appendectomy scar) for the past 2 years. Microscopy and culture of the pus discharge were done to isolate and identify the etiological agent. Finally, GenoType Mycobacterium CM/AS assay proved it to be a mixed infection caused by Mycobacterium szulgai and M. intermedium. The patient was advised a combination of rifampicin 600 mg once daily, ethambutol 600 mg once daily, and clarithromycin 500 mg twice daily to be taken along with periodic follow-up based upon clinical response as well as microbiological response. We emphasize that infections by NTM must be considered in the etiology of nonhealing wounds or sinuses, especially at postsurgical sites. PMID- 25789181 TI - An unusual presentation of a massive pulmonary embolism with misleading investigation results treated with tenecteplase. AB - Background. There is no foolproof strategy to identify a pulmonary embolism (PE) in the emergency department, and atypical presentations are common. Negative test results may mislead physicians away from the diagnosis of PE. Objectives. The current report aims to raise awareness of an unusual presentation of massive PE and its diagnosis and management, in the face of limited evidence in the scientific literature. Case Reports. We report the case of a patient with a negative D-Dimer and a negative Computed Tomography contrast angiography of the chest who was diagnosed twenty-seven hours later with a massive PE, as suggested by a bedside echocardiography. The patient was successfully treated with tenecteplase (TNK). Conclusions/Summary. Pulmonary embolism frequently presents atypically and is often a diagnostic challenge. There is limited literature about the treatment of massive PE. Further research on bedside echocardiography for diagnosing PE in unstable patients is warranted. In addition, further study into new thrombolytic agents like tenecteplase in the context of massive and submassive PE is warranted. PMID- 25789183 TI - Unusual presentation of pelizaeus-merzbacher disease: female patient with deletion of the proteolipid protein 1 gene. AB - Pelizaeus-Merzbacher disease (PMD) is neurodegenerative leukodystrophy caused by dysfunction of the proteolipid protein 1 (PLP1) gene on Xq22, which codes for an essential myelin protein. As an X-linked condition, PMD primarily affects males; however there have been a small number of affected females reported in the medical literature with a variety of different mutations in this gene. No affected females to date have a deletion like our patient. In addition to this, our patient has skewed X chromosome inactivation which adds to her presentation as her unaffected mother also carries the mutation. PMID- 25789182 TI - Complete remission of anaplastic thyroid carcinoma after concomitant treatment with docetaxel and radiotherapy. AB - Anaplastic thyroid carcinoma (ATC) although rare is the most lethal form of thyroid cancer. The mortality rate for ATC is very high, with a median survival time of only 5 months; the survival rate at 1 year after diagnosis is <20%. Management of ATC is extremely difficult and rife with uncertainties. Herein, we describe a 75-year-old woman who presented with ATC and was successfully treated using concomitant treatment with docetaxel and high-dose radiotherapy. This case appears to be the first to have been reported in the literature involving complete remission of ATC confirmed by autopsy, suggesting the therapeutic potential of this combination. PMID- 25789184 TI - Pulmonary Langerhans Cell Histiocytosis with Lytic Bone Involvement in an Adult Smoker: Regression following Smoking Cessation. AB - Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the proliferation and dissemination of histiocytes. These in turn may cause symptoms ranging from isolated, infiltrative lesions to severe multisystem disease. Pulmonary Langerhans cell histiocytosis (PLCH) presents as a localized polyclonal proliferation of Langerhans cells in the lungs causing bilateral cysts and fibrosis. In adults, this rare condition is considered a reactive process associated with cigarette smoking. Recently, clonal proliferation has been reported with the presence of BRAF V600E oncogenic mutation in a subset of PLCH patients. Spontaneous resolution was described; however, based on case series, smoking cessation remains the most effective way to achieve complete remission and prevent long term complications related to tobacco. Herein, we report the case of an adult woman with biopsy-proven PLCH presenting with thoracic (T8) vertebral bone destruction. Both the lung and the bone diseases regressed following smoking cessation, representing a rare case of synchronous disseminated PCLH with bone localization. This observation underscores the contribution of cigarette smoking as a systemic trigger of both pulmonary and extrapulmonary bone lesions. A review of similar cases in the literature is also presented. PMID- 25789185 TI - Transformation of an Unclassified Myeloproliferative Neoplasm with a Rare BCR JAK2 Fusion Transcript Resulting from the Translocation (9;22)(p24;q11). AB - BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1 negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated. PMID- 25789186 TI - Meningitis, clinical presentation of tetanus. AB - Background. Tetanus is an acute disease caused by a neurotoxin produced by Clostridium tetani. Tetanus immunization has been available since the late 1930s but sporadic cases still occur, usually in incompletely vaccinated or unvaccinated individuals. Case Report. An elderly previously vaccinated female contracted tetanus following foot injury. Clinically she presented with meningitis causing diagnostic and therapeutic delays. Why Should Physician Be Aware of This? Even in developed countries the differential diagnosis of meningitis, especially in the elderly, should include tetanus. Treatment in intensive care unit is required. General population might benefit from vaccine boosters and education on this potentially fatal disease. PMID- 25789187 TI - Bone marrow granuloma in typhoid Fever: a morphological approach and literature review. AB - Typhoid fever is one of the few bacterial infections in humans where bone marrow evaluation is routinely recommended. However, the morphological aspect of typhoid fever in bone marrow has been rarely described in the literature. We describe a 25-year-old male patient who presented with prolonged fever suspected to be of tubercular etiology. Bone marrow examination showed well-formed histiocytic and epithelioid granulomas and erythrophagocytosis; and the bone marrow aspirate culture grew Salmonella typhi A. In view of potential clinical implications, typhoid fever should be considered as a differential diagnosis to tuberculosis in the evaluation of prolonged fever; especially in high prevalent areas. We suggest that erythrophagocytosis may serve as a morphological marker in typhoid granulomas in the bone marrow; and bone marrow culture should be submitted in every suspected case for appropriate patient management. PMID- 25789188 TI - Prenatal diagnosis of concurrent achondroplasia and klinefelter syndrome. AB - Achondroplasia is the most frequent nonlethal skeletal dysplasia, with a prevalence of 1 : 5000 to 1 : 40,000 live births, and it is caused by a fibroblast growth factor receptor alteration. The combination of achondroplasia and Klinefelter syndrome is extremely rare and just four reports have been published in the literature, which were all diagnosed postnatally. We report the fifth case described of this uncommon association and its prenatal diagnosis. In cases of prenatal diagnosis of achondroplasia with additional suspicious morphological abnormalities, an invasive test such as amniocentesis must be carried out to assess the karyotype normality. PMID- 25789189 TI - New primary malignancy masquerading as metastatic prostate adenocarcinoma. AB - In the management of patients with prostate cancer, the development of new radiographic findings can mimic progression of the disease, thereby triggering changes in treatment. Typically, clinicians evaluate additional parameters, such as symptoms and prostate specific antigen (PSA) levels, for further evidence of disease progression. In the absence of additional findings, for example, elevated PSA, the possibility of an additional malignancy should be considered and evaluated. We present three cases of patients undergoing treatment for prostate adenocarcinoma and discovered on imaging to have findings suggestive of disease progression, but ultimately found to be a new primary malignancy. Our cases suggest that, in patients with prostate cancer, the appearance of new lymphadenopathy or bone lesions cannot be assumed to solely represent progression of the prostate cancer and warrant further investigation, especially in the presence of stable PSA levels. PMID- 25789190 TI - A challenging case of limb salvage requiring a combination of composite fixation and masquelet technique to address significant segmental bone loss. AB - Cases of limb salvage following skeletal trauma involving significant bone loss pose a particular challenge to the reconstructive surgeon. Certain techniques for addressing this complex issue have been advanced in recent years and have met with considerable success. The Masquelet technique involves a staged procedure in which a temporary skeletal stabilization is paired with implantation of an antibiotic spacer and left in place for 6-8 weeks, during which time a "pseudomembrane" forms around the cement spacer. During the second stage of the procedure, the pseudomembrane is incised, the antibiotic spacer removed, and bone graft is placed. We present a case of significant segmental femur loss in a 19 year-old male opting for limb salvage in which a 17-centimeter segmental loss of bone was essentially regrown using a combination of the Masquelet technique with supplemental endosteal fixation. PMID- 25789191 TI - The management of catatonia in bipolar disorder with stimulants. AB - Catatonia, while not a rare occurrence in bipolar disorder, has not been widely discussed in the literature. We present a case of a married Caucasian male with a history of bipolar disorder, exhibiting catatonia and experiencing difficulty in day-to-day functioning. He demonstrated impairment in cognition and an inability to organize simple activities of daily life. After exhausting a number of options for medical management, including benzodiazepines, atypical antipsychotics, and amantadine, he only displayed significant clinical improvement with the addition of a stimulant, methylphenidate. In time, the patient saw a complete return to normal functioning. The use of stimulants for catatonia in bipolar disorder may be an interesting and effective option for treatment. While this is not the first time this treatment has been suggested, there is very little data in support of it; our case confirms the discoveries of previous case reports. PMID- 25789192 TI - Tracheal Papilloma Treated with Cryotherapy and Interferon-alpha: A Case Report and Review of the Literature. AB - Tracheal papilloma (TP) is characterized by papillomatous growth of the bronchial epithelium that involves the trachea as a response to Human Papilloma Virus (HPV) infection. A 40-year-old male, with 3-month history of progressive dyspnea was admitted to our hospital, and there were no any other respiratory symptoms. Physical examination was unremarkable. Chest computed tomography (CT) showed that there was a papillomatous mass at the distal trachea. The lesion occupied 80% of tracheal lumen. This patient received cryotherapy and mechanical debridement under general anesthesia and postoperative pathology showed endotracheal papillomatosis. Patient was treated with interferon-alpha (IFN-alpha) and he showed no recurrence at the 8th month of his therapy. PMID- 25789194 TI - Acute Sickle Hepatic Crisis after Liver Transplantation in a Patient with Hb SC Disease. AB - Acute sickle hepatic crisis (ASHC) has been observed in approximately 10% of patients with sickle cell disease. It occurs predominantly in patients with homozygous (Hb SS) sickle cell anemia and to a lesser degree in patients with Hb SC disease, sickle cell trait, and Hb S beta thalassemia. Patients commonly present with jaundice, right upper quadrant pain, nausea, low-grade fever, tender hepatomegaly, and mild to moderate elevations in serum AST, ALT, and bilirubin. We describe the case of a patient with a history of hemoglobin SC disease and cirrhosis caused by hepatitis C presenting approximately 1 year after liver transplantation with an ASHC. The diagnosis was confirmed by liver biopsy. Our patient was treated with RBC exchange transfusions, IV hydration, and analgesia and made a complete recovery. Only a limited number of patients with sickle cell disease have received liver transplants, and, to our knowledge, this is the first case of ASHC after transplantation in a patient with Hb SC disease. PMID- 25789193 TI - De novo renal cell carcinoma in a kidney allograft 20 years after transplant. AB - Renal cell carcinoma (RCC) in a kidney allograft is rare. We report the successful diagnosis and treatment of a de novo RCC in a nonfunctioning kidney transplant 20 years after engraftment. A 54-year-old man received a kidney transplant from his mother when he was 34 years old. After 10 years, chronic rejection resulted in graft failure, and the patient became hemodialysis dependent. Intravenous contrast-enhanced computed tomography (CT) for the evaluation of gastrointestinal symptoms revealed a solid 13 mm tumor in the kidney graft. The tumor was confirmed on ultrasound examination. This tumor had not been detected on a surveillance noncontrast CT scan. Needle biopsy showed that the tumor was an RCC. Allograft nephrectomy was performed. Pathological examination showed that the tumor was a Fuhrman Grade 2 RCC. XY-fluorescence hybridization analysis of the RCC showed that the tumor cells were of donor origin. One year after the surgery, the patient is alive and has no evidence of tumor recurrence. Regardless of whether a kidney transplant is functioning, it should periodically be imaged for RCC throughout the recipient's lifetime. In our experience, ultrasonography or CT with intravenous contrast is better than CT without contrast for the detection of tumor in a nonfunctioning kidney transplant. PMID- 25789195 TI - Entomological investigations on malaria vectors in some war-torn areas in the trincomalee district of sri lanka after settlement of 30-year civil disturbance. AB - Background. Malaria was an endemic problem in Trincomalee District, Eastern Province of Sri Lanka. Very few recent data concerning Anopheles are available which transmit malaria. Therefore, the aim of this study is to identify various Anopheles species and the dynamics of anophelines including malaria vectors in Trincomalee District for effective vector control under the current malaria elimination program embarked in the country. Method. Entomological surveys were conducted on a monthly basis, using five entomological techniques, namely, indoor hand collection (HC), window trap collection (WTC), cattle-baited net collection (CBNC), and cattle-baited hut collection (CBHC) from June 2010 to June 2012 in 32 study areas under five entomological sentinel sites. Results. Seventeen anopheline species were encountered, of which Anopheles subpictus was the predominant species in all sampling methods. It is noted that A. culicifacies and A. subpictus have adapted to breed in polluted water in urban settings which may cause serious implications on the epidemiology of malaria in the country. Conclusions. It is important to determine the abundance, biology, distribution, and relationship with climatic factors of main and secondary malaria vectors in Sri Lanka in order to initiate evidence based controlling programs under the current malaria elimination program in Sri Lanka. PMID- 25789196 TI - Discrimination and content analysis of fritillaria using near infrared spectroscopy. AB - Fritillaria is a traditional Chinese herbal medicine which can be used to moisten the lungs. The objective of this study is to develop simple, accurate, and solvent-free methods to discriminate and quantify Fritillaria herbs from seven different origins. Near infrared spectroscopy (NIRS) methods are established for the rapid discrimination of seven different Fritillaria samples and quantitative analysis of their total alkaloids. The scaling to first range method and the partial least square (PLS) method are used for the establishment of qualitative and quantitative analysis models. As a result of evaluation for the qualitative NIR model, the selectivity values between groups are always above 2, and the mistaken judgment rate of fifteen samples in prediction sets was zero. This means that the NIR model can be used to distinguish different species of Fritillaria herbs. The established quantitative NIR model can accurately predict the content of total alkaloids from Fritillaria samples. PMID- 25789197 TI - Bioethics and why I hope to live beyond age 75 attaining wisdom!: A rebuttal to Dr. Ezekiel Emanuel's 75 age limit. AB - American bioethicists have been providing persuasive arguments for rationing medical care via the theory of the necessary "rational allocation of finite health care resources." Anticipating the need for the drastic rationing of medical care in the U.S. with the implementation of ObamaCare and assisted by various sectors of organized medicine in league with the State, bioethicists have deduced that more ingenious approaches are necessary to convince Americans who have been accustomed to receiving the best medical care that third-party payers are willing to pay for. It is in this context that the individual-based, patient oriented ethics of Hippocrates, including his fundamental dictum, "First Do No Harm," have to be supplanted by the utilitarian approach promoted by the bioethicists. And today's foremost proponent of the bioethics movement is Dr. Ezekiel Emanuel. This editorial proposes a rational rebuttal to Dr. Emanuel's proposal to limit life expectancy to age 75 as a rational paradigm to a better life. PMID- 25789198 TI - Fractured inlet connecting tube of the flat bottom flushing device of a posterior fossa cystoperitoneal shunt. AB - BACKGROUND: There are well-known complications for shunt procedures. Shunt fracture or disconnection is the second most frequent cause of shunt malfunction in children. Shunt disconnection is not a common cause of shunt malfunction in the early period after installation, especially in the adulthood. CASE DESCRIPTION: Fracture of the proximal (inlet) connector of a flat-based shunt installed for decompression of a large posterior fossa arachnoid cyst in a 31 year-old female with signs of increased intracranial pressure led to recurrence of her symptoms 6 months after surgery. CONCLUSION: Awareness of the possibility of fracture site in the junction of the inlet connector of flat bottom shunt systems is warranted and can be diagnosed by three-dimensional computed tomography (3D CT) imaging without performing shunt series study. PMID- 25789199 TI - Erratum: The future of high-grade glioma: Where we are and where are we going: Erratum. AB - [This corrects the article on p. S9 in vol. 6, PMID: 25722939.]. PMID- 25789200 TI - Measuring vaccine confidence: introducing a global vaccine confidence index. AB - BACKGROUND: Public confidence in vaccination is vital to the success of immunisation programmes worldwide. Understanding the dynamics of vaccine confidence is therefore of great importance for global public health. Few published studies permit global comparisons of vaccination sentiments and behaviours against a common metric. This article presents the findings of a multi country survey of confidence in vaccines and immunisation programmes in Georgia, India, Nigeria, Pakistan, and the United Kingdom (UK) - these being the first results of a larger project to map vaccine confidence globally. METHODS: Data were collected from a sample of the general population and from those with children under 5 years old against a core set of confidence questions. All surveys were conducted in the relevant local-language in Georgia, India, Nigeria, Pakistan, and the UK. We examine confidence in immunisation programmes as compared to confidence in other government health services, the relationships between confidence in the system and levels of vaccine hesitancy, reasons for vaccine hesitancy, ultimate vaccination decisions, and their variation based on country contexts and demographic factors. RESULTS: The numbers of respondents by country were: Georgia (n=1000); India (n=1259); Pakistan (n=2609); UK (n=2055); Nigerian households (n=12554); and Nigerian health providers (n=1272). The UK respondents with children under five years of age were more likely to hesitate to vaccinate, compared to other countries. Confidence in immunisation programmes was more closely associated with confidence in the broader health system in the UK (Spearman's rho=0.5990), compared to Nigeria (rho=0.5477), Pakistan (rho=0.4491), and India (rho=0.4240), all of which ranked confidence in immunisation programmes higher than confidence in the broader health system. Georgia had the highest rate of vaccine refusals (6 %) among those who reported initial hesitation. In all other countries surveyed most respondents who reported hesitating to vaccinate went on to receive the vaccine except in Kano state, Nigeria, where the percentage of those who ultimately refused vaccination after initially hesitating was as high as 76%) Reported reasons for hesitancy in all countries were classified under the domains of "confidence," "convenience," or "complacency," and confidence issues were found to be the primary driver of hesitancy in all countries surveyed. PMID- 25789202 TI - Why are young adults affected? Estimating measles vaccination coverage in 20-34 year old germans in order to verify progress towards measles elimination. AB - BACKGROUND: The introduction of measles vaccination into routine childhood vaccination programmes has led to a shift of disease burden and incidence among young adults. This was confirmed by the recent rise in measles cases and outbreaks throughout Europe. To prevent outbreaks and eliminate measles, one of the key objectives of the WHO Europe measles elimination framework is achieving overall vaccination coverage of >=95% in the population on a district level. In the absence of national registers, data on vaccination coverage in Germany is recorded at the age of school entry, through insurance refund claim data and population studies. Vaccination status (VS) of young adults is largely unknown. METHODS: We assessed measles vaccination coverage in young adults aged 20-34 years on a district level of the German Federal State of Rhineland-Palatinate. The knowledge and attitude towards immunization of unvaccinated to vaccinated young adults were compared using Likert questions. We used proportional allocation for stratified random sampling across 36 counties. We mailed a self administered questionnaire with pre-paid return envelopes along with an offer to complete online. Prior to calculating coverage we tested for non-responder bias using logistic regression. RESULTS: 465 (28%) of 1,637 persons contacted responded (mail: 23%, online: 5%). More women responded than men (odds ratio (OR)=2.1; 95% confidence intervall (CI)=1.7-2.6) but age did not vary between responders and non-responders. Vaccination coverage was 90% (95%CI=87%-93%) for one and 56% (95%CI=51%-61%) for two doses. We found a statistically significant association between receiving two doses and age group. The 20-24 years age group had a 2.3 higher incidence rate ratio (95%CI=1.7-3.2) than the reference group of 30-34 year old to have received two doses of measles vaccination. The group of 25 29 year old had a 1.5 higher incidence rate (95%CI=1.0-2.1) than the reference group to have received two doses of measles vaccination. CONCLUSIONS: Coverage has failed to reach the WHO Europe elimination goal of 95% measles vaccination in the general population. Targeted approaches including enlistment of occupational health services and checking vaccination status during general practitioner (GP) visits are needed to increase vaccination uptake in this age group in order to achieve measles elimination. PMID- 25789201 TI - Vaccine hesitancy: clarifying a theoretical framework for an ambiguous notion. AB - Today, according to many public health experts, public confidence in vaccines is waning. The term "vaccine hesitancy" (VH) is increasingly used to describe the spread of such vaccine reluctance. But VH is an ambiguous notion and its theoretical background appears uncertain. To clarify this concept, we first review the current definitions of VH in the public health literature and examine its most prominent characteristics. VH has been defined as a set of beliefs, attitudes, or behaviours, or some combination of them, shared by a large and heterogeneous portion of the population and including people who exhibit reluctant conformism (they may either decline a vaccine, delay it or accept it despite their doubts) and vaccine-specific behaviours. Secondly, we underline some of the ambiguities of this notion and argue that it is more a catchall category than a real concept. We also call into question the usefulness of understanding VH as an intermediate position along a continuum ranging from anti vaccine to pro-vaccine attitudes, and we discuss its qualification as a belief, attitude or behaviour. Thirdly, we propose a theoretical framework, based on previous literature and taking into account some major structural features of contemporary societies, that considers VH as a kind of decision-making process that depends on people's level of commitment to healthism/risk culture and on their level of confidence in the health authorities and mainstream medicine. PMID- 25789204 TI - Vaccine Narratives and Public Health: Investigating Criticisms of H1N1 Pandemic Vaccination. AB - Vaccine hesitancy is often understood and explored on the level of individual decision-making. However, questions surrounding the risk and efficacy of vaccination are evident in wider public discourse; social narratives of vaccination inform and impact on the individual level. This paper takes a narrative analysis approach from the sociology of health to examine data drawn from a wider study on global public health responses to the H1N1 pandemic. The paper concentrates upon criticisms to mass vaccination as recounted within the Council of Europe's debate of the handling of H1N1. It shows that three narratives were particularly dominant: problematizing the use of vaccination as a public health response; criticising the efficacy of the vaccines; and, questioning the safety of the strategy. This debate presents an important case study in understanding the way in which vaccines are problematized within the public discourse. PMID- 25789203 TI - Factors Associated with Intention to Receive Influenza and Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccines during Pregnancy: A Focus on Vaccine Hesitancy and Perceptions of Disease Severity and Vaccine Safety. AB - BACKGROUND: Improving influenza and tetanus, diphtheria and acellular pertussis (Tdap) vaccine coverage among pregnant women is needed. PURPOSE: To assess factors associated with intention to receive influenza and/or Tdap vaccinations during pregnancy with a focus on perceptions of influenza and pertussis disease severity and influenza vaccine safety. METHODS: Participants were 325 pregnant women in Georgia recruited from December 2012 - April 2013 who had not yet received a 2012/2013 influenza vaccine or a Tdap vaccine while pregnant. Women completed a survey assessing influenza vaccination history, likelihood of receiving antenatal influenza and/or Tdap vaccines, and knowledge, attitudes and beliefs about influenza, pertussis, and their associated vaccines. RESULTS: Seventy-three percent and 81% of women believed influenza and pertussis, respectively, would be serious during pregnancy while 87% and 92% believed influenza and pertussis, respectively, would be serious to their infants. Perception of pertussis severity for their infant was strongly associated with an intention to receive a Tdap vaccine before delivery (p=0.004). Despite perceptions of disease severity for themselves and their infants, only 34% and 44% intended to receive antenatal influenza and Tdap vaccines, respectively. Forty-six percent had low perceptions of safety regarding the influenza vaccine during pregnancy, and compared to women who perceived the influenza vaccine as safe, women who perceived the vaccine as unsafe were less likely to intend to receive antenatal influenza (48% vs. 20%; p < 0.001) or Tdap (53% vs. 33%; p < 0.001) vaccinations. CONCLUSIONS: Results from this baseline survey suggest that while pregnant women who remain unvaccinated against influenza within the first three months of the putative influenza season may be aware of the risks influenza and pertussis pose to themselves and their infants, many remain reluctant to receive influenza and Tdap vaccines antenatally. To improve vaccine uptake in the obstetric setting, our findings support development of evidence-based vaccine promotion interventions which emphasize vaccine safety during pregnancy and mention disease severity in infancy. PMID- 25789205 TI - Hesitancy, trust and individualism in vaccination decision-making. PMID- 25789206 TI - Effects of anesthetics pentobarbital sodium and chloral hydrate on urine proteome. AB - Urine can be a better source than blood for biomarker discovery since it accumulates many changes. The urine proteome is susceptible to many factors, including anesthesia. Pentobarbital sodium and chloral hydrate are commonly used anesthetics in animal experiments. This study demonstrated the effects of these two anesthetics on the rat urine proteome using liquid chromatography-tandem mass spectrometry (LC-MS/MS). With anesthesia, the urinary protein-to-creatinine ratio of all rats increased twofold. The relative abundance of 22 and 23 urinary proteins were changed with pentobarbital sodium or chloral hydrate anesthesia, respectively, as determined by label-free quantification. Among these changed proteins, fifteen had been considered as candidate biomarkers such as uromodulin, and sixteen had been considered stable in healthy human urine, which are more likely to be considered as potential biomarkers when changed, such as transferrin. The pattern of changed urinary proteins provides clues to the discovery of urinary proteins regulatory mechanisms. When determining a candidate biomarker, anesthetic-related effects can be excluded from future biomarker discovery studies. Since anesthetics take effects via nervous system, this study is the first to provide clues that the protein handling function of the kidney may possibly be regulated by the nervous system. PMID- 25789207 TI - The effect of listening to music on human transcriptome. AB - Although brain imaging studies have demonstrated that listening to music alters human brain structure and function, the molecular mechanisms mediating those effects remain unknown. With the advent of genomics and bioinformatics approaches, these effects of music can now be studied in a more detailed fashion. To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n = 48), and after a control study without music exposure (n = 15). As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls. Comparisons were made based on two subphenotypes of musical experience: musical aptitude and music education. In musically experiencd participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons (rank product non-parametric statistics, pfp 0.05, >1.2 fold change over time across conditions). Gene ontological overrepresentation analysis (hypergeometric test, FDR < 0.05) revealed that the up-regulated genes are primarily known to be involved in the secretion and transport of dopamine, neuron projection, protein sumoylation, long-term potentiation and dephosphorylation. Down-regulated genes are known to be involved in ATP synthase coupled proton transport, cytolysis, and positive regulation of caspase, peptidase and endopeptidase activities. One of the most up-regulated genes, alpha synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude. Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species. We observed no significant findings in musically inexperienced participants. PMID- 25789208 TI - Differences in neurocognitive aspects of dyslexia in Dutch and immigrant 6-7- and 8-9-years old children. AB - Detecting dyslexia in immigrant children can be jeopardized because of assessment bias, as a consequence of a limited word lexicon or differences in language development of these children. This is in contrast with the view of the universal neurocognitive basis for dyslexia. In this research, differences in screening children at risk for dyslexia with the Dyslexia Screening Test (DST) were studied in third and fifth graders of primary school of Dutch (mainstream) and immigrant descent. Mean group differences were found on a few subtests (Naming Letters, Semantic Fluency, Backward Digit Span and Verbal Fluency), probably as a consequence of bias because of the linguistic character of these subtests. The raw scores of word lexicon increased in the Dutch and immigrant group. The association of having a dyslexia diagnosis on DST scores was comparable for Dutch and immigrant children. Differences in the DST scores between non-dyslexic and dyslexic children were found between the third and fifth grade, with a stronger effect of having a dyslexia diagnosis in the fifth grade than the third grade, for Dutch as well as immigrant children. Screening of dyslexia seems easier in the fifth grade than in the third grade, dyslexic children show a slower reading development than their non-dyslexic peers, irrespective of their cultural background. PMID- 25789209 TI - Levels of essential and non-essential metals in ginger (Zingiber officinale) cultivated in Ethiopia. AB - BACKGROUND: Ginger (Zingiber officinale Roscoe) is a common condiment for various foods and beverages and widely used worldwide as a spice. Its extracts are used extensively in the food, beverage, and confectionary industries in the production of products such as marmalade, pickles, chutney, ginger beer, ginger wine, liquors, biscuits, and other bakery products. In Ethiopia, it is among the important spices used in every kitchen to flavor stew, tea, bread and local alcoholic drinks. It is also chiefly used medicinally for indigestion, stomachache, malaria, fevers, common cold, and motion sickness. The literature survey revealed that there is no study conducted on the determination of metals in ginger cultivated in Ethiopia. Hence it is worthwhile to determine the levels of essential and non-essential metals in ginger cultivated in Ethiopia. METHODS: The levels of essential (Ca, Mg, Fe, Zn, Cu, Co, Cr, Mn, and Ni) and non essential (Cd and Pb) metals in ginger (Zingiber officinale Roscoe) cultivated in four different regions of Ethiopia and the soil where it was grown were determined by flame atomic absorption spectrometry. 0.5 g of oven dried ginger and soil samples were digested using 3 mL of HNO3 and 1 mL of HClO4 at 210 degrees C for 3 h and a mixture of 6 mL aqua-regia and 1.5 mL H2O2 at 270 degrees C for 3 h, respectively. RESULTS: The mean metal concentration (MUg/g dry weight basis) ranged in the ginger and soil samples, respectively, were: Ca (2000-2540, 1770-3580), Mg (2700-4090, 1460-2440), Fe (41.8-89.0, 21700-46900), Zn (38.5 55.2, 255-412), Cu (1.1-4.8, 3.80-33.9), Co (2.0-7.6, 48.5-159), Cr (6.0-10.8, 110-163), Mn (184-401, 1760-6470), Ni (5.6-8.4, 14.1-79.3) and Cd (0.38-0.97, 0.24-1.1). The toxic metal Pb was not detected in both the ginger and soil samples. CONCLUSION: There was good correlation between some metals in ginger and soil samples while poor correlation between other metals (Fe, Ni, Cu). This study revealed that Ethiopian gingers are good source of essential metals and free from toxic metal Pb while containing negligible amount of Cd. PMID- 25789210 TI - A novel gene network analysis in liver tissues of diabetic rats in response to resistant starch treatment. AB - In this study, we investigated the genome-wide gene expression profiles in the liver tissue of diabetic rats before and after RS treatment. The microarray-based analysis revealed that a total of 173 genes were up-regulated and 197 genes were down-regulated in response to RS treatment. These genes were mainly related to glucose metabolism (e.g., hexokinase, pyruvate kinase and phosphotransferase etc.), and lipid metabolism (e.g., carnitine palmitoyl transfer 1, fatty acid transporter, beta hydroxyl butyric dehydrogenase etc.). Cluster analysis results showed that the up/down-regulated genes were highly responsive to RS treatment, and were considered to be directly or indirectly associated with reducing plasma glucose and body fat. To interpret the mechanism of RS regulation at the molecular level, a novel gene network was constructed based on 370 up/down regulated genes coupled with 718 known diabetes-related genes. The topology of the network showed the characteristics of small-world and scale-free network, with some pathways demonstrating a high degree. Forkhead class A signaling pathway, with a degree of 8, was analyzed and was found to have an effect mainly on glucose and lipid metabolism processes. The results indicate that RS can suppress the development of type 2 diabetes in the STZ rat model through modulating the expression of multiple genes involved in glucose and lipid metabolism. The potential application of this novel gene network is also discussed. PMID- 25789211 TI - Trichuris spp. infecting domestic cats on St. Kitts: identification based on size or vulvar structure? AB - BACKGROUND: On St. Kitts, a high number of cats are found to be infected with Trichuris. Necropsies have shown pathologic changes related to the infections. In order to determine if these changes were related to a particular Trichuris species, a review of the original identifications of Trichuris campanula and Trichuris serrata was conducted. FINDINGS: Based on the review of published descriptions of T. campanula and T. serrata, it is hypothesized that the presence or absence of a vulvar projection and a bacillary band can be used to differentiate the two species and these criteria are more accurate than nematode or egg size. The Trichuris in cats on St. Kitts were similar in size to the description of T. campanula, but had both a vulvar projection and bacillary band. CONCLUSIONS: Based on the morphological characteristics, all of the Trichuris found in twelve domestic cats were determined to be T. serrata. Cats without pathologic changes are required to further investigate if the changes are species or strain related. PMID- 25789212 TI - Reconstruction of delayed diagnoses simultaneous bilateral distal biceps tendon ruptures using semtendinosus and quadriceps tendon autografts. AB - INTRODUCTION: Simultaneous bilateral distal biceps rupture is rarely reported, but several issues has to be taken into account and the here presented case brings up some of these aspects. CASE DESCRIPTION: This case presents a simultaneous bilateral distal biceps ruptures, and due to delayed diagnosis, bilateral muscle retraction had occurred. Surgical reconstruction was challenged both by social circumstances and by previous harvesting of the Semitendinous tendon on one side. The surgery was performed as a staged approach, using a Semitendinosus graft at one side and later using a Quadriceps tendon graft on the opposite site. At follow-up 14 month postoperatively the Oxford Elbow Score was 92 percent for both elbows and the MRI's bilaterally demostrates that the grafts are tight. DISCUSSION AND EVALUATION: The Quadriceps tendon is a previously non reported type of graft material for this type of surgery. Based on the experience from this case it is concluded that six weeks after trauma the degree of retraction of the distal biceps tendon can impair direct repair. CONCLUSION: When reconstruction of the ruptured distal biceps tendon is needed, subjective normal forces can be obtained using both the semitendosus graft as well as the quadriceps graft, however with a minor increased donor site morbidity with respect to the quadriceps graft. PMID- 25789214 TI - Role of solvents in improvement of dissolution rate of drugs: crystal habit and crystal agglomeration. AB - Crystallization is often used for manufacturing drug substances. Advances of crystallization have achieved control over drug identity and purity, but control over the physical form remains poor. This review discusses the influence of solvents used in crystallization process on crystal habit and agglomeration of crystals with potential implication for dissolution. According to literature it has been known that habit modification of crystals by use of proper solvents may enhance the dissolution properties by changing the size, number and the nature of crystal faces exposed to the dissolution medium. Also, the faster dissolution rate of drug from the agglomerates of crystals compared with the single crystals may be related to porous structure of the agglomerates and consequently their better wettability. It is concluded from this review that in-depth understanding of role of the solvents in crystallization process can be applied to engineering of crystal habit or crystal agglomeration, and predictably dissolution improvement in poorly soluble drugs. PMID- 25789213 TI - An overview on the proposed mechanisms of antithyroid drugs-induced liver injury. AB - Drug-induced liver injury (DILI) is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU) are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s) of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs. PMID- 25789215 TI - Antimicrobial activity of carbon-based nanoparticles. AB - Due to the vast and inappropriate use of the antibiotics, microorganisms have begun to develop resistance to the commonly used antimicrobial agents. So therefore, development of the new and effective antimicrobial agents seems to be necessary. According to some recent reports, carbon-based nanomaterials such as fullerenes, carbon nanotubes (CNTs) (especially single-walled carbon nanotubes (SWCNTs)) and graphene oxide (GO) nanoparticles show potent antimicrobial properties. In present review, we have briefly summarized the antimicrobial activity of carbon-based nanoparticles together with their mechanism of action. Reviewed literature show that the size of carbon nanoparticles plays an important role in the inactivation of the microorganisms. As major mechanism, direct contact of microorganisms with carbon nanostructures seriously affects their cellular membrane integrity, metabolic processes and morphology. The antimicrobial activity of carbon-based nanostructures may interestingly be investigated in the near future owing to their high surface/volume ratio, large inner volume and other unique chemical and physical properties. In addition, application of functionalized carbon nanomaterials as carriers for the ordinary antibiotics possibly will decrease the associated resistance, enhance their bioavailability and provide their targeted delivery. PMID- 25789217 TI - Cyclodextrine screening for the chiral separation of amlodipine enantiomers by capillary electrophoresis. AB - PURPOSE: Amlodipine is a long acting, dihydropyridine type calcium channel blocker frequently used in the treatment of hypertension and coronary insufficiency. The calcium channel blocking activity resides primarily in the S amlodipine enantiomer, while R-amlodipine is a potent inhibitor of smooth muscle cell migration. METHODS: In this study capillary electrophoresis was applied for the enantiomeric separation of amlodipine using different native and derivatized; neutral and charged cyclodextrines as chiral selectors. The effects of pH and composition of the background electrolyte, concentration and type of chiral selector, capillary temperature, running voltage and injection parameters have been investigated. RESULTS: Stereoselective interactions were observed when using alpha-CD, beta-CD, HP-beta-CD, RAMEB, CM-beta-CD and SBE-beta-CD. Optimized separation conditions consisted on a 50 mM phosphate buffer, pH - 3.0, 20 mM RAMEB as chiral selector, + 25 kV applied voltage, 15 degrees C temperature and UV detection at 238 nm. Using the optimized electrophoretic conditions we succeeded the chiral separation of amlodipine enantiomers in approximately 6 minute, the order of migration being R-amlodipine followed by S-amlodipine. The method was successfully applied for the determination of amlodipine enantiomers from commercially available pharmaceuticals. The linearity range, limits of detection and quantification, precision and accuracy were determined and the results obtained confirmed that the method was suitable for this purpose. CONCLUSION: It can be concluded that the proposed capillary electrophoresis methods can be useful for routine pharmaceutical applications with benefits of its effectivity, simplicity, short analysis time and low consumption of analytes, solvents and chiral selectors. PMID- 25789216 TI - Lipid Vesicles for the Skin Delivery of Diclofenac: Cerosomes vs. Other Lipid Suspensions. AB - PURPOSE: Lipid suspensions as drug carriers, including conventional liposomes, ethosomes, transferosomes, proniosomes, niosomes, PEG-PPG-PEG niosomes and stratum corneum liposomes (cerosomes), were formulated and compared. METHODS: Lipid vesicles were formulated and assessed with regards to enhancement of skin permeation of diclofenac and stability profiles of the formulations. Formulation induced changes of the biophysical structure of excised human skin were monitored using the Fourier transform infrared spectroscopy. RESULTS: The stability profiles of these suspensions over 12 weeks did not show any significant drug leakage from the vesicles of interest (p > 0.05). FTIR observations indicated that the vesicles increased stratum corneum (SC) lipid fluidization and altered protein conformation. Skin permeability experiments showed that the free unencapsulated drug in the cerosomal formulations caused significant increase in drug permeation across the skin (p < 0.01). Low skin permeability of drug from the other lipid suspensions could be due to the entrapment of diclofenac within these vesicles which decreased the solubility of the hydrophilic drug in the skin lipids and the partition coefficient of the drug from these vesicles into the SC. CONCLUSION: Optimal drug entrapment in vesicles or alteration of the skin structure may not necessarily enhance the permeation of hydrophilic drugs across the human skin. These lipid vesicles may be further developed into carriers of both hydrophilic and hydrophobic drugs for topical and transdermal delivery, respectively. PMID- 25789218 TI - Synthesis and in vitro evaluation of amphiphilic peptides and their nanostructured conjugates. AB - PURPOSE: Breast cancer is the second leading cancer type among people of advanced countries. Various methods have been used for cancer treatment such as chemotherapy and radiotherapy. In the present study we have designed and synthesized a new group of drug delivery systems (DDS) containing a new class of Cell Penetrating Peptides (CPPs) named Peptide Amphiphiles (PAs). METHODS: Two PAs and anionic peptides were synthesized using solid phase peptide synthesis (SPPS), namely [KW]4, [KW]5, E4 and E8. Then nano-peptides were synthesized by non-covalent binding between PAs and poly anions as [KW]4-E4, [KW]4-E8, [KW]5-E4 and [KW]5-E8. RESULTS: Flow cytometry studies showed that increased chain length of PAs with a higher ratio between hydrophobicity and net charge results in increased intracellular uptake by MCF7 cells after 2h incubation. Moreover, nano peptides showed greater intracellular uptake compared to PAs. Anti-proliferative assay revealed that by increasing chain length of PAs, the toxicity effect on MCF7 cells is reduced, however nano-peptides did not show significant toxicity on MCF7 cells even at high concentration levels. CONCLUSION: These data suggest that due to the lack of toxicity effect at high concentration levels and also high cellular uptake, nano-peptides are more suitable carrier compared to PAs for drug delivery. PMID- 25789219 TI - Synthesis of PCEC Copolymers with Controlled Molecular Weight Using Full Factorial Methodology. AB - PURPOSE: Polycaprolactone (PCL) is a biodegradable polyester and has attracted attention as a suitable carrier for development of controlled drug delivery due to its non-toxicity and biocompatibility. It has been reported that the biodegradability of PCL can be enhanced by copolymerization with PEG. Molecular weight (Mw) and CL block lengths optimization in a series of synthesized PCEC copolymers was the main purpose of this study. METHODS: The composition of copolymers was designed using full factorial methodology. Molecular weight of used PEG (4 levels) and weight ratio of epsilon-caprolactone/PEG (3 levels) were selected as independent variables. The PCEC copolymers were synthesized by ring opening polymerization. Formation of copolymers was confirmed by FT-IR spectroscopy as well as H-NMR. The Mn of PCEC copolymers was calculated from HNMR spectra. The thermal behavior of copolymers was characterized on differential scanning calorimeter. RESULTS: Molecular weight of twelve synthesized copolymers was ranged from 1782 to 9264. In order to evaluate the effect of selected variables on the copolymers composition and Mw, a mathematical model for each response parameter with p-value less than 0.001were obtained. Average percent error for prediction of total Mn of copolymers and Mn of CL blocks were 13.81% and 14.88% respectively. CONCLUSION: In conclusion, the proposed model is significantly valid due to obtained low percent error in Mn prediction of test sets. PMID- 25789220 TI - Selection of a suitable method for the preparation of polymeric nanoparticles: multi-criteria decision making approach. AB - PURPOSE: The present study is aimed to select the suitable method for preparation of camptothecin loaded polymeric nanoparticles by utilizing the multi-criteria decision making method. Novel approaches of drug delivery by formulation using nanotechnology are revolutionizing the future of medicine. Recent years have witnessed unprecedented growth of research and application in the area of nanotechnology. Nanoparticles have become an important area of research in the field of drug delivery because they have the ability to deliver a wide range of drug to varying areas of body. METHODS: Despite of extensive research and development, polymeric nanoparticles are frequently used to improve the therapeutic effect of drugs. A number of techniques are available for the preparation of polymeric nanoparticles. The Analytical Hierarchy Process (AHP) is a method for decision making, which are derived from individual judgements for qualitative factors, using the pair-wise comparison matrix. In AHP, a decision hierarchy is constructed with a goal, criteria and alternatives. RESULTS: The model uses three main criteria 1) Instrument, 2) Process and Output and 3) Cost. In addition, there are eight sub-criteria's as well as eight alternatives. Pair wise comparison matrixes are used to obtain the overall priority weight and ranking for the selection of suitable method. Nanoprecipitation technique is the most suitable method for the preparation of camptothecin loaded polymeric nanoparticles with the highest overall priority weight of 0.297 CONCLUSION: In particular, the result indicates that the priority weights obtained from AHP could be defined as a multiple output for finding out the most suitable method for preparation of camptothecin loaded polymeric nanoparticles. PMID- 25789221 TI - Preparation of Proper Immunogen by Cloning and Stable Expression of cDNA coding for Human Hematopoietic Stem Cell Marker CD34 in NIH-3T3 Mouse Fibroblast Cell Line. AB - PURPOSE: Transmembrane CD34 glycoprotein is the most important marker for identification, isolation and enumeration of hematopoietic stem cells (HSCs). We aimed in this study to clone the cDNA coding for human CD34 from KG1a cell line and stably express in mouse fibroblast cell line NIH-3T3. Such artificial cell line could be useful as proper immunogen for production of mouse monoclonal antibodies. METHODS: CD34 cDNA was cloned from KG1a cell line after total RNA extraction and cDNA synthesis. Pfu DNA polymerase-amplified specific band was ligated to pGEMT-easy TA-cloning vector and sub-cloned in pCMV6-Neo expression vector. After transfection of NIH-3T3 cells using 3 MUg of recombinant construct and 6 MUl of JetPEI transfection reagent, stable expression was obtained by selection of cells by G418 antibiotic and confirmed by surface flow cytometry. RESULTS: 1158 bp specific band was aligned completely to reference sequence in NCBI database corresponding to long isoform of human CD34. Transient and stable expression of human CD34 on transfected NIH-3T3 mouse fibroblast cells was achieved (25% and 95%, respectively) as shown by flow cytometry. CONCLUSION: Cloning and stable expression of human CD34 cDNA was successfully performed and validated by standard flow cytometric analysis. Due to murine origin of NIH-3T3 cell line, CD34-expressing NIH-3T3 cells could be useful as immunogen in production of diagnostic monoclonal antibodies against human CD34. This approach could bypass the need for purification of recombinant proteins produced in eukaryotic expression systems. PMID- 25789222 TI - Comparison of the Analgesic Effect of Diclofenac Sodium-Eudragit((r)) RS100 Solid Dispersion and Nanoparticles Using Formalin Test in the Rats. AB - PURPOSE: In this study the intensity and duration of analgesic effect of diclofenac Na - Eudragit((r)) RS100 solid dispersion and nanoparticles were evaluated by using formalin test in the rats. METHODS: The animals received different formulations of diclofenac Na and subsequently 50 MUl of formalin solution (2.5%) was injected subcutaneously in the right paws after 1 h, 2 h and 3 h. The paw licking behavior was then evaluated in two phases. A dose of 20 mg/kg of pure diclofenac Na powder was determined as effective dose. RESULTS: In the first phase, in term of reduced paw licking time, no significant differences were found in any of the groups compared to the control group. However, in the second phase, the animals which received pure drug powder and the physical mixture of diclofenac Na with Eudragit((r)) RS100 showed significant differences at the first and second hours. In the animals received the nanoparticles and solid dispersion, significant differences were observed in the third hour compared to the control group. CONCLUSION: The analgesic effect of diclofenac Na could be improved by formulating its nanoparticles and solid dispersion with Eudragit((r)) RS100. However, the nanoparticles revealed significantly higher analgesic effect than solid dispersion. PMID- 25789223 TI - Effect of intrahippocampal administration of vitamin C and progesterone on learning in a model of multiple sclerosis in rats. AB - PURPOSE: The purpose of this study was to evaluate the effect of intrahippocampal injection of vitamin C and progesterone, alone or in combination, on passive avoidance learning (PAL) in multiple sclerosis. METHODS: Sixty- three male wistar rats were divided into nine groups (n=7) as following: control (saline), lesion, vitamin C (0.2, 1, 5 mg/kg), progesterone (0.01, 0.1, 1 ug/ul) and combination therapy. Lesion was induced by intrahippocampal injection of ethidium bromide. In combination therapy, animals were treated with vitamin C (5 mg/kg) plus progesterone (0.01 mg/kg). Animals in experimental groups received different treatments for 7 days, and then all groups were tested for step through latency (STL). RESULTS: Our results showed that intrahippocampal injection of ethidium bromide destroys PAL significantly (p<0.001). Treatment with vitamin C (5mg/kg) significantly (p<0.05) improved PAL. Lower doses of progesterone did not affect latency but dose of 1 ug/ul significantly (p<0.05) increased STL. In combination therapy group STL was significantly (p<0.05) more than in the lesion group, although it was not significantly different from the vitamin C group. CONCLUSION: Based on our results, we concluded that intrahippocampal injection of vitamin C improves memory for PAL, but progesterone alone or in combination with vitamin C had no improving effects on memory. PMID- 25789224 TI - Vasorelaxant effect of 17alpha-ethynylestradiol on human saphenous vein. AB - PURPOSE: A protective effect for estrogens against cardiovascular problems has long been known. The aim of this study was to investigate the vasorelaxant effect of 17alpha-Ethynylestradiol (17alpha-EE) on human saphenous vein. METHODS: The veins were suspended horizontally between two triangular stainless steel hooks for the measurement of isometric tension in individual organ baths containing 10ml Krebs solution, at 37 degrees C and gassed with carbogen under 3gr optimum tension. The effect of different concentrations of 17alpha-EE (2-40 MUM) on vascular tone was investigated in veins precontracted with PGF2alpha. Relaxation was measured after 40min and expressed as the percent decrease of initial contraction. To determine the involvement of potassium channels, endothelium, nitric oxide synthase, guanylylcyclase and prostaglandins in the vasorelaxant effect of estrogen, the veins were incubated with tetraethyl ammonium, N-nitro-L arginine methyl ester, methylene blue or indomethacin, respectively for 20min prior to experimentation. Responses to 17alpha-EE were directly compared to those obtained in the same tissues in the absence of the inhibitors. RESULTS: The mean relaxations induced by 17alpha-EE with concentrations of 2, 5, 10, 20 and 40MUM in tissues precontracted with PGF2alpha were 19.8 +/-5.5%, 26.1+/-10.8%, 32.2+/ 7.4%, 48.6+/-10.8%and56+/-7.6%, respectively. The results of the inhibition of potassium channels, nitric oxide synthase, guanylylcyclase, cyclooxygenase and removing endothelium in relaxation induced by 17alpha-EE on precontracted veins with PGF2alpha proved no significant differences. CONCLUSION: This study showed that 17alpha-EE has significant vasorelaxant effect on human saphenous vein in a concentration-dependent manner. This effect is probably independent of potassium channels, nitric oxide synthase, guanylylcyclase, prostaglandin synthesis and endothelium functions. PMID- 25789225 TI - Large scale generation and characterization of anti-human IgA monoclonal antibody in ascitic fluid of BALB/c mice. AB - PURPOSE: Monoclonal antibodies are potentially powerful tools used in biomedical research, diagnosis, and treatment of infectious diseases and cancers. The monoclonal antibody against Human IgA can be used as a diagnostic application to detect infectious diseases. The aim of this study was to improve an appropriate protocol for large-scale production of mAbs against IgA. METHODS: For large-scale production of the monoclonal antibody, hybridoma cells that produce monoclonal antibodies against Human IgA were injected intraperitoneally into Balb/c mice that were previously primed with 0.5 ml Pristane. After ten days, ascitic fluid was harvested from the peritoneum of each mouse. The ELISA method was carried out for evaluation of the titration of produced mAbs. The ascitic fluid was investigated in terms of class and subclass by a mouse mAb isotyping kit. MAb was purified from the ascitic fluid by ion exchange chromatography. The purity of the monoclonal antibody was confirmed by SDS-PAGE, and the purified monoclonal antibody was conjugated with HRP. RESULTS: Monoclonal antibodies with high specificity and sensitivity against Human IgA were prepared by hybridoma technology. The subclass of antibody was IgG1 and its light chain was the kappa type. CONCLUSION: This conjugated monoclonal antibody could have applications in designing ELISA kits in order to diagnose different infectious diseases such as toxoplasmosis and H. Pylori. PMID- 25789226 TI - Effect of taurine on febrile episodes in acute lymphoblastic leukemia. AB - PURPOSE: The purpose of our study was to evaluate the effect of oral taurine on the incidence of febrile episodes during chemotherapy in young adults with acute lymphoblastic leukemia. METHODS: Forty young adults with acute lymphoblastic leukemia, at the beginning of maintenance course of their chemotherapy, were eligible for this study. The study population was randomized in a double blind manner to receive either taurine or placebo (2 gram per day orally). Life quality and side effects including febrile episodes were assessed using questionnaire. Data were analyzed using Pearson's Chi square test. RESULTS: Of total forty participants, 43.8% were female and 56.3 % were male. The mean age was 19.16+/ 1.95 years (ranges: 16-23 years). The results indicated that the levels of white blood cells are significantly (P<0.05) increased in taurine treated group. There was no elevation in blasts count. A total of 70 febrile episodes were observed during study, febrile episodes were significantly (P<0.05) lower in taurine patients in comparison to the control ones. CONCLUSION: The overall incidence of febrile episodes and infectious complications in acute lymphoblastic leukemia patients receiving taurine was lower than placebo group. Taurine's ability to increase leukocyte count may result in lower febrile episodes. PMID- 25789227 TI - Production and Purification of a Polyclonal Antibody Against Purified Mouse IgG2b in Rabbits Towards Designing Mouse Monoclonal Isotyping Kits. AB - PURPOSE: Mouse IgG subclasses containing IgG1, IgG2a, IgG2b and IgG3 have been defined and described both physiochemically and immunologically. METHODS: Sepharose beads conjugated with protein A affinity chromatography was used for purification of mouse IgG2b. Sodium citrate buffer (0.1 M, pH: 3.5) was used for separation of mouse IgG2b. Verification of the purified fractions was monitored by SDS-PAGE (polyacrylamide gel electrophoresis) in reducing condition. Immunized rabbit serum was collected and precipitated at the final concentration of 50% ammonium sulfate. After dialysis against tris-phosphate buffer (pH: 8.1) ion exchange chromatography column was used for purification of rabbit anti-mouse IgG2b. The periodate method was performed for conjugation with some variations. After conjugation, direct ELISA was used to determine the titer of HRP conjugated rabbit IgG against mouse IgG2b. RESULTS: The titer of rabbit anti-mouse IgG2b that determined by ELISA was 32000. The purity of rabbit anti-mouse IgG2b was about 95%. The optimum dilution of prepared HRP conjugated IgG was 1:10000. This study showed that ion-exchange chromatography and affinity chromatography could be appropriate techniques for purification of mouse IgG and IgG subclasses respectively. CONCLUSION: This study showed that affinity chromatography could be an appropriate method for purification of IgG2b antibodies. PMID- 25789228 TI - pH-Triggered Magnetic-Chitosan Nanogels (MCNs) For Doxorubicin Delivery: Physically vs. Chemically Cross Linking Approach. AB - PURPOSE: This paper evaluates the impact of cross linking strategy on the characteristics of magnetic chitosan nanogels (MCNs) as targeted drug delivery system for doxorubicin. METHODS: Sodium tripolyphosphate (TPP) and glutaraldehyde were used as physical (electrostatic) and chemical (covalent binding) cross linker agents, respectively. MCNs were characterized by means of X-ray diffraction (XRD), Scanning electron microscopy (SEM), fourier transform infrared (FT-IR) spectroscopy and vibrating sample magnetometer (VSM). Scanning electron microscopy (SEM) indicated the formation of spherical nanostructures with the final average particle size of around 35-40 nm. RESULTS: The finding proved the superparamagnetic properties of the MCNs with relatively high-magnetization values which indicate that the MCNs were enough sensitive to external magnetic fields as a magnetic drug carrier. To understand the differences between the drug delivery properties of chemically and physically cross linked MCNs, the drug release studies were also conducted. Altogether, the results of this study clearly indicate that, however, both MCNs exhibited sustained drug release behaviour, the chemically cross linked MCNs provided enhanced controlled drug release characteristics in comparison to physically cross linked MCNs. Besides, according to the drug release behaviour of MCNs in buffer solutions in two different medium with the pH values of 5.3 and 7.4, it was clear that both nanoparticles exhibited pH sensitivity where the extent of drug release in the acidic media was significantly higher than neutral media. CONCLUSION: It can be concluded that chemically cross linked MCNs may serve as an ideal carrier for stimuli-triggered and controlled anticancer drug delivery. PMID- 25789229 TI - Investigating the mutagenic effects of three commonly used pulpotomy agents using the ames test. AB - PURPOSE: The mutagenic potency of materials used in dentistry is of great concern. The Ames test is a bacterial reverse mutation assay, which is used to determine the mutagenicity potential of chemicals. In this study, the Ames test was used to compare mutagenic effects of three pulpotomy agents, namely, CEM cement, formocresol and ferric sulfate. METHODS: TA100 strain of Salmonella typhimurium was used to evaluate mutagenicity of different concentrations of pulpotomy materials in the presence and absence of enzymatic system found in rat liver S9 fraction. Negative controls were 1% dimethyl sulfoxide and water. The positive controls were sodium azide and 2-aminoanthracene. The number of colonies per plate was counted. The material was regarded mutagenic if the number of histidine revertant colonies was twice or more than the spontaneous revertant colonies (Ames mutagenicity ratio). RESULTS: Ferric sulfate was found mutagenic in the concentrations prepared by addition of 50 uL of its 1 in 100 and 1 in 1000 times diluted solutions to the culture medium in the absence of S9 fraction (Ames test ratios of 2.8 and 2.2, respectively). Formocresol showed strong toxicity toward TA100 strain of S. typhimurium up to the concentration as low achieved using 1000 times diluted solution of the original preparation, particularly in the presence of S9 fraction. Ames assay failed to detect significant reverse mutations in all the concentrations of CEM cement. CONCLUSION: In contrast to formocresol and ferric sulfate, CEM cement is a less toxic and non-mutagenic agent. PMID- 25789230 TI - The Effect of Regular Moderate Exercise on miRNA-192 Expression Changes in Kidney of Streptozotocin-Induced Diabetic Male Rats. AB - PURPOSE: The purpose of this study was to investigate the regular moderate exercise effect on the miR-192 expression changes in kidney of Streptozotocin- induced diabetic rats. METHODS: Forty adult male Wistar rats were divided into four groups of 10, including Sedentary Control group, Healthy 60 days Exercise group, diabetic group and Diabetic 60 days Exercise. Diabetes was induced by injection of 60 mg/kg Streptozotocin and after 48 hour blood glucose levels higher than 250 mg/dl were included to diabetic rats. After 48 hour of induction diabetes, exercise protocol was begun. Animals performed 5 days of consecutive treadmill exercise (60 min/day) with 22 m/min speeds for 60 days. Kidney of the rats has removed and MicroRNA was extracted from kidney using miRCURY(TM) RNA isolation kit. RESULTS: Exercise upregulated miR-192 expression level significantly in the kidney of diabetic rats in comparison to healthy group. There is not any significant change in miR-192 expression in diabetic 60 days exercise compared to control group. CONCLUSION: These results may indicate that exercise can help to prevent the progression of diabetic nephropathy. PMID- 25789231 TI - Optimized and Validated RP-UPLC Method for the Determination of Losartan Potassium and Chlorthalidone in Pharmaceutical Formulations. AB - PURPOSE: A validated ultra performance liquid chromatography (UPLC) method has been developed and validated for the simultaneous determination of losartan potassium and chlorthalidone in pharmaceutical preparations. METHODS: Waters Acquity UPLC system equipped with Auto Sampler, PDA detector and operated with Empower-2 software was used for the present study. Detection was done at wavelength of 230 nm, HSS C18, 100 mm x 2.1x 1.8 MUm column with a reverse phase elution and mobile phase composed of A and B mixed in the ratio 56:44 v/v (Where mobile phase A consists of potassium dihydrogen phosphate buffer of pH 3.0 and Mobile phase B consists of acetonitrile and methanol mixed in the ratio of 90:10 v/v) used at a flow rate of 0.4ml per minute. RESULTS: The retention times for losartan potassium and chlorthalidone were observed at 0.72 and 1.89 minutes. The developed method was validated as per ICH guidelines. Linearity ranges were found to be 12.5-125 MUg/ml and 3.125-31.25 MUg/ml for losartan potassium and chlorthalidone, respectively. CONCLUSION: This method is fast, accurate, precise and sensitive hence it can be employed for routine quality control of tablets containing both drugs in industries. PMID- 25789232 TI - Evaluation of Association Between HLA Class II DR4-DQ8 Haplotype and Type I Diabetes Mellitus in Children of East Azerbaijan State of Iran. AB - PURPOSE: Association between HLA-DR4-DQ8 haplotype and type 1 Diabetes Mellitus (DM-1A) was investigated in children of East Azerbaijan state of Iran because such an association has not been previously studied in this population. METHODS: HLA-typing was performed by polymerase chain reaction sequence-specific priming. For haplotype analysis, the logistic regression model was performed. RESULTS: Of the three investigated alleles, the frequency of DRB1*0401 was significantly higher among patients compared with that in healthy subjects (76.74% vs. 23.26%). CONCLUSION: The findings of the current study are consistent with those of previous studies and show that DRB1*0401 is associated with DM-1A; the frequencies of the two other alleles were also higher among patients, although the differences were not statistically significant. Two haplotypes associated with these alleles were also surveyed, and DRB1*0401--DQA1*0301-, and DRB1*0401- DQA1*0301--DQB1*0302- were the most frequent haplotypes among the patient group. PMID- 25789233 TI - Continuous peripheral nerve catheters in pediatric complex regional pain syndrome. PMID- 25789234 TI - A new technique to treat facet joint pain with pulsed radiofrequency. AB - INTRODUCTION: Facet joint pain affects 5% to 15% of the population with low back pain and the prevalence increases with age due to progression of arthritis. While conservative treatments are often unsuccessful, the scientific evidence on minimally invasive therapies such as intra-articular steroid infiltration and continuous and pulsed radiofrequency (PRF) of the medial branches is contradictory. Since PRF has recently been reported to successfully treat joint pain, a new application of this method is proposed for facetogenic lumbar pain via an intra-articular subcapsular approach. Here we reported two cases with successful treatment. CASE PRESENTATION: A 71-year-old patient presented because of persisting pain in the left gluteal region radiating to the lateral thigh and calf when standing. Anti-inflammatory drugs produced only short-lasting insufficient relief. A 52-year-old employee was admitted in June 2012 because of axial lower lumbar pain with intermittent diffuse radiation to the right lower extremity that worsened during walking and lying down despite receiving analgesics and physiotherapy. CONCLUSIONS: A new approach to treat lumbar facet joint pain with PRF is simple to perform and without serious complications. In view of the good long-lasting results obtained with the two reported cases, randomized control trials are necessary to validate this new approach. PMID- 25789235 TI - Efficacy of a Modified Bier's Block in Patients Undergoing Upper Limb Bone Surgery. AB - BACKGROUND: Intravenous regional block, called the Bier's block, refers to an analgesic technique applied for soft tissue surgeries and closed bone manipulations of the limbs. There are a number of complications in traditional method of block, including pain in tourniquet site, immediate return of pain after tourniquet deflation, wound hemostasis and some others. OBJECTIVES: The aim of this study was to assess the outcomes and complications of our new method of blockage. PATIENTS AND METHODS: In this experimental study, twenty-five patients undergoing hand surgery were prospectively studied. Induced anesthesia was a modification of the Bier's block with two concurrent changes including insertion of the intravenous cannula at the antecubital region rather than distal and the proximal anesthetic direction by an elastic band wrapped tightly around the proximal forearm distal to the cannulation site. The pain relief was measured by the verbal descriptive scale at intervals after block, during the operation, after deflation of the tourniquet and one hour after the operation. RESULTS: This study showed the presence of analgesia at surgical and tourniquet sites during the operation in 96% of patients, as well as considerable pain relief at surgical site during one hour after deflation of the tourniquet. CONCLUSIONS: The study indicated advantages of this modified Bier's block compared to the traditional one including ability to perform surgery on upper limb bones and considerable pain relief at surgical and tourniquet sites during the operation until one hour thereafter. PMID- 25789236 TI - Recovery following desflurane versus sevoflurane anesthesia for outpatient urologic surgery in elderly females. AB - BACKGROUND: An unresolved question is the time required for the ability to return to complex tasks following anesthesia. OBJECTIVES: This study aims to characterize the severity and duration of cognitive impairment following sevoflurane or desfluane anesthesia after brief surgery using tests of cognitive ability to objectively testing performance. PATIENTS AND METHODS: This study is a double blinded randomized controlled trial. Patients were randomized to receive either a desflurane or sevoflurane-based anesthetic. On the morning of the surgery the subjects performed baseline cognitive task tests (Mini Mental Status exam, Trail Making Test Part A and B, Digit Symbol Coding, Hopkins Verbal Learning Test, Stroop Color and Word Test to determine baseline cognitive function. Cognitive testing was repeated 30 minutes and 1 hour after surgery whereas Modified Telephone Interview for Cognitive Status (TICS-M) and Memory Aging Telephone Screen (MATS) was used on the following day of surgery. RESULTS: Trail Making Test Part B cognitive test showed statistically significant in comparison for pre and post exposure of anesthetics. This difference was seen in the desflurane group. Other cognitive tests did not show differences on exposure to the anesthetic gases. CONCLUSIONS: This study questioned the difference between volatile anesthetic agent's effects on patients completing a battery of neurocognitive tests attempting to answer if one agent has a more profound effect. Our study shows no statistically significant cognitive decline except for those in the Trail Making Part B in the Desflurane group. This conclusion is limited by the inherent limitations of the study, but does reinforce that the systemic inflammatory response from the surgery contributes cognitive impairment. PMID- 25789237 TI - The effect of gabapentin on reducing pain after laparoscopic gastric bypass surgery in patients with morbid obesity: a randomized clinical trial. AB - BACKGROUND: Pain after laparoscopic gastric bypass surgery (LGBP) is a major problem. Gabapentin is an anticonvulsant drug that can be effective in postoperative pain control. OBJECTIVES: This study examined the effect of preoperative administration of gabapentin on reducing pain after LGBP in patients with morbid obesity. PATIENTS AND METHODS: This randomized clinical trial was performed in Hazrat Rasoul Akram Medical Center in Tehran. A total of 60 patients undergoing LGBP were randomly allocated into two groups; one group received 100 mg of oral gabapentin and the other group received placebo. Pain was evaluated at recovery time, and at the first, second, fourth and sixth hour of surgery by visual analog scale. The number and dose of opioid use after surgery and incidence of postoperative complications, such as nausea and vomiting, agitation, and headache, were also recorded. RESULTS: The mean pain score in the group receiving gabapentin was significantly lower than the placebo group (P < 0.001). Indications and dose of opioid consumption between the two groups were not statistically significant. Incidence of nausea/vomiting (P = 0.028) as well as agitation (P = 0.037) was significantly lower in the gabapentin group. CONCLUSIONS: Administration of gabapentin before surgery can reduce pain after LGBP. Furthermore, it is not accompanied by significant short-term adverse effects. PMID- 25789238 TI - Impact of Extraperitoneal Dioxyde Carbon Insufflation on Respiratory Function in Anesthetized Adults: A Preliminary Study Using Electrical Impedance Tomography and Wash-out/Wash-in Technic. AB - BACKGROUND: Extraperitoneal laparoscopy has become a common technique for many surgical procedures, especially for inguinal hernia surgery. Investigations of physiological changes occurring during extraperitoneal carbon dioxide (CO2) insufflation mostly focused on blood gas changes. To date, the impact of extraperitoneal CO2 insufflation on respiratory mechanics remains unknown, whereas changes in respiratory mechanics have been extensively studied in intraperitoneal insufflation. OBJECTIVES: The aim of this study was to investigate the effects of extraperitoneal CO2 insufflation on respiratory mechanics. PATIENTS AND METHODS: A prospective and observational study was performed on nine patients undergoing laparoscopic inguinal hernia repair. Anesthetic management and intraoperative care were standardized. All patients were mechanically ventilated with a tidal volume of 8 mL/kg using an Engstrom Carestation ventilator (GE Healthcare). Ventilation distribution was assessed by electrical impedance tomography (EIT). End-expiratory lung volume (EELV) was measured by a nitrogen wash-out/wash-in method. Ventilation distribution, EELV, ventilator pressures and hemodynamic parameters were assessed before extraperitoneal insufflation, and during insufflation with a PEEP of 0 cmH2O, 5 cmH20 and of 10 cmH20. RESULTS: EELV and thoracopulmonary compliance were significantly decreased after extraperitoneal insufflation. Ventilation distribution was significantly higher in ventral lung regions during general anesthesia and was not modified after insufflation. A 10 cmH20 PEEP application resulted in a significant increase in EELV, and a shift of ventilation toward the dorsal lung regions. CONCLUSIONS: Extraperitoneal insufflation decreased EELV and thoracopulmonary compliance. Application of a 10 cmH20 PEEP increased EELV and homogenized ventilation distribution. This preliminary clinical study showed that extraperitoneal insufflation worsened respiratory mechanics, which may justify further investigations to evaluate the clinical impact. PMID- 25789239 TI - The Effect of Intravenous Administration of Active Recombinant Factor VII on Postoperative Bleeding in Cardiac Valve Reoperations; A Randomized Clinical Trial. AB - BACKGROUND: Postoperative bleeding after cardiac reoperations is among the most complicating problems, both for the physicians and for the patients. Many modalities have been used to decrease its adverse effects and the need for blood products administration. OBJECTIVES: In a randomized double-blinded clinical trial of redo cardiac valve surgery in adult, the effect of active recombinant factor VII (rFVIIa) on postoperative bleeding was compared with placebo. Chest tube drainage was used for comparison of bleeding between the two groups. PATIENTS AND METHODS: Two groups of 18 patients undergoing redo valve surgeries were treated and compared regarding chest tube drainage, need for blood products, prothrombin time (PT), partial thromboplastin time (PTT), hemoglobin and hematocrit, platelet count, and international normalized ratio (INR) in first 24 hours after surgery. Bleeding was assessed at 3rd, 12th, and 24th hour after operation. In rFVIIa group, 40 ug/kg of AryoSeven was administered before end of surgery and same volume of normal saline was administered as placebo in the control group. RESULTS: Study groups showed no difference regarding baseline variables. Three patients in rFVIIa group (16.67%) and 13 in placebo group (72.23%) received blood products (P < 0.01). Chest tube blood drainage at 24th hour after operation was 315 +/- 177 mL in rFVIIa group and 557 +/- 168 mL in control group (P = 0.03). At third and 12th hour after operation, the difference was not statistically significant (P = 0.71 and P = 0.22, respectively). Postoperative ICU stay was not different; while extubation was longer in the placebo group (352 +/- 57 vs. 287 +/- 46 minutes; P = 0.003). CONCLUSIONS: Our study demonstrated the efficacy of rFVIIa in controlling postoperative bleeding in redo cardiac valve surgeries regarding subsequent blood loss and transfusion requirement; however, outcome results remains to be defined. PMID- 25789240 TI - Efficacy of fentanyl transdermal patch in the treatment of chronic soft tissue cancer pain. AB - BACKGROUND: Cancer pain may be a major problem for health care providers worldwide. According to different studies reporting the pain severity, one-third of patients reported to have moderate to severe pain. Management of cancer pain is one of the most important goals of palliative care. Recently, different research results on the efficacy of opioid analgesics in chronic pain management have played a role to implement standards in pain control by government agencies worldwide. OBJECTIVES: This study aimed to investigate the efficacy of fentanyl transdermal patch in the treatment of chronic soft tissue cancer pain. PATIENTS AND METHODS: In a prospective descriptive study, we evaluated 86 patients with soft tissue tumors with chronic pain referred to cancer institute of Imam Khomeini Hospital, Tehran, Iran, during 2006-2007. For all patients, transdermal fentanyl patch (25 MUg/h) was administered. The appearance of patches was the same. Pain severity was measured by Visual Analogue Scale (VAS) initially and 24, 48 and 72 hours after the initiation of treatment. RESULTS: Patients' characteristics and VAS score before the treatment were not significantly different (P > 0.05). According to our findings, the pain severity was significantly reduced after the treatment (P = 0.001). The incidence of adverse events in patients was significantly high (72%). The most common adverse events were sleepiness, nausea and vomiting in 30.2% and 18.6%, respectively. CONCLUSIONS: Transdermal fentanyl patch was an effective and safe method to reduce pain in patients with soft tissue tumors. Moreover, it could improve the quality of life in these patients, but adverse events occurred in approximately 72% of patients. PMID- 25789241 TI - Efficacy of epidural injections in the treatment of lumbar central spinal stenosis: a systematic review. AB - CONTEXT: Lumbar central spinal stenosis is common and often results in chronic persistent pain and disability, which can lead to multiple interventions. After the failure of conservative treatment, either surgical or nonsurgical modalities such as epidural injections are contemplated in the management of lumbar spinal stenosis. EVIDENCE ACQUISITION: Recent randomized trials, systematic reviews and guidelines have reached varying conclusions about the efficacy of epidural injections in the management of central lumbar spinal stenosis. The aim of this systematic review was to determine the efficacy of all three anatomical epidural injection approaches (caudal, interlaminar, and transforaminal) in the treatment of lumbar central spinal stenosis. A systematic review was performed on randomized trials published from 1966 to July 2014 of all types of epidural injections used in the management of lumbar central spinal stenosis. Methodological quality assessment and grading of the evidence was performed. RESULTS: The evidence in managing lumbar spinal stenosis is Level II for long term improvement for caudal and lumbar interlaminar epidural injections. For transforaminal epidural injections, the evidence is Level III for short-term improvement only. The interlaminar approach appears to be superior to the caudal approach and the caudal approach appears to be superior to the transforaminal one. CONCLUSIONS: The available evidence suggests that epidural injections with local anesthetic alone or with local anesthetic with steroids offer short- and long-term relief of low back and lower extremity pain for patients with lumbar central spinal stenosis. However, the evidence is Level II for the long-term efficacy of caudal and interlaminar epidural injections, whereas it is Level III for short-term improvement only with transforaminal epidural injections. PMID- 25789242 TI - The role of inhalational anesthetic drugs in patients with hepatic dysfunction: a review article. AB - CONTEXT: Anesthetic drugs including halogenated anesthetics have been common for many years. Consequent hepatic injury has been reported in the literature. The mechanism of injury is immunoallergic. The first generation drug was halothane; it had the most toxicity when compared to other drugs. The issue becomes more important when the patient has an underlying hepatic dysfunction. EVIDENCE ACQUISITION: In this paper, reputable internet databases from 1957-2014 were analyzed and 43 original articles, 3 case reports, and 3 books were studied. A search was performed based on the following keywords: inhalational anesthesia, hepatic dysfunction, halogenated anesthetics, general anesthesia in patients with hepatic diseases, and side effects of halogenated anesthetics from reliable databases. Reputable websites like PubMed and Cochrane were used for the searches. RESULTS: In patients with hepatic dysfunction in addition to hepatic system and dramatic hemostatic dysfunction, dysfunction of cardiovascular, renal, respiratory, gastrointestinal, and central nervous systems may occur. On the other hand, exposure to inhalational halogenated anesthetics may have a negative impact (similar to hepatitis) on all aforementioned systems in addition to direct effects on liver function as well as the effects are more pronounced in halothane. CONCLUSIONS: Despite the adverse effects of inhalational halogenated anesthetics (especially halothane) on hepatic patients when necessary. The effects on all systems must be considered and the necessary preparations must be provided. These drugs are still used, if necessary, due to the presence of positive effects and advantages mentioned in other studies as well as the adverse effects of other drugs. PMID- 25789243 TI - Mid-Term Patency in Radial Artery and Saphenous Vein After Coronary Artery Bypass Grafting in Asymptomatic Patients Using 128-Slice CT Coronary Angiography. AB - BACKGROUND: Patency of the revascularization conduit is an essential predictor of long-standing survival after coronary artery bypass grafting. OBJECTIVES: We have conducted this study to compare the mid-term patency rates of radial artery (RA), left internal thoracic artery (LITA) and also saphenous vein (SV) grafts in asymptomatic patients following coronary artery bypass graft surgery (CABG) undergoing total IV anesthesia. PATIENTS AND METHODS: In this study, 30 three vessel disease patients with 104 RA, LITA, and SV grafts used concomitantly for primary isolated non-emergent CABG surgery were assessed. The primary end point was CT angiographic graft patency rate. After 53.5 (24-97) months' follow-up, graft patency was assessed using 128-slice CT coronary angiography. Logistic regression analysis was used to detect the independent predictors of graft failure. RESULTS: A total of 104 grafts, including 30 LITA, 44 SV, and 30 RA grafts, were studied. Cumulative graft patency rates were 93.3% in LITA, 83.3% in RA, and 70.5% in SV grafts. Statistically significant difference was found between the LITA and the SV graft patency rates (P = 0.019), whereas the difference between the RA conduit patency and the LITA or SV graft patency rates did not have any statistical significance (P = 0.424 and P = 0.273, respectively). Independent predictors of RA grafts occlusion were native coronary stenosis < 70% and female gender. CONCLUSIONS: In our patients, the RA grafts had an acceptable patency rate in 2 to 5 years' follow-up. Although the SV grafts had a relatively higher patency rate than RA grafts in our asymptomatic patients, the patency rates in RA and SV grafts were close to each other. The RA graft function was poor in the patients with a higher number of risk factors and in the females. PMID- 25789244 TI - Impact of vitamin C supplementation on post-cardiac surgery ICU and hospital length of stay. AB - BACKGROUND: Prolonged intensive care unit (ICU) and hospital stay after cardiac surgery is vitally important and is influenced by both intraoperative and postoperative factors. OBJECTIVES: This randomized clinical trial study was designed to assess whether vitamin C supplementation could reduce the length of ICU and hospital stay in post-cardiac surgery patients. PATIENTS AND METHODS: Two hundred and ninety patients scheduled for adult cardiac surgery including coronary, valve and congenital operations were randomized into two groups: an intervention group, who received 2 g of vitamin C (ascorbic acid) intravenously, immediately before surgery in the operating theatre, followed by 1 g daily oral doses for the first 4 postoperative days; and a placebo group, who received an equal number of identical tablets in the same shape and size. RESULTS: Hospital length of stay was significantly different between the two groups (10.17 +/- 4.63 days in the intervention group vs. 12 +/- 4.51 days in the placebo group; P = 0.01), while there was no significant difference in the ICU stay between the groups (3.42 +/- 1.06 days in intervention group vs. 3.43 +/- 1.09 days in the placebo group; P = 0.88). There were significant differences in the intubation time and the drainage volume in the ICU and the first 24 postoperative hours between the two groups (P for both = 0.003). CONCLUSIONS: Vitamin C can decrease the length of hospital stay, drainage volume in the ICU and in the first 24 postoperative hours, intubation time and some complications in patients after cardiac surgery; perhaps by decreasing inflammatory factors. PMID- 25789246 TI - Determinants of immunization coverage in lucknow district. AB - BACKGROUND: Immunization remains one of the most important public health interventions and a cost-effective strategy to reduce both the morbidity and mortality associated with infectious diseases. Over two million deaths are delayed through immunization each year worldwide. AIMS: This study sought to identify specific factors associated with immunization coverage in order to advance improved intervention, policies/strategies therefore raising overall immunization coverage. MATERIALS AND METHODS: A cross-sectional study was conducted among a total of 198 children aged 12-23 months at Urban Health and Training Centre (UHTC), Era's Lucknow Medical College, Lucknow, over a period of 6 months i.e., from July 2012-December 2012. Data were collected, compiled and tabulated using Microsoft Excel and analyzed using SPSS 17.0 version. RESULTS: A total of 198 children of age 12-23 months were included in this study, of which 74.7% of children were fully immunized, 11.1% were partially immunized and 14.1% were not immunized at all. The most common reason for partial or non-immunization was family problems (24%) of the respondents followed by lack of knowledge of immunization (20%), and fear of side effects (16%). The odds of risk of partial/non-immunization in illiterate women is 5.78 more than the graduate women (P = 0.039). CONCLUSIONS: Although in the present study, majority of the children were immunized, it is still not up to the mark. We have to make it 100%, so that we can reduce mortality due to vaccine-preventable diseases. Increasing awareness and reducing fear of side effects of immunization among parents through health education, counseling, etc. can increase the percentage of immunized children. PMID- 25789245 TI - Proteomics identification of novel fibrinogen-binding proteins of Streptococcus suis contributing to antiphagocytosis. AB - Streptococcus suis serotype 2 (SS2) induced sepsis and meningitis are often accompanied by bacteremia. However, the mechanism whereby it helps S. suis to evade PMN-mediated phagocytosis remain unclear. Because of the central roles of bacteria-human fibrinogen (hFg) interaction in innate immunity, here, a proteomics based Far-western blotting (PBFWB) was developed to identify the fibrinogen-binding surface proteins of S. suis (SsFBPs) on a large-scale. And then thirteen potential SsFBPs were identified by PBFWB and we selected seven potential surface proteins to further confirm their binding ability to hFg, of which the gene mutant strains of MRP displayed significantly decrease in binding to immobilized hFg. Additionally, the polyclonal antibodies against Enolase were found to significantly inhibit the binding of SS2 to hFg. Strikingly, MRP and Enolase were found to improve the antiphagocytic ability of SS2 to PMNs by interacting with hFg and enhance the survival of SS2 in human blood. Taken together, the PBFWB method provides useful clues to the bacteria-host interactions. These studies firstly disclose MRP and Enolase were involved in immune evasion of SS2 at least in part by binding to Fg, which make them potential targets for therapies for SS2 infection. PMID- 25789248 TI - Combined use of frontal sinus and nasal septum patterns as an aid in forensics: a digital radiographic study. AB - BACKGROUND: Skull radiographic examination is a potentially useful procedure for the personal identification in cases where fragments of skull persist with no likelihood of identification based on dental arch. AIMS: The study was to determine the uniqueness and reliability of combined frontal sinus (FS) and nasal septum (NS) patterns as observed on posterioanterior (PA) cephalograms for personal identification. MATERIALS AND METHODS: The randomly selected 149 digital PA cephalograms taken on Kodak 8000C Digital Panoramic and Cephalometric system were evaluated for patterns of FS and NS. Also the distribution of lobulations, area, and ratio of height/width of FS was calculated. The data obtained was statistical analyzed using Pearson's coefficient correlation. RESULTS: FS symmetry was observed in 78.5% and asymmetry in 7.3% subjects. Bilateral aplasia was noticed in 5.3% and unilateral aplasia in 8.7% of subjects. The total lobulation of FS was noted more in males on both sides while center lobes were observed slightly more in females. The straight NS was maximally seen followed by reverse sigmoid. The mean ratio of width/height of FS was observed more in males and highly significant correlation was observed with both sexes. The mean area of FS was noted more in males. There was significant correlation found between patterns of NS and FS except in right dominated asymmetrical FS. CONCLUSION: The combined use of FS and NS patterns could be used as method for identification by exclusion in forensics. PMID- 25789247 TI - Cardiovascular effects of copper deficiency on activity of superoxide dismutase in diabetic nephropathy. AB - BACKGROUND: Copper (Cu) is essential both for its role in antioxidant enzymes, like Cu/zinc (Zn) superoxide dismutase (SOD) and ceruloplasmin, as well as its role in lysyl oxidase, essential for the strength and integrity of the heart and blood vessels. With such a central role in cardiovascular health, Cu has been generally overlooked in the debate over improving our cardiovascular health. Cu deficiency has produced many of the same abnormalities present in cardiovascular disease. It seems almost certain that Cu plays a large role in the development of this killer disease, not because of its excess in the diet, but rather its deficiency. AIM: This study was undertaken to investigate the cardiovascular effects of Cu deficiency on the activity of SOD in patients with type 2 diabetes mellitus (T2DM) with and without diabetic nephropathy. MATERIALS AND METHODS: Fifty-five patients with T2DM were recruited in this study which were divided into two subgroups based on the presence of microalbuminuria, the first group (microal buminuric group, n = 31) had a microalbuminuria between 30 and 299 MUg/mg. The second group (normoal buminuric group, n = 29) had an albumin level less than 30 MUg/mg. The two diabetic groups were compared to the control group (n = 37). RESULTS: The results of our study showed a significant reduction in the levels of SOD enzyme associated with an increased urinary Cu excretion in microalbuminuric group compared to the control group at P < 0.05. CONCLUSIONS: The current study illustrates that the regulation of the blood concentrations of Cu may be a potential therapeutic target for prevention and treatment of diabetic nephropathy. PMID- 25789249 TI - Metabolic syndrome and prediabetes in ndokwa community of Nigeria: preliminary study. AB - BACKGROUND: Global prevalence of metabolic syndrome (MS) and diabetes is increasing, but the reference ranges for MS indices have yet to be established for sub-Saharan African countries. As part of the international research collaboration agenda for Prediabetes and Cardiovascular Complications Study (PACCS), a pilot study was conducted in one of the Ndokwa communities of Nigeria in 2013. AIM: The study was to obtain preliminary indication of prevalence and reference values of MS in the rural communities of a low-mid income country. MATERIALS AND METHODS: Seventy-four volunteer participants were recruited, after public lectures in high schools and churches in the community. Body mass index (BMI), blood pressure and waist circumference (WC), blood glucoselevel, and lipid profile were measured. Percentage prevalence MS was determined using commonest three criteria (Third Adult Treatment Panel (ATP III) 2001, International Diabetes Federation (IDF) 2005, and World Health Organization (WHO) 1999). RESULTS: When individual indices of MS are considered separately; the males seem healthier than females. However, the prevalence of high-density lipoprotein (HDL) cholesterol was higher in males than in females. Equal 3% prevalence of MS was seen in both genders using the WHO standard. Other criteria show prevalence of 8% females and 11% males (ATP III), 5% females and 8% males (IDF 2005 European), and 14% females and 17% males (IDF 2005 Ethnic). CONCLUSION: The prevalence of MS is higher in males than females; and relative to ATP III 2001 criteria, either the IDF 2005 European may underestimate MS, or the ethnic specific could overestimate the prevalence. Hence, it is important to define the criteria to be used. PMID- 25789250 TI - N (G)-nitro-L-arginine Methyl Ester Protects Against Hormonal Imbalances Associated with Nicotine Administration in Male Rats. AB - BACKGROUND: The administration of nicotine is associated with altered hormonal imbalances and increased serum and testicular nitric oxide (NO) level. AIM: This study sought to investigate the effects of NO inhibition with N (G)-nitro-L arginine methyl ester (L-NAME) on altered hormonal imbalance in adult male albinorats. MATERIALS AND METHODS: Rats were administered with 0.5 mg/kg body weight (BW) and 1.0 mg/kg BW nicotine and were treated with L-NAME in the drinking water or drinking water alone for 30 days. Serum was analyzed for testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin using radioimmunoassay. RESULTS: Nicotine administration significantly decreased (P < 0.05) testosterone in the low and high dose treated groups and FSH in the high dose treated group when compared with the control group. There was a significant increase (P < 0.05) in mean LH and prolactin level in the high dose treated group when compared with the control. Concomitant treatment with nicotine and L-NAME produced significant increases in testosterone and FSH, and a decrease in prolactin in 1.0 mg/kg BW. L-NAME alone did not lead to a significant increase in testosterone when compared with control. CONCLUSION: These data demonstrate that the suppressive effects of nicotine on testosterone level of the adult male rat can be prevented by NOS blockade with L-NAME. It appears that these beneficial effects are mediated primarily within the gonad; however, the involvement of the pituitary cannot be totally ruled out. PMID- 25789251 TI - Glandular odontogenic cyst of the anterior mandible. AB - CONTEXT: Glandular odontogenic cyst (GOC) is a rare cyst occurring in the middle age people with mandibular anterior as the common site of occurrence. CASE REPORT: We report a case of massive GOC in a 65-year-old female with an emphasis on its clinical course, histological features, and treatment modalities. CONCLUSION: The aggressiveness and recurrences of GOC warrants clinicians for the careful examination, treatment, and long-term follow-up. PMID- 25789252 TI - Digital Gangrene an Unusual Presentation of Takayasu's Arteritis. AB - CONTEXT: Takayasu arteritis (TA) is a chronic inflammatory disease involving large vessels like aorta and its major branches. It presents to clinician with features of arm claudication, stroke, asymmetrical pulse, or asymmetrical blood pressure in both limbs. Digital gangrene may be occurred secondary to various systemic diseases like diabetes, thrombophilic states, vascular embolism, and medium and small vessel vasculitis or infections. Through evaluation to diagnose the exact etiology and timely intervention is needed to prevent progression of the gangrene which at the time can be life-threatening. Digital gangrene as an initial presentation in TA is very rare. In medical literature, there are only few case reports have been reported. CASE REPORT: We are reporting a case of a 26 year-old female patient presented with right little finger and index finger gangrene, ultimately diagnosed as TA and responded dramatically to treatment. CONCLUSION: Though rare, TA should be taken in the differential diagnosis for work up in a case of digital gangrene and it necessitates more studies in this field to uncover the exact pathophysiology for such presentation. PMID- 25789253 TI - Post septorhinoplasty custom-made unilateral nasal stent for nasal cleft deformity. AB - CONTEXT: Nasal cleft deformity is a complicated problem. Utilization of nasal stent in post septorhinoplastyaims at establishing and maintaining airway patency, tissue position, and reduces tissue contracture after surgery. CASE REPORT: A 16-year-old female patient presented with history of surgical reconstruction of congenital cleft lip and cleft palate with secondary septorhinoplasty of nasal cleft deformity. Patient was referred for nasal stent 1 week after septorhinoplasty. This case report provides a novel technique for fabrication of esthetic nasal stent after postseptorhinoplasty for secondary cleft nose deformity correction. CONCLUSION: This case report presents a simple, convenient technique for nasal stent fabrication for prevention of restenosis for cleft nose deformity post secondary septorhinoplasty. Provision of nasal stent allows breathing, maintains esthetics, comfort, nasal patency, and contour with minimal discomfort. PMID- 25789254 TI - Plagiarism: an egregious form of misconduct. AB - BACKGROUND: Publishing research papers for academic fraternity has become important for career advancement and promotion. Number of publications in peer reviewed journals and subsequent citations are recognized as measures of scientific success. Non-publishing academicians and researchers are invisible to the scientific community. DISCUSSION: With pressure to publish, misconduct has crept into scientific writing with the result that research misconduct, plagiarism, misappropriation of intellectual property, and substantial unattributed textual copying of another's publication have become common. The Office of Research Integrity, USA, defines research misconduct as "fabrication, falsification or plagiarism in proposing, performing or reviewing research, or in reporting research results." Although plagiarism is difficult to define in few words, it can be viewed as the stealing of another person's ideas, methods, results, or words without giving proper attribution. The Office of Research Integrity defines plagiarism as being "theft or misappropriation of intellectual property and the substantial unattributed textual copying of another's work." Plagiarism is one of the most vehemently derided breaches of research integrity as it undermines the original and honest contribution to an existing body of knowledge. CONCLUSION: Plagiarism has many forms viz. blatant plagiarism, technical plagiarism, patchwork plagiarism, and self-plagiarism. In any form, the plagiarism is a threat to the research integrity and is unacceptable. We do need to detect such acts and effectively prosecute the offenders. PMID- 25789255 TI - The association between bone health indicated by calcaneal quantitative ultrasound and metabolic syndrome in Malaysian men. AB - BACKGROUND: Previous studies on the relationship between bone health and metabolic syndrome (MS) have revealed heterogeneous results. There are limited studies employing bone quantitative ultrasonometry in evaluating this relationship. This study aimed to determine the relationship between MS and bone health in a group of Malaysian middle-aged and elderly men using bone quantitative ultrasonometry. METHODS: This cross-sectional study recruited 309 free living Chinese and Malay men aged 40 years and above residing in Klang Valley, Malaysia. Their demographic and anthropometric data were collected. Their calcaneal speed of sound (SOS) was measured using a CM-200 bone ultrasonometer. Their blood was collected for the evaluation of lipid profile, total testosterone and sex hormone-binding globulin. The joint interim MS definition was used for the classification of subjects. Multiple linear regression analysis was used to assess the association between SOS and indicators of MS and the presence of MS, with suitable adjustment for confounders. RESULTS: There was no significant difference in SOS value between MS and non-MS subjects (p > 0.05). The SOS values among subjects with different MS scores did not differ significantly (p > 0.05). There were no significant associations between SOS values and indicators of MS or the presence of MS (p > 0.05). CONCLUSIONS: The relationship between bone health and MS is not significant in Malaysian middle-aged and elderly men. A longitudinal study should be conducted to evaluate the association between bone loss and MS to confirm this finding. PMID- 25789256 TI - Effects of resveratrol treatment on bone and cartilage in obese diabetic mice. AB - BACKGROUND: Resveratrol is a polyphenolic phytoalexin that has been shown to exhibit osteoprotective and chondroprotective properties. We examine the effects of resveratrol treatment on bone and cartilage tissue of obese, diabetic ob/ob mice. METHODS: Eight-week-old ob/ob and lean control mice were given trans resveratrol at an oral dose of 25 mg/kg for 3 weeks. Histomorphometric and cross sectional-geometric variables were analyzed. RESULTS: Ob/ob mice in our study exhibit significantly reduced femoral length, resistance to loading, and tibial growth plate total area and calcified area than lean controls (P < 0.05). Resveratrol treatment significantly increased cortical area in both ob/ob and control mice, but did not improve cross-sectional indicators of resistance to bending. Resveratrol treatment also reduced tibial length and calcified growth plate cartilage area in comparison to untreated mice (P < 0.05). CONCLUSION: Resveratrol treatment of ob/ob mice had mixed effects on bone histomorphometry at the femoral midshaft. Treatment increased cortical area but decreased bone length. PMID- 25789257 TI - Metabolic Syndrome is Associated With Higher Wall Motion Score and Larger Infarct Size After Acute Myocardial Infarction. AB - BACKGROUND: Infarct size is an important surrogate end point for early and late mortality after acute myocardial infarction. Despite the high prevalence of metabolic syndrome in patients with atherosclerotic diseases, adequate data are still lacking regarding the extent of myocardial necrosis after acute myocardial infarction in these patients. OBJECTIVES: In the present study we aimed to compare myocardial infarction size in patients with metabolic syndrome to those without metabolic syndrome using peak CK-MB and cardiac troponin I (cTnI) at 72 hours after the onset of symptoms. PATIENTS AND METHODS: One-hundred patients with metabolic syndrome (group I) and 100 control subjects without metabolic syndrome (group II) who experienced acute myocardial infarction were included in the study. Diagnosis of metabolic syndrome was based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines published in 2001. Myocardial infarction size was compared between the two groups of patients using peak CK-MB and cTnI level in 72 hours after the onset of symptoms. RESULTS: Peak CK-MB and cTnI in 72 hours were found to be significantly higher in patients with metabolic syndrome compared with control subjects (both P < 0.001). Patients with metabolic syndrome also had markedly higher wall motion abnormality at 72 hours after the onset of symptoms as assessed by echocardiographically derived Wall Motion Score Index (WMSI) (P < 0.001). Moreover, statistically significant relationships were found between WMSI and peak CK-MB and also cTnI at 72 hours (Spearman's rho = 0.56, P < 0.001 and Spearman's rho = 0.5, P < 0.001; respectively). However, association between WMSI and left ventricular ejection fraction was insignificant (Spearman's rho = -0.05, P = 0.46). CONCLUSIONS: We showed that patients with metabolic syndrome have larger infarct size compared to control subjects. PMID- 25789258 TI - Ionizing radiation-induced cataract in interventional cardiology staff. AB - BACKGROUND: The use of ionizing radiation has led to advances in medical diagnosis and treatment. OBJECTIVES: The purpose of this study was to determine the risk of radiation cataractogenesis in the interventionists and staff performing various procedures in different interventional laboratories. PATIENTS AND METHODS: This cohort study included 81 interventional cardiology staff. According to the working site, they were classified into 5 groups. The control group comprised 14 professional nurses who did not work in the interventional sites. Participants were assigned for lens assessment by two independent trained ophthalmologists blinded to the study. RESULTS: The electrophysiology laboratory staff received higher doses of ionizing radiation (17.2 +/- 11.9 mSv; P < 0.001). There was a significant positive correlation between the years of working experience and effective dose in the lens (P < 0.001). In general, our findings showed that the incidence of lens opacity was 79% (95% CI, 69.9-88.1) in participants with exposure (the case group) and our findings showed that the incidence of lenses opacity was 7.1% (95% CI:2.3-22.6) with the relative risk (RR) of 11.06 (P < 0.001). CONCLUSIONS: We believe that the risk of radiation induced cataract in cardiology interventionists and staff depends on their work site. As the radiation dose increases, the prevalence of posterior eye changes increases. PMID- 25789259 TI - Comparison of outcomes of diseased coronary arteries ectasia, stenosis and combined. AB - BACKGROUND: Coronary artery ectasia (CAE) is a localized or diffuse abnormal dilatation of coronary arteries. Controversy still remains about its cardiovascular events rate, prognosis, and etiology. Adverse effects of CAE coinciding with coronary artery stenosis (CAS) (and in isolated form) are unclear. OBJECTIVES: We aimed to investigate the cardiovascular event rate of CAE in comparison to 'CAS only', and comparing their etiology. PATIENTS AND METHODS: This cross-sectional study was conducted on 200 patients between May 2011 and June 2012. Of them, 40 had CAE (case group) and 160 had only CAS (control group). Patients with CAE were divided into 2 subgroups according to the absence (E1) or presence (E2) of CAS. They were followed up for at least 6 month for cardiovascular events, including death, unstable angina and myocardial infarction (MI). Finally, we compared findings in CAE, CAS, and E1 and E2 subgroups and evaluated the relationship between severity of ectasia (1-1.5 times, 1.5-2 times, and > 2 times) and CAS. RESULTS: Hypertension (HTN), dyslipidemia (DLP), and male sex were matched in both groups without significant difference. Cigarette smoking (C/S) was significantly higher and diabetes mellitus (DM) was significantly lower in CAE compared to CAS patients. A subgroup of CAE patients with CAS (E2 subgroup) had significantly higher mortality rate than isolated CAS (P = 0.043). MI was seen in several isolated CAE patients (E1) subgroup. Severity of ectasia showed no significant relationship with CAS. CONCLUSIONS: Presence of CAE in patients with CAS increases its cardiovascular event rate. Isolated CAE is not a benign finding and MI can occur. Risk factors of CAE are similar to CAS, but C/S is more associated with CAE than CAS. DM is seen in CAE patients less than CAS. PMID- 25789260 TI - Single Dose Corticosteroid Therapy After Surgical Repair of Fallot's Tetralogy; A Randomized Controlled Clinical Trial. AB - BACKGROUND: Inflammatory reaction can produce several complications after cardiac surgery. Many attempts have been made to reduce these complications; perioperative corticosteroid therapy is one of the simplest methods. OBJECTIVES: We conducted a randomized study to evaluate the efficacy of single dose methylprednisolone, prescribed after surgery, for reducing the complications. Repair of Tetralogy of Fallot was chosen as a homogenous large group for the study. PATIENTS AND METHODS: One hundred children who underwent total repair of Tetralogy of Fallot were enrolled in this study. After the surgery, all patients were transferred to pediatric ICU and were randomized (in a double-blind fashion) in 2 groups (A and B); a single dose of methylprednisolone (30 mg/kg of body weight) was injected to participants of group "A" just at the time of ICU entrance. Group "B" received no drug. Then, clinical outcomes and laboratory data were compared between the two groups. RESULTS: The only significant differences were lower incidence of bacteremia and higher incidence of hyperglycemia in the group who were used methylprednisolone. CONCLUSIONS: Using a single postsurgical dose of methylprednisolone does not significantly alter the clinical outcome after repairing Tetralogy of Fallot. PMID- 25789261 TI - Prevention of postoperative nausea and vomiting with a subhypnotic dose of Propofol in patients undergoing lower abdominal surgery: A prospective, randomized, double-blind study. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after general anesthesia in patients undergoing elective lower abdominal surgery. We aimed to compare the effect of a sub hypnotic dose of Propofol in the prevention of PONV after lower abdominal surgery with that of the conventional antiemetic drug Metoclopramide. MATERIALS AND METHODS: In this prospective, randomized, double-blind, placebo-controlled study, 104 patients with American Society of Anesthesiologists (ASA) class I or II status, aged 18-65 years, and undergoing elective lower abdominal surgery were randomized to one of four groups (n = 26 each). The patients in the four groups were administered intravenously Propofol 20 mg (G1), Propofol 30 mg (G2), Metoclopramide 10 mg (G3), and placebo (G4), 15 min before skin closure. All episodes of PONV during the first 24 h after anesthesia were recorded by an investigator who was blinded to treatment assignment. RESULTS: There were no significant differences between the treatment groups with regard to their gender, age, ASA class, duration of surgery, duration of recovery time and hospital stay, and also body mass index (BMI) (P > 0.05). The prevalence of PONV 0-6 h after anesthesia was 23.08% with Propofol 20 mg (P = 0.005), 15.38% with Propofol 30 mg (P = 0.016), 15.38% with Metoclopramide 10 mg (P = 0.016), compared to 30.77% with placebo (P = 0.005). CONCLUSIONS: Administration of a subhypnotic dose of Propofol (30 mg) was found to be as effective as 10 mg Metoclopramide in reducing the incidence and severity of PONV in adult patients undergoing elective lower abdominal surgeries under Isoflurane based anesthesia in the early postoperative period. PMID- 25789262 TI - Stenotrophomonas maltophilia: Complicating treatment of ESBL UTI. AB - Stenotrophomonas maltophilia (S. maltophilia) is a gram-negative bacillus emerging as an opportunistic, nosocomial pathogen associated with a high mortality rate. The organism has been shown to survive several biocides used in the hospital setting. Hospital water sources can serve as a reservoir for S. maltophilia. The transmission of S. maltophilia to susceptible individuals may occur through direct contact with the source or through the hands of health care personnel. S. maltophilia is usually resistant to third-generation cephalosporins, aminoglycosides and antipseudomonal penicillins. These microorganisms are intrinsically resistant to carbapenems, and exposure to these agents has been linked to selection of S. maltophilia. There have also been reports of the organism developing resistance to trimethoprim-sulfamethoxazole (TMP-SMX), which was initially considered as the drug of choice for S. maltophillia infections. We describe a case of nosocomial urinary tract infection (UTI) due to S. maltophilia in a diabetic patient, which the patient developed during treatment with meropenem for UTI due to Klebsiella pneumonia that was resistant to TMP-SMX. PMID- 25789263 TI - Frontotemporal dementia parkinsonism: Clinical findings in a large Iranian family. AB - Frontotemporal dementia (FTD) is a group of neurodegenerative disorders characterized by atrophy of the frontal and temporal lobes. Clinical features suggestive of FTD include pre-senile onset before the age of 65, behavioral changes, social and interpersonal disinhibition, fluent and nonfluent aphasia, and loss of insight. FTD and parkinsonism linked to chromosome 17 (FTDP-17) was defined during the International Consensus Conference in Ann Arbor, Michigan in 1996. FTDP-17 is an autosomally dominant inherited condition. Most genotypic alterations do not correlate with clinical phenotypes. However, mutations affecting exon 10 splicing are associated with parkinsonism. In the present study, a male case with FTDP who presented with insidious onset of speech difficulty at a young age that was associated with signs of parkinsonism and a positive family history of FTD with MAPT gene mutation at exon 13 has been reported. PMID- 25789264 TI - Assessment of risk factors associated with hypertension among undergraduate medical students in a medical college in Odisha. AB - BACKGROUND: Hypertension is a non communicable disease of major public health problem resulting increased morbidity and mortality among population. Prehypertension in adolescents and young adults again an important risk factor for developing hypertension in future. So the present study was carried out among medical students with the objectives of (1) to find out the risk factors associated with prehypertension and hypertension, (2) to suggest measures to decrease risk factors. MATERIALS AND METHODS: It was a cross-sectional study and study duration was from september 2011 to November 2011. The sample size was 200 and the study subjects was selected by systematic random sampling method. A predesigned pretested schedule was used to collect data. Blood pressure (BP) was measured in sitting posture using a standard sphygmomanometer on two different settings and the average was taken for analysis. RESULTS: All the participants were between 18-21 years. Out of 200 study subjects,112 were males and 88 were females. The prehypertension and hypertension percentage was 67% among study subjects. Statistical analysis done was percentage, Chi-square test. CONCLUSION: Health-care providers should recognize the increased CVD risk of prehypertension and should seek to identify and treat the modifiable risk factors in these persons. PMID- 25789265 TI - Scaphoid nonunion fracture and results of the modified Matti-Russe technique. AB - BACKGROUND: The best treatment for scaphoid nonunion fractures is still controversial. The main aim of this study was to determine the results of the modified Matti-Russe method of surgery on scaphoid nonunion. MATERIALS AND METHODS: In this prospective interventional study, 30 patients with nonunion scaphoid fracture recruited from clinics of the Isfahan University of Medical Sciences between October 2007 and March 2011 underwent the modified Matti-Russe method of surgery. Union rate was evaluated four and six months after the procedure. Mayo wrist score (MWS) was calculated for the subjects six months after surgery. RESULTS: Mean age of the subjects was 25.9 +/- 7.8 years, ranging from 16 to 35 years. Twenty-seven (90%) were men, and three (10%) were women. Four and six months after surgery, 10 (33%) and 26 (86.7%) subjects had a united fracture. Mean MWS was 75.0 +/- 8.8 in all the subjects, ranging from 54 to 90 six months after surgery. Three subjects (10%) were grouped as excellent, 9 (30%) good, 16 (53.3%) satisfactory, and 3 (6.7%) poor. CONCLUSION: A fracture or nonunion of the scaphoid bone can be a complex and troubling injury, but the modified Matti-Russe method showed satisfactory results six months after surgery. PMID- 25789267 TI - The effects of kisspeptin-10 on migration and proliferation of endothelial cell. AB - BACKGROUND: Migration, expansion and survival of endothelial cells that are an important cellular component of blood vessels plays an important role in the induction of tumor growth. Kisspeptins (kp), peptides that bind to coupled-G protein receptor (GPR54), inhibit each step of metastatic cascade include invasion, migration and homing, angiogenesis, survival and proliferation. In this study we investigated effects of kisspeptin-10, the most potent member of kisspeptin family, on Migration and proliferation of endothelial cells that are necessary for angiogenesis and tumor metastasis. MATERIALS AND METHODS: We compared migration of Human Umbilical Vein Endothelial Cells (HUVECs) were treated with 10-100 or 500 nM kp-10 for 24 hours and no treated cells using an in vitro trans membrane migration assay and HUVEC proliferation of treated endothelial cells with 10-100 or 500 nM kp-10 for 48 hours and no treated cells was measured by MTT Cell Proliferation Assay Kit. Analysis of data was performed using the Kruskal-Wallis test followed by the Mann-Whitney test. RESULTS: Migration and proliferation of endothelial cells were increased at lower concentration of kp-10 specially at 100 nM while higher concentration reduced both migration and proliferation. CONCLUSION: Our data showed that different concentrations of kp-10 have distinct effects on migration and proliferation of endothelial cells. PMID- 25789266 TI - The effect of hydroalcoholic extract of P. crispum on sperm parameters, testis tissue and serum nitric oxide levels in mice. AB - BACKGROUND: Sperm dysfunction is one of the main causes of male infertility. Petroselinum crispum (P. crispum) is a member of umbelliferae family that contains different vitamins and minerals and has numerous therapeutic properties. The aim of this study was to evaluate P. crispum effect on sperm parameters, testis tissue and serum nitric oxid levels in mice. MATERIALS AND METHODS: Hydroalcoholic extract of P. crispum was prepared and administered intraperitoneally (0,100, 150 and 200 mg/kg) to 40 mice, which were divided into four groups (n = 10), one control group and three experimental groups, for 14 consequent days. The sperm parameter such as motility, sperm count, morphology, and seminiferous tubules diameter, and weight of prostate and testis, and serum nitric oxide levels were analyzed. RESULTS: P. crispum administration (100, 150 and 200 mg/kg) significantly increased mean percentage of sperm motility, testis and prostate weight and serum nitric oxide compared to the control group (P < 0.05). However, no significant effect was reported for different doses of P. crispum extract on sperm parameters. CONCLUSION: Administrating hydroalcoholic extract of P. crispum has positive effects on some reproductive parameters. PMID- 25789268 TI - Investigation of Astragalus honey and propolis extract's cytotoxic effect on two human cancer cell lines and their oncogen and proapoptotic gene expression profiles. AB - BACKGROUND: Cancer is one of the major fatal human diseases. Natural products have been used in the treatment of cancer for long time. Bee products including honey and propolis have been introduced for malignancy treatment in recent decades. In this study cytotoxicity of bee products and their effects on the expression of proapoptotic genes have been investigated. MATERIALS AND METHODS: Cytotoxic effects of Astragalus honey, ethanol extract of propolis and a sugar solution (as control) against HepG2, 5637 and L929 cell lines have been evaluated by the MTT assay. Total RNAs of treated cells were isolated and p53 and Bcl-2 gene expression were evaluated, using real-time PCR. RESULTS: Propolis IC50 values were 58, 30 and 15 MUg/ml against L929, HepG2 and 5637, respectively. These values for honey were 3.1%, 2.4% and 1.9%, respectively. Propolis extract has increased the expression of the Bcl-2 gene in all cell lines whereas the honey decreased that significantly (P < 0.05). Also, we found that honey and propolis decreased p53 gene expression in HepG2 and 5637 significantly but not in L929 cells. The sugar solution increased the expression of p53 in two cancer cell lines but no significant changes were observed in the expression of this gene in L929 as normal mouse cell. CONCLUSION: By downregulation of Bcl-2 expression it could be concluded that the cytotoxicity of honey was more than two fold against tested cancer cells compared with the sugar solution. No significant changes were observed in the expression of p53 in honey-treated cells. Propolis had no significant effect on Bcl-2 and p53 gene expressions (P > 0.05). PMID- 25789269 TI - The effect of estrogen on the expression of cartilage-specific genes in the chondrogenesis process of adipose-derived stem cells. AB - BACKGROUND: During adolescence, sex hormones play an important role in regulating proliferation, differentiation, maturation, and the scheduled death of chondrocytes. Although some studies have reported the regulatory role of estrogen in the development and progression of cartilage, some of the mechanisms still remain unclear, including the role of estrogen in the expression of cartilage specific genes in chondrogenesis process, which we cover in this study. MATERIALS AND METHODS: In the present study, we used adipose-derived stem cells (ADSCs) to differentiate into cartilage. Differentiated cartilage cells were used in the control (without estrogen E2 in the culture medium) and experimental (with estrogen in the culture medium) groups to evaluate the expression of type II collagen and aggrecan as chondrogenic genes markers, with -real-time polymerase chain reaction technique. RESULTS: Our results indicated that estrogen leads to inhibition of type II collagen gene expression and reduction of aggrecan gene expression. CONCLUSION: Therefore, estrogen probably has negative effects on chondrogenesis process of ADSCs. PMID- 25789270 TI - Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer. AB - BACKGROUND: Oral mucositis is a debilitating side effect of cancer treatment for which there is not much successful treatments at yet. We evaluated the effectiveness of topical morphine compared with a routine mouthwash in managing cancer treatment-induced mucositis. MATERIALS AND METHODS: Thirty head and neck cancer patients with severe mucositis (World Health Organization Grade III or IV) were randomized into the morphine and magic mouthwash groups. Patients received morphine sulfate 2% or magic solution (contained magnesium aluminum hydroxide, viscous lidocaine, and diphenhydramine), 10 ml for every 3 h, six times a day, for 6 days. Both groups received same dietary and oral hygiene instructions and care. Mucositis was graded at baseline and every 3 days after treatment. Patients' satisfaction and drug effect maintenance were also evaluated. RESULTS: Twenty-eight patients (mean age of 49.5 +/- 13.2 years, 63.3% female) completed the trial; 15 in the morphine group and 13 in the magic group. There was a decrease in mucositis severity in both of the morphine (P < 0.001) and magic (P = 0.049) groups. However, at the 6(th) day, more reduction was observed in mucositis severity in the morphine compared with magic group (P = 0.045). Drug effect maintenance was similar between the two groups, but patients in the morphine group were more satisfied by their treatments than those in the magic group (P = 0.008). CONCLUSIONS: Topical morphine is more effective and more satisfactory to patients than the magic mouthwash in reducing severity of cancer treatment-induced oral mucositis. More studies with larger sample size and longer follow-up are required in this regard. PMID- 25789271 TI - Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide problem that threatens the public health and economies of all countries. A multifactorial etiology and interaction between environmental factors and genetic components are responsible for triggering and progression of T2DM. Recently, rs7754840 single nucleotide polymorphism (SNP) in the CDKAL1 gene was reported to be associated with T2DM in various populations. However, due to inconsistent results in various populations about the association of rs7754840 with T2DM, and lack of information in the Iranian population, we have evaluated its association with T2DM in a subset of the Iranian population from Isfahan province, central part of Iran. MATERIALS AND METHODS: The study included 140 patients and 140 controls selected based on the World Health Organization guidelines. Genomic DNA was extracted from blood samples and the rs7754840 SNP was genotyped using a polymerase chain reaction restriction fragment length polymorphism assay with specific primers and restriction enzyme (Ac1I). RESULTS: The frequency of the C allele in the cases was higher than that in the controls (72.9% vs. 65%; P = 0.045). Using logistic regression analysis, we found a significant risk association of CC genotype with T2DM susceptibility (OR = 2.319, 95% CI = 1.436-3.744, P = 0.001). Furthermore, compared with the CC genotype, individuals with the GC genotype had a lower risk (protective association) of developing T2DM (OR = 0.332, 95% CI = 0.202-0.547, P < 0.001). CONCLUSIONS: We confirmed that there is a significant risk association between rs7754840 polymorphism and development of T2DM in a subset of the Iranian population from Isfahan province. PMID- 25789272 TI - Comparing the impact of acupuncture and pethidine on reducing labor pain. AB - BACKGROUND: Generally 50 to 70 percent of women suffer from a severe and unbearable pain during their childbirth. Abnormal fetal heart patterns, an increase of caesarian delivery rate, prolonged labor and low APGAR score in newborn are some of adverse effects of labor pain. Disagreement between different studies regarding the efficiency and effectiveness of acupuncture on labor pain led us to do this study. MATERIALS AND METHODS: This is a clinical trial study. Sampling was done randomly in Esfahan, Shahid Beheshti Hospital, based on the subjects' characteristics. Patients were classified into three groups of control, Pethidine and acupuncture (27-30 women in each group). All women with a first and second pregnancy. VAS pain ruler was used as data collection tool. Data were analyzed in SPSS software, and using ANOVA and kruskal-Wallis tests. RESULTS: The average pain score in control group 30 min after intervention was 7.80, while in Pethidine and acupuncture groups respectively were 6.87 and 5.77. Kruskal-Walis test showed that three groups in pain severity had significant difference at this time. The average length of the active phase of labor in Pethidine and acupuncture groups was 175 min while this time in control group was 243 min that ANOVA test showed a significant difference (P = 0.000). CONCLUSION: Results showed that acupuncture can significantly reduce labor pain in 30 min after intervention, while it had no effect on labor pain at full dilatation. However, both in Pethidine and acupuncture groups, the length of the active phase has been considerably shortened. PMID- 25789273 TI - Comparing the APACHE II score and IBM-10 score for predicting mortality in patients with ventilator-associated pneumonia. AB - BACKGROUND: VAP is defined as pneumonia in patients who use ventilators. The acute physiology and chronic health evaluation (APACHE II) scoring system was originally developed for predicting mortality in patients who were admitted to the intensive care unit. Due to the complexity, a simpler score called IBMP-10 was developed. We designed the study to confirm and further investigate these two methods. MATERIALS AND METHODS: This cross-sectional and analysis-descriptive study was done at the moment of VAP diagnosis on 60 patients in intensive care units. APACHE II and the IBMP-10 scores were calculated. ROC curves were generated to compare the new prediction rule with the APACHE II score. Results were reported as adjusted odds ratios with 95% confidence intervals (CIs). Analyses were performed using SPSS, version 20 and P values of 0.05 were considered to be statistically significant. RESULTS: APACHE II Score means (P < 0.001) and IBMP-10 score (P < 0.001) means had significant increase in Non survivor patient than in patients who survived. APACHE II can be used as a good prediction measure for mortality rate. In IBMP-10 method, specificity and PPV were greater than APACHE II, but in mc-nemar test, there was no significant difference between the two methods (P = 0.55). Both prediction rules had high NPV. In our study, survivors' prediction value in APACHE II was 46.7%, and in IBMP-10, it was 46.7%. CONCLUSION: IBMP-10, compared to APACHE II, has greater sensitivity, specificity, and AUC to predict mortality. So the consequence of the use of IBMP-10 was better than APACHE II. PMID- 25789274 TI - [Not Available]. AB - BACKGROUND: Since the pioneering work of Jacobson and Suarez, microsurgery has steadily progressed and is now used in all surgical specialities, particularly in plastic surgery. Before performing clinical procedures it is necessary to learn the basic techniques in the laboratory. OBJECTIVE: To assess an animal model, thereby circumventing the following issues: ethical rules, cost, anesthesia and training time. METHODS: Between July 2012 and September 2012, 182 earthworms were used for 150 microsurgical trainings to simulate discrepancy microanastomoses. Training was undertaken over 10 weekly periods. Each training session included 15 simulations of microanastomoses performed using the Harashina technique (earthworm diameters >1.5 mm [n=5], between 1.0 mm and 1.5 mm [n=5], and <1.0 mm [n=5]). The technique is presented and documented. A linear model with main variable as the number of the week (as a numeric covariate) and the size of the animal (as a factor) was used to determine the trend in time of anastomosis over subsequent weeks as well as differences between the different size groups. RESULTS: The linear model showed a significant trend (P<0.001) in time of anastomosis in the course of the training, as well as significant differences (P<0.001) between the groups of animal of different sizes. For diameter >1.5 mm, mean anastomosis time decreased from 19.6+/-1.9 min to 12.6+/-0.7 min between the first and last week of training. For training involving smaller diameters, the results showed a reduction in execution time of 36.1% (P<0.01) (diameter between 1.0 mm and 1.5 mm) and 40.6% (P<0.01) (diameter <1.0 mm) between the first and last weeks. The study demonstrates an improvement in the dexterity and speed of nodes' execution. CONCLUSION: The earthworm appears to be a reliable experimental model for microsurgical training of discrepancy microanastomoses. Its numerous advantages, as discussed in the present report, show that this model of training will significantly grow and develop in the near future. PMID- 25789275 TI - Open-access metabolomics databases for natural product research: present capabilities and future potential. AB - Various databases have been developed to aid in assigning structures to spectral peaks observed in metabolomics experiments. In this review article, we discuss the utility of currently available open-access spectral and chemical databases for natural products discovery. We also provide recommendations on how the research community can contribute to further improvements. PMID- 25789276 TI - Embolization of spontaneous intratumoral hemorrhage with the hemodynamic characteristics of arteriovenous fistula in renal angiomyolipoma. AB - Aneurysms within renal angiomyolipomas (AML) may rupture into the tumor or pararenal space. Transcatheter arterial embolization is the first-choice treatment to control bleeding. Here, we describe the use of coil embolization in two cases of spontaneous intratumoral hemorrhage with the hemodynamic characteristics of renal arteriovenous (AV) fistula in renal AML. In case 1, renal angiography showed several intratumoral aneurysms, one of which had ruptured into the tumor, resulting in the formation of an intratumoral hematoma. Blood flow within the hematoma was rapid and the blood was immediately returned to the systemic circulation through the left renal vein. In case 2, renal angiography showed that the rupture of an intratumoral aneurysm of a tumor feeding artery had resulted in formation of an intratumoral hematoma and direct renal vein communication. No extratumoral hemorrhage was observed in either case. The hemodynamics of both hematomas resembled those of a high-flow renal AV fistula. The ruptured aneurysms were embolized with detachable and pushable coils (case 1) or pushable coils only (case 2). To our knowledge, this is the first report of successful embolization of AV fistula-like intratumoral hemorrhage in renal AML. PMID- 25789277 TI - EUS-guided drainage of pancreatic fluid collections: Double pigtails, metal biliary, or dedicated transluminal stents? PMID- 25789278 TI - How to learn and to perform endoscopic ultrasound and endobronchial ultrasound for lung cancer staging: A structured guide and review. AB - The learning of transesophageal ultrasound guided fine needle aspiration (FNA) (endoscopic ultrasound-FNA), and endobronchial ultrasound guided transbronchial needle aspiration (endosonography) should be based on the following steps: Acquiring theoretical knowledge, training on simulators, and supervised performance on patients. Each step should be completed by passing a validated exam before proceeding to the next step. This approach will assure basic competency on all levels, and testing also facilitates learning and improves retention. Competence in endosonography can be based on a systematic an easy principle consisting of 2 times six anatomical landmarks. PMID- 25789279 TI - Endoscopic ultrasound features of chronic pancreatitis: A pictorial review. AB - As endoscopic ultrasound (EUS) is the most sensitive imaging modality for diagnosing pancreatic disorders, it can demonstrate subtle alterations in the pancreatic parenchymal and ductal structure even before traditional imaging and functional testing demonstrate any abnormality. In spite of this fact and abundant literature, the exact role of EUS in the diagnosis of chronic pancreatitis (CP) is still not established. The EUS features to diagnose CP have evolved over a period from a pure qualitative approach to more advanced and complicated scoring systems incorporating multiple parenchymal and ductal EUS features. The rosemont criteria have attempted to define precisely each EUS criterion and thus have good inter-observer agreement. However, initial studies have failed to demonstrate any significant improvement in the inter-observer variability and further validation studies are needed to define the exact role of these criteria. The measurement of strain ratio using quantitative EUS elastography and thus allowing quantification of pancreatic fibrosis seems to be a promising new technique. PMID- 25789280 TI - Imaging of peritoneal ligaments by endoscopic ultrasound (with videos). AB - Double layered peritoneal folds or ligaments act as conduits for the passage of blood vessels in intraperitoneal organs and also provide a pathway for the spread of disease. It is difficult to identify these normal peritoneal folds at imaging. Computed tomography is the most common imaging modality used to detect diseases of the peritoneum. The ultrasound (US) has been also used for evaluation of diseases involving ligaments. Endoscopic ultrasound (EUS) is being increasingly used both for diagnostic and interventional purposes in abdomen. In this article, we have described the normal EUS anatomy of the peritoneal ligaments. PMID- 25789281 TI - Comparison of endoscopic ultrasound guided 22-gauge core needle with standard 25 gauge fine-needle aspiration for diagnosing solid pancreatic lesions. AB - BACKGROUND AND OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the standard modality for diagnosing pancreatic masses. We compared the diagnostic yield of a new EUS-guided 22-gauge core needle biopsy to a standard 25-gauge FNA in sampling the same pancreatic lesions during the same EUS. PATIENTS AND METHODS: The main outcomes of the study were the sample adequacy of each method to provide a final pathological diagnosis, and the concordance in diagnosis between core and FNA specimens. The secondary outcomes were the sensitivity and specificity of the findings for each needle and the incremental yield of using both needles compared with using each needle alone. RESULTS: A total of 56 patients with 61 solid pancreatic lesions were evaluated. The mean number of passes with FNA was 3.5 (ranges 1-8) and with core biopsy needle was 1.7 (ranges 1-5). The proportions of adequate samples were 50/61 (81.9%) for FNA and 45/61 (73.8%) for core biopsy (P = 0.37). The diagnostic yield was 46/61 (75.4%), 42/61 (68.9%) and 47/61 (77.1%) for FNA, core, and both, respectively. There was a substantial agreement of 87.5% (kappa = 0.77; P < 0.001) in the findings of core and FNA specimens. The sensitivity for the diagnosis of malignancy for FNA and core biopsy were 68.1% and 59.6%, respectively (P = no significant [NS]). The specificity was 100% for both methods. The incremental increase in sensitivity and specificity by combining both methods are 1.5% and 0%, respectively. CONCLUSION: There are NS differences in the diagnostic yield between EUS-guided 22-gauge core biopsy and standard 25 gauge FNA for diagnosing pancreatic lesions, but core biopsy required fewer numbers of passes. There was NS incremental diagnostic yield when using both needles during the same procedure. PMID- 25789282 TI - New ex-vivo porcine model for endoscopic ultrasound-guided training in transmural puncture and drainage of pancreatic cysts and fluid collections (with videos). AB - BACKGROUND AND OBJECTIVES: Endoscopic transmural puncture cysts and drainage pancreatic fluid collections are an important part of endoscopic ultrasound practices, but can be technically difficult to master, particularly with regards to placing stents. We developed an ex-vivo model that is inexpensive and can be used for cyst puncture and fluid collection drainage. METHODS: Over the last 5 years, we have perfected the creation of this ex-vivo model. The model is easy and inexpensive to create and multiple aspirations and device placements and removals into a single cavity with decompression. The model allows the use of cautery devices and placement of expandable metal stents. Additionally, the contents in the model can be altered to appear as walled-off necrotic collections endosonographically. RESULTS: The model can be created for <300 US dollars. It has been used at multiple international conferences for teaching purposes and can withstand up to 10 puncture and drainages without having to replace the "cyst." The cyst can easily be exchanged for other prepared cysts. Preliminary surveys obtained from users show ratings that are realistic. CONCLUSIONS: A new ex-vivo model can be easily and economically created, is realistic and can be used multiple times during the single training session. PMID- 25789283 TI - Endoscopic ultrasound and/or endobronchial ultrasound-guided needle biopsy of central intraparenchymal lung lesions not adjacent to airways or esophagus. AB - BACKGROUND AND OBJECTIVES: It is usually challenging to diagnose intraparenchymal pulmonary nodules and masses that are not adjacent to central airways or esophagus. We evaluated the diagnostic accuracy and safety of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) and/or endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) for these lesions. MATERIALS AND METHODS: We performed an Internal Review Board-approved retrospective analysis of all patients who underwent EBUS, EUS, or both for the diagnosis of centrally located pulmonary nodules and masses between November 2008 and July 2013. We report results as median values with ranges. RESULTS: We identified 16 consecutive patients who underwent EBUS-TBNA and/or EUS-FNA of pulmonary nodules and masses not adjacent to airways or esophagus. We performed EBUS-FNA in 10 patients, EUS-FNA in five patients, and both EBUS-FNA and EUS-FNA in one patient. Median lung lesion size was 22.5 mm (11-45 mm) and median distance from airway or esophagus was 19 mm (5-30 mm). We obtained a tissue diagnosis in 15 patients (93.8%). There were no procedure-related complications. CONCLUSION: We conclude that EBUS-TBNA and/or EUS-FNA are accurate and safe for the diagnosis of intraparenchymal pulmonary lesions that are not adjacent to central airways or esophagus. PMID- 25789284 TI - Intraductal ultrasonographic anatomy of biliary varices in patients with portal hypertension. AB - BACKGROUND AND OBJECTIVES: The term, portal biliopathy, denotes various biliary abnormalities, such as stenosis and/or dilatation of the bile duct, in patients with portal hypertension. These vascular abnormalities sometimes bring on an obstructive jaundice, but they are not clear which vessels participated in obstructive jaundice. The aim of present study was clear the bile ductal changes in patients with portal hypertension in hopes of establishing a therapeutic strategy for obstructive jaundice caused by biliary varices. MATERIALS AND METHODS: Three hundred and thirty-seven patients who underwent intraductal ultrasound (IDUS) during endoscopic retrograde cholangiography for biliary abnormalities were enrolled. Portal biliopathy was analyzed using IDUS. RESULTS: Biliary varices were identified in 11 (2.7%) patients. IDUS revealed biliary varices as multiple, hypoechoic features surrounding the bile duct wall. These varices could be categorized into one of two groups according to their location in the sectional image of bile duct: epicholedochal and paracholedochal. Epicholedochal varices were identified in all patients, but paracholedochal varices were observed only in patients with extrahepatic portal obstruction. CONCLUSION: IDUS was useful to characterize the anatomy of portal biliopathy in detail. PMID- 25789285 TI - Diagnostic yield of endoscopic ultrasound in patients with hypoglicemia and insulinoma suspected. AB - BACKGROUND AND OBJECTIVES: Noninvasive imaging techniques have shown limitations to identify insulinomas. In few studies reported so far, endoscopic ultrasound (EUS) has proven to be able to locate lesions. The aim of this study was to compare the performance of computed tomography versus EUS for the detection of insulinomas. MATERIALS AND METHODS: In a retrospective manner prospectively collected data were analyzed. Patients with hypoglucemia and hyperinsulinemia were included. Diagnostic yield was measured in relationship to sensitivity, specificity, positive predictive value, negative predictive value and accuracy. Surgical specimens were considered the gold standard. RESULTS: Sensitivity, positive predictive value, and accuracy of EUS was 100%, 95.4% and 95.4%, respectively. In the case of CT the sensitivity was 60%, specificity 100%, positive predictive value 100%, negative predictive value 7%, and accuracy were 68%. CONCLUSIONS: EUS is useful in the preoperative assessment of patients with hypoglycemia and serum hyperinsulinemia. PMID- 25789286 TI - Pancreatic cancer in an Asian population. AB - BACKGROUND AND OBJECTIVES: Most of the available data on pancreatic cancer are from Western countries. The aim was to characterize pancreatic cancer in Asian patients and to compare it with pancreatic cancer in Caucasians. MATERIALS AND METHODS: Inpatients with histologically proven pancreatic cancer were retrospectively recruited at King Chulalongkorn Memorial Hospital from January 2005 to December 2011. RESULTS: The study enrolled 100 patients (male:female = 55:45, mean age 62.7 +/- 12.9 years). The amount of time between symptom onset and disease diagnosis was 59.89 +/- 63.12 days. The common presenting symptoms included abdominal pain or discomfort (71%), weight loss (70%), and jaundice (60%). Fifty-three of the 100 patients had stage 4 pancreatic cancer. The most common metastatic organ was the liver (n = 42, 79.25%). The survival rates after 1 and 3 years were 24 and 6%, respectively. The overall median time for survival was 5.1 months (range, 3 days to 62.4 months). According to the multivariate analysis, the staging at the time of diagnosis, serum albumin level, and tumor size were found to independently affect the survival rate. Twenty-two patients underwent endoscopic ultrasound-fine-needle aspiration with the sensitivity rate of 86.4% (19/22). CONCLUSION: Because pancreatic cancer in Asians may be clinically similar to the disease in Caucasians, the goals of future research of the disease may also be similar in the two populations. PMID- 25789287 TI - Location of recurrent asymptomatic ovarian cancer through endoscopic ultrasound. AB - Ovarian cancer is frequent and recurrence happens in about 75% of patients. As it presents high rates of relapse, the exams for this diagnosis are widely discussed. Beside this, there have been discussions about benefits for early anatomic diagnosis and whether endoscopic ultrasound (EUS) can be used to track the relapse of the disease. We present a case, in which anatomic location and histological definition of an asymptomatic recurrence of the ovarian cancer was misdiagnosed with conventional methods, but was possible through EUS. PMID- 25789288 TI - Endoscopic ultrasound of isolated gastric corrosive stricture mimicking linitis plastica. AB - Isolated gastric outlet obstruction after 1 month of asymptomatic ingestion of corrosive is a rare phenomenon and rarely reported. In this type of cases, diagnosis is very difficult due to no symptoms at the time of poisoning, and biased history. We report a case of a young male presented with isolated gastric outlet obstruction after 1 month of asymptomatic ingestion of toilet cleaner, which was known to us later, mimicking linitis plastica. On upper endoscopy, the stomach was grossly edematous, antrum edematous and inflamed with reduced distensibility and narrow pyloric canal. Endoscopic ultrasound of the stomach revealed diffuse thickening of the gastric wall, mainly the antrum, involving submucosa and muscularis propria. We propose corrosive injury to be in the differential diagnosis of gastric linitis plastica. PMID- 25789289 TI - Diagnosis of lymphoma by endoscopic ultrasound-assisted transendoscopic direct retroperitoneal lymph node biopsy: A case report (with video). AB - Since its introduction in the early 1990s, endoscopic ultrasound-assisted fine needle aspiration (EUS-FNA) has been used for sampling of extraintestinal mass lesions and peri-intestinal lymphadenopathy. Although EUS-FNA is highly accurate, lymphomas can be challenging to diagnose using EUS-FNA. We present the case of a 60-year-old male who had experienced upper abdominal discomfort for 1 month. Computerized tomography (CT) examination revealed multiple soft-tissue shadows located above the pancreatic body. The biggest shadow had a cross-sectional area of 7.7 cm * 7.2 cm. Positron emission tomography-CT (PET-CT) imaging showed increased uptake of (18)F-FDG by these soft-tissue shadows. To investigate further, EUS was performed and it revealed the presence of multiple hypoechoic round lymph nodes. During the procedure, EUS-FNA was performed, but only a few dyskaryotic cells were observed by cytological evaluation. EUS-assisted retroperitoneoscopy and lymph node biopsy were performed to obtain more tissue for immunohistochemical analysis and subclassification of lymphoma. Finally, the patient was diagnosed with non-Hodgkin lymphoma, germinal center B-cell-like diffuse large B-cell lymphoma by this technique. EUS-assisted transendoscopic retroperitoneal lymph node biopsy is an alternative procedure for the diagnosis of lymphomas. PMID- 25789290 TI - Unusual cause of obstructive jaundice revealed by endoscopic ultrasound guided fine-needle aspiration of mediastinal lymph node. PMID- 25789291 TI - Paracholedochal varices causing biliopathy in a case of portal vein thrombosis. PMID- 25789292 TI - Eosinophilic gastroenteritis mimicking as a malignant gastric ulcer with lymphadenopathy as shown by computed tomography and endoscopic ultrasound. PMID- 25789293 TI - Minimizing right ventricular pacing in sinus node disease: Sometimes the cure is worse than the disease. AB - Traditional right ventricular (RV) apical pacing has been associated with heart failure, atrial fibrillation and increased mortality. To avoid the negative consequences of RV apical pacing different strategies have been developed, among these a series of pacing algorithms designed to minimize RV pacing. These functions are particularly useful when there is not the need for continuous RV pacing: intermittent atrio-ventricular blocks and, mainly, sinus node disease. However, in order to avoid RV pacing, the operational features of these algorithms may lead to adverse (often under-appreciated) consequences in some patients. We describe a case of a patient with sinus node disease, in whom right atrial only pacing involved long atrio-ventricular delay to allow intrinsic ventricular conduction, which led to symptomatic hypotension that could be overcome only by "forcing" also right ventricular apical pacing. We subsequently discuss this case in the context of current available literature. PMID- 25789294 TI - Current status and emerging challenges in the treatment of hepatitis C virus genotypes 4 to 6. AB - Hepatitis C virus (HCV) genotypes 4, 5 and 6 are mainly present in Africa, the Middle East and Asia and they have been less extensively studied with respect to epidemiology, natural disease history and therapeutic endpoints. Response rates to a 48-wk combined peginterferon/ribavirin treatment range to 40%-69% for HCV 4, 55%-60% for HCV 5 and 60%-90% for HCV 6. Response-guided schedules are recommended to optimize the outcomes of peginterferon/ribavirin treatment in HCV 4 and, in form of preliminary data, for HCV 6, but no data are yet available to support such an individualization of therapy for HCV 5. Recently, the direct acting antivirals (DAAs) with pan-genotypic activities simeprevir, sofosbuvir and daclatasvir have been recommended in triple regimens with peginterferon/ribavirin for the treatment of HCV genotypes 4 to 6 infections. In the future, DAA-based interferon-free therapies are awaited to drastically improve treatment outcomes in HCV. However, efforts to improve treatment outcomes with peginterferon/ribavirin should continue, as the HCV 4-6 infected population is mainly based in resource-limited settings with restricted access to the costly DAAs. PMID- 25789295 TI - Highlights in pathogenesis of vitiligo. AB - Vitiligo is a common pigmentary disorder. Many studies across decades and all over the world have attempted to illustrate the pathogenesis behind it; however, the pathogenesis of vitiligo remains elusive. This review article, we present the findings behind the most and updated theories behind this psychologically debilitating and disfiguring disease. The discussion begun with the role of genetic predisposition followed by neural theory first proposed in the 1950s. We highlight the autoimmune hypothesis, followed by the reactive oxygen species model, zinc-alpha2-glycoprotein deficiency hypothesis, viral theory, intrinsic theory and biochemical, molecular and cellular alterations accounting for loss of functioning melanocytes in vitiligo. Many theories were elaborated to clarify vitiligo pathogenesis. It is a multifactorial disease involving the interplay of several factors. Future research is needed to clarify the interaction of these factors for better understanding of vitiligo pathogenesis and subsequent successful treatment. PMID- 25789296 TI - Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread. AB - The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly. PMID- 25789298 TI - Robotics and surgery: A sustainable relationship? AB - Robotic surgery is increasingly being employed to overcome the disadvantages associated with use of conventional techniques such as laparoscopy. However, despite significant promise, there are some clear disadvantages and robust evidence base supporting the use of robotic assistance remains lacking. In this paper, the advantages and drivers for robotics will be discussed, its drawbacks and its future role in surgery. PMID- 25789297 TI - Fluoroscopy guided percutaneous renal access in prone position. AB - Percutaneous nephrolithotomy is a very commonly done procedure for management of renal calculus disease. Establishing a good access is the first and probably the most crucial step of this procedure. A proper access is the gateway to success. However, this crucial step has the steepest learning curve for, in a fluoroscopy guided access, it involves visualizing a three dimensional anatomy on a two dimensional fluoroscopy screen. This review describes the anatomical basis of the renal access. It provides a literature review of all aspects of percutaneous renal access along with the advances that have taken place in this field over the years. The article describes a technique to determine the site of skin puncture, the angle and depth of puncture using a simple mathematical principle. It also reviews the common problems faced during the process of puncture and dilatation and describes the ways to overcome them. The aim of this article is to provide the reader a step by step guide for percutaneous renal access. PMID- 25789299 TI - Endoscopic treatment of orbital tumors. AB - Different orbital and transcranial approaches are performed in order to manage orbital tumors, depending on the location and size of the lesion within the orbit. These approaches provide a satisfactory view of the superior and lateral aspects of the orbit and the optic canal but involve risks associated with their invasiveness because they require significant displacement of orbital structures. In addition, external approaches to intraconal lesions may also require deinsertion of extraocular muscles, with subsequent impact on extraocular mobility. Recently, minimally invasive techniques have been proposed as valid alternative to external approaches for selected orbital lesions. Among them, transnasal endoscopic approaches, "pure" or combined with external approaches, have been reported, especially for intraconal lesions located inferiorly and medially to the optic nerve. The avoidance of muscle detachment and the shortness of the surgical intraorbital trajectory makes endoscopic approach less invasive, thus minimizing tissue damage. Endoscopic surgery decreases the recovery time and improves the cosmetic outcome not requiring skin incisions. The purpose of this study is to review and discuss the current surgical techniques for orbital tumors removal, focusing on endoscopic approaches to the orbit and outlining the key anatomic principles to follow for safe tumor resection. PMID- 25789300 TI - Clinical and diagnostic aspects of gluten related disorders. AB - Gluten is one of the most abundant and widely distributed components of food in many areas. It can be included in wheat, barley, rye, and grains such as oats, barley, spelt, kamut, and triticale. Gluten-containing grains are widely consumed; in particular, wheat is one of the world's primary sources of food, providing up to 50% of the caloric intake in both industrialized and developing countries. Until two decades ago, celiac disease (CD) and other gluten-related disorders were believed to be exceedingly rare outside of Europe and were relatively ignored by health professionals and the global media. In recent years, however, the discovery of important diagnostic and pathogenic milestones led CD from obscurity to global prominence. In addition, interestingly, people feeding themselves with gluten-free products greatly outnumber patients affected by CD, fuelling a global consumption of gluten-free foods with approximately $2.5 billion in United States sales each year. The acknowledgment of other medical conditions related to gluten that has arisen as health problems, providing a wide spectrum of gluten-related disorders. In February 2011, a new nomenclature for gluten-related disorders was created at a consensus conference in London. In this review, we analyse innovations in the field of research that emerged after the creation of the new classification, with particular attention to the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for CD and the most recent research about non-celiac gluten sensitivity. PMID- 25789302 TI - Voltage gated calcium channel antibody-related neurological diseases. AB - Voltage gated calcium channel (VGCC) antibodies are generally associated with Lambert-Eaton myasthenic syndrome. However the presence of this antibody has been associated with paraneoplastic as well as non-paraneoplastic cerebellar degeneration. Most patients with VGCC-antibody-positivity have small cell lung cancer (SCLC). Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the presynaptic part of the neuromuscular junction. Its classical clinical triad is proximal muscle weakness, areflexia and autonomic dysfunction. Fifty to sixty percent of LEMS patients have a neoplasia, usually SCLC. The co-occurrence of SCLC and LEMS causes more severe and progressive disease and shorter survival than non-paraneoplastic LEMS. Treatment includes 3,4 diaminopyridine for symptomatic purposes and immunotherapy with prednisolone, azathioprine or intravenous immunoglobulin in patients unresponsive to 3,4 diaminopyridine. Paraneoplastic cerebellar degeneration (PCD) is a syndrome characterized with severe, subacute pancerebellar dysfunction. Serum is positive for VGCC antibody in 41%-44% of patients, usually with the co-occurrence of SCLC. Clinical and electrophysiological features of LEMS are also present in 20%-40% of these patients. Unfortunately, PCD symptoms do not improve with immunotherapy. The role of VGCC antibody in the immunopathogenesis of LEMS is well known whereas its role in PCD is still unclear. All patients presenting with LEMS or PCD must be investigated for SCLC. PMID- 25789303 TI - Evaluation of functional, autonomic and inflammatory outcomes in children with asthma. AB - Asthma is common in childhood. This respiratory disease is characterized by persistent inflammation of the airways even when the child is not in the throes of an attack. Chronic inflammation is caused by an imbalance between pro inflammatory and anti-inflammatory mechanisms as well as autonomic dysfunction, which plays an important role in the pathogenesis and control of this condition. The impact of these physiopathological aspects leads to inactivity and a sedentary lifestyle, which exerts an influence on functional capacity and control of the disease. The main objective of non-pharmacological therapy is the clinical control of asthma and the minimization of airway obstruction and hyperinflation during an attack. These factors can be controlled with noninvasive ventilation. The aim or the present review was to describe important neural, inflammatory and functional mechanisms that affect children with asthma. PMID- 25789301 TI - Asthma and metabolic syndrome: Current knowledge and future perspectives. AB - Asthma and obesity are epidemiologically linked; however, similar relationships are also observed with other markers of the metabolic syndrome, such as insulin resistance and dyslipidemia, which cannot be accounted for by increased body mass alone. Obesity appears to be a predisposing factor for the asthma onset, both in adults and in children. In addition, obesity could make asthma more difficult to control and to treat. Although obesity may predispose to increased Th2 inflammation or tendency to atopy, other mechanisms need to be considered, such as those mediated by hyperglycaemia, hyperinsulinemia and dyslipidemia in the context of metabolic syndrome. The mechanisms underlying the association between asthma and metabolic syndrome are yet to be determined. In the past, these two conditions were believed to occur in the same individual without any pathogenetic link. However, the improvement in asthma symptoms following weight reduction indicates a causal relationship. The interplay between these two diseases is probably due to a bidirectional interaction. The purpose of this review is to describe the current knowledge about the possible link between metabolic syndrome and asthma, and explore potential application for future studies and strategic approaches. PMID- 25789304 TI - Endoscopic ear surgery: A case series and first United Kingdom experience. AB - AIM: To present the United Kingdom's first case series of 70 otological cases of endoscopic and non-endoscopic ear surgeries. METHODS: Prospective case series incorporating a range of endoscopic procedures performed using a 4 mm, 18 cm rigid endoscope, performed by a single surgeon at a single centre. Primary outcome measures included mean average pre and post-operative air-bone gap hearing thresholds and duration of surgery. RESULTS: Thirty-eight patients underwent endoscopic assisted ear surgery and 32 underwent non-endoscopic assisted ear surgery. In both surgical groups, there was a significant difference between pre and post-operative mean air-bone gaps (P = 0.02). Mean operating time was comparable between both groups. Eight patients developed post-operative complications. CONCLUSION: Endoscopic ear surgery can be performed safely in a range of otological procedures. This has the potential to become a well established surgical option for middle ear surgery in the near future. Advantages and limitations are discussed. PMID- 25789305 TI - May-Thurner syndrome: High output cardiac failure as a result of iatrogenic iliac fistula. AB - May-Thurner syndrome (MTS) also termed iliocaval compression or Cockett-Thomas syndrome is a common, although rarely diagnosed, condition in which the patient has an anatomical variant wherein the right common iliac artery overlies and compresses the left common iliac vein against the fifth lumbar spine resulting in increased risk of iliofemoral deep venous thrombosis. This variant has been shown to be present in over 23% of the population but most go undetected. We present a patient with MTS who developed high output cardiac failure due to an iatrogenic iliac fistula. The patient underwent an extensive workup for a left to right shunt including MRI and arterial duplex in the vascular lab. He was ultimately found to have a 2.1 cm left common iliac artery aneurysm and history of common iliac stent. We took the patient to the operating room for aortogram with placement of an endovascular plug of the left internal iliac artery and aorto-bi iliac stent graft placement with CO2 and IV contrast. Subsequently the patient underwent successful stent placement in the area that was compressed followed by 6 mo of anticoagulation with warfarin. The flow from the fistula decreased significantly. PMID- 25789306 TI - Intraparotid facial nerve schwannoma: A case report. AB - Facial nerve schwannoma occurring within the parotid gland is a rare tumour. We report a case of schwannoma within the parotid gland in a young female patient, who underwent ultrasound and magnetic resonance imaging (MRI) and subsequent surgical excision of the lesion. The lesion showed hyperintensity on T2-weighted and diffusion-weighted MRI. There was no adjacent lymphadenopathy. Although hyperintensity on diffusion-weighted MRI could suggest malignant tumours, the characteristic "string sign" provided the clue for the diagnosis of schwannoma. PMID- 25789307 TI - Rare case of upper gastrointestinal bleeding in achalasia. AB - Achalasia is a prototypic esophageal motility disorder with complications including aspiration-pneumonia, esophagitis, esophageal-tracheal fistula, spontaneous rupture of the esophagus, and squamous cell carcinoma. However, achalasia is rarely associated with esophageal stones and ulcer formation that lead to upper gastrointestinal bleeding. Here, we report the case of a 61-year old woman who was admitted to our department after vomiting blood for six hours. Physical examination revealed that the patient had severe anemia and mild palpitation in the upper abdomen. CT revealed lower esophageal dilatation and esophageal wall thickening, and an emergency upper endoscopy showed that the esophagus was substantially expanded by a dark round stone, with multiple ulcers on the esophageal wall and a slit in the cardiac mucosa with a large clot attached. The patient's history included ingestion of 1 kg hawthorn three days prior. The acute upper gastrointestinal bleeding was caused by Mallory-Weiss syndrome associated with achalasia and an esophageal stone. For patients with achalasia, preventing excessive ingestion of tannins is crucial to avoid complications such as bleeding and rupture. PMID- 25789309 TI - Advances in Alzheimer's disease: from bench to bedside. PMID- 25789308 TI - Milk proteins, peptides, and oligosaccharides: effects against the 21st century disorders. AB - Milk is the most complete food for mammals, as it supplies all the energy and nutrients needed for the proper growth and development of the neonate. Milk is a source of many bioactive components, which not only help meeting the nutritional requirements of the consumers, but also play a relevant role in preventing various disorders. Milk-derived proteins and peptides have the potential to act as coadjuvants in conventional therapies, addressing cardiovascular diseases, metabolic disorders, intestinal health, and chemopreventive properties. In addition to being a source of proteins and peptides, milk contains complex oligosaccharides that possess important functions related to the newborn's development and health. Some of the health benefits attributed to milk oligosaccharides include prebiotic probifidogenic effects, antiadherence of pathogenic bacteria, and immunomodulation. This review focuses on recent findings demonstrating the biological activities of milk peptides, proteins, and oligosaccharides towards the prevention of diseases of the 21st century. Processing challenges hindering large-scale production and commercialization of those bioactive compounds have been also addressed. PMID- 25789310 TI - Assessment of morphological and functional changes in organs of rats after intramuscular introduction of iron nanoparticles and their agglomerates. AB - The research was performed on male Wistar rats based on assumptions that new microelement preparations containing metal nanoparticles and their agglomerates had potential. Morphological and functional changes in tissues in the injection site and dynamics of chemical element metabolism (25 indicators) in body were assessed after repeated intramuscular injections (total, 7) with preparation containing agglomerate of iron nanoparticles. As a result, iron depot was formed in myosymplasts of injection sites. The quantity of muscle fibers having positive Perls' stain increased with increasing number of injections. However, the concentration of the most chemical elements and iron significantly decreased in the whole skeletal muscle system (injection sites are not included). Consequently, it increased up to the control level after the sixth and the seventh injections. Among the studied organs (liver, kidneys, and spleen), Caspase-3 expression was revealed only in spleen. The expression had a direct dependence on the number of injections. Processes of iron elimination from preparation containing nanoparticles and their agglomerates had different intensity. PMID- 25789311 TI - Sacrocolpopexy with polypropylene tape as valuable surgical modification during cystectomy with orthotopic ileal bladder: functional results. AB - Introduction. Urinary diversion is very often associated with urinary retention and urinary incontinence. In this study, a surgical modification during cystectomy with orthotopic ileal neobladder is presented. Material and Methods. Female patients enrolled in the study (n-24) were subjected to sacrocolpopexy during the operation. Apart from oncological control, the follow-up consisted of 1-hour inlay test and questionnaires (UDI-6 and IIQ-7) in the 3rd, 6th, and 12th month after the operation. In the 12th month after the surgery, the urodynamic pressure-flow test was performed. Outcomes were compared with the control group (n-18) in which sacrocolpopexy was not implemented. Results. The study group was characterised by reduced urinary retention and improved continence. Conclusion. Sacrocolpopexy during cystectomy with orthotopic ileal bladder is a valuable surgical method which provides patients with a better quality of life. PMID- 25789312 TI - Real-time scintigraphic assessment of intravenous radium-223 administration for quality control. AB - Radium-223 ((223)Ra) dichloride is an approved intravenous radiotherapy for patients with osseous metastases from castration-resistant prostate cancer (CRPC). In addition to the therapeutic alpha radiation, there is additional (223)Ra radiation generated which produces photons that can be imaged with conventional gamma cameras. No studies have evaluated real-time and quality imaging during intravenous (223)Ra administration to verify systemic circulation and exclude (223)Ra extravasation at the injection site. A retrospective review was performed for fifteen (223)Ra administrations for CRPC patients which were imaged using a large field of view portable gamma camera (LFOVPGC) for the purposes of quality control and patient safety. Dynamic imaging of the chest was performed before, during, and after the (223)Ra administration to verify systemic circulation, per institutional clinical protocol. Before and after (223)Ra administration, a static image was obtained of the intravenous access site. Dynamic imaging of the chest confirmed systemic administration early during the 1 minute injection period for all patients. There were no cases of focal (223)Ra extravasation at the site of intravenous access. These results verify that systemic (223)Ra administrations can be quantified with real-time imaging using an LFOVPGC. This simple approach can confirm and quantify systemic circulation of (223)Ra early during injection and exclude focal extravasation for the purposes of quality control. PMID- 25789313 TI - Prevalence of protozoa species in drinking and environmental water sources in Sudan. AB - Protozoa are eukaryotic cells distributed worldwide in nature and are receiving increasing attention as reservoirs and potential vectors for the transmission of pathogenic bacteria. In the environment, on the other hand, many genera of the protozoa are human and animal pathogens. Only limited information is available on these organisms in developing countries and so far no information on their presence is available from Sudan. It is necessary to establish a molecular identification of species of the protozoa from drinking and environmental water. 600 water samples were collected from five states (Gadarif, Khartoum, Kordofan, Juba, and Wad Madani) in Sudan and analysed by polymerase chain reaction (PCR) and sequencing. 57 out of 600 water samples were PCR positive for protozoa. 38 out of the 57 positive samples were identified by sequencing to contain 66 protozoa species including 19 (28.8%) amoebae, 17 (25.7%) Apicomplexa, 25 (37.9%) ciliates, and 5 (7.6%) flagellates. This study utilized molecular methods identified species belonging to all phyla of protozoa and presented a fast and accurate molecular detection and identification of pathogenic as well as free living protozoa in water uncovering hazards facing public health. PMID- 25789314 TI - Altered interhemispheric functional coordination in chronic tinnitus patients. AB - Purpose. Recent studies suggest that tinnitus may be due in part to aberrant callosal structure and interhemispheric interaction. To explore this hypothesis we use a novel method, voxel-mirrored homotopic connectivity (VMHC), to examine the resting-state interhemispheric functional connectivity and its relationships with clinical characteristics in chronic tinnitus patients. Materials and Methods. Twenty-eight chronic tinnitus patients with normal hearing thresholds and 30 age-, sex-, education-, and hearing threshold-matched healthy controls were included in this study and underwent the resting-state fMRI scanning. We computed the VMHC to analyze the interhemispheric functional coordination between homotopic points of the brain in both groups. Results. Compared to the controls, tinnitus patients showed significantly increased VMHC in the middle temporal gyrus, middle frontal gyrus, and superior occipital gyrus. In tinnitus patients, a positive correlation was found between tinnitus duration and VMHC of the uncus. Moreover, correlations between VMHC changes and tinnitus distress were observed in the transverse temporal gyrus, superior temporal pole, precentral gyrus, and calcarine cortex. Conclusions. These results show altered interhemispheric functional connectivity linked with specific tinnitus characteristics in chronic tinnitus patients, which may be implicated in the neuropathophysiology of tinnitus. PMID- 25789316 TI - Perineal urethrostomy: surgical and functional evaluation of two techniques. AB - INTRODUCTION: PU is an option to manage complex and/or recurrent urethral strictures and is necessary after urethrectomy and/or penectomy. PU is generally assumed to be the last option before abandoning the urethral outlet. METHOD: Between 2001 and 2013, 51 patients underwent PU. Mean age (+/- standard deviation) was 60 +/- 15 years. Only 13 patients (25.5%) did not undergo previous urethral interventions. PU was performed according to the Johanson (n = 35) or Blandy (n = 16) technique and these 2 groups were compared for surgical failure, maximum urinary flow (Qmax), urinary symptoms, and quality of life (according to the International Prostate Symptom Score). RESULTS: Both groups were similar for patient's and stricture characteristics. Only follow-up duration was significantly longer after Johanson PU (47.9 months versus 11.1 months; P = 0.003). For the entire cohort, 11 patients (21.6%) were considered a failure (9 or 25.7% for Johanson group and 2 or 12.5% for Blandy group; P = 0.248). There was a significant improvement of Qmax in both groups. Quality of life after PU was comparable in both groups. CONCLUSIONS: PU is associated with a 21.6% recurrence rate and the patient should be informed about this risk. PMID- 25789315 TI - The roles of SNF2/SWI2 nucleosome remodeling enzymes in blood cell differentiation and leukemia. AB - Here, we review the role of sucrose nonfermenting (SNF2) family enzymes in blood cell development. The SNF2 family comprises helicase-like ATPases, originally discovered in yeast, that can remodel chromatin by changing chromatin structure and composition. The human genome encodes 30 different SNF2 enzymes. SNF2 family enzymes are often part of multisubunit chromatin remodeling complexes (CRCs), which consist of noncatalytic/auxiliary subunit along with the ATPase subunit. However, blood cells express a limited set of SNF2 ATPases that are necessary to maintain the pool of hematopoietic stem cells (HSCs) and drive normal blood cell development and differentiation. The composition of CRCs can be altered by the association of specific auxiliary subunits. Several auxiliary CRC subunits have specific functions in hematopoiesis. Aberrant expressions of SNF2 ATPases and/or auxiliary CRC subunit(s) are often observed in hematological malignancies. Using large-scale data from the International Cancer Genome Consortium (ICGC) we observed frequent mutations in genes encoding SNF2 helicase-like enzymes and auxiliary CRC subunits in leukemia. Hence, orderly function of SNF2 family enzymes is crucial for the execution of normal blood cell developmental program, and defects in chromatin remodeling caused by mutations or aberrant expression of these proteins may contribute to leukemogenesis. PMID- 25789317 TI - Effects of tetrahydrocurcumin on hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in cervical cancer cell-induced angiogenesis in nude mice. AB - Tetrahydrocurcumin (THC), one of the important in vivo metabolites of curcumin, inhibits tumor angiogenesis. Its effects on angiogenesis in cervical cancer- (CaSki-) implanted nude mice and its mechanisms on hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression were investigated. Female BALB/c nude mice were divided into control (CON) and CaSki-implanted groups (CaSki group). One month after the injection with cervical cancer cells, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. The microvascular density (MVD) was evaluated using the CD31 expression. VEGF, VEGFR-2, and HIF-1alpha expression were also detected by immunohistochemistry. The MVD in CaSki + vehicle group was significantly increased compared to the CON + vehicle group. Interestingly, when treated with THC at all doses, the CaSki group showed a significant smaller number of the MVD. The CaSki + vehicle group also showed significantly increased VEGF, VEGFR-2, and HIF-1alpha expressions, but they were downregulated when mice were treated with THC at all doses. THC demonstrated an inhibitory effect against tumor angiogenesis in CaSki-implanted nude mice model. This effect is likely to be mediated by the downregulation of HIF-1-alpha, VEGF expression, and its receptor. THC could be developed into a promising agent for cancer therapy in the future. PMID- 25789318 TI - Association of polymorphisms of the receptor for advanced glycation end products gene and susceptibility to sporadic abdominal aortic aneurysm. AB - Accumulating evidence has suggested that receptor for advanced glycation end products (RAGE) is involved in the development and progression of human abdominal aortic aneurysms (AAAs). However, the association between RAGE gene polymorphisms and AAA has not yet been determined. The present study was aimed at analyzing the potential association between the RAGE gene polymorphisms and AAAs. A cohort of 381 patients and 436 age-matched healthy controls were genotyped to detect the three RAGE polymorphisms (-374 T/A, -429 T/C, and G82S) using SNaPshot. Our study demonstrated a significant difference in the genotype and allele frequencies of the RAGE G82S polymorphism between the AAA patients and the controls. Further stratification by gender and smoking status revealed that the presence of the RAGE 82S allele confers a higher risk for developing AAA in men and smokers. Moreover, AAA patients with the variant 82S allele of RAGE presented with reduced serum soluble RAGE (sRAGE) production, and this decrease was more significant in men and smokers with AAA. Our study provides preliminary evidence that the 82S allele of RAGE is a risk factor for AAA. This new piece of knowledge regarding RAGE may be clinically important for the prevention and therapy of AAAs. PMID- 25789319 TI - A miRNA-driven inference model to construct potential drug-disease associations for drug repositioning. AB - Increasing evidence discovered that the inappropriate expression of microRNAs (miRNAs) will lead to many kinds of complex diseases and drugs can regulate the expression level of miRNAs. Therefore human diseases may be treated by targeting some specific miRNAs with drugs, which provides a new perspective for drug repositioning. However, few studies have attempted to computationally predict associations between drugs and diseases via miRNAs for drug repositioning. In this paper, we developed an inference model to achieve this aim by combining experimentally supported drug-miRNA associations and miRNA-disease associations with the assumption that drugs will form associations with diseases when they share some significant miRNA partners. Experimental results showed excellent performance of our model. Case studies demonstrated that some of the strongly predicted drug-disease associations can be confirmed by the publicly accessible database CTD (www.ctdbase.org), which indicated the usefulness of our inference model. Moreover, candidate miRNAs as molecular hypotheses underpinning the associations were listed to guide future experiments. The predicted results were released for further studies. We expect that this study will provide help in our understanding of drug-disease association prediction and in the roles of miRNAs in drug repositioning. PMID- 25789321 TI - Effects of dantrolene on arrhythmogenicity in isolated regional ischemia reperfusion rabbit hearts with or without pacing-induced heart failure. AB - Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n = 9 in each group). Simultaneous voltage and intracellular Ca(2+) (Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 MUM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model. PMID- 25789320 TI - Alpha-linolenic acid: an omega-3 fatty acid with neuroprotective properties-ready for use in the stroke clinic? AB - Alpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brain's vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders. PMID- 25789322 TI - What are the risk factors associated with urinary retention after orthopaedic surgery? AB - This study investigates the overall rate of urinary retention in a large cohort of unselected orthopaedic patients who had either general or regional anesthesia and defines the risk factors for postoperative urinary retention in that cohort of patients. A total of 15,681 patients who underwent major orthopaedic surgery with general or spinal/epidural anesthesia were included. Postoperative urinary retention was defined as any patient who required a postoperative consultation to the urologic department regarding voiding difficulty. Age at surgery, sex, type of surgery, medical history including hypertension and diabetes mellitus, and type of anesthesia were analyzed as potential predictor variables. There were 365 postoperative patients who required urology consults for urinary retention (2.3%). Older age at surgery (OR, 1.035; P < 0.0001), male sex (OR, 1.522; P = 0.0004), type of surgery (OR, 1.506; P = 0.0009), history of hypertension (OR, 1.288; P = 0.0436), and history of diabetes mellitus (OR, 2.038; P < 0.0001) were risk factors for urinary retention after orthopaedic surgery. Advanced age, male sex, joint replacement surgery, history of hypertension, and diabetes mellitus significantly increased the risk of urinary retention. In patients with these risk factors, careful postoperative urological management should be performed. PMID- 25789323 TI - Behaviour of endothelial cells in a tridimensional in vitro environment. AB - Angiogenesis is a fundamental process in healing, tumor growth, and a variety of medical conditions. For this reason, in vitro angiogenesis is an area of interest for researchers. Additionally, in vitro angiogenesis is important for the survival of prevascularized tissue-engineering models. The aim of this study was to observe the self-tubular organization behaviour of endothelial cells in the self-assembly method. In this study, bilayered and dermal substitutes were prepared using the self-assembly method. Histological, immunostaining, and biochemical tests were performed. The behavioural dynamics of endothelial cells in this biological environment of supportive cells were observed, as were the steps of the in vitro angiogenic cascade with self-organizing capillary-like structures formation. The epidermal component of the substitutes was seen to promote network expansion and density. It also increased the quantity of angiogenic factors (VEGF and Ang-1) without increasing the proinflammatory factor (IL-8). In addition, the increased MMP activity contributed to matrix degradation, which facilitated capillary formation. PMID- 25789324 TI - Retrospective analysis of bevacizumab in combination with fotemustine in chinese patients with recurrent glioblastoma multiforme. AB - The aim of this study was to assess the activity and safety of bevacizumab (BEV) and fotemustine (FTM) for the treatment of recurrent glioblastoma multiforme (GBM) patients and explore the potential prognostic parameters on survival. This study retrospectively analyzed all patients with GBM who were treated with at least one cycle of BEV and FTM from July 2010 to October 2012. A total of 176 patients with recurrent GBM were enrolled. The response rate and disease control rate were 46.6% and 90.9%, respectively. A 6-month PFS rate of 33.3% (95% CI: 26.5%-40.3%) and a median PFS of 5.0 (95% CI: 2.4-7.5) months were observed. The median OS was 8.0 (95% CI: 6.7-9.2) months. Multivariate analysis showed that risk factors with a significant influence on the PFS of all patients were Karnofsky Performance Status (KPS) (>=70 versus <70, HR = 0.53, 95% CI: 0.39 0.73, and P = 0.01) and MGMT status (methylated versus unmethylated, HR = 0.69, 95% CI: 0.52-0.97, and P = 0.04). The most common treatment-related adverse events were fatigue, proteinuria, hypophonia, hypertension, thrombocytopenia, anemia, and neutropenia. In conclusion, combination of BEV with FTM is well tolerated and may derive some clinical benefits in recurrent GBM patients. Higher KPS and MGMT promoter hypermethylation were suggested to be associated with prolonged survival. PMID- 25789326 TI - Myofibroblast expression in skin wounds is enhanced by collagen III suppression. AB - Generally speaking, the excessive expression of myofibroblasts is associated with excessive collagen production. One exception is seen in patients and animal models of Ehlers-Danlos syndrome type IV in which the COL3A1 gene mutation results in reduced collagen III but with concurrent increased myofibroblast expression. This paradox has not been examined with the use of external drugs/modalities to prevent hypertrophic scars. In this paper, we injected the rabbit ear wound model of hypertrophic scarring with two doses of a protein called nAG, which is known to reduce collagen expression and to suppress hypertrophic scarring in that animal model. The higher nAG dose was associated with significantly less collagen III expression and concurrent higher degree of myofibroblast expression. We concluded that collagen III content of the extracellular matrix may have a direct or an indirect effect on myofibroblast differentiation. However, further research is required to investigate the pathogenesis of this paradoxical phenomenon. PMID- 25789325 TI - Sudden sensorineural hearing loss and polymorphisms in iron homeostasis genes: new insights from a case-control study. AB - Background. Even if various pathophysiological events have been proposed as explanations, the putative cause of sudden hearing loss remains unclear. Objectives. To investigate and to reveal associations (if any) between the main iron-related gene variants and idiopathic sudden sensorineural hearing loss. Study Design. Case-control study. Materials and Methods. A total of 200 sudden sensorineural hearing loss patients (median age 63.65 years; range 10-92) were compared with 400 healthy control subjects. The following genetic variants were investigated: the polymorphism c.-8CG in the promoter of the ferroportin gene (FPN1; SLC40A1), the two isoforms C1 and C2 (p.P570S) of the transferrin protein (TF), the amino acidic substitutions p.H63D and p.C282Y in the hereditary hemochromatosis protein (HFE), and the polymorphism c.-582AG in the promoter of the HEPC gene, which encodes the protein hepcidin (HAMP). Results. The homozygous genotype c.-8GG of the SLC40A1 gene revealed an OR for ISSNHL risk of 4.27 (CI 95%, 2.65-6.89; P = 0.001), being overrepresented among cases. Conclusions. Our study indicates that the homozygous genotype FPN1 -8GG was significantly associated with increased risk of developing sudden hearing loss. These findings suggest new research should be conducted in the field of iron homeostasis in the inner ear. PMID- 25789327 TI - Topically applied connective tissue growth factor/CCN2 improves diabetic preclinical cutaneous wound healing: potential role for CTGF in human diabetic foot ulcer healing. AB - AIMS/HYPOTHESIS: Topical application of CTGF/CCN2 to rodent diabetic and control wounds was examined. In parallel research, correlation of CTGF wound fluid levels with healing rate in human diabetic foot ulcers was undertaken. METHODS: Full thickness cutaneous wounds in diabetic and nondiabetic control rats were treated topically with 1 MUg rhCTGF or vehicle alone, on 2 consecutive days. Wound healing rate was observed on day 14 and wound sites were examined for breaking strength and granulation tissue. In the human study across 32 subjects, serial CTGF regulation was analyzed longitudinally in postdebridement diabetic wound fluid. RESULTS: CTGF treated diabetic wounds had an accelerated closure rate compared with vehicle treated diabetic wounds. Healed skin withstood more strain before breaking in CTGF treated rat wounds. Granulation tissue from CTGF treatment in diabetic wounds showed collagen IV accumulation compared with nondiabetic animals. Wound alpha-smooth muscle actin was increased in CTGF treated diabetic wounds compared with untreated diabetic wounds, as was macrophage infiltration. Endogenous wound fluid CTGF protein rate of increase in human diabetic foot ulcers correlated positively with foot ulcer healing rate (r = 0.406; P < 0.001). CONCLUSIONS/INTERPRETATION: These data collectively increasingly substantiate a functional role for CTGF in human diabetic foot ulcers. PMID- 25789328 TI - Alloxan-induced diabetes causes morphological and ultrastructural changes in rat liver that resemble the natural history of chronic fatty liver disease in humans. AB - PURPOSE: This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. METHODS: Thirty nondiabetic control rats (NC) and 30 untreated diabetic (UD) rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. RESULTS: UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. CONCLUSION: Alloxan induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis. PMID- 25789329 TI - The role of some chemokines from the CXC subfamily in a mouse model of diabetic neuropathy. AB - The mechanism involved in the development of diabetic neuropathy is complex. Currently, it is thought that chemokines play an important role in this process. The aim of this study was to determine how the level of some chemokines from the CXC subfamily varies in diabetic neuropathy and how the chemokines affect nociceptive transmission. A single intraperitoneal (i.p.) injection of streptozotocin (STZ; 200 mg/kg) resulted in an increased plasma glucose. The development of allodynia and hyperalgesia was measured at day 7 after STZ administration. Using Antibody Array techniques, the increases in CXCL1 (KC), CXCL5 (LIX), CXCL9 (MIG), and CXCL12 (SDF-1) protein levels were detected in STZ injected mice. No changes in CXCL11 (I-TAC) or CXCL13 (BLC) protein levels were observed. The single intrathecal (i.t.) administration of CXCL1, CXCL5, CXCL9, and CXCL12 (each in doses of 10, 100, and 500 ng/5 MUL) shows their pronociceptive properties as measured 1, 4, and 24 hours after injection using the tail-flick, von Frey, and cold plate tests. These findings indicate that the chemokines CXCL1, CXCL5, CXCL9, and CXCL12 are important in nociceptive transmission and may play a role in the development of diabetic neuropathy. PMID- 25789330 TI - Combination therapy with oleanolic acid and metformin as a synergistic treatment for diabetes. AB - AIMS AND BACKGROUND: Type 2 diabetes is a chronic disease that cannot be treated adequately using the known monotherapies, especially when the disease progresses to an advanced stage. In this study, we explore the possibility of treating the disease with a novel combination approach of oleanolic acid (OA), a glycogen phosphorylase (GP) inhibitor, and metformin. METHODS: Db/db mice were randomly divided into four groups: a db/db control group, db/db mice treated with OA (250 mg/kg), db/db mice treated with metformin (100 mg/kg), and db/db mice treated with a combination of OA and metformin. All mice were treated for four weeks. The effects of the treatments on glucose homeostasis were measured using an OGTT, an assessment of insulin sensitivity and signaling in the liver, and the hepatic glucose production. RESULTS: Combination therapy with OA and metformin significantly reduced the blood glucose and insulin levels and improved the liver pathology compared with that for the monotherapy in the db/db diabetic mouse model. We also found that the combination therapy significantly increased the mRNA expression of glycogen synthesis and decreased the GP, PGC-1alpha, PEPCK1, and G-6-Pase levels. In addition, the combination therapy with OA and metformin significantly increased the phosphorylation of AKT, PI3K, AMPK, and ACC and decreased the protein expression levels of G-6-Pase, PEPCK1, and TORC compared with those for either monotherapy. The combination therapy also reduced the phosphorylation of mTOR and CREB. CONCLUSIONS: Our results suggest that the combination therapy with OA and metformin has synergistic effects on the symptoms of db/db diabetic mice by improving glucose and insulin homeostasis. PMID- 25789332 TI - Quality of life and symptoms following stereotactic body radiotherapy in early stage lung cancer patients. AB - BACKGROUND: Stereotactic body radiotherapy (SBRT) has emerged in recent years as a clinically viable treatment option for early-stage non-small-cell lung cancer (NSCLC) patients. Comprehensive assessment of quality of life (QoL) after SBRT is relatively sparse. OBJECTIVE: To describe QoL and symptoms in a small, prospective cohort of early-stage NSCLC patients treated with SBRT. METHODS: 19 NSCLC patients who were medically unfit for surgery or chose not to undergo surgery were included in the study. All of the patients were treated with SBRT between 2009 and 2013 at a single comprehensive cancer center. Patients completed a baseline assessment of functional and cognitive status, symptoms, psychological distress, and overall QoL. Questionnaires were repeated at 6 and 12 weeks after accrual. RESULTS: There were no significant differences in all outcomes across the 3 evaluation time points. Overall QoL scores were moderate, and the lowest score was observed for the functional well-being domain. The most severe symptoms at baseline were pain, lack of energy, cough, nervousness, difficulty sleeping, shortness of breath, and worry. Severity scores for pain, lack of energy, and cough increased, whereas nervousness, difficulty sleeping, and worry decreased at the 12 week evaluation. LIMITATIONS: Small sample size and lack of sufficient diversity in the cohort. CONCLUSIONS: QoL scores remained relatively stable across time. Anxiety improved after SBRT, whereas symptoms such as generalized pain, lack of energy, and cough worsened. The findings suggest that SBRT is overall a well-tolerated treatment with no significant decrement in patient centered outcomes. PMID- 25789331 TI - Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody for juvenile idiopathic arthritis. AB - OBJECTIVE: To estimate the diagnostic accuracy of the anti-CCP test in JIA and to evaluate factors associated with higher accuracy. METHODS: Two investigators performed an extensive search of the literature published between January 2000 and January 2014. The included articles were assessed by the Quality Assessment of Diagnostic Accuracy Studies tool. The meta-analysis was performed using a summary ROC (SROC) curve and a bivariate random-effect model to estimate sensitivity and specificity across studies. RESULTS: The bivariate meta-analysis yielded a pooled sensitivity and specificity of 10% (95% confidence interval (CI): 6.0%-15.0%) and 99.0% (95% CI: 98.0%-100.0%). The area under the SROC curve was 0.96. Sensitivity estimates were highly heterogeneous, which was partially explained by the higher sensitivity in the rheumatoid factor-positive polyarthritis (RF+ PA) subtype (48.0%; 95% CI: 31.0%-65.0%) than in the other subtypes (17.0%; 95% CI: 14.0%-20.0%) and the higher sensitivity of the Inova assay (17.0%; 95% CI: 14.0%-20.%%) than the other assays (0.05%; 95% CI: 2.0% 11.0%). CONCLUSIONS: Anti-CCP antibody test has a high specificity for the diagnosis of JIA. The sensitivity of this test is low and varies across populations but is higher in RF+ PA than in other JIA subtypes. PMID- 25789333 TI - Linear dispersion relation and depth sensitivity to swell parameters: application to synthetic aperture radar imaging and bathymetry. AB - Long gravity waves or swell dominating the sea surface is known to be very useful to estimate seabed morphology in coastal areas. The paper reviews the main phenomena related to swell waves propagation that allow seabed morphology to be sensed. The linear dispersion is analysed and an error budget model is developed to assess the achievable depth accuracy when Synthetic Aperture Radar (SAR) data are used. The relevant issues and potentials of swell-based bathymetry by SAR are identified and discussed. This technique is of particular interest for characteristic regions of the Mediterranean Sea, such as in gulfs and relatively close areas, where traditional SAR-based bathymetric techniques, relying on strong tidal currents, are of limited practical utility. PMID- 25789334 TI - A mathematical model for the flow of a Casson fluid due to metachronal beating of cilia in a tube. AB - A mathematical model is developed to study the transport mechanism of a Casson fluid flow inspired by the metachronal coordination between the beating cilia in a cylindrical tube. A two-dimensional system of nonlinear equations governing the flow problem is formulated by using axisymmetric cylindrical coordinates and then simplified by employing the long wavelength and low Reynolds number assumptions. Exact solutions are derived for the velocity components, the axial pressure gradient, and the stream function. However, the expressions for the pressure rise and the volume flow rate are evaluated numerically. The features of the flow characteristics such as pumping and trapping are illustrated and discussed with the help of graphs. It is observed that the volume flow rate is influenced significantly by the width of plug flow region H p as well as the cilia length parameter epsilon. The analysis is also applied and compared with the estimated value of the volume flow rate of epididymal fluid in the ductus efferentes of the human male reproductive tract. PMID- 25789335 TI - Kinetics of NiO and NiCl2 hydrogen reduction as precursors and properties of produced Ni/Al2O3 and Ni-Pd/Al2O3 catalysts. AB - The objects of this investigation were the comparative kinetic analysis of the NiO and NiCl2 reduction by hydrogen during an induction period and elimination of the calcination during the synthesis of Ni/Al2O3 catalysts. The effect of temperature and time on NiO and NiCl2 reduction degrees was studied. Avrami I equation was selected as the most favorable kinetic model and used to determine activation energy of the NiO and NiCl2 reduction for the investigated temperature range (623-923 K) and time intervals (1-5 minutes). The investigation enabled reaching conclusions about the reaction ability and rate of the reduction processes. Afterward, Ni/Al2O3 catalysts were obtained by using oxide and chloride precursor for Ni. The catalysts were supported on alumina-based foam and prepared via aerosol route. Properties of the samples before and after low temperature hydrogen reduction (633 K) were compared. Obtained results indicated that the synthesis of Ni/Al2O3 catalysts can be more efficient if chloride precursor for Ni is directly reduced by hydrogen during the synthesis process, without the calcination step. In addition, Ni-Pd/Al2O3 catalysts with different metal content were prepared by using chloride precursors. Lower reduction temperature was utilized and the chlorides were almost completely reduced at 533 K. PMID- 25789336 TI - Association between urine fluoride and dental fluorosis as a toxicity factor in a rural community in the state of San Luis Potosi. AB - OBJECTIVE: The aim of this study is to investigate urine fluoride concentration as a toxicity factor in a rural community in the state of San Luis Potosi, Mexico. MATERIALS AND METHODS: A sample of 111 children exposed to high concentrations of fluoride in drinking water (4.13 mg/L) was evaluated. Fluoride exposure was determined by measuring urine fluoride concentration using the potentiometric method with an ion selective electrode. The diagnosis of dental fluorosis was performed by clinical examination, and the severity of damage was determined using Dean's index and the Thylstrup-Fejerskov (TF) index. RESULTS: The range of exposure in the study population, evaluated through the fluoride content in urine, was 1.1 to 5.9 mg/L, with a mean of 3.14+/-1.09 mg/L. Dental fluorosis was present in all subjects, of which 95% had severe cases. Higher urine fluoride levels and greater degrees of severity occurred in older children. CONCLUSIONS: The results show that dental fluorosis was determined by the presence of fluoride exposure finding a high positive correlation between the severity of fluorosis and urine fluoride concentration and the years of exposure suggested a cumulative effect. PMID- 25789337 TI - Radiofrequency transoral microsurgical procedures in benign and malignant laryngeal and hypopharyngeal lesions (institutional experiences). AB - Besides cold-steel and laser instruments, the use of radiofrequency (RF) devices in transoral microsurgery is getting increasing popularity mainly due to its minimal thermal effect on the collateral soft tissue. Authors summarize their surgical technique, results, and experience gained with RF applied during laryngeal interventions at the Department of Otorhinolaryngology, Head and Neck Surgery at Medical School, University of Pecs. Transoral microsurgery using radiofrequency was carried out in 23 cases in total between 1 January 2011 and 1 March 2013. Fourteen histopathologically different benign lesions and 9 malignant planocellular carcinomas of the larynx were removed using different Micro-Larynx RF Probes powered by Surgitron Dual 4.0 MHz Frequency RF (Ellman International, Oceanside, NY, USA) device. No major bleeding event occurred during or after the procedures and neither laryngeal oedema nor significant postoperative pain was recorded. Authors also reviewed the international literature in this topic while detailing some of their most interesting cases. PMID- 25789339 TI - Power, control, and optimization. PMID- 25789338 TI - Antimycobacterial and nitric oxide production inhibitory activities of Ocotea notata from Brazilian restinga. AB - The genus Ocotea (Lauraceae) is distributed mainly in tropical and subtropical regions. Some species of this genus as O. puberula and O. quixos have been described in the literature, showing antibacterial activity. And Ocotea macrophylla showed anti-inflammatory activity with inhibition of COX-1, COX-2, and LOX-5. The purpose of this study was the phytochemical investigation of the plant species Ocotea notata from Restinga Jurubatiba National Park, Macae, RJ, Brazil, and the search for antimycobacterial fractions and compounds. The crude extract was evaluated for antimycobacterial activity and presented 95.75 +/- 2.53% of growth inhibition at 100 ug/mL. Then, it was subjected to a liquid liquid partition and subsequently was chemically investigated by HPLC, revealing the major presence of flavonoids. In this process the partition fractions hexane, ethyl acetate, and butanol are shown to be promising in the antimycobacterial assay. In addition, ethyl acetate fraction was chromatographed and afforded two flavonoids identified by MS and NMR as afzelin and isoquercitrin. The isolated flavonoids afzelin and isoquercitrin were evaluated for their antimycobacterial activity and for their ability to inhibit NO production by macrophages stimulated by LPS; both flavonoids isoquercitrin (Acet22) and afzelin (Acet32) were able to inhibit the production of NO by macrophages. The calculated IC50 of Acet22 and Acet32 was 1.03 and 0.85 ug/mL, respectively. PMID- 25789340 TI - Learning and memory during aggression in Drosophila: handling affects aggression and the formation of a "loser" effect. AB - Aggressive behavior in Drosophila melanogaster serves to acquire or defense vital resources such as food, territory or access to mates. Flies learn from previous fighting experience and modify and adapt their behavior to new situations, suggesting that learning and memory play a major role in agonistic encounters. Prior fighting experience influences the outcome of later contests: losing a fight increases the probability of losing second contests, revealing the formation of a "loser" effect. In a recent publication, we developed a new behavioral arena that eliminates handling of flies prior to, during and after fights to study the learning and memory associated with aggression. We compared two handling procedures commonly used in laboratories to study aggression with the new chambers and demonstrated that handling negatively influences aggression and prevents "loser" effect formation. In addition, we observed new aspects of behavior such as the formation of robust winner effects. PMID- 25789341 TI - Team-based care: worth a second look. PMID- 25789342 TI - Turning team-based care into a winning proposition. AB - Team-based care can go a long way toward improving patient outcomes. This review- with accompanying tips and resource lists--can help. PMID- 25789343 TI - Intrathecal analgesia: time to consider it for your patient? AB - When systemic analgesics or antispasmodics fail to control chronic pain or cause intolerable adverse effects, an intrathecal drug delivery system may be the best bet. PMID- 25789344 TI - Immunization update: what's changed, what's on the way. PMID- 25789345 TI - PURLs: A new adjunctive Tx option for venous stasis ulcers. AB - Adding simvastatin to standard wound care improves ulcer healing rates and times as well as the patient's quality of life. PMID- 25789346 TI - Painless penile papule. PMID- 25789347 TI - Clinical inquiry: How well do antivirals shorten genital herpes pain duration? PMID- 25789348 TI - Clinical inquiry: Does the presence of a trained support person during labor decrease C-section rates? PMID- 25789349 TI - What you must know before you recommend a probiotic. AB - Evidence for using probiotics for diarrhea and other GI ailments is mixed. This article--with an at-a-glance guide--summarizes when it's worth considering. PMID- 25789350 TI - Weight loss . diarrhea . mild eosinophilia . Dx? PMID- 25789351 TI - Clinical inquiry: Are inhaled steroids effective for a postviral cough? PMID- 25789352 TI - Speech, language, hearing delays: time for early intervention? AB - A wait-and-see approach may not be best for the child exhibiting delayed development. This review--complete with extensive resource lists--can facilitate an expeditious referral. PMID- 25789354 TI - Influence of Environmental Tobacco Smoke on Gingival Pigmentation in Schoolchildren. AB - PURPOSE: To examine the relationship between environmental tobacco smoke (ETS) and oral pigmentation in schoolchildren. MATERIALS AND METHODS: Oral photographs of 117 systemically healthy, nonsmoking children and young adults (aged 10 to 21 years) were randomly selected from two rural schools. Closed-ended questionnaires were designed for this age group and used to record answers given by the subjects. The subjects were divided into two groups based on age: group 1 (10 to 14 years) and group 2 (15 to 21 years). There were 58 subjects in group 1 and 59 in group 2. Gingival pigmentation was classified using the Melanin Index Score (MIS) into MIS-0 (no pigmentation), MIS-1 (solitary unit(s) of pigmentation in papillary gingiva) and MIS-2 (continuous band extending from 2 neighbouring solitary units). RESULTS: In group 1, 17.24% of subjects displayed MIS-0 compared to only 5.08% in group 2. The difference between the groups was found to be statistically significant according to Student's t-test (p < 0.001). In group 2, 38.98% of subjects showed MIS-2 as compared to only 17.24% subjects in group 1. CONCLUSION: Despite the relatively small sample size, the results of the present study confirmed previously reported findings that ETS has an influence on both the prevalence and the severity of gingival pigmentation. PMID- 25789353 TI - Plaques on dorsal hands & arms. AB - This patient's slow-growing lesions hadn't responded to topical steroids or antifungals. Careful consideration of her work environment led us to a curious diagnosis. PMID- 25789355 TI - Self-medication Practice Amongst Patients Visiting a Tertiary-care Dental Hospital in Central India. AB - PURPOSE: To assess self-medication practice-related awareness for correct usage and its association with demographic factors among patients reporting to a dental college. MATERIALS AND METHODS: This descriptive cross-sectional questionnaire based study was conducted among 300 patients reporting to the People's College of Dental Sciences and Research Centre, Bhopal, India. Only patients >= 18 years of age were included and consenting participants anonymously completed the questionnaire, with incomplete questionnaires being excluded from the study. The semi-structured questionnaire containing both open- and closedended questions was prepared in the local language and included demographic data, name of self medication, frequency of self-medication, periods of illness, duration, dose, frequency of drug administration, symptoms for which drugs were used, satisfaction with healthcare facilities, source of information for self medication, presence of chronic illness, adverse effects to self-medication seen in patients and drug interactions. The unpaired t-test and chi-square test were used for statistical analysis. p-values < 0.05 were considered statistically significant. RESULTS: A significant association was seen between education and self-medication. It was observed that the subjects who fell ill more frequently consumed medications on their own more often. Medications were most commonly taken for cough, cold and fever. The most preferred medicine was paracetamol. Most of the subjects found the medicines effective in helping them relieve their symptoms. However, not even half of the subjects were aware of the dose, duration, side-effects or interactions of medicines. There was a significant association between knowledge about side-effects and side-effects experienced from medication. A significant association was also seen between knowledge about side-effects and frequency of self-medication. CONCLUSION: Self-medication and non-doctor prescribing are relatively common in Bhopal. Knowledge regarding the appropriate usage of medication is inadequate. Education to help patients decide on the appropriateness of selfmedication is required. PMID- 25789356 TI - Association Between Oral Hygiene Status and Halitosis Among Smokers and Nonsmokers. AB - PURPOSE: To study the association of smoking with poor oral hygiene status and halitosis in a comparative cross-sectional study. MATERIALS AND METHODS: 100 smokers and 100 nonsmokers ages 18-50 years were recruited for this study in Kota Bharu, Malaysia. Oral hygiene (good/fair vs poor) was determined using the Simplified Oral Hygiene Index, and the halitosis level was measured using a Halimeter. Subjects were instructed to refrain from consuming foods containing garlic, onions, strong spices, alcohol and using mouthwashes 48 h prior to the examination. The halitosis levels were quantified by recording volatile sulphur compounds (VSCs) three times at 3-min intervals, resulting in a mean halitosis score. Various statistical analyses were performed, ranging from simple frequency analysis to multivariable modelling. RESULTS: The proportions of subjects with poor oral hygiene and high halitosis were 24.0% and 41.5%, respectively. According to bivariate analyses, both problems were significantly less frequent among younger adults (halitosis), females, subjects with higher education, those with adequate habits to maintain good oral hygiene, those who had recent dental visits and those self-reporting fewer health problems. The percentages of poor oral hygiene and high halitosis were significantly higher in smokers (p < 0.001). However, almost all these variables failed to show significance in the multivariate analyses, with the exceptions of smoking for both poor oral hygiene and halitosis, education for poor oral hygiene, and age, self-reported health problems and time since the previous dental visit for halitosis. CONCLUSION: These findings demonstrate a significantly higher level of halitosis and poorer oral hygiene in smokers than nonsmokers. PMID- 25789357 TI - Oral Health Related Quality of Life in Young Individuals with Dental Anxiety and Exaggerated Gag Reflex. AB - PURPOSE: To measure the oral health-related quality of life (OHRQoL) among young individuals presenting with dental anxiety and exaggerated gag reflex and to compare it to the OHRQoL among young individuals attending restorative dental treatment. MATERIALS AND METHODS: Patients with dental anxiety and/or exaggerated gag reflex who were referred to the Department of Oral Medicine were included. Clinical examinations included DMFT index (Decayed, Missing and Filled Teeth) according to the WHO criteria and oral hygiene was assessed with the plaque index (PI). The survey included the validated Hebrew version of the Oral Health Impact Profile (OHIP-14). RESULTS: Overall, 322 patients completed the study. The dental anxiety group consisted of 68 patients, the exaggerated gag reflex group of 54 patients and the control group of 200 patients. Control group patients presented with lower PI and DMFT values. Patients with dental anxiety and/or exaggerated gag exhibited worse OHIP-14 scores overall as well as on each separate subscale. PI and DMFT were found to be in strong relation to the OHIP-14. Multivariable logistic regression analysis of factors influencing the OHIP-14 scores revealed a significant influence of the DMFT score. CONCLUSIONS: Patients with dental anxiety and exaggerated gag reflex were shown to suffer considerably from impaired oral health-related quality of life. This impairment may be attributed to a higher prevalence of caries and avoidance of dental treatment. Those populations should be identified and monitored carefully as well as encouraged to seek the appropriate behavioural treatment in order to improve their dental heath and oral health related quality of life. PMID- 25789358 TI - Impact of Oral Health Status on the Oral Health-Related Quality of Life of Brazilian Male Incarcerated Adolescents. AB - PURPOSE: To assess the impact of oral health status on the oral health-related quality of life (OHRQoL) of incarcerated Brazilian male adolescents. MATERIALS AND METHODS: A cross-sectional survey with 102 male adolescents incarcerated at the Sao Francisco Juvenile Detention Facility, Piraquara, Brazil in 2010 was carried out. Dental caries, oral hygiene, periodontal status, malocclusion, dental fluorosis and dental trauma were analysed. The Oral Health Impact Profile (OHIP-14) was administered to measure OHRQoL, along with a questionnaire addressing sociodemographic variables, health-related aspects and dental experience. Descriptive statistical analysis and univariate and multiple Poisson regression with robust variance were performed. RESULTS: The prevalence of adolescents who reported an impact on OHRQoL was 64% (95% CI: 54-73) and the mean OHIP-14 score was 6.69 (SD = 8.79; median = 3.00). In the multiple regression model, the prevalence of a negative impact on OHRQoL was significantly higher among individuals with untreated caries (PR = 1.74; 95% CI: 1.10-2.77), those who reported having discomfort in the teeth or mouth (PR = 1.33; 95% CI: 1.03-1.73), using tobacco prior to internment (PR = 1.53; 95% CI: 1.04-2.24) and maintaining a stable relationship (PR = 1.31; 95% CI: 1.01-1.70) in comparison to individuals who did not exhibit these conditions. Moreover, each month of internment represented an increase in the prevalence of an impact on OHRQoL (PR = 1.03; 95% CI: 1.01-1.06). CONCLUSION: Incarcerated male adolescents reported that oral health problems exerted an influence on quality of life, with untreated caries exhibiting the greatest impact. PMID- 25789359 TI - Knowledge of Dentists on the Management of Tooth Avulsion Injuries in Rio de Janeiro, Brazil. AB - PURPOSE: To evaluate dentists' professional experience and knowledge of emergency management of tooth avulsion injuries in Rio de Janeiro, Brazil. MATERIALS AND METHODS: A total of 100 questionnaires were evaluated. The first part of the questionnaire consisted of questions regarding personal information. The second part evaluated dentists' knowledge of emergency management in cases of dental avulsion. The responses for each question were counted and expressed as percentages. RESULTS: All dentists had a college degree or above. Only three dentists had a Master's or PhD degree. Most of the dentists (94.5%) considered time and storage media important for the prognosis of avulsed teeth. However, the dentists did not show consistent responses about the adequate time and ideal storage media to transport avulsed teeth. CONCLUSION: The study highlighted Brazilian dentists' need for continuing education in order to improve current knowledge in emergency management of avulsed teeth. PMID- 25789360 TI - Knowledge, Attitude and Practice Regarding Tobacco Cessation Among Indian Dentists. AB - PURPOSE: To assess the knowledge, attitude and practice regarding tobacco cessation among dentists in Hyderabad city, India. MATERIALS AND METHODS: A cross sectional questionnaire study was conducted among 264 dentists registered in the local Indian Dental Association branch, Hyderabad, Andhra Pradesh, India. The questionnaire comprised of 35 items and used a five-point Likert scale to assess tobacco use prevention and cessation counseling. RESULTS: The majority of the study participants were females (55.7%) with a mean age of 29.9 +/- 7.5 years. No significant gender difference was observed for any of the mean domain scores. A statistically significant difference was noted between age groups in the 'Knowledge' domain, 'professional role and identity' item (P = 0.03) vs the 'Practice' domain, 'social influences' item (P = 0.05) with 40+ years having a higher mean score (6.5 +/- 1.5). In terms of the education, those possessing Bachelor's of Dental Science had a significantly higher mean score (10.8 +/- 2.2) for the 'Attitude' question 'belief about consequences' (P = 0.05) than did those with a Master's degree. The reported barriers were insufficient reimbursement (48.1%), lack of tobacco-related self-help material/pamphlets for patients (46.5%) and lack of patient motivation to receive tobacco cessation counseling (43.6%). CONCLUSION: In the present study, although dentists possessed knowledge about tobacco cessation, it was not adequate. Dental professionals play an important role in educating patients regarding the oral health risks of tobacco use and motivating them to quit. PMID- 25789361 TI - Satisfaction with dental care and its role in dental health-related behaviour among lithuanian university employees. AB - PURPOSE: To assess factors related to satisfaction with dental care and its role in dental health-related behaviour among Lithuanian university employees. MATERIALS AND METHODS: Our cross-sectional survey collected data on respondents' satisfaction with dental care using 24 statements. The self-administered questionnaire also inquired about dental attendance, dental health-related behaviour and attitudes, self-assessed dental status and background details. All 35- to 44-year-old employees (n = 862) of four universities in Lithuania were invited to participate; 64% (n = 553) responded, 78% of them were women. Statements on satisfaction with technical, personal and organisational dimensions of the dental surgery were assessed using a five-point scale, ranging from entirely agree to entirely disagree, with higher scores indicating stronger agreement. Overall satisfaction scores were summed and subjects divided into tertiles to evaluate dental health-related behaviour. For the logistic regression model, subjects were divided into two groups of satisfaction level (below and above the mean of the sum score). RESULTS: Subjects were highly satisfied with dental care, with the mean sum score being 99.5 (SD = 12.62, range 59-120). Stronger satisfaction was reported by those visiting private practices (p < 0.001) and the same dentist longer (p = 0.006) and by those who entirely agreed with the statements on dental health-related attitudes (p <= 0.001). The logistic regression model showed that higher satisfaction with dental care level was more likely for those who indicated check-up-based regular dental attendance (OR = 1.7) and brushing their teeth at least twice daily (OR = 1.6). CONCLUSIONS: Satisfaction with dental care is positively related to individuals' dental health related attitudes and behaviour among highly-educated subjects in particular. PMID- 25789363 TI - An open-source practical manual for home hemodialysis: a catalyst for change! PMID- 25789362 TI - Antimicrobial Efficacy of Salvadora persica Extracts on a Monospecies Biofilm on Orthodontic Brackets In Vitro. AB - PURPOSE: The oral cavity is a rich ecosystem with a plethora of microorganisms, and different components of fixed orthodontic appliances may contribute to a shift in the balance of oral ecology. The purpose of this study was to investigate the antimicrobial potential of hexane and ethanol extracts of Salvadora persica on a monospecies biofilm model established on orthodontic brackets in vitro. MATERIALS AND METHODS: Streptococcus mutans biofilm was formed on mini diamond orthodontic brackets following three days of anaerobic incubation at 37C. The bacterial cell viability of this biofilm was measured after their exposure to saline, hexane extract of S. persica, ethanol extract of S. persica and 0.2% chlorhexidine using 3-(4, 5-dimethylthiazol- 2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) assay. On half of the brackets, the colony forming units (CFU) were counted. Both experiments were performed in triplicate. RESULTS: The absorbance values obtained from the MTS reduction assay after exposure to the different test agents showed a decline in the bacterial cell viability of the S. mutans biofilm as follows: chlorhexidine (+)0.05). The CFU counts of S. mutans obtained from chlorhexidine exposure were lower than from hexane and ethanol extracts. CONCLUSION: S. persica extracts were found to have antimicrobial effects on S. mutans biofilm established in vitro on orthodontic brackets suggestive of its potential use as an oral antimicrobial agent for orthodontic patients. PMID- 25789364 TI - Editorial, supportive care and psychological issues around cancer. PMID- 25789365 TI - Novavax' H7N9 avian influenza VLP vaccine positive in Phase 1/2. PMID- 25789366 TI - Gut microbiota influence immunity to vaccination. PMID- 25789367 TI - Challenges on the way to polio eradication. PMID- 25789368 TI - Investigational 9-valent HPV vaccine could prevent almost 90% of cervical cancers. PMID- 25789369 TI - Half of all flu shots in the US are provided by pharmacists. PMID- 25789370 TI - FDA grants Fast Track designation for Pfizer's C. diff vaccine candidate. PMID- 25789371 TI - [In Process Citation]. PMID- 25789372 TI - Down on one knee: soft tissue knee injuries across the lifespan. AB - Joint injury is a potent risk factor for osteoarthritis, the most important musculoskeletal disease affecting humankind. Yet the population incidence of soft tissue knee injury is not well documented. Using health-care register data from Sweden, Peat and colleagues report that soft tissue knee injuries are common, peak in adolescence and early adulthood, have a second spike in women who are 35 to 49 years old, and continue throughout the lifespan. The study highlights the need for more knowledge on the natural history of knee injuries, their impact on knee osteoarthritis development and progression, and the potential for prevention programs to reduce the incidence of these injuries. PMID- 25789373 TI - The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. AB - The peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters modulate osteo chondrogenic differentiation of mesenchymal progenitor cells during endochondral ossification in limb development. In adults, sensory and sympathetic neurotransmitters are critical for bone regeneration after fracture and are involved in the pathology of inflammatory diseases as rheumatoid arthritis which manifests mainly in joints. Possibly, they might also play a role in pathogenesis of degenerative joint disorders, such as osteoarthritis. All together, accumulating data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper limb formation during embryonic skeletal growth. In adults, they modulate bone regeneration, bone remodeling, and articular cartilage homeostasis in addition to their classic neurological actions. PMID- 25789374 TI - Use of next-generation DNA sequencing to analyze genetic variants in rheumatic disease. AB - Next-generation DNA sequencing has revolutionized the field of genetics and genomics, providing researchers with the tools to efficiently identify novel rare and low frequency risk variants, which was not practical with previously available methodologies. These methods allow for the sequence capture of a specific locus or small genetic region all the way up to the entire six billion base pairs of the diploid human genome. Rheumatic diseases are a huge burden on the US population, affecting more than 46 million Americans. Those afflicted suffer from one or more of the more than 100 diseases characterized by inflammation and loss of function, mainly of the joints, tendons, ligaments, bones, and muscles. While genetics studies of many of these diseases (for example, systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease) have had major successes in defining their genetic architecture, causal alleles and rare variants have still been elusive. This review describes the current high-throughput DNA sequencing methodologies commercially available and their application to rheumatic diseases in both case-control as well as family-based studies. PMID- 25789375 TI - The sympathetic nervous response in inflammation. AB - Over the past decades evidence has accumulated clearly demonstrating a pivotal role for the sympathetic nervous system (SNS) and its neurotransmitters in regulating inflammation. The first part of this review provides the reader with an overview showing that the interaction of the SNS with the immune system to control inflammation is strongly context-dependent (for example, depending on the activation state of the immune cell or neuro-transmitter concentration). In the second part we focus on autoimmune arthritis as a well investigated example for sympathetically controlled inflammation to show that the SNS and catecholamines play a differential role depending on the time point of ongoing disease. A model will be developed to explain the proinflammatory effects of the SNS in the early phase and the anti-inflammatory effects of catecholamines in the later phase of autoimmune arthritis. In the final part, a conceptual framework is discussed that shows that a major purpose of increased SNS activity is nourishment of a continuously activated immune system at a systemic level using energy-rich fuels (glucose, amino acids, lipids), while uncoupling from central nervous regulation occurs at sites of inflammation by repulsion of sympathetic fibers and local adrenoceptor regulation. This creates zones of 'permitted local inflammation'. However, if this 'inflammatory configuration' persists and is strong, as in autoimmunity, the effects are detrimental because of the resultant chronic catabolic state, leading to cachexia, high blood pressure, insulin resistance, and increased cardiovascular mortality, and so on. Today, the challenge is to translate this conceptual knowledge into clinical benefit. PMID- 25789376 TI - Correlates of pain symptoms among Iraq and Afghanistan military personnel following combat-related blast exposure. AB - Pain complaints are highly prevalent among military servicemembers and Veterans of the recent combat operations in Iraq and Afghanistan. The high comorbidity of pain with conditions such as posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) underscores the importance of a greater understanding of factors associated with complex polytraumatic injuries among military personnel. The present study aimed to identify correlates of current pain among 201 U.S. military personnel who reported at least one blast experience during combat deployment (age [mean +/- standard deviation]: 27.20 +/- 7.58 yr). Theoretically derived subsets of variables were analyzed in successive hierarchical regression models to determine correlates of self-reported pain symptoms. Preliminary models evaluated demographic features, medical and injury characteristics (e.g., TBI classification), psychosocial history (e.g., trauma exposure), and psychiatric variables. A final model was then derived, in which older age, possible or probable mild TBI, depression symptoms, and PTSD re-experiencing symptoms emerged as significant correlates of pain. The findings further the understanding of polytrauma symptoms among military personnel by identifying specific patient characteristics and comorbidity patterns related to pain complaints. Increased awareness of demographic, psychiatric, or medical factors implicated in pain will enhance comprehensive clinical assessment and intervention efforts. PMID- 25789377 TI - Author's reply. PMID- 25789378 TI - Author's Reply. PMID- 25789379 TI - Author's Reply. PMID- 25789380 TI - Insulin nasal spray for treating cognitive impatient. PMID- 25789381 TI - Mobility disabilities among older adults. PMID- 25789382 TI - Funding Alzheimer's research. PMID- 25789383 TI - Author's reply. PMID- 25789384 TI - Author's reply: To PMID 24818973. PMID- 25789385 TI - Author's reply. PMID- 25789386 TI - Author's reply. PMID- 25789387 TI - Author's reply. PMID- 25789388 TI - Mitochondrial medicine. Preface. PMID- 25789389 TI - Author response. PMID- 25789390 TI - Author response. PMID- 25789391 TI - Engagement with international veterinary associations. PMID- 25789392 TI - Emergency animal diseases bulletin. The Timor Leste Village Poultry Health and Biosecurity Program. PMID- 25789393 TI - Rallying together to respond to another bushfire animal emergency. PMID- 25789394 TI - Veterinary volunteering. PMID- 25789395 TI - Early detection of chronic renal disease. PMID- 25789396 TI - Re: Ixodes holocyclus in cooler climate regions. PMID- 25789397 TI - Peer review--loopholes, hackers and scams. PMID- 25789398 TI - Count us in: addressing gender disparities in autism research. PMID- 25789399 TI - Circulating tumor DNA: the future of personalized medicine in oncology? PMID- 25789400 TI - Recommended reading for rookie LC-MS users. PMID- 25789402 TI - Ischaemia-modified albumin during experimental apnoea. AB - Ischaemia-modified albumin (IMA) is a marker of the release of reactive oxygen species (ROS) during hypoxaemia. In elite divers, breath-hold induces ROS production. Our aim was to evaluate the kinetics of IMA serum levels during apnea. Twenty breath-hold divers were instructed to perform a submaximal static breath-hold. Twenty non-diver subjects served as controls. Blood samples were collected at rest, every minute, at the end of breath-hold, and 10 min after recovery. The IMA level increased after 1 min of breath-hold (p < 0.003) and remained high until recovery. Divers were separated into 2 groups: subjects who held their breath for less than 4 min (G-4) and those who held it for more than 4 min (G+4). After 3 min of apnoea, the increase of IMA was higher in the G-4 group than in the G+4 group (p < 0.008). However, at the end of apnoea, the IMA level did not differ between groups. If IMA level was globally correlated with the apnoea duration, it is interesting to note that the higher IMA level was not found in the best divers. Similarly, if arterial blood oxygen saturation (SpO2) was globally inversely correlated with apnoea duration, the lowest SpO2 at the end of breath-hold was not found in the divers that performed the best apnoea. We concluded that these divers save their oxygen. The IMA level provides a useful measure of resistance to hypoxaemia. PMID- 25789401 TI - Stranglehold on the spindle assembly checkpoint: the human papillomavirus E2 protein provokes BUBR1-dependent aneuploidy. AB - The Human Papillomavirus (HPV) E2 protein, which inhibits the E6 and E7 viral oncogenes, is believed to have anti-oncogenic properties. Here, we challenge this view and show that HPV-18 E2 over-activates the Spindle Assembly Checkpoint (SAC) and induces DNA breaks in mitosis followed by aneuploidy. This phenotype is associated with interaction of E2 with the Mitotic Checkpoint Complex (MCC) proteins Cdc20, MAD2 and BUBR1. While BUBR1 silencing rescues the mitotic phenotype induced by E2, p53 silencing or presence of E6/E7 (inactivating p53 and increasing BUBR1 levels respectively) both amplify it. This work pinpoints E2 as a key protein in the initiation of HPV-induced cervical cancer and identifies the SAC as a target for oncogenic pathogens. Moreover, our results suggest a role of p53 in regulating the mitotic process itself and highlight SAC over-activation in a p53-negative context as a highly pathogenic event. PMID- 25789403 TI - Impact of body mass index on postoperative complications and long-term survival in patients with esophageal squamous cell cancer. AB - Undernutrition and cachexia have been suggested to be risk factors for postoperative complications and survival in cancer patients. The aim of this study was to investigate whether body mass index (BMI) is related to the short term and long-term outcomes in patients who undergo an esophagectomy for the resection of esophageal squamous cell cancer (ESCC). Three hundred forty patients who underwent an esophagectomy for the resection of ESCC between 2003 and 2008 were retrospectively reviewed. The patients were divided into two groups: an L BMI group characterized by a BMI < 18.5 kg/m(2) and an N-BMI group characterized by a BMI >= 18.5 kg/m(2). Clinical and pathological outcome were compared between groups. The study included 40 patients in the L-BMI group and 300 patients in the N-BMI group. A clinicopathological assessment showed that nodal involvement was seen more frequently in the L-BMI group (P = 0.016). Pulmonary complications seemed to occur more frequently in the L-BMI group (P = 0.006). The 5-year overall survival rate was higher in the N-BMI group (63.6%) than in the L-BMI group (32.3%) (P < 0.001). The 5-year disease-free survival rate was also higher in the N-BMI group (58.0%) than in the L-BMI group (33.6%) (P = 0.001). In multivariate analysis, the BMI (hazard ratio, 2.154; 95% CI, 1.349-3.440, P = 0.001) was found to be an independent prognostic factor for overall survival. Our data suggested that a lower BMI not only increased pulmonary complications but also impaired overall and disease-free survival after an esophagectomy for the resection of ESCC. PMID- 25789404 TI - Impact of recommendations on crushing medications in geriatrics: from prescription to administration. AB - The practice of crushing drugs is very common in geriatric units. In 2009 a first study, performed in all geriatric units of a university hospital, showed that numerous errors were made during prescription, preparation and administration. The aim of this second prospective study was to assess the impact of regional and national recommendations in the same geriatric units. A survey of 719 patients (85.3 +/- 6.7 years) was performed in 2013. For each patient who received crushed drugs, we recorded the reason the drugs were crushed, pharmacological classes, galenic presentations and the technique used for preparation and administration. Results were compared to the previous study. The number of patients receiving drugs after crushing was significantly lower than in the previous study (22.9% vs. 32.3%, P < 0.001). The number of crushed drugs was lower too (594 per 165 patients vs. 966 per 224 patients (P < 0.01). The main indication for crushing drugs remained swallowing disorders. The dosage form prevented crushing in 24.9% of drugs (vs. 42.0% in 2009, P < 0.001), but the drugs generally remained crushed all together. A mortar was used less often (38.6% vs. 92.6%, P < 0.001), with preference for individual-specific cups (56.1%). Mortars were more often cleaned between each patient (56.0% vs. 11.6%). The vehicle was more often neutral (water 88.5% vs. 5.7%, P < 0.001). This second study shows that regional and national recommendations have led to an overall improvement of practices for crushing drugs. Technical improvements are still possible, in association with appropriate pharmacological studies. PMID- 25789405 TI - Role of positively charged residues of the second transmembrane domain in the ion transport activity and conformation of human uncoupling protein-2. AB - Residing at the inner mitochondrial membrane, uncoupling protein-2 (UCP2) mediates proton transport from the intermembrane space (IMS) to the mitochondrial matrix and consequently reduces the rate of ATP synthesis in the mitochondria. The ubiquitous expression of UCP2 in humans can be attributed to the protein's multiple physiological roles in tissues, including its involvement in protective mechanisms against oxidative stress, as well as glucose and lipid metabolisms. Currently, the structural properties and ion transport mechanism of UCP2 and other UCP homologues remain poorly understood. UCP2-mediated proton transport is activated by fatty acids and inhibited by di- and triphosphate purine nucleotides. UCP2 also transports chloride and some other small anions. Identification of key amino acid residues of UCP2 in its ion transport pathway can shed light on the protein's ion transport function. On the basis of our previous studies, the second transmembrane helix segment (TM2) of UCP2 exhibited chloride channel activity. In addition, it was suggested that the positively charged residues on TM2 domains of UCPs 1 and 2 were important for their chloride transport activity. On this basis, to further understand the role of these positively charged residues on the ion transport activity of UCP2, we recombinantly expressed four TM2 mutants: R76Q, R88Q, R96Q, and K104Q. The wild type UCP2 and its mutants were purified and reconstituted into liposomes, and their conformation and ion (proton and chloride) transport activity were studied. TM2 Arg residues at the matrix interface of UCP2 proved to be crucial for the protein's anion transport function, and their absence resulted in highly diminished Cl(-) transport rates. On the other hand, the two other positively charged residues of TM2, located at the UCP2-IMS interface, could participate in the salt-bridge formation in the protein and promote the interhelical tight packing in the UCP2. Absence of these residues did not influence Cl(-) transport rates, but disturbed the dense packing in UCP2 and resulted in higher UCP2 mediated proton transport rates in the presence of long chain fatty acids. Overall, the outcome of this study provides a deeper and more detailed molecular image of UCP2's ion transport mechanism. PMID- 25789406 TI - Mechanistic studies of photoinduced spin crossover and electron transfer in inorganic complexes. AB - Electronic excited-state phenomena provide a compelling intersection of fundamental and applied research interests in the chemical sciences. This holds true for coordination chemistry, where harnessing the strong optical absorption and photocatalytic activity of compounds depends on our ability to control fundamental physical and chemical phenomena associated with the nonadiabatic dynamics of electronic excited states. The central events of excited-state chemistry can critically influence the dynamics of electronic excited states, including internal conversion (transitions between distinct electronic states) and intersystem crossing (transitions between electronic states with different spin multiplicities), events governed by nonadiabatic interactions between electronic states in close proximity to conical intersections, as well as solvation and electron transfer. The diversity of electronic and nuclear dynamics also makes the robust interpretation of experimental measurements challenging. Developments in theory, simulation, and experiment can all help address the interpretation and understanding of chemical dynamics in organometallic and coordination chemistry. Synthesis presents the opportunity to chemically engineer the strength and symmetry of the metal-ligand interactions. This chemical control can be exploited to understand the influence of electronic ground state properties on electronic excited-state dynamics. New time-resolved experimental methods and the insightful exploitation of established methods have an important role in understanding, and ideally controlling, the photophysics and photochemistry of transition metal complexes. Techniques that can disentangle the coupled motion of electrons and nuclear dynamics warrant emphasis. We present a review of electron localization dynamics in charge transfer excited states and the dynamics of photoinitiated spin crossover dynamics. Both electron localization and spin crossover have been investigated by numerous research groups with femtosecond resolution spectroscopy, but challenges in experimental interpretation have left significant uncertainty about the molecular properties that control these phenomena. Our Account will emphasize how tailoring the experimental probe, femtosecond resolution vibrational anisotropy for electron localization, and femtosecond resolution hard X-ray fluorescence for spin crossover can make a significant impact on the interpretability of experimental measurements. The emphasis on thorough and robust interpretation has also led to an emphasis on simpler molecular systems. This enables iteration between experiment and theory, a requirement for the development of a more predictive understanding of electronic excited-state phenomena and an essential step to the development of design rules for solar materials. PMID- 25789407 TI - Prevalence and antimicrobial resistance profile of Staphylococcus species in chicken and beef raw meat in Egypt. AB - Coagulase-positive (CPS) and coagulase-negative (CNS) staphylococci cause staphylococcal food poisoning. Recently, CPS and CNS have received increasing attention due to their potential role in the dissemination of antibiotic resistance markers. The present study aimed to evaluate CPS and CNS species distribution and their antibiotic resistance profile isolated from chicken and beef meat. Fifty fresh, uncooked chicken parts and 50 beef meat cuts (local n=27; imported n=23) were used. One hundred staphylococcal isolates belonging to 11 species were isolated and identified from chicken (n=50) and beef (n=50) raw meat samples. Staphylococcus hyicus (26/100), lugdunensis (18/100), aureus (15/100) and epidermidis (14/100) were dominant. S. aureus was 100% resistant to penicillin and sulfamethoxazole/trimethoprim. Vancomycin-resistant S. aureus showed intermediate resistance (51%), which might indicate the dissemination of vancomycin resistance in the community and imply food safety hazards. The percentage of resistance to beta-lactams was variable, with the highest resistance being to penicillin (94%) and lowest to ampicillin-sulbactam (22%). Antimicrobial resistance was mainly against penicillin (94%), clindamycin (90%) and sulfamethoxazole/trimethoprim (82%). The results indicate that chicken and beef raw meat are an important source of antibiotic-resistant CPS and CNS. PMID- 25789408 TI - Laparoscopic liver resection for intrahepatic cholangiocarcinoma. AB - BACKGROUND: Reports on laparoscopic liver resection for intrahepatic cholangiocarcinoma are still scarce. With increased experience in laparoscopic liver resection, its application to intrahepatic cholangiocarcinoma can now be considered. Our aim is to determine the feasibility and safety of laparoscopic liver resection for intrahepatic cholangiocarcinoma and to analyze its clinical and oncologic outcomes. PATIENTS AND METHODS: Among the 84 patients with intrahepatic cholangiocarcinoma operated on from March 2004 to April 2012, 37 patients with a T-stage of 2b or less were included in the study. Eleven patients underwent laparoscopic liver resection, and 26 underwent open liver resection. Treatment and survival outcomes were analyzed. RESULTS: Intraoperative blood loss was significantly greater in the open group (P=.024), but with no difference in the blood transfusion requirement between groups (P=.074), and no operative mortality occurred. The median operative time, postoperative resection margin, and length of hospital stay were comparable between groups (P=.111, P=.125, and P=.077, respectively). Four (36.4%) patients in the laparoscopic group developed recurrence compared with 12 (46.2%) patients in the open group (P=.583). After a median follow-up of 17 months, the 3- and 5-year overall survival rates were 77.9% and 77.9%, respectively, in the laparoscopic group compared with 66.2% and 66.2%, respectively, in the open group (P=.7). There was also no significant difference in the 3- and 5-year disease-free survival rates for the laparoscopic group at 56.2% and 56.2%, respectively, versus the open group at 39.4% and 39.4%, respectively (P=.688). CONCLUSIONS: Laparoscopic liver resection for intrahepatic cholangiocarcinoma is technically safe with survival outcome comparable to that of open liver resection in selected cases. PMID- 25789409 TI - Quality-of-life issues in survivors to anaphylactic reactions to drugs. AB - The aim of this cross-sectional observational study was to explore quality of life and well-being in patients with drug-induced anaphylaxis. Two validated tools were used: the Drug Hypersensitivity Quality-of-Life Questionnaire (DrHy-Q) and the Psychological General Well-Being Index (PGWBI). Sixty-five patients (13 males) underwent data analysis. The mean DrHy-Q score was 62.82 +/- 12.1. Mean PGWBI score was 64.03 +/- 17.66. DrHy-Q score was significantly correlated with PGWBI total score (r = -0.314; P = 0.011) and with the following domains: Anxiety (r = -0.260; P = 0.036), Depressed mood (r = -0.406; P = 0.001), Positive well being (r = -0.251; P = 0.004), and General Health (r = -0.352; P = 0.004). Compared with the Italian reference population, patients had a significantly reduced PGWBI total and domain score. Our results highlight for the first time how impaired HRQoL and distress commonly feature in survivors to anaphylactic reactions to drug. PMID- 25789410 TI - Aranciamycins I and J, Antimycobacterial Anthracyclines from an Australian Marine Derived Streptomyces sp. AB - Chemical analysis of an Australian marine-derived Streptomyces sp. (CMB-M0150) yielded two new anthracycline antibiotics, aranciamycins I (1) and J (2), as well as the previously reported aranciamycin A (3) and aranciamycin (4). The aranciamycins 1-4, identified by detailed spectroscopic analysis, were noncytotoxic when tested against selected Gram-negative bacteria and fungi (IC50 >30 MUM) and exhibited moderate and selective cytotoxicity against Gram-positive bacteria (IC50 >1.1 MUM) and a panel of human cancer cell lines (IC50 > 7.5 MUM). Significantly, 1-4 were cytotoxic (IC50 0.7-1.7 MUM) against the Mycobacterium tuberculosis surrogate M. bovis bacille Calmette-Guerin. PMID- 25789411 TI - Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F. AB - RATIONALE: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease. OBJECTIVES: To characterize T-cell immunity to the PA antigen outer membrane porin F (OprF) by analyzing immunodominant epitopes in relation to infection status. METHODS: Patients with non-CF bronchiectasis were stratified by frequency of PA isolation. T-cell IFN-gamma immunity to OprF and its immunodominant epitopes was characterized. Patterns of human leukocyte antigen (HLA) restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response, and T-cell activation transcripts. MEASUREMENTS AND MAIN RESULTS: Patients were stratified according to whether PA was never, sometimes (<50%), or frequently (>=50%) isolated from sputum. Patients with frequent PA sputum-positive isolates were more likely to be infected by mucoid PA, and they showed a narrow T-cell epitope response and a relative reduction in Th1 polarizing transcription factors but enhanced immunity with respect to antibody production, innate cytokines, and chemokines. CONCLUSIONS: We have defined the immunodominant, HLA-restricted T-cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity. PMID- 25789412 TI - Increased Network Excitability Due to Altered Synaptic Inputs to Neocortical Layer V Intact and Axotomized Pyramidal Neurons after Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) can produce long lasting cognitive dysfunction. There is typically no cell death and only diffuse structural injury after mTBI. Thus, functional changes in intact neurons may contribute to symptoms. We have previously shown altered intrinsic properties of axotomized and intact neurons within 2 d after a central fluid percussion injury in mice expressing yellow fluorescent protein (YFP) that allow identification of axonal state prior to recording. Here, whole-cell patch clamp recordings were used to examine synaptic properties of YFP(+) layer V pyramidal neurons. An increased frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was recorded from axotomized neurons at 1 d and intact neurons at 2 d after injury, likely reflecting an increased number of afferents. This also was reflected in the increased amplitude of the EPSC evoked by local extracellular stimulation for all neurons from injured cortex and increased likelihood of producing an action potential for intact cells. Field potentials recorded in superficial layers after online deep layer stimulation contained a single negative peak in controls but multiple negative peaks in injured tissue. The amplitude of this evoked negativity was significantly larger than controls over a series of stimulus intensities at both the 1 d and 2 d survival times. Interictal like spikes never occurred in the field potential recordings from controls but were observed in 20-80% of stimulus presentations in injured cortex. Together, these results suggest an overall increase in network excitability and the production of particularly powerful (intact) neurons that have both increased intrinsic and synaptic excitability. PMID- 25789413 TI - Mitochondrial fragmentation in excitotoxicity requires ROCK activation. AB - Mitochondria morphology constantly changes through fission and fusion processes that regulate mitochondrial function, and it therefore plays a prominent role in cellular homeostasis. Cell death progression is associated with mitochondrial fission. Fission is mediated by the mainly cytoplasmic Drp1, which is activated by different post-translational modifications and recruited to mitochondria to perform its function. Our research and other studies have shown that in the early moments of excitotoxic insult Drp1 must be nitrosylated to mediate mitochondrial fragmentation in neurons. Nonetheless, mitochondrial fission is a multistep process in which filamentous actin assembly/disassembly and myosin-mediated mitochondrial constriction play prominent roles. Here we establish that in addition to nitric oxide production, excitotoxicity-induced mitochondrial fragmentation also requires activation of the actomyosin regulator ROCK. Although ROCK1 has been shown to phosphorylate and activate Drp1, experiments using phosphor-mutant forms of Drp1 in primary cortical neurons indicate that in excitotoxic conditions, ROCK does not act directly on Drp1 to mediate fission, but may act on the actomyosin complex. Thus, these data indicate that a wider range of signaling pathways than those that target Drp1 are amenable to be inhibited to prevent mitochondrial fragmentation as therapeutic option. PMID- 25789414 TI - Dynamic Changes in Nociception and Pain Perception After Spinal Cord Stimulation in Chronic Neuropathic Pain Patients. AB - OBJECTIVES: Patients with an implanted spinal cord stimulation (SCS) system for pain management present an opportunity to study dynamic changes in the pain system in a situation where patients are not stimulated (ie, experiencing severe pain) compared with a situation in which patients have just been stimulated (ie, pain free or greatly reduced pain). The aims of this study were (1) to determine if there are differences in nociceptive withdrawal reflex thresholds (NWR-T) and electrical pain thresholds (EP-T) before and after SCS; and (2) to establish if these differences are related to psychological factors associated with chronic pain. METHODS: Seventeen volunteers with chronic neuropathic pain participated in the experiment. Electrical stimuli were applied to assess the NWR-T and the EP-T. In addition, psychological factors (ie, pain characteristics, depression, anxiety, and disability indexes) were also recorded. The NWR-T and EP-T were assessed with the SCS system off (at least 8 h before the experiment), and then reassessed 1 hour after the SCS system was turned on. RESULTS: Ongoing pain intensity ratings decreased (P=0.018), whereas the NWR-T increased (P=0.028) after the SCS was turned on, whereas no significant difference was found for EP-T (P=0.324). Psychological factors were significant predictors for EP-T but not for NWR-T. DISCUSSION: The results of this study suggest that pain relief after SCS is partially mediated by a decrease in the excitability of dorsal horn neurons in the spinal cord. PMID- 25789415 TI - Electrochromic bis(terpyridine)metal complex nanosheets. AB - A series of electrochromic metal complex nanosheets comprising 1,3,5-tris(4 (2,2':6',2"-terpyridyl)phenyl)benzene or 1,3,5-tris((2,2':6',2" terpyridyl)ethynyl)benzene and Fe(2+) or Co(2+) was synthesized. The preparation of multilayered nanosheets was achieved by liquid/liquid interfacial synthesis using an organic ligand solution and an aqueous metal-ion solution. The resultant nanosheet had a flat, smooth morphology and was several hundreds of nanometers thick. Upon its deposition on an indium tin oxide (ITO) electrode, the nanosheet underwent a reversible and robust redox reaction (Fe(3+)/Fe(2+) or Co(2+)/Co(+)) accompanied by a distinctive color change. Electrochromism was achieved in a solidified device composed of the nanosheet, a pair of ITO electrodes, and a polymer-supported electrolyte. The combination of Fe(2+) and Co(2+) nanosheets in one device-deposited on each ITO electrode-demonstrated dual-electrochromic behavior. PMID- 25789416 TI - Genomic evidence for role of inversion 3RP of Drosophila melanogaster in facilitating climate change adaptation. AB - Chromosomal inversion polymorphisms are common in animals and plants, and recent models suggest that alternative arrangements spread by capturing different combinations of alleles acting additively or epistatically to favour local adaptation. It is also thought that inversions typically maintain favoured combinations for a long time by suppressing recombination between alternative chromosomal arrangements. Here, we consider patterns of linkage disequilibrium and genetic divergence in an old inversion polymorphism in Drosophila melanogaster (In(3R)Payne) known to be associated with climate change adaptation and a recent invasion event into Australia. We extracted, karyotyped and sequenced whole chromosomes from two Australian populations, so that changes in the arrangement of the alleles between geographically separated tropical and temperate areas could be compared. Chromosome-wide linkage disequilibrium (LD) analysis revealed strong LD within the region spanned by In(3R)Payne. This genomic region also showed strong differentiation between the tropical and the temperate populations, but no differentiation between different karyotypes from the same population, after controlling for chromosomal arrangement. Patterns of differentiation across the chromosome arm and in gene ontologies were enhanced by the presence of the inversion. These data support the notion that inversions are strongly selected by bringing together combinations of genes, but it is still not clear if such combinations act additively or epistatically. Our data suggest that climatic adaptation through inversions can be dynamic, reflecting changes in the relative abundance of different forms of an inversion and ongoing evolution of allelic content within an inversion. PMID- 25789417 TI - Grafted alpha-hydroxyphosphonic acids onto polymeric supports: preparation, characterization, and antimicrobial effect. AB - The paper deals with the preparation and characterization of compounds with antimicrobial activity: alpha-hydroxyphosphonic acids grafted onto styrene-12% (15%)-divinylbenzene copolymer. These products proved to have antimicrobial effect against two species of gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and two species of gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) and a species of yeast (Candida albicans). Tests showed the reduction of bacterial load at different time intervals during the 18 h of contact. PMID- 25789418 TI - Proton pencil beam scanning for mediastinal lymphoma: the impact of interplay between target motion and beam scanning. AB - The purpose of this study was to assess the feasibility of proton pencil beam scanning (PBS) for the treatment of mediastinal lymphoma. A group of 7 patients of varying tumor size (100-800 cc) were planned using a PBS anterior field. We investigated 17 fractions of 1.8 Gy(RBE) to deliver 30.6 Gy(RBE) to the internal target volume (ITV). Spots with sigma ranging from 4 mm to 8 mm were used for all patients, while larger spots (sigma = 6-16 mm) were employed for patients with motion perpendicular to the beam (?5 mm), based on initial 4-dimensional computed tomography (4D CT) motion evaluation. We considered volumetric repainting such that the same field would be delivered twice in each fraction. The ratio of extreme inhalation amplitude and regular tidal inhalation amplitude (free breathing variability) was quantified as an indicator of potential irregular breathing during the scanning. Four-dimensional dose was calculated on the 4D CT scans based on the respiratory trace and beam delivery sequence, implemented by partitioning the spots into separate plans on each 4D CT phase. Four starting phases (end of inhalation, end of exhalation, middle of inhalation and middle of exhalation) were sampled for each painting and 4 energy switching times (0.5 s, 1 s, 3 s and 5 s) were tested, which resulted in 896 dose distributions for the analyzed cohort. Plan robustness was measured for the target and critical structures in terms of the percent difference between 'delivered' dose (4D evaluated) and planned dose (calculated on average CT). It was found that none of the patients exhibited highly variable or chaotic breathing patterns. For all patients, the ITV D98% was degraded by <2% (standard deviations ~ 0.1%) when averaged over the whole treatment course. For six out of seven patients, the average degradation of ITV D98% per fraction was within 5% . For one patient with motion perpendicular to the beam (?5 mm), the degradation of ITV D98% per fraction was up to 15%, which was mitigated to 2% by employing larger spots and repainting. Deviation of mean lung dose was at most 0.2 Gy(RBE) (less than 1% of prescribed dose, 30.6 Gy(RBE)), while the deviation of heart maximum dose and cord maximum dose could exceed 5% of the prescribed dose. No significant difference in either target coverage or normal tissue dose was observed for different energy switching times compared via two-sided Wilcoxon signed-rank tests (p < 0.05). This feasibility study demonstrates that, for mediastinal lymphoma, the impact of the interplay effect on the PBS plan robustness is minimal when volumetric repainting and/or larger spots are employed. PMID- 25789419 TI - Learning and evolving. AB - It is an honour to present the Anthony Chang lecture at this 10th International Conference of the Pediatric Cardiac Intensive Care Society. I have had the privilege of knowing Dr Chang for over 20 years, and although we only worked for a short period of time together at the Children's Hospital, Boston, in the Cardiac Intensive Care Unit, we have remained close colleagues and friends since that time. The contributions of Dr Chang to the development of paediatric cardiac intensive care are very clear, based on his clinical expertise, research and scholarship, and the development of the Pediatric Cardiac Intensive Care Society in its early days. More than this, Dr Chang is an individual with vision; in many respects, he has been ahead of the curve, anticipating and leading the direction of paediatric cardiac intensive care. PMID- 25789420 TI - A retrospective study of the impact of 21-gene recurrence score assay on treatment choice in node positive micrometastatic breast cancer. AB - To assess clinical utility of the 21-gene assay (Oncotype DX(r) Recurrence Score(r)), we determined whether women with HER2(-)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high scores (>=31). This was a multicenter chart review of >=18 year old women with pN1mi breast cancer, HER2(-)/ER+ tumors, ductal/lobular/mixed histology, with the assay ordered on or after 1 January 2007. One hundred and eighty one patients had a mean age of 60.7 years; 82.9% had ECOG performance status 0; 33.7% had hypertension, 22.7% had osteoporosis, 18.8% had osteoarthritis, and 8.8% had type-2 diabetes. Mean Recurrence Score was 17.8 (range: 0-50). 48.6% had a mastectomy; 55.8% had a lumpectomy. 19.8% of low-risk group patients were recommended chemotherapy vs. 57.9% in the intermediate-risk group and 100% in the high-risk group (p < 0.001). A total of 80.2% of the low risk group were recommended endocrine therapy alone, while 77.8% of the high-risk group were recommended both endocrine and chemotherapy (p < 0.001). The Oncotype DX Recurrence Score result provides actionable information that can be incorporated into treatment planning for women with HER2(-)/ER+ pN1mi breast cancer. The Recurrence Score result has clinical utility in treatment planning for HER2(-)/ER+ pN1mi breast cancer patients. PMID- 25789421 TI - Optimising abdominal space with deep neuromuscular blockade in gynaecologic laparoscopy--a randomised, blinded crossover study. AB - BACKGROUND: Insufflation of the abdomen during laparoscopy improves surgical space, but may cause post-operative shoulder pain. The incidence of shoulder pain is reduced using a lower insufflation pressure, but this may, however, compromise the surgical space. We aimed at investigating whether deep neuromuscular blockade (NMB) would enlarge surgical space, measured as the distance from the sacral promontory to the trocar in patients undergoing gynaecologic laparoscopy. METHODS: Fourteen patients were randomised in an assessor-blinded crossover design. The distance from the sacral promontory to the trocar was measured during deep NMB and without NMB at pneumoperitoneum 8 and 12 mmHg both. Additionally, we assessed surgical conditions while suturing the abdominal fascia using a 4-point subjective rating scale. Deep NMB was established with rocuronium and reversed with sugammadex. RESULTS: At 12 mmHg pneumoperitoneum, deep NMB improved surgical space with a mean of 0.33 cm (95% confidence interval 0.07-0.59) (P=0.01, paired t-test) compared with no NMB. At 8 mmHg pneumoperitoneum deep NMB improved surgical space with a mean of 0.3 cm (95% confidence interval, 0.06-0.54) (P=0.005) compared with no NMB. Deep NMB resulted in significantly better ratings of surgical conditions during suturing of the fascia (P=0.03, Mann-Whitney U test). CONCLUSION: Deep NMB enlarged surgical space measured as the distance from the sacral promontory to the trocar. The enlargement, however, was minor and the clinical significance is unknown. Moreover, deep NMB improved surgical conditions when suturing the abdominal fascia. PMID- 25789422 TI - Cherenkov luminescence imaging in transparent media and the imaging of thin or shallow sources. AB - In this work, we demonstrated the possibility of high spatial resolution Cherenkov luminescence imaging (CLI) for objects in transparent media. We also demonstrated the possibility of the CLI of thin opaque objects using optical transducers. Results demonstrate that submillimeter resolution CLI is achievable for beta-emitting radionuclides, including 76Br that emits positrons of very high energy. The imaging of beta-emitters through scintillation detectors exhibits lower resolution when compared to CLI of the same sources. The application of optical transducers for the CLI was demonstrated using plants labeled with 11CO2 and phantoms containing beta-emitters. PMID- 25789423 TI - Ultrasound-modulated fluorescence based on donor-acceptor-labeled microbubbles. AB - A fluorescence resonance energy transfer (FRET)-based microbubble contrast agent system was designed to experimentally demonstrate the concept of ultrasound modulated fluorescence (UMF). Microbubbles were simultaneously labeled with donor and acceptor fluorophores on the surface to minimize self-quenching and maximize FRET. In response to ultrasound, the quenching efficiency was greatly modulated by changing the distance between the donor and acceptor molecules through microbubble size oscillations. Both donors and acceptors exhibited UMF on individual microbubbles. The UMF strength of the donor was more significant compared to that of the acceptor. Furthermore, the UMF of the donor was observed from a microbubble solution in a turbid media. This study exploits the feasibility of donor-acceptor labeled microbubbles as UMF contrast agents. PMID- 25789424 TI - Impact of age on haematological markers pre- and post-marathon running. AB - This study investigated whether haematological markers differ between young and masters marathon participants, running at similar performance levels. Nine young (31.89 +/- 4.96 years) and eight masters (63.13 +/- 4.61 years) runners participated. At five time points (pre-race through 54 h post-race), a complete blood cell count, basic metabolic panel and creatine kinase (CK) isoenzyme panel were assessed. Race performance was standardised using the World Masters Association Age Grading Performance Tables. Total CK levels were elevated for all participants at all time points post-race (P < 0.001). The CK-isoenzyme MB% was elevated across groups at 6, 30 and 54 h post-race (P < 0.01, P < 0.01 and P < 0.05), with masters runners having a higher CK-MB% at 30 and 54 h (P < 0.05, P < 0.05). Total white blood cell and neutrophil counts were elevated through 6 h post-race (P < 0.001), with higher levels found in younger runners (P < 0.001). When considering all blood work, masters runners had a higher number of abnormal values at 6, 30 and 54 h post-race (P < 0.05, P < 0.01 and P < 0.05). In conclusion, masters runners demonstrated sustained CK-MB elevation, which may suggest greater cardiac stress. However, future studies using additional cardiac markers should be completed to confirm these findings. In addition, masters runners showed an increased number of laboratory values outside normal range, indicating the body's reduced capacity to respond to marathon running. PMID- 25789426 TI - Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms? AB - Neuropathic pain (NP) is a significant medical and socioeconomic burden. Epidemiological surveys have indicated that many patients with NP do not receive appropriate treatment for their pain. A number of pharmacological agents have been found to be effective in NP on the basis of randomized controlled trials including, in particular, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitor antidepressants, pregabalin, gabapentin, opioids, lidocaine patches, and capsaicin high-concentration patches. Evidence-based recommendations for the pharmacotherapy of NP have recently been updated. However, meta-analyses indicate that only a minority of patients with NP have an adequate response to drug therapy. Several reasons may account for these findings, including a modest efficacy of the active drugs, a high placebo response, the heterogeneity of diagnostic criteria for NP, and an inadequate classification of patients in clinical trials. Improving the current way of conducting clinical trials in NP could contribute to reduce therapeutic failures and may have an impact on future therapeutic algorithms. PMID- 25789427 TI - Spinal excitatory mechanisms of pathological pain. AB - An important property of the nociceptive system is its plasticity, ie, the ability to change in an experience-dependent manner, which is implicated in the transition from acute pain to chronic pathological pain. Disease-induced plasticity can occur at both structural and functional levels and manifests as changes in individual molecules, synapses, cellular function, and network activity. In this short review, the author discusses how synaptic plasticity may mediate pathophysiological alterations linked to chronic pain by virtue of shifting the balance between excitation and inhibition, with a particular emphasis on the spinal dorsal horn. In particular, mechanisms of spinal synaptic potentiation and how these are manifest as nociceptive hypersensitivity represent an avenue with recent advances. Structural remodeling and reorganization represent another exciting area of advance in our understanding of pain. Here, new insights into maladaptive structural plasticity of spinal synapses and molecular determinants thereof will be discussed. Finally, the role of synapse-to nucleus communication in mediating long-term changes in nociceptive sensitivity is discussed from the view point of pain chronicity. PMID- 25789428 TI - Palliative care and pain treatment in the global health agenda. AB - The Global Atlas of Palliative Care at the End of Life, published by the Worldwide Palliative Care Alliance (WPCA) jointly with the World Health Organization (WHO) estimated that every year >20 million patients need palliative care (PC) at the end of life. Six percent of these are children. According to the Atlas, in 2011, approximately 3 million patients received PC and only 1 in 10 people in need is currently receiving it. Although most PC is provided in high income countries (HIC), almost 80% of the global need is in low- and middle income countries (LMIC). Only 20 countries have PC well integrated into their health-care systems. In regards to opioids, >5 billion people (83% of the world's population) live in countries with low to nonexistent access, 250 million (4%) have moderate access, and only 460 million (7%) have adequate access. In order for PC and pain treatment strategies to be effective, they must be incorporated by governments into all levels of their health care systems. In 1990, the WHO pioneered a public health strategy to integrate PC into existing health care systems which includes four components: (1) appropriate policies, (2) adequate availability of medications, (3) education of health care workers and the public, and (4) implementation of PC services at all levels throughout the society. This topical review describes the current status of the field, and presents several initiatives by United Nations (UN) organizations and the civil society to improve access to PC and to pain treatment for patients in need. PMID- 25789429 TI - Pharmacotherapy for pain: efficacy and safety issues examined by subgroup analyses. AB - Responses to pharmacotherapy for acute and chronic pain are highly variable, and efficacy is often compromised by some form of toxicity. To increase our understanding of complexities of pharmacotherapy, the authors discuss an approach to identify analgesic responder subgroups and predictors of response. Additionally, analgesic efficacy and toxicity were combined in a single risk benefit index (utility function) to quantify the probability of side effects in high- vs low-analgesic responders. The subgroup analysis consists of a mathematical description or time series analysis, mixture analysis, and covariate analysis. Applied to ketamine treatment of chronic pain in complex regional pain syndrome and capsaicin 8% patch treatment in post-herpetic neuralgia patients, the analyses yielded homogenous subgroups that differed in distribution frequency between treatments. For capsaicine, a high variability in pretreatment pain reporting was associated with a high probability of falling into a full analgesic subgroup, irrespective of treatment. The utility function was applied to opioid induced analgesia and respiratory depression. An important observation was that, irrespective of dose, low-analgesic responders to fentanyl had a greater probability of respiratory depression than analgesia while the reverse was true for high-analgesic responders. These data show dissociation between 2 MU-opioid end-points and explain the danger of treating poor analgesic responders with increasingly higher opioid doses. Apart from being valuable in drug development programs, the outlined approach can be used to determine the choice of drug and dose in the treatment of pain in patients with potent and toxic analgesics. PMID- 25789430 TI - Why are children still crying? Going beyond "evidence" in guideline development to improve pain care for children: the HELPinKIDS experience. AB - The failure to translate research evidence into day-to-day clinical practices is identified as a significant reason for suboptimal quality care across the health system, including procedural pain management in children. Clinical practice guidelines (CPGs) have been developed to assist in this process by synthesizing and interpreting research evidence for end users. Numerous CPGs have been developed for procedural pain management in children, yet gaps persist in the adoption of best practices. This article reviews the experience and approach of 1 guideline development group, the Help ELiminate Pain in KIDS Team (HELPinKIDS), in incorporating implementation considerations and knowledge translation (KT) strategies within the process of guideline development for the HELPinKIDS CPG about childhood vaccination pain management to facilitate greater uptake of the CPG. Specific areas that will be addressed include partnerships with stakeholders, rigor of guideline development, issues of implementation, and editorial independence. The work of HELPinKIDS was guided by a KT map, which identified, at a high level, the target audiences, key messages, tools, and strategies that could be used to communicate, disseminate, and implement the CPG into diverse settings. Examples of impact at both the individual and systems levels from HELPinKIDS KT activities are also presented. PMID- 25789431 TI - Learning mechanisms in pain chronification--teachings from placebo research. AB - This review presents a general model for the understanding of pain, placebo, and chronification of pain in the framework of cognitive neuroscience. The concept of a computational cost-function underlying the functional imaging responses to placebo manipulations is put forward and demonstrated to be compatible with the placebo literature including data that demonstrate that placebo responses as seen on the behavioural level may be elicited on all levels of the neuroaxis. In the same vein, chronification of pain is discussed as a consequence of brain mechanisms for learning and expectation. Further studies are necessary on the reversal of chronic pain given the weak effects of treatment but also due to alarming findings that suggest morphological changes in the brain pain regulatory systems concurrent with the chronification process. The burden of chronic pain is devastating both on the individual level and society level and affects more than one-quarter of the world's population. Women are greatly overrepresented in patients with chronic pain. Hence, both from a general standpoint and from reasons of health equity, it is of essence to advance research and care efforts. Success in these efforts will only be granted with better theoretical concepts of chronic pain mechanisms that maps into the framework of cognitive neuroscience. PMID- 25789433 TI - Role of endogenous pain modulation in chronic pain mechanisms and treatment. AB - Development and application of psychophysical test paradigms to assess endogenous pain modulation in healthy controls and in patients yielded large body of data over the last 2 decades. These tests can assist in predicting pain acquisition, in characterizing pain syndromes and related dysfunctions of pain modulation, and in predicting response to treatment. This chapter reviews the development of thought on pain modulation in the clinical setup, focusing on conditioned pain modulation, and update on accumulated data regarding the mechanism, protocols of administration, and applications in the clinic. PMID- 25789434 TI - What pain tells us about cancer. AB - Cancer pain sends a message. It is frightening to the patient. It heralds progression or recurrence to the oncologist. It is a biological readout of the cancer-nerve interaction for the scientist. Nerves have been considered bystanders within the cancer microenvironment. However, emerging information suggests that nerves are recruited and participate in the carcinogenic process. These newly formed fibers respond to mediators secreted by constituents of the cancer microenvironment. In this manner, these nerves serve as bellwethers and sensors embedded within the cancer. When we rigorously assess patients' cancer pain, we gain insight into the action of cancer. An enhanced understanding of cancer pain offers biological questions that if answered might not only provide relief from cancer pain but might also improve survival. PMID- 25789435 TI - Social modulation of and by pain in humans and rodents. AB - The social domain of the biopsychosocial model of pain has been greatly understudied compared with the biological and psychological domains but holds great promise for furthering our understanding, and better treatment, of pain. Recent years have seen an explosion of interest in social neuroscience and have revealed the ability of pain stimuli to alter social interactions. These experiments suggest that rodents are capable of producing simplified versions of any number of social phenomena involving empathy, previously thought to be the sole province of human beings. This review describes the state of science in both humans and nonhuman animals, and notes intriguing parallels in observations from both species. Indeed, my laboratory is starting to demonstrate perfectly translatable findings regarding social modulation of pain in rodents and humans. PMID- 25789432 TI - Lipid kinases as therapeutic targets for chronic pain. AB - Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal excitability. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, the focus has shifted toward targeting downstream convergence points of nociceptive signaling. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2), are attractive targets, as these molecules are required for signaling downstream of G-protein-coupled receptors and receptor tyrosine kinases. Furthermore, PIP2 regulates the activity of various ion channels. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels, and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons. PMID- 25789438 TI - From migraine genes to mechanisms. AB - Migraine is a common multifactorial episodic brain disorder with strong genetic basis. Monogenic subtypes include rare familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, familial advanced sleep-phase syndrome (FASPS), and retinal vasculopathy with cerebral leukodystrophy. Functional studies of disease-causing mutations in cellular and/or transgenic models revealed enhanced (glutamatergic) neurotransmission and abnormal vascular function as key migraine mechanisms. Common forms of migraine (both with and without an aura), instead, are thought to have a polygenic makeup. Genome-wide association studies have already identified over a dozen genes involved in neuronal and vascular mechanisms. Here, we review the current state of molecular genetic research in migraine, also with respect to functional and pathway analyses. We will also discuss how novel experimental approaches for the identification and functional characterization of migraine genes, such as next-generation sequencing, induced pluripotent stem cell, and optogenetic technologies will further our understanding of the molecular pathways involved in migraine pathogenesis. PMID- 25789437 TI - Imaging brain mechanisms in chronic visceral pain. AB - Chronic visceral pain syndromes are important clinical problems with largely unmet medical needs. Based on the common overlap with other chronic disorders of visceral or somatic pain, mood and affect, and their responsiveness to centrally targeted treatments, an important role of central nervous system in their pathophysiology is likely. A growing number of brain imaging studies in irritable bowel syndrome, functional dyspepsia, and bladder pain syndrome/interstitial cystitis has identified abnormalities in evoked brain responses, resting state activity, and connectivity, as well as in gray and white matter properties. Structural and functional alterations in brain regions of the salience, emotional arousal, and sensorimotor networks, as well as in prefrontal regions, are the most consistently reported findings. Some of these changes show moderate correlations with behavioral and clinical measures. Most recently, data-driven machine-learning approaches to larger data sets have been able to classify visceral pain syndromes from healthy control subjects. Future studies need to identify the mechanisms underlying the altered brain signatures of chronic visceral pain and identify targets for therapeutic interventions. PMID- 25789439 TI - Pain and sleep in post-concussion/mild traumatic brain injury. AB - Concussion after a force to the head is called mild traumatic brain injury (mTBI). Approximately 1 in 5 patients with mTBI will develop chronic pain (headache and widespread pain, possibly of central origin) and/or sleep problems (insomnia, disordered breathing, periodic limb movements). However, the predisposing mechanisms for chronic pain in patients with mTBI are unknown. Mild traumatic brain injury is a rare model to prospectively assess the risk factors and mechanisms for pain chronification from the injury onset in the absence of pretrauma comorbidity or medication. In the acute phase, headaches and sleep disturbances seem to predict the poorest long-term cognitive and mood outcomes. Although recent studies suggest that certain brain biomarkers and mood alterations (eg, anxiety, depression) contribute, the causality of chronic pain remains unclear. In mTBI patients with pain, poor sleep quality was correlated with fast beta and gamma electroencephalographic activity in frontal, central, and occipital electroencephalographic (EEG) derivations in all sleep stages. Sleep recuperative function seems to be disturbed by persistent wake EEG activity, corroborating patient complaints such as feeling awake when asleep. Pain and sleep management in mTBI is not yet evidence-based. Treatments include cognitive behavioral and light therapies, medications, and continuous positive airway pressure (CPAP) or oral appliances for disordered sleep breathing. Customized approaches are indicated for mTBI, pain, and sleep complaints. Further studies in pediatric, sport, and transportation populations are needed to prevent TBI chronification. Improvements are emerging in biomarker sensitivity and specificity and management strategies for TBI, pain, and sleep comorbidities. PMID- 25789440 TI - Learning to predict and control harmful events: chronic pain and conditioning. AB - Pain is a biologically relevant signal and response to bodily threat, associated with the urge to restore the integrity of the body. Immediate protective responses include increased arousal, selective attention, escape, and facial expressions, followed by recuperative avoidance and safety-seeking behaviors. To facilitate early and effective protection against future bodily threat or injury, learning takes place rapidly. Learning is the observable change in behavior due to events in the internal and external environmental and includes nonassociative (habituation and sensitization) and associative learning (Pavlovian and operant conditioning). Once acquired, these knowledge representations remain stored in memory and may generalize to perceptually or functionally similar events. Moreover, these processes are not just a consequence of pain; they may directly influence pain perception. In contrast to the rapid acquisition of learned responses, their extinction is slow, fragile, context dependent and only occurs through inhibitory processes. Here, we review features of associative forms of learning in humans that contribute to pain, pain-related distress, and disability and discuss promising future directions. Although conditioning has a long and honorable history, a conditioning perspective still might open new windows on novel treatment modalities that facilitate the well-being of individuals with chronic pain. PMID- 25789441 TI - Complex regional pain syndrome-significant progress in understanding. AB - Research into complex regional pain syndrome (CRPS) has made significant progress. First, there was the implementation of the official IASP "Budapest" diagnostic criteria. It would be desirable to also define exclusion and outcome criteria that should be reported in studies. The next step was to recognize the complex pathophysiology. After trauma, some inflammation is physiological; in acute CRPS, this inflammation persists for months. There is an abundance of inflammatory and a lack of anti-inflammatory mediators. This proinflammatory network (cytokines and probably also other mediators) sensitizes the peripheral and spinal nociceptive system, it facilitates the release of neuropeptides from nociceptors inducing the visible signs of inflammation, and it stimulates bone cell or fibroblast proliferation, and endothelial dysfunction leading to vascular changes. Trauma may also expose nervous system structures to the immune system and triggers autoantibodies binding to adreno- and acetylcholine receptors. In an individual time frame, the pain in this inflammatory phase pushes the transition into "centralized" CRPS, which is dominated by neuronal plasticity and reorganization. Sensory-motor integration becomes disturbed, leading to a loss of motor function; the body representation is distorted leading to numbness and autonomic disturbances. In an attempt to avoid pain, patients neglect their limb and learn maladaptive nonuse. The final step will be to assess large cohorts and to analyze these data together with data from public resources using a bioinformatics approach. We could then develop diagnostic toolboxes for individual pathophysiology and select focused treatments or develop new ones. PMID- 25789442 TI - Can Producing Oil Store Carbon? Greenhouse Gas Footprint of CO2EOR, Offshore North Sea. AB - Carbon dioxide enhanced oil recovery (CO2EOR) is a proven and available technology used to produce incremental oil from depleted fields while permanently storing large tonnages of injected CO2. Although this technology has been used successfully onshore in North America and Europe, there are currently no CO2EOR projects in the United Kingdom. Here, we examine whether offshore CO2EOR can store more CO2 than onshore projects traditionally have and whether CO2 storage can offset additional emissions produced through offshore operations and incremental oil production. Using a high-level Life Cycle system approach, we find that the largest contribution to offshore emissions is from flaring or venting of reproduced CH4 and CO2. These can already be greatly reduced by regulation. If CO2 injection is continued after oil production has been optimized, then offshore CO2EOR has the potential to be carbon negative--even when emissions from refining, transport, and combustion of produced crude oil are included. The carbon intensity of oil produced can be just 0.056-0.062 tCO2e/bbl if flaring/venting is reduced by regulation. This compares against conventional Saudi oil 0.040 tCO2e/bbl or mined shale oil >0.300 tCO2e/bbl. PMID- 25789436 TI - Effect of environment on the long-term consequences of chronic pain. AB - Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum but has varied comorbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that lifestyle choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by nonpharmacological interventions. PMID- 25789443 TI - DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. AB - In response to various inflammatory stimuli, neutrophils secrete neutrophil extracellular traps (NETs), web-like meshworks of DNA, histones and granular components forming supplementary scaffolds in venous and arterial thrombi. Isolated DNA and histones are known to promote thrombus formation and render fibrin clots more resistant to mechanical forces and tissue-type plasminogen activator (tPA)-induced enzymatic digestion. The present study extends our earlier observations to a physiologically more relevant environment including plasma clots and NET-forming neutrophils. A range of techniques was employed including imaging (scanning electron microscopy (SEM), confocal laser microscopy, and photoscanning of macroscopic lysis fronts), clot permeability measurements, turbidimetric lysis and enzyme inactivation assays. Addition of DNA and histones increased the median fibre diameter of plasma clots formed with 16 nM thrombin from 108 to 121 and 119 nm, respectively, and decreased their permeability constant from 6.4 to 3.1 and 3.7*10(-9) cm(2). Histones effectively protected thrombin from antithrombin-induced inactivation, while DNA inhibited plasminogen activation on the surface of plasma clots and their plasmin-induced resolution by 20 and 40 %, respectively. DNA and histones, as well as NETs secreted by phorbol myristate-acetate-activated neutrophils, slowed down the tPA-driven lysis of plasma clots and the latter effect could be reversed by the addition of DNase (streptodornase). SEM images taken after complete digestion of fibrin in NET containing plasma clots evidenced retained NET scaffold that was absent in DNase treated clots. Our results show that DNA and histones alter the fibrin architecture in plasma clots, while NETs contribute to a decreased lytic susceptibility that can be overcome by DNase. PMID- 25789444 TI - Hydration Status over 24-H Is Not Affected by Ingested Beverage Composition. AB - OBJECTIVE: To investigate the 24-h hydration status of healthy, free-living, adult males when given various combinations of different beverage types. METHODS: Thirty-four healthy adult males participated in a randomized, repeated-measures design in which they consumed: water only (treatment A), water+cola (treatment B), water+diet cola (treatment C), or water+cola+diet cola+orange juice (treatment D) over a sedentary 24-h period across four weeks of testing. Volumes of fluid were split evenly between beverages within each treatment, and when accounting for food moisture content and metabolic water production, total fluid intake from all sources was equal to 35 +/- 1 ml/kg body mass. Urine was collected over the 24-h intervention period and analyzed for osmolality (Uosm), volume (Uvol) and specific gravity (USG). Serum osmolality (Sosm) and total body water (TBW) via bioelectrical impedance were measured after the 24-h intervention. RESULTS: 24-h hydration status was not different between treatments A, B, C, and D when assessed via Uosm (590 +/- 179; 616 +/- 242; 559 +/- 196; 633 +/- 222 mOsm/kg, respectively) and Uvol (1549 +/- 594; 1443 +/- 576; 1690 +/- 668; 1440 +/- 566 ml) (all p > 0.05). A -difference in 24-h USG was observed between treatments A vs. D (1.016 +/- 0.005 vs. 1.018 +/- 0.007; p = 0.049). There were no differences between treatments at the end of the 24-h with regard to Sosm (291 +/- 4; 293 +/- 5; 292 +/- 5; 293 +/- 5 mOsm/kg, respectively) and TBW (43.9 +/- 5.9; 43.8 +/- 6.0; 43.7 +/- 6.1; 43.8 +/- 6.0 kg) (all p > 0.05). CONCLUSIONS: Regardless of the beverage combination consumed, there were no differences in providing adequate hydration over a 24-h period in free-living, healthy adult males. This confirms that beverages of varying composition are equally effective in hydrating the body. PMID- 25789445 TI - The role of ghrelin on apoptosis, cell proliferation and oxidant-antioxidant system in the liver of neonatal diabetic rats. AB - Ghrelin is a multifunctional peptide hormone which stimulates appetite and regulates glucose metabolism and adipogenesis. The purpose of this study was to investigate whether ghrelin has protective effects in the liver of streptozocin (STZ) diabetic rats or not. Wistar-type neonatal rats were divided into four groups: I. Controls, II. Ghrelin administrated controls, III. STZ-diabetic rats, and IV. Ghrelin administrated diabetic rats. On the second day after birth, 100 mg/kg STZ was administered intraperitoneally in a single dose to induce diabetes in rats. 100 ug/kg/day ghrelin was administrated to rats subcutaneously for 4 weeks. Ghrelin administration improved histopathologic changes in STZ-diabetic liver. Obestatin immunoreactivity has been shown in livers of neonatal rats. The immunoreactivity of obestatin increased in diabetic rats and a decline was observed in ghrelin administrated diabetic rats. Caspase 8 and 3 immunoreactivities increased in diabetic rats; however, ghrelin administration differently affected caspases 8 and 3 immunoreactivities. Proliferating cell nuclear antigen immunoreactivities decreased in diabetic rats and in ghrelin administrated diabetic rats. Serum alanine (P < 0.05) and aspartate transaminase (P < 0.0001) and serum alkaline phosphatase (P < 0.0001) activities were decreased in ghrelin administrated diabetic rats compared to the diabetic rats. Gamma glutamyl transferase activity (P < 0.001) decreased in ghrelin administrated diabetic rats compared to the diabetic rats. The response of antioxidants including glutathione levels, catalase and superoxide dismutase activities were altered in ghrelin administrated diabetic rats. Our findings indicate that ghrelin administration affects hepatic functions in neonatal diabetic rats and might be considered as a therapeutic agent. PMID- 25789446 TI - Erratum: Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis. PMID- 25789447 TI - The effect of days since last concussion and number of concussions on cognitive functioning in Division I athletes. AB - OBJECTIVE: Cognitive recovery from sports concussion may be incomplete after resolution of other symptoms. It was hypothesized that independent effects of the number of days since last concussion (Days) and total number of concussions (Number) would predict poorer cognitive functioning. METHODS AND PROCEDURES: Cognition was assessed in an NCAA Division I student-athlete population (n = 87) using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery. In a MANOVA, the five ImPACT Composite scores were dependent variables, with Group (Concussion, Unaffected) as the independent variable and prior number of concussions (Number) and days since last concussion (Days; 68-2495 days) entered as covariates. OUTCOMES AND RESULTS: The hypothesis that Days and Number would each independently affect cognitive functioning (as assessed by ImPACT Composite scores) was only partly supported. A significant, multivariate, main effect of Days (p = 0.01) indicated that more Days predicted better cognitive functioning overall (p = 0.01). Univariate effects emerged such that more Days specifically predicted better visual memory (p = 0.004) and faster reaction times (p = 0.02). A trend toward a Group*Days*Number three-way interaction for reaction time emerged (p = 0.06), such that smaller Number and more Days each predicted slower reaction time. CONCLUSIONS: Cognitive recovery following sports concussion may take far longer than was previously thought, the aetiology of cognitive reductions may be very complex and the ImPACT appears to be sensitive to subtle changes in cognition across time. PMID- 25789448 TI - The Orbit and the Brain--Reply. PMID- 25789449 TI - Mesityl phenanthroline-modified 2'-deoxyuridine for heteroleptic complexes in metal ion-mediated assembly of DNA. AB - The synthesis of a new DNA building block that bears the metal ion ligand 2,9-bis mesityl-3-ethynyl-phenanthroline attached to the 5-position of 2'-deoxyuridine is presented. In the presence of Zn(2+), Cu(2+), Fe(2+) and Ni(2+) the complex formation of an accordingly modified DNA double strand with a second DNA duplex bearing the 2,2':6',2''-terpyridine ligand was studied by optical spectroscopy. The selective formation of heteroleptic assemblies between the two different DNA pieces was evidenced by denaturing polyacrylamide gel electrophoresis. PMID- 25789450 TI - Future directions in high-pressure neutron diffraction. AB - The ability to manipulate structure and properties using pressure has been well known for many centuries. Diffraction provides the unique ability to observe these structural changes in fine detail on lengthscales spanning atomic to nanometre dimensions. Amongst the broad suite of diffraction tools available today, neutrons provide unique capabilities of fundamental importance. However, to date, the growth of neutron diffraction under extremes of pressure has been limited by the weakness of available sources. In recent years, substantial government investments have led to the construction of a new generation of neutron sources while existing facilities have been revitalized by upgrades. The timely convergence of these bright facilities with new pressure-cell technologies suggests that the field of high-pressure (HP) neutron science is on the cusp of substantial growth. Here, the history of HP neutron research is examined with the hope of gleaning an accurate prediction of where some of these revolutionary capabilities will lead in the near future. In particular, a dramatic expansion of current pressure-temperature range is likely, with corresponding increased scope for extreme-conditions science with neutron diffraction. This increase in coverage will be matched with improvements in data quality. Furthermore, we can also expect broad new capabilities beyond diffraction, including in neutron imaging, small angle scattering and inelastic spectroscopy. PMID- 25789451 TI - The science of salt: a systematic review of clinical salt studies 2013 to 2014. AB - The authors provided a systematic review of the clinical and population health impact of increased dietary salt intake during 1 year. Randomized controlled trials or cohort studies or meta-analyses on the effect of sodium intake were examined from Medline searches between June 2013 to May 2014. Quality indicators were used to select studies that were relevant to clinical and public health. A total of 213 studies were reviewed, of which 11 (n=186,357) were eligible. These studies confirmed a causal relationship between increasing dietary salt and increased blood pressure and an association between several adverse health outcomes and increased dietary salt. A new association between salt intake and renal cell cancer was published. No study that met inclusion criteria found harm from lowering dietary salt. The findings of this systematic review are consistent with previous data relating increased dietary salt to increased blood pressure and adverse health outcomes. PMID- 25789452 TI - Perioperative enhanced recovery programmes for gynaecological cancer patients. AB - BACKGROUND: Gynaecological malignancies contribute to 10% to 15% of cancers in women internationally. In recent years, a trend towards new perioperative care strategies has been documented as 'Fast Track (FT) surgery', or 'Enhanced Recovery Programmes' to replace some traditional approaches in surgical care. The FT multimodal programmes may enhance the postoperative recovery by means of reducing surgical stress. This systematic review aims to assess fully the beneficial and harmful effects of FT programmes in gynaecological cancer care. OBJECTIVES: To evaluate the beneficial and harmful effects of FT programmes in gynaecological cancer care. SEARCH METHODS: We searched the following databases, The Cochrane Gynaecological Cancer Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 4, 2009, MEDLINE and EMBASE to November 2009. In addition, all reference lists of included trials were searched and experts in the gynaecological oncology community were contacted in an attempt to locate trials. This search was updated and re-run in May 2012 and November 2014. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing any type of FT programmes for surgery in gynaecological cancer to conventional recovery strategies were included. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion. Since no RCTs were identified, data collection and analysis could not be performed. MAIN RESULTS: No studies were identified that met the inclusion criteria. AUTHORS' CONCLUSIONS: We currently have no evidence from high-quality studies to support or refute the use of perioperative enhanced recovery programmes for gynaecological cancer patients. Further well-designed RCTs with standard FT programmes are needed. This review has been updated in 2012 and 2014. The results of the original review published in 2010 remain unchanged. PMID- 25789453 TI - Arginase 1 activity worsens lung-protective immunity against Streptococcus pneumoniae infection. AB - Type 2 helper cell (Th2) dominated chronic lung diseases such as asthma are characterized by an increased risk for bacterial lung infections. However, the underlying mechanisms are poorly defined. Arginase 1 (Arg1) has been suggested to play an important role in the pathophysiology of asthma, and is rapidly induced in lung macrophages by Th2 cytokines, thereby limiting macrophage-derived antimicrobial nitric oxide (NO) production. Here we examined the effect of Th2 cytokine induced upregulation or lung myeloid cell specific conditional knockdown of Arg1 on lung resistance against Streptococcus pneumoniae (Spn) in mice. Lung macrophages responded with a profound induction of Arg1 mRNA and protein to treatment with IL-13 both in vitro and in vivo. IL-13-induced Arg1 activity in the lungs of mice led to significantly attenuated lung-protective immunity against Spn, while conditional Arg1 knockdown had no effect on lung-protective immunity against Spn. Collectively, the data show that Th2 cytokine induced increased Arg1 activity worsens lung-protective immunity against Spn, and interventions to block Th2 cytokine induced lung Arg1 activity may thus be a novel immunomodulatory strategy to lower the risk of bacterial infections in asthmatic patients. PMID- 25789455 TI - Spatial distribution of lead in Sacramento, California, USA. AB - Chronic exposure to lead remains a health concern in many urban areas; Sacramento, California is one example, with state surveillance data showing nearly 3% of screened children reported with blood lead levels over 4.5 MUg/dL in 2009. To investigate the environmental exposure, 91 soil samples were collected and analyzed by ICP-AES and ICP-MS for 14 elements. An additional 28 samples were collected from areas of focus and analyzed by hand-held X-ray fluorescence spectrometry for Pb and Zn. Analysis of the metals data revealed non-normal distributions and positive skewness, consistent with anthropogenic input. In addition, high correlation coefficients (>=0.75) of metal concentrations in Cd Pb, Cd-Zn, Pb-Zn, and Sb-Sn pairs suggest similarities in the input mechanisms. Semivariograms generated from Pb and associated metals reveal these metals to exhibit spatial correlation. A prediction map of lead concentrations in soil was generated by ordinary kriging, showing elevated concentrations in soil located in the central, older area of Sacramento where historic traffic density and industrial activity have been historically concentrated. XRF analysis of Pb and Zn from additional samples verifies elevated concentrations in the central areas of Sacramento as predicted. PMID- 25789456 TI - Community trial on heat related-illness prevention behaviors and knowledge for the elderly. AB - This study aims to explore whether broadcasting heat health warnings (HHWs), to every household and whether the additional home delivery of bottled water labeled with messages will be effective in improving the behaviors and knowledge of elderly people to prevent heat-related illness. A community trial on heat-related illness-prevention behaviors and knowledge for people aged between 65 and 84 years was conducted in Nagasaki, Japan. Five hundred eight subjects were selected randomly from three groups: heat health warning (HHW), HHW and water delivery (HHW+W), and control groups. Baseline and follow-up questionnaires were conducted in June and September 2012, respectively. Of the 1524 selected subjects, the 1072 that completed both questionnaires were analyzed. The HHW+W group showed improvements in nighttime AC use (p=0.047), water intake (p=0.003), cooling body (p=0.002) and reduced activities in heat (p=0.047) compared with the control, while the HHW group improved hat or parasol use (p=0.008). An additional effect of household water delivery was observed in water intake (p=0.067) and cooling body (p=0.095) behaviors. HHW and household bottled water delivery improved heat related-illness-prevention behaviors. The results indicate that home water delivery in addition to a HHW may be needed to raise awareness of the elderly. PMID- 25789457 TI - The components of self-perceived health in the Kailali district of Nepal: a cross sectional survey. AB - Self-perceived health is a health measure with well-established links with mortality, healthcare services utilization, and future health. Various components of self-perceived health have been identified in different populations. In this study, we aimed to investigate the components of self-perceived health in a Nepali population. This was a cross-sectional survey conducted in the Kailali district of Nepal in 2014. The sample was initially consisted of 309 households, representative of the population of one municipality and one village; however, 304 participants were included in the analyses. Information on socio-demographic characteristics, health condition, satisfaction with healthcare services, psychological factors, and health behaviors was extracted. Logistic regression analyses were carried out to identify putative components of self-perceived health. Among the 304 respondents, 244 (80.3%) and 60 (19.7%) perceived their health as good and poor, respectively. Middle age and lower satisfaction with healthcare services were associated with worse self-perceived health, accounting for 10.3% of variance. No regular exercise, drinking, smoking, and being unhappy were also related with worse self-perceived health, after adjustment for age and satisfaction level. In the final model, however, drinking status did not significantly contribute. Our findings support previous findings that individuals with positive health behaviors and psychological wellbeing are more likely to perceive their health better. This study may direct public health policies toward more targeted interventions. PMID- 25789458 TI - The Feasibility, Accuracy, and Impact of Xpert MTB/RIF Testing in a Remote Aboriginal Community in Canada. AB - BACKGROUND: Xpert MTB/RIF testing for Mycobacterium tuberculosis and rifampin resistance is being used extensively in countries with a high burden of TB. However, recent evidence suggests that it may not have the same accuracy or impact in high-income, low-burden TB countries. METHODS: A prospective, pragmatic study was done between March 2012 and March 2014 to determine the feasibility, accuracy, and impact on TB disease management provided by the Xpert test in a remote, medically underserved, predominantly Inuit population in Iqaluit, Nunavut, Canada. RESULTS: A total of 453 Xpert tests were run on sputum samples from 344 patients with suspected TB. Twenty-seven patients were identified as having active TB disease by culture. There were no cases of drug-resistant TB. Using culture as the gold standard, one Xpert test compared with one, two, or three sputum samples cultured per patient had a sensitivity of 85% (95% CI, 66% 95%) and a specificity of 99% (95% CI, 97%-100%) for detection of M tuberculosis. The indeterminate rate was 4.4% of all samples run. Treatment initiation was significantly shortened using Xpert vs the national standard of three smears (1.8 days vs 7.7 days, P < .007) and particularly shorter in smear-negative, culture positive cases (1.8 days vs 37.1 days, P < .008). CONCLUSIONS: In a predominantly Inuit population in a remote region of Canada where the burden of TB is high and no TB testing facilities are available, onsite Xpert testing was feasible and accurate and shortened the time to TB treatment initiation. PMID- 25789459 TI - Cell uptake, intracellular distribution, fate and reactive oxygen species generation of polymer brush engineered CeO(2-x) NPs. AB - Cerium Oxide nanoparticles (CeO(2-x) NPs) are modified with polymer brushes of negatively charged poly (3-sulfopropylmethacrylate) (PSPM) and positively charged poly (2-(methacryloyloxy)ethyl-trimethylammonium chloride) (PMETAC) by Atom Transfer Radical Polymerisation (ATRP). CeO(2-x) NPs are fluorescently labelled by covalently attaching Alexa Fluor(r) 488/Fluorescein isothiocyanate to the NP surface prior to polymerisation. Cell uptake, intracellular distribution and the impact on the generation of intracellular Reactive Oxygen Species (ROS) with respect to CeO(2-x) NPs are studied by means of Raman Confocal Microscopy (CRM), Transmission Electron Microscopy (TEM) and Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). PSPM and PMETAC coated CeO(2-x) NPs show slower and less uptake compared to uncoated Brush modified NPs display a higher degree of co localisation with cell endosomes and lysosomes after 24 h of incubation. They also show higher co-localisation with lipid bodies when compared to unmodified CeO(2-x) NPs. The brush coating does not prevent CeO(2-x) NPs from displaying antioxidant properties. PMID- 25789460 TI - Fully laparoscopic left-sided donor hepatectomy is safe and associated with shorter hospital stay and earlier return to work: A comparative study. AB - Living donor liver transplantation has failed to become a major means of transplantation in the United States, where <5% of the transplants are performed with living donors. At least 30% to 50% of the complications of donor hepatectomy appear to be related to abdominal wall trauma, including hernia, bowel obstruction, and chronic abdominal discomfort. We analyzed our experience with laparoscopically procured donor hepatectomy. We compared 22 full laparoscopic donor hepatectomies to 20 open/hybrid hepatectomies over an 11-year period. Donor and recipient demographics, complications, and graft and recipient outcomes were analyzed. All 22 laparoscopically procured liver allografts were transplanted successfully. The laparoscopically procured grafts took longer to procure (7 hours 58 minutes versus 6 hours 38 minutes; P < 0.001). The laparoscopically procured cases had lower blood loss (177.3 versus 3753 cc; P < 0.001), a shorter length of stay, and significantly reduced days off work (P = .01). The 1-year graft survival was not different (90% in the laparoscopic group and 85% in the open group; P = 0.70). The 1-year patient survival was not different (95% in the laparoscopic group and 85% in the open group; P = 0.32). There was a trend toward lower wound issues in the laparoscopic group, but this did not reach significance (the hybrid/open group had a 15% hernia rate versus 5% for the laparoscopic group). In experienced living donor centers, laparoscopic liver donation appears to be feasible for all pediatric recipients and some adult recipients. Outcomes for the recipients of laparoscopically procured grafts do not appear significantly different from outcomes with hybrid/open techniques. PMID- 25789461 TI - Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction. AB - Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease. PMID- 25789462 TI - Fabrication of buckling free ultrathin silicon membranes by direct bonding with thermal difference. AB - An innovative method to fabricate large area (up to several squared millimeters) ultrathin (100 nm) monocrystalline silicon (Si) membranes is described. This process is based on the direct bonding of a silicon-on-insulator wafer with a preperforated silicon wafer. The stress generated by the thermal difference applied during the bonding process is exploited to produce buckling free silicon nanomembranes of large areas. The thermal differences required to achieve these membranes (>=1 mm(2)) are estimated by analytical calculations. An experimental study of the stress achievable by direct bonding through two specific surface preparations (hydrophobic or hydrophilic) is reported. Buckling free silicon nanomembranes secured on a 2 * 2 cm(2) frame with lateral dimensions up to 5 * 5 mm(2) are successfully fabricated using the optimized direct bonding process. The stress estimated by theoretical analysis is confirmed by Raman measurements, while the flatness of the nanomembranes is demonstrated by optical interferometry. The successful fabrications of high resolution (50 nm half pitch) tungsten gratings on the silicon nanomembranes and of focused ion beam milling nanostructures show the promising potential of the Si membranes for X-ray optics and for the emerging nanosensor market. PMID- 25789463 TI - An in-depth assessment into simultaneous monitoring of dissolved reactive phosphorus (DRP) and low-molecular-weight organic phosphorus (LMWOP) in aquatic environments using diffusive gradients in thin films (DGT). AB - Long-term laborious and thus costly monitoring of phosphorus (P) fractions is required in order to provide reasonable estimates of the levels of bioavailable phosphorus for eutrophication studies. A practical solution to this problem is the application of passive samplers, known as Diffusive Gradient in Thin films (DGTs), providing time-average concentrations. DGT, with the phosphate adsorbent Fe-oxide based binding gel, is capable of collecting both orthophosphate and low molecular weight organic phosphorus (LMWOP) compounds, such as adenosine monophosphate (AMP) and myo-inositol hexakisphosphate (IP6). The diffusion coefficient (D) is a key parameter relating the amount of analyte determined from the DGT to a time averaged ambient concentration. D at 20 degrees C for AMP and IP6 were experimentally determined to be 2.9 * 10(-6) cm(2) s(-1) and 1.0 * 10( 6) cm(2) s(-1), respectively. Estimations by conceptual models of LMWOP uptake by DGTs indicated that this fraction constituted more than 75% of the dissolved organic phosphorus (DOP) accumulated. Since there is no one D for LMWOP, a D range was estimated through assessment of D models. The models tested for estimating D for a variety of common LMWOP molecules proved to be still too uncertain for practical use. The experimentally determined D for AMP and IP6 were therefore used as upper and lower D, respectively, in order to estimate minimum and maximum ambient concentrations of LMWOP. Validation of the DGT data was performed by comparing concentrations of P fractions determined in natural water samples with concentration of P fractions determined using DGT. Stream water draining three catchments with different land-use (forest, mixed and agriculture) showed clear differences in relative and absolute concentrations of dissolved reactive phosphorus (DRP) and dissolved organic P (DOP). There was no significant difference between water sample and DGT DRP (p > 0.05). Moreover, the upper and lower limit D for LMWOP proved reasonable as water sample determined DOP was found to lie in-between the limits of DGT LMWOP concentrations, indicating that on average DOP consists mainly of LMWOP. "Best fit" D was determined for each stream in order to practically use the DGTs for estimating time average DOP. Applying DGT in a eutrophic lake provided insight into P cycling in the water column. PMID- 25789465 TI - Thermocline regulated seasonal evolution of surface chlorophyll in the Gulf of Aden. AB - The Gulf of Aden, although subject to seasonally reversing monsoonal winds, has been previously reported as an oligotrophic basin during summer, with elevated chlorophyll concentrations only occurring during winter due to convective mixing. However, the Sea-Viewing Wide Field-of-View Sensor (SeaWiFS) ocean color data reveal that the Gulf of Aden also exhibits a prominent summer chlorophyll bloom and sustains elevated chlorophyll concentrations throughout the fall, and is a biophysical province distinct from the adjacent Arabian Sea. Climatological hydrographic data suggest that the thermocline, hence the nutricline, in the entire gulf is markedly shoaled by the southwest monsoon during summer and fall. Under this condition, cyclonic eddies in the gulf can effectively pump deep nutrients to the surface layer and lead to the chlorophyll bloom in late summer, and, after the transition to the northeast monsoon in fall, coastal upwelling driven by the northeasterly winds produces a pronounced increase in surface chlorophyll concentrations along the Somali coast. PMID- 25789464 TI - Sublingual immunization of trivalent human papillomavirus DNA vaccine in baculovirus nanovector for protection against vaginal challenge. AB - Here, we report the immunogenicity of a sublingually delivered, trivalent human papillomavirus (HPV) DNA vaccine encapsidated in a human endogenous retrovirus (HERV) envelope-coated, nonreplicable, baculovirus nanovector. The HERV envelope coated, nonreplicable, baculovirus-based DNA vaccine, encoding HPV16L1, -18L1 and -58L1 (AcHERV-triHPV), was constructed and sublingually administered to mice without adjuvant. Following sublingual (SL) administration, AcHERV-triHPV was absorbed and distributed throughout the body. At 15 minutes and 1 day post-dose, the distribution of AcHERV-triHPV to the lung was higher than that to other tissues. At 30 days post-dose, the levels of AcHERV-triHPV had diminished throughout the body. Six weeks after the first of three doses, 1*10(8) copies of SL AcHERV-triHPV induced HPV type-specific serum IgG and neutralizing antibodies to a degree comparable to that of IM immunization with 1*10(9) copies. AcHERV triHPV induced HPV type-specific vaginal IgA titers in a dose-dependent manner. SL immunization with 1*10(10) copies of AcHERV-triHPV induced Th1 and Th2 cellular responses comparable to IM immunization with 1*10(9) copies. Molecular imaging revealed that SL AcHERV-triHPV in mice provided complete protection against vaginal challenge with HPV16, HPV18, and HPV58 pseudoviruses. These results support the potential of SL immunization using multivalent DNA vaccine in baculovirus nanovector for induction of mucosal, systemic, and cellular immune responses. PMID- 25789466 TI - HDAC1 regulates the proliferation of radial glial cells in the developing Xenopus tectum. AB - In the developing central nervous system (CNS), progenitor cells differentiate into progeny to form functional neural circuits. Radial glial cells (RGs) are a transient progenitor cell type that is present during neurogenesis. It is thought that a combination of neural trophic factors, neurotransmitters and electrical activity regulates the proliferation and differentiation of RGs. However, it is less clear how epigenetic modulation changes RG proliferation. We sought to explore the effect of histone deacetylase (HDAC) activity on the proliferation of RGs in the visual optic tectum of Xenopus laevis. We found that the number of BrdU-labeled precursor cells along the ventricular layer of the tectum decrease developmentally from stage 46 to stage 49. The co-labeling of BrdU-positive cells with brain lipid-binding protein (BLBP), a radial glia marker, showed that the majority of BrdU-labeled cells along the tectal midline are RGs. BLBP-positive cells are also developmentally decreased with the maturation of the brain. Furthermore, HDAC1 expression is developmentally down-regulated in tectal cells, especially in the ventricular layer of the tectum. Pharmacological blockade of HDACs using Trichostatin A (TSA) or Valproic acid (VPA) decreased the number of BrdU-positive, BLBP-positive and co-labeling cells. Specific knockdown of HDAC1 by a morpholino (HDAC1-MO) decreased the number of BrdU- and BLBP-labeled cells and increased the acetylation level of histone H4 at lysine 12 (H4K12). The visual deprivation-induced increase in BrdU- and BLBP-positive cells was blocked by HDAC1 knockdown at stage 49 tadpoles. These data demonstrate that HDAC1 regulates radial glia cell proliferation in the developing optical tectum of Xenopus laevis. PMID- 25789467 TI - Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug induced hepatitis in a nested case-control study. AB - OBJECTIVES: To investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH) in Chinese Han population. METHODS: The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (+/-5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH. RESULTS: A total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107), STAT3 (rs1053004, rs1053023, rs1053005) and HSPA1L (rs2227956). In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004) haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001). CONCLUSION: This study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings. PMID- 25789468 TI - Prognostic significance of anti-aminoacyl-tRNA synthetase antibodies in polymyositis/dermatomyositis-associated interstitial lung disease: a retrospective case control study. AB - BACKGROUND: In polymyositis/dermatomyositis (PM/DM), anti-aminoacyl-tRNA synthetase (ARS) antibodies are closely associated with interstitial lung disease (ILD), a frequent pulmonary complication. However, the clinical significance of anti-ARS antibodies is not well established. OBJECTIVE: We aimed to evaluate the clinical significance of anti-ARS antibodies in PM/DM-ILD patients. METHODS: Forty-eight consecutive PM/DM-ILD patients were studied retrospectively. Anti-ARS antibodies were screened by ELISA and confirmed by RNA immunoprecipitation test. Medical records, high-resolution computed tomography images, and surgical lung biopsy specimens were compared between ARS-positive (ARS group) and ARS-negative patients (non-ARS group). RESULTS: Anti-ARS antibodies were detected in 23 of 48 patients (48%). Radiologically, nonspecific interstitial pneumonia (NSIP) pattern was observed more frequently in the ARS group than in the non-ARS group (73.9% vs. 40%, P = 0.02). Pathologically, NSIP was the most frequent in both groups. Ten-year survival rate was also significantly higher in the ARS group than in the non-ARS group (91.6% vs. 58.7%, P = 0.02). Univariate Cox hazards analysis revealed that the presence of anti-ARS antibodies was associated with better prognosis (HR = 0.34, 95% CI 0.08-0.80; P = 0.01). CONCLUSIONS: The presence of anti-ARS antibodies is a possible prognostic marker in patients with PM/DM-ILD. PMID- 25789470 TI - Easy to use plastic optical fiber-based biosensor for detection of butanal. AB - The final goal of this work is to achieve a selective detection of butanal by the realization of a simple, small-size and low cost experimental approach. To this end, a porcine odorant-binding protein was used in connection with surface plasmon resonance transduction in a plastic optical fiber tool for the selective detection of butanal by a competitive assay. This allows to reduce the cost and the size of the sensing device and it offers the possibility to design a "Lab-on a-chip" platform. The obtained results showed that this system approach is able to selectively detect the presence of butanal in the concentration range from 20 MUM to 1000 MUM. PMID- 25789469 TI - Spatial heterogeneity in drug concentrations can facilitate the emergence of resistance to cancer therapy. AB - Acquired resistance is one of the major barriers to successful cancer therapy. The development of resistance is commonly attributed to genetic heterogeneity. However, heterogeneity of drug penetration of the tumor microenvironment both on the microscopic level within solid tumors as well as on the macroscopic level across metastases may also contribute to acquired drug resistance. Here we use mathematical models to investigate the effect of drug heterogeneity on the probability of escape from treatment and the time to resistance. Specifically we address scenarios with sufficiently potent therapies that suppress growth of all preexisting genetic variants in the compartment with the highest possible drug concentration. To study the joint effect of drug heterogeneity, growth rate, and evolution of resistance, we analyze a multi-type stochastic branching process describing growth of cancer cells in multiple compartments with different drug concentrations and limited migration between compartments. We show that resistance is likely to arise first in the sanctuary compartment with poor drug penetrations and from there populate non-sanctuary compartments with high drug concentrations. Moreover, we show that only below a threshold rate of cell migration does spatial heterogeneity accelerate resistance evolution, otherwise deterring drug resistance with excessively high migration rates. Our results provide new insights into understanding why cancers tend to quickly become resistant, and that cell migration and the presence of sanctuary sites with little drug exposure are essential to this end. PMID- 25789471 TI - Pentoxifylline reverses chronic experimental Chagasic cardiomyopathy in association with repositioning of abnormal CD8+ T-cell response. AB - BACKGROUND: Chronic chagasic cardiomyopathy (CCC), the main clinical sign of Chagas disease, is associated with systemic CD8+ T-cell abnormalities and CD8 enriched myocarditis occurring in an inflammatory milieu. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has immunoregulatory and cardioprotective properties. Here, we tested PTX effects on CD8+ T-cell abnormalities and cardiac alterations using a model of experimental Chagas' heart disease. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6 mice chronically infected by the Colombian Trypanosoma cruzi strain and presenting signs of CCC were treated with PTX. The downmodulation of T-cell receptors on CD8+ cells induced by T. cruzi infection was rescued by PTX therapy. Also, PTX reduced the frequency of CD8+ T cells expressing activation and migration markers in the spleen and the activation of blood vessel endothelial cells and the intensity of inflammation in the heart tissue. Although preserved interferon-gamma production systemically and in the cardiac tissue, PTX therapy reduced the number of perforin+ cells invading this tissue. PTX did not alter parasite load, but hampered the progression of heart injury, improving connexin 43 expression and decreasing fibronectin overdeposition. Further, PTX reversed electrical abnormalities as bradycardia and prolonged PR, QTc and QRS intervals in chronically infected mice. Moreover, PTX therapy improved heart remodeling since reduced left ventricular (LV) hypertrophy and restored the decreased LV ejection fraction. CONCLUSIONS/SIGNIFICANCE: PTX therapy ameliorates critical aspects of CCC and repositioned CD8+ T-cell response towards homeostasis, reinforcing that immunological abnormalities are crucially linked, as cause or effect, to CCC. Therefore, PTX emerges as a candidate to treat the non-beneficial immune deregulation associated with chronic Chagas' heart disease and to improve prognosis. PMID- 25789473 TI - Correction: Elucidation of the RamA regulon in Klebsiella pneumoniae reveals a role in LPS regulation. PMID- 25789472 TI - Nuclear-cytoplasmic conflict in pea (Pisum sativum L.) is associated with nuclear and plastidic candidate genes encoding acetyl-CoA carboxylase subunits. AB - In crosses of wild and cultivated peas (Pisum sativum L.), nuclear-cytoplasmic incompatibility frequently occurs manifested as decreased pollen fertility, male gametophyte lethality, sporophyte lethality. High-throughput sequencing of plastid genomes of one cultivated and four wild pea accessions differing in cross compatibility was performed. Candidate genes for involvement in the nuclear plastid conflict were searched in the reconstructed plastid genomes. In the annotated Medicago truncatula genome, nuclear candidate genes were searched in the portion syntenic to the pea chromosome region known to harbor a locus involved in the conflict. In the plastid genomes, a substantial variability of the accD locus represented by nucleotide substitutions and indels was found to correspond to the pattern of cross-compatibility among the accessions analyzed. Amino acid substitutions in the polypeptides encoded by the alleles of a nuclear locus, designated as Bccp3, with a complementary function to accD, fitted the compatibility pattern. The accD locus in the plastid genome encoding beta subunit of the carboxyltransferase of acetyl-coA carboxylase and the nuclear locus Bccp3 encoding biotin carboxyl carrier protein of the same multi-subunit enzyme were nominated as candidate genes for main contribution to nuclear-cytoplasmic incompatibility in peas. Existence of another nuclear locus involved in the accD mediated conflict is hypothesized. PMID- 25789474 TI - Kinetic evaluation of photosensitivity in bi-stable variants of chimeric channelrhodopsins. AB - Channelrhodopsin-1 and 2 (ChR1 and ChR2) form cation channels that are gated by light through an unknown mechanism. We tested the DC-gate hypothesis that C167 and D195 are involved in the stabilization of the cation-permeable state of ChRWR/C1C2 which consists of TM1-5 of ChR1 and TM6-7 of ChR2 and ChRFR which consists of TM1-2 of ChR1 and TM3-7 of ChR2. The cation permeable state of each ChRWR and ChRFR was markedly prolonged in the order of several tens of seconds when either C167 or D195 position was mutated to alanine (A). Therefore, the DC gate function was conserved among these chimeric ChRs. We next investigated the kinetic properties of the ON/OFF response of these bi-stable ChR mutants as they are important in designing the photostimulation protocols for the optogenetic manipulation of neuronal activities. The turning-on rate constant of each photocurrent followed a linear relationship to 0-0.12 mW mm(-2) of blue LED light or to 0-0.33 mW mm(-2) of cyan LED light. Each photocurrent of bi-stable ChR was shut off to the non-conducting state by yellow or orange LED light in a manner dependent on the irradiance. As the magnitude of the photocurrent was mostly determined by the turning-on rate constant and the irradiation time, the minimal irradiance that effectively evoked an action potential (threshold irradiance) was decreased with time only if the neuron, which expresses bi-stable ChRs, has a certain large membrane time constant (eg. taum > 20 ms). On the other hand, in another group of neurons, the threshold irradiance was not dependent on the irradiation time. Based on these quantitative data, we would propose that these bi-stable ChRs would be most suitable for enhancing the intrinsic activity of excitatory pyramidal neurons at a minimal magnitude of irradiance. PMID- 25789476 TI - Screening for major depressive disorder with the Patient Health Questionnaire (PHQ-9 and PHQ-2) in an outpatient clinic staffed by primary care physicians in Japan: a case control study. AB - OBJECTIVE: The Patient Health Questionnaire (PHQ-9) is a self-report questionnaire commonly used to screen for depression, with >=8-11 generally recommended as the cut-off. In Japan, studies of the validity of the PHQ-9 and PHQ-2 have been limited. In this study, we examined the utility of the PHQ-9 and PHQ-2 at an outpatient clinic in a Medical University Hospital in Japan. METHODS: New consecutive outpatients were included in the study. We administered the PHQ-9 to 574 patients, and acquired complete PHQ-9 and PHQ-2 data for 521 patients. Major depressive disorders were diagnosed according to the DSM-IV-TR. RESULTS: Forty-two patients were diagnosed with major depressive disorders. The mean PHQ-9 (15.7) and PHQ-2 (3.8) scores of the patients with major depressive disorders were significantly higher than the scores of the patients without depression (6.0 (PHQ-9) and 1.8 (PHQ-2)). The best cut-off points for the PHQ-9 and PHQ-2 summary scores were >=11 (sensitivity 0.76, specificity 0.81) and >=3 (sensitivity 0.76, specificity 0.82), respectively. No relationship was observed between the age and PHQ-9 scores. CONCLUSION: The PHQ-9 and PHQ-2 were useful instruments for screening for major depressive disorders. The best cut-off point for the PHQ-9 summary score should be >=11 to detect depression in the primary care setting in Japan. PMID- 25789477 TI - Prevalence of mobile phones and factors influencing usage by caregivers of young children in daily life and for health care in rural China: a mixed methods study. AB - INTRODUCTION: To capitalise on mHealth, we need to understand the use of mobile phones both in daily life and for health care. OBJECTIVE: To assess the prevalence and factors that influence usage of mobile phones by caregivers of young children. MATERIALS AND METHODS: A mixed methods approach was used, whereby a survey (N=1854) and semi-structured interviews (N=17) were conducted concurrently. The quantitative and qualitative data obtained were compared and integrated. Participants were caregivers of young children in Zhao County, Hebei Province, China. RESULTS: Four main themes were found: (i) trends in mobile phone ownership; (ii) usage of mobile phone functions; (iii) factors influencing replying to text messages; and (iv) uses of mobile phones for health care. The majority of 1,854 survey participants (1,620; 87.4%) used mobile phones, but usage was much higher among mothers (1,433; 92.6%) and fathers (41; 100.0%) compared to grandparents (142; 54.6%). Parents were able to send text messages, grandparents often not. Factors influencing the decision to reply to text messages in daily life were checking the mobile phone, trusting the sender, emotion or feeling when receiving a text message, the importance of replying and ease of use of text messages. Of 1,620 survey participants who used a mobile phone, about one in four (432; 26.7%) had used it for health care in the past three months and most (1,110; 93.5%) of 1,187 who had not wished to use their phone to receive health information. CONCLUSION: We found that usage of mobile phones is high, several factors influencing usage and an interest of caregivers to use phones for health care in Zhao County, rural China, which can be used to inform studies in settings with similar characteristics. Future work needs to assess factors influencing mobile phone usage in-depth to optimize experiences of users for specific mHealth-based interventions. PMID- 25789478 TI - Clinician experiences assessing work disability related to mental disorders. AB - OBJECTIVE: Medical certification is one of the basic administrative mechanisms used by social policies aimed at income protection. The assessment of work disability is central to the income protection application. Yet, there is evidence suggesting that determining work disability related to mental disorders is challenging. Although essential to the disability application process, few studies have looked at physician and other clinician experiences with the process. However, this type of information is critical to developing processes to support providers who participate in the assessments. This purpose of this paper is to explore the experiences of physicians and other clinicians assessing public long-term work disability related to mental disorders. METHODS: This is an exploratory and descriptive study using qualitative methods. Clinician input was gathered through focus groups and individual in-depth interviews. Verbatim transcripts were analyzed to identify recurrent and significant themes that arose during the focus groups and individual interviews. RESULTS: Many of the experiences that the clinicians in this sample discussed related to the difficulty of trying to fill the roles of advocate and medical expert as well as the challenge of determining the impact of functional capacity and work ability. The findings also highlight the current gap in knowledge about the factors that affect successful functioning in general and at work in particular. CONCLUSIONS: Given the challenges created by the current state of knowledge, it may be useful to consider a category of "partial disability". In addition, the fact that work disability depends on the interaction between the experience of the mental disorder and specific job requirements and the fact that people applying for public long-term disability are not working, it might be helpful to offer a clear description and guidelines of the meaning of work ability. PMID- 25789475 TI - Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study. AB - BACKGROUND: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. METHODS: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex stratified analyses were performed across studies. RESULTS: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e 4). CONCLUSIONS: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes. PMID- 25789479 TI - Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam induced cell death. AB - Tamoxifen (Tam) is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+) breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1) promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS) mutant of PELP1 (PELP1-cyto) were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERRgamma) promoted cell survival in the presence of Tam. Overexpression of ERRgamma in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRgamma sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERRgamma reduced Tam-induced LC3-II accumulation, and knockdown of ERRgamma increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERRgamma target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERRgamma to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERRgamma activation could be developed as tissue biomarkers for Tam responsiveness. PMID- 25789480 TI - Peer-selected "best papers"-are they really that "good"? AB - BACKGROUND: Peer evaluation is the cornerstone of science evaluation. In this paper, we analyze whether or not a form of peer evaluation, the pre-publication selection of the best papers in Computer Science (CS) conferences, is better than random, when considering future citations received by the papers. METHODS: Considering 12 conferences (for several years), we collected the citation counts from Scopus for both the best papers and the non-best papers. For a different set of 17 conferences, we collected the data from Google Scholar. For each data set, we computed the proportion of cases whereby the best paper has more citations. We also compare this proportion for years before 2010 and after to evaluate if there is a propaganda effect. Finally, we count the proportion of best papers that are in the top 10% and 20% most cited for each conference instance. RESULTS: The probability that a best paper will receive more citations than a non best paper is 0.72 (95% CI = 0.66, 0.77) for the Scopus data, and 0.78 (95% CI = 0.74, 0.81) for the Scholar data. There are no significant changes in the probabilities for different years. Also, 51% of the best papers are among the top 10% most cited papers in each conference/year, and 64% of them are among the top 20% most cited. DISCUSSION: There is strong evidence that the selection of best papers in Computer Science conferences is better than a random selection, and that a significant number of the best papers are among the top cited papers in the conference. PMID- 25789481 TI - Neuroprotective effect of 6-paradol in focal cerebral ischemia involves the attenuation of neuroinflammatory responses in activated microglia. AB - Paradols are non-pungent and biotransformed metabolites of shogaols and reduce inflammatory responses as well as oxidative stress as shogaols. Recently, shogaol has been noted to possess therapeutic potential against several central nervous system (CNS) disorders, including cerebral ischemia, by reducing neuroinflammation in microglia. Therefore, paradol could be used to improve neuroinflammation-associated CNS disorders. Here, we synthesized paradol derivatives (2- to 10-paradols). Through the initial screening for anti inflammatory activities using lipopolysaccharide (LPS)-stimulated BV2 microglia, 6-paradol was chosen to be the most effective compound without cytotoxicity. Pretreatment with 6-paradol reduced neuroinflammatory responses in LPS-stimulated BV2 microglia by a concentration-dependent manner, which includes reduced NO production by inhibiting iNOS upregulation and lowered secretion of proinflammatory cytokines (IL-6 and TNF-alpha). To pursue whether the beneficial in vitro effects of 6-paradol leads towards in vivo therapeutic effects on transient focal cerebral ischemia characterized by neuroinflammation, we employed middle cerebral artery occlusion (MCAO)/reperfusion (M/R). Administration of 6 paradol immediately after reperfusion significantly reduced brain damage in M/R challenged mice as assessed by brain infarction, neurological deficit, and neural cell survival and death. Furthermore, as observed in cultured microglia, 6 paradol administration markedly reduced neuroinflammation in M/R-challenged brains by attenuating microglial activation and reducing the number of cells expressing iNOS and TNF-alpha, both of which are known to be produced in microglia following M/R challenge. Collectively, this study provides evidences that 6-paradol effectively protects brain after cerebral ischemia, likely by attenuating neuroinflammation in microglia, suggesting it as a potential therapeutic agent to treat cerebral ischemia. PMID- 25789483 TI - Hepatitis B e antigen status and hepatitis B DNA levels in women of childbearing age with chronic hepatitis B infection screening for clinical trials. AB - BACKGROUND: Perinatal or mother-to-child transmission of hepatitis B virus (HBV) results in a high frequency of chronic infection. Risk of mother-to-child transmission is associated with maternal viral factors including hepatitis B e antigen (HBeAg) positivity and viral load. AIM: To investigate associations between age, HBeAg status, HBV DNA levels and genotype in female patients screened for inclusion into two contemporary, randomized HBV trials. METHODS: Retrospective analyses focused on differences between women of childbearing age (<=44 years) and older women. Female patients (N = 355; 18-69 years) were included in the analysis: 41.7% of patients were Asian. In total, 44.4% were HBeAg-positive. RESULTS: Significantly more women aged <=44 years were HBeAg positive compared to women >=45 years (57.2% versus 27.5%, respectively, p<0.0001), this proportion declined with increasing age. Younger women were significantly more likely to have high HBV viral load (HBV DNA>108 copies mL: <=44 years 46.0% vs >=45 years 25.5%, respectively; p<0.0001), and this declined with increasing age. HBeAg positivity was slightly higher in Asian women, associated with a higher proportion of HBV genotypes B and C in this population. There was no obvious relationship between genotype and viral load. CONCLUSIONS: Women of childbearing age with CHB are more likely to have high HBV viral load and HBeAg positivity than older women; this likelihood decreases with age. Maternal serological and virological status should therefore be established early in pregnancy, taking into account age and genotype, and a risk-reducing strategy implemented in any patient who is HBeAg positive and has a high viral load. PMID- 25789484 TI - Functional analysis of the molecular interactions of TATA box-containing genes and essential genes. AB - Genes can be divided into TATA-containing genes and TATA-less genes according to the presence of TATA box elements at promoter regions. TATA-containing genes tend to be stress-responsive, whereas many TATA-less genes are known to be related to cell growth or "housekeeping" functions. In a previous study, we demonstrated that there are striking differences among four gene sets defined by the presence of TATA box (TATA-containing) and essentiality (TATA-less) with respect to number of associated transcription factors, amino acid usage, and functional annotation. Extending this research in yeast, we identified KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways that are statistically enriched in TATA-containing or TATA less genes and evaluated the possibility that the enriched pathways are related to stress or growth as reflected by the individual functions of the genes involved. According to their enrichment for either of these two gene sets, we sorted KEGG pathways into TATA-containing-gene-enriched pathways (TEPs) and essential-gene-enriched pathways (EEPs). As expected, genes in TEPs and EEPs exhibited opposite results in terms of functional category, transcriptional regulation, codon adaptation index, and network properties, suggesting the possibility that the bipolar patterns in these pathways also contribute to the regulation of the stress response and to cell survival. Our findings provide the novel insight that significant enrichment of TATA-binding or TATA-less genes defines pathways as stress-responsive or growth-related. PMID- 25789482 TI - Reported radiation overexposure accidents worldwide, 1980-2013: a systematic review. AB - BACKGROUND: Radiation overexposure accidents are rare but can have severe long term health consequences. Although underreporting can be an issue, some extensive literature reviews of reported radiation overexposures have been performed and constitute a sound basis for conclusions on general trends. Building further on this work, we performed a systematic review that completes previous reviews and provides new information on characteristics and trends of reported radiation accidents. METHODS: We searched publications and reports from MEDLINE, EMBASE, the International Atomic Energy Agency, the International Radiation Protection Association, the United Nations Scientific Committee on the Effects of Atomic Radiation, the United States Nuclear Regulatory Commission, and the Radiation Emergency Assistance Center/Training Site radiation accident registry over 1980 2013. We retrieved the reported overexposure cases, systematically extracted selected information, and performed a descriptive analysis. RESULTS: 297 out of 5189 publications and reports and 194 records from the REAC/TS registry met our eligibility criteria. From these, 634 reported radiation accidents were retrieved, involving 2390 overexposed people, of whom 190 died from their overexposure. The number of reported cases has decreased for all types of radiation use, but the medical one. 64% of retrieved overexposure cases occurred with the use of radiation therapy and fluoroscopy. Additionally, the types of reported accidents differed significantly across regions. CONCLUSIONS: This review provides an updated and broader view of reported radiation overexposures. It suggests an overall decline in reported radiation overexposures over 1980 2013. The greatest share of reported overexposures occurred in the medical fields using radiation therapy and fluoroscopy; this larger number of reported overexposures accidents indicates the potential need for enhanced quality assurance programs. Our data also highlights variations in characteristics of reported accidents by region. The main limitation of this study is the likely underreporting of radiation overexposures. Ensuring a comprehensive monitoring and reporting of radiation overexposures is paramount to inform and tailor prevention interventions to local needs. PMID- 25789485 TI - A functional characterisation of a wide range of cover crop species: growth and nitrogen acquisition rates, leaf traits and ecological strategies. AB - Cover crops can produce ecosystem services during the fallow period, as reducing nitrate leaching and producing green manure. Crop growth rate (CGR) and crop nitrogen acquisition rate (CNR) can be used as two indicators of the ability of cover crops to produce these services in agrosystems. We used leaf functional traits to characterise the growth strategies of 36 cover crops as an approach to assess their ability to grow and acquire N rapidly. We measured specific leaf area (SLA), leaf dry matter content (LDMC), leaf nitrogen content (LNC) and leaf area (LA) and we evaluated their relevance to characterise CGR and CNR. Cover crop species were positioned along the Leaf Economics Spectrum (LES), the SLA LDMC plane, and the CSR triangle of plant strategies. LA was positively correlated with CGR and CNR, while LDMC was negatively correlated with CNR. All cover crops could be classified as resource-acquisitive species from their relative position on the LES and the SLA-LDMC plane. Most cover crops were located along the Competition/Ruderality axis in the CSR triangle. In particular, Brassicaceae species were classified as very competitive, which was consistent with their high CGR and CNR. Leaf functional traits, especially LA and LDMC, allowed to differentiate some cover crops strategies related to their ability to grow and acquire N. LDMC was lower and LNC was higher in cover crop than in wild species, pointing to an efficient acquisitive syndrome in the former, corresponding to the high resource availability found in agrosystems. Combining several leaf traits explained approximately half of the CGR and CNR variances, which might be considered insufficient to precisely characterise and rank cover crop species for agronomic purposes. We hypothesised that may be the consequence of domestication process, which has reduced the range of plant strategies and modified the leaf trait syndrome in cultivated species. PMID- 25789486 TI - When problem size matters: differential effects of brain stimulation on arithmetic problem solving and neural oscillations. AB - The problem size effect is a well-established finding in arithmetic problem solving and is characterized by worse performance in problems with larger compared to smaller operand size. Solving small and large arithmetic problems has also been shown to involve different cognitive processes and distinct electroencephalography (EEG) oscillations over the left posterior parietal cortex (LPPC). In this study, we aimed to provide further evidence for these dissociations by using transcranial direct current stimulation (tDCS). Participants underwent anodal (30min, 1.5 mA, LPPC) and sham tDCS. After the stimulation, we recorded their neural activity using EEG while the participants solved small and large arithmetic problems. We found that the tDCS effects on performance and oscillatory activity critically depended on the problem size. While anodal tDCS improved response latencies in large arithmetic problems, it decreased solution rates in small arithmetic problems. Likewise, the lower-alpha desynchronization in large problems increased, whereas the theta synchronization in small problems decreased. These findings reveal that the LPPC is differentially involved in solving small and large arithmetic problems and demonstrate that the effects of brain stimulation strikingly differ depending on the involved neuro-cognitive processes. PMID- 25789487 TI - Polysaccharide hydrogel combined with mesenchymal stem cells promotes the healing of corneal alkali burn in rats. AB - Corneal chemical burns are common ophthalmic injuries that may result in permanent visual impairment. Although significant advances have been achieved on the treatment of such cases, the structural and functional restoration of a chemical burn-injured cornea remains challenging. The applications of polysaccharide hydrogel and subconjunctival injection of mesenchymal stem cells (MSCs) have been reported to promote the healing of corneal wounds. In this study, polysaccharide was extracted from Hardy Orchid and mesenchymal stem cells (MSCs) were derived from Sprague-Dawley rats. Supplementation of the polysaccharide significantly enhanced the migration rate of primarily cultured rat corneal epithelial cells. We examined the therapeutic effects of polysaccharide in conjunction with MSCs application on the healing of corneal alkali burns in rats. Compared with either treatment alone, the combination strategy resulted in significantly better recovery of corneal epithelium and reduction in inflammation, neovascularization and opacity of healed cornea. Polysaccharide and MSCs acted additively to increase the expression of anti inflammatory cytokine (TGF-beta), antiangiogenic cytokine (TSP-1) and decrease those promoting inflammation (TNF-alpha), chemotaxis (MIP-1alpha and MCP-1) and angiogenesis (VEGF and MMP-2). This study provided evidence that Hardy Orchid derived polysaccharide and MSCs are safe and effective treatments for corneal alkali burns and that their benefits are additive when used in combination. We concluded that combination therapy with polysaccharide and MSCs is a promising clinical treatment for corneal alkali burns and may be applicable for other types of corneal disorder. PMID- 25789488 TI - Dosimetric properties of high energy current (HEC) detector in keV x-ray beams. AB - We introduce a new x-ray radiation detector. The detector employs high-energy current (HEC) formed by secondary electrons consisting predominantly of photoelectrons and Auger electrons, to directly convert x-ray energy to detector signal without externally applied power and without amplification. The HEC detector is a multilayer structure composed of thin conducting layers separated by dielectric layers with an overall thickness of less than a millimeter. It can be cut to any size and shape, formed into curvilinear surfaces, and thus can be designed for a variety of QA applications. We present basic dosimetric properties of the detector as function of x-ray energy, depth in the medium, area and aspect ratio of the detector, as well as other parameters. The prototype detectors show similar dosimetric properties to those of a thimble ionization chamber, which operates at high voltage. The initial results obtained for kilovoltage x-rays merit further research and development towards specific medical applications. PMID- 25789489 TI - Stride segmentation during free walk movements using multi-dimensional subsequence dynamic time warping on inertial sensor data. AB - Changes in gait patterns provide important information about individuals' health. To perform sensor based gait analysis, it is crucial to develop methodologies to automatically segment single strides from continuous movement sequences. In this study we developed an algorithm based on time-invariant template matching to isolate strides from inertial sensor signals. Shoe-mounted gyroscopes and accelerometers were used to record gait data from 40 elderly controls, 15 patients with Parkinson's disease and 15 geriatric patients. Each stride was manually labeled from a straight 40 m walk test and from a video monitored free walk sequence. A multi-dimensional subsequence Dynamic Time Warping (msDTW) approach was used to search for patterns matching a pre-defined stride template constructed from 25 elderly controls. F-measure of 98% (recall 98%, precision 98%) for 40 m walk tests and of 97% (recall 97%, precision 97%) for free walk tests were obtained for the three groups. Compared to conventional peak detection methods up to 15% F-measure improvement was shown. The msDTW proved to be robust for segmenting strides from both standardized gait tests and free walks. This approach may serve as a platform for individualized stride segmentation during activities of daily living. PMID- 25789490 TI - A solid-state thin-film Ag/AgCl reference electrode coated with graphene oxide and its use in a pH sensor. AB - In this study, we describe a novel solid-state thin-film Ag/AgCl reference electrode (SSRE) that was coated with a protective layer of graphene oxide (GO). This layer was prepared by drop casting a solution of GO on the Ag/AgCl thin film. The potential differences exhibited by the SSRE were less than 2 mV for 26 days. The cyclic voltammograms of the SSRE were almost similar to those of a commercial reference electrode, while the diffusion coefficient of Fe(CN)63- as calculated from the cathodic peaks of the SSRE was 6.48 * 10-6 cm2/s. The SSRE was used in conjunction with a laboratory-made working electrode to determine its suitability for practical use. The average pH sensitivity of this combined sensor was 58.5 mV/pH in the acid-to-base direction; the correlation coefficient was greater than 0.99. In addition, an integrated pH sensor that included the SSRE was packaged in a secure digital (SD) card and tested. The average sensitivity of the chip was 56.8 mV/pH, with the correlation coefficient being greater than 0.99. In addition, a pH sensing test was also performed by using a laboratory made potentiometer, which showed a sensitivity of 55.4 mV/pH, with the correlation coefficient being greater than 0.99. PMID- 25789491 TI - Cooperative environment scans based on a multi-robot system. AB - This paper proposes a cooperative environment scan system (CESS) using multiple robots, where each robot has low-cost range finders and low processing power. To organize and maintain the CESS, a base robot monitors the positions of the child robots, controls them, and builds a map of the unknown environment, while the child robots with low performance range finders provide obstacle information. Even though each child robot provides approximated and limited information of the obstacles, CESS replaces the single LRF, which has a high cost, because much of the information is acquired and accumulated by a number of the child robots. Moreover, the proposed CESS extends the measurement boundaries and detects obstacles hidden behind others. To show the performance of the proposed system and compare this with the numerical models of the commercialized 2D and 3D laser scanners, simulation results are included. PMID- 25789492 TI - Sparse component analysis using time-frequency representations for operational modal analysis. AB - Sparse component analysis (SCA) has been widely used for blind source separation(BSS) for many years. Recently, SCA has been applied to operational modal analysis (OMA), which is also known as output-only modal identification. This paper considers the sparsity of sources' time-frequency (TF) representation and proposes a new TF-domain SCA under the OMA framework. First, the measurements from the sensors are transformed to the TF domain to get a sparse representation. Then, single-source-points (SSPs) are detected to better reveal the hyperlines which correspond to the columns of the mixing matrix. The K-hyperline clustering algorithm is used to identify the direction vectors of the hyperlines and then the mixing matrix is calculated. Finally, basis pursuit de-noising technique is used to recover the modal responses, from which the modal parameters are computed. The proposed method is valid even if the number of active modes exceed the number of sensors. Numerical simulation and experimental verification demonstrate the good performance of the proposed method. PMID- 25789493 TI - Game design to measure reflexes and attention based on biofeedback multi-sensor interaction. AB - This paper presents a multi-sensor system for implementing biofeedback as a human computer interaction technique in a game involving driving cars in risky situations. The sensors used are: Eye Tracker, Kinect, pulsometer, respirometer, electromiography (EMG) and galvanic skin resistance (GSR). An algorithm has been designed which gives rise to an interaction logic with the game according to the set of physiological constants obtained from the sensors. The results reflect a 72.333 response to the System Usability Scale (SUS), a significant difference of p = 0.026 in GSR values in terms of the difference between the start and end of the game, and an r = 0.659 and p = 0.008 correlation while playing with the Kinect between the breathing level and the energy and joy factor. All the sensors used had an impact on the end results, whereby none of them should be disregarded in future lines of research, even though it would be interesting to obtain separate breathing values from that of the cardio. PMID- 25789494 TI - Single- and two-phase flow characterization using optical fiber bragg gratings. AB - Single- and two-phase flow characterization using optical fiber Bragg gratings (FBGs) is presented. The sensor unit consists of the optical fiber Bragg grating positioned transversely to the flow and fixed in the pipe walls. The hydrodynamic pressure applied by the liquid or air/liquid flow to the optical fiber induces deformation that can be detected by the FBG. Given that the applied pressure is directly related to the mass flow, it is possible to establish a relationship using the grating resonance wavelength shift to determine the mass flow when the flow velocity is well known. For two phase flows of air and liquid, there is a significant change in the force applied to the fiber that accounts for the very distinct densities of these substances. As a consequence, the optical fiber deformation and the correspondent grating wavelength shift as a function of the flow will be very different for an air bubble or a liquid slug, allowing their detection as they flow through the pipe. A quasi-distributed sensing tool with 18 sensors evenly spread along the pipe is developed and characterized, making possible the characterization of the flow, as well as the tracking of the bubbles over a large section of the test bed. Results show good agreement with standard measurement methods and open up plenty of opportunities to both laboratory measurement tools and field applications. PMID- 25789495 TI - Zinc delays clot lysis by attenuating plasminogen activation and plasmin-mediated fibrin degradation. AB - Zinc circulates free in plasma at a concentration of 0.1-2 uM, but its levels increase locally when it is released from activated platelets. Although zinc influences many processes in haemostasis, its effect on fibrinolysis has not been thoroughly investigated. Using a fluorescent zinc-binding probe, we demonstrated that zinc binds tissue-type plasminogen activator (tPA) and plasmin with high affinity (Kd values of 0.2 uM), and surface plasmon resonance studies revealed that zinc binds fibrin with a Kd of 12.8 uM. Zinc had no effect on the affinity of plasminogen or plasmin for fibrin, but increased the affinity of tPA by two fold. In the presence of 5 uM zinc, the catalytic efficiency of plasminogen activation by tPA was reduced by approximately two-fold, both in the absence or presence of fibrin. Zinc attenuated plasmin-mediated degradation of the fibrinogen alpha-chain by 43 %, but had no effect on trypsin degradation. tPA mediated fibrin clot lysis was prolonged 2.5-fold by zinc in a concentration dependent fashion, and tPA-mediated plasma clot lysis was attenuated by 1.5-fold. Therefore, our data indicate that zinc modulates fibrinolysis by attenuating tPA mediated plasminogen activation and plasmin-induced fibrin degradation. These findings suggest that local release of zinc by platelets attenuates fibrinolysis. PMID- 25789496 TI - Exposure to secondhand tobacco smoke and interventions among pregnant women in China: a systematic review. AB - INTRODUCTION: Smoking prevalence is high among men in China. One result is that a large number of nonsmoking Chinese women may be exposed daily to secondhand smoke (SHS). Exposure is particularly problematic for pregnant women because of potential adverse reproductive effects. To determine the extent of this exposure and to summarize existing intervention studies designed to reduce SHS exposure in China, a systematic review of the literature published from 1995 through 2012 was conducted. METHODS: We searched the PubMed and Wanfang databases for studies published from 1995 through 2012 using various search terms including SHS, pregnant women, and China. Only articles on prevalence of SHS exposure and interventions to reduce exposure to SHS were selected. RESULTS: We identified 132 studies during the initial searches. Eight of 13 eligible studies reported the prevalence of SHS exposure among pregnant women; estimates ranged from 38.9% to 75.1%. Few SHS prevention interventions among pregnant women in China have been studied; we found only 5 such studies. The interventions primarily focused on changing husbands' smoking behaviors; some interventions focused on women's avoidance behaviors. CONCLUSION: Prevalence of exposure to SHS among pregnant women is high in China. Information is limited on effective interventions to protect pregnant women from exposure. The results of this review can provide the basis for the design and evaluation of interventions to help pregnant women avoid SHS exposure. PMID- 25789497 TI - Breast cancer stage, surgery, and survival statistics for Idaho's National Breast and Cervical Cancer Early Detection Program population, 2004-2012. AB - INTRODUCTION: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides access to breast and cervical cancer screening for low-income, uninsured, and underinsured women in all states and US territories. In Idaho, a rural state with very low breast and cervical cancer screening rates, this program is called Women's Health Check (WHC). The program has been operating continuously since 1997 and served 4,719 enrollees in 2013. The objective of this study was to assess whether disparities existed in cause-specific survival (a net survival measure representing survival of a specified cause of death in the absence of other causes of death) between women screened by WHC and outside WHC and to determine how type of surgery or survival varies with stage at diagnosis. METHODS: WHC data were linked to Idaho's central cancer registry to compare stage distribution, type of surgery, and cause-specific survival between women with WHC linked breast cancer and a comparison group of women whose records did not link to the WHC database (nonlinked breast cancer). RESULTS: WHC-linked breast cancer was significantly more likely to be diagnosed at a later stage of disease than nonlinked breast cancer. Because of differences in stage distribution between WHC linked and nonlinked breast cancers, overall age-standardized, cause-specific breast cancer survival proportions diverged over time, with a 5.1 percentage point deficit in survival among WHC-linked cases at 5 years of follow-up (83.9% vs 89.0%). Differences in type of surgery and cause-specific survival were attenuated when controlling for stage. CONCLUSION: This study suggests that disparities may exist for Idaho WHC enrollees in the timely diagnosis of breast cancer. To our knowledge, this is the first study to publish comparisons of cause specific breast cancer survival between NBCCEDP-linked and nonlinked cases. PMID- 25789498 TI - Process evaluation of a regional public health model to reduce chronic disease through policy and systems changes, Washington State, 2010-2014. AB - INTRODUCTION: Although the regionalization of public health systems has been well documented in the case of emergency preparedness, there is little literature on the application of regional approaches to other aspects of public health. From 2011 through 2014 the Washington State Department of Health implemented a Community Transformation Grant to support community-level policy and systems changes to decrease chronic disease risk factors and increase access to clinical preventive services. The Department of Health implemented the grant through a regional model, grouping 32 of the state's 35 local health jurisdictions into 5 regions. Our process evaluation identifies the challenges and facilitators to Community Transformation Grant planning and implementation. METHODS: We conducted 34 key informant interviews with people directly involved in the implementation of the Community Transformation Grant. We interviewed state and local partners, including representatives from each region, the Department of Health, external consultants, and regional partners. We collected data from October 2013 through July 2014. RESULTS: Challenges for planning, building, and implementing a regional model for chronic disease prevention included stakeholder buy-in, regional geography, and communication; facilitators included shared regional history and infrastructure, strong leadership, collaborative relationships, shared vision and goals, sufficient funding, and direct technical assistance and training. CONCLUSION: Lessons learned in Washington State provide a foundation for other states interested in using a regional approach to reduce chronic disease risk. Policy and systems changes require adequate time, funding, and staffing. States and funders should work closely with local leaders to address these challenges and facilitators. PMID- 25789499 TI - Unemployment and depression among emerging adults in 12 states, Behavioral Risk Factor Surveillance System, 2010. AB - INTRODUCTION: The high rate of unemployment among emerging adults (aged 18 to 25 years) is a public health concern. The risk of depression is higher among the unemployed than among the employed, but little is known about the relationship between unemployment and mental health among emerging adults. This secondary data analysis assessed the relationship between unemployment and depression among emerging adults. METHODS: Data from the 2010 Behavioral Risk Factor Surveillance System (BRFSS) were analyzed. Responses to the Patient Health Questionnaire-8 provided data about the prevalence of depression. Bivariate relationships were assessed using chi(2) tests, and multivariable adjusted odds ratios were calculated with logistic regressions. Sociodemographic variables were sex, race/ethnicity, marital status, and education. In addition, logistic regression models adjusted for health insurance status, disability, smoking, and body mass index. The analyses were completed using SAS 9.3 survey procedures to account for the complex sampling design. RESULTS: Almost 12% of emerging adults were depressed (PHQ-8 >=10) and about 23% were unemployed. Significantly more unemployed than employed emerging adults were classified with depression. In the final model, the odds of depression were about 3 times higher for unemployed than employed emerging adults. CONCLUSION: The relationship between unemployment and depression is significant among emerging adults. With high rates of unemployment for this age group, this population may benefit from employment- and mental health-focused interventions. PMID- 25789500 TI - In vitro corrosion and cytocompatibility properties of nano-whisker hydroxyapatite coating on magnesium alloy for bone tissue engineering applications. AB - We report here the successful fabrication of nano-whisker hydroxyapatite (nHA) coatings on Mg alloy by using a simple one-step hydrothermal process in aqueous solution. The nHA coating shows uniform structure and high crystallinity. Results indicate that nHA coating is promising for improving the in vitro corrosion and cytocompatibility properties of Mg-based implants and devices for bone tissue engineering. In addition, the simple hydrothermal deposition method used in the current study is also applicable to substrates with complex shapes or surface geometries. PMID- 25789501 TI - Chemopreventive potential of green tea catechins in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), which is a common malignancy worldwide, usually develops in a cirrhotic liver due to hepatitis virus infection. Metabolic syndrome, which is frequently complicated by obesity and diabetes mellitus, is also a critical risk factor for liver carcinogenesis. Green tea catechins (GTCs) may possess potent anticancer and chemopreventive properties for a number of different malignancies, including liver cancer. Antioxidant and anti-inflammatory activities are key mechanisms through which GTCs prevent the development of neoplasms, and they also exert cancer chemopreventive effects by modulating several signaling transduction and metabolic pathways. Furthermore, GTCs are considered to be useful for the prevention of obesity- and metabolic syndrome related carcinogenesis by improving metabolic disorders. Several interventional trials in humans have shown that GTCs may ameliorate metabolic abnormalities and prevent the development of precancerous lesions. The purpose of this article is to review the key mechanisms by which GTCs exert chemopreventive effects in liver carcinogenesis, focusing especially on their ability to inhibit receptor tyrosine kinases and improve metabolic abnormalities. We also review the evidence for GTCs acting to prevent metabolic syndrome-associated liver carcinogenesis. PMID- 25789502 TI - Polyoxygenated cembrane diterpenoids from the soft coral Sarcophyton ehrenbergi. AB - Five new polyoxygenated cembranoids, named (+)-1,15-epoxy-2-methoxy-12 methoxycarbonyl-11E-sarcophytoxide (1), (+)-2-epi-12-methoxycarbonyl-11E sarcophine (2), 3,4-epoxyehrenberoxide A (3), ehrenbergol D (4) and ehrenbergol E (5), were obtained from the soft coral Sarcophyton ehrenbergi. The structures of 1-5 were established on the basis of comprehensive NMR and HR-ESI-MS analyses and by comparison with reported data in the literature. Compounds 4 and 5 showed moderate cytotoxicity against P-388 (mouse lymphocytic leukemia) cancer cell line with EC50 values of 2.0 and 3.0 MUM, respectively. Compound 2 exhibited slight antiviral activity against HCMV (human cytomegalovirus) with IC50 values of 25.0 MUg/mL. PMID- 25789505 TI - Effect of chemical treatments on flax fibre reinforced polypropylene composites on tensile and dome forming behaviour. AB - Tensile tests were performed on two different natural fibre composites (same constituent material, similar fibre fraction and thickness but different weave structure) to determine changes in mechanical properties caused by various aqueous chemical treatments and whether any permanent changes remain on drying. Scanning electronic microscopic examinations suggested that flax fibres and the flax/polypropylene interface were affected by the treatments resulting in tensile property variations. The ductility of natural fibre composites was improved significantly under wet condition and mechanical properties (elongation-to failure, stiffness and strength) can almost retain back to pre-treated levels when dried from wet condition. Preheating is usually required to improve the formability of material in rapid forming, and the chemical treatments performed in this study were far more effective than preheating. The major breakthrough in improving the formability of natural fibre composites can aid in rapid forming of this class of material system. PMID- 25789506 TI - Knowledge and behavior of dentists in a dental school regarding toothbrush disinfection. AB - The aim of this study was to evaluate the knowledge and behavior of dentists regarding toothbrush disinfection. This study included 147 dentists (88 women and 59 men) who were actively employed at a dental school in Ankara, Turkey. Participants were asked to fill out a standard questionnaire, which contained questions regarding their demographics, brushing habits, toothbrush storage and disinfection habits, toothpaste use, knowledge about toothbrush disinfection, and whether they advised their patients about toothbrush storage. Descriptive statistics were calculated, and statistical analyses were performed with t-tests, chi-squared tests, and Fisher exact tests, where appropriate. Among the 147 surveyed dentists, 62.6% and 85.7% reported that they did not have any knowledge about toothbrush disinfection and did not disinfect their toothbrushes, respectively. However, approximately two thirds of surveyed dentists thought that toothbrush disinfection should be performed by everyone, including healthy individuals. Significant associations were found between knowledge about toothbrush disinfection and the professional title of dentists, how they stored their toothbrushes, and whether their toothbrushes were in contact with each other during storage (p < 0.05). A minority of dentists reported that they disinfected their toothbrushes. PMID- 25789504 TI - DNA damage: a sensible mediator of the differentiation decision in hematopoietic stem cells and in leukemia. AB - In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche. PMID- 25789503 TI - New therapies for dedifferentiated papillary thyroid cancer. AB - The number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, which fails to respond to RAI, exhibiting a more aggressive behavior. The lack of specific, effective and well-tolerated drugs, the scarcity of data about the association of multi-targeting drugs, and the limited role of radioiodine for dedifferentiated thyroid cancer, call for further efforts in the field of new drugs development. Rearranged during transfection (RET)/papillary thyroid carcinoma gene rearrangements, BRAF (B-RAF proto-oncogene, serine/threonine kinase) gene mutations, RAS (rat sarcoma) mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways playing a crucial role in the development of thyroid cancer. Targeted novel compounds have been demonstrated to induce clinical responses and stabilization of disease. Sorafenib has been approved for differentiated thyroid cancer refractory to RAI. PMID- 25789507 TI - Effectiveness and satisfaction evaluation of patients submitted to TMJ arthrocenthesis: a case series. AB - The aim of this study was to evaluate the effectiveness and level of satisfaction of patients who underwent TMJ arthrocentesis under local anesthesia by considering the following parameters: joint pain, mouth opening, mastication, and satisfaction. Fourteen patients (13 women and one man; mean age, 37.6 years with TMJ arthralgia were selected. The patients underwent arthrocentesis under local anesthesia, and pain intensity was measured before, during, and 1 year after treatment using a visual analog pain scale (VAS 0-100 mm). A Likert scale was used to assess patients' opinion regarding the improvement of mouth opening and mastication. After treatment, patients were questioned on levels of satisfaction provided by arthrocentesis in regard to their quality of life. At the end of 1 year, patients showed a marked improvement in their pain clinical picture (p < 0.0001). Mouth opening and mastication, evaluated separately and then correlated (R2 = 0.925, p < 0.0001), also showed a marked improvement. When questioned, all patients reported being satisfied with the treatment outcome. PMID- 25789508 TI - Saliva, supragingival biofilm and root canals can harbor gene associated with resistance to lactamic agents. AB - This study aimed to determine the presence of Prevotella strains and genes associated with resistance to lactamics in different oral niches from patients with/without primary endodontic infections. Saliva (S) and supragingival biofilm (SB) were collected from three patient groups: Group I - no endodontic infection (n = 15); Group II - acute endodontic infection (n = 12); and Group III - chronic endodontic infection (n = 15). Root canal (RC) samples were collected from Groups II and III. The presence of P. intermedia, P nigrescens, P. tannerae and cfxA/cfxA2 gene was assessed by PCR. The cfxA/cfxA2 gene was not detected in all environments within the same patient. The cfxA/cfxA2 gene was present in 23.81% of S samples, 28.57% of SB samples, and 7.41% of RC samples. Prevotella species were detected in 53.97%, 47.62% and 34.56% of the S, SB, and RC samples, respectively. P. intermedia had a high frequency in saliva samples from Group 3. Saliva samples from Group 1 had higher detection rates of P. nigrescens than did Groups 2 and 3. Patients without endodontic disease had high frequencies of P. nigrescens in the SB samples. The presence or absence of spontaneous symptoms was not related to the detection rates for resistance genes in the RC samples. Saliva, supragingival biofilm and root canals can harbor resistant bacteria. The presence of symptomatology did not increase the presence of the cfxA/cfxA2 gene in the supragingival biofilm and inside root canals. PMID- 25789509 TI - Genetic diversity of koala retroviral envelopes. AB - Genetic diversity, attributable to the low fidelity of reverse transcription, recombination and mutation, is an important feature of infectious retroviruses. Under selective pressure, such as that imposed by superinfection interference, gammaretroviruses commonly adapt their envelope proteins to use alternative receptors to overcome this entry block. The first characterized koala retroviruses KoRV subgroup A (KoRV-A) were remarkable in their absence of envelope genetic variability. Once it was determined that KoRV-A was present in all koalas in US zoos, regardless of their disease status, we sought to isolate a KoRV variant whose presence correlated with neoplastic malignancies. More than a decade after the identification of KoRV-A, we isolated a second subgroup of KoRV, KoRV-B from koalas with lymphomas. The envelope proteins of KoRV-A and KoRV-B are sufficiently divergent to confer the ability to bind and employ distinct receptors for infection. We have now obtained a number of additional KoRV envelope variants. In the present studies we report these variants, and show that they differ from KoRV-A and KoRV-B envelopes in their host range and superinfection interference properties. Thus, there appears to be considerable variation among KoRVs envelope genes suggesting genetic diversity is a factor following the KoRV-A infection process. PMID- 25789510 TI - ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression. AB - Abdominal aortic aneurysm (AAA) evolution is unpredictable, and there is no therapy except surgery for patients with an aortic size> 5 cm (large AAA). We aimed to identify new potential biomarkers that could facilitate prognosis and treatment of patients with AAA. A differential quantitative proteomic analysis of plasma proteins was performed in AAA patients at different stages of evolution [small AAA (aortic size=3-5 cm) vs large AAA] using iTRAQ labelling, high throughput nano-LC-MS/MS and a novel multi-layered statistical model. Among the proteins identified, ApoA-I was decreased in patients with large AAA compared to those with small AAA. These results were validated by ELISA on plasma samples from small (n=90) and large AAA (n=26) patients (150+/- 3 vs 133+/- 5 mg/dl, respectively, p< 0.001). ApoA-I levels strongly correlated with HDL-Cholesterol (HDL-C) concentration (r=0.9, p< 0.001) and showed a negative correlation with aortic size (r=-0.4, p< 0.01) and thrombus volume (r=-0.3, p< 0.01), which remained significant after adjusting for traditional risk factors. In a prospective study, HDL-C independently predicted aneurysmal growth rate in multiple linear regression analysis (n=122, p=0.008) and was inversely associated with need for surgical repair (Adjusted hazard ratio: 0.18, 95 % confidence interval: 0.04-0.74, p=0.018). In a nation-wide Danish registry, we found lower mean HDL-C concentration in large AAA patients (n=6,560) compared with patients with aorto-iliac occlusive disease (n=23,496) (0.89+/- 2.99 vs 1.59+/- 5.74 mmol/l, p< 0.001). Finally, reduced mean aortic AAA diameter was observed in AngII-infused mice treated with ApoA-I mimetic peptide compared with saline injected controls. In conclusion, ApoA-I/HDL-C systemic levels are negatively associated with AAA evolution. Therapies targeting HDL functionality could halt AAA formation. PMID- 25789511 TI - Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo. AB - To reduce the toxic side effects of traditional chemotherapeutics in vivo, we designed and constructed a biocompatible, matrix metalloproteinases (MMPs) responsive drug delivery system based on mesoporous silica nanoparticles (MSNs). MMPs substrate peptide containing PLGLAR (sensitive to MMPs) was immobilized onto the surfaces of amino-functionalized MSNs via an amidation reaction, serving as MMPs sensitive intermediate linker. Bovine serum albumin was then covalently coupled to linker as end-cap for sealing the mesopores of MSNs. Lactobionic acid was further conjugated to the system as targeting motif. Doxorubicin hydrochloride was used as the model anticancer drug in this study. A series of characterizations revealed that the system was successfully constructed. The peptide-functionalized MSNs system demonstrated relatively high sensitivity to MMPs for triggering drug delivery, which was potentially important for tumor therapy since the tumor's microenvironment overexpressed MMPs in nature. The in vivo experiments proved that the system could efficiently inhibit the tumor growth with minimal side effects. This study provides an approach for the development of the next generation of nanotherapeutics toward efficient cancer treatment. PMID- 25789513 TI - Relationship of the total atrial conduction time to subclinical atherosclerosis, inflammation and echocardiographic parameters in patients with type 2 diabetes mellitus. AB - OBJECTIVES: The aim of our study was to evaluate the total atrial conduction time and its relationship to subclinical atherosclerosis, inflammation and echocardiographic parameters in patients with type 2 diabetes mellitus. METHODS: A total of 132 patients with type 2 diabetes mellitus (mean age 54.5 +/- 9.6 years; 57.6% male) and 80 age- and gender-matched controls were evaluated. The total atrial conduction time was measured by tissue-Doppler imaging and the carotid intima-media thickness was measured by B-mode ultrasonography. RESULTS: The total atrial conduction time was significantly longer in the patients with type 2 diabetes mellitus than in the control group (131.7 +/- 23.6 vs. 113.1 +/- 21.3, p<0.001). The patients with type 2 diabetes mellitus had significantly increased carotid intima-media thicknesses, neutrophil to lymphocyte ratios and high-sensitivity C-reactive protein levels than those of the controls. The total atrial conduction time was positively correlated with the high-sensitivity C reactive protein level, neutrophil to lymphocyte ratio, carotid intima-media thickness and left atrial volume index and negatively correlated with the early diastolic velocity (Em), Em/late diastolic velocity (Am) ratio and global peak left atrial longitudinal strain. A multiple logistic regression analysis demonstrated that the neutrophil to lymphocyte ratio, carotid intima-media thickness and global peak left atrial longitudinal strain were independent predictors of the total atrial conduction time. CONCLUSIONS: We suggest that subclinical atherosclerosis and inflammation may represent a mechanism related to prolonged total atrial conduction time and that prolonged total atrial conduction time and impaired left atrial myocardial deformation may be represent early subclinical cardiac involvement in patients with type 2 diabetes mellitus. PMID- 25789514 TI - Immunohistochemical analysis of the neural structures of the posterior cruciate ligament in osteoarthritis patients submitted to total knee arthroplasty: an analysis of thirty-four cases. AB - OBJECTIVES: Many authors recommend posterior cruciate ligament-retaining arthroplasty with the intention to maintain the proprioception properties of this ligament. Preservation of the neuroreceptors and nervous fibers may be essential for retaining the proprioception function of the posterior cruciate ligament. The present study was thus developed to evaluate the presence of neural structures in the posterior cruciate ligament resected during posterior stabilized arthroplasty in osteoarthritis patients. In particular, clinical, radiographic and histological parameters were correlated with the presence or absence of neural structures in the posterior cruciate ligament. METHODS: In total, 34 posterior cruciate ligament specimens were stained with hematoxylin-eosin and Gomori trichrome. An immunohistochemical analysis using antibodies against the S100 protein and neurofilaments was also performed. The presence of neural structures was correlated with parameters such as tibiofemoral angulation, histological degeneration of the posterior cruciate ligament, Ahlback radiological classification, age, gender and the histologic pattern of the synovial neurovascular bundle around the posterior cruciate ligament. RESULTS: In total, 67.5% of the cases presented neural structures in the posterior cruciate ligament. In 65% of the cases, the neurovascular bundle was degenerated. Nervous structures were more commonly detected in varus knees than in valgus knees (77% versus 50%). Additionally, severe histologic degeneration of the posterior cruciate ligament was related to neurovascular bundle degeneration. CONCLUSIONS: Severe posterior cruciate ligament degeneration was related to neurovascular bundle compromise. Neural structures were more commonly detected in varus knees. Intrinsic neural structures were detected in the majority of the posterior cruciate ligaments of patients submitted to knee arthroplasty for osteoarthritis. PMID- 25789512 TI - COMP-1 promotes competitive advantage of nematode sperm. AB - Competition among sperm to fertilize oocytes is a ubiquitous feature of sexual reproduction as well as a profoundly important aspect of sexual selection. However, little is known about the cellular mechanisms sperm use to gain competitive advantage or how these mechanisms are regulated genetically. In this study, we utilize a forward genetic screen in Caenorhabditis elegans to identify a gene, comp-1, whose function is specifically required in competitive contexts. We show that comp-1 functions in sperm to modulate their migration through and localization within the reproductive tract, thereby promoting their access to oocytes. Contrary to previously described models, comp-1 mutant sperm show no defects in size or velocity, thereby defining a novel pathway for preferential usage. Our results indicate not only that sperm functional traits can influence the outcome of sperm competition, but also that these traits can be modulated in a context-dependent manner depending on the presence of competing sperm. PMID- 25789515 TI - Excess body weight in children may increase the length of hospital stay. AB - OBJECTIVES: To investigate the prevalence of excess body weight in the pediatric ward of University Hospital and to test both the association between initial nutritional diagnosis and the length of stay and the in-hospital variation in nutritional status. METHODS: Retrospective cohort study based on information entered in clinical records from University Hospital. The data were collected from a convenience sample of 91 cases among children aged one to 10 years admitted to the hospital in 2009. The data that characterize the sample are presented in a descriptive manner. Additionally, we performed a multivariate linear regression analysis adjusted for age and gender. RESULTS: Nutritional classification at baseline showed that 87.8% of the children had a normal weight and that 8.9% had excess weight. The linear regression models showed that the average weight loss z-score of the children with excess weight compared with the group with normal weight was -0.48 (p = 0.018) and that their length of stay was 2.37 days longer on average compared with that of the normal-weight group (p = 0.047). CONCLUSIONS: The length of stay and loss of weight at the hospital may be greater among children with excess weight than among children with normal weight. PMID- 25789516 TI - Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study. AB - OBJECTIVE: Rheumatoid arthritis (RA) is a costly and crippling autoimmune disease that can lead to the development of depression, contributing to suboptimal clinical outcomes. However, no longitudinal studies have identified an association between rheumatoid arthritis and subsequent depression. This study aimed to investigate the incidence and risk factors of depression among RA patients in Taiwan. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 3,698 newly diagnosed RA patients aged 18 years or older, together with 7,396 subjects without RA matched by sex, age and index date, between 2000 and 2004. The incidence of depression and the risk factors among RA cases were evaluated using Cox proportional-hazard regression. RESULTS: The incidence of depression was 1.74-fold greater in the RA cohort than in the non-RA cohort (11.80 versus 6.89 per 1,000 person-years; p<0.01). Multivariate analysis showed that RA subjects who were female, were older, or had comorbidities such as stroke, chronic kidney disease, or cancer had a significantly greater risk of depression compared with those without these conditions. CONCLUSION: This population-based cohort study showed a strong relationship between RA and a subsequent risk of depression. The findings could be beneficial to healthcare providers for identifying individuals with a higher predisposition for depression, thereby possibly facilitating the provision of an appropriate rehabilitation intervention after RA onset to support the patient's adaptation. PMID- 25789517 TI - Comparison of pre- and post-levothyroxine high-sensitivity c-reactive protein and fetuin-a levels in subclinical hypothyroidism. AB - OBJECTIVE: The objective of this trial was to determine the levels of inflammatory markers, high-sensitivity C-reactive protein and fetuin-A pre- and post-levothyroxine treatment in cases of subclinical hypothyroidism. MATERIALS AND METHODS: A total of 32 patients with a diagnosis of subclinical hypothyroidism and a control group of 30 healthy individuals were tested for high sensitivity C-reactive protein and fetuin-A, followed by the administration of 50 ug of levothyroxine in the patient group for 3 months. During the post-treatment stage, high-sensitivity C-reactive protein and fetuin-A levels in the patient group were re-assessed and compared with pre-treatment values. RESULTS: Pre treatment levels of both high-sensitivity C-reactive protein and fetuin-A were observed to be higher in the patient group than in the control group. The decrease in high-sensitivity C-reactive protein levels during the post-treatment stage was not statistically significant. However, the decrease observed in post treatment fetuin-A levels was found to be statistically significant. CONCLUSION: The decrease in fetuin-A levels in subclinical hypothyroidism cases indicates that levothyroxine treatment exerts anti-inflammatory and anti-apoptotic effects. Although the decrease in high-sensitivity C-reactive protein levels was statistically non-significant, it is predicted to reach significance with sustained treatment. PMID- 25789518 TI - Improvement in medication adherence and self-management of diabetes with a clinical pharmacy program: a randomized controlled trial in patients with type 2 diabetes undergoing insulin therapy at a teaching hospital. AB - OBJECTIVE: To evaluate the impact of a clinical pharmacy program on health outcomes in patients with type 2 diabetes undergoing insulin therapy at a teaching hospital in Brazil. METHOD: A randomized controlled trial with a 6-month follow-up period was performed in 70 adults, aged 45 years or older, with type 2 diabetes who were taking insulin and who had an HbA1c level >=8%. Patients in the control group (CG) (n = 36) received standard care, patients in the intervention group (IG) (n = 34) received an individualized pharmacotherapeutic care plan and diabetes education. The primary outcome measure was change in HbA1c. Secondary outcomes included diabetes and medication knowledge, adherence to medication, insulin injection and home blood glucose monitoring techniques and diabetes related quality of life. Outcomes were evaluated at baseline and 6 months using questionnaires. RESULTS: Diabetes knowledge, medication knowledge, adherence to medication and correct insulin injection and home blood glucose monitoring techniques significantly improved in the intervention group but remained unchanged in the control group. At the end of the study, mean HbA1c values in the control group remained unchanged but were significantly reduced in the intervention group. Diabetes-related quality of life significantly improved in the intervention group but worsened significantly in the control group. CONCLUSION: The program improved health outcomes and resulted in better glycemic control in patients with type 2 diabetes undergoing insulin therapy. PMID- 25789519 TI - What is the influence of hormone therapy on homocysteine and crp levels in postmenopausal women? AB - OBJECTIVE: To evaluate the influence of estrogen therapy and estrogen-progestin therapy on homocysteine and C-reactive protein levels in postmenopausal women. METHODS: In total, 99 postmenopausal women were included in this double-blind, randomized clinical trial and divided into three groups: Group A used estrogen therapy alone (2.0 mg of 17beta-estradiol), Group B received estrogen-progestin therapy (2.0 mg of 17 beta-estradiol +1.0 mg of norethisterone acetate) and Group C received a placebo (control). The length of treatment was six months. Serum measurements of homocysteine and C-reactive protein were carried out prior to the onset of treatment and following six months of therapy. RESULTS: After six months of treatment, there was a 20.7% reduction in homocysteine levels and a 100.5% increase in C-reactive protein levels in the group of women who used estrogen therapy. With respect to the estrogen-progestin group, there was a 12.2% decrease in homocysteine levels and a 93.5% increase in C-reactive protein levels. CONCLUSION: Our data suggested that hormone therapy (unopposed estrogen or estrogen associated with progestin) may have a positive influence on decreasing cardiovascular risk due to a significant reduction in homocysteine levels. PMID- 25789520 TI - Surgical treatment of the osteoporotic spine with bone cement-injectable cannulated pedicle screw fixation: technical description and preliminary application in 43 patients. AB - OBJECTIVES: To describe a new approach for the application of polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws. METHODS: Between June 2010 and February 2013, 43 patients with degenerative spinal disease and osteoporosis (T-score <-2.5) underwent lumbar fusion using cement-injectable cannulated pedicle screws. Clinical outcomes were evaluated using a Visual Analog Scale and the Oswestry Disability Index. Patients were given radiographic follow-up examinations after 3, 6, and 12 months and once per year thereafter. RESULTS: All patients were followed for a mean of 15.7 +/- 5.6 months (range, 6 to 35 months). The Visual Analog Scale and Oswestry Disability Index scores showed a significant reduction in back pain (p = 0.018) and an improvement in lower extremity function (p = 0.025) in patients who underwent lumbar fusion using the novel screw. Intraoperative cement leakage occurred in four patients, but no neurological complications were observed. Radiological observation indicated no loosening or pulling out of the novel screw, and bone fusion was excellent. CONCLUSIONS: The described polymethylmethacrylate augmentation technique using bone cement-injectable cannulated pedicle screws can reduce pain and improve spinal dysfunction in osteoporotic patients undergoing osteoporotic spine surgery. PMID- 25789521 TI - Repeated microendoscopic discectomy for recurrent lumbar disk herniation. AB - OBJECTIVES: To explore the microendoscopic discectomy technique and inclusion criteria for the treatment of recurrent lumbar disc herniation and to supply feasible criteria and technical notes to avoid complications and to increase the therapeutic effect. METHODS: A consecutive series of 25 patients who underwent posterior microendoscopic discectomy for recurrent lumbar disc herniation were included. The inclusion criteria were as follows: no severe pain in the lumbar region, no lumbar instability observed by flexion-extension radiography and no intervertebral discitis or endplate damage observed by magnetic resonance imaging. All patients were diagnosed by clinical manifestations and imaging examinations. RESULTS: Follow-up visits were carried out in all cases. Complications, such as nerve injuries, were not observed. The follow-up outcomes were graded using the MacNab criteria. A grade of excellent was given to 12 patients, good to 12 patients and fair to 1 patient. A grade of excellent or good occurred in 96% of cases. One patient relapsed 3 months after surgery and then underwent lumbar interbody fusion and inner fixation. The numerical rating scale of preoperative leg pain was 7.4 +/- 1.5, whereas it decreased to 2.1 +/- 0.8 at 7 days after surgery. The preoperative Oswestry disability index of lumbar function was 57.5 +/- 10.0, whereas it was 26.0 +/- 8.5 at 7 days after surgery. CONCLUSION: In these cases, microendoscopic discectomy was able to achieve satisfactory clinical results. Furthermore, it has advantages over other methods because of its smaller incision, reduced bleeding and more efficient recovery. PMID- 25789522 TI - Effects of ischemic preconditioning in a pig model of large-for-size liver transplantation. AB - OBJECTIVE: In most cases of pediatric liver transplantation, the clinical scenario of large-for-size transplants can lead to hepatic dysfunction and a decreased blood supply to the liver graft. The objective of the present experimental investigation was to evaluate the effects of ischemic preconditioning on this clinical entity. METHODS: Eighteen pigs were divided into three groups and underwent liver transplantation: a control group, in which the weights of the donors were similar to those of the recipients, a large-for-size group, and a large-for-size + ischemic preconditioning group. Blood samples were collected from the recipients to evaluate the pH and the sodium, potassium, aspartate aminotransferase and alanine aminotransferase levels. In addition, hepatic tissue was sampled from the recipients for histological evaluation, immunohistochemical analyses to detect hepatocyte apoptosis and proliferation and molecular analyses to evaluate the gene expression of Bax (pro-apoptotic), Bcl-XL (anti-apoptotic), c-Fos and c-Jun (immediate-early genes), ischemia-reperfusion related inflammatory cytokines (IL-1, TNF-alpha and IL-6, which is also a stimulator of hepatocyte regeneration), intracellular adhesion molecule, endothelial nitric oxide synthase (a mediator of the protective effect of ischemic preconditioning) and TGF-beta (a pro-fibrogenic cytokine). RESULTS: All animals developed acidosis. At 1 hour and 3 hours after reperfusion, the animals in the large-for-size and large-for-size + ischemic preconditioning groups had decreased serum levels of Na and increased serum levels of K and aspartate aminotransferase compared with the control group. The molecular analysis revealed higher expression of the Bax, TNF-alpha, I-CAM and TGF-beta genes in the large for-size group compared with the control and large-for-size + ischemic preconditioning groups. Ischemic preconditioning was responsible for an increase in c-Fos, IL-1, IL-6 and e-NOS gene expression. CONCLUSION: Ischemia-reperfusion injury in this model of large-for-size liver transplantation could be partially attenuated by ischemic preconditioning. PMID- 25789523 TI - Trypsin inhibitor from tamarindus indica L. seeds reduces weight gain and food consumption and increases plasmatic cholecystokinin levels. AB - OBJECTIVES: Seeds are excellent sources of proteinase inhibitors, some of which may have satietogenic and slimming actions. We evaluated the effect of a trypsin inhibitor from Tamarindus indica L. seeds on weight gain, food consumption and cholecystokinin levels in Wistar rats. METHODS: A trypsin inhibitor from Tamarindus was isolated using ammonium sulfate (30-60%) following precipitation with acetone and was further isolated with Trypsin-Sepharose affinity chromatography. Analyses were conducted to assess the in vivo digestibility, food intake, body weight evolution and cholecystokinin levels in Wistar rats. Histological analyses of organs and biochemical analyses of sera were performed. RESULTS: The trypsin inhibitor from Tamarindus reduced food consumption, thereby reducing weight gain. The in vivo true digestibility was not significantly different between the control and Tamarindus trypsin inhibitor-treated groups. The trypsin inhibitor from Tamarindus did not cause alterations in biochemical parameters or liver, stomach, intestine or pancreas histology. Rats treated with the trypsin inhibitor showed significantly elevated cholecystokinin levels compared with animals receiving casein or water. CONCLUSION: The results indicate that the isolated trypsin inhibitor from Tamarindus reduces weight gain by reducing food consumption, an effect that may be mediated by increased cholecystokinin. Thus, the potential use of this trypsin inhibitor in obesity prevention and/or treatment should be evaluated. PMID- 25789524 TI - Steroidogenesis-related gene expression in the rat ovary exposed to melatonin supplementation. AB - OBJECTIVE: To analyze steroidogenesis-related gene expression in the rat ovary exposed to melatonin supplementation. METHODS: Thirty-two virgin adult female rats were randomized to two groups as follows: the control group GI received vehicle and the experimental group GII received melatonin supplementation (10 ug/night per animal) for 60 consecutive days. After the treatment, animals were anesthetized and the collected ovaries were immediately placed in liquid nitrogen for complementary deoxyribonucleic acid microarray analyses. A GeneChip((r)) Kit Rat Genome 230 2.0 Affymetrix Array was used for gene analysis and the experiment was repeated three times for each group. The results were normalized with the GeneChip((r)) Operating Software program and confirmed through analysis with the secondary deoxyribonucleic acid-Chip Analyzer (dChip) software. The data were confirmed by real-time reverse transcription polymerase chain reaction analysis. Genes related to ovarian function were further confirmed by immunohistochemistry. RESULTS: We found the upregulation of the type 9 adenylate cyclase and inhibin beta B genes and the downregulation of the cyclic adenosine monophosphate response element modulator and cytochrome P450 family 17a1 genes in the ovarian tissue of GII compared to those of the control group. CONCLUSION: Our data suggest that melatonin supplementation decreases gene expression of cyclic adenosine monophosphate, which changes ovarian steroidogenesis. PMID- 25789525 TI - Psychosocial factors and T lymphocyte counts in Brazilian peacekeepers. AB - OBJECTIVE: To investigate the associations between psychosocial factors and peripheral blood CD4 and CD8 T lymphocyte numbers in Brazilian peacekeepers. METHODS: Venous blood was collected from 759 peacekeepers who had just returned from a peace mission in Haiti. Among the 759 soldiers, 642 individuals completed the psychosocial measures. CD4 and CD8 T lymphocyte counts were measured by flow cytometry using a commercially available kit. Psychosocial factors, including military peace force stressors, clinical stress, anxiety and depression, were recorded. As a reference for T lymphocyte numbers, we measured T lymphocyte counts in 75 blood donors from the Instituto de Biologia do Exercito, Rio de Janeiro. RESULTS: The median numbers of CD4 and CD8 T lymphocytes in the blood donors were 819 cells/ul and 496 cells/ul, respectively, with a CD4:CD8 ratio of 1.6. Significantly (p<0.05) lower CD4 T cell counts (759 cells/ul) were recorded for peacekeepers, with similar CD8 levels (548 cells/ul) and smaller CD4:CD8 ratios (1.3, p<0.001) compared to blood donors. These differences were due to a group of 14 military personnel with CD4 and CD8 medians of 308 and 266 cells/ul, respectively. Only one (7.1%) of these 14 individuals was diagnosed with clinical stress compared with 13.5% of the individuals with normal levels of CD4 T lymphocytes. One individual out of 628 (0.16%) had a Lipp's Stress Symptom Inventory score of 3, indicating near exhaustion. CONCLUSION: The prevalence of psychological disorders was low and there were no associations with CD4 or CD8 T cell numbers. PMID- 25789528 TI - Godspeed: the journey to simple, systematic, and sustainable scientific exchange. PMID- 25789526 TI - EML4 promotes the loading of NUDC to the spindle for mitotic progression. AB - Echinoderm microtubule-associated protein (EMAP)-like (EML) family proteins are microtubule-associated proteins that have a conserved hydrophobic EMAP-like protein (HELP) domain and multiple WD40 domains. In this study, we examined the role of EML4, which is a member of the EML family, in cell division. Time-lapse microscopy analysis demonstrated that EML4 depletion induced chromosome misalignment during metaphase and delayed anaphase initiation. Further analysis by immunofluorescence showed that EML4 was required for the organization of the mitotic spindle and for the proper attachment of kinetochores to microtubules. We searched for EML4-associating proteins by mass spectrometry analysis and found that the nuclear distribution gene C (NUDC) protein, which is a critical factor for the progression of mitosis, was associated with EML4. This interaction was mediated by the WD40 repeat of EML4 and by the C-terminus of NUDC. In the absence of EML4, NUDC was no longer able to localize to the mitotic spindle, whereas NUDC was dispensable for EML4 localization. Our results show that EML4 is critical for the loading of NUDC onto the mitotic spindle for mitotic progression. PMID- 25789530 TI - Reproducible and Reliable Real-time PCR Assay to Measure Mature Form of miR-141. AB - miR-141 is one of the miRNAs that has significant expression variations in different human malignancies including prostate cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, gastric cancer, and ovarian cancer. Furthermore, various studies have designated miR-141 as a prognostic and diagnostic biomarker in different types of cancer. Thus, accurate and precise quantification of miR-141 is very essential for clinical diagnostics. In this regard, development of a reproducible and reliable assay for miR-141 can be the first step to standardize quantification of this valuable biomarker for in vitro diagnostics assays. Using stem-loop approach, we designed a Taqman real-time PCR assay for miR-141. This method allowed us to reproducibly and reliably quantify miR-141. The specificity, sensitivity, interassay and intraassay, and the dynamic range of the method were determined. The assay had a linear dynamic range of 3E 9.6E copies/reaction and the limit of detection was determined to be between 960 and 192 copies/reaction with 95% confidence interval. In addition, the R2 rate was >0.99 and the slope of the standard curve >-3.27, indicating great amplification efficiency, which is >99%. The coefficient of variation for Ct values was <1.9% and 2.39% for intraassay and interassay, respectively. Therefore, this study can be the first step to standardize miR-141 evaluations, which consequently assist the physicians for improved prognosis, diagnosis, and treatment. PMID- 25789531 TI - Close relation of large cell carcinoma to adenocarcinoma by hierarchical cluster analysis: implications for histologic typing of lung cancer on biopsies. AB - Determining histologic types of lung cancer on biopsies can be difficult. This study addresses the role of immunohistochemistry in histologic typing, using a tissue microarray (TMA) as "model biopsies," and presents a classification generated by an unsupervised hierarchical cluster analysis. A TMA was made from resection specimens of a consecutive series of 165 lung tumors. In a "tissue-spot review" with hematoxylin and eosin sections all the large cell carcinomas (N=22) were assigned to the noncommittal class of non-small cell lung cancer (NSCLC), as were an additional 37 tumors of defined histologic types. Adenocarcinomas and squamous cell carcinomas included with these NSCLC could be diagnosed by immunohistochemistry with antibodies against TTF-1, Napsin A, cytokeratin (CK)7, p40, p63, and CK5/6 with moderate to good sensitivities and specificities. Unsupervised hierarchical clustering was done with these data and additional high molecular-weight cytokeratins, CD56, synaptophysin, and chromogranin immunohistochemistry. This delineated separate clusters for adenocarcinomas, large cell carcinomas, neuroendocrine tumors, and squamous cell carcinomas. Notably, adenocarcinoma and large cell carcinoma clusters were closely related and clearly set off from the squamous cell carcinoma cluster. As would be expected for a clinically well-staged series CDX2, GATA3, estrogen, and progesterone receptor immunohistochemistry remained negative in the vast majority of the tumors and, if positive, were restricted to very few cells. These results, the clustering data in particular, underpin the pragmatic recommendation canvassed with the IASLC/ATS/ERS classification of lung cancers that adenocarcinoma-type molecular studies should include NSCLC with a nonsquamous cell carcinoma immunophenotype. PMID- 25789532 TI - Immunohistochemical Localization of Wild-type EGFR, E746-A750 Frame Deletion in Exon 19, and L858R Point Mutation in Exon 21 in Triple-negative Breast Cancer. AB - AIM: This study evaluated wild-type EGFR, E746-A750 frame deletion in exon 19, and L858R point mutation in exon 21 by immunohistochemistry in patients with triple-negative breast cancer (TNBC). METHODS: A retrospective study included 99 untreated early-stage and advanced-stage TNBC patients. Immunohistochemical localization of wild-type EGFR, EGFR E746-A750 deletion in exon 19, and EGFR L858R mutation in exon 21 was performed on formalin-fixed paraffin-embedded tissue blocks using mutation-specific primary antibodies. RESULTS: EGFR protein expression was noted in 27% (27/99) of patients with 2+ or 3+ staining intensity in 7% (7/99) of patients. Significant correlation of EGFR protein expression with subgroups of clinicopathologic parameters was not found. In univariate and multivariate survival analysis, high EGFR expression (2+ or 3+) emerged as a significant prognostic factor for disease-free survival. With respect to mutation status, exon 19 deletion was observed in 3% (3/99) of patients. One patient with exon 19 deletion having high EGFR protein (2+) expression developed lung metastasis, whereas the other 2 patients with exon 19 deletion had low EGFR protein (1+) expression and remained disease free during the study period. CONCLUSIONS: EGFR protein overexpression was observed in one fourth of TNBCs with very low incidence of EGFR-activating mutations in patients of western India. PMID- 25789533 TI - Malignant Transformation in Von-Meyenburg Complexes: Histologic and Immunohistochemical Clues With Illustrative Cases. AB - Benign developmental defects known as Von-Meyenburg complexes (VMCs) have been postulated to progress to cholangiocarcinoma (CC) in rare instances. Although a gradual, sequential histologic transition from VMCs to CC has been described in some of these cases, the underlying genetic mechanism is yet to be elucidated. Here, we review the literature to put together a report on the clinicopathologic features and immunohistochemical changes associated with such transformation. We also review the documented association between CC and p16 inactivation, and discuss a possible role for this mechanism to contribute in VMCs to CC progression. In addition, using 2 illustrative cases encountered at our institute, we provide morphologic and immunohistochemical clues that can be used to detect such progression from hamartoma to malignancy. These cases and the accompanying review of literature further solidify the association between VMCs and CC. PMID- 25789534 TI - Determination of True ERBB2 Gene Amplification in Breast Cancer by Quantitative PCR Using a Reference and a Novel Control Gene. AB - Human epidermal growth factor receptor 2 (ERBB2/HER2) is amplified and overexpressed in 20% to 25% of breast carcinomas, correlates with poor outcome, and is an indication for treatment with trastuzumab. Accurate assessment of ERBB2 status is crucial for proper prognosis and to offer appropriate treatment for patients. ERBB2 status is generally determined by immunohistochemistry or fluorescence in situ hybridization (FISH), and sporadically by quantitative real time polymerase chain reaction (PCR). We developed a new algorithm, termed quantitative PCR algorithm (QPA) score, and compared its performance with the gold standard FISH assay. The QPA is a computation of the relative number of copies of the ERBB2 gene with respect to a nonstandard, short-arm centromeric sequence on chromosome 17, and referenced to a single-copy gene, RPP30. This provides a more reliable determination of ERBB2 amplification, reducing the false polysomy 17 error. A total of 69 breast carcinoma samples were tested for quantitative real-time PCR and FISH, and the degree of concordance was analyzed. Sixty-two cases were in agreement between the 2 methods, and the contingency study assigned a kappa value of 0.729 for their correlation. A receiver operating characteristic analysis was used to determine the optimal cut-off point for ERBB2 amplification, which was estimated at a QPA=1.53 (sensitivity=0.863; specificity=0.944). Our data conclude that the QPA is able to determine ERBB2 gene status with high accuracy, while also overcoming the limitations of conventional techniques and providing better cost-effectiveness. PMID- 25789535 TI - EGFR Promoter Methylation, EGFR Mutation, and HPV Infection in Chinese Cervical Squamous Cell Carcinoma. AB - Therapy strategy toward epidermal growth factor receptor (EGFR) inhibition in cervical cancer has been ongoing. EGFR promoter methylation status and EGFR tyrosine kinase inhibitor-sensitive mutations in cervical cancer may be significant for clinical outcome prediction using anti-EGFR treatment. In this study, EGFR tyrosine kinase inhibitor-sensitive mutations, EGFR exons 18, 19, and 21 mutations, were detected by sequencing in a total of 293 Chinese cervical squamous cell carcinoma tissue samples. EGFR promoter methylation status was detected by an EGFR asymmetric PCR and hybridization-fluorescence polarization assay and sequencing in 293 Chinese cervical squamous cell carcinoma tissue samples. High-risk human papillomavirus (HPV) genotypes in 293 Chinese cervical squamous cell carcinoma tissue samples were detected by an asymmetric GP5+/6+ PCR and hybridization-fluorescence polarization assay. No EGFR exons 18, 19, and 21 mutations were detected, EGFR promoter methylation status was identified in 98 samples, and HPV 16 infection was the first frequent HPV genotype. The methylated EGFR promoter was identified most frequently in cervical squamous cell carcinoma samples with HPV 16 infection (53.4%). Statistical significant difference of EGFR promoter methylation prevalence was found between HPV 16 and other HPV genotypes (P<0.01). This study suggested that there was no EGFR tyrosine kinase inhibitor sensitive mutation in EGFR exons 18, 19, and 21 in Chinese cervical squamous cell carcinoma tissue samples. EGFR promoter methylation was common and it might be associated with HPV 16 infection in Chinese cervical squamous cell carcinoma. The results provided a novel understanding and an applicable pharmacogenomic tool for individualized management of cervical cancer patients. PMID- 25789536 TI - The Long-term Prognostic Performance of Ki-67 in Primary Operable Breast Cancer and Evaluation of Its Optimal Cutoff Value. AB - Markers of proliferation are considered to have prognostic importance in breast cancer (BC). The Ki-67 index has been reported as a prognostic factor, but standardized cutoff values and counting methods are not yet established. We assayed the Ki-67 labeling index (LI) of 589 consecutive operable BC patients who underwent surgical resection. Ki-67 immunostaining was performed, and the LI was manually counted using an image processing program. We also compared the manual cell count (MCC) of Ki-67 to the whole-section eyeballed estimate count (EEC). Univariate survival analysis showed statistically significant differences in long term BC-specific survival in the following factors: tumor size, histologic grade, nuclear grade, lymph node metastasis stage, estrogen receptor, progesterone receptor, human epidermal growth factor-2 (HER2) status, and intrinsic type (P<0.05). The MCC and EEC Ki-67 evaluations were statistically well correlated (Pearson correlation=0.683, P<0.001). Their agreement rate was highest at a 20% cutoff (kappa-coefficient=0.464). With cutoff values of 14% and 20%, high Ki-67 LI was associated with poor BC-specific survival (P=0.028 and 0.012, respectively), and a 20% cutoff had a higher hazard ratio. High Ki-67 LI with a 20% cutoff was also associated with poor survival in the hormone receptor positive and lymph node-positive subgroups (P=0.015 and 0.016, respectively). In conclusion, Ki-67 LI had prognostic significance, especially in hormone receptor positive and lymph node-positive BC patients. EEC was relatively reliable counting method with a higher cutoff value. We suggest that the 20% cutoff value be the preferable value in clinical practice. PMID- 25789537 TI - Pseudosarcomatous Spindle Cell Proliferation With Osteoid Matrix Mimicking Osteosarcoma: A Distinct Histologic Phenotype in Giant Cell Tumor of Bone Following Denosumab Therapy. PMID- 25789538 TI - Altered Splicing of JARID1B in Development of Human Cutaneous Melanoma? AB - Upregulated expression of histone H3K4 demethylase JARID1B has been found in several types of human cancer, but the expression pattern of this protein in benign naevi and human cutaneous melanomas seems to differ from that described for other tumors. We demonstrate that the apparent contradiction may be because of the fact that the malignant transformation of melanocytes is associated not so much with a general enhancement of a total expression of JARID1B but rather with a change in relative expression levels of individual splicing variants of the protein. Our data indicate that parallel immunohistochemical assays of the expression levels of all the isoforms and of the RBP2-H1 variant of JARID1B may be an efficient technique of differentiating between benign naevi and melanomas. PMID- 25789539 TI - Incidental Finding of Cystic Pancreatic Schwannoma Mimicking a Neuroendocrine Tumor. PMID- 25789540 TI - Molecular Characterization, Antibiotic Resistance, and Virulence Factors of Methicillin-Resistant Staphylococcus aureus Strains Isolated from Imported and Domestic Meat in Korea. AB - During a nationwide surveillance in Korea, 13 methicillin-resistant Staphylococcus aureus (MRSA) strains were isolated from imported and domestic meat between 2009 and 2011. The predominant MRSA genotype was SCCmec type V, and only two agr types (I and II) were found. Unexpectedly, sequence type ST72 comprised more than 50% of the isolates; this is the first instance of type ST72 in food from Canada. Two Spanish pork isolates were ST398, which caused human disease in Europe, and they carried leukotoxin genes, lukS, lukF, and lukE-lukD. Furthermore, P71 and P6 harbored all of the known leukocidin genes, lukS-lukF lukE-lukD-lukM. Our collected MRSA strains were multidrug resistant with various antimicrobial and heavy-metal resistance genes. Toxin genes that are commonly found in clinical MRSA also were detected in our meat strains. One MRSA strain exhibited an uncommon type of enterotoxin, sec-see-seg-sei-sel-sem-sen-seo-sep. Plasmids (1.5-15.0 kb) were found in 12 of the 13 MRSA isolates. Repetitive sequence-based polymerase chain reaction of the genomic DNA showed 3 clusters with 95% similarity. The presence of multidrug-resistant and toxigenic MRSA in meat products suggests that comprehensive surveillance should be continued for imported meats in Korea. PMID- 25789541 TI - Long-term results of laparoscopic pancreaticoduodenectomy for pancreatic and periampullary cancer-experience of 130 cases from a tertiary-care center in South India. AB - BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD), although an advanced surgical procedure, is being increasingly used for pancreatic head and periampullary tumors. We present our experience of 15 years with the largest series in total LPD for periampullary and pancreatic head tumors with data on oncological outcome and long-term survival. MATERIALS AND METHODS: Prospective and retrospective data of patients undergoing LPD from March 1998 to April 2013 were reviewed. Of the 150 cases, 20 cases of LPD (7 cases done for chronic pancreatitis and 13 cases for benign cystic tumors of the pancreas) have been excluded, which leaves us with 130 cases of LPD performed for malignant indications. RESULTS: In total, 130 patients were chosen for the study. The male:female ratio was 1:1.6, with a median age of 54 years. We had one conversion to open surgery in our series, the overall postoperative morbidity was 29.7%, and the mortality rate was 1.53%. The pancreatic fistula rate was 8.46%. The mean operating time was 310+/-34 minutes, and the mean blood loss was 110+/-22 mL. The mean hospital stay was 8+/-2.6 days. Resected margins were positive in 9.23% of cases. The mean tumor size was 3.13+/-1.21 cm, and the mean number of retrieved lymph nodes was 18.15+/-4.73. The overall 5-year actuarial survival was 29.42%, and the median survival was 33 months. CONCLUSIONS: LPD has evolved over a period of two decades and has the potential to become the standard of care for select periampullary and pancreatic head tumors with acceptable oncological outcomes, especially in high-volume centers. Randomized controlled trials are needed to establish the advantages of LPD. PMID- 25789542 TI - Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects. AB - We have recently shown that dipyrone (metamizole), a non-opioid analgesic, can nullify aspirin (acetylsalicylic acid; ASA) antiplatelet effects in patients with coronary artery disease (CAD). In this study, we analysed the aspirin and dipyrone drug-drug interaction in order to identify strategies to prevent the dipyrone induced inhibition of asprin antiplatelet effects. Platelet function was measured by arachidonic acid-induced light-transmission aggregometry, thromboxane (TX) B2- formation by immunoassay. Dipyrone metabolite plasma levels were determined by high-performance-liquid-chromatography (HPLC). In seven healthy individuals, in vitro ASA (30 uM/ 100 uM/ 300 uM/ 1,000 uM) and dipyrone (10 uM) coincubation revealed, that the aspirin and dipyrone interaction can be overcome by increasing doses of aspirin. In 36 aspirin and dipyrone comedicated CAD patients, addition of ASA (30 uM/ 100 uM) in vitro inhibited, but did not completely overcome the dipyrone induced reduction of aspirin antiplatelet effects. Notably, the inhibition of thromboxane formation in aspirin and dipyrone comedicated CAD patients coincided with dipyrone plasma levels. In a cross-over designed study in four healthy individuals, we were able to prove that inhibition of aspirin (100 mg/ day) effects by dipyrone (750 mg/ day) was reversible. Furthermore, aspirin (100 mg/ day) medication prior to dipyrone (750 mg/ day) intake prevented the inhibition of antiplatelet effects by dipyrone in 12 healthy individuals. In conclusion, aspirin medication prior to dipyrone intake preserves antiplatelet effects, circumventing the pharmacodynamic drug-drug interaction at the level of cyclooxygenase-1. PMID- 25789543 TI - Serum Glial Fibrillary Acidic Protein Predicts Tissue Glial Fibrillary Acidic Protein Break-Down Products and Therapeutic Efficacy after Penetrating Ballistic Like Brain Injury. AB - Acute traumatic brain injury (TBI) is associated with neurological dysfunction, changes in brain proteins, and increased serum biomarkers. However, the relationship between these brain proteins and serum biomarkers, and the ability of these serum biomarkers to indicate a neuroprotective/therapeutic response, remains elusive. Penetrating ballistic-like brain injury (PBBI) was used to systematically analyze several key TBI biomarkers, glial fibrillary acidic protein (GFAP) and its break-down products (BDPs)-ubiquitin C-terminal hydrolase L1 (UCH-L1), alpha-II spectrin, and alpha-II spectrin BDPs (SBDPs)-in brain tissues and serum during an extended acute-subacute time-frame. In addition, neurological improvement and serum GFAP theranostic value was evaluated after neuroprotective treatment. In brain tissues, total GFAP increased more than three fold 2 to 7 d after PBBI. However, this change was primarily due to GFAP-BDPs which increased to 2.7-4.8 arbitrary units (AU). Alpha-II spectrin was nearly ablated 3 d after PBBI, but somewhat recovered after 7 d. In conjunction with alpha-II spectrin loss, SBDP-145/150 increased approximately three-fold 2 to 7 d after PBBI (vs. sham, p<0.05). UCH-L1 protein levels were slightly decreased 7 d after PBBI but otherwise were unaffected. Serum GFAP was elevated by 3.2- to 8.8 fold at 2 to 4 h (vs. sham; p<0.05) and the 4 h increase was strongly correlated to 3 d GFAP-BDP abundance (r=0.66; p<0.05). Serum GFAP showed such a strong injury effect that it also was evaluated after therapeutic intervention with cyclosporin A (CsA). Administration of 2.5 mg/kg CsA significantly reduced serum GFAP elevation by 22.4-fold 2 h after PBBI (vs. PBBI+vehicle; p<0.05) and improved neurological function 1 d post-injury. Serum biomarkers, particularly GFAP, may be correlative tools of brain protein changes and feasible theranostic markers of TBI progression and recovery. PMID- 25789544 TI - PEGylated human serum albumin (HSA) nanoparticles: preparation, characterization and quantification of the PEGylation extent. AB - Modification with poly(ethylene glycol) (PEG) is a widely used method for the prolongation of plasma half-life of colloidal carrier systems such as nanoparticles prepared from human serum albumin (HSA). However, the quantification of the PEGylation extent is still challenging. Moreover, the influence of different PEG derivatives, which are commonly used for nanoparticle conjugation, has not been investigated so far. The objective of the present study is to develop a method for the quantification of PEG and to monitor the influence of diverse PEG reagents on the amount of PEG linked to the surface of HSA nanoparticles. A size exclusion chromatography method with refractive index detection was established which enabled the quantification of unreacted PEG in the supernatant. The achieved results were confirmed using a fluorescent PEG derivative, which was detected by photometry and fluorimetry. Additionally, PEGylated HSA nanoparticles were enzymatically digested and the linked amount of fluorescently active PEG was directly determined. All the analytical methods confirmed that under optimized PEGylation conditions a PEGylation efficiency of up to 0.5 mg PEG per mg nanoparticle could be achieved. Model calculations made a 'brush' conformation of the PEG chains on the particle surface very likely. By incubating the nanoparticles with fetal bovine serum the reduced adsorption of serum proteins on PEGylated HSA nanoparticles compared to non-PEGylated HSA nanoparticles was demonstrated using sodium dodecylsulfate polyacrylamide gel electrophoresis. Finally, the positive effect of PEGylation on plasma half-life was demonstrated in an in vivo study in mice. Compared to unmodified nanoparticles the PEGylation led to a four times larger plasma half-life. PMID- 25789545 TI - Therapeutic potential of mitotic interaction between the nucleoporin Tpr and aurora kinase A. AB - Spindle poles are defined by centrosomes; therefore, an abnormal number or defective structural organization of centrosomes can lead to loss of spindle bipolarity and genetic integrity. Previously, we showed that Tpr (translocated promoter region), a component of the nuclear pore complex (NPC), interacts with Mad1 and dynein to promote proper chromosome segregation during mitosis. Tpr also associates with p53 to induce autophagy. Here, we report that Tpr depletion induces mitotic catastrophe and enhances the rate of tetraploidy and polyploidy. Mechanistically, Tpr interacts, via its central domain, with Aurora A but not Aurora B kinase. In Tpr-depleted cells, the expression levels, centrosomal localization and phosphorylation of Aurora A were all reduced. Surprisingly, an Aurora A inhibitor, Alisertib (MLN8237), also disrupted centrosomal localization of Tpr and induced mitotic catastrophe and cell death in a time- and dose dependent manner. Strikingly, over-expression of Aurora A disrupted Tpr centrosomal localization only in cells with supernumerary centrosomes but not in bipolar cells. Our results highlight the mutual regulation between Tpr and Aurora A and further confirm the importance of nucleoporin function in spindle pole organization, bipolar spindle assembly, and mitosis; functions that are beyond the conventional nucleocytoplasmic transport and NPC structural roles of nucleoporins. Furthermore, the central coiled-coil domain of Tpr binds to and sequesters extra Aurora A to safeguard bipolarity. This Tpr domain merits further investigation for its ability to inhibit Aurora kinase and as a potential therapeutic agent in cancer treatment. PMID- 25789546 TI - Pseudoloma neurophilia: a retrospective and descriptive study of nervous system and muscle infections, with new implications for pathogenesis and behavioral phenotypes. AB - Pseudoloma neurophilia is a microsporidium of zebrafish (Danio rerio) that preferentially infects neural tissue. It is one of the most common pathogens of zebrafish in research laboratories based on diagnostic data from the Zebrafish International Resource Center diagnostic service (Eugene, OR). Five hundred fifty nine zebrafish infected with P. neurophilia submitted to ZIRC from 86 laboratories between the years 2000 and 2013 were examined via histopathology to develop a retrospective study of the features of neural microsporidiosis. Parasite clusters (PCs) occurred in distinct axonal swellings, frequently with no associated inflammation. Inflammation was observed in viable cell bodies distant from PCs. Multiple PCs occasionally occurred within a single axon, suggesting axonal transport. PCs occurred most frequently in the spinal cord ventral white matter (40.3% of all PCs) and the spinal nerve roots (25.6%). Within the rhombencephalon, PCs were most common in the primary descending white matter tracts. Within the rhombencephalon gray matter, PCs occurred most frequently in the reticular formation and the griseum centrale (61% and 39%, respectively). High numbers of PCs within brain and spinal cord structures mediating startle responses and anxiety suggest that related behaviors could be altered by neural microsporidiosis. Infection could, therefore, introduce unacceptable variation in studies utilizing these behaviors. PMID- 25789547 TI - (D)-Ribose supplementation in the equine: lack of effect on glycated plasma proteins suggesting safety in humans. AB - BACKGROUND: d-Ribose is a popular dietary supplement for humans and the equine because of its crucial role in cellular bioenergetics. However, as a reducing sugar, it has been suggested that ingestion of d-ribose might promote the formation of glycated proteins in vivo with potential adverse consequences. OBJECTIVE: The aim of this study was to examine if d-Ribose would promote the formation of glycated proteins in vivo following exercise in training thoroughbred racehorses. METHODS: Two groups of horses received the supplement (30 and 50 g d-Ribose daily) for 17 weeks, during which period the horses were subjected to low-intensity exercises followed by high-intensity exercises. Blood samples were analyzed for glycated plasma proteins at baseline and following the 2 exercise regimens. RESULTS: This study shows that long-term ingestion of d Ribose at 30-50 g a day does not promote the formation of glycated plasma proteins in thoroughbred racehorses. Ribose supplementation also protected the horses from cramping while enhancing muscle recovery at the same time. No adverse effects were reported. CONCLUSION: Ribose supplementation is safe and does not cause glycation in vivo. This investigation also establishes safety of d-Ribose in thoroughbred racehorses, suggesting similar implications in humans as well. PMID- 25789549 TI - Typical weekly workload of under 15, under 17, and under 19 elite Portuguese football players. AB - This study aims to describe the time-motion and physiological performance profiles of footballers whose ages are under 15 (U15), under 17 (U17), and under 19 (U19) during a typical week of a competitive season. A total of 151 elite Portuguese players U15 (age 14.0 +/- 0.2; n = 56), U17 (age 15.8 +/- 0.4; n = 66), and U19 (age 17.8 +/- 0.6; n = 19) were monitored during 33 training sessions (TSs) (U15 n = 12; U17 n = 11; and U19 n = 10 TSs). The TS data were captured at 15 Hz by global positioning systems devices and divided into post match (session after the match), prematch (session before the match), and middle week (average of remaining sessions). The U15 middle week showed a higher number of sprints, distance covered in intermediate speed zones, and time spent above 90% HRmax, while the prematch presented a higher distance covered above 18 km . h(-1) and time spent below 75% HRmax. In U17, both prematch and post-match data presented lower values than middle-week data in most of the variables. The post match data in U19 presented higher values of distance covered above 13 km . h( 1), body impacts above 10 G, and time spent above 85% HRmax, while middle week showed higher values in body impacts in most of the zones. In addition, the prematch data presented 35% to 100% less values than the middle-week data. Understanding the weekly workload variations according to the competition and the developmental ages of the players can contribute to optimising short- and mid term planning. PMID- 25789550 TI - Higher haemoglobin levels and dedicated trauma admission are associated with survival after severe traumatic brain injury. AB - BACKGROUND: Prevention of secondary brain injury is a key component of acute management of patients with severe traumatic brain injury (TBI). Haemoglobin concentration may have an impact on optimization of cerebral oxygenation. Patients with TBI may best be served by an organized trauma service. The objective is to determine if haemoglobin concentration or dedicated trauma admission has an impact on outcomes after severe TBI. METHODS: This study retrospectively analysed consecutive patients with severe TBI admitted to a level I trauma centre over 3 years. Patients <16 years-old and with length of stay (LOS) <24 hours were excluded. Data were collected on demographics; injury severity; LOS; admission service; survival to discharge; and haemoglobin levels from hospital days 1-7. Data were also collected on number of transfusions of packed red blood cells. The sample was stratified based on admission service and survival to discharge. RESULTS: Of 147 patients (age = 54.1 +/- 3.7 years), overall mortality rate was 15.4% (n = 23). Overall, non-survivors had lower daily and 7-day mean haemoglobin levels (10.7 +/- 0.9 vs. 12.9 +/- 0.4 g dL(-1), p < 0.001). Non-surgical admissions had lower haemoglobin levels and a higher mortality rate (28.9% vs. 12.2%, p < 0.001) compared to dedicated trauma admissions. CONCLUSIONS: Among patients with severe TBI, higher haemoglobin levels and maintenance as a dedicated trauma admission are associated with higher survival to discharge. PMID- 25789548 TI - Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating, leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. Individuals with PCD caused by defective radial spoke (RS) heads are difficult to diagnose owing to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most mutations identified in human radial spoke genes (RSPH) are loss-of-function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the RS complex to improve diagnostics in PCD. We report 21 individuals with PCD (16 families) with biallelic mutations in RSPH9, RSPH4A, and RSPH1, including seven novel mutations comprising missense variants, and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with RS defects. Absence of RSPH4A due to mutations in RSPH4A results in deficient axonemal assembly of the RS head components RSPH1 and RSPH9. RSPH1 mutant cilia, lacking RSPH1, fail to assemble RSPH9, whereas RSPH9 mutations result in axonemal absence of RSPH9, but do not affect the assembly of the other head proteins, RSPH1 and RSPH4A. Interestingly, our results were identical in individuals carrying loss-of-function mutations, missense variants, or one amino acid deletion. Immunofluorescence analysis can improve diagnosis of PCD in patients with loss-of-function mutations as well as missense variants. RSPH4A is the core protein of the RS head. PMID- 25789551 TI - Highly Iterated Palindromic Sequences (HIPs) and Their Relationship to DNA Methyltransferases. AB - The sequence GCGATCGC (Highly Iterated Palindrome, HIP1) is commonly found in high frequency in cyanobacterial genomes. An important clue to its function may be the presence of two orphan DNA methyltransferases that recognize internal sequences GATC and CGATCG. An examination of genomes from 97 cyanobacteria, both free-living and obligate symbionts, showed that there are exceptional cases in which HIP1 is at a low frequency or nearly absent. In some of these cases, it appears to have been replaced by a different GC-rich palindromic sequence, alternate HIPs. When HIP1 is at a high frequency, GATC- and CGATCG-specific methyltransferases are generally present in the genome. When an alternate HIP is at high frequency, a methyltransferase specific for that sequence is present. The pattern of 1-nt deviations from HIP1 sequences is biased towards the first and last nucleotides, i.e., those distinguish CGATCG from HIP1. Taken together, the results point to a role of DNA methylation in the creation or functioning of HIP sites. A model is presented that postulates the existence of a GmeC-dependent mismatch repair system whose activity creates and maintains HIP sequences. PMID- 25789552 TI - Phylogeny and Taxonomy of Archaea: A Comparison of the Whole-Genome-Based CVTree Approach with 16S rRNA Sequence Analysis. AB - A tripartite comparison of Archaea phylogeny and taxonomy at and above the rank order is reported: (1) the whole-genome-based and alignment-free CVTree using 179 genomes; (2) the 16S rRNA analysis exemplified by the All-Species Living Tree with 366 archaeal sequences; and (3) the Second Edition of Bergey's Manual of Systematic Bacteriology complemented by some current literature. A high degree of agreement is reached at these ranks. From the newly proposed archaeal phyla, Korarchaeota, Thaumarchaeota, Nanoarchaeota and Aigarchaeota, to the recent suggestion to divide the class Halobacteria into three orders, all gain substantial support from CVTree. In addition, the CVTree helped to determine the taxonomic position of some newly sequenced genomes without proper lineage information. A few discrepancies between the CVTree and the 16S rRNA approaches call for further investigation. PMID- 25789553 TI - Aggregatibacter actinomycetemcomitans Invasion Induces Interleukin-1beta Production Through Reactive Oxygen Species and Cathepsin B. AB - Interleukin-1 (IL-1) cytokines, IL-1alpha, IL-1beta, and IL-18 play a crucial role in inflammatory responses in a variety of diseases including periodontitis. In this study, the periodontopathic bacterial pathogen, Aggregatibacter actinomycetemcomitans, induced cell death and cytokine release in macrophages. Cell viability was reduced by A. actinomycetemcomitans invasion using (3-[4, 5 dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assay. The production of IL-1beta in A. actinomycetemcomitans-invaded macrophage cells was detected by real-time reverse transcriptase-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Treatment with a caspase-1 inhibitor and silencing of the caspase-1 gene had no effect on IL-1beta secretion induced by A. actinomycetemcomitans invasion. Pattern recognition receptor, NLRP3 was upregulated in A. actinomycetemcomitans-invaded macrophages. However, NLRP3 knockdown had no effect on the secretion of IL-1beta in A. actinomycetemcomitans invaded RAW 264 cells. In addition, A. actinomycetemcomitans invasion induced the generation of reactive oxygen species (ROS) and the release of cathepsin B in RAW 264 cells. Interestingly, CA074-Me, a cathepsin B inhibitor, and N-Acetyl-l cysteine, a ROS inhibitor, prevented the production of IL-1beta induced by A. actinomycetemcomitans. Taken together, these results suggest A. actinomycetemcomitans induce IL-1beta production in RAW 264 cells through the production of ROS and cathepsin B, but not through the NLRP3/caspase-1 pathway. PMID- 25789554 TI - The zinc finger proteins ZNF644 and WIZ regulate the G9a/GLP complex for gene repression. AB - The G9a/GLP complex mediates mono- and dimethylation of Lys9 of histone H3 at specific gene loci, which is associated with transcriptional repression. However, the molecular mechanism by which the G9a/GLP complex is targeted to the specific gene loci for H3K9 methylation is unclear. In this study, with unbiased protein affinity purification, we found ZNF644 and WIZ as two core subunits in the G9a/GLP complex. ZNF644 and WIZ interact with the transcription activation domain of G9a and GLP, respectively. Moreover, both ZNF644 and WIZ contain multiple zinc finger motifs that recognize consensus DNA sequences. ZNF644 and WIZ target G9a and GLP to the chromatin and mediate the G9a/GLP complex-dependent H3K9 methylation as well as gene repression. Thus, our studies reveal two key subunits in the G9a/GLP complex that regulate the function of this histone methyltransferase complex. PMID- 25789555 TI - Lower limb muscle strength is associated with functional performance and quality of life in patients with systemic sclerosis. AB - BACKGROUND: Complaints of peripheral muscle weakness are quite common in patients with systemic sclerosis (SSc). It is likely that the muscle impairments may reduce the patients' exercise performance, which in turn may decrease their functional capacity and exert a direct impact on their quality of life. OBJECTIVES: To assess the peripheral and respiratory muscle strength in individuals with SSc and to investigate their correlation with the 6-min walk distance (6 MWD) and quality of life measurements. Moreover, we aimed to characterize their nutritional status, pulmonary function, functional capacity, and quality of life compared to the controls. METHOD: The present cross-sectional study included 20 patients with SSc and 20 control subjects. All of the participants were subjected to isometric dynamometry, surface electromyography, bioelectrical impedance analysis, pulmonary function testing, and the 6-min walk test. Patients with SSc also responded to the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: The individuals with SSc exhibited a reduction in quadriceps strength (p=0.0001), increased quadriceps fatigability (p=0.034), impaired pulmonary function, and a reduced 6 MWD (p=0.0001) compared to the controls. Quadriceps strength was significantly correlated with the 6 MWD (Rho=0.719; p=0.0004) and the HAQ-DI (Rho=-0.622; p=0.003). We also found significant correlations between quadriceps fatigability and maximal inspiratory (Rho=0.684; p=0.0009) and maximal expiratory (Rho=0.472; p=0.035) pressure. CONCLUSIONS: Patients with SSc exhibited reduced respiratory muscle and quadriceps strength and an increase in its fatigability. In these individuals, there was a relationship between quadriceps strength, functional capacity, and quality of life. PMID- 25789556 TI - Are 30 minutes of rest between two incremental shuttle walking tests enough for cardiovascular variables and perceived exertion to return to baseline values? AB - OBJECTIVE: To verify whether 30 minutes of rest between two incremental shuttle walking tests (ISWT) are enough for cardiovascular variables and perceived exertion to return to baseline values in healthy subjects in a broad age range. METHOD: The maximal exercise capacity of 334 apparently healthy subjects (age >= 18) was evaluated using the ISWT. The test was performed twice with 30 minutes of rest in between. Heart rate (HR), arterial blood pressure (ABP), dyspnea, and leg fatigue were evaluated before and after each test. Subjects were allocated to 6 groups according to their age: G1: 18-29 years; G2: 30-39 years; G3: 40-49 years; G4: 50-59 years; G5: 60-69 years and G6: >= 70 years. RESULTS: All groups had a good performance in the ISWT (median >90% of the predicted distance). The initial HR (HRi) of the second ISWT was higher than the first ISWT in the total sample (p<0.0001), as well as in all groups (p<0.0001). No difference was observed in the behavior of ABP (systolic and diastolic) and dyspnea between the two tests, but this difference occurred for leg fatigue (greater before the second ISWT) in G1 (p<0.05). Most subjects (58%) performed better in the second test. CONCLUSION: 30 minutes of rest between two ISWTs are not enough for all cardiovascular variables and perceived exertion to return to baseline values. However, this period appears to be sufficient for blood pressure and performance to recover in most subjects. PMID- 25789557 TI - Kinesio Taping effects on knee extension force among soccer players. AB - BACKGROUND: Kinesio Taping (KT) is widely used, however the effects of KT on muscle activation and force are contradictory. OBJECTIVE: To evaluate the effects of KT on knee extension force in soccer players. METHOD: This is a clinical trial study design. Thirty-four subjects performed two maximal isometric voluntary contractions of the lower limbs pre, immediately post, and 24 hours after tape application on the lower limbs. Both lower limbs were taped, using K-Tape and 3M Micropore tape randomly on the right and left thighs of the participants. Isometric knee extension force was measured for dominant side using a strain gauge. The following variables were assessed: peak force, time to peak force, rate of force development until peak force, time to peak rate of force development, and 200 ms pulse. RESULTS: There were no statistically significant differences in the variables assessed between KT and Micropore conditions (F=0.645, p=0.666) or among testing sessions (pre, post, and 24h after) (F=0.528, p=0.868), and there was no statistical significance (F=0.271, p=0.986) for interaction between tape conditions and testing session. CONCLUSION: KT did not affect the force-related measures assessed immediately and 24 hours after the KT application compared with Micropore application, during maximal isometric voluntary knee extension. PMID- 25789558 TI - Aptamer-based polyvalent ligands for regulated cell attachment on the hydrogel surface. AB - Natural biomolecules are often used to functionalize materials to achieve desired cell-material interactions. However, their applications can be limited owing to denaturation during the material functionalization process. Therefore, efforts have been made to develop synthetic ligands with polyvalence as alternatives to natural affinity biomolecules for the synthesis of functional materials and the control of cell-material interactions. This work was aimed at investigating the capability of a hydrogel functionalized with a novel polyvalent aptamer in inducing cell attachment in dynamic flow and releasing the attached cells in physiological conditions through a hybridization reaction. The results show that the polyvalent aptamer could induce cell attachment on the hydrogel in dynamic flow. Moreover, cell attachment on the hydrogel surface was significantly influenced by the value of shear stress. The cell density on the hydrogel was increased from 40 cells/mm(2) to nearly 700 cells/mm(2) when the shear stress was decreased from 0.05 to 0.005 Pa. After the attachment onto the hydrogel surface, approximately 95% of the cells could be triggered to detach within 20 min by using an oligonucleotide complementary sequence that displaced polyvalent aptamer strands from the hydrogel surface. While it was found that the cell activity was reduced, the live/dead staining results show that >=98% of the detached cells were viable. Therefore, this work has suggested that the polyvalent aptamer is a promising synthetic ligand for the functionalization of materials for regulated cell attachment. PMID- 25789559 TI - Probing and Exploiting the Interplay between Nuclear and Electronic Motion in Charge Transfer Processes. AB - The Born-Oppenheimer approximation refers to the assumption that the nuclear and electronic wave functions describing a molecular system evolve and can be determined independently. It is now well-known that this approximation often breaks down and that nuclear-electronic (vibronic) coupling contributes greatly to the ultrafast photophysics and photochemistry observed in many systems ranging from simple molecules to biological organisms. In order to probe vibronic coupling in a time-dependent manner, one must use spectroscopic tools capable of correlating the motions of electrons and nuclei on an ultrafast time scale. Recent developments in nonlinear multidimensional electronic and vibrational spectroscopies allow monitoring both electronic and structural factors with unprecedented time and spatial resolution. In this Account, we present recent studies from our group that make use of different variants of frequency-domain transient two-dimensional infrared (T-2DIR) spectroscopy, a pulse sequence combining electronic and vibrational excitations in the form of a UV-visible pump, a narrowband (12 cm(-1)) IR pump, and a broadband (400 cm(-1)) IR probe. In the first example, T-2DIR is used to directly compare vibrational dynamics in the ground and relaxed electronic excited states of Re(Cl)(CO)3(4,4'-diethylester 2,2'-bipyridine) and Ru(4,4'-diethylester-2,2'-bipyridine)2(NCS)2, prototypical charge transfer complexes used in photocatalytic CO2 reduction and electron injection in dye-sensitized solar cells. The experiments show that intramolecular vibrational redistribution (IVR) and vibrational energy transfer (VET) are up to an order of magnitude faster in the triplet charge transfer excited state than in the ground state. These results show the influence of electronic arrangement on vibrational coupling patterns, with direct implications for vibronic coupling mechanisms in charge transfer excited states. In the second example, we show unambiguously that electronic and vibrational movement are coupled in a donor bridge-acceptor complex based on a Pt(II) trans-acetylide design motif. Time resolved IR (TRIR) spectroscopy reveals that the rate of electron transfer (ET) is highly dependent on the amount of excess energy localized on the bridge following electronic excitation. Using an adaptation of T-2DIR, we are able to selectively perturb bridge-localized vibrational modes during charge separation, resulting in the donor-acceptor charge separation pathway being completely switched off, with all excess energy redirected toward the formation of a long lived intraligand triplet state. A series of control experiments reveal that this effect is mode specific: it is only when the high-frequency bridging C=C stretching mode is pumped that radical changes in photoproduct yields are observed. These experiments therefore suggest that one may perturb electronic movement by stimulating structural motion along the reaction coordinate using IR light. These studies add to a growing body of evidence suggesting that controlling the pathways and efficiency of charge transfer may be achieved through synthetic and perturbative approaches aiming to modulate vibronic coupling. Achieving such control would represent a breakthrough for charge transfer-based applications such as solar energy conversion and molecular electronics. PMID- 25789560 TI - Chemical methods for the simultaneous quantitation of metabolites and proteins from single cells. AB - We describe chemical approaches for integrated metabolic and proteomic assays from single cells. Quantitative assays for intracellular metabolites, including glucose uptake and three other species, are designed as surface-competitive binding assays with fluorescence readouts. This enables integration into a microarray format with functional protein immunoassays, all of which are incorporated into the microchambers of a single-cell barcode chip (SCBC). By using the SCBC, we interrogate the response of human-derived glioblastoma cancer cells to epidermal growth factor receptor inhibition. We report, for the first time, on both the intercellular metabolic heterogeneity as well as the baseline and drug-induced changes in the metabolite-phosphoprotein correlation network. PMID- 25789561 TI - Mechanistic studies on the Rh(III)-mediated amido transfer process leading to robust C-H amination with a new type of amidating reagent. AB - Mechanistic investigations on the Cp*Rh(III)-catalyzed direct C-H amination reaction led us to reveal the new utility of 1,4,2-dioxazol-5-one and its derivatives as highly efficient amino sources. Stepwise analysis on the C-N bond forming process showed that competitive binding of rhodium metal center to amidating reagent or substrate is closely related to the reaction efficiency. In this line, 1,4,2-dioxazol-5-ones were observed to have a strong affinity to the cationic Rh(III) giving rise to dramatically improved amidation efficiency when compared to azides. Kinetics and computational studies suggested that the high amidating reactivity of 1,4,2-dioxazol-5-one can also be attributed to the low activation energy of an imido-insertion process in addition to the high coordination ability. While the characterization of a cationic Cp*Rh(III) complex bearing an amidating reagent was achieved, its facile conversion to an amido inserted rhodacycle allowed for a clear picture on the C-H amidation process. The newly developed amidating reagent of 1,4,2-dioxazol-5-ones was applicable to a broad range of substrates with high functional group tolerance, releasing carbon dioxide as a single byproduct. Additional attractive features of this amino source, such as they are more convenient to prepare, store, and use when compared to the corresponding azides, take a step closer toward an ideal C-H amination protocol. PMID- 25789562 TI - Selective N-chelation-directed C-H activation reactions catalyzed by Pd(II) nanoparticles supported on multiwalled carbon nanotubes. AB - N-Chelation-directed C-H activation reactions that utilize the Pd(II)/Pd(IV) catalytic cycle have been previously reported. To date, these reactions employ only homogeneous palladium catalysts. The first use of a solid-supported Pd(II) catalyst [Pd(II) nanoparticles on multiwalled carbon nanotubes, Pd(II)/MWCNT] to carry out N-chelation-directed C-H to C-O, C-Cl, and C-Br transformations is reported. The results presented demonstrate that the solid-supported Pd(II)/MWCNT catalyst can effectively catalyze C-H activation reactions using the Pd(II)/Pd(IV) catalytic cycle. PMID- 25789563 TI - Massive hiatal hernia: a review. PMID- 25789564 TI - Fabrication of La2Ti2O7 crystals using an alkali-metal molybdate flux growth method and their nitridability to form LaTiO2N crystals under a high-temperature NH3 atmosphere. AB - Flux growth is a promising method that allows one to control over the crystalline phase, crystal shape, crystal size, and crystal surface through the selection of a suitable flux. In this work, lanthanum titanate (La2Ti2O7) crystals with different morphologies were grown using the Na2MoO4, K2MoO4, NaCl, and mixed NaCl + K2MoO4 (molar ratio = 3:7) fluxes, and their nitridability to form LaTiO2N crystals under a high-temperature NH3 atmosphere was also investigated. The effects of the solute concentration and cooling rate on the growth of the La2Ti2O7 crystals were also studied. The X-ray diffraction results revealed that the {100} plane was dominant in the La2Ti2O7 platelet crystals grown using the alkali-metal molybdate fluxes. When the solute concentration was increased from 1 to 20 mol %, the average size of the crystals decreased without considerable alteration of the overall crystal morphology. The La2Ti2O7 crystals with the preferred ?010? and ?001? growth directions along the b and c axes were grown using the Na2MoO4 and K2MoO4 fluxes, respectively. Compared to the Na2MoO4 flux, the K2MoO4 flux did not show a cooling-rate-dependent effect on the growth of the La2Ti2O7 crystals. It was found that conversion of the La2Ti2O7 crystals to the LaTiO2N crystals was strongly dependent on the flux used to grow the precursor La2Ti2O7 crystals. That is, the La2Ti2O7 crystals grown using the K2MoO4 and NaCl fluxes were nearly completely converted into the LaTiO2N crystals, while conversion of the La2Ti2O7 crystals grown using the Na2MoO4 and mixed NaCl + K2MoO4 fluxes to the LaTiO2N crystals seemed to be not completed yet even after nitridation at 950 degrees C for 15 h using NH3 because of the larger crystal size and the presence of unintentional impurities (sodium and molybdenum from the flux) in the La2Ti2O7 crystal lattice. Nevertheless, the LaTiO2N crystals fabricated by nitriding the La2Ti2O7 crystals grown using the K2MoO4 and NaCl fluxes should be suitable for direct solar water splitting. PMID- 25789566 TI - Parasitism overrides herbivore identity allowing hyperparasitoids to locate their parasitoid host using herbivore-induced plant volatiles. AB - Foraging success of predators profoundly depends on reliable and detectable cues indicating the presence of their often inconspicuous prey. Carnivorous insects rely on chemical cues to optimize foraging efficiency. Hyperparasitoids that lay their eggs in the larvae or pupae of parasitic wasps may find their parasitoid hosts developing in different herbivores. They can use herbivore-induced plant volatiles (HIPVs) to locate parasitized caterpillars. Because different herbivore species induce different HIPV emission from plants, hyperparasitoids may have to deal with large variation in volatile information that indicates host presence. In this study, we used an ecogenomics approach to first address whether parasitized caterpillars of two herbivore species (Pieris rapae and P. brassicae) induce similar transcriptional and metabolomic responses in wild Brassica oleracea plants and, second, whether hyperparasitoids Lysibia nana are able to discriminate between these induced plant responses to locate their parasitoid host in different herbivores under both laboratory and field conditions. Our study revealed that both herbivore identity and parasitism affect plant transcriptional and metabolic responses to herbivory. We also found that hyperparasitoids are able to respond to HIPVs released by wild B. oleracea under both laboratory and field conditions. In addition, we observed stronger attraction of hyperparasitoids to HIPVs when plants were infested with parasitized caterpillars. However, hyperparasitoids were equally attracted to plants infested by either herbivore species. Our results indicate that parasitism plays a major role in HIPV-mediated plant-hyperparasitoid interactions. Furthermore, these findings also indicate that plant trait-mediated indirect interaction networks play important roles in community-wide species interactions. PMID- 25789565 TI - p38/p53/miR-200a-3p feedback loop promotes oxidative stress-mediated liver cell death. AB - Although our previous studies have provided evidence that oxidative stress has an essential role in total parenteral nutrition (TPN)-associated liver injury, the mechanisms involved are incompletely understood. Here, we show the existence of crosstalk between the miR-200 family of microRNAs and oxidative stress. The members of the miR-200 family are markedly enhanced in hepatic cells by hydrogen peroxide (H2O2) treatment. The upregulation of miR-200-3p in turn modulates the H2O2-mediated oxidative stress response by targeting p38alpha. The enhanced expression of miR-200-3p mimics p38alpha deficiency and promotes H2O2-induced cell death. Members of the miR-200 family that are known to inhibit the epithelial to mesenchymal transition (EMT) are induced by the tumor suppressor p53. Here, we show that p53 phosphorylation at Ser 33 contributes to H2O2-induced miR-200s transcription. In addition, we show that p38alpha can directly phosphorylate p53 at serine 33 upon H2O2 exposure. Thus, we suggest that in liver cells, the oxidative stress-induced, p38alpha-mediated phosphorylation of p53 at Ser33 is essential for the functional regulation of oxidative stress-induced miR 200 transcription by p53. Collectively, our data indicate that the p53-dependent expression of miR-200a-3p promotes cell death by inhibiting a p38/p53/miR-200 feedback loop. PMID- 25789567 TI - Mitral valve replacement after MitraClip therapy. AB - BACKGROUND: MitraClip therapy (MCT) is becoming more popular to treat mitral regurgitation (MR) in high-risk patients. It is, however, expanding to lower risk patients with the idea that mitral valve (MV) repair can be performed if surgery will be necessary. We report our surgical experience in patients who underwent MCT and subsequently required MV surgery. METHODS: From February 2012 to September 2014, three patients out of 34 who underwent MCT (8.8%) needed surgery because of lesions resulting in new MR. Two of them had functional and the third one degenerative MR. Two patients with functional MR underwent emergency surgery for MV lesions adding a new severe MR, the third one, with degenerative MR, had surgery 377 days after MCT. RESULTS: The MV showed a perforation of the anterior leaflet in one case and P2 completely torn in the second case. MitraClip opening was difficult and caused further injury to the leaflets. The third case developed a severe MV stenosis. All three patients underwent MV replacement with a tissue valve. The postoperative course was uneventful and, after a mean of 14 months, all patients are alive and in NYHA class I or II. CONCLUSIONS: The risk of urgent or elective surgery after MCT reduces the possibility of conservative surgery, as the possibility of valve reconstruction is less likely following the severe clip implantation-induced tissue damages. PMID- 25789568 TI - Effects of the jaw-thrust manoeuvre in the semi-sitting position on securing a clear airway during fibreoptic intubation. AB - Securing a clear airway is important for successful fibreoptic intubation. We investigated whether the jaw-thrust manoeuvre in the 25 degrees semi-sitting position improves airway clearance compared with the supine position in 88 anaesthetised patients randomly assigned to the two positions. After induction of anaesthesia, the fibreoptic bronchoscope was advanced into the mouth along the dorsum of the tongue during the jaw-thrust manoeuvre. Airway clearance was assessed at the level of the soft palate and epiglottis. Patients in the 25 degrees semi-sitting position had clearer airways (judged subjectively by a three-level scale) than those in the supine position at the soft palate level (p = 0.012). At the level of the epiglottis, airway clearance was equally good in both positions. The mean (SD) times to view the vocal cord and carina were shorter in the 25 degrees semi-sitting position (4 (1) s and 8 (1) s, respectively) compared with the supine position (6 (3) s and 11 (3) s; p < 0.001, respectively). The time to achieve intubation was also shorter in the 25 degrees semi-sitting position (21 (5) s) than in the supine position (25 (7) s; p = 0.018). PMID- 25789569 TI - Jasmonoyl isoleucine accumulation is needed for abscisic acid build-up in roots of Arabidopsis under water stress conditions. AB - Phytohormones are central players in sensing and signalling numerous environmental conditions like drought. In this work, hormone profiling together with gene expression of key enzymes involved in abscisic acid (ABA) and jasmonate biosynthesis were studied in desiccating Arabidopsis roots. Jasmonic acid (JA) content transiently increased after stress imposition whereas progressive and concomitant ABA and Jasmonoyl Isoleucine (JA-Ile) accumulations were detected. Molecular data suggest that, at least, part of the hormonal regulation takes place at the biosynthetic level. These observations also point to a possible involvement of jasmonates on ABA biosynthesis under stress. To test this hypothesis, mutants impaired in jasmonate biosynthesis (opr3, lox6 and jar1-1) and in JA-dependent signalling (coi1) were employed. Results showed that the early JA accumulation leading to JA-Ile build up was necessary for an ABA increase in roots under two different water stress conditions. Signal transduction between water stress-induced JA-Ile accumulation and COI1 is necessary for a full induction of the ABA biosynthesis pathway and subsequent hormone accumulation in roots of Arabidopsis plants. The present work adds a level of interaction between jasmonates and ABA at the biosynthetic level. PMID- 25789570 TI - Erwinia amylovora pyrC mutant causes fire blight despite pyrimidine auxotrophy. AB - Erwinia amylovora bacteria cause fire blight disease, which affects apple and pear production worldwide. The Erw. amylovora pyrC gene encodes a predicted dihydroorotase enzyme involved in pyrimidine biosynthesis. Here, we discovered that the Erw. amylovora pyrC244::Tn5 mutant was a uracil auxotroph. Unexpectedly, the Erw. amylovora pyrC244::Tn5 mutant grew as well as the wild-type in detached immature apple and pear fruits. Fire blight symptoms caused by the pyrC244::Tn5 mutant in immature apple and pear fruits were attenuated compared to those caused by the wild-type. The pyrC244::Tn5 mutant also caused severe fire blight symptoms in apple tree shoots. A plasmid-borne copy of the wild-type pyrC gene restored prototrophy and symptom induction in apple and pear fruit to the pyrC244::Tn5 mutant. These results suggest that Erw. amylovora can obtain sufficient pyrimidine from the host to support bacterial growth and fire blight disease development, although de novo pyrimidine synthesis by Erw. amylovora is required for full symptom development in fruits. Significance and impact of the study: This study provides information about the fire blight host-pathogen interaction. Although the Erwinia amylovora pyrC mutant was strictly auxotrophic for pyrimidine, it grew as well as the wild-type in immature pear and apple fruits and caused severe fire blight disease in apple trees. This suggests that Erw. amylovora can obtain sufficient pyrimidines from host tissue to support growth and fire blight disease development. This situation contrasts with findings in some human bacterial pathogens, which require de novo pyrimidine synthesis for growth in host blood, for example. PMID- 25789571 TI - Seroepidemiology of Norovirus GII.3 and GII.4 Infections in Children with Diarrhea in Xi'an, China. AB - OBJECTIVE: The objective of this study was to investigate the seroepidemiology of immunoglobulin G (IgG) antibodies against Norovirus (NoV) GII.3 and GII.4 genotypes among children younger than 5 years with acute diarrhea in Xi'an, China. MATERIALS AND METHODS: A total of 362 serum samples were collected from diarrheal children in the Department of Digestive Diseases of Xi'an Children's Hospital between March 2009 and October 2012. Recombinant capsid proteins of NoV genotypes GII.3 and GII.4 were expressed using the baculovirus expression system. The viruslike particles (VLPs) were examined by electron microscopy and Western blot, and VLPs were used as antigens for serological IgG tests using enzyme linked immunosorbent assays. RESULTS: The overall seroprevalence for GII.4 (86.2%) was significantly higher (p<0.01) than for GII.3 (67.9%). The seroprevalence remained in a high and stable level (70.9% for GII.3 and 88.7% for GII.4) in children under 1 year of age, then dropped in the age group 12-17 months (49.3% for GII.3 and 68.1% for GII.4), and finally increased to 77.8% for GII.3 and 96.8% for GII.4 in the group >18 months. The seroprevalence in the age group 12-17 months showed more statistically significant differences than the other age groups for both GII.3 and GII.4 (p<0.05). CONCLUSIONS: In conclusion, seroprevalence of NoV GII.3 and GII.4 was high in young children in Xi'an, China, and the anti-GII.4-positive rates were statistically higher than GII.3 across all the age groups. PMID- 25789572 TI - Global incidence of rhabdomyolysis after cooked seafood consumption (Haff disease). AB - CONTEXT: Haff disease is a syndrome of myalgia and rhabdomyolysis that occurs after consuming cooked seafood. OBJECTIVES: (1) To identify the most common seafood vectors of Haff disease worldwide. (2) To describe and to compare the most commonly recurring clinical and laboratory manifestations of Haff disease. (3) To compare the Haff disease toxidrome with other similar toxidromes. METHODS: Internet search engines were queried with the keywords, and selected articles were stratified by reporting Old World or New World nations. Continuous variables were reported as means with standard deviations; categorical values were reported as proportions. RESULTS: Over 1,000 cases of Haff disease were initially described in Eastern Europe and Sweden during and following the ingestion of several species of cooked freshwater fish including burbot, pike, freshwater eel, and whitefish. More recent case reports followed consumption of cooked freshwater pomfret and boiled crayfish in China, and cooked or raw boxfish in Japan. There were 29 case reports of Haff disease in the United States with most following consumption of buffalo fish, crayfish, or Atlantic salmon. CONCLUSION: The consumption of several species of cooked fish has caused Haff disease outbreaks worldwide. The bioaccumulation of a new heat-stable, fresh, and/or brackish/ salt water algal toxin in seafood, similar to palytoxin, but primarily myotoxic and not neurotoxic, is suspected for causing Haff disease. PMID- 25789575 TI - Errors in author affiliations, corresponding author address, and end matter. Evaluation of the effect of platelet-rich plasma on recovery after ablative fractional photothermolysis. PMID- 25789576 TI - The Use of Indwelling Tunneled Pleural Catheters for Recurrent Pleural Effusions in Patients With Hematologic Malignancies: A Multicenter Study. AB - BACKGROUND: Malignant pleural effusion is a common complication of advanced malignancies. Indwelling tunneled pleural catheter (IPC) placement provides effective palliation but can be associated with complications, including infection. In particular, hematologic malignancy and the associated immunosuppressive treatment regimens may increase infectious complications. This study aimed to review outcomes in patients with hematologic malignancy undergoing IPC placement. METHODS: A retrospective multicenter study of IPCs placed in patients with hematologic malignancy from January 2009 to December 2013 was performed. Inclusion criteria were recurrent, symptomatic pleural effusion and an underlying diagnosis of hematologic malignancy. Records were reviewed for patient demographics, operative reports, and pathology, cytology, and microbiology reports. RESULTS: Ninety-one patients (mean +/- SD age, 65.4 +/- 15.4 years) were identified from eight institutions. The mean * SD in situ dwell time of all catheters was 89.9 +/- 127.1 days (total, 8,160 catheter-days). Seven infectious complications were identified, all of the pleural space. All patients were admitted to the hospital for treatment, with four requiring additional pleural procedures. Two patients died of septic shock related to pleural infection. CONCLUSIONS: We present, to our knowledge, the largest study examining clinical outcomes related to IPC placement in patients with hematologic malignancy. An overall 7.7% infection risk and 2.2% mortality were identified, similar to previously reported studies, despite the significant immunosuppression and pancytopenia often present in this population. IPC placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy. PMID- 25789577 TI - Cardiovascular Adverse Effects of Phenylephrine Eyedrops: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Topical phenylephrine hydrochloride is routinely administered with few safety precautions, but evidence regarding its systemic safety to date is controversial. As even short-term variations in 24-hour blood pressure (BP) and heart rate (HR) can adversely affect cardiovascular health, better evidence on phenylephrine's effects on HR and BP is required. OBJECTIVE: To perform a meta analysis of available evidence regarding cardiovascular adverse effects of topical phenylephrine. DATA SOURCES: PubMed, MEDLINE, and the Cochrane Database of Systematic Reviews and Clinical Trials were searched for relevant literature from January 1, 1970, to January 1, 2014, using a combination of the following search terms: topical, ocular, ophthalmic, phenylephrine, tropicamide, cardiovascular effect, side effect, blood pressure, heart rate, mydriatic, and eye drops. A total of 70 articles related to the topic were identified and all full texts were retrieved. STUDY SELECTION: Randomized clinical trials reporting change in BP and HR for adults were included in this review. All studies reporting results for neonates or infants, not reporting standard deviations, or not specifying the time of measurement or the concentration of phenylephrine used were excluded. DATA EXTRACTION AND SYNTHESIS: Data from randomized clinical trials that reported BP and/or HR as well as the time following administration of topical phenylephrine at which measurements were obtained by concentration of phenylephrine as a mean change and its standard deviation were extracted. Data were synthesized by concentration of phenylephrine and time of measurement following topical application using random-effects models with inverse variance weighting to account for heterogeneity across studies. MAIN OUTCOMES AND MEASURES: Difference in BP and HR after topical administration of phenylephrine. RESULTS: Eight RCTs with a total of 916 participants were included. Data were available for phenylephrine, 2.5%, at 20 to 30 minutes and 60 minutes or longer after administration, and neither BP nor HR changed at either time. Following application of phenylephrine, 10%, BP increased at 5 and 10 minutes (mean difference for both, +15 mm Hg; 95% CI, 11.94-18.54; P < .001) but decreased at 20 to 30 minutes and 60 minutes or longer with no changes detected against baseline. A mean increase in HR by 4.48 beats/min (95% CI, 1.09-7.88; P = .01) was present at 20 to 30 minutes following application of phenylephrine, 10%, and HR decreased by 60 minutes or longer with no changes detected compared with baseline. CONCLUSIONS AND RELEVANCE: Phenylephrine, 2.5%, leads to no clinically relevant change in BP or HR, and the changes in BP and HR seen with phenylephrine, 10%, are short lived. Thus, phenylephrine, 2.5%, is safe to use in clinical routine. PMID- 25789578 TI - Thermochemical hydrogen sensor based on chalcogenide nanowire arrays. AB - The hydrogen gas-sensing properties have been investigated of two types of thermochemical hydrogen (TCH) sensors composed of thermoelectric layers based on chalcogenide nanowire arrays and anodic aluminum oxide (AAO) templates. The monomorphic-type TCH sensor, which had only Bi2Te3 nanowire arrays, showed an output signal of 23.7 MUV in response to 5 vol% hydrogen gas at room temperature, whereas an output signal of 215 MUV was obtained from an n-p junction-type TCH sensor made of connected Bi2Te3 and Sb2Te3 nanowire arrays in an AAO template. Despite its small deposition area, the output signal of the n-p sensor was more than nine times that of the monomorphic sensor. This observation can be explained by the difference in electrical connections (parallel and serial conversions) in the TCH sensor between each type of nanowire array. Also, our n-p sensor had a wide detection range for hydrogen gas (from 400 ppm to 45 vol%) and a fast response time of 1.3 s at room temperature without requiring external power. PMID- 25789579 TI - Molecular Characterization of Community-Associated Methicillin-Resistant Staphylococcus aureus Isolated from Skin and Pus Samples of Outpatients in Japan. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is now endemic in the United States. In Japan, CA-MRSA infections and CA-MRSA surveillance have been scarcely reported. In this study, we conducted a nationwide survey of CA-MRSA in Japan. We collected MRSA strains isolated from outpatients with skin and soft-tissue infection (SSTI) at 107 medical facilities from 24 prefectures in 2010 and 2012. Among 10,385 clinical samples from SSTI patients, 3,581 S. aureus isolates (35%) were obtained and 673 of the S. aureus strains (19%) were identified as MRSA. Among 625 MRSA strains tested in this study, 266 strains (43%) and 114 strains (18%) were classified as SCCmec types IV and V, respectively. Detection of virulence genes was as follows: Panton Valentine leukocidin (PVL) gene (57 strains, 9%), exfoliative toxin (ET) gene (179 strains, 29%), toxic shock syndrome toxin-1 (TSST-1) gene (195 strains, 31%), or none. PVL-positive strains were classified into eight sequence types (STs) (i.e., ST1, ST5, ST8, ST22, ST30, ST452, ST59, and ST154) and six clonal complexes (i.e., CC1, CC5, CC8, CC22, CC30, and CC59). Only 10 PVL-positive strains (2%) were pulsed-field type USA300 clone. There were a wide variety of CA MRSA clones in Japan, which were different from the situation in the United States. PMID- 25789580 TI - Acute phase treatment of venous thromboembolism: advanced therapy. Systemic fibrinolysis and pharmacomechanical therapy. AB - Venous thromboembolism, which encompasses deep-vein thrombosis and acute pulmonary embolism (PE), represents a major contributor to global disease burden worldwide. For patients who present with cardiogenic shock or persistent hypotension (acute high-risk PE), there is consensus that immediate reperfusion treatment applying systemic fibrinolysis or, in the case of a high bleeding risk, surgical or catheter-directed techniques, is indicated. On the other hand, for the large, heterogeneous group of patients presenting without overt haemodynamic instability, the indications for advanced therapy are less clear. The recently updated guidelines of the European Society of Cardiology emphasise the importance of clinical prediction rules in combination with imaging procedures (assessment of right ventricular function) and laboratory biomarkers (indicative of myocardial stress or injury) for distinguishing between an intermediate and a low risk for an adverse early outcome. In intermediate-high-risk PE defined by the presence of both right ventricular dysfunction on echocardiography (or computed tomography) and a positive troponin (or natriuretic peptide) test, the bleeding risks of full-dose fibrinolytic treatment have been shown to outweigh its potential clinical benefits unless clinical signs of haemodynamic decompensation appear (rescue fibrinolysis). Recently published trials suggest that catheter directed, ultrasound-assisted, low-dose local fibrinolysis may provide an effective and particularly safe treatment option for some of these patients. PMID- 25789581 TI - Susceptibility Weighted Imaging and Mapping of Micro-Hemorrhages and Major Deep Veins after Traumatic Brain Injury. AB - Micro-hemorrhages are a common result of traumatic brain injury (TBI), which can be quantified with susceptibility weighted imaging and mapping (SWIM), a quantitative susceptibility mapping approach. A total of 23 TBI patients (five women, 18 men; median age, 41.25 years old; range, 21.69-67.75 years) with an average Glasgow Coma Scale score of 7 (range, 3-15) at admission were recruited at mean 149 d (range, 57-366) after injury. Susceptibility-weighted imaging data were collected and post-processed to create SWIM images. The susceptibility value of small hemorrhages (diameter <=10 mm) and major deep veins (right septal, left septal, central septal, right thalamostriate, left thalamostriate, internal cerebral, right basal vein of Rosenthal, left basal vein of Rosenthal, and pial veins) were evaluated. Different susceptibility thresholds were tested to determine SWIM's sensitivity and specificity for differentiating hemorrhages from the veins. A total of 253 deep veins and 173 small hemorrhages were identified and evaluated. The mean susceptibility of hemorrhages was 435+/-206 parts per billion (ppb) and the mean susceptibility of deep veins was 108+/-56 ppb. Hemorrhages showed a significantly higher susceptibility than all deep veins (p<0.001). With different thresholds (250, 227 and 200 ppb), the specificity was 97%, 95%, and 92%, and the sensitivity was 84%, 90%, and 92%, respectively. These results show that SWIM could be used to differentiate hemorrhages from veins in TBI patients in a semi-automated manner with reasonable sensitivity and specificity. A larger cohort will be needed to validate these findings. PMID- 25789583 TI - A review on citation amnesia in depression and inflammation research. AB - Once original scientific results are published the author has the "intellectual property" and may claim ownership. Discovery credit is one of the most important "rewards" for scientists and thus incorrect credits undermine the reward system of science. Scientists who publish should therefore give proper credit and acknowledge the primary sources. Failure to do so is regarded as "citation negligence", "the disregard syndrome", "citation amnesia", "plagiarism by omission", "bibliographic plagiarism" or "citation plagiarism", and may range from an unconscious or conscious "failure to credit a prior discoverer so as to give an improper impression of priority" to "the appropriation of another person's ideas or results without given proper credit". False discovery credit is considered to be "a menace to honest science", "a serious transgression" or "intellectual theft, be it intentional or not". This paper describes some examples of citation amnesia showing that scientists often fail to credit prior sources and give false discovery credit to other scientists. One example is the association between major depression and activated immuno-inflammatory pathways, a discovery by European groups and published in many papers since 1990. Now, 25 years later, it is commonplace that these theories are credited to secondary American sources whose work in "the last decade", did or did not examine these pathways in major depression. This gives an improper impression of priority of American-based scientists. Here it is proposed that this citation amnesia and plagiarism reinforced the wrong science and had negative effects on the development of immune-inflammatory biomarkers and new immune-related treatments for depression. It is concluded that journal editors should improve their citation standards to guarantee correct assignment of discovery credit for example by demanding a signed pledge from the authors that correct citations to the primary sources were made. PMID- 25789582 TI - Processing of protein ADP-ribosylation by Nudix hydrolases. AB - ADP-ribosylation is a post-translational modification (PTM) of proteins found in organisms from all kingdoms of life which regulates many important biological functions including DNA repair, chromatin structure, unfolded protein response and apoptosis. Several cellular enzymes, such as macrodomain containing proteins PARG [poly(ADP-ribose) glycohydrolase] and TARG1 [terminal ADP-ribose (ADPr) protein glycohydrolase], reverse protein ADP-ribosylation. In the present study, we show that human Nudix (nucleoside diphosphate-linked moiety X)-type motif 16 (hNUDT16) represents a new enzyme class that can process protein ADP-ribosylation in vitro, converting it into ribose-5'-phosphate (R5P) tags covalently attached to the modified proteins. Furthermore, our data show that hNUDT16 enzymatic activity can be used to trim ADP-ribosylation on proteins in order to facilitate analysis of ADP-ribosylation sites on proteins by MS. PMID- 25789584 TI - AKAP5 signaling complexes: focal points and functional properties. AB - OBJECTIVE: Kinase Anchoring Proteins (AKAPs) have evolved to regulate the spatial and temporal organization of cellular signal transduction. As a typical member, AKAP5 which consisting of three orthologues: bovine AKAP75, rodent AKAP150 and human AKAP79, is the best known model in the anchoring and targeting properties. It is shown that AKAP5 can bind beta2-adrenergic receptor, which is a member of GPCR superfamily, and orchestrate the interactions of various protein kinases, protein phosphatases and cytoskeletal element. AKAP5 is originally identified as a component of the postsynaptic density in neurons and plays a vital role in modulating neuronal activities. Subsequently, the AKAP5 complexes are also detected in other tissues and participated in various processes. PMID- 25789585 TI - Chronobiological changes in arterial blood pressure in participants of the 5th and 6th Czech Antarctic Scientific Expeditions. AB - OBJECTIVE: To evaluate potential changes in arterial blood pressure (ABP) and heart rate (HR) during a 2-month stay in Antarctica, using chronobiological analysis. METHODS: An observational study performed at Mendel research base, Antarctica, during 2011 and 2012. The studied group consisted of 24 participants of the 5th and 6th Czech Antarctic Scientific Expeditions. Three series of 24 hour ABP monitoring were performed, of these two in Antarctica and one in the Czech Republic. Chronobiological analyses of the data were performed (Halberg Chronobiology Center, Minnesota) using population-mean cosinor. The values of MESOR (Midline Estimating Statistic Of Rhythm), double amplitude and the acrophase were obtained for SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure) and HR. These rhythm characteristics were compared between the two locations by parameter tests and by the paired t-test. RESULTS: On the average, the MESORs of SBP, DBP and HR were significantly higher in Antarctica than in the Czech Republic, as were the double amplitudes of the 12-hour component of SBP and DBP. High prevalence of CHAT (Circadian Hyper-Amplitude-Tension) was detected in Antarctica (8/24 = 33%); only 2 persons had CHAT in the Czech Republic (chi2=3.945, p=0.047). CONCLUSIONS: A prolonged stay in Antarctica clearly affected certain chronobiological parameters of ABP and HR. PMID- 25789586 TI - Damage to vascular endothelial cells by high insulin levels is associated with increased expression of ChemR23, and attenuated by PPAR-gamma agonist, rosiglitazone. AB - OBJECTIVE: This study investigated the effect of different insulin concentrations on the activity of vascular endothelial cells (VECs), and the role of PPARgamma activator rosiglitazone (RGZ) on the expression of the chemerin receptor, ChemR23, in insulin-treated human umbilical vein endothelial cells (HUVECs). METHODS: Cell viability was determined in HUVECs treated with different insulin concentrations. Immunofluorescence staining was used to detect ChemR23 expression in insulin-treated HUVECs. Western blot assays were used to evaluate ChemR23 and PPARgamma protein expression in insulin-treated HUVECs after pretreatment with PPARgamma activator (RGZ) or inhibitor (GW9662). RESULTS: High insulin concentrations significantly inhibited HUVEC cell viability compared to low insulin concentrations, and this inhibition was attenuated by pretreatment with RGZ. High concentrations of insulin caused a significant upregulation of ChemR23 and a significant downregulation of PPARgamma. These effects were attenuated by RGZ pretreatment, while PPARgamma antagonist, GW9662 reversed this attenuation. CONCLUSION: ChemR23 upregulation may play a role in VEC damage caused by high concentrations of insulin. The protective effect of PPARgamma activation in VECs may be mediated via ChemR23 downregulation. PMID- 25789587 TI - Heart rate variability in children with inflammatory bowel diseases. AB - OBJECTIVE: Heart rate variability (HRV) oscillations are used in the detection of autonomic instabilities in various clinical disorders. METHODS: We compared the HRV as a possible marker of chronic distress in children with inflammatory bowel disease (IBD) with HRV frequencies in the healthy controls. Participants were 29 children with IBD (19 Crohn's disease and 10 ulcerative colitis), 25 children were in remission and 4 presented mild disease activity. They were compared with the control group of 35 healthy children of the same age (13-16 years-old). RESULTS: In HRV assessment, adolescents with IBD had significantly lower levels of the spectral activity in an LF band in all three positions; lower levels of VLF in both supine positions; and the ratio of the spectral activity at LF/HF was significantly lower in the second post (standing). CONCLUSION: These results indicate children with IBD have less adaptability to stress. PMID- 25789588 TI - Histopathological findings in goiter: A review of 624 thyroidectomies. AB - OBJECTIVES: To identify the histopathological patterns of goiter in thyroidectomy specimens and their frequency in relation to age and gender of the patients. METHODOLOGY: We present a retrospective data of 624 thyroidectomy specimens diagnosed over a period of six year (2007-2012) at the Department of Pathology, Holy Family Hospital, Rawalpindi, Pakistan. RESULTS: A total of 624 consecutive thyroidectomy specimens were selected. Patient's age ranges from 11-89 years, 541 females and 83 males. There were 512 (82%) non-neoplastic lesions, which includes; 475 (76.1%) multi-nodular goiter (MNG), 16 (2.6%) Hashimoto thyroiditis, 11 (1.8%) colloid goiter, 4 (0.6%) toxic goiter, 2 (0.3%) chronic lymphocytic thyroiditis, 2 (0.3%) tuberculous thyroiditis and 2 (0.3%) miscellaneous. From 112 (18%) neoplastic lesions, 43 (6.9%) were adenomas (41 females and 2 males) and 69 (11.0%) were carcinomas (58 females and 11 males). Peak age for thyroid malignancy was 3rd to 4th decades. The histological subtypes of thyroid carcinomas includes, 35 (5.6%) follicular variant of papillary carcinoma (FVPC), 15 (2.5%) well-differentiated tumor of uncertain malignant potential (WDT-UMP), 6 (1%) medullary carcinomas, 6 (1%) papillary carcinomas, 3 (0.5%) anaplastic carcinomas, 2 (0.3%) follicular carcinomas and 2 (0.3%) other carcinomas. Twenty-nine (4.6%) neoplastic lesions were associated with MNG, includes; 2 (3.5%) follicular adenomas, 3 (0.5%) WDT-UMP and 4 (0.6%) FVPC. CONCLUSIONS: MNG is common and FVPC is the common thyroid cancer seen in females. The overall frequency of thyroid cancer is 11%. Follicular adenoma and FVPC appears to be associated with long standing MNG of iodine deficiency. PMID- 25789589 TI - Immediate effect of blue-enhanced light on reproductive hormones in women. AB - OBJECTIVE: Light is known to stimulate reproductive function in women. We here investigated the immediate effect of light on reproductive hormones, addressing the role of blue-sensitive (~480 nm) melanopsin-based photoreception mediating the non-visual effects of light. METHODS: Sixteen healthy women attended the Institute at ~07:25 (shortly after waking; sunglasses worn) twice in 2-3 days in April-May, within days 4-10 of their menstrual cycle. During one session, a broad spectrum white-appearing light with a superimposed peak at 469 nm was presented against 5-10 lux background; during the other session, short-spectrum red light peaked at 651 nm with similar irradiance level (~7.0 W/m2, corresponds to ~1200 lux) was used. Venous blood was taken at 0, 22 and 44 minutes of light exposure to measure concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin, estradiol, progesterone and cortisol, and saliva was sampled to measure melatonin as a recognised indicator of the spectral-specific action of light. RESULTS: Melatonin values, as expected, were lower with white vs. red light (p=0.014), with the greatest difference at 22 minutes. Of the other hormones, only FSH concentrations differed significantly: they were mildly higher at white vs. red light (again, at 22 minutes; p=0.030; statistical analysis adjusted for menstrual cycle day and posture change [pre-sampling time seated]). CONCLUSION: Moderately bright blue-enhanced white light, compared to matched-by irradiance red light, transiently (within 22 minutes) and mildly stimulated morning secretion of follicle-stimulating hormone in women in mid-to-late follicular phase of their menstrual cycle suggesting a direct functional link between the light and reproductive system. PMID- 25789590 TI - Impairment of endothelial function in patients with multiple sclerosis. AB - OBJECTIVE: Large epidemiological studies suggest higher risk of vascular events in patients with multiple sclerosis (MS). Chronic inflammatory response and oxidative stress, key-players in a process of atherogenesis, are also suspected to play a role in pathophysiology of MS. Prospective studies elucidating risk of atherosclerosis in MS patients are currently missing. The aim of the study was to assess endothelial function in patients with MS and in healthy controls. METHODS: We enrolled 46 patients with diagnosis of relapsing-remitting MS and age-matched population of 31 healthy subjects. Endothelial function was assessed using peripheral arterial tonometry and expressed as reperfusion hyperemia index (RHI). RESULTS: RHI in MS population was significantly lower than in controls (1.77 vs 2.30; p=0.001), even though control population seemed to have higher burden of known vascular risk factors (significantly higher portion of male sex and significantly higher body mass index; p <= 0.001 for both parameters). The presence of MS was the only significant independent variable associated with the RHI (beta=0.396, p<0.001) in multiple linear regression model. CONCLUSION: Results of our study suggest significant impairment of endothelial function in MS population compared to age matched control population with low burden of vascular risk factors. PMID- 25789591 TI - Iron and Parkinson's disease. AB - In this case presentation, a man with a diagnosis of Parkinson's disease was treated with Chelation Therapy against iron without iron serum level correlation. The patient, who suffered from motor and non-motor symptoms of the disease, showed an improved condition after the Therapy. This clinical test was evaluated with UPDRS III score. The rationale and the limits of the Therapy are discussed. This case suggests that iron-dependent oxidative stress could represent a promising therapy for this dramatic disease; the necessity to deeply study the iron metabolism in neuro-degeneration appears really significant. PMID- 25789592 TI - Living with ME/CFS. challenge for scientists? AB - A Graded Exercise Therapy (GET) - Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) Running Anomaly. Imagine you have been disabled with ME/CFS's cluster of symptoms for 19 years. Yet, this morning you just ran an easy 10K with no flare up of your exercise intolerance symptoms during the run or post exertional malaise after the run. Then later in the day you go browsing for books and after 30 minutes or so your exercise intolerance and post-exertional malaise symptoms flare up. You experience a wave of exhaustion, achy muscles and additional cognitive fog, all of which carry into the next day. To me, this is a confusing anomaly that needs an explanation. PMID- 25789593 TI - Neuroendocrine and stress-related aspects of endometriosis. AB - Endometriosis is a model of a benign gynecologic disease associated with two major symptoms: pain and infertility. When becomes chronic, severe psychological and neuroendocrine changes may occur. The high levels of perceived stress caused by symptoms cause a neuroendocrine disequilibrium thus contributing to the progression of the disease. Elevated stress levels alter hormonal secretions, mood and behavior, sexual disorders and appetite custom. Inflammatory comorbidities may be associated with elevated stress in endometriotic patients (inflammatory bowel disease, fibromyalgia, chronic fatigue) and even autoimmune diseases (thyroid disease, systemic lupus erythematosus, multiple sclerosis). Neurogenic mechanisms are described in endometriotic lesions and they affect peripheral and central nervous system of these patients increasing pain sensitivity and stress reactivity. In conclusion, endometriosis is a disease which affects reproductive and neuroendocrine functions with a great impact on women's health and quality of life. PMID- 25789594 TI - Neuroprotective impact of a vitamin trace element composition - a randomized, double blind, placebo controlled clinical trial with healthy volunteers. AB - OBJECTIVES: Neurotoxic metabolites and oxidative and nitrosative stress reactions play a crucial role in the pathways leading to neuronal cell death and neurodegeneration. The bioavailability of the many antioxidant ingredients a vitamin and trace element composition was investigated, to reveal the neuroprotective (preventive) potential of the composition. METHODS: We recruited 159 healthy volunteers, assigned them randomly and double blind to a placebo and verum group. Physicians excluded volunteers with severe chronic diseases or interfeering medications. 142 participants finished the six month trial. Laboratory parameters were determined 1) before participation, and 2) after three and 3) six months. We confirmed the bioavailability of ingredients, and determined metabolic parameters associated with the integrity of the blood brain barrier, mitochondrial deficiency (Q 10), neurodegeneration (homocystein), and antioxidative capacity (e.g. lipidperoxidation), and superoxiddismutase activity. RESULTS: Starting from baseleine, after three months neuroprotective ingredients increased within their physiological borders, folic acid (p<0.003), pyridoxin (p<0.001), cobalamin (p=0.001), and the fat soluble vitamin tocopherol (p<0.001). In parallel, homocytein decreased after 3 and 6 months (p<0.001, and p<0.025, respectively). Other paramters like zinc reacted slower, significant changes were observed only after 6 months. CONCLUSION: The observed metabolic changes and alteration of the oxidative status after 3 and six month of regular intake underlines the compositions' potential to ameliorate neurodegenerative processes. We conclude that the subsitution of vitamins and trace-elements with natural source in a proper manner may be effective for neuroprotection in healthy population. PMID- 25789595 TI - Prolactin secretion in polycystic ovary syndrome (PCOS). AB - OBJECTIVES: Hyperprolactinemia and polycystic ovary syndrome (PCOS) are on the list of the most frequent causes of female infertility. Both pathologies are characterized in common by several clinical features. At the same time, there are essential discrepancies in medical literature on mutual relations between PCOS and hyperprolactinemia. The objective of our study was to answer several questions, e.g. about frequency of hyperprolactinemia in PCOS patients, typical concentrations of prolactin (Prl) in PCOS patients vs women without polycystic ovaries and/or an assessment of circadian Prl level profiles vs single Prl sampling, as regards diagnostic usefulness. METHODS: The study was retrospective analysis of medical records of female patients in whom nine (9) points daily profile of prolactinemia had been performed. RESULTS: Prl levels appeared to be slightly higher in women without PCOS but the difference did not reach a border of statistical significance. The incidence of elevated Prl concentrations in 8:00 AM and 11:00 AM samples was higher in women without PCOS than in PCOS patients (32.0% vs 16.3% - 8:00 AM, and 8.5% vs 4.6% - 11:00 AM, respectively). Also, elevated mean daily prolactinemia, assessed as area under the curve (AUC) of Prl concentrations, was more frequent in the group of women without PCOS than in those with PCOS (22.0% vs 13.9%). CONCLUSIONS: Polycystic overy syndrome is not associated with higher levels of Prl, measured in daily profiles. Hyperprolactinemia does not seem to be more frequent in PCOS women than in healthy subjects and it should not be considered as characteristic feature of PCOS - both are distinct clinical entities. Prolactin concentrations should be assessed in each woman with PCOS suspicion because of certain common clinical signs in both disorders. Every woman diagnosed with PCOS and hyperprolactinemia should further be examined in terms of the actual causes of hyperprolactinemia because the coexistence of these two disease entities - as distinct - is also possible. PMID- 25789596 TI - Rapid improvement in visual loss with cabergoline treatment in a giant prolactinoma case: 5 years survey. AB - Giant prolactinoma is a rare subset of macroadenomas. Limited studies demonstrated which therapy could be successfully used in the first-line therapy of giant prolactinoma. We presented a case with a 54 * 40 * 40 mm pituitary adenoma and optic chiasmatic compression with left sphenoid sinus invasion. The tumor caused a loss of visual field of the right side. Cabergoline treatment was started with dose of 1.5 mg/week. Fifteen days later, the clinical visual acuity examination showed a significant improvement in the patient with visual field defect. After the five years follow-up magnetic resonance imagining showed reduction of the adenoma size (17 * 12 mm) was significant. Our findings suggest that, cabergoline can be used as a first-line therapy in giant prolactinomas because tumoral shrinkage without a surgical procedure and rapid improvement in visual field defect is achieved with this medical treatment. PMID- 25789597 TI - The role of lateral preference of lower limbs in a postural stabilization task. AB - OBJECTIVE: Postural control is a complex skill based on the interaction of dynamic sensorimotor processes. This study assessed the effect of lateral perturbations on postural re-stabilization regarding lower limb preference. METHODS: A group of 14 physically active individuals (9 male, 5 female) randomly underwent postural perturbations in lateral-left and lateral-right directions at a velocity of 0.2 m.s-1 and a platform shift of 6 cm. Perturbation to the preferred limb side (PS) was noted when the contralateral body movement was primarily controlled by the preferred limb and perturbation to the non-preferred limb side (NS) was noted when the contralateral body movement was primarily controlled by the non-preferred (stabilizing) limb. Prior to, during and after the perturbation centre of pressure (CoP) was registered using a computerized motor driven FiTRO Dynamic Posturography System based on force plate (Fitro Sway Check) with a sampling rate of 100 Hz. The basic stabilographic parameters of peak displacement (Peak 1), peak-to-peak displacement (Peak 2), time to peak displacement (Time 1), time to peak-to-peak displacement (Time 2) and re stabilization time (Time 3) were analyzed. RESULTS: Results showed significantly larger Time 3 on PS than on NS (2.81 +/- 1.32 s and 1.73 +/- 1.10 s; p=0.02). However, there were no significant differences in other parameters between PS and NS. CONCLUSION: It may be concluded that the observed shorter re-stabilization time at NS was due to the stabilization role of the non-preferred limb. PMID- 25789598 TI - Thyroid hormones are needed to sustain "inappropriately" normal TSH during non thyroidal illness syndrome: a clinical observation in severely ill patients with primary hypothyroidism. AB - OBJECTIVES: Non-thyroidal illness syndrome (NTIS) is a form of hypothyroidism that occurs during illness. NTIS is characterized by low thyroid hormones (TH) level in the serum and tissues, with normal serum TSH levels that are considered "inappropriately" normal. The mechanisms responsible for a lack of increase in serum TSH during NTIS are unknown. However, a decreased expression of hypothalamic TRH has been documented in deceased humans with NTIS. It has been suggested that pro-inflammatory cytokines are responsible for the inhibition of TRH release. If a similar TSH response occurs in severely ill patients with primary hypothyroidism has not been reported. DESIGN: Seven severely ill patients with unknown or poorly treated primary hypothyroidism are presented. Serum TSH and TH were measured at admission and during TH replacement. SETTING: Tertiary university hospital. RESULTS: Besides suffering severe illness, patient's serum TSH was high and decreased once TH replacement was given. Levothyroxine administration was enough to down regulate TSH secretion. Serum reverse T3 (rT3) was normal or high and showed further elevation with stepwise increase in levothyroxine doses. CONCLUSIONS: The thyroid axis inhibitory feedback system is fully preserved in primary hypothyroidism during severe illness. In NTIS, serum TSH levels remain within normal limits because the supply of TH to TRH neurons is sustained normally. Pro-inflammatory cytokines does not play a major role inhibiting TRH release during NTIS associated to primary hypothyroidism. D3 activity increases in humans with severe illness, a mechanism behind the increased requirements in TH replacement to achieve normal serum TH. PMID- 25789600 TI - Exposure Assessment of a High-energy Tensile Test With Large Carbon Fiber Reinforced Polymer Cables. AB - This study investigated the particle and fiber release from two carbon fiber reinforced polymer cables that underwent high-energy tensile tests until rupture. The failing event was the source of a large amount of dust whereof a part was suspected to be containing possibly respirable fibers that could cause adverse health effects. The released fibers were suspected to migrate through small openings to the experiment control room and also to an adjacent machine hall where workers were active. To investigate the fiber release and exposure risk of the affected workers, the generated particles were measured with aerosol devices to obtain the particle size and particle concentrations. Furthermore, particles were collected on filter samples to investigate the particle shape and the fiber concentration. Three situations were monitored for the control room and the machine hall: the background concentrations, the impact of the cable failure, and the venting of the exposed rooms afterward. The results showed four important findings: The cable failure caused the release of respirable fibers with diameters below 3 MUm and an average length of 13.9 MUm; the released particles did migrate to the control room and to the machine hall; the measured peak fiber concentration of 0.76 fibers/cm(3) and the overall fiber concentration of 0.07 fibers/cm(3) in the control room were below the Permissible Exposure Limit (PEL) for fibers without indication of carcinogenicity; and the venting of the rooms was fast and effective. Even though respirable fibers were released, the low fiber concentration and effective venting indicated that the suspected health risks from the experiment on the affected workers was low. However, the effect of long-term exposure is not known therefore additional control measures are recommended. PMID- 25789599 TI - A role of WT1 in cell division and genomic stability. AB - Wilms' tumor-1 protein (WT1) is a transcription factor that can either activate or repress genes to regulate cell growth, apoptosis and differentiation. WT1 can act as either a tumor suppressor or an oncogene. The cellular functions of WT1 are predominantly regulated by its various interacting partners. Recently we have found that WT1 can regulate the fidelity of chromosome segregation through its interaction with the spindle assembly checkpoint protein, Mitotic arrest deficient-2 (MAD2). WT1 delays anaphase entry by inhibiting the ubiquitination activity of the Anaphase promoting complex/cyclosome (APC/C). Our findings have revealed an important role of WT1 in the regulation of mitotic checkpoint and genomic stability. PMID- 25789601 TI - A new cyclic hexapeptide and a new isocoumarin derivative from the marine sponge associated fungus Aspergillus similanensis KUFA 0013. AB - A new isocoumarin derivative, similanpyrone C (1), a new cyclohexapeptide, similanamide (2), and a new pyripyropene derivative, named pyripyropene T (3) were isolated from the ethyl acetate extract of the culture of the marine sponge associated fungus Aspergillus similanensis KUFA 0013. The structures of the compounds were established based on 1D and 2D NMR spectral analysis, and in the case of compound 2 the stereochemistry of its amino acid constituents was determined by chiral HPLC analysis of the hydrolysate by co-injection with the d and l amino acids standards. Compounds 2 and 3 were evaluated for their in vitro growth inhibitory activity against MCF-7 (breast adenocarcinoma), NCI-H460 (non small cell lung cancer) and A373 (melanoma) cell lines, as well as antibacterial activity against reference strains and the environmental multidrug-resistant isolates (MRS and VRE). Only compound 2 exhibited weak activity against the three cancer cell lines, and neither of them showed antibacterial activity. PMID- 25789602 TI - Ciona intestinalis as a marine model system to study some key developmental genes targeted by the diatom-derived aldehyde decadienal. AB - The anti-proliferative effects of diatoms, described for the first time in copepods, have also been demonstrated in benthic invertebrates such as polychaetes, sea urchins and tunicates. In these organisms PUAs (polyunsaturated aldehydes) induce the disruption of gametogenesis, gamete functionality, fertilization, embryonic mitosis, and larval fitness and competence. These inhibitory effects are due to the PUAs, produced by diatoms in response to physical damage as occurs during copepod grazing. The cell targets of these compounds remain largely unknown. Here we identify some of the genes targeted by the diatom PUA 2-trans-4-trans-decadienal (DD) using the tunicate Ciona intestinalis. The tools, techniques and genomic resources available for Ciona, as well as the suitability of Ciona embryos for medium-to high-throughput strategies, are key to their employment as model organisms in different fields, including the investigation of toxic agents that could interfere with developmental processes. We demonstrate that DD can induce developmental aberrations in Ciona larvae in a dose-dependent manner. Moreover, through a preliminary analysis, DD is shown to affect the expression level of genes involved in stress response and developmental processes. PMID- 25789603 TI - Purification and partial characterization of a new antitumor protein from Tegillarca granosa. AB - A new protein, coded as D2-3, was obtained from the marine organism Tegillarca granosa L. by anion exchange and hydrophobic chromatography. The purity of D2-3 was over 99.0% as measured by RP-HPLC. Its molecular weight was shown to be 20.320 kDa by ESI-MS/MS, and the isoelectric point of D2-3 was 4.70. The antitumor activity of D2-3 against four human tumor cell lines was measured by MTT assay. The conformational structure of D2-3 was further characterized by UV vis, FT-IR and CD spectroscopy. Partial amino acid sequences of D2-3 were determined to be LMMTDVEESR, SSHMLSECRRK, KNGRNVDISHKDKG, SSDPTLMDPDDTNKDR, SSDKNTCSKTEYYTR and SSETMPYDVLDTNEMR via MALDI-TOF-MS and de novo sequencing. PMID- 25789604 TI - Cordyceps militaris mushroom and cordycepin inhibit RANKL-induced osteoclast differentiation. AB - Cordyceps militaris is a medicinal mushroom and its bioactive compound, cordycepin, is reported to have many pharmacological activities. The goal of this study was to investigate the effects of C. militaris extract (CME) and cordycepin on osteoclast differentiation in vitro and on an inflammatory bone loss in vivo. In RAW 264.7 cells, CME and cordycepin showed dose-dependent inhibition of receptor activator of the nuclear factor kappa B (NF-kappaB) ligand (RANKL) induced osteoclast differentiation by TRAP (tartrate-resistant acid phosphatase) staining. Moreover, the mRNA expression of osteoclastogenesis-related genes (TRAP, cathepsin K, MMP-9, and NFATc1) was also inhibited by CME and cordycepin. Also, cordycepin significantly inhibited RANKL-induced phosphorylation of p38 and NF-kappaB, but not that of other members of mitogen-activated protein kinase families. To examine the effect of CME on bone loss in vivo, we used a mouse model of lipopolysaccharide (LPS)-mediated bone loss. Micro-CT analysis of the femurs showed that LPS treatment caused bone loss. However, bone loss was significantly attenuated in mice treated with CME. These results suggest that cordycepin or/and CME have inhibitory effects on osteoclast differentiation in vitro and that they suppress inflammatory bone loss in vivo. PMID- 25789605 TI - Girl adoption in China-A less-known side of son preference. AB - In 1987, 4 per cent of girls were adopted within China. Why? Unlike infanticide, abandonment rids parents of daughters while preserving the supply of potential brides. In fact, an erstwhile tradition common in Fujian and Jiangxi provinces had parents of sons adopting an infant girl to serve as a future daughter-in-law and household help. Analysing a nationally representative 1992 survey of children, we found that: (1) girl adoptions were concentrated in the above mentioned provinces; (2) girls were predominantly adopted by families with sons; (3) adopted girls faced substantial disadvantage as measured by school attendance at ages 8-13. In the 1990s, as the sex ratio at birth climbed, were girls aborted rather than abandoned? Observing that in the 2000 census too many girls appear in families with older sons, we estimated that at least 1/25 girls were abandoned in the 1990s, a proportion that in Fujian and Jiangxi may have peaked at 1/10 in 1994. PMID- 25789607 TI - Traumatic intracranial aneurysm in blunt trauma. AB - INTRODUCTION: Computed Tomography Angiography (CTA) is being used to identify traumatic intracranial aneurysms (TICA) in patients with findings such as skull fracture and intracranial haemorrhage on initial Computed Tomography (CT) scans after blunt traumatic brain injury (TBI). However, the incidence of TICA in patients with blunt TBI is unknown. The aim of this study is to report the incidence of TICA in patients with blunt TBI and to assess the utility of CTA in detecting these lesions. METHODS: A 10-year retrospective study (2003-2012) was performed at a Level 1 trauma centre. All patients with blunt TBI who had an initial non-contrasted head CT scan and a follow-up head CTA were included. Head CTAs were then reviewed by a single investigator and TICAs were identified. The primary outcome measure was incidence of TICA in blunt TBI. RESULTS: A total of 10 257 patients with blunt TBI were identified, out of which 459 patients were included in the analysis. Mean age was 47.3 +/- 22.5, the majority were male (65.1%) and median ISS was 16 [9-25]. Thirty-six patients (7.8%) had intracranial aneurysm, of which three patients (0.65%) had TICAs. CONCLUSION: The incidence of traumatic intracranial aneurysm was exceedingly low (0.65%) over 10-years. This study adds to the growing literature questioning the empiric use of CTA for detecting vascular injuries in patients with blunt TBI. PMID- 25789606 TI - A secretory kinase complex regulates extracellular protein phosphorylation. AB - Although numerous extracellular phosphoproteins have been identified, the protein kinases within the secretory pathway have only recently been discovered, and their regulation is virtually unexplored. Fam20C is the physiological Golgi casein kinase, which phosphorylates many secreted proteins and is critical for proper biomineralization. Fam20A, a Fam20C paralog, is essential for enamel formation, but the biochemical function of Fam20A is unknown. Here we show that Fam20A potentiates Fam20C kinase activity and promotes the phosphorylation of enamel matrix proteins in vitro and in cells. Mechanistically, Fam20A is a pseudokinase that forms a functional complex with Fam20C, and this complex enhances extracellular protein phosphorylation within the secretory pathway. Our findings shed light on the molecular mechanism by which Fam20C and Fam20A collaborate to control enamel formation, and provide the first insight into the regulation of secretory pathway phosphorylation. PMID- 25789608 TI - Immunomodulation of airway epithelium cell activation by mesenchymal stromal cells ameliorates house dust mite-induced airway inflammation in mice. AB - Allergic asthma is underpinned by T helper 2 (Th2) inflammation. Redundancy in Th2 cytokine function and production by innate and adaptive immune cells suggests that strategies aimed at immunomodulation may prove more beneficial. Hence, we sought to determine whether administration of mesenchymal stromal cells (MSCs) to house dust mite (HDM) (Dermatophagoides pteronyssinus)-sensitized mice would suppress the development of Th2 inflammation and airway hyperresponsiveness (AHR) after HDM challenge. We report that the intravenous administration of allogeneic donor MSCs 1 hour before allergen challenge significantly attenuated the features of allergic asthma, including tissue eosinophilia, Th2 cytokine (IL-5 and IL-13) levels in bronchoalveolar lavage fluid, and AHR. The number of infiltrating type 2 innate lymphoid cells was not affected by MSC transfer, suggesting that MSCs may modulate the adaptive arm of Th2 immunity. The effect of MSC administration was long lasting; all features of allergic airway disease were significantly suppressed in response to a second round of HDM challenge 4 weeks after MSC administration. Further, we observed that MSCs decreased the release of epithelial cell-derived alarmins IL-1alpha and high mobility group box-1 in an IL 1 receptor antagonist-dependent manner. This significantly decreased the expression of the pro-Th2 cytokine IL-25 and reduced the number of activated and antigen-acquiring CD11c(+)CD11b(+) dendritic cells in the lung and mediastinal lymph nodes. Our findings suggest that MSC administration can ameliorate allergic airway inflammation by blunting the amplification of epithelial-derived inflammatory cytokines induced by HDM exposure and may offer long-term protection against Th2-mediated allergic airway inflammation and AHR. PMID- 25789609 TI - Electron spin relaxation of C60 monoanion in liquid solution: applicability of Kivelson-Orbach mechanism. AB - We report the results of our investigation on the electron spin relaxation mechanism of the monoanion of C60 fullerene in liquid solution. The solvent chosen was carbon disulfide, which is rather uncommon in EPR spectroscopy but proved very useful here because of its liquid state over a wide temperature range. The conditions for exclusive formation of the monoanion of C60 in CS2 were first determined using electrochemical measurements. Using these results, only the monoanion of C60 was prepared by chemical reduction using Hg2I2/Hg as the reducing agent. The EPR line width was measured over a wide temperature range of 120-290 K. The line widths show weak dependence on temperature, changing by a factor of only about 2, over this temperature range. We show that the observed temperature dependence does not obey the Kivelson-Orbach mechanism of electron spin relaxation in liquids, applicable for radicals with low-lying, thermally accessible excited electronic states. The observed temperature dependence can be empirically fitted to an Arrhenius type of exponential function, from which an activation energy of 74 +/- 3 cm(-1) is obtained. From the qualitative similarities in the characteristics of the spin relaxation rates of C60 monoanion radical and the cyclohexane type of cation radicals reported in the literature, we propose that a pseudorotation-induced electron spin relaxation process could be operating in the C60 monoanion radical in liquid solution. The low activation energy of 74 cm(-1) observed here is consistent with the pseudorotation barrier of C60 monoanion, estimated from reported Jahn-Teller energy levels. PMID- 25789610 TI - Effect of feeding palm oil by-products based diets on muscle fatty acid composition in goats. AB - The present study aims to evaluate the effects of feeding palm oil by-products based diets on different muscle fatty acid profiles in goats. Thirty-two Cacang * Boer goats were randomly assigned to four dietary treatments: (1) control diet (CD), (2) 80% decanter cake diet (DCD), (3) 80% palm kernel cake diet (PKCD) and (4) CD plus 5% palm oil (PO) supplemented diet (CPOD). After 100 days of feeding, four goats from each group were slaughtered and longissimus dorsi (LD), infraspinatus (IS) and biceps femoris (BF) were sampled for analysis of fatty acids. Goats fed the PKCD had higher (P<0.05) concentration of lauric acid (C12:0) than those fed the other diets in all the muscles tested. Compared to the other diets, the concentrations of palmitic acid (C16:0) and stearic acid (C18:0) were lower (P<0.05) and that of linoleic acid (C18:2 n-6) was higher (P<0.05) in the muscles from goats fed the CD. It was concluded that palm kernel cake and decanter cake can be included in the diet of goats up to 80% with more beneficial than detrimental effects on the fatty acid profile of their meat. PMID- 25789612 TI - Advancing analysis of spatio-temporal variations of soil nutrients in the water level fluctuation zone of China's Three Gorges Reservoir using self-organizing map. AB - The ~350 km2 water level fluctuation zone (WLFZ) in the Three Gorges Reservoir (TGR) of China, situated at the intersection of terrestrial and aquatic ecosystems, experiences a great hydrological change with prolonged winter inundation. Soil samples were collected in 12 sites pre- (September 2008) and post submergence (June 2009) in the WLFZ and analyzed for soil nutrients. Self organizing map (SOM) and statistical analysis including multi-way ANOVA, paired-T test, and stepwise least squares multiple regression were employed to determine the spatio-temporal variations of soil nutrients in relation to submergence, and their correlations with soil physical characteristics. Results showed significant spatial variability in nutrients along ~600 km long shoreline of the TGR before and after submergence. There were higher contents of organic matter, total nitrogen (TN), and nitrate (NO3-) in the lower reach and total phosphorus (TP) in the upper reach that were primarily due to the spatial variations in soil particle size composition and anthropogenic activities. Submergence enhanced soil available potassium (K), while significantly decreased soil N, possibly due to the alterations of soil particle size composition and increase in soil pH. In addition, SOM analysis determined important roles of soil pH value, bulk density, soil particle size (i.e., silt and sand) and nutrients (TP, TK, and AK) on the spatial and temporal variations in soil quality. Our results suggest that urban sewage and agricultural runoffs are primary pollutants that affect soil nutrients in the WLFZ of TGR. PMID- 25789611 TI - Parallel faster-X evolution of gene expression and protein sequences in Drosophila: beyond differences in expression properties and protein interactions. AB - Population genetics models predict that the X (or Z) chromosome will evolve at faster rates than the autosomes in XY (or ZW) systems. Studies of molecular evolution using large datasets in multiple species have provided evidence supporting this faster-X effect in protein-coding sequences and, more recently, in transcriptomes. However, X-linked and autosomal genes differ significantly in important properties besides hemizygosity in males, including gene expression levels, tissue specificity in gene expression, and the number of interactions in which they are involved (i.e., protein-protein or DNA-protein interactions). Most important, these properties are known to correlate with rates of evolution, which raises the question of whether differences between the X chromosome and autosomes in gene properties, rather than hemizygosity, are sufficient to explain faster-X evolution. Here I investigate this possibility using whole genome sequences and transcriptomes of Drosophila yakuba and D. santomea and show that this is not the case. Additional factors are needed to account for faster-X evolution of both gene expression and protein-coding sequences beyond differences in gene properties, likely a higher incidence of positive selection in combination with the accumulation of weakly deleterious mutations. PMID- 25789613 TI - Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. AB - Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH. Liver histology of gp78 /- mice revealed typical steatosis, hepatic inflammation and fibrosis, followed by progression to hepatocellular tumors. Acute ER stress revealed that loss of gp78 results in up regulation of unfolded protein response (UPR) pathways and SREBP-1 regulating de novo lipogenesis, responsible for fatty liver. Tissue array of human hepatocellular carcinoma (HCC) demonstrated that the expression of gp78 was inversely correlated with clinical grades of cancer. Here, we have described the generation of the first preclinical experimental model system which spontaneously develops age-related NASH and HCC, linking ERAD to hepatosteatosis, cirrhosis, and cancer. It suggests that gp78 is a regulator of normal liver homeostasis and a tumor suppressor in human liver. PMID- 25789615 TI - Spatial variability of the topsoil organic carbon in the Moso bamboo forests of southern China in association with soil properties. AB - Understanding the spatial variability of soil organic carbon (SOC) must be enhanced to improve sampling design and to develop soil management strategies in terrestrial ecosystems. Moso bamboo (Phyllostachys pubescens Mazel ex Houz.) forests have a high SOC storage potential; however, they also vary significantly spatially. This study investigated the spatial variability of SOC (0-20 cm) in association with other soil properties and with spatial variables in the Moso bamboo forests of Jian'ou City, which is a typical bamboo hometown in China. 209 soil samples were collected from Moso bamboo stands and then analyzed for SOC, bulk density (BD), pH, cation exchange capacity (CEC), and gravel content (GC) based on spatial distribution. The spatial variability of SOC was then examined using geostatistics. A Kriging map was produced through ordinary interpolation and required sample numbers were calculated by classical and Kriging methods. An aggregated boosted tree (ABT) analysis was also conducted. A semivariogram analysis indicated that ln(SOC) was best fitted with an exponential model and that it exhibited moderate spatial dependence, with a nugget/sill ratio of 0.462. SOC was significantly and linearly correlated with BD (r = -0.373**), pH (r = 0.429**), GC (r = -0.163*), CEC (r = 0.263**), and elevation (r = 0.192**). Moreover, the Kriging method requires fewer samples than the classical method given an expected standard error level as per a variance analysis. ABT analysis indicated that the physicochemical variables of soil affected SOC variation more significantly than spatial variables did, thus suggesting that the SOC in Moso bamboo forests can be strongly influenced by management practices. Thus, this study provides valuable information in relation to sampling strategy and insight into the potential of adjustments in agronomic measure, such as in fertilization for Moso bamboo production. PMID- 25789614 TI - Airway response to methacholine following eucapnic voluntary hyperpnea in athletes. AB - AIM: To evaluate the changes in airway responsiveness to methacholine inhalation test (MIT) when performed after an eucapnic voluntary hyperpnea challenge (EVH) in athletes. METHODS: Two MIT preceded (visit 1) or not (visit 2) by an EVH, were performed in 28 athletes and 24 non-athletes. Twelve athletes and 13 non-athletes had airway hyperresponsiveness (AHR) to methacholine, and 11 athletes and 11 non athletes had AHR to EVH (EVH+). RESULTS: The MIT PC20 post-EVH was significantly lower compared to baseline MIT PC20 by 1.3+/-0.7 doubling-concentrations in EVH+ athletes only (p<0.0001). No significant change was observed in EVH- athletes and EVH+/EVH- non-athletes. A significant correlation between the change in MIT PC20 post-EVH and EVH+/EVH- status and athlete/nonathlete status was found (Adjusted R2=0.26 and p<0.001). Three (11%) athletes and one (4%) non-athlete had a change in the diagnosis of AHR when MIT was performed consecutively to EVH. CONCLUSION: The responsiveness to methacholine was increased by a previous indirect challenge in EVH+ athletes only. The mechanisms for such increase remain to be determined. MIT and EVH should ideally be performed on separate occasions as there is a small but possible risk to obtain a false-positive response to methacholine when performed immediately after the EVH. TRIAL REGISTRATION: ClinicalTrials.gov NCT00686491. PMID- 25789617 TI - Experimental evidence of biological interactions among different isolates of Trypanosoma cruzi from the Chaco Region. AB - Many infectious diseases arise from co-infections or re-infections with more than one genotype of the same pathogen. These mixed infections could alter host fitness, the severity of symptoms, success in pathogen transmission and the epidemiology of the disease. Trypanosoma cruzi, the etiological agent of Chagas disease, exhibits a high biological variability often correlated with its genetic diversity. Here, we developed an experimental approach in order to evaluate biological interaction between three T. cruzi isolates belonging to different Discrete Typing Units (DTUs TcIII, TcV and TcVI). These isolates were obtained from a restricted geographical area in the Chaco Region. Different mixed infections involving combinations of two isolates (TcIII + TcV, TcIII + TcVI and TcV + TcVI) were studied in a mouse model. The parameters evaluated were number of parasites circulating in peripheral blood, histopathology and genetic characterization of each DTU in different tissues by DNA hybridization probes. We found a predominance of TcVI isolate in blood and tissues respect to TcIII and TcV; and a decrease of the inflammatory response in heart when the damage of mice infected with TcVI and TcIII + TcVI mixture were compared. In addition, simultaneous presence of two isolates in the same tissue was not detected. Our results show that biological interactions between isolates with different biological behaviors lead to changes in their biological properties. The occurrence of interactions among different genotypes of T. cruzi observed in our mouse model suggests that these phenomena could also occur in natural cycles in the Chaco Region. PMID- 25789616 TI - First administration of the Fc-attenuated anti-beta amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study. AB - OBJECTIVE: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-beta amyloid (Abeta) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer's disease (AD) or mild cognitive impairment (MCI). METHODS: This was a two-part, single blind, placebo controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001-6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1-6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436). RESULTS: There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or -hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10-15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Abeta42 and Abeta increased whereas plasma levels of free Abeta decreased dose dependently; no changes were observed for placebo. For total Abeta42 the peak:trough ratio was <=2 at doses >=3 mg/kg; for total Abeta the ratio was <=2 at 6 mg/kg. CSF concentrations of Abeta showed increases from baseline to week 12 for Abeta X-38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Abeta X-42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses. CONCLUSION: In this FTIH study the Fc-inactivated anti-Abeta mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00459550. PMID- 25789618 TI - Two half-sandwiched ruthenium (II) compounds containing 5-fluorouracil derivatives: synthesis and study of DNA intercalation. AB - Two novel coordination compounds of half-sandwiched ruthenium(II) containing 2-(5 fluorouracil)-yl-N-(pyridyl)-acetamide were synthesized, and their intercalation binding modes with calf thymus DNA were revealed by hyperchromism of ultraviolet visible spectroscopy; the binding constants were determined according to a Langmuir adsorption equation that was deduced on the base of careful cyclic voltammetry measurements. The two compounds exhibited DNA intercalation binding activities with the binding constants of 1.13*106 M-1 and 5.35 *105 M-1, respectively. PMID- 25789619 TI - Hyperbaric oxygen treatment at various stages following chronic constriction injury produces different antinociceptive effects via regulation of P2X4R expression and apoptosis. AB - PURPOSE: The aims of this study were to investigate the effect of hyperbaric oxygen (HBO) treatment at various stages following chronic constriction injury (CCI) and to explore the underlying mechanisms of HBO treatment. METHODS: Forty adult male Sprague-Dawley rats were randomly assigned to five groups (n = 8 for each group): the sham group, CCI group, HBO1 group, HBO2 group, and HBO3 group. Neuropathic pain was induced by CCI of the sciatic nerve. HBO treatment began on postoperative days 1, 6, and 11 and continued for 5 days. The mechanical withdrawal threshold and thermal withdrawal latency were tested on preoperative day 3 and postoperative days 1, 3, 5, 7, 10, 14, and 21. The expression of P2X4R was determined by immunohistochemistry and western blot analysis. Cell apoptosis was measured using TUNEL staining. The expression of caspase 3 was measured using reverse transcription polymerase chain reaction (RT-PCR). Electron microscopy was used to determine the ultrastructural changes. RESULTS: Early HBO treatment beginning on postoperative day 1 produced a persistent antinociceptive effect and inhibited the CCI-induced increase in the expression of P2X4R without changing CCI-induced apoptosis. In contrast, late HBO treatment beginning on postoperative day 11 produced a persistent antinociceptive effect and inhibited CCI-induced apoptosis and upregulation of caspase-3 without changing the expression of P2X4R. In addition, late HBO treatment reduced CCI-induced ultrastructural damage. However, HBO treatment beginning on postoperative day 6 produced a transient antinociceptive effect without changing the expression of P2X4R or CCI-induced apoptosis. CONCLUSION: HBO treatment at various stages following CCI can produce antinociceptive effects via different mechanisms. Early HBO treatment is associated with inhibition of P2X4R expression, and late HBO treatment is associated with inhibition of cell apoptosis. PMID- 25789620 TI - A deep catalog of autosomal single nucleotide variation in the pig. AB - A comprehensive catalog of variability in a given species is useful for many important purposes, e.g., designing high density arrays or pinpointing potential mutations of economic or physiological interest. Here we provide a genomewide, worldwide catalog of single nucleotide variants by simultaneously analyzing the shotgun sequence of 128 pigs and five suid outgroups. Despite the high SNP missing rate of some individuals (up to 88%), we retrieved over 48 million high quality variants. Of them, we were able to assess the ancestral allele of more than 39M biallelic SNPs. We found SNPs in 21,455 out of the 25,322 annotated genes in pig assembly 10.2. The annotation showed that more than 40% of the variants were novel variants, not present in dbSNP. Surprisingly, we found a large variability in transition / transversion rate along the genome, which is very well explained (R2=0.79) primarily by genome differences in in CpG content and recombination rate. The number of SNPs per window also varied but was less dependent of known factors such as gene density, missing rate or recombination (R2=0.48). When we divided the samples in four groups, Asian wild boar (ASWB), Asian domestics (ASDM), European wild boar (EUWB) and European domestics (EUDM), we found a marked correlation in allele frequencies between domestics and wild boars within Asia and within Europe, but not across continents, due to the large evolutive distance between pigs of both continents (~1.2 MYA). In general, the porcine species showed a small percentage of SNPs exclusive of each population group. EUWB and EUDM were predicted to harbor a larger fraction of potentially deleterious mutations, according to the SIFT algorithm, than Asian samples, perhaps a result of background selection being less effective due to a lower effective population size in Europe. PMID- 25789621 TI - Yeast three-hybrid screen identifies TgBRADIN/GRA24 as a negative regulator of Toxoplasma gondii bradyzoite differentiation. AB - Differentiation of the protozoan parasite Toxoplasma gondii into its latent bradyzoite stage is a key event in the parasite's life cycle. Compound 2 is an imidazopyridine that was previously shown to inhibit the parasite lytic cycle, in part through inhibition of parasite cGMP-dependent protein kinase. We show here that Compound 2 can also enhance parasite differentiation, and we use yeast three hybrid analysis to identify TgBRADIN/GRA24 as a parasite protein that interacts directly or indirectly with the compound. Disruption of the TgBRADIN/GRA24 gene leads to enhanced differentiation of the parasite, and the TgBRADIN/GRA24 knockout parasites show decreased susceptibility to the differentiation-enhancing effects of Compound 2. This study represents the first use of yeast three-hybrid analysis to study small-molecule mechanism of action in any pathogenic microorganism, and it identifies a previously unrecognized inhibitor of differentiation in T. gondii. A better understanding of the proteins and mechanisms regulating T. gondii differentiation will enable new approaches to preventing the establishment of chronic infection in this important human pathogen. PMID- 25789622 TI - Reprogramming of HUVECs into induced pluripotent stem cells (HiPSCs), generation and characterization of HiPSC-derived neurons and astrocytes. AB - Neurodegenerative diseases are characterized by chronic and progressive structural or functional loss of neurons. Limitations related to the animal models of these human diseases have impeded the development of effective drugs. This emphasizes the need to establish disease models using human-derived cells. The discovery of induced pluripotent stem cell (iPSC) technology has provided novel opportunities in disease modeling, drug development, screening, and the potential for "patient-matched" cellular therapies in neurodegenerative diseases. In this study, with the objective of establishing reliable tools to study neurodegenerative diseases, we reprogrammed human umbilical vein endothelial cells (HUVECs) into iPSCs (HiPSCs). Using a novel and direct approach, HiPSCs were differentiated into cells of central nervous system (CNS) lineage, including neuronal, astrocyte and glial cells, with high efficiency. HiPSCs expressed embryonic genes such as nanog, sox2 and Oct-3/4, and formed embryoid bodies that expressed markers of the 3 germ layers. Expression of endothelial-specific genes was not detected in HiPSCs at RNA or protein levels. HiPSC-derived neurons possess similar morphology but significantly longer neurites compared to primary human fetal neurons. These stem cell-derived neurons are susceptible to inflammatory cell-mediated neuronal injury. HiPSC-derived neurons express various amino acids that are important for normal function in the CNS. They have functional receptors for a variety of neurotransmitters such as glutamate and acetylcholine. HiPSC-derived astrocytes respond to ATP and acetylcholine by elevating cytosolic Ca2+ concentrations. In summary, this study presents a novel technique to generate differentiated and functional HiPSC-derived neurons and astrocytes. These cells are appropriate tools for studying the development of the nervous system, the pathophysiology of various neurodegenerative diseases and the development of potential drugs for their treatments. PMID- 25789623 TI - Association of TLR5 gene polymorphisms in ulcerative colitis patients of north India and their role in cytokine homeostasis. AB - BACKGROUND AND AIM: In health, TLR signaling protects the intestinal epithelial barrier and in disease, aberrant TLR signaling stimulates diverse inflammatory responses. Association of TLR polymorphisms is ethnicity dependent but how they impact the complex pathogenesis of IBD is not clearly defined. So we propose to study the status of polymorphisms in TLR family of genes and their effect on cytokines level in UC patients. METHODS: The genotypes of the six loci TLR1-R80T, TLR2-R753Q, TLR3-S258G, TLR5-R392X, TLR5-N592S and TLR6-S249P were determined in 350 controls and 328 UC patients by PCR-RFLP and sequencing. Cytokine levels were measured by ELISA in blood plasma samples. Data were analyzed statistically by SPSS software. RESULTS: TLR5 variants R392X and N592S showed significant association (p = 0.007, 0.021) with UC patients but TLR 1, 2, 3, 6 variants did not show any association. Unlike other studies carried out in different ethnic groups, TLR 6 (S249P) SNP was universally present in our population irrespective of disease. Genotype-phenotype correlation analysis revealed that the patients having combination of multiple SNPs both in TLR5 and TLR4 gene suffered from severe disease condition and diagnosed at an early age. The level of TNFalpha (p = 0.004), IL-6 (p = 0.0001) and IFNgamma (p = 0.006) significantly increased in patients as compared to controls having wild genotypes for the studied SNPs. However, there was decreased level of TNFalpha (p = 0.014), IL-6 (p = 0.028) and IFNgamma (p = 0.001) in patients carrying TLR5-R392X variant as compared to wild type patients. Patients carrying two simultaneous SNPs D299G in TLR4 gene and N592S in TLR5 gene showed significant decrease in the levels of TNFalpha (p = 0.011) and IFNgamma (p = 0.016). CONCLUSION: Polymorphisms in TLR 5 genes were significantly associated with the UC in North Indian population. The cytokine level was significantly modulated in patients with different genotypes of TLR4 and TLR5 SNPs. PMID- 25789624 TI - The potential for spatial distribution indices to signal thresholds in marine fish biomass. AB - The frequently observed positive relationship between fish population abundance and spatial distribution suggests that changes in distribution can be indicative of trends in abundance. If contractions in spatial distribution precede declines in spawning stock biomass (SSB), spatial distribution reference points could complement the SSB reference points that are commonly used in marine conservation biology and fisheries management. When relevant spatial distribution information is integrated into fisheries management and recovery plans, risks and uncertainties associated with a plan based solely on the SSB criterion would be reduced. To assess the added value of spatial distribution data, we examine the relationship between SSB and four metrics of spatial distribution intended to reflect changes in population range, concentration, and density for 10 demersal populations (9 species) inhabiting the Scotian Shelf, Northwest Atlantic. Our primary purpose is to assess their potential to serve as indices of SSB, using fisheries independent survey data. We find that metrics of density offer the best correlate of spawner biomass. A decline in the frequency of encountering high density areas is associated with, and in a few cases preceded by, rapid declines in SSB in 6 of 10 populations. Density-based indices have considerable potential to serve both as an indicator of SSB and as spatially based reference points in fisheries management. PMID- 25789625 TI - Reliability and responsiveness of cardiopulmonary exercise testing in fatigued persons with multiple sclerosis and low to mild disability. AB - BACKGROUND: Peak oxygen uptake (VO2peak) via cardiopulmonary exercise testing is considered the gold standard for testing aerobic capacity in healthy participants and people with various medical conditions. The reliability and responsiveness of cardiopulmonary exercise testing outcomes in persons with MS (PwMS) have not been extensively studied. OBJECTIVE: (1) to investigate the reliability of cardiopulmonary exercise parameters in PwMS; (2) to determine the responsiveness, in terms of the smallest detectable change (SDC), for each parameter. DESIGN: Two repeated measurements of cardiopulmonary exercise outcomes were obtained, with a median time interval of 16 days. METHODS: Thirty-two PwMS suffering from subjective fatigue performed cardiopulmonary exercise tests on a cycle ergometer, to voluntary exhaustion. We calculated the reliability, in terms of the intra class correlation coefficient (ICC [2,k]; absolute agreement), and the measurement error, in terms of standard error of measurement (SEM) and SDC at individual (SDCindividual) and group level (SDCgroup). RESULTS: The ICC for VO2peak was 0.951, with an SEM of 0.131 L?min(-1) and an SDCindividual of 0.364 L?min(-1). When corrected for bodyweight, the ICC of VO2peak was 0.933, with an SEM of 1.7 mL?kg(-1)?min(-1) and in an SDCindividual of 4.6 mL?kg(-1)?min(-1). LIMITATIONS: Generalization of our study results is restricted to fatigued PwMS with a low to mild level of disability. CONCLUSIONS: At individual level, cardiopulmonary exercise testing can be used reliably to assess physical fitness in terms of VO2peak, but less so to determine significant changes. At group level, VO2peak can be reliably used to determine physical fitness status and establish change over time. PMID- 25789626 TI - Antenatal depressive symptoms and the risk of preeclampsia or operative deliveries: a meta-analysis. AB - BACKGROUND: The purpose of the study was to investigate the association between depression and/or depressive symptoms during pregnancy and the risk of an operative delivery or preeclampsia, and to quantify the strength of the association. METHODS: A search of the PubMed, SCI/SSCI, Proquest PsycARTICLES and CINAHL databases was supplemented by manual searches of bibliographies of key retrieved articles and review articles. We aimed to include case control or cohort studies that reported data on antenatal depression and /or depressive symptoms and the risk of an operative delivery and/or preeclampsia. RESULTS: Twelve studies with self-reported screening instruments were eligible for inclusion with a total of 8400 participants. Seven articles that contained 4421 total participants reported the risk for an operative delivery, and five articles that contained 3979 total participants reported the risk for preeclampsia. The pooled analyses showed that both operative delivery and preeclampsia had a statistically significant association with antenatal depressive symptoms (RR = 1.24; 95% CI, 1.14 to 1.35, and OR = 1.63, 95% CI, 1.32 to 2.02, respectively). When the pre-pregnancy body mass indices were controlled in their initial design, the risk for preeclampsia still existed (OR = 1.48, 95% CI, 1.04 to 2.01), while the risk for an operative delivery became uncertain (RR = 1.01, 95% CI, 0.85 to 1.22). CONCLUSIONS: Antenatal depressive symptoms are associated with a moderately increased risk of an operative delivery and preeclampsia. An abnormal pre-pregnancy body mass index may modify this association. PMID- 25789628 TI - Soluble Scavenger Receptor CD163 Is Associated with Severe Acute Kidney Injury in Patients with Hantaan Virus Infection. AB - CD163, a hemoglobin scavenger receptor for haptoglobin-hemoglobin complexes, is expressed by monocytes/macrophages and is often shed as soluble CD163 (sCD163) in response to inflammatory stimuli. This scavenger receptor is reported to dampen the inflammatory response, and high plasma levels of sCD163, which are thought to reflect the total level of CD163 expression, may predict the severity of disease. To understand the role of sCD163 in the pathogenesis of hemorrhagic fever with renal syndrome (HFRS) better, the concentrations of sCD163 in plasma from 66 patients were quantified, and the relationships between sCD163 level and disease course, severity, and clinical parameters were analyzed. The level of plasma sCD163 in HFRS patients was elevated from fever onset and during the course of the disease, and it peaked in the oliguria stage at 874.5 (549.9-1138.0) ng/mL compared with controls at 192.8 (54.9-282.1) ng/mL. The correlations between plasma sCD163 and renal dysfunction suggest that sCD163 may play an important role in the development of acute renal failure in patients infected with Hantaan virus. PMID- 25789627 TI - Identification of five driver gene mutations in patients with treatment-naive lung adenocarcinoma in Taiwan. AB - BACKGROUND: It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. METHODS: This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). RESULTS: From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. CONCLUSION: This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials. PMID- 25789629 TI - Time-course association mapping of the grain-filling rate in rice (Oryza sativa L.). AB - Detecting quantity trait locus (QTLs) and elite alleles that are associated with grain-filling rate (GFR) in rice is essential for promoting the utilization of hybrid japonica rice and improving rice yield. Ninety-five varieties including 58 landraces and 37 elite varieties from the core germplasm collection were genotyped with 263 simple sequence repeat (SSR) markers. The GFR of the 95 varieties was evaluated at five stages, 7, 14, 21, 28 and 35 days after flowering (DAF) both in 2011 and 2012. We found abundant phenotypic and genetic diversity in the studied population. A population structure analysis identified seven subpopulations. A linkage disequilibrium (LD) analysis indicated that the levels of LD ranged from 60.3 cM to 84.8 cM and artificial selection had enhanced the LD. A time-course association analysis detected 31 marker-GFR associations involving 24 SSR markers located on chromosomes 1, 2, 3, 4, 5, 6, 8, 9, 11 and 12 of rice at five stages. The elite alleles for high GFR at each stage were detected. Fifteen excellent parental combinations were predicted, and the best parental combination 'Nannongjing62401*Laolaihong' could theoretically increase 4.086 mg grain(-1) d(-1) at the five stages. Our results demonstrate that the time-course association mapping for GFR in rice could detect elite alleles at different filling stages and that these elite alleles could be used to improve the GFR via pyramiding breeding. PMID- 25789630 TI - Step detection and activity recognition accuracy of seven physical activity monitors. AB - The aim of this study was to compare the seven following commercially available activity monitors in terms of step count detection accuracy: Movemonitor (Mc Roberts), Up (Jawbone), One (Fitbit), ActivPAL (PAL Technologies Ltd.), Nike+ Fuelband (Nike Inc.), Tractivity (Kineteks Corp.) and Sensewear Armband Mini (Bodymedia). Sixteen healthy adults consented to take part in the study. The experimental protocol included walking along an indoor straight walkway, descending and ascending 24 steps, free outdoor walking and free indoor walking. These tasks were repeated at three self-selected walking speeds. Angular velocity signals collected at both shanks using two wireless inertial measurement units (OPAL, ADPM Inc) were used as a reference for the step count, computed using previously validated algorithms. Step detection accuracy was assessed using the mean absolute percentage error computed for each sensor. The Movemonitor and the ActivPAL were also tested within a nine-minute activity recognition protocol, during which the participants performed a set of complex tasks. Posture classifications were obtained from the two monitors and expressed as a percentage of the total task duration. The Movemonitor, One, ActivPAL, Nike+ Fuelband and Sensewear Armband Mini underestimated the number of steps in all the observed walking speeds, whereas the Tractivity significantly overestimated step count. The Movemonitor was the best performing sensor, with an error lower than 2% at all speeds and the smallest error obtained in the outdoor walking. The activity recognition protocol showed that the Movemonitor performed best in the walking recognition, but had difficulty in discriminating between standing and sitting. Results of this study can be used to inform choice of a monitor for specific applications. PMID- 25789632 TI - Detailed contact data and the dissemination of Staphylococcus aureus in hospitals. AB - Close proximity interactions (CPIs) measured by wireless electronic devices are increasingly used in epidemiological models. However, no evidence supports that electronically collected CPIs inform on the contacts leading to transmission. Here, we analyzed Staphylococcus aureus carriage and CPIs recorded simultaneously in a long-term care facility for 4 months in 329 patients and 261 healthcare workers to test this hypothesis. In the broad diversity of isolated S. aureus strains, 173 transmission events were observed between participants. The joint analysis of carriage and CPIs showed that CPI paths linking incident cases to other individuals carrying the same strain (i.e. possible infectors) had fewer intermediaries than predicted by chance (P < 0.001), a feature that simulations showed to be the signature of transmission along CPIs. Additional analyses revealed a higher dissemination risk between patients via healthcare workers than via other patients. In conclusion, S. aureus transmission was consistent with contacts defined by electronically collected CPIs, illustrating their potential as a tool to control hospital-acquired infections and help direct surveillance. PMID- 25789633 TI - Risk threshold for starting low dose aspirin in pregnancy to prevent preeclampsia: an opportunity at a low cost. AB - BACKGROUND: Preeclampsia (PE) increases maternal and perinatal morbidity and mortality. Based on a multitude of data from randomized clinical trials, clinical practice guidelines endorse using ASA to prevent PE in women who are "at risk." However, data are lacking about the level of absolute risk to warrant starting ASA prophylaxis. METHODS AND FINDINGS: We present two approaches for objectively determining the minimum absolute risk for PE at which ASA prophylaxis is justified. The first is a new approach-the minimum control event rate (CERmin). The second approach uses a pre-existing concept-the minimum event rate for treatment (MERT). Here we show how the CERmin is derived, and then use the CERmin and the MERT to guide us to a reasonable risk threshold for starting a woman on ASA prophylaxis against PE based on clinical risk assessment. We suggest that eligible women need not be at "high risk" for preeclampsia to warrant ASA, but rather at some modestly elevated absolute risk of 6-10%. CONCLUSIONS: Given its very low cost, its widespread availability, ease of administration and its safety profile, ASA is a highly attractive agent for the prevention of maternal and perinatal morbidity worldwide. PMID- 25789631 TI - Effect of extended CT perfusion acquisition time on ischemic core and penumbra volume estimation in patients with acute ischemic stroke due to a large vessel occlusion. AB - BACKGROUND AND PURPOSE: It has been suggested that CT Perfusion acquisition times <60 seconds are too short to capture the complete in and out-wash of contrast in the tissue, resulting in incomplete time attenuation curves. Yet, these short acquisitions times are not uncommon in clinical practice. The purpose of this study was to investigate the occurrence of time attenuation curve truncation in 48 seconds CT Perfusion acquisition and to quantify its effect on ischemic core and penumbra estimation in patients with acute ischemic stroke due to a proximal intracranial arterial occlusion of the anterior circulation. MATERIALS AND METHODS: We analyzed CT Perfusion data with 48 seconds and extended acquisition times, assuring full time attenuation curves, of 36 patients. Time attenuation curves were classified as complete or truncated. Ischemic core and penumbra volumes resulting from both data sets were compared by median paired differences and interquartile ranges. Controlled experiments were performed using a digital CT Perfusion phantom to investigate the effect of time attenuation curve truncation on ischemic core and penumbra estimation. RESULTS: In 48 seconds acquisition data, truncation was observed in 24 (67%) cases for the time attenuation curves in the ischemic core, in 2 cases for the arterial input function and in 5 cases for the venous output function. Analysis of extended data resulted in smaller ischemic cores and larger penumbras with a median difference of 13.2 (IQR: 4.3-26.0) ml (P<0.001) and; 12.4 (IQR: 4.1-25.7) ml (P<0.001), respectively. The phantom data showed increasing ischemic core overestimation with increasing tissue time attenuation curve truncation. CONCLUSIONS: Truncation is common in patients with large vessel occlusion and results in repartitioning of the area of hypoperfusion into larger ischemic core and smaller penumbra estimations. Phantom experiments confirmed that truncation results in overestimation of the ischemic core. PMID- 25789634 TI - Epigallocatechin-3-O-Gallate Protects Against Hepatic Damage and Testicular Toxicity in Male Mice Exposed to Di-(2-Ethylhexyl) Phthalate. AB - The aim of this study was to examine the effects of epigallocatechin-3-O-gallate (EGCG) on hepatic damage and testicular toxicity in male mice exposed to daily oral administration of di-(2-ethylhexyl) phthalate (DEHP). A mouse model was used to assess the effects of daily intraperitoneal EGCG injection on hepatic and testicular damage. Histological and mitochondrial membrane potential results revealed that EGCG treatment significantly arrested the progression of hepatic damage. EGCG treatment resulted in significant suppression of liver injury (i.e., reduced activities of alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The development of DEHP-induced hepatic and testicular damage altered the testosterone concentration in mouse serum, which could affect the reproductive ability of male mice. Moreover, EGCG treatment markedly attenuated testes lesions, sperm deformity, and spermatogenic cell apoptosis. At the molecular level, hepatic CYP3A4 expression was substantially reduced by EGCG treatment in mice exposed to DEHP compounds, whereas testicular aromatase expression was increased significantly in testes. Thus, these results demonstrate that EGCG administration may protect against liver damage and reproductive toxicity in males exposed to DEHP. PMID- 25789636 TI - Health, sex, and gender: the inequalities as challenges. PMID- 25789635 TI - Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation. AB - Growing evidence suggests that pretransplant alpha-fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-gamma-carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow-up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP-L3%, and DCP in a blinded fashion with the MUTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9-6.7; P < 0.0001] for DCP >= 7.5 ng/mL and 2.8 (95% CI, 1.4-5.4; P = 0.002) for AFP >= 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3-12.0; P < 0.0001) when AFP >= 250 ng/mL and DCP >=7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4-4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0-24.6; P < 0.0001) for outside the Milan criteria and AFP >= 250 ng/mL and to 7.2 (95% CI, 2.8-18.1; P < 0.0001) for outside the Milan criteria and DCP >=7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility. PMID- 25789637 TI - [Assistive technology for visually impaired women for use of the female condom: a validation study]. AB - OBJECTIVE: To validate assistive technology for visually impaired women to learn how to use the female condom. METHOD: a methodological development study conducted on a web page, with data collection between May and October 2012. Participants were 14 judges; seven judges in sexual and reproductive health (1st stage) and seven in special education (2nd stage). RESULTS: All items have reached the adopted parameter of 70% agreement. In Stage 1 new materials were added to represent the cervix, and instructions that must be heard twice were included in the 2nd stage. CONCLUSION: The technology has been validated and is appropriate for its objectives, structure / presentation and relevance. It is an innovative, low cost and valid instrument for promoting health and one which may help women with visual disabilities to use the female condom. PMID- 25789638 TI - [Social representation of domestic violence against women among Nursing Technicians and Community Agents]. AB - OBJECTIVE: To analyze the social representations of the Nursing Technicians and Community Health Agents about domestic violence against women. METHOD: A qualitative study carried out in the city of Rio Grande, RS, in which evocations and interviews were collected between July and November 2013. For the treatment of data were used the EVOC 2005 software and the context analysis. RESULTS: It is a structured representation, in which the central nucleus contains conceptual, imaging and attitudinal elements, namely: abuse, aggression, physical aggression, cowardice and lack of respect. Such terms were present in the context of the interviews. The professionals acknowledged that violence is not limited to physical aspects and were judgemental about the acts of the aggressor. CONCLUSION: This knowledge may enable the problematization of the studied phenomenon with the team, and facilitate the search for prevention and intervention strategies for victims, offenders and managers of health services. PMID- 25789639 TI - [Children's health care assistance according to their families: a comparison between models of Primary Care]. AB - OBJECTIVE: To compare the health assistance models of Basic Traditional Units (UBS) with the Family Health Strategy (ESF) units for presence and extent of attributes of Primary Health Care (APS), specifically in the care of children. METHOD: A cross-sectional study of a quantitative approach with families of children attended by the Public Health Service of Colombo, Parana. The Primary Care Assessment Tool (PCA-Tool) was applied to parents of 482 children, 235 ESF units and 247 UBS units covering all primary care units of the municipality, between June and July 2012. The results were analyzed according to the PCA-Tool manual. RESULTS: ESF units reached a borderline overall score for primary health care standards. However, they fared better in their attributes of Affiliation, Integration of care coordination, Comprehensiveness, Family Centeredness and Accessibility of use, while the attributes of Community Guidance/Orientation, Coordination of Information Systems, Longitudinality and Access attributes were rated as insufficient for APS. UBS units had low scores on all attributes. CONCLUSION: The ESF units are closer to the principles of APS (Primary Health Care), but there is need to review actions of child care aimed at the attributes of APS in both care models, corroborating similar studies from other regions of Brazil. PMID- 25789640 TI - [Needs of psychopedagogical training for the care of children with chronic disease: perceptions of hospital nursing]. AB - OBJECTIVE: To identify the psychopedagogical training needs of the pediatric nurses in the largest public hospital of the Balearic Islands, Spain. METHOD: This study was developed with a quantitative and qualitative design, where 78 nurses (97.5% of the service) answered a questionnaire, and 15 participated in interviews that were analyzed via content analysis. RESULTS: The quantitative results show gaps in the knowledge and psychopedagogical skills of the staff. These aspects could facilitate the development of tasks tailored to the personality and the psychoevolutional time of children with chronic diseases, as well as to the emotional state of families. The qualitative data was organized into four categories: family support; hospital and education; psychopedagogical training and difficulties in practice. The little communication between nurses and teachers is evident. CONCLUSION: The data reinforces the need to implement training strategies and interdisciplinary work among health professionals, educators and families. PMID- 25789641 TI - [Hospital admissions due to ambulatory care sensitive conditions among children by age group and health region]. AB - OBJECTIVE: to describe hospital admissions for ambulatory care sensitive conditions in children under five years of age in the State of Parana, Brazil by condition type, age group and health region. METHOD: a temporal ecological study was conducted using data from the Unified Health System Hospital Information System for the period 2000 to 2011. Conditions were grouped in accordance with the list of ambulatory care sensitive conditions in Brazil. RESULTS: there was an increase in the rate of admissions for ambulatory care sensitive conditions in all age groups in 50% of the health regions, with a marked increase in children under the age of one. Pneumonia, gastroenteritis and asthma were the main causes of admissions. There was an increase in the proportion of overall admissions accounted for by pneumonia and gastroenteritis. CONCLUSION: the increase in admissions reveals the need for actions to improve access to primary healthcare and provide effective treatment of the main ambulatory care sensitive conditions in order to prevent hospital admissions among children. PMID- 25789642 TI - [Construction and validation of nursing diagnoses for individuals with diabetes in specialized care]. AB - OBJECTIVE: To construct statements of nursing diagnoses related to nursing practice for individuals with diabetes in Specialized Care, on the basis of the Database of Nursing Practice Terms related to diabetes, in the International Classification for Nursing Practice (ICNP((r))) and in the Theory of Basic Human Needs and to validate them with specialist nurses in the area. METHOD: Methodological research, structured into sequential stages of construction, cross mapping, validation and categorization of nursing diagnoses. RESULTS: A list was indicated of 115 statements of diagnostic, including positive, negative and improvement statements; 59 nursing diagnoses present in and 56 nursing diagnoses absent from the ICNP((r)) Version 2011. 66 diagnoses with CVI >= 0.50 were validated, being categorized on the basis of human needs. CONCLUSION: It was observed that the use of the ICNP((r)) 2011 favored the specifications of the concepts of professional practice in care with individuals with diabetes. PMID- 25789643 TI - [Association between self-reported health and sociodemographic characteristics with cardiovascular diseases in adults]. AB - OBJECTIVE: To assess the association of sociodemographic and self-rated health in the presence of cardiovascular diseases and the association of this perception with the type of disease. METHODS: A cross-sectional population survey study carried out with 1,232 individuals aged between 20 and 59 years of both genders living in the metropolitan region of Maringa-PR. Data were analyzed using multiple and simple logistic regression. RESULTS: In multivariate analysis, the age range and self-rated health were associated with cardiovascular disease, and in the univariate analysis self-rated regular health was associated with arterial hypertension, while self-rated poor health was associated to heart failure, stroke, and to acute myocardial infarction (heart attack). CONCLUSION: The differences in association of self-rated health with these diseases can indicate how individuals with certain characteristics cope with the disease, allowing for more individualized and specific health care. PMID- 25789644 TI - [Pharmacotherapy and analysis of gaseous mediators in hypertensive patients]. AB - OBJECTIVE: To evaluate the effect of using antihypertensive classes of drugs of the calcium channel antagonists and inhibitors of angiotensin-converting enzyme in plasma concentrations of hydrogen sulfide and nitric oxide in patients with hypertension. METHODS: Cross-sectional study with quantitative approach conducted with hypertensive patients in use of antihypertensive classes of drugs: angiotensin-converting enzyme inhibitors or calcium channel antagonists. RESULTS: It was found that the concentration of plasma nitric oxide was significantly higher in hypertensive patients that were in use of angiotensin-converting enzyme inhibitors (p<0.03) and the hydrogen sulphide concentration was significantly higher in hypertensive plasma in use of calcium channel antagonists (p<0.002). CONCLUSION: The findings suggest that these medications have as additional action mechanism the improvement of endothelial dysfunction by elevate plasma levels of vasodilatory substances. PMID- 25789645 TI - [Analysis of the physical aspects of quality of life of kidney recipients]. AB - OBJECTIVE: To identify the main factors of the physical domain modified after kidney transplantation and analyze the influence of those aspects in the perception of Overall quality of life (QOL). METHOD: Longitudinal study, conducted with 63 chronic kidney patients, evaluated before and after kidney transplant, using the quality of life scale proposed by the World Health Organization. RESULTS: We observed significant improvement in the physical aspects of QOL after kidney transplantation. Significant correlations were observed between physical aspects and the Overall QOL. CONCLUSION: The kidney transplant generated improvement in all physical aspects of QOL. The factors that showed stronger correlation with the Overall QOL before the transplant were the capacity to work and pain. After the transplant, the perception of need for treatment was the factor that showed stronger correlation with the Overall QOL. PMID- 25789646 TI - [Facilitators of the transition process for the self-care of the person with stoma: subsidies for Nursing]. AB - OBJECTIVE: To know the facilitating factors of the transition process from dependency to the self-care of people with a stoma. METHOD: This is a descriptive study of qualitative approach, including 27 people with permanent stomas due to cancer. The data were collected through semi-structured interviews and submitted to content analysis based on the Transition Theory as theoretical reference. RESULTS: The self-care facilitators related to the person were the positive significance of ostomy; the preparation for this experience already in the preoperative period; emotional stability; faith; religiousness; and a sense of normalcy acquired from a next image similar to the previous one. The facilitators related to the community were the following: receiving equipment for free from the government; support from family and the multidisciplinary team, especially the nurses; and having contact with other people with stomata. CONCLUSION: The results allow that nurses develop strategies to help people with stomata to resume their self-care. PMID- 25789647 TI - [Contributory factors for the functional independence of oldest old]. AB - OBJECTIVE: To investigate the socioeconomic and clinical factors that contribute to the functional independence of the oldest old of a community. METHOD: Cross sectional quantitative study whose sample consisted of 214 elderly people registered in Basic Health Units. Data were collected through structured interviews and application of the Functional Independence Measure. We used descriptive statistics, and for association of the variables we used the Student t-test, ANOVA and Tukey's test for multiple comparisons. RESULTS: The significant variables that contributed to the functional independence were remaining economically active, practicing physical and leisure activities, having a social life, eating fruits, vegetables and meat. The orientation to conduct these practices reduces the demand for care and help needed in everyday activities. CONCLUSION: Maintaining independence is primordial to delay disability and presents itself as an excellent field of work for nursing. PMID- 25789648 TI - [Empowering a group of seniors in a rural community]. AB - OBJECTIVE: To describe the stages of the empowerment process of a group of seniors in a rural community. METHOD: Convergent care research whose foundation is to use the scope of practice. Conducted with the proposal to change the practice of 21 seniors and nine health professionals, with the aim of health promotion empowerment. Data were collected during 22 meetings, and group interviews at the end of the intervention. RESULTS: Showed that despite the initial impact of the change, the group was able to welcome the new change, taking advantage of the space to express anxieties, share joys, and build new knowledge, which led to the incorporation of changes that reflected in the development of healthy habits and improvements in interpersonal relationships. CONCLUSION: The convergent care research consisted of strategy that changed the group's lives, empowering them with health promoting actions. PMID- 25789650 TI - [Evaluation of digital educational student-technology interaction in neonatal nursing]. AB - OBJECTIVE: To assess the digital educational technology interface Caring for the sensory environment in the neonatal unit: noise, lighting and handling based on ergonomic criteria. METHODS: Descriptive study, in which we used the guidelines and ergonomic criteria established by ISO 9241-11 and an online Likert scale instrument to identify problems and interface qualities. The instrument was built based on Ergolist, which follows the criteria of ISO 9141-11. There were 58 undergraduate study participants from the School of Nursing of Ribeirao Preto, University of Sao Paulo, who attended the classes about neonatal nursing content. RESULTS: All items were positively evaluated by more than 70% of the sample. CONCLUSION: Educational technology is appropriate according to the ergonomic criteria and can be made available for teaching nursing students. PMID- 25789649 TI - Evaluating the intervening factors in patient safety: focusing on hospital nursing staff. AB - OBJECTIVE: To evaluate intervening factors in patient safety, focusing on hospital nursing staff. METHOD: The study is descriptive, with qualitative approach, excerpt from a larger study with analytical nature. It was undertaken in a public hospital in Fortaleza, CE, Brazil, between January and June 2013, with semi-structured interviews to 70 nurses, using Thematic Content Analysis. RESULTS: The principal intervening factors in patient safety related to hospital nursing staff were staff dimensioning and workload, professional qualification and training, team work, being contracted to the institution, turnover and lack of job security, and bad practice/disruptive behaviors. These aspects severely interfere with the establishment of a safety culture in the hospital analyzed. CONCLUSION: It is necessary for managers to invest in nursing staff, so that these workers may be valued as fundamental in the promotion of patient safety, making it possible to develop competences for taking decisions with focus on the improvement of quality care. PMID- 25789651 TI - [Perioperative thirst: an analysis from the perspective of the Symptom Management Theory]. AB - A theoretical study aimed to analyze the existing knowledge in the literature on the perioperative thirst symptom from the perspective of Symptom Management Theory, and supplemented with the experience of the study group and thirst research. Thirst is described as a very intense symptom occurring in the perioperative period, and for this reason it cannot be ignored. The Symptom Management Theory is adequate for understanding the thirst symptom and is a deductive theory, focused on the domains of the Person, Environment and Health / Illness Status, as well as on the dimensions of Experience, Management Strategies and Symptom Outcomes. Using the theory leads us to consider perioperative thirst in its multifactorial aspects, analyzing the interrelation of its domains and dimensions in order to draw attention to this symptom that has been insufficiently valued, recorded and treated in clinical practice. PMID- 25789652 TI - [Determination or determinants? A debate based on the Theory on the Social Production of Health]. AB - This article aims to discuss the concepts of Social Determination of Health and Social Determinants of Health, by establishing a comparison between each of their guiding perspectives and investigating their implications on the development of health policies and health actions. We propose a historical and conceptual reflection, highlighting the Theory on the Social Production of Health, followed by a debate on the concepts, with a comparative approach among them. PMID- 25789653 TI - [Strategies for self-management support by patients with stroke: integrative review]. AB - OBJECTIVE: To analyze strategies for self-management support by patients with stroke in the light of the methodology of the five A's (ask, advice, assess, assist and arrange). METHODS: Integrative review conducted at the following databases CINAHL, SCOPUS, PubMed, Cochrane and LILACS. RESULTS: A total of 43 studies published between 2000 and 2013 comprised the study sample. All proposed actions in the five A's methodology and others were included. We highlight the Assist and Arrange, in which we added actions, especially with regard to the use of technological resources and joint monitoring between patients, families and professionals. No study included all five A's, which suggests that the actions of supported self-management are developed in a fragmented way. CONCLUSION: The use of five A's strategy provides guidelines for better management of patients with stroke with lower cost and higher effectiveness. PMID- 25789654 TI - [Scientific Literature on the Reliability and Validity of the Manchester Triage System (MTS) Protocol: A Integrative Literature Review]. AB - OBJECTIVE: To analyze the scientific production about the validity and reliability of the Manchester Triage System (MTS) protocol. METHOD: A descriptive study of an integrative literature review. Articles on the validity and reliability of the MTS developed with children and adults published between 1999 and 2013 were included. RESULTS: 14 articles were selected from a total of 8438, nine of validity and five of reliability. The reliability of the MTS ranged from moderate to almost perfect, with higher intra-evaluation. Regarding validity, the results seem to point to equivalent and satisfactory sensibility and specificity levels of the MTS. The instrument proved to be a good predictor of the need for hospitalization and of hospital mortality. CONCLUSION: The reliability and validity of the MTS obtained in the studies is varied. It is recommended that new studies indicate necessary modifications to the MTS so that it is more safely used by nurses. PMID- 25789655 TI - [Effectiveness of enteral nutritional therapy in the healing process of pressure ulcers: a systematic review]. AB - OBJECTIVE: To evaluate the effectiveness of enteral nutritional therapy (ENT) in the healing process of pressure ulcers (PU) in adults and the elderly. METHOD: A systematic review whose studies were identified through the databases of Cochrane, MEDLINE/PubMed, SciELO, LILACS, EMBASE, CINAHL, Web of Science, and manual searches. It included randomized clinical trials (RCTs) without delimiting the period or language of publication, which addressed adults and elderly patients with pressure ulcers in a comparative treatment of enteral nutritional therapy and placebo or between enteral nutritional therapy with different compositions and dosages. RESULTS: We included ten studies that considered different interventions. It resulted in more pressure ulcers healed in the groups that received the intervention. The included studies were heterogeneous with regard to patients, the type of intervention, the sample and the follow-up period, all of which made meta-analysis impossible. CONCLUSION: Although the enteral nutritional therapy demonstrates a promotion of pressure ulcer healing, sufficient evidence to confirm the hypothesis was not found. PMID- 25789656 TI - [Trauma in the elderly caused by traffic accident: integrative review]. AB - OBJECTIVE: To describe the scientific knowledge produced about trauma in the elderly caused by traffic accidents in healthcare area studies. METHODS :Integrative review of studies from 2003 to 2013 searched in LILACS, SciELO, PubMed and CINHAL databases. We used combination of the descriptors injuries, wounds and accidents, in English, Portuguese and Spanish languages. RESULTS: 32 studies were selected. In the thematic analysis, three categories emerged: epidemiological data from traffic accidents involving elderly; traffic accidents with elderly pedestrians; and trauma care in the elderly. We observed increased incidence of trauma in most countries and pedestrians represented a large part of the victims. Among these, the elderly are the most vulnerable group. CONCLUSION: Studies showed that trauma care in the elderly need protocols and professionals with training in gerontology specialized in trauma care services. PMID- 25789657 TI - Nuclear Overhauser Enhancement imaging of glioblastoma at 7 Tesla: region specific correlation with apparent diffusion coefficient and histology. AB - OBJECTIVE: To explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells. PATIENTS AND METHODS: For 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTRasym) at 3.3ppm, B1 = 0.7 MUT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTRasym values within both regions of interest were correlated voxelwise yielding the correlation coefficient rSpearman (rSp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTRasym and ADC values of the biopsy site. RESULTS: Eight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16<=rSp<=0.53, p<0.05). Seven correlations were statistically insignificant (p>0.05, n = 4) or yielded rSp~0 (p<0.05, n = 3). No trend towards a correlation between MTRasym and ADC was found in CE-T1 tumor (-0.310.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTRasym values in two of the three patients (rSppatient3 = 0.69 and rSppatient15 = 0.87, p<0.05), while the correlation of ADC and cellularity was heterogeneous (rSppatient3 = 0.545 (p = 0.067), rSppatient4 = -0.021 (p = 0.948), rSppatient15 = -0.755 (p = 0.005)). DISCUSSION: NOE-imaging is a new contrast promising insight into pathophysiologic processes in glioblastoma regarding cell density and protein content, setting itself apart from DWI. Future studies might be based on the assumption that NOE mediated CEST visualizes cellularity more accurately than ADC, especially in the CE-T1 tumor region. PMID- 25789664 TI - Missing conflict of interest disclosures statement. Staged laryngotracheoplasty in adult laryngotracheal stenosis: predictors of long-term decannulation. PMID- 25789660 TI - Podosomes and invadopodia: tools to breach vascular basement membrane. AB - The vascular basement membrane (BM) is a thin and dense cross-linked extracellular matrix layer that covers and protects blood vessels. Understanding how cells cross the physical barrier of the vascular BM will provide greater insight into the potentially critical role of vascular BM breaching in cancer extravasation, leukocyte trafficking and angiogenic sprouting. In the last year, new evidence has mechanistically linked the breaching of vascular BM with the formation of specific cellular micro-domains known as podosomes and invadopodia. These structures are specialized cell-matrix contacts with an inherent ability to degrade the extracellular matrix. Specifically, the formation of podosomes or invadopodia was shown as an important step in vascular sprouting and tumor cell extravasation, respectively. Here, we review and comment on these recent findings and explore the functions of podosomes and invadopodia within the context of pathological processes such as tumor dissemination and tumor angiogenesis. PMID- 25789666 TI - New possibilities of accurate particle characterisation by applying direct boundary models to analytical centrifugation. AB - Analytical centrifugation (AC) is a powerful technique for the characterisation of nanoparticles in colloidal systems. As a direct and absolute technique it requires no calibration or measurements of standards. Moreover, it offers simple experimental design and handling, high sample throughput as well as moderate investment costs. However, the full potential of AC for nanoparticle size analysis requires the development of powerful data analysis techniques. In this study we show how the application of direct boundary models to AC data opens up new possibilities in particle characterisation. An accurate analysis method, successfully applied to sedimentation data obtained by analytical ultracentrifugation (AUC) in the past, was used for the first time in analysing AC data. Unlike traditional data evaluation routines for AC using a designated number of radial positions or scans, direct boundary models consider the complete sedimentation boundary, which results in significantly better statistics. We demonstrate that meniscus fitting, as well as the correction of radius and time invariant noise significantly improves the signal-to-noise ratio and prevents the occurrence of false positives due to optical artefacts. Moreover, hydrodynamic non-ideality can be assessed by the residuals obtained from the analysis. The sedimentation coefficient distributions obtained by AC are in excellent agreement with the results from AUC. Brownian dynamics simulations were used to generate numerical sedimentation data to study the influence of diffusion on the obtained distributions. Our approach is further validated using polystyrene and silica nanoparticles. In particular, we demonstrate the strength of AC for analysing multimodal distributions by means of gold nanoparticles. PMID- 25789661 TI - A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. AB - Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males. PMID- 25789658 TI - Proteomic analysis of proteins surrounding occludin and claudin-4 reveals their proximity to signaling and trafficking networks. AB - Tight junctions are complex membrane structures that regulate paracellular movement of material across epithelia and play a role in cell polarity, signaling and cytoskeletal organization. In order to expand knowledge of the tight junction proteome, we used biotin ligase (BioID) fused to occludin and claudin-4 to biotinylate their proximal proteins in cultured MDCK II epithelial cells. We then purified the biotinylated proteins on streptavidin resin and identified them by mass spectrometry. Proteins were ranked by relative abundance of recovery by mass spectrometry, placed in functional categories, and compared not only among the N- and C- termini of occludin and the N-terminus of claudin-4, but also with our published inventory of proteins proximal to the adherens junction protein E cadherin and the tight junction protein ZO-1. When proteomic results were analyzed, the relative distribution among functional categories was similar between occludin and claudin-4 proximal proteins. Apart from already known tight junction- proteins, occludin and claudin-4 proximal proteins were enriched in signaling and trafficking proteins, especially endocytic trafficking proteins. However there were significant differences in the specific proteins comprising the functional categories near each of the tagging proteins, revealing spatial compartmentalization within the junction complex. Taken together, these results expand the inventory of known and unknown proteins at the tight junction to inform future studies of the organization and physiology of this complex structure. PMID- 25789667 TI - The strong influence of internal stresses on the nucleation of a nanosized, deeply undercooled melt at a solid-solid phase interface. AB - The effect of elastic energy on nucleation and disappearance of a nanometer size intermediate melt (IM) region at a solid-solid (S1S2) phase interface at temperatures 120 K below the melting temperature is studied using a phase-field approach. Results are obtained for broad range of the ratios of S1S2 to solid melt interface energies, k(E), and widths, k(delta). It is found that internal stresses only slightly promote barrierless IM nucleation but qualitatively alter the system behavior, allowing for the appearance of the IM when k(E) < 2 (thermodynamically impossible without mechanics) and elimination of what we termed the IM-free gap. Remarkably, when mechanics is included within this framework, there is a drastic (16 times for HMX energetic crystals) reduction in the activation energy of IM critical nucleus. After this inclusion, a kinetic nucleation criterion is met, and thermally activated melting occurs under conditions consistent with experiments for HMX, elucidating what had been to date mysterious behavior. Similar effects are expected to occur for other material systems where S1S2 phase transformations via IM take place, including electronic, geological, pharmaceutical, ferroelectric, colloidal, and superhard materials. PMID- 25789668 TI - More than just fibers: an aqueous method for the production of innovative recombinant spider silk protein materials. AB - Spider silk is a striking and robust natural material that has an unrivaled combination of strength and elasticity. There are two major problems in creating materials from recombinant spider silk proteins (rSSps): expressing sufficient quantities of the large, highly repetitive proteins and solvating the naturally self-assembling proteins once produced. To address the second problem, we have developed a method to rapidly dissolve rSSps in water in lieu of traditional organic solvents and accomplish nearly 100% solvation and recovery of the protein. Our method involves generating pressure and temperature in a sealed vial by using short, repetitive bursts from a conventional microwave. The method is scalable and has been successful with all rSSps used to date. From these easily generated aqueous solutions of rSSps, a wide variety of materials have been produced. Production of fibers, films, hydrogels, lyogels, sponges, and adhesives and studies of their mechanical and structural properties are reported. To our knowledge, ours is the only method that is cost-effective and scalable for mass production. This solvation method allows a choice of the physical form of product to take advantage of spider silks' mechanical properties without using costly and problematic organic solvents. PMID- 25789669 TI - Polymorphisms in Plasmodium falciparum K13-propeller in Angola and Mozambique after the introduction of the ACTs. AB - We report the presence of SNPs in Plasmodium falciparum K13-propeller gene in two African countries, Angola and Mozambique, where malaria is a serious public health problem. Samples were collected before and after ACT introduction as first line treatment. In each country 50 samples collected before and 50 after ACT introduction were analysed. A total of three different mutations (R471R and R575R in Angola and V494I in Mozambique) were identified in five samples, all collected after the introduction of ACT. The R471R mutation detected in Angola has already been reported in Africa (DR-Congo and Gabon). However, the mutations R575R (Angola) and V494I (Mozambique), have never been reported. V494I is adjacent to the known K13 resistance-associated mutation Y493H, although functional analysis did not predict a deleterious effect on protein function. PMID- 25789670 TI - Plk1 Manages DNA break repair during mitosis. PMID- 25789671 TI - Two-photon responsive metal-organic framework. AB - Two-photon processing presents a facile means to tailor the properties of materials in three-dimensions. A two-photon responsive metal-organic framework (MOF) has been realized through the incorporation of a photoactive linker into a MOF via a multivariate strategy. The resulting MOF exhibits a significant one photon and two-photon excited fluorescence change in response to UV light and infrared femtosecond laser, enabling spatial modulation of the fluorescence property of the MOF. It thus demonstrates the capacity of two-photon patterning and imaging inside the crystal, and the formation of three-dimensional two-photon excited fluorescent structure in a high resolution. PMID- 25789672 TI - Announcement: double-blind peer review. PMID- 25789674 TI - Sox2 as a servant of two masters. PMID- 25789673 TI - Immune mechanisms at the maternal-fetal interface: perspectives and challenges. PMID- 25789675 TI - Thymic IL-7 signaling goes beyond survival. PMID- 25789676 TI - The lymph node filter revealed. PMID- 25789677 TI - A new receptor for LPS. PMID- 25789685 TI - A minor (<50%) signet-ring cell component associated with poor prognosis in colorectal cancer patients: a 26-year retrospective study in China. AB - BACKGROUND: We performed a retrospective study to determine the cancer-specific survival of colorectal cancer patients with a component of signet-ring cells or mucin comprising < 50% of the tumor mass. METHODS: A total of 2454 patients seen in our hospital from 1985 to 2011 were retrospectively studied. The patients were divided into five groups according to type of cancer: signet-ring cell carcinoma (with > 50% signet-ring cell, n = 36), partial signet-ring cell carcinoma (with < 50% signet-ring cell, n = 28), mucinous adenocarcinoma (with > 50% mucin lacking signet-ring cell, n = 267), partial mucinous adenocarcinoma (with < 50% mucin lacking signet-ring cell, n = 145), and classic adenocarcinoma (with absence of either mucin or signet-ring cell, n = 1978). RESULTS: Patients with > 50% or < 50% signet-ring cell had the lowest 5-year survival rates (35.5% and 29.7%, respectively), followed by patients with > 50% mucin (48.8%). Patients who had partial mucinous adenocarcinoma with < 50% mucin and classic adenocarcinoma patients had the highest 5-year survival rates (64.8% and 65.3%, respectively). Stratified and multivariate analysis showed that signet-ring cell carcinoma, partial signet-ring cell carcinoma and mucinous adenocarcinoma were independent predictors of decreased survival (hazard ratio 1.699, P = 0.016; hazard ratio 2.182, P = 0.005; hazard ratio 1.532, P < 0.001; respectively), and partial mucinous adenocarcinoma was not (hazard ratio 1.137, P = 0.431). CONCLUSIONS: Patients with a component of signet-ring cells, regardless of the extent, had poor prognoses. Patients with mucinous adenocarcinoma containing >50% mucin had poor prognoses as well, whereas those with < 50% mucin had survival rates similar to those of classic adenocarcinoma patients. Therefore, in clinical practice, patients with a component of signet-ring cells, regardless of the extent, should be given significant clinical attention. PMID- 25789684 TI - Control of adaptive immunity by the innate immune system. AB - Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity. PMID- 25789686 TI - Role of saliva in esophageal defense: implications in patients with nonerosive reflux disease. AB - BACKGROUND: It has been previously demonstrated that patients with reflux esophagitis exhibit a significant impairment in the secretion of salivary protective components versus controls. However, the secretion of salivary protective factors in patients with nonerosive reflux disease (NERD) is not explored. The authors therefore studied the secretion of salivary volume, pH, bicarbonate, nonbicarbonate glycoconjugate, protein, epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and prostaglandin E2 in patients with NERD and compared with the corresponding values in controls (CTRL). METHODS: Salivary secretion was collected during basal condition, mastication and intraesophageal mechanical (tubing, balloon) and chemical (initial saline, acid, acid/pepsin, final saline) stimulations, respectively, mimicking the natural gastroesophageal reflux. RESULTS: Salivary volume, protein and TGF-alpha outputs in patients with NERD were significantly higher than CTRL during intraesophageal mechanical (P < 0.05) and chemical stimulations (P < 0.05). Salivary bicarbonate was significantly higher in NERD than CTRL group during intraesophageal stimulation with both acid/pepsin (P < 0.05) and saline (P < 0.01). Salivary glycoconjugate secretion was significantly higher in the NERD group than the CTRL group during chewing (P < 0.05), mechanical (P < 0.05) and chemical stimulation (P < 0.01). Salivary EGF secretion was higher in patients with NERD during mechanical stimulation (P < 0.05). CONCLUSIONS: Patients with NERD demonstrated a significantly stronger salivary secretory response in terms of volume, bicarbonate, glycoconjugate, protein, EGF and TGF-alpha than asymptomatic controls. This enhanced salivary esophagoprotection is potentially mediating resistance to the development of endoscopic mucosal changes by gastroesophageal reflux. PMID- 25789687 TI - Finasteride reduces microvessel density and expression of vascular endothelial growth factor in renal tissue of diabetic rats. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of diabetic microvascular complications. Finasteride has been confirmed to decrease VEGF expression in prostate and prostatic suburethral tissue resulting in limiting hematuria from human benign prostatic hyperplasia. The purpose of this study was to evaluate the effects of finasteride on microvessel density (MVD), VEGF protein and mRNA expressions in the renal tissue of diabetic rats. METHODS: Diabetic rats induced by streptozotocin were intragastrically given finasteride at 30 mg/kg body weight once a day for 4 weeks. Histomorphologic changes in kidney were observed under light microscope. Immunohistochemistry for CD34 and VEGF on kidney sections was performed to assess MVD and VEGF protein expression in glomeruli of rats, respectively. The VEGF mRNA expression in the renal tissue was examined using reverse transcription polymerase chain reaction analysis. RESULTS: The glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue were significantly increased in diabetic rats and finasteride treated rats when compared with controls (P < 0.01, P < 0.05). When compared with diabetic rats, the glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue of finasteride-treated rats were significantly decreased (P < 0.05, P < 0.01). CONCLUSIONS: Finasteride reduces the VEGF expression and decreases the MVD in the renal tissue of diabetic rats, suggesting the therapeutic potential of finasteride on diabetic microvascular complications. PMID- 25789688 TI - Intracerebral Pial Arteriovenous Fistula With Aneurysm. PMID- 25789689 TI - An Overview of Current Regulatory Requirements for Approval of Biosimilar Insulins. AB - Insulin analog patent expiry is likely to mean that, increasingly, copies of original biopharmaceutical products will be submitted for authorization. Experience with biosimilars in other therapeutic areas suggests that careful regulation and caution are needed. Published guidelines of regulatory authorities around the world on approval of biosimilars and, where available, insulin biosimilars were reviewed. Information was sourced through Internet searching and cross-referencing guidelines. As of August 2014, general biosimilar and insulin specific guidelines are available in 34 countries and two countries/regulatory domains, respectively. Many guidelines are clearly related to, or partly derived from, the general and insulin-specific European Medicines Agency (EMA) guidelines. Areas covered by these guidelines are fairly consistent, covering preclinical, pharmacokinetic (PK), and pharmacodynamic (PD) studies in humans and clinical areas; however, there are differences in emphasis. The EMA insulin specific guidelines include detailed criteria on PK/PD studies, as do most other general biosimilar guidelines and, to a lesser extent, clinical studies. The U.S. Food and Drug Administration has general biosimilar guidelines, emphasizing consideration of the whole package of in vitro, biological, and human studies, rather than concentrating on any one aspect. In countries such as Mexico, guidelines are broad, leaving wide discretion to the regulatory authority. In conclusion, from a global perspective, this area of drug regulation is heterogeneous and evolving, and the authors call for an initiative aimed at harmonizing the requirements for biosimilar insulins. PMID- 25789690 TI - The locus of sexual selection: moving sexual selection studies into the post genomics era. AB - Sexual selection drives fundamental evolutionary processes such as trait elaboration and speciation. Despite this importance, there are surprisingly few examples of genes unequivocally responsible for variation in sexually selected phenotypes. This lack of information inhibits our ability to predict phenotypic change due to universal behaviours, such as fighting over mates and mate choice. Here, we discuss reasons for this apparent gap and provide recommendations for how it can be overcome by adopting contemporary genomic methods, exploiting underutilized taxa that may be ideal for detecting the effects of sexual selection and adopting appropriate experimental paradigms. Identifying genes that determine variation in sexually selected traits has the potential to improve theoretical models and reveal whether the genetic changes underlying phenotypic novelty utilize common or unique molecular mechanisms. Such a genomic approach to sexual selection will help answer questions in the evolution of sexually selected phenotypes that were first asked by Darwin and can furthermore serve as a model for the application of genomics in all areas of evolutionary biology. PMID- 25789691 TI - Description of bovine major histocompatibility complex class IIa haplotypes using parthenogenetic embryo-derived cells. AB - In this study, we report an approach to characterize individual BoLA haplotypes using cells from parthenogenetic bovine embryos derived from slaughterhouse ovaries. Eight of the 15 parthenogenetic embryos so obtained had not undergone meiotic recombination on the BoLA region and were suitable to describe BoLA haplotypes. Detailed analysis of the BoLA class IIa region identified seven different class IIa haplotypes, including six not previously described and two new alleles of BoLA-DQA and one BoLA-DQB. Our method provided reliable sources of homozygous DNA to describe BoLA haplotypes. PMID- 25789693 TI - Osmolarity of prevalent eye drops, side effects, and therapeutic approaches. AB - PURPOSE: Little is known about how the osmolarity of ophthalmic formulations affects the ocular surface. Because hyperosmolar eye drops could be therapeutic for treating corneal edema, this article presents an ex vivo model of corneal edema for testing ophthalmic drugs based on their osmolarity. The respective osmolarity of common eye drops found in the German market is also analyzed here. METHODS: For modeling corneal edema, an Ex Vivo Eye Irritation Test was used to simulate an ocular anterior chamber with a physiological corneal barrier. To induce corneal edema, the anterior chamber was supplied with a hypoosmolar medium (148 mOsm/L) for 24 hours. Preserved and preservative-free 5% sodium chloride (hyperosmolar Omnisorb and Ocusalin 5% UD) were used for 1 hour, on 5 corneas each, to test their efficiency to reduce corneal edema in this model. Corneal thickness was determined by optical coherence tomography. Osmolarity of 87 common eye drops was measured by freezing point osmometry. RESULTS: Ex vivo, the tested hypoosmolar condition induced corneal edema from 450 MUm (+/-50 MUm) at baseline to 851 MUm (+/-94 MUm, P < 0.0001). Omnisorb and Ocusalin 5% UD significantly reduced the corneal thickness by 279 MUm (+/-28 MUm, P < 0.001) for Omnisorb and 258 MUm (+/-29 MUm, P < 0.001) for Ocusalin 5% UD. Forty-three (49%) of the tested products had an osmolarity below and 44 (51%) above the physiological tear osmolarity of 289 mOsm/L. Osmolarity values of less than 200 mOsm/L were found in lubricant drops. The highest osmolarity was detected in Omnisorb (1955 mOsm/L). CONCLUSIONS: The Ex Vivo Eye Irritation Test has proven to be a reliable novel model of corneal edema for evaluating osmotic eye drops. Osmolarity measurements revealed a wide range from hypotonic to hypertonic formulations for commonly marketed ophthalmic drugs. PMID- 25789692 TI - Autosomal Dominant Retinal Dystrophy With Electronegative Waveform Associated With a Novel RAX2 Mutation. AB - IMPORTANCE: The patients evaluated in this study, to our knowledge, represent the first complete clinical description of a family with an autosomal dominant inheritance pattern of retinal dystrophy associated with a novel mutation in RAX2. OBJECTIVES: To clinically evaluate 4 patients and 5 unaffected family members, characterize the disease phenotype over time, and identify the associated genetic mutation. DESIGN, SETTING, AND PARTICIPANTS: A prospective, longitudinal, observational, case-series analysis of 9 members of an affected family at the Casey Eye Institute, Oregon Health and Science University, Portland. The dates of the study were from July 31, 1992, to August 11, 2014. INTERVENTIONS: Clinical evaluations included eye examination, color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography, kinetic visual field testing, and electroretinography. Genetic mutation screening was performed with next-generation sequencing, and identified mutations were confirmed with Sanger sequencing. MAIN OUTCOMES AND MEASURES: Clinical diagnosis and longitudinal characterization of retinal dystrophy and identification of genetic mutation. RESULTS: Six members of the family were identified as having retinal dystrophy (4 were examined, and 3 were genetically tested). Five unaffected family members were clinically evaluated (2 were genetically tested). The age at onset of retinal dystrophy was variable. All affected individuals presented with declining visual acuity, central scotomas, waxy disc pallor, attenuated vasculature, small yellow macular deposits and/or macular pigment mottling, and abnormal electroretinograms demonstrating mixed cone and rod dysfunction and a scotopic electronegative response to bright flashes. There were no other causes of an electronegative electroretinogram identified in any of the affected patients. Genetic testing revealed, to our knowledge, a novel frameshift heterozygous mutation in RAX2 in the patients with retinal dystrophy. CONCLUSIONS AND RELEVANCE: A frameshift heterozygous mutation in RAX2 inherited in an autosomal dominant fashion was associated with mixed cone and rod dysfunction. Among the patients, there was variability in the age at onset and in the specific pattern of photoreceptor dysfunction, but the clinical course was nevertheless slowly progressive. Screening for RAX2 mutation could provide prognostic value for patients and families with scotopic electronegative responses to bright flashes. PMID- 25789694 TI - Systematic review and meta-analysis on transplantation of ex vivo cultivated limbal epithelial stem cell on amniotic membrane in limbal stem cell deficiency. AB - PURPOSE: Ex vivo cultured limbal epithelial transplantation (CLET) with amniotic membrane (AM) as the substrate is a relatively new type of surgical therapy in treating limbal stem cell deficiency (LSCD). We summarize available evidence for determining the efficiency of this technique by a systematic review and meta analysis. METHODS: Searching the following electronic databases, MEDLINE, EMBASE, and the Cochrane Library, we analyzed the selected articles in 5 main aspects: donor screening, culture methods, evidence of cultivated stem cells, subjective symptoms, and adverse events through systematic review. Specifically, meta analysis was used in evaluating improvements in ocular surface and visual acuity. RESULTS: A total of 18 articles involving 572 eyes of 562 patients were available. The rate of success and 2-line improvement in best-corrected visual acuity (BCVA) was 67% [95% confidence interval (CI), 0.59-0.75; I = 60%] and 62% (95% CI, 0.57-0.66; I = 37.7%), respectively; and no difference was found both in success rate [odds ratio (OR), 1.35; 95% CI, 0.63-2.89; I = 46%] and visual acuity outcome (OR, 1.53; 95% CI, 0.67-3.45; I = 42.1%) between autograft and allograft. CONCLUSIONS: CLET is efficacious in patients with LSCD, and no difference both in success rate and visual acuity outcome between autograft and allograft was found. Overall safety profile was good, with most side effects being transient and amenable to subsequent treatments. The long-term results of autograft and allograft will inform future treatment algorithms and techniques with random control trials and better-designed analysis. PMID- 25789695 TI - Iontophoretic transepithelial corneal cross-linking to halt keratoconus in pediatric cases: 15-month follow-up. AB - PURPOSE: To report the results 15 months after transepithelial corneal cross linking by iontophoresis of riboflavin performed in pediatric patients affected by keratoconus. METHODS: Fourteen eyes of 14 pediatric patients [mean age 13 +/- 2.4 (SD) years; range, 10-18 years] were treated. Riboflavin solution was administered by iontophoresis for 5 minutes, and then UVA irradiation (10 mW/cm) was performed for 9 minutes. The corrected distance visual acuity measured as decimal number, spherical equivalent, refractive astigmatism, simulated K, corneal coma, spherical aberration, and high-order aberrations for 5.0-mm pupil and the thinnest point were measured preoperatively and 3, 6, 12, and 15 months postoperatively. The endothelial cell density was evaluated. The paired Student t test was used to compare data during the follow-up. RESULTS: Fifteen months after the procedure, the corrected distance visual acuity improved from 0.7 +/- 1.7 to 0.8 +/- 1.8 (P = 0.005). Spherical equivalent and refractive astigmatism as well as topographic and aberrometric data did not show significant changes. Also, the mean thinnest point and the endothelial cell density remained unchanged. The optical coherence tomography showed a nonhomogeneous but deep hyperreflective band with a fading effect extending through the anterior 180 MUm of the cornea. No side effects were recorded. CONCLUSIONS: Transepithelial collagen cross linking by iontophoresis, unlike other transepithelial techniques, seems to halt pediatric keratoconus progression over 15 months. However, we did not record significant improvement in higher-order aberrations and topographic indices. PMID- 25789696 TI - Comparison of anchored conjunctival rotation flap and conjunctival autograft techniques in pterygium surgery. PMID- 25789697 TI - Association between diabetes and keratoconus: a case-control study. PMID- 25789698 TI - Ventilation in day care centers and sick leave among nursery children. AB - Several studies have reported poor indoor air quality (IAQ) in day care centers (DCCs), and other studies have shown that children attending them have an increased risk of respiratory and gastrointestinal infections. The aim of this study was to investigate whether there is an association between ventilation in DCCs and sick leave among nursery children. Data on child sick leave within an 11 week period were obtained for 635 children attending 20 DCCs. Ventilation measurements included three proxies of ventilation: air exchange rate (ACR) measured with the decay method, ACR measured by the perfluorocarbon tracer gas (PFT) method, and CO2 concentration measured over a 1-week period. All but two DCCs had balanced mechanical ventilation system, which could explain the low CO2 levels measured. The mean concentration of CO2 was 643 ppm, exceeding 1000 ppm in only one DCC. A statistically significant inverse relationship between the number of sick days and ACR measured with the decay method was found for crude and adjusted analysis, with a 12% decrease in number of sick days per hour increase in ACR measured with the decay method. This study suggests a relationship between sick leave among nursery children and ventilation in DCCs, as measured with the decay method. PMID- 25789699 TI - Lymphangioleiomyomatosis and Tuberous Sclerosis Complex in Quebec: Prevalence and Health-care Utilization. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a manifestation of tuberous sclerosis complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health-care utilization are lacking for TSC and LAM. METHODS: Data on demographics, clinical outcomes, and health-care utilization in the Quebec ministerial provincial health-care database were analyzed for their association with TSC and LAM. RESULTS: A total of 1,004 subjects with TSC were identified using International Classification of Diseases, Ninth and 10th Revisions, codes for a prevalence of one in 7,872 people. There were 38 subjects with LAM, nine of whom also had TSC. Mean ages as well as the mean age at death were lower in the LAM and TSC group than in the control group. Mortality rates were higher in subjects with LAM than in those with TSC or in control subjects. Subjects with LAM experienced more medical visits and hospitalizations than did those with TSC and control subjects; these were associated with higher health-care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mammalian target of rapamycin inhibitors was uncommon. CONCLUSIONS: The prevalence of TSC in Quebec, Canada, is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. Health care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Mental health disorders may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM. PMID- 25789700 TI - Tandem Thien- and benzannulations of alpha-alkenoyl-alpha-alkynyl ketene dithioacetals with cyanoacetates: synthesis of functionalized benzo[b]thiophenes. AB - A novel domino annulation strategy for the construction of benzo[b]thiophenes has been developed. In the presence of Cs2CO3 and Ag2CO3, a wide range of alpha alkenoyl-alpha-alkynyl ketene dithioacetals readily react with cyanoacetates in CH3CN at 110 degrees C under N2 to afford multisubstituted benzo[b]thiophenes efficiently via tandem thien- and benzannulations. A plausible mechanism is also proposed. PMID- 25789701 TI - IL-31 Induces Chemotaxis, Calcium Mobilization, Release of Reactive Oxygen Species, and CCL26 in Eosinophils, Which Are Capable to Release IL-31. PMID- 25789702 TI - The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis. AB - Several inflammatory diseases including scleroderma and atopic dermatitis display dermal thickening, epidermal hypertrophy, or excessive accumulation of collagen. Factors that might promote these features are of interest for clinical therapy. We previously reported that LIGHT, a TNF superfamily molecule, mediated collagen deposition in the lungs in response to allergen. We therefore tested whether LIGHT might similarly promote collagen accumulation and features of skin fibrosis. Strikingly, injection of recombinant soluble LIGHT into naive mice, either subcutaneously or systemically, promoted collagen deposition in the skin and dermal and epidermal thickening. This replicated the activity of bleomycin, an antibiotic that has been previously used in models of scleroderma in mice. Moreover skin fibrosis induced by bleomycin was dependent on endogenous LIGHT activity. The action of LIGHT in vivo was mediated via both of its receptors, HVEM and LTbetaR, and was dependent on the innate cytokine TSLP and TGF-beta. Furthermore, we found that HVEM and LTbetaR were expressed on human epidermal keratinocytes and that LIGHT could directly promote TSLP expression in these cells. We reveal an unappreciated activity of LIGHT on keratinocytes and suggest that LIGHT may be an important mediator of skin inflammation and fibrosis in diseases such as scleroderma or atopic dermatitis. PMID- 25789703 TI - Association with Genetic Variants in the IL-23 and NF-kappaB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease. AB - Psoriasis is clinically heterogeneous, and symptoms can vary from mild almost cosmetic symptoms to severe disease requiring systemic therapy. Biomarkers predicting disease development are lacking. Herein we explored the genetic background in two polarized cohorts of carefully phenotyped patients with long term follow-up: consistent mild phenotype (n=696) and severe disease course requiring systemic therapy (n=715). All patients were treated at the same dermatology department ensuring homogenous assessment. Genotyping included known psoriasis-associated variants, with special focus on the IL-23 and NF-kappaB pathways. A case-case study comparing severe and mild psoriasis phenotypes, controlling for age at disease onset and gender, revealed significant differences between the two groups for SNPs in IL23R, NFKB1, IL21, IL12B, NFKBIL1 and IL23A. HLA-C*06 associated equally in the mild and severe disease cohorts. Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis. No protective gene was identified in the mild cohort, suggesting that current screens have primarily identified psoriasis variants associated with a more severe phenotype. These results demonstrate the importance of careful phenotyping and long-term clinical follow-up in genetic studies. PMID- 25789704 TI - Large-Scale Electron Microscopy Maps of Patient Skin and Mucosa Provide Insight into Pathogenesis of Blistering Diseases. AB - Large-scale electron microscopy ("nanotomy") allows straight forward ultrastructural examination of tissue, cells, organelles, and macromolecules in a single data set. Such data set equals thousands of conventional electron microscopy images and is freely accessible (www.nanotomy.org). The software allows zooming in and out of the image from total overview to nanometer scale resolution in a 'Google Earth' approach. We studied the life-threatening human autoimmune blistering disease pemphigus, using nanotomy. The pathomechanism of cell-cell separation (acantholysis) that underlies the blistering is poorly understood. Ultrastructural examination of pemphigus tissue revealed previously unreported findings: (i) the presence of double-membrane structures between cells in all pemphigus types; (ii) the absence of desmosomes around spontaneous blisters in pemphigus foliaceus (PF); (iii) lower level blistering in PF when force induced; and (iv) intercellular widening at non-acantholytic cell layers. Thus, nanotomy delivers open-source electron microscopic maps of patient tissue, which can be analyzed for additional anomalies from any computer by experts from different fields. PMID- 25789705 TI - Ruxolitinib Attenuates Cutaneous Lupus Development in a Mouse Lupus Model. PMID- 25789706 TI - EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma. AB - Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell-specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer. PMID- 25789707 TI - MITF Modulates Therapeutic Resistance through EGFR Signaling. AB - Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF (V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs), although the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR-induced vemurafenib resistance is ligand dependent. We employed whole-genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor (MITF), along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance, and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition. PMID- 25789709 TI - A new T-cell activation mode for suboptimal doses of antigen under the full activation of T cells with different specificity. AB - Loss of tolerance for autoantigens is a common feature in autoimmune diseases. Bystander T-cell activation is the activation of T cells to produce functional changes through TCR-independent stimulation. Although bystander activation may be related to tolerance loss to multiple autoantigens, the activation mechanism of T cells directed to an autoantigen with limited amount is not clear. We investigated an activation mode of T cells (designated as "associator T cells") directed to a suboptimal dose of cognate antigen X in the presence of fully activated T cells (designated as "responder T cells") directed to an optimal dose of antigen Y. In in vitro coculture, the activation of associator T cells was dependent on the presentation of antigen X, and soluble factors from activated responder T cells were not sufficient. Therefore, we conclude this activation mode is different from bystander activation and named it "extended antigen priming (EAP)". T cells with EAP showed a different phenotype compared to conventionally primed cells, suggesting the unique nature of EAP. Intriguingly, EAP was dependent on the CD40-CD40L signaling pathway. Thus, the EAP model is a T cell activation mode for suboptimal dose of antigen and presumably related to the immune response to autoantigens in autoimmune status. PMID- 25789710 TI - alpha,beta-Unsaturated diazoketones as useful platforms in the synthesis of nitrogen heterocycles. AB - Among the different types of diazocarbonyl substrates found in the literature to date, alpha,beta-unsaturated diazoketones have proven to be very promising as multifunctional intermediates. Possessing a diazo group, a ketone function and a double bond all together in a single molecule, these compounds constitute versatile building blocks for synthesis. For example, double bond functionalization, followed by intramolecular insertion reactions, can be a short alternative to prepare several rings or heterocyclic compounds. Although there are many efficient methods to prepare diazoketones, very few can be extended to the synthesis of the a,beta-unsaturated diazoketones; this is likely responsible for their limited application in synthesis. Unfortunately, the classical methods to prepare saturated- or aryl-diazoketones (acylation of diazomethane with acyl chlorides or mixed anhydrides) are not suitable for preparing a,beta-unsaturated diazoketones, since pyrazolines (dipolar cycloaddition products from the reaction between diazomethane and the double bond) are formed. Although Danheiser's two step detrifluoroacetylative procedure (starting from a,beta-unsaturated methyl ketones) is considered the best general method, it cannot be applied to the synthesis of all types of a,beta-unsaturated diazoketones. For example, the synthesis of more complex unsaturated diazoketones, as well as those with epimerizable stereocenters in the gamma position, was never described before. Another point is related to the geometry of the double bond, since practically all examples described thus far refer to unsaturated diazoketones with E geometry. In recent years, our research group developed two new Horner-Wadsworth Emmons reagents (containing a diazocarbonyl function) that could be easily applied in the one-step preparation of alpha,beta-unsaturated diazoketones from aldehydes. Not only were we able to selectively synthesize E- and Z-unsaturated diazoketones, but also to employ these useful platforms in the short synthesis of several nitrogen heterocycles such as indolizidines, quinolizidines, piperidines, and pyrrolidines. Our purpose in this Account is to introduce this class of diazoketone and provide a brief historical overview, culminating in how we developed a general methodology to prepare them. In continuation, we wish to call of the reader's attention to these important building blocks, showing how we could apply them to the synthesis of several nitrogen heterocycles, including the very short preparation of some popular alkaloids. The reader will also notice that the combination of these three important functions in the same molecule makes these compounds special as well as provides powerful platforms to access many important molecules in a direct fashion. PMID- 25789708 TI - Neural tube defects: from a proteomic standpoint. AB - Neural tube defects (NTDs) are congenital birth defects classified according to their resulting morphological characteristics in newborn patients. Current diagnosis of NTDs relies largely on the structural evaluation of fetuses using ultrasound imaging, with biochemical characterization used as secondary screening tools. The multigene etiology of NTDs has been aided by genetic studies, which have discovered panels of genes mutated in these diseases that encode receptors and cytoplasmic signaling molecules with poorly defined functions. Animal models ranging from flies to mice have been used to determine the function of these genes and identify their associated molecular cascades. More emphasis is now being placed on the identification of biochemical markers from clinical samples and model systems based on mass spectrometry, which open novel avenues in the understanding of NTDs at protein, metabolic and molecular levels. This article reviews how the use of proteomics can push forward the identification of novel biomarkers and molecular networks implicated in NTDs, an indispensable step in the improvement of patient management. PMID- 25789711 TI - Red and NIR light dosimetry in the human deep brain. AB - Photobiomodulation (PBM) appears promising to treat the hallmarks of Parkinson's Disease (PD) in cellular or animal models. We measured light propagation in different areas of PD-relevant deep brain tissue during transcranial, transsphenoidal illumination (at 671 and 808 nm) of a cadaver head and modeled optical parameters of human brain tissue using Monte-Carlo simulations. Gray matter, white matter, cerebrospinal fluid, ventricles, thalamus, pons, cerebellum and skull bone were processed into a mesh of the skull (158 * 201 * 211 voxels; voxel side length: 1 mm). Optical parameters were optimized from simulated and measured fluence rate distributions. The estimated MUeff for the different tissues was in all cases larger at 671 than at 808 nm, making latter a better choice for light delivery in the deep brain. Absolute values were comparable to those found in the literature or slightly smaller. The effective attenuation in the ventricles was considerably larger than literature values. Optimization yields a new set of optical parameters better reproducing the experimental data. A combination of PBM via the sphenoid sinus and oral cavity could be beneficial. A 20-fold higher efficiency of light delivery to the deep brain was achieved with ventricular instead of transcranial illumination. Our study demonstrates that it is possible to illuminate deep brain tissues transcranially, transsphenoidally and via different application routes. This opens therapeutic options for sufferers of PD or other cerebral diseases necessitating light therapy. PMID- 25789712 TI - Patterns of post-acute health care utilization after a severe traumatic brain injury: Results from the PariS-TBI cohort. AB - OBJECTIVE: To assess brain injury services utilization and their determinants using Andersen's model. METHODS: Prospective follow-up of the PariS-TBI inception cohort. Out of 504 adults with severe traumatic brain injury (TBI), 245 survived and 147 received a 4-year outcome assessment (mean age 33 years, 80% men). Provision rates of medical, rehabilitation, social and re-entry services and their relations to patients' characteristics were assessed. RESULTS: Following acute care discharge, 78% of patients received physiotherapy, 61% speech/cognitive therapy, 50% occupational therapy, 41% psychological assistance, 63% specialized medical follow-up, 21% community re-entry assistance. Health related need factors, in terms of TBI severity, were the main predictors of services. Provision of each therapy was significantly associated with corresponding speech, motor and psychological impairments. However, care provision did not depend on cognitive impairments and cognitive therapy was related to pre-disposing and geographical factors. Community re-entry assistance was provided to younger and more independent patients. CONCLUSIONS: These quantitative findings illustrate strengths and weaknesses of late brain injury care provision in urban France and highlight the need to improve treatment of cognitive impairments. PMID- 25789713 TI - A method to discriminate between closely related bovine major histocompatibility complex class I alleles by combining established PCR-SSP assays with RFLPs. AB - We have developed a polymerase chain reaction-sequence-specific primers restriction fragment length polymorphism (PCR-SSP-RFLP) method to rapidly differentiate between the A18 and A18 variant (v) BoLA haplotypes and between A14 and A15/A15v BoLA haplotypes in Holstein/Friesian cattle. We used published SSP to PCR amplify BoLA alleles expressed in animals of known haplotype and exposed the amplicons to the restriction enzyme PvuII that was predicted to cut at a unique site in the middle of BoLA-6*01302 (A18v) and BoLA-1*00901 (A15) but not in BoLA-6*01301 (A18) or BoLA-1*02301 (A14) alleles. Whereas the method does not discriminate between the A15 and A15v haplotypes, as the BoLA-1*00902 allele associated with A15v also contains a PvuII site, we are interested in cattle of A18 and A14 haplotype for vaccine related studies. Our results also indicated that the BoLA-6*01302 (A18v) allele is much more abundant than BoLA-6*01301 (A18) in the cattle that we sampled. PMID- 25789714 TI - Electrochemical and spectroelectrochemical studies of diphosphorylated metalloporphyrins. Generation of a phlorin anion product. AB - Two series of diphosphoryl-substituted porphyrins were synthesized and characterized by electrochemistry and spectroelectrochemistry in nonaqueous media containing 0.1 M tetra-n-butylammonium perchlorate (TBAP). The investigated compounds are 5,15-bis(diethoxyphosphoryl)-10,20-diphenylporphyrins (Ph)2(P(O)(OEt)2)2PorM and 5,15-bis(diethoxyphosphoryl)-10,20-di(para carbomethoxyphenyl)porphyrins (PhCOOMe)2(P(O)(OEt)2)2PorM where M = 2H, Co(II), Ni(II), Cu(II), Zn(II), Cd(II), or Pd(II). The free-base and five metalated porphyrins with nonredox active centers undergo two ring-centered oxidations and two ring-centered reductions, the latter of which is followed by a chemical reaction of the porphyrin dianion to give an anionic phlorin product. The phlorin anion is electroactive and can be reoxidized by two electrons to give back the starting porphyrin, or it can be reversibly reduced by one electron at more negative potentials to give a phlorin dianion. The chemical conversion of the porphyrin dianion to a phlorin anion proceeds at a rate that varies with the nature of the central metal ion and the solvent. This rate is slowest in the basic solvent pyridine as compared to CH2Cl2 and PhCN, giving further evidence for the involvement of protons in the chemical reaction leading to phlorin formation. Calculations of the electronic structure were performed on the Ni(II) porphyrin dianion, and the most favorable atoms for electrophilic attack were determined to be the two phosphorylated carbon atoms. Phlorin formation was not observed after the two-electron reduction of the cobalt porphyrins due to the different oxidation state assignment of the doubly reduced species, a Co(I) pi anion radical in one case and an M(II) dianion for all of the other derivatives. Each redox reaction was monitored by thin-layer UV-visible spectroelectrochemistry, and an overall mechanism for each electron transfer is proposed on the basis of these data. PMID- 25789715 TI - Proton beam versus photon beam dose to the heart and left anterior descending artery for left-sided breast cancer. AB - PURPOSE: The purpose of this study was to compare the dose to heart, left anterior descending (LAD) artery and lung between proton and photon beam irradiation for left-sided early stage breast cancer. MATERIAL AND METHODS: Ten women with early stage left-sided breast cancer were treated with breast conserving surgery and radiation. Whole breast radiation was delivered for actual treatment via a tangential technique with deep inspiration breath hold (DIBH) utilizing inverse planned intensity-modulated radiation therapy (IMRT). Each patient was replanned on an Institutional Review Board (IRB)-approved prospective study using en face proton beam radiation with both uniform scanning (US) and pencil beam scanning (PBS) techniques. RESULTS: Both PBS (0.011 Gy) and US (0.009 Gy) proton plans resulted in a significantly lower mean heart dose compared to IMRT (1.612 Gy) (p < 0.05 for PBS vs. IMRT and US vs. IMRT). The Dmean, Dmin, Dmax, and D0.2cm(3) of the LAD with either proton technique were significantly lower (p = 0.005) compared to IMRT. Both US and PBS reduced the mean dose to the lungs compared to IMRT. The coverage of the breast planning target volume was comparable between photon and proton plans. CONCLUSIONS: The dose to whole heart was relatively low in this study of patients treated under conditions of DIBH. However, proton beam radiation was associated with lower minimum, maximum, and dose to 0.2 cm(3) of the LAD, which is the critical structure for late radiation therapy effects, compared to even the most optimized photon beam plan with DIBH and IMRT. PMID- 25789721 TI - Alkali metal-mediated dehydrocoupling of Me2NH.BH3. AB - Bis(trimethylsilyl)amide derivatives of the group 1 elements (Li, Na, K) are competent pre-catalysts for the dehydrocoupling of Me2NH.BH3 via the formation of intermediates containing [H3BNMe2BH2Me2N](-) anions. PMID- 25789722 TI - Increased Frequencies of Circulating IFN-gamma-Producing Vdelta1(+) and Vdelta2(+) gammadelta T Cells in Patients with Asymptomatic Persistent Hepatitis B Virus Infection. AB - Hepatitis B virus (HBV) is a leading cause of liver cirrhosis and hepatocellular carcinoma. The outcome of HBV infection is largely determined by the host immune response, with virus-specific cytotoxic T cells being able to mediate immunity against HBV as well as causing liver pathology. gammadelta T cells are reported to be depleted in patients with HBV-associated liver disease. However, it is not known if these cells control HBV infection in patients with asymptomatic chronic HBV infection. In this study, the frequencies, phenotypes, and interferon-gamma production were examined by circulating gammadelta T cell subsets in a group of asymptomatic HBV carriers with low viral loads and little evidence of liver disease. It is shown that gammadelta T cells expressing Vdelta1 and Vdelta2 T cell receptors and effector-memory phenotypes are found at higher frequencies in these patients compared to controls. Vdelta2 T cells from the patients expressed interferon-gamma significantly more frequently than Vdelta2 T cells from healthy donors in the absence of ex vivo stimulation. These data suggest that effector memory IFN-gamma-producing Vdelta2 T cells may contribute to the control of HBV in patients with asymptomatic infection, without mediating liver pathology. PMID- 25789723 TI - Insights into the potential use of microRNAs as a novel class of biomarkers in esophageal cancer. AB - MicroRNAs (abbreviated miRNAs) have been demonstrated to be involved in tumorigenesis and cancer development and proposed as promising biomarkers in cancer diagnosis. Numerous studies have observed the aberrant expression of miRNAs in esophageal cancer. However, there are some discrepant results. Thus, we conducted this meta-analysis to identify the overall accuracy of miRNAs in the diagnosis of esophageal cancer. A comprehensive literature search was conducted in PubMed and other databases using combinations of key words. The summary receiver operator characteristic curves were plotted to assess the overall diagnostic performance of miRNAs. Chi-squared and I(2) tests were used to assess the heterogeneity between studies. Additionally, we conducted subgroup and sensitivity analyses to analyze the potential sources of heterogeneity. In total, 33 studies from 12 articles were available in this meta-analysis. The pooled sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR) diagnostic odds ratio, and area under the curve were 0.80, 0.80, 4.0, 0.25, 16, and 0.87, respectively. Subgroup analyses based on the sample types (saliva-, serum- and plasma-based) showed no differences in the diagnostic accuracy of each subgroup. An independent meta-analysis of eight articles was conducted to evaluate the diagnostic accuracy of miRNAs in patients with esophageal squamous cell carcinoma, with a pooled sensitivity of 0.77, specificity of 0.83, PLR of 4.4, NLR of 0.27, diagnostic odds ratio of 16, and area under the curve of 0.87. In conclusion, this meta-analysis demonstrates the feasibility of using miRNAs as non-invasive biomarkers to discriminate esophageal cancer from healthy controls. However, further high-quality studies on more clearly defined esophageal cancer patient are needed to confirm our conclusion. PMID- 25789724 TI - Synergistic Effects Between Thioxanthones and Oxacillin Against Methicillin Resistant Staphylococcus aureus. AB - The extensive use of antimicrobials is leaving medicine with few effective therapeutic options to treat many infections due to the fact that many organisms developed resistance to commonly used drugs. It is therefore pertinent to search not only for new antimicrobials but also for compounds able to restore or potentiate the activity of existing antibiotics. We have screened a library consisting of 40 (thio)xanthone derivatives for antibacterial activity and possible synergistic effects when used in combination with antibiotics. Nine out of the 40 compounds exhibited antibacterial activity against Gram-positive bacteria. Two xanthone derivatives, 1-formyl-4-hydroxy-3-methoxy (7), 2-formyl-3 hydroxy-4-methoxyxanthone (8) and the thioxanthone derivative 1-((2 (diethylamino)ethyl)amino)-4-propoxythioxanthone (10) and its hydrochloride form 13, showed activity against a methicillin-resistant Staphylococcus aureus (MRSA) isolate with minimum inhibitory concentration (MIC) values lower than 256 MUg/ml. Thioxanthone 10 demonstrated antibacterial activity and also synergy when combined with ampicillin and oxacillin against MRSA. Additionally, thioxanthone 1 (piperidin-1-yl)-4-propoxythioxanthone (9), despite not having antibacterial activity presented remarkable synergy with oxacillin against MRSA; the MIC of tioxanthone 9 and oxacillin when both were in combination were 128 and 8 MUg/ml, respectively. Thioxanthones 9 and 10 were also found to be synergistic when both were combined. Subsequently, docking simulations between thioxanthones 9 and 10 and the allosteric domain of penicillin-binding protein 2A (PBP2A) were undertaken in AutoDock Vina. Both compounds had the ability to bind with an allosteric domain of PBP2A, which may explain their synergy with oxacillin. These two thioxanthone derivatives with different profiles may be promising tools for restoring the activity of oxacillin against MRSA. PMID- 25789726 TI - Proteomic analysis provides new insights into the adaptive response of a dinoflagellate Prorocentrum donghaiense to changing ambient nitrogen. AB - Nitrogen (N) is the major nutrient limiting phytoplankton growth and productivity over large ocean areas. Dinoflagellates are important primary producers and major causative agents of harmful algal blooms in the ocean. However, very little is known about their adaptive response to changing ambient N. Here, we compared the protein profiles of a marine dinoflagellate Prorocentrum donghaiense grown in inorganic N-replete, N-deplete and N-resupplied conditions using 2-D fluorescence differential gel electrophoresis. The results showed that cell density, chlorophyll a and particulate organic N contents presented low levels in N deplete cells, while particulate organic carbon content and glutamine synthetase (GS) activity maintained high levels. Comparison of the protein profiles of N replete, N-deplete and N-resupplied cells indicated that proteins involved in photosynthesis, carbon fixation, protein and lipid synthesis were down-regulated, while proteins participating in N reallocation and transport activity were up regulated in N-deplete cells. High expressions of GS and 60 kDa chaperonin as well as high GS activity in N-deplete cells indicated their central role in N stress adaptation. Overall, in contrast with other photosynthetic eukaryotic algae, P. donghaiense possessed a specific ability to regulate intracellular carbon and N metabolism in response to extreme ambient N deficiency. PMID- 25789725 TI - Fate of distal lung epithelium cultured in a decellularized lung extracellular matrix. AB - Type II cells are the defenders of the alveolus. They produce surfactant to prevent alveolar collapse, they actively transport water to prevent filling of the air sacs that would otherwise prevent gas exchange, and they differentiate to type I epithelial cells. They are an indispensable component of functional lung tissue. To understand the functionality of type II cells in isolation, we sought to track their fate in decellularized matrices and to assess their ability to contribute to barrier function by differentiation to type I alveolar epithelial cells. Rat type II cells were isolated from neonatal rat lungs by labeling with the RTII-70 surface marker and separation using a magnetic column. This produced a population of ~50% RTII-70-positive cells accompanied by few type I epithelial cells or alpha-actin-positive mesenchymal cells. This population was seeded into decellularized rat lung matrices and cultured for 1 or 7 days. Culture in Dulbecco's modified Eagle's medium +10% fetal bovine serum (FBS) resulted in reduced expression of epithelial markers and increased expression of mesenchymal markers. By 7 days, no epithelial markers were visible by immunostaining; nearly all cells were alpha-actin positive. Gene expression for the mesenchymal markers, alpha-actin, vimentin, and TGF-betaR, was significantly upregulated on day 1 (p=0.0005, 0.0005, and 2.342E-5, respectively). Transcript levels of alpha-actin and TGF-betaR remained high at 7 days (p=1.364E-10 and 0.0002). Interestingly, human type II cells cultured under the same conditions showed a similar trend in the loss of epithelial markers, but did not display high expression of mesenchymal markers. Rat cells additionally showed the ability to produce and degrade the basement membrane and extracellular matrix components, such as fibronectin, collagen IV, and collagen I. Quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) showed significant increases in expression of the fibronectin and matrix metalloprotease-2 (MMP-2) genes after 1 day in culture (p=0.0135 and 0.0128, respectively) and elevated collagen I expression at 7 days (p=0.0016). These data suggest that the original type II enriched population underwent a transition to increased expression of mesenchymal markers, perhaps as part of a survival or wound-healing program. These results suggest that additional medium components and/or the application of physiologically appropriate stimuli such as ventilation may be required to promote lung-specific epithelial phenotypes. PMID- 25789727 TI - Answer the call: let's make 2015 the year of magical thinking in CTO PCI. AB - Prevalence of chronic total occlusions (CTO's) is as high as 50% in angiographic series Patients are helped with successful recanalization of CTO's In spite of current improved success rates in CTO percutaneous coronary intervention (PCI), only 10-12% of CTO's are currently attempted. PMID- 25789728 TI - PCI of CTOs: hope or hype? AB - Compared with successful PCI, failed PCI of CTOs is associated with higher rates of in-hospital death, MI, CABG, perforation, and cardiac tamponade, but the absolute risk difference is small. Since 1991, the overall rates of in-hospital complications are declining, due to significant improvements in CTO technology and operator expertise. Outcomes after CTO-PCI may be enhanced by proper patient selection (resistant angina; large areas of ischemia; and anatomic suitability for antegrade, retrograde, and/or subintimal recanalization) and by reliance on expert operators using a flexible incremental approach to recanalization. PMID- 25789729 TI - Percutaneous coronary intervention: ever closer to real world silver bullets!? AB - Bare metal and early drug eluting stents have not meaningfully reduced subsequent rates of death and myocardial infarction compared to balloon angioplasty. Second generation drug eluting stents are associated with meaningful reductions in death and myocardial infarction compared to first generation drug eluting stents. PMID- 25789730 TI - Smaller may not be better if you cut corners. AB - 5-Fr transradial sheathless guide technique using a 4-Fr mother-child technique can be accomplished with excellent clinical success An enhanced risk for local traumatic injury to the radial artery was observed that may stem from the imperfect transition and taper between catheters, or friction inherent in the catheter surface design, that technologic advances may be able to address in the future If larger sheath technology is not feasible, this sheathless approach presents an option whether the risk/benefits appear favorable despite the potential from radial artery trauma. PMID- 25789731 TI - Radial artery occlusion: preventing insult to injury. AB - Intra-arterial nitroglycerin prior to transradial sheath removal may reduce the incidence of radial artery occlusion (RAO). Operators must observe careful attention to all aspects of transradial catheterization, particularly patent hemostasis; as well as independently monitor the institutional incidence of RAO to prompt improvements in practice. Future studies on the impact of pre-puncture ultrasound, novel sheaths, hemostatic devices, and potent oral and intravenous antithrombotic therapy on 30-day RAO diagnosed by ultrasound may allow further reduction of RAO in a real-world practice. PMID- 25789732 TI - What's past is prologue. AB - Above knee and below knee patency for synthetic endografts are vastly different. Long-term data is encouragingly similar to synthetic bypass grafting. Optimize use of synthetic endografts in above knee femoropopliteal segments in non critical limb ischemia patients. PMID- 25789733 TI - CO2 angiography for peripheral arterial imaging: the good, bad, and ugly. AB - This article demonstrates that carbon dioxide (CO2) based angiography can be performed in patients at risk of acute kidney injury (AKI) with a resulting rate of AKI of ~5%. The study also demonstrates a high rate of complications from CO2 angiography--ranging from pain to death. Future research will need to focus on clarifying the role of CO2 angiography given the safety profile noted in the literature. PMID- 25789734 TI - The path of least resistance to success in chronic hypertension? AB - The ROX Coupler is a stented arterial-venous anastomosis intended for implantation in the external iliac artery and vein. Prior studies of the ROX Coupler show that it increases cardiac output, oxygen delivery, and decreases systemic vascular resistance, thereby lowering blood pressure. Clinical data for the ROX Coupler demonstrates significant reduction in blood pressure but proximal venous stenoses have been seen post-implantation requiring treatment. PMID- 25789735 TI - Misogyny in heart disease? AB - Overall, mid-term outcomes of edge-to-edge mitral valve repair with the MitraClip system do not seem to be markedly affected by gender. Nevertheless, there seems to be subtle differences in the results of men and women treated with MitraClip, which might affect patient selection and therapeutic strategy. Further studies with larger sample sizes are required to fully assess the potential differences in specific subsets. PMID- 25789736 TI - Should MitraClip be preferred over surgery in high-risk patients with severe MR and CKD? AB - Severe mitral regurgitation (MR) may lead to worsening renal function due to a decrease in stroke volume, increase in systemic vascular resistance, and venous pooling. Percutaneous treatment with MitraClip seems to improve renal function in certain patient groups. Larger studies are needed to prove that MitraClip is the preferred strategy in patients with severe MR and chronic kidney disease. PMID- 25789738 TI - Effects of a Single Bout of Aerobic Exercise Versus Resistance Training on Cognitive Vulnerabilities for Anxiety Disorders. AB - The purpose of this study was to compare the relative effects of a single bout of aerobic exercise versus resistance training on cognitive vulnerabilities for anxiety disorders. Seventy-seven participants (60% female; 84% Caucasian) were randomized to complete 20 min of moderate-intensity aerobic exercise, resistance training, or rest, followed by a 35% CO2/65% O2 inhalation challenge task. Results indicated that aerobic exercise and resistance training were significantly and equally effective in reducing anxiety sensitivity (AS) compared with rest ((eta(2)(p ) = 52), though only aerobic exercise significantly attenuated reactivity to the CO2 challenge task. Neither form of exercise generated observable effects on distress tolerance, discomfort intolerance, or state anxiety (all ps >.10). The results of this study are discussed with regard to their implications for the use of exercise interventions for anxiety and related forms of psychopathology, and potential directions for future research are discussed. PMID- 25789737 TI - Detection of BRAF V600 mutations in melanoma: evaluation of concordance between the Cobas(r) 4800 BRAF V600 mutation test and the methods used in French National Cancer Institute (INCa) platforms in a real-life setting. AB - Vemurafenib is approved for the treatment of metastatic melanoma in patients with BRAF V600 mutation. In pivotal clinical trials, BRAF testing has always been done with the approved cobas 4800 BRAF test. In routine practice, several methods are available and are used according to the laboratories usual procedures. A national, multicenter, non-interventional study was conducted with prospective and consecutive collection of tumor samples. A parallel evaluation was performed in routine practice between the cobas 4800 BRAF V600 mutation test and home brew methods (HBMs) of 12 national laboratories, labelled and funded by the French National Cancer Institute (INCa). For 420 melanoma samples tested, the cobas method versus HBM showed a high concordance (93.3%; kappa = 0.86) in BRAF V600 genotyping with similar mutation rates (34.0% versus 35.7%, respectively). Overall, 97.4% and 98.6% of samples gave valid results using the cobas and HBM, respectively. Of the 185 samples strictly fulfilling the cobas guidelines, the concordance rate was even higher (95.7%; kappa = 0.91; 95%CI [0.85; 0.97]). Out of the 420 samples tested, 28 (6.7%) showed discordance between HBM and cobas. This prospective study shows a high concordance rate between the cobas 4800 BRAF V600 test and home brew methods in the routine detection of BRAF V600E mutations. PMID- 25789739 TI - "The art of procreation and the members employed therein are so repulsive, that if it were not for the beauty of the faces and the adornments of the actors and the pent-up impulse, nature would lose the human species". PMID- 25789740 TI - Knockdown of glutamate cysteine ligase catalytic subunit by siRNA causes the gold nanoparticles-induced cytotoxicity in lung cancer cells. AB - Gold nanoparticles (GNPs) have shown promising medical applications in cancer treatment involved in the regulation of intracellular redox balance. Previously, we have reported that GNPs can trigger apoptosis and necrosis in human lung cancer cells (A549) when L-buthionine-sulfoximine (BSO) was used to decrease the expression of intracellular glutathione (GSH). Herein, we investigated the cytotoxicity of GNPs toward lung cancer cells under the glutamate cysteine ligase catalytic subunit (GCLC) was silenced by siRNA. Our results showed that GNPs cause apoptosis and necrosis in cells transfected with GCLC siRNA by elevating intracellular reactive oxygen species (ROS). These findings demonstrated that the regulation of glutathione synthesis by GCLC siRNA in A549 cells can initiate the gold nanoparticles-induced cytotoxicity. PMID- 25789741 TI - Tuberculosis trends--United States, 2014. AB - In 2014, a total of 9,412 new tuberculosis (TB) cases were reported in the United States, with an incidence rate of 3.0* cases per 100,000 persons, a decrease of 2.2% from 2013. Although overall numbers of TB cases and rates continue to decline, the percentage decrease in rate is the smallest decrease in over a decade (1). This report summarizes provisional TB surveillance data reported to CDC's National Tuberculosis Surveillance System for 2014. TB cases and rates decreased among U.S.-born persons, and although the case rate also decreased among foreign-born persons, there was an increase in total number of cases among foreign-born persons. The rate among foreign-born persons in the United States in 2014 was 13.4 times higher than among U.S.-born persons. Racial/ethnic minorities continue to be disproportionately affected by TB within the United States. Asians continue to be the racial/ethnic group with the largest number of TB cases. Compared with non-Hispanic whites, the TB rate among Asians was 28.5 times higher, whereas rates among non-Hispanic blacks and Hispanics were each eight times higher. Four states (California, Texas, New York, and Florida), representing approximately one third of the U.S. population, accounted for half of all TB cases reported in 2014. Continued progress toward TB elimination in the United States will require focused TB control efforts among populations and in geographic areas with disproportionate burdens of TB. PMID- 25789742 TI - HIV infection and HIV-associated behaviors among persons who inject drugs--20 cities, United States, 2012. AB - In the United States, an estimated 7% of new diagnoses of human immunodeficiency virus (HIV) infection in 2012 were attributed to injection drug use, and an additional 3% to male-to-male sexual contact and injection drug use. To monitor HIV prevalence and behaviors associated with HIV risk and prevention among persons who inject drugs (PWID), CDC's National HIV Behavioral Surveillance (NHBS) system conducts interviews and HIV testing in selected cities. This report summarizes HIV prevalence and behaviors among PWID interviewed and tested in 20 cities in 2012. Of the 10,002 PWID tested, 11% had a positive HIV test result. Among 9,425 PWID included in the behavioral analysis, 30% receptively shared syringes, 70% had vaginal sex without a condom, 25% had heterosexual anal sex without a condom, and 5% of males had male-to-male sexual contact without a condom in the previous 12 months. Fifty-one percent of PWID included in the behavioral analysis had been tested for HIV, 25% participated in an HIV behavioral intervention, and 39% participated in substance abuse treatment in the previous 12 months. Additional efforts are needed to reduce risk behaviors and increase access to HIV testing, drug treatment, and other HIV prevention programs to further reduce HIV infections among PWID. PMID- 25789743 TI - Healthful food availability in stores and restaurants--American Samoa, 2014. AB - American Samoa, one of the U.S.-affiliated Pacific Islands, has documented the highest prevalence of adults with obesity (75%) in the world. The nutritionally poor food and beverage environment of food retail venues has been suspected to be a contributing factor, although an evaluation of these venues in American Samoa has not been conducted. In January 2014, American Samoa established an Obesity Task Force to develop policies and strategies to combat obesity. To inform the efforts of the task force, the American Samoa Department of Health and CDC conducted a baseline assessment of the availability, pricing, and promotion of healthful foods at retail food venues. Previously validated food environment assessment tools were modified to incorporate American Samoa foods and administered in a geographically representative sample of 70 stores (nine grocery stores and 61 convenience stores) and 20 restaurants. In convenience stores, healthful items were not found as available as less healthful counterparts, and some healthful items were more expensive than their less healthful counterparts. For restaurants, 70% offered at least one healthful entree, whereas only 30% had healthful side dishes, such as vegetables. Actions to promote healthy eating, such as providing calorie information, were rare among restaurants. Improving availability, affordability, and the promotion of healthful foods in American Samoa stores and restaurants could support healthy eating among American Samoa residents. PMID- 25789744 TI - Notes from the field: fatal yellow fever vaccine-associated viscerotropic disease -Oregon, September 2014. AB - In September 2014, a previously healthy Oregon woman in her 60s went to a hospital emergency department with malaise, dyspnea, vomiting, and diarrhea of 3 5 days' duration. She reported no recent travel, ill contacts, or dietary changes. Six days earlier, she had received a single dose of yellow fever vaccine and typhoid vaccine before planned travel to South America. PMID- 25789745 TI - Notes from the field: listeriosis associated with stone fruit--United States, 2014. AB - On July 19, 2014, a packing company in California (company A) voluntarily recalled certain lots of stone fruits, including whole peaches, nectarines, plums, and pluots, because of concern about contamination with Listeria monocytogenes based on internal company testing. On July 31, the recall was expanded to cover all fruit packed at their facility during June 1-July 17. After the initial recall, clinicians, state and local health departments, CDC, and the Food and Drug Administration (FDA) received many inquiries about listeriosis from concerned consumers, many of whom had received automated telephone calls informing them that they had purchased recalled fruit. During July 19-31, the CDC Listeria website received >500,000 page views, more than seven times the views received during the previous 52 weeks. However, no molecular information from L. monocytogenes isolates was available to assess whether human illnesses might be linked to these products. PMID- 25789746 TI - Mo-CBP3, an antifungal chitin-binding protein from Moringa oleifera seeds, is a member of the 2S albumin family. AB - Mo-CBP3 is a chitin-binding protein from M. oleifera seeds that inhibits the germination and mycelial growth of phytopathogenic fungi. This protein is highly thermostable and resistant to pH changes, and therefore may be useful in the development of new antifungal drugs. However, the relationship of MoCBP3 with the known families of carbohydrate-binding domains has not been established. In the present study, full-length cDNAs encoding 4 isoforms of Mo-CBP3 (Mo-CBP3-1, Mo CBP3-2, Mo-CBP3-3 and Mo-CBP3-4) were cloned from developing seeds. The polypeptides encoded by the Mo-CBP3 cDNAs were predicted to contain 160 (Mo-CBP3 3) and 163 amino acid residues (Mo-CBP3-1, Mo-CBP3-2 and Mo-CBP3-4) with a signal peptide of 20-residues at the N-terminal region. A comparative analysis of the deduced amino acid sequences revealed that Mo-CBP3 is a typical member of the 2S albumin family, as shown by the presence of an eight-cysteine motif, which is a characteristic feature of the prolamin superfamily. Furthermore, mass spectrometry analysis demonstrated that Mo-CBP3 is a mixture of isoforms that correspond to different mRNA products. The identification of Mo-CBP3 as a genuine member of the 2S albumin family reinforces the hypothesis that these seed storage proteins are involved in plant defense. Moreover, the chitin-binding ability of Mo-CBP3 reveals a novel functionality for a typical 2S albumin. PMID- 25789747 TI - Molecular mechanisms of 2, 3', 4, 4', 5-pentachlorobiphenyl-induced thyroid dysfunction in FRTL-5 cells. AB - Polychlorinated biphenyls (PCBs) can severely interfere with multiple animals and human systems. To explore the molecular mechanisms underlying 2, 3', 4, 4', 5- pentachlorobiphenyl (PCB118)-induced thyroid dysfunction, Fischer rat thyroid cell line-5(FRTL-5) cells were treated with either different concentrations of PCB118 or dimethyl sulfoxide (DMSO). The effects of PCB118 on FRTL-5 cells viability and apoptosis were assessed by using a Cell Counting Kit-8 assay and apoptosis assays, respectively. Quantitative real-time polymerase chain reaction was used to quantify protein kinase B (Akt), Forkhead box protein O3a (FoxO3a), and sodium/iodide symporter (NIS) mRNA expression levels. Western blotting was used to detect Akt, phospho-Akt (p-Akt), FoxO3a, phospho-FoxO3a (p-FoxO3a), and NIS protein levels. Luciferase reporter gene technology was used to detect the transcriptional activities of FoxO3a and NIS promoters. The effects of the constitutively active Akt (CA-Akt) and dominant-negative Akt (DN-Akt) plasmids on p-Akt, p-FoxO3a, and NIS levels were examined in PCB118-treated FRTL-5 cells. The effects of FoxO3a siRNA on FoxO3a, p-FoxO3a, and NIS protein levels were examined in the PCB118-treated FRTL-5 cells. The effects of pcDNA3 (plsmid vectors designed for high-level stable and transient expression in mammalian host)-FoxO3a on NIS promoter activity were examined in the PCB118-treated FRTL-5 cells. Our results indicated that relatively higher PCB118 concentrations can inhibit cell viability in a concentration- and time-dependent manner. Akt, p-Akt, and p-FoxO3a protein or mRNA levels increased significantly in PCB118-treated groups and NIS protein and mRNA levels decreased considerably compared with the control groups. FoxO3a promoter activity increased significantly, whereas NIS promoter activity decreased. These effects on p-FoxO3a and NIS could be decreased by the DN-Akt plasmid, enhanced by the CA-Akt plasmid, and blocked by FoxO3a siRNA. The overexpressed FoxO3a could reduce NIS promoter activity. Our results suggested that PCB118 induces thyroid cell dysfunction through the Akt/FoxO3a/NIS signaling pathway. PMID- 25789748 TI - Complementary sex determination in the parasitic wasp Diachasmimorpha longicaudata. AB - We studied the sex determination in Diachasmimorpha longicaudata, a parasitoid braconid wasp widely used as biological control agent of fruit pest tephritid flies. We tested the complementary sex determination hypothesis (CSD) known in at least 60 species of Hymenoptera. According to CSD, male or female development depends on the allelic composition of one sex locus (single-locus CSD) or multiple sex loci (multiple-locus CSD). Hemizygote individuals are normal haploid males, and heterozygotes for at least one sex locus are normal diploid females, but homozygotes for all the sex loci are diploid males. In order to force the occurrence of diploid males in D. longicaudata, we established highly inbred lines and examined their offspring using chromosome counting, flow cytometry, and sex ratio analysis. We found that when mother-son crosses were studied, this wasp produced about 20% of diploid males out of the total male progeny. Our results suggest that this parasitoid may represent the second genus with multiple-locus CSD in Hymenoptera. Knowledge about the sex determination system in D. longicaudata is relevant for the improvement of mass rearing protocols of this species. This information also provides the necessary background for further investigations on the underlying molecular mechanisms of sex determination in this species, and a better insight into the evolution of this pathway in Hymenoptera in particular and insects in general. PMID- 25789749 TI - Casting a genome-wide net for learning mutants. AB - Wolman et al. (2015) report a forward genetic screen in zebrafish that implicated pregnancy-associated plasma protein-aa in habituation of the acoustic startle response. PAPP-AA is expressed in the underlying circuit, including Mauthner cells, and regulates habituation via IGF signaling. PMID- 25789750 TI - Excitement about inhibitory presynaptic terminals. AB - Based on extrapolation from excitatory synapses, it is often assumed that depletion of the releasable pool of synaptic vesicles is the main factor underlying depression at inhibitory synapses. In this issue of Neuron, using subcellular patch-clamp recording from inhibitory presynaptic terminals, Kawaguchi and Sakaba (2015) show that at Purkinje cell-deep cerebellar nuclei neuron synapses, changes in presynaptic action potential waveform substantially contribute to synaptic depression. PMID- 25789751 TI - Glycine at the gate--from model to mechanism. AB - In this issue of Neuron, Foster et al. (2015) show that ablating, silencing, or activating spinal glycinergic inhibitory neurons with viral vectors all have dramatic effects on pain and itch. These results provide molecular insights into pain gate control and useful tools for the rapid analysis of other CNS circuits. PMID- 25789752 TI - Noisy neurons, neat networks. AB - In this issue of Neuron, Kiani et al. (2015) show that the correlated activity of multiple simultaneously recorded neurons can be used to identify, in a completely un-biased manner, distinct functional domains within prefrontal and (pre)motor cortex of macaque monkeys. PMID- 25789754 TI - Traumatic brain injury and the neuronal microenvironment: a potential role for neuropathological mechanotransduction. AB - Traumatic brain injury (TBI) is linked to several pathologies for which there is a lack of understanding of disease mechanisms and therapeutic strategies. To elucidate injury mechanisms, it is important to consider how physical forces are transmitted and transduced across all spatial scales of the brain. Although the mechanical response of the brain is typically characterized by its material properties and biological structure, cellular mechanotransduction mechanisms also exist. Such mechanisms can affect physiological processes by responding to exogenous mechanical forces directed through sub-cellular components, such as extracellular matrix and cell adhesion molecules, to mechanosensitive intracellular structures that regulate mechanochemical signaling pathways. We suggest that cellular mechanotransduction may be an important mechanism underlying the initiation of cell and sub-cellular injuries ultimately responsible for the diffuse pathological damage and clinical symptoms observed in TBI, thereby providing potential therapeutic opportunities not previously explored in TBI. PMID- 25789753 TI - Immunotherapeutic approaches for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid beta (Abeta) and tau proteins. Oligomeric forms of Abeta and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Abeta. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Abeta and tau species. PMID- 25789755 TI - Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes. AB - Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington's disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remains unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knockin mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target. PMID- 25789757 TI - Development of an amperometric-based glucose biosensor to measure the glucose content of fruit. AB - An amperometric enzyme-electrode was introduced where glucose oxidase (GOD) was immobilized on chitosan membrane via crosslinking, and then fastened on a platinum working electrode. The immobilized enzyme showed relatively high retention activity. The activity of the immobilized enzyme was influenced by its loading, being suppressed when more than 0.6 mg enzyme was used in the immobilization. The biosensor showing the highest response to glucose utilized 0.21 ml/cm2 thick chitosan membrane. The optimum experimental conditions for the biosensors in analysing glucose dissolved in 0.1 M phosphate buffer (pH 6.0) were found to be 35 degrees C and 0.6 V applied potential. The introduced biosensor reached a steady-state current at 60 s. The apparent Michaelis-Menten constant ([Formula: see text]) of the biosensor was 14.2350 mM, and its detection limit was 0.05 mM at s/n > 3, determined experimentally. The RSD of repeatability and reproducibility of the biosensor were 2.30% and 3.70%, respectively. The biosensor was showed good stability; it retained ~36% of initial activity after two months of investigation. The performance of the biosensors was evaluated by determining the glucose content in fruit homogenates. Their accuracy was compared to that of a commercial glucose assay kit. There was no significance different between two methods, indicating the introduced biosensor is reliable. PMID- 25789756 TI - Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. AB - The gate control theory of pain proposes that inhibitory neurons of the spinal dorsal horn exert critical control over the relay of nociceptive signals to higher brain areas. Here we investigated how the glycinergic subpopulation of these neurons contributes to modality-specific pain and itch processing. We generated a GlyT2::Cre transgenic mouse line suitable for virus-mediated retrograde tracing studies and for spatially precise ablation, silencing, and activation of glycinergic neurons. We found that these neurons receive sensory input mainly from myelinated primary sensory neurons and that their local toxin mediated ablation or silencing induces localized mechanical, heat, and cold hyperalgesia; spontaneous flinching behavior; and excessive licking and biting directed toward the corresponding skin territory. Conversely, local pharmacogenetic activation of the same neurons alleviated neuropathic hyperalgesia and chloroquine- and histamine-induced itch. These results establish glycinergic neurons of the spinal dorsal horn as key elements of an inhibitory pain and itch control circuit. PMID- 25789759 TI - Symptom Burden and Performance Status among Community-Dwelling Patients with Serious Illness. AB - BACKGROUND: Predicting when burdensome symptoms will arise or worsen is important to preserving quality of life in patients with serious illness. OBJECTIVES: We explored the relationship between prevalence and severity of symptoms and underlying performance status. METHODS: We performed a retrospective cohort analysis of patients receiving community palliative care, investigating relationships between symptom burden and performance status. Patient data were obtained from the Carolinas Palliative Care Consortium Database, a central registry of community consultation data for research and quality improvement. We measured symptom prevalence and severity using the McCorkle Symptom Distress Scale and performance status using the Palliative Performance Scale. RESULTS: We analyzed data of 4994 patients, most (90%) with noncancer, serious illnesses. Thirty percent had one or more moderate/severe symptoms. In addition to identifying the high prevalence of fatigue and pain, we found distinct groupings of symptoms with high burden associated with different levels of performance status. This includes high prevalence of fatigue, anorexia, and dyspnea in patients with high performance. Patients with low performance status, however, reported more pain, depression, and constipation. CONCLUSION: Bothersome symptoms change as patients' performance status worsens. Using performance status as a common language, both medical professionals and informal caregivers can monitor impending changes in symptom burden. This should inform development of community based delivery systems to detect and manage distress in patients with palliative care needs. PMID- 25789758 TI - Photoperiod regulates lean mass accretion, but not adiposity, in growing F344 rats fed a high fat diet. AB - In this study the effects of photoperiod and diet, and their interaction, were examined for their effects on growth and body composition in juvenile F344 rats over a 4-week period. On long (16L:8D), relative to short (8L:16D), photoperiod food intake and growth rate were increased, but percentage adiposity remained constant (ca 3-4%). On a high fat diet (HFD), containing 22.8% fat (45% energy as fat), food intake was reduced, but energy intake increased on both photoperiods. This led to a small increase in adiposity (up to 10%) without overt change in body weight. These changes were also reflected in plasma leptin and lipid levels. Importantly while both lean and adipose tissue were strongly regulated by photoperiod on a chow diet, this regulation was lost for adipose, but not lean tissue, on HFD. This implies that a primary effect of photoperiod is the regulation of growth and lean mass accretion. Consistent with this both hypothalamic GHRH gene expression and serum IGF-1 levels were photoperiod dependent. As for other animals and humans, there was evidence of central hyposomatotropism in response to obesity, as GHRH gene expression was suppressed by the HFD. Gene expression of hypothalamic AgRP and CRH, but not NPY nor POMC, accorded with the energy balance status on long and short photoperiod. However, there was a general dissociation between plasma leptin levels and expression of these hypothalamic energy balance genes. Similarly there was no interaction between the HFD and photoperiod at the level of the genes involved in thyroid hormone metabolism (Dio2, Dio3, TSHbeta or NMU), which are important mediators of the photoperiodic response. These data suggest that photoperiod and HFD influence body weight and body composition through independent mechanisms but in each case the role of the hypothalamic energy balance genes is not predictable based on their known function. PMID- 25789760 TI - Redox properties of the nitronyl nitroxide antioxidants studied via their reactions with nitroxyl and ferrocyanide. AB - Nitronyl nitroxides (NNs) are the paramagnetic probes that are capable of scavenging physiologically relevant reactive oxygen (ROS) and nitrogen (RNS) species, namely superoxide, nitric oxide (NO), and nitroxyl (HNO). NNs are increasingly considered as potent antioxidants and potential therapeutic agents. Understanding redox chemistry of the NNs is important for their use as antioxidants and as paramagnetic probes for discriminative detection of NO and HNO by electron paramagnetic resonance (EPR) spectroscopy. Here we investigated the redox properties of the two most commonly used NNs, including determination of the equilibrium and rate constants of their reduction by HNO and ferrocyanide, and reduction potential of the couple NN/hydroxylamine of nitronyl nitroxide (hNN). The rate constants of the reaction of the NNs with HNO were found to be equal to (1-2) * 10(4) M(-1)s(- 1) being close to the rate constants of scavenging superoxide and NO by NNs. The reduction potential of the NNs and iminonitroxides (INs, product of NNs reaction with NO) were calculated based on their reaction constants with ferrocyanide. The obtained values of the reduction potential for NN/hNN (E'0 ~ 285 mV) and IN/hIN (E' ~ 495 mV) are close to the corresponding values for vitamin C and vitamin E, correspondingly. The "balanced" scavenging rates of the NNs towards superoxide, NO, and HNO, and their low reduction potential being thermodynamically close to the bottom of the pecking order of oxidizing radicals, might be important factors contributing into their antioxidant activity. PMID- 25789761 TI - SIRT1/PGC-1alpha signaling protects hepatocytes against mitochondrial oxidative stress induced by bile acids. AB - Oxidative stress and mitochondrial dysfunction are hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Silent information regulator 1 (SIRT1) attenuates oxidative stress and improves mitochondrial biogenesis in numerous mitochondrial-related diseases; however, a functional role for SIRT1 in chronic liver cholestasis, characterized by increased levels of toxic bile acids, remains unknown. We show decrease in SIRT1 levels and its activity and impairment of mitochondrial biogenesis in the liver of patients with extrahepatic cholestasis. Moreover, we found that glycochenodeoxycholic acid (GCDCA) stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content in L02 cells. Consistent with this finding, GCDCA was found to decrease SIRT1 protein expression and activity, thus promoting the deacetylation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha), a key enzyme involved in mitochondrial biogenesis and function. Conversely, GCDCA-induced mitochondrial injury was efficiently attenuated by SIRT1 overexpression. In summary, these findings indicate that the loss of SIRT1 may play a crucial role in the pathogenesis of liver damage observed in patients with extrahepatic cholestasis. The findings also indicate that genetic supplementation of SIRT1 can ameliorate GCDCA-induced hepatotoxicity through the activation of PGC-1alpha-dependent mitochondrial biogenesis. PMID- 25789762 TI - Imaging mitochondrial reactive oxygen species with fluorescent probes: current applications and challenges. AB - Mitochondrial reactive oxygen species (ROS) is a key element in the regulation of several physiological functions and in the development or progression of multiple pathological events. A key task in the study of mitochondrial ROS is to establish reliable methods for measuring the ROS level in mitochondria with high selectivity, sensitivity, and spatiotemporal resolution. Over the last decade, imaging tools with fluorescent indicators from either small-molecule dyes or genetically encoded probes that can be targeted to mitochondria have been developed, which provide a powerful method to visualize and even quantify mitochondrial ROS level not only in live cells, but also in live animals. These innovative tools that have bestowed exciting new insights in mitochondrial ROS biology have been further promoted with the invention of new techniques in indicator design and fluorescent detection. However, these probes present some limitations in terms of specificity, sensitivity, and kinetics; failure to recognize these limitations often results in inappropriate interpretations of data. This review evaluates the recent advances in mitochondrial ROS imaging approaches with emphasis on their proper application and limitations, and highlights the future perspectives in the development of novel fluorescent probes for visualizing all species of ROS. PMID- 25789763 TI - Expression of c-fos was associated with clinicopathologic characteristics and prognosis in pancreatic cancer. AB - It has long been regarded that pancreatic cancer (PC) is a life-threatening malignant tumor. Thus, much attention has been paid for factors, especially relative molecules, predictive for prognosis of PC. However, c-fos expression in PC was less investigated. In addition, its association with clinicopathologic variables and prognosis remains unknown. In the present study, expression of c fos was detected by tissue microarray-based immunohistochemical staining in cancer and adjacent tissues from 333 patients with PC. The staining results were correlated with clinicopathologic parameters and overall survival. Furthermore, prognostic significance of c-fos in subsets of PC was also evaluated. It was shown that low expression of c-fos was more often in cancer than in adjacent tissues of PC (P<0.001). Besides, high cancerous c-fos expression was significantly associated with tumor site and T stage, whereas peri-neural invasion was of a borderline significant relevance. Log-rank test revealed that high expression of c-fos in cancer tissues was a significant marker of poor overall survival, accompanied by some conventional clinicopathologic variables, such as sex, grade, peri-neural invasion, T and N stages. More importantly, cancerous c-fos expression was identified as an independent prognosticator in multivariate analysis. Finally, the prognostic implication of c-fos expression was proven in four subsets of patients with PC. These data suggested that c-fos expression was of relationships with progression and dismal prognosis of PC. PMID- 25789764 TI - A new approach to reduce uncertainties in space radiation cancer risk predictions. AB - The prediction of space radiation induced cancer risk carries large uncertainties with two of the largest uncertainties being radiation quality and dose-rate effects. In risk models the ratio of the quality factor (QF) to the dose and dose rate reduction effectiveness factor (DDREF) parameter is used to scale organ doses for cosmic ray proton and high charge and energy (HZE) particles to a hazard rate for gamma-rays derived from human epidemiology data. In previous work, particle track structure concepts were used to formulate a space radiation QF function that is dependent on particle charge number Z, and kinetic energy per atomic mass unit, E. QF uncertainties where represented by subjective probability distribution functions (PDF) for the three QF parameters that described its maximum value and shape parameters for Z and E dependences. Here I report on an analysis of a maximum QF parameter and its uncertainty using mouse tumor induction data. Because experimental data for risks at low doses of gamma-rays are highly uncertain which impacts estimates of maximum values of relative biological effectiveness (RBEmax), I developed an alternate QF model, denoted QFgammaAcute where QFs are defined relative to higher acute gamma-ray doses (0.5 to 3 Gy). The alternate model reduces the dependence of risk projections on the DDREF, however a DDREF is still needed for risk estimates for high-energy protons and other primary or secondary sparsely ionizing space radiation components. Risk projections (upper confidence levels (CL)) for space missions show a reduction of about 40% (CL~50%) using the QFgammaAcute model compared the QFs based on RBEmax and about 25% (CL~35%) compared to previous estimates. In addition, I discuss how a possible qualitative difference leading to increased tumor lethality for HZE particles compared to low LET radiation and background tumors remains a large uncertainty in risk estimates. PMID- 25789766 TI - Correction: Cardiac mass and function decrease in bronchiolitis obliterans syndrome after lung transplantation: relationship to physical activity? PMID- 25789765 TI - Mast cells present protrusions into blood vessels upon tracheal allergen challenge in mice. AB - Mast cells (MC) and myeloid dendritic cells (DC) act proximally in detecting and processing antigens and immune insults. We sought to understand their comparative dynamic behavior with respect to the airway epithelium in the steady state and in response to an allergic stimulus in mouse trachea. We devised methods to label MC in living trachea and to demonstrate that MC and DC occupy distinct layers of the tracheal mucosa, with DC being closer to the lumen. DC numbers doubled after allergen challenge, but MC numbers remained stable. MC and DC migrated minimally in either steady state or allergen-challenge conditions, and their interactions with one another appeared to be stochastic and relatively infrequent. While DC, unlike MC, exhibited probing behaviors involving dendrites, these projections did not cross the epithelium into the airway lumen. MC typically were located too far from the epithelial surface to contact the tracheal lumen. However, MC had protrusions toward and into blood vessels, likely to load with IgE. Thus, DC and MC occupy distinct niches and engage in sessile surveillance in the mouse trachea. Little or no access of these cell types to the airway lumen suggests that trans-epithelial transport of proteins in the steady state would be required for them to access luminal antigens. PMID- 25789767 TI - Gene-based mapping and pathway analysis of metabolic traits in dairy cows. AB - The metabolic adaptation of dairy cows during the transition period has been studied intensively in the last decades. However, until now, only few studies have paid attention to the genetic aspects of this process. Here, we present the results of a gene-based mapping and pathway analysis with the measurements of three key metabolites, (1) non-esterified fatty acids (NEFA), (2) beta hydroxybutyrate (BHBA) and (3) glucose, characterizing the metabolic adaptability of dairy cows before and after calving. In contrast to the conventional single marker approach, we identify 99 significant and biologically sensible genes associated with at least one of the considered phenotypes and thus giving evidence for a genetic basis of the metabolic adaptability. Moreover, our results strongly suggest three pathways involved in the metabolism of steroids and lipids are potential candidates for the adaptive regulation of dairy cows in their early lactation. From our perspective, a closer investigation of our findings will lead to a step forward in understanding the variability in the metabolic adaptability of dairy cows in their early lactation. PMID- 25789768 TI - Combinations of Ashwagandha leaf extracts protect brain-derived cells against oxidative stress and induce differentiation. AB - BACKGROUND: Ashwagandha, a traditional Indian herb, has been known for its variety of therapeutic activities. We earlier demonstrated anticancer activities in the alcoholic and water extracts of the leaves that were mediated by activation of tumor suppressor functions and oxidative stress in cancer cells. Low doses of these extracts were shown to possess neuroprotective activities in vitro and in vivo assays. METHODOLOGY/PRINCIPAL FINDINGS: We used cultured glioblastoma and neuroblastoma cells to examine the effect of extracts (alcoholic and water) as well as their bioactive components for neuroprotective activities against oxidative stress. Various biochemical and imaging assays on the marker proteins of glial and neuronal cells were performed along with their survival profiles in control, stressed and recovered conditions. We found that the extracts and one of the purified components, withanone, when used at a low dose, protected the glial and neuronal cells from oxidative as well as glutamate insult, and induced their differentiation per se. Furthermore, the combinations of extracts and active component were highly potent endorsing the therapeutic merit of the combinational approach. CONCLUSION: Ashwagandha leaf derived bioactive compounds have neuroprotective potential and may serve as supplement for brain health. PMID- 25789769 TI - Proteomic study related to vascular connections in watermelon scions grafted onto bottle-gourd rootstock under different light intensities. AB - Although grafting is broadly used in the production of crops, no information is available about the proteins involved in vascular connections between rootstock and scion. Similarly, proteome changes under the light intensities widely used for grafted seedlings are of practical use. The objective of this study was to determine the proteome of vascular connections using watermelon (Citrullus vulgaris Schrad.) 'Sambok Honey' and 'Speed' as the scion and bottle gourd (Lagenaria siceraria Stanld.) 'RS Dongjanggun' as the rootstock grown under different light intensities (25, 50, 75 and 100 MUmol m-2 s-1). Our proteomic analysis revealed 24 and 27 differentially expressed proteins in 'Sambok Honey' and 'Speed', respectively, under different light intensities. The identified proteins were largely involved in ion binding, amino acid metabolism, transcriptional regulation and defense response. The enhancement of ion-binding, transcriptional regulation, amino acid metabolism, and defense response proteins suggests a strengthening of the connection between the rootstock and scion under high light intensity. Indeed, the accumulation of key enzymes in the biological processes described above appears to play an important role in the vascular connections of grafted seedlings. Moreover, it appears that 100 MUmol m-2 s-1 results in better protein expression responses in grafted seedlings. PMID- 25789770 TI - Gout. AB - INTRODUCTION: Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of xanthine oxidase inhibitors to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and xanthine oxidase inhibitors. PMID- 25789771 TI - Comorbidities against quality control of VKA therapy in non-valvular atrial fibrillation: a French national cross-sectional study. AB - BACKGROUND: Given the prevalence of non-valvular atrial fibrillation in the geriatric population, thromboembolic prevention by means of vitamin K antagonists (VKA) is one of the most frequent daily concerns of practitioners. The effectiveness and safety of treatment with VKA correlates directly with maximizing the time in therapeutic range, with an International Normalized Ratio (INR) of 2.0-3.0. The older population concentrates many of factors known to influence INR rate, particularly concomitant medications and concurrent medical conditions, also defined as comorbidities. OBJECTIVE: Determine whether a high burden on comorbidities, defined by a Charlson Comorbidity Index (CCI) of 3 or greater, is associated a lower quality of INR control. STUDY-DESIGN: Cross sectional study. SETTINGS: French geriatric care units nationwide. PARTICIPANTS: 2164 patients aged 80 and over and treated with vitamin K antagonists. MEASUREMENTS: Comorbidities were assessed using the Charlson Comorbidity Index (CCI). The recorded data included age, sex, falls, kidney failure, hemorrhagic event, VKA treatment duration, and the number and type of concomitant medications. Quality of INR control, defined as time in therapeutic range (TTR), was assessed using the Rosendaal method. RESULTS: 487 patients were identified the low-quality control of INR group. On multivariate logistic regression analysis, low-quality control of INR was independently associated with a CCI >=3 (OR = 1.487; 95% CI [1.15; 1.91]). The other variables associated with low quality control of INR were: hemorrhagic event (OR = 3.151; 95% CI [1.64; 6.07]), hospitalization (OR = 1.614, 95% CI [1.21; 2.14]). CONCLUSION: An elevated CCI score (>=3) was associated with low-quality control of INR in elderly patients treated with VKA. Further research is needed to corroborate this finding. PMID- 25789772 TI - The effects of attention pre-allocation and target-background integration on object-based attention. AB - Object-based attention has been documented as an important mechanism with which to control attention in several studies. To date, two main hypotheses have been proposed to interpret object-based attention: attention spreading and prioritization of search. There is evidence that supports these hypotheses in the literature. In the present study, we sought to compare these two hypotheses systematically by manipulating two factors: the integration of the target and background and the presence of attention pre-allocation. For this purpose, we used a flanker task in which the location of the task-relevant target was fixed, but the relationship between the target and the background varied. In addition, attention pre-allocation was presented in only half of the conditions. The results revealed that the attention spreading hypothesis was supported only when attention was not pre-allocated and target-background integration was high; however, the prioritization hypothesis was supported in all other conditions. Our findings provide insight into the comparisons of the attention spreading and prioritization hypotheses. Furthermore, our findings suggest that attention resources may be the underlying factor determining appropriate strategy in the control of attention. PMID- 25789773 TI - A genomic duplication is associated with ectopic eomesodermin expression in the embryonic chicken comb and two duplex-comb phenotypes. AB - Duplex-comb (D) is one of three major loci affecting comb morphology in the domestic chicken. Here we show that the two Duplex-comb alleles, V-shaped (D*V) and Buttercup (D*C), are both associated with a 20 Kb tandem duplication containing several conserved putative regulatory elements located 200 Kb upstream of the eomesodermin gene (EOMES). EOMES is a T-box transcription factor that is involved in mesoderm specification during gastrulation. In D*V and D*C chicken embryos we find that EOMES is ectopically expressed in the ectoderm of the comb developing region as compared to wild-type embryos. The confinement of the ectopic expression of EOMES to the ectoderm is in stark contrast to the causal mechanisms underlying the two other major comb loci in the chicken (Rose-comb and Pea-comb) in which the transcription factors MNR2 and SOX5 are ectopically expressed strictly in the mesenchyme. Interestingly, the causal mutations of all three major comb loci in the chicken are now known to be composed of large-scale structural genomic variants that each result in ectopic expression of transcription factors. The Duplex-comb locus also illustrates the evolution of alleles in domestic animals, which means that alleles evolve by the accumulation of two or more consecutive mutations affecting the phenotype. We do not yet know whether the V-shaped or Buttercup allele correspond to the second mutation that occurred on the haplotype of the original duplication event. PMID- 25789774 TI - Correction: GABenchToB: a genome assembly benchmark tuned on bacteria and benchtop sequencers. PMID- 25789776 TI - Gene expression dosage regulation in an allopolyploid fish. AB - How allopolyploids are able not only to cope but profit from their condition is a question that remains elusive, but is of great importance within the context of successful allopolyploid evolution. One outstanding example of successful allopolyploidy is the endemic Iberian cyprinid Squalius alburnoides. Previously, based on the evaluation of a few genes, it was reported that the transcription levels between diploid and triploid S. alburnoides were similar. If this phenomenon occurs on a full genomic scale, a wide functional ''diploidization'' could be related to the success of these polyploids. We generated RNA-seq data from whole juvenile fish and from adult livers, to perform the first comparative quantitative transcriptomic analysis between diploid and triploid individuals of a vertebrate allopolyploid. Together with an assay to estimate relative expression per cell, it was possible to infer the relative sizes of transcriptomes. This showed that diploid and triploid S. alburnoides hybrids have similar liver transcriptome sizes. This in turn made it valid to directly compare the S. alburnoides RNA-seq transcript data sets and obtain a profile of dosage responses across the S. alburnoides transcriptome. We found that 64% of transcripts in juveniles' samples and 44% in liver samples differed less than twofold between diploid and triploid hybrids (similar expression). Yet, respectively 29% and 15% of transcripts presented accurate dosage compensation (PAA/PA expression ratio of 1 instead of 1.5). Therefore, an exact functional diploidization of the triploid genome does not occur, but a significant down regulation of gene expression in triploids was observed. However, for those genes with similar expression levels between diploids and triploids, expression is not globally strictly proportional to gene dosage nor is it set to a perfect diploid level. This quantitative expression flexibility may be a strong contributor to overcome the genomic shock, and be an immediate evolutionary advantage of allopolyploids. PMID- 25789777 TI - Determination of a cutoff value for pelvic floor distensibility using the Epi-no balloon to predict perineal integrity in vaginal delivery: ROC curve analysis. Prospective observational single cohort study. AB - CONTEXT AND OBJECTIVE: Several risk factors are involved in perineal lacerations during vaginal delivery. However, little is known about the influence of perineal distensibility as a protective factor. The aim here was to determine a cutoff value for pelvic floor distensibility measured using the Epi-no balloon, which could be used as a predictive factor for perineal integrity in vaginal delivery. DESIGN AND SETTING: Prospective observational single cohort study conducted in a maternity hospital. METHODS: A convenience sample of 227 consecutive at-term parturients was used. All women had a single fetus in the vertex presentation, with up to 9.0 cm of dilation. The maximum dilation of the Epi-no balloon was measured using a tape measure after it had been inflated inside the vagina up to the parturients' maximum tolerance. The receiver operating characteristic (ROC) curve was used to obtain the Epi-no circumference measurement with best sensitivity and specificity. RESULTS: Among the 161 patients who were included in the study, 50.9% underwent episiotomy, 21.8% presented lacerations and 27.3% retained an intact perineum. Age > 25.9 years; number of pregnancies > 3.4; number of deliveries > 2.2 and circumference measured by Epi-no > 21.4 cm were all directly correlated with an intact perineum. Circumference measurements using the Epi-no balloon that were greater than 20.8 cm showed sensitivity and specificity of 70.5% and 66.7% (area under curve = 0.713), respectively, as a predictive factor for an intact perineum in vaginal delivery. CONCLUSION: Circumferences greater than 20.8 cm achieved using the Epi-no balloon are a predictive factor for perineal integrity in parturients. PMID- 25789778 TI - Relationship between the Brazilian version of the Montreal-Toulouse language assessment battery and education, age and reading and writing characteristics. A cross-sectional study. AB - CONTEXT AND OBJECTIVE: There is growing concern about understanding how sociodemographic variables may interfere with cognitive functioning, especially with regard to language. This study aimed to investigate the relationship between performance in the Brazilian version of the Montreal-Toulouse language assessment battery (MTL-BR) and education, age and frequency of reading and writing habits (FRWH). DESIGN AND SETTING: Cross-sectional study conducted in university and work environments in Rio Grande do Sul, Brazil. METHOD: The MTL-BR was administered to a group of 233 healthy adults, aged 19 to 75 years (mean = 45.04, standard deviation, SD = 15.47), with at least five years of formal education (mean = 11.47, SD = 4.77). RESULTS: A stepwise multiple linear regression model showed that, for most tasks, the number of years of education, age and FRWH were better predictors of performance when analyzed together rather than separately. In separate analysis, education was the best predictor of performance in language tasks, especially those involving reading and writing abilities. CONCLUSION: The results suggested that the number of years of education, age and FRWH seem to influence performance in the MTL-BR, especially education. These data are important for making diagnoses of greater precision among patients suffering from brain injuries, with the aim of avoiding false positives. PMID- 25789779 TI - Whole-body diffusion-weighted magnetic resonance imaging versus FDG-PET/CT for initial lymphoma staging: systematic review on diagnostic test accuracy studies. AB - CONTEXT AND OBJECTIVE: Positron emission tomography with [18]F-fluoro-2 deoxyglucose (FDG-PET/CT) has been advocated as the method of choice for lymphoma staging, since it enables whole-body analysis with high sensitivity for detection of affected areas and because it combines capacities for anatomical and functional assessment. With technological advances, magnetic resonance imaging (MRI) has emerged as an alternative to FDG-PET/CT. This systematic review with meta-analysis aimed to compare whole-body diffusion-weighted MRI (WB-MRI) with FDG-PET/CT for lymphoma staging. DESIGN AND SETTING: Systematic review on diagnostic test accuracy studies conducted at a public university. METHODS: The Medline, Scopus, Embase and Lilacs databases were searched for studies published up to September 2013 that compared WB-MRI and FDG-PET/CT for lymphoma staging. The reference lists of included studies were checked for any relevant additional citations. RESULTS: Six studies that evaluated the initial lymphoma staging in 116 patients were included. WB-MRI and FDG-PET/CT agreed in 90.5% of the cases (kappa = 0.871; P < 0.0001). In most of the studies, when there was disagreement between the methods, WB-MRI overstaged in relation to FDG-PET/CT. The sensitivity of WB-MRI and FDG-PET/CT, in comparison with the clinical-radiological standard, ranged from 59 to 100% and from 63 to 100% respectively. CONCLUSION: WB-MRI is a highly sensitive method for initial lymphoma staging. It has excellent agreement with FDG-PET/CT and is a great alternative for managing lymphoma patients, without using ionizing radiation or an intravenous contrast agent. PMID- 25789781 TI - Characteristics of fetuses evaluated due to suspected anencephaly: a population based cohort study in southern Brazil. AB - CONTEXT AND OBJECTIVE: Anencephaly is considered to be the most common type of neural tube defect. Our aim was to assess the clinical and gestational features of a cohort of fetuses with suspected anencephaly. DESIGN AND SETTING: Population based retrospective cohort study in a referral hospital in southern Brazil. METHODS: The sample consisted of fetuses referred due to suspected anencephaly, to the Fetal Medicine Service of Hospital Materno Infantil Presidente Vargas, between January 2005 and September 2013. Clinical, radiological, pathological and survival data were gathered. RESULTS: Our sample was composed of 29 fetuses. The diagnosis of suspected anencephaly was made on average at 21.3 weeks of gestation. Seven fetuses had malformations that affected other organs, and these included oral clefts (n = 4) and congenital heart defects (n = 2). In 16 cases, there was termination of pregnancy (n = 12) or intrauterine death (n = 4). Regarding those who were born alive (n = 13), all of them died in the first week of life. After postnatal evaluation, the diagnosis of anencephaly was confirmed in 22 cases (75.9%). Other conditions included amniotic band disruption complex (6.9%), microhydranencephaly (6.9%), merocrania (3.4%) and holoprosencephaly (3.4%). CONCLUSIONS: Different conditions involving the cranial vault may be confused with anencephaly, as seen in our sample. However, these conditions also seem to have a poor prognosis. It seems that folic acid supplementation is not being properly performed. PMID- 25789782 TI - Optimization of treatment with recombinant FGF-2 for proliferation and differentiation of human dental stem cells, mesenchymal stem cells, and osteoblasts. AB - Basic fibroblast growth factor (bFGF or FGF-2) is widely used to modulate the proliferation and differentiation of certain cell types. An expression and purification system for recombinant human FGF-2 in Escherichia coli was established for the purpose of securing a continuous supply of this protein. The purified recombinant FGF-2 significantly increased the population of human embryonic stem cells. The optimal concentrations of FGF-2 for cell proliferative induction in various adult stem cells including human dental pulp stem cells, full term human periodontal ligament stem cells, human gingival fibroblasts, mesenchymal stem cells, and osteogenic oseosarcoma were established in a dose dependent manner. When cells were treated with recombinant FGF-2 for 6 days before osteogenic induction, the mRNA expression of the bone markers was upregulated in cells originated from human dental pulp tissue, indicating that pretreatment with FGF-2 during culture increase stem cell/progenitor population and osteogenic potential. PMID- 25789783 TI - [A Solitary PSA-Negative Late Metastasis of Prostate Cancer on the Penis]. AB - Metastatic involvement of the penis is rare. Secondary lesions generally originate from pelvic tumours. Bladder and prostate are the most common primary tumours. Commonly, penile metastases occur in cases of disseminated cancer disease. We present the case of a prostatic mucinous adenocarcinoma with a solitary, PSA-negative, asymptomatic metastasis to the glans 6 years after radical prostatectomy, which was successfully treated by local excision. PMID- 25789784 TI - Fate of cellulose nanocrystal aerosols deposited on the lung cell surface in vitro. AB - When considering the inhalation of high-aspect ratio nanoparticles (HARN), the characterization of their specific interaction with lung cells is of fundamental importance to help categorize their potential hazard. The aim of the present study was to assess the interaction of cellulose nanocrystals (CNCs) with a multicellular in vitro model of the epithelial airway barrier following realistic aerosol exposure. Rhodamine-labeled CNCs isolated from cotton (c-CNCs, 237 +/- 118 * 29 +/- 13 nm) and tunicate (t-CNCs, 2244 +/- 1687 * 30 +/- 8 nm) were found to display different uptake behaviors due to their length, although also dependent upon the applied concentration, when visualized by laser scanning microscopy. Interestingly, the longer t-CNCs were found to exhibit a lower clearance by the lung cell model compared to the shorter c-CNCs. This difference can be attributed to stronger fiber-fiber interactions between the t-CNCs. In conclusion, nanofiber length and concentration has a significant influence on their interaction with lung cells in vitro. PMID- 25789787 TI - Correction to Shape- and symmetry-dependent mechanical properties of metallic gold and silver on the nanoscale. PMID- 25789785 TI - Regulation of Notch signaling and endocytosis by the Lgl neoplastic tumor suppressor. AB - The evolutionarily conserved neoplastic tumor suppressor protein, Lethal (2) giant larvae (Lgl), plays roles in cell polarity and tissue growth via regulation of the Hippo pathway. In our recent study, we showed that in the developing Drosophila eye epithelium, depletion of Lgl leads to increased ligand-dependent Notch signaling. lgl mutant tissue also exhibits an accumulation of early endosomes, recycling endosomes, early-multivesicular body markers and acidic vesicles. We showed that elevated Notch signaling in lgl(-) tissue can be rescued by feeding larvae the vesicle de-acidifying drug chloroquine, revealing that Lgl attenuates Notch signaling by limiting vesicle acidification. Strikingly, chloroquine also rescued the lgl(-) overgrowth phenotype, suggesting that the Hippo pathway defects were also rescued. In this extraview, we provide additional data on the regulation of Notch signaling and endocytosis by Lgl, and discuss possible mechanisms by which Lgl depletion contributes to signaling pathway defects and tumorigenesis. PMID- 25789789 TI - Simplified three-dimensional model provides anatomical insights in lizards' caudal autotomy as printed illustration. AB - Lizards' caudal autotomy is a complex and vastly employed antipredator mechanism, with thorough anatomic adaptations involved. Due to its diminished size and intricate structures, vertebral anatomy is hard to be clearly conveyed to students and researchers of other areas. Three-dimensional models are prodigious tools in unveiling anatomical nuances. Some of the techniques used to create them can produce irregular and complicated forms, which despite being very accurate, lack didactical uniformity and simplicity. Since both are considered fundamental characteristics for comprehension, a simplified model could be the key to improve learning. The model here presented depicts the caudal osteology of Tropidurus itambere, and was designed to be concise, in order to be easily assimilated, yet complete, not to compromise the informative aspect. The creation process requires only basic skills in manipulating polygons in 3D modeling softwares, in addition to the appropriate knowledge of the structure to be modeled. As reference for the modeling, we used microscopic observation and a photograph database of the caudal structures. This way, no advanced laboratory equipment was needed and all biological materials were preserved for future research. Therefore, we propose a wider usage of simplified 3D models both in the classroom and as illustrations for scientific publications. PMID- 25789788 TI - Altered telomere homeostasis and resistance to skin carcinogenesis in Suv39h1 transgenic mice. AB - The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compaction is paralleled by telomere shortening, indicating that telomere length is controlled by H3K9me3 density at telomeres. We further show that increased Suv39h1 levels result in an impaired clonogenic potential of transgenic epidermal stem cells and Ras/E1A transduced transgenic primary mouse embryonic fibroblasts. Importantly, Suv39h1 overexpression in mice confers resistance to a DMBA/TPA induced skin carcinogenesis protocol that is characterized by the accumulation of activating H-ras mutations. Our results provide genetic evidence that Suv39h1 controls telomere homeostasis and mediates resistance to oncogenic stress in vivo. This identifies Suv39h1 as an interesting target to improve oncogene induced senescence in premalignant lesions. PMID- 25789790 TI - Lippia alba essential oil promotes survival of silver catfish (Rhamdia quelen) infected with Aeromonas sp. AB - In vitro and in vivo activity of the Lippia alba essential oil (EO) against Aeromonas sp. was evaluated. In the in vitro assay the minimum inhibitory concentration (MIC) and a minimum bactericidal concentration (MBC) of EO for Aeromonas cells were determined using the microdilution method. Twenty five strains of Aeromonas sp. isolated from infected fish obtained from local fish farms were used. MIC and MBC values were 2862 and 5998 ug mL-1 for L. alba EO and 0.5 and 1.2 ug mL-1 for gentamicin, respectively. In the in vivo assay silver catfish juveniles (Rhamdia quelen) (7.50 +/- 1.85 g and 10.0 +/- 1.0 cm) with typical injuries associated to Aeromonas infection were divided into four treatments (in triplicate n=10): untreated fish (negative control), 10 mg L-1 of gentamicin, and 20 or 50 uL L-1 of EO. Fish were maintained in aerated 20 L plastic boxes. After 10 days survival of silver catfish infected with Aermonas sp. and treated with essential oil (50 uL L-1) was greater than 90%. PMID- 25789791 TI - Butia capitata (Mart.) Becc. lamina anatomy as a tool for taxonomic distinction from B. odorata (Barb. Rodr.) Noblick comb. nov (Arecaceae). AB - The distinction between Butia capitata and B. odorata is based only on a few morphological characteristics, therefore there is a need for additional studies for supporting the separation of the species. As lamina anatomy characteristics are relevant in circumscribing Arecaceae taxa, this work aimed to describe B. capitata lamina anatomy and compare it with B. odorata. Samples from the middle portion of the pinnae were collected and processed in accordance with standard plant anatomy techniques. The epidermis is uniseriate and composed of a thick cuticle and epicuticular waxes into like hooked filaments. The subsidiary cells that arch over the guard cells are located at the hypodermis. The mesophyll is isobilateral and compact. The vascular bundles are collateral with a sclerenchymatic sheath extension that reaches the hypodermis. The stegmata cells have spherical and druse-like silica bodies. The midrib faces the adaxial surface with a thick fibrous layer surrounding the vascular bundles adjacent to the chlorenchyma. The stratified expansion tissue is on the abaxial surface, within the boundary between the mesophyll and midrib. Raphides are only found in B. capitata. Small bundles of the midrib fully surround the fibrous cylinder only in B. odorata. These characteristics are diagnostic and useful for supporting the proposed separation. PMID- 25789792 TI - Isolation, characterization and evaluation of antimicrobial and cytotoxic activity of estragole, obtained from the essential oil of Croton zehntneri (Euphorbiaceae). AB - Croton zehntneri (Euphorbiaceae) is a native aromatic plant from Northeast region of Brazil. The monoterpenoid estragole (ESL) has been isolated by classical chromatographic methods from the essential oil (EO) of C. zehnteneri leaves and characterized by GC-FID and GC-MS, its antimicrobial and cytotoxic potentials being assessed. The analysis of the EO enabled the identification of 100% of the integrated constituents, of which yield was about 1.8%. The main components identified were: eucalyptol, estragole (84.7%) and spathulenol. The dosage of 50 MUg/disk of ESL presented fairly significant zones of inhibition against Gram positive bacteria and fungi. The ESL presented toxicity against Artemia salina with LC50 and LC90 of 4,54 and 8,47 MUg mL-1. However, in tumor inhibition assays (human cells), there were no rewarding inhibition in any of the human cancer cell lines (MCF-7, HEP-2 and NCI-H292). PMID- 25789793 TI - Three new species of Cladonia (Cladoniaceae, Ascomycota) from Southern Brazil. AB - Cladonia maculata, C. paranaensis and C. quiririensis are described as new to science. These species were found between the altitudes of 900 to 1887 meters on the Serra do Mar Mountain in Southern Brazil. PMID- 25789794 TI - O-tert-Butyltyrosine, an NMR tag for high-molecular-weight systems and measurements of submicromolar ligand binding affinities. AB - O-tert-Butyltyrosine (Tby) is an unnatural amino acid that can be site specifically incorporated into proteins using established orthogonal aminoacyl tRNA synthetase/tRNA systems. Here we show that the tert-butyl group presents an outstanding NMR tag that can readily be observed in one-dimensional (1)H NMR spectra without any isotope labeling. Owing to rapid bond rotations and the chemical equivalence of the protons of a solvent-exposed tert-butyl group from Tby, the singlet resonance from the tert-butyl group generates an easily detectable narrow signal in a spectral region with limited overlap with other methyl resonances. The potential of the tert-butyl (1)H NMR signal in protein research is illustrated by the observation and assignment of two resonances in the Bacillus stearothermophilus DnaB hexamer (320 kDa), demonstrating that this protein preferentially assumes a 3-fold rather than 6-fold symmetry in solution, and by the quantitative measurement of the submicromolar dissociation constant Kd (0.2 MUM) of the complex between glutamate and the Escherichia coli aspartate/glutamate binding protein (DEBP, 32 kDa). The outstanding signal height of the (1)H NMR signal of the Tby tert-butyl group allows Kd measurements using less concentrated protein solutions than usual, providing access to Kd values 1 order of magnitude lower than established NMR methods that employ direct protein detection for Kd measurements. PMID- 25789795 TI - Versatile method for AFM-tip functionalization with biomolecules: fishing a ligand by means of an in situ click reaction. AB - A facile and universal method for the functionalization of an AFM tip has been developed for chemical force spectroscopy (CFS) studies of intermolecular interactions of biomolecules. A click reaction between tripod-acetylene and an azide-linker-ligand molecule was successfully carried out on the AFM tip surface and used for the CFS study of ligand-receptor interactions. PMID- 25789796 TI - Novel equations better predict lung age: a retrospective analysis using two cohorts of participants with medical check-up examinations in Japan. AB - BACKGROUND: The lung age equations developed by the Japanese Respiratory Society encounter several problems when being applied in a clinical setting. AIMS: To establish novel spirometry-derived lung age (SDL age) equations using data from a large number of Japanese healthy never-smokers with normal spirometric measurements and normal body mass indices (BMIs). METHODS: The participants had undergone medical check-ups at the Center for Preventive Medicine of St Luke's International Hospital between 2004 and 2012. A total of 15,238 Japanese participants (5,499 males and 9,739 females) were chosen for the discovery cohort. The other independent 2,079 individuals were selected for the validation cohort. The original method of Morris and Temple was applied to the discovery cohort. RESULTS: As a result of the linear regression analysis for forced expiratory volume in 1 s (FEV1), spirometric variables using forced vital capacity (FVC) improved the adjusted R(2) values to greater than 0.8. On the basis of the scatter plots between chronological age and SDL age, the best model included the equations using FEV1 and %FVC in females and males (R(2)=0.66 and 0.55, respectively), which was confirmed by the validation cohort. The following equations were developed: SDL age (females)=0.84*%FVC+50.2-40*FEV1 (l) and SDL age (males)=1.00*%FVC+50.7-33.3*FEV1 (l). CONCLUSIONS: This study produced novel SDL age equations for Japanese adults using data from a large number of healthy never-smokers with both normal spirometric measurements and BMIs. PMID- 25789797 TI - Destruction of methyl bromide sorbed to activated carbon by thiosulfate or electrolysis. AB - Methyl bromide (CH3Br) is widely used as a fumigant for postharvest and quarantine applications for agricultural products at port facilities due to the short treatment period required, but it is vented from fumigation chambers to the atmosphere after its use. Due to the potential contributions of CH3Br to stratospheric ozone depletion, technologies for the capture and degradation of the CH3Br are needed to enable its continued use. Although granular activated carbon (GAC) has been used for CH3Br capture and thiosulfate has been used for destruction of CH3Br in aqueous solution, this research explored techniques for direct destruction of CH3Br sorbed to GAC. Submerging the GAC in an aqueous thiosulfate solution achieved debromination of CH3Br while sorbed to the GAC, but it required molar concentrations of thiosulfate because of the high CH3Br loading and produced substantial concentrations of methyl thiosulfate. Submergence of the GAC in water and use of the GAC as the cathode of an electrolysis unit also debrominated sorbed CH3Br. The reaction appeared to involve a one-electron transfer, producing methyl radicals that incorporated into the GAC. Destruction rates increased with decreasing applied voltage down to ~-1.2 V vs the standard hydrogen electrode. Cycling experiments conducted at -0.77 V indicated that >80% debromination of CH3Br was achieved over ~ 30 h with ~ 100% Coulombic efficiency. Sorptive capacity and degradation efficiency were maintained over at least 3 cycles. Capture of CH3Br fumes from fumigation chambers onto GAC, and electrolytic destruction of the sorbed CH3Br could mitigate the negative impacts of CH3Br usage pending the development of suitable replacement fumigants. PMID- 25789798 TI - Combination therapy for patients with uncontrolled type 2 diabetes mellitus: adding empagliflozin to pioglitazone or pioglitazone plus metformin. AB - INTRODUCTION: For patients with type 2 diabetes mellitus (T2DM), there is a growing interest in sodium glucose co-transporter 2 (SGLT2) inhibitors, a class of glucose-lowering agents that act independently of insulin secretion and insulin action and also have a weight-lowering effect. Empagliflozin is an SGLT2 inhibitor that has been demonstrated to significantly reduce blood glucose levels and is well tolerated in patients with T2DM. AREAS COVERED: Kovacs et al. have reported a randomized, placebo-controlled study of empagliflozin as add-on to pioglitazone or pioglitazone plus metformin in patients with T2DM. The study results are evaluated, and potential impact on clinical practice is considered. EXPERT OPINION: The addition of empagliflozin to pioglitazone or pioglitazone plus metformin treatment may offer some advantages. Together, their complementary mechanisms of action result in significant reductions in glycated hemoglobin levels, weight, and blood pressure, with a low risk of hypoglycemia, but were associated with an increased risk of events consistent with genital mycotic infections. PMID- 25789799 TI - A post-genomic surprise. The molecular reinscription of race in science, law and medicine. AB - The completion of the first draft of the Human Genome Map in 2000 was widely heralded as the promise and future of genetics-based medicines and therapies - so much so that pundits began referring to the new century as 'The Century of Genetics'. Moreover, definitive assertions about the overwhelming similarities of all humans' DNA (99.9 per cent) by the leaders of the Human Genome Project were trumpeted as the end of racial thinking about racial taxonomies of human genetic differences. But the first decade of the new century brought unwelcomed surprises. First, gene therapies turned out to be far more complicated than any had anticipated - and instead the pharmaceutical industry turned to a focus on drugs that might be 'related' to population differences based upon genetic markers. While the language of 'personalized medicine' dominated this frame, research on racially and ethnically designated populations differential responsiveness to drugs dominated the empirical work in the field. Ancestry testing and 'admixture research' would play an important role in a new kind of molecular reification of racial categories. Moreover, the capacity of the super computer to map differences reverberated into personal identification that would affect both the criminal justice system and forensic science, and generate new levels of concern about personal privacy. Social scientists in general, and sociologists in particular, have been caught short by these developments - relying mainly on assertions that racial categories are socially constructed, regionally and historically contingent, and politically arbitrary. While these assertions are true, the imprimatur of scientific legitimacy has shifted the burden, since now 'admixture research' can claim that its results get at the 'reality' of human differentiation, not the admittedly flawed social constructions of racial categories. Yet what was missing from this framing of the problem: 'admixture research' is itself based upon socially constructed categories of race. PMID- 25789800 TI - Is personalized medicine different? (Reinscription: the sequel). A response to Troy Duster. PMID- 25789801 TI - Race, genes, power. PMID- 25789802 TI - Science, critical race theory and colour-blindness. PMID- 25789803 TI - Response to 'A post-genomic surprise. The molecular reinscription of race in science, law and medicine'. PMID- 25789804 TI - A different kind of association between socio-histories and health. PMID- 25789805 TI - 'When are you from?' Time, space, and capital in the molecular reinscription of race. PMID- 25789806 TI - Race, post-genomic science and good intentions: from racial science to anti racism? PMID- 25789807 TI - Response to comments on 'A post-genomic surprise'. AB - In response to the seven authors who offered comments on my paper, I have tried to synthesize and distill common themes. Foremost among them is the charge to look forward, not only to consider probable developments and implications for how this 'molecular reinscription of race' will unfold in forensics and clinical medicine, but as well to suggest how the discipline of Sociology can and should respond. But as several of the commentators noted, this is not just a matter for a single discipline, but should be fertile ground for coordinated empirical investigation by such fields as the Social Studies of Science, Anthropology of Medicine, and Critical Race Theory. For sociologically informed reasons, social scientists should be wary of the unanticipated consequences of collaboration with human molecular geneticists who come to the table deploying databases with pre fabricated categories of race, thereby poised to provide genetic explanations of social outcomes based upon race and ethnicity. A cautionary note is provided explaining how and why some joint projects are advised, some are ill-advised. PMID- 25789809 TI - Characterization of the intestinal absorption of seven flavonoids from the flowers of Trollius chinensis using the Caco-2 cell monolayer model. AB - The human Caco-2 cell monolayer model was used to investigate the absorption property, mechanism, and structure-property relationship of seven representative flavonoids, namely, orientin, vitexin, 2"-O-beta-L-galactopyranosylorientin, 2"-O beta-L-galactopyranosylvitexin, isoswertisin, isoswertiajaponin, and 2"-O-(2"' methylbutanoyl)isoswertisin from the flowers of Trollius chinensis. The results showed that these flavonoids were hardly transported through the Caco-2 cell monolayer. The compounds with 7-OCH3 including isoswertisin, isoswertiajaponin and 2"-O-(2"'-methylbutanoyl)isoswertisin were absorbed in a passive diffusion manner, and their absorbability was increased in the same order as their polarity. The absorption of the remaining compounds with 7-OH including orientin, vitexin, 2"-O-beta-L-galactopyranosylorientin, and 2"-O-beta-L galactopyranosylvitexin involved transporter mediated efflux in addition to passive diffusion. Among the four compounds with 7-OH, those with a free hydroxyl group at C-2" such as orientin and vitexin were the substrates of P-glycoprotein (P-gp) and that with a free hydroxyl group at C-2' such as 2"-O-beta-L galactopyranosylorientin was the substrate of multidrug resistance protein 2 (MRP2). The results of this study also implied that the absorbability of the flavonoids should be taken into account when estimating the effective components of T. chinensis. PMID- 25789808 TI - Pathogenic E. coli exploits SslE mucinase activity to translocate through the mucosal barrier and get access to host cells. AB - SslE is a zinc-metalloprotease involved in the degradation of mucin substrates and recently proposed as a potential vaccine candidate against pathogenic E. coli. In this paper, by exploiting a human in vitro model of mucus-secreting cells, we demonstrated that bacteria expressing SslE have a metabolic benefit which results in an increased growth rate postulating the importance of this antigen in enhancing E. coli fitness. We also observed that SslE expression facilitates E. coli penetration of the mucus favouring bacteria adhesion to host cells. Moreover, we found that SslE-mediated opening of the mucosae contributed to the activation of pro-inflammatory events. Indeed, intestinal cells infected with SslE-secreting bacteria showed an increased production of IL-8 contributing to neutrophil recruitment. The results presented in this paper conclusively designate SslE as an important colonization factor favouring E. coli access to both metabolic substrates and target cells. PMID- 25789810 TI - Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder. AB - Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6*10-6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness. PMID- 25789811 TI - Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers. AB - The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation specific counseling and be more aggressively managed for risk reduction. PMID- 25789813 TI - Genetic testing for age-related macular degeneration: not indicated now. AB - Age-related macular degeneration is a very common condition that is caused by a complex interplay of genetic and environmental factors. It is likely that, in the future, genetic testing will allow physicians to achieve better clinical outcomes by administering specific treatments to patients based on their genotypes. However, improved outcomes for genotyped patients have not yet been demonstrated in a prospective clinical trial, and as a result, the costs and risks of routine genetic testing currently outweigh the benefits for patients with age-related macular degeneration. PMID- 25789812 TI - Are individual differences in reading speed related to extrafoveal visual acuity and crowding? AB - Readers differ considerably in their speed of self-paced reading. One factor known to influence fixation durations in reading is the preprocessing of words in parafoveal vision. Here we investigated whether individual differences in reading speed or the amount of information extracted from upcoming words (the preview benefit) can be explained by basic differences in extrafoveal vision--i.e., the ability to recognize peripheral letters with or without the presence of flanking letters. Forty participants were given an adaptive test to determine their eccentricity thresholds for the identification of letters presented either in isolation (extrafoveal acuity) or flanked by other letters (crowded letter recognition). In a separate eye-tracking experiment, the same participants read lists of words from left to right, while the preview of the upcoming words was manipulated with the gaze-contingent moving window technique. Relationships between dependent measures were analyzed on the observational level and with linear mixed models. We obtained highly reliable estimates both for extrafoveal letter identification (acuity and crowding) and measures of reading speed (overall reading speed, size of preview benefit). Reading speed was higher in participants with larger uncrowded windows. However, the strength of this relationship was moderate and it was only observed if other sources of variance in reading speed (e.g., the occurrence of regressive saccades) were eliminated. Moreover, the size of the preview benefit--an important factor in normal reading- was larger in participants with better extrafoveal acuity. Together, these results indicate a significant albeit moderate contribution of extrafoveal vision to individual differences in reading speed. PMID- 25789814 TI - Heterogeneity of crow's feet line patterns in clinical trial subjects. AB - BACKGROUND: Patterns of crow's feet lines (CFLs) vary among individuals. OBJECTIVE: To characterize distribution and predictors of CFL patterns. METHODS: Patterns of CFLs (full fan, lower fan, central fan, and upper fan) were evaluated at maximum smile and at rest from photographs of subjects with moderate-to-severe CFLs. Relationships between CFL pattern and severity, age, gender, and subject reported outcomes were explored. RESULTS: Evaluations of 2,699 photographs from 1,392 subjects were conducted; 1,389 and 1,310 had evaluable CFL patterns at maximum smile and at rest, respectively. Lower-fan, central-fan, and full-fan patterns were identified in 28.4% to 34.7% at maximum smile and 27.7% to 33.9% at rest; upper fan was found in ~5%. The pattern distribution of CFLs demonstrated a relationship to baseline CFL severity, age, and gender; full-fan and lower-fan patterns were more common in severe versus moderate CFL at maximum smile; full fan increased with age. Lower fan was more common in males. Subjects with full fan at maximum smile were most dissatisfied with their appearance and perceived themselves to look older versus other patterns. CONCLUSION: Baseline CFL severity, age, and gender may predict fan pattern. Patterns may progress with age from central to lower fan or full fan. Pattern heterogeneity of CFLs suggests that tailored treatment may be warranted. PMID- 25789815 TI - The successful management of a Bronchoesophageal fistula after lung transplantation: a case report. AB - We describe an unprecedented, disastrous complication after bilateral lung transplantation (BLT), a bilateral bronchial dehiscence with a right bronchoesophageal fistula leading to life-threatening septic shock. We also report the successful endoscopic management of this complication by double stenting and stress the efficacy of the multidisciplinary approach to this critical case. PMID- 25789816 TI - Clinical and billing review of extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is a temporary technique for providing life support for cardiac dysfunction, pulmonary dysfunction, or both. The two forms of ECMO, veno-arterial (VA) and veno-venous (VV), are used to support cardiopulmonary and pulmonary dysfunction, respectively. Historically, ECMO was predominantly used in the neonatal and pediatric populations, as early adult studies failed to improve outcomes. ECMO has become far more common in the adult population because of positive results in published case series and clinical trials during the 2009 influenza A(H1N1) pandemic in 2009 to 2010. Advances in technology that make the technique much easier to implement likely fueled the renewed interest. Although exact criteria for ECMO are not available, patients who are good candidates are generally considered to be relatively young and suffering from acute illness that is believed to be reversible or organ dysfunction that is otherwise treatable. With the increase in the use in the adult population, a number of different codes have been generated to better identify the method of support with distinctly different relative value units assigned to each code from a very simple prior coding scheme. To effectively be reimbursed for use of the technique, it is imperative that the clinician understands the new coding scheme and works with payers to determine what is incorporated into each specific code. PMID- 25789817 TI - Racial/ethnic differences in self-reported and biologic measures of chronic stress in pregnancy. AB - OBJECTIVE: Racial differences in chronic maternal stress may contribute to disparities in pregnancy outcomes. The objective is to identify racial and ethnic differences in self-reported and biologic measures of stress between non-Hispanic black (NHB) and non-Hispanic white (NHW) pregnant women. STUDY DESIGN: NHB and NHW pregnant women were enrolled before 23 weeks of gestation in this prospective cohort study. Equal numbers of women were recruited with public vs private insurance in each racial group. Self-reported stress was measured and blood samples collected in the second and third trimesters were analyzed for serum Epstein-Barr virus antibody, C-reactive protein (CRP), corticotropin-releasing hormone (CRH) and adenocorticotropic hormone (ACTH). RESULTS: One hundred and twelve women were enrolled. NHW women reported more buffers against stress (P=0.04) and neighborhood satisfaction (P=0.02). NHB women reported more discrimination (P<0.001), food insecurity (P=0.04) and had significantly higher mean CRP levels and mean ACTH levels in the second and third trimesters. CONCLUSION: Significant differences in self-reported and biologic measures of chronic stress were identified between NHB and NHW pregnant women with similar economic characteristics. Future studies should investigate mechanisms underlying these differences and their relationship to pregnancy outcomes. PMID- 25789818 TI - Stillbirth and the small fetus: use of a sex-specific versus a non-sex-specific growth standard. AB - OBJECTIVE: To determine if the use of a sex-specific standard to define small-for gestational age (SGA) will improve prediction of stillbirth. STUDY DESIGN: We performed a retrospective cohort study of singleton pregnancies excluding anomalies, aneuploidy, undocumented fetal sex or birthweight. SGA was defined as birthweight <10th percentile by the non-sex-specific and sex-specific Alexander standards. The association between SGA and stillbirth using these standards was assessed using logistic regression. RESULT: Among 57,170 pregnancies meeting inclusion criteria, 319 (0.6%) pregnancies were complicated by stillbirth. The area under the receiver operating characteristic curve for the prediction of stillbirth was greater for the sex-specific compared to the non-sex-specific standard (0.83 vs 0.72, P<0.001). CONCLUSION: Our findings suggest adoption of a sex-specific standard for diagnosis of SGA as it is more discriminative in identifying the SGA fetus at risk for stillbirth. PMID- 25789819 TI - Palladium-catalyzed difunctionalization of internal alkynes via highly regioselective 6-endo cyclization and alkenylation of enynoates: synthesis of multisubstituted pyrones. AB - An efficient Pd(II)-catalyzed difunctionalization reaction of internal alkynes is reported. In this reaction, various enynoates and electron-deficient alkenes were used for the syntheses of useful highly substituted pyrone derivatives via a 6 endo cyclization and subsequent alkenylation pathway. The corresponding products could be obtained in moderate to good yields under very mild reaction conditions. The high regioselectivity and wide compatibility with different functional groups found in the desired products demonstrate this method to be a general and useful tool for the synthesis of highly substituted pyrone derivatives. PMID- 25789820 TI - QSAR-assisted virtual screening of lead-like molecules from marine and microbial natural sources for antitumor and antibiotic drug discovery. AB - A Quantitative Structure-Activity Relationship (QSAR) approach for classification was used for the prediction of compounds as active/inactive relatively to overall biological activity, antitumor and antibiotic activities using a data set of 1746 compounds from PubChem with empirical CDK descriptors and semi-empirical quantum chemical descriptors. A data set of 183 active pharmaceutical ingredients was additionally used for the external validation of the best models. The best classification models for antibiotic and antitumor activities were used to screen a data set of marine and microbial natural products from the AntiMarin database 25 and four lead compounds for antibiotic and antitumor drug design were proposed, respectively. The present work enables the presentation of a new set of possible lead like bioactive compounds and corroborates the results of our previous investigations. By other side it is shown the usefulness of quantum chemical descriptors in the discrimination of biologically active and inactive compounds. None of the compounds suggested by our approach have assigned non antibiotic and non-antitumor activities in the AntiMarin database and almost all were lately reported as being active in the literature. PMID- 25789821 TI - Modification of purine and pyrimidine nucleosides by direct C-H bond activation. AB - Transition metal-catalyzed modifications of the activated heterocyclic bases of nucleosides as well as DNA or RNA fragments employing traditional cross-coupling methods have been well-established in nucleic acid chemistry. This review covers advances in the area of cross-coupling reactions in which nucleosides are functionalized via direct activation of the C8-H bond in purine and the C5-H or C6-H bond in uracil bases. The review focuses on Pd/Cu-catalyzed couplings between unactivated nucleoside bases with aryl halides. It also discusses cross dehydrogenative arylations and alkenylations as well as other reactions used for modification of nucleoside bases that avoid the use of organometallic precursors and involve direct C-H bond activation in at least one substrate. The scope and efficiency of these coupling reactions along with some mechanistic considerations are discussed. PMID- 25789822 TI - Preliminary biological evaluation of 18F-FBEM-Cys-Annexin V a novel apoptosis imaging agent. AB - A novel annexin V derivative (Cys-Annexin V) with a single cysteine residue at its C-terminal has been developed and successfully labeled site-specifically with 18F-FBEM. 18F-FBEM was synthesized by coupling 18F-fluorobenzoic acid (18F-FBA) with N-(2-aminoethyl)maleimide using optimized reaction conditions. The yield of 18F-FBEM-Cys-Annexin V was 71.5% +/- 2.0% (n = 4, based on the starting 18F-FBEM, non-decay corrected). The radiochemical purity of 18F-FBEM-Cys-Annexin V was >95%. The specific radioactivities of 18F-FBEM and 18F-FBEM-Cys-Annexin V were >150 and 3.17 GBq/umol, respectively. Like the 1st generation 18F-SFB-Annexin V, the novel 18F-FBEM-Cys-Annexin V mainly shows renal and to a lesser extent, hepatobiliary excretion in normal mice. In rat hepatic apoptosis models a 3.88 +/ 0.05 (n = 4, 1 h) and 10.35 +/- 0.08 (n = 4, 2 h) increase in hepatic uptake of 18F-FBEM-Cys-Annexin V compared to normal rats was observed after injection via the tail vein. The liver uptake ratio (treated/control) at 2 h p.i. as measured via microPET correlated with the ratio of apoptotic nuclei in liver observed using TUNEL histochemistry, indicating that the novel 18F-FBEM-Cys-Annexin V is a potential apoptosis imaging agent. PMID- 25789823 TI - Validation of a prototype DiodeAir for small field dosimetry. AB - Standard commercial diode detectors over-respond within small radiation fields, an effect largely attributable to the relatively high mass-density of silicon. However, Monte Carlo studies can be used to optimise dosimeter designs and have demonstrated that 'mass-density compensation'-for example, introducing a low density air-gap upstream of a diode's high-density silicon volume-can substantially improve instrument response. In this work we used egs_chamber Monte Carlo simulations to predict the ideal air-gap thickness for a PTW 60017 unshielded diode detector. We then developed a prototype instrument incorporating that air-gap and, for a 6 MV linac, tested it experimentally against EBT3 film. We also tested a further three prototypes with different air-gap thicknesses. Our results demonstrate that for a 10 * 10 cm(2) reference field the DiodeAir, a PTW 60017 diode with a built-in air-gap of 1 mm, has on-axis correction factors near unity. Laterally the DiodeAir performs very well off-axis and reports FWHM and penumbra values consistent with those measured using EBT3. For PDD measurement, the performance of the DiodeAir matches that of the original PTW 60017. The experimental focus of this work was 6 MV but we also simulated the on-axis response of the DiodeAir within 15 MV beams and found that our modification proved robust to this substantial increase in beam energy. However, the original diode 60017 does exhibit low energy scatter dependencies and may over-respond to high linac dose-rates such that applying the mass-density compensation method to an alternative instrument (particularly a diamond detector) could ultimately take us even closer to the small-field ideal. PMID- 25789824 TI - Clinical correlates of retrograde amnesia in mild traumatic brain injury. AB - PRIMARY OBJECTIVE: The purpose of this study was to examine the clinical significance of retrograde amnesia (RA) in patients with acute mild traumatic brain injuries (MTBI). METHODS AND PROCEDURES: An emergency department sample of patients (n = 75), aged 18-60 years, with no pre-morbid medical or psychiatric conditions, who met the WHO criteria for MTBI were enrolled in this prospective, descriptive, follow-up study. This study examined the presence and duration of RA in relation to socio-demographics, MTBI severity markers including neuroimaging (CT, MRI) and clinical outcomes (Rivermead post-concussion symptoms questionnaire, post-concussion syndrome (PCS) diagnosis and return to work (RTW) status) at 2 weeks, 1 month and 6 months post-injury. MAIN OUTCOMES AND RESULTS: GCS scores and duration of post-traumatic amnesia (PTA) were related to RA. Those with GCS scores of 14 vs. 15 were more likely to have RA (chi(2)(1) = 13.70, p < 0.0001) and a longer duration (Mann-Whitney U = 56.0, p < 0.0001, d = 1.15) of RA. The duration of RA and PTA correlated positively (Spearman rho(75) = 0.42, p < 0.0001) and those with RA had longer durations of PTA (Mann-Whitney U = 228.5, p = 0.001, d = 1.21). During the follow-up, the presence and duration of RA were not significantly associated with PCS diagnosis or time to RTW. CONCLUSIONS: In this study, the presence and duration of RA was not associated with outcome. PMID- 25789825 TI - CePd2Al2, CePd3Al3, and CePd4Al4-A new homologous series built of CaBe2Ge2- and CsCl-type units. AB - The aluminides CePd2Al2, CePd3Al3, and CePd4Al4 were synthesized and their properties studied by X-ray diffraction, magnetic, heat capacity, and electrical transport measurements. The crystal structures of CePd2Al2 and CePd4Al4 were determined and refined from the single-crystal X-ray diffraction data, while that of CePd3Al3 was designed by the trial-and-error method on the basis of crystal chemistry considerations and refined by the Rietveld method from the X-ray powder diffraction data. All three compounds were found to crystallize in the tetragonal space group P4/nmm with Z = 2. The lattice parameters of CePd2Al2 are a = 4.3974(9) A and c = 9.871(4) A. Those of CePd3Al3 are a = 4.3045(7) A and c = 13.4426(18) A, while those of CePd4Al4 are a = 4.325(2) A and c = 16.230(5) A. The structures represent a new homologous series built of structural units of the CaBe2Ge2- and CsCl-type. The three compounds were established to order antiferromagnetically at 2.5(1) K, 3.5(1) K, and 2.6(1) K for CePd2Al2, CePd3Al3, and CePd4Al4, respectively. All of them are Kondo lattices with the characteristic energy scale of 3-7 K. PMID- 25789826 TI - Determination of HLA-A, -C, -B, -DRB1 allele and haplotype frequency in Japanese population based on family study. AB - The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B-DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies. PMID- 25789827 TI - Randomized multicentre feasibility trial of intermediate care versus standard ward care after emergency abdominal surgery (InCare trial). AB - BACKGROUND: Emergency abdominal surgery carries a considerable risk of death and postoperative complications. Early detection and timely management of complications may reduce mortality. The aim was to evaluate the effect and feasibility of intermediate care compared with standard ward care in patients who had emergency abdominal surgery. METHODS: This was a randomized clinical trial carried out in seven Danish hospitals. Eligible for inclusion were patients with an Acute Physiology And Chronic Health Evaluation (APACHE) II score of at least 10 who were ready to be transferred to the surgical ward within 24 h of emergency abdominal surgery. Participants were randomized to either intermediate care or standard surgical ward care after surgery. The primary outcome was 30-day mortality. RESULTS: In total, 286 patients were included in the modified intention-to-treat analysis. The trial was terminated after the interim analysis owing to slow recruitment and a lower than expected mortality rate. Eleven (7.6 per cent) of 144 patients assigned to intermediate care and 12 (8.5 per cent) of 142 patients assigned to ward care died within 30 days of surgery (odds ratio 0.91, 95 per cent c.i. 0.38 to 2.16; P = 0.828). Thirty (20.8 per cent) of 144 patients assigned to intermediate care and 37 (26.1 per cent) of 142 assigned to ward care died within the total observation period (hazard ratio 0.78, 95 per cent c.i. 0.48 to 1.26; P = 0.310). CONCLUSION: Postoperative intermediate care had no statistically significant effect on 30-day mortality after emergency abdominal surgery, nor any effect on secondary outcomes. The trial was stopped prematurely owing to slow recruitment and a much lower than expected mortality rate among the enrolled patients. REGISTRATION NUMBER: NCT01209663 (http://www.clinicaltrials.gov). PMID- 25789830 TI - Plasma-based tumor genetics for monitoring disease progression: what can we learn from a tube of blood? PMID- 25789831 TI - ALK FISH and IHC: you cannot have one without the other. PMID- 25789832 TI - Comparisons between mouse and human studies will help the prevention, diagnosis, and treatment of the deadliest type of lung cancer. PMID- 25789828 TI - Towards genome-wide experimental genetics in the in vivo malaria model parasite Plasmodium berghei. AB - Plasmodium berghei was identified as a parasite of thicket rats (Grammomys dolichurus) and Anopheles dureni mosquitoes in African highland forests. Successful adaptation to a range of rodent and mosquito species established P. berghei as a malaria model parasite. The introduction of stable transfection technology, permitted classical reverse genetics strategies and thus systematic functional profiling of the gene repertoire. In the past 10 years following the publication of the P. berghei genome sequence, many new tools for experimental genetics approaches have been developed and existing ones have been improved. The infection of mice is the principal limitation towards a genome-wide repository of mutant parasite lines. In the past few years, there have been some promising and most welcome developments that allow rapid selection and isolation of recombinant parasites while simultaneously minimising animal usage. Here, we provide an overview of all the currently available tools and methods. PMID- 25789833 TI - Comparison of methods in the detection of ALK and ROS1 rearrangements in lung cancer. AB - INTRODUCTION: The use of targeted therapies toward specific oncogenic driver mutations has become a critical factor in the treatment of patients with lung cancer. It is therefore essential to utilize tests with high performance characteristics. Fluorescence in situ hybridization (FISH) is the standard method for detecting anaplastic lymphoma kinase (ALK) and ROS1 rearrangements in non small-cell lung cancer but the utility of other methods such as immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) is unclear. METHODS: Three hundred and sixty-two lung cancer patients were tested with FISH, CISH, and IHC using three ALK antibodies (ALK1, 5A4, D5F3) and one ROS1 antibody in the detection of ALK and ROS1 rearrangements. RESULTS: There was a 97.4% concordance (298 of 306) between FISH and CISH for detection of ALK rearrangements. The ROS1 rearrangement status had a 97% (291 of 300) concordance between CISH and FISH. ALK protein expression was observed in 6 of 341 samples with the ALK1 and 5A4 antibodies and 5 of 341 samples with D5F3. All three antibodies stained each of the ALK FISH-positive samples (100% sensitivity). ROS1 protein expression was observed in 2 of 322 samples. One of three samples with a ROS1 rearrangement by FISH showed ROS1 protein expression (33.3% sensitivity). CONCLUSION: Our findings show good correlation between FISH versus CISH in the detection of ALK and ROS1 rearrangements. FISH versus IHC showed good correlation in the detection of ALK rearrangements but showed weak correlation in the detection of ROS1 rearrangements. These results suggest CISH and IHC could be complimentary detection methods to FISH in the detection of ALK and ROS1 rearrangements. PMID- 25789834 TI - Transient hyperesthesia and radicular pain: an unrecognised complication of thoracic radiotherapy. AB - Radiotherapy may be associated with both permanent and transient neurological adverse effects. We report seven cases of previously undocumented type of transient hyperesthesia and radicular pain occurring after radiotherapy for thoracic malignancies and describe the potential mechanisms. This is different to Lhermitte's sign in its character, location, and duration of symptoms. Knowledge of such adverse effects will prevent inappropriate investigations and anxiety for patients. PMID- 25789836 TI - Life-threatening bronchomediastinal fistula complicating a first cycle of chemotherapy in a stage IV NSCLC case. PMID- 25789835 TI - A novel, highly sensitive ALK antibody 1A4 facilitates effective screening for ALK rearrangements in lung adenocarcinomas by standard immunohistochemistry. AB - INTRODUCTION: Successful treatment of lung cancer patients with crizotinib depends on the accurate diagnosis of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements. The approved fluorescence in-situ hybridization test is complex and difficult to use in daily diagnostic practice. Immunohistochemical assays-rapid and perfectly adapted for routine pathology practice-have been proposed as alternatives. We evaluated the novel high affinity ALK 1A4 antibody for routine diagnostics in formalin fixed, paraffin-embedded tumor specimens. METHODS: Detection of ALK protein expression was investigated by comparing the new 1A4 antibody and the established D5F3 antibody/Ventana system in 218 lung cancer specimens with known ALK status preanalyzed by quantitative reverse transcription-polymerase chain reaction and fluorescence in-situ hybridization (20 ALK-positive cases, 198 ALK-negative cases). RESULTS: The accuracy of both immunohistochemical assays for the detection of ALK rearrangements was high. Using a conventional staining procedure without signal enhancement, the 1A4 antibody assay identified all 20 ALK-rearranged tumors (100% sensitivity) and correctly characterized 196 of 198 negative cases (99.1% specificity). The D5F3/Ventana assay detected 19 ALK-rearranged tumors and typed 217 of 218 tumors correctly (95% sensitivity, 99.5 % specificity). CONCLUSIONS: The novel 1A4 antibody represents a promising candidate for screening lung tumors for the presence of ALK rearrangements. PMID- 25789837 TI - Unexpectedly fludeoxyglucose (18F) avid well-differentiated adenocarcinoma of the lung. PMID- 25789838 TI - Rapid response to trastuzumab emtansine in a patient with HER2-driven lung cancer. PMID- 25789839 TI - Novel association of elastofibroma with aortic stenosis: report of a case report interfering with a thoracotomy procedure and a reassessment of typical patient demographics and tumor location. PMID- 25789840 TI - Adding bevacizumab to chemotherapy effectively control radioresistant brain metastases in ALK-positive lung adenocarcinoma. PMID- 25789841 TI - Organo-palladium(II) complexes bearing unsymmetrical N,N,N-pincer ligands: synthesis, structures and oxidatively induced coupling reactions. AB - The 2-(2'-aniline)-6-imine-pyridines, 2-(C6H4-2'-NH2)-6-(CMe=NAr)C5H3N (Ar = 4-i PrC6H4 (HL1a), 2,6-i-Pr2C6H3 (HL1b)), have been synthesised via sequential Stille cross-coupling, deprotection and condensation steps from 6-tributylstannyl-2-(2 methyl-1,3-dioxolan-2-yl)pyridine and 2-bromonitrobenzene. The palladium(II) acetate N,N,N-pincer complexes, [{2-(C6H4-2'-NH)-6-(CMe=NAr)C5H3N}Pd(OAc)] (Ar = 4-i-PrC6H4 (1a), 2,6-i-Pr2C6H3 (1b)), can be prepared by reacting HL1 with Pd(OAc)2 or, in the case of 1a, more conveniently by the template reaction of ketone 2-(C6H4-2'-NH2)-6-(CMe=O)C5H3N, Pd(OAc)2 and 4-isopropylaniline; ready conversion of 1 to their chloride analogues, [{2-(C6H4-2'-NH)-6 (CMe=NAr)C5H3N}PdCl] (Ar = 4-i-PrC6H4 (2a), 2,6-i-Pr2C6H3 (2b)), has been demonstrated. The phenyl-containing complexes, [{2-(C6H4-2'-NH)-6 (CMe=NAr)C5H3N}PdPh] (Ar = 4-i-PrC6H4 (3a), 2,6-i-Pr2C6H3 (3b)), can be obtained by treating HL1 with (PPh3)2PdPh(Br) in the presence of NaH or with regard to 3a, by the salt elimination reaction of 2a with phenyllithium. Reaction of 2a with silver tetrafluoroborate or triflate in the presence of acetonitrile allows access to cationic [{2-(C6H4-2'-NH)-6-(CMe=N(4-i-PrC6H4)C5H3N}Pd(NCMe)][X] (X = BF4 (4), X = O3SCF3 (5)), respectively; the pyridine analogue of 5, [{2-(C6H4-2' NH)-6-(CMe=N(4-i-PrC6H4)C5H3N}Pd(NC5H5)][O3SCF3] (5'), is also reported. Oxidation of phenyl-containing 3a with one equivalent of 1-chloromethyl-4-fluoro 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectfluorTM) in acetonitrile at low temperature leads to a new palladium species that slowly decomposes to give 4 and biphenyl; biphenyl formation is also observed upon reaction of 3a with XeF2. However, no such oxidatively induced coupling occurs when using 3b. Single crystal X-ray diffraction studies have been performed on HL1b, 1a, 1b, 2a, 2b, 3a, 3b and 5'. PMID- 25789842 TI - Esophagogastric junction distensibility in hiatus hernia. AB - Hiatus hernia is known to be an important risk factor for developing gastroesophageal reflux disease. We aimed to use the endoscopic functional lumen imaging probe (EndoFLIP) to evaluate the functional properties of the esophagogastric junction. EndoFLIP assessments were made in 30 patients with hiatus hernia and Barrett's esophagus, and in 14 healthy controls. The EndoFLIP was placed straddling the esophagogastric junction and the bag distended stepwise to 50 mL. Cross-sectional areas of the bag and intra-bag pressures were recorded continuously. Measurements were made in the separate sphincter components and hiatus hernia cavity. EndoFLIP measured functional aspects such as sphincter distensibility and pressure of all esophagogastric junction components and visualized all hiatus hernia present at endoscopy. The lower esophageal sphincter in hiatus hernia patients had a lower pressure (e.g. 47.7 +/- 13.0 vs. 61.4 +/- 19.2 mm Hg at 50-mL distension volume) and was more distensible (all P < 0.001) than the common esophagogastric junction in controls. In hiatus hernia patients, the crural diaphragm had a lower pressure (e.g. 29.6 +/- 10.1 vs. 47.7 +/- 13.0 mm Hg at 50-mL distension volume) and was more distensible (all P < 0.001) than the lower esophageal sphincter. There was a significant association between symptom scores in patients and EndoFLIP assessment. Conclusively, EndoFLIP was a useful tool. To evaluate the presence of a hiatus hernia and to measure the functional properties of the esophagogastric junction. Furthermore, EndoFLIP distinguished the separate esophagogastric junction components in hiatus hernia patients, and may help us understand the biomechanics of the esophagogastric junction and the mechanisms behind hiatal herniation. PMID- 25789843 TI - Discordance in recovery between altered locomotion and muscle atrophy induced by simulated microgravity in rats. AB - Exposure to a microgravity environment leads to adverse effects in motion and musculoskeletal properties. However, few studies have investigated the recovery of altered locomotion and muscle atrophy simultaneously. The authors investigated altered locomotion in rats submitted to simulated microgravity by hindlimb unloading for 2 weeks. Motion deficits were characterized by hyperextension of the knees and ankle joints and forward-shifted limb motion. Furthermore, these locomotor deficits did not revert to their original form after a 2-week recovery period, although muscle atrophy in the hindlimbs had recovered, implying discordance in recovery between altered locomotion and muscle atrophy, and that other factors such as neural drives might control behavioral adaptations to microgravity. PMID- 25789844 TI - Association between worse metabolic control and increased thyroid volume and nodular disease in elderly adults with metabolic syndrome. AB - BACKGROUND: Metabolic syndrome has been associated with nodular goiter. Our aim was to evaluate which metabolic parameters in elderly patients with metabolic syndrome are associated with thyroid enlargement or increased prevalence of thyroid nodules. METHODS: In this cross-sectional study, 77 patients >65 years of age with metabolic syndrome were included. We evaluated the presence of thyroid nodules and thyroid volume by ultrasonography and several biochemical, metabolic and anthropometric parameters. Only patients with thyrotropin (thyroid stimulating hormone, TSH) levels between 0.3 and 6 mU/L were included. We further divided subjects into two groups-type 2 diabetes mellitus (T2DM) and non-T2DM and established comparisons between them. RESULTS: Among all parameters analyzed we found a significant correlation between glycated hemoglobin (HbA1c) and volume (r=0.261, P=0.027) or number of nodules (r=0.266, P=0.023). Neither sex, age, body mass index (BMI), metformin, nor levothyroxine use were associated with thyroid volume or nodularity. Within the whole cohort, those patients with T2DM had larger thyroid volumes compared to non-T2DM [median (confidence interval, CI) 6.976 (5.220-10.789) vs. 5.034 (3.796-6.034) mL, P<0.008). Furthermore, a larger proportion of T2DM patients presented thyroid volumes >5.8 mL [69 vs. 23%, P<0.001; odds ratio=7.25 (CI 2.04-25.56)]. CONCLUSIONS: In elderly patients with metabolic syndrome, worse metabolic control, represented by higher HbA1c levels, was found associated to increased prevalence of thyroid nodules and larger thyroid volume. Moreover, within the whole metabolic syndrome group, patients with T2DM had the largest thyroid volumes. PMID- 25789845 TI - Cell Therapy for Stress Urinary Incontinence. AB - Urinary incontinence (UI) is the involuntary loss of urine and is a common condition in middle-aged and elderly women and men. Stress urinary incontinence (SUI) is caused by leakage of urine when coughing, sneezing, laughing, lifting, and exercise, even standing leads to increased intra-abdominal pressure. Other types of UI also exist such as urge incontinence (also called overactive bladder), which is a strong and unexpected sudden urge to urinate, mixed forms of UI that result in symptoms of both urge and stress incontinence, and functional incontinence caused by reduced mobility, cognitive impairment, or neuromuscular limitations that impair mobility or dexterity. However, for many SUI patients, there is significant loss of urethral sphincter muscle due to degeneration of tissue, the strain and trauma of pregnancy and childbirth, or injury acquired during surgery. Hence, for individuals with SUI, a cell-based therapeutic approach to regenerate the sphincter muscle offers the advantage of treating the cause rather than the symptoms. We discuss current clinically relevant cell therapy approaches for regeneration of the external urethral sphincter (striated muscle), internal urethral sphincter (smooth muscle), the neuromuscular synapse, and blood supply. The use of mesenchymal stromal/stem cells is a major step in the right direction, but they may not be enough for regeneration of all components of the urethral sphincter. Inclusion of other cell types or biomaterials may also be necessary to enhance integration and survival of the transplanted cells. PMID- 25789846 TI - Clinical outcomes of botulinum toxin injection in patients with cerebral palsy and esotropia. AB - PURPOSE: To assess the efficacy of botulinum toxin (Novotox) injection in patients with cerebral palsy (CP) and esotropia. PATIENTS AND METHODS: In a non comparative, prospective interventional case series botulinum toxin injection was done in 44 patients with CP and esotropia. A single dose of botulinum toxin was injected in both medial rectus muscles of all patients and was repeated in 12 patients. Angle of deviation within 10 prism diopters (PD) of orthotropia was defined as a successful outcome. RESULT: Forty-four patients (21 males) with the mean age of 47.56 +/- 35.86 months were included in the study. The mean esotropia in all patients was 52.27 +/- 18.40 PD (25-123 PD). The range of follow-up was 12 24 months. Thirty patients (68.18%) were treated successfully one year after surgery. The rates of success, consecutive exotropia, and residual esotropia were 61.4%, 13.63%, and 25% in the last follow-up, respectively. The logistic regression showed statistically significant results between success result and lower age, higher pre-injection deviation, one month post-injection deviation, and severe ptosis. Complications included subconjunctival hemorrhage and ptosis. CONCLUSION: Botulinum toxin injection is reasonably less invasive with light anesthesia, scar free, and a therapeutic alternative for the patient with esotropia and CP. Therefore, it can provide more possible surgical options in future. PMID- 25789847 TI - Phytochemical regulation of the tumor suppressive microRNA, miR-34a, by p53 dependent and independent responses in human breast cancer cells. AB - The tumor suppressive microRNA miR-34a is transcriptionally regulated by p53 and shown to inhibit breast cancer cell proliferation as well as being a marker of increased disease free survival. Indole-3-carbinol (I3C) derived from cruciferous vegetables, artemisinin, extracted from the sweet wormwood plant, and artesunate, a semi-synthetic derivative of artemisinin, are phytochemicals with anti tumorigenic properties however, little is known about the role of microRNAs in their mechanism of action. Human breast cancer cells expressing wild-type (MCF-7) or mutant p53 (T47D) were treated with a concentration range and time course of each phytochemical under conditions of cell cycle arrest as detected by flow cytometry to examine the potential connection between miR-34a expression and their anti-proliferative responses. Real-time PCR and western blot analysis of extracted RNA and total protein revealed artemsinin and artesunate increased miR 34a expression in a dose-dependent manner correlating with down-regulation of the miR-34a target gene, CDK4. I3C stimulation of miR-34a expression required functional p53, whereas, both artemisinin and artesunate up-regulated miR-34a expression regardless of p53 mutational status or in the presence of dominant negative p53. Phytochemical treatments inhibited the luciferase activity of a construct containing the wild-type 3'UTR of CDK4, but not those with a mutated miR-34a binding site, whereas, transfection of miR-34a inhibitors ablated the phytochemical mediated down-regulation of CDK4 and induction of cell cycle arrest. Our results suggest that miR-34a is an essential component of the anti proliferative activities of I3C, artemisinin, and artesunate and demonstrate that both wild-type p53 dependent and independent pathways are responsible for miR-34a induction. PMID- 25789848 TI - Spinal neuronal activation during locomotor-like activity enabled by epidural stimulation and 5-hydroxytryptamine agonists in spinal rats. AB - The neural networks that generate stepping in complete spinal adult rats remain poorly defined. To address this problem, we used c-fos (an activity-dependent marker) to identify active interneurons and motoneurons in the lumbar spinal cord of adult spinal rats during a 30-min bout of bipedal stepping. Spinal rats were either step trained (30 min/day, 3 days/week, for 7.5 weeks) or not step trained. Stepping was enabled by epidural stimulation and the administration of the serotonergic agonists quipazine and 8-OHDPAT. A third group of spinal rats served as untreated (no stimulation, drugs, or stepping) controls. The numbers of activated cholinergic central canal cluster cells and partition neurons were higher in both step-trained and nontrained rats than in untreated rats and were higher in nontrained than in step-trained rats. The latter finding suggests that daily treatment with epidural stimulation plus serotonergic agonist treatment without step training enhances the excitability of a broader cholinergic interneuronal population than does step training. The numbers of activated interneurons in laminae II-VI of lumbar cross-sections were higher in both step trained and nontrained rats than in untreated rats, and they were highest in step trained rats. This finding suggests that this population of interneurons is responsive to epidural stimulation plus serotonergic treatment and that load bearing induced when stepping has an additive effect. The numbers of activated motoneurons of all size categories were higher in the step-trained group than in the other two groups, reflecting a strong effect of loading on motoneuron recruitment. In general, these results indicate that the spinal networks for locomotion are similar with and without brain input. SIGNIFICANCE: We identified neurons within the spinal cord networks that are activated during assisted stepping in paraplegic rats. We stimulated the spinal cord and administered a drug to help the rats step. One group was trained to step and another was not trained. We observed a lower percentage of activated neurons in specific spinal cord regions in trained rats than in nontrained rats after a 1-hr stepping bout, suggesting that step training reduces activation of some types of spinal neurons. This observation indicates that training makes the spinal networks more efficient and suggests a "learning" phenomenon in the spinal cord without any brain input. PMID- 25789849 TI - Homolytic C-O cleavage in phosphates and sulfonates. AB - The C-O homolytic bond dissociation enthalpies(BDEs) were calculated by high level ab initio including G4, G3B3, G3, CBS-QB3 and a series of density function theory (DFT) methods. It is found that the wB97 method gave the most reliable C-O BDEs and the root-mean-square deviation (RMSD) is 7.6 kJ/mol. Therefore, the C(sp(2))-O BDE predictions and the substituent effects of alkenyl phosphates/sulfonates and aryl phosphates/sulfonates were investigated in detail by using the wB97 method. Interestingly, there exist different substituent effects in alpha- and beta-substituted alkenyl phosphates/sulfonates. Excellent linear relationships between the C-O BDEs of beta-substituted alkenyl phosphates/sulfonates with substituent constant sigmap(+) were found. In addition, the NBO analysis further disclosed the essence of the substituent effects on C-O BDEs. PMID- 25789851 TI - Use of rhamnolipid biosurfactant for membrane biofouling prevention and cleaning. AB - Rhamnolipids were evaluated as biofouling reducing agents in this study. The permeability of the bacterial outer membrane was increased by rhamnolipids while the growth rate of Pseudomonas aeruginosa was not affected. The surface hydrophobicity was increased through the release of lipopolysaccharides and extracellular polymeric substances from the outer cell membrane. Rhamnolipids were evaluated as agents for the prevention and cleaning of biofilms. A high degree of biofilm detachment was observed when the rhamnolipids were used as a cleaning agent. In addition, effective biofilm reduction occurred when rhamnolipids were applied to various species of Gram-negative bacteria isolated from seawater samples. Biofilm reduction using rhamnolipids was comparable to commercially available surfactants. In addition, 20% of the water flux was increased after rhamnolipid treatment (300 MUg ml(-1), 6 h exposure time) in a dead-end filtration system. Rhamnolipids appear to have promise as biological agents for reducing membrane biofouling. PMID- 25789850 TI - Prevalence of clinical anxiety, clinical depression and associated risk factors in chinese young and middle-aged patients with osteonecrosis of the femoral head. AB - OBJECTIVE: To investigate the prevalence of clinical anxiety and clinical depression in Chinese young and mid-aged patients with osteonecrosis of the femoral head (ONFH) and to analyze their potential risk factors. METHODS: Two hundred and sixteen Chinese patients with ONFH were consecutively enrolled in this cross-sectional study from January 2010 to December 2010. The Zung self rating anxiety scale (SAS) and the Zung self-rating depression scale (SDS) were used to assess the prevalence of clinical anxiety and clinical depression. An additional questionnaire containing seventeen items of potential risk factors was completed by all patients. Binary logistic regression analysis was employed to reveal potential risk factors of anxiety and depression. RESULTS: The prevalence of clinical anxiety and clinical depression was 20.4% and 21.8% in Chinese young and middle-aged patients with ONFH, respectively. Binary regression analysis showed that independent risk factors correlated with high incidence of clinical anxiety included involved femoral head (OR = 3.168, 95% CI: 1.496 - 6.708) and stages of ONFH (ORIV-V / II = 5.383, 95% CI: 1.664-17.416). Independent risk factors correlated with high incidence of depression included gender (OR = 2.853, 95% CI: 1.467-5.778), comorbid diseases (OR = 4.243, 95% CI: 1.940-9.278) and stages of the disease (OR IV-V/II = 16.963, 95% CI: 4.404-65.331). CONCLUSIONS: Patients with bilateral ONFH are inclined to have clinical anxiety, while female patients and patients with comorbid diseases might tend to get clinical depression. Advanced stages of ONFH are independent risk factors for both clinical anxiety and clinical depression. PMID- 25789853 TI - JSI-124 suppresses invasion and angiogenesis of glioblastoma cells in vitro. AB - Glioblastoma multiforme (GBM) is one of the utmost malignant tumors. Excessive angiogenesis and invasiveness are the major reasons for their uncontrolled growth and resistance toward conventional strategies resulting in poor prognosis. In this study, we found that low-dose JSI-124 reduced invasiveness and tumorigenicity of GBM cells. JSI-124 effectively inhibited VEGF expression in GBM cells. In a coculture study, JSI-124 completely prevented U87MG cell-mediated capillary formation of HUVECs and the migration of HUVECs when cultured alone or cocultured with U87MG cells. Furthermore, JSI-124 inhibited VEGF-induced cell proliferation, motility, invasion and the formation of capillary-like structures in HUVECs in a dose-dependent manner. JSI-124 suppressed VEGF-induced p-VEGFR2 activity through STAT3 signaling cascade in HUVECs. Immunohistochemistry analysis showed that the expression of CD34, Ki67, p-STAT3 and p-VEGFR2 protein in xenografts was remarkably decreased. Taken together, our findings provide the first evidence that JSI-124 effectively inhibits tumor angiogenesis and invasion, which might be a viable drug in anti-angiogenesis and anti-invasion therapies. PMID- 25789852 TI - Cell cycle, cytoskeleton dynamics and beyond: the many functions of cyclins and CDK inhibitors. AB - While targeting experiments carried out on the genes encoding many cell cycle regulators have challenged our views of cell cycle control, they also suggest that redundancy might not be the only explanation for the observed perplexing phenotypes. Indeed, several observations hint at functions of cyclins and CDK inhibitors that cannot be accounted for by their sole role as kinase regulators. They are found involved in many cellular transactions, depending or not on CDKs that are not directly linked to cell cycle control, but participating to general mechanisms such as transcription, DNA repair or cytoskeleton dynamics. In this review we discuss the roles that these alternative functions might have in cancer cell proliferation and migration that sometime even challenge their definition as proliferation markers. PMID- 25789854 TI - Carriage of Streptococcus pneumoniae in aged adults with influenza-like-illness. AB - Incidence of pneumococcal disease is disproportionally high in infants and elderly. Nasopharyngeal colonisation by Streptococcus pneumoniae is considered a prerequisite for disease but unlike in children, carriage in elderly is rarely detected. Here, we tested for S. pneumoniae in nasopharyngeal and saliva samples collected from community-dwelling elderly with influenza-like-illness (ILI). Trans-nasal nasopharyngeal, trans-oral nasopharyngeal and saliva samples (n = 270 per sample type) were collected during winter/spring 2011/2012 from 135 persons aged 60-89 at onset of ILI and 7-9 weeks later following recovery. After samples were tested for pneumococci by conventional culture, all plate growth was collected. DNA extracted from plate harvests was tested by quantitative-PCRs (qPCR) specific for S. pneumoniae and serotypes included in the 13-valent pneumococcal conjugated vaccine (PCV13). Pneumococci were cultured from 14 of 135 (10%) elderly with none of the sampled niches showing superiority in carriage detection. With 76/270 (28%) saliva, 31/270 (11%) trans-oral and 13/270 (5%) trans-nasal samples positive by qPCR, saliva was superior to nasopharyngeal swabs (p<0.001) in qPCR-based carriage detection. Overall, from all methods used in the study, 65 of 135 (48%) elderly carried pneumococci at least once and 26 (19%) at both study time points. The difference between carriage prevalence at ILI (n = 49 or 36%) versus recovery (n = 42 or 31%) was not significant (p = 0.38). At least 23 of 91 (25%) carriage events in 19 of 65 (29%) carriers were associated with PCV13-serotypes. We detected a large reservoir of pneumococci in saliva of elderly, with PCV13-serotype distribution closely resembling the contemporary carriage of serotypes reported in the Netherlands for PCV-vaccinated infants. PMID- 25789855 TI - A non-invasive method to assess cerebral perfusion pressure in geriatric patients with suspected cerebrovascular disease. AB - BACKGROUND: Cerebral perfusion pressure (CPP) can adversely impact cerebrovascular hemodynamics but cannot be practically measured in most clinical settings. Here, we aimed to establish a representative mathematical model for CPP in geriatric patients with suspected cerebrovascular disease. METHODS: A total of 100 patients (54 males and 46 females between 60-80 years of age) with suspected cerebrovascular disease and no obvious cerebrovascular stenosis were selected for invasive CPP monitoring via catheterization of the middle segment of the common carotid arteries and openings of the vertebral arteries bilaterally. Curves were function-fitted using MATLAB 7.0, and data was statistically processed by SPSS 20.0. RESULTS: MATLAB 7.0 constructed eighth-order Fourier functions that fit all recorded CPP curves. Since the coefficients of the 100 functions were significantly different, all functions were standardized to derive one representative function. By manipulating the heart rate and maximum/minimum CPP of the representative function, estimated CPP curves can be constructed for patients with differing heart rates, intracranial pressures (ICPs) and blood pressures. CONCLUSIONS: CPP can be well-modeled through an eighth-order Fourier function that can be constructed from a patient's brachial artery blood pressure (BABP), ICP and heart rate. This function is representative of geriatric patients with cerebrovascular disease and can be used in the future study of cerebral hemodynamics. PMID- 25789856 TI - Secular trends in reported portion size of food and beverages consumed by Irish adults. AB - The present analysis aimed to investigate the changes in the reported portion sizes (PS) of foods and beverages commonly consumed by Irish adults (18-64 years) from the North South Ireland Food Consumption Survey (NSIFCS) (1997-2001) and the National Adult Nutrition Survey (NANS) (2008-10). Food PS, which are defined as the weight of food (g) consumed per eating occasion, were calculated for comparable foods and beverages in two nationally representative cross-sectional Irish food consumption surveys and were published in NSIFCS and NANS. Repeated measure mixed model analysis compared reported food PS at the total population level as well as subdivided by sex, age, BMI and social class. A total of thirteen commonly consumed foods were examined. The analysis demonstrated that PS significantly increased for five foods ('white sliced bread', 'brown/wholemeal breads', 'all meat, cooked', 'poultry, roasted' and 'milk'), significantly decreased for three ('potatoes', 'chips/wedges' and 'ham, sliced') and did not significantly change for five foods ('processed potato products', 'bacon/ham', 'cheese', 'yogurt' and 'butter/spreads') between the NSIFCS and the NANS. The present study demonstrates that there was considerable variation in the trends in reported food PS over this period. PMID- 25789857 TI - Advanced application of porcine intramuscular adipocytes for evaluating anti adipogenic and anti-inflammatory activities of immunobiotics. AB - We previously established a clonal porcine intramuscular preadipocyte (PIP) line and we were able to establish a protocol to obtain functional mature adipocytes from PIP cells. We hypothesized that both PIP cells and mature adipocytes are likely to be useful in vitro tools for increasing our understanding of immunobiology of adipose tissue, and for the selection and study of immunoregulatory probiotics (immunobiotics) able to modulate adipocytes immune responses. In this study, we investigated the immunobiology of PIP cells and mature adipocytes in relation to their response to TNF-alpha stimulation. In addition, we evaluated the possibility that immunobiotic microorganisms modify adipogenesis and immune functions of porcine adipose tissue through Peyer's patches (PPs) immune-competent cells. We treated the porcine PPs immune cells with different probiotic strains; and we evaluated the effect of conditioned media from probiotic-stimulated immune cells in PIP cells and mature adipocytes. The Lactobacillus GG and L. gasseri TMC0356 showed remarkable effects, and were able to significantly reduce the expression of pro-inflammatory factors and negative regulators (A20, Bcl-3, and MKP-1) in adipocytes challenged with TNF alpha. The results of this study demonstrated that the evaluation of IL-6, and MCP-1 production, and A20 and Bcl-3 down-regulation in TNF-alpha-challenged adipocytes could function as biomarkers to screen and select potential immunobiotic strains. Taking into consideration that several in vivo and in vitro studies clearly demonstrated the beneficial effects of Lactobacillus GG and L. gasseri TMC0356 in adipose inflammation, the results presented in this work indicate that the PIP cells and porcine adipocytes could be used for the screening and the selection of new immunobiotic strains with the potential to functionally modulate adipose inflammation when orally administered. PMID- 25789859 TI - A scalable distribution network risk evaluation framework via symbolic dynamics. AB - BACKGROUND: Evaluations of electric power distribution network risks must address the problems of incomplete information and changing dynamics. A risk evaluation framework should be adaptable to a specific situation and an evolving understanding of risk. METHODS: This study investigates the use of symbolic dynamics to abstract raw data. After introducing symbolic dynamics operators, Kolmogorov-Sinai entropy and Kullback-Leibler relative entropy are used to quantitatively evaluate relationships between risk sub-factors and main factors. For layered risk indicators, where the factors are categorized into four main factors - device, structure, load and special operation - a merging algorithm using operators to calculate the risk factors is discussed. Finally, an example from the Sanya Power Company is given to demonstrate the feasibility of the proposed method. CONCLUSION: Distribution networks are exposed and can be affected by many things. The topology and the operating mode of a distribution network are dynamic, so the faults and their consequences are probabilistic. PMID- 25789858 TI - Molecular interaction of a kinase inhibitor midostaurin with anticancer drug targets, S100A8 and EGFR: transcriptional profiling and molecular docking study for kidney cancer therapeutics. AB - The S100A8 and epidermal growth factor receptor (EGFR) proteins are proto oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC). S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs. We undertook transcriptional profiling in Saudi KCs using Affymetrix HuGene 1.0 ST arrays. We identified 1478 significantly expressed genes, including S100A8 and EGFR overexpression, using cut-off p value <0.05 and fold change >=2. Additionally, we compared and confirmed our findings with expression data available at NCBI's GEO database. A significant number of genes associated with cancer showed involvement in cell cycle progression, DNA repair, tumor morphology, tissue development, and cell survival. Atherosclerosis signaling, leukocyte extravasation signaling, notch signaling, and IL-12 signaling were the most significantly disrupted signaling pathways. The present study provides an initial transcriptional profiling of Saudi KC patients. Our analysis suggests distinct transcriptomic signatures and pathways underlying molecular mechanisms of KC progression. Molecular docking analysis revealed that the kinase inhibitor "midostaurin" has amongst the selected drug targets, the best ligand properties to S100A8 and EGFR, with the implication that its binding inhibits downstream signaling in KC. This is the first structure-based docking study for the selected protein targets and anticancer drug, and the results indicate S100A8 and EGFR as attractive anticancer targets and midostaurin with effective drug properties for therapeutic intervention in KC. PMID- 25789860 TI - Development by three-dimensional approaches and four-dimensional imaging: to the knowledge frontier and beyond. AB - Many advances have been taken on elucidating embryonic development and tissue homeostasis and repair by the use of experimental strategies that preserve the three-dimensional (3D) organization and allow quantitative analysis of images over time (four-dimensional). Ranging from the understanding about the relationship between blastomeres and the events that take place during gastrulation by the use of time-lapse imaging through 3D cultures that mimic organogenesis, the advances in this area are of critical value. The studies on embryonic development without disrupting the original architecture and the development of 3D organoid cultures pave a new avenue for unprecedented experimental advances that will positively impact the emergence of new treatments applying regenerative principles for both tissue repair and organ transplant. PMID- 25789861 TI - Dedicated severe asthma services improve health-care use and quality of life. AB - BACKGROUND: Systematic assessment of severe asthma can be used to confirm the diagnosis, identify comorbidities, and address adherence to therapy. However, the prospective usefulness of this approach is yet to be established. The objective of this study was to determine whether the systematic assessment of severe asthma is associated with improved quality of life (QoL) and health-care use and, using prospective data collection, to compare relevant outcomes in patients referred with severe asthma to specialist centers across the United Kingdom. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics, and health-care use between initial assessment and a median follow-up of 286 days. RESULTS: The study population consisted of 346 patients with severe asthma. At follow-up, there were significant reductions in health-care use in terms of primary care or ED visits (66.4% vs 87.8%, P < .0001) and hospital admissions (38% vs 48%, P = .0004). Although no difference was noted in terms of those requiring maintenance oral corticosteroids, there was a reduction in steroid dose (10 mg [8-20 mg] vs 15 mg [10-20 mg], P = .003), and fewer subjects required short-burst steroids (77.4% vs 90.8%, P = .01). Significant improvements were seen in QoL and control using the Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire. CONCLUSIONS: To our knowledge, this is the first time that a prospective study has shown that a systematic assessment at a dedicated severe asthma center is associated with improved QoL and asthma control and a reduction in health-care use and oral steroid burden. PMID- 25789862 TI - Default mode network, motor network, dorsal and ventral basal ganglia networks in the rat brain: comparison to human networks using resting state-fMRI. AB - Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats. PMID- 25789863 TI - The altered renal and hepatic expression of solute carrier transporters (SLCs) in type 1 diabetic mice. AB - Diabetes mellitus is a chronic metabolic disorder that significantly affects human health and well-being. The Solute carrier transporters (SLCs), particularly the Organic anion/cation transporters (Oats/Octs/Octns), Organic anion transporting polypeptides (Oatps) and Oligopeptide transporters (Pepts) are essential membrane proteins responsible for cellular uptake of many endogenous and exogenous substances such as clinically important drugs. They are widely expressed in mammalian key organs especially the kidney and liver, in which they facilitate the influx of various drug molecules, thereby determining their distribution and elimination in body. The altered expression of SLCs in diabetes mellitus could have a profound and clinically significant influence on drug therapies. In this study, we extensively investigated the renal and hepatic expression of twenty essential SLCs in the type 1 diabetic Ins2Akita murine model that develops both hyperglycemia and diabetes-related complications using real time PCR and immunoblotting analysis. We found that the renal expression of mOatp1a1, mOatp1a6, mOat1, mOat3, mOat5, mOct2 and mPept2 was decreased; while that of mPept1 was increased at the mRNA level in the diabetic mice compared with non-diabetic controls. We found up-regulated mRNA expression of mOatp1a4, mOatp1c1, mOctn2, mOct3 and mPept1 as well as down-regulation of mOatp1a1 in the livers of diabetic mice. We confirmed the altered protein expression of several SLCs in diabetic mice, especially the decreased renal and hepatic expression of mOatp1a1. We also found down-regulated protein expression of mOat3 and mOctn1 in the kidneys as well as increased protein expression of mOatp1a4 and mOct3 in the livers of diabetic mice. Our findings contribute to better understanding the modulation of SLC transporters in type 1 diabetes mellitus, which is likely to affect the pharmacokinetic performance of drugs that are transported by these transporters and therefore, forms the basis of future therapeutic optimization of regimens in patients with type 1 diabetes mellitus. PMID- 25789865 TI - Correction: Transcriptome analysis of Arabidopsis GCR1 mutant reveals its roles in stress, hormones, secondary metabolism and phosphate starvation. PMID- 25789864 TI - Plasma protein biomarkers of hepatocellular carcinoma in HCV-infected alcoholic patients with cirrhosis. AB - Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world, with limited options for treatment unless timely diagnosed. Chronic hepatitis C virus (HCV) infection and persistent heavy alcohol consumption are independent risk factors for HCC development, which may induce a specific protein expression pattern different from those caused separately. The aim of the study was to identify protein biomarkers for the detection of HCC in HCV-infected alcoholic patients with cirrhosis in order to improve survival. We compared protein expression profiles of plasma samples from 52 HCV-infected alcoholic patients with and without HCC, using 2-D DIGE coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analyzed statistically using Decyder software, and verified by western-blot and ELISA. In plasma samples from HCV infected alcoholic patients, we found significantly differential expression profiles of carboxypeptidase-N, ceruloplasmin (CP), complement component 4a (C4a), fibrinogen-alpha (FGA), immunoglobulin mu chain C region, serum albumin, and serum paraoxonase/arylesterase 1 (PON1). Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression. In the validation through ELISA, C4a serum concentration was increased in HCC patients (2.4+/-1 ng/mg vs 1.8+/-0.6 ng/mg; p = 0.029), being the only independent predictor of HCC in the multivariate analysis (OR = 2.15; p = 0.015), with an AUROC = 0.70. The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81). In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC. Among them, C4a, and its combination with CP, FGA and PON1, could be considered as potentially reliable biomarkers for the detection of HCC in HCV-infected alcoholic patients. PMID- 25789866 TI - Mechanisms of basin-scale nitrogen load reductions under intensified irrigated agriculture. AB - Irrigated agriculture can modify the cycling and transport of nitrogen (N), due to associated water diversions, water losses, and changes in transport flow paths. We investigate dominant processes behind observed long-term changes in dissolved inorganic nitrogen (DIN) concentrations and loads of the extensive (465,000 km2) semi-arid Amu Darya River basin (ADRB) in Central Asia. We specifically considered a 40-year period (1960-2000) of large irrigation expansion, reduced river water flows, increased fertilizer application and net increase of N input into the soil-water system. Results showed that observed decreases in riverine DIN concentration near the Aral Sea outlet of ADRB primarily were due to increased recirculation of irrigation water, which extends the flow-path lengths and enhances N attenuation. The observed DIN concentrations matched a developed analytical relation between concentration attenuation and recirculation ratio, showing that a fourfold increase in basin-scale recirculation can increase DIN attenuation from 85 to 99%. Such effects have previously only been observed at small scales, in laboratory experiments and at individual agricultural plots. These results imply that increased recirculation can have contributed to observed increases in N attenuation in agriculturally dominated drainage basins in different parts of the world. Additionally, it can be important for basin scale attenuation of other pollutants, including phosphorous, metals and organic matter. A six-fold lower DIN export from ADRB during the period 1981-2000, compared to the period 1960-1980, was due to the combined result of drastic river flow reduction of almost 70%, and decreased DIN concentrations at the basin outlet. Several arid and semi-arid regions around the world are projected to undergo similar reductions in discharge as the ADRB due to climate change and agricultural intensification, and may therefore undergo comparable shifts in DIN export as shown here for the ADRB. For example, projected future increases of irrigation water withdrawals between 2005 and 2050 may decrease the DIN export from arid world regions by 40%. PMID- 25789867 TI - Dispersing carbon nanotubes by chiral network surfactants. AB - Chiral network surfactants (CNSs) possessing miscibility with carbon nanotubes (CNTs) and chiral materials are applied to disperse CNTs. Ultraviolet-visible absorption spectroscopy is used to quantitatively determine the CNT concentration in homogeneous CNT-CNS dispersions, results indicate that CNSs with more mole fraction of polycyclic conjugated structure have better ability to load and disperse CNTs and the maximal concentration reaches 0.79 mg mL(-1). Fourier transform infrared imaging system is utilized to analyze the dispersibility of CNTs in CNT-CNS composites, and CNS with 6 mol % nonmesogens (S6) induces the best dispersibility. The CNT doped CNSs exhibit lower glass transition temperature, strengthened thermal stability, decreased the thermochromic temperature and enriched reflected colors of CNSs. Furthermore, S6 are used as a promoter to disperse CNTs in chiral host, here, a left-handed chiral liquid crystal (CLC) is selected, the miscibility between CNTs and CLCs is studied by polarized optical microscope, and CNTs can be effectively dispersed in CLCs by S6. The CNT dispersed CLCs can exhibit a faster electro-optical response process than neat CLCs. PMID- 25789868 TI - Sympathoadrenal activation and endothelial damage are inter correlated and predict increased mortality in patients resuscitated after out-of-hospital cardiac arrest. a post Hoc sub-study of patients from the TTM-trial. AB - OBJECTIVE: Sympathoadrenal activation and endothelial damage are hallmarks of acute critical illness. This study investigated their association and predictive value in patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: Post-hoc analysis of patients included at a single site in The Targeted Temperature Management at 33 degrees versus 36 degrees after Cardiac Arrest (TTM) trial. The main study reported similar outcomes with targeting 33 versus 36 degrees. TTM main study ClinicalTrials.gov: NCT01020916. One hundred sixty three patients resuscitated from OHCA were included at a single site ICU. Blood was sampled a median 135 min (Inter Quartile Range (IQR) 103-169) after OHCA. Plasma catecholamines (adrenaline, noradrenaline) and serum endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) were measured at admission (immediately after randomization). We had access to data on demography, medical history, characteristics of the OHCA, patients and 180-day outcome. RESULTS: Adrenaline and noradrenaline correlated positively with syndecan-1 and thrombomodulin i.e., biomarkers reflecting endothelial damage (both p<0.05). Overall 180-day mortality was 35%. By Cox analyses, plasma adrenaline, serum sE selectin, reflecting endothelial cell activation, and thrombomodulin levels predicted mortality. However, thrombomodulin was the only biomarker independently associated with mortality after adjusting for gender, age, rhythm (shockable vs. non-shockable), OHCA to return of spontaneous circulation (ROSC) time, shock at admission and ST elevation myocardial infarction (30-day Hazards Ratio 1.71 (IQR 1.05-2.77), p=0.031 and 180-day Hazards Ratio 1.65 (IQR 1.03-2.65), p=0.037 for 2 fold higher thrombomodulin levels). CONCLUSIONS: Circulating catecholamines and endothelial damage were intercorrelated and predicted increased mortality. Interventions aiming at protecting and/or restoring the endothelium may be beneficial in OHCA patients. PMID- 25789870 TI - Different conformational dynamics of PDZ1 and PDZ2 in full-length EBP50 analyzed by hydrogen/deuterium exchange mass spectrometry. AB - Ezrin-radixin-moesin-binding protein 50 (EBP50) is a scaffolding protein expressed in polarized epithelial cells in various organs, including the liver, kidney, and small intestine, in which it regulates the trafficking and targeting cellular proteins. EBP50 contains two postsynaptic density-95/disk-large/ZO-1 homology (PDZ) domains (e.g., PDZ1 and PDZ2) and an ezrin/radixin/moesin-binding (EB) domain. PDZ domains are one of the major scaffolding domains regulating protein-protein interactions with critical biological roles in cell polarity, migration, proliferation, recognition, and cell-cell interaction. PDZ1 and PDZ2 in EBP50 have different ligand selectivity, although several high-resolution structural studies of isolated PDZ1 and PDZ2 showed similar structures. We studied the conformations of full-length EBP50 and isolated PDZ1 and PDZ2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS). The deuterium uptake profiles of isolated PDZ1 and PDZ2 were similar to those of full-length EBP50. Interestingly, PDZ1 was more dynamic than PDZ2, and these PDZ domains underwent different conformational changes upon ligand binding. These results might explain the differences in ligand-selectivity between PDZ1 and PDZ2. PMID- 25789871 TI - Membrane-active macromolecules resensitize NDM-1 gram-negative clinical isolates to tetracycline antibiotics. AB - Gram-negative 'superbugs' such as New Delhi metallo-beta-lactamase-1 (blaNDM-1) producing pathogens have become world's major public health threats. Development of molecular strategies that can rehabilitate the 'old antibiotics' and halt the antibiotic resistance is a promising approach to target them. We report membrane active macromolecules (MAMs) that restore the antibacterial efficacy (enhancement by >80-1250 fold) of tetracycline antibiotics towards blaNDM-1 Klebsiella pneumonia and blaNDM-1 Escherichia coli clinical isolates. Organismic studies showed that bacteria had an increased and faster uptake of tetracycline in the presence of MAMs which is attributed to the mechanism of re-sensitization. Moreover, bacteria did not develop resistance to MAMs and MAMs stalled the development of bacterial resistance to tetracycline. MAMs displayed membrane active properties such as dissipation of membrane potential and membrane permeabilization that enabled higher uptake of tetracycline in bacteria. In-vivo toxicity studies displayed good safety profiles and preliminary in-vivo antibacterial efficacy studies showed that mice treated with MAMs in combination with antibiotics had significantly decreased bacterial burden compared to the untreated mice. This report of re-instating the efficacy of the antibiotics towards blaNDM-1 pathogens using membrane-active molecules advocates their potential for synergistic co-delivery of antibiotics to combat Gram-negative superbugs. PMID- 25789872 TI - Plasma omentin-1 levels are related to exercise performance in obese women and increase upon aerobic endurance training. AB - INTRODUCTION: Omentin-1 is an adipokine that is primarily released from visceral adipose tissue stromal cells. The effects of exercise on omentin-1 regulation are not clear so far. Therefore, the effect of endurance training on circulating omentin-1 levels and its relation to exercise performance was assessed in obese women. METHODS: 13 obese women (age: 44.8+/-3.3 years; BMI: 37.8+/-1.3 kg.m(-2)) participated in a 6-week endurance training program. Omentin-1, metabolic traits (glucose, insulin, HOMA-IR, lipids profile), and exercise performance (cardiopulmonary exercise test (VO2,peak, Wpeak), 6 min walking test, 6MWT) were assessed before and after the training. RESULTS: After the training program circulating omentin-1 were 10.4% higher than before the program (690+/-50 ng.ml( 1) vs. 618+/-42; p=0.04), while body weight remained unchanged (p=0.9). Before training, omentin-1 levels were significantly correlated with Wpeak (given in absolute and relative values) as well as with 6MWT (all r>=0.603; all p<=0.029) and the correlations with absolute as well as relativeVO2,peak approached significance (both r>=0.534; both p<=0.060). After training, respective correlations were generally weaker and did not reach significance any longer (all r<=0.465; all p>=0.109). Neither before nor after the training program were significant correlations found between omentin-1 levels and the other measured metabolic blood markers (all p>=0.157). DISCUSSION: Data show a rather strong relationship between exercise performance and circulating omentin-1 levels as well as an increase of the adipokine in response to 6-week of endurance training in obese women. Our findings may hint to a skeletal muscle-adipose tissue crosstalk in regard of omentin-1 regulation. PMID- 25789873 TI - Phosphorylation-dependent degradation of MEF2C contributes to regulate G2/M transition. AB - The Myocyte Enhancer Factor 2C (MEF2C) transcription factor plays a critical role in skeletal muscle differentiation, promoting muscle-specific gene transcription. Here we report that in proliferating cells MEF2C is degraded in mitosis by the Anaphase Promoting Complex/Cyclosome (APC/C) and that this downregulation is necessary for an efficient progression of the cell cycle. We show that this mechanism of degradation requires the presence on MEF2C of a D-box (R-X-X-L) and 2 phospho-motifs, pSer98 and pSer110. Both the D-box and pSer110 motifs are encoded by the ubiquitous alternate alpha1 exon. These two domains mediate the interaction between MEF2C and CDC20, a co-activator of APC/C. We further report that in myoblasts, MEF2C regulates the expression of G2/M checkpoint genes (14-3 3gamma, Gadd45b and p21) and the sub-cellular localization of CYCLIN B1. The importance of controlling MEF2C levels during the cell cycle is reinforced by the observation that modulation of its expression affects the proliferation rate of colon cancer cells. Our findings show that beside the well-established role as pro-myogenic transcription factor, MEF2C can also function as a regulator of cell proliferation. PMID- 25789874 TI - Evaluating the impact of the community-based health planning and services initiative on uptake of skilled birth care in Ghana. AB - BACKGROUND: The Community-based Health Planning and Services (CHPS) initiative is a major government policy to improve maternal and child health and accelerate progress in the reduction of maternal mortality in Ghana. However, strategic intelligence on the impact of the initiative is lacking, given the persistant problems of patchy geographical access to care for rural women. This study investigates the impact of proximity to CHPS on facilitating uptake of skilled birth care in rural areas. METHODS AND FINDINGS: Data from the 2003 and 2008 Demographic and Health Survey, on 4,349 births from 463 rural communities were linked to georeferenced data on health facilities, CHPS and topographic data on national road-networks. Distance to nearest health facility and CHPS was computed using the closest facility functionality in ArcGIS 10.1. Multilevel logistic regression was used to examine the effect of proximity to health facilities and CHPS on use of skilled care at birth, adjusting for relevant predictors and clustering within communities. The results show that a substantial proportion of births continue to occur in communities more than 8 km from both health facilities and CHPS. Increases in uptake of skilled birth care are more pronounced where both health facilities and CHPS compounds are within 8 km, but not in communities within 8 km of CHPS but lack access to health facilities. Where both health facilities and CHPS are within 8 km, the odds of skilled birth care is 16% higher than where there is only a health facility within 8km. CONCLUSION: Where CHPS compounds are set up near health facilities, there is improved access to care, demonstrating the facilitatory role of CHPS in stimulating access to better care at birth, in areas where health facilities are accessible. PMID- 25789875 TI - Determining antioxidant activities of lactobacilli cell-free supernatants by cellular antioxidant assay: a comparison with traditional methods. AB - Antioxidant activity of lactic acid bacteria is associated with multiple health protective effects. Traditional indexes of chemical antioxidant activities poorly reflect the antioxidant effects of these bacteria in vivo. Cellular antioxidant activity (CAA) assay was used in this study to determine the antioxidant activity of cell-free supernatants (CFSs) of 10 Lactobacillus strains. The performance of the CAA assay was compared with that of four chemical antioxidant activity assays, namely, DPPH radical scavenging, hydroxyl radical scavenging (HRS), reducing power (RP), and inhibition of linoleic acid peroxidation (ILAP). Results of the CAA assay were associated with those of DPPH and ILAP assays, but not with those of RP and HRS assays. The inter- and intra-specific antioxidant activities of CFS were characterized by chemical and CAA assays. L. rhamnosus CCFM 1107 displayed a high antioxidative effect similar to positive control L. rhamnosus GG ATCC 53103 in all of the assays. The CAA assay is a potential method for the detection of antioxidant activities of lactobacilli CFSs. PMID- 25789877 TI - Unconventional resistive switching behavior in ferroelectric tunnel junctions. AB - We investigate an unconventional resistive switching (RS) behavior in La0.67Sr0.33MnO3/BaTiO3/metal (LSMO/BTO) ferroelectric tunnel junctions (FTJs), which is dominated by the variation of the barrier potential profile modulated by the migration of oxygen vacancies in the p-LSMO/n-BTO junction. The LSMO/BTO/Co junction exhibits a remarkable self-rectifying effect ascribed to the high density interface state at the BTO/Co interface, in contrast to the symmetric conductivity when the top metal electrode is inert Pt. The effects of ferroelectric polarization on the RS behavior are also emphasized. Our work builds a bridge between FTJs and resistive random access memory devices. PMID- 25789876 TI - Arfaptin-1 negatively regulates Arl1-mediated retrograde transport. AB - The small GTPase Arf-like protein 1 (Arl1) is well known for its role in intracellular vesicular transport at the trans-Golgi network (TGN). In this study, we used differential affinity chromatography combined with mass spectrometry to identify Arf-interacting protein 1b (arfaptin-1b) as an Arl1 interacting protein and characterized a novel function for arfaptin-1 (including the arfaptin-1a and 1b isoforms) in Arl1-mediated retrograde transport. Using a Shiga-toxin subunit B (STxB) transportation assay, we demonstrated that knockdown of arfaptin-1 accelerated the retrograde transport of STxB from the endosome to the Golgi apparatus, whereas Arl1 knockdown inhibited STxB transport compared with control cells. Arfaptin-1 overexpression, but not an Arl1 binding-defective mutant (arfaptin-1b-F317A), consistently inhibited STxB transport. Exogenous arfaptin-1 expression did not interfere with the localization of the Arl1 interacting proteins golgin-97 and golgin-245 to the TGN and vice versa. Moreover, we found that the N-terminal region of arfaptin-1 was involved in the regulation of retrograde transport. Our results show that arfaptin-1 acts as a negative regulator in Arl1-mediated retrograde transport and suggest that different functional complexes containing Arl1 form in distinct microdomains and are responsible for different functions. PMID- 25789878 TI - Defective interfaces in yttrium-doped barium zirconate films and consequences on proton conduction. AB - Yttrium-doped barium zirconate (BZY) thin films recently showed surprising electric transport properties. Experimental investigations conducted mainly by electrochemical impedance spectroscopy suggested that a consistent part of this BZY conductivity is of protonic nature. These results have stimulated further investigations by local unconventional techniques. Here, we use electrochemical strain microscopy (ESM) to detect electrochemical activity in BZY films with nanoscale resolution. ESM in a novel cross-sectional measuring setup allows the direct visualization of the interfacial activity. The local electrochemical investigation is compared with the structural studies performed by state of art scanning transmission electron microscopy (STEM). The ESM and STEM results show a clear correlation between the conductivity and the interface structural defects. We propose a physical model based on a misfit dislocation network that introduces a novel 2D transport phenomenon, whose fingerprint is the low activation energy measured. PMID- 25789879 TI - Checking the cycle by ERRbeta splice variants. PMID- 25789869 TI - Amyloid beta Protein and Alzheimer's Disease: When Computer Simulations Complement Experimental Studies. PMID- 25789880 TI - Multidimensional mapping method using an arrayed sensing system for cross reactivity screening. AB - When measuring chemical information in biological fluids, challenges of cross reactivity arise, especially in sensing applications where no biological recognition elements exist. An understanding of the cross-reactions involved in these complex matrices is necessary to guide the design of appropriate sensing systems. This work presents a methodology for investigating cross-reactions in complex fluids. First, a systematic screening of matrix components is demonstrated in buffer-based solutions. Second, to account for the effect of the simultaneous presence of these species in complex samples, the responses of buffer-based simulated mixtures of these species were characterized using an arrayed sensing system. We demonstrate that the sensor array, consisting of electrochemical sensors with varying input parameters, generated differential responses that provide synergistic information of sample. By mapping the sensing array response onto multidimensional heat maps, characteristic signatures were compared across sensors in the array and across different matrices. Lastly, the arrayed sensing system was applied to complex biological samples to discern and match characteristic signatures between the simulated mixtures and the complex sample responses. As an example, this methodology was applied to screen interfering species relevant to the application of schizophrenia management. Specifically, blood serum measurement of antipsychotic clozapine and antioxidant species can provide useful information regarding therapeutic efficacy and psychiatric symptoms. This work proposes an investigational tool that can guide multi-analyte sensor design, chemometric modeling and biomarker discovery. PMID- 25789881 TI - Education to a Healthy Lifestyle Improves Symptoms and Cardiovascular Risk Factors - AsuRiesgo Study. AB - BACKGROUND: Cardiovascular diseases are the current leading causes of death and disability globally. OBJECTIVE: To assess the effects of a basic educational program for cardiovascular prevention in an unselected outpatient population. METHODS: All participants received an educational program to change to a healthy lifestyle. Assessments were conducted at study enrollment and during follow-up. Symptoms, habits, ATP III parameters for metabolic syndrome, and American Heart Association's 2020 parameters of cardiovascular health were assessed. RESULTS: A total of 15,073 participants aged >= 18 years entered the study. Data analysis was conducted in 3,009 patients who completed a second assessment. An improvement in weight (from 76.6 +/- 15.3 to 76.4 +/- 15.3 kg, p = 0.002), dyspnea on exertion NYHA grade II (from 23.4% to 21.0%) and grade III (from 15.8% to 14.0%) and a decrease in the proportion of current active smokers (from 3.6% to 2.9%, p = 0.002) could be documented. The proportion of patients with levels of triglycerides > 150 mg/dL (from 46.3% to 42.4%, p < 0.001) and LDL cholesterol > 100 mg/dL (from 69.3% to 65.5%, p < 0.001) improved. A >= 20% improvement of AHA 2020 metrics at the level graded as poor was found for smoking (-21.1%), diet ( 29.8%), and cholesterol level (-23.6%). A large dropout as a surrogate indicator for low patient adherence was documented throughout the first 5 visits, 80% between the first and second assessments, 55.6% between the second and third assessments, 43.6% between the third and fourth assessments, and 38% between the fourth and fifth assessments. CONCLUSION: A simple, basic educational program may improve symptoms and modifiable cardiovascular risk factors, but shows low patient adherence. PMID- 25789882 TI - Evolution of Cardiovascular Diseases Mortality in the Counties of the State of Rio de Janeiro from 1979 to 2010. AB - BACKGROUND: Cardiovascular Diseases (CVD) are the leading cause of death in Brazil. OBJECTIVE: To estimate total CVD, cerebrovascular disease (CBVD), and ischemic heart disease (IHD) mortality rates in adults in the counties of the state of Rio de Janeiro (SRJ), from 1979 to 2010. METHODS: The counties of the SRJ were analysed according to their denominations stablished by the geopolitical structure of 1950, Each new county that have since been created, splitting from their original county, was grouped according to their former origin. Population Data were obtained from the Brazilian Institute of Geography and Statistics (IBGE), and data on deaths were obtained from DataSus/MS. Mean CVD, CBVD, and IHD mortality rates were estimated, compensated for deaths from ill-defined causes, and adjusted for age and sex using the direct method for three periods: 1979 1989, 1990-1999, and 2000-2010, Such results were spatially represented in maps. Tables were also constructed showing the mortality rates for each disease and year period. RESULTS: There was a significant reduction in mortality rates across the three disease groups over the the three defined periods in all the county clusters analysed, Despite an initial mortality rate variation among the counties, it was observed a homogenization of such rates at the final period (2000-2010). The drop in CBVD mortality was greater than that in IHD mortality. CONCLUSION: Mortality due to CVD has steadily decreased in the SRJ in the last three decades. This reduction cannot be explained by greater access to high technology procedures or better control of cardiovascular risk factors as these facts have not occurred or happened in low proportion of cases with the exception of smoking which has decreased significantly. Therefore, it is necessary to seek explanations for this decrease, which may be related to improvements in the socioeconomic conditions of the population. PMID- 25789883 TI - Predictors of Conversion from Radial Into Femoral Access in Cardiac Catheterization. AB - BACKGROUND: Fewer bleeding complications and early ambulation make radial access a privileged route for cardiac catheterization. However, transradial (TR) approach is not always successful, requiring its conversion into femoral access. OBJECTIVES: To evaluate the rate of conversion from radial into femoral access in cardiac catheterization and to identify its predictors. METHODS: Prospective dual center registry, including 7632 consecutive patients undergoing catheterization via the radial access between Jan/2009 and Oct/2012. We evaluated the incidence of conversion into femoral access and its predictors by logistic regression analysis. RESULTS: The patients' mean age was 66 +/- 11 years, and 32% were women. A total of 2969 procedures (38.4%) were percutaneous coronary interventions (PCI), and the most used first intention arterial access was the right radial artery (97.6%). Radial access failure rate was 5.8%. Independent predictors of conversion from radial into femoral access were the use of short introducer sheaths (OR 3.047, CI: 2.380-3.902; p < 0.001), PCI (OR 1.729, CI: 1.375-2.173; p < 0.001), female sex (OR 1.569, CI: 1.234-1.996; p < 0.001), multivessel disease (OR 1.457, CI: 1.167-1.819; p = 0.001), body surface area (BSA) <= 1.938 (OR 1.448, CI: 1.120-1.871; p = 0.005) and age > 66 years (OR 1.354, CI: 1.088-1.684; p = 0.007). CONCLUSION: Transradial approach for cardiac catheterization has a high success rate and the need for its conversion into femoral access in this cohort was low. Female sex, older age, smaller BSA, the use of short introducer sheaths, multivessel disease and PCI were independent predictors of conversion into femoral access. PMID- 25789884 TI - Morphological mutations: lessons from the cockscomb. PMID- 25789885 TI - Instrument and method to determine the electrophoretic mobility of nanoparticles and proteins by combining electrical and flow field-flow fractionation. AB - A new FFF method is presented which combines asymmetrical flow-FFF (AF4) and electrical FFF (ElFFF) in one channel to electrical asymmetrical flow-FFF (EAF4) to overcome the restrictions of pure ElFFF. It allows for measuring electrophoretic mobility (MU) as a function of size. The method provides an absolute value and does not require calibration. Results of MU for two particle standards are in good agreement with values determined by phase analysis light scattering (PALS). There is no requirement for low ionic strength carriers with EAF4. This overcomes one of the main limitations of ElFFF, making it feasible to measure proteins under physiological conditions. EAF4 has the capability to determine MU for individual populations which are resolved into separate peaks. This is demonstrated for a mixture of three polystyrene latex particles with different sizes as well as for the monomer and dimer of BSA and an antibody. The experimental setup consists of an AF4 channel with added electrodes; one is placed beneath the frit at the bottom wall and the other covers the inside of the upper channel plate. This design minimizes contamination from the electrolysis reactions by keeping the particles distant from the electrodes. In addition the applied voltage range is low (1.5-5 V), which reduces the quantity of gaseous electrolysis products below a threshold that interferes with the laminar flow profile or detector signals. Besides measuring MU, the method can be useful to improve the separation between sample components compared to pure flow-FFF. For two proteins (BSA and a monoclonal antibody), enhanced resolution of the monomer and dimer is achieved by applying an electric field. PMID- 25789887 TI - Palladium-catalyzed alpha-arylation of carbonyls in the de novo synthesis of aromatic heterocycles. AB - Aromatic heterocycles are a very well represented motif in natural products and have found various applications in chemistry and material science, as well as being commonly found in pharmaceutical agents. Thus, new and efficient routes towards this class of compound are always desirable, particularly if they expand the scope of chemical methodology or facilitate more effective pathways to complex substitution patterns. This perspective covers recent developments in the de novo synthesis of aromatic heterocycles via palladium-catalysed alpha arylation reactions of carbonyls, which is itself a powerful transformation that has undergone significant development in recent years. PMID- 25789888 TI - Postgraduate training and support. PMID- 25789886 TI - Integrating epigenetic modulators into NanoScript for enhanced chondrogenesis of stem cells. AB - N-(4-Chloro-3-(trifluoromethyl)phenyl)-2-ethoxybenzamide (CTB) is a small molecule that functions by altering the chromatin architecture to modulate gene expression. We report a new CTB derivative with increased solubility and demonstrate CTB's functionality by conjugating it on the recently established NanoScript platform to enhance gene expression and induce stem cell differentiation. NanoScript is a nanoparticle-based artificial transcription factor that emulates the structure and function of transcription factor proteins (TFs) to effectively regulate endogenous gene expression. Modifying NanoScript with CTB will more closely replicate the TF structure and enhance CTB functionality and gene expression. To this end, we first conjugated CTB onto NanoScript and initiated a time-dependent increase in histone acetyltransferase activity. Next, because CTB is known to trigger the pathway involved in regulating Sox9, a master regulator of chondrogenic differentiation, we modifed a Sox9-specific NanoScript with CTB to enhance chondrogenic gene activity and differentiation. Because NanoScript is a tunable and robust platform, it has potential for various gene-regulating applications, such as stem cell differentiation. PMID- 25789889 TI - Writing for publication and avoiding pitfalls. PMID- 25789890 TI - Training across boundaries. AB - BACKGROUND: This project arises from recent literature that has challenged a conventional view of training as being professional-specific or 'silo' based. Various authors have recommended that to train psychiatrists for the future, it will be helpful to provide opportunities for exposure to different medical specialties, including general practice. METHODOLOGY: Training Across Boundaries (TAB) started in February 2013, aiming to develop training links between core psychiatry and medical specialties and primary care. The project encouraged the use of up to six sessions in a medical speciality or in primary care during a 6 month core psychiatry placement, and evaluated the benefits gained from this experience. Feedback was obtained from all the participants by means of structured interviews. To train psychiatrists it will be helpful to provide opportunities for exposure to different medical specialties RESULTS: Results from the structured interviews with the participants are presented. Overall the project seems to have broadly achieved its aims, in the first year of activity. DISCUSSION AND CONCLUSIONS: The pilot programme seems to have opened up opportunities for cooperation and learning between doctors from different disciplines. The experience of TAB has helped trainees to see many of the commonalities of practice, but also the cultural differences that operate in different parts of the health service. The results of the project show us that we need to think more about the potential value of bringing training in psychiatry, primary care and medical specialties closer, to improve the breadth and quality of training and patient care. PMID- 25789891 TI - Bullying workshops for obstetric trainees: a way forward. AB - BACKGROUND: In sector-wide surveys, trainees in obstetrics and gynaecology have consistently reported the experience of being undermined in the workplace. Bullying has serious implications within the UK's National Health Service (NHS), for both the individual experiencing it and the wider system. CONTEXT: Obstetrics and gynaecology is a high-pressure specialty: the workload is intense, staffing is often suboptimal and litigation levels are high. Obstetrics alone accounted for 50 per cent of litigation claims in the NHS in 2012. This 'cocktail', when combined with the target-based management style common in the current financial climate, easily lends itself to a culture of bullying. INNOVATION: In order to manage this problem a workshop was developed with the initial aim of raising awareness, entitled 'Undermining and Harassment: A Practical Workshop for Trainees'. A typical workshop comprises the following interlinking topics relevant to bullying: (1) what is bullying (interactive session); (2) case scenarios (based on real events) and discussion (audiovisual clips); (3) how bullying affects patient safety (presentation); (4) how to support senior staff displaying bullying behaviour (interactive session); (5) how to be assertive without being aggressive (role-play); and (6) practical tips, including the 'Survivors' Guide to Bullying' (interactive session). EVALUATION: These workshops were designed as practical tools to raise awareness of workplace harassment, and not as a research project to assess the longitudinal impact of the workshops. Feedback from six such workshops as well as informal focus groups from trainees who had previously attended indicated that the subject was useful and necessary. CONCLUSION: The aim of the workshops was to raise awareness of bullying and undermining in the workplace, and the serious implications they can have for the individual, patients and the NHS as a whole. This will enable a positive culture shift and encourage health care professionals to think before they speak or act. PMID- 25789892 TI - Teaching: aligning faculty member and resident perceptions. AB - PURPOSE: This study sought to examine and address concerns received from residents regarding their perception of the length of time faculty members devoted to intraoperative teaching. METHOD: Faculty members and residents were surveyed on their perceptions of intraoperative teaching. The survey was evaluated using descriptive methods. A disparity was noted between faculty member and resident perceptions of time devoted to intraoperative teaching. To better understand the disparity, a series of focus groups to discuss the survey results were held with both faculty members and residents. To address the disparity, a teaching tool was developed using the keywords of the American Board of Anesthesiology's in-training examination. Faculty members and residents used this tool in the intraoperative environment for 2 months. After 2 months, faculty members and residents were surveyed to see whether a change in perception took place. The use of the teaching tool was continued. Faculty members and residents were surveyed after 1 year of continued use to assess usage and satisfaction with the tool. RESULTS: The pre-intervention survey yielded responses from 29.6 per cent (n = 64) of the teaching faculty members and 29.2 per cent (n = 24) of the residents. The post-intervention survey yielded responses from 64 per cent of the faculty members and 62.5 per cent of the residents. After implementation of the tool, an improved alignment of resident and faculty member perceptions of the time faculty members spent teaching intraoperatively was observed. The majority of faculty members and residents reported continued use and satisfaction with the keyword tool after 1 year of use. DISCUSSION: This experience revealed the importance of making simple, pragmatic changes to improve resident perceptions of intraoperative teaching time. PMID- 25789893 TI - Bedside rounds versus board rounds in an emergency department. AB - BACKGROUND: Our objective was to gain insight into whether bedside rounding at shift turnover in the emergency department improved education quality, as compared with board rounds. Board rounds are commonly used in the emergency department, where the teams review the patient and transfer care near a computer screen or written board, rather than at the patient's bedside. The impact on teaching or patient care has not been extensively compared between the two approaches. METHODS: We conducted a prospective study in an academic emergency department to compare bedside rounds versus board rounds. A convenience sample of 408-hour clinical shifts were randomised to either bedside or board rounds. Data collected included frequency of discussion of differential diagnosis, questions asked per patient, total time for which alternative therapies were discussed, total time for which alternative tests were discussed, total time for which exam findings were discussed and demonstrated, and resident impression of education quality. RESULTS: The randomisation of 20 shifts in each cohort provided a total of 274 patient cases. Our primary outcome was an increased frequency of discussion of the differential diagnosis, which occurred more often in the bedside group (72 versus 53%). We also detected that with bedside rounding more questions per patient were asked, and alternative therapies and tests, exam findings and results were discussed more often. CONCLUSIONS: Bedside rounding in the emergency department, as compared with board rounding, appears to increase the frequency of learner education measures. Emergency medicine residents reported the quality of education was better with bedside rounding. Bedside rounds took on average 4 minutes longer, without achieving statistical significance. PMID- 25789894 TI - A workshop to introduce residents to effective handovers. AB - BACKGROUND: Patient safety is associated with the quality of handover, yet many residents train in settings that lack a formal procedure for handover. Thus, they have few opportunities to observe or participate in effective practices. The purpose of our project was to design an educational experience that would introduce residents to the essentials of an effective handover. CONTEXT: Through a review of the literature, conversations with our residents and teaching doctors, and needs analysis survey, we determined that a formal, didactic, large group, face-to-face educational experience focusing on lower-level educational objectives would meet the needs of our learners. INNOVATION: Our curriculum development culminated in a 90-minute, multifaceted workshop comprising a brief introduction to handover, a dramatisation of effective and ineffective practices, and a role-play activity, followed by a debriefing session. IMPLICATIONS: Objective, constructed response tests, administered before and after the workshop, suggested that the workshop provided residents with the knowledge that a good handover is structured, free of distraction and prioritised. Some of the misconceptions that were apparent at the beginning of the workshop, however, were unchanged by the learning activities. PMID- 25789895 TI - 'I see you're angry': actor-reported anger scores. AB - BACKGROUND: Teaching communication skills using role-play addresses an important learning need for medical students, with the debriefing process being central to the learning that occurs. In this work we examine the feasibility of using actor reported 'anger scores', during a challenging communication scenario, as a tool to stimulate debriefing. METHODS: This teaching session was delivered to 10 groups of final-year MBBS (Bachelor of Medicine and Bachelor of Surgery) students at Newcastle University. One student from each group took on the role of the foundation year 1 (F1) doctor and had 10 minutes to talk to an angry relative (actor), who was unhappy with the care her mother had received. During the scenario the actor recorded her level of anger on a 10-point Likert scale (1, 'no anger'; 10, 'extreme anger') at 1-minute intervals. Once the scenario was complete, the in-room tutor graphically presented these scores against time. During debriefing, students were asked to examine the graph produced: fluctuations in anger levels were identified, discussion was held regarding possible precipitants for the changes seen and strategies were developed for tackling future such incidents. RESULTS: Examples of graphs produced during the session are presented, including annotations highlighting the discussion topics that arose. Feedback on the session from both students and actor was positive, with no reports that the scoring process interfered with the fidelity of the scenario. DISCUSSION: We believe that actor-reported 'anger scores' provide a quick, simple and cheap method of producing a visual aid to the debriefing process that, in the context of a challenging communication scenario, provided a stimulus for discussion. PMID- 25789896 TI - Pre-interns: ready to perform? AB - BACKGROUND: There is an expectation that interns can perform the core procedural skill of male catheterisation; however, it is unclear if our medical graduates are competent to do so, because there is no formal practical skills exit assessment in our current programme. AIM: We sought to investigate the level of experience, the self-reported confidence, and measured competency of our pre intern (PRINT) students to perform the procedural skill of male catheterisation. METHODS: We asked 100/147 (68%) PRINT students to complete a questionnaire to elucidate their experience and confidence prior to being practically assessed on a plastic manikin, using a faculty member validated 26-item checklist. Students were also invited to attend focus groups to help identify factors that had contributed to their practical performance. RESULTS: Between 2010 and 2012, 100/147 (68%) PRINT students completed a questionnaire prior to being formatively assessed. The mean score for self-reported confidence was 78.3/100 (95% CI 74.8 81.8), and the mean performance score was 85.6/100 (95% CI 83.2-87.9); however, the correlation coefficient between the confidence score and performance score was weak (r = 0.18). Three focus groups were conducted, with a total of 12/100 (12%) students attending. Although students reported that they had sound knowledge of the skill, the lack of opportunity to perform the skill in the clinical setting had led to mediocre performance outcomes. CONCLUSION: We found no significant correlation among the level of experience, the self-reported ability and actual performance when students were assessed under direct observation. PMID- 25789897 TI - A prolonged assistantship for final-year students. AB - BACKGROUND: The transition from medical student to junior doctor is challenging, therefore adequate preparation during medical school is crucial for a smooth transition. Tomorrow's Doctors expects students to undertake a student assistantship, separate from the local shadowing period prior to commencing employment. Sheffield Medical School initiated a 6-week assistantship within the Yorkshire and Humber deanery. This mixed-methodology study explores this experience from the perspective of final-year medical students. METHODS: Final year medical students responded to a questionnaire about anxieties surrounding their forthcoming foundation year 1 (FY1). Students were purposefully sampled and semi-structured interviews (SSIs) were conducted, with 20 participants exploring their experience of the assistantship. Interviews were transcribed verbatim and thematic analysis was carried out. RESULTS: The questionnaire results highlighted that most students felt anxious about becoming a FY1 doctor, and subsequent interviews demonstrate that the assistantship mostly met with students' expectations. Major themes regarding their anxieties included the value of building professional relationships, familiarisation with the work environment, level of supervision and the value of targeted teaching. DISCUSSION: Student assistantships clearly improve preparedness and confidence in the transition to FY1 by enabling supervised, stepwise responsibility. In the future a nationally cohesive programme should be created for shadowing and assistantships matched with students' prospective jobs. PMID- 25789899 TI - Role-play without humiliation: is it possible? PMID- 25789898 TI - Learning opportunities in 'student assistantships'. AB - BACKGROUND: In order to gain experience of the skills required when they begin practice, all final-year medical students in the UK undertake a 'student assistantship', working alongside first-year postgraduate doctors. In this study, we examined the learning opportunities open to students in one locality during two periods of assistantship: one in medicine; one in surgery. METHODS: Final year students and their supervisors completed online questionnaires. The students' questionnaire explored general perceptions of the placement, and whether 15 potential learning opportunities (identified as 'desk-' or 'patient oriented') had been 'taken', 'missed' or were 'not available'. The supervisors' questionnaire explored their perceptions of students' learning during the assistantship. RESULTS: Overall, 86 student questionnaires and 17 supervisor questionnaires were returned (response rates of 57 and 63%, respectively). Students reported more desk-based learning opportunities, of which more were taken up, than patient-oriented learning opportunities. Surgical placements were associated with more 'missed' opportunities than medical placements. Across all tasks, many students felt that some learning opportunities were not present in their assistantship. By contrast, supervisors felt students 'made the most' of assistantships. Students' overall perceptions of the assistantship were positively related to the level of experience that they had attained (r = 0.40 0.54). DISCUSSION: The assistantship fulfils its aims for many students, but individual experience gained varies considerably. Some opportunities are not being taken, with 'patient-oriented' opportunities more likely to be missed, whereas others are not available during placements. Supervisors may overestimate the educational value of the assistantship, with implications for its management and delivery. PMID- 25789900 TI - Continued professional development in rural Africa. PMID- 25789901 TI - Teaching medical students organisational behaviour. PMID- 25789902 TI - Clinical teaching fellows: best of both worlds? PMID- 25789908 TI - Teaching future surgeons: a step towards better training? PMID- 25789909 TI - Cutting edge: a further response. PMID- 25789910 TI - Social media: paternalism versus professionalism. PMID- 25789911 TI - Assessing the methodological quality of systematic reviews. PMID- 25789912 TI - Sorption mechanisms of organic compounds by carbonaceous materials: site energy distribution consideration. AB - Sorption of naphthalene, lindane, and atrazine on 10 kinds of carbonaceous materials which included four kinds of graphene, three kinds of graphite, two kinds of carbon nanotubes and one kind of mesoporous carbon was investigated. The approximate sorption site energy distributions were calculated based on Dubinin Ashtakhov (DA) model. The average sorption site energy and standard deviation of the site energy distribution were deduced and applied to analyze the interaction between sorbents and sorbates, and the sorption site heterogeneity. The introduction of oxygen-containing functional groups to the sorbents caused a decrease in their average sorption energy for the studied compounds. However, relative to the decrease in average site energy, the reduction in number of sorption sites as indicated by surface area more strongly reduced their sorption capacity to the tested carbonaceous materials based on the result of the linear regression analysis. Sorption site heterogeneity of the sorbents decreased as their oxygen contents increased, which is attributed to the better dispersion of the oxygen-containing materials as indicated by their TEM images. The method proposed in this study to quantify the average sorption site energy and heterogeneity is helpful for a better understanding of the sorption mechanisms of organic pollutants to carbonaceous materials. PMID- 25789913 TI - It Is Not Always the Pulmonary Embolism. AB - One of the leading reasons for emergency department visits happens to be chest pain and shortness of breath with estimated 6.3 million visits for chest pain and 3 million visits for shortness of breath. Over the years, there has been an upward trend in these demographics. The primary workup is usually toward cardio pulmonary causes. Paraesophageal hernia is a term to describe the herniation of gastroesophageal junction and the gastric fundus through the paraesophageal membrane. Paraesophageal hernias account for 5% of all the hiatal hernias, and patients are usually asymptomatic or have complaints of gastroesophageal reflux. However, on rare occasions, they are notorious to develop complications such as incarceration, gangrene, obstruction of intrathoracic stomach, collapse of the lung, and even death. We take this opportunity to present a 49-year-old man who presented with shortness of breath and chest pain. The initial workup revealed a pulmonary embolism on a computerized tomography scan. However, with better clinical judgment and more imaging, he was diagnosed with a paraesophageal hernia with gastric obstruction and early strangulation causing his symptoms. PMID- 25789914 TI - Epilepsy in Rett syndrome--lessons from the Rett networked database. AB - OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 +/- (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48 6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence. SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome. PMID- 25789915 TI - The hydrolyzable gallotannin, penta-O-galloyl-beta-D-glucopyranoside, inhibits the formation of advanced glycation endproducts by protecting protein structure. AB - Glycation is a spontaneous process initiated by a condensation reaction between reducing sugars and proteins that leads to the formation of advanced glycation endproducts (AGEs). The in vivo accumulation of AGEs is associated with several chronic human diseases and, thus, the search for AGE inhibitors is of great research interest. Hydrolyzable tannins (gallotannins and ellagitannins) are bioactive plant polyphenols which show promise as natural inhibitors of glycation and AGE formation. Notably, the gallotannin, 1,2,3,4,6-penta-O-galloyl-beta-D glucose (PGG), is a key intermediate involved in the biosynthesis of hydrolyzable tannins in plants. Herein, we investigated the effects of PGG on the individual stages of protein glycation and on protein structure (using bovine serum albumin; BSA). MALDI-TOF data demonstrated that PGG inhibited early glycation by 75% while the synthetic AGE inhibitor, aminoguanidine (AG), was not active (both at 50 MUM). In addition, PGG reduced the formation of middle and late stage AGEs by 90.1 and 60.5%, respectively, which was superior to the positive control, AG. While glycation induced conformational changes in BSA from alpha-helix to beta sheets (from circular dichroism and congo red binding studies), PGG (at 50 MUM) reduced this transition by 50%. Moreover, BSA treated with PGG was more stable in its structure and retained its biophysical properties (based on zeta potential and electrophoretic mobility measurements). The interaction between PGG and BSA was further supported by molecular docking studies. Overall, the current study adds to the growing body of data supporting the anti-AGE effects of hydrolyzable tannins, a ubiquitous class of bioactive plant polyphenols. PMID- 25789916 TI - Confinement of a tris-aqua Gd(iii) complex in silica nanoparticles leads to high stability and high relaxivity and supresses anion binding. AB - The water soluble tris-aqua complex [Gd(dhqN-SO3)(H2O)3](3-) based on a hexadentate hydroxyquinoline ligand shows high thermodynamic stability and high relaxivity (12.54 mM(-1) s(-1) at 1.2 T). Its non-covalent confinement in 25 nm silica nanoparticles prevents transmetallation and endogenous anion binding and leads to higher relaxivity over a wide range of magnetic fields. PMID- 25789918 TI - Self-Directed Learning Favors Local, Rather Than Global, Uncertainty. AB - Collecting (or "sampling") information that one expects to be useful is a powerful way to facilitate learning. However, relatively little is known about how people decide which information is worth sampling over the course of learning. We describe several alternative models of how people might decide to collect a piece of information inspired by "active learning" research in machine learning. We additionally provide a theoretical analysis demonstrating the situations under which these models are empirically distinguishable, and we report a novel empirical study that exploits these insights. Our model-based analysis of participants' information gathering decisions reveals that people prefer to select items which resolve uncertainty between two possibilities at a time rather than items that have high uncertainty across all relevant possibilities simultaneously. Rather than adhering to strictly normative or confirmatory conceptions of information search, people appear to prefer a "local" sampling strategy, which may reflect cognitive constraints on the process of information gathering. PMID- 25789917 TI - Screening magnetic resonance imaging recommendations and outcomes in patients at high risk for breast cancer. AB - The purpose of this study was to determine magnetic resonance imaging (MRI) screening recommendations and the subsequent outcomes in women with increased risk for breast cancer evaluated by oncology subspecialists at an academic center. Patients evaluated between 1/1/2007 and 3/1/2011 under diagnosis codes for family history of breast or ovarian cancer, genetic syndromes, lobular carcinoma in situ or atypical hyperplasia were included. Patients with a history of breast cancer were excluded. Retrospective review of prospectively acquired demographics, lifetime risk of breast cancer, and screening recommendations were obtained from the medical record. Retrospective review of the results of prospectively interpreted breast imaging examinations and image-guided biopsies were analyzed. 282 women were included. The majority of patients were premenopausal with a median age of 43. Most (69%) were referred due to a family history of breast or ovarian cancers. MRI was recommended for 84% of patients based on a documented lifetime risk >20%. Most women referred for MRI screening (88%) were compliant with this recommendation. A total of 299 breast MRI examinations were performed in 146 patients. Biopsy was performed for 32 (11%) exams and 10 cancers were detected for a positive predictive value (PPV) of 31% (based on biopsy performed) and an overall per exam cancer yield of 3.3%. Three cancers were detected in patients who did not undergo screening MRI. The 13 cancers were Stage 0-II; all patients were without evidence of disease with a median follow-up of 22 months. In a cohort of women seen by breast subspecialty providers, screening breast MRI was recommended according to guidelines, and used primarily in premenopausal women with a family history or genetic predisposition to breast cancer. Adherence to MRI screening recommendations was high and cancer yield from breast MRI was similar to that in clinical trials. PMID- 25789919 TI - A man with painful nodules on both ears. Chondrodermatitis nodularis chronica helicis. PMID- 25789920 TI - Validation of the Pancreas Donor Risk Index for use in a UK population. AB - Pancreas graft failure rates remain substantial. The PDRI can be used at the time of organ offering, to predict one-year graft survival. This study aimed to validate the PDRI for a UK population. Data for 1021 pancreas transplants were retrieved from a national database for all pancreas transplants. Cases were categorized by PDRI quartile and compared for death-censored graft survival. Significant differences were observed between the UK and US cohorts. The PDRI accurately discriminated graft survival for SPK and was associated with a hazard ratio of 1.52 (P = 0.009) in this group. However, in the PTA and PAK groups, no association between PDRI quartile and graft survival was observed. This is the largest study to validate the PDRI in a European cohort and has shown for the first time that the PDRI can be used as a tool to predict graft survival in SPK transplantation, but not PTA or PAK transplantation. PMID- 25789921 TI - Variation in incidence of pediatric Crohn's disease in relation to latitude and ambient ultraviolet radiation: a systematic review and analysis. AB - BACKGROUND: Pediatric Crohn's disease (CD) is a lifelong, debilitating, and costly disease. In previous studies, CD incidence increased with higher geographic latitude in the Northern Hemisphere. This may indicate a role for lower vitamin D status as a risk factor for CD. Analysis of worldwide incidence of pediatric CD has not been previously reported. METHODS: We undertook a systematic review of population-based studies reporting incidence of pediatric CD and published between 2003 and 2013. Included studies had well-defined diagnostic criteria for CD, evidence of high case ascertainment, reported incidence according to age group, and provided a specific location. Average daily ambient ultraviolet radiation (UVR) for each location was derived from satellite data. Negative binomial regression was used to assess the association between pediatric CD incidence and latitude and ambient UVR, adjusting for the study year. RESULTS: Twenty-eight articles provided 39 incidence data points. Incidence of pediatric CD increased with higher latitude, and in association with a greater number of months where the average daily UVR was lower than a previously published threshold of 1.488 kJ/m. Incidence of pediatric CD increased over calendar time. CONCLUSIONS: After applying rigorous quality assessment criteria, and including only population-based studies, there was a modest increase in incidence of pediatric CD with higher latitude and greater number of months with low ambient UVR. Reporting using nonconsistent diagnostic criteria and age groups, with poorly defined geographic locations, makes it difficult to compare data across different studies. PMID- 25789922 TI - Concomitant use of azathioprine/6-mercaptopurine decreases the risk of anti-TNF induced skin lesions. AB - BACKGROUND: Anti-tumor necrosis factor (anti-TNF) agents are widely used to treat patients with moderate-to-severe inflammatory bowel disease (IBD). We aimed to identify the risk factors for adverse skin lesions in patients with IBD receiving anti-TNF agents and assess the effect of concomitant use of azathioprine/6 mercaptopurine (AZA/6 MP). METHODS: A total of 500 patients (404 with Crohn's disease, 96 with ulcerative colitis) who received anti-TNF agents between June 2002 and July 2013 were identified and retrospectively investigated. We compared 47 patients with IBD with skin lesions with 443 patients with IBD without skin lesions to identify risk factors by univariate and multivariate analysis. The Kaplan-Meier method was used to estimate the cumulative incidence of adverse skin lesions in relation to the concomitant use of AZA/6 MP. RESULTS: Eczematiform eruptions (n = 18, 38%) were the most common skin lesion type, followed by psoriasiform lesions (n = 13, 28%). A response to topical steroids was seen in 70% (33/47) of patients with skin lesions, and anti-TNF agents had to be discontinued in 9% (4/47). Concomitant use of AZA/6 MP decreased the risk of skin lesions in univariate (hazard ratio, 0.452; 95% CI, 0.251-0.814; P = 0.008) and multivariate (hazard ratio, 0.437; 95% CI, 0.242-0.790; P = 0.006) analysis. In addition, the cumulative incidence of adverse skin lesions was lower in patients on concomitant maintenance with AZA/6 MP (P = 0.009) than in those on anti-TNF monotherapy. CONCLUSIONS: Concomitant use of AZA/6 MP may decrease the occurrence of adverse skin lesions in patients receiving anti-TNF therapy. PMID- 25789924 TI - Sexual dysfunction in inflammatory bowel disease: "don't ask, don't tell" doesn't work. PMID- 25789923 TI - Getting personal: a review of sexual functioning, body image, and their impact on quality of life in patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic relapsing disorder associated with distressing physical and psychological symptoms. Many patients with IBD have impaired quality of life. Sexual functioning and body image are rated high among concerns of patients with IBD and may impact quality of life. A better understanding of the roles of sexual functioning and body image in quality of life for patients with IBD is needed because improvement in quality of life is a primary therapeutic goal. The aim of this review was to summarize the current literature on sexual functioning and body image in patients with IBD, emphasizing their impact on quality of life. METHODS: An electronic search of the literature was conducted using the PubMed, PsycINFO, and Cochrane databases. Key phrases included: "Ulcerative Colitis/Crohn's disease/Inflammatory Bowel Disease and sexual function," and "Ulcerative Colitis/Crohn's disease/Inflammatory Bowel Disease and body image." The search produced 1284 citations. We identified 56 studies, which were conducted from 1990 through April 2014, written in English, and included at least 10 adults with IBD. CONCLUSIONS: Few studies have tested directly the association between quality of life and sexual functioning and body image among patients with IBD. Results preliminarily suggest a positive relationship between quality of life and sexual functioning and body image postoperatively among patients with IBD. Future studies comprised of patients who have not had surgery are necessary to better understand the relationship between sexual functioning, body image, and quality of life in patients with active and inactive IBD. PMID- 25789925 TI - Using a Narrative Approach to Enhance Clinical Care for Patients With Asthma. AB - There are currently > 230 million people in the world with asthma, and asthma attacks result in the hospitalization of someone every 7 min. The National Heart, Lung, and Blood Institute outlines four components of clinical practice guidelines for the diagnosis and management of asthma, which tend to take a biomedical focus: (1) measures of assessment and monitoring, obtained by objective tests, physical examination, patient history, and patient report, to diagnose and assess the characteristics and severity of asthma and to monitor whether asthma control is achieved and maintained; (2) education for a partnership in asthma care; (3) control of environmental factors and comorbid conditions that affect asthma; and (4) pharmacologic therapy. Many national guidelines include providing patients with asthma with (1) written action plans, (2) inhaler technique training, and (3) structured annual reviews. Although current guidelines help improve clinical processes of care for asthma, there is also a need to improve self-care of asthma by empowering individuals to take more control of their condition. There is a growing appreciation that a narrative approach with patients with asthma, which focuses on the illness experience and aims to enhance patient-clinician understanding, might improve self-care. We explore how a framework for clinicians to listen to patients' stories, developed from research on individuals with asthma, might enhance communication, improve patient-clinician relationship, and foster better patient self-care. The article closes with the implications of this approach for clinical practice and future research. PMID- 25789926 TI - Swedish public health policy: Impact on regional and local public health practice and priorities. AB - We evaluated the Swedish National Public Health Policy to determine its impact on public health priorities and practice at regional and local levels between 2004 and 2013. We conducted a survey by questionnaire in February 2013 among Swedish county councils/regions (n=19/21), and municipalities (n=219/290). The National Public Health Policy facilitated systematic public health practice, particularly for planning, for high priority concerns, including conditions during childhood and adolescence, physical activity, and tobacco prevention. Respondents expressed need for a comprehensive monitoring system with comparable indicators nationwide and explicit measurable objectives. To ensure effective monitoring and follow-up, the measurable outcomes need direct relevance to decision making and high priority public health issues addressing Sweden's "overarching public health goal" - to create societal conditions for good health on equal terms for the entire population. PMID- 25789927 TI - Nontraumatic hypotension and shock in the emergency department and the prehospital setting, prevalence, etiology, and mortality: a systematic review. AB - BACKGROUND: Acute patients presenting with hypotension in the prehospital or emergency department (ED) setting are in need of focused management and knowledge of the epidemiology characteristics might help the clinician. The aim of this review was to address prevalence, etiology and mortality of nontraumatic hypotension (SBP <= 90 mmHg) with or without the presence of shock in the prehospital and ED setting. METHODS: We performed a systematic literature search up to August 2013, using Medline, Embase, Cinahl, Dare and The Cochrane Library. The analysis and eligibility criteria were documented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-guidelines) and The Cochrane Collaboration. No restrictions on language, publication date, or status were imposed. We used the Newcastle-Ottawa quality assessment scale (NOS scale) and the Strengthening the Reporting of Observational studies in Epidemiology (STROBE-statement) to assess the quality. RESULTS: Six observational studies were considered eligible for analysis based on the evaluation of 11,880 identified papers. Prehospital prevalence of hypotension was 19.5/1000 emergency medicine service (EMS) contacts, and the prevalence of hypotensive shock was 9.5 19/1000 EMS contacts with an inhospital mortality of shock between 33 to 52%. ED prevalence of hypotension was 4-13/1000 contacts with a mortality of 12%. Information on mortality, prevalence and etiology of shock in the ED was limited. A meta-analysis was not feasible due to substantial heterogeneity between studies. CONCLUSION: There is inadequate evidence to establish concise estimates of the characteristics of nontraumatic hypotension and shock in the ED or in the prehospital setting. The available studies suggest that 2% of EMS contacts present with nontraumatic hypotension while 1-2% present with shock. The inhospital mortality of prehospital shock is 33-52%. Prevalence of hypotension in the ED is 1% with an inhospital mortality of 12%. Prevalence, etiology and mortality of shock in the ED are not well described. PMID- 25789929 TI - Synthesis of cysteine-rich peptides by native chemical ligation without use of exogenous thiols. AB - Native chemical ligation (NCL) performed without resorting to the use of thiol additives was demonstrated to be an efficient and effective procedure for synthesizing Cys-rich peptides. This method using tris(2-carboxyethyl)phosphine (TCEP) as a reducing agent facilitates the ligation reaction even at the Thr-Cys or Ile-Cys site and enables one-pot synthesis of Cys-rich peptides throughout NCL and oxidative folding. PMID- 25789928 TI - Modelling and analysis of the feeding regimen induced entrainment of hepatocyte circadian oscillators using petri nets. AB - Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system. PMID- 25789931 TI - AANEM's top five choosing wisely recommendations. AB - OBJECTIVE: To discuss the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM)'s Top Five Recommendations in the Choosing Wisely campaign educating physicians and patients on high quality electrodiagnostic and neuromuscular medicine. The AANEM published its Top Five Recommendations in February 2015 in collaboration with the American Board of Internal Medicine Foundation and Consumer Reports. METHODS: The Professional Practice Committee (PPC) of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) developed this list of recommendations. The PPC members identified areas to be included on this list based on the greatest potential for overuse/misuse, quality improvement,and availability of strong evidence-based research/support in the literature. RESULTS AND RECOMMENDATIONS: Recommendation 1: Don't do a needle electromyography (EMG) test for isolated neck or back pain after a motor vehicle accident, as a needle EMG is unlikely to be helpful. Recommendation 2: Don't perform dermatomal somatosensory evoked potentials (SEPs) for a pinched nerve in the neck or back, as they are an unproven diagnostic procedure. Recommendation 3: Don't do a four limb needle EMG/nerve conduction study (NCS) testing for neck and back pain after trauma. Recommendation 4: Don't do nerve conduction studies without also doing a needle EMG for testing for radiculopathy, a pinched nerve in the neck or back.Recommendation 5: Don't do a magnetic resonance imaging(MRI) scan of the spine or brain for patients with only peripheral neuropathy (without signs or symptoms suggesting a brain or spine disorder). PMID- 25789937 TI - VMATc: VMAT with constant gantry speed and dose rate. AB - This article considers the treatment plan optimization problem for Volumetric Modulated Arc Therapy (VMAT) with constant gantry speed and dose rate (VMATc). In particular, we consider the simultaneous optimization of multi-leaf collimator leaf positions and a constant gantry speed and dose rate. We propose a heuristic framework for (approximately) solving this optimization problem that is based on hierarchical decomposition. Specifically, an iterative algorithm is used to heuristically optimize dose rate and gantry speed selection, where at every iteration a leaf position optimization subproblem is solved, also heuristically, to find a high-quality plan corresponding to a given dose rate and gantry speed. We apply our framework to clinical patient cases, and compare the resulting VMATc plans to idealized IMRT, as well as full VMAT plans. Our results suggest that VMATc is capable of producing treatment plans of comparable quality to VMAT, albeit at the expense of long computation time and generally higher total monitor units. PMID- 25789930 TI - Role of 5-HT3 receptor on food intake in fed and fasted mice. AB - BACKGROUND: Many studies have shown that 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the regulation of feeding behavior. However, the relative contribution of 5-HT3 receptor remains unclear. The present study was aimed to investigate the role of 5-HT3 receptor in control of feeding behavior in fed and fasted mice. METHODOLOGY/PRINCIPAL FINDINGS: Food intake and expression of c-Fos, tyrosine hydroxylase (TH), proopiomelanocortin (POMC) and 5-HT in the brain were examined after acute treatment with 5-HT3 receptor agonist SR-57227 alone or in combination with 5-HT3 receptor antagonist ondansetron. Food intake was significantly inhibited within 3 h after acute treatment with SR 57227 in fasted mice but not fed mice, and this inhibition was blocked by ondansetron. Immunohistochemical study revealed that fasting-induced c-Fos expression was further enhanced by SR 57227 in the brainstem and the hypothalamus, and this enhancement was also blocked by ondansetron. Furthermore, the fasting-induced downregulation of POMC expression in the hypothalamus and the TH expression in the brain stem was blocked by SR 57227 in the fasted mice, and this effect of SR 57227 was also antagonized by ondansetron. CONCLUSION/SIGNIFICANCE: Taken together, our findings suggest that the effect of SR 57227 on the control of feeding behavior in fasted mice may be, at least partially, related to the c-Fos expression in hypothalamus and brain stem, as well as POMC system in the hypothalamus and the TH system in the brain stem. PMID- 25789938 TI - Traumatic brain injury and adverse life events: Group differences in young adults injured as children. AB - OBJECTIVES: To investigate whether individuals with a history of traumatic brain injury (TBI) experience a greater number of adverse life events (ALE) compared to controls, to identify significant predictors of experiencing ALE and whether the severity of childhood TBI negatively influences adult life outcomes. DESIGN: A total of 167 individuals, injured prior to age 18, 5 or more years post-injury and 18 or more years of age, were recruited in the Canterbury region of New Zealand, with 124 having sustained childhood TBI (62 mild, 62 moderate/severe) and 43 orthopaedic injury controls. Participants were asked about ALE they had experienced and other adult life outcomes. RESULTS: Individuals with a history of TBI experienced more ALE compared to controls. The number of ALE experienced by an individual was associated with more visits to the doctor, lower education level and lower satisfaction with material standard of living. CONCLUSIONS: Childhood TBI is associated with an increased number of ALE and adult negative life outcomes. Understanding factors that contribute to negative outcomes following childhood TBI will provide an avenue for rehabilitation and support to reduce any problems in adulthood. PMID- 25789940 TI - Heterolytic Activation of C-H Bonds on Cr(III)-O Surface Sites Is a Key Step in Catalytic Polymerization of Ethylene and Dehydrogenation of Propane. AB - We describe the reactivity of well-defined chromium silicates toward ethylene and propane. The initial motivation for this study was to obtain a molecular understanding of the Phillips polymerization catalyst. The Phillips catalyst contains reduced chromium sites on silica and catalyzes the polymerization of ethylene without activators or a preformed Cr-C bond. Cr(II) sites are commonly proposed active sites in this catalyst. We synthesized and characterized well defined chromium(II) silicates and found that these materials, slightly contaminated with a minor amount of Cr(III) sites, have poor polymerization activity and few active sites. In contrast, chromium(III) silicates have 1 order of magnitude higher activity. The chromium(III) silicates initiate polymerization by the activation of a C-H bond of ethylene. Density functional theory analysis of this process showed that the C-H bond activation step is heterolytic and corresponds to a sigma-bond metathesis type process. The same well-defined chromium(III) silicate catalyzes the dehydrogenation of propane at elevated temperatures with activities similar to those of a related industrial chromium based catalyst. This reaction also involves a key heterolytic C-H bond activation step similar to that described for ethylene but with a significantly higher energy barrier. The higher energy barrier is consistent with the higher pKa of the C-H bond in propane compared to the C-H bond in ethylene. In both cases, the rate-determining step is the heterolytic C-H bond activation. PMID- 25789939 TI - Bovine rhinitis viruses are common in U.S. cattle with bovine respiratory disease. AB - Bovine rhinitis viruses (BRV) are established etiological agents of bovine respiratory disease complex however little research into their epidemiology and ecology has been published for several decades. In the U.S., only bovine rhinitis A virus 1 (BRAV1) has been identified while bovine rhinitis A virus 2 (BRAV2) and bovine rhinitis B virus (BRBV) were previously only identified in England and Japan, respectively. Metagenomic sequencing of a nasal swab from a bovine respiratory disease (BRD) diagnostic submission from Kansas identified contigs with approximately 90% nucleotide similarity to BRAV2 and BRBV. A combination of de novo and templated assemblies using reference genomes yielded near complete BRAV2 and BRBV genomes. The near complete genome of bovine rhinitis A virus 1 (BRAV1) was also determined from a historical isolate to enable further molecular epidemiological studies. A 5'-nuclease reverse transcription PCR assay targeting the 3D polymerase gene was designed and used to screen 204 archived BRD clinical specimens. Thirteen (6.4%) were positive. Metagenomic sequencing of six positive samples identified mixed BRAV1/BRAV2, BRAV1/BRBV and BRAV2/BRBV infections for five samples. One sample showed infection only with BRAV1. Seroprevalence studies using a cell culture adapted BRBV found immunofluorescence assay-reactive antibodies were common in the herds analyzed. Altogether, these results demonstrate that BRV infections are common in cattle with respiratory disease and that BRAV1, BRAV2 and BRBV co-circulate in U.S. cattle and have high similarity to viruses isolated more than 30 years ago from diverse locations. PMID- 25789941 TI - Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases. AB - BACKGROUND: The management of patients with colorectal cancer and simultaneously diagnosed liver and lung metastases (SLLM) remains controversial. METHODS: The LiverMetSurvey registry was interrogated for patients treated between 2000 and 2012 to assess outcomes after resection of SLLM, and the factors associated with survival. SLLM was defined as liver and lung metastases diagnosed 3 months or less apart. Survival was compared between patients with resected isolated liver metastases (group 1, control), those with resected liver and lung metastases (group 2), and patients with resected liver metastases and unresected (or unresectable) lung metastases (group 3). An Akaike test was used to select variables for assessment of survival adjusted for confounding variables. RESULTS: Group 1 (isolated liver metastases, hepatic resection alone) included 9185 patients, group 2 (resection of liver and lung metastases) 149 patients, and group 3 (resection of liver metastases, no resection of lung metastases) 285 patients. Ten variables differed significantly between groups and seven were included in the model for adjusted survival (age, number of liver metastases, synchronicity of liver metastases with primary tumour, carcinoembryonic antigen level, node status of the primary tumour, initial resectability of liver metastases and inclusion in group 3). Adjusted overall 5-year survival was similar for groups 1 and 2 (51.5 and 44.5 per cent respectively), but worse for group 3 (14.3 per cent) (P = 0.001). CONCLUSION: Patients who had resection of liver and lung metastases had similar overall survival to those who had undergone removal of isolated liver metastases. PMID- 25789942 TI - Intravenous ketamine during spinal and general anaesthesia for caesarean section: systematic review and meta-analysis. AB - BACKGROUND: Intravenous ketamine has been used during general and regional anaesthesia for caesarean section. No systematic review and meta-analysis on the desired effects and adverse effects of ketamine administration during caesarean section have yet been performed. METHODS: After a systematic literature search a meta-analysis was conducted with the random effects model. Weighted mean difference (WMD) or risk ratio and 95% confidence intervals (CIs) were computed. RESULTS: Twelve randomised controlled double-blind trials comprising 953 patients were included: seven studies reported on spinal anaesthesia and five on general anaesthesia. Significant differences in the aforementioned outcome variables were found only in the spinal anaesthesia studies. In the spinal anaesthesia studies the time to the first analgesic request was significantly longer in ketamine treated women, the WMD was 49.36 min (95% CI 43.31-55.41); visual analogue scale pain scores at rest 2 h after surgery were significantly lower. No differences were observed for maternal nausea, vomiting, pruritus, and psychomimetic effects. Only few data were found for neonatal outcomes. CONCLUSIONS: We conclude that ketamine enhances post-operative analgesia after caesarean section under spinal anaesthesia. There is a paucity of data for several maternal adverse effects as well as for neonatal well-being. Further studies are needed for general anaesthesia. PMID- 25789943 TI - Downregulation of tumorogenicity and changes in the actin cytoskeleton of murine hepatoma after irradiation with polychromatic visible and IR light. AB - OBJECTIVE: This study evaluated the function and structural consequences of direct exposure of murine hepatoma MH-22a cells to polychromatic polarized light, to determine potential risk of malignancy following irradiation. BACKGROUND DATA: Visible (VIS) and infrared (IR) light have been actively used for prevention and treatment of complications developed after conventional tumor therapy. However, the safety associated with this irradiation has not been determined. MATERIALS AND METHODS: Polychromatic light (480-3400 and 385-750 nm), were used at different doses (4.8-38.4 J/cm(2)) to determine the viability, proliferation, and actin cytoskeleton in vitro by flow cytometry and confocal microscopy. Tumorogenic properties of cells were studied in vivo after transplantation in C3HA mice. RESULTS: Polychromatic light of a wide range of doses did not change the viability and proliferation of cells. After transplantation of cells irradiated with VIS-IR light (4.8 and 9.6 J/cm(2)) and VIS light (38.4 J/cm(2)) the tumor volume was lower in the treated group than in the control group in vivo. Transplantability of the irradiated cells also decreased, whereas survival of tumor-bearing mice increased. Three cell populations with different cytoskeleton structure were identified. After irradiation, the reorganized part of the actin cytoskeleton changed its localization to the submembranous area. CONCLUSIONS: A decrease of tumorigenicity in cells irradiated with polychromatic light used in non-damaging doses correlated with an increase in the number of cells with reorganized actin in the submembranous area. The results of the present study argue in favor of the oncological safety of polychromatic VIS-IR light (480-3400 nm). PMID- 25789944 TI - Stereochemistry for engineering spin crossover: structures and magnetic properties of a homochiral vs. racemic [Fe(N3O2)(CN)2] complex. AB - The Schiff-base condensation of the R,R-(+)-diamine () with 2,6-diacetyl pyridine in the presence of Fe(II) affords the macrocyclic complex [Fe(dpN3O2)(CN)2] () (dp = diphenyl) with ligand centred chirality comprising of a 1 : 1 mixture of LS 6- and HS 7-coordinate Fe(II) centres. Variable temperature magnetic susceptibility and Mossbauer studies reveal that () undergoes an incomplete thermal SCO transition with a T1/2 = 250 K as well as a LIESST effect. In contrast its racemic counterpart () comprises of mostly LS Fe(II) and exhibits no LIESST properties. PMID- 25789945 TI - Analysis of 30-day postdischarge morbidity and readmission after radical gastrectomy for gastric carcinoma: a single-center study of 2107 patients with prospective data. AB - PD morbidity and readmission pose a substantial clinical and economic burden to the healthcare system. Comprehensive PD complications and readmission data are essential for developing initiatives to improve patient care. No previous studies have extensively investigated PD complications after gastric cancer surgery.We investigated the incidence, types, treatment, and risk factors of 30-day postdischarge (PD) complications after gastric cancer surgery.Between 2010 and 2013, data concerning complications and readmission within 30 days of hospital discharge were prospectively collected in 2107 patients undergoing gastric cancer surgery.In total, 1642 patients (77.9%) underwent distal gastrectomy, 418 (19.8%) total gastrectomy, and 47 (2.3%) other procedures. Postoperative morbidity and mortality were 17.4% and 0.6%, respectively, with a mean 8.8-day hospital stay. Sixty-one patients (2.9%) developed 30-day PD morbidity (58 local and 3 systemic complications), accounting for 16.6% of overall morbidity; 47 (2.2%) were readmitted; and 7 (0.3%) underwent a reoperation. The mean time to PD complications was 9.5 days after index hospital discharge. The most common complication was intra-abdominal abscess (n = 14), followed by wound, ascites, and anastomosis leakage. No mortality occurred resulting from PD complications. In the univariate and multivariate analyses, underlying comorbidity (hypertension and liver cirrhosis) and obesity were independent risk factors for developing PD complications.The early PD period is a vulnerable time for surgical patients with substantial risk of complication and readmission. Tailored discharge plans along with appropriate PD patient support are essential for improving the quality of patient care. PMID- 25789946 TI - No differences of immune activation and microbial translocation among HIV infected children receiving combined antiretroviral therapy or protease inhibitor monotherapy. AB - This is a cross-sectional study of 15 aviremic chronic HIV-infected children revealing no differences in immune activation (IA; HLA-DRCD38 CD4 and CD8 T cells, and sCD14) and microbial translocation (MT; lipopolysaccharides (LPS) and 16S rDNA) among HIV-infected patients under combined antiretroviral treatment (cART; n = 10) or ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv; n = 5). In both cases, IA and MT were lower in healthy control children (n = 32). This observational study suggests that ritonavir boosted protease inhibitor monotherapy (mtPI/rtv) is not associated with an increased state of IA or MT as compared with children receiving cART. PMID- 25789947 TI - Short and long-term outcomes of robotic versus laparoscopic total mesorectal excision for rectal cancer: a case-matched retrospective study. AB - The true benefits of robotic surgery are controversial, and whether robotic total mesorectal excision (R-TME) can be justified as a standard treatment for rectal cancer patients needs to be clarified. This case-matched study aimed to compare the postoperative complications and short- and long-term outcomes of R-TME and laparoscopic TME (L-TME) for rectal cancer.Among 1029 patients, we identified 278 rectal cancer patients who underwent R-TME. Propensity score matching was used to match this group with 278 patients who underwent L-TME.The mean follow-up period was similar between both groups (L-TME vs R-TME: 52.5 +/- 17.1 vs 51.0 +/- 13.1 months, P = 0.253), as were patient characteristics. The operation time was significantly longer in the R-TME group than in the L-TME group (361.6 +/- 91.9 vs 272.4 +/- 83.8 min; P < 0.001), whereas the conversion rate, length of hospital stay, and recovery of pain and bowel motility were similar between both groups. The rates of circumferential resection margin involvement and early complications were similar between both groups (L-TME vs R-TME: 4.7% vs 5.0%, P = 1.000; and 23.7% vs 25.9%, P = 0.624, respectively), as were the 5-year overall survival, disease-free survival, and local recurrence rates (93.1% vs 92.2%, P = 0.422; 79.6% vs 81.8%, P = 0.538; 3.9% vs 5.9%, P = 0.313, respectively).The oncologic quality, short- and long-term outcomes, and postoperative morbidity in the R-TME group were comparable with those in the L-TME group. PMID- 25789948 TI - Interventions for treating displaced midshaft clavicular fractures: a Bayesian network meta-analysis of randomized controlled trials. AB - Displaced midshaft clavicle fractures are frequent injuries. There are 3 treatment methods including conservative treatment, plate fixation, and intramedullary pin fixation. However, which is the best treatment remains a topic of debate.To establish the optimum treatment for displaced midshaft clavicular fractures, we did a network meta-analysis to compare 3 treatments in terms of postoperative nonunion and infection.We searched PubMed, the Cochrane Library, and Embase for relevant randomized controlled trials (RCTs) until the end of October 2014. Two investigators independently reviewed the abstract and full text of eligible studies and extracted information. We used WinBUGS 1.4 (Imperial College School of Medicine at St Mary's, London) to perform our Bayesian network meta-analysis. We used the graphical tools in STATA12 (StataCorp, Texas) to present the results of statistical analyses of WinBUGS14. Nonunion and infection were presented as odd ratios (ORs) with 95% confidence intervals (CIs). We also presented the results using surface under the cumulative ranking curve (SUCRA). A higher SUCRA value suggests better results for respective treatment method.Thirteen RCTs were included in our network meta-analysis, with a total of 894 patients randomized to receive 1 of 3 treatments. Nonunion rates were 0.9%, 2.4%, and 11.4% for intramedullary pin fixation, plate fixation, and conservative method, respectively. Nonunion occurred more commonly in patients treated with conservative method than in patients treated with either plate fixation (OR, 0.18; 95% CI, 0.05-0.46) or intramedullary pin fixation (OR, 0.12; 95% CI, 0.01 0.50). There was no significant difference between plate and intramedullary pin fixation in nonunion (OR, 3.64; 95% CI, 0.31-17.27). Furthermore, SUCRA probabilities were 87.8%, 62.0%, and 0.2% for intramedullary pin fixation, plate fixation, and conservative method, respectively. Infection rates were 3.6% and 3.9% for intramedullary pin fixation and plate fixation, respectively. There was no significant difference between plate and intramedullary pin fixation in infection (OR, 3.64; 95% CI, 0.31-17.27). SUCRA probabilities were 46.5% and 8.5% for intramedullary pin and plate fixation, respectively.Our network meta-analysis suggested that intramedullary pin fixation is the optimum treatment method for displaced midshaft clavicle fracture because of the low probabilities of nonunion and infection. PMID- 25789949 TI - Intramedullary nail versus plate fixation for humeral shaft fractures: a systematic review of overlapping meta-analyses. AB - Multiple meta-analyses have been published to compare intramedullary nail and plate for treating humeral shaft fractures; however, results are discordant.The purposes of current study were to perform a systematic review of overlapping meta analyses comparing intramedullary nail and plate fixation for the treatment of humeral shaft fractures, to appraise the methodological quality and the quality of reporting of meta-analyses, and to propose a guide through the currently discordant available evidence.This systematic review was performed according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta analysis. The literature was systematically reviewed to identify meta-analyses comparing intramedullary nail and plate fixation for the treatment of humeral shaft fractures. Only meta-analyses exclusively including randomized clinical trials (RCTs) met eligibility criteria in this systematic review. Methodological quality for each included study was assessed using the Oxford Levels of Evidence and the Assessment of Multiple Systematic Reviews Instrument. We extracted all variables from the included studies and listed the results reported by them. Heterogeneity information of each variable was extracted for the included studies. An I of <60% is accepted in this systematic review. The Jadad algorithm was then applied to determine which meta-analyses provided the best evidence.Seven studies met the inclusion criteria in this study. All studies included RCTs or quasi-RCT and were Level II of evidence. Assessment of Multiple Systematic Reviews scores varied from 6 to 10 with a median of 7.86. Heterogeneity of each outcome was acceptable in those meta-analyses pooled results. The Jadad algorithm suggested that the meta-analyses can be selected based on the search strategies and application of selection. As a result, 2 meta analyses with more RCTs were selected in this systematic review. The best available evidence suggested that the differences between intramedullary nail and plate fixation were not significant in fracture union, radial nerve injury, and infection. But intramedullary nail significantly increased the risk of shoulder complications (shoulder impingement and restriction of shoulder movement) and reoperation.We concluded that plate fixation is superior to intramedullary nail for the treatment of humeral shaft fractures. PMID- 25789950 TI - Assessment of ankle and hindfoot stability and joint pressures using a human cadaveric model of a large lateral talar process excision: a biomechanical study. AB - Lateral talar process fragment excision may be followed by hindfoot instability and altered biomechanics. There is controversy regarding the ideal fragment size for internal fixation versus excision and a concern that excision of a large fragment may lead to significant instability. The aim of this study was to assess the effect of a simulated large lateral talar process excision on ankle and subtalar joint stability.A custom-made seesaw rig was designed to apply inversion/eversion stress loading on 7 fresh-frozen human cadaveric lower legs and investigate them in pre-excision, 5 cm and 10 cm lateral talar process fragment excision states. Anteroposterior radiographs were taken to assess ankle and subtalar joint tilt and calculate angular change from neutral hindfoot alignment to 10-kg forced inversion/eversion. Ankle joint pressures and contact areas were measured under 30-kg axial load in neutral hindfoot alignment.In comparison to the pre-excision state, no significantly different mediolateral angular change was observed in the subtalar joint after 5 and 10 cm lateral talar process fragment excision in inversion and eversion. With respect to the ankle joint, 10-cm fragment excision produced significantly bigger inversion tibiotalar tilt compared with the pre-excision state, P = .04. No significant change of the ankle joint pressure and contact area was detected after 5 and 10-cm excision in comparison with the pre-excison state.An excision of up to 10 cm of the lateral talar process does not cause a significant instability at the level of the subtalar joint but might be a destabilizing factor at the ankle joint under inversion stress. The latter could be related to extensive soft tissue dissection required for resection. PMID- 25789951 TI - Network meta-analysis of randomized controlled trials: efficacy and safety of UDCA-based therapies in primary biliary cirrhosis. AB - Major ursodeoxycholic acid (UDCA)-based therapies for primary biliary cirrhosis (PBC) include UDCA only, or combined with either methotrexate (MTX), corticosteroids (COT), colchicine (COC), or bezafibrate (BEF). As the optimum treatment regimen is unclear and warrants exploration, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse events (AE).PubMed, the Cochrane Library, and Scopus were searched for randomized controlled trials up to August 31, 2014. We estimated the hazard ratios (HRs) for MOLT and odds ratios (ORs) for AE. A sensitivity analysis based on the dose of UDCA was also executed.Thirty-one eligible articles were included. Compared with COT plus UDCA, UDCA (HR 0.38, 95% confidence interval [CI] 0.09 1.39), BEF plus UDCA (HR 0.29, 95% CI 0.02-4.83), COC plus UDCA (HR 0.39, 95% CI 0.07-2.25), MTX plus UDCA (HR 0.28, 95% CI 0.05-1.63), or OBS (HR 0.49, 95% CI 0.11-2.01) all provided an increased risk of MOLT. With respect to drug AE profile, although not differing appreciably, BEF plus UDCA was associated with more AEs compared with UDCA (OR 3.16, 95% CI 0.59-20.67), COT plus UDCA (OR 2.27, 95% CI 0.15-33.36), COC plus UDCA (OR 1.00, 95% CI 0.09-12.16), MTX plus UDCA (OR 2.03, 95% CI 0.23-17.82), or OBS (OR 3.00, 95% CI 0.53-20.75). The results of sensitivity analyses were highly consistent with previous analyses.COT plus UDCA was the optimal UDCA-based regimen for both MOLT and AEs. BEF plus UDCA was most likely to cause AEs, whereas monotherapy with UDCA and coadministriation of COT plus UDCA appeared to be associated with the fewest AEs for PBC treatment. PMID- 25789952 TI - Comparison of doxorubicin anticancer drug loading on different metal oxide nanoparticles. AB - Nanomaterials are being vigorously investigated for their use in anticancer drug delivery regimes or as biomarkers agents and are considered to be a candidate to provide a way to combat severe weaknesses of anticancer drug pharmacokinetics, such as their nonspecificity. Because of this weakness, a bigger proportion of the drug-loaded nanomaterials flow toward healthy tissues and result in undesirable side effects. It is very important to evaluate drug loading and release efficiency of various nanomaterials to find out true pharmacokinetics of these drugs.This observational study aims to evaluate various surface functionalized and naked nanomaterials for their drug loading capability and consequently strengthens the Reporting of Observational Studies in Epidemiology (STROBE). We analyzed naked and coated nanoparticles of transition metal oxides for their further loading with doxorubicin, a representative water-soluble anticancer drug.Various uncoated and polyethylene glycol-coated metal oxide nanoparticles were synthesized and loaded with anticancer drug using simple stirring of the nanoparticles in a saturated aqueous solution of the drug. Results showed that surface-coated nanoparticles have higher drug-loading capabilities; however, certain naked metal oxide nanoparticles, such as cobalt oxide nanoparticles, can load a sufficient amount of drug. PMID- 25789953 TI - Gender-related differences in maximum gait speed and daily physical activity in elderly hospitalized cardiac inpatients: a preliminary study. AB - Maximum gait speed and physical activity (PA) relate to mortality and morbidity, but little is known about gender-related differences in these factors in elderly hospitalized cardiac inpatients. This study aimed to determine differences in maximum gait speed and daily measured PA based on sex and the relationship between these measures in elderly cardiac inpatients.A consecutive 268 elderly Japanese cardiac inpatients (mean age, 73.3 years) were enrolled and divided by sex into female (n = 75, 28%) and male (n = 193, 72%) groups. Patient characteristics and maximum gait speed, average step count, and PA energy expenditure (PAEE) in kilocalorie per day for 2 days assessed by accelerometer were compared between groups.Gait speed correlated positively with in-hospital PA measured by average daily step count (r = 0.46, P < 0.001) and average daily PAEE (r = 0.47, P < 0.001) in all patients. After adjustment for left ventricular ejection fraction, step counts and PAEE were significantly lower in females than males (2651.35 +/- 1889.92 vs 4037.33 +/- 1866.81 steps, P < 0.001; 52.74 +/- 51.98 vs 99.33 +/- 51.40 kcal, P < 0.001), respectively.Maximum gait speed was slower and PA lower in elderly female versus male inpatients. Minimum gait speed and step count values in this study might be minimum target values for elderly male and female Japanese cardiac inpatients. PMID- 25789954 TI - Peripheral neuropathies due to systemic lupus erythematosus in China. AB - This article aims to analyze the frequency and clinical characteristics of peripheral neuropathy (PN) in patients with systemic lupus erythematosus (SLE).A total of 4924 SLE patients admitted to the Peking Union Medical College Hospital, Beijing, China, from January 1995 to September 2013 were included in this retrospective analysis. The individuals designated as control patients were selected from the pool of SLE patients without PN using the systematic sampling method of 1:2 during the same time.The prevalence of SLE-associated PN (SLE-PN) in SLE patients was 1.5% (73/4924). Seventy-nine cases of PN affected 73 patients and 6 of these patients (8.2%) presented with 2 types of PN. Among the 7 types of PN, polyneuropathy was the most frequent and was diagnosed in 47 cases (59.5%); the remaining patients suffered from mononeuropathy (13.9%), cranial neuropathy (12.7%), myasthenia gravis (10.1%), autonomic neuropathy (2.5%), or acute inflammatory demyelinating polyradiculoneuropathy (1.3%). Five patients developed PN before the onset of SLE (3 out of 5 patients had myasthenia gravis). The most common PN-related symptoms were myasthenia and numbness (50.6%), followed by pain in affected regions (35.9%). PN symptoms were relieved in a majority of the patients (76.7%) after treatment. Compared with non-SLE-PN patients, patients with SLE-PN had a higher frequency of fever (65.8% vs 45.9%, P < 0.01), mucocutaneous involvement (73.9% vs 36.3%, P < 0.01), arthritis (42.5% vs 28.1%, P < 0.05), myositis (17.8% vs 5.5%, P < 0.01), and central nervous system involvement (38.4% vs 21.9%, P < 0.05) as well as being positive for the anti-Sm antibody (31.4% vs 18.8%), immunoglobulin G (IgG) elevation (53.6% vs 37.1%, P < 0.01), and reduction in complement 3 (54.8% vs 36.9%, P < 0.05). A statistically significant difference was found between the Systemic Lupus Erythematosus Disease Activity Index scores in SLE-PN patients compared with the non-SLE-PN patients (P < 0.05). Multivariate logistic regression showed that the only risk factor for PN was IgG elevation (odds ratio =2.553, 1.224-5.327, P = 0.012).The prevalence of PN in SLE occurs more frequently in patients with an active form of the disease. IgG elevation is a risk factor for SLE-PN and should be assessed in these patients. Young female patients with myasthenia gravis should be closely monitored for the development of SLE. PMID- 25789955 TI - PiCO2 monitoring of transferred jejunum perfusion using an air tonometry technique after hypopharyngeal cancer surgery. AB - This study aimed to investigate the usefulness of intraluminal PCO2 (PiCO2) monitoring by air tonometry for the assessment of the vascular condition of the transferred jejunum after surgery for hypopharyngeal cancer.PiCO2 in the transplanted jejunum of 24 patients was monitored using air tonometry after radical surgery for hypopharyngeal cancer from 2003 to 2010.All but 1 patient, who removed the catheter before monitoring began, were monitored safely. PiCO2 in the transferred jejunum correlated with arterial PCO2 (PaCO2) that was measured concurrently, and dissociation of PiCO2 from PaCO2 was observed in cases with vascular complication. In those cases without postoperative vascular complication, the PiCO2 value gradually increased for 3 hours but then decreased by 12 hours after surgery. Three patients experienced major vascular complication. All 3 patients had continuous elevation of PiCO2 >100 mm Hg, although vascular flow in 1 patient recovered by removal of a venous thrombosis and reanastomosis of the vein 7.5 hours after surgery. Four other patients who experienced elevation of PiCO2 had their skin suture released for decompression of their neck wound, resulting in a decrease in PiCO2 after treatment.The current results demonstrated that continuous monitoring of PiCO2 by air tonometry accurately reflects the vascular condition of the transferred jejunum, and this method is one of the best options for postoperative monitoring of jejunum blood perfusion. PMID- 25789956 TI - Sox17 promoter methylation in plasma DNA is associated with poor survival and can be used as a prognostic factor in breast cancer. AB - Aberrant DNA methylation that leads to the inactivation of tumor suppressor genes is known to play an important role in the development and progression of breast cancer. Methylation status of cancer-related genes is considered to be a promising biomarker for the early diagnosis and prognosis of tumors. This study investigated the methylation status of the Sox17 gene in breast cancer tissue and its corresponding plasma DNA to evaluate the association of methylation levels with clinicopathological parameters and prognosis.The methylation status of the Sox17 gene promoter was evaluated with methylation-specific polymerase chain reaction (MSP) in 155 paired breast cancer tissue and plasma samples and in 60 paired normal breast tissue and plasma samples. Association of Sox17 methylation status with clinicopathological parameters was analyzed by chi tests. Overall and disease-free survival (DFS) curves were calculated using Kaplan-Meier analysis, and the differences between curves were analyzed by log-rank tests.The frequency of Sox17 gene methylation was 72.9% (113/155) in breast cancer tissues and 58.1% (90/155) in plasma DNA. Sox17 gene methylation was not found in normal breast tissues or in their paired plasma DNA. There was a significant correlation of Sox17 methylation between corresponding tumor tissues and paired plasma DNA (r = 0.688, P < 0.001). Aberrant Sox17 methylation in cancer tissues and in plasma DNA was significantly associated with the tumor node metastasis stage (P = 0.035 and P = 0.001, respectively) and with lymph node metastasis (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves showed that aberrant Sox17 promoter methylation in cancer tissues and plasma DNA was associated with poor DFS (P < 0.005) and overall survival (OS) (P < 0.005). Multivariate analysis showed that Sox17 methylation in plasma DNA was an independent prognostic factor in breast cancer for both DFS (P = 0.020; hazard ratio [HR] = 2.142; 95% confidence interval [CI]: 1.128-4.067) and for OS (P = 0.001; HR = 4.737; 95% CI: 2.088 10.747).Sox17 gene promoter methylation may play an important role in breast cancer progression and could be used as a prognostic biomarker to identify patients at risk of developing metastasis or recurrence after mastectomy. PMID- 25789957 TI - Pretreatment neutrophil-lymphocyte ratio: an independent predictor of survival in patients with hepatocellular carcinoma. AB - The neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with prognosis in various types of cancer. We evaluated pretreatment NLR as a predictor of poor prognosis in patients with hepatocellular carcinoma (HCC), and we compared the prognostic value of NLR with other prognostic scores.We retrospectively analyzed 825 patients diagnosed with HCC between October 2008 and May 2012. Baseline data, including the NLR and the Child-Pugh class or Model for End-Stage Liver Disease (MELD) score, were recorded before treatment. The relationships between overall survival (OS) and the study variables were assessed using univariate and multivariate analyses and receiver operating characteristic (ROC) curves. The prognostic value of NLR was assessed using a Kaplan-Meier survival analysis and compared with that of the Barcelona-Clinic Liver Cancer (BCLC) and Tumor, Node, Metastasis (TNM) staging.The NLR, gamma glutamyltranspeptidase, alpha-fetoprotein >= 400 ng/mL, tumor number >= 3, tumor size >= 5 cm, lymph node metastasis, portal vein involvement, and Child-Pugh class were significantly associated with OS. The NLR demonstrated the strongest prognostic value (area under ROC curve = 0.811). An NLR >= 2.7 was a significant predictor of poor OS (P < 0.0001), and the survival period of patients with an NLR >= 2.7 decreased with more advanced BCLC and TNM stage.Pretreatment NLR is a useful prognostic biomarker in HCC patients. The prognostic value of NLR >= 2.7 is superior to that of MELD stage or Child-Pugh class, and correlates with that of BCLC and TNM staging scores. PMID- 25789958 TI - Intravascular myopericytoma in the heel: case report and literature review. AB - Intravascular myopericytoma (IVMP), regarded as a variant of myopericytoma, is a rare tumor. Very few cases have been described, none in the foot.The first case of IVMP located in the heel of the foot is described in this article. A literature review is reported of all cases of IVMP published in the English literature.A 48-year-old man possessed an IVMP on the heel of the right foot. The physical examination and histopathological and ultrasound studies are described. The literature review yielded 5 cases of IVMP, 2 of which were in the thigh and 1 each in the oral mucosa, the periorbital region, and the leg.The possibility that these lesions may be malignant suggests that the histopathological study of vascular tumors should include immunohistochemical tests. PMID- 25789959 TI - Changes in tumor necrosis factor-alpha, heat shock protein 70, malondialdehyde, and superoxide dismutase in patients with different severities of alcoholic fatty liver disease: a prospective observational study. AB - The relationships among inflammation, oxidative balance, and the severity of alcoholic fatty liver disease (AFLD) remain unknown. The aim of this study is to explore the relationships among tumor necrosis factor alpha (TNF-alpha), heat shock protein 70 (HSP70), malondialdehyde (MDA), superoxide dismutase (SOD), and the severity of AFLD.From January 2012 to December 2013, 162 participants were enrolled in this study and divided into 4 groups: 44 cases of mild AFLD (group A), 55 cases of moderate-to-severe AFLD (group B), 44 cases of alcohol consumption without AFLD (group C), and 20 cases of no alcohol consumption without AFLD (group D). A cross-sectional study was conducted by detecting the serum levels of TNF-alpha, HSP70, MDA, and SOD by enzyme-linked immunosorbent assay.The median serum levels of TNF-alpha and HSP70 among the 4 groups were statistically significant (P = 0.000 and 0.001, respectively). The median serum levels of TNF-alpha in groups A and B were significantly lower than in group C (P = 0.002 and 0.000, respectively), and the median serum level of TNF-alpha in group B was significantly lower than in group D (P = 0.023). In addition, the median serum level of HSP70 in group B was significantly lower than in groups A and C (P = 0.002 and 0.000, respectively), and the median serum level of HSP70 in group C was significantly higher than in group D (P = 0.044). However, the median serum level of MDA in group B was significantly lower than only group C (P = 0.008).Chronic alcohol ingestion without AFLD may result in a significant increase in the circulation of certain inflammatory markers; the severity of AFLD is associated with circulating inflammatory markers, and moderate-to-severe AFLD may result in a more significant reduction of these markers. However, moderate-to severe AFLD may also result in a significant downregulation of oxidative stress products. PMID- 25789960 TI - Importance of continuous sequential chemotherapy and multimodal treatment for advanced testicular cancer: a high-volume Japanese center experience. AB - Patients with "difficult-to-treat" advanced testicular cancer can require multiple therapies. We retrospectively assessed our patients with advanced germ cell tumors (GCTs) and characterized the clinical efficacy, outcomes, and factors affecting overall survival (OS).Two hundred fifty-three patients with advanced GCTs were treated at Kyoto Prefectural University of Medicine, Kyoto, Japan, from June 1998 to September 2013. Of 253 patients, 142 patients had salvage chemotherapy.As first-line therapy, bleomycin, etoposide, and cisplatin, and etoposide and cisplatin therapies were performed in 234 cases (92.5%). As second line therapy, etoposide, ifosfamide, and cisplatin/vinblastine, ifosfamide, and cisplatin, and paclitaxel, ifosfamide, and cisplatin/paclitaxel, ifosfamide, and nedaplatin therapies were carried out in 44 and 59 cases, respectively. Furthermore, 111, 72, 44, and 28 cases had third, fourth, fifth, and sixth-or later-line chemotherapy, respectively. Five-year OS rate stratified by chemotherapy line was 95.5% in the first line, 89.4% in the second line, 82.1% in the third line, 45.1% in the fourth line, and 58.9% in the fifth or after line. A statistical significant difference was found when comparing fourth-or-after-line versus first to third-line therapy. Additional procedures were performed, including retroperitoneal lymph node dissection (RPLND) (n = 168), extra-RPLN resection (n= 114), and external beam radiotherapy/stereotactic radiotherapy (n = 78).Multivariate analysis showed that factors predicting better outcomes were in serum tumor marker (STM) normalization, RPLND, and extra-RPLN resection.Good outcomes were obtained in patients who completed chemotherapy up to third line. After fourth-line chemotherapy, approximately 50% of "difficult-to-treat" patients could be cured with normalization of STM levels and residual mass resection. Continuous or sequential chemotherapy with multimodality therapy is important for patients with "difficult-to-treat" advanced GCTs. Effective chemotherapy after third line should be developed. PMID- 25789961 TI - Clinical and histologic description of ocular anatomy in captive black-tailed prairie dogs (Cynomys ludovicianus). AB - OBJECTIVE: To describe the clinical and histologic ocular anatomy of the black tailed prairie dog (PD). ANIMALS STUDIED: Seventeen captive black-tailed PDs (11 males and six females), ranging in age from approximately 4 months to 4.5 years. PROCEDURES: Complete ocular examinations, including slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, were performed under isoflurane anesthesia. The globes (n = 2) of one black-tailed PD were harvested immediately after euthanasia and processed after formalin fixation. Staining with hematoxylin eosin, cytokeratin AE1/AE3, glial fibrillary acidic protein, chromogranin A, claudin-5, smooth muscle actin, and vimentin was performed for light microscopic evaluation. RESULTS: A thick mucinous precorneal tear film was present on the ocular surface. A vestigial nictitating membrane was identified in the medial canthus area. The limbus was heavily pigmented, the iris was a dark homogenous brown, and the pupil was round. Funduscopically, there was no tapetum lucidum, the retinal vascular pattern was holangiotic, and a horizontally elongated optic disk was visualized. The most common ocular abnormalities were acquired eyelid margin defects, present in seven eyes of six black-tailed PDs (35.3%). On histologic examination, the retina was asymmetric, thicker below the optic disk and thinner above it. CONCLUSIONS: The black-tailed PD fundus is atapetal with a holangiotic retinal vessel pattern and a horizontally elongated optic disk. Acquired lesions of the peri-ocular and eyelid region were the most common documented abnormality. Unique anatomic features of the globe and adnexa were confirmed with histologic and immunohistochemical analysis. PMID- 25789962 TI - The changes in the low-frequency fluctuations of cingulate cortex and postcentral gyrus in the treatment of panic disorder: The MRI study. AB - OBJECTIVES: The default brain activities in the treatment of panic disorder (PD) have not been studied well. Therefore we designed this longitudinal study to survey the accompanying changes in the fractional amplitude of low-frequency fluctuations (fALFF) when panic disorder (PD) patients achieved remission. METHODS: We enrolled 21 medicine-naive patients who finished a 6-week therapy of antidepressant. The trial antidepressant was escitalopram. The acquisitions of fALFF in the patients and controls were assessed at baseline and the sixth week. The treatment-related effects and group-related differences (baseline versus sixth week) were obtained by the comparisons of the fALFF data of each group. RESULTS: The treatment-related effects showed increases in the fALFF values of the right middle cingulate cortex (MCC) and left postcentral gyrus (PCG) after remission in PD patients. The improvements in panic severity and antidepressant dose also correlated positively with the increases in the fALFF values of the right middle cingulate cortex. There were still residual group-related differences of fALFF in the occipital lobe and thalamus after remission. CONCLUSIONS: The results probably revealed the treatment-related effects of fALFF in the MCC-PCG regions and group-related differences of fALFF in the occipito thalamic regions for the antidepressant treatment and remission in PD. PMID- 25789963 TI - Electrical Atrial Alternans Recorded by Cardiac Rhythm Devices during Atrial Flutter. PMID- 25789964 TI - Non-destructive detection of pesticide residues in cucumber using visible/near infrared spectroscopy. AB - The feasibility of using visible/near-infrared (Vis/NIR) spectroscopy was assessed for non-destructive detection of diazinon residues in intact cucumbers. Vis/NIR spectra of diazinon solution and cucumber samples without and with different concentrations of diazinon residue were analysed at the range of 450 1000 nm. Partial least squares-discriminant analysis (PLS-DA) models were developed based on different spectral pre-processing techniques to classify cucumbers with contents of diazinon below and above the MRL as safe and unsafe samples, respectively. The best model was obtained using a first-derivative method with the lowest standard error of cross-validation (SECV = 0.366). Moreover, total percentages of correctly classified samples in calibration and prediction sets were 97.5% and 92.31%, respectively. It was concluded that Vis/NIR spectroscopy could be an appropriate, fast and non-destructive technology for safety control of intact cucumbers by the absence/presence of diazinon residues. PMID- 25789965 TI - Frequency of convergence and accommodative disorders in a clinical population of Mashhad, Iran. AB - PURPOSE: To investigate the frequency of convergence and accommodation anomalies in an optometric clinical setting in Mashhad, Iran, and to determine tests with highest accuracy in diagnosing these anomalies. METHODS: From 261 patients who came to the optometric clinics of Mashhad University of Medical Sciences during a month, 83 of them were included in the study based on the inclusion criteria. Near point of convergence (NPC), near and distance heterophoria, monocular and binocular accommodative facility (MAF and BAF, respectively), lag of accommodation, positive and negative fusional vergences (PFV and NFV, respectively), AC/A ratio, relative accommodation, and amplitude of accommodation (AA) were measured to diagnose the convergence and accommodation anomalies. The results were also compared between symptomatic and asymptomatic patients. The accuracy of these tests was explored using sensitivity (S), specificity (Sp), and positive and negative likelihood ratios (LR+, LR-). RESULTS: Mean age of the patients was 21.3 +/- 3.5 years and 14.5% of them had specific binocular and accommodative symptoms. Convergence and accommodative anomalies were found in 19.3% of the patients; accommodative excess (4.8%) and convergence insufficiency (3.6%) were the most common accommodative and convergence disorders, respectively. Symptomatic patients showed lower values for BAF (p = .003), MAF (p = .001), as well as AA (p = .001) compared with asymptomatic patients. Moreover, BAF (S = 75%, Sp = 62%) and MAF (S = 62%, Sp = 89%) were the most accurate tests for detecting accommodative and convergence disorders in terms of both sensitivity and specificity. CONCLUSIONS: Convergence and accommodative anomalies are the most common binocular disorders in optometric patients. Including tests of monocular and binocular accommodative facility in routine eye examinations as accurate tests to diagnose these anomalies requires further investigation. PMID- 25789966 TI - Microcystin-LR promotes migration and invasion of colorectal cancer through matrix metalloproteinase-13 up-regulation. AB - Microcystin-LR (MC-LR) is an environmental toxin from blooms of cyanobacteria and it has been shown to be one of the environmental carcinogens for the progression of colorectal carcinoma. However, there is no direct evidence that MC-LR can induce colorectal cancer migration and invasion. In the present study, 0.04 or 40 ug/kg/d (human tolerable daily intake value of MC-LR) MC-LR treatment was observed to induce Matrix Metalloproteinase-13 (MMP-13) expression in tumor tissues and local invasion in DLD-1 xenograft model. The results are consistent with those of cell test showing that MC-LR treatment enhanced migration and invasion of DLD-1, HT-29, and SW480 cells and are also correlated with the increased mRNA and protein levels of MMP-13 by Quantitative real-time PCR, Luciferase assay, and Western blot assay respectively in DLD-1 cells and HT-29 cells after MC-LR exposure. In addition, MMP-13 siRNA inhibited MC-LR induced migration and invasion enhancement and MMP-13 over-expression in DLD-1 cells and HT-29 cells. This is the first paper confirming MC-LR-induced MMP-13 expression can promote colorectal cancer invasion and migration. Further investigation revealed that phosphorylation of AKT increased in MC-LR-treated cells, and the phosphatidylinositol 3-kinase/Akt. (PI3-K/AKT) inhibitor LY294002 effectively abolished MC-LR-enhanced migration and invasion and MMP-13 expression. Therefore, based on these observations, we concluded that the activation of PI3K/AKT by MC LR results in MMP-13 expression, leading to the migration and invasion of DLD-1 cells and HT-29 cells. The study provides a mechanistic insight into the promoting colorectal cancer functions of MC-LR. PMID- 25789967 TI - Diverse impact of neuronal activity at theta frequency on hippocampal long-term plasticity. AB - Brain oscillatory activity is considered an essential aspect of brain function, and its frequency can vary from <1 Hz to >200 Hz, depending on the brain states and projection. Episodes of rhythmic activity accompany hippocampus-dependent learning and memory in vivo. Therefore, long-term synaptic potentiation (LTP) and long-term depression, which are considered viable substrates of learning and memory, are often experimentally studied in paradigms of patterned high-frequency (>50 Hz) and low-frequency (<5 Hz) stimulation. However, the impact of intermediate frequencies on neuronal plasticity remains less well understood. In particular, hippocampal neurons are specifically tuned for activity at theta frequency (4-8 Hz); this band contributes significantly to electroencephalographic signals, and it is likely to be involved in shaping synaptic strength in hippocampal circuits. Here, we review in vitro and in vivo studies showing that variation of theta-activity duration may affect long-term modification of synaptic strength and neuronal excitability in the hippocampus. Such theta-pulse-induced neuronal plasticity 1) is long-lasting, 2) may be built on previously stabilized potentiation in the synapse, 3) may produce opposite changes in synaptic strength, and 4) requires complex molecular machinery. Apparently innocuous episodes of low-frequency synaptic activity may have a profound impact on network signaling, thereby contributing to information processing in the hippocampus and beyond. In addition, theta-pulse-induced LTP might be an advantageous protocol in studies of specific molecular mechanisms of synaptic plasticity. PMID- 25789968 TI - Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma. AB - Glaucoma is the second leading cause of blindness worldwide and is characterized by gradual visual impairment owing to progressive loss of retinal ganglion cells (RGCs) and their axons. Glutamate excitotoxicity has been implicated as a mechanism of RGC death in glaucoma. Consistent with this claim, we previously reported that glutamate/aspartate transporter (GLAST)-deficient mice show optic nerve degeneration that is similar to that observed in glaucoma. Therefore, drugs that upregulate GLAST may be useful for neuroprotection in glaucoma. Although many compounds are known to increase the expression of another glial glutamate transporter, EAAT2/GLT1, few compounds are shown to increase GLAST expression. Arundic acid is a glial modulating agent that ameliorates delayed ischemic brain damage by attenuating increases in extracellular glutamate. We hypothesized that arundic acid neuroprotection involves upregulation of GLAST. To test this hypothesis, we examined the effect of arundic acid on GLAST expression and glutamate uptake. We found that arundic acid induces GLAST expression in vitro and in vivo. In addition, arundic acid treatment prevented RGC death by upregulating GLAST in heterozygous (GLAST(+/-)) mice. Furthermore, arundic acid stimulates the human GLAST ortholog, EAAT1, expression in human neuroglioblastoma cells. Thus, discovering compounds that can enhance EAAT1 expression and activity may be a novel strategy for therapeutic treatment of glaucoma. PMID- 25789970 TI - IGFBP-rP1 suppresses epithelial-mesenchymal transition and metastasis in colorectal cancer. AB - Epithelial-mesenchymal transition (EMT) was initially recognized during organogenesis and has recently been reported to be involved in promoting cancer invasion and metastasis. Cooperation of transforming growth factor-beta (TGF beta) and other signaling pathways, such as Ras and Wnt, is essential to inducing EMT, but the molecular mechanisms remain to be fully determined. Here, we reported that insulin-like growth factor binding protein-related protein 1 (IGFBP rP1), a potential tumor suppressor, controls EMT in colorectal cancer progression. We revealed the inhibitory role of IGFBP-rP1 through analyses of clinical colorectal cancer samples and various EMT and metastasis models in vitro and in vivo. Moreover, we demonstrated that IGFBP-rP1 suppresses EMT and tumor metastasis by repressing TGF-beta-mediated EMT through the Smad signaling cascade. These data establish that IGFBP-rP1 functions as a suppressor of EMT and metastasis in colorectal cancer. PMID- 25789969 TI - T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. AB - Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the 'exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD 1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV specific CD8(+) T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study. PMID- 25789971 TI - Autophagy is a regulator of TGF-beta1-induced fibrogenesis in primary human atrial myofibroblasts. AB - Transforming growth factor-beta(1) (TGF-beta(1)) is an important regulator of fibrogenesis in heart disease. In many other cellular systems, TGF-beta(1) may also induce autophagy, but a link between its fibrogenic and autophagic effects is unknown. Thus we tested whether or not TGF-beta(1)-induced autophagy has a regulatory function on fibrosis in human atrial myofibroblasts (hATMyofbs). Primary hATMyofbs were treated with TGF-beta(1) to assess for fibrogenic and autophagic responses. Using immunoblotting, immunofluorescence and transmission electron microscopic analyses, we found that TGF-beta(1) promoted collagen type Ialpha2 and fibronectin synthesis in hATMyofbs and that this was paralleled by an increase in autophagic activation in these cells. Pharmacological inhibition of autophagy by bafilomycin-A1 and 3-methyladenine decreased the fibrotic response in hATMyofb cells. ATG7 knockdown in hATMyofbs and ATG5 knockout (mouse embryonic fibroblast) fibroblasts decreased the fibrotic effect of TGF-beta(1) in experimental versus control cells. Furthermore, using a coronary artery ligation model of myocardial infarction in rats, we observed increases in the levels of protein markers of fibrosis, autophagy and Smad2 phosphorylation in whole scar tissue lysates. Immunohistochemistry for LC3beta indicated the localization of punctate LC3beta with vimentin (a mesenchymal-derived cell marker), ED-A fibronectin and phosphorylated Smad2. These results support the hypothesis that TGF-beta(1)-induced autophagy is required for the fibrogenic response in hATMyofbs. PMID- 25789972 TI - Homology and enzymatic requirements of microhomology-dependent alternative end joining. AB - Nonhomologous DNA end joining (NHEJ) is one of the major double-strand break (DSB) repair pathways in higher eukaryotes. Recently, it has been shown that alternative NHEJ (A-NHEJ) occurs in the absence of classical NHEJ and is implicated in chromosomal translocations leading to cancer. In the present study, we have developed a novel biochemical assay system utilizing DSBs flanked by varying lengths of microhomology to study microhomology-mediated alternative end joining (MMEJ). We show that MMEJ can operate in normal cells, when microhomology is present, irrespective of occurrence of robust classical NHEJ. Length of the microhomology determines the efficiency of MMEJ, 5 nt being obligatory. Using this biochemical approach, we show that products obtained are due to MMEJ, which is dependent on MRE11, NBS1, LIGASE III, XRCC1, FEN1 and PARP1. Thus, we define the enzymatic machinery and microhomology requirements of alternative NHEJ using a well-defined biochemical system. PMID- 25789973 TI - Novel function of cytoplasmic p53 at the interface between mitochondria and the endoplasmic reticulum. PMID- 25789974 TI - Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer. AB - The Kruppel-like transcription factors (KLFs) 4 and 5 (KLF4/5) are coexpressed in mouse embryonic stem cells, where they function redundantly to maintain pluripotency. In mammary carcinoma, KLF4/5 can each impact the malignant phenotype, but potential linkages to drug resistance remain unclear. In primary human breast cancers, we observed a positive correlation between KLF4/5 transcript abundance, particularly in the human epidermal growth factor receptor 2 (HER2)-enriched subtype. Furthermore, KLF4/5 protein was rapidly upregulated in human breast cancer cells following treatment with the HER2/epidermal growth factor receptor inhibitor, lapatinib. In addition, we observed a positive correlation between these factors in the primary tumors of genetically engineered mouse models (GEMMs). In particular, the levels of both factors were enriched in the basal-like tumors of the C3(1) TAg (SV40 large T antigen transgenic mice under control of the C3(1)/prostatein promoter) GEMM. Using tumor cells derived from this model as well as human breast cancer cells, suppression of KLF4 and/or KLF5 sensitized HER2-overexpressing cells to lapatinib. Indicating cooperativity, greater effects were observed when both genes were depleted. KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL). Moreover, MCL1 was upregulated by lapatinib in a KLF4/5-dependent manner, and enforced expression of MCL1 in KLF4/5-deficient cells restored drug resistance. In addition, combined suppression of KLF4/5 in cultured tumor cells additively inhibited anchorage-independent growth, resistance to anoikis and tumor formation in immunocompromised mice. Consistent with their cooperative role in drug resistance and other malignant properties, KLF4/5 levels selectively stratified human HER2-enriched breast cancer by distant metastasis-free survival. These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies. PMID- 25789976 TI - Modeling the radical chemistry in an oxidation flow reactor: radical formation and recycling, sensitivities, and the OH exposure estimation equation. AB - Oxidation flow reactors (OFRs) containing low-pressure mercury (Hg) lamps that emit UV light at both 185 and 254 nm ("OFR185") to generate OH radicals and O3 are used in many areas of atmospheric science and in pollution control devices. The widely used potential aerosol mass (PAM) OFR was designed for studies on the formation and oxidation of secondary organic aerosols (SOA), allowing for a wide range of oxidant exposures and short experiment duration with reduced wall loss effects. Although fundamental photochemical and kinetic data applicable to these reactors are available, the radical chemistry and its sensitivities have not been modeled in detail before; thus, experimental verification of our understanding of this chemistry has been very limited. To better understand the chemistry in the OFR185, a model has been developed to simulate the formation, recycling, and destruction of radicals and to allow the quantification of OH exposure (OHexp) in the reactor and its sensitivities. The model outputs of OHexp were evaluated against laboratory calibration experiments by estimating OHexp from trace gas removal and were shown to agree within a factor of 2. A sensitivity study was performed to characterize the dependence of the OHexp, HO2/OH ratio, and O3 and H2O2 output concentrations on reactor parameters. OHexp is strongly affected by the UV photon flux, absolute humidity, reactor residence time, and the OH reactivity (OHR) of the sampled air, and more weakly by pressure and temperature. OHexp can be strongly suppressed by high OHR, especially under low UV light conditions. A OHexp estimation equation as a function of easily measurable quantities was shown to reproduce model results within 10% (average absolute value of the relative errors) over the whole operating range of the reactor. OHexp from the estimation equation was compared with measurements in several field campaigns and shows agreement within a factor of 3. The improved understanding of the OFR185 and quantification of OHexp resulting from this work further establish the usefulness of such reactors for research studies, especially where quantifying the oxidation exposure is important. PMID- 25789977 TI - A deut of mTORC1/2 for cell adhesion. PMID- 25789975 TI - Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53 dependent apoptosis in keratinocytes. AB - LincRNA-p21 is a long noncoding RNA and a transcriptional target of p53 and HIF 1alpha. LincRNA-p21 regulates gene expression in cis and trans, mRNA translation, protein stability, the Warburg effect, and p53-dependent apoptosis and cell cycle arrest in doxorubicin-treated mouse embryo fibroblasts. p53 plays a key role in the response of skin keratinocytes to UVB-induced DNA damage by inducing cell cycle arrest and apoptosis. In skin cancer development, UVB-induced mutation of p53 allows keratinocytes upon successive UVB exposures to evade apoptosis and cell cycle arrest. We hypothesized that lincRNA-p21 has a key functional role in UVB-induced apoptosis and/or cell cycle arrest in keratinocytes and loss of lincRNA-p21 function results in the evasion of apoptosis and/or cell cycle arrest. We observed that lincRNA-p21 transcripts are highly inducible by UVB in mouse and human keratinocytes in culture and in mouse skin in vivo. LincRNA-p21 is regulated at the transcriptional level in response to UVB, and the UVB induction of lincRNA-p21 in keratinocytes and in vivo in mouse epidermis is primarily through a p53-dependent pathway. Knockdown of lincRNA-p21 blocked UVB induced apoptosis in mouse and human keratinocytes, and lincRNA-p21 was responsible for the majority of UVB-induced and p53-mediated apoptosis in keratinocytes. Knockdown of lincRNA-p21 had no effect on cell proliferation in untreated or UVB-treated keratinocytes. An early event in skin cancer is the mutation of a single p53 allele. We observed that a mutant p53(+/R172H) allele expressed in mouse epidermis (K5Cre(+/tg);LSLp53(+/R172H)) showed a significant dominant-negative inhibitory effect on UVB-induced lincRNA-p21 transcription and apoptosis in epidermis. We conclude lincRNA-p21 is highly inducible by UVB and has a key role in triggering UVB-induced apoptotic death. We propose that the mutation of a single p53 allele provides a pro-oncogenic function early in skin cancer development through a dominant inhibitory effect on UVB-induced lincRNA p21 expression and the subsequent evasion of UVB-induced apoptosis. PMID- 25789978 TI - Glycaemic and insulin responses, glycaemic index and insulinaemic index values of rice between three Asian ethnic groups. AB - Asians exhibit larger glycaemic response (GR) and insulin response (IR) than Caucasians, predisposing to an increased risk of type 2 diabetes mellitus (T2DM). We aimed to determine the GR and IR as well as the glycaemic index (GI) and insulinaemic index (II) of two rice varieties among three ethnic groups in Singapore. A total of seventy-five healthy males (twenty-five Chinese, twenty five Malay and twenty-five Asian-Indians) were served the available equivalent carbohydrate amounts (50 g) of test foods (Jasmine rice and Basmati rice) and a reference food (glucose) on separate occasions. Postprandial blood glucose and plasma insulin concentrations were measured at fasting ( -5 and 0 min) and at 15, 30, 45, 60, 90 and 120 min after food consumption. Using the trapezoidal rule, GR, IR, GI and II values were determined. The GR did not differ between ethnic groups for Jasmine rice and Basmati rice. The IR was consistently higher for Jasmine rice (P=0.002) and Basmati rice (P=0.002) among Asian-Indians, probably due to compensatory hyperinsulinaemia to maintain normoglycaemia. The GI and II of both rice varieties did not differ significantly between ethnicities. The overall mean GI for Jasmine rice and Basmati rice were 91 (sd 21) and 59 (sd 15), respectively. The overall mean II for Jasmine rice was 76 (sd 26) and for Basmati rice was 57 (sd 24). We conclude that the GI values presented for Jasmine rice and Basmati rice were applicable to all three ethnic groups in Singapore. Future studies should include deriving the II for greater clinical utility in the prevention and management of T2DM. PMID- 25789980 TI - Evaluation of the association of zoonotic Ljungan virus with perinatal deaths and fetal malformation. AB - More and more epidemiologic and experimental data support the notion that Ljungan virus (LV), originally isolated from some rodent populations in Sweden, Denmark, and the United States, plays an important role in stillbirth and fetal malformation. Mouse dams infected with LV may result in uterine resorption and perinatal deaths that may cross generations, and their offspring may suffer high rates of malformations including cranial, brain, and limb malformations. In humans, researches founded that LV infection is related to malformation, intrauterine fetal death, and even central nervous system malformation. Although molecularly characterized, little is known about the biophysical nature of LV. Consequently, the role of LV infections in sudden infant death syndrome is still confusing, and the mechanism of how LV infections cause diseases is not clear. More research is clearly necessary to explore the mechanisms of LV infection in human and animal diseases to bring improvement to the clinical outcomes. PMID- 25789979 TI - Pulmonologists' Reported Use of Guidelines and Shared Decision-making in Evaluation of Pulmonary Nodules: A Qualitative Study. AB - BACKGROUND: Selecting a strategy (surveillance, biopsy, resection) for pulmonary nodule evaluation can be complex given the absence of high-quality data comparing strategies and the important tradeoffs among strategies. Guidelines recommend a three-step approach: (1) assess the likelihood of malignancy, (2) evaluate whether the patient is a candidate for invasive intervention, and (3) elicit the patient's preferences and engage in shared decision-making. We sought to characterize how pulmonologists select a pulmonary nodule evaluation strategy and the extent to which they report following the guideline-recommended approach. METHODS: We conducted semistructured qualitative interviews with 14 pulmonologists who manage patients with pulmonary nodules at four clinical sites. Transcripts of audiorecorded interviews were analyzed using the principles of grounded theory. RESULTS: Pulmonologists reported consistently performing steps 1 and 2 but described diverse approaches to step 3 that ranged from always engaging the patient in decision-making to never doing so. Many described incorporating patients' preferences only in particular circumstances, such as when the patient appeared particularly anxious or was aggressive in questioning management options. Indeed, other factors, including convenience, physician preferences, physician anxiety, malpractice concerns, and physician experience, appeared to drive decision-making as much as, if not more than, patient preferences. CONCLUSIONS: Although pulmonologists appear to routinely personalize pulmonary nodule evaluation strategies based on the individual patient's risk-benefit tradeoffs, they may not consistently take patient preferences into account during the decision-making process. In the absence of high-quality evidence regarding the optimal methods of pulmonary nodule evaluation, physicians should strive to ensure that management decisions are consistent with patients' values. PMID- 25789981 TI - Experimental evidence shows no fractionation of strontium isotopes ((87)Sr/(86)Sr) among soil, plants, and herbivores: implications for tracking wildlife and forensic science. AB - Strontium isotopes ((87)Sr/(86)Sr) can be useful biological markers for a wide range of forensic science applications, including wildlife tracking. However, one of the main advantages of using (87)Sr/(86)Sr values, that there is no fractionation from geological bedrock sources through the food web, also happens to be a critical assumption that has never been tested experimentally. We test this assumption by measuring (87)Sr/(86)Sr values across three trophic levels in a controlled greenhouse experiment. Adult monarch butterflies were raised on obligate larval host milkweed plants that were, in turn, grown on seven different soil types collected across Canada. We found no significant differences between (87)Sr/(86)Sr values in leachable Sr from soil minerals, organic soil, milkweed leaves, and monarch butterfly wings. Our results suggest that strontium isoscapes developed from (87)Sr/(86)Sr values in bedrock or soil may serve as a reliable biological marker in forensic science for a range of taxa and across large geographic areas. PMID- 25789982 TI - Light-enhanced bacterial killing and wash-free imaging based on AIE fluorogen. AB - The rapid acquisition of antibiotic resistance poses difficulties in the development of effective methods to eliminate pathogenic bacteria. New bactericides, especially those do not induce the emergence of resistance, are thus in great demand. In this work, we report an aggregation-induced emission fluorogen, TPE-Bac, for bacterial imaging and elimination. TPE-Bac can be readily dissolved in aqueous solution with weak emission. The presence of bacteria can turn on its emission, and thus no washing step is required in the imaging process. Meanwhile, TPE-Bac can be applied as a bactericide for elimination of bacteria. The amphiphilic TPE-Bac bearing two long alkyl chains and two positively charged amines can intercalate into the membrane of bacteria, increase membrane permeability and lead to dark toxicity. The efficiency of bacteria killing is greatly enhanced under light irradiation. TPE-Bac can serve as a photosensitizer to induce reactive oxygen species (ROS) generation, which ensures the efficient killing of bacteria. The TPE-Bac-containing agar plates can be continuously used for bacteria killing by applying light to induce ROS generation. PMID- 25789983 TI - Heavy-Metal Phytostabilizing Potential of Agrostis castellana Boiss. & Reuter. AB - The soils of many abandoned mine sites in the central region of Spain are heavily polluted with a number of different metals. Having frequently found Agrostis castellana growing at these old mine sites, this study was designed to assess its remediation capacity for this type of setting. In an initial field study, plant specimens were collected from 4 abandoned mine sites to determine pollutant concentrations in their roots and shoots. This was followed by a 4-year bioassay in a controlled environment in which soils collected from the mines were used to set up microcosms. Maximum root concentrations of the most polluting elements present in the bioassay were 3625 mg kg(-1) Zn, 2793 mg kg(-1) Cu, 13042 mg kg( 1) Pb, 49 mg kg(-1) Cd and 957 mg kg(-1) As. These concentrations represent root bioaccumulation indices of over 1 and usually >2. In contrast, indices of transfer to above-ground phytomass were always < 1, indicating this species is a good candidate for use as a phytostabilizer. However, the high metal concentrations that could reach the above-ground mass of this plant determines a need for close monitoring and avoiding the use of areas under restoration for hunting or grazing. PMID- 25789984 TI - Molecular mechanism of metal-independent decomposition of organic hydroperoxides by halogenated quinoid carcinogens and the potential biological implications. AB - Halogenated quinones (XQ) are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. Organic hydroperoxides (ROOH) can be produced both by free radical reactions and enzymatic oxidation of polyunsaturated fatty acids. ROOH have been shown to decompose to alkoxyl radicals via catalysis by transition metal ions, which may initiate lipid peroxidation or transform further to the reactive aldehydes. However, it is not clear whether XQ react with ROOH in a similar manner to generate alkoxyl radicals metal-independently. By complementary applications of ESR spin-trapping, HPLC/high resolution mass spectrometric and other analytical methods, we found that 2,5-dichloro-1,4-benzoquinone (DCBQ) could significantly enhance the decomposition of a model ROOH tert-butylhydroperoxide, resulting in the formation of t-butoxyl radicals independent of transition metals. On the basis of the above findings, we detected and identified, for the first time, an unprecedented C-centered quinone ketoxy radical. Then, we extended our study to the more physiologically relevant endogenous ROOH 13-hydroperoxy-9,11 octadecadienoic acid and found that DCBQ could also markedly enhance its decomposition to generate the reactive lipid alkyl radicals and the genotoxic 4 hydroxy-2-nonenal (HNE). Similar results were observed with other XQ. In summary, these findings demonstrated that XQ can facilitate ROOH decomposition to produce reactive alkoxyl, quinone ketoxy, lipid alkyl radicals, and genotoxic HNE via a novel metal-independent mechanism, which may explain partly their potential genotoxicity and carcinogenicity. PMID- 25789985 TI - Ethnopedology in the study of toponyms connected to the indigenous knowledge on soil resource. AB - In taking an integrated ethnopedological approach, this study aims to investigate the meaning of the distribution of the toponyms used in traditional and recent cartography of Sardinia (southern Italy). It is particularly, but not only, focused on those related to soil resources. Sardinia is particularly interesting in this respect, as its unique history, geography, and linguistic position makes it one of the Italian and Mediterranean regions with the greatest number of toponyms. This research investigated the toponyms belonging to an important sub region of Sardinia, called Ogliastra (central-eastern Sardinia). The research was conducted through the following integrated approach: i) toponymy research and collection from different sources; ii) database creation and translation of toponyms from the Sardinian language (SL); iii) categorization of toponyms; and iv) graphical, statistical, and cartographic data processing. Distribution and diversity of toponyms were assessed using the compiled database, coupled with a geographical information system (GIS). Of around 7700 toponyms collected, 79% had already been reported in SL, while just 21% were in Italian. Of the toponyms in SL, 77% are of known meaning and 54% of these toponyms were characterized by a meaning directly and/or indirectly connected to specific environmental features. On the whole, morphology would appear to be the primary environmental factor able to explain the complex, articulated presence, distribution, and typology of the investigated toponyms. A least squares regression analysis of pedodiversity vs. topodiversity shows a very closed distribution, with an impressive high correlation index (R2 = 0.824). The principal factor analysis (PFA) shows that such a connection may be morphologically based, thereby confirming that pedodiversity and topodiversity are strongly linked each other. Overall, the research shows that an integrated ethnopedological approach, combining indigenous and scientific knowledge may be of great interest in order to mitigate the impressive phenomena of the indigenous knowledge lost. PMID- 25789986 TI - Neuroendocrine Responses to Transvascular Autonomic Modulation: A Modified Balloon Angioplasty in Multiple Sclerosis Patients. AB - Balloon angioplasty (BA) is a treatment modality to correct vascular lesions in multiple sclerosis (MS) patients, who present with chronic cerebrospinal venous insufficiency (CCSVI). We hypothesized that BA clinical benefits stems in part from improvement in cardiovascular autonomic nervous system (ANS) function. We adopted the Transvascular Autonomic Modulation (TVAM), as a modified BA technique, with the objective of further enhancing ANS functional activities. TVAM involved dilation of multiple vascular beds, including IJVs, azygos and renal veins, and application of manual compression. Since the ANS regulates the function of the hypothalamus pituitary (HPA) axis, we examined TVAM effects on HPA axis in MS patients, and determined the relationship between ANS function and HPA activity. The adrenocorticotropic hormone (ACTH) and cortisol serum levels, systolic and diastolic blood pressure (BP), and heart rate variability (HRV) parameters were measured before and 24 h after TVAM procedure in 72 MS patients. Baseline ACTH and cortisol serum levels were lower than normal ranges in 18% and 25% MS patients respectively. The intervention resulted in significant reductions in both ACTH and cortisol (p<0.001), with a more marked ACTH reduction in males compared to females (p<0.001). Post-TVAM BP increased in patients who presented with baseline BP within lower limits of normal ranges, but decreased in patients with baseline BP above the normal ranges. In a univariate analysis, the changes (Delta) in ACTH serum levels correlated weakly, although significantly, with Delta in diastolic BP (r=-0.265, p=0.03), and Delta in cortisol serum levels correlated weakly, but significantly, with Delta in systolic BP (r=-0.283, p=0.01). The observed ACTH and cortisol reductions are counter to the stress mediated increases in serum levels of these hormones, which are expected following an invasive procedure. The clinical implications of this unexpected response warrant further investigations. PMID- 25789987 TI - Quinoline compound KM11073 enhances BMP-2-dependent osteogenic differentiation of C2C12 cells via activation of p38 signaling and exhibits in vivo bone forming activity. AB - Recombinant human bone morphogenetic protein (rhBMP)-2 has been approved by the FDA for clinical application, but its use is limited due to high cost and a supra physiological dose for therapeutic efficacy. Therefore, recent studies have focused on the generation of new therapeutic small molecules to induce bone formation or potentiate the osteogenic activity of BMP-2. Here, we show that [4 (7-chloroquinolin-4-yl) piperazino][1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4 yl]methanone (KM11073) strongly enhances the BMP-2-stimulated induction of alkaline phosphatase (ALP), an early phase biomarker of osteoblast differentiation, in bi-potential mesenchymal progenitor C2C12 cells. The KM11073 mediated ALP induction was inhibited by the BMP antagonist noggin, suggesting that its osteogenic activity occurs via BMP signaling. In addition, a pharmacological inhibition study suggested the involvement of p38 activation in the osteogenic action of KM11073 accompanied by enhanced expression of BMP-2, -6, and -7 mRNA. Furthermore, the in vivo osteogenic activity of KM11073 was confirmed in zebrafish and mouse calvarial bone formation models, suggesting the possibility of its single use for bone formation. In conclusion, the combination of rhBMP-2 with osteogenic small molecules could reduce the use of expensive rhBMP-2, mitigating the undesirable side effects of its supra-physiological dose for therapeutic efficacy. Moreover, due to their inherent physical properties, small molecules could represent the next generation of regenerative medicine. PMID- 25789988 TI - A bioengineered nisin derivative to control biofilms of Staphylococcus pseudintermedius. AB - Antibiotic resistance and the shortage of novel antimicrobials are among the biggest challenges facing society. One of the major factors contributing to resistance is the use of frontline clinical antibiotics in veterinary practice. In order to properly manage dwindling antibiotic resources, we must identify antimicrobials that are specifically targeted to veterinary applications. Nisin is a member of the lantibiotic family of antimicrobial peptides that exhibit potent antibacterial activity against many gram-positive bacteria, including human and animal pathogens such as Staphylococcus, Bacillus, Listeria, and Clostridium. Although not currently used in human medicine, nisin is already employed commercially as an anti-mastitis product in the veterinary field. Recently we have used bioengineering strategies to enhance the activity of nisin against several high profile targets, including multi-drug resistant clinical pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) and also against staphylococci and streptococci associated with bovine mastitis. However, newly emerging pathogens such as methicillin resistant Staphylococcus pseudintermedius (MRSP) pose a significant threat in terms of veterinary health and as a reservoir for antibiotic resistance determinants. In this study we created a nisin derivative with enhanced antimicrobial activity against S. pseudintermedius. In addition, the novel nisin derivative exhibits an enhanced ability to impair biofilm formation and to reduce the density of established biofilms. The activities of this peptide represent a significant improvement over that of the wild-type nisin peptide and merit further investigation with a view to their use to treat S. pseudintermedius infections. PMID- 25789989 TI - A pilot study of omalizumab in eosinophilic esophagitis. AB - Eosinophilic disorders of the gastrointestinal tract are an emerging subset of immune pathologies within the spectrum of allergic inflammation. Eosinophilic Esophagitis (EoE), once considered a rare disease, is increasing in incidence, with a rate of over 1 in 10,000 in the US, for unknown reasons. The clinical management of EoE is challenging, thus there is an urgent need for understanding the etiology and pathophysiology of this eosinophilic disease to develop better therapeutic approaches. In this open label, single arm, unblinded study, we evaluated the effects of an anti-IgE treatment, omalizumab, on local inflammation in the esophagus and clinical correlates in patients with EoE. Omalizumab was administered for 12 weeks to 15 subjects with long standing EoE. There were no serious side effects from the treatment. Esophageal tissue inflammation was assessed both before and after therapy. After 3 months on omalizumab, although tissue Immunoglobulin E (IgE) levels were significantly reduced in all but two of the subjects, we found that full remission of EoE, which is defined as histologic and clinical improvement only in 33% of the patients. The decrease in tryptase positive cells and eosinophils correlated significantly with the clinical outcome as measured by improvement in endoscopy and symptom scores, respectively. Omalizumab-induced remission of EoE was limited to subjects with low peripheral blood absolute eosinophil counts. These findings demonstrate that in a subset of EoE patients, IgE plays a role in the pathophysiology of the disease and that anti-IgE therapy with omalizumab may result in disease remission. Since this study is open label there is the potential for bias, hence the need for a larger double blind placebo controlled study. The data presented in this pilot study provides a foundation for proper patient selection to maximize clinical efficacy. PMID- 25789991 TI - Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression. AB - The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1alpha (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1alpha, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-kappaB (Nuclear factor-kappaB) signaling. PMID- 25789990 TI - Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies. AB - The enzymes decaprenylphosphoryl-beta-D-ribose oxidase (DprE1) and decaprenylphosphoryl-beta-D-ribose-2-epimerase (DprE2) catalyze epimerization of decaprenylphosporyl ribose (DPR) todecaprenylphosporyl arabinose (DPA) and are critical for the survival of Mtb. Crystal structures of DprE1 so far reported display significant disordered regions and no structural information is known for DprE2. We used homology modeling, protein threading, molecular docking and dynamics studies to investigate the structural and dynamic features of Mtb DprE1 and DprE2 and DprE1-DprE2 complex. A three-dimensional model for DprE2 was generated using the threading approach coupled with ab initio modeling. A 50 ns simulation of DprE1 and DprE2 revealed the overall stability of the structures. Principal Component Analysis (PCA) demonstrated the convergence of sampling in both DprE1 and DprE2. In DprE1, residues in the 269-330 area showed considerable fluctuation in agreement with the regions of disorder observed in the reported crystal structures. In DprE2, large fluctuations were detected in residues 95 113, 146-157, and 197-226. The study combined docking and MD simulation studies to map and characterize the key residues involved in DprE1-DprE2 interaction. A 60 ns MD simulation for DprE1-DprE2 complex was also performed. Analysis of data revealed that the docked complex is stabilized by H-bonding, hydrophobic and ionic interactions. The key residues of DprE1 involved in DprE1-DprE2 interactions belong to the disordered region. We also examined the docked complex of DprE1-BTZ043 to investigate the binding pocket of DprE1 and its interactions with the inhibitor BTZ043. In summary, we hypothesize that DprE1-DprE2 interaction is crucial for the synthesis of DPA and DprE1-DprE2 complex may be a new therapeutic target amenable to pharmacological validation. The findings have important implications in tuberculosis (TB) drug discovery and will facilitate drug development efforts against TB. PMID- 25789992 TI - Risky business: factor analysis of survey data - assessing the probability of incorrect dimensionalisation. AB - This paper undertakes a systematic assessment of the extent to which factor analysis the correct number of latent dimensions (factors) when applied to ordered-categorical survey items (so-called Likert items). We simulate 2400 data sets of uni-dimensional Likert items that vary systematically over a range of conditions such as the underlying population distribution, the number of items, the level of random error, and characteristics of items and item-sets. Each of these datasets is factor analysed in a variety of ways that are frequently used in the extant literature, or that are recommended in current methodological texts. These include exploratory factor retention heuristics such as Kaiser's criterion, Parallel Analysis and a non-graphical scree test, and (for exploratory and confirmatory analyses) evaluations of model fit. These analyses are conducted on the basis of Pearson and polychoric correlations. We find that, irrespective of the particular mode of analysis, factor analysis applied to ordered categorical survey data very often leads to over-dimensionalisation. The magnitude of this risk depends on the specific way in which factor analysis is conducted, the number of items, the properties of the set of items, and the underlying population distribution. The paper concludes with a discussion of the consequences of over-dimensionalisation, and a brief mention of alternative modes of analysis that are much less prone to such problems. PMID- 25789993 TI - Identifying new targets for cancer drug 5'-fluorouracil. PMID- 25789994 TI - Molecular hazard identification of non-O157 Shiga toxin-producing Escherichia coli (STEC). AB - The complexity regarding Shiga toxin-producing Escherichia coli (STEC) in food safety enforcement as well as clinical care primarily relates to the current inability of an accurate risk assessment of individual strains due to the large variety in serotype and genetic content associated with (severe) disease. In order to classify the clinical and/or epidemic potential of a STEC isolate at an early stage it is crucial to identify virulence characteristics of putative pathogens from genomic information, which is referred to as 'predictive hazard identification'. This study aimed at identifying associations between virulence factors, phylogenetic groups, isolation sources and seropathotypes. Most non-O157 STEC in the Netherlands belong to phylogroup B1 and are characterized by the presence of ehxA, iha and stx2, but absence of eae. The large variability in the number of virulence factors present among serogroups and seropathotypes demonstrated that this was merely indicative for the virulence potential. While all the virulence gene associations have been worked out, it appeared that there is no specific pattern that would unambiguously enable hazard identification for an STEC strain. However, the strong correlations between virulence factors indicate that these arrays are not a random collection but are rather specific sets. Especially the presence of eae was strongly correlated to the presence of many of the other virulence genes, including all non-LEE encoded effectors. Different stx-subtypes were associated with different virulence profiles. The factors ehxA and ureC were significantly associated with HUS-associated strains (HAS) and not correlated to the presence of eae. This indicates their candidacy as important pathogenicity markers next to eae and stx2a. PMID- 25789995 TI - Platinum anniversary: virus and lichen alga together more than 70 years. AB - Trebouxia aggregata (Archibald) Gartner (phylum Chlorophyta, family Trebouxiaceae), a lichen symbiotic alga, has been identified as host of the well known herbaceous plant virus Cauliflower mosaic virus (CaMV, family Caulimoviridae). The alga had been isolated from Xanthoria parietina more than 70 years ago and has been maintained in a collection since that time. The CaMV detected in this collection entry has now been completely sequenced. The virus from T. aggregata is mechanically transmissible to a herbaceous host and induces disease symptoms there. Its genome differs by 173 nt from the closest European CaMV-D/H isolate from cauliflower. No site under positive selection was found on the CaMV genome from T. aggregata. We therefore assume that the virus's presence in this alga was not sufficiently long to fix any specific changes in its genome. Apart from this symbiotic alga, CaMV capsid protein sequences were amplified from many other non-symbiotic algae species maintained in a collection (e.g., Oonephris obesa, Elliptochloris sp., Microthamnion kuetzingianum, Chlorella vulgaris, Pseudococcomyxa sp.). CaMV-free Chlorella vulgaris was treated with CaMV to establish virus infection. The virus was still detected there after five passages. The virus infection is morphologically symptomless on Chlorella algae and the photosynthesis activity is slightly decreased in comparison to CaMV-free alga culture. This is the first proof as to the natural presence of CaMV in algae and the first demonstration of algae being artificially infected with this virus. PMID- 25789996 TI - Effects of separation distance on the charge transfer interactions in quantum dot dopamine assemblies. AB - We explored the effects of changing the separation distance on the charge transfer interactions between luminescent QD and proximal dopamine (in QD dopamine assemblies), and the ensuing photoluminescence (PL) quenching. The separation distance was controlled using a tunable size bridge between the QD and dopamine via a poly(ethylene glycol) (PEG) chain where the average number of monomers was discretely varied. Using steady-state and time-resolved fluorescence measurements, we found that the photoluminescence losses were substantially more pronounced for QD-dopamine complexes prepared with the shortest PEG bridge, but progressively decreased with increasing PEG size. We also found that the charge transfer interactions can be affected by the nature of the capping ligand used. In particular, we found that interactions and PL quenching in these assemblies tracked the effects of separation distance, conjugate valence and the energy mismatch between the dopamine redox levels and QD energy levels, when a compact zwitterion was used to control the conjugate configuration. However, additional effects of shielding the access of reactive dopamine to amine groups on the QD surface, when a longer inert PEG ligand was used, were found to produce heterogeneous conjugates, alter the interactions and produce weaker PL quenching. PMID- 25789997 TI - Methane dynamics in an alpine fen: a field-based study on methanogenic and methanotrophic microbial communities. AB - Wetlands are important sources of the greenhouse gas methane (CH4). We provide an in situ study of CH4 dynamics in the permanently submerged soil of a Swiss alpine fen. Physico-chemical pore water analyses were combined with structural and microbiological analyses of soil cores at high vertical resolution down to 50 cm depth. Methanotrophs and methanogens were active throughout the depth profile, and highest abundance of active methanotrophs and methanogens [6.1 * 10(5) and 1.1 * 10(7) pmoA and mcrA transcripts (g soil)(-1), respectively] was detected in the uppermost 2 cm of the soil. Active methanotrophic communities in the near surface zone, dominated by viable mosses, varied from the communities in the deeper zones, but further changes with depth were not pronounced. Apart from a distinct active methanogenic community in the uppermost sample, a decrease of acetoclastic Methanosaetaceae with depth was observed in concomitance with decreasing root surface area. Overall, root surface area correlated with mcrA transcript abundance and CH4 pore water concentrations, which peaked (137.1 MUM) at 10 to 15 cm depth. Our results suggest that stimulation of methanogenesis by root exudates of vascular plants had a stronger influence on CH4 dynamics than stimulation of CH4 oxidation by O2 input. PMID- 25789999 TI - Correction: Role of macrophage migration inhibitory factor (MIF) in pollen induced allergic conjunctivitis and pollen dermatitis in mice. PMID- 25789998 TI - Dendrimer-Inspired Nanomaterials for the in Vivo Delivery of siRNA to Lung Vasculature. AB - Targeted RNA delivery to lung endothelial cells has the potential to treat conditions that involve inflammation, such as chronic asthma and obstructive pulmonary disease. To this end, chemically modified dendrimer nanomaterials were synthesized and optimized for targeted small interfering RNA (siRNA) delivery to lung vasculature. Using a combinatorial approach, the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length. The top performing materials from in vivo screens were found to primarily target Tie2-expressing lung endothelial cells. At high doses, the dendrimer-lipid derivatives did not cause chronic increases in proinflammatory cytokines, and animals did not suffer weight loss due to toxicity. We believe these materials have potential as agents for the pulmonary delivery of RNA therapeutics. PMID- 25790000 TI - shRNA off-target effects in vivo: impaired endogenous siRNA expression and spermatogenic defects. AB - RNA interference (RNAi) is widely used to determine the function of genes. We chose this approach to assess the collective function of the highly related reproductive homeobox 3 (Rhox3) gene paralogs. Using a Rhox3 short hairpin (sh) RNA with 100% complementarity to all 8 Rhox3 paralogs, expressed from a CRE regulated transgene, we successfully knocked down Rhox3 expression in male germ cells in vivo. These Rhox3-shRNA transgenic mice had dramatic defects in spermatogenesis, primarily in spermatocytes and round spermatids. To determine whether this phenotype was caused by reduced Rhox3 expression, we generated mice expressing the Rhox3-shRNA but lacking the intended target of the shRNA-Rhox3. These double-mutant mice had a phenotype indistinguishable from Rhox3-shRNA expressing mice that was different from mice lacking the Rhox3 paralogs, indicating that the Rhox3 shRNA disrupts spermatogenesis independently of Rhox3. Rhox3-shRNA transgenic mice displayed few alterations in the expression of protein-coding genes, but instead exhibited reduced levels of all endogenous siRNAs we tested. This supported a model in which the Rhox3 shRNA causes spermatogenic defects by sequestering one or more components of the endogenous small RNA biogenesis machinery. Our study serves as a warning for those using shRNA approaches to investigate gene functions in vivo. PMID- 25790001 TI - TRIMming down tumor suppressors in breast cancer. PMID- 25790003 TI - Fasting does not induce gastric emptying in rats. AB - PURPOSE: To evaluate the effect of fasting on gastric emptying in mice. METHODS: Twenty-eight mice were distributed into three study groups: a normal group (N=4): normal standard animals; a total fasting group (N=12): subjected to food and water deprivation and a partial fasting group (N=12): subjected to food deprivation only. The fasting groups were subdivided into three subgroups of four animals each, according to the date of euthanasia: 24, 48 and 72 hours. Was analyzed: the gastric volume, degree of the gastric wall distention and the presence of food debris in gastrointestinal tract. RESULTS: The mean gastric volume was 1601 mm3 in the normal group, 847 mm3 in total fasting group and 997 mm3 in partial fasting group. There was difference between the fasting groups in any analyzed period (p<0.05). Regarding the presence of food debris in the gastrointestinal tract and the degree of distension of the stomach, there was no difference between the groups that underwent total or partial fasting (p>0.05). CONCLUSION: Total fasting or only-solids deprivation does not induce gastric emptying in mice. PMID- 25790004 TI - Clotting factor XIII and desmopressin improve hemostasis in uncontrolled bleeding. AB - PURPOSE: To investigate hemostatic effects of supplementary factor XIII and desmopressin (DDAVP) in resuscitation of uncontrolled bleeding. METHODS: Fifty four rabbits were randomized in nine groups: G1: Sham; G2: FXIII and normotensive resuscitation (NBP); G3: FXIII and permissive hypotension (PH) (MAP 60% baseline); G4: FXIII/DDAVP/NBP; G5: FXIII/DDAVP/PH; G6: NBP only; G7: FXIII no hemorrhage; G8: FXIII/DDAVP no hemorrhage; G9: PH only. Thromboelastometry and intra-abdominal blood loss were assessed. Scanning electron microscopy (EM) of the clots was performed. RESULTS: Compared to Sham, only G8 (FXIII/DDAVP w/o hemorrhage) showed clotting time (CT) significantly lower (p<0.05). NBP alone (G6) resulted in significantly prolonged CT compared to G2, G3 and G5 (p<0.05). Similarly, median alpha angle was significantly larger in G3,4,5, and 9 compared to G6 (p<0.05). Area under the curve was significantly greater in G5 than G2. Intra-abdominal blood loss was lower in G5 and G9 compared to G2 and G6. FXIII/DDAVP and PH resulted in more robust fibrin mesh by EM. CONCLUSIONS: Normotensive resuscitation provokes more bleeding and worsens coagulation compared to pH, that is partially reversed by factor XIII and desmopressin. FXIII and DDAVP can synergistically improve coagulation. Permissive hypotension reduces bleeding regardless of those agents. PMID- 25790005 TI - Respiratory immunohistochemical study in rats exposed to cigarette smoke and alcohol. AB - PURPOSE: To investigate the effects of exposure to cigarette and alcohol on immunohistochemical disorders caused by these attacks to respiratory system of rats. METHODS: Sixty male Wistar rats in four groups: control, cigarette smoke, alcohol and cigarette smoke + alcohol during 260 days. Immunohistochemistry was performed by researching survivin and protein P53 expressions and apoptotic index in parenchymal lung and trachea using TUNEL technique. RESULTS: There was body growth impairment in all experimental groups. Both smoker groups animals had higher trachea survivin expression and bronchial higher apoptotic index. The trachea apoptotic index was also higher in the cigarette smoke group as well as in the alveoli in the cigarette smoke + alcohol group. The three experimental groups showed negative immunoexpression for P53. CONCLUSIONS: this model resulted in immunohistochemical changes caused mainly by exposure to cigarette smoke. There was a synergistic action between alcohol and tobacco in the growth impairment in animals as well as in the cellular apoptotic index. The positive immunoexpression for tracheal survivin in animals from both groups exposed to tobacco smoke and associated with a negative P53 immunoexpression suggests that despite the aggression, carcinogenesis has not happened yet. In addition, the bronchial higher apoptotic index in smokers may be responsible for emphysema. PMID- 25790002 TI - Default mode network connectivity as a function of familial and environmental risk for psychotic disorder. AB - BACKGROUND: Research suggests that altered interregional connectivity in specific networks, such as the default mode network (DMN), is associated with cognitive and psychotic symptoms in schizophrenia. In addition, frontal and limbic connectivity alterations have been associated with trauma, drug use and urban upbringing, though these environmental exposures have never been examined in relation to DMN functional connectivity in psychotic disorder. METHODS: Resting state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 non-psychotic siblings of patients with psychotic disorder and 72 healthy controls. Posterior cingulate cortex (PCC) seed-based correlation analysis was used to estimate functional connectivity within the DMN. DMN functional connectivity was examined in relation to group (familial risk), group * environmental exposure (to cannabis, developmental trauma and urbanicity) and symptomatology. RESULTS: There was a significant association between group and PCC connectivity with the inferior parietal lobule (IPL), the precuneus (PCu) and the medial prefrontal cortex (MPFC). Compared to controls, patients and siblings had increased PCC connectivity with the IPL, PCu and MPFC. In the IPL and PCu, the functional connectivity of siblings was intermediate to that of controls and patients. No significant associations were found between DMN connectivity and (subclinical) psychotic/cognitive symptoms. In addition, there were no significant interactions between group and environmental exposures in the model of PCC functional connectivity. DISCUSSION: Increased functional connectivity in individuals with (increased risk for) psychotic disorder may reflect trait related network alterations. The within-network "connectivity at rest" intermediate phenotype was not associated with (subclinical) psychotic or cognitive symptoms. The association between familial risk and DMN connectivity was not conditional on environmental exposure. PMID- 25790006 TI - Effect of sugarcane biopolymer in vocal fold of rabbits. Comparative study with calcium hydroxyapatite. AB - PURPOSE: To compare the inflammatory reaction caused by the injection of a sugarcane biopolymer (SCB) into the vocal fold of rabbits with that caused by calcium hydroxyapatite (CaH). METHODS: CaH (Radiesse(r)) and SCB gel were injected respectively into the right and left vocal cords of thirty rabbits. The rabbits were distributed into two equal groups and sacrificed at three and twelve weeks after injection. We then evaluated the intensity of the inflammatory reaction, plus levels of neovascularization, fibrogenesis and inflammatory changes in the vocal mucosa. RESULTS: The vocal cords injected with CaH had a stronger inflammatory reaction by giant cells in both study periods. The SCB group had a more intense inflammatory involvement of polymorphonuclear cells three weeks after injection. SCB caused a higher level of neovascularization compared with CaH three weeks after the procedure. CONCLUSION: Whereas calcium hydroxyapatite triggers a more intense and lasting inflammatory reaction mediated by giant cells, sugarcane biopolymer causes a greater response from polymorphonuclear leukocytes, as well as higher levels of vneoascularization three weeks after injection. PMID- 25790007 TI - Prevention of peritoneal adhesion using a bacterial cellulose hydrogel, in experimental study. AB - PURPOSE: To analyze the effectiveness of bacterial cellulose hydrogel as a barrier in preventing postoperative peritoneal adhesion in rat model. METHODS: Experimental study with 45 Wistar rats (Rattus norvegicus) that were divided into three groups for the following treatments: A. Saline, B. Oxidized Regenerated Cellulose (ORC) barrier, and C Bacterial Cellulose Hydrogel (BCH) barrier. After 45 days of the surgery the adhesions were classified and graded according to the qualitative score. The histological parameters were evaluated using a modified semi-quantitative scale to rate the extent of fibrosis, inflammatory reaction and vascular proliferation. RESULTS: Compared with the saline group (A), the treatments with ORC barrier (B) and BHC barrier (C) resulted in a smaller number of adhesions (p=0.019 and p=0.003 on Fisher's exact test, respectively). Data from inflammation and neovascularization showed no statistically significant difference between the groups BHC and ORC (p=0.426 and 0.446 on chi-square test, respectively). CONCLUSION: Bacterial cellulose hydrogel is effective as a bio-re absorbable barrier for preventing postoperative peritoneal adhesions. PMID- 25790008 TI - Preconditioning with L-alanyl-glutamine upon cerebral edema and hypocampus red neurons counting in rats subjected to brain ischemia/reperfusion injury. AB - PURPOSE: To evaluate the effects of the dipeptide L-alanyl-glutamine (L-Ala-Gln) as a preconditioning agent to potentially promote reduction in the intensity of lesion or induction of resilience in rats subjected to global cerebral ischemia/reperfusion (I/R) injury. METHODS: Thirty-six male Wistar rats weighing 280-300 g were randomly assigned to six groups (n = 6). Groups Sham 1h and 24h were treated with saline and spared of further interventions. The remaining groups were submitted to clamping of the common carotid arteries for 30 minutes (ischemia) and treated with saline (SS) or L-Ala-Gln. Brain reperfusion was allowed for 1 or 24 h. L-Ala-Gln was administered intravenously (0.75 g/kg) 30 minutes before sham procedure or induction of global brain I/R injury. Brain edema and red neuron counting were determined. Results were expressed as Mean +/- SD for normal results and Median +/- Percentile for non parametric data. Significance was established at p < 0.05. RESULTS: Global I/R injury promoted an increase in brain edema at 24 h after reperfusion, whereas preconditioning with L Ala-Gln induced no change in edema. On the other hand, L-Ala-Gln preconditioning decreased significantly red neurons counting both at 1h and 24h post reperfusion (p < 0.05). CONCLUSION: There was a significant preconditioning effect with L-Ala Gln decreasing cell death (red neurons counting) at early (1h) and late reperfusion (24h) in the cerebral tissue. PMID- 25790009 TI - Use of low-power laser to assist the healing of traumatic wounds in rats. AB - PURPOSE: To investigate the morphological aspects of the healing of traumatic wounds in rats using low-power laser. METHODS: Twenty four non isogenic, young adult male Wistar rats (Rattus norvegicus) weighing between 200 and 300 g was used. The animals were randomly distributed into two groups: Control (GC) and Laser (GL), with 12 animals each. After shaving, anesthesia was performed in the dorsal region and then a surgical procedure using a scalpel was carried out to make the traumatic wound. GL received five sessions of laser therapy in consecutive days using the following laser parameters: wavelength 660 nm, power 100 mW, dose 10 J/cm2. The wounds were evaluated through measurement of the area and depth of the wound (MW) and histological analysis (HA). RESULTS: When comparing the GC with the GL in MW there was a difference in area (p<0.001) and depth (p=0.003) measurement of the wounds in GL. The laser group presented more epithelization than GC (p=0.03). The other histological parameters were similar. CONCLUSION: The healing of wounds in rats was improved with the use of the laser. PMID- 25790010 TI - Effects of heterologous platelet-rich plasma gel on standardized dermal wound healing in rabbits. AB - PURPOSE: To evaluate the potential of heterologous platelet-rich plasma (PRP) gel for surgical skin wound healing in rabbits. METHODS: Blood from a single healthy dog was used for PRP production, with calcium gluconate added to the PRP to form the gel. Two surgical excisions, one to the right and the other to the left of the dorsal midline, were made in six rabbits. One side was randomly allocated to topical application of a physiological solution, and the other was allocated to treatment with heterologous PRP gel. Clinical assessments (weight, pain sensitivity, coloring, edema, hyperemia, exudation, crust, and granulation) and morphometric evaluations were performed 0, 3, 7, 10, 14, and 17 days postoperatively. Histological analysis was performed on the 17th day. RESULTS: With the exception of the presence of a crust at day 10, clinical variables did not differ significantly between the experimental groups. In both the control and PRP-treated groups, differences were identified when comparing time-points in terms of wound area reduction. Histological results indicated no significant differences between the control group and the PRP-treated group. CONCLUSION: Heterologous platelet-rich plasma gel promoted dermal wound healing in rabbits with no adverse effects. PMID- 25790011 TI - Reduction of contractility and reactivity in isolated lymphatics from hemorrhagic shock rats with resuscitation. AB - PURPOSE: To evaluate the changes of contractility and reactivity in isolated lymphatics from hemorrhagic shock rats with resuscitation. METHODS: Six rats in the shock group suffered hypotension for 90 min by hemorrhage, and resuscitation with shed blood and equal ringer's solution. Then, the contractility of lymphatics, obtained from thoracic ducts in rats of the shock and sham groups, were evaluated with an isolated lymphatic perfusion system using the indices of contractile frequency (CF), tonic index (TI), contractile amplitude (CA) and fractional pump flow (FPF). The lymphatic reactivity to substance P (SP) was evaluated with the different volume of CF, CA, TI and FPF between pre- and post treatment of SP at different concentrations. RESULTS: The CF, FPF, and TI of lymphatics obtained from the shocked rats were significantly decreased than that of the sham group. After SP stimulation, the ?CF (1 * 10(-8), 3 * 10(-8), 1 * 10( 7), 3 * 10(-7) mol/L), ?FPF (1 * 10(-8), 3 * 10(-8), 1 * 10(-7) mol/L), and ?TI (1 * 10(-8) mol/L) of lymphatics in the shock group were also obviously lower compared with the sham group. In addition, there were no statistical differences in CA and ?CA between two groups. CONCLUSION: Lymphatic contractility and reactivity to substance P appears reduction following hemorrhagic shock with resuscitation. PMID- 25790012 TI - Effects of ropivacaine combined with morphine at 0.15 and 0.2 mg kg(-1) in bitches undergoing epidural anesthesia. AB - PURPOSE: To investigate cardiorespiratory effects and serum concentration of ropivacaine combined with morphine at different doses. METHODS: Sixteen healthy adult female dogs weighting 9.8 +/- 4.1 kg were included in the study. Twenty minutes after being premedicated with acepromazine and midazolam, the animals were randomly assigned to receive an epidural injection according to each group: RM0.15 = ropivacaine + morphine (0.15 mg kg(-1)) and RM0.2 = ropivacaine + morphine (0.2 mg kg(-1)). Variables recorded consisted of: heart rate and cardiac rhythm, respiratory rate, oxyhemoglobin saturation, inspired oxygen fraction, end tidal carbon dioxide tension, systolic, mean and diastolic arterial pressures, serum cortisol, plasma ropivacaine and morphine. RESULTS: SAP, MAP and DAP were significantly increased at TPR in RM0.15 but returned to normal values at the end of the procedure. Arterial pH was decreased in T30 and TESu in both groups and also returned to acceptable ranges at TR. Both PaO2 and PaCO2 were increased along the duration period of the epidural blockade (T30 and TESu) and returned to acceptable values at TR. Serum cortisol was lower at TB, T30 and TR when compared to TESu. CONCLUSION: The procedures were performed safely and minimal changes in cardiovascular and respiratory variables. PMID- 25790013 TI - Is previous experience in laparoscopic necessary to perform robotic radical prostatectomy? A comparative study with robotic and the classic open procedure in patients with prostate cancer. AB - PURPOSE: To assess comparative results of robot-assisted radical laparoscopic prostatectomy (RARP) performed by surgeons without any experience in laparoscopic prostatectomy and the open procedure performed by surgeons with large experience. METHODS: We analyzed 84 patients (50 subjected to robotic surgery) from June 2012 to September 2013. Data were prospectively collected in a customized database. Two surgeons carried out all the RARP cases. These two surgeons and six more performed the open cases. The perioperative outcomes between the two groups were analyzed with a minimum followup of 12 months. RESULTS: The corporal mass index (BMI) was higher in the open group (p=0.001). There was more operatve time, less hospitalization and blood loss, better trifecta and pentafecta and earlier continence (p=0.045) in the robotic group (p=0.001). There was no difference in positive surgical margins but with greater extraprostatic extension in the open group (p=0.002). CONCLUSIONS: Robot-assisted radical prostatectomy is a safe procedure even in the hands of surgeons with no previous experience. Besides this, better operative outcomes can be reached with this modern approach. PMID- 25790014 TI - White-light-exciting, layer-by-layer-assembled ZnCdHgSe quantum dots/polymerized ionic liquid hybrid film for highly sensitive photoelectrochemical immunosensing of neuron specific enolase. AB - ZnCdHgSe quantum dots (QDs) functionalized with N-acetyl-l-cysteine were synthesized and characterized. Through layer-by-layer assembling, the ZnCdHgSe QDs was integrated with a polymerized 1-decyl-3-[3-pyrrole-1-yl propyl]imidazolium tetrafluoroborate (PDPIT) ionic liquid film modified indium tin oxide (ITO) electrode to fabricated a photoelectrochemical interface for the immobilization of rabbit antihuman neuron specific enolase (anti-NSE). After being treated with glutaraldehyde vapor and bovine serum albumin successively, an anti-NSE/ZnCdHgSe QDs/PDPIT/ITO sensing platform was established. Simplely using a white-light LED as an excitation source, the immunoassay of neuron specific enolase (NSE) was achieved through monitoring the photocurrent variation. The polymerized ionic liquid film was demonstrated to be an important element to enhance the photocurrent response of ZnCdHgSe QDs. The anti-NSE/ZnCdHgSe QDs/PDPIT/ITO based immunosensor presents excellent performances in neuron specific enolase determination. The photocurrent variation before and after being interacted with NSE exhibits a good linear relationship with the logarithm of its concentration (log cNSE) in the range from 1.0 pg mL(-1) to 100 ng mL(-1). The limit of detection of this immunosensor is able to reach 0.2 pg mL(-1) (S/N = 3). The determination of NSE in clinical human sera was also demonstrated using anti NSE/ZnCdHgSe QDs/PDPIT/ITO electrode. The results were found comparable with those obtained by using enzyme-linked immunosorbent assay method. PMID- 25790015 TI - Enhancing mechanical performance of a covalent self-healing material by sacrificial noncovalent bonds. AB - Polymers that repair themselves after mechanical damage can significantly improve their durability and safety. A major goal in the field of self-healing materials is to combine robust mechanical and efficient healing properties. Here, we show that incorporation of sacrificial bonds into a self-repairable network dramatically improves the overall mechanical properties. Specifically, we use simple secondary amide side chains to create dynamic energy dissipative hydrogen bonds in a covalently cross-linked polymer network, which can self-heal via olefin cross-metathesis. We envision that this straightforward sacrificial bonding strategy can be employed to improve mechanical properties in a variety of self-healing systems. PMID- 25790016 TI - Lipid-membrane-incorporated hydrophobic photochromic molecules prepared by the exchange method using cyclodextrins. AB - It was found that the exchange method for the preparation of lipid-membrane incorporated guest molecules was applicable not only to fullerenes but also to other hydrophobic molecules such as azobenzene and stilbene. The advantages of this method are that the long-term stability of the lipid-membrane-incorporated azobenzene solution and the maximum ratio of [stilbene]/[lipid] were higher than those prepared by the classical method, which we call the 'premixing method'. Photoisomerisations of these photochromic guest molecules in the lipid membranes maintained the morphology of liposomes. PMID- 25790017 TI - East London experience with enteric fever 2007-2012. AB - PURPOSE: The clinical presentation and epidemiology for patients with enteric fever at two hospitals in East London during 2007-2012 is described with the aim to identify preventive opportunities and to reduce the cost of treatment. METHODS: A retrospective analysis of case notes from patients admitted with enteric fever during 2007 to 2012 with a microbiologically confirmed diagnosis was undertaken. Details on clinical presentation, travel history, demographic data, laboratory parameters, treatment, patient outcome and vaccination status were collected. RESULTS: Clinical case notes were available for 98/129 (76%) patients including 69 Salmonella enterica serovar Typhi (S. Typhi) and 29 Salmonella enterica serovar Paratyphi (S. Paratyphi). Thirty-four patients (35%) were discharged from emergency medicine without a diagnosis of enteric fever and then readmitted after positive blood cultures. Seventy-one of the 98 patients (72%) were UK residents who had travelled abroad, 23 (23%) were foreign visitors/new entrants to the UK and four (4%) had not travelled abroad. Enteric fever was not considered in the initial differential diagnosis for 48/98 (49%) cases. The median length of hospital stay was 7 days (range 0-57 days). The total cost of bed days for managing enteric fever was L454,000 in the two hospitals (mean L75,666/year). Median time to clinical resolution was five days (range 1 20). Seven of 98 (7%) patients were readmitted with relapsed or continued infection. Six of the 71 (8%) patients had received typhoid vaccination, 34 (48%) patients had not received vaccination, and for 31 cases (44%) vaccination status was unknown. CONCLUSIONS: Further interventions regarding education and vaccination of travellers and recognition of the condition by emergency medicine clinicians in travellers to South Asia is required. PMID- 25790018 TI - Circuit class therapy or seven-day week therapy for increasing rehabilitation intensity of therapy after stroke (CIRCIT): a randomized controlled trial. AB - BACKGROUND: Increased therapy has been linked to improvements in functional ability of people with stroke. AIM: To determine the effectiveness of two alternative models of increased physiotherapy service delivery (seven-day week therapy or group circuit class therapy five days a week) to usual care. METHOD: Three-armed randomized controlled trial with blinded assessment of outcome. People admitted with a diagnosis of stroke, previously independently ambulant and with a moderate level of disability were recruited. 'Usual care' was individual physiotherapy provided five-days a week. Seven-day week therapy was usual care physiotherapy provided seven-days a week. Participants in the circuit class therapy arm of the trial received physiotherapy in group circuit classes in two 90-min sessions, five-days a week. Primary outcome was distance walked on the six minute walk test at four-weeks post-randomization. RESULTS: Two hundred eighty three participants were randomized; primary outcome data were available for 259 (92%). In the seven-day arm participants received an additional three hours of physiotherapy and those in the circuit class arm an additional 22 h. There were no significant between-group differences at four-weeks in walking distance (P = 0.72). Length of stay was shorter for seven-day (mean difference -2.9 days, 95% confidence interval -17.9 to 12.0) and circuit class participants (mean difference -9.2 days, 95% confidence interval -24.2 to 5.8) compared to usual care, but this was not significant. CONCLUSIONS: Both seven-day therapy and group circuit class therapy increased physiotherapy time, but walking outcomes were equivalent to usual care. PMID- 25790019 TI - Genome wide analysis of flowering time trait in multiple environments via high throughput genotyping technique in Brassica napus L. AB - The prediction of the flowering time (FT) trait in Brassica napus based on genome wide markers and the detection of underlying genetic factors is important not only for oilseed producers around the world but also for the other crop industry in the rotation system in China. In previous studies the low density and mixture of biomarkers used obstructed genomic selection in B. napus and comprehensive mapping of FT related loci. In this study, a high-density genome-wide SNP set was genotyped from a double-haploid population of B. napus. We first performed genomic prediction of FT traits in B. napus using SNPs across the genome under ten environments of three geographic regions via eight existing genomic predictive models. The results showed that all the models achieved comparably high accuracies, verifying the feasibility of genomic prediction in B. napus. Next, we performed a large-scale mapping of FT related loci among three regions, and found 437 associated SNPs, some of which represented known FT genes, such as AP1 and PHYE. The genes tagged by the associated SNPs were enriched in biological processes involved in the formation of flowers. Epistasis analysis showed that significant interactions were found between detected loci, even among some known FT related genes. All the results showed that our large scale and high-density genotype data are of great practical and scientific values for B. napus. To our best knowledge, this is the first evaluation of genomic selection models in B. napus based on a high-density SNP dataset and large-scale mapping of FT loci. PMID- 25790020 TI - Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine. AB - Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol. PMID- 25790021 TI - The Dissociative Subtype of Posttraumatic Stress Disorder: Unique Resting-State Functional Connectivity of Basolateral and Centromedial Amygdala Complexes. AB - Previous studies point towards differential connectivity patterns among basolateral (BLA) and centromedial (CMA) amygdala regions in patients with posttraumatic stress disorder (PTSD) as compared with controls. Here we describe the first study to compare directly connectivity patterns of the BLA and CMA complexes between PTSD patients with and without the dissociative subtype (PTSD+DS and PTSD-DS, respectively). Amygdala connectivity to regulatory prefrontal regions and parietal regions involved in consciousness and proprioception were expected to differ between these two groups based on differential limbic regulation and behavioral symptoms. PTSD patients (n=49) with (n=13) and without (n=36) the dissociative subtype and age-matched healthy controls (n=40) underwent resting-state fMRI. Bilateral BLA and CMA connectivity patterns were compared using a seed-based approach via SPM Anatomy Toolbox. Among patients with PTSD, the PTSD+DS group exhibited greater amygdala functional connectivity to prefrontal regions involved in emotion regulation (bilateral BLA and left CMA to the middle frontal gyrus and bilateral CMA to the medial frontal gyrus) as compared with the PTSD-DS group. In addition, the PTSD+DS group showed greater amygdala connectivity to regions involved in consciousness, awareness, and proprioception-implicated in depersonalization and derealization (left BLA to superior parietal lobe and cerebellar culmen; left CMA to dorsal posterior cingulate and precuneus). Differences in amygdala complex connectivity to specific brain regions parallel the unique symptom profiles of the PTSD subgroups and point towards unique biological markers of the dissociative subtype of PTSD. PMID- 25790023 TI - Characterization of synergistic embryotoxicity of nickel and buprofezin in zebrafish. AB - Multiple pollutants, usually at low levels, coexist and may interact in the environment. It is therefore important to analyze the toxicity of mixtures of coexisting chemicals to evaluate the potential ecological risk. Concern regarding the co-occurrence and combined bioeffects of heavy metals and organic insecticides in aquatic settings has existed for many years, but a clear understanding of the interactions between and potential combined toxicity of these chemicals remains elusive. In the present study, the combined effects of the heavy metal nickel (NiSO4) and insect growth regulator buprofezin on the induction of embryo toxicity in zebrafish were assessed. By applying nonlinear regression to the concentration-response data with each of the chemicals using the Hill and Langmuir functions and computing the predictions using the model of concentration addition (CA), we confirmed that NiSO4 and buprofezin acted together to produce synergistic embryotoxicity in zebrafish. Subsequently, we further found that the combination of NiSO4 and buprofezin formed a complex that facilitated the uptake of nickel (Ni) and buprofezin by the embryos. Following this, we clarified that an oxidative mechanism of the complex might underlie the synergistic embryotoxicity of NiSO4 and buprofezin. PMID- 25790022 TI - Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. AB - Attention deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders, and is often treated with stimulant medication. Nonpharmacological treatments include dietary supplementation with omega-3 fatty acids, although their effectiveness remains to be shown conclusively. In this study, we investigated the effects of dietary omega-3 fatty acid supplementation on ADHD symptoms and cognitive control in young boys with and without ADHD. A total of 40 boys with ADHD, aged 8-14 years, and 39 matched, typically developing controls participated in a 16-week double-blind randomized placebo-controlled trial. Participants consumed 10 g of margarine daily, enriched with either 650 mg of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) each or placebo. Baseline and follow-up assessments addressed ADHD symptoms, fMRI of cognitive control, urine homovanillic acid, and cheek cell phospholipid sampling. EPA/DHA supplementation improved parent-rated attention in both children with ADHD and typically developing children. Phospholipid DHA level at follow-up was higher for children receiving EPA/DHA supplements than placebo. There was no effect of EPA/DHA supplementation on cognitive control or on fMRI measures of brain activity. This study shows that dietary supplementation with omega-3 fatty acids reduces symptoms of ADHD, both for individuals with ADHD and typically developing children. This effect does not appear to be mediated by cognitive control systems in the brain, as no effect of supplementation was found here. Nonetheless, this study offers support that omega-3 supplementation may be an effective augmentation for pharmacological treatments of ADHD (NCT01554462: The Effects of EPA/DHA Supplementation on Cognitive Control in Children with ADHD; http://clinicaltrials.gov/show/NCT01554462). PMID- 25790024 TI - At what level of heat load are age-related impairments in the ability to dissipate heat evident in females? AB - Studies have reported that older females have impaired heat loss responses during work in the heat compared to young females. However, it remains unclear at what level of heat stress these differences occur. Therefore, we examined whole-body heat loss [evaporative (HE) and dry heat loss, via direct calorimetry] and changes in body heat storage (?Hb, via direct and indirect calorimetry) in 10 young (23+/-4 years) and 10 older (58+/-5 years) females matched for body surface area and aerobic fitness (VO2peak) during three 30-min exercise bouts performed at incremental rates of metabolic heat production of 250 (Ex1), 325 (Ex2) and 400 (Ex3) W in the heat (40 degrees C, 15% relative humidity). Exercise bouts were separated by 15 min of recovery. Since dry heat gain was similar between young and older females during exercise (p=0.52) and recovery (p=0.42), differences in whole-body heat loss were solely due to HE. Our results show that older females had a significantly lower HE at the end of Ex2 (young: 383+/-34 W; older: 343+/ 39 W, p=0.04) and Ex3 (young: 437+/-36 W; older: 389+/-29 W, p=0.008), however no difference was measured at the end of Ex1 (p=0.24). Also, the magnitude of difference in the maximal level of HE achieved between the young and older females became greater with increasing heat loads (Ex1=10.2%, Ex2=11.6% and Ex3=12.4%). Furthermore, a significantly greater ?Hb was measured for all heat loads for the older females (Ex1: 178+/-44 kJ; Ex2: 151+/-38 kJ; Ex3: 216+/-25 kJ, p=0.002) relative to the younger females (Ex1: 127+/-35 kJ; Ex2: 96+/-45 kJ; Ex3: 146+/-46 kJ). In contrast, no differences in HE or ?Hb were observed during recovery (p>0.05). We show that older habitually active females have an impaired capacity to dissipate heat compared to young females during exercise-induced heat loads of >=325 W when performed in the heat. PMID- 25790025 TI - On disciplinary fragmentation and scientific progress. AB - Why are some scientific disciplines, such as sociology and psychology, more fragmented into conflicting schools of thought than other fields, such as physics and biology? Furthermore, why does high fragmentation tend to coincide with limited scientific progress? We analyzed a formal model where scientists seek to identify the correct answer to a research question. Each scientist is influenced by three forces: (i) signals received from the correct answer to the question; (ii) peer influence; and (iii) noise. We observed the emergence of different macroscopic patterns of collective exploration, and studied how the three forces affect the degree to which disciplines fall apart into divergent fragments, or so called "schools of thought". We conducted two simulation experiments where we tested (A) whether the three forces foster or hamper progress, and (B) whether disciplinary fragmentation causally affects scientific progress and vice versa. We found that fragmentation critically limits scientific progress. Strikingly, there is no effect in the opposite causal direction. What is more, our results shows that at the heart of the mechanisms driving scientific progress we find (i) social interactions, and (ii) peer disagreement. In fact, fragmentation is increased and progress limited if the simulated scientists are open to influence only by peers with very similar views, or when within-school diversity is lost. Finally, disciplines where the scientists received strong signals from the correct answer were less fragmented and experienced faster progress. We discuss model's implications for the design of social institutions fostering interdisciplinarity and participation in science. PMID- 25790026 TI - Neural control of enhanced filtering demands in a combined Flanker and Garner conflict task. AB - Several studies demonstrated that visual filtering mechanisms might underlie both conflict resolution of the Flanker conflict and the control of the Garner effect. However, it remains unclear whether the mechanisms involved in the processing of both effects depend on similar filter mechanisms, such that especially the Garner effect is able to modulate filtering needs in the Flanker conflict. In the present experiment twenty-four subjects participated in a combined Garner and Flanker task during two runs of functional magnetic resonance imaging (fMRI) recordings. Behavioral data showed a significant Flanker but no Garner effect. A run-wise analysis, however, revealed a Flanker effect in the Garner filtering condition in the first experimental run, while we found a Flanker effect in the Garner baseline condition in the second experimental run. The fMRI data revealed a fronto-parietal network involved in the processing of both types of effects. Flanker interference was associated with activity in the inferior frontal gyrus, the anterior cingulate cortex, the precuneus as well as the inferior (IPL) and superior parietal lobule (SPL). Garner interference was associated with activation in middle frontal and middle temporal gyrus, the lingual gyrus as well as the IPL and SPL. Interaction analyses between the Garner and the Flanker effect additionally revealed differences between the two experimental runs. In the first experimental run, activity specifically related to the interaction of effects was found in frontal and parietal regions, while in the second run we found activity in the hippocampus, the parahippocampal cortex and the basal ganglia. This shift in activity for the interaction effects might be associated with a task-related learning process to control filtering demands. Especially perceptual learning mechanisms might play a crucial role in the present Flanker and Garner task design and, therefore, increased performance in the second experimental run could be the reason for the lack of behavioral Garner interference on the level of the whole experiment. PMID- 25790027 TI - Modeling the anesthetic effect of ropivacaine after a femoral nerve block in orthopedic patients: a population pharmacokinetic-pharmacodynamic analysis. AB - BACKGROUND: Even though ropivacaine is frequently used during orthopedic surgery, the relationship between plasma concentrations and degree of sensory anesthesia after a peripheral nerve block is currently unknown. The aim of this study was to characterize this relation using population pharmacokinetic-pharmacodynamic modeling. METHODS: Femoral nerve block was performed by the anterior approach using a single injection (20 ml) of 0.5% ropivacaine hydrochloride in 20 patients scheduled for total knee arthroplasty under spinal anesthesia. Sensory thresholds in response to a gradual increase in transcutaneous electrical stimulation (primary endpoints), loss and recovery of ice-cold sensation, as well as total ropivacaine plasma concentrations were determined up to 4 days after administration of the local anesthetic. Using NONMEM (ICON, USA), sensory block was modeled by assuming an equilibration delay (ke0) between amount in the depot and effect-site compartments. RESULTS: Mean effect-site amount producing 90% of the maximum possible effect (AE90) was estimated as 20.2 mg. At 2 * AE90, the sigmoid Emax model predicted a mean onset time of 23.4 min and mean duration of 22.9 h. Interindividual variability (IIV) for AE50 was 49%. Typical ke0 half-life was 34.7 min (IIV = 52%) and steepness parameter 8.7 (IIV = 48%). None of the pharmacodynamic model parameters showed sex, age, or body weight dependency. CONCLUSIONS: A population pharmacokinetic/pharmacodynamic model was developed that quantitatively describes the sensory component of a femoral nerve block in orthopedic patients. Further clinical studies will be needed to validate the clinical relevance of this finding. PMID- 25790028 TI - Trauma Fifty-Four. PMID- 25790029 TI - Intercarrier interference reduction in MC-CDMA system through second order duobinary coded phase rotated conjugate cancellation scheme. AB - Multi-carrier code division multiple access (MC-CDMA) technique is one of the strong candidates for next generation wireless mobile communication systems. Multi-carrier systems are very much sensitive to carrier frequency offset (CFO) results in intercarrier interference (ICI). To mitigate ICI without any spectral loss, a second order duobinary coded phase rotated conjugate cancellation algorithm is proposed in this paper. In the conventional phase rotated conjugate cancellation (PRCC) technique, one path carries the MC-CDMA signal with a phase spin of phi and the other path carries the conjugate of the first path signal with -phi phase spin. This artificial phase rotation allows the transmitter to tune the transmitted signals so that the ICI effects could be mutually cancelled at the receiver. Although the PRCC technique reduces the spectral efficiency, the limitation can be overcome by the joint second order duobinary coding scheme with PRCC technique. In the proposed method, the correlative coding between the binary symbols modulated on adjacent subcarriers is used to reduce the ICI without any spectral loss. Simulation results show that the proposed PRCC method provides better carrier to interference ratio (CIR) and bit error rate (BER) performances compared to the conventional conjugate cancellation (CC) technique. PMID- 25790030 TI - The interpretation of selection coefficients. AB - Evolutionary biologists have an array of powerful theoretical techniques that can accurately predict changes in the genetic composition of populations. Changes in gene frequencies and genetic associations between loci can be tracked as they respond to a wide variety of evolutionary forces. However, it is often less clear how to decompose these various forces into components that accurately reflect the underlying biology. Here, we present several issues that arise in the definition and interpretation of selection and selection coefficients, focusing on insights gained through the examination of selection coefficients in multilocus notation. Using this notation, we discuss how its flexibility-which allows different biological units to be identified as targets of selection-is reflected in the interpretation of the coefficients that the notation generates. In many situations, it can be difficult to agree on whether loci can be considered to be under "direct" versus "indirect" selection, or to quantify this selection. We present arguments for what the terms direct and indirect selection might best encompass, considering a range of issues, from viability and sexual selection to kin selection. We show how multilocus notation can discriminate between direct and indirect selection, and describe when it can do so. PMID- 25790033 TI - GSH- and pH-responsive drug delivery system constructed by water-soluble pillar[5]arene and lysine derivative for controllable drug release. AB - Novel GSH- and pH-responsive supramolecular vesicles constructed by an amphiphilic inclusion complex formed from water-soluble pillar[5]arene and lysine derivative have been successfully developed, which can efficiently encapsulate anticancer drug MTZ and show rapid MTZ-release in a simulated acidic tumor environment with high GSH concentration, and exhibit potent antitumor activity. PMID- 25790031 TI - Small regulatory RNA-induced growth rate heterogeneity of Bacillus subtilis. AB - Isogenic bacterial populations can consist of cells displaying heterogeneous physiological traits. Small regulatory RNAs (sRNAs) could affect this heterogeneity since they act by fine-tuning mRNA or protein levels to coordinate the appropriate cellular behavior. Here we show that the sRNA RnaC/S1022 from the Gram-positive bacterium Bacillus subtilis can suppress exponential growth by modulation of the transcriptional regulator AbrB. Specifically, the post transcriptional abrB-RnaC/S1022 interaction allows B. subtilis to increase the cell-to-cell variation in AbrB protein levels, despite strong negative autoregulation of the abrB promoter. This behavior is consistent with existing mathematical models of sRNA action, thus suggesting that induction of protein expression noise could be a new general aspect of sRNA regulation. Importantly, we show that the sRNA-induced diversity in AbrB levels generates heterogeneity in growth rates during the exponential growth phase. Based on these findings, we hypothesize that the resulting subpopulations of fast- and slow-growing B. subtilis cells reflect a bet-hedging strategy for enhanced survival of unfavorable conditions. PMID- 25790034 TI - Double localization and multiple recurrences of dermatofibrosarcoma protuberans of the female breast: a rare clinical case. PMID- 25790032 TI - New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies. AB - Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 +/- 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90-110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of -35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with (14)C, with a final activity of 0.097 nCi mg(-1) of NPs. In chronic studies, the biodistribution profile is tracked using low level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical functionality as their non-radiolabeled counterparts. Identical chemical functionality of the radiolabeled probes to the non-radiolabeled probes was an important consideration to generate statistically similar biodistribution data sets using multiple imaging and detection techniques. The radiolabeling approach described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials. PMID- 25790035 TI - Metal-free nitro-carbocyclization of 1,6-enynes with (t)BuONO and TEMPO. AB - A novel and convenient metal-free nitration and cyclization of 1,6-enynes has been developed. Two C-C bonds and one C-N bond were constructed in one process in this reaction. This transformation is proven to have relatively good functional group applicability and can be scaled up to gram quantities in satisfactory yields. According to the following experimental facts and related literature reports, a radical pathway was involved in this transformation. PMID- 25790036 TI - A painless right facial mass. Osteolipoma. PMID- 25790037 TI - Neurological complications after liver transplantation as a consequence of immunosuppression: univariate and multivariate analysis of risk factors. AB - Neurological complications (NCs) can frequently and significantly affect morbidity and mortality of liver transplant (LT) recipients. We analysed incidence, risk factors, outcome and impact of the immunosuppressive therapy on NC development after LT. We analysed 478 LT in 440 patients, and 93 (19.5%) were followed by NCs. The average LOS was longer in patients experiencing NCs. The 1-, 3- and 5-year graft survival and patient survival were similar in patients with or without a NC. Multivariate analysis showed the following as independent risk factors for NC: a MELD score >=20 (OR = 1.934, CI = 1.186-3.153) and an immunosuppressive regimen based on calcineurin inhibitors (CNIs) (OR = 1.669, CI = 1.009-2.760). Among patients receiving an everolimus-based immunosuppression, the 7.1% developed NCs, vs. the 16.9% in those receiving a CNI (P = 0.039). There was a 1-, 3- and 5-year NC-free survival of 81.7%, 81.1% and 77.7% in patients receiving a CNI-based regimen and 95.1%, 93.6% and 92.7% in those not receiving a CNI-based regimen (P < 0.001). In patients undergoing a LT and presenting with nonmodifiable risk factors for developing NCs, an immunosuppressive regimen based on CNIs is likely to result in a higher rate of NCs compared to mTOR inhibitors. PMID- 25790039 TI - Transport of neutral solute across articular cartilage: the role of zonal diffusivities. AB - Transport of solutes through diffusion is an important metabolic mechanism for the avascular cartilage tissue. Three types of interconnected physical phenomena, namely mechanical, electrical, and chemical, are all involved in the physics of transport in cartilage. In this study, we use a carefully designed experimental computational setup to separate the effects of mechanical and chemical factors from those of electrical charges. Axial diffusion of a neutral solute Iodixanol into cartilage was monitored using calibrated microcomputed tomography micro-CT images for up to 48 hr. A biphasic-solute computational model was fitted to the experimental data to determine the diffusion coefficients of cartilage. Cartilage was modeled either using one single diffusion coefficient (single-zone model) or using three diffusion coefficients corresponding to superficial, middle, and deep cartilage zones (multizone model). It was observed that the single-zone model cannot capture the entire concentration-time curve and under-predicts the near equilibrium concentration values, whereas the multizone model could very well match the experimental data. The diffusion coefficient of the superficial zone was found to be at least one order of magnitude larger than that of the middle zone. Since neutral solutes were used, glycosaminoglycan (GAG) content cannot be the primary reason behind such large differences between the diffusion coefficients of the different cartilage zones. It is therefore concluded that other features of the different cartilage zones such as water content and the organization (orientation) of collagen fibers may be enough to cause large differences in diffusion coefficients through the cartilage thickness. PMID- 25790038 TI - Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. AB - Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches. PMID- 25790041 TI - Outcomes of ovarian germ cell tumors: ten years of experience at the Brazilian National Cancer Institute. AB - OBJECTIVE: Ovarian germ cell malignancies are a rare group of chemosensitive malignances that predominantly occur in young women. Bleomycin, etoposide, cisplatin (BEP) regimen was consolidated, by previous studies, as the standard treatment. This Brazilian single institutional study was performed to evaluate our experience in treating patients with ovarian germ cell tumors (OGCTs). METHODS/MATERIALS: A retrospective analysis of all patients as having OGCTs, from April 2003 to July 2013, was carried out at the Brazilian National Cancer Institute. RESULTS: Data on 30 patients were obtained, and 19 patients were treated with BEP. Median overall survival and progression-free survival were not reached. Just 4 (13.3%) patients had progressed and 5 (16.7%) had died up to the date of analysis. The proportion of patients who had dysgerminoma was 53.3%. From the 18 patients considered to have had an incomplete resection, 84.6% achieved objective response (partial or complete response) with chemotherapy. Patients with stage IV and incomplete resection had markedly ominous prognosis. Alopecia was the most frequent adverse event; grade 2 was presented in 17 (89.4%) patients. Nausea and vomiting were related by more than one-half of the patients. Grade 3 and 4 neutropenia was presented in 5 (26.3%) patients. One patient died of pneumonitis related to bleomycin. CONCLUSIONS: Our study confirms the effectiveness of BEP regimen and the great prognosis for patients with OGCTs. Advanced-stage and persistent disease configured as an important risk factor for survival. The chemotherapy regimen was associated with significant but manageable toxicity. PMID- 25790040 TI - Allomyrina dichotoma (Arthropoda: Insecta) larvae confer resistance to obesity in mice fed a high-fat diet. AB - To clarify the anti-obesity effect of Allomyrina dichotoma larvae (ADL), we previously reported that ADL block adipocyte differentiation on 3T3-L1 cell lines through downregulation of transcription factors, such as peroxisome proliferator activated receptor-gamma (PPARG) and CCAAT/enhancer binding protein-alpha (CEBPA). In this study, we tested whether ADL prevent obesity in mice fed a high fat diet (HFD) and further investigated the mechanism underlying the effects of ADL. All mice were maintained on a normal-fat diet (NFD) for 1 week and then assigned to one of five treatment groups: (1) NFD; (2) HFD; (3) HFD and 100 mg.kg(-1).day(-1) ADL; (4) HFD and 3000 mg.kg(-1).day(-1) ADL; or (5) HFD and 3000 mg.kg(-1).day(-1) yerba mate (Ilex paraguariensis, positive control). ADL and yerba mate were administered orally daily. Mice were fed experimental diets and body weight was monitored weekly for 6 weeks. Our results indicated that ADL reduced body weight gain, organ weight and adipose tissue volume in a dose dependent manner. Body weight gain was approximately 22.4% lower compared to mice fed only HFD, but the difference did not reach the level of statistical significance. Real-time polymerase chain reaction (PCR) analysis revealed that gene expression levels of PPARG, CEBPA and lipoprotein lipase (LPL) in the epididymal fat tissue of HFD-fed mice receiving 3000 mg.kg(-1).day(-1) ADL were reduced by 12.4-, 25.7-, and 12.3-fold, respectively, compared to mice fed HFD only. Moreover, mice administered ADL had lower serum levels of triglycerides and leptin than HFD-fed mice that did not receive ADL. Taken together our results suggest that ADL and its constituent bioactive compounds hold potential for the treatment and prevention of obesity. PMID- 25790042 TI - A series of malignant ovarian cancers arising from within a mature cystic teratoma: a single institution experience. AB - BACKGROUND: Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. METHODS: A single institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. RESULTS: During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. CONCLUSIONS: A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors. PMID- 25790043 TI - Isolated port-site metastases after minimally invasive hysterectomy for endometrial cancer: outcomes of patients treated with radiotherapy. AB - OBJECTIVE: The management and prognosis of isolated port-site metastases after laparoscopic surgery for endometrial cancer is poorly understood and rarely described in the literature. We report a series of cases treated with radiotherapy to better characterize outcomes in these patients. METHODS: We retrospectively reviewed medical records of patients with endometrial cancer who developed isolated port-site metastases and were treated with radiation therapy at MD Anderson Cancer Center from 1996 to 2013. Seven patients met these criteria for whom treatment and outcome data were collected. RESULTS: The median interval from initial surgery to port-site recurrence was 15 months. Recurrent tumor size varied from 0.5 to 9 cm as measured on axial imaging. Six of the 7 patients underwent surgical resection of the recurrence. All received radiotherapy to a dose of 45 to 66 Gy. At a median follow-up of 2 years from the time of the port site recurrence, the rate of disease-free survival at 1 and 2 years after the recurrence was 100% and 44%, respectively. The rate of local control and overall survival at 2 years was 100%. CONCLUSIONS: Isolated port-site metastases in the setting of endometrial cancer are associated with high rates of local control when treated with multimodality therapy including radiotherapy. Long-term disease free outcomes in some patients suggest the potential for cure and justify aggressive local therapy. The optimal integration of surgery, chemotherapy, and radiation is unknown. PMID- 25790044 TI - Ultrasound-guided subcostal transversus abdominis plane infiltration with liposomal bupivacaine for patients undergoing robotic-assisted hysterectomy: a retrospective study. AB - OBJECTIVE: We sought to determine the effect of a subcostal transversus abdominis plane (TAP) block with liposomal bupivacaine on postoperative maximal pain score and length of hospital stay among women undergoing robotic-assisted hysterectomy. METHODS: This was a retrospective study comparing patients before and after consistent implementation of TAP blocks with liposomal bupivacaine during robotic assisted hysterectomies at a single academic institution. Analysis compared patient demographic and operative characteristics by TAP block use, along with outcomes of interest, including postoperative pain and length of hospital stay. RESULTS: There was a statistically significant decrease in maximal numerical rating scale pain scores, presence of nausea and vomiting, and length of hospital stay in those who had a TAP block with liposomal bupivacaine compared with those who did not receive a TAP block. These differences remained even after adjustment for potential confounders. CONCLUSIONS: In this retrospective study, liposomal bupivacaine used in a TAP block was a useful method to provide postoperative pain control in patients undergoing robotic-assisted hysterectomy and was associated with lower postoperative maximal pain scores and length of hospital stay. PMID- 25790045 TI - Next generation sequencing technologies: tool to study avian virus diversity. AB - Increased globalisation, climatic changes and wildlife-livestock interface led to emergence of novel viral pathogens or zoonoses that have become serious concern to avian, animal and human health. High biodiversity and bird migration facilitate spread of the pathogen and provide reservoirs for emerging infectious diseases. Current classical diagnostic methods designed to be virus-specific or aim to be limited to group of viral agents, hinder identifying of novel viruses or viral variants. Recently developed approaches of next-generation sequencing (NGS) provide culture-independent methods that are useful for understanding viral diversity and discovery of novel virus, thereby enabling a better diagnosis and disease control. This review discusses the different possible steps of a NGS study utilizing sequence-independent amplification, high-throughput sequencing and bioinformatics approaches to identify novel avian viruses and their diversity. NGS lead to the identification of a wide range of new viruses such as picobirnavirus, picornavirus, orthoreovirus and avian gamma coronavirus associated with fulminating disease in guinea fowl and is also used in describing viral diversity among avian species. The review also briefly discusses areas of viral-host interaction and disease associated causalities with newly identified avian viruses. PMID- 25790046 TI - Possible role of different animal species in maintenance and spread of murine gammaherpesvirus 68 in the nature. AB - Murine gammaherpesvirus 68 (MHV-68), isolated from a bank vole (Clethrionomys glareolus) in Slovakia in 1976 is a natural pathogen of wild murid rodents. This review is focused to biological properties of this pathogen, the mode of its maintenance in murid rodents as reservoir animals, mechanisms of its spread to other animals in the same biotope as well as to livestock and household animals. Potential role of ticks as vectors and the possibility of infection of humans with this virus are considered as well. All the above evidence of the virus infection of various hosts is based on serological or molecular analytical data. The presented knowledge indicates important epizootologic consequences, namely harboring and permanent maintenance of the virus in murid rodents as reservoir animals with a real possibility of spread to other animals in the same biotope. These relationships imply a cross-species virus transmission with potential serious consequences for the infected animals or humans. PMID- 25790047 TI - Tandem overexpression of five human factors renders murine hepatocytes susceptible to hepatitis C virus. AB - Development of mouse model of hepatitis C virus (HCV) infection has great significance in drug screening and vaccine research. The barriers of interspecies transmission of HCV are increasingly better understood. Human factors, namely low density lipoprotein receptor (hLDLR), CD81 (hCD81), scavenger receptor class B type I (hSCARB1), occludin (hOCLN) and claudin 1 (hCLDN1) are all required for rendering mouse hepatocytes permissive to HCV. With the aim to humanize mouse hepatocytes we constructed two recombinant vectors tandemly expressing the first three and the last two HCV entry factors mentioned above, respectively. Cotransfection of mouse hepatocytes with these vectors made them permissive to HCV binding and entry. Tandem overexpression of hLDLR, hSCARB1, hCD81, hCLDN1 and hOCLN is a novel approach to tailoring mouse hepatocytes to HCV binding and entry which can be further used to establish a mouse model of HCV infection as a basis for developing antiviral drugs and vaccines. PMID- 25790048 TI - Molecular epidemiology of avian influenza virus and incidence of H5 and H9 virus subtypes among poultry in Egypt in 2009-2011. AB - Egypt has experienced outbreaks of avian influenza (AI) since 2006. A total of 3583 cloacal swabs were collected from chickens, ducks, geese and turkeys from commercial farms, backyards and local bird markets in Qena and Luxor governorates in South Egypt during 2009-2011. These samples were examined for the presence of AI virus (AIV) and positive samples were further subtyped for the H5 and H9 by real time RT-PCR. In this way, 202 (5.64%) samples were found to be AIV-positive of which 186 (92.08%) and 7 (3.46%) belonged to H5 and H9 subtypes, respectively. Higher infection rates were observed in backyard birds and birds from local bird markets in comparison to birds from commercial farms. In conclusion, the predominance of H5 infection indicates a need for continuous monitoring of AIV among avian species and the awareness against public health risk. PMID- 25790049 TI - Production, characterization and immunogenicity of P particles derived from norovirus GII.4 genotype 2004 variant. AB - Norovirus (NoV) is the main cause of nonbacterial infectious gastroenteritis. Due to the difficulty of culturing the virus, research on vaccine against NoV is focused on virus-like particles (VLPs). On the other hand, the P particles assembled from the P domains of NoV capsid protein become a promising vaccine candidate. GII.4 is the most prevalent genotype of NoV. While the immunogenicity of P particles derived from the GII.4 1996 variant has been investigated, the research on P particles of more recently prevalent variants is lacking. In this study, the P domain of the capsid protein of GII.4 genotype 2004 variant was expressed in Escherichia coli, purified and auto-assembled into P particles of 14 25 nm. Immunization with P particles induced specific serum antibodies with titers of 245,600 and 145,700 in mice and rabbits, respectively. The GII.4 NoV 2004 variant bound to type A, B and O secretor-positive saliva and immune sera blocked this binding, suggesting induction of neutralizing activity in such sera. Thus, this study demonstrated the immunogenicity of NoV P particles generated from E. coli and provided evidence supporting the development of this approach. PMID- 25790050 TI - The effect of BM67 gene deletion on Bombyx mori nuclear polyhedrosis virus replication. AB - Homologs of Bombyx mori nuclear polyhedrosis virus (BmNPV) Bm67 gene ORF67 have been found in the genome of all lepidopteran nuclear polyhedrosis viruses, but their function is still not very clear. In order to analyze it we employed a bacmid harboring the complete BmNPV genome including the Bm67 gene and expressing infectious virus (wtBacmid) for the construction of its Bm67-deficient variant (Bm67-KO-Bacmid) using the Red recombination system and the Bm67-repaired variant (Bm67-Re-Bacmid) using the Bac-to-Bac system. By transfecting BmN cells with these bacmids we demonstrated that the Bm67-deficient virus did not generate infectious virus, while the repaired virus restored its infectivity, indicating that the Bm67 gene is essential for the formation of infectious budding virus (BV). Electron microscopy of BmN cells transfected with the abovementioned bacmids showed many mature rodshaped virus particles in both wtBacmid- and Bm67 Re-Bacmid-transfected cells but none in Bm67-KO-Bacmid-transfected ones. Moreover, the real-time RT-PCR showed that the deletion of Bm67 from wtBacmid significantly reduced the levels of viral genomic DNA and transcripts of viral early genes dnapol, ie-1 and lef-3 but not those of transcripts of late gene vp39 and very late gene p10. The finding that the Bm67-deficient virus generated reduced levels of infectious virus and transcripts of early dnapol gene but not those of late genes indicates that the Bm67 gene is essential for BmNPV replication. PMID- 25790051 TI - Completion sequence and cloning of the infectious cDNA of a chb isolate of cucumber green mottle mosaic virus. AB - Cucumber green mottle mosaic virus (CGMMV) is an important and widespread seed borne virus that infects Cucurbitaceous plants. It is a member of the genus Tobamovirus in the family Virgaviridae with a monopartite (+) ssRNA genome. Here we report the complete genome sequence, construction and testing of the infectious clones of a chb isolate of CGMMV. Full-length CGMMV cDNA was cloned into the vector pUC19. The linearized vector containing full-length cDNA was used as template for in vitro transcription, and the synthesized capped transcript was highly infectious in Chenopodium amaranticolor and cucumber (Cucumis sativus). Inoculated plants showed symptoms typical of CGMMV infection. The infectivity was confirmed by mechanical transmission to new plants, RT-PCR and western blot. Progeny virus derived from infectious transcripts had the same biological and biochemical properties as wild-type virus. To our knowledge, this is the first detailed report of a biologically active transcript from CGMMV. PMID- 25790052 TI - Phylogenetic analysis and biolistic infectivity of a cloned Sri Lankan cassava mosaic virus DNA-A from Tamil Nadu, India on Nicotiana benthamiana. AB - The complete nucleotide sequence of Sri Lankan cassava mosaic virus (SLCMV) DNA-A isolated from cassava in southern India was analyzed, a phylogenetic analysis with other begomoviral nucleotide sequences was performed and an efficient inoculation method of Nicotiana benthamiana with the cloned DNA was developed utilizing a biolistic device. The nucleotide sequence showed the conservation of all functional begomoviral protein domains and aligned most closely with begomoviruses reported from the Indian subcontinent, except for begomoviruses of cucurbits and legumes. Upon biolistic inoculation of N. benthamiana with the cloned DNA, most plants became symptomatic and showed the accumulation of viral DNA within 21-28 days post-inoculation. PMID- 25790053 TI - Indole derivatives inhibit hepatitis C virus replication through induction of pro inflammatory cytokines. AB - Previously, we discovered a series of indole derivatives as a new class of hepatitis C virus (HCV) replication inhibitors by using a target-free chemical genetic strategy. Through a structure-activity relationship study, the compound 12e was identified as the most potent inhibitor of this class (EC50 = 1.1 MUmol/l) with minimal cytotoxicity (CC50 = 61.8 MUmol/l). In order to gain insight into its detailed antiviral mechanism of action, we performed PCR array analyses and found that 12e was able to activate transcription of a number of pro inflammatory as well as antiviral cytokine genes including CXCL-8, IL-1alpha, TNF alpha, IL-3, IRAK-1, and DDX58. Their induction by 12e was verified by individual RT-PCR analyses. In addition, 12e was found to stimulate secretion of soluble factors with anti-HCV replication activity. Among the 12e-induced pro inflammatory cytokines, CXCL-8 showed a strong positive correlation between its transcriptional activation and antiviral potency. Interestingly, a recombinant CXCL-8 protein also reduced HCV replication, though only moderately. In conclusion, we found a novel mode of action of indole derivatives in inhibiting HCV replication, particularly the induction of pro-inflammatory cytokines. PMID- 25790054 TI - Receptor tyrosine kinase signaling regulates replication of the peste des petits ruminants virus. AB - In this study, we found out that blocking the receptor tyrosine kinase (RTK) signaling in Vero cells by tryphostin AG879 impairs the in vitro replication of the peste des petits ruminants virus (PPRV). A reduced virus replication in Trk1 knockdown (siRNA) Vero cells confirmed the essential role of RTK in the virus replication, in particular a specific regulation of viral RNA synthesis. These data represent the first evidence that the RTK signaling regulates replication of a morbillivirus. PMID- 25790055 TI - Immunoreactivity and trypsin sensitivity of recombinant virus-like particles of foot-and-mouth disease virus. AB - Foot-and-mouth disease (FMD) is an important infection affecting the health and productivity of cloven-hoofed livestock. Development of improved vaccines and diagnostic reagents is being explored to facilitate the disease control. There is an emerging interest in virus-like particles (VLPs), as their constituent structural proteins are the major immunogens. The VLPs are similar to natural virus particles but lack viral nucleic acid. The objective of the present study was to express the VLPs of FMD virus (FMDV) serotype Asia-1 (IND 63/72), using baculovirus system and characterize them for antigenic structure. The VLPs expressed in insect cells showed immunoreactivity similar to inactivated cell culture FMDV. Further they possess similar sensitivity to trypsin as the inactivated cell culture FMDV, suggesting that trypsin-sensitive antigenic sites could be similarly arranged. Our findings suggest that the FMD VLPs have similar antigenic conformational feature like the wild type virus, thus supporting their utility in development of non-infectious FMD vaccines and/or diagnostic assays. PMID- 25790056 TI - Self-priming on the plant viral RNAs during reverse transcription-PCR. AB - The occurrence of the primer-independent cDNA synthesis during RT-PCR analysis of human and animal RNA viruses has been well documented. Conversely, there is scant knowledge about this event in plant RNA viruses. Here we show that the primer independent cDNA synthesis occurs in all eight different plant RNA viruses tested in this study, suggesting a common phenomenon for RT-PCR analysis of plant RNA viruses. Additional experiments indicate that the event is likely contributed to by RNA self-priming, and can be effectively reduced or eliminated through increasing temperature of the RT reaction. PMID- 25790057 TI - Comparison of bronchiolitis of human metapneumovirus and human respiratory syncytial virus. PMID- 25790058 TI - A review on protein-protein interaction network of APE1/Ref-1 and its associated biological functions. AB - Apurinic/apyrimidinic endonuclease 1 (APE1) is a classic example of functionally variable protein. Besides its well-known role in (i) DNA repair of oxidative base damage, APE1 also plays a critical role in (ii) redox regulation of transcription factors controlling gene expression for cell survival pathways, for which it is also known as redox effector factor 1 (Ref-1), and recent evidences advocates for (iii) coordinated control of other non-canonical protein-protein interaction(s) responsible for significant biological functions in mammalian cells. The diverse functions of APE1 can be ascribed to its ability to interact with different protein partners, owing to the attainment of unfolded domains during evolution. Association of dysregulation of APE1 with various human pathologies, such as cancer, cardiovascular diseases and neurodegeneration, is attributable to its multifunctional nature, and this makes APE1 a potential therapeutic target. This review covers the important aspects of APE1 in terms of its significant protein protein interaction(s), and this knowledge is required to understand the onset and development of human pathologies and to design or improve the strategies to target such interactions for treatment and management of various human diseases. PMID- 25790059 TI - A segmentation and point-matching enhanced efficient deformable image registration method for dose accumulation between HDR CT images. AB - Deformable image registration (DIR) of fractional high-dose-rate (HDR) CT images is challenging due to the presence of applicators in the brachytherapy image. Point-to-point correspondence fails because of the undesired deformation vector fields (DVF) propagated from the applicator region (AR) to the surrounding tissues, which can potentially introduce significant DIR errors in dose mapping. This paper proposes a novel segmentation and point-matching enhanced efficient DIR (named SPEED) scheme to facilitate dose accumulation among HDR treatment fractions. In SPEED, a semi-automatic seed point generation approach is developed to obtain the incremented fore/background point sets to feed the random walks algorithm, which is used to segment and remove the AR, leaving empty AR cavities in the HDR CT images. A feature-based 'thin-plate-spline robust point matching' algorithm is then employed for AR cavity surface points matching. With the resulting mapping, a DVF defining on each voxel is estimated by B-spline approximation, which serves as the initial DVF for the subsequent Demons-based DIR between the AR-free HDR CT images. The calculated DVF via Demons combined with the initial one serve as the final DVF to map doses between HDR fractions. The segmentation and registration accuracy are quantitatively assessed by nine clinical HDR cases from three gynecological cancer patients. The quantitative analysis and visual inspection of the DIR results indicate that SPEED can suppress the impact of applicator on DIR, and accurately register HDR CT images as well as deform and add interfractional HDR doses. PMID- 25790060 TI - The utility of MRI for pre-operative T and N staging of gastric carcinoma: a systematic review and meta-analysis. AB - OBJECTIVE: To perform a meta-analysis and literature review regarding the diagnostic accuracy of MRI for pre-operative tumour depth invasion (T) and regional lymph node invasion (N) staging of gastric carcinoma (GC). METHODS: Articles were identified through systematic search of Medline, PubMed, Cochrane Library, Web of Science, Springerlink and several Chinese databases. The study quality was assessed by the quality assessment for studies of diagnostic accuracy. 2 reviewers independently extracted and assessed the data from 11 eligible studies. A meta-analysis was then carried out. Subgroup and sensitivity analyses were also performed. RESULTS: 11 studies (439 patients) were finally included in the current review. Among these studies, the significant evidence of heterogeneity was only discovered for specificity in T4 stage (I(2) = 59.8%). Pooled sensitivity and specificity of MRI to diagnose T stage tumour (T3-4 vs T1 2) were 0.93 [95% confidence interval (CI), 0.89-0.96] and 0.91 (95% CI, 0.87 0.95), respectively. Pooled estimates of sensitivity and specificity of MRI to diagnose N stage tumour (N0 vs N+) were 0.86 (95% CI, 0.80-0.92) and 0.67 (95% CI, 0.54-0.79), respectively. Subgroup analyses showed that diffusion-weighted imaging was more helpful for T staging. CONCLUSION: The present systematic review suggests that MRI has a good diagnostic accuracy for pre-operative T staging of GC and should be widely used in clinical work. However, the ability for N staging is relatively poor on MRI. ADVANCES IN KNOWLEDGE: In the pre-operative staging of GC, MRI was a useful tool and may enhance accuracy for the T staging of advanced GC. PMID- 25790061 TI - Development of a diffusion-weighted MRI protocol for multicentre abdominal imaging and evaluation of the effects of fasting on measurement of apparent diffusion coefficients (ADCs) in healthy liver. AB - OBJECTIVE: To assess the effect of fasting and eating on estimates of apparent diffusion coefficient (ADC) in the livers of healthy volunteers using a diffusion weighted MRI protocol with b-values of 100, 500 and 900 s mm(-2) in a multicentre study at 1.5 T. METHODS: 20 volunteers were scanned using 4 clinical 1.5-T MR scanners. Volunteers were scanned after fasting for at least 4 h and after eating a meal; the scans were repeated on a subsequent day. Median ADC estimates were calculated from all pixels in three slices near the centre of the liver. Analysis of variance (ANOVA) was used to assess the difference between ADC estimates in fasted and non-fasted states and between ADC estimates on different days. RESULTS: ANOVA showed no difference between ADC estimates in fasted and non fasted states (p = 0.8) nor between ADC estimates on different days (p = 0.8). The repeatability of the measurements was good, with coefficients of variation of 5.1% and 4.6% in fasted and non-fasted states, respectively. CONCLUSION: There was no significant difference in ADC estimates between fasted and non-fasted measurements, indicating that the perfusion sensitivity of ADC estimates obtained from b-values of 100, 500 and 900 s mm(-2) is sufficiently low that changes in blood flow in the liver after eating are undetectable beyond the variability in the measurements. ADVANCES IN KNOWLEDGE: Assessment of the effect of prandial state on ADC estimates is critical, in order to determine the appropriate patient preparation for biological validation in clinical trials. PMID- 25790062 TI - Forward and reverse (retro) iron(III) or gallium(III) desferrioxamine E and ring expanded analogues prepared using metal-templated synthesis from endo-hydroxamic acid monomers. AB - A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6 amino-N-hydroxyhexanamido)propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals ([M + H(+)](+), m/zcalc 654.3, m/zobs 654.3), yet for [Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded analogues of for-[Fe(DFOE)] and ret [Fe(DFOE)] were prepared from endo-hydroxamic acid monomers with one additional methylene unit in the amine-containing region, 4-[(6-aminohexyl)(hydroxy)amino]-4 oxobutanoic acid (for-HBH) or 3-(7-amino-N-hydroxyheptanamido)propanoic acid (ret HBH), to give the corresponding tris(homoferrioxamine E) macrocycles, for [Fe(HHDFOE)] or ret-[Fe(HHDFOE)] ([M + H(+)](+), m/zcalc 696.3, m/zobs 696.4). The MTS reaction using a constitutional isomer of for-HBH that transposed the methylene unit to the carboxylic acid containing region, 5-[(5 aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (for-PPH), gave the macrocycle for-[Fe(HPDFOE)] in a yield significantly less than that for for-[Fe(HHDFOE)], with the gallium(III) analogue for-[Ga(HPDFOE)] unable to be detected. The work demonstrates the utility and limits of MTS for the assembly of macrocyclic siderophores from endo-hydroxamic acid monomers. Indirect measures (RP-HPLC order of elution, c log P values, molecular mechanics, and density functional theory calculations) of the relative water solubility of the ligands, the iron(III) macrocycles, and the apomacrocycles were consistent in identifying for-DFOE as the most water-soluble macrocycle from for-DFOE, ret-DFOE, for-HHDFOE, ret HHDFOE, and for-HPDFOE. From this group, only for-DFOE is known in nature, which could suggest that water solubility is an important trait in its natural selection. PMID- 25790063 TI - Factors associated with fatal occupational accidents among Mexican workers: a national analysis. AB - OBJECTIVE: To identify the factors associated with fatal occupational injuries in Mexico in 2012 among workers affiliated with the Mexican Social Security Institute. METHODS: Analysis of secondary data using information from the National Occupational Risk Information System, with the consequence of the occupational injury (fatal versus non-fatal) as the response variable. The analysis included 406,222 non-fatal and 1,140 fatal injuries from 2012. The factors associated with the lethality of the injury were identified using a logistic regression model with the Firth approach. RESULTS: Being male (OR=5.86; CI95%: 4.22-8.14), age (OR=1.04; CI95%: 1.03-1.06), employed in the position for 1 to 10 years (versus less than 1 year) (OR=1.37; CI95%: 1.15-1.63), working as a facilities or machine operator or assembler (OR: 3.28; CI95%: 2.12- 5.07) and being a worker without qualifications (OR=1.96; CI95%: 1.18-3.24) (versus an office worker) were associated with fatality in the event of an injury. Additionally, companies classified as maximum risk (OR=1.90; CI 95%: 1.38-2.62), workplace conditions (OR=7.15; CI95%: 3.63-14.10) and factors related to the work environment (OR=9.18; CI95%:4.36-19.33) were identified as risk factors for fatality in the event of an occupational injury. CONCLUSIONS: Fatality in the event of an occupational injury is associated with factors related to sociodemographics (age, sex and occupation), the work environment and workplace conditions. Worker protection policies should be created for groups with a higher risk of fatal occupational injuries in Mexico. PMID- 25790064 TI - High-resolution sequence-function mapping of full-length proteins. AB - Comprehensive sequence-function mapping involves detailing the fitness contribution of every possible single mutation to a gene by comparing the abundance of each library variant before and after selection for the phenotype of interest. Deep sequencing of library DNA allows frequency reconstruction for tens of thousands of variants in a single experiment, yet short read lengths of current sequencers makes it challenging to probe genes encoding full-length proteins. Here we extend the scope of sequence-function maps to entire protein sequences with a modular, universal sequence tiling method. We demonstrate the approach with both growth-based selections and FACS screening, offer parameters and best practices that simplify design of experiments, and present analytical solutions to normalize data across independent selections. Using this protocol, sequence-function maps covering full sequences can be obtained in four to six weeks. Best practices introduced in this manuscript are fully compatible with, and complementary to, other recently published sequence-function mapping protocols. PMID- 25790065 TI - Surgeons' and trainees' perceived self-efficacy in operating theatre non technical skills. AB - BACKGROUND: An important factor that may influence an individual's performance is self-efficacy, a personal judgement of capability to perform a particular task successfully. This prospective study explored newly qualified surgeons' and surgical trainees' self-efficacy in non-technical skills compared with their non technical skills performance in simulated scenarios. METHODS: Participants undertook surgical scenarios challenging non-technical skills in two simulation sessions 6 weeks apart. Some participants attended a non-technical skills workshop between sessions. Participants completed pretraining and post-training surveys about their perceived self-efficacy in non-technical skills, which were analysed and compared with their performance in surgical scenarios in two simulation sessions. Change in performance between sessions was compared with any change in participants' perceived self-efficacy. RESULTS: There were 40 participants in all, 17 of whom attended the non-technical skills workshop. There was no significant difference in participants' self-efficacy regarding non technical skills from the pretraining to the post-training survey. However, there was a tendency for participants with the highest reported self-efficacy to adjust their score downwards after training and for participants with the lowest self efficacy to adjust their score upwards. Although there was significant improvement in non-technical skills performance from the first to second simulation sessions, a correlation between participants' self-efficacy and performance in scenarios in any of the comparisons was not found. CONCLUSION: The results suggest that new surgeons and surgical trainees have poor insight into their non-technical skills. Although it was not possible to correlate participants' self-belief in their abilities directly with their performance in a simulation, in general they became more critical in appraisal of their abilities as a result of the intervention. PMID- 25790066 TI - Day-night variation in heart rate variability changes induced by endotoxaemia in healthy volunteers. AB - BACKGROUND: Morbidity and mortality in response to sepsis may be dependent on clock time for the initiation of sepsis. Endotoxaemia, an experimental model for systemic inflammation, induces alterations in sympatico-vagal balance in the autonomic nervous system (ANS). The activity of sympathetic and parasympathetic activity can be estimated by measuring heart rate variability (HRV). Based on the intimate link between ANS and the inflammatory response, we hypothesized, that HRV changes seen during endotoxaemia would be different based on time of the day the endotoxaemia is initiated. We investigated day/night variation in endotoxaemia-induced changes in HRV. METHODS: A randomized, crossover study with 12 healthy men (age 18-31) was conducted. Endotoxaemia were induced by lipopolysaccharide (LPS) endotoxin 0.3 ng/kg b.w. in two visits (day visit and night visit). At the day visit, endotoxaemia were induced at 12:00 h, and at the night visit it was induced at 24:00 h. Holter recordings were started 1 h before administration of LPS, and continued for 10 h. Time-domain and frequency-domain parameters of HRV were analysed. RESULTS: A total of nine persons finished the study with valid recordings. Endotoxaemia at both night and day resulted in a significant depression in HRV parameters high-frequency power (HF), low-frequency power (LF), standard deviation of normal-to-normal (NN) intervals, root mean square of successive differences and proportion of NN50 divided by total number of NNs (P<0.001). The ratio LF/HF and mean heart rate significantly increased by endotoxaemia (P<0.001). At night-time endotoxaemia, a more pronounced depression of LF, HF and SDNN (P<0.01) and a more pronounced increase in the ratio of LF/HF and mean heart rate (P<0.01) occurred compared with day-time endotoxaemia. CONCLUSION: Endotoxaemia induced changes in HRV exhibit a day-night difference. This difference may have clinical consequences in patients with sepsis. PMID- 25790067 TI - From rational design of organometallic precursors to optimized synthesis of core/shell Ge/GeO2 nanoparticles. AB - The synthesis of germanium nanoparticles has been carried out, thanks to the design of novel aminoiminate germanium(II) precursors: (ATI)GeZ (with Z = OMe, NPh2, and ATI = N,N'-diisopropyl-aminotroponiminate) and (Am)2Ge (Am = N,N' bis(trimethylsilyl)phenyl amidinate). These complexes were fully characterized by spectroscopic techniques as well as single crystal X-ray diffraction. The thermolysis of both complexes yielded NPs which display similar features that are a Ge/GeO2 core/shell structure with a mean diameter close to 5 nm with a narrow size distribution (<15%). Whereas the high temperatures (>300 degrees C) classically reported in the literature for the preparation of germanium-based NPs were necessary for thermolysis of the complexes (ATI)GeZ, the use of amidinate based precursors allows the preparation at an unprecedented low temperature (160 degrees C) for the thermolytic route. As suggested by a mechanistic study, the lower reactivity of (ATI)GeZ (for which the concomitant use of high temperature and acidic reagent is required) was explained in terms of lower ring strain compared to the case of (Am)2Ge. PMID- 25790068 TI - Serial Imaging Surveillance for Patients With a History of Intracranial Aneurysm: Risk of De Novo Aneurysm Formation. AB - BACKGROUND: Although rare, de novo intracranial aneurysms (DNIAs) may develop in patients with a history of intracranial aneurysms (IAs). OBJECTIVE: To evaluate the benefit of routine radiographic screening for DNIAs. METHODS: Data for 2153 patients with IAs were retrospectively analyzed. A total of 185 patients underwent screening for DNIAs at frequent intervals. RESULTS: Overall, DNIAs were detected in 26 patients (1.2%). Of the 185 patients with surveillance, DNIAs developed in 9 (4.9%). The risk of DNIA detection was 1.14% per person-year of follow-up (95% confidence interval: 0.6%-2.2%). Patients with imaging follow-up had a significantly higher rate of DNIA detection compared with patients without regular imaging surveillance (4.9% vs 0.86%; P < .001), but surveillance was associated with smaller lesions (with surveillance: 3.8 +/- 1.8 mm, without: 7.0 +/- 4.4 mm, mean +/- standard deviation; P = .026). A unimodal distribution of time to detection was found in those with surveillance, with a peak between 0 and 2 years. There was a trend toward an association of cigarette smoking and DNIA detection within 10 years (P = .06); 6 of the 26 patients (23.1%) with DNIAs had a history of cigarette smoking, with all 6 patients continuing to smoke up to the detection of the DNIAs, which were detected in 2.5 +/- 1.8 years. CONCLUSION: The low 1.14% per-person year risk of DNIA detection and small DNIA size at detection cannot justify routine screening for DNIAs in all patients with a personal history of IAs. If imaging follow-up is considered for selected patients, early screening will likely yield the most benefit in patients who continue to smoke cigarettes. PMID- 25790069 TI - Establishing Standard Performance Measures in Adult Traumatic Brain Injury Patients. AB - BACKGROUND: The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and Centers for Medicare and Medicaid Services hospital acquired conditions (HACs) are publicly reported metrics that illustrate the overall quality of care provided at an institution. The national incidences of PSIs and HACs in traumatic brain injury (TBI) patients were estimated using the Nationwide Inpatient Sample database. OBJECTIVE: To establish baseline incidences of PSIs and HACs among surgical TBI patients treated at nonfederal hospitals in the United States, and to identify patient factors contributing to these adverse events. METHODS: The Nationwide Inpatient Sample database was queried for patients admitted with International Classification of Diseases, Ninth Revision diagnosis codes consistent with TBI between 2002 and 2011. The incidences of PSIs and HACs were estimated for TBI patients and evaluated for correlation with multiple factors, including comorbidity score, teaching hospital status, and insurance status. RESULTS: There were 15403 total PSIs among 24012 TBI patients. There were only 165 HACs among 24012 TBI patients. Only sepsis, deep vein thrombosis, and pressure ulcers occurred in more than 1% of patients. Patient age, sex, comorbidity score, and teaching hospital status were all found to significantly impact PSI incidence. Comorbidity score was found to significantly impact HAC incidence. Compared with private insurance, Medicaid patients developed significantly more HACs. CONCLUSION: These data may be used as reference values for hospitals reporting their own rates and seeking to improve the quality of care they provide for TBI patients. PMID- 25790070 TI - Covered Stents for the Prevention and Treatment of Carotid Blowout Syndrome. AB - BACKGROUND: Carotid blowout syndrome (CBS) is a life-threatening emergency resulting from compromise of the carotid artery caused by malignancy in the head and neck. OBJECTIVE: To report our experience with covered stents for the prevention or treatment of carotid blowout syndrome secondary to head and neck cancer to ascertain the safety and efficacy of this technique. METHODS: We reviewed the characteristics and outcome of all patients who underwent covered stent placement in the extracranial carotid artery in the setting of head and neck malignancy between 2006 and 2013 at the University of Miami. Patient demographics, presenting symptoms, devices used, perioperative complications, imaging, and follow-up data were reviewed. RESULTS: Seventeen carotids in 15 patients, whose ages ranged from 20 to 84 years (mean, 70.4 years), were treated with 20 covered nitinol (Viabahn Endoprosthesis, Gore, Flagstaff, Arizona) stents. Three patients were treated acutely for bleeding from carotid blowout, and 12 were treated prophylactically for threatened carotid blowout. All patients were given periprocedural dual antiplatelet therapy. No thromboembolic or ischemic complications were noted. Hemorrhage after treatment occurred in 4 patients. In 2 patients, the hemorrhage was from a source not covered by the stent. CONCLUSION: The use of covered stents is a simple, safe, and effective method for treating or preventing carotid blowout syndrome in patients with head and neck malignancy. Carotid artery reconstruction with covered stents may minimize the risk of ischemic complications associated with endovascular or surgical carotid sacrifice. PMID- 25790071 TI - Recurrence Rates After Surgical or Endovascular Treatment of Spinal Dural Arteriovenous Fistulas: A Meta-analysis. AB - BACKGROUND: There is an increasing tendency to treat spinal dural arteriovenous fistulas (SDAVFs) endovascularly despite the lack of clear evidence favoring embolization over surgery. OBJECTIVE: To compare the initial failure and recurrence rates of primary treatment of SDAVFs by surgery and endovascular techniques. METHODS: A meta-analysis using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standard was performed. All the English literature from 2004 onward was evaluated. From each article that compared the 2 treatment modalities, the odds ratio (OR) was calculated. Combined ORs were calculated with Review Manager 5.3 of The Cochrane Collaboration. RESULTS: A total of 35 studies harboring 1112 patients were assessed. Initial definitive fistula occlusion was observed in 588 of 609 surgical patients (96.6%; 95% confidence interval [CI], 94.8-97.8) vs 363 of 503 endovascularly treated patients (72.2%; 95% CI, 68.1-75.9; P < .001). The combined OR from 18 studies that assessed both treatment modalities (730 patients) was 6.15 (95% CI, 3.45 11.0) in favor of surgical treatment. Late recurrence (13 studies, 480 patients) revealed an OR of 3.15 (95% CI, 1.66-5.96; P < .001) in favor of surgery. In a subgroup, recurrence was reported in 10 of 22 patients (45%) treated with Onyx vs 8 of 35 (23%) treated with n-butyle-2-cyanoacrylate (OR, 2.51; 95% CI, 0.75-8.37; P = .13). CONCLUSION: Although hampered by inclusion of poor quality studies, this meta-analysis shows a definite advantage of primary surgical treatment of SDAVF over endovascular treatment in initial failure rate and late recurrences. The often-used argument that endovascular techniques have improved and therefore outweigh surgery is not supported by this meta-analysis. PMID- 25790073 TI - Defibrillator Threshold Testing at Generator Replacement: Is it Time to Abandon the Practice? PMID- 25790072 TI - Senescence-inducible LEC2 enhances triacylglycerol accumulation in leaves without negatively affecting plant growth. AB - The synthesis of fatty acids and glycerolipids in wild-type Arabidopsis leaves does not typically lead to strong triacylglycerol (TAG) accumulation. LEAFY COTYLEDON2 (LEC2) is a master regulator of seed maturation and oil accumulation in seeds. Constitutive ectopic LEC2 expression causes somatic embryogenesis and defects in seedling growth. Here, we report that senescence-inducible LEC2 expression caused a threefold increase in TAG levels in transgenic leaves compared with that in the leaves of wild-type plants. Plant growth was not severely affected by the accumulation the TAG in response to LEC2 expression. The levels of plastid-synthesized lipids, mono- and di-galactosyldiacylglycerol and phosphatidylglycerol were reduced more in senescence-induced LEC2 than in endoplasmic reticulum-synthesized lipids, including phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol. Senescence-induced LEC2 up regulated the expression of many genes involved in fatty acid and TAG biosynthesis at precise times in senescent leaves, including WRINKLED1 (WRI1), which encodes a fatty acid transcription factor. The expressions of glycerol-3 phosphate dehydrogenase 1 and phospholipid:diacylglycerol 2 were increased in the transgenic leaves. Five seed-type oleosin-encoding genes, expressed during oil body formation, and the seed-specific FAE1 gene, which encodes the enzyme responsible for the synthesis of C20:1 and C22:1 fatty acids, were also expressed at higher levels in senescing transgenic leaves than in wild-type leaves. Senescence-inducible LEC2 triggers the key metabolic steps that increase TAG accumulation in vegetative tissues. PMID- 25790074 TI - Larval starvation to satiation: influence of nutrient regime on the success of Acanthaster planci. AB - High density populations of the crown-of-thorns seastar, Acanthaster planci, are a major contributor to the decline of coral reefs, however the causes behind periodic outbreaks of this species are not understood. The enhanced nutrients hypothesis posits that pulses of enhanced larval food in eutrophic waters facilitate metamorphic success with a flow-on effect for population growth. The larval resilience hypothesis suggests that A. planci larvae naturally thrive in tropical oligotrophic waters. Both hypotheses remain to be tested empirically. We raised A. planci larvae in a range of food regimes from starvation (no food) to satiation (excess food). Algal cell concentration and chlorophyll levels were used to reflect phytoplankton conditions in nature for oligotrophic waters (0-100 cells ml(-1); 0-0.01 MUg chl a L(-1)), natural background levels of nutrients on the Great Barrier Reef (GBR) (1,000-10,000 cells ml(-1); 0.1-1.0 MUg chl a L( 1)), and enhanced eutrophic conditions following runoff events (100,000 cells ml( 1); 10 MUg chl a L(-1)). We determine how these food levels affected larval growth and survival, and the metamorphic link between larval experience and juvenile quality (size) in experiments where food ration per larvae was carefully controlled. Phytoplankton levels of 1 MUg chl a L(-1), close to background levels for some reefs on the GBR and following flood events, were optimal for larval success. Development was less successful above and below this food treatment. Enhanced larval performance at 1 MUg chl a L(-1) provides empirical support for the enhanced nutrients hypothesis, but up to a limit, and emphasizes the need for appropriate mitigation strategies to reduce eutrophication and the consequent risk of A. planci outbreaks. PMID- 25790075 TI - Traumatic transection of the lateral rectus muscle with chorioretinitis sclopetaria. AB - A man, aged 67 years, sustained monocular trauma to the left eye while gardening, presenting with light perception, complete absence of abduction, and chorioretinitis sclopetaria. At surgery, the lateral rectus was found to be transected at the equator of the globe, with an area of locally abraded sclera. A few posterior muscle fibers were identified and sutured to the residual anterior fibers. With a partial improvement of the esodeviation, after a further 6 months he proceeded to lateral transposition of the superior and inferior recti to healthy sclera 4 mm from the limbus, with adjunctive medial rectus botulinum toxin. Six months later, the angle of primary deviation remained stable at 4 prism diopters base out with improved abduction. Vision in the eye remained reduced at 20/200 (with eccentric fixation) due to macular changes secondary to the sclopetaria. In conclusion, this case describes a rare example of complete traumatic transection of the lateral rectus with chorioretinitis sclopetaria, due to orbital injury. With appropriate surgery, the angle of deviation can be considerably improved despite complete muscle transection and scleral injury. PMID- 25790076 TI - Mortality among MDR-TB cases: comparison with drug-susceptible tuberculosis and associated factors. AB - BACKGROUND: An increase in multidrug-resistant tuberculosis (MDR-TB) cases is evident worldwide. Its management implies a complex treatment, high costs, more toxic anti-tuberculosis drug use, longer treatment time and increased treatment failure and mortality. The aims of this study were to compare mortality between MDR and drug-susceptible cases of tuberculosis, and to determine risk factors associated with mortality among MDR-TB cases. METHODS AND RESULTS: A retrospective cohort study was performed using data from clinical records of the National Strategy for Prevention and Control of Tuberculosis in Lima, Peru. In the first objective, MDR-TB, compared to drug-susceptible cases, was the main exposure variable and time to death, censored at 180 days, the outcome of interest. For the second objective, different variables obtained from clinical records were assessed as potential risk factors for death among MDR-TB cases. Cox regression analysis was used to determine hazard ratios (HR) and 95% confidence intervals (95%CI). A total of 1,232 patients were analyzed: mean age 30.9 +/-14.0 years, 60.0% were males. 61 patients (5.0%) died during treatment, whereas the MDR-TB prevalence was 19.2%. MDR-TB increased the risk of death during treatment (HR = 7.5; IC95%: 4.1-13.4) when compared to presumed drug-susceptible cases after controlling for potential confounders. Education level (p = 0.01), previous TB episodes (p<0.001), diabetes history (p<0.001) and HIV infection (p = 0.04) were factors associated with mortality among MDR-TB cases. CONCLUSIONS: MDR-TB is associated with an increased risk of death during treatment. Lower education, greater number of previous TB episodes, diabetes history, and HIV infection were independently associated with mortality among MDR-TB cases. New strategies for appropriate MDR-TB detection and management should be implemented, including drug sensitivity tests, diabetes and HIV screening, as well as guarantee for a complete adherence to therapy. PMID- 25790077 TI - Polymer-albumin conjugate for the facilitated delivery of macromolecular platinum drugs. AB - The delivery of macromolecular platinum drugs into cancerous cells is enhanced by conjugating the polymer to albumin. The monomers N-(2 hydroxypropyl)methacrylamide (HPMA) and Boc protected 1,3-diaminopropan-2-yl acrylate (Ac-DAP-Boc) are copolymerized in the presence of a furan protected maleimide functionalized reversible addition-fragmentation chain transfer (RAFT) agent. The resulting polymer with a composition of P(HPMA14 -co-(Ac-DAP-Boc)9 ) and a molecular weight of Mn = 7600 g mol(-1) (D = 1.24) is used as a macromolecular ligand for the conjugation to the platinum drug. Thermogravimetric analysis reveals full conjugation. After deprotection of the maleimide functionality of the polymer, the reactive polymer is conjugated to albumin using the Cys34 functionality. The conjugation is monitored using size exclusion chromatography, MALDI-TOF (matrix assisted laser desorption ionization time-of flight), and SDS Page (sodium dodecyl sulphate polyacrylamide gel electrophoresis). The polymer-albumin conjugates self-assemble in water into nanoparticles of sizes of around 80 nm thanks to the hydrophobic nature of the platinum drugs. The albumin coated nanoparticles are readily taken up by ovarian cancer cell lines and they show superior toxicity compared to a control sample without protein coating. PMID- 25790078 TI - Olfactory sphere cells are a cell source for gamma-aminobutyric acid-producing neurons. AB - Olfactory sphere cells (OSCs) are stem cells generated by culturing olfactory mucosa. Adult rat OSCs express oligodendrocyte progenitor cell (OPC) markers and differentiate into mature oligodendrocytes. Although OSCs also express nestin, a marker of neural stem cells (NSCs), it remains unclear whether adult rat OSCs are multipotent and capable of giving rise to neurons as well as oligodendrocytes. Valproic acid (VPA) is a histone deacetylase inhibitor that has the contradictory capacity to induce both differentiation of NSCs and dedifferentiation of OPCs. This study investigates a potential role for VPA in inducing either differentiation or dedifferentiation of adult rat OSCs. Treatment of OSCs with VPA induced hyperacetylation of histones and decreased cell proliferation in the absence of changes in the number of nestin-positive cells. Furthermore, VPA promoted the genesis of gamma-aminobutyric acid (GABA)-producing neurons identified by expression of Tuj1/GAD67/GABA while repressing oligodendrocyte production. These findings suggest that OSCs treated with VPA did not exhibit stem cell properties indicative of dedifferentiation but rather switched to a neuronal identity during their terminal differentiation. OSCs were then transplanted into the hippocampus of rats with kainic acid-induced temporal lobe epilepsy and were systemically given VPA. Although grafted OSCs expressed Tuj1 and GAD67, these cells did not sufficiently inhibit epileptic activity. These results suggest that OSCs are a transplantable cell source for GABA-producing neurons that can be modulated by VPA. However, further investigation is required to develop them for clinical applications. PMID- 25790080 TI - To go or not to go? PMID- 25790079 TI - Mapping of a quantitative trait locus controlling susceptibility to Coxsackievirus B3-induced viral hepatitis. AB - The pathogenesis of coxsackieviral infection is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a mouse model of Coxsackievirus B3 infection to characterize the contribution of host genetics to infection survival and to viral hepatitis. Twenty-five AcB/BcA recombinant congenic mouse strains were screened. One, BcA86, was found to be particularly susceptible to early mortality; 100% of BcA86 mice died by day 6 compared with 0% of B6 mice (P=0.0012). This increased mortality was accompanied by an increased hepatic necrosis as measured by serum alanine aminotransferase (ALT) levels (19547+/-10556 vs 769+/-109, P=0.0055). This occurred despite a predominantly resistant (C57BL/6) genetic background. Linkage analysis in a cohort (n=210) of (BcA86x C56Bl/10)F2 animals revealed a new locus on chromosome 13 (peak linkage 101.2 Mbp, lod 4.50 and P=0.003). This locus controlled serum ALT levels as early as 48 h following the infection, and led to an elevated expression of type I interferon. Another locus on chromosome 17 (peak linkage 57.2 Mbp) was significantly linked to heart viral titer (lod 3.4 and P=0.046). These results provide new evidence for the presence of genetic loci contributing to the susceptibility of mice to viral hepatitis. PMID- 25790081 TI - COMMUNITY MEMBERS' PERCEPTIONS OF MASS DRUG ADMINISTRATION FOR CONTROL OF LYMPHATIC FILARIASIS IN RURAL AND URBAN TANZANIA. AB - Lymphatic filariasis is one of several neglected tropical diseases with severely disabling and stigmatizing manifestations that are referred to as 'neglected diseases of poverty'. It is a mosquito-borne disease found endemically and exclusively in low-income contexts where, concomitantly, general public health care is often deeply troubled and fails to meet the basic health needs of impoverished populations. This presents particular challenges for the implementation of mass drug administration (MDA), which currently is the principal means of control and eventual elimination. Several MDA programmes face the dilemma that they are unable to attain and maintain the required drug coverage across target groups. In recognition of this, a qualitative study was conducted in the Morogoro and Lindi regions of Tanzania to gain an understanding of community experiences with, and perceptions of, the MDA campaign implemented in 2011 by the National Lymphatic Filariasis Elimination Programme. The study revealed a wide variation of perceptions and experiences regarding the aim, rationale and justification of MDA. There were positive sentiments about the usefulness of the drugs, but many study participants were sceptical about the manner in which MDA is implemented. People were particularly disappointed with the limited attempts by implementers to share information and mobilize residents. In addition, negative sentiments towards MDA for lymphatic filariasis reflected a general feeling of desertion and marginalization by the health care system and political authorities. However, the results suggest that if the communities are brought on board with genuine respect for their integrity and informed self determination, there is scope for major improvements in community support for MDA based control activities. PMID- 25790082 TI - Primary Care Providers and a System Problem: A Qualitative Study of Clinicians Caring for Patients With Incidental Pulmonary Nodules. AB - BACKGROUND: As lung cancer screening with low-dose CT scanning is implemented, an increasing number of people will be diagnosed with pulmonary nodules. Primary care clinicians care for the vast majority of these patients, but their experiences with communication and managing distress in this population are not well understood. METHODS: We conducted qualitative interviews of 15 primary care providers (PCPs) at two academic medical centers who care for patients with pulmonary nodules. We used qualitative description analysis, focusing on clinicians' information exchange and other communication behaviors. RESULTS: Most PCPs believed they had inadequate information to counsel patients regarding lung nodules, although this information is desired. PCPs were concerned patients could "fall through the cracks" but did not have access to a reliable system to ensure follow-up adherence. They were limited by time, knowledge, and resources in providing the preferred level of care. Most PCPs did not discuss the specific risk a nodule was lung cancer, in part because they did not have ready access to this information. PCPs believed most patients did not have substantial distress as a result of nodule detection. Most PCPs did not include patients when making decisions about the follow-up plan. CONCLUSIONS: PCPs often lack systemic resources to optimize patient-centered approaches when discussing incidental pulmonary nodules with patients. With the advent of lung cancer screening, pulmonologists can assist primary care colleagues by providing accurate information to counsel patients and assisting in managing conversations about the risk of cancer. Pulmonologists should support efforts to implement reliable systems to ensure adherence to follow-up. PMID- 25790083 TI - Antibiotic use from conception to diagnosis of child leukaemia as compared to the background population: A nested case-control study. AB - BACKGROUND: The role of infection in the aetiology of childhood leukaemia is unknown. We used prescriptions of antibiotics from Danish pharmacies as a proxy measure for the occurrence of infections. PROCEDURE: We investigated the association between exposure to antibiotics, from conception to leukaemia diagnosis, and the risk of leukaemia. Incident cases of leukaemia among children in Denmark, 1995-2008, with mothers having their earliest conception date in 1995, were individually matched to population controls by age, sex and municipality. Conditional logistic regression analyses assessed antibiotic redemptions in different time periods from conception up to 6 months before the diagnoses of all leukaemia types, acute lymphoblastic leukaemia [ALL] and ALL in 2- to 5-year-old children, adjusting for several potential confounders. RESULTS: A total of 120/360 (33.3%) leukaemia mothers and 1,081/3,509 (30.8%) control mothers redeemed antibiotics during pregnancy (P = 0.32). For children, the equivalent numbers were 276 (76.7%) and 2,665 (75.9%) (P = 0.76). Histograms of antibiotic redemptions showed no temporal differences between leukaemia mothers/children and controls, which was confirmed in adjusted regression analyses (OR [95% CI]: 1.02 [0.75-1.38]). Only antibiotics redeemed during the first year after birth differed from this (OR [95% CI] for ALL diagnosed in 2- to 5-year-old children: 0.46 [0.31-0.66]). CONCLUSIONS: In this hypothesis generating study, the similar amount and pattern of antibiotic redemptions in children with and without leukaemia indicate that infections play a minor role in the aetiology of childhood leukaemia. However, less antibiotic redemptions during the first year of life conform to Greaves' 'delayed infection hypothesis'. PMID- 25790084 TI - Characterisation of aroma profiles of commercial sufus by odour activity value, gas chromatography-olfactometry, aroma recombination and omission studies. AB - Sufu is a solid-state fermented product made from soya beans. For the sake of quality control and regulation purposes, it is essential to be able to identify key odorants of various commercial sufus. To identify the aroma-active compounds in sufus, gas chromatography-olfactometry/aroma extract dilution analysis (GC O/AEDA) was performed, and odour activity value (OAV) was estimated. The correlations between aroma profiles and identified aroma-active compounds were also investigated by principal component analysis. Results showed that 35 aroma active compounds were detected through OAV calculation, while 28 compounds were identified by using GC-O/AEDA. Quantitative descriptive analysis revealed that aroma recombination model based on OAV calculation was more similar to original sufu in terms of aroma comparing to aroma recombination model based on GC-O/AEDA. Omission experiments further confirmed that the aroma compounds, such as ethyl butanoate, ethyl 2-methylbutanoate, ethyl hexanoate, (E,E)-2,4-decadienal and 2,6 dimethylpyrazine, contributed most significantly to the characteristic aroma of a commercial sufu. PMID- 25790085 TI - Blue and blue-green light-emitting cationic iridium complexes: synthesis, characterization, and optoelectronic properties. AB - Two new cationic iridium complexes, [Ir(ppy)2(phpzpy)]PF6 (complex 1) and [Ir(dfppy)2(phpzpy)]PF6 (complex 2), bearing a 2-(3-phenyl-1H-pyrazol-1 yl)pyridine (phpzpy) ancillary ligand and either 2-phenylpyridine (Hppy) or 2 (2,4-difluorophenyl)pyridine (Hdfppy) cyclometalating ligands, were synthesized and fully characterized. The photophysical and electrochemical properties of these complexes were investigated by means of UV-visible spectroscopy, emission spectroscopy, and cyclic voltammetry. Density functional theory (DFT) and time dependent DFT (TD-DFT) calculations were performed to simulate and study the photophysical and electrochemical properties of both complexes. Light-emitting electrochemical cells (LECs) were fabricated by incorporating complexes 1 and 2, which respectively exhibit blue-green (488 and 516 nm) and blue (463 and 491 nm) emission colors, achieved through the meticulous design of the ancillary ligand. The luminance and current efficiency measurements recorded for the LEC based on complex 1 were 1246 cd m(-2) and 0.46 cd A(-1), respectively, and were higher than those measured for complex 2 because of the superior balanced carrier injection and recombination properties of the former. PMID- 25790086 TI - Outcomes from mild and moderate traumatic brain injuries among children and adolescents: A systematic review of studies from 2008-2013. AB - AIM: To systematically review existing empirical evidence concerning neuropsychological, psychosocial and academic outcomes following mild and moderate TBI during childhood and adolescence. METHOD: The studies reviewed include data on 8553 children and adolescents from ages 0-18 that experienced mild and moderate TBIs. A literature search using MeSH terms for 'children' cross referenced with terms associated with 'head injuries' and 'cognition' was conducted using Pubmed, CINAHL Plus and Scopus databases as well as other data sources to retrieve grey literature results. Articles published between 1 January 2008 and 22 April 2013 were included. RESULTS: Fifty-five studies were included in the review, with multiple studies including information on both mild and moderate TBI; 46 studies focused on mild TBI outcomes and 22 studies focused on moderate TBI outcomes. The majority of outcomes were described as psychosocial (50%) or neuropsychological (40%); 51% of studies presented adverse outcomes. CONCLUSIONS: The results suggest that not all children with mild or moderate TBI recover without long-term problems. Few studies followed children and adolescents with mild TBIs for extended periods of time, although it is clinically important to monitor patients over time. PMID- 25790087 TI - The Reliability of Running Performance in a 5 km Time Trial on a Non-motorized Treadmill. AB - The purpose of the study was to establish the reliability of performance and physiological responses during a self-paced 5 km running time trial on a non motorized treadmill. 17 male runners (age: 32+/-13 years, height: 177+/-7 cm, body mass: 71+/-9 kg, sum of 7 skinfolds: 55+/-21 mm) performed familiarization then 2 separate maximal 5 km running time trials on a non-motorized treadmill. Physiological responses measured included heart rate, oxygen uptake, expired air volume, blood lactate concentration, tissue saturation index and integrated electromyography. Running time (1,522+/-163 s vs. 1,519+/-162 s for trials 1 and 2, respectively) demonstrated a low CV of 1.2% and high ICC of 0.99. All physiological variables had CVs of less than 4% and ICCs of >0.92, with the exception of blood lactate concentration (7.0+/-2 mmol.L(-1) vs. 6.5+/-1.5 mmol.L(-1) for trials 1 and 2, respectively; CV: 12%, ICC: 0.83) and the electromyography measures (CV: 8-27%, ICC: 0.71-0.91). The data demonstrate that performance time in a 5 km running time trial on a non-motorized treadmill is a highly reliable test. Most physiological responses measured across the 5 km run also demonstrated good reliability. PMID- 25790088 TI - miR-125a--does the difference lie in the isoform? PMID- 25790089 TI - 3'RR targeting in lymphomagenesis: a promising strategy? PMID- 25790090 TI - Germline/meiotic genes in cancer: new dimensions. PMID- 25790091 TI - Fibroblast-induced matrix remodeling paves the path for invasion. PMID- 25790092 TI - Unveiling physiological functions of extended synaptotagmins. PMID- 25790094 TI - Kinetic analysis of the reduction of 4-nitrophenol catalyzed by Au/Pd nanoalloys immobilized in spherical polyelectrolyte brushes. AB - We present a detailed study of the catalytic activity of Au/Pd nanoalloys with Au : Pd molar ratio 75 : 25 synthesized using spherical polyelectrolyte brushes (SPB) as carrier system. The reduction of 4-nitrophenol (Nip) by sodium borohydride (BH4(-)) has been used as a model reaction. This reaction proceeds in two steps: 4-nitrophenol is first reduced to 4-hydroxylaminophenol which in a second step is reduced to the final product 4-aminophenol. Both steps of the reaction proceed on the surface of the nanoparticles (Langmuir-Hinshelwood mechanism). We use this model to analyze the experimental data obtained by catalysis with the Au/Pd-nanoalloys. Good agreements between theory and experiments were found up to 30% conversion of Nip. The kinetic parameters were compared with the data derived from neat Au and Pd nanoparticles immobilized in the same SPB carrier system. The addition of 25% molar ratio of Pd to the nanoalloys increases the reaction rate of the first step nearly 10 times compared with that of SPB-Au and 60 times compared with that of SPB-Pd. Analysis of the nanoalloy by high-resolution transmission electron microscopy suggests that the surface defects of the nanoalloys play an important role for the enhanced catalytic activity. PMID- 25790093 TI - TAp63gamma is required for the late stages of myogenesis. AB - p53 family members, p63 and p73, play a role in controlling early stage of myogenic differentiation. We demonstrated that TAp63gamma, unlike the other p53 family members, is markedly up-regulated during myogenic differentiation in murine C2C7 cell line. We also found that myotubes formation was inhibited upon TAp63gamma knock-down, as also indicated by atrophyic myotubes and reduction of myoblasts fusion index. Analysis of TAp63gamma-dependend transcripts identified several target genes involved in skeletal muscle contractility energy metabolism, myogenesis and skeletal muscle autocrine signaling. These results indicate that TAp63gamma is a late marker of myogenic differentiation and, by controlling different sub-sets of target genes, it possibly contributes to muscle growth, remodeling, functional differentiation and tissue homeostasis. PMID- 25790095 TI - Aluminum nanocrystals. AB - We demonstrate the facile synthesis of high purity aluminum nanocrystals over a range of controlled sizes from 70 to 220 nm diameter with size control achieved through a simple modification of solvent ratios in the reaction solution. The monodisperse, icosahedral, and trigonal bipyramidal nanocrystals are air-stable for weeks, due to the formation of a 2-4 nm thick passivating oxide layer on their surfaces. We show that the nanocrystals support size-dependent ultraviolet and visible plasmon modes, providing a far more sustainable alternative to gold and silver nanoparticles currently in widespread use. PMID- 25790096 TI - Rapid and liquid-based selection of genetic switches using nucleoside kinase fused with aminoglycoside phosphotransferase. AB - The evolutionary design of genetic switches and circuits requires iterative rounds of positive (ON-) and negative (OFF-) selection. We previously reported a rapid OFF selection system based on the kinase activity of herpes simplex virus thymidine kinase (hsvTK) on the artificial mutator nucleoside dP. By fusing hsvTK with the kanamycin resistance marker aminoglycoside-(3')-phosphotransferase (APH), we established a novel selector system for genetic switches. Due to the bactericidal nature of kanamycin and nucleoside-based lethal mutagenesis, both positive and negative selection could be completed within several hours. Using this new selector system, we isolated a series of homoserine lactone-inducible genetic switches with different expression efficiencies from libraries of the Vibrio fischeri lux promoter in two days, using only liquid handling. PMID- 25790097 TI - IGF1 regulates PKM2 function through Akt phosphorylation. AB - Pyruvate kinase M2 (PKM2) acts at the crossroad of growth and metabolism pathways in cells. PKM2 regulation by growth factors can redirect glycolytic intermediates into key biosynthetic pathway. Here we show that IGF1 can regulate glycolysis rate, stimulate PKM2 Ser/Thr phosphorylation and decrease cellular pyruvate kinase activity. Upon IGF1 treatment we found an increase of the dimeric form of PKM2 and the enrichment of PKM2 in the nucleus. This effect was associated to a reduction of pyruvate kinase enzymatic activity and was reversed using metformin, which decreases Akt phosphorylation. IGF1 induced an increased nuclear localization of PKM2 and STAT3, which correlated with an increased HIF1alpha, HK2, and GLUT1 expression and glucose entrapment. Metformin inhibited HK2, GLUT1, HIF-1alpha expression and glucose consumption. These findings suggest a role of IGFIR/Akt axis in regulating glycolysis by Ser/Thr PKM2 phosphorylation in cancer cells. PMID- 25790098 TI - A chimeric 18L1-45RG1 virus-like particle vaccine cross-protects against oncogenic alpha-7 human papillomavirus types. AB - Persistent infection with oncogenic human papillomaviruses (HPV) types causes all cervical and a subset of other anogenital and oropharyngeal carcinomas. Four high risk (hr) mucosal types HPV16, 18, 45, or 59 cause almost all cervical adenocarcinomas (AC), a subset of cervical cancer (CxC). Although the incidence of cervical squamous cell carcinoma (SCC) has dramatically decreased following introduction of Papanicolaou (PAP) screening, the proportion of AC has relatively increased. Cervical SCC arise mainly from the ectocervix, whereas AC originate primarily from the endocervical canal, which is less accessible to obtain viable PAP smears. Licensed (bivalent and quadrivalent) HPV vaccines comprise virus-like particles (VLP) of the most important hr HPV16 and 18, self-assembled from the major capsid protein L1. Due to mainly type-restricted efficacy, both vaccines do not target 13 additional hr mucosal types causing 30% of CxC. The papillomavirus genus alpha species 7 (alpha7) includes a group of hr types of which HPV18, 45, 59 are proportionally overrepresented in cervical AC and only partially (HPV18) targeted by current vaccines. To target these types, we generated a chimeric vaccine antigen that consists of a cross-neutralizing epitope (homologue of HPV16 RG1) of the L2 minor capsid protein of HPV45 genetically inserted into a surface loop of HPV18 L1 VLP (18L1-45RG1). Vaccination of NZW rabbits with 18L1-45RG1 VLP plus alum-MPL adjuvant induced high-titer neutralizing antibodies against homologous HPV18, that cross-neutralized non-cognate hr alpha7 types HPV39, 45, 68, but not HPV59, and low risk HPV70 in vitro, and induced a robust L1-specific cellular immune response. Passive immunization protected mice against experimental vaginal challenge with pseudovirions of HPV18, 39, 45 and 68, but not HPV59 or the distantly related alpha9 type HPV16. 18L1-45RG1 VLP might be combined with our previously described 16L1-16RG1 VLP to develop a second generation bivalent vaccine with extended spectrum against hr HPV. PMID- 25790099 TI - Sociality as a natural mechanism of public goods provision. AB - In the recent literature, several hypotheses have been offered to explain patterns of human behavior in social environments. In particular, these patterns include 'prosocial' ones, such as fairness, cooperation, and collective good provision. Psychologists suggest that these prosocial behaviors are driven not by miscalculations, but by salience of social identity, in-group favoritism, emotion, or evolutionary adaptations. This paper imports psychology scholarship into an economic model and results in a sustainable solution to collective action problems without any external enforcement mechanisms. This natural mechanism of public goods provision is created, analyzed, and observed in a controlled laboratory environment using experimental techniques. PMID- 25790100 TI - Optimization of imaging parameters for SPECT scans of [99mTc]TRODAT-1 using Taguchi analysis. AB - Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the basal ganglia. Single photon emission computed tomography (SPECT) scans using [99mTc]TRODAT-1 can image dopamine transporters and provide valuable diagnostic information of PD. In this study, we optimized the scanning parameters for [99mTc]TRODAT-1/SPECT using the Taguchi analysis to improve image quality. SPECT scans were performed on forty five healthy volunteers according to an L9 orthogonal array. Three parameters were considered, including the injection activity, uptake duration, and acquisition time per projection. The signal-to-noise ratio (SNR) was calculated from the striatum/occipital activity ratio as an image quality index. Ten healthy subjects and fifteen PD patients were used to verify the optimal parameters. The estimated optimal parameters were 962 MBq for [99mTc]TRODAT-1 injection, 260 min for uptake duration, and 60 s/projection for data acquisition. The uptake duration and time per projection were the two dominant factors which had an F value of 18.638 (38%) and 25.933 (53%), respectively. Strong cross interactions existed between the injection activity/uptake duration and injection activity/time per projection. Therefore, under the consideration of as low as reasonably achievable (ALARA) for radiation protection, we can decrease the injection activity to 740 MBq. The image quality remains almost the same for clinical applications. PMID- 25790101 TI - Hepatitis B virus DNA stability in plasma samples under short-term storage at 42 degrees C. AB - We evaluated the stability of hepatitis B virus (HBV) DNA in plasma samples stored at 42 degrees C for external quality assessment (EQA) panels of viral load. To assess the stability of plasma samples containing different concentrations of HBV DNA, serial dilutions of HBV-infected samples with a viral load of 6.40 log(10) IU/mL were made to yield viral loads of 5, 4, and 3 log(10) IU/mL. These were incubated at 42 degrees C for up to 7 days and then frozen at 70 degrees C. Viral load testing for HBV DNA was performed for all samples using COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HBV Test (v.2.0, Roche, Switzerland). Results were compared with fresh frozen plasma samples as a benchmark to establish acceptable measurements on the days following sample collection. Although the results of this study demonstrated a decrease in HBV DNA viral load ranging from 0.005 to 0.30 log(10) IU/mL after storage at 42 degrees C for up to 7 days, these values did not exceed 0.5 log(10), which is the estimated intra assay variation for molecular tests. Thus, the insignificant decrease in viral load suggests that shipment of HBV in plasma samples at temperatures of up to 42 degrees C is permissible if they are frozen within 7 days. PMID- 25790103 TI - A hybrid antenna array design for 3-d direction of arrival estimation. AB - A 3-D beam scanning antenna array design is proposed that gives a whole 3-D spherical coverage and also suitable for various radar and body-worn devices in the Body Area Networks applications. The Array Factor (AF) of the proposed antenna is derived and its various parameters like directivity, Half Power Beam Width (HPBW) and Side Lobe Level (SLL) are calculated by varying the size of the proposed antenna array. Simulations were carried out in MATLAB 2012b. The radiators are considered isotropic and hence mutual coupling effects are ignored. The proposed array shows a considerable improvement against the existing cylindrical and coaxial cylindrical arrays in terms of 3-D scanning, size, directivity, HPBW and SLL. PMID- 25790102 TI - Apoprotein Structure and Metal Binding Characterization of a de Novo Designed Peptide, alpha3DIV, that Sequesters Toxic Heavy Metals. AB - De novo protein design is a biologically relevant approach that provides a novel process in elucidating protein folding and modeling the metal centers of metalloproteins in a completely unrelated or simplified fold. An integral step in de novo protein design is the establishment of a well-folded scaffold with one conformation, which is a fundamental characteristic of many native proteins. Here, we report the NMR solution structure of apo alpha3DIV at pH 7.0, a de novo designed three-helix bundle peptide containing a triscysteine motif (Cys18, Cys28, and Cys67) that binds toxic heavy metals. The structure comprises 1067 NOE restraints derived from multinuclear multidimensional NOESY, as well as 138 dihedral angles (psi, phi, and chi1). The backbone and heavy atoms of the 20 lowest energy structures have a root mean square deviation from the mean structure of 0.79 (0.16) A and 1.31 (0.15) A, respectively. When compared to the parent structure alpha3D, the substitution of Leu residues to Cys enhanced the alpha-helical content of alpha3DIV while maintaining the same overall topology and fold. In addition, solution studies on the metalated species illustrated metal-induced stability. An increase in the melting temperatures was observed for Hg(II), Pb(II), or Cd(II) bound alpha3DIV by 18-24 degrees C compared to its apo counterpart. Further, the extended X-ray absorption fine structure analysis on Hg(II)-alpha3DIV produced an average Hg(II)-S bond length at 2.36 A, indicating a trigonal T-shaped coordination environment. Overall, the structure of apo alpha3DIV reveals an asymmetric distorted triscysteine metal binding site, which offers a model for native metalloregulatory proteins with thiol-rich ligands that function in regulating toxic heavy metals, such as ArsR, CadC, MerR, and PbrR. PMID- 25790104 TI - Controlled synthesis of phosphorylcholine derivatives of poly(serine) and poly(homoserine). AB - We report methods for the synthesis of polypeptides that are fully functionalized with desirable phosphorylcholine, PC, groups. Because of the inherent challenges in the direct incorporation of the PC group into alpha-amino acid N carboxyanhydride (NCA) monomers, we developed a synthetic approach that combined functional NCA polymerization with efficient postpolymerization modification. While poly(L-phosphorylcholine serine) was found to be unstable upon synthesis, we successfully prepared poly(L-phosphorylcholine homoserine) with controlled chain lengths and found these to be water-soluble with disordered chain conformations. PMID- 25790105 TI - Inherited variation at MC1R and histological characteristics of primary melanoma. AB - Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype. PMID- 25790106 TI - A novel testing model for opportunistic screening of pre-diabetes and diabetes among U.S. adults. AB - OBJECTIVE: The study aim was to evaluate the performance of a novel simultaneous testing model, based on the Finnish Diabetes Risk Score (FINDRISC) and HbA1c, in detecting undiagnosed diabetes and pre-diabetes in Americans. RESEARCH DESIGN AND METHODS: This cross-sectional analysis included 3,886 men and women (>= 20 years) without known diabetes from the U.S. National Health and Nutrition Examination Survey (NHANES) 2005-2010. The FINDRISC was developed based on eight variables (age, BMI, waist circumference, use of antihypertensive drug, history of high blood glucose, family history of diabetes, daily physical activity and fruit & vegetable intake). The sensitivity, specificity, and the receiver operating characteristic (ROC) curve of the testing model were calculated for undiagnosed diabetes and pre-diabetes, determined by oral glucose tolerance test (OGTT). RESULTS: The prevalence of undiagnosed diabetes was 7.0% and 43.1% for pre diabetes (27.7% for isolated impaired fasting glucose (IFG), 5.1% for impaired glucose tolerance (IGT), and 10.3% for having both IFG and IGT). The sensitivity and specificity of using the HbA1c alone was 24.2% and 99.6% for diabetes (cutoff of >=6.5%), and 35.2% and 86.4% for pre-diabetes (cutoff of >=5.7%). The sensitivity and specificity of using the FINDRISC alone (cutoff of >=9) was 79.1% and 48.6% for diabetes and 60.2% and 61.4% for pre-diabetes. Using the simultaneous testing model with a combination of FINDRISC and HbA1c improved the sensitivity to 84.2% for diabetes and 74.2% for pre-diabetes. The specificity for the simultaneous testing model was 48.4% of diabetes and 53.0% for pre-diabetes. CONCLUSIONS: This simultaneous testing model is a practical and valid tool in diabetes screening in the general U.S. population. PMID- 25790108 TI - Customizing wormlike mesoscale structures via self-assembly of amphiphilic star polymers. AB - We examine the phase behavior of end-functionalized diblock copolymer stars by means of Grand Canonical Monte Carlo simulations. We focus on solutions of diblock copolymer stars with a solvophobic outer block shorter than the solvophilic inner block, which are expected to nucleate microphase aggregates. By tuning the temperature and rigidity of the molecules, we target specific mesoscale structures, which can act as powerful rheology modifiers. In particular, we control the hierarchical self-assembly of single micelles in a "pearl-necklace" fashion, which eventually merge into elongated, wormlike supermicelles. PMID- 25790107 TI - Lack of an association between angiotensin receptor blocker based therapy and increased risk of cancer: evidence from large observational studies. AB - BACKGROUND: A previous meta-analysis of randomized controlled studies that were not designed to investigate cancer as a primary outcome suggested that ARB-based therapy is associated with increased risk of cancer; however, results of recent observational studies considering the association have been contradictory. This study sought to evaluate the association between angiotensin receptor blocker (ARB)-based therapy and risk of cancer by conducting a meta-analysis of observational studies. METHODS: Relevant articles published before February 2014 were identified by searching PubMed and the Cochrane Library. Pooled relative risks (RRs) were determined using a random effects model and were used to assess the strength of association between use of ARB-based therapy and risk of cancer. RESULTS: Six retrospective cohort studies involving a total of 3,827,109 participants and four case-control studies involving a total of 193,029 cases were included. The present study found that ARB-based therapy was not significantly associated with an increased risk of cancer (RR = 0.87, 95%CI: [0.75, 1.01]). However, an analysis including only cohort studies suggested a significantly decreased risk of cancer among individuals with any history of ARB use as compared to those with no history of ARB use (RR = 0.80, 95%CI: [0.55, 0.95]); no significant association was found between ARB use and risk of cancer when the case-control studies were separately considered (RR = 1.03, 95%CI: [0.93, 1.13]). Subgroup analyses showed that use of ARB-based therapy was associated with decreased risk of lung cancer (RR = 0.81, 95%CI: [0.69, 0.94]); however, no significant associations were found with the other cancer sites investigated. Furthermore, no association was observed upon adjustment by type of ARB drug. No publication bias was detected. CONCLUSION: Overall, ARB-based therapy was not associated with increased risk of cancer. However, its use may be related to decreased incidence of lung cancer; this finding should be considered carefully and confirmed with further studies. PMID- 25790109 TI - ICSH guidelines for the laboratory diagnosis of nonimmune hereditary red cell membrane disorders. AB - INTRODUCTION: Hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary stomatocytosis (HSt) are inherited red cell disorders caused by defects in various membrane proteins. The heterogeneous clinical presentation, biochemical and genetic abnormalities in HS and HE have been well documented. The need to raise the awareness of HSt, albeit its much lower prevalence than HS, is due to the undesirable outcome of splenectomy in these patients. METHODS: The scope of this guideline is to identify the characteristic clinical features, the red cell parameters (including red cell morphology) for these red cell disorders associated, respectively, with defective cytoskeleton (HS and HE) and abnormal cation permeability in the lipid bilayer (HSt) of the red cell. The current screening tests for HS are described, and their limitations are highlighted. RESULTS: An appropriate diagnosis can often be made when the screening test result(s) is reviewed together with the patient's clinical/family history, blood count results, reticulocyte count, red cell morphology, and chemistry results. SDS-polyacrylamide gel electrophoresis of erythrocyte membrane proteins, monovalent cation flux measurement, and molecular analysis of membrane protein genes are specialist tests for further investigation. CONCLUSION: Specialist tests provide additional evidence in supporting the diagnosis and that will facilitate the management of the patient. In the case of a patient's clinical phenotype being more severe than the affected members within the immediate family, molecular testing of all family members is useful for confirming the diagnosis and allows an insight into the molecular basis of the abnormality such as a recessive mode of inheritance or a de novo mutation. PMID- 25790110 TI - Levels of protein C and soluble thrombomodulin in critically ill patients with acute kidney injury: a multicenter prospective observational study. AB - Endothelial dysfunction contributes to the development of acute kidney injury (AKI) in animal models of ischemia reperfusion injury and sepsis. There are limited data on markers of endothelial dysfunction in human AKI. We hypothesized that Protein C (PC) and soluble thrombomodulin (sTM) levels could predict AKI. We conducted a multicenter prospective study in 80 patients to assess the relationship of PC and sTM levels to AKI, defined by the AKIN creatinine (AKI Scr) and urine output criteria (AKI UO). We measured marker levels for up to 10 days from intensive care unit admission. We used area under the curve (AUC) and time-dependent multivariable Cox proportional hazard model to predict AKI and logistic regression to predict mortality/non-renal recovery. Protein C and sTM were not different in patients with AKI UO only versus no AKI. On intensive care unit admission, as PC levels are usually lower with AKI Scr, the AUC to predict the absence of AKI was 0.63 (95%CI 0.44-0.78). The AUC using log10 sTM levels to predict AKI was 0.77 (95%CI 0.62-0.89), which predicted AKI Scr better than serum and urine neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, urine kidney injury molecule-1 and liver-fatty acid-binding protein. In multivariable models, PC and urine NGAL levels independently predicted AKI (p=0.04 and 0.02) and PC levels independently predicted mortality/non-renal recovery (p=0.04). In our study, PC and sTM levels can predict AKI Scr but are not modified during AKI UO alone. PC levels could independently predict mortality/non-renal recovery. Additional larger studies are needed to define the relationship between markers of endothelial dysfunction and AKI. PMID- 25790111 TI - Spheroidal carbonaceous fly ash particles provide a globally synchronous stratigraphic marker for the Anthropocene. AB - Human impacts on Earth are now so great that they have led to the concept of a new geological epoch defined by this global human influence: the Anthropocene. While not universally accepted, the term is increasingly popular and widely used. However, even among proponents, there is considerable debate regarding when the epoch may have started, from coeval with the Holocene, through the Industrial Revolution, to the mid-20th century when unprecedented human activities resulted in exponential increases in population, resource consumption, and pollutant emission. Recently, this latter period, known as the Great Acceleration, appears to be becoming the more widely accepted start date. To define any start point, a global stratigraphic marker or Global Boundary Stratotype Section and Point (GSSP) is typically required. Here, spheroidal carbonaceous fly ash particles (SCPs), byproducts of industrial fossil-fuel combustion, are proposed as a primary marker for a GSSP at the time of the Great Acceleration. Data from over 75 lake sediment records show a global, synchronous, and dramatic increase in particle accumulation starting in c. 1950 driven by the increased demand for electricity and the introduction of fuel-oil combustion, in addition to coal, as a means to produce it. SCPs are morphologically distinct and solely anthropogenic in origin, providing an unambiguous marker. This is a clear signal of great stratigraphic utility representing a primary driving force for global anthropogenic change. PMID- 25790113 TI - Correction: Temporal-spatial correlation between angiogenesis and corticogenesis in the developing chick optic tectum. PMID- 25790112 TI - Preparation of abiotic polymer nanoparticles for sequestration and neutralization of a target peptide toxin. AB - Synthetic polymer nanoparticles (NPs) with intrinsic affinity for target biomacromolecules hold great promise in the development of novel tools for biological and biomedical research. We recently reported the design and synthesis of abiotic, synthetic polymer NPs with high intrinsic affinity for a peptide toxin melittin. The NP was selected by screening a small library of NPs (~100 nm) composed of various ratios of monomers that contain functional groups complementary to the peptide melittin. The selected polymer NP, a co-polymer of acrylic acid (AAc), N-tert-butylacrylamide (TBAm), N-isopropylacrylamide (NIPAm) and N,N'-methylenebisacrylamide (BIS), effectively captures and neutralizes the toxicity of the peptide through a combination of electrostatic and hydrophobic interactions. This protocol describes a step-by-step procedure for the preparation and evaluation of synthetic polymer NPs for sequestration and neutralization of the target peptide toxin. The polymer NPs can be synthesized in a one-step polymerization reaction using commercially available reagents. The polymerization reaction for the synthesis of polymer NPs takes several hours, and the total protocol including subsequent purification and characterization by dynamic light scattering, NMR and toxicity neutralization assays takes 1-2 weeks in total. PMID- 25790114 TI - Transcriptomic analysis of American ginseng seeds during the dormancy release process by RNA-Seq. AB - American ginseng (Panax quinquefolius L.) is an important herb that is cultivated in China, North American, and South Korea. It is propagated from seed, but the seed has deep dormancy characteristics described as morphophysiological dormancy. Two-stage temperature stratification, a warm (15-20 degrees C) and cold (2 degrees C) stratification period of 6 months, has been used successfully for seed dormancy release. However, little is known about the molecular mechanisms of seed dormancy release in the stratification process. In this study, seed development after pollination and seed development in the dormancy release process were investigated in American ginseng. The transcriptome during seed dormancy release was analyzed using RNA-Seq technology and 78,207 unigenes (mean length 531 bp) were generated. Based on similarity searches of public databases, 54,292 of the unigenes (69.4%) were functionally annotated. Further, three digital gene expression (DGE) libraries were sequenced and differences in gene expression at three stages during seed cold stratification were examined. The greatest number of differentially expressed genes occurred in the 90DCS versus 180DCS libraries, while the lowest number of differentially expressed genes occurred in the 135DCS verus 180DCS libraries. GO enrichment analysis revealed that 59, 29, and 39 GO terms were significantly enriched in the biological process, molecular function, and cell component GO categories, respectively. There were 25,190 genes with KEGG pathway annotation in the three DGE libraries and their enrichment pathways were compared. The gene expressions of 30 selected unigenes were validated using quantitative PCR. This study is the first to provide the transcriptome sequences for seed dormancy release in American ginseng, and demonstrates the successful use of DGE profiling data for analyzing transcriptomic variation during dormancy release. These data provide a basis for future researches of seed dormancy in morphophysiological dormancy seeds in non-model plants. PMID- 25790115 TI - Rhamnolipids as platform molecules for production of potential anti-zoospore agrochemicals. AB - Rhamnolipid biosurfactants have potential applications in the control of zoosporic plant pathogens. However, rhamnolipids have not been closely investigated for the anti-zoospore mechanism or for developing new anti-zoospore chemicals. In this study, RhL-1 and RhL-3 groups of rhamnolipids were used to generate the corresponding RhL-2 and RhL-4 groups and the free diacids. Conversion of RhL-3 to RhL-1 was also accomplished in vitro with cellobiase as the catalyst. The anti-zoospore effects of RhL-1-RhL-4 and the diacids were investigated with zoospores of Phytophthora sojae. For RhL-1-RhL-4, approximately 20, 30, 40, and 40 mg/L, respectively, were found to be the lowest concentrations required to stop movement of all zoospores, which indicates that the anti zoospore effect remains strong even after RhL-1 and RhL-3 are hydrolyzed into RhL 2 and RhL-4. The free diacids required a significantly higher critical concentration of about 125 mg/L. Rhamnose can be obtained as a co-product. PMID- 25790116 TI - Authors' Response to Lingeman. PMID- 25790117 TI - Effect of femtosecond laser treatment on the shear bond strength of a metal bracket to prepared porcelain surface. AB - OBJECTIVE: The aim of this study was to investigate the effects of femtosecond laser treatment (Group FS) on the shear bond strength (SBS) of a metal bracket to prepared porcelain surface, and to compare it with other surface treatment techniques [50 MUm Al2O3 sandblasting (Group SB), 9.6% hydrofluoric acid gel (Group HF), and neodymium-doped yttrium aluminium garnet (Nd:YAG laser) (Group NY)]. BACKGROUND DATA: Because of the increasing number of adult patients in current orthodontic practice, achieving sufficient bond strength of composite resin to porcelain restorations without bond failure during the treatment is a challenge for orthodontists. METHODS: In total, 80 glazed feldspathic porcelain samples were prepared and randomly assigned to four groups of 20. Treated surfaces were treated with a silane agent. Brackets were bonded to porcelain samples. The specimens were stored in distilled water for 24 h and then thermocycled for 500 cycles between 5 degrees and 55 degrees C. The SBS of the brackets was tested with a universal testing machine at a crosshead speed of 1 mm/min, until bonding failure occurred. The data were analyzed statistically using analysis of variance (ANOVA) and Tamhane multiple comparisons tests. The results of ANOVA indicated that the SBS values varied according to the surface treatment method (p<0.001). RESULTS: Results of the Tamhane post-hoc tests indicated that the bond strength in Group NY (5.11+/-1.53) was significantly lower than the other groups (p<0.05). There were no statistically significant differences among Groups SB (9.07+/-3.76), HF (9.09+/-3.51), and FS (11.58+/ 4.16) (p=0.28). CONCLUSIONS: The results of this study showed that FS treatment produced high SBS of the processes assessed; therefore, it appears to be an effective method for bonding orthodontic metal brackets to prepared porcelain surfaces. PMID- 25790119 TI - Atom-resolved analysis of an ionic KBr(001) crystal surface covered with a thin water layer by frequency modulation atomic force microscopy. AB - An ionic KBr(001) crystal surface covered with a thin water layer was observed with a frequency modulation atomic force microscope (FM-AFM) with atomic resolution. By immersing only the tip apex of the AFM cantilever in the thin water layer, the Q-factor of the cantilever in probing the solid-liquid interface can be maintained as high as that of FM-AFM operation in air, leading to improvement of the minimum detection of a differential force determined by the noise. Two types of images with atom-resolved contrast were observed, possibly owing to the different types of ions (K(+) or Br(-)) adsorbed on the tip apex that incorporated into the hydration layers on the tip and on the sample surface. The force-distance characteristics at the solid-water interface were analyzed by taking spatial variation maps of the resonant frequency shift of the AFM cantilever with the high Q-factor. The oscillatory frequency shift-distance curves exhibited atomic site dependence. The roles of hydration and the ions on the tip and on the sample surface in the measurements were discussed. PMID- 25790118 TI - Aberrant CCR4 expression is involved in tumor invasion of lymph node-negative human gastric cancer. AB - Cellular chemotaxis is the best-known function of chemokine receptors which are closely linked with tumor metastasis. In fact, positive expression of chemokine receptors could also be identified even in some patients without metastatic tumors, while the clinical relevance of this data has not been fully established. Our studies were designed to clarify the CCR4 expression profiles and to explore its potential role in histologically node-negative (pN0) gastric cancer (GC). Immunohistochemistry (IHC) or immunohistofluorescence (IHF) analysis was performed on specimens obtained from 108 patients with pN0 GC. We found that CCR4 was aberrantly over-expressed inpN0 GC tissues, with different expression patterns on tumor cells and being associated with T-stage (P = 0.002). The matrigel in vitro invasion assay revealed that over-expression of CCR4 in GC cell lines significantly enhanced the invasive capacity of these cells. Results from real-time RT-PCR and gelatinzymography showed a significant increase in matrix metalloproteinase (MMP)-9 production induced by the forced expression of CCR4 in GC cell lines. Our data suggest that the aberrant CCR4 expression is involved in tumor invasion of pN0 GC and, conceivably, antagonists of CCR4 might be useful candidates for controlling early events in tumor progression. PMID- 25790120 TI - The Influence of Hospital Volume on Circumferential Resection Margin Involvement: Results of the Dutch Surgical Colorectal Audit. AB - This population-based study evaluates the association between hospital volume and CRM (circumferential resection margin) involvement, adjusted for other confounders, in rectal cancer surgery. A low hospital volume (<20 cases/year) was independently associated with a higher risk of CRM involvement (odds ratio=1.54; 95% CI: 1.12-2.11). OBJECTIVE: To evaluate the association between hospital volume and CRM (circumferential resection margin) involvement in rectal cancer surgery. BACKGROUND: To guarantee the quality of surgical treatment of rectal cancer, the Association of Surgeons of the Netherlands has stated a minimal annual volume standard of 20 procedures per hospital. The influence of hospital volume has been examined for different outcome variables in rectal cancer surgery. Its influence on the pathological outcome (CRM) however remains unclear. As long-term outcomes are best predicted by the CRM status, this parameter is of essential importance in the debate on the justification of minimal volume standards in rectal cancer surgery. METHODS: Data from the Dutch Surgical Colorectal Audit (2011-2012) were used. Hospital volume was divided into 3 groups, and baseline characteristics were described. The influence of hospital volume on CRM involvement was analyzed, in a multivariate model, between low- and high-volume hospitals, according to the minimal volume standards. RESULTS: This study included 5161 patients. CRM was recorded in 86% of patients. CRM involvement was 11% in low-volume group versus 7.7% and 7.9% in the medium- and high-volume group (P<=0.001). After adjustment for relevant confounders, the influence of hospital volume on CRM involvement was still significant odds ratio (OR) = 1.54; 95% CI: 1.12-2.11). CONCLUSIONS: The outcomes of this pooled analysis support minimal volume standards in rectal cancer surgery. Low hospital volume was independently associated with a higher risk of CRM involvement (OR = 1.54; 95% CI: 1.12-2.11). PMID- 25790121 TI - From local checklists to online identification portals: a case study on vascular plants. AB - Checklists, the result of time-consuming exploration and painstaking bibliographic research, can be easily converted into online databases, which have the advantage of being updatable online in real time, and of reaching a much wider audience. However, thousands of local checklists (Natural Parks, protected areas, etc.) are still available on paper only, and most of those published online appear as dry lists of latin names, which strongly reduces their outreach for a wider audience. The University of Trieste has recently started the publication of several local checklists in a way that may be more appealing for the general public, by linking species' names to archives of digital resources, and especially to digital identification tools produced by software FRIDA (FRiendly IDentificAtion). The query interfaces were developed on the basis of feedback from a wide range of users. The result is no longer a simple list of names accessible on the Web, but a veritable multimedial, interactive portal to the biodiversity of a given area. This paper provides an example of how relevant added value can be given to local lists of taxa by embedding them in a complex system of biodiversity-related resources, making them usable for a much wider audience than a restricted circle of specialists, as testified by the almost 1.000.000 unique visitors reached in 2014. A critical mass of digital resources is also put at disposal of the scientific community by releasing them under a Creative Commons license. PMID- 25790123 TI - An Ag-grid/graphene hybrid structure for large-scale, transparent, flexible heaters. AB - Recently, carbon materials such as carbon nanotubes and graphene have been proposed as alternatives to indium tin oxide (ITO) for fabricating transparent conducting materials. However, obtaining low sheet resistance and high transmittance of these carbon materials has been challenging due to the intrinsic properties of the materials. In this paper, we introduce highly transparent and flexible conductive films based on a hybrid structure of graphene and an Ag-grid. Electrohydrodynamic (EHD) jet printing was used to produce a micro-scale grid consisting of Ag lines less than 10 MUm wide. We were able to directly write the Ag-grid on a large-area graphene/flexible substrate due to the high conductivity of graphene. The hybrid electrode could be fabricated using hot pressing transfer and EHD jet printing in a non-vacuum, maskless, and low-temperature environment. The hybrid electrode offers an effective and simple route for achieving a sheet resistance as low as ~4 Omega per square with ~78% optical transmittance. Finally, we demonstrate that transparent flexible heaters based on the hybrid conductive films could be used in a vehicle or a smart window system. PMID- 25790122 TI - Dipeptidyl-peptidase IV activity is correlated with colorectal cancer prognosis. AB - BACKGROUND: Dipeptidyl-peptidase IV (EC 3.4.14.5) (DPPIV) is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC). METHODS AND PRINCIPAL FINDINGS: The activity and mRNA and protein expression of DPPIV was prospectively analyzed in adenocarcinomas, adenomas, uninvolved colorectal mucosa and plasma from 116 CRC patients by fluorimetric, quantitative RT-PCR and immunohistochemical methods. Results were correlated with the most important classic pathological data related to aggressiveness and with 5-year survival rates. Results showed that: 1) mRNA levels and activity of DPPIV increased in colorectal neoplasms (Kruskal-Wallis test, p<0.01); 2) Both adenomas and CRCs displayed positive cytoplasmic immunostaining with luminal membrane reinforcement; 3) Plasmatic DPPIV activity was lower in CRC patients than in healthy subjects (Mann-U test, p<0.01); 4) Plasmatic DPPIV activity was associated with worse overall and disease-free survivals (log-rank p<0.01, Cox analysis p<0.01). CONCLUSION/SIGNIFICANCE: 1) Up regulation of DPPIV in colorectal tumors suggests a role for this enzyme in the neoplastic transformation of colorectal tissues. This finding opens the possibility for new therapeutic targets in these patients. 2) Plasmatic DPPIV is an independent prognostic factor in survival of CRC patients. The determination of DPPIV activity levels in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice. PMID- 25790124 TI - Developmental changes in the corpus callosum from infancy to early adulthood: a structural magnetic resonance imaging study. AB - Previous research has reported on the development trajectory of the corpus callosum morphology. However, there have been only a few studies that have included data on infants. The goal of the present study was to examine the morphology of the corpus callosum in healthy participants of both sexes, from infancy to early adulthood. We sought to characterize normal development of the corpus callosum and possible sex differences in development. We performed a morphometric magnetic resonance imaging (MRI) study of 114 healthy individuals, aged 1 month to 25 years old, measuring the size of the corpus callosum. The corpus callosum was segmented into seven subareas of the rostrum, genu, rostral body, anterior midbody, posterior midbody, isthmus and splenium. Locally weighted regression analysis (LOESS) indicated significant non-linear age-related changes regardless of sex, particularly during the first few years of life. After this increase, curve slopes gradually became flat during adolescence and adulthood in both sexes. Age of local maximum for each subarea of the corpus callosum differed across the sexes. Ratios of total corpus callosum and genu, posterior midbody, as well as splenium to the whole brain were significantly higher in females compared with males. The present results demonstrate that the developmental trajectory of the corpus callosum during early life in healthy individuals is non-linear and dynamic. This pattern resembles that found for the cerebral cortex, further suggesting that this period plays a very important role in neural and functional development. In addition, developmental trajectories and changes in growth do show some sex differences. PMID- 25790125 TI - Assessing the impact of case sensitivity and term information gain on biomedical concept recognition. AB - Concept recognition (CR) is a foundational task in the biomedical domain. It supports the important process of transforming unstructured resources into structured knowledge. To date, several CR approaches have been proposed, most of which focus on a particular set of biomedical ontologies. Their underlying mechanisms vary from shallow natural language processing and dictionary lookup to specialized machine learning modules. However, no prior approach considers the case sensitivity characteristics and the term distribution of the underlying ontology on the CR process. This article proposes a framework that models the CR process as an information retrieval task in which both case sensitivity and the information gain associated with tokens in lexical representations (e.g., term labels, synonyms) are central components of a strategy for generating term variants. The case sensitivity of a given ontology is assessed based on the distribution of so-called case sensitive tokens in its terms, while information gain is modelled using a combination of divergence from randomness and mutual information. An extensive evaluation has been carried out using the CRAFT corpus. Experimental results show that case sensitivity awareness leads to an increase of up to 0.07 F1 against a non-case sensitive baseline on the Protein Ontology and GO Cellular Component. Similarly, the use of information gain leads to an increase of up to 0.06 F1 against a standard baseline in the case of GO Biological Process and Molecular Function and GO Cellular Component. Overall, subject to the underlying token distribution, these methods lead to valid complementary strategies for augmenting term label sets to improve concept recognition. PMID- 25790127 TI - Recent initiatives in evidence-based veterinary medicine. PMID- 25790126 TI - Photophobia in primary headaches. AB - BACKGROUND: Photophobia is a debilitating feature of many headache disorders. OVERVIEW: Clinical and preclinical research has identified several potential pathways involved in enhanced light sensitivity. Some of these structures include trigeminal afferents in the eye, second-order neurons in the trigeminal nucleus caudalis, third-order neurons in the posterior thalamus, modulatory neurons in the hypothalamus, and fourth-order neurons in the visual and somatosensory cortices. It is unclear to what degree each site plays a role in establishing the different temporal patterns of photophobia across different disorders. Peptides such as calcitonin gene-related peptide and pituitary adenylate cyclase activating polypeptide may play a role in photophobia at multiple levels of the visual and trigeminal pathways. CONCLUSION: While our understanding of photophobia has greatly improved in the last decade, there are still unanswered questions. These answers will help us develop new therapies to provide relief to patients with primary headache disorders. PMID- 25790128 TI - Genetic analysis of cold tolerance at the germination and booting stages in rice by association mapping. AB - Low temperature affects the rice plants at all stages of growth. It can cause severe seedling injury and male sterility resulting in severe yield losses. Using a mini core collection of 174 Chinese rice accessions and 273 SSR markers we investigated cold tolerance at the germination and booting stages, as well as the underlying genetic bases, by association mapping. Two distinct populations, corresponding to subspecies indica and japonica showed evident differences in cold tolerance and its genetic basis. Both subspecies were sensitive to cold stress at both growth stages. However, japonica was more tolerant than indica at all stages as measured by seedling survival and seed setting. There was a low correlation in cold tolerance between the germination and booting stages. Fifty one quantitative trait loci (QTLs) for cold tolerance were dispersed across all 12 chromosomes; 22 detected at the germination stage and 33 at the booting stage. Eight QTLs were identified by at least two of four measures. About 46% of the QTLs represented new loci. The only QTL shared between indica and japonica for the same measure was qLTSSvR6-2 for SSvR. This implied a complicated mechanism of old tolerance between the two subspecies. According to the relative genotypic effect (RGE) of each genotype for each QTL, we detected 18 positive genotypes and 21 negative genotypes in indica, and 19 positive genotypes and 24 negative genotypes in japonica. In general, the negative effects were much stronger than the positive effects in both subspecies. Markers for QTL with positive effects in one subspecies were shown to be effective for selection of cold tolerance in that subspecies, but not in the other subspecies. QTL with strong negative effects on cold tolerance should be avoided during MAS breeding so as to not cancel the effect of favorable QTL at other loci. PMID- 25790129 TI - The suppurative panniculitis of the breast. PMID- 25790130 TI - Chronic cough in children. AB - IMPORTANCE: Chronic cough is a common complaint among pediatric patients, but little information exists on the types of diagnoses in these patients and therapeutic outcomes. OBJECTIVE: To characterize pediatric patients with chronic cough presenting to otolaryngology clinics, identify common causes and treatments, and evaluate therapeutic outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective analysis, all medical records for pediatric patients seen at 2 otolaryngology clinics at a single tertiary care academic medical center from January 2009 through June 2013 were searched for relevant diagnostic codes. Patients younger than 18 years presenting with chronic cough (cough of >4 weeks' duration) were selected for study; 58 patients met the inclusion criteria and were selected for analysis. INTERVENTIONS: Each patient was evaluated by the clinician via history, physical examination, and various tests and procedures, depending on the individual case, including flexible laryngoscopy, imaging tests, and/or airway evaluations. Each patient underwent treatment based on the working diagnosis. MAIN OUTCOMES AND MEASURES: Primary outcomes included final diagnosis, response to treatment (as indicated by resolution of cough after initial therapy), and diagnostic workup undergone. RESULTS: Among the 58 included patients, the 3 most common diagnoses were related to infection (n = 23; 34%), airway hyperreactivity (n = 14; 24%), or gastroesophageal reflux disease (n = 14; 24%). Initial response to treatment was observed in 83% of patients (n = 48), while the remaining 17% (n = 10) required further evaluation. All 10 patients for whom initial treatment failed (100%) had a diagnosis involving airway hyperreactivity (P < .001). In addition, chest radiography was more likely to be ordered (odds ratio [OR], 16.4; 95% CI, 1.91-140.8; P = .002) and to contain pertinent positive findings (OR, 12.8; 95% CI, 1.15-142.6; P = .04) in patients for whom treatment failed. CONCLUSIONS AND RELEVANCE: Chronic cough in the pediatric otolaryngology setting differs from the typical presentation in the primary care setting. The top 3 causes encountered by the practicing otolaryngologist in a pediatric patient are infection, airway hyperreactivity, and gastroesophageal reflux disease. If initial otolaryngologic treatment fails, chest radiography and early pulmonary consult are recommended. PMID- 25790131 TI - Pancreas-Kidney transplantation: Impact of dialysis modality on the outcome. AB - It remains controversial whether dialysis modality prior to SPKT (simultaneous pancreas-kidney transplantation) affects the outcome. We analyzed outcomes in type 1 diabetic patients undergoing SPKT, comparing peritoneal dialysis (PD) and hemodialysis (HD) groups: 119 had been on HD; 39 on PD. They were comparable except regarding dialysis time, higher in HD patients (30 +/- 23 vs. 21 +/- 15 months, P = 0.003). Thrombosis-driven relaparotomy was more frequent in PD patients (12.8% vs. 1.7%, P = 0.014). Pancreas loss due to infection was higher in PD patients (12.8% vs. 3.4%, P = 0.042). Thrombosis-related kidney loss was more frequent in PD patients (5.1%, vs. 0% in HD patients, P = 0.058). Thirteen deaths occurred, more within the PD group (17.9% vs. 5%; P = 0.011), being infection the leading cause (13.5%, vs. 1.7% in HD patients, P = 0.010). Patient survival was inferior in PD patients. Besides PD, cardiovascular disease and graft failure were independent predictors of patient death. In conclusion, PD patients more frequently complicated with intra-abominal infection leading to pancreatic loss and with renal thrombosis, with adverse impact on survival. As a PD first strategy in end-stage renal disease patients is generally associated with good outcomes, these gloomier results after SPKT urge for careful adjustment of infection and thrombosis prophylactic protocols in PD patients. PMID- 25790132 TI - Effect of protruding ears on visual fixation time and perception of personality. AB - IMPORTANCE: Protruding ears are often thought to be a stigma, supposedly drawing attention and negatively influencing the perception of personality. These purported negative effects that may indicate corrective aesthetic otoplasty in patients too young to provide informed consent have not been quantified. OBJECTIVE: To quantify attention directed toward protruding ears and its effect on the perception of selected personality traits. DESIGN, SETTING, AND PARTICIPANTS: In this observational study conducted from August 1, 2013, to October 31, 2013, visual scan paths were recorded of 20 lay observers looking at photographs of faces of 20 children (age range, 5-19 years) with either protruding ears or ears morphed via computer software to appear nonprotruding. Subsequently, the observers rated 10 perceived personality traits based on the same photographs. MAIN OUTCOMES AND MEASURES: Visual fixation time on protruding vs nonprotruding ears was compared and correlated with observers' scores for personality traits. RESULTS: Fixation time on protruding ears was significantly longer compared with that for morphed nonprotruding ears (mean [SD], 9.6% [5.6%] vs 5.8% [3.2%] of total fixation time, P = .04). The difference between the overall personality questionnaire scores and between individual scores for assiduousness, intelligence, and likeability was not significant for protruding and nonprotruding ears. Faces in which the protruding auricles received the highest percentage of visual attention scored higher than average for the overall personality scores (mean [SD], 66.09 [4.50] vs. 55.81 [13.36]) and for assiduousness (6.64 [0.74] vs. 5.59 [1.41]), intelligence (6.78 [0.74] vs. 5.83 [1.31]), and likeability (7.29 [0.47] vs. 6.28 [1.40]). CONCLUSIONS AND RELEVANCE: Protruding ears had the potential to draw viewers' attention but did not cause a negative perception of personality traits. This study therefore does not provide confirmatory evidence for the stigmatizing nature of protruding ears. LEVEL OF EVIDENCE: 3. PMID- 25790133 TI - Polymer-metal hybrid transparent electrodes for flexible electronics. AB - Despite nearly two decades of research, the absence of ideal flexible and transparent electrodes has been the largest obstacle in realizing flexible and printable electronics for future technologies. Here we report the fabrication of 'polymer-metal hybrid electrodes' with high-performance properties, including a bending radius <1 mm, a visible-range transmittance>95% and a sheet resistance <10 Omega sq(-1). These features arise from a surface modification of the plastic substrates using an amine-containing nonconjugated polyelectrolyte, which provides ideal metal-nucleation sites with a surface-density on the atomic scale, in combination with the successive deposition of a facile anti-reflective coating using a conducting polymer. The hybrid electrodes are fully functional as universal electrodes for high-end flexible electronic applications, such as polymer solar cells that exhibit a high power conversion efficiency of 10% and polymer light-emitting diodes that can outperform those based on transparent conducting oxides. PMID- 25790134 TI - TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis. AB - Recent studies show that CD4+CD25+Foxp3+ regulatory cells (Tregs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in Tregs is less clear. Here we show that CD4+Foxp3+Tregs produce the effector cytokine IL-17A during oropharyngeal candidiasis (OPC) and inflammatory bowel disease in a TLR-2/Myd88 signaling dependent manner. TLR-2 ligands promote proliferation in Tregs in the presence and absence of TCR signals and inflammatory cytokines in vitro. The proliferation is directly dependent on TLR-2 expression in Tregs. Consistent with this, Tlr2-/- mice harbor fewer thymically derived Tregs and peripheral Tregs under homeostatic conditions in vivo. However, under Th17 inducing conditions, IL-6 and TLR-2 signaling both in Tregs as well as antigen presenting cells (APC) are critical for maximal ROR gammat and IL-17A up-regulation in Foxp3+ Tregs. The minimal and transient loss of Foxp3 expression and suppressive properties are due to the presence of IL-6 in the milieu, but not the direct effect of TLR-2 signaling in Tregs. Taken together, our data reveal that TLR-2 signaling promotes not only proliferation, but also IL-17A in Tregs, depending on the cytokine milieu. These IL-17A producing Tregs may be relevant in mucosal infections and inflammation. PMID- 25790135 TI - Impact of soil cadmium on land snails: a two-stage exposure approach under semi field conditions using bioaccumulative and conchological end-points of exposure. AB - Land snails are highly tolerant to cadmium exposure and are able to accumulate soil cadmium independently of food ingestion. However, little information exists on the kinetics of cadmium retention in terrestrial gastropods exposed to an increase in the soil cadmium content, over time. There is also little knowledge about how exposure to cadmium-polluted soils influences shell growth and architecture. In this context, we examined cadmium accumulation in the hepatopancreas and shell of juvenile Cantareus aspersus exposed to elevating high levels of cadmium in soil. Also, the toxicity of cadmium to snails was assessed using a range of conchological endpoints, including shell height, width, volume, allometry and integrity. Test snails, aged three months, were reared under semi field conditions, fed an uncontaminated diet and exposed first, for a period of 30 days, to a series of soil cadmium concentrations, and then, for a second period of 30 days, to soils with higher cadmium content. Cadmium showed a dose dependent accumulation in both the hepatopancreas and shell. The kinetics of cadmium retention in the hepatopancreas of snails previously exposed to cadmium spiked soils was significantly influenced by a new exposure event. The shell was not a relevant bioaccumulator for soil cadmium. Under the present experimental conditions, only high cadmium exposure significantly affected either the shell growth or snail survival. There was no consistent effect on shell allometry, but the shell integrity, especially in rapidly growing parts, appeared to be affected by high cadmium exposure. Our results attest to the value of hepatopancreas for describing cadmium retention in land snails and to the difficulty of using conchological parameters in field surveys for estimating the environmental hazard of soil cadmium. PMID- 25790136 TI - Materials analyses and electrochemical impedance of implantable metal electrodes. AB - Implantable electrodes with high flexibility, high mechanical fixation and low electrochemical impedance are desirable for neuromuscular activation because they provide safe, effective and stable stimulation. In this paper, we report on detailed materials and electrical analyses of three metal implantable electrodes gold (Au), platinum (Pt) and titanium (Ti) - using X-ray photoelectron spectroscopy (XPS), scanning acoustic microscopy, drop shape analysis and electrochemical impedance spectroscopy. We investigated the cause of changes in electrochemical impedance of long-term immersed Au, Pt and Ti electrodes on liquid crystal polymers (LCPs) in phosphate buffered saline (PBS). We analyzed the surface wettability, surface and interface defects and the elemental depth profile of the electrode-adhesion layers on the LCP. The impedance of the electrodes decreased at lower frequencies, but increased at higher frequencies compared with that of the short-term immersion. The increase of impedances was influenced by the oxidation of the electrode/adhesion-layers that affected the double layer capacitance behavior of the electrode/PBS. The oxidation of the adhesion layer for all the electrodes was confirmed by XPS. Alkali ions (sodium) were adsorbed on the Au and Pt surfaces, but diffused into the Ti electrode and LCPs. The Pt electrode showed a higher sensitivity to surface and interface defects than that of Ti and Au electrodes. These findings may be useful when designing electrodes for long-term implantable devices. PMID- 25790138 TI - Demeclocycline as a contrast agent for detecting brain neoplasms using confocal microscopy. AB - Complete resection of brain tumors improves life expectancy and quality. Thus, there is a strong need for high-resolution detection and microscopically controlled removal of brain neoplasms. The goal of this study was to test demeclocycline as a contrast enhancer for the intraoperative detection of brain tumors. We have imaged benign and cancerous brain tumors using multimodal confocal microscopy. The tumors investigated included pituitary adenoma, meningiomas, glioblastomas, and metastatic brain cancers. Freshly excised brain tissues were stained in 0.75 mg ml(-1) aqueous solution of demeclocyline. Reflectance images were acquired at 402 nm. Fluorescence signals were excited at 402 nm and registered between 500 and 540 nm. After imaging, histological sections were processed from the imaged specimens and compared to the optical images. Fluorescence images highlighted normal and cancerous brain cells, while reflectance images emphasized the morphology of connective tissue. The optical and histological images were in accordance with each other for all types of tumors investigated. Demeclocyline shows promise as a contrast agent for intraoperative detection of brain tumors. PMID- 25790137 TI - Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53. AB - The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms. PMID- 25790140 TI - When am I dead? Another case for some applied philosophy... PMID- 25790139 TI - Laboratory-confirmed HIV and sexually transmitted infection seropositivity and risk behavior among sexually active transgender patients at an adolescent and young adult urban community health center. AB - The sexual health of transgender adolescents and young adults who present for health care in urban community health centers is understudied. A retrospective review of electronic health record (EHR) data was conducted from 180 transgender patients aged 12-29 years seen for one or more health-care visits between 2001 and 2010 at an urban community health center serving youth in Boston, MA. Analyses were restricted to 145 sexually active transgender youth (87.3% of the sample). Laboratory-confirmed HIV and sexually transmitted infections (STIs) seroprevalence, demographics, sexual risk behavior, and structural and psychosocial risk indicators were extracted from the EHR. Analyses were descriptively focused for HIV and STIs. Stratified multivariable logistic regression models were fit for male-to-female (MTF) and female-to-male (FTM) patients separately to examine factors associated with any unprotected anal and/or vaginal sex (UAVS). The mean age was 20.0 (SD=2.9); 21.7% people of color, 46.9% white (non-Hispanic), 21.4% race/ethnicity unknown; 43.4% MTF, and 56.6% FTM; and 68.3% were on cross-sex hormones. Prevalence of STIs: 4.8% HIV, 2.8% herpes simplex virus, 2.8% syphilis, 2.1% chlamydia, 2.1% gonorrhea, 2.8% hepatitis C, 1.4% human papilloma virus. Only gonorrhea prevalence significantly differed by gender identity (MTF 2.1% vs. 0.0% FTM; p=0.046). Nearly half (47.6%) of the sample engaged in UAVS (52.4% MTF, 43.9% FTM, p=0.311). FTM more frequently had a primary sex partner compared to MTF (48.8% vs. 25.4%; p=0.004); MTF more frequently had a casual sex partner than FTM (69.8% vs. 42.7% p=0.001). In multivariable models, MTF youth who were younger in age, white non-Hispanic, and reported a primary sex partner had increased odds of UAVS; whereas, FTM youth reporting a casual sex partner and current alcohol use had increased odds of UAVS (all p<0.05). Factors associated with sexual risk differ for MTF and FTM youth. Partner type appears pivotal to understanding sexual risk in transgender adolescents and young adults. HIV and STI prevention efforts, including early intervention efforts, are needed in community-based settings serving transgender youth that attend to sex-specific (biological) and gender-related (social) pathways. PMID- 25790146 TI - Structures, thermal behaviors, and luminescent properties of anhydrous lanthanum iodate polymorphs. AB - The structural and thermal studies of six anhydrous lanthanum iodate polymorphs are presented. The variation of the [IO3(-)]:[La(3+)] molar ratio in the starting solution and the evaporation rate of the solution leads to either the centric La(IO3)3(HIO3) or the acentric La(IO3)3(HIO3)1.33 phases. The crystal structure of La(IO3)3(HIO3)1.33 was determined. The thermal treatments of these two phases up to 490 degrees C lead to beta-La(IO3)3, observed at room temperature. To better understand the similar thermal behaviors of La(IO3)3(HIO3)1.33 and La(IO3)3(HIO3) compounds and their structural evolution, thermogravimetry differential thermal analysis (TG-DTA), differential scanning calorimetry (DSC) analyses and in situ temperature-dependent powder X-ray diffraction (XRD) experiments were carried out. These experiments allowed us to highlight the successive formation of delta-La(IO3)3 and gamma-La(IO3)3. delta-La(IO3)3 is observed from the beginning of thermal decomposition of La(IO3)3(HIO3)1.33 (at 340 degrees C) or La(IO3)3(HIO3) (at 300 degrees C) up to 440 degrees C. A phase transition from delta-La(IO3)3 to gamma-La(IO3)3 then occurs at 440 degrees C. Finally, the phase transition from gamma-La(IO3)3 to beta-La(IO3)3 occurs at 140 degrees C. A cycle of heating and cooling shows the reversible phase transition at 185 and 140 degrees C, respectively. beta-, gamma-, and delta-La(IO3)3 are three polymorph phases of the first alpha-La(IO3)3 already characterized. The structure of beta-La(IO3)3 and gamma-La(IO3)3 were determined on powder XRD analyses. The iodate compounds present a very broad domain of transparency from the visible range to the beginning of the far-infrared range. The intensities of SHG light generated by alpha-La(IO3)3, beta-La(IO3)3, La(IO3)3(HIO3)1.33, and alpha-LiIO3 compounds with acentric structures were compared: beta-La(IO3)3 < La(IO3)3(HIO3)1.33 < alpha-La(IO3)3 ~ alpha-LiIO3. Finally, the luminescence spectroscopy of La(IO3)3(HIO3)1.33:Nd(3+), alpha La(IO3)3:Nd(3+), and alpha-La(IO3)3:Yb(3+) is studied. PMID- 25790147 TI - Pretreatment health measures and complications after surgical management of elderly women with breast cancer. AB - BACKGROUND: Elderly patients with breast cancer are less likely to be offered surgery, partly owing to co-morbidities and reduced functional ability. However, there is little consensus on how best to assess surgical risk in this patient group. METHODS: The ability of pretreatment health measures to predict complications was investigated in a prospective cohort study of a consecutive series of women aged at least 70 years undergoing surgery for operable (stage I IIIa) breast cancer at 22 English breast units between 2010 and 2013. Data on treatment, surgical complications, health measures and tumour characteristics were collected by case-note review and/or patient interview. Outcome measures were all complications and serious complications within 30 days of surgery. RESULTS: The study included 664 women. One or more complications were experienced by 41.0 per cent of the patients, predominantly seroma or primary/minor infections. Complications were serious in 6.5 per cent. More extensive surgery predicted a higher number of complications, but not serious complications. Older age did not predict complications. Several health measures were associated with complications in univariable analysis, and were included in multivariable analyses, adjusting for type/extent of surgery and tumour characteristics. In the final models, pain predicted a higher count of complications (incidence rate ratio 1.01, 95 per cent c.i. 1.00 to 1.01; P = 0.004). Fatigue (odds ratio (OR) 1.02, 95 per cent c.i. 1.01 to 1.03; P = 0.004), low platelet count (OR 4.19, 1.03 to 17.12: P = 0.046) and pulse rate (OR 0.96, 0.93 to 0.99; P = 0.010) predicted serious complications. CONCLUSION: The risk of serious complications from breast surgery is low for older patients. Surgical decisions should be based on patient fitness rather than age. Health measures that predict surgical risk were identified in multivariable models, but the effects were weak, with 95 per cent c.i. close to unity. PMID- 25790148 TI - Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest. AB - BACKGROUND: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets. METHODS: A total of 26 immature male piglets were subjected to 12-min VF followed by 8-min CPR. The treatment group (n=13) received i.v. (intravenous) boluses vasopressin 0.4 U/kg, esmolol 250 MUg/kg and milrinone 25 MUg/kg after 13 min, followed by i.v. boluses esmolol 375 MUg/kg and milrinone 25 MUg/kg after 18 min and continuous esmolol 15 MUg/kg/h infusion during 180 min reperfusion, whereas controls (n=13) received equal amounts of vasopressin and saline. A 200 J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200 J defibrillation and bolus vasopressin 0.4 U/kg would be administered in both groups. Direct current shocks at 360 J were applied as one shot per minute over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded. RESULTS: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (P<0.05). The treatment group received less norepinephrine (P<0.01) and had greater diuresis (P<0.01). There was no difference in survival between groups. CONCLUSION: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. PMID- 25790149 TI - Synthesis, structures and magnetic properties in 3d-electron-rich isostructural complexes based on chains with sole syn-anti carboxylate bridges. AB - To evaluate magnetic properties of isostructural compounds, a series of 3D carboxylate coordination polymers [M(H2bpta)]n, (H4bpta = 2,2',4,4' biphenyltetracarboxylic acid, M = Fe(II) (1), Ni(II) (2), Cu(II) (3) and Zn(II) (4)), was synthesized in H2O-CH3CN or H2O solvents, respectively. Structurally, complexes 1-4 have isostructural features with (5,5)-connected 3D framework, wherein the M(II) centre takes an octahedral coordination environment consisting of six oxygen atoms from carboxylates of ligands. The M(II) sites are linked by syn-anti carboxylates to form chains with an M...M separation of 4.880(2) (M = Fe), 4.784(2) (M = Ni), 4.541(2) (M = Cu), and 4.607(2) A (M = Zn), respectively. The shortest M...M distances between interchains locate 9.122(4), 9.077(3), 9.361(3), and 8.767(2) A, respectively. Magnetically, the isostructural polymers show different magnetic behaviors due to different spins of central ions. Theoretical analysis indicates that couplings between magnetic ions obey uniform chain models. The magnetic susceptibility of 1 and 2 are perfectly fitted by the modified Fisher model to yield an effective intra-chain exchange coupling constant of -0.81(1) and 3.67(2) cm(-1), respectively. For 3, a Heisenberg ferromagnetic S = 1/2 chain included the intra-chain magnetic exchange interaction (J = 9.28(1) cm(-1), and zj' = -0.068(3) cm(-1)), weak ferromagnetic interactions in intra-chains, and weak antiferromagnetic interactions between interchains. The phenomena of 1-3 accord with the common view that the exchange interaction between two magnetic M(II) ions bridged by the syn-anti carboxylate bridge is dominantly weak ferro- or anti-ferromagnetic interactions. In addition, the M-O-C-O-M spin exchange interactions |J| of M2(CO2)2 (M = Mn(3d(5))(20), Fe(3d(6)), Co(3d(7))(20), Ni(3d(8)), Cu(3d(9))) decrease in strength with Cu2(CO2)2 > Ni2(CO2)2 > Co2(CO2)2 > Fe2(CO2)2 > Mn2(CO2)2, consistent with orbit order. PMID- 25790150 TI - Ocular adverse effects after facial cosmetic procedures: a review of case reports. AB - To review indexed literature concerning adverse ocular effects of the most common aesthetic facial procedures (light-emitting therapy, dermal fillers injection, and botulinum toxin). Literature search using three online databases - PubMed, SciELO, and Capes - selecting case reports, series of cases and reviews, with no language restriction, published in a period of the last twenty years (1995-2015). After reviewing 48 case reports and most recent reviews, the authors found the most common ocular adverse effects of dermal fillers were related to vascular occlusion; light-emitting therapy was associated with pigmented tissue damage leading to anterior uveitis and iris atrophy, and ptosis presented the higher relative risk associated with botulinum toxin. Even though ocular adverse effects are not very frequent, some of them can lead to permanent ocular dysfunction and visual impairment. Professionals involved in cosmetic procedures should be aware of the risks. PMID- 25790151 TI - Clinical Significance of Nonsustained Ventricular Tachycardia on Routine Monitoring of Pacemaker Patients. AB - BACKGROUND: Permanent pacemakers (PPMs) are capable of recording tachyarrhythmic events including nonsustained ventricular tachycardia (NSVT), though the clinical significance of NSVT on routine PPM evaluation is unknown. Our goals: assess the prevalence of NSVT on routine PPM follow-up and survival of PPM patients with NSVT, without NSVT, and with ventricular high rate (VHR) episodes of undefined origin. METHODS: A single-center retrospective, cohort study was performed on patients implanted with PPMs capable of recording NSVT, defined as >=5 consecutive ventricular beats at >=170/minutes lasting <30 seconds. Patients were categorized: (1) no NSVT; (2) NSVT; or (3) VHR episodes of uncertain etiology. The primary endpoint was all-cause mortality within 6 months of last follow-up. RESULTS: Note that in 1,125 enrollees (51.8% male, age 74.2 +/- 15.5 years, ejection fraction 57.0 +/- 9.0%), 742 (66%) had no NSVT, 223 had NSVT (20%), and 160 (14%) had VHR. There were no differences in ejection fraction, diabetes, hypertension, coronary disease, prior myocardial infarction, baseline creatinine, QRS duration, prevalence of left bundle branch block, or beta-blocker use among groups. "No NSVT" patients were older (P = 0.013), NSVT patients had more males (P = 0.012); atrial fibrillation and digoxin use were more prevalent in VHR patients (P < 0.01). During median follow-up of 2.8 years there were 93 deaths within 6 months of last follow-up with no differences in survival among groups (log rank P = 0.47). Age, ejection fraction at time of implant, and beta-blocker use were independent predictors of survival. CONCLUSION: NSVT detected on routine PPM follow-up in this patient population with a preserved ejection fraction is not associated with long-term mortality. PMID- 25790152 TI - Neuroenergetic Response to Prolonged Cerebral Glucose Depletion after Severe Brain Injury and the Role of Lactate. AB - Lactate may represent a supplemental fuel for the brain. We examined cerebral lactate metabolism during prolonged brain glucose depletion (GD) in acute brain injury (ABI) patients monitored with cerebral microdialysis (CMD). Sixty episodes of GD (defined as spontaneous decreases of CMD glucose from normal to low [<1.0 mmol/L] for at least 2 h) were identified among 26 patients. During GD, we found a significant increase of CMD lactate (from 4 +/- 2.3 to 5.4 +/- 2.9 mmol/L), pyruvate (126.9 +/- 65.1 to 172.3 +/- 74.1 MUmol/L), and lactate/pyruvate ratio (LPR; 27 +/- 6 to 35 +/- 9; all, p < 0.005), while brain oxygen and blood lactate remained normal. Dynamics of lactate and glucose supply during GD were further studied by analyzing the relationships between blood and CMD samples. There was a strong correlation between blood and brain lactate when LPR was normal (r = 0.56; p < 0.0001), while an inverse correlation (r = -0.11; p = 0.04) was observed at elevated LPR >25. The correlation between blood and brain glucose also decreased from r = 0.62 to r = 0.45. These findings in ABI patients suggest increased cerebral lactate delivery in the absence of brain hypoxia when glucose availability is limited and support the concept that lactate acts as alternative fuel. PMID- 25790153 TI - Thyroidectomy in the professional singer-neural monitored surgical outcomes. AB - BACKGROUND: Voice changes commonly occur from thyroidectomy and may be due to neural or nonneural causes. Such changes can be a source of significant morbidity for any patient, but thyroidectomy in the professional singer carries special significance. We test the hypothesis that the career of singers and professional voice users is not impaired after neural monitored thyroid surgery. METHODS: A quantitative analysis of pre- and postoperative neural monitored thyroid surgery voice outcomes utilizing three validated vocal instruments-Voice Handicap Index (VHI), Singing Voice Handicap Index (SVHI), and Evaluation of Ability to Sing Easily (EASE)-in a unique series of professional singers/voice users was performed. Additional quantitative analysis related to final intraoperative electromyography (EMG) amplitude, the time to return to performance, and vocal parameters affected during this interval was performed. RESULTS: Twenty-seven vocal professionals undergoing thyroidectomy were identified, of whom 60% had surgery for thyroid cancer. Pre- and postsurgery flexible fiberoptic laryngeal exams were normal in all patients. Return to performance rate was 100%, and mean time to performance was 2.26 months (+/-1.61). All three vocal instrument mean scores, pre-op vs. post-op, were unchanged: VHI, 4.15 (+/-5.22) vs. 4.04 (+/ 3.85), p=0.9301; SVHI, 11.26 (+/-14.41) vs.12.07 (+/-13.09), p=0.8297; and EASE, 6.19 (+/-9.19) vs. 6.00 (+/-7.72), p=0.9348. The vocal parameters most affected from surgery until first performances were vocal fatigue (89%), high range (89%), pitch control and modulation (74%), and strength (81%). Final mean intraoperative EMG amplitude was within normal limits for intraoperative stimulation and had no relationship with time to first professional performance (p=0.7199). CONCLUSIONS: Neural monitored thyroidectomy, including for thyroid malignancy, in professional voice users is safe without any changes in three different voice/singing instruments, with 100% return to performance. Intraoperative EMG data at the conclusion of surgery and postoperative laryngeal exam were normal in all patients. Specific vocal parameters are transiently affected during the postoperative recovery phase, which is important to outline in the consent process of this unique patient population and may provide insight into the physiologic state of the larynx subsequent to thyroid surgery. PMID- 25790154 TI - A pilot study examining density of suppression measurement in strabismus. AB - PURPOSE: Establish whether the Sbisa bar, Bagolini filter (BF) bar, and neutral density filter (NDF) bar, used to measure density of suppression, are equivalent and possess test-retest reliability. Determine whether density of suppression is altered when measurement equipment/testing conditions are changed. METHODS: Our pilot study had 10 subjects aged >=18 years with childhood-onset strabismus, no ocular pathologies, and no binocular vision when manifest. Density of suppression upon repeated testing, with clinic lights on/off, and using a full/reduced intensity light source, was investigated. Results were analysed for test-retest reliability, equivalence, and changes with alteration of testing conditions. RESULTS: Test-retest reliability issues were present for the BF bar (median 6 filter change from first to final test, p = 0.021) and NDF bar (median 5 filter change from first to final test, p = 0.002). Density of suppression was unaffected by environmental illumination or fixation light intensity variations. Density of suppression measurements were higher when measured with the NDF bar (e.g. NDF bar = 1.5, medium suppression, vs BF bar = 6.5, light suppression). CONCLUSIONS: Test-retest reliability issues may be present for the two filter bars currently still under manufacture. Changes in testing conditions do not significantly affect test results, provided the same filter bar is used consistently for testing. Further studies in children with strabismus having active amblyopia treatment would be of benefit. Despite extensive use of these tests in the UK, this is to our knowledge the first study evaluating filter bar equivalence/reliability. PMID- 25790155 TI - Correction: Fishing for space: fine-scale multi-sector maritime activities influence fisher location choice. PMID- 25790156 TI - Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients. AB - Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the alpha3 and beta4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-alpha3 and -beta4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG. PMID- 25790157 TI - Mussel-inspired one-pot synthesis of a fluorescent and water-soluble polydopamine polyethyleneimine copolymer. AB - Inspired by the molecular mechanics of mussel adhesive formation, a novel water soluble fluorescent macromolecule (polydopamine-polyethyleneimine (PDA-PEI)) is prepared by one-pot copolymerization of dopamine (DA) and PEI. In this method, DA is polymerized to form PDA, which is then coupled with PEI mainly through Michael addition. The fluorescence property of PDA-PEI is mainly attributed to the Michael addition of PEI on the 5,6-dihydroxyindole (DHI) units of PDA, where PEI can form hydrogen bonds with oxidative products such as DHI and force the DHI units to twist out of plane, resulting in a decrease in the intra- and intermolecular coupling of PDA. In addition, the influence of various metal cations on the fluorescence of the PDA-PEI copolymer is investigated. This work may facilitate the development of new strategies for controlling the emission characteristics of PDA. PMID- 25790158 TI - The current status in hematopoietic stem cell mobilization. AB - Hemotopoietic stem cell mobilization with cytokines alone, has still been widely accepted as the initial attempt for stem cell mobilization. Chemotherapy based mobilization can be preferred as first choice in high risk patients or for remobilization. But mobilization failure still remains to be a problem in one third of patients. Salvage mobilization strategies have been composed to give one more chance to 'poor mobilizers'. Synergistic effect of a reversible inhibitor of CXCR4, plerixafor, with G-CSF has opened a new era for these patients. Preemptive approach in predicted poor mobilizers, immediate salvage approach for patients with suboptimal mobilization or remobilization approach of plerixafor in failed mobilizers have all been demonstrated convincing results in various studies. Alternative CXCR4 inhibitors, VLA4 inhibitors, bortezomib, parathormone have also been emerged as novel agents for mobilization failure. PMID- 25790159 TI - Pushing the envelope in genomics education. PMID- 25790160 TI - A genome sequencing program for novel undiagnosed diseases. AB - PURPOSE: The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene-disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study. METHODS: A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician-scientist review panel, and 17 patients (14.0%) and their family members were enrolled. RESULTS: 60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene-disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings. CONCLUSION: Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking. PMID- 25790161 TI - Too much, too soon?: Commercial provision of noninvasive prenatal screening for subchromosomal abnormalities and beyond. PMID- 25790163 TI - Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies. AB - Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies. PMID- 25790162 TI - Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. AB - PURPOSE: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. METHODS: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. RESULTS: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. CONCLUSION: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect. PMID- 25790164 TI - Molecular details of alpha-synuclein membrane association revealed by neutrons and photons. AB - alpha-Synuclein (alpha-syn) is an abundant neuronal protein associated with Parkinson's disease that is disordered in solution, but it exists in equilibrium between a bent-helix and an elongated-helix on negatively charged membranes. Here, neutron reflectometry (NR) and fluorescence spectroscopy were employed to uncover molecular details of the interaction between alpha-syn and two anionic lipids, phosphatidic acid (PA) and phosphatidylserine (PS). Both NR and site specific Trp measurements indicate that penetration depth of alpha-syn is similar for either PA- or PS-containing membranes (~9-11 A from bilayer center) even though there is a preference for alpha-syn binding to PA. However, closer examination of the individual Trp quenching profiles by brominated lipids reveals differences into local membrane interactions especially at position 39 where conformational heterogeneity was observed. The data also indicate that while W94 penetrates the bilayer as deeply as W4, W94 resides in a more polar surrounding. Taken together, we suggest the N- and C-terminal regions near positions 4 and 94 are anchored to the membrane, while the putative linker spanning residue 39 samples multiple conformations, which are sensitive to the chemical nature of the membrane surface. This flexibility may enable alpha-syn to bind diverse biomembranes in vivo. PMID- 25790165 TI - The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. AB - Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor. PMID- 25790166 TI - The transcriptome of equine peripheral blood mononuclear cells. AB - Complete transcriptomic data at high resolution are available only for a few model organisms with medical importance. The gene structures of non-model organisms are mostly computationally predicted based on comparative genomics with other species. As a result, more than half of the horse gene models are known only by projection. Experimental data supporting these gene models are scarce. Moreover, most of the annotated equine genes are single-transcript genes. Utilizing RNA sequencing (RNA-seq) the experimental validation of predicted transcriptomes has become accessible at reasonable costs. To improve the horse genome annotation we performed RNA-seq on 561 samples of peripheral blood mononuclear cells (PBMCs) derived from 85 Warmblood horses. The mapped sequencing reads were used to build a new transcriptome assembly. The new assembly revealed many alternative isoforms associated to known genes or to those predicted by the Ensembl and/or Gnomon pipelines. We also identified 7,531 transcripts not associated with any horse gene annotated in public databases. Of these, 3,280 transcripts did not have a homologous match to any sequence deposited in the NCBI EST database suggesting horse specificity. The unknown transcripts were categorized as coding and noncoding based on predicted coding potential scores. Among them 230 transcripts had high coding potential score, at least 2 exons, and an open reading frame of at least 300 nt. We experimentally validated 9 new equine coding transcripts using RT-PCR and Sanger sequencing. Our results provide valuable detailed information on many transcripts yet to be annotated in the horse genome. PMID- 25790168 TI - Apoptogenic effects of beta-sitosterol glucoside from Castanopsis indica leaves. AB - beta-Sitosterol glucoside (BSSG) is a natural biologically active substance isolated from the Castanopsis indica leaves. This study explored the apoptogenic mechanistic studies of BSSG against Ehrlich's ascites carcinoma (EAC) treated mice through morphological study, comet assay, flow cytometry (FACS) and Western blotting assay method. AO/EB staining and FACS analysis showed that BSSG possessed apoptosis induction activities on EAC cells. Dose dependent induction of DNA damage was observed after BSSG treatment. Increase the expression of apoptotic protein p53 and p21 in EAC, multiple downstream factors contributing to apoptosis pathway. The increase of caspase-9 and caspase-3 activities revealed that caspase was a key mediator of the apoptotic pathway induced by BSSG, and up regulation of Bax and down-regulation of anti-apoptotic protein Bcl-2 resulted in the decrease of Bcl-2/Bax ratio. Owing to the combination of significant antitumour activity by inducing apoptosis, BSSG holds the promise of being an interesting chemo-preventive agent active in cancer therapy. PMID- 25790169 TI - Electrodeposition of nanoflake Pd structures: structure-dependent wettability and SERS activity. AB - The characteristic properties of metal surfaces, i.e., wettability and surface enhanced Raman scattering (SERS) activity, have been the subject of intensive research because of their useful applications. In the present work, we report a simple electrodeposition of nanoflake Pd structures onto clean Au surfaces without the use of additives. The fine structure of the nanoflake Pd surfaces was regulated by controlling the deposition charge, and the effect of the structural variations on the wettability and SERS activity was examined. The wettability of nanoflake Pd structures in terms of water contact angle was closely related to the fine structures of Pd deposits and their surface roughness. The SERS activity of the nanoflake Pd surfaces was highly dependent on the presence of sharp edge sites on the Pd structures. Well-defined nanoflake Pd structures prepared using a deposition charge of 0.04 C exhibited superhydrophobic natures and reproducible SERS activity. The effect of the metal surface structures on the wettability and the SERS activity demonstrated in this work provides insight into the fabrication of functional metal nanostructures. PMID- 25790167 TI - Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD. AB - BACKGROUND: Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. METHODS: Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. RESULTS: Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. CONCLUSIONS: O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations. PMID- 25790170 TI - Prognostic impact of cytogenetic abnormalities in children and adolescents with mature B-cell non-Hodgkin lymphoma: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). AB - Little information is available on cytogenetic abnormalities and their prognostic importance in childhood mature B-cell non-Hodgkin lymphoma (B-NHL). We performed a review of 79 abnormal karyotypes in childhood B-NHL treated by a uniform protocol. Del(17p) was independently associated with significantly inferior event free survival in Burkitt or Burkitt-like lymphoma. The adverse prognosis of MYC/8q24 rearrangement, +7q or del(13q), was not observed, which had been suggested as risk factors in FAB/LMB96. Our results imply the possible existence of a biological difference among ethnicities and should be useful to narrow down the gene causing poor prognosis in childhood B-NHL. PMID- 25790171 TI - Predictors of behavioural health service use and associated expenditures: Individuals with TBI in Pinellas County. AB - OBJECTIVE: Traumatic brain injury (TBI) is a major public health concern. Such injuries often result in dramatic changes in the individual's life-course due to the associated complex co-morbidities. Limited research exists on the use and expenditures incurred for behavioural healthcare services post-TBI. This study examined predictors of behavioural service use, incarceration and associated expenditures for individuals with TBI. METHODS: Emergency Medical Services and Medicaid Claims data were used to identify individuals diagnosed with a TBI in Pinellas County, Florida, in FY 2005. Ten statewide and local administrative data sets from 2005-2008 were employed to determine subject's demographic characteristics, criminal justice encounters, behavioural health services use and associated expenditures. Average annual expenditures and use of mental health, substance abuse and criminal justice services over a 3-year period were determined. RESULTS: A total of 1005 individuals diagnosed with TBI were identified and, of these, 910 survived the 3-year period. Study participants were grouped into high and low behavioural health expenditure groups. Those in the high expenditure group were more likely to be male, white and to have received behavioural health services. CONCLUSIONS: This study provides new information about predictors of behavioural health service use and Medicaid expenditures for Floridians with TBI. PMID- 25790173 TI - Toward enhanced hydrogen generation from water using oxygen permeating LCF membranes. AB - Hydrogen production from water thermolysis can be enhanced by the use of perovskite-type mixed ionic and electronic conducting (MIEC) membranes, through which oxygen permeation is driven by a chemical potential gradient. In this work, water thermolysis experiments were performed using 0.9 mm thick La0.9Ca0.1FeO3 delta (LCF-91) perovskite membranes at 990 degrees C in a lab-scale button-cell reactor. We examined the effects of the operating conditions such as the gas species concentrations and flow rates on the feed and sweep sides on the water thermolysis rate and oxygen flux. A single step reaction mechanism is proposed for surface reactions, and three-resistance permeation models are derived. Results show that water thermolysis is facilitated by the LCF-91 membrane especially when a fuel is added to the sweep gas. Increasing the gas flow rate and water concentration on the feed side or the hydrogen concentration on the sweep side enhances the hydrogen production rate. In this work, hydrogen is used as the fuel by construction, so that a single-step surface reaction mechanism can be developed and water thermolysis rate parameters can be derived. Both surface reaction rate parameters for oxygen incorporation/dissociation and hydrogen oxygen reactions are fitted at 990 degrees C. We compare the oxygen fluxes in water thermolysis and air separation experiments, and identify different limiting steps in the processes involving various oxygen sources and sweep gases for this 0.9 mm thick LCF-91 membrane. In the air feed-inert sweep case, the bulk diffusion and sweep side surface reaction are the two limiting steps. In the water feed-inert sweep case, surface reaction on the feed side dominates the oxygen permeation process. Yet in the water feed-fuel sweep case, surface reactions on both the feed and sweep sides are rate determining when hydrogen concentration in the sweep side is in the range of 1-5 vol%. Furthermore, long term studies show that the surface morphology changes and silica impurities have little impact on the oxygen flux for either water thermolysis or air separation. PMID- 25790172 TI - Influence of probe flexibility and gelatin embedding on neuronal density and glial responses to brain implants. AB - To develop long-term high quality communication between brain and computer, a key issue is how to reduce the adverse foreign body responses. Here, the impact of probe flexibility and gelatine embedding on long-term (6w) tissue responses, was analyzed. Probes of same polymer material, size and shape, flexible mainly in one direction, were implanted in rat cerebral cortex (nimplants = 3 x 8) in two orientations with respect to the major movement direction of the brain relative to the skull: parallel to (flex mode) or transverse to (rigid mode). Flex mode implants were either embedded in gelatin or non-embedded. Neurons, activated microglia and astrocytes were visualized using immunohistochemistry. The astrocytic reactivity, but not microglial response, was significantly lower to probes implanted in flex mode as compared to rigid mode. The microglial response, but not astrocytic reactivity, was significantly smaller to gelatin embedded probes (flex mode) than non-embedded. Interestingly, the neuronal density was preserved in the inner zone surrounding gelatin embedded probes. This contrasts to the common reports of reduced neuronal density close to implanted probes. In conclusion, sheer stress appears to be an important factor for astrocytic reactivity to implanted probes. Moreover, gelatin embedding can improve the neuronal density and reduce the microglial response close to the probe. PMID- 25790174 TI - Nanotopography facilitates in vivo transdermal delivery of high molecular weight therapeutics through an integrin-dependent mechanism. AB - Transdermal delivery of therapeutics is restricted by narrow limitations on size and hydrophobicity. Nanotopography has been shown to significantly enhance high molecular weight paracellular transport in vitro. Herein, we demonstrate for the first time that nanotopography applied to microneedles significantly enhances transdermal delivery of etanercept, a 150 kD therapeutic, in both rats and rabbits. We further show that this effect is mediated by remodeling of the tight junction proteins initiated via integrin binding to the nanotopography, followed by phosphorylation of myosin light chain (MLC) and activation of the actomyosin complex, which in turn increase paracellular permeability. PMID- 25790175 TI - An alternative assay to hydrophobic interaction chromatography for high throughput characterization of monoclonal antibodies. AB - The effectiveness of therapeutic monoclonal antibodies (mAbs) is governed not only by their bioactivity, but also by their biophysical properties. Assays for rapidly evaluating the biophysical properties of mAbs are valuable for identifying those most likely to exhibit superior properties such as high solubility, low viscosity and slow serum clearance. Analytical hydrophobic interaction chromatography (HIC), which is performed at high salt concentrations to enhance hydrophobic interactions, is an attractive assay for identifying mAbs with low hydrophobicity. However, this assay is low throughput and thus not amenable to processing the large numbers of mAbs that are commonly generated during antibody discovery. Therefore, we investigated whether an alternative, higher throughput, assay could be developed that is based on evaluating antibody self-association at high salt concentrations using affinity-capture self interaction nanoparticle spectroscopy (AC-SINS). Our approach is to coat gold nanoparticles with polyclonal anti-human antibodies, use these conjugates to immobilize human mAbs, and evaluate mAb self-interactions by measuring the plasmon wavelengths of the antibody conjugates as a function of ammonium sulfate concentration. We find that hydrophobic mAbs, as identified by HIC, generally show significant self-association at low to moderate ammonium sulfate concentrations, while hydrophilic mAbs typically show self-association only at high ammonium sulfate concentrations. The correlation between AC-SINS and HIC measurements suggests that our assay, which can evaluate tens to hundreds of mAbs in a parallel manner and requires only small (microgram) amounts of antibody, will enable early identification of mAb candidates with low hydrophobicity and improved biophysical properties. PMID- 25790176 TI - Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes. AB - Maternal obese environment has been reported to induce oxidative stress and meiotic defects in oocytes, however the underlying molecular mechanism remains unclear. Here, using mice fed a high fat diet (HFD) as an obesity model, we first detected enhanced reactive oxygen species (ROS) content and reduced Sirt3 expression in HFD oocytes. We further observed that specific depletion of Sirt3 in control oocytes elevates ROS levels while Sirt3 overexpression attenuates ROS production in HFD oocytes, with significant suppression of spindle disorganization and chromosome misalignment phenotypes that have been reported in the obesity model. Candidate screening revealed that the acetylation status of lysine 68 on superoxide dismutase (SOD2K68) is dependent on Sirt3 deacetylase activity in oocytes, and acetylation-mimetic mutant SOD2K68Q results in almost threefold increase in intracellular ROS. Moreover, we found that acetylation levels of SOD2K68 are increased by ~80% in HFD oocytes and importantly, that the non-acetylatable-mimetic mutant SOD2K68R is capable of partially rescuing their deficient phenotypes. Together, our data identify Sirt3 as an important player in modulating ROS homeostasis during oocyte development, and indicate that Sirt3 dependent deacetylation of SOD2 plays a protective role against oxidative stress and meiotic defects in oocytes under maternal obese conditions. PMID- 25790177 TI - Adenine phosphoribosyltransferase from Sulfolobus solfataricus is an enzyme with unusual kinetic properties and a crystal structure that suggests it evolved from a 6-oxopurine phosphoribosyltransferase. AB - The adenine phosphoribosyltransferase (APRTase) encoded by the open reading frame SSO2342 of Sulfolobus solfataricus P2 was subjected to crystallographic, kinetic, and ligand binding analyses. The enzyme forms dimers in solution and in the crystals, and binds one molecule of the reactants 5-phosphoribosyl-alpha-1 pyrophosphate (PRPP) and adenine or the product adenosine monophosphate (AMP) or the inhibitor adenosine diphosphate (ADP) in each active site. The individual subunit adopts an overall structure that resembles a 6-oxopurine phosphoribosyltransferase (PRTase) more than known APRTases implying that APRT functionality in Crenarchaeotae has its evolutionary origin in this family of PRTases. Only the N-terminal two-thirds of the polypeptide chain folds as a traditional type I PRTase with a five-stranded beta-sheet surrounded by helices. The C-terminal third adopts an unusual three-helix bundle structure that together with the nucleobase-binding loop undergoes a conformational change upon binding of adenine and phosphate resulting in a slight contraction of the active site. The inhibitor ADP binds like the product AMP with both the alpha- and beta phosphates occupying the 5'-phosphoribosyl binding site. The enzyme shows activity over a wide pH range, and the kinetic and ligand binding properties depend on both pH and the presence/absence of phosphate in the buffers. A slow hydrolysis of PRPP to ribose 5-phosphate and pyrophosphate, catalyzed by the enzyme, may be facilitated by elements in the C-terminal three-helix bundle part of the protein. PMID- 25790178 TI - Proton-coupled electron transfer dynamics in the catalytic mechanism of a [NiFe] hydrogenase. AB - The movement of protons and electrons is common to the synthesis of all chemical fuels such as H2. Hydrogenases, which catalyze the reversible reduction of protons, necessitate transport and reactivity between protons and electrons, but a detailed mechanism has thus far been elusive. Here, we use a phototriggered chemical potential jump method to rapidly initiate the proton reduction activity of a [NiFe] hydrogenase. Coupling the photochemical initiation approach to nanosecond transient infrared and visible absorbance spectroscopy afforded direct observation of interfacial electron transfer and active site chemistry. Tuning of intramolecular proton transport by pH and isotopic substitution revealed distinct concerted and stepwise proton-coupled electron transfer mechanisms in catalysis. The observed heterogeneity in the two sequential proton-associated reduction processes suggests a highly engineered protein environment modulating catalysis and implicates three new reaction intermediates; Nia-I, Nia-D, and Nia-SR(-). The results establish an elementary mechanistic understanding of catalysis in a [NiFe] hydrogenase with implications in enzymatic proton-coupled electron transfer and biomimetic catalyst design. PMID- 25790179 TI - Nail-gun Injury through the Spinal Canal. PMID- 25790180 TI - Experimental tests of priority effects and light availability on relative performance of Myriophyllum spicatum and Elodea nuttallii propagules in artificial stream channels. AB - Submersed macrophytes have important ecological functions in many streams, but fostering growth of beneficial native species while suppressing weedy invasives may be challenging. Two approaches commonly used in management of terrestrial plant communities may be useful in this context: (1) altering resource availability and (2) establishing desirable species before weeds can invade (priority effects). However, these approaches are rarely used in aquatic systems, despite widespread need for sustainable solutions to aquatic weed problems. In artificial stream channels in California, USA, I conducted experiments with asexual propagules of non-native invasive Myriophyllum spicatum (Eurasian watermilfoil) and native Elodea nuttallii (western waterweed) to address the questions: (1) How does light availability affect relative performance of the two species?; (2) Does planting the native earlier than the invasive decrease survival or growth rate of the invasive?; and (3) Do light level and priority effects interact? The relative performance between E. nuttallii and M. spicatum had an interesting and unexpected pattern: M. spicatum had higher growth rates than E. nuttallii in the zero and medium shade levels, but had similar performance in the low and high shade levels. This pattern is most likely the result of E. nutallii's sensitivity to both very low and very high light, and M. spicatum's sensitivity to very low light only. Native priority did not significantly affect growth rate or survival of M. spicatum, possibly because of unexpectedly poor growth of the E. nuttallii planted early. This study suggests that altering light levels could be effective in reducing growth of an invasive macrophyte, and for changing the competitive balance between a native and a non native species in the establishment phase. Further investigations into the use of priority effects and resource alteration for submersed macrophyte management are warranted, given their mixed results in other (limited) studies. PMID- 25790181 TI - Correction: Application and evaluation of interactive 3D PDF for presenting and sharing planning results for liver surgery in clinical routine. PMID- 25790182 TI - Correction: Lack of association between human plasma oxytocin and interpersonal trust in a prisoner's dilemma paradigm. PMID- 25790183 TI - Tunable dipolar capillary deformations for magnetic Janus particles at fluid fluid interfaces. AB - Janus particles have attracted significant interest as building blocks for complex materials in recent years. Furthermore, capillary interactions have been identified as a promising tool for directed self-assembly of particles at fluid fluid interfaces. In this paper, we develop theoretical models describing the behaviour of magnetic Janus particles adsorbed at fluid-fluid interfaces interacting with an external magnetic field. Using numerical simulations, we test the models predictions and show that the magnetic Janus particles deform the interface in a dipolar manner. We suggest how to utilise the resulting dipolar capillary interactions to assemble particles at a fluid-fluid interface, and further demonstrate that the strength of these interactions can be tuned by altering the external field strength, opening up the possibility to create novel, reconfigurable materials. PMID- 25790184 TI - Design of pyrazolo-pyrrolo-pyrazines and pyrazolo-pyrrolo-diazepines via AuCl3 catalyzed and NaH-supported cyclization of N-propargyl pyrazoles. AB - A concise synthetic methodology for new heterocyclic scaffolds, such as pyrazolo pyrrolo-pyrazine and pyrazolo-pyrrolo-diazepine skeletons, was developed. The key features of this method include (i) synthesis of pyrrole-derived alpha,beta alkynyl ketones, (ii) introduction of various substituents into the alkyne functionality by Sonogashira cross-coupling, (iii) synthesis of pyrazole units by the reaction of alpha,beta-alkynyl compounds with hydrazine monohydrate, (iv) gold-catalyzed cyclization of pyrazoles with alkyne units, and (v) cyclization with NaH. Furthermore, this methodology allows various substituents to be introduced into all positions of the target compounds. PMID- 25790186 TI - Impacts of aqueous Mn(II) on the sorption of Zn(II) by hexagonal birnessite. AB - We used a combination of batch studies and spectroscopic analyses to assess the impacts of aqueous Mn(II) on the solubility and speciation of Zn(II) in anoxic suspensions of hexagonal birnessite at pH 6.5 and 7.5. Introduction of aqueous Mn(II) into pre-equilibrated Zn(II)-birnessite suspensions leads to desorption of Zn(II) at pH 6.5, but enhances Zn(II) sorption at pH 7.5. XAS results show that Zn(II) adsorbs as tetrahedral and octahedral triple-corner-sharing complexes at layer vacancy sites when reacted with birnessite in the absence of Mn(II). Addition of aqueous Mn(II) causes no discernible change in Zn(II) surface speciation at pH 6.5, but triggers conversion of adsorbed Zn(II) into spinel Zn(II)1-xMn(II)xMn(III)2O4 precipitates at pH 7.5. This conversion is driven by electron transfer from adsorbed Mn(II) to structural Mn(IV) generating Mn(III) surface species that coprecipitate with Zn(II) and Mn(II). Our results demonstrate substantial production of these reactive Mn(III) surface species within 30 min of contact of the birnessite substrate with aqueous Mn(II). Their importance as a control on the sorption and redox reactivity of Mn-oxides toward Zn(II) and other trace metal(loid)s in environments undergoing biogeochemical manganese redox cycling requires further study. PMID- 25790185 TI - CD4 enumeration technologies: a systematic review of test performance for determining eligibility for antiretroviral therapy. AB - BACKGROUND: Measurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration. METHODS AND FINDINGS: Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/MUl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/MUl, bias ranged from -35.2 to +13.1 cells/MUl while at counts >350 cells/MUl, bias ranged from -70.7 to +47 cells/MUl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/MUl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained. CONCLUSIONS: A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed. PMID- 25790187 TI - In vivo assessment of NS1-truncated influenza virus with a novel SLSYSINWRH motif as a self-adjuvanting live attenuated vaccine. AB - Mutants of influenza virus that encode C-terminally truncated NS1 proteins (NS1 truncated mutants) characteristically induce high interferon responses. The dual activity of interferon in blocking virus replication and enhancing the development of adaptive immune responses makes these mutants promising as self adjuvanting live-attenuated influenza vaccine (LAIV) candidates. Yet, among the NS1-truncated mutants, the length of NS1 is not directly correlated with the interferon-inducing efficiency, the level of attenuation, or effectiveness as LAIV. Using quantitative in vitro biologically active particle subpopulation analysis as a tool to identify potential LAIV candidates from a pool of NS1 truncated mutants, we previously predicted that a NS1-truncated mutant pc2, which was less effective as a LAIV in chickens, would be sufficiently effective as a LAIV in mammalian hosts. In this study, we confirmed that pc2 protected mice and pigs against heterologous virus challenge in terms of preventing clinical signs and reducing virus shedding. pc2 expresses a unique SLSYSINWRH motif at the C terminus of its truncated NS1. Deletion of the SLSYSINWRH motif led to ~821-fold reduction in the peak yield of type I interferon induced in murine cells. Furthermore, replacement of the SLSYSINWRH motif with the wildtype MVKMDQAIMD sequence did not restore the interferon-inducing efficiency. The diminished interferon induction capacity in the absence of the SLSYSINWRH motif was similar to that observed in other mutants which are less effective LAIV candidates. Remarkably, pc2 induced 16-fold or more interferon in human lung and monkey kidney cells compared to the temperature-sensitive, cold-adapted Ann Arbor virus that is currently used as a master backbone for LAIVs such as FluMist. Although the mechanism by which the SLSYSINWRH motif regulates the vaccine properties of pc2 has not been elucidated, this motif has potential use in engineering self adjuvanting NS1-truncated-based LAIVs. PMID- 25790189 TI - Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. AB - Correction to: Oncogene (2015) 34, 1475-1486; doi:10.1038/ onc.2014.96; published online 14 April 2014 .The authors wish to amend the wording of the following sentence on page 2, replacing 'intracellular acidification' with 'intracellular alkalinization' PMID- 25790188 TI - A method for multiplex gene synthesis employing error correction based on expression. AB - Our ability to engineer organisms with new biosynthetic pathways and genetic circuits is limited by the availability of protein characterization data and the cost of synthetic DNA. With new tools for reading and writing DNA, there are opportunities for scalable assays that more efficiently and cost effectively mine for biochemical protein characteristics. To that end, we have developed the Multiplex Library Synthesis and Expression Correction (MuLSEC) method for rapid assembly, error correction, and expression characterization of many genes as a pooled library. This methodology enables gene synthesis from microarray synthesized oligonucleotide pools with a one-pot technique, eliminating the need for robotic liquid handling. Post assembly, the gene library is subjected to an ampicillin based quality control selection, which serves as both an error correction step and a selection for proteins that are properly expressed and folded in E. coli. Next generation sequencing of post selection DNA enables quantitative analysis of gene expression characteristics. We demonstrate the feasibility of this approach by building and testing over 90 genes for empirical evidence of soluble expression. This technique reduces the problem of part characterization to multiplex oligonucleotide synthesis and deep sequencing, two technologies under extensive development with projected cost reduction. PMID- 25790190 TI - Perioperative Outcomes of Laparoscopic Partial Nephrectomy Stratified by Body Mass Index. AB - BACKGROUND AND PURPOSE: Increased body mass index (BMI) has been shown to have inferior perioperative outcomes in patients undergoing laparoscopic partial nephrectomy (LPN). The aim of this study was to determine the differences in perioperative outcomes for patients undergoing LPN in normal, overweight, and obese persons using established BMI risk categories. METHODS: A retrospective review of 488 patients undergoing LPN was performed stratifying patients according to BMI of <25 kg/m(2), 25 to 30 kg/m(2), and >30 kg/m(2). The analysis of variance test, chi-square analysis, and bivariate regression models were used to compare comorbidities and perioperative outcomes among the groups. RESULTS: One hundred and eighty nine of 369 patients were identified as being obese. Obese patients were found to have a significantly higher American Society of Anesthesiologists class (2.4 vs 2.1) than normal weight patients (P=0.03). No significant differences were demonstrated in estimated blood loss, operative time, transfusion requirement, or rate of conversion between the groups. In addition, there was no significant difference in cardiovascular, pulmonary, thromboembolic, or infectious complications between the groups. Obesity was significantly associated with bleeding necessitating angioembolization (P=0.033). CONCLUSION: LPN demonstrates equivalent perioperative outcomes in normal, overweight, and obese patients. The minimally invasive approach achieves equivalent outcomes in patients undergoing major abdominal surgery although further studies of alternate procedures are needed to validate our findings. PMID- 25790191 TI - LOX expression and functional analysis in astrocytomas and impact of IDH1 mutation. AB - Lysyl oxidase (LOX) is involved in vital biological processes such as cell motility, cell signaling and gene regulation. Deregulation of this protein can contribute to tumor formation and progression. Although it is known that LOX is involved in invasion, proliferation and tumor migration in other types of tumors, studies of LOX in astrocytomas of different grades are scarce. The purpose of our study was to characterize LOX, BMP1 and HIF1A expression by real-time PCR in astrocytomas with WHO grades I to IV compared to non-neoplastic brain tissue. IDH1 mutational status was determined by PCR and sequencing. LOX protein expression was also analyzed by immunohistochemistry. LOX functional analyses were performed using siRNA knockdown and the specific inhibitor BAPN in two glioblastoma cell lines. The expression levels of LOX, BMP1 and HIF1A were correlated and analyzed according to IDH1 mutation status and to the clinical end point of overall survival of glioblastoma patients. The results demonstrate that increased expression and activity of LOX, BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas. LOX protein expression also increased according to the degree of malignancy, with localization in the cytoplasm and nucleus and staining observed in endothelial cells. Glioblastoma with a mutation in IDH1 expressed lower levels of LOX in the nucleus, and IDH1 mutated cases showed lower LOX expression levels when compared to wild-type IDH1 cases. LOX knockdown and inhibition by BAPN in U87MG and A172 cell lines affected migration, invasion and soft agar colony formation. Taken together, these results corroborate the role of LOX in the migration, invasion and angiogenesis of astrocytomas. Furthermore, LOX expression is influenced by IDH1 mutational status. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas. PMID- 25790193 TI - Knowledge to practice in developmental coordination disorder: impact of an evidence-based online module on physical therapists' self-reported knowledge, skills, and practice. AB - AIMS: To evaluate the impact of an evidence-based online module on Developmental Coordination Disorder (DCD) on self-reported physical therapist (PT) knowledge, skills, and practice. METHODS: Fifty PTs completed a questionnaire before and after the completion of the online module, with 41 PTs completing the same questionnaire 2 months later. The questionnaires included items rated using a 7 point Likert Scale and short open-ended questions. RESULTS: There was a significant effect of Time for 17 out of 18 items on self-reported knowledge, and all 19 items for self-reported skills. Post-hoc analyses indicated that mean scores at Time 2 and Time 3 were higher than the mean scores at Time 1. Forty-six (92%) participants reported an increase in their confidence to provide evidence based services. Forty-three (86%) participants indicated their intentions to modify their evaluative practices (e.g., involving children in goal setting) and their management of DCD (e.g., using the best practice principles, providing resources to families). At the 2-month follow-up, 19 (46%) participants had returned to the module to review information (e.g., video, resources) or to download handouts. CONCLUSIONS: The online DCD module appears to be an effective knowledge translation strategy to increase PTs' self-reported knowledge and skills, and to support evidence-informed practice. PMID- 25790192 TI - Expression of Toll-like receptor -7 and -9 in B cell subsets from patients with primary Sjogren's syndrome. AB - INTRODUCTION: Sjogren's syndrome (SS) is a rheumatic autoimmune disease characterized by inflammation of exocrine glands. As autoantibodies are present in a majority of patients, B cells have been suggested to play an important role in onset and development of the disease. Toll-like receptors (TLRs) are pattern recognition receptors triggering innate immune responses. Since an increased expression of TLRs has been detected in other rheumatic diseases the purpose of this study was to explore TLRs in B cells of SS patients. METHODS: The expression of TLR-7 and -9 in B cell subsets of 25 patients with primary SS (pSS) and 25 healthy controls was analysed in peripheral blood using flow cytometry and real time quantitative PCR. RESULTS: We detected similar levels of CD19+ B cells in pSS patients and healthy controls. An increased number of naive B cells, as well as fewer pre-switched memory B cells were found in pSS patients. No significant differences were observed in TLR-7 and -9 expression in B cells between pSS patients and healthy controls. CONCLUSION: This study shows that pSS patients have an alteration in the B cell subpopulation composition compared to controls, with less pre-switched memory B cells and more naive B cells. We did not detect any significant disparities in TLR-7 and -9 expression between the two groups. PMID- 25790194 TI - Electrowetting of partially wetting thin nanofluid films. AB - It is observed that the presence of negatively charged, suspended nanoparticles significantly changes the electric-field-induced spreading and contact line dynamics of partially wetting liquid films. Image-analyzing interferometry is used to accurately measure the meniscus profile, including the spatial change in the meniscus curvature. The nanoparticle-containing meniscus exhibits enhanced spreading with an increase in the particle size and weight fraction. The instantaneous contact line velocities are measured using video microscopy and a frame-by-frame analysis of the extracted images. The effects of electric field polarity reversal on the flow toward the contact line are explored as well. The movement of the meniscus is analyzed taking into account the capillary forces and Maxwell-stress-induced flows. An analytical model based on the Young-Laplace equation is used to analyze the electric-field-induced contact line motion, and the model-predicted velocities are compared to the experiments. PMID- 25790195 TI - The influence of diurnal temperature variation on degree-day accumulation and insect life history. AB - Ectotherms, such as insects, experience non-constant temperatures in nature. Daily mean temperatures can be derived from the daily maximum and minimum temperatures. However, the converse is not true and environments with the same mean temperature can exhibit very different diurnal temperate ranges. Here we apply a degree-day model for development of the grape berry moth (Paralobesia viteana, a significant vineyard pest in the northeastern USA) to investigate how different diurnal temperature range conditions can influence degree-day accumulation and, hence, insect life history. We first consider changes in diurnal temperature range independent of changes in mean temperatures. We then investigate grape berry moth life history under potential climate change conditions, increasing mean temperature via variable patterns of change to diurnal temperature range. We predict that diurnal temperature range change can substantially alter insect life history. Altering diurnal temperature range independent of the mean temperature can affect development rate and voltinism, with the magnitude of the effects dependent on whether changes occur to the daily minimum temperature (Tmin), daily maximum temperature (Tmax), or both. Allowing for an increase in mean temperature produces more marked effects on life history but, again, the patterns and magnitude depend on the nature of the change to diurnal temperature range together with the starting conditions in the local environment. The study highlights the importance of characterizing the influence of diurnal temperature range in addition to mean temperature alone. PMID- 25790196 TI - Synthesis of polybenzoxazine based nitrogen-rich porous carbons for carbon dioxide capture. AB - Nitrogen-rich porous carbons (NPCs) were synthesized from 1,5 dihydroxynaphthalene, urea, and formaldehyde based on benzoxazine chemistry by a soft-templating method with KOH chemical activation. They possess high surface areas of 856.8-1257.8 m(2) g(-1), a large pore volume of 0.15-0.65 cm(3) g(-1), tunable pore structure, high nitrogen content (5.21-5.32 wt%), and high char yields. The amount of the soft-templating agent F127 has multiple influences on the textural and chemical properties of the carbons, affecting the surface area and pore structure, impacting the compositions of nitrogen species and resulting in an improvement of the CO2 capture performance. At 1 bar, high CO2 uptake of 4.02 and 6.35 mmol g(-1) at 25 and 0 degrees C was achieved for the sample NPC-2 with a molar ratio of F127:urea = 0.010:1. This can be attributed to its well developed micropore structure and abundant pyridinic nitrogen, pyrrolic nitrogen and pyridonic nitrogen functionalities. The sample NPC-2 also exhibits a remarkable selectivity for CO2/N2 separation and a fast adsorption/desorption rate and can be easily regenerated. This suggests that the polybenzoxazine-based NPCs are desirable for CO2 capture because of possessing a high micropore surface area, a large micropore volume, appropriate pore size distribution, and a large number of basic nitrogen functionalities. PMID- 25790197 TI - Making a difference in perioperative infection. PMID- 25790198 TI - Bacterial reservoirs in the operating room. PMID- 25790199 TI - Fecal patina in the anesthesia work area. PMID- 25790200 TI - If one is good, are two always better? PMID- 25790201 TI - Prophylactic perioperative antibiotic administration: is it time to infuse our practices with new approaches? PMID- 25790202 TI - Pediatric preoperative preparation: "the Eagle has landed" or not? PMID- 25790203 TI - The trouble with using provider assessments for rating clinical performance: it's a matter of bias. PMID- 25790204 TI - Sum of the parts. PMID- 25790205 TI - Developing better local anesthetics. PMID- 25790206 TI - The World Federation of Societies of Anaesthesiologists, International Anesthesia Research Society, and Anesthesia & Analgesia: a shared global vision. PMID- 25790207 TI - Ventricular tachycardia ablation: a comprehensive review for anesthesiologists. AB - Percutaneous catheter ablation is being increasingly performed in patients with recurrent ventricular tachycardia (VT) unresponsive to medical treatment. Optimal management of patients requires careful consideration of the severity of the underlying cardiac disease, the anesthetic drug interactions, and the procedural technique during VT mapping and ablation. The goal is to choose an anesthetic technique that has the least effect on arrhythmogenicity, allowing reproducibility of the VT in the electrophysiology laboratory. Anesthetics can alter action potential and ventricular depolarization directly through their effects on ion channels and gap junctions, as well as indirectly via their effects on the autonomic nervous system. Furthermore, maintaining hemodynamic stability and monitoring for adequate end-organ perfusion are additional challenges. In this review, we provide a comprehensive update on the currently performed VT ablation procedures and their anesthetic considerations. PMID- 25790208 TI - Anesthetic management during cardiopulmonary bypass: a systematic review. AB - Cardiopulmonary bypass (CPB) required for cardiac surgery presents unique challenges to the cardiac anesthesiologist responsible for providing the 3 most basic facets of any anesthetic: amnesia, analgesia, and muscle relaxation. Unique pathophysiologic changes during CPB result in pharmacokinetic alterations that impact the serum and tissue concentrations of IV and volatile anesthetics. Similarly, CPB causes pharmacodynamic alterations that impact anesthetic efficacy. The clinical significance of these alterations represents a "moving target" as practice evolves and the technology of CPB circuitry advances. In addition, perfusionists choose, modify, and maintain the CPB circuitry and membrane oxygenator. Thus, their significance may not be fully appreciated by the anesthesiologist. These issues have a profound impact on the anesthetic state of the patient. The delivery and maintenance of anesthesia during CPB present unique challenges. The perfusionist may be directly responsible for the delivery of anesthetic during CPB, a situation unique to the cardiac suite. In addition, monitors of anesthetic depth-assessment of clinical signs, hemodynamic indicators, the bispectral index monitor, end-tidal anesthetic concentration, or twitch monitoring-are often absent, unreliable, or directly impacted by the unique pathophysiology associated with CPB. The magnitude of these challenges is reflected in the higher incidence of intraoperative awareness during cardiac surgery. Further complicating matters are the lack of specific clinical guidelines and varying international policies regarding medical device specifications that add further layers of complexity and introduce practice variability both within institutions and among nations. We performed a systematic survey of the literature to identify where anesthetic practice during CPB is evidence based (or not), identify gaps in the literature to guide future investigations, and explore the implications of evolving surgical practice, perfusion techniques, and national policies that impact amnesia, analgesia, and muscle relaxation during CPB. PMID- 25790209 TI - Transmission dynamics of gram-negative bacterial pathogens in the anesthesia work area. AB - BACKGROUND: Gram-negative organisms are a major health care concern with increasing prevalence of infection and community spread. Our primary aim was to characterize the transmission dynamics of frequently encountered gram-negative bacteria in the anesthesia work area environment (AWE). Our secondary aim was to examine links between these transmission events and 30-day postoperative health care-associated infections (HCAIs). METHODS: Gram-negative isolates obtained from the AWE (patient nasopharynx and axilla, anesthesia provider hands, and the adjustable pressure-limiting valve and agent dial of the anesthesia machine) at 3 major academic medical centers were identified as possible intraoperative bacterial transmission events by class of pathogen, temporal association, and phenotypic analysis (analytical profile indexing). The top 5 frequently encountered genera were subjected to antibiotic disk diffusion sensitivity to identify epidemiologically related transmission events. Complete multivariable logistic regression analysis and binomial tests of proportion were then used to examine the relative contributions of reservoirs of origin and within- and between-case modes of transmission, respectively, to epidemiologically related transmission events. Analyses were conducted with and without the inclusion of duplicate transmission events of the same genera occurring in a given study unit (first and second case of the day in each operating room observed) to examine the potential effect of statistical dependency. Transmitted isolates were compared by pulsed-field gel electrophoresis to disease-causing bacteria for 30-day postoperative HCAIs. RESULTS: The top 5 frequently encountered gram-negative genera included Acinetobacter, Pseudomonas, Brevundimonas, Enterobacter, and Moraxella that together accounted for 81% (767/945) of possible transmission events. For all isolates, 22% (167/767) of possible transmission events were identified by antibiotic susceptibility patterns as epidemiologically related and underwent further study of transmission dynamics. There were 20 duplicates involving within- and between-case transmission events. Thus, approximately 19% (147/767) of isolates excluding duplicates were considered epidemiologically related. Contaminated provider hand reservoirs were less likely (all isolates, odds ratio 0.12, 95% confidence interval 0.03-0.50, P = 0.004; without duplicate events, odds ratio 0.05, 95% confidence interval 0.01-0.49, P = 0.010) than contaminated patient or environmental sites to serve as the reservoir of origin for epidemiologically related transmission events. Within- and between-case modes of gram-negative bacilli transmission occurred at similar rates (all isolates, 7% between-case, 5.2% within-case, binomial P value 0.176; without duplicates, 6.3% between-case, 3.7% within-case, binomial P value 0.036). Overall, 4.0% (23/548) of patients suffered from HCAIs and had an intraoperative exposure to gram negative isolates. In 8.0% (2/23) of those patients, gram-negative bacteria were linked by pulsed-field gel electrophoresis to the causative organism of infection. Patient and provider hands were identified as the reservoirs of origin and the environment confirmed as a vehicle for between-case transmission events linked to HCAIs. CONCLUSIONS: Between- and within-case AWE gram-negative bacterial transmission occurs frequently and is linked by pulsed-field gel electrophoresis to 30-day postoperative infections. Provider hands are less likely than contaminated environmental or patient skin surfaces to serve as the reservoir of origin for transmission events. PMID- 25790210 TI - The dynamics and implications of bacterial transmission events arising from the anesthesia work area. AB - Health care-associated infections are a hospital-wide concern associated with a significant increase in patient morbidity, mortality, and health care costs. Bacterial transmission in the anesthesia work area of the operating room environment is a root cause of 30-day postoperative infections affecting as many as 16% of patients undergoing surgery. A better understanding of anesthesia related bacterial transmission dynamics may help to generate improvements in intraoperative infection control and improve patient safety. PMID- 25790211 TI - Administration of parenteral prophylactic beta-lactam antibiotics in 2014: a review. AB - The role of the anesthesiologist in reducing the incidence of surgical-site infections by the administration of prophylactic parenteral beta-lactam antibiotics is reviewed. Suggestions are made with regard to timing, dosing, and method of administration of these drugs to potentially reduce the risk of surgical-site infection. PMID- 25790212 TI - Web-based tailored intervention for preparation of parents and children for outpatient surgery (WebTIPS): development. AB - BACKGROUND: As a result of cost-containment efforts, preparation programs for outpatient surgery are currently not available to the majority of children and parents. The recent dramatic growth in the Internet presents a unique opportunity to transform how children and their parents are prepared for surgery. In this article, we describe the development of a Web-based Tailored Intervention for Preparation of parents and children undergoing Surgery (WebTIPS). DEVELOPMENT OF PROGRAM: A multidisciplinary taskforce agreed that a Web-based tailored intervention consisting of intake, matrix, and output modules was the preferred approach. Next, the content of the various intake variables, the matrix logic, and the output content was developed. The output product has a parent component and a child component and is described in http://surgerywebtips.com/about.php. The child component makes use of preparation strategies such as information provision, modeling, play, and coping skills training. The parent component of WebTIPS includes strategies such as information provision, coping skills training, and relaxation and distraction techniques. A reputable animation and Web design company developed a secured Web-based product based on the above description. CONCLUSIONS: In this article, we describe the development of a Web based tailored preoperative preparation program that can be accessed by children and parents multiple times before and after surgery. A follow-up article in this issue of Anesthesia & Analgesia describes formative evaluation and preliminary efficacy testing of this Web-based tailored preoperative preparation program. PMID- 25790213 TI - Web-based tailored intervention for preparation of parents and children for outpatient surgery (WebTIPS): formative evaluation and randomized controlled trial. AB - BACKGROUND: The purpose of this 2-phase project was to conduct a formative evaluation and to test the preliminary efficacy of a newly developed Web-based Tailored Intervention for Preparation of parents and children undergoing Surgery (WebTIPS). METHODS: Phase 1 enrolled 13 children 2 to 7 years of age undergoing outpatient elective surgery and their parents for formative evaluation of WebTIPS. Parent participation focus groups are common in qualitative research and are a method of asking research participants about their perceptions and attitudes regarding a product or concept. In phase 2, children 2 to 7 years of age in 2 medical centers were assigned randomly to receive the WebTIPS program (n = 38) compared with children receiving the standard of care (n = 44). The primary outcome of phase II was child and parent preoperative anxiety. RESULTS: In phase 2, parents reported WebTIPS to be both helpful (P < 0.001) and easy to use (P < 0.001). In phase 2, children in the WebTIPS group (36.2 +/- 14.1) were less anxious than children in the standard of care group (46.0 +/- 19.0) at entrance to the operating room (P = 0.02; Cohen d = 0.59) and introduction of the anesthesia mask (43.5 +/- 21.7 vs 57.0 +/- 21.2, respectively, P = 0.01; Cohen d = 0.63). Parents in the WebTIPS group (32.1 +/- 7.4) also experienced less anxiety compared with parents in the control group (36.8 +/- 7.1) in the preoperative holding area (P = 0.004; Cohen d = 0.65). CONCLUSIONS: WebTIPS was well received by parents and children and led to reductions in preoperative anxiety. PMID- 25790214 TI - The incidence of propofol vial coring with blunt needle use is reduced with angled puncture compared with perpendicular puncture. PMID- 25790215 TI - Still missing something huge. PMID- 25790216 TI - In response. PMID- 25790217 TI - Other new players in medical management of postpartum hemorrhage? PMID- 25790218 TI - In response. PMID- 25790219 TI - Dental therapists' expanded scope of practice in Australia: a 12-month follow-up of an educational bridging program to facilitate the provision of oral health care to patients 26+ years. AB - OBJECTIVES: Prior to 2009, dental therapists' scope of clinical practice in Victoria was limited to patients 25 years or younger. However, increases in dental demand by adults 26+ years required an alternative approach to service delivery. This paper outlines the self-reported confidence and knowledge level of dental therapists at 3, 6, and 12 months postcompletion of an educational program aimed at providing them with the skills to treat adults aged 26+ years. The study also surveyed dentists in the practice about the dental therapists' knowledge and the impact of their extended scope of practice on the clinics' operation. METHODS: After completion of their educational program, the dental therapists who participated were surveyed at 3, 6, and 12 months postcompletion to assess their self-reported confidence levels and knowledge. Senior dentists at the clinic were surveyed to understand the impact of the subsequent change in practice of the dental therapists who undertook this training, as well as any concerns of perceived educational gaps. RESULTS: Surveys showed increased self-reported confidence levels by the dental therapists at 3, 6, and 12 months after completion of the program. Dental therapists and mentoring dentists identified that further education was needed in areas such as oral medicine, pathology, medically compromised patients, medications, prosthodontics, and referrals. CONCLUSIONS: Dental therapists felt confident and knowledgeable postprogram to treat patients 26+ years, within their scope of practice. Dentists generally felt that dental therapists, after completing the educational program, were confident and knowledgeable. Educational areas to focus on in future programs were identified. PMID- 25790220 TI - Equivalence between invasive and oscillometric blood pressures at different anatomic locations in healthy normotensive anaesthetised horses. AB - REASONS FOR PERFORMING STUDY: Accurate blood pressure measurement is essential for effective clinical assessment and appropriate interventions in anaesthetised horses. Information on the accuracy of oscillometry for blood pressure measurement on the appendages of mature horses is limited. OBJECTIVES: To assess equivalence between invasive and oscillometric blood pressures at different anatomic locations in horses. STUDY DESIGN: Prospective experimental study using 6 healthy mature horses. METHODS: Blood pressure was measured invasively in the right transverse facial artery and noninvasively by oscillometry in nondependent limbs and tail of laterally recumbent sevoflurane- or desflurane-anaesthetised horses. Cuff widths of 5-12 cm were tested on the tail, metatarsus, metacarpus and distal radius/ulna. Equivalence between mean arterial pressure (MAP) oscillometric and MAP invasive was assessed using a linear mixed effects model with a significance level of P<=0.05. RESULTS: Twenty paired measurements were obtained for each cuff size in each of the locations, totalling 340 measurements. There was only one location (tail) and one cuff width (6 cm; cuff width-to-tail circumference ratio of 0.25) that resulted in equivalence between MAP measured with the oscillometric and the invasive methods (P = 0.8). All other locations (metacarpus, radius/ulna, metatarsus) and cuff widths were not equivalent (P<=0.01). CONCLUSIONS: A cuff width-to-tail circumference ratio of 0.25 is recommended for accurate oscillometric blood pressure measurement in mature, laterally recumbent anaesthetised normotensive horses. Studies with variable haemodynamics are warranted. Oscillometric measurements at other extremities and/or with other cuff sizes cannot be recommended for clinical use. PMID- 25790221 TI - "Decarbonization" of an imino-N-heterocyclic carbene ligand via triple benzyl migration from hafnium. AB - An imino-N-heterocyclic carbene underwent three sequential benzyl migrations upon reaction with tetrabenzylhafnium, resulting in complete removal of the carbene carbon from the ligand. The resulting eneamido-amidinato hafnium complex showed alkene polymerization activity comparable to that of a precatalyst containing the intact iminocarbene ligand. PMID- 25790222 TI - Screening of miners and millers at decreasing levels of asbestos exposure: comparison of chest radiography and thin-section computed tomography. AB - BACKGROUND: Chest radiography (CXR) is inferior to Thin-section computed tomography in the detection of asbestos related interstitial and pleural abnormalities. It remains unclear, however, whether these limitations are large enough to impair CXR's ability in detecting the expected reduction in the frequency of these asbestos-related abnormalities (ARA) as exposure decreases. METHODS: Clinical evaluation, CXR, Thin-section CT and spirometry were obtained in 1418 miners and millers who were exposed to progressively lower airborne concentrations of asbestos. They were separated into four groups according to the type, period and measurements of exposure and/or procedures for controlling exposure: Group I (1940-1966/tremolite and chrysotile, without measurements of exposure and procedures for controlling exposure); Group II (1967-1976/chrysotile only, without measurements of exposure and procedures for controlling exposure); Group III (1977-1980/chrysotile only, initiated measurements of exposure and procedures for controlling exposure) and Group IV (after 1981/chrysotile only, implemented measurements of exposure and a comprehensive procedures for controlling exposure). RESULTS: In all groups, CXR suggested more frequently interstitial abnormalities and less frequently pleural plaques than observed on Thin-section CT (p<0.050). The odds for asbestosis in groups of decreasing exposure diminished to greater extent at Thin-section CT than on CXR. Lung function was reduced in subjects who had pleural plaques evident only on Thin section CT (p<0.050). In a longitudinal evaluation of 301 subjects without interstitial and pleural abnormalities on CXR and Thin-section CT in a previous evaluation, only Thin-section CT indicated that these ARA reduced as exposure decreased. CONCLUSIONS: CXR compared to Thin-section CT was associated with false positives for interstitial abnormalities and false-negatives for pleural plaques, regardless of the intensity of asbestos exposure. Also, CXR led to a substantial misinformation of the effects of the progressively lower asbestos concentrations in the occurrence of asbestos-related diseases in miners and millers. PMID- 25790223 TI - To be or not IIb: a multi-step process for Epstein-Barr virus latency establishment and consequences for B cell tumorigenesis. PMID- 25790224 TI - Pharmacokinetics of trastuzumab in haemodialysis. PMID- 25790225 TI - Impact of current smoking and alcohol consumption on gastrostomy duration in patients with head and neck cancer undergoing definitive chemoradiotherapy. AB - IMPORTANCE: Prophylactic gastrostomy tube (GT) insertion prior to chemoradiotherapy is a valuable nutritional adjunct in patients with head and neck cancer undergoing nonsurgical treatment. However, concerns have been expressed regarding high rates of GT dependence. There is little information in the literature regarding the impact of modifiable risk factors such as smoking and alcohol consumption on duration of GT use and dependence rates. OBJECTIVE: To study the duration of GT use in patients with head and neck cancer at our institution and to investigate risk factors for prolonged GT duration and dependence, including the impact of smoking and alcohol consumption. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study at an academic teaching hospital included 104 patients with squamous cell carcinoma of the head and neck undergoing definitive treatment with either chemoradiotherapy (n = 84) or radiotherapy alone (n = 20). INTERVENTIONS: Prophylactic GT insertion prior to commencement of treatment. MAIN OUTCOMES AND MEASURES: Duration of GT use after completion of chemoradiotherapy or radiotherapy and the impact of risk factors on same. Duration of GT use was analyzed using Kaplan-Meier survival curves, with censoring of patients who developed cancer recurrence or died. RESULTS: The median duration of GT use was 9 months. The actuarial GT persistence rate at 1 year was 35%. Current smoking (hazard ratio [HR], 0.47; 95% CI, 0.27-0.81; P = .01) and current heavy alcohol consumption (HR, 0.55; 95% CI, 0.32-0.97; P = .04) were significant predictors of GT persistence. On multivariate analysis, only current smoking remained significant (HR, 0.53; 95% CI, 0.30-0.94; P = .03). Age 65 years or older, advanced T classification, larynx and/or hypopharynx primary site, and posttreatment neck dissection were not significant risk factors. CONCLUSIONS AND RELEVANCE: Current smoking and current heavy alcohol consumption are predictive of prolonged GT requirement in patients with head and neck cancer undergoing prophylactic GT insertion before definitive radiotherapy or chemoradiotherapy. Further study is required to investigate whether smoking or drinking cessation can reduce GT dependence rates in this population. PMID- 25790226 TI - Eculizumab for aHUS post-transplantation: when and how to stop a good thing. PMID- 25790227 TI - Moving toward objective measurement of facial deformities: exploring a third domain of social perception. PMID- 25790228 TI - Nanoscale probing of image-dipole interactions in a metallic nanostructure. AB - An emitter near a surface induces an image dipole that can modify the observed emission intensity and radiation pattern. These image-dipole effects are generally not taken into account in single-emitter tracking and super-resolved imaging applications. Here we show that the interference between an emitter and its image dipole induces a strong polarization anisotropy and a large spatial displacement of the observed emission pattern. We demonstrate these effects by tracking the emission of a single quantum dot along two orthogonal polarizations as it is deterministically positioned near a silver nanowire. The two orthogonally polarized diffraction spots can be displaced by up to 50 nm, which arises from a Young's interference effect between the quantum dot and its induced image dipole. We show that the observed spatially varying interference fringe provides a useful measure for correcting image-dipole-induced distortions. These results provide a pathway towards probing and correcting image-dipole effects in near-field imaging applications. PMID- 25790229 TI - Randomized phase II study of 5-fluorouracil hepatic arterial infusion with or without antineoplastons as an adjuvant therapy after hepatectomy for liver metastases from colorectal cancer. AB - BACKGROUND: Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. METHODS: Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. FINDINGS: Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm. INTERPRETATION: Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov UMIN000012099. PMID- 25790230 TI - Interspecific and geographic variation in the diets of sympatric carnivores: dingoes/wild dogs and red foxes in south-eastern Australia. AB - Dingoes/wild dogs (Canis dingo/familiaris) and red foxes (Vulpes vulpes) are widespread carnivores in southern Australia and are controlled to reduce predation on domestic livestock and native fauna. We used the occurrence of food items in 5875 dingo/wild dog scats and 11,569 fox scats to evaluate interspecific and geographic differences in the diets of these species within nine regions of Victoria, south-eastern Australia. The nine regions encompass a wide variety of ecosystems. Diet overlap between dingoes/wild dogs and foxes varied among regions, from low to near complete overlap. The diet of foxes was broader than dingoes/wild dogs in all but three regions, with the former usually containing more insects, reptiles and plant material. By contrast, dingoes/wild dogs more regularly consumed larger mammals, supporting the hypothesis that niche partitioning occurs on the basis of mammalian prey size. The key mammalian food items for dingoes/wild dogs across all regions were black wallaby (Wallabia bicolor), brushtail possum species (Trichosurus spp.), common wombat (Vombatus ursinus), sambar deer (Rusa unicolor), cattle (Bos taurus) and European rabbit (Oryctolagus cuniculus). The key mammalian food items for foxes across all regions were European rabbit, sheep (Ovis aries) and house mouse (Mus musculus). Foxes consumed 6.1 times the number of individuals of threatened Critical Weight Range native mammal species than did dingoes/wild dogs. The occurrence of intraguild predation was asymmetrical; dingoes/wild dogs consumed greater biomass of the smaller fox. The substantial geographic variation in diet indicates that dingoes/wild dogs and foxes alter their diet in accordance with changing food availability. We provide checklists of taxa recorded in the diets of dingoes/wild dogs and foxes as a resource for managers and researchers wishing to understand the potential impacts of policy and management decisions on dingoes/wild dogs, foxes and the food resources they interact with. PMID- 25790231 TI - In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain. AB - Erythropoietin (Epo) and its receptor (EpoR) are required for the regulation of erythropoiesis. Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformational change is sufficient for the initiation of Epo-EpoR signal transduction. Here, we established a system of chemically regulated erythropoiesis in transgenic mice expressing a modified EpoR intracellular domain (amino acids 247-406) in which dimerization is induced using a specific compound (chemical inducer of dimerization, CID). Erythropoiesis is reversibly induced by oral administration of the CID to the transgenic mice. Because transgene expression is limited to hematopoietic cells by the Gata1 gene regulatory region, the effect of the CID is limited to erythropoiesis without adverse effects. Additionally, we show that the 160 amino acid sequence is the minimal essential domain of EpoR for intracellular signaling of chemically inducible erythropoiesis in vivo. We propose that the CID dependent dimerization system combined with the EpoR intracellular domain and the Gata1 gene regulatory region generates a novel peroral strategy for the treatment of anemia. PMID- 25790232 TI - Inhibiting EGFR dimerization using triazolyl-bridged dimerization arm mimics. AB - The epidermal growth factor receptor (EGFR) is overexpressed in multiple carcinomas and is the focus of a variety of targeted therapies. Here we report the design of peptide-based compounds that mimic the EGFR dimerization arm and inhibit allosteric activation of EGFR. These peptides are modified to contain a triazolyl bridge between the peptide strands to constrain the EGFR dimerization arm beta-loop. In this study, we demonstrate that these peptides have significantly improved proteolytic stability over the non-modified peptide sequence, and their inhibitory effects are dependent on the number of the methylene units and orientation of the introduced triazolyl bridge. We identified a peptide, EDA2, which downregulates receptor phosphorylation and dimerization and reduces cell viability. This is the first example of a biologically active triazolyl-bridged peptide targeting the EGFR dimerization interface that effectively downregulates EGFR activation. PMID- 25790233 TI - Effect of rectal indomethacin for preventing post-ERCP pancreatitis depends on difficulties of cannulation: results from a randomized study with sequential biliary intubation. AB - GOALS AND BACKGROUND: The greatest challenges for endoscopists performing biliary therapy in endoscopic retrograde cholangiopancreatography (ERCP) are to achieve selective biliary cannulation and prevent post-ERCP pancreatitis (PEP). Nonsteroidal anti-inflammatory drugs have proven prophylactic effect in PEP. However, the patient population that would benefit from this approach has not been defined. STUDY: A total of 539 patients undergoing our cannulation protocol with early precut were randomized into a placebo-controlled, prospective, double blind study to rectally receive either 100 mg indomethacin or placebo. The effect of indomethacin on PEP was stratified based on difficulties of cannulation and analyzed in patients with different risks. RESULTS: In 70.3% of patients, biliary intubation was successful in the first 5 atraumatic attempts, PEP rate was low, and indomethacin was ineffective (7.4% in the placebo group and 5.2% in the indomethacin group, P=0.406). In the next phase of intubation using guidewire, the success rate increased up to 83.5%, and PEP rate rose up to 8.7%, the effect of indomethacin was significant (11.9% vs. 5.4%, P=0.018). Applying early precut success rate of biliary cannulation increased up to 98.1% and overall indomethacin diminished the frequency of PEP from 13.8% to 6.7% (P=0.007). Preventive effect of indomethacin was demonstrated in cases with defined procedure-related risk (28.3% vs. 13.8%, P=0.028) and with defined patient related risk (16.3% vs. 7.0%, P=0.004), but not in patients without risk factors. CONCLUSIONS: Rectally administered 100 mg indomethacin results in significantly lower PEP rate, particularly in cases with difficult cannulation and with identifiable patient-related or procedure-related risk factors. PMID- 25790234 TI - Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice. AB - Pharmacological administration of fibroblast growth factor 21 (FGF21) improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB)/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (s.c.) bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability). Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW) loss and glucose reduction during an oral glucose tolerance test (OGTT) following SC and intravenous (i.v.) administration in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits. PMID- 25790235 TI - Ligand binding to the FA3-FA4 cleft inhibits the esterase-like activity of human serum albumin. AB - The hydrolysis of 4-nitrophenyl esters of hexanoate (NphOHe) and decanoate (NphODe) by human serum albumin (HSA) at Tyr411, located at the FA3-FA4 site, has been investigated between pH 5.8 and 9.5, at 22.0 degrees C. Values of Ks, k+2, and k+2/Ks obtained at [HSA] >= 5*[NphOXx] and [NphOXx] >= 5*[HSA] (Xx is NphOHe or NphODe) match very well each other; moreover, the deacylation step turns out to be the rate limiting step in catalysis (i.e., k+3 << k+2). The pH dependence of the kinetic parameters for the hydrolysis of NphOHe and NphODe can be described by the acidic pKa-shift of a single amino acid residue, which varies from 8.9 in the free HSA to 7.6 and 7.0 in the HSA:NphOHe and HSA:NphODe complex, respectively; the pK>a-shift appears to be correlated to the length of the fatty acid tail of the substrate. The inhibition of the HSA-Tyr411-catalyzed hydrolysis of NphOHe, NphODe, and 4-nitrophenyl myristate (NphOMy) by five inhibitors (i.e., diazepam, diflunisal, ibuprofen, 3-indoxyl-sulfate, and propofol) has been investigated at pH 7.5 and 22.0 degrees C, resulting competitive. The affinity of diazepam, diflunisal, ibuprofen, 3-indoxyl-sulfate, and propofol for HSA reflects the selectivity of the FA3-FA4 cleft. Under conditions where Tyr411 is not acylated, the molar fraction of diazepam, diflunisal, ibuprofen, and 3-indoxyl sulfate bound to HSA is higher than 0.9 whereas the molar fraction of propofol bound to HSA is ca. 0.5. PMID- 25790236 TI - 6-Hydroxyflavone and derivatives exhibit potent anti-inflammatory activity among mono-, di- and polyhydroxylated flavones in kidney mesangial cells. AB - Inflammatory responses by kidney mesangial cells play a critical role in the glomerulonephritis. The anti-inflammatory potential of nineteen mono-, di- and polyhydroxylated flavones including fisetin, quercetin, morin, tricetin, gossypetin, apigenin and myricetin were investigated on rat mesangial cells with lipopolysaccharide (LPS) as the inflammatory stimuli. 6-Hydroxyflavone and 4',6 dihydroxyflavone exhibited high activity with IC50 in the range of 2.0 MUM, a much better inhibition potential in comparison to the well-studied polyhydroxylated flavones. Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals. Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6 methoxyflavone was the most potent with an IC50 of 192 nM. Mechanistic study indicated that the anti-inflammatory activity of 6-methoxyflavone arose via the inhibition of LPS-induced downstream inducible NO synthase in mesangial cells. The identification of 6-hydroxyflavone and 6-methoxyflavone with potent anti inflammatory activity in kidney mesangial cells provides a new flavone scaffold and direction to develop naturally derived products for potential nephritis prevention and treatment. PMID- 25790237 TI - HIV stigma and disclosure experiences of people living with HIV in an urban and a rural setting. AB - Human immunodeficiency virus (HIV) remains a highly stigmatised condition for people living with HIV (PLWH) and people living close to them (PLC) globally. The research objectives for this study were to explore and describe how HIV stigma and disclosure experiences impact the lives of PLWH and to explore whether there are differences between experiences in urban and rural settings. A qualitative approach was followed and participants were selected through purposive voluntary sampling. Data collection took place using in-depth interviews with 23 PLWH, 11 of whom resided in an urban setting in North-West, South Africa, and 12 resided in a rural setting in the same province. The data were manually analysed through open coding. The HIV stigma experiences expressed by PLWH depicted negative behavioural patterns and attitudes towards them, fear from the community of being infected by PLWH and lastly negative self-judgement by PLWH themselves. During disclosure, PLWH were unsure and they described it as a stressful event. They cautiously considered to whom to disclose their condition and what benefits disclosure will hold. They further had to handle forced disclosure due to being identifiable in health-care settings. HIV stigma and related disclosure practices remained a problem, which detrimentally affected treatment and support efforts. Recommendations focused on HIV stigma reduction in the community that needed to involve PLWH and PLC. PMID- 25790238 TI - Synthesis and characterization of NaNiF3.3H2O: an unusual ordered variant of the ReO3 type. AB - A new hydrated sodium nickel fluoride with nominal composition NaNiF3.3H2O was synthesized using an aqueous solution route. Its structure was solved by means of ab initio methods from powder X-ray diffraction and neutron diffraction data. NaNiF3.3H2O crystallizes in the cubic crystal system, space group Pn3 with a = 7.91968(4) A. The framework, derived from the ReO3 structure type, is built from NaX6 and NiX6 (X = O, F) corner-shared octahedra, in which F and O atoms are randomly distributed on a single anion site. The 2a * 2a * 2a superstructure arises from the strict alternate three-dimensional linking of NaX6 and NiX6 octahedra together with the simultaneous tilts of the octahedra from the cube axis (phi = 31.1 degrees ), with a significant participation of hydrogen bonding. NaNiF3.3H2O corresponds to a fully cation-ordered variant of the In(OH)3 structure, easily recognizable when formulated as NaNi(XH)6 (X = O, F). It constitutes one of the rare examples for the a(+)a(+)a(+) tilting scheme with 1:1 cation ordering in perovskite-related compounds. The Curie-like magnetic behavior well-reflects the isolated paramagnetic Ni(2+) centers without worth mentioning interactions. While X-ray and neutron diffraction data evidence Na/Ni order in combination with O/F disorder as a main feature of this fluoride, results from Raman and magic-angle spinning NMR spectroscopies support the existence of specific anion arrangements in isolated square windows identified in structural refinements. In particular, formation of water molecules derives from unfavorable FH bond formation. PMID- 25790239 TI - Functional and radioligand binding characterization of the alpha1L-adrenoceptor subtype of the human vas deferens. AB - Alpha1 -adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via alpha1A adrenoceptors, and this study investigated whether the low affinity state of this receptor (alpha1L -adrenoceptor) is involved in mediating contractions of this tissue. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [(3) H]tamsulosin binding experiments to identify the alpha1 -adrenoceptor subtype population present in the human vas deferens. The alpha1A -adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (alpha1D -adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (alpha1A - and alpha1D -adrenoceptor selective) had a high affinity (pKd = 9.9). [(3) H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [(3) H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively). These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of alpha1 -adrenoceptors which have the pharmacological properties of the putative alpha1L -adrenoceptor, the same functional receptor previously identified in the human prostate. PMID- 25790240 TI - Stoichiometric and catalytic Si-N bond formation using the p-block base Al(NMe2)3. AB - The aluminium amide Al(NMe2)3 acts as a stoichiometric or catalytic reagent in dehydrogenic Si-N bond formation using amines and silanes. Although of limited substrate scope, this represents the first p-block metal catalytic system for N H/Si-H dehydrocoupling. The observed catalytic rate law for the formation of aminosilane products in a model study of one of the catalytic reactions suggests a mechanism involving the silane component in the deprotonation of the amine (possibly in the form of a hypervalent silicon hydride). PMID- 25790241 TI - Nitric oxide dysregulation in patients with heart failure: the association of depressive symptoms with L-arginine, asymmetric dimethylarginine, symmetric dimethylarginine, and isoprostane. AB - OBJECTIVE: Nitric oxide (NO) regulation plays a critical role in cardiovascular diseases including heart failure (HF). Markers of NO dysregulation have been found in individuals with depression without cardiovascular disease. Because depression is associated with poor HF outcomes, the present study tested the hypothesis that depression is associated with a dysregulated NO pathway in patients with HF. METHODS: Serum levels of NO regulation (L-arginine, asymmetric dimethylarginine [ADMA], and symmetric dimethylarginine [SDMA]) and oxidative stress (isoprostane 8-epi prostaglandin F2alpha) were measured in 104 patients with HF (mean [standard deviation] age = 65.7 [8.4] years, 28% women) at baseline and 12 months. Depressive symptoms were measured using the Beck Depression Inventory. The associations between depressive symptoms with markers of NO regulation were examined with mixed-model analysis, adjusted for age, sex, time of assessment, left ventricular ejection fraction, creatinine, and hypertension. RESULTS: Depressive symptoms were correlated with a lower L-arginine/ADMA ratio (r = -0.22, p = .003) and higher SDMA levels (r = 0.28, p < .001). Associations were similar for somatic depressive symptoms and cognitive-affective symptoms (L arginine/ADMA ratio: r = -0.20 [p = .009] versus r = -0.19 [p = .013]; ADMA: r = 0.16 [p = .043] versus r = 0.10 [p = .20]; SDMA: r = 0.27 [p < .001] versus r = 0.22 [p = .005], respectively). No associations were found between depressive symptoms and isoprostane. The association between depression and the L arginine/ADMA ratio remained significant in multivariate adjusted models. CONCLUSIONS: Depressive symptoms were associated with markers of NO dysregulation, particularly the L-arginine/ADMA ratio and SDMA, in patients with HF. The lower L-arginine/ADMA ratio indicates less available NO, suggesting that NO-related endothelial dysfunction may play a role in the adverse risk of HF progression associated with depression. PMID- 25790242 TI - One-year outcome after prehospital intubation. AB - BACKGROUND: The aim of physician staffed emergency medical services (EMS) is to supplement other EMS units in the care of prehospital patients. The need for advanced airway management in critical prehospital patients can be considered as one indicator of the severity of the patient's condition. Our primary aim was to study the long-term outcome of critically ill patients (excluding cardiac arrest) who were intubated by EMS physicians in the prehospital setting. METHODS: Data of 845 patients, whose airways were secured by the EMS physicians during a 5-year (2007-2011) period, were retrospectively evaluated. After exclusions, the outcome of 483 patients (8.9% of all patients treated by EMS) was studied. Evaluation was based on hospital patient records 1 year after the incident. For assessment of neurological outcome, a modified Glasgow Outcome Score (GOS) was used. Time and cause of death were recorded. RESULTS: 55.3% of the study patients had a good neurological recovery (GOS 4-5) with independent life 1 year after the event. The overall 1-year mortality (GOS 1) was 35.0%. Poor neurological outcome (GOS 2-3) was found in 9.7% of the patients. Patients with intoxication or convulsions survived best, while those with suspected intracranial pathology had the worst prognosis. Of all survivors, 85% recovered well. CONCLUSION: The majority of the study patients had a favourable neurological recovery with independent life at 1 year after the incident. More than 80% of all deaths occurred within 30 days of the incident. PMID- 25790243 TI - Diagnostic Dilemma in a Narrow Complex Tachycardia. PMID- 25790244 TI - Simple and rapid quantification of thrombocytes in zebrafish larvae. AB - Platelets are a critical component of hemostasis, with disorders of number or function resulting in coagulation disturbances. Insights into these processes have primarily been realized through studies using mammalian models or tissues. Increasingly, zebrafish embryos and larvae have been used to study the protein and cellular components of hemostasis and thrombosis, including the thrombocyte, a nucleated platelet analog. However, investigations of thrombocytes have been somewhat limited due to lack of a robust and simple methodology for quantitation, an important component of platelet studies in mammals. Using video capture, we have devised an assay that produces a rapid, reproducible, and precise measurement of thrombocyte number in zebrafish larvae by counting fluorescently tagged cells. Averaging 1000 frames, we were able to subtract background fluorescence, thus limiting assessment to circulating thrombocytes. This method facilitated rapid assessment of relative thrombocyte counts in a population of 372 zebrafish larvae by a single operator in less than 3 days. This technique requires basic microscopy equipment and rudimentary programming, lends itself to high throughput analysis, and will enhance future studies of thrombopoiesis in the zebrafish. PMID- 25790245 TI - Epidemiological trends of dengue disease in Colombia (2000-2011): a systematic review. AB - A systematic literature review was conducted to describe the epidemiology of dengue disease in Colombia. Searches of published literature in epidemiological studies of dengue disease encompassing the terms "dengue", "epidemiology," and "Colombia" were conducted. Studies in English or Spanish published between 1 January 2000 and 23 February 2012 were included. The searches identified 225 relevant citations, 30 of which fulfilled the inclusion criteria defined in the review protocol. The epidemiology of dengue disease in Colombia was characterized by a stable "baseline" annual number of dengue fever cases, with major outbreaks in 2001-2003 and 2010. The geographical spread of dengue disease cases showed a steady increase, with most of the country affected by the 2010 outbreak. The majority of dengue disease recorded during the review period was among those <15 years of age. Gaps identified in epidemiological knowledge regarding dengue disease in Colombia may provide several avenues for future research, namely studies of asymptomatic dengue virus infection, primary versus secondary infections, and under-reporting of the disease. Improved understanding of the factors that determine disease expression and enable improvement in disease control and management is also important. PMID- 25790246 TI - Patient Outcomes of an International Telepediatric Cardiac Critical Care Program. AB - BACKGROUND: An optimal model for telemedicine use in the international care setting has not been established. Our objective was to describe variables associated with patient outcome during the implementation of an international pediatric cardiac critical care (PCCC) telemedicine program. MATERIALS AND METHODS: A retrospective review was performed of clinical records and a telemedicine database of patients admitted to the cardiac intensive care unit (CICU) at the Fundacion Cardiovascular de Colombia, Bucaramanga, Colombia, during the initial 10 months of our program, compared with patients admitted during a previous period. Information collected included demographic data, cardiac diagnosis and associated factors, Risk Adjustment for Congenital Heart Surgery (RACHS)-1 classification, and perioperative events. Primary outcome was composed of CICU and hospital mortality. Secondary outcomes were CICU and hospital length of stay (LOS). RESULTS: Of the 553 patients who were included, teleconsultation was done for 71 (12.4%), with a total of 156 encounters, including 19 for patients on extracorporeal membrane oxygenation. Three hundred twenty-one recommendations were given, and 42 real-time interventions were documented. RACHS 1 distribution was similar between study periods (p=0.427). Teleconsulted patients were significantly younger (44 versus 24 months; p=0.03) and had higher surgical complexity than nonteleconsulted patients (p=0.01). RACHS-1 adjusted hospital survival was similar between study periods. CICU and hospital LOS intervals were significantly shorter in the telemedicine period (10 versus 17 days [p=0.02] and 22 versus 28 days [p<0.001]). In surgical cases, preoperative CICU LOS was significantly shorter (3 versus 6 days; p<0.001). Variables associated with hospital mortality were higher RACHS-1 categories, lower weight, bypass time longer than 150 min, and use of circulatory arrest, as well as the presence of sepsis or necrotizing enterocolitis. Those associated with increased LOS were lower weight, extracorporeal membrane oxygenation, and cross-clamp time longer than 60 min. CONCLUSIONS: An international telemedicine service in PCCC was associated with lower CICU and hospital LOS. Prospective telemedicine interventions aimed to decrease mortality and LOS should focus on patients with higher RACHS-1 categories, lower-weight infants, and those with prolonged operative time and selective perioperative complications. PMID- 25790247 TI - Internuclear ophthalmoplegia associated with anti-TNFalpha medication. AB - AIM: To describe the presentation of an internuclear ophthalmoplegia (INO) associated with the use of anti-tumor necrosis factor alpha (anti-TNFalpha) medication. METHODS: A case report of a woman, aged 27 years, who developed facial numbness, blurred vision, and diplopia on right gaze. She had a history of Crohn's disease, which was being treated by the anti-TNFalpha drug, adalimumab. On examination, a left INO was found. TREATMENT: The patient was prescribed a short course of corticosteroids and adalimumab treatment was discontinued. RESULTS: Magnetic resonance imaging demonstrated typical demyelinating lesions including one responsible for the INO. Following a short course of corticosteroids and the discontinuation of the adalimumab treatment, the INO resolved, resulting in a swift improvement of ocular motility over a 2-week period. CONCLUSION: Anti-TNFalpha therapies have been associated with the development of demyelinating diseases. The presentation of a brainstem syndrome in a patient on anti-TNFalpha therapy should lead to investigation for central nervous system demyelination and cessation of the medication. PMID- 25790248 TI - The Vestibular Effects of Repeated Low-Level Blasts. AB - The objective of this study was to use a prospective cohort of United States Marine Corps (USMC) instructors to identify any acute or long-term vestibular dysfunction following repeated blast exposures during explosive breaching training. They were assessed in clinic and on location during training at the USMC Methods of Entry School, Quantico, VA. Subjects received comprehensive baseline vestibular assessments and these were repeated in order to identify longitudinal changes. They also received shorter assessments immediately following blast exposure in order to identify acute findings. The main outcome measures were the Neurobehavioral Symptom Inventory, vestibular Visual Analog Scale (VAS) of subjective vestibular function, videonystagmography (VNG), vestibular evoked myogenic potentials (VEMP), rotary chair (including the unilateral centrifugation test), computerized dynamic posturography, and computerized dynamic visual acuity. A total of 11 breachers and 4 engineers were followed for up to 17 months. No acute effects or longitudinal deteriorations were identified, but there were some interesting baseline group differences. Upbeat positional nystagmus was common, and correlated (p<0.005) with a history of mild traumatic brain injury (mTBI). Several instructors had abnormally short low-frequency phase leads on rotary chair testing. This study evaluated breaching instructors over a longer test period than any other study, and the results suggest that this population appears to be safe from a vestibular standpoint at the current exposure levels. Upbeat positional nystagmus correlated with a history of mTBI in this population, and this has not been described elsewhere. The data trends also suggest that this nystagmus could be an acute blast effect. However, the reasons for the abnormally short phase leads seen in rotary chair testing are unclear at this time. Further investigation seems warranted. PMID- 25790249 TI - Translation of clinical practice guidelines for childhood obesity prevention in primary care mobilizes a rural Midwest community. AB - PURPOSE: The purpose of this project was to implement clinic system changes that support evidence-based guidelines for childhood obesity prevention. Adherence rates for prevention and screening of children in a rural Midwest primary care setting were used to measure the success of the program. DATA SOURCES: Retrospective chart reviews reflected gaps in current practice and documentation. An evidence-based toolkit for childhood obesity prevention was used to implement clinic system changes for the identified gaps. CONCLUSIONS: The quality improvement approach proved to be effective in translating knowledge of obesity prevention guidelines into rural clinic practices with significant improvements in documentation of prevention measures that may positively impact the childhood obesity epidemic. IMPLICATIONS FOR PRACTICE: Primary care providers, including nurse practitioners (NPs), are at the forefront of diagnosing, educating, and counseling children and families on obesity prevention and need appropriate resources and tools to deliver premier care. The program successfully demonstrated how barriers to practice, even with the unique challenges in a rural setting, can be overcome. NPs fulfill a pivotal primary care role and can provide leadership that may positively impact obesity prevention in their communities. PMID- 25790250 TI - Plasma vs. cryoprecipitate for fibrinogen replacement in therapeutic plasma exchange procedures. PMID- 25790251 TI - Thermal and structural studies of imidazolium-based ionic liquids with and without liquid-crystalline phases: the origin of nanostructure. AB - To clarify the origin of the nanostructure of ionic liquids (ILs), we have investigated two series of ILs 1-alkyl-3-methylimidazolium hexafluorophosphate (CnmimPF6, n = 4-16, n is an alkyl-carbon number) and 1-alkyl-3-methylimidazolium chloride (CnmimCl, n = 4-14) using differential scanning calorimetry and X-ray diffraction techniques. The PF6 samples with n > 13 and the Cl samples with n > 10 exhibited the liquid-crystalline (LC) to liquid (L) phase transitions, as reported before. We found that both samples with smaller n also exhibited the LC to L transitions under supercooled states as far as the ionic motions were not frozen-in at the glass transition temperatures Tg. The Tg of the LC phase was close to that of the L phase, indicating that the characteristic length of the glass transition is shorter than that of the nanostructure. A low-Q peak due to the nanostructure in the L phase and a diffraction peak due to the layer structure in the LC phase appeared at almost the same Q positions in both samples. On the basis of the above results and some thermodynamic analysis, we argue that the nanostructures of ILs are essentially the same as the layer structures in the LC phases. PMID- 25790252 TI - Unexpected role of CDK4 in a G2/M checkpoint. PMID- 25790253 TI - Fundamental studies and development of nickel-catalyzed trifluoromethylthiolation of aryl chlorides: active catalytic species and key roles of ligand and traceless MeCN additive revealed. AB - A catalytic protocol to convert aryl and heteroaryl chlorides to the corresponding trifluoromethyl sulfides is reported herein. It relies on a relatively inexpensive Ni(cod)2/dppf (cod = 1,5-cyclooctadiene; dppf = 1,1' bis(diphenylphosphino)ferrocene) catalyst system and the readily accessible coupling reagent (Me4N)SCF3. Our computational and experimental mechanistic data are consistent with a Ni(0)/Ni(II) cycle and inconsistent with Ni(I) as the reactive species. The relevant intermediates were prepared, characterized by X ray crystallography, and tested for their catalytic competence. This revealed that a monomeric tricoordinate Ni(I) complex is favored for dppf and Cl whose role was unambiguously assigned as being an off-cycle catalyst deactivation product. Only bidentate ligands with wide bite angles (e.g., dppf) are effective. These bulky ligands render the catalyst resting state as [(P-P)Ni(cod)]. The latter is more reactive than Ni(P-P)2, which was found to be the resting state for ligands with smaller bite angles and suffers from an initial high-energy dissociation of one ligand prior to oxidative addition, rendering the system unreactive. The key to effective catalysis is hence the presence of a labile auxiliary ligand in the catalyst resting state. For more challenging substrates, high conversions were achieved via the employment of MeCN as a traceless additive. Mechanistic data suggest that its beneficial role lies in decreasing the energetic span, therefore accelerating product formation. Finally, the methodology has been applied to synthetic targets of pharmaceutical relevance. PMID- 25790255 TI - Determination of foraging thresholds and effects of application on energetic carrying capacity for waterfowl. AB - Energetic carrying capacity of habitats for wildlife is a fundamental concept used to better understand population ecology and prioritize conservation efforts. However, carrying capacity can be difficult to estimate accurately and simplified models often depend on many assumptions and few estimated parameters. We demonstrate the complex nature of parameterizing energetic carrying capacity models and use an experimental approach to describe a necessary parameter, a foraging threshold (i.e., density of food at which animals no longer can efficiently forage and acquire energy), for a guild of migratory birds. We created foraging patches with different fixed prey densities and monitored the numerical and behavioral responses of waterfowl (Anatidae) and depletion of foods during winter. Dabbling ducks (Anatini) fed extensively in plots and all initial densities of supplemented seed were rapidly reduced to 10 kg/ha and other natural seeds and tubers combined to 170 kg/ha, despite different starting densities. However, ducks did not abandon or stop foraging in wetlands when seed reduction ceased approximately two weeks into the winter-long experiment nor did they consistently distribute according to ideal-free predictions during this period. Dabbling duck use of experimental plots was not related to initial seed density, and residual seed and tuber densities varied among plant taxa and wetlands but not plots. Herein, we reached several conclusions: 1) foraging effort and numerical responses of dabbling ducks in winter were likely influenced by factors other than total food densities (e.g., predation risk, opportunity costs, forager condition), 2) foraging thresholds may vary among foraging locations, and 3) the numerical response of dabbling ducks may be an inconsistent predictor of habitat quality relative to seed and tuber density. We describe implications on habitat conservation objectives of using different foraging thresholds in energetic carrying capacity models and suggest scientists reevaluate assumptions of these models used to guide habitat conservation. PMID- 25790254 TI - Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability. AB - Multiple myeloma (MM) is a hematological malignancy characterized by frequent chromosome abnormalities. However, the molecular basis for this genome instability remains unknown. Since both impaired and hyperactive double strand break (DSB) repair pathways can result in DNA rearrangements, we investigated the functionality of DSB repair in MM cells. Repair kinetics of ionizing-radiation (IR)-induced DSBs was similar in MM and normal control lymphoblastoid cell lines, as revealed by the comet assay. However, four out of seven MM cell lines analyzed exhibited a subset of persistent DSBs, marked by gamma-H2AX and Rad51 foci that elicited a prolonged G2/M DNA damage checkpoint activation and hypersensitivity to IR, especially in the presence of checkpoint inhibitors. An analysis of the proteins involved in DSB repair in MM cells revealed upregulation of DNA-PKcs, Artemis and XRCC4, that participate in non-homologous end joining (NHEJ), and Rad51, involved in homologous recombination (HR). Accordingly, activity of both NHEJ and HR were elevated in MM cells compared to controls, as determined by in vivo functional assays. Interestingly, levels of proteins involved in a highly mutagenic, translocation-promoting, alternative NHEJ subpathway (Alt-NHEJ) were also increased in all MM cell lines, with the Alt-NHEJ protein DNA ligase IIIalpha, also overexpressed in several plasma cell samples isolated from MM patients. Overactivation of the Alt-NHEJ pathway was revealed in MM cells by larger deletions and higher sequence microhomology at repair junctions, which were reduced by chemical inhibition of the pathway. Taken together, our results uncover a deregulated DSB repair in MM that might underlie the characteristic genome instability of the disease, and could be therapeutically exploited. PMID- 25790256 TI - Chiroptical study and absolute configuration of securinine oxidation products. AB - Time-dependant density functional theory-electronic circular dichroism spectra prediction was carried out to study the absolute configuration of phyllanthidine type derivatives 5 and 6, derived from securinine (1) and its enantiomer virosecurinine (2), respectively. This method demonstrated to be very reliable in this alkaloid series. Thus, 5 and 6 shared the same stereochemistry as their parent precursors, confirming the retentive nature of the oxidation sequence. In addition, this study highlighted the key role of the methylene bridge (BC ring) in the chiroptical activity of these compounds. These results fully clarified the stereochemical relationships between the phyllanthidine and the securinine subgroups. PMID- 25790257 TI - Robust composite-shell microcapsules via pickering emulsification. AB - Microencapsulation technology has been increasingly applied toward the development of self-healing paints. Added to paint as a dry powder prior to spraying, the microcapsules store a liquid that can repair the protective barrier layer if released into a scratch. However, self-healing will not occur unless the microcapsules can withstand spray-painting, aggressive solvents in the paint, and long-term exposure to the elements. We have therefore developed a one-pot synthesis for the production of Pickering microcapsules with outstanding strength, solvent resistance, and barrier properties. Octadecyltrimethoxysilane filled (OTS) microcapsules form via standard interfacial polycondensation, except that silica nanopowder (10-20 nm diameter) replaces the conventional surfactant or hydrocolloid emulsifier. Isophorone diisocyanate (IPDI) in the OTS core reacts with diethylenetriamine, polyethylenimine, and water to form a hard polymer shell along the interface. Compared to pure polyurea, the silica-polyurea composite improves the shelf life of the OTS by 10 times. The addition of SiO2 prevents leaching of OTS into xylenes and hexanes for up to 80 days, and the resulting microcapsules survive nebulization through a spray gun at 620 kPa in a 500 cSt fluid. PMID- 25790258 TI - Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma. AB - BACKGROUND: We previously determined that radiation could be safely administered using a mouse-flank in vivo model to both alveolar (Rh30) and embryonal (Rh18) rhabdomyosarcoma xenografts. Mice from both tumor lines in this experiment developed metastases, an event not previously described with these models. We sought to determine if radiation-induced changes in gene expression underlie an increase in the metastatic behavior of these tumor models. PROCEDURE: Parental Rh18 and Rh30 xenografts, as well as tumor that recurred locally after radiotherapy (Rh18RT and Rh30RT), were grown subcutaneously in the flanks of SCID mice and then subjected to either fractionated radiotherapy or survival surgery alone. Metastasis formation was monitored and recorded. Gene expression profiling was also performed on RNA extracted from parental, recurrent, and metastatic tissue of both tumor lines. RESULTS: Rh30 and Rh30RT xenografts demonstrated metastases only if they were exposed to fractionated radiotherapy, whereas Rh18 and Rh18RT xenografts experienced significantly fewer metastatic events when treated with fractionated radiotherapy compared to survival surgery alone. Mean time to metastasis formation was 40 days in the recurrent tumors and 73 days in the parental xenografts. Gene expression profiling noted clustering of Rh30 recurrent and metastatic tissue that was independent of the parental Rh30 tissue. Rh18RT xenografts lost radiosensitivity compared to parental Rh18. CONCLUSION: Radiation therapy can significantly decrease the formation of metastases in radio sensitive tumors (Rh18) and may induce a more pro-metastatic phenotype in radio resistant lines (Rh30). PMID- 25790259 TI - Exploring researchers' experiences of working with people with acquired brain injury. AB - PURPOSE: This study aimed to investigate the challenges and positive experiences of researchers who work with people who have experienced an acquired brain injury and their families. METHODS: People who were currently or had previously worked as a researcher in the field of acquired brain injury (using either quantitative or qualitative methods) were invited to participate in a focus group or individual interview about their experiences. An expert reference group meeting was held to discuss strategies that could be implemented to enhance the researcher experience based on the interview data. RESULTS: A total of 19 researchers who worked across four different research teams took part in the study. Six inter-connected themes were identified: researcher motivation, meaning and fulfillment; human connection; knowing and understanding the role; complexity of brain injury in the research context; the research process; and state of the researcher. A number of recommendations for supporting researchers more effectively were identified. DISCUSSION: Researchers described a number of positive aspects as well as tensions they encountered in their role. The findings highlight the need to ensure researchers are supported effectively to ensure the quality of research studies in the field of brain injury. PMID- 25790260 TI - Identification of genomic regions and the isoamylase gene for reduced grain chalkiness in rice. AB - Grain chalkiness is an important grain quality related to starch granules in the endosperm. A high percentage of grain chalkiness is a major problem because it diminishes grain quality in rice. Here, we report quantitative trait loci identification for grain chalkiness using high-throughput single nucleotide polymorphism genotyping of a chromosomal segment substitution line population in which each line carried one or a few introduced japonica cultivar Nipponbare segments in the genetic background of the indica cultivar ZS97. Ten quantitative trait loci regions were commonly identified for the percentage of grain chalkiness and the degree of endosperm chalkiness. The allelic effects at nine of these quantitative trait loci reduced grain chalkiness. Furthermore, a quantitative trait locus (qPGC8-2) on chromosome 8 was validated in a chromosomal segment substitution line-derived segregation population, and had a stable effect on chalkiness in a multiple-environment evaluation of the near-isogenic lines. Residing on the qPGC8-2 region, the isoamylase gene (ISA1) was preferentially expressed in the endosperm and revealed some nucleotide polymorphisms between two varieties, Nipponbare and ZS97. Transgenic lines with suppression of ISA1 by RNA interference produced grains with 20% more chalkiness than the control. The results support that the gene may underlie qPGC8-2 for grain chalkiness. The multiple-environment trials of the near-isogenic lines also show that combination of the favorable alleles such as the ISA1 gene for low chalkiness and the GS3 gene for long grains considerably improved grain quality of ZS97, which proves useful for grain quality improvement in rice breeding programs. PMID- 25790261 TI - Adrenaline with lidocaine for digital nerve blocks. AB - BACKGROUND: Surgery on fingers is a common procedure in emergency and day care surgery. Adrenaline combined with lidocaine can prolong digital nerve block and provide a bloodless operating field. Extended postoperative pain relief can reduce the need for analgesics and can facilitate hand rehabilitation. Conventionally, adrenaline is avoided at anatomical sites with end arteries such as digits, penis and pinna because of concerns about arterial spasm, ischaemia and gangrene distal to the site of drug infiltration. OBJECTIVES: To assess the safety and efficacy of use of adrenaline (any dilution) combined with lidocaine (any dilution) for digital nerve blocks (fingers and toes). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2014), MEDLINE via Ovid SP (1966 to 18 November 2014) and EMBASE via Ovid SP (1980 to 18 November 2014). We also searched specific websites, such as www.indmed.nic.in; www.cochrane-sadcct.org; and www.Clinicaltrials.gov. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the use of adrenaline with lidocaine and plain lidocaine in patients undergoing surgery on digits (fingers and toes). Our primary outcomes were duration of anaesthesia, adverse outcomes such as ischaemia distal to the injection site and cost analysis. Our secondary outcomes were duration of postoperative pain relief and reduced bleeding during surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. We performed all analyses on an intention-to-treat basis. We used a fixed-effect model when no evidence of significant heterogeneity between studies was found and a random effects model when heterogeneity was likely. MAIN RESULTS: We included four RCTs with 167 participants. Risk of bias of the included studies was high, as none of them reported method of randomization, allocation concealment or blinding. Only one trial mentioned our primary outcome of duration of anaesthesia. The mean difference in duration of anaesthesia with use of adrenaline with lidocaine was 3.20 hours (95% confidence interval (CI) 2.48 to 3.92 hours; one RCT, 20 participants; low-quality evidence). No trial reported adverse events such as ischaemia distal to the injection site, and no trial reported cost analysis. One trial mentioned the secondary outcome of duration of postoperative pain relief, but available data were insufficient for analysis of the findings. Two trials reported the secondary outcome of reduced bleeding during surgery.Bleeding during surgery was observed in nine out of 52 participants as compared with 25 out of 51 participants in the adrenaline with lidocaine and plain lidocaine groups, respectively. The risk ratio for bleeding in the adrenaline with lidocaine group was 0.35 (95% CI 0.19 to 0.65; two RCTs, 103 participants; low-quality evidence). AUTHORS' CONCLUSIONS: From the limited data available, evidence is insufficient to recommend use or avoidance of adrenaline in digital nerve blocks. The evidence provided in this review indicates that addition of adrenaline to lidocaine may prolong the duration of anaesthesia and reduce the risk of bleeding during surgery, although the quality of the evidence is low. We have identified the need for researchers to conduct large trials that focus on other important outcomes such as adverse events, cost analysis and duration of postoperative pain relief. PMID- 25790263 TI - Solid-state (185/187)Re NMR and GIPAW DFT study of perrhenates and Re2(CO)10: chemical shift anisotropy, NMR crystallography, and a metal-metal bond. AB - Advances in solid-state nuclear magnetic resonance (SSNMR) methods, such as dynamic nuclear polarization (DNP), intricate pulse sequences, and increased applied magnetic fields, allow for the study of systems which even very recently would be impractical. However, SSNMR methods using certain quadrupolar probe nuclei (i.e., I > 1/2), such as (185/187)Re remain far from fully developed due to the exceedingly strong interaction between the quadrupole moment of these nuclei and local electric field gradients (EFGs). We present a detailed high field (B0 = 21.1 T) experimental SSNMR study on several perrhenates (KReO4, AgReO4, Ca(ReO4)2.2H2O), as well as ReO3 and Re2(CO)10. We propose solid ReO3 as a new rhenium SSNMR chemical shift standard due to its reproducible and sharp (185/187)Re NMR resonances. We show that for KReO4, previously poorly understood high-order quadrupole-induced effects (HOQIE) on the satellite transitions can be used to measure the EFG tensor asymmetry (i.e., etaQ) to nearly an order-of magnitude greater precision than competing SSNMR and nuclear quadrupole resonance (NQR) approaches. Samples of AgReO4 and Ca(ReO4)2.2H2O enable us to comment on the effects of counter-ions and hydration upon Re(vii) chemical shifts. Calcium 43 and (185/187)Re NMR tensor parameters allow us to conclude that two proposed crystal structures for Ca(ReO4)2.2H2O, which would be considered as distinct, are in fact the same structure. Study of Re2(CO)10 provides insights into the effects of Re-Re bonding on the rhenium NMR tensor parameters and rhenium oxidation state on the Re chemical shift value. As overtone NQR experiments allowed us to precisely measure the (185/187)Re EFG tensor of Re2(CO)10, we were able to measure rhenium chemical shift anisotropy (CSA) for the first time in a powdered sample. Experimental observations are supported by gauge-including projector augmented-wave (GIPAW) density functional theory (DFT) calculations, with NMR tensor calculations also provided for NH4ReO4, NaReO4 and RbReO4. These calculations are able to reproduce many of the experimental trends in rhenium deltaiso values and EFG tensor magnitudes. Using KReO4 as a prototypical perrhenate-containing system, we establish a correlation between the tetrahedral shear strain parameter (|psi|) and the nuclear electric quadrupolar coupling constant (CQ), which enables the refinement of the structure of ND4ReO4. Shortcomings in traditional DFT approaches, even when including relativistic effects via the zeroth-order regular approximation (ZORA), for calculating rhenium NMR tensor parameters are identified for Re2(CO)10. PMID- 25790264 TI - Associations between Benzodiazepine Use and Neuropsychological Test Scores in Older Adults. AB - Benzodiazepines are widely prescribed for anxiety, although use of this class of medications has been associated with dependency and cognitive changes. This article describes the study in which we investigated the relationship between the class of benzodiazepine available for use and associated performance on neuropsychological tests in a community sample of 1,754 older Canadians from the Canadian Study of Health and Aging. Benzodiazepines were classified as short-, intermediate-, and long-acting. Associations were calculated between each class of benzodiazepine and eight neuropsychological measures, using multiple regression analysis and controlling for demographic variables. Results showed different effects of the co-variates across the three drug classes, and short half-life benzodiazepines were not associated with any neuropsychological measure. Intermediate half-life and long half-life benzodiazepine use were each associated with two measures. Increased focus on specific domains of cognitive function is needed to improve our understanding of how benzodiazepine use influences cognition. PMID- 25790262 TI - The expression level and prognostic value of Y-box binding protein-1 in rectal cancer. AB - The aims of this study were to simultaneously evaluate the expression of Y-box binding protein-1 (YB-1) in non-neoplastic rectal tissue and rectal cancer tissue, and to collect clinical follow-up data for individual patients. Additionally, we aimed to investigate the developmental functions and prognostic value of YB-1 in rectal cancer. We performed immunohistochemical studies to examine YB-1 expression in tissue samples from 80 patients with rectal cancer, 30 patients with rectal tubular adenoma, and 30 patients with rectitis. The mean YB 1 histological scores for rectal cancer, rectal tubular adenoma, and rectitis tissue specimens were 205.5, 164.3, and 137.7, respectively. Shorter disease-free and overall survival times were found in patients with rectal cancer who had higher YB-1 expression than in those with lower expression (38.2 months vs. 52.4 months, P = 0.013; and 44.4 months vs. 57.3 months, P = 0.008, respectively). Our results indicate that YB-1 expression is higher in rectal cancer tissue than in rectal tubular adenoma and rectitis tissue and that it may be an independent prognostic factor for rectal cancer. PMID- 25790265 TI - Investigation of the beta-sheet interactions between dHP1 chromodomain and histone 3. AB - Methylated lysine 9 on the histone 3 (H3) tail recruits heterochromatin protein 1 from Drosophila (dHP1) via its chromodomain and results in gene silencing. The dHP1 chromodomain binds H3 K9Me3 with an aromatic cage surrounding the trimethyllysine. The sequence selectivity of binding comes from insertion of the histone tail between two beta-strands of the chromodomain to form a three stranded beta-sheet. Herein, we investigated the sequence selectivity provided by the beta-sheet interactions and how those interactions compare to other model systems. Residue Thr6 of the histone tail forms cross-strand interactions with Ala25 and Asp62 of the chromodomain. Each of these three residues was substituted for amino acids known to have high beta-sheet propensities and/or to form favorable side chain-side chain (SC-SC) interactions in beta-sheets, including hydrophobic, H-bonding, and aromatic interactions. We found that about 50% of the chromodomain mutants resulted in equal or tighter binding to the histone tail and about 25% of the histone tail mutants provided tighter binding compared to that of the native histone tail sequence. These studies provide novel insights into the sequence selectivity of the dHP1 chromodomain for the histone tail and relates the information gleaned from model systems and statistical studies to beta-sheet-mediated protein-protein interactions. Moreover, this work suggests that the development of designer histone-chromodomain pairs for chemical biology applications is feasible. PMID- 25790266 TI - Asymmetric syntheses of nakinadine D, nakinadine E, and nakinadine F: confirmation of their relative (RS,SR)-configurations and proposal of their absolute (2S,3R)-configurations. AB - The syn- and anti-diastereoisomeric forms of the reported structures of the marine alkaloids nakinadines D-F have been synthesized, for the first time in all cases, via an approach involving asymmetric Mannich-type (imino-aldol) reactions of methyl phenylacetate with N-tert-butylsulfinyl imines as the key steps to control the stereochemistry. Comparison of the (1)H and (13)C NMR spectroscopic data reported for the natural materials with those acquired for these synthetic samples confirms the initially assigned relative (RS,SR)-configurations of these three alkaloids. In the absence of specific rotation (or other diagnostic) data for the natural materials, it is not possible to unambiguously assign their absolute configurations, although given the absolute (2S)-configurations assigned to nakinadines B and C, and the absolute (2S,3R)-configuration previously established for nakinadine A, the data herein uphold our proposal that nakinadines D-F share the absolute (2S,3R)-configuration. PMID- 25790267 TI - The first case of robotic pudendal nerve decompression in pudendal nerve entrapment syndrome. AB - OBJECTIVE: To report the first case of robotic pudendal nerve (PN) decompression for bilateral PN entrapment (PNE). PN decompression is a safe and effective treatment for PNE and can be accomplished laparoscopically with a better exploration of the sacral roots and of the PN. MATERIALS AND METHODS: We describe in detail all the steps of our surgery, performed on a 38-year-old female patient suffering from PNE. All the anatomic landmarks are clearly shown. RESULTS: Our technique was successful, and the patient's postoperative course was uneventful. Six months after surgery, the pain had completely resolved, and the patient was drug-free. CONCLUSIONS: We showed the feasibility and effectiveness of robotic PN decompression, with surgical advantages that could potentially extend the indications of robot-assisted surgery. PMID- 25790268 TI - In situ laser-imprinted surface realignment of a nematic liquid crystal. AB - We present a new method for the in-plane realignment of nematic liquid crystals in already fully assembled cells with uni-directionally rubbed polyimide as an aligning layer. We use nematic liquid crystals (NLCs) with a relatively high nematic-isotropic transition temperature and we focus the IR laser beam of the laser tweezers selectively onto one or the other of the inner interfaces. The heat generated by the IR absorption locally melts the liquid crystal and creates an isotropic island with well-defined molecular anchoring at the nematic isotropic interface. By scanning the laser beam along a pre-defined line, the moving isotropic-nematic interface leaves behind a well oriented LC domain, with LC molecules aligned at 45 degrees to the rubbing direction. If we in addition move the sample with respect to this scanning line, we would be able to selectively realign micro-domains of the liquid crystal with respect to the original alignment induced by the PI rubbing. The realignment can be performed independently on each LC-glass interface, thereby producing predefined domains with customized and controllable alignment within an otherwise uniformly aligned cell. PMID- 25790269 TI - Component-selective and stereocontrolled one-step three-component reaction among aldehydes, amines, and allenyl boronic acids or allenyl pinacolboronates. AB - A one-step, three-component condensation of allenyl boronic acids or allenyl pinacolboronates with amines and aldehydes affords alpha-allenyl or alpha propargyl alpha-amino acids and anti-beta-amino alcohols. This process gives the allenyl or propargyl product depending on the amine and boron components. Secondary amines generate exclusively alpha-allenyl alpha-amino acids, while primary aliphatic amines lead to alpha-propargyl alpha-amino acids. Secondary aliphatic amines react with chiral alpha-hydroxy aldehydes and allenyl boron derivatives to form stereoselectively allenyl anti-beta-amino alcohol products. PMID- 25790271 TI - Rational design of a fluorescent sensor to simultaneously determine both the enantiomeric composition and the concentration of chiral functional amines. AB - A fluorescent molecular probe, a 1,1'-bi-2-naphthol (BINOL)-based bis(naphthylimine) compound (R)-4, is designed to exhibit very different fluorescent responses at two emission wavelengths toward a variety of chiral functional amines including diamines, amino alcohols, and amino acids. At one emission wavelength (lambda1), it shows high sensitivity toward the substrates, and at another wavelength (lambda2), it shows high enantioselectivity. This is the first rational design of such a dual responsive fluorescent sensor which can be used to simultaneously determine both the concentration and the enantiomeric composition of functional chiral amines by one fluorescent measurement. This strategy is potentially generally applicable for the construction of sensors for rapid assay of structurally diverse chiral substrates. When (R)-4 is treated with various chiral functional amines in the presence of Zn(OAc)2, its 2-naphthylamine units are displaced off to show large fluorescent enhancement at lambda1 = 427 nm (I1) due to the restored emission of 2-naphthylamine. The combination of the remaining chiral binaphthyl unit with the chiral substrates leads to highly enantioselective fluorescent enhancement at lambda2 > 500 nm (I2). Since I1 is only concentration dependent but independent of the chiral configuration, it allows the determination of the substrate concentration. The highly enantioselective I2 allows the determination of the enantiomeric composition. Thus, using one fluorescent probe with one fluorescent measurement, both the concentration and the enantiomeric composition are determined. The dual responsive mechanism of (R)-4 is studied by using various spectroscopic methods including fluorescence, UV-vis, NMR, and mass analyses. PMID- 25790272 TI - Meta-analysis of greenhouse gas emissions from anaerobic digestion processes in dairy farms. AB - This meta-analysis quantifies the changes in greenhouse gas (GHG) emissions from dairy farms, caused by anaerobically digesting (AD) cattle manure. As this is a novel quantifiable synthesis of the literature, a database of GHG emissions from dairy farms is created. Each case in the database consists of a baseline (reference with no AD system) and an AD scenario. To enable interstudy comparison, emissions are normalized by calculating relative changes (RCs). The distributions of RCs are reported by specific GHGs and operation units. Nonparametric tests are applied to the RCs in order to identify a statistical difference of AD with respect to baseline scenarios (Wilcoxon rank test), correlations (Spearman test), and best estimation for changes in emissions (Kernel density distribution estimator). From 749 studies identified, 30 papers yield 89 independent cases. The median reductions in emissions from the baseline scenarios, according to operation units, are -43.2% (n.s.) for storage, -6.3% for field application of slurries, -11.0% for offset of energy from fossil fuel, and +0.4% (n.s.) for offset of inorganic fertilizers. The leaks from digesters are found to significantly increase the emissions from baseline scenarios (median = +1.4%). PMID- 25790273 TI - Outcomes in Pediatric Robot-Assisted Laparoscopic Heminephrectomy Compared with Contemporary Open and Laparoscopic Series. AB - PURPOSE: To compare our renal and clinical outcomes for robot-assisted laparoscopic heminephrectomy (RAL-HN) in the pediatric population with duplicated systems with those of current contemporary open and laparoscopic series. PATIENTS AND METHODS: Sixteen children underwent RAL-HN from 2009 to 2014. Data were collected via retrospective chart review including demographics, preoperative and postoperative imaging, operative time, estimated blood loss (EBL), length of stay (LOS), complications, and renal outcomes. RESULTS: Mean age at surgery was 37.5+/ 49.2 months. Mean operative time was 135+/-36 minutes with an EBL of 10+/-5 mL. Mean LOS was 2+/-0.8 days, and no major perioperative complications were observed. Mean follow-up was 22.1+/-17.2 months. Two patients needed secondary ureterectomy for recurrent urinary tract infection in the setting of a refluxing ureteral stump. One of these patients also underwent a ureteral reimplantation of the ipsilateral normal ureter. No patients lost their remaining healthy moiety. Asymptomatic cyst formation was seen in four (25%) patients, and self- limited postoperative urinoma was seen in 2 (13%) patients. Postoperative perinephric abscess did not develop in any patient. Mean change in renal function based on nuclear renography of the duplex kidney was -2.7%+/-4.6%. CONCLUSIONS: Compared with previously published literature evaluating open and laparoscopic heminephrectomy, RAL-HN provides comparable outcomes in regard to complication rate and renal function of the remnant moiety. PMID- 25790274 TI - Anesthetic use in newborn infants: the urgent need for rigorous evaluation. AB - Approximately 1.5 million neonates receive general anesthesia each year for a surgical procedure. Despite this being an essential practice, a number of recent studies now indicate that anesthetic exposure could cause toxicity and neuronal apoptosis in the developing brain. This could potentially influence long-term neurodevelopmental outcome, especially premature infants in need of multiple surgical procedures. Most anesthetic drugs routinely administered to neonates have not been adequately tested for safety or efficacy. Given the number of confounders, dosing is often extrapolated from adults. This is concerning since many different drugs can be administered concurrently, with few of these agents actually approved for use by the Food and Drug Administration. Since 1997, legislation has been passed in the United States and abroad encouraging more drug investigation in infants and children. This has resulted in over 500 labeling changes to products regarding safety and efficacy in various pediatric age groups. However, only three drugs routinely used as anesthetic agents in newborn infants have had any updated labeling (none in very premature infants). This "off label" use without adequate testing must be addressed. Therefore, more clinical trials of common anesthetic agents used alone and in combination in neonates are urgently needed. PMID- 25790275 TI - Hair cortisol as a novel biomarker of HPA suppression by inhaled corticosteroids in children. AB - BACKGROUND: Asthma is the most common chronic condition in childhood, and the recommended pharmacotherapy for long-term control includes the use of inhaled corticosteroids (ICS). ICS were designed to act at the site of inflammation in the lung, thus decreasing systemic absorption and reducing the risk of adverse effects associated with corticosteroid use (e.g., HPA suppression and its consequent effects). Available data show that measurement of hair cortisol successfully reflects endogenous cortisol levels. We sought to examine whether hair cortisol measurements can be used to identify HPA suppression surrounding ICS therapy in children with asthma. METHODS: Hair samples were collected from the vertex posterior region of the head of 18 asthmatic children. We compared their hair cortisol concentration during ICS use with the concentration prior to ICS use. RESULTS: During ICS therapy, median hair cortisol levels were twofold lower compared with the period of no ICS use (median 89.8 ng/g vs. 198.2 ng/g, P = 0.0015). CONCLUSION: Hair cortisol is an effective biomarker of the HPA suppression associated with ICS therapy and can be a sensitive tool for determining systemic effects of ICS use and monitoring adherence. Future research is needed to characterize the effect of untreated asthma on hair cortisol concentrations, if any. PMID- 25790276 TI - Abnormal intra-aural pressure waves associated with death in African children with acute nontraumatic coma. AB - BACKGROUND: We explored the relationship between tympanic membrane displacement (TMD) measurements, a tool to monitor intracranial pressure noninvasively, and clinical features and death in children with acute coma in Kilifi, Kenya. METHODS: Between November 2007 and September 2009, we made serial TMD measurements and clinical observations on children with acute coma (Blantyre coma score (BCS) <= 2) on the pediatric high dependency unit of Kilifi District Hospital, and on well children presenting to the hospital's outpatient department for routine follow-up. We examined middle ear function using tympanometry and measured cardiac pulse (CPA) and respiratory pulse pressure amplitudes (RPA) using the TMD analyzer. RESULTS: We recruited 75 children (32 (43%) females; median age 3.3 (IQR: 2.0, 4.3) years). Twenty-one (28%) children died. Higher TMD measurements predicted death. Adjusting for diagnosis, every 50 nl rise in both semirecumbent and recumbent CPA was associated with increased odds of death associated with intracranial herniation (OR: 1.61, 95% confidence interval (CI): 1.07, 2.41; P = 0.02 and OR: 1.35, 95% CI: 1.10, 1.66; P <= 0.01 respectively). CONCLUSION: Raised TMD pulse pressure measurements are associated with death and may be useful in detecting and monitoring risk of intracranial herniation and intracranial pressure in childhood coma. PMID- 25790277 TI - Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections. AB - BACKGROUND: The identification of acute pyelonephritis (APN) is still a challenge. METHODS: Patients admitted for their first urinary tract infection (UTI) were enrolled. Plasma neutrophil gelatinase-associated lipocalin (NGAL) levels were measured at admittance and after treatment. Laboratory, clinical, and imaging results were compared between children with and without APN. RESULTS: A total of 123 patients were enrolled (53 APN and 70 lower UTI). After adjusting for age and gender, plasma NGAL levels were higher in the APN group than in the lower UTI group (233 (129-496) ng/ml vs. 71 (50.8-110) ng/ml, P < 0.001). NGAL levels were correlated with the serum levels of leukocytes, C-reactive protein, and creatinine, as well as fever duration (P < 0.05). Multivariable analysis revealed that log-transformed plasma NGAL was an independent predictor of APN (P < 0.05). Receiver operating curve analysis showed a good diagnostic profile of NGAL for identifying APN (area under the curve 0.864) with a best cut-off value of 102.5 ng/ml. The NGAL levels in both two groups decreased after treatment compared to levels before treatment (P < 0.001). CONCLUSION: Plasma NGAL can be a sensitive predictor for identifying APN and monitoring the treatment response of pediatric UTI. PMID- 25790280 TI - Control of membrane permeability in air-stable droplet interface bilayers. AB - Air-stable droplet interface bilayers (airDIBs) on oil-infused surfaces are versatile model membranes for synthetic biology applications, including biosensing of airborne species. However, airDIBs are subject to evaporation, which can, over time, destabilize them and reduce their useful lifetime compared to traditional DIBs that are fully submerged in oil. Here, we show that the lifetimes of airDIBs can be extended by as much as an order of magnitude by maintaining the temperature just above the dew point. We find that raising the temperature from near the dew point (which was 7 degrees C at 38.5% relative humidity and 22 degrees C air temperature) to 20 degrees C results in the loss of hydrated water molecules from the polar headgroups of the lipid bilayer membrane due to evaporation, resulting in a phase transition with increased disorder. This dehydration transition primarily affects the bilayer electrical resistance by increasing the permeability through an increasingly disordered polar headgroup region of the bilayer. Temperature and relative humidity are conveniently tunable parameters for controlling the stability and composition of airDIB membranes while still allowing for operation in ambient environments. PMID- 25790278 TI - Ensemble-based virtual screening for cannabinoid-like potentiators of the human glycine receptor alpha1 for the treatment of pain. AB - The human glycine receptors (hGlyRs) are chloride-selective ion channels that mediate inhibitory neurotransmission in the brain stem and spinal cord. They are also targets for compounds of potential use in analgesic therapies. Here, we develop a strategy to discover analgesic drugs via structure-based virtual screening based on the recently published NMR structure of the hGlyR-alpha1 transmembrane domain (PDB ID: 2M6I ) and the critical role of residue S296 in hGlyR-alpha1 potentiation by Delta(9)-tetrahydrocannabinol (THC). We screened 1549 FDA-approved drugs in the DrugBank database on an ensemble of 180 hGlyR alpha1 structures generated from molecular dynamics simulations of the NMR structure of the hGlyR-alpha1 transmembrane domain in different lipid environments. Thirteen hit compounds from the screening were selected for functional validation in Xenopus laevis oocytes expressing hGlyR-alpha1. Only one compound showed no potentiation effects; seven potentiated hGlyR-alpha1 at a level greater than THC at 1 MUM. Our virtual screening protocol is generally applicable to drug targets with lipid-facing binding sites. PMID- 25790281 TI - Dynamical analysis and visualization of tornadoes time series. AB - In this paper we analyze the behavior of tornado time-series in the U.S. from the perspective of dynamical systems. A tornado is a violently rotating column of air extending from a cumulonimbus cloud down to the ground. Such phenomena reveal features that are well described by power law functions and unveil characteristics found in systems with long range memory effects. Tornado time series are viewed as the output of a complex system and are interpreted as a manifestation of its dynamics. Tornadoes are modeled as sequences of Dirac impulses with amplitude proportional to the events size. First, a collection of time series involving 64 years is analyzed in the frequency domain by means of the Fourier transform. The amplitude spectra are approximated by power law functions and their parameters are read as an underlying signature of the system dynamics. Second, it is adopted the concept of circular time and the collective behavior of tornadoes analyzed. Clustering techniques are then adopted to identify and visualize the emerging patterns. PMID- 25790282 TI - Combined effect of TLR2 gene polymorphism and early life stress on the age at onset of bipolar disorders. AB - Gene-environment interactions may play an important role in modulating the impact of early-life stressful events on the clinical course of bipolar disorder (BD), particularly associated to early age at onset. Immune dysfunction is thought to be an important mechanism linking childhood trauma with early-onset BD, thus the genetic diversity of immune-related loci may account for an important part of the interindividual susceptibility to this severe subform. Here we investigated the potential interaction between genetic variants of Toll-like receptors 2 (TLR2) and 4 (TLR4), major innate immune response molecules to pathogens, and the childhood trauma questionnaire (CTQ) in age at onset of BD. We recruited 531 BD patients (type I and II or not otherwise specified), genotyped for the TLR2 rs4696480 and rs3804099 and TLR4 rs1927914 and rs11536891 single-nucleotide polymorphisms and recorded for history of childhood trauma using the CTQ. TLR2 and TLR4 risk genotype carrier state and history of childhood emotional, physical and sexual abuses were evaluated in relation to age at onset as defined by the age at first manic or depressive episode. We observed a combined effect of TLR2 rs3804099 TT genotype and reported sexual abuse on determining an earlier age at onset of BD by means of a Kaplan-Meier survival curve (p = 0.002; corrected p = 0.02). Regression analysis, however, was non-significant for the TLR2-CTQ sexual abuse interaction term. The negative effects of childhood sexual abuse on age at onset of BD may be amplified in TLR2 rs3804099 risk genotype carriers through immune-mediated pathways. Clinical characteristics of illness severity, immune phenotypes and history of early life infectious insults should be included in future studies involving large patient cohorts. PMID- 25790283 TI - Comparative analysis of disease-linked single nucleotide polymorphic markers from Brassica rapa for their applicability to Brassica oleracea. AB - Numerous studies using single nucleotide polymorphisms (SNPs) have been conducted in humans, and other animals, and in major crops, including rice, soybean, and Chinese cabbage. However, the number of SNP studies in cabbage is limited. In this present study, we evaluated whether 7,645 SNPs previously identified as molecular markers linked to disease resistance in the Brassica rapa genome could be applied to B. oleracea. In a BLAST analysis using the SNP sequences of B. rapa and B. oleracea genomic sequence data registered in the NCBI database, 256 genes for which SNPs had been identified in B. rapa were found in B. oleracea. These genes were classified into three functional groups: molecular function (64 genes), biological process (96 genes), and cellular component (96 genes). A total of 693 SNP markers, including 145 SNP markers [BRH--developed from the B. rapa genome for high-resolution melt (HRM) analysis], 425 SNP markers (BRP--based on the B. rapa genome that could be applied to B. oleracea), and 123 new SNP markers (BRS--derived from BRP and designed for HRM analysis), were investigated for their ability to amplify sequences from cabbage genomic DNA. In total, 425 of the SNP markers (BRP-based on B. rapa genome), selected from 7,645 SNPs, were successfully applied to B. oleracea. Using PCR, 108 of 145 BRH (74.5%), 415 of 425 BRP (97.6%), and 118 of 123 BRS (95.9%) showed amplification, suggesting that it is possible to apply SNP markers developed based on the B. rapa genome to B. oleracea. These results provide valuable information that can be utilized in cabbage genetics and breeding programs using molecular markers derived from other Brassica species. PMID- 25790284 TI - Hypoxia precondition promotes adipose-derived mesenchymal stem cells based repair of diabetic erectile dysfunction via augmenting angiogenesis and neuroprotection. AB - The aim of the present study was to examine whether hypoxia preconditioning could improve therapeutic effects of adipose derived mesenchymal stem cells (AMSCs) for diabetes induced erectile dysfunction (DED). AMSCs were pretreated with normoxia (20% O2, N-AMSCs) or sub-lethal hypoxia (1% O2, H-AMSCs). The hypoxia exposure up regulated the expression of several angiogenesis and neuroprotection related cytokines in AMSCs, including vascular endothelial growth factor (VEGF) and its receptor FIK-1, angiotensin (Ang-1), basic fibroblast growth factor (bFGF), brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). DED rats were induced via intraperitoneal injection of streptozotocin (60 mg/kg) and were randomly divided into three groups-Saline group: intracavernous injection with phosphate buffer saline; N-AMSCs group: N-AMSCs injection; H-AMSCs group: H-AMSCs injection. Ten rats without any treatment were used as normal control. Four weeks after injection, the mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured. The contents of endothelial, smooth muscle, dorsal nerve in cavernoursal tissue were assessed. Compared with N-AMSCs and saline, intracavernosum injection of H-AMSCs significantly raised ICP and ICP/MAP (p<0.05). Immunofluorescent staining analysis demonstrated that improved erectile function by MSCs was significantly associated with increased expression of endothelial markers (CD31 and vWF) (p<0.01) and smooth muscle markers (alpha-SMA) (p<0.01). Meanwhile, the expression of nNOS was also significantly higher in rats receiving H-AMSCs injection than those receiving N-AMSCs or saline injection. The results suggested that hypoxic preconditioning of MSCs was an effective approach to enhance their therapeutic effect for DED, which may be due to their augmented angiogenesis and neuroprotection. PMID- 25790285 TI - Risk of ischemic stroke associated with the use of antipsychotic drugs in elderly patients: a retrospective cohort study in Korea. AB - OBJECTIVE: Strong concerns have been raised about whether the risk of ischemic stroke differs between conventional antipsychotics (CAPs) and atypical antipsychotics (AAPs). This study compared the risk of ischemic stroke in elderly patients taking CAPs and AAPs. METHOD: We conducted a retrospective cohort study of 71,584 elderly patients who were newly prescribed the CAPs (haloperidol or chlorpromazine) and those prescribed the AAPs (risperidone, quetiapine, or olanzapine). We used the National Claims Database from the Health Insurance Review and Assessment Service (HIRA) from January 1, 2006 to December 31, 2009. Incident cases for ischemic stroke (ICD-10, I63) were identified. The hazard ratios (HR) for AAPs, CAPs, and for each antipsychotic were calculated using multivariable Cox regression models, with risperidone as a reference. RESULTS: Among a total of 71,584 patients, 24,668 patients were on risperidone, 15,860 patients on quetiapine, 3,888 patients on olanzapine, 19,564 patients on haloperidol, and 7,604 patients on chlorpromazine. A substantially higher risk was observed with chlorpromazine (HR = 3.47, 95% CI, 1.97-5.38), which was followed by haloperidol (HR = 2.43, 95% CI, 1.18-3.14), quetiapine (HR = 1.23, 95% CI, 0.78-2.12), and olanzapine (HR = 1.12, 95% CI, 0.59-2.75). Patients who were prescribed chlorpromazine for longer than 150 days showed a higher risk (HR = 3.60, 95% CI, 1.83-6.02) than those who took it for a shorter period of time. CONCLUSIONS: A much greater risk of ischemic stroke was observed in patients who used chlorpromazine and haloperidol compared to risperidone. The evidence suggested that there is a strong need to exercise caution while prescribing these agents to the elderly in light of severe adverse events with atypical antipsychotics. PMID- 25790286 TI - Neuroprotective effects of oligodendrocyte progenitor cell transplantation in premature rat brain following hypoxic-ischemic injury. AB - Periventricular leukomalacia (PVL) is a common ischemic brain injury in premature infants for which there is no effective treatment. The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL. Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h. Animals were assigned to OPC transplantation or sham control groups and injected with OPCs or PBS, respectively, and sacrificed up to 6 weeks later for immunohistochemical analysis to investigate the survival and differentiation of transplanted OPCs. Apoptosis was evaluated by double immunolabeling of brain sections for caspase-3 and neuronal nuclei (NeuN), while proliferation was assessed using a combination of anti-Nestin and bromodeoxyuridine antibodies. The expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 was examined 7 days after OPC transplantation. The Morris water maze was used to test spatial learning and memory. The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals. Moreover, deficits in spatial learning and memory resulting from HI were improved by OPC transplantation. These results demonstrate an important neuroprotective role for OPCs that can potentially be exploited in cell-based therapeutic approaches to minimize HI-induced brain injury. PMID- 25790287 TI - Preventing hepatitis B reactivation due to immunosuppressive drug treatments. PMID- 25790288 TI - Isotope-ratio infrared spectroscopy: a reliable tool for the investigation of plant-water sources? AB - Stable isotopes are extensively used as tracers for the study of plant-water sources. Isotope-ratio infrared spectroscopy (IRIS) offers a cheaper alternative to isotope-ratio mass spectroscopy (IRMS), but its use in studying plant and soil water is limited by the spectral interference caused by organic contaminants. Here, we examine two approaches to cope with contaminated samples in IRIS: on line oxidation of organic compounds (MCM) and post-processing correction. We assessed these methods compared to IRMS across 136 samples of xylem and soil water, and a set of ethanol- and methanol-water mixtures. A post-processing correction significantly improved IRIS accuracy in both natural samples and alcohol dilutions, being effective with concentrations up to 8% of ethanol and 0.4% of methanol. MCM outperformed the post-processing correction in removing methanol interference, but did not effectively remove interference for high concentrations of ethanol. By using both approaches, IRIS can overcome with reasonable accuracy the analytical uncertainties associated with most organic contaminants found in soil and xylem water. We recommend the post-processing correction as the first choice for analysis of samples of unknown contamination. Nevertheless, MCM can be more effective for evaluating samples containing contaminants responsible for strong spectral interferences at low concentrations, such as methanol. PMID- 25790289 TI - Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with neonatal epidermolysis bullosa acquisita. AB - We report the case of a 2-week-old boy who presented with a vesiculopustular, bullous eruption in the setting of autoimmune enteropathy, hypothyroidism, membranous nephropathy, Coombs-positive hemolytic anemia, and persistent eosinophilia. Immunologic testing revealed a deficiency of FOXP3-expressing regulatory T cells, and a diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome was made. Histologic analysis, immunofluorescence, and enzyme-linked immunosorbent assay confirmed the bullous eruption as epidermolysis bullosa acquisita with associated collagen VII autoantibody production. The skin lesions responded to systemic immunosuppressant therapy and have regressed after allogeneic bone marrow transplantation. PMID- 25790290 TI - Formation of a nanometer-thick water layer at high humidity on a dynamic crystalline material composed of multi-interactive molecules. AB - Crystalline powders self-assembled from interactive discrete molecules reversibly transformed from a porous structure to a 2D one with a nanometer-thick H2O layer by hydration/dehydration. Multi-point weak intermolecular interactions contributed to maintenance of each phase. This structure transformation induced a humidity-dependent ion conductivity change from insulator to 3.4 * 10(-3) S cm( 1). PMID- 25790291 TI - Functional analysis of free fatty acid receptor GPR120 in human eosinophils: implications in metabolic homeostasis. AB - Recent evidence has shown that eosinophils play an important role in metabolic homeostasis through Th2 cytokine production. GPR120 (FFA4) is a G protein-coupled receptor (GPCR) for long-chain fatty acids that functions as a regulator of physiological energy metabolism. In the present study, we aimed to investigate whether human eosinophils express GPR120 and, if present, whether it possesses a functional capacity on eosinophils. Eosinophils isolated from peripheral venous blood expressed GPR120 at both the mRNA and protein levels. Stimulation with a synthetic GPR120 agonist, GW9508, induced rapid down-regulation of cell surface expression of GPR120, suggesting ligand-dependent receptor internalization. Although GPR120 activation did not induce eosinophil chemotactic response and degranulation, we found that GW9508 inhibited eosinophil spontaneous apoptosis and Fas receptor expression. The anti-apoptotic effect was attenuated by phosphoinositide 3-kinase (PI3K) inhibitors and was associated with inhibition of caspase-3 activity. Eosinophil response investigated using ELISpot assay indicated that stimulation with a GPR120 agonist induced IL-4 secretion. These findings demonstrate the novel functional properties of fatty acid sensor GPR120 on human eosinophils and indicate the previously unrecognized link between nutrient metabolism and the immune system. PMID- 25790292 TI - Acceptance and adherence of oral endocrine therapy in women with metastatic breast cancer: exacampania group study. PMID- 25790294 TI - Successful treatment with sirolimus for an angiomyolipoma mimicking renal cell carcinoma in a transplanted kidney. AB - Angiomyolipoma (AML) is a benign mesenchymal tumor composed of blood vessels, smooth muscle, and mature adipose tissue. AMLs in the kidney allografts are rare. We report a case of AML that was incidentally found 1 year after transplantation. Abdominal computed tomography showed a 4-cm renal tumor with contrast enhancement and an early washout pattern, resembling a renal cell carcinoma. Tumor biopsy proved a lipid-poor AML. Tumor diameter decreased to 2.4 cm after 6 months of treatment with sirolimus. Sirolimus not only reduces tumor size, but also benefits a transplant patient who needs immunosuppression. PMID- 25790293 TI - Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. AB - There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse. PMID- 25790296 TI - The Orbit and the Brain: Cheek by Jowl or Very Far Away? PMID- 25790295 TI - Smoking p66Shc knocked out mice develop respiratory bronchiolitis with fibrosis but not emphysema. AB - The adaptor protein p66Shc regulates intracellular oxidant levels through the modulation of a forkhead-related transcription factor (FOXO3a). The genetic ablation of p66Shc (p66Shc-/-) renders mice resistant to oxidative stress and p53 dependent apoptosis. We investigated whether p66Shc ablation in mice modifies lung cellular and molecular responses to cigarette smoke (CS) exposure. No differences between wild type (WT) and p66Shc-/- mice were observed in terms of inflammation and oxidant burden after acute CS exposure; however,p66Shc ablation modifies specific features of chronic inflammation induced by repeated exposure to CS. Unlike WT mice, p66Shc-/- mice did not develop emphysema, showing protection toward oxidative damage to DNA and apoptosis as revealed by a trivial 8-hydroxyguanosine staining and faint TUNEL and caspase-3 positivity on alveolar epithelial cells. Unexpectedly, CS exposure in p66Shc-/- mice resulted in respiratory bronchiolitis with fibrosis in surrounded alveoli. Respiratory bronchiolitis was characterized by peribronchiolar infiltrates of lymphocytes and histiocytes, accumulation of ageing pigmented macrophages within and around bronchioles, and peribronchiolar fibrosis. The blockage of apoptosis interferes with the macrophage "clearance" from alveolar spaces, favouring the accumulation of aging macrophages into alveoli and the progressive accumulation of iron pigment in long-lived senescent cells. The presence of areas of interstitial and alveolar fibrosis in peripheral parenchyma often accompanied the bronchiolar changes. Macrophages from smoking p66Shc-/- mice elaborate M2 cytokines (i.e., IL 4 and IL-13) and enzymes (i.e., chitinase and arginase I), which can promote TGF beta expression, collagen deposition, and fibrosis in the surrounding areas. We demonstrate here that resistance to oxidative stress and p53-dependent apoptosis can modify tissue responses to CS caused by chronic inflammation without influencing early inflammatory response to CS exposure. PMID- 25790298 TI - A 9-year-old girl with persistent obsessive and compulsive behaviors in a primary care pediatric practice. AB - CASE: Chloe is a 9-year-old gal whose mother made an initial visit to a new pediatrician for concerns about her behavior. Chloe is apprehensive about the visit and frequently hides behind her mother.Her parents first noticed Chloe becoming angry and more emotional 3 years ago, which her parents did not initially understand. However, over the past year, she has started to have more worries and unusual behavior.Chloe and her mother report that when she walks through doorways, she will almost always go back and walks through again. At home, she will walk through doorways multiple times and at school, she will pretend she forgot something so her friends do not notice. She often will not walk downstairs and occasionally her mother has to carry her. Clothes are problematic for Chloe. If her father touches something of a specific color and then touches Chloe, she will have to change her clothes or take a shower. Sometimes, she will never be able to wear those clothes again. She had a recent episode where she could not stop tapping a red paper, because if she stopped, she said it would burst into flame. During the 2 weeks before the pediatric visit, symptoms increased to the point that she is now refusing to go to school. When she stays home, she lays in 1 place all day.Chloe is a fourth grade student. The family does not report academic concerns. She has friends. She denies any appetite or sleep problems. She endorses periods of sadness, lack of energy, and decreased interest in social activities, mostly because she worries and is embarrassed. She kept her behaviors hidden from her 5 siblings for the past year, and she talked only to her mother about them. She is worried her friends might discover her behaviors.The family history is notable for multiple paternal family members with anxiety and bipolar disorder and depression on mother's side. A few months ago, Chloe's family adopted a 7-year-old child with special needs from China.Her growth, vital signs, and physical examination are unremarkable. Her mother filled out the Short Mood and Feelings Questionnaire and the Screen for Child Anxiety-Related Emotional Disorders, which both had elevated scores. PMID- 25790297 TI - Serum interferon-related microRNAs as biomarkers to predict the response to interferon therapy in chronic hepatitis C genotype 4. AB - MicroRNAs are messengers during interferon-virus interplay and are involved in antiviral immunity, however, little is known about interferon-related microRNAs regarding their detection in serum and their potential use as non-invasive diagnostic and prognostic biomarkers in chronic hepatitis C (CHC). To elucidate some of the molecular aspects underlying failure of pegylated interferon alpha/ribavirin therapy, we investigated pretreatment expression profiles of seven selected interferon-related microRNAs (miR-146a, miR-34a, miR-130a, miR 19a, miR-192, miR-195, and miR-296) by quantitative RT-PCR custom array technology in serum of Egyptian CHC genotype 4 patients and whether their pretreatment levels would predict patient response to the combination therapy. One hundred and six CHC patients and forty matched healthy controls were included. Patients were divided into sustained virological response (SVR) and non responder (NR) groups. Serum miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296 were upregulated, whereas serum miR-146a was downregulated in CHC compared to controls. Significant correlations were found between expression levels of studied microRNAs and also with clinical data. Pretreatment levels of miR-34a, miR-130a, and miR-195 were significantly higher, whereas miR-192 and miR 296 levels were significantly lower in SVR than NR patients. miR-19a and miR-146a levels were not significantly different between the two groups. miR-34a was superior to differentiate CHC from controls, whereas miR-296 was superior to discriminate SVR from NR patients by receiver operating characteristic analysis. Multivariate logistic analysis revealed miR-34a and miR-195 as independent predictors for SVR and miR-192 as an independent variable for non-response. In conclusion, pretreatment expression profiles of five interferon-related microRNAs are associated with treatment outcome in CHC. Of these, miR-34a, miR-195, and miR 192 could predict treatment response. The profiling results could be used as novel non-invasive diagnostic and prognostic pharmacogenetic biomarkers for treatment personalization in CHC and could help to identify new microRNA-based antivirals. PMID- 25790299 TI - A computer-assisted 3D model for analyzing the aggregation of tumorigenic cells reveals specialized behaviors and unique cell types that facilitate aggregate coalescence. AB - We have developed a 4D computer-assisted reconstruction and motion analysis system, J3D-DIAS 4.1, and applied it to the reconstruction and motion analysis of tumorigenic cells in a 3D matrix. The system is unique in that it is fast, high resolution, acquires optical sections using DIC microscopy (hence there is no associated photoxicity), and is capable of long-term 4D reconstruction. Specifically, a z-series at 5 MUm increments can be acquired in less than a minute on tissue samples embedded in a 1.5 mm thick 3D Matrigel matrix. Reconstruction can be repeated at intervals as short as every minute and continued for 30 days or longer. Images are converted to mathematical representations from which quantitative parameters can be derived. Application of this system to cancer cells from established lines and fresh tumor tissue has revealed unique behaviors and cell types not present in non-tumorigenic lines. We report here that cells from tumorigenic lines and tumors undergo rapid coalescence in 3D, mediated by specific cell types that we have named "facilitators" and "probes." A third cell type, the "dervish", is capable of rapid movement through the gel and does not adhere to it. These cell types have never before been described. Our data suggest that tumorigenesis in vitro is a developmental process involving coalescence facilitated by specialized cells that culminates in large hollow spheres with complex architecture. The unique effects of select monoclonal antibodies on these processes demonstrate the usefulness of the model for analyzing the mechanisms of anti-cancer drugs. PMID- 25790301 TI - A series of new lanthanoid thioarsenates: insights into the influence of lanthanide contraction on the formation of new lanthanoid thioarsenates. AB - A series of new lanthanoid thioarsenates [Ln(teta)(MU-eta(1):eta(2):eta(1) As(III)S3)]n {Ln = Ce (Ia), Pr (Ib), Nd (Ic), and Sm (Id); teta = triethylenetetramine} and [Ln(teta)(en)(MU-eta(1):eta(1):eta(1)-As(V)S4)]n {Ln = La (IIa), Ce (IIb), Pr (IIc), and Nd (IId); en = ethylenediamine} were prepared by the solvothermal reaction of K3AsO3, S, LnCl3 and organic amines and structurally characterized. Compounds Ia-d crystallise in the orthorhombic space group Aba2 and display 1-D neutral chains [Ln(teta)(MU-eta(1):eta(2):eta(1) As(III)S3)]n, which represent the first examples of 1-D organic hybrid lanthanoid sulfides built up from trigonal-pyramidal [As(III)S3](3-) acting as tetradentate bridging ligands to interlink [Ln(teta)](3+) ions, while compounds IIa-d crystallise in the orthorhombic space group P2(1)2(1)2(1) and consist of other 1 D neutral chains [Ln(teta)(en)(MU-eta(1):eta(1):eta(1)-As(V)S4)]n, which are built up from the linkages of the tetrahedral [As(V)S4](3-) ion and the [Ln(teta)(en)](3+) ion. To learn more about the influence of lanthanide contraction on the formation of lanthanoid thioarsenates, three organic hybrid lanthanoid thioarsenates [Ln(teta)(en)As(V)S4] [Ln = Dy (IIIa), Ho (IIIb), and Tm (IIIc)] with the neutral molecular structure type in the monoclinic centrosymmetric space group P2(1)/c are also presented. Their optical and magnetic properties have been investigated, and density functional theory calculations of Ia and IIa have also been performed. PMID- 25790300 TI - Coping with stress and the emergence of multidrug resistance in fungi. PMID- 25790302 TI - Triboelectric generators and sensors for self-powered wearable electronics. AB - In recent years, the field of wearable electronics has evolved at a rapid pace, requiring continued innovation in technologies in the fields of electronics, energy devices, and sensors. In particular, wearable devices have multiple applications in healthcare monitoring, identification, and wireless communications, and they are required to perform well while being lightweight and having small size, flexibility, low power consumption, and reliable sensing performances. In this Perspective, we introduce two recent reports on the triboelectric generators with high-power generation achieved using flexible and lightweight textiles or miniaturized and hybridized device configurations. In addition, we present a brief overview of recent developments and future prospects of triboelectric energy harvesters and sensors, which may enable fully self powered wearable devices with significantly improved sensing capabilities. PMID- 25790303 TI - "Mortui vivos docent" or who gives his body to science? The analysis of the personal questionnaires of Polish donors in the Conscious Body Donation Program. AB - The Conscious Body Donation Program conducted since 2003 by the Department of Human Anatomy, Medical University of Silesia in Katowice was the first innovative project aimed at obtaining informed donors' bodies for the purpose of teaching anatomy in Poland. The aim of this prospective study was to determine the declared donors' characteristics and to establish the possible motivation for body donation. A total of 244 application files were reviewed and the following information was analyzed: donor's age, age at which the decision to donate the body was made, donor's place of residence and declared nationality, family background, education and profession, family structure and religion. Our results showed that mainly elderly people decided to donate their bodies (68.5 +/- 11.84 years), living mostly in large and medium-sized cities. Men--donors often lived in small towns. Most of the donors were of blue-collar parentage, completed secondary education and at the time of taking decision to donate where married and retired. Widows were more likely to make the decision to donate than widowers. Most of our donors were Catholic. Our analysis of the profile of Polish donors may be useful to understand better for which groups of people death is not to be perceived as the end, and may become a value, which can be beneficial to living people. PMID- 25790304 TI - Specificity protein 1 transcription factor regulates human ARTS promoter activity through multiple binding sites. AB - Apoptosis-related protein in the TGF-beta signaling pathway (ARTS) is an unusual mitochondrial Septin-like protein which functions as a tumor suppressor. There are various splice variants derived from the human Septin4 gene, one of which is ARTS, also known as Septin4_i2. Unlike other Septin4 members, ARTS can induce apoptosis in many cells, however, the underlying molecular mechanism for the transcriptional regulation of ARTS has yet to be deciphered. In this study, we attempted to analyze the promoter region of ARTS in cultured HEK-293T and LX-2 cells with the purpose of elucidating the underlying transcriptional mechanisms driving ARTS expression. We effectively demonstrated that the -824 to -5 bp region of the ARTS promoter was essential for ARTS transcription and identified four putative specificity protein 1 (Sp1) binding sites within this core promoter region. ChIP analysis showed that Sp1 protein could bind to two of these sites ( 735/-718 and -173/-157) and mutation of each Sp1 binding site led to a significant decrease in ARTS promoter activity. In conclusion, all the results indicated that the Sp1 transcription factor could contribute to ARTS gene transcription. The underlying molecular events of the specific promoter of ARTS could also be used to explain why ARTS is selectively silenced during some human diseases. This would provide basis for further study on the function of ARTS on cell apoptosis. PMID- 25790305 TI - Surveillance and clinical characterization of influenza in a university cohort in Singapore. AB - BACKGROUND: Southeast Asia is a potential locus for the emergence of novel influenza strains. However, information on influenza within the region is limited. OBJECTIVES: This study was to determine the proportion of influenza-like illness (ILI) caused by influenza A and B viruses in a university cohort in Singapore, identify important distinctive clinical features of influenza infection and potential factors associated with influenza infection compared with other causes of ILI. METHODOLOGY: A surveillance study was conducted from 2007 to 2009, at the University Health and Wellness Centre, National University of Singapore (NUS). Basic demographic information and nasopharyngeal swabs were collected from consenting students and staff with ILI, with Influenza A and B identified by both culture and molecular methods. RESULTS: Proportions of influenza A and B virus infections in subjects with ILI were 153/500 (30.6%) and 11/500 (2.2%) respectively. The predominant subtype was A/H1N1, including both the seasonal strain (20/153) and the pandemic strain (72/153). The clinical symptom of fever was more common in subjects with laboratory confirmed influenza than other ILIs. On-campus hostel residence and being a student (compared with staff) were associated with increased risk of laboratory confirmed influenza A/H1N1 2009 infection. CONCLUSIONS: This study provides a baseline prevalence of influenza infection within young adults in Singapore in a university setting. Potential risk factors, such as hostel residence, were identified, allowing for more targeted infection control measures in the event of a future influenza pandemic. PMID- 25790306 TI - Development of a prototype over-actuated biomimetic prosthetic hand. AB - The loss of a hand can greatly affect quality of life. A prosthetic device that can mimic normal hand function is very important to physical and mental recuperation after hand amputation, but the currently available prosthetics do not fully meet the needs of the amputee community. Most prosthetic hands are not dexterous enough to grasp a variety of shaped objects, and those that are tend to be heavy, leading to discomfort while wearing the device. In order to attempt to better simulate human hand function, a dexterous hand was developed that uses an over-actuated mechanism to form grasp shape using intrinsic joint mounted motors in addition to a finger tendon to produce large flexion force for a tight grip. This novel actuation method allows the hand to use small actuators for grip shape formation, and the tendon to produce high grip strength. The hand was capable of producing fingertip flexion force suitable for most activities of daily living. In addition, it was able to produce a range of grasp shapes with natural, independent finger motion, and appearance similar to that of a human hand. The hand also had a mass distribution more similar to a natural forearm and hand compared to contemporary prosthetics due to the more proximal location of the heavier components of the system. This paper describes the design of the hand and controller, as well as the test results. PMID- 25790307 TI - Transcriptomic analysis of the underground renewal buds during dormancy transition and release in 'Hangbaishao' peony (Paeonia lactiflora). AB - Paeonia lactiflora is one of the most famous species of herbaceous peonies with gorgeous flowers. Bud dormancy is a crucial developmental process that allows P. lactiflora to survive unfavorable environmental conditions. However, little information is available on the molecular mechanism of the bud dormancy in P. lactiflora. We performed de novo transcriptome sequencing using the Illumina RNA sequencing platform for the underground renewal buds of P. lactiflora 'Hangbaishao' to study the molecular mechanism underlying its bud dormancy transition (the period from endodormancy to ecodormancy) and release (the period from ecodormancy to bud elongation and sprouting). Approximately 300 million high quality clean reads were generated and assembled into 207,827 (mean length = 828 bp) and 51,481 (mean length = 1250 bp) unigenes using two assembly methods named "Trinity" and "Trinity+PRICE", respectively. Based on the data obtained by the latter method, 32,316 unigenes were annotated by BLAST against various databases. Approximately 1,251 putative transcription factors were obtained, of which the largest number of unique transcripts belonged to the basic helix-loop-helix protein (bHLH) transcription factor family, and five of the top ten highly expressed transcripts were annotated as dehydrin (DHN). A total of 17,705 simple sequence repeat (SSR) motifs distributed in 13,797 sequences were obtained. The budbreak morphology, levels of indole-3-acetic acid (IAA) and abscisic acid (ABA), and activities of guaiacol peroxidase (POD) and catalase (CAT) were observed. The expression of 20 interested unigenes, which annotated as DHN, heat shock protein (HSP), histone, late elongated hypocotyl (LHY), and phytochrome (PHY), and so on, were also analyzed. These studies were based on morphological, physiological, biochemical, and molecular levels and provide comprehensive insight into the mechanism of dormancy transition and release in P. lactiflora. Transcriptome dataset can be highly valuable for future investigation on gene expression networks in P. lactiflora as well as research on dormancy in other non model perennial horticultural crops of commercial significance. PMID- 25790309 TI - Modeling forest fire occurrences using count-data mixed models in Qiannan autonomous prefecture of Guizhou province in China. AB - Forest fires can cause catastrophic damage on natural resources. In the meantime, it can also bring serious economic and social impacts. Meteorological factors play a critical role in establishing conditions favorable for a forest fire. Effective prediction of forest fire occurrences could prevent or minimize losses. This paper uses count data models to analyze fire occurrence data which is likely to be dispersed and frequently contain an excess of zero counts (no fire occurrence). Such data have commonly been analyzed using count data models such as a Poisson model, negative binomial model (NB), zero-inflated models, and hurdle models. Data we used in this paper is collected from Qiannan autonomous prefecture of Guizhou province in China. Using the fire occurrence data from January to April (spring fire season) for the years 1996 through 2007, we introduced random effects to the count data models. In this study, the results indicated that the prediction achieved through NB model provided a more compelling and credible inferential basis for fitting actual forest fire occurrence, and mixed-effects model performed better than corresponding fixed effects model in forest fire forecasting. Besides, among all meteorological factors, we found that relative humidity and wind speed is highly correlated with fire occurrence. PMID- 25790308 TI - Characterization and phylogenetic analysis of the mitochondrial genome of Shiraia bambusicola reveals special features in the order of pleosporales. AB - Shiraia bambusicola P. Henn. is a pathogenic fungus of bamboo, and its fruiting bodies are regarded as folk medicine. We determined and analyzed its complete mitochondrial DNA sequence (circular DNA molecule of 39,030 bp, G + C content of 25.19%). It contains the typical genes encoding proteins involved in electron transport and coupled oxidative phosphorylation (nad1-6 and nad4L, cob and cox1 3), one ATP synthase subunit (atp6), 4 hypothetical proteins, and two genes for large and small rRNAs (rnl and rns). There is a set of 32 tRNA genes comprising all 20 amino acids, and these genes are evenly distributed on the two strands. Phylogenetic analyses based on concatenated mitochondrial proteins indicated that S. bambusicola clustered with members of the order Pleosporales, which is in agreement with previous results. The gene arrangements of Dothideomycetes species contained three regions of gene orders partitioned in their mitochondrial genomes, including block 1 (nad6-atp6), block 2 (nad1-cox3) and block 3 (genes around rns). S. bambusicola displayed unique special features that differed from the other Pleosporales species, especially in the coding regions around rns (trnR trnY). Moreover, a comparison of gene orders in mitochondrial genomes from Pezizomycotina revealed that although all encoded regions are located on the same strand in most Pezizomycotina mtDNAs, genes from Dothideomycetes species had different orientations, as well as diverse positions and colocalization of genes (such as cox3, cox1-cox2 and nad2-nad3); these distinctions were regarded as class-specific features. Interestingly, two incomplete copies of the atp6 gene were found on different strands of the mitogenomic DNA, a finding that has not been observed in the other analyzed fungal species. In our study, mitochondrial genomes from Dothideomycetes species were comprehensively analyzed for the first time, including many species that have not appeared in previous reports. PMID- 25790310 TI - Time to resize the role of liver transplant for Budd-Chiari syndrome. PMID- 25790311 TI - Photochemistry of the permanganate ion in low-temperature frozen matrices. AB - Photolysis of the permanganate anion, MnO4(-), in tetralkylammonium tetrafluoroborate matrices at 85 K results in formation of a single product, the metastable manganese(V) peroxo complex MnO2(eta(2)-O2)(-). Although previously unobserved, this peroxo species has been postulated to be an intermediate in the photodecomposition of permanganate, yielding O2 and MnO2(-). Results from variable-temperature and intensity-dependence photolysis experiments in solution, however, suggest that MnO2(eta(2)-O2)(-) does not lose O2 thermally or photochemically and is not an intermediate in the photodecomposition reaction. A mechanism is proposed in which MnO2(eta(2)-O2)(-) is formed through vibrational relaxation of an excited [MnO4(-)]* species, which may also follow an alternative relaxation pathway that results in the formation of MnO2(-) and O2 photodecomposition products. PMID- 25790312 TI - Neglected tropical disease control and elimination: is human displacement an Achilles heel? PMID- 25790313 TI - General anaesthesia vs. spinal anaesthesia for total hip arthroplasty. PMID- 25790314 TI - Mildly Reduced Brain Swelling and Improved Neurological Outcome in Aquaporin-4 Knockout Mice following Controlled Cortical Impact Brain Injury. AB - Brain edema following traumatic brain injury (TBI) is associated with considerable morbidity and mortality. Prior indirect evidence has suggested the involvement of astrocyte water channel aquaporin-4 (AQP4) in the pathogenesis of TBI. Here, focal TBI was produced in wild type (AQP4(+/+)) and knockout (AQP4(-/ )) mice by controlled cortical impact injury (CCI) following craniotomy with dura intact (parameters: velocity 4.5 m/sec, depth 1.7 mm, dwell time 150 msec). AQP4 deficient mice showed a small but significant reduction in injury volume in the first week after CCI, with a small improvement in neurological outcome. Mechanistic studies showed reduced intracranial pressure at 6 h after CCI in AQP4(-/-) mice, compared with AQP4(+/+) control mice (11 vs. 19 mm Hg), with reduced local brain water accumulation as assessed gravimetrically. Transmission electron microscopy showed reduced astrocyte foot-process area in AQP4(-/-) mice at 24 h after CCI, with greater capillary lumen area. Blood-brain barrier disruption assessed by Evans blue dye extravasation was similar in AQP4(+/+) and AQP4(-/-) mice. We conclude that the mildly improved outcome in AQP4(-/-) mice following CCI results from reduced cytotoxic brain water accumulation, though concurrent cytotoxic and vasogenic mechanisms in TBI make the differences small compared to those seen in disorders where cytotoxic edema predominates. PMID- 25790316 TI - Sterile endophthalmitis after intravitreal ocriplasmin injection: report of a single case. AB - PURPOSE: To report a case of presumed sterile endophthalmitis after intravitreal ocriplasmin injection. METHODS: Observational case report. Review of clinical examination, ocular imaging, and published literature. RESULTS: A 67-year-old woman with early cataracts presented with decreased vision in the left eye related to vitreomacular adhesion. She was treated with intravitreal ocriplasmin injection and developed a severe anterior chamber inflammatory reaction in less than 24 hours after the injection. Inflammation responded completely to topical steroids alone, without topical or intravitreal antibiotics. CONCLUSION: Patients treated with intravitreal ocriplasmin may develop an acute inflammatory reaction, which can be severe. PMID- 25790315 TI - Endothelial cell dynamics during anastomosis in vitro. AB - Vascular anastomosis - the fusion of vessels from two distinct branches of the vascular system - represents a critical step in vascular growth under both healthy and pathological conditions, in vivo, and presents an important target for engineering of vascularized tissues, in vitro. Recent works in animal models have advanced our understanding of the molecular and cellular players in vascular anastomosis, but questions remain related to cellular dynamics and control of this process, in vitro. In this study, we exploited a three-dimensional (3-D) culture platform to examine the dynamics of endothelial cell (EC) during and after vascular anastomosis by allowing angiogenesis and vasculogenesis to proceed in parallel. We show that anastomosis occurs between sprouts formed by angiogenesis from an endothelium and tubes formed by vasculogenesis in the bulk of a 3-D matrix. This fusion leads to highly connected vessels that span from the surface of the matrix into the bulk in a manner that depends on cell density and identity. Further, we observe and analyze intermixing of endothelial cells of distinct origin (surface versus bulk) within the vessels structures that are formed; we provide evidence that the cells migrate along pre-existing vessels segments as part of this intermixing process. We conclude that anastomosis can occur between vessels emerging by angiogenesis and vasculogenesis and that this process may play an important role in contexts such as wound healing. PMID- 25790317 TI - Multifocal choroiditis and panuveitis presenting with progressive equatorial linear streaks: evolution of Schlaegel lines documented with multimodal imaging. AB - PURPOSE: To describe the progressive, peripheral linear streaks of the equatorial retina, known as Schlaegel lines, in multifocal choroiditis and panuveitis (MCP). METHODS: A case report of a 13-year-old girl with MCP showed progression of retinal linear streaks. Extensive systemic and ophthalmologic investigations were performed. RESULTS: Linear streaks in MCP showed progression before the institution of immunomodulatory treatment. Infrared imaging showed hyperreflectivity of the lesions with surrounding hyporeflectivity. Optical coherence tomography showed elevated and irregular hyperreflectivity of the retinal pigment epithelium and choroidal hyperreflectivity. These findings, including the clinical progression before immunomodulatory therapy and negative systemic evaluation for infectious entities, are consistent with MCP. CONCLUSION: Patients with linear streaks in the setting of atypical MCP can progress and should be treated with adequate systemic corticosteroids and immunomodulatory agents. This case is unique in that it shows the evolution of Schlaegel lines using a multimodal imaging approach. Multimodal imaging can provide ancillary evidence of disease activity. PMID- 25790318 TI - Central serous chorioretinopathy treatment with spironolactone: a challenge rechallenge case. AB - PURPOSE: To present a case of central serous chorioretinopathy (CSC) treatment with spironolactone in a challenge-rechallenge pattern. METHODS: At presentation, fundus photography, fluorescein angiography, spectral domain optical coherence tomography, and enhanced depth imaging ocular coherence tomography were performed in both eyes. The patient was prescribed 25 mg spironolactone daily along with serum potassium monitoring. At follow-ups, spectral domain optical coherence tomography and enhanced depth imaging ocular coherence tomography were performed. RESULTS: A 37-year-old white male accountant presenting with CSC. Spironolactone treatment resolved the CSC. After the patient discontinued treatment, it returned. After returning to daily treatment, the CSC again resolved. CONCLUSION: Spironolactone was an effective treatment of CSC in this case. Other groups have reported similar findings with eplerenone, a similar drug. PMID- 25790319 TI - Bilateral choroidal osteoma: visual acuity at 45-year follow-up. AB - PURPOSE: To report a case of bilateral choroidal osteoma, which demonstrated different visual outcomes in both eyes over a long follow-up of 45 years. METHODS: Case report. RESULTS: After 45 years of follow-up, choroidal osteoma showed slight enlargement in each eye and choroidal neovascularization and retinal pigment epithelium (RPE) changes had developed in the right eye. Visual acuity of the right eye was decreased to 20/200 from macular RPE loss and choroidal neovascularization scarring. The left eye preserved a visual acuity of 20/30 where choroidal osteoma demonstrated only partial decalcification of the nasal margin with preservation of RPE in the macular region. Spectral domain optical coherence tomography of the right macula confirmed broad RPE and choroidal atrophy and scarring related to previous choroidal neovascularization. Spectral domain optical coherence tomography of the left macula showed preserved retinal layers and RPE with underlying calcified choroidal osteoma. CONCLUSION: Choroidal osteoma can occasionally demonstrate intact calcification, preserved RPE, and photoreceptors with excellent vision. PMID- 25790320 TI - Catheter Ablation of Atrial Fibrillation Using Zero-Fluoroscopy Technique: A Randomized Trial. AB - BACKGROUND: Recent advances in 3D mapping systems, such as simultaneous visualization of multiple catheters and contact force measurement, have allowed a significant reduction in fluoroscopic times during radiofrequency (RF) ablation (RFA) procedures. The objective was to investigate whether RFA of paroxysmal atrial fibrillation (PAF) using the CARTO 3 system (Biosense Webster, Diamond Bar, CA, USA) and intracardiac echocardiography (ICE) can be performed safely without fluoroscopy. METHODS AND RESULTS: Eighty patients with PAF were randomized in a 1:1 ratio to undergo either fluoroscopically guided pulmonary vein isolation (PVI) (X+) or PVI without fluoroscopy (X-). In the X- fluoroscopy group, catheter placement, transseptal puncture, left atrial geometry reconstruction, and PVI were accomplished solely using ICE imaging and CARTO mapping. The total procedure duration and RF application time in both the X- and X+ groups were comparable (92.5 +/- 22.9 minutes vs 99.9 +/- 15.9 minutes, P = 0.11 and 1785 +/- 548 seconds vs 1755 +/- 450 seconds, P = 0.79, respectively). Zero fluoroscopic time was achieved in all patients in the X- group with the exception of one patient, where 8 seconds of fluoroscopy was needed to assess proper position of the guide-wire in the femoral vein. No serious procedure related complications were recorded and no differences in arrhythmia-free survival at 12 months were found between the groups. CONCLUSION: RFA using ICE imaging and the CARTO 3 mapping system with contact force measurement is capable of eliminating fluoroscopy in patients undergoing PVI. Exclusion of fluoroscopic imaging does not seem to compromise patient safety and does not affect overall procedure duration, RF application time, or mid-term efficacy. PMID- 25790321 TI - Being and feeling liked by others: how social inclusion impacts health. AB - This study examined the effects of perceived and actual social inclusion on health across and within individuals from a network perspective. During the first semester, 75 freshmen students provided bi-weekly ratings on their perceived social inclusion and health. To capture actual social inclusion, each student nominated liked and disliked fellow students. Perceived social inclusion mediated the effect of actual social inclusion on health. Specifically, students with more 'likes' perceived more social inclusion and those with higher perceived inclusion reported a better health status (between-person effect). In addition, at time points, when students received more 'likes' they also perceived more social inclusion. They reported better health at times when they felt more included (within-person effect). Thus, the perception of social inclusion is rooted in reality and actual social inclusion has an impact on health when passing the filter of perception. PMID- 25790322 TI - Fortification of foods with vitamin D in India: strategies targeted at children. AB - Vitamin D deficiency is endemic in India, despite abundant sunshine, due to several socioeconomic and cultural constraints. Fortification of staple foods with vitamin D is a viable population-based strategy for the general population in India. These strategies are discussed in the review article entitled, "Fortification of Foods With Vitamin D in India" [1]. The quantity of foods consumed by children is much smaller compared to adults. Therefore, children need energy-dense and micronutrient-dense foods to meet their daily nutritional requirements. Targeted food fortification programs are needed to meet the special needs of children. This review explores potential strategies that could be used for fortification of foods with vitamin D for children in India. Sattu has the potential to be a valuable vehicle for vitamin D fortification in India. The salient characteristics and merits of sattu as an ideal food to be fortified with micronutrients, especially vitamin D, are reviewed here. Key teaching points: * Fortification of foods with vitamin D, specifically targeted towards the nutritional requirements of infants and children, is a viable strategy in the Indian scenario. *Government programs targeting the nutritional needs of children in India, especially via midday meal programs in schools, should incorporate indigenous ready-to-eat foods fortified with micronutrients including vitamin D. These foods would need to have longer shelf life, require minimal preparation, and have economic and technological feasibility. * Sattu, a protein rich Indian fast food, comprised of roasted flour made from cereals and legumes, has immense potential to serve as an economically and technologically feasible fortification vehicle for vitamin D fortification strategies. PMID- 25790323 TI - Review of X-linked syndromes with arthrogryposis or early contractures-aid to diagnosis and pathway identification. AB - The following is a review of 50 X-linked syndromes and conditions associated with either arthrogryposis or other types of early contractures. These entities are categorized as those with known responsible gene mutations, those which are definitely X-linked, but the responsible gene has not been identified, and those suspected from family history to be X-linked. Several important ontology pathways for known disease genes have been identified and are discussed in relevance to clinical characteristics. Tables are included which help to identify distinguishing clinical features of each of the conditions. PMID- 25790324 TI - Preparation of nitrogen-doped carbon nanotubes with different morphologies from melamine-formaldehyde resin. AB - We report a facile method for the synthesis of nitrogen-doped carbon nanotubes (NCNTs) from melamine-formaldehyde (MR) resin using FeCl3 or supported FeCl3 as catalysts. The growth of NCNTs follows a decomposition-reconstruction mechanism, in which the polymer precursor would totally gasify during pyrolysis process and then transformed into carbon nanotubes. The morphology of the NCNTs could be adjusted via applying different catalyst supports and three kinds of carbon nanotubes with outer-diameter of 20-200 nm and morphologies of either bamboo-like or hollow interiors were obtained. Nitrogen atoms in the materials were mainly in the form of pyridinic and quaternary form while the formation of iron species strongly depended on the interaction between iron precursor and organic carbon/nitrogen sources. All MR resin derived NCNTs are efficient toward oxygen reduction reaction (ORR). NCNTs prepared using FeCl3 as catalyst showed the highest ORR activity with half-wave potentials of -0.17 V, which is comparable with commercial Pt/C. This is probably because of a close contact between MR resin and iron precursor could enhance the iron-ligand coordination strength and thus steadily improve the performance of the catalyst. PMID- 25790325 TI - Use of a dual lumen port for automated red cell exchange in adults with sickle cell disease. AB - Red cell exchange (RCE) is a common procedure in adults with sickle cell disease (SCD). Implantable dual lumen Vortex (DLV) ports can be used for RCE in patients with poor peripheral venous access. We performed a retrospective cohort study of RCE procedures performed in adults with SCD. The main objective of the study was to compare the inlet speed, duration of procedures and rate of complications performed through DLV ports to those performed through temporary central venous and peripheral catheters. Twenty-nine adults with SCD underwent a total of 318 RCE procedures. Twenty adults had DLV ports placed and 218 procedures were performed using DLV ports. Mean length of follow-up after DLV port placement was 397 +/- 263 days. Six DLV ports were removed due to infection and 1 for malfunction after a mean of 171 +/- 120 days. Compared to temporary central venous and peripheral catheters, DLV port procedures had a greater rate of procedural complications, a longer duration, and a lower inlet speed (all P < 0.01). When accounting for the maximum allowable inlet speed to avoid citrate toxicity, 40% of DLV port procedures were greater than 10% below maximum speed, compared to 7 and 14% of procedures performed through temporary central venous and peripheral catheters (P < 0.0001). In conclusion, DLV ports can be used for RCE in adults with SCD, albeit with more procedural complications and longer duration. The smaller internal diameter and longer catheter of DLV ports compared to temporary central venous catheters likely accounts for the differences noted. PMID- 25790326 TI - Endoscopic or surgical intervention for painful obstructive chronic pancreatitis. AB - BACKGROUND: Endoscopy and surgery are the treatment modalities of choice for patients with chronic pancreatitis and dilated pancreatic duct (obstructive chronic pancreatitis). Physicians face, without clear consensus, the choice between endoscopy or surgery for this group of patients. OBJECTIVES: To assess and compare the effects and complications of surgical and endoscopic interventions in the management of pain for obstructive chronic pancreatitis. SEARCH METHODS: We searched the following databases in The Cochrane Library: CENTRAL (2014, Issue 2), the Cochrane Database of Systematic Reviews (2014, Issue 2), and DARE (2014, Issue 2). We also searched the following databases up to 25 March 2014: MEDLINE (from 1950), Embase (from 1980), and the Conference Proceedings Citation Index - Science (CPCI-S) (from 1990). We performed a cross reference search. Two review authors independently performed the selection of trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) of endoscopic or surgical interventions in obstructive chronic pancreatitis. We included trials comparing endoscopic versus surgical interventions as well as trials comparing either endoscopic or surgical interventions to conservative treatment (i.e. non invasive treatment modalities). We included relevant trials irrespective of blinding, the number of participants randomised, and the language of the article. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two authors independently extracted data from the articles. We evaluated the methodological quality of the included trials and requested additional information from study authors in the case of missing data. MAIN RESULTS: We identified three eligible trials. Two trials compared endoscopic intervention with surgical intervention and included a total of 111 participants: 55 in the endoscopic group and 56 in the surgical group. Compared with the endoscopic group, the surgical group had a higher proportion of participants with pain relief, both at middle/long-term follow-up (two to five years: risk ratio (RR) 1.62, 95% confidence interval (CI) 1.22 to 2.15) and long-term follow-up (>= five years, RR 1.56, 95% CI 1.18 to 2.05). Surgical intervention resulted in improved quality of life and improved preservation of exocrine pancreatic function at middle/long-term follow-up (two to five years), but not at long-term follow-up (>= 5 years). No differences were found in terms of major post interventional complications or mortality, although the number of participants did not allow for this to be reliably evaluated. One trial, including 32 participants, compared surgical intervention with conservative treatment: 17 in the surgical group and 15 in the conservative group. The trial showed that surgical intervention resulted in a higher percentage of participants with pain relief and better preservation of pancreatic function. The trial had methodological limitations, and the number of participants was relatively small. AUTHORS' CONCLUSIONS: For patients with obstructive chronic pancreatitis and dilated pancreatic duct, this review shows that surgery is superior to endoscopy in terms of pain relief. Morbidity and mortality seem not to differ between the two intervention modalities, but the small trials identified do not provide sufficient power to detect the small differences expected in this outcome.Regarding the comparison of surgical intervention versus conservative treatment, this review has shown that surgical intervention in an early stage of chronic pancreatitis is a promising approach in terms of pain relief and pancreatic function. Other trials need to confirm these results because of the methodological limitations and limited number of participants assessed in the present evidence. PMID- 25790327 TI - Subjective visual vertical and postural capability in children born prematurely. AB - PURPOSE: We compared postural stability and subjective visual vertical performance in a group of very preterm-born children aged 3-4 years and in a group of age-matched full-term children. MATERIALS AND METHODS: A platform (from TechnoConcept) was used to measure postural control in children. Perception of subjective visual vertical was also recorded with posture while the child had to adjust the vertical in the dark or with visual perturbation. Two other conditions (control conditions) were also recorded while the child was on the platform: for a fixation of the vertical bar, and in eyes closed condition. RESULTS: Postural performance was poor in preterm-born children compared to that of age-matched full-term children: the surface area, the length in medio-lateral direction and the mean speed of the center of pressure (CoP) were significantly larger in the preterm-born children group (p < 0.04, p < 0.01, and p < 0.04, respectively). Dual task in both groups of children significantly affected postural control. The subjective visual vertical (SVV) values were more variable and less precise in preterm-born children. DISCUSSION-CONCLUSIONS: We suggest that poor postural control as well as perception of verticality observed in preterm-born children could be due to immaturity of the cortical processes involved in the motor control and in the treatment of perception and orientation of verticality. PMID- 25790329 TI - Selective synthesis of alkylboronates by copper(I)-catalyzed borylation of allyl or vinyl arenes. AB - An efficient copper-catalyzed borylation reaction of allyl or vinyl arenes with bis(pinacolato)diboron has been developed, without using ligands. Markovnikov selectivity is observed in the borylation of allyl arenes with bis(pinacolato)diboron, while the regioselectivity is completely opposite when styrene derivatives are used as substrates. A mechanism involving Cu-B species regioselectively adding olefin double bonds to form the alkylcopper or eta(3) benzyl copper intermediate, which is followed by protonation to obtain products, is proposed. PMID- 25790328 TI - Resveratrol does not influence metabolic risk markers related to cardiovascular health in overweight and slightly obese subjects: a randomized, placebo controlled crossover trial. AB - BACKGROUND: In vitro and animal studies have shown positive effects of resveratrol on lipid and lipoprotein metabolism, but human studies specifically designed to examine these effects are lacking. OBJECTIVE: The primary outcome parameter of this study in overweight and slightly obese subjects was the effect of resveratrol on apoA-I concentrations. Secondary outcome parameters were effects on other markers of lipid and lipoprotein metabolism, glucose metabolism, and markers for inflammation and endothelial function. DESIGN: This randomized, placebo-controlled crossover study was conducted in 45 overweight and slightly obese men (n = 25) and women (n = 20) with a mean age of 61 +/- 7 years. Subjects received in random order resveratrol (150 mg per day) or placebo capsules for 4 weeks, separated by a 4-week wash-out period. Fasting blood samples were collected at baseline and at the end of each intervention period. RESULTS: Compliance was excellent as indicated by capsule count and changes in resveratrol and dihydroresveratrol concentrations. No difference between resveratrol and placebo was found in any of the fasting serum or plasma metabolic risk markers (mean +/- SD for differences between day 28 values of resveratrol vs. placebo: apoA-I; 0.00 +/- 0.12 g/L (P = 0.791), apoB100; -0.01 +/- 0.11 g/L (P = 0.545), HDL cholesterol; 0.00 +/- 0.09 mmol/L (P = 0.721), LDL cholesterol -0.03 +/- 0.57 mmol/L (P = 0.718), triacylglycerol; 0.10 +/- 0.54 mmol/L (P = 0.687), glucose; 0.08 +/- 0.28 mmol/L (P = 0.064), insulin; -0.3 +/- 2.5 mU/L (P = 0.516)). Also, no effects on plasma markers for inflammation and endothelial function were observed. No adverse events related to resveratrol intake were observed. CONCLUSION: 150 mg of daily resveratrol intake for 4 weeks does not change metabolic risk markers related to cardiovascular health in overweight and slightly obese men and women. Effects on glucose metabolism warrant further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01364961. PMID- 25790330 TI - UV spectroscopy of cold ions as a probe of the protonation site. AB - The best determination of the most stable protonation site in aromatic molecules relies nowadays on the IR spectroscopy and ab initio calculations. It appears that these methods are not necessarily unambiguous and cannot always be safely employed. We present in this paper an example showing that electronic spectroscopy of cold ions complemented with ab initio calculations gives clear results on the protonation site. In the example given on the aminophenol isomers (in ortho, meta and para positions), the protonation site is assigned from the electronic spectroscopy and in particular we show that for the meta isomer the proton is not on the amino group as observed for the other isomers. It shows also that the protonation site is not conserved in the electrospray evaporation ionization process. PMID- 25790331 TI - Birth weight and polycystic ovary syndrome in adult life: is there a causal link? AB - OBJECTIVES: Several studies have demonstrated associations of birth weight with metabolic and reproductive abnormalities in adults. The aim of this study was to investigate the birth weight in women with PCOS and its correlation with clinical and biochemical characteristics of the syndrome. MATERIALS AND METHODS: We studied 288 women with PCOS according to the NIH criteria and 166 women with normal cycle and without clinical hyperandrogenism. Birth weight and anthropometric characteristics were recorded, and levels of serum androgens, SHBG, insulin and fasting glucose were measured. RESULTS: Birth weight data were available for 243/288 women with PCOS and age- and BMI-matched 101/166 controls. No differences were found (p> 0.05) in birth weight among women with PCOS and normal controls. Birth weight of PCOS women was negatively correlated with DHEAS levels (p = 0.031, r = -0.143) and positively correlated with waist circumference (p <0.001, r = 0.297) and body mass index (BMI) (p = 0.040, r = 0.132). Birth weight of controls was negatively correlated with SHBG levels (p = 0.021, r = 0.234). Women from both groups were further divided in 6 categories according to birth weight (A. <2.500 gr, B. 2.501-3.000 gr, C. 3.001-3.500 gr, D. 3.501-4.000 gr, E. 4.001-4.500 gr, F. > 4.500 gr). No statistically significant differences were observed in the distribution percentages between PCOS women and controls. (A. 7% vs 7.9%, B. 26.8% vs 20.8%, C. 39.1% vs 48.5%, D. 21.4% vs 20.8%, E. 4.9% vs 2%, F. 0.8% vs 0%), (in all comparisons, p> 0.05). CONCLUSIONS: Women with PCOS do not differ from controls in birth weight distribution. However, birth weight may contribute to subtypes of the syndrome that are characterized by adrenal hyperandrogenism and central obesity. PMID- 25790332 TI - Apolipoprotein AI deficiency inhibits serum opacity factor activity against plasma high density lipoprotein via a stabilization mechanism. AB - The reaction of Streptococcal serum opacity factor (SOF) against plasma high density lipoproteins (HDL) produces a large cholesteryl ester-rich microemulsion (CERM), a smaller neo HDL that is apolipoprotein (apo) AI-poor, and lipid-free apo AI. SOF is active versus both human and mouse plasma HDL. In vivo injection of SOF into mice reduces plasma cholesterol ~40% in 3 h while forming the same products observed in vitro, but at different ratios. Previous studies supported the hypothesis that labile apo AI is required for the SOF reaction vs HDL. Here we further tested that hypothesis by studies of SOF against HDL from apo AI-null mice. When injected into apo AI-null mice, SOF reduced plasma cholesterol ~35% in 3 h. The reaction of SOF vs apo AI-null HDL in vitro produced a CERM and neo HDL, but no lipid-free apo. Moreover, according to the rate of CERM formation, the extent and rate of the SOF reaction versus apo AI-null mouse HDL were less than that against wild-type (WT) mouse HDL. Chaotropic perturbation studies using guanidine hydrochloride showed that apo AI-null HDL was more stable than WT HDL. Human apo AI added to apo AI-null HDL was quantitatively incorporated, giving reconstituted HDL. Both SOF and guanidine hydrochloride displaced apo AI from the reconstituted HDL. These results support the conclusion that apo AI-null HDL is more stable than WT HDL because it lacks apo AI, a labile protein that is readily displaced by physicochemical and biochemical perturbations. Thus, apo AI-null HDL is less SOF-reactive than WT HDL. The properties of apo AI-null HDL can be partially restored to those of WT HDL by the spontaneous incorporation of human apo AI. It remains to be determined what other HDL functions are affected by apo AI deletion. PMID- 25790333 TI - Persistence of pristine deep-sea coral gardens in the Mediterranean Sea (SW Sardinia). AB - Leiopathes glaberrima is a tall arborescent black coral species structuring important facies of the deep-sea rocky bottoms of the Mediterranean Sea that are severely stifled by fishing activities. At present, however, no morphological in vivo description, ecological characterization, age dating and evaluation of the possible conservation actions have ever been made for any population of this species in the basin. A dense coral population was reported during two Remotely Operated Vehicle (ROV) surveys conducted on a rocky bank off the SW coasts of Sardinia (Western Mediterranean Sea). L. glaberrima forms up to 2 m-tall colonies with a maximal observed basal diameter of nearly 7 cm. The radiocarbon dating carried out on a colony from this site with a 4 cm basal diameter revealed an approximately age of 2000 years. Considering the size-frequency distribution of the colonies in the area it is possible to hypothesize the existence of other millennial specimens occupying a supposedly very stable ecosystem. The persistence of this ecosystem is likely guaranteed by the heterogeneous rocky substrate hosting the black coral population that represents a physical barrier against the mechanical impacts acted on the surrounding muddy areas, heavily exploited as trawling fishing grounds. This favorable condition, together with the existence of a nursery area for catsharks within the coral ramifications and the occurrence of a meadow of the now rare soft bottom alcyonacean Isidella elongata in small surviving muddy enclaves, indicates that this ecosystem have to be considered a pristine Mediterranean deep-sea coral sanctuary that would deserve special protection. PMID- 25790335 TI - Electrostatic swelling of bicontinuous cubic lipid phases. AB - Lipid bicontinuous cubic phases have attracted enormous interest as bio compatible scaffolds for use in a wide range of applications including membrane protein crystallisation, drug delivery and biosensing. One of the major bottlenecks that has hindered exploitation of these structures is an inability to create targeted highly swollen bicontinuous cubic structures with large and tunable pore sizes. In contrast, cubic structures found in vivo have periodicities approaching the micron scale. We have been able to engineer and control highly swollen bicontinuous cubic phases of spacegroup Im3m containing only lipids by (a) increasing the bilayer stiffness by adding cholesterol and (b) inducing electrostatic repulsion across the water channels by addition of anionic lipids to monoolein. By controlling the composition of the ternary mixtures we have been able to achieve lattice parameters up to 470 A, which is 5 times that observed in pure monoolein and nearly twice the size of any lipidic cubic phase reported previously. These lattice parameters significantly exceed the predicted maximum swelling for bicontinuous cubic lipid structures, which suggest that thermal fluctuations should destroy such phases for lattice parameters larger than 300 A. PMID- 25790334 TI - Understanding meal patterns: definitions, methodology and impact on nutrient intake and diet quality. AB - Traditionally, nutrition research has focused on individual nutrients, and more recently dietary patterns. However, there has been relatively little focus on dietary intake at the level of a 'meal'. The purpose of the present paper was to review the literature on adults' meal patterns, including how meal patterns have previously been defined and their associations with nutrient intakes and diet quality. For this narrative literature review, a comprehensive search of electronic databases was undertaken to identify studies in adults aged >= 19 years that have investigated meal patterns and their association with nutrient intakes and/or diet quality. To date, different approaches have been used to define meals with little investigation of how these definitions influence the characterisation of meal patterns. This review identified thirty-four and fourteen studies that have examined associations between adults' meals patterns, nutrient intakes and diet quality, respectively. Most studies defined meals using a participant-identified approach, but varied in the additional criteria used to determine individual meals, snacks and/or eating occasions. Studies also varied in the types of meal patterns, nutrients and diet quality indicators examined. The most consistent finding was an inverse association between skipping breakfast and diet quality. No consistent association was found for other meal patterns, and little research has examined how meal timing is associated with diet quality. In conclusion, an understanding of the influence of different meal definitions on the characterisation of meal patterns will facilitate the interpretation of the existing literature, and may provide guidance on the most appropriate definitions to use. PMID- 25790337 TI - Adsorption of ethanol and water on calcite: dependence on surface geometry and effect on surface behavior. AB - Molecular dynamics (MD) simulations were used to explore adsorption on calcite, from a 1:1 mixture of ethanol and water, on planar {10.4} and stepped, i.e. vicinal, surfaces. Varying the surface geometry resulted in different adsorption patterns, which would directly influence the ability of ethanol to control calcite crystal growth, dissolution, and adsorption/desorption of other ions and molecules. Ethanol forms a well-ordered adsorbed layer on planar faces and on larger terraces, such as between steps and defects, providing little chance for water, with its weaker attachment, to displace it. However, on surfaces with steps, adsorption affinity depends on the length of the terraces between the steps. Long terraces allow ethanol to form a well-ordered, hydrophobic layer, but when step density is high, ethanol adsorption is less ordered, allowing water to associate at and near the steps and even displacing pre-existing ethanol. Water adsorbed at steps forms mass transport pathways between the bulk solution and the solid surface. Our simulations confirm the growth inhibiting properties of ethanol, also explaining how certain crystal faces are more stabilized because of their surface geometry. The -O(H) functional group on ethanol forms tight bonds with calcite; the nonpolar, -CH3 ends, which point away from the surface, create a hydrophobic layer that changes surface charge, thus wettability, and partly protects calcite from precipitation and dissolution. These tricks could easily be adopted by biomineralizing organisms, allowing them to turn on and off crystal growth. They undoubtedly also play a role in the wetting properties of mineral surfaces in commercial CaCO3 manufacture, oil production, and contamination remediation. PMID- 25790336 TI - Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators. AB - A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down regulating antagonists, such as 33. Subsequent optimization and removal of the 7 hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020. PMID- 25790338 TI - Tunable transition from hydration to monomer-supported lubrication in zwitterionic monolayers revealed by molecular dynamics simulation. AB - The tribology of 2-methacryloyloxyethyl phosphorylcholine monolayers in water is studied using molecular dynamics simulations. Our results show two distinct shear regimes where the first is dominated by hydration lubrication, exhibiting near zero friction coefficients, and the second by chain-chain interactions, resembling monomer-supported lubrication. These results provide insight into the hydration lubrication mechanism - a phenomena thought to underlie the extremely efficient lubrication provided by surfaces functionalized with polyzwitterionic polymer brushes and the mammalian synovial joint. PMID- 25790339 TI - Spectroscopic and redox studies of valence-delocalized [Fe2S2](+) centers in thioredoxin-like ferredoxins. AB - Reduced forms of the C56S and C60S variants of the thioredoxin-like Clostridium pasteurianum [Fe2S2] ferredoxin (CpFd) provide the only known examples of valence delocalized [Fe2S2](+) clusters, which constitute a fundamental building block of all higher nuclearity Fe-S clusters. In this work, we have revisited earlier work on the CpFd variants and carried out redox and spectroscopic studies on the [Fe2S2](2+,+) centers in wild-type and equivalent variants of the highly homologous and structurally characterized Aquifex aeolicus ferredoxin 4 (AaeFd4) using EPR, UV-visible-NIR absorption, CD and variable-temperature MCD, and protein-film electrochemistry. The results indicate that the [Fe2S2](+) centers in the equivalent AaeFd4 and CpFd variants reversibly interconvert between similar valence-localized S = 1/2 and valence-delocalized S = 9/2 forms as a function of pH, with pKa values in the range 8.3-9.0, because of protonation of the coordinated serinate residue. However, freezing high-pH samples results in partial or full conversion from valence-delocalized S = 9/2 to valence-localized S = 1/2 [Fe2S2](+) clusters. MCD saturation magnetization data for valence delocalized S = 9/2 [Fe2S2](+) centers facilitated determination of transition polarizations and thereby assignments of low-energy MCD bands associated with the Fe-Fe interaction. The assignments provide experimental assessment of the double exchange parameter, B, for valence-delocalized [Fe2S2](+) centers and demonstrate that variable-temperature MCD spectroscopy provides a means of detecting and investigating the properties of valence-delocalized S = 9/2 [Fe2S2](+) fragments in higher nuclearity Fe-S clusters. The origin of valence delocalization in thioredoxin-like ferredoxin Cys-to-Ser variants and Fe-S clusters in general is discussed in light of these results. PMID- 25790340 TI - Can China comply with its 12th five-year plan on industrial emissions control: a structural decomposition analysis. AB - China's rapid economic growth has caused serious environmental problems, resulting in the implementation of two major measures-end-of-pipe facilities and the phasing out of backward capacity-to reduce China's industrial emissions as part of its 11th Five-Year Plan (FYP, 2006-2010). It is important to determine whether China can meet the targets set forth in its 12th FYP (2011-2015) for industrial pollution reduction using these same solutions. In this paper, structural decomposition analysis (SDA) was used to identify the contributions of the adopted measures-as well as other underlying factors-and to evaluate the feasibility of the reduction target in China's 12th FYP. Results show that the decrease in major industrial pollutant emissions achieved during the 11th FYP resulted from improved technological efficiency, including end-of-pipe abatement efficiency and pollutant generation intensity. The same measures adopted during China's 12th FYP can address the problem of industrial wastewater emissions resulting from economic growth when the economic structure is kept constant. But it may not fulfill its commitment of reducing industrial atmospheric pollutants emissions unless the economic structure and growth patterns are drastically reformed. PMID- 25790341 TI - Telomerase redux: ready for prime time? AB - By maintaining genome integrity, controlling cell proliferation, and regulating tissue homeostasis, telomerase plays a critical role in the pathology of aging and cancer. Telomerase is composed of telomerase RNA, or telomerase RNA component (TERC), which serves as a template for telomeric DNA synthesis, and a catalytic subunit, telomerase reverse transcriptase (TERT). The canonical function of TERT is the synthesis of telomeric DNA repeats and the maintenance of telomere length. Recent studies suggest that adeno-associated virus (AAV)-expressed TERT in adult mice can increase life span and health span. Because TERT physically interacts with proteins that regulate gene expression, and because TERT's expression at high levels is associated with oncogenic transformation, its synthesis needs to be carefully regulated. Due to safety concerns, transient expression of TERT mRNA may be preferred for tissue engineering and adoptive stem cell therapy. PMID- 25790343 TI - 5-Aminolevulinic acid induced protoporphyrin IX as a fluorescence marker for quantitative image analysis of high-grade dysplasia in Barrett's esophagus cellular models. AB - Early detection and treatment of high-grade dysplasia (HGD) in Barrett's esophagus may reduce the risk of developing esophageal adenocarcinoma. Confocal endomicroscopy (CLE) has shown advantages over routine white-light endoscopic surveillance with biopsy for histological examination; however, CLE is compromised by insufficient contrast and by intra- and interobserver variation. An FDA-approved PDT photosensitizer was used here to reveal morphological and textural features similar to those found in histological analysis. Support vector machines were trained using the aforementioned features to obtain an automatic and robust detection of HGD. Our results showed 95% sensitivity and 87% specificity using the optimal feature combination and demonstrated the potential for extension to a three-dimensional cell model. PMID- 25790344 TI - Carious affected dentine: its behaviour in adhesive bonding. AB - BACKGROUND: Carious affected dentine (CAD) represents a very common substrate in adhesive dentistry. Despite its ability to interact with adhesive systems, the intrinsic character of CAD leads to lower bonding compared with sound dentine, regardless of the adhesive systems used. This low bonding may be more susceptible to leakage and hydrolysis of the interface by matrix metalloproteinases (MMPs). This systematic review aimed to determine current knowledge of CAD bonding, together with bond strength and MMP inhibitors' ability to prevent hybrid layer instability. METHODS: MEDLINE/Pubmed, Scopus and The Cochrane Library databases were electronically searched for articles published from 1 January 1960 to 31 August 2014. Two reviewers independently screened and included papers according to predefined selection criteria. RESULTS: The electronic searches identified 320 studies. After title, abstract and full-text examinations, 139 articles met the inclusion criteria. Data highlighted that a poor resin saturation of the already demineralized collagen matrix in CAD is strictly related to nanoleakage in interdiffusion and is the basis of the progressive decrease in strength with hydrolysis by MMPs. The use of mild self-etching systems seems to be the more accredited method to establish bonding in CAD. Inhibitors of MMPs may ensure better performance of CAD bonding, allowing undisturbed remineralization of the affected matrix. CONCLUSIONS: CAD bonding needs further understanding and improvement, particularly to enhance the strength and durability of the hybrid layer. PMID- 25790345 TI - Spatiotemporal isolation of attosecond soft X-ray pulses in the water window. AB - Attosecond pulses at photon energies that cover the principal absorption edges of the building blocks of materials are a prerequisite for time-resolved probing of the triggering events leading to electronic dynamics such as exciton formation and annihilation. We demonstrate experimentally the isolation of individual attosecond pulses at the carbon K-shell edge (284 eV) in the soft X-ray water window with pulse duration below 400 as and with a bandwidth supporting a 30-as pulse duration. Our approach is based on spatiotemporal isolation of long wavelength-driven harmonics and validates a straightforward and scalable approach for robust and reproducible attosecond pulse isolation. PMID- 25790346 TI - Cardiotoxicity related to long-term trastuzumab therapy in metastatic breast cancer: the potential role of treatment duration and cardiac risk factors. PMID- 25790347 TI - Successful topical rapamycin treatment for facial angiofibromata in two children. AB - Topical sirolimus, or rapamycin, is known to inhibit tumorigenesis in tuberous sclerosis. We report two cases of successful treatment of children with facial angiofibromata and summarize the encouraging evidence of the effectiveness of this therapy in the literature. PMID- 25790348 TI - Evaluation of shear wave velocity and human bone morphogenetic protein-7 for the diagnosis of diabetic kidney disease. AB - PURPOSE: The aim of this study was to determine the diagnostic values of kidney shear wave velocity (SWV) and bone morphogenetic protein-7 (BMP-7), and their correlation in the diagnosis of early diabetic kidney disease. METHODS: A total of 150 patients with type 2 diabetes mellitus were divided into three equal groups based on the urinary albumin-creatinine ratio (ACR): normal albuminuria (normo- group, ACR < 30 mg/g creatinine, n = 50), microalbuminuria (micro- group, 30 <= ACR < 300 mg/g creatinine, n = 50), and macroalbuminuria (macro- group, ACR >= 300 mg/g creatinine and estimated glomerular filtration rate (eGFR) >=30 ml/min/1.73 m2, n = 50). Fifty healthy volunteers were recruited to serve as controls (control group). The levels of serum BMP-7 were detected, and virtual touch tissue quantification was used to detect the renal SWV value in all study subjects. Correlations between groups as well as SWV and BMP-7 were analyzed. RESULTS: Serum BMP-7 and SWV were significantly and progressively decreased and increased, respectively, during the development of renal disease, from the normo- to the micro- and to the macro- groups (all P < 0.01 between each other for BMP-7 and SWV). Moreover, no significant differences between the normo- and control groups were observed for either BMP-7 or SWV (both P > 0.05). In addition, a significant correlation was found between SWV and BMP-7, with a coefficient of 0.569 (P < 0.05). CONCLUSION: The determination of SWV together with serum BMP-7 may play an important role in the diagnosis of diabetic kidney disease. PMID- 25790349 TI - Contributions of electric and acoustic hearing to bimodal speech and music perception. AB - Cochlear implant (CI) users have difficulty understanding speech in noisy listening conditions and perceiving music. Aided residual acoustic hearing in the contralateral ear can mitigate these limitations. The present study examined contributions of electric and acoustic hearing to speech understanding in noise and melodic pitch perception. Data was collected with the CI only, the hearing aid (HA) only, and both devices together (CI+HA). Speech reception thresholds (SRTs) were adaptively measured for simple sentences in speech babble. Melodic contour identification (MCI) was measured with and without a masker instrument; the fundamental frequency of the masker was varied to be overlapping or non overlapping with the target contour. Results showed that the CI contributes primarily to bimodal speech perception and that the HA contributes primarily to bimodal melodic pitch perception. In general, CI+HA performance was slightly improved relative to the better ear alone (CI-only) for SRTs but not for MCI, with some subjects experiencing a decrease in bimodal MCI performance relative to the better ear alone (HA-only). Individual performance was highly variable, and the contribution of either device to bimodal perception was both subject- and task-dependent. The results suggest that individualized mapping of CIs and HAs may further improve bimodal speech and music perception. PMID- 25790350 TI - Differential gene expression in ovaries of Qira black sheep and Hetian sheep using RNA-Seq technique. AB - The Qira black sheep and the Hetian sheep are two local breeds in the Northwest of China, which are characterized by high-fecundity and low-fecundity breed respectively. The elucidation of mRNA expression profiles in the ovaries among different sheep breeds representing fecundity extremes will helpful for identification and utilization of major prolificacy genes in sheep. In the present study, we performed RNA-seq technology to compare the difference in ovarian mRNA expression profiles between Qira black sheep and Hetian sheep. From the Qira black sheep and the Hetian sheep libraries, we obtained a total of 11,747,582 and 11,879,968 sequencing reads, respectively. After aligning to the reference sequences, the two libraries included 16,763 and 16,814 genes respectively. A total of 1,252 genes were significantly differentially expressed at Hetian sheep compared with Qira black sheep. Eight differentially expressed genes were randomly selected for validation by real-time RT-PCR. This study provides a basic data for future research of the sheep reproduction. PMID- 25790352 TI - Clonal integration enhances the performance of a clonal plant species under soil alkalinity stress. AB - Clonal plants have been shown to successfully survive in stressful environments, including salinity stress, drought and depleted nutrients through clonal integration between original and subsequent ramets. However, relatively little is known about whether clonal integration can enhance the performance of clonal plants under alkalinity stress. We investigated the effect of clonal integration on the performance of a typical rhizomatous clonal plant, Leymus chinensis, using a factorial experimental design with four levels of alkalinity and two levels of rhizome connection treatments, connected (allowing integration) and severed (preventing integration). Clonal integration was estimated by comparing physiological and biomass features between the rhizome-connected and rhizome severed treatments. We found that rhizome-connected treatment increased the biomass, height and leaf water potential of subsequent ramets at highly alkalinity treatments but did not affect them at low alkalinity treatments. However, rhizome-connected treatment decreased the root biomass of subsequent ramets and did not influence the photosynthetic rates of subsequent ramets. The biomass of original ramets was reduced by rhizome-connected treatment at the highest alkalinity level. These results suggest that clonal integration can increase the performance of clonal plants under alkalinity stress. Rhizome connected plants showed dramatically increased survival of buds with negative effects on root weight, indicating that clonal integration influenced the resource allocation pattern of clonal plants. A cost-benefit analysis based on biomass measures showed that original and subsequent ramets significantly benefited from clonal integration in highly alkalinity stress, indicating that clonal integration is an important adaptive strategy by which clonal plants could survive in local alkalinity soil. PMID- 25790351 TI - Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study. AB - Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid beta-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the beta-oxidation pipeline, primarily due to a reduction in myocardial carnitine content. PMID- 25790353 TI - Comorbid attention deficit hyperactivity disorder and substance use disorder complexity and chronicity in treatment-seeking adults. AB - INTRODUCTION AND AIMS: Attention deficit hyperactivity disorder (ADHD) is a known risk factor for substance use disorder (SUD); however, the potential additive contribution of comorbid ADHD to drug-specific dependence in SUD populations is largely unknown. The current study aimed to assess this association between ADHD symptoms and drug-specific SUD complexity and chronicity. DESIGN AND METHODS: A cross-sectional survey was administered to a convenience sample of 489 adults receiving SUD treatment at 16 Australian drug and alcohol treatment centres between September 2010 and August 2011. Participants were screened for adult ADHD symptoms using the Adult ADHD Self-Report Scale. Associations between ADHD screening status and drug-specific SUD complexity and chronicity were assessed using multivariate logistic and modified Poisson regression analysis, controlling for a range of potential confounders. RESULTS: Overall, 215 (44%) patients screened positive for concurrent adult ADHD and SUD. After Simes' correction, a significant positive association was observed between ADHD screening status and current amphetamine SUD (odds ratio (OR) = 1.85; 95% confidence interval (CI): 1.19-2.36). Patients who screened positive for ADHD were significantly more likely to report SUD history for heavy alcohol use (OR = 2.05; 95% CI: 1.21-3.45) and amphetamine (OR = 1.96; 95% CI: 1.26-3.06) as well as significantly increased risk of moderate (3-4 years) duration for benzodiazepine and amphetamine SUDs and long (>=5 years) duration for alcohol, opiates other than heroin or methadone, and amphetamine SUDs. DISCUSSION AND CONCLUSIONS: The findings provide evidence that there is increased drug dependence complexity and chronicity in treatment seeking SUD patients who screen positively for ADHD, specifically for amphetamine, alcohol, opiates other than heroin or methadone, and benzodiazepines. PMID- 25790354 TI - Pigmented Limbal Nodule Consistent With a Ciliary Body Nevus in an Organ Donor. PMID- 25790355 TI - Trust me, I'm a nurse. PMID- 25790356 TI - Reflection as an educational strategy in nursing professional development: an integrative review. AB - Reflection is a critical component of professional nursing practice and a strategy for learning through practice. This integrative review synthesizes the literature addressing the use of reflection as an educational strategy and reports outcomes from the use of reflective strategies. Reflection education is primarily nested in programs to meet specific clinical goals, structured with group facilitation. Findings suggest that reflective strategies stimulate learning in practice, enhance readiness to apply new knowledge, and promote practice change. PMID- 25790357 TI - Utilization of evidence-based practice knowledge, attitude, and skill of clinical nurses in the planning of professional development programming. AB - This collaborative study explored nurses' knowledge, attitudes, and skills related to the evidence-based practice (EBP) process. It also explored the nurses' perceptions of the barriers and facilitators that they face related to fully using EBP in the workplace. Findings will afford the healthcare system the information to develop, plan, and restructure the educational services to meet the demand of enhancing EBP strategies and utilization. PMID- 25790358 TI - Implementation of shift report at the bedside to promote patient- and family centered care in a pediatric critical care unit. AB - In the pediatric critical care setting, change of shift report/handoff does not traditionally occur at the bedside. During report, the nurses share important information that promotes patient safety and continuity of care. The goal of educating the nursing staff about family-centered care and shift report at the bedside is to promote better communication, a more comprehensive handoff, enhanced patient safety, engagement of the patient/family, and increased patient/family and staff satisfaction. PMID- 25790359 TI - The efficiency and economy of two learning modes: text with illustration and video with narration. AB - The aim of this study was to determine whether video or text was more effective at knowledge transfer and retention. In this study, knowledge transfer with video and text was similar, and text consumed fewer resources to create. PMID- 25790360 TI - Competencies within a professional clinical ladder: differences in understanding between nurse managers and staff nurses. AB - Clinical ladders provide a framework for professional nursing development and have shown increased personal and professional satisfaction. This article describes a standardized approach for clinical ladder implementation. Managers' and staff nurses' knowledge of the model must align for important stakeholders to perceive the clinical ladder as valuable. Understanding differences and perspectives can be useful as the basis for education and further clinical ladder refinement augmenting the potential for increased nursing satisfaction and professional development. PMID- 25790361 TI - Balancing innovation and evidence. AB - Nurse educators are encouraged to use evidence to guide their teaching strategies. However, evidence is not always available. How can educators make decisions regarding strategies when data are limited or absent? Where do innovation and creativity fit? How can innovation be balanced with evidence? This article provides a discussion regarding other sources of evidence, such as extrapolations, theories and principles, and collective expertise. Readers are encouraged to review the options and then analyze how they might be applied to innovation in education. PMID- 25790362 TI - Development and reliability testing of a survey: measuring trusting and deference behaviors in microethical nursing practice. AB - Novice post-licensure nurses are frequently exposed to microethical nursing practice problems during their first 24 months of formative practice. Often, novice nurses trust the advice of experienced nurse coworkers, deferring to such advice even when they know the advice contradicts evidence-based practice. This study revealed the prevalence of deference behaviors and associated rationale. Study findings emphasize the importance of incorporating conflict management, effective communication techniques, ethical frameworks, and EBP standards within pre- and post-licensure education. PMID- 25790363 TI - Nursing professionalism: innate, taught, or caught? PMID- 25790364 TI - The financial case for nurse residency programs, part 3. PMID- 25790365 TI - Using simulation to effectively employ the change agent/team member elements of practice for the nursing professional development specialist. PMID- 25790366 TI - Analyzing performance discrepancies. PMID- 25790367 TI - National risk manager leading simulation education. PMID- 25790370 TI - Cu(II)-specific metallogel formation by an amido-anthraquinone-pyridyloxalamide ligand in DMSO-water. AB - This study on the CuCl2-induced and water-mediated metallogel formation by a pyridine containing anthraquinone-based ligand in DMSO provides significant insights on the relationship between the coordination geometry and metallo gelation aptitude for a series of variably substituted pyridyloxalamide ligands. PMID- 25790369 TI - A genome-wide siRNA screen in mammalian cells for regulators of S6 phosphorylation. AB - mTOR complex1, the major regulator of mRNA translation in all eukaryotic cells, is strongly activated in most cancers. We performed a genome-wide RNAi screen in a human cancer cell line, seeking genes that regulate S6 phosphorylation, readout of mTORC1 activity. Applying a stringent selection, we retrieved nearly 600 genes wherein at least two RNAis gave significant reduction in S6-P. This cohort contains known regulators of mTOR complex 1 and is significantly enriched in genes whose depletion affects the proliferation/viability of the large set of cancer cell lines in the Achilles database in a manner paralleling that caused by mTOR depletion. We next examined the effect of RNAi pools directed at 534 of these gene products on S6-P in TSC1 null mouse embryo fibroblasts. 76 RNAis reduced S6 phosphorylation significantly in 2 or 3 replicates. Surprisingly, among this cohort of genes the only elements previously associated with the maintenance of mTORC1 activity are two subunits of the vacuolar ATPase and the CUL4 subunit DDB1. RNAi against a second set of 84 targets reduced S6-P in only one of three replicates. However, an indication that this group also bears attention is the presence of rpS6KB1 itself, Rac1 and MAP4K3, a protein kinase that supports amino acid signaling to rpS6KB1. The finding that S6 phosphorylation requires a previously unidentified, functionally diverse cohort of genes that participate in fundamental cellular processes such as mRNA translation, RNA processing, DNA repair and metabolism suggests the operation of feedback pathways in the regulation of mTORC1 operating through novel mechanisms. PMID- 25790372 TI - Ultrathin, rollable, paper-based triboelectric nanogenerator for acoustic energy harvesting and self-powered sound recording. AB - A 125 MUm thickness, rollable, paper-based triboelectric nanogenerator (TENG) has been developed for harvesting sound wave energy, which is capable of delivering a maximum power density of 121 mW/m(2) and 968 W/m(3) under a sound pressure of 117 dBSPL. The TENG is designed in the contact-separation mode using membranes that have rationally designed holes at one side. The TENG can be implemented onto a commercial cell phone for acoustic energy harvesting from human talking; the electricity generated can be used to charge a capacitor at a rate of 0.144 V/s. Additionally, owing to the superior advantages of a broad working bandwidth, thin structure, and flexibility, a self-powered microphone for sound recording with rolled structure is demonstrated for all-sound recording without an angular dependence. The concept and design presented in this work can be extensively applied to a variety of other circumstances for either energy-harvesting or sensing purposes, for example, wearable and flexible electronics, military surveillance, jet engine noise reduction, low-cost implantable human ear, and wireless technology applications. PMID- 25790371 TI - GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript. AB - During human fetal ovary development, the process of primordial follicle formation is immediately preceded by a highly dynamic period of germ cell and somatic cell reorganisation. This is regulated by germ-cell specific transcription regulators, by the conserved RNA binding proteins DAZL and BOLL and by secreted growth factors of the TGFbeta family, including activin betaA: these all show changing patterns of expression preceding follicle formation. In mice, the transcription factor Nobox is essential for follicle formation and oocyte survival, and NOBOX regulates the expression of GDF9 in humans. We have therefore characterised the expression of GDF9 in relation to these known key factors during follicle formation in the human fetal ovary. mRNA levels of GDF9, BMP15 and NOBOX were quantified by qRT-PCR and showed dramatic increases across gestation. GDF9 protein expression was localised by immunohistochemistry to the same population of germ cells as those expressing activin betaA prior to follicle formation but did not co-localise with either BOLL or DAZL. A novel NOBOX isoform was identified in fetal ovary that was shown to be capable of up-regulating the GDF9 promoter in reporter assays. Thus, during oogenesis in humans, oocytes go through a dynamic and very sharply demarcated sequence of changes in expression of these various proteins, even within individual germ cell nests, likely to be of major functional significance in determining selective germ cell survival at this key stage in ovarian development. Transcriptional variation may contribute to the range of age of onset of POI in women with NOBOX mutations. PMID- 25790374 TI - Treatment of vitamin D deficiency/insufficiency with ergocalciferol is associated with reduced vascular access dysfunction in chronic hemodialysis patients. AB - Vitamin D deficiency or insufficiency is highly prevalent among patients with chronic kidney disease (CKD). This study aims to determine the relationship between vitamin D and frequency of vascular access dysfunction (VAD) in hemodialysis (HD) patients. We reviewed medical records of all HD patients who had serum 25-hydroxyvitamin D (25OHD) levels at 4 outpatient dialysis facilities between January 2011 and January 2012. Patients were included if they were >=18 years of age, had been on maintenance dialysis for >=3 months, and had native arteriovenous fistula or synthetic polytetrafluoroethylene grafts for dialysis access. Patients with catheters were excluded. 25-Hydroxyvitamin D levels <30 ng/mL were documented in 183 patients (86%). Median and interquartile range [Q1, Q3] of 25OHD level was 16 [11, 25] ng/mL. Among 213 dialysis patients, 102 had VAD. Median 25OHD level was significantly lower in patients who had VAD than in those without VAD (14.5 [10, 22] vs. 19 [12, 27.5] ng/mL; P = 0.003). There was significant association between VAD and the lowest quartile relative to the highest quartile of 25OHD level. A 25OHD level <12 ng/mL was associated with more than doubling of risk for VAD (OR 2.56; 95% CI [1.05-6.23], P < 0.05). Of 213 patients, 140 were treated with ergocalciferol and 73 were not treated. Treatment was associated with significant reduction in VAD (OR = 0.36; 95% CI [0.19-0.68], P = 0.002). Vitamin D deficiency or insufficiency is an independent risk factor for VAD in HD patients; its treatment with ergocalciferol is associated with decreased VAD. PMID- 25790373 TI - Disruption of Escherichia coli Nissle 1917 K5 capsule biosynthesis, through loss of distinct kfi genes, modulates interaction with intestinal epithelial cells and impact on cell health. AB - Escherichia coli Nissle 1917 (EcN) is among the best characterised probiotics, with a proven clinical impact in a range of conditions. Despite this, the mechanisms underlying these "probiotic effects" are not clearly defined. Here we applied random transposon mutagenesis to identify genes relevant to the interaction of EcN with intestinal epithelial cells. This demonstrated mutants disrupted in the kfiB gene, of the K5 capsule biosynthesis cluster, to be significantly enhanced in attachment to Caco-2 cells. However, this phenotype was distinct from that previously reported for EcN K5 deficient mutants (kfiC null mutants), prompting us to explore further the role of kfiB in EcN:Caco-2 interaction. Isogenic mutants with deletions in kfiB (EcNDeltakfiB), or the more extensively characterised K5 capsule biosynthesis gene kfiC (EcNDeltakfiC), were both shown to be capsule deficient, but displayed divergent phenotypes with regard to impact on Caco-2 cells. Compared with EcNDeltakfiC and the EcN wild type, EcNDeltakfiB exhibited significantly greater attachment to Caco-2 cells, as well as apoptotic and cytotoxic effects. In contrast, EcNDeltakfiC was comparable to the wild-type in these assays, but was shown to induce significantly greater COX-2 expression in Caco-2 cells. Distinct differences were also apparent in the pervading cell morphology and cellular aggregation between mutants. Overall, these observations reinforce the importance of the EcN K5 capsule in host-EcN interactions, but demonstrate that loss of distinct genes in the K5 pathway can modulate the impact of EcN on epithelial cell health. PMID- 25790375 TI - Ancillary ligand control of electronic structure in o-benzoquinonediimine ruthenium complex redox series: structures, electron paramagnetic resonance (EPR), and ultraviolet-visible-near-infrared (UV-vis-NIR) spectroelectrochemistry. AB - The compounds Ru(acac)2(Q) (1), [Ru(bpy)2(Q)](ClO4)2 ([2](ClO4)2), and [Ru(pap)2(Q)]PF6 ([3]PF6), containing Q = N,N'-diphenyl-o-benzoquinonediimine and donating 2,4-pentanedionate ligands (acac(-)), pi-accepting 2,2(/)-bipyridine (bpy), or strongly pi-accepting 2-phenylazopyridine (pap) were prepared and structurally identified. The electronic structures of the complexes and several accessible oxidized and reduced forms were studied experimentally (electrochemistry, magnetic resonance, ultraviolet-visible-near-infrared (UV-vis NIR) spectroelectrochemistry) and computationally (DFT/TD-DFT) to reveal significantly variable electron transfer behavior and charge distribution. While the redox system 1(+)-1(-) prefers trivalent ruthenium with corresponding oxidation states Q(0)-Q(2-) of the noninnocent ligand, the series 2(2+)-2(0) and 3(2+)-3(-) retain Ru(II). The bpy and pap co-ligands are not only spectators but can also be reduced prior to a second reduction of Q. The present study with new experimental and computational evidence on the influence of co-ligands on the metal is complementary to a report on the substituent effects in o-quinonediimine ligands [Kalinina et al., Inorg. Chem. 2008, 47, 10110] and to the discussion of the most appropriate oxidation state formulation Ru(II)(Q(0)) or Ru(III)(Q(* -)). PMID- 25790376 TI - Genetic and chemical activation of TFEB mediates clearance of aggregated alpha synuclein. AB - Aggregation of alpha-synuclein (alpha-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of alpha-syn aggregates results from aberrant accumulation of misfolded alpha-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of alpha-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated alpha-syn by inducing autophagic clearance of alpha-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-beta cyclodextrin promotes autophagic clearance of aggregated alpha-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of alpha-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of alpha-syn aggregates. PMID- 25790377 TI - Aspiration-related acute respiratory distress syndrome in acute stroke patient. AB - BACKGROUND: Aspiration of oral or gastric contents into the larynx and lower respiratory tract is a common problem in acute stroke patients, which significantly increases the incidence of acute respiratory distress syndrome (ARDS). However, little is known about the clinical characteristics of aspiration related ARDS in acute stroke patients. METHODS: Over 17-month period a retrospective cohort study was done on 1495 consecutive patients with acute stroke. The data including demographic characteristics, clinical manifestations, laboratory examinations, chest imaging, and hospital discharge status were collected to analysis. RESULTS: Aspiration-related ARDS was diagnosed in 54 patients (3.6%). The most common presenting symptom was tachypnea (respiratory rate >=25 breaths/min) in 50 cases. Computed tomography (CT) images usually demonstrated diffuse ground-glass opacities (GGOs) and inhomogeneous patchy consolidations involving the low lobes. Age, NIHSS score, GCS score, dysphagia, dysarthria, hemoglobin concentration, serum aspertate aminotransferase (AST), serum albumin, serum sodium, and admission glucose level were independently associated with aspiration-related ARDS (odds ratio (OR) 1.05, 95% confidence interval (CI) (1.04-1.07); OR 2.87, (2.68-3.63); OR 4.21, (3.57-5.09); OR 2.18, (1.23-3.86); OR 1.67, (1.31-2.14); OR 2.31, (1.11-4.84); OR 1.68, (1.01-2.80); OR 2.15, (1.19-3.90); OR 1.92, (1.10-3.36) and OR 1.14, (1.06-1.21) respectively). CONCLUSIONS: Aspiration-related ARDS frequently occurs in acute stroke patient with impairment consciousness. It is advisable that performing chest CT timely may identify disease early and prompt treatment to rescue patients. PMID- 25790378 TI - Biphasic effects of FGF2 on adipogenesis. AB - Although stem cells from mice deficient of FGF2 have been reported to display enhanced capacity for adipogenesis, the literature using in vitro cell culture system has so far reported conflicting results on the role of FGF2 in adipogenesis. We here demonstrate that FGF2, depending on concentration, can function as either a positive or negative factor of in vitro adipogenesis by regulating activation of the ERK signaling pathway. FGF2 at concentrations lower than 2 ng/ml enhanced in vitro adipogenesis of human adipose-derived stem cells (hASCs). However, FGF2 at concentrations higher than 10 ng/ml was able to suppress adipogenesis by maintaining sustained phosphorylation of ERK and function as a dominant negative adipogenic factor toward BMP ligands. Expression levels of FGF2 in the fat tissues from high fat diet induced obese C57BL/6 mice were lower than those from normal chow diet mice, indicating that expression levels of FGF2 in the fat tissues might be in reverse correlation with the size of fat tissues. Our observation of concentration dependent biphasic effect as well as dominant negative effect of FGF2 on adipogenesis provides a mechanistic basis to understand roles of FGF2 in adipogenesis and development of fat tissues. PMID- 25790379 TI - IL-4Ralpha-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice. AB - Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL 4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor alpha on macrophages (LysMcreIL-4Ralpha-/lox) with Mtb. We show that absence of IL-4Ralpha on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild type (WT) and LysMcreIL-4Ralpha-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Ralpha driven pathway. Together, these results suggest that IL-4Ralpha-macrophages do not play a central role in TB disease progression. PMID- 25790380 TI - From subject to participant: ethics and the evolving role of community in health research. AB - Belmont Report principles focus on the well-being of the research subject, yet community-engaged investigators often eschew the role of subject for that of participant. We conducted semistructured interviews with 29 community and academic investigators working on 10 community-engaged studies. Interviews elicited perspectives on ethical priorities and ethical challenges. Interviewees drew on the Belmont Report to describe 4 key principles of ethical community engaged research (embodying ethical action, respecting participants, generalizing beneficence, and negotiating justice). However, novel aspects of the participant role were the source of most ethical challenges. We theorize that the shift in ethical focus from subject to participant will pose new ethical dilemmas for community-engaged investigators and for other constituents interested in increasing community involvement in health research. PMID- 25790381 TI - Transactional sex among men who have sex with men in Latin America: economic, sociodemographic, and psychosocial factors. AB - OBJECTIVES: We assessed factors associated with engagement in transactional sex among men who have sex with men recruited from one of the largest Internet sites for men seeking social or sexual interactions with other men in Latin America. METHODS: We constructed multilevel logistic regression models to analyze factors associated with engagement in transactional sex in 17 Latin American countries in 2012. RESULTS: Of 24 051 respondents, 1732 (7.2%) reported being paid for sexual intercourse in the past 12 months. In a multivariable model, higher country-level unemployment was associated with increased odds of transactional sex (adjusted odds ratio [AOR] = 1.07 per 1% increase in unemployment; 95% confidence interval [CI] = 1.00, 1.13). Individual or interpersonal factors associated with increased odds of engagement in transactional sex included self-reported HIV (AOR = 1.33; 95% CI = 1.04, 1.69) or sexually transmitted infection (AOR = 1.33; 95% CI = 1.11, 1.59), childhood sexual abuse history (AOR = 1.75; 95% CI = 1.48, 2.06), intimate partner violence (past 5 years, AOR = 1.68; 95% CI = 1.45, 1.95), and sexual compulsivity (AOR = 1.77; 95% CI = 1.49, 2.11). CONCLUSIONS: Structural level economic interventions and those that address individual and interpersonal factors may improve HIV prevention efforts among men who have sex with men who engage in transactional sex. PMID- 25790382 TI - Neighborhood blight, stress, and health: a walking trial of urban greening and ambulatory heart rate. AB - We measured dynamic stress responses using ambulatory heart rate monitoring as participants in Philadelphia, Pennsylvania walked past vacant lots before and after a greening remediation treatment of randomly selected lots. Being in view of a greened vacant lot decreased heart rate significantly more than did being in view of a nongreened vacant lot or not in view of any vacant lot. Remediating neighborhood blight may reduce stress and improve health. PMID- 25790383 TI - "When you're in a crisis like that, you don't want people to know": mortgage strain, stigma, and mental health. AB - OBJECTIVES: We analyzed experiences of stigmatization, concealment, and isolation among African American homeowners who were experiencing mortgage strain. METHODS: We conducted semistructured interviews between March 2012 and May 2013 with 28 African American homeowners in a northeastern US city who were experiencing mortgage strain. We coded all of the transcripts and reviewed data for codes relating to stigma, sharing information, social support, social isolation, and the meaning of homeownership. RESULTS: Our data showed that mortgage strain can be a concealable stigma. Participants internalized this stigma, expressing shame about their mortgage situation. Additionally, some participants anticipated that others would view them as less worthy given their mortgage trouble. In an effort to avoid stigmatization, many concealed their mortgage trouble, which often led to isolation. This stigmatization, concealment, and isolation seemed to contribute to participants' depression, anxiety, and emotional distress. CONCLUSIONS: Stigma may exacerbate stress associated with mortgage strain and contribute to poor mental health, particularly among upwardly mobile African Americans who have overcome significant structural barriers to home ownership. Reducing stigma associated with mortgage strain may help to reduce the health consequences of this stressful life event. PMID- 25790384 TI - Longitudinal effects of school drug policies on student marijuana use in Washington State and Victoria, Australia. AB - OBJECTIVES: We examined the longitudinal effect of schools' drug policies on student marijuana use. METHODS: We used data from the International Youth Development Study, which surveyed state-representative samples of students from Victoria, Australia, and Washington State. In wave 1 (2002), students in grades 7 and 9 (n = 3264) and a school administrator from each participating school (n = 188) reported on school drug policies. In wave 2 (2003), students reported on their marijuana use. We assessed associations between student-reported and administrator-reported policy and student self-reported marijuana use 1 year later. RESULTS: Likelihood of student marijuana use was higher in schools in which administrators reported using out-of-school suspension and students reported low policy enforcement. Student marijuana use was less likely where students reported receiving abstinence messages at school and students violating school policy were counseled about the dangers of marijuana use. CONCLUSIONS: Schools may reduce student marijuana use by delivering abstinence messages, enforcing nonuse policies, and adopting a remedial approach to policy violations rather than use of suspensions. PMID- 25790385 TI - Modeling the injury prevention impact of mandatory alcohol ignition interlock installation in all new US vehicles. AB - OBJECTIVES: We estimated the injury prevention impact and cost savings associated with alcohol interlock installation in all new US vehicles. METHODS: We identified fatal and nonfatal injuries associated with drinking driver vehicle crashes from the Fatality Analysis Reporting System and National Automotive Sampling System's General Estimates System data sets (2006-2010). We derived the estimated impact of universal interlock installation using an estimate of the proportion of alcohol-related crashes that were preventable in vehicles < 1 year old. We repeated this analysis for each subsequent year, assuming a 15-year implementation. We applied existing crash-induced injury cost metrics to approximate economic savings, and we used a sensitivity analysis to examine results with varying device effectiveness. RESULTS: Over 15 years, 85% of crash fatalities (> 59 000) and 84% to 88% of nonfatal injuries (> 1.25 million) attributed to drinking drivers would be prevented, saving an estimated $342 billion in injury-related costs, with the greatest injury and cost benefit realized among recently legal drinking drivers. Cost savings outweighed installation costs after 3 years, with the policy remaining cost effective provided device effectiveness remained above approximately 25%. CONCLUSIONS: Alcohol interlock installation in all new vehicles is likely a cost-effective primary prevention policy that will substantially reduce alcohol-involved crash fatalities and injuries, especially among young vulnerable drivers. PMID- 25790386 TI - The Influence of Provider Communication Behaviors on Parental Vaccine Acceptance and Visit Experience. AB - OBJECTIVES: We investigated how provider vaccine communication behaviors influence parental vaccination acceptance and visit experience. METHODS: In a cross-sectional observational study, we videotaped provider-parent vaccine discussions (n = 111). We coded visits for the format providers used for initiating the vaccine discussion (participatory vs presumptive), parental verbal resistance to vaccines after provider initiation (yes vs no), and provider pursuit of recommendations in the face of parental resistance (pursuit vs mitigated or no pursuit). Main outcomes were parental verbal acceptance of recommended vaccines at visit's end (all vs >= 1 refusal) and parental visit experience (highly vs lower rated). RESULTS: In multivariable models, participatory (vs presumptive) initiation formats were associated with decreased odds of accepting all vaccines at visit's end (adjusted odds ratio [AOR] = 0.04; 95% confidence interval [CI] = 0.01, 0.15) and increased odds of a highly rated visit experience (AOR = 17.3; 95% CI = 1.5, 200.3). CONCLUSIONS: In the context of 2 general communication formats used by providers to initiate vaccine discussions, there appears to be an inverse relationship between parental acceptance of vaccines and visit experience. Further exploration of this inverse relationship in longitudinal studies is needed. PMID- 25790387 TI - Incidence and prevalence of systemic lupus erythematosus among Arab and Chaldean Americans in southeastern Michigan: the Michigan Lupus Epidemiology and Surveillance Program. AB - OBJECTIVES: We assessed the burden of systemic lupus erythematosus (SLE) among Arab and Chaldean Americans residing in southeast Michigan. METHODS: For those meeting SLE criteria from the Michigan Lupus Epidemiology and Surveillance Registry, we determined Arab or Chaldean ethnicity by links with demographic data from birth certificates and with a database of Arab and Chaldean names. We compared prevalence and incidence of SLE for Arab and Chaldean Americans with estimates for non-Arab and non-Chaldean American Whites and Blacks. RESULTS: We classified 54 individuals with SLE as Arab and Chaldean Americans. The age adjusted incidence and prevalence estimates for Arab and Chaldean Americans were 7.6 and 62.6 per 100 000, respectively. Arab and Chaldean Americans had a 2.1 fold excess SLE incidence compared with non-Arab and non-Chaldean American Whites. Arab and Chaldean American women had both significantly higher incidence rates (5.0-fold increase) and prevalence estimates (7.4-fold increase) than did Arab and Chaldean American men. CONCLUSIONS: Recognizing that Arab and Chaldean Americans experience different disease burdens from Whites is a first step toward earlier diagnosis and designing targeted interventions. Better methods of assigning ethnicity would improve research in this population. PMID- 25790388 TI - Systematic review and meta-analysis of the impact of restaurant menu calorie labeling. AB - We conducted a systematic review and meta-analysis evaluating the relationship between menu calorie labeling and calories ordered or purchased in the PubMed, Web of Science, PolicyFile, and PAIS International databases through October 2013. Among 19 studies, menu calorie labeling was associated with a -18.13 kilocalorie reduction ordered per meal with significant heterogeneity across studies (95% confidence interval = -33.56, -2.70; P = .021; I(2) = 61.0%). However, among 6 controlled studies in restaurant settings, labeling was associated with a nonsignificant -7.63 kilocalorie reduction (95% confidence interval = -21.02, 5.76; P = .264; I(2) = 9.8%). Although current evidence does not support a significant impact on calories ordered, menu calorie labeling is a relatively low-cost education strategy that may lead consumers to purchase slightly fewer calories. These findings are limited by significant heterogeneity among nonrestaurant studies and few studies conducted in restaurant settings. PMID- 25790389 TI - Considering whether Medicaid is worth the cost: revisiting the Oregon Health Study. AB - The Oregon Health Study was a groundbreaking experiment in which uninsured participants were randomized to either apply for Medicaid or stay with their current care. The study showed that Medicaid produced numerous important socioeconomic and health benefits but had no statistically significant impact on hypertension, hypercholesterolemia, or diabetes. Medicaid opponents interpreted the findings to mean that Medicaid is not a worthwhile investment. Medicaid proponents viewed the experiment as statistically underpowered and, irrespective of the laboratory values, suggestive that Medicaid is a good investment. We tested these competing claims and, using a sensitive joint test and statistical power analysis, confirmed that the Oregon Health Study did not improve laboratory values. However, we also found that Medicaid is a good value, with a cost of just $62 000 per quality-adjusted life-years gained. PMID- 25790390 TI - Factors influencing the health and wellness of urban aboriginal youths in Canada: insights of in-service professionals, care providers, and stakeholders. AB - We addressed the positive and negative factors that influence the health and wellness of urban Aboriginal youths in Canada and ways of restoring, promoting, and maintaining the health and wellness of this population. Fifty-three in service professionals, care providers, and stakeholders participated in this study in which we employed the Glaserian grounded theory approach. We identified perceived positive and negative factors. Participants suggested 5 approaches-(1) youth based and youth driven, (2) community based and community driven, (3) culturally appropriate, (4) enabling and empowering, and (5) sustainable-as well as some practical strategies for the development and implementation of programs. We have provided empirical knowledge about barriers to and opportunities for improving health and wellness among urban Aboriginal youths in Canada. PMID- 25790391 TI - Factors associated with increased cesarean risk among African American women: evidence from California, 2010. AB - OBJECTIVES: We studied if both observed and unobserved maternal health in African American women in hospitals or communities were associated with cesarean delivery of infants. METHODS: We examined the relationship between African American race and cesarean delivery among 493 433 women discharged from 255 Californian hospitals in 2010 using administrative data; we adjusted for patient comorbidities and maternal, fetal, and placental risk factors, as well as clustering of patients within hospitals. RESULTS: Cesarean rates were significantly higher overall for African American women than other women (unadjusted rate 36.8% vs 32.7%), as were both elective and emergency primary cesarean rates. Elevated risks persisted after risk adjustment (odds ratio generally > 1.27), but the prevalence of particular risk factors varied. Although African American women were clustered in some hospitals, the proportion of African Americans among all women delivering in a hospital was not related to its overall cesarean rate. CONCLUSIONS: To address the higher likelihood of elective cesarean delivery, attention needs to be given to currently unmeasured patient level health factors, to the quality of provider-physician interactions, as well as to patient preferences. PMID- 25790392 TI - Public health departments and accountable care organizations: finding common ground in population health. AB - We examined areas of potential collaboration between accountable care organizations and public health agencies, as well as perceived barriers and facilitators. We interviewed 9 key informants on 4 topics: advantages of public health agency involvement in accountable care organizations; services public health agencies could provide; practical, cultural, and legal barriers to accountable care organization-public health agency involvement; and business models that facilitate accountable care organization-public health agency collaboration. Public health agencies could help accountable care organizations partner with community organizations and reach vulnerable patients, provide population-based services and surveillance data, and promote policies that improve member health. Barriers include accountable care organizations' need for short-term financial yield, limited public health agency technical and financial capacity, and the absence of a financial model. PMID- 25790393 TI - The Health at Every Size paradigm and obesity: missing empirical evidence may help push the reframing obesity debate forward. AB - A Health at Every Size (HAES) approach has been proposed to address weight bias and stigma in individuals living with obesity, and more recently articulated as a promising public health approach beyond the prevailing focus on weight status as a health outcome. The purpose of this article is to examine our understanding of HAES within the context of public health approaches to obesity, and to present strengths and limitations of the available evidence. Advancing our understanding of HAES from a public health perspective requires us to move beyond an ideological debate and give greater attention to the need for empirical studies across a range of populations. Only then can the value of HAES, as a weight neutral, public health approach for the prevention of obesity and other chronic diseases, be fully understood. PMID- 25790394 TI - Population health, public health, and accountable care: emerging roles and relationships. AB - To identify roles for public health agencies (PHAs) in accountable care organizations (ACOs), along with their obstacles and facilitators, we interviewed individuals from 9 ACOs, including Medicare, Medicaid, and commercial payers. We learned that PHAs participate in ACO-like partnerships with state Medicaid agencies, but interviewees identified barriers to collaboration with Medicare and commercial ACOs, including Medicare participation requirements, membership cost, risk-bearing restrictions, data-sharing constraints, differences between medicine and public health, and ACOs' investment yield needs. Collaboration was more likely when organizations had common objectives, ACO sponsors had substantial market share, PHA representatives served on ACO advisory boards, and there were preexisting contractual relationships. ACO-PHA relationships are not as straightforward as their shared use of the term "population health" would suggest, but some ACO partnerships could give PHAs access to new revenue streams. PMID- 25790395 TI - Ebola crisis of 2014: are current strategies enough to meet the long-run challenges ahead? AB - The outbreak of the Ebola virus disease (EVD) in 2014 mobilized international efforts to contain a global health crisis. The emergence of the deadly virus in the United States and Europe among health care workers intensified fears of a worldwide epidemic. Market incentives for pharmaceutical firms to allocate their research and development resources toward Ebola treatments were weak because the limited number of EVD cases were previously confined to rural areas of West Africa. We discuss 3 policy recommendations to address the long-term challenges of EVD in an interconnected world. PMID- 25790396 TI - Association between assisted reproductive technology conception and autism in California, 1997-2007. AB - OBJECTIVES: We assessed the association between assisted reproductive technology (ART) and diagnosed autistic disorder in a population-based sample of California births. METHODS: We performed an observational cohort study using linked records from the California Birth Master Files for 1997 through 2007, the California Department of Developmental Services autism caseload for 1997 through 2011, and the Centers for Disease Control and Prevention's National ART Surveillance System for live births in 1997 through 2007. Participants were all 5 926 251 live births, including 48 865 ART-originated infants and 32 922 cases of autism diagnosed by the Department of Developmental Services. We compared births originated using ART with births originated without ART for incidence of autism. RESULTS: In the full population, the incidence of diagnosed autism was twice as high for ART as non-ART births. The association was diminished by excluding mothers unlikely to use ART; adjustment for demographic and adverse prenatal and perinatal outcomes reduced the association substantially, although statistical significance persisted for mothers aged 20 to 34 years. CONCLUSIONS: The association between ART and autism is primarily explained by adverse prenatal and perinatal outcomes and multiple births. PMID- 25790398 TI - Predicted probabilities' relationship to inclusion probabilities. AB - It has been shown that under a general multiplicative intercept model for risk, case-control (retrospective) data can be analyzed by maximum likelihood as if they had arisen prospectively, up to an unknown multiplicative constant, which depends on the relative sampling fraction. (1) With suitable auxiliary information, retrospective data can also be used to estimate response probabilities. (2) In other words, predictive probabilities obtained without adjustments from retrospective data will likely be different from those obtained from prospective data. We highlighted this using binary data from Medicare to determine the probability of readmission into the hospital within 30 days of discharge, which is particularly timely because Medicare has begun penalizing hospitals for certain readmissions. (3). PMID- 25790397 TI - Development of the policy indicator checklist: a tool to identify and measure policies for calorie-dense foods and sugar-sweetened beverages across multiple settings. AB - OBJECTIVES: We developed the policy indicator checklist (PIC) to identify and measure policies for calorie-dense foods and sugar-sweetened beverages to determine how policies are clustered across multiple settings. METHODS: In 2012 and 2013 we used existing literature, policy documents, government recommendations, and instruments to identify key policies. We then developed the PIC to examine the policy environments across 3 settings (communities, schools, and early care and education centers) in 8 communities participating in the Childhood Obesity Research Demonstration Project. RESULTS: Principal components analysis revealed 5 components related to calorie-dense food policies and 4 components related to sugar-sweetened beverage policies. Communities with higher youth and racial/ethnic minority populations tended to have fewer and weaker policy environments concerning calorie-dense foods and healthy foods and beverages. CONCLUSIONS: The PIC was a helpful tool to identify policies that promote healthy food environments across multiple settings and to measure and compare the overall policy environments across communities. There is need for improved coordination across settings, particularly in areas with greater concentration of youths and racial/ethnic minority populations. Policies to support healthy eating are not equally distributed across communities, and disparities continue to exist in nutrition policies. PMID- 25790399 TI - Trends in sexual orientation missing data over a decade of the California Health Interview Survey. AB - OBJECTIVES: We explored changes in sexual orientation question item completion in a large statewide health survey. METHODS: We used 2003 to 2011 California Health Interview Survey data to investigate sexual orientation item nonresponse and sexual minority self-identification trends in a cross-sectional sample representing the noninstitutionalized California household population aged 18 to 70 years (n = 182 812 adults). RESULTS: Asians, Hispanics, limited-English proficient respondents, and those interviewed in non-English languages showed the greatest declines in sexual orientation item nonresponse. Asian women, regardless of English-proficiency status, had the highest odds of item nonresponse. Spanish interviews produced more nonresponse than English interviews and Asian-language interviews produced less nonresponse when we controlled for demographic factors and survey cycle. Sexual minority self-identification increased in concert with the item nonresponse decline. CONCLUSIONS: Sexual orientation nonresponse declines and the increase in sexual minority identification suggest greater acceptability of sexual orientation assessment in surveys. Item nonresponse rate convergence among races/ethnicities, language proficiency groups, and interview languages shows that sexual orientation can be measured in surveys of diverse populations. PMID- 25790400 TI - Forces of change. PMID- 25790401 TI - The longitudinal joint effect of obesity and major depression on work performance impairment. AB - OBJECTIVES: We examined the longitudinal effect of obesity, major depression, and their combination on work performance impairment (WPI). METHODS: We collected longitudinal data (2004-2013) on 1726 paid employees from the Netherlands Study of Depression and Anxiety at baseline and 2-, 4-, and 6-year follow-up. We defined obesity with body mass index and waist circumference. We diagnosed major depression with the Composite International Diagnostic Interview 2.1. We assessed work performance impairment with a questionnaire for illness-associated costs. We used generalized estimating equations for modeling, and estimated interaction on the additive scale. RESULTS: Obesity, abdominal obesity, and major depression were longitudinally associated with increased risk of high WPI. The combinations of obesity and major depression, and of abdominal obesity and major depression were associated with increased risk of high WPI (odds ratios of 2.36 [95% confidence interval = 1.61, 3.44] and 1.88 [95% confidence interval = 1.40, 2.53], respectively), but the relative excess risks attributable to interaction were nonsignificant. CONCLUSIONS: The longitudinal joint effect of obesity and major depression on high WPI implies that obesity intervention may be more beneficial for individuals with major depression than those without regarding risk of high WPI, if confirmed in a large, representative sample. PMID- 25790402 TI - Colla et al. respond. PMID- 25790403 TI - Advancing suicide prevention research with rural American Indian and Alaska Native populations. AB - As part of the National Action Alliance for Suicide Prevention's American Indian and Alaska Native (AI/AN) Task Force, a multidisciplinary group of AI/AN suicide research experts convened to outline pressing issues related to this subfield of suicidology. Suicide disproportionately affects Indigenous peoples, and remote Indigenous communities can offer vital and unique insights with relevance to other rural and marginalized groups. Outcomes from this meeting include identifying the central challenges impeding progress in this subfield and a description of promising research directions to yield practical results. These proposed directions expand the alliance's prioritized research agenda and offer pathways to advance the field of suicide research in Indigenous communities and beyond. PMID- 25790404 TI - The impact of reproductive health legislation on family planning clinic services in Texas. AB - We examined the impact of legislation in Texas that dramatically cut and restricted participation in the state's family planning program in 2011 using surveys and interviews with leaders at organizations that received family planning funding. Overall, 25% of family planning clinics in Texas closed. In 2011, 71% of organizations widely offered long-acting reversible contraception; in 2012-2013, only 46% did so. Organizations served 54% fewer clients than they had in the previous period. Specialized family planning providers, which were the targets of the legislation, experienced the largest reductions in services, but other agencies were also adversely affected. The Texas experience provides valuable insight into the potential effects that legislation proposed in other states may have on low-income women's access to family planning services. PMID- 25790406 TI - Equipping the physician assistant workforce to end oral health disparities. PMID- 25790405 TI - Partners in health: a conceptual framework for the role of community health workers in facilitating patients' adoption of healthy behaviors. AB - We formulated a conceptual framework that begins to answer the national call to improve health care access, delivery, and quality by explaining the processes through which community health workers (CHWs) facilitate patients' adoption of healthy behaviors. In September 2011 to January 2012, we conducted a qualitative study that triangulated multiple data sources: 26 in-depth interviews, training documents, and patient charts. CHWs served as partners in health to immigrant Filipinos with hypertension, leveraging their cultural congruence with intervention participants, employing interpersonal communication techniques to build trust and rapport, providing social support, and assisting with health behavior change. To drive the field forward, this work can be expanded with framework testing that may influence future CHW training and interventions. PMID- 25790407 TI - Mortality hazard and survival after tuberculosis treatment. AB - OBJECTIVES: We compared mortality among tuberculosis (TB) survivors and a similar population. METHODS: We used local health authority records from 3 US sites to identify 3853 persons who completed adequate treatment of TB and 7282 individuals diagnosed with latent TB infection 1993 to 2002. We then retrospectively observed mortality after 6 to 16 years of observation. We ascertained vital status as of December 31, 2008, using the Centers for Disease Control and Prevention's National Death Index. We analyzed mortality rates, hazards, and associations using Cox regression. RESULTS: We traced 11 135 individuals over 119 772 person years of observation. We found more all-cause deaths (20.7% vs 3.1%) among posttreatment TB patients than among the comparison group, an adjusted average excess of 7.6 deaths per 1000 person-years (8.8 vs 1.2; P < .001). Mortality among posttreatment TB patients varied with observable factors such as race, site of disease, HIV status, and birth country. CONCLUSIONS: Fully treated TB is still associated with substantial mortality risk. Cure as currently understood may be insufficient protection against TB-associated mortality in the years after treatment, and TB prevention may be a valuable opportunity to modify this risk. PMID- 25790409 TI - The impact of texting bans on motor vehicle crash-related hospitalizations. AB - We used a panel design and the Nationwide Inpatient Sample from 19 states between 2003 and 2010 to examine the impact of texting bans on crash-related hospitalizations. We conducted conditional negative binomial regressions with state, year, and month fixed effects to examine changes in crash-related hospitalizations in states after the enactment of a texting ban relative to those in states without such bans. Results indicate that texting bans were associated with a 7% reduction in crash-related hospitalizations among all age groups. Texting bans were significantly associated with reductions in hospitalizations among those aged 22 to 64 years and those aged 65 years or older. Marginal reductions were seen among adolescents. States that have not passed strict texting bans should consider doing so. PMID- 25790408 TI - Violence Against Women in Selected Areas of the United States. AB - OBJECTIVES: We determined the prevalence of recent emotional, physical, and sexual violence against women and their associations with HIV-related risk factors in women living in the United States. METHODS: We performed an assessment of women ages 18 to 44 years with a history of unprotected sex and 1 or more personal or partner HIV risk factors in the past 6 months from 2009 to 2010. We used multivariable logistic regression to examine the association of experiencing violence. RESULTS: Among 2099 women, the prevalence of emotional abuse, physical violence, and sexual violence in the previous 6 months was 31%, 19%, and 7%, respectively. Nonmarried status, food insecurity, childhood abuse, depression symptomology, and posttraumatic stress disorder were significantly associated with multiple types of violence. All types of violence were associated with at least 3 different partner or personal HIV risk behaviors, including unprotected anal sex, previous sexually transmitted infection diagnosis, sex work, or partner substance abuse. CONCLUSIONS: Our data suggested that personal and partner HIV risk behaviors, mental illness, and specific forms of violence frequently co occurred in the lives of impoverished women. We shed light on factors purported to contribute to a syndemic in this population. HIV prevention programs in similar populations should address these co-occurring issues in a comprehensive manner. PMID- 25790411 TI - Rothstein responds. PMID- 25790410 TI - Neighborhood availability of convenience stores and diet quality: findings from 20 years of follow-up in the coronary artery risk development in young adults study. AB - OBJECTIVES: We examined the association between neighborhood convenience stores and diet outcomes for 20 years of the Coronary Artery Risk Development in Young Adults study. METHODS: We used dietary data from the Coronary Artery Risk Development in Young Adults study years 1985-1986, 1992-1993, and 2005-2006 (n = 3299; Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA) and geographically and temporally matched neighborhood-level food resource and US Census data. We used random effects repeated measures regression to estimate associations between availability of neighborhood convenience stores with diet outcomes and whether these associations differed by individual-level income. RESULTS: In multivariable-adjusted analyses, greater availability of neighborhood convenience stores was associated with lower diet quality (mean score = 66.3; SD = 13.0) for participants with lower individual-level income (b = -2.40; 95% CI = 3.30, -1.51); associations at higher individual-level income were weaker. We observed similar associations with whole grain consumption across time but no statistically significant associations with consumption of sugar-sweetened beverages, artificially sweetened beverages, snacks, processed meats, fruits, or vegetables. CONCLUSIONS: The presence of neighborhood convenience stores may be associated with lower quality diets. Low-income individuals may be most sensitive to convenience store availability. PMID- 25790412 TI - Analysis of hospital community benefit expenditures' alignment with community health needs: evidence from a national investigation of tax-exempt hospitals. AB - OBJECTIVES: We investigated whether federally tax-exempt hospitals consider community health needs when deciding how much and what types of community benefits to provide. METHODS: Using 2009 data from hospital tax filings to the Internal Revenue Service and the 2010 County Health Rankings, we employed both univariate and multivariate analyses to examine the relationship between community health needs and the types and levels of hospitals' community benefit expenditures. The study sample included 1522 private, tax-exempt hospitals throughout the United States. RESULTS: We found some patterns between community health needs and hospitals' expenditures on community benefits. Hospitals located in communities with greater health needs spent more as a percentage of their operating budgets on benefits directly related to patient care. By contrast, spending on community health improvement initiatives was unrelated to community health needs. CONCLUSIONS: Important opportunities exist for tax-exempt hospitals to improve the alignment between their community benefit activities and the health needs of the community they serve. The Affordable Care Act requirement that hospitals conduct periodic community health needs assessments may be a first step in this direction. PMID- 25790413 TI - Loneliness as a public health issue: the impact of loneliness on health care utilization among older adults. AB - OBJECTIVES: We aimed to determine whether loneliness is associated with higher health care utilization among older adults in the United States. METHODS: We used panel data from the Health and Retirement Study (2008 and 2012) to examine the long-term impact of loneliness on health care use. The sample was limited to community-dwelling persons in the United States aged 60 years and older. We used negative binomial regression models to determine the impact of loneliness on physician visits and hospitalizations. RESULTS: Under 2 definitions of loneliness, we found that a sizable proportion of those aged 60 years and older in the United States reported loneliness. Regression results showed that chronic loneliness (those lonely both in 2008 and 4 years later) was significantly and positively associated with physician visits (beta = 0.075, SE = 0.034). Loneliness was not significantly associated with hospitalizations. CONCLUSIONS: Loneliness is a significant public health concern among elders. In addition to easing a potential source of suffering, the identification and targeting of interventions for lonely elders may significantly decrease physician visits and health care costs. PMID- 25790414 TI - Effects of a 2009 Illinois Alcohol Tax Increase on Fatal Motor Vehicle Crashes. AB - OBJECTIVES: We examined the effects of a 2009 increase in alcohol taxes in Illinois on alcohol-related fatal motor vehicle crashes. METHODS: We used an interrupted time-series design, with intrastate and cross-state comparisons and measurement derived from driver alcohol test results, for 104 months before and 28 months after enactment. Our analyses used autoregressive moving average and generalized linear mixed Poisson models. We examined both population-wide effects and stratifications by alcohol level, age, gender, and race. RESULTS: Fatal alcohol-related motor vehicle crashes declined 9.9 per month after the tax increase, a 26% reduction. The effect was similar for alcohol-impaired drivers with positive alcohol levels lower than 0.15 grams per deciliter (-22%) and drivers with very high alcohol levels of 0.15 or more (-25%). Drivers younger than 30 years showed larger declines (-37%) than those aged 30 years and older ( 23%), but gender and race stratifications did not significantly differ. CONCLUSIONS: Increases in alcohol excise taxes, such as the 2009 Illinois act, could save thousands of lives yearly across the United States as part of a comprehensive strategy to reduce alcohol-impaired driving. PMID- 25790415 TI - Emergency department visits for nontraumatic dental problems: a mixed-methods study. AB - OBJECTIVES: We documented emergency department (ED) visits for nontraumatic dental problems and identified strategies to reduce ED dental visits. METHODS: We used mixed methods to analyze claims in 2010 from a purposive sample of 25 Oregon hospitals and Oregon's All Payer All Claims data set and interviewed 51 ED dental visitors and stakeholders from 6 communities. RESULTS: Dental visits accounted for 2.5% of ED visits and represented the second-most-common discharge diagnosis in adults aged 20 to 39 years, were associated with being uninsured (odds ratio [OR] = 5.2 [reference: commercial insurance]; 95% confidence interval [CI] = 4.8, 5.5) or having Medicaid insurance (OR = 4.0; 95% CI = 3.7, 4.2), resulted in opioid (56%) and antibiotic (56%) prescriptions, and generated $402 (95% CI = $396, $408) in hospital costs per visit. Interviews revealed health system, community, provider, and patient contributors to ED dental visits. Potential solutions provided by interviewees included Medicaid benefit expansion, care coordination, water fluoridation, and patient education. CONCLUSIONS: Emergency department dental visits are a significant and costly public health problem for vulnerable individuals. Future efforts should focus on implementing multilevel interventions to reduce ED dental visits. PMID- 25790416 TI - Images of a Healthy Worksite: A Group-Randomized Trial for Worksite Weight Gain Prevention With Employee Participation in Intervention Design. AB - OBJECTIVES: We assessed the effects of a worksite multiple-component intervention addressing diet and physical activity on employees' mean body mass index (BMI) and the percentage of employees who were overweight or obese. METHODS: This group randomized trial (n = 3799) was conducted at 10 worksites in the northeastern United States. Worksites were paired and allocated into intervention and control conditions. Within- and between-groups changes in mean BMIs and in the percentage of overweight or obese employees were examined in a volunteer sample. RESULTS: Within-group mean BMIs decreased by 0.54 kilograms per meter squared (P = .02) and 0.12 kilograms per meter squared (P = .73) at the intervention and control worksites, respectively, resulting in a difference in differences (DID) decrease of 0.42 kilograms per meter squared (P = .33). The within-group percentage of overweight or obese employees decreased by 3.7% (P = .07) at the intervention worksites and increased by 4.9% (P = .1) at the control worksites, resulting in a DID decline of 8.6% (P = .02). CONCLUSIONS: Our findings support a worksite population strategy that might eventually reduce the prevalence of overweight and obesity by minimizing environmental exposures to calorically dense foods and increasing exposures to opportunities for energy expenditure within worksite settings. PMID- 25790417 TI - A comparison of liver disease mortality with HIV and overdose mortality among Georgia prisoners and releasees: a 2-decade cohort study of prisoners incarcerated in 1991. AB - OBJECTIVES: We investigated whether eventual causes of death among a cohort of inmates imprisoned in the southeastern United States differed from those in previous prisoner studies. METHODS: We matched 23 510 prisoners in Georgia, a state with historically low levels of heroin consumption but moderate amounts of injection drug use, who were incarcerated on June 30, 1991, to death registries through 2010. Main exposure was 4-year time intervals over 2 decades of observation; main outcome was mortality from liver disease, HIV, and overdose. RESULTS: Although the HIV-related mortality rate exceeded that from liver-related conditions before 2003, liver disease subsequently surpassed HIV as a cause of death. Among 3863 deaths, 22 (0.6%) occurred within 2 weeks after release from prison. Of these, only 2 were caused by accidental poisoning (likely drug overdose). Cardiovascular disease and cancer were the most frequent causes of death in this aging cohort. CONCLUSIONS: Our study design deemphasized immediate deaths but highlighted long-term sequelae of exposure to viral hepatitis and alcohol. Treating hepatitis C and implementing interventions to manage alcohol use disorders may improve survival among prisoners in the Southeast. PMID- 25790418 TI - Impact of the Garrett Lee Smith youth suicide prevention program on suicide mortality. AB - OBJECTIVES: We examined whether a reduction in youth suicide mortality occurred between 2007 and 2010 that could reasonably be attributed to Garrett Lee Smith (GLS) program efforts. METHODS: We compared youth mortality rates across time between counties that implemented GLS-funded gatekeeper training sessions (the most frequently implemented suicide prevention strategy among grantees) and a set of matched counties in which no GLS-funded training occurred. A rich set of background characteristics, including preintervention mortality rates, was accounted for with a combination of propensity score-based techniques. We also analyzed closely related outcomes that we did not expect to be affected by GLS as control outcomes. RESULTS: Counties implementing GLS training had significantly lower suicide rates among the population aged 10 to 24 years the year after GLS training than similar counties that did not implement GLS training (1.33 fewer deaths per 100 000; P = .02). Simultaneously, we found no significant difference in terms of adult suicide mortality rates or nonsuicide youth mortality the year after the implementation. CONCLUSIONS: These results support the existence of an important reduction in youth suicide rates resulting from the implementation of GLS suicide prevention programming. PMID- 25790419 TI - Ebola outbreak: from the perspective of African migrants in China. PMID- 25790420 TI - Haber et al. respond. PMID- 25790421 TI - Suicide ideation and bullying among US adolescents: examining the intersections of sexual orientation, gender, and race/ethnicity. AB - OBJECTIVES: We examined how race/ethnicity, gender, and sexual orientation shape adolescents' likelihood of being bullied and vulnerability to suicide ideation. METHODS: We analyzed pooled data from the 2009 and 2011 Youth Risk Behavior Surveys (n = 75 344) to assess race/ethnicity, gender, and sexual orientation variation in being bullied and suicide ideation. RESULTS: White and Hispanic gay and bisexual males, White lesbian and bisexual females, and Hispanic bisexual females were more likely to be bullied than were White heterosexual adolescents. Black lesbian, gay, and bisexual youths' vulnerability to being bullied was not significantly different from that of White heterosexual youths. Black and Hispanic heterosexual youths were less likely to be bullied than were White heterosexual youths. Despite differences in the likelihood of being bullied, sexual minority youths were more likely to report suicide ideation, regardless of their race/ethnicity, their gender, or whether they have been bullied. CONCLUSIONS: Future research should examine how adolescents' intersecting identities shape their experience of victimization and suicidality. School personnel should develop antibullying and antihomophobia policies in response to the disproportionate risk of being bullied and reporting suicidality among sexual minority youths. PMID- 25790422 TI - Perspectives of Maryland adults regarding caries prevention. AB - OBJECTIVES: We obtained in-depth information from low-income parents and caregivers of young children about their knowledge and understanding of and practices related to the prevention and control of dental caries (tooth decay). METHODS: In 2010, we conducted 4 focus groups in Maryland communities with low income, English-speaking parents and caregivers who had at least 1 child aged 6 years or younger or who were pregnant. We developed a focus group guide based on findings of a previous statewide random telephone survey of adults with young children. RESULTS: Most participants had limited understanding of and extensive misinformation about how to prevent dental caries. They were confused about the use of juice and its impact on their child's teeth and had limited understanding of the use of fluorides to prevent caries. Most did not drink tap water and did not give it to their children; rather, they used bottled water. CONCLUSIONS: These results and those of the statewide telephone survey strongly suggest the need for educational interventions designed for those with limited levels of education. PMID- 25790423 TI - Neighborhood disadvantage, preconception stressful life events, and infant birth weight. AB - OBJECTIVES: We sought to determine whether the effects of preconception stressful life events (PSLEs) on birth weight differed by neighborhood disadvantage. METHODS: We drew our data from the Early Childhood Longitudinal Study, Birth Cohort (2001-2002; n = 9300). We created a neighborhood disadvantage index (NDI) using county-level data from the 2000 US Census. We grouped the NDI into tertiles that represented advantaged, middle advantaged, and disadvantaged neighborhoods. Stratified multinomial logistic regressions estimated the effect of PSLEs on birth weight, controlling for confounders. RESULTS: We found a gradient in the relationship between women's exposure to PSLEs and having a very low birth weight (VLBW) infant by NDI tertile; the association was strongest in disadvantaged neighborhoods (adjusted odd ratio [AOR] = 1.62; 95% confidence interval [CI] = 1.04, 2.53), followed by middle (AOR = 1.39; 95% CI = 1.00, 1.93) and advantaged (AOR = 1.29; 95% CI = 0.91, 1.82) neighborhoods. We observed a similar gradient for women with chronic conditions and among minority mothers. CONCLUSIONS: Women who experienced PSLEs, who had chronic conditions, or were racial/ethnic minorities had the greatest risk of having VLBW infants if they lived in disadvantaged neighborhoods; this suggests exacerbation of risk within disadvantaged environments. Interventions to reduce rates of VLBW should focus on reducing the deleterious effects of stressors and on improving neighborhood conditions. PMID- 25790424 TI - Medicaid Expansion Under the Affordable Care Act: Potential Changes in Receipt of Mental Health Treatment Among Low-Income Nonelderly Adults With Serious Mental Illness. AB - OBJECTIVES: We designed this study to examine differences in receipt of mental health treatment between low-income uninsured nonelderly adults with serious mental illness (SMI) who were eligible for Medicaid under the Affordable Care Act (ACA) and their existing Medicaid counterparts. Assessing these differences might estimate the impact of the Medicaid expansion efforts under the ACA on receipt of mental health treatment among uninsured nonelderly adults with SMI. METHODS: We examined data from 2000 persons aged 18 to 64 years who participated in the 2008 to 2013 National Survey on Drug Use and Health, had income below 138% of the federal poverty level, met SMI criteria, and either were uninsured (n = 1000) or had Medicaid-only coverage (n = 1000). We defined SMI according to the Alcohol, Drug Abuse, and Mental Health Administration Reorganization Act. We used descriptive analyses and logistic regression modeling. RESULTS: In the 28 states currently expanding Medicaid, the model-adjusted prevalence (MAP) of receiving mental health treatment among Medicaid-only enrollees with SMI (MAP = 71.3%; 95% confidence interval [CI] = 65.74%, 76.29%) was 30.1% greater than their uninsured counterparts (MAP = 54.8%; 95% CI = 48.16%, 61.33%). In the United States, the MAP of receiving mental health treatment among Medicaid-only enrollees with SMI (MAP = 70.4%; 95% CI = 65.67%, 74.70%) was 35.9% higher than their uninsured counterparts (MAP = 51.8%; 95% CI = 46.98%, 56.65%). CONCLUSIONS: Estimated increases in receipt of mental health treatment because of enrolling in Medicaid among low-income uninsured adults with SMI might help inform planning and implementation efforts for the Medicaid expansion under the ACA. PMID- 25790425 TI - Friends matter: protective and harmful aspects of male friendships associated with past-year sexual aggression in a community sample of young men. AB - OBJECTIVES: We extended past research on sexual violence etiology by examining the impact of perceived pressure to have sex by any means and the types of objectifying and egalitarian language that friends used when discussing women. METHODS: We examined a community sample of young single men interested in dating women (n = 423) who completed audio computer-assisted self-interviews at baseline (spring/summer 2008) and 1 year later (spring/summer 2009). We used hierarchical logistic regression analyses that controlled for baseline sexual aggression. RESULTS: Approximately one quarter of participants (n = 108) reported that they made a woman engage in some type of sexual activity during the past year when they knew she was unwilling or unable to consent. Past-year perpetrators perceived more pressure from their friends to have sex by any means, felt less comfortable with their friends making egalitarian statements about women, and used more objectifying statements when describing how their friends talked about women compared with nonperpetrators. Seventy-eight percent of men were correctly classified by these predictors. CONCLUSIONS: Men's discussions with each other about women could foster an environment that encourages or discourages sexual violence. We discussed future research and prevention implications. PMID- 25790427 TI - Increasing access to fruits and vegetables: perspectives from the New York City experience. AB - Broad recognition now exists that price, availability, and other structural factors are meaningful barriers to fruit and vegetable consumption, particularly among low-income adults. Beginning in 2005, the New York City Department of Health and Mental Hygiene used the social-ecological model to develop a multifaceted effort to increase fruit and vegetable access citywide, with emphasis in low-income neighborhoods. Overall, the percentage of New York City adults who reported consuming no fruits and vegetables in the previous day decreased slightly over a 10-year period (2002: 14.3% [95% confidence interval = 13.4%, 15.2%]; 2012: 12.5% [95% confidence interval = 11.4%, 13.6%]; P for trend < .001). Our approach hypothesizes that complementary initiatives, implemented simultaneously, will create a citywide food environment that fuels changes in social norms and cultural preferences, increases consumer demand, and supports sustainable access to affordable produce. PMID- 25790426 TI - Racial/ethnic and socioeconomic differences in short-term breast cancer survival among women in an integrated health system. AB - OBJECTIVES: We examined the combined influence of race/ethnicity and neighborhood socioeconomic status (SES) on short-term survival among women with uniform access to health care and treatment. METHODS: Using electronic medical records data from Kaiser Permanente Northern California linked to data from the California Cancer Registry, we included 6262 women newly diagnosed with invasive breast cancer. We analyzed survival using multivariable Cox proportional hazards regression with follow-up through 2010. RESULTS: After consideration of tumor stage, subtype, comorbidity, and type of treatment received, non-Hispanic White women living in low-SES neighborhoods (hazard ratio [HR] = 1.28; 95% confidence interval [CI] = 1.07, 1.52) and African Americans regardless of neighborhood SES (high SES: HR = 1.44; 95% CI = 1.01, 2.07; low SES: HR = 1.88; 95% CI = 1.42, 2.50) had worse overall survival than did non-Hispanic White women living in high-SES neighborhoods. Results were similar for breast cancer-specific survival, except that African Americans and non-Hispanic Whites living in high-SES neighborhoods had similar survival. CONCLUSIONS: Strategies to address the underlying factors that may influence treatment intensity and adherence, such as comorbidities and logistical barriers, should be targeted at low-SES non-Hispanic White and all African American patients. PMID- 25790428 TI - Isolation and characterization of two cellulose morphology mutants of Gluconacetobacter hansenii ATCC23769 producing cellulose with lower crystallinity. AB - Gluconacetobacter hansenii, a Gram-negative bacterium, produces and secrets highly crystalline cellulose into growth medium, and has long been used as a model system for studying cellulose synthesis in higher plants. Cellulose synthesis involves the formation of beta-1,4 glucan chains via the polymerization of glucose units by a multi-enzyme cellulose synthase complex (CSC). These glucan chains assemble into ordered structures including crystalline microfibrils. AcsA is the catalytic subunit of the cellulose synthase enzymes in the CSC, and AcsC is required for the secretion of cellulose. However, little is known about other proteins required for the assembly of crystalline cellulose. To address this question, we visually examined cellulose pellicles formed in growth media of 763 individual colonies of G. hansenii generated via Tn5 transposon insertion mutagenesis, and identified 85 that produced cellulose with altered morphologies. X-ray diffraction analysis of these 85 mutants identified two that produced cellulose with significantly lower crystallinity than wild type. The gene disrupted in one of these two mutants encoded a lysine decarboxylase and that in the other encoded an alanine racemase. Solid-state NMR analysis revealed that cellulose produced by these two mutants contained increased amounts of non crystalline cellulose and monosaccharides associated with non-cellulosic polysaccharides as compared to the wild type. Monosaccharide analysis detected higher percentages of galactose and mannose in cellulose produced by both mutants. Field emission scanning electron microscopy showed that cellulose produced by the mutants was unevenly distributed, with some regions appearing to contain deposition of non-cellulosic polysaccharides; however, the width of the ribbon was comparable to that of normal cellulose. As both lysine decarboxylase and alanine racemase are required for the integrity of peptidoglycan, we propose a model for the role of peptidoglycan in the assembly of crystalline cellulose. PMID- 25790429 TI - GC-MS metabolomics on PPARalpha-dependent exacerbation of colitis. AB - Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, was found to exacerbate inflammation and tissue injury in experimental acute colitis mice. Through lipidomics analysis, bioactive sphingolipids were significantly up-regulated in the colitis group. In this study, to provide further insight into the PPARalpha-dependent exacerbation of colitis, gas chromatography-mass spectrometry (GC/MS) based metabolomics was employed to investigate the serum and colon of dextran sulfate sodium (DSS)-induced colitis mice treated with fenofibrate, with particular emphasis on changes in low molecular-weight metabolites. With the aid of multivariate analysis and metabolic pathway analysis, potential metabolite markers in the amino acid metabolism, urea cycle, purine metabolism, and citrate cycle were highlighted, such as glycine, serine, threonine, malic acid, isocitric acid, uric acid, and urea. The level changes of these metabolites in either serum or colons of colitis mice were further potentiated following fenofibrate treatment. Accordingly, the expression of threonine aldolase and phosphoserine aminotransferase 1 was significantly up regulated in colitis mice and further potentiated in fenofibrate/DSS-treated mice. It was revealed that beyond the control of lipid metabolism, PPARalpha also shows effects on the above pathways, resulting in enhanced protein catabolism and energy expenditure, increased bioactive sphingolipid metabolism and proinflammatory state, which were possibly related to the exacerbated colitis. PMID- 25790430 TI - Correction: The M3 muscarinic receptor is required for optimal adaptive immunity to helminth and bacterial infection. PMID- 25790432 TI - Inferring resilience to fragmentation-induced changes in plant communities in a semi-arid Mediterranean ecosystem. AB - Predicting the capacity of ecosystems to absorb impacts from disturbance events (resilience), including land-use intensification and landscape fragmentation, is challenging in the face of global change. Little is known about the impacts of fragmentation on ecosystem functioning from a multi-dimensional perspective (multiple traits). This study used 58 500-m linear transects to quantify changes in the functional composition and resilience of vascular plant communities in response to an increase in landscape fragmentation in 18 natural scrubland fragments embedded within a matrix of abandoned crop fields in Cabo de Gata-Nijar Natural Park, Almeria, Spain. Changes in functional community composition were measured using functional diversity indices (functional richness and functional dispersion) that were based on 12 plant traits. Resilience was evaluated using the functional redundancy and response diversity from the perspective of plant dispersal, which is important, particularly, in fragmented landscapes. Scrubland fragmentation was measured using the Integral Index of Connectivity (IIC). The functional richness of the plant communities was higher in the most fragmented scrubland. Conversely, the functional dispersion (i.e., spread) of trait values among species in the functional trait space was lower at the most fragmented sites; consequently, the ecological tolerance of the vegetation to scrubland fragmentation decreased. Classifying the plant species into four functional groups indicated that fragmentation favoured an increase in functional redundancy in the 'short basal annual forbs and perennial forbs' group, most of which are species adapted to degraded soils. An assessment based on the traits associated with plant dispersal indicated that the resilience of 'woody plants', an important component in the Mediterranean scrubland, and habitat fragmentation were negatively correlated; however, the correlation was positive in the 'short basal annual forbs and perennial forbs' and the 'grasses' groups. PMID- 25790433 TI - Effect of the surface modification, size, and shape on cellular uptake of nanoparticles. AB - Nowadays successful application of nanoparticles for therapeutic objects needs the effective uptake of them by cells. Hence, studying of the interaction of nanoparticles with cell membrane for effective cellular uptaking seems to be vital and important. Trafficking of lipids, proteins, glucose, and other biomaterials into the cells is possible from two major exocytic and endocytic pathways. The penetration ability of nanoparticles into the cells must be considered in engineering of these particles. Enormous in vivo and in vitro experiments in the field of nanotechnology have confirmed the effect of physiochemistry properties in state of cell-nanoparticles interactions. Thus, the optimization of parameters directly related to physicochemical characteristics through the preparation process seems to be necessary for improving therapeutic effects of nanocarriers. Besides, biological medium and cell division also affect the amount of nanoparticle uptaking into the cells. This study reviews the influence of size, shape, the surface modification of nano particles, medium, and cell division effects on the cellular absorption of drug/gene nanocarriers. PMID- 25790431 TI - Transcriptional regulation of chemokine expression in ovarian cancer. AB - The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for their stringent transcriptional regulation. In this Review, we highlight the key mechanisms that regulate the transcription of pro-inflammatory chemokines in ovarian cancer cells, and that have important roles in controlling ovarian cancer progression. We further discuss the potential mechanisms underlying the increased chemokine expression in drug resistance, along with our perspective for future studies. PMID- 25790434 TI - Catheter Ablation of Ventricular Arrhythmias using a Fluoroscopy Image Integration Module. AB - BACKGROUND: The impact of the CartoUnivuTM technology (Biosense Webster, Diamond Bar, CA, USA) on fluoroscopy exposure compared to a conventional approach using electroanatomical mapping (Carto 3TM) was evaluated in patients undergoing radiofrequency ablation for ventricular tachyarrhythmias (VT). METHODS AND RESULTS: We prospectively evaluated 23 patients undergoing VT ablation using the CartoUnivuTM technology. The CartoUnivuTM Module integrates fluoroscopic images and cine loops into the electroanatomical mapping system. As a control group, 23 out of 88 VT patients (ablated using conventional fluoroscopy supplemented by electromagnetic mapping with the Carto 3TM System) were matched for age, gender, body surface area, operator, redo-procedure, presence of coronary artery disease, and left ventricular dysfunction using propensity score matching. A significant reduction in fluoroscopy exposure was observed in the CartoUnivuTM group when compared to the conventional group (10.57 +/- 7.93 minutes vs 18.52 +/- 11.24 minutes, P_= 0.008; 611 cGy/cm(2) vs 1650 cGy/cm(2) , P = 0.001). In multivariate analysis, the CartoUnivuTM module was an independent predictor of reduced fluoroscopy use. CONCLUSION: This is a report on the clinical application of the CartoUnivu system for VT ablation. CartoUnivuTM markedly reduced fluoroscopy time and dose compared to conventional fluoroscopy/electroanatomical mapping. PMID- 25790435 TI - The GerW protein is not involved in the germination of spores of Bacillus species. AB - Germination of dormant spores of Bacillus species is initiated when nutrient germinants bind to germinant receptors in spores' inner membrane and this interaction triggers the release of dipicolinic acid and cations from the spore core and their replacement by water. Bacillus subtilis spores contain three functional germinant receptors encoded by the gerA, gerB, and gerK operons. The GerA germinant receptor alone triggers germination with L-valine or L-alanine, and the GerB and GerK germinant receptors together trigger germination with a mixture of L-asparagine, D-glucose, D-fructose and KCl (AGFK). Recently, it was reported that the B. subtilis gerW gene is expressed only during sporulation in developing spores, and that GerW is essential for L-alanine germination of B. subtilis spores but not for germination with AGFK. However, we now find that loss of the B. subtilis gerW gene had no significant effects on: i) rates of spore germination with L-alanine; ii) spores' levels of germination proteins including GerA germinant receptor subunits; iii) AGFK germination; iv) spore germination by germinant receptor-independent pathways; and v) outgrowth of germinated spores. Studies in Bacillus megaterium did find that gerW was expressed in the developing spore during sporulation, and in a temperature-dependent manner. However, disruption of gerW again had no effect on the germination of B. megaterium spores, whether germination was triggered via germinant receptor-dependent or germinant receptor-independent pathways. PMID- 25790436 TI - Evaluation of intestinal phosphate binding to improve the safety profile of oral sodium phosphate bowel cleansing. AB - Prior to colonoscopy, bowel cleansing is performed for which frequently oral sodium phosphate (OSP) is used. OSP results in significant hyperphosphatemia and cases of acute kidney injury (AKI) referred to as acute phosphate nephropathy (APN; characterized by nephrocalcinosis) are reported after OSP use, which led to a US-FDA warning. To improve the safety profile of OSP, it was evaluated whether the side-effects of OSP could be prevented with intestinal phosphate binders. Hereto a Wistar rat model of APN was developed. OSP administration (2 times 1.2 g phosphate by gavage) with a 12h time interval induced bowel cleansing (severe diarrhea) and significant hyperphosphatemia (21.79 +/- 5.07 mg/dl 6h after the second OSP dose versus 8.44 +/- 0.97 mg/dl at baseline). Concomitantly, serum PTH levels increased fivefold and FGF-23 levels showed a threefold increase, while serum calcium levels significantly decreased from 11.29 +/- 0.53 mg/dl at baseline to 8.68 +/- 0.79 mg/dl after OSP. OSP administration induced weaker NaPi 2a staining along the apical proximal tubular membrane. APN was induced: serum creatinine increased (1.5 times baseline) and nephrocalcinosis developed (increased renal calcium and phosphate content and calcium phosphate deposits on Von Kossa stained kidney sections). Intestinal phosphate binding (lanthanum carbonate or aluminum hydroxide) was not able to attenuate the OSP induced side effects. In conclusion, a clinically relevant rat model of APN was developed. Animals showed increased serum phosphate levels similar to those reported in humans and developed APN. No evidence was found for an improved safety profile of OSP by using intestinal phosphate binders. PMID- 25790438 TI - Correction: Standardizing visual control devices for tsetse flies: East African species Glossina fuscipes fuscipes and Glossina tachinoides. PMID- 25790437 TI - Dual role of cAMP in the transcriptional regulation of multidrug resistance associated protein 4 (MRP4) in pancreatic adenocarcinoma cell lines. AB - Cyclic AMP represents one of the most studied signaling molecules and its role in proliferation and differentiation processes has been well established. Intracellular cAMP levels are tightly regulated where the MRP4 transporter plays a major role. In the present study, we sought to establish whether cAMP modulated MRP4 expression in pancreatic adenocarcinoma cell lines. Quantitative PCR and western blot studies showed that cAMP-increasing agents enhanced MRP4 transcripts and protein levels in PANC-1 cells. Reporter luciferase experiments carried out in pancreatic AR42J cells showed that intracellular cAMP up-regulates MRP4 through an Epac2- and Rap1-mediated mechanism whereas extracellular cAMP reduced MRP4 promoter activity by a MEK/ERK-mediated pathway. Present results show that cAMP regulates MRP4 promoter activity, and further indicate that the balance between intracellular and extracellular cAMP levels determines MRP4 expression. PMID- 25790439 TI - Hidden benefits of electric vehicles for addressing climate change. AB - There is an increasingly hot debate on whether the replacement of conventional vehicles (CVs) by electric vehicles (EVs) should be delayed or accelerated since EVs require higher cost and cause more pollution than CVs in the manufacturing process. Here we reveal two hidden benefits of EVs for addressing climate change to support the imperative acceleration of replacing CVs with EVs. As EVs emit much less heat than CVs within the same mileage, the replacement can mitigate urban heat island effect (UHIE) to reduce the energy consumption of air conditioners, benefitting local and global climates. To demonstrate these effects brought by the replacement of CVs by EVs, we take Beijing, China, as an example. EVs emit only 19.8% of the total heat emitted by CVs per mile. The replacement of CVs by EVs in 2012 could have mitigated the summer heat island intensity (HII) by about 0.94 degrees C, reduced the amount of electricity consumed daily by air conditioners in buildings by 14.44 million kilowatt-hours (kWh), and reduced daily CO2 emissions by 10,686 tonnes. PMID- 25790440 TI - Peeling the onion: a revised model of the electron count for matryoshka clusters. AB - We have provided a model for understanding two isoelectronic matryoshka clusters, [Sn@Cu12@Sn20](12-) and [As@Ni12@As20](3-). By dividing each of the clusters in a layer-by-layer manner and allowing each layer to follow a simple electron-filling rule, we can formulate a consistent model to explain experimental and computed properties of both matryoshka clusters that cannot be adequately explained by existing models. By analysing these clusters in a way analogous to peeling an onion, we can not only have an understanding of the structure and bonding of the two matryoshka clusters under study, but also have a generalizable model to handle certain p/d-block@d-block endohedral clusters. PMID- 25790441 TI - Haloperidol and sudden cardiac death in dementia: autopsy findings in psychiatric inpatients. AB - OBJECTIVE: Treatment with haloperidol has been shown, in studies using death certificates and prescription files, to be associated with an excess of sudden cardiac deaths, and regulatory warnings highlight this risk in patients with dementia. We used autopsy findings to determine whether the rate of sudden cardiac death is greater in cases of unexpected deaths of patients with dementia treated with haloperidol. METHODS: From 1989 through 2013, 1219 patients with a primary diagnosis of dementia with behavioral disturbance were admitted to a psychiatric hospital, and 65 (5.3%) died suddenly. Sixty-five patients (5.3%) died unexpectedly. Complete post-mortem examinations after the sudden death were performed in 55 (84.6%) patients. Twenty-seven of the autopsied cases (49.1%) had been treated with haloperidol orally (2.2 mg +/- 2.1 mg/day), the only antipsychotic used in this cohort. Univariable comparisons and multivariable regression analyses compared the groups of patients with or without sudden cardiac death. RESULTS: The leading causes of death were sudden cardiac death (32.7%), myocardial infarction (25.5% of patients), pneumonia (23.6%), and stroke (10.9%). Patients with sudden cardiac death and those with anatomically established cause of death were similar regarding the use of haloperidol (p = 0.5). Sudden cardiac death patients were more likely to suffer from Alzheimer's dementia (p = 0.027) and to have a past history of heart disease (p = 0.0094), and less likely to have been treated with a mood stabilizer (p = 0.024), but none of these variables were independent predictors of sudden cardiac death. CONCLUSION: Autopsy data suggest that oral haloperidol is not associated with increased risk of sudden cardiac death in psychiatric inpatients with dementia. PMID- 25790442 TI - Titrating haemophilia B phenotypes using siRNA strategy: evidence that antithrombotic activity is separated from bleeding liability. AB - Haemophilia A and B are characterised by a life-long bleeding predisposition, and several lines of evidence suggest that risks of atherothrombotic events may also be reduced. Establishing a direct correlation between coagulation factor levels, thrombotic risks and bleeding propensity has long been hampered by an inability to selectively and specifically inhibit coagulation factor levels. Here, the exquisite selectivity of gene silencing combined with a gene knockout (KO) approach was used to define the relative contribution of factor IX (fIX) to thrombosis and primary haemostasis in the rat. Using a lipid nanoparticle (LNP) formulation, we successfully delivered fIX siRNAs to the liver by intravenous administration. The knockdown (KD) of target gene mRNA was achieved rapidly (within 24 hour post-siRNA dosing), sustained (maintained for at least 7 days post dosing) and not associated with changes in mRNA expression levels of other coagulation factors. We found that intermediate levels of liver fIX mRNA silencing (60-95 %) translating into a 50-99 % reduction of plasma fIX activity provided protection from thrombosis without prolonging the cuticle bleeding time. Over 99 % inhibition of fIX activity was required to observe increase in bleeding, a phenotype confirmed in fIX KO rats. These data provide substantial evidence of a participation of fIX in the mechanisms regulating thrombosis prior to those regulating primary haemostasis, therefore highlighting the potential of fIX as a therapeutic target. In addition, hepatic mRNA silencing using LNP encapsulated siRNAs may represent a promising novel approach for the chronic treatment and prevention of coagulation-dependent thrombotic disorders in humans. PMID- 25790443 TI - The financial impact of the 'zero-markup policy for essential drugs' on patients in county hospitals in western rural China. AB - OBJECTIVE: With a quasi-experimental design, this study aims to assess whether the Zero-markup Policy for Essential Drugs (ZPED) reduces the medical expense for patients at county hospitals, the major healthcare provider in rural China. METHODS: Data from Ningshan county hospital and Zhenping county hospital, China, include 2014 outpatient records and 9239 inpatient records. Quantitative methods are employed to evaluate ZPED. Both hospital-data difference-in-differences and individual-data regressions are applied to analyze the data from inpatient and outpatient departments. RESULTS: In absolute terms, the total expense per visit reduced by 19.02 CNY (3.12 USD) for outpatient services and 399.6 CNY (65.60 USD) for inpatient services. In relative terms, the expense per visit was reduced by 11% for both outpatient and inpatient services. Due to the reduction of inpatient expense, the estimated reduction of outpatient visits is 2% among the general population and 3.39% among users of outpatient services. The drug expense per visit dropped by 27.20 CNY (4.47 USD) for outpatient services and 278.7 CNY (45.75 USD) for inpatient services. The proportion of drug expense out of total expense per visit dropped by 11.73 percentage points in outpatient visits and by 3.92 percentage points in inpatient visits. CONCLUSION: Implementation of ZPED is a benefit for patients in both absolute and relative terms. The absolute monetary reduction of the per-visit inpatient expense is 20 times of that in outpatient care. According to cross-price elasticity, the substitution between inpatient and outpatient due to the change in inpatient price is small. Furthermore, given that the relative reductions are the same for outpatient and inpatient visits, according to relative thinking theory, the incentive to utilize outpatient or inpatient care attributed to ZPED is equivalent, regardless of the 20-times price difference in absolute terms. PMID- 25790446 TI - Semiconductor/relaxor 0-3 type composites without thermal depolarization in Bi0.5Na0.5TiO3-based lead-free piezoceramics. AB - Commercial lead-based piezoelectric materials raised worldwide environmental concerns in the past decade. Bi0.5Na0.5TiO3-based solid solution is among the most promising lead-free piezoelectric candidates; however, depolarization of these solid solutions is a longstanding obstacle for their practical applications. Here we use a strategy to defer the thermal depolarization, even render depolarization-free Bi0.5Na0.5TiO3-based 0-3-type composites. This is achieved by introducing semiconducting ZnO particles into the relaxor ferroelectric 0.94Bi0.5Na0.5TiO3-0.06BaTiO3 matrix. The depolarization temperature increases with increasing ZnO concentration until depolarization disappears at 30 mol% ZnO. The semiconducting nature of ZnO provides charges to partially compensate the ferroelectric depolarization field. These results not only pave the way for applications of Bi0.5Na0.5TiO3-based piezoceramics, but also have great impact on the understanding of the mechanism of depolarization so as to provide a new design to optimize the performance of lead-free piezoelectrics. PMID- 25790445 TI - Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. AB - Tuberculosis (TB) remains an eminent global burden with one third of the world's population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-beta), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interferon-gamma (IFN-gamma), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection. PMID- 25790447 TI - Identification of genetic loci affecting the severity of symptoms of Hirschsprung disease in rats carrying Ednrbsl mutations by quantitative trait locus analysis. AB - Hirschsprung's disease (HSCR) is a congenital disease in neonates characterized by the absence of the enteric ganglia in a variable length of the distal colon. This disease results from multiple genetic interactions that modulate the ability of enteric neural crest cells to populate developing gut. We previously reported that three rat strains with different backgrounds (susceptible AGH-Ednrbsl/sl, resistant F344-Ednrbsl/sl, and LEH-Ednrbsl/sl) but the same null mutation of Ednrb show varying severity degrees of aganglionosis. This finding suggests that strain-specific genetic factors affect the severity of HSCR. Consistent with this finding, a quantitative trait locus (QTL) for the severity of HSCR on chromosome (Chr) 2 was identified using an F2 intercross between AGH and F344 strains. In the present study, we performed QTL analysis using an F2 intercross between the susceptible AGH and resistant LEH strains to identify the modifier/resistant loci for HSCR in Ednrb-deficient rats. A significant locus affecting the severity of HSCR was also detected within the Chr 2 region. These findings strongly suggest that a modifier gene of aganglionosis exists on Chr 2. In addition, two potentially causative SNPs (or mutations) were detected upstream of a known HSCR susceptibility gene, Gdnf. These SNPs were possibly responsible for the varied length of gut affected by aganglionosis. PMID- 25790448 TI - PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines. AB - While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF related apoptosis-inducing ligand (TRAIL). Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells. PMID- 25790449 TI - Beyond traumatic events and chronic low back pain: assessment and treatment implications of avoided emotional experiences. PMID- 25790450 TI - Distinct quantitative sensory testing profiles in nonspecific chronic back pain subjects with and without psychological trauma. AB - Psychological trauma is associated with an increased risk for chronification of nonspecific chronic back pain (nsCLBP) independent of posttraumatic stress disorder (PTSD). However, the mechanisms underlying the role of psychological trauma in nsCLBP are less clear than in PTSD. Therefore, this study considered whether psychological trauma exposure (TE) is accompanied by specific alterations in pain perception. The study included 56 participants with nsCLBP and TE (nsCLBP TE), 93 participants with nsCLBP without TE (nsCLBP-W-TE), and 31 pain-free controls. All participants underwent a thorough clinical evaluation. The standardized quantitative sensory testing protocol of the "German Research Network on Neuropathic Pain" was used to obtain comprehensive profiles on somatosensory functions in painful (back) and non-painful areas (hand). The protocol consisted of thermal and mechanical detection as well as pain thresholds, vibration thresholds, and pain sensitivity to sharp and blunt mechanical stimuli. Psychological trauma was validated by structured clinical interview. Trauma-associated symptom severity, anxiety, and depressive symptomatology were assessed by self-report questionnaires. Differences in somatosensory function were seen only for pressure pain thresholds. Compared with controls, nsCLBP-TE revealed hyperalgesia generalized in space with lower thresholds in painful and non-painful areas, whereas nsCLBP-W-TE demonstrated localized alterations with decreased thresholds only in the pain-affected area of the back (P <= 0.006). Our findings suggest an augmented central pain processing in nsCLBP-TE (alterations in painful and non-painful areas), whereas nsCLBP-W-TE show only local changes (alterations only in the painful area) suggesting regional sensitization processes. This finding might explain why TE without PTSD is associated with an increased prevalence of chronic pain. PMID- 25790452 TI - Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA induced inflammatory pain in rats. AB - Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia. PMID- 25790451 TI - Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. AB - Omega-3 and omega-6 fatty acids are precursors of bioactive lipid mediators posited to modulate both physical pain and psychological distress. In a randomized trial of 67 subjects with severe headaches, we recently demonstrated that targeted dietary manipulation-increasing omega-3 fatty acids with concurrent reduction in omega-6 linoleic acid (the H3-L6 intervention)-produced major reductions in headache compared with an omega-6 lowering (L6) intervention. Because chronic pain is often accompanied by psychological distress and impaired health-related quality of life (HRQOL), we used data from this trial to examine whether the H3-L6 intervention favorably impacted these domains. Additionally, we examined the effect of the interventions on the number of cases with substantial physical or mental impairments as defined by cutoff values in the Brief Symptom Inventory (BSI-18), Medical Outcomes Study Short Forms 12 (SF-12), Headache Impact Test (HIT-6), and the number of headache days per month. In the intention to-treat analysis, participants in the H3-L6 group experienced statistically significant reductions in psychological distress (BSI-18 mean difference: -6.56; 95% confidence interval [CI]: -11.43 to -1.69) and improvements in SF-12 mental (mean difference: 6.01; 95% CI: 0.57 to 11.45) and physical (mean difference: 6.65; 95% CI: 2.14 to 11.16) health summary scores. At 12 weeks, the proportion of subjects experiencing substantial impairment according to cutoff values in the BSI-18, SF-12 physical, HIT-6, and headache days per month was significantly lower in the H3-L6 group. Dietary manipulation of n-3 and n-6 fatty acids, previously shown to produce major improvements in headache, was found to also reduce psychological distress and improve HRQOL and function. PMID- 25790453 TI - Clinically derived early postoperative pain trajectories differ by age, sex, and type of surgery. AB - The objective of this study was to determine the effects of age, sex, and type of surgery on postoperative pain trajectories derived in a clinical setting from pain assessments in the first 24 hours after surgery. This study is a retrospective cohort study using a large electronic medical records system to collect and analyze surgical case data. The sample population included adult patients undergoing nonambulatory nonobstetric surgery in a single institution over a 1-year period. Analyses of postoperative pain trajectories were performed using a linear mixed-effects model. Pain score observations (91,708) from 7293 patients were included in the statistical analysis. On average, the pain score decreased about 0.042 (95% confidence interval [CI]: -0.044 to -0.040) points on the numerical rating scale (NRS) per hour after surgery for the first 24 postoperative hours. The pain score reported by male patients was approximately 0.27 (95% CI: -0.380 to -0.168) NRS points lower than that reported by females. Pain scores significantly decreased over time in all age groups, with a slightly more rapid decrease for younger patients. Pain trajectories differed by anatomic location of surgery, ranging from -0.054 (95% CI: -0.062 to -0.046) NRS units per hour for integumentary and nervous surgery to -0.104 (95% CI: -0.110 to -0.098) NRS units per hour for digestive surgery, and a positive trajectory (0.02 [95% CI: 0.016 to 0.024] NRS units per hour) for musculoskeletal surgery. Our data support the important role of time after surgery in considering the influence of biopsychosocial and clinical factors on acute postoperative pain. PMID- 25790454 TI - Dry-needling and exercise for chronic whiplash-associated disorders: a randomized single-blind placebo-controlled trial. AB - This randomized controlled trial investigated the effectiveness and cost effectiveness of dry-needling and exercise compared with sham dry-needling and exercise for chronic whiplash-associated disorders (WAD). The setting was a single university centre and 4 physiotherapy practices in Queensland, Australia. Eighty patients with chronic WAD (>3 months) were enrolled between June 2009 and August 2012 with 1-year follow-up completed in August 2013. The interventions were 6 weeks of dry-needling to posterior neck muscles (n = 40) and exercise or sham dry-needling and exercise (n = 40). The primary outcomes of the Neck Disability Index (NDI) and self-rated recovery were measured at baseline, 6 and 12 weeks, 6 and 12 months by a blinded assessor. Analysis was intention to treat. An economic evaluation was planned but missing data deemed further analysis unwarranted. Seventy-nine patients (99%) were followed up at 6 weeks, 78 (98%) at 12 weeks, 74 (93%) at 6 months, and 73 (91%) at 12 months. The dry-needling and exercise intervention was more effective than sham dry-needling and exercise in reducing disability at 6 and 12 months but not at 6 and 12 weeks. The treatment effects were small and not clinically worthwhile. At 6 weeks, the treatment effect on the 0-100 NDI was -0.3 (95% confidence interval -5.4 to 4.7), 12 weeks 0.3 (-5.2 to 4.9), 6 months -4.4 (-9.6 to -0.74), and 12 months -3.8 (-9.1 to 0.5). There was no effect for self-rated recovery. In patients with chronic WAD, dry-needling and exercise has no clinically worthwhile effects over sham dry needling and exercise. PMID- 25790455 TI - GABAAergic inhibition or dopamine denervation of the A11 hypothalamic nucleus induces trigeminal analgesia. AB - Descending pain-modulatory systems, either inhibitory or facilitatory, play a critical role in both acute and chronic pain. Compared with serotonin and norepinephrine, little is known about the function of dopamine (DA). We characterized the anatomical organization of descending DA pathways from hypothalamic A11 nuclei to the medullary dorsal horn (MDH) and investigated their role in trigeminal pain. Immunochemistry analysis reveals that A11 is a heterogeneous nucleus that contains at least 3 neuronal phenotypes, DA, GABA, and alpha-calcitonin gene-related peptide (alpha-CGRP) neurons, exhibiting different distribution patterns, with a large proportion of GABA relative to DA neurons. Using fluorogold, we show that descending pathways from A11 nuclei to MDH originate mainly from DA neurons and are bilateral. Facial nociceptive stimulation elevates Fos immunoreactivity in both ipsilateral and contralateral A11 nuclei. Fos immunoreactivity is not detected in DA or projecting neurons but, interestingly, in GABA neurons. Finally, inactivating A11, using muscimol, or partially lesioning A11 DA neurons, using the neurotoxin 6-hydroxydopamine, inhibits trigeminal pain behavior. These results show that A11 nuclei are involved in pain processing. Interestingly, however, pain seems to activate GABAergic neurons within A11 nuclei, which suggests that pain inhibits rather than activates descending DA controls. We show that such inhibition produces an antinociceptive effect. Pain-induced inhibition of descending DA controls and the resulting reduced DA concentration within the dorsal horn may inhibit the transfer of nociceptive information to higher brain centers through preferential activation of dorsal horn D2-like receptors. PMID- 25790456 TI - Selective keratinocyte stimulation is sufficient to evoke nociception in mice. AB - The skin epidermis is densely innervated by peripheral sensory nerve endings. Nociceptive neurons, whose terminals are in close contact with epidermal keratinocytes, can be activated directly by noxious physical and chemical stimuli to trigger pain. However, whether keratinocytes can signal acutely to sensory nerve terminals to initiate pain in vivo remains unclear. Here, using the keratin 5 promoter to selectively express the capsaicin receptor TRPV1 in keratinocytes of TRPV1-knockout mice, we achieved specific stimulation of keratinocytes with capsaicin. Using this approach, we found that keratinocyte stimulation was sufficient to induce strong expression of the neuronal activation marker, c-fos, in laminae I and II of the ipsilateral spinal cord dorsal horn and to evoke acute paw-licking nocifensive behavior and conditioned place aversion. These data provide direct evidence that keratinocyte stimulation is sufficient to evoke acute nociception-related responses. PMID- 25790457 TI - Pain, agitation, and behavioural problems in people with dementia admitted to general hospital wards: a longitudinal cohort study. AB - Pain is underdetected and undertreated in people with dementia. We aimed to investigate the prevalence of pain in people with dementia admitted to general hospitals and explore the association between pain and behavioural and psychiatric symptoms of dementia (BPSD). We conducted a longitudinal cohort study of 230 people, aged above 70, with dementia and unplanned medical admissions to 2 UK hospitals. Participants were assessed at baseline and every 4 days for self reported pain (yes/no question and FACES scale) and observed pain (Pain Assessment in Advanced Dementia scale [PAINAD]) at movement and at rest, for agitation (Cohen-Mansfield Agitating Inventory [CMAI]) and BPSD (Behavioural Pathology in Alzheimer Disease Scale [BEHAVE-AD]). On admission, 27% of participants self-reported pain rising to 39% on at least 1 occasion during admission. Half of them were able to complete the FACES scale, this proportion decreasing with more severe dementia. Using the PAINAD, 19% had pain at rest and 57% had pain on movement on at least 1 occasion (in 16%, this was persistent throughout the admission). In controlled analyses, pain was not associated with CMAI scores but was strongly associated with total BEHAVE-AD scores, both when pain was assessed on movement (beta = 0.20, 95% confidence interval [CI] = 0.07 0.32, P = 0.002) and at rest (beta = 0.41, 95% CI = 0.14-0.69, P = 0.003). The association was the strongest for aggression and anxiety. Pain was common in people with dementia admitted to the acute hospital and associated with BPSD. Improved pain management may reduce distressing behaviours and improve the quality of hospital care for people with dementia. PMID- 25790458 TI - Within-person variability in relationship satisfaction moderates partners' pain estimation in vulvodynia couples. AB - Models of pain communication propose that the social environment contributes to partners' pain estimation. This study examined partners' pain estimation in vulvodynia, an idiopathic vulvovaginal pain condition that disrupts the sexuality and relationships of affected couples. Specifically, we investigated (1) the overall bias and tracking accuracy of male partners' perceptions of women's pain during intercourse and (2) the influence of men's within-person variability in relationship satisfaction on bias and accuracy. Sixty-nine women (mean age = 28.1, SD = 6.7) diagnosed with vulvodynia and their cohabiting male partners (mean age = 29.7, SD = 8.1) participated in an 8-week daily diary study. On sexual intercourse days (mean = 6.1, SD = 5.4), men reported their perception of women's pain during intercourse and women self-reported their pain. Men reported their daily relationship satisfaction on all diary days. Men's within-person variability in relationship satisfaction was represented by the SD of relationship satisfaction scores across all daily diaries. Results indicated that men's perceptions were both accurate in that they tracked changes in women's pain and biased in that they generally underestimated this pain. Men's variability in relationship satisfaction moderated tracking accuracy such that men with higher variability manifested lower tracking accuracy for women's pain. Men's higher variability in relationship satisfaction may interfere with their motivation to accurately infer their female partner's pain. Poorer pain estimation may impair men's ability to adjust their emotional and behavioral responses to women's pain, which may have negative consequences for the couples' coping with vulvodynia. PMID- 25790459 TI - Projections of on-farm salinity in coastal Bangladesh. AB - This paper quantifies the expected impacts of climate change, climate variability and salinity accumulation on food production in coastal Bangladesh during the dry season. This forms part of a concerted series of actions on agriculture and salinity in Bangladesh under the UK funded Ecosystems for Poverty Alleviation programme and the British Council INSPIRE scheme. The work was undertaken by developing simulation models for soil water balances, dry season irrigation requirements and the effectiveness of the monsoon season rainfall at leaching accumulated salts. Simulations were run from 1981 to 2098 using historical climate data and a daily climate data set based on the Met Office Hadley Centre HadRM3P regional climate model. Results show that inter-seasonal and inter-annual variability are key factors that affect the viability of dry season vegetable crop growing. By the end of the 21(st) century the dry season is expected to be 2 3 weeks longer than now (2014). Monsoon rainfall amounts will remain the same or possibly slightly increase but it will occur over a slightly shorter wet season. Expectations of sea level rise and additional saline intrusion into groundwater aquifers mean that dry season irrigation water is likely to become more saline by the end of the 21(st) century. A study carried out at Barisal indicates that irrigating with water at up to 4 ppt can be sustainable. Once the dry season irrigation water quality goes above 5 ppt, the monsoon rainfall is no longer able to leach the dry season salt deposits so salt accumulation becomes significant and farm productivity will reduce by as a much as 50%, threatening the livelihoods of farmers in this region. PMID- 25790460 TI - Saccharomyces cerevisiae expressing Gp43 protects mice against Paracoccidioides brasiliensis infection. AB - The dimorphic fungus Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis (PCM). It is believed that approximately 10 million people are infected with the fungus and approximately 2% will eventually develop the disease. Unlike viral and bacterial diseases, fungal diseases are the ones against which there is no commercially available vaccine. Saccharomyces cerevisiae may be a suitable vehicle for immunization against fungal infections, as they require the stimulation of different arms of the immune response. Here we evaluated the efficacy of immunizing mice against PCM by using S. cerevisiae yeast expressing gp43. When challenged by inoculation of P. brasiliensis yeasts, immunized animals showed a protective profile in three different assays. Their lung parenchyma was significantly preserved, exhibiting fewer granulomas with fewer fungal cells than found in non-immunized mice. Fungal burden was reduced in the lung and spleen of immunized mice, and both organs contained higher levels of IL-12 and IFN-gamma compared to those of non-vaccinated mice, a finding that suggests the occurrence of Th1 immunity. Taken together, our results indicate that the recombinant yeast vaccine represents a new strategy to confer protection against PCM. PMID- 25790461 TI - Cloning, identification and functional characterization of bovine free fatty acid receptor-1 (FFAR1/GPR40) in neutrophils. AB - Long chain fatty acids (LCFAs), which are ligands for the G-protein coupled receptor FFAR1 (GPR40), are increased in cow plasma after parturition, a period in which they are highly susceptible to infectious diseases. This study identified and analyzed the functional role of the FFAR1 receptor in bovine neutrophils, the first line of host defense against infectious agents. We cloned the putative FFAR1 receptor from bovine neutrophils and analyzed the sequence to construct a homology model. Our results revealed that the sequence of bovine FFAR1 shares 84% identity with human FFAR1 and 31% with human FFAR3/GPR41. Therefore, we constructed a homology model of bovine FFAR1 using human as the template. Expression of the bovine FFAR1 receptor in Chinese hamster ovary (CHO) K1 cells increased the levels of intracellular calcium induced by the LCFAs, oleic acid (OA) and linoleic acid (LA); no increase in calcium mobilization was observed in the presence of the short chain fatty acid propionic acid. Additionally, the synthetic agonist GW9508 increased intracellular calcium in CHO K1/bFFAR1 cells. OA and LA increased intracellular calcium in bovine neutrophils. Furthermore, GW1100 (antagonist of FFAR1) and U73122 (phospholipase C (PLC) inhibitor) reduced FFAR1 ligand-induced intracellular calcium in CHO-K1/bFFAR1 cells and neutrophils. Additionally, inhibition of FFAR1, PLC and PKC reduced the FFAR1 ligand-induced release of matrix metalloproteinase (MMP)-9 granules and reactive oxygen species (ROS) production. Thus, we identified the bovine FFAR1 receptor and demonstrate a functional role for this receptor in neutrophils activated with oleic or linoleic acid. PMID- 25790462 TI - Molecular characterization and phylogenetic analysis of porcine epidemic diarrhea viruses associated with outbreaks of severe diarrhea in piglets in Jiangxi, China 2013. AB - Porcine epidemic diarrhea (PED), caused by porcine epidemic diarrhea virus (PEDV), is a highly contagious, acute enteric viral disease of swine characterized by vomiting, watery diarrhea, dehydration and death. To identify and characterize the field PEDVs associated with the outbreaks of severe diarrhea in piglets in Jiangxi, 2013, the complete genome sequences of two representative strains of PEDV, designated CH/JX-1/2013 and CH/JX-2/2013, were determined and analyzed. The genome sequences of both emergent Jiangxi PEDV strains, CH/JX 1/2013 and CH/JX-2/2013, were 28,038 nucleotides in length excluding 3' poly (A) tail. Compared to the PEDV CV777 strain, CH/JX-1/2013 and CH/JX-2/2013 had some unique genetic characteristics in the proximal region of the 5'-UTRs. Phylogenetic analysis of the complete genomes and the structural proteins revealed that CH/JX-1/2013 and CH/JX-2/2013 had a close relationship with post 2010 Chinese PEDV strains and US strains identified in 2013. The nucleotide identity between the two Jiangxi strains (CH/JX-1/2013 and CH/JX-2/2013) and 30 strains of PEDV identified ante-2010 and post-2010 ranged from 96.3-97.0% and 97.3-99.7%, respectively. Multiple nucleotide and deduced amino acid mutations were observed in the ORF1a/b, S, ORF3, E, M and N genes among the current field PEDV strains when compared to the CV777 strain. Some of the mutations altered the amino acid charge and hydrophilicity, and notably, there was an amino acid substitution in the middle of one neutralizing epitope (L1371I) of the S gene of both CH/JX-1/2013 and CH/JX-2/2013. Taken together, the accumulated genetic variations of the current field PEDV strains might have led to antigenic changes of the viruses, which might confer the less effectiveness or failure of the CV777 based vaccines currently being widely used in Jiangxi, China. PMID- 25790463 TI - Modeling solute transport by DLA in soils of northeastern Egypt. AB - Arid soils in Egypt display large variability in solute transport properties, causing problems in soil management. To characterize this variability, dye infiltration experiments were conducted on four plots representing three main soil types in northeastern Egypt. The plots represented both cultivated and uncultivated land use. The observed dye patterns displayed a large variability and especially the clay soils indicated a high degree of preferential flow. The loamy sand and sandy soils displayed a more uniform dye distribution indicating more homogeneous soil properties. The observed dye patterns were modeled using a diffusion limited aggregation (DLA) model. The DLA is a random walk model where model parameters can be optimized using genetic algorithms (GA). The DLA model reproduced the observed dye patterns for all soils in an excellent way. The best fit was obtained with a specific combination of directional random walk probabilities Pu, Pd, Pr, and Pl for each plot (correlation 0.97-0.99). To account for soil layers with different hydraulic properties a two layer DLA model was developed. For all plots the Pu (upward random walk probability) was higher for the upper more homogeneous soil layer. The overall results showed that spatial variability resulting from solute transport for the investigated soils can be modeled using a DLA approach. PMID- 25790464 TI - Managing small-scale commercial fisheries for adaptive capacity: insights from dynamic social-ecological drivers of change in Monterey Bay. AB - Globally, small-scale fisheries are influenced by dynamic climate, governance, and market drivers, which present social and ecological challenges and opportunities. It is difficult to manage fisheries adaptively for fluctuating drivers, except to allow participants to shift effort among multiple fisheries. Adapting to changing conditions allows small-scale fishery participants to survive economic and environmental disturbances and benefit from optimal conditions. This study explores the relative influence of large-scale drivers on shifts in effort and outcomes among three closely linked fisheries in Monterey Bay since the Magnuson-Stevens Fisheries Conservation and Management Act of 1976. In this region, Pacific sardine (Sardinops sagax), northern anchovy (Engraulis mordax), and market squid (Loligo opalescens) fisheries comprise a tightly linked system where shifting focus among fisheries is a key element to adaptive capacity and reduced social and ecological vulnerability. Using a cluster analysis of landings, we identify four modes from 1974 to 2012 that are dominated (i.e., a given species accounting for the plurality of landings) by squid, sardine, anchovy, or lack any dominance, and seven points of transition among these periods. This approach enables us to determine which drivers are associated with each mode and each transition. Overall, we show that market and climate drivers are predominantly attributed to dominance transitions. Model selection of external drivers indicates that governance phases, reflected as perceived abundance, dictate long-term outcomes. Our findings suggest that globally, small scale fishery managers should consider enabling shifts in effort among fisheries and retaining existing flexibility, as adaptive capacity is a critical determinant for social and ecological resilience. PMID- 25790465 TI - Nuclear envelope protein Lem2 is required for mouse development and regulates MAP and AKT kinases. AB - The nuclear lamina, along with associated nuclear membrane proteins, is a nexus for regulating signaling in the nucleus. Numerous human diseases arise from mutations in lamina proteins, and experimental models for these disorders have revealed aberrant regulation of various signaling pathways. Previously, we reported that the inner nuclear membrane protein Lem2, which is expressed at high levels in muscle, promotes the differentiation of cultured myoblasts by attenuating ERK signaling. Here, we have analyzed mice harboring a disrupted allele for the Lem2 gene (Lemd2). No gross phenotypic defects were seen in heterozygotes, although muscle regeneration induced by cardiotoxin was delayed. By contrast, homozygous Lemd2 knockout mice died by E11.5. Although many normal morphogenetic hallmarks were observed in E10.5 knockout embryos, most tissues were substantially reduced in size. This was accompanied by activation of multiple MAP kinases (ERK1/2, JNK, p38) and AKT. Knockdown of Lem2 expression in C2C12 myoblasts also led to activation of MAP kinases and AKT. These findings indicate that Lemd2 plays an essential role in mouse embryonic development and that it is involved in regulating several signaling pathways. Since increased MAP kinase and AKT/mTORC signaling is found in other animal models for diseases linked to nuclear lamina proteins, LEMD2 should be considered to be another candidate gene for human disease. PMID- 25790466 TI - Overexpression of a novel thermostable and chloride-tolerant laccase from Thermus thermophilus SG0.5JP17-16 in Pichia pastoris and its application in synthetic dye decolorization. AB - Laccases have been used for the decolorization and detoxification of synthetic dyes due to their ability to oxidize a wide variety of dyes with water as the sole byproduct. A putative laccase gene (LacTT) from Thermus thermophilus SG0.5JP17-16 was screened using the genome mining approach, and it was highly expressed in Pichia pastoris, yielding a high laccase activity of 6130 U/L in a 10-L fermentor. The LacTT open reading frame encoded a protein of 466 amino acid residues with four putative Cu-binding regions. The optimal pH of the recombinant LacTT was 4.5, 6.0, 7.5 and 8.0 with 2,2'-azino-bis(3-ethylbenzothazoline-6 sulfonic acid) (ABTS), syringaldazine (SGZ), guaiacol, and 2,6-dimethoxyphenol (2,6-DMP) as the substrate, respectively. The optimal temperature of LacTT was 90 degrees C with guaiacol as the substrate. LacTT was highly stable at pH 4.0-11.0 and thermostable at 40 degrees C-90 degrees C, confirming that it is a pH-stable and thermostable laccase. Furthermore, LacTT also exhibited high tolerance to halides such as NaCl, NaBr and NaF, and decolorized 100%, 94%, 94% and 73% of Congo Red, Reactive Black B and Reactive Black WNN, and Remazol Brilliant Blue R, respectively. Interestingly, addition of high concentration of NaCl increased the RBBR decolorization efficiency of LacTT. These results suggest that LacTT is a good candidate for industrial applications such as dyestuff processing and degradation of dyes in textile wastewaters. PMID- 25790468 TI - Precision printing and optical modeling of ultrathin SWCNT/C60 heterojunction solar cells. AB - Semiconducting single-walled carbon nanotubes (s-SWCNTs) are promising candidates as the active layer in photovoltaics (PV), particularly for niche applications where high infrared absorbance and/or semi-transparent solar cells are desirable. Most current fabrication strategies for SWCNT PV devices suffer from relatively high surface roughness and lack nanometer-scale deposition precision, both of which may hamper the reproducible production of ultrathin devices. Additionally, detailed optical models of SWCNT PV devices are lacking, due in part to a lack of well-defined optical constants for high-purity s-SWCNT thin films. Here, we present an optical model that accurately reconstructs the shape and magnitude of spectrally resolved external quantum efficiencies for ultrathin (7,5) s-SWCNT/C60 solar cells that are deposited by ultrasonic spraying. The ultrasonic spraying technique enables thickness tuning of the s-SWCNT layer with nanometer-scale precision, and consistently produces devices with low s-SWCNT film average surface roughness (Rq of <5 nm). Our optical model, based entirely on measured optical constants of each layer within the device stack, enables quantitative predictions of thickness-dependent relative photocurrent contributions of SWCNTs and C60 and enables estimates of the exciton diffusion lengths within each layer. These results establish routes towards rational performance improvements and scalable fabrication processes for ultra-thin SWCNT-based solar cells. PMID- 25790467 TI - Development and characterization of recombinant antibody fragments that recognize and neutralize in vitro Stx2 toxin from Shiga toxin-producing Escherichia coli. AB - BACKGROUND: Stx toxin is a member of the AB5 family of bacterial toxins: the active A subunit has N-glycosidase activity against 28S rRNA, resulting in inhibition of protein synthesis in eukaryotic cells, and the pentamer ligand B subunits (StxB) bind to globotria(tetra)osylceramide receptors (Gb3/Gb4) on the cell membrane. Shiga toxin-producing Escherichia coli strains (STEC) may produce Stx1 and/or Stx2 and variants. Strains carrying Stx2 are considered more virulent and related to the majority of outbreaks, besides being usually associated with hemolytic uremic syndrome in humans. The development of tools for the detection and/or neutralization of these toxins is a turning point for early diagnosis and therapeutics. Antibodies are an excellent paradigm for the design of high affinity, protein-based binding reagents used for these purposes. METHODS AND FINDINGS: In this work, we developed two recombinant antibodies; scFv fragments from mouse hybridomas and Fab fragments by phage display technology using a human synthetic antibody library. Both fragments showed high binding affinity to Stx2, and they were able to bind specifically to the GKIEFSKYNEDDTF region of the Stx2 B subunit and to neutralize in vitro the cytotoxicity of the toxin up to 80%. Furthermore, the scFv fragments showed 79% sensitivity and 100% specificity in detecting STEC strains by ELISA. CONCLUSION: In this work, we developed and characterized two recombinant antibodies against Stx2, as promising tools to be used in diagnosis or therapeutic approaches against STEC, and for the first time, we showed a human monovalent molecule, produced in bacteria, able to neutralize the cytotoxicity of Stx2 in vitro. PMID- 25790469 TI - Cancer in Women over 50 Years of Age: A Focus on Smoking. AB - The increase in life expectancy worldwide has resulted in a greater prevalence of chronic non-communicable diseases. This study aims to evaluate the prevalence and factors associated with the occurrence of cancer among Brazilian women over the age of 50. A cross-sectional study with 622 women over the age of 50 was performed using a population survey. The outcome variable was the occurrence of a malignant tumor in any location. The independent variables were sociodemographic characteristics, self-perception of health, health-related habits and morbidities. Statistical analysis was carried out using the chi-square test and Poisson regression. The mean age of the women was 64.1 years. The prevalence of cancer was 6.8%. The main sites of occurrence of malignant tumors were the breast (31.9%), colorectal (12.7%) and skin (12.7%). In the final statistical model, the only factor associated with cancer was smoking > 15 cigarettes/day either currently or in the past: PR 2.03 (95% CI 1.06-3.89). The results have improved understanding of the prevalence and factors associated with cancer in Brazilian women aged 50 years or more. They should be encouraged to maintain a healthy lifestyle and pay particular attention to modifiable risk factors such as smoking. PMID- 25790470 TI - Towards Achieving the Full Clinical Potential of Proton Therapy by Inclusion of LET and RBE Models. AB - Despite increasing use of proton therapy (PBT), several systematic literature reviews show limited gains in clinical outcomes, with publications mostly devoted to recent technical developments. The lack of randomised control studies has also hampered progress in the acceptance of PBT by many oncologists and policy makers. There remain two important uncertainties associated with PBT, namely: (1) accuracy and reproducibility of Bragg peak position (BPP); and (2) imprecise knowledge of the relative biological effect (RBE) for different tissues and tumours, and at different doses. Incorrect BPP will change dose, linear energy transfer (LET) and RBE, with risks of reduced tumour control and enhanced toxicity. These interrelationships are discussed qualitatively with respect to the ICRU target volume definitions. The internationally accepted proton RBE of 1.1 was based on assays and dose ranges unlikely to reveal the complete range of RBE in the human body. RBE values are not known for human (or animal) brain, spine, kidney, liver, intestine, etc. A simple efficiency model for estimating proton RBE values is described, based on data of Belli et al. and other authors, which allows linear increases in alpha and beta with LET, with a gradient estimated using a saturation model from the low LET alpha and beta radiosensitivity parameter input values, and decreasing RBE with increasing dose. To improve outcomes, 3-D dose-LET-RBE and bio-effectiveness maps are required. Validation experiments are indicated in relevant tissues. Randomised clinical studies that test the invariant 1.1 RBE allocation against higher values in late reacting tissues, and lower tumour RBE values in the case of radiosensitive tumours, are also indicated. PMID- 25790471 TI - Mutational analysis of Trypanosoma brucei RNA editing ligase reveals regions critical for interaction with KREPA2. AB - The Trypanosoma brucei parasite causes the vector-borne disease African sleeping sickness. Mitochondrial mRNAs of T. brucei undergo posttranscriptional RNA editing to make mature, functional mRNAs. The final step of this process is catalyzed by the essential ligase, T. brucei RNA Editing Ligase 1 (TbREL1) and the closely related T. brucei RNA Editing Ligase 2 (TbREL2). While other ligases such as T7 DNA ligase have both a catalytic and an oligonucleotide/oligosaccharide-binding (OB)-fold domain, T. brucei RNA editing ligases contain only the catalytic domain. The OB-fold domain, which is required for interaction with the substrate RNA, is provided in trans by KREPA2 (for TbREL1) and KREPA1 (for TbREL2). KREPA2 enhancement of TbREL1 ligase activity is presumed to occur via an OB-fold-mediated increase in substrate specificity and catalysis. We characterized the interaction between TbREL1 and KREPA2 in vitro using full-length, truncated, and point-mutated ligases. As previously shown, our data indicate strong, specific stimulation of TbREL1 catalytic activity by KREPA2. We narrowed the region of contact to the final 59 C-terminal residues of TbREL1. Specifically, the TbREL1 C-terminal KWKE (441-444) sequence appear to coordinate the KREPA2-mediated enhancement of TbREL1 activities. N-terminal residues F206, T264 and Y275 are crucial for the overall activity of TbREL1, particularly for F206, a mutation of this residue also disrupts KREPA2 interaction. Thus, we have identified the critical TbREL1 regions and amino acids that mediate the KREPA2 interaction. PMID- 25790472 TI - Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin-induced DNA damage checkpoint arrest. AB - The DNA damage checkpoint arrests cell cycle progression to allow time for DNA repair. After completion of DNA repair, checkpoint activation is terminated, and cell cycle progression is resumed in a process called checkpoint recovery. The activation of the checkpoint has been studied in depth, but little is known about recovery from the DNA damage checkpoint. Recently we showed that Src family kinases promote recovery from the G2 DNA damage checkpoint. Here we show that imatinib inhibits inactivation of ATM/ATR signaling pathway to suppress recovery from Adriamycin/doxorubicin-induced DNA damage checkpoint arrest. Imatinib and pazopanib, two distinct inhibitors of PDGFR/c-Kit family kinases, delayed recovery from checkpoint arrest and inhibited the subsequent S-G2-M transition after Adriamycin exposure. By contrast, imatinib and pazopanib did not delay the recovery from checkpoint arrest in the presence of an ATM/ATR inhibitor caffeine. Consistently, imatinib induced a persistent activation of ATR-Chk1 signaling. By the way, the maintenance of G2 checkpoint arrest is largely dependent on ATR-Chk1 signaling. However, unlike Src inhibition, imatinib did not delay the recovery from checkpoint arrest in the presence of an ATM inhibitor KU-55933. Furthermore, imatinib induced a persistent activation of ATM-KAP1 signaling, and a possible involvement of imatinib in an ATM-dependent DNA damage response is suggested. These results reveal that imatinib inhibits recovery from Adriamycin-induced DNA damage checkpoint arrest in an ATM/ATR-dependent manner and raise the possibility that imatinib may inhibit resumption of tumor proliferation after chemo- and radiotherapy. PMID- 25790473 TI - Functional and morphological changes in endocrine pancreas following cola drink consumption in rats. AB - AIM: We report the effects of long-term cola beverage drinking on glucose homeostasis, endocrine pancreas function and morphology in rats. METHODS: Wistar rats drank: water (group W), regular cola beverage (group C, sucrose sweetened) or "light" cola beverage (group L, artificially sweetened). After 6 months, 50% of the animals in each group were euthanized and the remaining animals consumed water for the next 6 months when euthanasia was performed. Biochemical assays, insulinemia determination, estimation of insulin resistance (HOMA-IR), morphometry and immunohistochemistry evaluations were performed in pancreas. RESULTS: Hyperglycemia (16%, p<0.05), CoQ10 (coenzyme-Q10) decrease ( 52%,p<0.01), strong hypertriglyceridemia (2.8-fold, p<0.01), hyperinsulinemia (2.4 fold, p<0.005) and HOMA-IR increase (2.7 fold, p<0.01) were observed in C. Group C showed a decrease in number of alpha cells (-42%, p<0.01) and beta cells (-58%, p<0.001) and a moderate increase in alpha cells' size after wash-out (+14%, p<0.001). Group L showed reduction in beta cells' size (-9%, p<0.001) and only after wash-out (L12) a 19% increase in size (p<0.0001) with 35% decrease in number of alpha cells (p<0.01). Groups C and L showed increase in alpha/beta-cell ratio which was irreversible only in C (alpha/beta = +38% in C6,+30% in C12, p<0.001vs.W6). Regular cola induced a striking increase in the cytoplasmic expression of Trx1 (Thioredoxin-1) (2.25-fold in C6 vs. W6; 2.7-fold in C12 vs. W12, p<0.0001) and Prx2 (Peroxiredoxin-2) (3-fold in C6 vs. W6; 2-fold in C12 vs. W12, p<0.0001). Light cola induced increase in Trx1 (3-fold) and Prx2 (2-fold) after wash-out (p<0.0001, L12 vs. W12). CONCLUSION: Glucotoxicity may contribute to the loss of beta cell function with depletion of insulin content. Oxidative stress, suggested by increased expression of thioredoxins and low circulating levels of CoQ10, may follow sustained hyperglycemia. A likely similar panorama may result from the effects of artificially sweetened cola though via other downstream routes. PMID- 25790474 TI - Single amino acid change in STING leads to constitutive active signaling. AB - The production of cytokines by the immune system in response to cytosolic DNA plays an important role in host defense, autoimmune disease, and cancer immunogenicity. Recently a cytosolic DNA signaling pathway that is dependent on the endoplasmic reticulum adaptor and cyclic dinucleotide sensor protein STING has been identified. Association of cytosolic DNA with cyclic-GMP-AMP synthase (cGAS) activates its enzymatic activity to synthesize the cyclic dinucleotide second messenger cGAMP from GTP and ATP. Direct detection of cGAMP by STING triggers the activation of IRF3 and NF-kB, and the production of type I interferons and proinflammatory cytokines. The mechanism of how STING is able to mediate downstream signaling remains incompletely understood although it has been shown that dimerization is a prerequisite. Here, we identify a single amino acid change in STING that confers constitutive active signaling. This mutation appears to both enhance ability of STING to both dimerize and associate with its downstream target TBK1. PMID- 25790475 TI - Both ubiquitin ligases FBXW8 and PARK2 are sequestrated into insolubility by ATXN2 PolyQ expansions, but only FBXW8 expression is dysregulated. AB - The involvement of the ubiquitin-proteasome system (UPS) in the course of various age-associated neurodegenerative diseases is well established. The single RING finger type E3 ubiquitin-protein ligase PARK2 is mutated in a Parkinson's disease (PD) variant and was found to interact with ATXN2, a protein where polyglutamine expansions cause Spinocerebellar ataxia type 2 (SCA2) or increase the risk for Levodopa-responsive PD and for the motor neuron disease Amyotrophic lateral sclerosis (ALS). We previously reported evidence for a transcriptional induction of the multi-subunit RING finger Skp1/Cul/F-box (SCF) type E3 ubiquitin-protein ligase complex component FBXW8 in global microarray profiling of ATXN2-expansion mouse cerebellum and demonstrated its role for ATXN2 degradation in vitro. Now, we documented co-localization in vitro and co-immunoprecipitations both in vitro and in vivo, which indicate associations of FBXW8 with ATXN2 and PARK2. Both FBXW8 and PARK2 proteins are driven into insolubility by expanded ATXN2. Whereas the FBXW8 transcript upregulation by ATXN2- expansion was confirmed also in qPCR of skin fibroblasts and blood samples of SCA2 patients, a FBXW8 expression dysregulation was not observed in ATXN2-deficient mice, nor was a PARK2 transcript dysregulation observed in any samples. Jointly, all available data suggest that the degradation of wildtype and mutant ATXN2 is dependent on FBXW8, and that ATXN2 accumulation selectively modulates FBXW8 levels, while PARK2 might act indirectly through FBXW8. The effects of ATXN2-expansions on FBXW8 expression in peripheral tissues like blood may become useful for clinical diagnostics. PMID- 25790476 TI - Myotubes from severely obese type 2 diabetic subjects accumulate less lipids and show higher lipolytic rate than myotubes from severely obese non-diabetic subjects. AB - About 80% of patients with type 2 diabetes are classified as overweight. However, only about 1/3 of severely obese subjects have type 2 diabetes. This indicates that several severely obese individuals may possess certain characteristics that protect them against type 2 diabetes. We therefore hypothesized that this apparent paradox could be related to fundamental differences in skeletal muscle lipid handling. Energy metabolism and metabolic flexibility were examined in human myotubes derived from severely obese subjects without (BMI 44+/-7 kg/m2) and with type 2 diabetes (BMI 43+/-6 kg/m2). Lower insulin sensitivity was observed in myotubes from severely obese subjects with type 2 diabetes. Lipolysis rate was higher, and oleic acid accumulation, triacylglycerol content, and fatty acid adaptability were lower in myotubes from severely obese subjects with type 2 diabetes compared to severely obese non-diabetic subjects. There were no differences in lipid distribution and mRNA and protein expression of the lipases HSL and ATGL, the lipase cofactor CGI-58, or the lipid droplet proteins PLIN2 and PLIN3. Glucose and oleic acid oxidation were also similar in cells from the two groups. In conclusion, myotubes established from severely obese donors with established type 2 diabetes had lower ability for lipid accumulation and higher lipolysis rate than myotubes from severely obese donors without diabetes. This indicates that a difference in intramyocellular lipid turnover might be fundamental in evolving type 2 diabetes. PMID- 25790477 TI - Rhadinovirus host entry by co-operative infection. AB - Rhadinoviruses establish chronic infections of clinical and economic importance. Several show respiratory transmission and cause lung pathologies. We used Murid Herpesvirus-4 (MuHV-4) to understand how rhadinovirus lung infection might work. A primary epithelial or B cell infection often is assumed. MuHV-4 targeted instead alveolar macrophages, and their depletion reduced markedly host entry. While host entry was efficient, alveolar macrophages lacked heparan - an important rhadinovirus binding target - and were infected poorly ex vivo. In situ analysis revealed that virions bound initially not to macrophages but to heparan+ type 1 alveolar epithelial cells (AECs). Although epithelial cell lines endocytose MuHV-4 readily in vitro, AECs did not. Rather bound virions were acquired by macrophages; epithelial infection occurred only later. Thus, host entry was co-operative - virion binding to epithelial cells licensed macrophage infection, and this in turn licensed AEC infection. An antibody block of epithelial cell binding failed to block host entry: opsonization provided merely another route to macrophages. By contrast an antibody block of membrane fusion was effective. Therefore co-operative infection extended viral tropism beyond the normal paradigm of a target cell infected readily in vitro; and macrophage involvement in host entry required neutralization to act down-stream of cell binding. PMID- 25790478 TI - In vitro culture of functionally active buffalo hepatocytes isolated by using a simplified manual perfusion method. AB - BACKGROUND: In farm animals, there is no suitable cell line available to understand liver-specific functions. This has limited our understanding of liver function and metabolism in farm animals. Culturing and maintenance of functionally active hepatocytes is difficult, since they survive no more than few days. Establishing primary culture of hepatocytes can help in studying cellular metabolism, drug toxicity, hepatocyte specific gene function and regulation. Here we provide a simple in vitro method for isolation and short-term culture of functionally active buffalo hepatocytes. RESULTS: Buffalo hepatocytes were isolated from caudate lobes by using manual enzymatic perfusion and mechanical disruption of liver tissue. Hepatocyte yield was (5.3 +/- 0.66)*107 cells per gram of liver tissue with a viability of 82.3 +/- 3.5%. Freshly isolated hepatocytes were spherical with well contrasted border. After 24 hours of seeding onto fibroblast feeder layer and different extracellular matrices like dry collagen, matrigel and sandwich collagen coated plates, hepatocytes formed confluent monolayer with frequent clusters. Cultured hepatocytes exhibited typical cuboidal and polygonal shape with restored cellular polarity. Cells expressed hepatocyte-specific marker genes or proteins like albumin, hepatocyte nuclear factor 4alpha, glucose-6-phosphatase, tyrosine aminotransferase, cytochromes, cytokeratin and alpha1-antitrypsin. Hepatocytes could be immunostained with anti-cytokeratins, anti-albumin and anti alpha1-antitrypsin antibodies. Abundant lipid droplets were detected in the cytosol of hepatocytes using oil red stain. In vitro cultured hepatocytes could be grown for five days and maintained for up to nine days on buffalo skin fibroblast feeder layer. Cultured hepatocytes were viable for functional studies. CONCLUSION: We developed a convenient and cost effective technique for hepatocytes isolation for short term culture that exhibited morphological and functional characteristics of active hepatocytes for studying gene expression, regulation, hepatic genomics and proteomics in farm animals. PMID- 25790479 TI - Predation-related costs and benefits of conspecific attraction in songbirds--an agent-based approach. AB - Songbirds that follow a conspecific attraction strategy in the habitat selection process prefer to settle in habitat patches already occupied by other individuals. This largely affects the patterns of their spatio-temporal distribution and leads to clustered breeding. Although making informed settlement decisions is expected to be beneficial for individuals, such territory clusters may potentially provide additional fitness benefits (e.g., through the dilution effect) or costs (e.g., possibly facilitating nest localization if predators respond functionally to prey distribution). Thus, we hypothesized that the fitness consequences of following a conspecific attraction strategy may largely depend on the composition of the predator community. We developed an agent-based model in which we simulated the settling behavior of birds that use a conspecific attraction strategy and breed in a multi-predator landscape with predators that exhibited different foraging strategies. Moreover, we investigated whether Bayesian updating of prior settlement decisions according to the perceived predation risk may improve the fitness of birds that rely on conspecific cues. Our results provide evidence that the fitness consequences of conspecific attraction are predation-related. We found that in landscapes dominated by predators able to respond functionally to prey distribution, clustered breeding led to fitness costs. However, this cost could be reduced if birds performed Bayesian updating of prior settlement decisions and perceived nesting with too many neighbors as a threat. Our results did not support the hypothesis that in landscapes dominated by incidental predators, clustered breeding as a byproduct of conspecific attraction provides fitness benefits through the dilution effect. We suggest that this may be due to the spatial scale of songbirds' aggregative behavior. In general, we provide evidence that when considering the fitness consequences of conspecific attraction for songbirds, one should expect a trade off between the benefits of making informed decisions and the costs of clustering. PMID- 25790482 TI - Correction: Rapid diagnostic tests for dengue virus infection in febrile Cambodian children: diagnostic accuracy and incorporation into diagnostic algorithms. PMID- 25790481 TI - Regulatory T cells in early life: comparative study of CD4+CD25high T cells from foals and adult horses. AB - The immune system of mammals is subject to continuous development during the postnatal phase of life. Studies following the longitudinal development of the immune system in healthy children are limited both by ethical considerations and sample volumes. Horses represent a particular valuable large animal model for T regulatory (Treg) cells and allergy research. We have recently characterised Treg cells from horses, demonstrated their regulatory capability and showed both their expansion and induction in vitro. Insect bite hypersensitivity (IBH) is a common allergy in horses resembling atopic dermatitis and studies have shown that first exposure to allergens in adult life results in an increased incidence of IBH. The aim of the present study was to characterize circulating CD4+CD25highFoxP3+cells in foals, evaluate their suppressive capability and their in vitro induction compared to adult horses. 19 foals (age range, 1-5 months), their adult mothers and six one-year-old horses (yearlings) were included in the study. The proportion of FoxP3+ cells within the circulating CD4+CD25high population was significantly higher in foals (47%) compared to their mothers (18%) and to yearlings (26%). Treg cells from foals also displayed a higher suppressive capability. Furthermore, CD4+CD25high cells in foals could be induced in vitro from CD4+CD25- cells in a significantly higher proportion compared to mares. These cells also displayed a significantly enhanced suppressive capability. In summary these findings support the notion that exposure of horses to allergens during maturation of the immune system assists the establishment of induced (i)Treg driven tolerance. PMID- 25790480 TI - Point-of-care autofluorescence imaging for real-time sampling and treatment guidance of bioburden in chronic wounds: first-in-human results. AB - BACKGROUND: Traditionally, chronic wound infection is diagnosed by visual inspection under white light and microbiological sampling, which are subjective and suboptimal, respectively, thereby delaying diagnosis and treatment. To address this, we developed a novel handheld, fluorescence imaging device (PRODIGI) that enables non-contact, real-time, high-resolution visualization and differentiation of key pathogenic bacteria through their endogenous autofluorescence, as well as connective tissues in wounds. METHODS AND FINDINGS: This was a two-part Phase I, single center, non-randomized trial of chronic wound patients (male and female, >=18 years; UHN REB #09-0015-A for part 1; UHN REB #12 5003 for part 2; clinicaltrials.gov Identifier: NCT01378728 for part 1 and NCT01651845 for part 2). Part 1 (28 patients; 54% diabetic foot ulcers, 46% non diabetic wounds) established the feasibility of autofluorescence imaging to accurately guide wound sampling, validated against blinded, gold standard swab based microbiology. Part 2 (12 patients; 83.3% diabetic foot ulcers, 16.7% non diabetic wounds) established the feasibility of autofluorescence imaging to guide wound treatment and quantitatively assess treatment response. We showed that PRODIGI can be used to guide and improve microbiological sampling and debridement of wounds in situ, enabling diagnosis, treatment guidance and response assessment in patients with chronic wounds. PRODIGI is safe, easy to use and integrates into the clinical workflow. Clinically significant bacterial burden can be detected in seconds, quantitatively tracked over days-to-months and their biodistribution mapped within the wound bed, periphery, and other remote areas. CONCLUSIONS: PRODIGI represents a technological advancement in wound sampling and treatment guidance for clinical wound care at the point-of-care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01651845; ClinicalTrials.gov NCT01378728. PMID- 25790483 TI - Integrating interactive computational modeling in biology curricula. AB - While the use of computer tools to simulate complex processes such as computer circuits is normal practice in fields like engineering, the majority of life sciences/biological sciences courses continue to rely on the traditional textbook and memorization approach. To address this issue, we explored the use of the Cell Collective platform as a novel, interactive, and evolving pedagogical tool to foster student engagement, creativity, and higher-level thinking. Cell Collective is a Web-based platform used to create and simulate dynamical models of various biological processes. Students can create models of cells, diseases, or pathways themselves or explore existing models. This technology was implemented in both undergraduate and graduate courses as a pilot study to determine the feasibility of such software at the university level. First, a new (In Silico Biology) class was developed to enable students to learn biology by "building and breaking it" via computer models and their simulations. This class and technology also provide a non-intimidating way to incorporate mathematical and computational concepts into a class with students who have a limited mathematical background. Second, we used the technology to mediate the use of simulations and modeling modules as a learning tool for traditional biological concepts, such as T cell differentiation or cell cycle regulation, in existing biology courses. Results of this pilot application suggest that there is promise in the use of computational modeling and software tools such as Cell Collective to provide new teaching methods in biology and contribute to the implementation of the "Vision and Change" call to action in undergraduate biology education by providing a hands-on approach to biology. PMID- 25790484 TI - The manganese-responsive regulator MntR represses transcription of a predicted ZIP family metal ion transporter in Corynebacterium glutamicum. AB - Manganese is an important trace element required as an enzyme cofactor and for protection against oxidative stress. In this study, we characterized the DtxR type transcriptional regulator MntR (cg0741) of Corynebacterium glutamicum ATCC 13032 as a manganese-dependent repressor of the predicted ZIP family metal transporter Cg1623. Comparative transcriptome analysis of a DeltamntR strain and the wild type led to the identification of cg1623 as potential target gene of MntR which was about 50-fold upregulated when cells were grown in glucose minimal medium. Using electrophoretic mobility shift assays, a conserved 18 bp inverted repeat (TGTTCAATGCGTTGAACA) was identified as binding motif of MntR in the cg1623 promoter and confirmed by mutational analysis. Promoter fusion of Pcg1623 to eyfp confirmed that the MntR-dependent repression is only abolished in the absence of manganese. However, neither deletion of mntR nor cg1623 resulted in a significant growth phenotype in comparison to the wild type--strongly suggesting the presence of further manganese uptake and efflux systems in C. glutamicum. The control of cg1623 by the DtxR-type regulator MntR represents the first example of a predicted ZIP family protein that is regulated in a manganese-dependent manner in bacteria. PMID- 25790485 TI - An efficient bacterial surface display system based on a novel outer membrane anchoring element from the Escherichia coli protein YiaT. AB - In a bacterial surface display system, the display of a successful recombinant protein is highly dependent on the choice of anchoring motif. In this study, we developed an efficient Escherichia coli display system using novel anchoring motifs derived from the protein YiaT. To determine the best surface-anchoring motif, full-length YiaT and two of its C-terminal truncated forms, cut at the R181 and R232 sites, were evaluated. Two industrial enzymes, a lipase from Pseudomonas fluorescens SIK W1 and an alpha-amylase from Bacillus subtilis, were used as the target proteins for display. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot, immunofluorescence microscopy and whole-cell enzyme activity measurements confirmed the expression of the fusion proteins on the E. coli surface. Using YiaTR181 or YiaTR232 as the anchoring motif, the fusion proteins showed very high enzyme activities and did not exert any adverse effects on either cell growth or the outer membrane integrity. Additionally, these fusion proteins were suitable for displaying proteins of large molecular size in an active form. Compared with the previous anchoring motifs FadL and OprF, YiaTR181 and YiaTR232 had approximately 10-fold and 20-fold higher enzyme activities, respectively. These results suggest that YiaT can be used as an E. coli anchoring motif to efficiently display various enzymes; hence, this system could be employed in a variety of biotechnological and industrial applications. PMID- 25790486 TI - Identification and catalytic residues of the arsenite methyltransferase from a sulfate-reducing bacterium, Clostridium sp. BXM. AB - Arsenic methylation is an important process frequently occurring in anaerobic environments. Anaerobic microorganisms have been implicated as the major contributors for As methylation. However, very little information is available regarding the enzymatic mechanism of As methylation by anaerobes. In this study, one novel sulfate-reducing bacterium isolate, Clostridium sp. BXM, which was isolated from a paddy soil in our laboratory, was demonstrated to have the ability of methylating As. One putative arsenite S-Adenosyl-Methionine methyltransferase (ArsM) gene, CsarsM was cloned from Clostridium sp. BXM. Heterologous expression of CsarsM conferred As resistance and the ability of methylating As to an As-sensitive strain of Escherichia coli. Purified methyltransferase CsArsM catalyzed the formation of methylated products from arsenite, further confirming its function of As methylation. Site-directed mutagenesis studies demonstrated that three conserved cysteine residues at positions 65, 153 and 203 in CsArsM are necessary for arsenite methylation, but only Cysteine 153 and Cysteine 203 are required for the methylation of monomethylarsenic to dimethylarsenic. These results provided the characterization of arsenic methyltransferase from anaerobic sulfate-reducing bacterium. Given that sulfate-reducing bacteria are ubiquitous in various wetlands including paddy soils, enzymatic methylation mediated by these anaerobes is proposed to contribute to the arsenic biogeochemical cycling. PMID- 25790487 TI - Degradation of poly(epsilon-caprolactone) (PCL) by a newly isolated Brevundimonas sp. strain MRL-AN1 from soil. AB - A poly(epsilon-caprolactone) (PCL)-degrading bacterium designated as strain MRL AN1 was isolated from soil. The bacterium was identified as Brevundimonas sp. strain MRL-AN1 through biochemical tests and 16S rRNA gene sequencing. Scanning electron microscopy and Fourier transform infrared spectroscopy results confirmed the degradation of PCL by strain MRL-AN1. An extracellular PCL depolymerase was purified to homogeneity by column chromatography and molecular weight was estimated to be approximately 63.49 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PCL depolymerase could degrade not only PCL but also other aliphatic polyesters. The enzyme was stable at wide range of temperature (20-45 degrees C) and pH (5-9) as well as stable in the presence of various metal ions, surfactants and organic solvents. Phenylmethylsulfonyl fluoride inhibited enzyme activity that indicates this enzyme belongs to the serine hydrolase family. It is concluded from the results that the enzymes from strain MRL-AN1 might be applied in the process of biochemical monomer recycling in the polyester-contaminated environments. PMID- 25790488 TI - Draft genome sequence of the agarolytic haloarchaeon Halobellus rufus type strain CBA1103. AB - The extremely halophilic archaeon Halobellus rufus type strain CBA1103(T) (CECT 8423(T) and JCM 19434(T)) was isolated from non-purified solar salt and characterized as an agarase producer. The draft genome sequence contains 3852 303 bp with a G + C content of 64.1% and includes genomic information on various carbohydrate-active enzymes. This is the first sequenced genome of the genus Halobellus, and is expected to provide general sequence information for halophilic carbohydrate-active enzymes and opportunities for biotechnological applications of novel halophilic enzymes. PMID- 25790489 TI - Species determination within Staphylococcus genus by extended PCR-restriction fragment length polymorphism of saoC gene. AB - Genetic methods based on PCR-restriction fragment length polymorphism (RFLP) are widely used for microbial species determination. In this study, we present the application of saoC gene as an effective tool for species determination and within-species diversity analysis for Staphylococcus genus. The unique sequence diversity of saoC allows us to apply four restriction enzymes to obtain RFLP patterns, which appear highly distinctive even among closely related species as well as atypical isolates of environmental origin. Such patterns were successfully obtained for 26 species belonging to Staphylococcus genus. What is more, tracing polymorphisms detected by different restriction enzymes allowed for basic phylogeny analysis for Staphylococcus aureus, which is potentially applicable for other staphylococcal species. PMID- 25790490 TI - Laboratory-acquired lethal infections by potential bioweapons pathogens including Ebola in 2014. AB - Researchers studying both cellular and viral disease agents in the laboratory have become infected since the early days of microbiology 150 years ago. However, in the early 21st century, new concerns about bioweapons being used to generate terror and also with a series of newly emerging or newly understood disease causing microbes have resulted in infections and deaths of workers studying these microbes in the laboratory, generally to gain understanding and to develop treatments and vaccines. Here, five examples are summarized: (i) smallpox virus escaped from a UK laboratory where it was being maintained and stored, (ii) the 2014 infections and deaths of five researchers who were isolating West African Ebola virus for DNA sequencing epidemiology studies, (iii) and (iv) two recent infections that happened in the same US laboratory where researchers were infected with agents causing septicemic Yersinia plague and Bacillus anthrax and (v) the 2012 death in California from laboratory infection by Neisseria meningitidis resulting in spinal meningitis. PMID- 25790491 TI - Complete genome sequence of Lysinibacillus varians GY32, a bacterium with filament-to-rod cell cycle. AB - The complete genome sequence of Lysinibacillus varians GY32 was determined to be 4,662,822 base pairs in a single circular chromosome. Genes in cell division, cell cycle, surface layer and cell wall synthesis are foundation of its unique cell morphology. The genome contains multiple clusters of transcriptional regulator, two-component system and sigma factors, providing the organism with the ability to regulate a filament-to-rod cell cycle progression. L. varians GY32 was, to our knowledge, the first bacterium with a filament-to-rod cell cycle to be sequenced and its annotated genome might provide new insights into our understanding of bacterial cell cycle regulation. PMID- 25790492 TI - HrpG and HrpV proteins from the Type III secretion system of Erwinia amylovora form a stable heterodimer. AB - Bacterial type III secretion systems (T3SSs) are specialized multicomponent nanomachines that mediate the transport of proteins either to extracellular locations or directly into eukaryotic host cell cytoplasm. Erwinia amylovora, the main agent of rosaceous plants fireblight disease, employs an Hrp/Hrc1 T3SS to accomplish its pathogenesis. The regulatory network that controls the activation of this T3SS is largely unknown in E. amylovora. However, in Pseudomonas syringae pathovars, the HrpG/HrpV complex has been shown to directly regulate the activity of transcription factor HrpS and consequently the upregulation of the Hrp/Hrc1 T3SS related genes. In this work, we report the successful recombinant production and purification of a stable E. amylovora HrpG/HrpV complex, using pPROpET, a bicistronic expression vector. Furthermore, we present the first solution structure of this complex based on small-angle X-ray scattering data. PMID- 25790493 TI - The infection process of Piscirickettsia salmonis in fish macrophages is dependent upon interaction with host-cell clathrin and actin. AB - Piscirickettsia salmonis is an aggressive fish pathogen that causes Piscirickettsiosis, a systemic disease that threatens the sustainability of salmon production in Chile. To date, the infection strategies of this bacterium are poorly characterized, a Dot/Icm Type IV Secretion System homolog for intracellular multiplication and survival in macrophages is suggested. Since an invading pathogen and its host develop a complex interaction in which the pathogen strives to survive and replicate, while the host tries to eliminate infected cells and the invading pathogen, we decided to evaluate how the bacterium enters macrophages, its preferred target in vivo, and to follow its fate while struggling with its host using actin cytoskeleton as a molecular marker. We were able to demonstrate that clathrin is required for internalization and that actin cytoskeleton plays a demonstrative role throughout the infective process. Indeed, unlike other fish pathogens, P. salmonis fully exploits the actin monomers both from the disorganized cytoskeleton and an apparently pathogen induced de novo synthesis of actin, generating tridimensional vacuoles that are increasingly detected at later stages of infection. We expect our results to contribute to a better understanding of the pathogenesis of this important fish pathogen. PMID- 25790494 TI - Role of transcription factor NimR (YeaM) in sensitivity control of Escherichia coli to 2-nitroimidazole. AB - The binding site(s) on the Escherichia coli genome was determined for an uncharacterized AraC/XylS superfamily transcription factor YeaM by using the in vitro genomic SELEX screening system. The only one clear binding target of YeaM was found to locate in the spacer between the divergently transcribed yeaM and yeaN genes. After the phenotype microarray analysis, the major facilitator superfamily transporter YeaN was found to confer E. coli the resistance to 2 nitroimidazole, the antibacterial and antifungal antibiotic, suggesting that YeaN plays a role in 2-nitromidazole efflux. Purified YeaM bound to three sites within this yeaM-yeaN spacer region. Several lines of in vitro and in vivo evidence indicate that YeaM regulates transcription of both the yeaM gene itself and the yeaNO operon. Taken together we propose to rename yeaN to nimT (nitroimidazole transporter) and yeaM to nimR (regulator of nimT). PMID- 25790495 TI - Analyses of black fungi by matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS): species-level identification of clinical isolates of Exophiala dermatitidis. AB - Conventional mycological identifications based on the recognition of morphological characteristics can be problematic. A relatively new methodology applicable for the identification of microorganisms is based on the exploitation of taxon- specific mass patterns recorded from abundant cell proteins directly from whole-cell preparations, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). This study reports the application of MALDI-TOF MS for the differentiation and identifications of black yeasts, isolated from the respiratory tracts of patients with cystic fibrosis (CF). Initial phenotypic and DNA sequence-based analyses identified these isolates to be Exophiala dermatitidis. The type strains of E. dermatitidis (CBS 207.35(T)) and other species of Exophiala were included in the MALDI-TOF MS analyses to establish the references for comparing the mass spectra of the clinical isolates of Exophiala. MALDI-TOF MS analyses exhibited extremely close relationships among the clinical isolates and with the spectra generated from the type strain of E. dermatitidis. The relationships observed between the E. dermatitidis strains from the MALDI-TOF MS profiling analyses were supported by DNA sequence-based analyses of the rRNA ITS1 and ITS2 regions. These data demonstrated the applicability of MALDI-TOF MS as a reliable, rapid and cost effective method for the identification of isolates of E. dermatitidis and other clinically relevant fungi and yeasts that typically are difficult to identify by conventional methods. PMID- 25790496 TI - Coexistence of SFO-1 and NDM-1 beta-lactamase genes and fosfomycin resistance gene fosA3 in an Escherichia coli clinical isolate. AB - This study aims to characterize antimicrobial resistance and antimicrobial resistance genetic determinants of an Escherichia coli clinical isolate HD0149 from China in 2012. This strain displayed high-level resistance to cephalosporins, carbapenems, fluoroquinolones, aminoglycosides and fosfomycin. A range of antimicrobial resistance genes was detected responsible for its multiple antimicrobial resistances, involving the blaCMY-2, blaCTX-M-65, blaNDM-1, blaSFO 1, blaTEM-1, fosA3, rmtB, sul1 and sul2 genes. Four amino acid substitutions were detected in the quinolone resistance-determining regions (QRDRs) of GyrA (S83L and D87N), ParC (S80I) and ParE (S458A). Conjugation experiments revealed two multiresistance plasmids present in E. coli HD0149. The blaSFO-1 gene associated with blaNDM-1 gene was located in a 190 kb IncA/C plasmid and the blaCTX-M-65, fosA3 and rmtB genes were located in a 110 kb IncF plasmid. This is the first identification of the blaSFO-1 gene in an E. coli isolate and on a conjugative IncA/C plasmid. This may dramatically enhance the international prevalence and dissemination of blaSFO-1 among Enterobacteriaceae. PMID- 25790498 TI - The flagellar adenylate kinases of Trypanosoma cruzi. AB - Adenylate kinases (ADK) are key enzymes involved in cell energy management. Trypanosomatids present the highest number of variants in a single cell in comparison with the rest of the living organisms. In this work, we characterized two flagellar ADKs from Trypanosoma cruzi, called TcADK1 and TcADK4, which are also located in the cell cytosol. Interestingly, TcADK1 presents a stage-specific expression. This variant was detected in epimastigotes cells, and was completely absent in trypomastigotes and amastigotes, while TcADK4 is present in the major life cycle stages of T. cruzi. Both variants are also regulated, in opposite ways, along the parasite growth curve suggesting that their expression depends on the intra- and extracellular conditions. Both, TcADK1 and TcADK4 present N terminal extension that could be responsible for their subcellular localization. The presence of ADK variants in the flagellum would be critical for the provision of energy in a process of high ATP consumption such as cell motility. PMID- 25790497 TI - Lytic activity of the staphylolytic Twort phage endolysin CHAP domain is enhanced by the SH3b cell wall binding domain. AB - Increases in the prevalence of antibiotic-resistant strains of Staphylococcus aureus have elicited efforts to develop novel antimicrobials to treat these drug resistant pathogens. One potential treatment repurposes the lytic enzymes produced by bacteriophages as antimicrobials. The phage Twort endolysin (PlyTW) harbors three domains, a cysteine, histidine-dependent amidohydrolases/peptidase domain (CHAP), an amidase-2 domain and a SH3b-5 cell wall binding domain (CBD). Our results indicate that the CHAP domain alone is necessary and sufficient for lysis of live S. aureus, while the amidase-2 domain is insufficient for cell lysis when provided alone. Loss of the CBD results in ~10X reduction of enzymatic activity in both turbidity reduction and plate lysis assays compared to the full length protein. Deletion of the amidase-2 domain resulted in a protein (PlyTW Delta172-373) with lytic activity that exceeded the activity of the full length construct in both the turbidity reduction and plate lysis assays. Addition of Ca(2+) enhanced the turbidity reduction activity of both the full length protein and truncation constructs harboring the CHAP domain. Chelation by addition of EDTA or the addition of zinc inhibited the activity of all PlyTW constructs. PMID- 25790499 TI - The impact of oregano (Origanum heracleoticum) essential oil and carvacrol on virulence gene transcription by Escherichia coli O157:H7. AB - The aim of the current study was to determine, via reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis, the effect of oregano essential oil (Origanum heracleoticum) and carvacrol, its major component, on the expression of virulence-associated genes in enterohaemorrhagic Escherichia coli (EHEC) O157:H7 ATCC strain 35150. Both oregano oil and carvacrol demonstrated their efficacy firstly, by inhibiting the transcription of the ler gene involved in upregulation of the LEE2, LEE3 and LEE4 promoters and of attaching and effacing lesions and secondly by decreasing both Shiga toxin and fliC genes expression. In addition, a decrease in luxS gene transcription involved in quorum sensing was observed. These results were dose dependent and showed a specific effect of O. heracleoticum and carvacrol in downregulating the expression of virulence genes in EHEC O157:H7. These findings suggest that oregano oil and carvacrol have the potential to mitigate the adverse health effects caused by virulence gene expression in EHEC O157:H7, through the use of these substances as natural antibacterial additives in foods or as an alternative to antibiotics. PMID- 25790500 TI - Bacterial genome remodeling through bacteriophage recombination. AB - Bacteriophages co-exist and co-evolve with their hosts in natural environments. Virulent phages lyse infected cells through lytic cycles, whereas temperate phages often remain dormant and can undergo lysogenic or lytic cycles. In their lysogenic state, prophages are actually part of the host genome and replicate passively in rhythm with host division. However, prophages are far from being passive residents: they can modify or bring new properties to their host. In this review, we focus on two important phage-encoded recombination mechanisms, i.e. site-specific recombination and homologous recombination, and how they remodel bacterial genomes. PMID- 25790501 TI - The 5' untranslated mRNA region base content can greatly affect translation initiation in the absence of secondary structures in Prevotella bryantii TC1-1. AB - It has become clear lately that many bacteria and even whole bacterial phyla do not use the classical Shine-Dalgarno sequence mediated pathway of protein translation initiation. The prominent phylum Bacteroidetes is one of them, and this was shown not only using bioinformatic but also functional reporter gene studies in its representative Prevotella bryantii. The latter studies revealed much higher sensitivity toward secondary structures in 5(') untranslated mRNA regions (5(') UTRs) during translation initiation compared to Escherichia coli. It was proposed that in the absence of Shine-Dalgarno sequence interaction the key elements enabling translation initiation are local absence of secondary structures in 5(') UTRs, and the ribosomal protein S1 which binds to mRNA. Here, we evaluate the 5(') UTRs devoid of secondary structures but containing divergent nucleotide compositions in P. bryantii reporter assay. We show that base composition profoundly affects the amount of the reporter synthesized, and further that these amounts were in agreement with S1 protein binding affinity for adenine/uracil bases in mRNA. This is the first, though indirect, clue that S1 is actually involved in translation initiation in Bacteroidetes and adds the second layer of control beside mRNA secondary structure affecting translation initiation in this phylum. PMID- 25790502 TI - Overview of the glucansucrase equipment of Leuconostoc citreum LBAE-E16 and LBAE C11, two strains isolated from sourdough. AB - The whole set of putative glucansucrases from Leuconostoc citreum LBAE-E16 and LBAE-C11 was retrieved from the draft genome sequence of these two sourdough strains previously suggested as alternan producers. Four and five putative glycoside hydrolase family 70 (GH70) encoding genes were identified in the genome sequence of strain C11 and E16, respectively. Some putative genes have high sequence identity to known Leuconostoc dextransucrases. Molecular and biochemical data confirmed that L. citreum C11 could be considered as a new alternan producing strain, unlike strain E16. In the latter, two new putative glucansucrases with unusual structural features were retrieved. In particular, the GSE16-5 gene encodes for a protein of 2063 amino acids with a theoretical molecular mass of 229 kDa that shares 61% identity with the alternansucrase (ASR) of L. citreum NRRL B-1355, due to the presence of seven APY repeats identified in the C-terminal peptide sequence. Cloning and expression of the corresponding coding sequence revealed synthesis of a low molecular weight (10(4) Da) linear dextran polymer with glucosyl residues only linked by alpha-1,6 linkages. This novel GH70 enzyme may thus be viewed as a natural chimeric enzyme resulting from the addition of the ASR C-terminal region in a dextransucrase. PMID- 25790503 TI - Growth and adaptation of microorganisms on the cheese surface. AB - Microbial communities living on cheese surfaces are composed of various bacteria, yeasts and molds that interact together, thus generating the typical sensory properties of a cheese. Physiological and genomic investigations have revealed important functions involved in the ability of microorganisms to establish themselves at the cheese surface. These functions include the ability to use the cheese's main energy sources, to acquire iron, to tolerate low pH at the beginning of ripening and to adapt to high salt concentrations and moisture levels. Horizontal gene transfer events involved in the adaptation to the cheese habitat have been described, both for bacteria and fungi. In the future, in situ microbial gene expression profiling and identification of genes that contribute to strain fitness by massive sequencing of transposon libraries will help us to better understand how cheese surface communities function. PMID- 25790504 TI - First report of a Klebsiella pneumoniae ST466 strain causing neonatal sepsis harbouring the blaCTX-M-15 gene in Rabat, Morocco. AB - Klebsiella pneumoniae is one of the Gram-negative bacilli most commonly found in urine of pregnant women and causing neonatal sepsis. The aim of this study was to analyse in terms of epidemiology and antimicrobial resistance of 23 K. pneumoniae isolates collected from vaginal swabs or urine of pregnant women, from pharyngeal and ear swabs of apparently healthy newborns and from peripheral cultures and hemocultures of newborns with suspected invasive neonatal infection in Rabat, Morocco. The prevalence of K. pneumoniae was 0.6 and 0.9% among pregnant women and neonates, respectively. These strains showed lower antimicrobial resistance levels regarding the developed countries. Thus, only one strain from a neonate presented an ESBL. This is the first report of a K. pneumoniae strain causing neonatal sepsis harbouring the blaCTX-M-15 gene in an IncFII plasmid and belonging to ST466 in this area. PMID- 25790505 TI - Identification of a mutant locus that bypasses the BsgA protease requirement for social development in Myxococcus xanthus. AB - The BsgA protease is required for the earliest morphological changes observed in Myxococcus xanthus development. We hypothesize that the BsgA protease is required to cleave an inhibitor of the developmental program, and isolation of genetic bypass suppressors of a bsgA mutant was used to identify signaling components controlling development downstream of the BsgA protease. Strain M955 was created by transposon mutagenesis of a bsgA mutant followed by screening for strains that could develop despite the absence of the BsgA protease. Strain M955 was able to aggregate, form fruiting bodies, and partially restored the production of viable spores in comparison to the parental bsgA mutant. The bsgA Tn5Omega955 strain partially restored developmental expression to a subset of genes normally induced during development, and expressed one developmentally induced fusion at higher amounts during vegetative growth in comparison to wild-type cells. The transposon in strain M955 was localized to a Ribonuclease D homolog that appears to exist in an operon with a downstream aminopeptidase-encoding gene. The identification of a third distinct bypass suppressor of the BsgA protease suggests that the BsgA protease may regulate a potentially complex pathway during the initiation of the M. xanthus developmental program. PMID- 25790507 TI - Editorial: a time of great change. PMID- 25790506 TI - Molecular characterization of Shewanella and Aeromonas isolates associated with spoilage of Common carp (Cyprinus carpio). AB - Storage in ice is a common way of preserving commercial fish species but some microorganisms can still contaminate and participate in the spoilage of the product; therefore, identification of potential harmful microbes is important. Thirteen colonies were isolated from common carp (Cyprinus carpio) that had been stored in ice, whose phenotypic identification revealed that they belonged to the genera Aeromonas (n = 5) and Shewanella (n = 8). Molecular genotyping with ERIC PCR showed clonality only among two of the five Aeromonas isolates and for two groups (n = 3; n = 2) of the eight Shewanella isolates. Sequencing the rpoD gene showed that four Aeromonas isolates belonged to the species Aeromonas salmonicida and one to A. sobria. Of the eight Shewanella, seven isolates cluster with Shewanella putrefaciens and one with Shewanella profunda in the 16S rRNA phylogenetic tree. However, analysis of the gyrB gene showed that these eight isolates could constitute a new species closely related to S. baltica. The Shewanella and A. salmonicida isolates produce off-odours and reduce trimethylamine oxide, indicating that they might contribute to the spoilage of the fish. PMID- 25790508 TI - Draft genome sequence of Acinetobacter sp. neg1 capable of degrading ochratoxin A. AB - Ochratoxin A (OTA) is a nephrotoxic and potentially carcinogenic mycotoxin produced by several species of Aspergillus and Penicillium. It is one of the major mycotoxins contaminating grain, grapes and a variety of food products, and the development of methods for reducing pre- and post-harvest contamination has drawn considerable attention. In the current study, we isolated and sequenced the genome of a novel free-living Acinetobacter strain able to degrade OTA. Biochemical studies suggest that the degradation reaction proceeds via peptide bond hydrolysis. PMID- 25790509 TI - Vibrio vulnificus detected in the spleen leads to fatal outcome in a mouse oral infection model. AB - Vibrio vulnificus causes rapid disseminating septicemia by oral infection in infected individuals who have an underlying disease, especially chronic liver diseases. Although the elucidation of specific risk factors for V. vulnificus infection in patients with liver diseases is of urgent importance, no appropriate experimental animal model that mimics the liver diseases in this bacterial infection has been available so far. To discover these risk factors, we generated a liver disordered mouse by performing bile duct ligation (BDL). Hepatitis developed in the BDL mice; however, this did not affect mortality in mice after orogastric administration of V. vulnificus, suggesting that the liver disorders caused by the BDL were not risk factors for V. vulnificus septicemia. When the dead and surviving mice were compared, V. vulnificus could be detected from the spleen only in the dead group. Furthermore, significantly higher numbers of V. vulnificus were detected from the intestines in the dead group than in the surviving group ( P < 0.001). These findings suggested that proliferation of the challenge inoculum in the intestine was needed for the oral infection with V. vulnificus, and that the elimination of V. vulnificus in the liver and/or spleen plays a critical role in survival of the host. PMID- 25790510 TI - Clinical judgment and decision making in wound assessment and management: is experience enough? AB - The assessment and management of wounds forms a large proportion of community nurses' workload, often requiring judgment and decision-making in complex, challenging and uncertain circumstances. The processes through which nurses form judgments and make decisions within this context are reviewed in this article against existing theories on these on these subjects. There is variability in wound assessment and management practice which may be attributed to uncertainties within the context, a lack of knowledge in appropriate treatment choices and the inability to correctly value the importance of the clinical information presented. Nurses may be required to draw on intuition to guide their judgments and decision-making by association with experience and expertise. In addition, a step-by-step analytical approach underpinned by an evidence base may be required to ensure accuracy in practice. Developing an understanding of the different theories of judgment and decision-making may facilitate nurses' abilities to reflect on their own decision tasks, thereby enhancing the care provided. PMID- 25790512 TI - [Etiological mechanism of viral infections--the mechanism by which virus causes diseases]. PMID- 25790511 TI - Thoughts on the assisted dying bill. PMID- 25790513 TI - Artificial neural network modeling of the water quality index using land use areas as predictors. AB - This paper describes the design of an artificial neural network (ANN) model to predict the water quality index (WQI) using land use areas as predictors. Ten year records of land use statistics and water quality data for Kinta River (Malaysia) were employed in the modeling process. The most accurate WQI predictions were obtained with the network architecture 7-23-1; the back propagation training algorithm; and a learning rate of 0.02. The WQI forecasts of this model had significant (p < 0.01), positive, very high correlation (rhos = 0.882) with the measured WQI values. Sensitivity analysis revealed that the relative importance of the land use classes to WQI predictions followed the order: mining > rubber > forest > logging > urban areas > agriculture > oil palm. These findings show that the ANNs are highly reliable means of relating water quality to land use, thus integrating land use development with river water quality management. PMID- 25790514 TI - Application of artificial neural networks for prediction of photocatalytic reactor. AB - In this paper, forecasting of kinetic constant and efficiency of photocatalytic process of TiO2 nano powder immobilized on light expanded clay aggregates (LECA) was investigated. Synthetic phenolic wastewater, which is toxic and not easily biodegradable, was selected as the pollutant. The efficiency of the process in various operation conditions, including initial phenol concentration, pH, TiO2 concentration, retention time, and UV lamp intensity, was then measured. The TiO2 nano powder was immobilized on LECA using slurry and sol-gel methods. Kinetics of photocatalytic reactions has been proposed to follow the Langmuir-Hinshelwood model in different initial phenol concentration and pH. Several steps of training and testing of the models were used to determine the appropriate architecture of the artificial neural network models (ANNs). The ANN-based models were found to provide an efficient and robust tool in predicting photocatalytic reactor efficiency and kinetic constant for treating phenolic compounds. PMID- 25790515 TI - Behavior of metals in a combined wastewater collection system in Ostrava, Czech Republic. AB - In combined wastewater collection systems, the concentrations of metals and the form of metal occurrence (dissolved form and bonding of metals to total suspended solids) influence the efficiency of capturing metals into sludge in wastewater treatment plants. The variability of metal concentrations was determined for 12 sampling sites during dry weather periods (DWP) and wet weather periods (WWP). Wastewater during DWP contain in dissolved form 77% of cadmium, 75% of nickel, 66% of arsenic, 57% of manganese and 50% of zinc and copper. Other metals are preferably bound to suspended particulates: 65% of chromium, iron, vanadium, mercury and 91% of lead. Comparison of metal concentrations in wastewater during DWP and WWP can be used to determine non-point source contributions. During WWP, metal concentrations increase by 24 to 25% for cadmium and zinc, 22% for nickel and 18% for copper. Urine and feces are responsible for a very small portion (<15%) of the total content of metals. Households are the main source of cadmium and copper (64% of total concentrations of these metals in wastewater). PMID- 25790516 TI - Characterization of priority substances in effluents from an integrated steelworks in the United Kingdom. AB - In the Water Framework Directive, a list of priority substances that are deemed to be persistent, toxic, and liable to bioaccumulate have been identified. Within this list, a range of polycyclic aromatic hydrocarbons (PAHs) and certain trace metals are relevant to the steel industry. This study summarizes work carried out by Tata Steel Europe (Rotherham, U.K.) to characterize the emissions of PAHs and trace metals from wastewater streams at one of its main integrated steelworks in the United Kingdom over a 3-year period (2010 to 2012). The emissions inventory revealed that PAH emissions to water were almost entirely attributable to the cokemaking process, with emissions factors ranging from 20 to 55 mg/tonne of coke. Furthermore, analysis of the PAH distribution in coke oven effluents revealed that medium- and high-molecular-weight PAHs were associated with the suspended solids (particle-bound). Regarding trace metals, both ironmaking and steelmaking processes were the most important emission sources. PMID- 25790517 TI - PCBs in sludge: development of a practical extraction procedure and its application in an urban water resource recovery facility. AB - Sludges originating from water resource recovery facilities act as a sink for various contaminants including polychlorinated biphenyls (PCBs). Investigation of such pollutants provides detailed information about the pollutant burden of the region from which incoming wastewater is derived. However, the current extraction methods for PCBs in wastewater and sludge are both time- and solvent-consuming. Therefore, the purposes of this study were to develop a practical PCB extraction procedure and to monitor PCB levels in sludge originating from an urban water resource recovery facility (WRRF). Procedure applicability was shown by comparing the extraction results of certified reference materials with that of Soxhlet and by checking surrogate recovery. Diethyl ether, hexane, and hexane:acetone mixture were evaluated as the PCB extraction solvent; hexane was the most efficient solvent with the recovery results (89 to 102%) in an acceptable range of 70 to 130%. The PCB concentrations of the WRRF sludges were in the range of 3.6 +/- 0.3 to 64.4 +/- 9.3 MUg/kg dry matter. PMID- 25790518 TI - Hydrogeological features and environmental impacts of geothermal waters in the Yildiz River Basin (Sivas, Turkey). AB - The study area, located in the Yildiz River Basin (Sivas), has eight geothermal waters, which are used for balneotherapy. The aim of this study was to investigate the natural and/or anthropogenic water pollution in terms of drinking and irrigation water in the Sicak Cermik, Uyuz Cermigi, and Hamzaseyh Cermigi geothermal areas. Na+, Cl-, SO4(-2), B, Mn, Fe, As, and Se concentrations of the geothermal waters generally exceed the upper limits stated in the Turkish Standards for Water Intended for Human Consumption and World Health Organization regulations. Based on the irrigation water classification by the U.S. Salinity Laboratory Diagram, it is concluded that these waters may have hazardous levels of salinity and sodium when used as irrigation water. Wastewater from these health and tourism centers is discharged into the Yildiz River and to agricultural land. This procedure causes increase in the concentrations of major and minor elements and negatively affects the river water quality. PMID- 25790519 TI - Total phosphorus input to the Cache la Poudre River in Northern Colorado. AB - The objectives of this study were to monitor total phosphorus concentrations and loads along the Cache la Poudre River in Northern Colorado as it flows from a pristine area through urban regions and, finally, through mixed land uses. The study attempted to evaluate the sources and influences of total phosphorus under different hydrologic conditions. Nine sampling events were completed from April 2010 to May 2011 to assess the influence of various hydrologic conditions on aqueous and riverbed sediment total phosphorus concentrations. Total phosphorus concentrations and loads exceeded the in-stream limits proposed by the Colorado Department of Public Health and Environment in all observed hydrologic conditions, and nonpoint sources were significant in high-flow conditions. Reducing nutrients only at water resource recovery facilities (WRRFs) could not achieve the in-stream limits without substantial reduction of non-point-source loads. The study exposed a need for flexibility in WRRF discharge limits based on the overall total phosphorus load in the river from other sources. PMID- 25790521 TI - Culture change in the ED: there is still ample room for improvement. PMID- 25790520 TI - Effect of postmining waters on cyanobacterial photosynthesis. AB - New waterbodies have been created in a postmining area of the brown-coal basin in Sokolov, Czech Republic. The former open-cast quarry, Medard, has been filling with water from a local river, the surrounding catchment spoil heaps, and acid mine drainages. The effect of acidic (pH down to 2.5) and high-conductivity water (up to 1400 mS/m) on selected cyanobacteria and the possibility of cyanobacterial water bloom in the newly formed Lake Medard were studied by means of chlorophyll fluorometry (actual photosystem II [PSII] quantum yield, DeltaF/Fm', and relative electron transport rate, rETR). The acidic spoil-heap waters caused a decrease in cyanobacterial photosynthetic activity of 52 to 100% of the initial DeltaF/Fm' value. The Dolichospermum strains were about 10 times more sensitive than Microcystis viridis. The high concentration of dissolved ions appeared to have less effect on cyanobacterial PSII. Although the bottom meta- and hypolimnion layers were proven to negatively influence the cyanobacteria, the perennial stratification of the lake does not enable the water characteristics of the upper layers to change extensively and thus possibly suppresses the undesirable cyanobacterial bloom. The response of cyanobacteria to spoil-heap waters appears to be species-specific and can promote selection of those resistant to postmining environments. PMID- 25790522 TI - Ebola viral disease: What should be done to combat the epidemic in 2014? AB - Ebola virus disease (EVD) was defined first in 1976. Since then, more than 24 epidemics have been reported from Africa, predominantly with the Zaire species. On 21 March 2014, the current West Africa outbreak was reported by the World Health Organization, the largest one ever recorded. The Congo epidemic was reported in July 2014. It was considered that the two epidemics had unrelated origins with 96.8% identical genomic sequence of the virus. EVD outbreaks occurred in areas with limited resources but it has a potentially global effect due to the possibility of imported infection and the potential misuse of the virus as a bioweapon agent. Although EVD is a zoonotic disease with the reservoir of fruit bats, human-to-human transmission is essential in the spread of the infection. The case-fatality rate of EVD was reported as 70.8%. There is no approved prophylaxis, effective treatment, or licensed vaccine. Early diagnosis and isolation of the patients, contact tracing, appropriate use of personal protective equipment, and adherence to the guidance for safe funeral practices constitute the essential requirements to control the epidemics. This article provides a review of the literature regarding the characteristics and management of EVD outbreak. PMID- 25790523 TI - Utility of M30, an apoptotic serum marker, in liver diseases. AB - The aim of this paper is to evaluate the role of apoptosis in some common liver diseases, and the utility of M30, an apoptotic serum marker, in the diagnosis of the severity of underlying hepatic injury. As is widely known, apoptosis is programmed cell death, and its deregulation results in an uncontrolled inflammatory process leading to upregulation of liver fibrogenesis. Both extrinsic and intrinsic pathways are crucial in apoptosis, and caspase cleavage of cytokeratin proteins occurs in both. Therefore, the measurement of caspase- cleaved cytokeratin fragments could be a novel method to assess the intensity of apoptotic cell numbers in epithelial tissue damage. M30 levels were found to increase not only in acute liver disorders, but also in some chronic liver injuries. We tried to summarize the recent studies focused on the role of apoptotic processes in liver diseases, mainly those that investigated the use of M30 in determining the severity of, or in predicting, ongoing liver injury. PMID- 25790524 TI - Beneficial effects of melatonin and BQ-123 on the rat testis damage caused by cigarette smoke. AB - BACKGROUND/AIM: Several studies have demonstrated that cigarette smoke has detrimental effects on testicular function. However, it is unknown whether melatonin or BQ-123 has beneficial effects on the rat testis damage caused by cigarette smoke. The aim of the present study was to investigate the beneficial effects of melatonin or BQ-123 on the testicular damage caused by cigarette smoke. MATERIALS AND METHODS: Twenty Wistar rats were randomly divided into 4 equal groups: control group (n = 5), cigarette smoke group (n = 5), melatonin group (n = 5), and BQ-123 group (n = 5). At the end of 4 weeks, all the rats were sacrificed for histopathological evaluation and subsequent stereological analysis. The optical fractionator counting method, the most efficient and unbiased method, was used to estimate the total number of spermatogonia and spermatocytes. RESULTS: All the control testes demonstrated complete spermatogenesis. There was a significant decrease in the germ cells of rats exposed to cigarette smoke for 4 weeks. After the application of melatonin or BQ 123, the total number of spermatogonia and spermatocytes in the testes was significantly higher. CONCLUSION: Based on these findings, melatonin and BQ-123 are able to minimize the degenerative effects of cigarette smoke by increasing the germ cell count. PMID- 25790525 TI - PARP inhibition prevents acetaminophen-induced liver injury and increases survival rate in rats. AB - BACKGROUND/AIM: Acetaminophen (APAP) overdose results in severe liver damage that may develop into acute liver failure. Recent studies have demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) decreases tissue necrosis and inflammation. We evaluated the efficacy of 3-aminobenzamide (3-AB), a PARP inhibitor, in a rodent model of APAP-induced hepatotoxicity. MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were divided equally into 3 experimental groups: sham group, APAP group, and APAP + 3-AB group. In the experimental treatment groups APAP was administered orally at 1 g/kg and, in the APAP + 3-AB group, 3-AB was administered intraperitoneally at a dose of 20 mg/kg exactly 1 h after APAP treatment. Surviving animals were euthanized 48 h after initial APAP administration. Blood samples and liver tissues were collected for histopathological and biochemical analysis. RESULTS: A panel of oxidative stress parameters, as well as serum aspartate aminotransferase, alanine aminotransferase, neopterin, and nitrite/nitrate and histological injury scores, were significantly reduced among the APAP + 3-AB treatment group relative to the group treated with APAP alone (P < 0.05, APAP vs. APAP + 3-AB). CONCLUSION: The present study demonstrates that 3-AB inhibited APAP-induced hepatic injury and reduced neopterin levels. Results of the present study indicate that PARP inhibitors may be an effective adjuvant therapy resulting in improved outcomes in APAP-induced hepatotoxicity. PMID- 25790526 TI - Protective effects of royal jelly against testicular damage in streptozotocin induced diabetic rats. AB - BACKGROUND/AIM: TO examine the effects of royal jelly (RJ) on testicular damage in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Eighteen adult Wistar albino rats were used, 6 in each of the 3 treatment groups: Group A: control, Group B: STZ-induced diabetes (untreated), Group C: STZ-induced diabetes plus RJ (400 mg/kg daily for 4 weeks). Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). Four weeks after the onset of diabetes, testicular apoptotic cell death was examined using immunohistochemical staining for caspase-3 and Ki67 staining for localization of proliferative cells. RESULTS: Compared with the control, the body and testicular weights of the RJ treated and untreated diabetic rats were decreased (P < 0.05). The histopathological examination showed a significant increase in degenerative changes in the seminiferous tubules and in spermatogenesis of the STZ-treated rats. In contrast, the RJ treatment group showed near-normal morphology, in addition to an increased intensity of immunohistochemical staining for Ki67 positive cells. CONCLUSION: Diabetes induced a significant increase in testicular apoptotic cell death (caspase-3-positive cells). Caspase-3-positive cells were significantly decreased in the STZ plus RJ-treated group compared with the untreated STZ-induced diabetic group (P < 0.05). PMID- 25790527 TI - Protective effects of erdosteine, vitamin E, and vitamin C on renal injury induced by the ischemia-reperfusion of the hind limbs in rats. AB - BACKGROUND/AIM: To compare the protective efficacy of erdosteine and vitamins C and E against renal injury caused by hind limb ischemia-reperfusion (I/R). MATERIALS AND METHODS: Rats were split into 4 groups: group I as the control, group II as I/R, group III as I/R + erdosteine, and group IV as I/R + vitamins C and E. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) tissue levels were determined. RESULTS: MDA levels were found comparable with the control group in groups II and III. However, they were considerably decreased in group IV when compared to group II (P < 0.01). Additionally, SOD, CAT, and GSH-Px activities were considerably (P < 0.05) decreased in group II. While CAT and GSH-Px activities were restored (P <0.01) by vitamin E and C treatment, SOD activity was not significantly affected. While GSH-Px activities were higher (P < 0.05) with erdosteine administration, SOD and CAT activities were unchanged. CONCLUSION: The protective effect of vitamins C and E is higher than that of erdosteine treatment in reducing the oxidative stress after renal ischemia in this animal model. PMID- 25790528 TI - An in vitro and in vivo investigation of the cytotoxic effects of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester and bortezomib in multiple myeloma cells. AB - BACKGROUND/AIM: In this study, the in vitro and in vivo effectiveness of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) in combination with bortezomib, a proteasome inhibitor, was explored in multiple myeloma (MM) cells. MATERIALS AND METHODS: The cytotoxic effects of CAPE and bortezomib were determined by XTT cell proliferation assay. Apoptosis levels were analyzed with annexin V-fluorescein isothiocyanate, nuclear factor kappa beta (NF-kappaB) was analyzed with electrophoretic mobility-shift assay, and interleukin (IL)-6 levels were analyzed with enzyme-linked immunosorbent assay to evaluate CAPE's mechanism of action. To investigate the in vivo effectiveness of CAPE and bortezomib, an experimental plasmacytoma model was induced in BALB/c mice. RESULTS: Increasing concentrations of CAPE and bortezomib decreased the proliferation of ARH-77 cells in a dose-dependent manner. With doses of CAPE IC50, a significant increase in apoptosis and a significant decrease in IL-6 levels were detected. The NF-kappaB DNA- binding activity decreased compared to the basal ARH-77 level. The administration of CAPE alone or in combination with bortezomib increased the rate of survival compared to the control group. CONCLUSION: We think that our study, which is the first to demonstrate the in vitro and in vivo effectiveness of the.combined use of CAPE and bortezomib, will be a pioneer for future human applications of CAPE in MM. PMID- 25790529 TI - Polymorphism characteristics of HIV-1 gpl20 and 5 hypervariable regions. AB - BACKGROUND/AIM: To investigate polymorphism characteristics of HIV-1 gpl20 and its 5 hypervariable regions. MATERIALS AND METHODS: Length polymorphism, potential number of N-linked glycosylation sites (PNGSs), and sequence characteristics of nearly all available global gp120 and its 5 hypervariable regions from HIV-1 subtypes A, B, C, D, G, and H were analyzed. RESULTS: We found that the majority of HIV-1 gpl20s have 496-515 amino acids and 21-30 PNGSs, suggesting that a gp120 with this length might be a good virus candidate for vaccine development. Among 5 hypervariable regions, the V3 regions had the lowest levels of length polymorphism and heterogeneity and less PNGSs, while V1 and V4 regions had high levels of length polymorphism and heterogeneity and more PNGSs. These results suggest that reducing the polymorphism, heterogeneity, and PNGSs of the 4 hypervariable regions should be taken into account in AIDS vaccine development for effectively eliciting immune response. Except for subtype D, other subtypes have the consensus V3 sequences with R5 tropism, implying that the majority of HIV-1 strains are R5 strains. CONCLUSION: The results suggest that CCR5 antagonists may be extremely efficient for AIDS treatment and R5 strains should be used as candidates for AIDS vaccine development. PMID- 25790530 TI - Effects on quinolone resistance due to the biofilm formation activity in Ureaplasma urealyticum. AB - BACKGROUND/AIM: To detect the effects on quinolone resistance due to biofilm formation activity in Ureaplasma urealyticum. MATERIALS AND METHODS: An improved checkerboard dilution susceptibility test was used to analyze the quinolone resistance of clinical Ureaplasma isolates and a postbiofilm formation susceptibility assay was used to compare the effects on the quinolone susceptibility between pre- and postbiofilm formations. Several important functional gene expressions were detected to evaluate their roles in the process of the quinolone resistance mechanism. RESULTS: The quinolone-resistant isolates produced more biofilms than the sensitive isolates. In both the quinolone resistant and -sensitive groups, the minimal inhibitory concentrations after biofilm formation were higher than those before biofilm formation. The expression of the metabolism-related gene ureC in postbiofilm formation was higher than those in prebiofilm formation. CONCLUSION: It seems that biofilm formation is quite important in the generation of quinolone resistance in Ureaplasma. It is very useful to detect biofilm formation activity as well as to analyze other laboratory parameters for Ureaplasma. PMID- 25790531 TI - Comparative study of virulence factors among ESbetaL-producing and nonproducing Pseudomonas aeruginosa clinical isolates. AB - BACKGROUND/AIM: beta-Lactamase production is considered one of the most important resistance mechanisms amongvirulent Pseudomonas aeruginosa isolates. The aim of this study was to compare the production and antimicrobial resistance patterns of some virulence factors in extended spectrum beta-lactamase (ESbetaL)-producing and nonproducing P. aeruginosa clinical isolates. MATERIALS AND METHODS: Out of 183 different clinical specimens, 104 Pseudomonas aeruginosa isolates were recovered. The isolates were screened for ESbetaL production using the double disk diffusion test and phenotypic confirmatory disk diffusion test. All isolates were tested for susceptibility to 25 antimicrobials, as well as for expression of various virulence factors including pigment, hemolysin, gelatinase, protease, lipase, rhamnolipids, biofilm, and cell surface hydrophobicity. The results of ESbetaL producers and honproducers were statistically compared. RESULTS: All isolates showed a high frequency of multiple resistance to at least 14 and up to 25 of the tested antimicrobials. Nevertheless, most virulence factors were produced at higher rates in ESbetaL-producing than in ESbetaL-nonproducing Pseudomonas aeruginosa isolates. CONCLUSION: The results of this study suggest a correlation between ESbetaL phenotype and the production of some factors that are reported to be involved in the virulence of P. aeruginosa. PMID- 25790532 TI - Distribution of viral genotypes and extrahepatic manifestations in patients with chronic hepatitis C in Eastern Turkey. AB - BACKGROUND/AIM: To investigate the distribution of viral genotypes, the extrahepatic manifestations, and the relationship between genotypes and extrahepatic manifestations in patients with chronic hepatitis C. MATERIALS AND METHODS: The study included 62 treatment-naive patients with chronic hepatitis C infection. Genotype determination was performed by DNA sequencing analysis. To investigate extrahepatic manifestations, the patients' data, recorded prospectively during the pretreatment period, were analyzed. RESULTS: Genotype determination was successful in 74.2% of the cases. All patients were infected with hepatitis C virus (HCV) genotype lb. At least 1 extrahepatic manifestation was identified in 37.1% of the patients. The most frequent clinical manifestations were type II diabetes mellitus (8.1%) and arthralgia or arthritis (8.0%). There was no relationship between extrahepatic manifestations and fibrosis or transaminase levels, but female sex and advanced age were risk factors. Because all patients were infected with the same genotype, the relationship between extrahepatic manifestations and genotype could not be examined. CONCLUSION: HCV genotype 1b is predominant in patients with chronic hepatitis C in the Eastern Anatolian Region of Turkey. In total, 37.1% of the patients had at least 1 extrahepatic manifestation. Female sex and advanced age were risk factors for having extrahepatic manifestations. PMID- 25790533 TI - A molecular epidemiological investigation of multistate outbreaks of Salmonella Enteritidis from clinical and environmental samples in Turkey, 2000-2010. AB - BACKGROUND/AIM: To analyze interrelated Salmonella Enteritidis strains isolated in Turkey. Fifty-five S. Enteritidis surveillance strains were isolated from human feces and environmental samples from different regions in Turkey between 2000 and 2010. MATERIALS AND METHODS: Clinical isolates were selected from different outbreaks in the Turkish National Reference Laboratory. All isolates were submitted to antimicrobial susceptibility test, plasmid profile analysis, and XbaI-digested pulsed-field gel electrophoresis. RESULTS: The strains were scanned against 20 antibiotics and for 3 of them (amikacin, ciprofloxacin, gentamicin), all strains were found to be sensitive. Five isolates had no plasmid. Most of test strains carried the 57-kb plasmid in common and 15 genotypes were identified among the 55 isolates. Six genotypes were related closely, 3 genotypes were undistinguished, and 6 genotypes were unrelated. CONCLUSION: To our knowledge, this is the first report on the phenotypic and molecular characterization of S. Enteritidis isolates from both environmental samples and clinical isolates in Turkey. PMID- 25790534 TI - Investigation of West Nile virus among healthy blood donors in the western part of Turkey. AB - BACKGROUND/AIM: THE West Nile virus (WNV) is a mosquito-borne flavivirus causing different forms of infection among humans, varying from asymptomatic illness to fetal central nervous system infection. Turkeylies within an endemic region for WNV. Transfusion of infected blood products is another well-documented major route of transmission. The aim of our study was to investigate the presence of WNV viremia among a healthy donor population from the western part of the country. MATERIALS AND METHODS: A total of 438 healthy volunteer blood donors were included in the study. The presence of WNV RNA was investigated by quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) and anti-WNV IgG was detected by a commercial ELISA test. RESULTS: Ages of volunteer donors were 18-62 years (mean: 34.7) and 34 (7.76%) were women. All samples were negative for WNV RNA by qRT-PCR. Eleven (2.51%) samples, 1 of which was borderline, were positive for anti-WNV IgG. All positive samples were from the western part of the country and 9 of them were from Izmir. CONCLUSION: Although all donor samples were negative for WNV RNA by qRT-PCR, the risk of WNV transmission via blood products should not be ignored in endemic regions. PMID- 25790535 TI - Mucocutaneous manifestations and the relationship to CD4 lymphocyte counts among Turkish HIV/AIDS patients in Istanbul, Turkey. AB - BACKGROUND/AIM: Dermatologic findings differ among countries but no sufficient data about Turkish HIV-infected patients exist in the literature. Therefore, our aim in this study was to document the dermatologic manifestations and their relationships with CD4 cell counts among HIV/AIDS patients visiting our clinic for the first time in Istanbul, Turkey. MATERIALS AND METHODS: A retrospective analysis of 306 HIV/AIDS patients (260 men, mean age: 38.3 years) was done in a tertiary hospital in Istanbul from January 2006 to September 2012. Information on age, sex, transmission routes, socioeconomic and educational status, CD4 counts, and dermatologic findings was collected retrospectively from medical records. RESULTS: Our analyses revealed at least 1 dermatologic disease in 111 of the 306 (36.2%) patients. Mean CD4 count of the patients was 393.64 cells/mm3 (range: 4 1270 cells/mm3). Oral candidiasis (12.4%), herpes zoster (5.9%), dermatophytosis (5.4%), hyperpigmentation (5.2%), and folliculitis (4.6%) were the most common skin problems. Statistically significant correlation (P < 0.05) with low CD4 cell counts was found for oral candidiasis, folliculitis, herpes zoster, hyperpigmentation, xerosis, and Kaposi's sarcoma. CONCLUSION: Dermatologic manifestations in this study were identical to those described in most studies from Asia, and there were more manifestations as the HIV infection progressed and immune functions declined. PMID- 25790536 TI - Prognostic value of hemostasis-related parameters for prediction of organ dysfunction and mortality in sepsis. AB - BACKGROUND/AIM: Clinical manifestations of sepsis are not caused directly by the invading pathogens, but rather mostly by systemic inflammation that leads to activation of the coagulation system. The aim of this study was to determine whether levels of hemostasis- related parameters measured in intensive care unit admissions are associated with mortality and severity in patients with sepsis. MATERIALS AND METHODS: Eighty-five patients who fulfilled criteria for a diagnosis of sepsis were included in our study. Platelet count, activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time, D-dimer, and fibrinogen levels were determined within the first 24 h from sepsis onset. Differences between groups of septic patients were assessed by Mann-Whitney U test and Kruskal-Wallis test. Logistic regression analysis was performed to test the joint effect of different predictors. RESULTS: Prolonged aPTT and PT with higher D-dimer concentrations in patients with sepsis are associated with more severe forms of the disease, aPTT was prolonged in nonsurvivors, while platelet count and fibrinogen levels were higher in survivors. Platelet count and aPTT ratio are independent predictors of fatal outcome in our logistic regression model. CONCLUSION: Hemostasis-related parameters have a significant impact on severity and outcome in sepsis. PMID- 25790537 TI - Efficacy of entecavir treatment among chronic hepatitis B nucleos(t)ide-naive and -experienced patients. AB - BACKGROUND/AIM: To evaluate the efficacy of entecavir (ETV) among chronic hepatitis B (CHB) nucleos(t)ide-naive and -experienced patients in clinical practice. MATERIALS AND METHODS: In this retrospective study 85 CHB patients who had been receiving ETV and who attended our clinic since 2007 were included. Fifty patients were nucleos(t)ide analogue (NA)-naive. Factors including sex, positive HBeAg, baseline HBV DNA level, baseline alanine aminotransferase level, and prior lamivudine (LAM) resistance were evaluated in terms of their predictive role in treatment response, which was defined as a serum HBV DNA decrease of <31.4 copies/mL. RESULTS: Resistance was detected in 18 (51.4%) of 35 lamivudine experienced patients. Virological response (VR) was achieved in 48 (96.0%) of NA naive patients, while 16 (45.7%) of NA-experienced patients achieved VR. LAM resistant patients had significantly lower response rates (P < 0.001). More responders with a low initial viral load achieved VR at the end of the 12-month follow-up period compared to those with a high initial viral load (91.7% vs. 70.0%, P = 0.004). CONCLUSION: ETV has greater efficacy in NA-naive patients and in NA-experienced patients without prior LAM resistance. The rate of VR achievement at 12 months was higher in patients who initially had a low viral load with ETV treatment. PMID- 25790538 TI - A new utilization area for hyperbaric oxygen? Improving quality of stored blood. AB - BACKGROUND/AIM: Since blood bags have the ability for diffusion of gases, we investigated whether hyperbaric oxygen (HBO) exposure affects several vital parameters of stored blood. MATERIALS AND METHODS: Bloods obtained from the same persons were used as both control and HBO groups and stored in pediatric bags with citrate-phosphate-dextrose solution. HBO administration was performed at 2.5 atm for 90 min, started 1 day after blood collection and repeated every 2 days for a total of 10 times. The study was terminated on the 21st day. Complete blood count, glucose, pH, and osmotic fragility values were measured every week. RESULTS: Glucose and pH levels decreased in stored blood. In the HBO-exposed group, these decreases were less than in the control. In addition, mean corpuscular and platelet volumes tended to increase during storing process, but with HBO, these indexes remained lower, near physiologic levels. Another interesting finding of the study was the relative stable osmotic fragility ratio in the HBO group compared to the control blood. CONCLUSION: HBO exposure has positive effects on pH, stability of erythrocytes, and energy source (glucose) of the medium. Thus, we concluded that HBO may be a useful application for life and quality of stored blood. PMID- 25790539 TI - Serum VEGF levels in gastric cancer patients: correlation with clinicopathological parameters. AB - BACKGROUND/AIM: To evaluate the predictive role of the circulating levels of vascular endothelial growth factor (VEGF) in gastric cancer patients. MATERIALS AND METHODS: This study is a case-control study. We measured serum VEGF levels of 30 patients aged between 34 and 83 years with gastric cancer and 30 patients without malignant pathology, operated on for benign pathologies, with ages ranging from 18 to 69. RESULTS: Serum levels of VEGF were correlated with the tumor type classification (signet cell adenocarcinoma) and the presence of adjacent tissue invasion. There was also a positive correlation between serum VEGF and carcinoembryonic antigen levels. CONCLUSION: In gastric cancer patients, serum VEGF levels may provide additional prognostic information for preoperative evaluation of invasion and tumor type. PMID- 25790540 TI - Clinicopathological importance of Ki-67, p27, and p53 expression in gastric cancer. AB - BACKGROUND/AIM: To assess the prognostic value of Ki-67, p27, and p53 immunoreactivity in human gastric cancer. MATERIALS AND METHODS: A total of 84 patients with gastric cancer participated in our study. We categorized tumors as intestinal and diffuse types, with reference to Lauren's classification. Ki-67, p27, and p53 immunoreactivity were correlated with patient's age, tumor type, grade, lymph node status, extent of invasion, tumor-node-metastasis (TNM) stage, and survival. RESULTS: Decreased expression of p27 (<20% positivity of cells) and increased p53 staining (>50% positivity of cells) were determined in 41 (48.8%) and 29 (36.9%) tumor specimens, respectively, and were connected with both the TNM stage (P = 0.007 and P = 0.039, respectively), and the extent of tumor invasion (P = 0.025 and P = 0.004, respectively). Kaplan-Meier methods showed a remarkable effect of reduced p27 expression on survival time (P = 0.003). In contrast, we observed no notable relationship between survival time and p53 or Ki 67 immunoreactivity (P = 0.372 and P = 0.401, respectively). CONCLUSION: A decrease in p27 expression and overexpression of p53 or Ki-67 may cause advancing and metastatic illness in patients with gastric carcinoma. In addition, immunopathological identification of p27 may be helpful to define patients with gastric cancer who are at an increased risk of death. PMID- 25790541 TI - Is there any impact of PET/CT on radiotherapy planning in rectal cancer patients undergoing preoperative IMRT? AB - BACKGROUND/AIM: To investigate the effect of positron emission tomography computed tomography (PET/CT)-based contouring on dosimetric parameters in rectal cancer patients undergoing preoperative intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: Preoperative radiation therapy plans with conformal radiotherapy (CRT) or IMRT were created and examined according to the CT- and PET/CT-based contouring of 20 rectal cancer patients, retrospectively. RESULTS: The target volumes delineated with PET/CT were significantlylarger than the volumes created by CT (P= 0.043). Dose delivered to 98% of the planning target volume was high in IMRT planning contouring with CT and PET/CT compared with CRT planning, but the difference was not statistically significant (P = 0.056). Percent volumes receiving 105% of dose and 110% of dose were low in IMRT planning when compared with CRT (P < 0.0001 and P = 0.044, respectively). The volumes receiving 45 Gy for the small intestine, femur heads, and bladder and the maximum dose received by the bladder were significantly lower in IMRT. CONCLUSION: We showed that the target volumes created with PET/CT are significantly larger than the target volumes created with CT and that IMRT provides lower radiation exposure to the tumor-free tissues compared to the CRT planning. The dosimetric results primarily favor IMRT planning in rectal cancer patients and consequently present the significant alteration in target volumes. PMID- 25790542 TI - Evaluation of autoinflammatory disease genes in nasal polyposis. AB - BACKGROUND/AIM: To investigate cold-induced autoinflammatory syndrome 1 (CIAS 1) gene polymorphisms that cause autoinflammatory diseases in patients with nasal polyposis (NP). MATERIALS AND METHODS: The study included 30 patients diagnosed with NP and 30 healthy age-matched individuals as a control group. CIAS1 polymorphisms were assessed by DNA sequence analysis. Patients with nasal polyps and the control group were compared in terms of gene polymorphisms. Each of the 8 polymorphisms of the CIAS1 gene was analyzed separately in the patient group. RESULTS: The most frequently observed polymorphisms in the patient group were c.732G > A in 83%, c.663C > T in 23%, and c.1308C > A in 23% of the patients. c.732G > A polymorphism was evaluated separately. Guanine was transformed to adenine at the 732nd nucleotide position of the CIAS1 gene in the cDNA of chromosome 1. CONCLUSION: The CIAS1 gene c.732G > A polymorphism was thought to be responsible for an increase in disease susceptibility. The frequency of the "A" allele is higher in the patient group compared to the control group. Autoinflammatory diseases seem like a candidate to be one of these factors. This is the first report to define the role of autoinflammatory diseases among these factors. PMID- 25790543 TI - Salivary glucose and antioxidant defense markers in type II diabetes mellitus. AB - BACKGROUND/AIM: To evaluate salivary antioxidant defense markers, their correlation with salivary glucose, and glycemic status in type II diabetes mellitus (DM). MATERIALS AND METHODS: The study included 53 diabetic patients and 40 healthy subjects. Salivary glucose, blood glucose, and uric acid (UA) were determined by specific enzymatic methods. Total antioxidant activity (AOA), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and total protein were determined spectrophotometrically. RESULTS: Salivary UA (3.12 vs. 1.89 mg/dL), GSH (47 vs. 11.92 jg/mL), and total protein (375.12 vs. 202.23 mg/dL) were significantly higher (P < 0.001; r = 0.455, 0.735, 0.498 respectively) and AOA (653.1 vs. 897.3 umol/L) was significantly lower in the DM group (P <0.001, r = -0.431) compared to healthy controls. Among the antioxidant enzymes, CAT was significantly lower (1214 vs. 9468.9 kat) in the DM group (P < 0.001, r = 0.886). Spearman correlation analyses within the diabetic group showed a strong positive association between salivary glucose and blood glucose (P <0.001, r = 0.9), salivary glucose and GSH, and salivary glucose and UA. Salivary glucose showed a negative correlation with AOA and CAT (P = 0.008, r = -0.447) in the diabetic group. CONCLUSION: Findings of this study, showing a strong correlation between salivary glucose and blood glucose as well as changes in antioxidant components in the DM group, suggest that saliva can be used for the diagnosis and management of DM. PMID- 25790544 TI - Stress-responsive factor regulation in patients suffering from type 2 diabetes and myocardial infarction. AB - BACKGROUND/AIM: Pro-free radical oxidative stresses, as well as regulatory factors, are believed to be the key players in the development of diabetes and heart-related disorders such as myocardial infarction. The aim of the present study was to highlight the role of oxidative stress-responsive factors (reactive oxygen species [ROS], super oxide dismutase [SOD], and calpain-1) in type 2 diabetes and myocardial infarction. MATERIALS AND METHODS: A total of 100 type 2 diabetes patients with myocardial infarction and 50 normal individuals were selected for this analysis. The levels of ROS and activities of SOD in the serum were determined. Serum calpain-1 expression was checked using western blotting. RESULTS: The serum level of ROS and the expression of calpain-1 were significantly higher while the activity of SOD was significantly lower in diabetic patients with myocardial infraction compared to normal individuals. CONCLUSION: These findings suggest a possible link between decreased antioxidant (SOD) and increased ROS levels as well as calpain-1 expression, supporting the role of oxidative stress-regulatory factors in diabetes and myocardial infraction. PMID- 25790545 TI - An alternative marker of low-density lipoprotein cholesterol in coronary artery disease: non-high-density lipoprotein cholesterol. AB - BACKGROUND/AIM: Dyslipidemia is one of the most important risk factors for coronary artery disease (CAD), and low-densitylipoprotein cholesterol (LDL-C) is used to measure dyslipidemia. Non-high-density lipoprotein cholesterol (non-HDL C) seems to be an alternative parameter to LDL-C as it is not influenced by triglyceride (TG) levels. The aim of this study is to compare non-HDL-C and LDL-C levels as risk markers in CAD patients. MATERIALS AND METHODS: One hundred and ten CAD patients and 42 individuals with normal coronary angiography results were included in this study. Patients were divided into 2 groups: TG < 200 mg/dL (n = 75) as group 1 and TG > 200 mg/dL (n = 35) as group 2. Total cholesterol (TC), TG, and HDL-C levels were analyzed with a Roche Modular P800 autoanalyzer. LDL-C and non-HDL-C levels were calculated. RESULTS: There were statistically significant differences in TC, TG, HDL-C, and non-HDL-C levels when the groups were compared. Non-HDL-C levels of group 2 were statistically higher than those of group 1 and the control group. There was no significant difference in LDL-C levels between the groups. CONCLUSION: Non-HDL-C levels are better risk markers than LDL-C levels, especially in patients with TG > 200 mg/dL, and non-HDL-C levels should be taken into consideration when evaluating the risk of CAD. PMID- 25790546 TI - Pregnancy-associated plasma protein A and procalcitonin as markers of myocardial injury in patients with acute coronary syndrome. AB - BACKGROUND/AIM: To evaluate pregnancy-associated plasma protein A (PAPP-A), ischemia-modified albumin (IMA), procalcitonin, and troponin I levels as diagnostic markers of acute coronary syndrome in patients admitted to the emergency department. MATERIALS AND METHODS: The serum PAPP-A, IMA, procalcitonin, and troponin I levels were measured in 100 patients with acute coronary syndrome admitted to the emergency department and 100 healthy control subjects. RESULTS: Patients with acute coronary syndrome had significantly greater mean serum PAPP-A (patients, 10 +/- 10 mIU/L; control subjects, 6 +/- 10 mIU/L; P < 0.001), procalcitonin (patients, 2 +/- 10 ug/L; control subjects, 0.4 +/- 2 ug/L; P < 0.001), and troponin I levels (patients, 6 +/- 8 ug/L; control subjects, 0.2 +/- 0.3 ug/L; P < 0.001) than control subjects. There was no difference in mean IMA levels between patients and control subjects. There were no significant correlations between PAPP-A levels and IMA, procalcitonin, or troponin I levels in patients with acute coronary syndrome. CONCLUSION: The PAPP A, procalcitonin, and troponin I levels were increased in patients with acute coronary syndrome. Therefore, elevated PAPP-A and procalcitonin levels, in addition to troponin I levels, may be useful markers of myocardial injury on admission to the emergency department. PMID- 25790547 TI - Investigation of TNF-alpha gene (G308A) and GSTP1 gene (Ilel05Val) polymorphisms in Turkish patients with retinopathy of prematurity. AB - BACKGROUND/AIM: Retinopathy of prematurity (ROP) is one of the most frequent causes of blindness in newborn babies. Currently, its etiology is not fully understood.-In this study we aimed to investigate the correlation between a patient group with ROP and a control group in terms of the tumor necrosis factor alpha (TNF-alpha) (G308A) gene and glutathione-S-transferase P1 (GSTP1) (Ilel05Val) gene polymorphism. MATERIALS AND METHODS: Sixty-two patients diagnosed with ROP and 58 control subjects were included in this study. For TNF alpha (G308A) gene and GSTP1 (Ilel05Val) gene polymorphisms, the polymerase chain reaction-restriction fragment length polymorphism method was used. In statistical analysis the significance level was determined as P < 0.05. RESULTS: When the patient and control groups were compared in terms of TNF-alpha (G308A) gene and GSTP1 (Ilel05Val) gene polymorphisms, no statistically significant difference was found (P > 0.05). CONCLUSION: In our study, no correlation was identified between TNF-alpha (G308A) gene and GSTP1 (Ilel05Val) gene polymorphisms and susceptibility for development of ROP. Further studies are required with more cases of ROP patients and other gene polymorphisms that could be related. PMID- 25790548 TI - Analysis of vacA/cagA genotypes/status in Helicobacter pylori isolates from Iranian children and their association with clinical outcome. AB - BACKGROUND/AIM: More than 50% of Iranian children are infected with Helicobacterpylori; however, no data exist about the association of vacA/cagA genotype/status with disease outcomes in them. We analyzed association of vacA/cagA genotypes/status of children's isolates with gastric inflammation status as the first step in H. pylori pathogenesis. MATERIALS AND METHODS: Antral biopsies for culture and histopathology were taken from 328 children in 1997 2009. vacA (s, m) alleles and cagA statuses of the isolates were determined by PCR. Histopathology was performed according to the Sydney system; gastritis was scored as normal, mild, moderate, severe, and follicular. RESULTS: A total of 159 culture-positive cases, with no mixed infections, were enrolled in the study. Of them, 60% were cagA-positive; 21.4%, 37.1%, 16.3%, and 25.2% cases were slm1, slm2, s2m1, and s2m2, respectively. Histopathology showed normal (4.4%), mild- chronic (31.4%), moderate-chronic (38.4%), severe-chronic (10.7%), and follicular gastritis (15.1%) cases. Thirty-four (21.4%) of the children had ulcers. Correlation (P < 0.05) was observed between more severe (moderate, severe, follicular) status and both vacAs1 allele and cagA-positive status. No significant relation was observed between genotype/status of vacA/cagA and ulcers (P > 0.05). CONCLUSION: vacAs1 and cagA are associated with more severe gastric inflammation in Iranian children. Association ofvacAs1 and cagA with more severe pathology in Iran may be similar to that of other parts of the world. PMID- 25790549 TI - Hypo- and hypervolemic edema in children with steroid sensitive nephrotic syndrome. AB - BACKGROUND/AIM: The mechanism of edema formation in nephrotic syndrome is still poorly understood. We aimed to evaluate the volume status in children with steroid-sensitive nephrotic syndrome (SSNS) and to emphasize the importance of echocardiography in demonstrating of volume changes. MATERIALS AND METHODS: Thirty-two SSNS patients and 30 healthy children were enrolled in this study. The volume statuses of patients were evaluated by clinical and laboratory features, including fractional sodium excretion (FENa) and distal sodium/potassium exchange (UK/UNa+K ratio). Inferior vena cava collapsibility index (IVCCI), left atrial diameter (LAD), aortic diameter (AD), and left ventricular mass index (LVMI) were measured using conventional echocardiographic methods. RESULTS: FENa was lower in children with NS; however, the distal K/Na ratio of the patient and control groups did not differ. In addition, IVCCI, LAD, AD, and LVMI were not different among groups. When evaluating the volume status of patients, 8 patients (25%) were hypovolemic while 24 patients (75%) were nonhypovolemic (normovolemic or hypervolemic). LAD was significantly lower in hypovolemic patients. CONCLUSION: The majority of children with SSNS are normovolemic or hypervolemic and echocardiography is an easy and valuable method for the evaluation of volume status in these patients. PMID- 25790550 TI - Gastrointestinal system lesions in children due to the ingestion of alkali and acid corrosive substances. AB - BACKGROUND/AIM: TO examine esophageal and gastric lesions in children due to the ingestion of alkali and acid corrosive substances and to emphasize all related complications. MATERIALS AND METHODS: The reports of 103 children who ingested or were suspected to have ingested corrosive substances and who then underwent upper gastrointestinal endoscopic inspections were evaluated retrospectively. RESULTS: Of the patients, the mean age was 41 +/- 3.6 months, and 57.3% were male. Vomiting was the most common symptom (44.7%). Eighteen different commercial products were defined as corrosive substances: 59.2% of them were alkali, 39.8% were acids, and 1% had a neutral pH. These corrosive agents most frequently contained sodium hydroxide, followed by hydrochloric acid, sodium hypochlorite, and sulfuric acid. Endoscopic inspections were abnormal in 68% of the cases. Esophageal lesions were observed in 56.3% of the patients, while gastric lesions were observed in 35%. During the follow-up period, esophageal strictures developed in 4.9% of patients, while gastric outlet obstructions developed in 1%. CONCLUSION: Of the patients, the mean age was 41 +/- 3.6 months, and 57.3% were male. Vomiting was the most common symptom (44.7%). Eighteen different commercial products were defined as corrosive substances: 59.2% of them were alkali, 39.8% were acids, and 1% had a neutral pH. These corrosive agents most frequently contained sodium hydroxide, followed by hydrochloric acid, sodium hypochlorite, and sulfuric acid. Endoscopic inspections were abnormal in 68% of the cases. Esophageal lesions were observed in 56.3% of the patients, while gastric lesions were observed in 35%. During the follow-up period, esophageal strictures developed in 4.9% of patients, while gastric outlet obstructions developed in 1%. PMID- 25790551 TI - The effect of total intravenous anesthesia on the postoperative cognitive functions of young and elderly patients after lumbar disk surgery. AB - BACKGROUND/AIM: The negative effects of surgery and anesthesia on cognitive functions and their relationships with many factors are well known. In the present study we aimed to investigate the effect of the total intravenous anesthesia (TIVA) method on the postoperative cognitive functions between young and elderly patients scheduled to undergo lumbar disk surgery. MATERIALS AND METHODS: The TIVA method was applied to 40 patients less than 65 years old (young, Group Y) and >=65 years old (old, Group O), whose Mini Mental State Examination (MMSE) results and serum S-100 beta protein levels were compared preoperatively and postoperatively at the 24th hour. RESULTS: Postoperative cognitive dysfunction was not observed in any of the groups in the early stage. MMSE results and mean S-100 beta protein levels determined before and after the operation did not have statistically significant differences between the groups over time. CONCLUSION: In the present study, the TIVA method did not affect postoperative early cognitive functions in either old or young patients who underwent lumbar disk surgery. PMID- 25790552 TI - Assessment of nasal mucociliary clearance in anesthetists. AB - BACKGROUND/AIM: To assess mucociliary clearance in anesthetists who were exposed to waste anesthetic gases occupationally. MATERIALS AND METHODS: The first group consisted of 30 anesthetists who had been working at least 2 years. The control group of 30 subjects was selected from hospital staff with no history of occupational exposure to waste anesthetic gases. Mucociliary clearance time was assessed by measuring the saccharine nasal transit time (SNTT). RESULTS: Thirty six women and 24 men aged between 25 and 60 years were enrolled in the study. There were no differences between the anesthetist and control groups in terms of age, sex, height, or weight. The median SNTT for the anesthetists (10 min) was longer than that for the control group (8.3 min). The difference was significant (P = 0.025). In addition, there was a significant correlation between the SNTT and the working time (P = 0.02). Furthermore, anesthetists who had worked for 4 years or more had prolonged SNTT compared to those who had worked less than 4 years (P < 0.001). CONCLUSION: The present study demonstrated the impairment of mucociliary clearance in anesthetists. Increasing impairment with increasing working time was also detected. PMID- 25790553 TI - The long-term changes in pain-related symptomatology of inguinal hernia following 2 different herniorrhaphy techniques. AB - BACKGROUND/AIM: To compare the changes in pain-related symptoms of inguinal hernias from initial admission to postoperative month 6 following 2 herniorrhaphy techniques. MATERIALS AND METHODS: Patients with unilateral inguinal hernias were scheduled for either Lichtenstein or self-gripping polypropylene mesh repair. Patients were preoperatively evaluated with a visual analog scale (VAS) and a Turkish version ofthe Douleur Neuropathique 4 (DN4) questionnaire and the complaints related to pain were noted. After surgery, patients were discharged without early complications. Patients were reassessed at postoperative month 6. The late-term complaints of pain as well as neurological findings were evaluated using the VAS and the Turkish version of the DN4 questionnaire. Quality of life was also assessed with the Nottingham Health Profile (NHP). RESULTS: Thirty-four patients underwent conventional Lichtenstein repair and 19 patients underwent self-gripping polypropylene mesh repair. Even though decreases in VAS intensity scores for both hernia repair techniques were noted at postoperative month 6 when compared to the preoperative period, no significant changes were found in pain, VAS, total DN4, or NHP scores between groups. CONCLUSION: Despite its ease of application and short time duration, self-gripping polypropylene mesh repair was not found to be superior to conventional Lichtenstein hernia repair in terms of reducing pain related to inguinal hernia. PMID- 25790554 TI - Structural chromosomal abnormalities in couples with recurrent abortion in Egypt. AB - BACKGROUND/AIM: To evaluate the incidence of chromosomal abnormalities in couples who experience recurrent abortion and identify additional factors that may be predictive of abortion, such as parental age and unfavorable obstetric or abnormal semen analysis. MATERIALS AND METHODS: The present study examined 125 couples who had experienced recurrent abortion. All subjects provided a detailed personal medical history and ancestral history and underwent a physical examination. Women in the study group underwent biochemical testing and pelvic ultrasound examinations, and men underwent a semen analysis. RESULTS: Among the 125 couples tested, 8 c6uples (6.4%) displayed a balanced translocation, among which 7 (5.6%) showed a reciprocal translocation and 1 (0.8%) showed a Robertsonian translocation. All carriers of these translocations were aged <35 years. A significant proportion of carriers reported a poor obstetric history and a past fetal malformation. All male carriers had a normal semen analysis. CONCLUSION: Couples who experience >=2 pregnancy losses of unknown origin should undergo a cytogenetic analysis, and findings showing a chromosomal abnormality in either parent must be followed by genetic counseling. PMID- 25790555 TI - Aberrant expression of leukemia inhibitory factor receptor (LIFR) and leukemia inhibitory factor (LIF) is associated with tubal pregnancy occurrence. AB - BACKGROUND/AIM: Tubal pregnancy is a major cause of maternal death in the first trimester and exploration of its underlying molecular mechanism is of great importance. This study aimed to explore the association of tubal pregnancy with leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) expression in oviduct tissues. MATERIALS AND METHODS: Immunohistochemistry was performed to probe the differential expression of LIF and LIFR in oviduct tissues among a control group (including NP group, n = 11; and IP group, n = 12), tubal pregnancy group (Ect-N group, n = 31; and Ect-A group, n = 40), and chronically inflamed group (including Inf-S group, n = 11; and Inf-P group, n = 9), followed by semiquantitative analysis. RESULTS: Semiquantitative immunohistochemical analysis demonstrated that there was no significant difference in LIF expression in either the epithelial or stromal cells of oviduct tissues between the tubal pregnancy group and the control group (P < 0.05). However, LIF expression was remarkably elevated in the Inf-S and Inf-P group compared to the other groups (P < 0.05). In the epithelial cells of the fallopian tubes, LIFR expression was highest in the chronically inflamed group, followed by the tubal pregnancy group, outnumbering the control group (P < 0.05). More interestingly, an opposite expression trend of LIFR was observed in the stromal cells of the fallopian tubes among these groups (P <0.05). CONCLUSION: Aberratn expression of LIF and LIFR might be associated with the occurrence of tubal pregnancy. PMID- 25790556 TI - The effect of extracorporeal shock wave lithotripsy on distribution of interstitial cells of Cajal in rabbit renal pelvis and proximal ureter. AB - BACKGROUND/AIM: An experimental study was performed to evaluate the effect of extracorporeal shock wave lithotripsy (ESWL) on the distribution of interstitial cells of Cajal (ICC) in rabbit renal pelvis and proximal ureter. MATERIALS AND METHODS: Six New Zealand rabbits were included. Right kidneys were exposed to a total of 3000 shock waves (14 kV) by using an electrohydraulic-type ESWL device. Right sides were allocated as the ESWL group (EG, n = 6) and left sides as the control group (CG, n = 6). Tissues were harvested on day 7. Tissues were examined histopathologically for the presence of edema, inflammation, congestion, hemorrhage, fibrosis, and vascularization. Mast cell tryptase and CD 117 (c-kit) staining was performed for ICC distribution. RESULTS: Although increased tissue edema in renal pelvises and increased inflammation in ureters were observed in EG, no statistical difference was detected between groups (P > 0.05). In CG, positive CD117 staining was detected in 2 renal pelvises and ureters. None of the EG samples showed CD117 staining and no statistical difference was detected between groups (P > 0.05). CONCLUSION: Rabbit does not appear to be a good model for investigating ICCs. ESWL may cause histopathological alterations in the renal pelvis and ureter. Since it has not been statistically proven, reduced contractility of the ureter after ESWL may not be attributed to altered distribution of ICCs in the renal pelvis and ureter. PMID- 25790557 TI - Is there an association between histopathological changes in the lower ureter and renal functions? Evaluation of patients who underwent ureteroneocystostomy for ureterovesical obstruction or vesicoureteral reflux. AB - BACKGROUND/AIM: We aimed to assess the relationship between the histological changes of the ureterovesical junction (UVJ) and renal functions. Therefore, we evaluated histological changes of the lower ureter and renal scintigraphy findings of patients for whom ureteroneocystostomy was performed because of vesicoureteral reflux (VUR) or ureterovesical junction obstruction (UVO). MATERIALS AND METHODS: UVJ specimens were obtained from 18 children. We investigated the changes in neuronal innervation, muscular morphology, extracellular matrix, and apoptosis rate with renal scintigraphy findings. RESULTS: Seven UVO and 11 VUR patients were treated. Alpha-actin expression in smooth muscle cells was found to be lower (P < 0.001) while neuronal defect was more prominent in the UVO group (P = 0.002). The renal functions decreased as the smooth muscle structural defect increased in the VUR group (P < 0.05). CONCLUSION: Neuronal tissue and muscle tissue were more defective in the UVO group. The decrease in neuronal fibers and muscle cells explains the pathogenesis of the obstructive group, but no difference was observed regarding the accumulation of collagen type 3 and cellular apoptosis between the VUR and UVO groups. In the VUR group, renal functions decreased while the smooth muscle defect at the distal end of the ureter increased. PMID- 25790558 TI - Comparison of perioperative oxidative stress in endovascular and open repair of abdominal aortic aneurysm. AB - BACKGROUND/AIM: To investigate the differences in perioperative oxidative stress (OS) in abdominal aortic aneurysm (AAA) patients treated with either endovascular repair (EVAR) or open repair (OR). MATERIALS AND METHODS: Twenty patients (11 OR, 9 EVAR) treated for AAA with no known malignant or inflammatory disease and an aneurysm diameter of over 5 cm and no rupture were included in the study. Blood samples were obtained preoperatively, during aortic occlusion, and 1 h and 24 h after reperfusion. Total antioxidant status (TAS), total oxidative stress (TOS), and malondialdehyde (MDA) levels were measured and oxidative stress index (OSI) was calculated. RESULTS: OSI at 1 h and 24 h after reperfusion was higher in the EVAR group (P = 0.004 and P = 0.002, respectively). TAS levels were higher (P = 0.001, P = 0,029). MDA levels showed no difference (P = 0.291, P = 0.076). TOS levels were lower 24 h after reperfusion in the EVAR group (P = 0.018). CONCLUSION: Markers of oxidative stress were lower in the EVAR group. This may be associated with advantages of EVAR. More studies are required for a clear-cut conclusion. PMID- 25790559 TI - The protective effect of syringic acid on ischemia injury in rat brain. AB - BACKGROUND/AIM: Brain ischemia and treatment are important topics in neurological science. Free oxygen radicals and inflammation formed after ischemia are accepted as the most significant causes of damage. Currently there are studies on many chemopreventive agents to prevent cerebral ischemia damage. Our aim is to research the preventive effect of the active ingredient in syringic acid, previously unstudied, on oxidative damage in cerebral ischemia. MATERIALS AND METHODS: The rats were randomly divided into 4 groups: control group (no medication or surgical procedure), sham group (artery occlusion), artery occlusion + syringic acid group sacrificed at 6 h, and artery occlusion + syringic acid group sacrificed at 24 h. Obtained brain tissue from the right hemisphere was investigated histopathologically and for tissue biochemistry. RESULTS: Superoxide dismutase and nuclear respiratory factor 1 values decreased after ischemia and they increased after syringic acid treatment, while increased malondialdehyde levels after ischemia were reduced after treatment. Caspase-3 and caspase-9 values increased after ischemia and decreased after treatment; this reduction was more pronounced at 24 h. CONCLUSION: Our study revealed that syringic acid treatment in cerebral ischemia reduced oxidative stress and neuronal degeneration. In the light of the biochemical and histopathologic results of the present study, we think that syringic acid treatment may be an alternative treatment method. PMID- 25790560 TI - Oral mucosal lesions: a retrospective review of one institution's 13-year experience. AB - BACKGROUND/AIM: To investigate the relative frequency of biopsied nonneoplastic oral mucosal lesions in Ankara, Turkey. MATERIALS AND METHODS: Biopsy records of a single center from 2000-2012 were retrospectively collected. Diagnosis was recorded and evaluated with respect to patient demographics (age, sex) and location of the lesion. RESULTS: Of 11,980 biopsies, 1732 (14.5%) were mucosal nonneoplastic lesions. Hyperplastic lesions (n= 1000, 57.7%) with fibroepithelial hyperplasia in 30.9% of patients were the most common type of oral nonneoplastic lesions. The mean age of patients differed with respect to type of mucosal lesion, tending to be lower in patients with reactive lesions. Dermatoses showed a female predominance. CONCLUSION: Our ,findings revealed that hyperplastic lesions were the most common among nonneoplastic oral mucosa lesions. Geographic and ethnic.differences of patients with various types of oral mucosal lesions require further investigation. PMID- 25790561 TI - Acute effect of hemodialysis on arterial elasticity. AB - BACKGROUND/AIM: Reduced arterial elasticity is an independent predictor of cardiovascular mortality in patients with end-stage renal disease (ESRD). Hemodialysis (HD) treatment per se can bring additional risk factors for vascular disease. Our study was designed to determine whether a single hemodialysis session leads to an acute alteration in parameters of arterial elasticity in ESRD. MATERIALS AND METHODS: In this study, 58 patients undergoing chronic hemodialysis and 29 healthy controls were enrolled. Large artery elasticity index (LAEI) and the small artery elasticity index (SAEI) were measured by applanation tonometry. The acute effect of a hemodialysis session on arterial elasticity indices was assessed by comparison of prehemodialysis and posthemodialysis determinations. RESULTS: At baseline, LAEI did not differ significantly in patients compared with controls. In contrast, the SAEI was significantly lower in patients (4.1 +/- 2.6 mL/mmHg x 100) than in healthy individuals (8.9 +/- 3.4 mL/mmHg x 100, P < 0.05). In patients with ESRD, no significant changes in LAEI was observed after HD, but SAEI deteriorated significantly (from 4.1 +/- 2.6 mL/mmHg x 100 to 3.4 +/- 2.3, P < 0.05). CONCLUSION: We conclude that ESRD patients face a significant reduction in SAEI, which is exacerbated by a dialysis procedure. PMID- 25790562 TI - Just how wrong are you? PMID- 25790563 TI - It is time to start walking the talk of transparency, experts say. PMID- 25790564 TI - 10 tech issues to consider, according to ECRI. PMID- 25790565 TI - Why are your surgical patients coming back? PMID- 25790566 TI - Breaking bad habits, forming good ones. PMID- 25790567 TI - Should drivers be operating within an automation-free bandwidth? Evaluating haptic steering support systems with different levels of authority. AB - OBJECTIVE: The aim of this study was to compare continuous versus bandwidth haptic steering guidance in terms of lane-keeping behavior, aftereffects, and satisfaction. BACKGROUND: An important human factors question is whether operators should be supported continuously or only when tolerance limits are exceeded. We aimed to clarify this issue for haptic steering guidance by investigating costs and benefits of both approaches in a driving simulator. METHODS: Thirty-two participants drove five trials, each with a different level of haptic support: no guidance (Manual); guidance outside a 0.5-m bandwidth (Band1); a hysteresis version of Band1, which guided back to the lane center once triggered (Band2); continuous guidance (Cont); and Cont with double feedback gain (ContS). Participants performed a reaction time task while driving. Toward the end of each trial, the guidance was unexpectedly disabled to investigate aftereffects. RESULTS: All four guidance systems prevented large lateral errors (>0.7 m). Cont and especially ContS yielded smaller lateral errors and higher time to line crossing than Manual, Band1, and Band2. Cont and ContS yielded short lasting aftereffects, whereas Band1 and Band2 did not. Cont yielded higher self reported satisfaction and faster reaction times than Band1. CONCLUSIONS: Continuous and bandwidth guidance both prevent large driver errors. Continuous guidance yields improved performance and satisfaction over bandwidth guidance at the cost of aftereffects and variability in driver torque (indicating human automation conflicts). APPLICATION: The presented results are useful for designers of haptic guidance systems and support critical thinking about the costs and benefits of automation support systems. PMID- 25790568 TI - Analyzing the effects of human-aware motion planning on close-proximity human robot collaboration. AB - OBJECTIVE: The objective of this work was to examine human response to motion level robot adaptation to determine its effect on team fluency, human satisfaction, and perceived safety and comfort. BACKGROUND: The evaluation of human response to adaptive robotic assistants has been limited, particularly in the realm of motion-level adaptation. The lack of true human-in-the-loop evaluation has made it impossible to determine whether such adaptation would lead to efficient and satisfying human-robot interaction. METHOD: We conducted an experiment in which participants worked with a robot to perform a collaborative task. Participants worked with an adaptive robot incorporating human-aware motion planning and with a baseline robot using shortest-path motions. Team fluency was evaluated through a set of quantitative metrics, and human satisfaction and perceived safety and comfort were evaluated through questionnaires. RESULTS: When working with the adaptive robot, participants completed the task 5.57% faster, with 19.9% more concurrent motion, 2.96% less human idle time, 17.3% less robot idle time, and a 15.1% greater separation distance. Questionnaire responses indicated that participants felt safer and more comfortable when working with an adaptive robot and were more satisfied with it as a teammate than with the standard robot. CONCLUSION: People respond well to motion-level robot adaptation, and significant benefits can be achieved from its use in terms of both human robot team fluency and human worker satisfaction. APPLICATION: Our conclusion supports the development of technologies that could be used to implement human aware motion planning in collaborative robots and the use of this technique for close-proximity human-robot collaboration. PMID- 25790569 TI - Are well-calibrated users effective users? Associations between calibration of trust and performance on an automation-aided task. AB - OBJECTIVE: We present alternative operationalizations of trust calibration and examine their associations with predictors and outcomes. BACKGROUND: It is thought that trust calibration (correspondence between aid reliability and user trust in the aid) is a key to effective human-automation performance. We propose that calibration can be operationalized in three ways. Perceptual accuracy is the extent to which the user perceives the aid's reliability accurately at one point in time. Perceptual sensitivity and trust sensitivity reflect user adjustment of perceived reliability and trust as the aid's actual reliability changes over time. METHOD: One hundred fifty-five students completed an X-ray screening task with an automated screener. Awareness of the aid's accuracy trajectory and error type was examined as predictors, and task performance and aid failure detection were examined as outcomes. RESULTS: Awareness of accuracy trajectory was significantly associated with all three operationalizations of calibration, but awareness of error type was not when considered in conjunction with accuracy trajectory. Contrary to expectations, only perceptual accuracy was significantly associated with task performance and failure detection, and combined, the three operationalizations accounted for only 9% and 4% of the variance in these outcomes, respectively. CONCLUSION: Our results suggest that the potential importance of trust calibration warrants further examination. Moderators may exist. APPLICATION: Users who were better able to perform the task unaided were better able to identify and correct aid failure, suggesting that user task training and expertise may benefit human-automation performance. PMID- 25790570 TI - Match between classroom dimensions and students' anthropometry: re-equipment according to European educational furniture standard. AB - OBJECTIVE: The aim of this study was to investigate mismatch between students and classroom furniture dimensions and evaluate the improvement in implementing the European furniture standard. BACKGROUND: In Portugal, school furniture does not meet any national ergonomic criteria, so it cannot fit students' anthropometric measures. METHOD: A total of 893 students belonging to third (7th through 9th grades) and secondary (10th through 12th grades) cycles participated in the study. Anthropometric measurements of the students were gathered in several physical education classes. The furniture dimensions were measured for two models of tables and seats. Several two-way equations for match criteria based on published studies were applied to data. RESULTS: The percentage of students who match with classroom furniture dimensions is low (24% and 44% between table and students, 4% and 9% between seat and students at 7th and 12th grades, respectively). Table is high for the third cycle, seat is high for both cycles, and seat depth fits well to students. No significant relationship was found between ergonomic mismatch and prevalence of pain. CONCLUSION: For each cycle, at least two different sizes indicated in the European standard should be available to students, considering the large variability in body dimensions within each cycle. The match criteria used gives a large percentage of students without pain in a mismatch situation. APPLICATION: Future measures applying to secondary schools should revise the decision of selecting a single size of classroom furniture and improve the implementation of the European standard. New criteria for ergonomic mismatch are needed that more closely model the responses about discomfort/pain. PMID- 25790571 TI - Display clutter: a review of definitions and measurement techniques. AB - OBJECTIVE: We aimed to synthesize the literature on display clutter by reviewing definitions and measurement techniques and to develop a comprehensive, ergonomics oriented perspective on clutter. We provide guidance for the selection of measurement approaches that can capture the various aspects and effects of clutter on visual search in particular. BACKGROUND: There is agreement that clutter may represent a significant problem to operators. The challenge is to determine the ideal middle ground between excessive data and insufficient information. However, definitions of clutter vary widely, which explains the range of measurement approaches, including image-processing algorithms, performance evaluation, subjective evaluation, and eye tracking. It is important to understand the affordances of each technique and provide guidance for their use. METHOD: We provide a systematic review of clutter definitions and develop a performance-oriented perspective for ergonomics research. Next, we present a critical overview of clutter measurement approaches. The benefits and limitations of each technique are detailed, and recommendations for best practice are provided. RESULTS: From an ergonomics perspective, clutter matters to the extent that it affects performance, particularly, visual search. A combination of measurement techniques can be employed in order to assess the performance costs stemming from the multiple aspects of clutter. CONCLUSION: Display clutter is a multifaceted construct that is a problem when it results in performance and attentional costs. The assessment of these costs is critical and requires the use of appropriate and complementary techniques. APPLICATION: It is important that the performance costs of clutter are detected reliably to be able to better support attention management. PMID- 25790572 TI - Thinking aloud influences perceived time. AB - OBJECTIVE: We investigate whether thinking aloud influences perceived time. BACKGROUND: Thinking aloud is widely used in usability evaluation, yet it is debated whether thinking aloud influences thought and behavior. If thinking aloud is restricted to the verbalization of information to which a person is already attending, there is evidence that thinking aloud does not influence thought and behavior. METHOD: In an experiment, 16 thinking-aloud participants and 16 control participants solved a code-breaking task 24 times each. Participants estimated task duration. The 24 trials involved two levels of time constraint (timed, untimed) and resulted in two levels of success (solved, unsolved). RESULTS: The ratio of perceived time to clock time was lower for thinking-aloud than control participants. Participants overestimated time by an average of 47% (thinking aloud) and 94% (control). The effect of thinking aloud on time perception also held separately for timed, untimed, solved, and unsolved trials. CONCLUSION: Thinking aloud (verbalization at Levels 1 and 2) influences perceived time. Possible explanations of this effect include that thinking aloud may require attention, cause a processing shift that overshadows the perception of time, or increase mental workload. APPLICATION: For usability evaluation, this study implies that time estimates made while thinking aloud cannot be compared with time estimates made while not thinking aloud, that ratings of systems experienced while thinking aloud may be inaccurate (because the experience of time influences other experiences), and that it may therefore be considered to replace concurrent thinking aloud with retrospective thinking aloud when evaluations involve time estimation. PMID- 25790573 TI - Predictive displays for a process-control schematic interface. AB - OBJECTIVE: Our objective was to examine the extent to which increasing precision of predictive (rate of change) information in process control will improve performance on a simulated process-control task. BACKGROUND: Predictive displays have been found to be useful in process control (as well as aviation and maritime industries). However, authors of prior research have not examined the extent to which predictive value is increased by increasing predictor resolution, nor has such research tied potential improvements to changes in process control strategy. METHOD: Fifty nonprofessional participants each controlled a simulated chemical mixture process (honey mixer simulation) that simulated the operations found in process control. Participants in each of five groups controlled with either no predictor or a predictor ranging in the resolution of prediction of the process. RESULTS: Increasing detail resolution generally increased the benefit of prediction over the control condition although not monotonically so. The best overall performance, combining quality and predictive ability, was obtained by the display of intermediate resolution. The two displays with the lowest resolution were clearly inferior. CONCLUSION: Predictors with higher resolution are of value but may trade off enhanced sensitivity to variable change (lower resolution discrete state predictor) with smoother control action (higher resolution continuous predictors). APPLICATION: The research provides guidelines to the process-control industry regarding displays that can most improve operator performance. PMID- 25790574 TI - The psychometrics of mental workload: multiple measures are sensitive but divergent. AB - OBJECTIVE: A study was run to test the sensitivity of multiple workload indices to the differing cognitive demands of four military monitoring task scenarios and to investigate relationships between indices. BACKGROUND: Various psychophysiological indices of mental workload exhibit sensitivity to task factors. However, the psychometric properties of multiple indices, including the extent to which they intercorrelate, have not been adequately investigated. METHOD: One hundred fifty participants performed in four task scenarios based on a simulation of unmanned ground vehicle operation. Scenarios required threat detection and/or change detection. Both single- and dual-task scenarios were used. Workload metrics for each scenario were derived from the electroencephalogram (EEG), electrocardiogram, transcranial Doppler sonography, functional near infrared, and eye tracking. Subjective workload was also assessed. RESULTS: Several metrics showed sensitivity to the differing demands of the four scenarios. Eye fixation duration and the Task Load Index metric derived from EEG were diagnostic of single-versus dual-task performance. Several other metrics differentiated the two single tasks but were less effective in differentiating single- from dual-task performance. Psychometric analyses confirmed the reliability of individual metrics but failed to identify any general workload factor. An analysis of difference scores between low- and high workload conditions suggested an effort factor defined by heart rate variability and frontal cortex oxygenation. CONCLUSIONS: General workload is not well defined psychometrically, although various individual metrics may satisfy conventional criteria for workload assessment. APPLICATION: Practitioners should exercise caution in using multiple metrics that may not correspond well, especially at the level of the individual operator. PMID- 25790575 TI - Motion-cuing algorithms: characterization of users' perception. AB - OBJECTIVE: The aim of this study was to characterize the human response to motion cuing algorithms (MCAs) by comparing users' perception to several proposed objective indicators. BACKGROUND: Other researchers have proposed several MCAs, but few improvements have been achieved lately. One of the reasons for this lack of progress is that fair comparisons between different algorithms are hard to achieve, for their evaluation needs to be performed with humans and the tuning process is slow. METHOD: This characterization is performed by means of a comparison of the subjective perception of vehicle simulation users (90 participants) against several proposed objective indicators that try to measure MCA performance. Two motion platforms (3 and 6 degrees of freedom [DoF]) and two vehicle simulators (a driving simulator and a speedboat simulator) were tested using the classical washout algorithm, considered to be the main reference in MCA literature. RESULTS: Results show that users are more sensitive to correlation and delay with respect to the expected motion rather than its magnitude and that specific force is more of a factor than angular speed in the driving simulator. The opposite happens in the speedboat simulator. CONCLUSIONS: Human drivers' reaction to MCA is mainly characterized by the normalized Pearson correlation between output and input signals of the algorithm. This finding validates the main MCA strategy that consists of downscaling the signals and slightly distorting their frequency spectrum. The 6-DoF simulator is perceived as a modest improvement of the 3-DoF platform. APPLICATIONS: These results set the basis for future automatic tuning, evaluation, and comparison of MCA in motion platforms. PMID- 25790576 TI - Team members' interaction anxiety and team-training effectiveness: a catastrophic relationship? AB - OBJECTIVE: In the present study, we examined the relationship between team members' interaction anxiety and team-training effectiveness. BACKGROUND: Training in the context of teams can be focused on either individual or team outcomes. Relatedly, the individual differences of team members can hinder or facilitate the effectiveness of training for both individuals and the team as a collective. Interaction anxiety is an understudied individual difference that has been shown to be negatively related to training effectiveness in individual contexts. However, its effects in team-training contexts are yet to be investigated. METHOD: A sample of 492 students in 123 four-person teams was trained to operate a complex, computer-based team task RESULTS: Interaction anxiety negatively related to team cohesion and team-training effectiveness. A cusp catastrophe model fit the data and showed that teams with more than one high interaction-anxiety member were negatively affected. CONCLUSION: Interaction anxiety inhibits the social activities of team training, in turn reducing team training effectiveness when there is more than one high-interaction-anxiety individual on the training team. APPLICATION: These results highlight the importance of examining interaction anxiety as a training team compositional variable that may inhibit behaviors and team processesnecessary to capitalize on the positive social activities on which team training depends since the interaction anxiety composition of training teams may serve as an important boundary condition on the effectiveness team-training interventions. PMID- 25790577 TI - Understanding the impact of electric vehicle driving experience on range anxiety. AB - OBJECTIVE: The objective of the present research was to increase understanding of the phenomenon of range anxiety and to determine the degree to which practical experience with battery electric vehicles (BEVs) reduces different levels of range anxiety. BACKGROUND: Limited range is a challenge for BEV users. A frequently discussed phenomenon in this context is range anxiety. There is some evidence suggesting that range anxiety might be a problem only for inexperienced BEV drivers and, therefore, might decrease with practical experience. METHOD: We compared 12 motorists with high BEV driving experience (M = 60,500 km) with 12 motorists who had never driven a BEV before. The test drive was designed to lead to a critical range situation (remaining range < trip length). We examined range appraisal and range stress (i.e., range anxiety) on different levels (cognitive, emotional, and behavioral). RESULTS: Experienced BEV drivers exhibited less negative range appraisal and range anxiety than inexperienced BEV drivers, revealing significant, strong effects for all but one variable. CONCLUSION: Hence, BEV driving experience (defined as absolute kilometers driven with a BEV) seems to be one important variable that predicts less range anxiety. APPLICATION: In order to reduce range anxiety in BEV drivers even when there is a critical range situation, it is important to increase efficiency and effectiveness of the learning process. PMID- 25790578 TI - On being bullied... . PMID- 25790579 TI - Our OSMA Foundation. PMID- 25790580 TI - Head and neck skin cancer in the immunocompromised patient: a quantitative analysis. AB - BACKGROUND: Non-melanoma skin cancers (NMSC) are especially prone to develop in the immunosuppressed population. There is insufficient data regarding outcomes and mortality for immunosuppressed individuals with NMSC of the head and neck. CLINICAL QUESTION: What are the mortality indicators for immunosuppressed subjects with head and neck NMSC? METHODS: This retrospective chart review analyzes all immunosuppressed patients diagnosed with any stage NMSC at an academic tertiary care institution from 2006-2011. RESULTS: Thirty four patients are analyzed. Odds of mortality is significantly increased for patients who required multiple surgeries (adjusted odds ratio (aOR)=23.98, 95%CI=(1.411, 407.599)) and those who were immunocompromised secondary to leukemia (aOR=28.27, 95%CI=(1.838, 434.73)). CONCLUSION: Patients with leukemia and NMSC may have an increased risk of mortality compared to other immunocompromised patients with NMSC. Immunocompromised patients with NMSC may have a worse prognosis if multiple surgeries are required. Knowledge of mortality indicators may aid in the management of these immunocompromised patients. PMID- 25790581 TI - Lung cancer screening: where have we been? Where are we going? AB - Recent evidence suggests that lung cancer screening with low-dose chest CT (LDCT) has a moderate net benefit on lung cancer mortality when applied to a high-risk population. This review article examines this evidence in light of the earlier failures of lung cancerscreening using chest radiography and/or sputum cytology. Harms associated with LDCT lung cancer screening include false positive results, false negative results, incidental findings, radiation exposure, and overdiagnosis. A number of issues related to implementation are unresolved. PMID- 25790582 TI - SFY 2016 budget outlook. PMID- 25790583 TI - Aggressive end-of-life (EOL) care. PMID- 25790584 TI - Living and dying by patient surveys... . PMID- 25790585 TI - Disruptive technology. PMID- 25790586 TI - The impact of a Medical Home for children with developmental disability within a pediatric resident continuity clinic. . AB - Primary care provided in a Medical Home (MH) can improve outcomes for Children with Special Health Care Needs. It is important for residents to experience MH in their training. The Oklahoma Family Support 360 project, a five-year collaborative initiative, established a MH in a pediatric primary care resident continuity clinic at the University of Oklahoma Health Sciences Center. A study of the effects of enhancement of the seven key MH attributes showed a significant decrease in Emergency Service use, a significant increase in Dental Service use, high satisfaction with MH activities, and high ratings for a positive impact on quality of life for the child and family. The project demonstrated that a MH could be established in a pediatric academic program, improved health service use, and had a high level of satisfaction from participating families. This model provides a good example of the MH qualities for residents in training. PMID- 25790587 TI - Are at-home sleep studies performed using portable monitors (PMs) as effective at diagnosing obstructive sleep apnea (OSA) in adults as sleep laboratory-based polysomnography (PSG)? AB - RESIDENCY PROGRAM: University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, Oklahoma City, OK. ANSWER: In patients with suspected OSA, it is reasonable to use PMs if the patient has a high pretest probability (based on an Epworth Sleepiness Scale (ESS) >=10 and clinical symptoms*) without significant co-morbid heart disease or other sleep disorders and he/she is able to prove competency in setting up the home equipment properly without assistance. However, if the patient has a negative PM, it is standard to perform PSG as it appears approximately 20% will have a false negative PM. (*Clinical symptoms include snoring, witnessed apneas, obesity, pulmonary hypertension, refractory hypertension, morning headaches, increased neck circumference-->17 inches in men, >16 inches in women--daytime sleepiness.) LEVEL OF EVIDENCE FOR THE ANSWER: A. SEARCH TERMS: obstructive sleep apnea, polysomnography, portable home monitors, efficacy. INCLUSION CRITERIA: polysomnography, ambulatory, adults, humans. ESCLUSION CRITERIA: children. PMID- 25790588 TI - Mindfulness: the untapped innate catalyst for healing, happiness and health. PMID- 25790589 TI - Childhood impressions. PMID- 25790590 TI - Childhood impressions... PMID- 25790591 TI - Take a hike! PMID- 25790592 TI - Developing a statewide public health initiative to reduce infant mortality in Oklahoma. AB - The Preparing for a Lifetime, It's Everyone's Responsibility initiative was developed to improve the health and well- being of Oklahoma's mothers and infants. The development phase included systematic data collection, extensive data analysis, and multi-disciplinary partnership development. In total, seven issues (preconception/interconception health, tobacco use, postpartum depression, breastfeeding, infant safe sleep, preterm birth, and infant injury prevention) were identified as crucial to addressing infant mortality in Oklahoma. Workgroups were created to focus on each issue. Data and media communications workgroups were added to further partner commitment and support for policy and programmatic changes across multiple agencies and programs. Leadership support, partnership, evaluation, and celebrating small successes were important factors that lead to large scale adoption and support for the state-wide initiative to reduce infant mortality. PMID- 25790593 TI - Oklahoma's fetal and infant mortality review projects. AB - In Oklahoma, the infant mortality rate is higher than the national rate. Fetal Infant Mortality Review (FIMR) is an effective perinatal systems intervention. FIMR gathers information from medical, social, and community sources taking a comprehensive look at how well these systems are serving women and infants. It is important to understand that FIMR is a method to develop community-based plans to reduce fetal and infant mortality. It is not a quick-fix solution to a complex problem, a research study, an institutional review, or a system for assigning blame or responsibility for a death. FIMR has been instrumental in identifying what health care providers, community leaders, and citizens can do to improve the health and lives of babies in Oklahoma. Key steps include: (1.) Data abstraction (2.) A home interview (3.) A review of individual case summaries (4.) Development of community-based solutions and interventions designed to improve service systems and resources PMID- 25790594 TI - OCCY Substance Exposed Newborn Subcommittee. PMID- 25790595 TI - Hospital efforts to improve breastfeeding outcomes: becoming baby-friendly in Oklahoma. AB - A key component of the Preparing for a Lifetime initiative to reduce infant mortality and improve infant outcomes in Oklahoma focuses on improving breastfeeding outcomes. The evidence is well-established on the short and long term positive health impact of breastfeeding and lactation on both infant and mother. A new collaborative effort was launched in 2012 to support Oklahoma hospitals to achieve designation as a Baby-Friendly hospital, the Becoming Baby Friendly in Oklahoma project. Baby-Friendly hospitals comply with the evidence based Ten Steps to Successful Breastfeeding and do not market formula products directly to patients. This article describes the progress of this statewide project. PMID- 25790596 TI - Establishing level II neonatal services in southwestern Oklahoma. AB - Historically, Neonatal Services in Oklahoma have relied upon Level III and IV NICUs within the largest metropolitan areas to provide services for premature and other sick newborns. Smaller, regional Level II nurseries have delivered care according to previous American Academy of Pediatrics (AAP) Guidelines for Levels of Care. With changing guidelines in perinatal and neonatal care, there has been the need to add to available neonatal resources to continue to allow infants to remain in their home. This article is a description of a partnership between Comanche County Memorial Hospital (CCMH) and the Department of Pediatrics, Neonatal-Perinatal Medicine Section at OU Health Sciences Center (OUHSC) to establish a regional Level II NICU and the planning and implementation required to meet local, state, and national standards. The process, which involved neonatologists, nurse practitioners, nurses, laboratory services, pharmacy services, radiology, and respiratory therapy, resulted in a fully-functioning 8 bed Level II NICU. PMID- 25790597 TI - Childhood functional abdominal pain syndrome: a clinical review update. PMID- 25790598 TI - Children's emotional and behavioral reactions to disasters: role of the primary care physician. AB - BACKGROUND: Children are especially vulnerable to the effects of disasters. The coming tornado season raises concerns about enduring problems and anniversary reactions related to the May 2013 tornadoes as well as anxiety about the possibility of new events. METHODS: This article describes common emotional and behavioral disaster reactions in children and also identifies reactions unique to a particular age. Reactions are clustered into depressive, anxious, and behavioral symptoms and physiological responses. PRIMARY RESULTS: This article outlines the key elements in assessing children's disaster reactions and provides specific recommendations for situations that would indicate the need for a mental health evaluation such as for directly-exposed children, children who experience disaster-related losses, those with pre-existing vulnerabilities, and those with significant symptoms. PRINCIPAL CONCLUSIONS: Primary care physicians can help identify the emotional and behavioral effects of disasters in children, educate parents to recognize children's reactions, and refer children in need of specialized care. PMID- 25790599 TI - Schools for healthy lifestyles addressing the issue of children's health in Oklahoma. PMID- 25790600 TI - Adolescent vaccination in Oklahoma: a work in progress. AB - BACKGROUND: Nationally, uptake of adolescent vaccines is variable. OBJECTIVE: To compare adolescent immunization rates and clinician recommendation for adolescent vaccines over time in Oklahoma with the U.S. METHODS: We analyzed the 2010-2012 National Immunization Survey of Teens (NIS-Teen). RESULTS: MCV4 and Tdap are consistently lower in Oklahoma compared to the U.S. HPV rates have been comparable. Parents report that health care providers in Oklahoma are less likely to recommend adolescent vaccines compared to the national average. Intention to not receive HPV in the next 12 months is distressingly high both in Oklahoma and across the nation with both improving. CONCLUSION: Over the three years, Oklahoma's immunization rates consistently underperform national estimates for MCV4 and Tdap but not for HPV. We recommend Oklahoma health care providers improve their vaccination rates through making clear their vaccine recommendations to the parent and patient in the clinical encounter. PMID- 25790601 TI - Childhood obesity management in primary care: a needs assessment of pediatricians to guide resource development. AB - Pediatric primary care physicians often report low efficacy in managing childhood overweight and obesity. The objectives of this study were to assess Oklahoma pediatric providers' attitudes, practices, and training needs related to childhood obesity management. A 24-item survey was emailed to members of the Oklahoma Chapter of the American Academy of Pediatrics (OKAAP). 46 of the 254 members (18%) participated in the survey. Respondents identified overweight and obesity and recognized the importance of management; however, they reported limited proficiency in behavioral management and lack of resources to assist with management. PMID- 25790602 TI - Patient pages. What do parents need to know about serving size and portion size? PMID- 25790604 TI - Patient pages. Energy out: daily physical activity recommendations. PMID- 25790605 TI - Patient pages. Diet tips to prevent dental problems. PMID- 25790606 TI - Patient pages. Secondhand smoke harms children. PMID- 25790607 TI - Patient pages. Secondhand smoke causes cardiovascular disease. PMID- 25790609 TI - Patient pages. Secondhand smoke causes SIDS. PMID- 25790610 TI - Patient pages. For parents: vaccines for your children. PMID- 25790611 TI - Determinants of persistent or recurrent congestive heart failure after contemporary surgical aortic valve replacement. AB - BACKGROUND AND AIM OF THE STUDY: Although one of the goals of surgical aortic valve replacement (AVR) is to alleviate congestive heart failure (CHF), the latter often occurs after AVR. Surprisingly, the incidence of CHF after AVR remains unclear, as outcomes are reported according to valve-related complications, each of which may result in CHF. The study aim was to: (i) validate a previously described model predicting persistent or recurrent CHF after AVR in a contemporary cohort; and (ii) apply the model to predict late outcomes following AVR with the Trifecta valve. METHODS: A previously described statistical model was validated in a cohort of 1,014 patients who received the St. Jude Trifecta prosthesis between 2007 and 2009. A sensitivity analysis was performed to determine the influence of risk factors associated with late CHF. Model prediction was verified with a Monte Carlo simulation employing 10,000 iterations. RESULTS: The model accurately predicted late CHF events in a contemporary cohort. Sensitivity analysis identified mean transprosthesis gradient (MTG), body surface area (BSA), and preoperative NYHA class as important CHF risk factors. Based on the model, a 5 mmHg decrease in MTG was associated with 2.5% and 10.4% reductions in late CHF at five and 15 years, respectively. A 10% decrease in mean BSA and preoperative NYHA class IV symptoms were associated with a 1% decrease and a 5% increase in CHF events at 15 years after AVR. CONCLUSION: The authors' previously described model predicting persistent or recurrent CHF after AVR was validated in a contemporary cohort. This model may be applied to predict outcomes in patients who receive modern prostheses, without long-term follow up. PMID- 25790612 TI - Minimally invasive aortic valve replacement in octogenarians performed via a right anterior thoracotomy approach. AB - BACKGROUND AND AIM OF THE STUDY: A significant number of patients aged > or =80 years are denied aortic valve surgery due to the assumption of poor outcomes with surgery. The study aim was to evaluate the outcomes of minimally invasive aortic valve replacement (AVR), performed via a right anterior thoracotomy approach, in octogenarians. METHODS: A retrospective review was conducted of all minimally invasive isolated AVRs in patients aged > or =80 years performed at the authors' institution between February 2009 and April 2014. The operative times, postoperative complications, hospital length of stay and mortality were analyzed. RESULTS: A total of 255 consecutive patients (133 males, 122 females; mean age 83.5 +/- 3 years) was identified. The mean left ventricular ejection fraction was 57 +/- 10%, and 31 patients (12.2%) had prior cardiac surgery. The median predicted Society of Thoracic Surgeons mortality score was 3.2% (IQR 2.4-4.4%). Postoperatively, four patients (1.6%) had cerebrovascular accidents, 38 (14.9%) had prolonged ventilation, four (1.6%) required reoperation for bleeding, and eight (3.1%) had acute kidney injury. The median intensive care unit length of stay was 48.5 h (IQR 27-92 h) and the postoperative length of stay was 7 days (IQR 5-9 days). The 30-day mortality was 3.1% (n=8), and the combined end point of morbidity and mortality was 19.2% (n=49). The all-cause mortality at one and three years was 6.7%, and 10.2%, respectively. CONCLUSION: Minimally invasive AVR in octogenarians, performed via a right anterior thoracotomy approach, is associated with a low morbidity and mortality. This applies to both primary or reoperative surgery. PMID- 25790613 TI - Post-procedural arterial hypertension: implications for clinical outcome after transcatheter aortic valve implantation. AB - BACKGROUND AND AIM OF THE STUDY: Persistent arterial hypertension (HT) has been associated with increased morbidity and mortality after surgical aortic valve replacement (AVR). The impact of increased blood pressure (BP) after transcatheter aortic valve implantation (TAVI) has not yet been fully elucidated. METHODS: The mean systolic and diastolic BP after TAVI were calculated from the last 10 non-invasive recordings performed before discharge in 176 patients. The primary end-point was symptomatic improvement after 6-12 months according to BP control at the time of discharge. RESULTS: In patients with controlled BP (<140/90 mmHg), the symptomatic response after TAVI was significantly better compared to patients with uncontrolled BP (> or =140/90 mmHg), as reflected by NYHA functional class (+1.4 +/- 0.8 versus +0.8 +/- 1.0, p = 0.002) and six minute walk test (6-MWT) distance improvement (+100 +/- 71 m versus +30 +/- 64 m, p < 0.001) at 6-12 months' follow up. A 10 mmHg decrease in systolic BP was associated with an 18 m increase in 6-MWT distance (p = 0.001). In addition, reverse left ventricular (LV) remodeling was significantly impaired in uncontrolled BP individuals, as reflected by regression of LV mass (-15 +/- 61 g versus -37 +/- 54 g, p = 0.041) and relative wall thickness (-0.02 +/- 0.09 versus -0.07 +/- 0.1, p = 0.01). Cumulative all-cause and cardiovascular mortality were significantly lower in patients with controlled BP compared to those with uncontrolled BP (6.5% versus 16%, p = 0.04; cardiovascular 3.7% versus 11.6%, p = 0.035). CONCLUSION: Uncontrolled HT after TAVI may contribute to diminished symptomatic improvement. PMID- 25790614 TI - Modeling study of aortic root for ross procedure: a structural finite element analysis. AB - BACKGROUND AND AIM OF THE STUDY: The Ross procedure involves replacing the diseased aortic valve with the patient's own pulmonary valve (autograft) to form the neoaortic valve, reimplanting the coronary arteries, and inserting a cadaveric homograft into the pulmonary position. METHODS: In order to model a neoaortic root for the Ross procedure in patients with aortic valve disease, the three-dimensional geometry of a reference aortic valve was reconstructed (reference model A). The diameters of the sinotubular junction (STJ) and maximum sinus were then modified to create four geometric models named B, C, D, and E, with different dimensions. The mechanical behavior of the aortic root was simulated, and the performance of the aortic leaflets assessed in terms of maximum geometric orifice area (GOA) during all cardiac cycle and leaflet contact pressure during closing phase. RESULTS: The neoaortic valve model showed a maximum GOA of 274.4 mm2 and a maximum leaflet stress of 682 kPa. For models B and C, the leaflet contact pressure was increased by 27.4% and decreased by 4.42%, with STJ diameter increased 1.1-fold and decreased 0.9-fold compared to reference model A. The leaflet contact pressure in models D and E was increased by 3.04% and decreased by 11.5%, while the sinus diameter was increased 1.1-fold and decreased 0.9-fold compared to model A. CONCLUSION: Increasing the STJ and sinus diameters within a range of 10% can increase the leaflet contact pressure for the aortic root, and vice versa. This may be the reason why neoaortic valve insufficiency occurs long after patients have undergone the Ross procedure. PMID- 25790615 TI - Does the number of redo mitral valve replacements for structural valve deterioration affect early and late outcomes?: experience from 114 reoperative cases. AB - BACKGROUND AND AIM OF THE STUDY: Whether the number of reoperative mitral valve replacements (MVRs) for structural valve deterioration (SVD) affects early or late survival is unclear. Hence, the aim of the present study was to investigate this issue. METHODS: A total of 114 consecutive patients (84 females, 30 males; mean age 63.4 +/- 11.9 years) who underwent 141 redo MVRs for SVD during a 20 year period was retrospectively analyzed. Of these patients, 87 (76.3%) had undergone first-time reoperations (87 redos; group A), while the remaining 27 (23.7%) had undergone two or more reoperations (54 redos; group B). The mean follow up period was 8.5 +/- 6.8 years, and the follow up rate was 96.2%. RESULTS: NYHA functional class III or IV was noted in 34 patients (39.1%) of group A, and in 17 patients (63.0%) of group B (p = 0.0292). The EuroSCORE and logistic EuroSCORE in group B were significantly higher than those in group A. The hospital mortality rate was 4.6% in group A and 11.1% in group B (p = 0.1430). Logistic regression analysis revealed risk factors for hospital mortality to be the number of reoperations (OR 4.399; p = 0.0467) and NYHA class III or IV (OR 9.090; p = 0.0483). There were no significant differences in five-, 10- or 15-year survival rates between groups A and B (log-rank test, p = 0.3369). A Cox regression analysis showed advanced age to be the only predictor of late mortality (HR = 1.098; p = 0.0013). CONCLUSION: Irrespective of whether a patient has undergone two or more reoperative MVRs, a better long-term survival can be expected before progression of the patient's NYHA functional class. PMID- 25790616 TI - Asymmetric ring annuloplasty for ischemic mitral regurgitation: early and mid term outcomes. AB - BACKGROUND AND AIM OF THE STUDY: The Carpentier-McCarthy-Adams IMR ETlogix annuloplasty ring was specifically designed to treat ischemic mitral regurgitation (IMR) associated with asymmetric mitral annular dilation and leaflet tethering. The study aim was to review, retrospectively, the results of mitral annuloplasty with this asymmetric ring in a representative number of patients. METHODS: Between January 2005 and July 2012, the IMR ETlogix ring was implanted in 190 consecutive patients (mean age 69.5 +/- 7.6 years) with grade > or =2+ IMR (graded from 0 to 3+). Preoperatively, 37 patients (19.5%) were in NYHA class IV, and 73 (38.4%) suffered from unstable angina. The operative risk according to the European System for Cardiac Operative Risk Evaluation II was 15.6 +/- 14.5%. Using two- dimensional echocardiography, postoperative changes in mitral annular diameter (MAD) and tenting height (TH) of the mitral valve in four chamber, two-chamber and long-axis views, were assessed at mid-systole. RESULTS: Thirty-eight patients (20.0%) received one or more concomitant major cardiac surgical procedure(s) other than, or in addition to, coronary artery bypass grafting or tricuspid valve annuloplasty. Nineteen (10.0%) hospital deaths occurred, and one patient underwent immediate reoperation for residual MR. During the follow up (mean 4.8 +/- 2.1 years) there were 26 cardiac deaths, 14 non cardiac deaths, and three mitral valve replacements. The seven-year actuarial survival, freedom from grade > or =2+ MR and reoperation were 62.0%, 93.1% and 97.6%, respectively. Renal impairment (p = 0.012) and extracardiac arteriopathy (p = 0.047) were predictors of death; bilateral internal thoracic artery grafting was a protective factor (p = 0.033). Heart failure symptoms were improved (p <0.01). Left ventricular reverse remodeling was achieved in 50.6% of patients. The MAD and TH were each decreased in all three echocardiographic views (p < 0.001), the reductions being greater in the long-axis view. CONCLUSION: By restoring the mitral apparatus geometry and competence, asymmetric annuloplasty with the IMR ETlogix ring provides good mid-term outcomes and helps left ventricular reverse remodeling in IMR. PMID- 25790617 TI - Progression of degenerative mitral stenosis: insights from a cohort of 254 patients. AB - BACKGROUND AND AIM OF THE STUDY: Degenerative mitral stenosis (DMS) is an increasingly common echocardiographic finding, yet the clinical and biological behavior and rate of progression of the condition are unknown. METHODS: A total of 254 patients was identified from the authors' echocardiographic database with DMS, defined as severe mitral annular calcification with extension into the mitral leaflets resulting in transmitral flow acceleration with a mean diastolic gradient of >2 mmHg in the absence of commissural fusion. Each patient required paired echocardiograms to have been recorded at least three months apart. Clinical, biochemical and pharmacological data were collected from each patient and related to the annualized rate of increase in mean diastolic mitral gradient and stenosis severity on a scale of 0 to 3. RESULTS: The characteristics of the patients were as follows: mean age 71 +/- 15 years; female gender 73%; and left ventricular ejection fraction 66 +/- 13%. Diabetes was present in 50% of patients, renal insufficiency in 40%, and coronary artery disease in 50%. Over a follow up period of 2.6 +/- 2.2 years, the mean gradient was increased by 0.8 +/- 2.4 mmHg (range: 0-15 mmHg) per year, while the stenosis grade was increased by 0.18 +/- 0.5 (range: 0-3) per year. The rate of progression was faster in patients with lesser degrees of stenosis (p = 0.01) and low serum albumen levels (p = 0.04), and slower in those receiving beta-blockers (p = 0.01). Milder stenosis, diabetes mellitus and lack of beta-blocker use were independent predictors of faster DMS progression. CONCLUSION: DMS progression is highly variable, but generally slow; its progression is accelerated in the presence of diabetes mellitus, but is retarded by beta-blocker use. DMS may be an active biological process offering potentially modifiable targets for intervention. PMID- 25790618 TI - A model of ischemic mitral regurgitation in pigs with three-dimensional echocardiographic assessment. AB - BACKGROUND AND AIM OF THE STUDY: Ischemic mitral regurgitation (IMR), the incidence of which is increasing, results from annular and subvalvular remodeling after myocardial infarction (MI). Although a sheep model of IMR has been used extensively over the past two decades, the ventricular, coronary and leaflet anatomy in sheep is significantly different from that in humans. In contrast, pigs are more similar to humans with regard to these parameters, and therefore may serve as a better animal to test emerging new technologies designed to treat IMR. METHODS: Twenty-nine pigs (body weight 30-35 kg) underwent left thoracotomy and ligation of the mid main circumflex and distal right posterior descending coronary arteries to create a posterolateral MI. Of these pigs, 18 were used for acute data acquisition, while 11 surviving animals in the chronic group were assessed at eight weeks after MI. Real-time three-dimensional echocardiography was performed at baseline, and at 30 min and eight weeks after MI, to assess geometric changes in the mitral annulus, mitral leaflets and left ventricle. RESULTS: Compared to baseline, the MR grade was increased significantly at eight weeks (0.7 + 0.5 versus 2.0 +/- 1.2), together with a significant decrease in left ventricular ejection fraction (40.3 +/- 6.6% versus 25.8 +/- 7.7%). Significant increases were also noted at eight weeks in the commissural width (30.1 +/- 3.2 mm versus 35.1 +/- 2.9 mm) and septolateral diameter (25.0 +/- 2.0 mm versus 33.8 +/- 5.9 mm), with a resultant increase in mitral annular area (596 +/- 85 versus 931 +/- 181 mm3) and a decrease in the annular height to commissural width ratio (15.7 +/- 2.6% versus 13.7 +/- 1.9%). The mitral valve tenting volume was also increased significantly (1577 +/- 645 versus 2440 +/- 755 mm3). The distance between the papillary muscle tips at baseline and at eight weeks was increased significantly (23.9 +/- 2.5 versus 30.9 +/- 5.2 mm), as was the distance between the posterior papillary muscle tip and the posterior commissure (20.9 +/- 2.7 versus 24.1 +/- 2.8 mm). CONCLUSION: The surgical model described here reliably replicates the changes seen in humans with IMR. Hence, this model can be used for further studies of the pathophysiology of IMR, and of any novel interventions in this challenging clinical area. PMID- 25790619 TI - Real-world echocardiography in patients referred for mitral valve surgery: the gap between guidelines and clinical practice. AB - BACKGROUND AND AIM OF THE STUDY: Mitral regurgitation (MR) is a common disorder for which mitral valve surgery is an established therapy. Although surgical indications are clearly defined for the management of valvular heart disease, a gap exists between current guidelines and their effective application. The study aim was to provide an insight into the diagnostic information provided for cardiac surgeons before performing mitral valve surgery. METHODS: The source documents and echocardiographic studies of 100 patients, referred by nine hospitals, were screened for arguments for MR severity justifying referral for surgery. Details of the documented MR mechanism, mitral annulus (MA) size, tricuspid regurgitation (TR) severity and annulus size were also noted. RESULTS: According to the referring physician, MR was severe in 83% and moderate-to-severe in 17%. In the great majority of patients (98%) the MR mechanism was mentioned, although specific information on the prolapsing scallops was available in only 17% of cases. The recommended primary determinants of MR severity, vena contracta and proximal isovelocity surface area (PISA) were measured in only 22% and 31% of patients, respectively. In 94% of patients with available PISA information this was described only qualitatively. Correct image expansion using the zoom mode was performed in only 25% of these patients, and a correct adaptation of the Nyquist limit in only 6%. Tricuspid annulus measurements guiding the need for concomitant tricuspid valvuloplasty in patients with less than severe TR were reported in only 6% of patients. CONCLUSION: These data demonstrate a clear and important gap between current guidelines and real-world practice with regards to the echocardiographic diagnostic information provided to the surgeon before performing mitral valve surgery. PMID- 25790620 TI - Effect of mitral annuloplasty device shape and size on leaflet and myofiber stress following repair of posterior leaflet prolapse: a patient-specific finite element simulation. AB - BACKGROUND AND AIM OF THE STUDY: Mitral annuloplasty (MA) devices are available in different shapes and sizes, but the preferred shape and size are unclear. METHODS: A previously described and validated finite element (FE) model of the left ventricle (LV) with mitral valve (MV) based on magnetic resonance imaging and three-dimensional echocardiography images from a patient with posterior leaflet (PL; P2) prolapse was used in this study. FE models of MA devices with different shapes (flat partial, shallow saddle, pronounced saddle) and sizes (36 30) were created. Virtual leaflet resection + MA with each shape and size were simulated. Leaflet geometry, stresses in the leaflets and base of the LV, and forces in the chordae and MA sutures were calculated. RESULTS: All MA shapes increased the mitral coaptation length, reduced the elevated PL stress at end diastole (ED) and end-systole (ES) that occurred after leaflet resection, and reduced anterior leaflet (AL) stress at ES. MA devices of all shapes and sizes modestly reduced myofiber stress at the LV base in ED and ES. In general, saddle shaped devices had the greatest effect. CONCLUSION: All MA shapes increased coaptation length and reduced mitral leaflet stress and myofiber stress in the base of the LV. an additional reduction in MA size further increased coaptation length and reduced leaflet and myofiber stress. In general, saddle-shaped devices had the greatest effect. PMID- 25790621 TI - Latent Q fever endocarditis in patients undergoing routine valve surgery. AB - BACKGROUND AND AIM OF THE STUDY: Q fever is a worldwide zoonosis caused by a fastidious bacterium, Coxiella burnetii. A recent major outbreak of which in the Netherlands will most likely lead to the emergence of hundreds of cases of C. burnetii endocarditis during the next decade. Patients undergoing cardiac valve surgery may carry undiagnosed Q fever endocarditis with possible disastrous outcomes, and hence may benefit from a screening strategy. The study aim was to evaluate the frequency of unsuspected latent Q fever endocarditis in patients undergoing routine valve surgery. METHODS: At the present authors' institution, all resected cardiac valves/prostheses are examined routinely histologically, microbiologically and on a molecular biological basis, in addition to serological testing for fastidious microorganisms. A retrospective review was conducted of data relating to all patients who had unsuspected Q fever endocarditis that had been diagnosed after routine valve/prosthesis replacement/repair between 2000 and 2013 at the authors' institution. RESULTS: Among 6,401 patients undergoing valve surgery, postoperative examinations of the explanted valves/prostheses led to an unexpected diagnosis of Q fever endocarditis in 14 cases (0.2%), who subsequently underwent appropriate medical treatments. Only two of the patients (14%) had intraoperative findings suggestive of endocarditis. On serological analysis of the blood samples, 11 patients (79%) presented an evocative Phase I IgG antibody titer > or =800. Valvular tissue-sample analyses yielded positive cultures and PCR in the same 13 patients (93%), whereas pathological and immunohistochemical examinations alone were suggestive of endocarditis in only seven Cases (50%). CONCLUSION: This screening strategy led to an unexpected diagnosis of Q fever endocarditis in 0.2% of patients undergoing routine valve surgery, who received subsequent appropriate antibiotic therapy. Systematic serological analysis should be mandatory before performing heart valve surgery in countries where C. burnetii is endemic. A positive serology should lead to appropriate valve-specimen analyses, including microbiological, molecular biological and histological evaluations. PMID- 25790622 TI - Efficacy of nafamostat mesilate as anticoagulation during cardiopulmonary bypass for early surgery in patients with active infective endocarditis complicated by stroke. AB - BACKGROUND AND AIM OF THE STUDY: Recent brain complications (e.g., bleeding or infarction) in patients with active infective endocarditis (AIE) are recognized as a contraindication for early surgery. Nafamostat mesilate (NM) is a synthetic protease-inhibiting agent that has not only potent inhibitory activity against coagulation factors (Xlla, Xa) but also an anti-inflammatory action. Herein is reported the authors' successful surgical experience using NM with low-dose heparinization in patients with AIE complicated by recent cerebral complications. METHODS: Twenty-eight patients (mean age 54.9 +/- 18.7 years) who had undergone surgery for AIE of the native valve (n = 21) or prosthetic valve (n = 7) were reviewed retrospectively. AIE was present in the aortic (n = 8), mitral (n = 16), aortic/mitral (n = 4) and tricuspid (n = 1) valves. Twenty-two of 28 patients had preoperative stroke, and six had active brain bleeding. Surgery was performed at a mean of 2.4 +/- 2.1 days after the onset of stroke. NM (209 +/- 152 mg) with low-dose heparin (3796 +/- 1218 IU; 67.4 +/- 20.3 IU/kg) was used for anticoagulation during cardiopulmonary bypass (CPB). The activated clotting time (ACT) was maintained at 350-450 s by the precise administration of NM into a cardiotomy reservoir (0.5 mg/kg/h) and a venous reservoir (sliding controlled dose at 1.5 mg/kg/h). RESULTS: The CPB time was 181.3 +/- 92.6 min. Five patients (17.8%) died during hospitalization due to persistent sepsis (n = 3), brain death caused by massive brain embolism before CPB establishment (n = 1), and pneumonia (n = 1). There was no further aggravation of intracranial bleeding, and no new hemorrhagic stroke. CONCLUSION: Nafamostat mesilate, administered in conjunction with low-dose heparinization, served as an effective anticoagulant for early surgery in patients with AIE complicated by stroke, and caused no further deterioration of the cerebral lesions. PMID- 25790623 TI - Determinants for increased resource utilization after surgery for prosthetic valve endocarditis. AB - Mechanical circulatory support (11 intra-aortic balloon pump; two right ventricular assist device; one left ventricular assist device) was required in 14 patients (9.4%). At 30 days, mortality was 12.8% (n=17) and morbidity 78.5% (117 patients experienced at least one complication). At one, five and 10 years, the overall survival was 78.4 +/- 3.5%, 76.7 +/- 3.6% and 74.9 +/- 3.8%, respectively. The duration of postoperative MV was 8 +/- 20.7 days, while ICU and hospital stays were 11 +/- 20.8 and 37 +/- 30.2 days, respectively. The following predictors for increased resource utilization were identified: preoperative ventilatory support, mechanical circulatory support, recent myocardial infarction, and urgency for MV >3 days; preoperative ventilator support and mechanical circulatory support for ICU >7 days; and urgency and age for HS >42 days. CONCLUSION: A critical preoperative state and perioperative mechanical circulatory were strongly predictive of increased resource utilization. Hence, if resource utilization is to be reduced, an early operation seems more appropriate than to postpone surgery until an uncertain or unattainable re-normalization of organ dysfunction becomes evident. BACKGROUND AND AIM OF THE STUDY: Surgery for prosthetic valve endocarditis (PVE) is associated with significant morbidity and mortality. As treatment also demands substantial healthcare resources, a search was made for determinants of increased resource utilization. METHODS: Between 2000 and 2010, a total of 149 consecutive patients (107 males, 42 females; mean age 63.5 +/- 13.8 years) underwent re-do surgery for PVE at the authors' institution; 92 patients (61.7%) had aortic valve replacement, 42 (28.2%) had mitral valve replacement, and 15 (10.1%) had double valve replacement. Multivariate binary regression analysis was used to identify predictors of increased resource utilization, defined as mechanical ventilation (MV) >3 days, intensive care unit (ICU) stay >7 days, and hospital stay (HS) >42 days. RESULTS: Preoperatively, 14 patients (9.4%) presented with shock and 17 (11.4%) with acute renal failure. Ventilatory and pharmacological circulatory support was required in 17 (11.4%) and 19 (12.8%) patients, respectively. The logistic EuroSCORE was >20% in 121 patients (81.2%). Staphylococci were the most common infecting microorganisms (41 patients; 27.5%), while 53 cases (35.6%) were culture negative. The operative, cardiopulmonary bypass and aortic cross-clamp times were 259 + 88.3 min, 149 +/- 62.4 min, and 112 +/- 44.3 min, respectively. PMID- 25790624 TI - Permanent lone atrial fibrillation and atrioventricular valve regurgitation: may the former lead to the latter? AB - BACKGROUND AND AIM OF THE STUDY: Atrioventricular valve regurgitation (AVVR) has been described in patients with long-standing atrial fibrillation (AF) despite normal valve anatomy and leaflet mobility. The study aim was to examine the association between permanent lone AF and AVVR. METHODS: A total of 47 patients with lone AF was studied. Patients provided information regarding the time since onset of arrhythmia, and mitral regurgitation (MR) and tricuspid regurgitation (TR) were graded using color-mapping Doppler echocardiography. AVVR was defined as any degree of valve regurgitation. Annular diameters (in mm) and atrial areas (in cm2) were measured at enddiastole, using digital analysis. RESULTS: Of the 47 patients, 19 (40%) had paroxysmal AF and 28 (60%) had permanent AF. Mild MR was present in nine of 19 patients (47%) with paroxysmal AF and in 15 of 28 (53%) with permanent AF (p = 0.68). Mild TR was identified in nine (47%) patients with paroxysmal AF, and in 16 (58%) of those with permanent AF (p = 0.08). None of the patients with paroxysmal AF had either moderate or severe AVVR. In 28 patients with permanent lone AF, significant MR and TR were detected in six (21%) and five (19%) patients, respectively. Patients with permanent lone AF had a 6.5-fold higher likelihood of having TR (p = 0.0031) and were marginally more likely to have MR (p = 0.053) compared to those with paroxysmal AF. Relative to patients with paroxysmal AF, those with permanent AF had larger atrial areas and annular diameters, while patients with TR had higher atrial areas and mitral annular diameters than those without. The mean follow up of patients with permanent AF and significant AVVR was 54 + 13 months, compared to 13 +/- 7 months for those without significant AVVR (p = 0.002). CONCLUSION: Permanent lone AF is associated with TR and, less strongly, with MR. Atrial size and mitral annular diameter are increased in patients with lone AF who have TR. PMID- 25790625 TI - Patient-specific finite element analysis of ascending thoracic aortic aneurysm. AB - BACKGROUND AND AIM OF THE STUDY: Rupture/dissection of ascending thoracic aortic aneurysm (aTAA) is a cardiovascular emergency. Elective surgical repair is primarily based on maximum diameter, but complications have occurred under the size limits for surgical intervention. aTAA wall stress may be a better predictor of patient-specific rupture risk, but cannot be directly measured in vivo. The study aim was to develop an aTAA computational model associated with tricuspid aortic valve (TAV) to determine patient-specific wall stresses. METHODS: A TAV associated aTAA was excised intact during surgery. Zero-pressure geometry was generated from microcomputed tomography, and an opening angle was used to calculate residual stress. Material properties determined from stress-strain data were incorporated into an Ogden hyperelastic model. Wall stress distribution and magnitudes at systemic pressure were determined using finite element analyses (FEA) in LS-DYNA. RESULTS: Regional material property differences were noted: the left aTAA region had a higher stiffness compared to the right, and anterior/posterior walls. During systole, the mean principal wall stresses were 172.0 kPa (circumferential) and 71.9 kPa (longitudinal), while peak wall stresses were 545.1 kPa (circumferential) and 430.1 kPa (longitudinal). Elevated wall stress pockets were seen in anatomic left and right aTAA regions. CONCLUSION: A validated computational approach was demonstrated to determine aTAA wall stresses in a patient-specific fashion, taking into account the required zero-stress geometry, wall thickness, material properties and residual stress. Regions of maximal wall stress may indicate the sites most prone to rupture. The creation of a patient-specific aTAA model based on a surgical specimen is necessary to serve as the 'gold standard' for comparing models based on in-vivo data alone. Validated data using the surgical specimen are essential for establishing wall stress and rupture-risk relationships. PMID- 25790626 TI - Double arterial perfusion strategy for acute type a dissection after extra anatomic bypass for aortic coarctation. AB - The complex nature of reoperative ascending and thoracic aortic surgery requires creative solutions to protect vital organs during extended periods of ischemia. The case is presented of a Type A dissection in a young man who previously had undergone two aortic coarctation repairs via a posterior pericardial, ascending to-descending, extra-anatomic aortic bypass. A step-by-step review of the planning, operative repair, and outcome is described. PMID- 25790627 TI - Platelet activation after sorin freedom solo valve implantation: a comparative study with Carpentier-Edwards Perimount Magna. AB - BACKGROUND AND AIM OF THE STUDY: As platelet activation is known to be a side effect of cardiac surgery, recent analyses have been conducted to identify the association between thrombocytopenia and aortic valve replacement (AVR) using a bioprosthesis. The type of bioprosthesis has been indicated as an independent risk factor for a lower postoperative platelet count, an association which has been mainly observed with the Sorin Freedom Solo valve. The study aim was to analyze platelet activation after AVR with two different bioprostheses, the Sorin Freedom SOLO (FS) and the Carpentier-Edwards Magna (CE). METHODS: Thirty-eight consecutive patients undergoing aortic valve surgery were enrolled prospectively and assigned to either the FS group (n = 18) or the CE group (n = 20) according to their clinical evaluation. Five patients who underwent isolated coronary artery bypass graft (CABG) with cardiopulmonary bypass (CPB) were included as a control group. Clinical biochemical parameters (von Willebrand factor (vWF), prothrombin fragments 1+2 (F1+2), P-selectin, and beta-thromboglobulin (beta-TG)) were assessed preoperatively (TO), and at 1 h (T1), 48 h (T2) and seven days (T3) postoperatively. RESULTS: The two groups differed in terms of age (FS 77.3 +/- 7.0 years; CE 65.4 +/- 8.4 years; p < 0.05). Intraoperatively, parameters such as CPB time (FS 106.8 +/- 25.5 min; CE 108.2 +/- 23.4 min, p = NS) and aortic cross clamp time (FS 78.1 +/- 22.8 min; CE 80.7 +/- 19.4 min, p = NS) were comparable. The platelet count was significantly reduced after FS implantation compared to the other groups. Factors involving platelet activation and blood coagulation activation assessed by means of prothrombin F1+2 (FS: TO = 0.48; T1 = 0.66; T2 = 0.46; T3 = 0.52 nmol/ml versus CE: T0 = 0.38; T1 = 0.68; T2 = 0.41; T3 = 0.49 nmol/ml); P-selectin (FS: T0 = 89.6; T1= 130.4; T2 = 92.6; T3 = 94.3 ng/ml versus CE: T0 = 81.4; T1 = 115.9; T2 = 92.2; T3 = 85.7 ng/ml); and beta-TG (FS: T0 = 6.7; T1 = 17.6; T2 = 8.6; T3 = 7.7 ng/ml versus CE: T0 = 7.1; T1 = 15.6; T2 = 9,1; T3 = 7.5 ng/ml) were not significantly different. CONCLUSION: The previously described phenomenon of enhanced platelet reduction shortly after valve implantation in the FS group compared to another bioprosthesis is likely to be confirmed, but platelet activation should not be considered as the underlying mechanism. Superior (but not significant) preoperative values of biochemical parameters were found in FS versus CE patients, influencing postoperative levels without any variation in the trend pattern. The type of bioprosthesis implanted appeared not to influence platelet and blood coagulation activation. PMID- 25790628 TI - Minimally invasive approach for isolated tricuspid valve surgery. AB - BACKGROUND AND AIM OF THE STUDY: Isolated tricuspid valve surgery has been associated with a high morbidity and mortality. The study aim was to analyze the feasibility of a minimally invasive approach for isolated tricuspid valve surgery. METHODS: A total of 2,945 heart operations performed at the authors' institution between January 2009 and April 2013 was retrospectively reviewed to identify patients who had undergone isolated, minimally invasive tricuspid valve surgery via a right mini-thoracotomy approach. Details of operative times, intensive care unit (ICU) and hospital lengths of stay, postoperative complications, and mortality were analyzed. RESULTS: A total of 12 patients (eight females, four males; mean age 68 +/- 18 years) was identified. The median left ventricular ejection fraction was 58% (IQR 47-64%), and prior valve or coronary artery bypass graft surgery was noted in four patients (33%) and two patients (17%), respectively. Most of the patients underwent tricuspid valve repair (92%), with a median cardiopulmonary bypass time of 106 min (IQR 82-122 min). The median ICU and total hospital lengths of stay were 84 h (IQR 47-157 h) and 7 days (IQR 6-12 days), respectively. Postoperative complications included prolonged ventilation (50%), reintubation (17%), atrial fibrillation (17%), and acute kidney injury (8%). There were no postoperative cerebrovascular accidents, myocardial infarctions, reoperations for bleeding, or deep wound infections. The 30-day mortality rate was 17%, and two-year survival 67%. CONCLUSION: A minimally invasive approach for isolated tricuspid valve surgery is feasible, with a high rate of valve repair. PMID- 25790629 TI - Papillary muscle force distribution after total tricuspid reconstruction using porcine extracellular matrix: in-vitro valve characterization. AB - BACKGROUND AND AIM OF THE STUDY: The use of extracellular matrix (ECM) from the porcine small intestinal submucosa has shown promising results in reconstructive heart surgery. The study aim was to compare native and ECM tricuspid valves with regards to tricuspid leaflet coaptation geometry and force development in the three papillary muscles, under normal ventricular pressures. METHODS: Six native porcine tricuspid valves and five ECM valves were examined in a static pressure right-heart simulator. Water was used in the ventricular chamber to induce adequate pressure changes (from 5 to 40 mmHg). Dedicated force transducers were used to measure force development in the three papillary muscles in parallel with ventricular pressure measurements. Relative leaflet area was defined as the percentage that one leaflet area comprised of the whole orifice area. The estimated peak leaflet pressure force was defined as leaflet area x peak ventricular pressure, and peak leaflet tethering force was calculated as the average of two adjacent papillary muscles forces. Valve competence and leaflet areas were documented using digital photography. RESULTS: The relative leaflet area of the anterior leaflet was significantly smaller (0.4 versus 0.5, p < 0.01) and that of the posterior leaflet was significantly larger (0.3 versus 0.2; p < 0.001) in ECM tube grafts compared to native valves. No difference was found between septal leaflet relative areas (p > 0.1). Accordingly, estimated peak leaflet pressure forces were greater in anterior leaflets and smaller in the posterior leaflets of native valves compared to ECM valves (p < 0.01). However, peak papillary muscle forces and peak leaflet tethering forces did not differ significantly between the valves. CONCLUSION: A competent and functional tricuspid valve can be constructed in vitro from ECM. In spite of different leaflet area distributions, the force distribution and tethering forces were not significantly different between the two valve types, indicating that a physiologically functioning tricuspid valve can be constructed from ECM. PMID- 25790630 TI - Aortic valve replacement with the perceval S bioprosthesis: single-center experience in 143 patients. AB - BACKGROUND AND AIM OF THE STUDY: Aortic stenosis (AS) is the most frequent heart valve disease in western countries, and its prevalence increases with age. Sutureless valves have recently become available that allow the surgical procedures to be shortened. The study aim was to assess clinical outcome after sutureless aortic valve replacement (SAVR) performed with the Perceval S bioprosthesis at the authors' institution. METHODS: Between June 2007 and November 2011, a total of 143 patients (78 females, 65 males; mean age 79.4 +/- 5.9 years) was prospectively enrolled and followed at the authors' center. The median preoperative logistic EuroSCORE was 12.04 +/- 10.7. Preoperatively, 58.8% of patients were in NYHA class III or IV, and the mean gradient and effective orifice area (EOA) were 38.8 +/- 17 mmHg and 0.76 +/- 0.24 cm2, respectively. Isolated SAVR was performed in 95 patients (66.4%), while associated procedures were necessary in 48 patients (33.6%). The follow up was 100% complete (mean 13.4 +/- 11.6 months; range: 0-5 years; total cumulative follow up 155 patient-years). RESULTS: The procedural success rate was 99.3%. The mean cross-clamp and cardiopulmonary bypass times were 32.0 +/- 14.9 min and 44.7 +/- 18.6 min, respectively. In-hospital mortality was 4.9% (n=7). Pacemaker implantation was required in seven patients (4.9%). Survival at five years was 85.5%. Reoperation was necessary in seven patients (4.9%); early reoperations were due to paravalvular leak (n = 3; 2.0%) and intra-prosthetic regurgitation (n=3; 2.0%). One late reoperation (at 29 months) was required, due to fibrous pannus overgrowth. One late endocarditis (0.7%) occurred at 26 months and was medically treated. No structural valve deterioration occurred during the follow up. At 12 months, 94.4% of survivors were in NYHA class I-II, and the mean pressure gradient and EOA were 9.0 +/- 3.4 mmHg and 1.60 +/- 0.3 cm2, respectively. CONCLUSION: The Perceval S valve appears to be a safe option for SAVR, though further follow up is needed to evaluate the long-term outcome with this bioprosthesis. PMID- 25790631 TI - Quantitative cardiology: back to square one. PMID- 25790632 TI - Awaiting Ebola at our posts. PMID- 25790633 TI - Basic skin care: a pragmatic approach to better skin using over-the-counter cosmeceuticals. AB - Environmental exposures to ultraviolet radiation, wind, and tobacco smoke progressively damage the skin's cellular and extracellular structures resulting in wrinkles, sagging skin, irregular pigmentation, and skin cancers. These undesirable effects can be minimized with avoidance of the sun, tanning salons, and smoking. The topical application of prescription and non-prescription agents (cosmeceuticals) can provide additional benefits. Considering the vast array of topical non-prescription agents marketed to protect or repair damaged skin, it is difficult for consumers and physicians to choose the best options. Therefore, this article discusses recommendations from a dermatologist concerning the choice and use of over-the-counter cleansers, moisturizers, sunscreens, and rejuvenators to create individualized, daily skin care regimens for patients. PMID- 25790634 TI - All dressed up with no place to go. PMID- 25790635 TI - About smoking cessation. PMID- 25790636 TI - The MSMA Physician Leadership Academy. PMID- 25790637 TI - Round and round she goes.... PMID- 25790639 TI - An apology long overdue. PMID- 25790638 TI - Images in Mississippi Medicine. PMID- 25790640 TI - Medical student education in the Department of Surgery at the University of Mississippi Medical Center in the 21st Century. AB - The approach of the Department of Surgery at the University of Mississippi to the education of medical students is considerably different from that of earlier eras. An overview of the current strategies for medical student education adopted by the Department in recent years and the philosophies behind them is presented. PMID- 25790641 TI - Oseltamivir for influenza in adults and children. PMID- 25790643 TI - Mississippi Mental Health System - in crisis. PMID- 25790642 TI - Race and health care in Mississippi during the civil rights years. PMID- 25790644 TI - The Meeting. AB - A group of black physicians whose request to attend educational programs at the University of Mississippi Medical Center had been rebuffed by the school's second dean played a central role in helping UMMC survive a federal investigation for non-compliance with the Civil Rights Act of 1964. Unknown to Dean Robert Marston, these physicians had been active in civil rights activities at both state and national levels and were in dialogue with federal civil rights agencies and with the NAACP who filed the complaint against UMMC. Marston called on them as part of a marathon of preparation for the inspection, and they assisted him in achieving an improbable outcome, a finding of compliance. In the process, Marston developed a positive relationship and ongoing dialogue with these black physicians and realized their value to Mississippi. In turn, they elected him to membership in the Mississippi Medical and Surgical Society. PMID- 25790645 TI - [This must not happen again]. PMID- 25790646 TI - ["A perfect storm" - it could have been prevented]. PMID- 25790647 TI - ["One does one's best every day, so that patients will survive"]. PMID- 25790648 TI - [How Geneva has prepared for the worst case scenario]. PMID- 25790649 TI - [Patient care expertise and daily presence]. PMID- 25790650 TI - [Autonomous nursing care in general practice]. PMID- 25790651 TI - [Clinical competence is crucial]. PMID- 25790652 TI - ["Central is the leadership culture"]. PMID- 25790653 TI - [Supporting nursing in the multi-professional treatment team]. PMID- 25790655 TI - [Return after family leave]. PMID- 25790654 TI - [Preventing aspiration with deglutition screening]. PMID- 25790656 TI - [A tribute to neglected personnel]. PMID- 25790657 TI - ["Our golden rule with Ebola: take no risks"]. PMID- 25790658 TI - [Professionals perfectly prepared]. PMID- 25790659 TI - [The beginning of an atypical career]. PMID- 25790660 TI - [Nursing for self enrichment, living a paradox]. PMID- 25790661 TI - [1st Salon Planete Sante]. PMID- 25790662 TI - [Towards evidence-based nursing ]. PMID- 25790663 TI - [A pilot offer for family caregivers]. PMID- 25790664 TI - [A machine with questionable benefits]. PMID- 25790665 TI - [A virus of solidarity]. PMID- 25790666 TI - [Heritance and prospect of Professor Xie Zhu-fan's researches and thoughts on cold and heat syndrome differentiation of Chinese medicine]. PMID- 25790667 TI - [Integrative medicine is a realistic and necessary choice for developing Chinese medicine]. PMID- 25790668 TI - [The necessity and feasibility of establishing technical specifications for registry of Chinese medicine clinical study]. AB - International clinical trials register is one of the global measures to realize transparency in clinical trials and also one of a powerful measure to improve the quality of clinical trials. Many scholars studying the quality of TCM clinical trials find that they are poor in quality and lack transparency. Furthermore, they find that TCM clinical trial registry has many problems. We must base on the successful experiences of WHO and international clinical trial registry to establish technical specifications for registry of traditional Chinese medicine clinical study of their own. Then, it can effectively improve the overall level of TCM clinical studies. We have suggested some concrete and feasible measures to establish technical specifications for registry of traditional Chinese medicine clinical study of their own based on the problems of TCM clinical trial registry. PMID- 25790669 TI - [The correlation study on syndrome differentiation of rheumatoid arthritis and joint high frequency ultrasound performance]. AB - OBJECTIVE: To observe the differential effect of joint ultrasound on the syndrome differentiation of rheumatoid arthritis (RA) by observing the high frequency ultrasound performances among inactive stage and different syndromes in active stage. METHODS: Totally 83 RA patients in the active stage were assigned to the dampness heat syndrome group (DHS, 59 cases)and the cold dampness syndrome group (CDS, 24 cases) according to Chinese medicine (CM) syndrome typing. Besides, 20 RA patients in the remission stage were recruited as the control group (abbreviated as the remission group). By using high frequency ultrasound and power Doppler ultrasound technology, a comparative observation of synovitis, tenosynovitis, synovial blood flow, and bone erosion in the 2nd-5th metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, wrist joints, knee joints, the second and the fifth metatarsophalangeal (MTP) joints (a total of 24 joints) was performed in all patients. Correlation analyses were performed between the ultrasound performance, laboratory indices, and the disease activity. Ultrasound data of each RA patient were analyzed by their total scores. Chi2 test was used for enumeration data. The measurement data was expressed as x +/- s. One-way ANOVA was used for data of normal distribution, while non- parametric test was used for data of non-normal distribution. Correlation analysis of two variables was performed for clinical indicators and ultrasound indicators. Its significance was detected using Pearson correlation. RESULTS: Compared with the remission group, the severity degree of synovitis, tenosynovitis, synovial blood flow, and bone erosion significantly increased in the DHS group (P < 0.01). There was statistical difference in ESR, CRP, anti-CCP, DAS28 score, and the positive rate of RF (P < 0.05, P < 0.01). There was statistical difference in the severity degree of synovitis and synovial blood flow, and DAS28 score in the CDS group (P < 0.05). Compared with the CDS group, there was statistical difference in the four ultrasound indices (P < 0.05, P < 0.01), ESR, CRP, anti-CCP, DAS28 score, and the positive rate of RF in the DHS group (P < 0.05, P < 0.01). There was no statistical difference in G, IgG, IgA, or IgM among the three groups (P > 0.05). There existed positive correlation between ESR and the synovitis degree, synovial blood flow, and bone erosion in the DHS group (r = 0.444, 0.397, 0.486, P < 0.05).There existed positive correlation between ESR and the synovitis degree, bone erosion, and synovial blood flow in the DHS group (r = 0.378, 0.270, P < 0.05). There existed positive correlation between the DAS28 score and the synovitis degree and synovial blood flow in the DHS group (r = 0.304, 0.351, P < 0.05). CONCLUSIONS: The inflammation degree was the most severe in RA patients of DHS. High frequency ultrasound could provide better evidence for Chinese medical syndrome differentiation of RA patients. PMID- 25790670 TI - [Exploration of the mechanism of xinfeng capsule in the treatment of ankylosing spondylitis based on B and T lymphocyte attenuator and oxidative stress]. AB - OBJECTIVE: To explore changes of B and T lymphocyte attenuator (BTLA), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAOC), reactive oxygen species (ROS), reactive nitrogen species (RNS), malondialdehyde (MDA) in ankylosing spondylitis (AS) patients, and the effect of Xinfeng Capsule (XFC) on them. METHODS: Totally 120 AS patients were assigned to two groups according to random digit table method, the XFC group (3 XFC pills each time, 3 times a day) and the SASP group (4 SASP tablets each time, twice a day), 60 in each group. All patients were treated for 3 months. Another 60 healthy subjects were recruited as a healthy control group. The expression frequency and activation levels of BTLA were detected using flow cytometry. Serum oxidative stress indices (such as SOD and CAT, TAOC, ROS, RNS, MDA) and contents of cytokines [tumor necrosis factor alpha (TNF-alpha), IL-1beta, IL-4, and IL-10] were detected using enzyme-linked immunoassay (ELISA). Erythrocyte sedimentation rate (ESR) was detected using Westergren method. High-sensitivity C-reactive protein (Hs-CRP) was detected using HITACHI 7060 type automatic biochemical analyzer. Clinical efficacies of ASAS 20 and BASDAI50 were assessed using VAS. Correlation analysis between scoring for quality of life and BTLA expression frequency was performed. RESULTS: (1) Clinical efficacies of ASAS 20 and BASDAI50 were significantly better in the XFC group than in the SASP group (P < 0.01). (2) Compared with the healthy control group, BTLA expressions in the peripheral blood of AS patients decreased significantly (P <0. 05); SOD, CAT, and TAOC values significantly decreased (P < 0.01, P < 0.05); ROS, RNS, and MDA values significantly increased (P < 0.01, P < 0.05); TNF-alpha, IL-1beta, ESR, and Hs-CRP values significantly increased (P < 0.01); IL-4 and IL-10 values decreased significantly (P < 0.01, P < 0.05). (3) Compared with pre-treatment in the same group, BTLA/CD19 + B, BTLA/CD24 + B, SOD, TAOC, IL-4, SF-36 [physical functioning (PF), social functioning (SF), role limitation due to physical problems (RP), role limitation due to emotional problems (RE), body pain (BP), mental health (MH), vitality (VT), general health (GH)] were significantly elevated; ROS, MDA, TNF-alpha, ESR, Hs- CRP, VAS, BASDAI and BASFI, BAS-G were significantly lower in the peripheral blood of the two groups after treatment (P < 0.01, P < 0.05). Better effect was shown in the XFC group in elevating BTLA/CD19+ B, BTLA/CD24 + B, SOD, TAOC, IL-10, BP, MH, VT, and SF; and lowering ROS, IL-1beta, MDA, TNF-alpha, ESR, Hs-CRP, VAS, BASDAI, BASFI, and BAS-G (P < 0.01, P < 0.05). (4) Pearson correlation analysis showed, BTLA/CD19 + B expression of the peripheral blood was positively correlated with SOD, CAT, TAOC, IL-4, IL-10, GH, RP, BP, and SF (r = 0.431, 0.325, 0.318, 0.316, 0.348, 0.314, 0.358, 0.318, 0.326, respectively, P < 0.05, P < 0.01), while it was negative correlated with ROS, MDA, TNF-alpha, IL-1beta, ESR, VAS, and BASDAI (r = -0.342, -0.368, -0.334, -0.354, -0.324, -0.372, -0.342, respectively, P < 0.05, P < 0.01). BTLA/CD24 B expression of the peripheral blood was positively correlated with SOD, TAOC, IL-4, IL-10, GH, RP, BP, SF, RE, MH, VT (r = 0.358, 0.352, 0.372, 0.436, 0.435, 0.326, 0.352, 0.345, 0.326, 0.343, 0.332, respectively, P < 0.05, P < 0.01), while it was negative correlated with ROS, RNS, MDA, ESR, Hs-CRP, VAS, BASDAI, and BASFI (r = -0.447, -0.336, -0.405, -0. 395, -0. 358, -0.436, -0.338, -0.425, respectively, P < 0.05, P < 0.01). CONCLUSION: XFC could improve BTLA expression in the peripheral blood of AS patients, negatively regulate activation and proliferation of B cells, and reduce abnormal immune responses and oxidative stress injury, thereby effectively alleviating joint stiffness and pain. PMID- 25790671 TI - [Effect of Sanhuang Yilong Decoction combined MTX on the expression of serum IL 1, IL-6, and IL-17 in rheumatoid arthritis patients of accumulated dampness-heat syndrome]. AB - OBJECTIVE: To study the effect of bitter-cold herbs easing dampness method (BCHEDM) plus Sanhuang Yilong Decoction (SYD) combined with methotrexate (MTX) on expression levels of interleukin-1 (IL-1), IL-6, and IL-17 in rheumatoid arthritis (RA) patients of accumulated dampness-heat syndrome (ADHS). METHODS: From January 2011 to January 2013 recruited were 90 RA inpatients of ADHS at Department of Integrative Medicine on Rheumatoid Disease, General Hospital of Chengdu Military Region. They were assigned to the treatment group (45 cases) and the control group (45 cases) according to the random digit table produced by SPSS 11.5 Software. Patients in the treatment group were treated by heavy bitter-cold herbs plus SYD combined with MTX, while those in the control group were treated by MTX alone. Expressional levels of IL-1, IL-6, and IL-17 in serum were detected by enzyme linked immunosorbent assay (ELISA) before treatment, at week 2 and 4 after treatment. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and disease activity score in 28 joints (DAS28) were detected as well. RESULTS: After two or four weeks of treatment, ESR, CRP, and DAS28 decreased more in the treatment group than in the control group with statistical difference (P < 0.05, P < 0.01). After four weeks of treatment, IL-1, IL-6, IL-17, ESR, CRP, and DAS28 in the treatment group were all lower than before treatment and those of the control group at corresponding time points with statistical difference (P < 0.01). CONCLUSION: SYD combined MTX could play roles of improving inflammatory indices within 2 weeks, and inhibiting the expression of IL-1, IL-6, and IL-17 within 4 weeks. PMID- 25790672 TI - [Adjunctive treatment of axial undifferentiated spondyloarthritis by Qiangji Recipe: a clinical study]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of Qiangji Recipe (QR) in ad- junctive treatment of axial undifferentiated spondyloarthritis (axuSpA) through a four-week open study. METHODS: Fifty-four axuSpA patients of Shen deficiency Du-channel cold syndrome (SDDCS) in line with inclusive criteria were recruited and assigned to the treatment group and the control group according to random digit table, 27 in each group. Patients in the control group took Celecoxib Capsule (0.2 g each time, twice per day). Patients in the treatment group additionally took QR (consisting of Herba Epimedii 15 g, antler glue 15 g, Cibotium Barometz 15 g, eucommia bark 20 g, dipsacus asper 10 g, two toothed achyranthes root 15 g, drynaria 15 g, Taxillus Chinensis 20 g, ground beetle 10 g, scorpion 5 g, wild celery 10 g, notopterygium incisium 10 g, cow-fat seed 10 g, white mustard seed 6 g, and licorice root 6 g, one dose per day, twice daily). The therapeutic course for all was 4 weeks. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath AS Metrology Index (BASMI), total body pain and spinal pain, patient and physician global assessment on a four-point scale, the Ankylosing Spondylitis Quality of Life (ASQoL), erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured before and after 4 weeks of treatment. The primary end point in this study was the proportion of patients with a 20%improvement response accord- ing to the ASAS International Working Group Criteria (ASAS 20 responders) at week 4. RESULTS: Totally 50 patients completed this trial, 26 in the treatment group and 24 in the control group. Improvement of BASDAI, BASFI, BASMI, ASQoL, ESR, and CRP was shown in both groups after treatment. Better effect was shown in the treatment group in all indices except ESR and BASMI after treatment (P < 0.05, P < 0.01). Twenty cases (accounting for 76.92%) in the treatment group achieved ASAS 20 response at week 4, while 12 cases (accounting for 50.00%) in the control group achieved ASAS 20 response at week 4 (P < 0.05). No obvious adverse reaction occurred in the two groups. CONCLUSION: QR combined Celecoxib Capsule showed better effect in treating axuSpA patients than using Celecoxib Capsule alone. PMID- 25790673 TI - [Nourishing Xin and Shen method improved mild cognitive impairment due to subcortical small vessel disease: a clinical study]. AB - OBJECTIVE: To observe the intervention effect of nourishing Xin and Shen method (NXSM) on the cognitive function of mild cognitive impairment due to subcortical small vessel disease (MCI-SSVD). METHODS: All 54 MCI-SSVD patients came from Department of Traditional Chinese Medicine, Affiliated Union Hospital of Fujian Medical University from June 2010 to August 2013. They were randomly assigned to the treatment group (28 cases) and the control group (26 cases). Another 33 volunteers were recruited as a healthy control group. On the basis of targeting risk factors of blood vessels, MCI-SSVD patients were treated respectively with NXSM and donepezil hydrochloride, with the therapeutic course of 12 weeks. Neuropsychological scales [mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA)], and Chinese medical dementia syndrome scales were performed in all subjects, and results were compared among groups or intra-group before and after treatment. RESULTS: MMSE and MoCA scores of the two treatment groups decreased more, when compared with those of the healthy control group (P < 0.05). In particular, MoCA score was significantly decreased (P < 0.01). MMSE and MoCA scores of the two treatment groups increased more after treatment than before treatment (P < 0.05). But there was no statistical difference in MMSE or MOCA score after treatment between the two groups (P > 0.05). Chinese medical dementia syndrome scales decreased more significantly in the treatment group, when compared with before treatment (P < 0.01). But there was no statistical difference in Chinese medical dementia syndrome scales in the control group between before and after treatment (P > 0.05). Visual spatial and executive function scores or delayed recall scores of the two treatment groups increased more, when compared with the same group before treatment (P < 0.05, P < 0.01). CONCLUSION: NXSM could effectively improve cognitive functions of MCI-SSVD. PMID- 25790674 TI - [Treatment of vascular dementia by Chinese herbal medicine: a systematic review of randomized controlled trials of clinical studies]. AB - OBJECTIVE: Chinese herbal medicine has been extensively used in the treatment of vascular dementia (VaD), but lacked systematic review on its efficacy and safety. So we conducted a systematic review to assess the efficacy and safety of Chinese herbal medicine in treating VaD. METHODS: CNKI, CBM, PubMed, and Wiley Online Library were retrieved for randomized trials (RCTs) on Chinese herbal medicine treating VaD patients. Randomized parallel control trials by taking Chinese herbal medicine as one treatment method and placebos/cholinesterase inhibitors/Memantine hydrochloride as the control were included. Quality rating and data extraction were performed. RevMan5.2.0 Software was used for meta analysis. Standardized mean difference (SMD) at 95% confidence interval (CI) was used to indicate effect indicators of results. RESULTS: Seven RCTs met the inclusive criteria. Totally 677 VaD patients were randomly assigned to the treatment group and the control group. Descriptive analyses were performed in inclusive trials. The cognitive function was assessed in all trials. Results showed Mini-Mental state examination (MMSE) score was better in the Chinese herbal medicine group than in the placebo group, but with no significant difference when compared with the donepezil group (P > 0.05). Adverse reactions were mainly manifested as gastrointestinal symptoms such as abdominal pain in the Chinese herbal medicine group. But they occurred more in the donepezil group than in the Chinese herbal medicine group. CONCLUSIONS: The methodological quality of included trials was poor with less samples. Results of different trials were lack of consistency. Present evidence is not sufficient to prove or disapprove the role of Chinese herbal medicine in improving clinical symptoms and outcome indicators of VaD patients. Their clinical efficacy and safety need to be supported by more higher quality RCTs. PMID- 25790675 TI - [Treatment of myelodysplastic syndrome by hematopoietic stem cell transplantation combined with Chinese medical syndrome typing: a clinical study]. AB - OBJECTIVE: To evaluate the clinical efficacy of treating myelodysplastic syndrome (MDS) by hematopoietic stem cell transplantation (HSCT) combined with Chinese medical syndrome typing. METHODS: From July 2009 to July 2013, 6 MDS patients were treated with allo-HSCT combined with Chinese medical syndrome typing from HLA-identical sibling donors at Department of Hematology, Zhejiang Provincial Hospital of Chinese Medicine. Patients were classified as refractory anemia (RA, 2 cases), refractory anemia with ringed sideroblast (RARS, 1 case), refractory cytopenia with multilineage dysplasia (RCMD, 2 cases), and RA with excess blasts I (RAEB-I , 1 case). Modified BuCy conditioning regimen was used in all 6 cases. Two patients received bone marrow transplantation (BMT), 1 patient received peripheral blood stem cell transplantation (PBSCT), and 3 patients received BMT + PBSCT. In order to prevent the occurrence of graft-versus-host disease (GVHD), all patients were treated with cyclosporine + methotrexate + mycophenolate mofetil. Different Chinese medical treatment methods (by syndrome typing) were given to patients according to different criticality of international prognostic scoring system (IPSS, 5 at moderate risk and 1 at high risk). RESULTS: All 6 patients successfully reconstructed their hematopoietic system. The time from transplantation to ANC >= 0.5 x 10(9)/L and platelet (PLT) >= 20 x10(9)/L were 13 (9-15) days and 11 (9-22) days respectively. Main complications were GVHD. Acute GVHD (aGVHD) occurred in 4 cases, 3 cases of grade I and 1 case of grade II, and local chronic GVHD (cGVHD) occurred in 1 patient. All cases survived with median follow-up of 18 (11-58) months. The overall survival (OS) and disease-free survival (DFS) rate were 100%. CONCLUSIONS: HSCT combined with Chinese medical syndrome typing could improve clinical symptoms, reduce transplant as- sociated complications. So it was an effective treatment choice for MDS. PMID- 25790676 TI - [Effect of Brucea javanica fruit oil emulsion combined cisplatin on the growth inhibition of transplanted tumor in human ovarian cancer SKOV3 nude mice: an experimental study]. AB - OBJECTIVE: To study the growth inhibition effect of Brucea javanica Fruit Oil Emulsion (BJFOE) on human ovarian caner SKOV3 cells and the transplanted tumor of SKOV3 nude mice. METHODS: Growth inhibition effects of different concentrations BJFOE alone or its combination with cisplatin on human ovarian cancer cell SKOV3 were measured using MTT method. The orthotopic transplantation tumor model of human ovarian cancer SKOV3 cell lines was established in nude mice. Totally 32 ovarian cancer nude mice were randomly divided into 4 groups, i.e., the blank control group (Group A), the BJFOE group (Group B), the BJFOE combined Cisplatin group (Group C), and the Cisplatin control group (Group D), 8 in each group. Mice in Group A were intraperitoneally injected with normal saline (0.2 mL/ 20 g), once per two days. Mice in Group B were intraperitoneally injected with BJFOE (0.2 mL/20 g), once per two days. Mice in Group C were intraperitoneally injected with cisplatin (3 mg/kg) 0.2 mL on the first day, and intraperitoneally injected with BJFOE on the second day. Mice in Group D were intraperitoneally injected with cisplatin (3 mg/kg) 0.2 mL, once per two days. All mice were injected for six times, and sacrificed 48 h after the last injection. The lesion formation of the abdominal tumor tissue was observed. Tumor specimens were obtained to perform HE staining. Expression levels of MRP-1/CD9 and integrinalpha-5 were detected using Western blot. RESULTS: The inhibition of BJFOE was time-dose depend- ently correlated with its inhibition effect of SKOV3 cells. The inhibition effect of BJFOE in combination of cisplatin was significantly superior to that of using any of the two drugs alone. Western blot results showed expression levels of MRP 1/CD9 and integrinalpha-5 were up-regulated in Group B and Group D with statistical difference (P < 0.05). But they were down-regulated in Group C with statistical difference (P < 0.05). CONCLUSIONS: Intraperitoneal injecting BJFOE was feasible and effective for treating ovarian cancer. BJFOE also could inhibit the invasion and migration of tumor cells targeting at MRP-1/CD9 and integrinalpha-5. But its specific anti-tumor mechanism was not clearly probed. PMID- 25790677 TI - [Changes of inherent immune response and acquired immune response in the tung tissue and the intestinal tissue of ulcerative colitis rats and the intervention of Chinese compound: an experimental research]. AB - OBJECTIVE: To explore Chinese medical theory of Fei and Dachang being interior exteriorly correlated by observing changes of inherent immune response and acquired immune response in the lung tissue and the intestinal tissue of ulcerative colitis (UC) model rats and the intervention of Chinese compounds (CM). METHODS: Seventy rats were randomly divided into 5 groups, i.e., the normal control group (n = 10), the model group (n = 15), the treatment 1 group (n = 15, treated from Fei), the treatment 2 group (n = 15, treated from the intestine), and the Western medicine (WM) group [n = 15, treated with Sulfasalazine (SASP). Except those in the normal control group, the UC rat model was prepared by allergizing colon mucosa combined with TNBS-alcohol (50%) enema, and then intervened by medication (treated with CM complex prescription of treatment from lung, CM complex prescription of treatment from intestine, and SASP). After intragastric administration for 4 weeks, rats were sacrificed and samples taken. The expression of tumor necrosis factor alpha (TNF-alpha) and IL-8 contents in the lung tissue, the intestinal tissue, and the serum were detected by radioimmunoassay. Serum MedCAM-1 contents were detected using ELISA. Changes of the expression of Toll-like receptor 4 (TLR4), nuclear factor kappaB (NF-kappaB), neutrophil migration inhibition factor (MIF), mucosal addressin cell adhesion molecule-1 (MadCAM-1) mRNA in the lung tissue and the intestinal tissue were detected by real time PCR. RESULTS: Compared with the normal control group, the expression levels of TNF-alpha, TLR4 mRNA, IL-8, MIF mR- NA, and MadCAM-1 mRNA obviously increased in the model group (P < 0.01). Compared with the model group, the expression levels of TNF-alpha, TLR4 mRNA, IL-8, MIF mRNA, and MadCAM-1 mRNA obviously decreased in the treatment 1 and 2 groups (P < 0.01). The expression of MadCAM-1 mRNA in the intestinal tissue was obviously higher in the model group than in the normal control group (P < 0.01), while the expressions of TNF-alpha and NF-kappaB mRNA was obviously lower in the model group than in the normal control group (P < 0.05, P < 0.01). Compared with the model group, the expression of MadCAM-1 mRNA all significantly deceased in each treatment group (P < 0.05, P < 0.01). Serum TNF-alpha contents were higher in the model group than in the normal control group (P < 0.05). Compared with the model group, serum TNF-alpha contents could be lowered in the treatment 1 and 2 groups (P < 0.05, P < 0.01). CONCLUSIONS: The main mechanisms of the intestinal injury in this UC model might be related with activation of acquired immune response, accompanied with lowered functions of inherent immune response. The main mechanisms of the lung injury in this UC model might be related acquired immune response and inherent immune response. Treatment from Fei and treatment from Dachang both could obviously improve the immunodissonance of Fei and Dachang, indicating the special relation between the lung tissue and the intestinal tissue, thus providing experimental evidence for Chinese medical theory of Fei and Dachang being interior-exteriorly correlated. PMID- 25790678 TI - [Effect of two Pi deficiency syndrome models on the configuration and function of the skeletal muscle in mice]. AB - OBJECTIVE: To observe the relation between Pi deficiency syndrome (PDS) and the configuration and functions of extensor digitorum longus (EDL)and soleus (SOL). METHODS: Totally 36 ICR mice were randomly divided into 3 groups according to weight matching principle, the control group, the exhausted group, and the rhubarb group, 12 in each group. Two PDS models were established by either purgation with rhubarb diarrhea (as Group A) or exhausted swimming plus sleep deprivation (as Group B).The cross sectional area (CSA) of type I and II fibers of extensor digitorum longus (EDL) and soleus (SOL), relative proportions of type I and II fibers were measured by m-ATPase histochemical method. The isotonic contraction and the maximum tetanus contraction of EDL and SOL were detected by PowerLab system. RESULTS: Compared with the control group, the body weight, body temperature, and the general health condition of PDS model rats obviously decreased; the spleen index and the thymus index were also lower; the maximal isotonic contraction and the maximum tetanus contraction obviously decreased; the cross section areas of EDL and SOL were reduced with loosely arranged cells. In EDL, the proportion of type I fibers was added and the proportion of type II fibers was lowered. In SOL, there was no change in the proportion of type I and type II fibers. CONCLUSIONS: EDL and SOL were obviously atrophied in the two PDS model mice. The type I fibers of SOL was more significantly atrophied in Group B. PMID- 25790679 TI - [Effect of Guishen Pill on expression levels of Oct-4, MVH, and Egr-1 in mice with diminished ovarian reserve]. AB - OBJECTIVE: To study the effect of Guishen Pill (GSP) on expression levels of Oct 4, MVH, and Egr-1 in mice with diminished ovarian reserve (DOR). METHODS: Totally 40 female C57BL/6J mice were randomly divided into 4 groups, the normal control group, the model group, the GSP group, and the dehydroepiandrosterone (DHEA) group, 10 in each group. Pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG), and prostaglandin F2alpha (PGF2alpha) were sequentially administrated to produce superovulation. The DOR model was established by exposing to ozone inhalation. Mice in the GSP group were intragastrically administered with GSP at 0.3 mL. Those in the DHEA group were intragastrically administered with DHEA at 0.3 mL. Equal volume of normal saline was intragastrically administered to mice in the normal control group and the model group. All mice wer treated for 21 days. Serum levels of estrogen (E2), progestogen (P), and anti-Mullerian hormone (AMH) were measured by ELISA. Changes of Oct-4, anti-AMH, and early growth response gene-1 (Egr-1) mRNA in ovaries were dtected by Real-time PCR. RESULTS: Compared with the model group, serum levels of E2, P, and AMH, as well as contents of estrogen receptor (ER), progestogen receptor (PR), MVH, and Oct-4 mRNA significantly increased in the GSP group and the DHEA group (P < 0.05). CONCLUSION: GSP could improve expression levels of Oct 4, MVH, and Egr-1 mRNA in DOR mice and their ovarian function. PMID- 25790680 TI - [Effect of Paidu Baoshen Pill on renal fibrosis in 5/6 nephrectomized rats]. AB - OBJECTIVE: To observe the anti-renal fibrosis effect of Paidu Baoshen Pill (PBP) on 5/6 nephrectomized rats and to explore its mechanism. METHODS: Totally 50 SD male healthy rats were randomly divided into the normal control group (n = 10), the sham-operation group (n = 10), and the nephrectomy model group (n = 30) according to the proportion of 1:1:3. Rats in the sham-operation group had their renal capsule isolated without nephrectomy. Rats in the nephrectomy model group had their kidneys 5/6 nephrectomized. Then 24 h urine was collected and 24 h urinary protein (24 h UP) detected. Serum blood urea nitrogen (BUN) and serum creatitine (SCr) were also tested. According to the SCr level 30 rats of the model group were further randomly divided into the model group, the PBP group, and the Niaoduqing Granule (NG) group, 10 in each group. Rats in the PBP group and the NG group were respectively administered with PBP (at the daily dose of 1.0 g/kg) and NG (at the daily dose of 3.33 g/kg) by gastrogavage (they were dissolved in distilled water). At the same time, 2 mL distilled water was administered by gastrogavage to rats in the normal control group, the sham operation group, and the nephrectomy model group, once daily for 4 successive weeks. Mental conditions, activities, hair color, shape of stool, and the body weight were observed during administration. After 4 weeks, urine was collected to detect 24 h UP. Blood was sampled to detect SCr, BUN, transforming growth factor beta1 (TGF-beta1), type III procollagen (PC III), collagen type IV (Col IV), laminin (LN), and fibronectin (FN). After rats were killed, their left remnant renal tissues were collected for pathological examinations. The protein expression quantity of TGF-beta1 and FN was detected by immunohistochemical method. mRNA expression levels of TGF-beta1 and FN were detected using real time fluorescent quantitative PCR. RESULTS: There was no statistical difference in the above indices between the normal control group and the sham-operation group (P > 0.05). Compared with the sham-operation group, rats' general condition was poorer in the model group, their body weight grew slower, and 24 h UP increased; serum levels of BUN, SCr, TGF-beta1, PC III, Col IV, LN, and FN increased; the residual renal pathological lesion was serious; expression levels of TGF-beta1, TGF-beta1, mRNA, FN, and FN mRNA increased in the renal tissue (all P < 0.01). Compared with the model group, rats' general condition was better, their body weight grew faster, 24 h UP reduced (P < 0.05), blood levels of BUN and SCr decreased significantly (P < 0.01), serum levels of TGF-beta1, PC III, CoL IV, LN, and FN decreased (P < 0.05, P < 0.01); the residual renal pathological lesion was attenuated in the PBP group and the NG group; expression levels of TGF-beta1, TGF beta1, mRNA, FN, and FN mRNA decreased (P < 0.01). Compared with the NG group, blood levels of SCr and FN, and expression levels of FN and FN mRNA decreased more in the PBP group (P < 0.05). CONCLUSIONS: PBP had the effect of anti-renal fibro- sis in 5/6 nephrectomized rats. Down-regulating expression levels of TGF beta1, and FN from gene transcription and protein translation levels might be one of its mechanisms. PMID- 25790681 TI - [Effect of Tangshenkang Granule containing serum on renal mesangial cells' proliferation and TGF-beta1/Smad2/3 pathway in the high glucose condition]. AB - OBJECTIVE: To study the effect of Tangshenkang Granule (TG) containing serum on renal mesangial cells' (RMCs) proliferation and TGF-beta1/Smad2/3 pathway in the high glucose condition. METHODS: Twelve SD rats were randomly divided into four groups, i.e., the low dose TG group, the middle dose TG group, the high dose TG group, and the blank control group, 3 in each group. After 7-day gastrogavage via portal vein blood, rats were sacrificed and their serum samples were collected. RMCs were cultured in common rat serum and TG containing serum respectively. The proliferation of mesangial cells was determined by methly thiazolyl tetrazolium (MTT) assay to determine the optimal TG containing serum concentration. Expression levels of TGF-beta1 mRNA and protein were determined by real time quantitative PCR and ELISA. Smad2/3 protein expression and phosphorylation were determined by Western blot and immunofluorescence. RESULTS: TG containing serum at different doses could inhibit high glucose induced RMC cells' proliferation, TGF-beta1 over-expression and Smad2/3 phosphorylation. CONCLUSION: TG containing serum could inhibit high glucose induced RMC cells' proliferation, and its mechanism might be possibly associated with inhibiting TGF-beta1/Smad2/3 signaling pathway. PMID- 25790682 TI - [Total ginsenosides fought against right ventricular hypertrophy through inhibiting calcineurin signal pathway]. AB - OBJECTIVE: To observe the effect of total ginsenosides (TG) on monocrotaline (MCT) induced right ventricular hypertrophy rats, and to explore its correlation with calcineurin (CaN) pathway. METHODS: Fifty male Sprague Dawley rats were randomly divided into the normal control group, the MCT model group, and the low, middle, high dose TG treatment groups, 10 in each group. All medication was performed by peritoneal injection for 18 days. Right ventricular peak systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and right ventricular weight/body weight (RVW/BW) were measured. Intracellular free calcium concentrations were measured by Ca2+ fluorescence indicator Fura2/AM. The atrial natriuretic factor (ANF) and CaN mRNA expression of the myocardial tissue were quantitatively analyzed by Real-time PCR. The protein expression of CaN was detected by Western blot. RESULTS: Compared with the MCT model group, preventive treatment of TG at the 3 doses could significantly reduce RVSP, RVHI, RVW/BW, and ANF mRNA expression, and decrease Ca2+ concentration in myocardial cells, CaN mRNA and protein expression in the myocardial tissue. CONCLUSION: TG could obviously improve MCT-induced right ventricular hypertrophy, which was possibly achieved through suppressing MCT-activated CaN signal transduction. PMID- 25790683 TI - [Gastric dynamics analysis of TEAS combined SNP induced general anesthesia when controlled hypotension dropped to 60% of the MAP baseline]. AB - OBJECTIVE: To observe the effect of gastric dynamics by transcutaneous electrical acupoint stimulation (TEAS) combined general anesthesia when controlled hypotension dropped to 60% of the mean arterial prenssure (MAP) baseline, and to provide experimental evidence for organ protection in clinical controlled hypotension. METHODS: Eighteen male beagles were randomly divided into three groups, the general anesthesia group (blank), the general anesthesia induced controlled hypotension group (control), and the general anesthesia combined TEAS induced controlled hypotension group (experiment), 6 in each group. Controlled hypotension was performed in the latter two groups with isoflurane inhalation and intravenous injection of sodium nitroprusside (SNP). The mean arterial pressure (MAP) was lowered to 60% of the MAP baseline and kept for 60 min. Controlled hypotension was not performed in Beagles of the control group. For Beagles in the experiment group, TEAS [2/100 Hz, (4 +/- 1) mA] was applied to bilateral Hegu (LI4), Quchi (LI11), Zusanli (ST36), and Sanyinjiao (SP6) from stable physiological conditions to the end of maintaining stages. Changes of EGG frequencies and EGG amplitudes were monitored. Serum levels of gastrin (GAS) and motilin (MTL) were also detected at corresponding time points during and after experiment. RESULTS: As for the pressure control effect of TEAS combined general anesthesia in the controlled hypotension, during the process of controlled hypotension (T1-T4), MAP levels of two controlled pressure groups remained relatively stable, and were kept at 60% of the MAP baseline. When the blood pressure dropped to the target low MAP and maintained at 60 min (T1-T4), EGG amplitudes of Beagles in all the three groups showed decreasing tendency. But it was more obviously lower than its basic level in the control group (P <0.05), while it was not obviously decreased in the experiment group (P < 0.05). EGG frequencies of Beagles in all the three groups showed no obvious change during this stage. By the end of the MAP rising stage (T8), the EGG amplitude of the experimental group was significantly higher than that of the control group and the blank group (P < 0.05), while it didn' t show any obvious increase in the control group. During this period, EGG frequencies of the two controlled hypotension groups decreased more than those of the blank group. Two h after rising blood pressure (at T9), EGG amplitudes and frequencies in the two controlled hypotension groups basically restored to their respective baselines and levels of the blank group at T9. At 2 h (T9) after controlled hypotension, serum levels of GAS and MTL were lower than those of basic levels in the two controlled hypotension groups (P <0.05). However, serum levels of GAS and MTL had an increasing trend in the two controlled hypotension groups at 24-72 h (T10 T12). Besides, the increasing speed and amplitude was better in experiment group than in the control group at T10-T12. However, there was no statistical difference between the two groups (P > 0.05). At 72 h (T12) serum levels of GAS and MTL had basically restored to their basic levels in the two controlled hypotension groups and that of the blank control group. CONCLUSION: EGG amplitudes could be effectively improved in TEAS combined general anesthesia for controlled hypotension at 60% of the MAP baseline, the recovery of the serum GAS level accelerated, gastric power improved and stomach protected. PMID- 25790685 TI - [The Schema study of culture-loaded words in TCM literature translation]. PMID- 25790684 TI - [Discussion of tumor treatment from the theory of ascending and descending activities of qi]. AB - The theory of ascending and descending activities of qi is one basic theory that guides diagnosis and treatment of disease clinically. It has been esteemed by ancient physicians throughout their academic thinking and clinical diagnosis. As a kind of unbalanced disease in the whole body, the basic internal mechanism of tumor formation may be caused by unbalanced ascending and descending activities of qi. Better clinical efficacy is liable to get by applying the theory of ascending and descending activities of qi in cancer treatment. Therefore, we hope to provide a reference for clinicians from the following aspects: historical status and academic value of the theory of ascending and descending activities of qi, case examples and classical prescriptions. PMID- 25790686 TI - [Treatment of cryptogenic organizing pneumonia by heat clearing, blood activating qi benefiting, and yin nourishing method: a case report of two cases]. PMID- 25790687 TI - [Treatment of one neuropsychiatric lupus disease patient by integrative medicine]. PMID- 25790688 TI - [Recent Researches on Optical in vivo Imaging: a review]. PMID- 25790689 TI - [Enriching shen to moisten gan method intervened adverse reactions of using hormone therapy in treating breast cancer: a review]. PMID- 25790690 TI - [Possibilities for targeted therapy of neuroendocrine tumours]. AB - The treatment of patients with neuroendocrine tumours and hormonally active distant metastases traditionally included surgical removal of the primary neoplasm, embolization of metastases in the liver, therapy with somatostatin analogs and interferon-alpha to prevent excessive production of regulatory peptides (carcinoid and other endocrine syndromes). Patients with neuroendocrine pancreatic tumours were also treated with alkylating chemotherapeutic drugs including streptosocin and temozolomide. The results of such treatment are far from being satisfactory. Recent progress in the treatment of such patients is due to radiotherapy using somatostatin analogs. Moreover, large-scale randomized studies demonstrated the effectiveness of targeted preparations acting on receptors of vascular growth factors and ripamycin target inhibitors ofmammals. Results of the studies on comparative effectiveness of targeted drugs for combined therapy of neuroendocrine tumours are presented. PMID- 25790691 TI - [Melatonin and arterial hypertension: from understanding pathogenesis to therapeutic modalities]. AB - Biological rhythms are driven by the hypothalamic circadian pacemaker. Its action is mediated through epiphyseal melatonin that transmits regulatory signals directly to target organs. Circadian fluctuations of arterial pressure suggest participation of melatonin in regulation of this important indicator of cardiovascular activity. Melatonin is a key endogenous hypotensive factor. Some studies demonstrated that additional prescription ofmelatonin to patients with nocturnal hypertension refractory to traditional hypotensive agents significantly lowered arterial pressure during sleep. Moreover, melatonin was shown to exert meteo- and magnetoprotective action and thereby reduce the dependence ofpatients with arterial hypertension on the adverse environmental factors. PMID- 25790692 TI - [The importance of thrombocytic indices in patients operated for chronic rheumatic heart disease]. AB - We studied the importance of thrombocytic indices in patients operated for chronic rheumatic heart disease and showed that a decrease in the platelet count is accompanied by increased thrombocytic indices including platelet width and mean volume, the relative number of large platelets in peripheral blood The increase was regarded as a compensatory response to the decrease in the platelet count; it suggests enhanced thrombocytopoiesis. It is concluded that deretmination of thrombocytic indices in cardiosurgical patients using automated hematological analyzers allows to evaluate the prcesses of thrombocytopoiesis. PMID- 25790693 TI - [Composition of microorganism community in the airways of patients with chronic obstructive pulmonary disease]. AB - This review summarizes results of research on the composition of microorganism community in the airways of patients with chronic obstructive pulmonary disease. Modern technologies for molecular genetic identification of microorganisms provide a deep insight into the microbiota of patients with chronic broncho obstructive diseases for the better understanding of bronchopulmonary pathology in man and effect of microbiotic communities on the clinical course of diseases and formation of resistance to antibiotics. PMID- 25790694 TI - [Thyroid functional activity and hemodynamic parameters in upper-class schoolchildren presenting with endemic goiter]. AB - We studied the relationship between iodine deficiency, blood cortisol levels, andhemodynamicparameters in 536schoolchildren of Vladikavkaz aged 13-17 years. Urine iodine was measured using cerium arsenite reaction, thyroid function was evaluated from thyrotropin, T3, and free T4 levels, blood cortisol was determined by the immonoenzyme assay using Alcor Bio kits. The study group included 24 subjects with endemic goiter, control group was comprised of 14 healthy adolescents. Hemodynamic parameters were studied using a Vivid 7 Dimension scanner. PMID- 25790695 TI - [Peculiarities of desynchronosis associated with shift-based jobs and in the patients with severe somatic pathology]. AB - Disturbances in coordination between physiological functions of the cardiovascular system develop in healthy people as a result ofdisordered sleep wake cycle especially associated with psycho-emotional stress. A classical example is desynchronosis in locomotive drivers. Similar condition develops in association with severe somatic pathology e.g. in oncological patients. The study was designed to analyse peculiarities of desynchronosis associated with shift based jobs and in the patients with oncological diseases. The control group was comprised of the students and teachers of the University of People's Friendship. Diagnostics and evaluation of desynchronosis severity were performed by complex correlation-regressive analysis and pre-trip AP and HR measurements in locomotive drivers. In healthy subjects, all regression coefficients were positive and significant in combination with middle-strength correlation coefficients which ensured maximum coordination in the work of the coupled systems without the loss of plasticity between physiological contours. Patients with severe somatic pathology showed multidirectional functioning of physiological contours (stable dyscoordination) with the enhanced relationship between the parameters of interest and with manifestations of "rigidity". Multidirectional functioning of coupled systems was equally characteristic of locomotive drivers, but the relationship between the parameters being studied was less expressed and attributable to an adaptive reaction because the relationship recovered during the rest periods between shifts. PMID- 25790696 TI - [The system of hemostasis in patients with diabetic foot syndrome undergoing surgical treatment]. AB - Characteristics of hemostasis system were studied in 185 patients with diabetic foot syndrome undergoing surgical treatment. Disturbances of procoagulative activity persisted within days 1 and 5 after surgery in patients with complicated forms of DFS due to enhanced formation of blood and tissue prothrombinase; simultaneously, the formerly increased fibrinogen level decreased by virtue of intravascular blood coagulation. The activity of natural anticoagulants (antithrombin 111, proteins C andS) continued to be low as a result of their utilization to activate coagulation processes. Resistance of Va factor to activated C protein remained as high as preoperatively. XIIa-Hageman dependentfJibrinolysis was suppressed and showed no tendency toward recovery. PMID- 25790697 TI - [The level of neurospecific proteins in patients with type 1 diabetes mellitus and cognitive disorders]. AB - Type I diabetes mellitus (DM1) is a widespread metabolic disease ofsocial significance due to early disability in youngpatients and reduced life expectancy. One of the DMI complications is CNS lesions resulting in cognitive dysfunction mediated through metabolic disorders. This condition can be partly or completely reversed if diagnosed and treated'at an early stage. The aim of this study was to determine the level ofneurospecific proteins in 58 patients aged 16 30years with type I diabetes mellitus and cognitive disorders in comparison with 29 healthy controls of simnilar age. All the participants underwent neuropsychological testing based on the Montreal scale for rapid screening of cognitive disorders (MoCA-test). Protein S100, glial fibrillary acidic protein, and myelin basic protein served as early markers of cognitive dysfunction. The study revealed an enhanced level of neurospecific proteins that correlated with hyperglycemia and cognitive deficit (MoCA score 26). PMID- 25790698 TI - [The use of succinate-containing preparations in combine therapy of diffuse toxic goiter]. AB - We studied dynamics of hormonal status, lipid peroxidation, protein oxidative modification, enzymatic activity of the antioxidative system in the patients with newly diagnosed diffuse toxic goiter (Graves' disease). It was shown that the use of succinate-containing antioxidant reamnberin accelerates normalization of hormonal status and free radical oxidation; it reduces the duration of hospitalization. PMID- 25790699 TI - [Selective cyclooxygenase-2 inhibitors and protected nonsteroidal anti inflammatory agents: two methods for the prevention of iatrogenic complications]. PMID- 25790700 TI - [Successful treatment of severe HCV-cryoglobulinemic vasculitis with the use of CD20 monoclonalantibodies and antiviral agents]. AB - This paper reports a case of successfuid treatment of severe HCV-cryoglobulinemic vasculitis with ulcerative necrotic skin lesions, digital necrosis, cryoglobulinemic glomnerulonephritis and sensorimotor neuropathy. Possibilities for the change of prognosis in the patients with HCV-cryoglobulinemic vasculitis are discussed along with the prospects for the improvement of antiviral and pathogenetic therapy. PMID- 25790701 TI - [Present-day organization of the teaching process at the Department of Propedeutics of Internal Diseases]. AB - The experience with organization of the teaching process at the Department ofPropedeutics of Internal Diseases is reported. The role of the rating system for knowledge and skill control is discussed along with the possibilities of its application for the improvement of training students in compliance with the Bologna process principles and their integration into the education system. PMID- 25790702 TI - [The metabolic syndrome]. AB - This paper expounds the author's view of metabolic syndrome and its components based on the extensive personal experience PMID- 25790703 TI - [The wound and death of the Russian military commander P.I. Bagration. Part 2]. AB - Medical care provided to P.I. Bagration wounded in the battle of Borodino is described on the day-to-day basis. PMID- 25790704 TI - [Vegetative regulation of the cardiovascular system in patients with chronic heart failure with chronic renal insufficiency]. AB - This review deals with vegetative regulation of cardiovascular system in patients with chronic heart failure (CHF) and signs of chronic renal insufficiency. CHF is currently regarded as a disturbance of neurohumoral mechanisms controlling blood circulation. At the same time, both prognosis and outcome of CHF depend on the presence of chronic renal insufficiency whose pathogenesis is poorly understood The authors emphasize the importance of elucidation of common pathogenetic mechanisms of these mutually complicating conditions. PMID- 25790705 TI - [Therapeutic hypothermia: the potential and prospects]. AB - Hypothermia is a most powerful tool for the protection of various organs especially brain. The review is focused on the mechanisms of protective action (modulation ofmetabolism and local inflammatory reaction, prevention of blood brain barrier disorders, normalization of nitric oxide synthesis) and technology of therapeutic hypothermia. Main clinical situations in which the most effective and safe application of this technology was achieved are described. PMID- 25790706 TI - [The diagnostic value of systemic inflammation biomarkers in chronic obstructive pulmonary disease]. AB - Chronic obstructive pulmonary disease (COPD) is a cause of appreciable social and economic losses. Airway inflammation is the main factor at the early stages of COPD pathogenesis and persists for many years after cessation of the action of provoking factors. In the last years, researchers have shown much interest in biomarkers associated with various diseases including COPD. Biomarkers of COPD are related to pathophysiology ofthe disease and inflammatory processes in the lungs. This review is designed to summarize the currently available data on systemic COPD biomarkers, their use for the assessment of activity of the disease and the possible role in the formation of COPD phenotype. Most systemic biomarkers are not specific for COPD. Moreove, evaluation of their significance encounters difficulties due to the presence of concomitant pathologies, in the first place cardiovascular diseases. Nevertheless, studies involving a large number of patients with COPD provided information about the role of biomarkers in the activity of COPD and formation of its phenotype with systemic inflammation. The introduction ofbiomarkers in protocols ofexamination ofCOPD patients needs further substantiation. PMID- 25790707 TI - [Treatment and prevention of erosive and ulcerative lesions in the stomach and duodenum caused by intake of non-steroidalanti-inflammatory drugs]. AB - Therapy with non-steroidal anti-inflammatory drugs (NSAIDs) is a diffcult task. Good anti-inflammatory effect increases the risk of gastrointestinal complications with a frequency of 10-50%. The risk further increases with age (above 60-70 yr), the history of ulcer disease concomitant intake of acetylsalicylic acid, anticoagulants, and glucocorticosteroids. Long-term antisecretory therapy with proton pump inhibitors, e.g., esomeprazole, was shown to be an effective prophylactic tool. This drug maintains the intragastric pH value above 4 for 15 hr on the average. The risk of erosive and ulceraive lesions in the stomach and duodenum significantly decreases by selective cyclooxygenase-2 inhibitors, e.g., coxibs, that however increase the risk of thrombotic cardiovascular complications. The author proposes recommendations on the use of NSAIDs in the patients at risk of serious gastrointestinal and cardiovascular pathology. Naproxen in combination with proton pitmp inhibitors is the drug of choice among NSAIDs. Vimovo is a fixed combination of naproxen and esomeprazole. Results of comparative studies on the efficacy of vimovo and celecoxib are presented along with the data on the safety of this. combination compared with that of naproxen monotherapy PMID- 25790708 TI - [The role of insulin resistance in pathogenesis of arterial hypertension]. AB - Arterial hypertension (AH) is a major challenge facing modern medicine. High frequency of AH patients with excess body mass and disturbances ofcarbohydrate metabolism is attributable to their common pathophysiological mechanisms underlain by insulin resistance and resulting compensatory hyperinsulinemia. The authors review modern concepts of AH development in patients with insulin resistance associated with enhanced blood insulin level and increased production of catecholamines playing an important role in AH pathogenesis mediated through sympathetic stimulation of heart, vessels while kidneys. Insulin resistance contributes to AH largely by activating sympathoadrenal system while increased glomerular filtration of glucose is accompanied by its back absorption together with sodium in proximal tubules. It results in hypervolemia and enhanced content of sodium and calcium in vascular walls which leads to their spasm and a rise in the total peripheral vascular tension (TP VT). Insulin promotes fibroblast proliferation and vascular smooth muscle cells via stimulation of tissue growth factors and collagen synthesis in atherosclerotic plaques. The concomitant narrowing of the vessels further increases TPVT. It in turn decreases renal blood flow and thereby activates renin-angiotensin-aldosterone system and development of AH. PMID- 25790709 TI - [Effectiveness of diagnostics and treatment of complicated hypertensive disease taking into account results of 3 day arterial pressure monitoring]. AB - Empirical choice of antihypertensive therapy (AGT) for patients with complicated hypertensive disease (HD) encounters difficulties due to high variability of arterial pressure (AP) and inadequate response to intake of medicines. The objective methods for the choice of AGT methods are absent. AIM: To evaluate effectiveness ofthe choice of AGT taking account of AP profile calculated based on the analysis of results of 3 day AP monitoring in patients with complicated HDfor whom the empirical prescription of medicines does not give the desirable result. MATERIALS AND METHODS: The study included 51 patients aged 56 +/- 19 yr with HD 18 +/- 13 yr in duration without adequate control of AP despite combined AGT AD was measured (BPLab, Nizhni Novgorod) every 30 min for 3 days, the AP profile was calculated by special FORM-based algorithm. Peak time and magnitude were calculated, the first and second derivatives of the process were determined, AGT was prescribed at the computed AD maximum points. RESULTS: Systolic and diastolic AP decreased within 2 weeks after AGT The number of patients with enhancedAP in the daytime and at night and those with highly variable AP decreased from 33 to 11% (chi2 = 8.4, p < 0.005), from 61 to 33% (chi2 = 10.1, p < 0.005), from 51 to 26% (chi2 = 8.2, p<0.005) respectively. The number ofpatients with inadequate lowering of night-time AP and those with abnormally high fluctuations of AP decreased from 53 to 24% (chi2 = 9.3, p < 0.005) and from 31 to 15%, (p < 0.005) respectively. The frequency of intake of AGT drugs did not change. CONCLUSION: Approximation of real AP circadian profile fluctuations based on results of 3 day monitoring is a sensitive diagnostic tool facilitating the choice of rational AGT for patients with markedly altered circadian rhythms when empirical prescription of AGT does not ensure desired control ofAP PMID- 25790710 TI - [Risk factors of contrast-induced nephropathy in patients with myocardial infarction]. AB - AIM: To identify predictors of contrast-induced nephropathy (CIN) and evaluate its significance for the hospital prognosis of myocardial infarction with elevated ST segment. MATERIALS AND METHODS: 722 (75.7%) of the total 954 patients underwent X ray examination with the use of contrast material (coronary angiography (CAG) and/or transcutaneous coronary intervention (TCI)) within 24 hr after the appearance of symptoms. In all cases, serum creatinine level was determined and glomerular filtration rate (GFR) calculated by the MDRD formula at admission, 2-3 days after CAG/TCI, and 10-14 days after hospitalization. CIN was defined as a more than 25% (44 mcmnol/l) rise in the creatinine level compared with the initial one within 48-72 hr after intravascular administration of contrast material in the absence of an alternative cause. The endpoints (adverse cardiovascular effects) were evaluated at the hospital stage of the study. RESULTS: Significantly more patients with CIN (n=52; 7.2%) had the history ofdiabetes mellitus (DM) and chronic renal disease (CRD), clinically manifest Killip class II-IV acute cardiac failure (ACF), and reduced left ventricular ejection fraction (LVEF) compared with the patients having normal renal function. The risk of RAEF in the presence of CIN increased by 2.5 times (95% CI 1.26 5.05), that of MI by 5.4% (95% CI 2.69-10.64), life-threatening and other complications by 4.1% (95% CI 1.99-8.29) and 5.1% (95% CI times 2.85-9.17) times respectively. The presence of Killip class II-IV ACF increased the risk of CIN and DM by afactor of 2.2. CONCLUSION: CIN was diagnosed in 7.2% of the patients with myocardial infarction and elevated ST segment; it is associated with the history of DM, CRD, pronounced Killip class II-IV ACF and decreased LVEF DM and clinically manifest ACF were independent predictors of CIN in patients with myocardial infarction and elevated ST segment. PMID- 25790711 TI - [New approaches to primary differentiation of dyspnea in patients with pulmonary and cardiac pathology]. AB - This study was aimed at searching new instruments for primary differentiation of dyspnea associated with lung or heart pathology. The study consisted of 3 stages and included analysis of "glossary dyspnea" of 482 patients aged 18-90yr. Stages i and II involved 359 patients with the known diagnosis: chronic obstructive pulmonary disease (COPD) (n=114, 31.8%), bronchial asthma (BA) (n=134, 3 7.3%), chronic heart failure (CHF) unrelated to lung pathology (n=111, 30.9%). The patients were 205 (57.1%) men and 154 (42.9%) women. Stage III involved 123 patients complaining ofdyspneapresumably ofpulmnonary or cardiac origin. 75 (61.0%) of these patients were men, 48 (39.0%) women aged 18-89 yr. Subsequent comprehensive diagnostics revealed BA in 47 (38.2%), COPD in 46 (37.4%), CHF in 30 (24.4%) patents. Stage I was designed to evaluate the dyspnea language based on the frequency of the phases of glossary dyspnea (Simon et al., 1999) and Fisher's Z criterion. It permitted to create the modified glossary dyspnea (MGD) consisting of 11i phrases and 7 clusters that revealed statistically significant differences between patients with BA, COPD, and CHE At stage II, we developed the model for estimating the probability of a priori diagnosis (PPD) as a possible cause of dyspnea based on the data of MGD and modified Bayesian classificator. At stage III, the PPD model was verified using blindly selected patients. Prior to verification, the patients filled MGD. The final diagnosis was specified in accordance with the national recommendations. on diagnostics of BA, COPD and CHE Comparison of the frequency of coincidence between preliminary (a priori) and definitive (a posteriori) diagnoses made it possible to evaluate sensitivity and specificity of the PPD model for BA, COPD, and CHF unrelated to lung pathology. PMID- 25790712 TI - [Bronchial hypersensitivity in children with the neutrophilic phenotype of bronchial asthma and GSTM1 and GSTT1 gene polymorphism]. AB - INTRODUCTION: The relationship between bronchial hypersensitivity as the key phenomenon ofbronchial asthma and detoxication GSTM1 or GSTT1 gene polymorphism in children with neutrophilic phenotype of this disease remains unclear MATERIALS AND METHODS: 33 children with bronchial asthma of neutrophile phenotype were examined in histamine and dosed physical exercise (running) tests. In addition GSTM1 and GSTT1 genotyping was performed. RESULTS: Histamine test revealed bronchial hypersensitivity (HTC < 0.3 mg/ml) in 30.7% of the children with GSTMI and/or GSTTI deletions versus 12.5% of those without deletions (P phi < 0.05). The relative risk ofhypersensitivity to histamine (HTC < 0.3 mg/mI) in the presence of deletions was estimnated as 3.1 (95% CI 1.4-6.4), at OR 2.4 (95% CI 1.08-3.1) andAR = 0.18. CONCLUSION: Children with the neutrophilic phenotype of bronchial asthma having deletions in the GSTT1/GSTM1 system are characterized by bronchial hypersensitivity to histamine and dosed physical exercises. PMID- 25790713 TI - [Association of leptin and total immunoglobulin E in obese patients]. AB - We measured by the immunoenzyme assay serum levels of total IgE and leptin in 17 men and 95 women with non-alcoholic fatty liver diseases (NAFLD) and in 57 men and 25 women with alcoholic liver disease (ALD) in comparison with 454 control men and 74 women without hepatic pathology. It was shown that the total serum IgE level in patients with ALD (229.5 +/- 31.0 IU/l) is on the average twice that in NAFLD and control patients (89.7 +/- 15.0 and 96.2 +/- 16.0 IU/l respectively). The IgE level in patients with NAFLD is related to BMI and waist circumference (WC). Leptin levels in patients with NAFLD andALD are higher than in control and correlate with obesity signs in all three groups. They correlate with the IgE level and reach the maximum value at a concentration of total IgE over 100 IU/l in men with NAFLD and WC >94 and in women with BMI = >30.0 kg/m2 and WC >80 cm. Positive correlation between IgE, leptin level and obesity signs in men and women with NAFLD suggests that leptin may be a link between obesity, hepatosteatosis, and atopic diseases. PMID- 25790714 TI - [Clinical features of persistent viral infections in women. Differential diagnostics]. AB - AIM: To study clinical synptoims in patients with persistent viral infection (P VI). METHODS: The study included 325 women with PVI diagnosed during examination of 1119 women. 151 of them with verified diagnosis of PVI presented with pregnancy, 64 with miscarriage, 89 with premature delivery, and 29 suffered infertility. These conditions were not detected in 635, 74, 33 and 52 women respectively. A variety of clinical symptoms included pathological vaginal discharge with putrefactive odor irritation, itchy and burning genitalia, painful intercourse, menstrual disorders, dysuria, drawing pain in the lower abdomen. RESULTS: Analysis of clinical data showed that vaginal discharge with putrefactive odor irritation, itchy and burning genitalia were the leading symptoms of PYVI documented in 59.4?2.7-76.9+2.3% of the examined patients. Each woman with PVI had at least 2 or 3 of these symnptoms which allows to regard them as markers of this condition. We distinguished 4 clinical forms of PVI: asymptomatic (14.5?2.0%), mild (34.8 +/- 32.1%), moderate (32.64 +/- 2.6%) and severe (18.2 +/- 2.1%). Asymptomatic form largely occurs in the patients using no antibiotics (47.7 +/- 6.2%) although the same group very frequently suffer severe PVI (34.4-6.1%). The presence of pathogenic microflora, Chlamydia and Trichomonads inr the genital tract increases the frequency of moderate and severe forms of PVI up to 23.6 +/- 4.1 and 32.2 +/- 6.1% which suggests the necessity of adequate choice and application of pharmaceuticals acting on all the above pathogens. CONCLUSION: PVI in pregnant women and patients with reproductive pathology shows up a specific clinical picture of diagnostic significance. PMID- 25790715 TI - [Combination of arterial hypertension and type 2 diabetes mellitus with obesity]. AB - The aim of the study was to elucidate dynamics of the incidence of arterial hypertension (AH), 2 type diabetes mellitus (DM), and obesity as the main risk factor of these conditions, combinations between them and certain circulation disorders in the patients admitted to our clinic from 2003 to 2011. We analysed 25,451 case histories. Patients were regarded as having AH, DM, obesity, coronary heart disease, cardiac rhythm disturbances and cerebovascular disorders if they had verified diagnosis of nosological forms corresponding to the respective ICD 10 codes. Their occurrence was calculatedfor 3 three-year periods with reference to the mean age of the patients in different groups. It was shown that increased incidence of AH in the above time periods was associated with the enhanced occurrence of combination of AH and obesity or AH, obesity and DM. Similarly, the increased incidence of DM was associated with the enhanced occurrence of combination DM, AH, and obesity. A significant increase of the mean age was documented only in women with AH and obesity and in men with AH or AH plus obesity. The presence of DM in AH patients had no appreciable effect on the frequency of cerebrovascular pathology that increased in the presence ofAH with obesity. PMID- 25790716 TI - [A case of favourable outcome of severe acute intoxication with an animal poison after a bite by the monocled cobra]. AB - This paper reports a case of severe acute intoxication with an animal poison after a bite by the monocled cobra. Combined treatment including artificial lung ventilation, infusion-detoxication and desensitizing (hormonal) therapy, hemosorption, correction of metabolic disorders with cytoflavin, antibacterial therapy had positive effect on the patient's condition and ensured the favourable outcome ofpotentially lethal poisoning without the use ofa specific anti-snake venom serum. PMID- 25790717 TI - [Does personalized medicine have a future?]. AB - Standardization of diagnostic and therapeutic methods finds an increasingly wider application in clinical practice. Despite obvious advantages of this approach, it sometimes does not ensure the choice of efficacious and safe treatment. Rapidly developing personalized medicine may be instrumental in overcoming drawbacks of standardization. PMID- 25790718 TI - [Peculiarities of post-graduate education of primary healthcare providers]. AB - Positive emotional environment, adequately organized verbal and non-verbal communication are the primary components of post-graduate education of primary healthcare providers. The ability of teachers to activate relevant sensor channels in the listeners during lessons is an indispensable prerequisite for enhancing their learning and training skills. PMID- 25790719 TI - [News from the Higher Attestation Commission (VAK)]. PMID- 25790720 TI - Core-shell hematite nanorods: a simple method to improve the charge transfer in the photoanode for photoelectrochemical water splitting. AB - We report a simple method to produce a stable and repeatable photoanode for water splitting with a core-shell hematite (alpha-Fe2O3) nanorods system by combining spray pyrolysis and hydrothermal synthesis. Impedance spectroscopy revealed passivation of the surface states by the shell layer, which results in an increase of the charge injection through the hematite conduction band. In pristine hematite more holes are accumulated on the surface and the charge transfer to the electrolyte occurs through surface states, whereas in the core shell hematite photoanode the majority of hole transfer process occurs through the valence band. As a result the photoactivity of the core-shell nanorods, 1.2 mA cm(-2), at 1.23 V vs RHE, is twice that of pristine hematite nanorods. The alteration of the interface energetics is supported by TEM, showing that the crystallinity of the surface has been improved by the deposition of the shell. PMID- 25790721 TI - Identification of metabolic markers in coronary artery disease using an untargeted LC-MS based metabolomic approach. AB - Coronary artery disease (CAD), a complex metabolic disorder, is one of the largest causes of death worldwide. Both environmental and genetic factors contribute to the etiology of this metabolic disease. The gene-environment interaction could lead to modulation of various metabolic pathways resulting in altered levels of various metabolites. Thus, identifying metabolites could aid in deciphering pathways that could be involved in the pathophysiology of the disease. With the advent of high resolution mass spectrometry based methodologies, it is now possible to screen thousands of metabolites in a single snapshot thus, allowing the identification of potential disease metabolite markers. In this work, using an untargeted metabolomic approach, we attempted to identify metabolites that have altered levels in CAD patients. Using reverse phase and HILIC based chromatography followed by mass spectrometry we identified a total of 32 metabolites (2 fold; p<0.05) in plasma whose levels were significantly altered in CAD samples. Further, we have validated the discriminative ability of these metabolites in an independent set of CAD and control samples using multivariate PLS-DA analysis. Interestingly, Lyso PC (18:0), Cortisol, Lyso PC (P-17:0), and glycerophosphocholine were among the top discriminators for CAD which implies involvement of phosphatidylcholine pathway in the pathogenesis of atherosclerosis. BIOLOGICAL SIGNIFICANCE: Herein, we report that an unbiased metabolomic study has the potential to identify newer markers which are involved in several important biological pathways like lipid metabolism, phosphatidylcholine pathway etc. which in turn are implicated in CAD. These markers could be of potential clinical importance for screening subjects at risk of CAD. This article is part of a Special Issue entitled: Proteomics in India. PMID- 25790722 TI - Multileaf collimator tongue-and-groove effect on depth and off-axis doses: a comparison of treatment planning data with measurements and Monte Carlo calculations. AB - To investigate how accurately treatment planning systems (TPSs) account for the tongue-and-groove (TG) effect, Monte Carlo (MC) simulations and radiochromic film (RCF) measurements were performed for comparison with TPS results. Two commercial TPSs computed the TG effect for Varian Millennium 120 multileaf collimator (MLC). The TG effect on off-axis dose profile at 3 depths of solid water was estimated as the maximum depth and the full width at half maximum (FWHM) of the dose dip at an interleaf position. When compared with the off-axis dose of open field, the maximum depth of the dose dip for MC and RCF ranged from 10.1% to 20.6%; the maximum depth of the dose dip gradually decreased by up to 8.7% with increasing depths of 1.5 to 10cm and also by up to 4.1% with increasing off-axis distances of 0 to 13cm. However, TPS results showed at most a 2.7% decrease for the same depth range and a negligible variation for the same off-axis distances. The FWHM of the dose dip was approximately 0.19cm for MC and 0.17cm for RCF, but 0.30cm for Eclipse TPS and 0.45cm for Pinnacle TPS. Accordingly, the integrated value of TG dose dip for TPS was larger than that for MC and RCF and almost invariant along the depths and off-axis distances. We concluded that the TG dependence on depth and off-axis doses shown in the MC and RCF results could not be appropriately modeled by the TPS versions in this study. PMID- 25790723 TI - Female medical physicists: The results of a survey carried out by the International Organization for Medical Physics. AB - INTRODUCTION: The gender composition of the existing medical physicist (MP) workforce around the world is basically unknown. The International Organization for Medical Physics (IOMP) performed a survey in order to investigate the number of MPs in countries around the world and the percentage of women MPs compared to total number of MPs. MATERIALS AND METHODS: A simple online questionnaire prepared as a Google Forms survey asking the country, the total number of MPs, the number of female MPs and finally the gender of the person providing the data was sent in mid-March 2013 to six regional member organizations of IOMP, as well as contact points in many member countries. RESULTS: Sixty-six countries responded to the survey by mid-July 2013. Fifty two percent of those who filled the form were females, the rest males. The total number of MPs was 17,024, of which 28% were female (4807). The median values of percentages of females were 21% in the USA, 47% in Europe, 35% in Asia, 33% in Africa and 24% in Latin America. CONCLUSION: This is the first international survey that investigates the number and percentage of female MPs around the world. There are European countries that are far away from the target set by European Commission (40%) whereas in countries in the Middle East and Asia, female MPs actually outnumber males. This study is the first step in a more in-depth study that needs to be taken in near future. PMID- 25790724 TI - Protein type and caloric density of protein supplements modulate postprandial amino acid profile through changes in gastrointestinal behaviour: A randomized trial. AB - BACKGROUND & AIMS: The requirement of leucine and essential amino acids (EAA) to stimulate muscle protein synthesis increases with age. To target muscle anabolism it is suggested that higher postprandial blood levels of leucine and EAA are needed in older people. The aim was to evaluate the impact of oral nutritional supplements with distinct protein source and energy density, resembling mixed meals, on serum amino acid profiles and on gastrointestinal behaviour. METHODS: Four iso-nitrogenous protein (21 g) supplements were studied containing leucine enriched whey protein with 150/320 kcal (W150/W320) or casein protein with 150/320 kcal (C150/C320); all products contained carbohydrates (10 or 32 g) and fat (3 or 12 g). Postprandial serum AA profiles were evaluated in twelve healthy, older subjects who participated in a randomized, controlled, single blind, cross over study. Gastrointestinal behaviour was studied in vitro by looking at gastric coagulation and cumulative intestinal protein digestion over time. RESULTS: The peak serum leucine concentration was twofold higher for W150 vs. C150 (521 +/- 15 vs. 260 +/- 15 MUmol/L, p < 0.001), higher for W320 vs. C320 (406 +/- 15 vs. 228 +/- 15 MUmol/L, p < 0.001), and higher for low-caloric vs. high-caloric products (p < 0.001 for pooled analyses; p < 0.001 for interaction protein source*caloric density). Similar effects were observed for the peak concentrations of EAA and total AA (TAA). In vitro gastric coagulation was observed only for the casein protein supplements. Intestinal digestion for 90 min resulted in higher levels of free TAA, EAA, and leucine for W150 vs. C150, for W150 vs. W320, and for C150 vs. C320 (p < 0.0125). CONCLUSIONS: A low caloric leucine-enriched whey protein nutritional supplement provides a higher rise in serum levels of TAA, EAA and leucine compared to casein protein or high caloric products in healthy, elderly subjects. These differences appear to be mediated in part by the gastrointestinal behaviour of these products. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02013466. PMID- 25790725 TI - Efficacy of albendazole:beta-cyclodextrin citrate in the parenteral stage of Trichinella spiralis infection. AB - Albendazole-beta-cyclodextrin citrate (ABZ:C-beta-CD) inclusion complex in vivo antiparasitic activity was evaluated in the parenteral phase of Trichinella spiralis infection in mice. An equimolar complex of ABZ:C-beta-CD was prepared by spray-drying and tested in CBi-IGE male mice orally infected with L1 infective larvae. Infected animals were treated with 50 or 30mg/kg albendazole, (ABZ) equivalent amounts of the ABZ:C-beta-CD complex and non treated (controls). Mice received a daily dose on days 28, 29 and 30 post-infection. A week later, larval burden and percentage of encysted dead larvae were assessed in the host by counting viable and non-viable larvae in the tongue. Complexation of ABZ with C beta-CD increased the drug dissolution efficiency nearly eightfold. At 37 days p i, the reduction percentage in muscle larval load was 35% in mice treated with 50mg/kg/day ABZ and 68% in those given the complex. Treatment with the lower dose showed a similar decrease in parasite burden. Treated animals showed a high percentage of nonviable larvae, the proportion being significantly higher in mice receiving the complex than in control animals (72-88% vs. 11%, P=0.0032). These data indicate that ABZ:C-beta-CD increases bioavailability and effectiveness of ABZ against encapsulated Trichinella larvae, thus allowing the use of small doses. PMID- 25790726 TI - Removal of fluoride from aqueous solution using Zr(IV) immobilized cross-linked chitosan. AB - In the present paper, zirconium immobilized cross-linked chitosan (Zr-CCS) was reported for the adsorption of fluoride. Zr-CCS was synthesized by methods of membrane-forming and subsequent cross-linking reaction. Zr-CCS was characterized by FTIR, XRD, and SEM technologies. Batch adsorption experiments were performed to evaluate the adsorption capacity of Zr-CCS toward fluoride. The adsorption of fluoride onto the Zr-CCS favored at low pH values, and reduced in the presence of other co-anions. The adsorption equilibrium data had a good agreement with the Langmuir isotherm model, and the maximum adsorption capacity was calculated as 48.26mg/g for fluoride at 303K and natural pH (6.0). Thermodynamic parameters indicate that the nature of fluoride adsorption was spontaneous and endothermic. The adsorption mechanism of fluoride onto the Zr-CCS was controlled by chemical ion-exchange and electrostatic attraction between Zr-CCS and fluoride. PMID- 25790727 TI - Commercial single-walled carbon nanotubes effects in fibrinolysis of human umbilical vein endothelial cells. AB - Recent studies have demonstrated that carbon nanotubes (CNTs) induce platelet aggregation, endothelial dysfunction and vascular thrombosis. However, there is little information on the effects of CNTs on fibrinolysis. We investigated the role of pristine-commercial single-walled carbon nanotubes (SWCNTs) with <3% Co content in fibrinolysis and their contribution to the induction of pro-thrombotic processes in human vein endothelial cells (HUVEC). SWCNTs alone produced concentration-dependent oxidation, as measured by a dithiothreitol oxidation assay. Internalized SWCNTs were located in HUVEC treated with 25 MUg/ml using transmission electron microscopy, whereas treatment with 50 MUg/ml compromised cell viability, and oxidative stress increased significantly at 5 MUg/ml. The study showed that in HUVEC treated with 25 MUg SWCNT/ml, fibrinolysis-related gene expression and protein levels had increased by 3-12 h after treatment (serpine-1: 13-fold; PLAT: 11-fold and PLAU: 2-fold), but only the PAI-1 protein was increased (1.5-fold), whereas tissue and urokinase plasminogen activator proteins (tPA and uPA, respectively) tended to decrease. In summary, pristine SWCNTs treatment resulted in evident HUVEC damage caused by cell fiber contact, internalization, and oxidative stress due to contaminant metals. The generation of endothelial dysfunction, as shown by the altered expression of genes and proteins involved in fibrinolysis, suggest that SWCNTs display pro-thrombotic effects. PMID- 25790728 TI - Gold nanoparticles do not induce myotube cytotoxicity but increase the susceptibility to cell death. AB - Gold nanoparticles (AuNP) have been widely used for many applications, including as biological carriers. A better understanding concerning AuNP safety on muscle cells is crucial, since it could be a potential tool in the nanomedicine field. Here, we describe the impact of polyethylene glycol-coated gold nanoparticles (PEG-AuNP) interaction with differentiated skeletal muscle C2C12 cells on cell viability, mitochondria function, cell signaling related to survival, cytokine levels and susceptibility to apoptosis. Intracellular localization of 4.5 nm PEG AuNP diameter size was evidenced by STEM-in-SEM in myotube cells. Methods for cytotoxicity analysis showed that PEG-AuNP did not affect cell viability, but intracellular ATP levels and mitochondrial membrane potential increased. Phosphorylation of ERK was not altered but p-AKT levels reduced (p<0.01). Pre treatment of cells with PEG-AuNP followed by staurosporine induction increased the caspases-3/7 activity. Indeed, cytokines analysis revealed a sharp increase of IFN-gamma and TGF-beta1 levels after PEG-AuNP treatment, suggesting that inflammatory and fibrotic phenotypes process were activated. These data demonstrate that PEG-AuNP affect the myotube physiology leading these cells to be more susceptible to death stimuli in the presence of staurosporine. Altogether, these results present evidence that PEG-AuNP affect the susceptibility to apoptosis of muscle cells, contributing to development of safer strategies for intramuscular delivery. PMID- 25790729 TI - Evaluation of the effect of skin cleaning procedures on the dermal absorption of chemicals. AB - To reduce the internal exposure, skin decontamination is the most important measure after dermal contact to chemicals. However, no harmonized skin cleaning procedure for experimental ex vivo studies is published. In our study, the impact of two skin cleaning techniques on dermal penetration kinetics and intradermal deposition of 1,4-dioxane, 5% hydrofluoric acid (HF, detected in terms of fluoride ions), and anisole was evaluated to develop a reliable ex vivo skin cleaning method using the diffusion cell technique. After exposure (duration: 3 min (HF); 1h (1,4-dioxane and anisole)) of excised human skin (n=6-8) decontamination was performed by (I) water-soaked cotton swabs or (II) direct application of water on the exposure area. The effect of skin cleaning was investigated by analysing the concentration time course of chemicals in the receptor fluid of diffusion cells and by determining the deposition in skin. Both skin cleaning procedures reduced the amount of fluoride in the skin compartments (p<0.05) and the receptor fluid (p<0.1). However, the effect of cleaning on the dermal absorption of the organic test compounds was not significant. The results demonstrate the suitability of the applied ex vivo protocol for investigating the effectiveness of skin cleaning measures following dermal exposure. In addition, data reveal that the determination of test compounds in both, skin compartments as well as receptor fluid as equivalent for the systemic uptake needs to be considered in studies assessing the effectiveness of skin decontamination procedures. PMID- 25790731 TI - Seasonal clustering in inflammatory bowel disease: a single centre experience. AB - BACKGROUNDS AND AIMS: External stimuli are considered as possible triggers for the onset of inflammatory bowel disease (IBD), and particularly chronic ulcerative colitis (CUC) in genetically susceptible individuals. Our aims were to investigate monthly clustering-patterns in the onset of symptoms and diagnosis of IBD, as well as health seeking behavior in those individuals. MATERIALS AND METHODS: Two hundred and eighty-two consecutive patients with IBD were included. Onset of symptoms (month) and delay to diagnosis were analyzed. Kruskal-Wallis and Roger's test were used to analyze for statistical patterns in seasonal clustering. RESULTS: There were 181 males and 101 females with IBD; mean age: 40 +/- 14.7 years (median: 38, range: 14-79 years). The peak number of IBD cases was seen in winter/early spring, with the lowest numbers in autumn, which reached statistical significance in the CUC group (p: 0.029). Seasonal changes were not significantly affected by gender. The time delay to diagnosis from symptom onset was 3.0 +/- 2.3 months in males (median: 2, range: 0-12 months) vs 3.2 +/- 3.2 months (median: 2, range: 0-18 months) in females (not statistically significant). CONCLUSION: Our results show a seasonal relation in IBD cases, particularly in CUC, which may suggest external stimuli acting as a precipitant to IBD in susceptible individuals. There was a delay between symptom onset and CUC diagnosis, which was not felt to be clinically significant. PMID- 25790730 TI - Characterizing the interactions of organic nanoparticles with renal epithelial cells in vivo. AB - Nanotechnology approaches are actively being pursued for drug delivery, novel diagnostics, implantable devices, and consumer products. While considerable research has been performed on the effects of these materials on targeted tumor or phagocytic cells, relatively little is known about their effects on renal cells. This becomes critical for supersmall nanoparticles (<10 nm), designed to be renally excreted. The active endocytic machinery of kidney proximal tubules avidly internalizes filtered proteins, which may also be the case for filtered nanoparticles. To test whether such interactions affect kidney function, we injected mice with either 5 nm dextran-based nanoparticles (DNP) that are similar in composition to FDA-approved materials or poly(amido amine) dendrimer nanoparticles (PNP) of comparable size. These fluorescently tagged nanoparticles were both filtered and internalized by renal tubular epithelial cells in a dose- and time-dependent fashion. The biological effects were quantitated by immunocytochemistry, measuring kidney injury markers and performing functional tests. DNP administration resulted in a dose-dependent increase in urinary output, while cellular albumin endocytosis was increased. The expression of megalin, a receptor involved in albumin uptake, was also increased, but AQP1 expression was unaffected. The effects after PNP administration were similar but additionally resulted in increased clathrin expression and increased endocytosis of dextran. We conclude that there are no major detrimental renal effects of DNP on overall kidney function, but changes in endocytosis-mediating protein expression do occur. These studies provide a framework for the testing of additional nanoparticle preparations as they become available. PMID- 25790732 TI - Transmission characteristics and optimal diagnostic samples to detect an FMDV infection in vaccinated and non-vaccinated sheep. AB - We wanted to quantify transmission of FMDV Asia-1 in sheep and to evaluate which samples would be optimal for detection of an FMDV infection in sheep. For this, we used 6 groups of 4 non-vaccinated and 6 groups of 4 vaccinated sheep. In each group 2 sheep were inoculated and contact exposed to 2 pen-mates. Viral excretion was detected for a long period (>21 days post-inoculation, dpi). Transmission of FMDV occurred in the non-vaccinated groups (R0=1.14) but only in the first week after infection, when virus shedding was highest. In the vaccinated groups no transmission occurred (Rv<1, p=0.013). The viral excretion of the vaccinated sheep and the viral load in their pens was significantly lower than that of the non-vaccinated sheep. FMDV could be detected in plasma samples from 12 of 17 infected non-vaccinated sheep, for an average of 2.1 days, but in none of the 10 infected vaccinated sheep. In contrast, FMDV could readily be isolated from mouth swab samples from both non-vaccinated and vaccinated infected sheep starting at 1 3 dpi and in 16 of 27 infected sheep up till 21 dpi. Serologically, after 3-4 weeks, all but one of the infected sheep were detected using the NS-ELISA. We conclude that vaccination of a sheep population would likely stop an epidemic of FMDV and that the use of mouth swab samples would be a good alternative (instead of using vesicular lesions or blood samples) to detect an FMD infection in a sheep population both early and prolonged after infection. PMID- 25790733 TI - Comparison of three commercial one-dose porcine circovirus type 2 (PCV2) vaccines in a herd with concurrent circulation of PCV2b and mutant PCV2b. AB - Porcine circovirus associated disease (PCVAD) occurred in a farm where pigs had been routinely vaccinated with a commercial PCV2a vaccine. A mutant PCV2b (mPCV2b) was isolated from pigs with PCVAD, perhaps implying a perceived vaccine failure. The objective of this study was to determine and compare the efficacy of 3 one-dose PCV2a vaccines of varying antigen type and dose in the same pig farm with concurrent PCV2b and mPCV2b infection based on clinical (average daily weight gain; ADWG), virological (evidence of viremia), immunological (presence of PCV2-specific neutralizing antibody; NA and interferon-gamma secreting cells; IFN gamma-SC), and pathological (lymphoid lesion and PCV2 antigen score within lesion) evaluation. Regardless of which commercial PCV2a vaccine was used, vaccinated animals improved ADWG, and reduced the amount of PCV2b and mPCV2b load in the blood compared to unvaccinated animals. The vaccination of piglets at 3 weeks of age effectively induced higher levels of PCV2b- and mPCV2b-specific NA and IFN-gamma-SC compared to unvaccinated animals. A reduction in mPCV2b load in the blood coincided with the appearance of both mPCV2b-specific NA and IFN-gamma SC in the vaccinated animals. The microscopic lymphoid lesions and PCV2-antigen scores within the lymph nodes were significantly lower in vaccinated animals. The perceived vaccine failure could not be explained by incomplete protection of the commercial PCV2a vaccine against mPCV2b. The results of the present study demonstrated that currently available commercial PCV2a vaccines are protective against concurrent PCV2b and mPCV2b infection based on clinical, virological, immunological, and pathological evaluations under field conditions. PMID- 25790734 TI - Transgenerational effects from early developmental exposures to bisphenol A or 17alpha-ethinylestradiol in medaka, Oryzias latipes. AB - The transgenerational consequences of environmental contaminant exposures of aquatic vertebrates have the potential for broad ecological impacts, yet are largely uninvestigated. Bisphenol A (BPA) and 17alpha-ethinylestradiol (EE2) are two ubiquitous estrogenic chemicals present in aquatic environments throughout the United States and many other countries. Aquatic organisms, including fish, are exposed to varying concentrations of these chemicals at various stages of their life history. Here, we tested the ability of embryonic exposure to BPA or EE2 to cause adverse health outcomes at later life stages and transgenerational abnormalities in medaka fish. Exposures of F0 medaka to either BPA (100 MUg/L) or EE2 (0.05 MUg/L) during the first 7 days of embryonic development, when germ cells are differentiating, did not cause any apparent phenotypic abnormalities in F0 or F1 generations, but led to a significant reduction in the fertilization rate in offspring two generations later (F2) as well as a reduction of embryo survival in offspring three generations later (F3). Our present observations suggest that BPA or EE2 exposure during development induces transgenerational phenotypes of reproductive impairment and compromised embryonic survival in fish of subsequent generations. These adverse outcomes may have negative impacts on populations of fish inhabiting contaminated aquatic environments. PMID- 25790735 TI - Enhanced photocurrent production by bio-dyes of photosynthetic macromolecules on designed TiO2 film. AB - The macromolecular pigment-protein complex has the merit of high efficiency for light-energy capture and transfer after long-term photosynthetic evolution. Here bio-dyes of A. platensis photosystem I (PSI) and spinach light-harvesting complex II (LHCII) are spontaneously sensitized on three types of designed TiO2 films, to assess the effects of pigment-protein complex on the performance of bio-dye sensitized solar cells (SSC). Adsorption models of bio-dyes are proposed based on the 3D structures of PSI and LHCII, and the size of particles and inner pores in the TiO2 film. PSI shows its merit of high efficiency for captured energy transfer, charge separation and transfer in the electron transfer chain (ETC), and electron injection from FB to the TiO2 conducting band. After optimization, the best short current (JSC) and photoelectric conversion efficiency (eta) of PSI SSC and LHCII-SSC are 1.31 mA cm(-2) and 0.47%, and 1.51 mA cm(-2) and 0.52%, respectively. The potential for further improvement of this PSI based SSC is significant and could lead to better utilization of solar energy. PMID- 25790736 TI - Descemet membrane endothelial keratoplasty as treatment for graft failure after descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To investigate the outcome of Descemet membrane endothelial keratoplasty (DMEK) in patients with graft failure after Descemet stripping automated endothelial keratoplasty (DSAEK). DESIGN: Retrospective cohort study. METHODS: setting: Institutional. STUDY POPULATION: Fifteen eyes of 15 patients that underwent DMEK for graft failure with corneal decompensation following DSAEK were analyzed; 15 eyes with primary DMEK for Fuchs corneal dystrophy were included as control group. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), endothelial cell density (ECD), central corneal thickness (CCT), and rebubbling rate. RESULTS: DMEK surgery was successful in all cases of both groups. Mean BCVA (logMAR) before DMEK was 1.27 +/- 0.34 in the DMEK after DSAEK group and 1.0 +/- 0.40 in the Primary DMEK group. After DMEK, mean BCVA increased significantly to 0.23 +/- 0.21 (P = .012, DMEK after DSAEK group) and 0.29 +/- 0.23 (P = .042, Primary DMEK group) after 3 months. There were no significant differences in mean BCVA between both groups at each visit. The rebubbling rate was 13% in the DMEK after DSAEK group and 40% in the Primary DMEK group (P = .1). Mean CCT decreased significantly in both groups 1 month after DMEK (P < .05). Mean ECD and change of ECD did not differ significantly between both groups at each visit (P > .05). CONCLUSION: The results after DMEK as a procedure to treat graft failure after DSAEK were as good as in patients that underwent DMEK as primary intervention to treat advanced Fuchs dystrophy. This indicates that the optical quality can be reestablished by DMEK in patients with failed DSAEK. PMID- 25790738 TI - IPSET-Thrombosis Better Identifies Thrombosis-Free Survival: A Turkish Cohort. AB - INTRODUCTION: Essential thrombocythemia (ET) is the most common of the myeloproliferative neoplasms. For better predicting the occurrence of thrombotic events, an International Prognostic Score of Thrombosis for ET (IPSET-Thrombosis) was recently developed. We aimed to investigate the validity of IPSET-Thrombosis in a Turkish patient cohort and to compare the efficacy of IPSET-Thrombosis and conventional risk scoring systems in predicting thrombosis-free survival. PATIENTS AND METHODS: We retrospectively evaluated the clinical characteristics and risk factors for thrombosis in 112 Turkish patients. Median thrombosis-free survival and Harrell C concordance indexes were calculated for both conventional and IPSET-Thrombosis. RESULTS: Median age of 112 patients included in the study was 61 (range, 27-90) years at the time of diagnosis. When patients were stratified according to the conventional risk stratification system, 43.8% of patients were in the low-risk group and 56.2% in the high-risk group. A total of 22.4% of low-risk and 42.9% of high-risk patients had at least one thromboembolic event. When patients were stratified according to the IPSET-Thrombosis, 33% were in the low-risk group, 26.8% in the intermediate-risk group, and 40.2% in the high-risk group. Considering IPSET-Thrombosis risk groups, 5.4% of low-risk, 26.7% of intermediate-risk, and 66.2% of high-risk patients had at least one thromboembolic event. Regarding IPSET-Thrombosis risk groups, 10-year thrombosis free survival was 86.8% for low-risk, 39.4% for intermediate-risk, and 32.9% for high-risk groups (P < .001). Harrell C concordance indexes of conventional and IPSET-Thrombosis were 0.60 and 0.77, respectively. CONCLUSION: By validating the reproducibility of IPSET-Thrombosis in Turkish ET patients, we found that IPSET Thrombosis identifies thrombosis-free survival better than the conventional risk stratification system. PMID- 25790737 TI - Luminal and stromal areas of choroid determined by binarization method of optical coherence tomographic images. AB - PURPOSE: To determine the proportion of luminal and stromal areas of normal choroids in the optical coherence tomographic (OCT) images obtained by enhanced depth imaging (EDI)-OCT. DESIGN: A prospective, masked, observational cross sectional study. METHODS: setting: This study was performed at the Kagoshima University Hospital, Japan. STUDY POPULATION: One hundred and eighty right eyes of 180 healthy volunteers (106 women; mean age of 55.9 years) without ocular pathology. observational procedures: The EDI-OCT images of the posterior choroid 7500 MUm from the optic disc in the horizontal plane were converted to binary images. The total cross-sectional choroidal area, luminal area, and stromal area of the choroid were measured. MAIN OUTCOME MEASURES: Correlations between clinical factors and each choroidal structure and ratio of luminal/stromal areas were determined. The correlations of each choroidal structure and the age, sex, axial length (AL), and refractive errors were calculated. RESULTS: The mean total cross-sectional choroidal area was 1.84 mm(2) (luminal area 1.21 mm(2) and stromal area 0.63 mm(2)). Multivariate analysis (standardized partial regression coefficient) showed that age (-0.723, P < .001) was significantly correlated with the reduced area of the choroid, and the correlation was greater than that for the AL (-0.408, P < .001). The ratio of luminal/stromal area was significantly reduced in eyes with longer ALs (-0.531, P < .001), and the strength of the correlation was greater than that of age (-0.389, P < .001). CONCLUSIONS: Although both the luminal and the stromal areas decrease with increasing age and with longer ALs, the degree of decrease and areas affected were not the same. PMID- 25790739 TI - [Trastuzumab emtansine (Kadcyla((r))) approval in HER2-positive metastatic breast cancers]. AB - HER2 (human epidermal growth factor receptor 2) is overexpressed in 15 to 20% of breast cancer. Anti-HER2 targeted therapies, notably trastuzumab, have transformed the natural history of this disease. Trastuzumab emtansine, consisting of trastuzumab coupled to a cytotoxic agent, emtansine (DM1), by a stable linker, has been approved in November 2013 by the European Medicine Agency. Trastuzumab emtansine targets and inhibits HER2 signaling, but also allows emtansine to be directly delivered inside HER2-positive cancer cells. It is indicated as single-agent in taxane and trastuzumab-pretreated HER2-positive breast cancer patients with metastatic and locally recurrent unresecable disease or relapsing within 6 months of the end of adjuvant therapy. This indication is based on the results of the EMILIA study, an open label phase III randomized trial comparing trastuzumab emtansine to lapatinib-capecitabine. The two primary endpoints were reached. The progression-free survival was 6.4 months in the lapatinib-capecitabine arm versus 9.6 months for the trastuzumab emtansine arm (HR=0.65; 95% CI=0.55-0.77, P<0.001). Overall survival at the second interim analysis was 25.1 months in the lapatinib-capecitabine arm versus 30.9 months in the trastuzumab emtansine arm (HR=0.68; 95% CI=0.55-0.85, P<0.001). Moreover, adverse events were more frequent in the lapatinib-capecitabine arm. PMID- 25790740 TI - [The impact of gynaecological cancers on woman's sexuality and her couple]. AB - This article, devoted specifically to gynaecological cancers and their impact on the sexual and marital lives, is a collaboration between the psychologists and onco-gynaecologist within a cancer center. In oncology, gynaecological cancers' treatments involve at the same time anatomical, physiological and functional modifications impacting, in a major way, on the sexual life of women. All the phases of the sexual answer can be touched. Beyond the physical and aesthetic consequences of the treatments, the sexual dysfunctions are generally caused by the deep psychological upheaval induced by the disease affecting a strongly invested female body. Female cancer is also a true test for the couple challenged in its emotional, functional and sexual cohesion: emotional distress, attachment link dysfunction, change of role within the couple, disordered state of communication. The couple cannot survive and find a harmonious intimate life without communication about sexual health between the medical team, the patient and her partner. All doctors and nurses must be able to initiate the subject throughout the course of care by respecting four prerequisites: to be aware of the importance to approach this subject, to create a climate of trust, to dare the questions and to respect the rhythm of the patient and her partner. PMID- 25790741 TI - Implant survival rates, marginal bone level changes, and complications in full mouth rehabilitation with flapless computer-guided surgery: a systematic review and meta-analysis. AB - This systematic review evaluated the implant survival rate, changes in marginal bone level, and complications associated with guided surgery for the treatment of fully edentulous patients followed up for longer than 1 year. A comprehensive literature search was conducted in MEDLINE/PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) to retrieve studies published up until July 2014 that met predefined eligibility criteria. Thirteen studies were included. In studies on the guided surgery technique, a survival rate of 97.2% and a mean marginal bone loss of 1.45 mm were found during 1-4 years of follow up. However, associated complications, such as implant loss, prosthesis or surgical guide fractures, and low primary stability, were often found, and there is a learning curve to achieve treatment success. Further longitudinal comparative studies should improve the technique and its success rate. PMID- 25790742 TI - Cost Efficacy of Metal Stents for Palliation of Extrahepatic Bile Duct Obstruction in a Randomized Controlled Trial. AB - BACKGROUND & AIMS: Endoscopic stents are placed for palliation of extrahepatic bile duct obstruction. Although self-expandable metal stents (SEMS) remain patent longer than plastic stents, they are more expensive. We aimed to evaluate which type of stent (plastic, uncovered SEMS [uSEMS], or partially covered SEMS [pcSEMS]) is the most effective and we assessed costs. METHODS: We performed a multicenter randomized trial in 219 patients at 18 hospitals in The Netherlands from February 2008 through February 2013. Patients were assigned randomly for placement of a plastic stent (n = 73), uSEMS (n = 75), or pcSEMS (n = 71) during endoscopic retrograde cholangiopancreatography. Patients were followed up for up to 1 year. Researchers were not blinded to groups. The main study end points included functional stent time and costs. RESULTS: The mean functional stent times were 172 days for plastic stents, 288 days for uSEMS, and 299 days for pcSEMS (P < .005 for uSEMS and pcSEMS vs plastic). The initial placement of plastic stents (?1042 or $1106) cost significantly less than placement of SEMS (?1973 or $2094) (P = .001). However, the total cost per patient at the end of the follow-up period did not differ significantly between plastic stents (?7320 or $7770) and SEMS (?6932 or $7356) (P = .61). Furthermore, in patients with short survival times (<=3 mo) or metastatic disease, the total cost per patient did not differ between plastic stents and SEMS. No differences in costs were found between pcSEMS and uSEMS. CONCLUSIONS: Although placement of SEMS (uncovered or partially covered) for palliation of extrahepatic bile duct obstruction initially is more expensive than placement of plastic stents, SEMS have longer functional time. The total costs after 1 year do not differ significantly with stent type. Dutch Clinical Trial Registration no: NTR1361. PMID- 25790743 TI - Mesenchymal Stem Cells Reduce Colitis in Mice via Release of TSG6, Independently of Their Localization to the Intestine. AB - BACKGROUND & AIMS: Mesenchymal stem cells (MSCs) are pluripotent cells that can promote expansion of immune regulatory cells and might be developed for the treatment of immune disorders, including inflammatory bowel diseases. MSCs were reported to reduce colitis in mice; we investigated whether MSC localization to the intestine and production of paracrine factors, including tumor necrosis factor-induced protein 6 (TSG6), were required for these effects. METHODS: MSCs were isolated from bone marrow (BM-MSCs) of 4- to 6-week-old C57BL/6, C57BL/6 green fluorescent protein, or Balb/c Tsg6-/- male mice. Colitis was induced by ad libitum administration of dextran sulfate sodium for 10 days; after 5 days the mice were given intraperitoneal injections of BM-MSCs or saline (controls). Blood samples and intestinal tissues were collected 24, 48, 96, and 120 hours later; histologic and flow cytometry analyses were performed. RESULTS: Injection of BM MSCs reduced colitis in mice, increasing body weight and reducing markers of intestinal inflammation, compared with control mice. However, fewer than 1% of MSCs reached the inflamed colon. Most of the BM-MSCs formed aggregates in the peritoneal cavity. The aggregates contained macrophages and B and T cells, and produced immune-regulatory molecules including FOXP3, interleukin (IL)10, transforming growth factor-beta, arginase type II, chemokine (C-C motif) ligand 22 (CCL22), heme oxygenase-1, and TSG6. Serum from mice given BM-MSCs, compared with mice given saline, had increased levels of TSG6. Injection of TSG6 reduced the severity of colitis in mice, along with the numbers of CD45+ cells, neutrophils and metalloproteinase activity in the mucosa, while increasing the percentage of Foxp3CD45+ cells. TSG6 injection also promoted the expansion of regulatory macrophages that expressed IL10 and inducible nitric oxide synthase, and reduced serum levels of interferon-gamma, IL6, and tumor necrosis factor. Tsg6-/- MSCs did not suppress the mucosal inflammatory response in mice with colitis. CONCLUSIONS: BM-MSCs injected into mice with colitis do not localize to the intestine but instead form aggregates in the peritoneum where they produce immunoregulatory molecules, including TSG6, that reduce intestinal inflammation. TSG6 is sufficient to reduce intestinal inflammation in mice with colitis. PMID- 25790745 TI - Evaluation of the Utility of in utero Treatment of Twin Anemia-Polycythemia Sequence. AB - OBJECTIVE: The aim of this study is to evaluate the interest in the in utero treatment of twin anemia-polycythemia sequence (TAPS). METHODS: The obstetrical and neonatal data on all cases of TAPS followed up in our institution between 2006 and 2013 were reviewed. Statistical analyses were conducted using Bayesian methods. RESULTS: Twenty cases of TAPS were included. Laser therapy or intrauterine transfusion (IUT) was performed on the donor twin in 9 cases. Eleven cases were included in the 'nontreated' group (managed expectantly or diagnosed at birth). The gestational age at diagnosis was lower in the group with treated TAPS [difference (diff) = -22.20 days (-57.13, 14.28), probability (Pr) (diff >0) = 10.6%]. The rate of preterm premature rupture of membranes was higher in the group with treated TAPS [diff = 22.5% (-14, 57), Pr (diff >0) = 89%], but overall mortality was similar. The interval between diagnosis and delivery was longer [diff = 44.37 days (9.41, 77.90), Pr (diff >0) = 99.2%], the TAPS resolution rate was higher [diff = 49.9% (12, 81), Pr (diff >0) = 99.4%], and the neonatal transfusion rate was lower [diff = -30.5% (-60, 0), Pr (diff >0) = 2.6%] in the treated group. CONCLUSION: In utero treatment for TAPS is associated with a higher resolution rate of TAPS and a longer time between diagnosis and birth, but overall mortality is the same as with expectant management. PMID- 25790744 TI - Effect of Leflunomide, Cidofovir and Ciprofloxacin on replication of BKPyV in a salivary gland in vitro culture system. AB - BK polyomavirus (BKPyV) is a known kidney tropic virus that has been detected at high levels in HIV-associated salivary gland disease (HIV-SGD), one of the most important AIDS associated oral lesions. BKPyV has been detected in HIV-SGD patient saliva and replicates in salivary gland cells in vitro. BKPyV antivirals are currently in wide use to guard against BKPyV mediated organ rejection in kidney transplant recipients. The goal of this study was to investigate the inhibitory effects of three such antiviral agents, Ciprofloxacin, Cidofovir, and Leflunomide in BKPyV infected salivary gland cells. Human salivary gland cells, and Vero cells, were infected with BKPyV, treated with antiviral drugs and assessed for BKPyV gene expression and viral replication for up to 5 days post infection. The kinetics of BKPyV replication were different in salivary gland cells compared to kidney cells. Ciprofloxacin and Cidofovir had minimal effect on metabolic activity and host cell DNA replication, however, cell toxicity was detected at the protein level with Leflunomide treatment. Ciprofloxacin decreased BKV T Ag and VP1 mRNA expression by at least 50% in both cell types, and decreased T Ag protein expression at days 3 and 4 post infection. A 2.5-4 log decrease in intracellular DNA replication and a 2-3 log decrease in progeny release were detected with Ciprofloxacin treatment. Cidofovir and Leflunomide also inhibited BKPyV gene expression and DNA replication. The three drugs diminished progeny release by 30-90% and 2- to 6-fold decreases in infectious virus were detected post drug treatment by fluorescence focus assay. Additionally, three clinical BKPyV isolates were assessed for their responses to these agents in vitro. Cidofovir and Leflunomide, but not Ciprofloxacin treatment resulted in statistically significant inhibition of BKPyV progeny release from salivary gland cells infected with HIVSGD BKPyV isolates. All three drugs decreased progeny release from cells infected with a transplant derived viral isolate. In conclusion, treatment of human salivary gland cells with each of the three drugs produced modest decreases in BKPyV genome replication. These data highlight the need for continued studies to discover more effective and less toxic drugs that inhibit BKPyV replication in salivary gland cells. PMID- 25790746 TI - Influence of carbohydrate mouth rinsing on running and jumping performance during early morning soccer scrimmaging. AB - Carbohydrate mouth rinse (CMR) is a novel method proposed to enhance endurance performance lasting <= 60 min. The current study examined the influence of CMR on anaerobic performance tasks in 11 collegiate female soccer players after an overnight fast. Athletes completed two experimental sessions, during which carbohydrate (CHO; 6% maltodextrin) or taste- and colour-matched placebo (PLA) mouth-rinse solutions were administered in a counterbalanced, double-blinded design. Three rounds of a 5-min scrimmage bout and series of performance tests including a single countermovement vertical jump (1VJ), a set of four consecutive vertical jumps, a 72-m shuttle run (SR72) and 18-m sprint comprised each trial. Thirst sensation (TS), session TS, ratings of perceived exertion (RPE) and session RPE were assessed as secondary outcomes. The first SR72 approached significance (p = 0.069), but no significant between-trials differences were observed for any of the mean performance tasks. The highest 1VJ scores did not differ for the first (CHO = 47.3 +/- 3.4, PLA = 47.7 +/- 3.5 cm; p = 0.43), second (CHO = 48.0 +/- 4.1, PLA = 47.9 +/- 3.5 cm; p = 0.82) or third bout (CHO = 47.4 +/- 3.9, PLA = 48.1 +/- 3.9 cm; p = 0.26). TS approached significance (p = 0.053) during the first bout. No significant differences (p > 0.05) were found for any of the perceptual variables. Current results fail to support ergogenic influence of CMR on anaerobic performance tasks in collegiate female athletes. PMID- 25790747 TI - Effect of cross-sex hormone treatment on cardiovascular risk factors in transsexual individuals. Experience in a specialized unit in Catalonia. AB - BACKGROUND AND AIMS: Since the onset of cross hormone therapy (CHT) in transsexual individuals, there has been concern about possible chronic side effects. Our objective was to assess baseline differences in lipid profile in individuals with gender identity disorder in relation to prior CHT, and changes in the lipid profile and other cardiovascular (CV) risk factors after 24 months of treatment. METHODS: Retrospective longitudinal study including all individuals assisted for the first time in the Gender Identity Unit of Catalonia from 2006 to 2010. Socio-demographical, anthropometric and laboratory data were collected. RESULTS: We evaluated 247 transsexuals, 150 male to female (MtF: 60.7%) and 97 female to male (FtM; 39.3%). At baseline, FtM transsexuals were younger and had started prior CHT less often than MtF (13.4% vs. 64.7%; p<0.001). During follow up, in MtF weight and BMI increased significantly, as well as systolic and diastolic blood pressure, though these latter remained within normal range. No significant differences in lipid profile were observed. FtM transsexuals also presented an increase in weight and BMI, without differences in blood pressure. A general worsening in lipid profile was observed in this group, with increased total cholesterol (166.0 +/- 35.1 vs. 175.6 +/- 38.2mg/dL; p=0.001), triglycerides (70.6 +/- 30.7 vs. 102.3 +/- 68.5 mg/dL; p<0.001) and LDL cholesterol (103.8 +/- 28.7 vs. 112.8 +/- 30.3 mg/dL; p=.013) and decreased HDL cholesterol (52.2 +/- 12.2 vs. 45.4 +/- 13.8 mg/dL; p=0.001), even though final levels were all within normal range. CONCLUSION: There is no detectable increase in CV risk factors in MtF transsexuals who were treated with currently prescribed estrogenic compounds, while a slight worsening in lipid profile takes place in the FtM group, though within normal limits. PMID- 25790748 TI - Estrogen regulates the expression of small-conductance Ca-activated K+ channels in colonic smooth muscle cells. AB - AIM: This study aimed to determine the effects of small-conductance Ca(2+) activated K(+) (SK) channels in colonic relaxation and the regulation of SK channels by estrogen. METHODS: The contractile activity of muscle strips from male rats was estimated, and drugs including vehicle (DMSO), 17beta-estradiol (E2), or apamin (SK blocker) were added, respectively. In a further experiment, muscle strips were preincubated with apamin before exposure to E2. The levels of the SK2 and SK3 protein expression in the colonic smooth muscle cells (SMCs) were detected. SMCs were treated with ICI 182780 (estrogen receptor [ER] antagonist) plus E2, BSA-E2, PPT (ERalpha agonist), or DPN (ERbeta agonist). SK3 mRNA and protein expression levels were detected. RESULTS: The muscle strips responded to E2 with a decrease and to apamin with a transient increase in tension. Preincubation with apamin partially prevented E2-induced relaxation. Two SK channel subtypes, SK2 and SK3, were coexpressed with alpha-actin in colonic SMCs. The quantitative ratio of the SK transcriptional expression in colonic SMCs was SK3 > SK2. The SK3 expression was upregulated by E2, and was downregulated by ICI 182780, but was not influenced by BSA-E2. Furthermore, the effect of PPT on the expression of SK3 was almost the same as that of E2, while DPN did not influence the protein expression of SK3. CONCLUSION: These findings indicate that SK3 is involved in the E2-induced relaxing effect on rat colonic smooth muscle. Furthermore, E2 upregulates the expression of SK3 in rat SMCs, and that this effect is mediated via the ERalpha receptor. PMID- 25790749 TI - Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells are selectively destroyed. beta cell-specific T cells are considered to be the major mediators of pathology. Accordingly, most immunotherapies tested in the clinic to date have focused on reestablishing self-tolerance within the T cell compartment. Monoclonal antibodies (Ab) targeting a variety of lymphocyte surface proteins have demonstrated benefits in preclinical and clinical settings. Indeed, the use of Ab to target T cells directly or indirectly has proven to be an effective strategy to rapidly suppress beta cell autoimmunity and establish tissue-specific, long-term tolerance in rodent T1D models. In this review, we describe a number of these Ab-based immunotherapies, discuss associated immune regulatory mechanisms, and highlight results obtained in T1D clinical trials. PMID- 25790750 TI - Graft diameter does not influence primary stability of ulnar collateral ligament reconstruction of the elbow. AB - BACKGROUND: Ulnar collateral ligament insufficiency may result in medial elbow pain, instability, and reduced athletic performance in throwing athletes. Several reconstruction methods have been described, but biomechanical studies suggest that in general, stability of the graft construct is inferior to the native ulnar collateral ligament. This study investigates whether a stronger graft would yield greater resistance to valgus load over the range of motion. METHODS: Ten cadaveric elbows were mounted to a testing fixture and incremental valgus moments of 2.5, 5, and 7.5 Nm were applied with the elbow in 120 degrees , 90 degrees , 60 degrees , 30 degrees and 0 degrees of flexion and in varying rotational forearm positions. The intact and the ulnar collateral ligament released elbow joint were compared with the docking ulnar collateral ligament reconstruction technique, using different graft sources with increasing cross-sectional areas: palmaris longus, tricpes brachii, extensor carpi radialis longus, and semitendinosus. The resulting angular displacement was evaluated and compared between graft sources and different elbow positions. RESULTS: Compared with the intact situation, ulnar collateral ligament release resulted in a significant increase in valgus deformation over the entire range of flexion-extension motion. Ligament reconstruction using any graft source significantly restored valgus stability at 60 degrees , 90 degrees , and 120 degrees , while at 0 degrees and 30 degrees , angular valgus deformation did not significantly differ from the ulnar collateral ligament deficient situation. There were no significant differences in angular valgus deformation between the graft sources over the range of flexion motion or forearm rotation. CONCLUSIONS: This study did not prove that a thicker graft yielded more resistance to valgus moments when using the docking technique. Thicker grafts require larger bone tunnels, cannot be adequately tensioned, and are non-anatomic. Therefore, the palmaris longus or a triceps tendon strip are considered more appropriate for ulnar collateral ligament reconstruction. PMID- 25790751 TI - CARD8 rs2043211 polymorphism is associated with gout in a Chinese male population. AB - BACKGROUND &AIM: Previous studies have suggested genetic factors are involved in the development of gout. We performed a case-control study to investigate the genetic association between CARD8 rs2043211 polymorphism and gout. METHODS: A total of 396 male patients with gout and 403 age- and sex- matched healthy controls were included in this study. Genotyping was performed using TaqMan SNP Genotyping Assays. An association analysis was carried out using the chi2 test. The genotype-phenotype analysis was also conducted. RESULTS: The genotype distribution of CARD8 rs2043211 polymorphism confirmed to HWE in the controls (P = 0.27). There was an obvious difference in the genotype distribution of CARD8 rs2043211 polymorphism between cases and controls (P = 0.017). In addition, there was an obvious association between CARD8 rs2043211 polymorphism and gout under the recessive comparison model (AA vs. TT/TA: OR = 0.65, 95%CI 0.47-0.88, P = 0.006). Patients carrying genotype TT of CARD8 rs2043211 polymorphism had higher triglycerides levels compared to those carrying the AA genotype (2.77+/-2.08 mmol/L vs. 2.07+/-1.15 mmol/L, P = 0.01). Patients with the TT genotype also had significantly higher systolic blood pressure compared with those with the AA genotype (142.11+/-21.10 mmHg vs. 135.38+/-14.66 mmHg, P = 0.03). Patients carrying TT genotype also had an increased risk of renal calculus compared with those carrying the AA genotype. CONCLUSION: CARD8 rs2043211 polymorphism is significantly associated with susceptibility to gout in Chinese Han males. PMID- 25790752 TI - Clustered distribution of natural product leads of drugs in the chemical space as influenced by the privileged target-sites. AB - Some natural product leads of drugs (NPLDs) have been found to congregate in the chemical space. The extent, detailed patterns, and mechanisms of this congregation phenomenon have not been fully investigated and their usefulness for NPLD discovery needs to be more extensively tested. In this work, we generated and evaluated the distribution patterns of 442 NPLDs of 749 pre-2013 approved and 263 clinical trial small molecule drugs in the chemical space represented by the molecular scaffold and fingerprint trees of 137,836 non-redundant natural products. In the molecular scaffold trees, 62.7% approved and 37.4% clinical trial NPLDs congregate in 62 drug-productive scaffolds/scaffold-branches. In the molecular fingerprint tree, 82.5% approved and 63.0% clinical trial NPLDs are clustered in 60 drug-productive clusters (DCs) partly due to their preferential binding to 45 privileged target-site classes. The distribution patterns of the NPLDs are distinguished from those of the bioactive natural products. 11.7% of the NPLDs in these DCs have remote-similarity relationship with the nearest NPLD in their own DC. The majority of the new NPLDs emerge from preexisting DCs. The usefulness of the derived knowledge for NPLD discovery was demonstrated by the recognition of the new NPLDs of 2013-2014 approved drugs. PMID- 25790753 TI - The survival benefit of dual dispatch of EMS and fire-fighters in out-of-hospital cardiac arrest may differ depending on population density--a prospective cohort study. AB - BACKGROUND: Outcome after out-of-hospital cardiac arrest (OHCA) varies between contexts. Dual dispatching of fire-fighters or police in addition to emergency medical services (EMS) has the potential to increase survival, but the effect in urban vs. rural areas is unknown. The aim of this study was to determine the effects of dual dispatching on response times and outcome in regions with different population density. METHODS AND RESULTS: The study design was a prospective cohort study of EMS-treated OHCAs from 2004 (historical controls, only EMS dispatch) and 2006-2009 (intervention, dual dispatch of EMS and fire fighters), with data on exact geographical coordinates. Patients were divided into four subgroups depending on population density: rural (<250 persons/km2), suburban (250-2999/km2), urban (3000-5999/km2) and downtown (>=6000/km2). Totally, 2513 OHCAs were included (historical controls, n=571 and intervention, n=1942). Median time to arrival of first unit shortened significantly in all subgroups, ranging from 0.8 to 3.2 min, with the main time gain in the rural area. There were significant differences in 30-day survival between the historical controls vs. the intervention group in the suburban population (3.1% vs. 7.0%, p=0.02) and in downtown (4.1 vs. 14.6, p=0.04). In the urban population the difference was 2.7 vs. 6.9% (p=0.06) and in the rural population (4.7 vs. 5.3, p=0.82). CONCLUSIONS: Dual dispatch of fire-fighters and EMS in OHCA significantly reduced response times in all studied regions. The 30-day survival increased significantly in the downtown and suburban populations, while a limited impact was seen in the rural areas. PMID- 25790754 TI - Reply to Letter: 'Benefits of simulation based training manuscript'. PMID- 25790755 TI - Improper Reprocessing of Neonatal Resuscitation Equipment in rural Kenya compromises function: Recommendations for more effective implementation of Helping Babies Breathe. PMID- 25790756 TI - HCV glycoprotein structures: what to expect from the unexpected. AB - Hepatitis C virus (HCV) is continuing to spread worldwide, adding three million new infections each year. Currently approved therapies are highly effective; however, access to them is limited due to the high cost of treatment. Therefore, a cost effective vaccine and alternative antivirals remain essential. HCV envelope glycoproteins, E1 and E2, heterodimerize on the virion surface and are the major determinant for virus pathogenicity and host immune response. Recent structural insights into amino-terminal domain of E1 and core of E2 have revealed unexpected folds not present in glycoproteins from related viruses. Here we discuss these structural findings with respect to their role in HCV entry and impact on potential vaccine design and new antivirals. PMID- 25790758 TI - NTangled. PMID- 25790759 TI - Technical difficulties due to poor acoustic insonation during transcranial Doppler recordings in Amerindians and individuals of European origin. A comparative study. AB - BACKGROUND: There is no information on transcranial Doppler (TCD) failures due to poor insonation among native inhabitants of Latin America. METHODS: Seventy Ecuadorian natives and 70 age- and sex-matched individuals of European origin underwent TCD. The same investigators performed all exams using the same equipment and protocol. Using the McNemar's test for correlated proportions, we compared TCD failures related to poor insonation across ethnic groups. RESULTS: Out of 140 participants, 56 (40%) had one or more suboptimal/absent acoustic windows. These persons were older (p = 0.01) and were more often women (p < 0.0001) than those with all optimal windows (irrespective of race/ethnicity). In the matched-pair analysis, Amerindians were more likely to have suboptimal/absent acoustic windows than individuals of European origin (OR: 2.8, 95% CI: 1.3-6.5, p = 0.006). CONCLUSION: Amerindians are almost three times more likely to have insonation failures related to poor acoustic windows than their European counterparts. PMID- 25790757 TI - RNA regulators of host immunity and pathogen adaptive responses in the oral cavity. AB - The recent explosion of RNA-seq studies has resulted in a newfound appreciation for the importance of riboregulatory RNAs in the posttranscriptional control of eukaryotic and prokaryotic genetic networks. The current review will explore the role of trans-riboregulatory RNAs in various adaptive responses of host and pathogen in the oral cavity. PMID- 25790760 TI - The impact of commercialisation and genetic data sharing arrangements on public trust and the intention to participate in biobank research. AB - OBJECTIVES: The necessity for biobanks to share their resources with third parties poses potential risks to public trust and the intention to participate in genetic research. We explore the effects of data sharing and the type of third party access (public vs. private) on public trust and, in turn, the intention to participate in biobank research. METHODS: An experimental design was used to assess a national sample of 1,701 Australians via a computer-assisted telephone interview. RESULTS: The results revealed that trust and the intention to participate significantly decreased in relation to private compared to public biobanks, and when access to third-party researchers was allowed compared to when it was not. Somewhat surprisingly, no differences were found in relation to the third party being international compared to Australian, but trust and the intention to participate were significantly eroded when private third parties were allowed access. Those with a university education were particularly distrustful of private biobanks and biobanks that allowed access, while those who were more aware of genetic databases appeared more confident with biobanks sharing with private-sector third parties. CONCLUSION: The pattern of results suggests that public awareness of the need for biobanks to share their resources widely needs to be increased to maintain public trust and support. PMID- 25790761 TI - Calcium plus vitamin D supplementation affects pregnancy outcomes in gestational diabetes: randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: The present study was designed to assess the effects of Ca+vitamin D supplementation on pregnancy outcomes in women with gestational diabetes mellitus (GDM). DESIGN: A randomized, double-blind, placebo-controlled trial was conducted among sixty women with GDM. Participants were divided into two groups to receive Ca+vitamin D supplements or placebo. Individuals in the Ca+vitamin D group (n 30) received 1000 mg Ca/d and two pearls containing 1250 ug (50 000 IU) of cholecalciferol (vitamin D(3)) during the intervention (one at study baseline and another at day 21 of the intervention); those in the placebo group (n 30) received two placebos of vitamin D at the mentioned times and placebos of Ca every day for 6 weeks. Pregnancy outcomes were determined. SETTING: A urban community setting in Arak, Iran. SUBJECTS: Sixty women with GDM and their newborns, living in Arak, Iran were enrolled. RESULTS: Women treated with Ca+vitamin D had a significant decrease in caesarean section rate (23.3 % v. 63.3 %, P=0.002) and maternal hospitalization (0 v. 13.3 %, P=0.03) compared with those receiving placebo. In addition, newborns of GDM women randomized to Ca+vitamin D had no case of macrosomia, while the prevalence of macrosomia among those randomized to placebo was 13.3 % (P=0.03). Lower rates of hyperbilirubinaemia (20.0 % v. 56.7 %, P=0.03) and hospitalization (20.0 % v. 56.7 %, P=0.03) were also seen in the supplemented group of newborns than in the placebo group. CONCLUSIONS: Ca+vitamin D supplementation for 6 weeks among pregnant women with GDM led to decreased caesarean section rate and maternal hospitalization, and decreased macrosomia, hyperbilirubinaemia and hospitalization in newborns. PMID- 25790762 TI - Pyrimidine-based functional fluorescent organic nanoparticle probe for detection of Pseudomonas aeruginosa. AB - A pyrimidine-based sensor () has been synthesized through the facile one pot reaction of pyrrole-2-carboxaldehyde, 2-aminobenzimidazole and 1, 3 dimethylbarbituric acid in methanol using a few drops of HCl as a catalyst. Further, compound was fabricated into its fluorescent organic nanoparticles (FONPs) and characterized using DLS and SEM. The photophysical evaluation of the FONPs was done against bacteria and fungi. It was observed that the fluorescence intensity of the FONPs was selectively enhanced in the presence of the Gram -ve bacterium Pseudomonas aeruginosa with a detection limit of 46 CFU. To the best of our knowledge, this study is the first report on the use of the FONPs of pyrimidine derivative for the detection of Pseudomonas aeruginosa in various samples. PMID- 25790763 TI - The impact of downstream coronary stenosis on fractional flow reserve assessment of intermediate left main coronary artery disease: human validation. AB - OBJECTIVES: The aim of this study was to determine the impact of downstream coronary stenosis in the left anterior descending coronary artery (LAD) or left circumflex coronary artery (LCx) on the assessment of fractional flow reserve (FFR) across an intermediate left main coronary artery (LMCA) stenosis in humans with the pressure wire positioned in the nondiseased downstream vessel. BACKGROUND: Accurate assessment of intermediate LMCA disease is critical for guiding decisions regarding revascularization. In theory, FFR across an intermediate LMCA stenosis will be affected by downstream disease, even if the pressure wire is positioned in the nondiseased downstream vessel. METHODS: After percutaneous coronary intervention of the LAD, LCx, or both, an intermediate LMCA stenosis was created with a deflated balloon catheter. FFR was measured in the LAD and LCx coronary arteries before and after creation of downstream stenosis by inflating an angioplasty balloon within the newly placed stent. The true FFR (FFRtrue) of the LMCA, measured in the nondiseased downstream vessel in the absence of stenosis in the other vessel, was compared with the apparent FFR (FFRapp) measured in the presence of stenosis. RESULTS: In 25 patients, 91 pairs of measurements were made, 71 with LAD stenosis and 20 with LCx stenosis. FFRtrue of the LMCA was significantly lower than FFRapp (0.81 +/- 0.08 vs. 0.83 +/- 0.08, p < 0.001), although the numerical difference was small. This difference correlated with the severity of the downstream disease (r = 0.35, p < 0.001). In all cases in which FFRapp was >0.85, FFRtrue was >0.80. CONCLUSIONS: In most cases, downstream disease does not have a clinically significant impact on the assessment of FFR across an intermediate LMCA stenosis with the pressure wire positioned in the nondiseased vessel. PMID- 25790764 TI - Incidence and severity of paravalvular aortic regurgitation with multidetector computed tomography nominal area oversizing or undersizing after transcatheter heart valve replacement with the Sapien 3: a comparison with the Sapien XT. AB - OBJECTIVES: This study sought to compare the influence of the extent of multidetector computed tomography (MDCT) area oversizing on the incidence of paravalvular aortic regurgitation (PAR) between the Sapien 3 and the Sapien XT transcatheter heart valve (THV) to define a new MDCT sizing guideline suitable for the Sapien 3 platform. BACKGROUND: The inverse relationship of PAR occurrence and oversizing has been demonstrated for the Sapien XT but the incidence of PAR with comparable oversizing with the Sapien 3 is not known. METHODS: Sixty-one prospectively enrolled patients who underwent transcatheter aortic valve replacement with the Sapien 3 THV were compared with 92 patients who underwent transcatheter aortic valve replacement with the Sapien XT THV. Patients were categorized depending on the degree of MDCT area oversizing percentage: undersizing (below 0%), 0% to 5%, 5% to 10%, and above 10%. The primary endpoint was mild or greater PAR on transthoracic echocardiography. RESULTS: Mild or greater PAR was present in 19.7% of patients (12 of 61) in the Sapien 3 group and in 54.3% of patients (50 of 92) in the Sapien XT group (p < 0.01). The Sapien 3 group, compared with the Sapien XT group, consistently demonstrated significantly lower rates of mild or greater PAR except for oversizing >10% (p for interaction = 0.54). Moderate or severe PAR rates were also lower in the Sapien 3 group than in the Sapien XT group (3.3% vs. 13.0%, p = 0.04). In the Sapien 3 group, a MDCT area oversizing percentage value of <=4.17% was identified as the optimal cutoff value to discriminate patients with or without mild or greater PAR. CONCLUSIONS: Our retrospective analysis suggests that the Sapien 3 THV displays significantly lower rates of PAR than does the Sapien XT THV. A lesser degree of MDCT area oversizing may be employed for this new balloon-expandable THV. PMID- 25790765 TI - Severe valve deformation following cardiopulmonary resuscitation in a patient with a transcatheter aortic valve. PMID- 25790766 TI - The religious fervor for the radial approach. PMID- 25790767 TI - Fate of side-branch jailing and a malapposed platinum marker after resorption of an everolimus-eluting bioresorbable vascular scaffold: serial optical coherence tomography observations. PMID- 25790769 TI - Enhancement of LPS-induced microglial inflammation response via TLR4 under high glucose conditions. AB - BACKGROUND: Microglia activation mediated by toll-like receptor 4 (TLR4) plays an important role in neuroinflammation and postoperative cognitive dysfunction (POCD). Diabetes mellitus (DM) has been recently suggested as an independent risk factor for POCD. In this study, we investigate the potential exacerbation of the inflammatory response in primary microglia due to high glucose conditions. METHODS: Primary microglial cells were exposed to normal glucose (25 mmol/L) and high glucose (35 mmol/L) levels alone or with lipopolyscaccharide (LPS 0, 2, 5, 10 ng/mL). The pro-inflammatory response of the cells was assessed by measuring changes in cytokine levels and the evaluation of associated signaling pathways. RESULTS: Neither high glucose nor low LPS (<=5 ng/ml) alone had an effect on TNF a and IL-6 levels, but the combination of low LPS and high glucose stimulated the inflammatory response. Analyses of the associated signaling pathways demonstrated that high glucose enhanced the LPS-induced microglial activation via the TLR4/JAK2/STAT3 pathway. CONCLUSION: This study demonstrates that high glucose, one of the key abnormalities characteristic of DM, can augment LPS-induced microglial activation and inflammatory cytokine levels through the TLR4/JAK2/STAT3 pathway, offering new insight into the pathophysiological relationship between DM and POCD. PMID- 25790768 TI - The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. AB - Inflammation is closely related to the extent of damage following cerebral ischaemia, and the targeting of this inflammation has emerged as a promising therapeutic strategy. Here, we present that hypoxia-induced glial T-cell immunoglobulin and mucin domain protein (TIM)-3 can function as a modulator that links inflammation and subsequent brain damage after ischaemia. We find that TIM 3 is highly expressed in hypoxic brain regions of a mouse cerebral hypoxia ischaemia (H/I) model. TIM-3 is distinctively upregulated in activated microglia and astrocytes, brain resident immune cells, in a hypoxia-inducible factor (HIF) 1-dependent manner. Notably, blockade of TIM-3 markedly reduces infarct size, neuronal cell death, oedema formation and neutrophil infiltration in H/I mice. Hypoxia-triggered neutrophil migration and infarction are also decreased in HIF 1alpha-deficient mice. Moreover, functional neurological deficits after H/I are significantly improved in both anti-TIM-3-treated mice and myeloid-specific HIF 1alpha-deficient mice. Further understanding of these insights could serve as the basis for broadening the therapeutic scope against hypoxia-associated brain diseases. PMID- 25790771 TI - Association of MDM2 polymorphism with risk and prognosis of leukemia: a meta analysis. AB - OBJECTIVE: In this study, we performed an updated meta-analysis by summarizing all available relevant association studies to evaluate whether the murine double minute-2 (MDM2) T309G polymorphism is associated with risk of leukemia and to determine its prognostic effect. MATERIAL AND METHODS: Studies published in PubMed, Embase and the Cochrane Controlled Trial Register were searched till June 2014 using the search terms 'MDM2', 'polymorphism' and 'leukemia'. RESULTS: Eleven studies were included in this meta-analysis, with a total of 2,478 patients accrued. There were 8 studies providing data on single nucleotide polymorphism at position 309 (SNP309) and risk of leukemia and 7 studies providing data on SNP309 and overall survival. Our analysis showed that patients having G/G mutations had a significantly higher risk of developing leukemia (HR 1.90, 95% CI 1.56-2.31, p < 0.00001), while the association between G/T and leukemia was not significant (HR 1.18, 95% CI 0.96-1.45, p = 0.11). In addition, SNP309 was not significantly associated with patient survival (HR 1.29, 95% CI 0.79-2.13, p = 0.31). CONCLUSIONS: Our meta-analysis showed that the MDM2 T309G variation, especially homozygous G/G, might be associated with an increased risk of leukemia. Additional studies are needed to confirm the findings as well as to understand the underlying mechanisms. PMID- 25790770 TI - Stability, survival, and tolerability of a 4.5-mm-wide bone-anchored hearing implant: 6-month data from a randomized controlled clinical trial. AB - The objective of this study was to compare the stability, survival, and tolerability of 2 percutaneous osseointegrated titanium implants for bone conduction hearing: a 4.5-mm diameter implant (test) and a 3.75-mm diameter implant (control). Fifty-seven adult patients were included in this randomized controlled clinical trial. Sixty implants were allocated in a 2:1 (test-control) ratio. Follow-up visits were scheduled at 7, 14, 21, and 28 days; 6 and 12 weeks; and 6 months. At every visit, implant stability quotient (ISQ) values were recorded by means of resonance frequency analysis (RFA) and skin reactions were evaluated according to the Holgers classification. Implants were loaded with the bone conduction device at 3 weeks. Hearing-related quality of life was evaluated using the Abbreviated Profile of Hearing Aid Benefit (APHAB), the Glasgow Benefit Inventory (GBI), and the Glasgow Health Status Inventory (GHSI). ISQ values were statistically significantly higher for the test implant compared to the control implant. No implants were lost and soft tissue reactions were comparable for both implants. Positive results were reported in the hearing-related quality of life questionnaires. These 6-month results indicate that both implants and their corresponding hearing devices are safe options for hearing rehabilitation in patients with the appropriate indications. Loading at 3 weeks did not affect the stability of either implant. PMID- 25790772 TI - Neonatal Acid-Base Status in Fetuses with Abnormal Vertebro- and Cerebro Placental Ratios. AB - OBJECTIVE: A low cerebro-placental ratio (CPR) at term suggests the existence of failure to reach growth potential (FRGP) with a higher risk of poor neonatal acid base status. This study aimed to evaluate whether similar findings were also seen in the vertebral artery (vertebro-placental ratio, VPR), supplying 30% of the cerebral flow. METHODS: We studied term fetuses classified into groups according to birth weight (BW), CPR and VPR. BW was expressed in centiles and ratios in multiples of the median (MoM). Subsequently, associations with neonatal pH values were evaluated by means of regression curves and Mann-Whitney tests. RESULTS: VPR MoM correlated with BW centiles (p < 0.0001, R2 = 0.042) and its distribution resembled that of CPR MoM (p < 0.001). When both arteries were compared, adequate for-gestational-age (AGA) fetuses with either low CPR or low VPR had lower neonatal venous pH values (p < 0.05, p < 0.01, respectively). However, in case of small-for-gestational-age (SGA) fetuses, only those with low VPR had significantly lower neonatal arterial and venous pH values (p < 0.05). CONCLUSIONS: Blood flow in the vertebral artery mimics that in the middle cerebral artery supporting the FRGP model. Both CPR and VPR identify AGA fetuses with lower neonatal pH values, but only VPR identifies SGA with lower pH values. Hypoxemia might be reflected as a generalized cerebral vasodilation demonstrated as low CPR and VPR. PMID- 25790773 TI - The Influence of Early Measurements Onto the Estimated Kidney Dose in [(177)Lu][DOTA(0),Tyr(3)]Octreotate Peptide Receptor Radiotherapy of Neuroendocrine Tumors. AB - PURPOSE: Multiple measurements have been required to estimate the radiation dose to the kidneys resulting from [(177)Lu]DOTATATE therapy for neuroendocrine tumors. The aim of this study was to investigate the influence of early time point measurement in the renal dose calculation. PROCEDURES: Anterior/posterior whole-body planar scintigraphy images were acquired at approx. 1, 24, 48, and 72 h after administration of [(177)Lu]DOTATATE. Furthermore, we acquired planar 1 bed dynamic recordings in 12 frames (5 min each) during the first hour. We assessed kidney exposure with a three-phase model consisting of a linear increase to the maximum within the initial minutes p.i., followed a bi-exponential decline. This three-phase-model served as reference for evaluating accuracy of dose estimates in 105 kidneys calculated by conventional mono-exponential fitting of the final three and four whole-body images. RESULTS: Mean effective half-life times for the reference model were 25.8 +/- 12.0 min and 63.9 +/- 17.6 h, predicting a mean renal dose of 5.7 +/- 2.1 Gy. The effective half-life time was 46.3 +/- 15.4 h for the last four and 63.3 +/- 17.0 h for the last three data points. The mean start of the first whole-body measurement was 1.2 +/- 0.1 h p.i. The ratio of fast to slow phases was 28.1 +/- 23.9% at this time point, which caused a mean absolute percentage dose deviation of 12.4% for four data points, compared to 3.1% for three data points. At a mean time of 2.4 h p.i. (max 5.1 h), the ratio of fast to slow phase declined below 5%. CONCLUSIONS: Kinetic analysis of renal uptake using dynamic planar scans from the first hour after injection revealed a fast and a slow washout phase. Although the fast phase did not contribute substantially to the estimated renal dose, it could influence planar measurements performed within the first hours. We found that the presence of two clearance phases can hamper accurate dose estimation based on a single-phase model, resulting in approximately 12.4% dose underestimation, thus potentially resulting in overtreatment. In the absence of dynamic initial recordings, the first dosimetry measurements should therefore be obtained later than 3-5 h after [(177)Lu]DOTATATE injection. Omitting the early whole-body image reduced the dose estimation error to 3.1%. PMID- 25790774 TI - Utilizing the Multiradionuclide Resolving Power of SPECT and Dual Radiolabeled Single Molecules to Assess Treatment Response of Tumors. AB - PURPOSE: Single photon emission computed tomography (SPECT) radionuclide pairs having distinct decay rates and different energy maxima enable simultaneous detection of dual gamma signals and real-time assessment of dynamic functional and molecular processes in vivo. Here, we report image acquisition and quantification protocols for a single molecule labeled with two different radionuclides for functional SPECT imaging. PROCEDURES: LS370 and LS734 were prepared using modular solid phase peptide synthesis. Each agent has a caspase-3 cleavable reporting motif, flanked by a tyrosine residue and a chelator at the opposite end of molecule. Cell uptake and efflux were assessed in human MDA-MB 231 breast cancer cells. Biodistribution studies were conducted in tumor naive and orthotopic 4T1 metastatic breast cancer tumor mice. NanoSPECT dual-imaging validation and attenuation correction parameters were developed using phantom vials containing varying radionuclide concentrations. Proof-of-principle SPECT imaging was performed in MMTV-PyMT transgenic mice. RESULTS: LS370 and LS734 were singly or dually radiolabeled with (125)I and (111)In or (99m)Tc. Cell assays demonstrated 11-fold higher percent uptake (P < 0.001) of [(125)I]LS734 (3.6 +/- 0.5) compared to [(125)I]LS370 (0.3 +/- 0.3) at 2 h. Following chemotherapy, cellular retention of [(125)I]LS734 was 3-fold higher (P < 0.05) than untreated cells. Pharmacokinetics at 1 h postinjection demonstrated longer blood retention (%ID/g) for [(125)I]LS734 (3.2 +/- 0.9) compared to [(125)I]LS370 (1.6 +/- 0.1). In mice bearing bilateral orthotopic 4T1 tumors, the uptake (%ID/g) was 2.4 +/- 0.3 for [(125)I]LS734 and 1.2 +/- 0.03 for [(125)I]LS370. The iodinated tyrosine peptide residue label was stable under in vitro conditions for up to 24 h; rapid systemic deiodination (high thyroid uptake) was observed in vivo. Phantom studies using standards demonstrated deconvolution of radionuclide signals based on different gamma ray energies. In MMTV-PyMT mice imaged with dual-labeled [(111)In]-[(125)I]LS734, the gamma signals were separable and quantifiable. CONCLUSIONS: Image processing protocols were developed for quantitative signal separation resulting from a caspase-3 responsive dual-radiolabeled SPECT probe. Crosstalk unmixing was obtained for multiradionuclide NanoSPECT imaging. In vitro and in vivo data demonstrated structure-activity relationships for developing functional agents for ratiometric SPECT imaging. PMID- 25790775 TI - Influence of Age on Outcome in Patients with Pulmonary Arterial Hypertension. AB - BACKGROUND: The development of effective orally administered medical therapy for pulmonary arterial hypertension (PAH) has made a significant impact on outcome in patients with PAH. Identification of patient groups likely to derive optimal benefit is important, given cost and potential side effects; the clinical effectiveness of these therapies in older patients with PAH is unclear as the presence of co-morbidity may limit benefits of therapy. AIMS: We evaluated the epidemiology of PAH in a contemporary cohort to assess the influence of age on long-term outcome using PAH-specific therapies. RESULTS: A total of 119 patients (88% female; mean age 65+/-12 years) were reviewed, comprising 52% with underlying connective tissue disease. Bosentan was the PAH specific agent most frequently used. The baseline 6MWT distance in the entire cohort was 304m with age associated with a significant decline in 6MWT. CONCLUSIONS: In a large cohort of patients treated with PAH-specific therapies, patients less than 55 years of age showed improvement in 6MWT with older patients demonstrating stabilisation or decline. PMID- 25790777 TI - Everglades restoration science and decision-making in the face of climate change: a management perspective. AB - Managers were invited to attend the two-day "Predicting Ecological Changes in the Florida Everglades in a Future Climate Scenario" workshop and to participate in discussion and panel sessions. This paper provides a management perspective on the technical presentations presented at the workshop, identifying information of particular interest to Everglades restoration decision-making. In addition, the paper highlights the points related to science and decision-making that emerged from the discussion sessions and provides thoughts for future discussion in a follow-up forum. Particular focus is dedicated to the importance of and challenges associated with integrating science and decision-making. In addition, the paper offers a management perspective on the uncertainties of climate science and the implications they have for influencing Everglades restoration decision making. The authors propose that on the one hand, even given uncertainties associated with predicting the ecological response to climate change, there remains a scientific consensus that Everglades restoration is generally on the right track. On the other hand, uncertainty can be a significant barrier to climate science influencing the implementation of restoration and adaptive management programs. PMID- 25790778 TI - Toward a stabilized lattice framework and surface structure of layered lithium rich cathode materials with Ti modification. AB - Layered lithium-rich oxides have several serious shortcomings such as fast voltage fading and poor cyclic stability of energy density which greatly hinder their practical applications. Fabrication of a stable framework of layered lithium-rich oxides during charging-discharging is crucial for addressing the above problems. In this work, we show that Ti modification is a promising way to realize this target with bifunctional roles. For example, it is able to substitute Mn in the lattice framework and form a stable surface layer. It therefore leads to an improved retention of energy density of the Ti-modified Li1.2Mn0.54-xTixNi0.13Co0.13O2 (x = 0.04, 0.08, and 0.15) materials during cycling. The evolution of dQ/dV curves show that the layered/spinel phase transformation is suppressed owing to the introduction of strong Ti-O bonds in the framework. In addition, SEM, TEM, and EIS results confirm that a more uniform and stable interface layer is formed on Ti-modified Li1.2Mn0.54 xTixNi0.13Co0.13O2 (x = 0.04, 0.08, and 0.15) materials compared with the Ti-free counterpart. The stable interface layer on the lithium-rich oxides is also beneficial for further reducing side reactions, resulting in stable interface layer resistance. Therefore, the improved cycling performance of the material is due to both contribution of the more stable framework and enhanced electrode/electrolyte interface by Ti modification. PMID- 25790776 TI - Vascular Dilation, Tachycardia, and Increased Inotropy Occur Sequentially with Increasing Epinephrine Dose Rate, Plasma and Myocardial Concentrations, and cAMP. AB - BACKGROUND: While epinephrine infusion is widely used in critical care for inotropic support, there is no direct method to detect the onset and measure the magnitude of this response. We hypothesised that surrogate measurements, such as heart rate and vascular tone, may indicate if the plasma and tissue concentrations of epinephrine and cAMP are in a range sufficient to increase myocardial contractility. METHODS: Cardiovascular responses to epinephrine infusion (0.05-0.5 mcgkg(-1)min(-1)) were measured in rats using arterial and left ventricular catheters. Epinephrine and cAMP levels were measured using ELISA techniques. RESULTS: The lowest dose of epinephrine infusion (0.05 mcgkg(-1)min( 1)) did not raise plasma epinephrine levels and did not lead to cardiovascular response. Incremental increase in epinephrine infusion (0.1 mcgkg(-1)min(-1)) elevated plasma but not myocardial epinephrine levels, providing vascular, but not cardiac effects. Further increase in the infusion rate (0.2 mcgkg(-1)min(-1)) raised myocardial tissue epinephrine levels sufficient to increase heart rate but not contractility. Inotropic and lusitropic effects were significant at the infusion rate of 0.3 mcgkg(-1)min(-1). Correlation of plasma epinephrine to haemodynamic parameters suggest that as plasma concentration increases, systemic vascular resistance falls (EC50=47 pg/ml), then HR increases (ED50=168 pg/ml), followed by a rise in contractility and lusitropy (ED50=346 pg/ml and ED50=324 pg/ml accordingly). CONCLUSIONS: The dose response of epinephrine is distinct for vascular tone, HR and contractility. The need for higher doses to see cardiac effects is likely due to the threshold for drug accumulation in tissue. Successful inotropic support with epinephrine cannot be achieved unless the infusion is sufficient to raise the heart rate. PMID- 25790779 TI - Spoils of war: iron at the crux of clinical and ecological fitness of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a versatile environmental microorganism that also causes life-threatening opportunistic infections. At the root of this bacterium's ability to survive in such diverse environments is its large suite of iron acquisition systems. More recently, studies have highlighted the ability of P. aeruginosa to compete with other organisms for this essential metallonutrient. This minireview provides an overview of the iron acquisition systems used by P. aeruginosa, with an emphasis on how these systems contribute to fitness in polymicrobial environments. We also provide an evolutionary perspective of how these systems were selected for in the native habitats of the Pseudomonads, while also highlighting factors that are unique to P. aeruginosa. PMID- 25790780 TI - Rab40b upregulation correlates with the prognosis of gastric cancer by promoting migration, invasion, and metastasis. AB - Gastric cancer (GC) is the fourth most common cancer worldwide and is associated with a low 5-year survival rate of <24 % due to the tendency of early invasion and metastasis. Rab GTPases, which are master regulators of intracellular trafficking, have been shown to a play new role in the control of multiple tumor related processes, including cell migration, invasion, proliferation, communication, and drug resistance. Here, we analyzed the mRNA expression levels of 63 Rab GTPases in samples from GC patients. Our data demonstrated that the expression level of Rab40b was significantly correlated with GC invasion classification (P < 0.01), lymph node metastasis (P < 0.01), and pathological stage (P < 0.01). High Rab40b mRNA expression was also correlated with shorter overall survival in patients with GC (P < 0.05). Moreover, knockdown of Rab40b protein reduced the migration and invasion of GC cells, while overexpression of Rab40b significantly promoted GC cell metastasis in nude mice. Our results also showed that Rab40b is a target gene of miR-204 and further demonstrated that Rab40b is negatively correlated with miR-204 in GC tissues. These findings indicate that Rab40b might be a novel prognostic marker and a candidate biological therapeutic target for GC. PMID- 25790781 TI - The effects of focal adhesion kinase on the motility, proliferation and apoptosis of Caco2 and SMMC-7721 cells. AB - Focal adhesion kinase (FAK) plays important roles in cancer development. However, the significance of FAK expression in colorectal carcinoma and hepatocellular carcinoma has not been clarified. This study aims to explore the roles FAK played in the progression of colorectal carcinoma and hepatocellular carcinoma. RNAi method was used to inhibit the expression of FAK in Caco2 and SMMC-7721 cells. Reverse transcriptase polymerase chain reaction analysis and Western blot analysis were used to examine mRNA and protein expression of FAK. Then, the proliferation, motility and apoptosis of both types of cells were detected using MTT assay, wound healing/transwell assay and nuclear staining assay. The microstructure changes (F-actin, beta-tubulin and lamin B1) of SMMC-7721 cells were visualized by immunofluorescence. FAK was overexpressed in both cell lines and down-regulation of FAK resulted in suppression of cell proliferation, inhibition of cell migration and invasion. The apoptosis of cells was increased significantly following the FAK expression inhibition. Moreover, actin polymerization, beta-tubulin and lamin B1 expression of cells were significantly decreased. The results highlight the role of FAK in the progression of cancers. These findings suggest FAK serve as a potential therapeutic target for cancer therapy. PMID- 25790782 TI - Neuro-imaging findings in infants with congenital cytomegalovirus infection: relation to trimester of infection. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) infection early in pregnancy may result in major disabilities. Cerebral abnormalities detected using cranial ultrasound (cUS) and magnetic resonance imaging (MRI) have been related to neurological sequelae. OBJECTIVE: To evaluate the additional value of MRI and assess the relationship between time of infection during pregnancy and outcome in infants with cCMV infection. METHODS AND STUDY DESIGN: Demographic and clinical data were collected in infants with cCMV infection (1992-2013). Trimester of infection, neuro-imaging results and outcome were reviewed. Cerebral abnormalities were categorized into none, mild (lenticulostriate vasculopathy, germinolytic cysts, high signal intensity on T2-weighted images) and severe (migrational disorder, ventriculomegaly, cerebellar hypoplasia). Results were statistically analysed. RESULTS: Thirty-six infants were eligible for analysis. cUS was performed in all and cranial MRI in 20 infants. Migrational disorders were only diagnosed using MRI (p < 0.01). In 17 infants trimester of infection was ascertained. Seven out of 10 infants infected during the first trimester had severe abnormalities on cUS (5 confirmed on MRI) and adverse sequelae; 3 had no/mild abnormalities on cUS/MRI and normal outcome. Two out of 3 infants infected during the second trimester with no/mild abnormalities on cUS/MRI had normal outcome; 1 with mild cUS and MRI abnormalities developed sensorineural hearing loss. Four infants infected during the third trimester with no/mild abnormalities on cUS/MRI had normal outcome. CONCLUSION: Infants with a first trimester cCMV infection are most at risk of severe cerebral abnormalities and neurological sequelae. MRI, and not cUS, enables an early diagnosis of migrational disorders, which can improve prediction of outcome. PMID- 25790783 TI - FQC: A novel approach for efficient compression, archival, and dissemination of fastq datasets. AB - Sequence data repositories archive and disseminate fastq data in compressed format. In spite of having relatively lower compression efficiency, data repositories continue to prefer GZIP over available specialized fastq compression algorithms. Ease of deployment, high processing speed and portability are the reasons for this preference. This study presents FQC, a fastq compression method that, in addition to providing significantly higher compression gains over GZIP, incorporates features necessary for universal adoption by data repositories/end users. This study also proposes a novel archival strategy which allows sequence repositories to simultaneously store and disseminate lossless as well as (multiple) lossy variants of fastq files, without necessitating any additional storage requirements. For academic users, Linux, Windows, and Mac implementations (both 32 and 64-bit) of FQC are freely available for download at: https://metagenomics.atc.tcs.com/compression/FQC . PMID- 25790784 TI - Grid-Assembly: An oligonucleotide composition-based partitioning strategy to aid metagenomic sequence assembly. AB - Metagenomics approach involves extraction, sequencing and characterization of the genomic content of entire community of microbes present in a given environment. In contrast to genomic data, accurate assembly of metagenomic sequences is a challenging task. Given the huge volume and the diverse taxonomic origin of metagenomic sequences, direct application of single genome assembly methods on metagenomes are likely to not only lead to an immense increase in requirements of computational infrastructure, but also result in the formation of chimeric contigs. A strategy to address the above challenge would be to partition metagenomic sequence datasets into clusters and assemble separately the sequences in individual clusters using any single-genome assembly method. The current study presents such an approach that uses tetranucleotide usage patterns to first represent sequences as points in a three dimensional (3D) space. The 3D space is subsequently partitioned into "Grids". Sequences within overlapping grids are then progressively assembled using any available assembler. We demonstrate the applicability of the current Grid-Assembly method using various categories of assemblers as well as different simulated metagenomic datasets. Validation results indicate that the Grid-Assembly approach helps in improving the overall quality of assembly, in terms of the purity and volume of the assembled contigs. PMID- 25790785 TI - Computationally predicting protein-RNA interactions using only positive and unlabeled examples. AB - Protein-RNA interactions (PRIs) are considerably important in a wide variety of cellular processes, ranging from transcriptional and post-transcriptional regulations of gene expression to the active defense of host against virus. With the development of high throughput technology, large amounts of PRI information is available for computationally predicting unknown PRIs. In recent years, a number of computational methods for predicting PRIs have been developed in the literature, which usually artificially construct negative samples based on verified nonredundant datasets of PRIs to train classifiers. However, such negative samples are not real negative samples, some even may be unknown positive samples. Consequently, the classifiers trained with such training datasets cannot achieve satisfactory prediction performance. In this paper, we propose a novel method PRIPU that employs biased-support vector machine (SVM) for predicting Protein-RNA Interactions using only Positive and Unlabeled examples. To the best of our knowledge, this is the first work that predicts PRIs using only positive and unlabeled samples. We first collect known PRIs as our benchmark datasets and extract sequence-based features to represent each PRI. To reduce the dimension of feature vectors for lowering computational cost, we select a subset of features by a filter-based feature selection method. Then, biased-SVM is employed to train prediction models with different PRI datasets. To evaluate the new method, we also propose a new performance measure called explicit positive recall (EPR), which is specifically suitable for the task of learning positive and unlabeled data. Experimental results over three datasets show that our method not only outperforms four existing methods, but also is able to predict unknown PRIs. Source code, datasets and related documents of PRIPU are available at: http://admis.fudan.edu.cn/projects/pripu.htm . PMID- 25790786 TI - Investigating noise tolerance in an efficient engine for inferring biological regulatory networks. AB - Biological systems are composed of biomolecules such as genes, proteins, metabolites, and signaling components, which interact in complex networks. To understand complex biological systems, it is important to be capable of inferring regulatory networks from experimental time series data. In previous studies, we developed efficient numerical optimization methods for inferring these networks, but we have yet to test the performance of our methods when considering the error (noise) that is inherent in experimental data. In this study, we investigated the noise tolerance of our proposed inferring engine. We prepared the noise data using the Langevin equation, and compared the performance of our method with that of alternative optimization methods. PMID- 25790787 TI - Accommodation of end-state comfort reveals subphonemic planning in speech. AB - Applying the 'end-state comfort' hypothesis of Rosenbaum et al. [J Exp Psych Learn Mem Cogn 1992;18:1058; Acta Psychol (Amst) 1996;94:59] to tongue motion provides evidence of long-distance subphonemic planning in speech. Speakers' tongue postures may anticipate upcoming speech up to three segments, two syllables, and a morpheme or word boundary later. We used M-mode ultrasound imaging to measure the direction of tongue tip/blade movements for known variants of flap/tap allophones of North American English /t/ and /d/. Results show that speakers produce different flap variants early in words or word sequences so as to facilitate the kinematic needs of flap/tap or other /r/ variants that appear later in the word or word sequence. Similar results were also observed across word boundaries, indicating that this is not a lexical effect. PMID- 25790788 TI - Aqueous hydrotrope: an efficient and reusable medium for a green one-pot, diversity-oriented synthesis of quinazolinone derivatives. AB - A library of quinazolinones was prepared by the one-pot three-component reaction of isatoic anhydride, ammonium salts/amines, and various electrophiles using aqueous hydrotropic solution as an efficient, economical, reusable, and green medium giving good to excellent yields of products in very short time. The method offers a versatile way for the development of diversity-oriented synthesis of quinazolinones. PMID- 25790791 TI - HIV: on the road to an HIV vaccine? PMID- 25790790 TI - Regulation of antiviral T cell responses by type I interferons. AB - Type I interferons (IFNs) are pro-inflammatory cytokines that are rapidly induced in different cell types during viral infections. The consequences of type I IFN signalling include direct antiviral activity, innate immune cell activation and regulation of adaptive immune responses. In this Review, we discuss recent conceptual advances in our understanding of indirect and direct regulation of T cell immunity by type I IFNs, which can either promote or inhibit T cell activation, proliferation, differentiation and survival. This regulation depends, to a large extent, on the timing of type I IFN exposure relative to T cell receptor signalling. Type I IFNs also provide activated T cells with resistance to natural killer cell-mediated elimination. PMID- 25790792 TI - Impact of Dietary Antioxidants on Sport Performance: A Review. AB - Many athletes supplement with antioxidants in the belief this will reduce muscle damage, immune dysfunction and fatigue, and will thus improve performance, while some evidence suggests it impairs training adaptations. Here we review the effect of a range of dietary antioxidants and their effects on sport performance, including vitamin E, quercetin, resveratrol, beetroot juice, other food-derived polyphenols, spirulina and N-acetylcysteine (NAC). Older studies suggest vitamin E improves performance at altitude, with possible harmful effects on sea-level performance. Acute intake of vitamin E is worthy of further consideration, if plasma levels can be elevated sufficiently. Quercetin has a small beneficial effect for exercise of longer duration (>100 min), but it is unclear whether this benefits athletes. Resveratrol benefits trained rodents; more research is needed in athletes. Meta-analysis of beetroot juice studies has revealed that the nitrate component of beetroot juice had a substantial but unclear effect on performance when averaged across athletes, non-athletes and modes of exercise (single dose 1.4 +/- 2.0%, double dose 0.5 +/- 1.9%). The effect of addition of polyphenols and other components to beetroot juice was trivial but unclear (single dose 0.4 +/- 3.2%, double dose -0.5 +/- 3.3%). Other food-derived polyphenols indicate a range of performance outcomes from a large improvement to moderate impairment. Limited evidence suggests spirulina enhances endurance performance. Intravenous NAC improved endurance cycling performance and reduced muscle fatigue. On the basis of vitamin E and NAC studies, acute intake of antioxidants is likely to be beneficial. However, chronic intakes of most antioxidants have a harmful effect on performance. PMID- 25790793 TI - The effects of repeated-sprint training on field-based fitness measures: a meta analysis of controlled and non-controlled trials. AB - BACKGROUND: Repeated-sprint training appears to be an efficient and practical means for the simultaneous development of different components of fitness relevant to team sports. OBJECTIVE: Our objective was to systematically review the literature and meta-analyse the effect of repeated-sprint training on a selection of field-based measures of athletic performance, i.e. counter-movement jump, 10 m sprint, 20 m sprint, 30 m sprint, repeated-sprint ability and high intensity intermittent running performance. DATA SOURCES: The SPORTDiscus, PubMed, MEDLINE and Web of Science databases were searched for original research articles. Search terms included 'repeated-sprint training', 'sprint training', 'aerobic endurance', 'repeated-sprint ability', 'counter-movement jump' and 'sprint performance'. STUDY SELECTION: Inclusion criteria included intervention consisting of a series of <=10 s sprints with <=60 s recovery; trained participants; intervention duration of 2-12 weeks; field-based fitness measures; running- or cycling-based intervention; published up to, and including, February 2014. DATA EXTRACTION: Our final dataset included six trials for counter-movement jump (two controlled trials), eight trials for 10 m sprint, four trials for 20 m sprint (three controlled trials), two trials for 30 m sprint, eight trials for repeated-sprint ability and three trials for high-intensity intermittent running performance. Analyses were conducted using comprehensive meta-analysis software. Uncertainty in the meta-analysed effect of repeated-sprint training was expressed as 95% confidence limits (CL), along with the probability that the true value of the effect was trivial, beneficial or harmful. Magnitude-based inferences were based on standardised thresholds for small, moderate and large changes of 0.2, 0.6 and 1.2 standard deviations, respectively. RESULTS: Repeated-sprint training had a likely small beneficial effect in non-controlled counter-movement jump trials (effect size 0.33; 95% CL +/-0.30), with a possibly moderate beneficial effect in controlled trials (0.63; 95% CL +/-0.44). There was a very likely small beneficial effect on 10 m sprint time in non-controlled trials (-0.42; 95% CL +/ 0.24), with a possibly moderate beneficial effect on 20 m sprint time in non controlled (-0.49; 95% CL +/-0.46) and controlled (-0.65; 95% CL +/-0.61) trials. Repeated-sprint training had a possibly large beneficial effect on 30 m sprint performance in non-controlled trials (-1.01; 95% CL +/-0.93), with possibly moderate beneficial effects on repeated-sprint ability (-0.62; 95% CL +/-0.25) and high-intensity intermittent running performance (-0.61; 95% CL +/-0.54). CONCLUSIONS: Repeated-sprint training can induce small to large improvements in power, speed, repeated-sprint ability and endurance, and may have relevance for training in team sports. PMID- 25790794 TI - Decline in the Quality of Family Relationships Predicts Escalation in Children's Internalizing Symptoms from Middle to Late Childhood. AB - An integration of family systems perspectives with developmental psychopathology provides a framework for examining the complex interplay between family processes and developmental trajectories of child psychopathology over time. In a community sample of 98 families, we investigated the evolution of family relationships, across multiple subsystems of the family (i.e., interparental, mother-child, father-child), and the impact of these changing family dynamics on developmental trajectories of child internalizing symptoms over 6 years, from preschool age to pre-adolescence. Parent-child relationship quality was observed during lengthy sessions, consisting of multiple naturalistic, carefully scripted contexts. Each parent completed reports about interparental relationship satisfaction and child internalizing symptoms. To the extent that mothers experienced a steeper decline in interparental relationship satisfaction over time, children developed internalizing symptoms at a faster rate. Further, symptoms escalated at a faster rate to the extent that negative mother-child relationship quality increased (more negative affect expressed by both mother and child, greater maternal power assertion) and positive mother-child relationship quality decreased (less positive affect expressed by both mother and child, less warmth and positive reciprocity). Time-lagged growth curve analyses established temporal precedence such that decline in family relationships preceded escalation in child internalizing symptoms. Results suggest that family dysfunction, across multiple subsystems, represents a driving force in the progression of child internalizing symptoms. PMID- 25790795 TI - Tibetan women's perspectives and satisfaction with delivery care in a rural birth center. AB - OBJECTIVE: To identify sociodemographic characteristics and factors involved in Tibetan women's decisions to deliver at the Tibetan Birth and Training Center (TBTC) in rural western China. METHODS: In the present mixed-methods study, a random sample of married women who delivered at the TBTC between June 2011 and June 2012 were surveyed. Additionally, four focus group discussions were conducted among married women living in the TBTC catchment area. Descriptive analyses were conducted, and dominant themes were identified. RESULTS: In focus group discussions, women (n=33) reported that improved roads and transportation meant that access to health facilities was easier than in the past. Although some of the 114 survey participants voiced negative perceptions of healthcare facilities and providers, 99 (86.8%) indicated that they chose to deliver at the TBTC because they preferred to have a doctor present. Most women (75 [65.8%]) said their mother/mother-in-law made the final decision about delivery location. Women valued logistic and cultural aspects of the TBTC, and 108 (94.7%) said that they would recommend the TBTC to a friend. CONCLUSION: Study participants preferred delivery care that combines safety and comfort. The findings highlight avenues for further promotion of facility delivery among populations with lower rates of skilled deliveries. PMID- 25790796 TI - Unexpected uterine malignancy in women who have undergone myomectomy. PMID- 25790797 TI - Transient recurrent laryngeal nerve paresis after shoulder dystocia. PMID- 25790798 TI - MEthods of ASsessing blood pressUre: identifying thReshold and target valuEs (MeasureBP): a review & study protocol. AB - Despite progress in automated blood pressure measurement (BPM) technology, there is limited research linking hard outcomes to automated office BPM (OBPM) treatment targets and thresholds. Equivalences for automated BPM devices have been estimated from approximations of standardized manual measurements of 140/90 mmHg. Until outcome-driven targets and thresholds become available for automated measurement methods, deriving evidence-based equivalences between automated methods and standardized manual OBPM is the next best solution. The MeasureBP study group was initiated by the Canadian Hypertension Education Program to close this critical knowledge gap. MeasureBP aims to define evidence-based equivalent values between standardized manual OBPM and automated BPM methods by synthesizing available evidence using a systematic review and individual subject-level data meta-analyses. This manuscript provides a review of the literature and MeasureBP study protocol. These results will lay the evidenced-based foundation to resolve uncertainties within blood pressure guidelines which, in turn, will improve the management of hypertension. PMID- 25790799 TI - The role of telemedicine in hypertension management: focus on blood pressure telemonitoring. AB - This review aims at updating and critically assessing the role of telemedicine, and in particular, of home blood pressure telemonitoring (HBPT), in the management of the hypertensive patient. Result from several randomized trials suggest that HBPT represents a promising tool for improving blood pressure (BP) control of hypertensive patients, in particular, those at high risk. Most studies documented a significant BP reduction with regular HBPT compared to usual care. HBPT interventions showed a very high degree of acceptance by patients, helped improving the patients' quality of life, and were associated with lower medical costs than standard care, even though such costs were offset by those of the technology, thus reducing the overall cost-effectiveness of HBPT. The high heterogeneity of the technologies, study designs, and type of patients in the various studies suggest that further well-designed, large cohort, prospective studies are needed to identify key elements of HBPT approach to be able to give impact on specific outcomes. Likely, patients who need a constant monitoring of multiple vital signs and a tight BP control, such as high risk patients with chronic diseases (ischemic heart disease or heart failure, diabetes, etc.), as well as non-adherent patients, may particularly benefit from HBPT. In general, HBPT can be an advantageous choice when a network among healthcare professionals (doctors, nurses, and pharmacists) is needed to improve the screening and management of hypertension and related comorbidities and to achieve an effective prevention of cardiovascular diseases in the community. PMID- 25790800 TI - Antiplatelet treatment in essential hypertension: where do we stand? AB - Antiplatelet agents represent a cornerstone in the management of patients at increased cardiovascular risk. Essential hypertension is considered a major public health problem leading to increased cardiovascular morbidity and mortality. The majority of patients with essential hypertension exhibit also additional cardiovascular risk factors and present with increased platelet activation. Despite recent innovations in the field of antiplatelet treatment and the introduction of novel agents, the role of antiplatelet treatment in patients with essential hypertension remains understudied. This review aims to shed light on novel experimental and clinical data in the evolving field of antiplatelet treatment in essential hypertension. In particular, recent data regarding aspirin, clopidogrel, novel P2Y12 inhibitors, and other agents with potential antiplatelet effects are critically reviewed. PMID- 25790802 TI - Assignment of Colletotrichum coccodes isolates into vegetative compatibility groups using infrared spectroscopy: a step towards practical application. AB - Colletotrichum coccodes (C. coccodes) is a pathogenic fungus that causes anthracnose on tomatoes and black dot disease in potatoes. It is considered as a seed tuber and soil-borne pathogen that is difficult to control. C. coccodes isolates are classified into Vegetative Compatibility Groups (VCGs). Early classification of isolates into VCGs is of great importance for a better understanding of the epidemiology of the disease and improving its control. Moreover, the differentiation among these isolates and the assignment of newly discovered isolates enable control of the disease at its early stages. Distinguishing between isolates using microbiological or genetic methods is time consuming and not readily available. Our results show that it is possible to assign the isolates into their VCGs and to classify them at the isolate level with a high success rate using Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA). PMID- 25790803 TI - The priming effect of soluble carbon inputs in organic and mineral soils from a temperate forest. AB - The priming effect (PE) is one of the most important interactions between C input and output in soils. Here we aim to quantify patterns of PE in response to six addition rates of (13)C-labeled water-soluble C (WSC) and determine if these patterns are different between soil organic and mineral layers in a temperate forest. Isotope mass balance was used to distinguish WSC derived from SOC-derived CO2 respiration. The relative PE was 1.1-3.3 times stronger in the mineral layer than in the organic layer, indicating higher sensitivity of the mineral layer to WSC addition. However, the magnitude of cumulative PE was significantly higher in the organic layer than in the mineral layer due to higher SOC in the organic layer. With an increasing WSC addition rate, cumulative PE increased for both layers, but tended to level off when the addition rate was higher than 400 mg C kg(-1) soil. This saturation effect indicates that stimulation of soil C loss by exogenous substrate would not be as drastic as the increase of C input. In fact, we found that the mineral layer with an WSC addition rate of 160-800 mg C kg(-1) soil had net C storage although positive PE was observed. The addition of WSC basically caused net C loss in the organic layer due to the high magnitude of PE, pointing to the importance of the organic layer in C cycling of forest ecosystems. Our findings provide a fundamental understanding of PE on SOC mineralization of forest soils and warrant further in situ studies of PE in order to better understand C cycling under global climate change. PMID- 25790801 TI - Blood pressure variability: assessment, predictive value, and potential as a therapeutic target. AB - A large body of evidence has consistently supported the relationship between blood pressure (BP) levels and the risk of cardiovascular complications. In recent years, several independent studies have also indicated that this risk may not only depend on the magnitude of the blood pressure elevation per se but also on the presence of other associated conditions such as increased blood pressure variability. This concept has been supported by a series of reports, most of which post hoc analyses of clinical trials in hypertension, showing that increasing values of BP variability (BPV) (either in the short term, in the midterm, or in the long term) may predict development, progression, and severity of cardiac, vascular, and renal organ damage, as well as cardiovascular events and mortality. Remarkably, studies conducted in populations at high cardiovascular risk have shown increasing values of BPV in the individual subjects (so-called intra- or within-individual BPV) to be strong predictors of cardiovascular morbidity and mortality, even to a larger extent than average BP values. However, in subjects at low to moderate cardiovascular risk, the contribution of BPV to cardiovascular risk prediction over and beyond average BP values has been shown to be only moderate. The aim of this paper is to critically review the evidence addressing the prognostic relevance of different components of BPV addressing a yet open question, i.e., whether routine assessment of BPV in clinical practice should be regarded as an additional target of antihypertensive treatment to improve cardiovascular protection. PMID- 25790804 TI - Local density effects on individual production are dynamic: insights from natural stands of a perennial savanna grass. AB - Perennial grasses are a dominant component of grasslands, and provide important ecosystem services. However, most knowledge of grasslands' functioning and production comes from plot-level studies, and drivers of individual-level production remain poorly explored. Extrapolation from existing experiments is hampered by the fact that these are mostly concentrated on even-aged cohorts, and/or on the early stages of a plant's life cycle. Here we explored how local density regulates individual production in mono-specific natural grassland, focusing on adult individuals of a perennial savanna grass (Stipagrostis uniplumis). We found individual production to increase with individuals' size, but to decrease with neighbour abundance. A metric of neighbour abundance that considered size was superior to a metric based solely on the number of individuals. This finding is particularly important for studying competitive effects in natural populations, where plants are normally not even-sized. The inferred competition kernel, i.e. the function describing how competitive strength varies with spatial distance from a target plant, was hump-shaped, indicating strongest intraspecific competition at intermediate distances (10-30 cm). The spatial signature of competitive effects changed with time since fire; peak effects moved successively away from the target plant. Our results suggest that inferred competition kernels of long-lived plant populations may have shapes that differ from exponential or sigmoidal decreases. More generally, results underline that competition among neighbouring plants is dynamic. Studies that address density-dependent and density-independent (fire-related) population dynamics of perennial grasses in their fire-prone environment may thus shed new light on the functioning and production of grasslands. PMID- 25790805 TI - Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor. AB - BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. METHODS: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. RESULTS: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. CONCLUSIONS: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world. PMID- 25790806 TI - Bacterial infection as an adverse effect of telaprevir-based triple therapy for chronic hepatitis C infection. AB - OBJECTIVE: There is little information regarding the incidence of bacterial infections as an adverse effect of telaprevir (TVR)-based triple therapy. This study was performed in order to evaluate the baseline and on-treatment predictors of bacterial infections in patients treated with TVR-based triple therapy. METHODS: This multicenter study evaluated 430 patients with chronic hepatitis C who received 12 weeks of TVR in combination with 24 weeks of pegylated interferon alpha2b plus ribavirin. The occurrence of a bacterial infection during anti-viral treatment was defined as the onset of local or systemic inflammation as a result of pathogenic bacteria. RESULTS: Bacterial infections occurred in 21 of the 430 (4.9%) patients during TVR-based triple therapy. Among these subjects, 71.4% (15 of 21) experienced bacterial infections during the initial eight weeks of treatment. Urinary tract infections were the most frequent infection, observed in 2.8% of cases (12 of 430). The rate of urinary tract infection among women (11 of 215, 5.1%) was significantly higher than that observed among men (1 of 215, 0.5%) (p<0.0001). According to a multivariable logistic regression analysis, the only significant independent predictor was the pretreatment serum albumin level (p=0.0008). Of the 21 patients who experienced bacterial infections, only one (4.8%) had to discontinue the treatment; however, the others were able to continue anti-viral treatment in combination with antibiotic treatment. CONCLUSION: Clinicians should be concerned regarding the incidence of bacterial infections among patients treated with TVR-based triple therapy, especially those with a low serum albumin level. PMID- 25790807 TI - Effects of hydrochlorothiazide on oxidative stress and pulse pressure in hypertensive patients with chronic stroke: the EMINENT study. AB - OBJECTIVE: Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan. METHODS: This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs. RESULTS: Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67+/-12 mmHg to 58+/-12, p<0.001; non-diuretic group: 72+/-12 to 61+/-12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group. CONCLUSION: In this study, hydrochlorothiazide treatment did not provide any additional benefits over non diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP. PMID- 25790808 TI - Revealing sub-MUm and MUm-scale textures in H2O ice at megabar pressures by time domain Brillouin scattering. AB - The time-domain Brillouin scattering technique, also known as picosecond ultrasonic interferometry, allows monitoring of the propagation of coherent acoustic pulses, having lengths ranging from nanometres to fractions of a micrometre, in samples with dimension of less than a micrometre to tens of micrometres. In this study, we applied this technique to depth-profiling of a polycrystalline aggregate of ice compressed in a diamond anvil cell to megabar pressures. The method allowed examination of the characteristic dimensions of ice texturing in the direction normal to the diamond anvil surfaces with sub micrometre spatial resolution via time-resolved measurements of the propagation velocity of the acoustic pulses travelling in the compressed sample. The achieved imaging of ice in depth and in one of the lateral directions indicates the feasibility of three-dimensional imaging and quantitative characterisation of the acoustical, optical and acousto-optical properties of transparent polycrystalline aggregates in a diamond anvil cell with tens of nanometres in-depth resolution and a lateral spatial resolution controlled by pump laser pulses focusing, which could approach hundreds of nanometres. PMID- 25790809 TI - Comparison of the lubricant eyedrops Optive(r), Vismed Multi(r), and Cationorm(r) on the corneal healing process in an ex vivo model. AB - PURPOSE: To evaluate the impact of lubricant eyedrops on the corneal healing process and corneal toxicity. METHODS: Optive(r) and Cationorm(r) were tested regarding corneal irritability against Vismed Multi(r) and 0.01% benzalkonium chloride as negative and positive control, respectively. Formulas were applied on rabbit corneas (n = 5) cultured on artificial anterior chambers (EVEIT system) hourly over 3 days. Initially, 4 corneal abrasions (2-5.4 mm2) were induced. All defects were monitored during drug application by fluorescein stains and photographs. To ensure corneal vitality, glucose and lactate concentrations were determined photometrically in artificial anterior chamber fluids. Corneal fluorescein sodium permeability was tested as an indicator of the corneal barrier function. RESULTS: Optive(r) and Vismed Multi(r) showed a complete corneal healing on day 2. In one cornea (Optive(r)), erosion reoccurred on day 3. Erosion sizes of Cationorm(r)-treated corneas increased significantly from 12.20 mm2 to a subtotal erosion of 51.89 mm2 on day 3. Histology revealed epithelial loss and severe alterations of the superficial stroma for Cationorm(r). Glucose and lactate concentrations did not change after application of Optive(r) and Vismed Multi(r). In contrast, Cationorm(r)- and BAC-treated corneas showed a significant increase in lactate concentrations. CONCLUSIONS: Vismed Multi(r) application resulted in rapid corneal healing. Whether the toxicity seen for Optive(r) in one cornea is a valid result should be examined further. Cationorm(r) showed considerable corneal toxicity that could be caused by its additive, cetalkonium chloride. Otherwise, the electrostatic properties of Cationorm(r) led to a drug film on the area of epithelial loss that could hinder epithelial cell migration and adhesion in order to heal the lesion. PMID- 25790810 TI - Effect of interferon alpha2a in cystoid macular edema due to intraocular infection. AB - PURPOSE: Cystoid macular edema (CME) is a severe complication and a major cause of visual loss in patients with intraocular infection. In this type of CME, therapeutic strategies remain controversial. We aimed to investigate the efficacy and tolerability of interferon (IFN)-alpha2a in cystoid macular edema caused by intraocular infection. METHODS: In this retrospective, noncomparative, interventional case series, 5 patients (6 eyes) who were diagnosed with intraocular infection with chronic CME were included. Interferon-alpha2a (3 million units 3 times a week) was administered subcutaneously. Clinical observations were recorded before and after treatment. RESULTS: The average duration of CME before treatment with IFN-alpha was 26 months. According to the preset criteria, IFN-alpha2a therapy was shown to be effective in 2 patients (3 eyes), effective dose-dependent in 2 patients, and partly effective in 1 patient, and was well-tolerated in 4 patients. The most common side effect was flu-like symptoms. CONCLUSIONS: Interferon alpha-2a may be an effective alternative treatment for CME due to intraocular infection that is resistant to other treatment. Studies with larger sample sizes are required to confirm this conclusion. PMID- 25790811 TI - Intravitreal dexamethasone implant for cystoid macular edema and inflammation after scleral buckling. AB - PURPOSE: Cystoid macular edema may occur following scleral buckling and therefore deteriorate the visual outcome. Inflammation may be the major causative factor in the development of postoperative cystoid macular edema. This case demonstrates the effectiveness of a dexamethasone implant as a treatment after the onset of choroidal inflammation and cystoid macular edema 6 months following scleral buckling and having visual acuity restored. METHODS: A 59-year-old phakic woman treated with scleral buckling for macula-off retinal detachment presented 2 months after surgery with cystoid macular edema with choroidal inflammation. Optical coherence tomography and fluorescein angiography were performed. From the time of the diagnosis, the patient's condition had been nonresponsive to medical therapy and only partially responsive to sub-Tenon triamcinolone acetonide. An intravitreal implant with a sustained release of 0.7 mg dexamethasone was implanted. RESULTS: Following an intravitreal injection with a dexamethasone implant, the macular edema subsided completely and optical coherence tomography showed decreased foveal thickness from 510 MUm to 220 MUm. Choroidal fluorescein leakage disappeared. Best-corrected visual acuity improved from 0.70 to 0.20 logMAR, a condition maintained throughout the 6 months of follow-up. CONCLUSIONS: Cystoid macular edema and choroidal inflammation are difficult to treat, but the improvement observed in this case of post scleral buckling macular edema and choroidal inflammation showed how a dexamethasone implant proved to be useful during the 6-month follow-up. PMID- 25790812 TI - Unique genomic profile associated with pediatric uveal melanoma. AB - PURPOSE: To determine genetic features of a pediatric uveal melanoma in a 6-year old girl by array-based comparative genomic hybridization (a-CGH) and assess prognosis, and to search for constitutional copy number variations (CNVs) encompassing oncosuppressor genes. METHODS: High-resolution a-CGH was performed on genomic DNA from cancer cells and from peripheral blood cells. Histopathology and clinical staging of the tumor were simultaneously assessed. RESULTS: Array based CGH revealed no CNVs on tumor cells associated with poor prognosis; namely, no monosomy 3, losses of 1p, 6q, or 8p, and no gains of 8q. A unique genomic profile was observed, consisting mainly of partial terminal duplications affecting chromosomes 1, 4, 5, 9, 10, 11, 16, and 19, and complete trisomy of chromosomes 6, 7, and 20. The nonmetastatic tumor had predominantly epithelioid histology. No constitutional CNVs encompassing oncosuppressor genes were detected. CONCLUSIONS: We report a very rare uveal melanoma characterized by low risk genomic profile and poor prognostic histologic and clinical features. The child is relapse-free at 1-year follow-up. The unusual CNVs detected by a-CGH suggest specific pathogenic mechanisms. PMID- 25790813 TI - Assessment of modifications in thickness, curvatures, and volume upon the cornea caused by disposable soft contact lens wear. AB - PURPOSE: To assess the effect of different disposable soft contact lenses on several corneal parameters-thickness, anterior and posterior curvature, and volume-by means of a Scheimpflug imaging-based device (Pentacam HR). Diurnal variations of these parameters were taken into account. METHODS: Twenty-one young, healthy subjects wore 4 different types of daily disposable soft contact lenses on 4 different days: Dailies AquaComfort Plus, SofLens, Dailies Total1, and Acuvue TruEye. The lenses had different material and water content. Pachymetry and curvature maps and corneal volume values were obtained using the Pentacam HR twice a day: one before putting the lens on and one after an 8-hour period of contact lens wear. Measurements were also taken without any contact lenses being worn. RESULTS: Regarding corneal thickness, the lens with the most similar behavior to the naked eye scenario was the Dailies Total1, causing a thickening of 0.2 +/- 0.1% in the central zone and 0.6 +/- 0.2% in the periphery. All 4 lenses caused a slight but not significant flattening in the anterior corneal curvature, whereas the posterior corneal curvature only experienced a significant but small steepening with the SofLens. The use of these lenses increased corneal volume slightly. CONCLUSIONS: Variations in corneal parameters seem to depend on the type of contact lens used (material, oxygen transmissibility, water content). However, the magnitude of the changes introduced by the use of soft contact lenses over the 8-hour period was small and probably not large enough to influence either visual acuity or comfort. PMID- 25790814 TI - Recent advances in multiple myeloma. PMID- 25790816 TI - Crossroads of age, diet and bladder function. PMID- 25790815 TI - Current updates on the molecular genetics and magnetic resonance imaging of focal nodular hyperplasia and hepatocellular adenoma. AB - Focal nodular hyperplasia (FNH) and hepatocellular adenomas (HCAs) constitute benign hepatic neoplasms in adults. HCAs are monoclonal neoplasms characterised by an increased predilection to haemorrhage and also malignant transformation. On the other hand, FNH is a polyclonal tumour-like lesion that occurs in response to increased perfusion and has an uneventful clinical course. Recent advances in molecular genetics and genotype-phenotype correlation in these hepatocellular neoplasms have enabled a new classification system. FNHs are classified into the typical and atypical types based on histomorphological and imaging features. HCAs have been categorised into four subtypes: (1) HCAs with HNF-1alpha mutations are diffusely steatotic, do not undergo malignant transformation, and are associated with familial diabetes or adenomatosis. (2) Inflammatory HCAs are hypervascular with marked peliosis and a tendency to bleed. They are associated with obesity, alcohol and hepatic steatosis. (3) HCAs with beta-catenin mutations are associated with male hormone administration and glycogen storage disease, frequently undergo malignant transformation and may simulate hepatocellular carcinoma on imaging. (4) The final type is unclassified HCAs. Each of these except the unclassified subtype has a few distinct imaging features, often enabling reasonably accurate diagnosis. Biopsy with immunohistochemical analysis is helpful in difficult cases and has strong implications for patient management. TEACHING POINTS: * FNHs are benign polyclonal neoplasms with no risk of haemorrhage or malignancy. * HCAs are benign monoclonal neoplasms classified into four subtypes based on immunohistochemistry. * Inflammatory HCAs show an atoll sign with a risk of bleeding and malignant transformation. * HNF-1alpha HCAs are steatotic HCAs with minimal complications and the best prognosis. * beta-Catenin HCA shows variable MRI features and a high risk of malignancy. PMID- 25790817 TI - Overuse of proton pump inhibitors. AB - Proton pump inhibitors (PPIs) are currently the most effective drugs inhibiting hydrochloric acid secretion. They have replaced histamine type 2 receptor antagonists in the majority of clinical indications, for example, functional dyspepsia, gastroesophageal reflux disease, or drug-induced upper gastrointestinal tract injury. High prevalence of acid-related upper gastrointestinal tract diseases, as well as the potency, good tolerance, and acceptable costs of treatment with PPIs have largely increased their use in hospitals and outpatient clinics. At present, PPIs are used more frequently, often long-term and in high doses, and not necessarily according to the current recommendations. PPI-induced inhibition of hydrochloric acid secretion causes iatrogenic hypochlorhydria and hypergastrinemia, which may result in parietal cell hypertrophy and enterochromaffin-like cell hyperplasia, exposing patients to rebound hydrochloric acid hypersecretion. It is believed that this phenomenon may be responsible for failure to discontinue pharmacotherapy with PPIs and to their overuse. As a result, an inappropriate, especially chronic, treatment increases the risk of some side effects as well as individual and institutional expenditures. Therefore, a reasonable approach to clinical indications, dosing, and treatment regimen in each individual patient should be recommended. PMID- 25790820 TI - Non-fatal acute haemorrhagic leukoencephalitis following snake bite: A case report. AB - Acute haemorrhagic leukoencephalitis (AHL) is a fulminant inflammatory disease of cerebral white matter, characterised by demyelination and haemorrhagic necrosis. The outcome is usually fatal with only few survivors. An unusual presentation of a 44-year-old South Indian farmer who developed AHL following a snake bite is reported. Though the initial brain imaging showed extensive involvement of the white matter with multiple haemorrhagic foci, the patient improved spontaneously with no specific therapy. A repeat magnetic resonance imaging of the brain 28 days after the snake bite confirmed radiological improvement. PMID- 25790819 TI - Phenoxy herbicides, soft-tissue sarcoma and non-Hodgkin lymphoma: a systematic review of evidence from cohort and case-control studies. AB - BACKGROUND: Phenoxy herbicides have been used widely in agriculture, forestry, parks and domestic gardens. Early studies linked them with soft-tissue sarcoma (STS) and non-Hodgkin lymphoma (NHL), but when last reviewed by the International Agency for Research on Cancer in 1986, the evidence for human carcinogenicity was limited. SOURCES OF DATA: We searched Medline and Embase, looking for cohort or case-control studies that provided data on risk of STS and/or NHL in relation to phenoxy herbicides, and checked the reference lists of relevant publications for papers that had been missed. AREAS OF AGREEMENT, AREAS OF CONTROVERSY: The extensive evidence is not entirely consistent, and a hazard of STS or NHL cannot firmly be ruled out. However, if there is a hazard, then absolute risks must be small. GROWING POINTS, AREAS TIMELY FOR DEVELOPING RESEARCH: Extended follow-up of previously assembled cohorts may be the most efficient way of further reducing uncertainties. PMID- 25790821 TI - A leap of faith? An interview study with professionals on the use of mitochondrial replacement to avoid transfer of mitochondrial diseases. AB - STUDY QUESTION: What are the opinions of professionals in the field of genetics, reproductive science and metabolic diseases on the development of mitochondrial replacement technologies to be used in the context of medically assisted reproduction? SUMMARY ANSWER: Although concerns regarding safety remain, interviewees supported the development of nuclear transfer techniques to help women who are at risk of transferring a mitochondrial DNA disease to their offspring conceive a genetically related child. WHAT IS KNOWN ALREADY: Technological developments in the field of nuclear transfer have sparked new interest in the debate on the acceptability of the use of donor oocytes to prevent the transmission of mitochondrial diseases. For example, in the UK, extensive public consultations have been done to investigate whether such techniques would allow the passing of a law that involves making changes to a human oocyte or embryo before transfer to a woman's body. Until now, continental European countries seem to await the outcome of the British debate before themselves considering the arguments for and against this technology. STUDY DESIGN, SIZE, AND DURATION: We interviewed 12 professionals from Belgium and The Netherlands. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: We conducted 12 interviews with fertility specialists, scientists, clinical geneticists, a pediatrician specialized in metabolic diseases and a specialist in metabolic diseases. The profiles of the interviewees varied but all had experience with mitochondrial diseases, either in treating patients or in providing counseling to patients or to prospective parents. The interviews were conducted face-to-face and took 30-45 min. The language of the interviews was Dutch. We analyzed the transcript of these interviews using QSR NVIVO 10 software to extract themes and categories. MAIN RESULTS AND THE ROLE OF CHANCE: This study has shown that, although amongst the professionals we interviewed there was support for the development and deployment of nuclear transfer, this support does not necessarily correspond to uniform opinions about the importance of having a genetically own child or the contribution of mitochondrial DNA to essential characteristics of an individual. LIMITATIONS, REASONS FOR CAUTION: In translating the quotes from Dutch to English some of the linguistic nuances may have been lost. We only interviewed 12 individuals, in two countries, whose view may not be representative of existing values and opinions that may be held by professionals worldwide on this matter. To further explore the issue at hand, a subsequent investigation of the opinions of people affected by mitochondrial diseases and of the general public is necessary. WIDER IMPLICATIONS OF THE FINDINGS: With this study we have demonstrated there is in principle support for the nuclear transfer technique from Dutch and Belgian professionals. Further research, both scientific and ethical, is needed to define the modalities of its possible introduction in the fertility clinic. STUDY FUNDING/COMPETING INTERESTS: This research was funded by GROW, School for Oncology and Developmental Biology, The Netherlands. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A. PMID- 25790822 TI - Sex hormone affects the severity of non-alcoholic steatohepatitis through the MyD88-dependent IL-6 signaling pathway. AB - Recent research has shown that the occurrence of gender disparity in liver cancer associated with sex differences in MyD88-dependent IL-6 production, but the role of this signaling pathway in sex differences of non-alcoholic steatohepatitis (NASH) remains unknown. To investigate the effects of sex hormone-specific intervention on pathology and progression of NASH, and on the inflammatory TLR MyD88-IL-6 signaling pathway NASH was modeled in C57/BL6 mice by feeding a methionine and choline-deficient (MCD) diet for 4 weeks. Male mice were subjected to sex hormone-related interventions such as orchidectomy, and orchidectomy combined with administration of either testosterone propionate or estradiol benzoate. Next, the degree of non-alcoholic fatty liver disease activity score (NAS), serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the expression level of MyD88 and IL-6, were compared between these groups. Males developed more serious inflammatory problems and had a higher NAS than the females. Sex-specific intervention in male mice by orchidectomy reduced NAS, ALT, and AST, and the expression level of MyD88 and IL 6. But administration of exogenous androgen had no influence on either NAS or the expression of ALT, AST, MyD88, and IL-6. On the other hand, exogenous estrogen could alleviate the pathological damage caused by NASH, as well as reduce NAS, ALT and AST, and the expression of MyD88 and IL-6. The result show different sex hormone-related interventions affected the severity of NASH, possibly by modulating the level of sex hormones and regulating the TLR-MyD88-IL-6 signaling pathway. PMID- 25790824 TI - Tracking of examination and dose: overview. AB - This paper reviews the developments in tracking of patient exposures and dose after the earlier paper published in the same journal in 2011. A global survey in which 76 countries responded indicated strong interest in programme and another survey among referring physicians showed vast majority (71.7 %) of physicians expressing that awareness of previous history of CT scans would always or mostly lead them to a better decision on referring patients for CT scans. A sizable number of countries have system of assigning permanent ID to individuals and nearly half of them use this ID in medical records. This can easily permit tracking of exposures. Templates for tracking at different levels of health care have been provided, and experience from a country where tracking is routinely practised has been published. PMID- 25790823 TI - Overcoming the hurdles for a reproducible generation of human functionally mature reprogrammed neurons. AB - The advent of cell reprogramming technologies has widely disclosed the possibility to have direct access to human neurons for experimental and biomedical applications. Human pluripotent stem cells can be instructed in vitro to generate specific neuronal cell types as well as different glial cells. Moreover, new approaches of direct neuronal cell reprogramming can strongly accelerate the generation of different neuronal lineages. However, genetic heterogeneity, reprogramming fidelity, and time in culture of the starting cells can still significantly bias their differentiation efficiency and quality of the neuronal progenies. In addition, reprogrammed human neurons exhibit a very slow pace in gaining a full spectrum of functional properties including physiological levels of membrane excitability, sustained and prolonged action potential firing, mature synaptic currents and synaptic plasticity. This delay poses serious limitations for their significance as biological experimental model and screening platform. We will discuss new approaches of neuronal cell differentiation and reprogramming as well as methods to accelerate the maturation and functional activity of the converted human neurons. PMID- 25790825 TI - National diagnostic reference level initiative for computed tomography examinations in Kenya. AB - The purpose of this study was to estimate the computed tomography (CT) examination frequency, patient radiation exposure, effective doses and national diagnostic reference levels (NDRLs) associated with CT examinations in clinical practice. A structured questionnaire-type form was developed for recording examination frequency, scanning protocols and patient radiation exposure during CT procedures in fully equipped medical facilities across the country. The national annual number of CT examinations per 1000 people was estimated to be 3 procedures. The volume-weighted CT dose index, dose length product, effective dose and NDRLs were determined for 20 types of adult and paediatric CT examinations. Additionally, the CT annual collective effective dose and effective dose per capita were approximated. The radiation exposure during CT examinations was broadly distributed between the facilities that took part in the study. This calls for a need to develop and implement diagnostic reference levels as a standardisation and optimisation tool for the radiological protection of patients at all the CT facilities nationwide. PMID- 25790826 TI - Paediatric doses during some common X-ray procedures at selected referral hospitals in Tanzania. AB - The aim of this study was to determine the radiation doses to paediatric patients of different age groups at three large hospitals for optimisation purposes. The entrance surface air kerma (ESAK) values were determined from the measured X-ray output values using calibrated ionisation chamber, TW 233612 and clinical patient parameters. The air kerma-area product (KAP) values were measured using a calibrated Diamentor E2 system. The volume computed tomography dose index (CTDIvol) and dose length product (DLP) values were obtained from the computed tomography (CT) equipment verified by a calibrated CT chamber, Unifors Xi CT. Irrespective of age groups, the results show that the median ESAK values ranged from 62.6 to 248.1 uGy. The median KAP values ranged from 135.6 to 1612 uGy cm(2), while the median DLP values ranged from 119.1 to 600 mGy cm. Analysis of the results indicates that optimisation can be achieved through good practice awareness and patient dose and image quality evaluations. PMID- 25790827 TI - A Missense Mutation in SLC45A2 Is Associated with Albinism in Several Small Long Haired Dog Breeds. AB - Homozygosity for a large deletion in the solute carrier family 45, member 2 (SLC45A2) gene causes oculocutaneous albinism (OCA) in the Doberman Pinscher breed. An albino Lhasa Apso did not have this g.27141_31223del (CanFam2) deletion in her SLC45A2 sequence. Therefore, SLC45A2 was investigated in this female Lhasa Apso to search for other possible variants that caused her albinism. The albino Lhasa Apso was homozygous for a nonsynonymous substitution in the seventh exon, a c.1478G>A base change that resulted in a glycine to aspartic acid substitution (p.G493D). This mutation was not found in a wolf, a coyote, or any of the 15 other Lhasa Apso dogs or 32 other dogs of breeds related to the Lhasa Apso. However, an albino Pekingese, 2 albino Pomeranians, and an albino mixed breed dog that was small and long haired were also homozygous for the 493D allele. The colored puppies of the albino Lhasa Apso and the colored dam of the 2 albino Pomeranians were heterozygous for this allele. However, an albino Pug was homozygous for the 493G allele and therefore although we suggest the 493D allele causes albinism when homozygous in several small, long haired dog breeds, it does not explain all albinism in dogs. A variant effect prediction for the albino Lhasa Apso confirms that p.G493D is a deleterious substitution, and a topology prediction for SLC45A2 suggests that the 11th transmembrane domain where the 493rd amino acid was located, has an altered structure. PMID- 25790828 TI - Admixture between historically isolated mitochondrial lineages in captive Western gorillas: recommendations for future management. AB - Although captive populations of western gorilla have been maintained in the United States for over a century, little is known about the geographic origins and genetic composition of the current zoo population. Furthermore, although previous mitochondrial analyses have shown that free-range gorilla populations exhibit substantial regional differentiation, nothing is known of the extent to which this variation has been preserved in captive populations. To address these questions, we combined 379 pedigree records with data from 52 mitochondrial sequences to infer individual haplogroup affiliations, geographical origin of wild founders and instances of inter-breeding between haplogroups in the United States captive gorilla population. We show that the current captive population contains all major mitochondrial lineages found within wild western lowland gorillas. Levels of haplotype diversity are also comparable to those found in wild populations. However, the majority of captive gorilla matings have occurred between individuals with different haplogroup affiliations. Although restricting crosses to individuals within the same haplogroup would preserve the phylogeographic structure present in the wild, careful management of captive populations is required to minimize the risk of drift and inbreeding. However, when captive animals are released back into the wild, we recommend that efforts should be made to preserve natural phylogeographic structure. PMID- 25790829 TI - Mitotic and Meiotic Behavior of B Chromosomes in Crenicichla lepidota: New Report in the Family Cichlidae. AB - B chromosomes are additional genetic elements to the standard complement. They display distinctive features and have been found in 15% of eukaryote species. In this study, we analyzed 4 populations of Crenicichla lepidota from hydrographic system of Laguna dos Patos/RS (Brazil). All specimens showed 2n = 48 with 6m + 42st - a, FN = 54, with a secondary constriction on the first pair of the complement. Among the 18 samples analyzed, 6 individuals belonging to the Gasometro and Saco da Alemoa populations presented 1-3 small-sized heterochromatic B chromosomes, with intra- and interindividual variation. Simple AgNORs coincident with 18S rDNA and CMA3 positive/DAPI negative sites were present in all populations. The extra chromosomes did not exhibit any 18S rDNA sites. The meiotic analyses showed heteropycnotic regions in leptotene and zygotene stages, which may be related to the presence of B chromosomes. During pachytene were found 24 bivalents and 1 spatially separated, as well as during metaphases I and diplotene, indicating that there is no association between B chromosomes and those of the A complement. During diakinesis, an unusual meiotic configuration was observed, revealing a proximity between the bivalent and chromosome B (univalent), that might be the result of a heterochromatin affinity between these chromosomes. In anaphase I, late migration of B chromosomes was detected. The low frequency of B chromosomes in the Cichlidae family and in Crenicichla suggests its recent origin in this group and may be ascribable to animal exposure to deleterious effects under certain environmental conditions. Moreover, this is the first report in C. lepidota. PMID- 25790830 TI - Multiplex serum cytokine immunoassay using nanoplasmonic biosensor microarrays. AB - Precise monitoring of the rapidly changing immune status during the course of a disease requires multiplex analysis of cytokines from frequently sampled human blood. However, the current lack of rapid, multiplex, and low volume assays makes immune monitoring for clinical decision-making (e.g., critically ill patients) impractical. Without such assays, immune monitoring is even virtually impossible for infants and neonates with infectious diseases and/or immune mediated disorders as access to their blood in large quantities is prohibited. Localized surface plasmon resonance (LSPR)-based microfluidic optical biosensing is a promising approach to fill this technical gap as it could potentially permit real time refractometric detection of biomolecular binding on a metallic nanoparticle surface and sensor miniaturization, both leading to rapid and sample-sparing analyte analysis. Despite this promise, practical implementation of such a microfluidic assay for cytokine biomarker detection in serum samples has not been established primarily due to the limited sensitivity of LSPR biosensing. Here, we developed a high-throughput, label-free, multiarrayed LSPR optical biosensor device with 480 nanoplasmonic sensing spots in microfluidic channel arrays and demonstrated parallel multiplex immunoassays of six cytokines in a complex serum matrix on a single device chip while overcoming technical limitations. The device was fabricated using easy-to-implement, one-step microfluidic patterning and antibody conjugation of gold nanorods (AuNRs). When scanning the scattering light intensity across the microarrays of AuNR ensembles with dark-field imaging optics, our LSPR biosensing technique allowed for high-sensitivity quantitative cytokine measurements at concentrations down to 5-20 pg/mL from a 1 MUL serum sample. Using the nanoplasmonic biosensor microarray device, we demonstrated the ability to monitor the inflammatory responses of infants following cardiopulmonary bypass (CPB) surgery through tracking the time-course variations of their serum cytokines. The whole parallel on-chip assays, which involved the loading, incubation, and washing of samples and reagents, and 10-fold replicated multianalyte detection for each sample using the entire biosensor arrays, were completed within 40 min. PMID- 25790833 TI - The clinical-psychological features of functional dyspepsia patients with weight loss: a multi-center study from China. AB - AIMS: To investigate the clinical features, appetite, quality of life (QOL), and their associated psychological factors of functional dyspepsia (FD) patients with weight loss. METHODS: For a multicenter study, FD patients were recruited and divided into two groups according to the degree of weight changes during the previous 12 months or less with the onset of dyspepsia symptoms: Group A (>=5%) and Group B (<5%). Patients were evaluated based on the Nepean dyspepsia index (NDI), appetite questionnaire, Hamilton Rating Scale of Anxiety/Depression (HAMA/HAMD). RESULTS: The body mass index in Group A was lower than in Group B, while, the frequency of physician visits in Group A was higher than in Group B. There were no differences in the total scores of NDI-symptom checklist or the items of intensity and bothersomeness between them (p > 0.05), but the frequency item for Group A was significantly higher than Group B (p = 0.035). The incidence of anxiety or depression, the proportion of poor or very poor appetite for Group A was higher than those for Group B (p < 0.05). Subscale scores of the NDI-QOL for Group A were significantly lower than those for Group B (p < 0.05). CONCLUSIONS: FD patients with weight loss have lower BMI, more frequent physician visits, higher psychological disorders, poorer appetite and QoL. PMID- 25790832 TI - Inflammation Combined with Ischemia Produces Myelin Injury and Plaque-Like Aggregates of Myelin, Amyloid-beta and AbetaPP in Adult Rat Brain. AB - BACKGROUND: Ischemia, white matter injury, and Alzheimer's disease (AD) pathologies often co-exist in aging brain. How one condition predisposes to, interacts with, or perhaps causes the others remains unclear. OBJECTIVES: To better understand the link between ischemia, white matter injury, and AD, adult rats were administered lipopolysaccharide (LPS) to serve as an inflammatory stimulus, and 24 h later subjected to 20-min focal cerebral ischemia (IS) followed by 30-min hypoxia (H). METHODS: Myelin and axonal damage, as well as amyloid-beta (Abeta) and amyloid-beta protein precursor (AbetaPP) deposition were examined by Western blot and immunocytochemistry following LPS/IS/H. Findings were compared to the 5XFAD mouse AD brain. RESULTS: Myelin/axonal injury was observed bilaterally in cortex following LPS/IS/H, along with an increase in IL 1, granzyme B, and LPS. AbetaPP deposition was present in ischemic striatum in regions of myelin loss. Abeta(1-42) and AbetaPP were deposited in small foci in ischemic cortex that co-localized with myelin aggregates. In the 5XFAD mouse AD model, cortical amyloid plaques also co-localized with myelin aggregates. CONCLUSIONS: LPS/IS/H produce myelin injury and plaque-like aggregates of myelin. AbetaPP and Abeta co-localize with these myelin aggregates. PMID- 25790834 TI - Evaluating eccentric hip torque and trunk endurance as mediators of changes in lower limb and trunk kinematics in response to functional stabilization training in women with patellofemoral pain. AB - BACKGROUND: Altered movement patterns of the trunk and lower limbs have been associated with patellofemoral pain (PFP). It has been assumed that increasing the strength of the hip and trunk muscles would improve lower limb and trunk kinematics in these patients. However, evidence in support of that assumption is limited. PURPOSE: To determine whether increases in the strength of hip muscles and endurance of trunk muscles in response to functional stabilization training will mediate changes in frontal plane lower limb kinematics in patients with PFP. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-one female athletes were randomized to either a functional stabilization training group that emphasized strengthening of the trunk and hip muscles or a standard training group that emphasized stretching and quadriceps strengthening. Patients attended a baseline assessment session, followed by 8 weeks of intervention, and were then reassessed at the end of the intervention period. The potential mediators that were evaluated included eccentric torque of hip muscles and endurance of the trunk muscles. The outcome variables were the lower limb and trunk kinematics in the frontal plane assessed during a single-legged squat task. RESULTS: The eccentric strength of the gluteus muscles showed a mediation effect ranging from 18% to 32% on changes to frontal plane kinematics (decreased ipsilateral trunk inclination, pelvis contralateral depression, and hip adduction excursions) observed in the functional stabilization training group after intervention. CONCLUSION: Although the mediation effects were small, the results suggest that improvements in the strength of the gluteus muscles can influence the frontal plane movement patterns of the lower limb and trunk in women with PFP. CLINICAL RELEVANCE: Patients with PFP might benefit from strengthening of the hip muscles to improve frontal plane lower limb and trunk kinematics during functional tasks. PMID- 25790835 TI - Do postoperative platelet-rich plasma injections accelerate early tendon healing and functional recovery after arthroscopic supraspinatus repair? A randomized controlled trial. AB - BACKGROUND: Tendon-bone healing after rotator cuff repair directly correlates with a successful outcome. Biological therapies that elevate local growth-factor concentrations may potentiate healing after surgery. PURPOSE: To ascertain whether postoperative and repeated application of platelet-rich plasma (PRP) to the tendon repair site improves early tendon healing and enhances early functional recovery after double-row arthroscopic supraspinatus repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 60 patients underwent arthroscopic double-row supraspinatus tendon repair. After randomization, half the patients received 2 ultrasound-guided injections of PRP to the repair site at postoperative days 7 and 14. Early structural healing was assessed with MRI at 16 weeks, and cuff appearances were graded according to the Sugaya classification. Functional scores were recorded with the Oxford Shoulder Score; Quick Disability of the Arm, Shoulder and Hand; visual analog scale for pain; and Short Form-12 quality-of-life score both preoperatively and at postoperative weeks 6, 12, and 16; isokinetic strength and active range of motion were measured at 16 weeks. RESULTS: PRP treatment did not improve early functional recovery, range of motion, or strength or influence pain scores at any time point after arthroscopic supraspinatus repair. There was no difference in structural integrity of the supraspinatus repair on MRI between the PRP group (0% full-thickness retear; 23% partial tear; 77% intact) and the control group (7% full-thickness retear; 23% partial tear; 70% intact) at 16 weeks postoperatively (P = .35). CONCLUSION: After arthroscopic supraspinatus tendon repair, image guided PRP treatment on 2 occasions does not improve early tendon-bone healing or functional recovery. PMID- 25790836 TI - Shoulder functional performance status of National Collegiate Athletic Association swimmers: baseline Kerlan-Jobe Orthopedic Clinic scores. AB - BACKGROUND: Shoulder trouble, described in the literature as "swimmer's shoulder," has been associated with competitive swimmers. The Kerlan-Jobe Orthopedic Clinic (KJOC) Shoulder and Elbow Score is a validated survey used to define functional and performance measures of the upper extremity in overhead athletes. To date, no study has investigated the baseline functional scores for swimmers actively competing in the sport. PURPOSE: To establish a baseline score for National Collegiate Athletic Association (NCAA) swimmers actively competing in the sport. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: After institutional review board approval, the KJOC Shoulder and Elbow Score was administered to 5 NCAA swim teams (N = 99 participants; 46 men, 53 women). The results on 10 specific individual questions and on the total score were calculated according to the survey's original description. The mean scores were calculated for all participants. The Mann-Whitney U test was used to determine differences between sexes, years swimming, and self-reported injury status. RESULTS: The mean +/- SD baseline KJOC score (out of a possible 100) for all participants was 79.0 +/- 18.7; the mean score for men was 81.9 +/- 15.6 and for women 76.6 +/- 20.8. The score for athletes identifying themselves as injured at baseline was 53.9 +/- 18.8, compared with 84.4 +/- 13.6 for those not reporting as injured (P < .001). Athletes competing >=11 years had a mean score of 72.0 +/- 22.1; those competing <=10 years scored 86.4 +/- 11.4 (P = .007). CONCLUSION: Baseline scores for swimmers, which were lower than expected, were lower than baseline scores seen in studies of other overhead sports athletes. The data corroborate previous studies identifying swimmers as having a high level of shoulder trouble. Further research is indicated for improving shoulder symptoms and performance in competitive swimmers. PMID- 25790837 TI - Surgical excision of posttraumatic ossifications at the proximal hamstrings in young athletes: technique and outcomes. AB - BACKGROUND: Proximal hamstring tears can be associated with chronic disability related to the unusual formation of heterotopic ossifications. The role for operative intervention in these circumstances has not been clearly defined. PURPOSE/HYPOTHESIS: The purpose of this study was to describe the surgical management of young athletes who had chronic disability related to proximal hamstring ossifications after eccentric load injuries. The hypothesis was that after surgical excision of posttraumatic heterotopic ossifications at the proximal hamstrings with concomitant repair of the tendons to the ischium, significant functional improvement with low risk of postoperative complications can be expected at minimum 2-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The cases of 11 consecutive male athletes who developed chronic disability associated with heterotopic ossifications at the proximal hamstring muscles after sports-related tears were reviewed. During surgery, the ossified mass was meticulously excised, and the tendons were debrided and fixed to the ischium. At minimum 2-year follow-up, self-reported outcome was rated as excellent, good, moderate, or poor. Operative reports and office visits were reviewed. Activity level before the injury and at latest follow-up was graded with the Tegner scale. RESULTS: The median age at injury was 17 years (range, 13 25 years). Sports activities included ice hockey, soccer, track and field athletics, and judo. Mean interval from injury to surgery was 45 months. The smallest ossified mass was 2 * 2 * 4 cm and the largest, 3 * 4 * 9 cm. Median follow-up was 4 years (range, 2-10 years). Six patients had excellent, 1 patient had good, and 4 patients had moderate outcomes; 7 of them were able to return to preinjury activities (Tegner score, 7-10). There were 2 cases of loss of skin sensation at the posterior femoral cutaneous nerve distribution, but neither patient described this as significantly interfering with any activity. All patients had symmetric side-to-side single-legged hop test and a 5 out of 5 on hamstring muscle strength at latest follow-up. CONCLUSION: Heterotopic ossifications that develop at the proximal hamstrings after eccentric load injuries can be associated with significant chronic disability. These cases can be effectively treated by surgical excision of the ossified masses and concomitant debridement with suture fixation of the proximal hamstring tendons to the ischium. Return to preinjury activities is expected in the majority of these cases, with low postoperative risks. PMID- 25790838 TI - Is the Geriatric Nutritional Risk Index a Significant Predictor of Postoperative Complications in Patients with Esophageal Cancer Undergoing Esophagectomy? AB - BACKGROUND: The Geriatric Nutritional Risk Index (GNRI) is a new index recently introduced for predicting the risk of nutrition-related complications. The GNRI has mainly been reported as a simple and accurate tool to assess the nutritional status and prognosis of elderly patients. So far, there have been no reports of the GNRI in patients with gastrointestinal cancer. Our objective was to examine the association between the GNRI and short-term outcomes, especially postoperative complications, in patients with esophageal cancer who underwent esophagectomy and gastric tube reconstruction. MATERIALS AND METHODS: The present study enrolled 122 consecutive patients with esophageal cancer who underwent esophagectomy and gastric tube reconstruction. The GNRI at admission to the hospital was calculated as follows: (1.489 * albumin in g/l) + (41.7 * present/ideal body weight). The characteristics and short-term outcomes were compared between two groups: the high (GNRI >=90) and the low (GNRI <90) GNRI group. The mortality and morbidity rates, especially the rates regarding respiratory complications and anastomotic leakage, were investigated. RESULTS: The mean age of the 122 patients was 63.9 +/- 9.1 years (range 43-83). There were no significant differences in either patient or operative characteristics. The low GNRI group had a significantly higher rate of respiratory complications (p = 0.002). A multivariate analysis demonstrated that the GNRI was the only independent significant factor predicting respiratory complications (hazard ratio 3.41, 95% confidence interval 1.19-9.76; p = 0.022). CONCLUSION: The GNRI is considered to be a clinically useful marker that can be used to assess the nutritional status and predict the development of postoperative respiratory complications in patients with esophageal cancer undergoing esophagectomy and gastric tube reconstruction. PMID- 25790839 TI - Midtrimester Isolated Short Femur Length as a Predictor of Adverse Pregnancy Outcome. AB - OBJECTIVE: The aim of this study was to investigate whether midtrimester isolated short femur length is associated with pregnancy complications. STUDY DESIGN: Retrospective analysis of pregnancies with a midtrimester femur length <5th percentile for gestational age compared to controls with a femur length >=5th percentile. Outcome measures included hypertensive disorders, being small for gestational age, oligohydramnios and preterm delivery. RESULTS: 2,105 women were eligible for this study, 85 (3.45%) of whom were in the study group and 2,020 were controls. Birth weight <10th percentile for gestational age (OR 4.4, 95% CI 2.5-7.8), birth weight <3rd percentile for gestational age (OR 31.0, 95% CI 13.3 72.3) and severe preeclampsia (OR 6.3, 95% CI 1.4-28.6) were significantly associated with midtrimester isolated short femur length. CONCLUSIONS: Midtrimester isolated short femur length is associated with higher rates of being small for gestational age and preeclampsia. PMID- 25790840 TI - An update on Middle East respiratory syndrome: 2 years later. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) was first recognized in 2012 and since then has resulted in cases in 23 countries in four continents. The majority of these cases were reported from the Kingdom of Saudi Arabia. The disease caused a spectrum of illness, from asymptomatic to severe and possibly fatal disease. Recent studies showed that the transmission of MERS-CoV among family contacts remains relatively low. Currently, there are no approved vaccines or therapeutics for MERS-CoV. PMID- 25790841 TI - Editorial: subjective perceptions of memory functioning in old age - nature, correlates, and developmental trajectories. AB - Subjective memory complaints are often used as diagnostic criteria for several neurocognitive disorders. Although a number of studies have examined subjective memory and its associations with memory functioning in adulthood and old age, it is still an open question whether subjective perceptions of one's memory indicate actual memory functioning or whether they are rather derived from factors other than memory, such as depressive symptoms. The studies in this special section examine subjective perceptions of memory functioning and their associations with objectively measured memory performance in general and in clinical populations. The four articles adopt cross-sectional and longitudinal methodologies and offer key insights into the nature, correlates, and developmental trajectories of subjective memory. To begin with, the studies compiled in this special section demonstrate that changes in subjective memory perceptions are indeed associated with changes in memory performance [Zimprich and Kurtz, this issue, pp. 223-231], but the size of associations between levels of and changes in subjective memory and memory performance is in part modulated by personality characteristics and depressive symptoms [Hulur et al., this issue, pp. 232-240]. Second, the studies compiled here show that factors other than memory are also closely associated with memory perceptions, including functional health as well as domain-general and health-specific control beliefs [Luszcz et al., this issue, pp. 241-250]. Third, the study by Thompson et al. [this issue, pp. 251-257] shows that self- and informant-reports of retrospective and prospective memory difficulties are not associated with performance-based measures and does not sufficiently differentiate between healthy controls and patients diagnosed with mild cognitive impairment or dementia. In our editorial, we put these findings in perspective and discuss implications for research and practice. To extend our knowledge, we conclude by outlining two key avenues for future research: (i) longitudinal multivariate studies of the construct space surrounding subjective memory and (ii) the viability of experience sampling studies with daily or hourly measurements to tackle some of the mechanisms underlying these associations. PMID- 25790842 TI - AMH and AMHR2 polymorphisms and AMH serum level can predict assisted reproduction outcomes: a cross-sectional study. AB - BACKGROUND: In human assisted reproduction, the ovarian response to exogenous recombinant Follicle-stimulating Hormone (FSH) therapy is variable and difficult to predict. The standard protocol of ovarian hyperstimulation can result in satisfactory response; however, an unsatisfactory response necessitates FSH dose adjustment or results in ovarian hyperstimulation syndrome (OHSS). Polymorphisms in AMH and AMHR2 genes appear to affect hormone biological activities, thus affecting follicle recruitment and development, leading to infertility. We aimed to evaluate AMH and AMHR2 polymorphisms in infertile women, and correlate those findings with AMH, FSH and estradiol serum level response to controlled ovarian hyperstimulation (COH), as well as assisted reproduction outcomes. METHODS: A cross-sectional study comprising 186 infertile women that underwent one cycle of high complexity assisted reproductive treatment. Blood samples were collected and a TaqMan assay was used for AMH G146T/rs10407022 and AMHR2 A-482G/rs2002555, A10G/rs11170555, C1749G/rs2071558 and G4952A/rs3741664 genotyping, and FSH, estradiol and AMH levels were measured. The findings were correlated to human reproduction outcomes. RESULTS: AMH rs10407022 and AMHR2 rs2002555 polymorphisms were not associated with hormonal measurements, whereas AMHR2 rs11170555 and rs3741664 were positively associated with AMH, estradiol and FSH levels. The genotype distribution of AMH and AMHR2 genes according to Controlled Ovarian Hyperstimulation did not show a positive association. However, an association with AFC, degree of oocyte maturation (allele G of AMHR2 rs2071558) the number of embryos produced (alleles T and G of AMH rs10407022 and AMHR2 rs2002555, respectively) and frozen embryo (allele G of AMHR2 rs11170555) were found to be statistically associated. Considering COH, serum AMH and AFC were a positive predictor to OHSS. Regarding serum AMH and assisted reproduction outcomes, a positive correlation with all variables studied was found. Comparing AFC and AMH as predictors of human reproduction outcomes, the AFC was less effective than serum AMH. Considering pregnancy rates, no marker was positively associated. CONCLUSION: AMHR2 polymorphisms were associated with estradiol, AMH and FSH measurements, as well as number and quality of embryos, while AMH polymorphisms was associated with number of embryos produced. Serum AMH was correlated with nearly all variables analyzed in assisted reproductive treatment, demonstrating that it represents a better biomarker of OHSS and human reproduction outcomes compared to AMH and AMHR2 polymorphisms. PMID- 25790843 TI - The shortcomings of clinical practice guidelines. AB - Accumulation of medical knowledge related to diagnosis and management over the last 5-6 decades has altered the course of diseases, improved clinical outcomes and increased survival. Thus, it has become difficult for the practicing physician to evaluate the long-term effects of a particular therapy on survival of an individual patient. Further, the approach by each physician to an individual patient with the same disease is not always uniform. In an attempt to assist physicians in applying newly acquired knowledge to patients, clinical practice guidelines were introduced by various scientific societies. Guidelines assist in facilitating the translation of new research discoveries into clinical practice; however, despite the improvements over the years, there are still several issues related to guidelines that often appear 'lost in translation'. Guidelines are based on the results of randomized clinical trials, other nonrandomized studies, and expert opinion (i.e. the opinion of most members of the guideline committees). The merits and limitations of randomized clinical trials, guideline committees, and presentation of guidelines will be discussed. In addition, proposals to improve guidelines will be presented. PMID- 25790831 TI - Soluble BACE-1 Activity and sAbetaPPbeta Concentrations in Alzheimer's Disease and Age-Matched Healthy Control Cerebrospinal Fluid from the Alzheimer's Disease Neuroimaging Initiative-1 Baseline Cohort. AB - beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays an important role in the development of Alzheimer's disease (AD), freeing the amyloid-beta (Abeta) N-terminus from the amyloid-beta protein precursor (AbetaPP), the first step in Abeta formation. Increased BACE1 activity in AD brain or cerebrospinal fluid (CSF) has been reported. Other studies, however, found either no change or a decrease with AD diagnosis in either BACE1 activity or sAbetaPPbeta, the N terminal secreted product of BACE1 (sBACE1) activity on AbetaPP. Here, sBACE1 enzymatic activity and secreted AbetaPPbeta (sAbetaPPbeta) were measured in Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1) baseline CSF samples and no statistically significant changes were found in either measure comparing healthy control, mild cognitively impaired, or AD individual samples. While CSF sBACE1 activity and sAbetaPPbeta demonstrated a moderate yet significant degree of correlation with each other, there was no correlation of either analyte to CSF Abeta peptide ending at residue 42. Surprisingly, a stronger correlation was demonstrated between CSF sBACE1 activity and tau, which was comparable to that between CSF Abeta42 and tau. Unlike for these latter two analytes, receiver operator characteristic curves demonstrate that neither CSF sBACE1 activity nor sAbetaPPbeta concentrations can be used to differentiate between healthy elderly and AD individuals. PMID- 25790844 TI - Sleep, anxiety and electronic device use by athletes in the training and competition environments. AB - This study subjectively assessed sleep quality and quantity, state anxiety and electronic device use during a 7-day training week (TRAIN) and a 7-day competitive tournament (COMP). Eight state-level netball players used wrist-watch actigraphy to provide indirect sleep measures of bedtime, wake time, sleep duration, sleep onset latency, sleep efficiency, wake after sleep onset and fragmentation index. State anxiety was reported using the anxiety sub-scale in the Profile of Mood States-Adolescents. Before bed duration of electronic device use and the estimated time to sleep after finishing electronic device use was also recorded. Significant main effects showed that sleep efficiency (p = 0.03) was greater in COMP as compared to TRAIN. Furthermore, the bedtime and wake time were earlier (p = 0.01) during COMP. No further differences existed between conditions (p > 0.05). However, strong negative associations were seen between state anxiety and the sleep quality rating. Here, sleep efficiency was likely greater in COMP due to the homeostatic need for recovery sleep, resulting from the change in environment from training to competition. Furthermore, an increased anxiety before bed seems to influence sleep quality and should be considered in athletes portraying poor sleep habits. PMID- 25790845 TI - Repeated fine-needle aspiration improves the diagnostics in selected atypia of undetermined significance/follicular lesion of undetermined significance cases, but further studies are needed. PMID- 25790846 TI - Randomized Controlled Trial Comparing the Efficacy of Impedance Control and Temperature Control of Radiofrequency Interstitial Thermal Ablation for Treating Small Hepatocellular Carcinoma. AB - OBJECTIVES: A randomized controlled trial was conducted to evaluate the efficacy of impedance control of a radiofrequency interstitial thermal ablation system (RITA) used to treat hepatocellular carcinoma (HCC). METHODS: Fifteen patients with hypervascular HCCs <20 mm in diameter were randomly treated with radiofrequency ablation (RFA) using conventional temperature control (group A) or impedance control methods (group B). RITA needle electrodes were used in all cases. We compared ablation time, extent of lesion ablation, and energy use between the two groups. RESULTS: The median long and short diameters of the axial cross sections of radiofrequency-induced necrotic areas visualized by CT were 32 mm (range, 26-36) and 25 mm (20-31) in group A and 32 mm (28-40) and 31 mm (24 37) in group B, respectively. The short diameter of group B patients was significantly greater than that of group A patients (p = 0.029). The median ablation time was 18.8 min in group A and 13.4 min in group B, thus significantly shorter in group B (p = 0.001). The energy requirement did not differ significantly between the groups. CONCLUSIONS: Impedance control of the RITA system resulted in an increased size of the ablation zone and a decreased ablation time. PMID- 25790847 TI - Hypocalcemia post denosumab in patients with chronic kidney disease stage 4-5. AB - BACKGROUND: Denosumab, a RANK-ligand inhibitor, is an effective treatment for osteoporosis in postmenopausal women and men. Unlike the bisphosphonates, it is not excreted by the kidney. Little is known, however, about its efficacy and safety in patients with severe chronic kidney disease (CKD). METHODS: A retrospective study was performed in CKD 4-5D patients from a tertiary referral hospital who were treated with denosumab between 1st January 2011 and 31st March 2014. Data collected included information about the following: CKD stage, fracture history, bone mineral density, serum calcium levels pre and post denosumab treatment, episodes of hypocalcemia, relevant medications and adverse events. RESULTS: Eight patients with CKD-5 and 6 patients with CKD-4 were identified (all female, mean age 77.1 +/- 9.9). The mean pre-denosumab calcium value was 2.42 +/- 0.12 mmol/l, PTH 20.2 +/- 14.7 pmol/l and 25-OH vitamin D 69.1 +/- 30.1 nmol/l. After denosumab treatment, 6/8 patients with CKD-5/5D, and 2/5 patients with CKD-4 developed severe hypocalcemia. Two patients developed direct adverse complications of hypocalcemia (seizure, laryngospasm, prolonged QTc). Among the patients who developed hypocalcemia, the median time to serum calcium nadir was 21 days and the median time to correction of hypocalcemia was 71 days. Treatment of hypocalcemia required large doses of oral calcium and calcitriol, and increases in dialysate calcium concentration. CONCLUSIONS: A high rate of severe hypocalcemia was observed in patients with advanced CKD treated with denosumab. If denosumab is used in patients with severe CKD, close monitoring and aggressive replacement of calcium and calcitriol is required to avoid the development of hypocalcemia. PMID- 25790848 TI - Effectiveness of a novel interactive health care education tool on clinical outcomes and quality of life in acne patients: A randomized controlled pilot study. AB - BACKGROUND: We developed an Internet-based education tool (My Personalized Application for health Care Education, MyPACE) to promote patient comprehension about acne. OBJECTIVE: To determine if MyPACE improves clinical outcomes and quality of life in acne patients. METHODS: Modeling the spaced education approach, 50 participants received weekly multiple-choice questions for 12 weeks. Those randomized to the intervention group received acne-related questions, while those in the control group received non-dermatologic health-related questions. Acne lesion counts and Dermatology Life Quality Index (DLQI) scores were recorded at initial enrollment and at 12 weeks. RESULTS: Within-group analysis for the intervention group showed a significant mean change in inflammatory and non inflammatory acne lesions per person (-3.2 +/- 1.3, p = 0.0219; -4.4 +/- 1.8, p = 0.0267, respectively). The control group only demonstrated a significant mean change in inflammatory lesions (-2.8 +/- 0.80, p = 0.0040). Both groups had statistically significant improvement in DLQI score. Compared with participants in the control group, those receiving acne-related questions experienced greater improvement in clinical outcomes and quality of life. LIMITATIONS: The small sample size limited our ability to detect statistically significant differences. CONCLUSION: Internet-based, disease-specific, spaced education tools may be more effective than non-targeted tools for improving clinical outcomes and quality of life. PMID- 25790849 TI - Time Spent per delta PASI (TSdP) among psoriasis patients undergoing UVB-therapy A pilot study. AB - BACKGROUND: Psoriasis often poses a significant challenge to treat. Ultraviolet light band (UVB) treatment is widely used and well recognized. However, the frequent visits to the dermatologist may indirectly present an impediment to many of the patients' careers and every day life due to the vast time burden with subsequent lost work earnings. We investigated the cost-effectiveness of the psoriasis UVB treatment from a patient's point of view using time as a surrogate measure. METHOD: Twenty-five patients participated (17 males and 8 females) in the study. We registered the number of UVB treatments per patient as well as the patients PASI (psoriasis area and severity index) score at each treatment session. The time spent in relation to each treatment session was reported in a questionnaire given to the patient. Time Spent per delta PASI (TSdP) was defined as number of minutes to reduce the PASI score by one. RESULTS: Seventeen (68%) of the participants needed less than 300 min to lower the PASI with one score. The rest (n = 7 (32%)) used more than 300 min to lower the PASI score by one. Thus, the TSdP distribution displayed two peaks; ><300 min/dPASI. Log-transformed linear regression model showed that the expected TSdP would decrease with 42% for each time the start PASI was doubled, i.e. the higher the PASI level at the beginning of the treatment, the lower the TSdP. CONCLUSION: The level of reduction in psoriasis severity compared with the amount of lost work time/earnings may pose a much higher impact for patients and society than what is currently recognized. PMID- 25790851 TI - The C. elegans COE transcription factor UNC-3 activates lineage-specific apoptosis and affects neurite growth in the RID lineage. AB - Mechanisms that regulate apoptosis in a temporal and lineage-specific manner remain poorly understood. The COE (Collier/Olf/EBF) transcription factors have been implicated in the development of many cell types, including neurons. Here, we show that the sole Caenorhabditis elegans COE protein, UNC-3, together with a histone acetyltransferase, CBP-1/P300, specifies lineage-specific apoptosis and certain aspects of neurite trajectory. During embryogenesis, the RID progenitor cell gives rise to the RID neuron and RID sister cell; the latter undergoes apoptosis shortly after cell division upon expression of the pro-apoptotic gene egl-1. We observe UNC-3 expression in the RID progenitor, and the absence of UNC 3 results in the failure of the RID lineage to express a Pegl-1::GFP reporter and in the survival of the RID sister cell. Lastly, UNC-3 interacts with CBP-1, and cbp-1 mutants exhibit a similar RID phenotype to unc-3. Thus, in addition to playing a role in neuronal terminal differentiation, UNC-3 is a cell lineage specific regulator of apoptosis. PMID- 25790852 TI - The retinal determination gene Dachshund restricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex. AB - The Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the Yorkie-Homothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ. PMID- 25790850 TI - Drosophila Vps4 promotes Epidermal growth factor receptor signaling independently of its role in receptor degradation. AB - Endocytic trafficking of signaling receptors is an important mechanism for limiting signal duration. Components of the Endosomal Sorting Complexes Required for Transport (ESCRT), which target ubiquitylated receptors to intra-lumenal vesicles (ILVs) of multivesicular bodies, are thought to terminate signaling by the epidermal growth factor receptor (EGFR) and direct it for lysosomal degradation. In a genetic screen for mutations that affect Drosophila eye development, we identified an allele of Vacuolar protein sorting 4 (Vps4), which encodes an AAA ATPase that interacts with the ESCRT-III complex to drive the final step of ILV formation. Photoreceptors are largely absent from Vps4 mutant clones in the eye disc, and even when cell death is genetically prevented, the mutant R8 photoreceptors that develop fail to recruit surrounding cells to differentiate as R1-R7 photoreceptors. This recruitment requires EGFR signaling, suggesting that loss of Vps4 disrupts the EGFR pathway. In imaginal disc cells mutant for Vps4, EGFR and other receptors accumulate in endosomes and EGFR target genes are not expressed; epistasis experiments place the function of Vps4 at the level of the receptor. Surprisingly, Vps4 is required for EGFR signaling even in the absence of Shibire, the Dynamin that internalizes EGFR from the plasma membrane. In ovarian follicle cells, in contrast, Vps4 does not affect EGFR signaling, although it is still essential for receptor degradation. Taken together, these findings indicate that Vps4 can promote EGFR activity through an endocytosis-independent mechanism. PMID- 25790853 TI - Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. AB - Epigenetic mechanisms involved in the establishment of lung epithelial cell lineage identities during development are largely unknown. Here, we explored the role of the histone methyltransferase Ezh2 during lung lineage determination. Loss of Ezh2 in the lung epithelium leads to defective lung formation and perinatal mortality. We show that Ezh2 is crucial for airway lineage specification and alveolarization. Using optical projection tomography imaging, we found that branching morphogenesis is affected in Ezh2 conditional knockout mice and the remaining bronchioles are abnormal, lacking terminally differentiated secretory club cells. Remarkably, RNA-seq analysis revealed the upregulation of basal genes in Ezh2-deficient epithelium. Three-dimensional imaging for keratin 5 further showed the unexpected presence of a layer of basal cells from the proximal airways to the distal bronchioles in E16.5 embryos. ChIP seq analysis indicated the presence of Ezh2-mediated repressive marks on the genomic loci of some but not all basal genes, suggesting an indirect mechanism of action of Ezh2. We found that loss of Ezh2 de-represses insulin-like growth factor 1 (Igf1) expression and that modulation of IGF1 signaling ex vivo in wild type lungs could induce basal cell differentiation. Altogether, our work reveals an unexpected role for Ezh2 in controlling basal cell fate determination in the embryonic lung endoderm, mediated in part by repression of Igf1 expression. PMID- 25790855 TI - Investigation on vitamin D knowledge, attitude and practice of university students in Nanjing, China - CORRIGENDUM. PMID- 25790854 TI - Infant Arterial Stiffness and Maternal Iron Status in Pregnancy: A UK Birth Cohort (Baby VIP Study). AB - BACKGROUND: In animal studies, iron deficiency during pregnancy has been linked to increased offspring cardiovascular risk. No previous population studies have measured arterial stiffness early in life to examine its association with maternal iron status. OBJECTIVE: This study aimed to examine the association between maternal iron status in early pregnancy with infant brachio-femoral pulse wave velocity (PWV). METHODS: The Baby VIP (Baby's Vascular Health and Iron in Pregnancy) study is a UK-based birth cohort which recruited 362 women after delivery from the Leeds Teaching Hospitals postnatal wards. Ferritin and transferrin receptor levels were measured in maternal serum samples previously obtained in the first trimester. Infant brachio-femoral PWV was measured during a home visit at 2-6 weeks. RESULTS: Iron depletion (ferritin <15 MUg/l) was detected in 79 (23%) women in early pregnancy. Infant PWV (mean = 6.7 m/s, SD = 1.3, n = 284) was neither associated with maternal ferritin (adjusted change per 10 MUg/l = 0.02, 95% CI: -0.01, 0.1), nor with iron depletion (adjusted change = 0.2, 95% CI: -0.6, 0.2). No evidence of association was observed between maternal serum transferrin receptor level and its ratio to ferritin with infant PWV. Maternal anaemia (<11 g/dl) at <=20 weeks' gestation was associated with a 1.0 m/s increase in infant PWV (adjusted 95% CI: 0.1, 1.9). CONCLUSION: This is the largest study to date which has assessed peripheral PWV as a measure of arterial stiffness in infants. There was no evidence of an association between markers of maternal iron status early in pregnancy and infant PWV. PMID- 25790856 TI - Magnesiothermic synthesis of sulfur-doped graphene as an efficient metal-free electrocatalyst for oxygen reduction. AB - Efficient metal-free electrocatalysts for oxygen reduction reaction (ORR) are highly expected in future low-cost energy systems. We have successfully prepared crumpled, sheet-like, sulfur-doped graphene by magnesiothermic reduction of easily available, low-cost, nontoxic CO2 (in the form of Na2CO3) and Na2SO4 as the carbon and sulfur sources, respectively. At high temperature, Mg can reduce not only carbon in the oxidation state of +4 in CO3(2-) to form graphene, but also sulfur in SO4(2-) from its highest (+6) to lowest valence which was hybridized into the carbon sp(2) framework. Various characterization results show that sulfur-doped graphene with only few layers has an appropriate sulfur content, hierarchically robust porous structure, large surface area/pore volume, and highly graphitized textures. The S-doped graphene samples exhibit not only a high activity for ORR with a four-electron pathway, but also superior durability and tolerance to MeOH crossover to 40% Pt/C. This is mainly ascribed to the combination of sulfur-related active sites and hierarchical porous textures, facilitating fast diffusion of oxygen molecules and electrolyte to catalytic sites and release of products from the sites. PMID- 25790858 TI - Broadband Lamb wave trapping in cellular metamaterial plates with multiple local resonances. AB - We have investigated the Lamb wave propagation in cellular metamaterial plates constructed by bending-dominated and stretch-dominated unit-cells with the stiffness differed by orders of magnitude at an ultralow density. The simulation results show that ultralight metamaterial plates with textured stubs deposited on the surface can support strong local resonances for both symmetric and anti symmetric modes at low frequencies, where Lamb waves at the resonance frequencies are highly localized in the vibrating stubs. The resonance frequency is very sensitive to the geometry of textured stubs. By reasonable design of the geometry of resonant elements, we establish a simple loaded-bar model with the array of oscillators having a gradient relative density (or weight) that can support multiple local resonances, which permits the feasibility of a broadband Lamb wave trapping. Our study could be potentially significant in designing ingenious weight-efficient acoustic devices for practical applications, such as shock absorption, cushioning, and vibrations traffic, etc. PMID- 25790857 TI - Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver. AB - Across phyla, reduced nicotinamide adenine dinucleotide phosphate (NADPH) transfers intracellular reducing power to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR), thereby supporting fundamental housekeeping and antioxidant pathways. Here we show that a third, NADPH-independent pathway can bypass the need for TrxR1 and GR in mammalian liver. Most mice genetically engineered to lack both TrxR1 and GR in all hepatocytes ('TR/GR-null livers') remain long-term viable. TR/GR-null livers cannot reduce oxidized glutathione disulfide using NADPH but still require continuous glutathione synthesis. Inhibition of cystathionine gamma-lyase causes rapid necrosis of TR/GR-null livers, indicating that methionine-fueled trans-sulfuration supplies the necessary cysteine precursor for glutathione synthesis via an NADPH-independent pathway. We further show that dietary methionine provides the cytosolic disulfide reducing power and all sulfur amino acids in TR/GR-null livers. Although NADPH is generally considered an essential reducing currency, these results indicate that hepatocytes can adequately sustain cytosolic redox homeostasis pathways using either NADPH or methionine. PMID- 25790859 TI - Rich stoichiometries of stable Ca-Bi system: structure prediction and superconductivity. AB - Using a variable-composition ab initio evolutionary algorithm implemented in the USPEX code, we have performed a systematic search for stable compounds in the Ca Bi system at different pressures. In addition to the well-known tI12-Ca2Bi and oS12-CaBi2, a few more structures were found by our calculations, among which phase transitions were also predicted in Ca2Bi (tI12 -> oI12 -> hP6), Ca3Bi2 (hP5 -> mC20 -> aP5) and CaBi (tI2 -> tI8), as well as a new phase (Ca3Bi) with a cF4 structure. All the newly predicted structures can be both dynamically and thermodynamically stable with increasing pressure. The superconductive properties of cF4-CaBi3, tI2-CaBi and cF4-Ca3Bi were studied and the superconducting critical temperature Tc can be as high as 5.16, 2.27 and 5.25 K, respectively. Different superconductivity behaviors with pressure increasing have been observed by further investigations. PMID- 25790864 TI - Molecular mechanisms in the regulation of adult neurogenesis during stress. AB - Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress. PMID- 25790865 TI - Determining the role of microRNAs in psychiatric disorders. AB - Recent studies have revealed that patients with psychiatric disorders have altered microRNA (miRNA) expression profiles in the circulation and brain. Furthermore, animal studies have shown that manipulating the levels of particular miRNAs in the brain can alter behaviour. Here, we review recent studies in humans, animal models, cellular systems and bioinformatics that have advanced our understanding of the contribution of brain miRNAs to the regulation of behaviour in the context of psychiatric conditions. These studies highlight the potential of miRNA levels to be used in the diagnosis of psychiatric disorders and suggest that brain miRNAs could become novel treatment targets for psychiatric disorders. PMID- 25790866 TI - Visual attention span deficits and assessing causality in developmental dyslexia. PMID- 25790867 TI - Visual attention deficits in developmental dyslexia cannot be ascribed solely to poor reading experience. PMID- 25790868 TI - The mealybug Phenacoccus solenopsis suppresses plant defense responses by manipulating JA-SA crosstalk. AB - Induced plant defenses against herbivores are modulated by jasmonic acid-, salicylic acid-, and ethylene-signaling pathways. Although there is evidence that some pathogens suppress plant defenses by interfering with the crosstalk between different signaling pathways, such evidence is scarce for herbivores. Here, we demonstrate that the mealybug Phenacoccus solenopsis suppresses the induced defenses in tomato. We found that exogenous JA, but not SA, significantly decreased mealybug feeding time and reduced nymphal performance. In addition, constitutive activation of JA signaling in 35s::prosys plants reduced mealybug survival. These data indicate that the JA signaling pathway plays a key role in mediating the defense responses against P. solenopsis. We also found that mealybug feeding decreased JA production and JA-dependent defense gene expression, but increased SA accumulation and SA-dependent gene expression. In SA deficient plants, mealybug feeding did not suppress but activated JA accumulation, indicating that the suppression of JA-regulated defenses depends on the SA signaling pathway. Mealybugs benefit from suppression of JA-regulated defenses by exhibiting enhanced nymphal performance. These findings confirm that P. solenopsis manipulates plants for its own benefits by modulating the JA-SA crosstalk and thereby suppressing induced defenses. PMID- 25790869 TI - Reduced ING4 Expression Is Associated with the Malignancy of Human Bladder. AB - INTRODUCTION: Inhibitor of growth 4 (ING4) is a tumor suppressor. However the role of ING4 in human bladder malignancy is unknown. In this study, ING4 expression in human bladder cancer and its potential effects were studied. MATERIALS AND METHODS: ING4 expression in 47 human bladder cancer tissues and paired adjacent normal tissues was detected by Western blotting, quantitative reverse transcription-polymerase chain reaction, and immunohistochemistry. The migration and cell cycle progression of SV-HUC-1 and T24 cells with aberrant ING4 expression were examined. RESULTS: ING4 protein and mRNA were significantly decreased in bladder cancer tissues. ING4 protein level was significantly lower in the group of patients over 50 years of age. ING4 knockdown caused more rapid cell migration and increased the population of SV-HUC-1 and T24 cells in the G2-M phase. CONCLUSION: Our data suggest a close connection between aberrant ING4 expression and the carcinogenesis of human bladder cells. ING4 may be a potential target for bladder cancer chemotherapy. PMID- 25790870 TI - Letter regarding "Developing a sustainable hip service in Cambodia", by Holt JA et al. PMID- 25790871 TI - Spinal Neurenteric Cyst in Association with Klippel-Feil Syndrome: Case Report and Literature Review. AB - BACKGROUND: Spinal neurenteric cysts, also known as endodermal or enterogenous cysts, are rare epithelium-lined structures of presumed endodermal origin. Congenital vertebral anomalies are frequently seen in patients with neurenteric cysts, most typically anterior spina bifida, butterfly vertebrae, and hemivertebrae. However, few series of intraspinal neurenteric cysts accompanied by Klippel-Feil syndrome have been reported previously. CASE DESCRIPTION: Our purpose is to present the clinical, radiological, and histological results of a 29-year-old patient with a spinal neurenteric cyst associated with Klippel-Feil syndrome and to review previous reported cases of neurenteric cysts associated with Klippel-Feil syndrome. In our patient, cervical radiography demonstrated C5 T1 vertebral fusion and magnetic resonance imaging revealed a large intradural cystic mass. The cystic lesion was removed successfully, and it was histopathologically diagnosed as a neurenteric cyst. CONCLUSION: Neurenteric cysts should always be considered in the differential diagnosis of an intraspinal cystic mass seen in the setting of vertebral anomalies. PMID- 25790872 TI - Functional Preservation After Planned Partial Resection Followed by Gamma Knife Radiosurgery for Large Vestibular Schwannomas. AB - OBJECTIVE: The treatment goal for vestibular schwannomas (VS) has been changed from total removal of the tumor to functional preservation with long-term tumor growth control. The small- to medium-sized VS can be treated by stereotactic radiosurgery, but large VS require surgical decompression for the relief of cerebellar dysfunction and increased intracranial pressure. We have been performing planned partial surgical resections followed by gamma knife radiosurgery (GKS) for large VS. Here, we evaluate a recent series of such cases from the standpoint of functional outcomes. METHODS: From January 2000 to May 2013, we treated 40 patients with large unilateral VS (maximum tumor diameter at least 25 mm) with planned partial tumor removal followed by GKS for functional preservation. The median maximum diameter of the tumors was 32.5 mm (range 25-52 mm). All patients underwent surgery via the retrosigmoid approach, and tumors situated on the ventral and in the internal auditory canal intentionally were not removed, thus preserving cranial nerve functions. GKS was performed 1-12 months after surgical resection (median interval 3 months). The median tumor volume at GKS was 3.3 cm(3) (range 0.4-10.4 cm(3)) and the median prescribed dose was 12 Gy (range 10-12 Gy). The median follow-up period after GKS was 65 months (18-156 months). RESULTS: At the final follow-up, facial nerve preservation (House Brackmann grade I-II) was achieved in 38 patients (95%; House-Brackmann grade I: 92.5%, II: 2.5%). Among the 14 patients with preoperative pure tone average (PTA) less than 50 dB, 6 of them (42.9%) maintained PTA less than 50 dB at the last follow-up. Two patients improved from severe hearing loss to PTA less than 50 dB (1 patient after surgery and 1 patient one and half years after GKS). Five- and 10-year tumor growth control occurred in 86% of patients. Four patients (10%) required salvage surgery; the predictive factor was tumor volume greater than 6 cm(3) at GKS (P = 0.01). CONCLUSIONS: Planned partial removal of large VS followed by GKS achieved a high rate of facial nerve and hearing preservation. To achieve long-term tumor growth control, the tumor volume at GKS after planned partial surgical resection should be smaller than 6 cm(3). Our results revealed that patients with hearing preservation postoperatively have a chance of maintaining hearing function, even though the possibility exists of deterioration by long-term follow-up after surgical intervention and GKS. Furthermore, some patients with severe hearing loss before treatment have the chance of hearing improvement, even those with large VS. PMID- 25790873 TI - How to Address Small- and Medium-Sized Acoustic Neuromas with Hearing: A Systematic Review and Decision Analysis. AB - OBJECTIVE: Small- and medium-sized acoustic neuromas (ANs) increase in both number and proportion. Observation, radiosurgery, and microsurgery are all used to treat this disease; however, the appropriate treatment is controversial, especially in patients with hearing. METHODS: We searched the MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Con-trolled Trials), LILACS (Latin American and Caribbean Center on Health Sciences Information), and CMB (Chinese Biomedical Database) databases without limits on the language and the time of publication. For the wait-and-scan strategy, we included the population-based prospective studies with sufficient follow-up time and information. We also attempted to locate high-level evidence that compared radiosurgery with microsurgery. The data were extracted from the studies to synthesize the probabilities. We surveyed 60 patients with small- and medium-sized ANs to plot the outcomes on a linear scale to measure the utility. RESULTS: Eight studies met the inclusion criteria of the wait-and-scan strategy, and 3 grade II evidence studies were found that compared microsurgery with radiosurgery. After synthesizing the data in 3 groups, the preservation of useful hearing was 58.9%, 60.2%, and 4.3%, whereas the rate of tumor control was 71.1%, 97.0%, and 94.3%, respectively. The expected value for radiosurgery was 0.68, whereas the expected values for wait-and-scan and surgery were 0.64 and 0.28, respectively. CONCLUSION: On the basis of the evidence, radiosurgery is the optimal choice for small- and medium-sized ANs. Because of the current difficulty with understanding the natural history of ANs, we suggest that there is a need for new evidence and a health economics assessment to update this result. PMID- 25790874 TI - Intraoperative Functional and Perfusion Monitoring During Surgery for Giant Serpentine Middle Cerebral Artery Aneurysms. AB - BACKGROUND: Giant serpentine aneurysms are a rare entity, which can be managed using either endovascular or surgical techniques. Although the perioperative morbidity and mortality have decreased since the development of bypass revascularization procedures, their surgical treatment is still challenging. Intraoperative functional and perfusion monitoring techniques can be precious to make better decisions and improve outcomes. CASE DESCRIPTION: We report on the case of a giant, unruptured, partially thrombosed, serpentine middle cerebral artery aneurysm that was treated with partial endovascular coiling of intra aneurysmal vascular channels, surgical resection of the aneurysm, and end-to-end M1-temporal M2 anastomosis. CONCLUSIONS: Intraoperative continuous motor evoked potentials monitoring, flowmetry, and indocyanine-green angiography provide precise and reproducible information about cerebral function and perfusion, respectively, allowing for more rational decision making during surgery for these challenging malformations. PMID- 25790875 TI - [Our digital health history]. PMID- 25790876 TI - Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study. AB - BACKGROUND: Although recent studies suggest that measuring coronary artery calcification (CAC) may be superior to indirect atherosclerotic markers in predicting cardiac risk, there are limited data evaluating imaging-based biomarkers that directly quantify atherosclerosis in different vascular beds performed in a single cohort. OBJECTIVES: The BioImage Study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population) sought to identify imaging biomarkers that predict near-term (3-year) atherothrombotic events. METHODS: The BioImage Study enrolled 5,808 asymptomatic U.S. adults (mean age: 69 years, 56.5% female) in a prospective cohort evaluating the role of vascular imaging on cardiovascular risk prediction. All patients were evaluated by CAC and novel 3-dimensional carotid ultrasound. Plaque areas from both carotid arteries were summed as the carotid plaque burden (cPB). The primary endpoint was the composite of major adverse cardiac events (MACE) (cardiovascular death, myocardial infarction, and ischemic stroke). A broader secondary MACE endpoint also included all-cause death, unstable angina, and coronary revascularization. RESULTS: Over a median follow-up of 2.7 years, MACE occurred in 216 patients (4.2%), of which 82 (1.5%) were primary events. After adjustment for risk factors, and compared with individuals without any cPB, hazard ratios for MACE were 0.78 (95% confidence interval [CI]: 0.31 to 1.91), 1.45 (95% CI: 0.67 to 3.14), and 2.36 (95% CI: 1.13 to 4.92) with increasing cPB tertile, with similar results for CAC. Net reclassification significantly improved with either cPB (0.23) or CAC (0.25). MACE rates increased simultaneously with higher levels of both cPB and CAC. CONCLUSIONS: Detection of subclinical carotid or coronary atherosclerosis improves risk predictions and reclassification compared with conventional risk factors, with comparable results for either modality. Cost effective analyses are warranted to define the optimal roles of these complementary techniques. (BioImage Study: A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population; NCT00738725). PMID- 25790877 TI - Quantifying atherosclerosis by "3D" ultrasound works!: But there is work to be done. PMID- 25790878 TI - Discordance between echocardiography and MRI in the assessment of mitral regurgitation severity: a prospective multicenter trial. AB - BACKGROUND: The decision to undergo mitral valve surgery is often made on the basis of echocardiographic criteria and clinical assessment. Recent changes in treatment guidelines recommending surgery in asymptomatic patients make the accurate assessment of mitral regurgitation (MR) severity even more important. OBJECTIVES: The purpose of this study was to compare echocardiography and magnetic resonance imaging (MRI) in the assessment of MR severity using the degree of left ventricular (LV) remodeling after surgery as the reference standard. METHODS: In this prospective multicenter trial, MR severity was assessed in 103 patients using both echocardiography and MRI. Thirty-eight patients subsequently had isolated mitral valve surgery, and 26 of these had an additional MRI performed 5 to 7 months after surgery. The pre-surgical estimate of regurgitant severity was correlated with the postoperative decrease in LV end diastolic volume. RESULTS: Agreement between MRI and echocardiographic estimates of MR severity was modest in the overall cohort (r = 0.6; p < 0.0001), and there was a poorer correlation in the subset of patients sent for surgery (r = 0.4; p = 0.01). There was a strong correlation between post-surgical LV remodeling and MR severity as assessed by MRI (r = 0.85; p < 0.0001), and no correlation between post-surgical LV remodeling and MR severity as assessed by echocardiography (r = 0.32; p = 0.1). CONCLUSIONS: The data suggest that MRI is more accurate than echocardiography in assessing the severity of MR. MRI should be considered in those patients when MR severity as assessed by echocardiography is influencing important clinical decisions, such as the decision to undergo MR surgery. PMID- 25790879 TI - Current assessment of mitral regurgitation: not making the grade. PMID- 25790880 TI - Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. AB - BACKGROUND: Randomized controlled trials comparing short- (<=6 months) with long term (>=1 year) dual antiplatelet therapy (DAPT) after drug-eluting stent(s) (DES) placement have been insufficiently powered to detect significant differences in the risk of major adverse cardiac events (MACE). OBJECTIVES: This study sought to compare clinical outcomes between short- (<=6 months) and long term (1 year) DAPT and among 3 months, 6 months, and 1 year of DAPT post-DES placement by performing an individual patient data pairwise and network meta analysis. METHODS: Randomized controlled trials comparing DAPT durations after DES placement were searched through the MEDLINE, EMBASE, and Cochrane databases and in international meeting proceedings. The primary study outcome was 1-year risk of MACE (cardiac death, myocardial infarction, or definite/probable stent thrombosis). RESULTS: Four trials including 8,180 randomized patients were identified. At 1-year follow-up, short-term DAPT was associated with similar rates of MACE (hazard ratio [HR]: 1.11; 95% confidence interval [CI]: 0.86 to 1.43; p = 0.44), but significantly lower rates of bleeding (HR: 0.66; 95% CI: 0.46 to 0.94; p = 0.03) versus prolonged DAPT. Comparable results were apparent in the landmark period between DAPT discontinuation and 1-year follow-up (for MACE: HR: 1.20; 95% CI: 0.77 to 1.89; p = 0.42) (for bleeding: HR: 0.44; 95% CI: 0.21 to 0.91; p = 0.03). There were no significant differences in 1-year rates of MACE among 3-month versus 1-year DAPT, 6-month versus 1-year DAPT, or 3-month versus 6-month DAPT. CONCLUSIONS: Compared with prolonged DAPT, short-term DAPT is associated with similar rates of MACE but lower rates of bleeding after DES placement. PMID- 25790881 TI - DAPT duration after DES: what is the "mandatory" duration? PMID- 25790882 TI - Smoking is associated with adverse clinical outcomes in patients undergoing revascularization with PCI or CABG: the SYNTAX trial at 5-year follow-up. AB - BACKGROUND: Cigarette smoking is a well-known risk factor for development of coronary artery disease (CAD). However, some studies have suggested a "smoker's paradox," meaning neutral or favorable outcomes in smokers who have developed CAD, especially myocardial infarction (MI). OBJECTIVES: The study aimed to examine the association of smoking status with clinical outcomes in the randomized controlled SYNTAX (SYNergy Between PCI With TAXUS and Cardiac Surgery) trial at 5-year follow-up. METHODS: Detailed smoking history was collected at baseline, 6-month, 1-year, 3-year, and 5-year follow-up. The composite endpoints included death/MI/stroke (primary endpoint) plus major adverse cardiac and cerebrovascular events (MACCE) (combination of death/MI/stroke and target lesion revascularization) according to patient smoking status. The comparison of 5-year clinical outcomes between the groups according to smoking status was performed with Cox regression using smoking status at baseline or smoking as a time dependent covariate. RESULTS: A sizeable proportion (n = 322, 17.9%) of patients had changing smoking status during 5-year follow-up. One in 5 patients with complex CAD was smoking at baseline. However, 60% stopped after revascularization while others continued to smoke. Smokers had worse clinical outcomes due to a higher incidence of recurrent MI in both revascularization arms. Smoking was an independent predictor of the composite endpoint of death/MI/stroke (hazard ratio [HR]: 1.8; 95% confidence interval [CI]: 1.3 to 2.5; p = 0.001) and MACCE (HR: 1.4; 95% CI: 1.1 to 1.7; p = 0.02). CONCLUSIONS: Smoking is associated with poor clinical outcomes after revascularization in patients with complex CAD. This places further emphasis on efforts at smoking cessation to improve revascularization benefits. (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries; NCT00114972). PMID- 25790883 TI - Clearing the air on the "smoker's paradox". PMID- 25790884 TI - Association between public reporting of outcomes with procedural management and mortality for patients with acute myocardial infarction. AB - BACKGROUND: Public reporting of procedural outcomes may create disincentives to provide percutaneous coronary intervention (PCI) for critically ill patients. OBJECTIVES: This study evaluated the association between public reporting with procedural management and outcomes among patients with acute myocardial infarction (AMI). METHODS: Using the Nationwide Inpatient Sample, we identified all patients with a primary diagnosis of AMI in states with public reporting (Massachusetts and New York) and regionally comparable states without public reporting (Connecticut, Maine, Maryland, New Hampshire, Rhode Island, and Vermont) between 2005 and 2011. Procedural management and in-hospital outcomes were stratified by public reporting. RESULTS: Among 84,121 patients hospitalized with AMI, 57,629 (69%) underwent treatment in a public reporting state. After multivariate adjustment, percutaneous revascularization was performed less often in public reporting states than in nonreporting states (odds ratio [OR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.96), especially among older patients (OR: 0.75, 95% CI: 0.62 to 0.91), those with Medicare insurance (OR: 0.75, 95% CI: 0.62 to 0.91), and those presenting with ST-segment elevation myocardial infarction (OR: 0.63, 95% CI: 0.56 to 0.71) or concomitant cardiac arrest or cardiogenic shock (OR: 0.58, 95% CI: 0.47 to 0.70). Overall, patients with AMI in public reporting states had higher adjusted in-hospital mortality rates (OR: 1.21, 95% CI: 1.06 to 1.37) than those in nonreporting states. This was observed predominantly in patients who did not receive percutaneous revascularization in public reporting states (adjusted OR: 1.30, 95% CI: 1.13 to 1.50), whereas those undergoing the procedure had lower mortality (OR: 0.71, 95% CI: 0.62 to 0.83). CONCLUSIONS: Public reporting is associated with reduced percutaneous revascularization and increased in-hospital mortality among patients with AMI, particularly among patients not selected for PCI. PMID- 25790885 TI - Public reporting of percutaneous coronary intervention outcomes: harm or benefit? PMID- 25790886 TI - How recent data have impacted the treatment of internal carotid artery stenosis. AB - Carotid atherosclerosis accounts for approximately 10% of ischemic stroke cases. Multifaceted medical therapy reduces the risk of stroke in patients with carotid stenosis. Revascularization with endarterectomy or stenting can benefit select patients. In recent years, new information has been obtained regarding optimal selection of revascularization candidates. In addition, new concepts have been formulated regarding the relationship between carotid stenosis and vascular cognitive impairment. Finally, the declining rate of stroke with improved medical therapy has led to the launch of new clinical trials to determine the contemporary risk/benefit ratio of revascularization relative to aggressive medical therapy. PMID- 25790887 TI - Examining the strategic plan: the heart of American College of Cardiology Advocacy. PMID- 25790888 TI - Why cardiology fellows should not give up on practicing internal medicine. PMID- 25790889 TI - Brain-derived neurotrophic factor as a marker for immediate assessment of the success of renal sympathetic denervation. PMID- 25790890 TI - "Add 10 min for your health": the new Japanese recommendation for physical activity based on dose-response analysis. PMID- 25790891 TI - Reply: "add 10 min for your health": the new Japanese recommendation for physical activity based on dose-response analysis. PMID- 25790892 TI - Reply: "add 10 min for your health": the new Japanese recommendation for physical activity based on dose-response analysis. PMID- 25790893 TI - Is the long-term outcome of PCI or CABG in insulin-treated diabetic patients really worse than non-insulin-treated ones? PMID- 25790894 TI - Marfan syndrome presenting with postpartum aortic dissection following dural puncture headache and epidural blood patch. PMID- 25790895 TI - Broadband high-efficiency half-wave plate: a supercell-based plasmonic metasurface approach. AB - We design, fabricate, and experimentally demonstrate an ultrathin, broadband half wave plate in the near-infrared range using a plasmonic metasurface. The simulated results show that the linear polarization conversion efficiency is over 97% with over 90% reflectance across an 800 nm bandwidth. Moreover, simulated and experimental results indicate that such broadband and high-efficiency performance is also sustained over a wide range of incident angles. To further obtain a background-free half-wave plate, we arrange such a plate as a periodic array of integrated supercells made of several plasmonic antennas with high linear polarization conversion efficiency, consequently achieving a reflection-phase gradient for the cross-polarized beam. In this design, the anomalous (cross polarized) and the normal (copolarized) reflected beams become spatially separated, hence enabling highly efficient and robust, background-free polarization conversion along with broadband operation. Our results provide strategies for creating compact, integrated, and high-performance plasmonic circuits and devices. PMID- 25790896 TI - Impact of transgenerational immune priming on the defence of insect eggs against parasitism. AB - Insects are known to prime the immune state of their offspring. However, although the beginning of insect life, the egg stage, is often greatly endangered by parasitism, no knowledge is available regarding whether transgenerational immune priming improves the immune responses of insect eggs to actual parasitoid attacks. Our study revealed suppression of the development of parasitoids in transgenerationally immune-primed Manduca sexta eggs and reduced emergence rates of parasitoids from these eggs. The higher defence efficiency of immune-primed M. sexta eggs against parasitoids was in agreement with the increased antibacterial activity and phenoloxidase activity of these eggs in response to parasitism compared to the eggs of control parents. Our study showed that immunochallenged insect parents could enable their offspring already in the egg stage to defend more efficiently against parasitic invaders. We discuss whether M. sexta benefits from transgenerational immune priming of eggs by limiting the population growth of egg parasitoids. PMID- 25790897 TI - Development of a new pentaplex real-time PCR assay for the identification of poly microbial specimens containing Staphylococcus aureus and other staphylococci, with simultaneous detection of staphylococcal virulence and methicillin resistance markers. AB - Staphylococcus aureus strains harbouring genes encoding virulence and antibiotic resistance are of public health importance. In clinical samples, pathogenic S. aureus is often mixed with putatively less pathogenic coagulase-negative staphylococci (CoNS), both of which can harbour mecA, the gene encoding staphylococcal methicillin-resistance. There have been previous attempts at distinguishing MRSA from MRCoNS, most of which were based on the detection of one of the pathognomonic markers of S. aureus, such as coa, nuc or spa. That approach might suffice for discrete colonies and mono-microbial samples; it is inadequate for identification of clinical specimens containing mixtures of S. aureus and CoNS. In the present study, a real-time pentaplex PCR assay has been developed which simultaneously detects markers for bacteria (16S rRNA), coagulase-negative staphylococcus (cns), S. aureus (spa), Panton-Valentine leukocidin (pvl) and methicillin resistance (mecA). Staphylococcal and non-staphylococcal bacterial strains (n = 283) were used to validate the new assay. The applicability of this test to clinical samples was evaluated using spiked blood cultures (n = 43) containing S. aureus and CoNS in mono-microbial and poly-microbial models, which showed that the 5 markers were all detected as expected. Cycling completes within 1 h, delivering 100% specificity, NPV and PPV with a detection limit of 1.0 * 10(1) to 3.0 * 10(1) colony forming units (CFU)/ml, suggesting direct applicability in routine diagnostic microbiology. This is the most multiplexed real-time PCR-based PVL-MRSA assay and the first detection of a unique marker for CoNS without recourse to the conventional elimination approach. There was no evidence that this new assay produced invalid/indeterminate test results. PMID- 25790898 TI - Cardiovascular disease among women with and without diabetes mellitus and bilateral oophorectomy. AB - AIMS: Women with type-2 diabetes (DM2) are at high risk of cardiovascular disease (CVD) which may be partly due to increased ovarian androgen production. Since the association of bilateral oophorectomy (BSO) with CVD remains controversial, we evaluated whether BSO is inversely associated with CVD among DM2. METHODS: Data were obtained from a national sample of 9599 postmenopausal women. Adjusted estimates and 95% confidence intervals (CIs) were calculated using logistic and Cox regression. RESULTS: At baseline 2426 women had type-2 diabetes, of whom 580 had BSO. DM2 had adverse CVD risk profiles compared to women without diabetes, as did women with BSO with or without diabetes compared to those with intact ovaries. In DM2, BSO was positively associated with prevalent CVD (odds ratio: 1.63, 95%CI: 1.16-2.30). However, the higher odds were limited to women who had BSO before age 45 years (OR: 2.11, CI: 1.45-3.08). During a mean follow-up of 12.7 years, BSO in DM2 was positively associated with CVD mortality (hazard ratio: 2.23, CI: 1.25-3.99). Among women with BSO, those with family members who had MI before age 50 had elevated odds of CVD (OR: 2.29, CI: 1.56-3.37) compared to those without such family history (OR: 0.90, CI: 0.67-1.20), Pinteraction=0.04. CONCLUSIONS: The risk of CVD is increased not decreased with BSO in DM2. Further, we propose that the association of BSO and CVD in young women with diabetes may partly reflect genetic susceptibility to CVD rather than an effect of ovarian hormones. PMID- 25790899 TI - Development and validation of the Asian Diabetes Quality of Life (AsianDQOL) Questionnaire. AB - AIM: To construct a type-2 diabetes specific quality of life (QOL) tool for Asian populations that is valid and reliable across different ethnicities, languages, and socio-economic backgrounds. METHODS: A focus group determined the domains affecting QOL in consultation with an expert group. A pilot study was conducted to validate the Asian Diabetes QOL (AsianDQOL) in English, Malay and Chinese Mandarin. The World Health Organization Brief Quality of Life Questionnaire (WHOQOL-BREF) was used for comparison. Exploratory factor analysis (EFA), reliability analysis (RA) using Cronbach's alpha, test-retest reliability, and confirmatory factor analysis (CFA) using structural equation modeling (SEM) was undertaken using the statistical software IBM SPSS Statistics version 20. RESULTS: EFA with eigenvalues (>1) and factor loadings >=0.3 for English and Malay language demonstrated 21 items (5 components). CFA (English version) confirmed the model (CMIN 201.08, p-value 0.071, GFI 0.88, RMSEA 0.036, CFI 0.978). CFA (Malay version) confirmed the 5-factor model (CMIN 189.39, p-value 0.085, GFI 0.937, RMSEA 0.025, CFI 0.987). The Cronbach's alpha scores (English version) were 0.917, 0.818, 0.816, 0.749 and 0.719, respectively. The Malay version scored 0.833, 0.819, 0.816, 0.775, 0.673, respectively, whilst the Chinese/Mandarin version scored 0.890, 0.719, 0.826, 0.862 and 0.759, respectively. Test-retest reliability showed Pearson correlation of 0.600 (English version), 0.700 (Malay version) and 0.500 (Chinese-Mandarin version). A scoring system was generated based on the 25th, 50th and 75th centiles for all the three languages. CONCLUSION: The AsianDQOL is a valid, reliable and stable tool for assessing QOL in multi-ethnic and multi-lingual T2DM Asian populations. PMID- 25790900 TI - [Unilateral isolated Raynaud's phenomenon leading to diagnosis of multifocal giant-cell arteritis complicated with renal ischemia]. AB - We report a case of a 76-year-old woman with isolated unilateral Raynaud phenomenon revealing giant-cell arteritis with diffuse arterial lesions and bilateral renal artery stenosis. Doppler ultrasonography showed bilateral stenosis of the subclavian and axillary arteries. Angio-CT PET enlightened diffuse arterial lesions, mainly involving the aorta and the brachial and femoral arteries as well as bilateral renal ostial stenosis with right kidney ischemia. Diagnosis of giant-cell arteritis was made on the temporal artery biopsy. Corticosteroid therapy led to rapid clinical and radiological improvement. Clinical manifestations of giant-cell arteritis may be atypical. Diffuse arterial disease may exist in the absence of cephalic symptoms or significant inflammatory biological features. Ostial renal artery stenosis may induce potentially threatening renal ischemia. PMID- 25790901 TI - Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene. PMID- 25790902 TI - Applications of commercial biosensors in clinical, food, environmental, and biothreat/biowarfare analyses. AB - The lack of specific, low-cost, rapid, sensitive, and easy detection of biomolecules has resulted in the development of biosensor technology. Innovations in biosensor technology have enabled many biosensors to be commercialized and have enabled biomolecules to be detected onsite. Moreover, the emerging technologies of lab-on-a-chip microdevices and nanosensors offer opportunities for the development of new biosensors with much better performance. Biosensors were first introduced into the laboratory by Clark and Lyons. They developed the first glucose biosensor for laboratory conditions. Then in 1973, a glucose biosensor was commercialized by Yellow Springs Instruments. The commercial biosensors have small size and simple construction and they are ideal for point of-care biosensing. In addition to glucose, a wide variety of metabolites such as lactate, cholesterol, and creatinine can be detected by using commercial biosensors. Like the glucose biosensors (tests) other commercial tests such as for pregnancy (hCG), Escherichia coli O157, influenza A and B viruses, Helicobacter pylori, human immunodeficiency virus, tuberculosis, and malaria have achieved success. Apart from their use in clinical analysis, commercial tests are also used in environmental (such as biochemical oxygen demand, nitrate, pesticide), food (such as glutamate, glutamine, sucrose, lactose, alcohol, ascorbic acid), and biothreat/biowarfare (Bacillus anthracis, Salmonella, Botulinum toxin) analysis. In this review, commercial biosensors in clinical, environmental, food, and biowarfare analysis are summarized and the commercial biosensors are compared in terms of their important characteristics. This is the first review in which all the commercially available tests are compiled together. PMID- 25790903 TI - UPSA-M: Feasibility and initial validity of a mobile application of the UCSD Performance-Based Skills Assessment. AB - OBJECTIVE: This study aimed to develop and validate a tablet mobile application version of the UCSD Performance-Based Skills Assessment (UPSA-M), a widely used test for assessing functional capacity in schizophrenia and other neurocognitively impaired patient populations. METHODS: The UPSA-M was developed for an iPad platform. Twenty-one middle-aged and older adults with schizophrenia and 13 healthy comparison (HC) participants completed a brief iPad tutorial, followed by the UPSA-M (full version, which includes all components of Brief UPSA M) and a computer usage questionnaire. During a separate visit, patients with schizophrenia and HC participants completed the Brief UPSA (UPSA-B), and patients with schizophrenia completed a symptom inventory and brief neuropsychological screening battery. RESULTS: The UPSA-M was feasible for use among middle aged and older adults with schizophrenia with no prior history of tablet usage. The UPSA-M was able to differentiate between schizophrenia and HC participants 80% of the time, and this differential ability increased to 87% with the UPSA-M Brief. Traditional UPSA scores, UPSA-B scores, and neuropsychological performance were related to UPSA-M scores, whereas symptoms of psychopathology, experience with tablet technology, or difficulties operating the device were not significantly associated with UPSA-M. CONCLUSIONS: The UPSA-M performed just as well as the standard-of-practice version. These preliminary results indicate that the UPSA-M Brief has greater sensitivity than the full version of the UPSA-M, and carries the advantage of a shorter administration time. Overall, the UPSA-M appears to be a promising mobile tool to assess functional capacity. PMID- 25790904 TI - Joint modeling of dropout and outcome in three pivotal clinical trials of schizophrenia. AB - BACKGROUND: Dropout is a serious challenge to clinical trials in psychiatry, yet standard outcome analyses with mixed models do not account for dropout, while joint modeling uses dropout from a survival model to adjust the outcome from a mixed model, but is untested in clinical trials of schizophrenia. AIMS: To compare mixed and joint modeling in three acute phase pivotal placebo controlled trials of schizophrenia. METHOD: Data were reanalyzed on 611 in-patients with acute schizophrenia who participated in three pivotal randomized controlled trials that compared placebo with olanzapine or risperidone (dropout rates placebo: 62.6% and medication: 37.4%). The outcome measures were BPRS or PANSS total change scores. Mixed-effects models for repeated measures and joint models were computed and compared to examine the time-treatment interaction. Effect size comparisons were made. RESULTS: Antipsychotic treatment was superior to placebo across analyses. Time treatment interactions were significant (p<.05) for the mixed (beta=2.33) and joint models (beta=2.62). Compared with mixed modeling, joint modeling reduced the estimated change score for treatment (21.24 vs 19.74) and placebo (1.64 vs -1.11). The effect size differences between placebo and treatment groups were greater for joint (ES=.89) than mixed modeling (ES=0.83). Sensitivity analysis replicated this trend of results in each of the three trials. CONCLUSION: Compared to mixed modeling, joint modeling results in a greater separation between treatment and placebo groups. This offers preliminary evidence that joint modeling may be useful in the analysis of antipsychotic placebo controlled RCTs. PMID- 25790905 TI - Novel mouse model to study T cell-dependent IgA induction in vivo. AB - Commensal microbiota at the mucosal surfaces controls multiple aspects of body homeostasis. Therefore, regulation of microflora composition by the host is crucial, and one of the mechanisms driving microbiota diversity is the production of large quantities of immunoglobulin A (IgA) at the mucosal surfaces. However, mechanisms of IgA induction in the gut are not completely understood. Here we further characterize a mouse model for studying T cell-dependent IgA production in the gut due to specific genetic ablation of LTbeta in RORgammat+ cells. Using in utero blockade of the mesenteric lymph node development, we showed that IgA induction in these mice occurs directly in the LP. Furthermore, T cell-dependent IgA inducing mechanism in these mice generates distinct IgA plasma cells producing commensal microflora-binding IgA antibodies. Thus, this model represents a unique in vivo tool for the analysis of T cell-dependent IgA plasma cell generation and their antibody specificity. PMID- 25790906 TI - "Ancient" schwannoma in the psoas muscle. PMID- 25790907 TI - Histone deacetylase inhibitor romidepsin induces efficient tumor cell lysis via selective down-regulation of LMP1 and c-myc expression in EBV-positive diffuse large B-cell lymphoma. AB - We investigated the role of the histone deacetylase inhibitor, romidepsin, in Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma with poor clinical outcomes. We used EBV-positive and EBV-negative DLBCL cell lines and generated two EBV-transfected cell lines, LY7/EBV and U2932/EBV. Romidepsin was cytotoxic to cultured EBV-positive cells via the activation of the caspase cascade. Moreover, in vivo mice xenograft models demonstrated the cytotoxicity of romidepsin to EBV-positive DLBCL cells. Romidepsin induced cytotoxicity via the reduction of LMP1 and c-myc expression in EBV-positive cells. Inhibiting either LMP1 or c-myc using small inhibitory RNAs caused partial cytotoxicity in EBV-positive Farage and U2932/EBV lines. The dual inhibition of LMP1 and c-myc showed a synergistic cytotoxic effect in EBV positive cells similar in magnitude to that of romidepsin alone. In addition, either double blockade of LMP1 and c-myc activity or romidepsin single treatment activated EBV lytic cycle in EBV-positive cells. In conclusion, romidepsin exerts strong anti-tumor activity in EBV-positive DLBCL via the inhibition of both LMP1 and c-myc. Our findings indicate that romidepsin might be a promising treatment for EBV-positive DLBCL. PMID- 25790908 TI - Kindlin-2 interacts with and stabilizes EGFR and is required for EGF-induced breast cancer cell migration. AB - Epidermal growth factor receptor (EGFR) mediates multiple signaling pathways that regulate cell proliferation, migration and tumor invasion. Kindlin-2 has been known as a focal adhesion molecule that binds to integrin to control cell migration and invasion. However, molecular mechanisms underlying the role of Kindlin-2 in breast cancer progression remain elusive. Here we report that Kindlin-2 interacts with EGFR and mediates EGF-induced breast cancer cell migration. We found that EGF treatment dramatically increases Kindlin-2 expression at both mRNA and protein levels in a variety of cancer cells. Inhibitors specific for EGFR or PI3K blocked Kindlin-2 induction by EGF. Importantly, Kindlin-2 interacted with EGFR kinase domain, which was independent of Kindlin-2 binding to integrin cytoplasmic domain. Intriguingly, Kindlin-2 stabilized EGFR protein by blocking its ubiquitination and degradation. Depletion of Kindlin-2 impaired EGF-induced cell migration. Our results demonstrated that Kindlin-2 participates in EGFR signaling and regulates breast cancer progression. PMID- 25790909 TI - Antiproliferative activity of the isoindigo 5'-Br in HL-60 cells is mediated by apoptosis, dysregulation of mitochondrial functions and arresting cell cycle at G0/G1 phase. AB - Our new compound, 5'-Br [(E)-1-(5'-bromo-2'-oxoindolin-3'-ylidene)-6-ethyl 2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f]quinoline-8-carboxylic acid], had shown strong, selective antiproliferative activity against different cancer cell lines. Here, we aim to comprehensively characterize the mechanisms associated with its cytotoxicity in the human promyelocytic leukemia HL-60 cells. We focused at studying the involvement of apoptotic pathway and cell cycle effects. 5'-Br significantly inhibited proliferation by inducing caspase-dependent apoptosis. Involvement of caspase independent mechanism is also possible due to observed inability of z-VAD-FMK to rescue apoptotic cells. 5'-Br was found to trigger intrinsic apoptotic pathway as indicated by depolarization of the mitochondrial inner membrane, decreased level of cellular ATP, modulated expression and phosphorylation of Bcl-2 leading to loss of its association with Bax, and increased release of cytochrome c. 5'-Br treated cells were found arrested at G0/G1 phase with modulation in protein levels of cyclins, dependent kinases and their inhibitors. Expression and enzymatic activity of CDK2 and CDK4 was found inhibited. Retinoblastoma protein (Rb) phosphorylation was also inhibited whereas p21 protein levels were increased. These results suggest that the antiproliferative mechanisms of action of 5'-Br could involve apoptotic pathways, dysregulation of mitochondrial functions and disruption of cell cycle checkpoint. PMID- 25790910 TI - Anti-diabetic effects of Ganoderma lucidum. AB - Ganoderma lucidum is a white rot fungus widely used as a tonic for the promotion of longevity and health. Extracts of G. lucidum have been recognized as an alternative adjuvant treatment for diabetes. Among the many biologically active constituents of G. lucidum, polysaccharides, proteoglycans, proteins and triterpenoids have been shown to have hypoglycemic effects. G. lucidum polysaccharides have been reported to have hypoglycemic activity by increasing plasma insulin levels and decreasing plasma sugar levels in mice. Protein tyrosine phosphatase 1B is a promising therapeutic target in diabetes, and G. lucidum proteoglycan can inhibit this enzyme in vitro. Moreover, G. lucidum triterpenoids were shown to have inhibitory activity on aldose reductase and alpha-glucosidase that can suppress postprandial hyperglycemia. In addition, a protein Ling Zhi-8 extracted from G. lucidum significantly decreased lymphocyte infiltration and increased the antibody detection of insulin in diabetic mice. This review summarizes most of the research about the hypoglycemic action effects of polysaccharides, proteoglycans, proteins and tritrerpenoids from G. lucidum as a guide for future research. PMID- 25790911 TI - Ventricular septal rupture in a patient with non-ST-segment elevation myocardial infarction caused by myocardial bridge. PMID- 25790912 TI - Meckel's diverticulum mesentery along with its band forming a hernial sac: A rare case of internal herniation. AB - INTRODUCTION: Meckel's diverticulum is the most common congenital gastrointestinal anomaly. However, only 2% of cases are symptomatic. It can cause intestinal obstruction by various mechanisms as volvulus, adhesions, Littre's hernia, intussusception. CASE PRESENTATION: An unusual case of internal herniation of small bowel loops into complete hernia sac formed by unusual mesentery of Meckel's diverticulum which was present upto the adhesive band, extending from tip of the Meckel's diverticulum to the adjacent mesentery of small intestine leading to small bowel obstruction (SBO). Diverticulectomy with resection of adjacent ileum with ileo-ileal anastomosis was done. DISCUSSION: Internal herniation by MD leading to SBO is an extremely rare complication. In literature, cases of internal hernia through mesentry of Meckel's diverticulum, through mesodiverticular band, adhesion of inflamed end of MD to corresponding base of mesentry, fibrous cord extending upto umblical wall have been reported but in our case, patient had both adhesion band along with internal herniation into sac formed by unusual mesentry of the meckel's diverticulum and the adhesion band. Preoperative diagnosis is often difficult with only 6-12% of cases diagnosed correctly. Surgical intervention is indicated for patients with intestinal obstruction or high risk of incarceration. CONCLUSION: Meckel's diverticulum causing internal hernia is rare event. It's presentation due to herniation of bowel loops into sac formed by mesentery attached to diverticulum and the adhesion is rarest, with non specific signs and symptoms. Early diagnosis and prompt treatment prevent further complications. PMID- 25790913 TI - Complete pathological response to transcatheter arterial infusion despite a rapidly progressing recurrent hepatocellular carcinoma with portal vein tumor thrombus: A case report. AB - INTRODUCTION: We report a patient with a rapidly progressing recurrence of hepatocellular carcinoma (HCC) with a portal vein tumor thrombus after radiofrequency ablation of the original lesion, then treated with transcatheter arterial infusion. Radical hepatic resection demonstrated a complete pathological response. PRESENTATION OF CASE: A 60-year old male with alcoholic cirrhosis and gastric varices was diagnosed with HCC measuring 12mm in segment 8. He underwent laparoscopic radiofrequency ablation, but recurred three months later. The lesion progressed rapidly and the right portal vein was occluded. He then underwent transcatheter arterial infusion with miriplatin and iodized oil, which was effective in reducing the size of the main lesion and portal vein tumor thrombus. Right anterior sectionectomy was then performed. Pathologically, there were no viable HCC cells in either the main lesion or the portal vein thrombus. He is alive two years and nine months after surgery without recurrence. DISCUSSION: A rapidly progressing HCC recurrence with portal vein tumor thrombus is usually associated with a poor prognosis. No effective treatments have been reported in this situation except hepatic resection. In this patient the tumor was effectively reduced after three courses of transarterial miriplatin and subsequent radical hepatic resection. This is the first report to achieve a complete pathological response for such an aggressive recurrence after initial radiofrequency ablation. CONCLUSION: This strategy may result in long-term survival of patients with rapidly progressing recurrent HCC with portal vein thrombus, and further study is warranted. PMID- 25790914 TI - Applicability of a novel osmotic membrane bioreactor using a specific draw solution in wastewater treatment. AB - This study aims to develop a new osmotic membrane bioreactor by combining a moving bed biofilm reactor (MBBR) with forward osmosis membrane bioreactor (FOMBR) to treat wastewater. Ethylenediaminetetraacetic acid disodium salt coupled with polyethylene glycol tert-octylphenyl ether was used as an innovative draw solution in this membrane hybrid system (MBBR-OsMBR) for minimizing the reverse salt flux and maintaining a healthy environment for the microorganism community. The results showed that the hybrid system achieved a stable water flux of 6.94 L/m(2) h and low salt accumulation in the bioreactor for 68 days of operation. At a filling rate of 40% (by volume of the bioreactor) of the polyethylene balls used as carriers, NH4(+)-N and PO4(3-)-P were almost removed (>99%) while producing relatively low NO3(-)-N and NO2(-)-N in the effluent (e.g. <0.56 and 0.96 mg/L, respectively). Furthermore, from analysis based on scanning electron microscopy, Fourier transform infrared spectroscopy, and fluorescence emission-excitation matrix spectrophotometry, there was a thin gel-like fouling layer on the FO membrane, which composed of bacteria as well as biopolymers and protein-like substances. Nonetheless, the formation of these fouling layers of the FO membrane in MBBR-OsMBR was reversible and removed by a physical cleaning technique. PMID- 25790915 TI - Investigation of the effects of unilateral total salpingectomy on ovarian proliferating cell nuclear antigen and follicular reserve: experimental study. AB - OBJECTIVE: We aimed to investigate the effects of unilateral total salpingectomy procedure on ovarian follicular reserve, apoptosis, and proliferating cell nuclear antigen (PCNA) staining in this study. STUDY DESIGN: Fourteen female Wistar Albino rats of 12 weeks were randomly divided into two groups. Abdomen midline incision was conducted under general anesthesia. Group 1(G1) (n=7): Group in which only the abdomen was opened and closed, Group 2(G2) (n=7): Group that underwent right total salpingectomy. After 1 month, abdomens of all rats were opened. Ovaries were macroscopically evaluated. Right ovarian tissue was quickly removed, fixed in 10% formaldehyde, and paraffin blocks were prepared.' The existence of fibrosis was identified with the usage of light microscope. Follicles were microscopically classified and counted. The prevalence of cytoplasmic immune staining and TUNEL staining was scored semi-quantitatively. STATISTICAL ANALYSIS: SPSS 17.0 software was used for the statistical analysis of data. First, Kruskal-Wallis variance analysis was conducted, and then Mann Whitney U test was utilized for inter-group dual comparisons for parameters found as p<0.05. RESULTS: While the number of CL was found out dramatically high, secondary follicle count was found out to be significantly low in G2. Also in G2, although the number of atretic follicle and fibrosis were found out significantly increased, and the score of the angiogenesis was found to be significantly decreased in CL. When compared PCNA immunoreactivity in granulosa cells with the control group, there was a significant decrease in G2. When compared the malondialdehyde (MDA) immunoreactivity with G1 a significant increase was established in G2. Apoptosis score of ovarian follicles in granulosa cells was significantly higher in G2. CONCLUSIONS: In this experimental study, the decrease in the ovarian reserve and PCNA staning of granulosa cells, an increase in apoptosis, fibrosis and the number of atretic follicles in unilateral total salpingectomy operation were analyzed in rats. We found out significantly higher MDA staining rates in G2 in comparison to in G1. According to the study, the unilateral total salpingectomy procedure can damage to the same side ovarian tissue by means of the ischemia and reperfusion injury at the ovarian tissue. PMID- 25790916 TI - Platelet function in patients with a history of unexplained recurrent miscarriage who subsequently miscarry again. AB - OBJECTIVE: This study was designed to evaluate platelet aggregation in pregnant women with a history of unexplained recurrent miscarriage (RM) and to compare platelet function in such patients who go on to have either another subsequent miscarriage or a successful pregnancy. STUDY DESIGN: A prospective longitudinal study was performed to evaluate platelet function in a cohort of patients with a history of unexplained RM. Platelet reactivity testing was performed at 4-7 weeks gestation, to compare platelet aggregation between those with a subsequent miscarriage and those who had successful live birth outcomes. Platelet aggregation was calculated using a modified assay of light transmission aggregometry with multiple agonists at different concentrations. RESULTS: In a cohort of 39 patients with a history of RM, 30 had a successful pregnancy outcome while nine had a subsequent miscarriage again. Women with subsequent miscarriage had reduced platelet aggregation in response to adenosine diphosphate (P value 0.0012) and thrombin receptor activating peptide (P value 0.0334) when compared to those with successful pregnancies. Women with subsequent miscarriages also had a trend towards reduced platelet aggregation in response to epinephrine (P value 0.0568). CONCLUSION: Patients with a background history of unexplained RM demonstrate reduced platelet function if they have a subsequent miscarriage compared to those who go on to have a successful pregnancy. PMID- 25790917 TI - Peroxisomes compensate hepatic lipid overflow in mice with fatty liver. AB - Major causes of lipid accumulation in liver are increased import or synthesis or decreased catabolism of fatty acids. The latter is caused by dysfunction of cellular organelles controlling energy homeostasis, i.e., mitochondria. Peroxisomes also appear to be an important organelle in lipid metabolism of hepatocytes, but little is known about their role in the development of non alcoholic fatty liver disease (NAFLD). To investigate the role of peroxisomes alongside mitochondria in excessive hepatic lipid accumulation, we used leptin resistant db/db mice on C57BLKS background, a mouse model that develops hyperphagia-induced diabetes with obesity and NAFLD. Proteome and gene expression analyses along with lipid analyses in the liver revealed differential expression of genes related to lipid metabolism and beta-oxidation, whereas genes for peroxisomal proteins were predominantly regulated. CONCLUSION: Our investigations show that in fatty liver disease in combination with obesity and diabetes, the hepatocyte-protecting organelle peroxisome is altered. Hence, peroxisomes might indicate a stage of pre-NAFLD, play a role in the early development of NAFLD and appear to be a potential target for treatment and prevention of NAFLD. PMID- 25790918 TI - Gynecological malignancy risk in colorectal cancer survivors: A population-based cohort study. AB - PURPOSE: This study was carried out to assess the risk of gynecological malignancy in colorectal cancer survivors using a population-based retrospective cohort study. METHOD: Using the National Health Insurance Research Database (NHIRD) of Taiwan, we identified 37,176 patients with colorectal cancer diagnosed in 1998-2009, aged 20 years and above, without other cancer history. We also randomly selected 148,700 women without any cancer in the comparison cohort, frequency matched by age and diagnosis date. Incidences and hazards of breast, cervix, endometrial and ovarian cancers were evaluated by 201l. RESULTS: The overall incidence of the 4 types of gynecological cancer was 39.0% higher in colorectal cancer patients than in comparisons (2.99 vs. 2.14 per 1000 person years) with an adjusted hazard ratio (HR) of 1.46 (95% confidence interval (CI) = 1.31-1.62). Breast cancer accounted for most subsequent cancer. The multivariable Cox method measured HR was the highest for endometrial cancer (3.40, 95% CI = 2.59-4.47) for the colorectal cohort relative to comparisons, followed by ovarian cancer and breast cancer, except cervix cancer. The risk of gynecological malignancies was apparently elevated for colorectal cancer survivors <50 years of age. CONCLUSIONS: Follow-up measures are suggested for women with colorectal cancer for early detection and prevention of the subsequent gynecological malignancy. PMID- 25790919 TI - Experiences of Brazilian children and family caregivers facing the recurrence of cancer. AB - PURPOSE: The aim of the study was to examine the different perspectives of the children and their family caregivers' experiences in the treatment of relapsed cancer. METHODS: We conducted 16 sessions of the Drawing-and-Story Procedure (D S) with 5 to 12-year-old children who were in treatment due to recurrence of cancer, and 8 in-depth interviews among their family caregivers. The D-S and the interviews were audio-recorded with the participants' consent; the transcripts were analyzed using the thematic content analysis. RESULTS: The children evidenced that they perceived the threatening and uncertainty, independently of their age or kind of communication established about the disease and prognosis. Caregivers expressed feelings of frustration, threat and loss of control in view of the relapsed cancer diagnosis and prognosis, which enhanced the fear of losing their children and hampered the process of attributing meaning to their existence. Dyads showed similar experiences related to the recurrent cancer issues, and the first treatment experience seemed to help them to give new meanings to the current situation. CONCLUSION: Understanding the experiences of the children and their family caregivers can support the planning of psychological interventions that favor coping with the peculiarities of the disease situation resulting from the relapse diagnosis of childhood cancers. PMID- 25790920 TI - New horizons in speech language pathology. Editorial. PMID- 25790921 TI - Educating speech-language pathologists for the 21st century: course design considerations for a distance education Master of Speech Pathology program. AB - The landscape of tertiary education is changing. Developments in information and communications technology have created new ways of engaging with subject material and supporting students on their learning journeys. Therefore, it is timely to reconsider and re-imagine the education of speech-language pathology (SLP) students within this new learning space. In this paper, we outline the design of a new Master of Speech Pathology course being offered by distance education at Charles Sturt University (CSU) in Australia. We discuss the catalyst for the course and the commitments of the SLP team at CSU, then describe the curriculum design process, focusing on the pedagogical approach and the learning and teaching strategies utilised in the course delivery. We explain how the learning and teaching strategies have been selected to support students' online learning experience and enable greater interaction between students and the subject material, with students and subject experts, and among student groups. Finally, we highlight some of the challenges in designing and delivering a distance education SLP program and identify future directions for educating students in an online world. PMID- 25790922 TI - A clinical education program for speech-language pathologists applying reflective practice, evidence-based practice and case-based learning. AB - This paper presents a comprehensive clinical education program for speech language pathology students while considering the learning process and gradual acquisition of knowledge and skills for becoming a practicing speech-language pathologist. It describes the clinical speech and language education program for speech-language pathology students at Hadassah Academic College Jerusalem (HAC) based on three facets of learning: reflective practice, evidence-based practice and case-based learning. Also described are the choice of the model of learning and its implementation. The clinical education program presented reflects the professional development of the faculty at HAC as well as recent trends in clinical education methods. PMID- 25790923 TI - Adopting public health approaches to communication disability: challenges for the education of speech-language pathologists. AB - Public health approaches to communication disability challenge the profession of speech-language pathology (SLP) to reconsider both frames of reference for practice and models of education. This paper reviews the impetus for public health approaches to communication disability and considers how public health is, and could be, incorporated into SLP education, both now and in the future. The paper describes tensions between clinical services, which have become increasingly specialized, and public health approaches that offer a broader view of communication disability and communication disability prevention. It presents a discussion of these tensions and asserts that public health approaches to communication are themselves a specialist field, requiring specific knowledge and skills. The authors suggest the use of the term 'communication disability public health' to refer to this type of work and offer a preliminary definition in order to advance discussion. Examples from three countries are provided of how some SLP degree programmes are integrating public health into the SLP curriculum. Alternative models of training for communication disability public health that may be relevant in the future in different contexts and countries are presented, prompting the SLP profession to consider whether communication disability public health is a field of practice for speech-language pathologists or whether it has broader workforce implications. The paper concludes with some suggestions for the future which may advance thinking, research and practice in communication disability public health. PMID- 25790924 TI - Competence-based curricula for the education of speech-language pathologists and audiologists in Brazil. AB - OBJECTIVE: The aim of this paper is to present the academic requirements for the education of speech-language pathologists (SLPs) and to discuss some of the challenges in providing quality supervised practice and the solutions proposed by some programs in Brazil. METHODS: Brazilian proposals regarding the training of SLPs are reviewed, with guidelines provided by the International Association of Logopedics and Phoniatrics (IALP) and the Comite Permanent de Liaison des Orthophonistes-Logopedes de l'UE (CPLOL), and descriptions of the specific experience of the oldest Brazilian program are provided. RESULTS: The bachelor's degree is the minimum level required for the independent practice of speech language pathology and audiology in Brazil, where there are 75 undergraduate programs. In several programs, students are encouraged to enjoy the diversity at their university, enrolling in courses of different areas to broaden their experience. The basic areas of the undergraduate program are mandatory as per recommendation of the Ministry of Education and include competences related to the health system, decision making, communication, leadership and continued education. Since practice training is part of the undergraduate programs, it is incorporated into the pedagogical concept and has a major role in it. CONCLUSION: The structure of the programs allows the dissociation of theory from practice to be attenuated; both educational strategies are used together as part of the pedagogical concept. PMID- 25790925 TI - Education of speech and language therapists/logopedists in selected Central and Southeastern European countries: challenges and new horizons. AB - OBJECTIVE: To provide an overview of student training in speech and language therapy/logopedics (SLT) in selected Central and Southeastern European countries (Poland, Slovenia, Bulgaria, Czech Republic, Serbia, Bosnia and Herzegovina and Turkey). METHOD: Data were collected using a special questionnaire developed by Soderpalm and supplemented by Georgieva. Results from 23 SLT programs in the seven countries were collected and organized. RESULTS: In all these countries, SLT has roots in special education or health and is centralized in the university environment. The training programs have positive accreditation provided by the national agencies of accreditation and evaluation. Results were examined specifically for evidence of the new paradigm of evidence-based practice (EBP) according to the revised International Association of Logopedics and Phoniatrics (IALP) guidelines and the application of research-based teaching in SLT. The professional bodies that govern clinical practice in public health and/or educational fields are in the process of EBP implementation. Most speech and language therapists/logopedists in the selected countries work in an educational setting, clinical organization and/or hospital as well as in social day care centers. Except in Turkey, private practices are not regulated by the law. CONCLUSIONS: In the seven countries examined in this survey, SLT is progressing as a professional discipline but must be supported by government funding of SLT education and services to relevant populations. PMID- 25790926 TI - Training a new generation of speech-language pathologists with competences in the management of literacy disorders and learning disabilities in Hong Kong. AB - One of the recent developments in the education of speech-language pathology is to include literacy disorders and learning disabilities as key training components in the training curriculum. Disorders in reading and writing are interwoven with disorders in speaking and listening, which should be managed holistically, particularly in children and adolescents. With extensive training in clinical linguistics, language disorders, and other theoretical knowledge and clinical skills, speech-language pathologists (SLPs) are the best equipped and most competent professionals to screen, identify, diagnose, and manage individuals with literacy disorders. To tackle the challenges of and the huge demand for services in literacy as well as language and learning disorders, the Hong Kong Institute of Education has recently developed the Master of Science Programme in Educational Speech-Language Pathology and Learning Disabilities, which is one of the very first speech-language pathology training programmes in Asia to blend training components of learning disabilities, literacy disorders, and social-emotional-behavioural-developmental disabilities into a developmentally and medically oriented speech-language pathology training programme. This new training programme aims to prepare a new generation of SLPs to be able to offer comprehensive support to individuals with speech, language, literacy, learning, communication, and swallowing disorders of different developmental or neurogenic origins, particularly to infants and adolescents as well as to their family and educational team. PMID- 25790927 TI - Educating globally conscious speech-language pathologists for collaborative professional practice. AB - Speech-language pathologists (SLPs) practicing in the US are facing significant changes in reimbursement, billing and practice in both health care and educational settings. Health care professionals need to convey and demonstrate the value of their services, measure functional patient outcomes and assess patient satisfaction. Documentation procedures for patient and student progress are changing, becoming more abbreviated and electronic. The content of curricula in accredited graduate programs and professional development programs for maintenance of certification for SLPs will need modifications to address the myriad of changes in clinical practice. University programs that design interprofessional education opportunities for students in speech-language pathology programs and educate students in other health professional programs, e.g. physical therapy, occupational therapy, nursing and pharmacy, will help practitioners who are prepared to engage in collaborative practice with other health care professionals in hospitals, schools and community-based environments. The American Speech-Language-Hearing Association (ASHA) is actively engaged in several initiatives to facilitate interprofessional education for graduate students, faculties and practicing professionals. Individuals and families with communication disorders in the US represent an array of cultures, and SLPs need to be prepared to work effectively with individuals from different cultural and linguistic backgrounds. PMID- 25790928 TI - Struggling to be seen and heard: the underserved and unserved populations. AB - OBJECTIVE: The purpose of this paper is to provide some current information on the topic of the underserved and unserved populations including modern-day slaves, stateless/displaced persons, refugees/migrants and indigenous populations. METHOD: Speech-language pathology education and services for the underserved as well as unserved populations are discussed. Three case studies which demonstrate knowledge transfer and exchange as potential models for future development are presented. CONCLUSION: These case studies lead to more inquiries, studies, innovations and involvement from individuals and groups who are concerned about the underserved and unserved populations. PMID- 25790929 TI - Public perceptions of disease severity but not actionability correlate with interest in receiving genomic results: nonalignment with current trends in practice. AB - PURPOSE: Frameworks highlighting disease actionability and severity are evolving to address the need to organize results from genome-wide analyses. This approach represents a paradigm shift from consultations focused on one or more genes to multiple genes for multiple disorders. Empirical input from the general population is lacking, yet seems essential for understanding how to maximize patient autonomy and satisfaction in the decision-making process. METHODS: We conducted a cross-sectional online survey with a representative sample of 900 US adults and assessed the participants' perceptions and attitudes toward disease actionability and severity, ranking hypothetical scenarios for these properties, and explored correlations with interest in learning test results. RESULTS: Most respondents (>85%) rated actionability and severity as useful concepts; 46.6% indicated actionability alone would be adequate for decision making. Over half of them (53.8%) reported being very/extremely confident in their ability to score for actionability and severity. The participants' scoring of medical scenarios varied significantly between individuals. Scores for severity but not actionability were correlated with interest in learning genetic results. Subsets of the respondents projected wanting all results (30%) or no results (16%). The use of expert-created lists was acceptable to 43%. CONCLUSIONS: The respondents from the general population were confident in making their own decisions. The responses suggested different priorities than current expert-driven approaches. The emphasis on binning genes may be missing a complementary, simplifying approach of grouping patients based upon their all/none interest in genomic results. This study illuminates important differences between the general public and genetic experts. PMID- 25790930 TI - Hereditary Angioedema: An Emergency Nursing Perspective. PMID- 25790931 TI - Emergency Nursing Triage: Keeping It Safe. PMID- 25790932 TI - Blood pressure variability in Alzheimer's disease and frontotemporal dementia: the effect on the rate of cognitive decline. AB - BACKGROUND: The link between vascular disease and cognitive impairment is a matter of an ongoing debate, and different cardiovascular conditions have been found to be predictors of the clinical development and progression of cognitive dysfunction. OBJECTIVE: To compare the influence of visit-to visit blood pressure (BP) variability on the rate of cognitive decline in Alzheimer's disease (AD) and frontotemporal dementia (FTD). METHODS: The patients affected by AD and FTD consecutively admitted to our center from January 2007 to September 2012 were evaluated every three months for a one-year period. The BP mean and coefficient of variation as index of variability were obtained for both systolic and diastolic values. Progression of cognitive decline was investigated using the Mini-Mental State Examination administered at entry and at the end of the follow up. RESULTS: Two-hundred and forty-eight AD and eighty-one FTD patients were enrolled. Systolic and diastolic BP mean and variability were comparable between the two groups. Systolic BP variability (BPV) was associated with the rate of cognitive impairment in AD (B = 0.367, beta = 0.739, R2 = 0.594, adjusted R(2) = 0.567; p < 0.001), but not in FTD patients; no relationship emerged between any other BP index and cognitive decline. CONCLUSION: The relationship between BPV and cognitive function is still not completely understood, and it may play different roles according to the types and stages of dementia. Fluctuations in systolic BP may contribute to the cognitive decline in AD patients and may represent a neglected therapeutic target. PMID- 25790933 TI - Memory Improvement in the AbetaPP/PS1 Mouse Model of Familial Alzheimer's Disease Induced by Carbamylated-Erythropoietin is Accompanied by Modulation of Synaptic Genes. AB - Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AbetaPP/PS1 mouse model of familial Alzheimer's disease. Groups of 5-month old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 U I/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative PCR were used for gene expression studies. No alterations in erythropoiesis were observed in CEPO-treated WT and AbetaPP/PS1 transgenic mice. EPO and CEPO improved memory in AbetaPP/PS1 animals. However, only EPO decreased amyloid-beta (Abeta)plaque burden and soluble Abeta(40). Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor 1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AbetaPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AbetaPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission. PMID- 25790934 TI - Microbiological analysis of fluids in postsurgical gastroesophageal intrathoracic leaks obtained by endoscopy: a new way to optimize antibiotic therapy. AB - BACKGROUND/AIMS: Postsurgical gastroesophageal intrathoracic leakage is a potentially life-threatening condition that is frequently accompanied by mediastinitis and subsequent sepsis. Aspiration of fluids from intrathoracic leaks during endoscopy for microbiological analysis is rarely performed in clinical routine. The aim was to evaluate the role of routine microbiological analysis of intrathoracic leaks via endoscopy and its impact on antibiotic therapy. METHODS: This is a prospective, observational single-center study. Seventeen consecutive patients who presented for endoscopic treatment of intrathoracic leaks were included. Concomitantly, fluids from intrathoracic leaks during endoscopic intervention and blood cultures were obtained and a microbiological analysis was performed. RESULTS: Bacteria and/or fungi were detected by culture of fluid aspirated from intrathoracic leaks in 88% cases, but in none of the blood cultures. In 15 patients, microbial colonization of the leakage was detected despite previous empiric antibiotic therapy; treatment had to be adjusted in all patients according to the observed antibiotic susceptibility profile. CONCLUSIONS: The microbiological colonization of postsurgical gastroesophageal intrathoracic leaks in patients is frequent. Only the direct microbiological analysis of fluids from intrathoracic leaks, but not of blood cultures, is effective for optimizing an antibiotic therapy in such patients. PMID- 25790935 TI - MiR-301a mediates the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis by regulating PTEN expression. AB - BACKGROUND/AIMS: IL-6 has been implicated in the pathogenesis of insulin resistance. MiR-301a plays an important role in various biological and pathological processes, including cellular development and differentiation, inflammation, apoptosis and cancer. However, whether miR-301a mediates IL-6 induced insulin resistance in hepatocytes remains unknown. METHODS: The activation of AKT/GSK pathway and the level of glycogenesis were examed in NCTC 1469 cells transfected miR-301a mimics and inhibitor. Using computational miRNA target prediction database, PTEN was a target of miR-301a. The effect of miR-301a on PTEN expression was evaluated using Luciferase assay and western blot. A PTEN specific siRNA was used to further determine the effect of PTEN on IL-6-induced insulin resistance. RESULTS: In vivo and in vitro treatment with IL-6 was led to down-regulation of miR-301a, accompanied by impairment of theAKT/GSK pathway and glycogenesis. Importantly, over-expression of miR-301a rescued IL-6-induced decreased activation of the AKT/GSK pathway and hepatic glycogenesis. In contrast, down-regulation of miR-301a induced impaired phosphorylation of AKT and GSK, accompanied by reduced glycogenesis in hepatocytes. Moreover, our results indicate that suppression of PTEN, a target of miR-301a, diminished the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis. CONCLUSION: We present novel evidence of the contribution of miR-301a to IL-6-induced insulin resistance by direct regulation of PTEN expression. PMID- 25790936 TI - Intramedullary nailing versus minimally invasive plate osteosynthesis for distal extra-articular tibial fractures: a prospective randomized clinical trial. AB - PURPOSE: The purpose of this randomized clinical trial is to compare intramedullary nailing (IMN) versus minimally invasive plate osteosynthesis (MIPO) for the treatment of extra-articular distal tibial shaft fractures. MATERIALS AND METHODS: Twenty-five consecutive patients with distal extra articular tibial fractures which were located between 4 and 12 cm from the tibial plafond (AO 42A1 and 43A1) were randomly assigned into IMN (n: 10) or MIPO (n: 15) treatment groups. All patients were followed for at least 1 year. Foot function index, time to weight bearing, union time, duration of operation, length of incision, intra-operative blood loss, intra-operative fluoroscopy time, rotational and angular malalignment, rate of infection, secondary interventions and complications were compared between groups. RESULTS: All patients completed the trial and were followed with a mean of 23.1 +/- 9.4 months (range 12-52). Foot function index, weight bearing time, union time, rate of malunion, rate of infection and rate of secondary interventions were all similar between groups (p = 0.807, p = 0.177, p = 0.402, p = 0.358, p = 0.404, p = 0.404, respectively). Intra-operative blood loss, length of surgical incision, radiation time and rotational malalignment were higher in the IMN group (p = 0.012, p = 0.019, p = 0.004 and p = 0.027, respectively). CONCLUSIONS: Results of our study showed that both treatment methods have similar therapeutic efficacy regarding functional outcomes and can be used safely for extra-articular distal tibial shaft fractures, and none of the techniques had a major advantage over the other. PMID- 25790937 TI - Kinetic method for assaying the halogenating activity of myeloperoxidase based on reaction of celestine blue B with taurine halogenamines. AB - Myeloperoxidase (MPO) is a challenging molecular target which, if put under control, may allow regulating the development of inflammatory reactions associated with oxidative/halogenative stress. In this paper, a new kinetic method for assaying the halogenating activity of MPO is described. The method is based on measuring the rate of iodide-catalyzed oxidation of celestine blue B (CB) by oxygen and taurine N-chloramine (bromamine). The latter is produced in a reaction of taurine with HOCl (HOBr). CB is not a substrate for the peroxidase activity of MPO and does not react with hydrogen peroxide and superoxide anion radical. Taurine N-chloramine (bromamine) reacts with CB in molar ratio of 1:2. Using the new method, we studied the dependence of MPO activity on concentration of substrates and inhibitors. The specificity of MPO inhibition by non proteolyzed ceruloplasmin is characterized. The inhibition of taurine N chloramine production by neutrophils and HL-60 cells in the presence of MPO affecting substances is demonstrated. The new method allows determining the kinetic parameters of MPO halogenating activity and studying its inhibition by various substances, as well as screening for potential inhibitors of the enzyme. PMID- 25790938 TI - Age-associated oxidative modifications of mitochondrial alpha-subunit of F1 ATP synthase from mouse skeletal muscles. AB - The objective of this study was to investigate the pattern of age-associated oxidative post-translational modifications in the skeletal muscles of a mammalian species and to address whether the modifications result in the loss of function of the oxidatively modified protein(s). Accordingly, proteins in the mitochondrial matrix of the hind limb of C57BL/6Nnia mice were examined for modifications by carbonylation--an established marker of oxidative post translational modifications--by Western blotting using anti-2,4-dinitrophenyl antibodies and tritiated sodium borohydride methods. An age-associated increase in carbonylation of mitochondrial matrix proteins was observed, but not all proteins were equally susceptible. A 55 kDa protein, identified as the alpha subunit of the F1 complex of ATP synthase (ATP phosphohydrolase [H(+) transporting]), had approximately 17% and 27% higher levels of protein carbonyls in adult and old animals, respectively, in comparison to the young controls as estimated using tritiated sodium borohydride. In addition, an age-associated decline in its activity was observed, with approximately 9% and 28% decrease in the activity in the adult and old animals, respectively, in comparison to young controls. It may be concluded that such oxidative post-translational modifications and the resultant attenuation of the protein activity may contribute to the age-related energy loss and muscular degeneracy. PMID- 25790940 TI - Impacts of comorbidities on the association between arterial stiffness and obstructive sleep apnea in the elderly. AB - BACKGROUND: Although the impact of obstructive sleep apnea (OSA) on cardiovascular risk is reasonably well established in middle-aged patients, the debate persists as to whether OSA also increases this risk in the elderly. Arterial stiffness has been used as an early independent predictor of cardiovascular risk. STUDY OBJECTIVES: We sought to determine whether OSA has significant effects on the arterial stiffness in the elderly population and evaluate the impact of comorbidities on the association between arterial stiffness and OSA. METHODS: We performed a cross-sectional study in a university hospital. Elderly participants (>=60 years) were invited to participate in our study between November 2010 and January 2013. OSA was diagnosed using gold standard polysomnography and arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV), cardio-ankle vascular index (CAVI) and central systolic and diastolic blood pressure (cSBP and cDBP). The high-sensitivity C reactive protein (hs-CRP) level was also measured. RESULTS: We found no significant association between the severity of OSA and the arterial stiffness related parameters cSBP, cDBP, baPWV, CAVI and hs-CRP. However, in patients with no comorbid medical conditions or use of medications (n = 101), we showed a modest association between OSA and arterial stiffness-related parameters and hs CRP. CONCLUSION: We conclude that OSA is associated with increased arterial stiffness in an otherwise healthy elderly population, although the association was obviated by comorbidities and medications perhaps due to ceiling effects. PMID- 25790939 TI - Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome. AB - Childhood nephrotic syndrome is mainly caused by minimal change disease which is named because only subtle ultrastructural alteration could be observed at electron microscopic level in the pathological kidney. Glomerular podocytes are presumed to be the target cells whose protein sieving capability is compromised by a yet unidentified permeability perturbing factor. In a cohort of children with non-hereditary idiopathic nephrotic syndrome, we found the complement fragment C5a was elevated in their sera during active disease. Administration of recombinant C5a induced profound proteinuria and minimal change nephrotic syndrome in mice. Purified glomerular endothelial cells, instead of podocytes, were demonstrated to be responsible for the proteinuric effect elicited by C5a. Further studies depicted a signaling pathway involving Rho/Rho-associated kinase/myosin activation leading to endothelial cell contraction and cell adhesion complex breakdown. Significantly, application of Rho-associated kinase inhibitor, Y27632, prevented the protein leaking effects observed in both C5a treated purified endothelial cells and mice. Taken together, our study identifies a previously unknown mechanism underlying nephrotic syndrome and provides a new insight toward identifying Rho-associated kinase inhibition as an alternative therapeutic option for nephrotic syndrome. PMID- 25790941 TI - CARD9 deficiencies linked to impaired neutrophil functions against Phialophora verrucosa. AB - Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule that is critical for NF-kappaB activation and forms a complex with B cell lymphoma 10 and mucosa-associated lymphoid tissue lymphoma translocation gene 1 that mediates C-type lectin receptors (CLRs)-triggered intracellular signaling during antifungal immunity. However, the role of CARD9 in the host defense against Phialophora verrucosa (P. verrucosa) infection remains to be elucidated. In the present study, we investigated the functions of polymorphonuclear neutrophils (PMNs) from patients with CARD9 deficiencies against P. verrucosa. By isolating PMNs from patients and healthy blood donors and subsequently challenging the cells with P. verrucosa, we demonstrated that, compared with healthy donors, CARD9-deficient PMNs exhibited defects in P. verrucosa killing and pro-inflammatory cytokine productions, which can be rescued in the presence of serum; however, the CARD9-deficient PMNs exhibited normal reactive oxygen species generation and phagocytotic ability. In conclusion, our results indicate that CARD9 is indispensable for P. verrucosa killing by PMNs, and serum opsonization acts as a CARD9-independent way, which could be a promising immunotherapy in the future. PMID- 25790942 TI - Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails. AB - Pulmonary aspergillosis is frequently reported in parrots, falcons, and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but its administration requires repeated oral dosing, and the safety margin is narrow. To investigate the efficacy of inhaled ITRA, six groups of ten young quails (Coturnix japonica) were inoculated intratracheally with 5 * 10(6) spores (3 groups) or 5 * 10(7) spores (3 groups). Animals were exposed to nebulized ITRA nanosuspension as 10 % suspension or 4 % suspension, once daily for 30 min, starting 2 h after inoculation for 6 days. Control groups were exposed to nebulized saline for the same period of time. Survival and clinical scores were evaluated, and animals were subjected to gross pathology. In control animals, aspergillosis resulted in systemic disease without pulmonary or air sac granulomas. Animals died from multiple organ failure. Inhalation of 10 % ITRA nanosuspension blocked lethality and prevented disease-related symptoms in the quails exposed to the low dose of spores, while the disease course in quails inoculated with the high-spore dose was retarded. Inhalation of 4 % ITRA nanosuspension was less effective. Both inhalations were well tolerated, and gross pathology did not reveal signs of local toxicity. The data indicate that inhaled administration of 10 % ITRA nanosuspension is capable of alleviating an acute A. fumigatus infection in quails. A lower ITRA concentration may be only active in chronic pulmonary aspergillosis. PMID- 25790943 TI - Poor tolerance and limited effects of isosorbide-5-mononitrate in microvascular angina. AB - OBJECTIVES: To assess the effects of isosorbide-5-mononitrate (ISMN) in patients with microvascular angina (MVA). METHODS: We randomized 20 MVA patients, treated with a beta-blocker or a calcium antagonist, to 60 mg slow-release ISMN (halved to 30 mg if not tolerated) or placebo once a day for 4 weeks; the patients were then switched to the other treatment for another 4 weeks. Their clinical status was assessed with the Seattle Angina Questionnaire (SAQ) and the EuroQoL score for quality of life. The exercise stress test (EST), coronary blood flow (CBF) response to nitrate and the cold pressor test (CPT), brachial artery flow mediated dilation (FMD) and nitrate-mediated dilation (NMD) were also assessed. RESULTS: Nine patients (45%) did not complete the ISMN phase due to side effects; 2 patients refused a follow-up. Nine patients completed the study. The SAQ and EuroQoL scores were significantly better with ISMN than with placebo, although the differences were small. No differences were found between the treatments in the EST results, CBF response to nitroglycerin (p = 0.55) and the CPT (p = 0.54), FMD (p = 0.26) and NMD (p = 0.35). CONCLUSIONS: In this study, a high proportion of MVA patients showed an intolerance to ISMN; in those tolerating the drug, significant effects on their angina status were observed, but the benefit appeared to be modest and independent of effects on coronary microvascular function. PMID- 25790944 TI - Tapered-slit membrane filters for high-throughput viable circulating tumor cell isolation. AB - This paper presents tapered-slit membrane filters for high-throughput viable circulating tumor cell (CTC) isolation. The membrane filter with a 2D array of vertical tapered slits with a gap that is wide at the entrance and gradually decreases with depth, provide minimal cell stress and reduce 82.14% of the stress generated in conventional straight-hole filters. We designed two types of tapered slit filters, Filters 6 and 8, respectively, containing the tapered slits with outlet widths of 6 MUm and 8 MUm at a slit density of 34,445/cm(2) on the membrane. We fabricated the vertical slits with a tapered angle of 2 degrees on a SU8 membrane by adjusting the UV expose dose and the air gap between the membrane and the photomask during lithography. In the experimental study, the proposed tapered-slit filter captured 89.87% and 82.44% of the cancer cells spiked in phosphate buffered saline (PBS) and diluted blood (blood: PBS = 1:4), respectively, at a sample flow rate of 5 ml per hour, which is 33.3 times faster than previous lateral tapered-slit filters. We further verified the capability to culture on chip after capturing: 72.33% of cells among the captured cells still remained viable after a 5-day culture. The proposed tapered-slit membrane filters verified high-throughput viable CTC isolation capability, thereby inaugurating further advanced CTC research for cancer diagnosis and prognosis. PMID- 25790945 TI - Merged Near-Infrared and White-Light Imaging in Minimally Invasive Surgery. PMID- 25790946 TI - The effect of rapid palatal expansion on sleep bruxism in children. AB - BACKGROUND: Sleep bruxism (SB) is a movement described as an involuntary mastication movement during sleep, also defined as rhythmic masticatory muscle activity (RMMA). It is observed in 2-40 % of the pediatric population. A link was suggested between respiratory events and RMMA. Rapid palatal expansion (RPE) is an effective orthopedic treatment for correcting maxillary transverse deficiency and sleep-disordered breathing (SDB) in children. The aim was to evaluate the possible reduction of SB after rapid palatal expansion (RPE) therapy. METHODS: A total of 32 patients (8-14 years old; 22 girls and 10 boys) received an orthodontic treatment for transverse maxillary deficiency (5 mm or more) at the orthodontics department of the Universite de Montreal. They underwent an ambulatory polysomnography (PSG) before, after expansion with the expander, and at the end of the study without the expander. They were classified into three subgroups based on sleep electromyography (EMG) data. RESULTS: Total sleep time and stage NREM 3 presented significant differences between the types of appliances. Moreover, there was a time effect observed for total sleep time, sleep cycles, stage NREM 2, and stage REM, while only a trend suggested for stage NREM 3. Significant differences were observed between subgroups for both RMMA episodes and burst indexes, similarly, for the oxygen desaturation index (ODI). A total of 50 % of the patients were classified as responders when RMMA episodes index decreased by more than 25 % when comparing treatment efficacy at baseline night. CONCLUSION: Most bruxers (65 %) reduced their RMMA episode index after expansion, but sleep and respiratory variables remained unchanged. PMID- 25790947 TI - Pregnancy during Ustekinumab Treatment for Severe Psoriasis. AB - We report the case of a 25-year-old patient who became pregnant during ustekinumab therapy. Treatment was suspended immediately after pregnancy had been confirmed. The patient had an uneventful pregnancy and her child is currently 14 months old, with adequate development to her age. Four reports of pregnancy during ustekinumab treatment have been reported and one resulted in miscarriage. PMID- 25790948 TI - Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia. AB - INTRODUCTION: After decades of research, pancreatic cancer is still a devastating disease. The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and S-1 (GS) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: Relevant trials were identified by searching databases. Five trials were selected in this article. The indicators we used were overall response rate, disease control rate, 1-year survival rate and haematological toxicities. RESULTS: Meta-analysis of the pooled data demonstrated that the overall response rate (risk ratio, RR = 2.52, 95% confidence interval, CI: 1.85 3.42, P < 0.00001) and disease control rate (RR = 1.24, 95% CI: 1.12-1.37, P < 0.0001) were significantly different for the GS and GEM alone chemotherapies. Among the group of patients, 43.4% in the GS group and 31.4% in the GEM group survived more than a year. According to this, patients who use the GS regiment may have a better prognosis than the GEM regiment (RR = 1.62, 95% CI: 1.12-2.33, P = 0.04). The combination chemotherapy with GEM and S-1 group had higher haematological toxicities including neutropaenia (RR = 1.58, 95% CI: 1.17-2.14, P = 0.003) and thrombocytopaenia (RR = 1.85, 95% CI: 1.28-2.67, P = 0.001). The incidence of anaemia was much the same in the two groups (RR = 1.22, 95% CI: 0.87 1.70, P = 0.24). DISCUSSION: Overall response rate and disease control rate as well as 1-year survival rate in patients who received GS were superior to those treated with GEM alone. Combination chemotherapy with GEM and S-1 may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. Combination chemotherapy with GEM and S-1 might be an option of first-line chemotherapy for pancreatic cancer patients, at least in Asia. Mini Abstract: This systematic review analysing randomized controlled trials (RCTs) comparing S-1 combination chemotherapy versus GEM alone for locally advanced and metastatic pancreatic cancer demonstrated greater efficacy for S-1 combination in term of response, disease control and 1 year survival proportion. PMID- 25790949 TI - Acoustic temporal modulation detection in normal-hearing and cochlear implanted listeners: effects of hearing mechanism and development. AB - Temporal modulation detection ability matures over many years after birth and may be particularly sensitive to experience during this period. Profound hearing loss during early childhood might result in greater perceptual deficits than a similar loss beginning in adulthood. We tested this idea by measuring performance in temporal modulation detection in profoundly deaf children and adults fitted with cochlear implants (CIs). At least two independent variables could constrain temporal modulation detection performance in children with CIs: altered encoding of modulation information due to the CI-auditory nerve interface, and atypical development of central processing of sound information provided by CIs. The effect of altered encoding was investigated by testing subjects with one of two different hearing mechanisms (normal hearing vs. CI) and the effect of atypical development was studied by testing two different age groups. All subjects were tested for their ability to detect acoustic temporal modulations of sound amplitude. A comparison of the slope, or cutoff frequency, of the temporal modulation transfer functions (TMTFs) among the four subject groups revealed that temporal resolution was mainly constrained by hearing mechanism: normal-hearing listeners could detect smaller amplitude modulations at high modulation frequencies than CI users. In contrast, a comparison of the height of the TMTFs revealed a significant interaction between hearing mechanism and age group on overall sensitivity to temporal modulation: sensitivity was significantly poorer in children with CIs, relative to the other three groups. Results suggest that there is an age-specific vulnerability of intensity discrimination or non-sensory factors, which subsequently affects sensitivity to temporal modulation in prelingually deaf children who use CIs. PMID- 25790950 TI - Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling. AB - The PI3K/Akt signaling pathway is involved in mediating survival of sensory hair cells. Here, we investigated the involvement of PI3K/Akt in noise-induced hearing loss in both temporary and permanent threshold shift noise models. The PI3K regulatory subunit p85alpha and phosphorylation of Akt on serine 473 (p-Akt S473) are downregulated in sensory hair cells, including both outer and inner hair cells, and supporting cells of the mouse organ of Corti 1 h after exposure to permanent-threshold-shift-inducing noise (PTS noise), but not with temporary threshold-shift-inducing noise (TTS noise). In contrast, the PI3K catalytic subunit p110alpha and phosphorylation of Akt on threonine 308 (p-Akt T308) do not change with PTS or TTS noise. Additionally, mice pretreated with p85alpha small interfering RNA (siRNA) have decreased expression of p-Akt1 (S473) in their sensory hair cells and increased sensitivity to TTS noise-induced hearing loss. Finally, Akt1-knockout mice also have enhanced sensitivity to TTS noise-induced hearing loss. In conclusion, this study suggests that endogenous PI3K/Akt signaling is an intrinsic protective mechanism of the inner ear. Blockade of PI3K/Akt signaling pathways increases sensitivity to TTS noise-induced hearing loss. PMID- 25790951 TI - Histopathologic Changes of the Inner ear in Rhesus Monkeys After Intratympanic Gentamicin Injection and Vestibular Prosthesis Electrode Array Implantation. AB - Bilateral vestibular deficiency (BVD) due to gentamicin ototoxicity can significantly impact quality of life and result in large socioeconomic burdens. Restoring sensation of head rotation using an implantable multichannel vestibular prosthesis (MVP) is a promising treatment approach that has been tested in animals and humans. However, uncertainty remains regarding the histopathologic effects of gentamicin ototoxicity alone or in combination with electrode implantation. Understanding these histological changes is important because selective MVP-driven stimulation of semicircular canals (SCCs) depends on persistence of primary afferent innervation in each SCC crista despite both the primary cause of BVD (e.g., ototoxic injury) and surgical trauma associated with MVP implantation. Retraction of primary afferents out of the cristae and back toward Scarpa's ganglion would render spatially selective stimulation difficult to achieve and could limit utility of an MVP that relies on electrodes implanted in the lumen of each ampulla. We investigated histopathologic changes of the inner ear associated with intratympanic gentamicin (ITG) injection and/or MVP electrode array implantation in 11 temporal bones from six rhesus macaque monkeys. Hematoxylin and eosin-stained 10-MUm temporal bone sections were examined under light microscopy for four treatment groups: normal (three ears), ITG-only (two ears), MVP-only (two ears), and ITG + MVP (four ears). We estimated vestibular hair cell (HC) surface densities for each sensory neuroepithelium and compared findings across end organs and treatment groups. In ITG-only, MVP-only, and ITG + MVP ears, we observed decreased but persistent ampullary nerve fibers of SCC cristae despite ITG treatment and/or MVP electrode implantation. ITG-only and ITG + MVP ears exhibited neuroepithelial thinning and loss of type I HCs in the cristae but little effect on the maculae. MVP-only and ITG + MVP ears exhibited no signs of trauma to the cochlea or otolith end organs except in a single case of saccular injury due to over-insertion of the posterior SCC electrode. While implanted electrodes reached to within 50-760 MUm of the target cristae and were usually ensheathed in a thin fibrotic capsule, dense fibrotic reaction and osteoneogenesis were each observed in only one of six electrode tracts examined. Consistent with physiologic studies that have demonstrated directionally appropriate vestibulo-ocular reflex responses to MVP electrical stimulation years after implantation in these animals, histologic findings in the present study indicate that although intralabyrinthine MVP implantation causes some inner ear trauma, it can be accomplished without destroying the distal afferent fibers an MVP is designed to excite. PMID- 25790952 TI - Kainic Acid-Induced Golgi Complex Fragmentation/Dispersal Shifts the Proteolysis of Reelin in Primary Rat Neuronal Cells: An In Vitro Model of Early Stage Epilepsy. AB - The endoplasmic reticulum-lysosome-Golgi network plays an important role in Reelin glycosylation and its proteolytic processing. Golgi complex fragmentation is associated with the separation of Reelin from this network. Kainic acid (KA) is an excitotoxic agent commonly used to induce epilepsy in rodents. The relationship between KA-induced neuronal damage and Golgi complex fragmentation has not been investigated, leaving a major gap in our understanding of the molecular mechanism underlying the development of pathophysiology in epilepsy. We cultured primary rat cortical neurons eitherin ambient condition (control) or treated with a range of KA doses to reveal whether Golgi complex fragmentation impaired neuronal function. The half-life maximal inhibitory concentration (IC50) value of KA was detected to be approximately 5 MUM, whereby at these concentrations, KA impaired neuronal viability, which was closely associated with initial Golgi complex fragmentation and subsequent reduction in both the expression and glycosylation patterns of Reelin. These findings implicate that Golgi complex fragmentation and Reelin dysfunction are key contributors to neuronal cell death in the early stage of epilepsy pathophysiology, thereby representing as novel disease biomarkers, as well as potent therapeutic targets for epilepsy. PMID- 25790953 TI - Differentiation Potential of Human Chorion-Derived Mesenchymal Stem Cells into Motor Neuron-Like Cells in Two- and Three-Dimensional Culture Systems. AB - Many people worldwide suffer from motor neuron-related disorders such as amyotrophic lateral sclerosis and spinal cord injuries. Recently, several attempts have been made to recruit stem cells to modulate disease progression in ALS and also regenerate spinal cord injuries. Chorion-derived mesenchymal stem cells (C-MSCs), used to be discarded as postpartum medically waste product, currently represent a class of cells with self renewal property and immunomodulatory capacity. These cells are able to differentiate into mesodermal and nonmesodermal lineages such as neural cells. On the other hand, gelatin, as a simply denatured collagen, is a suitable substrate for cell adhesion and differentiation. It has been shown that electrospinning of scaffolds into fibrous structure better resembles the physiological microenvironment in comparison with two-dimensional (2D) culture system. Since there is no report on potential of human chorion-derived MSCs to differentiate into motor neuron cells in two- and three-dimensional (3D) culture systems, we set out to determine the effect of retinoic acid (RA) and sonic hedgehog (Shh) on differentiation of human C-MSCs into motor neuron-like cells cultured on tissue culture plates (2D) and electrospun nanofibrous gelatin scaffold (3D). PMID- 25790954 TI - Prognostic Role of microRNA-21 Expression in Brain Tumors: a Meta-analysis. AB - Many studies have shown that microRNAs have important roles in the development and progression of various cancers. Recent studies also showed that microRNA-21 expression may be associated with the prognosis of patients with several common cancers. However, there was still lack of evidence for the prognostic role of microRNA-21 expression in brain tumors. We performed a systemic review and meta analysis of published and unpublished studies to assess the prognostic role of microRNA-21 expression in patients with brain tumors. PubMed, Embase, and Google Scholar databases were searched for eligible studies with data assessing the prognostic role of microRNA-21 expression in brain tumors. Pooled hazard ratios (HRs) of microRNA-21 expression for overall survival and 95% confidence intervals (CI) were calculated. Six studies from five publications were finally included into the meta-analysis. Those six studies included a total of 747 patients with brain tumors and 654 patients with gliomas. For overall survival, the pooled HR of higher microRNA-21 expression in patients with brain tumors was 1.82 (95% CI 1.29-2.58, P = 0.001). In patients with gliomas, the HR for overall survival of higher microRNA-21 expression was 1.83 (95% CI 1.09-3.09, P = 0.023). Sensitivity analysis by omitting one study by turns also showed there was no obvious influence of individual study on the pooled HRs. There was no obvious risk of publication bias in the meta-analysis. The present meta-analysis suggests that microRNA-21 is associated with the prognosis of patients with brain tumors, and high expression of microRNA-21 can predict poor prognosis in patients with brain tumors. PMID- 25790956 TI - Successful endovascular reconstruction of a recurrent giant middle cerebral artery aneurysm with multiple telescoping flow diverters in a pediatric patient. AB - Intracranial aneurysms of the pediatric population are rare, but giant fusiform aneurysms (GFAs) of the middle cerebral artery (MCA) are common within this cohort of patients. These aneurysms are difficult to treat and often require advanced microsurgical skills, as they are usually not amenable to direct clipping. Here, we report the successful treatment of a recurrent GFA of the MCA with three telescoping Pipeline Embolization Devices 6 months after attempted clip reconstruction in a pediatric patient. PMID- 25790955 TI - CGRP mechanism antagonists and migraine management. AB - Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP) based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management. PMID- 25790957 TI - The interaction between delayed rectifier channel alpha-subunits does not involve hetero-tetramer formation. AB - We have previously reported a physiologically relevant interaction between KCNQ1 (Q1) and KCNH2 (H2). While the H2 C-terminus has been suggested to play a role, so far, no more detailed information regarding the interaction site is available. The methods used in the study are cell culture, PCR for mutagenesis, patch clamp for ion current recordings, co-immunoprecipitation for determination of protein interaction. Co-expression of Q1 and H2 resulted in an increase of I H2 (tails after +50 mV; Q1 + H2, 36 +/- 6 pA/pF; H2, 14 +/- 2 pA/pF; n = 10; 12; P < 0.05). Upon expressing a non-conductive (dominant-negative) Q1-pore mutation (dnQ1), there was still an increase in I H2 (tails after +50 mV; H2 + dnQ1, 24 +/- 4 pA/pF; n = 10; P < 0.05) making the pore region unlikely as an interaction site. Experiments using the KCNH2-pore blocking agent quinidine supported these findings. If Q1 and H2 formed hetero-tetramers, steric changes within the pore should change the quinidine half-inhibitory concentrations (IC50). However, I H2 sensitivity did not significantly change in the presence or absence of Q1 (IC50 341 +/- 63 vs. 611 +/- 293 nmol/L, respectively, P = n.s.), providing further evidence that the pore is not a likely H2-Q1 interaction site. To obtain further insights into the role of intra-cytoplasmic structures, we used both C- and N terminally truncated mutant H2 proteins. Both H2 mutants co-immunoprecipitated with Q1, suggesting no specific role of C- or N-termini. Accordingly, rather than these, the transmembrane domains of the alpha-subunits appear relevant for the interaction. Our results largely exclude the formation of hetero-tetramers between H2 and Q1 comprising the pore region or H2 C- or N-termini. PMID- 25790958 TI - Age-related changes in diffusion tensor imaging metrics of fornix subregions in healthy humans. AB - OBJECTIVE: White matter diffusivity measures of the fornix change with aging, which likely relates to changes in memory and cognition in older adults. Subregional variations in forniceal diffusivity may exist, given its heterogeneous anatomy and connectivity; however, these have not been closely examined in vivo. We examined diffusivity parameters (fractional anisotropy, FA; radial diffusivity, RD; axial diffusivity, AD) in forniceal subregions of healthy subjects and correlated them with age and hippocampal volume. METHODS: Diffusion weighted imaging and streamline tractography of the fornix were performed on 20 healthy, right-handed females (23-66 years). Six anatomical subregions were defined: midline (body, column, precommissural fornix) or lateral (fimbria, crura, postcommissural fornix). Regression analysis was performed comparing diffusivities against age. Hippocampal and ventricular volumes were also compared. RESULTS: Diffusivity values revealed statistical changes with age in both midline and lateralized subregions. The fornix body and left crus showed age related alterations in all metrics (FA, RD, AD), whereas only right crus FA was altered. There was no significant change in hippocampal volumes, suggesting that forniceal changes may precede hippocampal age-related changes. CONCLUSIONS: Age related changes in fornix diffusivity measures appear subregion dependent and asymmetrical. Specific subregion diffusivity measures may be a more sensitive aging marker than hippocampal volume change. PMID- 25790959 TI - The Dark Side of EDX Tomography: Modeling Detector Shadowing to Aid 3D Elemental Signal Analysis. AB - A simple model is proposed to account for the loss of collected X-ray signal by the shadowing of X-ray detectors in the scanning transmission electron microscope. The model is intended to aid the analysis of three-dimensional elemental data sets acquired using energy-dispersive X-ray tomography methods where shadow-free specimen holders are unsuitable or unavailable. The model also provides a useful measure of the detection system geometry. PMID- 25790960 TI - Why not use a surfactant test for respiratory distress syndrome? PMID- 25790961 TI - Association between hypouricemia and reduced kidney function: a cross-sectional population-based study in Japan. AB - BACKGROUND: Hypouricemia, conventionally defined as a serum uric acid level of <=2 mg/dl, is considered a biochemical disorder with no clinical significance. However, individuals with renal hypouricemia have a high risk of urolithiasis and exercise-induced acute kidney injury, both of which are risk factors for reduced kidney function. METHODS: To test the hypothesis that individuals with hypouricemia would be at a higher risk of reduced kidney function, we conducted a population-based cross-sectional study using data from the Specific Health Checkups and Guidance System in Japan. Logistic analysis was used to examine the relationship between hypouricemia and reduced kidney function, defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2). RESULTS: Among 90,710 men (mean age, 63.8 years) and 136,935 women (63.7 years), 193 (0.2%) and 540 (0.4%) were identified as having hypouricemia, respectively. The prevalence of hypouricemia decreased with age in women (p for trend <0.001), but not in men (p for trend = 0.24). Hypouricemia was associated with reduced kidney function in men (odds ratio, 1.83; 95% confidence interval, 1.23-2.74), but not in women (0.61; 0.43-0.86), relative to the reference category (i.e., serum uric acid levels of 4.1-5.0 mg/dl) after adjusting for age, drinking, smoking, diabetes, hypertension, hypercholesterolemia, obesity, and history of renal failure. Sensitivity analyses stratified by diabetic status yielded similar results. CONCLUSIONS: This study is the first to provide evidence that hypouricemia is associated with reduced kidney function in men. Further research will be needed to determine the long-term prognosis of individuals with hypouricemia. PMID- 25790962 TI - Stereoselective synthesis of (all-Z)-hentriaconta-3,6,9,12,15,19,22,25,28 nonaene. AB - Several microorganisms produce small quantities of polyunsaturated hydrocarbons and such natural products are of interest. Starting from the ethyl ester of eicosapentaenoic acid, the total synthesis of the natural product (all-Z) hentriaconta-3,6,9,12,15,19,22,25,28-nonaene has been achieved in eight steps and 15% overall yield. The synthesis is based on a stereoselective Wittig reaction and confirms the all-Z-configuration of the nine double bonds in this highly unsaturated natural product. PMID- 25790963 TI - The adsorption of thiophenol on gold--a spectroelectrochemical study. AB - The adsorbate formed by adsorption of thiophenol on a polycrystalline gold electrode and brought into contact with aqueous solutions of 1 M HClO4 and 0.1 M KClO4 has been studied using cyclic voltammetry and surface-enhanced Raman spectroscopy. A strong adsorption is deduced from observations made using cyclic voltammetry. From the SER spectra, interactions of thiophenol with the gold surface via a gold-sulfur bond with the aromatic ring pointing away from the surface is concluded for both electrolyte solutions. PMID- 25790964 TI - Virtual water trade and time scales for loss of water sustainability: a comparative regional analysis. AB - Assessment and policy design for sustainability in primary resources like arable land and water need to adopt long-term perspective; even small but persistent effects like net export of water may influence sustainability through irreversible losses. With growing consumption, this virtual water trade has become an important element in the water sustainability of a nation. We estimate and contrast the virtual (embedded) water trades of two populous nations, India and China, to present certain quantitative measures and time scales. Estimates show that export of embedded water alone can lead to loss of water sustainability. With the current rate of net export of water (embedded) in the end products, India is poised to lose its entire available water in less than 1000 years; much shorter time scales are implied in terms of water for production. The two cases contrast and exemplify sustainable and non-sustainable virtual water trade in long term perspective. PMID- 25790965 TI - Effect of the ADIPOQ Gene -11391G/A Polymorphism Is Modulated by Lifestyle Factors in Mexican Subjects. AB - BACKGROUND/AIMS: Single nucleotide polymorphisms (SNPs) in the ADIPOQ gene could explain the adiponectin level. However, the knowledge about the influence of genetic and lifestyle factors is not sufficient. The aim was to analyze whether the effect of the -11391G/A SNP in the ADIPOQ gene is modulated by lifestyle factors in Mexican subjects. METHODS: A cross-sectional study was performed in which 394 participants were analyzed. Genetic, anthropometric, biochemical, dietary, clinical and physical activity parameters were measured. Statistical analysis was performed with SPSSv19 software. RESULTS: The distribution of the 11391G/A SNP genotypes was 55.6 and 44.4% for GG and AG, respectively. The adiponectin level was modulated by the -11391G/A SNP in response to the body mass index (BMI); A allele carriers showed a higher adiponectin level compared to G homozygous carriers but only in the minor BMI tertile group (p=0.032). Adiponectin level variability was explained by gender [(r)=1.5, 95% CI 1.1-1.9, p=0.000], insulin resistance [(r)=-1.2, 95% CI -0.8 to -1.6, p=0.000], physical activity [(r)=0.6, 95% CI 0.2-0.9, p=0.002] and monounsaturated fat intake [(r)=0.5, 95% CI 0.38-1.0, p=0.047]. CONCLUSIONS: The adiponectin level was modulated by the interaction between BMI and -11391G/A SNP; this suggests that the lifestyle rather than genetic factors modulates serum adiponectin. PMID- 25790966 TI - Di-oxime based selective fluorescent probe for arsenate and arsenite ions in a purely aqueous medium with living cell imaging applications and H-bonding induced microstructure formation. AB - A 2-hydroxy-5-methyl-benzene-1,3-dicarboxaldehyde di-oxime based turn-on blue emission fluorescent probe was found to recognize both AsO2(-) and H2AsO4(-) in a purely aqueous medium in intra and extra-cellular conditions. Self-organization of the ligand in the absence and presence of AsO2(-) and H2AsO4(-) was investigated by DLS, optical microscopy, optical fluorescence microscopy and FE SEM methods. PMID- 25790967 TI - Coherent creation and destruction of orbital wavepackets in Si:P with electrical and optical read-out. AB - The ability to control dynamics of quantum states by optical interference, and subsequent electrical read-out, is crucial for solid state quantum technologies. Ramsey interference has been successfully observed for spins in silicon and nitrogen vacancy centres in diamond, and for orbital motion in InAs quantum dots. Here we demonstrate terahertz optical excitation, manipulation and destruction via Ramsey interference of orbital wavepackets in Si:P with electrical read-out. We show milliradian control over the wavefunction phase for the two-level system formed by the 1s and 2p states. The results have been verified by all-optical echo detection methods, sensitive only to coherent excitations in the sample. The experiments open a route to exploitation of donors in silicon for atom trap physics, with concomitant potential for quantum computing schemes, which rely on orbital superpositions to, for example, gate the magnetic exchange interactions between impurities. PMID- 25790968 TI - Generation mechanism of hydroxyl radical species and its lifetime prediction during the plasma-initiated ultraviolet (UV) photolysis. AB - Through this work, we have elucidated the mechanism of hydroxyl radicals (OH(*)) generation and its life time measurements in biosolution. We observed that plasma initiated ultraviolet (UV) photolysis were responsible for the continues generation of OH(*) species, that resulted in OH(*) to be major reactive species (RS) in the solution. The density and lifetime of OH(*) species acted inversely proportional to each other with increasing depth inside the solution. The cause of increased lifetime of OH(*) inside the solution is predicted using theoretical and semiempirical calculations. Further, to predict the mechanism of conversion of hydroxide ion (OH(-)) to OH(*) or H2O2 (hydrogen peroxide) and electron, we determined the current inside the solution of different pH. Additionally, we have investigated the critical criterion for OH(*) interaction on cancer cell inducing apoptosis under effective OH(*) exposure time. These studies are innovative in the field of plasma chemistry and medicine. PMID- 25790969 TI - Ptychographic X-ray nanotomography quantifies mineral distributions in human dentine. AB - Bones are bio-composites with biologically tunable mechanical properties, where a polymer matrix of nanofibrillar collagen is reinforced by apatite mineral crystals. Some bones, such as antler, form and change rapidly, while other bone tissues, such as human tooth dentine, develop slowly and maintain constant composition and architecture for entire lifetimes. When studying apatite mineral microarchitecture, mineral distributions or mineralization activity of bone forming cells, representative samples of tissue are best studied at submicrometre resolution while minimizing sample-preparation damage. Here, we demonstrate the power of ptychographic X-ray tomography to map variations in the mineral content distribution in three dimensions and at the nanometre scale. Using this non destructive method, we observe nanostructures surrounding hollow tracts that exist in human dentine forming dentinal tubules. We reveal unprecedented quantitative details of the ultrastructure clearly revealing the spatially varying mineralization density. Such information is essential for understanding a variety of natural and therapeutic effects for example in bone tissue healing and ageing. PMID- 25790970 TI - Correlates and moderators of change in subjective memory and memory performance: findings from the health and retirement study. AB - Aging researchers have long been interested in understanding individuals' subjective perceptions of their own memory functioning. Previous research has shown that subjective memory ratings are partly based on memory performance but also reflect the influence of other factors, such as depressive symptoms. The aim of the present study was to examine (1) longitudinal associations between trajectories of subjective memory and memory performance, (2) variables that predict levels of and changes in subjective memory and memory performance, and (3) variables that moderate associations between these constructs. We applied a latent growth curve model to four occasions of data from 15,824 participants of the Health and Retirement Study (HRS; mean age at baseline=64.27 years, SD=9.90; 58% women). Results revealed that latent changes in subjective memory were correlated with latent changes in memory performance (phi=0.49), indicating that participants who reported steeper declines of subjective memory indeed showed steeper declines of memory performance over time. Three major patterns of associations emerged with respect to predictors of subjective memory and subjective memory change. First, the level of memory performance showed stronger associations with age, gender, and education, whereas subjective memory was more strongly associated with subjective age and personality traits. For example, women performed better than men on the episodic memory test, but there were no gender differences in subjective memory. Also, older age was associated with steeper declines of memory performance but with less decline of subjective memory. Second, personality traits that predicted subjective memory intercepts did not predict subjective memory slopes. Third, the strength of associations between levels and slopes of subjective memory and memory performance varied as a function of gender, education, depressive symptoms, and personality traits. Conscientiousness moderated the relationship of the level of subjective memory to the level of memory performance, consistent with the hypothesis that persons high in conscientiousness more accurately monitor memory successes and failures. The results reinforce the importance of depressive symptoms as a predictor of subjective memory but also indicate that a broader perspective on the reasons why memory complaints have modest correlations with memory itself is needed. PMID- 25790971 TI - MicroRNA-derived fragment length polymorphism assay. AB - MicroRNA (miRNA) studies are experiencing a transition from basic research applications to clinical applications. However, the lack of reliable and sensitive miRNA detection methods has become a bottleneck in the process. Here, we report an absolute quantification method based on the competitive PCR amplification of specific miRNAs and synthetic RNA spike-ins in a single reaction. RNA spike-ins are quantified as dynamic RNA copy number standards and are used to measure selected miRNAs free from the effects of intra-assay variables, including those from individual sample sources. Combined with the size differentiation power of capillary electrophoresis, the content of miRNAs was reproducibly measured, with verifiable detection limits of 10-46 copies over 5 log detection ranges. The direct measurements of miRNAs from 168 human serum samples and their considerable value as a diagnostic for bronchopneumonia and bronchiolitis demonstrate the potential of the assay in clinical applications. PMID- 25790972 TI - Influence of the two-layer preservation method on human pancreatic islet isolation: a meta-analysis. AB - INTRODUCTION: There has been continuous debate on whether the Two-Layer Method (TLM) is superior to the University of Wisconsin solution (UW) for preserving human pancreas prior to islet isolation. The objective of the current meta analysis is to assess which method is superior. METHODS: We searched electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) for relevant human trials published in the English language from January 2000 to October 2013. Data on donor characteristics and islet isolation outcomes were extracted. RESULTS: 14 articles containing 18 human studies were included in this meta-analysis. In comparison to UW alone, TLM alone produced a significantly higher islet yield (weighted mean difference, 776.32; 95% confidence interval; 370.82-1181.82; P = .0002). TLM alone also yielded higher proportion of transplantable preparations (odds ratio, 1.60; 95% confidence interval; 1.15 2.23; P = .005). The following measures did not differ: islet viability (weighted mean difference, 2.10; -2.41-6.60; P = .360), purity (weighted mean difference, 0.92; -3.75-1.91; P = .520) and function assessed by measuring the stimulation index (weighted mean difference, 0.17; -0.21-0.55; P = .380). When comparing TLM following UW storage with UW alone, the results were similar to the previous ones. CONCLUSIONS: This data indicates that the TLM can improve islet yield and increase the opportunities of human pancreatic islet transplantation. Therefore, the TLM should be recommended for preserving human pancreas prior to islet isolation. PMID- 25790973 TI - Multivariate crash modeling for motor vehicle and non-motorized modes at the macroscopic level. AB - Macroscopic traffic crash analyses have been conducted to incorporate traffic safety into long-term transportation planning. This study aims at developing a multivariate Poisson lognormal conditional autoregressive model at the macroscopic level for crashes by different transportation modes such as motor vehicle, bicycle, and pedestrian crashes. Many previous studies have shown the presence of common unobserved factors across different crash types. Thus, it was expected that adopting multivariate model structure would show a better modeling performance since it can capture shared unobserved features across various types. The multivariate model and univariate model were estimated based on traffic analysis zones (TAZs) and compared. It was found that the multivariate model significantly outperforms the univariate model. It is expected that the findings from this study can contribute to more reliable traffic crash modeling, especially when focusing on different modes. Also, variables that are found significant for each mode can be used to guide traffic safety policy decision makers to allocate resources more efficiently for the zones with higher risk of a particular transportation mode. PMID- 25790974 TI - Characteristics, cycling patterns, and crash and injury experiences at baseline of a cohort of transport and recreational cyclists in New South Wales, Australia. AB - This paper examines self-reported retrospective data for a 12 month period from 2038 adult cyclists from New South Wales (Australia), and compares cyclists according to whether they self-identify as riding mainly for transport or mainly for recreation. Statistically significant differences were found in the demographic characteristics, cycling patterns, and crash experiences between these two groups of cyclists. Transport cyclists tended to be younger, travel more days per week, and within morning and evening peak hours than recreational cyclists; recreational cyclists were more likely to identify fitness as a purpose for cycling. The proportion of cyclists experiencing a crash or crash-related injury in the previous 12 months was similar for transport and recreational cyclists, but there were differences in crash types and location which likely reflect different cycling environments. Heterogeneity within transport and recreational cyclists was also found, based on self-reported riding intensity. An understanding of the different cycling patterns and experiences of various types of cyclists is useful to inform road safety, transport and health promotion policy. PMID- 25790975 TI - Severe bicycling injury risk factors in children and adolescents: a case-control study. AB - BACKGROUND: Bicycling is the most common cause of sports and recreation injury in children and adolescents; yet, there is limited evidence on the factors associated with severe bicycling injuries in youth. METHODS: Case-control study of injured bicyclists less than 18 years old seen in seven emergency departments (EDs) from May 2008 to October 2010. Cases were bicyclists hospitalized after their ED visit (severe injury). Controls were bicyclists seen and discharged from the ED (non-severe injury). Personal, environmental, and crash characteristics were collected by interview. Injury data were collected from medical charts. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression were used to estimate the odds of hospitalization associated with risk factors. Multiple imputation techniques were employed to address missing data. RESULTS: There were 1470 participants including 119 cases. Those ages 13-17 had the highest proportion (23%) of severe injuries resulting from motor vehicle [MV] collision. In models including age, sex and MV collision, being male (OR: 2.02; 95% CI: 1.21-3.38), not wearing a helmet (OR: 2.18; 95% CI: 1.43-3.31) and MV collision (OR: 3.91; 95% CI: 2.26-6.78) were significant risk factors for severe injury. Riding on a paved surface (OR: 0.63; 95% CI: 0.41 0.97) and utilitarian (school, work) bicycling (OR: 0.44; 95% CI: 0.2-0.94) decreased injury risk. Results were similar, apart from utilitarian bicycling (OR: 0.49; 95% CI: 0.22-1.06), after imputation for missing data. CONCLUSION: Bicycle-MV collisions increase severe injury risk in youth, and adolescents are often injured in these events. This suggests separating bicyclists from MVs or traffic calming strategies could improve safety. PMID- 25790976 TI - Do you see what I see? Effects of national culture on employees' safety-related perceptions and behavior. AB - Growing international trade and globalization are increasing the cultural diversity of the modern workforce, which often results in migrants working under the management of foreign leadership. This change in work arrangements has important implications for occupational health and safety, as migrant workers have been found to be at an increased risk of injuries compared to their domestic counterparts. While some explanations for this discrepancy have been proposed (e.g., job differences, safety knowledge, and communication difficulties), differences in injury involvement have been found to persist even when these contextual factors are controlled for. We argue that employees' national culture may explain further variance in their safety-related perceptions and safety compliance, and investigate this through comparing the survey responses of 562 Anglo and Southern Asian workers at a multinational oil and gas company. Using structural equation modeling, we firstly established partial measurement invariance of our measures across cultural groups. Estimation of the combined sample structural model revealed that supervisor production pressure was negatively related to willingness to report errors and supervisor support, but did not predict safety compliance behavior. Supervisor safety support was positively related to both willingness to report errors and safety compliance. Next, we uncovered evidence of cultural differences in the relationships between supervisor production pressure, supervisor safety support, and willingness to report errors; of note, among Southern Asian employees the negative relationship between supervisor production pressure and willingness to report errors was stronger, and for supervisor safety support, weaker as compared to the model estimated with Anglo employees. Implications of these findings for safety management in multicultural teams within the oil and gas industry are discussed. PMID- 25790977 TI - Long-term data of gait characteristics and moment-knee angle relations in female total knee arthroplasty patients. AB - BACKGROUND: Despite the clinical success of total knee arthroplasty, impaired gait patterns and quadriceps and hamstring maximal voluntary force production might persist years post-surgery. Long-term data of gait patterns and quadriceps and hamstring maximal force production are rarely published with total knee arthroplasty patients. This work examined gait characteristics and the moment knee angle relations of the knee extensors and flexors about 10 years post-total knee arthroplasty. METHODS: About a decade post-surgery, 10 female total knee arthroplasty patients (64 years, mobile-bearing inlay) and 10 age-matched female controls were examined. Sagittal plane kinematics in the hip and knee joint during treadmill walking at 2 kilometres per hour were recorded using motion analysis. Spatiotemporal gait parameters were analyzed at self-selected walking speeds with a pressure-platform. The unilateral isometric moment-knee angle relations of the knee extensors and flexors and the electromyographic knee angle relation of the quadriceps were studied using dynamometry. Due to group differences for body mass index values, univariate analysis of variance (main effect: group, secondary effect: body mass index) was used for statistical analysis. FINDINGS: Total knee arthroplasty patients demonstrated significant (P<0.05) gait deficits during constant and self-selected walking speeds and lower average absolute values in the moment-knee angle relations of the knee extensors and flexors. Significant (P<0.05) lower body-mass-normalized knee extension moments were detected at all knee joint positions for the patients. INTERPRETATION: Long-term impairments of gait characteristics and maximal voluntary force production, especially for the knee extensors, might persist after total knee arthroplasty. PMID- 25790979 TI - PD-L1 Upregulation Drives Escape from Anti-CTLA4 and Radiation Therapy. PMID- 25790980 TI - Multiple Mechanisms Drive Resistance to ALK Inhibitors in Lung Cancer. PMID- 25790981 TI - Pre-B-cell Receptor Signaling Is a Therapeutic Target in Pre-B ALL. PMID- 25790983 TI - FDA approves first biosimilar, zarxio. PMID- 25790984 TI - Effect of high pressure processing on the survival of Shiga toxin-producing Escherichia coli (Big Six vs. O157:H7) in ground beef. AB - High pressure processing (HPP) is a safe and effective technology for improving food safety. Non-O157:H7 Shiga Toxin-producing Escherichia coli (STEC) have been increasingly implicated in foodborne illness outbreaks and recalls, and the USDA Food Safety Inspection Service (FSIS) has designated them as adulterants in meat (e.g. ground beef). In this study we compared the inactivation of multi-isolate cocktails of E. coli O157:H7 versus the non-O157:H7 STEC "Big Six" (i.e. O26, O45, O103, O111, O121, and O145) in ground beef (83% lean) using HPP at refrigeration temperature (4-7 degrees C). A >5-log CFU/g inactivation of both the Big Six and O157:H7 cocktails were observed at 450 MPa for 15 min. In general, the Big Six cocktail was found more sensitive to pressure stress (p < 0.05). In contrast, HPP treatment at 250 MPa (30 min) inactivated only 2.3 log of the Big Six versus 1.0 log of O157:H7. HPP treatment at 350 MPa (30 min) inactivated 4.7 log of the Big Six vs. 3.2 log of O157:H7. Multiple-cycle HPP cycles (250 or 350 MPa, three 5 min treatments) did not result in a 5 log reduction of the non-O157:H7 or O157:H7 STEC. Our results indicate that HPP inactivation parameters which are effective for O157:H7 STEC can be used for the non-O157:H7 Big Six isolates in ground beef. PMID- 25790985 TI - Spoilage evaluation, shelf-life prediction, and potential spoilage organisms of tropical brackish water shrimp (Penaeus notialis) at different storage temperatures. AB - Maintaining the freshness of shrimp is a concern to shrimp stakeholders. To improve shrimp quality management, it is of importance to evaluate shrimp spoilage characteristics. Therefore, microbiological, sensory, and chemical changes of naturally contaminated tropical brackish water shrimp (Penaeus notialis) during storage at 28 degrees C, 7 degrees C and 0 degrees C were assessed. H2S-producing bacteria were the dominant group of microorganisms at 28 degrees C and 7 degrees C whereas Pseudomonas spp. were dominant at 0 degrees C. Total volatile basic nitrogen and trimethylamine correlated well (R(2) > 0.90) with the sensory scores. An empirical model to predict the shelf-life of naturally contaminated tropical shrimp as a function of storage temperature was developed. Specific groups of organisms were isolated at the sensory rejection times and assessed for spoilage potential in shrimps of which the endogenous flora was heat inactivated. Isolates capable of producing strong off-odor identified by 16S rRNA sequencing were mainly lactic acid bacteria (LAB) and Enterobacteriaceae at 28 degrees C or 7 degrees C and Pseudomonas spp. and LAB at 0 degrees C. The study contributes to the knowledge about tropical shrimp spoilage and provides a basis for the development of methods and tools to improve shrimp quality management. PMID- 25790986 TI - Effects of oxygen-depleted atmospheres on survival and growth of Listeria monocytogenes on fresh-cut Iceberg lettuce stored at mild abuse commercial temperatures. AB - The effects of oxygen-depleted atmospheres, 0.25% O2+12% CO2 (balance N2) and 2% O2 + 6% CO2 (balance N2), on growth of Listeria monocytogenes on fresh-cut Iceberg lettuce were determined. The study was carried out at mild abuse temperatures using controlled atmosphere chambers. During storage at a constant temperature of 7 degrees C, growth was enhanced at the lower oxygen level of 0.25% O2 by Day 10. Over 17 days of storage at temperatures designed to mimic mild abuse commercial conditions, there were again significantly higher counts under 0.25% O2 from Day 10 onwards. These were 0.9 and 0.7 log cycles higher on Days 14 and 17, respectively. When a model lettuce agar medium was used to eliminate possible interactions with competing flora the direct effects of the atmosphere enhancing the growth of L. monocytogenes was also observed. It is concluded that use of very O2-depleted atmospheres for control of enzymatic browning of fresh-cut Iceberg lettuce may introduce a potential hazard under some commercial conditions. There is a need for greater vigilance and possibly additional measures to ensure consumer safety. PMID- 25790987 TI - Alternative methods to determine infectivity of Tulane virus: a surrogate for human nororvirus. AB - Culturable animal caliciviruses are widely-used as surrogates for human norovirus (HuNoV). The infectivity of a culturable virus was traditionally determined by plaque assay and/or 50% tissue culture infectious dose (TCID50) assay, both of which are time-consuming and labor-intensive. Molecular approaches, such as quantitative real time RT-PCR (qRT-PCR) and RT-PCR, could be used for detection of the viral genome but yet fail to determine the infectivity of a virus. In this study, we evaluated different assays for determination of infectivity of Tulane virus (TV), a surrogate for HuNoV. The infectivity of TV was measured by RNase exposure assay, RT-PCR assays, cellular-receptor-mediated capture qRT-PCR assay, receptor-mediated in situ capture qRT-PCR assay, cell-culture-mediated amplification qRT-PCR, and confirmed by TCID50 assay. RNase exposure assay was only useful for measuring TV inactivation caused by heat. Short template RT-PCR assay did not reflect inactivation status of TV. Partial reduction in viral RNA signal could be measured by long-template RT-PCR only when TV was inactivated by thermal or chlorine treatments at full-inactivation levels. Cellular-receptor mediated capture qRT-PCR exhibited low sensitivity and specificity for the evaluation of virus infectivity. The in situ capture qRT-PCR assay could be used to evaluate virus inactivation deriving from damage to viral capsid caused by heat and chlorine. The cell-culture-mediated amplification qRT-PCR could be used as an alternative method to rapidly determine the infectivity of TV. PMID- 25790988 TI - Effect of water hardness on the production and microbicidal efficacy of slightly acidic electrolyzed water. AB - Slightly acidic electrolyzed water (SAEW) has been proved as an effective sanitizer against microorganisms attached to foods. However, its physical properties and inactivation efficacy are affected by several factors such as water hardness. Therefore, in this study the effect of water hardness on SAEW properties were studied. Pure cultures of foodborne bacteria were used in vitro and in vivo to evaluate the inactivation efficacy of the SAEWs produced. Results obtained showed water hardness to be an important factor in the production of SAEW. Low water hardness may result in the necessity of further optimization of production process. In this study the addition of 5% HCl and 2 M NaCl at 1.5 mL/min flow rate was found to be the best electrolyte concentration for the optimization of SAEW production from low hardness water (34 +/- 2 mg/L). Furthermore, the results showed that pre-heating was a better approach compared to post-production heating of SAEW, resulting in higher ACC values and therefor better sanitization efficacy. PMID- 25790989 TI - Effect of thymol in heating and recovery media on the isothermal and non isothermal heat resistance of Bacillus spores. AB - Members of the genus Bacillus include important food-borne pathogen and spoilage microorganisms for food industry. Essential oils are natural products extracted from herbs and spices, which can be used as natural preservatives in many foods because of their antibacterial, antifungal, antioxidant and anti-carcinogenic properties. The aim of this research was to explore the effect of the addition of different concentrations of thymol to the heating and recovery media on the thermal resistance of spores of Bacillus cereus, Bacillus licheniformis and Bacillus subtilis at different temperatures. While the heat resistance was hardly reduced when thymol was present in the heating medium, the effect in the recovery medium was greater, reducing the D100 degrees C values down to one third for B. subtilis and B. cereus when 0.5 mM thymol was added. This effect was dose dependent and was also observed at other heating temperatures. PMID- 25790990 TI - New insights into the capacity of commercial wine yeasts to grow on sparkling wine media. Factor screening for improving wine yeast selection. AB - During the production of sparkling wine, wine yeasts are subjected to many stress factors apart from ethanol, which lead to the need to achieve their acclimation in line with various industrial protocols. In the present work, 44 commercial wine Saccharomyces cerevisiae strains and one laboratory strain (BY4742) were firstly subjected to the influence of increasing concentrations of ethanol to cluster the yeasts using discriminant function analysis. Afterwards, non inhibitory concentration (NIC) and minimum inhibitory concentration (MIC) were estimated, revealing some differences between 24 of these strains. Meanwhile, this study confirms the negative synergistic effect of low pH with ethanol on the maximum specific growth rate (MUmax) and lag phase time. Moreover, a negative effect of increasing levels of glycerol in the growth medium was observed. Interestingly enough, an interactive positive effect was found between cysteine and medium-chain fatty acids (MCFA). While cysteine did not have a really significant effect in comparison to the control, it was able to restore the damage caused by MCFA, making the growth rate of cells recover and even reducing the formation of reactive oxygen species. Adequate culture aeration is also crucial for the composition of the cell fatty acid. The final results showed that few differences were observed between NIC and MIC estimations with respect to cells pre-cultured in the presence or absence of oxygen. PMID- 25790991 TI - Enhancing the antibacterial effect of 461 and 521 nm light emitting diodes on selected foodborne pathogens in trypticase soy broth by acidic and alkaline pH conditions. AB - Light emitting diodes (LEDs) with their antibacterial effect present a novel method for food preservation. This effect may be influenced by environmental conditions such as the pH of the food contaminated by the pathogen. Thus, it is necessary to investigate the influence of pH on the antibacterial effect of LEDs before their application to real food matrices. Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes in trypticase soy broth were illuminated using 10-W 461 (22.1 mW/cm(2)) and 521 nm (16 mW/cm(2)) LEDs at pH values of 4.5, 6.0, 7.3, 8.0 and 9.5 for 7.5 h at 15 degrees C. Using the 461 nm LEDs, the populations of E. coli O157:H7 decreased by 2.1 +/- 0.02, 1.2 +/- 0.08 and 4.1 +/- 0.42 log CFU/ml at pH 4.5, 7.3 and 9.5 respectively, after a dosage of 596.7 J/cm(2). For L. monocytogenes, approximately a 5.8 +/- 0.03 log reduction was observed after 238.7 J/cm(2) at pH 4.5 using the 461 nm LEDs, while the bacterial concentration was reduced by 1.8 +/- 0.01 log at pH 9.5 after 596.7 J/cm(2). Bacterial inactivation using the 521 nm LEDs showed similar trends to the 461 nm LEDs at both acidic and alkaline pH conditions but with lower (1-2 log CFU/ml) reductions after 432 J/cm(2). Lower D-values were observed for L. monocytogenes when exposed to LEDs at acidic pH values, while the sensitivity of E. coli O157:H7 and S. Typhimurium to LED was markedly increased at an alkaline pH. Regardless of the pH at which the cultures were illuminated, the percentage of sublethal injury increased with the treatment time. These results highlight the enhanced antibacterial effect of the 461 nm LED under acidic and alkaline pH conditions, proving its potential to preserve foods as well as to have synergistic effect with acidic and alkaline antimicrobials. PMID- 25790992 TI - Characteristics of oleuropeinolytic strains of Lactobacillus plantarum group and influence on phenolic compounds in table olives elaborated under reduced salt conditions. AB - The technological characteristics of five oleuropeinolytic strains of the Lactobacillus plantarum group selected within 135 isolates from table olives were investigated. The metabolism of phenolic compounds during elaboration of green (cv. Chalkidikis) and black (cv. Kalamata) olives under reduced salt conditions was evaluated. Olives of both cultivars were fermented in two different kinds of brine (Brine A containing 2.3% NaCl, 32.3 mM Ca-acetate and 33.9 mM Ca-lactate and Brine B containing 4% NaCl, pH 5.0 in both brines) by five selected strains of L. plantarum group. After 60 days of fermentation, the analysis of phenolic compounds was performed by HPLC and nine compounds were identified and quantified: oleuropein, hydroxytyrosol, tyrosol and vanillin and the phenolic acids protocatechuic, caffeic, p-hydroxybenzoic, vanillic and p-coumaric acid. The study can lead to the development of starter culture potentially active in biological debittering of olives during fermentation in order to unify the debittering and fermentation process during elaboration of table olives. PMID- 25790993 TI - Resistance of functional Lactobacillus plantarum strains against food stress conditions. AB - The survival of three Lactobacillus plantarum strains (Lp 790, Lp 813 and Lp 998) with functional properties was studied taking into account their resistance to thermal, osmotic and oxidative stress factors. Stress treatments applied were: 52 degrees C-15 min (Phosphate Buffer pH 7, thermal shock), H2O2 0.1% (p/v) - 30 min (oxidative shock) and NaCl aqueous solution at 17, 25 and 30% (p/v) (room temperature - 1 h, osmotic shock). The osmotic stress was also evaluated on cell growth in MRS broth added of 2, 4, 6, 8 and 10% (p/v) of NaCl, during 20 h at 30 degrees C. The cell thermal adaptation was performed in MRS broth, selecting 45 degrees C for 30 min as final conditions for all strains. Two strains (Lp 813 and Lp 998) showed, in general, similar behaviour against the three stress factors, being clearly more resistant than Lp 790. An evident difference in growth kinetics in presence of NaCl was observed between Lp 998 and Lp 813, Lp998 showing a higher optical density (OD570nm) than Lp 813 at the end of the assay. Selected thermal adaptation improved by 2 log orders the thermal resistance of both strains, but cell growth in presence of NaCl was enhanced only in Lp 813. Oxidative resistance was not affected with this thermal pre-treatment. These results demonstrate the relevance of cell technological resistance when selecting presumptive "probiotic" cultures, since different stress factors might considerably affect viability or/and performance of the strains. The incidence of stress conditions on functional properties of the strains used in this work are currently under research in our group. PMID- 25790994 TI - A novel gene, lstC, of Listeria monocytogenes is implicated in high salt tolerance. AB - Listeria monocytogenes, causative agent of human listeriosis, has been isolated from a wide variety of foods including deli meats, soft cheeses, cantaloupes, sprouts and canned mushrooms. Standard control measures for restricting microbial growth such as refrigeration and high salt are often inadequate as L. monocytogenes grows quite well in these environments. In an effort to better understand the genetic and physiological basis by which L. monocytogenes circumvents these controls, a transposon library of L. monocytogenes was screened for changes in their ability to grow in 7% NaCl and/ or at 5 degrees C. This work identified a transposon insertion upstream of an operon, here named lstABC, that led to a reduction in growth in 7% NaCl. In-frame deletion studies identified lstC which codes for a GNAT-acetyltransferase being responsible for the phenotype. Transcriptomic and RT-PCR analyses identified nine genes that were upregulated in the presence of high salt in the DeltalstC mutant. Further analysis of lstC and the genes affected by DeltalstC is needed to understand LstC's role in salt tolerance. PMID- 25790995 TI - Control of Salmonella on fresh chicken breasts by kappa-carrageenan/chitosan based coatings containing allyl isothiocyanate or deodorized Oriental mustard extract plus EDTA. AB - Control of Salmonella in poultry is a public health concern as salmonellosis is one of the most common foodborne diseases worldwide. This study aimed to screen the ability of 5 Salmonella serovars to degrade the mustard glucosinolate, sinigrin (by bacterial myrosinase) in Mueller-Hinton broth at 25 degrees C for 21 d and to reduce Salmonella on fresh chicken breasts by developing an edible 0.2% (w/v) kappa-carrageenan/2% (w/v) chitosan-based coating containing Oriental mustard extract, allyl isothiocyanate (AITC), EDTA or their combinations. Individual Salmonella serovars degraded 50.2%-55.9% of the sinigrin present in 21 d. kappa-Carrageenan/chitosan-based coatings containing 250 mg Oriental mustard extract/g or 50 MUl AITC/g reduced the numbers of Salmonella on chicken breasts 2.3 log10 CFU/g at 21 d at 4 degrees C. However, when either mustard extract or AITC was combined with 15 mg/g EDTA in kappa-carrageenan/chitosan-based coatings, Salmonella numbers were reduced 2.3 log10 CFU/g at 5 d and 3.0 log10 CFU/g at 21 d. Moreover, these treatments reduced numbers of lactic acid bacteria and aerobic bacteria by 2.5-3.3 log10 CFU/g at 21 d. kappa-Carrageenan/chitosan coatings containing either 50 MUl AITC/g or 250 mg Oriental mustard extract/g plus 15 mg EDTA/g have the potential to reduce Salmonella on raw chicken. PMID- 25790996 TI - The inhibitory effects of sorbate and benzoate against Clostridium perfringens type A isolates. AB - This study evaluated the inhibitory effects of sorbate and benzoate against Clostridium perfringens type A food poisoning (FP) and non-food-borne (NFB) disease isolates. No significant inhibition of germination of spores of both FP and NFB isolates was observed in rich medium (pH 7.0) supplemented with permissive level of sodium sorbate (0.3% ~ 0.13 mM undissociated sorbic acid) or sodium benzoate (0.1% ~ 0.01 mM undissociated benzoic acid) used in foods. However, these levels of sorbate and benzoate effectively arrested outgrowth of germinated C. perfringens spores in rich medium. Lowering the pH of the medium increases the inhibitory effects of sorbate and benzoate against germination of spores of NFB isolates, and outgrowth of spores of both FP and NFB isolates. Furthermore, sorbate and benzoate inhibited vegetative growth of C. perfringens isolates. However, the permissible levels of these organic salts could not control the growth of C. perfringens spores in chicken meat stored under extremely abusive conditions. In summary, although sorbate and benzoate showed inhibitory activities against C. perfringens in the rich medium, no such effect was observed in cooked chicken meat. Therefore, caution should be taken when applying these organic salts into meat products to reduce or eliminate C. perfringens spores. PMID- 25790997 TI - Campylobacter virulence and survival factors. AB - Despite over 30 years of research, campylobacteriosis is the most prevalent foodborne bacterial infection in many countries including in the European Union and the United States of America. However, relatively little is known about the virulence factors in Campylobacter or how an apparently fragile organism can survive in the food chain, often with enhanced pathogenicity. This review collates information on the virulence and survival determinants including motility, chemotaxis, adhesion, invasion, multidrug resistance, bile resistance and stress response factors. It discusses their function in transition through the food processing environment and human infection. In doing so it provides a fundamental understanding of Campylobacter, critical for improved diagnosis, surveillance and control. PMID- 25790998 TI - Antilisterial activity of bacteriocinogenic Pediococcus acidilactici HA6111-2 and Lactobacillus plantarum ESB 202 grown under pH and osmotic stress conditions. AB - Bacteriocin producing lactic acid bacteria (LAB) cultures can be used as biopreservatives in fermented food products; thus the food industry is interested in stable cultures that produce bacteriocins consistently. Inhibtion of Listeria spp. by bacteriocinogenic Pediococcus acidilactici and Lactobacillus plantarum (both isolated from fermented meats) was investigated under conditions of stress induced by low pH and high salt concentrations. Listeria monocytogenes serogroup IIb (from cheese), L. monocytogenes serogroup IVb (from cheese), L. monocytogenes serogroup IIb (from ground beef) and Listeria innocua NCTC 11288 were used as target strains. P. acidilactici and Lb. plantarum demonstrated antilisterial activity under the stress conditions investigated (pH 3.5; pH 8.5; 7.5% NaCl). However, activity was dependent on the stress conditions applied and on the target organism. L. monocytogenes serogroup IIb (from ground beef) and L. innocua C 11288 were, respectively the most sensitive and the most resistant to the cell free supernatants produced by the LAB investigated. PMID- 25790999 TI - Mapping the carriage of flaA-restriction fragment length polymorphism Campylobacter genotypes on poultry carcasses through the processing chain and comparison to clinical isolates. AB - Poultry are considered a major source for campylobacteriosis in humans. A total of 1866 Campylobacter spp. isolates collected through the poultry processing chain were typed using flaA-restriction fragment length polymorphism to measure the impact of processing on the genotypes present. Temporally related human clinical isolates (n = 497) were also typed. Isolates were obtained from whole chicken carcass rinses of chickens collected before scalding, after scalding, before immersion chilling, after immersion chilling and after packaging as well as from individual caecal samples. A total of 32 genotypes comprising at least four isolates each were recognised. Simpson's Index of Diversity (D) was calculated for each sampling site within each flock, for each flock as a whole and for the clinical isolates. From caecal collection to after packaging samples the D value did not change in two flocks, decreased in one flock and increased in the fourth flock. Dominant genotypes occurred in each flock but their constitutive percentages changed through processing. There were 23 overlapping genotypes between clinical and chicken isolates. The diversity of Campylobacter is flock dependant and may alter through processing. This study confirms that poultry are a source of campylobacteriosis in the Australian population although other sources may contribute. PMID- 25791000 TI - Identification and characterization of wild lactobacilli and pediococci from spontaneously fermented Mountain cheese. AB - The Traditional Mountain Malga (TMM) cheese is made from raw cow's milk by spontaneously fermentation in small farms called "Malga" located in Trentino region. This study was designed to characterize the lactic acid bacteria (LAB) growing on MRS medium, of TMM-cheese at the end of the ripening. Ninety-five LAB were isolated and genotypically characterized by Randomly Amplified Polymorphic DNA-Polymerase Chain Reaction (RAPD-PCR) with two primers, species-specific PCR and partial sequencing of 16S rRNA gene. The 95 LAB clustered in 70 biotypes. Pediococcus pentosaceus and Lactobacillus paracasei were the dominant species. Isolates were tested for their growth properties, carbohydrate metabolism, acidifying ability, proteolytic and lipolytic activities, acetoin production, amino-peptidase (AP) activity, biogenic amines production, bile salts hydrolysis, conjugated linoleic acid and gamma-aminobutyric acid production. Lb. paracasei isolates resulted to be well adapted to Malga environment and to show the best AP activity and acetoin production. TMM-cheese related LAB showed also interesting health promoting properties and produced bioactive substances. In particular, one Lb. brevis biotype produced a GABA mean value of 129 mg/L that is considered a high concentration. The results confirmed that TMM-cheese resident LAB could be exploited for dairy production. PMID- 25791001 TI - Evaluation of microbial loads and the effects of antimicrobial sprays in postharvest handling of California walnuts. AB - Changes in aerobic plate count (APC) and Escherichia coli/coliform count (ECC) of inshell walnuts and walnut kernels were evaluated during commercial harvest and postharvest handling. APC and ECC for inshell walnuts collected from the tree were 6 and 4 log CFU/nut, respectively; counts increased by 1 log during harvest and hulling and decreased by 1 log during drying. Application of up to 200 ppm peracetic acid after hulling with or without a subsequent 2% lauric arginate spray reduced APC and ECC by less than 1 log CFU/nut; counts were not significantly different from the water control. A decrease in shell integrity was evident after drying: visible shell damage increased from 4 to 47% of walnuts after drying. Counts on kernels extracted from visibly intact walnuts from the tree were near the limit of detection (1.7 log CFU/nut). These counts increased by at least 1.4 log CFU/nut after hulling for both thin- and hard-shell cultivars. Microbial populations were 1.6-2.2 log CFU/nut higher for kernels from walnuts with broken shells than for kernels from walnuts with visibly intact shells before, but not after, drying. A better understanding of how microbial populations are affected by postharvest handling practices is important in the development of walnut-specific food safety programs. PMID- 25791002 TI - Bacteriocin production and inhibition of Listeria monocytogenes by Lactobacillus sakei subsp. sakei 2a in a potentially synbiotic cheese spread. AB - Survival, bacteriocin(s) production, and antilisterial effect of Lactobacillus sakei subsp. sakei 2a were evaluated in a potentially synbiotic cheese spread, throughout storage at 4 degrees C and 15 degrees C for up to 28 days, using culture-dependent (plate count) and culture-independent (qPCR) methods. Bacteriocin(s) production in the food product was monitored by phenotypic and molecular (RT-qPCR) techniques. Three cheese spread trials (T) containing the prebiotic fiber inulin were produced in duplicates and studied: T1 (control - without inoculation of lactic acid bacteria); T2 (inoculated with the non bacteriocinogenic Lb. sakei ATCC 15521 strain), and T3 (inoculated with the bacteriocinogenic Lb. sakei 2a strain). The cheese spreads were challenged with Listeria monocytogenes serotypes 4b and 1/2a, individually added to the food product. The counts of Lb. sakei 2a in the cheese spread T3 remained high during storage and the growth of L. monocytogenes was inhibited at both temperatures, especially L. monocytogenes 4b in the food product kept at 15 degrees C due to the production of bacteriocins (up to 6,400 AU/mL). Expression of the genes sakP and sakQ encoding for bacteriocins production during the cheese spread storage was demonstrated. Lb. sakei 2a can be used for production of potentially synbiotic cheese spreads with increased safety. PMID- 25791003 TI - Modeling the behavior of Geobacillus stearothermophilus ATCC 12980 throughout its life cycle as vegetative cells or spores using growth boundaries. AB - Geobacillus stearothermophilus is recognized as one of the most prevalent micro organism responsible for flat sour in the canned food industry. To control these highly resistant spore-forming bacteria, the heat treatment intensity could be associated with detrimental conditions for germination and outgrowth. The purpose of this work was to study successively the impact of temperature and pH on the growth rate of G. stearothermophilus ATCC 12980, its sporulation ability, its heat resistance in response to various sporulation conditions, and its recovery ability after a heat treatment. The phenotypic investigation was carried out at different temperatures and pHs on nutrient agar and the heat resistance was estimated at 115 degrees C. The greatest spore production and the highest heat resistances were obtained at conditions of temperature and pH allowing maximal growth rate. The current observations also revealed that growth, sporulation and recovery boundaries are close. Models using growth boundaries as main parameters were extended to describe and quantify the effect of temperature and pH throughout the life cycle of G. stearothermophilus as vegetative cells or as spore after a heat treatment and during recovery. PMID- 25791004 TI - Lactose-mediated carbon catabolite repression of putrescine production in dairy Lactococcus lactis is strain dependent. AB - Lactococcus lactis is the lactic acid bacterial (LAB) species most widely used as a primary starter in the dairy industry. However, several strains of L. lactis produce the biogenic amine putrescine via the agmatine deiminase (AGDI) pathway. We previously reported the putrescine biosynthesis pathway in L. lactis subsp. cremoris GE2-14 to be regulated by carbon catabolic repression (CCR) via glucose but not lactose (Linares et al., 2013). The present study shows that both these sugars repress putrescine biosynthesis in L. lactis subsp. lactis T3/33, a strain isolated from a Spanish artisanal cheese. Furthermore, we demonstrated that both glucose and lactose repressed the transcriptional activity of the aguBDAC catabolic genes of the AGDI route. Finally, a screening performed in putrescine producing dairy L. lactis strains determined that putrescine biosynthesis was repressed by lactose in all the L. lactis subsp. lactis strains tested, but in only one L. lactis subsp. cremoris strain. Given the obvious importance of the lactose-repression in cheese putrescine accumulation, it is advisable to consider the diversity of L. lactis in this sense and characterize consequently the starter cultures to select the safest strains. PMID- 25791005 TI - Sensitive enumeration of Listeria monocytogenes and other Listeria species in various naturally contaminated matrices using a membrane filtration method. AB - For the enumeration of Listeria monocytogenes (L. monocytogenes) in food, a sensitive enumeration method has been recently developed. This method is based on a membrane filtration of the food suspension followed by transfer of the filter on a selective medium to enumerate L. monocytogenes. An evaluation of this method was performed with several categories of foods naturally contaminated with L. monocytogenes. The results obtained with this technique were compared with those obtained from the modified reference EN ISO 11290-2 method for the enumeration of L. monocytogenes in food, and are found to provide more precise results. In most cases, the filtration method enabled to examine a greater quantity of food thus greatly improving the sensitivity of the enumeration. However, it was hardly applicable to some food categories because of filtration problems and background microbiota interference. PMID- 25791006 TI - Associations between Campylobacter levels on chicken skin, underlying muscle, caecum and packaged fillets. AB - A study was performed with the aim to investigate associations between Campylobacter in chicken caecum, carcass skin, underlying breast muscle and packaged breast fillets. Samples were taken from 285 chickens from 57 flocks and analysed according to ISO 10272. Campylobacter spp. were isolated from caecal samples from 41 flocks. From birds of the same 41 flocks Campylobacter could be detected and quantified in 194 (68%) skin samples. Moreover, Campylobacter spp. were enumerated in 13 (5%) underlying muscle samples originating from 9 of the 41 flocks. The mean number of Campylobacter spp. in the 194 skin samples which could be counted was 2.3 log cfu/g and for the 13 underlying muscle samples 1.3 log cfu/g. Campylobacter could only be quantified in those breast muscle samples with a finding in corresponding skin sample. Five packaged chicken fillets were taken from each 25 of the 57 flocks and analysed both quantitatively and qualitatively. In qualitative analysis Campylobacter was detected in 79 (63%) fillets from 16 flocks and quantified in 24 (19%) samples from 11 flocks. The results showed a significant association (P < 0.05) between findings of Campylobacter on carcass skin (log cfu/g) and the proportion of Campylobacter positive breast muscle samples. PMID- 25791007 TI - Effect of exposure to stress conditions on propidium monoazide (PMA)-qPCR based Campylobacter enumeration in broiler carcass rinses. AB - Campylobacter quantification by qPCR is unable to distinguish viable vs. dead cells in contrast to the culture-based ISO 10272-2 reference method. Propidium monoazide (PMA) has been used to overcome this disadvantage. A Campylobacter PMA qPCR enumeration method was evaluated for its consistency and compared to the culture-based enumeration for both artificially and natural contaminated broiler carcass rinses. The PMA effect was further evaluated on stressed cells. Five conditions, commonly encountered during the slaughter process and storage (acid, heat, cold, oxidation and freezing), were inflicted to the broiler carcass rinses artificially contaminated with Campylobacter jejuni or Campylobacter coli. A better correlation between the reference method and the qPCR enumeration was obtained when PMA was used. The two cultured-based methods used showed a significant CFU reduction for heat, cold and acid stresses although the PMA-qPCR enumeration showed that viable bacteria were underestimated. Freezing showed the highest reduction effect, while the reduction extend was also overestimated by the microbiological enumeration procedure. Exposure to a mild oxidative stress was the only stress condition applied at temperatures permitting adaptation of Campylobacter and did not lead to either reduction in CFU nor in the PMA-qPCR signal. PMID- 25791008 TI - Bacterial community dynamics during cold storage of minced meat packaged under modified atmosphere and supplemented with different preservatives. AB - Since minced meat is very susceptible for microbial growth, characterisation of the bacterial community dynamics during storage is important to optimise preservation strategies. The purpose of this study was to investigate the effect of different production batches and the use of different preservatives on the composition of the bacterial community in minced meat during 9 days of cold storage under modified atmosphere (66% O2, 25% CO2 and 9% N2). To this end, both culture-dependent (viable aerobic and anaerobic counts) and culture-independent (454 pyrosequencing) analyses were performed. Initially, microbial counts of fresh minced meat showed microbial loads between 3.5 and 5.0 log cfu/g. The observed microbial diversity was relatively high, and the most abundant bacteria differed among the samples. During storage an increase of microbial counts coincided with a dramatic decrease in bacterial diversity. At the end of the storage period, most samples showed microbial counts above the spoilage level of 7 log cfu/g. A relatively similar bacterial community was obtained regardless of the manufacturing batch and the preservative used, with Lactobacillus algidus and Leuconostoc sp. as the most dominant microorganisms. This suggests that both bacteria played an important role in the spoilage of minced meat packaged under modified atmosphere. PMID- 25791009 TI - Fate of mesophilic aerobic bacteria and Salmonella enterica on the surface of eggs as affected by chicken feces, storage temperature, and relative humidity. AB - We compared the microbiological quality of chicken eggshells obtained from a traditional wholesale market and a modern supermarket. We also determined the survival and growth characteristics of naturally occurring mesophilic aerobic bacteria (MAB) and artificially inoculated Salmonella enterica on eggshells under various environmental conditions (presence of chicken feces, temperature [4, 12, or 25 degrees C], and relative humidity [RH; 43 or 85%]). The populations of MAB, coliforms, and molds and yeasts on eggshells purchased from a traditional wholesale market were significantly (P <= 0.05) higher than those from a modern supermarket. In the second study, when we stored uninoculated eggs under various storage conditions, the population of MAB on eggshells (4.7-4.9 log CFU/egg) remained constant for 21 days, regardless of storage conditions. However, when eggshells were inoculated with S. enterica and stored under the same conditions, populations of the pathogen decreased significantly (P <= 0.05) under all tested conditions. Survival of S. enterica increased significantly (P <= 0.05) in the presence of feces, at low temperatures, and at low RH. These observations will be of value when predicting the behavior of microorganisms on eggshells and selecting storage conditions that reduce the populations of S. enterica on eggshells during distribution. PMID- 25791010 TI - Phenotypic and molecular diversity of Meyerozyma guilliermondii strains isolated from food and other environmental niches, hints for an incipient speciation. AB - Meyerozyma guilliermondii is a yeast species widely isolated from several natural environments and from fruit; in medical microbiology it is known as the teleomorph of the opportunistic pathogen Candida guilliermondii, which causes about 2% of the human blood infections. This yeast is also promising in a variety of biotechnological applications as vitamins production and post-harvest control. The question if isolates from different sources are physiologically and genetically similar, or if the various environments induced significant differences, is crucial for the understanding of this species structure and to select strains appropriate for each application. This question was addressed using LSU and ITS sequencing for taxonomic assignment, i-SSR (GACA4) for the molecular characterization and FTIR for the metabolomic fingerprint. All data showed that fruit and environmental isolates cluster separately with a general good agreement between metabolomics and molecular analysis. An additional RAPD analysis was able to discriminate strains according to the isolation position within the pineapple fruit. Although all strains are members of the M. guilliermondii species according to the current standards, the distribution of large variability detected suggests that some specialization occurred in the niches inhabited by this yeast and that food related strains can be differentiated from the medical isolates. PMID- 25791011 TI - 2D Space-Confined Synthesis of Few-Layer MoS2 Anchored on Carbon Nanosheet for Lithium-Ion Battery Anode. AB - A facile and scalable 2D spatial confinement strategy is developed for in situ synthesizing highly crystalline MoS2 nanosheets with few layers (<=5 layers) anchored on 3D porous carbon nanosheet networks (3D FL-MoS2@PCNNs) as lithium-ion battery anode. During the synthesis, 3D self-assembly of cubic NaCl particles is adopted to not only serve as a template to direct the growth of 3D porous carbon nanosheet networks, but also create a 2D-confined space to achieve the construction of few-layer MoS2 nanosheets robustly lain on the surface of carbon nanosheet walls. In the resulting 3D architecture, the intimate contact between the surfaces of MoS2 and carbon nanosheets can effectively avoid the aggregation and restacking of MoS2 as well as remarkably enhance the structural integrity of the electrode, while the conductive matrix of 3D porous carbon nanosheet networks can ensure fast transport of both electrons and ions in the whole electrode. As a result, this unique 3D architecture manifests an outstanding long-life cycling capability at high rates, namely, a specific capacity as large as 709 mAh g(-1) is delivered at 2 A g(-1) and maintains ~95.2% even after 520 deep charge/discharge cycles. Apart from promising lithium-ion battery anode, this 3D FL-MoS2@PCNN composite also has immense potential for applications in other areas such as supercapacitor, catalysis, and sensors. PMID- 25791012 TI - A practical guide to the selection of independent components of the electroencephalogram for artifact correction. AB - BACKGROUND: Electroencephalographic data are easily contaminated by signals of non-neural origin. Independent component analysis (ICA) can help correct EEG data for such artifacts. Artifact independent components (ICs) can be identified by experts via visual inspection. But artifact features are sometimes ambiguous or difficult to notice, and even experts may disagree about how to categorise a particular component. It is therefore important to inform users on artifact properties, and give them the opportunity to intervene. NEW METHOD: Here we first describe artifacts captured by ICA. We review current methods to automatically select artifactual components for rejection, and introduce the SASICA software, implementing several novel selection algorithms as well as two previously described automated methods (ADJUST, Mognon et al. Psychophysiology 2011;48(2):229; and FASTER, Nolan et al. J Neurosci Methods 2010;48(1):152). RESULTS: We evaluate these algorithms by comparing selections suggested by SASICA and other methods to manual rejections by experts. The results show that these methods can inform observers to improve rejections. However, no automated method can accurately isolate artifacts without supervision. The comprehensive and interactive plots produced by SASICA therefore constitute a helpful guide for human users for making final decisions. CONCLUSIONS: Rejecting ICs before EEG data analysis unavoidably requires some level of supervision. SASICA offers observers detailed information to guide selection of artifact ICs. Because it uses quantitative parameters and thresholds, it improves objectivity and reproducibility in reporting pre-processing procedures. SASICA is also a didactic tool that allows users to quickly understand what signal features captured by ICs make them likely to reflect artifacts. PMID- 25791013 TI - WASICA: An effective wavelet-shrinkage based ICA model for brain fMRI data analysis. AB - BACKGROUND: Researches declared that the super-Gaussian property contributed to the success of some spatial independent component analysis (ICA) algorithms in brain fMRI source separation (e.g., Infomax and FastICA), which implied that sparse approximation transforming the sources (super-Gaussian or Gaussian-like) with stronger super-Gaussian feature would possibly improve the separation performance of these algorithms. NEW METHOD: This paper presented a novel wavelet shrinkage based ICA (WASICA) model, an extension of our previous SACICA, for single-subject analysis. In contrast, two main aspects had been effectively enhanced: (1) sparse approximation coefficients set formation, made up of two sub procedures: the wavelet-shrinkage of wavelet packet (WP) tree nodes, and the automatic nodes selection and integration based on the relative WP energy; (2) ICA-based decomposition and reconstruction, composed of temporal dynamics extraction using ICA, WP reconstruction based on the sparse approximation coefficients set and least-square-based functional networks reconstruction. RESULTS: The wavelet-shrinkage and the automatic nodes selection and integration simultaneously transformed both the mixtures and underlying sources into effective sparse approximation coefficients sets, exhibiting stronger super Gaussian distribution; WP projected-back approximation with nuisance-exclusion contributed to networks reconstruction. COMPARISON WITH EXISTING METHODS: Simulation 1 revealed WASICA successfully recovered super-Gaussian and some Gaussian-like sources. Simulation 2 and hybrid data experiments showed that WASICA with good temporal performance had stronger source recovery ability and signal detection sensitivity spatially than FastICA, Infomax and SACICA did; the higher intra-consistency in task-related experiments denoted WASICA occupied stronger spatial robustness against smooth kernels. CONCLUSIONS: WASICA was a promising brain signal separation model with charming spatial-temporal performance. PMID- 25791015 TI - Using off-the-shelf lossy compression for wireless home sleep staging. AB - BACKGROUND: Recently, there has been increasing interest in the development of wireless home sleep staging systems that allow the patient to be monitored remotely while remaining in the comfort of their home. However, transmitting large amount of Polysomnography (PSG) data over the Internet is an important issue needed to be considered. In this work, we aim to reduce the amount of PSG data which has to be transmitted or stored, while having as little impact as possible on the information in the signal relevant to classify sleep stages. NEW METHOD: We examine the effects of off-the-shelf lossy compression on an all-night PSG dataset from 20 healthy subjects, in the context of automated sleep staging. The popular compression method Set Partitioning in Hierarchical Trees (SPIHT) was used, and a range of compression levels was selected in order to compress the signals with various degrees of loss. In addition, a rule-based automatic sleep staging method was used to automatically classify the sleep stages. RESULTS: Considering the criteria of clinical usefulness, the experimental results show that the system can achieve more than 60% energy saving with a high accuracy (>84%) in classifying sleep stages by using a lossy compression algorithm like SPIHT. COMPARISON WITH EXISTING METHOD(S): As far as we know, our study is the first that focuses how much loss can be tolerated in compressing complex multi channel PSG data for sleep analysis. CONCLUSIONS: We demonstrate the feasibility of using lossy SPIHT compression for wireless home sleep staging. PMID- 25791014 TI - Evaluation of optimal electrode configurations for epidural spinal cord stimulation in cervical spinal cord injured rats. AB - BACKGROUND: Epidural spinal cord stimulation is a promising technique for modulating the level of excitability and reactivation of dormant spinal neuronal circuits after spinal cord injury (SCI). We examined the ability of chronically implanted epidural stimulation electrodes within the cervical spinal cord to (1) directly elicit spinal motor evoked potentials (sMEPs) in forelimb muscles and (2) determine whether these sMEPs can serve as a biomarker of forelimb motor function after SCI. NEW METHOD: We implanted EMG electrodes in forelimb muscles and epidural stimulation electrodes at C6 and C8 in adult rats. After recovering from a dorsal funiculi crush (C4), rats were tested with different stimulation configurations and current intensities to elicit sMEPs and determined forelimb grip strength. RESULTS: sMEPs were evoked in all muscles tested and their characteristics were dependent on electrode configurations and current intensities. C6(-) stimulation elicited more robust sMEPs than stimulation at C8( ). Stimulating C6 and C8 simultaneously produced better muscle recruitment and higher grip strengths than stimulation at one site. COMPARISON WITH EXISTING METHOD(S): Classical method to select the most optimal stimulation configuration is to empirically test each combination individually for every subject and relate to functional improvements. This approach is impractical, requiring extensively long experimental time to determine the more effective stimulation parameters. Our proposed method is fast and physiologically sound. CONCLUSIONS: Results suggest that sMEPs from forelimb muscles can be useful biomarkers for identifying optimal parameters for epidural stimulation of the cervical spinal cord after SCI. PMID- 25791016 TI - Feasibility of free-breathing, GRAPPA-based, real-time cardiac cine assessment of left-ventricular function in cardiovascular patients at 3T. AB - OBJECTIVES: To determine the feasibility of free-breathing, GRAPPA-based, real time (RT) cine 3T cardiac magnetic resonance imaging (MRI) with high acceleration factors for the assessment of left-ventricular function in a cohort of patients as compared to conventional segmented cine imaging. MATERIALS AND METHODS: In this prospective cohort study, subjects with various cardiac conditions underwent MRI involving two RT cine sequences (high resolution and low resolution) and standard segmented cine imaging. Standard qualitative and quantitative parameters of left-ventricular function were quantified. RESULTS: Among 25 subjects, 24 were included in the analysis (mean age: 50.5+/-21 years, 67% male, 25% with cardiomyopathy). RT cine derived quantitative parameters of volumes and left ventricular mass were strongly correlated with segmented cine imaging (intraclass correlation coefficient [ICC]: >0.72 for both RT cines) but correlation for peak ejection and filling rates were moderate to poor for both RT cines (ICC<0.40). Similarly, RT cines significantly underestimated peak ejection and filling rates (>103.2+/-178 ml/s). Among patient-related factors, heart rate was strongly predictive for deviation of measurements (p<0.05). CONCLUSIONS: RT cine MRI at 3T is feasible for qualitative and quantitative assessment of left ventricular function for low and high-resolution sequences but results in significant underestimation of systolic function, peak ejection and filling rates. PMID- 25791017 TI - Effect of azithromycin on the LPS-induced production and secretion of phospholipase A2 in lung cells. AB - Azithromycin is a member of macrolides, utilized in the treatment of infections. Independently, these antibiotics also possess anti-inflammatory and immunomodulatory properties. Phospholipase A2 isotypes, which are implicated in the pathophysiology of inflammatory lung disorders, are produced by alveolar macrophages and other lung cells during inflammatory response and can promote lung injury by destructing lung surfactant. The aim of the study was to investigate whether in lung cells azithromycin can inhibit secretory and cytosolic phospholipases A2, (sPLA2) and (cPLA2), respectively, which are induced by an inflammatory trigger. In this respect, we studied the lipopolysaccharide (LPS)-mediated production or secretion of sPLA2 and cPLA2 from A549 cells, a cancer bronchial epithelial cell line, and alveolar macrophages, isolated from bronchoalveolar lavage fluid of ARDS and control patients without cardiopulmonary disease or sepsis. Pre-treatment of cells with azithromycin caused a dose dependent decrease in the LPS-induced sPLA2-IIA levels in A549 cells. This inhibition was rather due to reduced PLA2G2A mRNA expression and secretion of sPLA2-IIA protein levels, as observed by western blotting and indirect immunofluorescence by confocal microscopy, respectively, than to the inhibition of the enzymic activity per se. On the contrary, azithromycin had no effect on the LPS-induced production or secretion of sPLA2-IIA from alveolar macrophages. The levels of LPS-induced c-PLA2 were not significantly affected by azithromycin in either cell type. We conclude that azithromycin exerts anti-inflammatory properties on lung epithelial cells through the inhibition of both the expression and secretion of LPS-induced sPLA2-IIA, while it does not affect alveolar macrophages. PMID- 25791018 TI - Dipygus: Computed tomography findings and management. PMID- 25791019 TI - Allosteric regulation of the Plasmodium falciparum cysteine protease falcipain-2 by heme. AB - During the erythrocytic cycle of Plasmodium falciparum malaria parasites break down host hemoglobin, resulting in the release of free heme (ferriprotoporphyrin IX). Heme is a generator of free radicals that cause oxidative stress, but it is detoxified by crystallization into hemozoin inside the food vacuole. We evaluated the interaction of heme and heme analogues with falcipain-2, a P. falciparum food vacuole cysteine protease that plays a key role in hemoglobin digestion. Heme bound to falcipain-2 with a 1:1 stoichiometry, and heme inhibited falcipain-2 activity against both human hemoglobin and chromogenic peptide substrates through a noncompetitive-like mechanism. A series of porphyrin analogues was screened for inhibition of falcipain-2, demonstrating a minor contribution of iron to heme falcipain-2 interaction, and revealing dependence on both propionic and vinyl groups for inhibition of falcipain-2 by heme. Docking and molecular dynamics simulation unveiled a novel, inducible heme-binding moiety in falcipain-2 adjacent to the catalytic site. Kinetic data suggested that the noncompetitive like inhibition was substrate inhibition induced by heme. Collectively these data suggest that binding of heme to falcipain-2 may limit the accumulation of free heme in the parasite food vacuole, providing a means of heme detoxification in addition to crystallization into hemozoin. PMID- 25791020 TI - Baculoviruses in populations of western spruce budworm. AB - Population studies of western spruce budworm, Choristoneura occidentalis, revealed that a baculovirus, ChocNPV, was widespread in outbreak populations over a broad geographical area of British Columbia, Canada although the rate of mortality was usually low (<5%). Elevated levels of ChocNPV-related mortality (~20%) were found when western spruce budworm populations reached high densities (~300 larvae per kg of Douglas-fir foliage) and contributed to declines in population densities in these areas. A subsample from budworm collections examined using a multiplex-PCR assay showed ChocNPV was the most prevalent virus but also often occurred in combination with a granulovirus, ChocGV and a cypovirus, CoCPV. PMID- 25791021 TI - Fitness costs of Cry1F resistance in two populations of fall armyworm, Spodoptera frugiperda (J.E. Smith), collected from Puerto Rico and Florida. AB - The development of resistance in target pest populations is a threat to the sustainability of transgenic crops expressing Bacillus thuringiensis (Bt) proteins. Fall armyworm, Spodoptera frugiperda (J.E. Smith), is a major target pest of Bt maize in North and South America. This insect is the first target pest that has developed field resistance to Bt maize at multiple locations in these regions. The objective of this study was to assess the fitness costs associated with the Cry1F resistance in two populations of S. frugiperda collected from Puerto Rico (RR-PR) and Florida (RR-FL). In the study, fitness costs were evaluated by comparing survival, growth, and developmental time of seven populations of S. frugiperda on (1) non-Bt meridic diet and (2) non-Bt maize leaf tissue and non-Bt diet. The seven populations were RR-PR, RR-FL, a Bt-susceptible strain (Bt-SS), and four F1 populations developed from reciprocal crosses between Bt-SS and the two resistant populations. Biological parameters measured were neonate-to-adult survivorship, neonate-to-adult developmental time, 10day larval weight on non-Bt maize leaf tissue, pupal weight, and sex ratios. Results of the study show that the Cry1F resistance in both RR-PR and RR-FL was associated with considerable fitness costs, especially for the Florida population. Compared to the Bt-susceptible population, RR-PR showed an average of 61.1% reduction in larval weight, 20.4% less in neonate-to-adult survivorship, and 3.7days delay in neonate-to-adult developmental time. These fitness costs for RR-FL were 66.9%, 31.7% and 4.4days, respectively. The fitness costs of RR-PR and RR-FL appeared to be non-recessive. The results indicate that a diversified genetic basis may exist for the Cry1F resistance in S. frugiperda. PMID- 25791022 TI - Overexpression of Bm65 correlates with reduced susceptibility to inactivation by UV light. AB - Ultraviolet (UV) light is one of the factors that causes baculovirus inactivation. However, little is known about the response of baculoviruses to UV light. In the present study, Bombyx mori nucleopolyhedrovirus (BmNPV) orf 65 (Bm65), the homolog of Autographa californica nucleopolyhedrovirus orf 79 (Ac79), a predicted endonuclease, was analyzed. Preliminary results indicated that Bm65 mainly accumulated within the nucleus and could improve the survival rate of Escherichia coli (E. coli) and BmNPV BVs after UV radiation, suggesting that Bm65 was involved in the repair of UV-induced DNA damage. PMID- 25791023 TI - Redox regulation of differentiation and de-differentiation. PMID- 25791024 TI - N-acetylglucosamine modification in the lumen of the endoplasmic reticulum. AB - BACKGROUND: O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of epidermal growth factor (EGF) domains catalyzed by EGF domain O-GlcNAc transferase (EOGT) is the first example of GlcNAc modification in the lumen of the endoplasmic reticulum (ER). SCOPE OF REVIEW: This review summarizes current knowledge on the EOGT-catalyzed O-GlcNAc modification of EGF domains obtained through biochemical characterization, genetic analysis in Drosophila, and identification of human EOGT mutation. Additionally, this review discusses GTDC2 another ER protein homologous to EOGT that catalyzes the GlcNAc modification of O mannosylated alpha-dystroglycan-and other components of the biosynthetic pathway involved in GlcNAc modification in the ER lumen. MAJOR CONCLUSIONS: GlcNAc modification in the ER lumen has been identified as a novel type of protein modification that regulates specific protein function. Moreover, abnormal GlcNAc modification in the ER lumen is responsible for Adams-Oliver syndrome and Walker Warburg syndrome. GENERAL SIGNIFICANCE: Elucidation of the biological function of GlcNAc modification in the ER lumen will provide new insights into the unique roles of O-glycans, whose importance has been demonstrated in multifunctional glycoproteins such as Notch receptors and alpha-dystroglyan. PMID- 25791025 TI - Response of biomarkers of inflammation and coagulation to short-term changes in central site, local, and predicted particle number concentrations. AB - PURPOSE: Previous studies have reported acute (hours-28 days) associations between ambient ultrafine particles (UFP; diameter <0.1) and biomarkers of cardiovascular health using central site data. We evaluated particle number concentration (a proxy measure for UFP) measured at a central site, a local near highway site and predicted residential concentrations with response of biomarkers of inflammation and coagulation in a near-highway population. METHODS: Participants provided two blood samples for analysis of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha receptor II, and fibrinogen. Mixed effect models were used to evaluate the association between PNC levels on the same day, prior 2 days, and moving averages of 3 to 28 days. RESULTS: Estimated effects on biomarkers of a 5000 unit increase in central site PNC generally increased with longer averaging times for IL-6, hs CRP, and fibrinogen. Effect estimates were highest for a 28-day moving average, with 91% (95% confidence interval [CI]: 9, 230) higher IL-6 levels, 74% (95% CI: 7, 220) higher hs-CRP levels, and 59% (95% CI: -13, 130) higher fibrinogen levels. We observed no clear trend between near-highway or predicted residential PNC and any of the biomarkers. CONCLUSIONS: Only central site PNC increased blood markers of inflammation while near-highway and predicted residential values did not. We cannot fully explain this result, although differing PNC composition is a possibility. Future studies would assist in understanding these findings. PMID- 25791026 TI - Educational attainment and longevity: results from the REGARDS U.S. national cohort study of blacks and whites. AB - BACKGROUND: Educational attainment may be an important determinant of life expectancy. However, few studies have prospectively evaluated the relationship between educational attainment and life expectancy using adjustments for other social, behavioral, and biological factors. METHOD: The data were from the REasons for Geographic and Racial Differences in Stroke study that enrolled 30,239 black and white adults (>=45 years) between 2003 and 2007. Demographic and cardiovascular risk information was collected and participants were followed for health outcomes. Educational attainment was categorized as less than high school education, high school graduate, some college, or college graduate. Proportional hazards analysis was used to characterize survival by level of education. RESULTS: Educational attainment and follow-up data were available on 29,657 (98%) of the participants. Over 6.3 years of follow-up, 3673 participants died. There was a monotonically increasing risk of death with lower levels of educational attainment. The same monotonic relationship held with adjustments for age, race, sex, cardiovascular risk factors, and health behaviors. The unadjusted hazard ratio for those without a high school education in comparison with college graduates was 2.89 (95% CI = 2.64-3.18). Although adjustment for income, health behaviors, and cardiovascular risk factors attenuated the relationship, the same consistent pattern was observed after adjustment. The relationship between educational attainment and longevity was similar for black and white participants. The monotonic relationship between educational attainment and longevity was observed for all age groups, except for those aged 85 years or more. CONCLUSIONS: Educational attainment is a significant predictor of longevity. Other factors including age, race, income, health behaviors, and cardiovascular risk factors only partially explain the relationship. PMID- 25791027 TI - Eight years of experience with Enhanced Recovery After Surgery in patients with colon cancer: Impact of measures to improve adherence. AB - BACKGROUND: Perioperative treatment of patients with colorectal cancer according to the Enhanced Recovery After Surgery (ERAS) protocol has proven to reduce complications and duration of stay. However, strict adherence remains a challenge and the benefits may decrease with lower adherence. In this study, we report on 8 years of adherence to the ERAS protocol and its effect on postoperative outcome in patients with colon cancer. METHODS: In 2006, the ERAS protocol was introduced for treatment of colon cancer patients in the Medical Center Alkmaar, a large teaching hospital. Patients scheduled for elective colon cancer resection were included in this study. Adherence to ERAS items was monitored and along with clinical data prospectively gathered in a database. In 2011, several measures to improve adherence were implemented. RESULTS: In total, 816 patients were included. Mean adherence rate was 73% in 2006 and 2007, 66% in 2008 and 2009, 63% in 2010 and 2011, and 82% in 2012 and 2013. There was a shorter duration of stay in the years with high adherence (5.7 days) compared with the years with low adherence (7.3 days; P < .001). The ERAS items that were the strongest predictors for a shorter duration of stay were no nasogastric tube, early mobilization, early oral nutrition, early removal of epidural, early removal of catheter, and nonopioid oral analgesia. CONCLUSION: It is possible to improve adherence to the ERAS protocol and related outcomes with specific measures. Adherence to the ERAS protocol was related inversely to duration of stay. Only postoperative items of the ERAS protocol were predictive for a shorter duration of stay. Keeping adherence optimal remains an ongoing challenge that requires repeated training and dedicated personnel. PMID- 25791028 TI - The influence of transection site on the development of pancreatic fistula in patients undergoing distal pancreatectomy: A review of 294 consecutive cases. AB - BACKGROUND: Pancreatic fistula (PF) is a significant cause of morbidity in patients undergoing distal pancreatectomy (DP), with an incidence of 15-40%. It remains unclear if the location of pancreatic transection affects the rate of PF occurrence. This study examines the correlation between the transection site of the pancreas during DP and the incidence of PF. METHODS: All cases of DP from October 2005 to January 2012 were reviewed retrospectively from an institutional review board-approved database at the Thomas Jefferson University Hospital. Patient demographics and perioperative outcomes were analyzed. The pancreatic transection location was determined by review of operative reports, and then dichotomized into 2 groups: neck/body or tail. PF were graded following the International Study Group on Pancreatic Fistula guidelines. RESULTS: During the study period, 294 DP were performed with 244 pancreas transections at the neck/body and 50 at the tail. Of the 294 patients, 52 (17.7%) developed a postoperative PF. The incidence of PF after transection at the tail of the pancreas was higher (28%) when compared with transection at the neck/body (15.6%; P = .04). When stratified by PF grade, grade A PF occurred more commonly when transection of the gland was at the tail (22% tail vs 8.2% neck/body; P = .007); however, no difference was found for grade B/C PF (6% tail vs 7.4% neck/body; P = 1). CONCLUSION: Our data suggest that PF occurs more often when the tail is transected during DP, although the majority are low grade and of minimal clinical significance. More severe PF occurred equally between the transection sites. PMID- 25791029 TI - Sustained methylene blue staining to guide anatomic hepatectomy for hepatocellular carcinoma: Initial experience and technical details. AB - BACKGROUND: The boundary of the target hepatic segment within the liver parenchyma cannot be marked by the use of a conventional anatomic hepatectomy approach. This study describes a novel methylene blue staining technique for guiding the anatomic resection of hepatocellular carcinoma (HCC). METHODS: Between February 2009 and February 2012, anatomic hepatectomy was performed in 106 patients with HCC via a novel, sustained methylene blue staining technique. Sustained staining was achieved by injecting methylene blue into the distal aspect of the portal vein after exposing Glisson's sheath. The hepatic pedicle was immediately ligated, and the hepatic parenchymal transection was performed along the interface between methylene blue stained tissue and unstained tissue. RESULTS: Anatomic hepatectomies included subsegmentectomy (n = 16), monosegmentectomy (n = 57), multisegmentectomy (n = 27), and hemihepatectomy (n = 6). The portal vein was injected successfully with methylene blue in 100% of cases, and complete staining of the target hepatic segment was achieved in 98 of 106 (92.5%) cases. Mean intraoperative bleeding was 360 +/- 90 mL, and the postoperative complication rate was 24.5% (26/106). No perioperative mortality occurred. Operative margins were all negative on pathologic examination. Mean duration of postoperative follow-up was 40 months (range, 24-60). No local recurrence (around the operative margin) occurred. CONCLUSION: This novel technique of achieving sustained staining by injecting methylene blue then immediately ligating the hepatic pedicle is simple and feasible. It can guide the selection of the operative margin during hepatic parenchyma transection to improve the accuracy of anatomic hepatectomy for the treatment of HCC. PMID- 25791030 TI - Long-term outcomes of laparoscopic versus open liver resection for liver metastases from colorectal cancer: A comparative analysis of 168 consecutive cases at a single center. AB - BACKGROUND: Laparoscopic liver resection for liver metastases from colorectal cancer (CRLM) is performed in a relatively small number of institutions. Its operative results have been reported to be comparable with that of open laparotomy; however, information on its oncologic outcomes is scarce. This study aimed to compare the long-term outcomes of laparoscopic hepatectomy (LH) and open hepatectomy (OH) to treat CRLM at a single institution. METHODS: We retrospectively reviewed data from 168 consecutive patients who underwent LH (n = 100) or OH (n = 68) for CRLM. The tumor characteristics, operative results, overall survival (OS) rate, recurrence-free survival (RFS) rate, and recurrence patterns were analyzed and compared. A previously published survival-predicting nomogram was applied to compare OS and RFS between the 2 patient groups. RESULTS: The largest tumor diameter and the number of tumors were significantly larger in the OH group than in the LH group; however, no differences in other tumor factors were observed between the 2 groups. When matched by the nomogram, OS and RFS remained comparable between the 2 groups in every examined stratum, not only for low-risk patients but also for those with high risk. The recurrence patterns also were similar (liver: 30.2% vs 26.8%, P = .72; lung: 22.6% vs 34.1%, P = .22; peritoneum: 7.6% vs 4.9%, P = .45). CONCLUSION: The long-term outcomes of laparoscopic liver resection for CRLM were comparable with those of the open procedure in not only low-risk but also high-risk patients. PMID- 25791031 TI - Initial antibiotic treatment for acute simple appendicitis in children is safe: Short-term results from a multicenter, prospective cohort study. AB - BACKGROUND: Initial antibiotic treatment for acute appendicitis has been shown to be safe in adults; so far, not much is known about the safety and efficacy of this treatment in children. The aims of this study were to investigate the feasibility of a randomized controlled trial (RCT) evaluating initial antibiotic treatment for acute appendectomy in children with acute simple appendicitis and to evaluate the safety of this approach. METHODS: In a multicenter, prospective cohort study patients aged 7-17 years with a radiologically confirmed simple appendicitis were eligible. Intravenous antibiotics (amoxicillin/clavulanic acid 250/25 mg/kg 4 times daily; maximum 6,000/600 mg/d and gentamicin 7 mg/kg once daily) were administered for 48-72 hours. Clinical reevaluation every 6 hours, daily blood samples, and ultrasound follow-up after 48 hours was performed. In case of improvement after 48 hours, oral antibiotics were given for a total of 7 days. At any time, in case of clinical deterioration or non-improvement after 72 hours, an appendectomy could be performed. Follow-up continued until 8 weeks after discharge. Adverse events were defined as major complications of antibiotic treatment, such as allergic reactions, perforated appendicitis, and recurrent appendicitis. RESULTS: Of 44 eligible patients, 25 participated (inclusion rate, 57%; 95% CI, 42%-70%). Delayed appendectomy was performed in 2, and the other 23 were without symptoms at the 8 weeks follow-up. Minor complications occurred in three patients. None of the patients suffered from an adverse event or a recurrent appendicitis. CONCLUSION: Our study shows that an RCT comparing initial antibiotic treatment strategy with urgent appendectomy is feasible in children; the intervention seems to be safe. PMID- 25791033 TI - Guidance matches osteoarthritis patients to NSAIDs according to risk of side effects. PMID- 25791032 TI - Colonic obstruction caused by endometriosis solved with a colonic stent as a bridge to surgery. AB - Self-expanding metal stents are an established treatment for malignant colon strictures, either as palliative treatment or as a bridge to later surgery. Little data exist regarding the use of stents for benign obstructions and the rate of subsequent complications related to the procedure is high. After reviewing the existing literature, we found only one case of stent placement in an intestinal obstruction caused by endometriosis, as a bridge to surgery. The use of prostheses in benign disease has a higher rate of complications such as stent migration and gut perforation. Such complications are even more likely to happen when the stent has been placed as a bridge to surgery and it is delayed for more than 7 days. This is the case of a young woman presenting an acute intestinal obstruction related to endometrioma. Stent placement was used in this case as a bridge to surgery with successful results. PMID- 25791034 TI - Occupational Outcomes and Return to Running Following Internal Fixation of Ankle Fractures in a High-Demand Population. AB - BACKGROUND: Literature evaluating surgical outcomes after ankle fixation in an active patient population is limited. This study determined occupational outcomes and return to running following ankle fracture fixation in a military cohort. METHODS: All service members undergoing ankle fracture fixation at a single military hospital from August 2007 to August 2012 were reviewed. Univariate analysis determined the association between patient demographic information, type of fracture fixation, and the development of posttraumatic ankle arthritis and functional outcomes, including medical separation, return to running, and reoperation. Seventy-two primary ankle fracture fixation procedures were performed on patients with mean age of 29.1 years. The majority of patients were male (88%), were 25 years of age or older (61%), were of junior rank (57%), underwent unimalleolar fracture fixation (78%), and did not require syndesmotic fixation (54%). The average follow-up was 35.9 months. RESULTS: The mean time to radiographic union was 8.6 weeks. Twelve service members (17%) were medically separated from the military due to refractory pain following ankle fracture fixation with a minimum of 2-year occupational follow-up. Among military service members undergoing ankle fracture fixation, 64% returned to running. Service members with higher occupational demands had a statistical trend to return to running (odds ratio [OR] 2.49; 95% CI, 0.93-6.68). Junior enlisted rank was a risk factor for medical separation (OR 11.00; 95% CI, 1.34-90.57). Radiographic evidence of posttraumatic ankle osteoarthritis occurred in 8 (11%) service members. CONCLUSIONS: At mean 3-year follow-up, 83% of service members undergoing ankle fracture fixation remained on active duty or successfully completed their military service, while nearly two-thirds returned to occupationally required daily running. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25791035 TI - Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca(2+), mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca(2+) level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients. PMID- 25791037 TI - Circumstances, Descriptive Characteristics, and Pathologic Findings in Dogs Suspected of Starving. AB - The authors reviewed the case circumstances, population characteristics, gross, and histopathologic findings in 40 cases of emaciated dogs with a suspected diagnosis of starvation. The dogs' estimated age ranged from 3 months to geriatric. Nineteen breeds were represented, including small-breed (n = 11), large-breed (n = 13), and pit bull-type (n = 16) dogs. The median body condition score was 1 out of 9 (Purina scale). Various diseases were identified as the cause of death in 7 dogs, while the cause of death in the other 33 dogs was starvation due to exogenous causes (SEC). Circumstances associated exclusively with SEC included being found in a vacated residence and death during temperature extremes or severe weather. Dogs with SEC did not differ significantly from diseased dogs in body condition score, sex, neuter status, or breed category (small, large, or pit bull type). Gross findings associated exclusively with SEC included severe hair matting and traumatic injuries. Diseased dogs had an empty stomach significantly more often than SEC dogs, which frequently had food and/or foreign material in the stomach. In 5 of the 7 cases where disease was the cause of death, disease involved the gastrointestinal tract. Gross and histopathologic changes commonly found in SEC and diseased dogs included the following: gross loss of muscle mass and absence of subcuticular fat; serous atrophy of omental, perirenal, epicardial, and bone marrow fat; atrophy of the liver, skin, thyroid gland, and testicle; gastric mucosal petechiae and ecchymoses; melena; and splenic hemosiderophages. PMID- 25791036 TI - Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats. AB - Infants born prematurely are at risk for cardiovascular events causing hypoxia ischemia (HI; reduced blood and oxygen to the brain). HI in turn can cause neuropathology, though patterns of damage are sometimes diffuse and often highly variable (with clinical heterogeneity further magnified by rapid development). As a result, though HI injury is associated with long-term behavioral and cognitive impairments in general, pathology indices for specific infants can provide only limited insight into individual prognosis. The current paper addresses this important clinical issue using a rat model that simulates unilateral HI in a late preterm infant coupled with long-term behavioral evaluation in two processing domains - auditory discrimination and spatial learning/memory. We examined the following: (1) whether deficits on one task would predict deficits on the other (suggesting that subjects with more severe injury perform worse across all cognitive domains) or (2) whether domain-specific outcomes among HI-injured subjects would be uncorrelated (suggesting differential damage to orthogonal neural systems). All animals (sham and HI) received initial auditory testing and were assigned to additional auditory testing (group A) or spatial maze testing (group B). This allowed within-task (group A) and between-task (group B) correlation. Anatomic measures of cortical, hippocampal and ventricular volume (indexing HI damage) were also obtained and correlated against behavioral measures. Results showed that auditory discrimination in the juvenile period was not correlated with spatial working memory in adulthood (group B) in either sham or HI rats. Conversely, early auditory processing performance for group A HI animals significantly predicted auditory deficits in adulthood (p = 0.05; no correlation in shams). Anatomic data also revealed significant relationships between the volumes of different brain areas within both HI and shams, but anatomic measures did not correlate with any behavioral measure in the HI group (though we saw a hippocampal/spatial correlation in shams, in the expected direction). Overall, current data provide an impetus to enhance tools for characterizing individual HI-related pathology in neonates, which could provide more accurate individual prognoses within specific cognitive/behavioral domains and thus improved patient-specific early interventions. PMID- 25791038 TI - Chordomas at High Prevalence in the Captive Population of the Endangered Perdido Key Beach Mouse (Peromyscus polionotus trissyllepsis). AB - The Perdido Key beach mouse (Peromyscus polionotus trissyllepsis) is a critically endangered subspecies of the oldfield mouse. The captive population, currently maintained by 3 Florida zoos, is entirely derived from just 3 wild-caught ancestor mice. Necropsy and histopathology revealed chordoma of the vertebral column in 38 of 88 (43%) mice. The tumors were locally expansile and invasive masses of large physaliferous (vacuolated) cells with small, round, hyperchromatic nuclei, similar to the "classic" form of chordomas described in humans. Primary tumors rarely contained small amounts of bone and cartilaginous matrix, characteristic of the "chondroid" form. Neoplastic cells contained abundant granules positive by the periodic acid-Schiff reaction. Brachyury and cytokeratin AE1/AE3 were detected in neoplastic cells by immunohistochemistry, but uncoupling protein 1 was not identified. Primary tumors occurred along the entire vertebral column--cervical, 5 of 38 (13%); thoracic, 16 (42%); lumbar, 13 (34%); and sacral, 10 (26%)--and 10 (26%) mice had multiple primary masses. Metastases to the lungs were noted in 13 of the 38 (34%) mice. Mice diagnosed with chordomas postmortem ranged from 424 to 2170 days old, with a mean of 1399 days. The prevalence of chordoma was not significantly different between males (n = 23 of 50; 46%) and females (n = 15 of 38; 39%). PMID- 25791039 TI - Waist circumference as an independent risk factor for NODAT. AB - BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) is a serious and frequent complication of solid organ transplantations. NODAT leads to 2-3 times higher cardiovascular morbidity and mortality. Visceral obesity is a key factor for diabetes mellitus type 2 and metabolic syndrome development, and is an independent risk factor for cardiovascular diseases. MATERIAL AND METHODS: The series consisted of 167 patients after primary kidney transplantation from a dead donor (64 patients had developed NODAT), average age of the series was 46.1+/-11.6 years. We retrospectively examined waist circumference, body mass index, and weight gain in the 12th month after transplantation. We examined average level of triglycerides, cholesterol, and immunosuppression throughout the 12 monitored months. RESULTS: Patients with NODAT were significantly older (P=0.004) and had greater waist circumference (P<0.0001) and higher average sirolimus level (P=0.0262). We identified the following independent risk factors for NODAT by using multivariate analysis: age at the time of transplantation above 50 years (HR=2.5038, [95% CI: 1.7179 to 3.6492], P<0.0001), waist circumference in men greater than 94 cm (HR=1.9492, [95% CI: 1.1697 to 3.2480], P=0.0104) and in women greater than 80 cm (HR=4.5018, [95% CI: 1.8669 to 10.8553], P=0.009). By using correlation coefficient we have proved that greater waist circumference was related to higher incidence of NODAT (r=0.1935, [95% CI: 0.01156 to 0.3630], P=0.0374). Graft survival (death censored) 12 months after kidney transplantation was 97.1% in the control group and 95.3% in the NODAT group (P=0.5381). Patient survival 12 months after kidney transplantation in the control group was 98.1% and in the NODAT group it was 96.9% (P=0.6113). CONCLUSIONS: We identified waist circumference as an independent risk factor for NODAT in our analysis. PMID- 25791040 TI - Crying tapir: the functionality of errors and accuracy in predator recognition in two neotropical high-canopy primates. AB - Predation is often considered to be a prime driver in primate evolution, but, as predation is rarely observed in nature, little is known of primate antipredator responses. Time-limited primates should be highly discerning when responding to predators, since time spent in vigilance and avoidance behaviour may supplant other activities. We present data from two independent studies describing and quantifying the frequency, nature and duration of predator-linked behaviours in 2 high-canopy primates, Ateles belzebuth and Cacajao ouakary. We introduce the concept of 'pseudopredators' (harmless species whose appearance is sufficiently similar to that of predators to elicit antipredator responses) and predict that changes in behaviour should increase with risk posed by a perceived predator. We studied primate group encounters with non-primate vertebrates across 14 (Ateles) and 19 (Cacajao) months in 2 undisturbed Amazonian forests. Although preliminary, data on both primates revealed that they distinguished the potential predation capacities of other species, as predicted. They appeared to differentiate predators from non-predators and distinguished when potential predators were not an immediate threat, although they reacted erroneously to pseudopredators, on average in about 20% of the responses given toward other vertebrates. Reacting to pseudopredators would be interesting since, in predation, one error can be fatal to the prey. PMID- 25791042 TI - [Dementia: an interdisciplinary challenge!]. PMID- 25791041 TI - Recurrence quantification analysis of surface electromyogram supports alterations in motor unit recruitment strategies by anodal transcranial direct current stimulation. AB - PURPOSE: Recent evidence indicates that anodal transcranial direct current stimulation (tDCS) can selectively alter the EMG/force relationship of agonist arm muscles; however, the mechanisms mediating those changes are less clear. The purpose of this study was to evaluate the effect of anodal tDCS on motor unit synchronization by using a sophisticated non-linear EMG analysis called recurrence quantification analysis (RQA). METHODS: Surface EMG signals were collected from the biceps brachii muscle of eighteen healthy young adults (9 tDCS and 9 control) at various force levels (12.5%, 25%, 37.5%, and 50% maximum) before and after the application of anodal tDCS over the primary motor cortex. RQA was employed to quantify the changes in percentage of determinism (% DET) and laminarity (% LAM) of the surface EMG signals, which are surrogate measures of motor unit synchronization. RESULTS: RQA analyses indicated that the changes in % DET and % LAM scores were significantly higher in the tDCS group than in the control group (p < 0.05) and this effect was particularly pronounced at higher force levels. CONCLUSION: The results of this study provide novel evidence supporting that anodal tDCS significantly alters motor unit firing strategies (i.e., the degree of synchronization) of the biceps brachii muscle. PMID- 25791043 TI - [Case finding in family practice and neuropsychological diagnosis at a memory clinic]. AB - To improve early diagnosis of cognitive impairment in the elderly a case-finding strategy should be adopted: general practitioners should only examine "suspicious" patients with a very efficient tool. The BrainCheck, a new case finding tool from Switzerland, comprises of three questions for the patient and the clock drawing test. In addition the family member fills out a short questionnaire. In a validation study with 113 patients and 70 cognitively healthy individuals the BrainCheck showed a correct classification rate of 89 % (sensitivity = 97 %; specificity = 82 %). Within the work of a memory clinic the neuropsychological assessment should use appropriately normed cognitive instruments, especially if one is to detect subtle cognitive impairment. DSM-5 proposes to replace the terms mild cognitive impairment and dementia with mild and severe neurocognitive disorder, respectively. A major improvement in DSM-5 is the list of cognitive domains, which need to be examined. However, no standardized or widely accepted tool exists today to assess the domain of social cognition. PMID- 25791044 TI - [Cognition and mobility]. AB - Felix Platter Hospital, University Center for Medicine of Aging, Basel, Switzerland; There is a strong association between cognition and mobility. Older adults with gait deficits have an increased risk of developing cognitive deficits, even dementia. Cognitive deficits, on the other hand, are associated with worsening gait. Cognitive as well as mobility deficits are associated with an increased fall risk. Assessments of cognition, particularly the executive functions, and functional mobility should therefore be an integral part of every comprehensive geriatric assessment. Some quick screening tests for mobility disorders can be performed in a clinical praxis. If those assessments provide pathological results, then consider patient referral for an in-depth gait analysis. Gait analyses that utilize dual task paradigms (walking and simultaneously performing a second task) are particularly meaningful for early detection of mobility and cognitive deficits. Early detection permits timely implementation of targeted interventions to improve gait and brain function. PMID- 25791045 TI - [Disclosing the diagnosis and guidance]. AB - Before the disclosure of the diagnosis, both the patients with dementia and their relatives experience a long time not only full of insecurity, uncertainty, fear and misgivings but also of conflicts. The beginning of a neurodegenerative disease is always associated with a lot of open questions. If young patients are still active in their professional life, already the stage of "Mild Cognitive Impairment" will cause mistakes, burnout, mobbing, depression and sick leaves. In the partner relationship conflicts and accusations may emerge. It is far too little recognized that those problems at the relational level are often more burdening than the typical deficiencies due to dementia. Unfortunately, it is still considered that a clarification and diagnosis are only worthwhile for diseases which are curable. However, the aim of every evidence-based medicine should be giving every patient and his relatives the best possible quality of life, including symptomatic treatment options and prevention of possible complications. A frank opening discussion of the diagnosis paves the way for the patient and his relatives to deal with the situation and to develop together a solution strategy in the challenging setting of dementia, which always affects the whole familial and social system. The patient is entitled to be informed about his/her diagnosis, including dementia. The diagnostic disclosure requires time and highest professionalism, the knowledge of the individual deficiencies and resources, the social situation, the biography and the personality of the patients but also of their relatives. The diagnostic disclosure arouses a lot of emotions, that need to be addressed and also be absorbed. Primarily, the conversation should be conducted with the patient, but preferably in the presence of the relatives. A very important point is the appreciation of the dementia patient, even with anosognosia. The relatives should not be given just general advice, there should rather be a therapeutic conversation responding to their sensation of permanent loss of the beloved person, their grief and anger. Only this way a solid fundament can be established for mutually finding a cooperative strategy in terms of a behavior-oriented systematic therapy. Therefore, the support of a patient with dementia and his relatives not only involves case management and expert advice, even though they are of great importance too, but also the commitment to the changed relationship and situation. After that, resilience might be developed, which is crucial to cope with this long-lasting disease, which is always associated with a step-by-step farewell. PMID- 25791046 TI - [Dementia of the Alzheimer type: non-drug and drug therapy]. AB - The optimal management of Alzheimer's disease (AD) involves a close alliance with AD caregivers and requires early diagnosis, multimodal management, including non drug and drug interventions, and multispecialty care. Non-pharmacological approaches such as cognitive stimulation programs mostly benefit behavior and psychiatric symptoms in dementia patients. Pharmacologic management of AD consists of eliminating therapeutic redundancies and potentially deleterious medications (Beers Criteria). A pharmacologic foundation of Ginkgo Biloba and combination therapy with a cholinesterase inhibitor and memantine reduces decline in cognition and function, decreases and/or delays the emergence and impact of neuropsychiatric symptoms, postpones institutionalization, and works best when appropriately instituted early and maintained. Despite an existing reimbursement limitation by the health-insurance system in Switzerland, the combination of cholinesterase inhibitor and memantine is possible within the admitted MMSE ranges. PMID- 25791047 TI - [Automobile driving capacity in dementia]. AB - Dementia influences at an early stage the driving aptitude of motor vehicle steering persons. Every year in Switzerland, around 16'000 driving permit holders suffer newly from dementia; therefore the driving aptitude is questioned, especially because of possibly limited executive functions. Individuals with early-stage dementia often may show a dangerous driving stile. However, a mild dementia does not a priori exclude the driving aptitude, and less than half of these drivers can continue driving for another 1 - 3 years. In contrast, there is no further driving aptitude in presence of moderate dementia. In the assessment of driving aptitude, the underlying cause of dementia is always taken into account. Cognitive short tests such as the Mini-Mental Status Exam, Clock Drawing Test and Trail-Making Test are not suitable to make reliable statements about the aptitude to drive, but these tests are very important for the initial diagnosis of dementia in primary care practice and can lead the way for further examination concerning driving aptitude. The legally prescribed regular check-up for motorists aged over 70 years in Switzerland provides an ideal opportunity for early detection of incipient dementia. The practical procedure for the assessment of aptitude to drive in the primary care practice is presented. The physician guided on-road driving test represents a meaningful, practical and relatively cost-effective tool for the evaluation of driving aptitude in cases of doubt. PMID- 25791048 TI - [Judgment capacity from the legal viewpoint - especially the evaluation by a notary public]. AB - The issue of the capacity of judgement or the lack thereof and the validity of legal actions performed in such conditions will become more and more important considering the longer life expectancy and the increasing number of people with diseases like dementia. This paper will discuss the capacity of judgement from a legal point of view. According to article 16 of the swiss civil code a person is capable of judgement within the meaning of the law if he or she does not lack the capacity to act rationally by virtue of being under age or because of a mental disability, mental disorder, intoxication or similar circumstances. Therefore, the incapacity of judgement requires the existence of one of the aforementioned conditions (objective aspect) which have to result in the lack of capacity to act rationally (subjective aspect). The capacity of judgement is relative and must always be evaluated within a given context, i. e. the capacity of judgement has to be confirmed or refuted for a specific transaction at a specific time. By law, the capacity of judgement is assumed (statutory presumption) and the opposite has to be proven. As part of a notarial procedure the capacity of judgement has to be verified by the notary public, although only in a brief and limited manner. If the capacity of judgement is disputed, only the competent civil judge has the power to render a legally binding judgement. PMID- 25791049 TI - [Behavioral and psychological symptoms of dementia (BPSD): how to proceed]. AB - The prevalence of the behavioral and psychological symptoms of dementia (BPSD) is very high in dementia patients. Alterations in multiple neurotransmitter systems are involved in the pathogenesis of BPSD. These symptoms complicate the therapy and outcome. Because of multimorbidity and polpharmacy the therapy of BPSD is difficult and needs continuous clinical observation of the patients. Non pharmacological interventions must be the first choice of therapy before medication and may accompany the pharmacological treatment. Several non pharmacological interventions are available and summarized in the following therapy recommendations of the Swiss medical societies. Pharmacological interventions are often accompanied by severe adverse events in dementia patients. Their use must be limited in time and quantity. A critical survey of pharmacological therapy options in dementia is necessary. PMID- 25791050 TI - [Possibilities of modern imaging technologies in early diagnosis of Alzheimer disease]. AB - Recent advances in neuroimaging technology and image analysis algorithms have significantly contributed to a better understanding of spatial and temporal aspects of brain change associated with Alzheimer Disease. The current review will demonstrate how functional (fMRI) and structural magnetic resonance imaging (MRI) techniques may be used to identify distinct patterns of brain change associated with disease progression and also increased risk for Alzheimer Disease. Moreover, Positron Emission Tomography (PET) based measures of glucosemetabolism (Fluorodeoxyglucose, FDG) and Amyloid-beta plaque density (11-C Pittsburgh Compound B, PiB and 18-F) will be reviewed regarding their diagnostic value for assessing the individual degree of Alzheimer -pathology and thus complement the information provided by MRI and other clinical measures. PMID- 25791051 TI - [Cerebrospinal fluid markers in early diagnosis of Alzheimer dementia]. AB - Cerebrospinal fluid-based neurochemical dementia diagnostics (CSF-NDD) is meanwhile validated on S3 evidence level and international dementia guidelines like those of the German neuropsychiatric associations (DGPPN, DGN; http://www.DGPPN.de) recommend CSF-NDD for the improved early and differential diagnostics of multigenetic (sporadic) Alzheimer's Dementia (AD). CSF-NDD does also offer a predictive diagnosis of incipient AD for high-risk patients when they are still within the prodromal stage of mild cognitive impairment (MCI). But since currently no (secondary) preventive therapy of AD is available, the use of CSF-NDD for the predictive molecular diagnosis of AD is not recommended by the latter guidelines. However, molecular diagnostics of preclinical AD by CSF-NDD and/or [18F]Amyloid-PET has meanwhile gained high clinical relevance for therapeutic clinical research, as this novel clinical model allows to systematically screen for promising (secondary) preventive therapy options. Moreover, future blood based neurochemical diagnostics of preclinical or early AD by means of multiplex assays seems to be promising. However, so far blood assays were not consistently validated by independent research groups and in contrast to CSF-NDD a blood-based diagnosis of AD is not yet available. PMID- 25791052 TI - [New therapeutic approaches]. AB - The most prevalent causes of dementia are progressive and irreversible neurodegenerative diseases of the brain. Alzheimer's disease ranks first and is follwed by Parkinson and Lewy body disease as well as the Frontotemporal lobar degenerations. These neurodegenerative processes are characterised by the production, aggregation and deposition of pathological proteins. These are beta amyloid and tau in Alzheimer's disease; alpha synuclein in der Parkinson's- and Lewy body disease, and tau, TDP-43 as well as FUS in the Frontotemporal lobar degenerations. Aggregation into oligomers and fibrils and subsequent sedimentation of these proteins lead to nerve cell dysfunction, synaptic failure and ultimately to the demise of neurons. The deficits and imbalance of neurotransmitter systems which represent an important target of the current pharmacological treatment of dementia are consequences of nerve cell loss. Many of the novel treatment approaches that are being tested in clinical trials are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins. Key strategies are inhibition of secretases which generate beta amyloid, active and passive immunisation against beta amyloid, restriction beta amyloid and tau aggregation as well as stimulation of beta amyloid clearance. In addition clinical trials are ongoing on symptomatic treatments including the simultaneous stimulation of multiple neurotransmitter systems, compensation of brain insulin resistance, and neuroprotection through certain nutrients. In addition to novel drug treatments non-pharmacological interventions are also being developed. PMID- 25791053 TI - Ozonation of ofloxacin in water: by-products, degradation pathway and ecotoxicity assessment. AB - Application of ozonation in water treatment involves complex oxidation pathways that could lead to the formation of various by-products, some of which may be harmful to living organisms. In this work, ozonation by-products of ofloxacin (OFX), a frequently detected pharmaceutical pollutant in the environment, were identified and their ecotoxicity was estimated using the Ecological Structure Activity Relationships (ECOSAR) computer program. In order to examine the role of ozone (O3) and hydroxyl radicals (?OH) in the degradation of ofloxacin, ozonation was performed at pH2, 7 and 12. In this study, 12 new structures have been proposed for the ozonation by-products detected during the ozonation of ofloxacin. According to the identified ozonation by-products, O3 and ?OH were found to react with ofloxacin during ozonation. The reaction between ofloxacin and O3 proceeded via hydroxylation and breakdown of heterocyclic ring with unsaturated double-bond. The reaction between ofloxacin and .OH generated various by-products derived from the breakdown of heterocyclic ring. Ecotoxicity assessment indicated that ozonation of OFX could yield by-products of greater toxicity compared with parent compounds. PMID- 25791054 TI - Distinct behaviors of infectious F-specific RNA coliphage genogroups at a wastewater treatment plant. AB - The present study aimed to determine the differences in the behaviors of four F specific RNA (F-RNA) coliphage genogroups (GI-GIV) during wastewater treatment. Raw sewage, aeration tank effluent, secondary-treated sewage, and return activated sludge were collected from a wastewater treatment plant in Japan at monthly intervals between March and December 2011 (n=10 each). F-specific coliphages were detected by plaque assay in all tested samples, with a concentration ranging from -0.10 to 3.66 log10 plaque-forming units/ml. Subsequently, eight plaques were isolated from each sample, followed by genogroup specific reverse-transcription quantitative PCR (qPCR) for F-RNA coliphages and qPCR for F-specific DNA (F-DNA) coliphages. GI F-RNA coliphages were the most abundant in the secondary-treated sewage samples (73% of the plaque isolates), while GII F-RNA coliphages were the most abundant in the other three sample types (41-81%, depending on sample type). Based on the results of the quantification and genotyping, the annual mean concentrations of each F-specific coliphage type were calculated, and their reduction ratios during wastewater treatment were compared with those of indicator bacteria (total coliforms and Escherichia coli) and enteric viruses (human adenoviruses and GI and GII noroviruses). The mean reduction ratio of GI F-RNA coliphages was the lowest (0.93 log10), followed by those of the indicator bacteria and enteric viruses (1.59-2.43 log10), GII-GIV F RNA coliphages (>2.60-3.21 log10), and F-DNA coliphages (>3.41 log10). These results suggest that GI F-RNA coliphages may be used as an appropriate indicator of virus reduction during wastewater treatment. PMID- 25791055 TI - Fetal and neonatal organ transplantation. PMID- 25791056 TI - Keeping babies warm: a non-inferiority trial of a conductive thermal mattress. AB - BACKGROUND: External thermal support is critical for preterm or ill infants due to altered thermoregulation. Incubators are the gold standard for long-term support and have been adopted successfully in many countries. Alternatives such as radiant warmers, blankets and others are often used as standard of care (SoC) in resource-limited settings when infants are otherwise not in Kangaroo Mother Care (KMC). METHODS: In this pilot study, we evaluate the feasibility of a conductive thermal mattress (CTM) using phase change materials as a low-cost warmer. We conducted a prospective multicentre open-label randomised controlled trial to determine non-inferiority of this CTM to SoC warming practices in low birthweight infants. The primary outcome was maintenance of axillary temperature. RESULTS: We equally randomised 160 infants to CTM or SoC. The latter cohort continued to receive warmth by radiant warmers (n=48), blankets (n=18), warmed cradles (n=7) or KMC (n=7) before, during and subsequent to the study. CTM was deemed non-inferior since warmed babies had higher axillary temperature compared with SoC (mean increase 0.11+/-0.03 degrees C SEM; p<0.001). Post hoc comparison to radiant warmers alone showed that CTM led to a higher axillary temperature (mean increase by 0.14+/-0.03 degrees C SEM; p<0.001). CONCLUSIONS: Short-term use of CTM compared with radiant warmers and other modes of warming is non inferior to SoC and efficacious in maintaining body temperature. No adverse effects were reported. An extended multinational trial, preferably one that demonstrates longer-term thermoregulation, is warranted. TRIAL REGISTRATION NUMBER: Clinical Trials Registry of India (CTRI/2010/091/002916 and CTRI/2011/04/001696). PMID- 25791057 TI - N-Terminal fatty acylation of peptides spanning the cationic C-terminal segment of bovine beta-defensin-2 results in salt-resistant antibacterial activity. AB - Peptides spanning the C-terminal segment of bovine-beta-defensin-2 (BNBD-2) rich in cationic amino acids, show antimicrobial activity. However, they exhibit considerably reduced activity at physiological concentration of NaCl. In the present study, we have investigated whether N-terminal acylation (acetylation and palmitoylation) of these peptides would result in improved antimicrobial activity. N-terminal palmitoylation though increased hydrophobicity of the peptides, did not enhance antimicrobial potency. However, antibacterial activity of these peptides was not attenuated by NaCl. Biophysical studies on the palmitoylated peptides have indicated that antibacterial activity in the presence of NaCl arises due to the ability of the peptides to interact with membranes more effectively. These peptides showed hemolytic activity which was attenuated considerably in the presence of serum and lipid vesicles. In defensin related peptides, fatty acylation would be a convenient way to generate analogs that are active in the presence of salt. PMID- 25791058 TI - Challenging the in-vivo assessment of biomechanical properties of the uterine cervix: A critical analysis of ultrasound based quasi-static procedures. AB - Measuring the stiffness of the uterine cervix might be useful in the prediction of preterm delivery, a still unsolved health issue of global dimensions. Recently, a number of clinical studies have addressed this topic, proposing quantitative methods for the assessment of the mechanical properties of the cervix. Quasi-static elastography, maximum compressibility using ultrasound and aspiration tests have been applied for this purpose. The results obtained with the different methods seem to provide contradictory information about the physiologic development of cervical stiffness during pregnancy. Simulations and experiments were performed in order to rationalize the findings obtained with ultrasound based, quasi-static procedures. The experimental and computational results clearly illustrate that standardization of quasi-static elastography leads to repeatable strain values, but for different loading forces. Since force cannot be controlled, this current approach does not allow the distinction between a globally soft and stiff cervix. It is further shown that introducing a reference elastomer into the elastography measurement might overcome the problem of force standardization, but a careful mechanical analysis is required to obtain reliable stiffness values for cervical tissue. In contrast, the maximum compressibility procedure leads to a repeatable, semi-quantitative assessment of cervical consistency, due to the nonlinear nature of the mechanical behavior of cervical tissue. The evolution of cervical stiffness in pregnancy obtained with this procedure is in line with data from aspiration tests. PMID- 25791059 TI - Cytoplasmic phospholipase A2 modulation of adolescent rat ethanol-induced protein kinase C translocation and behavior. AB - Ethanol consumption typically begins during adolescence, a developmental period which exhibits many age-dependent differences in ethanol behavioral sensitivity. Protein kinase C (PKC) activity is largely implicated in ethanol-behaviors, and our previous work indicates that regulation of novel PKC isoforms likely contributes to decreased high-dose ethanol sensitivity during adolescence. The cytoplasmic Phospholipase A2 (cPLA2) signaling cascade selectivity modulates novel and atypical PKC isoform activity, as well as adolescent ethanol hypnotic sensitivity. Therefore, the current study was designed to ascertain adolescent cPLA2 activity both basally and in response to ethanol, as well as it's involvement in ethanol-induced PKC isoform translocation patterns. cPLA2 expression was elevated during adolescence, and activity was increased only in adolescents following high-dose ethanol administration. Novel, but not atypical PKC isoforms translocate to cytosolic regions following high-dose ethanol administration. Inhibiting cPLA2 with AACOCF3 blocked ethanol-induced PKC cytosolic translocation. Finally, inhibition of novel, but not atypical, PKC isoforms when cPLA2 activity was elevated, modulated adolescent high-dose ethanol sensitivity. These data suggest that the cPLA2/PKC pathway contributes to the acute behavioral effects of ethanol during adolescence. PMID- 25791060 TI - Spot check analysis of gas exchange: invasive versus noninvasive methods. AB - BACKGROUND: Correct measurement of PO2 and PCO2 is essential to establish appropriate therapy such as long-term oxygen therapy (LTOT) in patients suffering from respiratory failure. OBJECTIVES: We aimed to compare common invasive and noninvasive methods for assessing blood gas components for spot check analysis. METHODS: Arterial (PaO2, PaCO2) and capillary blood gas (PCBGO2, PCBGCO2) measurements were taken consecutively in a randomized order and were compared with noninvasive measurements obtained from the transcutaneous monitoring of PO2 and PCO2 (PtcOv, PtcCO2, sensor-temperature 44 degrees C). Capillary samples were taken from both arterialized earlobes, where samples of right earlobes were defined as a reference value. Pain assessment of all measurements was evaluated by each subject using the 100-mm visual analogue scale. RESULTS: 83 patients and 17 healthy subjects were included. The mean difference between PaO2 and PtcO2 was 11.9 +/- 15.0 mm Hg, with lower limits of agreement (LLA) of -17.4 mm Hg (95% confidence interval (CI) -22.5 to -12.3 mm Hg), and upper limits of agreement (ULA) of 41.1 mm Hg (95% CI 36.0-46.2 mm Hg). The comparison of PaO2 with PCBGO2 showed a mean difference of 5.6 +/- 7.2 mm Hg (LLA -11.0; ULA 19.6 mm Hg). The mean difference between PaCO2 and PtcCO2 was 1.1 +/- 4.9 mm Hg (LLA -8.6; ULA 10.8 mm Hg) and that between PaCO2 and PCBGCO2 was 0.7 +/- 2.0 mm Hg (LLA -3.3; ULA 4.8 mm Hg). The analysis of capillary blood gases (36.2 +/- 22.3 mm) was rated as more painful than the analysis of arterial blood gases (26.1 +/- 20.6 mm), while transcutaneous measurement was rated as the least painful method (1.9 +/- 7.4 mm; all p < 0.0001). CONCLUSIONS: The comparison of different methods for blood gas measurements showed substantial differences between capillary and arterial PO2 and between transcutaneous and arterial PO2. Therefore, arterial PO2 analysis is the essential method evaluating indication for LTOT. Nevertheless, comparative analysis further indicated capillary PCO2 as an adequate surrogate for arterial PCO2. PMID- 25791061 TI - Corrected QT in ventricular paced rhythms: what is the validation for commonly practiced assumptions? AB - INTRODUCTION: Ventricular pacing (VP) may impact the accuracy of QT interval measurement, as it increases the QT by increasing the QRS duration amongst other mechanisms. We aimed to investigate the accuracy of the commonly used clinical practice of subtracting 50 ms from the corrected QT (QTc) in ventricular paced rhythms. METHODS: We conducted a prospective observational study on 23 consecutive pacemaker patients. Four ECGs were recorded for each subject, 2 in their native rate and 2 following an atrial paced, atrial sensed and inhibited response to sensing and then a dual pacing, dual sensing and dual response pacing of 100 bpm to allow for an intrinsic and a ventricular paced QRS, respectively. The averaged QTc in the ventricular paced rhythm was then compared with the non ventricular-paced QTc for individual subjects. RESULTS: At a mean spontaneous heart rate of 66 bpm (SD +/-8), the mean difference in QTc between the ventricular paced and nonpaced QRS was 48.27 ms (95% CI = 32-64.6 ms, p < 0.001). At faster paced rates, the mean QTc difference was 81.3 ms (95% CI = 35.8-126.8 ms, p = 0.002). CONCLUSIONS: The QTc measurement during VP confirms the current 50-ms subtraction assumption rule within a range of +/-16 ms at an average heart rate of 66 bpm. However, at faster heart rates, the 50-ms adjustment may underestimate the QTc discrepancy between a wide and normal QRS. PMID- 25791062 TI - Asymmetrically dividing Drosophila neuroblasts utilize two spatially and temporally independent cytokinesis pathways. AB - Precise cleavage furrow positioning is required for faithful chromosome segregation and cell fate determinant distribution. In most metazoan cells, contractile ring placement is regulated by the mitotic spindle through the centralspindlin complex, and potentially also the chromosomal passenger complex (CPC). Drosophila neuroblasts, asymmetrically dividing neural stem cells, but also other cells utilize both spindle-dependent and spindle-independent cleavage furrow positioning pathways. However, the relative contribution of each pathway towards cytokinesis is currently unclear. Here we report that in Drosophila neuroblasts, the mitotic spindle, but not polarity cues, controls the localization of the CPC component Survivin. We also show that Survivin and the mitotic spindle are required to stabilize the position of the cleavage furrow in late anaphase and to complete furrow constriction. These results support the model that two spatially and temporally separate pathways control different key aspects during asymmetric cell division, ensuring correct cell fate determinant segregation and neuroblast self-renewal. PMID- 25791063 TI - Robotic approach improves spleen-preserving rate and shortens postoperative hospital stay of laparoscopic distal pancreatectomy: a matched cohort study. AB - BACKGROUND: Spleen preservation (SP) is beneficial for patients undergoing distal pancreatectomy of benign and borderline tumors; however, the conventional laparoscopy approach (C-LDP) is less effective in controlling splenic vessel bleeding. The benefits of the robotic-assisted approach (RA-LDP) in SP have not been clearly described. This study aimed to evaluate whether a robotic approach could improve SP rate and effectiveness/safety profile of laparoscopic distal pancreatectomy (LDP). METHODS: Matched for scheduled SP, age, sex, ASA classification, tumor size, tumor location, and pathological type, 69 patients undergoing RA-LDP and 50 undergoing C-LDP between January 2005 and May 2014 were included. Main outcome measures included SP rate, operative time (OT), blood loss, transfusion frequency, morbidity, postoperative hospital stay (PHS), and oncologic safety. RESULTS: Among matched patients scheduled for SP, RA-LDP was associated with significantly higher overall (95.7 vs. 39.4%) and Kimura SP rates (72.3 vs. 21.2%), shorter OT (median 120 vs. 200 min), less blood loss (median 100 vs. 300 mL), lower transfusion frequency (2.1 vs. 18.2%), and shorter mean PHS (10.2 vs. 14.5 days). Among matched patients scheduled for splenectomy, RA LDP was associated with similar OT, blood loss, transfusion frequency, and PHS. The two approaches were similar in overall morbidity, frequency of pancreatic fistula, and oncologic outcome among patients undergoing splenectomy for malignant tumors. CONCLUSIONS: RA-LDP was associated with a significantly better SP rate and reduced OT, blood loss, transfusion requirement, and PHS for patients undergoing SP compared to C-LDP, but offered less benefits for patients undergoing splenectomy. PMID- 25791064 TI - Minimally invasive gastrectomy for cancer: current utilization in US academic medical centers. AB - BACKGROUND: Internationally, the utilization of minimally invasive techniques for gastric cancer resection has been increasing since first introduced in 1994. In the USA, the feasibility and safety of these techniques for cancer have not yet been demonstrated. METHODS: The University HealthSystem Consortium database was queried for gastrectomies performed between 2008 and 2013. Any adult patient with an abdominal visceral malignancy that necessitated gastric resection was included in the cohort. Clinicopathological and in-hospital outcome metrics were collected for open, laparoscopic, and robotic procedures. RESULTS: Open gastrectomies comprised 89.5% of the total study group, while 8.2% of procedures were performed laparoscopically, and 2.3% were performed with robotic assistance. When accounting for disparities in patient severity of illness and risk of mortality subclass designations, there were no significant differences in mean length of stay, 30-day readmission, and in-hospital mortality between the three groups; however, mean total cost was highest in the robotic-assisted group (P = 0.017). Overall, complication rates were also similar; however, there was a higher incidence of superficial infection in the laparoscopic group (P = 0.013) and a higher incidence of venous thromboembolism in the robotic group (P = 0.038). CONCLUSION: Despite widespread adoption for benign indications, minimally invasive gastrectomy for cancer remains underutilized in the USA. In these patients, laparoscopic and robot-assisted gastrectomies appear to be comparable to open resection with respect to overall complications, length of stay, 30-day readmission, and in-hospital mortality. However, when employing minimally invasive techniques, infection and thromboembolism risk reduction strategies should be emphasized in the operative and postoperative periods. PMID- 25791065 TI - Emodin ameliorates high glucose induced-podocyte epithelial-mesenchymal transition in-vitro and in-vivo. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. METHODS: Conditionally immortalized mouse podocytes were exposed to HG with 30 MUg /ml of EMO and 1 MUmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ) induced diabetic rats were treated with EMO at 20 mg. kg(-1). d(-1) and QLT0267 at 10 mg. kg(-1). w(-1) p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. RESULTS: HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. CONCLUSION: EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD. PMID- 25791066 TI - Melatonin is protective against 6-hydroxydopamine-induced oxidative stress in a hemiparkinsonian rat model. AB - Melatonin is known to reduce detrimental effects of free radicals by stimulating antioxidant enzymes; however, its role has not been studied in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease (PD). Therefore, we aimed to elucidate the effects of melatonin on motor activity and oxidative stress parameters in 6-OHDA-induced rat model of PD. Three-month-old male Wistar rats were divided into 5 groups: vehicle (V), melatonin-treated (M), 6-OHDA-injected (6-OHDA), 6-OHDA-injected + melatonin-treated (6-OHDA-Mel), and melatonin-treated + 6-OHDA-injected (Mel-6-OHDA) group. Melatonin was administered intraperitoneally at a dose of 10 mg/kg/day for 30 days in M and Mel-6-OHDA groups, for 7 days in 6-OHDA-Mel group. Rats received a unilateral stereotaxic injection of 6-OHDA into the right medial forebrain bundle. The 6-OHDA-Mel group started receiving melatonin when experimental PD was created and the treatment was continued for 7 days. In the Mel-6-OHDA group, experimental PD was created on the 23rd day of melatonin treatment and continued for the remaining 7 days. Locomotor activity decreased in 6-OHDA group compared with that in vehicle group; however, melatonin treatment did not improve this impairment. 6-OHDA injection caused an obvious reduction in tyrosine-hydroxylase-positive dopaminergic neuron viability as determined by immunohistochemistry. Melatonin supplementation decreased dopaminergic neuron death in 6-OHDA-Mel and Mel-6-OHDA groups compared with that in 6-OHDA group. Biochemical analysis confirmed the beneficial effects of melatonin displaying higher superoxide dismutase, catalase, and glutathione peroxidase activities and lower lipid peroxidation in substantia nigra samples in comparison to non-treated 6-OHDA group. Starting melatonin treatment before creating experimental PD was more effective on observed changes. PMID- 25791067 TI - CD4(+) T-Helper Type 1 Cytokines and Trastuzumab Facilitate CD8(+) T-cell Targeting of HER2/neu-Expressing Cancers. AB - Vaccination strategies incorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2369-377) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2369-377 specific CD8(+) T cells to recognize HLA-A2(pos)HER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2369-377 is directly recognized by high functional-avidity HER2369-377-specific CD8(+) T cells-either genetically modified to express a novel HER2369-377 TCR or sensitized using HER2369-377-pulsed type 1-polarized dendritic cells (DC1)-on class I-abundant HER2(low), but not class I-deficient HER2(high), cancer cells. Importantly, a critical cooperation between CD4(+) T helper type-1 (Th1) cytokines IFNgamma/TNFalpha and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2(high) cancers, thereby facilitating recognition and lysis of these cells by HER2369-377-specific CD8(+) T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNgamma/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2369-377-CD8(+) T-cell-mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNgamma/TNFalpha and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2369-377-CD8(+) cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4(+) Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neu CD8(+) T-cell-directed immunotherapy. PMID- 25791069 TI - Topping it up: methods to improve cord blood transplantation outcomes by increasing the number of CD34+ cells. AB - Cord blood is increasingly recognized for its excellent stem cell potential, lenient matching criteria, instant availability and clinical behavior in transplants when cell dose criteria can be met. However with 1-2 log fewer total (stem cell) numbers in the graft compared with other cell sources, the infused cell dose per kilogram is critical for engraftment and outcome, creating the need for development of stem cell support platforms. The co-transplant platforms of haplo cord and double unit cord blood (DUCB) transplantation are aimed toward increasing stem cell dose. Together with the optimization of reduced-intensity protocols, long-term sustained engraftment using cord blood has become available to most patients, including elderly patients. Haplo cord has a low incidence of both acute and chronic graft-versus-host disease but may require anti-thymocyte globulin ATG for effective neutrophil recovery. DUCB can be performed without anti-thymocyte globulin with excellent immune reconstitution and disease-free survival, but engraftment is considerably slower, and graft-versus-host disease incidence significant. Both haplo-cord and DUCB transplantation appear to both be valid alternatives to matched unrelated donors in adults. PMID- 25791068 TI - Primary care providers' views on using lung age as an aid to smoking cessation counseling for patients with chronic obstructive pulmonary disease. AB - PURPOSE: Smoking cessation is the primary goal for managing patients with chronic obstructive pulmonary disease (COPD) who smoke. However, previous studies have demonstrated poor cessation rates. The "lung age" concept (an estimate of the age at which the FEV(1) would be considered normal) was developed to present spirometry data in an understandable format and to serve as a tool to encourage smokers to quit. Primary care physicians' (PCPs) views of using lung age to help COPD patients to quit smoking were assessed. METHODS: Post-intervention interviews were conducted with PCPs in the U.S. who participated in the randomized clinical trial, "Translating the GOLD COPD Guidelines into Primary Care Practice." RESULTS: 29 physicians completed the interview. Themes identified during interviews included: general usefulness of lung age for smoking cessation counseling, ease of understanding the concept, impact on patients' thoughts of quitting smoking, and comparison to FEV(1). Most providers found lung age easy to communicate. Moreover, some found the tool to be less judgmental for smoking cessation and others remarked on the merits of having a simple, tangible number to discuss with their patients. However, some expressed doubt over the long-term benefits of lung age and several others thought that there might be a potential backfire for healthy smokers if their lung age was <= to their chronological age. CONCLUSIONS: This study suggests that lung age was well received by the majority of PCPs and appears feasible to use with COPD patients who smoke. However, further investigation in needed to explore COPD patients' perspectives of obtaining their lung age to help motivate them to quit in randomized clinical trials. PMID- 25791070 TI - Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy. AB - BACKGROUND AIMS: The term "cerebral palsy" (CP) encompasses many syndromes that emerge from brain damage at early stages of ontogenesis and manifest as the inability to retain a normal body position or perform controlled movements. Existing methods of CP treatment, including various rehabilitation strategies and surgical and pharmacological interventions, are mostly palliative, and there is no specific therapy focused on restoring injured brain function. METHODS: During a post-registration clinical investigation, the safety and efficacy of intravenous infusion of allogeneic human leukocyte antigen (HLA)-unmatched umbilical cord blood (UCB) cells were studied in 80 pediatric patients with cerebral palsy and associated neurological complications. Patients received up to 6 intravenous infusions of AB0/Rh-identical, red blood cell-depleted UCB cells at an average dose of 250 * 10(6) viable cells per infusion. RESULTS: Patients were followed for 3-36 months, and multiple cell infusions did not cause any adverse effects. In contrast, in most patients who received four or more UCB cell infusions, positive dynamics related to significant improvements in neurological status and/or cognitive functions were observed. CONCLUSIONS: The results confirm that multiple intravenous infusions of allogeneic AB0/Rh-identical UCB cells may be a safe and effective procedure and could be included in treatment and rehabilitation programs for juvenile patients with cerebral palsy. PMID- 25791071 TI - Intravenous delivery of adipose-derived mesenchymal stromal cells attenuates acute radiation-induced lung injury in rats. AB - BACKGROUND AIMS: Radiation-induced lung injury (RILI) commonly occurs in patients with thoracic cancer. However, an effective treatment option has not yet been established. Adipose-derived mesenchymal stromal cells (Ad-MSCs) have significant potential for clinical use, but their role in RILI is currently unknown. We aimed to evaluate the therapeutic capacity of Ad-MSCs to heal acute RILI in rats. METHODS: Sprague-Dawley rats were used in this study. Rat Ad-MSCs were delivered through the tail veins of rats 2 h after thorax irradiation. Lung histopathologic findings, pulmonary levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10 and tumor necrosis factor-alpha), pro-fibrotic factors (transforming growth factor [TGF]-beta1, connective tissue growth factor, alpha-smooth muscle actin and type 1 collagen), pro- or anti-apoptotic mediators (Bcl-2, Bax and caspase-3) and the multifunctional factor hepatocyte growth factor were evaluated after Ad MSC transplant. RESULTS: Intravenous delivery of Ad-MSCs attenuated acute RILI. Further studies showed that Ad-MSCs had anti-inflammation and anti-fibrotic effects and maintained lung epithelium integrity, as indicated by reduced serum levels of the pro-inflammatory cytokines IL-1, IL-6 and tumor necrosis factor alpha, increased levels of the anti-inflammatory cytokine IL-10, and downregulated transforming growth factor -beta1, alpha-smooth muscle actin and type 1 collagen levels in irradiated lung tissues. Ad-MSCs also regulated the expression of pro- and anti-apoptotic mediators (Bcl-2, Bax and caspase-3) to protect lung cells from apoptosis. CONCLUSIONS: Intravenous Ad-MSC delivery attenuated acute RILI through anti-inflammation, anti-fibrosis and anti-apoptosis mechanisms. PMID- 25791073 TI - Safety and Efficacy of Liposomal Cytarabine in the Treatment of Neoplastic Meningitis. AB - OBJECTIVES: Although rare, neoplastic meningitis (NM) has been increasingly observed in patients with cancer due to the prolonged course of the disease. Intrathecal chemotherapy with methotrexate or cytarabine with repeating injection schedules of 2-3 times per week is currently the mainstay of treatment. An efficacious and comfortable treatment alternative might be represented by liposomal cytarabine. METHODS: In this retrospective study, we reviewed all patients with NM due to solid tumors or hematological malignancies treated with liposomal cytarabine at our institution between March 2004 and September 2011. The primary endpoint was treatment response, which was defined as improvement in neurological symptoms and/or conversion of the initial cerebrospinal fluid cytology and/or response in the radiological findings. The main secondary endpoint was safety. RESULTS: Fifty-one adult patients were evaluable for safety and 44 patients for efficacy. In 36 patients (81.8%), a treatment response was achieved. The median overall survival after diagnosis of NM was 11 months (95% confidence interval 8.8-13.2). Adverse events grade 1-4 occurred in 31 patients (60.8%), whereas grade 3-4 occurred in 18 patients (35.3%). CONCLUSION: The encouraging efficacy and safety data obtained in our analysis and the convenient administration schedule make intrathecal liposomal cytarabine a favorable treatment option for NM patients. PMID- 25791072 TI - Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of upper and lower motor neurons, with variable involvement of extramotor brain regions. Currently, there are no established objective markers of upper motor neuron and extramotor involvement in ALS. Here, we review the potential diagnostic value of advanced neuroimaging techniques that are increasingly being used to study the brain in ALS. First, we discuss the role of different imaging modalities in our increasing understanding of ALS pathogenesis, and their potential to contribute to objective upper motor neuron biomarkers for the disease. Second, we discuss the challenges to be overcome and the required phases of diagnostic test development to translate imaging technology to clinical care. We also present examples of multidimensional imaging approaches to achieve high levels of diagnostic accuracy. Last, we address the role of neuroimaging in clinical therapeutic trials. Advanced neuroimaging techniques will continue to develop and offer significant opportunities to facilitate the development of new effective treatments for ALS. PMID- 25791074 TI - Effect of superoxidized water and sodium hypochlorite, associated or not with EDTA, on organic and inorganic components of bovine root dentin. AB - INTRODUCTION: This study aimed to evaluate the effects of Sterilox (Sx), a superoxidized water, 5% and 2% sodium hypochlorite (5NaOCl and 2NaOCl), and 17% EDTA (E) on the organic and inorganic components of bovine dentin. METHODS: Eighty bovine incisors were randomly divided into 8 groups (n = 10): 5NaOCl, 5NaOCl + E, 2NaOCl, 2NaOCl + E, Sx, Sx + E, E alone, and distilled water (H2O). Root canal instrumentation was performed by using the corresponding irrigant. The apical 15 mm was longitudinally sectioned into 2 fragments, one for light microscopy analysis in slides stained with picrosirius red (organic component) and the other for scanning electron microscopy analysis (inorganic component). Scores data obtained in the light microscopy analysis were submitted to the Kruskal-Wallis test, followed by multiple comparisons test (P < .05). Scanning electron microscopy images were analyzed descriptively. RESULTS: The chemical solution 5NaOCl had a greater effect on the organic component of dentin in area and depth than 2NaOCl. The chemical solutions 5NaOCl + E, 5NaOCl and 2NaOCl + E caused the greatest change in the collagenous organic matrix near the root canal lumen. The chemical solution 2NaOCl showed similar behavior to Sx, associated or not with E, promoting more superficial disorganization of collagen in a smaller area. Demineralization was observed in all groups in which E was used. However, areas of erosion and open dentinal tubules were detected only when it was combined with NaOCl. CONCLUSIONS: Five percent NaOCl promoted the most extensive damage to the organic component of dentin, and when associated to EDTA, dentinal erosion could be seen. Considering these specific aspects, 2% NaOCl and Sx had milder effects on bovine root dentin. PMID- 25791075 TI - The effect of 8.25% sodium hypochlorite on dental pulp dissolution and dentin flexural strength and modulus. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of various concentrations of sodium hypochlorite (NaOCl), including 8.25%, on dental pulp dissolution and dentin flexural strength and modulus. METHODS: Sixty dental pulp samples and 55 plane parallel dentin bars were retrieved from extracted human teeth. Five test groups (n = 10) were formed consisting of a pulp sample and dentin bar immersed in various NaOCl solutions. The negative control group (n = 5) consisted of pulp samples and dentin bars immersed in saline. The positive control group (n = 5) consisted of pulp samples immersed in 8.25% NaOCl without a dentin bar. Every 6 minutes for 1 hour, the solutions were refreshed. The dentin bars were tested for flexural strength and modulus with a 3-point bend test. The time until total pulp dissolution and any changes in dentin bar flexural strength and modulus for the different NaOCl solutions were statistically analyzed. RESULTS: An increase in NaOCl concentration showed a highly significant decrease in pulp dissolution time. The pulp dissolution property of 8.25% NaOCl was significantly faster than any other tested concentration of NaOCl. The presence of dentin did not have a significant effect on the dissolution capacity of NaOCl if the solutions were refreshed. NaOCl concentration did not have a statistically significant effect on dentin flexural strength or modulus. CONCLUSIONS: Dilution of NaOCl decreases its pulp dissolution capacity. Refreshing the solution is essential to counteract the effects of dentin. In this study, NaOCl did not have a significant effect on dentin flexural strength or modulus. PMID- 25791076 TI - Prevalence of treponema species detected in endodontic infections: systematic review and meta-regression analysis. AB - INTRODUCTION: This systematic review and meta-regression analysis aimed to calculate a combined prevalence estimate and evaluate the prevalence of different Treponema species in primary and secondary endodontic infections, including symptomatic and asymptomatic cases. METHODS: The MEDLINE/PubMed, Embase, Scielo, Web of Knowledge, and Scopus databases were searched without starting date restriction up to and including March 2014. Only reports in English were included. The selected literature was reviewed by 2 authors and classified as suitable or not to be included in this review. Lists were compared, and, in case of disagreements, decisions were made after a discussion based on inclusion and exclusion criteria. A pooled prevalence of Treponema species in endodontic infections was estimated. Additionally, a meta-regression analysis was performed. RESULTS: Among the 265 articles identified in the initial search, only 51 were included in the final analysis. The studies were classified into 2 different groups according to the type of endodontic infection and whether it was an exclusively primary/secondary study (n = 36) or a primary/secondary comparison (n = 15). The pooled prevalence of Treponema species was 41.5% (95% confidence interval, 35.9-47.0). In the multivariate model of meta-regression analysis, primary endodontic infections (P < .001), acute apical abscess, symptomatic apical periodontitis (P < .001), and concomitant presence of 2 or more species (P = .028) explained the heterogeneity regarding the prevalence rates of Treponema species. CONCLUSIONS: Our findings suggest that Treponema species are important pathogens involved in endodontic infections, particularly in cases of primary and acute infections. PMID- 25791077 TI - Evaluation of the Effect of Needle Position on Irrigant Flow in the C-shaped Root Canal Using a Computational Fluid Dynamics Model. AB - INTRODUCTION: The purpose of this study was to investigate the effect of the orientation of a side-vented needle on the irrigant flow pattern in a C-shaped root canal system using computational fluid dynamics and to evaluate the real time replacement of irrigant in the lateral canal (LC). METHODS: A mandibular second molar with a complete C-shaped canal system was chosen for this study. The root canals were prepared and scanned, and then the images were exported to design software. A 30-G, side-vented irrigation needle was positioned with the open notch facing the lateral canal (case A) and rotated 90 degrees , 180 degrees , and 270 degrees clockwise (cases B, C, and D, respectively). The flow pattern, irrigant replacement, velocity distribution, wall stress distribution, and apical pressure in the canal were analyzed. RESULTS: Most of the irrigant flowed to the canal outlet from the adjacent instrumented canal space with different trajectories in the 4 cases. The concentration of scalar immediately below the tip of the needle was exchanged quickly; the length of the cleared zone extended 3 mm beyond the tip of the needles. The depth of circulation in the LC in all cases increased during the first 0.2 seconds. After that, the exchange of irrigant reached a stable phase. Irrigant penetration in the LC was greatest in cases A and B (<1.1 mm). Apical pressure in case B was significantly lower than in other groups. CONCLUSIONS: The scalar concentration can be used to evaluate the replacement of irrigant in the root canal over time. Orientation of the opening of the side-vented needle influences the flow pattern, velocity, apical wall pressure, and penetration into the LC. PMID- 25791078 TI - Western European markets for biosimilar and generic drugs: worth differentiating. PMID- 25791079 TI - Suicidality among military-connected adolescents in California schools. AB - Previous research indicates that suicidal ideation is higher among military connected youth than non military-connected youth. This study extends prior work by examining suicidal ideation, plans, and attempts in military-connected and non military-connected adolescents. Data were gathered from 390,028 9th and 11th grade students who completed the 2012-2013 California Healthy Kids Survey. Bivariate comparisons and multivariate logistic analyses were conducted to examine differences in suicidal ideation, plans, attempts, and attempts requiring medical attention between military and not military-connected youth. In multivariate logistic analyses, military-connected youth were at increased risk for suicidal ideation (OR = 1.43, 95 % CI = 1.37-1.49), making a plan to harm themselves (OR = 1.19, CI = 1.06-1.34), attempting suicide (OR = 1.67, CI = 1.43 1.95), and an attempted suicide which required medical treatment (OR = 1.71, CI = 1.34-2.16). These results indicate that military-connected youth statewide are at a higher risk for suicidal ideation, plans, attempts, and attempts requiring medical care because of suicidal behaviors. It is suggested that policies be implemented to increase awareness and screening among primary care providers, school personnel, and military organizations that serve military-connected youth. PMID- 25791080 TI - Sex-specific and time-dependent effects of prenatal stress on the early behavioral symptoms of ADHD: a longitudinal study in China. AB - There is increasing evidence that prenatal stressful life events (SLEs) may be a potential risk factor for attention-deficit hyperactivity disorder (ADHD), but the sex-specific and time-dependent effects of prenatal stress on ADHD are less clear. In this prospective longitudinal study, data on prenatal SLEs during different stages of gestation and indicators of buffers against stress, including maternal social support and avoidance coping, were obtained from 1765 pregnant women at 32 weeks of gestation. The behavioral symptoms of ADHD in children aged 48-54 months were evaluated by reports from the parents. There were 226 children (12.8%) above the clinically significant cutoff for ADHD. After adjusting for potential confounders, boys whose mother experienced severe SLEs in the second trimester had a significantly increased risk (OR = 2.41, 95% CI: 1.03-5.66) of developing ADHD symptoms compared with boys whose mothers did not experience severe SLEs at this time. However, no significantly increased risk of ADHD symptoms was observed in girls born to mothers experienced prenatal severe SLEs. Additionally, significant interaction effects of prenatal SLEs, social support and coping style on ADHD symptoms were found in males. Boys whose mothers experienced severe SLEs during the second trimester accompanied by a higher score for avoidance coping (OR = 3.31, 95% CI: 1.13-9.70) or a lower score for social support (OR = 4.39, 95% CI: 1.05-18.31) were likely to be at a higher risk for ADHD symptoms. The epidemiological evidence in this prospective follow-up study suggests that the effect of prenatal SLEs on ADHD symptoms in offspring may depend on the timing of prenatal stress and may vary according to the sex of the offspring. PMID- 25791081 TI - Atrial fibrillation ablation in the era of cryoballoon and force-sensing catheters: freeze or burn? AB - OPINION STATEMENT: Atrial fibrillation can adversely affect the quality of life for many patients. Though antiarrhythmic drug therapy remains an option for the treatment of atrial fibrillation, the drugs are associated with numerous side effects. Atrial fibrillation ablation has been shown to be as efficacious as antiarrhythmic drug therapy. The field of atrial fibrillation ablations has evolved over time from utilizing radiofrequency energy to using cryoenergy. Newer technologies are being developed with efforts to improve outcomes in patients undergoing atrial fibrillation ablations. This article will highlight two such technologies: cryoballoon ablation catheters and contact force-sensing catheters. These novel catheters appear to be further revolutionizing this young field in electrophysiology. PMID- 25791082 TI - Supernovae. Old supernova dust factory revealed at the Galactic center. AB - Dust formation in supernova ejecta is currently the leading candidate to explain the large quantities of dust observed in the distant, early universe. However, it is unclear whether the ejecta-formed dust can survive the hot interior of the supernova remnant (SNR). We present infrared observations of ~0.02 solar masses of warm (~100 kelvin) dust seen near the center of the ~10,000-year-old Sagittarius A East SNR at the Galactic center. Our findings indicate the detection of dust within an older SNR that is expanding into a relatively dense surrounding medium (electron density ~10(3) centimeters(-3)) and has survived the passage of the reverse shock. The results suggest that supernovae may be the dominant dust-production mechanism in the dense environment of galaxies of the early universe. PMID- 25791083 TI - Biotechnology. A prudent path forward for genomic engineering and germline gene modification. PMID- 25791084 TI - Molecular nitrogen in comet 67P/Churyumov-Gerasimenko indicates a low formation temperature. AB - Molecular nitrogen (N2) is thought to have been the most abundant form of nitrogen in the protosolar nebula. It is the main N-bearing molecule in the atmospheres of Pluto and Triton and probably the main nitrogen reservoir from which the giant planets formed. Yet in comets, often considered the most primitive bodies in the solar system, N2 has not been detected. Here we report the direct in situ measurement of N2 in the Jupiter family comet 67P/Churyumov Gerasimenko, made by the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis mass spectrometer aboard the Rosetta spacecraft. A N2/CO ratio of (5.70 +/- 0.66) * 10(-3) (2sigma standard deviation of the sampled mean) corresponds to depletion by a factor of ~25.4 +/- 8.9 as compared to the protosolar value. This depletion suggests that cometary grains formed at low-temperature conditions below ~30 kelvin. PMID- 25791086 TI - Surface structure. Subatomic resolution force microscopy reveals internal structure and adsorption sites of small iron clusters. AB - Clusters built from individual iron atoms adsorbed on surfaces (adatoms) were investigated by atomic force microscopy (AFM) with subatomic resolution. Single copper and iron adatoms appeared as toroidal structures and multiatom clusters as connected structures, showing each individual atom as a torus. For single adatoms, the toroidal shape of the AFM image depends on the bonding symmetry of the adatom to the underlying structure [twofold for copper on copper(110) and threefold for iron on copper(111)]. Density functional theory calculations support the experimental data. The findings correct our previous work, in which multiple minima in the AFM signal were interpreted as a reflection of the orientation of a single front atom, and suggest that dual and triple minima in the force signal are caused by dimer and trimer tips, respectively. PMID- 25791085 TI - Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. AB - Aire is an important regulator of immunological tolerance, operating in a minute subset of thymic stromal cells to induce transcripts encoding peptides that guide T cell selection. Expression of Aire during a perinatal age window is necessary and sufficient to prevent the multiorgan autoimmunity characteristic of Aire deficient mice. We report that Aire promotes the perinatal generation of a distinct compartment of Foxp3(+)CD4(+) regulatory T (Treg) cells, which stably persists in adult mice. This population has a role in maintaining self-tolerance, a transcriptome and an activation profile distinguishable from those of Tregs produced in adults. Underlying the distinct Treg populations are age-dependent, Aire-independent differences in the processing and presentation of thymic stromal cell peptides, resulting in different T cell receptor repertoires. Our findings expand the notion of a developmentally layered immune system. PMID- 25791087 TI - Increasing Resident Knowledge and Skills in Quality Improvement Using Residents as-Teachers. PMID- 25791088 TI - Band gaps in jagged and straight graphene nanoribbons tunable by an external electric field. AB - Band gap control by an external field is useful in various optical, infrared and THz applications. However, widely tunable band gaps are still not practical due to a variety of reasons. Using the orthogonal tight-binding method for pi electrons, we have investigated the effect of the external electric field on a subclass of monolayer chevron-type graphene nanoribbons that can be referred to as jagged graphene nanoribbons. A classification of these ribbons was proposed and band gaps for applied fields up to the SiO2 breakdown strength (1 V nm(-1)) were calculated. According to the tight-binding model, band gap opening (or closing) takes place for some types of jagged graphene nanoribbons in the external electric field that lies on the plane of the structure and perpendicular to its longitudinal axis. Tunability of the band gap up to 0.6 eV is attainable for narrow ribbons. In the case of jagged ribbons with armchair edges larger jags forming a chevron pattern of the ribbon enhance the controllability of the band gap. For jagged ribbons with zigzag and armchair edges regions of linear and quadratic dependence of the band gap on the external electric field can be found that are useful in devices with controllable modulation of the band gap. PMID- 25791089 TI - Predictors of personal, perceived and self-stigma towards anxiety and depression. AB - BACKGROUND: Stigma towards individuals experiencing a mental illness is associated with a range of negative psychological, social and financial outcomes. Factors associated with stigma remain unclear; the relationship between stigma and various personal factors may depend on both the type of disorder being stigmatised and what type of stigma is assessed. Different forms of stigma include personal stigma (negative attitudes towards others), perceived stigma (perceived attitudes of others) and self-stigma (self-attribution of others' negative attitudes). METHOD: Three hundred and fifty university students and members of the general public completed an online survey assessing contact with and knowledge of both depression and anxiety, age, gender, current depression and anxiety symptoms, and personal, perceived and self-stigma for both depression and anxiety. RESULTS: Greater contact with, and knowledge of that illness predicted lower personal stigma for both anxiety and depression. Participants with greater levels of current depression symptomatology and females, reported higher perceived stigma towards depression. Males reported higher personal stigma for anxiety. For both anxiety and depression, higher current symptomatology was associated with greater levels of self-stigma towards the illness. CONCLUSIONS: Findings confirm the role of contact and knowledge in personal stigma for both disorders, consistent with previous findings. This finding also supports evidence that interventions addressing these factors are associated with a decline in personal stigma. However, lack of relationship between contact with, and knowledge of a mental illness and perceived and self-stigma for either depression or anxiety suggests that these factors may not play a major role in perceived or self-stigma. The identification of symptomatology as a key factor associated with self-stigma for both anxiety and depression is significant, and has implications for community-wide interventions aiming to increase help-seeking behaviour, as well as individual treatment strategies for clinicians. Further research should examine whether these relationships hold for groups with clinically diagnosed depression and anxiety disorders. PMID- 25791090 TI - Muscle temperature at the point of filleting--Subsequent effect on storage quality of prerigor filleted raw- and cold-smoked Atlantic salmon. AB - The impact of increased muscle temperature at the point of filleting on fillet quality of raw- and cold-smoked Atlantic salmon was investigated. Commercially reared fish (5.65 kg, Kf: 1.23, pH: 7.29, muscle temperature: 6.68 C) were killed and immediately tempered in three different containers. Muscle temperatures after filleting (<3 h postmortem) of the three groups were 2.08 C (hereafter named T 2); 9.07 C (hereafter named T-9), and 14.09 C (hereafter named T-14), respectively. The pH after filleting was significantly low for T-14 (6.93) followed by T-9 (7.06) and T-2 (7.22). Raised temperature at point of filleting was found to significantly alter development of rigor mortis, which subsequently affected muscle pH and the reflective properties of the fillet surface during 14 days' ice storage. Of cold-smoked fillets, however, a more distinct effect of raised temperature was observed on visual perception resulting in lighter and more yellowish cold-smoked fillets after 14 days' storage. In addition, raised temperature also affects the development of muscle pH in cold-smoked fillets during refrigerated storage. No effects of raised muscle temperature were found regarding drip loss, water-holding capacity, or fillet firmness either for raw- or cold-smoked fillets throughout the storage period. PMID- 25791091 TI - The relationship between intravascular ultrasound-derived percent total atheroma volume and fractional flow reserve in the intermediate stenosis of proximal or middle left anterior descending coronary artery. AB - BACKGROUND: It remains undefined whether the atherosclerotic disease extent of the conductive vessel (expressed as intravascular ultrasound [IVUS]-derived percent total atheroma volume [%TAV]), correlates with functional severity of intermediate stenosis of left anterior descending artery (LAD). METHODS: An IVUS study and fractional flow reserve (FFR) measurements performed in 130 patients with coronary angiographic intermediate stenosis of proximal or middle LAD. %TAV was calculated as the percentage of total vessel volume occupied by total atheroma volume on IVUS. RESULTS: A significant correlation was observed between %TAV and FFR (r=-0.71, p<0.001). Minimal lumen area (MLA) correlated moderately with FFR (r=0.54, p<0.001). The independent predictors of FFR<0.8 were %TAV (odds ratio [OR]: 1.29, 95% confidence interval [CI]=1.18-1.40, p<0.001) and MLA (OR: 0.37, 95% CI=0.16-0.85, p=0.019). A receiver-operating characteristic curve suggested %TAV >= 39.0% (sensitivity 85%, specificity 83% and area under curve [AUC]=0.90) and MLA <= 2.6mm(2) (sensitivity 72%, specificity 70% and AUC=0.75) as the best cut-off values for FFR<0.8. Forty-eight point five (48.5%) of total studied lesions (63/130) showed %TAV >= 39.0%. Eighty-four point four (84.4%) of lesions (38/45) with %TAV >= 39.0% and MLA <= 2.6mm(2), and 72.2% of lesions (13/18) with %TAV >= 39.0% and MLA>2.6mm(2), FFR was less than 0.8. CONCLUSIONS: Volumetric quantification of the atherosclerotic disease extent of the coronary artery, expressed as IVUS-derived %TAV, showed a strong correlation with FFR. Not only the segmental luminal narrowing but also the total plaque burden of conductive artery are major determinants for the presence of myocardial ischemia in intermediate stenosis of LAD. PMID- 25791092 TI - Composite outcome measures in a pragmatic clinical trial of chronic heart failure management: A comparative assessment. AB - BACKGROUND: A number of composite outcomes have been developed to capture the perspective of the patient, clinician and objective measures of health in assessing heart failure outcomes. To date there has been a limited examination in the composition of these outcomes. METHODS AND RESULTS: Three commonly used scoring systems in heart failure trials: Packer's composite, Patient Journey and the African American Heart Failure Trial (A-HeFT) scores were compared in assessing outcomes from the Which heart failure intervention is most cost effective & consumer friendly in reducing hospital care (WHICH(?)) Trial. Comparability and interpretability of these outcomes and the influence of each component to the final outcome were examined. Despite all three composite outcomes incorporating mortality, hospitalisation and quality of life (QoL), the contribution of each individual component to the final outcomes differed. The component with the most influence in deteriorating condition for the Packer's composite was hospitalisation (67.7%), while in Patient Journey it was QoL (61.5%) and for A-HeFT composite score it was mortality (45.4%). CONCLUSIONS: The contribution made by each component varied in subtle, but important ways. This study emphasises the importance of understanding the value system of the composite outcomes to enable meaningful interpretation of results. PMID- 25791093 TI - Prevalence and treatment of familial hypercholesterolaemia in Australian communities. PMID- 25791094 TI - Efficacy and safety of direct oral anticoagulants in patients undergoing cardioversion for atrial fibrillation: A systematic review and meta-analysis of the literature. AB - BACKGROUND: DOACs are increasingly used in patients with NVAF. Information on efficacy and safety of these compounds in patients undergoing electrical or pharmacological cardioversion is limited. Thus, we performed a systematic review and a meta-analysis of the literature to address this issue. METHODS: Randomized controlled trials comparing the efficacy and safety of DOACs and VKAs in patients with NVAF were systematically searched in Medline, Web of Science, Scopus, Cochrane, and EMBASE databases (up to September 2014). Pooled relative risk (RR) and the corresponding 95% confidence interval (CI) were calculated for each outcome. RESULTS: Four randomized controlled trials (3635 patients), for a total of 4517 cardioversions (2869 with DOACs and 1648 with VKAs), were included in the analysis. DOACs and VKAs appeared equally effective in the prevention of stroke/systemic embolism (0.41% vs 0.61%; RR: 0.73, 95% CI: 0.31, 1.72; P=0.48) and of post-cardiovascular death (0.52% vs 0.81%; RR: 0.73, 95% CI: 0.27, 2.03; P=0.55), with a similar risk of major bleeding complications (0.81% vs 0.60%; RR: 1.23, 95% CI: 0.55, 2.71). Heterogeneity among studies was generally absent. Furthermore, the Weighted Mean Incidence (WMI) of complications appeared very low in patients randomized to DOACs (WMI: 0.6% and 0.9% for stroke/systemic embolism and major bleeding, respectively). CONCLUSION: Our results suggest that DOACs are at least as effective and safe as VKAs in patients with NVAF undergoing to an electrical or pharmacological cardioversion. Thus, DOACs may be considered a valid and practical alternative to VKAs. PMID- 25791095 TI - Regression of severe bare metal stent restenosis: IVUS and OCT findings. PMID- 25791096 TI - Acute myocardial infarction after cilostazol use in a patient with systemic lupus erythematosus. PMID- 25791097 TI - KCa1.1-mediated frequency-dependent central and peripheral neuromodulation via Ah type baroreceptor neurons located within nodose ganglia and nucleus of solitary tract of female rats. PMID- 25791098 TI - Feasibility of a novel digital tool in automatic scoring of an online ECG examination. PMID- 25791099 TI - Multimodality imaging of cor triatriatum sinistrum diagnosed in an adult female. PMID- 25791100 TI - The Pavia Cardiac Arrest REgistry - Pavia CARE. It's time for Cardiologists to be engaged in cardiac arrest. PMID- 25791101 TI - Figure-of-eight artifact after successful percutaneous closure of left atrial appendage. PMID- 25791102 TI - Uncommon ventricular tachycardia originating from an interventricular septal aneurism: Mapping and ablation guided by real-time image integration. PMID- 25791103 TI - Relationship between the epicardial fat thickness and total atrial conduction time in patients with lone paroxysmal atrial fibrillation. PMID- 25791104 TI - Dose apolipoprotein AV has influence on the regulation of fatty acids and triglyceride metabolism in cardiomyocyte in case of obesity. PMID- 25791105 TI - "Asymptomatic" persistent or permanent atrial fibrillation: A misnomer in selected patients. PMID- 25791107 TI - MicroRNAs: New players in pharmacotherapy for ischemic heart diseases? PMID- 25791106 TI - Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia. PMID- 25791108 TI - Effects of dronedarone on ventricular repolarization and repolarization dynamics in patients with preserved left ventricular systolic function. PMID- 25791109 TI - Correlation between intrarenal arterial stiffness and exercise tolerance in systemic sclerosis patients without renal and cardiopulmonary impairment: The role of the microvascular damage. PMID- 25791110 TI - Serum uric acid as a predictor for cardiovascular and all-cause mortality in women versus men. PMID- 25791111 TI - Fractured mobile flap in pulmonary artery: One of possible mechanisms for residual or recurrent pulmonary hypertension after pulmonary endarterectomy. PMID- 25791112 TI - High dose atorvastatin therapy yields a better carotid atherosclerosis improvement in Chinese patients. PMID- 25791113 TI - Risk for cardiovascular disease among Seventh-day Adventists and Baptists in Denmark, 1977-2009. PMID- 25791114 TI - Provocable coved-type ST-segment elevation in right precordial leads as initial ECG feature after successful resuscitation with developing arrhythmogenic cardiomyopathy. PMID- 25791115 TI - Response to Bandera et al. PMID- 25791116 TI - Safety and Immunogenicity of a Live Attenuated Tetravalent Dengue Vaccine Candidate in Flavivirus-Naive Adults: A Randomized, Double-Blinded Phase 1 Clinical Trial. AB - BACKGROUND: Dengue viruses (DENVs) infect >300 million people annually, causing 96 million cases of dengue disease and 22 000 deaths [1]. A safe vaccine that protects against DENV disease is a global health priority [2]. METHODS: We enrolled 72 flavivirus-naive healthy adults in a phase 1 double-blinded, randomized, placebo-controlled dose-escalation trial (low and high dose) of a live attenuated recombinant tetravalent dengue vaccine candidate (TDV) given in 2 doses 90 days apart. Volunteers were followed for safety, vaccine component viremia, and development of neutralizing antibodies to the 4 DENV serotypes. RESULTS: The majority of adverse events were mild, with no vaccine-related serious adverse events. Vaccinees reported injection site pain (52% vs 17%) and erythema (73% vs 25%) more frequently than placebo recipients. Low levels of TDV serotype 2 (TDV-2), TDV-3, and TDV-4 viremia were observed after the first but not second administration of vaccine. Overall seroconversion rates and geometric mean neutralization titers after 2 doses were 84.2% and 54.1, respectively, for DENV serotype 1 (DENV-1); 92.1% and 292.8, respectively, for DENV-2; 86.8% and 32.3, respectively, for DENV-3; and 71.1% and 15.0, respectively, for DENV-4. More than 90.0% of high-dose recipients had trivalent or broader responses. CONCLUSIONS: TDV was generally well tolerated, induced trivalent or broader neutralizing antibodies to DENV in most flavivirus-naive vaccinees, and is undergoing further development. CLINICAL TRIALS REGISTRATION: NCT01110551. PMID- 25791117 TI - Natural Killer Cell Characteristics in Patients With Chronic Hepatitis B Virus (HBV) Infection Are Associated With HBV Surface Antigen Clearance After Combination Treatment With Pegylated Interferon Alfa-2a and Adefovir. AB - BACKGROUND: The role of natural killer (NK) cells in the process of hepatitis B virus (HBV) surface antigen (HBsAg) clearance and whether their phenotype is related to treatment outcome in patients with chronic hepatitis B are currently unknown. METHODS: Patients with chronic hepatitis B (HBV DNA load, >17 000 IU/mL) were treated with pegylated interferon alfa-2a and adefovir for 48 weeks. NK cell phenotype and function were analyzed in 7 responders (defined as individuals with HBsAg clearance by week 72; 3 HBV e antigen [HBeAg]-positive and 4 HBeAg negative), 7 matched nonresponders, and 7 healthy controls. Subsequently, 34 baseline samples from HBeAg-positive patients with chronic hepatitis B were analyzed. RESULTS: During treatment, the percentage and absolute number of CD56(bright) NK cells increased significantly, whereas the percentage and absolute number of CD56(dim) NK cells decreased. At baseline, responders had a significantly lower expression of chemokine receptor CX3CR1 on CD56(bright) NK cells and inhibitory receptor NKG2A on CD56(dim) NK cells, compared with nonresponders. In addition, responders had higher CD56(bright) TRAIL expression and interferon gamma production at end of treatment. These baseline differences were not found in HBeAg-positive patients who had HBeAg seroconversion without HBsAg clearance. CONCLUSIONS: Combination therapy significantly influences NK cell phenotype and function. Differences between patients with chronic hepatitis B with HBsAg clearance and nonresponders suggest that NK cells play a role in the clearance of HBsAg during interferon-based combination therapy. PMID- 25791118 TI - Characterization of Immune Failure by Monocyte Activation Phenotypes in HIV Infected Patients Receiving Antiretroviral Therapy. PMID- 25791119 TI - Expression patterns of CD200 and CD148 in leukemic B-cell chronic lymphoproliferative disorders and their potential value in differential diagnosis. AB - Different combinations of biomarkers analyzed by flow cytometry are critical for the accurate diagnosis of leukemic B-cell chronic lymphoproliferative disorders (B-CLPDs). We investigated CD200 and CD148 expression patterns of blood or bone marrow from 374 cases of B-CLPD by multicolor flow cytometry. Our results showed that CD200 and CD148 expression patterns distinguished different types of B-CLPD. CD200 mean fluorescence intensity (MFI) or CD148 MFI had a high sensitivity and specificity to differentiate mantle cell lymphoma (MCL) from chronic lymphocytic leukemia (CLL). Furthermore, CD148 MFI/CD200 MFI ratio>4.79 produced a specificity of 94.46% (95% confidence interval [CI]: 91.04-96.87%) and a sensitivity of 100% (95% CI: 88.78-100.0%) in establishing the diagnosis of MCL in differential diagnosis between MCL and CLL. We therefore conclude that the combination of CD200 and CD148 may have a potential differential diagnostic value in leukemic B-CLPDs, especially between CLL and MCL. PMID- 25791120 TI - NPM-RAR binding to TRADD selectively inhibits caspase activation, while allowing activation of NFkappaB and JNK. AB - The t(5;17) variant of acute promeylocytic leukemia (APL) expresses a fusion of nucleophosmin (NPM) with the retinoic acid receptor alpha (RARA). We have previously shown that NPM-RAR is a binding partner of the tumor necrosis factor (TNF) receptor type-I-associated DEATH domain protein, TRADD. Binding of TNF to its receptor, TNF-R, induces recruitment of TRADD, and subsequent recruitment of a cascade of proteins that ultimate activate caspase 3, nuclear factor kappaB (NFkappaB) and c-Jun N-terminal kinase (JNK). We have previously shown that NPM RAR interaction with TRADD blocks TNF activation of caspase 3, caspase 8, poly(ADP-ribose) polymerase (PARP) cleavage and, ultimately, apoptosis. We now report that NPM-RAR expression is permissive for TNF activation of NFkappaB and JNK. We propose that inhibition of TNF activation of apoptosis, while preserving TNF activation of NFkappaB and JNK pathways that stimulate cell growth and survival, represents a novel mechanism through which NPM-RAR contributes to development of the leukemic phenotype. PMID- 25791121 TI - Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone lymphoma: a Fondazione Italiana Linfomi phase II study. AB - Rituximab(r) provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in patients with SMZL who were either untreated or were splenectomized but had shown disease progression within 1 year after splenectomy. Treatment consisted of six courses of Rituximab with cyclophosphamide, vincristine, non pegylated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-year progression-free survival and overall survival were 54% and 72%, respectively. Toxicity was substantial (grade>=3 neutropenia: 26%; grade>=3 infections: 8%). Of the 15 deaths, two occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, four to secondary neoplasia, one to sepsis, one to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation. PMID- 25791123 TI - Brief Report: Influence of Physical Activity on Sleep Quality in Children with Autism. AB - Sleep-related problems are often documented in children with Autism Spectrum Disorders (ASD). This study examined physical activity as a variable that might influence sleep quality in children with ASD. Ten children, ages 9-16 years, were asked to wear accelerometer devices for 7 days in order to track objective measures of activity and sleep quality. Parents of the children also completed the Child's Sleep Habits Questionnaire and maintained a daily sleep log while their child wore the device. This study demonstrated that though over half of the children were identified as having at least one sleep-related problem, their activity levels were significantly related to their sleep patterns. Specifically, the more physically active children had overall higher sleep quality. PMID- 25791124 TI - Mother-Child Interaction as a Window to a Unique Social Phenotype in 22q11.2 Deletion Syndrome and in Williams Syndrome. AB - Mother-child interactions in 22q11.2 Deletion syndrome (22q11.2DS) and Williams syndrome (WS) were coded for maternal sensitivity/intrusiveness, child's expression of affect, levels of engagement, and dyadic reciprocity. WS children were found to express more positive emotions towards their mothers compared to 22q11.2DS children and those with developmental delay in a conflict interaction. During the same interaction, dyads of 22q11.2DS children were characterized by higher levels of maternal intrusiveness, lower levels of child's engagement and reduced reciprocity compared to dyads of typically developing children. Finally, 22q11.2DS children with the COMT Met allele showed less adaptive behaviors than children with the Val allele. Dyadic behaviors partially coincided with the distinct social phenotypes in these syndromes and are potential behavioral markers of psychopathological trajectory. PMID- 25791126 TI - Near-infrared-induced electron transfer of an uranyl macrocyclic complex without energy transfer to dioxygen. AB - Photoexcitation of dichloromethane solutions of an uranyl macrocyclic complex with cyclo[1]furan[1]pyridine[4]-pyrrole () at the near-infrared (NIR) band (1177 nm) in the presence of electron donors and acceptors resulted in NIR-induced electron transfer without producing singlet oxygen via energy transfer. PMID- 25791125 TI - Employment Interventions for Individuals with ASD: The Relative Efficacy of Supported Employment With or Without Prior Project SEARCH Training. AB - This paper presents findings from a retrospective observational records review study that compares the outcomes associated with implementation of supported employment (SE) with and without prior Project SEARCH with ASD Supports (PS-ASD) on wages earned, time spent in intervention, and job retention. Results suggest that SE resulted in competitive employment for 45 adults with ASD. Twenty-five individuals received prior intervention through PS-ASD while the other 20 individuals received SE only. Individuals in this sample who received PS-ASD required fewer hours of intervention. Additionally, individuals in the PS-ASD group achieved a mean higher wage and had higher retention rates than their peers who received SE only. Further research with a larger sample is needed to confirm these findings. PMID- 25791127 TI - The papers we choose to publish. PMID- 25791128 TI - Macronutrient intake and stomach cancer. AB - PURPOSE: This study examines the association between intake of selected macronutrients and the risk of stomach cancer in a Northern American population. METHODS: Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces by 1,181 incident, histologically confirmed cases of stomach cancer and 5,039 population controls. Information on nutrient intake was obtained using a food frequency questionnaire. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were derived through unconditional logistic regression to adjust for potential confounders, including an estimate of total energy intake. RESULTS: Intakes of total fat, saturated fat, and cholesterol were significantly associated with the risk of stomach cancer: The ORs for the highest versus the lowest quartile were 1.58 (95% CI 1.13-2.20), 1.86 (95% CI 1.37-2.52), and 1.75 (95% CI 1.36-2.25), respectively. Total fiber was inversely associated with stomach cancer (p = 0.03). The positive associations with intake of total fat and saturated fat were apparently stronger in women, overweight or obese subjects, and ever smokers. Saturated fat was specifically associated with increased risk of gastric cardia cancer, with an OR of 3.31 (95% CI 1.48-7.43). CONCLUSIONS: A diet high in saturated fat appears to increase the risk of stomach cancer, particularly among obese subjects and for gastric cardia cancer. PMID- 25791130 TI - Associations between objective and self-reported physical activity and vitamin D serum levels in the US population. AB - PURPOSE: Both low levels of vitamin D and of physical activity are associated with all-cause, cancer, and cardiovascular disease mortality. There is some evidence based on self-reported activity levels that physically more active individuals have higher vitamin D serum levels. The aim was to investigate associations between objectively measured and self-reported physical activity, respectively, and vitamin D serum concentrations in the US population. METHODS: Data from NHANES 2003-2006 (n = 6,370, aged >= 18 years) were analyzed using multiple regression analyses. A total of 6,370 individuals aged 18 years and older with valid data on vitamin D serum levels and physical activity were included. Objective physical activity was assessed using accelerometers; self reported physical activity was based on the NHANES physical activity questionnaire. RESULTS: An increase of 10 min of objectively measured and self reported moderate-to-vigorous activities per day was associated with an increase in circulating vitamin D of 0.32 ng/ml (95% CI 0.17, 0.48) and of 0.18 ng/ml (95% CI 0.12, 0.23), respectively. The odds ratio for being vitamin D deficient (< 20 ng/ml) if being insufficiently active compared with being sufficiently active was 1.32 (1.11, 1.57). Associations were not stronger for self-reported outdoor activities compared with indoor activities. CONCLUSIONS: Physical activity may be a way to achieve higher vitamin D serum levels in the population. Factors other than sun exposure that may be responsible for higher vitamin D levels in more active individuals need further investigation. PMID- 25791129 TI - Childhood folate, B6, B12, and food group intake and the risk of childhood brain tumors: results from an Australian case-control study. AB - PURPOSE: The etiology of childhood brain tumors (CBT) is poorly understood, but dietary factors could be involved. In this case-control study of CBT, the possible associations of childhood intake of dietary and supplemental folate, vitamin B6, and vitamin B12 with the risk of CBT were investigated, along with various food groups. METHODS: Cases diagnosed between 2005 and 2010 were identified from 10 pediatric oncology centers in Australia and controls by nationwide random-digit dialling. For study children of ages 3-14 years, diet in the year before diagnosis (or recruitment) was assessed using food frequency questionnaires. Folate intake was adjusted for bioavailability, and dietary micronutrient intake was energy-adjusted. Micronutrients and food groups were analyzed using logistic regression adjusting for relevant confounders. Principal components analysis was conducted to assess food group intake patterns for analysis. RESULTS: Food and micronutrient data were available for 216 cases and 523 controls. Folate intake was associated with a reduced risk of CBT overall (odds ratio for highest tertile vs. lowest: 0.63, 95% confidence interval 0.41, 0.97) and particularly low-grade gliomas (odds ratio for highest tertile vs. lowest: 0.52, 95% confidence interval 0.29, 0.92). Vitamin B6 and B12 intake was not associated with CBT risk, nor was processed meat. CONCLUSIONS: High folate intake during childhood may reduce the risk of CBT. This potentially important finding needs to be corroborated in other studies. If replicated, these results could have important implications for public health recommendations regarding diet during childhood. PMID- 25791131 TI - Expression and clinical significance of microRNA-1246 in human oral squamous cell carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that may function as oncogenes or tumor suppressors. Previous studies have shown that the expression level of miR-1246 was enhanced in multiple types of cancers. However, the expression of miR-1246 in human oral squamous cell carcinoma (OSCC) and its prognostic values remain unclear. MATERIAL AND METHODS: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to analyze the expression of miR-1246 in 106 pairs of matched normal and tumor tissue samples. The chi-square test was used to examine the associations between miR-1246 expression and the clinicopathological characters. The survival curves were constructed by the Kaplan-Meier method. The influence of each clinical variable on survival was examined by the Cox multivariate regression analysis. RESULTS: The expression level of miR-1246 was significantly higher in tumor tissues and oral cancer cell lines than in normal controls (p<0.01). High expression of miR 1246 was found to significantly correlate with nodal status (p=0.015), TNM stage (p=0.005), and tumor grade (p=0.002). Enhanced miR-1246 correlated significantly with patient survival (p<0.01). In multivariate analysis, we found that miR-1246 expression was an independent prognostic factor of poor patient survival (p= 0.036; HR=2.82; 95% CI=1.07-7.43). CONCLUSIONS: High miR-1246 expression is associated with poor prognosis in OSCC and may serve as a novel prognostic marker in OSCC. PMID- 25791132 TI - Uncommon CT imaging of the hepatic falciform artery in patients presenting with very unusual variants of gastrointestinal arteries: report of two cases. AB - The hepatic falciform artery (HFA) may be found in 68% of subjects in post-mortem dissections. It is well known by interventional radiologists who perform selective hepatic angiography. The reason essentially results from the potential supraumbilical skin complications which may produce by the distribution of chemotherapeutic agents through the HFA after transcatheter chemoinfusion or chemoembolization for liver tumors. Nevertheless, the spontaneous visualization of the HFA remains very unusual in current abdominal CT practice. We hereby report the demonstration of a patent HFA during conventional abdominal CT in two patients presenting without liver disease but in which very unusual variants of the gastrointestinal arteries were simultaneously found. The first patient had a common celiomesenteric trunk and the second had a severe compression of both the celiac trunk and superior mesenteric artery by the median arcuate ligament of the diaphragm. We shortly review the literature about these rare variants. We hypothesize that the HFA was spontaneously visible in our patients because of hypertrophy due supplying collateralization. PMID- 25791133 TI - Low early B-cell factor 1 (EBF1) activity in human subcutaneous adipose tissue is linked to a pernicious metabolic profile. AB - AIM: Recently, in both human and murine white adipose tissue (WAT), transcription factor early B-cell factor 1 (EBF1) has been shown to regulate adipocyte differentiation, adipose morphology and triglyceride hydrolysis (lipolysis). This study investigated whether EBF1 expression and biological activity in WAT is related to different metabolic parameters. METHODS: In this cross-sectional study of abdominal subcutaneous WAT, EBF1 protein levels were examined in 18 non-obese subjects, while biological activity was determined in 56 obese and non-obese subjects. Results were assessed by anthropometric measures and blood pressure as well as by plasma lipid levels and insulin sensitivity. RESULTS: EBF1 protein levels were negatively associated with waist circumference (r=-0.56; P=0.015), but not with body mass index (BMI) or body fat (P=0.10-0.29). Biological activity of EBF1 correlated negatively with plasma triglycerides (r=-0.46; P=0.0005) and plasma insulin (r=-0.39; P=0.0027), but positively with plasma HDL cholesterol (r=0.48; P=0.0002) and insulin sensitivity, as assessed by intravenous insulin tolerance test (r=0.64; P<0.0001). These relationships, except for plasma insulin, remained statistically significant after adjusting for BMI and adipose morphology. EBF1 activity was not associated with age, systolic/diastolic blood pressure or total plasma cholesterol (P=0.17-0.48). In contrast to EBF1 activity, after adjusting for BMI, EBF1 mRNA levels displayed only an association with plasma triglycerides. CONCLUSION: Low EBF1 protein expression and activity in abdominal subcutaneous WAT is a BMI-independent marker for several traits associated with the metabolic syndrome. However, whether EBF1 constitutes a novel treatment target remains to be demonstrated. PMID- 25791134 TI - Displacement of ethene from the decamethyltitanocene-ethene complex with internal alkynes, substituent-dependent alkyne-to-allene rearrangement, and the electronic transition relevant to the back-bonding interaction. AB - The titanocene-ethene complex [Ti(II)(eta(2)-C2H4)(eta(5)-C5Me5)2] (1) with simple internal alkynes R(1)C=CR(2) gives complexes [Ti(II)(eta(2) R(1)C=CR(2))(eta(5)-C5Me5)2] {R(1), R(2): Ph, Ph (3), Ph, Me (4), Me, SiMe3 (5), Ph, SiMe3 (6), t-Bu, SiMe3 (7), and SiMe3, SiMe3 (8). In contrast, alkynes with R(1) = Me and R(2) = t-Bu or i-Pr afford allene complexes [Ti(II)(eta(2) CH2=C=CHR(2))(eta(5)-C5Me5)2] (11) and (12), whereas for R(2) = Et a mixture of alkyne complex (13A) and minor allene (13) is obtained. Crystal structures of 4, 6, 7 and 11 have been determined; the latter structure proved the back-bonding interaction of the allene terminal double bond. Only the synthesis of 8 from 1 was inefficient because the equilibrium constant for the reaction [1] + [Me3SiC=CSiMe3] ? [8] + [C2H4] approached 1. Compound 9 (R(1), R(2): Me), not obtainable from 1, together with compounds 3-6 and 10 (R(1), R(2): Et) were also prepared by alkyne exchange with 8, however this reaction did not take place in attempts to obtain 7. Compounds 1 and 3-9 display the longest-wavelength electronic absorption band in the range 670-940 nm due to the HOMO -> LUMO transition. The assignment of the first excitation to be of predominantly a b2 -> a1 transition was confirmed by DFT calculations. The calculated first excitation energies for 3-9 followed the order of hypsochromic shifts of the absorption band relative to 8 that were induced by acetylene substituents: Me > Ph ? SiMe3. Computational results have also affirmed the back-bonding nature in the alkyne-to metal coordination. PMID- 25791135 TI - Rate-dependent elastic hysteresis during the peeling of pressure sensitive adhesives. AB - The modelling of the adherence energy during peeling of Pressure Sensitive Adhesives (PSA) has received much attention since the 1950's, uncovering several factors that aim at explaining their high adherence on most substrates, such as the softness and strong viscoelastic behaviour of the adhesive, the low thickness of the adhesive layer and its confinement by a rigid backing. The more recent investigation of adhesives by probe-tack methods also revealed the importance of cavitation and stringing mechanisms during debonding, underlining the influence of large deformations and of the related non-linear response of the material, which also intervenes during peeling. Although a global modelling of the complex coupling of all these ingredients remains a formidable issue, we report here some key experiments and modelling arguments that should constitute an important step forward. We first measure a non-trivial dependence of the adherence energy on the loading geometry, namely through the influence of the peeling angle, which is found to be separable from the peeling velocity dependence. This is the first time to our knowledge that such adherence energy dependence on the peeling angle is systematically investigated and unambiguously demonstrated. Secondly, we reveal an independent strong influence of the large strain rheology of the adhesives on the adherence energy. We complete both measurements with a microscopic investigation of the debonding region. We discuss existing modellings in light of these measurements and of recent soft material mechanics arguments, to show that the adherence energy during peeling of PSA should not be associated to the propagation of an interfacial stress singularity. The relevant deformation mechanisms are actually located over the whole adhesive thickness, and the adherence energy during peeling of PSA should rather be associated to the energy loss by viscous friction and by rate-dependent elastic hysteresis. PMID- 25791137 TI - Here/In this issue and there/abstract thinking: along a continuum. PMID- 25791136 TI - LEP -2548G>A Polymorphism of the Leptin Gene and Its Influence on the Lipid Profile in Obese Individuals. AB - BACKGROUND/AIM: We studied the molecular pathogenesis of obesity, involving complex interactions between environmental and genetic factors, with a focus on the leptin gene. It was our aim to characterize the LEP -2548G>A leptin polymorphism and lipid profile in obese and normal-weight individuals. METHODS: A total of 212 individuals were divided into the study group including 136 obese patients (body mass index, BMI>=30) and the control group with 76 normal-weight individuals (BMI>18.5 and <=24.9). DNA was amplified by polymerase chain reaction and restriction fragment length polymorphism. The lipid profile was analyzed by enzymatic colorimetric methods. The level of significance was set at p<0.05. RESULTS: There was a prevalence of the GA genotype in both groups. However, comparative group analysis showed an association of the recessive model (AA+GA) with increased triglycerides (TG) and decreased high-density lipoprotein cholesterol (HDL-C) levels in the study group. CONCLUSION: This study did not confirm an association between obesity and the LEP -2548G>A polymorphism. However, AA+GA genotypes, in the presence of obesity, seem to contribute to a reduction in HDL-C and an increase in TG compared with normal-weight individuals. This should be confirmed in further studies. PMID- 25791138 TI - Celebrity psychiatrists and science: time to close the gap. PMID- 25791139 TI - Collaborative mental health services using multiple technologies: the new way to practice and a new standard of practice? PMID- 25791140 TI - Meeting the intervention needs of military children and families. PMID- 25791141 TI - Attention-deficit/hyperactivity disorder is the extreme and impairing tail of a continuum. PMID- 25791144 TI - Group therapy for adolescents with attention-deficit/hyperactivity disorder: a randomized controlled trial. AB - OBJECTIVE: To determine the efficacy of group cognitive-behavioral therapy (CBT) on adolescents with attention-deficit/hyperactivity disorder (ADHD) who were in pharmacological treatment but still had persistent symptoms. METHOD: We conducted a multicenter, randomized, rater-blinded, controlled trial between April 2012 and May 2014 in a cohort of 119 adolescents (15-21 years of age). Participants were randomly assigned to 12 manualized group CBT sessions (n = 45) or a waiting list control group (n = 44). Primary outcomes were assessed by a blinded evaluator (ADHD Rating Scale [ADHD-RS], Clinical Global Impression Scale for Severity [CGI S], Global Assessment of Functioning [GAF]) before and after treatment, as well as by self-report and parent informant ratings. RESULTS: Of the initial 119 participants enrolled, 89 completed treatment. A mixed-effects model analysis revealed that participants who were assigned to the group CBT sessions experienced significantly reduced ADHD symptoms compared to the control group (ADHD-RS Adolescent: -7.46, 95% CI = -9.56 to -5.36, p < .001, d = 7.5; ADHD-RS Parents: -9.11, 95% CI = -11.48 to -6.75, p < .001, d = 8.38; CGI-S Self-Report: 0.68, 95% CI = -0.98 to -0.39, p < .001, d = 3.75; CGI-S Clinician: -0.79, 95% CI = -0.95 to -0.62, p < .001; d = 7.71). Functional impairment decreased significantly in the CBT group according to parents (Weiss Functional Impairment Scale -4.02, 95% CI = -7.76 to -0.29, p < .05, d = 2.29) and according to the blinded evaluator (GAF: -7.58, 95% CI = -9.1 to -6.05, p < .001, d = 7.51). CONCLUSION: Group CBT associated with pharmacological treatment is an efficacious intervention for reducing ADHD symptoms and functional impairment in adolescents. Clinical trial registration information-CBT Group for Adolescents With ADHD: a Randomized Controlled Trial; http://clinicaltrials.gov/; NCT02172183. PMID- 25791143 TI - Effectiveness of a telehealth service delivery model for treating attention deficit/hyperactivity disorder: a community-based randomized controlled trial. AB - OBJECTIVE: To test the effectiveness of a telehealth service delivery model for the treatment of children with attention-deficit/hyperactivity disorder (ADHD) that provided pharmacological treatment and caregiver behavior training. METHOD: The Children's ADHD Telemental Health Treatment Study (CATTS) was a randomized controlled trial with 223 children referred by 88 primary care providers (PCPs) in 7 communities. Children randomized to the experimental telehealth service model received 6 sessions over 22 weeks of combined pharmacotherapy, delivered by child psychiatrists through videoconferencing, and caregiver behavior training, provided in person by community therapists who were supervised remotely. Children randomized to the control service delivery model received treatment with their PCPs augmented with a telepsychiatry consultation. Outcomes were diagnostic criteria for ADHD and oppositional defiant disorder (ODD) and role performance on the Vanderbilt ADHD Rating Scale (VADRS) completed by caregivers (VADRS Caregivers) and teachers (VADRS-Teachers) and impairment on the Columbia Impairment Scale-Parent Version (CIS-P). Measures were completed at 5 assessments over 25 weeks. RESULTS: Children in both service models improved. Children assigned to the telehealth service model improved significantly more than children in the augmented primary care arm for VADRS-Caregiver criteria for inattention (chi(2)[4] = 19.47, p < .001), hyperactivity (chi(2)[4] = 11.91, p = .02), combined ADHD (chi(2)[4] = 14.90, p = .005), ODD (chi(2)[4] = 10.05, p = .04), and VADRS-Caregiver role performance (chi(2) [4] = 12.40, p = .01) and CIS P impairment (chi(2)[4] = 20.52, p < .001). For the VADRS-Teacher diagnostic criteria, children in the telehealth service model had significantly more improvement in hyperactivity (chi(2)[4] = 11.28, p = .02) and combined ADHD (chi(2)[4] = 9.72, p = .045). CONCLUSION: The CATTS trial demonstrated the effectiveness of a telehealth service model to treat ADHD in communities with limited access to specialty mental health services. Clinical trial registration information-Children's Attention Deficit Disorder With Hyperactivity (ADHD) Telemental Health Treatment Study; http://clinicaltrials.gov; NCT00830700. PMID- 25791142 TI - Assessment and management of treatment-refractory obsessive-compulsive disorder in children. AB - OBJECTIVE: To review the assessment and treatment of treatment-refractory pediatric obsessive-compulsive disorder (OCD). METHOD: A PubMed search was conducted to identify controlled trials in pediatric OCD. In addition, practice guidelines for the treatment of adults and children were further reviewed for references in treatment-refractory OCD across the lifespan. RESULTS: Pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT) were found to be effective treatments for pediatric OCD. Evidence suggests that CBT is also effective even in pediatric patients with refractory OCD symptoms. Antipsychotic augmentation, raising SSRI dosage, and several glutamate-modulating agents have some evidence of efficacy in adults with treatment-refractory OCD but have not been studied in pediatric populations. CONCLUSION: Several pharmacological treatment options exist for children with refractory OCD symptoms. However, little evidence-based data exist to guide treatment for our most challenging pediatric OCD patients. Further research is needed to evaluate the efficacy/side effect profile of commonly used interventions in treatment-refractory pediatric OCD. PMID- 25791145 TI - A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. AB - OBJECTIVE: To evaluate the efficacy, safety, and tolerability of the selective serotonin norepinephrine inhibitor duloxetine in children and adolescents with generalized anxiety disorder (GAD). METHOD: Youth aged 7 through 17 years with a primary diagnosis of GAD were treated with flexibly dosed duloxetine (30-120 mg daily, n = 135) or placebo (n = 137) for 10 weeks, followed by open-label duloxetine (30-120mg daily) for 18 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS), Clinical Global Impression-Severity (CGI Severity) scale, and Children's Global Assessment Scale (CGAS). Safety measures included the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as vital signs and electrocardiographic and laboratory monitoring. RESULTS: On the primary efficacy measure (PARS severity for GAD), mean improvement from baseline to 10 weeks was statistically significantly greater for duloxetine (-9.7) compared with placebo (-7.1, p <= .001, Cohen's d: 0.5). Symptomatic response (50% improvement on the PARS severity for GAD), remission (PARS severity for GAD <=8), and functional remission (CGAS >70) rates for the duloxetine group (59%, 50%, 37%, respectively) were statistically significantly greater than for the placebo group (42%, 34%, 24%, respectively, p <= .05) during acute treatment. Changes in systolic and diastolic blood pressure and discontinuation because of adverse events did not statistically differ between the duloxetine and placebo groups, although gastrointestinal-related adverse events, oropharyngeal pain, dizziness, cough, and palpitations were reported with a statistically significantly greater incidence for the duloxetine group compared with the placebo group. Mean changes in pulse and weight for the duloxetine group (+6.5 beats/min, -0.1 kg, respectively) were statistically different from the placebo group (+2.0 beats/min, +1.1 kg, respectively, p <= .01). CONCLUSION: In this study, duloxetine was superior to placebo on the primary efficacy analysis of mean change from baseline to week 10 on the PARS severity for GAD score, and safety results were consistent with the known safety profile of duloxetine in pediatric and adult patients. Clinical trial registration information-A Study in Pediatric Participants With Generalized Anxiety Disorder; http://clinicaltrials.gov; NCT01226511. PMID- 25791146 TI - Impact of parents' wartime military deployment and injury on young children's safety and mental health. AB - OBJECTIVE: Children are at risk for adverse outcomes during parental military deployments. We aim to determine the impact of parental deployment and combat injury on young children's postdeployment mental health, injuries, and maltreatment. METHOD: This is a population-based, retrospective cohort study of young children of active duty military parents during fiscal years (FY) 2006 to 2007, a high deployment period. A total of 487,460 children, 3 to 8 years of age, who received Military Health System care, were included. The relative rates of mental health, injury, and child maltreatment visits of children whose parents deployed and children of combat-injured parents were compared to children unexposed to parental deployment. RESULTS: Of the included children, 58,479 (12%) had a parent deploy, and 5,405 (1%) had a parent injured during deployment. Relative to children whose parents did not deploy, children of deployed and combat-injured parents, respectively, had additional visits for mental health diagnoses (incidence rate ratio [IRR] = 1.09 [95% CI = 1.02-1.17], IRR = 1.67 [95% CI = 1.47-1.89]), injuries (IRR = 1.07 [95% CI = 1.04-1.09], IRR = 1.24 [95% CI = 1.17-1.32]), and child maltreatment (IRR = 1.21 [95% CI = 1.11-1.32], IRR 2.30 = [95% CI 2.02-2.61]) postdeployment. CONCLUSION: Young children of deployed and combat-injured military parents have more postdeployment visits for mental health, injuries, and child maltreatment. Mental health problems, injuries, and maltreatment after a parent's return from deployment are amplified in children of combat-injured parents. Increased preventive and intervention services are needed for young children as parents return from deployments. Child health and mental health providers are crucial to effective identification of these at-risk children to ensure effective care provision. PMID- 25791147 TI - Psychiatric disorders and violence: a study of delinquent youth after detention. AB - OBJECTIVE: To examine the relationship between psychiatric disorders and violence in delinquent youth after detention. METHOD: The Northwestern Juvenile Project is a longitudinal study of youth from the Cook County Juvenile Temporary Detention Center (Chicago, Illinois). Violence and psychiatric disorders were assessed via self-report in 1,659 youth (56% African American, 28% Hispanic, 36% female, aged 13-25 years) interviewed up to 4 times between 3 and 5 years after detention. Using generalized estimating equations and logistic regression, we examined the following: the prevalence of violence 3 and 5 years after detention; the contemporaneous relationships between psychiatric disorders and violence as youth age; and whether the presence of a psychiatric disorder predicts subsequent violence. RESULTS: Rates of any violence decreased between 3 and 5 years after detention, from 35% to 21% (males), and from 20% to 17% (females). There was a contemporaneous relationship between disorder and violence. Compared to the group with no disorder, males and females with any disorder had greater odds of any violence (adjusted odds ratio [AOR] = 3.0, 95% CI = 1.9-4.7, and AOR = 4.4, 95% CI = 3.0-6.3, respectively). All specific disorders were associated contemporaneously with violence, except for major depressive disorder/dysthymia among males. Substance use disorders predicted subsequent violence. Males with other drug use disorder and females with marijuana use disorder 3 years after detention had greater odds of any violence 2 years later (AOR = 3.4, 95% CI = 1.4 8.2, and AOR = 2.0, 95% CI = 1.1-3.8, respectively). CONCLUSION: Aside from substance use disorders, the psychiatric disorders studied may not be useful markers of subsequent violence. Violence assessment and reduction must be key components of ongoing psychiatric services for high-risk youth. PMID- 25791148 TI - Antenatal maternal anxiety predicts variations in neural structures implicated in anxiety disorders in newborns. AB - OBJECTIVE: Antenatal maternal anxiety predicts offspring neurodevelopment and psychopathology, although the degree to which these associations reflect postnatal influences is unclear. To limit this possibility, we assessed newborn neuronal microstructures using diffusion tensor imaging (DTI) and assessed neonatal microstructure variation in relation to antenatal anxiety and in prediction of infant socio-emotional behavior at age 1 year. METHOD: Dyads were drawn from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort, and included mothers who completed the Speilberger State-Trait Anxiety Inventory (STAI) at 26 weeks gestation (scoring >90, n = 20; scoring <70, n = 34) and their neonates (5-17 days postnatal) who took part in DTI. RESULTS: Antenatal anxiety predicted variation in fractional anisotropy (FA) of regions important to cognitive-emotional responses to stress (i.e., the right insula and dorsolateral prefrontal cortex), sensory processing (e.g., right middle occipital), and socio emotional function (e.g., the right angular gyrus, uncinate fasciculus, posterior cingulate, and parahippocampus). In a subset of infants with Infant Toddler Socio Emotional Assessment (ITSEA) data, some of these right lateralized clusters predicted infant internalizing (e.g., insula: beta = 0.511, p = .03) but not externalizing behavior 1 year later, although these analyses failed to withstand the correction for multiple comparisons. CONCLUSION: These findings suggest the need for larger-scale investigations of the role that corticolimbic structures play in regulating cognitive-emotional responses to threat, and potentially in mediating the cross-generational transmission of anxiety, as well as in underscoring the importance of early mother-infant intervention programs. PMID- 25791150 TI - In memoriam: E. James Anthony, MD, FRCPsych (1916-2014). PMID- 25791149 TI - Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) traits in children and clinical ADHD. AB - OBJECTIVE: Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample. METHOD: Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case control status and severity of disorder in the clinical sample. RESULTS: Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08-1.28], p = .0003), higher ADHD symptom severity (beta = 0.29 [95% CI = 0.04-0.54], p = 0.02), and symptom domain severity in the clinical sample. CONCLUSION: This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD. PMID- 25791151 TI - Cocaine-induced isolated right ventricular infarction. PMID- 25791152 TI - The inadequacies of community consultation in emergency medicine research: a proposal for revising the rule. PMID- 25791153 TI - Initial serum lactate level is associated with inpatient mortality in patients with community-acquired pneumonia. AB - STUDY OBJECTIVE: The aim of the present study was to investigate the prognostic value of the initial serum lactate level in patients with community-acquired pneumonia (CAP). METHODS: We collected data on hospitalized adult patients with CAP via the study hospital emergency department between October 2012 and September 2013. Demographics, comorbidities, and physiologic and laboratory variables including initial C-reactive protein (CRP) and serum lactate level were extracted from the electronic medical record. The primary outcome was inpatient mortality. Comparisons between survivors and nonsurvivors were performed, and multivariable logistic regression analyses were constructed as dependent variables of both continuous and categorical varieties. RESULTS: A total of 397 patients were enrolled, and the mortality cases were 46 (11.6%). The mean lactate level was 1.7 +/- 1.4 mmol/L and was significantly higher in the nonsurvivor group than in the survivor group (2.4 +/- 2.2 mmol/L vs 1.6 +/- 1.2 mmol/L). In the multivariable logistic regression model for inpatient mortality constructed using lactate, CRP, and laboratory variables of pneumonia severity index (PSI), lactate and CRP remained as significant factors, but laboratory variables of PSI were not. In other multivariable logistic regression models for the outcome constructed using collected laboratory variables and PSI, lactate remained as a significant factor (adjusted odds ratio, 1.24; 95% confidence interval, 1.01 1.53; P = .042 by continuous variable; adjusted odds ratio of third tertile, 2.60; 95% confidence interval, 1.02-6.66; P = .046 by category variable). C reactive protein and albumin were also left as significant factors. CONCLUSIONS: The initial serum lactate level is independently associated with mortality in hospitalized patients with CAP. However, laboratory variables of PSI or others were not, except CRP and albumin. PMID- 25791155 TI - Highly conductive Li garnets by a multielement doping strategy. AB - Highly conductive Li7La3Zr2O12 (LLZ) garnet-type solid electrolytes were further optimized to improve Li-ion conduction by La(3+)-sites substitution with Ba(2+) and Zr(4+)-sites substitution with Ta(5+) and Nb(5+). Garnet-structured metal oxides of the nominal chemical compositions Li6.65La2.75Ba0.25Zr1.4Ta0.5Nb0.1O12, Li6.4La3Zr1.4Ta0.6-xNbxO12 (x = 0, 0.1, 0.2, and 0.3), and the parent LLZ, as a reference, were prepared via conventional solid-state reaction to investigate the effect of multielement doping on ionic conductivity. The phase formation, morphology, and Li ion conductivity were characterized using powder X-ray diffraction (PXRD), scanning electron microscopy, and alternating current impedance spectroscopy methods, respectively. In addition, solid-state (27)Al and (7)Li magic-angle spinning (MAS) NMR was used to study the effect of "Al doping" on the investigated multielement doped Li-stuffed garnet metal oxides. All the prepared samples obtained the cubic garnet-type structure (space group: Ia3d; No. 230) at 1150 degrees C, similar to that of cubic LLZ. Except for Li6.4La3Zr1.4Ta0.6O12, all the members show Al content by Al MAS NMR. However, it was not possible to detect Al-based impurity phases using PXRD in any of the investigated garnets. Among the samples investigated in this work, "Al-free" Li6.4La3Zr1.4Ta0.6O12 demonstrated a bulk Li ion conductivity of 0.72 mS cm(-1) at 25 degrees C, with apparent activation energy of 0.26 eV, significantly higher than the parent LLZ. PMID- 25791154 TI - Combining transtracheal catheter oxygenation and needle-based Seldinger cricothyrotomy into a single, sequential procedure. AB - BACKGROUND: Needle-based cricothyrotomy is a common procedure for emergency department patients requiring an emergent surgical airway. Percutaneous transtracheal jet ventilation is well studied to provide oxygenation. We propose to combine these procedures into a novel, single, and sequential procedure. METHODS: This study was a prospective manikin/human cadaver procedural feasibility study performed at a medical education center. Forty-eight emergency medicine attending physicians and fellows performed the procedure on a single TraumaMan (Simulab Corporation, Seattle, WA), and 26 were randomly selected to perform the procedure on fresh, unfixed human cadavers. The procedure is as follows: 15 gauge/6F catheter-over-needle punctures cricothyroid membrane, needle is removed, and Enk oxygen flow modulator is attached to the catheter (start to oxygenation). The Enk set is detached, a guide wire introduced, and Seldinger cricothyrotomy is performed (oxygenation to cricothyrotomy). Start-to oxygenation, oxygenation-to-cricothyrotomy, and start-to-cricothyrotomy times were recorded. Manikin procedures were verified by direct visualization, and cadaver procedures were verified by video laryngoscopy. RESULTS: All attempts were included in data analysis, and there was a 100% first-pass success rate. For the manikin trials, median start-to-oxygenation, oxygenation-to-cricothyrotomy, and start-to-cricothyrotomy times with interquartile ranges were 11 (8.5-13), 48 (42-57), and 59 (53-69) seconds, respectively. For the cadaver trials, median start-to-oxygenation, oxygenation-to-cricothyrotomy, and start-to-cricothyrotomy times with interquartile ranges were 12 (10-15), 59 (47-76), and 71 (61-94) seconds, respectively. Student t tests showed significant differences in start-to oxygenation and oxygenation-to-cricothyrotomy times (P < .01) within the manikin and cadaver groups. CONCLUSION: Percutaneous transtracheal jet ventilation and needle-based Seldinger cricothyrotomy can be performed by emergency medicine physicians, and a single, sequential procedure may significantly reduce time to oxygenation for patients already undergoing surgical cricothyrotomy. PMID- 25791156 TI - Phospho-p38 MAPK expression in COPD patients and asthmatics and in challenged bronchial epithelium. AB - BACKGROUND: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. OBJECTIVES: To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. METHODS: Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. RESULTS: No significant differences in p p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p < 0.003) and control non-smokers (p < 0.05). Hydrogen peroxide (H2O2), cytomix (tumour necrosis factor-alpha + IL-1beta + interferon-gamma) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKalpha mRNA was significantly increased after H2O2 and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H2O2, cytomix or LPS treatments. CONCLUSION: p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations. PMID- 25791157 TI - NSAID-induced small intestinal damage--roles of various pathogenic factors. AB - BACKGROUND/AIMS: NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. METHODS: Studies were performed in experimental animals. RESULTS: Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE2, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. CONCLUSION: These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs. PMID- 25791158 TI - The Last Breath: A MUCT-based method for investigating the tracheal system in Hexapoda. AB - In recent years, MUCT-based studies of the insect tracheal system have become an increasingly important area of research. Nevertheless, the methods proposed in previous research for investigating the respiratory system in the three dimensional space were described and tested based on a relatively small number of specimens. Additionally, the individuals studied in all these cases represented only a single post-embryonic stadium - pupa or imago - of a particular insect species. Therefore, in the current situation it is difficult to predict the reliability and possible limitations of these methods. To address this problem we conducted a methodological study, during which we used 65 individuals representing larvae, pupae and imagines of the mealworm beetle (Tenebrio molitor). In addition to the protocol previously described, which implicated freezing as a killing technique, we also tested a novel one, which was based on ethyl acetate fumigation of the specimens studied. We included step-by-step guides for the manual and semiautomatic approaches in order to facilitate the digital visualization of the tracheal system. Our investigations enabled us to generate multiple models of the tracheal system of all post-embryonic stages of the mealworm beetle. The methods used proved to be minimally invasive, thus allowing for the application of post-scanning manipulations, such as drying with critical point dryer (CPD). This approach enabled us to merge different three dimensional models into a single picture and analyse the relationship of the tracheal system with other tissues (e.g., muscles, nervous system). We comprehensively discuss the advantages and possible limitations of the tested methods and provide practical suggestions for conducting the analyses on a wider scale. The visualizations presented in this publication are the first three dimensional models of the respiratory system using a representative of the extremely diverse order Coleoptera. PMID- 25791159 TI - Drop splashing induced by target roughness and porosity: The size plays no role. AB - Drop splash as a result of an impact onto a dry substrate is governed by the impact parameters, gas properties and the substrate properties. The splash thresholds determine the boundaries between various splash modes. Various existing models for the splash threshold are reviewed in this paper. It is shown that our understanding of splash is not yet complete. The most popular, widely used models for splash threshold do not describe well the available experimental data. The scientific part of this paper is focused on the description of drop prompt splash on rough and porous substrates. It is found that the absolute length scales of the substrate roughness, like Ra or Rz, do not have any significant effect on the splash threshold. It is discovered that on rough substrates the main influencing splash parameters are the impact Weber number and the characteristic slope of the roughness of the substrate. The drop deposition without splash on porous substrates is enhanced by the liquid modified Reynolds number. Surprisingly, it is not influenced by the pore size, at least for the impact parameters used in the experiments. Finally, an empirical correlation for the prompt splash on rough and porous substrates is proposed, based on a rather amount of experimental data. PMID- 25791160 TI - Identification of biomarkers for the prognosis of pancreatic ductal adenocarcinoma with miRNA microarray data. AB - BACKGROUND: The aim of this study was to explore the mechanism of chemotherapy resistance and to screen biomarkers of pancreatic ductal adenocarcinoma (PDAC). METHODS: MicroRNA (miRNA) expression profile data for GSE38781 were downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs between short-overall survival (OS) and long-OS patients were screened with the limma package in R. The function and protein-protein interaction (PPI) network of the miRNA target genes were further investigated. Finally, multivariate statistical analysis was performed to verify the significant miRNAs obtained in our work. RESULTS: In total, 66 miRNAs were identified to be differentially expressed. Gene ontology (GO) and pathway enrichment analysis showed that 163 miRNA target genes were mainly enriched in heart function, cancer development and angiogenesis. Ten nodes, including TGFBR1, TGFBR2, ACVR1 and SHC1, were found to be hub nodes in the PPI network. Multivariate statistical analysis showed 8 of the most significant miRNAs could completely distinguish the 2 groups of samples. Seven target genes (i.e., RET, ETS1, RHOA, NUMB, TIAM, ITGA5 and YY1) of the 8 significant miRNAs were found to be associated with control of cell fate decisions, T-cell lymphoma invasion and angiogenesis enhancement. CONCLUSIONS: The heart function-related pathway, cell cycle, immune system and angiogenesis may be dysregulated in patients with poorer prognosis. The significant nodes (e.g., TGFBR1, TGFBR2, ACVR1 and SHC1) in the PPI network may be potential biomarkers for predicting outcomes for patients with pancreatic cancer. The significant miRNAs and gene targets may be potential biomarkers or therapeutic targets for PDAC. PMID- 25791161 TI - Robustness of steady state recycling chromatography with an integrated solvent removal unit. AB - The robustness of a hybrid separation process where the performance of mixed recycle steady state recycling chromatography is enhanced by integrating it with a solvent removal unit is analysed theoretically and by means of numerical simulations. The equilibrium theory of chromatography is applied to derive equations for boundaries of feasible operating parameters in such a hybrid process. Visualization of the feasible operating parameter ranges helps in analysing the influence of various physical and process parameters of robustness of an operating point. It is observed that process robustness can be improved by adjusting the solvent removal capacity or the cut times. When the solvent removal capacity increases, the region of feasible cut times becomes narrower due to increased non-linearity of the system. This makes it more difficult to maintain robust operation. PMID- 25791162 TI - Symptoms alone may lead to inaccurate diagnosis in men with possible bladder outlet obstruction. PMID- 25791163 TI - Effects of Satureja khuzistanica essential oils in drinking water on mortality, production performance, water intake, and organ weights in broiler chickens reared under heat stress condition. AB - An experiment was conducted to examine the effects on mortality, production performance, water intake (WI), and organ weight of Satureja khuzistanica essential oil (SkEO) using 720 1-day-old Arian broiler chicks in a 42-day trial. Experimental treatments were addition of 0 (control(-)), 200, 300, 400, and 500 mg/L SkEO or 500 mg/L polysorbate 80 (control(+)) into drinking water. The birds were kept under natural ambient temperatures 4 to 6 degrees C above standard recommendation from days 22 to 42 of age. Addition of SkEO into drinking water at 200 and 500 mg/L decreased weight gain (P < 0.05) of the birds from days 29 to 35 of age with no differences in feed intake (FI) and feed conversion ratio (FCR) compared to control groups (P > 0.05). Supplementation of drinking water with 200, 300, 400, and 500 mg/L SkEO resulted in a 0.47, 4.40, 8.60, and 12.93% decrease in WI, respectively, from days 1 to 42 of age. The calculated European broiler index was greater for the birds received 400 mg/L of SkEO in their drinking water compared with that of the other birds (P < 0.05). Pancreas percentage was increased for the birds received 200 to 500 mg/L SkEO at days 21 and 42 of age compared with that of the control(-) birds (P < 0.05). The gall bladder weight was 17.56, 40.50, 12.16, and 38.73% greater for the birds received 200, 300, 400, and 500 mg/L SkEO compared with that of the control(-) birds, respectively. The results showed that an addition of 400 mg/L SkEO into drinking water for heat-stressed broiler chickens improves economic efficiency possibly by promoting digestion process, creating miniscule improvement in FCR and lowered mortality rate. PMID- 25791164 TI - Modelling Trends in Ordered Correspondence Analysis Using Orthogonal Polynomials. AB - The core of the paper consists of the treatment of two special decompositions for correspondence analysis of two-way ordered contingency tables: the bivariate moment decomposition and the hybrid decomposition, both using orthogonal polynomials rather than the commonly used singular vectors. To this end, we will detail and explain the basic characteristics of a particular set of orthogonal polynomials, called Emerson polynomials. It is shown that such polynomials, when used as bases for the row and/or column spaces, can enhance the interpretations via linear, quadratic and higher-order moments of the ordered categories. To aid such interpretations, we propose a new type of graphical display-the polynomial biplot. PMID- 25791165 TI - Navigation-guided transmodiolar approach for auditory nerve implantation via the middle ear in humans. AB - The aim of this study was to assess the surgical feasibility of a transmodiolar approach via the middle ear cavity for an auditory nerve implantation in humans. In the first part of the study, 6 adult human temporal bones underwent a navigator-guided transmodiolar implantation via the middle ear space after a radical mastoidectomy. In the second part, 122 temporal bone CT scans were analyzed for anatomical parameters relevant to this approach. The nerve implantation was feasible in all temporal bones in laboratory conditions, with a mean target registration error of 0.065 +/- 0.0583 mm (n = 6). Evaluation of anatomical parameters on CT scans also supported the feasibility. There was a significant interindividual variation of the modiolar axis and the entry point in relation to visible anatomical landmarks, highlighting the necessity for surgical preplanning. PMID- 25791166 TI - A literature review of clinical outcomes associated with antipsychotic medication use in North American nursing home residents. AB - The benefits and harms of antipsychotic medication (APM) use in nursing home residents need to be examined because, although commonly used, APMs are considered an off-label use by the Food and Drug Administration for residents with dementia and behavioral problems. The objective of this study was to provide a realist literature review, summarizing original research studies on the clinical effects of conventional and atypical APM use in nursing home residents. Searches of multiple databases identified 424 potentially relevant research articles, of which 25 met the inclusion criteria. Antipsychotic medication use in nursing home residents was found to have variable efficacy when used off-label with an increased risk of many adverse events, including mortality, hip fractures, thrombotic events, cardiovascular events and hospitalizations. Findings suggested certain APM dosing regimens (e.g. fixed-dose) and shorter duration of use might have fewer adverse events. Non-pharmacological interventions should still be considered the first-line treatment option for nursing home residents with dementia related behavioral disturbances, as more studies are needed to establish safer criteria for APM use in nursing homes residents. PMID- 25791167 TI - 43rd European Mathematical Genetics Meeting (EMGM) 2015. April 16-17, 2015, Brest, France: Abstracts. PMID- 25791168 TI - RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form. AB - Hypercholesterolemia is a medical condition often characterized by high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. Despite the available therapies, not all patients show sufficient responses, especially those with very high levels of LDL-C or those with familial hypercholesterolemia. Regulation of plasma cholesterol levels is very complex and several proteins are involved (both receptors and enzymes). From these, the proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising pharmacologic target. The objective of this work is to develop a new approach to inactivate PCSK9 by splice-switching oligonucleotides (SSOs), converting the normal splice form to a natural, less abundant and inactive, splice variant. For this purpose, a new RNA therapeutic approach for hypercholesterolemia based on SSOs was developed for modulation of the splice pattern of human PCSK9 pre-mRNA. Our results show an increase of the selected splice form at both the mRNA and protein level when compared to non treated Huh7 and HepG2 cell lines, with concomitant increase of the protein level of the low-density lipoprotein receptor (LDLR) demonstrating the specificity and efficiency of the system. In vivo, full conversion to the splice form was achieved in a reporter system when mice were treated with the specific oligonucleotide, thus further indicating the therapeutic potential of the approach. In conclusion, PCSK9 activity can be modulated by splice-switching through an RNA therapeutic approach. The tuning of the natural active to non active isoforms represents a physiological way of regulating the cholesterol metabolism, by controlling the amount of LDL receptor available and the rate of LDL-cholesterol clearance. PMID- 25791169 TI - Non-sirtuin histone deacetylases in the control of cardiac aging. AB - Histone deacetylases (HDACs) catalyze the removal of acetyl-groups from lysine residues within nucelosomal histone tails and thousands of non-histone proteins. The 18 mammalian HDACs are grouped into four classes. Classes I, II and IV HDACs employ zinc as a co-factor for catalytic activity, while class III HDACs (also known as sirtuins) require NAD+ for enzymatic function. Small molecule inhibitors of zinc-dependent HDACs are efficacious in multiple pre-clinical models of pressure overload and ischemic cardiomyopathy, reducing pathological hypertrophy and fibrosis, and improving contractile function. Emerging data have revealed numerous mechanisms by which HDAC inhibitors benefit the heart, including suppression of oxidative stress and inflammation, inhibition of MAP kinase signaling, and enhancement of cardiac protein aggregate clearance and autophagic flux. Here, we summarize recent findings with zinc-dependent HDACs and HDAC inhibitors in the heart, focusing on newly described functions for distinct HDAC isoforms (e.g. HDAC2, HDAC3 and HDAC6). Potential for pharmacological HDAC inhibition as a means of treating age-related cardiac dysfunction is also discussed. This article is part of a Special Issue entitled: CV Aging. PMID- 25791170 TI - miR-200c-SUMOylated KLF4 feedback loop acts as a switch in transcriptional programs that control VSMC proliferation. AB - The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue because it has major implications for the prevention of pathological vascular conditions. Using microRNA array screen, we found the expression levels of 200 unique miRNAs in hyperplasic tissues. Among them, miR 200c expression substantially was down-regulated. The objective of this work was to assess the function of miR-200c and SUMOylated Krupsilonppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in both cultured cells and animal models of balloon injury. Under basal conditions, we found that miR-200c inhibited the expression of KLF4 and the SUMO-conjugating enzyme Ubc9. Upon PDGF-BB treatment, Ubc9 interacted with and promoted the SUMOylation of KLF4, which allowed the recruitment of transcriptional corepressors (e.g., nuclear receptor corepressor (NCoR) and HDAC2) to the miR 200c promoter. The reduction in miR-200c levels led to increased target gene expression (e.g., Ubc9 and KLF4), which further repressed miR-200c levels and accelerated VSMC proliferation. These results demonstrate that induction of a miR 200c-SUMOylated KLF4 feedback loop is a significant aspect of the PDGF-BB proliferative response in VSMCs and that targeting Ubc9 represents a novel approach for the prevention of restenosis. PMID- 25791171 TI - Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta analysis. AB - We conducted a meta-analysis to assess the association between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) and its subtypes simple steatosis(SS) and nonalcoholic steatohepatitis (NASH). The study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, with assessment for heterogeneity and publication bias. Twenty-three case control studies involving 6071 NAFLD patients and 10366 controls were identified. The combined results showed a significant association between NAFLD risk and the rs738409 polymorphism in all genetic models (additive model: OR = 3.41, 95% CI = 2.57-4.52; P < 0.00001). In addition, evidence indicated that the rs738409 polymorphism was significantly associated with NASH in all genetic models (additive model: OR = 4.44, 95% CI = 3.39-5.82; P < 0.00001). The subgroup and sensitivity analyses showed that these changes were not influenced by the ethnicities and ages of subjects or by the source of controls. The rs738409 polymorphism was only significantly associated with risk of simple steatosis in the allele contrast and had no effect in the other genetic models. These findings suggest that the rs738409 polymorphism in PNPLA3 gene confers high cross ethnicity risk for NAFLD and NASH development. PMID- 25791173 TI - A Pilot Study to Investigate the Efficacy of Fibrin Sealant (Tisseel(r)) in the Loop Electrosurgical Excision Procedure. AB - AIMS: The objective of the current study was to evaluate the efficacy and feasibility of fibrin sealant (Tisseel(r)) in the loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN 2 or 3). METHODS: We designed a single-blind, prospective, randomized study in 40 consecutive women undergoing LEEP for CIN 2 or 3 at our institute. Two milliliters of fibrin sealant (Tisseel) was applied to the uterine cervix of 20 women immediately after LEEP surgery (treatment group). We evaluated abdominal pain, vaginal bleeding, vaginal discharge and impairment in daily living after 1 week using visual analogue scale questionnaires and compared the results with those of 20 women who did not receive fibrin sealant (control group). RESULTS: Among 40 women who returned for a follow-up 1 week after LEEP, 25 women (62.5%) reported at least one moderate to severe postprocedural symptom. The mean duration of moderate to severe vaginal bleeding and impairment in daily living during postoperative week 1 for the treatment group and the control group was 0.3 +/- 0.80 versus 1.7 +/- 2.36 days (p = 0.015) and 0.9 +/- 1.37 versus 3.00 +/- 2.62 days (p = 0.060), respectively. CONCLUSION: Intraoperative application of fibrin sealant (Tisseel) in LEEP can decrease postoperative vaginal bleeding and impairment in daily living. PMID- 25791172 TI - Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. AB - When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2 [(18)F]fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pretreatment with rapamycin (mTOR inhibition) or metformin (enzyme 5'-AMP-activated protein kinase activation). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH. PMID- 25791174 TI - Secondary triage classification using an ensemble random forest technique. AB - BACKGROUND: Triage of patients in the emergency department is a complex task based on several uncertainties and ambiguous information. Triage must be implemented within two to five minutes to avoid potential fatality and increased waiting time. OBJECTIVE: An intelligent triage system has been proposed for use in a triage environment to reduce human error. METHODS: This system was developed based on the objective primary triage scale (OPTS) that is currently used in the Universiti Kebangsaan Malaysia Medical Center. Both primary and secondary triage models are required to develop this system. The primary triage model has been reported previously; this work focused on secondary triage modelling using an ensemble random forest technique. The randomized resampling method was proposed to balance the data unbalance prior to model development. RESULTS: The results showed that the 300% resampling gave a low out-of-bag error of 0.02 compared to 0.37 without pre-processing. This model has a sensitivity and specificity of 0.98 and 0.89, respectively, for the unseen data. CONCLUSION: With this combination, the random forest reduces the variance, and the randomized resembling reduces the bias, leading to the reduced out-of-bag error. PMID- 25791175 TI - Should age be part of multidimensional indices of risk in chronic obstructive pulmonary disease? PMID- 25791176 TI - HCV NS5A resistance-associated variants in a group of real-world Japanese patients chronically infected with HCV genotype 1b. AB - BACKGROUND: Recent advances in interferon-free treatment could lead to the eradication of hepatitis C virus (HCV) from patients infected with HCV. One of the direct-acting anti-viral agents, HCV NS5A inhibitor, is available for these combination therapies. However, naturally occurring resistance-associated variants (RAVs) to HCV NS5A inhibitors in treatment-naive patients chronically infected with HCV genotype 1b are still unknown. METHODS: We performed ultra-deep sequencing and analysed previously reported RAVs in a total 132 HCV genotype 1b infected Japanese patients who had never used HCV NS5A inhibitors. We also performed direct-sequencing by Sanger method in consecutively selected 50 of the total 132 samples, and the differences between the results of the two methods were compared. RESULTS: In the comparison of the variant frequencies of ultra deep sequencing with RAVs of direct-sequencing by Sanger method in 50 patients, we identified 32 RAVs by direct-sequencing with the Sanger method; minimum variant frequency was shown by ultra-deep sequencing to be 9%. A total of 110 RAVs were identified only by ultra-deep sequencing. In the samples from all 132 patients, L31W (2.3%), L31V (49.2%), L31F (41.7%), L31M (1.5%), L31I (5.3%), L31S (2.0%), L31P (3.0%) and L31R (0.8%), and Y93N (2.3%), Y93H (25%), Y93C (0.8%), Y93P (2.3%) and Y93D (0.8%) were identified. CONCLUSIONS: We demonstrated naturally-occurring RAVs of HCV NS5A inhibitors by ultra-deep sequencing and that several mutations including Y93H are common in HCV NS5A inhibitor-treatment-naive patients with chronic HCV genotype 1b. Careful attention should be paid to these RAVs, and further improvement of treatment options might be needed. PMID- 25791177 TI - Plain packaging and galloping consumption: respiratory disease in modern Ireland. PMID- 25791178 TI - NHE8 is essential for RPE cell polarity and photoreceptor survival. AB - A new N-ethyl-N-nitrosourea (ENU)-induced mouse recessive mutation, identified by fundus examination of the eye, develops depigmented patches, indicating retinal disorder. Histology data show aberrant retinal pigment epithelium (RPE) and late onset photoreceptor cell loss in the mutant retina. Chromosomal mapping and DNA sequencing reveal a point mutation (T to A) of the Slc9a8 gene, resulting in mutant sodium/proton exchanger 8 (NHE8)-M120K protein. The lysine substitution decreases the probability of forming the 3(rd) transmembrane helix, which impairs the pore structure of the Na(+)/H(+) exchanger. Various RPE defects, including mislocalization of the apical marker ezrin, and disrupted apical microvilli and basal infoldings are observed in mutant mice. We have further generated NHE8 knockout mice and confirmed similar phenotypes, including abnormal RPE cells and late-onset photoreceptor cell loss. Both in vivo and in vitro data indicate that NHE8 co-localizes with ER, Golgi and intracellular vesicles in RPE cells. Thus, NHE8 function is necessary for the survival of photoreceptor cells and NHE8 is important for RPE cell polarity and function. Dysfunctional RPE may ultimately lead to photoreceptor cell death in the NHE8 mutants. Further studies will be needed to elucidate whether or not NHE8 regulates pH homeostasis in the protein secretory pathways of RPE. PMID- 25791179 TI - Off-label intranasal oxytocin use in adults is associated with increased amygdala cingulate resting-state connectivity. AB - Intranasally administered oxytocin gained popularity as a hormone facilitating trust, cooperation, and affiliation. However, the long-term consequences of oxytocin use are not known. Given that intensive media attention and advertisements of the "love hormone" might lead to a new form of misuse, we conducted an online survey and identified 41 individuals with oxytocin misuse. Misuse will be proposed throughout the manuscript instead of the more accurate "off-label use" for reasons of simplicity. We compared the social functions of oxytocin users with that of 41 matched control volunteers. We administered the "Reading the Mind in the Eyes Test" (RMET) and the National Institute of Health (NIH) Toolbox Adult Social Relationship Scales (NIH-ASRS) to delineate affective "theory of mind" and real-life social functions, respectively. Resting-state functional brain connectivity analyses were also carried out. Results revealed no significant differences between individuals with oxytocin misuse and control participants on the RMET and NIH-ASRS. However, individuals with oxytocin misuse showed an increased connectivity between the right amygdala and dorsal anterior cingulate cortex relative to the control group. Higher estimated cumulative doses of oxytocin were associated with enhanced amygdala-cingulate connectivity. These results show that individuals who have self-selected for and pursued oxytocin use have increased amygdala-cingulate resting connectivity, compared to individuals who have not used oxytocin, despite the lack of differences in RMET and NIH-ASRS scores. Further longitudinal studies are warranted to investigate the cause effect relationship between oxytocin use and brain connectivity. PMID- 25791180 TI - Brain morphometry of individuals with schizophrenia with and without antipsychotic medication - The Northern Finland Birth Cohort 1966 Study. AB - BACKGROUND: In schizophrenia, brain morphometric changes may be associated with antipsychotic medication. Only limited data is available concerning individuals with schizophrenia without antipsychotic medication. We aimed to study the associations of: use versus no use of antipsychotic medication; length of continuous time without antipsychotic medication; cumulative dose of lifetime antipsychotic medication; and type of antipsychotic medication; with brain morphometry in schizophrenia after an average of 10 years of illness. METHODS: Data of 63 individuals with schizophrenia (mean duration of illness 10.4 years) from the Northern Finland Birth Cohort 1966 were gathered by interview and from hospital and outpatient records. Structural MRI data at age 34 years were acquired and grey matter volume maps with voxel-based morphometry were analyzed using FSL tools. RESULTS: Of the individuals studied, 15 (24%) had taken no antipsychotic medication during the previous year. Individuals with antipsychotic medication had lower total grey matter (TGM) volume compared with non-medicated subjects, although this association was not statistically significant (Cohen's d= 0.51, P=0.078). Time without antipsychotic medication associated with increased TGM (P=0.028). Longer time without antipsychotic medication associated with increased regional volume in right precentral gyrus and right middle frontal gyrus. There were no associations between cumulative dose of lifetime antipsychotic medication or type of antipsychotic medication and brain morphometry. CONCLUSIONS: Unlike some previous investigators, we found no association between cumulative dose of lifetime antipsychotic medication and brain morphological changes in this population-based sample. However, longer continuous time without antipsychotic medication preceding the MRI scan associated with increased gray matter volume. PMID- 25791181 TI - Bilateral deep brain stimulation: the placement of the second electrode is not necessarily less accurate than that of the first one. AB - BACKGROUND: Deep brain stimulation (DBS) is recognized as an effective treatment for movement disorders. We recently changed our technique, limiting the number of brain penetrations to three per side. OBJECTIVES: The first aim was to evaluate the electrode precision on both sides of surgery since we implemented this surgical technique. The second aim was to analyse whether or not the electrode placement was improved with microrecording and macrostimulation. METHODS: We retrospectively reviewed operation protocols and MRIs of 30 patients who underwent bilateral DBS. For microrecording and macrostimulation, we used three parallel channels of the 'Ben Gun' centred on the MRI-planned target. Pre- and post-operative MRIs were merged. The distance between the planned target and the centre of the implanted electrode artefact was measured. RESULTS: There was no significant difference in targeting precision on both sides of surgery. There was more intra-operative adjustment of the second electrode positioning based on microrecording and macrostimulation, which allowed to significantly approach the MRI-planned target on the medial-lateral axis. CONCLUSION: There was more electrode adjustment needed on the second side, possibly in relation with brain shift. We thus suggest performing a single central track with electrophysiological and clinical assessment, with multidirectional exploration on demand for suboptimal clinical responses. PMID- 25791182 TI - Reducing avoidable blindness and visual impairment in the region of the Americas. PMID- 25791183 TI - [National survey of blindness and avoidable visual impairment in Argentina, 2013]. AB - OBJECTIVE: Determine the prevalence of blindness and avoidable visual impairment in Argentina, its causes, the coverage of cataract surgery, and the barriers that hinder access to these services. METHODS: Cross-sectional population study conducted between May and November 2013 using the standard methodology for rapid assessment of avoidable blindness (RAAB), with a random cluster sampling of 50 people aged 50 years or more, -representative of the entire country. Participants' visual acuity (VA) was measured and the lens and posterior pole were examined by direct ophthalmoscopy. An assessment was made of the causes of having VA < 20/60, the coverage and quality of cataract surgery, and the barriers to accessing treatment. RESULTS: 3 770 people were assessed (92.0% of the projected number). The prevalence of blindness was 0.7% (confidence interval of 95%: 0.4-1.0%). Unoperated cataract was the main cause of blindness and severe visual impairment (44.0% and 71.1%, respectively), while the main cause of moderate visual impairment was uncorrected refractive errors (77.8%). Coverage of cataract surgery was of 97.1%, and 82.0% of operated eyes achieved VA >= 20/60. The main barriers to receiving this treatment were fear of the surgical procedure or of a poor result (34.9%), the cost (30.2%), and not having access to the treatment (16.3%). CONCLUSIONS: There is a low prevalence of blindness in the studied population and cataract is the main cause of blindness and severe visual impairment. Efforts should continue to extend coverage of cataract surgery, enhance preoperative evaluation, improve calculations of the intraocular lenses that patients need, and correct post-operative refractive errors with greater precision. PMID- 25791184 TI - A comparative assessment of avoidable blindness and visual impairment in seven Latin American countries: prevalence, coverage, and inequality. AB - OBJECTIVE: To conduct a comparative analysis of social inequalities in eye health and eye health care and generate baseline evidence for seven Latin American countries as a benchmarking exercise for monitoring progress toward three goals of the regional Plan of Action for the Prevention of Blindness and Visual Impairment: increasing eye health service coverage, minimizing barriers, and reducing eye health-related disease burden. METHODS: Results from cross-sectional eye health surveys conducted in six Latin American countries (Argentina, El Salvador, Honduras, Panama, Peru, and Uruguay) from 2011 to 2013 and recently published national surveys in Paraguay were analyzed. The magnitude of absolute and relative inequalities between countries in five dimensions of eye health across the population gradient defined by three equity stratifiers (educational attainment, literacy, and wealth) were explored using standard exploratory data analysis techniques. RESULTS: Overall prevalence of blindness in people 50 years old and older varied from 0.7% (95% CI: 0.4-1.0) in Argentina to 3.0% (95% CI: 2.3-3.6) in Panama. Overall prevalence of visual impairment (severe plus moderate) varied from 8.0% (95% CI: 6.5-11.0) in Uruguay to 14.3% (95% CI: 13.9 14.7) in El Salvador. The main reported cause of blindness was unoperated cataract and most cases of visual impairment were caused by uncorrected refractive error. Three countries had cataract surgical coverage of more than 90% for blind persons, and two-thirds of cataract-operated patients had good visual acuity. CONCLUSIONS: Blindness and moderate visual impairment prevalence were concentrated among the most socially disadvantaged, and cataract surgical coverage and cataract surgery optimal outcome were concentrated among the wealthiest. There is a need for policy action to increase services coverage and quality to achieve universality. PMID- 25791185 TI - [Intervention with rumba and nutrition education to modify cardiovascular risk factors in adults with metabolic syndrome]. AB - OBJECTIVE: Evaluate the effect of an intervention with rumba dance and nutrition education on the cardiovascular risk factors in a group of people with metabolic syndrome in a rural area of Colombia. METHODS: Controlled, randomized clinical trial that included 59 people between 30 and 60 years of age with metabolic syndrome. The intervention group (n = 30) participated in a 12-week exercise program of aerobic rumba (60 minutes, 3 days per week) and muscle-strengthening work (30 minutes, twice a week). Each week the group also received two hours of nutrition education. The control group (n = 29) continued with conventional care. An assessment was made of the effect on the cardiovascular risk factors (physiological, metabolic, anthropometric, and nutritional) in the intervention group. RESULTS: The intervention group showed a reduction in systolic blood pressure (-10.0 mmHg; CI95%: -14.3 to -5.6, P < 0.001), diastolic blood pressure (-4.8 mmHg; CI95%: -8.4 to -1.1, P < 0.05) and overall cardiovascular risk at 10 years (-1.5%; CI95%: -2.7 to -0.3, P < 0.05). Furthermore, there was an increase in peak oxygen con-sumption (1.7 ml O2?kg-1?min-1; CI95%: 0.1 to 3.3, P < 0.05) and muscular strength (P < 0.001). Positive changes were also observed in body composition, caloric intake, and consumption of macro and micronutrients (P < 0.05). No differences were detected between metabolic variables in the two groups or in inflammatory markers (P < 0.05). CONCLUSIONS: An exercise program with rumba and muscular strengthening, combined with nutrition education, favorably modifies cardiovascular risk factors in people with metabolic syndrome. PMID- 25791186 TI - A regional fight against Chagas disease: lessons learned from a successful collaborative partnership. AB - OBJECTIVE: To identify the intangible elements that characterize the successful effort to fight Chagas disease in the Americas, determine how they contributed to the overall success of the partnership, and learn lessons from the experience that could be applied to other programs. METHODS: This study was based on the Partnership Assessment Tool (PAT) developed by the Nuffield Institute for Health ("the Institute") at the University of Leeds (London). The PAT draws heavily on scientific literature and the extensive experience of sociologists and health experts working for the Institute. The Pan American Health Organization (PAHO) modified the tool slightly to adapt it to its needs and provide a general structure for the study. The six key principles of the PAT framework were applied in the design of the research questionnaires. RESULTS: The findings show that a successful collaboration requires a clear objective; a good-quality pool of data; and comprehensive qualitative and quantitative knowledge of the problem, its dimensions, and its impact. The collaboration was elaborated from a common idea and a shared, quantified plan based on data gathered by independent scientists plus a strategy with explicit milestones. The clarity of purpose allowed for an improved synergy of efforts and made it possible to resolve differences in opinions and approaches. CONCLUSIONS: PAHO's experience with effective collaborations such as the joint initiative to fight Chagas disease provides a rich knowledge base for analysis of the advantages, limitations, and paradigms of community involvement, collaborative practices, and partnerships. PMID- 25791187 TI - [Trends in mortality from cancer in Chile according to differences in educational level, 2000-2010]. AB - OBJECTIVE: Characterize the trends in mortality from cancer in Chile according to differences in educational level in the period 2000-2010 in the population over 20 years of age. METHODS: Calculation of specific mortality from cancer, age adjusted for different educational levels, for the period 2000-2010. The obtained rates were analyzed using a Poisson regression model, calculating the relative inequality index and the slope index of inequality for each year. RESULTS: 232 541 deaths from cancer were reported in the period 2000-2010. The most frequent types were breast, stomach, and gallbladder cancer in women; and stomach, prostate, and lung cancer in men. Age-standardized mortality from cancer was greater in the lower educational levels, except for breast cancer in woman and lung cancer in men. The greatest differences were found in gallbladder cancer in women and stomach cancer in men, with specific mortality rates up to 49 and 63 times higher, respectively, for low educational levels compared to higher ones. Between 2000 and 2010, the differences in mortality by educational level were smaller for all cancers combined in both genders, for breast cancer in women, and for lung and stomach in men. CONCLUSIONS: During the period studied, mortality from cancer in Chile was strongly associated with the educational level of the population. This information should be considered when designing national strategies to reduce specific mortality from cancer in the most vulnerable groups. PMID- 25791188 TI - [Rice fortification to correct micronutrient deficiency in children 6-59 months old]. AB - OBJECTIVE: To carry out a systematic review of the literature on the effectiveness of fortified rice consumption in terms of increasing levels of iron and other micro-nutrients in children aged 6-59 months, with a view to evaluating its usefulness as a public health intervention. METHODS: A search was conducted in MEDLINE, Embase, Cochrane Library, and LILACS databases. The review included randomized clinical trials (RCTs) that assessed the consumption of fortified rice, compared with a placebo or other forms of intervention, in terms of enhanced levels of iron and other micronutrients. The CONSORT(r) checklist was used to assess methodological quality. The risk of bias in the studies was assessed using the Cochrane(r) Collaboration methodology. RESULTS: Seven RCTs were included in the review. All the studies showed significant improvements in indicators of nutritional iron status in the intervention groups, without reporting adverse effects. There was no evidence of improvement in vitamin A levels or in anthropometric indicators of weight and height as a secondary result of the intervention. The included studies showed moderate methodological quality. CONCLUSIONS: Rice fortification was an effective intervention strategy to correct iron deficiency in children under age 5. For implementation as a public health measure, local studies are needed to assess its effectiveness in long-term and large-scale interventions. PMID- 25791189 TI - [Improving global access to new vaccines: intellectual property, technology transfer, and regulatory pathways]. AB - The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers. PMID- 25791190 TI - Psychopharmacological characterisation of the successive negative contrast effect in rats. AB - RATIONALE: Successive negative contrast (SNC) describes a change in the behaviour of an animal following a downshift in the quantitative or qualitative value of an expected reward. This behavioural response has been hypothesised to be linked to affective state, with negative states associated with larger and/or prolonged shifts in behaviour. OBJECTIVE: This study has investigated whether different psychopharmacological treatments have dissociable actions on the SNC effect in rats and related these findings to their actions on different neurotransmitter systems and affective state. METHODS: Animals were trained to perform a nose-poke response to obtain a high-value food reward (four pellets). SNC was quantified during devalue sessions in which the reward was reduced to one pellet. Using a within-subject study design, the effects of acute treatment with anxiolytic, anxiogenic, antidepressant and dopaminergic drugs were investigated during both baseline (four pellets) or devalue sessions (one pellet). RESULTS: The indirect dopamine agonist, amphetamine, attenuated the SNC effect whilst the D1/D2 antagonist, alpha-flupenthixol, potentiated it. The antidepressant citalopram, anxiolytic buspirone and anxiogenic FG7142 had no specific effects on SNC, although FG7142 induced general impairments at higher doses. The alpha2 adrenoceptor antagonist, yohimbine, increased premature responding but had no specific effect on SNC. Results for the anxiolytic diazepam were mixed with one group showing an attenuation of the SNC effect whilst the other showed no effect. CONCLUSIONS: These data suggest that the SNC effect is mediated, at least in part, by dopamine signalling. The SNC effect may also be attenuated by benzodiazepine anxiolytics. PMID- 25791191 TI - Heavy drinking, impulsivity and attentional narrowing following alcohol cue exposure. AB - RATIONALE: Research shows that alcohol-related stimuli have the propensity to capture attention among individuals motivated to consume alcohol. Research has further demonstrated that impulsive individuals are especially prone to this type of attentional bias. Recently, it is suggested that alcohol cue exposure can also produce a general narrowing of attention consistent with the activation of approach motivational states. OBJECTIVE: Based on previous models of addiction and recent research on the activation of approach motivational states, we predicted that impulsive individuals would demonstrate a constriction of attentional focus in response to alcohol cue exposure. METHODS: Participants (n = 392) completed a task assessing attentional breadth in response to alcohol and non-alcohol cues, followed by measures of alcohol use and impulsivity. RESULTS: The findings revealed that impulsivity scores predicted narrowing of attentional scope following the presentation of alcohol cues for heavier drinkers but not for light drinkers. CONCLUSION: These results suggest that impulsive individuals who drink more heavily demonstrate a narrowing of attention in the presence of alcohol-related incentive cues. Implications for how these findings might account for the link between impulsivity and alcohol use and misuse are discussed. PMID- 25791192 TI - [Arthritis as presentation of familial Mediterranean fever]. PMID- 25791193 TI - [Congenital depressed skull fracture: The steps to follow?]. PMID- 25791194 TI - [Physical activity, screen time and sleep patterns in Chilean girls]. AB - INTRODUCTION: Physical activity (PA), screen time (ST), and sleep are modifiable lifestyle habits for health. The objectives of this study were: a) to examine the association between PA, ST, and both, on sleep patterns; and b) to determine the influence of PA and ST on sleep problems in Chilean girls. PATIENTS AND METHODS: The study involved 196 children (12.2 years). Patterns and sleep problems were assessed using the Spanish version of the Sleep Self-Report, and the PA through the Physical Activity Questionnaire for Adolescents (PAQ-A), both in Castilian. The ST was assessed using several questions about television, game console and computer use. RESULTS: The ST recommendation (2h a day) was exceeded by 63.2% of the girls. In general, the most active girls (last quartile) that did not exceed the recommendations of ST reported higher sleep quality and total score values compared to those who did not meet both. The logistic regression analysis showed that girls who did not meet both habits were more likely to have sleep quality (odds ratio=17.8, P=.018), and general sleep problems (odds ratio=7.85, P=.025). CONCLUSIONS: Parents need to set limits on sedentary leisure time and encourage more active habits, as sleep is a parameter closely linked to a better health profile in youth. PMID- 25791195 TI - Liquid chromatography-mass spectrometry platform for both small neurotransmitters and neuropeptides in blood, with automatic and robust solid phase extraction. AB - Neurons communicate via chemical signals called neurotransmitters (NTs). The numerous identified NTs can have very different physiochemical properties (solubility, charge, size etc.), so quantification of the various NT classes traditionally requires several analytical platforms/methodologies. We here report that a diverse range of NTs, e.g. peptides oxytocin and vasopressin, monoamines adrenaline and serotonin, and amino acid GABA, can be simultaneously identified/measured in small samples, using an analytical platform based on liquid chromatography and high-resolution mass spectrometry (LC-MS). The automated platform is cost-efficient as manual sample preparation steps and one time-use equipment are kept to a minimum. Zwitter-ionic HILIC stationary phases were used for both on-line solid phase extraction (SPE) and liquid chromatography (capillary format, cLC). This approach enabled compounds from all NT classes to elute in small volumes producing sharp and symmetric signals, and allowing precise quantifications of small samples, demonstrated with whole blood (100 microliters per sample). An additional robustness-enhancing feature is automatic filtration/filter back-flushing (AFFL), allowing hundreds of samples to be analyzed without any parts needing replacement. The platform can be installed by simple modification of a conventional LC-MS system. PMID- 25791196 TI - Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat. AB - Several lines of evidence demonstrate that inhaled nitric oxide (iNO) not only acts locally on the pulmonary vasculature but also has remote effects on the mature and developing brain under basal or pathological conditions by modulating cerebral blood flow and microvascularization, white matter maturation, inflammation, and subsequent brain repair. Previously, consistent studies demonstrated that increased levels of guanosine 3',5' cyclic monophosphate (cGMP), the main effector of biological effect induced by nitric oxide (NO), significantly augment proliferation and neuronal differentiation of adult neural progenitor cells (NPCs). In the present study, we ask the question whether iNO could promote the proliferation of NPCs in the uninjured developing brain. We first reported that iNO exposure at a concentration of 20 ppm during the first 7 days of life was associated with a significant but transient elevation of brain cGMP concentration 2 h after the onset of iNO exposure and a subsequent increase in myelin content of the developing white matter at postnatal day (P) 10. Using BrDu labelling and colabelling with specific cell-type markers we found that iNO exposure of rat pups results in an increased NPC proliferation in several layers of the subventricular zone (SVZ) at both early (30 h) and late (P7) time points. These proliferating NPCs were found to be sustainably viable and subsequently differentiated into oligodendroglial cells in the developing white matter and cortex. We also found that NG2 immunoreactivity around vessel walls, labeling pericyte cells, was increased in NO-exposed rat pups in the periventricular SVZ. In conclusion, iNO appears to act on oligodendrocyte progenitor cells, leading to increased density of mature oligodendrocytes and myelin content in the immature rat brain. PMID- 25791197 TI - Transfer hydrogenation catalysis in cells as a new approach to anticancer drug design. AB - Organometallic complexes are effective hydrogenation catalysts for organic reactions. For example, Noyori-type ruthenium complexes catalyse reduction of ketones by transfer of hydride from formate. Here we show that such catalytic reactions can be achieved in cancer cells, offering a new strategy for the design of safe metal-based anticancer drugs. The activity of ruthenium(II) sulfonamido ethyleneamine complexes towards human ovarian cancer cells is enhanced by up to 50 * in the presence of low non-toxic doses of formate. The extent of conversion of coenzyme NAD(+) to NADH in cells is dependent on formate concentration. This novel reductive stress mechanism of cell death does not involve apoptosis or perturbation of mitochondrial membrane potentials. In contrast, iridium cyclopentadienyl catalysts cause cancer cell death by oxidative stress. Organometallic complexes therefore have an extraordinary ability to modulate the redox status of cancer cells. PMID- 25791199 TI - Comparison of Conjunctival Cytological Alterations following Conventional and Sutureless Sclerotomies. AB - PURPOSE: To assess the alterations in conjunctival impression cytology following 23-gauge transconjunctival sutureless versus conventional pars plana vitrectomy. PATIENTS AND METHODS: Sixty consecutive patients were enrolled in the study. Conjunctival impression cytology was performed on 30 eyes (of 30 subjects) with 23-gauge transconjunctival sutureless vitrectomy and on 30 eyes (of 30 subjects) with conventional vitrectomy. Conjunctival impression cytology was performed preoperatively on the 1st day and in the 3rd month after the surgery. Impression cytology specimens of each group were graded and scored using a range of 0-3 according to Nelson's method. RESULTS: In the conventional pars plana vitrectomy group, statistically significant alterations in the conjunctival impression cytology were detected on the 1st postoperative day (p = 0.001) and in the 3rd postoperative month (p = 0.001), whereas in the 23-gauge transconjunctival sutureless pars plana vitrectomy group, statistically significant changes were observed on the 1st postoperative day. However, no significant changes were observed in the following 3 postoperative months (p = 0.08). CONCLUSION: The properties of impression cytology were altered in the early postoperative period after sutureless and conventional vitrectomy. These changes were improved in the sutureless vitrectomy group only. Sutureless vitrectomy also had an advantageous effect on the conjunctival cytological changes and conjunctival structure. PMID- 25791198 TI - Electrical stimulation as a treatment intervention to improve function, edema or pain following acute lateral ankle sprains: A systematic review. AB - The purpose of this systematic review was to assess whether electrical stimulation (ES), when used in conjunction with a standard treatment, can reduce levels of functional impairment, edema, and pain compared to a standard treatment alone, in patients following a lateral ankle sprain. We searched PubMed, CINAHL, SportDiscus, and Medline (OVID) databases through June 2014 using the terms "ankle sprain or ankle sprains or ligament injury or ligamentous injury," and "electric stimulation or electric stimulation or electrotherapy." Our search identified four randomized control trials, of which, neuromuscular ES and high voltage pulsed stimulation were the only two ES modalities utilized. Effect sizes and 95% confidence intervals (CI) were estimated using Cohen's d for comparison between treatment groups. Three of four effect sizes for function had 95% CI that crossed zero. Twenty-four of the thirty-two effect sizes for edema had 95% CI that crossed zero. All effect sizes for pain had 95% CI that crossed zero. Therefore, the use of ES is not recommended as a means to improve function, reduce edema, or decrease pain in the treatment of acute lateral ankle sprains. PMID- 25791200 TI - Oviposition preference and offspring performance of Mechoris ursulus (Coleoptera: Attelabidae) in Cyclobalanopsis glaucoides (Fagales: Fagaceae) and Quercus franchetii (Fagales: Fagaceae) in Central Yunnan, China. AB - Mechoris ursulus (Roelofs) (Coleoptera: Attelabidae) is a pest weevil of Fagaceae oak trees in eastern Asia. The female has a distinct branch-cutting behavior in conjunction with oviposition in the acorns of its host plant. This study analyzed the factors influencing oviposition preference by carrying out continuous field surveys over the course of 2009-2010 and through laboratory rearing. The field survey showed that for both of the hosts, Cyclobalanopsis glaucoides Schottky (Fagales: Fagaceae) and Quercus franchetii Skan, M. ursulus preferred branches with fewer acorns and larger acorns on the same branch for oviposition. Laboratory rearing experiments showed offspring performance (i.e., survival rate and fresh weight of larvae) was significantly and positively correlated with acorn size. Preference for larger acorns could maximize the fitness of offspring by providing sufficient food source and space. PMID- 25791201 TI - Laparoscopy-assisted versus open distal gastrectomy for early gastric cancer: A meta-analysis based on seven randomized controlled trials. AB - OBJECTIVE: This study aims to answer the superiority of comparing laparoscopy assisted distal gastrectomy (LADG) with open distal gastrectomy (ODG) in the treatment early gastric cancer (EGC). MATERIAL AND METHODS: A comprehensive search up to May 31, 2014 was conducted on PubMed, Web of science, and the Cochrane Library. All eligible studies comparing LADG versus ODG were included. Data synthesis and statistical analysis were performed using RevMan 5.2 software. RESULTS: Seven randomized controlled trials (RCTs) totaling 390 patients (195 LADG and 195 ODG) were analyzed. Compared to ODG, LADG showed longer operative time (WMD = 79.60; 95%CI = 59.86 to 99.35; P < 0.00001), but was associated with less blood loss (WMD = -108.11; 95%CI = -145.97 to -70.26; P < 0.00001), fewer administered analgesics (WMD = -1.70; 95%CI = -2.19 to -1.22; P < 0.00001), fewer number of harvested lymph node (WMD = -2.77; 95%CI = -4.38 to -1.16; P = 0.0007), lower incidence of postoperative complications (OR = 0.26; 95%CI = 0.13 to 0.54; P = 0.0003), shorter postoperative hospital stay (WMD = -1.0; 95% CI = -1.83 to 0.16; P = 0.02) and earlier passage of flatus (WMD = -0.62; 95% CI = -0.96 to 0.27; P = 0.0005). CONCLUSION: This meta-analysis demonstrated that LADG significantly reduced blood loss, decreased the frequency of analgesic administration, faster recovery, a shorter hospital stay and fewer postoperative complications compared with ODG, though at the price of longer operative times and the number of harvested lymph nodes lesser as compared to ODG. PMID- 25791202 TI - Technical assessment of whole body angiography and cardiac function within a single MRI examination. AB - AIM: To evaluate a combined protocol for simultaneous cardiac MRI (CMR) and contrast-enhanced (CE) whole-body MR angiography (WB-MRA) techniques within a single examination. MATERIALS AND METHODS: Asymptomatic volunteers (n = 48) with low-moderate risk of cardiovascular disease (CVD) were recruited. The protocol was divided into four sections: (1) CMR of left ventricle (LV) structure and function; (2) CE-MRA of the head, neck, and thorax followed by the distal lower limbs; (3) CMR LV "late gadolinium enhancement" assessment; and (4) CE-MRA of the abdomen and pelvis followed by the proximal lower limbs. Multiple observers undertook the image analysis. RESULTS: For CMR, the mean ejection fraction (EF) was 67.3 +/- 4.8% and mean left ventricular mass (LVM) was 100.3 +/- 22.8 g. The intra-observer repeatability for EF ranged from 2.1-4.7% and from 9-12 g for LVM. Interobserver repeatability was 8.1% for EF and 19.1 g for LVM. No LV delayed myocardial enhancement was observed. For WB-MRA, some degree of luminal narrowing or stenosis was seen at 3.6% of the vessel segments (involving n = 29 of 48 volunteers) and interobserver radiological opinion was consistent in 96.7% of 1488 vessel segments assessed. CONCLUSION: Combined assessment of WB-MRA and CMR can be undertaken within a single examination on a clinical MRI system. The associated analysis techniques are repeatable and may be suitable for larger scale cardiovascular MRI studies. PMID- 25791203 TI - Between-Scanner and Between-Visit Variation in Normal White Matter Apparent Diffusion Coefficient Values in the Setting of a Multi-Center Clinical Trial. AB - PURPOSE: To study the between-scanner variation and the between-visit reproducibility of brain apparent diffusion coefficient (ADC) measurements in the setting of a multi-center chemotherapy clinical trial for glioblastoma multiforme. METHODS AND MATERIALS: ADC maps of 52 patients at six sites were calculated in-house from diffusion-weighted images obtained by seven individual scanner models of two vendors. The median and coefficient of variation (CV) of normal brain white matter ADC values from a defined region of interest were used to evaluate the differences among scanner models, vendors, magnetic fields, as well as successive visits. All patients participating in this study signed institutional review board approved informed consent. Data acquisition was performed in compliance with all applicable Health Insurance Portability and Accountability Act regulations. The study spanned from August 1, 2006, to January 29, 2008. RESULTS: For baseline median ADC, no difference was observed between the different scanner models, different vendors, and different magnetic field strength. For baseline ADC CV, a significant difference was found between different scanner models (p = 0.0002). No between-scanner difference was observed in ADC changes between two visits. For between-visit reproducibility, significant difference was seen between the ADC values measured at two successive visits for the whole patient group. CONCLUSION: The CVs varied significantly between scanners, presumably due to image noise. Consistent scanner parameter setup can improve reproducibility of the ADC measurements between visits. PMID- 25791204 TI - Wheel running decreases palatable diet preference in Sprague-Dawley rats. AB - Physical activity has beneficial effects on not only improving some disease conditions but also by preventing the development of multiple disorders. Experiments in this study examined the effects of wheel running on intakes of chow and palatable diet e.g. high fat (HF) or high sucrose (HS) diet in male and female Sprague-Dawley rats. Experiment 1 demonstrated that acute wheel running results in robust HF or HS diet avoidance in male rats. Although female rats with running wheel access initially showed complete avoidance of the two palatable diets, the avoidance of the HS diet was transient. Experiment 2 demonstrated that male rats developed decreased HF diet preferences regardless of the order of diet and wheel running access presentation. Running associated changes in HF diet preference in females, on the other hand, depended on the testing schedule. In female rats, simultaneous presentation of the HF diet and running access resulted in transient complete HF diet avoidance whereas running experience prior to HF diet access did not affect the high preference for the HF diet. Ovariectomy in females resulted in HF diet preference patterns that were similar to those in male rats during simultaneous exposure of HF and wheel running access but similar to intact females when running occurred before HF exposure. Overall, the results demonstrated wheel running associated changes in palatable diet preferences that were in part sex dependent. Furthermore, ovarian hormones play a role in some of the sex differences. These data reveal complexity in the mechanisms underlying exercise associated changes in palatable diet preference. PMID- 25791205 TI - Ultrasonic propagation: a technique to reveal field induced structures in magnetic nanofluids. AB - The paper reports the study of magnetic field induced structures in magnetic nanofluid investigated through ultrasonic wave propagation. Modified Tarapov's theory is used to study variation in velocity anisotropy with magnetic field. The types of field induced structures depend upon the chemical structure of the carrier in which magnetic nanoparticles are dispersed. Our study indicates formation of fractals and chain respectively, in transformer oil and kerosene based fluid. This difference is explained on the basis of particle-particle interaction and particle-medium interaction. PMID- 25791206 TI - New cytotoxic lignan glycosides from Phyllanthus glaucus. AB - During the process of exploring bioactive lead compounds from Phyllanthus species, two new glycosides including an arylnaphthalene lignan, diphyllin 4-O alpha-L-arabinopyranosyl-(1 -> 3)-alpha-L-arabinopyranoside (1), and a phenolic compound, 3,4,5-trimethoxybenzyl alcohol 7-O-alpha-L-arabinofuranosyl-(1 -> 6) beta-D-glucopyranoside (2), were isolated from the methanol extract of the whole plants of Phyllanthus glaucus Wall. ex Mull. Arg. In addition, 31 known compounds, including 19 lignan derivatives (3-21), four phenylpropanoids (22-25), seven simple phenolics (26-32) and one monoterpenoid (33) were obtained. Their structures were determined on the basis of the HR-ESI-MS, 1D and 2D NMR spectroscopic analysis, and pre-column derivative/chiral HPLC analysis in case of 1 for the absolute configurations. All these compounds were obtained from P. glaucus for the first time. Moreover, the known lignan glycoside, phyllanthusmin C (5) showed in vitro cytotoxicities against HL-60, MCF-7 and SW480 cells with IC50 values of 9.2 +/- 0.2, 19.2 +/- 1.7 and 20.5 +/- 0.9, respectively. PMID- 25791207 TI - Therapeutic strategies for hepatocellular carcinoma: new advances and challenges. AB - OPINION STATEMENT: Hepatocellular carcinoma (HCC) is the fastest growing malignancy in the USA, and its prognosis remains poor with a 5-year survival around 12 %. Clinical data demonstrate that 85 % of cases occur in individuals with underlying cirrhosis and only 15 % develop in non-cirrhotic livers. Therefore, American and European guidelines recommend routine HCC screening for high-risk individuals (patients with cirrhosis) with abdominal ultrasound every 6 months. Once a lesion is identified or suspected on ultrasound, dynamic imaging is then indicated. The diagnosis of HCC is established in a patient with cirrhosis when a lesion measures at least 1 cm in diameter and demonstrates arterial enhancement and portal venous washout on contrast-enhanced computerized tomography or magnetic resonance imaging. Indeterminate lesions should be followed with surveillance imaging or further investigated with biopsy according to the level of suspicion for malignancy. Given the clinical, pathological, and molecular heterogeneity of HCC, there are multiple therapeutic modalities available. These may be curative, such as surgical resection, liver transplantation, and local ablation, or palliative, such as catheter-directed therapies (transarterial chemo, radio, or bland embolization), and systemic therapy (sorafenib). Patients with a single lesion, good performance status, and preserved liver synthetic function should be offered curative surgical resection or ablation therapy. Patients with HCC and decompensated liver disease should be evaluated and listed for liver transplantation. For unresectable disease or tumor burden precluding transplantation or curative ablation, palliative therapeutic modalities should be offered. Sorafenib is indicated for patients with vascular invasion and/or extra-hepatic metastasis if the estimated life expectancy is more than 3 months. Systemic internal radiation therapy using yttrium-90 microspheres in cases of multifocal bi-lobar disease and/or portal vein occlusion is an emerging therapy. Best supportive care is recommended for patients who lack the hepatic reserve to tolerate therapy. PMID- 25791208 TI - Elemental bioimaging of thulium in mouse tissues by laser ablation-ICPMS as a complementary method to heteronuclear proton magnetic resonance imaging for cell tracking experiments. AB - Due to the fact that cellular therapies are increasingly finding application in clinical trials and promise success by treatment of fatal diseases, monitoring strategies to investigate the delivery of the therapeutic cells to the target organs are getting more and more into the focus of modern in vivo imaging methods. In order to monitor the distribution of the respective cells, they can be labeled with lanthanide complexes such as thulium-1,4,7,10 tetraazacyclodoecane-alpha,alpha,alpha,alpha-tetramethyl-1,4,7,10-tetraacetic acid (Tm(DOTMA)). In this study, experiments on a mouse model with two different cell types, namely, tumor cells and macrophages labeled with Tm(DOTMA), were performed. The systemic distribution of Tm(DOTMA) of both cell types was investigated by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICPMS). Using the high resolution of 25 MUm, distribution maps of Tm in different tissues such as tumor, liver, lung, and spleen as well as in explanted gel pellets were generated and the behavior of the labeled cells inside the tissue was investigated. Additionally, quantitative data were obtained using homemade matrix-matched standards based on egg yolk. Using this approach, limits of detection and quantification of 2.2 and 7.4 ng.g(-1), respectively, and an excellent linearity over the concentration range from 0.01 to 46 MUg.g(-1) was achieved. The highest concentration of the label agent, 32.4 MUg.g(-1), in tumor tissue was observed in the area of the injection of the labeled tumor cells. Regarding the second experiment with macrophages for cell tracking, Tm was detected in the explanted biogell pellet with relatively low concentrations below 60 ng.g(-1) and in the liver with a relatively high concentration of 10 MUg.g( 1). Besides thulium, aluminum was detected with equal distribution behavior in the tumor section due to a contamination resulting from the labeling procedure, which includes the usage of an Al electrode. PMID- 25791209 TI - Physical methods for evaluating the nutrition status of hemodialysis patients. AB - This article aims to provide an overview of the different nutritional markers and the available methodologies for the physical assessment of nutrition status in hemodialysis patients, with special emphasis on early detection of protein energy wasting (PEW). Nutrition status assessment is made on the basis of anamnesis, physical examination, evaluation of nutrient intake, and on a selection of various screening/diagnostic methodologies. These methodologies can be subjective, e.g. the Subjective Global Assessment score (SGA), or objective in nature (e.g. bioimpedance analysis). In addition, certain biochemical tests may be employed (e.g. albumin, pre-albumin). The various subjective-based and objective methodologies provide different insights for the assessment of PEW, particularly regarding their propensity to differentiate between the important body composition compartments-fluid overload, fat mass and muscle mass. This review of currently available methods showed that no single approach and no single marker is able to detect alterations in nutrition status in a timely fashion and to follow such changes over time. The most clinically relevant approach presently appears to be the combination of the SGA method with the bioimpedance spectroscopy technique with physiological model and, additionally, laboratory tests for the detection of micro-nutrient deficiency. PMID- 25791210 TI - Getting to the core of protein pharmaceuticals--Comprehensive structure analysis by mass spectrometry. AB - Protein pharmaceuticals are the fastest growing class of novel therapeutic agents, and have been a major research and development focus in the (bio)pharmaceutical industry. Due to their large size and structural diversity, biopharmaceuticals represent a formidable challenge regarding analysis and characterization compared to traditional small molecule drugs. Any changes to the primary, secondary, tertiary or quaternary structure of a protein can potentially impact its function, efficacy and safety. The analysis and characterization of (structural) protein heterogeneity is therefore of utmost importance. Mass spectrometry has evolved as a powerful tool for the characterization of both primary and higher order structures of protein pharmaceuticals. Furthermore, the chemical and physical stability of protein drugs, as well as their pharmacokinetics are nowadays routinely determined by mass spectrometry. Here we review current techniques in primary, secondary and tertiary structure analysis of proteins by mass spectrometry. An overview of established top-down and bottom up protein analyses will be given, and in particular the use of advanced technologies such as hydrogen/deuterium exchange mass spectrometry (HDX-MS) for higher-order structure analysis will be discussed. Modification and degradation pathways of protein drugs and their detection by mass spectrometry will be described, as well as the growing use of mass spectrometry to assist protein design and biopharmaceutical development. PMID- 25791211 TI - Thermodynamic phase behaviour of indomethacin/PLGA formulations. AB - In the current study, the phase behaviour of indomethacin and poly(lactic-co glycolic acid) (PLGA) formulations was investigated as a function of the molecular weight and the copolymer composition of PLGA. The formulations were prepared by ball milling, and the phase behaviour, comprised of the glass transition temperature of the formulations and the solubility of indomethacin in PLGA, was measured using modulated differential scanning calorimetry (mDSC). The results determined that the solubility of indomethacin in PLGA at room temperature was very low and increased with a corresponding decrease in the molecular weight of PLGA. The copolymer composition of PLGA had a minor effect on the indomethacin solubility. The effect of PLGA's molecular weight and copolymer composition on the solubility of indomethacin could be modelled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) with a high degree of accuracy when compared with the experimental data. The glass-transition temperatures had a negative deviation from the weighted mean of the glass transition temperatures of the pure substances, which could be described by the Kwei-equation. PMID- 25791212 TI - Highly efficient entanglement swapping and teleportation at telecom wavelength. AB - Entanglement swapping at telecom wavelengths is at the heart of quantum networking in optical fiber infrastructures. Although entanglement swapping has been demonstrated experimentally so far using various types of entangled photon sources both in near-infrared and telecom wavelength regions, the rate of swapping operation has been too low to be applied to practical quantum protocols, due to limited efficiency of entangled photon sources and photon detectors. Here we demonstrate drastic improvement of the efficiency at telecom wavelength by using two ultra-bright entangled photon sources and four highly efficient superconducting nanowire single photon detectors. We have attained a four-fold coincidence count rate of 108 counts per second, which is three orders higher than the previous experiments at telecom wavelengths. A raw (net) visibility in a Hong-Ou-Mandel interference between the two independent entangled sources was 73.3 +/- 1.0% (85.1 +/- 0.8%). We performed the teleportation and entanglement swapping, and obtained a fidelity of 76.3% in the swapping test. Our results on the coincidence count rates are comparable with the ones ever recorded in teleportation/swapping and multi-photon entanglement generation experiments at around 800 nm wavelengths. Our setup opens the way to practical implementation of device-independent quantum key distribution and its distance extension by the entanglement swapping as well as multi-photon entangled state generation in telecom band infrastructures with both space and fiber links. PMID- 25791213 TI - Coronary intervention: radial artery access comes of age. PMID- 25791215 TI - Outstanding JASMS manuscript reviewers, 2013-2014. PMID- 25791216 TI - Unstirred Water Layers and the Kinetics of Organic Cation Transport. AB - PURPOSE: Unstirred water layers (UWLs) present an unavoidable complication to the measurement of transport kinetics in cultured cells, and the high rates of transport achieved by overexpressing heterologous transporters exacerbate the UWL effect. This study examined the correlation between measured Jmax and Kt values and the effect of manipulating UWL thickness or transport Jmax on the accuracy of experimentally determined kinetics of the multidrug transporters, OCT2 and MATE1. METHODS: Transport of TEA and MPP was measured in CHO cells that stably expressed human OCT2 or MATE1. UWL thickness was manipulated by vigorous reciprocal shaking. Several methods were used to manipulate maximal transport rates. RESULTS: Vigorous stirring stimulated uptake of OCT2-mediated transport by decreasing apparent Kt (Ktapp) values. Systematic reduction in transport rates was correlated with reduction in Ktapp values. The slope of these relationships indicated a 1500 MUm UWL in multiwell plates. Reducing the influence of UWLs (by decreasing either their thickness or the Jmax of substrate transport) reduced Ktapp by 2-fold to >10-fold. CONCLUSIONS: Failure to take into account the presence of UWLs in experiments using cultured cells to measure transport kinetics can result in significant underestimates of the apparent affinity of multidrug transporters for substrates. PMID- 25791217 TI - Particle Image Velocimetry Evaluation of Fluid Flow Profiles in USP 4 Flow Through Dissolution Cells. AB - PURPOSE: To evaluate fluid flow profiles in the flow-through cell (FTC, USP apparatus 4) system with pulsatile and non-pulsatile pumps. METHODS: Instantaneous velocity vectors in the dissolution cells were obtained from images sequentially captured by a particle image velocimetry (PIV) system. The data were sorted to follow the pump pulse cycle. RESULTS: The analysis showed changes in the flow profiles during a pump pulse (0.5 s) at a 0.025-s interval in two sizes of cells installed in the FTC system. Supplying a slow flow from the pulsatile pump induced instantaneous downward (inner layer) and upward (outer layer) flow in the larger cell during the suction phase. Analysis at varied medium and cell temperatures strongly suggested a contribution of natural convection to the complex flow caused by relatively high cell temperature. Uniform upward flow was observed in other cells and flow rate conditions. The time-averaged vertical velocities in the cells were similar in the pulsatile and non-pulsatile pump systems. CONCLUSIONS: The PIV analysis provides information on how flow rate and pump pulse affect fluid flow profiles at multiple points in flow-through dissolution cells. An appropriate temperature control should reduce the complex flow of the medium in the FTC system. PMID- 25791219 TI - Directly probing redox-linked quinones in photosystem II membrane fragments via UV resonance Raman scattering. AB - In photosynthesis, photosystem II (PSII) harvests sunlight with bound pigments to oxidize water and reduce quinone to quinol, which serves as electron and proton mediators for solar-to-chemical energy conversion. At least two types of quinone cofactors in PSII are redox-linked: QA, and QB. Here, we for the first time apply 257-nm ultraviolet resonance Raman (UVRR) spectroscopy to acquire the molecular vibrations of plastoquinone (PQ) in PSII membranes. Owing to the resonance enhancement effect, the vibrational signal of PQ in PSII membranes is prominent. A strong band at 1661 cm(-1) is assigned to ring CC/CO symmetric stretch mode (nu8a mode) of PQ, and a weak band at 469 cm(-1) to ring stretch mode. By using a pump-probe difference UVRR method and a sample jet technique, the signals of QA and QB can be distinguished. A frequency difference of 1.4 cm(-1) in nu8a vibrational mode between QA and QB is observed, corresponding to ~86 mV redox potential difference imposed by their protein environment. In addition, there are other PQs in the PSII membranes. A negligible anharmonicity effect on their combination band at 2130 cm(-1) suggests that the 'other PQs' are situated in a hydrophobic environment. The detection of the 'other PQs' might be consistent with the view that another functional PQ cofactor (not QA or QB) exists in PSII. This UVRR approach will be useful to the study of quinone molecules in photosynthesis or other biological systems. PMID- 25791220 TI - Hospitals must take lead on new care models and work better with GPs, think tank says. PMID- 25791221 TI - A quick ward assessment of older patients by junior doctors. PMID- 25791218 TI - The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. AB - Osteocytes are the most abundant cells in bone and are the major orchestrators of bone remodeling and mineral homeostasis. They possess a specialized cellular morphology and a unique molecular feature. Osteocytes are a stellate shape with numerous long, slender dendritic processes. The osteocyte cell body resides in the bone matrix of the lacuna and the dendritic processes extend within the canaliculi to adjacent osteocytes and other cells on the bone surface. Osteocytes form extensive intercellular network to sense and respond to environmental mechanical stimulus by the lacunar-canalicular system and gap junction. Osteocytes are long-lived bone cells. They can undergo apoptosis, which may have specific regulatory effects on osteoclastic bone resorption. Osteocytes can secrete several molecules, including sclerostin, receptor activator of nuclear factor kappaB ligand and fibroblast growth factor 23 to regulate osteoblastic bone formation, osteoclastic bone resorption and mineral homeostasis. A deeper understanding of the complex mechanisms that mediate the control of osteoblast and osteoclast function by osteocytes may identify new osteocyte-derived molecules as potential pharmacological targets for treating osteoporosis and other skeletal diseases. PMID- 25791214 TI - Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. AB - BACKGROUND: It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management. METHODS: We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST segment elevation myocardial infarction, troponin positive or negative, non-ST segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided alpha was prespecified at 0.025. The trial is registered at ClinicalTrials.gov, number NCT01433627. FINDINGS: We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8.8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10.3%) patients with femoral access (rate ratio [RR] 0.85, 95% CI 0.74-0.99; p=0.0307), non-significant at alpha of 0.025. 410 (9.8%) patients with radial access had net adverse clinical events compared with 486 (11.7%) patients with femoral access (0.83, 95% CI 0.73-0.96; p=0.0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1.6% vs 2.3%, RR 0.67, 95% CI 0.49-0.92; p=0.013) and all-cause mortality (1.6% vs 2.2%, RR 0.72, 95% CI 0.53-0.99; p=0.045). INTERPRETATION: In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality. FUNDING: The Medicines Company and Terumo. PMID- 25791222 TI - Achieving type I, II, and III heterojunctions using functionalized MXene. AB - In the present work, type I, II, and III heterostructures are constructed with the same base material using three representative functionalized monolayer scandium carbides (Sc2CF2, Sc2C(OH)2, and Sc2CO2) by first-principles calculations based on density functional theory. In contrast to general bilayer heterosystems composed of two-dimensional semiconductors, type I and III heterojunctions are obtained in one Sc2CF2/Sc2CO2 system and the remains of the functionalized Sc2C heterostructures, respectively. It is noteworthy that the same monolayer Sc2CF2 and Sc2CO2 constituents lead to dissimilar heterostructure types in the two Sc2CF2/Sc2CO2 systems by modifying the stacking interface. In addition, in the two Sc2CF2/Sc2CO2 systems, remarkable changes in the heterojunction type are induced by a strain, and two distinct type-II heterostructures are generated where one layer with the conduction band minimum state and the other layer including the valence band maximum level are different. The present work suggests an attractive direction to obtain all heterostructure types with the same base material for novel nanodevices in various fields such as photonics, electronics, and optoelectronics using only the two monolayer components Sc2CF2 and Sc2CO2. PMID- 25791223 TI - A model of secreting murine mammary epithelial HC11 cells comprising endogenous Bcrp/Abcg2 expression and function. AB - Breast cancer resistance protein (Bcrp/Abcg2) and multidrug transporter 1 (Mdr1/Abcb1) are efflux proteins located in the apical membrane of mammary epithelial cells (MEC). Bcrp is induced in MEC during gestation and lactation, while Mdr1 is down-regulated during lactation. Numerous drugs and toxic compounds are known to be actively secreted into milk by Bcrp, but most chemicals have not been investigated in this respect, emphasizing the need for functional Bcrp studies in an established cell line with secreting mammary epithelial cells. The present study was undertaken to examine expressions of Bcrp and Mdr1 in mammary epithelial HC11 cells, derived from a mid-gestational murine mammary gland. In addition, Bcrp function was assessed by transport experiments with mitoxantrone (MX) in undifferentiated HC11 cells, in HC11 cells subjected to Bcrp RNA interference (RNAi), as well as in HC11 cells stimulated to differentiate by treatment with lactogenic hormones. Differentiated HC11 cells organized into alveolar-resembling structures and gene expression of the major milk protein beta casein was induced, whereas undifferentiated cells formed monolayers with lower beta-casein expression. Bcrp and Mdr1 gene and protein were expressed in both undifferentiated and differentiated HC11 cells. Differentiation of HC11 cells resulted in increased Bcrp protein expression, while Mdr1 gene and protein expressions were reduced. The Bcrp inhibitor elacridar (GF120918) reduced secretion and increased accumulation of MX in both undifferentiated and differentiated HC11 cells. Silencing of the Bcrp gene caused an increased accumulation of MX. The results indicate that the HC11 cell model provides a promising tool to investigate transport of potential Bcrp substrates in mammary epithelial cells. PMID- 25791224 TI - Differentiated clinical presentation of early and late-onset Alzheimer's disease: is 65 years of age providing a reliable threshold? AB - Early-onset and late-onset Alzheimer's disease (EOAD and LOAD) are two forms of the disease with the same characteristic neuropathological hallmarks. However, higher burdens of neuritic plaques and neurofibrillary tangles in frontal and parietal lobes have been found in EOAD than in LOAD patients. Thus, the EOAD subjects may have a differentiated clinical presentation compared to the LOAD ones. Some authors have found less hippocampal memory presentations and more focal cortical abnormalities (such as visuoconstructive or executive dysfunction) in EOAD than LOAD patients. The aim of the present study was to determine which initial clinical profiles differ between EOAD and LOAD; and to analyze whether another age cut-off could discriminate better between EOAD and LOAD clinical presentations than the conventional limit of 65. All patients fulfilling NINCDS ADRDA criteria for probable Alzheimer's disease who referred to our Hospital between October 2007 and December 2012 were included in the study. The conventional age limit of 65 was established to distinguish between EOAD and LOAD. Baseline neuropsychological scores, adjusted for age and education, were compared between both groups. A total of 181 patients (38 EOAD, 143 LOAD) entered in the analysis. Sex distribution and time of evolution of symptoms did not differ between groups. The EOAD patients performed worse than LOAD in attentional, imitation praxis and verbal learning tests. In addition, the age cut off of 70 was found to differentiate between early- and late-onset groups better than the standard cut-off of 65 years old. Our results support a differentiated neuropsychological impairment pattern in EOAD compared to LOAD. PMID- 25791225 TI - Obstructive sleep apnea is independently associated with arterial stiffness in ischemic stroke patients. AB - Obstructive sleep apnea (OSA) is a predictor of all-cause mortality and recurrent vascular events following stroke. However, few studies have investigated the pathophysiology of OSA in ischemic stroke patients. Whether OSA independently increases arterial stiffness in ischemic stroke patients is determined by measuring the carotid-femoral pulse wave velocity (PWV) and via the central augmentation index (AIx). This cross-sectional study consecutively recruited 127 subacute ischemic stroke patients who were admitted to a teaching hospital for inpatient rehabilitation (median age, 61.3 years; IQR 53.6-72.7 years). Vascular measurements were performed following polysomnography. Multivariate linear regression analysis was performed to determine the relationship between arterial stiffness and OSA. Patients with severe OSA were significantly older, had significantly higher PWV and mean blood pressure, and a significantly higher risk of hypertension than those with non-severe OSA. The significant bivariate correlation between AIx@75 and the desaturation index (DI) (Spearman's rho = 0.182, P = 0.040) became insignificant by multivariate regression analysis. The PWV was significantly correlated with the apnea-hypopnea index (AHI) (Pearson's r = 0.350, P = 0.000) and DI (Spearman's rho = 0.347, P = 0.000). The correlation between PWV and OSA parameters, including presence of severe OSA, AHI and DI, remained significant by multivariate regression analysis with age, systolic blood pressure, diabetic mellitus, hypertension and the Barthel index as potential confounders. Arterial stiffness is independently associated with OSA, and PWV can be applied as an intermediate endpoint in further intervention trials of ischemic stroke patients with OSA. PMID- 25791226 TI - Icariin exerts an antidepressant effect in an unpredictable chronic mild stress model of depression in rats and is associated with the regulation of hippocampal neuroinflammation. AB - Icariin (ICA), a flavonoid extracted from the traditional Chinese herb Herba Epimedii that can freely cross the blood-brain barrier, inhibits neuroinflammation and attenuates oxidative stress damage. Our previous studies demonstrated that icariin exerts an antidepressant-like activity in a social defeat mouse model. However, it is unknown whether icariin is beneficial for the treatment of depression via its modulation of oxidative stress and neuroinflammation. The objective of this study was to investigate the effects of icariin on the depression-like behaviors in an unpredictable chronic mild stress (CMS) model of depression in rats. Rats exposed to CMS showed behavioral deficits in physical state, the sucrose preference test (SPT) and the forced swimming test (FST) and exhibited a significant increase in oxidative-nitrosative stress markers, inflammatory mediators, including tumor necrosis factor-alpha (TNF alpha) and interleukin-1beta (IL-1beta), activation of the nuclear factor kappa B (NF-kappaB) signaling pathway and increased inducible nitric oxide synthase (iNOS) mRNA expression in the hippocampus, which was reversed by chronic treatment with icariin (20 or 40 mg/kg). Interestingly, icariin negatively regulated the activation of the nod-like receptor protein 3 (NLRP3) inflammasome/caspase-1/IL-1beta axis in the hippocampus of CMS rats. These results confirm that icariin exerts antidepressant-like effects, which may be mediated, at least in part, by enhanced antioxidant status and anti-inflammatory effects on the brain tissue via the inhibition of NF-kappaB signaling activation and the NLRP3-inflammasome/caspase-1/IL-1beta axis. Our findings provide new information to understand the antidepressant action of icariin, which is targeted to the NLRP3-inflammasom in brain. PMID- 25791227 TI - Memory reconsolidation of an inhibitory avoidance task in mice involves cytosolic ERK2 bidirectional modulation. AB - Reconsolidation has been defined as the process of memory stabilization after retrieval involving, among others, gene expression regulation and post translational modifications. Many of these mechanisms are shared with memory consolidation. Here, we studied hippocampal ERK participation on memory reconsolidation of an inhibitory avoidance task in CF-1 mice. We found a retrieval-induced cytosolic ERK2 activation in the hippocampus (HIP) 15 min after memory reactivation, and an inhibition at 45 min. PD098059, a MEK1/2 (MAPK/ERK kinase) inhibitor, administered in the HIP immediately after retrieval impaired memory in a dose-dependent fashion. However, infusions of the highest dose of PD098059 performed 40 min after retrieval enhanced memory in mice trained with a weaker footshock. These results suggest for the first time that ERK2 is involved in memory reconsolidation in a biphasic fashion. Furthermore, the inhibition of ERK could either impair or enhance mice performance depending on ERK state of activation. PMID- 25791228 TI - Astrocyte sodium signaling and neuro-metabolic coupling in the brain. AB - At tripartite synapses, astrocytes undergo calcium signaling in response to release of neurotransmitters and this calcium signaling has been proposed to play a critical role in neuron-glia interaction. Recent work has now firmly established that, in addition, neuronal activity also evokes sodium transients in astrocytes, which can be local or global depending on the number of activated synapses and the duration of activity. Furthermore, astrocyte sodium signals can be transmitted to adjacent cells through gap junctions and following release of gliotransmitters. A main pathway for activity-related sodium influx into astrocytes is via high-affinity sodium-dependent glutamate transporters. Astrocyte sodium signals differ in many respects from the well-described glial calcium signals both in terms of their temporal as well as spatial distribution. There are no known buffering systems for sodium ions, nor is there store-mediated release of sodium. Sodium signals thus seem to represent rather direct and unbiased indicators of the site and strength of neuronal inputs. As such they have an immediate influence on the activity of sodium-dependent transporters which may even reverse in response to sodium signaling, as has been shown for GABA transporters for example. Furthermore, recovery from sodium transients through Na(+)/K(+)-ATPase requires a measurable amount of ATP, resulting in an activation of glial metabolism. In this review, we present basic principles of sodium regulation and the current state of knowledge concerning the occurrence and properties of activity-related sodium transients in astrocytes. We then discuss different aspects of the relationship between sodium changes in astrocytes and neuro-metabolic coupling, putting forward the idea that indeed sodium might serve as a new type of intracellular ion signal playing an important role in neuron-glia interaction and neuro-metabolic coupling in the healthy and diseased brain. PMID- 25791229 TI - Termination of vestibulospinal fibers arising from the spinal vestibular nucleus in the mouse spinal cord. AB - The present study investigated the vestibulospinal system which originates from the spinal vestibular nucleus (SpVe) with both retrograde and anterograde tracer injections. We found that fluoro-gold (FG) labeled neurons were found bilaterally with a contralateral predominance after FG injections into the upper lumbar cord. Anterogradely labeled fibers from the rostral SpVe traveled in the medial part of the ventral funiculus ipsilaterally and the dorsolateral funiculus bilaterally in the cervical cord. They mainly terminated in laminae 5-8, and 10 of the ipsilateral spinal cord. The contralateral side had fewer fibers and they were found in laminae 6-8, and 10. In the thoracic cord, fibers were also found to terminate in bilateral intermediolateral columns. In the lumbar and lower cord, fibers were mainly found in the dorsolateral funiculus bilaterally and they terminated predominantly in laminae 3-7 contralaterally. Anterogradely labeled fibers from the caudal SpVe did not travel in the medial part of the ventral funiculus but in the dorsolateral funiculus bilaterally. They mainly terminated in laminae 3-8 and 10 contralaterally. The present study is the first to describe the termination of vestibulospinal fibers arising from the SpVe in the spinal cord. It will lay the anatomical foundation for those who investigate the physiological role of vestibulospinal fibers and potentially target these fibers during rehabilitation after stroke, spinal cord injury, or vestibular organ injury. PMID- 25791230 TI - Synaptic strength at the temporoammonic input to the hippocampal CA1 region in vivo is regulated by NMDA receptors, metabotropic glutamate receptors and voltage gated calcium channels. AB - The hippocampal CA1 region receives cortical information via two main inputs: directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway. Although synaptic plasticity has been reported at the pp-CA1 synapse of freely behaving animals, the mechanisms underlying this phenomenon have not been investigated. Here, we explored whether long-term potentiation (LTP) at the pp-CA1 synapse in freely behaving rats requires activation of N-methyl-d-aspartate receptors (NMDAR) and L-type voltage-gated calcium channels (VGCCs). As group II metabotropic glutamate (mGlu) receptors are densely localized on presynaptic terminals of the perforant path, and are important for certain forms of hippocampal synaptic plasticity, we also explored whether group II mGlu receptors affect LTP at the pp-CA1 synapse and/or regulate basal synaptic transmission at this synapse in vivo. In adult male rats, high frequency stimulation (200Hz) given as 3, or 10 trains, resulted in robust LTP that lasted for at least 4h in pp-CA1 or pp-dentate gyrus (DG) synapses, respectively. Pre-treatment with the NMDAR antagonist D-(-)-2-amino-5 phosphopentanoic acid (D-AP5) partially inhibited LTP at pp-CA1, and completely prevented LTP at pp-DG synapses. Combined antagonism of NMDAR using D-AP5 and the VGCC inhibitor, (-)-methoxyverapamil hydrochloride elicited a further inhibition of the LTP response at pp-CA1 synapses. Whereas activation of group II mGlu receptors using (1R,2R)-3-((1S)-1-amino-2-hydroxy-2-oxoethyl) cyclopropane-1,2 dicarboxylic acid (DCG-IV) dose-dependently reduced basal synaptic transmission elicited by test-pulse stimulation, DCG-IV did not affect LTP in a dose that inhibited LTP at pp-DG synapses in vivo. These data indicate that LTP at the pp CA1 synapse of freely behaving animals is dually dependent on NMDAR and VGCCs, whereby group II mGlu receptor activation affect basal synaptic tonus, but not LTP. The lower frequency-dependency of NMDA-VGCC LTP at pp-CA1 synapses compared to pp-DG synapses may comprise a mechanism to prioritize information processing at this synapse. PMID- 25791231 TI - Effect of monophasic pulsed current on heel pain and functional activities caused by plantar fasciitis. AB - BACKGROUND: Plantar fasciitis (PF) is a soft tissue disorder considered to be one of the most common causes of inferior heel pain. The aim of this study was to investigate the effect of monophasic pulsed current (MPC) and MPC coupled with plantar fascia-specific stretching exercises (SE) on the treatment of PF. MATERIAL AND METHODS: Forty-four participants (22 women and 22 men, with a mean age of 49 years) diagnosed with PF were randomly assigned to receive MPC (n=22) or MPC coupled with plantar fascia-specific SE (n=22). Prior to and after 4 weeks of treatment, participants underwent baseline evaluation; heel pain was evaluated using a visual analogue scale (VAS), heel tenderness threshold was quantified using a handheld pressure algometer (PA), and functional activities level was assessed using the Activities of Daily Living subscale of the Foot and Ankle Ability Measure (ADL/FAAM). RESULTS: Heel pain scores showed a significant reduction in both groups compared to baseline VAS scores (P<0.001). Heel tenderness improved significantly in both groups compared with baseline PA scores (P<0.001). Functional activity level improved significantly in both groups compared with baseline (ADL/FAAM) scores (P<0.001). However, no significant differences existed between the 2 treatment groups in all post-intervention outcome measures. CONCLUSIONS: This trial showed that MPC is useful in treating inferior heel symptoms caused by PF. PMID- 25791232 TI - Investigation of dye adsorption onto activated carbon from the shells of Macore fruit. AB - The activated carbon obtained from the shells of Macore fruit was used as an adsorbent for the removal of dyes such as methylene blue (MB) and methyl orange (MO) from synthetic contaminated aqueous solutions. It holds that the adsorption is more favourable at acidic pH, with an optimum adsorption at pH = 2. At this pH, the adsorption rate is more than 98% for the two dyes. The sorption capacity was enhanced by increasing the amount of activated carbon. Above room temperature, the adsorption rates remain constant at a value of approximately 99%. The study of the adsorption kinetics indicates that the adsorption on the studied dyes follows second-order kinetics. The isotherm adsorption data were found to be described by both Langmuir and Freundlich. In addition, the thermodynamic studies revealed that the adsorption process is a favourable, endothermic and spontaneous phenomenon. PMID- 25791233 TI - Prospect, isolation, and characterization of microorganisms for potential use in cases of oil bioremediation along the coast of Trindade Island, Brazil. AB - In the present study, acrylic coupons with a thin layer of oil on the surface were incubated in the coastal water of Trindade Island, Brazil, for 60 days. The microorganisms adhered to the coupons were isolated using enrichment medium with hexadecane and naphthalene as the sole carbon and energy source. A total of 15 bacterial isolates were obtained, and the ability of these isolates to use different hydrocarbons as the source of carbon and energy was investigated. None of the isolates produced biosurfactants under our experimental conditions. Subsequently, identification methods such as partial sequencing of the 16S rRNA gene and analysis of fatty acids (MIDI) profile were employed. Among the 15 isolates, representatives of Actinobacteria, Firmicutes, and Alphaproteobacteria were detected. The isolates Rhodococcus rhodochrous TRN7 and Nocardia farcinica TRH1 were able to use all the hydrocarbons added to the culture medium (toluene, octane, xylene, naphthalene, phenanthrene, pyrene, hexadecane, anthracene, eicosane, tetracosane, triacontane, and pentacontane). Polymerase chain reaction amplification of the DNA isolated by employing primers for catechol 2,3 dioxygenase, alkane dehydrogenase and the alpha subunit of hydroxylating dioxygenases polycyclic aromatic hydrocarbon rings genes demonstrated that various isolates capable of utilizing hydrocarbons do not exhibit genes of known routes of catabolism, suggesting the existence of unknown catabolic pathways in these microorganisms. Our findings suggest that the microbiota associated to the coast of tropical oceanic islands has the ability to assist in environmental regeneration in cases of accidents involving oil spills in its shore. Thus, it motivates studies to map bioremediation strategies using the autochthonous microbiota from these environments. PMID- 25791234 TI - An integrated environmental decision support system for water pollution control based on TMDL--A case study in the Beiyun River watershed. AB - This paper details the development and application of an integrated environmental decision support system (EDSS) for water pollution control based on total maximum daily load (TMDL). The system includes an infrastructure, simulation, and application platforms. Using the water pollution control of Beiyun River in China as a case study, the key development processes and technologies of the EDSS are discussed including relations and links between various environmental simulation models, and model integration, visualization and real-time simulation methods. A loose coupling method is used to connect the environmental models, and an XML file is used to complete data exchange between different models. Project configuration and scheme configuration are used for simulation data organization. The integration approach is easy to implement and enables different development languages and reuse of existing models. The EDSS has been applied to water environment management of Beiyun River, and can be applied to other geographic regions. PMID- 25791235 TI - Depression and quality of life in relation to decreased glomerular filtration rate among adults with hypertension in rural northeast China. AB - BACKGROUND/AIMS: We aim to investigate the extent to which depression and quality of life might be associated with decreased glomerular filtration rate (GFR) in a large hypertensive population in rural Northeast China. METHODS: A total of 5566 hypertensive participants aged 35 years and older were screened with a stratified cluster multistage sampling scheme in rural areas of Liaoning Province during 2012-2013. Decreased GFR was defined as estimated GFR <60 ml/min/1.73 m2. RESULTS: The overall prevalence of decreased GFR was 3.2%. In the multivariable regression model, participants with moderate or greater depression had a greater risk for having a decreased GFR (OR: 1.739, 95%CI: 1.004 to 3.014) after full adjustment. Every -point increase of all the domains in WHOQOL-BREF, except for physical and environment domains, was significantly related to a lower risk for decreased GFR adjusting for age, gender and race. However, after fully adjustment, only social relations remained significant (OR: 0.899, 95%CI: 0.820 to 0.985). Increasing in total scores of WHOQOL-BREF was a protective factor against decreased GFR after fully adjustment. CONCLUSION: We found that moderate or greater depression and lower quality of life were associated with higher risks for developing decreased GFR. PMID- 25791236 TI - A single-center case series of eight patients with the rare plasma cell dyscrasia of acquired Fanconi syndrome secondary to monoclonal gammopathy. AB - Acquired Fanconi syndrome (FS) is a rare presentation of monoclonal gammopathy. We retrospectively summarized the cases of eight patients with FS secondary to monoclonal gammopathy at Peking Union Medical College Hospital (PUMCH) from January 2007 to April 2014. All patients had generalized or partial impairment of proximal renal tubular function. Six patients were diagnosed with monoclonal gammopathy of undetermined significance (MGUS), and two were diagnosed with multiple myeloma (MM). Although chemotherapy was administered to the two patients with MM and to one patient with MGUS, decreased paraprotein levels did not lead to improvements in metabolic abnormalities. All patients received continuous supplementation with deficient nutrients, leading to marked remission of bone pain and improved quality of life. Although renal function in most patients gradually declined, none of the patients developed end-stage renal disease (ESRD) during an average follow-up time of 31 months, and no case of MGUS has yet transformed into MM. PMID- 25791237 TI - Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease "compartment"; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement. PMID- 25791238 TI - Age-dependency of cardiac and neuromuscular findings in adults with left ventricular hypertrabeculation/noncompaction. AB - Left ventricular hypertrabeculation/noncompaction (LVHT) is diagnosed in all ages and is frequently associated with neuromuscular disorders (NMDs). The aim of the study was to compare patients with LVHT depending on age at diagnosis. Included were 232 patients with LVHT (72 women, mean age 52+/-17 years) diagnosed from 1995 to 2014 at 1 echocardiographic laboratory. In 2014, their survival was assessed. Seventy-six percent of the patients were neurologically investigated, revealing specific NMDs in 18%, unspecific NMDs in 60%, and normal findings in 22%. Forty-five patients (19%) received electronic devices: implantable cardioverter-defibrillators in 26 patients, combined with cardiac resynchronization systems (n=14) or an antibradycardic pacemaker (n=1); antibradycardic pacemakers (n=8); cardiac resynchronization systems (n=4); implantable loop recorders (n=4); life vests (n=2); and a left ventricular assist device as a bridge to transplantation (n=1). During 72-month follow-up, mortality was 4.9% per year. In younger age groups, more patients were referred for syncope or palpitations, whereas in older age groups, more patients were referred for heart failure. Classic cardiovascular risk factors such as hypertension and diabetes, as well as coronary artery stenosis, were rare in the young age groups but were more prevalent in older age groups. Differences between age groups were found regarding cardiac symptoms, NMDs, electrocardiographic findings, rate of device implantation, and mortality but not in location and extension of LVHT. None of the neurologically investigated patients>=70 years of age was neurologically normal. Prevalence of heart failure, electrocardiographic abnormalities, and mortality were highest in the oldest age group. In conclusion, LVHT must be considered as an echocardiographic diagnosis in all age groups. The morphologic pattern of LVHT is similar, whereas clinical manifestations and prognosis are variable among age groups. PMID- 25791239 TI - Comparison of outcomes after one-versus-two transcatheter aortic valve implantation during a same procedure (from the FRANCE2 Registry). AB - Analysis of the causes, outcomes, and mortality of patients with severe symptomatic aortic stenosis requiring the implantation of 2 valves during transcatheter aortic valve implantation was conducted from the French Aortic National CoreValve and Edwards 2 (FRANCE2) registry. Pre- and postprocedural data from 3,919 patients from January 2010 to December 2011 (CoreValve or Edwards) were collated and analyzed. Characteristics of patients requiring immediate second valve procedures were compared with those of the other patients. The 72 patients (1.8%) who underwent implantation of a second valve were studied. Indications were device malpositioning (72%) and embolization (28%). Clinical and echocardiographic characteristics of patients receiving 2 valves were comparable with those of the other patients. The 2-year survival rate was 51.7% for patients with 2 valves as opposed to 62.3% for those with 1 valve (p<0.001). The need for a second valve was an independent predictor of all-cause (hazard ratio 2.32, 95% confidence interval 1.50 to 3.60, p<0.001) and cardiovascular (hazard ratio 2.64, 95% confidence interval 1.35 to 5.15, p<0.001) mortality at 2 years. During follow-up, clinical and echocardiographic data remained similar between the 2 groups. In conclusion, in the FRANCE2 study, the main causes for second valve implantation during the same procedure were malpositioning and embolization. Although the procedure was feasible, it was accompanied by excess mortality. Valve hemodynamic status was preserved during the course of follow-up. PMID- 25791240 TI - Relation of aortic valve calcium to chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study). AB - Although subjects with chronic kidney disease (CKD) are at markedly increased risk for cardiovascular mortality, the relation between CKD and aortic valve calcification has not been fully elucidated. Also, few data are available on the relation of aortic valve calcification and earlier stages of CKD. We sought to assess the relation of aortic valve calcium (AVC) with estimated glomerular filtration rate (eGFR), traditional and novel cardiovascular risk factors, and markers of bone metabolism in the Chronic Renal Insufficiency Cohort (CRIC) Study. All patients who underwent aortic valve scanning in the CRIC study were included. The relation between AVC and eGFR, traditional and novel cardiovascular risk factors, and markers of calcium metabolism were analyzed using both unadjusted and adjusted regression models. A total of 1,964 CRIC participants underwent computed tomography for AVC quantification. Decreased renal function was independently associated with increased levels of AVC (eGFR 47.11, 44.17, and 39 ml/min/1.73 m2, respectively, p<0.001). This association persisted after adjusting for traditional, but not novel, AVC risk factors. Adjusted regression models identified several traditional and novel risk factors for AVC in patients with CKD. There was a difference in AVC risk factors between black and nonblack patients. In conclusion, our study shows that eGFR is associated in a dose dependent manner with AVC in patients with CKD, and this association is independent of traditional cardiovascular risk factors. PMID- 25791241 TI - Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. AB - Over half of patients diagnosed with acute myeloid leukemia (AML) are 65 years or older. We examined patient characteristics, treatment patterns, and survival among elderly patients in routine clinical practice. We utilized a retrospective cohort analysis of first primary AML patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 and December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment. There were 3327 (40 %) patients who received chemotherapy within 3 months of diagnosis. Treated patients were more likely younger, male, and married, and less likely to have secondary AML and poor performance indicators and comorbidity score compared to untreated patients. In multivariate survival analysis, treated patients exhibited a significant 33 % lower risk of death compared to untreated patients. Significant survival benefits were noted with receipt of intensive and hypomethylating agent (HMA) therapies compared to no therapy. A survival benefit with allogeneic hematopoietic stem cell transplantation was seen in younger Medicare patients. This real-world study showed that about 60 % of elderly AML patients remain untreated following diagnosis. Use of anti-leukemic therapy was associated with a significant survival benefit in this elderly cohort. PMID- 25791242 TI - Myeloproliferative neoplasm in a thalassaemic patient: response to treatment with a JAK inhibitor. PMID- 25791243 TI - Remissions of different quality following rituximab, tocilizumab and rituximab, and allogeneic stem cell transplantation in a patient with severe idiopathic multicentric Castleman's disease. PMID- 25791244 TI - Overexpression of JMJD3 may contribute to demethylation of H3K27me3 in CD4+ T cells from patients with systemic sclerosis. PMID- 25791245 TI - The effect of mycophenolic acid on epigenetic modifications in lupus CD4+T cells. AB - Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease involving multiple organs and characterized by overproduction of autoantibodies and T and B cell abnormalities. The treatment for SLE has been restricted to immunosuppressants and corticosteroids. Mycophenolate mofetil (MMF), as a relatively new immunosuppressant, is now widely used in the treatment of SLE patients, particularly those with nephritis. However, it is unclear whether mycophenolic acid (MPA) could modulate the reported disorders of epigenetic status in CD4(+)T cells from SLE patients. In this study, we demonstrated that MPA can upregulate the histone H3/H4 global acetylation status by regulating HATs and HDACs in lupus CD4(+)T cells. Furthermore, we found that MPA also affected the histone H4 acetylation and histone H3K4 tri-methylation levels in CD40L promoter region that inhibited the expression of CD40L. These findings indicate the potential epigenetic mechanism of therapeutic effects of MPA in SLE. PMID- 25791246 TI - Characterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1. AB - SAMHD1 (SAM domain- and HD domain-containing protein 1) inhibits HIV-1 infection of myeloid cells and resting CD4+ T-cells. Two lineages of primate lentiviruses, the sooty mangabey SIV (simian immunodeficiency virus) (SIVsm)/macaque SIV (SIVmac)/HIV-2 lineage and the red-capped mangabey SIV (SIVrcm) lineage, carry a SAMHD1 antagonist called Vpx. Vpx recognizes SAMHD1 and recruits a ubiquitin E3 ligase complex that is composed of CUL4 (Cullin4), DDB1 (damaged DNA-binding protein 1) and a member of the DCAF (DDB1/CUL4-associated factor) family called DCAF1. This E3 ligase complex polyubiquitinates SAMHD1, which leads to proteasomal degradation of SAMHD1. As opposed to the well-characterized interaction of SIVmac Vpx with human SAMHD1 and DCAF1, SIVrcm Vpx adopts a different mode of interaction with SAMHD1 of red-capped mangabeys. In the present study, we have characterized the interactions that are essential for SIVrcm Vpx mediated degradation of rcmSAMHD1 (red-capped mangabey SAMHD1). Using mutagenesis and molecular modelling, we have determined the key role of the W23LHR26 peptide of SIVrcm Vpx in recognizing rcmSAMHD1. The amino acids Phe15, Leu36, Phe52, Arg55 and Arg56 at the N-terminal domain (NtD) of rcmSAMHD1 are involved in interaction with Vpxrcm (red-capped mangabey Vpx). The molecular model of rcmSAMHD1-NtD, Vpxrcm and C-terminal domain (CtD) of DCAF1 (DCAF1-CtD) complex reveals further that rcmSAMHD1-NtD and Vpxrcm utilize an interaction interface that is different from that used by human SAMHD1-CtD and Vpxsm. These findings provide further insights into the different modes of interaction between Vpx and SAMHD1 as the result of the 'arms race' of virus and host cell. PMID- 25791247 TI - Categorical effects in fricative perception are reflected in cortical source information. AB - Previous research in speech perception has shown that category information affects the discrimination of consonants to a greater extent than vowels. However, there has been little electrophysiological work on the perception of fricative sounds, which are informative for this contrast as they share properties with both consonants and vowels. In the current study we address the relative contribution of phonological and acoustic information to the perception of sibilant fricatives using event-related fields (ERFs) and dipole modeling with magnetoencephalography (MEG). We show that the field strength of neural responses peaking approximately 200 ms after sound onset co-varies with acoustic factors, while the cortical localization of earlier M100 responses suggests a stronger influence of phonological categories. We propose that neural equivalents of categorical perception for fricative sounds are best seen using localization measures, and that spectral cues are spatially coded in human cortex. PMID- 25791248 TI - Pre-participation screening for athletes and the role of advanced practice providers. AB - Pre-participation screening of athletes for underlying cardiovascular disease is recommended by the AHA/ACC. However, vigorous debate continues as to whether the ECG should be used as part of a broad-based screening program. The AHA/ACC "do not support national mandatory screening ECGs of athletes, because the logistics, manpower, financial and resource considerations make such a program inapplicable to US". In an effort to address these impediments and to increase access for communities, we explore the use of advanced practice providers (Nurse Practitioners and Physician Assistants) in providing pre-participation screening to athletes with ECG interpretation. In the current healthcare environment with limited primary care resources, advanced practice providers are an important new element in improving access to care. Pre-participation screening with ECG interpretation is currently within an advanced practice provider's scope of practice. Emerging data shows that advanced practice providers perform care that is within acceptable patient care standards, safely, and cost effectively, compared to physician counterparts. To further improve pre-participation screening, a national education and certification program on 12-lead ECG interpretation is needed. Standardized screening tools and mass screening protocols that include screening ECGs for targeted athlete populations who are at high risk for SCD are needed. These recommendations are aimed at addressing some of the barriers raised by the AHA/ACC group to pre-participation screening with ECG. PMID- 25791249 TI - Invasive home mechanical ventilation: living conditions and health-related quality of life. AB - BACKGROUND: The number of patients with invasive home mechanical ventilation (HMV) following unsuccessful weaning is steadily increasing, but little is known about the living conditions and health-related quality of life (HRQL) in these patients. OBJECTIVES: To establish detailed information on living conditions and HRQL in patients with invasive HMV. METHODS: The Severe Respiratory Insufficiency Questionnaire (SRI) was used to measure specific HRQL aspects in addition to patient interviews on individual living conditions during home visits. RESULTS: Thirty-two patients with lung disease, most prominently COPD (n = 18), and neuromuscular disorders (n = 14) were included. The overall mean SRI summary scale score (range 0-100) was 53 +/- 16, with a broad range amongst individuals (23-86). Neuromuscular patients were younger than those with lung diseases (49 +/ 18 vs. 67 +/- 11 years; p < 0.005), and although they had a higher nursing dependency and fewer comorbidities, they tended to have higher (better) SRI summary scale scores (58 +/- 16 vs. 48 +/- 15; p = 0.092). Living in a private home compared to living in nursing facilities did not influence the SRI scores. CONCLUSIONS: Patients undergoing invasive HMV primarily following unsuccessful weaning reported an individual HRQL which, when taken together, was highly heterogeneous and ranged from very good to extremely bad. Older patients with COPD and more comorbidities are likely to have a worse HRQL than neuromuscular patients, while the living situation does not influence the HRQL. PMID- 25791250 TI - Development of a real-time PCR method coupled with a selective pre-enrichment step for quantification of Morganella morganii and Morganella psychrotolerans in fish products. AB - Histamine fish poisoning is common and due to toxic concentrations of histamine often produced by Gram-negative bacteria in fin-fish products with a high content of the free amino acid histidine. The genus Morganella includes two species previously reported to cause incidents of histamine fish poisoning. Morganella morganii and Morganella psychrotolerans are both strong producer of histamine. However, little is known about the occurrence and critical stages for fish contamination with these bacteria. To elucidate contamination routes of Morganella, specific real-time quantitative PCR (RTi qPCR) methods for quantification of M. morganii and M. psychrotolerans have been developed. Selective primers amplified a 110 bp region of the vasD gene for M. psychrotolerans and a 171 bp region of the galactokinase gene for M. morganii. These primer-sets showed high specificity as demonstrated by using purified DNA from 23 other histamine producing bacteria and 26 isolates with no or limited histamine production. The efficiency of the qPCR reactions on artificially contaminated fish samples were 100.8% and 96.3% respectively. The limit of quantification (LOQ) without enrichment was 4 log CFU/g. A quantitative enrichment step with a selective medium was included and improved the sensitivity of the methods to a LOQ of below 50 CFU/g in seafood. RTi qPCR methods with or without enrichment were evaluated for enumeration of Morganella species in naturally contaminated fresh fish and lightly preserved seafood from Denmark. These new methods will contribute to a better understanding of the occurrence and histamine production by Morganella species in fish products, information that is essential to reduce the unacceptably high frequency of histamine fish poisoning. PMID- 25791251 TI - Trisodium phosphate and sodium hypochlorite are more effective as antimicrobials against Campylobacter and Salmonella on duck as compared to chicken meat. AB - Little work has been reported on the use of commercial antimicrobials against foodborne pathogens on duck meat. We investigated the effectiveness of trisodium phosphate (TSP) and sodium hypochlorite (SH) as antimicrobial treatments against Campylobacter and Salmonella on duck meat under simulated commercial water chilling conditions. The results were compared to the same treatments on well studied chicken meat. A six strain Campylobacter or Salmonella cocktail was inoculated (5 ml) at two dilution levels (10(4) and 10(8) cfu/ml) onto 25 g duck or chicken meat with skin and allowed to attach for 10 min. The meat was exposed to three concentrations of pH adjusted TSP (8, 10 and 12% (w/v), pH 11.5) or SH (40, 50 and 60 ppm, pH 5.5) in 30 ml water under simulated spin chiller conditions (4 degrees C, agitation) for 10 min. In a parallel experiment the meat was placed in the antimicrobial treatments before inoculation and bacterial cocktails were added to the meat after the antimicrobial solution was removed while all other parameters were maintained. Untreated controls and controls using water were included in all experiments. Bacterial numbers were determined on Campylobacter blood-free selective agar and Mueller Hinton agar or xylose deoxycholate agar and tryptone soya agar using the thin agar layer method for Campylobacter and Salmonella, respectively. All TSP concentrations significantly (p<0.05) reduced numbers of Campylobacter (~1.2-6.4 log cfu/cm(2)) and Salmonella (~0.4-6.6 log cfu/cm(2)) on both duck and chicken meat. On duck meat, numbers of Campylobacter were less than the limit of detection at higher concentrations of TSP and numbers of Salmonella were less than the limit of detection at all concentrations of TSP except one. On chicken meat, numbers of Campylobacter and Salmonella were less than the limit of detection only at the lower inoculum level and higher TSP concentrations. By contrast only some of the concentrations of SH significantly (p<0.05) reduced numbers of Campylobacter and Salmonella (~0.2-1.5 log cfu/cm(2)) on both duck and chicken meats. None of the SH treatments resulted in numbers of either pathogen being less than limit of detection. Results indicate that chicken meat has the ability to effectively protect Campylobacter and Salmonella against the impact of trisodium phosphate and sodium hypochlorite while duck meat does not. This study suggests that trisodium phosphate has a strong potential for application in a commercial poultry processing to reduce Campylobacter and Salmonella specifically on duck meat. PMID- 25791252 TI - Biodiversity of dairy Propionibacterium isolated from dairy farms in Minas Gerais, Brazil. AB - Dairy propionibacteria are used as ripening cultures for the production of Swiss type cheeses, and some strains have potential for use as probiotics. This study investigated the biodiversity of wild dairy Propionibacteria isolates in dairy farms that produce Swiss-type cheeses in Minas Gerais State, Brazil. RAPD and PFGE were used for molecular typing of strains and MLST was applied for phylogenetic analysis of strains of Propionibacterium freudenreichii. The results showed considerable genetic diversity of the wild dairy propionibacteria, since three of the main species were observed to be randomly distributed among the samples collected from different farms in different biotopes (raw milk, sillage, soil and pasture). Isolates from different farms showed distinct genetic profiles, suggesting that each location represented a specific niche. Furthermore, the STs identified for the strains of P. freudenreichii by MLST were not related to any specific origin. The environment of dairy farms and milk production proved to be a reservoir for Propionibacterium strains, which are important for future use as possible starter cultures or probiotics, as well as in the study of prevention of cheese defects. PMID- 25791253 TI - Monitoring the mycobiota of three plants manufacturing Culatello (a typical Italian meat product). AB - This study reports the composition of the mycobiota growing on the surface of Culatello (a typical Italian meat product) and occurring in the environments of three processing plants. Samples were collected in both winter and summer. A total of 84 culatelli and 14 samples from the plant environment were examined. A total of 331 (from food samples) and 2030 (from air samples) fungal isolates belonging to six genera and 29 species were identified. The substantial correspondence between air- and product-mycobiota in all the manufacturing plants studied seems to indicate a natural selection of those species that have adapted to the thermal-hygrometric conditions to which meat products were subjected. In particular, all sexual Aspergillus spp. with Eurotium-type ascomata, all Scopulariopsis spp. and Sporendonema casei from culatelli exactly matched with those from air samplings, and a prevalence of xerotolerant and xerophilic species belonging to Aspergillus or Penicillium was observed for both culatelli and environments, depending on the plant considered. Aspergillus candidus (16.0%), Penicillium solitum (19.6%), and Aspergillus cristatus (= Eurotium cristatum) (17.2%) were the prevalent species in Plants 1, 2, and 3, respectively. Fungal species producing unsightly spots on the casings (Scopulariopsis spp. and Sporendonema casei) were mainly found in the first steps of the aging, but tended to diminish or to change color throughout the process, so ultimately they did not represent a matter of concern. Fungal species potentially producing ochratoxin A (Penicillium nordicum and Aspergillus westerdijkiae) were the least prevalent species collected from a minor number of culatelli, so their presence could be defined as sporadic and did not represent a risk for consumers' health. This study reports the dominance of desirable species over undesirable molds on culatelli, but also highlights the importance of monitoring those meat products where no bacterial starter can degrade mycotoxins and where neither fungal starters nor a skin can inhibit fungal development. The control of the so-called "house mycobiota" in such products should be periodically assessed both in artisanal and industrial plants, since it proved to be fundamental to focus the potential risks connected to consumption of these meat products. PMID- 25791254 TI - Detection of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in vegetables, soil and water of the farm environment in Tunisia. AB - One-hundred-nine samples of 18 different farms (49 of food-vegetables, 41 of soil and 19 of irrigation water) and 45 vegetable food samples of 13 markets were collected in Tunisia. These samples were inoculated in MacConkey agar plates supplemented with cefotaxime (2 MUg/ml). ESBL-producing Enterobacteriaceae (ESBL Eb) were detected in 10 of the 109 farm samples (vegetables, 8.2%; soil, 7.3%; water, 15.8%), and in 4 of 45 vegetables of markets (8.9%), recovering 15 ESBL Eb. Isolates and ESBL genes detected were: Escherichia coli (n=8: 5 blaCTX-M-1, 2 blaCTX-M-15 and one blaCTX-M-14), Citrobacter freundii (n=4: 3 blaCTX-M-15 and one blaSHV-12), Enterobacter hormaechei (n=2: 2 blaCTX-M-15) and Klebsiella pneumoniae (n=1, blaCTX-M-15). The ISEcp1 sequence was found upstream of blaCTX-M genes in 13 of 14 strains (in three cases truncated by IS5), and orf477 or IS903 downstream. Class 1 integrons were detected in five strains and contained two gene cassette arrangements (dfrA17-aadA5 and aadA1). Most isolates tested showed a multiresistant phenotype. All blaCTX-M-15-positive strains carried the aac(6') 1b-cr gene, that affects to amikacin-tobramycin-kanamycin-ciprofloxacin. Five ESBL-Eb strains carried genes of the qnr family. The 8 ESBL-positive E. coli isolates were typed as: ST58/B1 (n=3) and ST117/D, ST131/B2, ST10/A, ST23/A, and the new ST3496/D (one strain, each). From 1-2 plasmids were detected in all ESBL positive E. coli isolates (63-179 kb). The ESBL genes were transferred by conjugation in 4 blaCTX-M-1-positive E. coli strains, and transconjugants acquired a 97 kb IncI1 plasmid. ESBL-Eb isolates are frequently disseminated in vegetable farms and potentially could be transmitted to humans through the food chain. PMID- 25791255 TI - The linguine sign. PMID- 25791256 TI - In Reply to: Confirmation of hCG Point-of-Care Qualitative Device Limitations in the Emergency Department. PMID- 25791257 TI - In reply: ultrasound-assisted lumbar puncture in pediatric patients. PMID- 25791258 TI - Plasma phosphatidylcholine alterations in cystic fibrosis patients: impaired metabolism and correlation with lung function and inflammation. AB - BACKGROUND: Liver impairment, ranging from steatosis to cirrhosis, is frequent in cystic fibrosis (CF) patients and is becoming increasingly significant due to their improved life expectancy. One aspect of hepatic alterations is caused by increased fecal loss of the essential nutrient choline, following enterohepatic bile phosphatidylcholine (PC) cycle impairment. Hepatic PC synthesis, both de novo and via phosphatidylethanolamine-N-methyl-transferase (PEMT), is essential for very low-density lipoprotein (VLDL) secretion. VLDL-PC in particular contributes to the organism's supply with polyunsaturated fatty acids (LC-PUFA), namely arachidonic (C20:4) and docosahexaenoic acid (C22:6). Consequently, choline deprivation and altered hepatic PC metabolism may affect plasma PC homeostasis and extrahepatic organ function. OBJECTIVES: To investigate relationships between altered plasma choline and PC homeostasis and markers of lung function and inflammation in CF. To assess alterations in hepatic choline and PC metabolism of CF patients. DESIGN: Quantification of plasma/serum choline and PC species in adult CF patients compared to controls. Correlation of PC with forced expiratory vital capacity (FEV1) and interleukin 6 (IL-6) concentrations. Analysis of choline and PC metabolism in CF compared to controls, using deuterated choline ([D9-methyl]-choline) labeling in vivo. RESULTS: Mean choline and PC concentrations in CF patients were lower than in controls. Choline and PC concentrations as well as fractions of C22:6-PC and C20:4-PC correlated directly with FEV1, but inversely with IL-6. Plasma concentrations of deuterated PC were decreased for both pathways, whereas only in PC synthesized via PEMT precursor enrichment was decreased. CONCLUSION: In CF patients, hepatic and plasma homeostasis of choline and PC correlate with lung function and inflammation. Impaired hepatic PC metabolism, exemplarily shown in three CF patients, provides an explanation for such correlations. Larger studies are required to understand the link between hepatic PC metabolism and overall clinical performance of CF patients, and the perspective of choline substitution of these patients. PMID- 25791259 TI - Macrophage activation syndrome with acute hepatitis E during tocilizumab treatment for rheumatoid arthritis. AB - Tocilizumab is a humanized antibody against the membrane and soluble receptors for interleukin-6. Tocilizumab is among the disease-modifying antirheumatic drugs (DMARDs) used to treat moderate-to-severe active rheumatoid arthritis (RA) refractory to conventional DMARDs. We report a case of macrophage activation syndrome that complicated acute hepatitis E and started within 24hours after the fourth tocilizumab infusion in a patient with RA. PMID- 25791261 TI - Incorporating non-adiabatic effects in embedded atom potentials for radiation damage cascade simulations. AB - In radiation damage cascade displacement spikes ions and electrons can reach very high temperatures and be out of thermal equilibrium. Correct modelling of cascades with molecular dynamics should allow for the non-adiabatic exchange of energy between ions and electrons using a consistent model for the electronic stopping, electronic temperature rise, and thermal conduction by the electrons. We present a scheme for correcting embedded atom potentials for these non adiabatic properties at the level of the second-moment approximation, and parameterize for the bcc transition metals above the Debye temperature. We use here the Finnis-Sinclair and Derlet-Nguyen-Manh-Dudarev potentials as models for the bonding, but the corrections derived from them can be applied to any suitable empirical potential. We show with two-temperature MD simulations that computing the electronic thermal conductivity during the cascade evolution has a significant impact on the heat exchange between ions and electrons. PMID- 25791260 TI - Cardiovascular complications in patients with autonomic failure. AB - Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure. PMID- 25791262 TI - Intraocular Pressure in Eyes Receiving Intravitreal Antivascular Endothelial Growth Factor Injections. AB - PURPOSE: The aim of the this study was to determine the effect of intravitreal antivascular endothelial growth factor injections on intraocular pressure (IOP) and identify possible risk factors for the development of increased IOP. MATERIALS AND METHODS: This prospective study included a total of 106 eyes receiving intravitreal injection of bevacizumab as treatment for macular edema or active choroidal neovascularization. IOP was measured by Goldmann applanation tonometry immediately before the intravitreal injection and 5 min, 1 h and 15 days after the procedure. The records of the study patients were reviewed for age, gender, history of glaucoma, diabetes mellitus, phakic status, systemic and topical medication and number of previous injections. Subconjunctival reflux was registered. IOP elevation was defined as IOP >=21 mm Hg and/or a change from baseline of >=5 mm Hg recorded at least on two or more measurements on the same visit. RESULTS: Mean preoperative IOP was 15.31 +/- 3.90 mm Hg and postoperative IOP values were 27.27 +/- 11.87 mm Hg (after 5 min), 17.59 +/- 6.24 mm Hg (after 1 h) and 16.86 +/- 3.62 mm Hg (after 15 days). The IOP variation was statistically significant between pre- and postoperative measurements (p < 0.05). Subconjunctival reflux was recorded in 11.3%, and in this subgroup the IOP at 5 min and at 1 h was lower than preoperative IOP (p < 0.05). CONCLUSIONS: More than one third of the eyes achieved IOPs >30 mm Hg 5 min after injection. Subconjunctival reflux contributed to a lower mean postoperative IOP (p < 0.05). Considerations for the management include prophylactic IOP lowering with medical therapy and/or preinjection ocular decompression for patients with a history of glaucoma or ocular hypertension and switching to an as-needed injection protocol in patients suffering a marked IOP rise in previous injections. PMID- 25791263 TI - Report on the fifth meeting of INRA's national network of ecotoxicologists, ECOTOX. AB - The fifth meeting of INRA's national network of ecotoxicologists took place on 25 to 27 November 2014 in Biarritz, France. The main aim of the meeting was to bring together ecotoxicologists from INRA and associated partners, providing them ample opportunity to share and discuss their latest scientific results as well as the national policy of research in ecotoxicology and to precise perspectives for the network. PMID- 25791264 TI - Arsenic removal by nanoparticles: a review. AB - Contamination of natural waters with arsenic, which is both toxic and carcinogenic, is widespread. Among various technologies that have been employed for arsenic removal from water, such as coagulation, filtration, membrane separation, ion exchange, etc., adsorption offers many advantages including simple and stable operation, easy handling of waste, absence of added reagents, compact facilities, and generally lower operation cost, but the need for technological innovation for water purification is gaining attention worldwide. Nanotechnology is considered to play a crucial role in providing clean and affordable water to meet human demands. This review presents an overview of nanoparticles and nanobased adsorbents and its efficiencies in arsenic removal from water. The paper highlights the application of nanomaterials and their properties, mechanisms, and advantages over conventional adsorbents for arsenic removal from contaminated water. PMID- 25791266 TI - Phytotoxicity of arsenic compounds on crop plant seedlings. AB - The effects of inorganic and organic arsenic on the germination and seedling growth of 10 crop plants were investigated to elucidate the relationship between toxicity and the arsenic chemical states. Two types of soils, soil A and B, were also tested to determine how physicochemical properties of soils were related to toxicity of arsenic and the sensitivity of the plants. All tested plant species, except mung bean and cucumber, showed inhibition of germination by two types of inorganic arsenic, arsenite, and arsenate, while the organic arsenic compound, dimethylarsinic acid (DMA), had no inhibitory effects on plants in soil A. In contrast, the growth of seedlings of all 10 plant species was sensitive to the presence of arsenic. The sensitivity of the plants toward inorganic arsenic compounds showed similar trends but differed for DMA. Overall, seedling growth was a more sensitive endpoint to arsenic toxicity than germination, and the relative toxicity of arsenic compounds on plants was arsenite > DMA > arsenate. Interestingly, the sensitivity of wheat varied significantly when the soil was changed, and the DMA was most toxic rather than arsenite in soil B. Thus, the systematic study employed here provides insights into the mechanisms of arsenic toxicity in different plant species and the role of physicochemical properties of soils. PMID- 25791265 TI - Responses of cytochrome P450, GST, and MXR in the mollusk Corbicula fluminea to the exposure to hospital wastewater effluents. AB - Pharmaceutical products are a major group of chemical compounds that are continuously released into the environment. The primary pathway of pharmaceuticals to the aquatic environment is the discharge of wastewater effluents. The Psychiatric hospital of Montpon (Dordogne, France) operates with its wastewater treatment plant. We first evaluated the presence and concentrations of 27 pharmaceuticals compounds in these effluents. All of the 27 compounds were detected in these wastewater effluents at concentrations ranging between 37,500 ng L(-1) (paracetamol) and 150 ng L(-1) (citalopram). The aim of the study was then to evaluate the exposure effects of the effluents on cytochrome P450, GST, and MXR responses in Corbicula fluminea gills and digestive glands. Experiments on clams exposed during 1, 3, 7 14, and 21 days revealed a strong and continuous overexpression of mdr1 (multidrug resistant 1) gene expression in gills and transitory variations in pi-gst expression and GST activity. EROD activity increased also transitory after 1 day in the digestive gland of exposed clams. These results indicated that in the effluent, some molecules have undergone metabolism of phase 1 and/or phase 2. PMID- 25791267 TI - Develop dynamic model for predicting traffic CO emissions in urban areas. AB - The greater the use of energy in the transportation sectors, the higher the emission of carbon monoxide (CO), and hence inevitable harm to environment and human health. In this concern, measuring and predicting of CO emission from transportation sector-especially large cities-is important as it constitute 90 % of all CO emission. Many urban cities in developing world have not properly experienced such measurements or predictions. In this paper, for the first time, field measurements of traffic characteristics data and corresponding CO concentration have been performed for developing a model for predicting CO emissions from transportation sector for New Borg El Arab (NBC), Egypt. The performance of Swiss-German Handbook Emission Factors for Road Transport (HBEFA v3.1) model has been assessed for predicting the CO concentration at roadside in the study area. Results indicated that HBEFA v3.1 underestimate emission figures. The developed CO dynamic emission model involves the traffic flow characteristics with roadside CO concentrations. Acceptable representation of measured CO concentration has been shown by the developed dynamic CO emission model which introduces R (2) = 0.77, mean biases and frictional biases of -0.27 mg m(-3) and 0.09, respectively. A comparison between predicted CO concentrations using HBEFA v3.1 and the promoted dynamic model indicate that HBEFA v3.1 estimates CO emission concentrations in the study area with a mean error and frictional biases 159.26 and 233.33 %, respectively, higher than those of the developed model. PMID- 25791269 TI - Methyltrioxorhenium-catalyzed highly selective dihydroxylation of 1,2-allenylic diphenyl phosphine oxides. AB - For the first time, methyltrioxorhenium (MTO) has been applied as a catalyst for the dihydroxylation of allenes in the presence of hydrogen peroxide as the oxidant. The regioselectivities turn out to be well controlled, affording beta carbonyl-gamma-hydroxyl diphenyl phosphine oxides as the only product. The axial chirality of optically active allenes can also be nicely transferred to the chirality center of the products. Based on chirality transfer experiments and ESI MS studies of (18)O-labeled products, a possible mechanism, proceeding via regioselective epoxidation of the electron-rich carbon-carbon double bond, a subsequent intermolecular nucleophilic attack of a water molecule on the in situ formed epoxide via neighboring group participation (NGP), followed by a rearrangement has been proposed as the major reaction pathway. PMID- 25791268 TI - Hartig' net formation of Tricholoma vaccinum-spruce ectomycorrhiza in hydroponic cultures. AB - For re-forestation of metal-contaminated land, ectomycorrhizal trees may provide a solution. Hence, the study of the interaction is necessary to allow for comprehensive understanding of the mutually symbiotic features. On a structural level, hyphal mantle and the Hartig' net formed in the root apoplast are essential for plant protection and mycorrhizal functioning. As a model, we used the basidiomycete Tricholoma vaccinum and its host spruce (Picea abies). Using an optimized hydroponic cultivation system, both features could be visualized and lower stress response of the tree was obtained in non-challenged cultivation. Larger spaces in the apoplasts could be shown with high statistical significance. The easy accessibility will allow to address metal stress or molecular responses in both partners. Additionally, the proposed cultivation system will enable for other experimental applications like addressing flooding, biological interactions with helper bacteria, chemical signaling, or other biotic or abiotic challenges relevant in the natural habitat. PMID- 25791270 TI - Solid state and solution studies of lithium tris(n-butyl)magnesiates stabilised by Lewis donors. AB - Several Lewis base adducts of the synthetically important lithium tris(n butyl)magnesiate LiMg((n)Bu)3 have been prepared and structurally characterised. The complexes were prepared by a co-complexation approach i.e., by combining the monometallic (n)BuLi and (n)Bu2Mg reagents in hydrocarbon solution before adding a molar equivalent of a donor molecule (a bidentate amine, tridentate amine or cyclic ether). The lithium magnesiates all adopt variants of the "Weiss motif" structure, i.e., contacted ion pair dimers with a linear arrangement and metals connected by butyl anions, where tetrahedral magnesium ions are in the central positions and the lithiums occupy the outer region, solvated by a neutral Lewis donor [(donor)Li(MU-(n)Bu)2Mg(MU-(n)Bu)2Mg(MU-(n)Bu)2Li(donor)]. When TMPDA, PMDETA or (R,R)-TMCDA [TMPDA = N,N,N'N'-tetramethylpropanediamine; PMDETA = N,N,N',N'',N''-pentamethyldiethylenetriamine; and (R,R)-TMCDA = (R,R)-N,N,N',N' tetramethylcyclohexane-1,2-diamine], are employed, dimeric tetranuclear lithium magnesiates are produced. Due to the tridentate nature of the ligand, the PMDETA containing structure (2) has an unusual 'open'-motif. When TMEDA (TMEDA = N,N,N',N'-tetramethylethylenediamine) is employed, a n-butoxide-containing complex [(TMEDA)Li(MU-(n)Bu)(MU-O(n)Bu)Mg2((n)Bu)2(MU-(n)Bu)(MU-O(n)Bu)Li(donor)] has been serendipitously prepared and adopts a ladder conformation which is commonly observed in lithium amide chemistry. This complex has also been prepared using a rational methodology. When 1,4-dioxane is employed, the donor stitches together a polymeric array of tetranuclear dimeric units (6). The hydrocarbon solution structures of the compounds have been characterised by (1)H, (7)Li, (13)C NMR spectroscopy; 2 has been studied by variable temperature and DOSY NMR. PMID- 25791271 TI - Molecular Genetic Evidence for Shared Etiology of Autism and Prodigy. AB - Child prodigies are rare individuals with an exceptional working memory and unique attentional skills that may facilitate the attainment of professional skill levels at an age well before what is observed in the general population. Some characteristics of prodigy have been observed to be quantitatively similar to those observed in autism spectrum disorder (ASD), suggesting possible shared etiology, though objectively validated prodigies are so rare that evidence has been sparse. We performed a family-based genome-wide linkage analysis on 5 nuclear and extended families to search for genetic loci that influence the presence of both prodigy and ASD, assuming that the two traits have the same genetic etiology in the analysis model in order to find shared loci. A shared locus on chromosome 1p31-q21 reached genome-wide significance with two extended family-based linkage methods consisting of the Bayesian PPL method and the LOD score maximized over the trait parameters (i.e., MOD), yielding a simulation based empirical significance of p = 0.000742 and p = 0.000133, respectively. Within linkage regions, we performed association analysis and assessed if copy number variants could account for the linkage signal. No evidence of specificity for either the prodigy or the ASD trait was observed. This finding suggests that a locus on chromosome 1 increases the likelihood of both prodigy and autism in these families. PMID- 25791272 TI - [Herbert Lochs, former rector of the Medical University of Innsbruck, passed away on 10 February 2015, 69th year of life]. PMID- 25791273 TI - The intracavitary ECG method for insertion of a tunneled dialysis catheter without using fluoroscopy. AB - PURPOSE: Recently, there have been many reports that exact central vein catheter tip positioning was possible using intracardiac electrocardiographic (ECG) monitoring. Ultrasonic guidance in combination with intracardiac ECG monitoring may allow for a tunneled dialysis catheter to be inserted at the bedside without using fluoroscopy. Therefore we report on the intracavitary ECG method for insertion of a tunneled dialysis catheter with ultrasound guidance and the feasibility, safety, effectiveness, complications and limitations of this method. METHODS: From April 2012 to June 2014, we evaluated 142 hemodialysis (HD) patients who were dialyzed by a tunneled dialysis catheter that was inserted using intracardiac ECG monitoring without fluoroscopic usage. We checked the intracardiac P wave and the point at which it gradually rose to the highest P wave morphology, we stopped inserting the catheter. RESULTS: Catheter flow during dialysis was adequate in 139 cases. There were three cases where it malfunctioned. Catheter malposition occurred in 6 out of 142 cases. The correct matching rate between the intracardiac ECG and chest posteroanterior (PA) view was 98.5%. No significant complications developed. CONCLUSIONS: To conclude, in this single-center study, the intracavitary ECG method for assessing the position of the tip of tunneled dialysis catheter was proven to be safe and feasible in virtually all adult patients who had an evident P wave at the basal ECG tracking. PMID- 25791274 TI - Persistent hoarseness following catheter placement in a renal transplant recipient. PMID- 25791275 TI - Hemodialysis Reliable Outflow device impingement in the subclavian position: a case report. AB - PURPOSE: The purpose of this study is to report a case of Hemodialysis Reliable Outflow (HeRO) device malfunction in the subclavian position secondary to costoclavicular impingement. METHODS AND RESULTS: The electronic medical record was reviewed for the patient in question and pertinent imaging was collected and photographs were taken with the patient's consent. The patient presented with signs of outflow obstruction after a period of HeRO venous outflow component function. The outflow component was found to be crushed between the first rib and the clavicle at the costoclavicular junction. CONCLUSIONS: This case suggests that costoclavicular impingement should be considered as a mode of outflow failure with the HeRO outflow component in the subclavian position. Other central venous access points should be considered first, and the central veins accessed through the lower extremities are possible alternatives if this failure mode was to arise. First rib resection would also be a viable strategy to relieve impingement at this site. PMID- 25791276 TI - Digital games for type 1 and type 2 diabetes: underpinning theory with three illustrative examples. AB - Digital games are an important class of eHealth interventions in diabetes, made possible by the Internet and a good range of affordable mobile devices (eg, mobile phones and tablets) available to consumers these days. Gamifying disease management can help children, adolescents, and adults with diabetes to better cope with their lifelong condition. Gamification and social in-game components are used to motivate players/patients and positively change their behavior and lifestyle. In this paper, we start by presenting the main challenges facing people with diabetes-children/adolescents and adults-from a clinical perspective, followed by three short illustrative examples of mobile and desktop game apps and platforms designed by Ayogo Health, Inc. (Vancouver, BC, Canada) for type 1 diabetes (one example) and type 2 diabetes (two examples). The games target different age groups with different needs-children with type 1 diabetes versus adults with type 2 diabetes. The paper is not meant to be an exhaustive review of all digital game offerings available for people with type 1 and type 2 diabetes, but rather to serve as a taster of a few of the game genres on offer today for both types of diabetes, with a brief discussion of (1) some of the underpinning psychological mechanisms of gamified digital interventions and platforms as self management adherence tools, and more, in diabetes, and (2) some of the hypothesized potential benefits that might be gained from their routine use by people with diabetes. More research evidence from full-scale evaluation studies is needed and expected in the near future that will quantify, qualify, and establish the evidence base concerning this gamification potential, such as what works in each age group/patient type, what does not, and under which settings and criteria. PMID- 25791277 TI - Enhancing medical named entity recognition with an extended segment representation technique. AB - OBJECTIVE: The objective of this paper is to formulate an extended segment representation (SR) technique to enhance named entity recognition (NER) in medical applications. METHODS: An extension to the IOBES (Inside/Outside/Begin/End/Single) SR technique is formulated. In the proposed extension, a new class is assigned to words that do not belong to a named entity (NE) in one context but appear as an NE in other contexts. Ambiguity in such cases can negatively affect the results of classification-based NER techniques. Assigning a separate class to words that can potentially cause ambiguity in NER allows a classifier to detect NEs more accurately; therefore increasing classification accuracy. RESULTS: The proposed SR technique is evaluated using the i2b2 2010 medical challenge data set with eight different classifiers. Each classifier is trained separately to extract three different medical NEs, namely treatment, problem, and test. From the three experimental results, the extended SR technique is able to improve the average F1-measure results pertaining to seven out of eight classifiers. The kNN classifier shows an average reduction of 0.18% across three experiments, while the C4.5 classifier records an average improvement of 9.33%. PMID- 25791278 TI - Citrate versus acetate-based dialysate in on-line haemodiafiltration. A prospective cross-over study. AB - BACKGROUND AND AIMS: A bicarbonate dialysate acidified with citrate (CD) has been reported to have local anticoagulant effect and improves biocompatibility. This study examines the effect of CD on dialysis efficiency, coagulation, acid-base status, electrolytes, and inflammation in patients in on-line hemodiafiltration (OL-HDF). METHODS: 35 patients in OL-HDF were enrolled in a prospective, cross over study for a 24-week period and two phases alternating CD and acetate dialysate fluid (AD). Parameters on study were predialysis levels of bicarbonate and ionic calcium, reactive C Protein (CRP), and beta-2 microglobulin (B2MG) and postdialysis levels of activated tromboplastine time, bicarbonate, and ionized calcium. RESULTS: No significant differences in coagulation parameters, pH, and predialysis bicarbonate were found. The postdialysis bicarbonate and postdialysis calcium were lower with CD. Dialysis efficiency was greater with CD. Regarding inflammatory parameters, both CRP and B2MG were lower using CD. CONCLUSION: The use of CD is safe and effective in OL-HDF, and it improves dialysis efficacy, postdialysis alkalosis, and inflammation. PMID- 25791279 TI - Poor tolerance and limited effects of isosorbide-5-mononitrate in microvascular angina. PMID- 25791280 TI - Identification of MicroRNAs Differentially Expressed in Lung Carcinoid Subtypes and Progression. AB - AIM: To extensively explore microRNA expression profiles in lung carcinoids in correlation with clinical and pathological features. METHODS: A PCR-based array was employed in the screening phase to analyze 752 microRNAs in a discovery set of 12 lung carcinoids, including 6 typical (3 with lymph node metastasis) and 6 atypical (3 with lymph node metastasis). The results were validated by means of real-time PCR in 37 carcinoids, including 22 typical (4 with lymph node metastasis) and 15 atypical (7 with lymph node metastasis), and 19 high-grade neuroendocrine carcinomas. RESULTS: Unsupervised cluster analysis segregated the pilot cases into 3 distinct groups. Twenty-four microRNAs were differentially regulated in atypical versus typical carcinoids, and 29 in metastatic versus nonmetastatic cases. Eleven microRNAs were selected for validation. All but 1 were significantly different among lung neuroendocrine tumor histotypes. Moreover, 5 (miR-129-5p, miR-409-3p, miR-409-5p, miR-185 and miR-497) were significantly upregulated in typical compared to atypical carcinoids. MiR-409-3p, miR-409-5p and miR-431-5p were also significantly downregulated in carcinoids metastatic to the lymph nodes. Predictive in silico analysis of specific target genes showed that these 3 latter microRNAs linked to metastatic potential are implicated in several cellular functions and highlighted several novel genes which may be worth exploring. CONCLUSIONS: Our findings demonstrate that lung carcinoids have distinct microRNA expression profiles as compared to high-grade neuroendocrine carcinomas and that specific microRNAs might have potential implications as diagnostic tools or clinical biomarkers. PMID- 25791281 TI - Gene expression mapping of histone deacetylases and co-factors, and correlation with survival time and 1H-HRMAS metabolomic profile in human gliomas. AB - Primary brain tumors are presently classified based on imaging and histopathological techniques, which remains unsatisfaying. We profiled here by quantitative real time PCR (qRT-PCR) the transcripts of eighteen histone deacetylases (HDACs) and a subset of transcriptional co-factors in non-tumoral brain samples from 15 patients operated for epilepsia and in brain tumor samples from 50 patients diagnosed with grade II oligodendrogliomas (ODII, n = 9), grade III oligodendrogliomas (ODIII, n = 22) and glioblastomas (GL, n = 19). Co-factor transcripts were significantly different in tumors as compared to non-tumoral samples and distinguished different molecular subgroups of brain tumors, regardless of tumor grade. Among all patients studied, the expression of HDAC1 and HDAC3 was inversely correlated with survival, whereas the expression of HDAC4, HDAC5, HDAC6, HDAC11 and SIRT1 was significantly and positively correlated with survival time of patients with gliomas. (1)H-HRMAS technology revealed metabolomically distinct groups according to the expression of HDAC1, HDAC4 and SIRT1, suggesting that these genes may play an important role in regulating brain tumorigenesis and cancer progression. Our study hence identified different molecular fingerprints for subgroups of histopathologically similar brain tumors that may enable the prediction of outcome based on the expression level of co factor genes and could allow customization of treatment. PMID- 25791282 TI - Estimating vocal repertoire size is like collecting coupons: a theoretical framework with heterogeneity in signal abundance. AB - Vocal repertoire size is an important behavioural measure in songbirds and mammals with complex vocal communication systems, and has traditionally been used as an indicator of individual fitness, cognitive ability, and social structure. Estimates of asymptotic repertoire size have typically been made using curve fitting techniques. However, the exponential model usually applied in these techniques has never been provided with a theoretical justification based on probability theory, and the model has led to inaccurate estimates. We derived the precise expression for the expected number of distinct signal types observed for a fixed sampling effort: a variation of what is known in the statistical literature as the "Coupon Collector's problem". We used empirical data from three species (northern mockingbird, Carolina chickadee, and rock hyrax) to assess the performance of the Coupon Collector model compared to commonly used techniques, such as exponential fitting and repertoire enumeration, and also tested the different models against simulated artificial data sets with the statistical properties of the empirical data. We found that when signal probabilities are dissimilar, the Coupon Collector model provides far more accurate estimates of repertoire size than traditional techniques. Enumeration and exponential curve fitting greatly underestimated repertoire size, despite appearing to have reached saturation. Application of the Coupon Collector model can generate more accurate estimates of repertoire size than the commonly used exponential model of repertoire discovery, and could go a long way towards re-establishing repertoire size as a useful indicator in animal communication research. PMID- 25791283 TI - The role of residence times in two-patch dengue transmission dynamics and optimal strategies. AB - The reemergence and geographical dispersal of vector-borne diseases challenge global health experts around the world and in particular, dengue poses increasing difficulties in the Americas, due in part to explosive urban and semi-urban growth, increases of within and between region mobility, the absence of a vaccine, and the limited resources available for public health services. In this work, a simple deterministic two-patch model is introduced to assess the impact of dengue transmission dynamics in heterogeneous environments. The two-patch system models the movement (e.g. urban versus rural areas residence times) of individuals between and within patches/environments using residence-time matrices with entries that budget within and between host patch relative residence times, under the assumption that only the human budgets their residence time across regions. Three scenarios are considered: (i) resident hosts in Patch i visit patch j, where i?j but not the other way around, a scenario referred to as unidirectional motion; (ii) symmetric bi-directional motion; and (iii) asymmetric bi-directional motion. Optimal control theory is used to identify and evaluate patch-specific control measures aimed at reducing dengue prevalence in humans and vectors at a minimal cost. Optimal policies are computed under different residence-matrix configurations mentioned above as well as transmissibility scenarios characterized by the magnitude of the basic reproduction number. Optimal patch-specific polices can ameliorate the impact of epidemic outbreaks substantially when the basic reproduction number is moderate. The final patch specific epidemic size variation increases as the residence time matrix moves away from the symmetric case (asymmetry). As expected, the patch where individuals spend most of their time or in the patch where transmissibility is higher tend to support larger patch-specific final epidemic sizes. Hence, focusing on intervention that target areas where individuals spend "most" time or where transmissibility is higher turn out to be optimal. Therefore, reducing traffic is likely to take a host-vector system into the world of manageable outbreaks. PMID- 25791284 TI - Model of complex chiral drug metabolic systems and numerical simulation of the remaining chirality toward analysis of dynamical pharmacological activity. AB - In this study, systems of complicated pathways involved in chiral drug metabolism were investigated. The development of chiral drugs resulted in significant improvement in the remedies available for the treatment of various severe sicknesses. Enantiopure drugs undergo various biological transformations that involve chiral inversion and thus result in the generation of multiple enantiomeric metabolites. Identification of the specific active substances determining a given drug's efficacy among such a mixture of different metabolites remains a challenge. To comprehend this complexity, we constructed a mathematical model representing the complicated metabolic pathways simultaneously involving chiral inversion. Moreover, this model is applied to the metabolism of thalidomide, which has recently been revived as a potentially effective prescription drug for a number of intractable diseases. The numerical simulation results indicate that retained chirality in the metabolites reflects the original chirality of the unmetabolized drug, and a higher level of enantiomeric purity is preserved during spontaneous degradation. In addition, chirality remaining after equilibration is directly related to the rate constant not only for chiral inversion but also for generation and degradation. Furthermore, the retention of chirality is quantitatively predictable using this combination of kinetic parameters. Our simulation results well explain the behavior of thalidomide in the practical biological experimental data. Therefore, this model promises a comprehensive understanding of dynamic metabolic systems involving chiral drugs that express multiple enantiospecific drug efficacies. PMID- 25791286 TI - Identifiability of the unrooted species tree topology under the coalescent model with time-reversible substitution processes, site-specific rate variation, and invariable sites. AB - The inference of the evolutionary history of a collection of organisms is a problem of fundamental importance in evolutionary biology. The abundance of DNA sequence data arising from genome sequencing projects has led to significant challenges in the inference of these phylogenetic relationships. Among these challenges is the inference of the evolutionary history of a collection of species based on sequence information from several distinct genes sampled throughout the genome. It is widely accepted that each individual gene has its own phylogeny, which may not agree with the species tree. Many possible causes of this gene tree incongruence are known. The best studied is the incomplete lineage sorting, which is commonly modeled by the coalescent process. Numerous methods based on the coalescent process have been proposed for the estimation of the phylogenetic species tree given DNA sequence data. However, use of these methods assumes that the phylogenetic species tree can be identified from DNA sequence data at the leaves of the tree, although this has not been formally established. We prove that the unrooted topology of the n-leaf phylogenetic species tree is generically identifiable given observed data at the leaves of the tree that are assumed to have arisen from the coalescent process under a time-reversible substitution process with the possibility of site-specific rate variation modeled by the discrete gamma distribution and a proportion of invariable sites. PMID- 25791287 TI - Practopoiesis: or how life fosters a mind. AB - The mind is a biological phenomenon. Thus, biological principles of organization should also be the principles underlying mental operations. Practopoiesis states that the key for achieving intelligence through adaptation is an arrangement in which mechanisms laying at a lower level of organization, by their operations and interaction with the environment, enable creation of mechanisms laying at a higher level of organization. When such an organizational advance of a system occurs, it is called a traverse. A case of traverse is when plasticity mechanisms (at a lower level of organization), by their operations, create a neural network anatomy (at a higher level of organization). Another case is the actual production of behavior by that network, whereby the mechanisms of neuronal activity operate to create motor actions. Practopoietic theory explains why the adaptability of a system increases with each increase in the number of traverses. With a larger number of traverses, a system can be relatively small and yet, produce a higher degree of adaptive/intelligent behavior than a system with a lower number of traverses. The present analyses indicate that the two well-known traverses - neural plasticity and neural activity - are not sufficient to explain human mental capabilities. At least one additional traverse is needed, which is named anapoiesis for its contribution in reconstructing knowledge e.g., from long term memory into working memory. The conclusions bear implications for brain theory, the mind-body explanatory gap, and developments of artificial intelligence technologies. PMID- 25791285 TI - Quantification and simulation of layer-specific mitral valve interstitial cells deformation under physiological loading. AB - Within each of the four layers of mitral valve (MV) leaflet tissues there resides a heterogeneous population of interstitial cells that maintain the structural integrity of the MV tissue via protein biosynthesis and enzymatic degradation. There is increasing evidence that tissue stress-induced MV interstitial cell (MVIC) deformations can have deleterious effects on their biosynthetic states that are potentially related to the reduction of tissue-level maintenance and to subsequent organ-level failure. To better understand the interrelationships between tissue-level loading and cellular responses, we developed the following integrated experimental-computational approach. Since in vivo cellular deformations are not directly measurable, we quantified the in-situ layer specific MVIC deformations for each of the four layers under a controlled biaxial tension loading device coupled to multi-photon microscopy. Next, we explored the interrelationship between the MVIC stiffness and deformation to layer-specific tissue mechanical and structural properties using a macro-micro finite element computational model. Experimental results indicated that the MVICs in the fibrosa and ventricularis layers deformed significantly more than those in the atrialis and spongiosa layers, reaching a nucleus aspect ratio of 3.3 under an estimated maximum physiological tension of 150N/m. The simulated MVIC moduli for the four layers were found to be all within a narrow range of 4.71-5.35kPa, suggesting that MVIC deformation is primarily controlled by each tissue layer's respective structure and mechanical behavior rather than the intrinsic MVIC stiffness. This novel result further suggests that while the MVICs may be phenotypically and biomechanically similar throughout the leaflet, they experience layer-specific mechanical stimulatory inputs due to distinct extracellular matrix architecture and mechanical behaviors of the four MV leaflet tissue layers. This also suggests that MVICs may behave in a layer-specific manner in response to mechanical stimuli in both normal and surgically modified MVs. PMID- 25791288 TI - Discovering short linear protein motif based on selective training of profile hidden Markov models. AB - Short linear motifs (SLiMs) in proteins are relatively conservative sequence patterns within disordered regions of proteins, typically 3-10 amino acids in length. They play an important role in mediating protein-protein interactions. Discovering SLiMs by computational methods has attracted more and more attention, most of which were based on regular expressions and profiles. In this paper, a de novo motif discovery method was proposed based on profile hidden Markov models (HMMs), which can not only provide the emission probabilities of amino acids in the defined positions of SLiMs, but also model the undefined positions. We adopted the ordered region masking and the relative local conservation (RLC) masking to improve the signal to noise ratio of the query sequences while applying evolutionary weighting to make the important sequences in evolutionary process get more attention by the selective training of profile HMMs. The experimental results show that our method and the profile-based method returned different subsets within a SLiMs dataset, and the performance of the two approaches are equivalent on a more realistic discovery dataset. Profile HMM based motif discovery methods complement the existing methods and provide another way for SLiMs analysis. PMID- 25791289 TI - Glucose-lowering and heart failure: risks of errors. PMID- 25791290 TI - Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. AB - BACKGROUND: Some glucose-lowering drugs or strategies adversely affect cardiovascular outcomes. We aimed to assess the extent to which glucose lowering by various drugs or strategies increases the risk of heart failure in patients with or at risk for type 2 diabetes, and to establish whether risk is associated with achieved differences in glycaemia or weight control. METHODS: We searched Ovid Medline, the Cochrane Library, and meeting abstracts up to Feb 20, 2015, for large randomised controlled trials of glucose-lowering drugs or strategies that assessed cardiovascular outcomes. The primary endpoint was incidence of heart failure. We derived pooled risk ratios (RRs) with random-effects models. FINDINGS: We included data from 14 trials, with mean duration 4.3 (2.3) years, comprising 95 502 patients, of whom 3907 (4%) patients developed a heart failure event. Glucose-lowering drugs or strategies were associated with a 0.50% (SD 0.33) reduction in HbA1c and a 1.7 kg (2.8) weight gain. Overall, glucose lowering drugs or strategies increased the risk of heart failure compared with standard care (RR 1.14, 95% CI 1.01-1.30; p=0.041). The magnitude of this effect varied dependent on the method of glucose lowering (p for interaction=0.00021). Across drug classes, risk was highest with peroxisome proliferator-activated receptor agonists (RR 1.42, 95% CI 1.15-1.76; six trials), intermediate with dipeptidyl peptidase-4 inhibitors (1.25, 1.08-1.45; two trials), and neutral with insulin glargine (0.90, 0.77-1.05; one trial). Target-based intensive glycaemic control strategies (RR 1.00, 95% CI 0.88-1.13; four trials) and intensive weight loss (0.80, 95% CI 0.62-1.04; one trial) were also not associated with development of heart failure. Meta-regression analysis showed that for every 1.0 kg of weight gain associated with glucose-lowering drugs or strategies, there was a 7.1% (95% CI 1.0-13.6) relative increase in the risk of heart failure compared with standard care (p=0.022). INTERPRETATION: Compared with standard care, glycaemic lowering by various drugs or strategies might increase the risk of heart failure, with the magnitude of risk dependent on the method of glucose lowering and, potentially, weight gain. FUNDING: None. PMID- 25791291 TI - Evaluation of HPV Genotyping Assays for Archival Clinical Samples. AB - Human papillomavirus (HPV) testing and genotyping of FFPE tissue samples is important in epidemiological investigations. Here, we compare four different HPV genotyping methods for use in FFPE clinical samples. Comparative testing was performed on 99 samples with a clinical suspicion of HPV. Specimens were analyzed with Anyplex II HPV28 detecting 28 genotypes using real-time PCR and melting curve analysis, CLART HPV2 detecting 35 genotypes using PCR and microarray detection, and MGP5+/6+ consensus primer system together with pyrosequencing. Results were compared to a real-time PCR reference protocol detecting 14 genotypes. In total, 68% of the samples were positive for an HPV genotype using the reference protocol and MGP5+/6+ primer system. Anyplex II HPV28 analysis and CLART HPV2 had 82% and 72% positive samples, respectively. All four methods showed good agreement when comparing the 14 genotypes included in the reference protocol. When evaluating all genotypes, the Anyplex II HPV28 assay and the CLART assay changed the status of the sample (individually or together) from negative with respect to the reference protocol to positive for either a Group 1 (n = 4) or Group 2 (n = 6) genotype. We conclude from this study that for an extended genotyping approach with a high sensitivity for FFPE specimens, both the Anyplex II HPV28 and CLART HPV2 assays are suitable alternatives despite minor intra assay differences. PMID- 25791292 TI - Genetic diversity of Trichoderma atroviride strains collected in Poland and identification of loci useful in detection of within-species diversity. AB - Molecular markers that enable monitoring of fungi in their natural environment or assist in the identification of specific strains would facilitate Trichoderma utilization, particularly as an agricultural biocontrol agent (BCA). In this study, sequence analysis of internal transcribed spacer regions 1 and 2 (ITS1 and ITS2) of the ribosomal RNA (rRNA) gene cluster, a fragment of the translation elongation factor 1-alpha (tef1) gene, and random amplified polymorphic DNA (RAPD) markers were applied to determine the genetic diversity of Trichoderma atroviride strains collected in Poland, and also in order to identify loci and PCR-based molecular markers useful in genetic variation assessment of that fungus. Although tef1 and RAPD analysis showed limited genetic diversity among T. atroviride strains collected in Poland, it was possible to distinguish major groups that clustered most of the analyzed strains. Polymorphic RAPD amplicons were cloned and sequenced, yielding sequences representing 13 T. atroviride loci. Based on these sequences, a set of PCR-based markers specific to T. atroviride was developed and examined. Three cleaved amplified polymorphic sequence (CAPS) markers could assist in distinguishing T. atroviride strains. The genomic regions identified may be useful for further exploration and development of more precise markers suitable for T. atroviride identification and monitoring, especially in environmental samples. PMID- 25791293 TI - VAV3 oncogene expression in colorectal cancer: clinical aspects and functional characterization. AB - Although colorectal cancer (CRC) is one of the most common malignancies worldwide, the current therapeutic approaches for advanced CRC are ineffective. In this study, we investigated the involvement of the VAV3 oncogene in tumor progression and in the prognosis of human CRC. The two patient cohorts in this study comprised 354 CRC cases from 1998 to 2005 with documented pathologic and clinical factors and clinical outcomes. VAV3 protein levels were significantly correlated with the depth of invasion (P = 0.0259), the nodal status (P < 0.0001), distant metastasis (P = 0.0354), the stage (P < 0.0001), and poor disease-free survival (P = 0.003). Multivariate Cox regression analysis showed that VAV3 overexpression is an independent prognostic marker for CRC (P = 0.041). In vitro experiments indicated that VAV3 knockdown inhibited CRC cell growth, spread, and xenograft proliferation. Mechanistic studies further revealed that VAV3 overexpression could dysregulate the expression of cell cycle control- and metastasis-related molecules by activating the PI3K-AKT signaling pathway in both CRC cells and xenografts. This study suggests that VAV3 overexpression could be a useful marker for predicting the outcomes of CRC patients and that VAV3 targeting represents a potential modality for treating CRC. PMID- 25791294 TI - Assessment of different sample preparation routes for mass spectrometric monitoring and imaging of lipids in bone cells via ToF-SIMS. AB - In ToF-SIMS analysis, the experimental outcome from cell experiments is to a great extent influenced by the sample preparation routine. In order to better judge this critical influence in the case of lipid analysis, a detailed comparison of different sample preparation routines is performed-aiming at an optimized preparation routine for systematic lipid imaging of cell cultures. For this purpose, human mesenchymal stem cells were analyzed: (a) as chemically fixed, (b) freeze-dried, and (c) frozen-hydrated. For chemical fixation, different fixatives, i.e., glutaraldehyde, paraformaldehyde, and a mixture of both, were tested with different postfixative handling procedures like storage in phosphate buffered saline, water or critical point drying. Furthermore, secondary lipid fixation via osmium tetroxide was taken into account and the effect of an ascending alcohol series with and without this secondary lipid fixation was evaluated. Concerning freeze-drying, three different postprocessing possibilities were examined. One can be considered as a pure cryofixation technique while the other two routes were based on chemical fixation. Cryofixation methods known from literature, i.e., freeze-fracturing and simple frozen-hydrated preparation, were also evaluated to complete the comparison of sample preparation techniques. Subsequent data evaluation of SIMS spectra in both, positive and negative, ion mode was performed via principal component analysis by use of peak sets representative for lipids. For freeze-fracturing, these experiments revealed poor reproducibility making this preparation route unsuitable for systematic investigations and statistic data evaluation. Freeze-drying after cryofixation showed improved reproducibility and well preserved lipid contents while the other freeze-drying procedures showed drawbacks in one of these criteria. In comparison, chemical fixation techniques via glutar- and/or paraformaldehyde proved most suitable in terms of reproducibility and preserved lipid contents, while alcohol and osmium treatment led to the extraction of lipids and are therefore not recommended. PMID- 25791295 TI - Use of cold atmospheric plasma in the treatment of cancer. AB - Cold atmospheric plasma (CAP) is an emerging modality for the treatment of solid tumors. In-vitro experiments have demonstrated that with increasing doses of plasma, tumor cells assays display decreased cell viability. CAP is theorized to induce tumor cells into apoptosis via multiple pathways including reactive oxygen and nitrogen species as well as cell cycle disruption. Studies have shown CAP treatment can decrease mouse model glioblastoma multiforme tumor volume by 56%, increase life span by 60%, and maintain up to 85% viability of normal cells. Emerging evidence suggests that CAP is a viable in-vivo treatment for a number of tumors, including glioblastoma, as it appears to selectively induce tumor cell death while noncancerous cells remain viable. PMID- 25791296 TI - The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs--A practical view. AB - The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours. PMID- 25791297 TI - Piwi-pathway alteration induces LINE-1 transposon derepression and infertility development in cryptorchidism. AB - Spermatogonia contain processing bodies that harbor P-element-induced wimpy testis (Piwi) proteins. Piwi proteins are associated specifically with Piwi interacting RNAs to silence transposable DNA elements. Loss-of-function mutations in the Piwi pathway lead to derepression of transposable elements, resulting in defective spermatogenesis. Furthermore, deletion of gametocyte-specific factor 1 (GTSF1), a factor involved in Piwi-mediated transcriptional repression, causes male-specific sterility and derepression of LINE-1 (L1) retrotransposons. No previous studies have examined GTSF1, L1 and PIWIL4 expression in cryptorchidism. We examined transposon-silencing genes and L1 transposon expression in testicular biopsies with Affymetrix microarrays and immunohistology. Seven members of the Tudor gene family, 3 members of the DEAD-box RNA helicase family, and the GTSF1 gene were found to show significantly lower RNA signals in the high-infertility risk group. In the immunohistochemical analysis, patients from the low infertility-risk group showed coherently stronger staining for GTSF1 and PIWIL4 proteins and weaker staining for L1 transposon when compared to the high infertility-risk samples. These new findings provide first evidence consistent with the idea that infertility in cryptorchidism is a consequence of alterations in the Piwi pathway and transposon derepression induced by the impaired function of mini-puberty. PMID- 25791298 TI - Surface-enhanced Raman spectroscopy of urine for prostate cancer detection: a preliminary study. AB - Surface-enhanced Raman scattering (SERS) spectra were obtained from urine samples from subjects diagnosed with prostate cancer as well as from healthy controls, using Au nanoparticles as substrates. Principal component analysis (PCA) of the spectral data, followed by linear discriminant analysis (LDA), leads to a classification model with a sensitivity of 100 %, a specificity of 89 %, and an overall diagnostic accuracy of 95 %. Even considering the very limited number of samples involved in this report, preliminary results from this approach are extremely promising, encouraging further investigation. PMID- 25791299 TI - High output piezo/triboelectric hybrid generator. AB - Recently, piezoelectric and triboelectric energy harvesting devices have been developed to convert mechanical energy into electrical energy. Especially, it is well known that triboelectric nanogenerators have a simple structure and a high output voltage. However, whereas nanostructures improve the output of triboelectric generators, its fabrication process is still complicated and unfavorable in term of the large scale and long-time durability of the device. Here, we demonstrate a hybrid generator which does not use nanostructure but generates much higher output power by a small mechanical force and integrates piezoelectric generator into triboelectric generator, derived from the simultaneous use of piezoelectric and triboelectric mechanisms in one press-and release cycle. This hybrid generator combines high piezoelectric output current and triboelectric output voltage, which produces peak output voltage of ~370 V, current density of ~12 MUA . cm(-2), and average power density of ~4.44 mW . cm( 2). The output power successfully lit up 600 LED bulbs by the application of a 0.2 N mechanical force and it charged a 10 MUF capacitor to 10 V in 25 s. Beyond energy harvesting, this work will provide new opportunities for developing a small, built-in power source in self-powered electronics such as mobile electronics. PMID- 25791300 TI - Cultural aspects regarding public health. PMID- 25791301 TI - [Smoking, alcohol consumption and sleep time of industrial workers in the state of Parana in Brazil]. AB - OBJECTIVE: This study was aimed at verifying smoking, alcohol consumption and sleep time associated with sociodemographic factors in physically active industrial workers in the state of Parana in Brazil. METHODS: Nine hundred and seven subjects volunteered (71% men and 29% women) to answer a questionnaire aimed at assessing their quality of life and health (QVS-80). The volunteers included 389 physically active workers. The Chi-square test and Chi-square test for linear trend were used for analyzing the data so collected (p<0.05). RESULTS: Physical activity (PA) prevalence was higher amongst men (49%) compared to women (22%) (p<0.01). Younger women (p<0.01) having a higher educational level (p<0.01) trended to engage in PA (p<0.01). Smoking was identified in 15% of the active workers; this was associated with age (p<0.05) and educational level (p<0.01) in male workers. Alcohol abuse was present in 8% of men and 3% of women (p<0.05). Inadequate sleep time was associated with increased age (p<0.01) in both genders and lower family income (p<0.05) in women. CONCLUSION: Physically active workers had lower tobacco and alcohol consumption compared to physically inactive workers in previous studies. PMID- 25791302 TI - [University students'? cardiovascular risk factors and their relationship with body composition]. AB - OBJECTIVE: Assessing the prevalence of major risk factors for cardiovascular disease in a sample population of university students and their relationship with body composition. METHODS: A prevalence study was carried out on a random sample of 193 16 to 26 year-old university students (94 females and 99 males). Total cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG) and glucose, resting blood pressure, waist circumference, height, weight and body fat and muscle mass percentages were measured. The participants answered a survey to assess their nutritional habits, lifestyle and stress. RESULTS: The major cardiovascular risk factors for males were >=100 mg/dl (60.6%) LDL-C, >20% (50.0%) body fat percentage (BF%) and <40 mg/dl (39.4%) HDL C; female risk factors were >33% (63.0%) BF%, >=100 mg/dl (39.4%) LDL-C and <50 mg/dl (91.5%) HDL-C. Both male (12.1%) and female students (21.3 %) had criteria for metabolic syndrome and males (19.2%) and females (27.7%) had a high atherogenic index of plasma (AIP). Significant correlations with body composition were found. CONCLUSION: Cardiovascular risk factors had high prevalence in this sample of undergraduate students due to alterations in their blood, lipid profile and anthropometric changes, suggesting that modifications must be made regarding their lifestyles and body composition. PMID- 25791303 TI - [Using the 6-minute walking test with obese people engaged in a physical activity program]. AB - OBJECTIVE: Evaluating the applicability of the 6-minute walking test (6MWT) on 22 obese adults (12 women and 10 men) engaged in a physical activity program lasting 6 months. METHODOLOGY: This longitudinal study involved using the 6MWT for evaluating cardiorespiratory capacity in people having different levels of obesity who were engaged in a physical activity program. RESULTS: The first set of 6MWT results revealed that the intervals having the highest frequency were 439.7-468.7=27.3 % (6) and 468.71-487.71=27.3 % (6). The 6MWT result at the end of the evaluation showed that the interval having the highest frequency was 463.01-501.01=45.5 % (10), without presenting clinical and/or physical signs which could have interrupted the test on the people being evaluated. CONCLUSIONS: This study showed the 6MWT to be applicable as an evaluation and tracking tool for obese people engaged in a physical activity program. It should be stressed that the 6MWT protocol must be closely followed when evaluating physical endurance. PMID- 25791304 TI - [The impact of subsidized healthcare insurance on access to cervical cytology in Medellin, Colombia]. AB - OBJECTIVE: Assessing the impact of subsidized healthcare insurance on access to cervical cytology in Medellin, Colombia. MATERIALS AND METHODS: Propensity score matching (PSM) was used with 2008 Life Quality Survey in Colombia figures to obtain a control group comparable to a treatment group. This involved using stratification estimates, the k-nearest-neighbor algorithm and kernel density for calculating impact size RESULTS: Access to cytology for 19 to 49 year-old women having subsidized healthcare insurance were 2.2 % to 2.9 % lower compared to women who did not have any healthcare insurance. Estimates were not statistically significant for women over 50 years-old. DISCUSSION: Women lacking healthcare insurance having increased access to cytology could be explained by charities or social programs aiding the population lacking healthcare insurance. PMID- 25791305 TI - [Postnatal depression in Colombian women: secondary analysis of the 2010 Colombian Demographic and Health Survey]. AB - OBJECTIVE: Examining the prevalence of self-reported postpartum depression (PD) in a representative sample of Colombian women. METHODS: A secondary analysis was made of the Colombian Demographic and Health Survey 2010; the survey included 53 521 women aged 13 to 49 years-old. A clinical diagnosis of depression by self report, during the first six months? postpartum as a perinatal complication, was defined as the dependent variable by interview. Logistic regression was used, taking into account the multistage study design and adjusting for potential confounders. The results were presented as adjusted odds ratios (OR) with 95 % confidence intervals (95 % CI). RESULTS: Overall PD prevalence was 12.9 %, being higher in urban areas (15.1 %) than in rural areas (6.8 %) and in women aged 20 34 years-old (13.4 %). The Amazonas and Guainia departments had lower PD prevalence (3.1 % and 3.5 % respectively), while the city of Bogota and the Quindio department had higher prevalence (18.1 % and 22.1 % PD, respectively). After adjustment, women aged 20 to 34 years-old (OR=1.15: 1.03 to 1.28 95 % CI), primigravidae (OR=1.42: 1.28-1.57 95 % CI), residing in urban areas (OR=2.43: 2.06 to 2.87 95 % CI) and having had university level education (OR=2.22: 1.98 to 2.48 95 % CI) were associated with PD. CONCLUSIONS: A high prevalence of postpartum depression was found in the study population. Socio-demographic and geographic factors contributed towards depression according to self-report. More research is needed to enable early identification of and intervention in women suffering from depression. PMID- 25791306 TI - [An assessment of the nutritional status of a school-aged population from Argelia, Colombia]. AB - OBJECTIVE: Malnutrition affects most rural areas in Colombian, mainly involving the school-aged population. The aim of this study was to assess the nutritional status of students (n=1,528) attending an Agricultural College in the town of Argelia in south-western Colombia in the Cauca department. METHODS: The school aged children?s weight and height were measured and their nutritional status was determined from their body mass index (BMI), according to criteria defined by the World Health Organization (WHO). Anthropometric measurements were analyzed by means of measures of central tendency, stratified by gender and age. The standard error of the difference was estimated to specify the statistical significance of some of the most important differences observed between study indicators; such significance was verified at 0.05 level. RESULTS: Prevalence regarding malnutrition and thinness in 5-10 years-old children, a trend towards obesity in adolescents and growth retardation in children and adolescents was established from analysis of the children?'s weight (P/E), height for age (H/A) and BMI. CONCLUSIONS: The results suggested that sports should be encouraged at an early age, as well as training school children and their families regarding healthy eating habits and thus provide scientific support for planning government healthcare agencies? prevention and control strategies. PMID- 25791307 TI - [Characterizing breastfeeding and associated factors in Puerto Carreno, Colombia]. AB - OBJECTIVE: Characterizing breastfeeding in Puerto Carreno and identifying factors associated with providing breast-milk for the newborn, exclusive breastfeeding and total breastfeeding. METHODS: This descriptive, cross-sectional study, using structured individual and non-random surveys, involved 609 mothers. The statistical analysis methods included univariate and bivariate analysis, survival curves, binary logistic regression and Cox proportional hazard models. RESULTS: The duration of total and exclusive breastfeeding was higher than reported times at national and regional level in most cases. The main factors associated with breastfeeding were related to occupation, family background, Indigenous status, previous maternal experience and access to healthcare services. CONCLUSIONS: Exclusive breastfeeding was influenced more by the mother'?s occupation, while the total duration of breastfeeding was influenced by home-based family support network. The results are significant regarding planning intervention measures addressed towards improving breastfeeding habits in the target municipality. PMID- 25791308 TI - [Communicative disorder prevalence and associated risk factors regarding informal workers in Popayan, Colombia]. AB - OBJECTIVE: Determining the prevalence of alterations in informal workers? audition, respiratory and vocal functions and their association with certain risk factors in Popayan, Colombia. METHODS: This was a descriptive, cross-sectional study of 186 informal workers (i.e. people selling things in the street). After signing an informed consent form, an interview was held to obtain data regarding sociodemographic and communicative variables. The workers were then evaluated using tests for tone audiometry, respiratory function and Wilson's voice profile. SPSS (v.19.0) was used for statistical analysis. RESULTS: Being older than 30 years of age (OR 5.84: 2.85-12.00 95%CI), having a poor educational level (2.81: 1.22-6.44 95%CI) and low socioeconomic status (4.54:1.89-10.91 95%CI) and prolonged working hours (2.64: 1.27-5.06 95%CI) were associated with auditive function disorders. Respiratory function disorders were associated with being female (1.83; 1.00-3.34 95%CI) and having prolonged working hours (2.04: 1.11 3.74 95%CI). Regarding vocal function, being over 30 years-old (3.36: 1.33-3.51 95%CI) and having a low educational level (3.67; 1.05-12.76 95%CI) were risk factors. Communicative factors related to auditive, respiratory and voice disorder were ear pain, hypertrophic tonsils, trauma, gastro-esophageal reflux, frequent cough, strong emotions and screaming. CONCLUSIONS: It is evident that alterations in informal workers'? communicative system are associated with certain sociodemographic and communicative risk factors. This information provides a baseline for improving healthcare promotion and disease prevention strategies aimed at this population. PMID- 25791309 TI - [Patients and relatives? perception regarding communication with healthcare professionals]. AB - OBJECTIVE: Understanding the strengths and difficulties regarding communication between healthcare workers and families and a family member suffering chronic illness or disability, from the perception of patients and families receiving healthcare services. METHODS: This was a qualitative, interpretative study. The psychological approach adopted was systemic, from a socio-constructionist perspective. The sample was drawn from people contacted at the Universidad de La Sabana?s clinic, Colombia. Question guidelines were based on deductive categories in the first phase; two focus groups were formed during the second phase by people suffering chronic diseases or disability and family members of people in such situation. A survey was then made using the results for data triangulation and saturation, including other patients and relatives. RESULTS: People saw professional teamwork, providing care, the sufficiency of the information received and the use of strategies for teaching procedures and answering questions as strengths. They pointed out communication difficulties, like healthcare workers making assumptions about negative prognostics and adopting superior attitudes, or lacking consistency and continuity, as well as high staff turnover. CONCLUSIONS: Patients and relatives generally adopted an attitude of acceptance concerning the relationship established with healthcare workers; however, when probing more specifically, aspects to be improved were made more explicit, where communication may enable a less hierarchic and more collaborative relationship, providing a space for emotional processes. PMID- 25791310 TI - [Leptospirosis percentage and related factors in patients having a presumptive diagnosis of dengue, 2010 -2012]. AB - OBJECTIVE: Using the microscopic agglutination test (MAT) from 2010-2012 for identifying leptospirosis-related and sociodemographic variables in patients having a confirmed diagnosis of dengue and those for whom it had been discarded. MATERIALS AND METHODS: This was a retrospective study of 238 sera samples. 106 patients died, 64 of their samples were negative for dengue and 42 proved positive. 132 samples from live patients proved positive for dengue; 29 were confirmed by PCR and/or virus isolation and 103 had positive IgM readings. MAT was used for all sera and diagnosing Leptospira, epidemiological records were reviewed and the data was analysed. RESULTS: 42 dengue positive patients died; 3 (7%) were positive for Leptospira interrogans sero group Australis autumnalis (two girls aged 5 and 17 years-old and a 14 year-old boy). Of the 64 deceased patients who proved negative for dengue, 7 (11%) were found positive for L.interrogans from sero groups Pomona, Autumnalis, Canicola and Ballum (5 males aged 8 to 58 years-old and 2 women aged 35 and 56 years-old). Of the 103 living patients who proved positive for dengue IgM, 3 (2.9%) were positive for Leptospira icterohaemorrhagiae from the Cynopteri, Javanica Proechimys and Autumnalis sero groups(1 male and 2 females). None of the 29 living patients confirmed as having dengue were positive for Leptospira. CONCLUSIONS: Leptospirosis should be suspected not only as the sole causative agent of febrile syndrome but also of co-infection which could compromise a patient and be related to mortality. PMID- 25791311 TI - [A microbiological analysis of the ethnopharmacological products used by the Misak people]. AB - OBJECTIVES: Evaluating microorganism presence, type and quantity in some of the most important ethnopharmacological products designed for oral administration currently being distributed by the Sierra Morena laboratory located in the Guambia Indian reservation (Cauca department, Colombia). MATERIALS AND METHODS: This was a cross-sectional descriptive study; it involved microbiological analysis using membrane filtration of six randomly-chosen samples which included the water being used by the laboratory and five of its ethnopharmacological products ready for commercial distribution and sale. RESULTS: The samples studied here were not microbiologically suitable for human consumption because they contained Escherichia coli and fecal coliforms. Colony forming unit (CFU) count/100 mL (reference 0 CFU/100 mL) was found to be up to 63,000 CFU/100 mL in water samples and 110 CFU/100 mL in ethnopharmacological samples. CONCLUSIONS: The quantitative results revealed the presence of pathogens, indicating failure in rural water supply and environmental sanitation infrastructure. On-going monitoring of water quality and an urgent intervention of the laboratory'?s ethnopharmacological production is necessary because of the contamination found there. PMID- 25791312 TI - [Mercury and lead prevalence in a sample of people living in Bogota, 2012-2013]. AB - OBJECTIVES: Establishing mercury and lead prevalence in a sample of people living in Bogota, potential effects on their health and the relationship with areas of environmental exposure. METHODS: This was a cross-sectional study involving a randomly and proportionally distributed sample of 401 people living in Bogota, according to locality and their high, medium and low risk environmental exposure. A medical assessment was made and lead (in blood) and mercury levels (blood, hair, urine) quantified. A preliminary descriptive analysis was made. RESULTS: The participants were aged 3-91 years-old (mean 46), the most frequently occurring occupation was that of housewife (45.1%, n=181). Mean mercury concentration in hair was 1ug/g, 3.13 ug/L in blood and 0.29 ug/L in urine; lead in blood was found to be 8.62 ug/dL. Fifty-four people (13.5%) had higher concentrations than international reference values for mercury (WHO) and 10 (2.5%) for lead (CDC). Clinical findings were non-specific; exposure areas did not seem to relate to the concentrations found. DISCUSSION: A significant percentage of the study population had high mercury and/or lead levels and such high prevalence highlights the need for identifying and controlling sources of exposure to mercury and lead which could have adverse consequences regarding the health of Bogota'?s general population. PMID- 25791313 TI - [Dry toilets: a means of alternative sanitation]. AB - OBJECTIVE: Evaluating dry toilet use in a rural area of Colombia. METHOD: Fifteen families were selected by convenience sampling from the rural area of a municipality in the Cundinamarca department in Colombia. A dry (composting) toilet was installed in one house and used for demonstration purposes over a five month period. An ex-post evaluation was made concerning technical and economic matters. RESULTS: A dry toilet is easy to construct/install and has environmental benefits associated with less contamination of water sources reduction and a reduced amount of chemical fertilizer. Dry toilets? construction and operating costs may represent savings of Col$616973456 (US$308487) in the municipality being studied, compared to the costs involved in conventional toilet use. However, cultural barriers were found regarding their use. DISCUSSION: A large percentage of households in many countries? rural sectors do not have a sewerage system for disposing of human waste. This situation creates significant challenges regarding environmental health and ecosystem conservation. Dry toilets represent an environmentally-acceptable solution from a technical and economic perspective; however, work is required concerning social and cultural factors producing cultural perceptions and prejudices about handling excreta to provide the necessary coverage and produce a significant impact on people?s awareness. PMID- 25791314 TI - Diurnal Variation in Choroidal and Retinal Thickness of the Early Treatment of Diabetic Retinopathy Study Macular Subfields Determined Using Swept-Source Optical Coherence Tomography. AB - PURPOSE: To describe diurnal variation in choroidal thickness (CT) and retinal thickness (RT) of the nine Early Treatment of Diabetic Retinopathy Study (ETDRS) macular subfields determined using swept-source optical coherence tomography. METHODS: A prospective study was conducted on 24 healthy Korean volunteers who underwent two sequential measurements of a randomly selected eye at 9 a.m., 1 p.m., and 6 p.m. The radial scan mode was used. To determine the repeatability and reliability, we applied intragrader agreement using the intraclass correlation coefficient (ICC). RESULTS: Significant diurnal variation in CT was observed. The highest mean CT was found at 9 a.m. The lowest mean CT occurred at 1 p.m. There was excellent intragrader agreement, with the ICC ranging from 0.961 to 0.997. There was no significant diurnal variation in RT. CONCLUSION: There was significant diurnal variation in CT. The choroid was thinner at 1 p.m. than at 9 a.m. and 6 p.m. PMID- 25791317 TI - Severe Sweet's Syndrome with Elevated Cutaneous Interleukin-1beta after Azathioprine Exposure: Case Report and Review of the Literature. AB - Sweet's syndrome (SS) is a dermatosis with systemic symptoms characterized by tender, red nodules or papules, occasionally covered with vesicles, pustules or bullae, usually affecting the upper limbs, face and neck. SS is frequently observed in patients with leukemia or connective tissue diseases, while it is rather seldom in patients with inflammatory bowel disease. The exact pathogenesis of SS is only partially understood. We report the case of a 50-year-old patient with indeterminate colitis, presenting with a febrile diffuse papulopustular and necrotizing skin eruption that healed with significant scarring and appeared 14 days after onset of treatment with azathioprine. Histological examination revealed the presence of features typical of SS, gene expression analysis very high levels of interleukin-1beta (IL-1beta) mRNA in lesional skin, and immunohistochemistry high levels of IL-1beta at the protein level. SS associated with azathioprine is being increasingly reported and is reviewed herein. PMID- 25791315 TI - Enterohemorrhagic Escherichia coli senses low biotin status in the large intestine for colonization and infection. AB - Enterohemorrhagic Escherichia coli (EHEC) is an important foodborne pathogen that infects humans by colonizing the large intestine. Here we identify a virulence regulating pathway in which the biotin protein ligase BirA signals to the global regulator Fur, which in turn activates LEE (locus of enterocyte effacement) genes to promote EHEC adherence in the low-biotin large intestine. LEE genes are repressed in the high-biotin small intestine, thus preventing adherence and ensuring selective colonization of the large intestine. The presence of this pathway in all nine EHEC serotypes tested indicates that it is an important evolutionary strategy for EHEC. The pathway is incomplete in closely related small-intestinal enteropathogenic E. coli due to the lack of the Fur response to BirA. Mice fed with a biotin-rich diet show significantly reduced EHEC adherence, indicating that biotin might be useful to prevent EHEC infection in humans. PMID- 25791318 TI - Tumor stratification by a novel graph-regularized bi-clique finding algorithm. AB - Due to involved disease mechanisms, many complex diseases such as cancer, demonstrate significant heterogeneity with varying behaviors, including different survival time, treatment responses, and recurrence rates. The aim of tumor stratification is to identify disease subtypes, which is an important first step towards precision medicine. Recent advances in profiling a large number of molecular variables such as in The Cancer Genome Atlas (TCGA), have enabled researchers to implement computational methods, including traditional clustering and bi-clustering algorithms, to systematically analyze high-throughput molecular measurements to identify tumor subtypes as well as their corresponding associated biomarkers. In this study we discuss critical issues and challenges in existing computational approaches for tumor stratification. We show that the problem can be formulated as finding densely connected sub-graphs (bi-cliques) in a bipartite graph representation of genomic data. We propose a novel algorithm that takes advantage of prior biology knowledge through a gene-gene interaction network to find such sub-graphs, which helps simultaneously identify both tumor subtypes and their corresponding genetic markers. Our experimental results show that our proposed method outperforms current state-of-the-art methods for tumor stratification. PMID- 25791316 TI - Down regulation of Tim50 in Trypanosoma brucei increases tolerance to oxidative stress. AB - Trypanosoma brucei, the causative agent for African trypanosomiasis, possesses a single mitochondrion that imports hundreds of proteins from the cytosol. However, the parasite only possesses a few homologs of the canonical protein translocases found in fungi and animals. We recently characterized a homolog of the translocase of the mitochondrial inner membrane, Tim50, in T. brucei. TbTim50 knockdown (KD) moderately reduced cell growth, decreased the mitochondrial membrane potential, and inhibited import of proteins into mitochondria. In contrast to Tim50 KD, we show here that TbTim50 overexpression (OE) increased the mitochondrial membrane potential as well as increased the production of cellular reactive oxygen species (ROS). Therefore, TbTim50 OE also inhibits cell growth. In addition, TbTim50 OE and KD cells showed different responses upon treatment with H2O2. Surprisingly, TbTim50 KD cells showed a greater tolerance to oxidative stress. Further analysis revealed that TbTim50 KD inhibits transition of cells from an early to late apoptotic stage upon exposure to increasing concentrations of H2O2. On the other hand TbTim50 OE caused cells to be in a pro-apoptotic stage and thus they underwent increased cell death upon H2O2 treatment. However, externally added H2O2 similarly increased the levels of cellular ROS and decreased the mitochondrial membrane potential in both cell types, indicating that tolerance to ROS is mediated through induction of the stress-response pathway due to TbTim50 KD. Together, these results suggest that TbTim50 acts as a stress sensor and that down regulation of Tim50 could be a survival mechanism for T. brucei exposed to oxidative stress. PMID- 25791319 TI - The level and distribution of heavy metals and changes in oxidative stress indices in humans from Lahore district, Pakistan. AB - Human biomonitoring is a well-recognized tool for estimating the exposure of humans to environmental pollutants. However, heavy metals' pollution from anthropogenic origin is a cause for concern because of its potential accumulation in the environment and living organisms, leading to long-term toxic effects. This study was aimed to assess the concentrations of cadmium (Cd), chromium (Cr), lead (Pb), copper (Cu), nickel (Ni), cobalt (Co), manganese (Mn), iron (Fe), and zinc (Zn) in human biological samples (urine, whole blood, hair, and nails) and antioxidant response in blood samples from 48 individuals exposed to heavy metals and to compare them with different age classes and sites. The results indicated that there were metal-specific differences in concentration in exposure groups among the studied sites. The concentration of heavy metals in blood samples showed the following order : Pb > Cd > Ni > Co > Cr. In urine samples, the order was Cu > Pb > Cr > Ni > Co > Cd; in nails samples, the order was Pb > Ni > Cr > Co > Cd > Mn; and in hair samples, the trend was Pb > Ni > Cr > Mn > Cd > Co. A significant (p > 0.05) decrease in antioxidants enzymes activity was observed with increase in heavy metals concentrations. This is the first study reporting biological evidence of altered toxic metals' concentration in humans in Lahore, Pakistan, due to environmental exposure. Further research, including risk analysis studies, food chain contamination, and epidemiological and clinical investigations, are needed to assess optimal levels for dietary exposure in the study area and associated adverse health outcomes. PMID- 25791320 TI - Hydrogen sulfide ameliorates cardiovascular dysfunction induced by cecal ligation and puncture in rats. AB - Hydrogen sulfide (H2S) is an endogenously produced gaseous messenger that participates in regulation of cardiovascular functions. This study evaluates the possible protective effect of H2S in cardiovascular dysfunction induced by cecal ligation and puncture (CLP) in rats. After 24 h of induction of CLP, heart rate (HR), mortality, cardiac and inflammation biomarkers (creatine kinase-MB (CK-MB) isozyme, cardiac troponin I (cTnI), C-reactive protein (CRP), and lactate dehydrogenase (LDH)), in vitro vascular reactivity, histopathological examination, and oxidative biomarkers (malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD)) were determined. CLP induced elevations in HR, mortality, serum CK-MB, cTnI, CRP, and LDH, in addition to impaired aortic contraction to potassium chloride and phenylephrine and relaxation to acetylcholine without affecting sodium nitroprusside responses. Moreover, CLP increased cardiac and aortic MDA and decreased SOD, without affecting GSH and caused a marked subserosal and interstitial inflammation in endocardium. Sodium hydrosulfide, but not the irreversible inhibitor of H2S synthesis dl-propargyl glycine, protected against CLP-induced changes in HR, mortality, cardiac and inflammatory biomarkers, oxidative stress, and myocardium histopathological changes without affecting vascular dysfunction. Our results confirm that H2S can attenuate CLP-induced cardiac, but not vascular, dysfunction possibly through its anti-inflammatory and antioxidant effects. PMID- 25791321 TI - Pityriasis rosea-like adverse reaction to atenolol. AB - A 56-year-old female patient was presented with diffuse, bright red to violet colour, scaly patches on trunk and extremities after using a hypertension drug, atenolol. The patient was diagnosed as pityriasis rosea-like adverse reaction to atenolol based on her history, dermatological examination and histopathological findings. To the best of our knowledge, this is the first reported case of pityriasis rosea-like adverse reaction to atenolol that is widely used in hypertension treatment. PMID- 25791322 TI - [Variation in closeness to reality of standardized resuscitation scenarios : Effects on the success of cognitive learning of medical students]. AB - INTRODUCTION: Simulation often relies on a case-based learning approach and is used as a teaching tool for a variety of audiences. The knowledge transfer goes beyond the mere exchange of soft skills and practical abilities and also includes practical knowledge and decision-making behavior; however, verification of knowledge or practical skills seldom unfolds during simulations. Simulation-based learning seems to affect many learning domains and can, therefore, be considered to be multifactorial in nature. At present, studies examining the effects of learning environments with varying levels of reality on the cognitive long-term retention of students are lacking. AIM: The present study focused on the question whether case scenarios with varying levels of reality produce differences in the cognitive long-term retention of students, in particular with regard to the learning dimensions knowledge, understanding and transfer. MATERIAL AND METHODS: The study was conducted on 153 students in the first clinical semester at the Justus-Liebig University of Giessen. Students were randomly selected and subsequently assigned, also in a random fashion, to two practice groups, i.e. realistic and unrealistic. In both groups the students were presented with standardized case scenarios consisting of three case studies, which were accurately defined with a case report containing a detailed description of each scenario and all relevant values so as to ensure identical conditions for both groups. The unrealistic group sat in an unfurnished practice room as a learning environment. The realistic group sat in a furnished learning environment with various background pictures and ambient noise. Students received examination questions before, immediately following and 14 days after the practice. Examination questions were identical at each of the three time points, classified into three learning dimensions following Bloom's taxonomy and evaluated. Furthermore, examination questions were supplemented by a questionnaire concerning the individual perception of reality and own learning success, to be filled in by students immediately after the practice. Examination questions and questionnaires were anonymous but associated with each other. RESULTS: Even with less experienced participants, realistic simulation design led to a significant increase of knowledge immediately after the end of the simulation. This effect, however, did not impact the cognitive long-term retention of students. While the realistic group showed a higher initial knowledge after the simulation, this "knowledge delta" was forgotten within 14 days, putting them back on par with the unrealistic comparison group. It could be significantly demonstrated that 2 weeks after the practice, comprehension questions were answered better than those on pure knowledge. Therefore, it can be concluded that even vaguely realistic simulation scenarios affect the learning dimension of understanding. CONCLUSION: For simulation-based learning the outcome depends not only on knowledge, practical skills and motivational variables but also on the onset of negative emotions, perception of own ability and personality profile. Simulation training alone does not appear to guarantee learning success but it seems to be necessary to establish a simulation setting suitable for the education level, needs and personality characteristics of the students. PMID- 25791323 TI - Adhesion of monocytes to periodontal fibroblasts requires activation of NOD1/2- and TLR4-mediated LFA-1 and VLA-4. AB - OBJECTIVE: The aim of this study was to investigate the roles of nucleotide binding oligomerization domain-containing protein 1/2 (NOD1/2) and Toll-like receptor 4 (TLR4) in mediating the adhesion of monocytes to periodontal fibroblasts through leucocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4). DESIGN: The expression of NOD1, NOD2, and TLR4 was detected in the gingival tissue of patients with chronic periodontitis by immunohistochemistry. Then the adhesion of cells of human monocytic cell line U937 to human gingival fibroblasts (hGFs) and human periodontal ligament cells (hPDLCs) was investigated after U937 cells were treated with the agonists of NOD1, NOD2, and TLR4 for 24 h, or transfected with small interfering RNAs (siRNAs) targeting NOD1, NOD2, and TLR4 for 48 h. Meanwhile, the expression of LFA-1 and VLA-4 was examined in U937 cells through real-time polymerase chain reaction (PCR), Western blot, and flow cytometry. To confirm the roles of LFA-1 and VLA-4 involved in the process of adhesion, the adhesion blockade assay was performed using the corresponding blocking antibodies against these adhesion molecules. RESULTS: The immunostaining results showed that NOD1, NOD2, and TLR4 were highly expressed in the gingival tissue of patients with periodontitis, especially in the monocyte-infiltrated area. The activation of these receptors by agonists upregulated the expression of LFA-1 and VLA-4 in U937 cells, and it increased the affinity of U937 cells to hGFs or hPDLCs. On the other hand, knockdown of these receptors by specific siRNAs resulted in the opposite results. In addition, blocking either LFA-1 or VLA-4 in U937 cells significantly attenuated the agonist-triggered adhesion of U937 to periodontal fibroblasts (P<0.001). CONCLUSIONS: These results suggested that NOD1/2 and TLR4 mediated monocyte-periodontal fibroblast adhesion via the modulation of LFA-1 and VLA-4. PMID- 25791324 TI - Expression of the transcription factor PITX2 in ameloblastic carcinoma. AB - Ameloblastic carcinoma is a rare odontogenic tumour that combines the histological features of ameloblastoma with cytological atypia. Until 2005, the incidence of ameloblastic carcinoma was unknown, and since then, fewer than 60 cases have been reported. These tumours may originate from pre-existing tumours or cysts, or they arise de novo from the activation or transformation of embryological cells. PITX2 is a transcription factor that is a product and regulator of the WNT cell signalling pathway, which has been involved in development of several tumours. To analyse whether PITX2 could be involved in the biological behaviour of ameloblastic carcinoma, we analysed the expression of this transcription factor in a sample of this tumour and nine benign ameloblastomas to compare. The results of Western blotting and RT-PCR analyses were positive, and considering the hundreds of genes that PITX2 regulates, we believe that its expression could be intimately linked to the behaviour of ameloblastic carcinoma and possibly other odontogenic lesions. PMID- 25791325 TI - In situ study of the anticariogenic potential of fluoride varnish combined with CO2 laser on enamel. AB - OBJECTIVE: This in situ study evaluated the effect of fluoride varnish combined with CO2 laser in controlling enamel demineralization caused by cariogenic challenges. DESIGN: In a crossover study conducted in 2 phases of 14 days each, 14 volunteers (n = 14) wore palatal appliances with bovine enamel slabs treated with fluoride varnish + CO2 laser (FV + CO2), fluoride varnish (FV), nonfluoride placebo varnish (PV) and nonfluoride placebo varnish + CO2 laser (PV + CO2). Drops of sucrose solution were dripped onto enamel slabs allowing the accumulation of biofilm. At the first phase, half of the volunteers received 4 enamel slabs treated with FV while the remainders received slabs exposed to the PV with and without CO2 laser. In the second phase, the vonlunteers were reversed treatments. The slabs were evaluated for cross-sectional microhardness (CSMH) and the concentration of loosely bound fluoride (CaF2) and firmly bound fluoride (FAp). The concentration of fluoride in biofilm were also determined. RESULTS: Two-way ANOVA showed that the CSMH values were higher in laser-irradiated enamel, regardless of the fluoride varnish. Friedman test showed that FV group presented significantly larger amount of fluoride in biofilm (P < 0.05). In the enamel, the largest amount of fluoride was found in the groups FV + CO2, which was not different from FV (P > 0.05). CONCLUSION: The synergistic effect of fluoride varnish and CO2 laser on enamel demineralization was not observed, however, CO2 laser reduces enamel demineralization. CLINICAL SIGNIFICANCE: CO2 laser might reduce the demineralization of subsurface enamel, although its association with a high concentrated fluoride therapy may not result in a positive synergistic interaction. PMID- 25791326 TI - Four-rooted permanent maxillary first and second molars in a northwestern Chinese population. AB - OBJECTIVES: To detect the incidence and anatomic features of 4-rooted permanent maxillary molars in a northwestern Chinese population by using cone-beam computed tomography (CBCT). DESIGN: A total of 725 Chinese patients with well-developed maxillary permanent first and/or second molars were examined by using CBCT. The number of roots and canals, shape, location, and division level of the roots were evaluated. Four-rooted maxillary first and second molars were classified according to modified Versiani's classification. The root length and cross sectional diameters of 4-rooted molars were measured by the software Galileos Implant 1.7 (SICAT GmbH & Co. KG, Bonn, Germany). One way analysis of variance followed by a Newman-Keuls post hoc test was used to compare the groups in relation to the root length and diameters (P = 0.05). RESULTS: Among 1365 maxillary first molars, only one tooth had four separated roots, whereas in second molars, 12 out of 1226 teeth (0.98%) exhibited an extra root; the incidences were 1.28% (7/549) for males and 0.74% (5/677) for females. All 4 rooted molars observed were unilateral. Out of a total of thirteen 4-rooted maxillary molars, six exhibited the type I root form, four exhibited the type II root form and one exhibited the type III root form; a type IV category (two molars) was added to Versiani's classification, which described maxillary molars with three buccal roots. A transitional root form between the typical 3-rooted form and double palatal roots was observed in six cases of 3-rooted molars. Measurements of root size showed that the diameter of the distopalatal roots was significantly larger than the extra mesiopalatal roots (P < 0.01). CONCLUSION: The prevalence of the 4-rooted maxillary first and second molars in the Chinese population is low. They usually occurred unilaterally, and the shape, location and size of the four roots may be variable. PMID- 25791327 TI - Oestrogen receptor beta mediates decreased occlusal loading induced inhibition of chondrocyte maturation in female mice. AB - OBJECTIVE: Temporomandibular joint (TMJ) disorders predominantly afflict women, suggesting that estrogen may play a role in the disease process. Defects in mechanical loading-induced TMJ remodelling are believed to be a major etiological factor in TMJ degenerative disease. Previously, we found that, decreased occlusal loading caused a significant decrease in early chondrocyte maturation markers (Sox9 and Col 2) in female, but not male, C57BL/6 wild type mice (1). The goal of this study was to examine the role of Estrogen Receptor (ER) beta in mediating these effects. DESIGN: 21-day-old male (n = 24) and female (n = 25) ER beta KO mice were exposed to decreased occlusal loading (soft diet administration and incisor trimming) for 4 weeks. At 49 days of age the mice were sacrificed. Proliferation, gene expression, Col 2 immunohistochemistry and micro-CT analysis were performed on the mandibular condyles. RESULTS: Decreased occlusal loading triggered similar effects in male and female ER beta KO mice; specifically, significant decreases in Col 10 expression, subchondral total volume, bone volume, and trabecular number. CONCLUSION: Decreased occlusal loading induced inhibition of chondrocyte maturation markers (Sox9 and Col 2) did not occur in female ER beta deficient mice. PMID- 25791328 TI - DNA methylation analysis of cancer-related genes in oral epithelial cells of healthy smokers. AB - AIM: The aim of this study was to investigate the smoking habit influence on DNA methylation status in the promoters of the cancer related-genes MLH1, hTERT and TP53 in oral epithelial cells of healthy subjects. MATERIALS AND METHODS: DNA methylation analysis was performed using methylation-sensitive restriction enzymes (MSRE) in oral epithelial cells from non-smokers, smokers and ex-smokers. RESULTS: The investigated CpG dinucleotides located at HhaI and HpaII sites in the MLH1 gene promoter were observed to be fully methylated in the majority of DNA samples from the smoker group and statistical differences were found between non-smokers and smokers and between smokers and ex-smokers (p<0.05). The same was observed in the hTERT gene promoter at HhaI sites (p<0.05) and for HpaII sites the unmethylated condition was more frequent in smokers in comparison to non smokers (p<0.05). For TP53, no differences were found among groups (p>0.05), with the fully methylated condition found to be a common event in healthy oral epithelial cells. CONCLUSION: We conclude that smoking may induce changes in DNA methylation status in cancer-related genes of oral epithelial cells and that the cessation of smoking is capable of reversing this process. Based on our data, we suggest that DNA methylation status of the hTERT and MLH1 gene promoters are promising markers for screening a set of smoking-related alterations in oral cells. PMID- 25791329 TI - Green tea polyphenol epigallocatechin-3-gallate and cranberry proanthocyanidins act in synergy with cathelicidin (LL-37) to reduce the LPS-induced inflammatory response in a three-dimensional co-culture model of gingival epithelial cells and fibroblasts. AB - OBJECTIVES: The human antimicrobial peptide cathelicidin (LL-37) possesses anti inflammatory properties that may contribute to attenuating the inflammatory process associated with chronic periodontitis. Plant polyphenols, including those from cranberry and green tea, have been reported to reduce inflammatory cytokine secretion by host cells. In the present study, we hypothesized that A-type cranberry proanthocyanidins (AC-PACs) and green tea epigallocatechin-3-gallate (EGCG) act in synergy with LL-37 to reduce the secretion of inflammatory mediators by oral mucosal cells. METHODS: A three-dimensional (3D) co-culture model of gingival epithelial cells and fibroblasts treated with non-cytotoxic concentrations of AC-PACs (25 and 50 MUg/ml), EGCG (1 and 5 MUg/ml), and LL-37 (0.1 and 0.2 MUM) individually and in combination (AC-PACs+LL-37 and EGCG+LL-37) were stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS). Multiplex ELISA assays were used to quantify the secretion of 54 host factors, including chemokines, cytokines, growth factors, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). RESULTS: LL-37, AC-PACs, and EGCG, individually or in combination, had no effect on the regulation of MMP and TIMP secretion but inhibited the secretion of several cytokines. AC-PACs and LL-37 acted in synergy to reduce the secretion of CXC-chemokine ligand 1 (GRO-alpha), granulocyte colony-stimulating factor (G CSF), and interleukin-6 (IL-6), and had an additive effect on reducing the secretion of interleukin-8 (IL-8), interferon-gamma inducible protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) in response to LPS stimulation. EGCG and LL-37 acted in synergy to reduce the secretion of GRO-alpha, G-CSF, IL 6, IL-8, and IP-10, and had an additive effect on MCP-1 secretion. CONCLUSION: The combination of LL-37 and natural polyphenols from cranberry and green tea acted in synergy to reduce the secretion of several cytokines by an LPS stimulated 3D co-culture model of oral mucosal cells. Such combinations show promising results as potential adjunctive therapies for treating inflammatory periodontitis. PMID- 25791330 TI - Treatment of African catfish, Clarias gariepinus wastewater utilizing phytoremediation of microalgae, Chlorella sp. with Aspergillus niger bio harvesting. AB - This study focuses on the evaluation of the performance of Chlorella sp. in removing nutrient in aquaculture wastewater and its correlation with the kinetic growth of Chlorella sp. The treatment was applied with various Chlorella sp. inoculation dosage ranging from 0% to 60% (v/v) of wastewater. The optimum inoculation dosage was recorded at 30% (v/v) with effluent concentration of ammonia and orthophosphate recording at 0.012mgL(-1) and 0.647mgL(-1), respectively on Day 11. The optimum dosage for bio-flocculation process was obtained at 30mgL(-1) of Aspergillus niger with a harvesting efficiency of 97%. This type of development of phytoremediation with continuous bio-harvesting could promote the use of sustainable green technology for effective wastewater treatment. PMID- 25791331 TI - Influence of temperature on volatile fatty acid production and microbial community structure during anaerobic fermentation of microalgae. AB - The objectives of this study were to investigate the effect of operating temperature on volatile fatty acids (VFAs) production from microalgal biomass, and to clarify the relationships between VFAs accumulation at different temperatures and the corresponding bacterial communities. The VFA yields were 0.10+/-0.017, 0.12+/-0.008, and 0.34+/-0.009 g/g VS at 35, 45, and 55 degrees C, respectively. The proportion of acetic acid decreased from 85.6% to 65.8% as operating temperature increased, whereas that of propionic acid increased from near 0% to 15.5% and that of iso-valeric acid remained relatively stable (10.2 11.2%). Bacterial communities at different operating temperatures consisted mostly of the phyla Proteobacteria, Bacteroidetes, and Firmicutes, which can degrade organic compounds effectively. Bacillus sp. was more predominant at 55 degrees C than at mesophilic temperatures, suggesting that this microorganism contributed significantly to the higher hydrolysis rate and VFA yield at this operating temperature. PMID- 25791332 TI - A dynamic flux balance model and bottleneck identification of glucose, xylose, xylulose co-fermentation in Saccharomyces cerevisiae. AB - A combination of batch fermentations and genome scale flux balance analysis were used to identify and quantify the rate limiting reactions in the xylulose transport and utilization pathway. Xylulose phosphorylation by xylulokinase was identified as limiting in wild type Saccharomyces cerevisiae, but transport became limiting when xylulokinase was upregulated. Further experiments showed xylulose transport through the HXT family of non-specific glucose transporters. A genome scale flux balance model was developed which included an improved variable sugar uptake constraint controlled by HXT expression. Model predictions closely matched experimental xylulose utilization rates suggesting the combination of transport and xylulokinase constraints is sufficient to explain xylulose utilization limitation in S. cerevisiae. PMID- 25791333 TI - On dealing with the innovations of the future. PMID- 25791334 TI - A Comparison of Retrievability: Celect versus Option Filter. AB - PURPOSE: To compare the retrievability of 2 potentially retrievable inferior vena cava filter devices. MATERIALS AND METHODS: A retrospective, institutional review board-approved study of Celect (Cook, Inc, Bloomington, Indiana) and Option (Rex Medical, Conshohocken, Pennsylvania) filters was conducted over a 33-month period at a single institution. Fluoroscopy time, significant filter tilt, use of adjunctive retrieval technique, and strut perforation in the inferior vena cava were recorded on retrieval. Fisher exact test and Mann-Whitney-Wilcoxon test were used for comparison. RESULTS: There were 99 Celect and 86 Option filters deployed. After an average of 2.09 months (range, 0.3-7.6 mo) and 1.94 months (range, 0.47-9.13 mo), respectively, 59% (n = 58) of patients with Celect filters and 74.7% (n = 65) of patients with Option filters presented for filter retrieval. Retrieval failure rates were 3.4% for Celect filters versus 7.7% for Option filters (P = .45). Median fluoroscopy retrieval times were 4.25 minutes for Celect filters versus 6 minutes for Option filters (P = .006). Adjunctive retrieval techniques were used in 5.4% of Celect filter retrievals versus 18.3% of Option filter retrievals (P = .045). The incidence of significant tilting was 8.9% for Celect filters versus 16.7% for Option filters (P = .27). The incidence of strut perforation was 43% for Celect filters versus 0% for Option filters (P < .0001). CONCLUSIONS: Retrieval rates for the Celect and Option filters were not significantly different. However, retrieval of the Option filter required a significantly increased amount of fluoroscopy time compared with the Celect filter, and there was a significantly greater usage of adjunctive retrieval techniques for the Option filter. The Celect filter had a significantly higher rate of strut perforation. PMID- 25791335 TI - Number of distinct sequence alignments with k-match and match sections. AB - BACKGROUND: Recent developments in sequence alignment have led to significant advances in our understanding of the functional, structural or evolutionary relationships among biological sequences. Great efforts have been made to count the total number of sequence alignments, but little attention has been paid to specific alignments associated with conserved patterns. METHODS: We propose a new combinatorial method to count specific alignments. First, we represent a sequence alignment as a system of cells. Using combinatorial techniques and Stirling's formula, we then count the numbers of specific alignments with a k-match or match section of size k. RESULTS: We developed three theorems related to different types of specific alignments. We found that the number of the alignments with match sections of at least k was less than that of k-match sections and the number of specific alignments was significantly lower than the results reported by Covington. DISCUSSION: The presence of a large number of alignments makes a direct search for the optimal alignment unfeasible for long sequences, whereas our proposed method based on specific alignments decreases the search space by many times. This facilitates the development of a faster algorithm for performing sequence comparisons. PMID- 25791337 TI - An amplified electrochemical immunosensor based on in situ-produced 1-naphthol as electroactive substance and graphene oxide and Pt nanoparticles functionalized CeO2 nanocomposites as signal enhancer. AB - In this work, an amplified electrochemical immunosensor based on 1-naphthol as electroactive substance and Pt/CeO2/GO composites as catalytic amplifier was constructed for sensitive detection influenza. Through "sandwich" reaction, the Pt/CeO2/GO functionalized bioconjugates were captured on electrode surface and the electrochemical signal directly originated from 1-naphthol, which was in situ produced with high local concentration though the hydrolysis of 1-naphthyl phosphate catalyzed by ALP. Then, 1-naphthol as new reactant was oxidized by Pt/CeO2/GO composites with outstanding catalytic performance, resulting in detection signal amplification. In addition, as compared to label electroactive substance to antibodies, a simplified preparative step of immunosensor could be achieved because the signal probe get rid of introducation other electroactive substances. The proposed immunosensor achieved a linear range of 1.0*10(-3) 1.0ngmL(-1) and 5.0 to 1.0*10(2)ngmL(-1) with a detection limit of 0.43pgmL(-1) (defined as S/N=3). PMID- 25791336 TI - Development of animal models against emerging coronaviruses: From SARS to MERS coronavirus. AB - Two novel coronaviruses have emerged to cause severe disease in humans. While bats may be the primary reservoir for both viruses, SARS coronavirus (SARS-CoV) likely crossed into humans from civets in China, and MERS coronavirus (MERS-CoV) has been transmitted from camels in the Middle East. Unlike SARS-CoV that resolved within a year, continued introductions of MERS-CoV present an on-going public health threat. Animal models are needed to evaluate countermeasures against emerging viruses. With SARS-CoV, several animal species were permissive to infection. In contrast, most laboratory animals are refractory or only semi permissive to infection with MERS-CoV. This host-range restriction is largely determined by sequence heterogeneity in the MERS-CoV receptor. We describe animal models developed to study coronaviruses, with a focus on host-range restriction at the level of the viral receptor and discuss approaches to consider in developing a model to evaluate countermeasures against MERS-CoV. PMID- 25791338 TI - Dual chronoamperometric detection of enzymatic biomarkers using magnetic beads and a low-cost flow cell. AB - In this work we report on the production of a low cost microfluidic device for the multiplexed electrochemical detection of magneto bioassays. As a proof of concept, the device has been used to detect myeloperoxidase (MPO), a cardiovascular biomarker. With this purpose, two bioassays have been optimized in parallel onto magnetic beads (MBs) for the simultaneous detection of MPO endogenous peroxidase activity and quantification of total MPO. Since the two bioassays produced signals of different magnitude for each concentration of MPO tested, two detection strategies have been compared, which entailed registering steady state currents (Iss) under substrate flow, and measuring the peak currents (Ip) produced in a stopped flow approach. As it will be shown, appropriate tuning of the detection and flow conditions can provide extremely sensitive detection, but also allow simultaneous detection of assays or parameters that would produce signals of different orders of magnitude when measured by a single detection strategy. In order to demonstrate the feasibility of the detection strategy reported, a dual MPO mass and activity assay has been finally applied to the study of 10 real plasma samples, allowing patient classification according to the risk of suffering a cardiovascular event. PMID- 25791339 TI - Perinatal outcomes of maternal overweight and obesity in term infants: a population-based cohort study in Canada. AB - The objective of this study was to assess the impact of increased pre-pregnancy maternal body mass index (BMI) on perinatal outcomes in term, singleton pregnancies who received prenatal care in community-based practices. The sample of 1996 infants included in the study was drawn from the All Our Babies Study, a prospective pregnancy cohort from Calgary. Multivariable logistic regression explored the relationship between the main outcomes, infant birth weight, Apgar score, admission to neonatal intensive care (NICU) and newborn duration of hospitalization, and BMI prior to pregnancy. Approximately 10% of the infants were macrosoms, 1.5% had a low Apgar score (<7 at 5 min), 6% were admitted to intensive care and 96% were discharged within 48 h after delivery. Although the infants of overweight and obese women were more likely to have increased birth weight as compared to infants of normal weight women, there were no differences in Apgar score, admission to NICU, or length of postnatal hospital stay among groups. This study suggests that in otherwise healthy term, singleton pregnancies, obesity does not seem to increase the risk of severe fetal impairment, neonatal admission to intensive care or duration of postnatal hospitalization. PMID- 25791340 TI - Multiple functional nanoprobe for contrast-enhanced bimodal cellular imaging and targeted therapy. AB - Many one-photon fluorescence-based theranostic nanosystems have been developed for simultaneous therapeutic intervention/monitoring for various types of cancers. However, for early diagnosis of cancer, two-photon fluorescence microscopy (TPFM) can realize deep-tissue imaging with higher spatial resolution. In this study, we first report a multiple functional nanoprobe for contrast enhanced bimodal cellular imaging and targeted therapy. Components of the nanoprobe include (1) two-photon dye-doped mesoporous silica nanoparticles (TPD MSNs); (2) MnO2 nanosheets that act as a (i) gatekeeper for TPD-MSNs, (ii) quencher for TP fluorescence, and (iii) contrast agent for MRI; (3) cancer cell targeting aptamers. Guided by aptamers, TPD-MSNs are rapidly internalized into the target cells. Next, intracellular glutathione reduces MnO2 to Mn(2+) ions, resulting in contrast-enhanced TP fluorescence and magnetic resonance signal for cellular imaging. Meanwhile, preloaded doxorubicin and Chlorin e6 are released for chemotherapy and photodynamic therapy, respectively, with a synergistic effect and significantly enhanced therapeutic efficacy. PMID- 25791342 TI - Connectedness and suicidal ideation among adolescents involved with child welfare: a national survey. AB - Using data from the National Survey of Child and Adolescent Well-Being, this study examined the relationship between connectedness in major social domains (i.e., caregiver, peers, deviant peers, and school) and suicidal ideation among adolescents (11-17 years old) investigated by child welfare agencies (N=995). Weighted logistic regression models were used to evaluate the relationships between connectedness variables and suicidal ideation, after adjusting for covariates. Youths with a stronger connection to caregivers were much less likely to report suicidal ideation, whereas youths with stronger deviant peer relationships were significantly more likely to report suicidal ideation. Significant associations found between primary caregiver and deviant peer connectedness and suicidal ideation highlight the need for attentive consideration of these relationships when working with this highly vulnerable population. Identifying domain-specific connectedness factors related to suicidal ideation presents an opportunity for the development of targeted early intervention for child welfare-involved youths. PMID- 25791341 TI - Monosodium L-Glutamate and Dietary Fat Differently Modify the Composition of the Intestinal Microbiota in Growing Pigs. AB - BACKGROUND: The Chinese have been undergone rapid transition to a high-fat diet consuming lifestyle, while monosodium L-glutamate (MSG) is widely used as a daily food additive. It has been reported that fat alters the composition of intestinal microbiota. However, little information is available on the effects of oral MSG on intestinal microbiota, and no study was done focusing on the interaction effect of fat and MSG with respect to intestinal microbiota. The present study thus aimed to determine the effects of MSG and/or fat on intestinal microbiota, and also to identify possible interactions between these two nutrients. METHODS: Four iso-nitrogenous and iso-caloric diets were provided to growing pigs. The microbiota from jejunum, ileum, cecum, and colon were analyzed. RESULTS: Our results show that both MSG and fat clearly increased the intestinal microbiota diversity. MSG and fat modified the composition of intestinal microbiota, particularly in the colon. Both MSG and fat promoted the colonization of microbes related to energy extraction in gastrointestinal tract via different ways. MSG promoted the colonization of Faecalibacterium prausnitzii and Roseburia, while fat increased the percentage of Prevotella in colon and other intestinal segments. CONCLUSION: Our results will help to understand how individual or combined dietary changes modify the microbiota composition to prevent obesity. PMID- 25791343 TI - Epigenetic regulation of polyomavirus JC involves acetylation of specific lysine residues in NF-kappaB p65. AB - Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by neurotropic polyomavirus, JC virus (JCV), a virus that causes lytic infection of CNS glial cells. After primary infection, JCV is controlled by the immune system but virus persists asymptomatically. Rarely, when immune function is impaired, it can reemerge to cause PML. The mechanisms of JCV persistence and reactivation are not well understood but our earlier work implicated epigenetic control by protein acetylation since histone deacetylase inhibitors such as trichostatin A (TSA) strongly stimulate JCV transcription. Since both TNF-alpha and TSA activate JCV transcription via the same unique NF-kappaB site in the JCV control region, we investigated a role for acetylation of NF-kappaB in JCV regulation. A site-directed mutagenesis strategy was employed targeting the known lysine acetylation sites of NF-kappaB p65: K218, K221, and K310. We individually mutated each lysine to arginine, which cannot be acetylated and retains a positive charge like lysine. K218R and K221R impaired transactivation of JCV early promoter transcription either alone or combined with TSA treatment or coexpression of acetyltransferase transcriptional coactivator p300 but K310R was largely without effect. Mutation of lysine to glutamine gives mutants with a negative charge like acetyllysine. However, K218Q and K221Q showed impaired activity and only K310Q showed enhanced transactivation. NF-kappaB acetylation can regulate several aspects of the process of activation including complex formation with IkappaB, translocation to the nucleus, and DNA binding and transcriptional activation. Cell fractionation studies revealed that the mutants had no defect in translocation to the nucleus whereas gel shift studies revealed reduced binding to the JCV NF-kappaB site. Thus, acetylation regulates NF-kappaB p65 activity toward JCV at the level of p65 binding to the JCV control region and activation of JCV transcription. PMID- 25791345 TI - Epidermal growth factor receptor inhibition by erlotinib prevents vascular smooth muscle cell and monocyte-macrophage function in vitro. AB - INTRODUCTION: Vascular smooth muscle cells (VSMCs) and monocyte-macrophages play a central role during the development of chronic allograft injury, which still remains an important challenge in organ transplantation. Inflammation, fibrosis and accelerated arteriosclerosis are typical features for chronic allograft injury. Growth factors participate in cell proliferation, differentiation and migration in this pathological process. OBJECTIVE: Here we studied the role of epidermal growth factor receptor (EGFR) in VSMC and monocyte-macrophage function in vitro. EGFR inhibition by erlotinib, a selective EGF tyrosine kinase inhibitor, was studied in VSMC proliferation and migration as well as monocyte macrophage proliferation and differentiation. MATERIALS AND METHODS: Rat coronary artery SMCs were used for VSMC studies. As a model for monocyte-macrophage proliferation and differentiation human monocytic cell line U937 was used. Phorbol ester TPA was used to induce these cells to differentiate into macrophages. RESULTS: Platelet-derived growth factor (PDGF)-B, a known VSMC inducer, caused 2.1-fold stimulation in VSMC proliferation compared to non stimulated VSMC. Erlotinib prevented this VSMC proliferation in a dose-dependent manner, p < 0.001 in all groups compared to controls. PDGF-B stimulation increased VSMC migration to 2.5-fold when compared with non-stimulated cells. Erlotinib decreased VSMC migration dose-dependently and this effect was significant with all doses, p < 0.05. Erlotinib inhibited dose-dependently the proliferation of U937 monocytic cells, p < 0.001. Erlotinib prevented also TPA induced macrophage differentiation in a dose-dependent way, p < 0.05. DISCUSSION: Erlotinib significantly prevents VSMC proliferation and migration in vitro. Erlotinib inhibited also significantly both monocyte proliferation and differentiation. Our data suggest that EGFR inhibition in VSMC and monocyte function has beneficial effects on chronic allograft injury. PMID- 25791344 TI - The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women. AB - In contrast to findings from cohorts comprised primarily of HIV-infected men, verbal memory deficits are the largest cognitive deficit found in HIV-infected women from the Women's Interagency HIV Study (WIHS), and this deficit is not explained by depressive symptoms or substance abuse. HIV-infected women may be at greater risk for verbal memory deficits due to a higher prevalence of cognitive risk factors such as high psychosocial stress and lower socioeconomic status. Here, we investigate the association between perceived stress using the Perceived Stress Scale (PSS-10) and verbal memory performance using the Hopkins Verbal Learning Test (HVLT) in 1009 HIV-infected and 496 at-risk HIV-uninfected WIHS participants. Participants completed a comprehensive neuropsychological test battery which yielded seven cognitive domain scores, including a primary outcome of verbal memory. HIV infection was not associated with a higher prevalence of high perceived stress (i.e., PSS-10 score in the top tertile) but was associated with worse performance on verbal learning (p < 0.01) and memory (p < 0.001), as well as attention (p = 0.02). Regardless of HIV status, high stress was associated with poorer performance in those cognitive domains (p's < 0.05) as well as processing speed (p = 0.01) and executive function (p < 0.01). A significant HIV by stress interaction was found only for the verbal memory domain (p = 0.02); among HIV-infected women only, high stress was associated with lower performance (p's < 0.001). That association was driven by the delayed verbal memory measure in particular. These findings suggest that high levels of perceived stress contribute to the deficits in verbal memory observed in WIHS women. PMID- 25791346 TI - Targeting cefuroxime plasma concentrations during coronary artery bypass graft surgery with cardiopulmonary bypass. AB - BACKGOUND: Patients are at risk for severe postoperative infections after coronary artery bypass graft (CABG) surgery. Clinical laboratory data showed that unbound plasma concentrations of cefuroxime were not always adequate, therefore we developed a new dosing regimen. OBJECTIVE: The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with cardiopulmonary bypass (CPB). SETTING: A Dutch teaching hospital. METHODS: In this prospective trial, patients scheduled for CABG surgery with CPB were included. A starting dose of 1500 mg cefuroxime was given with anesthesia induction, followed by 750 mg cefuroxime every hour until wound closure. In case of renal failure the dosing regimen was adapted. Serial blood samples were collected before, during and after the CPB process. Pharmacokinetic modelling was performed by using an 'iterative two-stage Bayesian population procedure'. MAIN OUTCOME MEASURE: Unbound plasma concentrations of cefuroxime. RESULTS: 22 patients were included, data could be evaluated of 21 patients. In 24 % of the patients the unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Patients with a bodyweight above 100 kg or age <60 years were more likely to have unbound plasma concentrations below the target range (P = 0.030 and P = 0.008). During CPB, the half-life of unbound cefuroxime increased by 17 % and the clearance decreased by 11 % compared to before CPB (P = 0.033 and P = 0.014). The mean pharmacokinetic parameters before, during and after CPB were as follows: elimination half-life 72, 84 and 76 min; clearance of unbound cefuroxime (Clu) 14.2, 12.7, 13.8 l/h and volume of distribution (Vu) 0.280, 0.284 and 0.290 l/kg respectively. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. CONCLUSION: Our results show that CPB during CABG surgery does not lead to inadequate unbound cefuroxime concentrations. Age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value. PMID- 25791347 TI - Pharmacists' care of diabetes patients during Ramadan. PMID- 25791348 TI - Evaluation of parenteral nutrition use in patients undergoing major upper gastro intestinal surgery. AB - BACKGROUND: After major upper gastro-intestinal surgery, enteral feeding is often hampered. There is still no consensus on which route of nutrition is preferable in patients undergoing this type of surgery. Current ESPEN guidelines recommend parenteral nutrition in undernourished patients, if caloric requirements cannot be met orally/enterally within 7 days and enteral nutrition is contraindicated. OBJECTIVE: The current practice of systematic parenteral nutrition at the thoracic surgery ward of the University Hospitals Leuven was evaluated based on the ESPEN guidelines. METHOD: This prospective observational study included patients undergoing upper gastro-intestinal surgery and receiving postoperative parenteral nutrition. Parenteral nutrition use was considered appropriate when patients were undernourished and unable to obtain adequate caloric requirements by oral or enteral feeding within 7 days. RESULTS: Twenty-five out of 35 patients were nutritionally at risk. In 9 of 25 patients, the indication for parenteral nutrition was considered justified. As the intestinal tract below the anastomosis site remains accessible in the total studied population, enteral nutrition might be an option. Unfortunately, an appropriate jejunostomy tube was not available at our institution. CONCLUSION: In accordance to the ESPEN guidelines, enteral nutrition can replace parenteral nutrition in most thoracic surgery patients, but only if an appropriate enteral access is available. PMID- 25791349 TI - Functional competition within a membrane: Lipid recognition vs. transmembrane helix oligomerization. AB - Binding of specific lipids to large, polytopic membrane proteins is well described, and it is clear that such lipids are crucial for protein stability and activity. In contrast, binding of defined lipid species to individual transmembrane helices and regulation of transmembrane helix monomer-oligomer equilibria by binding of distinct lipids is a concept, which has emerged only lately. Lipids bind to single-span membrane proteins, both in the juxta-membrane region as well as in the hydrophobic membrane core. While some interactions counteract transmembrane helix oligomerization, in other cases lipid binding appears to enhance oligomerization. As reversible oligomerization is involved in activation of many membrane proteins, binding of defined lipids to single-span transmembrane proteins might be a mechanism to regulate and/or fine-tune the protein activity. But how could lipid binding trigger the activity of a protein? How can binding of a single lipid molecule to a transmembrane helix affect the structure of a transmembrane helix oligomer, and consequently its signaling state? These questions are discussed in the present article based on recent results obtained with simple, single-span transmembrane proteins. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25791350 TI - Nicotinic acetylcholine receptor-lipid interactions: Mechanistic insight and biological function. AB - Membrane lipids are potent modulators of the nicotinic acetylcholine receptor (nAChR) from Torpedo. Lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of activatable versus non-activatable conformations, as well as influencing the transitions between these conformational states. Of note, some membranes stabilize an electrically silent uncoupled conformation that binds agonist but does not undergo agonist-induced conformational transitions. The uncoupled nAChR, however, does transition to activatable conformations in relatively thick lipid bilayers, such as those found in lipid rafts. In this review, we discuss current understanding of lipid-nAChR interactions in the context of increasingly available high resolution structural and functional data. These data highlight different sites of lipid action, including the lipid-exposed M4 transmembrane alpha-helix. Current evidence suggests that lipids alter nAChR function by modulating interactions between M4 and the adjacent transmembrane alpha-helices, M1 and M3. These interactions have also been implicated in both the folding and trafficking of nAChRs to the cell surface. We review current mechanistic understanding of lipid-nAChR interactions, and highlight potential biological roles for lipid-nAChR interactions in modulating the synaptic response. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25791351 TI - General and specific lipid-protein interactions in Na,K-ATPase. AB - The molecular activity of Na,K-ATPase and other P2 ATPases like Ca(2+)-ATPase is influenced by the lipid environment via both general (physical) and specific (chemical) interactions. Whereas the general effects of bilayer structure on membrane protein function are fairly well described and understood, the importance of the specific interactions has only been realized within the last decade due particularly to the growing field of membrane protein crystallization, which has shed new light on the molecular details of specific lipid-protein interactions. It is a remarkable observation that specific lipid-protein interactions seem to be evolutionarily conserved, and conformations of specifically bound lipids at the lipid-protein surface within the membrane are similar in crystal structures determined with different techniques and sources of the protein, despite the rather weak lipid-protein interaction energy. Studies of purified detergent-soluble recombinant alphabeta or alphabetaFXYD Na,K-ATPase complexes reveal three separate functional effects of phospholipids and cholesterol with characteristic structural selectivity. The observations suggest that these three effects are exerted at separate binding sites for phophatidylserine/cholesterol (stabilizing), polyunsaturated phosphatidylethanolamine (stimulatory), and saturated PC or sphingomyelin/cholesterol (inhibitory), which may be located within three lipid binding pockets identified in recent crystal structures of Na,K-ATPase. The findings point to a central role of direct and specific interactions of different phospholipids and cholesterol in determining both stability and molecular activity of Na,K-ATPase and possible implications for physiological regulation by membrane lipid composition. This article is part of a special issue titled "Lipid Protein Interactions." PMID- 25791352 TI - A computational study of intramolecular hydrogen bonds breaking/formation: impact on the structural flexibility of the ranitidine molecule. AB - Ranitidine is a histamine H2-receptor antagonist that reduces gastric acid secretion. We studied the flexibility of the ranitidine molecule with the special focus on the network of diverse intramolecular hydrogen bonds: N-H?O, N-H?N, C H?O, C-H?N and N-H?S. We performed static density functional theory calculations of global and local minima and analyzed their stability at finite temperature in the Car-Parrinello molecular dynamics simulations. We observed intramolecular H bonds breaking/formation crucial for the structural rearrangements leading to the folding process. The lifetimes of the closed structures of ranitidine were also estimated. The existence of hydrogen bonds and their strength were confirmed on the basis of topological parameters in the bond critical points utilizing Quantum Theory of Atoms in Molecules. PMID- 25791353 TI - Carborane tuning on iridium complexes: redox-switchable second-order NLO responses. AB - Much effort has been devoted to investigating the molecular geometries, electronic structures, redox properties and nonlinear optical (NLO) properties of Ir complexes involving o-, m- or p-carborane groups by density functional theory (DFT) methods. Switchable second-order NLO properties were induced by redox processes involving these complexes, and it was found that mainly the coordination bonds of Ir complexes changed during the oxidation process. Our calculations revealed that oxidation reactions have a significant influence on the second-order NLO response owing to the change in charge transfer pattern. The beta tot values of oxidized species are at least ~9 times larger for set I and ~5 times larger for set II than those of the corresponding parent complexes. Introduction of carborane groups into ppy (phenylpyridine) ligands can enhance the second-order NLO response by 1.2- 1.6 times by a metal-to-ligand charge transfer (MLCT) transition between the Ir atom and carborane. The beta tot of complex 2 [(ppy)2Ir(phen)](+) (phen = phenanthroline) is 3.3 times larger than that of complex 1 (ppy)2Ir(acce) (acce = acetylacetonate), which is caused by ligand-to-ligand charge transfer (LLCT) between ppy ligands and the ancillary ligand. Therefore, it can be concluded that the second-order NLO response can be effectively enhanced by oxidation reactions. PMID- 25791354 TI - Synthesis of magnetite-graphene oxide-layered double hydroxide composites and applications for the removal of Pb(II) and 2,4-dichlorophenoxyacetic acid from aqueous solutions. AB - Magnetic composites consisting of magnetite (Fe3O4), graphene oxide (GO), and Mg3Al-OH layered double hydroxide (LDH), denoted as MGL composites, with varying GO contents (RGO) were synthesized by a mechano-hydrothermal (MHT) route using Fe3O4, Mg(OH)2, and Al(OH)3 as the inorganic starting materials. The application of the synthesized MGLs for removing the heavy-metal Pb(II) and the hydrophobic organic pesticide 2,4-dichlorophenoxyacetic acid (2,4-D) from aqueous solutions was investigated. Chemical bonding among the GO, Fe3O4, and LDH components was observed in the MGLs. The MGL composites showed good water-dispersity, strong magnetic response, and high sorption capacities and removal efficiencies for both Pb(II) and 2,4-D pollutants. The sorption capacities of the MGL for the pollutants significantly increased with an increase in RGO. Increasing pH could increase the removal efficiency for Pb(II) but decrease that for 2,4-D. The MGLs showed more affinity for Pb(II) than for 2,4-D in the competitive sorption. In addition, the MGLs could remain almost constant removal efficiency for the pollutants after reuse over six cycles, indicating their potential use as sorbents in wastewater treatment. Furthermore, a Cs effect was observed in the sorption equilibriums, which could be described using the Langmuir-SCA and Freundlich-SCA isotherms. The removal mechanisms of the MGL for Pb(II) and 2,4-D were discussed. The MHT method provided a simple and environmentally friendly route for synthesizing GO-LDH composite materials. PMID- 25791355 TI - Notch Intracellular Domain (NICD) Suppresses Long-Term Memory Formation in Adult Drosophila Flies. AB - Notch receptor signaling is evolutionarily conserved and well known for its roles in animal development. Many studies in Drosophila have shown that Notch also performs important functions in memory formation in adult flies. An intriguing observation is that increased expression of the full-length Notch receptor (Nfull) triggers long-term memory (LTM) formation even after very weak training (single training). Canonical Notch signaling is mediated by Notch intracellular domain (NICD), but it is not known whether increased expression of NICD recapitulates the LTM enhancement induced by increased Nfull expression. Here, we report that increased NICD expression either has no impact on LTM formation or suppresses it. Furthermore, it either has no impact or decreases both the levels and activity of cAMP response element binding protein, a key factor supporting LTM. These results indicate that NICD signaling is not sufficient to explain Nfull-induced LTM enhancement. Our findings may also shed light on the molecular mechanisms of memory loss in neurological diseases associated with increased NICD expression and canonical Notch signaling. PMID- 25791357 TI - Choroidal involvement in Rosai-Dorfman syndrome may be depicted and followed using enhanced depth imaging optical coherence tomography (EDI-OCT). PMID- 25791358 TI - Comparison of SFA lesion treatment with Zilver PTX in diabetics vs. non diabetics: 2-year clinical and functional results. AB - BACKGROUND: Prospective single-arm study, aimed at evaluating safety and effectiveness at 12 and 24 months of the paclitaxel-eluting nitinol stent (Zilver PTX), and focused in particular on the treatment of complex lesions and/or diabetic patients. METHODS: Between May 2010 and March 2012, 67 patients (78% males) were treated by Zilver PTX, because of stenosis or occlusions of the superficial femoral artery in one of two centers. The mean age of patients was 70.1+/-8 years. Thirty-two of 67 (48%) were diabetics, 14 (21%) active smokers and 11 (14.6%) had chronic renal failure (end stage renal disease). The average length of lesions was 104+/-60 mm. Occlusion was complete in 46.3% of cases, whereas severely calcified lesions were present in 30% of patients (18.8% in diabetics and 31.4% in non-diabetics). Twenty-six patients (39%) had type C or D lesions according to TASC 2. RESULTS: One hundred-two stents were used (1.7+/-0.9 per patients); median 1 (range 1-4). All patients had successful stent placement. Primary patency, evaluated by Kaplan-Meier method was 88+/-0.06% at 12 months, and 68+/-0.1% at 24 months. In particular, the difference between diabetics (D) and non-diabetics (non-D) was not significant (P=0.07, Log-Rank). Patients turned from 4.2+/-1.3 to 1.6+/-1.3 Rutherford class. There were 5 deaths due to systemic comorbidities. There also were 3 major amputations, all of them also in the D group. Among the other patients, differences between D and non-D patients were not significant in terms of wound healing, bipedal stay and spontaneous ambulation. The mean follow-up length was 28+/-5 months (range 24-36 months). There was only one patient who had fracture and stent migration (1.5%). In 13 diabetic patients, tibial PTA was also associated. Additional treatment was required in 6 D and 1 non-D. CONCLUSIONS: The use of Zilver PTX is safe and effective in the treatment of SFA lesions. In particular, both stent patency and functional results on the basis of both clinical and instrumental tools were similar in D and non-D, suggesting a particularly favorable activity of PTX in a subpopulation of diabetics. Further studies are required to confirm these results, which seem to be particularly promising in diabetic patients. PMID- 25791356 TI - RhoA/mDia-1/profilin-1 signaling targets microvascular endothelial dysfunction in diabetic retinopathy. AB - BACKGROUND: Diabetic retinopathy (DR) is a major cause of blindness in the working-age populations of developed countries, and effective treatments and prevention measures have long been the foci of study. Patients with DR invariably demonstrate impairments of the retinal microvascular endothelium. Many observational and preclinical studies have shown that angiogenesis and apoptosis play crucial roles in the pathogenesis of DR. Increasing evidence suggests that in DR, the small guanosine-5'-triphosphate-binding protein RhoA activates its downstream targets mammalian Diaphanous homolog 1 (mDia-1) and profilin-1, thus affecting important cellular functions, including cell morphology, motility, secretion, proliferation, and gene expression. However, the specific underlying mechanism of disease remains unclear. CONCLUSION: This review focuses on the RhoA/mDia-1/profilin-1 signaling pathway that specifically triggers endothelial dysfunction in diabetic patients. Recently, RhoA and profilin-1 signaling has attracted a great deal of attention in the context of diabetes-related research. However, the precise molecular mechanism by which the RhoA/mDia-1/profilin-1 pathway is involved in progression of microvascular endothelial dysfunction (MVED) during DR has not been determined. This review briefly describes each feature of the cascade before exploring the most recent findings on how the pathway may trigger endothelial dysfunction in DR. When the underlying mechanisms are understood, novel therapies seeking to restore the endothelial homeostasis comprised in DR will become possible. PMID- 25791359 TI - An acellular cerebellar biological scaffold: Preparation, characterization, biocompatibility and effects on neural stem cells. AB - Biomaterial and regenerative medical research has diversified and developed rapidly. A biological scaffold consisting of an extracellular matrix (ECM) functions not only as a supportive material but also as a regulator of cellular functions. Although decellularized scaffolds have been widely applied for the repair of non-central nervous system (CNS) tissues, their efficacy in the CNS has not been extensively investigated. In this report, we describe a dynamic decellularization protocol that combined intracardial perfusion and a series of treatments to effectively remove the cellular components from the cerebellum, which is a unique and relatively simple CNS structure. The resulting cerebellar scaffold retained neurosupportive proteins and growth factors and, when tested with neural stem cells (NSCs) in vitro, was found to be cytocompatible and to stimulate the proliferation and migration of these cells. NSCs that were cultured in vitro on the scaffold differentiated into neurons and astrocytes, as indicated by their expression of betaIII-tubulin and glial fibrillary acidic protein (GFAP). Through subcutaneous and intracranial implantation experiments, this preliminary study demonstrated the in vivo biocompatibility of the cerebellar scaffold and indicated its potential for future applications. Thus, our study demonstrated that the cerebellar ECM scaffold provided tissue-specific advantages for regenerative medical applications. PMID- 25791360 TI - Response inhibition failure to visual stimuli paired with a "single-type" stressor in PTSD patients: an fMRI pilot study. AB - Patients with post-traumatic stress disorder (PTSD) tend to misinterpret innocuous stimuli as potential threats, possibly due to a conditioning provoked by traumatic episodes. Previous neuroimaging evidence has shown an abnormal activation of the amygdala and prefrontal cortex in PTSD patients during fear conditioning and extinction. Nevertheless, the effects of a single-type adverse stressor on that circuit remain poorly explored. We tested the hypothesis that a single-type adverse episode is able to affect the prefrontal cortex and amygdala response to conditioned stimuli. To test this hypothesis, fMRI recordings were performed in PTSD patients and trauma-exposed controls during the observation of neutral and negative paired or non-paired pictures with an adverse stimulus by means of a single association. Results showed that left amygdala activation during negative reinforced stimuli was correlated with the score of PTSD clinical scale across all subjects. Furthermore, in the traumatized non-PTSD group, the activation of the dorso-medial prefrontal cortex and bilateral amygdala was lower during the observation of the reinforced (CS(+)) versus non-reinforced pictures (CS(-)) in response to emotionally negative stimuli. This was not the case in the PTSD patients. These results suggest that in PTSD patients, a single-episode conditioning unveils the failure of an inhibitory mechanism moderating the activity of the prefrontal cortex and amygdala in response to adverse and neutral stimuli. PMID- 25791361 TI - The complete mitochondrial genome sequence of Schizopygopsis anteroventris (Cypriniformes: Cyprinidae). AB - Schizopygopsis anteroventris (Cyprinidae: Schizothoracinae) is an ecologically and economically important cyprinid endemic to Qinghai-Tibet Plateau, China. In this study, we sequenced the complete mitochondrial genome of S. anteroventris by DNA sequencing based on PCR fragments. The mitogenome of S. anteroventris is 16,620 in length, containing 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and two non-coding regions: the control region (D-loop) and the origin of light-strand replication (OL). The gene order in the mitogenome is identical with common vertebrate form. The complete mitogenome sequence is useful for further genetic studies, phylogenetic analysis and resource protection of S. anteroventris. PMID- 25791362 TI - Induction of apoptosis by hypertension via endoplasmic reticulum stress. AB - BACKGROUND/AIMS: Endoplasmic reticulum (ER) stress is one of the intrinsic apoptosis pathways, and cardiac apoptosis can occur in cardiovascular diseases, such as hypertension. However, the mechanisms by which ER stress leads to apoptosis remain enigmatic, particularly in the progression from cardiac hypertrophy to diastolic heart failure due to hypertension. METHODS: We used spontaneously hypertensive rats (SHRs) to investigate possible signalling pathways for ER stress. RESULTS: We found that cardiac protein and mRNA levels of glucoseregulated protein 78 were up-regulated. In addition, the CHOP- and caspase 12-dependent pathways, but not that of JNK, were activated in the SHR rats. CONCLUSIONS: These results suggest that ER stress can contribute to myocardial apoptosis during hypertensive disease. PMID- 25791365 TI - Identifying Deficiencies in National and Foreign Medical Team Responses Through Expert Opinion Surveys: Implications for Education and Training--ERRATUM. PMID- 25791363 TI - Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies. AB - PURPOSE: Combination therapy with trabectedin and docetaxel was evaluated in patients with advanced malignancies. METHODS: In this open-label phase 1 study, docetaxel (60 or 75 mg/m(2); 1-h intravenous infusion) was given on day 1 of a 21 day cycle in combination with escalating doses of trabectedin (0.4-1.3 mg/m(2) by 3-h intravenous infusion, 1 h after docetaxel) and prophylactic granulocyte colony-stimulating factor (G-CSF). Maximum tolerated dose (MTD) as primary objective and safety, plasma pharmacokinetics, and antitumor activity as secondary objectives were assessed. RESULTS: Patients (N = 49) received a median of four cycles of treatment. MTD was 1.3 mg/m(2) trabectedin and 60 mg/m(2) docetaxel for patients with limited and 1.1 mg/m(2) trabectedin and 60 mg/m(2) docetaxel for patients with unlimited prior chemotherapy. Dose-limiting toxicities (during cycle 1) included elevated alanine aminotransferase (ALT) and fatigue in patients with limited prior chemotherapy and elevated ALT and febrile neutropenia in those with unlimited prior chemotherapy. The most common drug related adverse events were nausea (65 %), fatigue (63 %), and neutropenia (53 %). One patient achieved a complete response. Thirty patients had stable disease, and 11 had stable disease for >=6 months. Pharmacokinetic results for trabectedin plus docetaxel were similar to those previously reported for the single agents. CONCLUSION: In patients with previously treated, advanced malignancies, the combination of therapeutic doses of trabectedin and docetaxel showed clinical activity and was tolerable with prophylactic G-CSF, with no evidence of clinically important drug interactions. PMID- 25791366 TI - Problem areas identified as important to older adults with lumbar spinal stenosis. AB - BACKGROUND CONTEXT: There is growing concern that patient-reported outcomes (PROs) commonly used in clinical research evaluating treatments such as epidural steroid injections (ESIs) for lumbar spinal stenosis may not adequately capture outcomes of greatest importance to older adults. PURPOSE: The purpose of the study was to determine what outcomes are most important to older adults with spinal stenosis, how well commonly used PROs reflect what is most important to these participants, and which outcomes older adults with spinal stenosis would want improved to consider having ESI. STUDY DESIGN/SETTING: This is an outcome prioritization study. PATIENT SAMPLE: Community sample of 33 older adults with spinal stenosis were included. OUTCOME MEASURES: The outcome measures were Swiss Spinal Stenosis Questionnaire and Roland-Morris Disability Questionnaire. METHODS: The methods involve individual sorting and ranking exercises followed by facilitated focus groups. RESULTS: Highest rated problem areas were "experiencing pain/discomfort" (88% of participants), "problems with physical function" (85%), "difficulty exercising" (73%), "difficulty participating in hobbies and leisure activities" (55%), and "problems with weakness" (52%). Only 10 of the 24 Roland Morris Disability Questionnaire items were rated by 50% or more of participants experiencing them as important enough to warrant ESI treatment. CONCLUSIONS: Older adults with spinal stenosis rated problems related to pain and physical function as the most important outcomes to them. However, difficulty exercising and difficulty participating in hobbies and leisure activities were also among the most highly rated and were two areas not typically assessed in treatment studies. Commonly used PROs in spinal stenosis treatment studies may be insufficient to comprehensively assess outcomes from the patient perspective. PMID- 25791367 TI - Cortical relapses in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a white and grey matter disease of the central nervous system (CNS). It is recognized that cortical damage (i.e. focal lesions and atrophy) plays a role in determining the accumulation of physical and cognitive disability that is observed in patients with progressive MS. To date, an association of cortical lesions with clinical relapses has not been described. RESULTS: We report clinical and magnetic resonance imaging (MRI) findings of five relapsing-remitting MS (RRMS) patients who had clinical relapses characterized by the acute appearance of cortical symptoms, due to the development of large, snake like, cortical inflammatory lesions. Symptoms were: acute Wernicke's aphasia mimicking stroke; agraphia with acalculia, not associated to a motor deficit nor linguistic disturbance; hyposthenia of the left arm, followed by muscle twitching of the hand, spreading to arm and face; acute onset of left lower limb paroxysmal hypertonia; and temporal lobe status epilepticus, with psychotic symptoms. CONCLUSIONS: Cortical relapses may occur in MS. MRI examination in MS should include sequences, such as double inversion recovery (DIR) or phase sensitive inversion recovery (PSIR), that are aimed at visualizing cortical lesions, especially in the presence of symptoms of cortical dysfunction. Our observation further stresses and extends the clinical relevance of cortical pathology in MS. PMID- 25791368 TI - Corticospinal tract integrity is related to primary motor cortex thinning in relapsing-remitting multiple sclerosis. AB - BACKGROUND: The relationship between white matter injury and cortical atrophy development in relapsing-remitting multiple sclerosis (RRMS) remains unclear. OBJECTIVES: To investigate the associations between corticospinal tract integrity and cortical morphology measures of the primary motor cortex in RRMS patients and healthy controls. METHODS: 51 RRMS patients and 30 healthy controls underwent MRI examination for cortical reconstruction and assessment of corticospinal tract integrity. Partial correlation and multiple linear regression analyses were used to investigate the associations of focal and normal appearing white matter (NAWM) injury of the corticospinal tract with thickness and surface area measures of the primary motor cortex. Relationships between MRI measures and clinical disability as assessed by the Expanded Disability Status Scale and disease duration were also investigated. RESULTS: In patients only, decreased cortical thickness was related to increased corticospinal tract NAWM mean, axial and radial diffusivities in addition to corticospinal tract lesion volume. The final multiple linear regression model for PMC thickness retained only NAWM axial diffusivity as a significant predictor (adjusted R(2)= 0.270, p= 0.001). Clinical measures were associated with NAWM corticospinal tract integrity measures. CONCLUSIONS: Primary motor cortex thinning in RRMS is related to alterations in connected white matter and is best explained by decreased NAWM integrity. PMID- 25791369 TI - A novel suture method to place and adjust peripheral nerve catheters. AB - We have developed a peripheral nerve catheter, attached to a needle, which works like an adjustable suture. We used in-plane ultrasound guidance to place 45 catheters close to the femoral, saphenous, sciatic and distal tibial nerves in cadaver legs. We displaced catheters after their initial placement and then attempted to return them to their original positions. We used ultrasound to evaluate the initial and secondary catheter placements and the spread of injectate around the nerves. In 10 cases, we confirmed catheter position by magnetic resonance imaging. We judged 43/45 initial placements successful and 42/43 secondary placements successful by ultrasound, confirmed in 10/10 cases by magnetic resonance imaging. PMID- 25791370 TI - Uniform functional structure across spatial scales in an intertidal benthic assemblage. AB - To investigate the causes of the remarkable similarity of emergent assemblage properties that has been demonstrated across disparate intertidal seagrass sites and assemblages, this study examined whether their emergent functional-group metrics are scale related by testing the null hypothesis that functional diversity and the suite of dominant functional groups in seagrass-associated macrofauna are robust structural features of such assemblages and do not vary spatially across nested scales within a 0.4 ha area. This was carried out via a lattice of 64 spatially referenced stations. Although densities of individual components were patchily dispersed across the locality, rank orders of importance of the 14 functional groups present, their overall functional diversity and evenness, and the proportions of the total individuals contained within each showed, in contrast, statistically significant spatial uniformity, even at areal scales <2 m(2). Analysis of the proportional importance of the functional groups in their geospatial context also revealed weaker than expected levels of spatial autocorrelation, and then only at the smaller scales and amongst the most dominant groups, and only a small number of negative correlations occurred between the proportional importances of the individual groups. In effect, such patterning was a surface veneer overlying remarkable stability of assemblage functional composition across all spatial scales. Although assemblage species composition is known to be homogeneous in some soft-sediment marine systems over equivalent scales, this combination of patchy individual components yet basically constant functional-group structure seems as yet unreported. PMID- 25791372 TI - Patient-provider concordance with behavioral change goals drives measures of motivational interviewing consistency. AB - OBJECTIVE: Motivational Interviewing (MI) consistent talk by a counselor is thought to produce "change talk" in clients. However, it is possible that client resistance to behavior change can produce MI inconsistent counselor behavior. METHODS: We applied a coding scheme which identifies all of the behavioral counseling about a given issue during a visit ("episodes"), assesses patient concordance with the behavioral goal, and labels providers' counseling style as facilitative or directive, to a corpus of routine outpatient visits by people with HIV. Using a different data set of comparable encounters, we applied the concepts of episode and concordance, and coded using the Motivational Interviewing Treatment Integrity system. RESULTS: Patient concordance/discordance was not observed to change during any episode. Provider directiveness was strongly associated with patient discordance in the first study, and MI inconsistency was strongly associated with discordance in the second. CONCLUSION: Observations that MI-consistent behavior by medical providers is associated with patient change talk or outcomes should be evaluated cautiously, as patient resistance may provoke MI-inconsistency. PRACTICE IMPLICATIONS: Counseling episodes in routine medical visits are typically too brief for client talk to evolve toward change. Providers with limited training may have particular difficulty maintaining MI consistency with resistant clients. PMID- 25791371 TI - How effective are antioxidant supplements in obesity and diabetes? AB - Obesity is a central health issue due to its epidemic prevalence and its association with type 2 diabetes and other comorbidities. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. It represents a state of chronic oxidative stress and low-grade inflammation whose intermediary molecules may include leptin, adiponectin and cytokines. It may progress to hyperglycemia, leading to type 2 diabetes. Whether or not dietary antioxidant supplements are useful in the management of obesity and type 2 diabetes is discussed in this review. Only the benefits for obesity and diabetes are examined here. Other health benefits of antioxidants are not considered. There are difficulties in comparing studies in this field because they differ in the time frame, participants' ethnicity, administration of antioxidant supplements, and even in how obesity was measured. However, the literature presents reasonable evidence for marginal benefits of supplementation with zinc, lipoic acid, carnitine, cinnamon, green tea, and possibly vitamin C plus E, although the evidence is much weaker for omega-3 polyunsaturated fatty acids, coenzyme Q10, green coffee, resveratrol, or lycopene. Overall, antioxidant supplements are not a panacea to compensate for a fast-food and video-game way of living, but antioxidant-rich foods are recommended as part of the lifestyle. Such antioxidant foods are commonly available. PMID- 25791373 TI - Patients' general satisfaction with telephone counseling by pharmacists and effects on satisfaction with information and beliefs about medicines: Results from a cluster randomized trial. AB - OBJECTIVE: Assess effects of pharmacists' counseling by telephone on patients' satisfaction with counseling, satisfaction with information and beliefs about medicines for newly prescribed medicines. METHODS: A cluster randomized trial in Dutch community pharmacies. Patients >=18 years were included when starting with antidepressants, bisphosphonates, RAS-inhibitors or statins. The intervention comprised counseling by telephone to address barriers to adherent behavior. It was supported by an interview protocol. Controls received usual care. Outcomes were effects on beliefs about medication, satisfaction with information and counseling. Data was collected with a questionnaire. RESULTS: Responses of 211 patients in nine pharmacies were analyzed. More intervention arm patients were satisfied with counseling (adj. OR 2.2 (95% CI 1.3, 3.6)). Patients with counseling were significantly more satisfied with information on 4 items, had less concerns and less frequently had a 'skeptical' attitude towards medication (adj. OR 0.5 (0.3-0.9)). Effects on most outcomes were more pronounced in men than in women. CONCLUSIONS: Telephone counseling by pharmacists improved satisfaction with counseling and satisfaction with information on some items. It had a small effect on beliefs about medicines. PRACTICE IMPLICATIONS: Pharmacists can use counseling by telephone, but more research is needed to find out which patients benefit most. PMID- 25791374 TI - Apoptosis and differentiation of Xenopus tail-derived myoblasts by thyroid hormone. AB - The metamorphosis of anuran amphibians is induced by thyroid hormone (TH). To study the molecular mechanisms underlying tail regression during metamorphosis, we established a cell line, XL-B4, from a Xenopus laevis tadpole tail at a premetamorphic stage. The cells expressed myoblast markers and differentiated into myotubes in differentiation medium. XL-B4 cells expressing fluorescent proteins were transplanted into tadpole tails. At 5 days post-transplantation, fluorescence was observed in myotube-like structures, indicating that the myoblastic cells could contribute to skeletal muscle. Exposure of XL-B4 cells to the TH triiodothyronine (T3) for several days significantly induced apoptotic cell death. We then examined an early response of expression of genes involved in apoptosis or myogenesis to T3. Treatment of the cells with T3 increased transcription of genes for matrix metalloproteinase-9 (MMP-9) and thyroid hormone receptor beta. Interestingly, the T3-treatment also increased myoD transcripts, but decreased the amounts of myogenin mRNA and myosin heavy chain. Importantly, we also observed upregulation of myoD expression and downregulation of myogenin expression in tails, but not in hind limbs, when tadpoles at a premetamorphic stage were treated with T3 for 1 day. These results indicated that T3 could not only induce apoptosis, but also attenuate myogenesis in tadpole tails during metamorphosis. PMID- 25791375 TI - FSH receptor-specific residues L501 and I505 in extracellular loop 2 are essential for its function. AB - The extracellular loop 2 (EL2) of FSH receptor (FSHR) plays a pivotal role in various events downstream of FSH stimulation. Because swapping the six FSHR specific residues in EL2 (chimeric EL2M) with those from LH/choriogonadotropin receptor resulted in impaired internalization of FSH-FSHR complex and low FSH induced cAMP production, six substitution mutants of EL2 were generated to ascertain the contribution of individual amino acids to the effects shown by chimeric EL2M. Results revealed that L(501)F mainly and I(505)V to a lesser extent contribute to the diminished receptor function in chimeric EL2M. HEK293 cells stably expressing WT and chimeric EL2M FSHR were generated to track the fate of the receptors post FSH induction. The chimeric EL2M FSHR stable clone showed weak internalization and cAMP response similar to transiently transfected cells. Furthermore, reduced FSH-induced ERK phosphorylation was also observed. The interaction of activated chimeric EL2M and L(501)F FSHR with beta-arrestins was weak compared with WT FSHR, thus explaining the impaired internalization of chimeric EL2M and corroborating the indispensable role of EL2 in receptor function. PMID- 25791376 TI - TNF-alpha- mediated-p38-dependent signaling pathway contributes to myocyte apoptosis in rats subjected to surgical trauma. AB - BACKGROUND: The accumulation of cytokines in the plasma after trauma can induce myocyte apoptosis. We aimed to identify which cytokine(s) present in the plasma responsible for myocyte apoptosis, and delineated the signal transduction mechanism in rats subjected to surgical trauma. METHODS: Rats were randomized into two groups: control and trauma groups, which was divided into five subgroups: posttraumatic 0, 3, 6, 12, and 24 h subgroups. Cardiomyocytes isolated from traumatized rats were incubated with one of the factors for 12 h (normal plasma; Cytomix; TNF-alpha; IL-1beta; IFN-gamma; trauma plasma; anti-TNF-alpha antibody; SB203580). Myocyte apoptosis, cytokine levels, and MAPKs activation, as the primary experimental outcomes, were measured by TUNEL, flow cytometry, ELISA and Western blot, respectively. RESULTS: Myocyte apoptosis was induced by surgical trauma during the early stage after trauma. Accompanying this change, plasma TNF-alpha, IL-1beta, and IFN-gamma levels were elevated in traumatized rats. Incubation of traumatized cardiomyocytes with cytomix or TNF-alpha alone induced myocyte apoptosis, and increased the activation of p38 and ERK1/2. Myocyte apoptosis and p38 activation were elevated in traumatized cardiomyocytes with trauma plasma, and these increases were partly abolished by anti-TNF-alpha antibody or SB203580. CONCLUSION: Our study demonstrated that there exists the TNF-alpha-mediated-p38-dependent signaling pathway that contributed to posttraumatic myocyte apoptosis of rats undergoing surgical trauma. PMID- 25791377 TI - Only the mother of all reorganisations can save the NHS. PMID- 25791379 TI - Annual report 2014. PMID- 25791378 TI - The Methanosarcina acetivorans thioredoxin system activates DNA binding of the redox-sensitive transcriptional regulator MsvR. AB - The production of biogas (methane) by an anaerobic digestion is an important facet to renewable energy, but is subject to instability due to the sensitivity of strictly anaerobic methanogenic archaea (methanogens) to environmental perturbations, such as oxygen. An understanding of the oxidant-sensing mechanisms used by methanogens may lead to the development of more oxidant tolerant (i.e., stable) methanogen strains. MsvR is a redox-sensitive transcriptional regulator that is found exclusively in methanogens. We show here that oxidation of MsvR from Methanosarcina acetivorans (MaMsvR) with hydrogen peroxide oxidizes cysteine thiols, which inactivates MaMsvR binding to its own promoter (P(msvR)). Incubation of oxidized MaMsvR with the M. acetivorans thioredoxin system (NADPH, MaTrxR, and MaTrx7) results in reduction of the cysteines back to thiols and activation of P msvR binding. These data confirm that cysteines are critical for the thiol-disulfide regulation of P(msvR) binding by MaMsvR and support a role for the M. acetivorans thioredoxin system in the in vivo activation of MaMsvR. The results support the feasibility of using MaMsvR and P(msvR), along with the Methanosarcina genetic system, to design methanogen strains with oxidant regulated gene expression systems, which may aid in stabilizing anaerobic digestion. PMID- 25791380 TI - Telemedicine in Parkinson's disease: A patient perspective at a tertiary care centre. AB - INTRODUCTION: To overcome travel distance and lack of local expertise, telemedicine programs have been implemented and are still pilot programs in many jurisdictions. Patient perspectives remain poorly understood. In the largest study to date, we examined user satisfaction and predictors of patient choice to use telemedicine among Parkinson's Disease (PD) patients in the context of a well developed telemedicine system. These data can help to optimize healthcare delivery by telemedicine. METHODS: A patient satisfaction questionnaire was administered to current or previous users via telephone. Patients' cost savings were determined. The proportion of non-users interested in using telemedicine was quantified. Demographic and clinical characteristics of those who expressed interest in the program vs. those who did not were compared. RESULTS: A total of 34 users and 103 non-users were recruited. Users reported an average cost reduction of $200 and 209 minutes of reduction in commute time (p < 0.01). While a majority (29/34 users) reported interest in continuing with telemedicine, inexperience of some telehealth nurses was a major source of patient dissatisfaction. Patients preferred a combination of telehealth and in-person visits. A majority of non-users (55/103, 53%) declared interest in telemedicine, but it had not been offered to them. A lower Hoehn and Yahr stage and a longer commute time were associated with patient interest in telemedicine. CONCLUSIONS: Training of nurses is an important determinant of patient satisfaction. Clinicians should consider offering telehealth to all patients for whom it is medically appropriate, especially those who experience long travel times. PMID- 25791381 TI - Model of spin accumulation and spin torque in spatially varying magnetisation structures: limitations of the micromagnetic approach. AB - We study the spin-transfer torque acting on the magnetisation when injecting polarised conduction electrons into a magnetic system. The spin accumulation is calculated self-consistently and naturally includes the adiabatic and non adiabatic contributions which depend on the rate of change of magnetisation in relation to the spin diffusion length. As an example we consider a system where a spin-polarised current is injected into a structure containing a domain wall. We calculate the spin torque and related parameters corresponding to the adiabatic and non-adiabatic terms directly from the spin accumulation, and find that the dynamic micromagnetic approach based on adiabatic and non-adiabatic terms with constant coefficients is valid only for systems with slowly spatially varying magnetisation. PMID- 25791382 TI - Breakthrough technologies in digital pathology. PMID- 25791383 TI - Microenvironmental remodeling as a parameter and prognostic factor of heterogeneous leukemogenesis in acute myelogenous leukemia. AB - Acute myelogenous leukemia (AML) is a heterogeneous disorder characterized by clonal proliferation of stem cell-like blasts in bone marrow (BM); however, their unique cellular interaction within the BM microenvironment and its functional significance remain unclear. Here, we assessed the BM microenvironment of AML patients and demonstrate that the leukemia stem cells induce a change in the transcriptional programming of the normal mesenchymal stromal cells (MSC). The modified leukemic niche alters the expressions of cross-talk molecules (i.e., CXCL12 and JAG1) in MSCs to provide a distinct cross-talk between normal and leukemia cells, selectively suppressing normal primitive hematopoietic cells while supporting leukemogenesis and chemoresistance. Of note, AML patients exhibited distinct heterogeneity in the alteration of mesenchymal stroma in BM. The distinct pattern of stromal changes in leukemic BM at initial diagnosis was associated with a heterogeneous posttreatment clinical course with respect to the maintenance of complete remission for 5 to 8 years and early or late relapse. Thus, remodeling of mesenchymal niche by leukemia cells is an intrinsic self reinforcing process of leukemogenesis that can be a parameter for the heterogeneity in the clinical course of leukemia and hence serve as a potential prognostic factor. PMID- 25791384 TI - Incidence of respiratory viral infections detected by PCR and real-time PCR in adult patients with community-acquired pneumonia: a meta-analysis. AB - BACKGROUND: With the development of more rapid and sensitive detection methods based on PCR techniques, the contributions of respiratory viral infections to community-acquired pneumonia (CAP) in adult patients are being more and more recognized. Yet, up to now, there has been a lack of synthetic data that clearly demonstrates the incidence of respiratory viral infections in adult patients with CAP. OBJECTIVES: We intended to demonstrate the incidence of respiratory viral infections detected by PCR and real-time PCR in adult patients with CAP. METHODS: We searched PubMed and Embase for studies providing the incidence of respiratory viral infections in adult patients with CAP. We investigated potential sources of heterogeneity by a univariant metaregression analysis and calculated the combined incidence of viral infections, viral infections mixed with other pathogens and individual respiratory virus species. RESULTS: We eventually identified 23 eligible reports with a total number of 6,404 patients. Incidences ranged from 8.6 to 56.2% for overall respiratory viral infections. We noted significant heterogeneity in incidence estimates for the incidence of viral infections (Cochran's chi(2) = 269.9, p < 0.0001, I(2) = 91.8%). The combined incidence of viral infections was 22.4% (95% CI = 19.0-25.7). Incidences of viral coinfections with other pathogens ranged from 3 to 28%. A high level of heterogeneity was identified as well during the estimates for incidences of coinfections (chi(2) = 200.9, p < 0.0001, I(2) = 91.5%). The combined incidence of viral coinfections with other pathogens was 12.4% (95% CI = 9.7-15.0). Our heterogeneity analyses suggested that a lower respiratory tract sample was associated with higher overall viral incidence. Moreover, the influenza virus, rhinovirus and coronavirus were the 3 most frequently detected viral pathogens in adult patients with CAP according to our study. CONCLUSIONS: Respiratory viruses are probably crucial pathogens of adult patients with CAP, with the influenza virus being the most frequent viral pathogen identified. More than half of the viral infections are characterized as mixed infections with other pathogens. PMID- 25791385 TI - One-pot synthesis of 2,3-disubstituted dihydrobenzofurans and benzofurans via rhodium-catalyzed intramolecular C-H insertion reaction. AB - Intramolecular sp(3) C-H insertion reaction of alpha-imino rhodium carbene generated from N-sulfonyl-1,2,3-triazoles has been described. A number of 2,3 dihydrobenzofuran and benzofuran derivatives have been obtained in good to excellent yields. PMID- 25791386 TI - Uterine scar dehiscence--a demanding defect. PMID- 25791387 TI - Limits of endorectal ultrasound in tailoring treatment of patients with rectal cancer. AB - BACKGROUND: Endorectal ultrasound (ERUS) is considered reliable in staging rectal cancer, but recently some critics have questioned its accuracy. The aim of this study was to evaluate how often an ERUS-based decision leads to an appropriate treatment. METHODS: Two hundred and twenty patients with rectal cancer staged with ERUS who underwent a surgical resection or a local excision without neoadjuvant therapy from 1997 to 2012 were included. According to ERUS, patients were divided into three groups of indication: (a) local excision (Tis-1 N0), (b) direct surgery (T2 N0), (c) preoperative chemoradiation (T3-4 or N+). Accuracy was explored by the correlation established with the final pathology. RESULTS: Accuracy for T and N staging was 65 and 64%, respectively. Indication to local excision and to chemoradiation was correct in 97 and 88% of patients staged by ERUS. Accuracy of indication to direct surgery was poor (37%), and 21% of patients were overtreated in this group. CONCLUSIONS: ERUS seems not able to fulfill all the needs of ideal tailored therapeutic strategies. T2 diagnosis needs to be confirmed by an excisional biopsy before a final decision is made because overstaging of early tumors may occur in a not-so-negligible proportion of patients. PMID- 25791388 TI - Phosphine, isocyanide, and alkyne reactivity at pentanuclear molybdenum/tungsten iridium clusters. AB - The trigonal bipyramidal clusters M2Ir3(MU-CO)3(CO)6(eta(5)-C5H5)2(eta(5)-C5Me4R) (M = Mo, R = Me 1a, R = H; M = W, R = Me, H) reacted with isocyanides to give ligand substitution products M2Ir3(MU-CO)3(CO)5(CNR')(eta(5)-C5H5)2(eta(5) C5Me4R) (M = Mo, R = Me, R' = C6H3Me2-2,6 3a; M = Mo, R = Me, R' = (t)Bu 3b), in which core geometry and metal atom locations are maintained, whereas reactions with PPh3 afforded M2Ir3(MU-CO)4(CO)4(PPh3)(eta(5)-C5H5)2(eta(5)-C5Me4R) (M = Mo, R = Me 4a, H 4c; M = W, R = Me 4b, H), with retention of core geometry but with effective site-exchange of the precursors' apical Mo/W with an equatorial Ir. Similar treatment of trigonal bipyramidal MIr4(MU-CO)3(CO)7(eta(5)-C5H5)(eta(5) C5Me5) (M = Mo 2a, W 2b) with PPh3 afforded the mono-substitution products MIr4(MU-CO)3(CO)6(PPh3)(eta(5)-C5H5)(eta(5)-C5Me5) (M = Mo 5a; M = W 5b), and further reaction of the molybdenum example 5a with excess PPh3 afforded the bis substituted cluster MoIr4(MU3-CO)2(MU-CO)2(CO)4(PPh3)2(eta(5)-C5H5)(eta(5)-C5Me5) (6). Reaction of 1a with diphenylacetylene proceeded with alkyne coordination and C=C cleavage, affording Mo2Ir3(MU4-eta(2)-PhC2Ph)(MU3-CPh)2(CO)4(eta(5) C5H5)2(eta(5)-C5Me5) (7a) together with an isomer. Reactions of 2a and 2b with PhC=CR afforded MIr4(MU3-eta(2)-PhC2R)(MU3-CO)2(CO)6(eta(5)-C5H5)(eta(5)-C5Me5) (M = Mo, R = Ph 8a; M = W, R = Ph 8b, H; M = W, R = C6H4(C2Ph)-3 9a, C6H4(C2Ph) 4), while addition of 0.5 equivalents of the diynes 1,3-C6H4(C2Ph)2 and 1,4 C6H4(C2Ph)2 to WIr4(MU-CO)3(CO)7(eta(5)-C5H5)(eta(5)-C5Me5) gave the linked clusters [WIr4(CO)8(eta(5)-C5H5)(eta(5)-C5Me5)]2(MU6-eta(4)-PhC2C6H4(C2Ph)-X) (X = 3, 4). The structures of 3a, 4a-4c, 5b, 6, 7a, 8a, 8b and 9a were determined by single-crystal X-ray diffraction studies, establishing the core isomerization of 4, the site selectivity for ligand substitution in 3-6, the alkyne C=C dismutation in 7, and the site of alkyne coordination in 7-9. For clusters 3-6, ease of oxidation increases on increasing donor strength of ligand, increasing extent of ligand substitution, replacing Mo by W, and decreasing core Ir content, the Ir-rich clusters 5 and 6 being the most reversible. For clusters 7-9, ease of oxidation diminishes on replacing Mo by W, increasing the Ir content, and proceeding from mono-yne to diyne, although the latter two changes are small. In situ UV-vis-near-IR spectroelectrochemical studies of the (electrochemically reversible) reduction process of 8b were undertaken, the spectra becoming increasingly broad and featureless following reduction. The incorporation of isocyanides, phosphines, or alkyne residues in these pentanuclear clusters all result in an increased ease of oxidation and decreased ease of reduction, and thereby tune the electron richness of the clusters. PMID- 25791389 TI - A Sequence Kernel Association Test for Dichotomous Traits in Family Samples under a Generalized Linear Mixed Model. AB - OBJECTIVE: The existing methods for identifying multiple rare variants underlying complex diseases in family samples are underpowered. Therefore, we aim to develop a new set-based method for an association study of dichotomous traits in family samples. METHODS: We introduce a framework for testing the association of genetic variants with diseases in family samples based on a generalized linear mixed model. Our proposed method is based on a kernel machine regression and can be viewed as an extension of the sequence kernel association test (SKAT and famSKAT) for application to family data with dichotomous traits (F-SKAT). RESULTS: Our simulation studies show that the original SKAT has inflated type I error rates when applied directly to family data. By contrast, our proposed F-SKAT has the correct type I error rate. Furthermore, in all of the considered scenarios, F SKAT, which uses all family data, has higher power than both SKAT, which uses only unrelated individuals from the family data, and another method, which uses all family data. CONCLUSION: We propose a set-based association test that can be used to analyze family data with dichotomous phenotypes while handling genetic variants with the same or opposite directions of effects as well as any types of family relationships. PMID- 25791390 TI - Palifermin for prevention of oral mucositis in allogeneic hematopoietic stem cell transplantation: a single-institution retrospective evaluation. AB - PURPOSE: The purpose of this study is to assess the impact of palifermin on oral mucositis (OM) and its sequelae in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were conditioned with fractionated total body irradiation (FTBI) and etoposide. METHODS: This retrospective chart review study compared the effect of palifermin on the development of OM in patients who received this agent during an allo-HSCT (n = 99) to those who did not (n = 30). The primary end points were severity and duration of OM. Secondary end points included requirements for opioids, total parenteral nutrition (TPN), and intensive oral care; incidence of infection; length of hospital stay; and overall survival. RESULTS: There was no significant difference in the incidence of all grades of OM, but incidence of severe OM was decreased in palifermin exposed patients (34 vs 80 %, p < 0.0001). In patients who developed OM (all grades), the median duration of OM was shorter in palifermin-exposed patients (13 vs 18 days, p = 0.0001); there was no difference in the median duration of severe OM. Patients who received palifermin used less opioids and required a shorter duration of intensive oral care. There was no difference in duration of TPN, incidence of infection, length of hospital stay, and overall survival. CONCLUSIONS: Our findings demonstrated a significant benefit with the use of palifermin for allo-HSCT recipients who were conditioned with FTBI and etoposide. Palifermin can potentially improve quality of life for this patient population and reduce complications and resources used during the transplant process. A randomized clinical trial is required to confirm these results. PMID- 25791391 TI - What bothers lung cancer patients the most? A prospective, longitudinal electronic patient-reported outcomes study in advanced non-small cell lung cancer. AB - PURPOSE: Patients with advanced non-small cell lung cancer (aNSCLC) face a significant symptom burden. Little is known about the frequency and severity of symptoms over time, so we longitudinally characterized patients' symptoms using the Patient Care Monitor (PCM) version 2.0, an electronic symptom-assessment tool. METHODS: Ninety-seven patients with aNSCLC completed the PCM at up to four clinic visits. We analyzed symptom data by incidence, severity, type (functional vs. nonfunctional), proximity to death, and cancer anorexia-cachexia syndrome status (CACS). RESULTS: Functional concerns predominated, even in the non-CACS group. Average severity among the top 5 symptoms was worse for functional than nonfunctional items (mean difference 0.62, 95% CI 0.22-1.01, P = 0.003). Severe dyspnea and fatigue were the most prevalent nonfunctional symptoms; moderate/severe dyspnea was reported by at least 29% of patients, and fatigue by over 50%. Depression was reported infrequently, with over half of patients at each visit reporting "none"; moderate or severe depression was reported in only 2.5-9.3 and 3.4-6.2% of patients, respectively. The average number of moderate/severe symptoms increased with proximity to death; 84% reported moderate/severe fatigue in the last 3 months of life, compared to 48% at >= 12 months from death (P = 0.007). CONCLUSIONS: Patients with aNSCLC face a significant symptom burden, which increases with proximity to death. Symptom type and severity vary by proximity to death, but even patients without overt CACS report significant functional symptoms throughout. We recommend an individualized approach to palliative symptom intervention in advanced lung cancer, based on detailed symptom assessment and tracking. PMID- 25791392 TI - Follow-up care practices and barriers to breast cancer survivorship: perspectives from Asian oncology practitioners. AB - PURPOSE: The aim of this study is to evaluate the perspectives of Asian oncology practitioners on the physical and psychosocial issues experienced by breast cancer survivors (BCS), current survivorship care practices, and the barriers to follow-up care. METHODS: This was a cross-sectional survey study. Oncology practitioners were recruited from a major cancer center in Singapore and through two regional cancer meetings that took place in Singapore and Malaysia in 2013. RESULTS: A total of 126 oncology practitioners from various Southeast Asian countries, mostly nurses (58.7 %) and physicians (37.3 %), were recruited. The majority of the respondents agreed that fatigue (78.4 %) and anxiety (69.1 %) were the most common physical and psychosocial problems experienced by BCS. Monitoring for physical and treatment-related adverse effects (80.7 %) and reviewing patients' noncancer medical history (65.3 %) were the most practiced aspects of follow-up care. Compared with the other practitioners, the physicians were more likely to communicate with other healthcare professionals (adjusted OR = 4.24, 95 % CI 1.54 to 11.72; p = 0.005). Most of the respondents also agreed that patient-specific barriers were the main impediments to follow-up care. CONCLUSION: This study provides insights into the various aspects of breast cancer survivorship care from the perspectives of oncology practitioners and shows that survivorship care is relatively inadequate in Asia. There is a need for new survivorship care models to meet the needs of Asian BCS and to complement the unique healthcare systems of Asia. PMID- 25791393 TI - Italian version of the M.D. Anderson Symptom Inventory--Head and Neck Module: linguistic validation. AB - BACKGROUND: Head and neck cancer (HNC) patients can experience symptoms due to the tumor itself or to the treatment, with an impact on health-related quality of life (HRQoL). Patient-reported outcome (PRO) measures pertaining to HRQoL are used in medical research and to support clinical decisions. PRO instrument applicability and cultural adaptation must be tested for each population. The aim of this study is to linguistically validate the Italian translation of the M.D. Anderson Symptom Inventory--Head and Neck Module (MDASI-HN). METHODS: Following forward and backward translation of the items of the English MDASI-HN into Italian, it was administered along with a cognitive debriefing to HNC patients able to read and understand Italian language. Individual and group responses are presented using descriptive statistics. RESULTS: From May 2013 through September 2013, 56 patients with HNC (18 during curative treatment, 20 in palliative chemotherapy, and 18 in follow-up period) completed the MDASI-HN followed by accompanying cognitive debriefing. Ninety-nine percent of the individual MDASI-HN items were completed. Average time to complete the MDASI-HN was 8.5 min (range 3 15). Results suggested overall ease of completion, relevance, and comprehensibleness of this translated self-report instrument in this Italian patient population. CONCLUSIONS: The Italian version of the MDASI-HN is linguistically valid; future research should explore dimensionality, reliability, and convergent, discriminant, and predictive validity of this patient-reported instrument, in order to use this translated version in outcomes research and clinical settings. PMID- 25791394 TI - Flank-suspended versus prone percutaneous nephrolithotomy: changes of haemodynamics, arterial blood gases and subjective feelings. AB - BACKGROUND: The flank-suspended position was adopted in percutaneous nephrolithotomy (PCNL), and haemodynamics, blood gas variables and subjective feelings were examined with an attempt to explore the effect of the operative position in PCNL on the body's inner environment and patient comfort. OBJECTIVE: The influence of the flank-suspended and prone position on haemodynamics, arterial blood gases and subjective feelings in patients receiving PCNL was examined. DESIGN, SETTING AND PARTICIPANTS: A total of 100 patients with kidney stones who underwent PCNL during January 2010 to January 2011 were divided into flank-suspended groups (n = 50) and prone groups (n = 50) at random in terms of the operative position. The blood pressure, heart rate, respiratory frequency and oxyhaemoglobin saturation and blood gas variables were determined at different time points (before the operation, after position change, 30 min after the start the operation and immediately after the operation). Visual analogue scale (VAS) scoring system was employed to define the posture comfort, dyspnoea and puncture site pain 24 h postoperation in the patients. All the measures were compared between patients in different positions at different time points. STATISTICAL ANALYSIS: Paired t-test was employed in the comparison of measures detected at different time points in the same group. Two-group comparison was subjected to t test. A p value less than 0.05 was considered statistically significant. RESULTS AND LIMITATIONS: The blood pressure was decreased within and after the operation in both groups, substantially in the prone group, significantly lower than that before the operation (p<0.05). No significant differences in the heart rate, respiratory frequency and oxyhaemoglobin saturation were noted among the different time points in the same group. Blood gas analysis showed that pH value and base excess were profoundly reduced within and after the operation in the two groups, significantly lower than those before the operation, and the decrease was most manifest in the prone group. There was no difference in the blood sodium and potassium among the different time points in each group. The flank-suspended group was superior to the prone group with regard to posture comfort and dyspnoea degree but not puncture-site pain 24 h postoperation. CONCLUSIONS: Flank suspended and prone PCNL affects the haemodynamics, blood gas variables and subjective feelings of patients to a varying degree. The flank-suspended PCNL possesses advantages over prone PCNL such as little influence on haemodynamics and blood gas variables, satisfactory posture comfort, less dyspnoea and easy access to vital sign observation. PMID- 25791395 TI - Web-based self-reported height, weight, and body mass index among Swedish adolescents: a validation study. AB - BACKGROUND: Web-collected height and weight are increasingly used in epidemiological studies; however, the validity has rarely been evaluated. OBJECTIVE: The aim of the study was to validate self-reported height, weight, and corresponding body mass index (BMI) among Swedish adolescents aged approximately 16 years. A secondary aim was to investigate possible prediction factors for validity of self-reported BMI. METHODS: The study included 1698 adolescents from the population-based cohort BAMSE. Height and weight were collected through a Web based questionnaire and subsequently measured using standard procedures. Differences between reported and measured height, weight, and corresponding BMI were compared by t tests and agreement was evaluated by Pearson correlation and Bland-Altman plots. Multivariable linear regression analysis was used to investigate whether lifestyle and demographic factors predicted validity of self reported BMI. RESULTS: On average, weight was underestimated by 1.1 kg and height was overestimated by 0.5 cm, leading to an underestimation of BMI by 0.5 kg/m2. Correlation coefficients were .98 for height, .97 for weight, and .94 for BMI, and highly significant. Females underestimated weight to a higher extent than males and overweight and obese participants underestimated weight to a higher extent than normal-weight participants, which resulted in higher underestimation of BMI. Underweight participants, on the contrary, overestimated weight and correspondingly BMI. Overall, a high proportion of participants were classified into the correct BMI category; however, among overweight and obese participants, only 60.2% (139/231) and 46% (20/44) were correctly classified, respectively. In the multivariable prediction model, only gender and BMI status significantly predicted discrepancy between reported and measured BMI. CONCLUSIONS: Web collected BMI may be used as a valid, quick, and cost-effective alternative to measured BMI among Swedish adolescents. The accuracy of self-reported BMI declines with increasing BMI and self-reported BMI should not be used to estimate the prevalence of overweight or obesity. PMID- 25791397 TI - Investigation of microRNA expression profiles associated with human alcoholic cardiomyopathy. AB - OBJECTIVES: We aimed to investigate the differentially expressed microRNAs (miRNAs) and their target genes in human alcoholic cardiomyopathy (ACM). METHODS: The expression levels of plasma miRNAs of 78 male ACM patients and 78 healthy men were detected by using the 6th-generation miRCURYTM LNA array (v.16.0). The prediction analysis for microarrays (PAM) method was used to identify the differentially expressed miRNAs. Target genes of the identified differentially expressed miRNAs were predicted using TargetScan 5.2 and Miranda. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform functional annotation and pathway enrichment analysis of target genes respectively, followed by real-time RT-PCR analysis to validate the expression changes of miRNAs. RESULTS: Twenty-one differentially expressed miRNAs were identified. Nine differentially expressed miRNAs (hsa-miR-506, hsa-miR-1285, hsa miR-512-3P, hsa-miR-138, hsa-miR-485-5P, hsa-miR-4262, hsa-miR-548c-3P, has-miR 548a-5P and kshv-miR-K12-1), involved in multiple functions and pathways, were selected for real-time RT-PCR confirmation. Moreover, two significantly important subpathways (neurotrophin signaling pathway and inositol phosphate metabolism) were predicted. CONCLUSION: The screened differentially expressed miRNAs may be involved in the development of ACM. Specific miRNAs, such as miR-138, may be considered as a new target for the early diagnosis and treatment of human ACM. PMID- 25791396 TI - Inclusion of attentional networks in the pre-surgical neuroimaging assessment of a large deep hemispheric cavernous malformation: an FMRI case report. AB - BACKGROUND AND IMPORTANCE: Functional magnetic resonance imaging (fMRI) is a noninvasive and reliable tool for mapping eloquent cortex in patients prior to brain surgery. Ensuring intact perceptual and cognitive processing is a key goal for neurosurgeons, and recent research has indicated the value of including attentional network processing in pre-surgical fMRI in order to help preserve such abilities, including reading, after surgery. CLINICAL PRESENTATION: We report a 42-year-old patient with a large cavernous malformation, near the left basal ganglia. The lesion measured 3.8 * 1.7 * 1.8 cm. In consultation with the patient and the multidisciplinary cerebrovascular team, the decision was made to offer the patient surgical resection. The surgical resection involved planned access via the left superior parietal lobule using stereotactic location. The patient declined an awake craniotomy; therefore, direct electrocortical stimulation (ECS) could not be used for intraoperative language localization in this case. Pre-surgical planning included fMRI localization of language, motor, sensory, and attentional processing. The key finding was that both reading and attention-processing tasks revealed consistent activation of the left superior parietal lobule, part of the attentional control network, and the site of the planned surgical access. Given this information, surgical access was adjusted to avoid interference with the attentional control network. The lesion was removed via the left inferior parietal lobule. The patient had no new neurologic deficits postoperatively but did develop mild neuropathic pain in the left hand. CONCLUSION: This case report supports recent research that indicates the value of including fMRI maps of attentional tasks along with traditional language processing tasks in preoperative planning in patients undergoing neurosurgery procedures. PMID- 25791398 TI - Annals of occupational hygiene performance, 2014. PMID- 25791399 TI - Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. METHODS: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP 1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. RESULTS: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher grade PNETs (p = 0.035). CONCLUSION: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs. PMID- 25791400 TI - Sedimentary geology of the middle Carboniferous of the Donbas region (Dniepr Donets Basin, Ukraine). AB - The Paleozoic Dniepr-Donets Basin in Belarus, Ukraine, and Russia forms a major hydrocarbon province. Although well- and seismic data have established a 20 km thick stratigraphy, field-studies of its sediments are scarce. The inverted Donbas segment (Ukraine) exposes the middle Carboniferous part of the basin's stratigraphy. Here, we provide detailed sedimentological data from 13 sections that cover 1.5 of the total of 5 km of the Bashkirian and Moscovian stages and assess the paleoenvironment and paleo-current directions. Middle Carboniferous deposition occurred in a shelf environment, with coal deposition, subordinate fluvial facies, and abundant lower and middle shoreface facies, comprising an intercalated package of potential source and reservoir rocks. Sedimentary facies indicate a paleodepth range from below storm wave base to near-coastal swamp environments. Sedimentation and subsidence were hence in pace, with subtle facies changes likely representing relative sea-level changes. Paleocurrent directions are remarkably consistently southeastward in time and space in the different sedimentary facies across the Donbas Fold Belt, illustrating a dominant sedimentary infill along the basin axis, with little basin margin influence. This suggests that the middle Carboniferous stratigraphy of the Dniepr-Donets basin to the northwest probably contains significant amounts of fluvial sandstones, important for assessing hydrocarbon reservoir potential. PMID- 25791401 TI - Stage 1 testicular seminoma: observation. PMID- 25791402 TI - Course and Moderators of Hot Flash Interference during Androgen Deprivation Therapy for Prostate Cancer: A Matched Comparison. AB - PURPOSE: Many men receiving androgen deprivation therapy for prostate cancer experience hot flashes. This study aimed to describe the course of hot flash interference with time in androgen deprivation therapy recipients relative to matched prostate cancer and cancer-free controls from before the start of androgen deprivation therapy to 12 months later. We also examined demographic, clinical and genetic predictors of the impact of androgen deprivation therapy on hot flash interference. MATERIALS AND METHODS: Three groups were examined, including 60 patients with prostate cancer recruited before or within 21 days of starting androgen deprivation therapy, 83 age and education matched patients with prostate cancer treated with prostatectomy only, and 86 age and education matched men with no history of cancer. Participants provided blood samples and completed the Hot Flash Related Daily Interference Scale at baseline as well as 6 and 12 months later. RESULTS: Androgen deprivation therapy recipients reported increasing hot flash interference with time relative to controls (p <0.001). Group differences were evident at 6 and 12 months (all p <0.001) with androgen deprivation therapy recipients reporting greater hot flash interference than controls. Several genetic polymorphisms were found to predict greater increases in hot flash interference (all p <0.01), including polymorphisms on genes associated with vasoconstriction, immune function, neurotransmission and circadian rhythms. Androgen deprivation therapy recipients who were younger and had a lower body mass index at baseline also showed greater increases in hot flash interference with time (all p <=0.01). CONCLUSIONS: This study, which is to our knowledge the first to prospectively examine hot flash interference in androgen deprivation therapy recipients, reveals that those with certain genetic polymorphisms, younger age and lower body mass index had greater increases in hot flash interference with time relative to controls. PMID- 25791403 TI - Stage 1 testicular seminoma: radiotherapy. PMID- 25791404 TI - The effects of workplace bullying on nurses. PMID- 25791405 TI - An ICU nurse with a history of tremors. AB - A 52-year-old female working as a registered nurse in the ICU developed tremors with fine motor activities in stressful situations. She was evaluated by a neurologist and was diagnosed with physiological tremors. Implications for practice are explored. PMID- 25791406 TI - Violence against nurses in emergency departments in jordan: nurses' perspective. AB - Violence against nurses in emergency departments (EDs) has become a widespread phenomenon affecting nurses' job satisfaction and work performance. Literature is scarce regarding prevalence rates and causes of violence directed toward nurses in Jordan. The present study investigated violence experienced by Jordanian nurses in EDs and causes of violence from their perspectives. This descriptive study collected data from 174 Jordanian ED nurses. The majority of the participants (91.4%) reported experiencing violence (verbal 95.3% vs. physical 23.3%). According to participants, the most common causes of violence in the ED were crowding and workload (75.9%), and the least was care of patients with dementia or Alzheimer's disease (35.6%). Violence is common in Jordanian EDs, giving rise to many heath and behavioral consequences. Health care administrators are obligated to protect nurses from violent incidents by providing adequate safety measures, beneficial administrative procedures, and sincere efforts to overcome the causes of this phenomenon. PMID- 25791407 TI - Multiple risk factors for work-related injuries and illnesses in korean-chinese migrant workers. AB - Korean-Chinese currently represent the largest group of migrant workers in Korea. The purpose of this study was to investigate the influence of risk factors on the occurrence of work-related injuries and illnesses (WII). Data for 486 Korean Chinese migrant workers were drawn from the 2010 Migrant Workers' Health and Safety Survey in Korea. Logistic regression was used to identify the association between WII and multiple risk factors. Individual health status (OR = 3.83, 95% CI [2.01, 7.30]), safety training (OR = 0.39, 95% CI [0.18, 0.85]), job satisfaction (OR = 1.90, 95% CI [1.07, 3.38]), physical and chemical hazard exposure (OR = 1.05, 95% CI [1.02, 1.08]), and length of stay (OR = 1.01, 95% CI [1.00, 1.01]) were identified as risk factors for WII. The findings suggest the need for a comprehensive approach to assess WII risk factors, including personal, work organization and psychosocial demands, and acculturation in Korean-Chinese migrant workers. PMID- 25791408 TI - Posttraumatic stress disorder in reserve veterans: important reintegration considerations for the occupational health nurse. AB - Posttraumatic stress disorder (PTSD) is a serious mental health concern for returning U.S. military personnel who have a higher prevalence rate of PTSD than the general population. Among the military population, reserve service members are at increased risk of developing PTSD compared with full-time active duty service members mainly due to difficulty reintegrating into civilian life. Understanding the social risk factors along with the protective effects social support has on PTSD in veterans will provide occupational health professionals the opportunity to support reserve veterans with adjustment into post-deployment life. This literature review examines PTSD in reserve veterans, with a focus on occupational factors, social factors, guideline recommendations, available resources, as well as provides suggestions for occupational health nurses caring for reserve veterans returning to the workplace. PMID- 25791409 TI - Occupational health nursing in Turkey: an international update. AB - This article discussed Turkey's occupational health system and the current education, legislation, and practice of occupational health nursing. PMID- 25791411 TI - Gaining insights. AB - Occupational and environmental health nurses should use insights to solve problems and promote worker health and safety. PMID- 25791413 TI - Ergonomics and people with disabilities. PMID- 25791414 TI - Extreme wettability of nanostructured glass fabricated by non-lithographic, anisotropic etching. AB - Functional glass surfaces with the properties of superhydrophobicity/or superhydrohydrophilicity, anti-condensation or low reflectance require nano- or micro-scale roughness, which is difficult to fabricate directly on glass surfaces. Here, we report a novel non-lithographic method for the fabrication of nanostructures on glass; this method introduces a sacrificial SiO2 layer for anisotropic plasma etching. The first step was to form nanopillars on SiO2 layer coated glass by using preferential CF4 plasma etching. With continuous plasma etching, the SiO2 pillars become etch-resistant masks on the glass; thus, the glass regions covered by the SiO2 pillars are etched slowly, and the regions with no SiO2 pillars are etched rapidly, resulting in nanopatterned glass. The glass surface that is etched with CF4 plasma becomes superhydrophilic because of its high surface energy, as well as its nano-scale roughness and high aspect ratio. Upon applying a subsequent hydrophobic coating to the nanostructured glass, a superhydrophobic surface was achieved. The light transmission of the glass was relatively unaffected by the nanostructures, whereas the reflectance was significantly reduced by the increase in nanopattern roughness on the glass. PMID- 25791415 TI - Finite Element Method (FEM) Modeling of Freeze-drying: Monitoring Pharmaceutical Product Robustness During Lyophilization. AB - Lyophilization is an approach commonly undertaken to formulate drugs that are unstable to be commercialized as ready to use (RTU) solutions. One of the important aspects of commercializing a lyophilized product is to transfer the process parameters that are developed in lab scale lyophilizer to commercial scale without a loss in product quality. This process is often accomplished by costly engineering runs or through an iterative process at the commercial scale. Here, we are highlighting a combination of computational and experimental approach to predict commercial process parameters for the primary drying phase of lyophilization. Heat and mass transfer coefficients are determined experimentally either by manometric temperature measurement (MTM) or sublimation tests and used as inputs for the finite element model (FEM)-based software called PASSAGE, which computes various primary drying parameters such as primary drying time and product temperature. The heat and mass transfer coefficients will vary at different lyophilization scales; hence, we present an approach to use appropriate factors while scaling-up from lab scale to commercial scale. As a result, one can predict commercial scale primary drying time based on these parameters. Additionally, the model-based approach presented in this study provides a process to monitor pharmaceutical product robustness and accidental process deviations during Lyophilization to support commercial supply chain continuity. The approach presented here provides a robust lyophilization scale-up strategy; and because of the simple and minimalistic approach, it will also be less capital intensive path with minimal use of expensive drug substance/active material. PMID- 25791416 TI - SMA screening system using dried blood spots on filter paper: application of COP PCR to the SMN1 deletion test. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in SMN1. More than 95% of SMA patients carry homozygous SMN1 deletions. Thus, the SMN1 deletion test should be performed initially as part of the diagnostic process. However, SMN2, a highly homologous gene, hampers detection of SMN1 deletion. To differentiate between SMN1 and SMN2, many analysis methods have been developed yet they are not all available worldwide. AIM: To establish a simple but accurate SMN1-deletion detection system that can be used worldwide. METHODS: Fifty DNA samples (29 SMA patients and 21 controls) from dried blood spots (DBS) on filter paper were assayed. All participants had previously been screened for SMA by PCR-restriction fragment length polymorphism (PCR-RFLP) using DNA extracted from freshly collected blood. DNA was extracted from DBS that had been stored at room temperature (20-25C) for between 1 and 8 years. Competitive oligonucleotide priming-PCR (COP-PCR) was performed to distinguish SMN1 and SMN2 exon7. RESULTS: DNA yield from an 11-mm diameter DBS circle was 21,171 +/- 7,485 ng (mean +/- SD), with an 260/280 OD ratio from 1.49 to 2.1(mean +/- SD; 1.67 +/-0.13). Nucleotide sequencing confirmed gene-specific amplification of SMN1 and SMN2 by COP-PCR. SMN1 and SMN2 COP-PCR results are completely consistent with those obtained by PCR-RFLP. CONCLUSION: We have combined DNA extraction from DBS on filter paper with COP-PCR that specifically detects SMN1 and SMN2, establishing a new SMN1-deletion detection system with practical application worldwide. PMID- 25791417 TI - Phosphorothioate modification of chimeric 2'-O-methyl RNA/ethylene-bridged nucleic acid oligonucleotides increases dystrophin exon 45 skipping capability and reduces cytotoxicity. AB - BACKGROUNDS: Antisense oligonucleotide (AO)-mediated exon skipping is the most promising way to express internally deleted dystrophin in Duchenne muscular dystrophy (DMD), by correcting the reading frame of dystrophin mRNA. An antisense chimeric oligonucleotide consisting of 2'-O-methyl RNA and ethylene-bridged nucleic acid (ENA), targeting exon 45 of the dystrophin gene, AO85, has been shown to induce exon 45 skipping efficiently. Since phosphorothioate (PS) modification of AO85 has never been explored, we produced a PS-modified AO85 (AO88) and examined its exon skipping capability and cytotoxicity. METHODS: Exon 45 skipping activity was examined in primary muscle cells established from a DMD patient carrying a deletion of dystrophin exon 44. Cytotoxicity was assessed by MTT assay. RESULTS: AO88 induced dystrophin exon 45 skipping from 50 nM. More than 90% of products lacked exon 45 at 400 nM. AO88 showed significantly higher exon skipping activity than AO85. The EC50 of AO88 was 94.8 nM, while EC50 of AO85 was 66.7 nM. Cytotoxicity was lower for AO88 than for AO85. CONCLUSION: the PS-modified RNA/ENA chimera displayed stronger exon skipping activity and lower cytotoxicity than the phosphodiester-RNA/ENA chimera. AO88 has better potential for clinical use than AO85. PMID- 25791418 TI - Biomimetic scaffolds based on hydroxyapatite nanorod/poly(D,L) lactic acid with their corresponding apatite-forming capability and biocompatibility for bone tissue engineering. AB - This study presents a facile synthesis of biomimetic hydroxyapatite nanorod/poly(D,L) lactic acid (HAp/PDLLA) scaffolds with the use of solvent casting combined with a salt-leaching technique for bone-tissue engineering. Field emission scanning electron microscopy, Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy were used to observe the morphologies, pore structures of synthesized scaffolds, interactions between hydroxyapatite nanorods and poly(D,L) lactic acid, as well as the compositions of the scaffolds, respectively. Porosity of the scaffolds was determined using the liquid substitution method. Moreover, the apatite-forming capability of the scaffolds was evaluated through simulated body fluid (SBF) incubation tests, whereas the viability, attachment, and distribution of human osteoblast cells (MG 63 cell line) on the scaffolds were determined through alamarBlue assay and confocal laser microscopy after nuclear staining with 4',6-diamidino-2 phenylindole and actin filaments of a cytoskeleton with Oregon Green 488 phalloidin. Results showed that hydroxyapatite nanorod/poly(D,L) lactic acid scaffolds that mimic the structure of natural bone were successfully produced. These scaffolds possessed macropore networks with high porosity (80-84%) and mean pore sizes ranging 117-183 MUm. These scaffolds demonstrated excellent apatite forming capabilities. The rapid formation of bone-like apatites with flower-like morphology was observed after 7 days of incubation in SBFs. The scaffolds that had a high percentage (30 wt.%) of hydroxyapatite demonstrated better cell adhesion, proliferation, and distribution than those with low percentages of hydroxyapatite as the days of culture increased. This work presented an efficient route for developing biomimetic composite scaffolds, which have potential applications in bone-tissue engineering. PMID- 25791419 TI - Breaking oil-in-water emulsions stabilized by yeast. AB - Several biotechnological processes can show an undesirable formation of emulsions making difficult phase separation and product recovery. The breakup of oil-in water emulsions stabilized by yeast was studied using different physical and chemical methods. These emulsions were composed by deionized water, hexadecane and commercial yeast (Saccharomyces cerevisiae). The stability of the emulsions was evaluated varying the yeast concentration from 7.47 to 22.11% (w/w) and the phases obtained after gravity separation were evaluated on chemical composition, droplet size distribution, rheological behavior and optical microscopy. The cream phase showed kinetic stability attributed to mechanisms as electrostatic repulsion between the droplets, a possible Pickering-type stabilization and the viscoelastic properties of the concentrated emulsion. Oil recovery from cream phase was performed using gravity separation, centrifugation, heating and addition of demulsifier agents (alcohols and magnetic nanoparticles). Long centrifugation time and high centrifugal forces (2 h/150,000*g) were necessary to obtain a complete oil recovery. The heat treatment (60 degrees C) was not enough to promote a satisfactory oil separation. Addition of alcohols followed by centrifugation enhanced oil recovery: butanol addition allowed almost complete phase separation of the emulsion while ethanol addition resulted in 84% of oil recovery. Implementation of this method, however, would require additional steps for solvent separation. Addition of charged magnetic nanoparticles was effective by interacting electrostatically with the interface, resulting in emulsion destabilization under a magnetic field. This method reached almost 96% of oil recovery and it was potentially advantageous since no additional steps might be necessary for further purifying the recovered oil. PMID- 25791420 TI - Inflammatory Morbidity due to Compound Mandibular Body Fractures: Does It Have a Relationship with Treatment Outcome? AB - OBJECTIVE: The aim of this study was to evaluate the relationship between the degree of preoperative pain and trismus with the development of complications following the repair of isolated unilateral compound mandibular body fractures using a closed reduction technique. SUBJECTS AND METHODS: This was a 7-year prospective study carried out at the Dental and Maxillofacial Surgery Clinic of the University of Calabar Teaching Hospital, Calabar, Nigeria. Of a total of 97 patients, 83 (85.6%) subjects (66 males, 17 females, ratio 5:1) were preoperatively evaluated for trismus and pain in a blinded manner by a single examiner, and complications were recorded postoperatively. The data obtained were statistically analyzed with EPI Info 2008 software. RESULTS: Of the 83 patients treated, 13 (15.7%) developed complications. The fractures were most common in the age range of 21-40 years (n = 45, 54.2%). The age (p = 0.02) and gender (p = 0.01) distribution of the subjects was significant. The more severe the limitation of mouth opening (p = 0.03) and pain (p = 0.04) before treatment, the more complications developed, and these significantly affected treatment outcome. Impaired mastication and facial asymmetry (n = 17, 41.5%) were the most common complications. CONCLUSION: This study showed that posttrauma pain and trismus due to unilateral mandibular body fractures may be associated with the development of complications. An adequately powered prospective study treating patients at 5 or 7 days is required in order to make the case for later intervention. PMID- 25791421 TI - Microswitch Technology for Enabling Self-Determined Responding in Children with Profound and Multiple Disabilities: A Systematic Review. AB - We reviewed 18 studies reporting on the use of microswitch technology to enable self-determined responding in children with profound and multiple disabilities. Identified studies that met pre-determined inclusion criteria were summarized in terms of (a) participants, (b) experimental design, (c) microswitches and procedures used, and (d) main results. The 18 studies formed three groups based on whether the microswitch technology was primarily intended to enable the child to (a) access preferred stimuli (7 studies), (b) choose between stimuli (6 studies), or (c) recruit attention/initiate social interaction (5 studies). The results of these studies were consistently positive and support the use of microswitch technology in educational programs for children with profound and multiple disabilities as a means to impact their environment and interact with others. Implications for delivery of augmentative and alternative communication intervention to children with profound and multiple disabilities are discussed. PMID- 25791422 TI - Factors affecting the success of endoscopic treatment of vesicoureteral reflux and comparison of two dextranomer based bulking agents: does bulking substance matter? AB - INTRODUCTION: Among the interventional treatment modalities for vesicoureteral reflux (VUR), endoscopic subureteric injection seems to be the least invasive method with acceptable outcomes when applied in appropriate patients. OBJECTIVE: The aim of the presented study is to investigate the parameters which may affect the outcomes of endoscopic injection and to compare the efficacy of two different bulking agents both composed of dextranomer-hyaluronic acid copolymer. STUDY DESIGN: The data of patients who underwent endoscopic VUR treatment between 2003 and 2012 were retrospectively reviewed. Patients with history of previous open antireflux surgery, more than one failed endoscopic treatment for reflux, VUR caused by posterior urethral valve, duplex system and overt spinal dysraphism were excluded. Surgical technique was the classical STING method. One of the two dextranomer-hyaluronic acid copolymer agents was used (Deflux in 109 and Dexell in 131 patients). Both agents were composed of similar amounts of hyaluronic acid gel (15 mg in Deflux versus 17 mg in Dexell) but different sized dextranomer microspheres (80-250 MUm in Deflux and 80-120 MUm in Dexell). During the follow up, ultrasonography was performed with 3-month interval, antibiotic prophylaxis was continued until the control voiding cystourethrography (VCUG) was taken. Patient based success was defined as the disappearance of reflux on control VCUG performed 3-6 months after the operation. RESULTS: Data were available for 240 patients. Mean age and mean postoperative follow-up were 78 +/- 41 months and 19 +/- 18 months. The overall success rate was 73.2%. Gender, laterality, grade of VUR, presence of voiding dysfunction, renal scar and preoperative breakthrough infection (BTI) were not found to affect the outcome, whereas age younger than 54 months and previous history of failed endoscopic injection were found to negatively affect the outcome both in univariate and multivariate analysis. The postoperative UTI (5 febrile and 43 nonfebrile) rate was 20%. Both univariate and multivariate analysis showed that postoperative UTI was more common in patients with persisting reflux, with preoperative breakthrough infections and in girls. Patient characteristics, treatment outcome and postoperative UTI rate were similar regarding the used bulking agent. No ureteral obstruction was experienced within the follow-up period. DISCUSSION: Our success rate for second injection is about 60%, which is significantly lower than for the patients who underwent first injection. We could not find any affecting factor for this difference. Contrary to the literature, our success rates were similar in different reflux grades. We can explain this finding that we value the intraoperative orifice configuration more than the grade which can be accepted as a patient selection bias. The lower success rate in children younger than 54 months can be explained by unstabilized bladder dynamics and higher voiding pressures in this age group, who are still in the toilet-training phase. Despite successful endoscopic treatment, UTI might occur. Postoperative UTI was more common in patients with persisting reflux, preoperative BTI and girls. The similar success rates of both bulking agents proved that dextranomer size does not affect the clinical outcome. Limitations of our study can be counted as follows: 1. the data do not include the number of patients in whom conversion to open surgery was decided intraoperatively because of the unfavorable orifice configuration, 2. our data do not include the injected volume records. CONCLUSION: Endoscopic treatment of VUR has satisfying outcomes in properly selected cases. Younger age (<54 months) and previous history of failed injection history were found to be related to unfavorable results. Postoperative UTI occurs more frequently in patients with persisting reflux, preoperative breakthrough infection history and girls. The choice of one of the dextranomer-based substances does not affect the surgical outcome and postoperative UTI development. PMID- 25791423 TI - Failed pyeloplasty in children: Is robot-assisted laparoscopic reoperative repair feasible? AB - OBJECTIVE: In this study we aim to demonstrate that robot-assisted laparoscopic (RAL) reoperative repair is safe and effective and even less technically demanding than open repair for recurrent ureteropelvic-junction obstruction (UPJO). STUDY DESIGN: A retrospective study was conducted of all cases of failed open pyeloplasties who underwent RAL reoperative repair at our institution between January 2010 and December 2013. The general surgical procedure was the same we previously described for robot-assisted laparoscopic pyeloplasty. Success was defined as: improvement in the degree of hydronephrosis at ultrasound, improvement of diuretic washout time at postoperative diuretic renogram (<15 min), improvement or at least stable differential renal function and absence of symptoms. These radiographic and symptomatic criteria of success were considered the primary outcomes. Secondary outcomes included complications and length of hospital stay. RESULTS: Between 2000 and 2013 a total of 153 patients underwent open Anderson-Hynes dismembered pyeloplasty. Of these 9 (6%) had recurrent UPJO. Four patients underwent open redo pyeloplasty. As a result, our study population comprised 5 children who underwent reoperative RALP repair. Patient characteristics and outcomes are summarized in the table below. Our success rate was 100%. DISCUSSION: Due to the low failure rate of open dismembered pyeloplasty there is no consensus on the best surgical approach for recurrent obstruction. While endoscopic approaches have been favored in adults, children have shown better success rates with repeat pyeloplasty. Laparoscopic salvage pyeloplasty for failed open procedures has become more popular and has been shown to result in excellent outcomes while providing the advantages of minimally invasive surgery. To date, the literature regarding the use of RALP for failed open procedures in the pediatric population is scarce. Only 2 pediatric series of robotic reoperative pyeloplasty have been reported by Helmal et al. (9 patients) and Lindgren et al. (16 patients) with a success rate of 100 and 88%, respectively. Although this is one of the first published studies about robot assisted laparoscopic reoperative repair for failed open pyeloplasty in pediatric patients, we acknowledge the limitations of our study due to the small number of patients, its retrospective nature and limited follow-up time. CONCLUSIONS: The incidence of failed open pyeloplasty is as low as 5% and management remains controversial. As reported by other authors, we believe that crossing vessels play a particularly important role in secondary obstruction and adversely impact the outcome. Redo pyeloplasty, open or minimally invasive, is associated with high success rates (80-100%) and therefore considered the treatment of choice by the majority of authors nowadays. Additionally, RALP for secondary procedures has demonstrated to be safe and even less technically demanding when compared to the open approach, providing the advantages of minimally invasive surgery. PMID- 25791424 TI - Identification of adolescent and adult patients receiving pediatric urologic care and establishment of a dedicated transition clinic. AB - INTRODUCTION: Pediatric patients with chronic urologic conditions frequently require lifelong evaluation and treatment. Transition to adult urologic care is critically important as these patients mature and the goals of care shift to include sexual function, fertility, and reconstruction. OBJECTIVE: Our objectives are to (1) quantify and describe the population of young adult patients with congenital or childhood-acquired urologic problems who continue to be followed in pediatric urology clinic, to (2) discuss the numerous obstacles to successful care transition, and to (3) outline the design features of the dedicated transition clinic we established in response to the identification of a sizeable population in need. STUDY DESIGN: We (1) performed a retrospective review of our electronic health record to identify young adult patients 19-35 years of age seen in pediatric urology clinic over a five year period. Patients without a chronic urologic diagnosis were excluded. We identified each patient's primary diagnosis and status with respect to transition of care. We then (2) established a dedicated transition clinic to facilitate progression to adult care services at our institution. RESULTS: Among 480 young adult patients seen in the pediatric clinic during the five-year period, 99 patients with an average age of 22.4 years were identified as having a chronic congenital or childhood-acquired diagnoses requiring urologic care. At the end of the five-year period, 40 of 99 patients (40.4%) had successfully transitioned to adult care while 59 patients (59.6%) continued care with pediatric urology. Among patients yet to transition, spinal dysraphism (30%) was the most common primary diagnosis. In this same group, discussion regarding transfer to adult care was documented during at least one visit in only 8 of the 59 patients (13.6%). All patients in this cohort had healthcare needs that included sexual function, fertility, or reconstruction. DISCUSSION: The present data confirm the presence of sizeable population of young adult patients with chronic urologic problems and maturing care needs who 1) continue to receive exclusively pediatric care, and 2) are rarely engaged in preparatory discussions regarding care transition. Obstacles to successful transition of care are numerous and include limited staff training, lack of identified staff member responsible for transition, financial and psychosocial barriers, and discomfort on the part of physicians, patients and families. We describe the additional challenges that are unique to transition of care in urology. We share a blueprint of our recently-established transition with the hope of prompting additional discussion and facilitating transitional urologic care elsewhere. CONCLUSION: Many young adult patients with chronic urologic conditions continue to receive care from pediatric urologists well into adulthood. We hope that our clinic might serve as a model for augmentation of urologic transition services at other institutions. We anticipate a future report evaluating our clinic's impact on long-term follow up, clinical outcomes, and patient satisfaction. PMID- 25791425 TI - Optical diagnosis of lower urinary tract infection: a pilot study in children. AB - Conventionally, diagnosis of lower urinary tract infection (LUTI) is made on the basis of history, urine microscopy and culture. But there are limitations to this methodology especially in children and special populations where there is difficulty in obtaining a full history and details of clinical symptoms. The aim of this study was to determine if monitoring bladder wall oxygenation as a measure of bladder mucosal inflammation using transcutaneous near-infrared spectroscopy (NIRS) allows detection of the presence or absence of LUTI in children. MATERIALS AND METHODS: A convenience sample of children referred to a pediatric urology clinic with an acute LUTI and a control group were studied. Diagnosis was confirmed by history, physical examination, laboratory investigations, and urine culture. Participants had transcutaneous measurement of an absolute measure of tissue oxygen saturation (TSI%) in their bladder wall, and a quadriceps muscle control site, using a spatially resolved (SR) wireless NIRS device. Average measures of bladder wall TSI% (B.TSI%) and quadriceps TSI% (Q.TSI%) and their differences (TSI.diff) were calculated and compared between those with LUTI and controls by performing a two-way repeated analysis of variance. RESULTS: Thirty-four patients met the inclusion criteria (LUTI n = 12 and controls n = 22). Comparing LUTI to controls B.TSI% and TSI.diff values were significantly higher in the LUTI group (p < 0.0001), while Q.TSI% values were not significantly different. CONCLUSIONS: Optical monitoring of bladder wall oxygenation is feasible in children. In this study a significant difference was evident in a SR NIRS-derived measure of absolute oxygen saturation in the bladder wall between children with UTI diagnosed by conventional testing methods, and those in a control group without infection. SR-NIRS monitoring of bladder wall oxygenation may offer a rapid and non-invasive means of bedside screening for LUTI where history and/or clinical signs are not available or adequate. PMID- 25791426 TI - Repair of megameatus: a modified approach. AB - OBJECTIVE: To demonstrate surgical reconstruction of a megameatus variant of hypospadias by using a modified, patient-specific approach. METHODS: An 8-month old male had a megameatus, which was discovered after newborn circumcision. In repair of megameatus, it is important to recognize the full extent to which the distal urethra is widened, in order to avoid inadvertent urethrotomy during mobilization of the glans wings and skin immediately proximal to the glans. In this case, a small wedge of tissue was excised from the ventral aspect of the urethra, and a midline relaxing incision of the urethral plate was made. Standard principles of hypospadias repair should be followed, with tension-free urethral tubularization, coverage of the neourethra with well-vascularized tissue, and adequate mobilization of the glans wings to allow midline reconstruction without compression of the underlying neourethra. RESULTS: There were no perioperative or postoperative complications in this case. The urethral meatus was positioned near the tip of the glans penis, and there was no evidence of meatal stenosis or urethrocutaneous fistula at 5-months follow-up. CONCLUSION: Each case of megameatus is unique, and a variety of surgical techniques can be used in formulating an approach that achieves optimal cosmetic and functional outcomes. PMID- 25791427 TI - Facilitation of Orai3 targeting and store-operated function by Orai1. AB - Orai1 subunits interacting with STIM1 molecules comprise the major components responsible for calcium release-activated calcium (CRAC) channels. The homologs Orai2 and Orai3 yield smaller store-operated currents when overexpressed and are mostly unable to substitute Orai1. Orai3 subunits are also essential components of store independent channel complexes and also tune inhibition of ICRAC by reactive oxygen species. Here we use patch-clamp, microscopy, Ca(2+)-imaging and biochemical experiments to investigate the interdependence of Orai2, Orai3 and Orai1. We demonstrate that store-operation and localization of Orai3 but not of Orai2 to STIM1 clusters in HEK cells or to the immunological synapse in T cells is facilitated by Orai1 while Orai3's store-independent activity remains unaffected. On the other hand, one Orai3 subunit confers redox-resistance to heteromeric channels. The inefficient store operation of Orai3 is partly due to the lack of three critical C-terminal residues, the insertion of which improves interaction with STIM1 and abrogates Orai3's dependence on Orai1. Our results suggest that Orai3 down-tunes efficient STIM1 gating when in a heteromeric complex with Orai1. PMID- 25791428 TI - mTor mediates tau localization and secretion: Implication for Alzheimer's disease. AB - Abnormally hyperphosphorylated tau aggregates form paired helical filaments (PHFs) in neurofibrillary tangles, a key hallmark of Alzheimer's disease (AD) and other tauopathies. The cerebrospinal fluid (CSF) levels of soluble total tau and phospho-tau from clinically diagnosed AD patients are significantly higher compared with controls. Data from both in vitro and in vivo AD models have implied that an aberrant increase of mammalian target of rapamycin (mTor) signaling may be a causative factor for the formation of abnormally hyperphosphorylated tau. In the present study, we showed that in post-mortem human AD brain, tau was localized within different organelles (autophagic vacuoles, endoplasmic reticulum, Golgi complexes, and mitochondria). In human SH SY5Y neuroblastoma cells stably carrying different genetic variants of mTor, we found a common link between the synthesis and distribution of intracellular tau. mTor overexpression or the lack of its expression was responsible for the altered balance of phosphorylated (p-)/-non phosphorylated (Np-) tau in the cytoplasm and different cellular compartments, which might facilitate tau deposition. Up regulated mTor activity resulted in a significant increase in the amount of cytosolic tau as well as its re-localization to exocytotic vesicles that were not associated with exosomes. These results have implicated that mTor is involved in regulating tau distribution in subcellular organelles and in the initiation of tau secretion from cells to extracellular space. PMID- 25791429 TI - The effects of acute arm crank ergometry and cycle ergometry on postural sway and attentional demands during quiet bipedal standing. AB - Current evidence suggests that acute bouts of lower limb exercise elicits a number of adverse effects on both sensory and motor components of postural control. The effects of acute exercise on quiet standing balance while concurrently performing an attentional task remains equivocal. This study aimed to compare the alterations in postural control and attentional demands elicited by upper and lower limb exercise. Twelve healthy young males (mean +/- SD age, 22.2 +/- 3.2 years) were examined on six separate occasions. The first two visits determined maximal aerobic fitness on an arm crank ergometer (ACE) and cycle ergometer (CYC). Subsequently, participant's postural sway was assessed during single- (ST) and dual-task (DT) conditions before and immediately after moderate- and high-intensity exercise engaging the upper or lower body musculature. The order of the four exercise tests was counterbalanced. The centre of pressure displacement in the anteroposterior (COPAP) and mediolateral (COPML) directions and the COP path length (COPL) were computed using a force platform. A time * mode interaction was observed for COPAP (ST; p = 0.011, DT; p = 0.018) and COPML (ST; p = 0.001). CYC elicited large (ES; 1.6-2.0) increases in COPAP and COPML, but there were no differences between aerobic and anaerobic tests (p > 0.05). The effect of cognitive load appeared to increase sway in the frontal plane following anaerobic CYC (p = 0.001) but not ACE (p < 0.05). Exercise has different effects on frontal and sagittal plane sway following different cognitive loads. In particular, COPML was increased at the cost of maintaining attentional performance following exercise. PMID- 25791430 TI - Epidemiology and classification of dog bite injuries to the face: A prospective study of 108 patients. AB - BACKGROUND: Dog bites are considered to be septic injuries, and their location on the face, with its highly symbolic topography and important social functions, is particularly pertinent. In addition to specific medical aspects, such as their psychological impact, they are also of relevance in terms of child protection measures. In light of the far-reaching importance of this subject, we were prompted to carry out a prospective study, over 13 years, to identify risk factors. Our results highlight specific risk factors, and they may hence assist with the implementation of concrete primary prevention measures against dog bites. METHODS: An information sheet was prepared and filled out during the intake of patients who had been bitten on the face. Data analysis was performed using Epi Info Version 6.04dfr software to find a correlation between the factors studied and the dog bite to the face. RESULTS: Dog bites to the face represented 0.83% of the emergency admissions to our service. A considerable majority of these involved children, with 68.5% of patients <16 years of age, and 33.3% of patients aged between 2 and 5 years. The wounds were multiple and of variable severity. The type of dog involved was frequently a German Shepherd. Strikingly, 91.3% of bites had occurred in a single-parent environment. CONCLUSIONS: Our study has determined that the fundamental factors that increase the probability of a dog bite to the face are as follows: the child being 2-5 years old, a single parent context, and involvement of a German Shepherd-type dog. PMID- 25791431 TI - Synergy between intention recognition and commitments in cooperation dilemmas. AB - Commitments have been shown to promote cooperation if, on the one hand, they can be sufficiently enforced, and on the other hand, the cost of arranging them is justified with respect to the benefits of cooperation. When either of these constraints is not met it leads to the prevalence of commitment free-riders, such as those who commit only when someone else pays to arrange the commitments. Here, we show how intention recognition may circumvent such weakness of costly commitments. We describe an evolutionary model, in the context of the one-shot Prisoner's Dilemma, showing that if players first predict the intentions of their co-player and propose a commitment only when they are not confident enough about their prediction, the chances of reaching mutual cooperation are largely enhanced. We find that an advantageous synergy between intention recognition and costly commitments depends strongly on the confidence and accuracy of intention recognition. In general, we observe an intermediate level of confidence threshold leading to the highest evolutionary advantage, showing that neither unconditional use of commitment nor intention recognition can perform optimally. Rather, our results show that arranging commitments is not always desirable, but that they may be also unavoidable depending on the strength of the dilemma. PMID- 25791432 TI - Is There a Role for Active Surveillance in Low-Risk Prostate Cancer? AB - BACKGROUND: Active surveillance (AS) represents an expectant treatment strategy for clinically localized prostate cancer (PCa) with low-risk features. OBJECTIVE: The actual management as well as the pros and cons of AS were evaluated. METHODS: A systematic review of the recent literature was performed using the Medline databases. CONCLUSIONS: Since a substantial number of men die with rather than from PCa, there is a considerable role for AS in carefully selected men. AS may also represent a strategy to reduce the burden of overtreatment rooted in intensified PSA testing. Facing the imprecision of risk stratification based on transrectal ultrasound-guided biopsy, accurate clinical staging represents a major medical challenge. Counseling and care require empathy as well as a profound understanding of the biology and the natural history of PCa. PMID- 25791434 TI - Segmentation of pulmonary nodules in computed tomography using a regression neural network approach and its application to the Lung Image Database Consortium and Image Database Resource Initiative dataset. AB - We present new pulmonary nodule segmentation algorithms for computed tomography (CT). These include a fully-automated (FA) system, a semi-automated (SA) system, and a hybrid system. Like most traditional systems, the new FA system requires only a single user-supplied cue point. On the other hand, the SA system represents a new algorithm class requiring 8 user-supplied control points. This does increase the burden on the user, but we show that the resulting system is highly robust and can handle a variety of challenging cases. The proposed hybrid system starts with the FA system. If improved segmentation results are needed, the SA system is then deployed. The FA segmentation engine has 2 free parameters, and the SA system has 3. These parameters are adaptively determined for each nodule in a search process guided by a regression neural network (RNN). The RNN uses a number of features computed for each candidate segmentation. We train and test our systems using the new Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) data. To the best of our knowledge, this is one of the first nodule-specific performance benchmarks using the new LIDC-IDRI dataset. We also compare the performance of the proposed methods with several previously reported results on the same data used by those other methods. Our results suggest that the proposed FA system improves upon the state-of-the-art, and the SA system offers a considerable boost over the FA system. PMID- 25791433 TI - Genome-wide identification of microRNA expression quantitative trait loci. AB - Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into regulatory mechanisms of microRNA transcription, and can help elucidate the role of microRNA as mediators of complex traits. Here we present a miR-eQTL mapping study of whole blood from 5,239 individuals, and identify 5,269 cis-miR-eQTLs for 76 mature microRNAs. Forty-nine per cent of cis-miR-eQTLs are located 300-500 kb upstream of their associated intergenic microRNAs, suggesting that distal regulatory elements may affect the interindividual variability in microRNA expression levels. We find that cis-miR-eQTLs are highly enriched for cis-mRNA-eQTLs and regulatory single nucleotide polymorphisms. Among 243 cis-miR eQTLs that were reported to be associated with complex traits in prior genome wide association studies, many cis-miR-eQTLs miRNAs display differential expression in relation to the corresponding trait (for example, rs7115089, miR 125b-5p and high-density lipoprotein cholesterol). Our study provides a roadmap for understanding the genetic basis of miRNA expression, and sheds light on miRNA involvement in a variety of complex traits. PMID- 25791435 TI - Unified heat kernel regression for diffusion, kernel smoothing and wavelets on manifolds and its application to mandible growth modeling in CT images. AB - We present a novel kernel regression framework for smoothing scalar surface data using the Laplace-Beltrami eigenfunctions. Starting with the heat kernel constructed from the eigenfunctions, we formulate a new bivariate kernel regression framework as a weighted eigenfunction expansion with the heat kernel as the weights. The new kernel method is mathematically equivalent to isotropic heat diffusion, kernel smoothing and recently popular diffusion wavelets. The numerical implementation is validated on a unit sphere using spherical harmonics. As an illustration, the method is applied to characterize the localized growth pattern of mandible surfaces obtained in CT images between ages 0 and 20 by regressing the length of displacement vectors with respect to a surface template. PMID- 25791437 TI - Investigating the relationship between competence and patient outcome with CBT. AB - Little is understood about the relationship between therapist competence and the outcome of patients treated for common mental health disorders. Understanding the relationship between competence and patient outcome is of fundamental importance to the dissemination and implementation of Cognitive Behavioural Therapy (CBT). The current study extends existing literature by exploring the relationship between CBT competence and patient outcome in routine clinical practice within the framework of the British Government's Improving Access to Psychological Therapies (IAPT) programme. Participants comprised 43 therapists treating 1247 patients over a training period of one year. Results found little support of a general association between CBT competence and patient outcome; however significantly more patients of the most competent therapists demonstrated a reliable improvement in their symptoms of anxiety than would be expected by chance alone, and fewer experienced no reliable change. Conversely, significantly more patients treated by the least competent therapists experienced a reliable deterioration in their symptoms than would be expected. The implications of these results for the dissemination and implementation of CBT are discussed. PMID- 25791436 TI - Large-scale automatic reconstruction of neuronal processes from electron microscopy images. AB - Automated sample preparation and electron microscopy enables acquisition of very large image data sets. These technical advances are of special importance to the field of neuroanatomy, as 3D reconstructions of neuronal processes at the nm scale can provide new insight into the fine grained structure of the brain. Segmentation of large-scale electron microscopy data is the main bottleneck in the analysis of these data sets. In this paper we present a pipeline that provides state-of-the art reconstruction performance while scaling to data sets in the GB-TB range. First, we train a random forest classifier on interactive sparse user annotations. The classifier output is combined with an anisotropic smoothing prior in a Conditional Random Field framework to generate multiple segmentation hypotheses per image. These segmentations are then combined into geometrically consistent 3D objects by segmentation fusion. We provide qualitative and quantitative evaluation of the automatic segmentation and demonstrate large-scale 3D reconstructions of neuronal processes from a 27,000 MUm(3) volume of brain tissue over a cube of 30 MUm in each dimension corresponding to 1000 consecutive image sections. We also introduce Mojo, a proofreading tool including semi-automated correction of merge errors based on sparse user scribbles. PMID- 25791438 TI - Age-Related Changes in Distractibility: Developmental Trajectory of Sustained Attention in ADHD. AB - OBJECTIVE: This study investigated age-related changes in sustained attention in children with ADHD and in their typically developed peers. METHOD: The study used a Continuous Performance Test (CPT) that includes visual and auditory stimuli serving as distractors. The rate of omission errors was used as a measurement of difficulty in sustained attention. Participants were children and adolescents aged 7 to 18 years (478 with ADHD and 361 without ADHD). RESULTS: Both groups of adolescents (with and without ADHD) showed reduced distractibility than younger children from the same group. However, distractibility tended to diminish in non ADHD adolescents, but not in adolescents with ADHD. CONCLUSION: Although part of the difficulties in ADHD could be explained by developmental delay that improves with time, other deficits, such as increased distractibility causing more omission errors, do not show a clear developmental trajectory. The results suggest that deficits in inhibitory control might be the core of ADHD. PMID- 25791439 TI - Cardiovascular pathology in 2 young adults with sudden, unexpected death due to coronary aneurysms from Kawasaki disease in childhood. AB - PURPOSE: Coronary artery aneurysms (CAA) may remain silent after Kawasaki disease (KD) until adulthood when myocardial ischemia can lead to sudden death. We postulated that there would be young adults with sudden, unexpected death due to CAA from KD who would have a state-mandated autopsy performed by the San Diego County Medical Examiner's Office (SDCMEO). METHODS: We reviewed all autopsy cases <35years of age from 1997 to 2012 at the SDCMEO with a cardiovascular cause of death (n=154). RESULTS: We found 2 cases meeting inclusion criteria. Case 1 was a 22-year-old Korean male with chronic ischemic changes due to a partially occluded and diffusely calcified 15mm aneurysm at the bifurcation of the left main coronary artery. Interview of the mother revealed that this patient had been diagnosed with KD complicated by giant aneurysms at age two years. Case 2 was a 30-year-old Hispanic male with myocardial infarction due to thrombosis of a calcified left anterior descending artery aneurysm. Histologic findings included diffuse myocardial fibrosis and a recanalized aneurysm in the right coronary artery. Interview of the family revealed a KD-compatible illness in childhood. Immunohistochemical staining showed expression of transforming growth factor beta pathway molecules in the aneurysmal arterial wall. CONCLUSIONS: In a medical examiner's office serving a population of approximately 3 million people, 2 of 154 (1.3%) cardiovascular deaths in persons <35years were attributed to cardiovascular complications of KD in childhood. Antecedent KD should be considered in the evaluation of all cases of sudden, unexpected death in young adults. PMID- 25791440 TI - Do Psychological Factors Predict Poor Outcome in Patients Undergoing TKA? A Systematic Review. AB - BACKGROUND: A subgroup of patients undergoing TKA is unhappy with the outcome of surgery and preoperative psychological factors may play a role in their dissatisfaction. QUESTIONS/PURPOSES: We asked whether (1) psychological factors, as measured by preoperative self-reported questionnaires, predicted poor outcome after TKA, and (2) whether certain psychological factors examined predicted poor outcome better than others. METHODS: We performed a systematic review and meta analysis of prospective observational studies published in MEDLINE, CINAHL(r), EMBASETM, and PsycINFO(r) databases from their date of inception to October 2013, augmented with a manual search of bibliographies. Study eligibility was performed according to an a priori protocol. Included studies were assessed for quality according to the Newcastle-Ottawa scale. Two reviewers independently performed the search, identified eligible studies, assessed their methodologic quality, and extracted data. Outcomes of interest included postoperative dissatisfaction, pain, or limited function of the patients. RESULTS: A total of 19 studies (17 cohort studies and two cross-sectional surveys) containing data on 9046 TKAs performed in 8704 adult patients were included in the review. Mean patient age was 68 years and followup ranged from 6 to 60 months (mean study followup, 14 months). Clinical and methodologic heterogeneity in study design prevented the statistical pooling of data and subsequent meta-analysis. Dissatisfaction rates with TKA ranged from 7.5% to 28.3%. Psychological health was deemed a significant predictor of satisfaction, pain, or function at a minimum of 6 months after TKA in 16 studies. The remaining three studies did not find this relationship. Baseline mental health factors may affect patient satisfaction, their long-term perception of pain, and their motivation to return to the desired level of function. We were unable to determine the most relevant psychological states or the most appropriate way to assess them with our systematic review. CONCLUSIONS: The preoperative psychological state of a patient may affect the outcome after a TKA. A comprehensive psychological assessment of patients is required to examine the long-term effect of such psychological factors on the eventual outcomes of TKA once the recovery phase is complete and to assess the effect that treatment for these psychological conditions may have on decreasing the dissatisfaction rate with TKA in this population. PMID- 25791441 TI - CORR Insights((r)): Standard Comorbidity Measures Do Not Predict Patient-reported Outcomes 1 Year After Total Hip Arthroplasty. PMID- 25791442 TI - Is a Revision a Revision? An Analysis of National Arthroplasty Registries' Definitions of Revision. AB - BACKGROUND: The reported survival of implants depends on the definition used for the endpoint, usually revision. When screening through registry reports from different countries, it appears that revision is defined quite differently. QUESTIONS/PURPOSES: The purposes of this study were to compare the definitions of revision among registry reports and to apply common clinical scenarios to these definitions. METHODS: We downloaded or requested reports of all available national joint registries. Of the 23 registries we identified, 13 had published reports that were available in English and were beyond the pilot phase. We searched these registries' reports for the definitions of the endpoint, mostly revision. We then applied the following scenarios to the definition of revision and analyzed if those scenarios were regarded as a revision: (A) wound revision without any addition or removal of implant components (such as hematoma evacuation); (B) exchange of head and/or liner (like for infection); (C) isolated secondary patella resurfacing; and (D) secondary patella resurfacing with a routine liner exchange. RESULTS: All registries looked separately at the characteristic of primary implantation without a revision and 11 of 13 registers reported on the characteristics of revisions. Regarding the definition of revision, there were considerable differences across the reports. In 11 of 13 reports, the primary outcome was revision of the implant. In one registry the primary endpoint was "reintervention/revision" while another registry reported separately on "failure" and "reoperations". In three registries, the definition of the outcome was not provided, however in one report a results list gave an indication for the definition of the outcome. Wound revision without any addition or removal of implant components (scenario A) was considered a revision in three of nine reports that provided a clear definition on this question, whereas two others did not provide enough information to allow this determination. Exchange of the head and/or liner (like for infection; scenario B) was considered a revision in 11 of 11; isolated secondary patella resurfacing (scenario C) in six of eight; and secondary patella resurfacing with routine liner exchange (scenario D) was considered a revision in nine of nine reports. CONCLUSIONS: Revision, which is the most common main endpoint used by arthroplasty registries, is not universally defined. This implies that some reoperations that are considered a revision in one registry are not considered a revision in another registry. Therefore, comparisons of implant performance using data from different registries have to be performed with caution. We suggest that registries work to harmonize their definitions of revision to help facilitate comparisons of results across the world's arthroplasty registries. PMID- 25791443 TI - Letter to the editor: the 2013 Frank Stinchfield award: diagnosis of infection in the early postoperative period after total hip arthroplasty. PMID- 25791444 TI - Reply to the letter to the editor: the 2013 Frank Stinchfield award: diagnosis of infection in the early postoperative period after total hip arthroplasty. PMID- 25791445 TI - Does Rotator Cuff Repair Improve Psychologic Status and Quality of Life in Patients With Rotator Cuff Tear? AB - BACKGROUND: Recently, psychological status, patient-centered outcomes, and health related quality of life (HRQoL) in patients with scheduled or who underwent orthopaedic surgeries have been emphasized. The relationship between preoperative psychological status and postoperative clinical outcome in patients with rotator cuff repair has not yet been investigated. QUESTIONS/PURPOSES: The primary objective of this study was to investigate changes in psychological status (depression, anxiety, insomnia) and HRQoL after rotator cuff repair. The secondary objective was to assess whether preoperative depression, anxiety, and insomnia predict clinical outcome after rotator cuff repair. METHODS: Forty-seven patients who underwent rotator cuff repair prospectively completed the visual analog scale (VAS) pain score, the UCLA Scale, the American Shoulder and Elbow Surgeons' Scale (ASES), the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), and the World Health Organization Quality of-life Scale Abbreviated Version (WHOQOL-BREF) before surgery and at 3, 6, and 12 months after surgery. Repeated-measures analysis of variance was used to evaluate the serial changes in psychological parameters and outcome measurements. The chi-square test was also used to compare preoperative and postoperative prevalence of depression, anxiety, and insomnia. Finally, multiple regression analysis was applied to determine the relationship between preoperative psychological status and postoperative clinical outcome. RESULTS: With surgery, depression, anxiety, and insomnia decreased, whereas quality of life increased. The mean HADS-D and HADS-A scores and the mean PSQI score decreased from 3.7 +/- 3.3, 4.3 +/- 4.3, and 6.6 +/- 3.6, respectively, before surgery to 2.1 +/- 2.3, 1.4 +/- 2.4, and 4.2 +/- 3.3, respectively, at 12 months after surgery (HADS-D mean difference 1.6 [95% confidence interval {CI}, 0.6-2.6], p = 0.003; HADS-A mean difference 2.9 [1.5-4.4], p < 0.001; PSQI mean difference 2.4 [1.3-3.4], p < 0.001). The mean WHOQOL-BREF score increased from 60.4 +/- 11.0 before surgery to 67.4 +/- 11.8 at 12 months after surgery (mean difference -7.0 [95% CI, -10.7 to 3.4], p < 0.001). At 12 months after surgery, there were decreases in the prevalence of depression (six of 47 [22.8%] versus three of 47 [6.4%], p = 0.002), anxiety (11 of 47 [23.4%] versus two of 47 [4.3%], p = 0.016), and insomnia (33 of 47 [70.2%] versus 20 of 47 [42.6%], p = 0.022). Preoperative HADS depression, HADS-anxiety, and PSQI scores did not correlate with the VAS pain score, UCLA, or ASES scores at 12 months after surgery. CONCLUSIONS: Psychological status and HRQoL improved with decreasing pain and increasing functional ability from 3 months after surgery. Preoperative depression, anxiety, and insomnia did not predict poor outcome after rotator cuff repair. Our findings suggest that successful rotator cuff repair may improve psychological status and HRQoL. LEVEL OF EVIDENCE: Level II, prospective study. PMID- 25791446 TI - The John Insall Award: No Functional Benefit After Unicompartmental Knee Arthroplasty Performed With Patient-specific Instrumentation: A Randomized Trial. AB - BACKGROUND: Component alignment can influence implant longevity as well as perhaps pain and function after unicompartmental knee arthroplasty (UKA), but correct alignment is not consistently achieved. To increase the likelihood that good alignment will be achieved during surgery, smart tools such as robotics or patient-specific instrumentation (PSI) have been introduced. QUESTIONS/PURPOSES: We hypothesized that UKA performed with PSI would result in improved level gait as ascertained with three-dimensional analysis, implant positioning, and patient reported outcomes measured by a validated scoring system when compared with conventional instrumentation 3 months and 1 year after surgery. METHODS: We randomized 60 patients into two groups using either the PSI technique or a conventional technique. All patients were operated on using the same technique and the same cemented metal-backed implant. Mean age of the patients was 63 +/- 4 years (range, 54-72 years) and mean body mass index was 28 +/- 3 kg/m(2). Patients were evaluated preoperatively, at 3 months, and 1 year after surgery by an independent observer blind to the type of technique. Gait parameters were assessed with three-dimensional analysis during level walking preoperatively and at 1 year, frontal and sagittal position of the implant was evaluated on full length radiographs at 3 months, and subjective functional outcome and quality of life using routine questionnaires (SF-12, new Knee Society Score [KSS], Knee Injury and Osteoarthritis Outcome Score) at 3 months and 1 year. This study had 80% power to detect a 15% difference in walking speed at the p < 0.05 level. RESULTS: One year after surgery, there were no differences between the two groups in the analyzed gait spatiotemporal parameters, respectively, for PSI UKA and conventional UKA : double limb support 31% (25%-54%) versus 30% (23%-56%; p = 0.67) and walking speed (1.59 m/s [0.86-1.87 m/s] versus 1.57 m/s [0.71-1.96 m/s]; p = 0.41). No difference was observed between the two groups in terms of lower limb alignment (PSI group 178 degrees +/- 3 degrees , conventional group 178 degrees +/- 4 degrees ; p = 0.24) or implant positioning on mediolateral and anteroposterior radiographs. There were no differences in the functional score between the PSI and conventional TKA groups at 3 months and 1 year after surgery: KSS objective knee scores (PSI: 85 +/- 8 points at 3 months, 87 +/- 5 points at 1 year and conventional instrumentation: 82 +/- 8 points at 3 months 83 +/- 6 points at 1 year; p = 0.10) and functional activity scores were similar in both group (PSI: 71 +/- 12 points at 3 months and 74 +/- 7 points at 1 year versus conventional group: 73 +/- 11 points at 3 months and 75 +/- 6 at 1 year; p = 0.9). CONCLUSIONS: Our observations suggest that PSI may confer small, if any, advantage in alignment, pain, or function after UKA. This argument can therefore not be used to justify the extra cost and uncertainty related to this technique. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 25791447 TI - CORR Insights((r)): What Is the Rerevision Rate After Revising a Hip Resurfacing Arthroplasty? Analysis From the AOANJRR. PMID- 25791448 TI - Evaluation of scavenging rate constants of DOPA and tyrosine enantiomers against multiple reactive oxygen species and methyl radical as measured with ESR trapping method. AB - The scavenging rates of DOPA (dl- and l-3-(3,4-dihydroxyphenyl)alanine) and Tyr (tyrosine (dl- and l-3-(4-hydroxyphenyl)alanine)) against five reactive oxygen species (ROS) and methyl radical were measured with the use of electron spin resonance (ESR) spin-trapping method and the scavenging rate constants of DOPA and Tyr were determined. The scavenging rate constants for multiple active species increased in the order of O2(-)100 ng/ml) was used as the indicator of metastasis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. RESULTS AND LIMITATIONS: In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. CONCLUSIONS: The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. PATIENT SUMMARY: The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer. PMID- 25791515 TI - Bovine pericardium for portal vein reconstruction in abdominal surgery: a surgical guide and first experiences in a single center. AB - BACKGROUND: Resection and reconstruction of infiltrated vessels achieve resectability of extended pancreatic tumors. The aim of the present study was to assess the feasibility of bovine pericardium as graft material for the individualised portal vein reconstruction and demonstrate a surgical technique for abdominal vein repair. METHODS: We performed a MEDLINE search to review the methods for complex abdominal vein reconstruction in the course of extended pancreatectomy. Moreover, clinical data of patients receiving portal vein reconstruction using a bovine pericardial patch at our institution were retrospectively analyzed. RESULTS: Based on the results of a review of the literature, autologous venous grafts using the internal jugular vein represent the most popular option for segmental portal vein reconstruction in case of impossible direct suture. At our center, segmental portal vein reconstruction with bovine pericardial patch in course of pancreatic surgery was performed in 4 patients. No case of vascular complications such as occlusion, segmental stenosis or thrombosis occurred. CONCLUSIONS: Our experience suggests a surgical procedure for an individual size-matched portal vein reconstruction using bovine pericardium. Although first results appear promising, prospective studies are required to objectively assess the patency of bovine pericardium compared with autologous and synthetic interposition grafts for portal vein reconstruction. PMID- 25791516 TI - MPs demand to know full cost of failed Hinchingbrooke trust franchise. PMID- 25791517 TI - Invariant natural killer T cell deficiency leads to the development of spontaneous liver inflammation dependent on gammadeltaT cells in mice. AB - BACKGROUND: Immune tolerance is maintained in the liver, and perturbation of tolerance can lead to immune-mediated liver diseases such as autoimmune hepatitis (AIH). Invariant natural killer T (iNKT) cells and gammadeltaT cells have been shown to maintain immune homeostasis as regulatory cells and to play pathogenic roles in immune-mediated diseases as effector cells. We hypothesized that iNKT cells and gammadeltaT cells are involved in the maintenance of hepatic immune tolerance and immune-mediated liver disease. METHODS: We measured liver inflammation and the cytokine profiles of liver mononuclear cells in BALB/c wild type (WT) mice and BALB/c Jalpha18-deficient (KO) mice lacking iNKT cells. We also examined the role of gammadeltaT cells in AIH using liver tissue from AIH patients and control subjects. RESULTS: Spontaneous liver inflammation, hepatocyte damage, and anti-nuclear-antibody production occurred in Jalpha18 KO mice but not in WT mice. Furthermore, liver mononuclear cells from Jalpha18 KO mice, but not those from WT mice, produced interleukin-17 (IL-17). gammadeltaT cells were the primary producers of the cytokine, and they were more abundant in the livers of Jalpha18 KO mice than in those of WT mice. In Jalpha18 KO mice, the administration of anti-gammadeltaT-cell-receptor antibody abolished liver inflammation, hepatocyte damage, and IL-17 production. gammadeltaT cells accumulated in the livers of AIH patients but not in those of the control subjects. CONCLUSIONS: Our results suggest a protective role for iNKT cells, a pathologic role for gammadeltaT cells, and an association between these cells in the pathogenesis of AIH. PMID- 25791518 TI - Accurate and rapid identification of feeding arteries with multidetector-row angiography-assisted computed tomography for transarterial chemoembolization for hepatocellular carcinoma. AB - BACKGROUND: Transarterial chemoembolization (TACE) is an important treatment modality for hepatocellular carcinoma (HCC). Accurate identification of feeding arteries and catheterization are necessary for achieving treatment efficacy, especially with selective TACE. However, this often requires multiple imaging studies. We evaluated the utility of a newly developed apparatus that combines multidetector-row computed tomography (MDCT) and angiography (angio-MDCT) to facilitate TACE for treatment of HCC. METHODS: A total of 73 patients who underwent selective TACE with angio-MDCT were compared with 57 patients who had undergone selective TACE with single-row computed tomography assisted by angiography (angio-CT) in terms of the number of imaging studies needed to complete TACE. RESULTS: The mean number of digital subtraction arteriography (DSA) and CT studies required for characterization of feeding arteries before embolization was 3.53 (range 1-8) and 5.16 (range 2-11), respectively, with single-row angio-CT, and 1.67 (range 1-5) and 2.90 (range 1-5), respectively, with angio-MDCT. Fewer studies were needed in patients who underwent TACE with angio-MDCT (p < 0.0001 for both DSA and CT). Whereas single-row angio-CT failed to identify extrahepatic feeders in three patients (37.5%), all extrahepatic feeders could be identified with angio-MDCT. CONCLUSIONS: Angio-MDCT facilitates rapid and accurate identification of feeding arteries in patients undergoing TACE through the three-dimensional image analyses by the reconstruction with the workstation. PMID- 25791519 TI - Obese-insulin resistance accelerates and aggravates cardiometabolic disorders and cardiac mitochondrial dysfunction in estrogen-deprived female rats. AB - Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but have an increased incidence of CVD and metabolic syndrome after menopause, indicating the possible protective effects of estrogen on cardiometabolic function. Although obesity is known to increase CVD risks, its impact on the heart on estrogen deprivation is still inconclusive. We investigated the effects of obese-insulin resistance on cardiometabolic function in estrogen-deprived ovariectomized rats. Adult female ovariectomized (O) or sham (S)-operated rats randomly received either normal diet (ND, 19.77 % fat) or high fat diet (HF, 57.60 % fat) (n = 6/group) for 12 weeks. The heart rate variability (HRV), left ventricular (LV) performance, cardiac autonomic balance, cardiac mitochondrial function, metabolic parameters, oxidative stress, and apoptotic markers were determined at 4, 8, and 12 weeks. Insulin resistance developed at week 8 in NDO, HFS, and HFO rats as indicated by increased plasma insulin and HOMA index. However, only HFO rats had elevated plasma cholesterol level at week 8, whereas HFS rats had showed elevation at week 12. In addition, only HFO rats had depressed HRV, impaired LV performance indicated by decreased fractional shortening (%FS) and cardiac mitochondrial dysfunction indicated by increased mitochondrial ROS level, mitochondrial depolarization and swelling, as early as week 8, whereas other groups exhibited them at week 12. Either estrogen deprivation or obesity alone may impair metabolic parameters, cardiac autonomic balance, and LV and mitochondrial function. However, an obese insulin-resistant condition further accelerated and aggravated the development of these cardiometabolic impairments in estrogen-deprived rats. PMID- 25791521 TI - Paediatric thyroid disorders: new insights. PMID- 25791520 TI - When you hear hoofbeats, think of horses but do not forget the zebras. AB - We report a case of a 68-year-old man who was admitted to the department of cardiology with increasing abdominal and chest pain during the day. The prehospital ECG showed clear ST segment elevation in inferior leads. The patient was routed directly to the catheterisation laboratory with acute myocardial infarction as a tentative diagnosis. The coronary angiography showed an occluded right coronary artery that was reopened with a plain old balloon angioplasty procedure. After the procedure, the patient was expected to feel better, but the abdominal pain worsened. The following bedside ultrasound examination was quite surprising. PMID- 25791522 TI - The effect of central and planar chirality on the electrochemical and chiral sensing properties of ferrocenyl urea H-bonding receptors. AB - A new series of chiral ureas containing one or two redox-active ferrocene units was synthesised and studied in order to investigate the effect of planar chirality and central chirality on electrochemical chiral sensing. Binding of chiral carboxylate anions in organic solvents through H-bond formation caused a negative shift in the potentials of the ferrocene/ferrocenium (Fc/Fc(+)) couples of the receptors, demonstrating their use as electrochemical sensors in solution. While the presence of two ferrocene units gave no marked improvement in the chiral sensing capabilities of these systems, the introduction of planar chirality, in addition to central chirality, switched the enantiomeric binding preference of the system and also caused an interesting change in the appearance of some voltammograms, with unusual two-wave behaviour observed upon binding a protected prolinate guest. PMID- 25791523 TI - Phosphazenes: efficient organocatalysts for the catalytic hydrosilylation of carbon dioxide. AB - Phosphazene superbases are efficient organocatalysts for the metal-free catalytic hydrosilylation of carbon dioxide. They react with CO2 to form the respective phosphine oxides, but in the presence of hydrosilanes, CO2 can be selectively reduced to silyl formates, which can in turn be reduced to methoxysilanes by addition of an extra loading of silanes. Activities reach a TOF of 32 h(-1) with a TON of 759. It is also shown that unexpectedly, N,N-dimethylformamide can reduce CO2 to a mixture of silyl formates, acetals and methoxides in the absence of any catalyst. PMID- 25791524 TI - Impaired intestinal mucosal immunity is associated with the imbalance of T lymphocyte sub-populations in intrauterine growth-restricted neonatal piglets. AB - Intrauterine growth restriction (IUGR) impairs the immunity of both piglets and humans. We hypothesized that the poor cytokine secreting ability of the small intestines of IUGR neonatal piglets might be associated with lower CD4(+) and CD8(+) T lymphocytes. Therefore, we used neonatal piglets as IUGR models to investigate the effects of IUGR on the CD4(+) and CD8(+) T lymphocyte cell populations. Six normal-birth-weight (NBW) and six IUGR neonatal piglets were chosen and divided into NBW and IUGR groups, respectively. The cytokine and immunoglobulin levels in the blood; the CD4(+) and CD8(+) T lymphocyte contents in the thymus, blood, spleen, mesenteric lymph nodes, jejunum and ileum; and the distribution of CD4(+) and CD8(+) T lymphocytes in the ileum were measured. We further compared the gene expression and protein distribution of MHC-II in the jejunum and ileum of the NBW and IUGR neonatal piglets. The results showed that the IUGR piglets exhibited lower (P<0.05) serum levels of IL1beta, IL2 and IL10, as well as increased percentages of CD8 cells in the blood, spleen and thymus (P<0.05) and increased CD4 gene expression in the thymus (P<0.05). However, the CD4:CD8 ratio in the blood was decreased (P<0.05), the CD8 content in the MLN was lowered (P<0.05), and the expression of the CD4, CD8 and MHC-II genes was down regulated (P<0.05) in the jejunum and ileum of the IUGR piglets compared with those of the NBW piglets. The results suggest that impaired intestinal mucosal immunity is associated with an imbalance in the T lymphocyte sub-populations in IUGR neonatal piglets. PMID- 25791525 TI - Molecular cloning and expression profile of an abiotic stress and hormone responsive MYB transcription factor gene from Panax ginseng. AB - The v-myb avian myeloblastosis viral oncogene homolog (MYB) family constitutes one of the most abundant groups of transcription factors and plays vital roles in developmental processes and defense responses in plants. A ginseng (Panax ginseng C.A. Meyer) MYB gene was cloned and designated as PgMYB1. The cDNA of PgMYB1 is 762 base pairs long and encodes the R2R3-type protein consisting 238 amino acids. Subcellular localization showed that PgMYB1-mGFP5 fusion protein was specifically localized in the nucleus. To understand the functional roles of PgMYB1, we investigated the expression patterns of PgMYB1 in different tissues and under various conditions. Quantitative real-time polymerase chain reaction and western blot analysis showed that PgMYB1 was expressed at higher level in roots, leaves, and lateral roots than in stems and seeds. The expression of PgMYB1 was up regulated by abscisic acid, salicylic acid, NaCl, and cold (chilling), and down regulated by methyl jasmonate. These results suggest that PgMYB1 might be involved in responding to environmental stresses and hormones. PMID- 25791527 TI - Novel robust in vitro hepatitis B virus infection model using fresh human hepatocytes isolated from humanized mice. AB - The molecular mechanisms underlying the hepatitis B virus (HBV) life cycle are poorly understood because of the lack of appropriate in vitro infection models. Herein, we report a highly effective in vitro HBV infection system using fresh human hepatocytes (HHs) isolated from chimeric mice with humanized livers. After the inoculation of sera collected from HBV-infected chimeric mice or patients to HHs, we measured levels of HBV DNA, mRNA, covalently closed circular DNA, and viral protein expression in HHs. We investigated the neutralization activity of hepatitis B immune globulin and the effects of siRNA against sodium taurocholate cotransporting polypeptide and clathrin heavy chain on HBV infection. We confirmed the expression of viral antigens in HHs and the presence of extracellular HBV DNA and hepatitis B surface antigen. The maximum infection rate was approximately 80%. Lamivudine and hepatitis B immune globulin treatment reduced HBV DNA levels in a dose-dependent manner. Knockdown of sodium taurocholate-cotransporting polypeptide and clathrin heavy chain significantly reduced the levels of hepatitis B surface antigen. Infection was successfully established using different donor HHs and inocula. Elevation of extracellular HBV DNA levels and the increase of HBV-positive HHs were blocked by continuous hepatitis B immune globulin treatment, indicating virus spread in this model. Chimeric mouse-derived HHs provide a robust in vitro infection model that can completely support the HBV life cycle. PMID- 25791526 TI - The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. AB - Neutrophil migration to sites of inflammation and the subsequent execution of multiple functions are designed to contain and kill invading pathogens. These highly regulated and orchestrated processes are controlled by interactions between numerous receptors and their cognate ligands. Unraveling and identifying those that are central to inflammatory processes may represent novel therapeutic targets for the treatment of neutrophil-dominant inflammatory disorders in which dysregulated neutrophil recruitment, function, and elimination serve to potentiate rather than resolve an initial inflammatory insult. The first G protein-coupled receptor to be described on human neutrophils, formyl peptide receptor 1 (FPR1), is one such receptor that plays a significant role in the execution of these functions through multiple intracellular signaling pathways. Recent work has highlighted important observations with regard to both receptor function and the importance and functional relevance of FPR1 in the pathogenesis of a range of both sterile and infective inflammatory conditions. In this review, we explore the multiple components of neutrophil migration and function in both health and disease, with a focus on the role of FPR1 in these processes. The current understanding of FPR1 structure, function, and signaling is examined, alongside discussion of the potential importance of FPR1 in inflammatory diseases suggesting that FPR1 is a key regulator of the inflammatory environment. PMID- 25791528 TI - A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates. AB - There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non human primates using the novel CB1R antagonist radioligand [(11)C]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CB1R with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around ~20-30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of 'neutral' vs. 'classical' CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [(11)C]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding. PMID- 25791530 TI - Defining minor symptoms in acute ischemic stroke. AB - BACKGROUND: Thrombolysis is often withheld from acute ischemic stroke patients presenting with mild symptoms; however, up to 40% of these patients end up with a poor outcome when left untreated. Since there is lack of consensus on the definition of minor symptoms, we aimed at addressing this issue by looking for features that would better predict functional outcomes at 3 months. METHODS: Among all acute ischemic stroke patients admitted to our Stroke Unit (n = 1,229), we selected a cohort of patients who arrived within 24 hours from symptoms onset, with baseline NIHSS <=6, not treated with thrombolysis (n = 304). Epidemiological data, comorbidities, radiological features and clinical presentation (NIHSS items) were collected to identify predictors of outcome. Our cohort was tested against minor stroke definitions selected from the literature and a newly proposed one. RESULTS: Three months after stroke onset, 97 patients (31.9%) had mRS >= 2. Independent predictors of poor outcome were age (OR 0.97 [95% CI 0.95 9.99]) and baseline NIHSS score (OR 0.79 [95% CI 0.67-0.94]), while cardioembolic aetiology was negatively associated (OR 3.29 [95% CI 1.51-7.14]). Items of NIHSS associated with poor outcome were impairment of right motor arm (OR 0.49 [95% CI 0.27-0.91]) or the involvement of any of the motor items (OR 0.69 [95% CI 0.48 0.99]). The definition of minor stroke as NIHSS <=3 and the new proposed definition had the highest sensitivity and accuracy and were independent predictors of outcome. CONCLUSIONS: Our study confirmed that in spite of a low NIHSS score, one third of patients had poor outcome. As already described, age and NIHSS score remained independent predictors of poor outcome even in mild stroke. Also, motor impairment appeared a major determinant of poor outcome. The new proposed definition of minor stroke featured the NIHSS score and the NIHSS items that better predicted functional outcome. Awareness that even minor stroke can yield to poor outcome should sensitize patients to arrive early to the ED and neurologists to administer rt-PA. PMID- 25791529 TI - Resveratrol up-regulates AMPA receptor expression via AMP-activated protein kinase-mediated protein translation. AB - Resveratrol is a phytoalexin that confers overall health benefits including positive regulation in brain function such as learning and cognition. However, whether and how resveratrol affects synaptic activity remains largely unknown. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are glutamatergic receptors that mediate the majority of fast excitatory transmission and synaptic plasticity, and thus play a critical role in higher brain functions, including learning and memory. We find that in rat primary neurons, resveratrol can rapidly increase AMPAR protein level, AMPAR synaptic accumulation and the strength of excitatory synaptic transmission. The resveratrol effect on AMPAR protein expression is independent of sirtuin 1 (SIRT1), the conventional downstream target of resveratrol, but rather is mediated by AMP-activated protein kinase (AMPK) and subsequent downstream phosphoinositide 3-kinase (PI3K)/Akt signaling. Application of the AMPK specific activator 5-aminoimidazole-4 carboxamide-1-beta-d-ribofuranoside (AICAR) mimics the effects of resveratrol on both signaling and AMPAR expression. The resveratrol-induced increase in AMPAR expression results from elevated protein synthesis via regulation of the eukaryotic initiation factor (eIF) 4E/4G complex. Disruption of the translation initiation complex completely blocks resveratrol-dependent AMPAR up-regulation. These findings indicate that resveratrol may regulate brain function through facilitation of AMPAR biogenesis and synaptic transmission. PMID- 25791531 TI - Circulating MicroRNAs as new biomarkers of ischaemia/reperfusion injury during cardiac surgery. PMID- 25791532 TI - Isolation of high-purity myenteric plexus from adult human and mouse gastrointestinal tract. AB - The enteric nervous system (ENS) orchestrates a broad range of important gastrointestinal functions such as intestinal motility and gastric secretion. The ENS can be affected by environmental factors, diet and disease. Changes due to these alterations are often hard to evaluate in detail when whole gut samples are used. Analyses based on pure ENS tissue can more effectively reflect the ongoing changes during pathological processes. Here, we present an optimized approach for the isolation of pure myenteric plexus (MP) from adult mouse and human. To do so, muscle tissue was individually digested with a purified collagenase. After incubation and a gentle mechanical disruption step, MP networks could be collected with anatomical integrity. These tissues could be stored and used either for immediate genomic, proteomic or in vitro approaches, and enteric neurospheres could be generated and differentiated. In a pilot experiment, the influence of bacterial lipopolysaccharide on human MP was analyzed using 2 dimensional gel electrophoresis. The method also allows investigation of factors that are secreted by myenteric tissue in vitro. The isolation of pure MP in large amounts allows new analytical approaches that can provide a new perspective in evaluating changes of the ENS in experimental models, human disease and aging. PMID- 25791533 TI - The relationship between CSE1L expression and axillary lymph node metastasis in breast cancer. AB - AIM: CSE1L is the human homologue to the yeast gene CSE1 and CSE1L is a gene related to cancer progression. Thus, CSE1L may regulate the invasion and metastasis of breast cancer. The aim of this study is to show the relationship between CSE1L and axillary lymph node metastasis. METHODS: Sixty-six breast cancer patients were evaluated according to patient and tumor characteristics. Immunohistochemistry was carried out on formalin-fixed, paraffin-embedded archival breast tumor tissues. The results of CSE1L staining were analyzed according to the percentage of immunoreactive cells. RESULTS: There were 29 patients without axillary lymph node metastasis and 37 patients with nodal metastasis. The mean age of the patients was 50.6 +/- 11.3 years. Age, tumor size, nuclear grade and hormone receptor status were similar in the axillary lymph node positive and negative groups. There was a statistically significant relationship between cytoplasmic CSE1L expression and axillary lymph node metastasis. However, nuclear CSE1L expression did not have any effect on axillary lymph node metastasis. CONCLUSIONS: Cytoplasmic CSE1L overexpression may be a valuable tool for prognosis of breast cancer in future. PMID- 25791534 TI - Management of patients with recurrent glioblastoma using hypofractionated stereotactic radiotherapy. AB - BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The chance of cure is very limited due to treatment-refractory disease course with frequent recurrences despite aggressive multimodality management. In this retrospective study, we evaluated treatment outcomes of hypofractionated stereotactic radiotherapy (HFSRT) in the management of recurrent GBM and report our single-center experience. METHODS: Twenty-eight patients receiving HFSRT for recurrent GBM between September 2008 and February 2014 were retrospectively assessed. Total radiotherapy dose was 25 Gy delivered in 5 fractions over 5 consecutive days for all patients. High-precision, image-guided volumetric modulated arc therapy was delivered with a linear accelerator using 6-MV photons using the frameless technique. Analyzed prognostic factors were age, gender, Karnofsky performance status (KPS), tumor location, planning target volume (PTV) size, overall survival (OS), progression-free survival (PFS), time interval between completion of treatment with Stupp protocol at primary diagnosis and recurrence. RESULTS: Median follow-up time was 42 months (range 2-68). Median time interval between primary chemoradiotherapy and HFSRT was 11.2 months (range 4-57.9). Median OS and PFS calculated from reirradiation was 10.3 months and 5.8 months, respectively. Longer interval between initial treatment and recurrence (p = 0.01), smaller PTV size (p = 0.001), KPS >=70 (p = 0.005) and younger age (p = 0.004) were associated with longer OS on statistical analysis. CONCLUSION: HFSRT offers a feasible and effective salvage treatment option for recurrent GBM management. Prognostic factors associated with longer OS in our study were longer interval between initial treatment and recurrence, smaller PTV size, KPS >=70 and younger age. PMID- 25791535 TI - Long-term clinical outcome of intensity-modulated radiation therapy for locally advanced esophageal squamous cell carcinoma. AB - PURPOSE: This study evaluated the effectiveness and safety of intensity-modulated radiation therapy (IMRT) for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Between August 2009 and December 2011, 112 patients with pathologically confirmed ESCC treated with IMRT at Jiangsu Province People's Hospital and Nantong Tumor Hospital were included in a retrospective analysis. Patients received either IMRT alone (group A) or concurrent chemoradiotherapy (CRT) (group B). A radiation dose of 60-66 Gy administered in 30-33 fractions was delivered to the tumor. The patients in group B simultaneously received 2 cycles of cisplatin-based doublets with either 5-fluorouracil or taxotere. The Kaplan Meier method was used to compute the survival time. Early and late toxicities were scored according to CTCAE v.3.0. RESULTS: The response rate of group B (91.07%) was not significantly greater than that of group A (89.29%) (chi2 = 0.10, p = 0.75). The 1- and 3-year survival rates of group B (87.5% and 57.14%, respectively) were greater than those of group A (69.64% and 37.50%, respectively). The difference in overall survival was statistically significant between groups A and B (chi2 = 5.30, p = 0.02; chi2 = 4.33, p = 0.04). Hematological toxicity, gastrointestinal toxicity, and treatment-related esophagitis were significantly higher in group B than group A (16.07% vs. 33.93%, p = 0.04; 10.71% vs. 26.79%, p = 0.03; 19.64% vs. 44.64%, p = 0.01). However, intergroup differences in terms of late toxicity were not significant. CONCLUSIONS: IMRT was a practical and feasible technique to treat ESCC. Concurrent CRT could increase local tumor control and long-term survival. The CRT regimen was associated with a higher incidence of acute gastrointestinal and hematological toxicity. PMID- 25791536 TI - Minimally invasive video-assisted thyroidectomy for papillary thyroid cancer: a prospective 5-year follow-up study. AB - BACKGROUND: Minimally invasive video-assisted thyroidectomy (MIVAT) was initially introduced for the treatment of selected patients who met certain thyroid volume, nodule size and pathological criteria. Recent studies indicate that the completeness of resection of malignant nodules is comparable to that obtained with conventional thyroidectomy. AIMS: To compare the 5-year outcomes in patients with papillary thyroid carcinoma (PTC) treated with MIVAT versus conventional thyroidectomy. METHODS: In this prospective cohort study conducted over 2 years (July 2005-June 2007), 172 patients with node-negative, nonmetastatic PTC underwent either MIVAT (n = 67) or conventional thyroidectomy (n = 105). Study outcomes were 1) the cumulative dose of radioactive iodine (RAI) to achieve a disease-free state, defined as a stimulated serum thyroglobulin (Tg) level <2 ng/mL with negative Tg antibody and no tumor on a whole-body scan or cross sectional imaging, and 2) the 5-year serum Tg level. RESULTS: The clinical parameters of the MIVAT and conventional thyroidectomy groups were comparable except for age (mean 43 +/- 12 vs. 59 +/- 17 years, respectively; p = 0.03) and operative time (mean 69 +/- 24 vs. 53 +/- 16 minutes, p = 0.02); the mean tumor size was similar between groups (1.3 +/- 0.7 vs. 1.6 +/- 0.9 cm, p = 0.14). Surgical morbidity was similar in both groups. Median follow-up was 5 years. RAI dose (mean 72 +/- 38 vs. 96 +/- 47 mCu, p = 0.34) and serum Tg at 5 years (mean 0.3 +/- 0.2 vs. 0.5 +/- 0.3 ng/mL, p = 0.30) were not significantly different between the MIVAT and conventional thyroidectomy groups. CONCLUSIONS: MIVAT can be safely utilized in patients with localized PTC, providing comparable completeness of resection and oncological outcome to conventional thyroidectomy. PMID- 25791538 TI - Diurnal Variation of Plasma Brain-Derived Neurotrophic Factor Levels in Women with Functional Hypothalamic Amenorrhea. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is strongly related to hormonal networks and is modulated by hypothalamic activity. OBJECTIVE: To evaluate plasma BDNF concentration in patients with functional hypothalamic amenorrhea (FHA), with reference to the BDNF circadian rhythm and its relation with the cortisol (F) rhythm, and to assess whether the duration of amenorrhea might influence the BDNF:F ratio in FHA. DESIGN: This was an observational study evaluating 36 amenorrheic and 30 eumenorrheic women. SETTING: Basal values of BDNF and hormones were examined in blood samples collected from 7:00 to 9:00 h in all the women. Basal BDNF and F levels were determined in blood samples collected in 12 subjects from each group at 8:00, 12:00, 16:00, 20:00, and 24:00 h. RESULTS: BDNF plasma levels are significantly lower in amenorrheic women (p < 0.001) than in the follicular phase of eumenorrheic women. There are no correlations between BDNF values (p > 0.05), sex steroids, and F in FHA. Low plasma BDNF levels in FHA are not significantly correlated with duration of amenorrhea. The 24-hour variation of BDNF in amenorrheic women is significantly lower when compared to the control group, and normal daily variations of BDNF disappeared in FHA patients. F preserved its circadian rhythm in both groups. CONCLUSIONS: Interactions between BDNF, the hypothalamus-pituitary-adrenal axis, and sex steroids might be critical in clinical conditions of modified homeostasis/adaptation, such as FHA. PMID- 25791539 TI - The first Clostridium difficile ribotype 027 strain isolated in Taiwan. PMID- 25791537 TI - Functional diversification and specialization of cytosolic 70-kDa heat shock proteins. AB - A fundamental question in molecular evolution is how protein functional differentiation alters the ability of cells and organisms to cope with stress and survive. To answer this question we used two paralogous Hsp70s from mouse and explored whether these highly similar cytosolic molecular chaperones, which apart their temporal expression have been considered functionally interchangeable, are differentiated with respect to their lipid-binding function. We demonstrate that the two proteins bind to diverse lipids with different affinities and therefore are functionally specialized. The observed lipid-binding patterns may be related with the ability of both Hsp70s to induce cell death by binding to a particular plasma-membrane lipid, and the potential of only one of them to promote cell survival by binding to a specific lysosomal-membrane lipid. These observations reveal that two seemingly identical proteins differentially modulate cellular adaptation and survival by having acquired specialized functions via sequence divergence. Therefore, this study provides an evolutionary paradigm, where promiscuity, specificity, sub- and neo-functionalization orchestrate one of the most conserved systems in nature, the cellular stress-response. PMID- 25791541 TI - Advancements in the Management of Pancreatic Cancer: 2015 ASCO Gastrointestinal Cancers Symposium (San Francisco, CA, USA. January 15-17, 2015). PMID- 25791540 TI - Intramuscular olanzapine versus intramuscular haloperidol plus lorazepam for the treatment of acute schizophrenia with agitation: An open-label, randomized controlled trial. AB - BACKGROUND/PURPOSE: To compare the efficacy and safety profile between intramuscular (IM) olanzapine and IM haloperidol plus IM lorazepam in acute schizophrenic patients with moderate to severe agitation. METHODS: This was a prospective, randomized, open-label study. Acutely agitated patients with schizophrenia or schizoaffective disorder (n = 67) were randomized to receive 10 mg IM olanzapine (n = 37) or 5 mg IM haloperidol plus 2 mg IM lorazepam (n = 30). Agitation was measured with Positive and Negative Syndrome Scale Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES) during the first 2 hours and at 24 hours after the first injection. Safety was assessed using the Simpson-Angus Scale and Barnes Akathisia Rating Scale and by recording adverse events at 24 hours following the first injection. The Clinical Global Impression-Severity scale was also rated. RESULTS: The PANSS-EC scores decreased significantly at 2 hours after the first injection in both groups (olanzapine: 10.2, p < 0.001; haloperidol + lorazepam: -9.9, p < 0.001). Haloperidol plus lorazepam was not inferior to olanzapine in reducing agitation at 2 hours. There were no significant differences in PANSS-EC or ACES scores between the two groups within 2 hours following the first injection. The frequencies of adverse events and changes in Clinical Global Impression-Severity, Simpson-Angus Scale, and Barnes Akathisia Rating Scale scores from baseline to 24 hours showed no significant differences between the groups. CONCLUSION: The findings suggest that IM haloperidol (5 mg) plus lorazepam (2 mg) is not inferior to IM olanzapine (10 mg) in the treatment of acute schizophrenic patients with moderate to severe agitation (ClinialTrials.gov identifier number NCT00797277). PMID- 25791542 TI - Pancreatitis developing in the context of acute hepatitis: a literature review. AB - Despite strong evidence suggestive of associations between hepatic diseases and pancreas injury, a potential relationship between acute hepatitis and acute pancreatitis has not been a matter of review; which we focused on in the current paper. Some of the main findings of this review article are: fulminant hepatitis failure represents the highest incident rate of hepatitis-related acute pancreatitis; so a screening program might be indicative in these patients. Specific characteristics of HAV-related pancreatitis are that it is a benign condition with no reported mortality; and a male preponderance in the incidence, with females developing in older ages and having shown the signs of both conditions simultaneously. The incidence of acute pancreatitis in HBV infection is the lowest, but the mortality was the highest. HEV-related acute pancreatitis was most likely to represent pseudocysts and there was an apparent ethnic priority with Indian descents, the only reported cases in the literature. Hepatitis-related pancreatitis in liver transplant recipients was most frequent in HBV infected patients; and in IFN-induced pancreatitis, cessation of the drug was most effective in treatment, with no catastrophic event reported. PMID- 25791543 TI - Neoadjuvant therapy in pancreatic cancer: review article. AB - CONTEXT: Pancreatic cancer is still associated with a high mortality and morbidity for affected patients. To this date the role of neoadjuvant therapy in the standard treatment of pancreatic cancer remains elusive. The aim of our study was to review the latest results and current approaches in neoadjuvant therapy of pancreatic cancer. METHODS: We performed a literature review for neoadjuvant therapy in pancreatic cancer. We divided the results into resectable disease and local advanced pancreatic cancer. RESULTS: Neoadjuvant therapy in pancreatic cancer is safe. But currently no standard guidelines exist in neoadjuvant approaches on pancreatic cancer. For local advanced pancreatic cancer the available data tends to show a positive effect on survival rates for neoadjuvant approaches. CONCLUSION: For resectable disease we found no benefit of neoadjuvant therapy. The negative or positive effects of neoadjuvant treatment in pancreatic cancer remain unclear for the lack of sufficient and prospective data. PMID- 25791544 TI - Postoperative Pancreatic Fistula: A Surgeon's Nightmare! An Insight with a Detailed Literature Review. AB - CONTEXT: Postoperative fistula formation is an important complication following pancreatic resections. OBJECTIVE: A large volume of literature without uniform conclusions is available regarding various controversies about postoperative pancreatic fistulae. The term postoperative pancreatic fistula includes fistula resulting from any surgery involving pancreas, most commonly pancreaticoduodenectomy and distal pancreatectomy. In this review, we have tried to present a comprehensive account of postoperative pancreatic fistula with particular emphasis on important controversies clouding the subject. METHODS: We performed MEDLINE literature search for relevant articles using the key words pancreas, pancreatic cancer, pancreatectomy, pancreatoduodenectomy, Whipple's operation, postoperative, complications, fistula, management and treatment in various combinations with the Boolean operators AND, OR and NOT. CONCLUSIONS: Postoperative pancreatic fistula is a troublesome complication of pancreaticoduodenectomy. Although the risk factors for postoperative pancreatic fistula have been extensively described, none of the methods recommended for preventing postoperative pancreatic fistula have been conclusively proved to be effective. While endoscopic treatment and percutaneous treatment form important aspects of treatment of postoperative pancreatic fistula, surgery may be required for select cases. PMID- 25791545 TI - Necrotizing pancreatitis: a review of multidisciplinary management. AB - The objective of this review is to summarize the current state of the art of the management of necrotizing pancreatitis, and to clarify some confusing points regarding the terminology and diagnosis of necrotizing pancreatitis, as these points are essential for management decisions and communication between providers and within the literature. Acute pancreatitis varies widely in its clinical presentation. Despite the publication of the Atlanta guidelines, misuse of pancreatitis terminology continues in the literature and in clinical practice, especially regarding the local complications associated with severe acute pancreatitis. Necrotizing pancreatitis is a manifestation of severe acute pancreatitis associated with significant morbidity and mortality. Diagnosis is aided by pancreas-protocol computed tomography or magnetic resonance imaging, ideally 72 h after onset of symptoms to achieve the most accurate characterization of pancreatic necrosis. The extent of necrosis correlates well with the incidence of infected necrosis, organ failure, need for debridement, and morbidity and mortality. Having established the diagnosis of pancreatic necrosis, goals of appropriately aggressive resuscitation should be established and adhered to in a multidisciplinary approach, ideally at a high-volume pancreatic center. The role of antibiotics is determined by the presence of infected necrosis. Early enteral feeds improve outcomes compared with parenteral nutrition. Pancreatic necrosis is associated with a multitude of complications which can lead to long term morbidity or mortality. Interventional therapy should be guided by available resources and the principle of a minimally invasive approach. When open debridement is necessary, it should be delayed at least 3-6 weeks to allow demarcation of necrotic from viable tissue. PMID- 25791546 TI - Crohn's disease and acute pancreatitis. A review of literature. AB - Crohn's disease, a transmural inflammatory bowel disease, has many well-known extra-intestinal manifestations and complications. Although acute pancreatitis has a higher incidence in patients with Crohn's disease as compared to the general population, acute pancreatitis is still relatively uncommon in patients with Crohn's disease. Patients with Crohn's disease are at an approximately fourfold higher risk than the general population to develop acute pancreatitis. The risk of developing acute pancreatitis is higher in females as compared to males. Acute pancreatitis can occur at any age with higher incidence reported in patients in their 20s and between 40-50 years of age. The severity and prognosis of acute pancreatitis in patients with Crohn's disease is the same as in general population. Acute pancreatitis can occur before onset of intestinal Crohn's disease, this presentation being more common in children than adults. It can also occur as the presenting symptom. However, most commonly it occurs after intestinal symptoms have manifest with a mean time interval between the initial presentation and development of acute pancreatitis being 2 years. There are several etiological factors contributing to acute pancreatitis in patients with Crohn's disease. It is not clear whether acute pancreatitis is a direct extra intestinal manifestation of Crohn's disease; however, majority of the cases of acute pancreatitis in patients with Crohn's disease are due to GS and medications. Drugs used for the treatment of Crohn's disease that have been reported to cause acute pancreatitis include 5-ASA agents, azathioprine and 6 mercaptopurine, metornidazole and corticosteroids. Recent evidence has emerged correlating both type 1 and 2 autoimmune pancreatitis with Crohn's disease. Understanding the association between the two disease entities is key to effectively manage patients with Crohn's disease and acute pancreatitis. PMID- 25791547 TI - The role of molecular analysis in the diagnosis and surveillance of pancreatic cystic neoplasms. AB - CONTEXT: Molecular analysis of pancreatic cyst fluid obtained by EUS-FNA may increase diagnostic accuracy. We evaluated the utility of cyst-fluid molecular analysis, including mutational analysis of K-ras, loss of heterozygosity (LOH) at tumor suppressor loci, and DNA content in the diagnoses and surveillance of pancreatic cysts. METHODS: We retrospectively reviewed the Columbia University Pancreas Center database for all patients who underwent EUS/FNA for the evaluation of pancreatic cystic lesions followed by surgical resection or surveillance between 2006-2011. We compared accuracy of molecular analysis for mucinous etiology and malignant behavior to cyst-fluid CEA and cytology and surgical pathology in resected tumors. We recorded changes in molecular features over serial encounters in tumors under surveillance. Differences across groups were compared using Student's t or the Mann-Whitney U test for continuous variables and the Fisher's exact test for binary variables. RESULTS: Among 40 resected cysts with intermediate-risk features, molecular characteristics increased the diagnostic yield of EUS-FNA (n=11) but identified mucinous cysts less accurately than cyst fluid CEA (P=0.21 vs. 0.03). The combination of a K-ras mutation and >=2 loss of heterozygosity was highly specific (96%) but insensitive for malignant behavior (50%). Initial data on surveillance (n=16) suggests that molecular changes occur frequently, and do not correlate with changes in cyst size, morphology, or CEA. CONCLUSIONS: In intermediate-risk pancreatic cysts, the presence of a K-ras mutation or loss of heterozygosity suggests mucinous etiology. K-ras mutation plus >=2 loss of heterozygosity is strongly associated with malignancy, but sensitivity is low; while the presence of these mutations may be helpful, negative findings are uninformative. Molecular changes are observed in the course of cyst surveillance, which may be significant in long term follow-up. PMID- 25791548 TI - Ultrasound-assisted focused open necrosectomy in the treatment of necrotizing pancreatitis. AB - CONTEXT: The surgical treatment of necrotizing pancreatitis includes percutaneous drainage of acute necrotic collections and sequestrectomy in the late phase of the disease. OBJECTIVE: The aim of the study was to compare the conventional open necrosectomy (CON) approach with the alternative focused open necrosectomy (FON) approach in patients with infected necrosis and progression of sepsis. METHODS: Patients with acute necrotizing pancreatitis were included in the study prospectively from January 2004 to July 2014. All patients had been admitted with the first or a new episode of disease. Symptomatic large fluid collections were drained percutaneously. The step-up approach was used in patients with several distant localizations of infected necrosis. The methods were analysed by comparing the individual severity according to the ASA, APACHE II and SOFA scores, infection rate, postoperative complication rate and mortality. RESULTS: A total of 31 patients were included in the FON group and 39 in the CON group. The incidence of infection was similar in groups. More ASA III comorbid conditions, a higher APACHE II score, a more frequent need for renal replacement therapy was observed in the CON group. The postoperative complication rate was in the range of 32% to 44%; mortality reached 6.5% in the FON group and 12.8% in the CON group. CONCLUSIONS: Comorbid conditions, organ failure, and infection are the main risk factors in patients with necrotizing pancreatitis. The step-up approach and perioperative ultrasonography navigation improves the clinical outcome and reduces the extent of invasive surgical intervention in patients unsuited to other minimally invasive procedures. PMID- 25791549 TI - Long-term outcomes after acute necrotizing pancreatitis: what happens to the pancreas and to the patient? AB - CONTEXT: Late consequences of acute pancreatitis have received little attention. It is controversial whether the pancreas fully recovers after an episode of acute pancreatitis, especially in the presence of necrosis. Therefore, the presence of late pancreatic dysfunction following acute necrotizing pancreatitis is uncertain and there are controversies about how it may affect long-term quality of life. OBJECTIVES: To evaluate pancreatic function and morphology, besides quality of life, in patients with prior acute necrotizing pancreatitis. PATIENTS: Patients who were admitted to our hospital with acute necrotizing pancreatitis in a ten year interval were identified and thirty-eight survivors were contacted to enroll in the study out of which sixteen patients were included. METHODS: Exocrine function was studied by qualitative fecal fat excretion. Endocrine function was evaluated by oral glucose tolerance test, HOMA-beta and C-peptide. Pancreatic morphology was examined by computed tomography. Quality of life was measured by 36-item short-form health survey. Tests were performed at least twelve months after the index episode of acute necrotizing pancreatitis. RESULTS: The prevalence of pancreatic exocrine insufficiency was 6.2%. Endocrine dysfunction was observed in half the cases, and no association with the extension of necrosis was found. Morphological changes were frequent (62.5%) and more prevalent in those who faced extensive necrosis. Quality of life was considered good, and its impairment was found exclusively in mental health domain, markedly in patients who had alcoholic pancreatitis. There was no correlation between quality of life and prognostic indicators. CONCLUSIONS: Exocrine function and quality of life were preserved in this group of patients. However, endocrine dysfunction and morphological abnormalities were frequent after acute necrotizing pancreatitis. These findings justify a long-term follow-up in order to initiate specific treatment promptly. PMID- 25791550 TI - Effect of Unripe Plantain (Musa paradisiaca) and Ginger (Zingiber officinale) on Renal Dysfunction in Streptozotocin-Induced Diabetic Rats. AB - CONTEXT: Although unripe plantain (Musa paradisiaca) and ginger (Zingiber officinale) are used as single plants to manage diabetes mellitus in Nigeria, the possibility of combining them in a typical diabetic diet and the glycemic response elicited as a result of such combination has not been investigated. OBJECTIVE: To determine the effect of unripe plantain and ginger on serum total proteins, albumin, creatinine and urea levels of streptozotocin induced diabetic rats. METHODS: Twenty four male albino rats were used and were divided into 4 groups of 6 rats each. Group 1 (non-diabetic) received standard rat feeds; Group 2 (diabetic) received standard rat feeds; Group 3 received unripe plantain pellets and Group 4 received unripe plantain+ginger pellets. RESULTS: There were significant increases (P=0.045) of both serum urea and creatinine, but significant decreases (P=0.045) of both serum total protein and albumin levels, in Group 2 rats compared with Group 1. There were significant decreases (P=0.033) of both serum urea and creatinine levels of Group 3 and 4 rats compared with Group 2. In addition, there were significant increases of both serum total protein and albumin levels (P=0.033) in Group 3 rats compared with Group 2, but the comparison of serum total protein and albumin levels between Group 4 and Group 2 did not reach the significant level (P=0.056 and P=0.065 for serum total protein and albumin levels, respectively. CONCLUSION: Combination of unripe plantain and ginger at the ratio used in the management of renal dysfunction in diabetics was not very effective compared with unripe plantain alone. PMID- 25791551 TI - Does etiology of acute pancreatitis matter? A review of 391 consecutive episodes. AB - CONTEXT: Acute pancreatitis can be triggered by a variety of factors ranging from short lasting to sustained disruptions. It is plausible that the characteristics and course of disease differ among etiologies. Data distinguishing characteristics of patients with pancreatitis of biliary, alcoholic, idiopathic or other origin are scarce and conflicting. OBJECTIVE: To compare patients' characteristics, baseline parameters on admission, and outcome in patients with an episode of acute pancreatitis in whom the etiology was thoroughly determined. DESIGN: Retrospective study. SETTING: Single center. PATIENTS: Three-hundreds and 91 consecutive episodes of acute pancreatitis through the years 2008 to 2011. MAIN OUTCOME MEASURES: Gender, age, body mass index, Charlson comorbidity index, history of pancreatitis, heart rate, blood pressure, plasma lipase, hematocrit, plasma creatinine, white blood cell count, rate of persistent organ failure and necrosis, maximum C-reactive protein, duration of hospitalization, mortality. RESULTS: There were marked differences between the groups. Biliary etiology was associated with higher age and body weight, female predominance, higher plasma lipase, and a favourable outcome. Alcoholic etiology had male predominance, a tendency for initial hemoconcentration, a lower plasma lipase, and the highest rate of necrosis. Idiopathic etiology had the highest rate of persistent organ failure and the highest mortality. CONCLUSIONS: Biliary, alcoholic and idiopathic acute pancreatitis should be treated as distinct entities. While alcoholic episodes have the highest risk of necrosis, the worst outcome was observed in the idiopathic group. Hence, finding no causality for an episode of acute pancreatitis after thorough investigation might be a predictor for poor outcome. Larger studies are warranted to confirm this. PMID- 25791552 TI - Lazaroid U-74389G Administration in Pancreatic Ischemia-Reperfusion Injury: A Swine Model Encompassing Ischemic Preconditioning. AB - CONTEXT: The potential of lazaroid U-74389G in attenuating injury after ischemia and reperfusion has been reported in various organs. OBJECTIVE: The present study focuses specifically on the pancreas and aims to examine any effects of U-74389G in a swine model of pancreatic ischemia and reperfusion, encompassing ischemic preconditioning. METHODS: Twelve pigs, weighing 28-35 kg, were randomized into two experimental groups. Group A (control group, n=6): Two periods of ischemic preconditioning (5 min each) separated by a 5-min rest interval; then ischemia time 30 min and reperfusion for 120 min. Group B (n=6): the same as above, with U 74389G intravenous injection in the inferior vena cava immediately prior to the initiation of reperfusion. Blood sampling and pancreatic biopsies were conducted at 0, 30, 60, 90 and 120 min after reperfusion. RESULTS: Repeated-measures ANOVA was undertaken to evaluate differences between the two study groups. No statistically significant differences were noted concerning the histopathological parameters in the control and therapy groups (P=0.563 for edema, P=0.241 for hemorrhage, P=0.256 for leukocyte infiltration, P=0.231 for acinar necrosis and P=0.438 for vacuolization). In accordance with the above, serum metabolic data (glucose, creatinine, urea, total and direct bilirubin, total calcium, amylase, lipase, SGOT/AST, SGPT/ALT, ALP, GGT, LDH, CRP, insulin) were not significantly different between the two groups; similarly, tumor necrosis factor-alpha values (P=0.705) and tissue malondialdehyde levels (P=0.628) did not differ between the two groups. CONCLUSION: This swine model of pancreatic ischemia and reperfusion, encompassing preconditioning, indicates that U-74389G lazaroid does not seem to exert protective effects from pancreatic damage. PMID- 25791553 TI - Small bowel perforation caused by pancreaticojejunal anastomotic stent migration after pancreaticoduodenectomy for periampullary carcinoma. AB - CONTEXT: Pancreaticoduodenectomy is the gold standard for patients with resectable periampullary carcinoma. The protection of the anastomosis by positioning of an intraluminal stent is a technique used to lower the frequency of anastomotic fistulas. However the use of anastomotic stents is still debated and stent related complications are reported. CASE REPORT: A fifty-three-year old male underwent pancreaticoduodenectomy (PD) for a T2N0 periampullary carcinoma with a pancreaticojejunal (duct to mucosa) anastomosis protected by a free floating 6 Fr Nelaton stent in the Wirsung duct. Twenty-three months after surgery the patient accessed Emergency Department for severe abdominal pain associated to temperature, high white blood cell count and an significant increase in C reactive protein. Method Abdominal CT scan shown the presence of a tubular stent in the mesogastrium/lower right quadrant. No evident free intra abdominal air was detected. The patient was submitted to explorative laparotomy. After debridement for localized peritonitis the Nelaton trans anastomotic stent was found in the abdomen. There was no evidence of bowel perforation, but intestinal loops covered with fibrin and suspect for impending perforation were resected. CONCLUSION: There is a lack of evidence about the true rate of post operative complications related to pancreatic stenting. We believe that in patients presenting with abdominal pain or peritonitis that previously underwent PD with stent-guided pancreaticojejunal anastomosis, the hypothesis of stent migration should at least be taken into consideration. PMID- 25791554 TI - A triad of complete dorsal pancreatic agenesis, pancake kidney and bicornuate uterus. An association or an incidental finding: first case in literature. AB - CONTEXT: Agenesis of the dorsal pancreas is a rare congenital anomaly which can be detected either incidentally during imaging or encountered during investigation for pancreas related pathologies such as pancreatitis or diabetes mellitus. Few associations of this condition with heterotaxy syndrome, pancreatic tumors and congenital heart disease have been described. CASE REPORT: We report a novel association of genitourinary anomalies in a case of complete dorsal pancreatic agenesis not previously described in the literature. CONCLUSION: Knowledge about dorsal pancreatic agenesis is essential for radiologist in patients presenting with unexplained pain abdomen and its association with various conditions may help radiologist in assisting clinician in management of these patients. PMID- 25791555 TI - Acute pancreatitis as initial presentation of cocaine-induced vasculitis: a case report. AB - CONTEXT: Levamisole-contaminated cocaine is an increasingly reported cause of vasculitis and immunologic abnormalities in cocaine abusers. The systemic effects of vasculitis are commonly seen in the dermatologic, hematologic and renal systems but rarely the gastrointestinal system. CASE REPORT: We present an atypical case of cocaine-induced vasculitis presenting initially as an acute pancreatitis and then rapidly progressing to involve multi-organ systems over the next couple of weeks. CONCLUSION: Internists should recognize that acute pancreatitis can present as an atypical and rare initial systemic manifestation of cocaine-induced vasculitis. PMID- 25791556 TI - Atypical presentation of disseminated intravascular coagulation with synchronous peripheral venous thromboembolism and arterial gangrene in a pancreatic cancer patient: a case report. AB - CONTEXT: Cancer is a prothrombotic state and anticancer therapies are often complicated by vascular events. The risk of developing thromboembolic events is substantially increased in patients with pancreatic cancer. One possible presentation of vascular events in pancreatic cancer is disseminated intravascular coagulation (DIC). CASE REPORT: In our case a patient with a diagnosis of pancreatic cancer initially presented with thrombosis and received low molecular weight heparin (LMWH) in addition to standard chemotherapy regimen. He was thought to have DIC by assessment of clinical and laboratory findings. CONCLUSION: Clinically, thrombosis was first located in the left femoral vein and encountered at right femoral artery after three weeks. This pattern was an unusual presentation of DIC. Subclinical DIC is common in patients presenting with pancreatic cancer and is considered a 'poor' prognostic factor. Acute DIC, on the other hand is a potentially mortal condition. PMID- 25791557 TI - Reconstructive strategy after pancreaticoduodenectomy in partially gastrectomized patients. AB - CONTEXT: Pancreaticoduodenectomy in partially-gastrectomized patients presents some peculiarities of the reconstructive phase. Above all, in B II and Roux-en-Y partial gastrectomies, a gastric re-resection with a redo gastrojejunal anastomosis should be avoided because it is often needlessly time-consuming and risky. In our series of 7 consecutive patients, either one of two reconstruction methods was used, depending upon the length of the pre-existing afferent loop. CASE REPORTS: In order to better illustrate this strategy, two cases of carcinoma of the duodenal papilla are reported. Both of the patients had previously undergone partial gastrectomy with B II reconstruction for peptic ulcers. Both were admitted to our hospital with a past history of jaundice. However, whereas in Case #2 a sufficiently long pre-existent afferent loop could be utilized for the pancreatic and bile duct anastomoses, in Case #1 a shorter afferent loop was removed and the efferent loop was utilized for the anastomoses. The postoperative course was uneventful in both patients. CONCLUSIONS: This reconstructive strategy for pancreaticoduodenectomy in gastrectomized patients, which uses either of the methods described above, has produced good results in our series of 7 patients and appears to be rational and straightforward. PMID- 25791558 TI - Acute pancreatitis secondary to diabetic ketoacidosis induced hypertriglyceridemia in a young adult with undiagnosed type 2 diabetes. AB - CONTEXT: The triad of acute pancreatitis, hypertriglyceridemia and diabetes is a rare occurrence. CASE REPORT: A previously well 19-year-old male presented to the emergency department with 24-hour history of epigastric pain, associated with polyuria and nausea. Biochemical markers showed the presence of hyperglycemia (blood sugar level 15 mmol/L) and ketonemia (5.3 mmol/L). Further investigation revealed severe hypertriglyceridemia (4,009 mg/dL) and elevated lipase (1,714 U/L). Abdominal ultrasound confirmed the diagnosis of acute pancreatitis. He was transferred to intensive care, where he received i.v. hydration, insulin and dextrose infusion. His metabolic derangements gradually resolved. His glycosylated hemoglobin was 13%, indicating the presence of chronically elevated blood sugars. CONCLUSION: The possible pathophysiology and management of this unusual triad: diabetic ketoacidosis, hypertriglyceridemia and acute pancreatitis, are explored in this paper. PMID- 25791559 TI - Seventy-two Cycles of FOLFIRINOX: Long Term Treatment in a Patient with Metastatic Adenocarcinoma of the Pancreatic Tail. AB - CONTEXT: Pancreatic adenocarcinoma is one of the most lethal malignancies worldwide. In patients with unresectable tumor there are several strategies of palliative chemotherapy, either gemcitabine based regimens or FOLFIRINOX, which is supposed to be most efficient but also most toxic. Hence, management of toxicity is crucial to perform a therapy consisting of FOLFIRINOX. CASE REPORT: We report on a 69-year-old female patient suffering from adenocarcinoma of the pancreatic tail with multiple liver metastases. Palliative chemotherapy comprising leucovorin, fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) was initiated in February 2011 and was tolerated very well. Subsequent computed tomography-scans showed significant reduction of the tumor load in the liver as well as in the primary pancreatic tumor. The serum levels of the tumor marker CA 19-9 were elevated initially and decreased concomitantly. Thus, chemotherapy was continued for more than 3 years, and up to 72 cycles were administered until April 2014. Due to intermittent neutropenia and mucositis the initial dose was reduced to 60% of the calculated standard dose. In April 2014, an intermediate staging by computed tomography and FDG-PET revealed significant reduction of the size of the primary pancreatic tumor compared with February 2011. Liver metastases could hardly be detected anymore. After pausing chemotherapy for 12 weeks, one liver metastasis reappeared and was treated by RFA in August 2014. Meanwhile, in October 2014 there is no radiological evidence on any existing tumor or metastasis. CONCLUSION: Our report demonstrates that a sufficient tolerance of chemotherapy with FOLFIRINOX is achievable, what makes a long term treatment with FOLFIRINOX feasible and can lead to impressive results. PMID- 25791560 TI - Undifferentiated (spindle cell) pancreatic carcinoma: a case report with osteochondroid differentiation. AB - CONTEXT: Undifferentiated (spindle cell) carcinomas of the pancreas are rare anaplastic variants of pancreatic ductal adenocarcinoma with a frequency of 2% of pancreatic exocrine tumors. Their clinicopathological features are limited and obtained by few previously case reports. We report a case of undifferentiated pancreatic carcinoma with a rare focal osteochondroid differentiation. CASE REPORT: A sixty-six-year-old woman was admitted to our hospital for abdominal pain and nonspecific nausea for almost 40 days. Imaging studies revealed a well defined cystic-solid mass with heterogeneous density involving the tail of the pancreas. We performed an en bloc distal pancreatectomy with splenectomy for radical excision, as well as regional lymphadenectomy. The resected specimen revealed a 4.0*5.0 cm exophytic clear-bordered neoplasm of the tail of the pancreas containing necrotic and calcified areas, without splenic invasion. The lymph node involvement was not detected (0/5) and the surgical margins were negative. Microscopy showed pleomorphism with giant cells, spindle-shaped cells with anaplasia, and osteochondroid differentiation. A diagnosis of undifferentiated (spindle cell) carcinoma of the pancreas with focal osteochondroid differentiation was made. The patient declined chemotherapy and extended lymphadenectomy. She suffered from liver and lymph nodes metastasis 9 months after surgery, and she subsequently died 4 months later due to high tumor burden. CONCLUSIONS: Undifferentiated pancreatic carcinoma with osteochondroid differentiation is rare but associated with extremely poor prognosis. It should be included in the differential diagnosis of pancreatic mass lesions. PMID- 25791561 TI - Comments on "risk factors associated with recurrence in patients with solid pseudopapillary tumors of the pancreas". PMID- 25791562 TI - Acute pancreatitis induced fluid collections - the naming game. PMID- 25791563 TI - Reply to "comments on the article: management of suspected acute inflammatory pancreatopathies in a "real-world" setting - a single-centre observational study". PMID- 25791564 TI - IgG4-Related Disease. PMID- 25791565 TI - Ablative Intravesical Chemotherapy for Small Recurrent Non-Muscle-Invasive Bladder Cancer: A Prospective Study. AB - OBJECTIVE: The efficacy of intravesical chemotherapy in abolishing small papillary recurrences of non-muscle-invasive bladder cancer (NMIBC), the disease free interval in responders and patients' preferences were explored. METHODS: When a small (<=1 cm) papillary recurrence of a NMIBC was diagnosed, the patient could choose between immediate transurethral resection of the bladder (TURB) or four weekly intravesical instillations with mitomycin C (MMC) or epirubicin (ERC). Control cystoscopy was scheduled 2-3 weeks after the last instillation. Complete remission was defined as total disappearance of all papillary tumours and negative cytology. RESULTS: 25 patients with 47 recurrence episodes were recruited from February 2003 until August 2011. The median follow-up was 35 months. After exclusion of 2 patients with intolerance to the instillations, 45 study episodes could be analysed. All patients to whom this was proposed preferred the instillations over immediate TURB. Complete, partial and no response was seen in 23 (51%), 6 (13%) and 16 (36%) out of 45 episodes, respectively. The median disease-free interval after complete remission was 16 months (95% confidence interval 9-24). CONCLUSIONS: Small papillary recurrences of NMIBC completely disappear in about half of the cases receiving four weekly bladder instillations with MMC or ERC. This is followed by a disease-free interval. Intravesical chemotherapy was preferred by all patients over immediate TURB. PMID- 25791566 TI - Elevated STMN1 Expression Correlates with Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma. AB - STMN1 is a cytosolic phosphoprotein that not only participates in cell division, but also plays an important role in other microtubule-dependent processes, such as cell motility. Furthermore, STMN1 acts as a "relay protein" in several intracellular signaling pathways that influence cell growth and differentiation. Thus, STMN1 is likely to support cellular processes essential for tumor progression: survival and migration. Indeed, elevated STMN1 expression has been reported in various types of human malignancies and is correlated with poor prognosis in these human malignancies. However, the clinical and prognostic significance of STMN1 in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, we assessed STMN1 in PDAC in this retrospective study. We first examined STMN1 expression in PDAC tissues from 27 cases and matched adjacent non-cancerous tissues by quantitative polymerase chain reaction (PCR) and western blot analyses. Next, immunohistochemistry was used to evaluate STMN1 expression in 87 archived paraffin-embedded PDAC specimens. STMN1 mRNA and protein expression levels were to a large extent up-regulated in PDAC tissue compared with their adjacent non-cancerous tissues. Moreover, STMN1 expression was closely correlated with histological differentiation, lymphatic metastasis, and TNM stage (P = 0.023, 0.047, and 0.014, respectively). In addition, PDAC patients with higher STMN1 expression died sooner than those with lower STMN1 expression (P < 0.01). Multivariate analysis demonstrated that STMN1 expression was an independent prognostic factor for PDAC patients (P < 0.01). Herein, we provide the first evidence that up-regulated STMN1 may contribute to tumor progression and poor prognosis in PDAC patients and may serve as a novel prognostic marker. PMID- 25791567 TI - A bibliometric analysis of global Ebola research. PMID- 25791568 TI - Differentiating benign and malignant salivary gland tumours: diagnostic criteria and the accuracy of dynamic contrast-enhanced MRI with high temporal resolution. AB - OBJECTIVE: To determine the optimal diagnostic criterion of dynamic contrast enhanced MRI (DCE-MRI) for predicting salivary gland malignancy using a dynamic sequence with high temporal resolution, as well as the accuracy of this technique. METHODS: The DCE-MRI findings of 98 salivary gland tumours (74 benign and 24 malignant) were reviewed. MR images were sequentially obtained at 5-s intervals for 370 s. Two parameters, peak time and washout ratio (WR) were determined from the time-signal intensity curve. The optimal thresholds of these parameters for differentiating benign and malignant tumours were determined, along with the diagnostic accuracy of the criterion using these thresholds. RESULTS: A peak time of 150 s and a WR of 30% were identified as optimal thresholds. As the criterion for malignancy, the combination of peak time <150 s and WR <30% provided a sensitivity of 79% (19/24), specificity of 95% (70/74) and an overall accuracy of 91% (89/98). Three of the five false-negative cases were malignant lymphomas of the parotid gland. CONCLUSION: Peak time <150 s with WR <30% comprised the optimal diagnostic criterion in predicting salivary gland malignancy, providing a sensitivity of 79% and specificity of 95%. The use of high temporal resolution might improve the accuracy of DCE-MRI. ADVANCES IN KNOWLEDGE: Although several studies have reported the usefulness of DCE-MRI in the differential diagnosis of salivary gland tumours, the specific diagnostic criteria employed have differed widely. We determined the optimal criterion and its accuracy using a dynamic sequence with high temporal resolution. PMID- 25791570 TI - Effects of Collagen Crosslinking on Bone Material Properties in Health and Disease. AB - Data have accumulated to show that various types of collagen crosslinking are implicated in the health of individuals, as well as in a number of disease states, such as osteoporosis, diabetes mellitus, chronic kidney disease, inflammatory bowel disease, or in conditions of mild hyperhomocysteinemia, or when glucocorticoid use is indicated. Collagen crosslinking is a posttranslational modification of collagen molecules and plays important roles in tissue differentiation and in the mechanical properties of collagenous tissue. The crosslinking of collagen in the body can form via two mechanisms: one is enzymatic crosslinking and the other is nonenzymatic crosslinking. Lysyl hydroxylases and lysyl oxidases regulate tissue-specific crosslinking patterns and quantities. Enzymatic crosslinks initially form via immature divalent crosslinking, and a portion of them convert into mature trivalent forms such as pyridinoline and pyrrole crosslinks. Nonenzymatic crosslinks form as a result of reactions which create advanced glycation end products (AGEs), such as pentosidine and glucosepane. These types of crosslinks differ in terms of their mechanisms of formation and function. Impaired enzymatic crosslinking and/or an increase of AGEs have been proposed as a major cause of bone fragility associated with aging and numerous disease states. This review focuses on the effects of collagen crosslinking on bone material properties in health and disease. PMID- 25791569 TI - Validation of a dose warping algorithm using clinically realistic scenarios. AB - OBJECTIVE: Dose warping following deformable image registration (DIR) has been proposed for interfractional dose accumulation. Robust evaluation workflows are vital to clinically implement such procedures. This study demonstrates such a workflow and quantifies the accuracy of a commercial DIR algorithm for this purpose under clinically realistic scenarios. METHODS: 12 head and neck (H&N) patient data sets were used for this retrospective study. For each case, four clinically relevant anatomical changes have been manually generated. Dose distributions were then calculated on each artificially deformed image and warped back to the original anatomy following DIR by a commercial algorithm. Spatial registration was evaluated by quantitative comparison of the original and warped structure sets, using conformity index and mean distance to conformity (MDC) metrics. Dosimetric evaluation was performed by quantitative comparison of the dose-volume histograms generated for the calculated and warped dose distributions, which should be identical for the ideal "perfect" registration of mass-conserving deformations. RESULTS: Spatial registration of the artificially deformed image back to the planning CT was accurate (MDC range of 1-2 voxels or 1.2-2.4 mm). Dosimetric discrepancies introduced by the DIR were low (0.02 +/- 0.03 Gy per fraction in clinically relevant dose metrics) with no statistically significant difference found (Wilcoxon test, 0.6 >= p >= 0.2). CONCLUSION: The reliability of CT-to-CT DIR-based dose warping and image registration was demonstrated for a commercial algorithm with H&N patient data. ADVANCES IN KNOWLEDGE: This study demonstrates a workflow for validation of dose warping following DIR that could assist physicists and physicians in quantifying the uncertainties associated with dose accumulation in clinical scenarios. PMID- 25791571 TI - Prevalence and pattern of radiographic intervertebral disc degeneration in Vietnamese: a population-based study. AB - Intervertebral disc degeneration (IDD) is one of the most common skeletal disorders, yet few data are available in Asian populations. We sought to assess the prevalence and pattern of radiographic IDD in a Vietnamese population. This population-based cross-sectional investigation involved 170 men and 488 women aged >=40 years, who were randomly sampled from the Ho Chi Minh City (Vietnam). Anthropometric data, clinical history and self-reported back and neck pain were ascertained by a questionnaire. Plain radiographs (from the cervical spine, thoracic spine to the lumbar spine) were examined for the presence of disc space narrowing and/or osteophytosis using the Kellgren-Lawrence (KL) grading system. The presence of radiographic IDD was defined if the KL grade was 2 or greater in at least one disc. The prevalence of radiographic IDD was 62.4% (n = 106) in men and 54.7% (n = 267) in women. The most frequently affected site was the lumbar spine with prevalence being 50.6 and 43.2% in men and women, respectively. The prevalence of IDD increased with advancing age: 18.8% among those aged 40-49 years, and increased to 83.4% in those aged >=60 years. Self-reported neck pain and lower back pain were found in 30 and 44% of individuals, respectively. There was no statistically significant association between self-reported neck pain and cervical spine OA. These data suggest that radiographic IDD is highly prevalent in the Vietnamese population, and that self-reported back pain is not a sensitive indicator of IDD. PMID- 25791572 TI - Fibrillar organic phases and their roles in rigid biological composites. AB - This study focused on determining the presence of organic phases in the siliceous components of rigid marine composites ("glass" sponge spicules), and thereby clarifying how such composites dissipate significant mechanical energy. Through the use of imaging by helium ion microscopy in the examination of the spicules, the organic phase that is present between the layers of hydrated silica was also detected within the silica cylinders of the composite, indicating the existence therein of a network, scaffolding, or other pattern that has not yet been determined. It was concluded that the presence of an interpenetrating network of some kind, and tenacious fibrillar interfaces are responsible for large energy dissipation in these siliceous composites by viscoelastic and other mechanical deformation processes. This discovery means that future mechanics analyses of large deformation behavior of such natural rigid composites (that may also include teeth and bones) should be based on the presence of interpenetrating phases. PMID- 25791573 TI - Elevated levels of perfluoroalkyl acids in family members of occupationally exposed workers: the importance of dust transfer. AB - The exposure pathways of perfluoroalkyl acids (PFAAs) to humans are still not clear because of the complex living environment, and few studies have simultaneously investigated the bioaccumulative behaviour of different PFAAs in humans. In this study, serum, dust, duplicate diet, and other matrices were collected around a manufacturing plant in China, and homologous series of PFAAs were analysed. PFAA levels in dust and serum of local residents in this area were considerably higher than those in non-polluted area. Although dietary intake was the major exposure pathway in the present study, dust ingestion played an important role in this case. Serum PFAAs in local residents was significantly correlated with dust PFAAs levels in their living or working microenvironment. Serum PFAAs and dust PFAAs were significantly higher in family members of occupational workers (FM) than in ordinary residents (OR) (p < 0.01). After a careful analysis of the PFAAs exposure pathway, a potential pathway in addition to direct dust ingestion was suggested: PFAAs might transferred from occupational worker's clothes to dinners via cooking processes. The bioaccumulative potential of PFHxS and PFOS were higher than other PFAAs, which suggested a substantial difference between the bioaccumulative ability of perfluorinated sulfonic acids and perfluorinated carboxylic acids. PMID- 25791574 TI - Humidity-enhanced wet adhesion on insect-inspired fibrillar adhesive pads. AB - Many insect species reversibly adhere to surfaces by combining contact splitting (contact formation via fibrillar contact elements) and wet adhesion (supply of liquid secretion via pores in the insects' feet). Here, we fabricate insect inspired fibrillar pads for wet adhesion containing continuous pore systems through which liquid is supplied to the contact interfaces. Synergistic interaction of capillarity and humidity-induced pad softening increases the pull off force and the work of adhesion by two orders of magnitude. This increase and the independence of pull-off force on the applied load are caused by the capillarity-supported formation of solid-solid contact between pad and the surface. Solid-solid contact dominates adhesion at high humidity and capillarity at low humidity. At low humidity, the work of adhesion strongly depends on the amount of liquid deposited on the surface and, therefore, on contact duration. These results may pave the way for the design of insect-inspired adhesive pads. PMID- 25791575 TI - Normal development of human brain white matter from infancy to early adulthood: a diffusion tensor imaging study. AB - Diffusion tensor imaging (DTI), which measures the magnitude of anisotropy of water diffusion in white matter, has recently been used to visualize and quantify parameters of neural tracts connecting brain regions. In order to investigate the developmental changes and sex and hemispheric differences of neural fibers in normal white matter, we used DTI to examine 52 healthy humans ranging in age from 2 months to 25 years. We extracted the following tracts of interest (TOIs) using the region of interest method: the corpus callosum (CC), cingulum hippocampus (CGH), inferior longitudinal fasciculus (ILF), and superior longitudinal fasciculus (SLF). We measured fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD). Approximate values and changes in growth rates of all DTI parameters at each age were calculated and analyzed using LOESS (locally weighted scatterplot smoothing). We found that for all TOIs, FA increased with age, whereas ADC, AD and RD values decreased with age. The turning point of growth rates was at approximately 6 years. FA in the CC was greater than that in the SLF, ILF and CGH. Moreover, FA, ADC and AD of the splenium of the CC (sCC) were greater than in the genu of the CC (gCC), whereas the RD of the sCC was lower than the RD of the gCC. The FA of right-hemisphere TOIs was significantly greater than that of left-hemisphere TOIs. In infants, growth rates of both FA and RD were larger than those of AD. Our data show that developmental patterns differ by TOIs and myelination along with the development of white matter, which can be mainly expressed as an increase in FA together with a decrease in RD. These findings clarify the long-term normal developmental characteristics of white matter microstructure from infancy to early adulthood. PMID- 25791576 TI - Grene and Hull on types and typological thinking in biology. AB - Marjorie Grene (1910-2009) and David Hull (1935-2010) were among the most influential voices in late twentieth-century philosophy of biology. But, as Grene and Hull pointed out in published discussions of one another's work over the course of nearly forty years, they disagreed strongly on fundamental issues. Among these contested issues is the role of what is sometimes called "typology" and "typological thinking" in biology. In regard to taxonomy and the species problem, Hull joined Ernst Mayr's construal of typological thinking as a backward relic of pre-Darwinian science that should be overcome. Grene, however, treated the suspicion of typological thinking that characterized Hull's views, as well as those of other architects of the New Evolutionary Synthesis, as itself suspicious and even unsustainable. In this paper I review three debates between Grene and Hull bearing on the question of the validity of so-called typological thinking in biology: (1) a debate about the dispensability of concepts of "type" within evolutionary theory, paleontology, and taxonomy; (2) a debate about whether species can be adequately understood as individuals, and thereby independently of those forms of thinking Hull and Mayr had construed as "typological"; and (3) a debate about the prospects of a biologically informed theory of human nature. PMID- 25791578 TI - Prostate MRI can reduce overdiagnosis and overtreatment of prostate cancer. AB - The contemporary management of prostate cancer (PCa) has been criticized as fostering overdetection and overtreatment of indolent disease. In particular, the historical inability to identify those men with an elevated PSA who truly warrant biopsy, and, for those needing biopsy, to localize aggressive tumors within the prostate, has contributed to suboptimal diagnosis and treatment strategies. This article describes how modern multi-parametric MRI of the prostate addresses such challenges and reduces both overdiagnosis and overtreatment. The central role of diffusion-weighted imaging (DWI) in contributing to MRI's current impact is described. Prostate MRI incorporating DWI achieves higher sensitivity than standard systematic biopsy for intermediate-to-high risk tumor, while having lower sensitivity for low-grade tumors that are unlikely to impact longevity. Particular applications of prostate MRI that are explored include selection of a subset of men with clinical suspicion of PCa to undergo biopsy as well as reliable confirmation of only low-risk disease in active surveillance patients. Various challenges to redefining the standard of care to incorporate solely MRI targeted cores, without concomitant standard systematic cores, are identified. These include needs for further technical optimization of current systems for performing MRI-targeted biopsies, enhanced education and expertise in prostate MRI among radiologists, greater standardization in prostate MRI reporting across centers, and recognition of the roles of pre-biopsy MRI and MRI-targeted biopsy by payers. Ultimately, it is hoped that the medical community in the United States will embrace prostate MRI and MRI-targeted biopsy, allowing all patients with known or suspected prostate cancer to benefit from this approach. PMID- 25791577 TI - Role of transcription factors in the transdifferentiation of pancreatic islet cells. AB - The alpha and beta cells act in concert to maintain blood glucose. The alpha cells release glucagon in response to low levels of glucose to stimulate glycogenolysis in the liver. In contrast, beta cells release insulin in response to elevated levels of glucose to stimulate peripheral glucose disposal. Despite these opposing roles in glucose homeostasis, alpha and beta cells are derived from a common progenitor and share many proteins important for glucose sensing and hormone secretion. Results from recent work have underlined these similarities between the two cell types by revealing that beta-to-alpha as well as alpha-to-beta transdifferentiation can take place under certain experimental circumstances. These exciting findings highlight unexpected plasticity of adult islets and offer hope of novel therapeutic paths to replenish beta cells in diabetes. In this review, we focus on the transcription factor networks that establish and maintain pancreatic endocrine cell identity and how they may be perturbed to facilitate transdifferentiation. PMID- 25791579 TI - Cloning and expression of the xynA1 gene encoding a xylanase of the GH10 group in Caulobacter crescentus. AB - Caulobacter crescentus (NA1000 strain) are aquatic bacteria that can live in environments of low nutritional quality and present numerous genes that encode enzymes involved in plant cell wall deconstruction, including five genes for beta xylosidases (xynB1-xynB5) and three genes for xylanases (xynA1-xynA3). The overall activity of xylanases in the presence of different agro-industrial residues was evaluated, and it was found that the residues from the processing of corn were the most efficient in inducing bacterial xylanases. The xynA1 gene (CCNA_02894) encoding a predicted xylanase of group 10 of glyco-hydrolases (GH10) that was efficiently overexpressed in Escherichia coli LMG194 using 0.02 % arabinose, after cloning into the vector pJet1.2blunt and subcloning into the expression vector pBAD/gIII, provided a fusion protein that contained carboxy terminal His-tags, named XynA1. The characterization of pure XynA1 showed an enzymatic activity of 18.26 U mL(-1) and a specific activity of 2.22 U mg-(1) in the presence of xylan from beechwood as a substrate. XynA1 activity was inhibited by EDTA and metal ions such as Cu(2+) and Mg(2+). By contrast, beta mercaptoethanol, dithiothreitol (DTT), and Ca(2+) induced recombinant enzyme activity. Kinetic data for XynA1 revealed K M and V max values of 3.77 mg mL-(1) and 10.20 MUM min-(1), respectively. Finally, the enzyme presented an optimum pH of 6 and an optimum temperature of 50 degrees C. In addition, 80 % of the activity of XynA1 was maintained at 50 degrees C for 4 h of incubation, suggesting a thermal stability for the biotechnological processes. This work is the first study concerning the cloning, overexpression, and enzymatic characterization of C. crescentus xylanase. PMID- 25791580 TI - PLEC1 mutation associated with left ventricular hypertrabeculation/noncompaction. PMID- 25791581 TI - Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy. PMID- 25791582 TI - Microvascular inflammation and acute tubular necrosis are major histologic features of hantavirus nephropathy. AB - Hantavirus nephropathy (HVN) is an uncommon etiology of acute renal failure due to hantavirus infection. Pathological features suggestive of HVN historically reported are medullary interstitial hemorrhages in a background of acute interstitial nephritis (AIN). However, interstitial hemorrhages may be lacking because of medullary sampling error. This emphasizes that other pathological criteria may be of interest. We performed a retrospective clinicopathological study of 17 serologically proven HVN cases with renal biopsy from 2 nephrology centers in northern France. Histologic analysis was completed by immunohistochemistry with anti-CD3, anti-CD68, and anti-CD34 antibodies. Three control groups were not related to hantavirus infection: acute tubular necrosis (ATN) of ischemic or toxic etiology and AIN were used for comparison. Renal biopsy analysis showed that almost all HVN cases with medullary sampling (9/10) displayed interstitial hemorrhages, whereas focal hemorrhages were detected in 2 of the 7 "cortex-only" specimens. ATN was common, as it was present in 15 (88.2%) of 17 HVN cases. By contrast, interstitial inflammation was scarce with no inflammation or only slight inflammation, representing 15 (88.2%) of 17 cases. Moreover, HVN showed inflammation of renal microvessels with cortical peritubular capillaritis and medullary vasa recta inflammation; peritubular capillaritis was significantly higher in HVN after comparison with ischemic and toxic ATN controls (P = .0001 and P = .003, respectively), but not with AIN controls. Immunohistochemical studies highlighted the involvement of T cells and macrophages in renal microvascular inflammation related to HVN. Our study showed that microvascular inflammation, especially cortical peritubular capillaritis, and ATN are important histologic features of HVN. PMID- 25791583 TI - Somatic DICER1 gene mutation in sporadic intraocular medulloepithelioma without pleuropulmonary blastoma syndrome. AB - Germline DICER1 gene mutation has been described in ocular medulloepithelioma associated with pleuropulmonary blastoma family tumor and dysplasia syndrome. We present a case of sporadic ocular medulloepithelioma in an 18-year-old woman with D1709N somatic mutation in DICER1 gene, which has not been previously described. This case highlights the potential use of DICER1 gene sequencing to resolve the diagnostic challenge in recurrent and metastatic malignant medulloepithelioma, when morphology and immunohistochemistry are inconclusive. Further studies in larger series of this type of tumor are needed to confirm the relevance of this molecular abnormality in the tumorigenesis of this embryonic-type ocular tumor. PMID- 25791584 TI - Helicobacter pylori dupA and smoking are associated with increased levels of interleukin-8 in gastric mucosa in Iraq. PMID- 25791585 TI - Small non-coding RNAs: a quick look in the rearview mirror. AB - The revolution of miRNA discovery, in the early 2000s, shed a new light in the exciting field of small non-coding RNAs. Since then, and owing to outstanding breakthroughs in RNomic techniques, novel small non-coding RNA families have been regularly discovered, e.g., piRNAs, tiRNAs, and many others.In this review, we provide a very succinct historical and functional overview on most prominent small non-coding RNA families. PMID- 25791586 TI - Alcoholic precipitation of small non-coding RNAs. AB - Alcoholic precipitation is a critical step to recover RNA of high purity. This chapter describes the principles of alcoholic precipitation as well as a standard, basic protocol with key advices to observe, but numerous variations on the theme are discussed. Indeed, several important parameters, such as the choice of salt, alcohol, or carrier, have to be considered to improve the efficiency of precipitation and the yield of RNA recovery. PMID- 25791587 TI - Quantification and quality control of a small non-coding RNA preparation. AB - Recent advances in high-throughput sequencing have shed some new light on the diversity of small non-coding RNA (sncRNA) classes and their crucial role in gene regulation and diseases. RNA quantification and control of RNA integrity are two key steps in sncRNA profiling. In this chapter, we will describe different gold standard methods used to achieve both purposes before the use of the RNAs in downstream applications. PMID- 25791588 TI - Impact of RNA isolation protocols on RNA detection by Northern blotting. AB - We prepared total RNA from the Gram-positive soil bacterium Bacillus subtilis by different RNA extraction procedures to compare their suitability for Northern blot detection of tiny RNAs (~14-mers) or RNAs of intermediate size (100-200 nt) in terms of signal quality, intensity, and reproducibility. Our analysis included two hot phenol methods and two TRIzol extraction procedures. We found that signal intensity/detection sensitivity makes the key difference. Total RNAs prepared by the hot phenol method comprise the length spectrum from tRNAs to large ribosomal RNAs. Larger RNAs are less abundant in TRIzol preparations which instead enrich for RNAs of tRNA size and smaller. Thus, hot phenol methods are the choice for the detection of intermediate-sized and longer RNAs, whereas TRIzol extraction procedures are more suited for the detection of tiny RNAs. PMID- 25791589 TI - Improved Northern blot detection of small RNAs using EDC crosslinking and DNA/LNA probes. AB - Successful detection of very small RNAs (tiny RNA, ~14 nt in length) by Northern blotting is dependent on improved Northern blot protocols that combine chemical crosslinking of RNA with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) to positively charged membranes, the use of native polyacrylamide gels, and the development of highly sensitive and specific probes modified with locked nucleic acids (LNA). In this protocol, we show that Northern blot detection of tiny RNAs with 5'-digoxigenin-labeled DNA/LNA mixmer probes is a highly sensitive and specific method and, in our hands, more sensitive than using a corresponding DNA/LNA mixmer probe with a 5'-(32)P-end label. PMID- 25791590 TI - Direct cloning of double-stranded RNAs. AB - Most annotated genomes show a large number of sense-antisense transcripts that can generate double-stranded RNAs. We describe a method to clone these dsRNAs from total RNA preparations. PMID- 25791591 TI - Detection and labeling of small non-coding RNAs by splinted ligation. AB - Discovery and characterization of microRNAs (miRNAs) and other families of small RNAs lead researchers to study their structures/functions and their expression patterns. The splinted ligation method described here is based on nucleic acid hybridization. It is optimized for the direct labeling and quantitative detection of small RNAs. A specific bridge DNA oligonucleotide is used, which is perfectly complementary to both the target small RNA and a labeled ligation nucleic acid. The target RNA is subsequently labeled by ligation, detected by analysis in denaturing conditions, and quantified by phosphorimaging. The protocol doesn't require any specific material, and the procedure is fast and sensitive. PMID- 25791592 TI - Fluorescence in situ hybridization of small non-coding RNAs. AB - RNA FISH is a powerful method to detect specific RNAs in fixed cells. It allows both localization and quantification of RNA molecules within individual cells and tissues. Refined RNA FISH methods have also been developed to determine RNA transcription and degradation rates. This chapter describes an RNA FISH protocol that we developed in order to study the expression and localization of satellite III RNAs. This specific class of non-coding RNAs is expressed in response to various cellular stresses including heat shock. This protocol is based on the use of a biotinylated LNA probe subsequently detected by a streptavidin-Alexa Fluor((r)) 488 conjugate. A protocol allowing efficient coupling of RNA FISH and protein detection by immunofluorescence is also described in this chapter. PMID- 25791593 TI - RT-qPCR-based quantification of small non-coding RNAs. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate messenger RNA (mRNA) translation into protein. MiRNAs play a key role in gene expression regulation, and their involvement in disease biology is well documented. This has fueled the development of numerous tools for the quantification of miRNA expression levels. These tools are based on three technologies: (microarray) probe hybridization, RNA sequencing, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). In this chapter, we describe a quantification system based on RT-qPCR technology, which is currently considered as the most sensitive, flexible, and accurate method for quantification of not only miRNA but also RNA expression in general. To this purpose, we have divided the protocol in three sections: reverse transcription (RT) reaction, optional preamplification (PA), and finally qPCR. Three quality control (QC) steps are implemented in this workflow for assessment of RNA extraction efficiency, sample purity (e.g., absence of inhibitors), and inter-run variations, by examining the detection level of different spike-in synthetic miRNAs. We conclude by demonstrating raw data preprocessing and normalization using expression data obtained from high-throughput miRNA profiling of human RNA samples. PMID- 25791594 TI - Stem-loop RT-PCR based quantification of small non-coding RNAs. AB - Stem-loop qRT-PCR is one of the most commonly used real-time PCR approach to quantify small non-coding RNAs such as microRNAs. The quantification method is divided in two steps. First, RNA is reverse-transcribed using a specific stem loop primer, and the resulting RT product is subsequently used as a template for quantitative real-time PCR. This fast and simple method provides quantitative data with high sensitivity and specificity to study miRNAs and their functions. PMID- 25791595 TI - miR-RACE: an effective approach to accurately determine the sequence of computationally identified miRNAs. AB - Computational prediction of microRNAs (miRNAs) is one of the most important approaches in microRNA studies. While validation of the predicted microRNAs' precise sequences is essential for further studies on their biogenesis, evolution, and functions, computational miRNA prediction methods, however, often fail to predict the accurate sequence of the mature miRNA within the precursor at the nucleotide precision level. Here, we depict a highly efficient method for determining the precise sequences of computationally predicted miRNAs. The method combines the generation of miRNA-enriched libraries, with 5'- and 3'-end adaptors being linked to the miRNA molecules, the reverse transcription of small RNAs with an oligo-d(T) anchor primer, two specific 5'- and 3'-miRNA-RACE (miR-RACE) PCR reactions and sequence-directed cloning. The efficiency of this method was demonstrated by the precise sequence validation of computationally predicted miRNAs in citrus, apple, and other fruit crops. Our ongoing research indicates that miR-RACE is also very useful to verify the sequences of putative miRNAs obtained by deep sequencing of small RNA libraries. The protocol of miR-RACE is rapid and can be completed within 2-3 days. miR-RACE should make the bioinformatic prediction of miRNAs more powerful and accurate. PMID- 25791596 TI - Probing small non-coding RNAs structures. AB - The diverse roles of RNAs depend on their ability to fold so as to form biologically functional structures. Thus, understanding the function of a given RNA molecule often requires experimental analysis of its secondary structure by in vitro RNA probing, which is more accurate than using prediction programs only. This chapter presents in vitro RNA probing protocols that we routinely use, from RNA transcript production and purification to RNA structure determination using enzymatic (RNases T1, T2, and V1) and chemical (DMS, CMCT, kethoxal, and Pb(2+)) probing performed on both unlabeled and end-labeled RNAs. PMID- 25791597 TI - cDNA library generation for the analysis of small RNAs by high-throughput sequencing. AB - The RNome of a cell is highly diverse and consists besides messenger RNAs (mRNAs), transfer RNAs (tRNAs), and ribosomal RNAs (rRNAs) also of other small and long transcript entities without apparent coding potential. This class of molecules, commonly referred to as non-protein-coding RNAs (ncRNAs), is involved in regulating numerous biological processes and thought to contribute to cellular complexity. Therefore, much effort is put into their identification and further functional characterization. Here we provide a cost-effective and reliable method for cDNA library construction of small RNAs in the size range of 20-500 residues. The effectiveness of the described method is demonstrated by the analysis of ribosome-associated small RNAs in the eukaryotic model organism Trypanosoma brucei. PMID- 25791598 TI - CLIP-seq to discover transcriptome-wide imprinting of RNA binding proteins in living cells. AB - UV cross-linking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) is used to characterize RNA targets of RNA binding proteins (RBP) in a large scale manner. This powerful method allows the stringent purification of direct RNA binding sites of RBPs in living cells. Here, we describe in detail the protocol we employed to identify RNA targets of the human RNA helicase eIF4AIII. PMID- 25791599 TI - Microarray analysis of small non-coding RNAs. AB - Microarray technology has evolved to efficiently profile the expression of RNAs. However, analysis of small non-coding RNAs (ncRNAs) is challenging due to their short length and highly divergent sequences with large variation in GC content leading to very different hybridization properties. To overcome these challenges, LNA-modified oligonucleotides have been used to enhance and normalize the melting temperature (Tm) of capture probes, which allows sensitive profiling of small ncRNAs regardless of their sequence. Here, we describe the isolation and labeling of small non-coding RNAs, as well as their hybridization to microarrays with LNA modified oligonucleotide probes using a semi-automated hybridization device. PMID- 25791600 TI - RLM-RACE, PPM-RACE, and qRT-PCR: an integrated strategy to accurately validate miRNA target genes. AB - MicroRNAs (miRNAs) are important regulators involved in most biological processes in eukarya. They play critical roles in growth, development, signal transduction, or stress response by controlling gene expression at the posttranscriptional level. Identification and characterization of miRNA-targeted mRNAs is essential for the analysis of miRNA functions. In plants, the perfect complementarity between most miRNAs and their targets enables the accurate predictions of their targets, while slicing of the targeted mRNAs facilitates target validation through RNA Ligase-Mediated (RLM)-Rapid Amplification of cDNA Ends (RACE) method. However, this method only determines the 5'-end of the cleavage product. To more accurately validate the predicted target genes of miRNAs and exactly determine the cleavage sites within the targets, an integrated strategy comprising RLM RACE, Poly(A) Polymerase-Mediated (PPM)-RACE, and qRT-PCR was developed. The efficiency of this method is illustrated by the precise sequence validation of predicted target mRNAs of miRNAs in grapevine, citrus, peach, and other fruit crops. Our on-going research indicates that RLM-RACE, PPM-RACE, and qRT-PCR are very effective in the verification of sequences of miRNA targets obtained by Degradome sequencing. The protocol for RLM-RACE, PPM-RACE, and qRT-PCR is rapid, effective, cheap, and can be completed within 2-3 days. PMID- 25791601 TI - Dual luciferase gene reporter assays to study miRNA function. AB - This chapter describes one of the most reliable quantitative assays to test the silencing of a possible target gene by a specific miRNA using a luciferase reporter gene. The experimental procedure first consists in cloning both the wild type and mutated forms of the 3'UTR of the miRNA predicted mRNA target downstream of a firefly luciferase reporter. Next, each construct is co-transfected together with the miRNA into HeLa cells, and the reporter expression is monitored. Changes in luciferase levels will indicate whether or not a miRNA can bind to the UTR and regulate its expression. PMID- 25791602 TI - Gene expression knockdown by transfection of siRNAs into mammalian cells. AB - SiRNA induced gene silencing or RNA interference is a powerful tool to knock down gene expression and perform gene function studies. In this chapter, we describe a basic method to silence gene expression by transfecting a specific synthetic siRNA into mammalian HeLa cells. PMID- 25791603 TI - Efficient and selective knockdown of small non-coding RNAs. AB - Small non-coding RNAs (ncRNAs), less than 200 nucleotides in length, play important roles in various biological processes, such as pre-mRNA splicing, pre rRNA processing and modification, and gene expression regulation. However, characterization of small ncRNAs remains difficult mainly due to methodological obstacles in selective reduction of these RNAs. Here we describe an approach to deplete small ncRNAs, in principle any types of RNAs, using second generation antisense oligonucleotide-directed RNase H cleavage pathway in human cells. This protocol includes oligonucleotide design, transfection, RNA preparation, and target RNA detection. PMID- 25791604 TI - Cell-SELEX: in vitro selection of synthetic small specific ligands. AB - Systematic Evolution of Ligands by Exponential Enrichment (SELEX) is an in vitro process enabling selection of nucleic acid molecules binding to target ligands with high binding affinity and specificity. The selection process involves several rounds of two successive steps: (1) binding of the oligonucleotides to the target under stringent conditions and (2) amplification of the target-bound nucleic acids by polymerase chain reaction. Using this strategy, RNA or DNA aptamers are selected upon recognition and binding to specific surface structures of the target. Aptamers generated during the final rounds of selection can be notably used in applications dedicated to diagnosis of diseases or therapeutic approaches. PMID- 25791605 TI - Small non-coding RNAs and aptamers in diagnostics and therapeutics. AB - Small non-coding RNAs (sncRNAs) such as small interfering RNAs (siRNAs), microRNAs (miRNAs) and RNA aptamers have recently emerged as highly versatile and valuable tools in disease diagnostics and therapeutics, largely due to their key regulatory functions in many human diseases including cancer, viral infections, genetic disorders, etc. Recent technological advancements as described in the previous chapters have greatly aided the discovery of sncRNAs and their applications for disease detection and therapy. Here, we describe the advantages of using sncRNAs as diagnostic and therapeutic tools, followed by some of the most recent examples of their use and a vision for the future perspectives. PMID- 25791606 TI - The P600 as a correlate of ventral attention network reorientation. AB - When, during language processing, a reader or listener is confronted with a structurally deviant phrase, this typically elicits a late positive ERP deflection (P600). The P600 is often understood as a correlate of structural analysis. This assumption has informed a number of neurocognitive models of language. However, the P600 strongly resembles the P3, likely a more general electrophysiological correlate of reorientation behaviour supported by noradrenergic input to the ventral attention network/VAN. Some researchers have proposed that the P600 is an instance of the P3, not a distinct component reflecting the analysis of structured inputs. Here, we tested the P600-as-P3 hypothesis by estimating the alignment of the P600 elicited in a visual sentence processing task to simultaneously collected behavioural measures. A similar analysis was undertaken for a P3 elicited in a separate non-linguistic (face detection) task. Since the P3 is usually aligned to reaction time/RT, the same should hold for the P600; a failure to find RT alignment of the P600 would pose a problem for the P600-as-P3 hypothesis. In contrast, RT alignment of the P600 would associate it with the well-established VAN/Locus Coeruleus - Noradrenaline Network subserving cortical reorientation. We failed to falsify the hypothesis of RT alignment. Secondary measures, while less unambiguous, were more in agreement with the P600-as-P3 hypothesis. We interpret our results as corroborating the hypothesis that the P600 is a P3, in that it shows that the P600 is RT-aligned. This perspective is unpredicted by an account of the P600 as indexing high-level processing. PMID- 25791607 TI - From local to global changes in proteins: a network view. AB - To fulfill the biological activities in living organisms, proteins are endowed with dynamics, robustness and adaptability. The three properties co-exist because they allow global changes in structure to arise from local perturbations (dynamics). Robustness refers to the ability of the protein to incur such changes without suffering loss of function; adaptability is the emergence of a new biological activity. Since loss of function may jeopardize the survival of the organism and lead to disease, adaptability may occur through the combination of two local perturbations that together rescue the initial function. The review highlights the relevancy of computational network analysis to understand how a local change produces global changes. PMID- 25791608 TI - Architecture of the polyketide synthase module: surprises from electron cryo microscopy. AB - Modular polyketide synthases (PKS) produce a vast array of bioactive molecules that are the basis of many highly valued pharmaceuticals. The biosynthesis of these compounds is based on ordered assembly lines of multi-domain modules, each extending and modifying a specific chain-elongation intermediate before transfer to the next module for further processing. The first 3D structures of a full polyketide synthase module in different functional states were obtained recently by electron cryo-microscopy. The unexpected module architecture revealed a striking evolutionary divergence of the polyketide synthase compared to its metazoan fatty acid synthase homolog, as well as remarkable conformational rearrangements dependent on its biochemical state during the full catalytic cycle. The design and dynamics of the module are highly optimized for both catalysis and fidelity in the construction of complex, biologically active natural products. PMID- 25791609 TI - The bacterial communities associated with fecal types and body weight of rex rabbits. AB - Rex rabbit is an important small herbivore for fur and meat production. However, little is known about the gut microbiota in rex rabbit, especially regarding their relationship with different fecal types and growth of the hosts. We characterized the microbiota of both hard and soft feces from rex rabbits with high and low body weight by using the Illumina MiSeq platform targeting the V4 region of the 16S rDNA. High weight rex rabbits possess distinctive microbiota in hard feces, but not in soft feces, from the low weight group. We detected the overrepresentation of several genera such as YS2/Cyanobacteria, and Bacteroidales and underrepresentation of genera such as Anaeroplasma spp. and Clostridiaceae in high weight hard feces. Between fecal types, several bacterial taxa such as Ruminococcaceae, and Akkermansia spp. were enriched in soft feces. PICRUSt analysis revealed that metabolic pathways such as "stilbenoid, diarylheptanoid, gingerol biosynthesis" were enriched in high weight rabbits, and pathways related to "xenobiotics biodegradation" and "various types of N-glycan biosynthesis" were overrepresented in rabbit soft feces. Our study provides foundation to generate hypothesis aiming to test the roles that different bacterial taxa play in the growth and caecotrophy of rex rabbits. PMID- 25791612 TI - Pharmacokinetics of Mirabegron, a beta3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects. AB - PURPOSE: The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a beta3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. METHODS: In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. FINDINGS: After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0-infinity was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. IMPLICATIONS: Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations. PMID- 25791613 TI - Pharmacokinetic properties and tolerability of rotigotine transdermal patch after repeated-dose application in healthy korean volunteers. AB - PURPOSE: Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. METHODS: In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. FINDINGS: A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC0-24h and Cmax values of unconjugated rotigotine were 5.88 ng.h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng.h/mL and 0.838 ng/mL. The mean t1/2 of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC0-24h and Cmax values of total rotigotine were 14.02 ng.h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng.h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. IMPLICATIONS: The mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573. PMID- 25791615 TI - A Research Note on Trends in Black Hypersegregation. AB - In this note, we use a consistently defined set of metropolitan areas to study patterns and trends in black hypersegregation from 1970 to 2010. Over this 40 year period, 52 metropolitan areas were characterized by hypersegregation at one point or another, although not all at the same time. Over the period, the number of hypersegregated metropolitan areas declined by about one-half, but the degree of segregation within those areas characterized by hypersegregation changed very little. As of 2010, roughly one-third of all black metropolitan residents lived in a hypersegregated area. PMID- 25791614 TI - Differential bacterial gene expression during experimental pneumococcal endophthalmitis. AB - Streptococcus pneumoniae (pneumococcus) is a potential cause of bacterial endophthalmitis in humans that can result in ocular morbidity. We sought to identify pneumococcal genes that are differentially expressed during growth in the vitreous humor of the eye in an experimental endophthalmitis model. Microarray analysis was used to identify genes that were differentially expressed when pneumococci replicated in the vitreous of rabbit eyes as compared with bacteria grown in vitro in Todd Hewitt medium. Array results were verified by quantitative real-time PCR analysis of representative genes. Select genes potentially playing a role in virulence during endophthalmitis were deleted, and mutants were tested for reduced eye pathogenesis and altered adhesion to host cells. Array analysis identified 134 genes that were differentially expressed during endophthalmitis; 112 genes demonstrated increased expression during growth in the eye whereas 22 were downregulated. Real-time analysis verified increased expression of neuraminidase A (NanA; SP1693), neuraminidase B (NanB; SP1687) and serine protease (SP1954), and decreased expression of RlrA (SP0461) and choline transporter (SP1861). Mutation of NanA and NanB had no major effect on pathogenesis. Loss of SP1954 led to increased adherence to host cells. S. pneumoniae enhances and represses the expression of a variety of genes during endophthalmitis. While some of these genes reflect changes in metabolic requirements, some appear to play a role in immune evasion and pathogenesis in the eye. PMID- 25791616 TI - Crystal structures of S-adenosylhomocysteine hydrolase from the thermophilic bacterium Thermotoga maritima. AB - S-adenosylhomocysteine (SAH) hydrolase catalyzes the reversible hydrolysis of SAH into adenosine and homocysteine by using NAD(+) as a cofactor. The enzyme from Thermotoga maritima (tmSAHH) has great potentials in industrial applications because of its hyperthermophilic properties. Here, two crystal structures of tmSAHH in complex with NAD(+) show both open and closed conformations despite the absence of bound substrate. Each subunit of the tetrameric enzyme is composed of three domains, namely the catalytic domain, the NAD(+)-binding domain and the C terminal domain. The NAD(+) binding mode is clearly observed and a substrate analogue can also be modeled into the active site, where two cysteine residues in mesophilic enzymes are replaced by serine and threonine in tmSAHH. Notably, the C terminal domain of tmSAHH lacks the second loop region of mesophilic SAHH, which is important in NAD(+) binding, and thus exposes the bound cofactor to the solvent. The difference explains the higher NAD(+) requirement of tmSAHH because of the reduced affinity. Furthermore, the feature of missing loop is consistently observed in thermophilic bacterial and archaeal SAHHs, and may be related to their thermostability. PMID- 25791617 TI - Structural insights into specific crRNA G-rich sequence binding by Meiothermus ruber Cse2. AB - CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats)-mediated defense against invading nucleic acids is a process recently discovered in prokaryotes, which includes recognition and incorporation of invading genetic elements, transcription and processing of CRISPR-RNA (crRNA) and targeting the invaders through base pair recognition. In the type I-E CRISPR-Cas system, Cse2 is proposed to provide a platform to facilitate the targeting of the invading dsDNA by crRNA. Here we report the crystal structure of Meiothermus ruber Cse2 at 2.8A. M. ruber Cse2 adopts an alpha-helical bundle scaffold, harbors a positive surface for nucleic acid binding and a conserved dimer interface with strikingly low buried surface area. M. ruber Cse2 selectively binds to G-rich crRNA sequence, which is stripped off from the Cse2-crRNA and Cascade-crRNA complexes by ssDNA or dsDNA with complementary sequence. Stable M. ruber Cascade is readily formed by co-expression of M. ruber Cascade proteins together with G-rich crRNA in vitro. Docking of M. ruber Cse2 structures into the Escherichia coli Cascade Cryo-EM envelope reveals a curved elongated shallow groove for ssRNA binding, which adopts a similar dimer interface discovered by high-resolution crystal structure of Cse2 within E. Coli Cascade. Taken together, our data provides the structural insights into crRNA G-rich sequence recognition by M. ruber Cse2 and reveals the potential structural mechanism for M. ruber Cascade assembly and function. PMID- 25791618 TI - Psychometric evaluation of the EORTC QLQ-PR25 questionnaire in assessing health related quality of life in prostate cancer survivors: a curate's egg. AB - PURPOSE: The EORTC QLQ-PR25 was primarily developed to measure disease-specific health-related quality of life (HRQoL) of prostate cancer (PCa) patients undergoing active treatment. The growing number of cancer survivors has focussed interest on assessing survivors' HRQoL. We evaluated psychometric properties of the EORTC QLQ-PR25 questionnaire amongst PCa survivors. METHODS: A postal questionnaire, including the QLQ-PR25, was administered to 6559 PCa survivors 2 18 years post-diagnosis, identified through population-based cancer registries in Ireland; 3348 participated. The QLQ-PR25 has been suggested to have five multi item subscales measuring urinary (US), bowel (BS) and hormone treatment-related symptoms (TS), sexual activity (SA) and sexual functioning (SF), and a single item measuring bother due to using incontinence aids (IA). Reliability analysis, divergent validity, discriminant validity (compared to EORTC QLQ-C30, DASS-21 and EuroQoL EQ-5D-5L), and exploratory and confirmatory factor analysis (EFA, CFA) were undertaken. RESULTS: The percentage of survivors completing QLQ-PR25 subscales was: US-79 %; IA-20 %; BS-83 %; TS-86 %; SA-87 %; and SF-26 %. Reliability was acceptable (Cronbach's alpha > 0.7) for three subscales (US, SA, SF). The instrument discriminated well between clinically distinct groups, especially those defined by primary treatment(s) and stage at diagnosis. The SA and SF subscales showed good discriminant validity compared to QLQ-C30, DASS-21 and EQ-5D-5L; other subscales did not. EFA reproduced a near fit to the proposed factor structure. CFA confirmed this. CONCLUSION: This is the largest ever QLQ PR25 validation study. When used in PCa survivors, although the proposed factor structure was confirmed, some of the subscales (e.g. BS and TS) showed poor reliability, a lack of discriminant validity and moderate levels of item non response. PMID- 25791619 TI - Dystonia and cerebellar degeneration in the leaner mouse mutant. AB - Cerebellar degeneration is traditionally associated with ataxia. Yet, there are examples of both ataxia and dystonia occurring in individuals with cerebellar degeneration. There is also substantial evidence suggesting that cerebellar dysfunction alone may cause dystonia. The types of cerebellar defects that may cause ataxia, dystonia, or both have not been delineated. In the current study, we explored the relationship between cerebellar degeneration and dystonia using the leaner mouse mutant. Leaner mice have severe dystonia that is associated with dysfunctional and degenerating cerebellar Purkinje cells. Whereas the density of Purkinje cells was not significantly reduced in 4 week-old leaner mice, approximately 50% of the neurons was lost by 34 weeks of age. On the other hand, the dystonia and associated functional disability became significantly less severe during this same interval. In other words, dystonia improved as Purkinje cells were lost, suggesting that dysfunctional Purkinje cells, rather than Purkinje cell loss, contribute to the dystonia. These results provide evidence that distorted cerebellar function may cause dystonia and support the concept that different types of cerebellar defects can have different functional consequences. PMID- 25791621 TI - MicroRNA-30b promotes axon outgrowth of retinal ganglion cells by inhibiting Semaphorin3A expression. AB - Semaphorin3A (Sema3A) is a major inhibitory factor of optic nerve (ON) regeneration post-injury. Many microRNAs (miRNAs) are expressed specifically in the mammalian brain and retina and are dynamically regulated during development, suggesting that this group of miRNAs may be associated with neural development. We found that microRNA-30b (miR-30b) bound to the three prime untranslated region (3' UTR) of Sema3A and inhibited the expression of Sema3A mRNA. The mRNA expression level of miR-30b and the protein expression levels of Sema3A, Neuropilin1 (NRP1), PlexinA1 (PlexA1), phosphorylated p38MAPK (p-p38MAPK), and active caspase-3 were all upregulated in retinas from rats with a damaged ON relative to those with an intact ON. Transfection of cultured retinal ganglion cells (RGCs) with an miR-30b mimic led to decreased levels of Sema3A, NRP1, PlexA1, p-p38MAPK, and active caspase-3 protein expression, as well as axon elongation and reduced levels of apoptosis. These findings provide evidence that miR-30b inhibits Sema3A expression. Decreased Sema3A expression promotes axon outgrowth in RGCs due to reduced levels of Sema3A binding to NRP1 and PlexA1 and simultaneously reduces apoptosis by inhibiting the p38MAPK and caspase-3 pathways. Our findings provide the first evidence that miR-30b-mediated Sema3A downregulation may serve as a new strategy for the clinical treatment of ON injury. PMID- 25791620 TI - Differences in AMPA and GABAA/B receptor subunit expression between the chronically reorganized cortex and brainstem of adult squirrel monkeys. AB - The primate somatosensory neuraxis provides a highly translational model system with which to investigate adult neural plasticity. Here, we report immunohistochemical staining data for AMPA and GABAA/B receptor subunits of area 3b cortex and cuneate nucleus of adult squirrel monkeys one to five years after median and ulnar nerve transection. In Area 3B cortex, the expression of GluR1 AMPAR subunits in reorganized regions are significantly increased, while the expression of GluR2/3 AMPAR subunits are not. GABAA alpha1 subunit expression in the reorganized region is not significantly different from control regions. Presynaptic GABABR1a subunit expression was also not significantly different between reorganized and control regions, while postsynaptic GABABR1b subunit expression was significantly decreased. In the cuneate nucleus of the brainstem, the expression of GluR1 AMPAR subunits in reorganized regions was not significantly different, while GluR2/3 AMPAR subunit expression was significantly elevated. GABAA alpha1 subunit expression in the reorganized region was significantly decreased. Presynaptic GABABR1a subunit expression was not significantly different, while postsynaptic GABABR1b subunit expression was significantly decreased. When subunit expression is compared, brainstem and cortical patterns diverge over longer periods of recovery. Persistent patterns of change in the cortex are stable by 1-year. Alternatively, subunit expression in the cuneate nucleus one to five years after nerve injury is similar to that seen 1-month after a reorganizing injury. This suggests that cortical plasticity continues to change over many months as receptive field reorganization occurs, while brainstem plasticity obtains a level of stable persistence by one month. PMID- 25791624 TI - Comment to "A comparison of Progrip(r) and Adhesix(r) self-adhering hernia meshes in an onlay model in the rat" Gruber-Blum S, Riepl N, Brand J, Keibl C, Redl H, Fortelny RH, Petter-Puchner AH (doi:10.1007/s10029-014-1258-0). PMID- 25791625 TI - Intraperitoneal mesh devices for small midline hernias: mesh behavior in a porcine model. AB - PURPOSE: Although clinical data on long-term efficacy are lacking, the use of self-expanding devices for intraperitoneal placement in the management of small midline hernias has been popularized. In the present experimental study, two different devices were investigated regarding tissue ingrowth, adhesion formation and solid mesh placement. METHODS: Two devices of 4.3 cm diameter, one ePTFE containing small pore polypropylene mesh (PP/ePTFE) and a multi-layered large pore polypropylene patch with an oxidized cellulose anti-adhesive barrier (PP/ORC), both containing a self-deployment system, were placed intraperitoneally at the linea alba of 24 female pigs. A first laparoscopy was performed to evaluate mesh positioning against the abdominal wall. 1 (n = 6), 2 (n = 6), 4 (n = 6) and 12 weeks (n = 6) later, mesh appearance was inspected and adhesion formation was assessed. All meshes were excised for histological evaluation. RESULTS: Folding of the patch was more frequently observed at PP/ePTFE, yet no excessive cupping was noticed. Adhesions predominantly presented at short-term evaluation. Overall adhesion formation at all samples was significantly more extensive for PP/ORC (p = 0.048). Massive shrinkage was observed for PP/ORC: after a 12-week period 22% residual surface was preserved, compared to 83% for PP/ePTFE (p < 0.001). While at short-term inflammatory reaction was comparable, at long-term PP/ORC induced a significant more pronounced inflammatory and foreign body reaction. CONCLUSIONS: Although a strong deployment system provides adequate initial placement, shrinkage and excessive adhesion formation are much more prominent in the large-pore multi-layered restorbable devices compared to the ePTFE patch. This might influence long-term clinical outcome and caution seems warranted. PMID- 25791626 TI - Scarless laparoscopic repair of epigastric hernia in children. AB - BACKGROUND: Despite the small size of the incision, the scar left by open repair of epigastric hernia in children is unaesthetic. Few laparoscopic approaches to epigastric hernia repair have been previously proposed, but none has gain wide acceptance from pediatric surgeons. In this study, we present our experience with a scarless laparoscopic approach using a percutaneous suturing technique for epigastric hernia repair in children. METHODS: Ten consecutive patients presenting with epigastric hernia 15 mm or further from the umbilicus were submitted to laparoscopic hernia repair. A 5-mm 30o-angle laparoscope is introduced through a umbilical trocar and a 3-mm laparoscopic dissector is introduced through a stab incision in the right flank. After opening and dissecting the parietal peritoneum, the fascial defect is identified and closed using 2-0 polyglactin thread through a percutaneous suturing technique. Intraoperative and postoperative clinical data were collected. RESULTS: All patients were successfully submitted to laparoscopic epigastric hernia repair. Median age at surgery was 79 months old and the median distance from the umbilicus to the epigastric defect was 4 cm. Operative time ranged from 35 to 75 min. Every hernia was successfully closed without any incidents. Follow-up period ranges from 2 to 12 months. No postoperative complications or recurrence was registered. No scar was visible in these patients. CONCLUSION: This scarless laparoscopic technique for epigastric hernia repair is safe and reliable. We believe this technique might become gold standard of care in the near future. PMID- 25791627 TI - Enhanced Ca(2+)-induced Ca(2+) release from intracellular stores contributes to catecholamine hypersecretion in adrenal chromaffin cells from spontaneously hypertensive rats. AB - Adrenal chromaffin cells (CCs) from spontaneously hypertensive rats (SHRs) secrete more catecholamine (CA) upon stimulation than CCs from normotensive Wistar Kyoto rats (WKY). Unitary CA exocytosis events, both spontaneous and stimulated, were amperometrically recorded from cultured WKY and SHR CCs. Both strains display spontaneous amperometric spikes but SHR CCs produce more spikes and of higher mean amplitude. After a brief stimulation with high K(+) or caffeine which produces voltage-gated Ca(2+) influx or intracellular Ca(2+) release, respectively, more spikes and of greater mean amplitude and unitary charge were recorded in SHR CCs. Consequently, peak cumulative charge was ~2-fold higher in SHR CCs. Ryanodine (10 MUM), a specific blocker of the ryanodine receptors reduced depolarization-induced peak cumulative charge by ~10 % in WKY and ~77 % in SHR CCs, suggesting, a larger contribution of Ca(2+)-induced Ca(2+) release to CA exocytosis in SHR CCs. Accordingly, Ca(2+) imaging showed larger [Ca(2+)]i signals induced both by depolarization and caffeine in SHR CCs. Distribution amplitude histograms showed that small amperometric spikes (0-50 pA) are more frequent in WKY than in SHR CCs. Conversely, medium (50-190 pA) and large (190-290 pA) spikes are more numerous in SHR than in WKY CCs. This study reveals that the enhanced CA secretion in SHR CCs results from a combination of (1) larger depolarization-induced Ca(2+) transients, due to a greater Ca(2+) induced intracellular Ca(2+) release, (2) more exocytosis events per time unit, and (3) a greater proportion of medium and large amperometric spikes probably due to a higher mean CA content per granule. Enhanced CA release by excessive amplification by Ca(2+) induced Ca(2+) release and larger granule catecholamine content contributes to the increased CA plasma levels and vasomotor tone in SHRs. PMID- 25791629 TI - Granulomatous vasculitis. AB - Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Wegener's granulomatosis and Churg-Strauss Syndrome respectively, are systemic granulomatous vasculitides affecting small- and medium-sized blood vessels. Both GPA and EGPA are included within the group of antineutrophilic cytoplasmic antibodies (ANCA)-associated vasculitides, on the basis of the detection of such autoantibodies in a significant proportion of affected patients. Two main settings of GPA, possibly overlapping each other, are recognized: a localized form, which is limited to the upper airways but is highly relapsing and refractory, and a diffuse form, which is initially more severe but then less commonly recurrent. In EGPA, a prodromic phase characterized by asthma and rhino-sinusitis is followed by an eosinophilic phase, marked by peripheral eosinophilia, and then by a vasculitic phase, in which skin lesions are a prominent feature together with peripheral neuropathy and renal involvement. Polymorphic cutaneous manifestations can occur during the course of both GPA and EGPA, and include palpable purpura, livedo reticularis, papules, nodules, vesiculo-bullae and necrotic-ulcerative lesions most commonly involving the lower extremities; pyoderma gangrenosum-like ulcers and lesions resembling erythema multiforme have been described in GPA and EGPA, respectively. Oral involvement is not uncommon in GPA and may manifest as nonspecific erosive lesions or as a hyperplastic gingivitis named strawberry gingivitis. Considering that skin involvement is common in ANCA-associated vasculitides and may also be their presenting sign, the role of dermatologist is crucial in the early diagnosis of these forms as well as of vasculitis in general. PMID- 25791630 TI - Involvement of dysregulated Wip1 in manganese-induced p53 signaling and neuronal apoptosis. AB - Overexposure to manganese (Mn) has been known to induce neuronal death and neurodegenerative symptoms. However, the precise mechanisms underlying Mn neurotoxicity remain incompletely understood. In the present study, we established a Mn-exposed rat model and found that downregulation of wild type p53 induced phosphatase 1 (Wip1) might contribute to p53 activation and resultant neuronal apoptosis following Mn exposure. Western blot and immunohistochemical analyses revealed that the expression of Wip1 was markedly decreased following Mn exposure. In addition, immunofluorescence assay demonstrated that Mn exposure led to significant reduction in the number of Wip1-positive neurons. Accordingly, the expression of Mdm2 was progressively decreased, which was accompanied with markedly increased expression of p53, as well as the ratio of Bax/Bcl-xl. Furthermore, we showed that Mn exposure decreased the viability and induced apparent apoptosis in NFG-differentiated neuron-like PC12 cells. Importantly, the expression of Wip1 decreased progressively, whereas the level of cellular p53 and the ratio of Bax/Bcl-xl were elevated, which resembled the expression of the proteins in animal model studies. Depletion of p53 significantly ameliorated Mn mediated cytotoxic effect in PC12 cells. In addition, ectopic expression of Wip1 attenuated Mn-induced p53 signaling as well as apoptosis in PC12 cells. Finally, we observed that depletion of Wip1 augmented Mn-induced apoptosis in PC12 cells. Collectively, these findings suggest that downregulated Wip1 expression plays an important role in Mn-induced neuronal death in the brain striatum via the modulation of p53 signaling. PMID- 25791632 TI - Drug resistant hypertension - no simple way out. AB - Hypertension poses growing challenge for health policy-makers and doctors worldwide. Recently published results of Symplicity-III trial (HTN-3), the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal-artery denervation, as compared with controls. In this paper we review clinical and experimental studies on renal denervation. In order to identify causes of inconsistent results in renal denervation studies we look at basic science support for renal denervation and at designs of clinical trials. PMID- 25791631 TI - Integrating motif, DNA accessibility and gene expression data to build regulatory maps in an organism. AB - Characterization of cell type specific regulatory networks and elements is a major challenge in genomics, and emerging strategies frequently employ high throughput genome-wide assays of transcription factor (TF) to DNA binding, histone modifications or chromatin state. However, these experiments remain too difficult/expensive for many laboratories to apply comprehensively to their system of interest. Here, we explore the potential of elucidating regulatory systems in varied cell types using computational techniques that rely on only data of gene expression, low-resolution chromatin accessibility, and TF-DNA binding specificities ('motifs'). We show that static computational motif scans overlaid with chromatin accessibility data reasonably approximate experimentally measured TF-DNA binding. We demonstrate that predicted binding profiles and expression patterns of hundreds of TFs are sufficient to identify major regulators of ~200 spatiotemporal expression domains in the Drosophila embryo. We are then able to learn reliable statistical models of enhancer activity for over 70 expression domains and apply those models to annotate domain specific enhancers genome-wide. Throughout this work, we apply our motif and accessibility based approach to comprehensively characterize the regulatory network of fruitfly embryonic development and show that the accuracy of our computational method compares favorably to approaches that rely on data from many experimental assays. PMID- 25791633 TI - Potential clinical relevant drug-drug interactions: comparison between different compendia, do we have a validated method? PMID- 25791628 TI - Much more than a leak: structure and function of K2p-channels. AB - Over the last decade, we have seen an enormous increase in the number of experimental studies on two-pore-domain potassium channels (K2P-channels). The collection of reviews and original articles compiled for this special issue of Pflugers Archiv aims to give an up-to-date summary of what is known about the physiology and pathophysiology of K2P-channels. This introductory overview briefly describes the structure of K2P-channels and their function in different organs. Its main aim is to provide some background information for the 19 reviews and original articles of this special issue of Pflugers Archiv. It is not intended to be a comprehensive review; instead, this introductory overview focuses on some unresolved questions and controversial issues, such as: Do K2P channels display voltage-dependent gating? Do K2P-channels contribute to the generation of action potentials? What is the functional role of alternative translation initiation? Do K2P-channels have one or two or more gates? We come to the conclusion that we are just beginning to understand the extremely complex regulation of these fascinating channels, which are often inadequately described as 'leak channels'. PMID- 25791634 TI - Concomitant ALK translocation and other non-EGFR gene in NSCLC: knowledge in the making. PMID- 25791635 TI - Anthropometric factors and endometrial cancer risk: a systematic review and dose response meta-analysis of prospective studies. AB - BACKGROUND: Greater body mass index (BMI) has been convincingly related to increased endometrial cancer risk, however, whether adiposity earlier in life or abdominal fatness is an independent risk factor and whether weight gain or greater height increases the risk is not clear. METHODS: As part of the Continuous Update Project of the World Cancer Research Fund International, we conducted a systematic review and meta-analysis of prospective studies of the association between anthropometric measures and endometrial cancer risk and searched PubMed and several other databases up to February 2015. Summary relative risks (RRs) were calculated using a random-effects model. RESULTS: Thirty prospective studies of BMI and endometrial cancer risk with 22 320 cases among 6 445 402 participants were included. The summary RR for a 5-unit increment was 1.54 [95% confidence interval (CI) 1.47-1.61, I(2) = 81%]. Although the test for non-linearity was significant, Pnon-linearity < 0.0001, and the curve was steeper within the overweight and obese BMI ranges, there was evidence of increased risk even within the high normal BMI range. The summary RR was 1.45 (95% CI 1.28-1.64, I(2) = 76%) per 5 BMI units for BMI in young adulthood, 1.18 (95% CI 1.14-1.23, I(2) = 67%) per 5 kg increase of weight, and 1.16 (95% CI 1.12-1.20, I(2) = 51%) per 5 kg of weight gained between young adulthood and study baseline, 1.27 (95% CI 1.17-1.39, I(2) = 71%) per 10 cm increase in waist circumference, 1.21 (95% CI 1.13-1.29, I(2) = 0%) per 0.1-unit increment in waist-to-hip ratio and 1.30 (95% CI 1.19-1.41, I(2) = 0%) per 10-cm increase in hips circumference. The summary RR was 1.15 (95% CI 1.09-1.22, I(2) = 61%) for a 10-cm increase in height. CONCLUSIONS: All measures of adiposity were associated with increased risk of endometrial cancer, and in addition increasing height was associated with increased risk. PMID- 25791636 TI - Disseminated tumor cells from the bone marrow of patients with nonmetastatic primary breast cancer are predictive of locoregional relapse. AB - BACKGROUND: Disseminated tumor cells (DTCs) are detectable in the bone marrow (BM) of patients with primary breast cancer (PBC) and predictive of an impaired prognosis. This large trial aimed to analyze the impact of DTC detection on locoregional relapse (LR). PATIENTS AND METHODS: Patients with nonmetastatic PBC were eligible for this analysis. BM aspiration (BMA1) was carried out during primary surgery and DTCs were detected by using immunocytochemistry (A45-B/B3 antibody against pancytokeratin) and morphological criteria. At the time of LR, a subgroup of patients with nonmetastatic and operable LR received a secondary BM aspiration (BMA2). RESULTS: A total of 3072 patients were included into the analysis. Of these, 732 (24%) presented with DTCs at BMA1. One hundred thirty nine patients experienced LR and 48 of these (35%) were initially DTC positive. DTC detection was significantly associated with an increased risk of LR in univariate (P = 0.002) and multivariate analysis (P = 0.009) with a hazard ratio of 1.65 (95% confidence interval 1.13-2.40). Of the patients with LR, 55 patients were available for BMA2 and 17 of these (32%) were DTC positive. DTC detection at the time of LR was indicative of impaired overall survival (univariate analysis, P = 0.037). CONCLUSIONS: DTC detection in patients with PBC is associated with an increased risk of LR, indicating that tumor cells may have the ability to recirculate from the BM to the site of the primary tumor. The impaired prognosis associated with DTC detection at the time of LR may help to identify patients that are in need for additional or more aggressive treatment. PMID- 25791637 TI - Clinical and molecular implications of MED15 in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) progression depends on various dysregulated pathways. Regulation of diverse pathways is mediated by the mediator complex. The mediator subunit MED15 is essential for transforming growth factor (TGF)-beta signaling and involved in breast and prostate cancers. We investigated the implication of MED15 in HNSCC. IHC for MED15 was performed on 324 tissue samples, and TGF-beta assessed the use of Ki-67 and pSMAD3 as markers. MED15 knockdown followed by proliferation and migration assays, as well as TGF-beta1 treatment followed by MED15 analysis, was also performed. MED15 was overexpressed in 35% of primary tumors, 30% of lymph node metastases, and 70% of recurrences in contrast to no or low expression in benign tumors. MED15 overexpression in primary tumors from patients who developed recurrences was associated with higher mortality rates and occurred at highest frequency in oral cavity or oropharyngeal tumors. Furthermore, MED15 expression correlated between primary tumors and corresponding lymph node metastases. MED15 correlated with proliferation in tissues, and MED15 knockdown reduced proliferation and migration. We observed an association between MED15 and TGF-beta activity in tissues because TGF-beta activation led to increased MED15 expression and reduced pSMAD3 on MED15 knockdown. Taken together, our results implicate MED15 in HNSCC and hint that MED15 overexpression is a clonal event during HNSCC progression. MED15 may serve as a prognostic marker for recurrence and as a therapeutic target. PMID- 25791638 TI - Effect of upright position on tonsillar level in adolescent idiopathic scoliosis. AB - PURPOSE: The aim of this study was to investigate the effect of an upright position on cerebellar tonsillar level in patients with adolescent idiopathic scoliosis (AIS). METHODS: Twenty-five patients with clinically diagnosed AIS and 18 normal controls were examined in both supine and upright positions using 0.25T MRI. The position of the inferior cerebellar tonsil tip relative to a reference line connecting the basion to the opisthion (BO line) was measured in millimetres. RESULTS: None of the 18 normal control subjects had cerebellar tonsillar descent below the BO line in either supine or the upright position. Forty-eight percent of AIS patients had tonsillar descent in the upright position, compared to 28 % in the supine position. In the upright position, cerebellar tonsillar position was lower in AIS patients than in normal subjects (mean -0.7 +/- 1.5 vs. +2.1 +/- 1.7, p < 0.00001). AIS patients also had a large degree of tonsillar excursion between upright and supine positions compared to normal subjects (mean -1.9 +/- 2.3 vs. -0.1 +/- 0.2, p < 0.00001). CONCLUSIONS: When considering the theoretical likelihood that a low tonsillar position may affect spinal cord function, one should bear in mind that tonsillar descent in AIS is significantly greater in the upright position. KEY POINTS: * AIS patients exhibited greater cerebellar tonsillar descent in upright than supine position. * Cerebellar tonsillar position was lower in AIS patients than normal subjects. * AIS patients exhibited greater tonsillar excursion between supine and upright positions. PMID- 25791639 TI - Chronic Aspergillosis of the Lungs: Unravelling the Terminology and Radiology. AB - The propensity for Aspergillus spp. to cause lung disease has long been recognised but the satisfactory classification of these disorders is challenging. The problems caused by invasive disease in severely neutropenic patients, saprophytic infection of pre-existing fibrotic cavities and allergic reactions to Aspergillus are well documented. In contrast, a more chronic form of Aspergillus related lung disease that has the potential to cause significant morbidity and mortality is under-reported. The symptoms of this form of Aspergillus infection may be non-specific and the radiologist may be the first to suspect a diagnosis of chronic pulmonary aspergillosis. The current review considers the classification conundrums in diseases caused by Aspergillus spp. and discusses the typical clinical and radiological profile of patients with chronic pulmonary aspergillosis. KEY POINTS: * The classification of Aspergillus -related lung disease is mired in confusion. * The chronic form of Aspergillus infection is associated with significant morbidity and mortality. * Progressive consolidation and cavitation with intracavitary material is the radiological hallmark. PMID- 25791640 TI - Cardiac pathologies in female carriers of Duchenne muscular dystrophy assessed by cardiovascular magnetic resonance imaging. AB - OBJECTIVES: Duchenne muscular dystrophy (DMD) is the most common and severe dystrophinopathy. DMD carriers rarely present with clinical symptoms, but may suffer from cardiac involvement. Because echocardiographic findings are inconsistent and cardiac magnetic resonance imaging (CMRI) data are limited, this study sought to investigate asymptomatic carriers for cardiac abnormalities using CMRI. METHODS: Fifteen genetically confirmed DMD carriers (age, 32.3 +/- 10.2 years) were prospectively examined on a 1.5T MR system. Cine, T2, and late gadolinium-enhanced (LGE) images were acquired, and were evaluated in consensus by two experienced readers. Left ventricular (LV) parameters were analysed semiautomatically, normalized to BSA. RESULTS: Normalized LV end-diastolic volume was increased in 7% (73.7 +/- 16.8 ml/m(2); range, 48-116 ml/m(2)) and normalized LV end-systolic volume in 20% (31.5 +/- 13.3 ml/m(2); range, 15-74 ml/m(2)). EF was reduced in 33% (58.4 +/- 7.6%; range, 37-69%) and normalized LV myocardial mass in 80% (40.5 +/- 6.8 g/m(2); range, 31-55 g/m(2)). In 80%, regional myocardial thinning was detected in more than one segment. In 13% and 40%, apical lateral accentuation of LV non-compaction was present. LGE was found in 60% (midmyocardial inferolateral accentuation). CONCLUSIONS: Given the high frequency of cardiac pathologies detected by CMRI, regular cardiac risk assessment is advisable for DMD carriers. Besides clinical examination, CMRI is an excellent tool for this purpose. KEY POINTS: * Fifteen Duchenne muscular dystrophy carriers investigated using CMRI all showed cardiac pathologies. * Myocardial mass reduction, regional myocardial thinning, and late gadolinium enhancement were common. * Regular cardiac risk assessment is thus advisable in Duchenne muscular dystrophy carriers. * Besides clinical examination, CMRI is an excellent tool for this purpose. PMID- 25791641 TI - Prevention of postsurgical atrial tachycardia with a modified right atrial free wall incision. AB - BACKGROUND: Most postsurgical macroreentry atrial tachycardias (PS-MATs) are atriotomy related; however, underlying mechanisms and prevention remain undefined. OBJECTIVE: The purpose of the present study was to investigate the electrophysiological and histologic bases of right atriotomy incision arrhythmogenicity and whether a modified atriotomy that extends the incisional line to the tricuspid annulus (TA) and inferior vena cava (IVC) prevents PS-MAT. METHODS: Atrial arrhythmia induction and electrophysiological and histologic characteristics were studied 8 weeks after right atriotomy in 30 adult swine according to incision distance to TA or IVC (groups A, B, and C: broad, narrow, and closed corridors, respectively; group D, no-incision sham; n = 6 per group, except n = 12 for group B). RESULTS: Sustained PS-MATs were induced and mapped in the broad- and narrow-corridor groups (A, 1 of 6 [16.7%] vs B, 5 of 12 [41.7%]) but not in the closed-corridor (C) or sham (D) groups (P = .087). With 20-ms pacing cycle-length decrements (from 350 to 270 ms), mean conduction time over 20 mm at the atriotomy-to-TA corridor was 29.2 +/- 2.2, 31.0 +/- 4.2, 26.0 +/- 1.9, and 17.0 +/- 1.4 ms for 5 and 10 mm (both group B), 15 mm (group A), and sham incision (P = .017), respectively. Conduction properties correlated with histologic findings: the wider the corridor, the healthier its tissue. In group C (modified atriotomy), both corridors were replaced by dense scar with complete conduction block. CONCLUSION: Atriotomy corridor width determines conduction properties and contributes to arrhythmogenicity. A modified right atriotomy that extends to the TA and IVC prevents PS-MAT. PMID- 25791642 TI - Recurrence of PVCs in patients with PVC-induced cardiomyopathy. AB - BACKGROUND: The natural history of premature ventricular complex (PVC)-induced cardiomyopathy is incompletely understood. OBJECTIVE: The purpose of this study was to assess long term follow-up data in patients who underwent successful PVC ablation for PVC-induced cardiomyopathy. METHODS: The subjects of this study were 60 patients (17 women; mean age 52.5 +/- 16.8 years; ejection fraction [EF] 37.3 +/- 8.5%, median 40%, interquartile range [IQR] 15) with PVC-induced cardiomyopathy who underwent successful ablation of their predominant PVCs between 2005 and 2012. Patients were followed up for a mean of 23.6 +/- 17.2 months. EF improved to 57.2 +/- 4.7% (median 55%, IQR 5; P = .0001) within 9.6 +/ 8.4 months of the ablation procedure. During follow-up, 10 of 60 patients (16.7%) had recurrent frequent PVCs and 50 patients (83.3%) did not. Patients underwent repeat assessment of EF and PVC burden. RESULTS: During follow-up of 23.6 +/- 17.2 months, 10 patients had recurrent frequent PVCs, with an increase of their PVC burden from 1.4 +/- 0.9% (median 1.05%, IQR 1.59) after the initial ablation to 27.2 +/- 8.8% (median 26.0%, IQR 18.2; P = .018). Their EF decreased from 55.7 +/- 3.4% (median 55%, IQR 5.8) after the initial ablation to 40.2 +/- 5.1% (median 40%, IQR 15; P = .005). In the remaining patients with PVC-induced cardiomyopathy, EF and PVC burden remained unchanged during follow-up. Patients with PVC recurrence had a higher number of pleomorphic PVC morphologies during initial presentation (4.7 +/- 2.2 vs 2.5 +/- 2.8, P = .002). CONCLUSION: Recurrence of frequent PVCs in patients with a history of PVC cardiomyopathy can result in recurrence of cardiomyopathy. Follow-up in patients with PVC-induced cardiomyopathy is important, especially if patients were asymptomatic from the PVCs and have pleomorphic PVCs. PMID- 25791643 TI - Effects of chemical and biological pesticides on plant growth parameters and rhizospheric bacterial community structure in Vigna radiata. AB - With increasing application of pesticides in agriculture, their non-target effects on soil microbial communities are critical to soil health maintenance. The present study aimed to evaluate the effects of chemical pesticides (chlorpyrifos and cypermethrin) and a biological pesticide (azadirachtin) on growth parameters and the rhizospheric bacterial community of Vigna radiata. Qualitative and quantitative analysis by PCR-denaturing gradient gel electrophoresis (DGGE) and q-PCR, respectively, of the 16S rRNA gene and transcript were performed to study the impact of these pesticides on the resident and active rhizospheric bacterial community. While plant parameters were not affected significantly by the pesticides, a shift in the bacterial community structure was observed with an adverse effect on the abundance of 16S rRNA gene and transcripts. Chlorpyrifos showed almost complete degradation toward the end of the experiment. These non-target impacts on soil ecosystems and the fact that the effects of the biopesticide mimic those of chemical pesticides raise serious concerns regarding their application in agriculture. PMID- 25791644 TI - [Respiratory infection: a challenge we have to face]. PMID- 25791645 TI - [How to determine short course antibiotic therapy for pneumonia]. PMID- 25791646 TI - [Rationally use of antimicrobial drugs under the guidance of pharmacokinetics and pharmacodynamics during serious drug resistant bacteria/infection]. PMID- 25791647 TI - [Antibiotic dosing in patients receiving renal replacement therapy]. PMID- 25791648 TI - [Disease spectrum and diagnostic strategy of pulmonary aspergillosis]. PMID- 25791649 TI - [Differences of pathogenic agents in adults with community acquired pneumonia in China and abroad]. PMID- 25791650 TI - [The prospectives and limitations of antibiotics inhalation for bronchiectasis]. PMID- 25791652 TI - [The clinical-radiologic-pathologic features of imported pulmonary histoplasmosis]. AB - OBJECTIVE: To describe the clinical features and treatment of imported pulmonary histoplasmosis and therefore to improve the recognition and differential diagnosis of this disease. METHODS: The clinical data of 3 patients with imported pulmonary histoplasmosis in our hospital were collected and analyzed. Literatures published since 1989 were retrieved with 'pulmonary histoplasmosis' from PubMed, China National Knowledge Infrastructure (CNKI), Wanfang Data and VIP data, of which all the literatures about imported pulmonary histoplasmosis were reviewed. The clinical manifestations, diagnostic methods and treatment were summarized. RESULTS: All the 3 cases of imported pulmonary histoplasmosis were immunocompetent hosts, all were males, age were from 44-67 years, and had a history of exploring the cave or tunnel inhabited by bats in the epidemic areas. All of them developed influenza-like symptoms varying in severity after the onset of the disease. Pulmonary multiple nodules and mediastinal lymphadenopathy were found on chest images. One patient underwent percutaneous lung biopsy and the other two received video-assisted thoracoscopic lung biopsy. All the 3 patients showed consistent histopathological findings, such as granulomatous inflammation with necrosis. Pathogen culture with lung biopsy in the first case was identified as histoplasma. All the 3 cases were treated with itraconazole, and recovered with good prognosis. Thirteen literatures in English were obtained, which reported 60 cases with imported pulmonary histoplasmosis. Forty-two of them were males, 16 were females and 2 undefined. The range of their age was from 17-64 years. No imported pulmonary histoplasmosis was reported so far in Chinese literature. Common features of imported pulmonary histoplasmosis were consistent with our patients, including epidemiology, influenza-like symptoms and bilateral pulmonary nodules, recovery with or without antifungal therapy. CONCLUSION: The epidemiologic history, influenza-like symptoms and bilateral pulmonary nodules provide valuable diagnostic clues for imported histoplasmosis. Clinical features with pathologic findings and good response to antifungal therapy could make the diagnosis even without pathogen detection if other etiology is unlikely. PMID- 25791651 TI - [Resistance surveillance of major pathogens for adult community-acquired respiratory tract infections in China: a multicenter study 2012]. AB - OBJECTIVE: To investigate antimicrobial resistance among pathogens responsible for adult community-acquired respiratory tract infections from 11 hospitals of China. METHODS: From January to December 2012, a total of 599 strains causing adult community-acquired respiratory tract infection were collected from 11 hospitals, including 381 Streptococcus pneumonia, 137 Haemophilus influenza, and 81 Moraxella catarrhalis. The minimal inhibitory concentration (MIC) of antibacterial agents was determined by agar dilution method. RESULTS: Of all the strains, 50% (300/599 strains) were from adults more than 60 years old and only 16.2% (97/599 strains) were from patients aged less than 40 years. According to oral penicillin breakpoints, 56.7% (216/381 strains) of Streptococcus pneumoniae were penicillin non-susceptible strains (PNSSP). More than 90% (345/381 strains) and 39.9% (152/381 strains)-50.7% (193/381 strains) of Streptococcus pneumoniae were resistant to macrolides and oral cephalosporins respectively, but over 97.8% (372/381 strains) and 99% (377/381 strains) were susceptible to levofloxacin and moxifloxacin. PNSSP strains exhibited significant higher resistance to ceftriaxone, amoxicillin/clavulanate, cefaclor and cefuroxime compared with penicillin susceptible Streptococcus pneumoniae (PSSP). The susceptibility rates of Haemophilus influenza to the antimicrobial agents were over 90% except for ampicillin (71.5%, 272/381 strains) and cefaclor (75.2%, 286/381 strains). The prevalence of beta-lactamase positive Haemophilus influenza were 21.9% (30/137 strains), and beta-lactamase positive Haemophilus influenza strains were more resistant to ampicillin, cefaclor, chloramphenicol and tetracycline compared with beta-lactamase-negative strains. Moraxella catarrhalis strains were extremely susceptible to all the antimicrobial agents tested except for clindamycin, azithromycin and clarithromycin. CONCLUSIONS: The activities of macrolides and oral cephalosporins against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were limited. Levofloxacin and moxifloxacin exhibited good activities against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. PMID- 25791653 TI - [The clinical value of urinary antigen detection of Legionella pneumonia]. AB - OBJECTIVE: To investigate the clinical value of urinary antigen detection of Legionella, and to describe the clinical characteristics of Legionella pneumonia. METHODS: Patients with suspected Legionella pneumonia were enrolled from the Respiratory departments of 3 tertiary hospitals in Shenyang during May 2011 to November 2013. Urinary Legionella antigen was detected for all the enrolled patients. Bacterial culture, polymerase chain reaction (PCR) for Legionella, and double Legionella antibody detection in sera were performed for each patient whose urinary antigen was positive. Patients confirmed to have Legionella pneumonia were pooled and analyzed. RESULTS: Totally 13 cases presenting with pneumonia were positive for Legionella by the urinary antigen method, and in one of them Legionella strain was isolated from the secretion of lower respiratory tract. PCR detection was performed in 8 patients, and 4 of them were positive. Legionella antibody detection was performed in 12 patients, and 7 of them were positive. Nine patients had a history of exposure to Legionella high-risk environments. The characteristics of the cases with Legionella pneumonia were as follows: characteristic orange sputum in 4 patients, digestive symptoms in 6, neurologic disorders in 8, hyponatremia in 10, hypoxia with oxygenation index < 300 mmHg (1 mmHg = 0.133 kPa) in 11, and severe pneumonia with PSI of grade V (PSI score > 130) in 8 patients . Chest CT scan showed bilateral involvement in 6, ground-glass opacity combined with consolidation in 11, and moderate pleural effusion in 11 patients. Cavity and reversed halo sign were found in one case, respectively. All of the patients received fluoroquinolone treatment, and 11 patients recovered completely while 2 died of multiple organ dysfunction syndrome, one of them was complicated with secondary infection. CONCLUSION: Detection of urinary antigen of Legionella is very useful in the diagnosis of Legionella pneumonia. Attention should be paid to exposure history to the high risk environments and multiple organ impairment when Legionella infection is suspected. Orange sputum may be characteristic for Legionella pneumonia and therefore a clue for diagnosis. In critical cases, secondary infection and additional lung injuries induced by high concentration oxygen therapy may occur. PMID- 25791654 TI - [Proteomic analysis of U937 cells expressing Mycobacterium tuberculosis heat shock protein 16.3]. AB - OBJECTIVE: To compare the protein expression differences between U937 macrophages expressing M. tuberculosis (MTB) Hsp16.3 protein and U937 macrophages expressing green fluorescent protein (GFP), and therefore to explore the protein expressions related to latent TB infection(LTBI). METHODS: U937 macrophages were infected with an integrase-deficient Lentivirus vector to transiently express MTB Hsp16.3, and green fluorescent protein (GFP) as a control. 2-DE was used to compare the differentially expressed proteins in the infected U937 cells. Then 5 significantly different expressed protein spots were identified by using mass spectrometry. RESULTS: The data of 6 protein spots in gel obtained from peptide mass fingerprinting were retrieved in protein database. They were identified as heat shock protein 70, actin, elongation factor I, peptidyl-prolyl cis-trans isomerase, ubiquitin-conjugation enzyme E2, and milk acyl glutathione lyase. CONCLUSION: The results showed that MTB specific protein intrusion resulted in changes of macrophage proteome expression, and this finding may help in understanding of the interaction between macrophages and MTB specific proteins. PMID- 25791655 TI - [The role of SDF-1/CXCR4 on airway inflammation and airway remodeling in a rat asthma model]. AB - OBJECTIVE: To explore the roles of stromal cell-derived factor 1 (SDF-1) and C-X C chemokine receptor 4 (CXCR4) on airway inflammation and airway remodeling in rat asthma models. METHODS: Eighteen female SD rats were randomly divided into 3 groups (n = 6): control group, asthmatic 4 weeks group and asthmatic 8 weeks group. The rats were sensitized and inhaled ovalbumin (OVA). After the asthma model was successfully established, the airway pressure was measured. The methods of HE staining and Image-Pro Plus image analysis software were used to detect the changes of eosinophils (EOS), the perimeter of inner bronchial lumen, the wall area, the area of bronchial smooth muscle and the number of smooth muscle cells of airway walls. RT-PCR and Western-blot were used to detect the expression of SDF-1 and CXCR4 in lung tissues among the 3 groups.Immunohistochemistry was used to detect the expression of SDF-1 in airway walls. RESULTS: Compared with the control group, the airway responsiveness, the count of EOS, the area of bronchial wall, the area of bronchial smooth muscle, the number of smooth muscle cells of airway walls in the asthmatic 4 weeks and asthmatic 8 weeks were significantly increased, and significant difference between the 2 asthmatic groups was also observed in the above indexes (P < 0.01) .RT-PCR showed that compared with the control group (SDF-1 was 0.146 +/- 0.003 and CXCR4 was 0.281 +/- 0.002) , the expression of SDF-1 (0.583 +/- 0.004 and 0.724 +/- 0.008) and CXCR4 (0.467 +/- 0.003 and 0.655 +/- 0.002) in lung tissues in the asthmatic 4 weeks and asthmatic 8 weeks were significantly increased (P < 0.01) . In addition, compared with the asthmatic 4 weeks group, the expression of SDF-1 and CXCR4 in lung tissues in the 8 weeks asthmatic group were significantly increased (P < 0.01) . Compared with the control group (0.180 +/- 0.009) , the expression of SDF-1 in airway walls in the asthmatic 4 weeks and asthmatic 8 weeks groups (0.270 +/- 0.006 and 0.350 +/- 0.009) were significantly increased (P < 0.01) . In addition, compared with the asthmatic 4 weeks group, the expression of SDF-1 in airway walls in the 8 weeks asthmatic group was significantly increased (P < 0.01) . The expression of SDF-1 and CXCR4 was correlated positively with the airway responsiveness, the number of EOS, the area of bronchial wall, the area of bronchial smooth muscle and the number of smooth muscle cells of airway walls (P < 0.01). CONCLUSIONS: SDF 1/CXCR4 axis may play a key role in airway inflammation and airway remodeling of asthma. PMID- 25791656 TI - [The effect of survivin expression on the apoptosis and proliferation of hypoxic human pulmonary arterial smooth muscle cells]. AB - OBJECTIVE: Survivin is a new member of the inhibitor of apoptosis (IAP) family of proteins, which is also the strongest inhibitor of apoptosis.It inhibits apoptosis and promotes cell proliferation. This study aims to explore the effect of survivin expression on the apoptosis and proliferation of hypoxic human pulmonary arterial smooth muscle cells (HPASMCs). METHODS: HPASMCs were divided randomly into 6 groups:Normoxia (N group):cultured under normoxia;Normoxia+YM155(NY group):cultured under normoxia with YM155, a selective survivin inhibitor, for 24 h;Hypoxia(H group):cultured under hypoxia for 24 h;Hypoxia+1 nmol/L YM155 (HY1 group):cultured under hypoxia with 1 nmol/L YM155 for 24 h; Hypoxia+10 nmol/L YM155 (HY10 group):cultured under hypoxia with 10 nmol/L YM155 for 24 h;Hypoxia+100 nmol/L YM155 (HY100 group):cultured under hypoxia with 100 nmol/L YM155 for 24 h. The mRNA and protein expressions of survivin were measured by real time PCR and Western Blot respectively. Cell proliferation was determined using a Cell Counting Kit-8 (CCK-8). Apoptosis was detected with a TUNEL test. RESULTS: The mRNA and protein expressions of survivin were observed in the H group (17 086 +/- 1 044, 0.837 +/- 0.027), but not in the N group (1, 0.016 +/- 0.06) . The cell proliferation in H group ( 1.44 +/- 0.12) was significantly increased compared with that of the N group (0.99 +/- 0.07, q = 6.484, P < 0.05). The apoptosis in the H group (0.61 +/- 0.50) was significantly decreased compared with that in the N group (2.68 +/- 1.36, q = 3.532, P < 0.05). As compared with the H group, the survivin mRNA, survivin protein and cell proliferation in hypoxia plus 1 nmol/L, 10 nmol/L, 100 nmol/L YM155 groups (8 074 +/- 2 135, 5 614 +/- 709, 1 382 +/- 347,0.382 +/- 0.041,0.281 +/- 0.025,0.021 +/- 0.002, 1.318 +/- 0.067, 1.168 +/- 0.071,0.845 +/- 0.129, q = 8.59, 11.14, 15.53, 20.26, 24.77, 36.36, 2.58, 3.98, 8.73, all P < 0.05) significant decreased , but the apoptosis in hypoxia plus 1 nmol/L, 10 nmol/L, 100 nmol/L YM155 groups (5.52 +/- 1.71, 6.66 +/- 1.49, 7.97 +/- 1.93, q = 6.014, 7.413, 9.023, all P < 0.05) enhanced in a dose-dependent manner. CONCLUSIONS: Survivin was expressed in hypoxic HPASMCs, but not in normal HPASMCs. Treatment with the survivin inhibitor YM155 led to decreased proliferation and enhanced apoptosis in hypoxic HPASMCs. Survivin might be a significant target for human hypoxic pulmonary hypertension. PMID- 25791657 TI - [The association between body composition and bone stiffness in patients with stable chronic obstructive pulmonary disease]. AB - OBJECTIVE: To determine the body composition and bone stiffness in patients with stable chronic obstructive pulmonary disease (COPD), and to explore the association between them. METHODS: Ninety-four male COPD patients in stable conditions and 47 healthy smokers were recruited from March 2013 to January 2014.Lung function, body composition and bone stiffness were measured.In COPD patients, the symptoms were assessed by COPD Assessment Test (CAT) and Modified British Medical Research Council (mMRC) respectively, and the acute exacerbation and hospitalization history in the previous 12 months were also recorded. RESULTS: The prevalence of muscle atrophy (FFMI<16 kg/m(2) ) and high risk of bone fracture (T<-1) were 24.5% and 72.3% respectively in stable male COPD patients. The patients with muscle atrophy, had lower FEV1%pred (39.0 +/- 15.2) vs (50.1 +/- 16.2), frequent acute exacerbations [1.0(0-3.0) vs 0 (0-1.0)] and lower bone stiffness index (75.5 +/- 13.3) vs (85.5 +/- 15.7), (test values were 2.904, -1.476, 2.728, all P < 0.05). Compared with patients with low risk of bone fracture(T >= -1), patients with high risk of bone fracture (T<-1) showed higher mMRC score [2.0(1.0-3.0) vs 1.0(0-2.0)] (Z = -2.297, P < 0.05). The FFMI correlated positively with SI (r = 0.294, P = 0.004) in COPD patients. CONCLUSIONS: Patients with stable COPD presented worse lung function and increased risk of future exacerbations when combined with muscle atrophy and high risk of bone fracture, and the two co-morbidities were correlated and should be assessed. PMID- 25791658 TI - [Characteristics of airway hyperresponsiveness in children with chronic cough of different causes]. AB - OBJECTIVE: To study the characteristics of airway hyperresponsiveness in children with different causes of chronic cough. METHODS: A prospective study was conducted in children suffering from chronic cough caused by a single reason at the department of respirology of Children's Hospital of Soochow University from April 2012 to December 2013. Bronchial provocation test, induced sputum eosinophil count, and exhale nitric oxide were detected at beginning and 4 weeks later. The severity of the CVA was classified according to the integral dose of histamine which resulted in a 20% (PD20) fall in forced expiratory volume in 1 s (FEV1). All patients received treatment according to the recommended guidelines for chronic cough in children of China. According to the responses to the treatment and the results of physical examinations and laboratory findings, a final diagnosis was confirmed. RESULTS: A total of 66 children were enrolled in this study, including cough variant asthma (CVA)in 17, upper airway cough syndrome (UACS) in 37, and post infection cough (PIC) in 12 cases. Positive AHR in CVA, UACS, and PIC groups was found in 17, 13, and 9 cases respectively at the first visit, and after 4 weeks, it was found in 17, 5, and 2 cases respectively. The severity of AHR in CVA, UACS and PIC at beginning and after 4 weeks were moderate to severe in 5, 0, 0 cases and 1, 0, 0 case; Mild to very mild in 12, 13, 9 cases and 16, 5, 2 cases.Negative response was found in 0, 24, 3 cases and 0, 32, 10 cases, respectively. The values of PD20 in CVA group (0.47 +/- 0.28) mg were statistically lower those in UACS group (1.8 +/- 0.64) mg and PIC group (1.2 +/- 0.80) mg (P < 0.01) . The sputum eosinophil count was > 3% in all cases of CVA but all <3% in UACS and PIC.FeNO and sputum eosinophil counts were positively correlated (r = 0.687, P = 0.000) . CONCLUSION: The characteristics of airway responsiveness of chronic cough caused by different causes were varied in different AHR severity and course. Bronchial provocation test combined with induced sputum showed certain values for confirming the cause of chronic cough in children. PMID- 25791659 TI - [Adjuvant therapeutic value of corticosteroids in severe community- acquired pneumonia]. PMID- 25791660 TI - [1, 3-beta-D-glucan detection in the diagnosis of fungal infection]. PMID- 25791661 TI - [Urine antigen test to improve detection rate of Streptococcus pneumonia in community acquired pneumonia]. PMID- 25791662 TI - [Memory T cells and asthma]. PMID- 25791663 TI - [Updating the relationship of chronic obstructive pulmonary disease and cardiovascular comorbidity]. PMID- 25791664 TI - Impact of airflow limitation on carotid atherosclerosis in coronary artery disease patients. AB - BACKGROUND: Both airflow limitation and smoking are established cardiovascular risk factors. However, their interaction as risk factors for the development of atherosclerosis in coronary artery disease patients remains unclear. OBJECTIVES: To evaluate the effect of the interaction between airflow limitation and smoking status on the severity of carotid atherosclerosis. METHODS: We categorized the 234 enrolled patients with coronary artery disease into four groups: never smokers with normal pulmonary function (group A), never-smokers with airflow limitation (group B), ever-smokers with normal pulmonary function (group C), and ever-smokers with airflow limitation (group D). RESULTS: The prevalence of airflow limitation in the enrolled patients was 23.1% (ever-smokers: 15.8%, never smokers: 7.3%). The prevalence of severe carotid atherosclerosis was 28.2, 29.4, 41.3, and 45.9%, respectively, in the four groups (group D vs. group A, p = 0.035). Even after multivariate adjusting for confounding factors, ever-smokers with airflow limitation were independently associated with severe carotid atherosclerosis (odds ratio 2.89, 95% confidence interval, 1.19-7.00, p = 0.019). CONCLUSIONS: Ever-smokers with airflow limitation were significantly associated with severe carotid atherosclerosis among patients with coronary artery disease. These findings also provide additional insight into the correlation between airflow limitation and poor cardiovascular clinical outcomes. PMID- 25791665 TI - Antagonistic joint toxicity assessment of two current-use phthalates with waterborne copper in liver of Carassius auratus using biochemical biomarkers. AB - Di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) are two kinds of widely-used phthalates, whereas Cu (II) is a common valence state of copper. They have been ubiquitously detected in the aquatic environment, but information on their joint toxicity on aquatic organisms is scarce. In this study, we evaluated the combined effects of copper and these two phthalates to the goldfish (Carassius auratus) by detecting the antioxidant responses in liver after exposure for 7 and 21 days. The exposure concentrations were in a range relevant to their levels in the natural aquatic environment. The results indicated that DBP, DEHP and Cu (II) can affect the antioxidant status in fish liver, evidenced by the significant alterations of antioxidant defenses (superoxide dismutase, catalase, glutathione) and malondialdehyde. Antagonistic effects were found in the joint toxicity of Cu (II) and DBP or DEHP using the integrated biomarker response (IBR) index. These findings have important implications in the risk assessments of phthalates mixed with some heavy metals in the aquatic environment. PMID- 25791666 TI - Sorption of heavy metal ions onto carboxylate chitosan derivatives--a mini review. AB - Chitosan is of importance for the elimination of heavy metals due to their outstanding characteristics such as the presence of NH2 and -OH functional groups, non-toxicity, low cost and, large available quantities. Modifying a chitosan structure with -COOH group improves it in terms of solubility at pH <=7 without affecting the aforementioned characteristics. Chitosan modified with a carboxylic group possess carboxyl, amino and hydroxyl multifunctional groups which are good for elimination of metal ions. The focal point of this mini-review will be on the preparation and characterization of some carboxylate chitosan derivatives as a sorbent for heavy metal sorption. PMID- 25791667 TI - The most popular terms for medically unexplained symptoms: the views of CFS patients. AB - OBJECTIVE: Medically unexplained symptoms/syndromes are common, highly distressing and are often associated with profound disability. One of the controversies surrounding this area relates to which umbrella term should be used to group such symptoms. The purpose of this research was to establish the preferences of patients with chronic fatigue syndrome (CFS) for an umbrella term for medically unexplained symptoms. METHODS: A cross-sectional mixed methods survey design was used. Participants were asked to indicate their three most preferred terms out of a list of commonly used terms and to provide any extra comments. Frequency analysis was employed to look at the preferences of terms for each rank. Comments were analysed using principles of inductive thematic analysis. RESULTS: Eighty-seven patients with CFS completed a self-report survey. The term "Persistent Physical Symptoms" was the most popular first choice term chosen by 20.7% of patients. Terms containing the word "physical" were consistently more likely to be chosen. Three main themes emerged from the thematic analysis: 1) Physical nature of the illness, 2) Stigma, and 3) Evaluation of the terms, giving a more in-depth understanding of the findings. CONCLUSION: According to CFS patients, an umbrella term has to reflect the physical experience of MUS. PMID- 25791668 TI - A randomized controlled trial of a 10 week group psychotherapeutic treatment added to standard medical treatment in patients with functional dyspepsia. AB - OBJECTIVE: Epidemiological evidence suggests an association between psychological factors and functional dyspepsia (FD). Yet few randomized controlled trials (RCTs) of psychological interventions have been conducted for FD. We conducted an RCT to evaluate the efficacy of psychotherapy among chronic FD. METHODS: One hundred fifty-eight consecutive patients with FD were randomized to medical therapy plus psychotherapy consisted in 8 group and 2 individual sessions focused on teaching techniques for coping with FD (intensive treatment (IT); n=76) or medical therapy alone (conventional treatment (CT); n=82). Patients completed validated self-reported questionnaires before and after the 10-week treatment and 6 months later. Linear mixed-effects models were used, in intention-to-treat analysis. RESULTS: At the end of treatment period, statistically significant improvements were observed for IT compared with CT for dyspepsia-related quality of life (DRQoL). DRQoL mean changes of 6.09 and 3.54 were obtained in IT and CT patients, respectively (p=<0.0001); and SS mean changes of 11.55 and 4.57 were obtained in IT and CT patients, respectively (p=0.0013). Those improvements, measured by minimum clinically important difference (MCID), were clinically significant (DRQoL: 77% of the IT patients exceeded the MCID vs. the 45% of the CT; SS: 75% vs. 48%). Six months after treatment, those statistically significant improvements persisted for DRQoL (p=0.0067) and for SS (p=0.0405). Clinical improvements persisted for SS (63% vs. 41%). CONCLUSIONS: These findings suggest that adding psychotherapy to standard medical therapy improves short-term outcomes in patients with FD and may have long-term effects as well. The cost effectiveness of intensive therapy needs to be evaluated. Registration number and name of trial registry: NCT01802710. PMID- 25791669 TI - Differential protein expression in white adipose tissue from obesity-prone and obesity-resistant mice in response to high fat diet and anti-obesity herbal medicines. AB - BACKGROUND: One of the most interesting issues in obesity research is why certain humans are obesity-prone (OP) while others are obesity-resistant (OR) upon exposure to a high-calorie diet. However, the pathways responsible for these phenotypic differences are still largely unknown. METHODS: In order to discover marker molecules determining susceptibility and/or resistance to obesity in response to high fat diet (HFD) or anti-obesity herbal medicine (TH), we conducted comparative proteomic analysis of white adipose tissue (WAT) from OP, OR, as well as TH-treated mice. RESULTS: OP mice fed HFD gained approximately 33% more body weight than OR mice, and TH significantly reduced body weight gain in HFD-fed mice by 30%. These mice were further subjected to proteomic analysis using two-dimensional electrophoresis (2-DE) combined with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Proteomic data revealed 59 spots that were differentially regulated from a total of 1,045 matched spots, and 57 spots of these were identified as altered WAT proteins between OP and OR mice by peptide mass finger printing. Interestingly, 45 proteins were similarly regulated in OR mice in response to TH treatment. Of these, 10 proteins have already been recognized in the context of obesity; however, other proteins involved in obesity susceptibility or resistance were identified for the first time in the present study. CONCLUSION: Our results suggest that TH actively contributed to body weight reduction in HFD-fed obese mice by altering protein regulation in WAT, and it was also found that TH responsive proteins can be used as potent molecules for obesity treatment. PMID- 25791670 TI - Total Knee Arthroplasty Within Six Months After Knee Arthroscopy Is Associated With Increased Postoperative Complications. AB - A national database was queried for patients who underwent TKA following ipsilateral knee arthroscopy. Three cohorts were created: TKA within 6 months of knee arthroscopy (n=681), TKA between 6 months and 1 year after knee arthroscopy (n=1301) and TKA between 1 and 2 years after knee arthroscopy (n=1069). An age matched control group of TKA without prior knee arthroscopy was also created (n=37,235). The incidences of infection (OR 2.0, P=0.004), stiffness (OR 2.0, P=0.001) and VTE (OR 1.6, P=0.047) were higher in patients who underwent TKA within 6 months after knee arthroscopy compared to controls. There was no increase in complications when TKA was performed more than six months after knee arthroscopy. PMID- 25791671 TI - Effect of Tibial Posterior Slope on Knee Kinematics, Quadriceps Force, and Patellofemoral Contact Force After Posterior-Stabilized Total Knee Arthroplasty. AB - We used a musculoskeletal model validated with in vivo data to evaluate the effect of tibial posterior slope on knee kinematics, quadriceps force, and patellofemoral contact force after posterior-stabilized total knee arthroplasty. The maximum quadriceps force and patellofemoral contact force decreased with increasing posterior slope. Anterior sliding of the tibial component and anterior impingement of the anterior aspect of the tibial post were observed with tibial posterior slopes of at least 5 degrees and 10 degrees , respectively. Increased tibial posterior slope contributes to improved exercise efficiency during knee extension, however excessive tibial posterior slope should be avoided to prevent knee instability. Based on our computer simulation we recommend tibial posterior slopes of less than 5 degrees in posterior-stabilized total knee arthroplasty. PMID- 25791672 TI - Evaluation of Elution and Mechanical Properties of High-Dose Antibiotic-Loaded Bone Cement: Comparative "In Vitro" Study of the Influence of Vancomycin and Cefazolin. AB - Use of antibiotic-loaded bone cements is one of the most effective methods for the prevention and treatment of prosthetic joint infection. However, there is still controversy about the optimal combination and doses of antibiotics that provide the maximum antimicrobial effect without compromising cement properties. In this study, vancomycin and cefazolin were added to a bone cement (Palacos R+G). Antibiotic release, fluid absorption, and mechanical properties were evaluated under physiological conditions. The results show that the type of antibiotic selected has an important impact on cement properties. In this study, groups with cefazolin showed much higher elution than those containing the same concentration of vancomycin. In contrast, groups with cefazolin showed a lower strength than vancomycin groups. PMID- 25791673 TI - Intraoperative Proximal Femoral Fracture in Primary Cementless Total Hip Arthroplasty. AB - Intraoperative proximal femoral fracture is a complication of primary cementless total hip arthroplasty (THA) at rates of 2.95-27.8%. A retrospective review of 2423 consecutive primary cementless THA cases identified 102 hips (96 patients) with fracture. Multivariate analysis compared fracture incidences between implants, Accolade (Stryker Orthopaedics) and Tri-Lock (DePuy Orthopaedics, Inc.), and evaluated potential risk factors using a randomized control group of 1150 cases without fracture. The fracture incidence was 4.4% (102/2423), 3.7% (36/1019) using Accolade and 4.9% using Tri-Lock (66/1404) (P=0.18). Female gender (OR=1.96; 95% CI 1.19-3.23; P=0.008) and smaller stem size (OR=1.64; 95% CI 1.04-2.63; P=0.03) predicted increased odds of fracture. No revisions of the femoral component were required in the fracture cohort. PMID- 25791674 TI - Advances in the discovery of novel antimicrobials targeting the assembly of bacterial cell division protein FtsZ. AB - Currently, wide-spread antimicrobials resistance among bacterial pathogens continues being a dramatically increasing and serious threat to public health, and thus there is a pressing need to develop new antimicrobials to keep pace with the bacterial resistance. Filamentous temperature-sensitive protein Z (FtsZ), a prokaryotic cytoskeleton protein, plays an important role in bacterial cell division. It as a very new and promising target, garners special attention in the antibacterial research in the recent years. This review describes not only the function and dynamic behaviors of FtsZ, but also the known natural and synthetic inhibitors of FtsZ. In particular, the small molecules recently developed and the future directions of ideal candidates are highlighted. PMID- 25791675 TI - Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium. AB - A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 MUM) toward HepG2 and CHO cells, nor mutagenic. Structure-activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages. PMID- 25791676 TI - Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell based models of neuroinflammation. AB - LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 MUM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show anti neuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL 1beta stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes. PMID- 25791677 TI - Discovery of orally active anticancer candidate CFI-400945 derived from biologically promising spirooxindoles: success and challenges. AB - The identification of novel anticancer agents with high efficacy and low toxicity has always been an intriguing topic in medicinal chemistry. The unique structural features of spirooxindoles together with diverse biological activities have made them promising structures in new drug discovery. Among spirooxindoles, CFI-400945 holds its promise as the first potent PLK4 inhibitor, the fumarate of CFI-400945 has entered phase I clinical trials for the treatment of solid tumors. However, questions remain as to whether PLK4 is the only relevant therapeutic target for CFI-400945. To highlight this significant progress of CFI-400945 in last two years, this review centers on the identification from a focused kinase library, structural optimizations and strategies involved, structure-activity relationships, modes of action, target validation, chemical synthesis and, more importantly, the kinase selectivity between PLK4 and other targets. PMID- 25791680 TI - Palladium(II)-catalyzed directed trifluoromethylthiolation of unactivated C(sp3) H bonds. AB - The synthesis of trifluoromethylthiolated aliphatic acid derivatives by Pd catalyzed C(sp(3))-H bond functionalization was developed. Using a bidentate directing group, the direct and selective introduction of a SCF3 moiety was possible on a range of amides with remarkable selectivity for C(sp(3))-centers with an electrophilic SCF3 source and pivalic acid as an additive. This work constitutes an example of the unactivated C(sp(3))-SCF3 bond formation by C-H activation offering a new access to relevant molecules. PMID- 25791681 TI - Editorial overview: Bioinorganic chemistry: bioinorganic catalysis for renewable energy. PMID- 25791679 TI - A Review of Infectious Agents in Polar Bears (Ursus maritimus) and Their Long Term Ecological Relevance. AB - Disease was a listing criterion for the polar bear (Ursus maritimus) as threatened under the Endangered Species Act in 2008; it is therefore important to evaluate the current state of knowledge and identify any information gaps pertaining to diseases in polar bears. We conducted a systematic literature review focused on infectious agents and associated health impacts identified in polar bears. Overall, the majority of reports in free-ranging bears concerned serosurveys or fecal examinations with little to no information on associated health effects. In contrast, most reports documenting illness or pathology referenced captive animals and diseases caused by etiologic agents not representative of exposure opportunities in wild bears. As such, most of the available infectious disease literature has limited utility as a basis for development of future health assessment and management plans. Given that ecological change is a considerable risk facing polar bear populations, future work should focus on cumulative effects of multiple stressors that could impact polar bear population dynamics. PMID- 25791682 TI - Photo-induced reactions from efficient molecular dynamics with electronic transitions using the FIREBALL local-orbital density functional theory formalism. AB - The computational simulation of photo-induced processes in large molecular systems is a very challenging problem. Firstly, to properly simulate photo induced reactions the potential energy surfaces corresponding to excited states must be appropriately accessed; secondly, understanding the mechanisms of these processes requires the exploration of complex configurational spaces and the localization of conical intersections; finally, photo-induced reactions are probability events, that require the simulation of hundreds of trajectories to obtain the statistical information for the analysis of the reaction profiles. Here, we present a detailed description of our implementation of a molecular dynamics with electronic transitions algorithm within the local-orbital density functional theory code FIREBALL, suitable for the computational study of these problems. As an example of the application of this approach, we also report results on the [2 + 2] cycloaddition of ethylene with maleic anhydride and on the [2 + 2] photo-induced polymerization reaction of two C60 molecules. We identify different deactivation channels of the initial electron excitation, depending on the time of the electronic transition from LUMO to HOMO, and the character of the HOMO after the transition. PMID- 25791683 TI - Novel superhydrophilic poly(l-lactic acid-co-epsilon-caprolactone)/fibrinogen electrospun patch for rat abdominal wall reconstruction. AB - A novel superhydrophilic hybrid scaffold was created by electrospinning a mixture of poly(l-lactic acid-co-epsilon-caprolactone) and formulated fibrinogen. The hybrid scaffolds possess the combined benefits of each individual component, such as moderate mechanical strength and excellent biocompatibility. In vitro studies also revealed that endothelial cells seeded on the hybrid scaffolds achieved a relatively high level of cell attachment after three days of culture and a significant increase in the proliferation rate after seven days of culture, compared with pure fibrinogen or poly(l-lactic acid-co-epsilon-caprolactone) scaffolds. A comparative study of hybrid and pure poly(l-lactic acid-co-epsilon caprolactone) patches was performed in an abdominal wall defect model in rats. In both groups, implants degraded by six months, but muscle reconstruction was only observed in the hybrid patch group. PMID- 25791684 TI - Dental pulp tissue engineering with bFGF-incorporated silk fibroin scaffolds. AB - The clinical translation of regenerative endodontics demands further development of suitable scaffolds. Here, we assessed the possibility of using silk fibroin scaffold for pulp regeneration with dental pulp stem cells (DPSCs) and basic fibroblast growth factor (bFGF) in ectopic root canal transplantation model. Porous silk fibroin scaffolds were fabricated using freeze-drying technique (with or without bFGF incorporation), and characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy. DPSCs were isolated, characterized, seeded onto scaffolds, and inserted into the tooth root fragments. Cell viability and morphology were tested in the 3D model in vitro using CCK8 assay and SEM. Furthermore, the ectopic transplantation model was used to verify the generation of pulp-like tissue in DPSCs seeded silk fibroin scaffold with bFGF, as examined by histological analysis. DPSCs seeded in silk fibroin scaffold survived, exhibited cytoplasmic elongation in scaffolds at least 4 weeks in culture. bFGF promoted DPSCs viability in tooth fragments/scaffolds (TSS) between 7 and 28 days. Pulp-like tissue was generated in the bFGF-incorporated TSS with DPSCs. Histologically, the generated tissue was shown to be with well vascularity, have new matrix deposition and dentin-like tissue formation, and consist of both the transplanted and host-derived cells. Collectively, these data support the use of bFGF-incorporated silk fibroin scaffold as a highly promising scaffold candidate for future treatment concepts in regenerative endodontics to save teeth. PMID- 25791685 TI - A simple and robust method for pre-wetting poly (lactic-co-glycolic) acid microspheres. AB - Poly (lactic-co-glycolic) acid microspheres are amenable to a number of biomedical procedures that support delivery of cells, drugs, peptides or genes. Hydrophilisation or wetting of poly (lactic-co-glycolic) acid are an important pre-requisites for attachment of cells and can be achieved via exposure to plasma oxygen or nitrogen, surface hydrolysis with NaOH or chloric acid, immersion in ethanol and water, or prolonged incubation in phosphate buffered saline or cell culture medium. The aim of this study is to develop a simple method for wetting poly (lactic-co-glycolic) acid microspheres for cell delivery applications. A one step ethanol immersion process that involved addition of serum-supplemented medium and ethanol to PLGA microspheres over 30 min-24 h is described in the present study. This protocol presents a more efficient methodology than conventional two-step wetting procedures. Attachment of human skeletal myoblasts to poly (lactic-co-glycolic) acid microspheres was dependent on extent of wetting, changes in surface topography mediated by ethanol pre-wetting and serum protein adsorption. Ethanol, at 70% (v/v) and 100%, facilitated similar levels of wetting. Wetting with 35% (v/v) ethanol was only achieved after 24 h. Pre-wetting (over 3 h) with 70% (v/v) ethanol allowed significantly greater (p <= 0.01) serum protein adsorption to microspheres than wetting with 35% (v/v) ethanol. On serum protein-loaded microspheres, greater numbers of myoblasts attached to constructs wetted with 70% ethanol than those partially wetted with 35% (v/v) ethanol. Microspheres treated with 70% (v/v) ethanol presented a more rugose surface than those treated with 35% (v/v) ethanol, indicating that more efficient myoblast adhesion to the former may be at least partially attributed to differences in surface structure. We conclude that our novel protocol for pre-wetting poly (lactic-co-glycolic) acid microspheres that incorporates biochemical and structural features into this biomaterial can facilitate myoblast delivery for use in clinical settings. PMID- 25791686 TI - Early identification of pituitary dysfunction in congenital nasal pyriform aperture stenosis: recommendations based on experience in a single centre. AB - BACKGROUND: Congenital nasal pyriform aperture stenosis (CNPAS) is an increasingly recognised cause of upper airway obstruction associated with midline abnormalities. Studies have described pituitary dysfunction in 40% of patients. We aimed to develop guidelines for: (a) the early identification of pituitary insufficiency to minimise surgical risk and (b) to stratify patients for follow up. METHODS: Retrospective case note review of patients with CNPAS between 2000 and 2014 in a tertiary paediatric unit. RESULTS: 20 patients (12 female:8 male) were analysed; 16 were diagnosed during the neonatal period while 4 were diagnosed later. There was no consistent approach in the evaluation of the pituitary axis at diagnosis. Pituitary dysfunction was identified in 3 (15%) patients, 2 of whom were found during evaluation of short stature in mid-late childhood. Hypoglycaemia and conjugated hyperbilirubinaemia, but not the degree of stenosis, were highly predictive of pituitary dysfunction (p < 0.05). Available height standard deviation score (SDS) data at 1 year of 70% of our patients identified both of the late-diagnosed growth hormone-deficient patients, with SDS of -2.6 and -3.6, respectively. CONCLUSION: All CNPAS patients should have MRI of the brain and baseline endocrine investigations at diagnosis. Growth monitoring for at least 1 year is recommended as low, or falling, height SDS at 1 year is a good predictor of pituitary dysfunction. PMID- 25791687 TI - EACTA-JCVA: cooperation to partnership. PMID- 25791688 TI - There's no lightning without a storm: complications of electrophysiology procedures in grown-up congenital heart disease. PMID- 25791689 TI - Outcome of emergency coronary artery bypass grafting. AB - OBJECTIVES: The aim of this study was to evaluate the immediate and late outcome of emergency coronary artery bypass grafting (CABG) in a multicenter setting. DESIGN: Multicenter, retrospective study. SETTING: Four university hospitals. PARTICIPANTS: 596 patients were included in this study. INTERVENTIONS: Included patients underwent isolated, emergency CABG. MEASUREMENTS AND MAIN RESULTS: Sixty patients (absolute rate: 10.1%, pooled rate: 8.7%) died during the in-hospital stay period. Increasing emergency CABG classes (p<0.0001), recent myocardial infarction (p=0.019), left ventricular ejection fraction<=30% (p=0.034), on-pump surgery (p=0.012), and participating centers (p<0.0001) were independent predictors of in-hospital mortality. Survival rates at 1, 3, and 5 years were 86.4%, 81.6%, and 76.1%, respectively. Extracorporeal membrane oxygenation was used in 6 patients and 3 of them (50.0%) survived the immediate postoperative period. Patient populations of participating centers differed significantly in most of baseline characteristics. The preoperative use of intra-aortic balloon pump (8% to 51%) and off-pump surgery (2.8% to 56.3%) varied significantly between institutions. In-hospital mortality (2.8%, 5.9%, 7.7% and 19.8%, p<0.0001), as well as midterm survival, significantly differed between institutions (at 3 years, 90.6%, 89.8%, 81.2%, and 67.2%, p<0.0001). CONCLUSIONS: The outcome after emergency CABG is satisfactory despite a significant operative risk. However, the results of emergency CABG significantly differed between the participating institutions, likely due to differences in the referral pathways and perioperative treatment strategies. Evaluation of these factors is crucial for implementation of treatment in centers with suboptimal results. PMID- 25791690 TI - Case 4-2015: use of the lariat device for left atrial appendage closure. PMID- 25791691 TI - Pro: Prophylactic preoperative use of an intra-aortic balloon pump is indicated in high-risk coronary patients undergoing coronary artery bypass grafting. PMID- 25791692 TI - Con: Prophylactic preoperative use of an intra-aortic balloon pump is not indicated in high-risk coronary patients undergoing coronary artery bypass grafting. PMID- 25791694 TI - Lateral basal approach with a supine, no-retractor method for microvascular decompression for hemifacial spasm. AB - BACKGROUND: We describe the details of our unique surgical procedures for microvascular decompression for hemifacial spasm. METHODS: A patient is just laid supine, skipping the complicated preparation for the lateral or park-bench position. The subfloccular approach from a small cranial window situated on the more lateral and basal side of the occipital cranium enables the surgeon to reach all the segments of the facial nerve root without cerebellar retraction by a spatula. CONCLUSIONS: We believe this approach is ideal for the safe and precise decompression of any part of the facial nerve root. PMID- 25791693 TI - Preoperative neutrophil-to-lymphocyte ratio for prognostication of patients with distal bile duct carcinomas undergoing surgery. AB - BACKGROUND: Surgical resection continues to be the current standard treatment for distal bile duct carcinoma (DBC), as no effective alternative treatment exists. However, even after resection, the long-term prognosis is poor. Simple biomarkers that can predict response or toxicity, and which are applicable to all community oncology settings worldwide, have not been identified. Differential white-cell counts, such as the neutrophil-to-lymphocyte ratio (NLR), as markers of inflammation, may be simple and readily available biomarkers. This study aimed to determine whether the NLR can be used as a predictor of surgical outcome in patients with DBC. MATERIALS AND METHODS: We enrolled 91 DBC patients who had undergone pancreatoduodenectomy (PD) at a single institution between April 2000 and December 2013. Blood was sampled on admission for determination of NLR. An NLR of >=5 was selected as the cut-off value for validation. RESULTS: Seventeen patients had an NLR of >=5 (Group 1; 18.7%), while 74 had an NLR of <5 (Group 2; 81.3%). The 1-, 3- and 5-year survival rates for Group 1 patients were 75.9, 34.5 and 34.5%, respectively, while those for Group 2 patients were 94.8, 55.2 and 46.6%, respectively (p = 0.02). There were no significant inter-group differences in clinicolaboratory background factors such as the mean operation time, bleeding volume, tumor size, CRP, neutrophil count and lactate dehydrogenase (LDH) level. On the other hand, there were significant inter-group differences for albumin level (p = 0.011), lymphocyte count (p = 0.001) and NLR (p < 0.001). Multivariate analyses were performed for factors such as gender, age, maximum tumor diameter, drainage method, operation time, bleeding volume, pathology, albumin, CRP, neutrophil count, lymphocyte count, LDH and NLR. The results revealed that NLR (odds ratio, 2.032; 95% CI, 0.999-4.134; p = 0.040) was associated with postoperative overall survival. CONCLUSIONS: An NLR of >=5 predicts a poor outcome in patients undergoing PD for DBC. NLR is an independent indicator of overall survival for such patients. PMID- 25791695 TI - Allergen-specific tolerance induction: of mice and men. PMID- 25791697 TI - A tetranuclear arylstibonic acid with an adamantane type structure. AB - Oxidative chlorination of ArSbCl2 (1) with SO2Cl2 provided ArSbCl4 (2), the base hydrolysis of which gave rise to the arylstibonic acid (ArSb)4O6(OH)4 (3) having an adamantane type structure. The intramolecularly coordinating substituent Ar = 6-diphenylphosphinoacenaphth-5-yl- modulates the Lewis acidity of 1-3 and prevents extensive aggregation. PMID- 25791696 TI - Optical and analytical investigations on dengue virus rapid diagnostic test for IgM antibody detection. AB - Evaluation of binding between analytes and its relevant ligands on surface plasmon resonance (SPR) biosensor is of considerable importance for accurate determination and screening of an interference in immunosensors. Dengue virus serotype 2 was used as a case study in this investigation. This research work compares and interprets the results obtained from analytical analysis with the experimental ones. Both the theoretical calculations and experimental results are verified with one sample from each category of dengue serotypes 2 (low, mid, and high positive), which have been examined in the database of established laboratorial diagnosis. In order to perform this investigation, the SPR angle variations are calculated, analyzed, and then validated via experimental SPR angle variations. Accordingly, the error ratios of 5.35, 6.54, and 3.72% were obtained for the low-, mid-, and high-positive-specific immune globulins of patient serums, respectively. In addition, the magnetic fields of the biosensor are numerically simulated to show the effect of different binding mediums. PMID- 25791698 TI - Two-coordinate hydrido-germylenes. AB - The first structurally characterised two-coordinate hydrido-germylenes, :Ge(H)L (L = -N(Ar){Si(OBu)}, Ar = C6H2{C(H)Ph2}2R-2,6,4; R = Pr(i) ((tBuO)L(?)), Me ((tBuO)L*)), have been prepared, and their dimerisation shown to be thermodynamically unfavourable, largely due to the extreme steric bulk of their amide ligands. PMID- 25791699 TI - [Ocular burn and scleral lenses]. PMID- 25791700 TI - Iris mammillations. PMID- 25791701 TI - [Lens subluxation in microspherophakia]. PMID- 25791702 TI - [OCT course in acute retinal pigment epithelitis]. PMID- 25791703 TI - [Purtscher retinopathy following a road traffic accident]. PMID- 25791704 TI - Exercise: not a miracle cure, just good medicine. PMID- 25791705 TI - De Novo Post-Diagnosis Aspirin Use and Mortality in Women with Stage I-III Breast Cancer. AB - BACKGROUND: Aspirin use has been associated with significant reductions in breast cancer-related mortality in some observational studies. However, these studies included women who initiated aspirin use before breast cancer diagnosis. It is unclear whether initiating aspirin use after diagnosis is associated with similar reductions in mortality. This study investigates associations between de novo post-diagnostic aspirin use and all cause, breast cancer-specific mortality. METHODS: Women, ages 50 to 80, with a diagnosis of stage I-III breast cancer were identified from Ireland's National Cancer Registry (N = 4,540). Initiation of de novo post-diagnostic aspirin use was identified from linked national prescription refill data (N = 764). Adjusted HRs were estimated for associations between de novo aspirin use and all-cause, breast cancer-specific mortality. RESULTS: The median time from diagnosis to aspirin initiation was 1.8 years. The mean number of days' supply of aspirin received was 631, and 95% of users were taking less than 150 mg/d. We found no association between de novo aspirin use and breast cancer-specific mortality [HR, 0.98; 95% confidence interval (CI), 0.74-1.30]. Similar null associations were found in women taking aspirin at high-intensity (HR, 1.03; 95% CI, 0.72-1.47) and women initiating use in the 1.5 years after diagnosis (HR, 1.04; 95% CI, 0.77-1.40). There was no effect modification by estrogen (Pinteraction = 0.81) or progesterone (Pinteraction = 0.41) receptor status. CONCLUSION: Initiating aspirin use after a breast cancer diagnosis was not associated with a reduction in breast cancer-specific mortality. IMPACT: On the basis of our findings, we suggest that a clearer understanding of aspirin's mechanism of action is needed to help inform the design of future studies in breast cancer. PMID- 25791706 TI - Confirmatory Factor Analysis of the Dutch Version of the Wechsler Memory Scale Fourth Edition (WMS-IV-NL). AB - The latent factor structure of the Dutch version of the Wechsler Memory Scale Fourth Edition (WMS-IV-NL) was examined with a series of confirmatory factor analyses. As part of the Dutch standardization, 1,188 healthy participants completed the WMS-IV-NL. Four models were tested for the Adult Battery (16-69 years; N = 699), and two models were tested for the Older Adult Battery (65-90 years; N = 489). Results corroborated the presence of three WMS-IV-NL factors in the Adult Battery consisting of Auditory Memory, Visual Memory, and Visual Working Memory. A two-factor model (consisting of Auditory Memory and Visual Memory) provided the best fit for the data of the Older Adult Battery. These findings provide evidence for the structural validity of the WMS-IV-NL, and further support the psychometric integrity of the WMS-IV. PMID- 25791707 TI - Magnetic resonance imaging in the evaluation of clinical treatment of otospongiosis: a pilot study. AB - OBJECTIVES: To evaluate the applicability of magnetic resonance imaging (MRI) as a method for monitoring the activity of otospongiotic lesions before and after clinical treatment. STUDY DESIGN: Prospective, randomized, controlled, double blind study. SETTING: One single tertiary care institution in a large, cosmopolitan city. METHODS: Twenty-six patients (n = 42 ears) with clinical, audiometric, and tomographic diagnosis of otosclerosis were enrolled. If computed tomography (CT) demonstrated active lesions, these patients underwent MRI to detect otospongiotic foci, seen as areas of gadolinium enhancement. Patients were divided into 3 groups and received treatment with placebo, sodium alendronate, or sodium fluoride for 6 months. After this period, clinical and audiometric evaluations and a second MRI were performed. Each MRI was evaluated by both a neuroradiologist and an otolaryngologist in a subjective (visual) and objective (using specific eFilm Workstation software) manner. RESULTS: Otospongiosis was most predominantly identified in the region anterior to the oval window, and this site was reliable for comparing pre- and posttreatment scans. The patients in the alendronate and sodium fluoride groups had MRI findings that suggested a decrease in activity of otospongiotic lesions, more relevant in the alendronate group. These findings were statistically significant for both subjective and objective MRI evaluations. CONCLUSIONS: MRI shows higher sensitivity than clinical or audiometric assessment for detecting reduction in activity of otospongiosis. The objective MRI evaluation based on software analysis was the most accurate method of monitoring clinical treatment response in otospongiosis. PMID- 25791708 TI - Vestibular Schwannoma Excision in Sporadic versus Neurofibromatosis Type 2 Populations. AB - OBJECTIVE: To understand the differences in characteristics of neurofibromatosis type 2 (NF2) and sporadic patients with surgically excised vestibular schwannomas in the state of California. STUDY DESIGN: Cross-sectional. SETTING, SUBJECTS, AND METHODS: The records of all patients who underwent vestibular schwannoma excision between 1997 and 2011 were extracted from the California Hospital Inpatient Discharge Databases (CHIDD). NF2 cases were identified using ICD-9-CM diagnosis code 237.72, neurofibromatosis, type 2. All other cases were recoded as sporadic. Trends in total number and population-adjusted rates (per 1 million California residents) of surgery, demographics, hospital case volume, state of residency, complications, length of stay, total charges, expected source of payment, and disposition were examined. RESULTS: Vestibular schwannoma (VS) excision was performed on 7017 patients, of which 464 patients (6.6%) had NF2. The population adjusted surgery rate declined from 11.8 to 6.2 (P < .001) for sporadic cases and from 0.3 to 0.2 (P = .01) for NF2 cases over the study period. NF2 was associated with younger age (mean, 32.9 vs 51.3), higher rate of other complications (8.8% vs 4.4%) and facial nerve complications (32.3% vs 16.8%), higher total charges (median $70,106 vs $46,395), longer stay (median 5 vs 4), and high volume hospitals (80.4% vs 48.8%) (all P < .001). CONCLUSION: The surgery rates for vestibular schwannoma excision for both sporadic and NF2 patients have declined, but the decline is more prominent for sporadic cases. NF2 patients tend to be younger and have a longer hospitalization and possibly higher corresponding hospital charges compared to patients with sporadic VS. PMID- 25791709 TI - Effects of self-directed and other-directed introspection and emotional valence on activation of the rostral prefrontal cortex during aesthetic experience. AB - The medial area of the rostral prefrontal cortex (rPFC) has been implicated in self-relevant processing, autobiographical memory and emotional processing, including the processing of pleasure during aesthetic experiences. The goal of this study was to investigate changes in rPFC activity using functional near infrared spectroscopy (fNIRS) in response to affective stimuli viewed in a self relevant or other-relevant context. Positive and negative images were displayed to 20 participants under two viewing conditions where participants were asked to think of their own emotions (self) or think about the emotions of the artist who created the work (other). The results revealed an increase of HbO when participants viewed images during the other-condition compared to the self condition. It was concluded that viewing stimuli from the perspective of another was associated with an increase of cognitive demand. The analysis of deoxygenated haemoglobin (HHb) at right hemispheric areas revealed that activation of the rPFC during the other-condition was specific to the negative images. When images were viewed from the perspective of the self, activation of the rPFC significantly increased at the right-medial area of the rPFC for positive images. Our findings indicate that the influence of valence on rPFC activation during aesthetic experience is contingent on the context of the viewing experience and there is a bias towards positive emotion when images are viewed from the context of the self. PMID- 25791710 TI - Left anterior cingulate activity predicts intra-individual reaction time variability in healthy adults. AB - Within-subject, or intra-individual, variability in reaction time (RT) is increasingly recognised as an important indicator of the efficiency of attentional control, yet there have been few investigations of the neural correlates of trial-to-trial RT variability in healthy adults. We sought to determine the neural correlates of intra-individual RT variability during a go/no go response inhibition task in 27 healthy, male participants. We found that reduced trial-to-trial RT variability (i.e. greater response stability) was significantly associated with greater activation in the left pregenual anterior cingulate. These results support the role of the left anterior cingulate in the dynamic control of attention and efficient response selection. Greater understanding of intra-individual RT variability and top-down attentional control in healthy adults may help to inform disorders that impact executive/attentional control, such as attention deficit hyperactivity disorder and schizophrenia. PMID- 25791711 TI - Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes. AB - BACKGROUND AND PURPOSE: Cerebral cavernous malformation (CCM) is a neurovascular dysplasia characterized by conglomerates of enlarged endothelial channels in the central nervous system, which are almost devoid of pericytes or smooth muscle cells. This disease is caused by loss-of-function mutations in CCM1, CCM2, or CCM3 genes in endothelial cells, making blood vessels highly susceptible to angiogenic stimuli. CCM1- and CCM3-silenced endothelial cells have a reduced expression of the Notch ligand Delta-like 4 (DLL4) resulting in impaired Notch signaling and irregular sprouting angiogenesis. This study aimed to address if DLL4, which is exclusively expressed on endothelial cells, may influence interactions of endothelial cells with pericytes, which express Notch3 as the predominant Notch receptor. METHODS: Genetic manipulation of primary human endothelial cells and brain pericytes. Transgenic mouse models were also used. RESULTS: Endothelial cell-specific ablation of Ccm1 and Ccm2 in different mouse models led to the formation of CCM-like lesions, which were poorly covered by periendothelial cells. CCM1 silencing in endothelial cells caused decreased Notch3 activity in cocultured pericytes. DLL4 proteins stimulated Notch3 receptors on human brain pericytes. Active Notch3 induced expression of PDGFRB2, N-Cadherin, HBEGF, TGFB1, NG2, and S1P genes. Notch3 signaling in pericytes enhanced the adhesion strength of pericytes to endothelial cells, limited their migratory and invasive behavior, and enhanced their antiangiogenic function. Pericytes silenced for Notch3 expression were more motile and could not efficiently repress angiogenesis. CONCLUSIONS: The data suggest that Notch signaling in pericytes is important to maintain the quiescent vascular phenotype. Deregulated Notch signaling may, therefore, contribute to the pathogenesis of CCM. PMID- 25791712 TI - Attention deficits after aneurysmal subarachnoid hemorrhage measured using the test of variables of attention. AB - BACKGROUND AND PURPOSE: The aim of this pilot study was to assess attention deficits in patients with aneurysmal subarachnoid hemorrhage using the test of variables of attention (TOVA). This is a computer-based continuous performance test providing objective measures of attention. We also compared the TOVA results with the attention and concentration domains of Montgomery Asberg Depression Rating Scale and Montreal cognitive assessment, 2 examiner-administrated neuropsychological instruments. METHODS: Nineteen patients with moderate to good recovery (Glasgow outcome scale, 4-5) were assessed using the TOVA, Montgomery Asberg Depression Rating Scale, and Montreal cognitive assessment. The measurements were done when the patients visited the hospital for a routine magnetic resonance imaging control of the aneurysm. RESULTS: TOVA performance was pathological in 58%. The dominating pattern was a worsening of performance in the second half of the test, commonly a failing to react to correct stimuli. We found no correlation between TOVA and the performance in concentration and attention domains of Montgomery Asberg Depression Rating Scale and Montreal cognitive assessment. CONCLUSIONS: Attention deficits, measured by the TOVA, were common after subarachnoid hemorrhage. This should be further studied to improve outcome. PMID- 25791713 TI - Surgeon case volume and 30-day mortality after carotid endarterectomy among contemporary medicare beneficiaries: before and after national coverage determination for carotid artery stenting. AB - BACKGROUND AND PURPOSE: After the 2005 National Coverage Determination to reimburse carotid artery stenting (CAS) for Medicare beneficiaries, the number of CAS procedures increased and carotid endarterectomy (CEA) decreased. We evaluated trends in surgeons' past-year CEA case-volume and 30-day mortality after CEA, and their association before and after the National Coverage Determination. METHODS: In a retrospective cohort study of patients undergoing CEA (2001-2008) and CAS (2005-2008) using Medicare data, we described yearly trends of CEA and CAS rates, patient characteristics, and 30-day mortality after CEA. We used logistic regression adjusting for patient- and surgeon-level factors to assess the effect of surgeon case volume on 30-day mortality after CEA. RESULTS: We identified 454 717 CEA and 27 943 CAS patients. Patients undergoing CEA in recent years were older and had more comorbidities than earlier years. CEA rates per 10 000 beneficiaries declined from 18.1 in 2002 to 12.7 in 2008, whereas median surgeon past-year case-volume declined from 27 to 21. The CAS rates peaked at 2.3 per 10 000 beneficiaries in 2006 but declined to 1.8 in 2008, resulting in declining overall revascularization procedure rates during 2005 to 2008. Thirty day post CEA mortality was 1.40% (95% confidence interval, 1.34-1.47) in 2001 to 2002 and 1.17% (1.10-1.24) in 2007 to 2008. Surgeon's past-year case-volume of <10 was associated with higher 30-day mortality consistently during 2001 to 2008. CONCLUSIONS: The rate of CEA procedures decreased substantially during 2001 to 2008, as did surgeon past-year case-volume. The postprocedural mortality in Medicare beneficiaries was high compared with trial patients but somewhat improved over time. Those operated by lower past-year case-volume surgeons had increased mortality. PMID- 25791714 TI - Purpose in life and cerebral infarcts in community-dwelling older people. AB - BACKGROUND AND PURPOSE: Purpose in life, the sense that life has meaning and direction, is associated with reduced risks of adverse health outcomes. However, it remains unknown whether purpose in life protects against the risk of cerebral infarcts among community-dwelling older people. We tested the hypothesis that greater purpose in life is associated with lower risk of cerebral infarcts. METHODS: Participants came from the Rush Memory and Aging Project. Each participant completed a standard measure of purpose in life. Uniform neuropathologic examination identified macroscopic infarcts and microinfarcts, blinded to clinical information. Association of purpose in life with cerebral infarcts was examined in ordinal logistic regression models using a semiquantitative outcome. RESULTS: Four hundred fifty-three participants were included in the analyses. The mean score on the measure of purpose was 3.5 (SD, 0.5; range, 2.1-5.0). Macroscopic infarcts were found in 154 (34.0%) people, and microinfarcts were found in 128 (28.3%) people. Greater purpose in life was associated with a lower odds of having more macroscopic infarcts (odds ratio, 0.535; 95% confidence interval, 0.346-0.826; P=0.005), but we did not find association with microinfarcts (odds ratio, 0.780; 95% confidence interval, 0.495 1.229; P=0.283). These results persisted after adjusting for vascular risk factors of body mass index, history of smoking, diabetes mellitus, and blood pressure, as well as measures of negative affect, physical activity, and clinical stroke. The association with macroscopic infarcts was driven by lacunar infarcts, and was independent of cerebral atherosclerosis and arteriolosclerosis. CONCLUSIONS: Purpose in life may affect risk for cerebral infarcts, specifically macroscopic lacunar infarcts. PMID- 25791715 TI - Functional role of regulatory lymphocytes in stroke: facts and controversies. PMID- 25791716 TI - Differential Effect of Baseline Computed Tomographic Angiography Collaterals on Clinical Outcome in Patients Enrolled in the Interventional Management of Stroke III Trial. AB - BACKGROUND AND PURPOSE: In the Interventional Management of Stroke (IMS) III trial, we sought to demonstrate evidence of a differential treatment effect of endovascular treatment of acute ischemic stroke compared with intravenous tissue type plasminogen activator, according to baseline collateral status measured using computed tomographic angiography. METHODS: Of 656 patients enrolled in Interventional Management of Stroke III trial, 306 had baseline computed tomographic angiography. Of these, 185 patients had M1 middle cerebral artery +/- intracranial internal carotid artery occlusion, where baseline collateral status could be measured. Collateral status was assessed by consensus using 3 different ordinal scales and categorized as good, intermediate, and poor. Multivariable modeling was used to assess the effect of collateral status and treatment type on clinical outcome by modified Rankin Scale (mRS 0-2, mRS 0-1, and the ordinal mRS). RESULTS: Of 185 patients, 126 randomized to endovascular therapy (87.6% recanalized, 41.3% 90-day mRS 0-2) and 59 to intravenous tissue-type plasminogen activator only (60.5% recanalized, 30.5% 90-day mRS 0-2). In multivariable modeling, collateral status was a significant predictor of all clinical outcomes (P<0.05). Maximal benefit with endovascular treatment across all clinical outcomes was seen in patients with intermediate collaterals, some benefit in patients with good collaterals, and none in patients with poor collaterals, although small sample size limited the power of the analysis to show a statistically significant interaction between collateral status and treatment type (P>0.05). CONCLUSION: Using data from a large randomized controlled trial (IMS III), we show that baseline computed tomographic angiography collaterals are a robust determinant of final clinical outcome and could be used to select patients for endovascular therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov/ct2/show/. Unique identifier: 0020NCT00359424. PMID- 25791718 TI - Prevalence of Pelvic Vein Pathology in Patients with Cryptogenic Stroke and Patent Foramen Ovale Undergoing MRV Pelvis. AB - BACKGROUND: A substantial proportion of ischemic strokes has no any identified underlying cause. Notably, the prevalence of a patent foramen ovale (PFO) is increased in cryptogenic stroke (CS) populations, which may serve as a conduit for paradoxical emboli originating from deep vein thrombosis (DVT) including the pelvic veins. Yet, there are no published guidelines for the assessment of pelvic veins as part of the stroke workup and few studies have systematically investigated pelvic veins as a potential source for paradoxical emboli in CS patients. Further, there is a relative paucity of data regarding pelvic DVT in CS and results have been conflicting. Hence, we sought to determine the prevalence of pelvic DVT in select CS patients with PFO who underwent magnetic resonance venography (MRV). METHODS: We retrospectively identified patients (n = 50) who underwent contrast-enhanced pelvic MRV at the discretion of the treating physician for the evaluation of CS in the presence of a PFO during hospitalization at a single academic stroke center between January 2011 through December 2013. Multivariable logistic regression analyses were used to assess for factors independently associated with the presence of an abnormal MRV pelvis. RESULTS: Patients (47 +/- 13 years of age) had MRV performed 4 +/- 3 days after their incident stroke. Nine patients had an abnormal MRV (18%). Of these, four (8%) had pelvic vein thrombosis and 5 (10%) a May-Thurner anatomic variant. All patients with pelvic DVT were subsequently anticoagulated with warfarin (none had abnormal hypercoagulability testing). Clinical clues suggesting paradoxical embolism were present in as many as 40% of patients. On multivariable logistic regression, a history of any risk factors predisposing to DVT (OR 6.7; coefficient 1.9; BCa 95% CI 0.08-20.2; p = 0.014) as well as the number of predisposing risk factors (OR 3.9; coefficient 1.4; BCa 95% CI 0.25-4.2; p = 0.005) predicted the presence of pelvic vein pathology on MRV. CONCLUSION: We demonstrate a relatively high prevalence of pelvic DVT among select CS patients emphasizing the importance of considering the pelvic veins as a potential source for emboli particularly in the presence of risk factors known to predispose DVT. Because patients were included at the treating physician's discretion, our results reflect 'real-life' practice. Our results may be of clinical importance as inclusion of pelvic vein imaging in CS patients with PFO had impactful therapeutic and nosologic implications. Further study is needed to define patients most likely to benefit from pelvic vein imaging. PMID- 25791717 TI - Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis. AB - BACKGROUND AND PURPOSE: Shortening door-to-needle time may lead to inadvertent intravenous thrombolysis (IVT) administration in stroke mimics (SMs). We sought to determine the safety of IVT in SMs using prospective, single-center data and by conducting a comprehensive meta-analysis of reported case-series. METHODS: We prospectively analyzed consecutive IVT-treated patients during a 5-year period at a tertiary care stroke center. A systematic review and meta-analysis of case series reporting safety of IVT in SMs and confirmed acute ischemic stroke were conducted. Symptomatic intracerebral hemorrhage was defined as imaging evidence of ICH with an National Institutes of Health Stroke scale increase of >=4 points. Favorable functional outcome at hospital discharge was defined as a modified Rankin Scale score of 0 to 1. RESULTS: Of 516 consecutive IVT patients at our tertiary care center (50% men; mean age, 60+/-14 years; median National Institutes of Health Stroke scale, 11; range, 3-22), SMs comprised 75 cases. Symptomatic intracerebral hemorrhage occurred in 1 patient, whereas we documented no cases of orolingual edema or major extracranial hemorrhagic complications. In meta-analysis of 9 studies (8942 IVT-treated patients), the pooled rates of symptomatic intracerebral hemorrhage and orolingual edema among 392 patients with SM treated with IVT were 0.5% (95% confidence interval, 0%-2%) and 0.3% (95% confidence interval, 0%-2%), respectively. Patients with SM were found to have a significantly lower risk for symptomatic intracerebral hemorrhage compared with patients with acute ischemic stroke (risk ratio=0.33; 95% confidence interval, 0.14-0.77; P=0.010), with no evidence of heterogeneity or publication bias. Favorable functional outcome was almost 3-fold higher in patients with SM in comparison with patients with acute ischemic stroke (risk ratio=2.78; 95% confidence interval, 2.07-3.73; P<0.00001). CONCLUSIONS: Our prospective, single center experience coupled with the findings of the comprehensive meta-analysis underscores the safety of IVT in SM. PMID- 25791719 TI - Graphene-enabled electrically switchable radar-absorbing surfaces. AB - Radar-absorbing materials are used in stealth technologies for concealment of an object from radar detection. Resistive and/or magnetic composite materials are used to reduce the backscattered microwave signals. Inability to control electrical properties of these materials, however, hinders the realization of active camouflage systems. Here, using large-area graphene electrodes, we demonstrate active surfaces that enable electrical control of reflection, transmission and absorption of microwaves. Instead of tuning bulk material property, our strategy relies on electrostatic tuning of the charge density on an atomically thin electrode, which operates as a tunable metal in microwave frequencies. Notably, we report large-area adaptive radar-absorbing surfaces with tunable reflection suppression ratio up to 50 dB with operation voltages <5 V. Using the developed surfaces, we demonstrate various device architectures including pixelated and curved surfaces. Our results provide a significant step in realization of active camouflage systems in microwave frequencies. PMID- 25791720 TI - Expression of Plasma microRNA-1/21/ 208a/499 in myocardial ischemic reperfusion injury. AB - OBJECTIVES: We aimed to measure changes in the levels of several miRNAs during open-heart surgery and to investigate the relationship between these changes and cardiac biomarkers. METHODS: Creatine kinase-muscle band (CK-MB), cardiac troponin (cTnI) and miRNA (miR-1/21/208a/499) levels were measured during open heart surgery in 15 patients undergoing combined mitral and aortic valve replacement. The levels of these markers were measured presurgically, 45 min after aortic clamping, 60 min after reperfusion and 24 h after surgery. RESULTS: Significant differences were found in miR-1/208a/499 levels but not in miR-21 levels. miR-1/208a levels were unchanged until 45 min after aortic clamping, increased 60 min after reperfusion (p < 0.001) and decreased significantly 24 h after surgery (p < 0.001). The changes in miR-1/208a levels exhibited a similar pattern to those observed for cTnI and CK-MB, although the changes in miR-208a levels reflected more rapidly than those in miR-1 levels. miR-499 levels decreased after reperfusion (p < 0.001) until 24 h after surgery; these levels were negatively correlated with cTnI and CK-MB levels at all of the time points. CONCLUSIONS: A time-dependent change in miR-1/208a/499 levels occurred during open-heart surgery, and these were associated with levels of cTnI and CK-MB. These results reveal that miRNAs may be sensitive biomarkers for I/R injury during open-heart surgery. PMID- 25791721 TI - The triathlon of magnetic actuation: rolling, propelling, swimming with a single magnetic material. AB - Magnetic actuation of microscopic devices in a liquid environment has been achieved in various ways, which can be grouped into rolling, propelling and swimming. Previous actuators were designed with a focus on one particular type of magnetic actuation. We have shown earlier that efficient magnetic propellers can be selected from randomly shaped magnetic nanostructures synthesized in solution. Here we show that these synthesized nanostructures can be used for all three types of magnetic actuation. Whereas it might not be surprising that single structures can roll in addition to propelling, swimming is unexpectedly also observed using the same material. In this case, however, the magnetically guided self-assembly of several individual particles into chain-like structures is necessary to obtain swimmers, since individual rigid nanostructures cannot swim. Interestingly, the direction of the swimming motion is not necessarily parallel to the long axis of the chain-like assembly, a finding that had been theoretically expected but experimentally not observed so far. Our findings show that the range of structures that can be effectively actuated by external magnetic fields is much broader than assumed until now. This could open up new opportunities for the design of magnetically actuated devices. PMID- 25791722 TI - Comment on "VEEG models of seizure frequency - Do SSRI medications or vitamin D supplements alter seizure collections?". PMID- 25791723 TI - Oligomerized, filamentous surface presentation of RANTES/CCL5 on vascular endothelial cells. AB - Vascular endothelial cells present luminal chemokines that arrest rolling leukocytes by activating integrins. It appears that several chemokines must form higher-order oligomers to elicit proper in vivo effects, as mutants restricted to forming dimers have lost the ability to recruit leukocytes to sites of inflammation. Here, we show for the first time that the chemokine RANTES/CCL5 binds to the surface of human endothelial cells in a regular filamentous pattern. Furthermore, the filaments bound to the surface in a heparan sulfate-dependent manner. By electron microscopy we observed labeling for RANTES on membrane projections as well as on the remaining plasma membrane. Mutant constructs of RANTES restricted either in binding to heparin, or in forming dimers or tetramers, appeared either in a granular, non-filamentous pattern or were not detectable on the cell surface. The RANTES filaments were also present after exposure to flow, suggesting that they can be present in vivo. Taken together with the lacking in vivo or in vitro effects of RANTES mutants, we suggest that the filamentous structures of RANTES may be of physiological importance in leukocyte recruitment. PMID- 25791724 TI - Utility of the CKD273 peptide classifier in predicting chronic kidney disease progression. AB - BACKGROUND: Chronic kidney disease (CKD) is a growing public health concern, afflicting approximately one-tenth of adults in developed countries. However, the clinical need for an accurate test, such as a biomarker and/or peptide classifier, for predicting CKD progression and related adverse outcomes remains unaddressed. Recently, a proteomics approach based on capillary electrophoresis mass spectrometry was employed to develop a urinary peptide-based high dimensional classifier, namely CKD273, for predicting CKD progression. OBJECTIVES: The study aims to critically appraise the evidence level of the CKD273 classifier's utility in predicting CKD progression, according to the Oxford Evidence-Based Medicine (EBM) and Strength of Recommendation Taxonomy (SORT) guidelines. METHODS: Eligible studies were identified by a literature search of MEDLINE and Web of Science Expanded Core Collection databases. Limitations were set to prospective cohort studies evaluating the classifier's accuracy in predicting CKD progression. Data extraction was undertaken according to a predefined protocol by two independent reviewers. The EBM and SORT guidelines were applied to appraise the CKD273 classifier's utility for predicting CKD progression. RESULTS: The query search results rendered four prospective cohort studies. The classifier performed independently of age, gender and the type of urine storage containers used. The classifier predicted the development of micro- or macroalbuminuria and rapid decline (i.e. >-5% annual decrease) in the estimated glomerular filtration rate. One study assessed the association of the classifier with end-stage renal disease and death but did not take confounding factors into account. The CKD273 classifier attained high evidence levels according to the EBM (score range 1b), supporting its utility for predicting CKD progression. However, lower scores were attained when the studies were scored according the SORT guidelines (score ranges 1-4). CONCLUSIONS: Initial promising evidence supports the CKD273 classifier's utility in predicting CKD progression. The classifier's applicability should be corroborated with additional evidence arising from inception cohort studies assessing patient oriented outcomes, which demonstrate its added value beyond currently available clinical risk predictors, as well as its cost-effectiveness in clinical practice. PMID- 25791725 TI - SOX3 Overdosage Permits Normal Sex Development in Females with Random X Inactivation. AB - Submicroscopic duplications involving SOX3 and/or its flanking regions have been identified in 46,XX individuals both with and without disorders of sex development, raising the question whether SOX3 overdosage is sufficient to induce testicular development in genetically female individuals. Here, we report a mother-daughter pair with female phenotypes and random X inactivation. The individuals carry complex X chromosomal rearrangements leading to a copy number gain of genomic regions involving SOX3 and its upstream region. The amplified DNA fragments were detected at Xq27. These results provide evidence that SOX3 overdosage permits normal sex development in 46,XX individuals with random X inactivation. PMID- 25791726 TI - Kidney Transplantation in HIV-Infected Recipients: Encouraging Outcomes, but Registry Data Are No Longer Enough. PMID- 25791727 TI - A National Study of Outcomes among HIV-Infected Kidney Transplant Recipients. AB - Kidney transplantation is a viable treatment for select patients with HIV and ESRD, but data are lacking regarding long-term outcomes and comparisons with appropriately matched HIV-negative patients. We analyzed data from the Scientific Registry of Transplant Recipients (SRTR; 2002-2011): 510 adult kidney transplant recipients with HIV (median follow-up, 3.8 years) matched 1:10 to HIV-negative controls. Compared with HIV-negative controls, HIV-infected recipients had significantly lower 5-year (75.3% versus 69.2%) and 10-year (54.4% versus 49.8%) post-transplant graft survival (GS) (hazard ratio [HR], 1.37; 95% confidence interval [95% CI], 1.15 to 1.64; P<0.001) that persisted when censoring for death (HR, 1.43; 95% CI, 1.12 to 1.84; P=0.005). However, compared with HIV negative/hepatitis C virus (HCV)-negative controls, HIV monoinfected recipients had similar 5-year and 10-year GS, whereas HIV/HCV coinfected recipients had worse GS (5-year: 64.0% versus 52.0%, P=0.02; 10-year: 36.2% versus 27.0%, P=0.004 [HR, 1.38; 95% CI, 1.08 to 1.77; P=0.01]). Patient survival (PS) among HIV-infected recipients was 83.5% at 5 years and 51.6% at 10 years and was significantly lower than PS among HIV-negative controls (HR, 1.34; 95% CI, 1.08 to 1.68; P<0.01). However, PS was similar for HIV monoinfected recipients and HIV negative/HCV-negative controls at both times. HIV/HCV coinfected recipients had worse PS compared with HIV-negative/HCV-infected controls (5-year: 67.0% versus 78.6%, P=0.007; 10-year: 29.3% versus 56.23%, P=0.002 [HR, 1.57; 95% CI, 1.11 to 2.22; P=0.01]). In conclusion, HIV-negative and HIV monoinfected kidney transplant recipients had similar GS and PS, whereas HIV/HCV coinfected recipients had worse outcomes. Although encouraging, these results suggest caution in transplanting coinfected patients. PMID- 25791728 TI - The endocannabinoid system and its therapeutic implications in rheumatoid arthritis. AB - Since the discovery of the endogenous receptor for Delta(9)-tetrahydrocannabinol, a main constituent of marijuana, the endocannabinoid system (comprising cannabinoid receptors and their endogenous ligands, as well as the enzymes involved in their metabolic processes) has been implicated as having multiple regulatory functions in many central and peripheral conditions, including rheumatoid arthritis (RA). RA is an immune-mediated inflammatory disease that is associated with the involvement of many kinds of cells (such as fibroblastlike synoviocytes [FLSs], osteoclasts, T cells, B cells, and macrophages) and molecules (such as interleukin-1beta, tumor necrosis factor-alpha, interleukin-6, matrix metalloproteinases [MMPs], and chemokines). Increasing evidence suggests that the endocannabinoid system, especially cannabinoid receptor 2 (CB2), has an important role in the pathophysiology of RA. Many members of the endocannabinoid system are reported to inhibit synovial inflammation, hyperplasia, and cartilage destruction in RA. In particular, specific activation of CB2 may relieve RA by inhibiting not only the production of autoantibodies, proinflammatory cytokines, and MMPs, but also bone erosion, immune response mediated by T cells, and the proliferation of FLSs. In this review, we will discuss the possible functions of the endocannabinoid system in the modulation of RA, which may be a potential target for treatment. PMID- 25791731 TI - Morphometric study of the testis and reproductive tract (including sperm granuloma) after vasectomy in mature rats. AB - By utilizing the rabbit model, previous studies have found good evidence indicating that vasectomy-induced spermatogenic damage is pressure-mediated: the damage occurs when the occluded reproductive tract is unable to accommodate additional spermatozoa produced by the testis. More studies with the more commonly used rat model have shown, however, controversial results on whether and why the damage occurs. In this study, 12 mature male Sprague-Dawley rats were subjected to unilateral vasectomy: double ligation (without severing) of the vas deferens exposed via a small inguinal incision; 37 days after the operation, the testes, epididymides, vasa deferentia (juxta-epididymal segments), and sperm granulomas (at the vasectomy site) were removed to obtain methacrylate resin embedded sections and morphometric studies carried out with light microscopy. Marked spermatogenic damage with spermatids and spermatocytes depleted in the seminiferous epithelium in 43% of the seminiferous tubule profiles was demonstrated in 5 of the 12 testes on the vasectomized side, and the damage was associated with smaller or absent sperm granulomas; in the other 7 testes with essentially normal spermatogenesis, there was an increase (by 111% on average) in the volume of the tubule lumen, associated with larger granulomas or granulomas containing more spermatozoa. There was an overall increase (by 66%) in the thickness of the rete testis in the 12 testes; the epididymis or vas deferens showed no distension. It seems therefore that the spermatogenic damage induced by vasectomy in rats is pressure-mediated as well, and that variation in the damage depends mainly on the postoperative development of the sperm granuloma. PMID- 25791732 TI - Renal tuberculosis tends to be low symptoms: how to improve the diagnosis and treatment of renal tuberculosis. PMID- 25791733 TI - Clinical outcome of treating intractable hematospermia using holmium laser incision through a ureteroscope. PMID- 25791730 TI - Sex determination in mammalian germ cells. AB - Germ cells are the precursors of the sperm and oocytes and hence are critical for survival of the species. In mammals, they are specified during fetal life, migrate to the developing gonads and then undergo a critical period during which they are instructed, by the soma, to adopt the appropriate sexual fate. In a fetal ovary, germ cells enter meiosis and commit to oogenesis, whereas in a fetal testis, they avoid entry into meiosis and instead undergo mitotic arrest and mature toward spermatogenesis. Here, we discuss what we know so far about the regulation of sex-specific differentiation of germ cells, considering extrinsic molecular cues produced by somatic cells, as well as critical intrinsic changes within the germ cells. This review focuses almost exclusively on our understanding of these events in the mouse model. PMID- 25791734 TI - How to make a human germ cell. AB - How the primordial germ cell (PGC) lineage, which eventually gives rise to spermatozoa in males and oocytes in females, is established in the developing mammalian embryo has been a critical topic in both developmental and reproductive biology for many years. There have been significant breakthroughs over the past two decades in establishing both the source of PGCs and the factors that regulate the specification of this lineage in mice, [1] but our understanding of the factors that control PGC development in the human is rudimentary. The SRY-related HMG-box (SOX) family of transcription factors consists of 20 genes in humans and mice that are involved in the maintenance of pluripotency, male sexual development, and other processes. A recent paper in Cell has identified one member of this family, SOX17, as an essential factor for inducing the PGC lineage in humans. [2] Surprisingly, this protein does not appear to have a role in PGC specification in mice. This work not only introduces a new and important player to the field of germ cell specification, but also emphasizes the uniqueness of human PGC development compared to more extensively studied mouse models. PMID- 25791735 TI - Immune modulation by virus-encoded secreted chemokine binding proteins. AB - Chemokines are chemoattractant cytokines that mediate the migration of immune cells to sites of infection which play an important role in innate and adaptive immunity. As an immune evasion strategy, large DNA viruses (herpesviruses and poxviruses) encode soluble chemokine binding proteins that bind chemokines with high affinity, even though they do not show sequence similarity to cellular chemokine receptors. This review summarizes the different secreted viral chemokine binding proteins described to date, with special emphasis on the diverse mechanisms of action they exhibit to interfere with chemokine function and their specific contribution to virus pathogenesis. PMID- 25791736 TI - A novel grapevine badnavirus is associated with the Roditis leaf discoloration disease. AB - Roditis leaf discoloration (RLD), a graft-transmissible disease of grapevine, was first reported in Greece in the 1980s. Even though various native grapevine viruses were identified in the affected vines, the etiology of the disease remained unknown. In the present study, we used an NGS platform for sequencing siRNAs from a twenty-year old Roditis vine showing typical RLD symptoms. Analysis of the NGS data revealed the presence of various known grapevine viruses and viroids as well as a hitherto uncharacterized DNA virus. The circular genome of the new virus was fully reassembled. It is 6988 nts long and includes 4 open reading frames (ORFs). ORF1, ORF2 and ORF4 code for proteins with unknown functions while ORF3 encodes a polyprotein with motifs related to the replication, encapsidation and movement of the virus. Phylogenetic analysis classified the novel virus within the genus Badnavirus, with closest relationship to Fig badnavirus 1. Further studies showed that the new badnavirus is closely related with the RLD disease and the provisional name grapevine Roditis leaf discoloration-associated virus (GRLDaV) is proposed. Our findings extend the number of DNA viruses identified in grapevine, further drawing attention to the potential importance of this virus group on grapevine pathology. PMID- 25791729 TI - Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis. AB - Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20-40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. It is expected that TGCT have carcinoma in situ(CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. The overall cure rate of TGCT is more than 90%, however, men surviving TGCT can present long-term side effects of systemic cancer treatment. In contrast, men diagnosed and treated for CIS only continue to live without these long-term side effects. Therefore, early detection of CIS has great health benefits, which will require an informative screening method. This review described the etiology and early pathogenesis of TGCT, as well as the possibilities of early detection and future potential of screening men at risk for TGCT. For screening, a well-defined risk profile based on both genetic and environmental risk factors is needed. Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. Prenatal, perinatal, and postnatal environmental factors also influence the onset of CIS. A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. Further research is needed to develop a well-defined TGCT risk profile, based on gene-environment interactions, combined with noninvasive detection method for CIS. PMID- 25791737 TI - Complete nucleotide sequences of two closely related tobacco rattle virus RNA2s for which previously possibly only deletion/recombination mutants had been described. AB - The almost complete nucleotide (nt) sequences lacking only short primer-derived 5' and 3' terminal portions were determined for the RNA2s of two closely related tobacco rattle virus (TRV) isolates which were detected in recently infected roots of Nicotiana benthamiana bait plants (isolate HaB) or of field-grown potato plants (isolate HaW), respectively. The sequences of c. 1350 5' proximal nts in these RNA2s were almost identical to those in four previously described TRV isolates from potatoes in the Netherlands and Poland which had been propagated in tobacco leaves. The RNA2s of the earlier isolates, however, consist of only c. 2000 nts, whereas the HaW and HaB RNA2s comprise more than 4000 nts. In addition to the coat protein gene which is present in the RNA2s of all isolates, the HaW and HaB RNA2s contain two further open reading frames which in the previous isolates were apparently lost either entirely or of which small remnants only were left. The RNA2s of the previously described isolates and of our new ones have different RNA1-related 3' ends which apparently have been acquired from different supporting RNA1s. After transmission to tobacco leaves HaB RNA2 formed deletion/recombination mutants which--as in the previous isolates--consisted of only c. 2000 nts. They had acquired the 3' end from their supporting RNA1. PMID- 25791738 TI - [In-phantom dosimetric measurements as quality control for brachytherapy: System check and constancy check]. AB - In brachytherapy dosimetric measurements are difficult due to the inherent dose inhomogenieties. Typically in routine clincal practice only the nominal dose rate is determined for computer controlled afterloading systems. The region of interest lies close to the source when measuring the spatial dose distribution. In this region small errors in the postioning of the detector, and its finite size, lead to large measurement uncertainties that exacerbate the routine dosimetric control of the system in the clinic. The size of the measurement chamber, its energy dependence, and the directional dependence of the measurement apparatus are the factors which have a significant influence on dosimetry. Although ionisation chambers are relatively large, they are employed since similar chambers are commonly found on clincal brachytherapy units. The dose is determined using DIN 6800 [11] since DIN 6809-2 [12], which deals with dosimetry in brachytherapy, is antiquated and is currently in the process of revision. Further information regarding dosimetry for brachytherapy can be found in textbooks [1] and [2]. The measurements for this work were performed with a HDR (High-Dose-Rate) (192)Ir source, type mHDR V2, and a Microselectron Afterloader V2 both from Nucletron/Elekta. In this work two dosimetric procedures are presented which, despite the aforemention difficulties, should assist in performing checks of the proper operation of the system. The first is a system check that measures the dose distribution along a line and is to be performed when first bringing the afterloader into operation, or after significant changes to the system. The other is a dosimetric constancy check, which with little effort can be performed monhtly or weekly. It simultaneously verifies the positioning of the source at two positions, the functionality of the system clock and the automatic re-calculation of the source activity. PMID- 25791739 TI - [Corneal power after descemet stripping automated endothelial keratoplasty (DSAEK) - Modeling and concept for calculation of intraocular lenses]. AB - BACKGROUND AND PURPOSE: Descemet stripping automated endothelial keratoplasty (DSAEK) is an established treatment option for pathologies of the corneal endothelium. It is typically accompanied with a hyperopic shift in refraction. The purpose of this work is to predict corneal geometry after DSAEK based on model data and to present a concept how to determine corneal power, e.g. for intraocular power calculation to prevent a refractive surprise with a subsequent cataract surgery. MATERIAL AND METHODS: Based on data of the Kooijman schematic model eye we simulated a microkeratome cut parallel to the corneal front surface for donor trephination to determine the radial thickness profile of the posterior corneal donor lamella. This donor lamella was tension-neutrally adapted to the back surface of the host and the profile of the cornea after DSAEK was derived and characterized by a quadric surface. Comparison with the curvature of the host without and with donor could resample hyperopic shift which was published in literature. A method was shown how to determine corneal power after DSAEK. RESULTS: From the data of the Kooijman schematic model eye and the donor characteristics central / peripheral corneal thickness was increased by 150 / 250MUm due to adaptation of the donor lamella. Geometry of corneal back surface showed a reduced radius of curvature (by about 0.9mm) and a change in conic constant (by about -0.13). Persistent clinically observed hyperopic shift correlates to the change in geometry of the cornea due to adaptation of the donor lamella, which reduces corneal power by 0.88 D. CONCLUSION: DSAEK leads to a hyperopic shift in refraction, which can be explained by a change in corneal back surface geometry. In case of subsequent cataract surgery, the intraocular lens power should be calculated with consideration of both corneal surfaces rather than keratometry or corneal topography in order to minimize a systematic hyperopic shift due to misinterpretation of corneal power after DSAEK. In case of a Triple-DSAEK, a target refraction of -1.5 D should be chosen in order to safely prevent postoperative hyperopia. PMID- 25791740 TI - The NUKDOS software for treatment planning in molecular radiotherapy. AB - The aim of this work was the development of a software tool for treatment planning prior to molecular radiotherapy, which comprises all functionality to objectively determine the activity to administer and the pertaining absorbed doses (including the corresponding error) based on a series of gamma camera images and one SPECT/CT or probe data. NUKDOS was developed in MATLAB. The workflow is based on the MIRD formalism For determination of the tissue or organ pharmacokinetics, gamma camera images as well as probe, urine, serum and blood activity data can be processed. To estimate the time-integrated activity coefficients (TIAC), sums of exponentials are fitted to the time activity data and integrated analytically. To obtain the TIAC on the voxel level, the voxel activity distribution from the quantitative 3D SPECT/CT (or PET/CT) is used for scaling and weighting the TIAC derived from the 2D organ data. The voxel S-values are automatically calculated based on the voxel-size of the image and the therapeutic nuclide ((90)Y, (131)I or (177)Lu). The absorbed dose coefficients are computed by convolution of the voxel TIAC and the voxel S-values. The activity to administer and the pertaining absorbed doses are determined by entering the absorbed dose for the organ at risk. The overall error of the calculated absorbed doses is determined by Gaussian error propagation. NUKDOS was tested for the operation systems Windows((r)) 7 (64 Bit) and 8 (64 Bit). The results of each working step were compared to commercially available (SAAMII, OLINDA/EXM) and in-house (UlmDOS) software. The application of the software is demonstrated using examples form peptide receptor radionuclide therapy (PRRT) and from radioiodine therapy of benign thyroid diseases. For the example from PRRT, the calculated activity to administer differed by 4% comparing NUKDOS and the final result using UlmDos, SAAMII and OLINDA/EXM sequentially. The absorbed dose for the spleen and tumour differed by 7% and 8%, respectively. The results from the example from radioiodine therapy of benign thyroid diseases and the example given in the latest corresponding SOP were identical. The implemented, objective methods facilitate accurate and reproducible results. The software is freely available. PMID- 25791741 TI - Physician knowledge about and perceptions of obesity management. AB - OBJECTIVE: Approximately 35% of US adults are obese. The purpose of this study was to assess the knowledge and practice patterns of primary care physicians (PCPs), endocrinologists (ENDOs), cardiologists (CARDs) and bariatricians (BARIs) regarding obesity. METHODS: A case vignette survey was distributed to 1625 US based PCPs, ENDOs, CARDs, and BARIs via email and fax in February 2013. Results were analysed with PASW Statistics 18. RESULTS: Respondents included 100 PCPs, 100 ENDOs, 70 CARDs, and 30 BARIs. The majority agreed obesity is a disease as defined by the AMA, however, half of PCPs, ENDOs, and CARDs also agreed obesity results from a lack of self-control. Familiarity with select obesity guidelines was low. Nearly all respondents used body mass index for obesity screening. No consensus as to when to initiate weight-loss medication was observed. Many physicians expected a larger weight loss with pharmacotherapy than is realistic (~ 30%) or were unsure (~ 22%). A majority of PCPs, ENDOs and CARDs expected less excess weight loss with gastric bypass surgery than is realistic, BARIs had a more reasonable expectation. CONCLUSIONS: Overall, respondents demonstrated knowledge gaps for obesity guidelines and pathophysiology and generally lacked understanding of obesity medication efficacy, safety and MOA. PMID- 25791742 TI - Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model. AB - Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 * 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naive control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes. PMID- 25791743 TI - Evaluation of a combined cognitive-behavioural and exercise intervention to manage fear of falling among elderly residents in nursing homes. AB - OBJECTIVES: Although the fear of falling is common among elderly residents in long-term care facilities, interventions developed for fear of falling management is very rare. Of these limited interventions, most were exercise interventions with only limited testing. The cognitive-behavioural intervention can decrease the fear of falling; however no intervention of the kind was developed and assessed to decrease fear of falling among the elderly in long-term care facilities. The purpose of this study was to examine the effectiveness of cognitive-behavioural strategies either with or without exercise in reducing fear of falling among elderly residents in nursing homes. METHOD: A prospective randomized control trial was conducted in six nursing homes in northern Taiwan. Seventy-five elderly participants were randomly assigned to one of the three groups: the comparison group, the cognitive-behavioural strategies with or without exercise group. The fear of falling, falls, depressive inclination, mobility, and muscle strength of extremities were collected at the two-month and five-month follow-up sessions, in which the progress of the patients were assessed. RESULTS: The mixed model analysis revealed that elderly adults in the combination experimental group had significant improvements compared with the other two groups on fear of falling, depressive inclination, mobility, and muscle strength at five months. The incidences of falls, post intervention, in both experimental groups were significantly lower than those in the comparison group. CONCLUSIONS: The results suggest that the combination intervention helped elderly residents manage their fear of falling and falls, decrease their depressive inclination, and enhance their mobility and muscle strength. PMID- 25791744 TI - Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice. AB - Genetic predisposition and environmental challenges interact to determine individual vulnerability to obesity and type 2 diabetes. We previously established a mouse model of chronic subordination stress-induced hyperphagia, obesity, metabolic like-syndrome and insulin resistance in the presence of a high fat diet. However, it remains to be established if social stress could also aggravate glucose intolerance in subjects genetically predisposed to develop obesity and type 2 diabetes. To answer this question, we subjected genetically obese mice due to deficiency of the leptin receptor (db/db strain) to chronic subordination stress. Over five weeks, subordination stress in db/db mice led to persistent hyperphagia, hyperglycemia and exacerbated glucose intolerance altogether suggestive of an aggravated disorder when compared to controls. On the contrary, body weight and fat mass were similarly affected in stressed and control mice likely due to the hyperactivity shown by subordinate mice. Stressed db/db mice also showed increased plasma inflammatory markers. Altogether our results suggest that chronic stress can aggravate glucose intolerance but not obesity in genetically predisposed subjects on the basis of a disrupted leptin circuitry. PMID- 25791745 TI - Molecular characterization of Hb Hamilton Hill (HBA2: c.388delC), a novel HBA2 variant generating a premature termination codon and truncated HBA2 chain. AB - In recent years, the identification of alpha-thalassemias caused by nondeletional mutations has increased significantly due to the advancement of sensitive molecular genetics tools. We report clinical and experimental data for a novel frameshift mutation caused by a single base deletion at position 388 in exon 3 of the alpha2-globin gene (HBA2: c.388delC; Hb Hamilton Hill), resulting in the phenotype of alpha-thalassemia (alpha-thal). Hb Hamilton Hill was identified in an adult female of unknown ethnicity investigated for unexplained microcytosis. Direct DNA sequencing of the HBA2 gene revealed a heterozygous mutation, HBA2: c.388delC, and the molecular effect of this mutation was assessed experimentally using our previously described in vitro model. The experimental analysis involved transfection of a human bladder carcinoma (5637) cell line with expression vectors carrying either HBA2-wild type (HBA2-WT) or HBA2: c.388delC followed by total RNA purification and cDNA synthesis. Both wild type and mutant gene expression was studied and compared at the transcriptional and translational levels using quantitative real time polymerase chain reaction (qReTi-PCR) and immunofluorochemistry (IFC), respectively. Our experimental data showed a significant reduction by 25.0% (p = 0.04) in the transcriptional activity generated from HBA2: c.388delC compared to HBA2-WT. As a result of this base deletion, a frameshift in the open reading frame generates a premature termination codon (PTC) at codon 132 of exon 3 resulting in the formation of a truncated alpha-globin chain. The truncated alpha-globin chain, observed by the IFC technique, is most likely unstable and undergoes a rapid turnover resulting in the thalassemic phenotype. PMID- 25791746 TI - Optogenetic and Chemogenetic Approaches To Advance Monitoring Molecules. AB - Fast-scan cyclic voltammetry (FSCV) is a high-resolution technique used to investigate neurotransmission in vitro, ex vivo, and in vivo. In this Viewpoint, I discuss how optogenetic and chemogenetic methods, when combined with FSCV, can impact and advance our understanding of neurotransmission and enable more detailed investigation of the roles of neurotransmitter systems in normal and disease states. PMID- 25791747 TI - The effects of Nordic school meals on concentration and school performance in 8- to 11-year-old children in the OPUS School Meal Study: a cluster-randomised, controlled, cross-over trial. AB - It is widely assumed that nutrition can improve school performance in children; however, evidence remains limited and inconclusive. In the present study, we investigated whether serving healthy school meals influenced concentration and school performance of 8- to 11-year-old Danish children. The OPUS (Optimal well being, development and health for Danish children through a healthy New Nordic Diet) School Meal Study was a cluster-randomised, controlled, cross-over trial comparing a healthy school meal programme with the usual packed lunch from home (control) each for 3 months (NCT 01457794). The d2 test of attention, the Learning Rating Scale (LRS) and standard tests on reading and mathematics proficiency were administered at baseline and at the end of each study period. Intervention effects were evaluated using hierarchical mixed models. The school meal intervention did not influence concentration performance (CP; primary outcome, n 693) or processing speed; however, the decrease in error percentage was 0.18 points smaller (P<0.001) in the intervention period than in the control period (medians: baseline 2.03%; intervention 1.46%; control 1.37%). In contrast, the intervention increased reading speed (0.7 sentence, P=0.009) and the number of correct sentences (1.8 sentences, P<0.001), which corresponded to 11 and 25%, respectively, of the effect of one school year. The percentage of correct sentences also improved (P<0.001), indicating that the number correct improved relatively more than reading speed. There was no effect on overall math performance or outcomes from the LRS. In conclusion, school meals did not affect CP, but improved reading performance, which is a complex cognitive activity that involves inference, and increased errors related to impulsivity and inattention. These findings are worth examining in future trials. PMID- 25791748 TI - Are Aquaporins the Missing Transmembrane Osmosensors? AB - Regulation of cell volume is central to homeostasis. It is assumed to begin with the detection of a change in water potential across the bounding membrane, but it is not clear how this is accomplished. While examples of general osmoreceptors (which sense osmotic pressure in one phase) and stretch-activated ion channels (which require swelling of a cell or organelle) are known, effective volume regulation requires true transmembrane osmosensors (TMOs) which directly detect a water potential difference spanning a membrane. At present, no TMO molecule has been unambiguously identified, and clear evidence for mammalian TMOs is notably lacking. In this paper, we set out a theory of TMOs which requires a water channel spanning the membrane that excludes the major osmotic solutes, responds directly without the need for any other process such as swelling, and signals to other molecules associated with the magnitude of changing osmotic differences. The most likely molecules that are fit for this purpose and which are also ubiquitous in eukaryotic cells are aquaporins (AQPs). We review experimental evidence from several systems which indicates that AQPs are essential elements in regulation and may be functioning as TMOs; i.e. the first step in an osmosensing sequence that signals osmotic imbalance in a cell or organelle. We extend this concept to several systems of current interest in which the cellular involvement of AQPs as simple water channels is puzzling or counter-intuitive. We suggest that, apart from regulatory volume changes in cells, AQPs may also be acting as TMOs in red cells, secretory granules and microorganisms. PMID- 25791749 TI - Sulfate addition as an effective method to improve methane fermentation performance and propionate degradation in thermophilic anaerobic co-digestion of coffee grounds, milk and waste activated sludge with AnMBR. AB - This study was conducted to investigate the effects of sulfate on propionate degradation and higher organic loading rate (OLR) achievement in a thermophilic AnMBR for 373days using coffee grounds, milk and waste activated sludge (WAS) as the co-substrate. Without the addition of sulfate, the anaerobic system failed at an OLR of 14.6g-COD/L/d, with propionate accumulating to above 2.23g-COD/L, and recovery by an alkalinity supplement was not successful. After sulfate was added into substrates at a COD/SO4(2-) ratio of 200:1 to 350:1, biogas production increased proportionally with OLR increasing from 4.06 to 15.2g-COD/L/d. Propionic acid was maintained at less than 100mg-COD/L due to the effective conversion of propionic acid to methane after the sulfate supplement was added. The long-term stable performance of the AnMBR indicated that adding sulfate was beneficial for the degradation of propionate and achieving a higher OLR under the thermophilic condition. PMID- 25791750 TI - Language knowledge and event knowledge in language use. AB - This paper examines how semantic knowledge is used in language comprehension and in making judgments about events in the world. We contrast knowledge gleaned from prior language experience ("language knowledge") and knowledge coming from prior experience with the world ("world knowledge"). In two corpus analyses, we show that previous research linking verb aspect and event representations have confounded language and world knowledge. Then, using carefully chosen stimuli that remove this confound, we performed four experiments that manipulated the degree to which language knowledge or world knowledge should be salient and relevant to performing a task, finding in each case that participants use the type of knowledge most appropriate to the task. These results provide evidence for a highly context-sensitive and interactionist perspective on how semantic knowledge is represented and used during language processing. PMID- 25791752 TI - In vitro cytotoxicity of gold nanorods in A549 cells. AB - Gold nanoparticles, which have unique physicochemical characteristics, are being used for an increasingly wide range of applications in biomedical research. In this study, gold nanorods (width of 25 nm, length of 52 nm) were found to be internalized by A549 cells and were primarily localized in the lysosomes and membranous vesicles. The integrity of the membranes of A549 cells exposed to gold nanorods for 4h was damaged, as indicated by laser scanning confocal microscopy (LSCM). Increased lactate dehydrogenase (LDH) leakage and decreased cell viability further indicated the concentration-dependent cytotoxicity of the gold nanorods to the A549 cells. Reactive oxygen species (ROS) production was induced in the A549 cells by the gold nanorods, and this effect was positively correlated with the concentration of the gold nanorods. The results of this study indicated that exposure to gold nanorods caused dose-dependent cytotoxicity in A549 cells and that oxidative stress may be the main factor causing cytotoxicity. PMID- 25791753 TI - Body mass index was associated with upstaging and upgrading in patients with low risk prostate cancer who met the inclusion criteria for active surveillance. AB - BACKGROUND: Obesity is associated with an increased risk of high-grade prostate cancer (PCa). The effect of body mass index (BMI) as a predictor of progression in men with low-risk PCa has been only poorly assessed. In this study, we evaluated the association of BMI with progression in patients with low-risk PCa who met the inclusion criteria for the active surveillance (AS) protocol. METHODS: We assessed 311 patients who underwent radical prostatectomy and were eligible for AS according to the following criteria: clinical stage T2a or less, prostate-specific antigen level < 10 ng/ml, 2 or fewer cores involved with cancer, Gleason score <= 6 grade, and prostate-specific antigen density < 0.2 ng/ml/cc. Reclassification was defined as upstaged (pathological stage > pT2) and upgraded (Gleason score >= 7; primary Gleason pattern 4) disease. Seminal vesicle invasion, positive lymph nodes, and tumor volume >= 0.5 ml were also recorded. RESULTS: We found that high BMI was significantly associated with upgrading, upstaging, and seminal vesicle invasion, whereas it was not associated with positive lymph nodes or large tumor volume. At multivariate analysis, 1 unit increase of BMI significantly increased the risk of upgrading, upstaging, seminal vesicle invasion, and any outcome by 21%, 23%, 27%, and 20%, respectively. The differences between areas under the receiver operating characteristics curves comparing models with and without BMI were statistically significant for upgrading (P = 0.0002), upstaging (P = 0.0007), and any outcome (P = 0.0001). CONCLUSIONS: BMI should be a selection criterion for inclusion of patients with low-risk PCa in AS programs. Our results support the idea that obesity is associated with worse prognosis and suggest that a close AS program is an appropriate treatment option for obese subjects. PMID- 25791754 TI - Biomarkers for immunotherapy in genitourinary malignancies. AB - Immunotherapy for genitourinary malignancies such as prostate, renal, and bladder cancers has experienced a resurgence since the development of 3 novel strategies: the autologous cellular product therapy, Sipuleucel-T for prostate cancer, the checkpoint inhibitors, anti-cytotoxic T-lymphocyte-associated protein 4 (anti CTLA-4), anti-programmed cell death ligand 1 (anti-PD1), and anti-programmed cell death ligand 1), respectively. These agents have led to strikingly durable responses in several of these solid tumors, but their efficacy has been inconsistent. Why all solid tumors are not equal in their response to these therapies is unclear. More importantly, changes in humoral or cellular responses which may reflect changes in a tumor's biology have been limited due to differences in immune monitoring and lack of consistency in established reliable immunologic endpoints. How to design immunologic end points that reflect a meaningful effect on the cancer remains a challenge for clinical trial development. The issues faced by clinical investigators and the current state of immune monitoring are discussed. PMID- 25791751 TI - Immunogenetics of Disease-Causing Inflammation in Sarcoidosis. AB - Sarcoidosis is a systemic inflammatory disorder characterised by tissue infiltration by mononuclear phagocytes and lymphocytes with associated non caseating granuloma formation. Originally described as a disorder of the skin, sarcoidosis can involve any organ with wide-ranging clinical manifestations and disease course. Recent studies have provided new insights into the mechanisms involved in disease pathobiology, and we now know that sarcoidosis has a clear genetic basis largely involving human leukocyte antigen (HLA) genes. In contrast to Mendelian-monogenic disorders--which are generally due to specific and relatively rare mutations often leading to a single amino acid change in an encoded protein--sarcoidosis results from genetic variations relatively common in the general population and involving multiple genes, each contributing an effect of varying magnitude. However, an individual may have the necessary genetic profile and yet the disease will not develop unless an environmental or infectious factor is encountered. Genetics appears also to contribute to the huge variability in clinical phenotype and disease behaviour. Moreover, it has been established that sarcoidosis granulomatous inflammation is a highly polarized T helper 1 immune response that starts with an antigenic stimulus followed by T cell activation via a classic HLA class II-mediated pathway. A complex network of lymphocytes, macrophages, and cytokines is pivotal in the orchestration and evolution of the granulomatous process. Despite these advances, the aetiology of sarcoidosis remains elusive and its pathogenesis incompletely understood. As such, there is an urgent need for a better understanding of disease pathogenesis, which hopefully will translate into the development of truly effective therapies. PMID- 25791755 TI - Next-generation sequencing technology in prostate cancer diagnosis, prognosis, and personalized treatment. AB - Next-generation sequencing (NGS) of the genetic information of cancer cells has revolutionized the field of cancer biology, including prostate cancer (PCa). New recurrent alterations have been identified in PCa (e.g., TMPRSS2-ERG translocation, SPOP and CHD1 mutations, and chromoplexy), and many previous ones in well-established pathways have been validated (e.g., androgen receptor overexpression and mutations; PTEN, RB1, and TP53 loss/mutations). With its highly heterogeneous nature, PCa continues to pose a tremendous challenge in terms of diagnosis and prognosis. Combining the information gained through NGS studies with clinicopathological and radiological data will help diagnose the aggressiveness of the cancer with greater accuracy. Furthermore, understanding the heterogeneity of tumor through single-cell or single-molecule sequencing technology will also strengthen the prognosis and provide better, patient specific drug identification. As this research becomes more prominent, it is important that urologic oncologists become familiar with the various NGS technologies and the results generated using them. We highlight the commonly used NGS tools and summarize recent discoveries relevant to PCa. PMID- 25791756 TI - Mitochondrial serine protease HTRA2 gene mutation in Asians with coexistent essential tremor and Parkinson disease. PMID- 25791757 TI - Resistance exercise and acute blood pressure responses. AB - AIM: Compare the acute hemodynamic and cardiovascular responses of high load/low repetition resistance training (RT) to low load/high repetition RT. METHODS: Thirteen healthy men performed four sets of 4 repetition maximum (RM) and 20RM leg--extensions without breath--holding. The RT was conducted in a randomized order and with 48 hours between bouts. Non--invasive beat--to--beat systolic and diastolic blood--pressure (SBP/DBP) was measured on the finger, while non- invasive cardiac output (CO) was assessed beat--to--beat by impedance- cardiography. RESULTS: Mean +/- SD resting SBP/DBP and CO were 126 +/- 14/73 +/- 9 mmHg and 5.6 +/- 9 L min --1 , respectively. Exercise SBP/DBP values increased to 154 +/- 22/99 +/-18 and 203 +/- 33/126 +/- 19 mmHg following 4RM and 20RM RT, respectively (compared to rest, all;; p < 0.001), and 20RM SBP/DBP values were higher than 4RM values (both, p < 0.001). The SBP increased from the first to the fourth set of exercise following the 20RM load (p < 0.01), but not so for the 4RM load. Exercise SBP/DBP values following the 4th rep of 20RM exercise (154 +/- 18/91 +/- 14), was similar to the 4RM values, but different to the 20th rep of the 20 RM loading (both; p < 0.001). CO increased to 10.8 +/- 2.6 and 13.9 +/- 2.2 L min --1 , following 4RM and 20RM RT, respectively (compared to rest, both; p < 0.001) and 20RM CO was higher than 4RM CO (p < 0.01). CONCLUSION: 20RM RT resulted in higher blood--pressure than 4RM RT when performed to voluntary exhaustion. Differences in hemodynamic responses seems to be related to training duration and not to difference in loading. PMID- 25791758 TI - Synthesis of Schiff base-Based 1,2,4-Oxadiazole Derivative as Fluorescence Turn On Sensor for High Selectivity of Pb(2.). AB - A new probe based on oxadiazole derivative (OXD) containing Schiff base moiety was synthesised as fluorescence turn-on sensor S1 . Furthermore, its fluorescents spectra (FS) result demonstrate that S1 selectively senses bivalent lead ion (Pb(2+)) in HEPES buffer solution (10 mM, pH = 7.0,DMF-H2O, 9:1, v/v), so S1 was a viable candidate as fluorescent receptor for a new Pb(2+) sensor. And the results of fluorescent spectral titration showed this sensor formed 1:1complex with Pb(2+). PMID- 25791759 TI - Characterising the disintegration properties of tablets in opaque media using texture analysis. AB - Tablet disintegration characterisation is used in pharmaceutical research, development, and quality control. Standard methods used to characterise tablet disintegration are often dependent on visual observation in measurement of disintegration times. This presents a challenge for disintegration studies of tablets in opaque, physiologically relevant media that could be useful for tablet formulation optimisation. This study has explored an application of texture analysis disintegration testing, a non-visual, quantitative means of determining tablet disintegration end point, by analysing the disintegration behaviour of two tablet formulations in opaque media. In this study, the disintegration behaviour of one tablet formulation manufactured in-house, and Sybedia Flashtab placebo tablets in water, bovine, and human milk were characterised. A novel method is presented to characterise the disintegration process and to quantify the disintegration end points of the tablets in various media using load data generated by a texture analyser probe. The disintegration times in the different media were found to be statistically different (P<0.0001) from one another for both tablet formulations using one-way ANOVA. Using the Tukey post-hoc test, the Sybedia Flashtab placebo tablets were found not to have statistically significant disintegration times from each other in human versus bovine milk (adjusted P value 0.1685). PMID- 25791760 TI - Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (A). Mechanisms of interaction. AB - This paper examines a perspective on the use of newly engineered nanomaterials as effective and safe carriers of genes for the therapy of cancer. Three different groups of cationic dendrimers (PAMAM, phosphorus and carbosilane) were complexed with anticancer siRNA and their biophysical properties of the dendriplexes analyzed. The potential of the dendrimers as nanocarriers for anticancer siBcl xl, siBcl-2, siMcl-1 siRNAs and a siScrambled sequence was explored. Dendrimer/siRNA complexes were characterized by methods including fluorescence, zeta potential, dynamic light scattering, circular dichroism, gel electrophoresis and transmission electron microscopy. Some of the experiments were done with heparin to check if siRNA can be easily disassociated from the complexes, and whether released siRNA maintains its structure after interaction with the dendrimer. The results indicate that siRNAs form complexes with all the dendrimers tested. Oligoribonucleotide duplexes can be released from dendriplexes after heparin treatment and the structure of siRNA is maintained in the case of PAMAM or carbosilane dendrimers. The dendrimers were also effective in protecting siRNA from RNase A activity. The selection of the best siRNA carrier will be made based on cell culture studies (Part B). PMID- 25791761 TI - Optimization of a pharmaceutical tablet formulation based on a design space approach and using vibrational spectroscopy as PAT tool. AB - The aim of the present study was to optimize a tablet formulation using a quality by design approach. The selected methodology was based on the variation of the filler grade, taking into account the particle size distribution (PSD) of active pharmaceutical ingredient (API) in order to improve five critical quality attributes (CQAs). Thus, a mixture design of experiments (DoE) was performed at pilot scale. The blending step was monitored using near infrared (NIR) spectroscopy as process analytical technology tool enabling real-time qualitative process monitoring. Furthermore, some tablets were analyzed by Raman imaging to evaluate the API distribution within the samples. Based on the DoE results, design spaces were computed using a risk-based Bayesian predictive approach to provide for each point of the experimental domain the expected probability to get the five CQAs jointly within the specifications in the future. Finally, the optimal conditions of the identified design space were successfully validated. In conclusion, a design space approach supported by NIR and Raman spectroscopy was able to define a blend that complies with the target product profile with a quantified guarantee or risk. PMID- 25791762 TI - In-situ forming composite implants for periodontitis treatment: How the formulation determines system performance. AB - Periodontitis is the primary cause of tooth loss in adults and a very wide-spread disease. Recently, composite implants, based on a drug release rate controlling polymer and an adhesive polymer, have been proposed for an efficient local drug treatment. However, the processes involved in implant formation and the control of drug release in these composite systems are complex and the relationships between the systems' composition and the implants' performance are yet unclear. In this study, advanced characterization techniques (e.g., electron paramagnetic resonance, EPR) were applied to better understand the in-situ forming implants based on: (i) different types of poly(lactic-co-glycolic acid) (PLGA) as drug release rate controlling polymers; (ii) hydroxypropyl methylcellulose (HPMC) as adhesive polymer; and (iii) doxycycline or metronidazole as drugs. Interestingly, HPMC addition to shorter chain PLGA slightly slows down drug release, whereas in the case of longer chain PLGA the release rate substantially increases. This opposite impact on drug release was rather surprising, since the only difference in the formulations was the polymer molecular weight of the PLGA. Based on the physico-chemical analyses, the underlying mechanisms could be explained as follows: since longer chain PLGA is more hydrophobic than shorter chain PLGA, the addition of HPMC leads to a much more pronounced facilitation of water penetration into the system (as evidenced by EPR). This and the higher polymer lipophilicity result in more rapid PLGA precipitation and a more porous inner implant structure. Consequently, drug release is accelerated. In contrast, water penetration into formulations based on shorter chain PLGA is rather similar in the presence and absence of HPMC and the resulting implants are much less porous than those based on longer chain PLGA. PMID- 25791763 TI - Localized scleroderma presenting as port-wine stains: report of two cases and a literature review. PMID- 25791764 TI - Showering effectiveness for human hair decontamination of the nerve agent VX. AB - In this work, our goals were to establish whether hair decontamination by showering one hour post-exposure to the highly toxic organophosphate nerve agent VX was effective, whether it required the addition of a detergent to water and, if it could be improved by using the adsorbent Fuller's Earth (FE) or the Reactive Skin Decontamination Lotion (RSDL) 30 min prior to showering. Hair exposure to VX and decontamination was performed by using an in vitro model. Hair showering led to 72% reduction of contamination. Addition of detergent to water slightly increased the decontamination effectiveness. Hair treatment with FE or RSDL improved the decontamination rate. Combination of FE use and showering, which yielded a decontamination factor of 41, was demonstrated to be the most effective hair decontamination procedure. Hair wiping after showering was shown to contribute to hair decontamination. Altogether, our results highlighted the importance of considering hair decontamination as an important part of body surface decontamination protocols. PMID- 25791765 TI - Mechanism for glutathione-mediated protection against the Pseudomonas aeruginosa redox toxin, pyocyanin. AB - Pseudomonas aeruginosa is an important human pathogen associated with several acute and chronic conditions, including diseases of the airways and wounds. The organism produces pyocyanin, an extracellular redox toxin that induces oxidative stress, depletes intracellular glutathione (GSH) and induces proliferative arrest and apoptosis, thus compromising the ability of tissue to repair itself. GSH is an important intra- and extracellular antioxidant, redox buffer and detoxifies xenobiotics by increasing their polarity, which facilitates their elimination. As previous studies have reported exogenous GSH to be protective against pyocyanin toxicity, this study was undertaken to explore the mechanism by which GSH protects host cells from the deleterious effects of the toxin. Co-incubation of pyocyanin with GSH resulted in a time-dependent diminished recovery of the toxin from the incubation medium. Concurrently, a highly polar green-colored metabolite was recovered that exhibited a UV-visible spectrum similar to pyocyanin and which was determined by mass spectrometry to have a major ion (m/z = 516) consistent with a glutathione conjugate. The ability of the conjugate to oxidize NADPH and to reduce molecular oxygen with the production of reactive oxygen species was comparable to pyocyanin yet it no longer demonstrated cytotoxicity towards host cells. These data suggest that GSH forms a cell-impermeant conjugate with pyocyanin and that availability of the thiol may be critical to minimizing the toxicity of this important bacterial virulence factor at infection sites. Our data indicate that for GSH to have a clinically effective role in neutralizing pyocyanin, the thiol needs to be available at millimolar concentrations. PMID- 25791766 TI - Is Clostridium difficile infection an increasingly common severe disease in adult intensive care units? A 10-year experience. AB - PURPOSE: Despite the high concentration of patients with known risk factors for Clostridium difficile infection (CDI) in intensive care units (ICUs), data on ICU patients are scarce. The aim of this study was describe the incidence, clinical characteristics, and evolution of CDI in critically ill patients. MATERIALS AND METHODS: From 2003 to 2012, adult patients admitted to an ICU (A-ICU) and positive for CDI were included and classified as follows: pre-ICU, if the positive sample was obtained within +/-3 days of ICU admission; in-ICU, if obtained after 3 days of ICU admission and up to 3 days after ICU discharge. RESULTS: We recorded 4095 CDI episodes, of which 328 were A-ICU (8%). Episodes of A-ICU decreased from 19.4 to 8.7 per 10000 ICU days of stay (P < .0001). Most A ICU CDIs (66.3%) were mild to moderate. Pre-ICU episodes accounted for 16.2% and were more severe complicated than in-ICU episodes (11% vs 0%; P = .020). Overall mortality was 28.6%, and CDI-attributable mortality was only 3%. CONCLUSION: The incidence of A-ICU CDI has decreased steadily over the last 10 years. A significant proportion of A-ICU CDI episodes are pre-ICU and are more severe than in-ICU CDI episodes. Most episodes of A-ICU CDI were nonsevere, with low associated mortality. PMID- 25791767 TI - Accidental spillage of breathing circuit condensate into airway leading to ventilator-associated pneumonia. PMID- 25791768 TI - Feasibility, safety, and outcome of very early enteral nutrition in critically ill patients: Results of an observational study. AB - BACKGROUND: In critically ill patients, early enteral nutrition (EN) within 24 to 72 hours is recommended. Although vasopressor-dependent shock after resuscitation is not a contraindication for EN initiation, feasibility and safety of very early (within 6 hours) EN initiation soon after resuscitation are unknown. OBJECTIVE: To evaluate the feasibility, safety, tolerance, and adequacy of very EN delivery in critically ill patients within 6 hours of intensive care unit (ICU) admission. MATERIAL AND METHODS: Prospectively collected data from a total of 308 medical and surgical patients admitted to the ICU for at least 3 days were analyzed. The patients in whom EN was initiated within 6 hours of ICU admission (n = 166) were compared with those in whom EN was initiated after 6 hours (n = 142). Comparisons were made between groups in the percentage of target calories and proteins delivered on day 3, percentages of patients achieving target calories and proteins on day 3, incidence of feed intolerance, ICU length of stay (LOS), hospital LOS, ICU/hospital discharge, and mortality. RESULTS: No significant differences were seen in percentage of calories (71.62% vs 71.83%; P = .09) and proteins (71.85% vs 68.89%; P = .2) delivered on day 3 between patients receiving EN within 6 hours and after 6 hours of admission. Similar number of patients achieved target calories (66.3% vs 67.6%; P = .8) and target proteins (66.9% vs 62.7%; P = .5) on day 3 in both groups. There were no significant differences between the groups for ICU LOS (11.41 days vs 11.72 days; P = .7) and hospital LOS (20.7 days vs 17.96 days; P = .1). A total of 77.1% patients were discharged in the group in whom EN was initiated within 6 hours and 67.6% patients were discharged in the group where EN was initiated after 6 hours (P = .07). The mortality rate was 22.9% and 32.4%, respectively (P = .07), in these groups. Overall incidence of EN interruption was 20.13% without significant difference between the 2 groups (<6 hours, 16.2%; >6 hours, 24.7%; P = .087). CONCLUSION: Initiation of EN within 6 hours of ICU admission is feasible and safe and can be implemented routinely in all ICU patients. PMID- 25791770 TI - The emerging role of rituximab in autoimmune blistering diseases. AB - Rituximab is a chimeric monoclonal antibody that selectively binds to the CD20 molecule on B cells, resulting in their lysis. In autoimmune blistering diseases, the auto-antibody-producing B cells are destroyed and auto-antibody levels are reduced or eliminated. In the majority of patients, rituximab produces rapid clinical response and early resolution. In part, this accounts for the increased use of rituximab. Rituximab does not distinguish normal from pathologic B cells. Hence, shortly after its use, B-cell levels are zero and remain so for several months. In most patients, the use of systemic corticosteroids and immunosuppressive agents are continued after rituximab therapy, while their dosages are significantly decreased. In the majority of patients rituximab is used according to the protocol used in treating lymphoma patients or patients with rheumatoid arthritis. Approximately 50% of patients experience a relapse, requiring additional therapy. Serious adverse events and fatal outcomes have been reported, although their incidence is less than that observed with conventional therapy. Nonetheless, the causes, i.e. infections and septicemia, are similar. Several gaps exist in our understanding of how to optimally benefit from the use of this valuable biological agent. Future studies need to be targeted in designing and implanting protocols that maximize the benefit of rituximab and result in producing sustained prolonged remissions with minimal adverse events and a high quality of life. PMID- 25791769 TI - Aripiprazole-induced chorioretinopathy: multimodal imaging and electrophysiological features. AB - PURPOSE: To report the first documented case of aripiprazole-induced chorioretinopathy. METHODS AND RESULTS: A 47-year-old schizophrenic patient with loss of vision due to an atypical retinopathy was investigated. She had been treated with aripiprazole for 8 years. Multimodal imaging showed in the right eye a large area of retinal atrophy predominating in the outer retina, including the posterior pole up to the upper temporal periphery, and in the left eye a serous retinal detachment. The electroretinogram exhibited decreased and delayed responses of both the rod and cone systems; the electrooculogram showed no light peak. CONCLUSION: Aripiprazole, an atypical antipsychotic, was introduced more recently than the antipsychotics commonly incriminated in chorioretinopathies, such as thioridazine. Optical coherence tomography was not used to document former cases of antipsychotic-related chorioretinopathies. Although pathophysiological mechanisms are poorly understood, imaging of the present case points toward an involvement of the retinal pigmentary epithelium. Clinicians should be aware of the potential chorioretinal toxicity of new atypical antipsychotics. PMID- 25791771 TI - Uncertainty relations and topological-band insulator transitions in 2D gapped Dirac materials. AB - Uncertainty relations are studied for a characterization of topological-band insulator transitions in 2D gapped Dirac materials isostructural with graphene. We show that the relative or Kullback-Leibler entropy in position and momentum spaces, and the standard variance-based uncertainty relation give sharp signatures of topological phase transitions in these systems. PMID- 25791772 TI - Human metabolism of orally administered radioactive cobalt chloride. AB - This study investigated the human gastrointestinal uptake (f1) and subsequent whole-body retention of orally administered inorganic radioactive cobalt. Of eight adult volunteers aged between 24 and 68 years, seven were given solutions of (57)Co (T1/2 = 272 d) containing a stable cobalt carrier, and six were given carrier-free (58)Co (T1/2 = 71 d). The administered activities ranged between 25 and 103 kBq. The observed mean f1, based on 6 days accumulated urinary excretion sampling and whole-body counting, was 0.028 +/- 0.0048 for carrier-free (58)Co, and 0.016 +/- 0.0021 for carrier-associated (57)Co. These values were in reasonable agreement with values reported from previous studies involving a single intake of inorganic cobalt. The time pattern of the total retention (including residual cobalt in the GI tract) included a short-term component with a biological half-time of 0.71 +/- 0.03 d (average +/- 1 standard error of the mean for the two nuclides), an intermediate component with a mean half-time of 32 +/- 8.5 d, and a long-term component (observed in two volunteers) with half-times ranging from 80 to 720 d for the two isotopes. From the present data we conclude that for the short-lived (57)Co and (58)Co, more than 95% of the internal absorbed dose was delivered within 7 days following oral intake, with a high individual variation influenced by the transit time of the unabsorbed cobalt through the gastro-intestinal tract. PMID- 25791773 TI - Racial and socioeconomic disparities in outcomes following pediatric cerebrospinal fluid shunt procedures. AB - OBJECT Racial and socioeconomic disparities within the US health care system are a growing concern. Despite extensive research and efforts to narrow such disparities, minorities and economically disadvantaged patients continue to exhibit inferior health care outcomes. Disparities in the delivery of pediatric neurosurgical care are understudied. Authors of this study examine the impact of race and socioeconomic status on outcomes following pediatric CSF shunting procedures. METHODS Discharge information from the 2000, 2003, 2006, and 2009 Kids' Inpatient Database for individuals (age < 21 years) with a diagnosis of hydrocephalus who had undergone CSF shunting procedures was abstracted for analysis. Multivariate logistic regression analyses, adjusting for patient and hospital factors and annual CSF shunt procedure volume, were performed to evaluate the effects of race and payer status on the likelihood of inpatient mortality and nonroutine hospital discharge (that is, not to home). RESULTS African American patients (p < 0.05) had an increased likelihood of inpatient death and nonroutine discharge compared with white patients. Furthermore, Medicaid patients had a significantly higher likelihood of nonroutine discharge (p < 0.05) as compared with privately insured patients. CONCLUSIONS Findings in this study, which utilized US population-level data, suggest the presence of racial and socioeconomic status outcome disparities following pediatric CSF shunting procedures. Further studies on health disparities in this population are warranted. PMID- 25791774 TI - Urinary candidate biomarker discovery in a rat unilateral ureteral obstruction model. AB - Urine has the potential to become a better source of biomarkers. Urinary proteins are affected by many factors; therefore, differentiating between the variables associated with any particular pathophysiological condition in clinical samples is challenging. To circumvent these problems, simpler systems, such as animal models, should be used to establish a direct relationship between disease progression and urine changes. In this study, a unilateral ureteral obstruction (UUO) model was used to observe tubular injury and the eventual development of renal fibrosis, as well as to identify differential urinary proteins in this process. Urine samples were collected from the residuary ureter linked to the kidney at 1 and 3 weeks after UUO. Five hundred proteins were identified and quantified by LC-MS/MS, out of which 7 and 19 significantly changed in the UUO 1- and 3-week groups, respectively, compared with the sham-operation group. Validation by western blot showed increased levels of Alpha-actinin-1 and Moesin in the UUO 1-week group, indicating that they may serve as candidate biomarkers of renal tubular injury, and significantly increased levels of Vimentin, Annexin A1 and Clusterin in the UUO 3-week group, indicating that they may serve as candidate biomarkers of interstitial fibrosis. PMID- 25791776 TI - Structural features, IgE binding and preliminary clinical findings of the 7kDa Lipid Transfer Protein from tomato seeds. AB - Allergic reactions caused by 9kDa Lipid Transfer Proteins (9k-LTP), such as Pru p 3, have been widely investigated, whereas a possible contribution of components of 7kDa LTP (7k-LTP) sub-family in triggering allergic symptoms has been overlooked so far. With the aim to investigate the contribution of 7k-LTPs to the food allergies, we have identified, isolated and characterised a tomato seed 7k LTP (Sola l 7k-LTP). The protein was purified by chromatographic separations, identified by direct protein sequencing and mass spectrometry and a molecular model was built. Functional evaluation of the allergen has been performed by skin testing. Sola l 7k-LTP consists of 68 amino acids producing a molecular mass of 7045Da and displays 41% sequence identity with Pru p 3, the allergenic 9k-LTP from peach. IgE antibodies specifically recognising Sola l 7k-LTP were found within the population claiming tomato ingestion-related symptoms, but also in subjects tolerant on tomato exposure. A few subjects were mono-sensitised to Sola l 7k-LTP, which is biologically active as shown by the positive skin test. In line with the immunological results, the molecular model shows structural similarities between the IgE binding regions of the two sub-families. Therefore, Sola l 7k-LTP shares some structural and immunological features with Pru p 3, but it also displays individual features that could be responsible for mono-specific IgE binding. In conclusion, Sola l 7k-LTP is a new identified allergenic LTP, the description of which may contribute to the improvement of allergy diagnosis and to the formulation of a safe and personalised diet. In addition, to avoid current confusing classifications, a new nomenclature policy for LTP sub-families is proposed in this paper. We now suggest that 7-kDa LTP (so far named LTP2) be renamed 7k-LTP and 9-kDa LTP (so far named LTP1) be renamed 9k-LTP. PMID- 25791775 TI - In vitro gamma-ray-induced inflammatory response is dominated by culturing conditions rather than radiation exposures. AB - The inflammatory pathway has a pivotal role in regulating the fate and functions of cells after a wide range of stimuli, including ionizing radiation. However, the molecular mechanisms governing such responses have not been completely elucidated yet. In particular, the complex activation dynamics of the Nuclear transcription Factor kB (NF-kB), the key molecule governing the inflammatory pathway, still lacks a complete characterization. In this work we focused on the activation dynamics of the NF-kB (subunit p65) pathway following different stimuli. Quantitative measurements of NF-kB were performed and results interpreted within a systems theory approach, based on the negative feedback loop feature of this pathway. Time-series data of nuclear NF-kB concentration showed no evidence of gamma-ray induced activation of the pathway for doses up to 5 Gy but highlighted important transient effects of common environmental stress (e.g. CO2, temperature) and laboratory procedures, e.g. replacing the culture medium, which dominate the in vitro inflammatory response. PMID- 25791777 TI - Pleurodesis: indications and radiologic appearance. AB - Pleurodesis is frequently performed to prevent recurrence of pneumothorax or recurrent pleural effusion in benign or malignant conditions. In essence, it involves producing an area of adhesion between the parietal and the visceral layers of the pleura. The approach to this procedure can be divided into chemical and mechanical methods. Chemical pleurodesis is performed by introducing various substances such as talc, bleomycin, povidone iodine or other chemicals into the pleural space typically using a pleural catheter. The instilled substances cause inflammation of the parietal and the visceral layers of the pleura and leads to adhesion of the pleural surfaces, preventing further fluid or air accumulation. Mechanical pleurodesis, which is performed with thoracotomy or thoracoscopy, involves mechanical irritation of the pleura or removal of parietal pleura. It is important for the radiologist to develop an understanding of the clinical indications for pleurodesis, methods for the procedure and post-procedure imaging appearance so the radiologist can provide a correct interpretation and avoid misdiagnosis of the radiologic appearance as chronic infection, tumor or other entities with a similar appearance. Thus, the aim of this article is to review the indications, techniques and post-procedural appearances of pleurodesis from an imaging perspective. PMID- 25791778 TI - Selection played a role in the evolution of the human chin. AB - Chins, which are unique to humans, have generated considerable debate concerning their evolutionary origins, yet a consensus has remained elusive. Many have argued that chins are adaptations for chewing stress, speech, or sexual ornamentation. Alternatively, some have suggested that chins are spandrels byproducts of selection operating elsewhere in the mandible or face. Lastly, chins could be the product of genetic drift. The questions addressed by this study are: [1] whether chins represent an exceptionally derived morphological condition, and [2] if this can be interpreted as the product of natural selection. These questions are important since the chin is one of the features used to define Homo sapiens in the fossil record. Quantitative measures that capture the degree of chin expression were gathered from a sample of 123 primate taxa, and evolutionary rates associated with these measures were reconstructed in the primate phylogeny. The evolutionary rate associated with these measures was reconstructed to be far higher along the Homo tip (~77 times greater than the primate background rate of evolution) than elsewhere in the primate phylogeny. These results suggest that human symphyseal morphology is exceptionally derived relative to other primates, and selection has been operational in producing the human chin. PMID- 25791779 TI - Are asthmatics enrolled in randomized trials representative of real-life outpatients? AB - BACKGROUND/OBJECTIVE: This study was aimed at exploring to what extent populations enrolled in randomized controlled trials (RCTs) of inhalation combination treatment for mild/moderate asthma in adults are fully representative of 'real-life' populations. The following is a retrospective analysis of the clinical records of outpatient subjects with an ascertained diagnosis of asthma. METHODS: A retrospective analysis was performed. Stable conditions, such as smoking habit and chronic diseases other than asthma, were identified as exclusion criteria for RCTs. The selected criteria were then applied to asthmatic outpatients, yielding a population that was potentially eligible for RCTs. RESULTS: Out of 1,909 subjects, 824 (43.2%) met at least one of the exclusion criteria for RCTs. Cigarette smoking (occurring in 34.3% of the entire population), lung diseases other than asthma (5.0%), anxiety and depression (3.3%), arrhythmias (2.3%), and coronary artery disease (1.2%) would have been the most frequent causes for exclusion from RCTs. The proportion of patients excluded from RCTs appears to increase with age, reaching 57.1% in patients aged >85 years. CONCLUSIONS: In a real-life setting, >40% of subjects with mild/moderate asthma are currently treated by protocols based on the results of RCTs for which they would not have been eligible. This proportion increases in elderly patients with comorbidities. These findings limit the generalizability of RCTs and advocate that complementary pragmatic studies be conducted. (c) 2015 S. Karger AG, Basel. PMID- 25791780 TI - Subjective and Objective Memory Changes in Old Age across Five Years. AB - Typically, subjective memory assessments (be it in form of single items or questionnaires) in old age only weakly correlate with the performance in objective memory tests at cross-section. It thus appears as if individual differences in subjective memory assessments hardly reflect individual differences in memory in old age. A shortcoming of cross-sectional studies, however, is that subjective assessments may rely on different individual standards, which are not taken into account. One solution to this problem has been to investigate subjective and objective memory longitudinally, thereby focusing on individual differences in intraindividual changes. Results from studies using this approach have been mixed, with some studies showing a significantly stronger relation between changes than between levels, and other studies showing no such significant difference. Using data from the Zurich Longitudinal Study on Cognitive Aging (n=236), we find that 5-year changes in subjective assessments of memory capacity and memory changes correlate with objective memory changes of 0.54 and -0.44, respectively. These correlations are significantly stronger than at cross-section. After controlling for age, depressive affect, and subjective health at the first measurement occasion, correlations are slightly attenuated, but the basic findings remain the same. PMID- 25791781 TI - Voxel-based morphometry at ultra-high fields. a comparison of 7T and 3T MRI data. AB - Recent technological progress enables MRI recordings at ultra-high fields of 7 T and above leading to brain images of higher resolution and increased signal-to noise ratio. Despite these benefits, imaging at 7 T exhibits distinct challenges due to B1 field inhomogeneities, causing decreased image quality and problems in data analysis. Although several strategies have been proposed, a systematic investigation of bias-corrected 7 T data for voxel-based morphometry (VBM) is still missing and it is an ongoing matter of debate if VBM at 7 T can be carried out properly. Here, an optimized VBM study was conducted, evaluating the impact of field strength (3T vs. 7 T) and pulse sequence (MPRAGE vs. MP2RAGE) on gray matter volume (GMV) estimates. More specifically, twenty-two participants were measured under the conditions 3T MPRAGE, 7 T MPRAGE and 7 T MP2RAGE. Due to the fact that 7 T MPRAGE data exhibited strong intensity inhomogeneities, an alternative preprocessing pipeline was proposed and applied for that data. VBM analysis revealed higher GMV estimates for 7 T predominantly in superior cortical areas, caudate nucleus, cingulate cortex and the hippocampus. On the other hand, 3T yielded higher estimates especially in inferior cortical areas of the brain, cerebellum, thalamus and putamen compared to 7 T. Besides minor exceptions, these results were observed for 7 T MPRAGE as well for the 7 T MP2RAGE measurements. Results gained in the inferior parts of the brain should be taken with caution, as native GM segmentations displayed misclassifications in these regions for both 7 T sequences. This was supported by the test-retest measurements showing highest variability in these inferior regions of the brain for 7 T and also for the advanced MP2RAGE sequence. Hence, our data support the use of 7 T MRI for VBM analysis in cortical areas, but direct comparison between field strengths and sequences requires careful assessment. Similarly, analysis of the inferior cortical regions, cerebellum and subcortical regions still remains challenging at 7 T even if the advanced MP2RAGE sequence is used. PMID- 25791782 TI - Miniaturized optical neuroimaging in unrestrained animals. AB - The confluence of technological advances in optics, miniaturized electronic components and the availability of ever increasing and affordable computational power have ushered in a new era in functional neuroimaging, namely, an era in which neuroimaging of cortical function in unrestrained and unanesthetized rodents has become a reality. Traditional optical neuroimaging required animals to be anesthetized and restrained. This greatly limited the kinds of experiments that could be performed in vivo. Now one can assess blood flow and oxygenation changes resulting from functional activity and image functional response in disease models such as stroke and seizure, and even conduct long-term imaging of tumor physiology, all without the confounding effects of anesthetics or animal restraints. These advances are shedding new light on mammalian brain organization and function, and helping to elucidate loss of this organization or 'dysfunction' in a wide array of central nervous system disease models. In this review, we highlight recent advances in the fabrication, characterization and application of miniaturized head-mounted optical neuroimaging systems pioneered by innovative investigators from a wide array of disciplines. We broadly classify these systems into those based on exogenous contrast agents, such as single- and two-photon microscopy systems; and those based on endogenous contrast mechanisms, such as multispectral or laser speckle contrast imaging systems. Finally, we conclude with a discussion of the strengths and weaknesses of these approaches along with a perspective on the future of this exciting new frontier in neuroimaging. PMID- 25791784 TI - Relationship between simultaneously acquired resting-state regional cerebral glucose metabolism and functional MRI: a PET/MR hybrid scanner study. AB - Recently introduced hybrid PET/MR scanners provide the opportunity to measure simultaneously, and in direct spatial correspondence, both metabolic demand and functional activity of the brain, hence capturing complementary information on the brain's physiological state. Here we exploited PET/MR simultaneous imaging to explore the relationship between the metabolic information provided by resting state fluorodeoxyglucose-PET (FDG-PET) and fMRI (rs-fMRI) in neurologically healthy subjects. Regional homogeneity (ReHo), fractional amplitude of low frequency fluctuations (fALFF), and degree of centrality (DC) maps were generated from the rs-fMRI data in 23 subjects, and voxel-wise comparison to glucose uptake distribution provided by simultaneously acquired FDG-PET was performed. The mutual relationships among each couple of these four metrics were explored in terms of similarity, both of spatial distribution across the brain and the whole group, and voxel-wise across subjects, taking into account partial volume effects by adjusting for grey matter (GM) volume. Although a significant correlation between the spatial distribution of glucose uptake and rs-fMRI derived metrics was present, only a limited percentage of GM voxels correlated with PET across subjects. Moreover, the correlation between the spatial distributions of PET and rs-fMRI-derived metrics is spatially heterogeneous across both anatomic regions and functional networks, with lowest correlation strength in the limbic network (Spearman rho around -0.11 for DC), and strongest correlation for the default mode network (up to 0.89 for ReHo and 0.86 for fALFF). Overall, ReHo and fALFF provided significantly higher correlation coefficients with PET (p=10(-8) and 10( 7), respectively) as compared to DC, while no significant differences were present between ReHo and fALFF. Local GM volume variations introduced a limited overestimation of the rs-fMRI to FDG correlation between the modalities under investigation through partial volume effects. These novel results provide the basis for future studies of alterations of the coupling between brain metabolism and functional connectivity in pathologic conditions. PMID- 25791783 TI - Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. AB - The locus coeruleus (LC) noradrenergic system regulates arousal and modulates attention through its extensive projections across the brain. LC dysfunction has been implicated in a broad range of neurodevelopmental, neurodegenerative and psychiatric disorders, as well as in the cognitive changes observed during normal aging. Magnetic resonance imaging (MRI) has been used to characterize the human LC (elevated contrast relative to surrounding structures), but there is limited understanding of the factors underlying putative LC contrast that are critical to successful biomarker development and confidence in localizing nucleus LC. We used ultra-high-field 7 T magnetic resonance imaging (MRI) to acquire T1-weighted microscopy resolution images (78 MUm in-plane resolution) of the LC from post mortem tissue samples. Histological analyses were performed to characterize the distribution of tyrosine hydroxylase (TH) and neuromelanin in the scanned tissue, which allowed for direct comparison with MR microscopy images. Our results indicate that LC-MRI contrast corresponds to the location of neuromelanin cells in LC; these also correspond to norepinephrine neurons. Thus, neuromelanin appears to serve as a natural contrast agent for nucleus LC that can be used to localize nucleus LC and may have the potential to characterize neurodegenerative disease. PMID- 25791785 TI - Copper acetate-DMSO promoted methylthiolation of arenes and heteroarenes. AB - An unprecedented copper acetate-DMSO promoted methylthiolation of arenes and heteroarenes in the presence of air has been developed. The reaction is highly regioselective under the directing group influence of pyridine and pyrimidine functional units and gives the thiomethylated product in moderate to high yields. PMID- 25791787 TI - Surgical learning curve for open radical prostatectomy: Is there an end to the learning curve? AB - OBJECTIVES: To analyze the impact of surgeon's experience on surgical margin status, postoperative continence and operative time after radical prostatectomy (RP) in a surgeon who performed more than 2000 open RP. PATIENTS AND METHODS: We retrospectively analyzed 2269 patients who underwent RP by one surgeon from April 2004 to June 2012. Multivariable logistic models were used to quantify the impact of surgeon's experience (measured by the number of prior performed RP) on surgical margin status, postoperative continence and operative time. RESULTS: Negative surgical margin rate was 86 % for patients with pT2 stage, and continence rate at 3 years after RP was 94 %. Patients with negative surgical margin had lower preoperative PSA level (p = 0.02), lower pT stage (p < 0.001) and lower Gleason score (p < 0.001). The influence of the experience of the surgeon was nonlinear, positive and highly significant up to 750 performed surgeries (75-90 % negative surgical margin) (p < 0.01). The probability of continence rises significantly with surgeon's experience (from 88-96 %) (p < 0.05). A reduction in operative time (90-65 min) per RP was observed up to 1000 RP. CONCLUSIONS: In the present study, we showed evidence that surgeon's experience has a strong positive impact on pathologic and functional outcomes as well as on operative time. While significant learning effects concerning positive surgical margin rate and preserved long-term continence were detectable during the first 750 and 300 procedures, respectively, improvement in operative time was detectable up to a threshold of almost 1000 RP and hence is relevant even for very high-volume surgeons. PMID- 25791788 TI - Erratum to: Skeletal Muscle Depletion is Associated with Severe Postoperative Complications in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Cancer. PMID- 25791786 TI - Outcome measures for stress urinary incontinence treatment: can we minimally agree? AB - PURPOSE: The aim of the study was to present the different outcome measures used to evaluate stress urinary incontinence (SUI) surgical treatments and to discuss their interests. METHOD: A review of the literature based on the PubMed and Cochrane Library databases was performed using the following keywords alone and/or in combination: SUI, outcomes, surgery, questionnaires, meta-analysis, and quality of life. The research was restricted to the English and French language between 1995 and 2014. RESULTS: To assess the outcomes of a SUI surgery, it is relevant to report objective measurements, subjective outcomes, and surgical complications. Discrepancies exist in the use of tools. Voiding diaries have not been regularly adopted in practice contrary to pad test. Urodynamic measures did not predict the outcomes after surgery for SUI. Less than 40 % of surgeons used the most scientifically validated urinary incontinence symptom and QOL questionnaires as outcome measures (IIQ, IIQ-7, KHQ, I-QOL, UDI, or UDI-6). Due to time constraints, unfamiliarity with many of the tools, and a lack of widely accepted efficacy criteria, validated quality of life and symptom-related questionnaires are underused by clinicians in routine practice. CONCLUSION: There is no consensus on the best way to define treatment success in the context of SUI. However, it is acknowledged that including patient-reported outcomes is essential. There is a need to uniform outcomes reporting tools to be able to compare data across studies and perform meaningful meta-analyses. PMID- 25791789 TI - Inflammatory Breast Cancer: Patterns of Failure and the Case for Aggressive Locoregional Management. AB - BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive subtype. This study analyzes the patterns of failure in patients with IBC treated at our institution. METHODS: We retrospectively analyzed the records of 227 women with IBC presenting between 1997 and 2011. Survival analysis was used to calculate overall survival (OS) and disease-free survival. Competing risk analysis was used to calculate locoregional recurrence (LRR). RESULTS: A total of 173 patients had locoregional-only disease at presentation (non-MET). Median follow-up in the surviving patients was 3.3 years. Overall, 132 (76.3 %) patients received trimodality therapy with chemotherapy, surgery, and radiotherapy. Three-year OS was 73.1 % [95 % confidence interval (CI) 64.9-82.4]. Cumulative LRR was 10.1, 16.9, and 21.3 % at 1, 2, and 3 years, respectively. No variable was significantly associated with LRR. Fifty-four patients had metastatic disease at presentation (MET). Median follow-up in the surviving patients was 2.6 years. Three-year OS was 44.3 % (95 % CI 31.4-62.5). Twenty-four (44.4 %) patients received non-palliative local therapy (radiotherapy and/or surgery). For these patients, median OS after local therapy was 2 years. Excluding six patients who received local therapy for symptom palliation, the crude incidence of locoregional progression or recurrence (LRPR) was 17 % (4/24) for those who received local therapy compared with 57 % (13/23) for those who did not. CONCLUSIONS: For non-MET patients, LRR remains a problem despite trimodality therapy. More aggressive treatment is warranted. For MET patients, nearly 60 % have LRPR with systemic therapy alone. Local therapy should be considered in the setting of metastatic disease to prevent potential morbidity of progressive local disease. PMID- 25791790 TI - Increased Expression of Circulating Cancer Stem Cell Markers During the Perioperative Period Predicts Early Recurrence After Curative Resection of Hepatocellular Carcinoma. AB - BACKGROUND: This study was designed to investigate the correlation between postoperative recurrence of hepatocellular carcinoma (HCC) and perioperative expression and dynamic changes in cancer stem cell (CSC) markers in tumors and peripheral blood. METHODS: In HCC patients who underwent curative resection (n = 64) or liver transplantation (LT) (n = 17), mRNA levels for K19, EpCAM, and CD44 in peripheral blood and HCC tissues before and after operation were examined using real-time RT-PCR. Postoperative recurrence was analyzed in patients who underwent resection. Study participants were divided into high and low ratio groups, according to the ratio of postoperative to preoperative mRNA levels for each marker. RESULTS: K19 and CD44 mRNA levels in HCC tissues were higher in patients with recurrence than those without recurrence (p < 0.05 for all). Preoperative peripheral levels of K19 and EpCAM mRNA were higher in LT patients than in resection patients, and they were also significantly higher in cirrhotic patients of Child-Pugh Class B or C than those of Child-Pugh Class A (p < 0.05 for all). A high ratio of K19 mRNA was associated with lower relapse-free rate. Additionally, a high ratio for both K19 and CD44 mRNA was an independent poor prognostic factor for relapse-free survival (hazard ratio = 3.382, p = 0.016). CONCLUSIONS: Preoperative peripheral levels of K19 and EpCAM mRNA were influenced by background liver status and HCC. Additionally, the ratio of postoperative to preoperative mRNA levels for CSC markers, especially K19 and CD44, was shown to be important to predict HCC recurrence. PMID- 25791791 TI - Histone Demethylase LSD1 Inhibitors Prevent Cell Growth by Regulating Gene Expression in Esophageal Squamous Cell Carcinoma Cells. AB - BACKGROUND: The expression of genes can be influenced by the balance of histone acetylation and/or histone demethylation, with an imbalance of these processes possibly observed in many cancers. The histone demethylase LSD1 inhibitor activity is associated with selective transcriptional regulation and alterations in the gene expression. However, the exact mechanisms underlying the antitumor effects of LSD1 inhibitors are not fully understood. METHODS: The antitumor effects of NCL1, an LSD1 inhibitor, in esophageal squamous cell cancer (ESCC) cell lines were evaluated. A comprehensive analysis of the changes in the gene expression in ESCC cell lines induced by NCL1 was carried out using a microarray analysis. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene. RESULTS: NCL1 strongly inhibited the cell growth of T.Tn and TE2 ESCC cells and induced apoptosis. According to the microarray analysis, 81 genes in the T.Tn cells and 149 genes in the TE2 cells were up- or down-regulated 2-fold or more by NCL1 exposure. Among these genes, 27 were contained in both cell lines and exhibited similar expression patterns. PHLDB2, one of the genes down-regulated by NCL1, was overexpressed in the ESCC tumor tissues. Moreover, a high expression level of PHLDB2 was found to be significantly correlated with poor prognosis. CONCLUSIONS: The present observations of the comprehensive analysis of the gene expression levels provide insight into the mechanisms underlying the antitumor effects of LSD1 inhibitors in ESCC patients. PMID- 25791792 TI - Prognostic Relevance of p53 Overexpression in Gastrointestinal Stromal Tumors of the Small Intestine: Potential Implication for Adjuvant Treatment with Imatinib. AB - PURPOSE: Although genetic p53 aberrations are correlated with the prognosis of various types of cancer, their prognostic relevance is currently unclear in patients with gastrointestinal stromal tumors (GISTs) of the small intestine. METHODS: Between 1994 and 2008, 113 patients with resected localized GISTs of the small intestine were included in this analysis. Patients who received pre- and/or postoperative chemotherapy were excluded. p53 overexpression was assessed by immunohistochemical staining and defined as expression in >10 % of tumor cells. RESULTS: p53 overexpression was identified in 38 patients (34 %) and was significantly associated with epithelioid histology (p = 0.040) and high cellularity (p = 0.004). Relapse-free survival (RFS) significantly differed according to p53 overexpression (5-year RFS rates, 57 vs. 78 %; p = 0.005). By multivariate analysis, which included tumor necrosis, tumor size, mitotic count, and primary genotype, p53 overexpression significantly affected RFS with a hazard ratio of 3.50 (95 % confidence interval 1.48-8.25; p = 0.004). CONCLUSIONS: p53 overexpression is an independent prognostic factor in patients with small intestinal GISTs. This suggests that p53 expression can be used to further stratify recurrence risk in patients with resected GISTs of the small intestine. PMID- 25791793 TI - A New Clinical Model for Prediction of Nodal Metastasis for Patients with Early Gastric Cancer: Is this Good Enough? PMID- 25791795 TI - Guided mass spectrum labelling in atom probe tomography. AB - Atom probe tomography (APT) is a valuable near-atomic scale imaging technique, which yields mass spectrographic data. Experimental correctness can often pivot on the identification of peaks within a dataset, this is a manual process where subjectivity and errors can arise. The limitations of manual procedures complicate APT experiments for the operator and furthermore are a barrier to technique standardisation. In this work we explore the capabilities of computer guided ranging to aid identification and analysis of mass spectra. We propose a fully robust algorithm for enumeration of the possible identities of detected peak positions, which assists labelling. Furthermore, a simple ranking scheme is developed to allow for evaluation of the likelihood of each possible identity being the likely assignment from the enumerated set. We demonstrate a simple, yet complete work-chain that allows for the conversion of mass-spectra to fully identified APT spectra, with the goal of minimising identification errors, and the inter-operator variance within APT experiments. This work chain is compared to current procedures via experimental trials with different APT operators, to determine the relative effectiveness and precision of the two approaches. It is found that there is little loss of precision (and occasionally gain) when participants are given computer assistance. We find that in either case, inter operator precision for ranging varies between 0 and 2 "significant figures" (2sigma confidence in the first n digits of the reported value) when reporting compositions. Intra-operator precision is weakly tested and found to vary between 1 and 3 significant figures, depending upon species composition levels. Finally it is suggested that inconsistencies in inter-operator peak labelling may be the largest source of scatter when reporting composition data in APT. PMID- 25791794 TI - Concentration depth distribution of grain boundary segregation measured by wavelength dispersive X-ray spectroscopy. AB - A method using wavelength dispersive X-ray spectroscopy (WDS) is applied to the measurement of grain boundary segregation of Sn in silicon steel. The quantification of monolayer concentration of Sn is acquired, which demonstrates an obvious segregation of Sn at grain boundaries. In consideration of the fact that segregated impurities (Sn or other species) distribute in multilayer and not just monolayer segregation can be characterized by WDS, the Gaussian distribution is applied to formulate the multilayer concentration depth distribution according to the measured total concentration. A correction factor is then put forward to improve the quantification. Based on the measured segregation of Sn and the derived formula of multilayer concentration depth distribution, the grain boundary concentrations of Sn are calculated for different thicknesses of segregated layer. From the experimental measurement, theoretical analyses and calculated results, an effective approach for the research of grain boundary segregation is provided. PMID- 25791796 TI - A procedure to create isoconcentration surfaces in low-chemical-partitioning, high-solute alloys. AB - A proximity histogram or proxigram is the prevailing technique of calculating 3D composition profiles of a second phase in atom probe tomography. The second phase in the reconstruction is delineated by creating an isoconcentration surface, i.e. the precipitate-matrix interface. The 3D composition profile is then calculated with respect to this user-defined isoconcentration surface. Hence, the selection of the correct isoconcentration surface is critical. In general, the preliminary selection of an isoconcentration value is guided by the visual observation of a chemically partitioned second phase. However, in low-chemical -partitioning systems, such a visual guide is absent. The lack of a priori composition information of the precipitate phase may further confound the issue. This paper presents a methodology of selecting an appropriate elemental species and subsequently obtaining an isoconcentration value to create an accurate isoconcentration surface that will act as the precipitate-matrix interface. We use the H-phase precipitate in the Ni-Ti-Hf shape memory alloy as our case study to illustrate the procedure. PMID- 25791797 TI - Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. AB - Gliomas are the most common primary brain tumors. Particularly in adult patients, the vast majority of gliomas belongs to the heterogeneous group of diffuse gliomas, i.e. glial tumors characterized by diffuse infiltrative growth in the preexistent brain tissue. Unfortunately, glioblastoma, the most aggressive (WHO grade IV) diffuse glioma is also by far the most frequent one. After standard treatment, the 2-year overall survival of glioblastoma patients is approximately only 25%. Advanced knowledge in the molecular pathology underlying malignant transformation has offered new handles and better treatments for several cancer types. Unfortunately, glioblastoma multiforme (GBM) patients have not yet profited as although numerous experimental drugs have been tested in clinical trials, all failed miserably. This grim prognosis for GBM is at least partly due to the lack of successful drug delivery across the blood-brain tumor barrier (BBTB). The human brain comprises over 100 billion capillaries with a total length of 400 miles, a total surface area of 20 m(2) and a median inter-capillary distance of about 50 MUm, making it the best perfused organ in the body. The BBTB encompasses existing and newly formed blood vessels that contribute to the delivery of nutrients and oxygen to the tumor and facilitate glioma cell migration to other parts of the brain. The high metabolic demands of high-grade glioma create hypoxic areas that trigger increased expression of VEGF and angiogenesis, leading to the formation of abnormal vessels and a dysfunctional BBTB. Even though the BBTB is considered 'leaky' in the core part of glioblastomas, in large parts of glioblastomas and, even more so, in lower grade diffuse gliomas the BBTB more closely resembles the intact blood-brain barrier (BBB) and prevents efficient passage of cancer therapeutics, including small molecules and antibodies. Thus, many drugs can still be blocked from reaching the many infiltrative glioblastoma cells that demonstrate 'within-organ-metastasis' away from the core part to brain areas displaying a more organized and less leaky BBTB. Hence, drug delivery in glioblastoma deserves explicit attention as otherwise new experimental therapies will continue to fail. In the current review we highlight different aspects of the BBTB in glioma patients and preclinical models and discuss the advantages and drawbacks of drug delivery approaches for the treatment of glioma patients. We provide an overview on methods to overcome the BBTB, including osmotic blood-brain barrier disruption (BBBD), bradykinin receptor-mediated BBTB opening, inhibition of multidrug efflux transporters, receptor-mediated transport systems and physiological circumvention of the BBTB. While our knowledge about the molecular biology of glioma cells is rapidly expanding and is, to some extent, already assisting us in the design of tumor tailored therapeutics, we are still struggling to develop modalities to expose the entire tumor to such therapeutics at pharmacologically meaningful quantities. Therefore, we must expand our knowledge about the fundamentals of the BBTB as a step toward the design of practical and safe devices and approaches for enhanced drug delivery into the diseased brain area. PMID- 25791798 TI - Hospital cost-analysis of complications after major abdominal surgery. AB - BACKGROUND: Complications after major abdominal surgery (MAS) are associated with increased morbidity and mortality. Rising costs in health care are of increasing interest and a major factor affecting hospital costs are postoperative complications. In this study, the costs associated with complications are assessed. METHODS: Retrospective cohort study of 399 consecutive patients that underwent MAS. Analysis of total costs for hospital stay, complications and treatment was performed, including bootstrapping; allowing for subtraction of data with 95% confidence intervals. RESULTS: For a single patient who underwent MAS the average costs, adjusted for ASA-classification and surgery type, adds up to EUR 8,584.81 (95% CI EUR 8,332.51 - EUR 8,860.81) in patients without complications. EUR 15,412.96 (95% CI EUR 14,250.22 - EUR 16,708.82) after minor complications, and EUR 29,198.23 (95% CI EUR 27,187.13 - EUR 31,295.78) after major complications (p < 0.001). CONCLUSION: The results provide an insight into the scope of hospital costs associated with complications. Major complications occur in 20% of patients undergoing MAS and account for 50% of the total costs of care. Implementation of a protocol aimed at early diagnosis and treatment of complications might lead to a decrease in morbidity and mortality, but also prove to be cost effective. PMID- 25791799 TI - [Prospective study of the new oral anticoagulants in private practice: cautious optimism]. AB - BACKGROUND: The new direct oral anticoagulants (DOA) such as dabigatran, rivaroxaban or apixaban are an evolution in the management of patients requiring curative anticoagulation. However, behind the simplicity of prescribing and monitoring, several questions remain about their daily use. The aim of this prospective study was to measure the feelings of general practitioners (GP), angiologists (AP) and cardiologists (CP), potential prescribers of this new anticoagulant family. METHOD: Between December 2012 and May 2013, a questionnaire including five open questions and 11 questions using a positioning on an analogic visual scale (AVS 0 to 10) was subjected to GP, AP and CP in Alsace. RESULTS: Responses from 224 physicians (150 GP, 35 AP and 39 CP) were collected. Thus, 83% of GP, 83% of AP and 100% of CP were prescribers of DOA. However, among these prescribing doctors, the feeling was not the same and the trend of prescription was lower in GP (2.0 [1.1-3.2] AVS units) than in AP (3.1 [2.0-5.6]) and in CP (5.0 [1.2-8.7]) (P<0.0001 in multivariate analysis). The female doctors tended to prescribe DOA in younger patients than male doctors (respectively 66.1 [52.5 76.7] vs. 75.0 [65.7-81.0] years; P=0.004). The DOA were more considered as progress by AP and CP (respectively 7.8 [5.3-9.0] and 7.9 [7.0-8.7] AVSu) than by GP (6.1 [4.8-8.2] AVSu; P=0.02 in multivariate analysis). The answer about the eventual replacement of vitamin K antagonists by the DOA was very mixed whatever the practitioner group (5.1 [3.0-7.8] AVSu; P=0.139). The ease to use and the lack of biological monitoring were the main arguments leading to the prescription but the attitude of practitioners was very balanced by the lack of experience on the bleeding risk and the lack of available antidote. CONCLUSIONS: If the DOA are considered as an improvement for the physicians, the enthusiasm remains cautious whatever the type of practiced medicine. The results of clinical trials and the clinical experience should better appreciate the ongoing change in the field of anticoagulation. PMID- 25791800 TI - Psoriasis and risk of diabetes-associated microvascular and macrovascular complications. AB - BACKGROUND: Psoriasis's effect on diabetes onset is well documented, but its effect on course of diabetes is poorly understood. OBJECTIVE: We sought to compare risks of developing microvascular and macrovascular complications between diabetic patients with and without psoriasis. METHODS: Adults with 2 or more diabetes diagnoses selected from MarketScan databases (Truven Health Analytics Inc, Ann Arbor, MI) (2000-2006) were classified into 2 cohorts: 2 or more psoriasis diagnoses and without psoriasis diagnosis. Patients with psoriasis were matched using propensity score, and exactly matched using age, sex, and diabetes characteristics with patients without psoriasis. Outcomes were compared between cohorts using Cox regression models. RESULTS: In all, 6164 diabetic patients with psoriasis (27% moderate to severe) were matched to 6164 diabetic patients without psoriasis. Patients with psoriasis were significantly more likely to develop microvascular events than patients without psoriasis overall (hazard ratio [HR] 1.14, P < .001) and by psoriasis severity (mild: HR 1.13, P = .004; moderate to severe: HR 1.16, P = .038). Risk of macrovascular events was higher for patients without psoriasis overall (HR 1.13, P = .001) and those with mild psoriasis (HR 1.15, P = .003), but not for moderate to severe cases (HR 1.10, P = .210). LIMITATIONS: Psoriasis to diabetes association may be underestimated. CONCLUSION: Among diabetic patients, psoriasis is generally associated with higher rates of microvascular and macrovascular complications. Greater psoriasis severity did not increase risk of diabetic complications. PMID- 25791801 TI - Imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type. AB - BACKGROUND: Surgical resection of lentigo maligna (LM) is complicated by noncontiguous, subclinical extension and actinic melanocytic hyperplasia in sun damaged skin of older individuals. OBJECTIVE: We sought to determine the long term effectiveness of imiquimod as primary or adjuvant therapy for LM. METHODS: Patients were retrospectively identified from January 1, 2003, to December 31, 2013, with LM, early/evolving LM, and LM melanoma who had used topical imiquimod 5% cream for either primary therapy after diagnostic biopsy, or adjuvant therapy after narrow-margin surgical resection or complete clinical but not histologic resection of LM. Follow-up occurred through December 31, 2014. RESULTS: In all, 63 cases were identified in 61 patients, mean (SD) age 71.1 (12.4) years; 58 were analyzed for local recurrence. Imiquimod was used as primary therapy in 22 of 63 (34.9%) and adjuvant therapy in 41 of 63 (65.1%) for mean duration of 11.7 (range 2-60) weeks. Fifty cases (86.2%) demonstrated clinical clearance at mean (SD) follow-up of 42.1 (27.4) months: 72.7% primary and 94.4% adjuvant at 39.7 (23.9) and 43.1 (28.9) months, respectively. LIMITATIONS: Retrospective cohort study and lack of standardized imiquimod application are limitations. CONCLUSION: Imiquimod cream appears to be a viable option for primary or adjuvant treatment of LM in older patients who are poor surgical candidates. PMID- 25791802 TI - [Posterior cortical atrophy. Pathology, diagnosis and treatment of a rare form of dementia]. AB - The syndrome of posterior cortical atrophy (PCA) is a rare clinical manifestation of several neurodegenerative diseases which affect the parieto-occipital cortex. The most frequent underlying pathology is Alzheimer's disease but some cases are caused by Lewy body disease, progressive subcortical gliosis, corticobasal degeneration or prion diseases. The most prominent clinical feature of PCA is complex visual disturbances including object agnosia, simultanagnosia, optical ataxia and oculomotor apraxia while basic visual functions remain intact. These deficits lead to multiple impairments in activities of daily living that require visual control. On progression of the disease amnestic, apraxic and dysexecutive symptoms occur so that a global dementia gradually emerges. At the core of the diagnostic work-up are a detailed patient history, accurate analysis of behavior and neuropsychological testing. Structural and functional brain imaging are suitable to demonstrate the localization of the disease process. Measurement of cerebrospinal fluid proteins (e.g. beta amyloid, tau, phospho-tau and 14-3-3) serves to confirm or exclude Alzheimer's disease or prion diseases. The mainstay of treatment are non-pharmacological interventions to support activities of daily living and personal independence. These treatments include cognitive training and compensatory strategies which can be prescribed as neuropsychological treatment or occupational therapy. If Alzheimer's disease or Lewy body disease is the likely cause, a treatment with cholinesterase inhibitor may be tried. Caregiver education and support are another essential part of the treatment regimen as with all forms of dementia. PMID- 25791803 TI - [Pseudomigraine with cerebrospinal fluid pleocytosis : Alice in Wonderland syndrome]. PMID- 25791804 TI - Folic acid-tagged protein nanoemulsions loaded with CORM-2 enhance the survival of mice bearing subcutaneous A20 lymphoma tumors. AB - Folic Acid (FA)-tagged protein nanoemulsions were found to be preferentially internalized on B-cell lymphoma cell line (A20 cell line), which, for the first time, is reported to express folate receptor (FR)-alpha. Carbon monoxide releasing molecule-2 (CORM-2) was incorporated in the oil phase of the initial formulation. FA-functionalized nanoemulsions loaded with CORM-2 exhibited a considerable antitumor effect and an increased survival of BALB/c mice bearing subcutaneous A20 lymphoma tumors. The developed nanoemulsions also demonstrated to be well tolerated by these immunocompetent mice. Thus, the results obtained in this study demonstrate that FA-tagged protein nanoemulsions can be successfully used in cancer therapy, with the important ability to delivery drugs intracellularly. FROM THE CLINICAL EDITOR: In this research, the authors developed folic acid tagged nanoemulsions containing a carbon monoxide releasing protein molecule for targeted cancer cell treatment. In-vitro and in-vivo experiments showed efficacy against B-cell lymphoma cells. The same nanocarrier platform could be applied to other tumor cells expressing folate receptors on the cell surface. PMID- 25791805 TI - Pharmaceutical development and preclinical evaluation of a GMP-grade anti inflammatory nanotherapy. AB - The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100nm+/-10nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3%-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which were compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects. Subsequently, non-invasive multimodal clinical imaging after liposomal nanotherapy's intravenous administration revealed anti-inflammatory effects on the vessel wall of atherosclerotic rabbits. The present program led to institutional review board approval for two clinical trials with patients with atherosclerosis. FROM THE CLINICAL EDITOR: In drug discovery, bringing production to industrial scale is an essential process. In this article the authors describe the development of an anti-inflammatory nanoparticle according to good manufacturing practice. As a result, this paves the way for translating laboratory studies to clinical trials in humans. PMID- 25791806 TI - Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration. AB - Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. FROM THE CLINICAL EDITOR: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases. PMID- 25791807 TI - Effects of singlet oxygen generated by a broad-spectrum viral fusion inhibitor on membrane nanoarchitecture. AB - Targeting membranes of enveloped viruses represents an exciting new paradigm to explore on the development of broad-spectrum antivirals. Recently, broad-spectrum small-molecule antiviral drugs were described, preventing enveloped virus entry at an intermediate step, after virus binding but before virus-cell fusion. Those compounds, including an oxazolidine-2,4-dithione named JL103 that presented the most promissing results, act deleteriously on the virus envelope but not at the cell membrane level. In this work, by using atomic force microscopy (AFM), we aimed at unraveling the effects that JL103 is able to induce in the lipid membrane architecture at the nanoscale. Our results indicate that singlet oxygen produced by JL103 decreases membrane thickness, with an expansion of the area per phospholipid, by attacking the double bonds of unsaturated phospholipids. This membrane reorganization prevents the fusion between enveloped virus and target cell membranes, resulting in viral entry inhibition. FROM THE CLINICAL EDITOR: The recent development of a family of innovative broad-spectrum small-molecule antiviral drugs that block virus cell entry has provided exciting armors against viruses. In this research paper, the authors utilize atomic force microscopy to investigate the mechanism of action of viral blockade. The findings have resulted in new understanding of cell membrane behavior, which may help in further drug design. PMID- 25791808 TI - Thermosensitive dendritic polyglycerol-based nanogels for cutaneous delivery of biomacromolecules. AB - Genetic skin diseases caused by mutations resulting in diminished protein synthesis could benefit from local substitution of the missing protein. Proteins, however, are excluded from topical applications due to their physicochemical properties. We prepared protein-loaded thermoresponsive poly(N isopropylacrylamide)-polyglycerol-based nanogels exhibiting a thermal trigger point at 35 degrees C, which is favorable for cutaneous applications due to the native thermal gradient of human skin. At>=35 degrees C, the particle size (~200nm) was instantly reduced by 20% and 93% of the protein was released; no alterations of protein structure or activity were detected. Skin penetration experiments demonstrated efficient intraepidermal protein delivery particularly in barrier deficient skin, penetration of the nanogels themselves was not detected. The proof of concept was provided by transglutaminase 1-loaded nanogels which efficiently delivered the protein into transglutaminase 1-deficient skin models resulting in a restoration of skin barrier function. In conclusion, thermoresponsive nanogels are promising topical delivery systems for biomacromolecules. FROM THE CLINICAL EDITOR: Many skin disorders are characterized by an absence of a specific protein due to underlying gene mutation. In this article, the authors described the use of a thermoresponsive PNIPAM-dPG nanogel for cutaneous protein delivery in a gene knock-down model of human skin. The results may have implication for nano-based local delivery of therapeutic agents in skin. PMID- 25791809 TI - Imaging the urinary pathways in mice by liposomal indocyanine green. AB - Intraoperative ureter identification can assist in the prevention of ureteral injury and consequently improve surgery outcomes. Our aim was to take advantage of the altered pharmacokinetics of liposomal indocyanine green (ICG), the only FDA-approved near-infrared (NIR) dye, for imaging of ureters during surgeries. ICG was passively adsorbed to liposomes. NIR whole mice body and isolated tissue imaging were used to study liposomal ICG properties vs. free ICG. In vivo, the urinary bladder could be clearly observed in most of the liposome-treated mice. Liposomal encapsulation of ICG enhanced ureteral emission up to 1.9 fold compared to free ICG (P<0.01). Increase in liposomal micropolarity and microviscosity and differential scanning calorimetry supported ICG localization within the liposomal bilayer. Our findings suggest that liposomal ICG could be utilized for ureteral imaging intra-operatively, thus potentially improving surgical outcomes. FROM THE CLINICAL EDITOR: Iatrogenic ureteral injury is a serious complication of abdominal surgery and intra-operative recognition of the ureters is usually the best method of injury prevention. In this article, the authors developed liposomal indocyanine green, which could be excreted via the urinary system and investigated its in-vivo use in mice. PMID- 25791810 TI - Intestinal absorption of fluorescently labeled nanoparticles. AB - Characterization of intestinal absorption of nanoparticles is critical in the design of noninvasive anticancer, protein-based, and gene nanoparticle-based therapeutics. Here we demonstrate a general approach for the characterization of the intestinal absorption of nanoparticles and for understanding the mechanisms active in their processing within healthy intestinal cells. It is generally accepted that the cellular processing represents a major drawback of current nanoparticle-based therapeutic systems. In particular, endolysosomal trafficking causes degradation of therapeutic molecules such as proteins, lipids, acid sensitive anticancer drugs, and genes. To date, investigations into nanoparticle processing within intestinal cells have studied mass transport through Caco-2 cells or everted rat intestinal sac models. We developed an approach to visualize directly the mechanisms of nanoparticle processing within intestinal tissue. These results clearly identify a mechanism by which healthy intestinal cells process nanoparticles and point to the possible use of this approach in the design of noninvasive nanoparticle-based therapies. FROM THE CLINICAL EDITOR: Advances in nanomedicine have resulted in the development of new therapies for various diseases. Intestinal route of administration remains the easiest and most natural. The authors here designed experiments to explore and characterize the process of nanoparticle transport across the intestinal tissue. In so doing, further insights were gained for future drug design. PMID- 25791812 TI - Safe lipid nanocapsule-based gel technology to target lymph nodes and combat mediastinal metastases from an orthotopic non-small-cell lung cancer model in SCID-CB17 mice. AB - The purpose of this study is the assessment of gel technology based on a lauroyl derivative of gemcitabine encapsulated in lipid nanocapsules delivered subcutaneously or intravenously after dilution to (i) target lymph nodes, (ii) induce less systemic toxicity and (iii) combat mediastinal metastases from an orthotopic model of human, squamous, non-small-cell lung cancer Ma44-3 cells implanted in severe combined immunodeficiency mice. The gel technology mainly targeted lymph nodes as revealed by the biodistribution study. Moreover, the gel technology induced no significant myelosuppression (platelet count) in comparison with the control saline group, unlike the conventional intravenous gemcitabine hydrochloride treated group (P<0.05). Besides, the gel technology, delivered subcutaneously twice a week, was able to combat locally mediastinal metastases from the orthotopic lung tumor and to significantly delay death (P<0.05) as was the diluted gel technology delivered intravenously three times a week. FROM THE CLINICAL EDITOR: Lung cancer is one of the leading causes of mortality worldwide. A significant proportion of patients with this disease have lymph node metastasis. In this study, the authors investigated the use of lipid nanocapsules, loaded with the lipophilic pro-drug gemcitabine for targeting tumors in lymph nodes after subcutaneous injection. This delivery method was shown to be effective in controlling tumor progression and may be useful in future clinical use. PMID- 25791813 TI - G5 PAMAM dendrimer versus liposome: a comparison study on the in vitro transepithelial transport and in vivo oral absorption of simvastatin. AB - This study compared formulation effects of a dendrimer and a liposome preparation on the water solubility, transepithelial transport, and oral bioavailability of simvastatin (SMV). Amine-terminated G5 PAMAM dendrimer (G5-NH2) was chosen to form SMV/G5-NH2 molecular complexes, and SMV-liposomes were prepared by using a thin film dispersion method. The effects of these preparations on the transepithelial transport were investigated in vitro using Caco-2 cell monolayers. Results indicated that the solubility and transepithelial transport of SMV were significantly improved by both formulations. Pharmacokinetic studies in rats also revealed that both the SMV/G5-NH2 molecular complexes and the SMV liposomes significantly improved the oral bioavailability of SMV with the liposomes being more effective than the G5-NH2. The overall better oral absorption of SMV-liposomes as compared to SMV/G5-NH2 molecular complexes appeared to arise from better liposomal solubilization and encapsulation of SMV and more efficient intracellular SMV delivery. FROM THE CLINICAL EDITOR: Various carrier systems have been designed to enhance drug delivery via the oral route. In this study, the authors compared G5 PAMAM dendrimers to liposome preparations in terms of solubility, transepithelial transport, and oral bioavailability of this poorly water-soluble drug. This understanding has improved our knowledge in the further development of drug carrier systems. PMID- 25791814 TI - A novel topical nano-propranolol for treatment of infantile hemangiomas. AB - Topical propranolol has been used for the therapy of superficial infantile hemangiomas (IH). A retrospective investigation was conducted in 50 patients to evaluate the clinical effect of a new type of topical nano-propranolol-dispersed hydrogel. Participants were treated 3 times per day for 2 weeks to 11 months. 68% of patients were female and 12% had received other treatments before therapy. The nano-propranolol 0.5% hydrogel was initiated at a mean age of 5.010 months and for a mean duration of 3.610 months. The response rate was 86%. No recurrence and rebound growth occurred after withdrawal of hydrogel. Slight side effects (application site itching, erosion and crusting) were observed in only 2 cases. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness. FROM THE CLINICAL EDITOR: The current recommended treatment for infantile hemangiomas is oral propranolol. Nonetheless, a small proportion of patients will have systemic side effects. In this article, the authors developed topical nano-propranolol hydrogel and tested this on clinical patients and found favorable response. PMID- 25791816 TI - Correction: chemistry of group 9 dimetallaborane analogues of octaborane(12). PMID- 25791817 TI - Catalysis at the room temperature ionic liquid|water interface: H2O2 generation. AB - H2O2 is produced at the interface between a room-temperature ionic liquid with decamethylferrocene as an electron donor and an acidic aqueous solution. The electron donor can be regenerated electrochemically. PMID- 25791815 TI - Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis. AB - Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of >50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with >99% killing of the Aspergillus and a 90% reduction in lung TNF-alpha; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections. FROM THE CLINICAL EDITOR: Aspergillus is an opportunistic pathogen, which affects immunocompromised patients. One novel way to help fight against this infection is pre-exposure prophylaxis. The authors here made PMA based anionic hydrogels carrying amphotericin B, with mucoadhesive behavior. They showed that aerosol route of the drug was very effective in protecting against the disease in an in vivo model and should provide a stepping-stone towards clinical trials in the future. PMID- 25791811 TI - Nanotechnology in bone tissue engineering. AB - Nanotechnology represents a major frontier with potential to significantly advance the field of bone tissue engineering. Current limitations in regenerative strategies include impaired cellular proliferation and differentiation, insufficient mechanical strength of scaffolds, and inadequate production of extrinsic factors necessary for efficient osteogenesis. Here we review several major areas of research in nanotechnology with potential implications in bone regeneration: 1) nanoparticle-based methods for delivery of bioactive molecules, growth factors, and genetic material, 2) nanoparticle-mediated cell labeling and targeting, and 3) nano-based scaffold construction and modification to enhance physicochemical interactions, biocompatibility, mechanical stability, and cellular attachment/survival. As these technologies continue to evolve, ultimate translation to the clinical environment may allow for improved therapeutic outcomes in patients with large bone deficits and osteodegenerative diseases. FROM THE CLINICAL EDITOR: Traditionally, the reconstruction of bony defects has relied on the use of bone grafts. With advances in nanotechnology, there has been significant development of synthetic biomaterials. In this article, the authors provided a comprehensive review on current research in nanoparticle-based therapies for bone tissue engineering, which should be useful reading for clinicians as well as researchers in this field. PMID- 25791818 TI - Inhibition of MMP-2-Mediated Mast Cell Invasion by NF-kappaB Inhibitor DHMEQ in Mast Cells. AB - BACKGROUND: Stimulation with antigen and IgE is known to activate NF-kappaB in mast cells. In the present research, we studied the role of NF-kappaB on cellular migration in mast cell-like RBL-2H3 cells and bone marrow-derived mast cells (BMMCs) using the NF-kappaB inhibitor (-)-DHMEQ. METHODS: A Matrigel invasion chamber was used to evaluate cell migration. A PCR array was used to screen the expression of 84 key genes involved in cell migration. RESULTS: (-)-DHMEQ inhibited antigen/IgE-induced NF-kappaB activation and expressions of its target genes such as IL-6 and TNF-alpha. (-)-DHMEQ was found to inhibit in vitro invasion toward the antigen without any toxicity. We then looked for NF-kappaB dependent genes that would be important for mast cell invasion using the PCR array. (-)-DHMEQ was found to lower the expression of matrix metalloproteinase (MMP)-2. The MMP inhibitor GM6001 also inhibited cellular invasion toward the antigen. These effects of (-)-DHMEQ were obtained in both RBL-2H3 cells and BMMCs. CONCLUSIONS: These findings indicate that (-)-DHMEQ suppressed mast cell migration via the inhibition of NF-kappaB-regulated MMP-2 expression. PMID- 25791819 TI - Relaxin-2 does not ameliorate nephropathy in an experimental model of type-1 diabetes. AB - BACKGROUND/AIMS: In diabetic nephropathy (DN), the current angiotensin-II blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti inflammatory, and vasoprotecting peptide - is a candidate drug for both. METHODS: Low-dose (32 MUg/kg/day) and high-dose (320 MUg/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS KO) mice by intraperitoneal injection of streptozotocin. RESULTS: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF beta pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. CONCLUSIONS: We investigated a model showing early DN without overt tubulointerstitial fibrosis and activation of the TGF-beta-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes. PMID- 25791820 TI - Synergistic anticancer potential of dichloroacetate and estradiol analogue exerting their effect via ROS-JNK-Bcl-2-mediated signalling pathways. AB - BACKGROUND: C9, a newly in silico-designed inhibitor of microtubule dynamics induces G2/M arrest culminating in apoptosis. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase, an enzyme that promotes pyruvate entry into mitochondria. The use of antitumor drugs targeting different cancer features can be a more effective way to overcome drug resistance. METHODS: The influence of C9 (130 nM) + DCA (7.5 mM) on MCF-7 and MCF-12 cells was assessed via microscopy spectrophotometry global gene expression and flow cytometry assays. RESULTS: An LDH assay showed that C9+DCA treatment decreased cell viability to 83.5% in MCF-7 cells when compared to the non-tumorigenic MCF-12A cells 92.4% (P < 0.05). C9- and C9+DCA treatment induced mitochondrial membrane potential depolarization in MCF-7 cells but not in MCF-12A cells (P < 0.05). The occurrence of apoptosis was associated with increased hypo- and hyper-phosphorylation of Bcl-2 Ser(70) and caspase 7 activation. Kinase inhibition revealed sustained activation of the JNK pathway caused increased Bcl-2 protein Ser(70) hypo-and hyper-phosphorylation. Elevated levels of DCF fluorescence was observed in DCA-, C9- and C9+DCA-exposed MCF-7 cells, but not in MCF-12A cells, indicating cytosolic H2O2/Fe(2+) formation in treated tumorigenic cells. LC3-II expression was elevated in C9+DCA-treated cells in both cell lines, indicating that autophagy was also induced. CONCLUSIONS: Synergistic effects of C9+DCA were demonstrated on breast carcinoma and non-tumorigenic cells with selectivity towards the MCF-7 cells. Antimitotic compound C9 in combination with a glycolytic inhibitor dichloroacetate eradicates breast cancer cells through ROS-JNK-Bcl-2-mediated signalling pathways in vitro and it is argued that autophagy acts as protective mechanism in the treated cells before apoptosis occurs. PMID- 25791822 TI - Enamel formation genes associated with dental erosive wear. AB - Dental erosive wear is a multifactorial condition that is greatly affected by environmental factors. So far, no study has investigated how dental erosive wear is influenced by variations in enamel formation genes. The aim of the present study was to investigate polymorphisms in genes involved in enamel formation and their influence on enamel susceptibility to dental erosion. DNA samples were collected from 795 Norwegian adolescents aged 16-18 years. Five single-nucleotide polymorphism markers were genotyped in selected candidate genes (ameloblastin, amelogenin, enamelin, tuftelin 1 and tuftelin interacting protein 11), reported to influence enamel formation. Allele and genotype frequencies were compared within two patient groups with dental erosions; all participants with dental erosion and only those with severe dental erosion (erosion extending into dentine). Overrepresentation of the G allele of the enamelin marker was seen in the erosion group compared to the unaffected group (p = 0.047). When erosion severity was considered, statistical significant difference in allele frequency was observed for amelogenin, with the C allele suggesting a protective role (p = 0.02). A suggestive overrepresentation of the TT genotype of the amelogenin marker was also seen in cases with severe erosion (p = 0.049) when compared to cases with no dentine erosion. Amelogenin was also associated with severe erosion in the recessive model; the TT genotype was significantly more frequent in the affected group than in the unaffected group (p = 0.01). The present study suggests that polymorphisms in enamel formation genes are statistically associated with an individual's susceptibility to dental erosive wear. PMID- 25791821 TI - Molecular origins of synaptotagmin 1 activities on vesicle docking and fusion pore opening. AB - Synaptotagmin 1 (Syt1), a major Ca(2+) sensor in neuroexocytosis, utilizes SNARE- and membrane-binding to regulate vesicle fusion, a required process for neurotransmitter release at the synapse. However, the mechanism by which Syt1 orchestrates SNARE- and membrane- binding to control individual vesicle fusion steps is still unclear. In this study, we used a number of single vesicle assays that can differentiate intermediates of neuroexocytosis, to focus on Syt1 mutants that might impair Syt1-SNARE/PIP2 interaction, Ca(2+)-binding, or membrane penetration. Our results show that, although putative Syt1-SNARE/PIP2 coupling through the polybasic region of the C2B domain is critical for vesicle docking, its disruption does not affect content release. In contrast, Ca(2+)-binding and membrane-penetration mutants significantly reduce content release. Our results thus delineate multiple functions of Syt1 along the pathway of Ca(2+)-triggered exocytosis in unprecedented detail. PMID- 25791823 TI - Heterovalent substitution to Enrich electrical conductivity in Cu2CdSn(1-x)GaxSe4 series for high thermoelectric performances. AB - Serials of Ga doping on Sn sites as heterovalent substitution in Cu2CdSnSe4 are prepared by the melting method and the spark plasma sintering (SPS) technique to form Cu2CdSn(1-x)GaxSe4 (x = 0, 0.025, 0.05, 0.075, 0.01, and 0.125). Massive atomic vacancies are found at x = 0.10 by the heterovalent substitution, which contributes significantly to the increase of electrical conductivity and the decrease of lattice thermal conductivity. The electrical conductivity is increased by about ten times at 300 K after Ga doping. Moreover, the seebeck coefficient only decreases slightly from 310 to 226 MUV/K at 723 K, and a significant increase of the power factor is obtained. As a result, a maximum value of 0.27 for the figure of merit (ZT) is obtained at x = 0.10 and at 723 K. Through an ab initio study of the Ga doping effect, we find that the Fermi level of Cu2CdSnSe4 is shifted downward to the valence band, thus improving the hole concentration and enhancing the electrical conductivity at low doping levels. Our experimental and theoretical studies show that a moderate Ga doping on Sn sites is an effective method to improve the thermoelectric performance of Cu2CdSnSe4. PMID- 25791824 TI - Ideal target arterial pressure after control of bleeding in a rabbit model of severe traumatic hemorrhagic shock: results from volume loading-based fluid resuscitation. AB - BACKGROUND: Previously reported ideal target mean arterial pressure (MAP) after control of bleeding in traumatic hemorrhagic shock (THS) requires further verification in more clinically related models. The authors explored this issue via gradient volume loading without vasopressor therapy. As certain volume loading can induce secretion of atrial natriuretic peptide (ANP), which has been shown to be protective, the authors also observed its potential role. MATERIALS AND METHODS: Fifty male New Zealand rabbits were submitted to 1.5 h of uncontrolled THS (with another eight rabbits assigned to the sham group). After bleeding control, treated rabbits were randomly (n = 10, respectively) resuscitated with blood and Ringer lactate (1:2) to achieve target MAP of 50, 60, 70, 80, and 90 mm Hg within 1 h. During the following 2 h, they were resuscitated toward baseline MAP. Rabbits were observed until 7 h. RESULTS: After resuscitation, infused fluid was lower and oxidative stress injury was milder in the 70 mm Hg group. Fluid volume loaded during the initial hour after hemostasis was negatively correlated with pH, oxygen saturation, and base excess at the end of resuscitation. It also correlated positively with proinflammatory responses in bronchoalveolar lavage fluid at 7 h and 7-h mortality. Moreover, after volume loading, the 80 mm Hg group showed significantly increased serum ANP level, which correlated with the expression of Akt protein in the jejunum at 7 h. CONCLUSIONS: In rabbits the ideal target MAP during the initial resuscitation of severe THS after hemostasis was 70 mm Hg. ANP may have a critical role in gut protection. PMID- 25791826 TI - The effects of neoadjuvant chemoradiation on pancreaticoduodenectomy-the American College of Surgeon's National Surgical Quality Improvement Program analysis. AB - BACKGROUND: The purpose of this study was to investigate the effects of preoperative chemoradiation therapy on postoperative outcomes of pancreaticoduodenectomy (PD). MATERIALS AND METHODS: The American College of Surgeon's National Surgical Quality Improvement Program Participant User File from 2005-2011 was used to analyze the outcomes of patients who underwent chemoradiation therapy before PD. Their outcomes were compared with those who underwent PD without neoadjuvant therapy. RESULTS: We identified 110 patients who received preoperative chemoradiation therapy before undergoing PD for pancreatic malignancies and compared them with 4915 patients who did not. The two groups were similar in their preoperative comorbidities and demographics. The neoadjuvant group experienced a significantly longer operative time with a higher rate of vascular reconstruction, transfusion requirement, and superficial wound infection compared with those who did not receive neoadjuvant therapy. However, mortality and the rate of major complications between the two groups were similar. CONCLUSIONS: Preoperative chemoradiation therapy is associated with an increase in transfusion requirement and superficial surgical site infection. However, it is not associated with an increase in 30-d mortality or major complications. PMID- 25791825 TI - Impact of mesothelioma histologic subtype on outcomes in the Surveillance, Epidemiology, and End Results database. AB - BACKGROUND: This study was conducted to determine how malignant pleural mesothelioma (MPM) histology was associated with the use of surgery and survival. METHODS: Overall survival of patients with stage I-III epithelioid, sarcomatoid, and biphasic MPM in the Surveillance, Epidemiology, and End Results database from 2004-2010 was evaluated using multivariate Cox proportional hazards models. RESULTS: Of 1183 patients who met inclusion criteria, histologic subtype was epithelioid in 811 patients (69%), biphasic in 148 patients (12%), and sarcomatoid in 224 patients (19%). Median survival was 14 mo in the epithelioid group, 10 mo in the biphasic group, and 4 mo in the sarcomatoid group (P < 0.01). Cancer-directed surgery was used more often in patients with epithelioid (37%, 299/811) and biphasic (44%, 65/148) histologies as compared with patients with sarcomatoid histology (26%, 58/224; P < 0.01). Among patients who underwent surgery, median survival was 19 mo in the epithelioid group, 12 mo in the biphasic group, and 4 mo in the sarcomatoid group (P < 0.01). In multivariate analysis, surgery was associated with improved survival in the epithelioid group (hazard ratio [HR] 0.72; P < 0.01) but not in biphasic (HR 0.73; P = 0.19) or sarcomatoid (HR 0.79; P = 0.18) groups. CONCLUSIONS: Cancer-directed surgery is associated with significantly improved survival for MPM patients with epithelioid histology, but patients with sarcomatoid and biphasic histologies have poor prognoses that may not be favored by operative treatment. The specific histology should be identified before treatment, so that surgery can be offered to patients with epithelioid histology, as these patients are most likely to benefit. PMID- 25791827 TI - Histological study of the elongated esophagus in a rat model. AB - BACKGROUND: Esophageal elongation by traction suture is used in pediatric patients to manage long-gap esophageal atresia (EA). There was no histological evidence of the esophageal elongation. Here, we sought to clarify the histologic effects of traction on the esophagus by using a rat EA model simulating Foker's method. MATERIALS AND METHODS: Rats were randomly assigned into three groups (n = 5 each). The traction group underwent daily stretching of the distal segment of the esophagus. The nontraction group underwent a sham operation, and the normal group served as controls. Seven days after the operation, the distal segments of the esophagus were removed. The length and thickness were measured, and samples were stained with Ki-67, nNOS, and S-100. RESULTS: The whole length of the esophagus in the traction group was significantly longer than that in the nontraction group (P < 0.01). The thickness of esophageal mucosa and muscle tended to become thin by traction, but not significantly. The Ki-67-positive ratio of mucosa and muscle was significantly higher in the traction group (P < 0.05). There were no significant differences in Ki-67 between two segments (cardia-middle and middle-stump) in any group. Auerbach's plexus was identified at all sites of elongated esophagus by nNOS and S-100 staining. CONCLUSIONS: By traction, the esophagus was elongated uniformly and cell proliferation activity was promoted in all parts of the elongated esophagus in the rat EA model. PMID- 25791829 TI - P21-activated kinase 1 and 4 were associated with colorectal cancer metastasis and infiltration. AB - BACKGROUND: P21-activated kinases (PAKs) are small guanosine triphosphate effectors that play critical roles in many fundamental cellular functions, including cytoskeletal reorganization and cell motility. PAKs are widely expressed in a variety of tissues and are often overexpressed in multiple cancer types. The aim of this study was to investigate the relationship between PAK1 and PAK4 and clinicopathologic features of colorectal cancer. METHODS: PAK1 and PAK4 expression in colorectal cancer patients were investigated via TaqMan real-time polymerase chain reaction and immunohistochemistry and clinical analysis. RESULTS: The relative expression levels of PAK1 and PAK4 gene in colorectal carcinoma tissues were significantly higher than those in normal tissues (P < 0.01). PAK4 expression was higher than PAK1 in the same cancer tissue. The expression of PAK1 and PAK4 increased gradually with the clinical stages in carcinoma tissues (P < 0.01). PAK1 expression was higher in lymph node positive patients, and PAK4 expression was higher in infiltration into serous layer patients (P < 0.05). PAK1 overexpression group has a higher recurrence/metastasis rate compared with that of the PAK1 low expression group. Follow-up analysis showed that the median progression-free survival time of the PAK1 high expression group was significantly shorter than that of the PAK1 low expression group. CONCLUSIONS: PAK1 and PAK4 expression were associated with colorectal cancer metastasis and infiltration, PAK1 high expression may indicate poor prognosis of colorectal cancer. PMID- 25791830 TI - Polymorphic phase transition mechanism of compressed coesite. AB - Silicon dioxide is one of the most abundant natural compounds. Polymorphs of SiO2 and their phase transitions have long been a focus of great interest and intense theoretical and experimental pursuits. Here, compressing single-crystal coesite SiO2 under hydrostatic pressures of 26-53 GPa at room temperature, we discover a new polymorphic phase transition mechanism of coesite to post-stishovite, by means of single-crystal synchrotron X-ray diffraction experiment and first principles computational modelling. The transition features the formation of multiple previously unknown triclinic phases of SiO2 on the transition pathway as structural intermediates. Coexistence of the low-symmetry phases results in extensive splitting of the original coesite X-ray diffraction peaks that appear as dramatic peak broadening and weakening, resembling an amorphous material. This work sheds light on the long-debated pressure-induced amorphization phenomenon of SiO2, but also provides new insights into the densification mechanism of tetrahedrally bonded structures common in nature. PMID- 25791831 TI - Training in communication skills should be integrated with mandatory resuscitation training. PMID- 25791828 TI - Abnormal myofiber morphology and limb dysfunction in claudication. AB - BACKGROUND: Peripheral artery disease (PAD), which affects an estimated 27 million people in Europe and North America, is caused by atherosclerotic plaques that limit blood flow to the legs. Chronic, repeated ischemia in the lower leg muscles of PAD patients is associated with loss of normal myofiber morphology and myofiber degradation. In this study, we tested the hypothesis that myofiber morphometrics of PAD calf muscle are significantly different from normal calf muscle and correlate with reduced calf muscle strength and walking performance. METHODS: Gastrocnemius biopsies were collected from 154 PAD patients (Fontaine stage II) and 85 control subjects. Morphometric parameters of gastrocnemius fibers were determined and evaluated for associations with walking distances and calf muscle strength. RESULTS: Compared with control myofibers, PAD myofiber cross-sectional area, major and minor axes, equivalent diameter, perimeter, solidity, and density were significantly decreased (P < 0.005), whereas roundness was significantly increased (P < 0.005). Myofiber morphometric parameters correlated with walking distances and calf muscle strength. Multiple regression analyses demonstrated myofiber cross-sectional area, roundness, and solidity as the best predictors of calf muscle strength and 6-min walking distance, whereas cross-sectional area was the main predictor of maximum walking distance. CONCLUSIONS: Myofiber morphometrics of PAD gastrocnemius differ significantly from those of control muscle and predict calf muscle strength and walking distances of the PAD patients. Morphometric parameters of gastrocnemius myofibers may serve as objective criteria for diagnosis, staging, and treatment of PAD. PMID- 25791832 TI - Changing Etiological Trends in Male Precocious Puberty: Evaluation of 100 Cases with Central Precocious Puberty over the Last Decade. AB - BACKGROUND/AIMS: There are few studies in the literature that have evaluated the etiological factors in boys with central precocious puberty (CPP), and these studies are limited in terms of the sample size. In the present study, we aimed to evaluate the etiological factors in male CPP cases. METHODS: One hundred male CPP subjects, aged between 9 months and 10.5 years, were included. The medical records were screened, and age at diagnosis, bone age, body weight, height, pubertal stage, imaging findings of the pituitary gland, testosterone, and basal and stimulated gonadotropin levels were recorded. RESULTS: There was no underlying cause in 74% of the cases, and an organic cause was determined in only 26%. Most of the organic cases had been diagnosed before the age of 7 years, whereas most of the idiopathic cases had been diagnosed after the age of 7 years. CONCLUSION: An organic cause was determined in 26% of the male patients with CPP. This rate is one of the lowest rates in the literature and indicates that the number of idiopathic male CPP cases is increasing over time. When a boy is diagnosed with CPP above the age of 7 years, the odds of detecting an underlying pathology are very low, and these cases are mostly idiopathic. PMID- 25791833 TI - Caring for Tube-Fed Children: A Review of Management, Tube Weaning, and Emotional Considerations. AB - Enteral nutrition is the practice of delivering nutrition to the gut either orally or through a tube or other device. Many children are reliant on enteral feedings to either supplement their nutrition or as a complete source of their nutrition. Managing children on tube feedings requires a team of providers to work through such dilemmas as feeding schedules, weaning from tube feeding, sensory implications of tube feeding, treatment of pain or nausea associated with eating, oral-motor issues, and behavioral issues in the child and family. The purpose of the current review is to summarize the multidisciplinary aspects of enteral feeding. The multidisciplinary team consists of a variable combination of an occupational therapist, speech-language pathologist, gastroenterologist, psychologist, nurse, pharmacist, and dietitian. Children who have minimal oral feeding experience and are fed via a nasogastric or gastrostomy tube often develop oral aversions. Limited data support that children with feeding disorders are more likely to have sensory impairment and that early life pain experiences contribute to feeding refusal. There are inpatient and outpatient programs for weaning patients from tube feeding to eating. The parent-child interaction is an important part of the assessment and treatment of the tube-fed child. This review also points out many information gaps, including data on feeding schedules, blenderized tube feedings, the best methods for weaning children off enteral feedings, the efficacy of chronic pain medications with tube-fed children, and, finally, the necessity of the assessment of parental stress among all parents of children who are tube fed. PMID- 25791834 TI - Reclaiming the name 'bronchiectasis'. PMID- 25791835 TI - Bio-inspired pulmonary surfactant-modified nanogels: A promising siRNA delivery system. AB - Inhalation therapy with small interfering RNA (siRNA) is a promising approach in the treatment of pulmonary disorders. However, clinical translation is severely limited by the lack of suitable delivery platforms. In this study, we aim to address this limitation by designing a novel bioinspired hybrid nanoparticle with a core-shell nanoarchitecture, consisting of a siRNA-loaded dextran nanogel (siNG) core and a pulmonary surfactant (Curosurf(r)) outer shell. The decoration of siNGs with a surfactant shell enhances the colloidal stability and prevents siRNA release in the presence of competing polyanions, which are abundantly present in biofluids. Additionally, the impact of the surfactant shell on the biological efficacy of the siNGs is determined in lung cancer cells. The presence of the surfactants substantially reduces the cellular uptake of siNGs. Remarkably, the lowered intracellular dose does not impede the gene silencing effect, suggesting a crucial role of the pulmonary surfactant in the intracellular processing of the nanoparticles. In order to surmount the observed reduction in cellular dose, folate is incorporated as a targeting ligand in the pulmonary surfactant shell to incite receptor-mediated endocytosis. The latter substantially enhances both cellular uptake and gene silencing potential, achieving efficient knockdown at siRNA concentrations in the low nanomolar range. PMID- 25791836 TI - Diameter of involved nerves is a valuable prognostic factor for gastric cancer. AB - The prognostic role of perineural invasion (PNI) in gastric cancer remains unclear. We hypothesized that the diameter of the tumor-involved nerves might be a useful indicator for prognosis. By labeling nerves and cancer cells in 204 cases of gastric cancer with single or double immunochemistry, we found that 146 cases were PNI positive and that 58 were PNI negative. For each case with PNI, the maximum diameter of the involved nerve was measured microscopically. Then, we correlated this parameter with the patients' 5-year overall survival, and receiver operating curves were used to determine the cutoff value. We found that the optimal cutoff value for predicting 5-year survival was 65 um (sensitivity 76.9%, specificity 70.0%). Next, all 204 patients were classified into two groups as follows: Group A, PNI-positive cases in which the largest involved nerves were >=65 um in diameter (110 cases); Group B, PNI-positive cases in which the largest involved nerves were P?65 um and all PNI-negative cases (94 cases). Compared with Group A, Group B had a better 5-year survival (74.5% vs 27.3%) and a better 5 year disease-free survival (63.8% vs 23.6%). Multivariate analysis suggested that a >=65 um maximum diameter of the involved nerves was an independent risk factor for both recurrence (P?0.001) and gastric cancer-related death (P?0.001) within 5 years. However, if all patients were classified simply based on whether PNI existed (regardless of the nerve size), this did not provide more information than traditional clinicopathological variables. In conclusion, the presence of cancer-involved nerves with a diameter >=65 um was a valuable prognostic factor for gastric cancer. PMID- 25791837 TI - Melanoma brain metastasis is independent of lactate dehydrogenase A expression. AB - BACKGROUND: The key metabolic enzyme lactate dehydrogenase A (LDHA) is overexpressed in many cancers, and several preclinical studies have shown encouraging results of targeted inhibition. However, the mechanistic importance of LDHA in melanoma is largely unknown and hitherto unexplored in brain metastasis. METHODS: We investigated the spatial, temporal, and functional features of LDHA expression in melanoma brain metastasis across multiple in vitro assays, in a robust and predictive animal model employing MRI and PET imaging, and in a unique cohort of 80 operated patients. We further assessed the genomic and proteomic landscapes of LDHA in different cancers, particularly melanomas. RESULTS: LDHA expression was especially strong in early and small brain metastases in vivo and related to intratumoral hypoxia in late and large brain metastases in vivo and in patients. However, LDHA expression in human brain metastases was not associated with the number of tumors, BRAF(V600E) status, or survival. Moreover, LDHA depletion by small hairpin RNA interference did not affect cell proliferation or 3D tumorsphere growth in vitro or brain metastasis formation or survival in vivo. Integrated analyses of the genomic and proteomic landscapes of LDHA indicated that LDHA is present but not imperative for tumor progression within the CNS, or predictive of survival in melanoma patients. CONCLUSIONS: In a large patient cohort and in a robust animal model, we show that although LDHA expression varies biphasically during melanoma brain metastasis formation, tumor progression and survival seem to be functionally independent of LDHA. PMID- 25791838 TI - Platonin preserves blood-brain barrier integrity in septic rats. AB - OBJECTIVES: Platonin possesses potent anti-inflammatory and antioxidative capacities. Because systemic inflammation and oxidative stress are crucial in mediating sepsis-induced blood-brain barrier (BBB) integrity loss, this study elucidated the effects of platonin on preserving BBB integrity in septic rats. METHODS: A total of 72 adult male rats (200-250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus platonin, sham operation, or sham operation plus platonin (n = 18 in each group). Systemic inflammation and oxidation levels and BBB integrity in the surviving rats were determined after 24 hour monitoring. RESULTS: Plasma levels of interleukin-6 (IL-6) and malondialdehyde (MDA)-markers of systemic inflammation and oxidation-and the grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels-markers of BBB integrity-in rats that received CLP were significantly higher than rats that received sham operation (all p < 0.001). By contrast, the plasma levels of IL-6 (p < 0.001) and MDA (p < 0.001), and the grading of Evans blue staining (p = 0.015), BBB permeability to Evans blue dye (p = 0.043), and brain edema levels (p = 0.034) in rats that received CLP plus platonin were significantly lower than rats that received CLP. Experimental data further revealed that the concentration of tight junction protein claudin-5, a major structural component of BBB, in rats that received CLP was significantly lower than rats that received CLP plus platonin (p = 0.023). CONCLUSION: Platonin could attenuate sepsis-induced BBB integrity loss in rats. PMID- 25791839 TI - Usefulness of Somatostatin Receptor Scintigraphy (Tc-[HYNIC, Tyr3]-Octreotide) and 123I-Metaiodobenzylguanidine Scintigraphy in Patients with SDHx Gene-Related Pheochromocytomas and Paragangliomas Detected by Computed Tomography. AB - AIMS: The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using (99m)Tc-[HYNIC, Tyr3]-octreotide (TOC) and 123I metaiodobenzylguanidine (mIBG) in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography and to establish an optimal imaging diagnostic algorithm in SDHx mutation carriers. METHODS: All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and 123I-mIBG. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis. RESULTS: We evaluated 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 SDHD, 16 SDHB and 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients, and malignant disease was diagnosed in 7 patients. In benign tumors, the sensitivity of SRS was estimated at 77% and of 123I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region dependent (p < 0.001). The highest SRS sensitivity was found in head and neck paragangliomas (HNP; 91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40 and 42.9%, respectively). The highest 123I-mIBG sensitivity was found in pheochromocytomas (sensitivity of 100%) and the lowest in HNP (sensitivity of 3.7%). In metastatic disease, SRS was superior to mIBG (sensitivity of 95.2 vs. 23.8%, respectively). CONCLUSION: SRS and 123I-mIBG single photon emission computed tomography (SPECT) sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I mIBG SPECT. PMID- 25791840 TI - Female genital mutilation: what every paediatrician should know. AB - Female genital mutilation (FGM) is almost always performed on children and consequently paediatricians should have a central role in the detection and prevention of FGM. FGM has no health benefits and can cause lifelong damage to physical and psychological health. Extensive migration of FGM practising communities means that FGM is now a global problem. Paediatricians worldwide need to be familiar with the identification and classification of FGM and its impact upon health as well as current trends in practice. However information about FGM is hampered by the secrecy surrounding the procedure and a lack of rigorous evidence based research. This review summarises what is currently known about the health aspects of FGM and how paediatricians should manage children with FGM in their clinical practice. PMID- 25791841 TI - Cognitive dysfunction in adolescents with chronic fatigue: a cross-sectional study. AB - OBJECTIVE: To compare cognitive function in adolescents with chronic fatigue with cognitive function in healthy controls (HC). STUDY DESIGN: Cross-sectional study. SETTING: Paediatric department at Oslo University Hospital, Norway. PARTICIPANTS: 120 adolescents with chronic fatigue (average age 15.4 years; range 12-18) and 39 HC (average age 15.2 years; range 12-18). METHODS: The adolescents completed a neurocognitive test battery measuring processing speed, working memory, cognitive inhibition, cognitive flexibility, verbal learning and verbal memory, and questionnaires addressing demographic data, depression symptoms, anxiety traits, fatigue and sleep problems. Parents completed the Behaviour Rating Inventory of Executive Function (BRIEF), which measures the everyday executive functions of children. RESULTS: Adolescents with chronic fatigue had impaired cognitive function compared to HC regarding processing speed (mean difference 3.3, 95% CI 1.1 to 5.5, p=0.003), working memory (-2.4, -3.7 to -1.1, p<0.001), cognitive inhibition response time (6.2, 0.8 to 11.7, p=0.025) and verbal learning (-1.7, 3.2 to -0.3, p=0.022). The BRIEF results indicated that everyday executive functions were significantly worse in the chronic fatigue group compared to the HC (11.2, 8.2 to 14.3, p<0.001). Group differences remained largely unaffected when adjusted for symptoms of depression, anxiety traits and sleep problems. CONCLUSIONS: Adolescents with chronic fatigue had impaired cognitive function of clinical relevance, measured by objective cognitive tests, in comparison to HC. Working memory and processing speed may represent core difficulties. PMID- 25791842 TI - What makes for a 'good' or 'bad' paediatric diabetes service from the viewpoint of children, young people, carers and clinicians? A synthesis of qualitative findings. AB - BACKGROUND: There is mounting evidence that experience of care is a crucial part of the pathway for successful management of long-term conditions. DESIGN AND OBJECTIVES: To carry out (1) a systematic mapping of qualitative evidence to inform selection of studies for the second stage of the review; and (2) a narrative synthesis addressing the question, What makes for a 'good' or a 'bad' paediatric diabetes service from the viewpoint of children, young people, carers and clinicians? RESULTS: The initial mapping identified 38 papers. From these, the findings of 20 diabetes-focused papers on the views on care of >=650 children, parents and clinicians were synthesised. Only five studies included children under 11 years. Children and young people across all age groups valued positive, non-judgemental and relationship-based care that engaged with their social, as well as physical, health. Parents valued provision responsive to the circumstances of family life and coordinated across services. Clinicians wanting to engage with families beyond a child's immediate physical health described finding this hard to achieve in practice. LIMITATIONS: Socioeconomic status and ethnicity were poorly reported in the included studies. CONCLUSIONS: In dealing with diabetes, and engaging with social health in a way valued by children, parents and clinicians, not only structural change, such as more time for consultation, but new skills for reworking relations in the consultation may be required. PMID- 25791843 TI - Effect of acupuncture on gait in Parkinson's disease: a case report. AB - This case report describes the treatment of gait disturbance in a 64-year-old woman with Parkinson's disease. Needling for 10 min of areas of muscle stiffness and of muscle tonus areas in both lower limbs resulted in immediate temporary alleviation of muscle stiffness and muscle tonus of the bilateral anterior surface of the thigh muscle, the biceps femoris muscle, and the semitendinosus muscle for the duration of the treatment, with improvement in the disturbed gait of the patient. This response occurred regularly on repeated treatment, and was maintained between treatments. PMID- 25791844 TI - Acupuncture-induced haemothorax: a rare iatrogenic complication of acupuncture. AB - This paper reports a rare iatrogenic complication of acupuncture-induced haemothorax and comments on the importance and need for special education of physicians and physiotherapists in order to apply safe and effective acupuncture treatment. A 37-year-old healthy woman had a session of acupuncture treatments for neck and right upper thoracic non-specific musculoskeletal pain, after which she gradually developed dyspnoea and chest discomfort. After some delay while trying other treatment, she was eventually transferred to the emergency department where a chest X-ray revealed a right pneumothorax and fluid collection. She was admitted to hospital and a chest tube inserted into the right hemithorax (under ultrasound guidance) drained 800 mL of bloody fluid (haematocrit (Hct) 17.8%) in 24 h and 1200 mL over the following 3 days. Her blood Hct fell from 39.0% to 30.8% and haemoglobin from 12.7 to 10.3 g/dL. The patient recovered completely and was discharged after 9 days of hospitalisation. When dyspnoea, chest pain and discomfort occur during or after an acupuncture treatment, the possibility of secondary (traumatic) pneumo- or haemopneumothorax should be considered and the patient should remain under careful observation (watchful waiting) for at least 48 h. To maximise the safety of acupuncture, specific training should be given for the safe use of acupuncture points of the anterior and posterior thoracic wall using dry needling, trigger point acupuncture or other advanced acupuncture techniques. PMID- 25791845 TI - Management of hypertension in hospitalized patients. AB - Elevated blood pressure (BP) is a common problem in patients hospitalized for reasons other than hypertension. Unexpected elevations commonly result in calls to physicians who too often prescribe medication to reduce the numbers without evaluating the patient or determining the cause of the elevation. This may result in unnecessary and sometimes harmful treatment. Such BP elevation has many potential causes. These include anxiety, post-operative salt and volume overload, failure to administer the patient's known antihypertensive medication, inability to give oral antihypertensive medication to patients who cannot take pills by mouth, incipient heart failure, previously unrecognized renal failure, obstructive uropathy and other causes. These must be identified and treated prior to addressing only the elevated BP numbers. We present an algorithm for evaluating hospitalized patients with elevated BP in order to assist physicians in identifying the true cause of the elevation, treating the identified cause, and giving appropriate drug treatment. We also note that this is a golden opportunity for communication with the outpatient providers who will follow the patient. PMID- 25791846 TI - Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety. AB - The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. (c) 2015 S. Karger AG, Basel. PMID- 25791847 TI - Characterization of a Novel Thermostable Oligopeptidase from Geobacillus thermoleovorans DSM 15325. AB - A gene (GT-SM3B) encoding a thermostable secreted oligoendopeptidase (GT-SM3B) was cloned from the thermophile Geobacillus thermoleovorans DSM 15325. GT-SM3B is 1,857 bp in length and encodes a single-domain protein of 618 amino acids with a 23-residue signal peptide having a calculated mass of 67.7 kDa after signal cleavage. The deduced amino acid sequence of GT-SM3B contains a conservative zinc metallopeptidase motif (His(400)-Glu(401)-X-XHis (404)). The described oligopeptidase belongs to the M3B subfamily of metallopeptidases and displays the highest amino acid sequence identity (40.3%) to the oligopeptidase PepFBa from mesophilic Bacillus amyloliquefaciens 23-7A among the characterized oligopeptidases. Secretory production of GT-SM3B was used, exploiting successful oligopeptidase signal peptide recognition by Escherichia coli BL21 (DE3). The recombinant enzyme was purified from the culture fluid. Homodimerization of GT SM3B was determined by SDS-PAGE. Both the homodimer and monomer were catalytically active within a pH range of 5.0-8.0, at pH 7.3 and 40 degrees C, showing the Km, Vmax, and kcat values for carbobenzoxy-Gly-Pro-Gly-Gly-Pro-Ala-OH peptidolysis to be 2.17 +/- 0.04 * 10(-6) M, 2.65 +/- 0.03 * 10(-3) micrometer/min, and 5.99 +/- 0.07 s(-1), respectively. Peptidase remained stable at a broad pH range of 5.0-8.0. GT-SM3B was thermoactive, demonstrating 84% and 64% of maximum activity at 50 degrees C and 60 degrees C, respectively. The recombinant oligopeptidase is one of the most thermostable M3B peptidase, retaining 71% residual activity after incubation at 60 degrees C for 1 h. GT-SM3B was shown to hydrolyze a collagenous peptide mixture derived from various types of collagen, but less preferentially than synthetic hexapeptide. This study is the first report on an extracellular thermostable metallo-oligopeptidase. PMID- 25791848 TI - Reduction of Acetate and Lactate Contributed to Enhancement of a Recombinant Protein Production in E. coli BL21. AB - Acetate and lactate in growth media are detrimental to the production of Thermus maltogenic amylase (ThMA), a heterologous protein, as well as to the growth of recombinant Escherichia coli. Only 50 mM of acetate or 10 mM of lactate reduced 90% of specific ThMA activity. In this study, mutant E. coli strains blocked in the ackA-pta or ackA-pta and ldh pathways were created, characterized, and assessed for their culture performace in 300 L-scale fermentation. The ackApta and ldh double-mutant strain formed significantly less lactate and acetate, and produced a concomitant increase in the excretion of pyruvate (17.8 mM) under anaerobic conditions. The ackA-pta mutant strain accumulated significant acetate but had an approximately 2-fold increase in the formation of lactate. The ackA pta and ldh double-mutant strain had superior overall performance in large-scale culture under suboptimal conditions, giving 67% higher cell density and 66% higher ThMA activity compared with those of the control strain. The doublemutant strain also achieved a 179% improvement in volumetric ThMA production. PMID- 25791849 TI - Promotion Effects of Ultra-High Molecular Weight Poly-gamma-Glutamic Acid on Wound Healing. AB - We examined the in vivo efficacy of ultra-high molecular weight poly-gamma glutamic acid (UHMW gamma-PGA) for wound healing. The wound area was measured by a ruler and documented by digital photography before the animals were sacrificed at days 8 and 16 post wounding. The areas of wounds treated with UHMW gamma-PGA were significantly decreased on days 8 and 16, as compared with those receiving a control treatment, and more than 70% of the UHMW gamma-PGAtreated area was repaired by day 8. Hematoxylin and eosin staining confirmed that the epidermis had regenerated in the UHMW gamma-PGA-treated wounds. At 16 days post wounding, collagen pigmentation and cross-linking were increased as compared with the control groups, and greater regeneration of blood vessels had occurred in UHMW gamma-PGA-treated groups. Increased levels of transforming growth factor-beta and beta-catenin were also observed in skin samples collected from UHMW gamma-PGA treated animals on days 8 and 16 post incision. Taken together, these findings suggest that UHMW gamma-PGA promotes wound healing in vivo. PMID- 25791850 TI - Various Enterotoxin and Other Virulence Factor Genes Widespread Among Bacillus cereus and Bacillus thuringiensis Strains. AB - Many strains of Bacillus cereus cause gastrointestinal diseases, and the closely related insect pathogen Bacillus thuringiensis has also been involved in outbreaks of diarrhea. The diarrheal diseases are attributed to enterotoxins. Sixteen reference strains of B. cereus and nine commercial and 12 reference strains of B. thuringiensis were screened by PCR for the presence of 10 enterotoxigenic genes (hblA, hblC, hblD, nheA, nheB, nheC, cytK, bceT, entFM, and entS), one emetogenic gene (ces), seven hemolytic genes (hlyA, hlyII, hlyIII, plcA, cerA, cerB, and cerO), and a pleiotropic transcriptional activator gene (plcR). These genes encode various enterotoxins and other virulence factors thought to play a role in infections of mammals. Amplicons were successfully generated from the strains of B. cereus and B. thuringiensis for each of these sequences, except the ces gene. Intriguingly, the majority of these B. cereus enterotoxin genes and other virulence factor genes appeared to be widespread among B. thuringiensis strains as well as B. cereus strains. PMID- 25791851 TI - Combined Treatment of Herbal Mixture Extract H9 with Trastuzumab Enhances Anti tumor Growth Effect. AB - Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC. PMID- 25791852 TI - Association of Helicobacter pylori cagA Gene with Gastric Cancer and Peptic Ulcer in Saudi Patients. AB - This study was conducted to assess the relationship between occurrence of gastric cancer and peptic ulcer, and the presence of H. pylori cagA gene and anti-CagA IgG, and to estimate the value of these antibodies in detecting infection by cagA gene-positive H. pylori strains in Saudi patients. The study included 180 patients who were subjected to upper gastrointestinal endoscopy in Taif province and Western region of Saudi Arabia (60 gastric cancer, 60 peptic ulcer, and 60 with non-ulcer dyspepsia). Gastric biopsy specimens were obtained and tested for H. pylori infection by rapid urease test and culture. PCR was performed on the isolated strains and biopsy specimens for detection of the cagA gene. Blood samples were collected and tested for CagA IgG by ELISA. H. pylori infection was detected among 72.8% of patients. The cagA gene and anti-CagA IgG were found in 63.4% and 61.8% of H. pylori-infected patients, respectively. They were significantly (p < 0.01) higher in patients with gastric cancer and peptic ulcer compared with those with non-ulcer dyspepsia. Detection of the CagA IgG was 91.6% sensitive, 89.6% specific, and 90.8% accurate compared with detection of the cagA gene. Its positive and negative predictive values were 93.8% and 86%, respectively. The study showed a significant association between the presence of the cagA gene and gastric cancer and peptic ulcer disease, and between anti-CagA IgG and the cagA gene in Saudi patients. However, a further larger study is required to confirm this finding. PMID- 25791853 TI - Characterization of Glutamate Decarboxylase (GAD) from Lactobacillus sakei A156 Isolated from Jeot-gal. AB - A gamma-aminobutyric acid (GABA)-producing microorganism was isolated from jeot gal (anchovy), a Korean fermented seafood. The isolate, A156, produced GABA profusely when incubated in MRS broth with monosodium glutamate (3% (w/v)) at 37 degrees C for 48 h. A156 was identified as Lactobacillus sakei by 16S rRNA gene sequencing. The GABA conversion yield was 86% as determined by GABase enzyme assay. The gadB gene encoding glutamate decarboxylase (GAD) was cloned by PCR. gadC encoding a glutamate/GABA antiporter was located immediately upstream of gadB. The operon structure of gadCB was confirmed by RT-PCR. gadB was overexpressed in Escherichia coli BL21(DE3) and recombinant GAD was purified. The purified GAD was 54.4 kDa in size by SDS-PAGE. Maximum GAD activity was observed at pH 5.0 and 55 degrees C and the activity was dependent on pyridoxal 5' phosphate. The Km and Vmax of GAD were 0.045 mM and 0.011 mM/min, respectively, when glutamate was used as the substrate. PMID- 25791854 TI - The Stability, and Efficacy Against Penicillin-Resistant Enterococcus faecium, of the Plectasin Peptide Efficiently Produced by Escherichia coli. AB - Plectasin, the first defensin extracted from a fungus (the saprophytic ascomycete Pseudoplectania nigrella), is attractive as a prospective antimicrobial agent. The purpose of this study was to establish a bacterium-based production system and evaluate the antimicrobial activity of the resulting plectasin. A gene encoding plectasin, with the codon preference of Escherichia coli, was optimized based on its amino acid sequence, synthesized using gene-splicing with overlap extension PCR, and inserted into the expression vector pGEX-4T-1. The fusion protein was expressed in the soluble fraction of E. coli and purified using glutathione Stransferase affinity chromatography. Plectasin was cleaved from the fusion protein with thrombin and purified by ultrafiltration. The purified plectasin showed strong, concentration-dependent antimicrobial activity against gram-positive bacteria, including antibiotic-resistant bacteria, especially penicillin-resistant Enterococcus faecium. This antimicrobial activity was equal to chemically synthesized plectasin and was maintained over a wide range of pH and temperatures. This soluble recombinant expression system in E. coli is effective for producing plectasin at a relatively lower cost, and higher purity and efficiency than prior systems, and might provide a foundation for developing a large-scale production system. Overall, plectasin shows potential as a novel, high-performance, and safe antibiotic for the treatment of refractory diseases caused by drug-resistant bacterial strains. PMID- 25791855 TI - Inhibition of Yeast Growth by Broadly Cross-Reactive Antisera Elicited by Heterologous Mannan-Protein Conjugate. AB - A new approach to obtain broadly cross-reactive antisera against important yeast pathogens by intensive hyperimmunization with polysaccharide-protein conjugates is described here. Surface mannan of Candida albicans and capsular galactoglucoxylomannan of Cryptococcus laurentii were isolated and chemically linked to human serum albumin. Antisera elicited by a 7-week vigorous immunization of rabbits with the conjugates showed effective cross-reactive growth inhibition of different representatives of Candida spp. as well as Cryptococcus spp. IgG antibodies are evidenced as the effective component of the antisera. PMID- 25791856 TI - Prebiotic Potential of Xylooligosaccharides Derived from Corn Cobs and Their In Vitro Antioxidant Activity When Combined with Lactobacillus. AB - In the present work, the in vitro prebiotic activity of xylooligosaccharides (XOS) derived from corn cobs combined with Lactobacillus plantarum, a probiotic microorganism, was determined. These probiotics exhibited different growth characteristics depending on strain specificity. L. plantarum S2 cells were denser and their growth rates were higher when cultured on XOS. Acetate was found to be the major short-chain fatty acid produced as the end-product of fermentation, and its amount varied from 1.50 to 1.78 mg/ml. The antimicrobial activity of XOS combined with L. plantarum S2 was determined against gastrointestinal pathogens. The results showed that XOS proved to be an effective substrate, enhancing antimicrobial activity for L. plantarum S2. In vivo evaluation of the influence of XOS and L. plantarum S2, used both alone and together, on the intestinal microbiota in a mouse model showed that XOS combined with L. plantarum S2 could increase the viable lactobacilli and bifidobacteria in mice feces and decrease the viable Enterococcus, Enterobacter, and Clostridia spp. Furthermore, in the in vitro antioxidant assay, XOS combined with L. plantarum S2 possessed significant 2,2-diphenyl-1- picrylhydrazyl, 2,2'-azino bis, and superoxide anion radical-scavenging activities, and the combinations showed better antioxidant activity than either XOS or L. plantarum S2 alone. PMID- 25791857 TI - "Goat eyes": Horizontal rectangular pupils: An unusual clinical presentation of orf. PMID- 25791858 TI - Extramammary Paget disease secondary to a transitional cell carcinoma of the bladder. PMID- 25791859 TI - In vitro antimicrobial susceptibility of Mycoplasma hominis genital isolates. PMID- 25791860 TI - Angioimmunoblastic T-cell lymphoma. PMID- 25791861 TI - Nanomaterial categorization for assessing risk potential to facilitate regulatory decision-making. AB - For nanotechnology to meet its potential as a game-changing and sustainable technology, it is important to ensure that the engineered nanomaterials and nanoenabled products that gain entry to the marketplace are safe and effective. Tools and methods are needed for regulatory purposes to allow rapid material categorization according to human health and environmental risk potential, so that materials of high concern can be targeted for additional scrutiny, while material categories that pose the least risk can receive expedited review. Using carbon nanotubes as an example, we discuss how data from alternative testing strategies can be used to facilitate engineered nanomaterial categorization according to risk potential and how such an approach could facilitate regulatory decision-making in the future. PMID- 25791862 TI - Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease. AB - BACKGROUND AND AIM: There has been a surge of interest in the cardiovascular effects of vitamin D (25(OH)D), preventing the processes leading to vascular wall degeneration and coronary artery disease (CAD). Gender differences have been suggested for vitamin D status, with a higher rate of deficiency occurring especially in post-menopausal women, increasing the risk of bone fractures and osteoporosis. However, to date, few studies have evaluated the differences in 25(OH)D levels according to gender and their impact on the extent of CAD, which was therefore the aim of the present study. METHODS AND RESULTS: In patients undergoing coronary angiography, fasting samples were collected for the assessment of 25(OH)D levels. Significant CAD was defined as at least one vessel stenosis >50%, while severe CAD was defined as left main and/or three-vessel disease. Of the 1811 patients included, 530 (29.3%) were females, who displayed older age (p < 0.001), higher rate of renal failure (p < 0.001), hypertension (p = 0.05), treatment with angiotensin-receptor blockers (p = 0.03) and diuretics (p < 0.001), acute presentation (p < 0.001), higher platelet count (p < 0.001), glycosylated haemoglobin (p = 0.02) and cholesterol (p = 0.001), but an inverse relationship with smoking (p < 0.001), previous cardiovascular events (p < 0.001), treatment with statins and acetylsalicylic acid (ASA) (p < 0.001), body mass index (p = 0.002), haemoglobin (p < 0.001), leucocytes (p = 0.03) and triglycerides (p < 0.001). Female gender was associated with lower vitamin D levels (14.5 +/- 10.9 vs. 15.9 +/- 9.5, p = 0.007) and independently associated with severe vitamin D deficiency (41.9% vs. 30.4%, p < 0.001; adjusted odds ratio (OR) (95% confidence interval (CI)) = 1.42 (1.08-1.87), p = 0.01). Lower tertiles of vitamin D were associated with an increased prevalence and severity of CAD in females (adjusted OR (95% CI = 1.26 (1.10-1.44), p = 0.001 for CAD; adjusted OR (95% CI) = 1.6 (1.39-1.87), p < 0.001 for severe CAD). In males, vitamin D status was independently related to the prevalence (adjusted OR (95% CI) = 1.28 (1.02 1.61), p = 0.03) of CAD, but not the extent of CAD (adjusted OR (95% CI) = 1.02 (0.86-1.2), p = 0.84). CONCLUSION: Gender significantly affects vitamin D status. The lower 25(OH)D levels observed in females, as compared to males, play a more relevant role in conditioning the severity of CAD. PMID- 25791863 TI - Effect of pistachio consumption on plasma lipoprotein subclasses in pre-diabetic subjects. AB - BACKGROUND AND AIMS: Nuts have been demonstrated to improve several cardiovascular risk factors and the lipid profile in diabetic and pre-diabetic subjects. However, analysis of conventional serum lipid profiles does not completely explain the atherogenic risk associated with pre-diabetes. We therefore investigated whether chronic consumption of pistachio modifies the lipoprotein subclasses to a healthier profile in pre-diabetic subjects. METHODS AND RESULTS: Randomized cross-over clinical trial in 54 subjects with pre diabetes. Subjects consumed a pistachio-supplemented diet (PD, 50% carbohydrates, 33% fat, including 57 g/d of pistachios daily) and a control diet (CD, 55% carbohydrates, 30% fat) for 4 months each, separated by a 2-week wash-out. Diets were isocaloric and matched for protein, fiber and saturated fatty acids. Nuclear magnetic resonance (NMR) was performed to determine changes in plasma lipoprotein subclasses. Small low-density lipoprotein particles (sLDL-P) significantly decreased after pistachio consumption compared to the nut-free diet (P = 0.023). The non-high-density lipoprotein particles (non-HDL-P i.e. VLDL-P plus LDL-P) significantly decreased under the PD compared to CD (P = 0.041). The percentage of sHDL-P increased by 2.23% after the PD compared with a reduction of 0.08% after the CD (P = 0.014). Consequently, the overall size of HDL-P significantly decreased in the PD (P = 0.007). CONCLUSION: Chronic pistachio consumption could modify the lipoprotein particle size and subclass concentrations independently of changes in total plasma lipid profile, which may help to explain the decreased risk of cardiovascular disease and mortality associated with those individuals who frequently consumed nuts. REGISTRATION NUMBER: This study is registered at www.clinicaltrials.gov as NCT01441921. PMID- 25791864 TI - Acute nitrogen dioxide inhalation induces mitochondrial dysfunction in rat brain. AB - Recent epidemiological literatures imply that NO2 is a potential risk factor of neurological disorders. Whereas, the pathogenesis of various neurological diseases has been confirmed correlate to mitochondrial dysfunction, and mitochondria play the crucial roles in energy metabolism, free radicals production and apoptosis triggering in response to neuronal injury. Therefore, to clarify the possible mechanisms for NO2-induced neurotoxicity, in the present study, we investigated the possible effects of acute NO2 inhalation (5, 10 and 20mg/m(3) with 5h/day for 7 days) on energy metabolism and biogenesis in rat cortex, mainly including mitochondrial ultrastructure, mitochondrial membrane potential, cytochrome c oxidase activity, cytochrome c oxidase (CO) and ATP synthase subunits, ATP content, and transcription factors. The results showed that NO2 exposure induced mitochondrial morphological changes in rat cortex, and the alteration was coupled with the abnormality of mitochondrial energy metabolism, including decreased respiratory complexes, reduced ATP production and increased production of ROS. Also, increased ROS in turn caused mitochondrial membrane damage, energy production defect and mitochondrial biogenesis inhibition. It suggests the significantly damaged mitochondrial energy metabolism and impaired biogenesis in rat brain after NO2 exposure, and provides a new understanding of the pathophysiological mechanisms of NO2-induced neurological disorders. PMID- 25791865 TI - Green job bio-aerosol exposure during anaerobic digestion for biomass energetic valorisation. AB - The continued expansion of the green economy increases the risk profile for green occupational jobs. One of the broadest green sectors in terms of growth is the anaerobic digestion of biomasses. In recent years, this development has also interested Italian regions. The management of biomass includes biological risk and the risk of particulate and endotoxin exposure. In the present study, we evaluated airborne exposure for anaerobic digestion workers at two real-scale plants. Digested biomass has different origins, ranging from cattle sludge and manure to poultry manure to agricultural harvesting or processing residues, particularly from maize and fruits. Two sampling points were chosen: at the first, the input biomasses were stored, and the hopper was loaded; at the second, the digested sludge exited the digester. The microbiological parameters, assessed using an active sampler and cultural method, were the total bacteria counts (at 22, 37, and 55 degrees C), yeasts, fungi, Pseudomonaceae, Clostridia spp., Enterobacteriaceae and Actinomycetes. Moreover, at the same sampling points, we evaluated six PM10 fraction levels (10.0-7.2, 7.2-3.0, 3.0-1.5, 1.5-0.95, 0.95 0.49, and <0.49um) and the endotoxin content of each fraction. In this investigation, the microbe contamination of the air varied from low to high levels, while the PM10 and endotoxin levels were limited, reaching rural environmental levels (61.40ug/m(3) and 18.88EU/m(3), respectively). However, contamination and occupational risk must be evaluated individually for each plant because numerous variables influence the risk magnitude, particularly digested sludge treatments, such as input biomass nature, storage, movement conditions, building configuration and technological processes. PMID- 25791866 TI - Total lead concentration in new decorative enamel paints in Lebanon, Paraguay and Russia. AB - Lead concentrations in new enamel decorative paints were determined in three countries in different areas of the world where data were not previously available. The average total lead concentration of the enamel decorative paints purchased in Lebanon, Paraguay and Russia was 24,500ppm (ppm, dry weight), more than 270 times the current limit of 90ppm in Canada and in the United States. Sixty-three percent of these paints contained concentrations greater than 90ppm. Fifty-nine percent contained concentrations greater than 600ppm, the current limit in some countries. The maximum concentrations found were 236,000ppm in Lebanon, 169,000ppm in Paraguay and 52,900ppm in Russia. An average of 29% of the samples contained exceedingly high lead concentrations, >=10,000ppm. Five brands of paint were sampled in each of Lebanon and Paraguay and seven in Russia. Three colors from each brand were analyzed. For five of the six samples of the two brands in Lebanon with affiliations outside the country, the lead concentrations ranged from 1360ppm to 135,000ppm. In Lebanon the maximum concentration in the Egypt-affiliated brand (Sipes) was 135,000ppm and the maximum for the USA affiliated brand (Dutch Boy) was 32,400ppm. Lead was not detected in any paints from the three of the four brands of paint purchased in Paraguay that had headquarters/affiliations in other countries (Brazil-Coralit), Germany (Suvinil) and USA (Novacor)). Two of the three paints from each of the other Paraguay brands contained high levels of lead with the maximum concentrations of 108,000 and 168,000ppm; one of these brands was manufactured under a license from ICI in the Netherlands. All of the paints purchased in Russia were from Russian brands and were manufactured in Russia. All three paints from one brand contained below detection levels of lead. The maximum levels of lead in the other six brands in Russia ranged from 3230 to 52,900ppm. The two brands with the highest lead concentration, TEKS and LAKRA, were produced by companies in the top three in market share.. Overall, lead concentrations were much higher in the colored paints such as red and yellow than in white paints. In each of the three countries a brand based in that country had a colored paint that either met a 90ppm limit or was close to meeting the limit-demonstrating that practical technology was available in each of these countries to produce low lead bright colored enamel decorative paints. Even though technology for producing paint without added lead existed in each of these countries, twenty-nine (29) percent of the paints analyzed contained exceedingly high concentrations (>=10,000ppm) of lead. PMID- 25791867 TI - Geographic dimensions of heat-related mortality in seven U.S. cities. AB - Spatially targeted interventions may help protect the public when extreme heat occurs. Health outcome data are increasingly being used to map intra-urban variability in heat-health risks, but there has been little effort to compare patterns and risk factors between cities. We sought to identify places within large metropolitan areas where the mortality rate is highest on hot summer days and determine if characteristics of high-risk areas are consistent from one city to another. A Poisson regression model was adapted to quantify temperature mortality relationships at the postal code scale based on 2.1 million records of daily all-cause mortality counts from seven U.S. cities. Multivariate spatial regression models were then used to determine the demographic and environmental variables most closely associated with intra-city variability in risk. Significant mortality increases on extreme heat days were confined to 12-44% of postal codes comprising each city. Places with greater risk had more developed land, young, elderly, and minority residents, and lower income and educational attainment, but the key explanatory variables varied from one city to another. Regression models accounted for 14-34% of the spatial variability in heat-related mortality. The results emphasize the need for public health plans for heat to be locally tailored and not assume that pre-identified vulnerability indicators are universally applicable. As known risk factors accounted for no more than one third of the spatial variability in heat-health outcomes, consideration of health outcome data is important in efforts to identify and protect residents of the places where the heat-related health risks are the highest. PMID- 25791868 TI - The efficacy of tonsillectomy in chronic tonsillitis patients as demonstrated by the neutrophil-to-lymphocyte ratio. AB - OBJECTIVES: Adenoidectomy and tonsillectomy are the oldest surgical procedures. The neutrophil-to-lymphocyte ratio is an inflammatory marker. This study aimed to investigate neutrophil-to-lymphocyte ratios in chronic tonsillitis patients and to determine whether this ratio reflects the pre- and post-operative inflammatory status in these patients. METHODS: Patients and healthy individuals were assigned to four groups: the adenoid hypertrophy, adenotonsillar hypertrophy, chronic tonsillitis and control groups. The neutrophil-to-lymphocyte ratio was calculated for each patient before surgery and one month post-surgery. Pre- and post operative white blood cell, neutrophil and lymphocyte counts and neutrophil-to lymphocyte ratios were compared both within and between groups. RESULTS: Pre- and post-operative neutrophil-to-lymphocyte ratios were significantly higher in the chronic tonsillitis group than in the adenoid hypertrophy and adenotonsillar hypertrophy groups (p < 0.01 and p < 0.05, respectively). In the chronic tonsillitis group, post-operative neutrophil-to-lymphocyte ratios were significantly lower than pre-operative ratios (p = 0.045). The pre-operative neutrophil-to-lymphocyte ratio was significantly higher in the chronic tonsillitis group than in the adenoid hypertrophy, adenotonsillar hypertrophy and control groups (p = 0.000). In contrast, there was no significant difference in post-operative neutrophil-to-lymphocyte ratios among all groups (p = 0.584). CONCLUSION: The neutrophil-to-lymphocyte ratio measurement can be used in chronic tonsillitis patients as an effective auxiliary method for determining the necessity and timing of tonsillectomy and post-operative follow up, thereby helping prevent complications due to delayed or inadequate treatment. PMID- 25791869 TI - Dynamic in-vivo assessment of navicular drop while running in barefoot, minimalist, and motion control footwear conditions. AB - Running-related injuries are common and previous research has suggested that the magnitude and/or rate of pronation may contribute to the development of these injuries. Accurately and directly measuring pronation can be challenging, and therefore previous research has often relied on navicular drop (under both static and dynamic conditions) as an indirect assessment of pronation. The objectives of this study were to use dynamic, biplane X-ray imaging to assess the effects of three footwear conditions (barefoot, minimalist shoes, motion control shoes) on the magnitude and rate of navicular drop during running, and to determine the association between static and dynamic measures of navicular drop. Twelve healthy distance runners participated in this study. The magnitude and rate of navicular drop were determined by tracking the 3D position of the navicular from biplane radiographic images acquired at 60Hz during the stance phase of overground running. Static assessments of navicular drop and foot posture were also recorded in each subject. Footwear condition was not found to have a significant effect on the magnitude of navicular drop (p=0.22), but motion control shoes had a slower navicular drop rate than running barefoot (p=0.05) or in minimalist shoes (p=0.05). In an exploratory analysis, static assessments of navicular drop and foot posture were found to be poor predictors of dynamic navicular drop in all footwear conditions (p>0.18). PMID- 25791870 TI - No transfer between conditions in balance training regimes relying on tasks with different postural demands: Specificity effects of two different serious games. AB - Despite the increasing use of video games involving whole body movements to enhance postural control in health prevention and rehabilitation, there is no consistent proof that training effects actually transfer to other balance tasks. The present study aimed to determine whether training effects on two different video-game-based training devices were task-specific or could be transferred to either postural control in quiet stance or to performance on the other device. 37 young healthy adults were split into three groups: two intervention groups that trained for 30min on either the Nintendo((r)) Wii Fit Balance Board or the MFT Challenge Disc((r)) three times per week for 4 weeks and a control group that received no training. All games require participants to control virtual avatars by shifting the center of mass in different directions. Both devices differ in their physical properties. The Balance Board provides a stable surface, whereas the Challenge Disc can be tilted in all directions. Dependent variables were the game scores on both devices and the center of pressure (COP) displacements measured via force plate. At posttest, both intervention groups showed significant increases in performance on the trained games compared to controls. However, there were no relevant transfer effects to performance on the untrained device and no changes in COP path length in quiet stance. These results suggest that training effects on both devices are highly specific and do not transfer to tasks with different postural demands. PMID- 25791871 TI - Interventions for reducing inflammation in familial Mediterranean fever. AB - BACKGROUND: Familial Mediterranean fever, a hereditary auto-inflammatory disease, mainly affects ethnic groups living in the Mediterranean region. Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever. For those people who are colchicine-resistant or intolerant, drugs such as rilonacept, anakinra, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial. OBJECTIVES: To evaluate the efficacy and safety of interventions for reducing inflammation in people with familial Mediterranean fever. SEARCH METHODS: We used detailed search strategies to search the following databases: CENTRAL; MEDLINE; Embase; Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure Database (CNKI); Wan Fang; and VIP. In addition, we also searched the clinical trials registries including ClinicalTrials.gov, the International Standard Randomized Controlled Trial Number Register, the WHO International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry, as well as references listed in relevant reports.Date of last search: 21 May 2014. SELECTION CRITERIA: Randomized controlled studies of people with diagnosis of familial Mediterranean fever, comparing active interventions (including colchicine, anakinra, rilonacept, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuardTM (a herbal dietary supplement) and non-steroidal anti-inflammatory drugs) with placebo or no treatment, or comparing active drugs to each other. DATA COLLECTION AND ANALYSIS: The authors independently selected studies, extracted data and assessed risk of bias. We pooled data to present the risk ratio or mean difference with their 95% confidence intervals. We assessed overall evidence quality according to the GRADE approach. MAIN RESULTS: We included four randomized placebo-controlled studies with a total of 75 participants (aged three to 53 years); three were of cross over and one of parallel design. Two studies used the active intervention of oral colchicine (0.6 mg three times daily or 0.5 mg twice daily), one study used oral ImmunoGuardTM and the fourth used rilonacept as a subcutaneous injection. The duration of each study arm ranged from one to three months.The two most recent studies were generally well-designed, except for an unclear risk of detection bias in one of these. However, some inadequacy existed in the other two older studies, where each had an unclear risk of selection bias, a high risk of attrition bias, an unclear risk of reporting bias and a high risk of other potential bias (baseline characteristics such as mutation status and disease severity were not described); one of these studies additionally had an unclear risk of detection bias.We aimed to report on the number of participants experiencing an attack, the timing of attacks, any adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack, but data were not available for all outcomes across all comparisons.Based on one study (15 participants), there was a significant reduction in the number of people experiencing attacks at three months when colchicine was administered at a dose of 0.6 mg three times daily (14% versus 100%), risk ratio 0.21 (95% confidence interval 0.05 to 0.95); however, the GRADE evidence quality was low. Based on two further studies, there was no significant reduction in the number of participants experiencing attacks at two months when colchicine was administered at a dose of 0.5 mg twice daily (22 participants) in people with familial Mediterranean fever, or at three months when rilonacept was used in individuals who were colchicine-resistant or colchicine-intolerant (14 participants). In the ImmunoGuardTM study (24 participants) acute phase response indicators (including erythrocyte sedimentation rate, white blood cell count and C-reactive protein) were not reduced after one month treatment. AUTHORS' CONCLUSIONS: There were limited randomized controlled studies assessing interventions for people with familial Mediterranean fever. Based on the evidence, colchicine appears to reduce the number of people experiencing attacks; however, only a few low-quality randomized controlled studies contributed data for analysis. Further randomized controlled studies examining active interventions, not only colchicine, are necessary before a comprehensive conclusion regarding the efficacy and safety of interventions for reducing inflammation in familial Mediterranean fever can be drawn. PMID- 25791873 TI - Using routinely collected data to stratify prostate cancer patients into phases of care in the United Kingdom: implications for resource allocation and the cancer survivorship programme. AB - BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in British men. The increasing use of PSA screening test has resulted in many more patients being diagnosed with this condition. Advances in its treatment have improved the survival rate among these patients. By 2040, the prevalence of prostate cancer survivors is expected to reach 830 000. Many of them will require medical support for the management of their progressive disease or long-term toxicities from previous treatments. Successful implementation of the cancer survivorship programme among these patients depends on a good understanding of their demand on the health care system. The aim of this study is to segment the population of prostate cancer survivors into different needs groups and to quantify them with respect to their phase of care. METHODS: Incidence, survival, prevalence and mortality data collected and reported by cancer registries across the United Kingdom have been used for the current study to provide indicative estimates as to the number of prostate cancer patients in each phase of the care pathway in a year. RESULTS: The majority of prostate cancer patients are in the post-treatment monitoring phase. Around a fifth of the patients are either receiving treatment or in the recovery and readjustment phase having completed their treatment in the preceding year. Thirteen percent have not received any anticancer treatment, a further 12% (32 000) have developed metastatic disease and 4% are in the final stage of their lives. CONCLUSION: On the basis of our estimates, patients undergoing post-treatment monitoring phase will constitute the biggest group among prostate cancer survivors. The pressure to provide adequate follow-up care to these patients will be a challenge. There is limited data available to definitively quantify the number of prostate cancer patients who follow different pathways of care, and we hope this study has highlighted the importance of collecting and reporting of such data to help future health care planning for these patients. PMID- 25791872 TI - Ancestral Reconstruction of a Pre-LUCA Aminoacyl-tRNA Synthetase Ancestor Supports the Late Addition of Trp to the Genetic Code. AB - The genetic code was likely complete in its current form by the time of the last universal common ancestor (LUCA). Several scenarios have been proposed for explaining the code's pre-LUCA emergence and expansion, and the relative order of the appearance of amino acids used in translation. One co-evolutionary model of genetic code expansion proposes that at least some amino acids were added to the code by the ancient divergence of aminoacyl-tRNA synthetase (aaRS) families. Of all the amino acids used within the genetic code, Trp is most frequently claimed as a relatively recent addition. We observe that, since TrpRS and TyrRS are paralogous protein families retaining significant sequence similarity, the inferred sequence composition of their ancestor can be used to evaluate this co evolutionary model of genetic code expansion. We show that ancestral sequence reconstructions of the pre-LUCA paralog ancestor of TyrRS and TrpRS have several sites containing Tyr, yet a complete absence of sites containing Trp. This is consistent with the paralog ancestor being specific for the utilization of Tyr, with Trp being a subsequent addition to the genetic code facilitated by a process of aaRS divergence and neofunctionalization. Only after this divergence could Trp be specifically encoded and incorporated into proteins, including the TyrRS and TrpRS descendant lineages themselves. This early absence of Trp is observed under both homogeneous and non-homogeneous models of ancestral sequence reconstruction. Simulations support that this observed absence of Trp is unlikely to be due to chance or model bias. These results support that the final stages of genetic code evolution occurred well within the "protein world," and that the presence-absence of Trp within conserved sites of ancient protein domains is a likely measure of their relative antiquity, permitting the relative timing of extremely early events within protein evolution before LUCA. PMID- 25791874 TI - Human papillomavirus DNA in men who have sex with men: type-specific prevalence, risk factors and implications for vaccination strategies. AB - BACKGROUND: Human papillomavirus (HPV) vaccination of girls will have relatively little effect on HPV-related disease in men who have sex with men (MSM). We determined HPV prevalence and risk factors in MSM to inform the potential effectiveness of vaccinating MSM. METHODS: Cross-sectional study of 522 MSM aged 18-40 attending a London sexual health clinic who completed a computer-assisted self-interview. Urine and two swabs (anal and penile/scrotal/perianal) were collected and tested using an in-house Luminex-based HPV genotyping system. RESULTS: Prevalence of DNA of the vaccine-preventable HPV types in ano-genital specimens of men was 87/511 (17.0%), 166/511 (32.5%) and 232/511 (45.4%) for the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18) and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccine types, respectively. A total of 25.1% had one of the quadrivalent types, and 7.4% had 2+ types. Median age at first anal sex was 19 (IQR 17-23) and at first clinic attendance was 24 (IQR 20-27). The increase in the odds of any HPV infection per year of age was 4.7% (95% CI 1.2 8.4). CONCLUSIONS: On the basis of the current infection status, most MSM, even among a high-risk population attending a sexual health clinic, are not currently infected with the vaccine-type HPV. A targeted vaccination strategy for MSM in the UK could have substantial benefits. PMID- 25791875 TI - Economic evaluation for the UK of nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreas cancer. AB - BACKGROUND: The combination of nab-paclitaxel plus gemcitabine (NAB-P+GEM) has shown superior efficacy over GEM monotherapy in metastatic pancreas cancer (MPC). Independent cost-effectiveness/utility analyses of NAB-P+GEM from the payer perspective have not been conducted for the UK. METHODS: A Markov model simulating the health outcomes and total costs was developed to estimate the life years gained (LYG) and quality-adjusted life years gained (QALY) and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) for patients with MPC in a base case and in a probabilistic (PSA) sensitivity analysis. Total cost included the cost of supportive care medications, administration, chemotherapy, disease monitoring, and adverse reactions; and was discounted at 3.5% per year. A full lifetime horizon and third party payer perspective was chosen. RESULTS: The total cost of NAB-P+GEM was L5466 higher than the cost for GEM. Respectively, LYGs were 0.97 vs 0.79 and QALYs were 0.52 vs 0.45, with ICER of L30 367/LYG and ICUR of L78 086/QALY, confirmed by PSA. CONCLUSIONS: The superior survival efficacy of NAB-P+GEM over GEM in the management of MPC is associated with positive cost-effectiveness and cost-utility. PMID- 25791877 TI - Documenting Cancer Information Seeking Behavior and Risk Perception in the Hualapai Indian Community to Inform a Community Health Program. AB - Cancer incidence among American Indians (AIs) is low, yet their 5-year relative survival rate is the second lowest of all U.S. populations. Culturally relevant cancer prevention education is key to achieve health equity. This collaborative project of the Hualapai Tribe and University of Arizona modified the National Cancer Institute's 2003 Health Information National Trends Survey (HINTS) to yield a more culturally relevant cancer information survey to document the health seeking behaviors and perceptions of cancer risks and preventability of AI adults residing in the Hualapai Indian community. A team of health care providers, educators and cancer survivors (six native and three non-natives) completed the adaptation. Four trained native surveyors administered the survey using a random household survey design. The Hualapai HINTS was well accepted (<5% refusal rate) and was completed by 205 adults (20.5% of all adult residents). Respondents reported a preference for and a trust in verbal cancer information and communication with health care professionals (77.1% preference; 57.4% trust) and at workshops (75.2% preference; 45.5% trust). Respondents were aware of some health behaviors associated with a reduced cancer risk, e.g., avoid tobacco use and need for screening. Respondents were less well informed about the role of diet and exercise. These findings were used to inform local cancer prevention education efforts and to develop a series of monthly workshops that engaged local health professionals to reinforce and discuss pathways of the primary role of lifestyle related factors, specifically diet and exercise in reducing cancer risk. PMID- 25791876 TI - The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. AB - Painful small fiber neuropathy is a challenging medical condition with no effective treatment. Non-genetic causes can be identified in one half of the subjects. Gain-of-function variants of sodium channels Nav1.7 and Nav1.8 have recently been associated with painful small fiber neuropathy. More recently, mutations of sodium channel Nav1.9 have been linked to human pain disorders, with two gain-of-function mutations found in patients with painful small fiber neuropathy. Here we report a novel Nav1.9 mutation, a glycine 699 substitution by arginine (G699R) in the domain II S4-S5 linker, identified in a patient with painful small fiber neuropathy. In this study, we assayed the mutant channels by voltage-clamp in superior cervical ganglion neurons, which do not produce endogenous Nav1.8 or Nav1.9 currents, and provide a novel platform where Nav1.9 is expressed at relatively high levels. Voltage-clamp analysis showed that the mutation hyperpolarizes (-10.1 mV) channel activation, depolarizes (+6.3 mV) steady-state fast inactivation, slows deactivation, and enhances ramp responses compared with wild-type Nav1.9 channels. Current-clamp analysis showed that the G699R mutant channels render dorsal root ganglion neurons hyperexcitable, via depolarized resting membrane potential, reduced current threshold and increased evoked firing. These observations show that the domain II S4-S5 linker plays an important role in the gating of Nav1.9 and demonstrates that a mutation in this linker is linked to a common pain disorder. PMID- 25791878 TI - Determination of energy and protein requirement for maintenance and growth and evaluation for the effects of gender upon nutrient requirement in Dorper * Hu Crossbred Lambs. AB - This study aimed to determine energy and protein requirement of Dorper * Hu crossbred lambs and further to evaluate the effect of gender upon nutrient requirement parameters. Forty-two female lambs (18.60 +/- 1.57 kg) and 42 male lambs (18.30 +/- 1.28 kg) were used. In comparative slaughter trial, 30 of animals from each gender group were randomly selected and assigned to ad libitum (AL), low restriction (LR) and high restriction (HR) group, and then were slaughtered when lambs under AL treatment reached target BW of 20, 28, and 35 kg, to determine body energy and nitrogen retained. In digestibility trial, remaining 12 female (18.01 +/- 1.66 kg) and 12 male lambs (18.43 +/- 1.17 kg) were randomly assigned to three feeding treatments in accordance with the design of comparative slaughter trial, to evaluate dietary energetic values at different feed intake levels. The combined data indicated that metabolizable energy (ME) requirement for maintenance (MEm; 400.61 +/- 20.31 vs. 427.24 +/- 18.70 kJ kg(-1) of shrunk BW(0.75); SBW(0.75)), partial efficiency of ME utilization for maintenance (k m; 0.64 +/- 0.02 vs. 0.65 +/- 0.03), partial efficiency of ME utilization for growth (k g ; 0.42 +/- 0.03 vs. 0.44 +/- 0.02), and net protein (NP) requirement for maintenance (NPm; 1.83 +/- 0.17 vs. 1.99 +/- 0.28 g kg(-1) of SBW(0.75)) did not differ (P > 0.05) due to gender; although not statistically different, the mean value of Net energy (NE) requirement for maintenance (NEm) for male lambs (260.62 +/- 13.21 kJ kg(-1) of SBW(0.75)) were 5 % greater than that (274.16 +/- 11.99 kJ kg(-1) of SBW(0.75)) of female lambs. Additionally, rams have greater amounts of NP requirement for growth (NPg, 15.94 to 44.32 g d(-1)) than those of ewes (13.07 to 32.95 g d(-1)) at the similar condition of BW and ADG. In conclusion, we suggested that our results of energy and protein requirement for growth ranged between the NRC recommendation for early and later maturating growing sheep, and the effect of gender upon energy requirement parameters was similar in tendency but was less evidently than those frequently recommended previously. PMID- 25791879 TI - Growth and characterization of organic NLO material: clobetasol propionate. AB - Single crystals of clobetasol propionate (CP) have been grown by slow evaporation solution technique using mixed solvent of methanol-acetone. The grown crystals were subjected to single crystal X-ray diffraction analysis to confirm their lattice parameter and space group. The powder X-ray diffraction pattern of the grown CP has been indexed. Thermal analysis was performed to study the thermal stability of the grown crystals. Photoluminescence spectrum shows broad emission peak observed at 421 nm. Nonlinear optical studies were carried out for the grown crystal and second harmonic generation (SHG) efficiency was found in the crystal. PMID- 25791880 TI - Effect of thermal annealing on the phase evolution of silver tungstate in Ag/WO3 films. AB - Silver/tungsten oxide multi-layer films are deposited over quartz substrates by RF magnetron sputtering technique and the films are annealed at temperatures 200, 400 and 600 degrees C. The effect of thermal annealing on the phase evolution of silver tungstate phase in Ag/WO3 films is studied extensively using techniques like X-ray diffraction, micro-Raman analysis, atomic force microscopy and photoluminescence studies. The XRD pattern of the as-deposited film shows only the peaks of cubic phase of silver. The film annealed at 200 degrees C shows the presence of XRD peaks corresponding to orthorhombic phase of Ag2WO4 and peaks corresponding to cubic phase of silver with reduced intensity. It is found that, as annealing temperature increases, the volume fraction of Ag decreases and that of Ag2WO4 phase increases and becomes highest at a temperature of 400 degrees C. When the temperature increases beyond 400 degrees C, the volume fraction of Ag2WO4 decreases, due to its decomposition into silver and oxygen deficient phase Ag2W4O13. The micro-Raman spectra of the annealed films show the characteristic bands of tungstate phase which is in agreement with XRD analysis. The surface morphology of the films studied by atomic force microscopy reveals that the particle size and r.m.s roughness are highest for the sample annealed at 400 degrees C. In the photoluminescence study, the films with silver tungstate phase show an emission peak in blue region centered around the wavelength 441 nm (excitation wavelength 256 nm). PMID- 25791881 TI - LED light stress induced biomass and fatty acid production in microalgal biosystem, Acutodesmus obliquus. AB - Microbial algal system can serve as a potential source for the production of much high value bioproducts and biofuels. The quality and intensity of light are the key elements to optimize the production of algal biomass and fatty acid contents. This study presents the effect of differential LED flashing light conditions on the growth of microalgae, Acutodesmus obliquus. The induced light stress was optimized for its biomass and fatty acid content. The microalgae are exposed to various frequency of intermittent LED flashing light (blue and red lights) at three different phases in the 18 day cell growth (log, lag and stationary phase). The frequency of light flashing rate was adjusted to 120, 10, 5, 3.75, and 1 times per min. The effect of light stress on growth and fatty acids composition of A. obliquus induced an increase in algae growth and fatty acid production. Different optimal timing for light stress was subjected to elucidate the effect of light stress on algae growth and fatty acid production. The results showed an increase in the algae growth (1.2mg/L of chl a content) under light stress condition at FT10 (flashing time, 10 times per min) from the initial day (log phase) compared with the control experiment (0.4 mg/L of chl a content). However, the total fatty acids (71 mg/g) and volumetric FAME production (9.4 ml/l) level was found to be significant under FT5 (flashing time, 5 times per min), adopting flashing light from day 10 (stationary phase). TEM studies also revealed the deposition of lipid to be largest in the 18 day old cells under flashing light (FT5) condition, representing maximum accumulation of lipids bodies (up to 770 nm diameter in particle size) occupying approximately 42% of the total area of the cell. PMID- 25791882 TI - A comparative study between three stability indicating spectrophotometric methods for the determination of diatrizoate sodium in presence of its cytotoxic degradation product based on two-wavelength selection. AB - Three sensitive, selective, and precise stability indicating spectrophotometric methods for the determination of the X-ray contrast agent, diatrizoate sodium (DTA) in the presence of its acidic degradation product (highly cytotoxic 3,5 diamino metabolite) and in pharmaceutical formulation, were developed and validated. The first method is ratio difference, the second one is the bivariate method, and the third one is the dual wavelength method. The calibration curves for the three proposed methods are linear over a concentration range of 2-24 MUg/mL. The selectivity of the proposed methods was tested using laboratory prepared mixtures. The proposed methods have been successfully applied to the analysis of DTA in pharmaceutical dosage forms without interference from other dosage form additives. The results were statistically compared with the official US pharmacopeial method. No significant difference for either accuracy or precision was observed. PMID- 25791883 TI - Spectroscopic investigation (FT-IR, FT-Raman), HOMO-LUMO, NBO analysis and molecular docking study of 4-chlorophenyl quinoline-2-carboxylate. AB - FT-IR and FT-Raman spectra of 4-chlorophenyl quinoline-2-carboxylate were recorded and analyzed. The vibrational wavenumbers were computed using DFT quantum chemical calculations. The data obtained from wavenumber calculations are used to assign vibrational bands obtained experimentally. Potential energy distribution was done using GAR2PED program. The geometrical parameters obtained theoretically are in agreement with the XRD data. NBO analysis, HOMO-LUMO, first hyperpolarizability and molecular electrostatic potential results are also reported. The calculated hyperpolarizability of the title compound is 77.53 times that of the standard NLO material urea and the title compound and its derivatives are attractive object for future studies of nonlinear optical properties. Molecular docking results suggest that the compound might exhibit inhibitory activity against GPb. PMID- 25791884 TI - Experimental and theoretical spectroscopic studies, HOMO-LUMO, NBO analyses and thione-thiol tautomerism of a new hybrid of 1,3,4-oxadiazole-thione with quinazolin-4-one. AB - The hybrid 3-(4-chlorophenyl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2 yl)methylthio]quinazolin-4(3H)-one has been synthesized and characterized using elemental analysis, FTIR and NMR spectroscopy. The thione-thiol tautomeric equilibria has been studied using both DFT/B3LYP and HF methods at different basis sets. The results of calculations showed predominance of the thione form. The molecular structure and vibrational spectra of the stable tautomer are predicted using the same level of theory. The complete assignments of the vibrational modes were performed on the basis of potential energy distribution (PED). The 6-311++G(d,p) gave the best results compared to the experimental data. The chemical shift values of the two tautomers are calculated using GIAO method. The NH proton of the thione tautomer have chemical shift value closer to the experimental data compared to the SH proton of the thiol one. The electronic transitions are predicted using the TD-DFT calculations at B3LYP/6-311++G(d,p) level of theory. The calculated polarizability and first hyperpolarizability showed that the studied compound has better NLO properties than urea. The molecular electrostatic potential (MEP) analysis reveals the sites for electrophilic and nucleophilic attack in the molecule. NBO analysis is carried out to investigate the stabilization energy of various intramolecular charge transfer interactions within the studied molecule. PMID- 25791885 TI - A novel and greener approach for shape controlled synthesis of gold and gold silver core shell nanostructure and their application in optical coatings. AB - Green and facile synthetic methods have gained marvellous fame for the production of polyhedral, anisotropic and spherical gold, and gold-silver bimetallic nanostructures. The useful pivotal characteristics of a green procedure are the usage of environment benign solvent medium, reducing and stabilising agents, and shorter reaction time. We describe here a novel, and greener method for the production of gold and gold-silver core shell nanostructures using aqueous fish scales extract of the Labeo rohita. The effect of various reaction parameters, such as temperature and concentration for the synthesis of the nanostructures were studied. Results indicated that triangular and decahedron gold nanostructures were formed at a lower temperature (40 degrees C) and concentration (10%). While, icosahedral and spherical gold nanostructures were produced at a comparatively higher temperature (100 degrees C) and concentration (40%). The study also revealed that the core-shell bimetallic nanostructures with different morphologies (spherical and oval-shape) were formed at different ratios of chloroaurate and silver nitrate solution. Thus, the present study indicated a simple shape controlled synthesis of gold and gold silver core-shell nanostructures. The synthesised gold nanotriangles were coated over the glass substrate and found to be highly efficient in absorbing infra-red radiations for potential architectural applications. Therefore, the study demonstrated the facile usage of gold nanotriangles for optical coatings. The present strategy depicted the dual functional ability of the fish scale extract as reducing and stabilising agents. This strategy also eliminates the usage of hazardous chemicals, toxic solvents and harsh reducing and stabilizing agents. PMID- 25791886 TI - Different approaches in manipulating ratio spectra applied for the analysis of Cefprozil in presence of its alkaline-induced degradation product: a comparative study. AB - Four simple, accurate and precise stability-indicating spectrophotometric methods manipulating ratio spectra were developed and validated for simultaneous determination of Cefprozil (CZ) and its alkaline-induced degradation product (DCZ) without prior separation namely; ratio difference, mean centering, derivative ratio using Savitsky-Golay filter and continuous wavelet transform. The accuracy, precision and linearity ranges of the proposed methods were determined. The methods were validated and the specificity was assessed by analyzing synthetic mixtures containing the drug and its degradate. The four methods were applied for the determination of the cited drug in tablets and the obtained results were statistically compared with those of a reported method. The comparison showed that there are no significant differences between the proposed methods and the reported method regarding both accuracy and precision. PMID- 25791887 TI - Crystal structure, complexation, spectroscopic characterization and antimicrobial evaluation of 3,4-dihydroxybenzylidene isonicotinyl-hydrazone. AB - A single crystal of 3,4-dihydroxybenzylidene isonicotinylhydrazone, HBINH, has been grown and solved by X-ray crystallography. The VO(2+), Zr(4+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Pd(2+) complexes of HBINH have been prepared and spectroscopically characterized. The data confirmed the formulae [Co(HBINH)(H2O)Cl]Cl.H2O, [Pd(HBINH)Cl2], [Zn(HBINH)2Cl2], [Cd(HBINH)(H2O)2Cl2].11/2H2O, [(VO)2(HBINH-3H)(OH)(H2O)], [Ni2(HBINH)(H2O)6Cl2]Cl2, [Cu2(HBINH-3H)(H2O)2(OAc)].3H2O, [Zr2(HBINH-3H)Cl4]Cl, [Hg2(HBINH)Cl4] and the dimer {[Cu(HBINH)Cl]Cl}2. Most of the complexes have intense colors and high melting points and some are electrolytes in DMSO solution. The ligand behaves as a neutral bidentate in the Co(II), Cu(II), Pd(II), Zn(II) and Cd(II) complexes; dibasic tetradentate in [Ni2(HBINH)(H2O)6Cl2]Cl2 and tribasic tetradentate in [Cu2(HBINH-3H)(OAc)].5H2O, [(VO)2(HBINH-3H)(OH)(H2O)] and [Zr2(HBINH-3H)Cl4]Cl by the loss of 3H(+) due to the deprotonation of the two hydroxyl groups and the enolization of the amide (OCNH) group. A tetrahedral geometry was proposed for the Co(II), Cu(II), Zn(II) and Hg(II) complexes; square-planar for the Pd(II) complex; square-pyramid for the VO(2+) complex and octahedral for the Ni(II) and Cd(II) complexes. The complexes [Cd(HBINH)(H2O)2Cl2].11/2H2O, [(VO)2(HBINH-3H)(OH)(H2O)] and [Cu2(HBINH 3H)-(H2O)2(OAc)].3H2O have activities against Bacillus sp. M3010, Candida albicans, Escherichia coli, Staphylococcus aureus and Slamonella sp. PA393. PMID- 25791888 TI - Disentangling the relationship between cognitive estimation abilities and executive functions: a study on patients with Parkinson's disease. AB - The cognitive estimation test (CET) measures cognitive estimation abilities: it assesses the ability to apply reasoning strategies to answer questions that usually cannot lead to a clear and exact reply. Since it requires the activation of an intricate ensemble of cognitive functions, there is an ongoing debate in the literature regarding whether the CET represents a measurement of global cognitive abilities or a pure measure of executive functions. In the present study, CET together with a neuropsychological assessment focused on executive functions was administered in thirty patients with Parkinson's disease without signs of dementia. The CET correlated with measures of verbal working memory and semantic knowledge, but not with other dimensions of executive domains, such as verbal phonemic fluency, ability to manage real-world interferences, or visuospatial reasoning. According to our results, cognitive estimation abilities appeared to trigger a defined cognitive path that includes executive functions, namely, working memory and semantic knowledge. PMID- 25791889 TI - A study of migraine characteristics in joint hypermobility syndrome a.k.a. Ehlers Danlos syndrome, hypermobility type. AB - Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping heritable connective tissue disorders strongly associated with musculoskeletal pain, fatigue and headache. Migraine with or without aura is considered the most common form of headache in JHS/EDS HT. In this population of chronically ill patients, we investigated whether migraine characteristics were different from those of a control population of migraine patients. The study was carried out on 33 selected JHS/EDS-HT patients, diagnosed according to current criteria. Sixty-six migraine subjects matching age and gender were consecutively selected as controls (MO group) among patients attending our Headache Clinic. JHS/EDS-HT and MO were screened for a series of headache characteristics, such as frequency, intensity, age of onset, level of disability, use of rescue and prophylactic medications. Differences between the two groups were tested by using independent group comparisons. Results showed that in JHS/EDS-HT: (1) migraine has an earlier onset (12.6 vs 17 years of age; p = 0.005); (2) the rate of migraine days/month is higher (15 vs 9.3 days/month; p = 0.01); (3) accompanying symptoms are usually more frequent; (4) HIT-6 and MIDAS scores are higher (p = 0.04 and p = 0.03); (5) efficacy of rescue medication is almost identical, although, total drug consumption is significantly lower (p < 0.04). Joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type patients have a more severe headache syndrome with respect to the MO group, therefore demonstrating that migraine has a very high impact on quality of life in this disease. PMID- 25791890 TI - The history of vaccination against cytomegalovirus. AB - Cytomegalovirus vaccine development started in the 1970s with attenuated strains. In the 1980s, one of the strains was shown to be safe and effective in renal transplant patients. Then, attention switched to glycoprotein gB, which was shown to give moderate but transient protection against acquisition of the virus by women. The identification of the pp65 tegument protein as the principal target of cellular immune responses resulted in new approaches, particularly DNA, plasmids to protect hematogenous stem cell recipients. The subsequent discovery of the pentameric protein complex that generates most neutralizing antibodies led to efforts to incorporate that complex into vaccines. At this point, there are many candidate CMV vaccines, including live recombinants, replication-defective virus, DNA plasmids, soluble pentameric proteins, peptides, virus-like particles and vectored envelope proteins. PMID- 25791891 TI - Stanley Plotkin: the bright spark of cytomegalovirus vaccines. PMID- 25791892 TI - Detection of sex chromosome aneuploidies using quantitative fluorescent PCR in the Hungarian population. AB - BACKGROUND: Aneuploidies are the most frequent chromosomal abnormalities at birth. Autosomal aneuploidies cause serious malformations like trisomy 21, trisomy 18 and trisomy 13. However sex chromosome aneuploidies are causing less severe syndromes. For the detection of these aneuploidies, the "gold standard" method is the cytogenetic analysis of fetal cells, karyograms show all numerical and structural abnormalities, but it takes 2-4 weeks to get the reports. Molecular biological methods were developed to overcome the long culture time, thus, FISH and quantitative fluorescent PCR were introduced. In this work we show our experience with a commercial kit for the detection of sex chromosome aneuploidies. METHODS: We analyzed 20.173 amniotic fluid samples for the period of 2006-2013 in our department. A conventional cytogenetic analysis was performed on the samples. We checked the reliability of quantitative fluorescent PCR and DNA fragment analysis on those samples where sex chromosomal aneuploidy was diagnosed. RESULTS: From the 20.173 amniotic fluid samples we found 50 samples with sex chromosome aneuploidy. There were 19 samples showing 46, XO, 17 samples with 46, XXY, 9 samples with 47, XXX and 5 samples with 47, XYY karyotypes. The applied quantitative fluorescent PCR and DNA fragment analyses method are suitable to detect all abnormal sex chromosome aneuploidies. CONCLUSIONS: Quantitative fluorescent PCR is a fast and reliable method for detection of sex chromosome aneuploidies. PMID- 25791893 TI - Correlation between efficacy of levetiracetam and serum levels among children with refractory epilepsy. AB - BACKGROUND: Levetiracetam is used as adjunctive therapy in various types of seizures. Studies evaluating the effect of levetiracetam on children with refractory epilepsy are scarce. The aim of this study was to evaluate the correlation between serum concentration of levetiracetam and either efficacy or tolerability in children with refractory epilepsy, and to determine the value of levetiracetam blood level monitoring. METHODS: Medical records of 50 children with refractory epilepsy treated with levetiracetam and regularly followed at Assaf Harofeh Medical Center were retrospectively reviewed. Trough serum levetiracetam concentration was determined using high-performance liquid chromatography and correlated with the administered dose and clinical report. RESULTS: No correlation between levetiracetam serum levels and clinical efficacy, tolerability or administered dosage was found. The average dose of levetiracetam was 43.7 +/- 20.0 (range 14-100) mg/kg/day and the average serum concentration was 16.0 +/- 9.5 (range 2.5-38.5) MUg/mL. Forty-five patients (95%) had more than a 50% reduction of seizure frequency, with 22 (44%) patients becoming seizure free for at least 6 months. Adverse events related to levetiracetam were reported in 15 (30%) patients. No correlation between serum concentrations and adverse events was found. These results were not affected by gender, age, type of seizure, and other drugs. CONCLUSIONS: Determination of serum concentration is not needed in all children treated with levetiracetam. Serum concentrations may be valuable either in patients with refractory epilepsy for compliance evaluation or in patients with satisfactory control of seizures for determination of their therapeutic baseline. PMID- 25791894 TI - Enzyme-linked Immunoassay Index for Anti-NC16a IgG and IgE Auto-antibodies Correlates with Severity and Activity of Bullous Pemphigoid. AB - Bullous pemphigoid (BP) is characterized by IgG and IgE autoantibodies to the NC16a domain of BP180. This study evaluated the correlation between body surface area (BSA), total serum IgE and enzyme-linked immunoassay (ELISA) for IgG and IgE anti-NC16a in 77 patients with BP in the active stage, and the degree of conversion to negative of the studied parameters in clinical remission. Statistically positive correlations were observed between BSA and examined parameters (correlation index 0.2548, 0.2491, 0.311, respectively). Originally, patients with BP with positive ELISAs for both IgG and IgE autoantibodies presented twice as extensive skin lesions as those with positive IgG and negative IgE ELISAs. Conversion of ELISAs for IgG and IgE to negative in clinical remission occurred in 9.3% and 81% of patients with BP, respectively. This confirmed that ELISA for IgE anti-NC16a is a helpful parameter in the modification of current treatment and the assessment of risk of relapse in BP. PMID- 25791895 TI - A semi-mechanistic integrated pharmacokinetic/pharmacodynamic model of the testosterone effects of the gonadotropin-releasing hormone agonist leuprolide in prostate cancer patients. AB - BACKGROUND AND OBJECTIVE: Leuprolide is a gonadotropin-releasing hormone (GnRH) agonist, which inhibits gonadotropin secretion by down-regulating pituitary GnRH receptor when administered continuously at therapeutic doses. The objectives of this analysis were to develop a population model that can describe the pharmacokinetics of the 6-month depot formulation of leuprolide acetate in patients with prostate cancer and to characterize the relationship of leuprolide plasma concentrations and serum testosterone concentrations. METHODS: The pharmacokinetic and pharmacodynamic analyses were performed using a non-linear mixed-effect modeling approach. Observations were pooled from studies on healthy male volunteers and prostate cancer patients, who were administered a single 1 mg intravenous dose of immediate-release leuprolide acetate and two intramuscular doses of 45 mg of the depot formulation, respectively. The covariates that were screened for the pharmacokinetic model included body weight, creatinine clearance, liver function markers (total bilirubin, blood urea nitrogen, AST, alanine aminotransferase), age, and body mass index. RESULTS: A two-compartment model with parallel first- and zero-order absorption processes and a delayed first-order process well-characterized the multi-phasic absorption profile of leuprolide acetate depot formulation. Typical population values of the absorption rate constant of the immediate and delayed processes were estimated to be 0.357 and 0.017 day(-1), respectively, with a mean transit time of 9.5 days. No covariates were significant in this analysis. A semi-mechanistic model, which accounts for down-regulation of the GnRH receptor via an inhibitory maximum effect (E max) model and the stimulatory effect of activated receptors on testosterone levels, adequately described serum testosterone profiles following dosing. The equilibrium dissociation constant of leuprolide and the typical leuprolide plasma concentration required to achieve a castration testosterone level of <=0.5 ng/mL were 0.3 and 0.03 ng/mL, respectively. CONCLUSION: Population pharmacokinetics and pharmacodynamics of the leuprolide depot formulation were characterized using an integrated semi-mechanistic model. The developed model adequately describes the leuprolide-testosterone relationship and can potentially be used to facilitate design of clinical studies for new formulations, to aid in the selection of candidate formulations, and for the optimization of doses and dosing schemes. PMID- 25791896 TI - Erratum to: Kinetically Guided Neoadjuvant Chemoradiotherapy Based on 5 Fluorouracil in Patients with Locally Advanced Rectal Cancer. PMID- 25791897 TI - Erratum to: Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment. PMID- 25791898 TI - The stability and surface termination of hexagonal LuFeO3. AB - The surface termination and the nominal valence states for hexagonal LuFeO3 thin films grown on Al2O3(0 0 0 1) substrates were characterized by angle resolved x ray photoemission spectroscopy. The Lu 4f, Fe 2p and O 1s core level spectra indicate that both the surface termination and the nominal valence depend on surface preparation, but the stable surface terminates in a Fe-O layer. This is consistent with the results of density functional calculations which predict that the Fe-O termination of LuFeO3(0 0 0 1) surface is energetically favorable and stable over a broad range of temperatures and oxygen partial pressures when it is reconstructed to eliminate surface polarity. PMID- 25791899 TI - Radiocesium leaching from contaminated litter in forest streams. AB - In Japanese forests suffering from the Fukushima Daiichi Nuclear Power Plant accident, litter fall provides a large amount of radiocesium from forests to streams. Submerged litter is processed to become a vital food resource for various stream organisms through initial leaching and subsequent decomposition. Although leaching from litter can detach radiocesium similarly to potassium, radiocesium leaching and its migration are poorly understood. We examined both radiocesium and potassium leaching to the water column and radiocesium allocation to minerals (glass beads, silica sand, and vermiculite) in the laboratory using soaked litter with and without minerals on a water column. The mineral types did not affect radiocesium leaching from litter, but soaking in water for 1, 7, and 30 days decreased the radiocesium concentration in litter by *0.71, *0.66, and *0.56, respectively. Meanwhile, the 1-, 7-, and 30-day experiments decreased potassium concentration in litter by *0.17, *0.11, and *0.09, respectively. Leached radiocesium remained in a dissolved form when there was no mineral phases present in the water, whereas there was sorption onto the minerals when they were present. In particular, vermiculite adsorbed radiocesium by two to three orders of magnitude more effectively than the other minerals. Because radiocesium forms (such as that dissolved or adsorbed to organic matter or minerals) can further mobilize to ecosystems, our findings will increase our understanding regarding the dynamics of radiocesium in stream ecosystems. PMID- 25791900 TI - Impact of former uranium mining activities on the floodplains of the Mulde River, Saxony, Germany. AB - The Mulde River drains the former uranium mining areas in Saxony (Germany), which has led to a large-scale contamination of the river and the adjacent floodplain soils with radionuclides of the uranium decay series. The objective of the investigation is to quantify the long-term effect of former uranium mining activities on a river system. All of the investigated environmental compartments (water, sediment, soil) still reveal an impact from the former uranium mining and milling activities. The contamination of water has decreased considerably during the last 20 years due to the operation of water treatment facilities. The uranium content of the sediments decreased as well (on average by a factor of 5.6), most likely caused by displacement of contaminated material during flood events. Currently, the impact of the mining activities is most obvious in soils. For some of the plots activity concentrations of >200 Bq/kg of soil were detected for uranium-238. Alluvial soils used as grassland were found to be contaminated to a higher degree than those used as cropland. PMID- 25791901 TI - Nature of radioactive contamination of components of ecosystems of streamflows from tunnels of Degelen massif. AB - The paper provides data on environmental contamination due to radionuclides' migration with water. As a result of investigations there was obtained data on character of contamination of soil cover, surface water and underflow from tunnels of Degelen massif. Character of radionuclides' spatial distribution in environment was also shown. Mobility ranges of radionuclides' vertical and horizontal movements have been established in soils both across and along the stream flow. There was also shown a possibility to forecast radionuclides' concentration in soil by specific activity of these radionuclides in water. Different concentrations of radionuclides in associated components of the ecosystem (surface waters - ground waters - soils) have shown disequilibrium of their condition in this system. Generalization of investigation results for tunnel water streams' with water inflows, chosen as investigation objects in this work, allows to forecast radionuclides' behavior in meadow soils and other ecosystems of water streams from tunnels of Degelen test site. Based on analysis of curves, describing radionuclides' behavior in horizontal direction, we can forecast, that at this stage (137)Cs and (239+240)Pu would not be distributed more than 1.5 km from the access to the daylight surface, (90)Sr - not more than 2 km. PMID- 25791902 TI - Sidetracked by trolleys: Why sacrificial moral dilemmas tell us little (or nothing) about utilitarian judgment. AB - Research into moral decision-making has been dominated by sacrificial dilemmas where, in order to save several lives, it is necessary to sacrifice the life of another person. It is widely assumed that these dilemmas draw a sharp contrast between utilitarian and deontological approaches to morality, and thereby enable us to study the psychological and neural basis of utilitarian judgment. However, it has been previously shown that some sacrificial dilemmas fail to present a genuine contrast between utilitarian and deontological options. Here, I raise deeper problems for this research paradigm. Even when sacrificial dilemmas present a contrast between utilitarian and deontological options at a philosophical level, it is misleading to interpret the responses of ordinary folk in these terms. What is currently classified as "utilitarian judgment" does not in fact share essential features of a genuine utilitarian outlook, and is better explained in terms of commonsensical moral notions. When subjects deliberate about such dilemmas, they are not deciding between opposing utilitarian and deontological solutions, but engaging in a richer process of weighing opposing moral reasons. Sacrificial dilemmas therefore tell us little about utilitarian decision-making. An alternative approach to studying proto-utilitarian tendencies in everyday moral thinking is proposed. PMID- 25791903 TI - Associations between vitamin D levels and depressive symptoms in healthy young adult women. AB - There have been few studies of whether vitamin D insufficiency is linked with depression in healthy young women despite women's high rates of both problems. Female undergraduates (n=185) living in the Pacific Northwest during fall, winter, and spring academic terms completed the Center for Epidemiologic Studies Depression (CES-D) scale weekly for 4 weeks (W1-W5). We measured serum levels of vitamin D3 and C (ascorbate; as a control variable) in blood samples collected at W1 and W5. Vitamin D insufficiency (<30ng/mL) was common at W1 (42%) and W5 (46%), and rates of clinically significant depressive symptoms (CES-D>=16) were 34-42% at W1-W5. Lower W1 vitamin D3 predicted clinically significant depressive symptoms across W1-W5 (beta=-0.20, p<0.05), controlling for season, BMI, race/ethnicity, diet, exercise, and time outside. There was some evidence that lower levels of depressive symptoms in Fall participants (vs. Winter and Spring) were explained by their higher levels of vitamin D3. W1 depressive symptoms did not predict change in vitamin D3 levels from W1 to W5. Findings are consistent with a temporal association between low levels of vitamin D and clinically meaningful depressive symptoms. The preventive value of supplementation should be tested further. PMID- 25791904 TI - Elevated CO2 shifts the functional structure and metabolic potentials of soil microbial communities in a C4 agroecosystem. AB - Atmospheric CO2 concentration is continuously increasing, and previous studies have shown that elevated CO2 (eCO2) significantly impacts C3 plants and their soil microbial communities. However, little is known about effects of eCO2 on the compositional and functional structure, and metabolic potential of soil microbial communities under C4 plants. Here we showed that a C4 maize agroecosystem exposed to eCO2 for eight years shifted the functional and phylogenetic structure of soil microbial communities at both soil depths (0-5 cm and 5-15 cm) using EcoPlate and functional gene array (GeoChip 3.0) analyses. The abundances of key genes involved in carbon (C), nitrogen (N) and phosphorus (P) cycling were significantly stimulated under eCO2 at both soil depths, although some differences in carbon utilization patterns were observed between the two soil depths. Consistently, CO2 was found to be the dominant factor explaining 11.9% of the structural variation of functional genes, while depth and the interaction of depth and CO2 explained 5.2% and 3.8%, respectively. This study implies that eCO2 has profound effects on the functional structure and metabolic potential/activity of soil microbial communities associated with C4 plants, possibly leading to changes in ecosystem functioning and feedbacks to global change in C4 agroecosystems. PMID- 25791906 TI - No gut syndrome: near total enterectomy. AB - In adult patients, removal of the entire jejunum and ileum (a near total enterectomy (NTE)) is considered a non-survivable event as patients undergoing this procedure might also suffer from an underlying illness that will lead to bowel necrosis such as septic or cardiac shock and respiratory failure. Parenteral nutrition (PN) dependency with its associated complications and quality of life issues further complicates management decisions in this group of patients. In the following report, we discuss our institutional experience with NTE and present a comprehensive review of the literature with patients undergoing NTE with the establishment of bowel continuity and successful outcomes even in cases dating as far back as the 1950s, over a decade prior to the implementation of PN. Review of the literature revealed 26 cases of NTE. Most of these patients are young (46.7 years old), and 57 % are women. These patients were reported to be alive at 21 months of follow-up. In this report, we present an individual 51 months following NTE. We also document the oldest patient receiving an NTE (76 years old). Both of these patients are alive on home PN. In cases where there is hemodynamic stability and patients request to continue with further care, the possibility of a NTE with bowel continuity and life-long PN might be entertained. PMID- 25791905 TI - Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window". AB - The cAMP signaling cascade is one of the most frequently targeted pathways for the development of pharmaceutics. A plethora of recent genetic and pharmacological studies suggest that exchange proteins directly activated by cAMP (EPACs) are implicated in multiple pathologies. Selective EPAC inhibitors have been recently developed. One specific inhibitor, ESI-09, has been shown to block EPAC activity and functions, as well as to recapitulate genetic phenotypes of EPAC knockout mice when applied in vivo. However, a recent study raised concern that ESI-09 might act as a non-specific protein denaturant. Herein, we present a detailed biochemical and pharmacological characterization, as well as a structure activity relationship (SAR) analysis of ESI-09. Our studies show that ESI-09 dose dependently inhibits activity of both EPAC1 and EPAC2 with apparent IC50 values well below the concentrations shown to induce "protein denaturation". Moreover, the ESI-09's action towards EPAC proteins is highly sensitive to minor modifications of the 3-chlorophenyl moiety. Taken together, these results demonstrate that ESI-09 indeed acts as an EPAC specific antagonist and does not significantly destabilize/denature proteins at pharmacological effective concentrations. This conclusion is further supported by NMR data showing that ESI 09 induces residue-dependent chemical shift changes at low concentrations, while preserving well dispersed peaks. PMID- 25791907 TI - Conduit Vascular Evaluation is Associated with Reduction in Anastomotic Leak After Esophagectomy. AB - BACKGROUND: Anastomotic leak following esophagectomy is associated with significant morbidity and mortality. A major factor determining anastomotic success is an adequate blood supply to the conduit. The aim of this study was to determine the impact of intraoperative evaluation of the conduit's vascular supply on anastomotic failure after esophagectomy. METHODS: We retrospectively analyzed data from 90 consecutive patients undergoing esophagectomy with gastric conduit reconstruction. A change in surgical practice occurred after 60 cases were completed, when we introduced the use of intraoperative indocyanine green fluorescence angiography and Doppler examination to evaluate blood supply and assist in construction of the conduit. The leak rates before and after implementation of conduit vascular evaluation were compared. RESULTS: After the introduction of intraoperative vascular evaluation of the gastric conduit, we noted a dramatic decrease in the rate of anastomotic leak from 20 % in the first 60 patients to 0 % in the succeeding 30 patients. CONCLUSIONS: Intraoperative vascular evaluation with indocyanine green fluorescence imaging and Doppler examination of the gastric conduit used to assist reconstruction after esophagectomy allows for enhanced construction of the conduit that maximizes blood supply to the anastomosis. This change in practice was associated with a significant reduction in anastomotic leak rate. PMID- 25791908 TI - Thrombin generation induced by tissue factor plus ADP in human platelet rich plasma: A potential new measurement to assess the effect of the concomitant use of an oral factor Xa inhibitor edoxaban and P2Y12 receptor antagonists. AB - INTRODUCTION: Patients with atrial fibrillation undergoing percutaneous coronary intervention may require combination therapy with anticoagulants and antiplatelet agents. The objectives of this study were to establish an assay which can evaluate the effects of both anticoagulants and P2Y12 receptor antagonists and determine the effects of edoxaban, a direct factor Xa inhibitor, and P2Y12 receptor antagonists (clopidogrel and ticagrelor) alone and when combined. MATERIAL AND METHODS: Human platelet-rich plasma (PRP) from healthy subjects was stimulated with adenosine diphosphate (ADP) plus tissue factor. Thrombin generation was measured by means of calibrated automated thrombography. RESULTS: Combination of 10MUM ADP and low concentration (0.25 pM) tissue factor induced reproducible thrombin generation in human PRP. Edoxaban (40 and 80ng/mL), active metabolite of clopidogrel (AM-clopidogrel, 10 and 20MUg/mL), and ticagrelor (3MUg/mL) alone inhibited ADP plus tissue factor-induced thrombin generation. Edoxaban suppressed all 5 parameters (lag time, peak, time to peak, endogenous thrombin potential, and maximum rate), whereas AM-clopidogrel and ticagrelor inhibited 4 and 3 parameters, respectively. Concomitant treatment with edoxaban and AM-clopidogrel or ticagrelor produced an additive inhibition of thrombin generation compared to the single treatments. CONCLUSIONS: The thrombin generation assay induced by ADP plus tissue factor can detect the activities of both edoxaban and P2Y12 receptor antagonists. Combination of edoxaban and a P2Y12 receptor antagonist shows additive inhibition. These results suggest that ADP plus tissue factor-induced thrombin generation may be a useful measurement to assess the combination effects of anticoagulants and P2Y12 receptor antagonists in a single assay. PMID- 25791909 TI - Nanoscale imaging of the growth and division of bacterial cells on planar substrates with the atomic force microscope. AB - With the use of the atomic force microscope (AFM), the Nanomicrobiology field has advanced drastically. Due to the complexity of imaging living bacterial processes in their natural growing environments, improvements have come to a standstill. Here we show the in situ nanoscale imaging of the growth and division of single bacterial cells on planar substrates with the atomic force microscope. To achieve this, we minimized the lateral shear forces responsible for the detachment of weakly adsorbed bacteria on planar substrates with the use of the so called dynamic jumping mode with very soft cantilever probes. With this approach, gentle imaging conditions can be maintained for long periods of time, enabling the continuous imaging of the bacterial cell growth and division, even on planar substrates. Present results offer the possibility to observe living processes of untrapped bacteria weakly attached to planar substrates. PMID- 25791910 TI - Early decline in six-minute walk distance from the time of diagnosis predicts clinical worsening in pulmonary arterial hypertension. AB - BACKGROUND: The six-minute walk distance (6MWD) is commonly used to assess pulmonary arterial hypertension (PAH). However, the role of 6MWD in predicting outcomes in PAH is controversial. Clinical worsening is being increasingly considered as a clinically meaningful end point in PAH. OBJECTIVES: We aimed to investigate whether early longitudinal changes in 6MWD (Delta6MWD) in meters and percent predicted (%pred) from the time of diagnosis predict clinical worsening of PAH. METHODS: One hundred patients with group I PAH were retrospectively assessed. 6MWD was calculated using American (%pred US) or Canadian (%pred CAN) reference equations. Delta6MWD at 6 months were recorded. Clinical worsening was defined as either: development of right heart failure, hospital admission for PAH, referral for lung transplantation or initiation of prostanoids after oral therapy failed. Optimal 6-month differences in 6MWD to detect worsening were defined with receiver operating characteristics (ROC) analysis. RESULTS: Progressors, i.e. patients with clinical worsening, and nonprogressors showed significant differences in Delta6MWD. The most clinically significant declines in 6MWD at 6 months were >=35 m, >=8%pred US and >=6%pred CAN. ROC and Cox proportional hazard analyses showed equivalent results for 6MWD %pred and meters. Six-month declines in 6MWD predicted worsening with a high specificity (94%) but a low sensitivity (33%). CONCLUSIONS: Early declines in 6MWD (within the first 6 months) predict future clinical worsening of PAH with high specificity. Delta6MWD may still be part of a comprehensive assessment of a patient's clinical status. However, given the poor sensitivity, a decline in 6MWD should be used with other clinical tools to make an appropriate assessment of the progression of PAH. PMID- 25791912 TI - Retraction of "Room-temperature Cu(II)-catalyzed chemo- and regioselective ortho nitration of arenes via C-H functionalization". PMID- 25791911 TI - Molecular phylogenetics of sculpins of the subfamily Oligocottinae (Cottidae). AB - The sculpin subfamily Oligocottinae includes 18-20 species of nearshore benthic fishes with a diverse array of reproductive strategies. As a first step toward understanding the evolution of that diversity, we conducted a phylogenetic study based on DNA sequences from eight genomic regions from 31 sculpin species aimed at testing monophyly and relationships of the Oligocottinae. Representatives from the perciform families Agonidae, Cottidae, Hemitripteridae, Hexagrammidae, Psychrolutidae, and Rhamphocottidae served as outgroups. The sequence data were analyzed in maximum likelihood and Bayesian phylogenetic inference frameworks. Results of these analyses show that a systematic revision of the group is warranted. The genus Clinocottus is a polyphyletic assemblage of three distinct lineages, which should be indicated by resurrection of the subgenera Blennicottus, Clinocottus, and Oxycottus; Leiocottus hirundo is more closely related to Clinocottus analis than C. analis is related to any other member of Clinocottus; the composition of the tribe Oligocottini should be revised to include only the genera Oligocottus, Clinocottus, and Orthonopias; and the genus Sigmistes should be removed from the subfamily Oligocottinae. PMID- 25791913 TI - Schwannoma of the Sinonasal Tract and the Pterygopalatine Fossa with or without Intracranial Extension. AB - AIMS: Compared with those in other head and neck regions, schwannomas in the nasal cavity or paranasal sinuses are rare. The aim of this study was to present the experience of the authors in 11 schwannoma cases of the sinonasal tract and pterygopalatine fossa over a decade. METHODS: A retrospective study from 2003 to 2014. RESULTS: Three female and 8 male patients from 22 to 61 years of age (mean age 42 years) were admitted. The most common complaints were unilateral nasal congestion. A total of 10 of the patients received surgery, including 6 functional endoscopic sinus surgeries (FESS). The postoperative course was generally uneventful. Among the patients, 10 remained regionally asymptomatic, and there has been no clinical or radiological evidence of recurrence or residual tumor. CONCLUSION: Surgical treatment is effective for schwannomas of the sinonasal tract and the pterygopalatine fossa with a low recurrence rate. Conducting CT and MRI (particularly fluid-attenuated inversion recovery) before surgery is mandatory. FESS could become the primary treatment of choice. PMID- 25791914 TI - Relation of heart rate recovery after exercise to insulin resistance and chronic inflammation in otherwise healthy adolescents and adults: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. AB - OBJECTIVE: Insulin resistance (IR) and chronic inflammation are inversely related to heart rate recovery (HRR), a marker of cardiac autonomic function. Little is known, however, about the joint effects of IR and inflammation on HRR. METHODS: The study sample consisted of 2649 healthy individuals aged 12-49 years with measures of submaximal cardiopulmonary fitness testing from the National Health and Nutrition Examination Survey 1999-2004. HRR 1-min (HRR1) and 2-min (HRR2) after recovery were recorded (bpm). IR was defined if homeostasis model assessment (HOMA-IR) was >= 2.73. C-reactive protein (CRP) was quantified by latex-enhanced nephelometry. RESULTS: In the fully adjusted model, participants with IR had attenuated HRR compared to those without (mean HRR1 11.8 vs. 12.7, p = 0.011; mean HRR2 31.2 vs. 33.4, p < 0.001). Mean HRR1 for participants with CRP >0.3 mg/dL, CRP 0.1-0.3 mg/dL, and CRP <0.1 mg/dL were 11.6, 12.0, and 12.8 (p for trend 0.002), respectively. Mean HRR2 in the three corresponding groups were 33.0, 32.5, and 31.8 (p for trend 0.033), respectively. Participants with IR and CRP elevation had slower HRR than those without IR and with normal CRP. The mean HRR1 comparing participants with IR/CRP >0.3 mg/dL to those with no IR/CRP <0.1 mg/dL were 10.5 and 13.1 (p < 0.001), while the mean HRR2 for the same comparison were 29.1 and 33.8 (p < 0.001). HRR (especially HRR2) was inversely correlated with various metabolic risks. CONCLUSIONS: Insulin resistance and CRP levels were inversely associated with HRR in healthy adolescents and adults. Participants with IR and elevated CRP had the worst HRR. Our findings suggest a joint effect of IR and inflammation on cardiac autonomic dysfunction. PMID- 25791915 TI - Therapeutic adherence and competence scales for Developmentally Adapted Cognitive Processing Therapy for adolescents with PTSD. AB - Background : The assessment of therapeutic adherence and competence is often neglected in psychotherapy research, particularly in children and adolescents; however, both variables are crucial for the interpretation of treatment effects. Objective : Our aim was to develop, adapt, and pilot two scales to assess therapeutic adherence and competence in a recent innovative program, Developmentally Adapted Cognitive Processing Therapy (D-CPT), for adolescents suffering from posttraumatic stress disorder (PTSD) after childhood abuse. Method : Two independent raters assessed 30 randomly selected sessions involving 12 D CPT patients (age 13-20 years, M age=16.75, 91.67% female) treated by 11 therapists within the pilot phase of a multicenter study. Results : Three experts confirmed the relevance and appropriateness of each item. All items and total scores for adherence (intraclass correlation coefficients [ICC]=0.76-1.00) and competence (ICC=0.78-0.98) yielded good to excellent inter-rater reliability. Cronbach's alpha was 0.59 for the adherence scale and 0.96 for the competence scale. Conclusions : The scales reliably assess adherence and competence in D-CPT for adolescent PTSD patients. The ratings can be helpful in the interpretation of treatment effects, the assessment of mediator variables, and the identification and training of therapeutic skills that are central to achieving good treatment outcomes. Both adherence and competence will be assessed as possible predictor variables for treatment success in future D-CPT trials. PMID- 25791916 TI - Mixed picture of readiness for adoption of evidence-based prevention programs in communities: exploratory surveys of state program delivery systems. AB - An emerging literature highlights the potential for broader dissemination of evidence-based prevention programs in communities through existing state systems, such as the land grant university Extension outreach system and departments of public education and health (DOE-DPH). This exploratory study entailed surveying representatives of the national Extension system and DOE-DPH, to evaluate dissemination readiness factors, as part of a larger project on an evidence-based program delivery model called PROSPER. In addition to assessing systems' readiness factors, differences among US regions and comparative levels of readiness between state systems were evaluated. The Extension web-based survey sample N was 958 and the DOE-DPH telephone survey N was 338, with response rates of 23 and 79 %, respectively. Extension survey results suggested only a moderate level of overall readiness nationally, with relatively higher perceived need for collaborative efforts and relatively lower perceived resource availability. There were significant regional differences on all factors, generally favoring the Northeast. Results from DOE-DPH surveys showed significantly higher levels for all readiness factors, compared with Extension systems. Overall, the findings present a mixed picture. Although there were clear challenges related to measuring readiness in complex systems, addressing currently limited dissemination resources, and devising strategies for optimizing readiness, all systems showed some readiness-related strengths. PMID- 25791917 TI - Engagement and disengagement in mutual-help addiction recovery housing: a test of affective events theory. AB - This study tested an affective events theory (AET) model in the Oxford House network of recovery homes. Residents' congruence with their home (P-E fit) was hypothesized to directly influence behavior that supported the house and other residents-citizenship behavior. We further hypothesized P-E fit would be related to member intentions to leave, with attitudes toward the home mediating that relationship. To assess this, we administered a cross-sectional national survey to 296 residents of 83 randomly selected Oxford Houses. Although the AET model demonstrated good fit with the data, an alternative model fit better. This alternative model suggested an additional indirect relationship between P-E fit and citizenship mediated by attitudes. Results suggested affective experiences such as feeling like one fits with a community may influence engagement and disengagement. There appears to be a direct influence of fit on citizenship behavior and an indirect influence of fit through recovery home attitudes on both citizenship and intentions to leave the home. We conclude affective experiences could be important for community engagement and disengagement but AET may need to integrate cognitive dissonance theory. PMID- 25791918 TI - Laryngeal morphologic changes and epidemiology in patients with inhalation injury: a retrospective study. AB - BACKGROUND AND OBJECTIVES: Laryngeal morphologic changes are important in risk assessment of upper airway obstruction (UAO) after inhalation injury. This retrospective study evaluates the clinical application of laryngeal burn classification system. MATERIALS AND METHODS: Clinical data from January 1999 to June 2013 were analyzed retrospectively. The following data collected: age, gender, total burned surface area (TBSA), third-degree burn surface area, co morbid injuries and complications, proportion of patients with tracheotomy, interval between tracheotomy and injury, incidence and mortality of UAO, and reasons for death. RESULTS: Four hundred and forty-three patients were included; 405 patients underwent multiple fibro-laryngoscopic observation, of which I, II and III types of laryngeal burns were present in 49.9, 38.0, and 12.1% patients, respectively. Laryngeal burn severity was related to TBSA and third-degree burn surface area. Overall tracheotomy rate (n=443) was 37.02%. The mean interval between tracheotomy and injury was 10.0+/-12.17h. Over 75% patients underwent tracheotomy within 12h. Compared with moderate inhalation burn group, the severe inhalation burn group showed a significantly higher tracheotomy rate within 12h and a significantly shorter interval between tracheotomy and injury. Patient mortality was significantly related to the severity of inhalation injury. CONCLUSION: The classification system of the morphologic laryngeal changes in laryngeal burn patients could effectively evaluate the UAO risk, enable earlier prophylactic tracheotomy after UAO onset, reduce surgical difficulties and risks, decrease clinical pressure of doctors, and prevent UAO. Laryngeal burn severity was related to TBSA and mortality and may be an important severity and prognosis indicator of inhalation injury. PMID- 25791919 TI - A reconsideration of the role of self-identified races in epidemiology and biomedical research. AB - A considerable number of studies in epidemiology and biomedicine investigate the etiology of complex diseases by considering (self-identified) race as a relevant variable and focusing on the differences in risk among racial groups in the United States; they extensively draw on a genetic hypothesis--viz. the hypothesis that differences in the risk of complex diseases among racial groups are largely due to genetic differences covarying with genetic ancestry--that appears highly problematic in the light of both current biological evidence and the theory of human genome evolution. Is this reason for dismissing self-identified races? No. An alternative promising use of self-identified races exists, and ironically is suggested by those studies that investigate the etiology of complex diseases without focusing on racial differences. These studies provide a large amount of empirical evidence supporting the primacy of the contribution of non-genetic as opposed to genetic factors to the risk of complex diseases. We show that differences in race--or, better, in racial self-identification--may be critically used as proxies for differences in risk-related exposomes and epigenomes in the context of the United States. Self-identified race is what we need to capture the complexity of the effects of present and past racism on people's health and investigate risk-related external and internal exposures, gene-environment interactions, and epigenetic events. In fact patterns of racial self identifications on one side, and patterns of risk-related exposomes and epigenomes on the other side, constantly coevolve and tend to match each other. However, there is no guarantee that using self-identified races in epidemiology and biomedical research will be beneficial all things considered: special attention must be paid at balancing positive and negative consequences. PMID- 25791920 TI - Wegener's granulomatosis with nervous system involvement: a hospital-based study. AB - BACKGROUND: The aim of this study was to ascertain the clinical manifestations of granulomatosis with polyangiitis (Wegener's) (GPA) with the involvement of the peripheral nervous system (PNS) and central nervous system (CNS). SUMMARY: All neurologic inpatients in a hospital over a 12-year period were reviewed. Nine patients met both the ACR 1990 traditional format criteria for the classification of GPA and the Chapel Hill nomenclature mandatory criteria for GPA. We focused on the clinical presentation, serological data, biopsy reports, disease activities [as assessed by the Birmingham Vasculitis Activity Score (BVAS)], electrophysiology, and brain images. Nine patients met the diagnostic criteria for GPA. The neurological signs of the initial manifestation of GPA were found in 6/9 (67%) patients. Eight patients had GPA-related CNS involvement, including four patients with chronic hypertrophic pachymeningitis, with either diffuse or focal thickening; three had intracranial hemorrhages and two had orbital mass lesions with optic nerve compression. In addition, six patients showed PNS involvement, including three with asymmetric sensorimotor polyneuropathy, two with symmetric sensorimotor polyneuropathy, and one with bilateral mononeuropathy. Key Messages: Neurological manifestation is not uncommon and can be the first clinical sign of GPA. The involvement of both CNS and PNS raises the possibility of GPA in hospitalized neurologic patients. PMID- 25791921 TI - TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis. AB - Arsenic trioxide (ATO) is a multi-target drug approved by the Food and Drug Administration as the first-line chemotherapeutic agent for the treatment of acute promyelocytic leukemia. In addition, several clinical trials are being conducted with arsenic-based drugs for the treatment of other hematological malignancies and solid tumors. However, ATO's modest clinical efficacy on some cancers, and potential toxic effects on humans have been reported. Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue. Previously, we demonstrated that the JNK induced complex formation of phosphorylated c-Jun and TG-interacting factor (TGIF) antagonizes ERK-induced cyclin-dependent kinase inhibitor CDKN1A (p21(WAF1/CIP1)) expression and resultant apoptosis in response to ATO in A431 cells. Surprisingly, at low-concentrations (0.1-0.2 MUM), ATO increased cellular proliferation, migration and invasion, involving TGIF expression, however, at high-concentrations (5-20 MUM), ATO induced cell apoptosis. Using a promoter analysis, TGIF was transcriptionally regulated by ATO at the FOXO3A binding site (-1486 to -1479bp) via the c-Src/EGFR/AKT pathway. Stable overexpression of TGIF promoted advancing the cell cycle into the S phase, and attenuated 20 MUM ATO induced apoptosis. Furthermore, blockage of the AKT pathway enhanced ATO-induced CDKN1A expression and resultant apoptosis in cancer cells, but overexpression of AKT1 inhibited CDKN1A expression. Therefore, we suggest that TGIF is transcriptionally regulated by the c-Src/EGFR/AKT pathway, which plays a role as a negative regulator in antagonizing ATO-induced CDKN1A expression and resultant apoptosis. Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO. PMID- 25791922 TI - Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. AB - Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1alpha and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKalpha with specific siRNA abrogated its inhibitory effects on IRE1alpha and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1beta secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1alpha, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. PMID- 25791923 TI - Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin. AB - Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. PMID- 25791924 TI - Off-pump coronary artery bypass reduces early stroke in octogenarians: a meta analysis of 18,000 patients. AB - BACKGROUND: Data comparing results of off-pump and conventional operations in octogenarians is very limited. Thus we chose to compare early adverse events between off-pump coronary artery bypass grafting (OPCABG) and on-pump CABG (ONCABG) in patients older than 80 years. METHODS: Systematic review of multiple databases was performed to obtain original studies fulfilling search criteria. End points--early mortality, stroke, respiratory failure, atrial fibrillation, and myocardial infarction--were compared between these cohorts. A random-effects weighted analysis was performed using the trim-fill adjustment when necessary. Results are presented as risk ratios (RRs) with 95% confidence intervals (CIs); p < 0.05 is considered statistically significant. RESULTS: Sixteen retrospective studies (9,744 ONCABG and 8,566 OPCABG patients) were included in the systematic review. OPCAGB patients received significantly fewer grafts (2.54 +/- 0.16) compared with ONCABG patients (3.22 +/- 0.41). Early mortality was comparable at 4.6% and 5.2% in the OPCABG and ONCABG cohorts, respectively (risk ratio [RR], 0.91; 95% CI, 0.64-1.28; p = 0.598). Stroke rates were higher in the ONCABG cohort (RR, 0.65; 95% CI, 0.49- 0.87; p < 0.01). Respiratory failure was higher with ONCABG (RR, 0.74; 95% CI, 0.57-0.97; p = 0.03). New-onset renal failure (p = 0.99), atrial fibrillation (p = 0.27), and myocardial infarction (p = 0.99) were comparable. CONCLUSIONS: Coronary artery bypass in octogenarians can be performed safely with low early mortality. Although off-pump operations reduce the risk of early stroke, all other adverse events are comparable in on- and off-pump coronary artery bypass operations. Data regarding late mortality is at present limited; however, both on- and off-pump procedures appear to produce comparable survival. PMID- 25791925 TI - Results of emergency postoperative re-angiography after cardiac surgery procedures. AB - BACKGROUND: The purpose of this study was to evaluate the diagnostic and therapeutic role of emergency coronary angiography (ECA) in the setting of acute ischemic or hemodynamic instability after cardiac surgery. METHODS: Between January 2005 and September 2014 we prospectively collected data from a consecutive cohort of 5,275 patients who underwent cardiac surgery. Patients who underwent ECA due to new ST-segment changes on electrocardiogram (ECG), ventricular arrhythmias, cardiac arrest or hemodynamic collapse, new changes in regional wall motion, or any other relevant suspect of myocardial ischemia during postoperative intensive care unit stay were included. RESULTS: Forty patients (0.7% of the overall population) were enrolled. Nineteen patients (47.5%) received isolated coronary surgery, 21 (52.5%) underwent valve or aortic or combined operations. The most common indications to ECA were new ECG or echo signs of acute ischemia (62.5%). The mean time from primary operation to ECA was 51 hours (27 minutes to 9 days). Graft failure was found in 17 cases (42.5%), native coronary artery occlusion in 7 (20%), and coronary spasm in 5 (12.5%). No pathologic alterations were found in 7 cases (17.5%). Three patients (7.5%) underwent reoperation (group 1), 15 (37.5%) underwent percutaneous interventions (PCI) (group 2), and 22 (55%) were managed conservatively (group 3). In-hospital mortality was 100% in group 1, 6% in group 2, and 0% in group 3; 93% of the patients who underwent PCI had complete resolution of the ischemic or hemodynamic problems. No complications related to angiography occurred. Kaplan-Meier survival curves differed significantly according to the post-angiography management. At multivariate analysis combined surgery and the strategy of treatment were independent predictors of long-term mortality. CONCLUSIONS: Emergency coronary angiography is safe and allows diagnosis and resolution of the instability in the great majority of cases. An ECA should be the first-line measure in case of acute ischemic or hemodynamic instability after cardiac surgery. PMID- 25791926 TI - Role of hot electrons and metal-oxide interfaces in surface chemistry and catalytic reactions. PMID- 25791927 TI - Epidemiology of infection and current guidelines for infection prevention in cystic fibrosis patients. AB - The spectrum of bacterial pathogens encountered in cystic fibrosis (CF) lung disease has expanded over the last decade. In addition to established pathogens, such as Pseudomonas aeruginosa, Burkholderia cepacia complex and Staphylococcus aureus, novel Gram-negative non-fermenter bacteria and non-tuberculous mycobacteria have gained in clinical significance. Air sampling performed in inpatient and outpatient clinics, and analysis of cough aerosols expelled by CF patients provides evidence for potential airborne transmission of CF pathogens. Two outbreaks of 'Mycobacterium abscessus subsp. massiliense' have been reported among CF patients, raising the question of airborne transmission of non tuberculous mycobacteria. In response to newer epidemiological evidence, international infection control guidance documents have changed. Guideline documents agree on the importance of specifications for ventilation when planning new CF inpatient facilities. New CF units should consider providing negative pressure inpatient and outpatient rooms to diminish the risk of airborne contamination of ward corridors and communal areas. Air exchange rates of inpatient rooms and pulmonary function testing rooms need to be considered and optimized whenever possible. International guidelines disagree as to whether patients should be requested to wear masks in the hospital environment. PMID- 25791928 TI - Creative use of novel glucose-lowering drugs for type 2 diabetes: where will we head in the next 50 years? AB - Research conducted over the last 50 years has produced discoveries on the importance of glucose control for reducing the risk of diabetic complications, the pathophysiology of type 2 diabetes, the development and validation of mechanistic glucose-lowering targets, and the preclinical and clinical development of individual drugs. This science established the different drug classes that are clinically used today in association with lifestyle changes for lowering glucose in type 2 diabetes. For the next 50 years, we can anticipate that science will explore (1) the use of current drugs and, as they become available, newly developed drugs in early (initial) oral combinations followed by intensification with injectable combinations when glycaemia deteriorates, (2) the validation of novel mechanistic biochemical and physiological targets, including indirect effects of future antiobesity drugs, and (3) the development of true disease-modifying strategies based on knowledge of islet cell biology and replacement. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). PMID- 25791929 TI - Molecular epidemiology and evolutionary dynamics of Echovirus 3 serotype. AB - Echovirus 3 (E3) serotype has been related with several neurologic diseases, although it constitutes one of the rarely isolated serotypes, with no report of epidemics in Europe. The aim of the present study was to provide insights into the molecular epidemiology and evolution of this enterovirus serotype, while an E3 strain was isolated from sewage in Greece, four years after the initial isolation of the only reported E3 strain in the same geographical region. Phylogenetic analysis of the complete VP1 genomic region of that E3 strain and of those available in GenBank suggested three main genogroups that were further subdivided into seven subgenogroups. Further evolutionary analysis suggested that VP1 genomic region of E3 was dominated by purifying selection, as the vast majority of genetic diversity presumably occurred through synonymous nucleotide substitutions and the substitution rate for complete and partial VP1 sequences was calculated to be 8.13*10(-3) and 7.72*10(-3) substitutions/site/year respectively. The partial VP1 sequence analysis revealed the composite epidemiology of this serotype, as the strains of the three genogroups presented different epidemiological characteristics. PMID- 25791931 TI - Intrapatient diversity of Achromobacter spp. involved in chronic colonization of Cystic Fibrosis airways. AB - Achromobacter spp. are increasingly identified in Cystic Fibrosis (CF) patients and their ability to persistently colonize the CF respiratory tract (CFRT) suggests that Achromobacter species possess adaptive characteristics. We studied genome dynamics in 118 isolates recovered from 13 patients with Achromobacter chronic colonization (5-26 isolates per patient recovered over 13-61 months). Isolates were identified to species level by nrdA gene sequencing, subjected to Pulsed-Field Gel Electrophoresis (PFGE) and multiplex rep-PCR (MR-PCR), and rrs intragenomic diversity was studied by PCR-Temporal Temperature Gel Electrophoresis (TTGE). Intrapatient diversity was assessed: (i) from dynamics of XbaI and/or SpeI-based pulsotypes, (ii) from comparison of MR-PCR profiles, and (iii) by longitudinal analysis of rrs intragenomic diversity. Patients were chronically colonized by Achromobacter xylosoxidans (n=10), Achromobacter dolens (n=1) or Achromobacter insuavis (n=2). All strains displayed genomic diversification over time but A. insuavis showed higher pulsotype diversity compared to other species. Intragenomic rrs heterogeneity was found in strains from 6 of 13 patients and may be persistently observed. Achromobacter genome evolution observed during chronic colonization of the CFRT warrants further investigation of the adaptation features of the different species, as well as of the selective forces driving this adaptation in the CFRT. PMID- 25791930 TI - Molecular epidemiology of pathogenic Leptospira spp. in the straw-colored fruit bat (Eidolon helvum) migrating to Zambia from the Democratic Republic of Congo. AB - The role played by bats as a potential source of transmission of Leptospira spp. to humans is poorly understood, despite various pathogenic Leptospira spp. being identified in these mammals. Here, we investigated the prevalence and diversity of pathogenic Leptospira spp. that infect the straw-colored fruit bat (Eidolon helvum). We captured this bat species, which is widely distributed in Africa, in Zambia during 2008-2013. We detected the flagellin B gene (flaB) from pathogenic Leptospira spp. in kidney samples from 79 of 529 E. helvum (14.9%) bats. Phylogenetic analysis of 70 flaB fragments amplified from E. helvum samples and previously reported sequences, revealed that 12 of the fragments grouped with Leptospira borgpetersenii and Leptospira kirschneri; however, the remaining 58 flaB fragments appeared not to be associated with any reported species. Additionally, the 16S ribosomal RNA gene (rrs) amplified from 27 randomly chosen flaB-positive samples was compared with previously reported sequences, including bat-derived Leptospira spp. All 27 rrs fragments clustered into a pathogenic group. Eight fragments were located in unique branches, the other 19 fragments were closely related to Leptospira spp. detected in bats. These results show that rrs sequences in bats are genetically related to each other without regional variation, suggesting that Leptospira are evolutionarily well-adapted to bats and have uniquely evolved in the bat population. Our study indicates that pathogenic Leptospira spp. in E. helvum in Zambia have unique genotypes. PMID- 25791933 TI - Reconfigurable microfluidic systems with reversible seals compatible with 2D and 3D surfaces of arbitrary chemical composition. AB - Microfluidic channels are typically fabricated in polydimethylsiloxane (PDMS) using soft lithography and sealed against a support substrate using various irreversible/reversible techniques-the most widely used method is the irreversible bonding of PDMS to glass using oxygen plasma. These techniques are limited in their ability to seal channels against rough, uneven, and/or three dimensional substrates. This manuscript describes the design and fabrication of soft microfluidic systems from combinations of silicone elastomers that can be reversibly sealed against an array of materials of various topographies/geometries using compression. These soft systems have channels with cross-sectional dimensions that can be decreased, reversibly, by hundreds of microns using compressive stress, and the ability to interface with virtually any support substrate. These capabilities go beyond that achievable with devices fabricated in PDMS alone and enable the integration of microfluidic functionality directly with rough and/or 3D surfaces, providing new opportunities in solution processing useful to, for example, materials science and the analytical/forensic sciences. PMID- 25791932 TI - Montpellier Infectious Diseases - Pole Rabelais (MID) 3rd annual meeting (2014). AB - For the third time, teams belonging to the "Montpellier Infectious Diseases" network in the Rabelais BioHealth Cluster held their annual meeting on the 27th and 28th of November in Montpellier, France. While the 2012 meeting was focused on the cooperation between the local force tasks in biomedical and medical chemistry and presented the interdisciplinary research programs designed to fight against virus, bacteria and parasites, the 2014 edition of the meeting was focused on the translational research in infectious diseases and highlighted the bench-to-clinic strategies designed by academic and private research groups in the Montpellier area. PMID- 25791935 TI - Palladium-catalyzed Csp(2)-H carbonylation of aromatic oximes: selective access to benzo[d][1,2]oxazin-1-ones and 3-methyleneisoindolin-1-ones. AB - A highly selective palladium-catalyzed carbonylation of Csp(2)-H bonds with aromatic oximes for the synthesis of benzo[d][1,2]oxazin-1-ones and 3 methyleneisoindolin-1-ones has been developed. Interestingly, we found that the N OH group of the oximes could be used as a directing group and/or an internal oxidant under different conditions. This transformation is supposed to proceed through a hydroxyl-directed ortho-Csp(2)-H carbonylation or activation of vinyl Csp(2)-H bond/ortho-Csp(2)-H carbonylation process. The uses of readily available starting materials, atmospheric pressure of carbon monoxide, as well as operational simplicity make this practical and atom-economical method particularly attractive. PMID- 25791934 TI - Genetic studies of the susceptibility of classical and wild-derived inbred mouse strains to monkeypox virus. AB - Previously, we screened 38 inbred mouse strains for susceptibility to monkeypox virus (MPXV) and focused on wild-derived CAST mice because of their extreme vulnerability. Here, we provide further analysis of inbred mouse strains. NZW/Lac and C58 mice exhibited more weight loss than other classical inbred strains but all survived intranasal challenges with 10(4) to 10(6)PFU of MPXV. Mice from three wild derived strains, in addition to CAST, exhibited severe weight loss and died or were euthanized. LD50 values for CASA, MOLF and PERA were 100, 6800 and >10(5)PFU, respectively. CASA was inbred independently from the same founders as CAST, whereas MOLF and PERA are genetically and geographically distinct. The MPXV susceptibility of the F1 progeny of CAST and either C57BL/6 or BALB/c indicated that resistance is dominant. Back-crossing the F1 progeny of C57BL/6 and CAST to CAST suggested more than one independent resistant locus. PMID- 25791936 TI - Involvement of Bim in Photofrin-mediated photodynamically induced apoptosis. AB - BACKGROUND/AIMS: Photodynamic therapy (PDT) is a promising noninvasive technique, which has been successfully applied to the treatment of human cancers. Studies have shown that the Bcl-2 family proteins play important roles in PDT-induced apoptosis. However, whether Bcl-2-interacting mediator of cell death (Bim) is involved in photodynamic treatment remains unknown. In this study, we attempt to determine the effect of Bim on Photofrin photodynamic treatment (PPT)-induced apoptosis in human lung adenocarcinoma ASTC-a-1 cells. METHODS: The translocation of Bim/Bax of the cells were monitored by laser confocal scanning microscope. The levels of Bim protein and activated caspase-3 in cells were detected by western blot assay. Caspase-3 activities were measured by Caspase-3 Fluorogenic Substrate (Ac-DEVD-AFC) analysis. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. The effect of Bim on PPT induced apoptosis was determined by RNAi. RESULTS: BimL translocated to mitochondria in response to PPT, similar to the downstream pro-apoptotic protein Bax activation. PPT increased the level of Bim and activated caspase-3 in cells and that knockdown of Bim by RNAi significantly protected against caspase-3 activity. PPT-induced apoptosis were suppressed in cells transfected with shRNA Bim. CONCLUSION: We demonstrated the involvement of Bim in PPT-induced apoptosis in human ASTC-a-1 lung adenocarcinoma cells and suggested that enhancing Bim activity might be a potential strategy for treating human cancers. PMID- 25791937 TI - Enhanced cell growth inhibition by thiacremonone in paclitaxel-treated lung cancer cells. AB - Activation of nuclear factor kappa-B (NF-kappaB) is implicated in drug resistant of lung cancer cells. Our previous data showed that thiacremonone inhibited activation of NF-kappaB. In the present study, we investigated whether thiacremonone enhanced susceptibility of lung cancer cells to a common anti cancer drug paclitaxel by further inhibition of NF-kappaB. Thus, we used the threefold lower doses of IC50 values (50 MUg/ml thiacremonone and 2.5 nM paclitaxel). We found that combination treatment with thiacremonone and paclitaxel was more susceptible (combination index; 0.40 in NCI-H460 cells and 0.46 in A549 cells) in cell growth inhibition of two types of lung cancer cell lines compared to a single agent treatment. Consistent with the combination effect on cancer cell growth inhibition, the combination treatment further induced apoptotic cell death and arrested the cancer cells in G2/M phase accompanied with a much lower expression of cdc2 and cyclin B1, and inhibited colony formation. Much more inactivation of NF-kappaB and greater expression of NF-kappaB target apoptosis regulated genes such as caspase-8 and PARPs were found by the combination treatment. Molecular model and pull down assay as well as MALDI-TOF analysis demonstrated that thiacremonone directly binds to p50. These data indicated that thiacremonone leads to increased apoptotic cell death in lung cancer cell lines through greater inhibition of NF-kappaB by the combination treatment with paclitaxel. PMID- 25791938 TI - Vitamin D supplementation modulates the immune system and improves atopic dermatitis in children. AB - BACKGROUND: Vitamin D seems to influence the evolution of atopic dermatitis (AD) in children. METHODS: We tested the vitamin D serum levels of 39 children with AD (AD group t0) and of 20 nonallergic healthy controls (C group). AD severity was evaluated using the AD scoring system (SCORAD index). Cytokine serum levels (IL 2, IL-4, IL-6, IFN-gamma, TNF-alpha) and atopy biomarkers were also measured. The patients were then treated with vitamin D oral supplementation of 1,000 IU/day (25 mg/day) for 3 months. We then reevaluated the vitamin D serum levels, AD severity and cytokine serum levels in all of the treated children (AD group t1). RESULTS: The cross-sectional analysis on patients affected by AD (AD group t0) showed that the initial levels of all the tested cytokines except for TNF-alpha were higher than those of the healthy control group (C group), falling outside the normal range. After 3 months of supplementation the patients had significantly increased vitamin D levels (from 22.97 +/- 8.03 to 29.41 +/- 10.73 ng/ml; p = 0.01). A concomitant significant reduction of both the SCORAD index (46.13 +/- 15.68 at the first visit vs. 22.57 +/- 15.28 at the second visit; p < 0.001) and of all the altered cytokines (IL-2, IL-4, IL-6, IFN-gamma) was also found. CONCLUSIONS: This study showed vitamin D supplementation to be an effective treatment in reducing AD severity in children through normalization of the Th1 and Th2 interleukin serum pattern. PMID- 25791939 TI - Cerebrospinal fluid biomarkers for Alzheimer's disease in patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis with the C9ORF72 repeat expansion. AB - BACKGROUND: The C9ORF72 expansion is one of the most common causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The C9ORF72 expansion is associated with TDP-43 and p62 neuropathology, and amyloid plaques and neurofibrillary tangles are not common in patients with the C9ORF72 expansion. Therefore, we hypothesized that cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease [AD; Abeta1-42, total tau (T-tau) and phospho tau] are normal in these patients. METHODS: The CSF Abeta1-42, T-tau and phospho tau levels were measured in 40 Finnish patients with the C9ORF72 expansion (29 FTLD, 10 ALS and 1 FTLD-ALS) using ELISA. RESULTS: A decreased Abeta1-42 level was found in 25% of cases, while there were only single cases with changes in the t-Tau or phospho-tau level. The patients with abnormal biomarkers fulfilled the clinical criteria of the behavioral variant frontotemporal dementia and expressed no clinical signs of AD. CONCLUSIONS: In clinical diagnostics, a decreased CSF Abeta1-42 level does not exclude the C9ORF72 expansion associated with FTLD. PMID- 25791940 TI - Urinary angiotensin converting enzyme 2 increases in patients with type 2 diabetic mellitus. AB - BACKGROUND/AIMS: Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and recognized to be renoprotective by degrading Angiotensin II to Angiotensin (1-7) in diabetic nephropathy. However, little is known about the role of urinary ACE2 (UACE2) in diabetes. The present study was performed to evaluate UACE2 levels in type 2 diabetic patients with various degrees of albuminuria and its associations with metabolic parameters. The effect of RAS inhibitors on UACE2 excretion was also assessed. METHODS: A total of 132 type 2 diabetic patients with different degrees of albuminuria and 34 healthy volunteers were studied. UACE2 levels and activity were measured. RESULTS: Compared to healthy controls, UACE2 to creatinine (UACE2/Cr) levels were significantly increased in both albuminuric and non-albuminuric diabetic patients. UACE2/Cr levels were much higher in hypertensive diabetic patients compared with their normotensive counterparts and treatment with RAS inhibitors markedly attenuated the augmentation. Furthermore, UACE2/Cr was positively correlated with fasting blood glucose, hemoglobin A1C (HbA1C), triglyceride, and total cholesterol. In multiple regression analysis, UACE2/Cr was independently predicted by HbA1C and RAS inhibitors treatment. CONCLUSIONS: UACE2 increased in type 2 diabetic patients with various degrees of albuminuria and RAS inhibitors suppresses UACE2 excretion. UACE2 might potentially function as a marker for monitoring the metabolic status and therapeutic response of RAS inhibitors in diabetes. PMID- 25791941 TI - In vitro susceptibility of tigecycline against multidrug-resistant gram-negative strains: Etest versus agar dilution. AB - BACKGROUND AND AIM: Tigecycline is a semi-synthetic tetracycline with activity against most multidrug-resistant (MDR) bacteria. METHODS: We studied in vitro activity of tigecycline by agar dilution (AD) and Etest methods to evaluate their correlation. The study included 206 isolates of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, Klebsiella pneumoniae and MDR Acinetobacter baumannii recovered from blood cultures of patients of Baskent University between 2008 and 2010. RESULTS: ESBL-producing E. coli had MIC50/MIC90 values of 0.5/0.5 ug/ml by AD and 0.25/0.5 ug/ml by Etest. ESBL-producing K. pneumoniae had MIC50/MIC90 values of 1/2 ug/ml by AD and 0.75/2 ug/ml by Etest, whereas MDR A. baumannii had MIC50/MIC90 values of 4/4 ug/ml by AD and 2/4 ug/ml by Etest. The correlation between AD and Etest was weak for ESBL-producing E. coli and strong for ESBL-producing K. pneumoniae and MDR A. baumannii. Tigecycline MIC values for ESBL-producing E. coli were lower than the tigecycline concentration, while they were higher than the concentrations attainable by treatment doses for A. baumannii. CONCLUSION: Tigecycline is an appropriate agent in the treatment of E. coli bacteremia, but it is not for treating A. baumannii bacteremia. Tigecycline could be used for K. pneumoniae bacteremia treatment after determining its MIC value. Determining the MIC value by gold-standard methods is more appropriate due to the correlation between Etest and AD at high MIC values. PMID- 25791942 TI - Ultrastructure of the stigma and style of Cabomba caroliniana Gray (Cabombaceae). AB - Cabomba Aubl. is a genus that presents a range of features that have made it to be considered a potential genetic model for studies of early angiosperm evolution. Therefore, any study that expands our knowledge of this genus is potentially useful for the understanding of the evolution of early angiosperms. This paper reports the study of the anatomy and the ultrastructure of the stigma and the style of Cabomba caroliniana Gray during the 2 days of anthesis using bright-field microscope, fluorescence microscope and transmission electron microscope. The stigma is dry and has pluricellular papillae. The style is hollow with a central canal coated by an epithelium. The papillae have fewer organelles than those typical of glandular cells, and they are covered by a cuticle that is broken when pollen germinates. The ultrastructure of epithelial cells indicates that the cells lining the canal are secretory. The canal is filled with a fibrillar and granular substance. The pollen tubes grow inside the canal through this substance. The results are discussed in the context of what is known for other species of angiosperms. PMID- 25791943 TI - Trehalose glycopolymer resists allow direct writing of protein patterns by electron-beam lithography. AB - Direct-write patterning of multiple proteins on surfaces is of tremendous interest for a myriad of applications. Precise arrangement of different proteins at increasingly smaller dimensions is a fundamental challenge to apply the materials in tissue engineering, diagnostics, proteomics and biosensors. Herein, we present a new resist that protects proteins during electron-beam exposure and its application in direct-write patterning of multiple proteins. Polymers with pendant trehalose units are shown to effectively crosslink to surfaces as negative resists, while at the same time providing stabilization to proteins during the vacuum and electron-beam irradiation steps. In this manner, arbitrary patterns of several different classes of proteins such as enzymes, growth factors and immunoglobulins are realized. Utilizing the high-precision alignment capability of electron-beam lithography, surfaces with complex patterns of multiple proteins are successfully generated at the micrometre and nanometre scale without requiring cleanroom conditions. PMID- 25791944 TI - I know what the studies say, but what should I do for my patient? PMID- 25791945 TI - A propensity-matched comparison of cost and outcomes after esophageal stent placement or primary surgical repair for iatrogenic esophageal perforation. AB - OBJECTIVES: Esophageal stent placement has been shown to be a safe and effective treatment for acute esophageal perforation in selected patients. However, a comparison between surgical repair and stent placement has not been reported. This investigation compares the outcomes and costs of the 2 treatment modalities. METHODS: The Premiere database for a single health system's hospitals was used to identify patients undergoing treatment for an acute intrathoracic esophageal perforation over a 4-year period. Patient cohorts for stent placement or surgical repair were formed using propensity matching. The 2 cohorts were compared for length of stay, morbidity, mortality, and costs. RESULTS: Between 2009 and 2012, 60 patients undergoing esophageal stent placement or surgical repair were propensity matched. Mean patient age and Charlson comorbidity scores did not differ significantly (P = .4 and P = .4, respectively). Significant differences in morbidity (4% vs 43%; P = .02), mean length of stay (6 vs 11 days; P = .0007), time to oral intake (3 vs 8 days; P = .0004), and cost ($91,000 vs $142,000; P < .0001) were identified in the esophageal stent cohort when compared with patients receiving surgical repair. Operative mortality did not differ significantly. CONCLUSIONS: Esophageal stent placement for the treatment of an acute esophageal perforation seems to be as effective as surgical repair when compared between propensity-matched patients. However, stent placement resulted in a shorter length of stay, lower rates of morbidity, and lower costs when compared with traditional surgical repair. PMID- 25791946 TI - A not-so-simple measure. PMID- 25791947 TI - National trends in utilization and in-hospital outcomes of mechanical versus bioprosthetic aortic valve replacements. AB - OBJECTIVE: Substantial controversy surrounds the choice between a mechanical versus bioprosthetic prosthesis for aortic valve replacement (AVR), based on age. This study aims to investigate national trends and in-hospital outcomes of the 2 prosthesis choices. METHODS: All patients aged >18 years in the National Inpatient Sample who received an AVR between 1998 and 2011 were considered. Valve type use was examined by patient, procedural, and hospital characteristics, after which we matched patients based on their propensity score for receiving a bioprosthetic valve and compared their in-hospital outcomes. RESULTS: Bioprosthetic valves comprised 53.3% of 767,375 implanted valves, an increase in use from 37.7% in the period 1998 to 2001 to 63.6% in the period 2007 to 2011. The median age was 74 years for patients receiving bioprosthetic valves, and 67 years for those receiving mechanical valves. Use of bioprosthetic valves increased across all age groups, most markedly in patients age 55 to 64 years. Compared with patients receiving mechanical valves, these patients had a higher incidence of renal disease (8.0% vs 4.2%), coronary artery disease (58.5% vs 50.5%), concomitant coronary artery bypass grafting (46.7% vs 41.9%), and having surgery in a high-volume (>250 cases per year) center (31.3% vs 18.5%). Patients receiving bioprosthetic valves had a higher occurrence of in-hospital complications (55.9% vs 48.6%), but lower in-hospital mortality (4.4% vs 4.9%) than patients receiving mechanical valves. This difference was confirmed in propensity-matched analyses (complications: 52.7% vs 51.5%; mortality: 4.3% vs 5.2%). CONCLUSIONS: Use of bioprosthetic valves in AVR increased dramatically from 1998 to 2011, particularly in patients age 55 to 64 years. Prosthesis selection varied significantly by facility, with low-volume facilities favoring mechanical valves. Aortic valve replacement with a bioprosthetic valve, compared with a mechanical valve, was associated with lower in-hospital mortality. PMID- 25791948 TI - Failure to rescue and pulmonary resection for lung cancer. AB - OBJECTIVE: Failure to rescue is defined as death after an acute inpatient event and has been observed among hospitals that perform general, vascular, and cardiac surgery. This study aims to evaluate variation in complication and failure to rescue rates among hospitals that perform pulmonary resection for lung cancer. METHODS: By using the Society of Thoracic Surgeons General Thoracic Surgery Database, a retrospective, multicenter cohort study was performed of adult patients with lung cancer who underwent pulmonary resection. Hospitals participating in the Society of Thoracic Surgeons General Thoracic Surgery Database were ranked by their risk-adjusted, standardized mortality ratio (using random effects logistic regression) and grouped into quintiles. Complication and failure to rescue rates were evaluated across 5 groups (very low, low, medium, high, and very high mortality hospitals). RESULTS: Between 2009 and 2012, there were 30,000 patients cared for at 208 institutions participating in the Society of Thoracic Surgeons General Thoracic Surgery Database (median age, 68 years; 53% were women, 87% were white, 71% underwent lobectomy, 65% had stage I). Mortality rates varied over 4-fold across hospitals (3.2% vs 0.7%). Complication rates occurred more frequently at hospitals with higher mortality (42% vs 34%, P < .001). However, the magnitude of variation (22%) in complication rates dwarfed the 4-fold magnitude of variation in failure to rescue rates (6.8% vs 1.7%, P < .001) across hospitals. CONCLUSIONS: Variation in hospital mortality seems to be more strongly related to rescuing patients from complications than to the occurrence of complications. This observation is significant because it redirects quality improvement and health policy initiatives to more closely examine and support system-level changes in care delivery that facilitate early detection and treatment of complications. PMID- 25791949 TI - Surgeon experience: Nothing learned! Or nothing to learn? PMID- 25791953 TI - The life in your years. PMID- 25791951 TI - Into another dimension: Assessing novel therapeutics in a more lifelike microenvironment. PMID- 25791950 TI - Adverse cardiac events in children with Williams syndrome undergoing cardiovascular surgery: An analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. AB - OBJECTIVE: Patients with Williams syndrome (WS) undergoing cardiac surgery are at risk for major adverse cardiac events (MACE). Prevalence and risk factors for such events have not been well described. We sought to define frequency and risk of MACE in patients with WS using a multicenter clinical registry. METHODS: We identified cardiac operations performed in patients with WS using the Society of Thoracic Surgeons Congenital Heart Surgery Database (2000-2012). Operations were divided into 4 groups: isolated supravalvular aortic stenosis, complex left ventricular outflow tract (LVOT), isolated right ventricular outflow tract (RVOT), and combined LVOT/RVOT procedures. The proportion of patients with MACE (in-hospital mortality, cardiac arrest, or postoperative mechanical circulatory support) was described and the association with preoperative factors was examined. RESULTS: Of 447 index operations (87 centers), median (interquartile range) age and weight at surgery were 2.4 years (0.6-7.4 years) and 10.6 kg (6.5 21.5 kg), respectively. Mortality occurred in 20 patients (5%). MACE occurred in 41 patients (9%), most commonly after combined LVOT/RVOT (18 out of 87; 21%) and complex LVOT (12 out of 131; 9%) procedures, but not after isolated RVOT procedures. Odds of MACE decreased with age (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.98-0.99), weight (OR, 0.97; 95% CI, 0.93-0.99), but increased in the presence of any preoperative risk factor (OR, 2.08; 95% CI, 1.06 4.00), and in procedures involving coronary artery repair (OR, 5.37; 95% CI, 2.05 14.06). CONCLUSIONS: In this multicenter analysis, MACE occurred in 9% of patients with WS undergoing cardiac surgery. Demographic and operative characteristics were associated with risk. Further study is needed to elucidate mechanisms of MACE in this high-risk population. PMID- 25791955 TI - Too much of a good thing? Reducing cannula size and flow rates during extracorporeal life support. PMID- 25791954 TI - The effect of statins on perioperative inflammation in cardiac and thoracic surgery. AB - Statins are being used with increasing frequency for indications beyond lipid lowering therapy. In the perioperative setting, the use of statins as anti inflammatory agents has been an area of growing interest. Despite the early clinical adoption, the data are controversial. Herein we review the available clinical trials examining the effects of statin therapy on perioperative markers of inflammation in cardiac and thoracic surgery. PMID- 25791956 TI - Discussion. PMID- 25791958 TI - One-pot synthesis of hierarchical FeZSM-5 zeolites from natural aluminosilicates for selective catalytic reduction of NO by NH3. AB - Iron-modified ZSM-5 zeolites (FeZSM-5s) have been considered to be a promising catalyst system to reduce nitrogen oxide emissions, one of the most important global environmental issues, but their synthesis faces enormous economic and environmental challenges. Herein we report a cheap and green strategy to fabricate hierarchical FeZSM-5 zeolites from natural aluminosilicate minerals via a nanoscale depolymerization-reorganization method. Our strategy is featured by neither using any aluminum-, silicon-, or iron-containing inorganic chemical nor involving any mesoscale template and any post-synthetic modification. Compared with the conventional FeZSM-5 synthesized from inorganic chemicals with the similar Fe content, the resulting hierarchical FeZSM-5 with highly-dispersed iron species showed superior catalytic activity in the selective catalytic reduction of NO by NH3. PMID- 25791957 TI - Upregulation of BMSCs osteogenesis by positively-charged tertiary amines on polymeric implants via charge/iNOS signaling pathway. AB - Positively-charged surfaces on implants have a similar potential to upregulate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) as electromagnetic therapy approved for bone regeneration. Generally, their osteogenesis functions are generally considered to stem from the charge-induced adhesion of extracellular matrix (ECM) proteins without exploring the underlying surface charge/cell signaling molecule pathways. Herein, a positively-charged surface with controllable tertiary amines is produced on a polymer implant by plasma surface modification. In addition to inhibiting the TNF-alpha expression, the positively-charged surface with tertiary amines exhibits excellent cytocompatibility as well as remarkably upregulated osteogenesis-related gene/protein expressions and calcification of the contacted BMSCs. Stimulated by the charged surface, these BMSCs display high iNOS expressions among the three NOS isoforms. Meanwhile, downregulation of the iNOS by L-Can or siRNA inhibit osteogenic differentiation in the BMSCs. These findings suggest that a positively charged surface with tertiary amines induces osteogenesis of BMSCs via the surface charge/iNOS signaling pathway in addition to elevated ECM protein adhesion. Therefore, creating a positively-charged surface with tertiary amines is a promising approach to promote osseointegration with bone tissues. PMID- 25791959 TI - The relationship between uric acid, allopurinol, cardiovascular events, and kidney disease progression: a step forward. PMID- 25791960 TI - Recovery from acute kidney injury: predicting outcomes. PMID- 25791961 TI - Hai-yan Wang, MD, 1937-2014. PMID- 25791962 TI - Quiz page April 2015: fever and encephalopathy in a kidney transplant recipient. PMID- 25791963 TI - Chips in black boxes? Convenience life span, parafood, brandwidth, families, and co-creation. AB - Any consumer who opens a bag of potato or corn chips (or crisps in the UK) knows there is no time to waste to enjoy or share them. The convenience life span of chips is limited: it is the shelf or storage life and a very limited time once outside the bag. Many technologies converge to generate the desired effect as a black box, not only of the packaging but also of the chips themselves. The concept of paratext can be applied to printed messages on the package, including the brand name and other texts like advertising (epitexts), which can be expanded into the concept of parafood. These concepts help to discuss technological developments and interpret why this has recently become a negotiation zone for co creation (see the Do us a flavor campaigns). They are symptoms of changing relations between production, research and development, marketing, and consumption. This paper pays special attention to back stories, underdog brand biographies and narratives about origin. The concept of brandwidth is introduced to sensitize about the limits of combining different stories about chips. A recent brand biography, a family history and a cookery book are used to discuss the phenomenon of cooking with Fritos. Together with the concepts of parafood, brandwidth and black boxes, more reflection and dialogue about the role of history and heritage in marketing put new challenging perspectives on the agenda. PMID- 25791964 TI - eComment. Let's get real: the problem is how to safely measure the neochordae. PMID- 25791965 TI - eComment. Postoperative urinary retention versus pulmonary complications: is perioperative fluid management in lung resection a balance of risk? PMID- 25791966 TI - eComment. Could this be a first depiction of Poland syndrome? PMID- 25791967 TI - Erratum to "Controlled lung reperfusion to reduce pulmonary ischaemia/reperfusion injury after cardiopulmonary bypass in a porcine model [Interact CardioVasc Thorac Surg 2014;19(6):962-970] ". PMID- 25791968 TI - Primary prevention of congenital anomalies: recommendable, feasible and achievable. AB - Primary prevention of congenital anomalies was identified as an important action in the field of rare diseases by the European Commission in 2008, but it was not included in the Council Recommendation on an action in the field of rare diseases in 2009. However, primary prevention of congenital anomalies is feasible because scientific evidence points to several risk factors (e.g., obesity, infectious and toxic agents) and protective factors (e.g., folic acid supplementation and glycemic control in diabetic women). Evidence-based community actions targeting fertile women can be envisaged, such as risk-benefit evaluation protocols on therapies for chronic diseases, vaccination policies, regulations on workplace and environmental exposures as well as the empowerment of women in their lifestyle choices. A primary prevention plan can identify priority targets, exploit and integrate ongoing actions and optimize the use of resources, thus reducing the health burden for the new generation. The EUROCAT-EUROPLAN recommendations for the primary prevention of congenital anomalies endorsed in 2013 by the European Union Committee of Experts on Rare Diseases present an array of feasible and evidence-based measures from which national plans can adopt and implement actions based on country priorities. Primary prevention of congenital anomalies can be achieved here and now and should be an integral part of national plans on rare diseases. PMID- 25791969 TI - Regional variation in mortality from ischaemic heart disease in Poland, 2006 2010. AB - BACKGROUND: Spatial differences in mortality in Poland are large and remain unexplained to a large extent. Ischaemic heart disease (IHD) is a good candidate for explaining regional inequalities in mortality in Poland due to the high level of mortality from this cause and the large spatial differences. AIM: We describe the contribution of IHD to all-cause mortality in Poland in 2006-2010 on a powiat (Polish district) level and explain the differences in mortality by selected socio-economic factors. METHODS: We use mortality data from the population registry at the NUTS-4 level for 2006-2010. We map age-standardised all-cause and IHD mortality rates. The contribution of IHD mortality to all-cause mortality was also assessed through variance decomposition. Correlation coefficients between age-standardised mortality rates and selected socio-economic variables were estimated for all powiats and for a group excluding large cities. RESULTS: We demonstrated that regional differences between powiats in IHD mortality do not constitute a major factor behind regional mortality disparities in Poland. However, the spatial patterns for all-cause and IHD mortality in Polish powiats were both related to the level of urbanisation, with group of powiats characterised by the lowest IHD mortality comprising only large cities. The negative effect of large cities on the level of all-cause and IHD mortality was confirmed by the significant correlation between the socio-economic contextual variables, standing for the level of urbanisation, and IHD mortality. CONCLUSIONS: Ease of access to medical care in large cities and in particular to cardiology units is an important factor behind the levels of all-cause and IHD mortality in Poland. PMID- 25791970 TI - The successful treatment of cardiogenic shock with primary percutaneous coronary intervention (T-stenting) of total occluded unprotected left main performed during cardiopulmonary resuscitation. PMID- 25791971 TI - A new variation in coronary artery anatomy: type VII dual left anterior descending artery. PMID- 25791972 TI - Persistent left superior vena cava found during pacemaker replacement. PMID- 25791973 TI - Lethal arrhythmia in a 58-year-old cyclist with early repolarisation in electrocardiogram and left main coronary artery disease. PMID- 25791974 TI - Pericarditis in a 56-year-old female with Hashimoto's disease. PMID- 25791975 TI - Potts shunt in child with suprasystemic pulmonary arterial hypertension. PMID- 25791976 TI - Echocardiography in the catheterisation laboratory. PMID- 25791977 TI - [Congenital absence of the pericardium--noninvasive imaging]. PMID- 25791978 TI - First European implantation of the new, thin-strut, sirolimus-eluting bioresorbable scaffold. PMID- 25791980 TI - Early renal dysfunction after iodine contrast administration: new insight into the actual problem. PMID- 25791979 TI - [Loop diuretics: old and new ones--which one to choose in clinical practice? Experts' Group Consensus endorsed by the Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy and Working Group on Heart Failure]. PMID- 25791981 TI - Infestation of the spur-thighed tortoise (Testudo graeca) by Hyalomma aegyptium in Tunisia. AB - We examined 210 spur-thighed tortoises (Testudo graeca) for the presence of ticks in Tunisia during May 2014. A total number of 602 adult ticks were collected and identified leading to the estimation of parasitological indicators. All the ticks belonged to a single species: Hyalomma aegyptium. The mean infestation prevalence was 66.2%, mean overall infestation intensity and abundance were 4.33 and 2.86 ticks/tortoise respectively. Our survey showed that tortoises were significantly more infested by male ticks than females (p<0.001). The ticks were mainly present in the posterior limbs compared to other body regions (p<0.05). There was no significance variation of length and weight of tortoises according to sex (p<0.05). There was a significant correlation between the tortoises' size (length and weight) and tick infestation. This study showed high tick burdens of spur thighed tortoises in Tunisia; further investigations are needed to determine exactly the role of this tick species in the transmission of different zoonotic pathogens. PMID- 25791982 TI - Impact of Thyroid Hormones on Estrogen Receptor alpha-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area. AB - Elevated levels of thyroid hormones (TH) reduce estradiol (E2)-dependent female sexual behavior. E2 stimulates progesterone receptor (Pgr) and oxytocin receptor (Oxtr) within the ventromedial hypothalamus and preoptic area, critical hypothalamic nuclei for sexual and maternal behavior, respectively. Here, we investigated the impact of TH on E2-dependent transcriptional mechanisms in female mice. First, we observed that triiodothyronine (T3) inhibited the E2 induction of Pgr and Oxtr. We hypothesized that differences in histone modifications and receptor recruitment could explain the influence of TH on E2 responsive Pgr and Oxtr expression. We observed that histone H3 acetylation (H3Ac) and methylation (H3K4me3) was gene and brain-region specific. We then analyzed the recruitment of estrogen receptor alpha (ERalpha) and TH receptor alpha (TRalpha) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T3 inhibited E2-induced ERalpha binding to a specific Pgr enhancer site, whereas TRalpha binding was not affected, corroborating our theory that the competitive binding of TRalpha to an ERalpha binding site can inhibit ERalpha transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T3 worked together to modulate ERalpha and TRalpha binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T3. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T3 interferes with the E2 regulation of Pgr and Oxtr expression by altering the recruitment of receptors to DNA and changing the availability of cofactors. Collectively, our findings provide insights into molecular mechanisms of response to E2 and TH interactions controlling sex behavior in the hypothalamus. PMID- 25791983 TI - Process evaluation of complex interventions: Medical Research Council guidance. PMID- 25791984 TI - Rates of hospitalization among patients with deep vein thrombosis before and after the introduction of rivaroxaban. AB - BACKGROUND: Compared to warfarin, the non-vitamin K antagonist oral anticoagulant rivaroxaban may have advantages in treating patients with venous thromboembolism, because injectable bridging therapy and routine laboratory monitoring are not required. The objective of this study was to compare the rate of hospitalization in patients treated with rivaroxaban after its introduction with what it would have been before the introduction of rivaroxaban. METHODS: A retrospective claims analysis was conducted using the MarketScan Hospital Drug Database from January 2011 to December 2013. Adult patients with a primary diagnosis of deep vein thrombosis (DVT) treated with rivaroxaban or low-molecular-weight heparin (LMWH) bridged to warfarin during the first day of an evaluation at a hospital were identified. Based on propensity-score methods, historical LMWH/warfarin patients (i.e., patients who received LMWH/warfarin before the approval of rivaroxaban) were matched 4:1 to rivaroxaban patients, and the rates of hospitalization were compared. RESULTS: All rivaroxaban-treated patients (n = 134) in the database were well matched with four historical LMWH/warfarin-treated patients (n = 536). Among the rivaroxaban cohort, 60% of the patients were admitted to the hospital, compared to 82% of the historical patients treated with LMWH/warfarin in the matched cohort. The difference was statistically significant and corresponded to a 27% reduction in hospital admissions (rate ratio [95% confidence interval]: 0.73 [0.62-0.84]). Hospital admission rates adjusted for time-trend analyses also led to similar results. CONCLUSION: The availability of rivaroxaban significantly reduced the hospitalization rate in patients with DVT treated with rivaroxaban compared to what it would have been if only LMWH/warfarin were available. PMID- 25791985 TI - Progressive multifocal leukoencephalopathy in an apparently healthy child: an unsuspected diagnosis. PMID- 25791986 TI - Time to move on? When entity theorists perform better than incremental theorists. AB - Previous research has shown that when confronted with failure, individuals with a fixed view of intelligence (entity theorists) perform worse on subsequent tasks than those with a malleable view of intelligence (incremental theorists). This study finds that entity theorists perform worse than incremental theorists only when they believe that a subsequent task measures the same ability as the task they previously failed. However, when individuals believe that the subsequent task measures an ability unrelated to the ability needed for the initial failed task, incremental theorists perform worse than entity theorists. Across five studies, we show that entity theorists are more likely to choose a different ability task as a second task and perform better than incremental theorists on that task. We also examine the role of thoughts about previous failure in the performance differences. PMID- 25791988 TI - Working together: spatial synchrony in the force and actin dynamics of podosome first neighbors. AB - Podosomes are mechanosensitive adhesion cell structures that are capable of applying protrusive forces onto the extracellular environment. We have recently developed a method dedicated to the evaluation of the nanoscale forces that podosomes generate to protrude into the extracellular matrix. It consists in measuring by atomic force microscopy (AFM) the nanometer deformations produced by macrophages on a compliant Formvar membrane and has been called protrusion force microscopy (PFM). Here we perform time-lapse PFM experiments and investigate spatial correlations of force dynamics between podosome pairs. We use an automated procedure based on finite element simulations that extends the analysis of PFM experimental data to take into account podosome architecture and organization. We show that protrusion force varies in a synchronous manner for podosome first neighbors, a result that correlates with phase synchrony of core F actin temporal oscillations. This dynamic spatial coordination between podosomes suggests a short-range interaction that regulates their mechanical activity. PMID- 25791987 TI - Healthcare-Associated Infections in Pediatric Intensive Care Units in Turkey: a National Point-Prevalence Survey. AB - Health care-associated infections (HCAIs) cause considerable morbidity and mortality in pediatric intensive care units (PICUs). The objective of this point prevalence study was to assess the burden of HCAIs in PICUs in Turkey. Fifty PICUs participated in this study. Data regarding demographics, microbiological findings, therapeutic interventions, and outcomes were collected for all PICU inpatients. A total of 327 patients participated in the study: 122 (37%) experienced 1 or more HCAI. The most frequently reported site of infection was lower respiratory tract (n=77, 63%). The most frequently isolated pathogens were Pseudomonas aeruginosa, Acinetobacter species, and Candida species. Two hundred and forty-seven patients (75%) were receiving antimicrobial therapy at the time of the survey, and the most frequently administered antimicrobials were third generation cephalosporins. Hospital type, male, PICU stay >7 days, and mechanical ventilation were found to be independent risk factors for HCAIs. At the 4-week follow up, 43 (13%) patients had died, 28 (65%) of whom died of HCAIs. Endotracheal intubation, urinary catheter, male, and HCAIs were independent risk factors for mortality. This national, multicenter study documented a high prevalence of HCAIs in Turkey. In light of the 'primum non nocere' principle, the prevention of these infections should be a priority of public health policy. PMID- 25791989 TI - In vitro and in vivo application of radiolabeled gastrin-releasing peptide receptor ligands in breast cancer. AB - Breast cancer (BC) consists of multiple subtypes defined by various molecular characteristics, for instance, estrogen receptor (ER) expression. Methods for visualizing BC include mammography, MR imaging, ultrasound, and nuclear medicine based methods such as (99m)Tc-sestamibi and (18)F-FDG PET, unfortunately all lacking specificity. Peptide receptor scintigraphy and peptide receptor radionuclide therapy are successfully applied for imaging and therapy of somatostatin receptor-expressing neuroendocrine tumors using somatostatin receptor radioligands. On the basis of a similar rationale, radioligands targeting the gastrin-releasing peptide receptor (GRP-R) might offer a specific method for imaging and therapy of BC. The aim of this study was to explore the application of GRP-R radioligands for imaging and therapy of BC by introducing valid preclinical in vitro and in vivo models. METHODS: GRP-R expression of 50 clinical BC specimens and the correlation with ER expression was studied by in vitro autoradiography with the GRP-R agonist (111)In-AMBA. GRP-R expression was also analyzed in 9 BC cell lines applying (111)In-AMBA internalization assays and quantitative reverse transcriptase polymerase chain reaction. In vitro cytotoxicity of (177)Lu-AMBA was determined on the GRP-R-expressing BC cell line T47D. SPECT/CT imaging and biodistribution were studied in mice with subcutaneous and orthotopic ER-positive T47D and MCF7 xenografts after injection of the GRP-R antagonist (111)In-JMV4168. RESULTS: Most of the human BC specimens (96%) and BC cell lines (6/9) were found to express GRP-R. GRP-R tumor expression was positively (P = 0.026, chi(2)(4) = 12,911) correlated with ER expression in the human BC specimens. Treatment of T47D cells with 10(-7) M/50 MBq of (177)Lu-AMBA resulted in 80% reduction of cells in vitro. Furthermore, subcutaneous and orthotopic tumors from both BC cell lines were successfully visualized in vivo by SPECT/CT using (111)In-JMV4168; T47D tumors exhibited a higher uptake than MCF7 xenografts. CONCLUSION: Targeting GRP-R-expressing BC tumors using GRP-R radioligands is promising for nuclear imaging and therapy, especially in ER positive BC patients. PMID- 25791990 TI - Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. AB - The expression of prostate-specific membrane antigen (PSMA) is increased in prostate cancer. Recently, (68)Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)]) was developed as a PSMA ligand. The aim of this study was to investigate the detection rate of (68)Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy. METHODS: Two hundred forty-eight of 393 patients were evaluable for a retrospective analysis. Median prostate-specific antigen (PSA) level was 1.99 ng/mL (range, 0.2-59.4 ng/mL). All patients underwent contrast-enhanced PET/CT after injection of 155 +/- 27 MBq of (68)Ga-PSMA ligand. The detection rates were correlated with PSA level and PSA kinetics. The influence of antihormonal treatment, primary Gleason score, and contribution of PET and morphologic imaging to the final diagnosis were assessed. RESULTS: Two hundred twenty-two (89.5%) patients showed pathologic findings in (68)Ga-PSMA ligand PET/CT. The detection rates were 96.8%, 93.0%, 72.7%, and 57.9% for PSA levels of >=2, 1 to <2, 0.5 to <1, and 0.2 to <0.5 ng/mL, respectively. Whereas detection rates increased with a higher PSA velocity (81.8%, 82.4%, 92.1%, and 100% in <1, 1 to <2, 2 to <5, and >=5 ng/mL/y, respectively), no significant association could be found for PSA doubling time (82.7%, 96.2%, and 90.7% in >6, 4-6, and <4 mo, respectively). (68)Ga-PSMA ligand PET (as compared with CT) exclusively provided pathologic findings in 81 (32.7%) patients. In 61 (24.6%) patients, it exclusively identified additional involved regions. In higher Gleason score (<=7 vs. >=8), detection efficacy was significantly increased (P = 0.0190). No significant difference in detection efficacy was present regarding antiandrogen therapy (P = 0.0783). CONCLUSION: Hybrid (68)Ga-PSMA ligand PET/CT shows substantially higher detection rates than reported for other imaging modalities. Most importantly, it reveals a high number of positive findings in the clinically important range of low PSA values (<0.5 ng/mL), which in many cases can substantially influence the further clinical management. PMID- 25791992 TI - Interim 18F-FDG PET in Diffuse Large B-Cell Lymphoma: Emerging Worldwide? PMID- 25791991 TI - Evidence of Cyclic Changes in the Metabolism of Abdominal Aortic Aneurysms During Growth Phases: 18F-FDG PET Sequential Observational Study. AB - The rates of growth of medically treated abdominal aortic aneurysms (AAA) are difficult to determine, and relationships with parietal inflammation and with metabolic parameters from (18)F-FDG PET remain unclear. This (18)F-FDG PET sequential observational study was aimed at analyzing the metabolic changes accompanying the growth phases of medically treated AAA. METHODS: Thirty-nine patients (37 men; age [mean +/- SD], 71 +/- 12 y) exhibiting small and medically treated AAA (maximal diameter, 46 +/- 3 mm) underwent (18)F-FDG PET and CT angiography at baseline and 9 mo later. Clinical and imaging parameter correlates of the 9-mo increase in maximal diameter were investigated; these included (18)F FDG maximal standardized uptake values (SUVmax) averaged for slices encompassing the AAA volume. RESULTS: Of the 39 patients, 9 (23%) had a significant (>=2.5 mm) increase in maximal diameter at 9 mo, whereas the remaining 30 did not. The patients with an increase in maximal diameter at 9 mo exhibited lower SUVmax within the AAA at baseline than patients who did not have such an increase (1.80 +/- 0.45 vs. 2.21 +/- 0.52; P = 0.04); they also displayed a trend toward greater changes in SUVmax at 9 mo (difference between 9 mo and baseline: +0.40 +/- 0.85 vs. -0.06 +/- 0.57; P = 0.07). Similar levels were ultimately reached in both groups at 9 mo (2.20 +/- 0.83 and 2.15 +/- 0.66). SUVmax was a significant, yet modest, baseline predictor of the absolute change in maximal diameter during follow-up (P = 0.049). CONCLUSION: The enhancement in the maximal diameter of small AAA was preceded by a stage with a low level of (18)F-FDG uptake, but this low level of uptake was no longer documented after the growth phases, suggesting a pattern of cyclic metabolic changes. PMID- 25791993 TI - Quantitative Analysis of 18F-(E)-N-(3-Iodoprop-2-Enyl)-2beta-Carbofluoroethoxy 3beta-(4'-Methyl-Phenyl) Nortropane Binding to the Dopamine Transporter in Parkinson Disease. AB - (18)F-(E)-N-(3-iodoprop-2-enyl)-2beta-carbofluoroethoxy-3beta-(4'-methyl-phenyl) nortropane ((18)F-FE-PE2I) is a recently developed radioligand for the in vivo quantification of the dopamine transporter (DAT) in the striatum and substantia nigra (SN). The aim of this study was to examine the suitability of (18)F-FE-PE2I as a tool for imaging the nigrostriatal pathway in Parkinson disease (PD) with PET. METHODS: Ten PD patients (9 men and 1 woman; mean age +/- SD, 60 +/- 9 y; Hoehn and Yahr, 1-2; Unified Parkinson Disease Rating Scale motor, 18.9 +/- 6.7) and 10 controls (9 men and 1 woman; mean age +/- SD, 60 +/- 7 y) were included. PET measurements with (18)F-FE-PE2I were conducted for 93 min using the High Resolution Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction, and radiometabolite composition in PD patients and controls. Regions of interest for the caudate, putamen, ventral striatum, SN, and cerebellum were drawn on coregistered MR images. The outcome measure was the binding potential (BP(ND)) estimated with the simplified reference tissue model and the Logan graphical analysis, using the cerebellum as a reference region. Time stability of BP(ND) was examined to define the shortest acquisition protocol for quantitative studies. The wavelet-aided parametric imaging method was used to obtain high-resolution BP(ND) images to compare DAT availability in the striatum and SN in PD patients and control subjects. Group differences were assessed with the unpaired t test (P < 0.05). RESULTS: Parent, radiometabolite fractions, plasma concentration, and cerebellar uptake of (18)F-FE-PE2I did not differ significantly between PD patients and controls. Stable estimates of BP(ND) (<8% of the 93-min value) were obtained with the simplified reference tissue model using approximately 66 min of data. BP(ND) values in PD patients were significantly lower than those in controls (P < 0.05) in the caudate (2.54 +/- 0.79 vs. 3.68 +/- 0.56), putamen (1.39 +/- 1.04 vs. 4.41 +/- 0.54), ventral striatum (2.26 +/- 0.93 vs. 3.30 +/- 0.46), and SN (0.46 +/- 0.20 vs. 0.68 +/- 0.15). CONCLUSION: (18)F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metabolism in controls and PD patients, suitability of the cerebellum as a reference region, and accuracy of quantification using approximately 66 min of PET data are advantages for noninvasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both the striatum and the SN, supporting the utility of (18)F-FE-PE2I as an imaging tool of the nigrostriatal pathway. PMID- 25791994 TI - Wound management with vacuum assisted closure in surgical site infection after ankle surgery. AB - OBJECTIVE: The aim of this study was to compare the efficacy of vacuum assisted closure (VAC) with standard moist wound care (SMWC) in surgical site infection after ankle surgery. METHODS: A prospective cohort was performed among patients with surgical site infection after ankle surgery between 2012 and 2013. The follow-up period was three month, and the efficacy end point was complete wound closure rate. RESULTS: Ninety-four patients were analyzed, with 61 patients in the VAC group and 33 in the SMWC group. The complete wound closure rate in the VAC group was higher than that in the SMWC group at 3 month follow up (90.2% Vs. 72.7%, p = 0.028). The median time to complete wound closure was 31 days (95% CI 20.2-41.8) for VAC, and 63 days (95% CI 46.9-79.1) for SMWC (chi(2) = 4.023, p = 0.045). In the superficial infection subgroup, the median times to complete wound closure were 20 days (95% CI 14.2-35.1) in the VAC group and 42 days (95% CI 35.4 69.4) in SMWC group (chi(2) = 4.331, p = 0.041). In the deep subgroup, the median times to complete wound closure were 46 days (95% CI 28.2-65.9) in the VAC group and 75 days (95% CI 43.2-79.6) in SMWC group (chi(2) = 6.475, p = 0.026). CONCLUSION: Our result showed that vacuum assisted closure was more effective than standard moist wound care in surgical site infection after ankle surgery. PMID- 25791995 TI - Air ions as indicators of short-term indoor radon variations. AB - Diurnal variations in the air ion concentration are subject to changes in the radon concentration. In this experiment, the air ion and radon concentrations were simultaneously measured using two air ion detectors and two continuous radon detectors. The results of the indoor measurements revealed a strong correlation between the concentrations of positive air ions and radon (with a correlation coefficient greater than 0.9). The radon-to-ion concentration ratio changes with an increase in the radon concentration from a linear to a square-root relation. This correlation provides a means of using air ion measurements as a high confidence indicator of changes in the radon concentration, especially for short term measurements on the order of seconds or minutes, which is too short a measurement interval for conventional radon monitors. The use of air ions as an indicator of changes in radon concentration allows for investigation of the behavior of indoor radon and also allows radon to be used as a tracer gas for air mass exchange. PMID- 25791996 TI - Meta-analysis of telemonitoring to improve HbA1c levels: promise for stroke survivors. AB - Monitoring glycemic control is useful not only in the primary prevention of stroke in diabetics, but also in the rehabilitation from and secondary prevention of stroke. In an often functionally and neurocognitively impaired population, however, poor compliance with treatment regimens is a major problem. Wireless, telemonitoring glucometers - often integrated into the patient's healthcare system - offer a solution to the compliance issue. We sought to evaluate the effectiveness of telemonitoring technologies in improving long-term glycemic control. A search on www.clinicaltrials.gov, using keywords such as "telemonitoring" and "self-care device" was performed, and five trials were identified that compared hemoglobin A1c (HbA1c) levels of a group receiving standard care (controls) to a group receiving a telemonitoring intervention. Four of the five studies showed a greater reduction in HbA1c in the intervention group compared to controls at 6 months, although only one was statistically significant. There was considerable heterogeneity between studies (I(2)=69.5%, p=0.02), and the random effects model estimated the aggregate effect size for mean difference in reduction of HbA1c levels to be 0.08% (95% confidence interval -0.12% to 0.28%), which was not statistically significant (p=0.42). The varying results may be due to specific factors in the trials that contributed to their large heterogeneity, and further trials are needed to support the role of telemonitoring in improving diabetes management in this population. Nonetheless, in the future telemonitoring may substantially help patients at risk of ischemic stroke and those who require close glucose monitoring. PMID- 25791997 TI - Genoprotective and hepatoprotective effects of Guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats. AB - CONTEXT: Several biological effects of Paullinia cupana (guarana) have been demonstrated, but little information is available on its effects on the liver. OBJECTIVE: The current study was designed to evaluate the hepatoprotective and genoprotective effects of powder seeds from guarana on CCl4-induced liver injury in rats. MATERIALS AND METHODS: Male Wistar rats were pretreated with guarana powder (100, 300 and 600 mg/kg) or silymarin 100 mg/kg daily for 14 days before treatment with a single dose of CCl4 (50% CCl4, 1 mL/kg, intraperitoneally). RESULTS: The treatment with CCl4 significantly increased the serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In addition, CCl4 increased the DNA damage index in hepatocytes. Guarana in all concentrations was effective in decreasing the ALT and AST activities when compared with the CCl4-treated group. The treatment with guarana decreased DNA damage index when compared with the CCl4-treated group. In addition, the DNA damage index showed a significant positive correlation with AST and ALT. DISCUSSION AND CONCLUSION: These results indicate that the guarana has hepatoprotective activity and prevents the DNA strand breakage in the CCl4-induced liver damage in rats. PMID- 25791998 TI - Synthesis, characterization and biological activity of some unsymmetrical Schiff base transition metal complexes. AB - In this study, several unsymmetrical Schiff bases and their cobalt and manganese complexes have been synthesized and characterized. The unsymmetrical Schiff bases were prepared from reaction of o-phenylendiamine derivatives with 1-hydroxy-2 acetonaphthone and then the product was reacted with the following aldehydes: salicyaldehyde, 2-hydroxynaphthaldehyde, 2-pyridinecarboxaldehyde and 2 qinolinecarboxaldehyde to produce the desired tetradentate unsymmetrical Schiff base ligands H2SL, H2NL, HPYL and HQN, respectively. Reaction of these ligands with cobalt and manganese salts produced complexes of the general formula [M(SL)], [(NL)], [M(PYL)] and [M(QL)]. All the complexes were characterized by elemental analysis, infrared spectroscopy, UV-visible spectroscopy, electrical conductivity and magnetic susceptibility measurements. The prepared complexes were examined for their anti-bacterial activity using gram-positive and gram negative pathogens. The following complexes showed strong antibacterial activity against Staphylococcus aureus: MnSL1, MnSL2 and MnSL3. The genotoxic activity of four complexes, which are MnNL1, MnSL1, CoNL1 and CoSL1, were examined using 8 hydroxy-2-deoxy guanosine (8-OHdG) assay in cultured human blood lymphocytes. All examined complexes were found to be genotoxic at examined concentrations (0.1-100 ug/mL), but with variable magnitudes (p < 0.05). The levels of 8-OHdG induced by MnNL1 and MnSL1 were significantly higher than that induced by CoNL1 and CoSL1 ones. In general, the order of mutagenicity of the compounds is MnSL1 > MnNL1 > CoSL1 > CoNL1. In conclusion, some of the prepared complexes showed some biological activities that might be of interest for future research. PMID- 25792000 TI - Validation of a Prescreening Program for Transcatheter Atrial Septal Defect Closure. AB - Prior to initiation of a formal screening program, 30 % of patients referred for device closure of an atrial septal defect (ASD) at our institution had atrial septal anatomy which precluded ASD device closure. This resulted in inefficiencies in workflow, staff utilization, and inconvenience for families. Our objective was to report our experience with an ASD prescreening evaluation/protocol and family consultation process. This is a retrospective study of pediatric patients who underwent a comprehensive ASD prescreening evaluation at Children's Healthcare of Atlanta between January 2011 and June 2013. The comprehensive prescreening process included a detailed transthoracic echocardiogram and family consultation. Upon establishing a formal prescreening process for patients with secundum ASDs, 138 patients were screened for appropriateness of ASD device closure. At time of prescreening, 40 patients (29 %) were deemed not to be suitable candidates for device ASD closure. In 9 patients (6.5 %), after discussion with the interventionalist, parents elected to pursue surgical ASD closure. A total of 78 patients (56.5 %) underwent successful transcutaneous ASD device closure. In addition, there was a significant discrepancy in the reported size of the ASD between the outside evaluation and the ASD size discovered during the prescreening process. The addition of a prescreening program for transcatheter ASD closure has decreased the incidence of unsuccessful ASD closure from 30 to 10.3 %. The use of a comprehensive evaluation process for ASD device closure improves the likelihood of successful device implantation and permits adequate preprocedural counseling for the patient and family. PMID- 25792001 TI - In response to wilderness search strategy and tactics, by Phillips et Al. PMID- 25791999 TI - Harvesting technique affects adipose-derived stem cell yield. AB - BACKGROUND: The success of an autologous fat graft depends in part on its total stromal vascular fraction (SVF) and adipose-derived stem cells (ASCs). However, variations in the yields of ASCs and SVF cells as a result of different harvesting techniques and donor sites are poorly understood. OBJECTIVE: To investigate the effects of adipose tissue harvesting technique and donor site on the yield of ASCs and SVF cells. METHODS: Subcutaneous fat tissues from the abdomen, flank, or axilla were harvested from patients of various ages by mechanical liposuction, direct surgical excision, or Coleman's technique with or without centrifugation. Cells were isolated and then analyzed with flow cytometry to determine the yields of total SVF cells and ASCs (CD11b-, CD45-, CD34+, CD90+, D7-FIB+). Differences in ASC and total SVF yields were assessed with one-way analysis of variance. Differentiation experiments were performed to confirm the multilineage potential of cultured SVF cells. RESULTS: Compared with Coleman's technique without centrifugation, direct excision yielded significantly more ASCs (P < .001) and total SVF cells (P = .007); liposuction yielded significantly fewer ASCs (P < .001) and total SVF cells (P < .05); and Coleman's technique with centrifugation yielded significantly more total SVF cells (P < .005), but not ASCs. The total number of SVF cells in fat harvested from the abdomen was significantly larger than the number in fat harvested from the flank or axilla (P < .05). Cultured SVF cells differentiated to adipocytes, osteocytes, and chondrocytes. CONCLUSIONS: Adipose tissue harvested from the abdomen through direct excision or Coleman's technique with centrifugation was found to yield the most SVF cells and ASCs. PMID- 25792002 TI - Management of a Pediatric Snake Envenomation After Presentation With a Tight Tourniquet. AB - We describe an illustrative case of pediatric snake envenomation presenting with a tightly wound tourniquet. A 10-year-old boy presented after a snake bite to the right calf. A tourniquet was in place just below the right knee. The species of snake was unknown. The patient was hemodynamically stable, but the entirety of the right leg distal to the tourniquet was discolored. Over concern for a potential venom bolus effect upon tourniquet removal, the decision was made to start a crotaline Fab antivenom infusion and gradually loosen the tourniquet. The patient tolerated the infusion and removal of the tourniquet without signs of anaphylaxis or decompensation. Dynamic improvements were observed in the right leg and wound site that appeared to be the result of vascular congestion. Tourniquets are generally not recommended for snakebites; however, if a tourniquet is already placed, we avoid removal until prepared to manage acute toxicity or immediate hypersensitivity. PMID- 25792003 TI - EPAS1 Gene Polymorphisms Are Associated With High Altitude Polycythemia in Tibetans at the Qinghai-Tibetan Plateau. AB - OBJECTIVE: To test the hypothesis that the polymorphisms in the EPAS1 gene are associated with the susceptibility to high altitude polycythemia (HAPC) in Tibetans at the Qinghai-Tibetan Plateau. METHODS: We enrolled 63 Tibetan HAPC patients and 131 matched healthy Tibetans as a control group, from the Yushu area in Qinghai where the altitude is greater than 3500 m. Eight single-nucleotide polymorphisms (SNPs) of the EPAS1 gene, including rs12619696, rs13420857, rs2881504, rs4953388, rs13419896, rs4953354, rs10187368, and rs7587138, were genotyped by the Sequenom MassARRAY SNP assay. RESULTS: The frequencies of the G allele of EPAS1 SNP rs13419896 were significantly higher in the HAPC group than in the control group (P < .05). Moreover, the A alleles of rs12619696 and rs4953354 were prevalent in the HAPC group, and their counterpart homozygotes were prevalent in the normal Tibetan group (P < .05). CONCLUSIONS: Compared with normal Tibetans, Tibetans with HAPC are maladapted and have a different haplotype in EPAS1 SNPs rs12619696, rs13419896, and rs4953354. PMID- 25792004 TI - Post-operative stimulated thyroglobulin and neck ultrasound as personalized criteria for risk stratification and radioactive iodine selection in low- and intermediate-risk papillary thyroid cancer. AB - The purpose of this study was to demonstrate the utility of a personalized risk stratification and radioactive iodine (RAI) selection protocol (PRSP) using post operative stimulated thyroglobulin (Stim-Tg) and neck ultrasound in low- and intermediate-risk papillary thyroid carcinoma (PTC) patients. Patients with PTC tumors >=1 cm were prospectively followed after total thyroidectomy and selective therapeutic central compartment neck dissection. Low/intermediate risk was defined as PTC confined to the thyroid or central (level VI) lymph nodes. Stim-Tg and neck ultrasound were performed approximately 3 months after surgery and used to guide RAI selection. Patients with Stim-Tg < 1 ug/L did not receive RAI, while those with Stim-Tg >5 ug/L routinely did. Those with Stim-Tg 1-5 ug/L received RAI on the basis of several clinical risk factors. Patients were followed for >6 years with serial neck ultrasound and basal/stimulated thyroglobulin. Among the 129 patients, 84 (65 %) had undetectable Stim-Tg after initial surgery, 40 (31 %) had Stim-Tg of 1-5 ug/L, and 5 (4 %) had Stim-Tg >5 ug/L. RAI was administered to 8 (20 %) patients with Stim-Tg 1-5 ug/L and 5 (100 %) with Stim-Tg >5 ug/L. Using this approach, RAI therapy was avoided in 17/20 (85 %) patients with tumors >4 cm, in 72/81 (89 %) patients older than 45 years, and in 6/9 (67 %) patients with central lymph node involvement. To date, 116 (90 %) patients in this cohort have not received RAI therapy with no evidence of residual/recurrent disease, whereas among the 13 patients who received RAI, 1 (8 %) had pathologic residual/recurrence disease. Using the proposed PRSP, RAI can be avoided in the majority of low/intermediate-risk PTC patients. Moreover, traditional risk factors considered to favor RAI treatment were not always concordant with the PRSP and may lead to overtreatment. PMID- 25792005 TI - Improved precision of exposure-response relationships by optimal dose-selection. Examples from studies of receptor occupancy using PET and dose finding for neuropathic pain treatment. AB - An understanding of the relationship between drug exposure and response is a fundamental basis for any dosing recommendation. We investigate optimal dose selection for two different types of studies, a receptor occupancy study assessed by positron emission tomography (PET) and a dose-finding study in neuropathic pain treatment. For the PET-study, an inhibitory E-max model describes the relationship between drug exposure and displacement of a radioligand from specific receptors in the brain. The model has a mechanistic basis in the law of mass action and the affinity parameter (Ki PL ) is of primary interest. For optimization of the neuropathic pain study, the model is empirical and the exposure response curve itself is of primary interest. An alternative parameterization of the sigmoid Emax model was therefore used where the plasma concentration corresponding to the minimum relevant efficacy was estimated as a parameter. Optimal design methodology was applied using the D-optimal criterion as well as the Ds-optimal criterion where parameters of interest were defined. For the PET-study it was shown that the precision of Ki PL can be improved by inclusion of brain regions with both high and low receptor density and that the need for high doses is reduced when a brain region with low receptor density is included in the analysis. In the case of the neuropathic pain study it was shown that a Ds-optimal study design using the reparameterized Emax model can improve the precision in the minimum effective dose compared to a D-optimal design. PMID- 25792006 TI - Underactive and overactive bladders are related to motor function and quality of life in Parkinson's disease. AB - AIM OF THE STUDY: Overactive bladder occurs in up to 70% and underactive bladder in up to 50% of patients with Parkinson's disease (PD), which is thought to reflect an altered frontal-basal ganglia circuit. However, it is not clear how bladder disorder is related to motor function and to quality of life (QOL) in PD. We studied these relationships by conducting multiple regression (MR) and bivariate correlation (BV) statistical analyses. METHODS: We recruited 58 PD patients, irrespective of the presence of bladder disorder: 35 men and 23 women of mean age 66.8 years, mean duration of the disease 5.4 years, and median score of Hoehn-Yahr stage 3. We administered a bladder questionnaire including two major types of lower urinary tract symptoms, 'overactive bladder (OAB)' and 'voiding difficulty,' in addition to a QOL index and a pressure-flow urodynamic study to detect detrusor overactivity (DO) during filling; and detrusor weakness, outlet obstruction, and post-void residuals (PVR) during voiding. We analyzed the results using the MR and BV methods. RESULTS: (1) Motor impairment (by HY grades) was significantly related to detrusor weakness (P < 0.05 MR); voiding difficulty, OAB (P < 0.05 BV) (by de novo, levodopa honeymoon, and wearing-off); and voiding difficulty (P < 0.05 MR). (2) Bladder QOL was significantly related to OAB, increased bladder sensation (P < 0.05 MR) and voiding difficulty (P < 0.05 BV). (3) Male gender was significantly related to outlet obstruction, DO (P < 0.05 MR). (4) Age was significantly related to DO and PVR (P < 0.05 MR). Disease duration was significantly related to OAB (P < 0.05 MR). CONCLUSION: From these results, detrusor weakness (relevant to motor impairment) and OAB (relevant to bladder QOL) are thought to be fundamental in PD. In contrast to the mechanism of OAB, the mechanism of detrusor weakness in PD remains unclear and warrants further exploration. PMID- 25792008 TI - NMDA and GABA receptors as potential targets in cough hypersensitivity syndrome. AB - Chronic cough is a common symptom that can be difficult to treat. It is proposed to be part of a cough hypersensitivity syndrome characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure. Upper airway and laryngeal neural dysfunction may also be present. There is evidence that this hypersensitivity may be due to sensory nerve damage caused by inflammatory, infective and allergic factors. Antitussive therapies based on opioid medications are generally not efficacious. Antagonists of N methyl-d-aspartate receptors in the brain stem and use of GABAB receptor agonists such as baclofen acting centrally and possibly peripherally may represent novel therapeutic approaches. PMID- 25792007 TI - Augmenter of liver regeneration attenuates inflammation of renal ischemia/reperfusion injury through the NF-kappa B pathway in rats. AB - PURPOSE: The effects of augmenter of liver regeneration (ALR) on the acute kidney injury (AKI) rats were investigated by measuring the inflammatory response associated with transcription factor nuclear factory (NF-kappaB) pathway. METHODS: The model of AKI rats was established by occluded the renal pedicles for 60 min and then released. After that, animals were treated with ALR (100 or 200 MUg/kg). All rats were killed at different time points (24, 48, 72 h). Renal function and kidney histological changes were measured. The apoptosis of tubular cells was evaluated by TdT-mediated dUTP nick end labeling assay. Cytokines and chemokines were assessed by immunohistochemistry, enzyme-linked immunosorbent assay and real-time polymerase chain reaction (RT-PCR). The NF-kappaB p65 protein was analyzed by immunohistochemistry and RT-PCR, respectively. RESULTS: Ischemia reperfusion induced tubular cells necrosis and apoptosis, and ALR can significantly reduce this damages. The productions of MCP-1, IL-1beta and IL-6 were lower in the group of ALR treatment, especially in the high-dose group. The inflammatory infiltrates were lower in the rats with administration of ALR. ALR mediated the level of cytokines and chemokines through inhibited the activation of NF-kappaB. CONCLUSION: ALR can improve renal function and inhibit the expression of inflammatory factors. This protects against renal ischemia reperfusion injury, which may be associated with preventing NF-kappaB activation in rats. PMID- 25792009 TI - A prognostic index model to predict the clinical outcomes for advanced pancreatic cancer patients following palliative chemotherapy. AB - PURPOSE: To establish a prognostic index model for advanced pancreatic cancer patients receiving palliative chemotherapy based on clinical variables. METHODS: The clinical data of 118 patients with advanced pancreatic cancer who received palliative chemotherapy between January 2006 and August 2013 in our center were retrospectively analyzed. Prognostic factors for overall survival were identified using Cox proportional hazards model. A prognostic index model was established by these pretreatment factors to predict prognosis. Kaplan-Meier estimation and log rank test were performed to compare the overall survival difference between low risk and high-risk group of patients. RESULTS: Median overall survival time for all patients was 8.8 months [95% confidence interval (CI) 7.0-10.6 months]. Multivariate analysis identified ECOG score = 2 (hazard ratio 2.03; 95% CI 1.07 3.85; P = 0.030), CA19-9 levels of >=1000 U/mL (hazard ratio 2.07; 95% CI 1.09 3.92; P = 0.026), and CRP levels of >=5 mg/L (hazard ratio 2.05; 95% CI 1.06 3.96; P = 0.033) as independent poor prognostic factors for overall survival. For the three factors, ECOG score = 2, CA19-9 levels of >=1000 U/mL, and CRP levels of >=5 mg/L were allocated 1 point each. There were 84 (71.2%) patients allocated to low-risk group with total score 0-1 point, and 34 (28.8%) patients were categorized as high-risk group with total scores 2-3 points. The median overall survival for low-risk group and high-risk group was 9.9 months (95% CI 6.8-13.0) and 5.3 months (95% CI 4.1-6.5), respectively (hazard ratio 0.27; 95 % CI 0.14 0.52; P < 0.001). The estimated 1-year survival rates for low-risk group and high risk group were 40.5 and 5.9%, respectively (P < 0.05). CONCLUSIONS: A novel prognostic index model based on three clinical parameters was established to predict the prognosis of patients with advanced pancreatic cancer receiving palliative chemotherapy. PMID- 25792010 TI - Naturally occurring hepatitis B virus surface antigen mutant variants in Malaysian blood donors and vaccinees. AB - Hepatitis B virus surface mutants are of enormous importance because they are capable of escaping detection by serology and can infect both vaccinated and unvaccinated populations, thus putting the whole population at risk. This study aimed to detect and characterise hepatitis B-escaped mutants among blood donors and vaccinees. One thousand serum samples were collected for this study from blood donors and vaccinees. Hepatitis B surface antigen, antibodies and core antibodies were tested using a commercial enzyme-linked immunosorbent assay (ELISA) kit. DNA detection was performed via nested polymerase chain reaction (PCR), and the S gene was sequenced and analysed using bioinformatics. Of the 1,000 samples that were screened, 5.5% (55/1,000) were found to be HBsAg-negative and anti-HBc- and HBV DNA-positive. All 55 isolates were found to belong to genotype B. Several mutations were found across all the sequences from synonymous and non-synonymous mutations, with the most nucleotide mutations occurring at position 342, where adenine was replaced by guanine, and cytosine at position 46 was replaced by adenine in 96.4% and 98% of the isolates, respectively. Mutation at position 16 of the amino acid sequence was found to be common to all the Malaysian isolates, with 85.7% of the mutations occurring outside the major hydrophilic region. This study revealed a prevalence of 5.5% for hepatitis B escaped mutations among blood donors and vaccinated undergraduates, with the most common mutation being found at position 16, where glutamine was substituted with lysine. PMID- 25792011 TI - CD4/CD8 double-negative T-cell lymphoma: a variant of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma? PMID- 25792012 TI - In vitro evaluation of the antiviral properties of Shilajit and investigation of its mechanisms of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shilajit, a herbomineral substance exuded from rocks in steep mountainous regions, has been used for thousands of years by the Indian Ayurvedic and Siddha systems of traditional medicine to relieve ailments and enhance quality of life. Although a large number of therapeutic properties have been ascribed to Shilajit, its therapeutic potential is still largely unexplored by modern research and many of its claimed bioactivities lack scientific validation. The present study was undertaken to investigate the antiviral activity of Shilajit against a panel of viruses including herpes simplex type 1 and 2 (HSV-1, HSV-2), human cytomegalovirus (HCMV), human respiratory syncytial virus (RSV), human rotavirus (HRV), and vesicular stomatitis virus (VSV). MATERIALS AND METHODS: The antiviral activity of Shilajit was assayed in vitro by plaque reduction and virus yield assays and the major mechanism of action was investigated by virucidal and time-of-addition assays. RESULTS: Shilajit exhibited a dose-dependent inhibitory activity against HSV1, HSV2, HCMV, and RSV infectivity in vitro (EC50 values: 31.08MUg/ml, 12.85MUg/ml, 34.54MUg/ml, and 30.35MUg/ml, respectively), but was inactive against HRV and VSV. Humic acid, a constituent of Shilajit, displayed the same spectrum of activity. Partial virus inactivation and interference with virus attachment were both found to contribute to the antiviral activity of Shilajit. CONCLUSIONS: The results of the present study demonstrate that Shilajit is endowed with broad, yet specific, antiviral activity in vitro and constitutes a natural source of antiviral substances. Further work remains to be done to assess its efficacy in vivo. PMID- 25792013 TI - Isolating the metabolic pathways involved in the hepatoprotective effect of Muntingia calabura against CCl4-induced liver injury using LC/MS Q-TOF. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Muntingia calabura L. has been used in Southeast Asia and tropical America as antipyretic, antiseptic, analgesic, antispasmodic and liver tonic. This study aims to determine the acute toxicity and the metabolic pathways involved in the hepatoprotective mechanism of M. calabura. MATERIALS AND METHODS: CCl4-induced hepatotoxic rat model was developed and a dose dependent effect of M. calabura was conducted. Body weight, food and water consumption were measured every day and rats were sacrificed to collect the serum samples at the end of the 10-days treatment. Liquid chromatography-mass spectrometry quadrapole time of flight (LC/MS-QTOF) combined with principal component analysis (PCA) were used to determine differentially expressed metabolites due to treatment with CCl4 and M. calabura extracts. Metabolomics Pathway Analysis (MetPA) was used for analysis and visualization of pathways involved. RESULTS: Body weight, food and water consumption were significantly decreased and histopathological study revealed steatosis in CCl4-induced rats. PCA score plots show distinct separation in the metabolite profiles of the normal group, CCl4-treated group and extract of M. calabura (MCME) pre-treated groups. Biomarkers network reconstruction using MetPA had identified 2 major pathways which were involved in the protective mechanism of MCME. These include the (i) biosynthesis of the primary bile acid, (ii) metabolism of arachidonic acid. CONCLUSION: This study has successfully isolated 2 major pathways involved in the hepatoprotecive effect of MCME against CCl4-induced liver injury using the LC/MS Q-TOF metabolomics approach. The involvement of archidonic acid and purine metabolism in hepatoprotection has not been reported previously and may provide new therapeutic targets and/or options for the treatment of liver injury. PMID- 25792014 TI - Helicteres sacarolha A. St.- Hil. et al.: gastroprotective and possible mechanism of actions in experimental animals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Helicteres sacarolha A. St.- Hil. et al. popularly known in Brazil as 'semente-de-macaco', is widely employed in the popular medicine in many of parts of Brazil in the alleviation of symptoms of ailments such as peptic ulcer and inflammation. Up to the present, there is no study addressing the gastroprotective activity of the hydroethanolic extract of H. sacarolha and its possible mechanism of actions. MATERIALS AND METHODS: The hydroethanolic (70%) extract of H. sacarolha (HEHs) was obtained by maceration. The gastroprotective activity was assessed using gastric ulcer models induced by acidified ethanol, piroxicam, and water restraint stress in mice and rats at doses of 20, 50 and 250mg/kg p.o. Mechanistic studies involved the antisecretory assay evaluated with pylorus ligation in rats and pre-treatments with appropriate antagonists/inhibitors such as yohimbine, glibenclamide, indomethacin and l-NAME, effect on catalase and myeloperoxidase activities and gastric mucus determination using acidified ethanol- induced ulcer in mice. RESULTS: HEHs at all doses tested demonstrated potent gastroprotective activities in the acute ulcer models. The gastroprotective activity of HEHs was attenuated by pre-treatments with yohimbine, glibenclamide, indomethacin and l-NAME. HEHs effectively reduced basal gastric juice production without any effect on the free and total acidity. The gastroprotective action of HEHs involved increasing the antioxidant enzyme catalase and mucus secretion and inhibition of neutrophyl infiltration as reflected by the reduction in the myeloperoxidase activity. CONCLUSION: The results of this study gave a scientific support for the popular use of the leaves of H. sacarolha in the treatment of gastric ulcers and that it has a multi targeted action. PMID- 25792015 TI - Antiplasmodial and anti-inflammatory effects of an antimalarial remedy from the Wayana Amerindians, French Guiana: takamalaime (Psidium acutangulum Mart. ex DC., Myrtaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Field investigations highlighted the use of Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh), a small tree used by the Wayana Amerindians in Twenke-Taluhwen and Antecume-Pata, French Guiana, for the treatment of malaria, and administered either orally in the form of a decoction or applied externally over the whole body. This use appears limited to the Wayana cultural group in French Guiana and has never been reported anywhere else. Our goal was to evaluate the antimalarial and anti-inflammatory activities of a P. acutangulum decoction to explain the good reputation of this remedy. MATERIALS AND METHODS: Interviews with the Wayana inhabitants of Twenke-Taluhwen and Antecume-Pata were conducted within the TRAMAZ project according to the TRAMIL methodology, which is based on a quantitative and qualitative analysis of medicinal plant uses. A decoction of dried aerial parts of P. acutangulum was prepared in consistency with the Wayana recipe. In vitro antiplasmodial assays were performed on chloroquine-resistant FcB1 ([(3)H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains and on chloroquine sensitive NF54 ([(3)H]-hypoxanthine bioassay) P. falciparum strain. In vitro anti-inflammatory activity (IL-1beta, IL-6, IL-8, TNFalpha) was evaluated on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the decoction was measured on L6 mammalian cells, PBMCs, and RAW cells. A preliminary evaluation of the in vivo antimalarial activity of the decoction, administered orally twice daily, was assessed by the classical four-day suppressive test against P. berghei NK65 in mice. RESULTS: The decoction displayed a good antiplasmodial activity in vitro against the three tested strains, regardless to the bioassay used, with IC50 values of 3.3ug/mL and 10.3ug/mL against P. falciparum FcB1 and NF54, respectively and 19.0ug/mL against P. falciparum 7G8. It also exhibited significant anti-inflammatory activity in vitro in a dose dependent manner. At a concentration of 50ug/mL, the decoction inhibited the secretion of the following pro-inflammatory cytokines: TNFalpha ( 18%), IL-1beta (-58%), IL-6 (-32%), IL-8 (-21%). It also exhibited a mild NO secretion inhibition (-13%) at the same concentration. The decoction was non cytotoxic against L6 cells (IC50>100ug/mL), RAW cells and PBMC. In vivo, 150uL of the decoction given orally twice a day (equivalent to 350mg/kg/day of dried extract) inhibited 39.7% average parasite growth, with more than 50% of inhibition in three mice over five. The absence of response for the two remaining mice, however, induced a strong standard deviation. CONCLUSIONS: This study highlighted the in vitro antiplasmodial activity of the decoction of P. acutangulum aerial parts, used by Wayana Amerindians from the Upper-Maroni in French Guiana in case of malaria. Its antioxidant and anti-inflammatory potential, which may help to explain its use against this disease, was demonstrated using models of artificially stimulated cells. PMID- 25792016 TI - The exposure to Trichilia catigua (catuaba) crude extract impairs fertility of adult female rats but does not cause reproductive damage to male offspring. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua is broadly used in folk medicine due to its mental and physical tonic activities and stimulant effects. In animal models, its antidepressant-like effects have been associated with the dopaminergic (DA) system modulation, which has an important role on maternal behavior and male offspring reproductive development. AIM OF THE STUDY: Since little is known about the adverse effects of the exposure to T. catigua crude extract (CAT) in rats, specially regarding maternal homeostasis and offspring development, the aim of the present study was to evaluate whether CAT exposure may influence maternal toxicity parameters and behavior or disrupt male offspring physical and reproductive development. MATERIAL AND METHODS: Dams were treated daily (by gavage) with 400mg/kg of CAT or vehicle (control=CTR) throughout pregnancy and lactation. Fertility and maternal behavior tests were conducted in dams. Male offspring reproductive and behavioral parameters were analyzed. RESULTS: Dams exposed to CAT showed increased pre- and post-implantation losses rates when compared to CTR group. No significant changes regarding maternal behavior or male offspring parameters were observed. CONCLUSION: In conclusion, maternal exposure to CAT interfered with implantation during the initial phases of pregnancy but did not induce changes on maternal behavior or male offspring reproductive and behavioral parameters. PMID- 25792018 TI - Effects and molecular mechanisms of the antidiabetic fraction of Acorus calamus L. on GLP-1 expression and secretion in vivo and in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The radix of Acorus calamus L. (AC) is widely used in diabetes therapies in traditional folk medicine from America and Indonesia, and we have previously reported that the ethyl acetate fraction of AC (ACE) acts as an antidiabetic through insulin sensitizing, insulin releasing and alpha-glucosidase inhibitory activities. The present study is designed to investigate the effects and molecular mechanisms of ACE on glucagon-like peptide 1 (GLP-1) expression and secretion related to its hypoglycemic effects. MATERIALS AND METHODS: The hypoglycemic effect of ACE (100mg/kg, i.g.) was confirmed by testing blood glucose levels or via oral glucose tolerance test (OGTT) in streptozotocin (STZ) induced hyperglycemic mice, db/db diabetic mice and diet induced obese (DIO) mice. Plasma insulin, GLP-1 levels and intestinal GLP-1 related gene expression were determined in STZ-induced and db/db diabetic mice. The in vitro effects of ACE (12.5MUg/ml) on the expression and secretion of GLP-1 were detected in NCI-H716 intestinal L-cells, and the correlation between ACE and molecules in the Wnt signaling pathway was further explored. RESULTS: ACE (100mg/kg) significantly lowered fasting blood glucose in STZ-induced and db/db diabetic mice and improved the OGTT in DIO mice. Insulin releasing and islet protective effects, along with the increased secretion of GLP-1, were observed. The expression of proglucagon gene (gcg) and post-translational processing gene prohormone convertase 3 (pc3) and the GLP-1 content in the culture medium of L cells notably increased after the ACE treatment (12.5MUg/ml). At the same time, beta-catenin nuclear translocation occurred, and its downstream protein cyclin D1 was activated, showing the involvement of Wnt signaling. CONCLUSIONS: ACE might activate Wnt signaling to increase the gene expression of gcg and pc3 and exert incretin effects, including insulinotropic and islet protection, to lower blood glucose levels via elevated GLP-1 secretion either directly or indirectly. PMID- 25792017 TI - Saucerneol D inhibits dendritic cell activation by inducing heme oxygenase-1, but not by directly inhibiting toll-like receptor 4 signaling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Saururus chinensis is a medicinal plant used to treat jaundice, pneumonia, edema, fever, and several inflammatory diseases. Saucerneol D (SD), a lignan constituent of this plant, has antioxidant, anti asthmatic, and anti-inflammatory activities. SD has been previously reported to inhibit the pro-inflammatory responses of RAW264.7 cells and primary mast cells. In this study, we investigated the effect of SD on the functions of dendritic cells (DCs). MATERIALS AND METHODS: SD was isolated from methanol extract of the roots of S. chinensis. Bone marrow-derived DCs were used as target cells. The effects of SD on the following DC functions were examined: surface molecule expression, cytokine expression, migration, allogenic T cell activation, heme oxygenase-1 expression, and Toll-like receptor 4 signaling. RESULTS: In lipopolysaccharide (LPS)-treated DCs, SD inhibited the expression of cell surface molecules (MHC I/II, CD40, CD80, and CD86), the production of inflammatory mediators (nitric oxide, IL-12, IL-1beta, and TNF-alpha), and allogenic T cell activation capacity. SD also inhibited DC migration toward MIP-3beta by down regulating CCR7 expression. SD attenuated LPS-induced activation of NF-kappaB and MAPK signaling in DCs, but did not directly inhibit kinase activities of IRAK1, IRAK4, TAK1, or IKKbeta in enzymatic assays. SD did not inhibit LPS binding to myeloid differentiation protein-2, co-receptor of TLR4. SD increased the production of reactive oxygen species, Nrf-2, and heme oxygenase (HO)-1, which degrades the heme to immunosuppressive carbon monoxide and biliverdin, which may underlie the anti-inflammatory effects in SD-treated DCs. CONCLUSIONS: Taken together, these data suggest that SD suppresses LPS-induced activation of DCs through the induction of HO-1, but not by directly affecting Toll-like receptor 4 signaling. PMID- 25792019 TI - Indigenous knowledge of folk medicines among tribal minorities in Khyber Pakhtunkhwa, northwestern Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mapping ethnomedicinal plants and associated indigenous knowledge of folk medicines can provide a comprehensive overview of individual herbs employed in health care. Reliance on medicinal plants in remote parts of northern Pakistan is high, especially among women, but no research has investigated specifically which plants are used. This study investigated indigenous knowledge of folk medicines among tribal minorities in selected sites in upper Swat, Buner and Chitral Districts in Khyber Pakhtunkhwa Province. MATERIALS AND METHODS: Interviews were conducted with gender-specific focus groups using questionnaires and standardized data sheets, followed by forest walks in each of the visited areas. General medicinal herb use, preparations, storage, marketing and collection habits for each gender group were ascertained from the questionnaires. RESULTS: In total 168 women and 390 men were interviewed and provided information on 127 different shared medicinal species. Species use consensus among the informants ranged from 2.3% to 83.3%, with Cynodon dactylon, Avena sativa, Celtis australis, Datura stramonium, Solanum nigrum, Skimmia laureola, Spiraea nervosa, Ziziphus jujuba, Rumex hastatus, Plantago lanceolata, Lathyrus aphaca and Ficus palmata having the highest reported consensus. The survey also revealed that a number of medicinal species were exploited by the community for both marketing and personal use, and many of these species were reported as being rare, vulnerable or even endangered. CONCLUSIONS: The results revealed that women in all the three districts were important custodians of medicinal plant knowledge, but elder women in general and the women from Buner district in particular had a superior understanding of folk medicine. The forest walks revealed that women's traditional medicinal knowledge was based on a more limited diversity of plant species. People in tribal communities have an expressed interest in learning efficient techniques for medicinal plant collection, preparation, storage and cultivation advice, and to learn more about the potential of marketing medicinal herbs and ways to reach local market centers. Education and awareness were considered to be essential for improved health care and successful marketing. PMID- 25792020 TI - Maternal plasma RNA sequencing. AB - This review discusses the question: which steps are essential or need to be optimized so that maternal plasma RNA sequencing for pre-eclampsia and related syndromes will become as specific and sensitive as maternal plasma DNA sequencing for trisomy? PMID- 25792021 TI - Soil properties discriminating Araucaria forests with different disturbance levels. AB - Soil biological, chemical, and physical properties can be important for monitoring soil quality under one of the most spectacular vegetation formation on Atlantic Forest Biome, the Araucaria Forest. Our aim was to identify a set of soil variables capable of discriminating between disturbed, reforested, and native Araucaria forest soils such that these variables could be used to monitor forest recovery and maintenance. Soil samples were collected at dry and rainy season under the three forest types in two state parks at Sao Paulo State, Brazil. Soil biological, chemical, and physical properties were evaluated to verify their potential to differentiate the forest types, and discriminant analysis was performed to identify the variables that most contribute to the differentiation. Most of physical and chemical variables were sensitive to forest disturbance level, but few biological variables were significantly different when comparing native, reforested, and disturbed forests. Despite more than 20 years following reforestation, the reforested soils were chemically and biologically distinct from native and disturbed forest soils, mainly because of the greater acidity and Al3+ content of reforested soil. Disturbed soils, in contrast, were coarser in texture and contained greater concentrations of extractable P. Although biological properties are generally highly sensitive to disturbance and amelioration efforts, the most important soil variables to discriminate forest types in both seasons included Al3+, Mg2+, P, and sand, and only one microbial attribute: the NO2- oxidizers. Therefore, these five variables were the best candidates, of the variables we employed, for monitoring Araucaria forest disturbance and recovery. PMID- 25792022 TI - Assessing threshold values for eutrophication management using Bayesian method in Yuqiao Reservoir, North China. AB - The eutrophication problem of drinking water source is directly related to the security of urban water supplication, and phosphorus has been proved as an important element to the water quality of the most northern hemisphere lakes and reservoirs. In the paper, 15-year monitoring records (1990~2004) of Yuqiao Reservoir were used to model the changing trend of the total phosphorus (TP), analyze the uncertainty of nutrient parameters, and estimate the threshold of eutrophication management at a specific water quality goal by the application of Bayesian method through chemical material balance (CMB) model. The results revealed that Yuqiao Reservoir was a P-controlled water ecosystem, and the inner concentration of TP in the reservoir was significantly correlated with TP loading concentration, hydraulic retention coefficient, and bottom water dissolved oxygen concentration. In the case, the goal of water quality for TP in the reservoir was set to be 0.05 mg L(-1) (the third level of national surface water standard for reservoirs according to GB3838-2002), management measures could be taken to improve water quality in reservoir through controlling the highest inflow phosphorus concentration (0.15~0.21 mg L(-1)) and the lowest DO concentration (3.76~5.59 mg L(-1)) to the threshold. Inverse method was applied to evaluate the joint manage measures, and the results revealed that it was a valuable measure to avoid eutrophication by controlling lowest dissolved oxygen concentration and adjusting the inflow and outflow of reservoir. PMID- 25792023 TI - Assessment of toxic interactions between deltamethrin and copper on the fertility and developmental events in the Mediterranean sea urchin, Paracentrotus lividus. AB - Deltamethrin pesticide and copper have intensively been used in agriculture and industrial activities and can finally reach the marine ecosystem at high concentrations affecting the health of organisms. In this study, we assessed under laboratory conditions the toxic interactions between deltamethrin and copper and their effects on the fertility rate, cell mitotic division rate, and embryo developmental events of the sea urchin (Paracentrotus lividus). The exposure of sperm to increasing concentrations of deltamethrin (6.10(-5) and 6.10(-2) MUg/L) and copper (50 and 100 MUg/L) or to their mixture (6.10(-5) MUg/L of deltamethrin and 50 MUg/L of CuSO4) caused a significant alteration on the fertilizing capability of spermatozoids. Concentration-dependent toxic effects on the early cleavage in P. lividus were observed in groups treated with copper, deltamethrin, and their mixture. The kinetics of early divisions was accelerated and the average size of pluteus larvae was decreased under pollutant treatments. Several developmental anomalies were identified in pluteus, including crossed skeletal tips at the hood apex, joined or atrophied arms, and alteration of general larva shape. In conclusion, the sea urchin represents a suitable and sensitive model for testing the toxicity and the effects of deltamethrin pesticide and copper in sea water. In addition, the sensitivity of various end points to studied contaminants, proved their utility in the infield biomonitoring studies. PMID- 25792025 TI - Phytoplankton succession in a tropical freshwater lake, Bhoj Wetland (Bhopal, India): spatial and temporal perspective. AB - Bhoj Wetland is tropical freshwater system in central India "Bhopal" serving the citizens as one of the major source of water since its inception. Understanding the process of phytoplankton variation can be particularly useful in water quality improvement and management decision. In this study, phytoplankton taxonomic composition, temporal and spatial distribution, and diversity along with limnological abiotic characteristics were studied based on monthly sampling from four sampling stations (between May 2005 and April 2006). A total of 4 classes, 68 genera, and 98 species which belong to Chlorophyceae (52 species), Cyanobacteria (24 species), Bacillariophyceae (19 species), and Euglenophyceae (3 species), respectively, were identified. Phytoplankton assemblages were dominated by Cyanobacteria during summer months and were the most abundant. On an annual average scale, the phytoplankton density varied between 0.24*10(4) units/l at station 4 to 0.46*10(4) units/l at station 2, and station 2 represented highest population density. The predominant indices of the most predominant species varied between 0.03 and 0.26. Among physicochemical variables, temperature and total dissolved solids played a key role in phytoplankton growth as represented by statistical linear regression drawn between temperature, total dissolved solids, nitrate, and phytoplankton with R2 values of 0.6, 0.46, and 0.5, respectively. PMID- 25792024 TI - Short-term relationships between emergency hospital admissions for respiratory and cardiovascular diseases and fine particulate air pollution in Beirut, Lebanon. AB - High levels of major outdoor air pollutants have been documented in Lebanon, but their health effects remain unknown. The Beirut Air Pollution and Health Effects study aimed to determine the relationship between short-term variations in ambient concentrations of particulate matter (PM10 and PM2.5) and emergency hospital admissions in the city of Beirut, and whether susceptible groups are more greatly affected. An autoregressive Poisson model was used to evaluate the association between daily concentrations of particulate matter and respiratory and cardiovascular emergency hospital admissions after controlling for confounders. All variables were measured during 1 year from January 2012 to December 2012. Relative risks of admissions for respiratory and cardiovascular diseases were calculated for an increase in 10 MUg.m(-3) of pollutant concentrations. Total respiratory admissions were significantly associated with the levels of PM10 (1.012 [95% CI 1.004-1.02]) per 10 MUg.m(-3) rise in daily mean pollutant concentration for PM10 and 1.016 [95% CI 1.000-1.032] for PM2.5 on the same day. With regard to susceptible groups, total respiratory admissions were associated with PM2.5 and PM10 within the same day in children (relative risk (RR), 1.013 and 1.014; 95% confidence interval, 0.985-1.042 and 1.000-1.029 for PM2.5 and PM10, respectively). Moreover, a nearly significant association was found between particles and total circulatory admissions for adults and elderly groups in the same day. These results are similar to other international studies. Therefore, air pollution control is expected to reduce the number of admissions of these diseases in Lebanon. PMID- 25792026 TI - Simultaneous spectrophotometric determination of Cu2+, Hg2+, and Cd2+ ions using 2-(3-hydroxy-1-methylbut-2-enylideneamino)pyridine-3-ol. AB - New complexes of Cu2+, Hg2+, and Cd2+ with a recently synthesized Schiff base derived from 2-(3-hydroxy-1-methylbut-2-enylideneamino)pyridine-3-ol were applied for their simultaneous determination with artificial neural networks. A new analytical method using principal component-feed forward neural networks (PC FFNNs) and principal component-radial basis function networks (PC-RBFNs) was used. Spectral data was reduced using principal component analysis and subjected to ANNs. The data obtained from synthetic mixtures of metal ions were processed by PC-FFNNs and PC-RBFNs. Performances of the proposed methods were tested with regard to relative standard error of prediction. Limit of detections and limit of quantifications were determined. The results obtained by PC-FFNNs and PC-RBFNs were compared to each other. Under the working conditions, the proposed methods were successfully applied to simultaneous determination of Hg2+, Cu2+, and Cd2+ in different water and soil samples. Concentrations of metal ions in the samples were also determined by flame atomic absorption spectrometry (FAAS) and standard addition method. The amounts of metal ions obtained by the proposed methods were in good agreement with those obtained by FAAS and standard addition method. PMID- 25792027 TI - Phyllodes tumor: review of key imaging characteristics. AB - Phyllodes tumor of the breast is rare and often resembles the more commonly seen fibroadenoma at imaging and histologically. As core biopsy cannot always distinguish the two, assessing radiologic-pathologic concordance is essential to guide appropriate clinical management. We review the imaging characteristics of phyllodes tumor at mammography, ultrasound, and MRI to help the interpreting radiologist be aware of key imaging features that should alert him to the possibility of a phyllodes tumor even if not verified by initial core biopsy. PMID- 25792029 TI - [The influence of minority sociolinguistic context on home support for seniors in a rural devitalized area: the case of Acadieville New Brunswick]. AB - New Brunswick is one of the provinces most affected by the aging of the population. Moreover, aging at home in Francophone minority communities is a major challenge in rural areas. The goal of this paper is to identify the main advantages and disadvantages of aging at home and to expose organizational strategies deployed by seniors and their families in order to promote aging in place. The case study is the method of analysis that we have recommended. Our methodology is based on content analysis of 13 semi-structured interviews with seniors and their children. The results show that family and community support, resourcefulness and resiliency, the practice of leisure activities as well as the living environment are among the principal means used by older adults to promote aging at home. PMID- 25792028 TI - Comparative safety and tolerability of endothelin receptor antagonists in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a condition that leads to progressive right heart failure and death unless recognized and treated early. Endothelin, a potent endogenous vasoconstrictor, has been identified as an important mediator of PAH. Endothelin receptor antagonists (ERAs) have been associated with an improvement in exercise capacity and time to clinical worsening in patients with Group 1 PAH, and three different ERAs are currently approved for use in this population: bosentan, ambrisentan, and macitentan. While all three ERAs are generally well-tolerated, they each have important adverse effects that need to be recognized and monitored. In particular, they may cause anemia, peripheral edema, and mild cardiac, respiratory, neurologic, and gastrointestinal adverse effects to varying degrees. Although bosentan increases a patient's risk of developing liver transaminitis, ambrisentan and macitentan do not appear to confer the same risk of hepatotoxicity at this time. Important drug-drug interactions, particularly involving other drugs metabolized via the cytochrome P450 pathway, are important to recognize when prescribing ERAs. In this review, we provide a brief overview of the current state of knowledge as it relates to the adverse effect profiles, tolerability, and drug-drug interactions of this class of medication as informed by the results of randomized clinical trials, drug surveillance programs, and regulatory agencies. PMID- 25792030 TI - Treatment of industrial effluents in constructed wetlands: challenges, operational strategies and overall performance. AB - The application of constructed wetlands (CWs) has significantly expanded to treatment of various industrial effluents, but knowledge in this field is still insufficiently summarized. This review is accordingly necessary to better understand this state-of-the-art technology for further design development and new ideas. Full-scale cases of CWs for treating various industrial effluents are summarized, and challenges including high organic loading, salinity, extreme pH, and low biodegradability and color are evaluated. Even horizontal flow CWs are widely used because of their passive operation, tolerance to high organic loading, and decolorization capacity, free water surface flow CWs are effective for treating oil field/refinery and milking parlor/cheese making wastewater for settlement of total suspended solids, oil, and grease. Proper pretreatment, inflow dilutions through re-circulated effluent, pH adjustment, plant selection and intensifications in the wetland bed, such as aeration and bioaugmentation, are recommended according to the specific characteristics of industrial effluents. PMID- 25792031 TI - Traumatic tracheal injury in children: a case series supporting conservative management. AB - OBJECTIVES: Injuries to the tracheobronchial region are rare, but have the potential for rapid progression and can become life-threatening. Etiologies of non-penetrating tracheobronchial injuries include blunt cervical trauma, endotracheal intubation, and other iatrogenic causes. Several options for treatment ranging from conservative to surgical exist, but no single treatment has been implemented with consensus. While early surgical repair was once considered the cornerstone of therapy, evidence supporting conservative treatment continues to gain strength. METHODS: All pediatric patients who suffered from non penetrating injuries to the tracheobronchial tree who were treated by the Otolaryngology Service at a tertiary children's hospital from May 2012 through March 2014 were recorded. A total of 8 patients were identified. The cases were collected from the patients treated by the Otolaryngology Department based on retrospective review. The available electronic medical records were reviewed for each patient. Data including type of injury, endoscopic assessment of injury, treatment received, and follow-up were collected. RESULTS: The ages ranged from 2 to 15 years old, with a mean of 9.25 years old. Six of the eight patients had injuries related to endotracheal intubation. Each patient was taken to the operating suite for diagnostic direct laryngoscopy and bronchoscopy, and treated with initial conservative management. All but one of the patients was treated with endotracheal intubation, and the average length of intubation was 11.71 days. All of the injuries healed spontaneously without requiring initial open surgery. Five patients (62.5%) developed some degree of tracheal stenosis. Three patients (37.5%) required further surgery; one received a tracheostomy and two patients required balloon dilation. CONCLUSIONS: This case series is the largest to date documenting the outcomes of conservative treatment of non-penetrating traumatic tracheal injuries in children. By using initial conservative therapy, we were able to avoid open surgical procedures in many of our patients. We believe that this case series provides further support for conservative management for children with tracheobronchial injuries. PMID- 25792032 TI - Unusual case of neonatal hypercalcemia. AB - We present a rare case of neonatal hyperparathyroidism secondary to a homozygous calcium sensing receptor (CASR) mutation, diagnosed by the genetics team. The CASR mutation is a homozygous inactivating mutation at the calcium sensing receptor. Inactivation of the receptor leads to hypercalcemia and activation leads to hypocalcemia. Heterozygous mutations can cause mild forms of asymptomatic hypercalcemia that often run in families. The homozygous mutation causes a rare form of neonatal severe hyperparathyroidism. PMID- 25792033 TI - Hypergravity exposure during gestation modifies the TCRbeta repertoire of newborn mice. AB - During spaceflight, organisms are subjected to mechanical force changes (gravity (G) changes) that affect the immune system. However, gravitational effects on lymphopoiesis have rarely been studied. Consequently, we investigated whether the TCRbeta repertoire, created by V(D)J recombination during T lymphopoiesis, is affected by hypergravity exposure during murine development. To address this question, C57BL/6j mice were mated in a centrifuge so that embryonic development, birth and TCRbeta rearrangements occurred at 2G. Pups were sacrificed at birth, and their thymus used to quantify transcripts coding for factors required for V(D)J recombination and T lymphopoiesis. We also created cDNA mini-libraries of TCRbeta transcripts to study the impact of hypergravity on TCRbeta diversity. Our data show that hypergravity exposure increases the transcription of TCRbeta chains, and of genes whose products are involved in TCR signaling, and affects the V(D)J recombination process. We also observed that ~85% of the TCRbeta repertoire is different between hypergravity and control pups. These data indicate that changing a mechanical force (the gravity) during ontogeny will likely affect host immunity because properties of loops constituting TCR antigen binding sites are modified in hypergravity newborns. The spectrum of peptides recognized by TCR will therefore likely be different. PMID- 25792035 TI - Synthesis, characterization, hydrolase and catecholase activity of a dinuclear iron(III) complex: Catalytic promiscuity. AB - Herein, we report the synthesis and characterization of the new di-iron(III) complex [(bbpmp)(H2O)(Cl)Fe(III)(MU-Ophenoxo)Fe(III)(H2O)Cl)]Cl (1), with the symmetrical ligand 2,6-bis{[(2-hydroxybenzyl)(pyridin-2-yl)methylamino]methyl}-4 methylphenol (H3bbpmp). Complexes 2 with the unsymmetrical ligand H2bpbpmp - {2 [[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl]-6-bis(pyridylmethyl) aminomethyl}-4-methylphenol and 3 with the ligand L(1)=4,11-dimethyl-1,8-bis{2-[N (di-2-pyridylmethyl)amino]ethyl}cyclam were included for comparison purposes. Complex 1 was characterized through elemental analysis, X-ray crystallography, magnetochemistry, electronic spectroscopy, electrochemistry, mass spectrometry and potentiometric titration. The magnetic data show a very weak antiferromagnetic coupling between the two iron centers of the dinuclear complex 1 (J=-0.29cm(-1)). Due to the presence of labile coordination sites in both iron centers the hydrolysis of both the diester model substrate 2,4-BDNPP and DNA was studied in detail. Complex 1 was also able to catalyze the oxidation of the substrate 3,5-di-tert-butylcatechol (3,5-DTBC) to give the corresponding quinone, and thus it can be considered as a catalytically promiscuous system. PMID- 25792034 TI - Calcium, ARMS2 genotype, and Chlamydia pneumoniae infection in early age-related macular degeneration: a multivariate analysis from the Nagahama study. AB - Although various risk factors have been identified for the development of age related macular degeneration (AMD), risk factors of early AMD have been relatively under studied. We aimed to investigate AMD risk factors by evaluating multiple factors in association with large drusen, an important component of AMD, simultaneously. In a community-based cross-sectional survey in Japan, 971 large drusen cases and 3,209 controls were compared for 65 variables, including systemic, environmental, and genetic factors. The association and the effect size of each factor were evaluated with logistic regression analysis using a backward elimination approach. Multivariate analyses identified a significant association in serum calcium level (odds ratio [OR] = 0.932, P = 1.05 * 10(-3)), ARMS2 A69S (rs10490924) genotype (OR = 1.046, P < 0.001), Chlamydia pneumoniae IgG (OR = 1.020, P = 0.0440), and age (OR = 1.013, P < 0.001) for large drusen. Hypocalcemia was observed in 7.2% of large drusen cases and in 5.5% of controls (P = 0.0490). C. pneumoniae infections was more frequent in large drusen cases (56.4%) than in controls (51.7%, P = 0.00956). These results suggest that calcium, ARMS2 genotype, C. pneumonia infection, and age are significant factors in the development of the early stages of AMD. PMID- 25792036 TI - Different pediatric brain tumors are associated with different gene expression profiling. AB - Malignant brain tumors are the most common pediatric solid tumors and are the leading cause of death from childhood cancers. These tumors include several histologic subtypes. Due to the particular properties of brain tumors, such as growth and division, examination of brain tumors and the analysis of results are not simple. Up to date there is a dearth of useful biomarkers that have been validated and clinically implemented for pediatric brain tumors. In order to identify the new genetic alterations we recognized, using microarray dataset, chitinases as new potential biomarkers of CNS tumors. The modulation of chitinases was confirmed also in the different histologic subtypes. Our study revealed that distinct patterns of chitinases expression characterize the diverse histological subtypes. In addition evaluating other lisosomal enzymes such as glycosidases and proteases we found that NEU4, CTBS and GBA2 belonging to glycosidases family and CTSC, CTSK and CTSF belonging to proteases family were differently modulated. Future investigations are needed to be performed before some of these enzymes could finally be used as biomarkers of specific types of CNS neoplasms. PMID- 25792037 TI - Intracranial aneurysms in sickle cell anemia: clinical and imaging findings. AB - BACKGROUND: Cerebral aneurysm formation is one of the cerebrovascular complications of sickle cell disease. OBJECTIVE: To report the clinical and imaging findings of intracerebral aneurysms and their treatment in pediatric and adult patients with sickle cell disease. METHODS: Review of clinical data via chart abstraction and radiologic features at the University of Pennsylvania and Children's Hospital of Philadelphia from 2000 to 2014 and review of the literature since 1942. RESULTS: Nineteen patients with aneurysms (2.7%) were found in 709 imaged patients, including 1.2% of imaged children and 10.8% of adults. A total of 44 aneurysms were detected (52.6% with multiple aneurysms, overall 2.3 per patient), 35 (79.5%) in the anterior circulation and 9 in the posterior circulation (20.4%). Thirty-eight unruptured aneurysms ranging in size from 2 to 6 mm and six ruptured aneurysms ranging in size from 3 to 9 mm in diameter were found. Of the patients with ruptured aneurysms, two were treated by stent-assisted coiling, two by clipping, and one patient with coiling. In the group without a rupture, one patient was treated by coil embolization and one patient with a peripheral middle cerebral artery aneurysm was treated by aneurysmectomy. Three pediatric patients with a previously normal MR angiogram demonstrated new aneurysm formation during the study. CONCLUSIONS: Adult patients with sickle cell disease have a high prevalence of aneurysm formation. Both pediatric and adult patients with sickle cell disease tend to develop multiple aneurysms with frequent involvement of atypical locations, in both anterior and posterior circulations. PMID- 25792038 TI - Towards a new treatment paradigm for ruptured blood blister-like aneurysms of the internal carotid artery? A rapid systematic review. AB - BACKGROUND AND PURPOSE: Owing to their peculiar features and rare occurrence, ruptured blood blister-like aneurysms (BBAs) of the internal carotid artery are challenging by both surgical and endovascular approaches and their proper management is uncertain. We therefore aimed to define the currently optimal treatment of ruptured BBAs in terms of mortality, outcome, rebleeding, and recurrence. METHOD: An in-depth search of electronic databases, gray literature and internet resources for ruptured BBAs was performed and complemented by data retrieval during neurosurgical congresses. Clinical and radiological characteristics, intervention details, outcomes, and the impact factor of the source journal were pooled. RESULTS: The pooled cohort comprised 311 patients. Neither surgical nor endovascular methods had an impact on clinical outcome, aneurysm regrowth, remote bleeding, or complication rate. By contrast, aneurysm clipping was a predictor of intraoperative bleeding (OR 6.5; 95% CI 1.2 to 34.3), and stent-assisted coiling increased the likelihood of a second treatment (OR 4.1; 95% CI 1.3 to 13.1), its conversion to another modality (OR 4.7; 95% CI 1.4 to 16.0), and incomplete aneurysm obliteration (OR 2.6; 95% CI 1.0 to 6.6). Higher impact journals were more likely to publish papers on endovascular techniques, particularly flow-diverter stents. CONCLUSIONS: None of the methods is unequivocally superior. Considering its inefficiency, stent-assisted coiling should be undertaken with caution. A time-delimited systematic review is needed to establish the most accurate treatment for ruptured BBAs. PMID- 25792039 TI - Complete Genome Sequence of Francisella guangzhouensis Strain 08HL01032T, Isolated from Air-Conditioning Systems in China. AB - We present the complete genome sequence of Francisella guangzhouensis strain 08HL01032(T), which consists of one chromosome (1,658,482 bp) and one plasmid (3,045 bp) with G+C contents of 32.0% and 28.7%, respectively. PMID- 25792040 TI - Draft Genome Sequences of 33 Salmonella enterica Clinical and Wildlife Isolates from Chile. AB - Salmonella enterica causes health problem worldwide. The relationships among strains that are from the same serotype but different hosts, countries, and continents remain elusive. Few genome sequences are available from S. enterica isolates from South America. Therefore, we sequenced the genomes of 33 strains from diverse sources isolated in Chile and determined that they were of different serotypes. These genomes will improve phylogenetic analysis of Salmonella strains from Chile and the rest of South America. PMID- 25792041 TI - Draft Genome Sequence of Pseudomonas abietaniphila KF717 (NBRC 110669), Isolated from Biphenyl-Contaminated Soil in Japan. AB - Pseudomonas abietaniphila KF717 utilizes biphenyl as a sole source of carbon and energy and degrades polychlorinated biphenyls (PCBs). We report here the 6,930,016-bp genome sequence of this strain, which contains 6,323 predicted coding sequences (CDSs), including the biphenyl-utilizing bph gene cluster. PMID- 25792042 TI - De novo assembly of a bell pepper endornavirus genome sequence using RNA sequencing data. AB - The genus Endornavirus is a double-stranded RNA virus that infects a wide range of hosts. In this study, we report on the de novo assembly of a bell pepper endornavirus genome sequence by RNA sequencing (RNA-Seq). Our result demonstrates the successful application of RNA-Seq to obtain a complete viral genome sequence from the transcriptome data. PMID- 25792043 TI - Draft Genome Sequences of Six Bordetella hinzii Isolates Acquired from Avian and Mammalian Hosts. AB - Bordetella hinzii is a Gram-negative bacterium known to infect poultry, humans, rabbits, and rodents. It is an opportunistic pathogen in immunocompromised humans, and some strains cause mild to moderate respiratory disease in turkeys. Little is known as to the degree of genetic diversity within the species or the genetic basis for virulence. Here, we report the genome sequences of six isolates of B. hinzii acquired from humans, rabbits, or turkeys. These data provide a framework for refining the population structure of the genus, establishing relationships among genetically distinct isolates, and developing an understanding of the possible virulence mechanisms of the bacterium. PMID- 25792044 TI - Genome Sequence of Bivens Arm Virus, a Tibrovirus Belonging to the Species Tibrogargan virus (Mononegavirales: Rhabdoviridae). AB - The new rhabdoviral genus Tibrovirus currently has two members, Coastal Plains virus and Tibrogargan virus. Here, we report the coding-complete genome sequence of a putative member of this genus, Bivens Arm virus. A genomic comparison reveals Bivens Arm virus to be closely related to, but distinct from, Tibrogargan virus. PMID- 25792045 TI - Complete Genome Sequence of Raoultella ornithinolytica Strain S12, a Lignin Degrading Bacterium Isolated from Forest Soil. AB - We report the complete genome sequence of Raoultella ornithinolytica strain S12, isolated from a soil sample collected from areas bordering rotten wood and wet soil on Mt. Zijin, Nanjing. The complete genome of this bacterium may contribute toward the discovery of efficient lignin-degrading pathways. PMID- 25792046 TI - Genome Sequence of the Solvent-Producing Clostridium beijerinckii Strain 59B, Isolated from Staffordshire Garden Soil. AB - The genome sequence of the solvent-producing, spore-forming, saccharolytic, mesophilic bacterium Clostridium beijerinckii strain 59B, isolated from Staffordshire garden soil, was obtained via a combination of sequencing with the 454 and Illumina platforms. This information will allow for metabolic engineering of a potentially industrially useful strain. PMID- 25792048 TI - The First Papillomavirus Isolated from Vulpes vulpes (VvulPV1) Is Basal to the Gammapapillomavirus Genus. AB - We report the complete genomic sequence of Vulpes vulpes papillomavirus type 1 (VvulPV1), isolated from the hair follicles of a red fox. VvulPV1 does not cluster with other carnivoran papillomaviruses, and is instead a sister taxon to the Gammapapillomavirus genus, thus sustaining the scenario of a biphasic evolution of papillomaviruses. PMID- 25792047 TI - Draft Genome Sequence of a Highly Virulent Strain of the Plant Pathogen Dickeya solani, IFB0099. AB - Dickeya solani is an important bacterial pathogen of potato cultivars in Europe. Here, we present the draft genome of D. solani strain IFB0099 isolated from potato in Poland that shows a high level of pectinolytic activity and a high virulence. This genome sequence is 5,094,121 bp and contains 4,365 protein-coding sequences. PMID- 25792049 TI - Draft Genome Sequence of Lactococcus lactis subsp. lactis JCM 5805T, a Strain That Induces Plasmacytoid Dendritic Cell Activation. AB - Lactococcus lactis subsp. lactis JCM 5805(T) is a dairy lactic acid bacterium that induces plasmacytoid dendritic cell (pDC) activation. Here, we report the 2.55-Mb draft genome and annotation of Lactococcus lactis JCM 5805(T). This genome information will provide further insights into the mechanisms underlying the immunomodulatory function of this strain. PMID- 25792050 TI - Complete Genome Sequence of Terribacillus aidingensis Strain MP602, a Moderately Halophilic Bacterium Isolated from Cryptomeria fortunei in Tianmu Mountain in China. AB - Terribacillus aidingensis strain MP602, which was isolated from an ancient tree (Cryptomeria forunei) in Tianmu Mountain in China, has antagonistic activity against several certain phytopathogenic fungi. Here, we report the genome sequence of this strain. This is the first complete genome report of the Terribacillus genus. PMID- 25792051 TI - Complete Genome Sequence of Halophilic Yeast Meyerozyma caribbica MG20W Isolated from Rhizosphere Soil. AB - Meyerozyma caribbica MG20W was originally isolated from rhizosphere soil on reclaimed land in the Republic of Korea. We describe herein the 10.64-Mbp-long genome sequence of M. caribbica MG20W, which exhibits high salt resistance. PMID- 25792052 TI - Emergence of new insect-restrictive viruses in the Amazon region. AB - The complete genome was determined for 12 viruses isolated from 8 different pools of mosquitoes (Culex sp. and Psorophora ferox) collected at Brejeira farm, Canaan dos Carajas, Para state in northern Brazil. Eight of the viruses were distantly related to Piura virus, hereafter designated as Brejeira virus; the other 4 were similar to Wallerfield virus. PMID- 25792054 TI - Genome Assembly of Schlumbergera Virus X Infecting Prickly Pear (Opuntia cochenillifera) in Brazil. AB - Potexviruses frequently infect plants from the family Cactaceae. We report the complete genome sequence of a new Schlumbergera virus X (SchVX) isolate. The genome has 6,615 nucleotides and shares 94% nucleotide identity with SchVX-K11 from Schlumbergera. This is the first sequence of an isolate of SchVX from the genus Opuntia. PMID- 25792053 TI - Draft Genome Sequence of Thauera sp. Strain SWB20, Isolated from a Singapore Wastewater Treatment Facility Using Gel Microdroplets. AB - We report here the genome sequence of Thauera sp. strain SWB20, isolated from a Singaporean wastewater treatment facility using gel microdroplets (GMDs) and single-cell genomics (SCG). This approach provided a single clonal microcolony that was sufficient to obtain a 4.9-Mbp genome assembly of an ecologically relevant Thauera species. PMID- 25792055 TI - Complete Genome Sequence of Escherichia coli Strain BL21. AB - Escherichia coli strain BL21 is one of the widely used bacterial hosts for high level recombinant protein production and for other applications. Here, we present the complete genome sequence of a commercial version of the Escherichia coli BL21 strain. PMID- 25792056 TI - Whole Genome Sequence of the Non-Microcystin-Producing Microcystis aeruginosa Strain NIES-44. AB - Microcystis aeruginosa is a typical algal bloom-forming cyanobacterium. This report describes the whole-genome sequence of a non-microcystin-producing strain of Microcystis aeruginosa, NIES-44, which was isolated from a Japanese lake. PMID- 25792057 TI - Draft Genome Sequence of Pseudomonas fluorescens SRM1, an Isolate from Spoiled Raw Milk. AB - Pseudomonas fluorescens is considered a major milk spoilage organism due to its psychrotrophic nature and ability to produce heat-stable proteases and lipases. Here, we report the draft genome and annotation of P. fluorescens SRM1 isolated from spoiled raw milk and the presence of an operon encoding spoilage enzymes. PMID- 25792058 TI - Complete Genome Sequence of Corynebacterium minutissimum, an Opportunistic Pathogen and the Causative Agent of Erythrasma. AB - Corynebacterium minutissimum was first isolated in 1961 from infection sites of patients presenting with erythrasma, a common cutaneous infection characterized by a rash. Since its discovery, C. minutissimum has been identified as an opportunistic pathogen in immunosuppressed cancer and HIV patients. Here, we report the whole-genome sequence of C. minutissimum. PMID- 25792059 TI - Genome Sequence of Bacillus anthracis Isolated from an Anthrax Burial Site in Pollino National Park, Basilicata Region (Southern Italy). AB - A Bacillus anthracis strain was isolated from a burial-site in Pollino National Park where a bovine died of anthrax and was buried in 2004. We report the first genome sequence of B. anthracis isolated in the Basilicata region (southern Italy), which is the highest risk area of anthrax infection in Italy. PMID- 25792060 TI - Draft Genome Sequence of the Polychlorinated Biphenyl-Degrading Bacterium Pseudomonas putida KF703 (NBRC 110666) Isolated from Biphenyl-Contaminated Soil. AB - Pseudomonas putida KF703 (NBRC 110666) utilizes biphenyl as a sole source of carbon and degrades polychlorinated biphenyls (PCBs). Here, we report the draft genome sequence of the KF703 strain, which provides insight into the molecular mechanisms of adaptation to an environment polluted by aromatic compounds. PMID- 25792061 TI - Draft Genome Sequence of the Polychlorinated Biphenyl-Degrading Bacterium Cupriavidus basilensis KF708 (NBRC 110671) Isolated from Biphenyl-Contaminated Soil. AB - We report the draft genome sequence of Cupriavidus basilensis KF708 (NBRC 110671), which utilizes biphenyl as a sole carbon source and degrades polychlorinated biphenyls (PCBs). The KF708 strain possesses genes for biphenyl catabolism and other genes involved in various aromatic compounds. PMID- 25792062 TI - Draft Genome Sequence of Lactobacillus kunkeei AR114 Isolated from Honey Bee Gut. AB - Lactobacillus kunkeei is a common inhabitant in honey bee gut, being present in several parts of the world. Here, we describe the draft genome of L. kunkeei AR114, an isolate from late foraging season in Norway. PMID- 25792063 TI - Analysis of Pectate Lyase Genes in Dickeya chrysanthemi Strain L11, Isolated from a Recreational Lake in Malaysia: a Draft Genome Sequence Perspective. AB - Dickeya chrysanthemi is well known as a plant pathogen that caused major blackleg in the European potato industry in the 1990s. D. chrysanthemi strain L11 was discovered in a recreational lake in Malaysia. Here, we present its draft genome sequence. PMID- 25792064 TI - Draft Genome Sequence of Xanthomonas sacchari Strain LMG 476. AB - We report the high-quality draft genome sequence of Xanthomonas sacchari strain LMG 476, isolated from sugarcane. The genome comparison of this strain with a previously sequenced X. sacchari strain isolated from a distinct environmental source should provide further insights into the adaptation of this species to different habitats and its evolution. PMID- 25792065 TI - Complete Genome Sequence of the Persistent Listeria monocytogenes Strain R479a. AB - The complete genome sequence of the persistent Listeria monocytogenes strain R479a isolated from smoked salmon in Denmark and belonging to lineage II, serovar 1/2a, and multilocus sequence type 8 (ST8) is presented here. PMID- 25792066 TI - Complete Genome Sequence of Pseudomonas aeruginosa Mucoid Strain FRD1, Isolated from a Cystic Fibrosis Patient. AB - We announce here the complete genome sequence of the Pseudomonas aeruginosa mucoid strain FRD1, isolated from the sputum of a cystic fibrosis patient. The complete genome of P. aeruginosa FRD1 is 6,712,339 bp. This genome will allow comparative genomics to be used to identify genes associated with virulence, especially those involved in chronic pulmonary infections. PMID- 25792067 TI - Whole-Genome Sequence of "Candidatus Liberibacter asiaticus" from a Huanglongbing Affected Citrus Tree in Central Florida. AB - Here, we report the draft genome sequence of "Candidatus Liberibacter asiaticus" strain FL17, isolated from a huanglongbing (HLB)-affected citrus tree in central Florida. The FL17 genome comprised 1,227,253 bp, with a G+C content of 36.5%, 1,175 predicted open reading frames, and 53 RNA genes. PMID- 25792068 TI - Complete Genome Sequence of SS52, a Strain of Escherichia coli O157:H7 Recovered from Supershedder Cattle. AB - Shiga toxin-producing Escherichia coli O157:H7 causes foodborne infections, and cattle are the primary reservoir. Some animals, known as supershedders, excrete orders of magnitude more E. coli O157:H7 in the feces than normal. Here, we report the complete genome sequence of the SS52 supershedder strain of E. coli O157:H7. PMID- 25792070 TI - Election 2015: making sure your voice is heard. PMID- 25792069 TI - Control Beliefs and Risk for Death, Stroke and Myocardial Infarction in Middle aged and Older Adults: An Observational Study. AB - BACKGROUND: Chronic health conditions account for the largest proportion of illness-related mortality and morbidity as well as most of healthcare spending in the USA. Control beliefs may be important for outcomes in individuals with chronic illness. OBJECTIVE: To determine whether control beliefs are associated with the risk for death, incident stroke and incident myocardial infarction (MI), particularly for individuals with diabetes mellitus (DM) and/or hypertension. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 5,662 respondents to the Health and Retirement Study with baseline health, demographic and psychological data in 2006, with no history of previous stroke or MI. MAIN MEASURES: Perceived global control, measured as two dimensions--"constraints" and "mastery"--and health-specific control were self-reported. Event-free survival was measured in years, where "event" was the composite of death, incident stroke and MI. Year of stroke or MI was self-reported; year of death was obtained from respondents' family. KEY RESULTS: Mean baseline age was 66.2 years; 994 (16.7%) had DM and 3,023 (53.4%) hypertension. Overall, 173 (3.1%) suffered incident strokes, 129 (2.3%) had incident MI, and 465 (8.2%) died. There were no significant interactions between control beliefs and baseline DM or hypertension in predicting event-free survival. Elevated adjusted hazard ratios (HRs) were associated with DM (1.33, 95 % CI 1.07-1.67), hypertension (1.31, 95% CI 1.07 1.61) and perceived constraints in the third (1.55, 95% CI 1.12-2.15) and fourth quartiles (1.61, 95% CI 1.14-2.26). Health-specific control scores in the third (HR 0.78, 95% CI 0.59-1.03) and fourth quartiles (HR 0.70, 95% CI 0.53-0.92) were protective, but only the latter category had a statistically significant decreased risk. Combined high perceived constraints and low health-specific control had the highest risk (HR 1.93, 95% CI 1.41-2.64). CONCLUSIONS: Control beliefs were not associated with differential risk for those with DM and/or hypertension, but they predicted significant differences in event-free survival for the general cohort. PMID- 25792071 TI - Alteration in Downstream Hypoxia Gene Signaling in Neonatal Glutathione Peroxidase Overexpressing Mouse Brain after Hypoxia-Ischemia. AB - We have previously shown that glutathione peroxidase (GPx) overexpressing mice (hGPx-tg) have reduced brain injury after neonatal hypoxia-ischemia (HI) as a consequence of reduced hydrogen peroxide accumulation. However, this protection is reversed with hypoxia preconditioning, raising the question of the roles of the genes regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and their transcription products, such as erythropoietin (EPO), in both the initial protection and subsequent reversal of protection. hGPx-tg and their wild-type (WT) littermates underwent the Vannucci procedure of HI brain injury at postnatal day 9 - left carotid artery ligation followed by exposure to 10% oxygen for 50 min. Brain cortices and hippocampi were subsequently collected 0.5, 4 and 24 h later for the determination of protein expression by Western blot for GPx, HIF 1alpha, HIF-2alpha, EPO, EPO receptor, ERK1/2, phospho-ERK1/2, spectrin 145/150 (as a marker of calpain-specific necrotic cell death), and spectrin 120 (as a marker of apoptotic cell death mediated via caspase-3). As expected, the GPx overexpressing mouse cortex had approximately 3 times the GPx expression as WT naive. Also, GPx expression remained higher in the GPx overexpressing brain than WT at all time points after HI (0.5, 4, 24 h). HIF-1alpha was not significantly changed in hGPx-tg as a consequence of HI but decreased in the WT cortex 4 h after HI. HIF-2alpha decreased in the WT hippocampus after HI. EPO was higher in the GPx overexpressing cortex and hippocampus 30 min after HI compared to WT, but the EPO receptor was unchanged by HI. ERK1/2 phosphorylation increased in the hippocampus at 4 h after HI and in the cortex at 24 h after HI in both WT and hGPx-tg. Spectrin 145/150 was increased in the WT cortex at 4 and 24 h after HI, and spectrin 120 increased 24 h after HI, perhaps reflecting greater injury in the WT brain, especially at 24 h when brain injury is more evident. The effect of GPx overexpression does not appear to upregulate the HIF pathway, yet EPO was upregulated, perhaps via ERK. This might explain, in part, why cell death takes a necrotic or apoptotic path. This may also be an explanation for why the GPx overexpressing brain cannot be preconditioned. This information may prove valuable in the development of therapies for neonatal HI brain injury. PMID- 25792072 TI - Neuromuscular correlates of subthalamic stimulation and upper limb freezing in Parkinson's disease. AB - OBJECTIVE: The pathophysiology of deep brain stimulation mechanisms and resistant freezing phenomena in idiopathic Parkinson's disease (iPD) remains incompletely understood. Further studies on the neuromuscular substrates are needed. METHODS: We analyzed 16 patients with advanced iPD and bilateral subthalamic nucleus stimulation, and 13 age- and gender-matched healthy controls. Patients were tested after overnight withdrawal of medication with 'stimulation off' (StimOff) and 'stimulation on' (StimOn). Subjects performed continuous tapping of the right index finger with simultaneous recordings of biomechanical registration, EMG of finger flexors and extensors, and EEG. First, we analyzed EEG and EMG spectral measures comparing StimOff with healthy controls and StimOff with StimOn (irrespective of freezing). Second, we contrasted 'regular (unimpaired) tapping' and 'freezing' resistant to subthalamic neurostimulation as obtained in StimOn. RESULTS: iPD showed increased intermuscular coherence around 8Hz in StimOff that was reduced in StimOn. This 8Hz muscular activity was not coherent to cortical activity. 'Freezing' episodes showed increased muscle activity of finger flexors and extensors at 6-9Hz, and increased cortical activity at 7-11Hz. During transition from regular tapping to 'freezing' the cortical activity first increased over the left sensorimotor area followed by a spread to the left frontal and right parietal areas. CONCLUSIONS: We identified neuromuscular motor network features of subthalamic neurostimulation therapy and resistant upper limb freezing that point to increased low-frequency muscular and cortical activity. SIGNIFICANCE: Together, our findings demonstrate several motor network abnormalities associated with upper limb freezing that may translate into future research on freezing of gait in iPD. PMID- 25792073 TI - A comparison of two methods for estimating 50% of the maximal motor evoked potential. AB - OBJECTIVES: Two commonly-used methods for setting stimulus intensities in transcranial magnetic brain stimulation studies were compared to determine which best approximated a motor evoked potential (MEP) of 50% of the maximal MEP amplitude (SI50); a suprathreshold intensity relative to resting motor threshold (rMT) or adjusting the intensity to evoke an MEP amplitude of 1mV. METHODS: Corticomotor stimulus-response curves and rMT for the right first dorsal interosseous (FDI) muscle of 176 subjects (aged 10-74 years) were retrospectively analysed. RESULTS: Regardless of subject age or sex, SI50 occurred at 127.5 +/- 11.3% rMT. Except in young children, MEPs of 1 mV were significantly smaller than those evoked at SI50. CONCLUSIONS: In the inactive FDI muscle, a stimulus intensity of 127-128% rMT consistently gives the best approximation of SI50 in most subjects, except perhaps young children. SIGNIFICANCE: Setting TMS stimulus intensities relative to rMT provides a less variable inter-subject comparator, with respect to individual differences in corticomotor input-output characteristics, than adjusting the stimulator output to give an absolute MEP magnitude. PMID- 25792074 TI - Static magnetic field can transiently alter the human intracortical inhibitory system. AB - OBJECTIVE: Although recent studies have shown the suppressive effects of static magnetic fields (SMFs) on the human primary motor cortex (M1) possibly due to the deformed neural membrane channels, the effect of the clinical MRI scanner bore has not been studied in the same way. METHODS: We tested whether the MRI scanner itself and compact magnet can alter the M1 function using single- and paired pulse transcranial magnetic stimulation (TMS). RESULTS: We found the transient suppression of the corticospinal pathway in both interventions. In addition, the transient enhancement of the short-latency intracortical inhibition (SICI) was observed immediately after compact magnet stimulation. CONCLUSIONS: The present results suggest that not only the inhomogeneous SMFs induced by a compact magnet but also the homogeneous SMF produced by the MRI scanner bore itself can produce the transient cortical functional change. SIGNIFICANCE: Static magnetic stimulation can modulate the intracortical inhibitory circuit of M1, which might be useful for clinical purposes. PMID- 25792075 TI - Are studies of motor cortex plasticity relevant in human patients with Parkinson's disease? AB - Over the last decade, electrophysiological studies in parkinsonian animals have shown that there are abnormalities of synaptic plasticity in motor areas of cortex and basal ganglia. In humans with Parkinson's disease (PD), cortical plasticity has been widely investigated using transcranial magnetic stimulation. A number of studies have reported abnormal responses to several different conditioning protocols, but their relationship to altered basal ganglia output and dopaminergic loss is still not entirely clear. Thus in the near future it seems unlikely that measures of cortical plasticity could be used as a biomarker of disease severity and progression. In this review we provide an overview on current knowledge of abnormalities of plasticity in PD in the light of recent advances in parkinsonian animal models. Finally we will discuss the relevance of abnormalities of plasticity in the clinical context of PD. PMID- 25792077 TI - Commentary to "Randomized controlled trial of oral glutathione supplementation on body stores of glutathione". PMID- 25792076 TI - Resetting tremor by single and paired transcranial magnetic stimulation in Parkinson's disease and essential tremor. AB - OBJECTIVE: The pathogenesis of tremor in Parkinson's disease (PD) and essential tremor (ET) is not fully understood. This study tested the role of primary motor cortex (M1), supplementary motor area (SMA) and cerebellar cortex on PD and ET tremor by single- and paired-pulse transcranial magnetic stimulation (TMS). METHODS: Ten PD patients with resting tremor, six of them also with postural tremor, and ten ET patients with postural tremor were studied. Randomized single- and paired-pulse TMS with an interstimulus interval of 100 ms were delivered over M1, SMA and cerebellum. TMS effects were evaluated by calculating a tremor resetting index (RI). RESULTS: Single- vs. paired-pulse TMS showed no difference. M1-TMS and SMA-TMS but not by cerebellar TMS induced a significant RI in PD and ET. M1-TMS resulted in a significantly higher RI in PD than ET. Furthermore, M1 TMS in PD but not in ET resulted in a significantly higher RI than SMA-TMS. CONCLUSIONS: Findings suggest a stronger involvement of M1 in resting and postural tremor in PD than postural tremor in ET. SIGNIFICANCE: RI provides a useful marker to explore the differential functional role of M1, SMA and cerebellum in PD vs. ET tremor. PMID- 25792078 TI - Grapefruit juice improves glucose intolerance in streptozotocin-induced diabetes by suppressing hepatic gluconeogenesis. AB - PURPOSE: Hypoglycemic effects of grapefruit juice (GFJ) are widely recognized, but the mechanism(s) by which GFJ lowers blood glucose levels have not previously been investigated. METHODS: Wistar rats [250-300 g body weight (BW)] were divided into eight groups (n = 7). Group 1 animals were orally treated with 3.0 ml/kg BW of distilled water for 60 days, while groups 3, 4, 5, 6 were similarly treated with 3.0 ml/kg BW of GFJ. Groups 4 and 7 as well as 2, 5, 6 and 8 were given 45.0 and 60.0 mg/kg BW intraperitoneal injections streptozotocin, respectively, while groups 2 and 6 animals were additionally injected with insulin (4.0 units/kg, S.C., b.d), respectively. Fasting blood glucose (FBG) and glucose tolerance tests were done. Hepatic glycogen content and glucokinase, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in homogenized liver tissues. RESULTS: Diabetic rats, groups 2 and 4-8 exhibited significantly reduced weight gain but increased polydipsia compared to controls. FBG was significantly increased in diabetic rats compared to controls but were significantly improved in GFJ-treated-compared to non-treated-diabetic rats. Similarly, diabetic rats showed significant glucose intolerance compared to controls which was improved by GFJ treatment. GFJ treatment did not improve fasting plasma insulin in diabetic rats. GFJ treatment significantly elevated glucokinase activity and hepatic glycogen concentrations but suppressed the activities of G6Pase and PEPCK, respectively, in diabetic animals. CONCLUSION: These findings show that GFJ is not insulinotropic but improves glucose intolerance in diabetic rats by suppressing hepatic gluconeogenesis. PMID- 25792079 TI - Relationship between treatment effects on progression-free survival and overall survival in multiple myeloma: a systematic review and meta-analysis of published clinical trial data. AB - BACKGROUND: Demonstrating improved overall survival (OS) with new multiple myeloma (MM) treatments is becoming difficult because of extended survival, so progression-free survival (PFS) is commonly used as a surrogate endpoint for OS. We evaluated PFS as a potential surrogate for OS by examining whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM. METHODS: A systematic literature review identified 21 randomized control trials reporting hazard ratios (HRs) for treatment effects on PFS and OS. Pearson's r estimated the relationship between HRs (HRPFS and HROS), and between log-transformed HRs (log(HRPFS) and log(HROS)). R(2) values were estimated from linear regression models of the HR and the log(HR) relationships. Sensitivity and subgroup analyses examined the robustness of the HR findings. RESULTS: Positive correlations were found between HRPFS and HROS (r = 0.82; p < 0.0001) and between log(HRPFS) and log(HROS) (r = 0.80; p < 0.0001). Linear regression models produced R(2) values of 0.67 and 0.63 when regressing HROS on HRPFS, and log(HROS) on log(HRPFS), respectively. Sensitivity analyses supported the HR findings. CONCLUSION: This analysis provides evidence for a positive association between treatment effects on PFS and OS. Studies involving patient level data are necessary to confirm whether PFS is a valid surrogate for OS in MM. PMID- 25792081 TI - Febrile neutropenia in a metastatic melanoma patient treated with ipilimumab - case report. AB - BACKGROUND: Ipilimumab is a fully human monoclonal antibody (mAb) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab is currently approved in the U.S. and Europe for the treatment of metastatic melanoma in the first- and second-line treatment. Treatment with ipilimumab is linked to immune-related adverse events (irAEs) occurring in the majority of patients. These specific AEs include dermatitis, gastrointestinal disorders (diarrhea, colitis), hepatitis, hypophysitis, hypothyroidism, neuropathy, and iritis/inflammation of the ciliary body. CASE REPORT: We report a case of febrile neutropenia with agranulocytosis in the blood smear of a 35-year-old metastatic melanoma patient treated with ipilimumab 3 mg/kg. CONCLUSION: This AE was probably caused by antineutrophil antibodies associated with ipilimumab treatment. To our knowledge this is the first case report of febrile neutropenia in a metastatic melanoma patient treated with ipilimumab 3 mg/kg. PMID- 25792080 TI - Postoperative intensity-modulated radiotherapy improved survival in lymph node positive or stage III thoracic esophageal squamous cell carcinoma. AB - BACKGROUND: The aim of this study was to retrospectively analyze the effect of postoperative intensity-modulated radiotherapy (IMRT) on recurrence and survival in lymph node-positive or stage III thoracic esophageal squamous cell carcinoma (TESCC) patients, and evaluate its role in TESCC therapy. METHODS: We enrolled 538 patients who underwent radical resection with (S + R) or without (S) postoperative IMRT. The median total postoperative IMRT dose was 60 Gy. The Kaplan-Meier method, log-rank test, and chi-square test were used for survival rate calculation, univariate analysis, and sites of failure analysis, respectively. RESULTS: The 5-year overall survival (OS) and disease-free survival rates were 32.7 and 27.3%, respectively. The 5-year OS rates of lymph node positive S and S + R patients were 28.4 and 38.8%, respectively (p < 0.001). The 5-year OS rates of stage III S and S + R patients were 24.0 and 38.0%, respectively (p = 0.001). Postoperative IMRT resulted in significantly decreased intrathoracic and supraclavicular recurrence, and obviously delayed median local recurrence and systemic metastases. Systemic metastases increased following postoperative IMRT. CONCLUSION: Postoperative IMRT reduces local recurrence and improves survival in lymph node-positive or stage III TESCC patients, providing a rationale for selection criteria for postoperative IMRT in TESCC. PMID- 25792082 TI - Vascular endothelial growth factor-C expression as a biomarker of poor prognosis in esophageal squamous cell carcinoma: a meta-analysis. AB - BACKGROUND: Vascular endothelial growth factor C (VEGF-C) is involved in the development and progression of tumor angio-/lymphangiogenesis. The purpose of this study is to evaluate whether VEGF-C expression is an indicator of aggressiveness and poor prognosis of esophageal squamous cell carcinoma (ESCC). METHOD: A meta-analysis was conducted to investigate the association between VEGF C expression with clinicopathological characteristics and survival of ESCC patients. The dataset was defined by searching PubMed, Embase, Google Scholar, and the Cochrane database for appropriate articles published until April 2014. RESULT: The final analysis was made from 9 studies, including 656 ESCC patients. Positive VEGF-C expression was defined by immunohistochemistry (IHC) or mRNA expression analysis. The results demonstrated that VEGF-C expression was significantly associated with advanced-stage disease (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.37-3.84, P = 0.002), deeper tumor invasion, lymph node metastasis, and lymphatic invasion. The 5-year survival of VEGF-C expression negative patients was found to be better than that of VEGF-C expression-positive patients (OR = 0.35, 95% CI = 0.21-0.58, P < 0.0001). However, there was no significant association between the VEGF-C expression levels and either poorer tumor differentiation or vascular invasion. CONCLUSION: The results of the meta analysis strongly indicate that VEGF-C expression could function as a marker for predicting the aggressiveness and prognosis of ESCC. PMID- 25792083 TI - Warburg effect or reverse Warburg effect? A review of cancer metabolism. AB - Cancer is a major threat to human health. A considerable amount of research has focused on elucidating the nature of cancer from its pathogenesis to treatment and prevention. Tumor cell metabolism has been considered a hallmark of cancer. Cancer cells differ from normal cells through unlimited cell division, and show a greater need for energy for their rapid growth and duplication. Research on glycometabolism, as the key point of energy metabolism, has played a unique role. In the 1920s, Warburg found that cancer cells prefer to produce adenosine triphosphate (ATP) by glycolysis, which is a less efficient pathway compared to oxidative phosphorylation. This striking discovery, called 'the Warburg effect', has influenced and guided the study of the mechanism and treatment of tumors for generations, but its causal relationship with cancer progression is still unclear. Some studies have now shown contradicting evidence and a new hypothesis, the reverse Warburg effect, has been put forward, in which cancer cells produce most of their ATP via glycolysis, even under aerobic conditions. In this review we discuss the new points concerning the energy metabolism of a tumor, as well as the current facts and perspectives. PMID- 25792084 TI - Cytarabine, venous catheter removal, sepsis, diagnosis of malignancy, and takotsubo syndrome. PMID- 25792085 TI - In-line and selective phase separation of medium-chain carboxylic acids using membrane electrolysis. AB - We had extracted n-caproate from bioreactor broth. Here, we introduced in-line membrane electrolysis that utilized a pH gradient between two chambers to transfer the product into undissociated n-caproic acid without chemical addition. Due to the low maximum solubility of this acid, selective phase separation occurred, allowing simple product separation into an oily liquid containing ~90% n-caproic and n-caprylic acid. PMID- 25792086 TI - The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson's disease. AB - BACKGROUND: To investigate the effect of creatine and coenzyme Q10 (CoQ10) combination therapy on mild cognitive impairment (MCI) in Parkinson's disease (PD; PD-MCI) and its influences on plasma phospholipid (PL) levels in PD-MCI. METHODS: The demographic data of 75 PD-MCI patients who enrolled in this collaborative PD study were collected. These patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) III and the Montreal Cognitive Assessment (MoCA). These 75 PD-MCI patients were randomly treated with creatine monohydrate 5 g b.i.d. and CoQ10 100 mg t.i.d. orally or placebo. MoCA evaluation and PL level measurements were performed after 12 and 18 months of treatment. RESULTS: After 12 and 18 months of treatment, the differences in the MoCA scores of the combination therapy and control groups were statistically significant (p < 0.05 at 12 months and p < 0.01 at 18 months), and the plasma PL levels of the combination therapy group were significantly lower than those of the control group (p < 0.01 at 12 months and p < 0.001 at 18 months). CONCLUSIONS: Combination therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients and could lower their plasma PL levels; therefore, this combination therapy may have a neuroprotective function. PMID- 25792087 TI - Methods used in preclinical assessment of anti-Buruli ulcer agents: A global perspective. AB - Buruli ulcer (BU) caused by Mycobacterium ulcerans is the third most common chronic mycobacterial infection in humans. Approximately 5000 cases are reported annually from at least 33 countries around the globe, especially in rural African communities. Even though anti-mycobacterial therapy is often effective for early nodular or ulcerative lesions, surgery is sometimes employed for aiding wound healing and correction of deformities. The usefulness of the antibiotherapy nonetheless is challenged by huge restrictive factors such as high cost, surgical scars and loss of income due to loss of man-hours, and in some instances employment. For these reasons, more effective and safer drugs are urgently needed, and research programs into alternative therapeutics including investigation of natural products should be encouraged. There is the need for appropriate susceptibility testing methods for the evaluation of potency. A number of biological assay methodologies are in current use, ranging from the classical agar and broth dilution assay formats, to radiorespirometric, dye based, and fluorescent/luminescence reporter assays. Mice, rats, armadillo, guinea pigs, monkeys, grass cutters and lizards have been suggested as animal models for Buruli ulcer. This review presents an overview of in vitro and in vivo susceptibility testing methods developed so far for the determination of anti Buruli ulcer activity of natural products and derivatives. PMID- 25792088 TI - Nuclear receptors in transgenerational epigenetic inheritance. AB - Nuclear Receptors are ligand-activated transcription factors that translate information about the lipid environment into specific genetic programs, a property that renders them good candidates to be mediators of rapid adaptation changes of a species. Lipid-based morphogens, endocrine hormones, fatty acids and xenobiotics might act through this class of transcription factors making them regulators able to fine-tune physiological processes. Here we review the basic concepts and current knowledge on the process whereby small molecules act through nuclear receptors and contribute to transgenerational changes. Several molecules shown to cause transgenerational changes like phthalates, BPA, nicotine, tributylin bind and activate nuclear receptors like ERs, androgen receptors, glucocorticoid receptors or PPARgamma. A specific subset of observations involving nuclear receptors has focused on the effects of environmental stress or maternal behaviour on the development of transgenerational traits. While these effects do not involve environmental ligands, they change the expression levels of Estrogen and glucocorticoid receptors of the second generation and consequently initiate an altered genetic program in the second generation. In this review we summarize the available literature about the role of nuclear receptors in transgenerational inheritance. PMID- 25792090 TI - Maternal diabetes, gestational diabetes and the role of epigenetics in their long term effects on offspring. AB - There is a global epidemic of obesity and diabetes, and current efforts to curb the diabetes epidemic have had limited success. Epidemiological studies have highlighted increased risk of obesity, diabetes and cardiovascular complications in offspring exposed to maternal diabetes, and gestational diabetes increases the risk of diabetes in subsequent generations, thereby setting up a vicious cycle of "diabetes begetting diabetes". This relationship between maternal hyperglycaemia and long-term health in the offspring is likely to become even more important with an increasing proportion of young woman being affected by diabetes, and the number of pregnancies complicated by hyperglycaemia continuing to rise. Animal models of gestational diabetes or maternal hyperglycaemia have highlighted long term changes in the offspring with some instances of sex bias, including increased adiposity, insulin resistance, beta-cell dysfunction, hypertension, as well as other structural and functional changes. Furthermore, several of these changes appear to be transmissible to later generations through the maternal line. Epigenetic changes play an important role in regulating gene expression, especially during early development. Recent studies have identified a number of epigenetic modifications in the offspring associated with maternal hyperglycaemia. In this review, we provide an overview of the epidemiological evidence linking maternal hyperglycaemia with adverse long-term outcome in the offspring, as well as of some of the studies that explore the underlying epigenetic mechanisms. A better understanding of the pathways involved may provide novel approaches for combating this global epidemic. PMID- 25792089 TI - Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease. AB - Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease. PMID- 25792091 TI - Sulfonylureas--a novel treatment to reduce tissue damage after acute spinal cord injury? PMID- 25792092 TI - Sulfonylureas--a novel treatment to reduce tissue damage after acute spinal cord injury?--Authors' reply. PMID- 25792093 TI - Message on a bottle. PMID- 25792094 TI - Andrew Engel: 50 years of neuromuscular disorder research. PMID- 25792095 TI - Lambert-Eaton myasthenia. PMID- 25792099 TI - Role of the innate and adaptive immune responses in the course of multiple sclerosis. AB - Multiple sclerosis is a chronic disease of the CNS that leads to substantial disability in most patients. The early phase is characterised by relapses and the later phase by progressive disability. Results from immunological, genetic, and histopathological studies and treatment trials have shown that the immune system plays a key part in the disease course. Findings from animal models and immunological studies of patients with multiple sclerosis suggest a change in the involvement of the immune system during disease initiation and progression. These findings suggest that a peripheral immune response targeting the CNS drives the disease process during the early phase, whereas immune reactions within the CNS dominate the progressive phase. These concepts for the differential involvement of immune responses in the early and progressive phase of this disease have important implications for future research in the pathogenesis and treatment of multiple sclerosis. PMID- 25792101 TI - Influenza virus prevalence in asymptomatic and symptomatic subjects during pandemic and postpandemic periods. AB - BACKGROUND: In 2009, Influenza A(H1N1)pdm09 had a major effect on global health, causing thousands of deaths. However, the results of asymptomatic infection in transmission has not been well studied. We analyzed asymptomatic influenza infection in individuals with different risk factors for acquiring influenza in a university hospital. METHODS: Respiratory samples from 100 children with respiratory symptoms, their asymptomatic caregivers, 100 asymptomatic HIV infected patients, and 100 health care workers collected during 2009-2011 were tested for influenza by real time real-time polymerase chain reaction. RESULTS: Influenza infection rate in symptomatic children was 44% and in asymptomatic adults it was 8.3% (P < .01). Children older than age 5 years had a 3.4 times greater chance of being infected during influenza season than younger children. Among the asymptomatic group, influenza was more frequent in caregivers (14%; P = .032) and a higher rate (31.8%) was observed if a child was infected during the 2009 pandemic. Contact with an infected child was an important risk factor for influenza acquisition (odds ratio, 3.8; 95% confidence interval, 1.1-13.2) among caregivers. The mean cluster of differentiation 4 T-cell count of HIV-positive patients infected with influenza was not statistically different from uninfected patients (P = .29). CONCLUSIONS: Asymptomatic household contacts of symptomatic children may play an important role in community transmission and a more proactive intervention should be considered during future pandemics. PMID- 25792100 TI - Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. AB - The congenital myasthenic syndromes (CMS) are a diverse group of genetic disorders caused by abnormal signal transmission at the motor endplate, a special synaptic contact between motor axons and each skeletal muscle fibre. Most CMS stem from molecular defects in the muscle nicotinic acetylcholine receptor, but they can also be caused by mutations in presynaptic proteins, mutations in proteins associated with the synaptic basal lamina, defects in endplate development and maintenance, or defects in protein glycosylation. The specific diagnosis of some CMS can sometimes be reached by phenotypic clues pointing to the mutated gene. In the absence of such clues, exome sequencing is a useful technique for finding the disease gene. Greater understanding of the mechanisms of CMS have been obtained from structural and electrophysiological studies of the endplate, and from biochemical studies. Present therapies for the CMS include cholinergic agonists, long-lived open-channel blockers of the acetylcholine receptor ion channel, and adrenergic agonists. Although most CMS are treatable, caution should be exercised as some drugs that are beneficial in one syndrome can be detrimental in another. PMID- 25792102 TI - Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention. AB - BACKGROUND: The Cleaning and Disinfecting in Healthcare Working Group of the National Institute for Occupational Safety and Health, National Occupational Research Agenda, is a collaboration of infection prevention and occupational health researchers and practitioners with the objective of providing a more integrated approach to effective environmental surface cleaning and disinfection (C&D) while protecting the respiratory health of health care personnel. METHODS: The Working Group, comprised of >40 members from 4 countries, reviewed current knowledge and identified knowledge gaps and future needs for research and practice. RESULTS: An integrated framework was developed to guide more comprehensive efforts to minimize harmful C&D exposures without reducing the effectiveness of infection prevention. Gaps in basic knowledge and practice that are barriers to an integrated approach were grouped in 2 broad areas related to the need for improved understanding of the (1) effectiveness of environmental surface C&D to reduce the incidence of infectious diseases and colonization in health care workers and patients and (2) adverse health impacts of C&D on health care workers and patients. Specific needs identified within each area relate to basic knowledge, improved selection and use of products and practices, effective hazard communication and training, and safer alternatives. CONCLUSION: A more integrated approach can support multidisciplinary teams with the capacity to maximize effective and safe C&D in health care. PMID- 25792103 TI - The role of endothelial dysfunction driven by adipocitokines in the development and progression of microvascular complications in patients with type 1 and type 2 diabetes. AB - Micro and macrovascular complications are the leading cause of morbidity and mortality in diabetic patients. During the last decades attention has been focused on their early diagnosis and prevention. Diabetes related metabolic abnormalities: insulin resistance, hyperglycaemia and dyslipidaemia along with oxidative stress and low-grade inflammation contribute to the development of endothelial dysfunction and macrovascular complications. Recent investigations indicate a potential role of adipocitokines originating from visceral adipose tissue: adiponectin, leptin, resistin and dipepetidyl peptidase-4 (DPP-4) activity in the development of microvascular complications in diabetes. The association of these adipocitokines with the activity of endothelial synthetase (eNOS) involved into the metabolism of nitric oxide (NO) was documented in animal and cell culture studies. We hypothesize that lower adiponectin and higher leptin and resistin plasma concentration and DPP-4 activity are associated with the development and progression of diabetic microvascular complications by endothelial function impairment. A possible identification of new markers of the complex pathophysiology development and progression of microvascular complications in diabetes will contribute to improved diagnosis followed by an individualized patients approach. PMID- 25792104 TI - Helicobacter pylori, Oxalobacter formigenes, and risk of kidney stones. PMID- 25792098 TI - Neuroinflammation in Alzheimer's disease. AB - Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease. PMID- 25792105 TI - Nanopotentiated combination cancer therapy: Chemotherapeutic and chemosensitizer (2C approach). AB - An insight into the complex cancer pathophysiology reveals that a dependable amelioration of the disease could only be envisaged with a multipronged treatment approach. It is highly evident that singular chemotherapeutic agents used in clinical practice have shown limitations like severe side effects, MDR and are often associated with poor QOL while combinations of drugs have yielded better therapeutic outcomes. The current hypothesis takes it a step forward wherein a chemotherapeutic agent is combined with a natural chemosensitizer, both loaded into a nanopotentiated particulate system, which would eventually deliver the drug cargo at the target site with certitude. The encapsulated natural bioactive would then favorably act on the tumor milieu through multiple portals and chemosensibilize the cells towards cytotoxic action of the synthetic drug moiety. This 2C (chemotherapeutic and chemosensitizer) approach along with nanosystem's attributes like high payload, prolonged action and diminished side effects would proffer a more dependable treatment modality. In conclusion, the proposed system would be a value addition to the currently available armamentarium of cancer treatment tools. PMID- 25792106 TI - Toxicology of Graphene Oxide Nanosheets Against Paecilomyces catenlannulatus. AB - Graphene oxide (GO) nanosheets have been extensively investigated to fabricate the graphene in recent years. The migration of GO nanosheets into the environment could lead to the instability of biological system. In this study, the GO nanosheets were synthesized and were characterized by SEM, high resolution TEM, XRD, Raman, FTIR and XPS techniques. Toxicology testing of GO nanosheets against Paecilomyces catenlannulatus (P. catenlannulatus) was performed by measuring the efflux of cytoplasmic materials of P. catenlannulatus. Approximate 35 % of the bacteria could survive on the surface of GO nanosheets compared to the control sample (~92 %) within 3 h, indicating that GO nanosheets presented significantly antibacterial activities. It was observed that the concentration of RNA in the solution was obviously higher than that of control sample, which could be due to direct contact of the bacterial cell. The results showed that the damage of cell membrane of P. catenlannulatus was attributed to the direct contact of the P. catenlannulatus with the extremely sharp edges of GO nanosheets, which resulted in the P. catenlannulatus inactivation. The less resistant to the damage of cell membrane was observed with increasing of GO concentration and contact time. PMID- 25792107 TI - Mismatch between sediment metal distribution and pollution source gradient: a case study of a small-size drainage basin (Southeastern Brazil). AB - Metal contamination in aquatic environments may occur when the anthropogenic emission exceeds the natural contribution although other factors might influence the metal distribution. In the small-size Macae river basin, most of the metal emission was originated from anthropogenic sources suggesting a contamination status. Total and exchangeable metal concentrations were determined in sediments from the pristine upstream to the urban estuary and compared to the metal content in rocks to establish contamination and background concentrations. The enrichment of Pb in sediments compared to the regional background and high exchangeable concentrations suggest the influence of anthropogenic sources on Pb distribution. Al, Fe Mn, Zn, Ba, Cu, Cr, Ni concentrations in sediments were similar to the rock content and the values were considered regional background. Spatial distribution did not follow the whole-basin emission source gradient suggesting that despite actual anthropogenic sources, the sediment mineralogy and basin geomorphology might influence the sediment metal distribution. PMID- 25792108 TI - Metabolomic analysis reveals distinct profiles in the plasma and urine of rats fed a high-protein diet. AB - A high-protein, low-carbohydrate diet has been regarded as a dietary intervention for weight loss in the obese population. We integrated metabolomics profiles and correlation-based network analysis to reveal the difference in metabolism under diets with different protein:carbohydrate ratios. Rats were fed a control diet (moderate-protein moderate-carbohydrate: MPMC; 20 % protein, 56 % carbohydrate) or HPLC diet (high-protein low-carbohydrate: 45 % protein, 30 % carbohydrate) for 6 weeks. The fat content was equal for both diets. HPLC feeding induced weight loss and reduced adipose weight and plasma triglyceride. Compared to the MPMC diet, HPLC significantly increased plasma alpha-tocopherol, pyruvate, 2 oxoisocaproate, and beta-hydroxybutyrate, and reduced linoleate, palmitate, alpha glycerophosphate and pyroglutamic acid. The HPLC-associated urinary metabolite profile was signified with an increase in palmitate and stearate and a reduction of citrate, 2-ketoglutarate, malate, and pantothenate. Pathway analysis implicated a significant alteration of the TCA cycle in urine. Biomarker screening demonstrated that individual metabolites, including plasma urea, pyruvate, and urinary citrate, robustly distinguished the HPLC group from the MPMC group. Correlation-based network analysis enabled to demonstrate that the correlation of plasma metabolite was strengthened after the HPLC diet, while the energy-metabolism relatives 2-ketoglutarate and fumarate correlated positively with phenylalanine, methionine, and serine. The correlation network between plasma-urinary metabolites revealed a negative correlation of plasma valine with urinary beta-hydroxybutyrate in MPMC rats. In HPLC rats, plasma 2-oxoisocaproate negatively correlated with urinary pyruvate and glycine. This study using metabolomics analysis revealed the systemic metabolism in response to diet treatment and identified the significantly distinct profiles associated with a HPLC diet. PMID- 25792109 TI - Plasma asymmetric and symmetric dimethylarginine in a rat model of endothelial dysfunction induced by acute hyperhomocysteinemia. AB - Hyperhomocysteinemia induces vascular endothelial dysfunction, an early hallmark of atherogenesis. While higher levels of circulating asymmetric dimethylarginine (ADMA) and symmetric dimethyl arginine (SDMA), endogenous inhibitors of nitric oxide synthesis, have been associated with increased cardiovascular risk, the role that ADMA and SDMA play in the initiation of hyperhomocysteinemia-induced endothelial dysfunction remains still controversial. In the present study, we studied the changes of circulating ADMA and SDMA in a rat model of acutely hyperhomocysteinemia-induced endothelial dysfunction. In healthy rats, endothelium-related vascular reactivity (measured as acetylcholine-induced transient decrease in mean arterial blood pressure), plasma ADMA and SDMA, total plasma homocysteine (tHcy), cysteine and glutathione were measured before and 2, 4 and 6 h after methionine loading or vehicle. mRNA expression of hepatic dimethylarginine dimethylaminohydrolase-1 (DDAH1), a key protein responsible for ADMA metabolism, was measured 6 h after the methionine loading or the vehicle. Expectedly, methionine load induced a sustained increase in tHcy (up to 54.9 +/- 1.9 uM) and a 30 % decrease in vascular reactivity compared to the baseline values. Plasma ADMA and SDMA decreased transiently after the methionine load. Hepatic mRNA expression of DDAH1, cathepsin D, and ubiquitin were significantly lower 6 h after the methionine load than after the vehicle. The absence of an elevation of circulating ADMA and SDMA in this model suggests that endothelial dysfunction induced by acute hyperhomocysteinemia cannot be explained by an up regulation of protein arginine methyltransferases or a down-regulation of DDAH1. In experimental endothelial dysfunction induced by acute hyperhomocysteinemia, down-regulation of the proteasome is likely to dampen the release of ADMA and SDMA in the circulation. PMID- 25792110 TI - Possible sources and functions of L-homoarginine in the brain: review of the literature and own findings. AB - L-Homoarginine is a cationic amino acid derivative, which is structurally related to L-arginine and lysine. Several lines of evidence point to nervous tissue as an important target of homoarginine action. In the mammalian brain homoarginine can be detected in noticeable quantities, but its origin is currently poorly explored. In part I of this review we try to show that both uptake and transport into brain (carried out by cationic amino acid transporters) and local synthesis in the brain (carried out by the homoarginine-synthesizing enzymes L arginine:glycine amidinotransferase and ornithine transcarbamylse) might contribute to homoarginine brain content. We then give a brief overview about the multiple effects of homoarginine on the healthy brain and show that both homoarginine excess and deficiency are potentially harmful to the central nervous system. In part II, we shortly report about own experiments with regard to the cellular localization of cationic amino acid transporters, as well the enzymes L arginine:glycine amidinotransferase and ornithine transcarbamylse, in human and rat brains. PMID- 25792111 TI - Synthesis and pharmacological characterization of a europium-labelled single chain antagonist for binding studies of the relaxin-3 receptor RXFP3. AB - Relaxin-3 and its endogenous receptor RXFP3 are involved in fundamental neurological signalling pathways, such as learning and memory, stress, feeding and addictive behaviour. Consequently, this signalling system has emerged as an attractive drug target. Development of leads targeting RXFP3 relies on assays for screening and ligand optimization. Here, we present the synthesis and in vitro characterization of a fluorescent europium-labelled antagonist of RXFP3. This ligand represents a cheap and safe but powerful tool for future mechanistic and cell-based receptor-ligand interaction studies of the RXFP3 receptor. PMID- 25792112 TI - The first anionic defensin from amphibians. AB - A variety of antimicrobial peptides against infection have been identified from the skin of amphibians. However, knowledge on amphibian defensins is very limited. A novel anionic defensin designated PopuDef was purified from the skin of tree frog Polypedates puerensis, and the cDNA encoding PopuDef precursor was cloned from the skin cDNA library. The amino acid sequence of PopuDef (net charge: -2, pI: 4.75) shared the highest identity of 57 % (25/44) with the salamander defensin CFBD-1 (net charge: 0, pI: 6.14) from urodela amphibians. PopuDef showed moderate antimicrobial activities against P. aeruginosa and S. aureus (MICs are 19.41 and 17.25 MUM, respectively), and relatively weak activities against E. coli and B. subtilis (MICs are 38.82 and 43.14 MUM, respectively). Tissue distribution analysis indicated that relatively high expression level of PopuDef mRNA was observed in immune-related tissues including skin, gut, lung and spleen. Furthermore, the expression level of PopuDef was significantly upregulated in these tissues after tree frogs were infected with different bacteria strains mentioned above. Interestingly, the induction of PopuDef challenged with E. coli or B. subtilis, which was less sensitive to PopuDef, was much higher than that did with P. aeruginosa or S. aureus. These findings highlight the key role of PopuDef in innate immunity against infection. To our knowledge, PopuDef is the first anionic defensin characterized from amphibians. PMID- 25792114 TI - Potassium-sodium niobate lead-free piezoelectric materials: past, present, and future of phase boundaries. PMID- 25792113 TI - Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation. AB - Mitochondria, once merely considered as the "powerhouse" of cells, as they generate more than 90 % of cellular ATP, are now known to play a central role in many metabolic processes, including oxidative stress and apoptosis. More than 40 known human diseases are the result of excessive production of reactive oxygen species (ROS), bioenergetic collapse and dysregulated apoptosis. Mitochondria are the main source of ROS in cells, due to the activity of the respiratory chain. In normal physiological conditions, ROS generation is limited by the anti-oxidant enzymatic systems in mitochondria. However, disregulation of the activity of these enzymes or interaction of respiratory complexes with mitochondriotropic agents may lead to a rise in ROS concentrations, resulting in oxidative stress, mitochondrial permeability transition (MPT) induction and triggering of the apoptotic pathway. ROS concentration is also increased by the activity of amine oxidases located inside and outside mitochondria, with oxidation of biogenic amines and polyamines. However, it should also be recalled that, depending on its concentration, the polyamine spermine can also protect against stress caused by ROS scavenging. In higher organisms, cell signaling pathways are the main regulators in energy production, since they act at the level of mitochondrial oxidative phosphorylation and participate in the induction of the MPT. Thus, respiratory complexes, ATP synthase and transition pore components are the targets of tyrosine kinases and phosphatases. Increased ROS may also regulate the tyrosine phosphorylation of target proteins by activating Src kinases or phosphatases, preventing or inducing a number of pathological states. PMID- 25792115 TI - Antibacterial activity of fosfomycin against uropathogens. AB - BACKGROUND: In recent years, the rising rates of resistance to antimicrobial drugs among pathogens have caused great difficulty for clinicians treating infectious diseases. The aim of the study was to assess the curative effect of fosfomycin in treating urinary tract infections (UTIs) in China. METHODS: We collected clinical isolates of UTIs to determine their susceptibility to fosfomycin by the agar dilution method and to analyze extended-spectrum beta lactamase (ESBL)-producing isolates by the double-disc method on Mueller-Hinton agar. Fosfomycin-modifying enzyme analysis was conducted by PCR. Differences between the different groups were determined by the chi(2) test. RESULTS: We collected 433 UTI isolates, and the result showed that the susceptibility rates of clinical isolates were all above 80%. Only Klebsiella pneumoniae was fosA positive, with a positive rate of 26.7%. No correlation was found for the resistance between the antibiotic drugs tested and fosfomycin in the other bacteria, except for cefepime, levofloxacin and ciprofloxacin in Enterobacter cloacae and imipenem in K. pneumoniae. CONCLUSION: Our data suggest that fosfomycin may be a suitable antimicrobial agent for UTI isolates and ESBL producing bacteria in our hospital. PMID- 25792116 TI - Prevalence of dementia and main subtypes in rural northern China. AB - BACKGROUND/AIMS: The aim of this article was to estimate the prevalence of and to determine the sociodemographic risk factors for dementia, Alzheimer's disease (AD) and vascular dementia (VaD) among individuals residing in rural northern China. METHODS: Between 2011 and 2012, residents aged >=60 years and residing in rural areas of northern China were clinically assessed for symptoms of dementia, AD and VaD. Diagnoses were made using established criteria and standard procedures. RESULTS: Among 5,578 enrolled study participants aged >=60 years, the prevalence rates of dementia, AD and VaD were 7.7, 5.4 and 1.7%, respectively. Older age (OR = 1.17; 95% CI: 1.14-1.19) and female gender (OR = 2.13; 95% CI: 1.51-3.00) were identified as independent risk factors for AD. In turn, a higher educational level (OR = 0.36; 95% CI: 0.21-0.60) and engagement in social activities (OR = 0.219; 95% CI: 0.163-0.295) were protective factors. Risk factors associated with VaD were older age (OR = 1.11; 95% CI: 1.1-1.12) and hypertension (OR = 1.83; 95% CI: 1.18-2.86), while a higher educational level (OR = 0.53, 95% CI: 0.44-0.65) and engagement in social activities (OR = 0.34; 95% CI: 0.29-0.41) were protective factors. CONCLUSION: High rates of dementia (7.7%) and AD (5.4%) were found in the rural areas of northern China. Older age and female gender were identified as risk factors for AD, while older age and hypertension were risk factors for VaD. A higher educational level and engagement in social activities were identified as protective factors against both AD and VaD. PMID- 25792117 TI - Microbial endocrinology: host-bacteria communication within the gut microbiome. AB - The human body is home to trillions of micro-organisms, which are increasingly being shown to have significant effects on a variety of disease states. Evidence exists that a bidirectional communication is taking place between us and our microbiome co-habitants, and that this dialogue is capable of influencing our health in a variety of ways. This review considers how host hormonal signals shape the microbiome, and what in return the microbiome residents may be signalling to their hosts. PMID- 25792119 TI - Light-emitting devices based on top-down fabricated GaAs quantum nanodisks. AB - Quantum dots photonic devices based on the III-V compound semiconductor technology offer low power consumption, temperature stability, and high-speed modulation. We fabricated GaAs nanodisks (NDs) of sub-20-nm diameters by a top down process using a biotemplate and neutral beam etching (NBE). The GaAs NDs were embedded in an AlGaAs barrier regrown by metalorganic vapor phase epitaxy (MOVPE). The temperature dependence of photoluminescence emission energies and the transient behavior were strongly affected by the quantum confinement effects of the embedded NDs. Therefore, the quantum levels of the NDs may be tuned by controlling their dimensions. We combined NBE and MOVPE in a high-throughput process compatible with industrial production systems to produce GaAs NDs with tunable optical characteristics. ND light emitting diode exhibited a narrow spectral width of 38 nm of high-intensity emission as a result of small deviation of ND sizes and superior crystallographic quality of the etched GaAs/AlGaAs layer. PMID- 25792118 TI - Pasireotide in Acromegaly: An Overview of Current Mechanistic and Clinical Data. AB - BACKGROUND: Acromegaly is an insidious neuroendocrine disorder caused by hypersecretion of growth hormone (GH) by a somatotroph adenoma. Somatostatin receptor ligands (SRLs) are recommended as first-line medical therapy in patients for whom surgery has failed or is contraindicated. There are 5 known somatostatin receptor subtypes (SSTRs), 2 of which, i.e. SSTR2 and SSTR5, are expressed by a majority of somatotroph adenomas. The currently available SRLs, i.e. octreotide and lanreotide, primarily bind to SSTR2. Pasireotide (SOM230) is a new multireceptor-targeted SRL which has a broader binding profile and an increased affinity for SSTR1, 2, 3, and 5. METHODS: PubMed searches were performed to identify all of the available published English language data on pasireotide with regard to the mechanism of action, in vitro effects, and clinical data. RESULTS: Preclinical studies have demonstrated that pasireotide has a broader range of functional activity than octreotide. Recently, the efficacy of pasireotide in attenuating GH and insulin-like growth factor 1 (IGF-1) levels in patients with acromegaly has been evaluated in phase III clinical trials. Pasireotide demonstrated superiority over octreotide in achieving biochemical control (i.e. GH <=2.5 ug/l and age- and sex-matched IGF-1 normalization) in patients with acromegaly, as well as significant efficacy in treating patients who were previously inadequately controlled on the maximum allowed doses of octreotide and lanreotide. Pasireotide-induced hyperglycemia was the most concerning adverse event but was reversible upon discontinuation of pasireotide. CONCLUSION: The clinical data support pasireotide as a promising new therapy for the treatment of acromegaly, and the long-acting formulation was recently approved in the US and Europe for the treatment of acromegaly. PMID- 25792120 TI - Levels of arsenic, cadmium, lead and mercury in the branchial plate and muscle tissue of mobulid rays. AB - Mobulid rays are targeted in fisheries for their branchial plates, for use in Chinese medicine. Branchial plate and muscle tissue from Mobula japanica were collected from fish markets in Sri Lanka, and muscle tissue biopsies from Manta alfredi in Australia. These were analysed for arsenic, cadmium, lead and mercury and compared to maximum levels (MLs) set by Food Standards Australia and New Zealand (FSANZ), European Commission (EC) and Codex Alimentarius Commission. The estimated intake for a vulnerable human age group was compared to minimal risk levels set by the Agency for Toxic Substances and Disease Registry. The mean inorganic arsenic concentration in M. japanica muscle was equivalent to the FSANZ ML while cadmium exceeded the EC ML. The mean concentration of lead in M. alfredi muscle tissue exceeded EC and Codex MLs. There were significant positive linear correlations between branchial plate and muscle tissue concentrations for arsenic, cadmium and lead. PMID- 25792121 TI - Spatial distribution and sources of heavy metals and petroleum hydrocarbon in the sand flats of Shuangtaizi Estuary, Bohai Sea of China. AB - The concentrations of heavy metals and petroleum hydrocarbons (PHCs) in surface sediments were investigated in the sand flats of Shuangtaizi Estuary, Bohai Sea of China in May, 2013. Ecological risk assessment indicated that most heavy metals cause low ecological risk to the estuarine environment, with the exception of Cd and Hg (considerable and moderate risk, respectively). Principal component analysis in combination with correlation analysis among heavy metals, PHCs and geological factors (e.g., granularity) was used to identify possible sources of pollutants in Shuangtaizi Estuary. Results showed that the main pollution sources of the area come from anthropogenic factors, such as sewage discharge and oil exploitation. PMID- 25792122 TI - Health campaigners condemn alcohol price cuts for prioritising business interests. PMID- 25792123 TI - Severe complication of acquired hemophilia: active bleeding into the gallbladder resulting in cholecystitis requiring surgery. PMID- 25792124 TI - Efficacy and safety of vorapaxar as approved for clinical use in the United States. AB - BACKGROUND: Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA). METHODS AND RESULTS: We examined the efficacy and safety of vorapaxar in the intended use population, considering 20,170 patients randomized in the multinational, double-blinded, placebo-controlled TRA 2 degrees P-TIMI 50 trial. Of these, 16,897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70. CONCLUSIONS: In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long-term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding. CLINICAL TRIAL REGISTRATION: URL: clinicaltrials.gov Unique Identifier: NCT00526474. PMID- 25792125 TI - Angiotensin-converting enzyme-2 overexpression improves atrial remodeling and function in a canine model of atrial fibrillation. AB - BACKGROUND: Atrial fibrosis is an important factor in initiating and maintaining atrial fibrillation. The purpose of this study was to test the hypothesis that atrial angiotensin-converting enzyme-2 (ACE2) overexpression might inhibit atrial collagen accumulation and improve atrial remodeling in a canine atrial pacing model. METHODS AND RESULTS: Thirty-two mongrel dogs of both genders were divided randomly into 4 groups: sham-operated, control, gene therapy with adenovirus enhanced green fluorescent protein (Ad-EGFP), and gene therapy with Ad-ACE2. All of the dogs in the control, Ad-EGFP, and Ad-ACE2 groups were paced at 450 bpm for a period of 14 days. The dogs in the sham group were instrumented without pacing. After 2 weeks, all of the dogs underwent a thoracotomy operation and received epicardial gene painting. On post-gene transfer day 21, the animals underwent electrophysiology, histology, and molecular studies. The percentage of fibrosis in the Ad-ACE2 group was markedly lower than the percentage in the control and Ad EGFP groups. Compared with the other groups, ACE2 expression was increased significantly in the Ad-ACE2 group. Compared with the sham and Ad-ACE2 groups, the expression levels of transforming growth factor-beta1 and Smad3 were significantly higher in the Ad-EGFP and control groups; however, the expression levels of Smad7 were lower in the atrial tissue as detected by Western blot and reverse transcription polymerase chain reaction. CONCLUSIONS: Our results demonstrate that the overexpression of ACE2 inhibits atrial collagen accumulation and improves left atrial remodeling and function in a canine model of atrial fibrillation. Thus, targeted gene ACE2 therapy provides a promising approach for the treatment of atrial fibrillation. PMID- 25792126 TI - Balancing the risks and benefits of long-term antiplatelet therapies for cardiovascular disease: clinical, research, and regulatory implications. PMID- 25792127 TI - Physical activity measured by accelerometry and its associations with cardiac structure and vascular function in young and middle-aged adults. AB - BACKGROUND: Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated. MEASURES AND RESULTS: We related objective measures of moderate- to vigorous-intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid-femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9+/-21.4 and 25.5+/-19.4 min/day, respectively. Higher values of MVPA (per 10-minute increment) were associated with lower carotid-femoral pulse wave velocity (estimate -0.53 ms/m; P=0.006) and lower forward pressure wave (estimate -0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with log(e) left ventricular mass (estimate 0.006 log(e) [g/m(2)]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus >=10 minutes. CONCLUSIONS: In our community based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling. PMID- 25792128 TI - Three-dimensional echocardiography and 2D-3D speckle-tracking imaging in chronic pulmonary hypertension: diagnostic accuracy in detecting hemodynamic signs of right ventricular (RV) failure. AB - BACKGROUND: Our aim was to compare three-dimensional (3D) and 2D and 3D speckle tracking (2D-STE, 3D-STE) echocardiographic parameters with conventional right ventricular (RV) indexes in patients with chronic pulmonary hypertension (PH), and investigate whether these techniques could result in better correlation with hemodynamic variables indicative of heart failure. METHODS AND RESULTS: Seventy three adult patients (mean age, 53+/-13 years; 44% male) with chronic PH of different etiologies were studied by echocardiography and cardiac catheterization (25 precapillary PH from pulmonary arterial hypertension, 23 obstructive pulmonary heart disease, and 23 postcapillary PH from mitral regurgitation). Thirty healthy subjects (mean age, 54+/-15 years; 43% male) served as controls. Standard 2D measurements (RV-fractional area change-tricuspid annular plane systolic excursion) and mitral and tricuspid tissue Doppler annular velocities were obtained. RV 3D volumes and global and regional ejection fraction (3D-RVEF) were determined. RV strains were calculated by 2D-STE and 3D-STE. RV 3D global free-wall longitudinal strain (3DGFW-RVLS), 2D global-free-wall longitudinal strain (GFW-RVLS), apical-free-wall longitudinal strain, basal-free-wall longitudinal strain, and 3D-RVEF were lower in patients with precapillary PH (P<0.0001) and postcapillary PH (P<0.01) compared to controls. 3DGFW-RVLS (hazard ratio 4.6, 95% CI 2.79 to 8.38, P=0.004) and 3D-RVEF (hazard ratio 5.3, 95% CI 2.85 to 9.89, P=0.002) were independent predictors of mortality. Receiver operating characteristic curves showed that the thresholds offering an adequate compromise between sensitivity and specificity for detecting hemodynamic signs of RV failure were 39% for 3D-RVEF (AUC 0.89), -17% for 3DGFW-RVLS (AUC 0.88), -18% for GFW-RVLS (AUC 0.88), -16% for apical-free-wall longitudinal strain (AUC 0.85), 16 mm for tricuspid annular plane systolic excursion (AUC 0.67), and 38% for RV-FAC (AUC 0.62). CONCLUSIONS: In chronic PH, 3D, 2D-STE and 3D-STE parameters indicate global and regional RV dysfunction that is associated with RV failure hemodynamics better than conventional echo indices. PMID- 25792130 TI - Self-Sensing, Ultralight, and Conductive 3D Graphene/Iron Oxide Aerogel Elastomer Deformable in a Magnetic Field. AB - Three-dimensional (3D) graphene aerogels (GA) show promise for applications in supercapacitors, electrode materials, gas sensors, and oil absorption due to their high porosity, mechanical strength, and electrical conductivity. However, the control, actuation, and response properties of graphene aerogels have not been well studied. In this paper, we synthesized 3D graphene aerogels decorated with Fe3O4 nanoparticles (Fe3O4/GA) by self-assembly of graphene with simultaneous decoration by Fe3O4 nanoparticles using a modified hydrothermal reduction process. The aerogels exhibit up to 52% reversible magnetic field induced strain and strain-dependent electrical resistance that can be used to monitor the degree of compression/stretching of the material. The density of Fe3O4/GA is only about 5.8 mg cm(-3), making it an ultralight magnetic elastomer with potential applications in self-sensing soft actuators, microsensors, microswitches, and environmental remediation. PMID- 25792131 TI - Income inequality and status seeking: searching for positional goods in unequal U.S. States. AB - It is well established that income inequality is associated with lower societal well-being, but the psychosocial causes of this relationship are poorly understood. A social-rank hypothesis predicts that members of unequal societies are likely to devote more of their resources to status-seeking behaviors such as acquiring positional goods. We used Google Correlate to find search terms that correlated with our measure of income inequality, and we controlled for income and other socioeconomic factors. We found that of the 40 search terms used more frequently in states with greater income inequality, more than 70% were classified as referring to status goods (e.g., designer brands, expensive jewelry, and luxury clothing). In contrast, 0% of the 40 search terms used more frequently in states with less income inequality were classified as referring to status goods. Finally, we showed how residual-based analysis offers a new methodology for using Google Correlate to provide insights into societal attitudes and motivations while avoiding confounds and high risks of spurious correlations. PMID- 25792132 TI - Young children show the bystander effect in helping situations. AB - Much research in social psychology has shown that otherwise helpful people often fail to help when bystanders are present. Research in developmental psychology has shown that even very young children help and that the presence of others can actually increase helping in some cases. In the current study, in contrast, 5 year-old children helped an experimenter at very high levels when they were alone but helped significantly less often in the presence of bystanders who were potentially available to help. In another condition designed to elucidate the mechanism underlying the effect, children's helping was not reduced when bystanders were present but confined behind a barrier and thus unable to help (a condition that has not been run in previous studies with adults). Young children thus show the bystander effect, and it is due not to social referencing or shyness to act in front of others but, rather, to a sense of a diffusion of responsibility. PMID- 25792129 TI - Renal tubule angiotensin II type 1 receptor-associated protein promotes natriuresis and inhibits salt-sensitive blood pressure elevation. AB - BACKGROUND: Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP; Agtrap gene) promotes AT1R internalization along with suppression of pathological AT1R activation. In this study, we examined whether enhancement of ATRAP in the renal distal tubules affects sodium handling and blood pressure regulation in response to high salt (HS) loading, using ATRAP transgenic mice on a salt sensitive C57BL/6J background. METHODS AND RESULTS: Renal ATRAP transgenic (rATRAP-Tg) mice, which exhibit renal tubule-dominant ATRAP enhancement, and their wild-type littermate C57BL/6J mice on a normal salt diet (0.3% NaCl) at baseline were subjected to dietary HS loading (4% NaCl) for 7 days. In rATRAP-Tg mice, the dietary HS loading-mediated blood pressure elevation was suppressed compared with wild-type mice, despite similar baseline blood pressure. Although renal angiotensin II level was comparable in rATRAP-Tg and wild-type mice with and without HS loading, urinary sodium excretion in response to HS loading was significantly enhanced in the rATRAP-Tg mice. In addition, functional transport activity of the amiloride-sensitive epithelial Na(+) channel was significantly decreased under saline volume-expanded conditions in rATRAP-Tg mice compared with wild-type mice, without any evident change in epithelial Na(+) channel protein expression. Plasma membrane AT1R expression in the kidney of rATRAP-Tg mice was decreased compared with wild-type mice. CONCLUSIONS: These results demonstrated that distal tubule-dominant enhancement of ATRAP inhibits pathological renal sodium reabsorption and blood pressure elevation in response to HS loading. The findings suggest that ATRAP-mediated modulation of sodium handling in renal distal tubules could be a target of interest in salt-sensitive blood pressure regulation. PMID- 25792133 TI - Magnetic micro-device for manipulating PC12 cell migration and organization. AB - Directing neuronal migration and growth has an important impact on potential post traumatic therapies. Magnetic manipulation is an advantageous method for remotely guiding cells. In the present study, we have generated highly localized magnetic fields with controllable magnetic flux densities to manipulate neuron-like cell migration and organization at the microscale level. We designed and fabricated a unique miniaturized magnetic device composed of an array of rectangular ferromagnetic bars made of permalloy (Ni80Fe20), sputter-deposited onto glass substrates. The asymmetric shape of the magnets enables one to design a magnetic landscape with high flux densities at the poles. Iron oxide nanoparticles were introduced into PC12 cells, making the cells magnetically sensitive. First, we manipulated the cells by applying an external magnetic field. The magnetic force was strong enough to direct PC12 cell migration in culture. Based on time lapse observations, we analysed the movement of the cells and estimated the amount of MNPs per cell. We plated the uploaded cells on the micro-patterned magnetic device. The cells migrated towards the high magnetic flux zones and aggregated at the edges of the patterned magnets, corroborating that the cells with magnetic nanoparticles are indeed affected by the micro-magnets and attracted to the bars' magnetic poles. Our study presents an emerging method for the generation of pre programmed magnetic micro-'hot spots' to locate and direct cellular growth, setting the stage for implanted magnetic devices. PMID- 25792134 TI - Influence of percutaneous mitral valve repair using the MitraClip(r) system on renal function in patients with severe mitral regurgitation. AB - BACKGROUND: In patients with mitral regurgitation (MR), changes in cardiac stroke volume, and thus renal preload and afterload may affect kidney function. Percutaneous mitral valve repair (PMVR) with the MitraClip(r) system can be a therapeutic alternative to surgical valve repair. The influence of MitraClip(r) therapy on renal function and clinical outcome parameters is unknown. METHODS AND RESULTS: Sixty patients with severe MR underwent PMVR using the MitraClip(r) system in an open-label observational study. Patients were stratified according to their renal function. All clips have been implanted successfully. Effective reduction of MR by 2-3 grades acutely improved KDOQI class. Lesser MR reduction (MR reduction of 0-1 grades) led to worsening of renal function in patients with pre-existing normal or mild (KDOQI 1-2) compared to severe (KDOQI 3-4) renal dysfunction. Reduction of MR was associated with improvement in Minnesota Living with Heart Failure Questionnaire (MLHFQ), NYHA-stadium, and 6-minute walk test. CONCLUSION: Successful PMVR was associated with an improvement in renal function. The improvement in renal function was associated with the extent of MR reduction and pre-existing kidney dysfunction. Our data emphasize the relevance of PVMR to stabilize the cardiorenal axis in patients with severe MR. PMID- 25792135 TI - hTERT, BICD1 and chromosome 18 polymorphisms associated with telomere length affect kidney allograft function after transplantation. AB - BACKGROUND/AIMS: It has been confirmed that telomere length (TL) correlates with chronological donor age and that telomere shortening is accelerated in allografts. The aim of this study was to analyse the associations between graft rs2735940 hTERT and rs2630578 BICD1 gene polymorphisms and rs7235755/rs2162440 chromosome 18 polymorphisms, relative TL and kidney function after transplantation. METHODS: The study enrolled 119 Polish Caucasian kidney allograft recipients (64M/55F, mean age 47.3+/-14.0 years). The relative TL was assessed in biopsy specimens. To identify genotypes of the studied polymorphisms, real-time PCR was performed. RESULTS: The graft rs2735940 hTERT gene polymorphism TT genotype was associated with a significantly lower risk of delayed graft function (DGF) (TT vs. TC+CC; OR=0, p=0.009) and significantly shorter TL in the '0' biopsy (TT vs. CC: 207+/-153 vs. 400+/-161, p=0.036). The graft rs2630578 BICD1 gene polymorphism CC genotype was associated with lower creatinine concentrations in the first month (CC vs. GC: 1.11+/-0.06 vs. 2.0+/-1.25 mg/dL, p=0.03). The AA genotype of the graft rs7235755 chromosome 18 polymorphism was associated with longer relative TL in specimens collected 12 to 60 months after transplantation (AA vs. GG+GA p=0.04; AA vs. GG: 489+/-152 vs. 246+/-145, p=0.035) and the presence of A allele was associated with higher creatinine concentrations one month after transplantation (GA+AA vs. GG p=0.026; GA vs. GG: 2.18+/-1.59 vs. 1.76+/-0.88 mg/dL, p=0.02). It was found that shorter TL in the first six months was associated with higher creatinine concentrations 12 and 18 months after transplantation (Rs=-0.32; p=0.07 and Rs=-0.54; p=0.006, respectively). CONCLUSIONS: Graft rs2735940 hTERT and rs2630578 BICD1 gene polymorphisms and rs7235755/rs2162440 chromosome 18 polymorphisms, apart from the association with TL, affect early kidney function after transplantation. Relative TL correlated negatively with creatinine concentrations, allowing the use of TL as a predictor of long-term kidney function. PMID- 25792137 TI - Arousal in response to neutral pictures is modified in temporal lobe epilepsy. AB - The objectives of the present study were to (i) better characterize visual emotional experience in patients with temporal lobe epilepsy (TLE), (ii) identify clinical risk factors that might be predictive of a change in emotional experience, and (iii) study the relationships between emotional experience and psychobehavioral/quality-of-life factors. Fifty patients with TLE and fifty matched controls evaluated the emotional content of unpleasant, pleasant, and neutral pictures with respect to their valence (unpleasant-to-pleasant) and arousal (low-to-high) levels. Demographic, cognitive, and psychobehavioral data were recorded for all participants, and clinical data and factors related to quality of life were also collected for patients with TLE. There were no significant differences between the group with TLE and the control group in terms of valence evaluations. However, arousal scores for neutral pictures were significantly higher in patients with TLE than in controls. There was also a nonsignificant trend towards lower arousal scores for pleasant pictures in patients with TLE than in controls. Although none of the recorded clinical factors were found to be related to emotional experience, the level of apathy was predictive of greater arousal experience for neutral pictures in patients with TLE. In conclusion, emotional experience appears to be modified in TLE and might be related to apathy. Changes in emotional experience should be taken into account in studies in which neutral stimuli are used to establish a baseline level when assessing emotional and cognitive processing. PMID- 25792136 TI - MAP kinase cascades regulating axon regeneration in C. elegans. AB - Mitogen-activated protein kinase (MAPK) signaling cascades are activated by diverse stimuli such as growth factors, cytokines, neurotransmitters and various types of cellular stress. Our evolving understanding of these signal cascades has been facilitated by genetic analyses and physiological characterization in model organisms such as the nematode Caenorhabditis elegans. Genetic and biochemical studies in C. elegans have shed light on the physiological roles of MAPK cascades in the control of cell fate decision, neuronal function and immunity. Recently it was demonstrated that MAPK signaling is also important for axon regeneration in C. elegans, and the use of C. elegans as a model system has significantly advanced our understanding of the largely conserved molecular mechanisms underlying axon regeneration. This review summarizes our current understanding of the role and regulation of MAPK signaling in C. elegans axon regeneration. PMID- 25792138 TI - A feasibility study: Can information collected to classify for mutagenicity be informative in predicting carcinogenicity? AB - Carcinogenicity is a complex endpoint of high concern yet the rodent bioassay still used is costly to run in terms of time, money and animals. Therefore carcinogenicity has been the subject of many different efforts to both develop short-term tests and non-testing approaches capable of predicting genotoxic carcinogenic potential. In our previous publication (Mekenyan et al., 2012) we presented an in vitro-in vivo extrapolation workflow to help investigate the differences between in vitro and in vivo genotoxicity tests. The outcomes facilitated the development of new (Q)SAR models and for directing testing. Here we have refined this workflow by grouping specific tests together on the basis of their ability to detect DNA and/or protein damage at different levels of biological organization. This revised workflow, akin to an Integrated Approach to Testing and Assessment (IATA) informed by mechanistic understanding was helpful in rationalizing inconsistent study outcomes and categorizing a test set of carcinogens with mutagenicity data on the basis of regulatory mutagenicity classifications. Rodent genotoxic carcinogens were found to be correctly predicted with a high sensitivity (90-100%) and a low rate of false positives (3 10%). The insights derived are useful to consider when developing future (non )testing approaches to address regulatory purposes. PMID- 25792140 TI - Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines. AB - A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I) catalyzed formal 1,3-dipolar cycloaddition of coumarins with alpha-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-substituted diastereomer with respect to the 1,3-dipole and shows a broad substrate scope. PMID- 25792141 TI - Triazine-benzimidazole hybrids: anticancer activity, DNA interaction and dihydrofolate reductase inhibitors. AB - A new series of triazine-benzimidazole hybrids has been synthesized with different substitution of primary and secondary amines at one of the position of triazine in moderate to good yields. These compounds were evaluated for their inhibitory activities over 60 human tumor cell lines at one dose and five dose concentrations. Compounds 6b, 8 and 9 showed broad spectrum of antitumor activities with GI50 values of 9.79, 2.58 and 3.81MUM, respectively. DNA binding studies also indicated strong interaction properties of these compounds. These synthesized compounds also showed inhibition of mammalian dihydrofolate reductase (DHFR). Compound 6b was depicted as the most active member of DHFR inhibitor with IC50 value of 1.05MUM. Molecular modelling studies were used to identify the stabilized interactions of Compound 6b within the active site of enzyme for DHFR. PMID- 25792142 TI - In vitro radical scavenging and cytotoxic activities of novel hybrid selenocarbamates. AB - Novel selenocyanate and diselenide derivatives containing a carbamate moiety were synthesised and evaluated in vitro to determine their cytotoxic and radical scavenging properties. Cytotoxic activity was tested against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non malignant, derived from bronchial epithelium). Most of the compounds displayed high antiproliferative activity with GI50 values below 10MUM in MCF-7, CCRF-CEM and PC-3 cells. Radical scavenging properties of the new selenocompounds were confirmed testing their ability to scavenge DPPH and ABTS radicals. Based on the activity of selenium-based glutathione peroxidases (GPxs), compounds 1a, 2e and 2h were further screened for their capacity to reduce hydrogen peroxide under thiol presence. Results suggest that compound 1a mimics GPxs activity. Cytotoxic parameters, radical scavenging activity and ADME profile point to 1a as promising drug candidate. PMID- 25792143 TI - Synthesis, structure-activity relationships, and anticonvulsant activities of 2 amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives as orally active AMPA receptor antagonists. AB - As part of a program aimed at discovering orally active 2-amino-3-(3-hydroxy-5 methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonists, we screened our compound library and identified 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2 e][1,3]thiazin-4-one (7) as a lead compound that inhibited kainate-induced neurotoxicity mediated by AMPA receptors in rat hippocampal cultures. Structure activity relationship studies of a series of 2-amino-4H-pyrido[3,2-e][1,3]thiazin 4-one derivatives revealed that substituents on the phenyl ring attached to the 2 amino group and the 4H-pyrido[3,2-e][1,3]thiazin-4-one ring system play an important role in inhibitory activity against kainate-induced neurotoxicity. Several analogs bearing a phenyl group with a 4-substituent or five- or six membered ring fused at the 3,4-positions exhibited potent inhibitory activity against kainate-induced neurotoxicity. Further, some of these compounds exhibited significant suppression of maximal electroshock seizure in mice following oral administration. Of these compounds, 2-[(4-chlorophenyl)(methyl)amino]-4H pyrido[3,2-e][1,3]thiazin-4-one (16i) (YM928) demonstrated the most potent inhibitory effect with an ED50 value of 7.4mg/kg. PMID- 25792145 TI - An adapted, four-week mind-body skills group for medical students: reducing stress, increasing mindfulness, and enhancing self-care. AB - OBJECTIVE: Despite the well-known stress of medical school, including adverse consequences for mental and behavioral health, there is little consensus about how to best intervene in a way that accommodates students' intense training demands, interest in science, and desire to avoid being stigmatized. The objective of this study, therefore, was to evaluate the feasibility, acceptability, and initial effectiveness of an adapted, four-week stress management and self-care workshop for medical students, which was based on the science and practice of mind-body medicine. METHODS: The current study used a prospective, observational, and mixed methods design, with pretest and posttest evaluations. Participants (n = 44) included medical and physician-scientist (MD/PhD) students from a large, southeastern medical school. Feasibility was assessed by rates of workshop enrollment and completion. Acceptability was assessed using qualitative ratings and open-ended responses that queried perceived value of the workshop. Quantitative outcomes included students' ratings of stress and mindfulness using validated self-report surveys. RESULTS: Enrollment progressively increased from 6 to 15 to 23 students per workshop in 2007, 2009, and 2011, respectively. Of the 44 enrolled students, 36 (82%) completed the workshop, indicating that the four-session extracurricular format was feasible for most students. Students reported that the workshop was acceptable, stating that it helped them cope more skillfully with the stress and emotional challenges of medical school, and helped increase self-care behaviors, such as exercise, sleep, and engaging in social support. Students also reported a 32% decrease in perceived stress (P < .001; d = 1.38) and a 16% increase in mindfulness (P < .001; d = 0.92) following the workshop. Changes in stress and mindfulness were significantly correlated (r = -0.42; P = .01). CONCLUSION: Together, these findings suggest that a brief, voluntary mind-body skills workshop specifically adapted for medical students is feasible, acceptable, and effective for reducing stress, increasing mindfulness, and enhancing student self care. PMID- 25792144 TI - Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: insight into functional group effects and biological activity. AB - The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin's biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT(c) nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation. PMID- 25792147 TI - A Sequencing-Based Linkage Map of Cucumber. PMID- 25792148 TI - Left ventricular apical masses: distinguishing benign tumours from apical thrombi. AB - Differential diagnoses for cardiac left ventricular apical masses presenting following acute myocardial infarction include thrombi and cardiac tumours. We present two such cases and the multidisciplinary assessment that is required to assist with diagnosis. PMID- 25792146 TI - The blue light-dependent phosphorylation of the CCE domain determines the photosensitivity of Arabidopsis CRY2. AB - Arabidopsis cryptochrome 2 (CRY2) is a blue light receptor that mediates light inhibition of hypocotyl elongation and long-day promotion of floral initiation. CRY2 is known to undergo blue light-dependent phosphorylation, which is believed to serve regulatory roles in the function of CRY2. We report here on a biochemical and genetics study of CRY2 phosphorylation. Using mass spectrometry analysis, we identified three serine residues in the CCE domain of CRY2 (S598, S599, and S605) that undergo blue light-dependent phosphorylation in Arabidopsis seedlings. A study of serine-substitution mutations in the CCE domain of CRY2 demonstrates that CRY2 contains two types of phosphorylation in the CCE domain, one in the serine cluster that causes electrophoretic mobility upshift and the other outside the serine cluster that does not seem to cause mobility upshift. We showed that mutations in the serine residues within and outside the serine cluster diminished blue light-dependent CRY2 phosphorylation, degradation, and physiological activities. These results support the hypothesis that blue light dependent phosphorylation of the CCE domain determines the photosensitivity of Arabidopsis CRY2. PMID- 25792149 TI - Use of the Prostate Health Index for the Detection of Aggressive Prostate Cancer at Radical Prostatectomy. AB - INTRODUCTION: In current study, we compared the accuracy of the PSA isoform p2PSA and its derivatives, the percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI) in the detection of prostate cancer (PC) characteristics at the xFB01;nal pathology with respect to reference standards. MATERIALS AND METHODS: This was an observational prospective study evaluating 43 consecutive PC patients treated with laparoscopic/robotic radical prostatectomy (RP). Logistic regression models were fitted to test the predictors of pT3 stage, pathologic Gleason score >= 8 or Gleason score upgrading, margin status, lymph node invasion, and the presence of high-risk disease (pT3 disease and/or Gleason score >= 8 and/or positive lymph node). The comparative base model included tPSA, clinical stage, biopsy Gleason score, and percentage of positive core. RESULTS: Seventeen patients (39.5%) were affected by pT3 disease or had a pathologic Gleason score >= 8; positive margins were detected in 12 patients (27.9%), lymph node invasion was found in 2 patients (4.7%), and 15 patients (34.8%) harbored high-risk disease. In the univariate analysis, p2PSA, %p2PSA, and PHI were significant predictors of pT3 disease, pathologic Gleason score, and the presence of high-risk disease (all p < 0.05), whereas only PHI was an independent predictor of pT3 disease, margin status, and presence of high-risk disease, increasing the accuracy of a base multivariable model by 6.3% (p < 0.05) and 4.2% (p < 0.05) for the prediction of pT3 and high-risk disease, respectively. CONCLUSIONS: p2PSA and its derivatives, primarily PHI, were significant predictors of unfavorable PC characteristics as detected at the xFB01;nal pathology, thus improving the clinical performance of standard prognostic factors for aggressive disease. PMID- 25792151 TI - Antimycin A sensitive pathway independent from PGR5 cyclic electron transfer triggers non-photochemical reduction of PQ pool and state transitions in Arabidopsis thaliana. AB - We investigated the mechanism involved in triggering state transitions at 40 degrees C in Arabidopsis thaliana. Leaves (1-6 week old) exposed to 40 degrees C exhibited state II transition indicating its role as one of the earliest stress responsive mechanism apart from regulation of light energy distribution between photosystem (PS)II and PSI. Post illumination transients (rise in Fo') revealed that non-photochemical reduction of PQ pool at 40 degrees C in dark is responsible for activation of STN7 kinase, consequently light harvesting complex (LHC)II phosphorylation leading to state II condition. Later, in pgr5 mutant, non photochemical reduction of PQ pool was observed indicating the involvement of alternative electron transfer routes. In chlororespiratory mutant crr2-2, state II transition occurred signifying that the reduction of PQ pool is independent from NDH mediated cyclic electron transfer. Further, antimycin A inhibitor studies in wt and mutants revealed its inhibitory action on non-photochemical reduction of PQ pool affecting both LHCII phosphorylation and migration to PSI which leads to state I. Thus, our study showed that antimycin A sensitive pathway independent from PGR5 dependent cyclic electron transfer, is responsible for inducing non-photochemical reduction of PQ pool and state transitions at 40 degrees C. PMID- 25792150 TI - The changes in quality ingredients of Qi chrysanthemum flowers treated with elevated UV-B radiation at different growth stages. AB - The paper mainly reported the changes in quality ingredients of Qi chrysanthemum flowers treated with elevated UV-B radiation at different growth stages. The experiment included two levels of UV-B radiation (ambient UV-B, a 10% increase in ambient UV-B). Elevated UV-B radiation was carried out for 10-days during seedling, vigorous growth, bud and flower stages of Qi chrysanthemum, respectively. Elevated UV-B treatments applied during four development stages did not significantly affect flower yield, the rate of superoxide radical production and malondialdehyde concentration in flowers, while increased free amino acid concentration. The amino acid concentration induced by elevated UV-B radiation applied during bud stage was higher than that during the other stages. Elevated UV-B radiation applied during vigorous growth (except for flavone), bud and flower stages of chrysanthemum significantly increased hydrogen peroxide concentration, phenylalanine ammonia lyase enzyme activity, vitamin C, chlorogenic acid and flavone concentrations in flowers. These results suggested that active and nutritional ingredients in flowers of chrysanthemum could be increased by elevated UV-B radiation applied during the later growth stages of chrysanthemum. The paper supplied a simple and environmental-friendly method to improve quality of medicinal plants. PMID- 25792153 TI - Has pediatric CT practice in Japan changed since the Fukushima nuclear disaster? PMID- 25792152 TI - Organizational Justice and Physiological Coronary Heart Disease Risk Factors in Japanese Employees: a Cross-Sectional Study. AB - BACKGROUND: Growing evidence has shown that lack of organizational justice (i.e., procedural justice and interactional justice) is associated with coronary heart disease (CHD) while biological mechanisms underlying this association have not yet been fully clarified. PURPOSE: The purpose of the present study was to investigate the cross-sectional association of organizational justice with physiological CHD risk factors (i.e., blood pressure, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglyceride) in Japanese employees. METHODS: Overall, 3598 male and 901 female employees from two manufacturing companies in Japan completed self-administered questionnaires measuring organizational justice, demographic characteristics, and lifestyle factors. They completed health checkup, which included blood pressure and serum lipid measurements. Multiple logistic regression analyses and trend tests were conducted. RESULTS: Among male employees, multiple logistic regression analyses and trend tests showed significant associations of low procedural justice and low interactional justice with high triglyceride (defined as 150 mg/dL or greater) after adjusting for demographic characteristics and lifestyle factors. Among female employees, trend tests showed significant dose-response relationship between low interactional justice and high LDL cholesterol (defined as 140 mg/dL or greater) while multiple logistic regression analysis showed only marginally significant or insignificant odds ratio of high LDL cholesterol among the low interactional justice group. Neither procedural justice nor interactional justice was associated with blood pressure or HDL cholesterol. CONCLUSION: Organizational justice may be an important psychosocial factor associated with increased triglyceride at least among Japanese male employees. PMID- 25792154 TI - Imaging neonates and children with Pierre Robin sequence before and after mandibular distraction osteogenesis: what the craniofacial surgeon wants to know. AB - Pierre Robin sequence is characterized by micrognathia and glossoptosis causing upper airway obstruction. Mandibular distraction osteogenesis is a mandibular lengthening procedure performed in neonates and children with Pierre Robin sequence to alleviate airway compromise. This pictorial review demonstrates the role of imaging in the preoperative and postoperative assessment of these children. It is important for pediatric radiologists to know what information about the mandible and airway the craniofacial surgeon needs from preoperative imaging and to identify any complications these children may encounter after surgery. PMID- 25792155 TI - Optimizing functional MR urography: prime time for a 30-minutes-or-less fMRU. AB - BACKGROUND: Current protocols for functional MR urography (fMRU) require long scan times, limiting its widespread use. OBJECTIVE: Our goal was to use pre defined criteria to reduce the number of sequences and thus the examination time without compromising the morphological and functional results. MATERIALS AND METHODS: The standard fMRU protocol in our department consists of eight sequences, including a 17-min dynamic post-contrast scan. Ninety-nine children and young adults (43 male, 56 female, mean age 7 years) were evaluated with this protocol. Each sequence was retrospectively analyzed for its utility and factors that affect its duration. RESULTS: Mean scan time to perform the eight sequences, without including the variable time between sequences, was 40.5 min. Five sequences were categorized as essential: (1) sagittal T2 for planning the oblique coronal plane, (2) axial T2 with fat saturation for the assessment of corticomedullary differentiation and parenchymal thickness, (3) coronal 3-D T2 with fat saturation for multiplanar and 3-D reconstructions, (4) pre-contrast coronal T1 with fat saturation to ensure an appropriate scan prior to injecting the contrast material and (5) the coronal post-contrast dynamic series. Functional information was obtained after 8 min of dynamic imaging in the majority of children. The coronal fat-saturated T2, coronal T1, and post-contrast sagittal fat-saturated T1 sequences did not provide additional information. Because of the effects of pelvicalyceal dilation and ureteropelvic angle on the renal transit time, prone position is recommended, at least in children with high grade pelvicalyceal dilation. CONCLUSION: Comprehensive fMRU requires approximately 19 min for sequence acquisition. Allowing for time between sequences and motion correction, the total study time can be reduced to about 30 min. Four pre-contrast sequences and a shortened post-contrast dynamic scan, optimally with the child in prone position, are sufficient. PMID- 25792156 TI - Fragmentation of amyloid fibrils occurs in preferential positions depending on the environmental conditions. AB - Understanding the mechanism of amyloid fibril breakage is of fundamental importance in various research fields including biomedicine and bionanotechnology. The aim of this work is to clarify the impact of temperature and agitation speed on the fibril breakage rate constant, which depends both on the fibril length as well as on the position of fragmentation along the fibril longitudinal axis. In particular, we intend to discriminate between three fibril fragmentation mechanisms: erosion (i.e., breakage occurs preferentially at the ends of the fibril), random (i.e., breakage occurs with the same likelihood at any position), or central (i.e., breakage occurs preferentially at the center of the fibril). To do so, we compare the time evolution of the fibril length distribution followed with atomic force microscopy with simulations from a kinetic model based on population balance equations (PBE). In this frame, we investigate the breakage mechanism of insulin fibrils, which turns out to be affected by the operative conditions employed. Moreover, we compare our findings with literature data obtained with beta-lactoglobulin and beta2-microglobulin. It is observed that high temperature drives the breakage toward an erosion mechanism, while a high agitation rate rather induces a central breakage. PMID- 25792157 TI - Ship's doctor qualifications: a response to the German recommendations. PMID- 25792158 TI - Acute chest pain on cruise ships. PMID- 25792159 TI - Non-cancer diseases requiring admission to hospital among German seafarers. AB - BACKGROUND: This study estimated the discharge diagnosis due to non-cancer diseases of German seamen employed on German vessels in comparison to the general German male population. MATERIALS AND METHODS: In a database, the German health insurance company for seafarers determined the discharge diagnoses from hospital for all German seafarers. In the time period from January 1997 to December 2007, this database encompassed on average more than 21,000 German seamen per year. It served as a source for comparison with the official national database on discharge diagnoses from the general German population. Thus, the standardised hospitalisation ratio (SHR) could be calculated. RESULTS: During the above mentioned time period, the most prominent non-cancer diagnoses among seafarers were diseases of the circulatory system, diseases of the digestive system, diseases of the musculoskeletal system, as well as injury and poisoning. Compared to the reference population, decreased SHRs were observed for almost all examined diseases with the exception of asbestosis (SHR: 1.79; 95% CI 0.65-3.90). In contrast to the deck and engine room crew, the galley staff demonstrated an increased SHR for almost all examined diseases, particularly for lifestyle related diseases. CONCLUSIONS: Although the presented data are likely biased by the healthy worker effect and by underreporting due to treatment on board or abroad, an elevated SHR for (lifestyle-related) diseases was observed in the galley staff. Therefore, especially this occupational group seems to need specific advice on healthy behaviours both on board and ashore. PMID- 25792160 TI - Assessment of oral health among seafarers in Mundra Port, Kutch, Gujarat: a cross sectional study. AB - BACKGROUND: A seafarer is a person who navigates waterborne vessels or assists as a crewmember in their operation and maintenance in all tough weather, but little research has been done to identify conditions that may lead to assess seafarer general health as well as oral health. AIM: To assess oral diseases including dental caries and periodontal conditions among seafarer's population arrived in Mundra Port, Kutch, Gujarat, India. MATERIALS AND METHODS: A descriptive cross sectional survey was conducted to assess oral health condition of seafarer community of Mundra Taluka of Kutch District, Gujarat, India, from July 2014 to September 2014. RESULTS: Total of 385 subjects participated in the survey. Adverse habits show the overall 72.3% prevalence among the study population. Occurrence rate of caries, periodontal disease and prosthetic status were 88%, 75.1% and 6.5%, respectively. The best predictors for Decayed Missing Filled Teeth (DMFT), Community Periodontal Index (CPI) and prosthetic status were oral hygiene practices, adverse habit and educational status. CONCLUSIONS: Findings of the present study suggest that oral health condition of seafarer community was relatively poor, with high caries prevalence and poor periodontal health. This epidemiological survey has provided baseline information to underpin the implementation of oral health programmes. PMID- 25792161 TI - Telemedicine at sea and onshore: divergences and convergences. AB - BACKGROUND: Telemedical Maritime Assistance Service (TMAS) is one of the fundamental components of medical assistance delivery at sea. However, while onshore telemedicine is undergoing a fast growth, these research and clinical investments unfortunately did not yet benefit for telemedicine at sea. DIVERGENCES BETWEEN TELEMEDICINE AT SEA AND ONSHORE: While telemedicine aims at providing distant health care, telemedicine at sea and onshore bear major differences, particularly for merchant vessels, and to a lesser extent for passenger vessels, which can be divided between structural differences, differences of practices, and policy differences. CONVERGENCES BETWEEN TELEMEDICINE AT SEA AND ONSHORE: Despite the existence of important divergences between telemedicine at sea and telemedicine onshore, these two major branches of distant health care delivery still converge in some respects. CONCLUSIONS: Identifying the convergences between telemedicine at sea and telemedicine onshore might contribute to increase and optimise the transfer from research on onshore telemedicine to maritime telemedicine, and to overcome the relatively low amount of research performed on telemedicine at sea compared to its onshore counterpart. PMID- 25792162 TI - Atypical myocardial infarction on a cruise ship. AB - A previously asymptomatic 44-year-old male crewmember on a cruise ship experienced several brief episodes of acute chest pain within a short time frame. He was ultimately diagnosed with myocardial infarction; 5 h earlier he had been discharged from the ship's medical centre after almost 8 h of monitoring to rule out infarction. Subsequent angiography ashore revealed a 99% occlusion of the right coronary artery. This case highlights the dangers of over-reliance on shipboard cardiac enzyme testing to clear a patient with chest pain. PMID- 25792163 TI - A "broken heart" on a cruise ship. AB - An elderly female cruise ship passenger developed chest pain shortly after an emotionally charged incident involving shipboard authorities. The electrocardiogram and cardiac enzyme profile were indicative of myocardial infarction but the final diagnosis, established after aeromedical evacuation, was stress-related cardiomyopathy. This case is an example of a relatively unknown clinical entity that is easily mistaken for acute myocardial infarction and which may be disproportionately prevalent in the cruise ship passenger population. PMID- 25792164 TI - Penile ulceration caused by a foreign body reaction in a crew member on board a cruise ship. AB - A crew member had a foreign body implanted subcutaneously on his dorsum penis stealthily 6 years earlier by a fellow crew member without any medical training. He presented to the ship's medical centre after a week of pain, erythema and oedema over the foreign body, which was eventually removed by the patient, leaving behind a penile ulceration. He was treated conservatively initially with intravenous and then with oral antibiotics until complete secondary wound closure was achieved. PMID- 25792165 TI - Neuropsychiatric manifestations of some tropical diseases. AB - Some tropical diseases are the direct cause of severe disturbances of cerebral function while others affect only finer cerebral systems controlling fears, anxiety and personality traits. The mechanisms by which psychiatric symptoms are produced in tropical disorders are not any different from the mechanisms that relate to any physical disorders. Neuropsychiatric symptoms may be caused by a number of different mechanisms including bacterial toxins, release of cytokines, hyperthermia, shock (poor perfusion), acute renal insufficiency, pulmonary failure (shock lung), coagulopathy, disruption of the blood-brain barrier, and/or the nest of pathogens into the central nervous system. The following tropical illnesses can be associated with neuropsychiatric symptoms: neurocysticercosis, malaria, trypanosomiasis, dengue, and schistosomiasis. Neurological and psychiatric impairments induced by tropical diseases both represent a major category of invalidating disorders, which cause profound changes in the nervous system functions, often associated with severe sequels or late-onset disturbances. It is therefore important to disseminate knowledge of the neuropsychiatric symptoms accompanying tropical diseases in order to increase the awareness of these problems and challenges. PMID- 25792166 TI - Theoretical tissue compartment inert gas pressures during a deep dive with and without deep decompression stops: a case analysis. AB - BACKGROUND: Deep decompression stops are increasingly common in recreational technical diving. Concerns exist that they shift decompression stress back into slower tissues. A diver recorded an exceptional exposure dive, with deeps stops, on a commercially available dive computer. MATERIAL AND METHODS: Using the R package SCUBA tissue inert gas pressures in 17 Buhlmann (ZH-L16A) compartments were estimated from the dive computer recorded profile. The RGBM dive plan generated by the diver's software was similarly interrogated, as was a third profile with reduced deep stops generated using the VPM-B/E model. RESULTS: In this dive the combination of 5 gas switches appeared to ameliorate the effect of deep stops from 76 m depth. CONCLUSIONS: A higher-than-anticipated inert gas content in a decompression mixture, coupled with climbing 200 stairs post decompression, appear possible risk factors for decompression sickness. Nonetheless, the physiological effect of deep decompression stops during exceptional exposure, even when diving with gas switches, remains urgently to be determined to improve safe decompression following exceptional exposures. Until algorithms utilising deep decompression stops are validated with human data, dive profiles incorporating deep decompression stops should be considered experimental. PMID- 25792167 TI - Symptoms of fatigue and coping strategies in maritime pilotage. AB - BACKGROUND: Little is known regarding the symptoms of fatigue that maritime pilots experience during shift work. Moreover, the strategies these individuals use to cope with the onset of fatigue are also unknown. The current study explored the symptoms of fatigue and coping strategies experienced by maritime pilots when on-shift. MATERIAL AND METHODS: Fifty maritime pilots were recruited via an advertisement in the national association's quarterly newsletter (Mage = 51.42; SD = 9.81). Participants responded to a modified version of the questionnaire used with aviation pilots that assessed overall fatigue, and the symptoms pilots associated with fatigue on duty. Methods pilots used to cope with fatigue before shift and when on the bridge were also assessed. RESULTS: There were significant effects for pilot vitality on 4 categories of fatigue: cognitive dysfunction; emotional disturbance; mean physical effects; and sleepiness. There were no significant effects for vitality on any of the self-reported coping strategy factors. CONCLUSIONS: The findings indicated that maritime pilots experience a variety of physical, behavioural, and cognitive fatigue symptoms when on shift. Some of these symptoms are similar to those reported by aviation pilots. However, unlike aviation pilots, maritime pilots reported utilising self sufficient coping strategies to deal with the experience of fatigue. PMID- 25792168 TI - Telepsychiatric assessment of a mariner expressing suicidal ideation. AB - This case report highlights the successful use of telepsychiatric consultation by secure video chat to remotely assess a mariner expressing suicidal ideation. As a result of this intervention, telemedicine providers initiated psychiatric stabilisation while the mariner was still aboard the vessel, determined that he was safe for repatriation under the care of qualified medical escorts, and facilitated admission to a psychiatric facility near his home in the United States. Mental health emergencies are a significant cause of morbidity and mortality among mariners. Telepsychiatry is a validated method of establishing a psychiatric diagnosis and disposition as well as assessing risk of suicidality and the potential for violent decompensation. It has the potential to be a valuable adjunct to any traditional maritime telemedicine service. PMID- 25792169 TI - The kilometre who sailed thousands of miles. PMID- 25792170 TI - Perceived utility and limits of psychological interviews among French physicians and firefighter divers. PMID- 25792171 TI - Editor's comment. PMID- 25792174 TI - A multifactorial analysis of the pregnancy outcomes in cytomegalovirus-infected women. AB - AIMS: To investigate the impacts of cytomegalovirus (CMV) viral load, TORCH (toxoplasmosis, others, rubella, CMV and herpes) coinfections, CMV glycoprotein B (gB) genotypes and maternal genetic polymorphisms on pregnancy outcomes among CMV infected women. METHODS: A total of 731 CMV-infected pregnant women (634 and 97 with normal and adverse pregnancy outcomes, respectively) were recruited. CMV load quantification and screening of TORCH coinfections were performed by using real-time polymerase chain reaction (PCR) and immunodetection techniques, respectively. Genotyping of CMV gB and maternal NFKB1 -94 ins/del, NFKBIA -826C/T and -881A/G polymorphisms was performed by using PCR-restriction fragment length polymorphism. RESULTS: We found that the mean CMV viral load in women with adverse pregnancy outcomes was significantly higher than that in women with normal outcomes at all pregnancy stages (p < 0.01). We also found that TORCH coinfections resulted in a 1.65-fold (95% CI = 1.00-2.73) increase in the risk of adverse pregnancy outcomes (p = 0.05). Additionally, we noticed no significant difference in the distribution of CMV gB genotypes between women with normal and adverse pregnancy outcomes (p = 0.42). We also observed that the ins/ins variant genotype of the NFKB1 polymorphism could reduce the risk of adverse pregnancy outcomes (OR = 0.38, 95% CI = 0.15-0.98; p = 0.04). CONCLUSION: CMV viral load, TORCH coinfections and maternal NFKB1 polymorphism could influence pregnancy outcomes among CMV-infected women. PMID- 25792175 TI - Comparing center-specific cumulative incidence functions. AB - The competing risks data structure arises frequently in clinical and epidemiologic studies. In such settings, the cumulative incidence function is often used to describe the ultimate occurrence of a particular cause of interest. If the objective of the analysis is to compare subgroups of patients with respect to cumulative incidence, imbalance with respect to group-specific covariate distributions must generally be factored out, particularly in observational studies. This report proposes a measure to contrast center- (or, more generally group-) specific cumulative incidence functions (CIF). One such application involves evaluating organ procurement organizations with respect to the cumulative incidence of kidney transplantation. In this case, the competing risks include (i) death on the wait-list and (ii) removal from the wait-list. The proposed method assumes proportional cause-specific hazards, which are estimated through Cox models stratified by center. The proposed center effect measure compares the average CIF for a given center to the average CIF that would have resulted if that particular center had covariate pattern-specific cumulative incidence equal to that of the national average. We apply the proposed methods to data obtained from a national organ transplant registry. PMID- 25792176 TI - Is magnesium sulfate effective for pain in chronic postherpetic neuralgia patients comparing with ketamine infusion therapy? AB - BACKGROUND: Postherpetic neuralgia (PHN) is a frequent debilitating complication and one of the most intractable pain disorders, particularly in elderly patients. Although tricyclic antidepressants, topical capsaicin, gabapentin, and oxycodone are effective for alleviating PHN, many patients remain refractory to current therapies. Here, the analgesic effects of ketamine or magnesium for PHN were assessed in an open prospective study. METHOD: Thirty patients with severe, intractable PHN who were unresponsive to conservative therapy participated. The effects of ketamine hydrochloride (Ketara, Parke Davis) 1 mg/kg and magnesium sulfate (Magnesin) 30 mg/kg were investigated. The patients were randomly divided into 2 groups of 15 patients each, and ketamine 1 mg/kg or magnesium 30 mg/kg was administered intravenously for 1 hour after midazolam sedation. Pain was rated on a visual analog scale (VAS) during a 2-week follow-up. All patients also completed the Doleur Neuropathique 4 questionnaire at baseline and final visits. RESULTS: Response to treatment, defined as a 50% reduction in VAS score 2 weeks after, was recorded in 10 of 15 patients in the ketamine group and 7 of 15 patients in the magnesium group. The difference in VAS reduction was not significant between the 2 groups. CONCLUSIONS: Ketamine and magnesium showed significant analgesic effects in patients with PHN. PMID- 25792178 TI - Efficacy of bronchofiberscope double-lumen tracheal tube intubation combined with McGRATH MAC for difficult airway. PMID- 25792177 TI - Feasibility of patient and peer surveys for Maintenance of Certification among diplomates of the American Board of Anesthesiology. AB - STUDY OBJECTIVE: The initial developmental standards for Maintenance of Certification programs proposed by the American Board of Medical Specialties included the administration of patient and peer surveys by the diplomate every 5 years. The aim of this pilot study was to determine the feasibility of Maintenance of Certification in Anesthesiology Program (MOCA) patient and peer surveys in a selected group of American Board of Anesthesiology (ABA) diplomates. DESIGN: The design was a pilot test of survey instruments-MOCA Patient Care Survey and MOCA Peer Survey. SETTING: The setting was the ABA, Raleigh, NC. SUBJECTS: The subjects were ABA-certified anesthesiologists who were active examiners for the primary certification oral examination as of January 2013. MEASUREMENTS: Fifty-one participating physicians in the patient survey group distributed brochures, which included a link to the MOCA Patient Care Survey, to up to 100 consecutive patients at the point of care. Fifty-one participating physicians in the peer survey group distributed invitations to MOCA Peer Survey via e-mail to 20 peers in a variety of roles. Participants developed and evaluated a practice improvement plan based on survey results. Participants were also surveyed on their opinions on the feasibility of implementing the piloted survey instrument in their practices. MAIN RESULTS: Response rates for the patient care and the peer surveys were 15% and 75%, respectively. Both surveys indicated a high level of satisfaction with the diplomates; approximately two thirds of physicians could not identify practice areas in need of improvement. CONCLUSIONS: These results suggest that threats to the validity of these surveys include distribution bias for peer surveys and response bias for patient surveys and that surveys often do not provide actionable information useful for practice improvement. Alternative approaches, such as including anesthesiologists within an integrated institutional evaluation system, could be explored to maximize the benefits of physician assessments provided by peers and patients. PMID- 25792180 TI - Relationship between the shape of the central and third tarsal bones and the presence of tarsal osteoarthritis. AB - Osteoarthritis (OA) of the low motion joints of the tarsus, commonly termed 'bone spavin', is common in horses. Whilst the aetiology of this condition is multifactorial, it has been suggested that dorsal wedging of the central tarsal bone (CTB) and third tarsal bone (TTB) may predispose to the development of this disease. The aim of this study was to investigate the relationship between tarsal bone conformation and osteoarthritis of the proximal intertarsal (PIT), distal intertarsal (DIT) and tarsometatarsal (TMT) joints. It was hypothesised that wedging of the CTB and TTB would be associated with OA in these joints. Multiplanar reconstructions based on computed tomographic (CT) images were used to measure the height of the central and third tarsal bones at their dorsal and plantar aspects in three parasagittal planes in cadaver specimens. A wedging index was calculated as the ratio between the dorsal and plantar measurements. All tarsal bones were graded for OA on CT images. There was a significant moderate negative correlation between the wedging index of the CTB and OA of the DIT (rho = -0.45, P <0.01), TMT (rho = -0.49, P <0.01) and PIT joints (rho = 0.43, P <0.01). Dorsal wedging of the TTB was seen in mild and moderate grades of OA, but severe cases of OA were associated with plantar wedging. Our study suggests that wedging of the small tarsal bones is associated with OA in the associated joints and hence care should be taken in foals to prevent the development of wedging. PMID- 25792179 TI - Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: A retrospective review. AB - OBJECTIVE: To describe the clinical outcome and tolerability of weekly ixabepilone (16-20mg/m(2) days 1, 8, 15 of a 28-day cycle)+/-biweekly bevacizumab (10mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. METHODS: A single-institution retrospective review was performed inclusive of all patients who received >=2cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. RESULTS: A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1-10) prior lines of chemotherapy. Patients completed a mean of 4.7+/-2.9cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7months (range:2-30). Median PFS and OS were 5.2 and 9.6months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0months, p=0.01, HR 0.2, 95% CI 0.05-0.77; 9.6 versus 4.2months, p=0.02, HR 0.58, 95% CI 0.04-0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. CONCLUSIONS: Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations. PMID- 25792181 TI - Magnetic resonance imaging diagnosis of brain tumors in dogs. AB - A great deal of information is now available regarding the range of magnetic resonance imaging (MRI) features of many primary and secondary brain tumors from dogs. In this review, these canine neoplasms are grouped into meningeal masses, ventricular masses, intra-axial enhancing lesions, intra-axial mildly to non enhancing lesions, and multifocal lesions. For each of these patterns, the major and sporadic neoplastic differential diagnoses are provided, and guidance on how to rank differential diagnoses for each individual patient is presented. The implication of MRI features such as contrast-enhancement, signal intensities and location is discussed. However, the information garnered from MRI must be correlated with all available clinical information and with epidemiological data before creating a differential diagnosis. PMID- 25792182 TI - Inferring cuisine--drug interactions using the linked data approach. AB - Food - drug interactions are well studied, however much less is known about cuisine - drug interactions. Non-native cuisines are becoming increasingly more popular as they are available in (almost) all regions in the world. Here we address the problem of how known negative food - drug interactions are spread in different cuisines. We show that different drug categories have different distribution of the negative effects in different parts of the world. The effects certain ingredients have on different drug categories and in different cuisines are also analyzed. This analysis is aimed towards stressing out the importance of cuisine - drug interactions for patients which are being administered drugs with known negative food interactions. A patient being under a treatment with one such drug should be advised not only about the possible negative food - drug interactions, but also about the cuisines that could be avoided from the patient's diet. PMID- 25792184 TI - Immobilization of feruloyl esterases on magnetic nanoparticles and its potential in production of ferulic acid. AB - Feruloyl esterase plays an indispensable role in hydrolyzing plant cell walls, and ferulic acid will be released as by-product, which has potential applications in food and medicine industry. This study presents immobilization of partially purified feruloyl esterases from the fermentation liquor of recombinant Pichia on magnetic Fe3O4 nanoparticles. Furthermore, the optimal conditions for the immobilization and some characteristics of immobilized enzyme were studied. The optimal immobilization conditions observed were enzyme 0.2 mg (1 mg/mL, 0.2 mL), magnetic Fe3O4 nanoparticles 4 mg, pH 6.0, immobilization time 3 h. The results showed that the optimal reaction temperature of immobilized enzyme was increased from 45 degrees C to 55 degrees C. Thermal stability of the immobilized enzyme also had an improvement, the residual activity retained 80% and 69% after 120 h at 40 degrees C and 50 degrees C, respectively, while free enzymes only showed 45% and 40% remnant activity at the same condition. The immobilized enzyme also exhibited good operational stability and 52.4% of its initial activity was observed during the fifth cycle. In terms of the thermal and operational stability, the immobilized enzyme could be better used in many more applications than the free enzymes. At last the destarched wheat bran was taken as substrate for immobilized and free feruloyl esterases to produce ferulic acid, the maximum ferulic acid yield was 11.2% and 12.3%, respectively, indicating a great potential in industrial application. PMID- 25792183 TI - Antiviral and Immunoregulatory Effects of Indoleamine-2,3-Dioxygenase in Hepatitis C Virus Infection. AB - In patients with hepatitis C virus (HCV) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (IDO) has been reported. IDO - a tryptophan catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. The molecular mechanism of IDO induction in HCV infection and its role in the antiviral immune response remain unknown. Using primary human hepatocytes, we show that HCV infection stimulates IDO expression. IDO gene induction was transient and coincided with the expression of types I and III interferons (IFNs) and IFN-stimulated genes in HCV infected hepatocytes. Overexpression of hepatic IDO prior to HCV infection markedly impaired HCV replication in hepatocytes, suggesting that IDO limits the spread of HCV within the liver. siRNA-mediated IDO knock-down revealed that IDO functions as an IFN-mediated anti-HCV effector. Hepatic IDO was most potently induced by IFN-x03B3;, and ongoing HCV replication could significantly upregulate IDO expression. IRF1 (IFN-regulatory factor 1) and STAT1 (signal transducer and activator of transcription 1) regulated hepatic IDO expression. Hepatic IDO expression also had a significant inhibitory effect on CD4+ T-cell proliferation. Our data suggest that hepatic IDO plays a dual role during HCV infection by slowing down viral replication and also regulating host immune responses. PMID- 25792185 TI - Nitrous oxide emission in autotrophic partial nitritation system: Macro- and microanalyses. AB - A laboratory-scale sequencing batch reactor fed with synthetic high-ammonium wastewater was operated for autotrophic partial nitritation, and the characteristics of N2O emission were investigated by both macro- and microanalysis. A N2O emission quantity of 5.98 +/- 1.24 mg (n = 17) was observed, accounting for 0.997% +/- 0.408% of the influent nitrogen. The N2O level in the off-gas first increased to a maximum of 91.5 ppmv in the initial 50 min, and then decreased and remained around 34.8 ppmv until the end of aeration. An asymptotic function (y = 14.3-14.2 * 0.992(x), R(2) = 0.997) could be used to estimate the quantity of N2O emitted. Microelectrodes were used to explore the variations in the nitrogen distribution and consumption rate within sludge flocs as the reaction proceeded. During the aeration phase, partial nitritation occurred mainly in the surface layer of flocs. This is where most N2O was produced, indicating that N2O was generated as a byproduct of the nitritation. During the settling phase, the N2O concentration and volumetric production rate were much higher than those in the aeration phase, suggesting that the settling phase contributes to the initial N2O emission peak. PMID- 25792186 TI - Absolute quantitation of glycolytic intermediates reveals thermodynamic shifts in Saccharomyces cerevisiae strains lacking PFK1 or ZWF1 genes. AB - Internal standard based absolute quantitation of glycolytic intermediates was performed to characterize the thermodynamic states of Saccharomyces cerevisiae metabolism. A mixture of (13)C-labeled glycolytic intermediates was prepared via extraction from S. cerevisiae cells cultivated using a synthetic medium containing [U-(13)C] glucose as the sole carbon source. The (13)C-labeled metabolite mixture was used as an internal standard for the analysis of S. cerevisiae cultivated in a medium containing natural glucose. The methodology was employed for the absolute quantitation of glycolytic intermediates of BY4742, pfk1Delta, and zwf1Delta strains of S. cerevisiae. Fructose-1,6-bisphosphate was the most abundant intermediate in the BY4742 strains in the log phase of growth. Estimation of the Gibbs free energy change (DeltaG) from the absolute concentration revealed that several reactions, such as those catalyzed by ribose 5-phosphate keto-isomerase and phosphoglucose isomerase, were commonly at near equilibrium in all three strains. A significant shift in thermodynamic state was also observed for the transketolase-transaldolase reaction, for which DeltaG was 6.6 +/- 0.5 kJ mol(-1) in the BY4742 strain and 5.4 +/- 0.3 kJ mol(-1) in the zwf1Delta strain. PMID- 25792187 TI - Optimization of cell line development in the GS-CHO expression system using a high-throughput, single cell-based clone selection system. AB - Therapeutic antibodies are commonly produced by high-expressing, clonal and recombinant Chinese hamster ovary (CHO) cell lines. Currently, CHO cells dominate as a commercial production host because of their ease of use, established regulatory track record, and safety profile. CHO-K1SV is a suspension, protein free-adapted CHO-K1-derived cell line employing the glutamine synthetase (GS) gene expression system (GS-CHO expression system). The selection of high producing mammalian cell lines is a crucial step in process development for the production of therapeutic antibodies. In general, cloning by the limiting dilution method is used to isolate high-producing monoclonal CHO cells. However, the limiting dilution method is time consuming and has a low probability of monoclonality. To minimize the duration and increase the probability of obtaining high-producing clones with high monoclonality, an automated single cell-based clone selector, the ClonePix FL system, is available. In this study, we applied the high-throughput ClonePix FL system for cell line development using CHO-K1SV cells and investigated efficient conditions for single cell-based clone selection. CHO-K1SV cell growth at the pre-picking stage was improved by optimizing the formulation of semi-solid medium. The efficiency of picking and cell growth at the post-picking stage was improved by optimization of the plating time without decreasing the diversity of clones. The conditions for selection, including the medium formulation, were the most important factors for the single cell-based clone selection system to construct a high-producing CHO cell line. PMID- 25792189 TI - Erratum to: Genetic characterization of border disease virus (BDV) isolates from small ruminants in Italy. PMID- 25792188 TI - Differential T-helper cell polarization after allergen-specific stimulation of autologous dendritic cells in polysensitized allergic patients. AB - BACKGROUND: Dendritic cells (DCs) play an important role in the induction and regulation of adaptive immune responses by polarizing T-helper (Th) cells. In allergic disease this response is dominated by Th2 cells. It is still unclear whether the activation of Th cells by DCs in atopic individuals is allergen specific. METHODS: Monocyte-derived DCs (MoDCs) obtained from polysensitized patients were stimulated with purified Bet v 1, Phl p 5 and Act d 10, and the surface marker expression was analysed. Proliferation and cytokine profiles of autologous naive CD4+ T cells co-cultured with allergen-pulsed MoDCs were assessed. RESULTS: The addition of either Bet v 1 or Phl p 5 did not further increase the expression of surface markers from matured MoDCs in all study groups. In co-cultures, autologous naive CD4+ T cells proliferated when DCs obtained from individuals allergic to birch and grass pollen were stimulated with Bet v 1 and Phl p 5, respectively. In the co-culture supernatants, significantly increased levels of IL-5 and IL-13 were detected. This effect correlated with the sensitization background and was absent when applying an unspecific allergen, Act d 10. The levels of IL-10 in supernatants of MoDCs and the levels of IL-10 and IFN-gamma in supernatants of T cells remained unchanged upon stimulation with allergens. CONCLUSIONS: In this study we observed that allergen-specific stimulation of MoDCs induces T-cell proliferation and upregulation of Th2-type cytokines. Interestingly, this Th2 polarization was only observed in cells stimulated with the allergen to which the patients were sensitized. PMID- 25792191 TI - Whole-body gamma-irradiation decelerates rat hepatocyte polyploidization. AB - PURPOSE: To characterize hepatocyte polyploidization induced by intermediate dose of gamma-ray. MATERIALS AND METHODS: Male Wistar strain rats were whole-body irradiated (WBI) with 2 Gy of gamma-ray at the age of 1 month, and 5-6 rats were sacrificed monthly at 0-25 months after irradiation. The nuclear DNA content of individual hepatocytes was measured by flow cytometry, then hepatocytes were classified into various ploidy classes. RESULTS: Survival percentage, after exposure up to the end of the study, did not indicate any differences between the irradiated groups and controls. The degree of polyploidization in hepatocytes of irradiated rats, was significantly lower than that for the control after 1 month of exposure, and it continued to be lower after up to 8 months. Thereafter, the degree of polyploidization in the irradiated group slowly returned to the control level when the irradiated rats reached the age of 10 months. CONCLUSION: Intermediate dose of ionizing radiation, in contrast to high doses, decelerate hepatocyte polyploidization, which may coincides with the hypothesis of the beneficial effects of low doses of ionizing radiation. PMID- 25792192 TI - Modulation of cytokine levels in ameliorative effects of pulsed magnetic field on an experimental model of Chronic Constriction Injury. AB - PURPOSE: Clinical chronic neuropathic pain is often resistant to currently used pharmacotherapeutic applications. A number studies have shown that pulsed magnetic field (PMF) application may ameliorate the pain associated with damages, surgeries or diseases. However, possible potential mechanisms of PMF treatments have not been well documented. This study aimed to assess the therapeutic effects of PMF treatment on a Chronic Constriction Injury model (CCI) which mimics clinical chronic neuropathic pain symptoms. MATERIALS AND METHODS: Effects of PMF treatments or sham PMF (SPMF) were investigated by measuring the latencies, thresholds and cytokine levels (interleukin [IL]-1 beta, IL-6 and IL-10) of sciatic nerve in CCI or sham surgery rats. PMF was treated on CCI rats before (a day after surgery, PMF-AD) and after (a week after surgery, PMF-AW) the development of pain signs. RESULTS: Rats exhibited hyperalgesia and allodynia within one week following surgery, and lasted through the experiment. PMF treatments, but not SPMF, significantly enhanced the latency and threshold. Both anti-hyperalgesic and anti-allodynic actions of PMF-AD were greater than those of PMF-AW treatment. Similarly, PMF-AD had more pronounced effects on the level of pro- and anti-inflammatory cytokines than did PMF-AW. CONCLUSIONS: The present findings may suggest that PMF treatment may reverse the CCI-induced changes in neuropathic pain behaviors by decreasing the production of pro-inflammatory cytokines and increasing the anti-inflammatory cytokine production at the site of injury. PMID- 25792190 TI - C6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKCzeta tumor-suppressive activities and regulating integrin affinity modulation. AB - Nanoliposomal formulation of C6-ceramide, a proapoptotic sphingolipid metabolite, presents an effective way to treat malignant tumor. Here, we provide evidence that acute treatment (30 min) of melanoma and breast cancer cells with nanoliposomal C6-ceramide (NaL-C6) may suppress cell migration without inducing cell death. By employing a novel flow migration assay, we demonstrated that NaL C6 decreased tumor extravasation under shear conditions. Compared with ghost nanoliposome, NaL-C6 triggered phosphorylation of PI3K and PKCzeta and dephosphorylation of PKCalpha. Concomitantly, activated PKCzeta translocated into cell membrane. siRNA knockdown or pharmacological inhibition of PKCzeta or PI3K rescued NaL-C6-mediated suppression of tumor migration. By inducing dephosphorylation of paxillin, PKCzeta was responsible for NaL-C6-mediated stress fiber depolymerization and focal adhesion disassembly in the metastatic tumor cells. PKCzeta and PI3K regulated cell shear-resistant adhesion in a way that required integrin alphavbeta3 affinity modulation. In conclusion, we identified a novel role of acute nanoliposomal ceramide treatment in reducing integrin affinity and inhibiting melanoma metastasis by conferring PI3K and PKCzeta tumor suppressive activities. PMID- 25792193 TI - Psychological interventions for post-traumatic stress disorder and comorbid substance use disorder: A systematic review and meta-analysis. AB - Co-morbid post-traumatic stress disorder (PTSD) and substance use disorder (SUD) are common, difficult to treat, and associated with poor prognosis. This review aimed to determine the efficacy of individual and group psychological interventions aimed at treating comorbid PTSD and SUD, based on evidence from randomised controlled trials. Our pre-specified primary outcomes were PTSD severity, drug/alcohol use, and treatment completion. We undertook a comprehensive search strategy. Included studies were rated for methodological quality. Available evidence was judged through GRADE. Fourteen studies were included. We found that individual trauma-focused cognitive-behavioural intervention, delivered alongside SUD intervention, was more effective than treatment as usual (TAU)/minimal intervention for PTSD severity post-treatment, and at subsequent follow-up. There was no evidence of an effect for level of drug/alcohol use post-treatment but there was an effect at 5-7 months. Fewer participants completed trauma-focused intervention than TAU. We found little evidence to support the use of individual or group-based non-trauma-focused interventions. All findings were judged as being of low/very low quality. We concluded that there is evidence that individual trauma-focused psychological intervention delivered alongside SUD intervention can reduce PTSD severity, and drug/alcohol use. There is very little evidence to support use of non-trauma focused individual or group-based interventions. PMID- 25792194 TI - A pulsed uniform Laval expansion coupled with single photon ionization and mass spectrometric detection for the study of large molecular aggregates. AB - We report on a new instrument that allows for the investigation of weakly-bound molecular aggregates under equilibrium conditions (constant temperature and pressure). The aggregates are formed in a Laval nozzle and probed with time-of flight mass spectrometry in the uniform postnozzle flow; i.e. in the equilibrium region of the flow. Aggregates over a very broad size range from the monomer to particle sizes of 10-20 nm can be generated and studied with this setup. Soft ionization of the aggregates is performed with single photons from a homemade vacuum ultraviolet laser. The mass spectrometric detection provides molecular level information on the size and chemical composition of the aggregates. This new instrument is useful for a broad range of cluster studies that require well defined conditions. PMID- 25792195 TI - Practice guideline for treatment of latent tuberculosis infection in children. PMID- 25792197 TI - Performance of the present-on-admission indicator for Clostridium difficile infection. AB - The performance of a hospital- and community-onset Clostridium difficile infection definition using administrative data with a present-on-admission indicator was compared with definitions using clinical surveillance. For hospital onset C. difficile infection, there was moderate sensitivity (68%) and high specificity (93%); for community-onset, sensitivity and specificity were high (both 85%). PMID- 25792196 TI - Bmp4 from the optic vesicle specifies murine retina formation. AB - Previous studies of mouse embryos concluded that after the optic vesicle evaginates from the ventral forebrain and contacts the surface ectoderm, signals from the ectoderm specify the distal region of the optic vesicle to become retina and signals from the optic vesicle induce the lens. Germline deletion of Bmp4 resulted in failure of lens formation. We performed conditional deletion of Bmp4 from the optic vesicle to test the function of Bmp4 in murine eye development. The optic vesicle evaginated normally and contacted the surface ectoderm. Lens induction did not occur. The optic cup failed to form and the expression of retina-specific genes decreased markedly in the distal optic vesicle. Instead, cells in the prospective retina expressed genes characteristic of the retinal pigmented epithelium. We conclude that Bmp4 is required for retina specification in mice. In the absence of Bmp4, formation of the retinal pigmented epithelium is the default differentiation pathway of the optic vesicle. Differences in the signaling pathways required for specification of the retina and retinal pigmented epithelium in chicken and mouse embryos suggest major changes in signaling during the evolution of the vertebrate eye. PMID- 25792198 TI - Parkinson's disease and restless legs syndrome. AB - AIMS: Various sleep-related complications are common in Parkinson's disease (PD). The prevalence of restless legs syndrome (RLS) and its association with other symptoms were studied. METHODS: Altogether, 1,447 Parkinson patients, aged 43-89, participated in a questionnaire study. RESULTS: The response rate was 59.0% and of these, 68% returned fully answered questionnaires (n = 577). RLS occurred in 20.3% of the PD subjects. In patients with RLS, the symptoms occurred in 81.9% at least once weekly. The degree of severity was moderate in 42.7%, severe in 23.9% and very severe in 15.4%. Daytime sleepiness, fatigue, chronic insomnia, sleep maintenance insomnia, intense dreaming, and low quality of life were more common in patients with RLS than in patients without RLS. The occurrence of early onset RLS (onset <= age of 45 years) was 4.2%. The occurrences of late onset (>45 years) drug naive RLS and late onset RLS (with dopaminergic medication) were 5.4 and 10.4%, respectively. CONCLUSION: In patients with PD, the early onset of RLS resembles idiopathic RLS with typical gender distribution and familial trait. Late onset of RLS is more common than idiopathic RLS. PMID- 25792199 TI - Eye extract improves cell migration out of lymphoid organ explants of L. vannamei and viability of the primary cell cultures. AB - Since no cell line from shrimp has been established up till now, an optimization of the primary cell culture protocol is necessary. In this context, the effect of extracts (supernatant of a 1:50 (w/v) suspension) from different shrimp organs (muscle, brain, ganglia, eyestalk, ovary, and eye) on the performance of primary lymphoid cell cultures was evaluated. Ten percent of eye extract and 3% of ovary extract enhanced maximally the migration and survival of cells of the lymphoid organ of Litopenaeus vannamei significantly at 48, 96, and 144 h post seeding. Extracts from the eyestalk (10%), muscle (10%), and brain (1%) significantly promoted the migration and survival of cells at 48 and 96 h post seeding but not anymore at 144 h post seeding. In conclusion, it may be advised to add 10% of eye extract or 3% of ovary extract to cells for the maximal health of primary cell cultures from the lymphoid organ of L. vannamei. PMID- 25792200 TI - Rescue therapy for refractory ARDS should be offered early: no. PMID- 25792201 TI - Rescue therapy for refractory ARDS should be offered early: we are not sure. PMID- 25792202 TI - Non-verbal communication to restore patient-provider trust. PMID- 25792205 TI - Rescue therapy for refractory ARDS should be offered early: yes. PMID- 25792203 TI - Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria. AB - The antibiotic pipeline continues to diminish and the majority of the public remains unaware of this critical situation. The cause of the decline of antibiotic development is multifactorial and currently most ICUs are confronted with the challenge of multidrug-resistant organisms. Antimicrobial multidrug resistance is expanding all over the world, with extreme and pandrug resistance being increasingly encountered, especially in healthcare-associated infections in large highly specialized hospitals. Antibiotic stewardship for critically ill patients translated into the implementation of specific guidelines, largely promoted by the Surviving Sepsis Campaign, targeted at education to optimize choice, dosage, and duration of antibiotics in order to improve outcomes and reduce the development of resistance. Inappropriate antimicrobial therapy, meaning the selection of an antibiotic to which the causative pathogen is resistant, is a consistent predictor of poor outcomes in septic patients. Therefore, pharmacokinetically/pharmacodynamically optimized dosing regimens should be given to all patients empirically and, once the pathogen and susceptibility are known, local stewardship practices may be employed on the basis of clinical response to redefine an appropriate regimen for the patient. This review will focus on the most severely ill patients, for whom substantial progress in organ support along with diagnostic and therapeutic strategies markedly increased the risk of nosocomial infections. PMID- 25792204 TI - Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. AB - PURPOSE: To evaluate the prognostic value of the Cv-aCO2/Da-vO2 ratio combined with lactate levels during the early phases of resuscitation in septic shock. METHODS: Prospective observational study in a 60-bed mixed ICU. One hundred and thirty-five patients with septic shock were included. The resuscitation protocol targeted mean arterial pressure, pulse pressure variations or central venous pressure, mixed venous oxygen saturation, and lactate levels. Patients were classified into four groups according to lactate levels and Cv-aCO2/Da-vO2 ratio at 6 h of resuscitation (T6): group 1, lactate >=2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; group 2, lactate >=2.0 mmol/L and Cv-aCO2/Da-vO2 <=1.0; group 3, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; and group 4, lactate <2.0 mmol/L and Cv aCO2/Da-vO2 <=1.0. RESULTS: Combination of hyperlactatemia and high Cv-aCO2/Da vO2 ratio was associated with the worst SOFA scores and lower survival rates at day 28 [log rank (Mantel-Cox) = 31.39, p < 0.0001]. Normalization of both variables was associated with the best outcomes. Patients with a high Cv-aCO2/Da vO2 ratio and lactate <2.0 mmol/L had similar outcomes to hyperlactatemic patients with low Cv-aCO2/Da-vO2 ratio. The multivariate analysis revealed that Cv-aCO2/Da-vO2 ratio at both T0 (RR 3.85; 95 % CI 1.60-9.27) and T6 (RR 3.97; 95 % CI 1.54-10.24) was an independent predictor for mortality at day 28, as well as lactate levels at T6 (RR 1.58; 95 % CI 1.13-2.22). CONCLUSION: Complementing lactate assessment with Cv-aCO2/Da-vO2 ratio during early stages of resuscitation of septic shock can better identify patients at high risk of adverse outcomes. The Cv-aCO2/Da-vO2 ratio may become a potential resuscitation goal in patients with septic shock. PMID- 25792206 TI - Effects of a recruitment maneuver on plasma levels of soluble RAGE in patients with diffuse acute respiratory distress syndrome: a prospective randomized crossover study. AB - PURPOSE: The soluble form of the receptor for advanced glycation end-products (sRAGE) is a promising marker for epithelial dysfunction, but it has not been fully characterized as a biomarker of acute respiratory distress syndrome (ARDS). Whether sRAGE could inform on the response to ventilator settings has been poorly investigated, and whether a recruitment maneuver (RM) may influence plasma sRAGE remains unknown. METHODS: Twenty-four patients with moderate/severe, nonfocal ARDS were enrolled in this prospective monocentric crossover study and randomized into a "RM-SHAM" group when a 6-h-long RM sequence preceded a 6-h-long sham evaluation period, or a "SHAM-RM" group (inverted sequences). Protective ventilation was applied, and RM consisted of the application of 40 cmH2O airway pressure for 40 s. Arterial blood was sampled for gas analyses and sRAGE measurements, 5 min pre-RM (or 40-s-long sham period), 5, 30 min, 1, 4, and 6 h after the RM (or 40-s-long sham period). RESULTS: Mean PaO2/FiO2, tidal volume, PEEP, and plateau pressure were 125 mmHg, 6.8 ml/kg (ideal body weight), and 13 and 26 cmH2O, respectively. Median baseline plasma sRAGE levels were 3,232 pg/ml. RM induced a significant decrease in sRAGE (-1,598 +/- 859 pg/ml) in 1 h (p = 0.043). At 4 and 6 h post-RM, sRAGE levels increased back toward baseline values. Pre-RM sRAGE was associated with RM-induced oxygenation improvement (AUC 0.84). CONCLUSIONS: We report the first kinetics study of plasma sRAGE after RM in ARDS. Our findings reinforce the value of plasma sRAGE as a biomarker of ARDS. PMID- 25792208 TI - A clinical prediction model to identify patients at high risk of death in the emergency department. AB - PURPOSE: Rapid assessment and intervention is important for the prognosis of acutely ill patients admitted to the emergency department (ED). The aim of this study was to prospectively develop and validate a model predicting the risk of in hospital death based on all available information available at the time of ED admission and to compare its discriminative performance with a non-systematic risk estimate by the triaging first health-care provider. METHODS: Prospective cohort analysis based on a multivariable logistic regression for the probability of death. RESULTS: A total of 8,607 consecutive admissions of 7,680 patients admitted to the ED of a tertiary care hospital were analysed. Most frequent APACHE II diagnostic categories at the time of admission were neurological (2,052, 24%), trauma (1,522, 18%), infection categories [1,328, 15%; including sepsis (357, 4.1%), severe sepsis (249, 2.9%), septic shock (27, 0.3%)], cardiovascular (1,022, 12%), gastrointestinal (848, 10%) and respiratory (449, 5%). The predictors of the final model were age, prolonged capillary refill time, blood pressure, mechanical ventilation, oxygen saturation index, Glasgow coma score and APACHE II diagnostic category. The model showed good discriminative ability, with an area under the receiver operating characteristic curve of 0.92 and good internal validity. The model performed significantly better than non systematic triaging of the patient. CONCLUSIONS: The use of the prediction model can facilitate the identification of ED patients with higher mortality risk. The model performs better than a non-systematic assessment and may facilitate more rapid identification and commencement of treatment of patients at risk of an unfavourable outcome. PMID- 25792210 TI - Biobanking. PMID- 25792209 TI - Dual lumen catheter cannulation for venovenous ECMO. PMID- 25792211 TI - The challenge for a European network of biobanks for rare diseases taken up by RD Connect. AB - Access to biological materials is a key prerequisite for scientific research in any medical field and in particular for research into rare diseases (RDs), for which obtaining high-quality samples and the related clinical data remains a major hurdle. RD biobanks play a pivotal role in making such materials and data available to the scientific community. In order to increase the effectiveness of RD biobanks, three major challenges need to be met: maximise access to rare biological samples stored in RD biobanks spread globally by the international scientific community, promote networking among such biobanks to share quality standards and procedures and allow collaboration with RD registries and databases, and finally adopt an efficient management model compliant with legal and ethical issues and ensuring biobank sustainability. The European program RD Connect, funded under the FP7 program, addresses all of these issues through an articulated action plan aimed at building a network of European RD biobanks. Ultimately, RD-Connect will offer access to precious, quality-controlled biological samples from RD patients through an online, searchable, dynamic catalogue in the context of an integrated platform that links RD patient registries to biobanks and to clinical bioinformatics data for RD research. PMID- 25792212 TI - The uniqueness of biobanks for neurological and psychiatric diseases: potentials and pitfalls. AB - OBJECTIVES: Central nervous system (CNS) biobanks are facing difficult and specific challenges due to the sensitive issue of collecting specimens of the CNS, and especially the brain. At present, there is no global network/central database to serve researchers, clinicians and pharma companies, or to supply the special specimens and the accompanying data in sufficient numbers and detail, respectively. The main challenge/objective is to standardize and harmonize all the facets involved in CNS biobanking in order to maximize efficient sample collection. METHODS: Since the number of CNS biospecimens stored in existing biobanks is relatively limited and the accompanying data are not always readily available and hard to identify, we propose using optimal procedures for handling and storage of these specimens, and the global standardization of the cliniconeuropathological diagnostic criteria. RESULTS: One of the prominent achievements of the current global activity in brain tissue biobanks (BTB-banks) is the development of an inventory of international standards, available specimens and concomitant data, and national registries. CONCLUSIONS: Taking into consideration the huge variety of the specimens stored in different repositories and the enormous differences in medicolegal systems and ethics regulations in different countries, we strongly recommend that healthcare systems and institutions who host BTB-banks make efforts to secure adequate funding for the infrastructure and daily activities. BTB-banks will refine standard operating procedures and their internal guides of best practices/codes of conduct. This in turn will enable the BTB-banks to share the collected specimens and data with the largest possible number of researchers, aiming at maximal scientific spin-off and advance of public health research. PMID- 25792207 TI - Impact of early nutrition and feeding route on outcomes of mechanically ventilated patients with shock: a post hoc marginal structural model study. AB - PURPOSE: Few data are available about optimal nutrition modalities in mechanically ventilated patients with shock. Our objective was to assess associations linking early nutrition (<48 h after intubation), feeding route and calorie intake to mortality and risk of ventilator-associated pneumonia (VAP) in patients with invasive mechanical ventilation (IMV) and shock. METHODS: In the prospective OutcomeRea database, we identified adults with IMV >72 h and shock (arterial systolic pressure <90 mmHg) within 48 h after intubation. A marginal structural Cox model was used to create a pseudo-population in which treatment was unconfounded by subject-specific characteristics. RESULTS: We included 3,032 patients. Early nutrition was associated with lower day-28 mortality [HR 0.89, 95 % confidence interval (CI) 0.81-0.98, P = 0.01] and day-7 mortality (HR 0.76, CI 0.66-0.87, P < 0.001) but not with lower day-7 to day-28 mortality (HR 1.00, CI 0.89-1.12, P = 0.98). Early nutrition increased VAP risk over the 28 days (HR 1.08, CI 1.00-1.17, P = 0.046) and until day 7 (HR 7.17, CI 6.27-8.19, P < 0.001) but decreased VAP risk from days 7 to 28 (HR 0.85, CI 0.78-0.92, P < 0.001). Compared to parenteral feeding, enteral feeding was associated with a slightly increased VAP risk (HR 1.11, CI 1.00-1.22, P = 0.04) but not with mortality. Neither mortality nor VAP risk differed between early calorie intakes of >=20 and <20 kcal/kg/day. CONCLUSION: In mechanically ventilated patients with shock, early nutrition was associated with reduced mortality. Neither feeding route nor early calorie intake was associated with mortality. Early nutrition and enteral feeding were associated with increased VAP risk. PMID- 25792213 TI - Biobanking trends, challenges, and opportunities. AB - OBJECTIVES: To review the different interests and needs of industry and academic users of human biomaterials. METHODS: A review of the current literature and interviews with involved parties. Questionnaires were e-mailed to assess current attitudes towards biobanking and opinions of trends and implications for the future. The organisations included commercial biobanks, charitable foundations, academic biobanks, and hospital sites. RESULTS: Biobanks have the potential to have a critical impact across several industrial sectors, and their future success will depend on satisfying the differing needs of each group. There is a growing need for greater collaboration between researchers and biobanks, and if the involvement of industry is not sought by biobanks to create conditions that support the effective use of resources, there is a risk that samples will not be collected or used to the best advantage. CONCLUSIONS: It is evident that industry can play a vital role in the innovation process of biobanking, both in terms of the collecting and processing methods and the nature of the disease and sample types collected. With this feedback, biobanks can be utilised effectively to advance research to the benefits of all to the best advantage. PMID- 25792214 TI - Infrastructure and facilities for human biobanking in low- and middle-income countries: a situation analysis. AB - OBJECTIVE: To collect information on biobanking facilities in low- and middle income countries (LMICs) as a first step towards establishing an LMIC biobank and cohort building network (BCNet) to support research, with a focus on cancer control. METHOD: Sixty centres were identified from sources including cancer centres, universities, hospitals, and public health facilities and invited to participate in a survey between December 2012 and March 2013. RESULTS: Of the 27 centres (45%) that responded, most have existed for <10 years. They store between 1,000 and 1,000,000 research samples as well as samples remaining after clinical diagnosis. Sample storage is mostly in freezers, although 45% (9/20) of the centres do not have regular access to electricity. Biobank managers, sample management systems, and mechanisms for follow-up using linkages are uncommon. Many (80%; 21/26) of the centres have regulations to govern research, but regulations for the use of biobank resources (samples and data) are not well developed. CONCLUSIONS: Biobanking facilities are being developed in LMICs. Shortcomings in international visibility, sample sharing regulations, standardization, quality assurance, and sample management systems could be alleviated by international networking. Stakeholders need to work together to increase access to high-quality biological resources for scientific research. PMID- 25792215 TI - Cell purification: a new challenge for biobanks. AB - Performing '-omics' analyses on heterogeneous biological tissue samples, such as blood or bone marrow, can lead to biased or even erroneous results, particularly when the targeted cells and/or molecules are present at relatively low percentages/amounts. In such cases, whole sample analysis will most probably dilute and mask the features of the cell and/or molecules of interest, and this will negatively impact the results and their interpretation. Therefore, frequently it is critically important to have well-characterized and high-quality purified cell populations for the reliable detection of subtle variations in their specific features, such as gene expression profile, protein expression pattern and metabolic status. Biobanks are technological platforms which aim to provide researchers access to a large number of high-quality biological samples and their associated data, particularly to support high-quality scientific and clinical research projects, and such projects will benefit enormously by having access to high-quality purified cell populations or their biological components (e.g. DNA, RNA, proteins). Therefore, a clear opportunity exists for preparative cell sorting techniques in biobanks. Although multiple different cell purification approaches exist or are under development (e.g. cell purification techniques based on cell adherence, density and/or cell size properties, methods based on antibody binding as well as new lab-on-a-chip purification techniques), the choice for a specific technology depends on multiple variables, including cell recovery, purity and yield, among others. In addition, most cell purification approaches are not well suited for high-throughput (HT) purification of multiple cell populations coexisting in a sample. Here we review the most (currently) used cell sorting methods that may be applied for sample preparation in biobanks. For the different approaches, technical considerations about their advantages and limitations are highlighted, and the requirements to be met by a HT cell sorting technology to be used in biobanks are also discussed. PMID- 25792216 TI - Population biobanking and international collaboration. AB - Population-based biobanks promise to be important resources for genetic research. However, the study of normal genomic variation across populations requires the collection of data and biological samples from individuals on a large scale. While international collaboration has become both a scientific and an ethical imperative, international sharing of data and samples poses many challenges. Significant variation persists among the legal and ethical norms governing population biobanks in different jurisdictions. Many of these norms do not clearly provide for international access. To illustrate these problems, we collected and compared applicable legislative instruments, as well as ethical guidelines issued by national, regional, and international bodies. In addition, harmonization is faced with important limitations and may not be sufficient to ensure effective international sharing. Population biobanks are therefore looking for new ways to promote sharing and improve interoperability. The formation of biobank networks and the development of common governance tools are two approaches that are setting the groundwork for international collaboration in genetic research. PMID- 25792217 TI - Implementation of a cost-accounting model in a biobank: practical implications. AB - Given the state of global economy, cost measurement and control have become increasingly relevant over the past years. The scarcity of resources and the need to use these resources more efficiently is making cost information essential in management, even in non-profit public institutions. Biobanks are no exception. However, no empirical experiences on the implementation of cost accounting in biobanks have been published to date. The aim of this paper is to present a step by-step implementation of a cost-accounting tool for the main production and distribution activities of a real/active biobank, including a comprehensive explanation on how to perform the calculations carried out in this model. Two mathematical models for the analysis of (1) production costs and (2) request costs (order management and sample distribution) have stemmed from the analysis of the results of this implementation, and different theoretical scenarios have been prepared. Global analysis and discussion provides valuable information for internal biobank management and even for strategic decisions at the research and development governmental policies level. PMID- 25792218 TI - The role of diagnostic tissue in research. AB - There are two broad classes (or categories) of excised human tissue: diagnostic tissue (DT) and research tissue (RT). Classification of excised human tissue does not define its ultimate use and ultimate use of excised human tissue does not define its classification. While both DT and RT can be used for research, DT has specific requirements with respect to how it must be handled if and when being accessed for research. We highlight distinguishing features of DT: (1) it is a clinical record, (2) it must be identifiable to a specific individual, (3) it is stewarded by pathology departments/clinical laboratories and (4) it has a mandatory retention period. We discuss how the further sub-classification of DT into archived DT (aDT) and excess DT (eDT) impacts the nature of its role in research. We examine the concept of DT as a clinical record and emphasize the impact of mandatory retention as it applies to how DT may be accessed for research purposes. We explain the role of post-retention eDT as a source of RT as well as procedures for access to in-retention aDT for research. Clarity of such issues will facilitate responsible access to DT for research. PMID- 25792219 TI - Paediatric biobanks: opinions, feelings and attitudes of parents towards the specimen donation of their sick children to a hypothetical biobank. AB - Over the last years, the storing of biological materials from children for research purposes in biobanks has become the subject of an intense debate in the scientific and ethical communities on a global level. Paediatric biobanks are an important resource for the development of translational research. At the same time, paediatric biobanks are ethically 'sensitive' due to the unique issues they raise. In this study, we explore opinions, feelings and attitudes of parents towards the specimen donation of their sick children to a hypothetical biobank. According to a qualitative methodology based on focus groups, we analysed parents' views, perceptions and inclinations towards typical ethical, legal and social aspects of paediatric biobanks such as proxy consent, minor assent, privacy protection and return of results. Our study confirms the need for specific policies dedicated to paediatric biobanks by highlighting how the nature of the disease affecting children may influence the parents' opinions and decisions towards the enrolment of their children in biobank-based research studies. PMID- 25792221 TI - Pegvisomant Treatment in Acromegaly. AB - Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy options has been available. Somatostatin analogues have become the cornerstones of medical treatment in acromegaly and are even seen as a primary treatment in a selected group of acromegaly patients. The most recent medical treatment available for acromegaly patients is pegvisomant, a growth hormone receptor antagonist. To date, it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article, we review clinical studies and cohorts that have documented the efficacy of pegvisomant monotherapy and combined therapy and give a concise overview of associated side effects. PMID- 25792220 TI - Euodia sutchuenensis Dode extract stimulates osteoblast differentiation via Wnt/beta-catenin pathway activation. AB - The Wnt/beta-catenin pathway has a role in osteoblast differentiation and bone formation. We screened 100 plant extracts and identified an extract from Euodia sutchuenensis Dode (ESD) leaf and young branch as an effective activator of the Wnt/beta-catenin pathway. ESD extract increased beta-catenin levels and beta catenin nuclear accumulation in murine primary osteoblasts. The ESD extract also increased mRNA levels of osteoblast markers, including RUNX2, BMP2 and COL1A1, and enhanced alkaline phosphatase (ALP) activity in murine primary osteoblasts. Both ESD extract-induced beta-catenin increment and ALP activation were abolished by beta-catenin knockdown, confirming that the Wnt/beta-catenin pathway functions in osteoblast differentiation. ESD extract enhanced terminal osteoblast differentiation as shown by staining with Alizarin Red S and significantly increased murine calvarial bone thickness. This study shows that ESD extract stimulates osteoblast differentiation via the Wnt/beta-catenin pathway and enhances murine calvarial bone formation ex vivo. PMID- 25792223 TI - Molecular design of near-IR dyes with different surface energy for selective loading to the heterojunction in blend films. AB - We have synthesized three silicon phthalocyanine dyes with different hydrophobic substituents in order to control surface energy in the solid state, aiming at selective loading of the dyes into blend films of poly(3-hexylthiophene) (P3HT) and polystyrene (PS). These three dyes are differently located at P3HT domains, at P3HT/PS interface, and at PS domains, respectively, which are fully consistent with the locations predicted by the wetting coefficient derived from the surface energy of each material. PMID- 25792224 TI - Locoregional control of recurrent papillary thyroid carcinoma by ultrasound guided percutaneous microwave ablation: A prospective study. AB - PURPOSE: The aim of this study was to evaluate the safety and efficiency of ultrasound-guided percutaneous microwave (MW) ablation for the control of locally recurrent papillary thyroid carcinoma (LR-PTC) in patients for whom surgery is not viable. MATERIALS AND METHODS: The inclusion criteria for MW ablation were three or fewer LR-PTCs and no recurrence beyond the neck, with ineligibility or refusal to undergo surgery. MW ablation was carried out using a 16-gauge MW antenna under local anaesthesia. Patients were then followed at 1, 3, 6 and 12 months after treatment and every 6 months thereafter. Technical success usually meant volume reduction more than 50%. RESULTS: Between October 2010 to March 2013 a total of 17 patients (14 women, 3 men; average age 54.1 years) with 23 LR-PTCs, were treated with MW ablation in our department. All the LR-PTCs were technical successes with the number of treatment sessions for one tumour ranging from 1 to 4 (mean, 2.3 +/- 0.9). The mean volume reduction ratio of the LR-PTCs was 1 +/- 86%, 47 +/- 12%, 70 +/- 33%, 91 +/- 14% at the 1, 3, 6 and 18 months follow-up visit respectively (all p < 0.05). All treated nodules decreased in size: 30.4% nodules (7/23) had completely disappeared, 52.2% nodules (12/23) remained as small scar-like lesions. One patient experienced transient dysphonia immediately after MW ablation. No other severe and permanent complications occurred. CONCLUSION: Although with some limitations, our preliminary results are encouraging and show MW ablation may be an alternative treatment option for the control of LR-PTCs in selected patients for whom surgery is not viable. PMID- 25792222 TI - Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice. AB - BACKGROUND: RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders. METHODS: RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction and a candidate lncRNA, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncRNA was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding RNA directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays. RESULTS: RNA sequencing analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncRNAs. In particular, we detected a significant downregulation of Gomafu lncRNA. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior. CONCLUSIONS: Experience-dependent expression of lncRNAs plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders. PMID- 25792226 TI - A human surrogate model of itch utilizing the TRPA1 agonist trans-cinnamaldehyde. AB - The thermoreceptive transient receptor potential ankyrin 1 (TRPA1) is important in the transmission of itch, and its agonist trans-cinnamaldehyde has occasionally been reported to be a pruritogen in humans. However, no studies have accurately quantified the capabilities of trans-cinnamaldehyde to induce itch and related dysesthetic sensations. The present study examined alterations in somatosensory and vasomotor parameters in response to topical trans cinnamaldehyde 5% and vehicle (ethanol) in 24 healthy subjects. During the study the following parameters were recorded: itch area and intensity, hyperknesis, alloknesis, neurogenic flare, skin blood flow and temperature. Trans cinnamaldehyde evoked moderate itch sensation, flare, hyperknesis and alloknesis (p < 0.001). Blood flow and skin temperature were elevated in the area of trans cinnamaldehyde application (p < 0.001). Significant positive correlations were found between blood flow and skin temperature, itch area and blood flow, and itch area and skin temperature. Topical trans-cinnamaldehyde proved feasible as a human itch model with applicability in studying itch mechanisms or anti-pruritic drug profiling. PMID- 25792225 TI - Emerging non-cancer applications of therapeutic ultrasound. AB - Ultrasound therapy has been investigated for over half a century. Ultrasound can act on tissue through a variety of mechanisms, including thermal, shockwave and cavitation mechanisms, and through these can elicit different responses. Ultrasound therapy can provide a non-invasive or minimally invasive treatment option, and ultrasound technology has advanced to the point where devices can be developed to investigate a wide range of applications. This review focuses on non cancer clinical applications of therapeutic ultrasound, with an emphasis on treatments that have recently reached clinical investigations, and preclinical research programmes that have great potential to impact patient care. PMID- 25792227 TI - Interactions of Pseudomonas aeruginosa and Corynebacterium spp. with non phagocytic brain microvascular endothelial cells and phagocytic Acanthamoeba castellanii. AB - Several lines of evidence suggest that Acanthamoeba interact with bacteria, which may aid in pathogenic bacterial transmission to susceptible hosts, and these interactions may have influenced evolution of bacterial pathogenicity. In this study, we tested if Gram-negative Pseudomonas aeruginosa and Gram-positive Corynebacterium spp. can associate/invade and survive inside Acanthamoeba castellanii trophozoites and cysts, as well as non-phagocytic human brain microvascular endothelial cells. The results revealed that both Corynebacterium spp. and P. aeruginosa were able to associate as well as invade and/or taken up by the phagocytic A. castellanii trophozoite. In contrast, P. aeruginosa exhibited higher association as well as invasion of non-phagocytic HBMEC compared with Corynebacterium spp. Notably, P. aeruginosa remained viable during the encystment process and exhibited higher levels of recovery from mature cysts (74.54 bacteria per amoebae) compared with Corynebacterium spp. (2.69 bacteria per amoeba) (P < 0.05). As Acanthamoeba cysts can be airborne, these findings suggest that Acanthamoeba is a potential vector in the transmission of P. aeruginosa to susceptible hosts. When bacterial-ridden amoebae were exposed to favourable (nutrient-rich) conditions, A. castellanii emerged as vegetative trophozoites and remained viable, and likewise viable P. aeruginosa were also observed but rarely any Corynebacterium spp. were observed. Correspondingly, P. aeruginosa but not Corynebacterium spp. exhibited higher cytotoxicity to non phagocytic HBMEC, producing more than 75% cell death in 24 h, compared to 20% cell death observed with Corynebacterium spp. Additionally, it was observed that the bacterial conditioned medium had no negative effect on A. castellanii growth. Further characterization of amoebal and bacterial interactions will assist in identifying the role of Acanthamoeba in the transmission and evolution of pathogenic bacteria. PMID- 25792228 TI - Colorimetric biosensing of pathogens using gold nanoparticles. AB - Rapid detection of pathogens is crucial to minimize adverse health impacts of nosocomial, foodborne, and waterborne diseases. Gold nanoparticles are extremely successful at detecting pathogens due to their ability to provide a simple and rapid color change when their environment is altered. Here, we review general strategies of implementing gold nanoparticles in colorimetric biosensors. First, we highlight how gold nanoparticles have improved conventional genomic analysis methods by lowering detection limits while reducing assay times. Then, we focus on emerging point-of-care technologies that aim at pathogen detection using simpler assays. These advances will facilitate the implementation of gold nanoparticle-based biosensors in diverse environments throughout the world and help prevent the spread of infectious diseases. PMID- 25792230 TI - Liquid anti-solvent recrystallization to enhance dissolution of CRS 74, a new antiretroviral drug. AB - This study concerns a new compound named CRS 74 which has the property of inhibiting Human Immunodeficiency Virus (HIV) protease, an essential enzyme involved in HIV replication process. It is proved in this study that the original CRS 74 exhibits poor aqueous solubility and a very low dissolution rate, which can influence its bioavailability and clinical response. In an attempt to improve the dissolution rate, CRS 74 was recrystallized by liquid anti-solvent (LAS) crystallization. Ethanol was chosen as solvent and water as the anti-solvent. Recrystallized solids were compared with the original drug crystals in terms of physical and dissolution properties. Recrystallization without additives did not modify the CRS 74 dissolution profile compared to the original drug. CRS 74 was then recrystallized using different additives to optimize the process and formulate physicochemical properties. Steric stabilizer in organic phase ensured size-controlling effect, whereas electrostatic stabilizer in aqueous phase decreased particle agglomeration. Cationic additives avoided drug adsorption onto stainless steel T-mixer. In general, additive improved drug dissolution rate due to improvement of wetting properties by specific interactions between the drug and the additives, and ensured continuous production of CRS 74 by electrostatic repulsion. PMID- 25792229 TI - Trends of fast food consumption among adolescent and young adult Saudi girls living in Riyadh. AB - Background : Saudi Arabia has passed through lifestyle changes toward unhealthy dietary patterns such as high fast food consumption. Adolescents and young adults, particularly girls, are the main groups exposed to and affected by these adverse eating behaviors. Objective : The aim of this study was to examine the trends of fast food consumption among adolescent and young adult Saudi girls living in Riyadh, and to compare between them. Design : In a cross-sectional survey, 127 adolescent Saudi girls (13-18 years) and 69 young adult Saudi girls (19-29 years) were randomly recruited to participate in this study. Weight, height, waist circumference, and hip circumference were measured using standardized methods. Twenty-four-hour diet recall and a face-to-face interview food questionnaire were performed. Results : Most of the participants had adequate intake of protein, riboflavin, iron, and sodium, but exhibited low intake for several other nutrients. Among study participants, 95.4% consume restaurants' fast food and 79.1% eat fast food at least once weekly. Burgers and carbonated soft drinks were the main kinds of fast food meals and beverages usually eaten by girls. Adolescent girls who usually ate large portion sizes of fast food had significantly higher mean waist circumference and hip circumference. Participants eat fast food primarily for enjoying the delicious taste, followed by convenience. Restaurants' hygiene and safety standards were the main concern regarding fast food for 62.2% of girls. Finally, international restaurants were preferable by participants to buy fast food compared with local restaurants (70.9% vs. 29.1%). Conclusion : Our findings provide evidence on the high prevalence of fast food consumption among Saudi girls, suggesting an urgent need for community-based nutrition interventions that consider the trends of fast food consumption and targeted eating behaviors of adolescent and young adult girls. PMID- 25792231 TI - Contextual fear conditioning in humans using feature-identical contexts. AB - Contextual fear conditioning studies in animals and humans found an involvement of the hippocampus and amygdala during fear learning. To exclude a focus on elements of the context we employed a paradigm, which uses two feature-identical contexts that only differ in the arrangement of the features and requires configural processing. We employed functional magnetic resonance imaging to determine the role of the hippocampus and neocortical areas during the acquisition of contextual fear in humans. For contextual fear acquisition, we paired one context (CS+) with an aversive electrical stimulus, whereas the other (CS-) was never followed by aversive stimulation. Blood oxygen level dependent activation to the CS+ was present in the insula, inferior frontal gyrus, inferior parietal lobule, superior medial gyrus and caudate nucleus. Furthermore, the amygdala and hippocampus were involved in a time-dependent manner. Psychophysiological interaction analyses revealed functional connectivity of a more posterior hippocampal seed region with the anterior hippocampus, posterior cingulate cortex and superior parietal lobule. The anterior hippocampus was functionally coupled with the amygdala and postcentral gyrus. This study complements previous findings in contextual fear conditioning in humans and provides a paradigm which might be useful for studying patients with hippocampal impairment. PMID- 25792232 TI - Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus. AB - The brain can be exposed to ionizing radiation in various ways, and such irradiation can trigger adverse effects, particularly on learning and memory. However, the precise mechanisms of cognitive impairments induced by cranial irradiation remain unknown. In the hippocampus, brain-derived neurotrophic factor (BDNF) plays roles in neurogenesis, neuronal survival, neuronal differentiation, and synaptic plasticity. The significance of BDNF transcript variants in these contexts is becoming clearer. In the present study, both object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice were assessed 1 month after a single exposure to cranial irradiation (10 Gy) to evaluate hippocampus-related behavioral dysfunction following such irradiation. Furthermore, changes in the levels of BDNF, the cAMP-response element binding protein (CREB) phosphorylation, and BDNF transcript variants were measured in the hippocampus 1 month after cranial irradiation. On object recognition memory and contextual fear conditioning tasks, mice evaluated 1 month after irradiation exhibited significant memory deficits compared to sham-irradiated controls, but no apparent change was evident in locomotor activity. Both phosphorylated CREB and BDNF protein levels were significantly downregulated after irradiation of the hippocampus. Moreover, the levels of mRNAs encoding common BDNF transcripts, and exons IIC, III, IV, VII, VIII, and IXA, were significantly downregulated after irradiation. The reductions in CREB phosphorylation and BDNF expression induced by differential regulation of BDNF hippocampal exon transcripts may be associated with the memory deficits evident in mice after cranial irradiation. PMID- 25792233 TI - Longitudinal trajectories of marijuana use from adolescence to young adulthood. AB - BACKGROUND: Marijuana use is increasingly widespread among adolescents and young adults; however, few studies have examined longitudinal trajectories of marijuana use during this important developmental period. As such, we examined adolescent trajectories of marijuana use and the psychosocial factors that may differentiate individuals who escalate their marijuana use over adolescence and young adulthood from those who do not. METHODS: Participants were 1204 9th and 10th graders at baseline who were over-sampled for cigarette use and were followed over 6-years, as part of an extensive longitudinal study, the Social and Emotional Contexts of Adolescent Smoking Patterns (SECASP) study. Growth Mixture Modeling (GMM) was used to model trajectories of marijuana use and Mixed Effects Regression analyses were used to examine psychosocial correlates of marijuana use escalation over time. RESULTS: Our results revealed three trajectories of non-escalating users (low users, medium users, and high users) and one escalating user trajectory. We found that relative to Non-escalators the Escalators had higher cigarette smoking (p<.0001), novelty-seeking (p=.02), aggressive and anti-social behavior (p<.007), and problem behavior related to peer context (p=.04). Moreover, there were important time and Group by Time interactions in some of these relationships. On the other hand, parental control and depression did not differ between escalators and low and medium non-escalating users. CONCLUSIONS: Cigarette smoking, novelty seeking, aggressive and anti-social behavior, and peer influence are related to 'escalating' marijuana use throughout adolescence and young adulthood. PMID- 25792235 TI - The role of sphingolipids and lipid rafts in determining cell fate. PMID- 25792234 TI - Zebrafish vitamin K epoxide reductases: expression in vivo, along extracellular matrix mineralization and under phylloquinone and warfarin in vitro exposure. AB - Vitamin K (VK) acts as a cofactor driving the biological activation of VK dependent proteins and conferring calcium-binding properties to them. As a result, VK is converted into VK epoxide, which must be recycled by VK epoxide reductases (Vkors) before it can be reused. Although VK has been shown to play a central role in fish development, particularly during skeletogenesis, pathways underlying VK actions are poorly understood, while good and reliable molecular markers for VK cycle/homeostasis are still lacking in fish. In the present work, expression of 2 zebrafish vkor genes was characterized along larval development and in adult tissues through qPCR analysis. Zebrafish cell line ZFB1 was used to evaluate in vitro regulation of vkors and other VK cycle-related genes during mineralization and upon 24 h exposure to 0.16 and 0.8 uM phylloquinone (VK1), 0.032 uM warfarin, or a combination of both molecules. Results showed that zebrafish vkors are differentially expressed during larval development, in adult tissues, and during cell differentiation/mineralization processes. Further, several VK cycle intermediates were differentially expressed in ZFB1 cells exposed to VK1 and/or warfarin. Present work provides data identifying different developmental stages and adult tissues where VK recycling is probably highly required, and shows how genes involved in VK cycle respond to VK nutritional status in skeletal cells. Expression of vkor genes can represent a reliable indicator to infer VK nutritional status in fish, while ZFB1 cells could represent a suitable in vitro tool to get insights into the mechanisms underlying VK action on fish bone. PMID- 25792236 TI - Activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) by free fatty acid receptor 1 (FFAR1/GPR40) protects from palmitate-induced beta cell death, but plays no role in insulin secretion. AB - AIMS: GPR40/FFAR1 mediates palmitate-induced stimulation of insulin secretion but its involvement in lipotoxicity is controversial. Our previous observations suggest that FFAR1/GPR40 agonists protect against lipotoxicity although the underlying mechanism remains elusive. The present study examines the role of ERK1/2 and GPR40/FFAR1 in palmitate-induced stimulation of insulin secretion and beta cell death. METHODS: Insulin secretion of INS-1E cells was measured by radioimmunoassay. Protein phosphorylation was examined on Western blots. Apoptosis was assessed by TUNEL staining. RESULTS: Palmitate and the GPR40/FFAR1 agonist TUG-469 increased phosphorylation of ERK1/2 at low (2.8 mmol/L) and high (12 mmol/L) glucose but stimulated insulin secretion only at high glucose. The MEK1 inhibitor PD98059 significantly reduced phosphorylation of ERK1/2 but did not reverse the stimulation of secretion induced by glucose, palmitate or TUG 469. PD98059 rather augmented glucose-induced secretion. Prolonged exposure to palmitate stimulated apoptosis, an effect counteracted by TUG-469. PD98059 accentuated palmitate-induced apoptosis and reversed TUG-469-mediated inhibition of cell death. CONCLUSIONS: Activation of ERK1/2 by palmitate and GPR40/FFAR1 agonist correlates neither with stimulation of insulin secretion nor with induction of apoptosis. The results suggest a significant anti-apoptotic role of ERK1/2 under conditions of lipotoxicity. PMID- 25792237 TI - Relationship between breast-feeding and bone mineral density among Korean women in the 2010 Korea National Health and Nutrition Examination Survey. AB - Breast-feeding has the deleterious effect of hypoestrogenemia coupled with loss of calcium in the maternal bone mass. It is not clear whether changes in bone metabolism in lactating women lead to changes in maternal bone mineral density (BMD) over a longer period. The aim of the present study was to investigate the relationship between the duration of breast-feeding and BMD in healthy South Korean women. We analyzed data from the 2010 Korea National Health and Nutrition Examination Survey, a cross-sectional survey of Korean citizens. A total of 1342 women older than 19 years were selected for analysis. In postmenopausal women, the duration of breast-feeding per child was associated with low lumbar spine BMD after adjustment for age, body mass index, smoking, alcohol intake, physical activity, serum 25-hydroxyvitamin D level, and daily intake of calcium and calories (P < 0.05, P trend < 0.005). Prolonged breast-feeding for more than 1 year per child was associated with a deleterious effect on lumbar spine BMD compared with never breast-feeding or a shorter duration of breast-feeding (P < 0.05). These effects were not shown in premenopausal women or in femur BMD. In conclusion, the duration of breast-feeding per child is negatively correlated with lumbar spine BMD in postmenopausal women, but not in premenopausal women. Although the cause of the different results between postmenopausal and premenopausal women is not clear, our findings suggest that proper protective strategies should be recommended during prolonged breast-feeding to maintain bone health later in life. PMID- 25792238 TI - Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells. AB - Fibroblast growth factor 23 (FGF23) has been shown to work as a phosphotropic hormone. Although FGF23 reduces the serum phosphate level, it has not been established that phosphate directly regulates FGF23 production. In this study, we investigated whether phosphate can enhance Fgf23 expression using the rat osteoblastic cell line UMR-106, which has been shown to express Fgf23 in response to 1,25-dihydroxyvitamin D [1,25(OH)2D]. Phosphate increased Fgf23 expression in a dose- and time-dependent manner in the presence of 1,25(OH)2D. Phosphate also increased Fgf23 promoter activity, but showed no effect on the half-life of Fgf23 messenger RNA. Phosphonoformic acid and PD98059, an inhibitor of MEK, inhibited the effects of phosphate on Fgf23 expression and promoter activity. In addition, phosphate enhanced production of reactive oxygen species (ROS) in UMR-106 cells, and hydrogen peroxide enhanced FGF23 production in a dose- and time-dependent manner. Hydrogen peroxide also enhanced Elk1 reporter activity, a target of the MEK-extracellular-signal-regulated kinase (ERK) pathway. Furthermore, the effect of phosphate on ROS production and Fgf23 expression was inhibited by apocynin, an inhibitor of NADPH oxidase. These results indicate that phosphate directly enhances Fgf23 transcription without affecting the stability of Fgf23 messenger RNA by stimulating NADPH-induced ROS production and the MEK-ERK pathway in UMR 106 cells. PMID- 25792239 TI - Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations. AB - TAR DNA-binding protein 43 (TDP-43) is a major component of the pathologic inclusions observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients. We examined TDP-43 expression in primary fibroblasts cultures from 22 ALS patients, including cases with SOD1 (n = 4), TARDBP (n = 4), FUS (n = 2), and C9ORF72 (n = 3) mutations and 9 patients without genetic defect. By using a phosphorylation-independent antibody, 15 patients showed notable alterations of TDP-43 level in the nuclear or cytoplasmic compartments. In particular, a marked accumulation of TDP-43 was observed in the cytoplasm of all cases with C9ORF72 and TARDBP mutations, 1 patient with FUS mutation and 3 patients without genetic defect. Patients with SOD1 mutations revealed a significant reduction of TDP-43 in the nuclei without cytoplasmic mislocalization. These changes were associated with the presence of truncated and phosphorylated TDP-43 species. Our results show that fibroblasts recapitulate some of hallmark TDP-43 abnormalities observed in neuronal cells. The reduction of full-length TDP-43 level in mutant SOD1 cells indicates that at least some SOD1 mutations alter TDP-43 metabolism. PMID- 25792240 TI - Clinical validity of the Mattis Dementia Rating Scale in differentiating mild cognitive impairment in Parkinson's disease and normative data. AB - BACKGROUND/AIMS: The aim of the present study was to provide normative data and determine the validity of the Czech version of the Mattis Dementia Rating Scale 2 (czDRS-2) in screening for mild cognitive impairment in Parkinson's disease (PD MCI) based on the Movement Disorder Society (MDS) Level II criteria. METHODS: For validation purposes, 41 healthy controls (HC), 46 patients with PD-NI (Parkinson's disease, no impairment) and 41 patients with PD-MCI (all groups assessed by the MDS Level II criteria for PD-MCI) were matched according to age and education. RESULTS: With screening and diagnostic cutoff scores determined at <=139 points, the czDRS-2 showed a sensitivity of 78% and a specificity of 88% in the detection of PD-MCI versus HC and a sensitivity of 78% and a specificity of 76% in the detection of PD-MCI versus PD-NI. The AUC (95% confidence interval) for the czDRS-2 was 84% (75-93) and 82% (73-91), respectively. We report percentile values for 286 subjects from the Czech population stratified by education level. CONCLUSION: Our results show that the czDRS-2 is a valid instrument at Level I for screening PD-MCI and support its construct validity and diagnostic equivalence in a cross-cultural setting. PMID- 25792241 TI - Endocrine Effects of Valproate versus Carbamazepine in Males with Epilepsy: A Prospective Study. AB - BACKGROUND/AIMS: To prospectively evaluate the long-term impact of valproate (VPA) versus carbamazepine (CBZ) on anthropometric, hormonal, and metabolic parameters in young male patients treated for epilepsy. METHODS: Of 61 boys with newly diagnosed epilepsy followed up, 24 were excluded from analysis (17 were lost to follow-up and 7 changed therapy within <1 year). Findings were compared by time, treatment (VPA or CBZ), and epilepsy type (generalized or partial) as well as against a matched control group with adequately treated hypothyroidism. RESULTS: Twenty-four boys were treated with VPA and 13 with CBZ. The weight standard deviation score (SDS) significantly increased during the first 6 months of treatment (p < 0.001), irrespective of the drug type, but decreased between the first and the last visit (p = 0.01). In patients with generalized epilepsy, there was a slight decrease in height- and weight-SDS between the first and the last visit (p = 0.04 and p = 0.01, respectively). The height-SDS at the last visit was comparable to the parental height-SDS. The mean age at puberty onset was 11.2 and 11.4 years in the study and the control group, respectively (p = 0.08). There were no significant differences in the other parameters by treatment or epilepsy type. CONCLUSIONS: Long-term therapy with VPA or CBZ has no significant endocrinological or metabolic adverse effect on male children and adolescents with epilepsy. PMID- 25792242 TI - Why are cancer drugs so expensive in the United States, and what are the solutions? AB - High cancer drug prices are a worsening trend in cancer care and are affecting patient care and our health care system. In the United States, the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000 to more than $100,000 by 2012, while the average household income has decreased by about 8% in the past decade. Further, although 85% of cancer basic research is funded through taxpayers' money, Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries. Bound by the Hippocratic Oath, oncologists have a moral obligation to advocate for affordable cancer drugs. In this article, we discuss the high cost of cancer drugs, the reasons for these high prices, the implications for patients and the health care system, and potential solutions to the problem. PMID- 25792243 TI - Exercise capacity and risk of chronic kidney disease in US veterans: a cohort study. AB - OBJECTIVE: To assess the association between exercise capacity and the risk of developing chronic kidney disease (CKD). PATIENTS AND METHODS: Exercise capacity was assessed in 5812 male veterans (mean age, 58.4+/-11.5 years) from the Veterans Affairs Medical Center, Washington, DC. Study participants had an estimated glomerular filtration rate of 60 mL/min per 1.73 m(2) or more 6 months before exercise testing and no evidence of CKD. Those who developed CKD during follow-up were initially identified by the International Classification of Diseases, Ninth Revision and further verified by at least 2 consecutive estimated glomerular filtration rate values of less than 60 mL/min per 1.73 m(2) 3 months or more apart. Normal kidney function for CKD-free individuals was confirmed by sequential normal eGFR levels. We established 4 fitness categories on the basis of age-stratified quartiles of peak metabolic equivalents (METs) achieved: least fit (<=25%; 4.8+/-0.90 METs; n=1258); low-fit (25.1%-50%; 6.5+/-0.96 METs; n=1614); moderate-fit (50.1%-75%; 7.7+/-0.91 METs; n=1958), and high-fit (>75%; 9.5+/-1.0 METs; n=1436). Multivariable Cox proportional hazard models were used to assess the association between exercise capacity and CKD. RESULTS: During a median follow-up period of 7.9 years, 1010 developed CKD (20.4/1000 person years). Exercise capacity was inversely related to CKD incidence. The risk was 22% lower (hazard ratio, 0.78; 95% CI, 0.75-0.82; P<.001) for every 1-MET increase in exercise capacity. Compared with the least-fit individuals, hazard ratios were 0.87 (95% CI, 0.74-1.03) for low-fit, 0.55 (95% CI, 0.47-0.65) for moderate-fit, and 0.42 (95% CI, 0.33-0.52) for high-fit individuals. CONCLUSION: Higher exercise capacity attenuated the risk of developing CKD. The association was independent and graded. PMID- 25792244 TI - A practical approach to the imaging interpretation of sphenoid sinus pathology. AB - The goal of this article is to provide a practical approach to the imaging interpretation of sphenoid sinus pathology. Basic anatomy and physiology is reviewed first. This is followed by a discussion of the imaging modalities used to evaluate the sphenoid sinuses and how to differentiate a benign from an aggressive lesion. Finally, disease entities are discussed, with attention to clinical presentation, expected imaging appearance, and treatment. Although the focus is on sphenoid sinus pathology, the concepts presented can be applied to interpretation of disease in any paranasal sinus. PMID- 25792245 TI - Eponymous cardiovascular surgeries for congenital heart diseases--imaging review and historical perspectives. AB - Advances in pediatric cardiology and cardiac surgical techniques over the past few decades have revolutionized the management of the patients with congenital heart disease, and many now survive into adulthood. Several eponymous surgical procedures performed for congenital heart disease have been named after eminent surgeons. In this article, we provide a short biography of the surgeons associated with these eponymous surgical procedures along with their other important scientific contributions. This is followed by a review of these surgical procedures and their most common complications. Imaging appearances of these surgical procedures along with common complications are described and illustrated, with particular emphasis on magnetic resonance imaging. The surgical procedures described in this review include Blalock-Taussig, Potts, Waterston, Glenn, Fontan, Kawashima, Norwood, Sano, Damus-Kaye-Stansel, Mustard, Senning, Jatene, LeCompte, Rastelli, Rashkind, Ross, and Waldenhausen. PMID- 25792246 TI - Carrier localization in In-rich InGaN/GaN multiple quantum wells for green light emitting diodes. AB - Carrier localization phenomena in indium-rich InGaN/GaN multiple quantum wells (MQWs) grown on sapphire and GaN substrates were investigated. Temperature dependent photoluminescence (PL) spectroscopy, ultraviolet near-field scanning optical microscopy (NSOM), and confocal time-resolved PL (TRPL) spectroscopy were employed to verify the correlation between carrier localization and crystal quality. From the spatially resolved PL measurements, we observed that the distribution and shape of luminescent clusters, which were known as an outcome of the carrier localization, are strongly affected by the crystalline quality. Spectroscopic analysis of the NSOM signal shows that carrier localization of MQWs with low crystalline quality is different from that of MQWs with high crystalline quality. This interrelation between carrier localization and crystal quality is well supported by confocal TRPL results. PMID- 25792247 TI - Obesity and the use of antibiotics and probiotics in rats. AB - BACKGROUND: Obesity has become a major public health challenge in recent years. Recent studies suggest that alterations of the gut microbiota by antibiotics could play an important role in obesity. METHODS: We investigated this topic using 60 Wistar rats, which were divided into 3 experimental groups: rats treated with amoxicillin, rats treated with amoxicillin plus Saccharomyces boulardii and controls. Treatments were administered over the course of 2 weeks. Tetrapolar bioelectric impedance analysis and anthropometric evaluations were conducted. RESULTS: The body mass index was significantly lower for the animals in the control group (p = 0.034). The same result was observed for the Lee index: the control group had a lower index than the 2 groups that received antibiotic treatment (p = 0.0019). The total body water data demonstrated that the control group had the greatest amount of body water (279.1 g, p = 0.0243). CONCLUSIONS: The groups treated with the antibiotic exhibited a greater accumulation of body fat than the control group. PMID- 25792248 TI - Robotic single-site myomectomy: initial report and technique. AB - OBJECTIVE: To report the first cases of robotic single-site (RSS) myomectomy with the use of the Da Vinci Si Surgical System with wristed semirigid instrumentation. DESIGN: Case series. SETTING: University hospital. PATIENT(S): Four patients with symptomatic uterine fibroids desiring conservative minimally invasive surgical treatment. INTERVENTION(S): Four RSS myomectomies were performed with the Da Vinci Single-Site platform. Data regarding patient characteristics, indication of surgery, and perioperative outcomes were collected. MAIN OUTCOME MEASURE(S): Safety and reproducibility of RSS myomectomy. RESULT(S): All RSS procedures were completed successfully. Median operative time was 210 minutes (range 202-254 min). Median blood loss was 103 mL (range 75-200 mL). No instrument failures were noted during the procedures. No operative or major postoperative complications occurred. Two patients were discharged on the day of surgery, and two were discharged after overnight observation. CONCLUSION(S): RSS myomectomy with the use of wristed semi-rigid instrumentation is a feasible procedure. Indications, safety, and use of the technique will be confirmed by growing experience. PMID- 25792250 TI - Implementation of in situ SAXS/WAXS characterization into silicon/glass microreactors. AB - A successful implementation of in situ X-ray scattering analysis of synthetized particle materials in silicon/glass microreactors is reported. Calcium carbonate (CaCO3) as a model material was precipitated inside the microchannels through the counter-injection of two aqueous solutions, containing carbonate ions and calcium ions, respectively. The synthesized calcite particles were analyzed in situ in aqueous media by combining Small Angle X-ray Scattering (SAXS) and Wide Angle X ray Scattering (WAXS) techniques at the ESRF ID02 beam line. At high wavevector transfer, WAXS patterns clearly exhibit different scattering features: broad scattering signals originating from the solvent and the glass lid of the chip, and narrow diffraction peaks coming from CaCO3 particles precipitated rapidly inside the microchannel. At low wavevector transfer, SAXS reveals the rhombohedral morphology of the calcite particles together with their micrometer size without any strong background, neither from the chip nor from the water. This study demonstrates that silicon/glass chips are potentially powerful tools for in situ SAXS/WAXS analysis and are promising for studying the structure and morphology of materials in non-conventional conditions like geological materials under high pressure and high temperature. PMID- 25792251 TI - Preformed nanoporous carbon nanotube scaffold-based multifunctional polymer composites. AB - Multifunctional polymer nanocomposites that simultaneously possess high modulus and strength, high thermal stability, novel optical responses, and high electrical and thermal conductivity have been actively researched. Carbon nanotubes are considered an ideal additive for composites because of their superlative physical, electronic and optical properties. While nanotubes have successfully added electrical conductivity, thermal stability, and novel optical responses to polymers, mechanical reinforcements, although substantial, have been well below any theoretical estimations. Here, we integrated preformed hydrogels and aerogels of individually dispersed nanotubes with polymer to increase elastic modulus of composites according to Halpin-Tsai model up to at least 25 vol % of nanotubes. Our solution-based fabrication method allowed us to create bulk composites with tunable form-factors, and with polymers that were incompatible with nanotubes. Further, in this approach, nanotubes were not covalently linked among themselves and to the polymer, so intrinsic optical, electrical, and thermal properties of nanotubes could be exploited. The optically active nanotubes, for example, added a strain-dependent, spatially resolved fluorescence to these composites. Finally, the nanoporous nanotube networks suppressed the polymer glass transition and extended the mechanical integrity of polymer well above its polymer melting point, and both the nanotubes and polymer remained thermally stable above their decomposition temperatures. PMID- 25792249 TI - Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. AB - OBJECTIVE: To determine whether BRCA mutation carriers who undergo fertility treatments are at increased risk of developing invasive epithelial ovarian cancer (IEOC). DESIGN: Historical cohort study. SETTING: Tertiary university-affiliated medical center and the National Cancer Registry. PATIENT(S): A total of 1,073 Jewish Israeli BRCA mutation carriers diagnosed in a single institution between 1995 and 2013, including 164 carriers (15.2%) who had fertility treatments that included clomiphene citrate (n = 82), gonadotropin (n = 69), in vitro fertilization (IVF) (n = 66), or a combination (n = 50), and 909 carriers not treated for infertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Odds ratios (OR) and 95% confidence intervals (CI) for IEOC association with fertility treatments and other hormone and reproductive variables. RESULT(S): In 175 (16.3%) mutation carriers, IEOC was diagnosed; 139 women carried BRCA1, 33 carried BRCA2, and 3 had unknown mutations. Fertility treatments were not associated with IEOC risk (age-adjusted OR 0.63; 95% CI, 0.38-1.05) regardless of treatment type (with clomiphene citrate, OR 0.87; 95% CI, 0.46-1.63; with gonadotropin, OR 0.59; 95% CI, 0.26-1.31; with IVF, OR 1.08, 95% CI, 0.57-2.06). Multivariate analysis indicated an increased risk of IEOC with hormone replacement therapy (OR 2.22; 95% CI, 1.33-3.69) and a reduced risk with oral contraceptives (OR 0.19; 95% CI, 0.13-0.28) in both BRCA1 and BRCA2 mutation carriers. Parity was a risk factor for IEOC by univariate but not multivariate analysis. CONCLUSION(S): According to our results, treatments for infertile BRCA mutation carriers should not be contraindicated or viewed as risk modifiers for IEOC. Parity as a risk factor in BRCA mutation carriers warrants further investigation. PMID- 25792252 TI - Ethylene Signaling Influences Light-Regulated Development in Pea. AB - Plant responses to light involve a complex network of interactions among multiple plant hormones. In a screen for mutants showing altered photomorphogenesis under red light, we identified a mutant with dramatically enhanced leaf expansion and delayed petal senescence. We show that this mutant exhibits reduced sensitivity to ethylene and carries a nonsense mutation in the single pea (Pisum sativum) ortholog of the ethylene signaling gene ETHYLENE INSENSITIVE2 (EIN2). Consistent with this observation, the ein2 mutation rescues the previously described effects of ethylene overproduction in mature phytochrome-deficient plants. In seedlings, ein2 confers a marked increase in leaf expansion under monochromatic red, far red, or blue light, and interaction with phytochromeA, phytochromeB, and long1 mutants confirms that ein2 enhances both phytochrome- and cryptochrome-dependent responses in a LONG1-dependent manner. In contrast, minimal effects of ein2 on seedling development in darkness or high-irradiance white light show that ethylene is not limiting for development under these conditions. These results indicate that ethylene signaling constrains leaf expansion during deetiolation in pea and provide further evidence that down-regulation of ethylene production may be an important component mechanism in the broader control of photomorphogenic development by phytochrome and cryptochrome. PMID- 25792254 TI - Comparison of conventional and ultrasound-guided needle biopsy techniques in the diagnosis of sarcoidosis: a randomized trial. AB - INTRODUCTION: Endoscopic biopsy techniques are useful in the diagnosis of sarcoidosis. There is a need for randomized trials to establish where these procedures fit in the diagnosis of sarcoidosis. OBJECTIVES: The aim of the study was to compare the diagnostic yield of conventional transbronchial needle aspiration (TBNA) with endobronchial ultrasound-guided TBNA (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in stages I and II of pulmonary sarcoidosis. PATIENTS AND METHODS: Patients suspected of sarcoidosis were randomized to undergo TBNA or EBUS-TBNA or EUS-FNA. Patients with negative TBNA and EBUS-TBNA results underwent EUS-FNA and those with negative EUS-FNA results-EBUS-TBNA. If both tests were negative, patients in stage I were scheduled for mediastinoscopy (MS) and those in stage II-for transbronchial lung biopsy (TBLB). RESULTS: In 100 patients, 34 TBNA, 30 EBUS-TBNA, and 36 EUS-FNA procedures were performed at baseline. TBNA was positive in 20 patients (58.8%); EBUS-TBNA, in 23 (76.7%); and EUS-FNA, in 31 patients (86.1%). In patients with negative biopsy results, the second procedure was performed. The results of EUS FNA were positive in 9 patients and of EBUS-TBNA-in none. Of 17 patients with negative results of both procedures, MS was performed in 6 patients and was positive in 2. In the remaining 11 patients, sarcoidosis was confirmed by TBLB. Sensitivity and accuracy of TBNA compared with EBUS-TBNA and EUS-FNA were 62.5% and 64.7%, 79.3% and 80%, and 88.6% and 88.9%, respectively. Sensitivity and accuracy of EBUS-TBNA were higher (P = 0.139) and of EUS-FNA were significantly higher compared with TBNA (P = 0.012). CONCLUSIONS: In stages I and II of pulmonary sarcoidosis, endoscopic ultrasound is a reasonable approach but EUS-FNA seems to be the method of choice. PMID- 25792253 TI - The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses. AB - Eukaryotic endoplasmic reticulum (ER)-plasma membrane (PM) contact sites are evolutionarily conserved microdomains that have important roles in specialized metabolic functions such as ER-PM communication, lipid homeostasis, and Ca(2+) influx. Despite recent advances in knowledge about ER-PM contact site components and functions in yeast (Saccharomyces cerevisiae) and mammals, relatively little is known about the functional significance of these structures in plants. In this report, we characterize the Arabidopsis (Arabidopsis thaliana) phospholipid binding Synaptotagmin1 (SYT1) as a plant ortholog of the mammal extended synaptotagmins and yeast tricalbins families of ER-PM anchors. We propose that SYT1 functions at ER-PM contact sites because it displays a dual ER-PM localization, it is enriched in microtubule-depleted regions at the cell cortex, and it colocalizes with Vesicle-Associated Protein27-1, a known ER-PM marker. Furthermore, biochemical and physiological analyses indicate that SYT1 might function as an electrostatic phospholipid anchor conferring mechanical stability in plant cells. Together, the subcellular localization and functional characterization of SYT1 highlights a putative role of plant ER-PM contact site components in the cellular adaptation to environmental stresses. PMID- 25792255 TI - England's largest hospital trust is put into special measures after catalogue of failings. PMID- 25792256 TI - Right Analysis-wrong conclusion: Obese youth with higher BP are at risk for target organ damage. PMID- 25792257 TI - Neural tube defects in Jarcho-Levin syndrome: study of twenty-eight cases. AB - Jarcho-Levin syndrome (JLS) is a congenital disorder consisting of various vertebral and costal anomalies. Congenital heart defects, abdominal wall malformations, urogenital and anal abnormalities, multiple skeletal anomalies, upper limb anomalies, spina bifida, and inguinal, umbilical and diaphragmatic hernias can be seen as components of JLS. Spina bifida appears to be a common finding in reported JLS cases. We retrospectively reviewed the medical records, plain X-rays and MRIs of patients with spina bifida between 2010 and 2014 and discussed the results. PMID- 25792258 TI - An information theory based framework for the measurement of population health. AB - This paper proposes a new framework for the measurement of population health and the ranking of the health of different geographies. Since population health is a latent variable, studies which measure and rank the health of different geographies must aggregate observable health attributes into one summary measure. We show that the methods used in nearly all the literature to date implicitly assume that all attributes are infinitely substitutable. Our method, based on the measurement of multidimensional welfare and inequality, minimizes the entropic distance between the summary measure of population health and the distribution of the underlying attributes. This summary function coincides with the constant elasticity of substitution and Cobb-Douglas production functions and naturally allows different assumptions regarding attribute substitutability or complementarity. To compare methodologies, we examine a well-known ranking of the population health of U.S. states, America's Health Rankings. We find that states' rankings are somewhat sensitive to changes in the weight given to each attribute, but very sensitive to changes in aggregation methodology. Our results have broad implications for well-known health rankings such as the 2000 World Health Report, as well as other measurements of population and individual health levels and the measurement and decomposition of health inequality. PMID- 25792259 TI - Evolutionary evidence of tumor necrosis factor super family members in the Japanese pufferfish (Takifugu rubripes): Comprehensive genomic identification and expression analysis. AB - Tumor necrosis factor (TNF) and its superfamily (TNFSF) members are important inflammatory cytokines. Although fish have fourteen TNFSF genes, their genomic location and existence are yet to be described and confirmed in the Japanese pufferfish (Fugu) (Takifugu rubripes). Therefore, we conducted in silico identification, synteny analysis of TNFSF genes from Fugu with that of zebrafish and human TNFSF loci and their expression analysis in various tissues. We identified ten novel TNFSF genes, viz. TNFSF5 (CD40L), TNFSF6 (FasL), three TNFSF10 (TRAIL) (-1, 2 and 3), TNFSF11 (RANKlg), TNFSF12 (TWEAK), two TNFSF13B (BAFF) (1 and 2) and TNFSF14 (LIGHT) belonging to seven TNFSFs in Fugu. Several features such as existence of TNF family signature, conservation of genes in TNF loci with human and zebrafish chromosomes and phylogenetic clustering with other teleost TNFSF orthologs confirmed their identity. Fugu TNFSF genes were constitutively expressed in all eight different tissues with most of them expressed highly in liver. Fugu TNFSF10 gene has three homologs present on chromosomes 10 (TNFSF10-1), 8 (TNFSF10-2) and 2 (TNFSF10-3). Moreover, a phylogenetic analysis containing all available vertebrate (mammals, birds, reptiles, amphibians and fish) TNFSF10 orthologs showed that Fugu TNFSF10-1 and 10-3 are present in all vertebrates, whereas TNFSF10-2 was not related to any mammalian and avian orthologs. Viral double-stranded RNA mimic poly (I:C) caused an elevated expression of three Fugu TNFSF10 genes in head kidney cells at 4h indicating probable role of these genes to induce apoptosis in virus-infected cells. In conclusion, Fugu possesses genes belonging to nine TNFSFs including the newly identified seven and previously reported two, TNFSF New (TNF-N) and TNFSF2 (TNF-alpha). Our findings would add up information to TNFSF evolution among vertebrates. PMID- 25792260 TI - Secondary pharmacology data to assess potential off-target activity of new drugs: a regulatory perspective. PMID- 25792262 TI - Eric Karran. PMID- 25792264 TI - Genotoxic properties of representatives of alkylindazoles and aminoalkyl-indoles which are consumed as synthetic cannabinoids. AB - Synthetic cannabinoids (SCs) cause similar effects as cannabis and are sold in herbal mixtures. Recent investigations indicate that some of these drugs possess genotoxic properties. Therefore, we tested representatives of two groups, namely, aminoalkylindoles (AM-2201 and UR-144) and 1-alkylindazoles (5F-AKB-48 and AM 2201-IC) in single cell gel electrophoresis and micronucleus (MN) assays with human lymphocytes and in Salmonella/microsome assays. All drugs except AM-2201 caused DNA-migration, the LOELs were between 50 and 75 uM. Furthermore, all SCs caused inhibition of cell division and significant induction of MN which reflect structural and numerical chromosomal aberrations. The LOEL values were 50 uM for UR-144 and 5-AKB-48 and 75 uM for the other drugs. Also the levels of nucleoplasmatic bridges which are formed from dicentric chromosomes were elevated under identical conditions while the frequencies of nuclear buds were not affected. These findings show that representatives of both groups cause chromosomal damage while the negative results in Salmonella assays (in strains TA98, TA100, TA1535, TA1537 and TA102) in absence and presence of metabolic activation indicate that they do not induce gene mutations. Taken together, these findings indicate that SCs may cause adverse health effects in users as a consequence of damage of the genetic material. PMID- 25792265 TI - A novel safety assessment strategy applied to non-selective extracts. AB - A main challenge in food safety research is to demonstrate that processing of foodstuffs does not lead to the formation of substances for which the safety upon consumption might be questioned. This is especially so since food is a complex matrix in which the analytical detection of substances, and consequent risk assessment thereof, is difficult to determine. Here, a pragmatic novel safety assessment strategy is applied to the production of non-selective extracts (NSEs), used for different purposes in food such as for colouring purposes, which are complex food mixtures prepared from reference juices. The Complex Mixture Safety Assessment Strategy (CoMSAS) is an exposure driven approach enabling to efficiently assess the safety of the NSE by focussing on newly formed substances or substances that may increase in exposure during the processing of the NSE. CoMSAS enables to distinguish toxicologically relevant from toxicologically less relevant substances, when related to their respective levels of exposure. This will reduce the amount of work needed for identification, characterisation and safety assessment of unknown substances detected at low concentration, without the need for toxicity testing using animal studies. In this paper, the CoMSAS approach has been applied for elderberry and pumpkin NSEs used for food colouring purposes. PMID- 25792261 TI - New treatment options for hearing loss. AB - Hearing loss is the most common form of sensory impairment in humans and affects more than 40 million people in the United States alone. No drug-based therapy has been approved by the Food and Drug Administration, and treatment mostly relies on devices such as hearing aids and cochlear implants. Over recent years, more than 100 genetic loci have been linked to hearing loss and many of the affected genes have been identified. This understanding of the genetic pathways that regulate auditory function has revealed new targets for pharmacological treatment of the disease. Moreover, approaches that are based on stem cells and gene therapy, which may have the potential to restore or maintain auditory function, are beginning to emerge. PMID- 25792267 TI - Screening of phthalates in polymer materials by pyrolysis GC/MS. AB - A study on the rapid identification of phthalates in polymer materials has been conducted by employing gas chromatography-mass spectrometry coupled with a pyrolyzer (Py-GC/MS). Since Py-GC/MS does not require any complex solvent extraction process, a rapid screening of phthalates should be possible. In this study, polymer samples were directly introduced into the pyrolyzer in order to thermally extract phthalates from the polymer under specific heating conditions. By optimizing the Py-GC/MS parameters, a sequential testing cycle of 35 min per sample was feasible without causing any major decomposition of the base materials. Thus, a rapid screening of over 20 samples per day was achieved without any time constraints by effectively utilizing specifically prepared reference polymer sheets for quality control. Py-GC/MS was found to be suitable and effective for identifying phthalates in polymer materials. PMID- 25792266 TI - Dietary exposure to volatile and non-volatile N-nitrosamines from processed meat products in Denmark. AB - Recent epidemiological studies show a positive association between cancer incidence and high intake of processed meat. N-nitrosamines (NAs) in these products have been suggested as one potential causative factor. Most volatile NAs (VNAs) are classified as probable human carcinogens, whereas the carcinogenicity for the majority of the non-volatile NA (NVNA) remains to be elucidated. Danish adults (15-75 years) and children (4-6 years) consume 20 g and 16 g of processed meat per day (95th percentile), respectively. The consumption is primarily accounted for by sausages, salami, pork flank (spiced and boiled) and ham. This consumption results in an exposure to NVNA of 33 and 90 ng kg bw(-1) day(-1) for adults and children, respectively. The exposure to VNA is significantly lower amounting to 0.34 and 1.1 ng kg bw(-1) day(-1) for adults and children, respectively. Based on a BMDL10 of 29 ug kg bw(-1) day(-1) a MOE value >=17,000 was derived for the exposure to NA known to be carcinogenic (VNA including NSAR), indicating an exposure of low concern. The exposure to the NVNA is substantially higher and if found to be of toxicological significance the exposure may be of concern. PMID- 25792263 TI - Organs-on-chips at the frontiers of drug discovery. AB - Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs - known as organs on-chips - that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology. PMID- 25792268 TI - Electrospray ionization mass spectrometry for the quantification of inorganic cations and anions. AB - Recent studies from our laboratory on electrospray ionization mass spectrometry (ESI-MS) for the quantification of inorganic cations and anions are reviewed. Metal ions were determined by ESI-MS in negative-ion mode as monovalent negative ions of their aminopolycarboxylate (APC) complexes, where excess amounts of the APC agents were added to sample solutions. Among the APCs studied, we found trans 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CyDTA, the chemical forms in a complex were expressed as H(n)cydta(n-4)) as the best chelating agent. A size exclusion column was used for on-line separation of the metal-APC complexes from matrix salts in samples. Total amounts of Al, Ni, Cu, Zn, and Pb in the biological certified reference materials (CRM), Olive Leaves (BCR-062) and Plankton (BCR-414), and in a soil CRM (JSAC-0401) were successfully determined by the proposed method. Halide ions (X(-) = F(-), Cl(-), Br(-) and I(-)) and cyanide (CN(-)) were determined by ESI-MS based on the formation of ternary complexes of metals, chelating agents and the analyte anions. Negative ions of the ternary complexes of group 13 elements, nitrilotriacetic acid (NTA, H(n)nta(n-3)), and halides, i.e., [AlF(nta)](-) for F(-), and [InX(nta)](-) for other halides, were measured; the limits of detection (LODs) were 10 nmol dm(-3) for F(-), 0.31 MUmol dm(-3) for Cl(-), 3.8 nmol dm(-3) for Br(-), and 1.6 nmol dm(-3) for I(-), respectively. In the case of CN(-), an LOD of 20 nmol dm(-3) was obtained based on measurements of the ternary complex of Cu(II), CN(-) and 4-(2 pyridylazo)resorcinol (PAR, Hnpar(n-2)), i.e., [(63)Cu(II)(CN)(par)](-) (m/z 302). Moreover, quantitative methods for Cr(VI) and Cr(III) by ESI-MS were developed, where HCrO4(-) (m/z 117) for Cr(VI) and [Cr(III)(cydta)](-) for Cr(III) were used for measurements. PMID- 25792269 TI - Evaluation of the water-treatment ability of silica-doped titanium dioxide-coated glass plates using a cationic coupling reagent based on a flow analytical system. AB - In this study, a photocatalytic plate bound to highly dispersible silica-doped titanium dioxide (SiT) on a trimethoxysilyl-propyldiethylenetriamine (dien) coated glass plate (dien-plate) was newly synthesized, and was evaluated by a flow analytical (FA) system, which consists of a photocatalytic reactor and a spectrophotometer, to continuously monitor the absorbance of tested chemicals. The method was not required to collect any sample solution at a constant period. The SiT-dien-plate facilitated the photodecomposition of methylene blue (MB) and indigo carmine (InC) in aqueous solutions. Notably, MB was quantitatively photo decomposed following 18 h of UV-light irradiation, related to the electrostatic adsorption of surface-bound particles. A water-treatment ability of visible-light responsive vanadium-modified nitrogen/silica co-doped titanium dioxide fixed on the dien-plate was also evaluated by the FA system. It clarified to decompose MB and InC under visible-light irradiation. Finally, the decomposition of a humic substance dissolved from Middle West China peaty soils by the SiT-dien-plate under UV-irradiation was assessed as applying the FA system with a photocatalytic plate. PMID- 25792270 TI - Ion sensing by charge transfer absorption variations of benzocrown-bipyridinium conjugates with an alkyl chain. AB - Two benzocrown ether-bipyridinium conjugates, 1 and 2, each having a different length of alkyl chains with butyl and dodecyl groups, respectively, have been synthesized for the purpose of developing a new guest-responsive color-change chemosensor. Both 1 and 2 showed yellow colors with broad absorption bands around 400 nm in acetonitrile. These are associated with the intramolecular charge transfer (CT) absorption, in which the benzocrown ether and bipyridinium units act as the donor and acceptor, respectively. Upon addition of the guest; such as Na(+), they faded in color due to the blue shift in their intramolecular charge transfer absorption bands. These are associated with the formation of 1:1 host guest inclusion complex. Analogues, 3 and 4, both being similar in structure to 1 and 2 with non-crown ether unit, also showed intramolecular CT absorptions around 400 nm, but did not change their absorption spectra upon addition of the guest because of the lack of guest-binding abilities. The guest-induced color change of 1 and 2 can be used for alkali and alkaline metal ion sensing. Both 1 and 2 could detect divalent cations such as Mg(2+) and Ca(2+) rather than univalent ones, Li(+), Na(+), K(+), Rb(+), and Cs(+). Although a marked difference between 1 and 2 was not observed in their guest sensing abilities, the remarkable recognition of 1 and 2 for Mg(2+) and Ca(2+) was found compared with that of 5, which has benzyl unit instead of alkyl chains of 1 and 2. The sensitivity values of 1 and 2 were roughly proportional to their binding constants, as shown by the binding constants with Li(+), Na(+), Mg(2+), and Ca(2+) with the values of 910, 260, 820, and 2300 M(-1) for 1 and 930, 290, 1270, and 2790 M(-1) for 2, while the binding constants of 5 were estimated to be 930, 440, 210, and 1200 M(-1) for Li(+), Na(+), Mg(2+), and Ca(2+), respectively. The limit concentration of detection of 2 for Ca(2+) was estimated to be 0.016 mM, which was the smallest value in this system. PMID- 25792271 TI - Ultrasensitive biosensor for detection of organophosphorus pesticides based on a macrocycle complex/carbon nanotubes composite and 1-methyl-3-octylimidazolium tetrafluoroborate as binder compound. AB - This work describes the highly sensitive detection of organophosphorus pesticides employing the cobalt(II) 4,4,4,4-tetrasulfo-phthalocyanine (CoTSPc) macrocycle complex, carbon nanotubes (CNT), and 1-methyl-3-octylimidazolium tetrafluoroborate (OMIM[BF4]). The technique is based on enzyme acetylcholinesterase (AChE) inhibition. The composite was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and amperometry. The AChE was immobilized on the composite electrode surface by cross-linking with glutaraldehyde and chitosan. The synergistic action of the CoTSPc/CNT/OMIM[BF4] composite showed excellent electrocatalytic activity, with a low applied potential for the amperometric detection of thiocholine (TCh) at 0.0 V vs. Ag/AgCl. The calculated catalytic rate constant, k(cat), was 3.67 * 10(3) mol(-1) L s(-1). Under the optimum conditions, the inhibition rates of these pesticides were proportional to their concentrations in the ranges of 1.0 pmol L(-1) to 1.0 nmol L(-1) (fenitrothion), 2.0 pmol L(-1) to 8.0 nmol L(-1) (dichlorvos), and 16 pmol L(-1) to 5.0 nmol L( 1) (malathion). PMID- 25792272 TI - Fluorescent derivatization of aromatic carboxylic acids with horseradish peroxidase in the presence of excess hydrogen peroxide. AB - The fluorescent derivatization of aromatic carboxylic acids by the catalytic activity of horseradish peroxidase (HRP) in the presence of excess H2O2 was investigated. Four monocarboxylic acids, nine dicarboxylic acids, and two tricarboxylic acids, all of which are non- or weakly fluorescent, were effectively converted into fluorescent compounds using this new method. This technique was further developed for the fluorometric determination of trace amounts of terephthalic acid (3c) and lutidinic acid (2b), and linear calibration curves for concentrations between 2.5 and 20.0 nmol of terephthalic acid (3c) and 1.0 and 10.0 nmol of lutidinic acid (2b) were demonstrated. Compound III, an intermediate of HRP, played an essential role in this process. Additionally, lactoperoxidase and manganese peroxidase, peroxidases similar to HRP, showed successful fluorescent derivatization of nicotinic acid (1b), lutidinic acid (2b), and hemimellitic acid (4a) in the presence of excess H2O2. PMID- 25792273 TI - Elution profile of di-peptides on a sulfonated ethylstyrene-divinylbenzene copolymer resin column by high-performance liquid chromatography. AB - This study investigates the characteristics of a partially sulfonated ethylstyrene-divinylbenzene copolymer for the separation of di-peptides by high performance liquid chromatography. Di-peptides (VE, VA, VH, VK, and VR) with different isoelectric points (pI, 4.0 to 9.7) and log P values (-1.63 to -0.72) were used to optimize the separation conditions of the columns packed with sulfonated copolymer resin. The retention factor (k) of the di-peptides on the column with a 0.81 wt% sulfo group content decreased with increasing concentrations of phosphate salts (2.5 - 20 mmol L(-1)) in the mobile phase. The complete separation of the five di-peptides was obtained with a gradient of 10% methanol containing 5 mmol L(-1) NaH2PO4 (pH 4.8) to 50% methanol containing 5 mmol L(-1) Na2HPO4 (pH 8.9) for 60 min at 0.5 mL min(-1) at 50 degrees C. Under the optimal conditions, a good relationship between the k and pI values of the di peptides, with the exception of VE (pI 4.0), was observed, suggesting that the retention of the di-peptides on the column packed with sulfonated copolymer resin was dependent on the pI value, when it was greater than 5. The log P value also influenced the separation characteristics of the column; peptides possessing the same pI value (6.4 for GH, VH, IH, and FH) showed a higher retention on the column with increasing log P values. In conclusion, the prototype sulfonated ethylstyrene-divinylbenzene copolymer column was applicable for the separation of basic di-peptides, and the separation depended on the pI and hydrophobicity of the di-peptides. PMID- 25792274 TI - Development of a novel optical sensing method for acid solution using Oil Red O supported by florisil. AB - A novel field sensing method for concentrated acid solutions was developed. The sensor is composed of a dye, Oil Red O, and florisil as a support for the dye. When the dye is supported on the florisil surface, its color change properties against the acid solution drastically changes compared to in solution, and the sensor is applicable to sensing for acids of relatively low concentration. The significant phenomenon could not be observed when silica gel was used as a support, suggesting that the florisil plays an important role in the color changing phenomenon. The amount of dye absorbed on the florisil surface is related to the color change properties. PMID- 25792275 TI - Autism and our intestinal microbiota. AB - Microbial products, released into the bloodstreams of mammals including humans, cross the blood-brain barrier and influence neurodevelopment. They can either promote or alleviate neurological disorders including autism spectrum disorders (ASD). This editorial describes how our microbiota influence our feelings, attitudes and mental states with particular reference to ASD. PMID- 25792276 TI - Characterization of nutrient removal and microalgal biomass production on an industrial waste-stream by application of the deceleration-stat technique. AB - Industrial wastewaters can serve as a nutrient and water source for microalgal production. In this study the effluent of an internal circulation (IC) reactor anaerobically treating the wastes of a biotechnology production facility were chosen as the cultivation medium for Chlorella sorokiniana in batch and continuous cultures. The aim was to evaluate the rates of nutrient removal and biomass production possible at various dilution rates. The results demonstrate that the industrial wastewater served as a highly effective microalgae culture medium and that dilution rate strongly influenced algae productivity in a short light-path photobioreactor. Batch culture on undiluted wastewater showed biomass productivity of 1.33 g L(-1)day(-1), while removing over 99% of the ammonia and phosphate from the wastewater. Deceleration-stat (D-stat) experiments performed at high and low intensities of 2100 and 200 (MUmol photon m(2)s(-1)) established the optimal dilution rates to reach volumetric productivity of 5.87 and 1.67 g L( 1)day(-1) respectively. The corresponding removal rates of nitrogen were 238 and 93 mg L(-1)day(-1) and 40 and 19 mg L(-1)day(-1) for phosphorous. The yield on photons at low light intensity was as high as had been observed in any previous report indicating that the waste stream allowed the algae to grow at its full potential. PMID- 25792277 TI - Dendritic cells subsets mediated immune response during Plasmodium berghei ANKA and Plasmodium yoelii infection. AB - The roles of dendritic cells (DCs) in mediating immunity against Plasmodium infection have been extensively investigated, but immune response during pathogenesis of malaria is still poorly understood. In the present study, we compared the splenic DCs phenotype and function during P. berghei ANKA (PbA) or P. yoelii (P. yoelii) infection in Swiss mice. We observed that PbA-infected mice developed more myeloid and mature DCs capable of secreting IL-12, while P. yoelii infected mice had more plasmacytoid and immature DCs secreting higher levels of IL-10. Expression of FoxP3, IL-17, TGF-beta and IL-6 were also different between these two infections. Thus, these results suggest that the phenotypic and functional subsets of splenic DCs are key factors for regulating immune responses to PbA and P. yoelii infections. PMID- 25792278 TI - Soluble interleukin 6 receptor levels are associated with reduced myocardial reperfusion after percutaneous coronary intervention for acute myocardial infarction. AB - AIMS: Interleukin-6 receptor (IL-6R) signalling has been suggested to play a causal role in the development and outcome of coronary heart disease (CHD). The aim of this study was to investigate the association of sIL-6R levels with myocardial reperfusion after percutaneous coronary intervention (PCI) for acute ST-elevated myocardial infarction (STEMI). METHODS: Blood was sampled from 70 patients presenting with STEMI at 6 different time-points (baseline, post-PCI, t=1h, t=6h, t=24h, t=2w). Coronary angiograms post-PCI were analysed for myocardial blush grade (MBG) as indicator of myocardial reperfusion. Serum IL-6 and sIL-6R were measured using IL-6 and sIL-6R enzyme-linked immunosorbent assays (ELISA). RESULTS: sIL-6R levels fluctuated biphasic during the two weeks after STEMI. Reduced MBG was associated with a larger change in sIL-6R levels between baseline and post-PCI compared to optimal MBG (-13.40; SEM 2.78ng/ml vs -1.99; SEM 2.35ng/ml, respectively; p<0.001). Patients with reduced MBG also showed a larger increase in sIL-6R levels after PCI and 1h after myocardial infarction (MI) compared to optimal MBG (respectively 11.56; SEM 2.68ng/ml vs 3.02; SEM 2.39ng/ml; p=0.018). IL-6/sIL-6R ratio was also more increased in patients with reduced MBG at 24h after myocardial infarction (0.23; SEM 0.08-0.51 vs 0.10; SEM 0.05-0.21; p=0.024). An optimal MBG was associated with a 10ng increase in sIL-6R level between baseline and post-PCI (OR 1.687, CI 1.095-2.598; p=0.018). CONCLUSIONS: sIL-6R levels fluctuate biphasic during the two weeks after MI with larger changes and increased IL-6/sIL-6R ratio in patients with reduced MBG. Further research is needed to increase our understanding of the possible causality of these associations. PMID- 25792279 TI - Core-shell designed scaffolds for drug delivery and tissue engineering. AB - Scaffolds that secure and deliver therapeutic ingredients like signaling molecules and stem cells hold great promise for drug delivery and tissue engineering. Employing a core-shell design for scaffolds provides a promising solution. Some unique methods, such as co-concentric nozzle extrusion, microfluidics generation, and chemical confinement reactions, have been successful in producing core-shelled nano/microfibers and nano/microspheres. Signaling molecules and drugs, spatially allocated to the core and/or shell part, can be delivered in a controllable and sequential manner for optimal therapeutic effects. Stem cells can be loaded within the core part on-demand, safely protected from the environments, which ultimately affords ex vivo culture and in vivo tissue engineering. The encapsulated cells experience three-dimensional tissue-mimic microenvironments in which therapeutic molecules are secreted to the surrounding tissues through the semi-permeable shell. Tuning the material properties of the core and shell, changing the geometrical parameters, and shaping them into proper forms significantly influence the release behaviors of biomolecules and the fate of the cells. This topical issue highlights the immense usefulness of core-shell designs for the therapeutic actions of scaffolds in the delivery of signaling molecules and stem cells for tissue regeneration and disease treatment. PMID- 25792281 TI - Community Analyses Uncover High Diversity of Lichenicolous Fungi in Alpine Habitats. AB - Lichens are frequently colonized by specialized, lichenicolous fungi. Symptomatic lichenicolous fungi usually display typical phenotypes and reproductive structures on the lichen hosts. The classification based on these structures revealed different host specificity patterns. Other fungi occur asymptomatically in the lichen thalli and are much less known. We aimed at studying the diversity of lichen-associated fungi in specific, lichen-rich communities on rocks in the Alps. We tested whether lichenicolous fungi developing symptomatically on their known hosts also occur asymptomatically in other thalli of the same or of different host species. We collected lichen thalli according to a uniform sampling design comprising individuals adjacent to thalli that showed symptoms of lichenicolous fungal infections. The total fungal communities in the selected lichen thalli were further studied by single-strand conformation polymorphism (SSCP) fingerprinting analyses and sequencing of internal transcribed spacer (ITS) fragments. The systematic, stratified sampling strategy helped to recover 17 previously undocumented lichenicolous fungi and almost exhaustively the species diversity of symptomatic lichenicolous fungi in the studied region. The results from SSCP and the sequencing analyses did not reveal asymptomatic occurrence of normally symptomatic lichenicolous fungi in thalli of both the same and different lichen host species. The fungal diversity did not correlate with the species diversity of the symptomatic lichenicolous fungus-lichen host associations. The complex fingerprint patterns recovered here for fungal communities, in associations of well-delimited lichen thalli, suggest lichen symbiosis as suitable subjects for fungal metacommunity studies. PMID- 25792280 TI - Biphasic silica/apatite co-mineralized collagen scaffolds stimulate osteogenesis and inhibit RANKL-mediated osteoclastogenesis. AB - The effects of a biphasic mineralized collagen scaffold (BCS) containing intrafibrillar silica and apatite on osteogenesis of mouse mesenchymal stem cells (mMSCs) and inhibition of receptor activator of nuclear factor kappaB ligand (RANKL)-mediated osteoclastogenesis were investigated in the present study. mMSCs were cultured by exposing to BCS for 7 days for cell proliferation/viability examination, and stimulated to differentiate in osteogenic medium for 7-21 days for evaluation of alkaline phosphatase activity, secretion of osteogenic deposits and expression of osteoblast lineage-specific phenotypic markers. The effect of BCS-conditioned mMSCs on osteoclastogenesis of RAW 264.7 cells was evaluated by tartrate-resistant acid phosphatase staining and resorption pit analysis. The contributions of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) signal transduction pathways to osteogenesis of mMSCs and their osteoprotegerin (OPG) and RANKL expressions were also evaluated. Compared with unmineralized, intrafibrillarly-silicified or intrafibrillarly-calcified collagen scaffolds, BCS enhanced osteogenic differentiation of mMSCs by activation of the extracellular signal regulated kinases (ERK)/MAPK and p38/MAPK signaling pathways. After mMSCs were exposed to BCS, they up-regulated OPG expression and down-regulated RANKL expression through activation of the p38/MAPK and PI3K/protein kinase B (Akt) pathways, resulting in inhibition of the differentiation of RAW 264.7 cells into multinucleated osteoclasts and reduction in osteoclast function. These observations collectively suggest that BCS has the potential to be used in bone tissue engineering when the demand for anabolic activities is higher than catabolic metabolism during the initial stage of wound rehabilitation. PMID- 25792282 TI - How valid are subjective ratings of prospective memory in mild cognitive impairment and early dementia? AB - BACKGROUND: Prospective memory refers to memory for future intentions and is a critical predictor of functional capacity in late adulthood. For many other cognitive abilities, self- and informant-rated methods of assessment are routinely used to guide clinical decision-making. However, little is known about the validity (and consequently the clinical utility) of subjective reports of prospective memory difficulties. OBJECTIVE: The aim of this study was to compare clinical [mild cognitive impairment (MCI), dementia] and nonclinical older adults (healthy controls) on self- and informant-rated versions of prospective and retrospective memory function, as well as objective measures of prospective memory. Critical here was not only the assessment of between-group differences, but also whether these different methods of assessing memory function would show appropriate convergent and discriminant validity. METHODS: A total of 138 participants aged between 64 and 92 years, diagnosed with dementia (n=37), MCI (n=48) or no impairment (n=53), were asked to complete self- and informant-rated versions of the Prospective and Retrospective Memory Questionnaire (PRMQ). Participants also completed behavioural measures of global cognitive function [the Mini-Mental State Examination (MMSE)], as well as a behavioural measure of prospective memory (Virtual Week). RESULTS: Self-reported impairments were equivalent across the three groups, and informant reports of impairment, while higher for those with dementia, did not distinguish MCI from controls. For the combined sample and for all three groups separately, both self- and informant reports of prospective memory showed poor convergent validity, at best correlating only weakly with Virtual Week. Self-reported prospective memory was correlated with informant report only in the dementia group, not in the control or MCI groups. Convergent and discriminant validity were poor, with self- and informant-rated prospective memory more strongly related to self- and informant rated retrospective memory than to scores on Virtual Week. CONCLUSION: These data indicate that self-report and informant report may neither accurately measure prospective memory of older people, nor be sensitive to objective prospective memory difficulties in people with MCI and dementia. These data have potentially important implications for clinical practice. PMID- 25792283 TI - Pterostilbene inhibits triple-negative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition. AB - Breast cancer is the leading cause of cancer-related deaths among females in economically developing countries. Greater than 95% of breast malignancies are of epithelial origin; the induction of epithelial-to-mesenchymal transition (EMT) has been shown to initiate the metastatic process in breast carcinoma and remains the key target for drug development. Here, we examine the anti-metastatic potential of pterostilbene in modulating EMT process in breast cancer cells both in vitro and in vivo. The differential invasive ability among MCF7, Hs578t and MDA-MB-231 breast cancer cell lines were closely correlated with the expression of EMT markers, determined by Western blots and Matrigel-coated transwells assay. Pterostilbene inhibited the migratory and invasive potential of triple-negative MDA-MB-231 and Hs578t cells, accompanied by the up-regulation of E-cadherin and down-regulation of Snail, Slug, vimentin and ZEB1. Mechanistic investigations revealed a significant up-regulation of miR-205, which resulted in the reduction of Src expression in pterostilbene-treated breast cancer cells. Importantly, pterostilbene suppressed tumor growth and metastasis in MDA-MB-231-bearing NOD/SCID mice by reducing Src/Fak signaling; this observation was consistent with the negative correlations between miR-205 and Src expression in both normal and malignant breast tissues. Our findings provide supports for the usage of pterostilbene as an inhibitor of EMT process and potential candidate for adjuvant therapy. PMID- 25792284 TI - Consumption of vitamin D2 enhanced mushrooms is associated with improved bone health. AB - Mushrooms are the best nonanimal food source of vitamin D2. Pulsed irradiation can enhance vitamin D2 in mushrooms quickly. We investigated the effect of supplementing high vitamin D2Pleurotus ferulae mushrooms in a mouse model of osteoporosis. Thirty-two female C57BL/6JNarl mice were divided into four groups including sham, ovariectomized (OVX), OVX+nonpulsed mushroom (NPM) and OVX+pulsed mushroom (PM). After 23 weeks of treatment, serum samples were analyzed for osteoblast and osteoclast indicators, as well as metabolites using NMR spectroscopy. To examine bone density, femurs were analyzed using micro-computed tomography. The NPM and PM treatment mice showed increased bone density in comparison with OVX mice. In addition, the PM mice showed higher osteoblast and lower osteoclast indicators in comparison with OVX mice. Serum metabolomics analysis indicated several metabolites that were different in PM mice, some of which could be correlated with bone health. Taken together, these results suggest that pulsed irradiated mushrooms are able to increase bone density in osteoporotic mice possibly through enhanced bone metabolism. Further studies in humans are needed to show their efficacy in preventing osteoporosis. PMID- 25792285 TI - Ductus Arteriosus Closure With Paracetamol: a Pilot Study. PMID- 25792286 TI - Changes in Clinical Profile, Epidemiology and Prognosis of Left-sided Native valve Infective Endocarditis Without Predisposing Heart Conditions. PMID- 25792288 TI - Media sources, credibility, and perceptions of science: Learning about how people learn about science. AB - Knowledge about science and technology has become increasingly important in this age of digital information overload. It is also becoming increasingly important to understand what contributes to scientific learning, including information sources and trust in those sources. In this study, we develop and test a multivariate model to explain scientific knowledge based on past theories on learning from the news from the fields of political communication, sociology, and media psychology. We focus on the impact of sources-by platform, such as television and online, and by expertise, such as scientists and the media-in understanding what predicts scientific knowledge. The results show that interest in science not only directly predicts knowledge but also has indirect effects on knowledge through its effects on Internet use, confidence in the press, and perception of scientists. In addition, distrust on the news sources is an important pathway to learning about science. PMID- 25792287 TI - Differential Effect of Glycosylated Hemoglobin Value and Antidiabetic Treatment on the Risk of 30-day Readmission Following a Hospitalization for Acute Heart Failure. AB - INTRODUCTION AND OBJECTIVES: In patients with heart failure and type 2 diabetes, low glycosylated hemoglobin has been related with higher risk of mortality but information regarding morbidity is scarce. We sought to evaluate the association between glycosylated hemoglobin and 30-day readmission in patients with type 2 diabetes and acute heart failure. METHODS: Glycosylated hemoglobin was measured before discharge in 835 consecutive patients with acute heart failure and type 2 diabetes. Cox regression analysis adapted for competing events was used. RESULTS: Mean (standard deviation) age was 72.9 (9.6) years and median glycosylated hemoglobin was 7.2% (6.5%-8.0%). Patients treated with insulin or insulin/sulfonylurea/meglitinides were 41.1% and 63.2% of the cohort, respectively. At 30 days post-discharge, 109 (13.1%) patients were readmitted. A multivariate analysis revealed that the effect of glycosylated hemoglobin on the risk of 30-day readmission was differentially affected by the type of treatment (P for interaction<.01). Glycosylated hemoglobin (per 1% decrease) was inversely associated with higher risk in those receiving insulin (hazard ratio = 1.45; 95% confidence interval, 1.13-1.86; P=.003) or insulin/sulfonylurea/meglitinides (hazard ratio = 1.44; 95% confidence interval, 1.16-1.80; P=.001). Conversely, glycosylated hemoglobin (per 1% increase) had no effect in non-insulin dependent diabetes (hazard ratio = 1.01; 95% confidence interval, 0.87-1.17; P=.897) or even a positive effect in patients not receiving insulin/sulfonylurea/meglitinides (hazard ratio = 1.12; 95% confidence interval, 1.03-1.22; P=.011). CONCLUSIONS: In acute heart failure, glycosylated hemoglobin showed to be inversely associated to higher risk of 30-day readmission in insulin dependent or those treated with insulin/sulfonylurea/meglitinides. A marginal effect was found in the rest. Whether this association reflects a treatment related effect or a surrogate of more advanced disease should be clarified in further studies. PMID- 25792289 TI - Effect of Jun N-terminal kinase 1 and 2 on the replication of Penicillium marneffei in human macrophages. AB - Penicillium marneffei (P. marneffei) is a human pathogen which persists in macrophages and threatens the immunocompromised patients. To clarify the mechanisms involved, we evaluated the effect of c-Jun N-terminal kinase 1 and 2 (JNK1/2) on cytokine expression, phagosomal maturation and multiplication of P. marneffei in P. marneffei-stimulated human macrophages. P. marneffei induced the rapid phosphorylation of JNK1/2. Using the specific inhibitor of JNK1/2 (SP600125), we found that the inhibition of JNK1/2 suppressed P. marneffei induced tumor necrosis factor-alpha and IL-10 production. In addition, the presence of SP600125 increased phagosomal acidification and maturation and decreased intracellular replication. These data suggest that JNK1/2 may play an important role in promoting the replication of P. marneffei. Our findings further indicate that the pathogen through the JNK1/2 pathway may attenuate the immune response and macrophage antifungal function. PMID- 25792290 TI - Chemotherapy treatment patterns, costs, and outcomes of patients with gastric cancer in the United States: a retrospective analysis of electronic medical record (EMR) and administrative claims data. AB - BACKGROUND: The aim of this study was to conduct a retrospective database analysis to describe the chemotherapy treatment patterns and outcomes of patients with gastric cancer. METHODS: Individuals diagnosed with gastric cancer were identified from the IMS Oncology Database, which contains electronic medical record (EMR) data collected from a variety of community practices, and the Truven Health MarketScan((r)) Research database, an administrative claims database. Eligible patients were 18 years of age or older and had an ICD-9 code 151.0 151.9. Patients were excluded if they had evidence of cancer within 6 months of the index diagnosis. RESULTS: There were 5257 eligible patients identified in EMR data: 1982 (37.7 %) of these patients also had data regarding chemotherapy treatments. Of the 1982 patients who received first-line therapy, 42.3 %, 18.1 %, and 7.9 % went on to receive a second, third, and fourth line of chemotherapy, respectively. There were 11891 eligible patients identified in the administrative database; 5299 (44.6 %) had data regarding chemotherapy. Of those initiating chemotherapy, 2888 (54.5 %) received a second line and 1598 (30.2 %) received a third line of treatment. The average total cost of care during first-line therapy was $40,811 [standard deviation (SD) = $49,916], which was incurred over an average of 53.5 (SD = 63.4) days. A similar pattern was evident in second-line treatment (mean/SD, $26,588/$33,301) over 41.2 (SD = 55.7) days. CONCLUSIONS: Costs and duration of care received vary among gastric cancer patients in the U.S. There is a need to understand which regimens may be associated with better health outcomes and to standardize treatment as appropriate. PMID- 25792291 TI - Methoxetamine, a ketamine derivative, produced conditioned place preference and was self-administered by rats: Evidence of its abuse potential. AB - Methoxetamine (MXE) is an N-methyl-d-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to ketamine. Recently, there have been many reports regarding its use/misuse in humans which have resulted in serious or even fatal outcomes. Despite these reports, MXE is not controlled or regulated in many countries which may be partly due to the lack of scientific evidence regarding its abuse potential. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of MXE through the conditioned place preference (CPP) and self-administration (SA) tests in Sprague-Dawley rats. In addition, locomotor activity during the conditioning phase of the CPP was also analyzed. Ketamine was used as a reference drug. MXE (2.5 and 5mg/kg) induced significant CPP in rats, an effect comparable to that of ketamine (5mg/kg). Interestingly, MXE did not produce any locomotor alterations while ketamine decreased the locomotor activity of rats. In the SA test, rats showed modest self administration of MXE (0.25, 0.5, 1.0mg/kg/infusion), while ketamine (0.5mg/kg/infusion) was robustly self-administered. These results demonstrate that MXE, similar to ketamine, has rewarding and reinforcing effects in rats. The present study strongly suggests that MXE has a potential for human abuse. In addition, the discrepant effects of MXE and ketamine on locomotor activity and rate of self-administration propose that the psychopharmacological effects of these drugs may diverge in some aspects. More importantly, this study advocates the careful monitoring and prompt regulation of MXE and its related substances. PMID- 25792292 TI - Pharmacological analyses of learning and memory in zebrafish (Danio rerio). AB - Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in behavioral pharmacology, opening a new avenue for understanding the relationships between drug action and behavior. This species offers a useful intermediate approach bridging the gap between in vitro studies and traditional mammalian models. Zebrafish offer great advantages of economy compared to their rodent counterparts, their complex brains and behavioral repertoire offer great translational potential relative to in vitro models. The development and validation of a variety of tests to measure behavior, including cognition, in zebrafish have set the stage for the use of this animal for behavioral pharmacology studies. This has led to research into the basic mechanisms of cognitive function as well as screening for potential cognition improving drug therapies, among other lines of research. As with all models, zebrafish have limitations, which span pharmacokinetic challenges to difficulties quantifying behavior. The use, efficacy and limitations associated with a zebrafish model of cognitive function are discussed in this review, within the context of behavioral pharmacology. PMID- 25792294 TI - Contest experience enhances aggressive behaviour in a fly: when losers learn to win. AB - In several animal species, aggressive experience influences the characteristics and outcomes of subsequent conflicts, such that winners are more likely to win again (the winner effect) and losers more likely to lose again (the loser effect). We tested the olive fruit fly, Bactrocera oleae (Diptera: Tephritidae), as a model system to evaluate the role of the winner and loser effects in male male territorial contests. Further, we conducted experiments to test if winning and losing probabilities are affected only by the outcome of the previous contests, or whether the fighting experience itself is sufficient to induce an effect. Both winners and losers of two consecutive encounters displayed higher intensity of aggression and fought longer in subsequent contests. In both cases, they achieved higher fighting success than naive males. The enhanced fighting performance of both winners and losers was stimulated by merely experiencing a contest, not necessarily by the relative outcome of previous fights. Overall, this study highlights the fact that previous victories and defeats both enhance aggressive behaviour in olive fruit flies, allowing them to achieve higher fighting success in subsequent contests against inexperienced males. PMID- 25792295 TI - Variation of expression defects in cell surface 190-kDa protein antigen of Streptococcus mutans. AB - Streptococcus mutans, which consists of four serotypes, c, e, f, and k, possesses a 190-kDa cell surface protein antigen (PA) for initial tooth adhesion. We used Western blot analysis to determine PA expression in 750 S. mutans isolates from 150 subjects and found a significantly higher prevalence of the isolates with PA expression defects in serotypes f and k compared to serotypes c and e. Moreover, the defect patterns could be classified into three types; no PA expression on whole bacterial cells and in their supernatant samples (Type N1), PA expression mainly seen in supernatant samples (Type N2), and only low expression of PA in the samples of whole bacterial cells (Type W). The underlying reasons for the defects were mutations in the gene encoding PA as well as in the transcriptional processing of this gene for Type N1, defects in the sortase gene for Type N2, and low mRNA expression of PA for Type W. Since cellular hydrophobicity and phagocytosis susceptibility of the PA-defective isolates were significantly lower than those of the normal expression isolates, the potential implication of such defective isolates in systemic diseases involving bacteremia other than dental caries was suggested. Additionally, multilocus sequence typing was utilized to characterize S. mutans clones that represented a proportion of isolates with PA defects of 65-100%. Therefore, we described the molecular basis for variation defects in PA expression of S. mutans. Furthermore, we also emphasized the strong association between PA expression defects and serotypes f and k as well as the clonal relationships among these isolates. PMID- 25792293 TI - Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series. AB - BACKGROUND: Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. METHODS: To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. RESULTS: Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0 1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. CONCLUSIONS: Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender. PMID- 25792296 TI - Exhaled Nitric Oxide and Airway Hyperresponsiveness to Adenosine 5'-monophosphate and Methacholine in Children with Asthma. AB - BACKGROUND: There is increasing interest in the role of indirect bronchial challenges because clinical studies have shown that indirect airway hyperresponsiveness (AHR) reflects underlying airway inflammation better than direct AHR. Fractional exhaled nitric oxide (FeNO) appears to be a useful clinical tool for assessing airway inflammation noninvasively. We examined whether FeNO is more closely related to AHR to indirect stimuli than AHR to direct stimuli in children with mild to moderate asthma. METHODS: Fifty-nine asthmatic children aged 6-16 years without rhinitis, underwent spirometry, FeNO measurement and blood tests for serum total IgE, blood eosinophil count and serum eosinophil cationic protein (ECP). All subjects underwent methacholine and adenosine 5-monophosphate (AMP) challenge tests at intervals of 3 days. RESULTS: In a univariate linear regression analysis, FeNO was significantly associated with both PC20 AMP (R(2) = 0.341, p < 0.001) and PC20 methacholine (R(2) = 0.188, p = 0.001). After adjustment for age, sex, serum total IgE and blood eosinophil count, the association between FeNO and PC20 AMP (beta = -1.98, p = 0.001) was more robust than that between FeNO and PC20 methacholine (beta = -0.87, p = 0.081). The significant correlation between FeNO and PC20 AMP was observed in the steroid-naive group (beta = -2.48, p = 0.001), but not in the steroid-treated group (beta = 0.88, p = 0.463). CONCLUSIONS: FeNO levels were more closely associated with PC20 AMP than with PC20 methacholine. This relationship could only be seen in the steroid-naive subjects. These results suggest that FeNO levels in children with asthma may be more closely related to indirect AHR than to direct AHR. PMID- 25792297 TI - Disorders of follicle development and steroidogenesis in ovaries of androgenised foetal sheep. AB - The prenatally androgenised (PA) sheep is a well-recognised model for the study of developmental programming of adult polycystic ovary syndrome (PCOS). Most of the studies to date have involved examination of the reproductive and metabolic effects in the offspring after puberty, but more recently, it has been reported that there is disruption of follicle formation and steroid gene expression in ovaries of foetal sheep after exposure of the mother to excess androgen. Our study examines evidence for precocious primordial follicle formation at day 90 of gestation in ovaries of foetal Poll Dorset sheep. Using a specific marker of germ cells (VASA homologue protein) in ovarian sections, we found that androgenised sheep had nearly double the proportion of germ cells enclosed in follicles compared with control animals. When analysed by follicle stage, there was no significant difference between groups in the proportion of primordial follicles and growing (transitional and primary) follicles. Differences between PA and control foetal sheep were found in both mRNA and in protein expression of steroidogenic enzymes and androgen receptor. Our results in Dorset ewes are complementary to previous reports, but suggest that the timing of follicle formation and steroidogenic activity may vary between different breeds as well as in response to androgen. These data show that granulosa cells constitute a specific target for programming by androgen in utero and raise key questions about the role of exposure to androgen in utero in developmental origins of PCOS. PMID- 25792299 TI - The challenge of reporting scientific excellence. PMID- 25792298 TI - Approaches for the generation of active papain-like cysteine proteases from inclusion bodies of Escherichia coli. AB - Papain-like cysteine proteases are widely expressed, fulfill specific functions in extracellular matrix turnover, antigen presentation and processing events, and may represent viable drug targets for major diseases. In depth and rigorous studies of the potential for these proteins to be targets for drug development require sufficient amounts of protease protein that can be used for both experimental and therapeutic purposes. Escherichia coli was widely used to express papain-like cysteine proteases, but most of those proteases are produced in insoluble inclusion bodies that need solubilizing, refolding, purifying and activating. Refolding is the most critical step in the process of generating active cysteine proteases and the current approaches to refolding include dialysis, dilution and chromatography. Purification is mainly achieved by various column chromatography. Finally, the attained refolded proteases are examined regarding their protease structures and activities. PMID- 25792300 TI - Retention in care and medication adherence: current challenges to antiretroviral therapy success. AB - Health behaviors such as retention in HIV medical care and adherence to antiretroviral therapy (ART) pose major challenges to reducing new HIV infections, addressing health disparities, and improving health outcomes. Andersen's Behavioral Model of Health Service Use provides a conceptual framework for understanding how patient and environmental factors affect health behaviors and outcomes, which can inform the design of intervention strategies. Factors affecting retention and adherence among persons with HIV include patient predisposing factors (e.g., mental illness, substance abuse), patient-enabling factors (e.g., social support, reminder strategies, medication characteristics, transportation, housing, insurance), and healthcare environment factors (e.g., pharmacy services, clinic experiences, provider characteristics). Evidence-based recommendations for improving retention and adherence include (1) systematic monitoring of clinic attendance and ART adherence; (2) use of peer or paraprofessional navigators to re-engage patients in care and help them remain in care; (3) optimization of ART regimens and pharmaceutical supply chain management systems; (4) provision of reminder devices and tools; (5) general education and counseling; (6) engagement of peer, family, and community support groups; (7) case management; and (8) targeting patients with substance abuse and mental illness. Further research is needed on effective monitoring strategies and interventions that focus on improving retention and adherence, with specific attention to the healthcare environment. PMID- 25792301 TI - Palbociclib: first global approval. AB - Palbociclib (Ibrance(r)) is an oral, reversible, selective, small-molecule inhibitor of cyclin-dependent kinases (CDK) 4 and CDK6 developed by Pfizer for the treatment of cancer. CDKs are important modulators of cell cycle entry and progression in response to growth signals, and inhibition of these kinases with palbociclib could enhance the activity of other anticancer drugs in tolerable regimens. Palbociclib, in combination with letrozole, was recently approved in the US for the first-line treatment of advanced breast cancer. Phase III development is underway worldwide investigating its use as first-line treatment in advanced breast cancer, as well as treatment of recurrent or advanced breast cancer and high-risk, early-stage breast cancer. A phase II trial is underway in the USA for non-small cell lung cancer under a US National Cancer Institute funded research collaboration, and several phase I and II investigations are being conducted for various other solid tumour types and haematological malignancies. This article summarizes the milestones in the development of palbociclib leading to this first approval for use in postmenopausal women with estrogen-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. PMID- 25792302 TI - Reliability of measurements of the extension-flexion ratio with surface EMG. AB - BACKGROUND: The surface electromyography (sEMG), by evaluating the paraspinal muscle activity, may be used for diagnosis and evaluation of rehabilitation effectiveness patients with low back pain. OBJECTIVE: The purpose of the study was to determine the intra- and inter-session reliability of the measurement of the activity of the lumbar erector spinae (LES) activity (extension-flexion ratio). METHODS: The study included 21 asymptomatic subjects, aged 14 to 27 years, mean 23.7 +/- 2.9. The LES muscle activity was assessed with using of the sEMG during forward trunk flexion and extension by two examiners. Based on the quotient of the LES muscle activity obtained during four concentric and eccentric tasks the extension-flexion ratio was calculated. RESULTS: The measurements displayed excellent or fair-to-good reliability (intraclass correlation coefficient ranged from 0.90 to 0.68). The typical error and coefficient of variations, ranged from 0.34 to 0.58, and from 13.7 to 21.9, respectively. CONCLUSIONS: The measurement of the extension-flexion ratio performed with the use of sEMG shows high level of intra- and inter-session reliability, suggesting that this parameter is a reliable tool in evaluation of the lumbar paraspinal muscles activity. However, the level of typical error should be taken into account. PMID- 25792304 TI - Ignorance is not an option. PMID- 25792303 TI - Early individualised manipulative rehabilitation following lumbar open laser microdiscectomy improves early post-operative functional disability: A randomized, controlled pilot study. AB - BACKGROUND: Lumbar open laser microdiscectomy has been shown to be an effective intervention and safe approach for lumbar disc prolapse. However early post operative physical disability affecting daily activities have been sporadically reported. OBJECTIVE: To evaluate the feasibility of using early individualised manipulative rehabilitation to improve early post-operative functional disability following lumbar discectomy. METHODS: Randomised controlled pilot trial. Setting at a major metropolitan spine surgery hospital. Twenty-one patients aged 25-69 years who underwent lumbar microdiscectomy were randomised to either the manipulative rehabilitation treatment group or the active control group. Rehabilitation was initiated 2-3 weeks after surgery, twice a week for 4 weeks. Each session was for 30 minutes. Primary outcomes were the Roland-Morris disability questionnaire and the visual analogue pain scale. Outcome measures were assessed at baseline and post-intervention. RESULTS: Early post-operative physical disability was improved with a 55% reduction by early individualised manipulative rehabilitation, compared to that of control care with a 5% increase. Early post-operative residual leg pain decreased with rehabilitation (55%) and control care (9%). CONCLUSION: This pilot study supports the feasibility of a future definitive randomised control trial and indicates this type of rehabilitation may be an important option for post-operative management after spinal surgery. PMID- 25792307 TI - Oceanography. New satellite radar could find 100,000 underwater mountains. PMID- 25792306 TI - Infectious diseases. MERS surges again, but pandemic jitters ease. PMID- 25792308 TI - Biochemistry. Origin-of-life puzzle cracked. PMID- 25792309 TI - Biomedicine. Woes for 'exercise hormone'. PMID- 25792310 TI - Biotechnology. Biologists devise invasion plan for mutations. PMID- 25792311 TI - Bioethics. Embryo engineering alarm. PMID- 25792312 TI - Lessons from the wild lab. PMID- 25792313 TI - Materials science. All that glitters need not be gold. PMID- 25792314 TI - Materials science. Building supermicelles from simple polymers. PMID- 25792315 TI - Neuroscience. Metabolic control of epilepsy. PMID- 25792316 TI - Vibrational dynamics. Taming CH5+, the "enfant terrible" of chemical structures. PMID- 25792317 TI - RNA. A TRICK'n way to see the pioneer round of translation. PMID- 25792318 TI - Climate and conservation. Creating a safe operating space for iconic ecosystems. PMID- 25792319 TI - Stem cells. Holding your breath for longevity. PMID- 25792320 TI - Drones: balancing risk and potential. PMID- 25792321 TI - Cyber-attack risk low for medical devices. PMID- 25792322 TI - Regulatory hurdles for agriculture GMOs. PMID- 25792323 TI - Micelle assembly. Multidimensional hierarchical self-assembly of amphiphilic cylindrical block comicelles. AB - Self-assembly of molecular and block copolymer amphiphiles represents a well established route to micelles with a wide variety of shapes and gel-like phases. We demonstrate an analogous process, but on a longer length scale, in which amphiphilic P-H-P and H-P-H cylindrical triblock comicelles with hydrophobic (H) or polar (P) segments that are monodisperse in length are able to self-assemble side by side or end to end in nonsolvents for the central or terminal segments, respectively. This allows the formation of cylindrical supermicelles and one dimensional (1D) or 3D superstructures that persist in both solution and the solid state. These assemblies possess multiple levels of structural hierarchy in combination with existence on a multimicrometer-length scale, features that are generally only found in natural materials. PMID- 25792324 TI - Solar physics. The crucial role of surface magnetic fields for the solar dynamo. AB - Sunspots and the plethora of other phenomena occurring in the course of the 11 year cycle of solar activity are a consequence of the emergence of magnetic flux at the solar surface. The observed orientations of bipolar sunspot groups imply that they originate from toroidal (azimuthally orientated) magnetic flux in the convective envelope of the Sun. We show that the net toroidal magnetic flux generated by differential rotation within a hemisphere of the convection zone is determined by the emerged magnetic flux at the solar surface and thus can be calculated from the observed magnetic field distribution. The main source of the toroidal flux is the roughly dipolar surface magnetic field at the polar caps, which peaks around the minima of the activity cycle. PMID- 25792325 TI - Superconductivity. Broken translational and rotational symmetry via charge stripe order in underdoped YBa2Cu3O(6+y). AB - After the discovery of stripelike order in lanthanum-based copper oxide superconductors, charge-ordering instabilities were observed in all cuprate families. However, it has proven difficult to distinguish between unidirectional (stripes) and bidirectional (checkerboard) charge order in yttrium- and bismuth based materials. We used resonant x-ray scattering to measure the two-dimensional structure factor in the superconductor YBa2Cu3O(6+y) in reciprocal space. Our data reveal the presence of charge stripe order (i.e., locally unidirectional density waves), which may represent the true microscopic nature of charge modulation in cuprates. At the same time, we find that the well-established competition between charge order and superconductivity is stronger for charge correlations across the stripes than along them, which provides additional evidence for the intrinsic unidirectional nature of the charge order. PMID- 25792326 TI - Vibrational dynamics. Experimental ground-state combination differences of CH5+. AB - Protonation of methane (CH4), a rather rigid molecule well described by quantum mechanics, produces CH5(+), a prototypical floppy molecule that has eluded definitive spectroscopic description. Experimental measurement of high-resolution spectra of pure CH5(+) samples poses a formidable challenge. By applying two types of action spectroscopy predicated on photoinduced reaction with CO2 and photoinhibition of helium cluster growth, we obtained low-temperature, high resolution spectra of mass-selected CH5(+). On the basis of the very high accuracy of the line positions, we determined a spectrum of combination differences. Analysis of this spectrum enabled derivation of equally accurate ground state-level schemes of the corresponding nuclear spin isomers of CH5(+), as well as tentative quantum number assignment of this enfant terrible of molecular spectroscopy. PMID- 25792327 TI - Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. AB - Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle. Inhibition of the enzyme LDH hyperpolarized neurons, which was reversed by the downstream metabolite pyruvate. LDH inhibition also suppressed seizures in vivo in a mouse model of epilepsy. We further found that stiripentol, a clinically used antiepileptic drug, is an LDH inhibitor. By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs. PMID- 25792328 TI - Translation. An RNA biosensor for imaging the first round of translation from single cells to living animals. AB - Analysis of single molecules in living cells has provided quantitative insights into the kinetics of fundamental biological processes; however, the dynamics of messenger RNA (mRNA) translation have yet to be addressed. We have developed a fluorescence microscopy technique that reports on the first translation events of individual mRNA molecules. This allowed us to examine the spatiotemporal regulation of translation during normal growth and stress and during Drosophila oocyte development. We have shown that mRNAs are not translated in the nucleus but translate within minutes after export, that sequestration within P-bodies regulates translation, and that oskar mRNA is not translated until it reaches the posterior pole of the oocyte. This methodology provides a framework for studying initiation of protein synthesis on single mRNAs in living cells. PMID- 25792329 TI - RNA biochemistry. Determination of in vivo target search kinetics of regulatory noncoding RNA. AB - Base-pairing interactions between nucleic acids mediate target recognition in many biological processes. We developed a super-resolution imaging and modeling platform that enabled the in vivo determination of base pairing-mediated target recognition kinetics. We examined a stress-induced bacterial small RNA, SgrS, which induces the degradation of target messenger RNAs (mRNAs). SgrS binds to a primary target mRNA in a reversible and dynamic fashion, and formation of SgrS mRNA complexes is rate-limiting, dictating the overall regulation efficiency in vivo. Examination of a secondary target indicated that differences in the target search kinetics contribute to setting the regulation priority among different target mRNAs. This super-resolution imaging and analysis approach provides a conceptual framework that can be generalized to other small RNA systems and other target search processes. PMID- 25792330 TI - Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. AB - Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR(mt)), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS(mt)), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR(mt)-mediated metabolic checkpoint as a reversible contributing factor for HSC aging. PMID- 25792331 TI - A grad school survival guide. PMID- 25792332 TI - Materials science. Materials that couple sensing, actuation, computation, and communication. AB - Tightly integrating sensing, actuation, and computation into composites could enable a new generation of truly smart material systems that can change their appearance and shape autonomously. Applications for such materials include airfoils that change their aerodynamic profile, vehicles with camouflage abilities, bridges that detect and repair damage, or robotic skins and prosthetics with a realistic sense of touch. Although integrating sensors and actuators into composites is becoming increasingly common, the opportunities afforded by embedded computation have only been marginally explored. Here, the key challenge is the gap between the continuous physics of materials and the discrete mathematics of computation. Bridging this gap requires a fundamental understanding of the constituents of such robotic materials and the distributed algorithms and controls that make these structures smart. PMID- 25792333 TI - Rearrangement of 1D conducting nanomaterials towards highly electrically conducting nanocomposite fibres for electronic textiles. AB - Nanocarbon-based conducting fibres have been produced using solution- or dry spinning techniques. Highly conductive polymer-composite fibres containing large amounts of conducting nanomaterials have not been produced without dispersants, however, because of the severe aggregation of conducting materials in high concentration colloidal solutions. Here we show that highly conductive (electrical conductivity ~1.5 * 10(5) S m(-1)) polymer-composite fibres containing carbon nanotubes and silver nanowires can be fabricated via a conventional solution-spinning process without any other treatment. Spinning dopes were fabricated by a simple mixing of a polyvinyl alcohol solution in dimethylsulfoxide with a paste of long multi-walled carbon nanotubes dispersed in organic solvents, assisted by quadruple hydrogen-bonding networks and an aqueous silver nanowire dispersion. The high electrical conductivity of the fibre was achieved by rearrangement of silver nanowires towards the fibre skin during coagulation because of the selective favourable interaction between the silver nanowires and coagulation solvents. The prepared conducting fibres provide applications in electronic textiles such as a textile interconnector of light emitting diodes, flexible textile heaters, and touch gloves for capacitive touch sensors. PMID- 25792334 TI - An investigation of classical swine fever virus seroprevalence and risk factors in pigs in East Nusa Tenggara, eastern Indonesia. AB - Classical swine fever virus (CSFV) is a highly infectious disease of pigs. It has had significant impacts on East Nusa Tenggara, eastern Indonesia since its introduction in 1997. In spite of its importance to this region, little is known about its seroprevalence and distribution, and pig-level and farmer-level factors that may have an impact on the serological status of an individual pig. To address this knowledge deficit, a cross-sectional seroprevalence survey was conducted in 2010 involving 2160 pigs and 805 farmers from four islands in the region. Farmer questionnaires and pig record forms were used to collect data about the farmers and pigs surveyed. Blood was collected from each pig to determine its CSFV serological status. Apparent and true prevalence were calculated for each island, district, subdistrict, and village surveyed. CSFV serological status was used as an outcome variable in mixed effects logistic regression analyses. Overall true CSFV seroprevalence was estimated at 17.5% (lower CI 16.0%; upper CI 19.5%). Seroprevalence estimates varied widely across the islands, districts, subdistricts, and villages. Manggarai Barat, a district on the western end of Flores Island, contained pigs that were positive for antibody to CSFV. This result was unexpected, as no clinical cases had been reported in this area. Older pigs and pigs that had been vaccinated for CSFV were more likely to test positive for antibody to CSFV. The final multivariable model accounted for a large amount of variation in the data, however much of this variation was explained by the random effects with less than 2% of the variation explained by pig age and pig CSFV vaccination status. In this study we documented the seroprevalence of CSFV across four islands in East Nusa Tenggara, eastern Indonesia. We also identified risk factors for the presence of antibody to CSFV. Further investigation is needed to understand why clinical CSFV has not been reported on the western end of Flores Island, and to identify additional risk factors that explain CSFV serological status to inform disease control strategies. PMID- 25792335 TI - Post-mortem findings and piglet mortality in relation to strategic use of straw at farrowing. AB - Piglet survival is the outcome of complex interactions between the sow, the piglet and their environment. In order to facilitate nest-building and to provide a suitable environment for the newborn piglets, a strategic method to supply loose housed sows with large quantities of straw at farrowing has been developed by Swedish piglet-producing farmers. The objectives of this cohort study were to use post-mortem findings to assess the causes of death and to quantify the effect of a large quantity of straw provided before farrowing compared to limited small daily amounts on stillbirths, post-mortem findings in piglets dying within 5 days after birth and the pre-weaning mortality. On each of four commercial piglet producing farms in South-West Sweden, one batch of sows was studied during two consecutive lactations. At inclusion, sows were randomly assigned to two treatment groups, and sows remaining in the batch during the next lactation switched treatment group. In the STRAW group (n=181 litters) sows were provided with 15-20 kg of chopped straw 2 days prior to the calculated date of farrowing. Sows in the CONTROL group (n=182 litters) received 0.5-1 kg of chopped straw on a daily basis plus about 2 kg for nest-building when the stockperson judged the sow to be about to farrow. After onset of farrowing, additionally 1-2 kg was given. Post-mortem examination was performed in all piglets that died within 5 days after birth (n=798). The three major post-mortem findings were starvation (34%) crushing by the sow (28%), and enteritis (24%). In conclusion, strategic use of large quantities of straw reduced the number of stillborn piglets per litter by 27% (p=0.007). Under the conditions studied, the pre-weaning mortality of liveborn piglets was not affected by treatment; however, the distribution of post mortem findings differed with fewer piglets dying due to starvation and more due to crushing and enteritis in STRAW litters. PMID- 25792336 TI - Structural evolution of an intermetallic Pd-Zn catalyst selective for propane dehydrogenation. AB - We report the structural evolution of Pd-Zn alloys in a 3.6% Pd-12% Zn/Al2O3 catalyst which is selective for propane dehydrogenation. High signal-to-noise, in situ synchrotron X-ray diffraction (XRD) was used quantitatively, in addition to in situ diffuse-reflectance infrared Fourier transform spectroscopy (DRIFTS) and extended X-ray absorption fine structure (EXAFS) to follow the structural changes in the catalyst as a function of reduction temperature. XRD in conjunction with DRIFTS of adsorbed CO indicated that the beta1-PdZn intermetallic alloy structure formed at reduction temperatures as low as 230 degrees C, likely first at the surface, but did not form extensively throughout the bulk until 500 degrees C which was supported by in situ EXAFS. DRIFTS results suggested there was little change in the surfaces of the nanoparticles above 325 degrees C. The intermetallic alloy which formed was Pd-rich at all temperatures but became less Pd-rich with increasing reduction temperature as more Zn incorporated into the structure. In addition to the beta1-PdZn alloy, a solid solution phase with face center cubic structure (alpha-PdZn) was present in the catalyst, also becoming more Zn-rich with increasing reduction temperature. PMID- 25792337 TI - Providing primary health care through integrated microfinance and health services in Latin America. AB - The simultaneous burdens of communicable and chronic non-communicable diseases cause significant morbidity and mortality in middle-income countries. The poor are at particular risk, with lower access to health care and higher rates of avoidable mortality. Integrating health-related services with microfinance has been shown to improve health knowledge, behaviors, and access to appropriate health care. However, limited evidence is available on effects of fully integrating clinical health service delivery alongside microfinance services through large scale and sustained long-term programs. Using a conceptual model of health services access, we examine supply- and demand-side factors in a microfinance client population receiving integrated services. We conduct a case study using data from 2010 to 2012 of the design of a universal screening program and primary care services provided in conjunction with microfinance loans by Pro Mujer, a women's development organization in Latin America. The program operates in Argentina, Bolivia, Mexico, Nicaragua, and Peru. We analyze descriptive reports and administrative data for measures related to improving access to primary health services and management of chronic diseases. We find provision of preventive care is substantial, with an average of 13% of Pro Mujer clients being screened for cervical cancer each year, 21% receiving breast exams, 16% having a blood glucose measurement, 39% receiving a blood pressure measurement, and 46% having their body mass index calculated. This population, with more than half of those screened being overweight or obese and 9% of those screened having elevated glucose measures, has major risk factors for diabetes, high blood pressure, and cardiovascular disease without intervention. The components of the Pro Mujer health program address four dimensions of healthcare access: geographic accessibility, availability, affordability, and acceptability. Significant progress has been made to meet basic health needs, but challenges remain to ensure that health care provided is of reliable quality to predictably improve health outcomes over time. PMID- 25792338 TI - Food for thought: an ethnographic study of negotiating ill health and food insecurity in a UK foodbank. AB - Emergency foodbanks have become an increasingly prominent and controversial feature of austerity in Europe and the USA. In the UK, foodbanks have been called a 'public health emergency'. Despite this, there has been no UK research examining the health of foodbank users. Through an ethnographic study, this paper is the first to explore the health and health perceptions of foodbank users via a case study of Stockton-on-Tees in the North East of England, UK during a period of welfare reform and austerity. Participant observation, field notes and interviews with foodbank users and volunteers were conducted over a seventeen month period (November 2013 to March 2015) inside a Trussell Trust foodbank. Foodbank users were almost exclusively of working age, both men and women, with and without dependent children. All were on very low incomes - from welfare benefits or insecure, poorly paid employment. Many had pre-existing health problems which were exacerbated by their poverty and food insecurity. The latter meant although foodbank users were well aware of the importance and constitution of a healthy diet, they were usually unable to achieve this for financial reasons - constantly having to negotiate their food insecurity. More typically they had to access poor quality, readily available, filling, processed foods. Foodbank users are facing the everyday reality of health inequalities at a time of ongoing austerity in the UK. PMID- 25792340 TI - Targeting brains, producing responsibilities: the use of neuroscience within British social policy. AB - Concepts and findings 'translated' from neuroscientific research are finding their way into UK health and social policy discourse. Critical scholars have begun to analyse how policies tend to 'misuse' the neurosciences and, further, how these discourses produce unwarranted and individualizing effects, rooted in middle-class values and inducing guilt and anxiety. In this article, we extend such work while simultaneously departing from the normative assumptions implied in the concept of 'misuse'. Through a documentary analysis of UK policy reports focused on the early years, adolescence and older adults, we examine how these employ neuroscientific concepts and consequently (re)define responsibility. In the documents analysed, responsibility was produced in three different but intersecting ways: through a focus on optimisation, self-governance, and vulnerability. Our work thereby adds to social scientific examinations of neuroscience in society that show how neurobiological terms and concepts can be used to construct and support a particular imaginary of citizenship and the role of the state. Neuroscience may be leveraged by policy makers in ways that (potentially) reduce the target of their intervention to the soma, but do so in order to expand the outcome of the intervention to include the enhancement of society writ large. By attending as well to more critical engagements with neuroscience in policy documents, our analysis demonstrates the importance of being mindful of the limits to the deployment of a neurobiological idiom within policy settings. Accordingly, we contribute to increased empirical specificity concerning the impacts and translation of neuroscientific knowledge in contemporary society whilst refusing to take for granted the idea that the neurosciences necessarily have a dominant role (to play). PMID- 25792339 TI - The long-run effect of maternity leave benefits on mental health: evidence from European countries. AB - This paper examines whether maternity leave policies have an effect on women's mental health in older age. We link data for women aged 50 years and above from countries in the Survey of Health, Ageing and Retirement in Europe (SHARE) to data on maternity leave legislation from 1960 onwards. We use a difference-in differences approach that exploits changes over time within countries in the duration and compensation of maternity leave benefits, linked to the year women were giving birth to their first child at age 16 to 25. We compare late-life depressive symptom scores (measured with a 12-item version of the Euro-D scale) of mothers who were in employment in the period around the birth of their first child to depression scores of mothers who were not in employment in the period surrounding the birth of a first child, and therefore did not benefit directly from maternity leave benefits. Our findings suggest that a more generous maternity leave during the birth of a first child is associated with a reduced score of 0.38 points in the Euro-D depressive symptom scale in old age. PMID- 25792341 TI - Validation of a search strategy to identify nutrition trials in PubMed using the relative recall method. AB - OBJECTIVES: To develop, assess, and maximize the sensitivity of a search strategy to identify diet and nutrition trials in PubMed using relative recall. STUDY DESIGN AND SETTING: We developed a search strategy to identify diet and nutrition trials in PubMed. We then constructed a gold standard reference set to validate the identified trials using the relative recall method. Relative recall was calculated by dividing the number of references from the gold standard our search strategy identified by the total number of references in the gold standard. RESULTS: Our gold standard comprised 298 trials, derived from 16 included systematic reviews. The initial search strategy identified 242 of 298 references, with a relative recall of 81.2% [95% confidence interval (CI): 76.3%, 85.5%]. We analyzed titles and abstracts of the 56 missed references for possible additional terms. We then modified the search strategy accordingly. The relative recall of the final search strategy was 88.6% (95% CI: 84.4%, 91.9%). CONCLUSION: We developed a search strategy to identify diet and nutrition trials in PubMed with a high relative recall (sensitivity). This could be useful for establishing a nutrition trials register to support the conduct of future research, including systematic reviews. PMID- 25792343 TI - Erratum. AB - Yasmine, Rola, Noura El Salibi, Faysal El Kak, and Lilian Ghandour. 2014. "Postponing sexual debut among university youth: how do men and women differ in their perceptions, values and non-penetrative sexual practices?" Culture, Health & Sexuality. doi:10.1080/13691058.2014.972457 When the above article was first published online, the article history dates were given incorrectly as: (Received 15 January 2005; accepted 30 September 2006) This has now been corrected in both the print and online versions to: (Received 15 January 2014; accepted 30 September 2014) Taylor & Francis apologises for this error. PMID- 25792342 TI - Using gait analysis to assess weight bearing in rats with Freund's complete adjuvant-induced monoarthritis to improve predictivity: Interfering with the cyclooxygenase and nerve growth factor pathways. AB - Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund's complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors>=anti-NGF antibody>COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain. PMID- 25792344 TI - Observation of Autoregulation Indices During Ventricular CSF Drainage After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study. AB - BACKGROUND: Cerebral autoregulation is increasingly recognized as a factor that requires evaluation when managing poor grade aneurysmal subarachnoidal hemorrhage (aSAH) patients. In this single center pilot study, we investigated whether intraventricular intracranial pressure (ICP) derived when extraventricular drain (EVD) is open can be used to calculate dynamic autoregulation estimates in ICU aSAH patients. METHODS: Ten patients with the diagnosis of aSAH as confirmed by computed tomography (CT) and CT-angiography were enrolled. ICP was monitored via a transducer connected to the most proximal side exit of the EVD catheter. From at least 30 min periods of brain monitoring before, during, and after temporarily EVD closure, commonly used indexes of dynamic cerebral autoregulation were calculated. RESULTS: Preserved pulsatile ICP signals were seen with open EVD. There were no significant changes in parameters describing cerebral autoregulation between EVD open and closed conditions. Power spectra of ABP and ICP showed no significant changes for the selected frequency ranges. There was a small significant increase in absolute ICP [2.4 (3.8) mmHg, p < 0.001] upon short term EVD closure. Cerebral spinal reserve capacity (RAP index) worsened significantly by short-term EVD closure. CONCLUSIONS: Due to preserved slow fluctuations in the ICP signal, an open EVD system can be used to calculate dynamic autoregulation indices in aSAH patients requiring intensive care monitoring with the pressure measurement from the most proximal part of drain. If these results are confirmed in larger study, this technique can open the way for investigating the role of autoregulation disturbance in aSAH patients. PMID- 25792345 TI - Failure of Induced Hypertension for Symptomatic Vasospasm in the Setting of Clozapine Therapy. AB - BACKGROUND: Hemodynamic augmentation is utilized as a treatment in the setting of symptomatic cerebral vasospasm. This approach includes the use of vasopressors to induce hypertension with the aim of improved cerebral blood flow. Agents with potent alpha-1 antagonism properties, including clozapine, can inhibit or blunt the response of several vasopressor agents. METHODS: Case report. RESULTS: A 54 year-old schizophrenic male with an aneurysmal subarachnoid hemorrhage required hemodynamic augmentation in which several vasopressor trials resulted in no or poor response. The addition of epinephrine resulted in a decrease of mean arterial pressure. Vasopressin initiation demonstrated an immediate vasopressor effect. CONCLUSIONS: Vasopressors are an important treatment modality in symptomatic cerebral vasospasm. This case highlights the potential for clozapine to blunt the effects of vasopressors; or in the case of epinephrine, it causes a reversal effect. Vasopressin may be considered an agent of choice in patients who have recently taken clozapine and require hemodynamic augmentation. PMID- 25792346 TI - Epidemiology of Mycoplasma acquisition in male HIV-1 infected patients: a multistage cross-sectional survey in Jiangsu, China. AB - Mycoplasma infections are most frequently associated with disease in the urogenital or respiratory tracts and, in most cases, mycoplasmas infect the host persistently. In HIV-infected individuals the prevalence and role of genital mycoplasmas has not been well studied. To investigate the six species of Mycoplasma and the risk factors for infection in Jiangsu province, first-void urine and venous blood samples were collected and epidemiological questionnaires were administered after informed consent. A total of 1541 HIV/AIDS patients were recruited in this study. The overall infection rates of six Mycoplasma species were: Ureaplasma urealyticum (26.7%), Mycoplasma hominis (25.3%), M. fermentans (5.1%), M. genitalium (20.1%), M. penetrans (1.6%) and M. pirum (15.4%). The Mycoplasma infection rate in the unmarried group was lower than that of the married, divorced and widowed groups [adjusted odds ratio (aOR) 1.432, 95% confidence interval (CI) 1.077-1.904, P < 0.05]. The patients who refused highly active antiretroviral therapy (HAART) had a much higher risk of Mucoplasma infection (aOR 1.357, 95% CI 1.097-1.679, P < 0.05). Otherwise, a high CD4+ T cell count was a protective factor against Mycoplasma infection (aOR 0.576, 95% CI 0.460-0.719, P < 0.05). Further research will be required to confirm a causal relationship and to identify risk factors for Mycoplasma infection in HIV/AIDS populations. PMID- 25792347 TI - Effectiveness of natalizumab in patients with highly active relapsing remitting multiple sclerosis. AB - INTRODUCTION: We evaluated the effectiveness of natalizumab in patients with highly active, relapsing-remitting multiple sclerosis (HA-RRMS) to identify baseline predictors associated with freedom from disease activity. METHODS: We analyzed 70 patients treated with natalizumab and followed for at least 1 year with progression of disability of >=1 point on the EDSS before starting therapy. We recorded freedom from clinical activity, radiological activity, and disease activity (clinical and radiological). RESULTS: The median (IQR) follow-up was 2.3 (2.0-3.8) years. Of the 52 patients who completed 2 years of treatment, 25 were free of disease activity (48.1%). The ARR decreased from a mean +/- SD of 2.49 +/ 0.86 at baseline to 0.47 +/- 0.83 at the end of the first year (p < 0.001) and 0.34 +/- 0.69 at the end of the second year (p < 0.001). The percentage of patients with gadolinium-enhanced lesions decreased from 21 at baseline to 5.7 at the end of the first year (p < 0.001) and to 5.8 during the second year (p < 0.005). Baseline EDSS <=3.0 was significantly associated with freedom from disease activity (OR, 2.49; 95% CI, 1.24-4.99; p = 0.010). CONCLUSIONS: Natalizumab is effective in patients with HA-RRMS. Baseline EDSS <=3.0 increases the probability of remaining disease-free in HA-RRMS treated with natalizumab. PMID- 25792348 TI - Risedronate as an intra-abdominal sepsis mimic: a case report. AB - This case report highlights the potential severity of bisphosphonate-associated reactions. CASE REPORT: A 76-year-old lady underwent several hospital admissions for investigation of fever associated with rigors, abdominal pain, and vomiting. DISCUSSION: Despite multiple investigations, no cause was found, but the timing of the symptoms coincided with monthly risedronate administration. PMID- 25792350 TI - A paraurethal cyst with calculi. PMID- 25792349 TI - Urological chronic pelvic pain syndrome flares and their impact: qualitative analysis in the MAPP network. AB - INTRODUCTION AND HYPOTHESIS: Although in-depth qualitative information is critical to understanding patients' symptom experiences and to developing patient centered outcome measures, only one previous qualitative study has assessed urological chronic pelvic pain syndrome (UCPPS) symptom exacerbations ("flares"). METHODS: We conducted eight focus groups of female UCPPS (interstitial cystitis/bladder pain syndrome) patients at four sites from the MAPP Research Network (n = 57, mean = 7/group) to explore the full spectrum of flares and their impact on patients' lives. RESULTS: Flare experiences were common and varied widely in terms of UCPPS symptoms involved, concurrent nonpelvic symptoms (e.g., diarrhea), symptom intensity (mild to severe), duration (minutes to years), and frequency (daily to < once/year), although the most commonly described flares were painful flares lasting days. These latter flares were also most disruptive to participants' lives, causing some to cancel social events, miss work or school, and in the worst cases, go to the emergency room or on disability leave. Participants also reported a longer-term impact of flares, including negative effects on their sexual functioning and marital, family, and social relationships; and the loss of employment or limited career or educational advancement. Emerging themes included the need for a sense of control over unpredictable symptoms and reduced social engagement. CONCLUSIONS: Given their negative impact, future research should focus on approaches to prevent flares, and to reduce their frequency, severity, and/or duration. Patients' quality of life may also be improved by providing them with a sense of control over their symptoms through ready access to flare medications/therapy, and by engaging them socially. PMID- 25792351 TI - General or Spinal Anaesthetic for Vaginal Surgery in Pelvic Floor Disorders (GOSSIP): a feasibility randomised controlled trial. AB - INTRODUCTION AND HYPOTHESIS: Spinal anaesthesia (SA) and general anaesthesia (GA) are widely used techniques for vaginal surgery for pelvic floor disorders with inconclusive evidence of the superiority of either. We conducted a randomised controlled trial (RCT) to assess the feasibility of a full scale RCT aiming to examine the effect of anaesthetic mode for vaginal surgery on operative, patient reported and length of hospital stay (LOHS) outcomes. METHODS: Patients undergoing vaginal surgery, recruited through a urogynaecology service in a University teaching hospital, were randomised to receive either GA or SA. Patients were followed up for 12 weeks postoperatively. Pain was measured on a visual analogue scale; nausea was assessed with a four-point verbal rating scale. Patient's subjective perception of treatment outcome, quality of life (QoL) and functional outcomes were assessed using the International Consultation on Incontinence Modular Questionnaire (ICIQ) on vaginal symptoms and the SF-36 questionnaire. RESULTS: Sixty women were randomised, 29 to GA and 31 to SA. The groups were similar in terms of age and type of vaginal surgery performed. No statistically significant differences were noted between the groups with regard to pain, nausea, quality of life (QoL), functional outcomes as well as length of stay in the postoperative recovery room, use of analgesia postoperatively and LOHS. CONCLUSION: This study has demonstrated that a full RCT is feasible and should focus on the length of hospital stay in a subgroup of patients undergoing vaginal surgery where SA may help to facilitate enhanced recovery or day surgery. PMID- 25792352 TI - Association of antepartum vitamin D levels with postpartum pelvic floor muscle strength and symptoms. AB - INTRODUCTION AND HYPOTHESIS: Vitamin D affects skeletal muscle strength and functions via various mechanisms. Strength and/or functional dysfunctions of the pelvic floor muscles may be associated with the distortion of pelvic floor functions. We hypothesized that vitamin D deficiency may contribute to pelvic floor dysfunction (PFD) by affecting pelvic floor muscle strength (PFMS). The aim of this study was to assess the effect of vitamin D deficiency during pregnancy on postpartum PFMS. METHODS: This cross-sectional study was conducted in a university hospital. One hundred and eighty pregnant women were admitted to our hospital in their third trimester and compared with 156 healthy nulliparous women. Venous blood samples for examining vitamin D levels were taken from each participant and stored at -80 degrees C. At 8-10 weeks postpartum, patients were invited to the hospital, asked about their PFD symptoms, and PFMS was measured using a perineometer. RESULTS: There was no statistical significance among groups regarding mean age, maternal age, and weight at delivery. Postpartum PFMS and duration in vitamin D-deficient women were significantly lower than those without the deficiency. Vitamin D-deficient vaginal delivery cases (group I) had a postpartum PFMS average of 21.96 +/- 7.91 cm-H2O, nonvitamin D-deficient normal delivery cases (group III) had a PFMS of 29.66 +/- 10.3 cm-H2O (p = 0.001). In the cesarean delivery groups, vitamin D-deficient (group II) and nonvitamin D deficient (group IV) cases had PFMS values of 32.23 +/- 9.66 and 35.53 +/- 15.58 cm-H2O respectively (p = 0.258). CONCLUSIONS: Lower vitamin D levels in the third trimester correlates with decreased PFMS. PMID- 25792353 TI - Refractory overactive bladder: a common problem? AB - INTRODUCTION AND HYPOTHESIS: Unsatisfactory treatment outcome sometimes is described as frequently occurring in patients treated with first-line therapy for overactive bladder (OAB). The present article reviews the different circumstances which may result in failure to respond to lifestyle interventions, behavioral therapy, and/or antimuscarinic treatment. METHODS: An extensive literature search was conducted to identify relevant articles on pathophysiological, clinical, and pharmacological aspects of refractory OAB. RESULTS: Missing definition, unrealistic individual expectation of treatment outcomes, lack of communication between physician and patient as well as pathophysiological and pharmacological processes were identified as relevant for failure to respond to first-line OAB treatment. Increase of patient's motivation to adhere to the prescribed treatment, critical examination of the patient in regard to the initial diagnosis, and individual adjustment of antimuscarinic therapy may be appropriate tools to improve treatment outcome in OAB patients. CONCLUSIONS: Overall, the incidence of refractory OAB seems to be overestimated. There are several approaches to improve therapy results. PMID- 25792354 TI - Inspiratory resistance improves postural tachycardia: a randomized study. AB - BACKGROUND: The objective of this study was to determine the effect of inspiratory resistance through an impedance threshold device (ITD) on orthostatic tolerance in patients with postural tachycardia syndrome. We hypothesized that the ITD would result in a greater negative intrathoracic pressure to enhance cardiac venous return, improve stroke volume, and reduce heart rate in these patients. METHODS AND RESULTS: We compared the effect of a sham device (sham, no resistance) versus an ITD (increased inspiratory resistance) in 26 patients with postural tachycardia syndrome in a randomized, single-blind, crossover study. Hemodynamic assessments were performed at baseline while supine and during head up tilt to 70 degrees for 10 minutes. We did not find differences in baseline hemodynamic parameters between the ITD and the sham devices. After 10 minutes of head-up tilt, the heart rate was lower with the ITD versus sham device (102+/-4 versus 109+/-4 beat/min, respectively; P=0.003). The ITD also improved stroke volume compared with the sham device (35+/-2 versus 26+/-1 mL; P=0.006). CONCLUSIONS: These findings suggest that increasing negative intrathoracic pressure with ITD breathing improves heart rate control in patients with postural tachycardia syndrome during upright posture. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Unique Identifier: NCT00962728. PMID- 25792355 TI - Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. PMID- 25792357 TI - Familial primary localized cutaneous amyloidosis results from either dominant or recessive mutations in OSMR. PMID- 25792356 TI - The relationship between lower limb bone and muscle in military recruits, response to physical training, and influence of smoking status. AB - The relationship between bone and skeletal muscle mass may be affected by physical training. No studies have prospectively examined the bone and skeletal muscle responses to a short controlled exercise-training programme. We hypothesised that a short exercise-training period would affect muscle and bone mass together. METHODS: Femoral bone and Rectus femoris Volumes (RFVOL) were determined by magnetic resonance imaging in 215 healthy army recruits, and bone mineral density (BMD) by Dual X-Ray Absorptiometry (DXA) and repeated after 12 weeks of regulated physical training. RESULTS: Pre-training, RFVOL was smaller in smokers than non-smokers (100.9 +/- 20.2 vs. 108.7 +/- 24.5, p = 0.018; 96.2 +/- 16.9 vs. 104.8 +/- 21.3, p = 0.002 for dominant/non-dominant limbs), although increases in RFVOL with training (of 14.2 +/- 14.5% and 13.2 +/- 15.6%] respectively, p < 0.001) were independent of prior smoking status. Pre-training RFVOL was related to bone cortical volume (r(2) = 0.21 and 0.30, p < 0.001 for dominant and non-dominant legs), and specifically to periosteal (r(2) = 0.21 and 0.23, p < 0.001) volume. Pre-training dominant RFVOL was independently associated with Total Hip BMD (p < 0.001). Training-related increases in RFVOL and bone volumes were related. Whilst smokers demonstrated lower muscle mass than non smokers, differences were abolished with training. Training-related increases in muscle mass were related to increases in periosteal bone volume in both dominant and non-dominant legs. PMID- 25792358 TI - Pilocytic astrocytoma: pathology, molecular mechanisms and markers. AB - Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10 year survival of over 90%. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one pathway disease. The most common mechanism is a tandem duplication of a ~2 Mb fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549 BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed. PMID- 25792359 TI - Characterization of 26 deletion CNVs reveals the frequent occurrence of micro mutations within the breakpoint-flanking regions and frequent repair of double strand breaks by templated insertions derived from remote genomic regions. AB - Copy number variations (CNVs) have increasingly been reported to cause, or predispose to, human disease. However, a large fraction of these CNVs have not been accurately characterized at the single-base-pair level, thereby hampering a better understanding of the mutational mechanisms underlying CNV formation. Here, employing a composite pipeline method derived from various inference-based programs, we have characterized 26 deletion CNVs [including three novel pathogenic CNVs involving an autosomal gene (EXT2) causing hereditary osteochondromas and an X-linked gene (CLCN5) causing Dent disease, as well as 23 CNVs previously identified by inference from a cohort of Canadian autism spectrum disorder families] to the single-base-pair level of accuracy from whole-genome sequencing data. We found that breakpoint-flanking micro-mutations (within 22 bp of the breakpoint) are present in a significant fraction (5/26; 19%) of the deletion CNVs. This analysis also provided evidence that a recently described error-prone form of DNA repair (i.e., repair of DNA double-strand breaks by templated nucleotide sequence insertions derived from distant regions of the genome) not only causes human genetic disease but also impacts on human genome evolution. Our findings illustrate the importance of precise CNV breakpoint delineation for understanding the underlying mutational mechanisms and have implications for primer design in relation to the detection of deletion CNVs in clinical diagnosis. PMID- 25792360 TI - Homozygous MED25 mutation implicated in eye-intellectual disability syndrome. AB - Genetic syndromes involving both brain and eye abnormalities are numerous and include syndromes such as Warburg micro syndrome, Kaufman oculocerebrofacial syndrome, Cerebro-oculo-facio-skeletal syndrome, Kahrizi syndrome and others. Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village. The protein encoded by MED25 belongs to Mediator complex or MED complex, which is an evolutionary conserved multi-subunit RNA polymerase II transcriptional regulator complex. The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells. PMID- 25792362 TI - Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza. AB - INTRODUCTION: Influenza viruses are a threat to human health. There are presently only two methods for treating influenza: vaccines, which require yearly updates, and two classes of antivirals that suffer with the problem of resistance by current human influenza viruses; this is especially the case with amantadine and rimantadine. Consequently, there is an urgent need for the development of new antivirals with new mechanisms of action. AREAS COVERED: In this review, the authors focus on viral protein domains, their associated activity and their inhibition by small molecules defined by a structure-based design with a special emphasis on the ribonucleoprotein complex and its inhibitors. Several new classes of antiviral candidates targeting viral replication through individual domains of the polymerase and the nucleoprotein (NP) have been developed through structure based design. EXPERT OPINION: To date, the antivirals targeting neuraminidase are by far the most developed and potent. Antiviral candidates targeting the NP and polymerase domains are in the pipeline but their pharmacokinetics needs further studies. The recently published structures of the polymerase expand the possibilities for development of new antivirals. Combination therapies targeting conserved viral targets and new cellular proteins or exploiting drug promiscuity hold promises to fight against the emergence of resistance. PMID- 25792361 TI - Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). AB - BACKGROUND: Obesity and atrial fibrillation (AF) frequently coexist. Weight loss reduces the burden of AF, but whether this is sustained, has a dose effect, or is influenced by weight fluctuation is unknown. OBJECTIVES: This study sought to evaluate the long-term impact of weight loss and weight fluctuation on rhythm control in obese individuals with AF. METHODS: Of 1,415 consecutive patients with AF, 825 had a body mass index >= 27 kg/m(2) and were offered weight management. After screening for exclusion criteria, 355 were included in this analysis. Weight loss was categorized as group 1 (>= 10%), group 2 (3% to 9%), and group 3 (<3%). Weight trend and/or fluctuation was determined by yearly follow-up. We determined the impact on the AF severity scale and 7-day ambulatory monitoring. RESULTS: There were no differences in baseline characteristics or follow-up among the groups. AF burden and symptom severity decreased more in group 1 compared with groups 2 and 3 (p < 0.001 for all). Arrhythmia-free survival with and without rhythm control strategies was greatest in group 1 compared with groups 2 and 3 (p < 0.001 for both). In multivariate analyses, weight loss and weight fluctuation were independent predictors of outcomes (p < 0.001 for both). Weight loss >= 10% resulted in a 6-fold (95% confidence interval: 3.4 to 10.3; p < 0.001) greater probability of arrhythmia-free survival compared with the other 2 groups. Weight fluctuation >5% partially offset this benefit, with a 2-fold (95% confidence interval: 1.0 to 4.3; p = 0.02) increased risk of arrhythmia recurrence. CONCLUSIONS: Long-term sustained weight loss is associated with significant reduction of AF burden and maintenance of sinus rhythm. (Long-Term Effect of Goal directed weight management on Atrial Fibrillation Cohort: A 5 Year follow-up study [LEGACY Study]; ACTRN12614001123639). PMID- 25792364 TI - Aestuariivivens insulae gen. nov., sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-motile, aerobic, ovoid or rod-shaped bacterium, designated AH-MY3T, was isolated from a tidal flat on Aphae island of the south western sea, South Korea, and subjected to a polyphasic taxonomic study. Strain AH-MY3T grew optimally at 35 degrees C, at pH 7.0-8.0 and in the presence of 2.0 3.0 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain AH-MY3T joined the cluster comprising the type strains of Yeosuana aromativorans, Snuella lapsa and Meridianimaribacter flavus, showing sequence similarities of 93.9, 93.7 and 92.6 %, respectively. Strain AH MY3T exhibited 16S rRNA gene sequence similarity values of 94.0-94.7 % to the type strains of 'Aestuariibaculum scopimerae', Winogradskyella aquimaris, Winogradskyella poriferorum and Gaetbulibacter aestuarii. Strain AH-MY3T contained MK-6 as the predominant menaquinone. The fatty acid and polar lipid profiles of strain AH-MY3T could be distinguished from those of the type strains of phylogenetically related taxa. The DNA G+C content of strain AH-MY3T was 37 mol%. The phylogenetic data and differential chemotaxonomic and other phenotypic properties revealed that strain AH-MY3T represents a novel genus and species within the family Flavobacteriaceae, for which the name Aestuariivivens insulae gen. nov., sp. nov. is proposed. The type strain of Aestuariivivens insulae is AH MY3T ( = KCTC 42350T = NBRC 110723T). PMID- 25792365 TI - Ogataea mangiferae sp. nov., a methylotrophic yeast isolated from mango leaves. AB - Five strains of a novel methanol-assimilating yeast species were isolated from mango (Mangifera indica) leaves collected at the campus of the Federal University of Minas Gerais in Brazil. The sequences of the internal transcribed spacer (ITS) region and the D1/D2 domains of the large subunit of the rRNA gene showed that this species belongs to the Ogataea clade and is related to O. allantospora, O. chonburiensis, O. dorogensis, O. kodamae, O. paradorogensis and Candida xyloterini (Ogataea clade). The novel species differs in the D1/D2 domains of the large subunit of the rRNA gene by 12 to 40 substitutions from these Ogataea species. The name Ogataea mangiferae sp. nov. is proposed for this novel species. The type strain of Ogataea mangiferae sp. nov. is UFMG-CM-Y253T ( = CBS 13492T). The Mycobank number is MB 811646. PMID- 25792366 TI - Paracoccus sanguinis sp. nov., isolated from clinical specimens of New York State patients. AB - Eight independent isolates of a Gram-reaction-negative, non-motile rod, were recovered from clinical specimens of New York State patients between the years 2005 and 2013. Four of these isolates were characterized in a taxonomic study using a polyphasic approach that involved phenotypic, phylogenetic and genotypic methodologies. Based on 16S rRNA gene sequence similarity and phylogenetic analysis, the closest relative type strain of the isolates is Paracoccus sphaerophysae HAMBI 3106T (97.7 % 16S rRNA gene sequence similarity). Among the four isolates, the 16S rRNA gene sequence similarity is 100 %. In silico genomic comparisons, including average nucleotide identity (ANI) and the genome-to-genome distance calculator (GGDC), were used as an alternative to DNA-DNA hybridization in this study to support designation of the four isolates as a novel species of the genus Paracoccus. Mass spectrometry profiles were also obtained for the novel isolates using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The predominant cellular fatty acids of the novel isolates were C18 : 1omega7c and C18 : 0. Biochemical analysis and morphological characteristics further contribute to designation of the four isolates as a novel species of the genus Paracoccus, for which the name Paracoccus sanguinis sp. nov. is proposed. The type strain is 05503T( = DSM 29303T = LMG 28451T). PMID- 25792367 TI - Marivita lacus sp. nov., isolated from a saline lake. AB - A Gram-staining-negative, strictly heterotrophic and aerobic bacterium, strain TS T44T, was isolated from a saline lake, Tuosu Lake in Qaidam basin, Qinghai province, China. Its taxonomic position was investigated using a polyphasic approach. Cells of strain TS-T44T were non-endospore-forming, non-motile rods, 0.8-1.2 MUm wide and 1.2-3.0 MUm long. Catalase- and oxidase-positive. Growth occurred in the presence of up to 8 % (w/v) NaCl (optimum, 3.0 %) and at 15-35 degrees C (optimum, 25 degrees C) and pH 7.0-10.0 (optimum, pH 7.5-8.5). C18 : 1omega7c was the predominant fatty acid. The major respiratory quinone was Q-10. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, an unidentified aminolipid and an unknown lipid. The DNA G+C content was 65.5 mol% [determined from the melting temperature (Tm)]. Phylogenetic trees based on 16S rRNA gene sequences showed that strain TS-T44T was associated with the genus Marivita and showed highest sequence similarity to Marivita cryptomonadis CL-SK44T (97.7 %), Marivita litorea CL-JM1T (97.5 %) and Marivita geojedonensis DPG-138T (97.3 %), and < 97 % to other species. DNA-DNA relatedness of strain TS-T44T to M. cryptomonadis JCM 15447T, M. litorea JCM 15446T and M. geojedonensis KCTC 23882T was 23 +/- 3 %, 33 +/- 4 % and 35 +/- 2 %, respectively. Based on the data presented, it is concluded that strain TS-T44T represents a novel species of the genus Marivita, for which the name Marivita lacus sp. nov. is proposed. The type strain is TS-T44T ( = CGMCC 1.12478T = JCM 19516T). PMID- 25792368 TI - Vibrio olivae sp. nov., isolated from Spanish-style green-olive fermentations. AB - Three isolates originating from Spanish-style green-olive fermentations in a manufacturing company in the province of Seville, Spain, were taxonomically characterized by a polyphasic approach. This included a phylogenetic analysis based on 16S rRNA gene sequences and multi-locus sequence analysis (MLSA) based on pyrH, recA, rpoA, gyrB and mreB genes. The isolates shared 98.0 % 16S rRNA gene sequence similarity with Vibrio xiamenensis G21T. Phylogenetic analysis based on 16S rRNA gene sequences using the neighbour-joining and maximum likelihood methods showed that the isolates fell within the genus Vibrio and formed an independent branch close to V. xiamenensis G21T. The maximum-parsimony method grouped the isolates to V. xiamenensis G21T but forming two clearly separated branches. Phylogenetic trees based on individual pyrH, recA, rpoA, gyrB and mreB gene sequences revealed that strain IGJ1.11T formed a clade alone or with V. xiamenensis G21T. Sequence similarities of the pyrH, recA, rpoA, gyrB and mreB genes between strain IGJ1.11T and V. xiamenensis G21T were 86.7, 85.7, 97.3, 87.6 and 84.8 %, respectively. MLSA of concatenated sequences showed that strain IGJ1.11T and V. xiamenensis G21T are two clearly separated species that form a clade, which we named Clade Xiamenensis, that presented 89.7 % concatenated gene sequence similarity, i.e. less than 92 %. The major cellular fatty acids (>5 %) of strain IGJ1.11T were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). Enzymic activity profiles, sugar fermentation patterns and DNA G+C content (52.9 mol%) differentiated the novel strains from the closest related members of the genus Vibrio. The name Vibrio olivae sp. nov. is proposed for the novel species. The type strain is IGJ1.11T ( = CECT 8064T = DSM 25438T). PMID- 25792369 TI - Desulfoplanes formicivorans gen. nov., sp. nov., a novel sulfate-reducing bacterium isolated from a blackish meromictic lake, and emended description of the family Desulfomicrobiaceae. AB - A novel sulfate-reducing bacterium, designated strain Pf12BT, was isolated from sediment of meromictic Lake Harutori in Japan. Cells were vibroid (1.0 * 3.0-4.0 MUm), motile and Gram-stain-negative. For growth, the optimum pH was 7.0-7.5 and the optimum temperature was 42-45 degrees C. Strain Pf12BT used sulfate, thiosulfate and sulfite as electron acceptors. The G+C content of the genomic DNA was 55.4 mol%. Major cellular fatty acids were C16 : 0 and C18 : 0. The strain was desulfoviridin-positive. Phylogenetic analysis based on the 16S rRNA gene revealed that the novel strain belonged to the order Desulfovibrionales in the class Deltaproteobacteria. The closest relative was Desulfomicrobium baculatum DSM 4028T with which it shared 91 % 16S rRNA gene sequence similarity. On the basis of phylogenetic and phenotypic characterization, a novel species of a new genus belonging to the family Desulfomicrobiaceae is proposed, Desulfoplanes formicivorans gen. nov., sp. nov. The type strain of Desulfoplanes formicivorans is Pf12BT ( = NBRC 110391T = DSM 28890T). PMID- 25792370 TI - Persistent pseudobulbar affect secondary to acute disseminated encephalomyelitis. AB - Pseudobulbar affect (PBA) is a common complication of central nervous system diseases such as stroke, multiple sclerosis, and other neurological diseases, but it remains under-recognized and under-treated in the clinic. PBA caused by acute disseminated encephalomyelitis (ADEM) has rarely been reported. Here, we report a 30-year-old Chinese woman who has experienced PBA from ADEM for 7 years. The patient's principal manifestations were extreme emotions or tears when she saw, heard, or spoke about sad news or other sad things; the durations of these unmanageable emotions were often less than 30 sec, and they occurred at frequencies that ranged from one to several times a day. Occasionally, she laughed uncontrollably while people were talking despite a lack of funny or sad stimuli in the conversation or the surrounding environment. Thus, her social functioning was impaired. This case indicates that the long-term PBA can occur secondarily to ADEM, and this possibility should be considered clinically to ensure timely identification and treatment. PMID- 25792371 TI - Low Counts of Plasmacytoid Dendritic Cells after Engraftment Are Associated with High Early Mortality after Allogeneic Stem Cell Transplantation. AB - Dendritic cells (DCs) are antigen-presenting cells that drive immune responses and tolerance and are divided in different subsets: myeloid DCs (mDCs: lineage-; HLA-DR+, 11c+), plasmacytoid dendritic cells (pDCs: HLA-DR+, CD123+), and monocyte-derived DCs (moDC: lineage-, 11c+, 16+). After hematopoietic stem cell transplantation (HSCT), low DC counts in the recipients' peripheral blood (PB) have been associated with worse outcomes, but the relevance of DC graft content remains unclear, and there are few data in the setting of unrelated donor HSCT. We evaluated the DC graft content and monitored DC recovery in PB from 111 HSCT recipients (median age, 17 years; range 1 to 74), who received bone marrow (46%), umbilical cord blood (32%), or PB (22%) from unrelated (81%) or related donors (19%). In 86 patients with sustained allogeneic recovery, patients with higher counts of all DC subsets (pDC, mDC, and moDC) 3 weeks after engraftment had lower incidence of nonrelapse mortality (NMR) and acute graft-versus-host disease (aGVHD) and better survival. pDC counts were associated with more striking results: patients with higher pDC counts had much lower incidences of NRM (3% versus 47%, P < .0001), lower incidence of aGVHD (24% versus 67%, P < .0001), and better overall survival (92% versus 45%, P < .0001). In contrast, higher pDC counts in the graft was associated with an increased risk of aGVHD (55% versus 26%, P = .02). Our results indicate that DC counts are closely correlated with HSCT outcomes and warrant further prospective evaluation and possible early therapeutic interventions to ameliorate severe aGVHD and decrease mortality. PMID- 25792372 TI - Next-generation sequencing detects repetitive elements expansion in giant genomes of annual killifish genus Austrolebias (Cyprinodontiformes, Rivulidae). AB - Among Neotropical fish fauna, the South American killifish genus Austrolebias (Cyprinodontiformes: Rivulidae) constitutes an excellent model to study the genomic evolutionary processes underlying speciation events. Recently, unusually large genome size has been described in 16 species of this genus, with an average DNA content of about 5.95 +/- 0.45 pg per diploid cell (mean C-value of about 2.98 pg). In the present paper we explore the possible origin of this unparallel genomic increase by means of comparative analysis of the repetitive components using NGS (454-Roche) technology in the lowest and highest Rivulidae genomes. Here, we provide the first annotated Rivulidae-repeated sequences composition and their relative repetitive fraction in both genomes. Remarkably, the genomic proportion of the moderately repetitive DNA in Austrolebias charrua genome represents approximately twice (45%) of the repetitive components of the highly related rivulinae taxon Cynopoecilus melanotaenia (25%). Present work provides evidence about the impact of the repeat families that could be distinctly proliferated among sublineages within Rivulidae fish group, explaining the great genome size differences encompassing the differentiation and speciation events in this family. PMID- 25792373 TI - Effects of ageing and experimental diabetes on insulin-degrading enzyme expression in male rat tissues. AB - Due to an increasing life expectancy in developing countries, cases of type 2 diabetes and Alzheimer's disease (AD) in the elderly are growing exponentially. Despite a causative link between diabetes and AD, general molecular mechanisms underlying pathogenesis of these disorders are still far from being understood. One of the factors leading to cell death and cognitive impairment characteristic of AD is accumulation in the brain of toxic aggregates of amyloid-beta peptide (Abeta). In the normally functioning brain Abeta catabolism is regulated by a cohort of proteolytic enzymes including insulin-degrading enzyme (IDE) and their deficit with ageing can result in Abeta accumulation and increased risk of AD. The aim of this study was a comparative analysis of IDE expression in the brain structures involved in AD, as well as in peripheral organs (the liver and kidney) of rats, during natural ageing and after experimentally-induced diabetes. It was found that ageing is accompanied by a significant decrease of IDE mRNA and protein content in the liver (by 32 and 81%) and brain structures (in the cortex by 58 and 47% and in the striatum by 53 and 68%, respectively). In diabetic animals, IDE protein level was increased in the liver (by 36%) and in the striatum (by 42%) while in the brain cortex and hippocampus it was 20-30% lower than in control animals. No significant IDE protein changes were observed in the kidney of diabetic rats. These data testify that ageing and diabetes are accompanied by a deficit of IDE in the brain structures where accumulation of Abeta was reported in AD patients, which might be one of the factors predisposing to development of the sporadic form of AD in the elderly, and especially in diabetics. PMID- 25792374 TI - Reduced sleep quality and depression associate with decreased quality of life in patients with pituitary adenomas. AB - OBJECTIVES: Several studies reported decreased quality of life (QoL) and sleep as well as increased rates of depression for patients with pituitary adenomas. Our aim was to explore to what extent differences in depression and sleep quality contribute to differences in QoL between patients with pituitary adenomas and controls. DESIGN: A cross-sectional case-control study. SETTING: Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry, Munich, Department of Internal Medicine, Ludwig-Maximilians-University, Munich, and the Institute of Clinical Psychology and Psychotherapy, Technical University, Dresden. PARTICIPANTS: Patients with pituitary adenomas (n=247) and controls (from the DETECT cohort, a large epidemiological study in primary care patients) matched individually by age and gender (n=757). MEASUREMENTS: Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and QoL was measured by the generic EQ-5D and calculated by the time trade-off- and VAS-method. Depression was categorized as 'no depression', 'subclinical depression', and 'clinical depression' according to the Beck Depressions Inventory for patients and the Depression Screening Questionnaire for control subjects. STATISTICAL ANALYSES: General linear and generalized, logistic mixed models as well as proportional odds mixed models were calculated for analyzing differences in baseline characteristics and in different subgroups. RESULTS: Patients with pituitary adenomas showed decreased QoL (VAS index: 0.73+/-0.19) and sleep (PSQI score: 6.75+/-4.17) as well as increased rates of depression (subclinical or clinical depression: 41.4%) compared with their matched control subjects (VAS index: 0.79+/-0.18, PSQI score: 5.66+/-4.31, subclinical or clinical depression: 25.9%). We have shown that a substantial proportion of the reduced QoL (48% respectively 65%) was due to the incidence of depression and reduced sleep quality. CONCLUSIONS: These findings emphasize the importance of diagnosing depressive symptoms and sleep disturbances in patients with pituitary disease, with the ultimate goal to improve QoL in patients with pituitary adenomas. PMID- 25792375 TI - Giant GH-secreting pituitary adenomas: management of rare and aggressive pituitary tumors. AB - OBJECTIVES: Patients with acromegaly usually harbor macroadenomas measuring between 10 and 30 mm in maximal diameter. Giant (adenoma size >=40 mm) GH secreting pituitary tumors are rarely encountered and the aim of this study is to analyze different methods for managing them. DESIGN AND METHODS: We have identified 34 patients (15 men and 19 females) with giant adenomas among 762 subjects (4.5%) with acromegaly in our records, and characterized their clinical characteristics and response to treatment. RESULTS: Mean age at diagnosis was 34.9+/-12.5 years (range, 16-67 years). Mean adenoma size was 49.4+/-9.4 mm (range, 40-80 mm); 30 adenomas showed cavernous sinus invasion and 32 had suprasellar extension. Twenty-nine (85%) patients had visual field defects. Mean baseline IGF1 was 3.4+/-1.8*ULN. All patients except one underwent pituitary surgery (one to three procedures), but none achieved hormonal remission following first surgery. Among the 28 subjects with visual disturbances, 14 recovered post operatively and 13 improved. Treatment with somatostatin analogs was given to all patients after surgical failure. Six achieved remission, nine others were partially controlled (IGF1<1.5*ULN; 3/9 when combined with cabergoline), and 17 did not respond (two were lost). Nine patients were treated with pegvisomant, alone (n=4) or in combination with somatostatin analogs (n=5); five are in remission and two are partially controlled. Pasireotide-LAR achieved hormonal remission in one of the six patients. Currently, after a mean follow-up period of 8.9 years, 17 patients are in biochemical remission, eight are partially controlled, and seven are uncontrolled (two were lost to follow-up). CONCLUSIONS: Giant GH-secreting adenomas are invasive, uncontrolled by surgery, and respond poorly to medical treatment. Aggressive multimodal therapy is critical for their management, enhancing control rate and biochemical remission. PMID- 25792376 TI - Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. AB - CONTEXT: A sex difference in the progression of prolactin (PRL) tumors has been disputed for years. OBJECTIVE: To compare tumor characteristics and postoperative clinical course between men and women, and correlate data with estrogen receptor alpha (ERalpha (ESR1)) expression status. DESIGN, PATIENTS, AND METHODS: Eighty nine patients (59 women and 30 men) operated on for a prolactinoma and followed for at least 5 years were selected. Tumors were classified into five grades according to their size, invasion, and proliferation characteristics. The ERalpha expression was detected by immunohistochemistry and a score (0-12) calculated as the product of the percentage of positive nuclei and the staining intensity. RESULTS: We found a significant preponderance of high-grade tumors among men and a lower surgical cure rate in men (23%) than in women (71%). Patients resistant to medical treatment were mainly men (7/8), six of whom showed tumor progression despite postoperative medical treatment, which led to multiple therapies and eventually death in three. The median score for ERalpha expression was 1 in men (range, 0-8) and 8 in women (range, 0-12) (P<0.0001). The expression of ERalpha was inversely correlated with tumor size (r=-0.59; P<0.0001) and proliferative activity. All dopamine agonist-resistant tumors and all grade 2b (invasive and proliferative) tumors (from ten men and four women) were characterized by low ERalpha expression. CONCLUSIONS: PRL tumors in men are characterized by lower ERalpha expression, which is related to higher tumor grades, resistance to treatment, and an overall worse prognosis. PMID- 25792377 TI - MicroRNA-223 displays a protective role against cardiomyocyte hypertrophy by targeting cardiac troponin I-interacting kinase. AB - BACKGROUND/AIMS: MicroRNAs play regulatory role in cardiovascular disease. MicroRNA-223 (miR-223) was found to be expressed abundantly in myocardium. TNNI3K, a novel cardiac troponin I (cTnI)-interacting and cardiac hypertrophy related kinase, is computationally predicted as a potential target of miR-223. This study was designed to investigate the cellular and molecular effects of miR 223 on cardiomyoctye hypertrophy, focusing on the role of TNNI3K. METHODS: Neonatal rat cardiomyocytes (CMs) were cultured, and CMs hypertrophy was induced by endothelin-1 (ET-1). In vivo cardiac hypertrophy was induced by transverse aorta constriction (TAC) in rats. Expression of miR-223 in CMs and myocardium was detected by real-time PCR (RT-PCR). MiR-223 and TNNI3K were overexpressed in CMs via chemically modifed sense RNA (miR-223 mimic) transfection or recombinant adenovirus infection, respectively. Cell size was measured by surface area calculation using fluorescence microscopy after anti-alpha-actinin staining. Expression of hypertrophy-related genes was detected by RT-PCR. The protein expression of TNNI3K and cTnI was determined by Western blots. Luciferase assay was employed to confirm the direct binding of miR-223 to the 3'UTR of TNNI3K mRNA. Intracellular calcium was measured by sensitive fluorescent indicator (Furo 2). Video-based edge detection system was employed to measure cardiomyocyte contractility. RESULTS: MiR-223 was downregulated in ET-1 induced hypertrophic CMs and in hypertrophic myocardium compared with respective controls. MiR-223 overexpression in CMs alleviated ET-1 induced hypertrophy, evidenced by smaller cell surface area and downregulated ANP, alpha-actinin, Myh6 and Myh7 expression. Luciferase reporter gene assay showed that TNNI3K serves as a direct target gene of miR-223. In miR-223-overexpressed CMs, the protein expression of TNNI3K was significantly downregulated. MiR-223 overexpression also rescued the upregulated TNNI3K expression in hypertrophic CMs. Furthermore, cTnI phosphorylation was downregulated post miR-223 overexpression. Ad.rTNNI3K increased intracellular Ca(2+) concentrations and cell shortening in CMs, while miR-223 overexpression significantly rescued these hypertrophic effects. CONCLUSION: By direct targeting TNNI3K, miR-223 could suppress CMs hypertrophy via downregulating cTnI phosphorylation, reducing intracellular Ca(2+) and contractility of CMs. miR-223 / TNNI3K axis may thus be major players of CMs hypertrophy. PMID- 25792378 TI - Conformational control of the binding of diatomic gases to cytochrome c'. AB - The cytochromes c' (CYTcp) are found in denitrifying, methanotrophic and photosynthetic bacteria. These proteins are able to form stable adducts with CO and NO but not with O2. The binding of NO to CYTcp currently provides the best structural model for the NO activation mechanism of soluble guanylate cyclase. Ligand binding in CYTcps has been shown to be highly dependent on residues in both the proximal and distal heme pockets. Group 1 CYTcps typically have a phenylalanine residue positioned close to the distal face of heme, while for group 2, this residue is typically leucine. We have structurally, spectroscopically and kinetically characterised the CYTcp from Shewanella frigidimarina (SFCP), a protein that has a distal phenylalanine residue and a lysine in the proximal pocket in place of the more common arginine. Each monomer of the SFCP dimer folds as a 4-alpha-helical bundle in a similar manner to CYTcps previously characterised. SFCP exhibits biphasic binding kinetics for both NO and CO as a result of the high level of steric hindrance from the aromatic side chain of residue Phe 16. The binding of distal ligands is thus controlled by the conformation of the phenylalanine ring. Only a proximal 5-coordinate NO adduct, confirmed by structural data, is observed with no detectable hexacoordinate distal NO adduct. PMID- 25792379 TI - Impact of low- and high-molecular-mass components of human serum on NAMI-A binding to transferrin. AB - Imidazolium trans-tetrachloridodimethylsulfoxideimidazolruthenate(III), NAMI-A, a novel antimetastatic ruthenium complex was investigated towards affinity to transferrin (Tf), whether Tf-Ru adducts might be formed after its intravenous injection. Studies were focused on the holotransferrin due to its preferential binding to transferrin receptor. Here, we showed that holotransferrin is able to bind NAMI-A as readily as apotransferrin. The simulation of biological conditions of human serum performed by application of simplified serum models allowed to analyse ruthenium distribution between transferrin and albumin. The presence of physiological concentration of albumin (ca. 18-fold excess over Tf) resulted in a twofold decrease of ruthenium binding to Tf. Interestingly, the introducing of low-molecular-mass components of serum dramatically increased the ruthenation of Tf. Intermolecular competition binding studies between transferrin and albumin showed that both proteins bound similar amount of ruthenium species. Investigation of NAMI-A binding to Tf in human serum showed that this protein was not the major binding partner for Ru complex. However, in spite of many competing proteins still the ruthenation of Tf was observed. The lack of free Ru species (protein unbounded) after incubation with human serum allowed to make an assumption of high affinity of NAMI-A towards serum proteins. PMID- 25792380 TI - Detailed molecular dynamics simulations of human transferrin provide insights into iron release dynamics at serum and endosomal pH. AB - Human serum transferrin (hTf) transports ferric ions in the blood stream and delivers them to cells via receptor-mediated endocytosis. hTf is folded into two homologous lobes; we utilize three of the available crystal structures delineating large conformational changes involved in iron binding/dissociation. We address the problems of whether the release process follows the same trend at serum (~7.4) and endosomal (~5.6) pH, and if there is communication between the lobes. In the absence of the transferrin receptor, we study the dynamics of the full structure as well as the separate lobes in different closed, partially open, and open conformations under neutral and endosomal pH conditions. Results corroborate those experimental observations underscoring the distinguishing effect of pH on the dynamics of hTf. Furthermore, in a total of 2 MUs molecular dynamics simulations, residue fluctuations elucidate the cross talk between the lobes correlated by the peptide linker bridging them at serum pH, while their correlations are lost under endosomal conditions. At serum pH, interplay between relative mobility of the lobes is correlated with iron release rates, rendering the initial conformational change an important contributor to the dynamics under these conditions. Interestingly, C-lobe opening lags behind that of the N-lobe as long as there is at least one iron bound, making the more stable C-lobe an attractive target for recognition by receptors. At endosomal pH, both lobes readily open, making irons available for delivery. PMID- 25792382 TI - Student nurses' motivation to choose gerontological nursing as a career in China: a survey study. AB - BACKGROUND: The world's population is aging, and the need for nurses is increasing. Working with older adults, however, has always been an unpopular career choice among student nurses. It is important to understand student nurses' motivation for choosing gerontological nursing as a career. OBJECTIVES: The purpose of this study was to examine the motivation for choosing gerontological nursing as a career and to identify the associated factors among student nurses. DESIGN: Cross-sectional survey. SETTINGS AND PARTICIPANTS: Participants were last semester student nurses from 7 universities offering nursing undergraduate programs in Shandong, China. Of the 1290 student nurses, 916 completed the survey (a response rate of 71.0%). METHODS: The outcome variable was the motivation to choose gerontological nursing as a career. This was measured using a motivation questionnaire that included expectancy and value subscales. Other instruments included the Chinese version of the Facts on Aging Quiz I, the Geriatrics Attitudes Scale, the Anxiety about Aging Scale, a clinical practice environment questionnaire and a self-administered general information questionnaire. RESULTS: Student nurses' expectancy and value aspects of motivation for choosing gerontological nursing as a career were both at a moderate level; the highest value they held was of personal interest. Clinical practice environment, anxiety about aging and the attitudes about geriatrics were the main factors influencing student nurses' motivation to choose gerontological nursing as a career in China. CONCLUSIONS: It is imperative for nurse educators to improve the gerontological nursing clinical practice environment for student nurses. Moreover, cultivating student nurses' positive attitudes about geriatrics and relieving anxiety about aging could be beneficial. PMID- 25792383 TI - Urinary C-Peptide/Creatinine Ratio Can Distinguish Maturity-Onset Diabetes of the Young from Type 1 Diabetes in Children and Adolescents: A Single-Center Experience. AB - BACKGROUND: The urinary C-peptide/creatinine ratio (UCPCR) and fasting C-peptide level can assess beta-cell function in clinical practice. In the present study, the use of the UCPCR and fasting C-peptide levels was investigated in the differential diagnosis between maturity-onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM). METHODS: Twenty-seven patients with genetically confirmed MODY by next-generation sequence analysis and 42 children with T1DM were included. C-peptide levels were measured after an overnight fast before breakfast, and urine samples were collected 2 h after a standard lunch in the hospital. RESULTS: The UCPCR in the T1DM group was 0.17 +/- 0.5 nmol/mmol, and in the MODY group it was 1.27 +/- 1.03 nmol/mmol (p = 0.001). The receiver operating characteristic (ROC) curves showed excellent discrimination (area under the curve 0.93). A UCPCR >=0.22 nmol/mmol yielded a 96.3% sensitivity and an 85.7% specificity. The fasting C-peptide level in the T1DM group was lower than that in the MODY group (p = 0.001). The fasting C-peptide cutoff determined by ROC curve analysis was 0.62 ng/ml, with a sensitivity of 93% and a specificity of 90% for discriminating between MODY and T1DM. CONCLUSIONS: We showed that the UCPCR and fasting C-peptide levels in children and adolescents can distinguish patients with MODY from patients with T1DM with high specificity and sensitivity. A value of UCPCR >=0.22 nmol/mmol may indicate further genetic testing for MODY. PMID- 25792384 TI - Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells. AB - Toxin-antitoxin (TA) modules contribute to the generation of non-growing cells in response to stress. These modules abound in bacterial pathogens although the bases for this profusion remain largely unknown. Using the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as a model, here we show that a selected group of TA modules impact bacterial fitness inside eukaryotic cells. We characterized in this pathogen twenty-seven TA modules, including type I and type II TA modules encoding antisense RNA and proteinaceous antitoxins, respectively. Proteomic and gene expression analyses revealed that the pathogen produces numerous toxins of TA modules inside eukaryotic cells. Among these, the toxins HokST, LdrAST, and TisBST, encoded by type I TA modules and T4ST and VapC2ST, encoded by type II TA modules, promote bacterial survival inside fibroblasts. In contrast, only VapC2ST shows that positive effect in bacterial fitness when the pathogen infects epithelial cells. These results illustrate how S. Typhimurium uses distinct type I and type II TA modules to regulate its intracellular lifestyle in varied host cell types. This function specialization might explain why the number of TA modules increased in intracellular bacterial pathogens. PMID- 25792385 TI - Curcumin enhances the radiosensitivity of U87 cells by inducing DUSP-2 up regulation. AB - OBJECTIVE: Glioblastoma multiforme (GBM), an aggressive primary brain tumor, is radioresistant and recurs despite aggressive surgery, chemotherapy, and radiotherapy. Curcumin as a potential radiosensitizer has received extensive attention in cancer treatment. To explore an effectiveness of this radiosensitizer for GBM treatment, we evaluated the radiosensitizing effect of curcumin and investigated its potential molecular mechanisms in the human glioma cell line U87. METHODS: The cytotoxic effects of curcumin on U87 cells were evaluated using the Cell Counting Kit-8 assay, and the radiosensitivity of U87 cells treated with curcumin was accessed by colony information assay. The effects of curcumin on cell proliferation and cell cycle regulation were determined using the 5-ethynyl-2-deoxyuridine incorporation assay and flow cytometry, respectively. Western blotting was applied to determine the effects of curcumin on protein expression of dual-specificity phosphatase-2 (DUSP-2), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) as well as phosphorylated ERK and JNK. RESULTS: Curcumin significantly inhibited the proliferation of U87 cells in a dose-and time-dependent manner. Curcumin treatment at the concentrations of 5 uM and 10 M could significantly reduce the clonogenic activity and enhance the radiosensitivity of U87 cells with sensitive enhancement ratios (SERs) of 1.71 and 4.65, respectively. Curcumin resulted in G2/M cell cycle arrest in U87 cells, which were radiosensitive. Pre-treatment of U87-MG cells with 5 uM curcumin enhanced radiation-induced cell proliferation inhibition and apoptosis. Furthermore, we observed that curcumin increased DUSP-2 protein expression and decreased the phosphorylation of ERK and JNK. CONCLUSION: Our results suggest that low-dose curcumin may enhance the radiosensitivity of human glioma U87 cells in vitro by inducing G2/M cell cycle arrest through up regulation of DUSP-2 expression and inhibition of ERK and JNK phosphorylation. PMID- 25792386 TI - Quantitative contrast-enhanced harmonic EUS in differential diagnosis of focal pancreatic masses (with videos). AB - BACKGROUND: The role of EUS with contrast agents can be expanded through the use of time-intensity curve (TIC) analysis and computer-aided interpretation. OBJECTIVE: To validate the use of parameters derived from TIC analysis in an artificial neural network (ANN) classification model designed to diagnose pancreatic carcinoma (PC) and chronic pancreatitis (CP). SETTING: Prospective, multicenter, observational trial-endoscopy units from Romania, Denmark, Germany, and Spain. PATIENTS: A total of 167 consecutive patients with PC or CP. INTERVENTIONS: Contrast-enhanced harmonic EUS (CEH-EUS) and EUS-guided FNA (EUS FNA), TIC analysis, and ANN processing. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, positive and negative predictive values (PPV, NPV) for EUS-FNA, CEH EUS, and the ANN. RESULTS: After excluding all of the recordings that did not meet the technical and procedural criteria, 112 cases of PC and 55 cases of CP were included. EUS-FNA was performed in 129 patients, and the diagnosis was confirmed by surgery (n = 15) or follow-up (n = 23) in the remaining cases. Its sensitivity and specificity were 84.82% and 100%, respectively, whereas the PPV and NPV were 100% and 76.63%, respectively. The sensitivity of real-time quantitative assessment of CEH-EUS was 87.5%, specificity 92.72%, PPV 96.07%, and NPV 78.46%. Peak enhancement, wash-in area under the curve, wash-in rate, and the wash-in perfusion index were significantly different between the groups. No significant differences were found between rise time, mean transit time, and time to peak. For the ANN, sensitivity was 94.64%, specificity 94.44%, PPV 97.24%, and NPV 89.47%. LIMITATIONS: Only PC and CP lesions were included. CONCLUSION: Parameters obtained through TIC analysis can differentiate between PC and CP cases and can be used in an automated computer-aided diagnostic system with good diagnostic results. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01315548.). PMID- 25792388 TI - Structure and properties of composite films formed by cellulose nanocrystals and charged latex nanoparticles. AB - We report the structural and optical properties of composite films formed from mixed suspensions of cellulose nanocrystals (CNCs) and fluorescent latex nanoparticles (NPs). We explored the effect of NP concentration, size, surface charge, glass transition temperature and film processing conditions on film structure and properties. The chiral nematic order, typical of CNC films, was preserved in films with up to 50 wt% of negatively-charged latex NPs. Composite films were characterized by macroscopically close-to-uniform fluorescence, birefringence, and circular dichroism properties. In contrast, addition of positively charged latex NPs led to gelation of CNC-latex suspensions and disruption of the chiral nematic order in the composite films. Large latex NPs disrupted the chiral nematic order to a larger extend than small NPs. Furthermore, the glass transition of latex NPs had a dramatic effect on the structure of CNC-latex films. Latex particles in the rubbery state were easily incorporated in the ordered CNC matrix and improved the structural integrity of its chiral nematic phase. PMID- 25792387 TI - Predicting the likelihood of a persistent bile duct stone in patients with suspected choledocholithiasis: accuracy of existing guidelines and the impact of laboratory trends. AB - BACKGROUND: Existing guidelines aim to stratify the likelihood of choledocholithiasis to guide the use of ERCP versus a lower-risk diagnostic study such as EUS, MRCP, or intraoperative cholangiography. OBJECTIVE: To assess the performance of existing guidelines in predicting choledocholithiasis and to determine whether trends in laboratory parameters improve diagnostic accuracy. DESIGN: Retrospective cohort study. SETTING: Tertiary-care hospital. PATIENTS: Hospitalized patients presenting with suspected choledocholithiasis over a 6-year period. INTERVENTIONS: Assessment of the American Society for Gastrointestinal Endoscopy (ASGE) guidelines, its component variables, and laboratory trends in predicting choledocholithiasis. MAIN OUTCOME MEASUREMENTS: The presence of choledocholithiasis confirmed by EUS, MRCP, or ERCP. RESULTS: A total of 179 (35.9%) of the 498 eligible patients met ASGE high-probability criteria for choledocholithiasis on initial presentation. Of those, 99 patients (56.3%) had a stone/sludge on subsequent confirmatory test. Of patients not meeting high probability criteria on presentation, 111 (34.8%) had a stone/sludge. The overall accuracy of the guidelines in detecting choledocholithiasis was 62.1% (47.4% sensitivity, 73% specificity) based on data available at presentation. The accuracy was unchanged when incorporating the second set of liver chemistries obtained after admission (63.2%), suggesting that laboratory trends do not improve performance. LIMITATIONS: Retrospective study, inconsistent timing of the second set of biochemical markers. CONCLUSION: In our cohort of patients, existing choledocholithiasis guidelines lacked diagnostic accuracy, likely resulting in overuse of ERCP. Incorporation of laboratory trends did not improve performance. Additional research focused on risk stratification is necessary to meet the goal of eliminating unnecessary diagnostic ERCP. PMID- 25792389 TI - Autonomic cardiac nerves: literature review. AB - The aim of this paper was to summarise the knowledge about the autonomic cardiac innervation. It is generally known, that the cardiac nervous system consists of nerve plexoganglionic structures located mostly around the strategic regions of the heart. They consist of two main types of components: parasympathetic neurons, which exert an inhibitory effect, and sympathetic postganglionic nerve fibres, which stimulate the cardiac conduction system, and myocardial cells. However, many authors describe that cardiac ganglia contain various populations of neurons. The largest group are classical cholinergic neurons. The second group of cardiac neurons are cells of dual, cholinergic-adrenergic character. There is also subpopulation of small intensely fluoroscent cells of typically adrenergic phenotype. Moreover, many authors indicated the presence of various neurotransmitters in various combinations. In this way, the neurons in cardiac ganglia are a neurochemical complex beyond the classical vision of parasympathetic ganglia. PMID- 25792390 TI - Anatomy and physiology of directional hearing. AB - The aim of the paper is to present the most important neuroanatomical and neurophysiological studies concerning the phenomenon of sound localisation in space by people. The author analysed the available literature concerning this topic. The article presents different theories explaining the phenomenon of sound localisation, such as interaural differences in time, interaural differences in sound intensity, interaural and monaural differences in phase and the anatomical and physiological basis of these processes. It also describes methods of measurement of disturbances in sound localisation which are used around the world and in Poland, also by the author of this work. The author lists a number of reports on the neurological causes of disturbances in sound localisation, especially the ones connected with vascular damage of the brain. The reports indicate that it is the temporal and parietal lobes that play the role of cortical centres of sound localisation. Also, it should be pointed out that even though having two ears indeed makes it possible for humans to localise sources of sounds, the process itself takes place in the brain. PMID- 25792391 TI - Morphological evaluation of the protective role of dark soy sauce against acrylamide induced neurotoxicity in albino rats. AB - BACKGROUND: Acrylamide (ACR) exposure is associated with neurotoxicity, carcinogenicity, and reproductive toxicity. The use of soy sauce as a condiment is common and it has been found that it possesses high antioxidant activity. The objective of the current study is to evaluate the protective role of dark soy sauce (DSS) against ACR-induced neurotoxicity in rats. MATERIALS AND METHODS: Thirty-five adult male rats were divided into four groups: control, ACR given for 4 weeks, DSS given for 4 weeks before ACR, and DSS given with ACR for 4 weeks. The trigeminal ganglia and cerebellum were dissected and processed for histological staining with haematoxylin and eosin and immunohistochemistry for synaptophysin (SYP) and morphometric analysis. RESULTS: In the trigeminal ganglia, ACR group showed central chromatolysis, degeneration and cell loss. DSS before ACR group had less marked changes in the neuronal architecture, while in ACR with DSS group, better preservation was observed. In the cerebellum, ACR group showed shrunken Purkinje cells and nuclear pyknosis. Spacing and dissociation between Purkinje layer and other layers was seen. DSS before ACR group showed few degenerated Purkinje cells with normal pattern of the other layers of cerebellar cortex. ACR with DSS group showed less disturbed cerebellar layers architecture. Cerebellar SYP immunoexpression and its area per cent were decreased in ACR group compared with the control. It increased in both DSS treated groups, specifically DSS concomitantly given with ACR. CONCLUSIONS: ACR exerted marked cellular degenerative effects and administration of DSS and ACR at the same time had neuroprotective effect. DSS treatment before ACR exposure gave only marginal improvement. PMID- 25792392 TI - The coagulating gland in the male greater cane rat (Thryonomys swinderianus): morphological and immunohistochemical features. AB - This study reveals the structure, ultrastructure and immunoexpression of oestrogen alpha and beta receptors (ERalpha and ERbeta) in the coagulating glands of the greater cane rat. Gland samples from 15 adult male cane rats were processed for histological and ultrastructural studies while immunohistochemistry was also carried out. Coagulating gland in the cane rat is a paired, triangularly shaped, transparent gland weighing about 1 +/- 0.48 g. Histologically, each secretory acinus is composed of folded mucosa surrounded by fibromuscular stroma. The simple columnar epithelium consists of principal cells at different stages of secretion evidenced by their apical blebs of various heights and occasional basal cells. Fine structure of the principal cells revealed the presence of apical blebs that contained secretory granules of varying electron-density, secretory vesicles and vacuoles on both their luminal surfaces and the lumen. While supranuclear cytoplasm contained Golgi apparatus with different cisternal arrangements, the infranuclear part is covered with dilated rough endoplasmic reticulum cisternae. Nuclei, apical bleb and stroma of secretory epithelium all showed positive immunostaining for ERalpha and ERbeta. These findings revealed the prominence of apocrine secretion with no structural evidence of merocrine secretion and the uncommon ERalpha and ERbeta distribution pattern in the coagulating gland of the cane rat. PMID- 25792394 TI - The effect of liquid diet on the parotid gland and the protective role of L carnitine: immunohistochemical and ultrastructural study. AB - BACKGROUND: The moisture content of diet and the dryness of the mouth alter the volume of parotid saliva secreted in rats and it plays an important part in mastication and swallowing. Temporary or permanent liquid diet feeding provides a nutritional regime for patients in certain medical situations. The aim of the present work is to investigate the sequel of liquid diet on parotid gland in rats and the possible protective role of L-carnitine (L-car). MATERIALS AND METHODS: Thirty adult male albino rats were divided into three groups (10 per group) - CONTROL GROUP: rats were fed on regular pellet diet, Liquid diet group and Liquid diet supplemented with L-car group were received liquid diet. The parotid glands were dissected for histological, immunohistochemical and ultrastructural analysis. RESULTS: By light microscope, liquid fed group showed some areas with degenerated irregularly shaped acini and atrophic acini with vacuolated cytoplasm and pyknotic nuclei. Acinar cells of parotid gland group on liquid diet supplemented with L-car, had normally eosinophilic cytoplasm with few vacuoles in their acinar cells. Periodic acid Schiff (PAS) staining, in liquid fed group showed that the serous acini were weakly stained with PAS that was localised in the apical portion of the cells where the secretory granules lie with lack of staining of the vacuoles. However, moderately stained acinar epithelial cell and fewer vacuoles was seen in group given liquid diet supplemented with L-car. Immunohistochemistry of Caspase 3 showed more apoptotic cells with increased area per cent of Caspase 3 immunoexpression, seen in the acini and more in the ductal epithelium in liquid fed group. It was markedly reduced in the acinar cells in group on liquid diet supplemented with L-car. Electron microscopic study revealed in liquid fed group acini with multiple cytoplasmic vacuoles and reduced secretory granules, degenerated swollen mitochondria and dilated cisternae of endoplasmic reticulum. Degenerated condensed nuclear mass or indented nuclear membrane, nuclei with karyorrhexis and chromatin material leaked in the cytoplasm with rupture of the nuclear membranes were also seen. In parotid gland of liquid fed group supplemented with L-car, acinar cells showed normally distributed secretory granules and few cytoplasmic vacuoles. They showed normal appearance of the nuclei and their cytoplasmic organelles. CONCLUSIONS: Liquid diet caused cellular degenerative damages and apoptotic changes in parotid gland and these changes can be prevented by L-car supplementation probably by its antioxidant properties. PMID- 25792395 TI - Characterisation of myocardial bridges in pigs: a comparative anatomical analysis with the human heart. AB - BACKGROUND: Few studies have been conducted in pigs concerning the presence of myocardial bridges (MB) on the coronary arteries and their branches, and some of them have evaluated small samples. The objective of this study was to characterise MB in pigs of commercial breeds. MATERIALS AND METHODS: One hundred and fifty eight hearts of pigs destined to the slaughterhouse with stunning method were studied. The coronary arteries were perfused with polyester resin (palatal 85% and styrene 15%) and then subjected to potassium hydroxide infusion to remove the subepicardial fat. RESULTS: Ninety three MB were found in 67 (42.4%) specimens, 43 (46%) of which were located on branches of the right coronary artery, 38 (41%) on branches of the left coronary artery and 12 (13%) on both vessels. The MB occurred in 26 (38.8%) females and 41 (61.2%) males, but the difference was not statistically significant (p = 0.23). Single MB were most common (70%), followed by the presence of 2 (21%) MB in different vessels. the subsinusal interventricular artery was the vascular structure with the largest number of MB (46.2%), with its middle third being the most compromised segment (79%). The mean length of the MB was 11.23 +/- 5.67 mm and the thickness of the suprapontine myocardium was 1.13 +/- 0.48 mm. CONCLUSIONS: The frequency, localisation, and length of the MB reported in pigs are consistent with the findings of the present study, whereas in humans the MB involve mainly the anterior interventricular artery and are longer. PMID- 25792393 TI - Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation. AB - The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Muller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Muller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings. PMID- 25792397 TI - An anatomic study of the accessory anterolateral talar facet. AB - BACKGROUND: A small accessory facet with articular surface morphology is occasionally seen on the talus, bordering on the lateral end of the sinus tarsi. This facet has been named the accessory anterolateral talar facet. However, few anatomical studies have addressed this facet. Here we present the precise morphology of accessory anterolateral talar facet with emphasis on anatomical correlation between the presence of this facet and the angle of the infero lateral surface of the talus (talar infero-lateral surface - TILS angle). MATERIALS AND METHODS: A total of 22 (11 male, 11 female) adult cadavers with no known pathological conditions in the talocalcaneal joints were examined during educational dissection at Nagoya City University Medical School in 2013. After exclusion of 1 joint due to the poor condition of the talus, 43 talus (22 right, 21 left) were analysed. We judged the presence of the accessory anterolateral talar facet and measured TILS angle. We performed statistical analysis on the point of laterality, gender difference and the difference in the TILS angles in tali with or without the accessory anterolateral talar facets. RESULTS: An accessory anterolateral talar facet was identified in 11 (26%) of the 43 specimens. Of the 21 cadavers with paired talar specimens, 5 displayed the facet bilaterally. CONCLUSIONS: There was no sex difference and no significant laterality, however we found that TILS angle was significantly larger in accessory anterolateral talar facet positive samples than in negative ones. PMID- 25792396 TI - Pancreatic remnant fate. AB - There is eternal discussion on the best surgical method of pancreatoduodenectomy and reconstruction method. Several different methods of pancreatic stump anastomosis exist. The most popular argument taken into account in the discussion is the frequency of early postoperative complications. Relatively fewer papers analyse the late functional outcome of pancreatic surgery and the method of anastomosis employed. Authors presented short series of 12 patients after pancreatic surgery with analysis of pancreatic remnant morphology and function. Pancreatic remnant volume, pancreatic duct distension and stool elastase-1 test were analysed. There was no correlation of pancreatic exo- or endocrine insufficiency with the volume of pancreatic remnant or the kind of surgery or anastomosis performed. PMID- 25792398 TI - Analysis of immunohistochemical expression of proinflammatory cytokines (IL 1alpha, IL-6, and TNF-alpha) in gallbladder mucosa: comparative study in acute and chronic calculous cholecystitis. AB - BACKGROUND: Several studies have shown increased serum levels of proinflammatory cytokines (IL-1alpha, IL-6, and TNF-alpha) in patients with cholelithiasis. The local expression of the proteins involved in pathogenesis of the disease is poorly recognised. MATERIALS AND METHODS: The authors examined immunohistochemically (IHC) the expression status of IL-1alpha, IL-6, and TNF alpha in gallbladder mucosa of the patients with cholelithiasis as related to acute (ACC) and chronic (CCC) types of cholecystitis. Proinflammatory cytokines were quantitatively evaluated in gallbladder mucosa (epithelium and lamina propria) in ACC (n = 16) and CCC (n = 55) groups using modern spatial visualisation technique. RESULTS: Quantitative analysis of IHC signals showed no significant differences in IL-1alpha and IL-6, and immunoexpression in patients with ACC and CCC. A significantly greater IHC expression of TNF-alpha was detected in CCC as compared with ACC group. In either of the patient groups immunoexpression of IL-1alpha and of TNF-alpha was significantly higher than that of IL-6. Immunoexpression of TNF-alpha was significantly higher than that of IL 1alpha only in CCC group. A positive correlation was disclosed between IHC expression of IL-1alpha and body mass index in CCC group. IHC expression of TNF alpha correlated positively with expression of CD68 molecule (histiocytic marker), number of leukocytes in blood and higher grading of gallbladder wall in ACC group. CONCLUSIONS: A more pronounced IHC expression of TNF-alpha and IL 1alpha than IL-6 in both types of cholecystitis may suggest the role of these cytokines in pathogenesis of cholelithiasis. IHC expression of TNF- alpha shows better correlation with clinical/laboratory data in acute cholecystitis, and its quantitative prevalence over the remaining cytokines points to the role of the TNF-alpha in maintenance of inflammation in the course of cholelithiasis. PMID- 25792399 TI - Computed tomography in the evaluation of the anomalous origin of the coronary artery: coexistence with other congenital heart disease in an adult population. AB - BACKGROUND: The aim of the study is to assess the prevalence of anomalous origin of the coronary artery in cardiac computed tomography (CT) and to evaluate its coexistence with other congenital heart disease. MATERIALS AND METHODS: 7,115 patients, who underwent 64-slice or dual source cardiac CT in the years 2005-2011 were screened for the presence of anomalous origin of the coronary artery. RESULTS: Anomalous origin of coronary artery was found in 62 (0.87%) patients (34 males, mean age 57.4 +/- 15.1 years). Anomalous aortic and pulmonary origin of coronary artery concerned 59 (0.83%) and 3 (0.04%) cases, respectively. Concomitant heart defects were observed in 5 (0.07%) patients, all with anomalous aortic origin of coronary artery. Malformations included transposition of great arteries (4 patients) and single ventricle in (1 patient). CONCLUSIONS: The incidence of anomalous origin of a coronary artery in cardiac CT is similar to invasive coronary angiography. In an adult population the vast majority of those anomalies are isolated abnormalities without concomitant other congenital heart defects. PMID- 25792400 TI - Infraorbital groove localisation for the endoscopic decompression of the orbit in Graves' disease. AB - BACKGROUND: The aim of our study was to determine the localisation of the inferior margin of the optic canal in relation to the infraorbital canal/groove complex (IOC/G complex) and zygomaticoorbitale (ZO) as the potential useful landmarks for reducing dangerous complications following surgical and invasive procedures. MATERIALS AND METHODS: Sixty-four orbits of thirty-two human skulls were investigated. The distances between: the inferior margin of the optic canal and the posterior margin of the infraorbital groove measured at its medial border (OC-S); the inferior margin of the optic canal and the posterior margin of the roof of the infraorbital canal (OC-C); the inferior margin of the optic canal and the zygomaticoorbitale (OC-ZO) - were measured. The left/ /right symmetry ratio and the asymmetry index were counted. The symmetry between the contralateral measurements was analysed and statistical analysis was performed. RESULTS: On the right side the mean distance from the inferior margin of the optic canal to: the posterior margin of the infraorbital groove measured at its medial border; to the posterior margin of the roof of the infraorbital canal; and to the zygomaticoorbitale were: 23.41 +/- 3.10 mm; 34.44 +/- 5.30 mm; and 47.53 +/- 4.13 mm, respectively. On the left side the mean distance from the inferior margin of the optic canal to: the posterior margin of the infraorbital groove measured at its medial border; to the posterior margin of the roof of the infraorbital canal; to the zygomaticoorbitale were 23.69 +/- 2.80 mm; 36.75 +/- 5.10 mm; 46.84 +/- 3.24 mm, respectively. CONCLUSIONS: The presented measurements may be particularly helpful for endoscopic decompression in patients with the thyroid ophthalmopathy to avoid the complications. PMID- 25792401 TI - Endplate calcification and cervical intervertebral disc degeneration: the role of endplate marrow contact channel occlusion. AB - BACKGROUND: The aim of this study was to determine the fundamental relationships between cervical intervertebral disc (IVD) degeneration, endplate calcification, and the patency of endplate marrow contact channels (MCC). MATERIALS AND METHODS: Sixty cervical IVDs were excised from 30 human cadavers. After sectioning the specimens underwent micro computed tomography (microCT) - from all images the number, calibre, diameter and distribution of endplate openings were measured using ImageJ. Next, the specimens were scored for macroscopic degeneration (Thompson's classification), and subsequently underwent histological analysis for both IVD and endplate degeneration (Boos's classification) and calcification. RESULTS: The study group comprised 30 female and 30 male IVDs (mean age +/- SD: 51.4 +/- 19.5). Specimen's age, macroscopic and microscopic degeneration correlated negatively with the number of MCCs (r = -0.33-(-0.95); p < 0.0001), apart from the MCCs > 300 MUm in diameter (r = 0.66-0.79; p < 0.0001). The negative relationship was strongest for the MCCs 10-50 MUm in diameter. CONCLUSIONS: There is a strong negative correlation between the number of endplate MCCs, and both macroscopic and microscopic cervical IVD and endplate degeneration. This could further support the thesis that endplate calcification, through the occlusion of MCCs, leads to a fall in nutrient transport to the IVD, and subsequently causes its degeneration. PMID- 25792402 TI - Anatomical variations of the coeliac trunk in the homogeneous Polish population. AB - BACKGROUND: The abdominal vessels show a number of abnormalities and pathologies knowledge of which is important during open as well as laparoscopic surgeries. One of the most common vessels which pattern has many variations is the coeliac trunk. The present study was undertaken on homogeneous population to assess morphology of the coeliac trunk and to evaluate the possible variability of its branches. MATERIALS AND METHODS: Standard abdominal multidetector computed tomography examinations were performed on a total of 1569 patients diagnosed by 2 radiologists independently; in case of doubts common assessment was performed. RESULTS: The coeliac trunk followed the classic pattern in 92.7% of the cases (1455/1569 of patients). The gastrosplenic trunk was detected in 4.1% of cases (64/1569); the hepatosplenic trunk in 2.2% of cases (34/1569); the coeliac mesenteric trunk was observed in 0.5% of cases (8/1569); the hepatogastric trunk in 0.2% of cases (4/1569); the splenomesenteric trunk was detected in 0.1% of cases (2/1569). In the next 0.1% the coeliac trunk was absent. The hepatosplenomesenteric and the coeliac-colic trunk were not observed in the study population. CONCLUSIONS: Vascular anatomical abnormality is usually asymptomatic hovewer, its preoperative knowledge is helpful to reduce complications like vascular bleeding when dissecting the hapato-pancreatic region. The coeliac trunk and its branches can be fast and easy evaluated in computed tomography exams performed due to various symptoms from abdominal cavity. PMID- 25792403 TI - Quantification of the distal radial artery for improved vascular access. AB - BACKGROUND: There is no consensus in the literature as to which point of the radial artery (RA) is the safest to attempt vascular access. The purpose of this study was to measure the diameter, tortuosity and branching patterns of the distal RA. MATERIALS AND METHODS: 140 cadaveric RAs (66 male, 74 female) were dissected and measured. The external diameter of the RA was measured at 2 cm increments starting at the radial styloid process (SP), moving proximally. The location and degree of 2-dimensional arterial tortuosity were recorded if > 35 degrees. Branches of the RA were recorded with respect to their distance from the SP. RESULTS: We observed that the right RA significantly increased in diameter at distances beyond 4 cm proximal from the radial SP, regardless of the sex of the individual. This increase in size was not noted on the left RA's. Muscular artery branches of the distal RA were noted on average 1.82 cm proximal from the SP. Clinically significant tortuosity was present on average 3.47 cm proximal from the radial SP. The left RA did not significantly change in size along its course, but its statistically similar diameter when compared to the right RA allows us to make a recommendation this is applicable bilaterally. CONCLUSIONS: Our data suggests that regardless of gender, vascular access of the RA could be safely performed at distances greater than 4 cm from the SP to yield a vessel with a larger diameter, less tortuosity, and fewer branches. PMID- 25792404 TI - Can raisins ameliorate the hypercholesterolaemia-induced cardiac affection? AB - Raisins were investigated for their protective role on cardiac muscle both biochemically and histopathologically in high cholesterol diet (HCD)-fed rats. Wister male rats were randomly divided into four groups (n = 10): control, raisin fed, HCD-fed and HCD-raisin fed group. Animals were anaesthetized after 13 weeks. Hearts were dissected and processed for histopathological examination. Raisins administration with HCD significantly decreased the animals' blood glucose, insulin, cholesterol, triglycerides, and low density lipoprotein levels; while increased their high density lipoprotein levels compared with rats fed HCD alone. They also decreased cardiomyocytes' degeneration, cellular infiltration, haemorrhages and blood vessels affection. Raisins reduced fibrosis by decreasing the immuno-expression of alpha smooth muscle actin marker, whereas they significantly increased the immuno-expression of endothelial nitric oxide synthase. Raisins showed a cardioprotective effect and were able to alleviate the biochemical and the histopathological changes induced by the HCD. Consumption of raisins or their pharmaceutical product should be recommended specially for those eating a high-fat diet. PMID- 25792405 TI - Complex anatomic variation in the brachial region. AB - Authors describe a case of a complex anatomic variation discovered during dissection of the humeral region. On the right side, brachial artery followed a superficial course. Musculocutaneous nerve did not pierce coracobrachialis muscle but instead passed below the muscle before continuing in the forearm. On the left side, a communication between musculocutaneous and median nerve was dissected. Those variations are analytically presented with a brief review on their anatomic and clinical implications. Considerations on their embryological origin are attempted. PMID- 25792406 TI - Absence of the suprarenal segment of the inferior vena cava with a coexisting absence of the right brachiocephalic vein in a 22-year-old Caucasian male with arterial hypertension. AB - Congenital anomalies of the inferior vena cava (IVC) are rarely observed malformations of the venous system, occurring in 0.3% of otherwise healthy individuals, and in 0.6% to 2% of patients with coexisting cardiovascular defects. They are usually asymptomatic and recognised incidentally during imaging, operations or dissection studies. In this paper we report an extremely rare case of a 22-year-old Caucasian male, admitted for the purpose of excluding secondary causes of hypertension. During imaging of the abdomen and the thorax we found a complete lack of the suprarenal segment of the IVC, with a coexisting absence of the right brachiocephalic vein. We discuss the problem of congenital defects of the IVC and we review the relevant literature. PMID- 25792407 TI - Clinical, imaging and genetic analysis of double bilateral radix entomolaris. AB - BACKGROUND: Anatomy describes that first mandibular molars have two roots: 1 mesial, with 2 root canals, and 1 distal, with 1 root canal. The presence of three roots in these teeth is uncommon. Root anatomical variations have an impact, especially in endodontic, where the highest rates of nonsurgical treatment failures are due to the inability to identify and access roots and/or accessory canals. The aim of this research is to report a case of double three rooted mandibular first molar through clinical, imaging and genetic analysis. MATERIALS AND METHODS: Using a panoramic radiography, the presence of three roots in teeth 36 and 46 was diagnosed in a female patient. Additionally, it was indicated a cone beam computed tomography. Moreover, leukocyte genomic DNA was obtained from a blood sample of the patient to determine her ethnicity through analysis of mitochondrial DNA haplogroups using polymerase chain reaction-length restriction fragment polymorphism (PCR-RFLP). RESULTS: Both molars had three roots, 1 mesial (M), 1 distolingual (DL), also known as radix entomolaris (RE), and a distovestibular (DV). For both teeth, M root had 2 canals, and DV and DL roots presented just 1 canal. Mitochondrial DNA analysis determined presence of haplogroup C, corresponding to Amerindian ethnicity. CONCLUSIONS: The presence of RE is uncommon. This case report contributes to describe this rare anatomical variation. To our knowledge, this is the first molecular-genetic study applied to dental anatomy and gives basis to develop future research in the area. PMID- 25792408 TI - Persistent trigeminal artery as a rare cause of ischaemic lesion and migraine like headache. AB - The persistent trigeminal artery (PTA) is a rare remnant of the embryonic intracranial circulatory system that forms a carotid-vertebrobasilar anastomosis. In most cases PTA does not have clear clinical implications. However, some authors report the association of PTA occurrence with vertigo, dizziness and nerve palsy, resulting in diplopia, strabismus or trigeminal neuralgia in patients. In rare cases it may also be related to posterior cerebral circulation strokes. This work reports the case of a female patient who presented with migraine-like headache and an ischaemic lesion in the left temporal lobe in association with PTA. PMID- 25792409 TI - Properties of WZ21 (%wt) alloy processed by a powder metallurgy route. AB - Microstructure, mechanical properties and corrosion behaviour of WZ21 (%wt) alloy prepared by a powder metallurgy route from rapidly solidified powders have been studied. Results were compared to those of the same alloy prepared through a conventional route of casting and extrusion. The microstructure of the extruded ingot consisted of alpha-Mg grains and Mg3Zn3Y2 (W-phase) and LPSO-phase particles located at grain boundaries. Moreover, stacking faults were also observed within alpha-Mg grains. The alloy processed by the powder metallurgy route exhibited a more homogeneous and finer microstructure, with a grain size of 2 MUm. In this case W-phase and Mg24Y5 phase were identified, but not the LPSO phase. The microstructural refinement induced by the use of rapidly solidified powders strengthened the alloy at room temperature and promoted superplasticity at higher strain rates. Corrosion behaviour in PBS medium evidenced certain physical barrier effect of the almost continuous arrangements of second phases aligned along the extrusion direction in conventionally processed WZ21 alloy, with a stable tendency around 7 mm/year. On the other hand, powder metallurgy processing promoted significant pitting corrosion, inducing accelerated corrosion rate during prolonged immersion times. PMID- 25792410 TI - Enhancement of the mechanical properties of AZ31 magnesium alloy via nanostructured hydroxyapatite thin films fabricated via radio-frequency magnetron sputtering. AB - The structure, composition and morphology of a radio-frequency (RF) magnetron sputter-deposited dense nano-hydroxyapatite (HA) coating that was deposited on the surface of an AZ31 magnesium alloy were characterized using AFM, SEM, EDX and XRD. The results obtained from SEM and XRD experiments revealed that the bias applied during the deposition of the HA coating resulted in a decrease in the grain and crystallite size of the film having a crucial role in enhancing the mechanical properties of the fabricated biocomposites. A maximum hardness of 9.04 GPa was found for the HA coating, which was prepared using a bias of -50 V. The hardness of the HA film deposited on the grounded substrate (GS) was found to be 4.9 GPa. The elastic strain to failure (H/E) and the plastic deformation resistance (H(3)/E(2)) for an indentation depth of 50 nm for the HA coating fabricated at a bias of -50 V was found to increase by ~30% and ~74%, respectively, compared with the coating deposited at the GS holder. The nanoindentation tests demonstrated that all of the HA coatings increased the surface hardness on both the microscale and the nanoscale. Therefore, the results revealed that the films deposited on the surface of the AZ31 magnesium alloy at a negative substrate bias can significantly enhance the wear resistance of this resorbable alloy. PMID- 25792411 TI - Evaluation of damage progression and mechanical behavior under compression of bone cements containing core-shell nanoparticles by using acoustic emission technique. AB - In this work, the effect of the incorporation of core-shell particles on the fracture mechanisms of the acrylic bone cements by using acoustic emission (AE) technique during the quasi-static compression mechanical test was investigated. Core-shell particles were composed of a poly(butyl acrylate) (PBA) rubbery core and a methyl methacrylate/styrene copolymer (P(MMA-co-St)) outer glassy shell. Nanoparticles were prepared with different core-shell ratio (20/80, 30/70, 40/60 and 50/50) and were incorporated into the solid phase of bone cement at several percentages (5, 10 and 15 wt%). It was observed that the particles exhibited a spherical morphology averaging ca. 125 nm in diameter, and the dynamic mechanical analysis (DMA) thermograms revealed the desired structuring pattern of phases associated with core-shell structures. A fracture mechanism was proposed taking into account the detected AE signals and the scanning electron microscopy (SEM) micrographs. In this regard, core-shell nanoparticles can act as both additional nucleation sites for microcracks (and crazes) and to hinder the microcrack propagation acting as a barrier to its growth; this behavior was presented by all formulations. Cement samples containing 15 wt% of core-shell nanoparticles, either 40/60 or 50/50, were fractured at 40% deformation. This fact seems related to the coalescence of microcracks after they surround the agglomerates of core shell nanoparticles to continue growing up. This work also demonstrated the potential of the AE technique to be used as an accurate and reliable detection tool for quasi-static compression test in acrylic bone cements. PMID- 25792412 TI - An experimental and computational study of the hydrodynamics of high-velocity water microdrops for interproximal tooth cleaning. AB - The flow field and local hydrodynamics of high-velocity water microdrops impacting the interproximal (IP) space of typodont teeth were studied experimentally and computationally. Fourteen-day old Streptococcus mutans biofilms in the IP space were treated by a prototype AirFloss delivering 115 uL of water at a maximum exit-velocity of 60 ms(-1) in a 33-ms burst. Using high speed imaging, footage was generated showing the details of the burst, and demonstrating the removal mechanism of the biofilms. Footage was also generated to characterize the viscoelastic behavior of the biofilms when impacted by an air only burst, which was compared to the water burst. Image analysis demonstrated the importance of fluid forces on the removal pattern of interdental biofilms. X ray micro-Computed Tomography (u-CT) was used to obtain 3D images of the typodont and the IP spaces. Computational Fluid Dynamics (CFD) simulations were performed to study the effect of changing the nozzle position and design on the hydrodynamics within the IP space. Results confirmed our previous data regarding the wall shear stress generated by high-velocity water drops which dictated the efficacy of biofilm detachment. Finally, we showed how CFD models could be used to optimize water drop or burst design towards a more effective biofilm removal performance. PMID- 25792413 TI - Novel methodology for assessing biomaterial-biofluid interaction in cancellous bone. AB - Understanding the cement flow behaviour and accurately predicting the cement placement within the vertebral body is extremely challenging. Vertebral cancellous bone displays highly complex geometrical structures and architectural inhomogeneities over a range of length scales, thus making the scientific understanding of the cement injection behaviour difficult in clinical or cadaveric studies. Previous experimental studies on cement flow have used open porous aluminum foam to represent osteoporotic bone. Although the porosity was well controlled, the geometrical structure of each of the foams was inherently unique. This paper presents novel methodology using customized, reproducible and pathologically representative three-dimensional bone surrogates to help study biomaterial--biofluid interaction. The aim was to provide a robust tool for comprehensive assessment of biomaterial injection behaviour through controlling the bone surrogate morphology and the injection parameters (i.e. needle gauge, needle placement, flow rate and injected volume), measuring the injection pressure, and allowing the visualization and quantitative analysis of the spreading distribution. This methodology provides a clinically relevant representation of cement flow patterns and a tool for validating computational simulations. PMID- 25792414 TI - Influence of initial flaws on the mechanical properties of nacre. AB - Nacre is a bio-composite made up of hard mineral and soft protein, and has excellent mechanical properties. This paper examines the effect of naturally occurring defects (initial flaws) in nacre on its mechanical properties such as toughness and strength. A random fuse model is developed incorporating initial flaws. Numerical simulations show that initial flaws affect different mechanical properties at different rates. The variation in the experimentally obtained mechanical properties of nacre reported in the literature is shown to be due to initial flaws. The stress in the mineral and protein increases due to initial flaws, but by different amounts. The results obtained in this study are useful for gaining insight into the failure of nacre and development of nacre-inspired composites. PMID- 25792415 TI - Effect of water desorption on the rheology and dynamic response of human hair to a non-contact impact. AB - Human hair is a non-homogeneous complex material made of keratin fibers oriented along the longitudinal axis which offer anisotropic mechanical properties. Nowadays, it is possible to measure the mechanical properties of hairs with the classical tests, but most often, these tests are destructive and make hard to measure the influence of some external factors or treatments on the behavior of a same hair fiber. In the current paper, vibrations induced by a non-contact impact have been utilized as a representative response of the mechanical behavior of hair. The characteristics of the vibratory response allow measuring the variation in the mechanical properties and the instantaneous effect of an external factor on the properties of a same sample. First, load relaxation tests have been performed on hair samples after moisturization and for different times of an air drying process in order to characterize the change in the visco-elastic behavior of hair during the water desorption. Other hair samples have been tested with our non-contact impact and vibration technique in order to observe the change in the vibratory response during the water desorption. The vibratory response has then been correlated to the mechanical properties of the hair fiber. PMID- 25792416 TI - Ecology of sand flies in a low-density residential rural area, with mixed forest/agricultural exploitation, in north-eastern Brazil. AB - Cutaneous leishmaniasis caused by Leishmania braziliensis is endemic in Brazil, where Lutzomyia whitmani is the most important vector involved in the transmission to humans, particularly in the peridomestic environment. Herein, we assessed the ecology of sand flies, including Lu. whitmani, in a low-density residential rural area with mixed forest/agricultural exploitation in north eastern Brazil, where cutaneous leishmaniasis is endemic. Particularly, we hypothesized that sand fly abundance was correlated with climatic variables. Sand fly collections were carried out monthly from August 2013 to August 2014, using seven CDC light traps, for three consecutive nights, in three kinds of environments: indoor, peridomicile and forest. Collected sand flies were identified based on morphology and females of Lu. whitmani (n=169), Lu. amazonensis (n=134) and Lu. complexa (n=21) were selected and tested by PCR for Leishmania (Viannia) spp. In total, 5167 sand flies belonging to 19 species were identified, being that Lu. choti (43.2%) was the most frequent species, followed by Lu. amazonensis (16.6%), Lu. whitmani (15.8%), Lu. sordellii (10.7%) and Lu. quinquefer (5.8%), which together represented over 90% of the collected sand flies. All females tested by PCR were negative. The number of sand flies collected daily was positively correlated with temperature and negatively correlated with rainfall and relative humidity. Furthermore, there was a positive correlation between daily number of sand flies and daily average saturation deficit. This study points out that the number of sand flies captured daily is correlated to climatic variables, including saturation deficit, which may represent a useful parameter for monitoring sand fly populations in leishmaniasis endemic areas. PMID- 25792417 TI - Epitope analysis, expression and protection of SAG5A vaccine against Toxoplasma gondii. AB - Bioinformatics approaches were used to identify B-cell epitopes and T-cell epitopes on SAG5A protein. Compared to SAG1, SAG5A with good B-cell epitopes and T-cell epitopes had a potentiality to become a more successful vaccine against Toxoplasma gondii. Thereafter, SAG5A DNA vaccine was constructed successfully and was injected into mice with peptide to evaluate the immunoprotection. Compared to the control groups, the vaccine (DNA/peptide) could induce more effective cellular and humoral immune responses in immunized mice. Furthermore, a significant reduction of brain cyst was detected in the mice vaccinated with peptide (732+/-160), pSAG5A (815+/-197), or pSAG5A/peptide (436+/-174) compared by the mice injected by PBS (1260+/-241) or pEGFP-C1 (1350+/-268). The number of cysts in brains was 35% reduced in the mice immunized with DNA/peptide than in the control mice treated by PBS. The results indicated that the DNA vaccine encoding SAG5A significantly induced immune responses and enhanced protection against cysts of PRU strain, especially with the help of peptide. PMID- 25792418 TI - In vivo experimental drug resistance study in Trypanosoma vivax isolates from tsetse infested and non-tsetse infested areas of Northwest Ethiopia. AB - Ethiopia, particularly in the Northwest region, is affected by both tsetse fly and non-tsetse fly transmitted trypanosomosis with a significant impact on livestock productivity. The control of trypanosomosis in Ethiopia relies on either curative or prophylactic treatment of animals with diminazene aceturate (DA) or isometamidium chloride (ISM), respectively. However, since these two trypanocides have been on the market for more than 40 years, this may have resulted in drug-resistance. Therefore, in vivo drug resistance tests on two Ethiopian isolates of Trypanosoma vivax were completed, one from an area where tsetse flies are present and one from an area where tsetse flies are not present. Twenty four cattle (Bos indicus) aged between 6 and 12 months, purchased from a trypanosome-free area (Debre Brehan: Northcentral Ethiopia) and confirmed to be trypanosome-negative, were randomly assigned into four groups of six animals, which were infected with T. vivax isolated from a tsetse-infested or non-tsetse infested area, and in each case treated with curative doses of DA or ISM. Each animal were inoculated intravenously 3*10(6) trypanosomes from donor animals. Parasitaemia became patent earlier in infections with non-tsetse T. vivax (~7 days post-infection) than tsetse (~14 days post-infection). Both groups were treated at the highest peak parasitaemia with DA or ISM and nine cattle, four with non-tsetse T. vivax (two ISM- and two DA-treated) and five with tsetse T. vivax (three ISM- and two DA-treated) showed relapses of parasitaemia. Moreover, treatment did not improve diagnostic host markers of trypanosome infections in these animals. In conclusion, in vivo drug tests indicated the presence of resistant parasites (>20% of treated animals in each group relapsed) against recommended doses of both available trypanocidal drugs. PMID- 25792419 TI - St. Louis Encephalitis virus mosquito vectors dynamics in three different environments in relation to remotely sensed environmental conditions. AB - In Argentina the St. Louis Encephalitis virus (SLEV) is an endemic and widely distributed pathogen transmitted by the cosmopolitan mosquito Culex quinquefasciatus. During two outbreaks in Cordoba city, in 2005 and 2010, Culex interfor was also found infected, but its role as vector of SLEV is poorly known. This mosquito species is distributed from central Argentina to southern Brazil. The primary aim of this study was to analyze the population dynamic of Cx. interfor and Cx. quinquefasciatus in three different environments (urban, suburban and non-urban) in relation to remotely sensed environmental data for vegetation (NDVI and NDWI) and temperature (brightness temperature). Cx. quinquefasciatus and Cx. interfor were found at the three sampled sites, being both the most abundant Culex species, with peaks in early and midsummer. Temporal distribution patterns of both mosquito species were highly correlated in a non urban area of high SLEV risk transmission. Cx. quinquefasciatus and Cx. interfor were associated with the most urbanized site and the non-urban environment, respectively; high significant correlations were detected between vegetation indices and abundance of both mosquito species confirming these associations. These data provide a foundation for building density maps of these two SLEV mosquito vectors using remotely sensed data to help inform vector control programs. PMID- 25792420 TI - Nectar protein content and attractiveness to Aedes aegypti and Culex pipiens in plants with nectar/insect associations. AB - We chose five easily propagated garden plants previously shown to be attractive to mosquitoes, ants or other insects and tested them for attractiveness to Culex pipiens and Aedes aegypti. Long term imbibition was tested by survival on each plant species. Both mosquito species survived best on Impatiens walleriana, the common garden impatiens, followed by Asclepias curassavica, Campsis radicans and Passiflora edulis, which sponsored survival as well as the 10% sucrose control. Immediate preference for imbibition was tested with nectar dyed in situ on each plant. In addition, competition studies were performed with one dyed plant species in the presence of five undyed plant species to simulate a garden setting. In both preference studies I. walleriana proved superior. Nectar from all plants was then screened for nectar protein content by SDS-PAGE, with great variability being found between species, but with I. walleriana producing the highest levels. The data suggest that I. walleriana may have value as a model plant for subsequent studies exploring nectar delivery of transgenic mosquitocidal proteins. PMID- 25792421 TI - Multiple ways to regulate translation initiation in bacteria: Mechanisms, regulatory circuits, dynamics. AB - To adapt their metabolism rapidly and constantly in response to environmental variations, bacteria often target the translation initiation process, during which the ribosome assembles on the mRNA. Here, we review different mechanisms of regulation mediated by cis-acting elements, sRNAs and proteins, showing, when possible, their intimate connection with the translational apparatus. Indeed the ribosome itself could play a direct role in several regulatory mechanisms. Different features of the regulatory signals (sequences, structures and their positions on the mRNA) are contributing to the large variety of regulatory mechanisms. Ribosome heterogeneity, variation of individual cells responses and the spatial and temporal organization of the translation process add more layers of complexity. This hampers to define manageable set of rules for bacterial translation initiation control. PMID- 25792422 TI - Prolonged glutamate excitotoxicity increases GluR1 immunoreactivity but decreases mRNA of GluR1 and associated regulatory proteins in dissociated rat retinae in vitro. AB - Glutamate excitotoxicity contributes to damage following injury to the central nervous system via mechanisms including changes in the expression of receptors, calcium overload, oxidative stress and cell death. Excitotoxicity is triggered by glutamate binding to receptors, including calcium permeable AMPA receptors, which can be upregulated under injury conditions. However, the transcriptional response of AMPA receptor regulatory proteins to excitotoxic conditions is unknown. Here, we use real-time quantitative PCR (RT-qPCR), to determine the effect of prolonged glutamate excitotoxicity on the expression of mRNA encoding for GluR1 and AMPA receptor regulatory proteins in dissociated rat retinal cultures that include neuronal (retinal ganglion cell (RGCs)) and glial (Muller) cell populations. mRNA levels of GluR1 and regulators of the GluR1 subunit of AMPA receptors, including Sap97, Cnih2 and Cnih3, decreased following 6, 24 and 48 h incubation with 5 mM glutamate: related regulators not associated with GluR1 were unaffected. In contrast, GluR1 protein, assessed immunohistochemically, was increased in both RGCs and Muller cells after 24 h glutamate exposure: western blotting analysis was inconclusive. Reductions in mRNA of GluR1 and associated regulators occurred prior to cell death, which was first detected at 24 h, and substantial by 48 h. Exposure to glutamate acutely increased the intracellular calcium concentration in the cultures and by 24 h, reactive oxygen species were increased. Our data suggest a negative feedback mechanism in retinal cells, that down-regulates transcription of genes encoding GluR1 regulatory proteins in response to glutamate exposure. Despite this mechanism, GluR1 protein levels remain increased, and are associated with increased reactive species and cell death. Therapeutic strategies targeting calcium permeable AMPA receptors should take into account that increases in GluR1 protein are not necessarily associated with increases in associated mRNA levels over time. PMID- 25792424 TI - Remission of advanced EGFR-positive lung adenocarcinoma after short and intermittent erlotinib therapy. PMID- 25792425 TI - Privatisation of cancer and end of life care services in Staffordshire could threaten NHS providers, warn critics. PMID- 25792423 TI - Effects of demographic factors on survival time after a diagnosis of amyotrophic lateral sclerosis. AB - BACKGROUND: The Agency for Toxic Substances and Disease Registry established surveillance projects to determine the incidence, prevalence, and demographic characteristics of persons with Amyotrophic Lateral Sclerosis (ALS) in defined geographic areas. There is a need to characterize and account for the survival and prognostic factors among a population-based cohort of ALS cases in the United States. METHODS: A cohort of incident cases diagnosed from 2009-2011 in New Jersey was followed until death or December 31, 2013, whichever happened first. Survival was assessed using Kaplan-Meier curves and Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Sixty-four percent of incident cases died between 2009 and 2013, 93.7% specifically from ALS. Among the 456 cases studied in the survival analysis, the median survival from diagnosis was 21 months; 46% of cases survived longer than two years from diagnosis. Older age predicted shorter survival. While there is some indication of differences because of sex, race, and ethnicity, these differences were not statistically significant when accounting for age. CONCLUSIONS: New Jersey mortality data were queried to determine the vital status of a cohort of incident ALS cases and used to investigate relationships between demographic factors and survival. Results are consistent with other population-based studies. Older age was a strong predictor of shorter survival time. Additional follow-up time is needed to characterize longer-term survival. PMID- 25792426 TI - Non-tumor-Associated Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis in Chinese Girls With Positive Anti-thyroid Antibodies. AB - Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a new category of autoimmune encephalitis associated with anti-NMDA receptor antibodies. The disease was first described in 2007, and it predominantly affects young women with or without ovarian teratomas. Most patients typically present with seizures, a decreased consciousness level, dyskinesia, autonomic dysfunction, and psychiatric symptoms. The presence of anti-thyroid antibodies in non-tumor associated anti-NMDA receptor encephalitis was first described in 2010. Additionally, anti-thyroid antibodies were found in teratoma-associated anti-NMDA receptor encephalitis. We report the cases of 3 Chinese girls with non-tumor associated anti-NMDA receptor encephalitis with positive anti-thyroid antibodies. We followed up the details of their titers and suggest that anti-thyroid antibodies were an indicator of autoimmune predisposition in the development of non-tumor-associated anti-NMDA receptor encephalitis. PMID- 25792427 TI - Clinical and Electroencephalographic (EEG) Features Associated With Refractoriness in Benign Childhood Epilepsy With Centrotemporal Spikes. AB - The aim of this study is to identify clinical or electroencephalographic (EEG) features associated with refractoriness to the initial antiepileptic drug in typical benign childhood epilepsy with centrotemporal spikes. A total of 87 children with typical benign childhood epilepsy with centrotemporal spikes were retrospectively reviewed in the analyses. The patients were subdivided into 2 groups: patients whose seizures were controlled with monotherapy and patients requiring 2 medications. Sixty-three children achieved seizure freedom with monotherapy, whereas 24 received 2 medications for seizure control. Diffusing foci at the follow-up EEG and delayed treatment (duration >1 year) are 2 main risk factors associated with more refractory cases (P < .001). Delayed diagnosis (37.1%) and nonadherence to treatment (57.2%) contributed to delayed treatment. Our findings suggested that diffusing foci on EEG and delayed treatment are associated with more frequent seizures and refractoriness in benign childhood epilepsy with centrotemporal spikes. Diagnostic delays and nonadherence hindered timely care, which may represent opportunities for improved intervention. PMID- 25792429 TI - Predictors of Abnormal Neuroimaging of the Brain in Children With Epilepsy Aged 1 Month to 2 Years: Useful Clues in a Resource-Limited Setting. AB - Neuroimaging should be performed on infants with seizure. However, there are economic limitations in performing neuroimaging in a resource-limited setting. The younger the age, the higher the risk of having abnormal neuroimaging. The aim was to determine frequency and predictors of abnormal neuroimaging in children with epilepsy aged 1 month to 2 years. History, physical examination, electroencephalogram (EEG), and neuroimaging were reviewed. Thirty-seven of 49 (76%) had neuroimaging studies; 19 computed tomography (CT), 14 magnetic resonance imaging (MRI), and 4 had both. Abnormal neuroimaging was found in 19 (51%). Predictors of abnormal neuroimages are developmental delay, abnormal head circumference, and abnormal neurologic examination. Eight children (21%) had lesions on neuroimaging studies that altered or influenced management. Of 8 patients with normal examination and EEG, 1 had a brain tumor and another had arteriovenous malformation. Neuroimaging should be considered as an essential aid in the evaluation of infants with epilepsy, even in a resource-limited setting. PMID- 25792428 TI - Multiday Transcranial Direct Current Stimulation Causes Clinically Insignificant Changes in Childhood Dystonia: A Pilot Study. AB - Abnormal motor cortex activity is common in dystonia. Cathodal transcranial direct current stimulation may alter cortical activity by decreasing excitability while anodal stimulation may increase motor learning. Previous results showed that a single session of cathodal transcranial direct current stimulation can improve symptoms in childhood dystonia. Here we performed a 5-day, sham controlled, double-blind, crossover study, where we measured tracking and muscle overflow in a myocontrol-based task. We applied cathodal and anodal transcranial direct current stimulation (2 mA, 9 minutes per day). For cathodal transcranial direct current stimulation (7 participants), 3 subjects showed improvements whereas 2 showed worsening in overflow or tracking error. The effect size was small (about 1% of maximum voluntary contraction) and not clinically meaningful. For anodal transcranial direct current stimulation (6 participants), none showed improvement, whereas 5 showed worsening. Thus, multiday cathodal transcranial direct current stimulation reduced symptoms in some children but not to a clinically meaningful extent, whereas anodal transcranial direct current stimulation worsened symptoms. Our results do not support transcranial direct current stimulation as clinically viable for treating childhood dystonia. PMID- 25792430 TI - Goniometer Measurements of Oral Labial Angle and Evaluation of Oral Motor Reflexes in Preterm Infants: Comparison to Findings in Term Infants. AB - To date, no study has evaluated changes in oral labial angle as preterm infants mature. The main purpose of this study was to document goniometer measurements of the labial angle of the mouth in preterm infants, to assess changes with development, to compare to findings in healthy term infants, and also evaluate oral motor reflexes in these groups. Seventy-eight preterm infants and 45 healthy term infants were recruited for the prospective study. Labial angle was assessed via goniometer, and oral motor reflexes and the volume of milk ingested were evaluated. There was significant difference between term and preterm infants' labial angles (P < .01). The distribution of preterm infants' angles were similar to term infants' by 36 to 40 weeks' postmenstrual age. Goniometer measurements of the oral labial angle may reveal oral motor performance in preterm infants and may be relevant for feeding skills assessment in this group of infants. PMID- 25792431 TI - Fighting Against Disuse of the Masticatory System in Duchenne Muscular Dystrophy: A Pilot Study Using Chewing Gum. AB - Duchenne muscular dystrophy patients report masticatory problems. The aim was to determine the efficacy of mastication training in Duchenne muscular dystrophy using chewing gum for 4 weeks. In all, 17 patients and 17 healthy age-matched males participated. The masticatory performance was assessed using a mixing ability test and measuring anterior bite force before, shortly after and 1 month after the training. In the patient group the masticatory performance improved and remained after 1-month follow-up, no significant changes in anterior maximum bite force was observed after mastication training. In the healthy subject the bite force increased and remained at the 1-month follow-up; no significant differences in masticatory performance were observed. Mastication training by using sugar free chewing gum in Duchenne muscular dystrophy patients improved their masticatory performance. Since bite force did not improve, the working mechanism of the improvement in chewing may relate to changes of the neuromuscular function and coordination, resulting in improvement of skills in performing mastication. PMID- 25792432 TI - Motor control may support mirror neuron research with new hypotheses and methods: reply to comments on "Grasping synergies: a motor-control approach to the mirror neuron mechanism". PMID- 25792433 TI - Metagenomic insights into Cr(VI) effect on microbial communities and functional genes of an expanded granular sludge bed reactor treating high-nitrate wastewater. AB - In this study, a lab-scale expanded granular sludge bed reactor was continuously operated to treat high-nitrate wastewater containing different concentrations of hexavalent chromium (Cr(VI)). Nearly complete nitrate removal was achieved even at 120 mg/L influent Cr(VI). Pyrosequencing of 16S rRNA gene showed that Cr(VI) decreased the biodiversity of the bacterial community and potential denitrifiers. Proteobacteria dominated in the bioreactor, and Betaproteobacteria had increased abundance after Cr(VI) feeding. Thauera and Halomonas were the two predominant genera in the bioreactor fed with Cr(VI), demonstrating opposite responses to the Cr(VI) stress. Metagenomic analysis indicated that Cr(VI) feeding posed no obvious effect on the overall function of the bacterial community, but altered the abundance of specific denitrifying genes, which was evidenced by quantitative real time PCR. This study revealed that Halomonas mainly contributed to the denitrification under no or low Cr(VI) stress, while Thauera played a more important role under high Cr(VI) stress. PMID- 25792434 TI - Adaptation of Fusarium oxysporum and Fusarium dimerum to the specific aquatic environment provided by the water systems of hospitals. AB - Members of the Fusarium group were recently detected in water distribution systems of several hospitals in the world. An epidemiological investigation was conducted over 2 years in hospital buildings in Dijon and Nancy (France) and in non-hospital buildings in Dijon. The fungi were detected only within the water distribution systems of the hospital buildings and also, but at very low concentrations, in the urban water network of Nancy. All fungi were identified as Fusarium oxysporum species complex (FOSC) and Fusarium dimerum species complex (FDSC) by sequencing part of the translation elongation factor 1-alpha (TEF 1alpha) gene. Very low diversity was found in each complex, suggesting the existence of a clonal population for each. Density and heterogeneous distributions according to buildings and variability over time were explained by episodic detachments of parts of the colony from biofilms in the pipes. Isolates of these waterborne populations as well as soilborne isolates were tested for their ability to grow in liquid medium in the presence of increasing concentrations of sodium hypochlorite, copper sulfate, anti-corrosion pipe coating, at various temperatures (4 degrees -42 degrees C) and on agar medium with amphotericin B and voriconazole. The waterborne isolates tolerated higher sodium hypochlorite and copper sulfate concentrations and temperatures than did soilborne isolates but did not show any specific resistance to fungicides. In addition, unlike waterborne isolates, soilborne isolates did not survive in water even supplemented with glucose, while the former developed in the soil as well as soilborne isolates. We concluded the existence of homogeneous populations of FOSC and FDSC common to all contaminated hospital sites. These populations are present at very low densities in natural waters, making them difficult to detect, but they are adapted to the specific conditions offered by the complex water systems of public hospitals in Dijon and Nancy and probably other localities in the world. PMID- 25792435 TI - Comparison of different chelating agents to enhance reductive Cr(VI) removal by pyrite treatment procedure. AB - New technologies involving in-situ chemical hexavalent chromium [Cr(VI)] reduction to trivalent chromium [Cr(III)] with natural Fe(II)-containing minerals can offer viable solutions to the treatment of wastewater and subsurface systems contaminated with Cr(VI). Here, the effects of five different chelating agents including citrate, EDTA, oxalate, tartrate and salicylate on reductive Cr(VI) removal from aqueous systems by pyrite were investigated in batch reactors. The Cr(VI) removal was highly dependent on the type of ligand used and chemical conditions (e.g., ligand concentration). While salicylate and EDTA had no or little effect on Cr(VI) removal, the ligands including citrate, tartrate and oxalate significantly enhanced Cr(VI) removal at pH < 7 relative to non-ligand systems. In general, the efficiency of organic ligands on Cr(VI) removal decreased in the order: citrate >= oxalate ~ tartrate > EDTA > salicylate ~ non ligand system. Organic ligands enhanced Cr(VI) removal by 1) removing surface oxide layer via the formation of soluble Fe-Cr-ligand complexes, and 2) enhancing the reductive iron redox cycling for the regeneration of new surface sites. While citrate, oxalate and tartrate eliminated the formation of surface Cr (III) Fe(III)-oxides, the surface phase Cr (III) species was observed in the presence of EDTA and salicylate indicating that Cr(III) complexed with EDTA and salicylate sorbed or precipitated onto pyrite surface, thereby blocking the access of CrO4(2 ) to pyrite surface. The binding of Fe(III) with the disulfide reactive sites (=Fe-S-S-Fe(III)) was essential for the regeneration of new surface sites through pyrite oxidation. Although Fe(III)-S species was detected at the pyrite surface in the presence of citrate, oxalate and tartrate, Fe(III) complexed with EDTA and salicylate did not strongly interact with the disulfide reactive sites due to the formation of non-sorbing Fe(III)-ligand complexes. The absence of surface Fe(III) S species indicated that no new reactive sites were generated through Fe redox cycling in the presence of salicylate and EDTA. PMID- 25792436 TI - Predicting trace organic compound breakthrough in granular activated carbon using fluorescence and UV absorbance as surrogates. AB - This study investigated the applicability of bulk organic parameters like dissolved organic carbon (DOC), UV absorbance at 254 nm (UV254), and total fluorescence (TF) to act as surrogates in predicting trace organic compound (TOrC) removal by granular activated carbon in water reuse applications. Using rapid small-scale column testing, empirical linear correlations for thirteen TOrCs were determined with DOC, UV254, and TF in four wastewater effluents. Linear correlations (R(2) > 0.7) were obtained for eight TOrCs in each water quality in the UV254 model, while ten TOrCs had R(2) > 0.7 in the TF model. Conversely, DOC was shown to be a poor surrogate for TOrC breakthrough prediction. When the data from all four water qualities was combined, good linear correlations were still obtained with TF having higher R(2) than UV254 especially for TOrCs with log Dow>1. Excellent linear relationship (R(2) > 0.9) between log Dow and the removal of TOrC at 0% surrogate removal (y-intercept) were obtained for the five neutral TOrCs tested in this study. Positively charged TOrCs had enhanced removals due to electrostatic interactions with negatively charged GAC that caused them to deviate from removals that would be expected with their log Dow. Application of the empirical linear correlation models to full-scale samples provided good results for six of seven TOrCs (except meprobamate) tested when comparing predicted TOrC removal by UV254 and TF with actual removals for GAC in all the five samples tested. Surrogate predictions using UV254 and TF provide valuable tools for rapid or on-line monitoring of GAC performance and can result in cost savings by extended GAC run times as compared to using DOC breakthrough to trigger regeneration or replacement. PMID- 25792437 TI - Application of real-time PCR to determination of combined effect of antibiotics on Bacteria, Methanogenic Archaea, Archaea in anaerobic sequencing batch reactors. AB - This study evaluated the long-term effects of erythromycin-tetracycline sulfamethoxazole (ETS) and sulfamethoxazole-tetracycline (ST) antibiotic combinations on the microbial community and examined the ways in which these antimicrobials impact the performance of anaerobic reactors. Quantitative real time PCR was used to determine the effect that different antibiotic combinations had on the total and active Bacteria, Archae and Methanogenic Archae. Three primer sets that targeted metabolic genes encoding formylterahydrofolate synthetase, methyl-coenzyme M reductase and acetyl-coA synthetase were also used to determine the inhibition level on the mRNA expression of the homoacetogens, methanogens and specifically acetoclastic methanogens, respectively. These microorganisms play a vital role in the anaerobic degradation of organic waste and targeting these gene expressions offers operators or someone at a treatment plant the potential to control and the improve the anaerobic system. The results of the investigation revealed that acetogens have a competitive advantage over Archaea in the presence of ETS and ST combinations. Although the efficiency with which methane production takes place and the quantification of microbial populations in both the ETS and ST reactors decreased as antibiotic concentrations increased, the ETS batch reactor performed better than the ST batch reactor. According to the expression of genes results, the syntrophic interaction of acetogens and methanogens is critical to the performance of the ETS and ST reactors. Failure to maintain the stability of these microorganisms resulted in a decrease in the performance and stability of the anaerobic reactors. PMID- 25792438 TI - Environmental and resource implications of phosphorus recovery from waste activated sludge. AB - Phosphorus is an essential mineral resource for the growth of crops and thus necessary to feed the ever increasing global population. The essentiality and irreplaceability of phosphorus in food production has raised the concerns regarding the long-term phosphorus availability and the resulting food supply issues in the future. Hence, the recovery of phosphorus from waste activated sludge and other waste streams is getting huge attention as a viable solution to tackle the potential availability issues of phosphorus in the future. This study explores the environmental implications of phosphorus recovery from waste activated sludge in Denmark and further elaborates on the potential availability or scarcity issue of phosphorus today and 2050. Life cycle assessment is used to assess the possibility of phosphorus recovery with little or no environmental impacts compared to the conventional mining. The phosphorus recovery method assessed in this study consists of drying process, and thermal gasification of the waste activated sludge followed by extraction of phosphorus from the ashes. Our results indicate that the environmental impacts of phosphorus recovery in an energy efficient process are comparable to the environmental effects from the re use of waste activated sludge applied directly on farmland. Moreover, our findings conclude that the general recommendation according to the waste hierarchy, where re-use of the waste sludge on farmland is preferable to material and energy recovery, is wrong in this case. Especially when phosphorus is a critical resource due to its life threatening necessity, lack of substitution options and potential future supply risk originating due to the high level of global supply concentration. PMID- 25792439 TI - Effects of earthworm casts and zeolite on the two-stage composting of green waste. AB - Because it helps protect the environment and encourages economic development, composting has become a viable method for organic waste disposal. The objective of this study was to investigate the effects of earthworm casts (EWCs) (at 0.0%, 0.30%, and 0.60%) and zeolite (clinoptilolite, CL) (at 0%, 15%, and 25%) on the two-stage composting of green waste. The combination of EWCs and CL improved the conditions of the composting process and the quality of the compost products in terms of the thermophilic phase, humification, nitrification, microbial numbers and enzyme activities, the degradation of cellulose and hemicellulose, and physico-chemical characteristics and nutrient contents of final composts. The compost matured in only 21days with the optimized two-stage composting method rather than in the 90-270days required for traditional composting. The optimal two-stage composting and the best quality compost were obtained with 0.30% EWCs and 25% CL. PMID- 25792440 TI - Performance of green waste biocovers for enhancing methane oxidation. AB - Green waste aged 2 and 24months, labeled "fresh" and "aged" green waste, respectively, were placed in biocover test cells and evaluated for their ability to oxidize methane (CH4) under high landfill gas loading over a 15-month testing period. These materials are less costly to produce than green waste compost, yet satisfied recommended respiration requirements for landfill compost covers. In field tests employing a novel gas tracer to correct for leakage, both green wastes oxidized CH4 at high rates during the first few months of operation - 140 and 200g/m(2)/day for aged and fresh green waste, respectively. Biocover performance degraded during the winter and spring, with significant CH4 generated from anaerobic regions in the 60-80cm thick biocovers. Concurrently, CH4 oxidation rates decreased. Two previously developed empirical models for moisture and temperature dependency of CH4 oxidation in soils were used to test their applicability to green waste. Models accounted for 68% and 79% of the observed seasonal variations in CH4 oxidation rates for aged green waste. Neither model could describe similar seasonal changes for the less stable fresh green waste. This is the first field application and evaluation of these empirical models using media with high organic matter. Given the difficulty of preventing undesired CH4 generation, green waste may not be a viable biocover material for many climates and landfill conditions. PMID- 25792441 TI - Improved feature-based prediction of SNPs in human cytochrome P450 enzymes. AB - Single nucleotide polymorphisms (SNPs) make up the most common form of mutations in human cytochrome P450 enzymes family, and have the potential to bring with different drug responses or specific diseases in individual patients. Here, based on machine learning technology, we aim to explore an effective set of sequence based features for improving prediction of SNPs by using support vector machine algorithms. The features are derived from the target residues and flanking protein sequences, such as amino acid types, sequences composition, physicochemical properties, position-specific scoring matrix, phylogenetic entropy and the number of possible codons of target residues. In order to deal with the imbalance data with a majority of non-SNPs and a minority of SNPs, a preprocessing strategy based on fuzzy set theory was applied to the datasets. Our final model achieves the performance of 93.8% in sensitivity, 88.8% in specificity, 91.3% in accuracy and 0.971 of AUC value, which is significantly higher than the previous DNA sequence-based or protein sequence-based methods. Furthermore, our study also suggested the roles of individual features for prediction of SNPs. The most important features consist of the amino acid type, the number of available codons, position-specific scoring matrix and phylogenetic entropy. The improved model will be a promising tool for SNP predictions, and assist in the research of genome mutation and personalized prescriptions. PMID- 25792442 TI - Erratum to: Identification and characterization of alkaline protease producing bacillus firmus species EMBS023 by 16S rRNA gene sequencing. PMID- 25792443 TI - Describing Crouzon and Pfeiffer syndrome based on principal component analysis. AB - Crouzon and Pfeiffer syndrome are syndromic craniosynostosis caused by specific mutations in the FGFR genes. Patients share the characteristics of a tall, flattened forehead, exorbitism, hypertelorism, maxillary hypoplasia and mandibular prognathism. Geometric morphometrics allows the identification of the global shape changes within and between the normal and syndromic population. METHODS: Data from 27 Crouzon-Pfeiffer and 33 normal subjects were landmarked in order to compare both populations. With principal component analysis the variation within both groups was visualized and the vector of change was calculated. This model normalized a Crouzon-Pfeiffer skull and was compared to age-matched normative control data. RESULTS: PCA defined a vector that described the shape changes between both populations. Movies showed how the normal skull transformed into a Crouzon-Pfeiffer phenotype and vice versa. Comparing these results to established age-matched normal control data confirmed that our model could normalize a Crouzon-Pfeiffer skull. CONCLUSIONS: PCA was able to describe deformities associated with Crouzon-Pfeiffer syndrome and is a promising method to analyse variability in syndromic craniosynostosis. The virtual normalization of a Crouzon-Pfeiffer skull is useful to delineate the phenotypic changes required for correction, can help surgeons plan reconstructive surgery and is a potentially promising surgical outcome measure. PMID- 25792444 TI - New reflections on agency and body ownership: The moving rubber hand illusion in the mirror. AB - No previous study has simultaneously examined body ownership and agency in healthy subjects during mirror self-observation. We used a moving rubber hand illusion to examine how both body ownership and agency are affected by seeing (i) the body moving in a mirror, compared with (ii) directly viewing the moving hand, and (iii) seeing a visually identical hand rotated by 180 degrees . We elicited ownership of the hand using direct visual feedback, finding this effect was further enhanced when looking at the hand in a mirror, whereas rotating the hand 180 degrees abolished ownership. Agency was similarly elicited using direct visual feedback, and equally so in the mirror, but again reduced for the 180 degrees hand. We conclude that the reflected body in a mirror is treated as 'special' in the mind, and distinct from other external objects. This enables bodies and actions viewed in a mirror to be directly related to the self. PMID- 25792446 TI - Chemokines control mobilization, recruitment, and fate of monocytes in atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of large arteries and, among others, characterized by continuous influx of monocytes into the subendothelial space, subsequent macrophage accumulation, and foam cell formation. Chemokines and their receptors tightly orchestrate monocyte trafficking and fate from birth to death. This brief review summarizes our current understanding of the interplay between monocytes and chemokines entertaining crucial processes in atherosclerosis development, progression, and regression. PMID- 25792445 TI - Resolvin E1 (RvE1) Attenuates Atherosclerotic Plaque Formation in Diet and Inflammation-Induced Atherogenesis. AB - OBJECTIVE: Epidemiological and recent clinical studies implicate periodontitis as an independent risk factor for cardiovascular disease. Previously, we demonstrated that rabbits with experimental periodontitis and cholesterol diet exhibit more aortic plaque compared with diet alone. We also showed that a proresolution mediator, Resolvin E1 (RvE1), reverses the experimental periodontitis. Here, we determined whether oral/topical application of RvE1 attenuates aortic atherosclerosis induced by both diet and periodontal inflammation. APPROACH AND RESULTS: Thirty-nine rabbits on a 13-week regimen of 0.5% cholesterol diet were included. Periodontitis was induced by Porphyromonas gingivalis in 24 rabbits and 15 rabbits were placed in no-periodontitis groups. Interventions were no-treatment, vehicle, and RvE1 treatment (4 MUg/site or 0.4 MUg/site) topically applied 3* per week. At 13 weeks, both periodontitis and atherosclerosis were quantified. Atherosclerotic plaques were assessed by Sudan IV staining, histology, and ex vivo MRI. Serum levels of C-reactive protein were evaluated as a measure of systemic inflammation. RvE1, used as an oral/topical agent, significantly diminished atherogenesis and prevented periodontitis (P<0.05). In the absence of periodontal inflammation, oral/topical application of RvE1 resulted in significantly less arterial plaque, a lower intima/media ratio, and decreased inflammatory cell infiltration compared with no-treatment (P<0.001). Local oral RvE1 application significantly reduced systemic levels of C reactive protein (P<0.05). CONCLUSIONS: The results suggest that oral/topical RvE1 attenuates enhanced atherogenesis induced by periodontitis and prevents vascular inflammation and atherogenesis in the absence of periodontitis. The inhibition of vascular inflammation with endogenous mediators of resolution of inflammation provides a novel approach in the prevention of atherogenic events. PMID- 25792447 TI - Reduced Atherosclerosis in apoE-inhibitory FcgammaRIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages. AB - OBJECTIVE: Fcgamma receptors (FcgammaRs) are classified as activating (FcgammaRI, III, and IV) and inhibitory (FcgammaRII) receptors. We have reported that deletion of activating FcgammaRs in apolipoprotein E (apoE) single knockout mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory FcgammaRIIb exacerbates atherosclerosis. APPROACH AND RESULTS: ApoE-FcgammaRIIb double knockout mice, congenic to the C57BL/6 (apoE FcgammaRIIbB6 (-/-)), were generated and atherosclerotic lesions were assessed. In contrary to our hypothesis, when compared with apoE single knockout mice, arterial lesions were significantly decreased in apoE-FcgammaRIIbB6 (-/-) male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-FcgammaRIIbB6 (-/-) marrow into apoE single knockout mice also developed reduced lesions. CD4(+) T cells from apoE-FcgammaRIIbB6 (-/-) mice produced higher levels of interleukin-10 and transforming growth factor-beta than their apoE single knockout counterparts. As our findings conflict with a previous report using apoE-FcgammaRIIb129/B6 (-/-) mice on a mixed genetic background, we investigated whether strain differences contributed to the anti-inflammatory response. Macrophages from FcgammaRIIb129/B6 (-/-) mice on a mixed genetic background produced more interleukin-1beta and MCP-1 (monocyte chemoattractant protein-1) in response to immune complexes, whereas congenic FcgammaRIIbB6 (-/-) mice generated more interleukin-10 and significantly less interleukin-1beta. Interestingly, the expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed FcgammaRIIb129/B6 (-/-) mice. CONCLUSIONS: Our findings demonstrate a detrimental role for FcgammaRIIb signaling in atherosclerosis and the contribution of anti inflammatory cytokine responses in the attenuated lesions observed in apoE FcgammaRIIbB6 (-/-) mice. As 129/sv genome-derived lupus-associated genes have been implicated in lupus phenotype in FcgammaRIIb129/B6 (-/-) mice, our findings suggest possible epistatic mechanism contributing to the decreased lesions. PMID- 25792448 TI - Overview of the new oral anticoagulants: opportunities and challenges. AB - The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges. PMID- 25792449 TI - Monocytes in myocardial infarction. AB - Myocardial infarction (MI) is the leading cause of death in developed countries. Though timely revascularization of the ischemic myocardium and current standard therapy reduce acute mortality after MI, long-term morbidity and mortality remain high. During the first 1 to 2 weeks after MI, tissues in the infarcted myocardium undergo rapid turnover, including digestion of extracellular matrix and fibrosis. Post-MI repair is crucial to survival. Monocytes recruited to the infarcted myocardium remove debris and facilitate the repair process. However, exaggerated inflammation may also impede healing, as demonstrated by the association between elevated white blood cell count and in-hospital mortality after MI. Monocytes produced in the bone marrow and spleen enter the blood after MI and are recruited to the injured myocardium in 2 phases. The first phase is dominated by Ly 6c(high) monocytes and the second phase by Ly-6c(low) monocytes. Yet the number of Ly6C(low) monocytes recruited to the infarct is much lower, and Ly6C(high) monocytes can differentiate to Ly6C(low) macrophages in later healing stages. Understanding the signals regulating monocytosis after MI will help design new therapies to facilitate cardiac healing and limit heart failure. PMID- 25792450 TI - Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes. AB - OBJECTIVE: Very low-density lipoprotein assembly and secretion are regulated by the availability of triacylglycerol. Although compelling evidence indicates that the majority of triacylglycerol in very low-density lipoprotein is derived from re-esterification of lipolytic products released by endoplasmic reticulum associated lipases, little is known about roles of acyl-CoA:diacylglycerol acyltransferases (DGATs) in this process. We aimed to investigate the contribution of DGAT1 and DGAT2 in lipid metabolism and lipoprotein secretion in primary mouse and human hepatocytes. APPROACH AND RESULTS: We used highly selective small-molecule inhibitors of DGAT1 and DGAT2, and we tracked storage and secretion of lipids synthesized de novo from [(3)H]acetic acid and from exogenously supplied [(3)H]oleic acid. Inactivation of individual DGAT activity did not affect incorporation of either radiolabeled precursor into intracellular triacylglycerol, whereas combined inactivation of both DGATs severely attenuated triacylglycerol synthesis. However, inhibition of DGAT2 augmented fatty acid oxidation, whereas inhibition of DGAT1 increased triacylglycerol secretion, suggesting preferential channeling of separate DGAT-derived triacylglycerol pools to distinct metabolic pathways. Inactivation of DGAT2 impaired cytosolic lipid droplet expansion, whereas DGAT1 inactivation promoted large lipid droplet formation. Moreover, inactivation of DGAT2 attenuated expression of lipogenic genes. Finally, triacylglycerol secretion was significantly reduced on DGAT2 inhibition without altering extracellular apolipoprotein B levels. CONCLUSIONS: Our data suggest that DGAT1 and DGAT2 can compensate for each other to synthesize triacylglycerol, but triacylglycerol synthesized by DGAT1 is preferentially channeled to oxidation, whereas DGAT2 synthesizes triacylglycerol destined for very low-density lipoprotein assembly. PMID- 25792451 TI - New endoplasmic reticulum stress regulator, Gipie, regulates the survival of vascular smooth muscle cells and the neointima formation after vascular injury. AB - OBJECTIVE: The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an adaptive stress response, termed the unfolded protein response. Previous studies suggested that ER stress might be involved in the formation of neointima after vascular injury. We recently discovered a novel regulator of ER stress, 78-kDa glucose-regulated protein-interacting protein induced by ER stress (Gipie). The objective of this study was to elucidate the role of Gipie using models of vascular disease. APPROACH AND RESULTS: We investigated the functions of Gipie in cultured vascular smooth muscle cells (VSMCs) and in a vascular injury model of a rat carotid artery. The expression of Gipie was predominantly detected in synthetic VSMCs and to a much lesser extent in contractile VSMCs, which was augmented by treatment with thapsigargin. Gipie knockdown increased the phosphorylation levels of c-Jun N-terminal kinase and the number of apoptotic cells under ER stress. Moreover, Gipie knockdown decreased the mature form of collagen I in synthetic VSMCs. The expression of Gipie was rarely detected in the medial VSMCs of the intact carotid artery, whereas it was detected in most of the neointimal cells and some of the medial VSMCs after balloon injury. Depletion of Gipie in the rat carotid artery attenuated the neointimal thickening, which was accompanied by increased cell death in the neointima. Conversely, overexpression of Gipie augmented the neointimal thickening. CONCLUSIONS: Gipie participates in the ER stress response in VSMCs and plays an important role in neointima formation after vascular injury. PMID- 25792452 TI - Gap junction coupling is required for tumor cell migration through lymphatic endothelium. AB - OBJECTIVE: The lymphatic vasculature is a well-established conduit for metastasis, but the mechanisms by which tumor cells interact with lymphatic endothelial cells (LECs) to facilitate escape remain poorly understood. Elevated levels of the lymphangiogenic peptide adrenomedullin are found in many tumors, and we previously characterized that its expression is necessary for lymphatic vessel growth within both tumors and sentinel lymph nodes and for distant metastasis. APPROACH AND RESULTS: This study used a tumor cell-LEC coculture system to identify a series of adrenomedullin-induced events that facilitated transendothelial migration of the tumor cells through a lymphatic monolayer. High levels of adrenomedullin expression enhanced adhesion of tumor cells to LECs, and further analysis revealed that adrenomedullin promoted gap junction coupling between LECs as evidenced by spread of Lucifer yellow dye. Adrenomedullin also enhanced heterocellular gap junction coupling as demonstrated by Calcein dye transfer from tumor cells into LECs. This connexin-mediated gap junction intercellular communication was necessary for tumor cells to undergo transendothelial migration because pharmacological blockade of this heterocellular communication prevented the ability of tumor cells to transmigrate through the lymphatic monolayer. In addition, treatment of LECs with adrenomedullin caused nuclear translocation of beta-catenin, a component of endothelial cell junctions, causing an increase in transcription of the downstream target gene C-MYC. Importantly, blockade of gap junction intercellular communication prevented beta-catenin nuclear translocation. CONCLUSIONS: Our findings indicate that maintenance of cell-cell communication is necessary to facilitate a cascade of events that lead to tumor cell migration through the lymphatic endothelium. PMID- 25792453 TI - Tumour targeting and radiation dose of radioimmunotherapy with (90)Y-rituximab in CD20+ B-cell lymphoma as predicted by (89)Zr-rituximab immuno-PET: impact of preloading with unlabelled rituximab. AB - PURPOSE: To compare using immuno-PET/CT the distribution of (89)Zr-labelled rituximab without and with a preload of unlabelled rituximab to assess the impact of preloading with unlabelled rituximab on tumour targeting and radiation dose of subsequent radioimmunotherapy with (90)Y-labelled rituximab in CD20+ B-cell lymphoma. METHODS: Five patients with CD20+ B-cell lymphoma and progressive disease were prospectively enrolled. All patients underwent three study phases: initial dosimetric phase with baseline (89)Zr-rituximab PET/CT imaging without a cold preload, followed 3 weeks later by a second dosimetric phase with administration of a standard preload (250 mg/m(2)) of unlabelled rituximab followed by injection of (89)Zr-rituximab, and a therapeutic phase 1 week later with administration of unlabelled rituximab followed by (90)Y-rituximab. PET/CT imaging and tracer uptake by organs and lesions were assessed. RESULTS: With a cold rituximab preload, the calculated whole-body dose of (90)Y-rituximab was similar (mean 0.87 mSv/MBq, range 0.82-0.99 mSv/MBq) in all patients. Without a preload, an increase in whole-body dose of 59% and 87% was noted in two patients with preserved circulating CD20+ B cells. This increase in radiation dose was primarily due to a 12.4-fold to 15-fold higher dose to the spleen without a preload. No significant change in whole-body dose was noted in the three other patients with B-cell depletion. Without a preload, consistently higher tumour uptake was noticed in patients with B-cell depletion. CONCLUSION: Administration of the standard preload of unlabelled rituximab impairs radioconjugate tumour targeting in the majority of patients eligible for radioimmunotherapy, that is patients previously treated with rituximab-containing therapeutic regimens. This common practice may need to be reconsidered and further evaluated as the rationale for this high preload has its origin in the "prerituximab era". Clinical Trial Application: CTA 2011-005474-38 TRIAL REGISTRY: EudraCT. PMID- 25792454 TI - Towards tailored radiopeptide therapy. AB - PURPOSE: Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor. METHODS: Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving (90)Y-DOTATOC, (177)Lu-DOTATOC or their combination. RESULTS: (90)Y-DOTATOC plus (177)Lu-DOTATOC treatment was associated with longer survival than (90)Y-DOTATOC (66.1 vs. 47.5 months; n = 1,358; p < 0.001) or (177)Lu-DOTATOC alone (66.1 vs. 45.5 months; n = 390; p < 0.001). (177)Lu-DOTATOC was associated with longer survival than (90)Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1 0.7; n = 153; p = 0.005), extrahepatic metastases (HR 0.5, range 0.3 - 0.9; n = 256; p = 0.029) and metastases with low uptake (HR 0.1, range 0.05 - 0.4; n = 113; p = 0.001). (90)Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5% vs. 4.0%, p = 0.005) or (177)Lu-DOTATOC (9.5 vs. 1.4%, p = 0.002). Renal toxicity was similar among the treatments. CONCLUSIONS: Using (90)Y and (177)Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors. PMID- 25792455 TI - In memoriam: Ismael Mena, MD, 1928-2015. PMID- 25792456 TI - [(18)F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer's disease. AB - PURPOSE: Visualization of the spatial distribution of neurofibrillary tangles would help in the diagnosis, prevention and treatment of dementia. The purpose of the study was to evaluate the clinical utility of [(18)F]THK-5117 as a highly selective tau imaging radiotracer. METHODS: We initially evaluated in vitro binding of [(3)H]THK-5117 in post-mortem brain tissues from patients with Alzheimer's disease (AD). In clinical PET studies, [(18)F]THK-5117 retention in eight patients with AD was compared with that in six healthy elderly controls. Ten subjects underwent an additional [(11)C]PiB PET scan within 2 weeks. RESULTS: In post-mortem brain samples, THK-5117 bound selectively to neurofibrillary deposits, which differed from the binding target of PiB. In clinical PET studies, [(18)F]THK-5117 binding in the temporal lobe clearly distinguished patients with AD from healthy elderly subjects. Compared with [(11)C]PiB, [(18)F]THK-5117 retention was higher in the medial temporal cortex. CONCLUSION: These findings suggest that [(18)F]THK-5117 provides regional information on neurofibrillary pathology in living subjects. PMID- 25792457 TI - Global trends in antimicrobial use in food animals. AB - Demand for animal protein for human consumption is rising globally at an unprecedented rate. Modern animal production practices are associated with regular use of antimicrobials, potentially increasing selection pressure on bacteria to become resistant. Despite the significant potential consequences for antimicrobial resistance, there has been no quantitative measurement of global antimicrobial consumption by livestock. We address this gap by using Bayesian statistical models combining maps of livestock densities, economic projections of demand for meat products, and current estimates of antimicrobial consumption in high-income countries to map antimicrobial use in food animals for 2010 and 2030. We estimate that the global average annual consumption of antimicrobials per kilogram of animal produced was 45 mg?kg(-1), 148 mg?kg(-1), and 172 mg?kg(-1) for cattle, chicken, and pigs, respectively. Starting from this baseline, we estimate that between 2010 and 2030, the global consumption of antimicrobials will increase by 67%, from 63,151 +/- 1,560 tons to 105,596 +/- 3,605 tons. Up to a third of the increase in consumption in livestock between 2010 and 2030 is imputable to shifting production practices in middle-income countries where extensive farming systems will be replaced by large-scale intensive farming operations that routinely use antimicrobials in subtherapeutic doses. For Brazil, Russia, India, China, and South Africa, the increase in antimicrobial consumption will be 99%, up to seven times the projected population growth in this group of countries. Better understanding of the consequences of the uninhibited growth in veterinary antimicrobial consumption is needed to assess its potential effects on animal and human health. PMID- 25792458 TI - Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells. AB - Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (A-kinase anchor protein 12), AKAP12v2, in metastatic melanoma. In turn, through a kinome-wide phosphoproteomic and MS study, we demonstrate that this scaffolding protein regulates a shift in protein kinase A (PKA)-mediated phosphorylation events under hypoxia, causing alterations in tumor cell invasion and migration in vitro, as well as metastasis in an in vivo orthotopic model of melanoma. Mechanistically, the shift in AKAP12-dependent PKA-mediated phosphorylations under hypoxia is due to changes in AKAP12 localization vs. structural differences between its two variants. Importantly, our work defines a mechanism through which a scaffold protein can be regulated by the tumor microenvironment and further explains how a tumor cell can coordinate many critical signaling pathways that are essential for tumor growth through one individual scaffolding protein. PMID- 25792459 TI - Reframing the science and anthropology of autism. PMID- 25792461 TI - Cystadenomas of the liver and extrahepatic bile ducts: Morphologic and immunohistochemical characterization of the biliary and intestinal variants. AB - Cystadenomas of the liver and extrahepatic bile ducts (EHBD) are uncommon but distinctive neoplasms whose terminology and epithelial phenotype have been a source of controversy. We reviewed 20 cases, 16 arising in the liver and 4 in the EHBD. Eighteen patients were women, with a mean age of 36.5 years. Eighteen tumors were multiloculated and 2 were unilocular. The tumor size ranged from 4 to 29 cm (average, 11 cm). The cyst fluid in 13 tumors was described as serous, in 2 as clear, in 2 others as hemorrhagic, and in 1 as serous and mucinous. Only in 2 tumors was the fluid described as mucinous. In 18 cystadenomas, the predominant epithelial lining consisted of a single layer of cuboidal or low-columnar nondysplastic cells similar to those of the gallbladder or bile ducts. This epithelial lining was strongly positive for cytokeratins 7 and 19, and focally positive for MUC1. Only 2 cystadenomas showed predominant intestinal differentiation characterized by mature goblet cells and columnar absorptive cells. These cells expressed CDX2, MUC2, and cytokeratin 20. Admixed with the goblet and columnar cells, there were serotonin-containing cells and Paneth cells. These 2 tumors showed extensive areas of high-grade dysplasia and invasive adenocarcinoma with intestinal phenotype. A subepithelial ovarian-like stroma was present in all tumors. None of the patients died of the tumors. We believe that the term mucinous cystic tumor recommended by the World Health Organization for all cystadenomas of the liver and EHBD is a misnomer. PMID- 25792460 TI - Distinctive immunohistochemical staining in littoral cell angioma using ERG and WT-1. AB - Littoral cell angioma (LCA) is a rare vascular tumor of the spleen. It has an immunohistochemical staining pattern that is somewhat distinctive but can still be occasionally confused with other vascular and stromal proliferations in the spleen. In this study, LCA was evaluated using Ets-related gene (ERG) and Wilms tumor-1 (WT-1), relatively recently described vascular markers. In addition, other vascular lesions including normal spleen, hemangiomas, hamartoma, peliosis, and sclerosing angiomatoid nodular transformation were evaluated using these stains. In LCA, ERG stains the endothelial cells of the tumor as expected. ERG also was uniformly positive in vascular elements of other lesions except peliosis. However, in contrast to most other vascular elements, LCA was negative for WT-1 staining. This staining pattern may prove useful in diagnosing LCA and may provide insight into the derivation of the distinctive tumor. PMID- 25792462 TI - Complex trait architecture: the pleiotropic model revisited. AB - There is currently much debate about how much the genetic heritability of complex traits is due to very rare alleles. This issue is important because it determines sampling strategies for genetic association studies. Several recent theoretical papers based on a pleiotropic model for trait evolution suggest that it is possible that a large proportion of the genetic variance could be explained by rare alleles. This model assumes that mutations with a large effect on fitness also tend to have large positive or negative effects on phenotypic traits. We show that conclusions based on standard diffusion results are generally applicable to simulations of whole genomes with overlapping generations in a finite population, although the variance contribution of rare alleles is somewhat smaller than theoretical predictions. We show that under many scenarios the pleiotropic model predicts trait distributions that are unrealistically leptokurtic. We argue that this imposes a limit on the relationship between fitness and trait effects. PMID- 25792463 TI - Acute 'limited' magnetic resonance imaging in childhood stroke--an illustrative case. AB - Paediatric stroke is a major cause of morbidity and death in children. There is often a delay in making the diagnosis because common differential diagnoses such as migraine and seizures need to be considered and quick access to imaging is difficult. Early recognition is increasingly important for early treatment and to improve outcomes. We present the case of a 4-year-old boy who presented to the Emergency Department with acute hemiparesis. To target the provisional diagnosis of an acute ischaemic stroke, we requested magnetic resonance imaging (MRI) limited to two sequences only: diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI). We were able to confirm the diagnosis of acute ischaemic stroke within 90 min of presentation to hospital. PMID- 25792464 TI - Chronic low-dose gamma-irradiation of Drosophila melanogaster larvae induces gene expression changes and enhances locomotive behavior. AB - Although radiation effects have been extensively studied, the biological effects of low-dose radiation (LDR) are controversial. This study investigates LDR induced alterations in locomotive behavior and gene expression profiles of Drosophila melanogaster. We measured locomotive behavior using larval pupation height and the rapid iterative negative geotaxis (RING) assay after exposure to 0.1 Gy gamma-radiation (dose rate of 16.7 mGy/h). We also observed chronic LDR effects on development (pupation and eclosion rates) and longevity (life span). To identify chronic LDR effects on gene expression, we performed whole-genome expression analysis using gene-expression microarrays, and confirmed the results using quantitative real-time PCR. The pupation height of the LDR-treated group at the first larval instar was significantly higher (~2-fold increase in PHI value, P < 0.05). The locomotive behavior of LDR-treated male flies (~3 - 5 weeks of age) was significantly increased by 7.7%, 29% and 138%, respectively (P < 0.01), but pupation and eclosion rates and life spans were not significantly altered. Genome-wide expression analysis identified 344 genes that were differentially expressed in irradiated larvae compared with in control larvae. We identified several genes belonging to larval behavior functional groups such as locomotion (1.1%), oxidation reduction (8.0%), and genes involved in conventional functional groups modulated by irradiation such as defense response (4.9%), and sensory and perception (2.5%). Four candidate genes were confirmed as differentially expressed genes in irradiated larvae using qRT-PCR (>2-fold change). These data suggest that LDR stimulates locomotion-related genes, and these genes can be used as potential markers for LDR. PMID- 25792465 TI - Human mast cells are major IL-22 producers in patients with psoriasis and atopic dermatitis. AB - BACKGROUND: Psoriasis is a systemic inflammatory disease in which IL-17 and IL-22 levels are markedly increased in the skin and blood. The prevalent concept, using skin cells that are isolated from psoriatic plaques and examined after cell expansion and in vitro stimulation, is that IL-17 and IL-22 production essentially results from T cells and the rare type 3 innate lymphoid cells. OBJECTIVE: We sought to examine the cellular source of IL-17A and IL-22 at the protein and transcriptional single-cell level immediately after ex vivo skin cell isolation from psoriatic plaques. METHODS: Skin biopsy specimens were collected from patients with psoriasis, as well as from patients with atopic dermatitis. Cell suspensions were prepared by combining mild enzymatic digestion and mechanical dissociation and analyzed for cytokine expression without prior in vitro culture and stimulation. Expression of IL-17 and IL-22 was quantified at the protein and mRNA single-cell level by using flow cytometry. RESULTS: IL-22 is predominantly expressed by CD3(-)c-Kit(+) cells relative to CD3(+) T cells in lesional skin of patients with psoriasis and patients with atopic dermatitis. Strikingly, we identified c-Kit(+)FcepsilonRI(+) mast cells as major IL-22 producers. The proportion of mast cells that produce IL-22 ranges from 20% to 80% in patients with psoriasis or those with atopic dermatitis. Skin mast cells express IL-22 and IL-17 mRNA. Conversely, IL-17-producing T cells outnumber IL-17 producing mast cells, which also express IL-17 receptor. CONCLUSION: Human skin mast cells are previously unrecognized IL-22 producers. We further established that skin mast cells express IL-17. Thus mast cells might play an important role in the physiopathology of chronic inflammatory skin disorders. PMID- 25792467 TI - Acute symptoms during the course of head and neck radiotherapy or chemoradiation are strong predictors of late dysphagia. AB - PURPOSE: To determine if acute symptoms during definitive radiotherapy (RT) or chemoradiation (CHRT) are prognostic factors for late dysphagia in head and neck cancer (HNC). MATERIAL AND METHODS: This prospective cohort study consisted of 260 HNC patients who received definitive RT or CHRT. The primary endpoint was grade 2-4 swallowing dysfunction at 6 months after completing RT (SWALM6). During treatment, acute symptoms, including oral mucositis, xerostomia and dysphagia, were scored, and the scores were accumulated weekly and entered into an existing reference model for SWALM6 that consisted of dose-volume variables only. RESULTS: Both acute xerostomia and dysphagia were strong prognostic factors for SWALM6. When acute scores were added as variables to the reference model, model performance increased as the course of treatment progressed: the AUC rose from 0.78 at the baseline to 0.85 in week 6. New models built for weeks 3-6 were significantly better able to identify patients with and without late dysphagia. CONCLUSION: Acute xerostomia and dysphagia during the course of RT are strong prognostic factors for late dysphagia. Including accumulated acute symptom scores on a weekly basis in prediction models for late dysphagia significantly improves the identification of high-risk and low-risk patients at an early stage during treatment and might facilitate individualized treatment adaptation. PMID- 25792466 TI - B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach. OBJECTIVE: Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration. METHODS: We evaluated B-cell counts, B cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott Aldrich syndrome protein. RESULTS: After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19(+)CD21(-)CD35(-) and CD21(low) B cells and a reduction in B cell-activating factor levels. Immunoglobulin serum levels and autoantibody production improved in all treated patients. CONCLUSIONS: We provide evidence that lentiviral vector-mediated GT induces transgene expression in the B-cell compartment, resulting in ameliorated B-cell development and functionality and contributing to immunologic improvement in patients with WAS. PMID- 25792469 TI - Prognostic value of microRNA-145 in patients with various cancers: a meta analysis. AB - BACKGROUND: MicroRNA-145 (miR-145) plays a crucial role in cancer prognosis. OBJECTIVE: This study aimed to investigate the prognostic value of miR-145 in patients with various cancers. METHODS: We pooled published literature from PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews and calculated the hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate the correlation between miR-145 expression levels and survival of patients with general cancers. RESULTS: A total of 615 cases from 8 studies of multiple cancers were examined in this meta-analysis. The HR for overall survival (OS) of low miR-145 expression in multiple cancers was 1.80 (95% CI = 1.19-2.70). Furthermore, after excluding 1 study for its potential heterogeneity, the results suggested an increasing prognostic value of low miR-145 expression (HR = 2.20, 95% CI = 1.63-1.97). In addition, there was no significant difference between miR 145 expression levels and recurrence-free survival (RFS). CONCLUSION: In conclusion, our findings suggest that miR-145 expression is associated with OS in cancer patients and can serve as a promising biomarker for monitoring prognosis. PMID- 25792468 TI - Down-regulation of miR-206 is associated with Hirschsprung disease and suppresses cell migration and proliferation in cell models. AB - Hirschsprung disease (HSCR) is a well-known congenital digestive disease that originates due to the developmental disorder of neural crest cells. MiR-206 is kown to have a relationship with digestive malfunctions. Therefore, we investigated whether or not miR-206 was involved in the pathogenesis of HSCR. qRT PCR and Western blot assays were used to detect the expression levels of miRNA and mRNAs, and proteins in case and control tissue samples and two cell lines (293T and SH-SY5Y). The functions of miR-206 in vitro were measured by transwell assay, CCK8 assay and flow cytometry. Finally, we conducted dual-luciferase reporter assay to verify the connections between miR-206 and the target mRNA SDPR. Down-regulation of miR-206 was found in HSCR case tissue samples compared with controls, which was validated to be connected with the increased level of mRNA and protein of SDPR by qRT-PCR and dual-luciferase reporter assay. Moreover, miR-206 suppressed the cell migration and proliferation and silencing of SDPR could rescue the extent of the suppressing effects by miR-206 inhibitor. The findings suggest that miR-206 may play a significant role in the pathogenesis of HSCR, as well as inhibiting the cell migration and proliferation by targeting SDPR in disease models. PMID- 25792471 TI - Increased circulating CD14(+)HLA-DR-/low myeloid-derived suppressor cells are associated with poor prognosis in patients with small-cell lung cancer. AB - BACKGROUND: High expression of CD14(+)HLA-DR-/low myeloid-derived suppressor cells (MDSCs) is correlated with immunosuppressive activity in various cancers, however, no studies have shown a correlation of these immunosuppressive cells with clinical outcomes in small-cell lung cancer (SCLC) patients. OBJECTIVE: The purpose of the study was to investigate the number, frequency and clinical significance of CD14(+)HLA-DR-/low MDSCs in SCLC patients. METHODS: The peripheral blood of 42 patients with SCLC and 37 healthy controls was analyzed by using flow cytometry. The relationships between the number and frequency of MDSCs, clinicopathological features and overall survival(OS) were analyzed. The prognostic value of MDSCs was tested by using univariate and multivariate analysis. RESULTS: Our results demonstrated that number and frequency of peripheral CD14(+)HLA-DR-/low MDSCs were significantly increased in SCLC patients than in controls (p< 0.0001 and p< 0.0001, respectively). The frequency of MDSCs correlated with tumor stage (p= 0.02), serum LDH levels (p= 0.001) and with the poorer OS (log-rank test, p= 0.017). Univariate and multivariate analyses suggested that frequency of CD14(+)HLA-DR-/low MDSCs as an independent biomarker for poor prognosis in SCLC patients during follow-up. Our study provides the first evidence that the frequency of CD14(+)HLA-DR-/low MDSCs negatively correlates with clinical outcomes in SCLC patients. CONCLUSIONS: The frequency of CD14(+)HLA-DR-/low MDSCs could be considered as a poor prognostic predictor in SCLC and the elimination of MDSCs during medical interventions may improve the prognosis of SCLC patients. PMID- 25792470 TI - VEZT as a novel independent prognostic factor in gastric cancer. AB - BACKGROUND: Vezatin is an transmembrane protein associated with cell-cell adhesion junctions. In our previous studies, we found that the tumor suppressor function of VEZT was related to methylation of CpG island and were down-regulated in tumor tissue and cells compared to normal controls. However, the role of VEZT gene as a novel putative tumor suppressor in biological characteristics and the relationship with clinicopathological factors and prognosis of gastric cancer was not yet clear. Therefore, we sought to explore these questions and prepare for further research in this study. METHODS: We examined the vezatin expression levels in 119 gastric cancer tissues and adjacent normal tissues by immunohistochemistry. Furthermore, we evaluated the expression of VEZT and its relationship with clinicopathological factors, lymphatic metastasis and prognostic value for gastric cancer. RESULTS: The expression of VEZT was significantly down-regulated in gastric cancer tissues and cell lines and its expression levels was related to differentiation, TNM staging and lymphatic metastasis. Furthermore, analysis of 5-year survival of 119 gastric cancer patients showed that those with strong vezatin expression had significantly longer overall survival time than those with negative vezatin expression. CONCLUSIONS: These data provided an innovative insight that up-regulation of vezatin can be taken as a meaningful way for treating human gastric and other types of cancers. And VEZT expression levels can be considered as a biomarker for gastric cancer progression, lymphatic metastasis and as a novel independent prognostic factor. PMID- 25792473 TI - Clinical significance of the VEGF level in urinary bladder carcinoma. AB - OBJECTIVE: To investigate the correlation of Vascular Endothelial Growth Factor (VEGF) and micro-vessel density (MVD) with urinary bladder tumor and its stage. MATERIAL AND METHODS: The study was conducted between January 2010 and December 2012. The study included screening of 122 patients at elevated risk for bladder cancer, of which 35 patients were finally enrolled in the study. Diagnosis was made on the basis of urine cytology, radiological investigation (ultrasound KUB, and CT-scan) and histopathology. Thirty-five normal cancer-free individuals were enrolled as controls. Human VEGF levels were measured using an enzyme linked immunoassay and protein content (pg/mg protein) by Lowry method. SPSS for Windows version 10.0.7 (SPSS, Chicago, IL, USA) was used for statistical analysis of the data. RESULTS: Mean urine VEGF level in the cases was significantly higher in comparison to the control group. There was a direct correlation between VEGF level and tumor stage. Mean urine VEGF values were minimum in the control group (22.75 +/- 15.41 pg/mg creatinine) and maximum in stage IV patients (180.15 +/- 75.93 pg/mg creatinine). Tissue VEGF levels also showed a similar trend of increase with increase in stage. Urine VEGF level also showed a correlation with tissue VEGF level. Similarly, MVD showed a significant increase with increase in tumor stage. DISCUSSION: A correlation between bladder cancer and MVD and VEGF suggest that the latter can serve as markers for therapeutic guidance. This is the first study from India on clinical and pathological correlation among urine VEGF, tumor tissue VEGF levels, and Micro Vessel Density (MVD) in urinary bladder cancer patients. PMID- 25792474 TI - Proteometabolomics of bladder cancer: current and future prospects. AB - Urinary bladder cancer (BC) is fifth most common cancer worldwide; the diagnostic methods are mostly instrumental approaches including cystoscopy and cytology. Since BC recurrence rate is high, consequently requires long-term follow-up. The molecular assays that can precisely identify BC at an early stage are obligatory. Although several noninvasive urine and blood samples based biomarkers have been proposed in the last decade but only few have been approved by Food and drug administration (FDA) for clinical purpose. Hence the search for more suitable biomarker is still on. In this review, we summarize the urine and blood based metabolic and protein tests not only for determination but also BC patient surveillance. PMID- 25792475 TI - TiO2 incorporated in magnetic mesoporous SBA-15 by a facile inner-pore hydrolysis process toward enhanced adsorption-photocatalysis performances for As(III). AB - A facile inner-pore hydrolysis combining solvent evaporation method was used to decorate mesoporous silica, in which gamma-Fe2O3 nanoparticles was preloaded onto mesoporous SBA-15 followed by decoration of TiO2 nanoparticles. This decoration process exploited the homogeneous dispersivity of gamma-Fe2O3 and TiO2 nanoparticles in/on SBA-15 and inhibit aggregation of gamma-Fe2O3 and TiO2 nanoparticles, which in turn leaded to a synergistic photocatalytic oxidation and adsorption of As(III). It was found that the prepared nanocomposites had mesoporous structure, large specific surface area, high pore volume and superparamagetism according to SEM/TEM, N2 adsorption-desorption isotherms, XRD and VSM analysis. Experimental results show that SBA-15/gamma-Fe2O3-TiO2 can oxidize As(III) to As(V) efficiently in the photocatalysis reaction. At the same time, As(V) is effectively removed through adsorption by the composites. In addition, with the treatment of alkali solution, As(V) can be easily desorbed from SBA-15/gamma-Fe2O3-TiO2. After reusage for 5 times, the composites still retain comparable catalysis and adsorption performance compared with that of first use, revealing the excellent stability of the composites. PMID- 25792472 TI - D-dimer and international normalized ratio (INR) are correlated with tumor markers and disease stage in colorectal cancer patients. AB - BACKGROUND: The aim of this study is to evaluate the correlation of coagulation tests with various clinicopathological variables and tumor markers among colorectal cancer (CRC) patients. MATERIALS AND METHODS: Ninety-four CRC patients were included for evaluation of clinicopathological factors, coagulation assays and tumor marker levels. RESULTS: Metastatic disease was related with elevated INR (p= 0.03). Stage III patients had higher D-dimer values compared with stage II patients (p= 0.03). Correlation of tumor markers indicated a tendency towards elevated D-dimer levels for CEA values higher than median (p= 0.01). High CA 19-9 levels were also associated with higher INR (p= 0.007). Elderly age, distant metastasis, high CEA, CA-19-9 and LDH levels were associated with poorer overall survival. CEA level was the only independent prognostic factor in multivariate analysis. CONCLUSIONS: Coagulation assays can be utilized as predictors of disease extent in CRC. Elevated D-dimer and INR values may indicate higher disease stage. Correlation of D-dimer levels with CEA supports their value for assessing tumor burden. PMID- 25792476 TI - Equilibrium orientations of non-spherical and chemically anisotropic particles at liquid-liquid interfaces and the effect on emulsion stability. AB - The effective stabilization of emulsions by solid particles, a phenomenon known as Pickering stabilization, is well known to be highly dependent on the wettability and the adhesion energy of the stabilizer employed at the liquid liquid interface. We present a user-friendly computational model that can be used to determine equilibrium orientations and the adhesion energy of colloidal particles at interfaces. The model determines the free energy profile of particle adsorption at liquid-liquid interfaces using a triangular tessellation scheme. We demonstrate the use of the model, using a variety of anisotropic particles and demonstrate its ability to predict and explain experimental observations of particle behaviour at interfaces. In particular, we show that the concept of hydrophilic lipophilic balance commonly applied to molecular surfactants is insufficient to explain the complexity of the activity of colloidal particles at interfaces. In addition, we show the importance of the knowledge of the free energy adsorption profile of single particles at interfaces and the impact on overall free energy of emulsification of packed ensembles of particles. The delicate balance between optimization of adhesion energy, adsorption dynamics and particle packing is shown to be of great importance in the formation of thermodynamically stable emulsions. In order to use the model, the code is implemented by freely available software that can be readily deployed on personal computers. PMID- 25792477 TI - Surface silylation of natural mesoporous/macroporous diatomite for adsorption of benzene. AB - Naturally occurring porous diatomite (Dt) was functionalized with phenyltriethoxysilane (PTES), and the PTES-modified diatomite (PTES-Dt) was characterized using diffuse reflectance Fourier transform infrared spectroscopy, nitrogen adsorption, nuclear magnetic resonance spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis. After silylation, a functional group (-C6H5, phenyl) was successfully introduced onto the surface of Dt. PTES-Dt exhibited hydrophobic properties with a water contact angle (WCA) as high as 120 degrees +/-1 degrees , whereas Dt was superhydrophilic with a WCA of 0 degrees . The benzene adsorption data on both Dt and PTES-Dt fit well with the Langmuir isotherm equation. The Langmuir adsorption capacity of benzene on PTES-Dt is 28.1 mg/g, more than 4-fold greater than that on Dt. Moreover, the adsorption kinetics results show that equilibrium was achieved faster for PTES-Dt than for Dt, over the relative pressure range of 0.118-0.157. The excellent benzene adsorption performance of PTES-Dt is attributed to strong pi-system interactions between the phenyl groups and the benzene molecules as well as to the macroporosity of the PTES-Dt. These results show that the silylated diatomite could be a new and inexpensive adsorbent suitable for use in benzene emission control. PMID- 25792478 TI - Precipitation mechanism of amorphous silica nanoparticles: a simulation approach. AB - HYPOTHESIS: Despite its importance in numerous industrial and natural processes, many unsolved questions remain regarding the mechanism of silica precipitation in aqueous solutions: order of the reaction, role of silica oligomers, existence of an induction time and characteristics of the particle population. This may be traced back, in past models, to the lack of account of the first stages of nucleation, size dependence of the growth law, and full particle population. COMPUTATIONAL METHOD: A microscopic description of the nucleation and growth of amorphous silica nanoparticles is achieved which reproduces a large set of experimental measurements, under various thermodynamic conditions. The time evolution of the solution supersaturation and of the precipitate characteristics is established. FINDINGS: A growth law of order 6 allows reproducing experimental results, without being correlated to the presence of silica oligomers in the aqueous solution. The saturation plateaus are shown not to be due to an induction period. The characteristics of the particle population are more complex than assumed by simple precipitation models (Johnson-Mehl-Avrami-Kolmogorov or Chronomal models) and strongly depend on how supersaturation is reached. Such a microscopic approach thus proves to be well suited to elucidate the mechanism of nanoparticle formation in natural and industrial contexts. PMID- 25792479 TI - Hierarchical Bi based nanobundles: an excellent photocatalyst for visible-light degradation of Rhodamine B dye. AB - Hierarchical Bi based nanobundles were self-assembled via an aqueous reduction approach using hydrazine hydrate as reductive agent, and were used as photocatalysts for the degradation of Rhodamine B (RhB) under visible light. PVP molecules were designed as inducing agent to construct the Bi based nanobundles. The as-obtained samples were characterized by X-ray diffraction (XRD), energy dispersive X-ray (EDX), thermogravimetric-differential thermal analyzer (TG-DTA), infrared spectroscopy (IR) and field emission scanning electron microscopy (FESEM) to get clear information of the crystals. A possible formation mechanism for the interesting architectures was proposed in the paper. The Bi based nanobundles exhibited excellent photocatalytic activity and good cycling performance towards photodegradation of RhB under visible light. The pH-sensitive degradation can reach 96% in degradation rate after 90 min, which indicates potential applications of the Bi based nanobundles on the degradation of organic pollutants. Degradation mechanism is proposed on the combination of Bi and BiOCl crystals. PMID- 25792480 TI - Removal of hydrogen sulfide at ambient conditions on cadmium/GO-based composite adsorbents. AB - Cadmium-based materials with various hydroxide to carbonate ratios and their composites with graphite oxide were synthesized by a fast and simple precipitation procedure and then used as H2S adsorbents at ambient conditions in the dark or upon a visible light exposure. The structural properties and chemical features of the adsorbents were analyzed before and after hydrogen sulfide adsorption. The results showed that the high ratio of hydroxide to carbonate led to an improved H2S adsorption capacity. In moist conditions cadmium hydroxide was the best adsorbent. Moreover, it showed photoactive properties. While the incorporation of a graphene-based phase slightly decreased the extent of the improvement in the H2S adsorption capacity in moist conditions caused by photoactivity, its presence in the composites enhanced the performance in dry conditions. This was linked to photoactivity of CdS that can split H2S resulting in the formation of water in the system. The graphene-based phase enhanced the electron transfer and delayed the recombination of photoinduced charges. Carbonate-based materials showed a very good adsorption capacity in dark conditions in the presence of moisture. Upon the light exposure, CdS likely photocatalyzes the reduction of carbonate ions to formates/formaldehydes. Their deposition on the surface limits the number of sites available to H2S adsorption. PMID- 25792481 TI - Plasticity of motor network and function in the absence of corticospinal projection. AB - Despite the obvious clinical interest, our understanding of how developmental mechanisms are redeployed during degeneration and regeneration after brain and spinal cord injuries remains quite rudimentary. In animal models of spinal cord injury, although spontaneous regeneration of descending axons is limited, compensation by intact corticospinal axons, descending tracts from the brainstem, and local intrinsic spinal networks all contribute to the recovery of motor function. Here, we investigated spontaneous motor compensation and plasticity that occur in the absence of corticospinal tract, using Celsr3|Emx1 mice in which the corticospinal tract is completely and specifically absent as a consequence of Celsr3 inactivation in the cortex. Mutant mice had no paresis, but displayed hyperactivity in open-field, and a reduction in skilled movements in food pellet manipulation tests. The number of spinal motoneurons was reduced and their terminal arbors at neuromuscular junctions were atrophic, which was reflected in electromyography deficits. Rubrospinal projections, calretinin-positive propriospinal projections, afferent innervation of motoneurons by calretinin positive segmental interneurons, and terminal ramifications of monoaminergic projections were significantly increased. Contrary to control animals, mutants also developed a severe and persistent disability of forelimb use following the section of the rubrospinal tract at the C4 spinal level. These observations demonstrate for the first time that the congenital absence of the corticospinal tract induces spontaneous plasticity, both at the level of the motor spinal cord and in descending monoaminergic and rubrospinal projections. Such compensatory mechanisms could be recruited in case of brain or spinal cord lesion or degeneration. PMID- 25792483 TI - Ligand-assisted soft-chemical synthesis of self-assembled different shaped mesoporous Co3O4: efficient visible light photocatalysts. AB - Mesoporous self-assembled cobalt oxide (Co3O4) of different shapes was synthesized by a facile soft-chemical process using cobalt nitrate, oxalic acid and phosphoric acid in the presence of cationic templates, cetyltrimethylammonium bromide, 1-butyl-3-methylimidazolium bromide, and pyridinium bromide at 75 degrees C/2 h followed by calcination at 300 degrees C. The effect of cationic templates of the samples on the physico-chemical properties, and the photocatalytic efficiency for the degradation of Chicago Sky Blue 6B was studied. Pyridinium bromide and 1-butyl-3-methylimidazolium bromide facilitated formation of particles with different shaped morphology compared to cetyltrimethylammonium bromide. The rod-like particles having higher surface area exhibited higher photocatalytic performance. PMID- 25792484 TI - A Rare Case of Upper Gastrointestinal Bleeding: Duodenal Metastasis of Transitional Cell Carcinoma Originating from Renal Pelvis. PMID- 25792482 TI - Molecular regulators of nerve conduction - Lessons from inherited neuropathies and rodent genetic models. AB - Myelinated nerve fibers are highly compartmentalized. Helically wrapped lipoprotein membranes of myelin are integrated with subsets of proteins specifically in each compartment to shape the physiological behavior of these nerve fibers. With the advance of molecular biology and genetics, many functions of these proteins have been revealed over the past decade. In this review, we will first discuss how action potential propagation has been understood by classical electrophysiological studies. In particular, the discussion will be concentrated on how the geometric dimensions of myelinated nerve fibers (such as internodal length and myelin thickness) may affect nerve conduction velocity. This discussion will then extend into how specific myelin proteins may shape these geometric parameters, thereby regulating action potential propagation. For instance, periaxin may specifically affect the internodal length, but not other parameters. In contrast, neuregulin-1 may affect myelin thickness, but not axon diameter or internodal length. Finally, we will discuss how these basic neurobiological observations can be applied to inherited peripheral nerve diseases. PMID- 25792485 TI - Surviving Primary Pancreatic Squamous Cell Carcinoma: A Rare Entity. PMID- 25792486 TI - Comparative study of autologous stromal vascular fraction and adipose-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. AB - The abilities of intracavernous injection of autologous stromal vascular fraction (SVF) and adipose-derived stem cells (ADSCs) to facilitate recovery of erectile function in a rat model of cavernous nerve (CN) injury were compared. Forty male Sprague-Dawley rats were randomly divided into four groups: sham and control groups (intracavernous injection of phosphate-buffered saline), SVF group (intracavernous injection of SVF), and ADSC group (intracavernous injection of ADSCs). Rats in the latter three groups underwent bilateral CN injury prior to injection. The evaluation of erectile function and histomorphometric studies were performed 4 weeks after injection. The ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the control group than in the sham group (0.18 vs. 0.56, p < .001). Intracavernous injection of SVF (0.36, p = .035) significantly improved erectile function compared with that in the control group, whereas the ADSC group (0.35, p = .052) showed marginally significant improvement. The smooth muscle/collagen ratio, smooth muscle content, number of neuronal nitric-oxide synthase-positive nerve fibers, and expression of von Willebrand factor were significantly higher in the SVF and ADSC groups than in the control group. Expression of endothelial nitric-oxide synthase was significantly increased in the SVF group. The increases in the smooth muscle/collagen ratio and von Willebrand factor expression were larger in the SVF group than in the ADSC group. Intracavernous injection of SVF or ADSCs was equally effective in recovering penile erection in a rat model of CN injury. PMID- 25792487 TI - Translating and Transforming Care: People With Brain Injury and Caregivers Filling in a Disability Claim Form. AB - This article examines how the Disability Living Allowance claim form, used in the United Kingdom to allocate L13 billion of disability benefits, translates and transforms disability and care. Twenty-two people with acquired brain injury and their main informal caregivers (n = 44) were video-recorded filling in the disability claim form. Participants disagreed on 26% of the questions, revealing two types of problems. Translation problems arose as participants struggled to provide categorical responses to ambiguous questions and were unable to report contextual variability in care needs or divergences of perception. Transformation problems arose as participants resisted the way in which the form positioned them, forcing them to conceptualize their relationship in terms of dependency and burden. The disability claim form co-opts claimants to translate care and disability into bureaucratically predefined categories, and it transforms the care relationship that it purports to document. PMID- 25792488 TI - Metaphors of Distress: Photo-Elicitation Enhances a Discourse Analysis of Parents' Accounts. AB - In research on sensitive topics, photo-elicitation can be a profound aid to data collection and interpretation processes. Photo-elicitation methods were used in this manner in a discourse analysis of parents' distress at least 6 months after preterm birth. After an initial interview, participants were asked to take digital photographs representing their distress and to return for a second interview to discuss the photographs. The elicited photo representations supported participants' engagement with their current or past distress and generated new meanings from the reappraisal of old photographs. Photo-elicitation demonstrated the embodiment of parents' distress in the child and the placement of distress in specific locations. Photographs of documents showed the power of the written word in generating and maintaining distress. Participants used existing photographs from their child's photo history to generate rich metaphors for their distress as parents. These findings have implications for enhancing interpretive health research by incorporating photo-elicitation methods. PMID- 25792489 TI - Infant dietary patterns and bone mass in childhood: the Generation R Study. AB - Early life nutrition affects peak bone mass attainment. In this prospective cohort study, children with high adherence to a "dairy and whole grains" pattern in infancy had higher bone mineral density at the age of 6 years. Although the observed effects are small, our study provides insight into mechanisms linking early nutrition to bone acquisition in childhood. INTRODUCTION: Nutrition in early life may affect peak bone mass attainment. Previous studies on childhood nutrition and skeletal health mainly focused on individual nutrients, which does not consider the cumulative effects of nutrients. We investigated the associations between dietary patterns in infancy and childhood bone health. METHODS: This study included 2850 children participating in a population-based prospective cohort study. Dietary information was obtained from a food frequency questionnaire at the age of 13 months. Using principal component analysis, three major dietary patterns were extracted, explaining in total 30% of the variation in dietary intake. At the age of 6 years, a total body dual-energy X-ray absorptiometry (DXA) scan was performed, and bone mineral density (BMD), bone mineral content (BMC), area-adjusted BMC (aBMC), and bone area (BA) were analyzed. RESULTS: Higher adherence score to a "dairy and whole grains" pattern was positively associated with BMD and aBMC, but not with BMC and BA. Accordingly, children in the highest quartile of the "dairy and whole grains" pattern had higher BMD (difference 3.98 mg/cm(2), 95% confidence interval (CI) 0.36 to 7.61) and aBMC (difference 4.96 g, 95% CI 1.27 to 8.64) than children in the lowest quartile. Stratification for vitamin D supplementation showed that the positive associations between the "dairy and whole grains" pattern and bone outcomes were only observed in children who did not receive vitamin D supplementation. A "potatoes, rice, and vegetables" and a "refined grains and confectionery" pattern were not consistently associated with bone outcomes. CONCLUSIONS: An infant dietary pattern characterized by high intakes of dairy and cheese, whole grains, and eggs is positively associated with bone development in childhood. Further research is needed to investigate the consequences for bone health in later life. PMID- 25792490 TI - District nurses' perceptions of osteoporosis management: a qualitative study. AB - Underdiagnosis of osteoporosis is common. This study investigated Swedish district nurses' perceptions of osteoporosis management. They perceived the condition as having low priority, and the consequences of this perception were insufficient awareness of the condition and perceptions of bone-specific medication as unsafe. They perceived, though, competency when working with fall prevention. INTRODUCTION: Undertreatment of patients with osteoporosis is common. Sweden's medical care strategy dictates prioritisation of various conditions; while guidelines exist, osteoporosis is not prioritised. The aim of this study was to investigate district nurses' perceptions of osteoporosis management within Sweden's primary health care system. METHODS: Four semi-structured focus group interviews were conducted with 13 female district nurses. The interviews were analysed using thematic analysis. RESULTS: The overall theme was perceiving osteoporosis management as ambiguous. The themes were perceiving barriers and perceiving opportunities. These subthemes were linked to perceiving barriers: (i) insufficient procedures, lack of time and not aware of the condition; (ii) insufficient knowledge about diagnosis and about fracture risk assessment tools; (iii) low priority condition and unclear responsibility for osteoporosis management; and (iv) bone-specific medication was sometimes perceived to be unsafe. These subthemes were linked to perceiving opportunities: (i) professional competency when discussing fall prevention in home visit programs, (ii) willingness to learn more about osteoporosis management, (iii) collaboration with other professionals and (iv) willingness to identify individuals at high risk of fracture. CONCLUSIONS: Osteoporosis was reported, by the district nurses, to be a low-priority condition with consequences being unawareness of the condition, insufficient knowledge about bone-specific medications, fracture risk assessment tools and procedures. These may be some of the explanations for the undertreatment of osteoporosis. At the same time, the district nurses described competency performing the home visits, which emerged as an optimal opportunity to discuss fall prevention and to introduce FRAX with the aim to identify individuals at high risk of fracture. PMID- 25792491 TI - Changes in quality of life associated with fragility fractures: Australian arm of the International Cost and Utility Related to Osteoporotic Fractures Study (AusICUROS). AB - We investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture. PURPOSE: We aimed to quantify the change in health-related quality of life (HRQoL) that occurred as a consequence of a fracture using the EQ-5D-3 L questionnaire. METHODS: Adults aged >=50 years with a low to moderate energy fracture were recruited from eight study centres across Australia. This prospective study included an 18-month follow-up of participants recruited within 2 weeks of a fracture (hip, wrist, humerus, vertebral and ankle). Information collected at baseline and 4, 12 and 18 months included characteristics of participants such as income level, education and prior fracture status. At 12 months post-fracture, the cumulative loss of quality of life was estimated using multivariate regression analysis to identify the predictors of HRQoL loss. RESULTS: Mean HRQoL for all participants before fracture was 0.86, with wrist fracture having the highest pre-fracture HRQoL (0.90), while vertebral fracture had the lowest (0.80). HRQoL declined to 0.42 in the immediate post-fracture period. Only participants with a wrist, humerus or ankle fracture returned to their pre-fracture HRQoL after 18 months. An increased loss of HRQoL over 12 months was associated with HRQoL prior to the fracture, hospitalisation, education and fracture site. The multiple regression explained 30 % of the variation in the cumulative HRQoL loss at 12 months post-fracture for all fractures. CONCLUSION: Low to moderate energy fractures reduce HRQoL, and this loss is sustained for at least 12 months or, in the case of hip and spine fractures, at least 18 months. At a population level, this represents an average loss of 65 days in full health per fragility fracture. This significant burden reinforces the need for cost-effective fracture prevention strategies. PMID- 25792492 TI - Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled clinical trial. AB - In postmenopausal women with low bone mass and hormone-receptor-positive breast cancer on an aromatase inhibitor, risedronate maintained skeletal health assessed by bone density and turnover markers. Women with the greatest decreases in bone turnover markers at 12 months had the greatest increases in bone density at 24 months. INTRODUCTION: Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if (1) oral bisphosphonate therapy can prevent bone loss in women on an AI and (2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD). METHODS: We conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) for hormone-receptor-positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo, and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)], and safety. RESULTS: Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 +/- 0.7 percentage points at the spine and 3.2 +/- 0.5 percentage points at the hip (both p < 0.05). The adjusted difference between the active treatment and placebo groups were 0.09 +/- 0.04 nmol/LBCE for CTX and 23.3 +/- 4.8 MUg/mL for P1NP (both p < 0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD (p < 0.05). The oral therapy was safe and well tolerated. CONCLUSION: In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health. PMID- 25792493 TI - Inadequate management for secondary fracture prevention in patients with distal radius fracture by trauma surgeons. AB - We evaluated the secondary fracture prevention in 1445 patients with distal radius fracture by trauma surgeons. The rate of patients with distal radius fracture who underwent bone mineral density (BMD) examination was low, suggesting that appropriate treatment for osteoporosis by trauma surgeons is not performed at present. INTRODUCTION: To clarify the status of osteoporosis interventions after distal radial fractures by trauma surgeons who play the main role in treatment for these fractures, we performed a survey involving multiple institutions in Japan. METHODS: We asked 155 board members of the Japanese Society for Fracture Repair for their cooperation and performed a survey in 48 institutions with which members who gave cooperation were affiliated. The subjects consisted of consecutive patients with distal radial fractures occurring between January and December 2012. The presence or absence of a diagnosis of osteoporosis and bone mineral density examination after fracture was investigated. RESULTS: A total of 1445 patients with distal radial fractures were evaluated in this study. BMD examination for diagnosis and treatment for osteoporosis after fracture was performed respectively in 126 (8.7 %) and 193 (13.4 %) of 1445 patients. Treatment for osteoporosis was performed in 93 (73.8 %) of 126 patients who underwent BMD examination after fracture and 100 (8.2 %) of 1219 who did not undergo BMD examination. Of the 126 patients who underwent BMD examination after fracture, 89 showed a BMD <80 % of the young adult mean as a criterion for the initiation of drug treatment for osteoporosis in Japan and 77 (86.5 %) of the 89 patients were treated with drugs. CONCLUSIONS: The rate of patients with distal radial fractures who underwent BMD examination was low, suggesting that appropriate treatment for osteoporosis by trauma surgeons is not performed at present. PMID- 25792494 TI - Vertebroplasty increases trabecular microfractures in elderly female cadaver spines. AB - This study assessed whether vertebroplasty increases trabecular bone microfractures in adjacent vertebrae of elderly female cadavers. Results indicated microfractures were almost two times greater in superior adjacent vertebrae for vertebroplasty treated spines compared to non-treated controls. This finding may aid in developing improved treatments for osteoporotic women with vertebral fractures. INTRODUCTION: Although vertebroplasty may stabilize compression fractures and reduce pain, subsequent vertebral fractures occur in approximately 25 % of patients, reducing the overall safety of this procedure. This is particularly a concern in vertebrae surrounding the treated level where bone cement may cause abnormal transfer of forces to adjacent spinal structures. Therefore, the objective of this study was to quantify the effects of vertebroplasty on local trabecular bone damage in adjacent vertebrae. METHODS: Five level motion segments (T11-L3) from osteopenic/osteoporotic female cadaver spines (T-score -2.9 +/- 1.0) were assigned into either vertebroplasty or control (no vertebroplasty) groups (n = 10/group) such that T-score, trabecular microarchitecture, and age were similar between groups. Compression fractures were created in the L 1 vertebra of all specimens and PMMA bone cement was injected into the fractured vertebra of vertebroplasty specimens. All spine segments were subjected to cyclic axial compression (685-1370 N) for 115,000 cycles. Post-testing, trabecular cubes were cut from adjacent (T12 and L2) vertebral bodies and histologically processed. Trabecular microfractures were identified and normalized by bone area in each section. RESULTS: There were significantly more trabecular microfractures (p < 0.001) in superior adjacent vertebral bodies of the vertebroplasty group (0.091 +/- 0.025 microfractures/mm(2)) when compared to the control group (0.049 +/- 0.018 microfractures/mm(2)). However, there was no difference in trabecular microfractures (p = 0.835) between vertebroplasty (0.045 +/- 0.022 microfractures/mm(2)) and control groups (0.035 +/- 0.013 microfractures/mm(2)) for inferior adjacent vertebral bodies. CONCLUSIONS: Vertebroplasty specifically impacts the superior adjacent vertebrae of elderly female spines resulting in almost two times more trabecular microfractures when compared to non-treated controls. PMID- 25792495 TI - Combined double tarsal wedge osteotomy and transcuneiform osteotomy for correction of resistant club foot deformity (the bean-shaped foot). PMID- 25792496 TI - Targeting DNA methylation with green tea catechins. AB - Aberrant epigenetic alterations in the genome such as DNA methylation play a significant role in cancer development. Green tea catechins have been reported to modulate epigenetic processes. This review aims to synthesize evidence on the modulation of DNA methylation by green tea catechins. Green tea catechins have been reported to reverse DNA methylation of tumor suppressor genes and increase transcription of these genes. Green tea catechins and especially epigallocatechin gallate modulate DNA methylation by attenuating the effect of DNA methyltransferase 1 (DNMT1). However, the exact mechanism of DNMT1 inhibition is not delineated. Suggested mechanisms include direct enzymatic inhibition, indirect enzymatic inhibition, reduced DNMT1 expression and translation. The possible effect of green tea catechins on other pathways of DNA methylation, i.e. methyl-CpG binding domain proteins, has not been investigated. Furthermore, the link between redox properties and epigenetic modulation by green tea catechins has not been defined either. Since green tea catechins are natural compounds with a rather acceptable safety profile, further research on their action as inhibitors of DNA methylation seems worthwhile. PMID- 25792497 TI - Transcriptome comparison of the sex pheromone glands from two sibling Helicoverpa species with opposite sex pheromone components. AB - Differences in sex pheromone component can lead to reproductive isolation. The sibling noctuid species, Helicoverpa armigera and Helicoverpa assulta, share the same two sex pheromone components, Z9-16:Ald and Z11-16:Ald, but in opposite ratios, providing an typical example of such reproductive isolation. To investigate how the ratios of the pheromone components are differently regulated in the two species, we sequenced cDNA libraries from the pheromone glands of H. armigera and H. assulta. After assembly and annotation, we identified 108 and 93 transcripts putatively involved in pheromone biosynthesis, transport, and degradation in H. armigera and H. assulta, respectively. Semi-quantitative RT PCR, qRT-PCR, phylogenetic, and mRNA abundance analyses suggested that some of these transcripts involved in the sex pheromone biosynthesis pathways perform. Based on these results, we postulate that the regulation of desaturases, KPSE and LPAQ, might be key factor regulating the opposite component ratios in the two sibling moths. In addition, our study has yielded large-scale sequence information for further studies and can be used to identify potential targets for the bio-control of these species by disrupting their sexual communication. PMID- 25792498 TI - Antioxidant, antiradical, and anticholinergic properties of cynarin purified from the Illyrian thistle (Onopordum illyricum L.). AB - Cynarin is a derivative of hydroxycinnamic acid and it has biologically active functional groups constituent of some plants and food. We elucidated the antioxidant activity of cynarin by using different in vitro condition bioanalytical antioxidant assays like DMPD(*+), ABTS(*+), O2(*-), DPPH(*) and H2O2 scavenging effects, the total antioxidant influence, reducing capabilities, Fe(2+) chelating and anticholinergic activities. Cynarin demonstrated 87.72% inhibition of linoleic acid lipid peroxidation at 30 ug/mL concentration. Conversely, some standard antioxidants like trolox, alpha-tocopherol, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA) exhibited inhibitions of 90.32, 75.26, 97.61, 87.30%, and opponent peroxidation of linoleic acid emulsion at the identical concentration, seriatim. Also, cynarin exhibited effective DMPD(*+), ABTS(*+), O2(*-), DPPH(*), and H2O2 scavenging effects, reducing capabilities and Fe(2+) chelating effects. On the contrary, IC50 and K(i) parameters of cynarin for acetylcholinesterase enzyme inhibition were determined as 243.67 nM (r(2): 0.9444) and 39.34 +/- 13.88 nM, respectively. This study clearly showed that cynarin had marked antioxidant, anticholinergic, reducing ability, radical-scavenging, and metal-binding activities. PMID- 25792499 TI - Search for human DNA topoisomerase II poisons in the group of 2,5-disubstituted 1,3,4-thiadiazoles. AB - A series of six 2,5-disubstituted 1,3,4-thiadiazole derivatives was synthesized and examined for cytotoxic activity in MCF-7 and MDA-MB-231 breast cancer cells. MTT assay confirmed that 2-(3-fluorophenylamino)-5-(3-hydroxyphenyl)-1,3,4 thiadiazole (2), 2-(4-bromophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (3), 2-(4-fluorophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (4), had ability to inhibit MCF-7 and MDA-MB-231 cells proliferation. The IC50 values for the mentioned compounds ranged between 120 and 160 MUM (with respect to MCF-7 cells) and from 70 to 170 MUM (with respect to MDA-MB-231 cells). It turned out, moreover, that compound 2 is a human topoisomerase II (topoII) catalytic inhibitor whereas the two other compounds (i.e. 3 and 4) are capable of stabilizing DNA-topoII cleavage complex and thus are topoII poisons. PMID- 25792500 TI - Synthesis and inhibition potency of novel ureido benzenesulfonamides incorporating GABA as tumor-associated carbonic anhydrase IX and XII inhibitors. AB - New ureido benzenesulfonamides incorporating a GABA moiety as a linker between the ureido and the sulfonamide functionalities were synthesized and their inhibition potency determined against both the predominant cytosolic (hCA I and II) and the transmembrane tumor-associated (hCA IX and XII) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The majority of these compounds were medium potency inhibitors of the cytosolic isoform hCA I and effective hCA II inhibitors, whereas they showed strong inhibition of the two transmembrane tumor-associated isoforms hCA IX and XII, with KIs in nanomolar range. Only one derivative had a good selectivity for inhibition of the tumor associated hCA IX target isoform over the cytosolic and physiologically dominant off-target hCA I and II, being thus a potential tool to develop new anticancer agents. PMID- 25792501 TI - An alternative purification method for human serum paraoxonase 1 and its interactions with anabolic compounds. AB - In this study, an alternative purification method for human paraoxonase 1 (hPON1) enzyme was developed using two-step procedures, namely, ammonium sulfate precipitation and Sepharose-4B-L-tyrosine-3-aminophenantrene hydrophobic interaction chromatography. SDS-polyacrylamide gel electrophoresis of the enzyme indicates a single band with an apparent M(W) of 43 kDa. The enzyme was purified 219-fold with a final specific activity of 4,408,400 U/mg and a yield of 10%. Furthermore, we examined the in vitro effects of some anabolic compounds, such as zeranol, 17 beta-estradiol, diethylstilbestrol, oxytocin, and trenbolone on the enzyme activity to understand the better inhibitory properties of these molecules. The five anabolic compounds dose dependently decreased the activity of hPON1 with inhibition constants in the millimolar-micromolar range. The results show that these compounds exhibit inhibitory effects on hPON1 at low concentrations with IC50 values ranging from 0.064 to 16.900 uM. PMID- 25792502 TI - Crocus cancellatus subsp. damascenus stigmas: chemical profile, and inhibition of alpha-amylase, alpha-glucosidase and lipase, key enzymes related to type 2 diabetes and obesity. AB - Spices are appreciated for their medicinal properties besides their use as food adjuncts to enhance the sensory quality of food. In this study, Crocus cancellatus subsp. damascenus was investigated for its antioxidant activities employing different in vitro systems. Stigma extract demonstrated a radical scavenging activity against both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2' azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals with IC50 values of 34.6 and 21.6 ug/mL and a good ferric reducing ability (53.9 uM Fe(II)/g). In order to clarify the potential functional properties of this spice, the carbohydrate-hydrolysing enzymes and pancreatic lipase inhibitory properties were investigated. Crocus cancellatus subsp. damascenus extract inhibited alpha amylase and alpha-glucosidase with IC50 values of 57.1 and 68.6 ug/mL, respectively. The bioactivity was discussed in terms of phytochemicals content. The obtained results may be of interest from a functional point of view or as food additive and to promote the revalorization of this species. PMID- 25792503 TI - Pyrazolo[1,5-a]quinazoline scaffold as 5-deaza analogue of pyrazolo[5,1 c][1,2,4]benzotriazine system: synthesis of new derivatives, biological activity on GABAA receptor subtype and molecular dynamic study. AB - To investigate the binding affinity of GABAA receptor subtype, new pyrazolo [1,5 a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5 unsubstituted new derivative, compound 15, has receptor recognition (Ki = 834.7 nM). PMID- 25792504 TI - N-glycosyl-N-hydroxysulfamides as potent inhibitors of Brucella suis carbonic anhydrases. AB - We investigated a series of N-hydroxysulfamides obtained by Ferrier sulfamidoglycosylation for the inhibition of two bacterial carbonic anhydrases (CAs, EC 4.2.1.1) present in the pathogen Brucella suis. bsCA I was moderately inhibited by these compounds with inhibition constants ranging between 522 and 958 nM and no notable differences of activity between the acetylated or the corresponding deacetylated derivatives. The compounds incorporating two trans acetates and the corresponding deprotected ones were the most effective inhibitors in the series. bsCA II was better inhibited, with inhibition constants ranging between 59.8 and 799 nM. The acetylated derivatives were generally better bsCA II inhibitors compared to the corresponding deacetylated compounds. Although these compounds were not highly isoform-selective CA inhibitors (CAIs) for the bacterial over the human CA isoforms, some of them possess inhibition profiles that make them interesting leads for obtaining better and more isoform-selective CAIs targeting bacterial enzymes. PMID- 25792506 TI - Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease. AB - A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis. PMID- 25792505 TI - Biological evaluation and molecular modelling study of thiosemicarbazide derivatives as bacterial type IIA topoisomerases inhibitors. AB - In the present article, we describe the inhibitory potency of nine thiosemicarbazide derivatives against bacterial type IIA topoisomerases, their antibacterial profile and molecular modelling evaluation. We found that one of the tested compounds, compound 7, significantly inhibits activity of Staphylococcus aureus DNA gyrase with an IC(50) below 15 MUM. Besides, this compound displays antibacterial activity on reference Staphylococuss spp. and Enterococcus faecalis strains as well as clinical S. aureus isolates at non cytotoxic concentrations in mammalian cells with MIC values ranging from 16 to 32 MUg/mL thereby indicating, in some cases, equipotent or even more effective action than standard drugs such as vancomycin, ampicillin and nitrofurantoin. The computational studies showed that both molecular geometry and the electron density distribution have a great impact on antibacterial activity of thiosemicarbazide derivatives. PMID- 25792508 TI - High-resolution mapping of scar-related atrial arrhythmias using smaller electrodes with closer interelectrode spacing. AB - BACKGROUND: The resolution of mapping is influenced by electrode size and interelectrode spacing. Smaller electrodes with closer interelectrode spacing may improve mapping resolution, particularly in scar. The aims of this study were to establish normal electrogram criteria in the atria for both 3.5-mm electrode tip linear catheters (Thermocool) and 1-mm multielectrode-mapping catheters (Pentaray) and to compare their mapping resolution in scar-related atrial arrhythmias. METHODS AND RESULTS: Normal voltage amplitude cutoffs for both catheters were validated in 10 patients with structurally normal atria. In 20 additional patients with scar-related atrial arrhythmias, similar sequential mapping with both catheters was performed. Normal bipolar voltage amplitude was similar between 3.5- and 1-mm electrode catheters with a fifth percentile of 0.48 and 0.52 mV, respectively (P=0.65). In patients with scar-related atrial arrhythmias, the total area of bipolar voltage <0.5 mV measured using 1-mm electrode catheters was smaller than that measured using 3.5-mm catheter (14.7 versus 20.4 cm2; P=0.02). The mean bipolar voltage amplitude in this area of low voltage was significantly higher with 1-mm electrode catheters (0.28 and 0.17 mV; P=0.01). Importantly, 54.4% of all low voltage data points recorded with 1-mm electrode catheter had distinct electrograms that allowed annotation of local activation time compared with only 21.4% with 3.5-mm electrode tip catheters (P=0.01). Overdrive pacing with capture of the tachycardia from within the area of low voltage was more frequent with 1-mm electrode catheters (66.7 versus 33.4; P=0.01). CONCLUSIONS: Mapping with small closely spaced electrode catheters can improve mapping resolution within areas of low voltage. PMID- 25792510 TI - Retraction Note to: Total knee arthroplasty performed with either a mini subvastus or a standard approach: a prospective randomized controlled study with a minimum follow-up of 2 years. PMID- 25792509 TI - Orcokinin-like immunoreactivity in central neurons innervating the salivary glands and hindgut of ixodid ticks. AB - Orcokinins are conserved neuropeptides within the Arthropoda but their cellular distribution and functions in ticks are unknown. We use an antibody against the highly conserved N-terminal (NFDEIDR) of mature orcokinin peptides to examine their distribution in six ixodid species: Amblyomma variegatum, Dermacentor reticulatus, Hyalomma anatolicum, Ixodes scapularis, Ixodes ricinus and Rhipicephalus appendiculatus. Numerous immunoreactive neurons (~100) were detected in various regions of the synganglion (central nervous system) in all examined tick species. Immunoreactive projections of two prominent groups of efferent neurons in the post-oesophageal region were examined in detail: (1) neurons innervating the salivary glands; (2) neurons innervating the hindgut. Using matrix-assisted laser desorption/ionisation-time-of-flight (MALDI-TOF), we detected orcokinin peaks in extracts of the synganglia and hindguts but not in the salivary glands of I. scapularis females. Our data provide further evidence of the presence of orcokinin in ixodid ticks and establish a morphological basis for functional studies of identified peptidergic neuronal networks. PMID- 25792507 TI - Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2-P4 study. AB - Enterovirus 71 (EV71) is a highly infectious pathogen primarily responsible for Hand, Foot, and Mouth Disease, particularly among children. Currently, no approved antiviral drug has been developed against this disease. The EV71 3C protease is deemed an attractive drug target due to its crucial role in viral polyprotein processing. Rupintrivir, a peptide-based inhibitor originally developed to target the human rhinovirus 3C protease, was found to inhibit the EV71 3C protease. In this communication, we report the inhibitory activities of 30 Rupintrivir analogs against the EV71 3C protease. The most potent inhibitor, containing a P2 ring-constrained phenylalanine analog (compound 9), was found to be two-fold more potent than Rupintrivir (IC50 value 3.4 +/- 0.4 versus 7.3 +/- 0.8 MUM). Our findings suggest that employing geometrically constrained residues in peptide-based protease inhibitors can potentially enhance their inhibitory activities. PMID- 25792511 TI - Quorum-sensing linked RNA interference for dynamic metabolic pathway control in Saccharomyces cerevisiae. AB - Some of the most productive metabolic engineering strategies involve genetic modifications that cause severe metabolic burden on the host cell. Growth limiting genetic modifications can be more effective if they are 'switched on' after a population growth phase has been completed. To address this problem we have engineered dynamic regulation using a previously developed synthetic quorum sensing circuit in Saccharomyces cerevisiae. The circuit autonomously triggers gene expression at a high population density, and was linked with an RNA interference module to enable target gene silencing. As a demonstration the circuit was used to control flux through the shikimate pathway for the production of para-hydroxybenzoic acid (PHBA). Dynamic RNA repression allowed gene knock downs which were identified by elementary flux mode analysis as highly productive but with low biomass formation to be implemented after a population growth phase, resulting in the highest published PHBA titer in yeast (1.1mM). PMID- 25792512 TI - Anti-cancer activity of pegylated liposomal trans-anethole on breast cancer cell lines MCF-7 and T47D. AB - OBJECTIVE: To examine the role of liposomes for the encapsulation of drugs and their suitability for chemotherapy of breast cancer. RESULTS: Pegylated liposomal trans-anethole nanoparticles were synthesized through a reverse-phase evaporation technique. Nanoparticles were characterized in terms of mean diameter, size distribution, zeta potential, encapsulation and drug loading efficiency, drug release pattern and cytotoxicity effects. Size and zeta potential of pegylated nanoliposomal drug and blank pegylated nanoliposomal were 257 nm and -28 mV; 35.7 nm and -21 mV, respectively. Encapsulation and drug loading efficiency were 78 +/ 2.5 and 2.3 +/- 4.1 %, respectively. There was a 57 % release of trans-anethole from pegylated liposomal nanoparticles in 48 h. Compared to free drug, toxicological studies indicated around 9- and 8-fold cytotoxicity effect against MCF-7 and T47D cell lines respectively. CONCLUSIONS: PEG-liposomes provided a high stability and slow release of trans-anethole in two cancer cell lines. PMID- 25792513 TI - Plants and endophytes: equal partners in secondary metabolite production? AB - Well known plant production systems should be re-evaluated due to findings that the interesting metabolite might actually be produced by microbes intimately associated with the plant, so-called endophytes. Endophytes can be bacteria or fungi and they are characterized usually by the feature that they do not cause any harm to the host. Indeed, in some cases, such as mycorrhizal fungi or other growth promoting endophytes, they can be beneficial for the plant. Here some examples are reviewed where the host plant and/or endophyte metabolism can be induced by the other partner. Also, partial or complete biosynthesis pathways for plant secondary metabolites can be attributed to such endophytes. In other cases the host plant is able to metabolize substances from fungal origin. The question of the natural role of such metabolic changes for the endophyte will be briefly touched. Finally, the consequences for the use of plant cultures for secondary metabolite production is discussed. PMID- 25792514 TI - Emodin protects against concanavalin A-induced hepatitis in mice through inhibiting activation of the p38 MAPK-NF-kappaB signaling pathway. AB - BACKGROUND/AIMS: To investigate the effects of emodin on concanavalin A (Con A) induced hepatitis in mice and to elucidate its underlying molecular mechanisms. METHODS: A fulminant hepatitis model was established successfully by the intravenous administration of Con A (20 mg/kg) to male Balb/c mice. Emodin was administered to the mice by gavage before and after Con A injection. The levels of pro-inflammatory cytokines and chemokines, numbers of CD4(+) and F4/80(+) cells infiltrated into the liver, and amounts of phosphorylated p38 MAPK and NF kappaB in mouse livers and RAW264.7 and EL4 cells were measured. RESULTS: Pretreatment with emodin significantly protected the animals from T cell-mediated hepatitis, as shown by the decreased elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as reduced hepatic necrosis. In addition, emodin pretreatment markedly reduced the intrahepatic expression of pro-inflammatory cytokines and chemokines, including tumor necrosis factor (TNF) alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6, IL-12, inducible nitric oxide synthase (iNOS), integrin alpha M (ITGAM), chemokine (C-C motif) ligand 2 (CCL2), macrophage inflammatory protein 2 (MIP-2) and chemokine (CXC motif) receptor 2 (CXCR2). Furthermore, emodin pretreatment dramatically suppressed the numbers of CD4(+) and F4/80(+) cells infiltrating into the liver as well as the activation of p38 MAPK and NF-kappaB in Con A-treated mouse livers and RAW264.7 and EL4 cells. CONCLUSION: The results indicate that emodin pretreatment protects against Con A-induced liver injury in mice; these beneficial effects may occur partially through inhibition of both the infiltration of CD4(+) and F4/80(+) cells and the activation of the p38 MAPK-NF kappaB pathway in CD4(+) T cells and macrophages. PMID- 25792516 TI - The proposed planning method as a parallel element to a real service system for dynamic sharing of service lines. AB - This paper presents a solution to the bottleneck problem with dynamic sharing or leasing of service capacities. From this perspective the use of the proposed method as a parallel element in service capacities sharing is very important, because it enables minimization of the number of interfaces, and consequently of the number of leased lines, with a combination of two service systems with time opposite peak loads. In this paper we present a new approach, methodology, models and algorithms which solve the problems of dynamic leasing and sharing of service capacities. PMID- 25792517 TI - Adaptive control for a class of MIMO nonlinear time delay systems against time varying actuator failures. AB - This paper investigates an adaptive controller for a class of Multi Input Multi Output (MIMO) nonlinear systems with unknown parameters, bounded time delays and in the presence of unknown time varying actuator failures. The type of considered actuator failure is one in which some inputs may be stuck at some time varying values where the values, times and patterns of the failures are unknown. The proposed approach is constructed based on a backstepping design method. The boundedness of all the closed-loop signals is guaranteed and the tracking errors are proved to converge to a small neighborhood of the origin. The proposed approach is employed for a double inverted pendulums benchmark and a chemical reactor system. The simulation results show the effectiveness of the proposed method. PMID- 25792518 TI - A composite controller for trajectory tracking applied to the Furuta pendulum. AB - In this paper, a new composite scheme is proposed, where the total control action is composed of the sum of a feedback-linearization-based controller and an energy based compensation. This new proposition is applied to the rotary inverted pendulum or Furuta pendulum. The Furuta pendulum is a well-known underactuated mechanical system with two degrees of freedom. The control objective in this case is the tracking of a desired periodic trajectory in the actuated joint, while the unactuated link is regulated at the upward position. The closed-loop system is analyzed showing uniformly ultimately boundedness of the error trajectories. The design procedure is shown in a constructive form, such that it may be applied to other underactuated mechanical systems, with the proper definitions of the output function and the energy function. Numerical simulations and real-time experiments show the practical viability of the controller. Finally, the proposed algorithm is compared with a tracking controller previously reported in the literature. The new algorithm shows better performance in both arm trajectory tracking and pendulum regulation. PMID- 25792519 TI - A nanoglass alloying immiscible Fe and Cu at the nanoscale. AB - Synthesized from ultrafine particles with a bottom-up approach, nanoglasses are of particular importance in pursuing unique properties. Here, we design a metallic nanoglass alloy from two components of ~Cu64Sc36 and ~Fe90Sc10 nanoglasses. With nanoalloying mutually immiscible Fe and Cu, the properties of the nanoglass alloys can be tuned by varying the proportions of the ~Fe90Sc10 component. This offers opportunity to create novel metallic glass nanocomposites and sheds light on building a structure-property correlation for the nanoglass alloys. PMID- 25792520 TI - Occurrence of eight UV filters in beaches of Gran Canaria (Canary Islands). An approach to environmental risk assessment. AB - Due to the growing concern about human health effects of ultraviolet (UV) radiation, the use of UV filters has increased in recent decades. Unfortunately, some common UV filters are bioaccumulated in aquatic organisms and show a potential for estrogenic activity. The aim of the present study is to determine the presence of some UV filters in the coastal waters of six beaches around Gran Canaria Island as consequence of recreational seaside activities. Eight commonly used UV filters: benzophenone-3 (BP-3), octocrylene (OC), octyl-dimethyl-PABA (OD PABA), ethylhexyl methoxy cinnamate (EHMC), homosalate (HMS), butyl methoxydibenzoyl methane (BMDBM), 4-methylbenzylidene camphor (4-MBC) and diethylamino hydroxybenzoyl hexyl benzoate (DHHB), were monitored and, with the exception of OD-PABA, all were detected in the samples collected. 99% of the samples showed some UV filters and concentration levels reached up to 3316.7 ng/L for BP-3. Environmental risk assessment (ERA) approach showed risk quotients (RQ) higher than 10, which means that there is a significant potential for adverse effects, for 4-MBC and EHMC for those samples with highest levels of UV filters. PMID- 25792515 TI - Generating human intestinal tissues from pluripotent stem cells to study development and disease. AB - As one of the largest and most functionally complex organs of the human body, the intestines are primarily responsible for the breakdown and uptake of macromolecules from the lumen and the subsequent excretion of waste from the body. However, the intestine is also an endocrine organ, regulating digestion, metabolism, and feeding behavior. Intricate neuronal, lymphatic, immune, and vascular systems are integrated into the intestine and are required for its digestive and endocrine functions. In addition, the gut houses an extensive population of microbes that play roles in digestion, global metabolism, barrier function, and host-parasite interactions. With such an extensive array of cell types working and performing in one essential organ, derivation of functional intestinal tissues from human pluripotent stem cells (PSCs) represents a significant challenge. Here we will discuss the intricate developmental processes and cell types that are required for assembly of this highly complex organ and how embryonic processes, particularly morphogenesis, have been harnessed to direct differentiation of PSCs into 3-dimensional human intestinal organoids (HIOs) in vitro. We will further describe current uses of HIOs in development and disease research and how additional tissue complexity might be engineered into HIOs for better functionality and disease modeling. PMID- 25792521 TI - Exon4 amelogenin transcripts in enamel biomineralization. AB - Amelogenins are proteins formed by alternative splicing of the amelogenin gene, and are essential for tooth enamel formation. However, the unique functions of various alternatively spliced amelogenins in enamel formation are not well understood. In this study, we determined the spatiotemporal location of amelogenins derived from transcripts containing exon4 (AMG+4) in the enamel matrix, and the relative binding of recombinant AMG+4 to hydroxyapatite (HAP). Immunohistochemistry and mass spectrometry analyses showed that AMG+4 proteins were secreted into the enamel matrix at the early maturation stage. A stage specific increase in the synthesis of AMG+4 was further supported by our observation that in mice overexpressing leucine-rich amelogenin peptide (TgLRAP), in which ameloblasts differentiate earlier, AMG+4 transcripts were also upregulated earlier. In vitro binding studies, supported by in silico modeling of protein binding to calcium and phosphate, showed that more recombinant AMG+4 bound to hydroxyapatite (HAP) as compared with recombinant AMG-4. The temporal and spatial localization of amelogenins containing exon4 peptide, and their functional differences in HAP binding, suggests that the unique properties of amelogenins containing exon4 cause a specific enhancement of biomineralization related to stabilization of early-formed HAP at the maturation stage. PMID- 25792523 TI - Residents' reluctance to challenge negative hierarchy in the operating room: a qualitative study. AB - PURPOSE: Our aim was to clarify how hierarchy influences residents' reluctance to challenge authority with respect to clearly erroneous medical decision-making. METHODS: After research ethics approval, we recruited 44 anesthesia residents for a high-fidelity simulation scenario at two Ontario universities. During the scenario, an actor, whom the residents were told was an actual new staff anesthesiologist at their university, asked the trainees to give blood to a Jehovah's Witness in contradiction to the patient's explicitly stated wishes. Following the case, the trainees were debriefed and were interviewed for 30-40 min. The interviews were audio recorded and transcribed verbatim, and the text was coded using a qualitative approach informed by grounded theory. RESULTS: Qualitative analysis of the participants' interviews yielded rich descriptive accounts of hierarchical influences often characterized by fear and intimidation. Residents spoke about their coping strategies, which included adaptability, avoiding conflict, using inquiry as a method for patient advocacy, and relying on a diffusion of responsibility within the larger operating room team. CONCLUSIONS: Study results showed that hierarchy played a dominant role in the functioning of the operating room. Participants spoke of both the positive and negative effects of such a hierarchical learning environment. The majority of participants described a negative perception of hierarchy as the norm, and they employed many coping strategies. This study provides insight into how a negative hierarchical culture can adversely impact patient safety, resident learning, and team functioning. We propose a theoretical model to describe challenging authority in this context. PMID- 25792522 TI - Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. AB - Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions. PMID- 25792524 TI - Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells. AB - We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4(+)T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naive T cells, but also bound to PD-L1 and prevented tumor cell expressed PD-L1 from binding to its receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNgamma production by both human and murine PD-1(+) activated T cells in the presence of PD-L1(+) human or mouse tumor cells, respectively. In vitro studies with human tumor cells indicated that CD80-Fc was more effective than antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNgamma. Additionally, in vivo studies with a murine tumor demonstrated that CD80-Fc was more effective than antibodies to PD L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating tumor-reactive T cells. PMID- 25792525 TI - Prophylaxis of migraine in children and adolescents. AB - While it has been established that headaches in the pediatric age group are relatively common, the characterization of headache disorders and their treatment in this group has historically been limited. Due to the paucity of controlled studies on prophylaxis of the primary headache disorders in children, the diagnosis of migraine often rests on criteria similar to those used in adults. Data from adult studies are often extrapolated and applied to the pediatric patient. Although it appears that many prophylactic agents are safe, well tolerated and efficacious in children, currently only topiramate is FDA-approved for use in patients 12 years and over. As a result, despite often experiencing significant disability, many children who present to their physician with migraines do not receive preventive therapy. One-third of adolescents meet the criteria for warranting prophylactic therapy, yet few are offered a preventative medication. Moreover, controlled clinical trials investigating the use of both abortive and prophylactic medications in children have suffered from high placebo response rates. A diverse group of medications are used to prevent migraine attacks, including antidepressants, antiepileptics, antihistamines and antihypertensive agents, yet there still remains a serious lack of controlled studies on the pharmacological treatment of pediatric migraine. PMID- 25792527 TI - Antimicrobial prophylaxis for external ventricular drains in pediatric neurosurgical patients. AB - BACKGROUND: Our goal was to describe the use of antibiotics for surgical prophylaxis of external ventricular drains (EVDs) in a pediatric neurosurgical population and determine the incidence of EVD-related infections among different antimicrobial prophylaxis strategies. MAIN OUTCOME MEASURES: This retrospective chart review included patients up to 18 years old who underwent EVD insertion at either of two tertiary care academic hospitals in the same health system between August 1, 2008, and July 31, 2012. Patients were included if they received at least one dose of antibiotics before EVD insertion. Patients who received only perioperative antibiotics were compared with those who also received antibiotics after this period. The primary endpoint was incidence of EVD-related infection. Descriptive statistics were used to summarize baseline characteristics and compare antibiotic regimens between groups. Pearson's chi square and Mann Whitney U tests compared nonparametric data. RESULTS: A total of 182 EVD insertions were documented, and 88 included in the study. Of these 88, 27 were associated only with perioperative doses of antibiotics, and 61 with prolonged antibiotic use. Baseline characteristics and antibiotic choices were similar between the groups. At least 55 (63%) catheters were antibiotic-impregnated, but types of catheters couldn't be compared between groups due to insufficient data. No central nervous system infections were identified in either group, so the primary objective could not be evaluated statistically. CONCLUSION: No infections were identified in any study subjects during EVD treatment. An adequately powered, multi-center prospective study should be performed to determine if prolonged use of antibiotics beyond the perioperative period is of benefit. PMID- 25792526 TI - Eosinophilic esophagitis in children. AB - Eosinophilic esophagitis (EoE) is a relatively common chronic immune-mediated disease of the esophagus characterized clinically by symptoms of esophageal dysfunction that vary by age. Histologically, EoE results in marked esophageal eosinophilia despite treatment with high-dose proton pump inhibition. The cornerstone of treatment is dietary restriction and/or pharmacologic therapy, mainly with topical steroids. This review briefly describes dietary therapy, but focuses on the various medical options in the treatment of EoE, with an emphasis on steroid-based therapy. Numerous landmark studies are reviewed describing the symptomatic and histologic endpoints as well as safety data. The literature strongly supports the use of topical steroid therapy as a means of significantly decreasing eosinophilic mucosal disease. Specifically, high-dose fluticasone propionate appears to be very effective, and has been shown to result in the resolution of mucosal eosinophilia in a large percentage of treated patients. Long-term studies over many years will need to determine whether mucosal healing will change the natural history of this stricture-causing disease. In addition to topical therapy, various other drug-based therapies are reported, including newer immune-based monoclonal antibodies. PMID- 25792529 TI - REM sleep behaviour disorder: a window on the sleeping brain. PMID- 25792528 TI - Facilitation of epileptic activity during sleep is mediated by high amplitude slow waves. AB - Epileptic discharges in focal epilepsy are frequently activated during non-rapid eye movement sleep. Sleep slow waves are present during this stage and have been shown to include a deactivated ('down', hyperpolarized) and an activated state ('up', depolarized). The 'up' state enhances physiological rhythms, and we hypothesize that sleep slow waves and particularly the 'up' state are the specific components of non-rapid eye movement sleep that mediate the activation of epileptic activity. We investigated eight patients with pharmaco-resistant focal epilepsies who underwent combined scalp-intracerebral electroencephalography for diagnostic evaluation. We analysed 259 frontal electroencephalographic channels, and manually marked 442 epileptic spikes and 8487 high frequency oscillations during high amplitude widespread slow waves, and during matched control segments with low amplitude widespread slow waves, non widespread slow waves or no slow waves selected during the same sleep stages (total duration of slow wave and control segments: 49 min each). During the slow waves, spikes and high frequency oscillations were more frequent than during control segments (79% of spikes during slow waves and 65% of high frequency oscillations, both P ~ 0). The spike and high frequency oscillation density also increased for higher amplitude slow waves. We compared the density of spikes and high frequency oscillations between the 'up' and 'down' states. Spike and high frequency oscillation density was highest during the transition from the 'up' to the 'down' state. Interestingly, high frequency oscillations in channels with normal activity expressed a different peak at the transition from the 'down' to the 'up' state. These results show that the apparent activation of epileptic discharges by non-rapid eye movement sleep is not a state-dependent phenomenon but is predominantly associated with specific events, the high amplitude widespread slow waves that are frequent, but not continuous, during this state of sleep. Both epileptic spikes and high frequency oscillations do not predominate, like physiological activity, during the 'up' state but during the transition from the 'up' to the 'down' state of the slow wave, a period of high synchronization. Epileptic discharges appear therefore more associated with synchronization than with excitability. Furthermore, high frequency oscillations in channels devoid of epileptic activity peak differently during the slow wave cycle from those in channels with epileptic activity. This property may allow differentiating physiological from pathological high frequency oscillations, a problem that is unresolved until now. PMID- 25792530 TI - A randomized trial of unruptured brain arteriovenous malformations study: what impact on clinical care and therapeutic decision? PMID- 25792531 TI - Endoluminal Reconstruction for Nonsaccular Aneurysms of the Proximal Posterior Cerebral Artery with the Pipeline Embolization Device. AB - BACKGROUND AND PURPOSE: Treatment options for nonsaccular posterior cerebral artery aneurysms include a range of surgical and endovascular reconstructive and deconstructive methods. However, no truly satisfactory treatment option is available to date for lesions arising from the P1 and P2 segments. The purpose of the present case series is to investigate both the efficacy and safety of the Pipeline Embolization Device in treating these challenging aneurysms. MATERIALS AND METHODS: We present a series of 6 consecutive patients who underwent endoluminal reconstruction with the Pipeline Embolization Device for nonsaccular P1 or P2 segment aneurysms between January 2009 and June 2013. RESULTS: Aneurysm location included the P1 segment in 2 patients and the P2 segment in 4 patients. Mean aneurysm diameter was 23 mm (range, 5-44 mm). Mean length of the arterial segment involved was 10 mm (range, 6-19 mm). Clinical presentation included mass effect in 4 patients and perforator stroke and subacute aneurysmal subarachnoid hemorrhage in 1 patient each. Endovascular reconstruction was performed by using 1 Pipeline Embolization Device in 5 patients and 2 overlapping Pipeline Embolization Devices in the remaining patient. Angiographic aneurysm occlusion was immediate in 1 patient, within 6 months in 4 patients, and within 1 year in the remaining patient. Index symptoms resolved in 4 patients and stabilized in the remaining 2. No new permanent neurologic sequelae and no aneurysm recurrence were recorded during the mean follow-up period of 613 days (range, 540-725 days). CONCLUSIONS: Endovascular reconstruction with the Pipeline Embolization Device for nonsaccular aneurysms arising from the P1 and P2 segments compares favorably with historical treatment options in terms of occlusion rate, margin of safety, and neurologic outcome. PMID- 25792532 TI - Feasibility analysis of the parametric response map as an early predictor of treatment efficacy in head and neck cancer. AB - BACKGROUND AND PURPOSE: Estimating changes in the volume transfer constant, normalized area under the contrast-enhancement time curve at 60 seconds, and fractional blood plasma volume by using dynamic contrast-enhanced MR imaging may be useful in predicting tumor response to chemoradiation. We hypothesized that the parametric response map, a voxel-by-voxel analysis of quantitative dynamic contrast-enhanced MR imaging maps, predicts survival in patients with head and neck cancer. MATERIALS AND METHODS: Ten patients with locoregionally advanced head and neck squamous cell carcinoma underwent definitive concurrent chemoradiation therapy. For each patient, dynamic contrast-enhanced MR imaging data were collected before and 2 weeks after treatment initiation. Change in perfusion parameters within the primary tumor volume with time was analyzed by parametric response mapping and by whole-tumor mean percentage change. Outcome was defined as overall survival. The perfusion parameter and metric most predictive of outcome were identified. Overall survival was estimated by the log rank test and Kaplan-Meier survival curve. RESULTS: The volume transfer constant and normalized area under the contrast-enhancement time curve at 60 seconds were predictive of survival both in parametric response map analysis (volume transfer constant, P = .002; normalized area under the contrast-enhancement time curve at 60 seconds, P = .02) and in the percentage change analysis (volume transfer constant, P = .04; normalized area under the contrast-enhancement time curve at 60 seconds, P = .02). Blood plasma volume predicted survival in neither analysis. CONCLUSIONS: Parametric response mapping of MR perfusion biomarkers could potentially guide treatment modification in patients with predicted treatment failure. Larger studies are needed to determine whether parametric response map analysis or percentage signal change in these perfusion parameters is the stronger predictor of survival. PMID- 25792533 TI - Diffusion Tensor Imaging Mapping of Brain White Matter Pathology in Mitochondrial Optic Neuropathies. AB - BACKGROUND AND PURPOSE: Brain white matter is frequently affected in mitochondrial diseases; optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy are the most frequent mitochondrial monosymptomatic optic neuropathies. In this observational study, brain white matter microstructure was characterized by DTI in patients with optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy, in relation to clinical and genetic features. MATERIALS AND METHODS: Nineteen patients with optic atrophy gene 1-autosomal dominant optic atrophy and 17 with Leber hereditary optic neuropathy older than 18 years of age, all genetically diagnosed, and 19 healthy volunteers underwent DTI by using a 1.5T MR imaging scanner and neurologic and ophthalmologic assessments. Brain white matter DTI metrics were calculated for all participants, and, in patients, their correlations with genetics and clinical findings were calculated. RESULTS: Compared with controls, patients with optic atrophy gene 1-autosomal dominant optic atrophy had an increased mean diffusivity in 29.2% of voxels analyzed within major white matter tracts distributed throughout the brain, while fractional anisotropy was reduced in 30.3% of voxels. For patients with Leber hereditary optic neuropathy, the proportion of altered voxels was only 0.5% and 5.5%, respectively, of which half was found within the optic radiation and 3.5%, in the smaller acoustic radiation. In almost all regions, fractional anisotropy diminished with age in patients with optic atrophy gene 1-autosomal dominant optic atrophy and correlated with average retinal nerve fiber layer thickness in several areas. Mean diffusivity increased in those with a missense mutation. Patients with Leber hereditary optic neuropathy taking idebenone had slightly milder changes. CONCLUSIONS: Patients with Leber hereditary optic neuropathy had preferential involvement of the optic and acoustic radiations, consistent with trans-synaptic degeneration, whereas patients with optic atrophy gene 1-autosomal dominant optic atrophy presented with widespread involvement suggestive of a multisystemic, possibly a congenital/developmental, disorder. White matter changes in Leber hereditary optic neuropathy and optic atrophy gene 1-autosomal dominant optic atrophy may be exploitable as biomarkers. PMID- 25792534 TI - Endovascular treatment of wide-neck anterior communicating artery aneurysms using WEB-DL and WEB-SL: short-term results in a multicenter study. AB - BACKGROUND AND PURPOSE: Endovascular treatment of wide-neck anterior communicating artery aneurysms can often be challenging. The Woven EndoBridge (WEB) device is a recently developed intrasaccular flow disrupter dedicated to endovascular treatment of intracranial aneurysms. The aim of this study was to investigate the feasibility, safety, and efficacy of the WEB Dual-Layer and WEB Single-Layer devices for the treatment of wide-neck anterior communicating artery aneurysms. MATERIALS AND METHODS: Patients with anterior communicating artery aneurysms treated with the WEB device between June 2013 and March 2014 in 5 French centers were analyzed. Procedural success, technical complications, clinical outcome at 1 month, and immediate and 3- to 6-month angiographic follow up results were analyzed. RESULTS: Ten patients with unruptured anterior communicating artery aneurysms with a mean neck diameter of 5.4 mm were treated with the WEB. Treatment failed in 3 of the 10 aneurysms without further clinical complications. One patient developed a procedural thromboembolic event, and the other 6 had normal neurologic examination findings at 1-month follow-up. Immediate anatomic outcome evaluation showed adequate occlusion (total occlusion or neck remnant) in 6 of 7 patients. Angiographic control was obtained in all patients, including 6 adequate aneurysm occlusions (3 complete occlusions and 3 neck remnants) at short-term follow-up. CONCLUSIONS: In our small series, treatment of wide-neck anterior communicating artery aneurysms with the WEB device was feasible and safe. However, patient selection based on the aneurysm and initial angiographic findings in the parent artery is important due to the limitations of the WEB device navigation. PMID- 25792535 TI - Whole-Brain Susceptibility-Weighted Thrombus Imaging in Stroke: Fragmented Thrombi Predict Worse Outcome. AB - BACKGROUND AND PURPOSE: The prevalence and clinical importance of primarily fragmented thrombi in patients with acute ischemic stroke remains elusive. Whole brain SWI was used to detect multiple thrombus fragments, and their clinical significance was analyzed. MATERIALS AND METHODS: Pretreatment SWI was analyzed for the presence of a single intracranial thrombus or multiple intracranial thrombi. Associations with baseline clinical characteristics, complications, and clinical outcome were studied. RESULTS: Single intracranial thrombi were detected in 300 (92.6%), and multiple thrombi, in 24 of 324 patients (7.4%). In 23 patients with multiple thrombi, all thrombus fragments were located in the vascular territory distal to the primary occluding thrombus; in 1 patient, thrombi were found both in the anterior and posterior circulation. Only a minority of thrombus fragments were detected on TOF-MRA, first-pass gadolinium enhanced MRA, or DSA. Patients with multiple intracranial thrombi presented with more severe symptoms (median NIHSS scores, 15 versus 11; P = .014) and larger ischemic areas (median DWI ASPECTS, 5 versus 7; P = .006); good collaterals, rated on DSA, were fewer than those in patients with a single thrombus (21.1% versus 44.2%, P = .051). The presence of multiple thrombi was a predictor of unfavorable outcome at 3 months (P = .040; OR, 0.251; 95% CI, 0.067-0.939). CONCLUSIONS: Patients with multiple intracranial thrombus fragments constitute a small subgroup of patients with stroke with a worse outcome than patients with single thrombi. PMID- 25792536 TI - Contextualizing the Policy and Pragmatics of Reintegrating Sex Offenders. AB - As sanctions for those convicted of sex offenses have increased over recent years, the risk for reoffense presented by social isolation increases. Because most jurisdictions struggle with how best to manage and reintegrate sex offenders, this study analyzes bureaucratic and contextual issues with arranging community-based reintegration programs. Specifically, this qualitative, process oriented study examines and compares Circles of Support & Accountability (CoSA) programs from the United States (specifically, Vermont) and New Zealand. CoSAs provide support for medium- to high-risk sex offenders as they are released to communities. The programs are compared with regard to their structures, the relationship to Corrections, the role of communities, and core members' reentry challenges. The implications of each configuration are explored. As most of the existing research on CoSAs is focused on recidivism, and as the U.S. federal government is expanding the use of CoSA, this article fills a void in our understanding of the role that communities can play in reintegrating sexual offenders and how program structures shape reentry. PMID- 25792537 TI - Healthcare providers' perspectives on expedited partner therapy for chlamydia: a qualitative study. AB - OBJECTIVES: Expedited partner therapy (EPT) effectively reduces rates of reinfection with chlamydia and increases the number of partners treated for the infection. Healthcare provider (HCP) provision of EPT is low. The objective of this qualitative study was to understand HCP views and opinions regarding the use of EPT in a state where EPT is permissible but underused. METHODS: Using a purposive sampling strategy to include diverse HCPs who treat young women at risk for chlamydia, 23 semistructured, in-depth interviews were conducted between October and December 2013. The interviews included questions about knowledge, attitudes, experiences with, and barriers and facilitators regarding the use of EPT. RESULTS: Many respondents report using EPT and believe the practice is beneficial for their patients. Most providers were unaware of their colleagues' practices and had limited knowledge regarding institutional policies around EPT. HCPs noted a variety of barriers, such as fear of liability, confusion around the legal status of EPT and not being able to counsel patients' partners that make routine use of this practice a challenge. Facilitators of EPT include speaking on the phone with patients' partners and establishing legislation enabling EPT. CONCLUSIONS: This is the first study to qualitatively examine HCPs' perspectives on EPT in the USA. Barriers to EPT, including concerns about counselling patients' partners and the legal status of EPT, can be overcome. EPT recommendations could include the use of phone calls as part of their guidelines. Changing EPT legislation at the state level in the USA is an important factor to facilitate EPT use. PMID- 25792538 TI - The epidemiology of gonococcal arthritis in an Indigenous Australian population. AB - BACKGROUND: Disseminated Gonococcal Infection (DGI) is caused by Neisseria gonorrhoeae bacteraemia. Typically the primary source is a sexually acquired mucosal infection. If not recognised and treated promptly DGI can be associated with significant morbidity and, in rare cases, death. Central Australia has one of the highest rates of gonococcal notifications in Australia. Despite this, the nature and prevalence of complications arising from gonococcal infections within this at-risk population is unknown. METHODS: Enhanced surveillance and audit of patients with DGI discharged from Alice Springs Hospital between 2003 and 2012. Patient demographics and clinical management data were extracted from healthcare records and investigation databases. RESULTS: DGI cases were significantly more likely to present in young (<=29 years) Indigenous women compared with young Indigenous men (chi(2), p=0.020). Overall Indigenous women had nearly twice the risk of DGI compared with men (relative risk 1.92 (95% CI 1.45 to 2.53)). The incidence of DGI per all gonococcal notifications on average was 911/100 000 (95% CI 717 to 1142) gonococcal notifications. CONCLUSIONS: DGI represents a severe complication of N. gonorrhoeae infection. In Central Australia DGI is not a rare oddity but rather an important differential when dealing with patients with undefined sepsis and associated joint disease. PMID- 25792540 TI - A preliminary investigation into the effectiveness of a group-delivered sleep management intervention for parents of children with intellectual disabilities. AB - Sleep problems are more prevalent and severe among children with intellectual disabilities and autism compared to typically developing children. Training parents in behavioural approaches to manage sleep problems is advocated. However, delivering such interventions via groups is novel. This article reports the findings from a preliminary evaluation of a group-delivered intervention routinely delivered by a Child and Adolescent Mental Health Service Learning Disability team in England. For this purpose, parents (n = 23) of children with intellectual disabilities were recruited. The Children's Sleep Habits Questionnaire, Parents' Sense of Competence Scale and parent-set goals captured outcomes at pre-intervention, post-intervention and 3- and 6-month follow-up. Intervention delivery costs were collected. Take-up was high (86%), and no parent dropped out. Statistically significant improvements in night wakings, parent-set goals and parents' sense of efficacy were observed. The estimated mean cost of delivering each intervention was British (GBP) L1570. Findings suggest the intervention is a low-cost, acceptable service warranting further evaluation. PMID- 25792539 TI - Design and characterization of swapped-domain constructs of HIV-1 glycoprotein-41 as receptors for drug discovery. AB - Four new swapped-domain constructs of the ectodomain of human immunodeficiency virus type 1 glycoprotein-41 (gp41) were prepared. The gp41 ectodomain consists of 50-residue N-heptad repeat (NHR), 36-residue disulfide-bonded loop and 39 residue C-heptad repeat (CHR). It folds into a hairpin structure that forms a trimer along the NHR axis. The swapped-domain proteins feature CHR domains of length 39, 28 or 21 residues preceding a 4-residue loop and a 49- or 50-residue NHR domain. The effect of CHR truncation was to expose increasing lengths of the NHR groove, including the conserved hydrophobic pocket, an important drug target. A novel method for preparing proteins with extended exposed hydrophobic surfaces was demonstrated. Biophysical measurements, including analytical ultracentrifugation and ligand-detected Water-Ligand Observed via Gradient Spectroscopy and (1)H-(15)N-HSQC NMR experiments, were used to confirm that the proteins formed stable trimers in solution with exposed binding surfaces. These proteins could play an important role as receptors in structure-based drug discovery. PMID- 25792541 TI - 'Putting the TEA back into teaching': are trainees being taught optimal epidural techniques? PMID- 25792543 TI - Targeting unfolded protein response in cancer and diabetes. AB - The maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is tightly regulated by the unfolded protein response (UPR), a signal transduction pathway maintaining ER protein folding homeostasis. However, certain ER states are incompatible with cell survival and therefore the UPR may choose to eliminate severely disrupted cells by apoptosis. This is accomplished primarily through the activation of the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP). In the April 2015 issue of Endocrine-Related Cancer, researchers from the universities of South Carolina and Athens (Greece) suggested a novel mechanism of CHOP-mediated apoptosis connected with the suppression of a prominent cell cycle regulator with anti-apoptotic activity, p21. These findings and suggested clinical applications, such as potentiation of cancer chemotherapy and a novel therapeutic approach for type 2 diabetes, are discussed in the context of UPR. PMID- 25792544 TI - Evidence of cellular senescence during the development of estrogen-induced pituitary tumors. AB - Although pituitary adenomas represent 25% of intracranial tumors, they are usually benign, with the mechanisms by which these tumors usually avoid an invasive profile and metastatic growth development still remaining unclear. In this context, cellular senescence might constitute a plausible explanation for the benign nature of pituitary adenomas. In this study, we investigated the emergence of cellular senescence as a growth control mechanism during the progression of estrogen-induced pituitary tumors. The quantification of Ki67 immunopositive cells in the pituitaries of estrogenized male rats after 10, 20, 40, and 60 days revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the expression of cellular senescence features, such as the progressive rise in the enzymatic senescence-associated b-galactosidase (SA-b gal) activity, IL6, IL1b, and TGFb expression, was observed throughout pituitary tumor development. Furthermore, tumoral pituitary cells also displayed nuclear pATM expression, indicating activated DNA damage signaling, with a significant increase in p21 expression also being detected. The associations among DNA damage signaling activation, SA-b-gal expression, and p21 may provide a reliable combination of senescence-associated markers for in vivo pituitary senescence detection. These results suggest a role for this cellular process in the regulation of pituitary cell growth. Thus, cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation. PMID- 25792542 TI - Noninferiority studies with multiple reference treatments. AB - The increasing popularity of noninferiority trials reflects the ongoing efforts to replace existing treatments (reference treatments) with new treatments (experimental treatments) that retain a substantial fraction of the effect of the reference treatments. The adoption of any new treatment has to be vindicated by a demonstration of benefits that outweigh a possible clinically insignificant reduction in the reference treatment efficacy. Statistical methods have been developed to analyze data collected from noninferiority trials. However, these methods focus on cases with only one reference treatment. In this paper, we provide the statistical inferential procedures for situations with multiple reference treatments. The computation of the corresponding critical values for simultaneous testings of noninferiority of several new treatments to multiple reference treatments in the presence of a placebo is provided. Furthermore, for a prespecified level of test power, a technique to determine the optimal sample size before the onset of a noninferiority trial is derived. A clinical example is given to illustrate our proposed procedure. PMID- 25792546 TI - An unsuspected diagnosis of mucoepidermoid carcinoma of lung. AB - A 40-year-old man with dry cough for 5 years, no history of smoking, and a right lung mass, underwent a radiologically-guided core needle biopsy. The initial histopathological diagnosis was adenocarcinoma of the lung. After lobectomy, the final pathology was mucoepidermoid carcinoma. The initial biopsies sampled only a mucinous component of the tumor, leading to a diagnosis of adenocarcinoma. The possibility of mucoepidermoid carcinoma could be suspected on the basis of clinical history and radiologic evidence. This unusual case highlights the importance of adequate multidisciplinary review of patients who increasingly receive pathologic diagnoses based on ever smaller tissue samples. PMID- 25792545 TI - Surgical treatment of tetralogy of Fallot with absent pulmonary valve syndrome. AB - The patient was a 3-month-old girl weighting 3.6 kg, diagnosed with tetralogy of Fallot and absent pulmonary valve syndrome. We surgically repaired the tetralogy of Fallot by patch closure of the ventricular septal defect, right ventricular outflow tract reconstruction using an expanded polytetrafluoroethylene monocusp patch with a bulging sinus, and removal of the bronchial obstruction by anterior translocation of the pulmonary artery using the Lecompte maneuver. PMID- 25792547 TI - Androgen pathway manipulation and survival in patients with lung cancer. AB - The epidemiology of lung cancer differs between men and women. The role of androgens in lung cancer remains unclear. This study was performed to determine if exposure to androgen pathway manipulation (APM) is associated with greater survival in male patients diagnosed with lung cancer. Using a retrospective cohort design, all men diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified from the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases. Information from the Drug Program Information Network (DPIN) was used to determine prescriptions filled for antiandrogens, 5-alpha reductase inhibitors, and gonadotropin-releasing hormone (GnRH) agonists. Multivariable Cox proportional hazards analysis with time varying exposure variables was used to compare survival. A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (11.5%) were identified as having used a form of APM. The majority of patients received 5 alpha reductase inhibitors. Patients who received APM prior to the diagnosis of lung cancer had no significant difference in survival (HR 0.97, p = 0.69) compared to those who did not. Patients exposed to APM after their diagnosis were found to have a significantly better survival (HR 0.36, p = 0.0007), as were those exposed both before and after diagnosis (HR 0.53, p < 0.0001). In male patients diagnosed with lung cancer, exposure to APM is associated with significantly better survival when compared with no exposure. The association is only seen when some or all of the exposure has occurred after the diagnosis of lung cancer. PMID- 25792548 TI - Loss to follow-up and bias assessment among a cohort of Thai men who have sex with men in Bangkok, Thailand. AB - Minimising loss to follow-up is essential to obtain unbiased results. This study aimed to assess factors associated with loss to follow-up and effects on biasing exposure-outcome associations in a cohort of men who have sex with men in Bangkok. We enrolled sexually-active Thai men who have sex with men, at least 18 years old, in a study with four-monthly follow-up visits. At each visit, men answered HIV risk behaviour questions using audio computer-assisted self interview. Logistic regression was used to evaluate factors associated with loss to follow-up and bias between exposures and prevalent HIV infection were estimated using adjusted relative odds ratios. From 2006 to 2010, we enrolled 1744 men who have sex with men; as of April, 2014, 1256 (72%) had completed at least the month-36 visit; loss to follow-up was 9.6%. Factors independently associated with loss to follow-up were age (18-21 years), education (primary level or less, secondary or vocational education), living outside Bangkok and vicinity, sexual orientation (bisexual, heterosexual), previous HIV testing, HIV infection, and behaviour in the past 4 months (recreational drug use, reporting group sex). An effect of loss to follow-up on factors of prevalent HIV infection was found by sexual orientation (transgender) and unprotected anal intercourse (receptive/insertive). These findings highlight the need to strengthen post-HIV test counselling. Directed counselling for HIV care should be given to young men who have sex with men and recreational drug users. PMID- 25792549 TI - Coping strategies and behavioural changes following a genital herpes diagnosis among an urban sample of underserved Midwestern women. AB - This study focused on understanding the coping strategies and related behavioural changes of women who were recently diagnosed with herpes simplex virus type 2. In particular, we were interested in how coping strategies, condom use, and acyclovir uptake evolve over time. Twenty-eight women screening positive for herpes simplex virus type 2 were recruited through a public health STD clinic and the Indianapolis Community Court. Participants completed three semi-structured interviews with a woman researcher over a six-month period. The interviews focused on coping strategies for dealing with a diagnosis, frequency of condom use, suppressive and episodic acyclovir use, and the utilisation of herpes simplex virus type 2 support groups. Interview data were analysed using content analysis to identify and interpret concepts and themes that emerged from the interviews. Women employed a variety of coping strategies following an herpes simplex virus type 2 diagnosis. Of the women, 32% reported an increase in religious activities, 20% of women reported an increase in substance use, and 56% of women reported engaging in other coping activities. A total of 80% of women reported abstaining from sex immediately following the diagnosis, but 76% of women reported engaging in sex again by the six-month interview. Condom and medication use did not increase and herpes simplex virus type 2 support groups were not utilised by participants. All participants reported engaging in at least one coping mechanism after receiving their diagnosis. A positive diagnosis did not seem to result in increased use of condoms for the majority of participants and the use of acyclovir was low overall. PMID- 25792550 TI - iTagPlot: an accurate computation and interactive drawing tool for tag density plot. AB - MOTIVATION: Tag density plots are very important to intuitively reveal biological phenomena from capture-based sequencing data by visualizing the normalized read depth in a region. RESULTS: We have developed iTagPlot to compute tag density across functional features in parallel using multicores and a grid engine and to interactively explore it in a graphical user interface. It allows us to stratify features by defining groups based on biological function and measurement, summary statistics and unsupervised clustering. AVAILABILITY AND IMPLEMENTATION: http://sourceforge.net/projects/itagplot/. PMID- 25792551 TI - QSLiMFinder: improved short linear motif prediction using specific query protein data. AB - MOTIVATION: The sensitivity of de novo short linear motif (SLiM) prediction is limited by the number of patterns (the motif space) being assessed for enrichment. QSLiMFinder uses specific query protein information to restrict the motif space and thereby increase the sensitivity and specificity of predictions. RESULTS: QSLiMFinder was extensively benchmarked using known SLiM-containing proteins and simulated protein interaction datasets of real human proteins. Exploiting prior knowledge of a query protein likely to be involved in a SLiM mediated interaction increased the proportion of true positives correctly returned and reduced the proportion of datasets returning a false positive prediction. The biggest improvement was seen if a short region of the query protein flanking the interaction site was known. AVAILABILITY AND IMPLEMENTATION: All the tools and data used in this study, including QSLiMFinder and the SLiMBench benchmarking software, are freely available under a GNU license as part of SLiMSuite, at: http://bioware.soton.ac.uk. PMID- 25792552 TI - MAGNA++: Maximizing Accuracy in Global Network Alignment via both node and edge conservation. AB - MOTIVATION: Network alignment aims to find conserved regions between different networks. Existing methods aim to maximize total similarity over all aligned nodes (i.e. node conservation). Then, they evaluate alignment quality by measuring the amount of conserved edges, but only after the alignment is constructed. Thus, we recently introduced MAGNA (Maximizing Accuracy in Global Network Alignment) to directly maximize edge conservation while producing alignments and showed its superiority over the existing methods. Here, we extend the original MAGNA with several important algorithmic advances into a new MAGNA++ framework. RESULTS: MAGNA++ introduces several novelties: (i) it simultaneously maximizes any one of three different measures of edge conservation (including our recent superior [Formula: see text] measure) and any desired node conservation measure, which further improves alignment quality compared with maximizing only node conservation or only edge conservation; (ii) it speeds up the original MAGNA algorithm by parallelizing it to automatically use all available resources, as well as by reimplementing the edge conservation measures more efficiently; (iii) it provides a friendly graphical user interface for easy use by domain (e.g. biological) scientists; and (iv) at the same time, MAGNA++ offers source code for easy extensibility by computational scientists. AVAILABILITY AND IMPLEMENTATION: http://www.nd.edu/~cone/MAGNA++/ PMID- 25792553 TI - A robust approach for identifying differentially abundant features in metagenomic samples. AB - MOTIVATION: The analysis of differential abundance for features (e.g. species or genes) can provide us with a better understanding of microbial communities, thus increasing our comprehension and understanding of the behaviors of microbial communities. However, it could also mislead us about the characteristics of microbial communities if the abundances or counts of features on different scales are not properly normalized within and between communities, prior to the analysis of differential abundance. Normalization methods used in the differential analysis typically try to adjust counts on different scales to a common scale using the total sum, mean or median of representative features across all samples. These methods often yield undesirable results when the difference in total counts of differentially abundant features (DAFs) across different conditions is large. RESULTS: We develop a novel method, Ratio Approach for Identifying Differential Abundance (RAIDA), which utilizes the ratio between features in a modified zero-inflated lognormal model. RAIDA removes possible problems associated with counts on different scales within and between conditions. As a result, its performance is not affected by the amount of difference in total abundances of DAFs across different conditions. Through comprehensive simulation studies, the performance of our method is consistently powerful, and under some situations, RAIDA greatly surpasses other existing methods. We also apply RAIDA on real datasets of type II diabetes and find interesting results consistent with previous reports. AVAILABILITY AND IMPLEMENTATION: An R package for RAIDA can be accessed from http://cals.arizona.edu/%7Eanling/sbg/software.htm. PMID- 25792554 TI - Automatic determination of NET (neutrophil extracellular traps) coverage in fluorescent microscopy images. AB - MOTIVATION: Neutrophil extracellular traps (NETs) are believed to be essential in controlling several bacterial pathogens. Quantification of NETs in vitro is an important tool in studies aiming to clarify the biological and chemical factors contributing to NET production, stabilization and degradation. This estimation can be performed on the basis of fluorescent microscopy images using appropriate labelings. In this context, it is desirable to automate the analysis to eliminate both the tedious process of manual annotation and possible operator-specific biases. RESULTS: We propose a framework for the automated determination of NET content, based on visually annotated images which are used to train a supervised machine-learning method. We derive several methods in this framework. The best results are obtained by combining these into a single prediction. The overall Q(2) of the combined method is 93%. By having two experts label part of the image set, we were able to compare the performance of the algorithms to the human interoperator variability. We find that the two operators exhibited a very high correlation on their overall assessment of the NET coverage area in the images (R(2) is 97%), although there were consistent differences in labeling at pixel level (Q(2), which unlike R(2) does not correct for additive and multiplicative biases, was only 89%). AVAILABILITY AND IMPLEMENTATION: Open source software (under the MIT license) is available at https://github.com/luispedro/Coelho2015_NetsDetermination for both reproducibility and application to new data. PMID- 25792555 TI - Solubis: optimize your protein. AB - MOTIVATION: Protein aggregation is associated with a number of protein misfolding diseases and is a major concern for therapeutic proteins. Aggregation is caused by the presence of aggregation-prone regions (APRs) in the amino acid sequence of the protein. The lower the aggregation propensity of APRs and the better they are protected by native interactions within the folded structure of the protein, the more aggregation is prevented. Therefore, both the local thermodynamic stability of APRs in the native structure and their intrinsic aggregation propensity are a key parameter that needs to be optimized to prevent protein aggregation. RESULTS: The Solubis method presented here automates the process of carefully selecting point mutations that minimize the intrinsic aggregation propensity while improving local protein stability. PMID- 25792556 TI - Public report cards for in-hospital cardiac arrest: empowering the public with location-specific data. PMID- 25792557 TI - Prospective randomized trial of moderately strenuous aerobic exercise after an implantable cardioverter defibrillator. AB - BACKGROUND: Despite its salutary effects on health, aerobic exercise is often avoided after receipt of an implantable cardioverter defibrillator (ICD) because of fears that exercise may provoke acute arrhythmias. We prospectively evaluated the effects of a home aerobic exercise training and maintenance program (EX) on aerobic performance, ICD shocks, and hospitalizations exclusively in ICD recipients. METHODS AND RESULTS: A total of 160 patients (124 men and 36 women) were randomly assigned who had an ICD for primary (43%) or secondary (57%) prevention to EX or usual care (UC). The primary outcome was peak oxygen consumption, measured with cardiopulmonary exercise testing at baseline and 8 and 24 weeks. EX consisted of 8 weeks of home walking for 1 h/d, 5 d/wk at 60% to 80% of heart rate reserve, followed by 16 weeks of maintenance home walking for 150 min/wk. Adherence to EX was determined from exercise logs, ambulatory heart rate recordings of exercise, and weekly telephone contacts. Patients assigned to UC received no exercise directives and were monitored by monthly telephone contact. Adverse events were identified by ICD interrogations, patient reports, and medical charts. ICD recipients averaged 55+/-12 years and mean ejection fraction of 40.6+/-15.7; all were taking beta-blocker medications. EX significantly increased peak oxygen consumption (EX, 26.7+/-7.0 mL/kg per minute; UC, 23.9+/ 6.6 mL/kg per minute; P=0.002) at 8 weeks, which persisted during maintenance exercise at 24 weeks (EX, 26.9+/-7.7 mL/kg per minute; UC, 23.4+/-6.0 mL/kg per minute; P<0.001). ICD shocks were infrequent (EX=4 versus UC=8), with no differences in hospitalizations or deaths between groups. CONCLUSIONS: Prescribed home exercise is safe and significantly improves cardiovascular performance in ICD recipients without causing shocks or hospitalizations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00522340. PMID- 25792559 TI - Disparities in ST-elevation myocardial infarction management for the young goose and young gander: clinical, organizational, and educational challenges. PMID- 25792558 TI - Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study. AB - BACKGROUND: Sex disparities in reperfusion therapy for patients with acute ST segment-elevation myocardial infarction have been documented. However, little is known about whether these patterns exist in the comparison of young women with men. METHODS AND RESULTS: We examined sex differences in rates, types of reperfusion therapy, and proportion of patients exceeding American Heart Association reperfusion time guidelines for ST-segment-elevation myocardial infarction in a prospective observational cohort study (2008-2012) of 1465 patients 18 to 55 years of age, as part of the US Variations in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study at 103 hospitals enrolling in a 2:1 ratio of women to men. Of the 1238 patients eligible for reperfusion, women were more likely to be untreated than men (9% versus 4%, P=0.002). There was no difference in reperfusion strategy for the 695 women and 458 men treated. Women were more likely to exceed in-hospital and transfer time guidelines for percutaneous coronary intervention than men (41% versus 29%; odds ratio, 1.65; 95% confidence interval, 1.27-2.16), more so when transferred (67% versus 44%; odds ratio, 2.63; 95% confidence interval, 1.17-4.07); and more likely to exceed door-to-needle times (67% versus 37%; odds ratio, 2.62; 95% confidence interval, 1.23-2.18). After adjustment for sociodemographic, clinical, and organizational factors, sex remained an important factor in exceeding reperfusion guidelines (odds ratio, 1.72; 95% confidence interval, 1.28-2.33). CONCLUSIONS: Young women with ST-segment-elevation myocardial infarction are less likely to receive reperfusion therapy and more likely to have reperfusion delays than similarly aged men. Sex disparities are more pronounced among patients transferred to percutaneous coronary intervention institutions or who received fibrinolytic therapy. PMID- 25792560 TI - Regional variation in the incidence and outcomes of in-hospital cardiac arrest in the United States. AB - BACKGROUND: Regional variation in the incidence and outcomes of in-hospital cardiac arrest (IHCA) is not well studied and may have important health and policy implications. METHODS AND RESULTS: We used the 2003 to 2011 Nationwide Inpatient Sample databases to identify patients>=18 years of age who underwent cardiopulmonary resuscitation (International Classification of Diseases, Ninth Edition, Clinical Modification procedure codes 99.60 and 99.63) for IHCA. Regional differences in IHCA incidence, survival to hospital discharge, and resource use (total hospital cost and discharge disposition among survivors) were analyzed. Of 838,465 patients with IHCA, 162,270 (19.4%) were in the Northeast, 159,581 (19.0%) were in the Midwest, 316,201 (37.7%) were in the South, and 200,413 (23.9%) were in the West. Overall IHCA incidence in the United States was 2.85 per 1000 hospital admissions. IHCA incidence was lowest in the Midwest and highest in the West (2.33 and 3.73 per 1000 hospital admissions, respectively). Compared with the Northeast, risk-adjusted survival to discharge was significantly higher in the Midwest (odds ratio, 1.33; 95% confidence interval, 1.31-1.36), South (odds ratio, 1.21; 95% confidence interval, 1.19-1.23), and West (odds ratio, 1.25; 95% confidence interval, 1.23-1.27). IHCA survival increased significantly from 2003 to 2011 in the United States and in all regions (all Ptrend<0.001). Total hospital cost was highest in the West, whereas discharge to skilled nursing facility and use of home health care among survivors was highest in the Northeast. CONCLUSIONS: We observed significant regional variation in IHCA incidence, survival, and resource use in the United States. This variation was explained only partially by differences in patient and hospital characteristics. Further studies are needed to identify other potential factors responsible for these regional differences to improve outcomes after IHCA. PMID- 25792561 TI - Functional significance of SPINK1 promoter variants in chronic pancreatitis. AB - Chronic pancreatitis is a progressive inflammatory disorder of the pancreas, which often develops as a result of genetic predisposition. Some of the most frequently identified risk factors affect the serine protease inhibitor Kazal type 1 (SPINK1) gene, which encodes a trypsin inhibitor responsible for protecting the pancreas from premature trypsinogen activation. Recent genetic and functional studies indicated that promoter variants in the SPINK1 gene might contribute to disease risk in carriers. Here, we investigated the functional effects of 17 SPINK1 promoter variants using luciferase reporter gene expression assay in four different cell lines, including three pancreatic acinar cell lines (rat AR42J with or without dexamethasone-induced differentiation and mouse 266-6) and human embryonic kidney 293T cells. We found that most variants caused relatively small changes in promoter activity. Surprisingly, however, we observed significant variations in the effects of the promoter variants in the different cell lines. Only four variants exhibited consistently reduced promoter activity in all acinar cell lines, confirming previous reports that variants c.-108G>T, c. 142T>C, and c.-147A>G are risk factors for chronic pancreatitis and identifying c.-52G>T as a novel risk variant. In contrast, variant c.-215G>A, which is linked with the disease-associated splice-site mutation c.194 + 2T>C, caused increased promoter activity, which may mitigate the overall effect of the pathogenic haplotype. Our study lends further support to the notion that sequence evaluation of the SPINK1 promoter region in patients with chronic pancreatitis is justified as part of the etiological investigation. PMID- 25792562 TI - Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity. AB - Visceral hypersensitivity represents an important hallmark in the pathophysiology of irritable bowel syndrome (IBS), of which the mechanisms remain elusive. The present study was designed to examine whether cation-chloride cotransporter (CCC) mediated chloride (Cl(-)) homeostasis of the spinal cord is involved in chronic stress-induced visceral hypersensitivity. Chronic visceral hypersensitivity was induced by exposing male Wistar rats to water avoidance stress (WAS). RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of CCCs in the spinal cord. Patch-clamp recordings were performed on adult spinal cord slices to evaluate Cl(-) homeostasis and Cl(-) extrusion capacity of lamina I neurons. Visceral sensitivity was estimated by measuring the abdominal withdrawal reflex in response to colorectal distension (CRD). After 10 days of WAS exposure, levels of both total protein and the oligomeric form of the K(+) Cl(-) cotransporter isoform 2 (KCC2), but not Na(+)-K(+)-2Cl(-) transporter isoform 1 (NKCC1), were significantly decreased in the dorsal horn of the lumbosacral spinal cord. The downregulation of KCC2 resulted in a depolarizing shifted equilibrium potential of GABAergic inhibitory postsynaptic current and impaired Cl(-) extrusion capacity in lamina I neurons of the lumbosacral spinal cord from WAS rats. Acute noxious CRD disrupted spinal KCC2 expression and function 2 h after the final distention in sham rats, but not in WAS rats. Pharmacological blockade of KCC2 activity by intrathecal injection of a KCC2 inhibitor [(dihydroindenyl)oxy] alkanoic acid enhanced visceral nociceptive sensitivity in sham rats, but not in WAS rats. These results suggest that KCC2 downregulation-mediated impairment of spinal cord Cl(-) homeostasis may play an important role in chronic stress-induced visceral hypersensitivity. PMID- 25792563 TI - Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP dependent HCO3(-) secretion in colon. AB - Colonic bicarbonate (HCO3(-)) secretion is a well-established physiological process that is closely linked to overall fluid and electrolyte movement in the mammalian colon. These present studies show that extracellular calcium-sensing receptor (CaSR), a fundamental mechanism for sensing and regulating ionic and nutrient compositions of extracellular milieu in the small and large intestine, regulates HCO3(-) secretion. Basal and induced HCO3(-) secretory responses to CaSR agonists were determined by pH stat techniques used in conjunction with short-circuit current measurements in mucosa from rat distal colon mounted in Ussing chambers. R568, a specific CaSR activator, stimulated lumen Cl(-)- and short-chain fatty acid (SCFA)-dependent HCO3(-) secretion but inhibited cyclic nucleotide-activated HCO3(-) secretion. Consequently, at physiological conditions (either at basal or during lumen acid challenge) when electroneutral Cl(-)/HCO3( ) and SCFA/HCO3(-) exchangers dominate, CaSR stimulates HCO3(-) secretion; in contrast, in experimental conditions that stimulate fluid and HCO3(-) secretion, e.g., when forskolin activates electrogenic cystic fibrosis transmembrane conductance regulator-mediated HCO3(-) conductance, CaSR activation inhibits HCO3(-) secretion. Corresponding changes in JHCO3 (MUeq.h(-1).cm(-2), absence vs. presence of R568) were 0.18 +/- 0.03 vs. 0.31 +/- 0.08 under basal nonstimulated conditions and 1.85 +/- 0.23 vs. 0.45 +/- 0.06 under forskolin-stimulated conditions. Similarly, activation of CaSR by R568 stimulated Cl(-)- and SCFA dependent HCO3(-) secretion and inhibited cAMP-dependent HCO3(-) secretion in colon mucosa of wild-type mice; such effects were abolished in CaSR-null mice. These results suggest a new paradigm for regulation of intestinal ion transport in which HCO3(-) secretion may be fine-tuned by CaSR in accordance with nutrient availability and state of digestion and absorption. The ability of CaSR agonists to inhibit secretagogue-induced intestinal HCO3(-) secretion suggests that modulation of CaSR activity may provide a new therapeutic approach to correct HCO3(-) deficit and metabolic acidosis, a primary cause of morbidity and mortality in acute infectious diarrheal illnesses. PMID- 25792566 TI - Insights into the role of connexins in mammary gland morphogenesis and function. AB - Gap junctions formed of connexin subunits link adjacent cells by direct intercellular communication that is essential for normal tissue homeostasis in the mammary gland. The mammary gland undergoes immense remodeling and requires exquisite regulation to control the proliferative, differentiating, and cell death mechanisms regulating gland development and function. The generation of novel genetically modified mice with reduced or ablated connexin function within the mammary gland has advanced our understanding of the role of gap junctions during the complex and dynamic process of mammary gland development. These studies have revealed an important stage-specific role for Cx26 (GJA1) and Cx43 (GJB2), while Cx30 (GJB6) and Cx32 (Gjb1) can be eliminated without compromising the gland. Yet, there remain gaps in our understanding of the role of mammary gland gap junctions. PMID- 25792564 TI - Glutamine and alanyl-glutamine promote crypt expansion and mTOR signaling in murine enteroids. AB - L-glutamine (Gln) is a key metabolic fuel for intestinal epithelial cell proliferation and survival and may be conditionally essential for gut homeostasis during catabolic states. We show that L-alanyl-L-glutamine (Ala-Gln), a stable Gln dipeptide, protects mice against jejunal crypt depletion in the setting of dietary protein and fat deficiency. Separately, we show that murine crypt cultures (enteroids) derived from the jejunum require Gln or Ala-Gln for maximal expansion. Once expanded, enteroids deprived of Gln display a gradual atrophy of cryptlike domains, with decreased epithelial proliferation, but stable proportions of Paneth and goblet cell differentiation, at 24 h. Replenishment of enteroid medium with Gln selectively activates mammalian target of rapamycin (mTOR) signaling pathways, rescues proliferation, and promotes crypt regeneration. Gln deprivation beyond 48 h leads to destabilization of enteroids but persistence of EGFP-Lgr5-positive intestinal stem cells with the capacity to regenerate enteroids upon Gln rescue. Collectively, these findings indicate that Gln deprivation induces a reversible quiescence of intestinal stem cells and provides new insights into nutritional regulation of intestinal epithelial homeostasis. PMID- 25792565 TI - Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions. AB - Adherens junctions (AJs) and tight junctions (TJs) are crucial regulators of the integrity and restitution of the intestinal epithelial barrier. The structure and function of epithelial junctions depend on their association with the cortical actin cytoskeleton that, in polarized epithelial cells, is represented by a prominent perijunctional actomyosin belt. The assembly and stability of the perijunctional cytoskeleton is controlled by constant turnover (disassembly and reassembly) of actin filaments. Actin-interacting protein (Aip) 1 is an emerging regulator of the actin cytoskeleton, playing a critical role in filament disassembly. In this study, we examined the roles of Aip1 in regulating the structure and remodeling of AJs and TJs in human intestinal epithelium. Aip1 was enriched at apical junctions in polarized human intestinal epithelial cells and normal mouse colonic mucosa. Knockdown of Aip1 by RNA interference increased the paracellular permeability of epithelial cell monolayers, decreased recruitment of AJ/TJ proteins to steady-state intercellular contacts, and attenuated junctional reassembly in a calcium-switch model. The observed defects of AJ/TJ structure and functions were accompanied by abnormal organization and dynamics of the perijunctional F-actin cytoskeleton. Moreover, loss of Aip1 impaired the apico basal polarity of intestinal epithelial cell monolayers and inhibited formation of polarized epithelial cysts in 3-D Matrigel. Our findings demonstrate a previously unanticipated role of Aip1 in regulating the structure and remodeling of intestinal epithelial junctions and early steps of epithelial morphogenesis. PMID- 25792567 TI - Nitric oxide in follicle development and oocyte competence. AB - Apart from its well-known role in regulating endothelial function, in mammals, nitric oxide (NO) is an important signaling molecule involved in many processes, regulating different biological functions. It has been demonstrated that NO plays a role in the physiology of the reproductive system, where it acts in controlling the activity of reproductive organs in both sexes. In the female of several animal species, experimental data suggest the presence of an intraovarian NO generating system, which could be involved in the control of follicular development. The role of NO in regulating follicular atresia by apoptosis is still controversial, as a dual action depending mostly on its concentration has been documented. NO also displays positive effects on follicle development and selection related to angiogenic events and it could also play a modulatory role in steroidogenesis in ovarian cells. Both in monovulatory and poliovulatory species, the increase in PGE2 production induced by NO via a stimulatory effect on COX-2 activity appears to be a common ovulatory mechanism. Considerable evidence also exists to support an involvement of the NO/NO synthase system in the control of meiotic maturation of cumulus-oocyte complexes. PMID- 25792568 TI - Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma. AB - Smoothened inhibitors represent the first class of targeted drugs approved for use in advanced and metastatic basal cell carcinoma. For many patients with limited treatment options, this drug class has led to significant clinical improvements, but is not without side effects. In this review, we outline the basic mechanism of smoothened inhibitors and the most commonly observed cutaneous and extracutaneous side effects. We also highlight possible mechanisms for these adverse events and current management strategies. PMID- 25792569 TI - Chorionic bump in pregnant patients and associated live birth rate: a systematic review and meta-analysis. AB - OBJECTIVES: A chorionic bump on first-trimester sonography has been considered a risk factor for nonviability in pregnant patients with this rare finding, although the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between a chorionic bump and nonviability. METHODS: A comprehensive literature search was performed. We included all studies except case reports. A meta analysis was performed using a random-effects model. RESULTS: After screening 5 studies, 2 studies with a total of 67 patients met inclusion criteria. These were combined with a study (n = 52) from our institution. Overall, the live birth rate was 62% (74 of 119). Fifty-one chorionic bump pregnancies were otherwise normal (ie, pregnancies in which a gestational sac, a yolk sac, and an embryo with a heartbeat was seen at some point), and in this subset, the live birth rate was 83% (42 of 51). There was no significant relationship found between vaginal bleeding and live birth (P = .857); there was no significant difference in bump volume between live birth and no live birth (P = .198); and for the subset analysis of pooled odds ratios for the relationship between live birth and history of infertility, there was no significant relationship found (P = .186). CONCLUSIONS: A chorionic bump remains a risk factor for nonviability in pregnancy; however, if the pregnancy is otherwise normal, then most result in live birth. PMID- 25792570 TI - A novel sonographic scoring system for antenatal risk assessment of obstetric complications in suspected morbidly adherent placenta. AB - OBJECTIVES: The purpose of this study was to evaluate a novel sonographic scoring system for risk assessment of complications in patients suspected of having morbidly adherent placenta. METHODS: This retrospective study evaluated the association between maternal complications and a grayscale sonographic scoring system for adherent placenta before surgery. Criteria for adherent placenta included uteroplacental and uterobladder demarcation lines and the presence of lacunae. Placentas were classified into 4 stages: stage 0, normal placentation; stage 1, low probability of adherence; stage 2, moderate possibility of adherence; and stage 3, high suspicion of adherence. Placental adherence as assessed by a surgical team, estimated blood loss, and postoperative hospitalization days were determined for each group, as well as the rates of the need for packed blood cells, cryoprecipitate units, and hysterectomy. RESULTS: One hundred nine women were included in the study. Twenty-six (23.8%) women were given a score of stage 0, 22 (20.2%) stage 1, 28 (25.7%) stage 2, and 33 (30.3%) stage 3. Linear regression analysis demonstrated that the sonographic staging was the only variable significantly associated with the number of packed cells or cryoprecipitate units transfused (P< .001) and a clinical diagnosis of adherent placenta (P< .001). In addition, both sonographic staging and a history of cesarean delivery were significantly associated with hysterectomy (P = .01; P = .03, respectively), treatment with any blood products (P< .001; P= .01), and the duration of postoperative hospitalization (P< .001; P = .006). CONCLUSIONS: A scoring system based on simple grayscale parameters may be effective for antenatal risk assessment of maternal complications in cases of suspected morbidly adherent placenta. PMID- 25792571 TI - Do Doppler studies enhance surveillance of uncomplicated monochorionic diamniotic twins? AB - OBJECTIVES: To determine whether isolated abnormal Doppler indices before 28 weeks predict adverse pregnancy outcomes in uncomplicated monochorionic diamniotic (MCDA) twins. METHODS: A retrospective cohort study of MCDA twin pregnancies receiving antenatal testing at a single center between 2007 and 2013 was conducted. Sonographic surveillance, including Doppler velocimetric studies of the umbilical artery, ductus venosus, and middle cerebral artery of each twin, was initiated by 28 weeks and repeated at least every 2 weeks. All pregnancies were deemed "uncomplicated" at initial sonography, without evidence of polyhydramnios, oligohydramnios, intrauterine growth restriction, twin growth discordance of at least 20%, structural or chromosomal anomalies, or unclear chorionicity. Pregnancies were divided into 2 groups: those with isolated Doppler abnormalities before 28 weeks and those with normal Doppler indices. The primary outcome was a composite including twin-twin transfusion syndrome, intrauterine growth restriction of more than 1 twin, growth discordance of at least 20%, preterm delivery before 34 weeks for fetal indications, or demise of more than 1 fetus. RESULTS: Ninety-six patients were included, with 22 (22.9%) having isolated Doppler abnormalities before 28 weeks. The incidence of the primary outcome did not differ between groups (36.4% versus 28.4%; P = .47). The abnormal Doppler group underwent a greater number of sonographic examinations (15 versus 10; P= .001) and more antenatal admissions for fetal concerns (50.0% versus 12.2%; P < .001). CONCLUSIONS: Isolated Doppler abnormalities are commonly encountered in uncomplicated MCDA pregnancies before 28 weeks yet are not clearly predictive of twin-specific complications. Doppler abnormalities were associated with increased sonographic surveillance and antenatal hospitalizations, suggesting an influence on physician practice patterns. Data may not support Doppler studies before 28 weeks for routine MCDA twin monitoring. PMID- 25792572 TI - Reference ranges for the pulsatility index of the fetal aortic isthmus in singleton and twin pregnancies. AB - OBJECTIVES: The purpose of this study was to estimate reference ranges for the pulsatility index (PI) of the fetal aortic isthmus in uncomplicated singleton and twin pregnancies during the second half of pregnancy. METHODS: We conducted a cross-sectional observational study involving 543 healthy fetuses: 361 singleton pregnancies and 182 twin pregnancies between 19 and 36 weeks' gestation. The aortic isthmus PI was measured in 2 sonographic planes: the longitudinal aortic arch view and the 3-vessel and trachea view. We evaluated the reproducibility of aortic isthmus PI measurements between these planes by calculating intraclass correlation coefficients and limits of agreement. Scans were performed by 2 physicians, and intraobserver agreement was also measured. Regression analysis was used to estimate gestational age reference values for the aortic isthmus PI. RESULTS: The aortic isthmus PI was significantly correlated with gestational age in singletons and twins during the second half of pregnancy (P < .01). We did not find significant differences between reference ranges in singletons and twins or between the sonographic views. CONCLUSIONS: This study offers reference ranges for the aortic isthmus PI during the second half of gestation in singleton and twin pregnancies. Mean aortic isthmus PI values were similar in both types of gestations as well as both sonographic views. The aortic isthmus PI may be reliably obtained from either sonographic view. PMID- 25792573 TI - Prenatal detection of congenital heart defects at the 11- to 13-week scan using a simple color Doppler protocol including the 4-chamber and 3-vessel and trachea views. AB - OBJECTIVES: The first goal of this study was to analyze the diagnostic performance of the 4-chamber view, 3-vessel and trachea view, and their combination in color mapping during early cardiac evaluations for selecting cases suspicious of congenital heart defects. The second goal was to describe the most common abnormal flow patterns at the levels of the 4-chamber and 3-vessel and trachea views in the late first trimester. METHODS: We conducted a prospective observational study in which a simple cardiac sonographic protocol was applied in fetuses at gestational ages of 11 weeks to 13 weeks 6 days. RESULTS: A total of 1084 patients with known postnatal or autopsy findings were included in the study. The median maternal age was 32.3 years (range, 27-40 years). The median crown-rump length was 62.2 mm (range, 45-84 mm). Overall, there were 35 cases with a confirmed congenital heart defect (3.22%), including 16 accompanied by aneuploidy. We found that our simple first-trimester cardiac protocol was an effective screening method for congenital heart defects. The most effective approach of the 3 evaluated by us was the combined application of the 4-chamber and 3-vessel and trachea views in color mapping compared to the 4-chamber and 3 vessel and trachea views alone. We defined the most common ventricular inflow patterns and the V sign. The technique we used was simple and easy to reproduce. CONCLUSIONS: We confirmed that evaluation by two basic cardiac views allows for selection of most cases with a univentricular heart, atrioventricular septal defects, coarctation of the aorta, pulmonary stenosis, pulmonary atresia, and conotruncal defects. PMID- 25792574 TI - Outcome of cesarean scar pregnancies diagnosed sonographically in the first trimester. AB - OBJECTIVES: The purpose of this study was to determine the outcome of cesarean scar pregnancies diagnosed during the first trimester. METHODS: We retrospectively identified all cesarean scar implantation pregnancies diagnosed by sonography before 14 weeks' gestation between 2000 and 2012 at our institution. We reviewed the patients' sonograms and medical records and recorded sonographic findings and pregnancy outcomes. RESULTS: Thirty-four cases met study entry criteria. Ten patients presented with no embryonic cardiac activity, of whom 7 underwent interventions, and 3 were expectantly managed. One of the former 7 and none of the latter 3 required hysterectomy for bleeding. Among the 24 patients with embryonic cardiac activity, 8 were managed expectantly: 5 (62.5%) ultimately delivered a live-born neonate, 3 (60.0%) of whom required hysterectomy due to placenta accreta; and 3 had fetal demise. Sixteen of the 24 underwent interventions, 2 opting for gravid hysterectomy (10 and 11 weeks' gestation, respectively) and 14 treated by a minimally invasive method: intrasac potassium chloride injection (3 cases); intrasac potassium chloride injection plus intramuscular methotrexate (4 cases); sonographically guided dilation and curettage (6 cases); and laparascopic resection (1 case). None of the latter 14 subsequently required hysterectomy. CONCLUSIONS: If a woman has a first-trimester diagnosis of a cesarean scar implantation pregnancy and embryonic cardiac activity is present, expectant management offers the possibility of delivering a live-born neonate (62.5% in our study) but carries a substantial likelihood of hysterectomy at delivery due to placenta accreta (37.5% in our study), whereas minimally invasive therapy that interrupts the pregnancy largely eliminates the need for hysterectomy. PMID- 25792575 TI - Cesarean scar pregnancies: experience of 60 cases. AB - OBJECTIVES: To evaluate the management, clinical courses, and outcomes of cesarean scar pregnancies diagnosed in the first trimester. METHODS: We identified 60 cases of cesarean scar pregnancies diagnosed between 5 and 14 weeks. Group A contained 48 patients with fetal/embryonic cardiac activity; group B comprised 12 patients without cardiac activity; and group C included 11 patients with cardiac activity who chose expectant management. RESULTS: Five of the 48 patients (10.4%) in group A were successfully treated for vaginal bleeding. Thirty-three (68.7%) received methotrexate injections, and all had full resolution. Three (6.3%) required uterine artery embolization for late-developing arteriovenous malformations. Ten of the 12 patients (83.3%) in group B were managed expectantly and had full recovery. Two of the 10 (20.0%) had arteriovenous malformations; 1 had unsuccessful uterine artery embolization followed by a hysterectomy, and the second requested a hysterectomy. Ten of the 11 patients (90.9%) in group C continued the pregnancies. One declined local injection. Four of the 10 (40.0%) delivered live offspring by successive elective cesarean deliveries. Three (30.0%) had hysterectomies for placenta percreta, and 1 did not have a hysterectomy after delivery. Five (50%) had second-trimester complications, all leading to hysterectomies. Of the 60 patients, 20 (33.3%) had serious complications: 5 had arteriovenous malformations; 4 had uterine artery embolization; and 11 had hysterectomies. CONCLUSIONS: A cesarean scar pregnancy is a serious complication for patients who have had cesarean deliveries. Counseling, treatment, and follow-up are challenging for patients and caregivers. However, emerging data from different management approaches confirm that a cesarean scar pregnancy may progress and result in a live neonate at the expense of further fertility. This study confirmed that expectant management of a cesarean scar pregnancy is associated with a high risk of hysterectomy due to morbidly adherent placenta. PMID- 25792577 TI - Biopsy versus conservative management of sonographically benign-appearing solid breast masses in adolescents. AB - OBJECTIVES: To determine whether the size of palpable solid breast masses in adolescents at initial sonography and their growth at follow-up sonography could be used to decide between conservative management and tissue biopsy. METHODS: This retrospective study included 37 adolescent female patients with 45 palpable benign-appearing solid breast masses on initial sonography. They were grouped as follows: group I, masses undergoing follow-up sonography with subsequent biopsy (n = 9); group II, masses undergoing biopsy without follow-up sonography (n = 13); and group III, masses undergoing follow-up sonography without biopsy (n = 23). The largest dimension, volume, volume change per month, and change in the sonographic appearance were analyzed to predict the need for biopsy. A combination of a largest dimension greater than 3 cm and volume change per month greater than 16% was used to assess the need for biopsy. Sonograms of 22 masses were correlated with histopathologic diagnoses. RESULTS: None of the masses that underwent follow-up sonography showed changes in their sonographic appearance. All masses that underwent biopsy were benign on histopathologic analysis. There was no significant difference in the largest dimension among the groups at initial sonography or between groups I and III at follow-up sonography. The volume change was smaller for fibroadenomas (n = 7; mean, 22.67%) than benign phyllodes tumors (n = 2; mean, 45.30%) in group I, but the difference was not significant (P = .384). However, the volume change for groups I and III showed a significant difference (P = .026). Neither size greater than 3 cm nor volume change greater than 16% predicted pathologic outcomes. CONCLUSIONS: If the combined criteria for assessing benignity of palpable breast masses had been used, biopsy could have been reduced by 89% in group I and deemed not necessary in 96% of group III breast masses. PMID- 25792576 TI - Sonographic characteristics of the uterus in asymptomatic women after second trimester medical termination of pregnancy. AB - OBJECTIVES: The purpose of this study was to evaluate the sonographic characteristics of the uterus after apparently uncomplicated second-trimester medical termination of pregnancy and to follow the evolution of these findings until the return of menstruation. METHODS: Twenty-three women who requested termination of pregnancy at gestational ages between 14 and 20 weeks were recruited. Uterine characteristics were measured by 2- and 3-dimensional transvaginal with or without transabdominal sonography. The uterine anteroposterior diameter, length, and width, endometrial thickness, presence of an endometrial mass, intrauterine vascularity, and endometrial volume were measured within 24 hours, 1, 2, 4, 6, and 8 weeks after termination, and during the postmenstrual phase. RESULTS: The mean uterine anteroposterior diameter, uterine length, uterine width, endometrial thickness, and endometrial volume +/- SD deceased gradually from 66.1 +/- 9.7 to 40.9 +/- 5.3 mm, 131.4 +/- 14.7 to 81.3 +/- 13.8 mm, 84.6 +/- 10.3 to 54.2 +/- 7.6 mm, 25.6 +/- 8.1 to 4.5 +/- 2.6 mm, and 39.4 +/- 22.6 to 2.5 +/- 2.1 mL, respectively, from within 24 hours after termination to the postmenstrual phase. Endometrial masses were identified in 8 women (34.8%) within 4 weeks after termination, which could persist for up to 8 weeks. However, all endometrial masses resolved after menstruation. Minimal and moderate endometrial vascularity was detectable in up to 21.7% after termination; none was detectable in any women after menstruation. CONCLUSIONS: This study provides information on the normal sonographic parameters of the uterus after second-trimester medical termination of pregnancy, which has been lacking in the literature. Also, our findings suggest that all endometrial masses regress with time; therefore, asymptomatic women with an incidental finding of an endometrial mass can be followed without the need for an immediate intervention. PMID- 25792579 TI - Utility of semiquantitative strain elastography for differentiation between benign and malignant solid renal masses. AB - OBJECTIVES: The aim of this study was to determine the role of semiquantitative strain elastography for differentiation of benign and malignant solid renal masses. METHODS: Seventy-one patients with solid renal masses were prospectively examined with ultrasound elastography after grayscale sonography. Strain elastography was used to compare the stiffness of the renal masses and renal parenchyma. The ratio of strain in a renal mass and nearby renal parenchyma was defined as the strain index value. Mean strain index values for benign masses (n = 29; 24 angiomyolipomas and 5 oncocytomas) and malignant masses (n = 42; 34 renal cell carcinomas, 4 transitional cell carcinomas, 3 metastases, and 1 lymphoma) and mean strain index values for angiomyolipomas and renal cell carcinomas were compared. RESULTS: There were no significant differences in the mean age of the patients, mean diameter of the masses, and mean probe-mass distance between benign and malignant groups. The mean strain index value +/- SD for malignant masses (4.05 +/- 2.17) was significantly higher than the value for benign masses (1.43 +/- 0.94; P < .05). The mean strain index value for renal cell carcinomas (4.30 +/- 2.27) was significantly higher than the value for angiomyolipomas (1.28 +/- 1.01; P < .0001). CONCLUSIONS: Strain elastography may be a useful imaging technique for differentiation between benign and malignant solid renal masses. PMID- 25792578 TI - Diagnostic influence of routine point-of-care pocket-size ultrasound examinations performed by medical residents. AB - OBJECTIVES: We aimed to investigate the potential benefit of adding goal-directed ultrasound examinations performed by on-call medical residents using a pocket size imaging device in patients admitted to a medical department. METHODS: A total of 992 emergency admissions to the medical department at a nonuniversity hospital in Norway were included. Patients admitted on dates with an on-call medical resident randomized to use a pocket-size imaging device were eligible for pocket-size cardiac and abdominal ultrasound examinations or standard care. The cardiac examination included estimation of right and left ventricular sizes and global systolic function and regional left ventricular systolic function, evaluation for pleural and pericardial effusion, and valvular disease. The abdominal examination looked for signs of gross abnormalities of the liver, gallbladder, abdominal aorta, inferior vena cava, and urinary system. Six of 12 medical residents with limited ultrasound experience were randomized to perform the examinations. Diagnostic corrections were made, and findings were confirmed by reference standard diagnostics. RESULTS: A total of 199 patients were examined. Median times used were 5.7 minutes for the cardiac examination and 4.7 minutes for the abdominal examination. In 13 patients (6.5%), the examination resulted in a major change in the primary diagnosis. In 21 patients (10.5%), the diagnosis was verified, and in 48 (24.0%), an additional important diagnosis was made. CONCLUSIONS: By implementing pocket-size ultrasound examinations that took less than 11 minutes to the usual care, we corrected, verified, or added important diagnoses in more than 1 of 3 emergency medical admissions. Point-of care examinations with a pocket-size imaging device increased medical residents' diagnostic accuracy and capability. PMID- 25792580 TI - Relationship between the estimated glomerular filtration rate and kidney shear wave speed values assessed by acoustic radiation force impulse elastography: a pilot study. AB - OBJECTIVES: The aim of the study was to establish the relationship between the estimated glomerular filtration rate (GFR) and kidney shear wave speed values assessed by acoustic radiation force impulse (ARFI) elastography. METHODS: Our study included 104 patients with or without chronic kidney disease in which the kidney shear wave speed was evaluated by ARFI elastography and correlated with the estimated GFR. Five ARFI measurements were performed in the parenchyma of each kidney. A median value expressed as meters per second was calculated. RESULTS: Five valid ARFI elastographic measurements were obtained in the right kidney in all patients and in the left kidney in 97.1% of patients. The mean kidney shear wave speed values +/- SD in the right and left kidneys were similar: 2.17 +/- 0.81 versus 2.06 +/- 0.75 m/s (P = .30). The mean kidney shear wave speed decreased with the decrease in the estimated GFR. Statistically significant differences were obtained only when kidney shear wave speed values obtained in patients with an estimated GFR of greater than 90 mL/min/1.73 m(2) were compared to values in patients with stage 4 (estimated GFR, 15-29 mL/min/1.73 m(2)) and stage 5 (estimated GFR, <15 mL/min/1.73 m(2)) chronic kidney disease: 2.32 +/- 0.83 versus 1.62 +/- 0.75 m/s (P = .03) and 2.32 +/- 0.83 versus 1.66 +/- 0.72 m/s (P = .04), respectively. For a cutoff value of 2.26 m/s or lower, kidney shear wave speed had 86.7% sensitivity, 48.3% specificity, a 22.1% positive predictive value, and a 95.6% negative predictive value (area under the receiver operating characteristic curve, 0.692; P = .008) for predicting the presence of an estimated GFR of less than 30 mL/min/1.73 m(2). CONCLUSIONS: Kidney shear wave speed values obtained by ARFI elastography decrease with the decrease in the estimated GFR. PMID- 25792581 TI - Sonographic evaluation of hydronephrosis in the pediatric population: is well tempered sonography necessary? AB - OBJECTIVES: Standardized protocols exist for diuretic renography. There are no specific guidelines regarding hydration before renal sonography. This study assessed the importance of the hydration status by sonographic measurements of the anteroposterior diameter and its effect on Society for Fetal Urology (SFU) hydronephrosis grading. METHODS: Children aged 6 weeks to 16 years (mean age, 22 months) with unilateral SFU grade 3 or 4 hydronephrosis requiring diuretic renal scintigraphy were recruited to undergo prehydration and posthydration renal sonography. Hydrated diuretic renal scintigraphy, or "well-tempered" renography, was then performed. Renal sonograms were reviewed by a blinded pediatric radiologist and pediatric urologist. Two-sided statistical tests assessed whether SFU grades and the anteroposterior diameter changed significantly after hydration. RESULTS: Among 67 kidneys, the pediatric urologist (L.P.M.) and pediatric radiologist (V.J.R.) reported no SFU grade change in 45 (67%) and 52 (78%) kidneys after hydration. In kidneys that changed, the posthydration grade was more likely to be higher. This difference was statistically significant (14 of 22 and 13 of 15 differences were higher grades after hydration for L.P.M. and V.J.R., respectively; P= .06; P= .007). Most kidneys that changed with hydration differed by only 1 SFU grade. Differences greater than 1 grade were seen in 5 control kidneys, which increased from SFU grade 0 to 2. The mean anteroposterior diameter increased significantly between prehydration and posthydration sonography for both hydronephrotic kidneys (1.46 versus 1.72 cm; P< .001) and control kidneys (0.22 versus 0.39 cm; P= .019), but did not correlate with increased SFU grades. CONCLUSIONS: Hydration does have a substantial effect on the anteroposterior diameter, but it does not correlate with a substantial effect on the SFU grade; therefore, well-tempered sonography seems unnecessary. PMID- 25792582 TI - Feasibility and reliability of quantifying passive muscle stiffness in young children by using shear wave ultrasound elastography. AB - OBJECTIVES: The purpose of this study was to investigate the feasibility and reliability of passive muscle stiffness measurements in children by shear wave ultrasound elastography. METHODS: We conducted a prospective cross-sectional study quantifying the passive stiffness of bilateral lateral gastrocnemius muscles during passive stretching in 20 typically developing children (age range, 2.0-12.6 years). Data collected included passive stiffness of the lateral gastrocnemius muscle (shear modulus in kilopascals) at 4 positions of progressive passive foot dorsiflexion, demographic characteristics of the participants, and comparison of demographic characteristics with the shear modulus. RESULTS: Passive stiffness increased with increasing stretching (mean [SD] range of stiffness, 7.1 [2.0] to 36.2 [22.0] kPa). For all 4 foot positions, no significant difference was found between right and left legs (range, P = .42 to P = .98) or between the sexes (range, P = .28 to P > .99). No correlation of passive muscle stiffness with age, body mass index, or ankle range of motion was found. The reliability of measurements was good to excellent (mean [95% confidence interval] range of reliability, 0.67 [0.44-0.83] to 0.80 [0.63-0.90]). CONCLUSIONS: Measurements of passive stiffness of the lateral gastrocnemius muscle are feasible and reliable in children as young as 2 years. Because this study found no significant difference between sex and the side tested in this age group, future studies involving children of this age range may not need to be stratified on the basis of these parameters. Defining normal passive muscle stiffness in children is critical for identifying and understanding the implications of abnormal passive muscle stiffness in children with neuromuscular disorders. PMID- 25792583 TI - Real-time sonoelastography of the quadriceps tendon in patients undergoing chronic hemodialysis. AB - OBJECTIVES: This study aimed to compare sonoelastographic findings for the quadriceps tendon in patients with chronic renal failure who were in a dialysis program to findings in a control group. METHODS: Fifty-three randomly allocated patients (mean age, 54.3 years; range, 27-86 years) with chronic renal failure who were in a dialysis program 3 days a week between January and May 2012 were included. The measurements were performed in both knees of 53 patients undergoing dialysis and 25 individuals in the control group. The tendons were classified as follows: type 1, very stiff tissue (blue); type 2, stiff tissue (blue-green); and type 3, intermediate tissue (green-yellow) according to color mapping. RESULTS: The mean quadriceps tendon thicknesses in the patient group were 4.9 mm (range, 1.9-6.5 mm) for the right knee and 4.9 mm (1.4-6.5 mm) for the left knee; the values in the control group were 5.4 mm (3.6-7.0 mm) for the right knee and 5.4 mm (3.4-7.0 mm) for the left knee. The mean elasticity scores in the patient group were 3.14 (1.03-5.23) for the right knee and 3.33 (1.29-5.00) for the left knee; in the control group, the values were 3.79 (1.73-5.23) and 3.69 (1.23-5.53) for the right and left knees, respectively (right knee, P = .025; left knee, P = .018; Mann-Whitney U test). The quadriceps tendons were significantly thinner in the patient group (right knee, P = .054; left knee, P = .015; Mann-Whitney U test). CONCLUSIONS: Quadriceps tendons in patients with chronic renal failure are thinner and have lower elasticity scores compared to controls. PMID- 25792584 TI - Validation of color Doppler sonography for evaluating relative displacement between the flexor tendon and subsynovial connective tissue. AB - OBJECTIVES: A common pathologic finding in carpal tunnel syndrome is fibrosis and thickening of the subsynovial connective tissue. This finding suggests an etiology of excessive shear forces, with relative longitudinal displacement between the flexor tendon and adjacent subsynovial connective tissue. The purpose of this study was to validate color Doppler sonography for measurement of tendon displacement over time. METHODS: Eight unmatched fresh frozen cadaver arms were used to evaluate color Doppler sonography for measurement of tendon displacement. The middle flexor digitorum superficialis tendon was moved through a physiologic excursion of 20 mm at 3 different tendon velocities (50, 100, and 150 mm/s). RESULTS: We found that color Doppler sonography provided accurate measurement of tendon displacement, with absolute errors of -0.05 mm (50 mm/s), -1.24 mm (100 mm/s), and -2.36 mm (150 mm/s) on average throughout the tendon excursion range. Evaluating relative displacement between the tendon and subsynovial connective tissue during finger flexion-extension movements also offered insight into the gliding mechanism of the subsynovial connective tissue. During flexion, we observed a curvilinear increase in relative displacement, with greater differential motion at the end range of displacement, likely due to the sequential stretch of the fibrils between successive layers of the subsynovial connective tissue. In extension, there was a linear return in relative displacement, suggesting a different unloading mechanism characterized by uniform relaxation of fibrils. CONCLUSIONS: We demonstrated the validity of color Doppler displacement for use in the evaluation of relative motion. Color Doppler sonography is useful in our understanding of the behavior of the subsynovial connective tissue during tendon excursion, which may elucidate the role of finger motion in the etiology of shear injury. PMID- 25792585 TI - Sonographic features of thyroid nodules that may help distinguish clinically atypical subacute thyroiditis from thyroid malignancy. AB - OBJECTIVES: The purpose of this study was to evaluate sonographic features for distinguishing clinically atypical subacute thyroiditis from malignant thyroid nodules. METHODS: A total of 165 hypoechoic thyroid nodules without calcification in 135 patients with histologic diagnosis were included in this study. These nodules were classified into 2 groups: a thyroiditis group (55 nodules in 36 patients) and a malignancy group (110 nodules in 99 patients). The sonographic features of the groups were retrospectively reviewed. RESULTS: No significant differences were detected for the variables of marked echogenicity, a taller-than wide shape, and mixed vascularity. However, a poorly defined margin was detected more frequently in the thyroiditis group than the malignancy group (P < .05); it yielded a high capability for differential diagnosis of atypical subacute thyroiditis, with sensitivity and specificity of 87.3% and 80.9%, respectively. Centripetal reduction echogenicity was observed exclusively in the thyroiditis group, with high specificity (100%) but low sensitivity (21.8%) for atypical subacute thyroiditis diagnosis. All of the thyroiditis nodules with a positive color signal showed noninternal vascularity (negative predictive value, 100%). CONCLUSIONS: There is a considerable overlap between the sonographic features of atypical subacute thyroiditis and thyroid malignancy. However, the margin, echogenicity, and vascularity type are helpful indicators for differential diagnosis of atypical subacute thyroiditis. PMID- 25792586 TI - Sonographic appearance of thyroid cancer in patients with Hashimoto thyroiditis. AB - OBJECTIVES: To determine whether the sonographic appearance of thyroid cancer differs in patients with and without Hashimoto thyroiditis. METHODS: Patients with histologically proven thyroid cancer who had thyroid peroxidase (TPO) antibodies measured and sonography performed preoperatively were included. We evaluated each nodule for size, echogenicity, composition, margins, halo, and vascularity and evaluated the background heterogeneity of the gland. RESULTS: There were 162 thyroid cancers in 145 patients. Forty-two patients (29.0%) had Hashimoto thyroiditis with positive TPO antibodies, and 103 patients (71.0%) had negative TPO antibodies. The background echogenicity was more often heterogeneous in TPO antibody-positive patients compared to those who had negative TPO antibodies (57.1% versus 26.2%; P= .0005). Comparing cancers in TPO antibody positive to TPO antibody-negative patients, there was no significant difference in the size, echogenicity, composition, margins, halo presence, calcification presence and type, or vascularity of the cancerous nodule (P > .05). Among TPO antibody-positive patients, comparing thyroid cancerous nodules in patients with heterogeneous glands to those with homogeneous glands, there was no significant difference in any sonographic characteristic except the margin of the nodule, which was more often irregular or poorly defined in heterogeneous glands and more often smooth in homogeneous glands (P< .05). CONCLUSIONS: Sonographic features of thyroid cancer are similar in patients with and without Hashimoto thyroiditis. Among patients with Hashimoto thyroiditis and thyroid cancer, the sonographic appearance of the cancerous nodule is similar, except that cancerous nodule margins are more likely to be irregular or poorly defined when the gland is heterogeneous. PMID- 25792588 TI - Gel pad application for automated breast sonography. AB - The purpose of this study was to describe the technical aspects of gel pad application for automated breast sonography and to show its effects on pain relief, scan coverage, and image quality. Twenty patients underwent 2 sets of automated breast sonography with and without gel pad application and were then asked to provide feedback on the examination-related pain. Scan coverage and image quality were compared quantitatively and qualitatively. The degree of pain was significantly decreased after gel pad application (P < .0001). The scan coverage was expanded particularly at the mid-portion of the breast. Image quality was satisfactory without significant differences between the sets. Gel pad application for automated breast sonography is easy and provides significant pain relief. The scan coverage was expanded, while the image quality was maintained. PMID- 25792587 TI - Sonographic evaluation of common peroneal neuropathy in patients with foot drop. AB - The common peroneal nerve arises from the sciatic nerve and is subject to a variety of abnormalities. Although diagnosis is often is based on the clinical findings and electrodiagnostic tests, high-resolution sonography has an increasing role in determining the type and location of common peroneal nerve abnormalities and other peripheral nerve disorders. This article reviews the normal sonographic appearance of the common peroneal nerve and the findings in 21 patients with foot drop related to common peroneal neuropathy. PMID- 25792589 TI - Sonographically guided posteromedial approach for intra-articular knee injections: a safe, accurate, and efficient method. AB - Osteoarthritis of the knee can be a debilitating and extremely painful condition. In patients who desire to postpone knee arthroplasty or in those who are not surgical candidates, percutaneous knee injection therapies have the potential to reduce pain and swelling, maintain joint mobility, and minimize disability. Published studies cite poor accuracy of intra-articular knee joint injections without imaging guidance. We present a sonographically guided posteromedial approach to intra-articular knee joint injections with 100% accuracy and no complications in a consecutive series of 67 patients undergoing subsequent computed tomographic or magnetic resonance arthrography. Although many other standard approaches are available, a posteromedial intra-articular technique is particularly useful in patients with a large body habitus and theoretically allows for simultaneous aspiration of Baker cysts with a single sterile preparation and without changing the patient's position. The posteromedial technique described in this paper is not compared or deemed superior to other standard approaches but, rather, is presented as a potentially safe and efficient alternative. PMID- 25792591 TI - Antepartum diagnosis of complete fetal bladder duplication in the sagittal plane. PMID- 25792590 TI - Focused cardiac ultrasound: uncommon but critical diagnoses made at the point of care. AB - Cardiovascular and respiratory conditions in acute care require rapid, critical decision making, often with limited clinical information. Focused cardiac ultrasound (FOCUS) can aid in diagnosis by providing information that may not be evident from a patient's medical history, physical examination, and ancillary tests. Eight cases are presented in which FOCUS drastically altered the management of patient care, shortened the differential diagnosis, or allowed for the development of a definitive diagnosis. In 3 cases, diagnoses that were not initially suspected were identified by FOCUS. In the remaining cases, uncommon yet critical diagnoses were established at early stages along the patients' courses of care. PMID- 25792592 TI - Prenatal sonographic diagnosis of a pericardial cyst. PMID- 25792593 TI - Monochorionic twins misclassified as dichorionic: was there an empty tent? PMID- 25792594 TI - Reply: To PMID 21210485. PMID- 25792596 TI - Two distinct modes for propagation of histone PTMs across the cell cycle. AB - Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC (stable isotope labeling with amino acids in cell culture) labeling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and trimethylation marks are diluted twofold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle. PMID- 25792595 TI - Viral noncoding RNAs: more surprises. AB - Eukaryotic cells produce several classes of long and small noncoding RNA (ncRNA). Many DNA and RNA viruses synthesize their own ncRNAs. Like their host counterparts, viral ncRNAs associate with proteins that are essential for their stability, function, or both. Diverse biological roles--including the regulation of viral replication, viral persistence, host immune evasion, and cellular transformation--have been ascribed to viral ncRNAs. In this review, we focus on the multitude of functions played by ncRNAs produced by animal viruses. We also discuss their biogenesis and mechanisms of action. PMID- 25792597 TI - Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex. AB - ATP-dependent chromatin remodeling complexes alter chromatin structure through interactions with chromatin substrates such as DNA, histones, and nucleosomes. However, whether chromatin remodeling complexes have the ability to regulate nonchromatin substrates remains unclear. Saccharomyces cerevisiae checkpoint kinase Mec1 (ATR in mammals) is an essential master regulator of genomic integrity. Here we found that the SWI/SNF chromatin remodeling complex is capable of regulating Mec1 kinase activity. In vivo, Mec1 activity is reduced by the deletion of Snf2, the core ATPase subunit of the SWI/SNF complex. SWI/SNF interacts with Mec1, and cross-linking studies revealed that the Snf2 ATPase is the main interaction partner for Mec1. In vitro, SWI/SNF can activate Mec1 kinase activity in the absence of chromatin or known activators such as Dpb11. The subunit requirement of SWI/SNF-mediated Mec1 regulation differs from that of SWI/SNF-mediated chromatin remodeling. Functionally, SWI/SNF-mediated Mec1 regulation specifically occurs in S phase of the cell cycle. Together, these findings identify a novel regulator of Mec1 kinase activity and suggest that ATP dependent chromatin remodeling complexes can regulate nonchromatin substrates such as a checkpoint kinase. PMID- 25792598 TI - Protein arginine methyltransferase CARM1 attenuates the paraspeckle-mediated nuclear retention of mRNAs containing IRAlus. AB - In many cells, mRNAs containing inverted repeated Alu elements (IRAlus) in their 3' untranslated regions (UTRs) are inefficiently exported to the cytoplasm. Such nuclear retention correlates with paraspeckle-associated protein complexes containing p54(nrb). However, nuclear retention of mRNAs containing IRAlus is variable, and how regulation of retention and export is achieved is poorly understood. Here we show one mechanism of such regulation via the arginine methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1). We demonstrate that disruption of CARM1 enhances the nuclear retention of mRNAs containing IRAlus. CARM1 regulates this nuclear retention pathway at two levels: CARM1 methylates the coiled-coil domain of p54(nrb), resulting in reduced binding of p54(nrb) to mRNAs containing IRAlus, and also acts as a transcription regulator to suppress NEAT1 transcription, leading to reduced paraspeckle formation. These actions of CARM1 work together synergistically to regulate the export of transcripts containing IRAlus from paraspeckles under certain cellular stresses, such as poly(I:C) treatment. This work demonstrates how a post translational modification of an RNA-binding protein affects protein-RNA interaction and also uncovers a mechanism of transcriptional regulation of the long noncoding RNA NEAT1. PMID- 25792602 TI - Retraction: Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis. PMID- 25792600 TI - Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. AB - Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA. PMID- 25792599 TI - A retrovirus packages nascent host noncoding RNAs from a novel surveillance pathway. AB - Although all retroviruses recruit host cell RNAs into virions, both the spectrum of RNAs encapsidated and the mechanisms by which they are recruited remain largely unknown. Here, we used high-throughput sequencing to obtain a comprehensive description of the RNAs packaged by a model retrovirus, murine leukemia virus. The major encapsidated host RNAs are noncoding RNAs (ncRNAs) and members of the VL30 class of endogenous retroviruses. Remarkably, although Moloney leukemia virus (MLV) assembles in the cytoplasm, precursors to specific tRNAs, small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs) are all enriched in virions. Consistent with their cytoplasmic recruitment, packaging of both pre-tRNAs and U6 snRNA requires the nuclear export receptor Exportin-5. Adenylated and uridylated forms of these RNAs accumulate in cells and virions when the cytoplasmic exoribonuclease DIS3L2 and subunits of the RNA exosome are depleted. Together, our data reveal that MLV recruits RNAs from a novel host cell surveillance pathway in which unprocessed and unneeded nuclear ncRNAs are exported to the cytoplasm for degradation. PMID- 25792603 TI - Retraction: Activation of miR-31 function in already-established metastases elicits metastatic regression. PMID- 25792601 TI - SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer. AB - Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-kappaB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-kappaB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4 NF-kappaB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention. PMID- 25792604 TI - Asc1, homolog of human RACK1, prevents frameshifting in yeast by ribosomes stalled at CGA codon repeats. AB - Quality control systems monitor and stop translation at some ribosomal stalls, but it is unknown if halting translation at such stalls actually prevents synthesis of abnormal polypeptides. In yeast, ribosome stalling occurs at Arg CGA codon repeats, with even two consecutive CGA codons able to reduce translation by up to 50%. The conserved eukaryotic Asc1 protein limits translation through internal Arg CGA codon repeats. We show that, in the absence of Asc1 protein, ribosomes continue translating at CGA codons, but undergo substantial frameshifting with dramatically higher levels of frameshifting occurring with additional repeats of CGA codons. Frameshifting depends upon the slow or inefficient decoding of these codons, since frameshifting is suppressed by increased expression of the native tRNA(Arg(ICG)) that decodes CGA codons by wobble decoding. Moreover, the extent of frameshifting is modulated by the position of the CGA codon repeat relative to the translation start site. Thus, translation fidelity depends upon Asc1-mediated quality control. PMID- 25792606 TI - Epidemiologic design and analysis for proteomic studies: a primer on -omic technologies. AB - Proteome analysis is increasingly being used in investigations elucidating the molecular basis of disease, identifying diagnostic and prognostic markers, and ultimately improving patient care. We appraised the current status of proteomic investigations using human samples, including the state of the art in proteomic technologies, from sample preparation to data evaluation approaches, as well as key epidemiologic, statistical, and translational issues. We systematically reviewed the most highly cited clinical proteomic studies published between January 2009 and March 2014 that included a minimum of 100 samples, as well as strategies that have been successfully implemented to enhance the translational relevance of proteomic investigations. Limited comparability between studies and lack of specification of biomarker context of use are frequently observed. Nevertheless, there are initial examples of successful biomarker discovery in cross-sectional studies followed by validation in high-risk longitudinal cohorts. Translational potential is currently hindered, as limitations in proteomic investigations are not accounted for. Interdisciplinary communication between proteomics experts, basic researchers, epidemiologists, and clinicians, an orchestrated assimilation of required resources, and a more systematic translational outlook for accumulation of evidence may augment the public health impact of proteomic investigations. PMID- 25792605 TI - TeloPIN: a database of telomeric proteins interaction network in mammalian cells. AB - Interaction network surrounding telomeres has been intensively studied during the past two decades. However, no specific resource by integrating telomere interaction information data is currently available. To facilitate the understanding of the molecular interaction network by which telomeres are associated with biological process and diseases, we have developed TeloPIN (Telomeric Proteins Interaction Network) database (http://songyanglab.sysu.edu.cn/telopin/), a novel database that points to provide comprehensive information on protein-protein, protein-DNA and protein-RNA interaction of telomeres. TeloPIN database contains four types of interaction data, including (i) protein--protein interaction (PPI) data, (ii) telomeric proteins ChIP-seq data, (iii) telomere-associated proteins data and (iv) telomeric repeat-containing RNAs (TERRA)-interacting proteins data. By analyzing these four types of interaction data, we found that 358 and 199 proteins have more than one type of interaction information in human and mouse cells, respectively. We also developed table browser and TeloChIP genome browser to help researchers with better integrated visualization of interaction data from different studies. The current release of TeloPIN database includes 1111 PPI, eight telomeric protein ChIP-seq data sets, 1391 telomere-associated proteins and 183 TERRA-interacting proteins from 92 independent studies in mammalian cells. The interaction information provided by TeloPIN database will greatly expand our knowledge of telomeric proteins interaction network. PMID- 25792608 TI - Adjusting for bias due to incomplete case ascertainment in case-control studies of birth defects. AB - Case-control studies of birth defects might be subject to selection bias when there is incomplete ascertainment of cases among pregnancies that are terminated after a prenatal diagnosis of the defect. We propose a simple method to estimate inverse probability of selection weights (IPSWs) for cases ascertained from both pregnancies that end in termination and those that do not end in termination using data directly available from the National Birth Defects Prevention Study and other published information. The IPSWs can then be used to adjust for selection bias analytically. We can also allow for uncertainty in the selection probabilities through probabilistic bias analysis. We provide an illustrative example using data from National Birth Defects Prevention Study (1997-2009) to examine the association between prepregnancy obesity (body mass index, measured as weight in kilograms divided by height in meters squared, of >=30 vs. <30) and spina bifida. The unadjusted odds ratio for the association between prepregnancy obesity and spina bifida was 1.48 (95% confidence interval: 1.26, 1.73), and the simple selection bias-adjusted odds ratio was 1.26 (95% confidence interval: 1.04, 1.53). The probabilistic bias analysis resulted in a median adjusted odds ratio of 1.22 (95% simulation interval: 0.97, 1.47). The proposed method provides a quantitative estimate of the IPSWs and the bias introduced by incomplete ascertainment of cases among terminated pregnancies conditional on a set of assumptions. PMID- 25792607 TI - Tuberculosis control in South African gold mines: mathematical modeling of a trial of community-wide isoniazid preventive therapy. AB - A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006-2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial ("optimized intervention"), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus-positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens. PMID- 25792610 TI - Evidence for widespread subfunctionalization of splice forms in vertebrate genomes. AB - Gene duplication and alternative splicing are important sources of proteomic diversity. Despite research indicating that gene duplication and alternative splicing are negatively correlated, the evolutionary relationship between the two remains unclear. One manner in which alternative splicing and gene duplication may be related is through the process of subfunctionalization, in which an alternatively spliced gene upon duplication divides distinct splice isoforms among the newly generated daughter genes, in this way reducing the number of alternatively spliced transcripts duplicate genes produce. Previously, it has been shown that splice form subfunctionalization will result in duplicate pairs with divergent exon structure when distinct isoforms become fixed in each paralog. However, the effects of exon structure divergence between paralogs have never before been studied on a genome-wide scale. Here, using genomic data from human, mouse, and zebrafish, we demonstrate that gene duplication followed by exon structure divergence between paralogs results in a significant reduction in levels of alternative splicing. In addition, by comparing the exon structure of zebrafish duplicates to the co-orthologous human gene, we have demonstrated that a considerable fraction of exon divergent duplicates maintain the structural signature of splice form subfunctionalization. Furthermore, we find that paralogs with divergent exon structure demonstrate reduced breadth of expression in a variety of tissues when compared to paralogs with identical exon structures and singletons. Taken together, our results are consistent with subfunctionalization partitioning alternatively spliced isoforms among duplicate genes and as such highlight the relationship between gene duplication and alternative splicing. PMID- 25792609 TI - Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells. AB - Recently, a handful of intergenic long noncoding RNAs (lncRNAs) have been shown to compete with mRNAs for binding to miRNAs and to contribute to development and disease. Beyond these reports, little is yet known of the extent and functional consequences of miRNA-mediated regulation of mRNA levels by lncRNAs. To gain further insight into lncRNA-mRNA miRNA-mediated crosstalk, we reanalyzed transcriptome-wide changes induced by the targeted knockdown of over 100 lncRNA transcripts in mouse embryonic stem cells (mESCs). We predicted that, on average, almost one-fifth of the transcript level changes induced by lncRNAs are dependent on miRNAs that are highly abundant in mESCs. We validated these findings experimentally by temporally profiling transcriptome-wide changes in gene expression following the loss of miRNA biogenesis in mESCs. Following the depletion of miRNAs, we found that >50% of lncRNAs and their miRNA-dependent mRNA targets were up-regulated coordinately, consistent with their interaction being miRNA-mediated. These lncRNAs are preferentially located in the cytoplasm, and the response elements for miRNAs they share with their targets have been preserved in mammals by purifying selection. Lastly, miRNA-dependent mRNA targets of each lncRNA tended to share common biological functions. Post-transcriptional miRNA-mediated crosstalk between lncRNAs and mRNA, in mESCs, is thus surprisingly prevalent, conserved in mammals, and likely to contribute to critical developmental processes. PMID- 25792611 TI - Surviving the unsurvivable. PMID- 25792612 TI - Pay-for-performance and primary care physicians: lessons from the U.K Quality and Outcomes Framework for local incentive schemes. PMID- 25792613 TI - In defence of Romberg's test. PMID- 25792614 TI - Practice only makes permanent. Perfect practice makes perfect. PMID- 25792615 TI - Virtue ethics--an old answer to a new dilemma? Part 2. The case for inclusive virtue ethics. AB - While Principlism is a widely accepted consensus statement for ethics, the moral theory that underpins it faces serious challenges. This two-part paper proposes a version of virtue theory as a more grounded system of moral analysis. Part 2 examines the role of basic moral theory as the foundation to ethics and suggests how virtue theory can be used as a central framework for ethics while being inclusive of insights from deontology and consequentialism. PMID- 25792618 TI - A radical new structure for general practice in the U.K. PMID- 25792617 TI - Advantages of concurrent preparation and reporting of systematic reviews of quantitative and qualitative evidence. PMID- 25792616 TI - Lessons learned from the casualties of war: battlefield medicine and its implication for global trauma care. AB - According to the Global Burden of Disease, trauma is now responsible for five million deaths each year. High-income countries have made great strides in reducing trauma-related mortality figures but low-middle-income countries have been left behind with high trauma-related fatality rates, primarily in the younger population. Much of the progress high-income countries have made in managing trauma rests on advances developed in their armed forces. This analysis looks at the recent advances in high-income military trauma systems and the potential transferability of those developments to the civilian health systems particularly in low-middle-income countries. It also evaluates some potential lifesaving trauma management techniques, proven effective in the military, and the barriers preventing these from being implemented in civilian settings. PMID- 25792622 TI - Hypothesis testing at the extremes: fast and robust association for high throughput data. AB - A number of biomedical problems require performing many hypothesis tests, with an attendant need to apply stringent thresholds. Often the data take the form of a series of predictor vectors, each of which must be compared with a single response vector, perhaps with nuisance covariates. Parametric tests of association are often used, but can result in inaccurate type I error at the extreme thresholds, even for large sample sizes. Furthermore, standard two-sided testing can reduce power compared with the doubled [Formula: see text]-value, due to asymmetry in the null distribution. Exact (permutation) testing is attractive, but can be computationally intensive and cumbersome. We present an approximation to exact association tests of trend that is accurate and fast enough for standard use in high-throughput settings, and can easily provide standard two-sided or doubled [Formula: see text]-values. The approach is shown to be equivalent under permutation to likelihood ratio tests for the most commonly used generalized linear models (GLMs). For linear regression, covariates are handled by working with covariate-residualized responses and predictors. For GLMs, stratified covariates can be handled in a manner similar to exact conditional testing. Simulations and examples illustrate the wide applicability of the approach. The accompanying mcc package is available on CRAN http://cran.r project.org/web/packages/mcc/index.html. PMID- 25792623 TI - Bayesian partial linear model for skewed longitudinal data. AB - Unlike majority of current statistical models and methods focusing on mean response for highly skewed longitudinal data, we present a novel model for such data accommodating a partially linear median regression function, a skewed error distribution and within subject association structures. We provide theoretical justifications for our methods including asymptotic properties of the posterior and associated semiparametric Bayesian estimators. We also provide simulation studies to investigate the finite sample properties of our methods. Several advantages of our method compared with existing methods are demonstrated via analysis of a cardiotoxicity study of children of HIV-infected mothers. PMID- 25792625 TI - Reading Achievement, Mastery, and Performance Goal Structures Among Students With Learning Disabilities: A Nonlinear Perspective. AB - The purpose of the present study was to examine the hypothesis that a nonlinear relationship exists between a performance-classroom climate and the reading achievement of adolescent students with learning disabilities (LD). Participants were 62 students with LD (Grades 5-9) from public elementary schools in northern Greece. Classroom climate was assessed using the Patterns of Adaptive Learning Styles. Achievement in reading was assessed using a normative reading assessment. Data were analyzed by means of catastrophe theory in which the behavior is predicted as a function of two control variables, the asymmetry factor and the bifurcation factor. Reading achievement (word identification) was predicted by students' ability to decode pseudowords (asymmetry variable) and by a mastery or performance motivational discourse (bifurcation factor). Results indicated that in classrooms with a performance goal structure, the cusp model fit the data and accounted for 54% of the variance in real word identification. In this condition, the association between pseudoword reading and real word reading was nonlinear. When a mastery climate was tested as a bifurcation variable, results indicated that its effect was nonsignificant and that instead the linear model fitted the data more adequately. Thus, increases in a classroom's performance motivational discourse are associated with sudden, unpredictable, and discontinued changes in students' reading performance. PMID- 25792624 TI - Markov counting models for correlated binary responses. AB - We propose a class of continuous-time Markov counting processes for analyzing correlated binary data and establish a correspondence between these models and sums of exchangeable Bernoulli random variables. Our approach generalizes many previous models for correlated outcomes, admits easily interpretable parameterizations, allows different cluster sizes, and incorporates ascertainment bias in a natural way. We demonstrate several new models for dependent outcomes and provide algorithms for computing maximum likelihood estimates. We show how to incorporate cluster-specific covariates in a regression setting and demonstrate improved fits to well-known datasets from familial disease epidemiology and developmental toxicology. PMID- 25792626 TI - Posterior subtenon triamcinolone acetonide injection as a primary treatment in eyes with acute Vogt-Koyanagi-Harada disease. AB - BACKGROUND/AIMS: To investigate the effectiveness of isolated subtenon triamcinolone acetonide injection (STI) as a primary treatment in eyes with acute Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Retrospective, observational, cross sectional study. METHODS: The data from 27 eyes in 14 patients with acute VKH treated with STI therapy were analysed retrospectively. The time course change in ocular inflammation, best corrected visual acuity (BCVA) and numbers of recurrences were examined. RESULTS: STI led to prompt improvement of BCVA within a week after the primary treatment. After completing therapy, patients with VKH had improved BCVA compared with baseline. In six eyes of three patients (22.2%) treated with STI, ocular inflammation was refractory, or VKH was recurrent despite the treatment. There was significant difference between groups with and without recurrences of inflammation in the frequency of headaches before treatment. In the present study, 21 eyes of 11 patients (77.8%) achieved complete resolution of VKH without recurrence after STI therapy alone. CONCLUSIONS: This study demonstrated that isolated STI therapy is a useful, minimally invasive, primary treatment option for patients with acute VKH without systemic disorders. PMID- 25792627 TI - Comparison of antiresorptive effect of hormone therapy and ibandronate in postmenopausal osteoporotic women by assessing type I collagen C-telopeptide levels. AB - OBJECTIVES: The aim of this study is to compare the antiresorptive effect of hormone therapy and oral ibandronate in postmenopausal osteoporotic women by measuring bone mineral density (BMD) and degradation products of C-terminal telopeptide of type I collagen (CTX) using serum crosslaps ELISA. STUDY DESIGN: The study is a randomized comparative trial. METHODS: About 60 women with age > 40 years, having either surgical or medical menopause with T- or Z-score below 2.5 SD were included in the study. They were randomized into two groups of 30 each; one group received conventional hormone therapy (group I) and the other group received ibandronate monthly (group II). The treatment was given for 6 months. RESULTS: The BMD increased from 0.894 g/cm(2) to 0.933 g/cm(2) (p < 0.01) in group I and from 0.865 g/cm(2) to 0.934 g/cm(2) (p < 0.01) in group II. The increase in BMD in group I (4.3%) was less than group II (7.9%) which was significant (p < 0.01). The serum CTX levels also showed significant reduction in both groups after 6 months of therapy; more reduction was seen in group II as compared to group I (41.5% vs. 4.6%, p < 0.01). CONCLUSION: Ibandronate can be used as a substitute to hormone therapy in women presenting with osteoporosis. Long-term studies are needed to authenticate the observation. PMID- 25792629 TI - Noninterventional statistical comparison of BTS and CHEST guidelines for size and severity in primary pneumothorax. PMID- 25792631 TI - Influenza virus-induced lung injury: pathogenesis and implications for treatment. AB - The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy. PMID- 25792632 TI - Video directly observed therapy for treatment of tuberculosis is patient-oriented and cost-effective. PMID- 25792633 TI - Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia. AB - Infant 13-valent pneumococcal conjugate vaccination (PCV13) was introduced to the UK in 2010. Its impact on serotypes implicated in adult non-bacteraemic pneumococcal pneumonia is not known. Beginning in 2008, a 5-year prospective cohort study of adults admitted to hospital with community-acquired pneumonia (CAP) was conducted. Pneumococcal serotype was established using a validated multiplex immunoassay (Bio-Plex; Bio-Rad, Hercules, CA, USA). The overall incidence for hospitalised CAP and pneumococcal CAP was 79.9 (95% CI 76.6-83.3) and 23.4 (95% CI 21.6-25.3) per 100,000 population, respectively. A decline in CAP (incidence rate ratio (IRR) per year 0.96, 95% CI 0.94-0.99; p=0.016) and pneumococcal CAP (IRR per year 0.84, 95% CI 0.80-0.89; p<0.001) was observed over the 5-year period of the study. Between the pre- and post-PCV13 periods of the study, the incidence of CAP due to serotypes included in the PCV7 declined by 88% (IRR 0.12, 95% CI 0.08-0.20; p<0.001), and CAP due to the additional 6 serotypes in PCV13 declined by 30% (IRR 0.70, 95% CI 0.51-0.96; p=0.024). Incidence of adult pneumococcal pneumonia declined over the last 5 years, with serotypes included in PCV13 declining post-PCV13 introduction, indicating early herd protection effects from PCV13 infant vaccination on adult non-bacteraemic disease. These effects may accrue over the coming years with implications for national pneumococcal vaccination policies in adults. PMID- 25792630 TI - Towards tuberculosis elimination: an action framework for low-incidence countries. AB - This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards "pre-elimination" (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions. PMID- 25792636 TI - Myeloid-related protein-14 deficiency promotes inflammation in staphylococcal pneumonia. AB - Staphylococcus aureus has evolved as an important cause of pneumonia in both hospital and community settings. Staphylococcal lung infection can lead to overwhelming pulmonary inflammation. During infection, neutrophils release complexes of myeloid-related protein (MRP)8 and MRP14 (MRP8/14). MRP8/14 has been shown to exert pro-inflammatory and chemotactic activity, and to assist in the killing of S. aureus. In the current study we sought to determine the role of MRP8/14 in the host response during S. aureus pneumonia.Pneumonia was induced in wildtype and MRP14-deficient mice (mice unable to form MRP8/14) by intranasal inoculation of 1*10(7) CFU of S. aureus USA300. Mice were sacrificed at 6, 24, 48 or 72 h after infection for analyses.S. aureus pneumonia was associated with a strong rise in MRP8/14 in bronchoalveolar lavage fluid and lung tissue. Surprisingly, MRP14 deficiency had a limited effect on bacterial clearance and was associated with increased cytokine levels in bronchoalveolar lavage fluid and aggravated lung histopathology. MRP14 deficiency in addition was associated with a diminished transmigration of neutrophils into bronchoalveolar lavage fluid at late time-points after infection together with reduced release of nucleosomes.MRP8/14 serves in an unexpected protective role for the lung in staphylococcal pneumonia. PMID- 25792635 TI - Management of bronchiectasis in adults. AB - Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis. The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life. Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation. This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials. PMID- 25792634 TI - Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells. AB - The epithelial response to bacterial airway infection, a common feature of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied. However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to investigate its impact on DeltaF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells. CFTR expression/maturation was evaluated by immunoblotting and its function by short-circuit current measurements. A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells. In CFBE-DeltaF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT-325. We also confirmed a deleterious impact of PsaDM on wt CFTR currents in non-cystic fibrosis primary airway cells as well as on the rescue of DeltaF508-CFTR function induced by VRT-325 in primary cystic fibrosis cells. These findings show that CFTR function could be impaired in non-cystic fibrosis patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be affected by infectious components, which should be taken into account in screening assays of correctors. PMID- 25792637 TI - Suboptimal specificity of Xpert MTB/RIF among treatment-experienced patients. PMID- 25792639 TI - Future trends in cystic fibrosis demography in 34 European countries. AB - Median survival has increased in people with cystic fibrosis (CF) during the past six decades, which has led to an increased number of adults with CF. The future impact of changes in CF demographics has not been evaluated. The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Data were obtained from the European Cystic Fibrosis Society Patient Registry. Population forecasts were performed for countries that have extensive CF population coverage and at least 4 years of longitudinal data by modelling future entering and exiting flows in registry cohorts. For the other countries, population projections were performed based on assumptions from knowledge of current CF epidemiology. Western European countries' forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase.It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required. PMID- 25792638 TI - Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected nonsquamous nonsmall cell lung cancer. AB - Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab. Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg.kg(-1) on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg.m(-2) on day 1, every 3 weeks) and gemcitabine (1250 mg.m(-2) on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg.kg(-1) on day 1, every 3 weeks) (PGB) until progression. 224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39-2.45; p<0.0001) and overall survival (median 12.6 versus 17.8 months; HR 1.41, 95% CI 1.01-1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB. Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection. PMID- 25792640 TI - Large trials, new knowledge: the changing face of COPD management. AB - Large, well-designed, drug-treatment trials have allowed useful advances to be made in the treatment and diagnosis of chronic obstructive pulmonary disease (COPD). The two main clinical trial designs that provide evidence of effectiveness are randomised controlled trials (RCTs) and observational studies. RCTs are generally considered to provide more robust evidence than that obtained from observational studies and can generate informative secondary analyses in addition to the primary research query. In COPD, however, well-designed comparator-controlled RCTs, although successful, have been shown to have some limitations, such as a lack of generalisability. The findings of observational studies, whilst prone to bias, can generate valuable data and have also provided useful information relating to the efficacy of treatments in the current COPD management guidelines. This review focuses on major COPD studies published since 2007 (including UPLIFT, TIOSPIR, ECLIPSE and COPDGene), and assesses the influence such RCTs and large observational studies have had on our knowledge of COPD, and how these may impact future trial designs. PMID- 25792642 TI - Review: Antibiotic discovery in the age of structural biology - a comprehensive overview with special reference to development of drugs for the treatment of Pseudomonas aeruginosa infection. AB - Due to the persistence and spread of antibiotic resistance, the discovery and exploitation of new antibiotic targets should be the subject of intensive research. Effective strategies are required to develop antibiotic alternatives. Antibiotics that act on new targets or via novel mechanisms have the greatest likelihood of overcoming resistance. In particular, there is a lack of specific antibiotics for Pseudomonas aeruginosa, one of the leading causes of healthcare associated infections, exhibiting high resistance levels. Herein we describe how structure-based drug design can be used to achieve new antibiotics for the treatment of Pseudomonas aeruginosa infection, using an essential enzyme of the fatty acid synthesis pathway from P. aeruginosa as an example. PMID- 25792641 TI - Multidimensional Dyspnea Profile: an instrument for clinical and laboratory research. AB - There is growing awareness that dyspnoea, like pain, is a multidimensional experience, but measurement instruments have not kept pace. The Multidimensional Dyspnea Profile (MDP) assesses overall breathing discomfort, sensory qualities, and emotional responses in laboratory and clinical settings. Here we provide the MDP, review published evidence regarding its measurement properties and discuss its use and interpretation. The MDP assesses dyspnoea during a specific time or a particular activity (focus period) and is designed to examine individual items that are theoretically aligned with separate mechanisms. In contrast, other multidimensional dyspnoea scales assess recalled recent dyspnoea over a period of days using aggregate scores. Previous psychophysical and psychometric studies using the MDP show that: 1) subjects exposed to different laboratory stimuli could discriminate between air hunger and work/effort sensation, and found air hunger more unpleasant; 2) the MDP immediate unpleasantness scale (A1) was convergent with common dyspnoea scales; 3) in emergency department patients, two domains were distinguished (immediate perception, emotional response); 4) test retest reliability over hours was high; 5) the instrument responded to opioid treatment of experimental dyspnoea and to clinical improvement; 6) convergent validity with common instruments was good; and 7) items responded differently from one another as predicted for multiple dimensions. PMID- 25792643 TI - Review: MicroRNAs in assisted reproduction and their potential role in IVF failure. AB - MicroRNAs (miRNAs) have recently emerged as important regulators of gene expression stability. In the endometrium, miRNAs are involved in the dynamic changes associated with the menstrual cycle, implicated in implantation and in reproductive disorders. We performed a review in an attempt to assess the potential biological pathways linking altered miRNAs profiles with in vitro fertilisation (IVF) failure. Crucially, as miRNAs appear to have a significant role in the course of reproduction, they are excellent research candidates with the potential to enable a better understanding over the underlying molecular activities that prevent implantation and further progression of the embryo. Further steps include in-depth pathway mapping of the implantation process and the characterization of the respective miRNAs and associated links. The efficiency of any intervention should determine whether miRNA profiling could possibly be adopted in routine practice to substantially improve the diagnostic accuracy and, in parallel, the directed treatment of the next-generation IVF. PMID- 25792644 TI - pKC modulates integrin expression that contributes to fibrotic changes in irradiated thyroid tissue. AB - AIM: We hypothesized that radiation-induced fibrosis was, in part, a result of altered signal transduction that directly modulates integrin expression and may indirectly affect the extracellular matrix (ECM). Major focus was given on protein kinase C (pKC). MATERIALS AND METHODS: Rat FRTL-5 and primary thyroid cells were exposed to proton radiation (5 and 10 Gy). Hours to days after exposure, a series of assays were performed. In addition, the neck region of Lewis rats was proton-irradiated to 40 Gy (5 Gy/day or 10 Gy/day). At 11 weeks after exposure, thyroid tissue was evaluated. RESULTS: Accumulation of ECM in irradiated FRTL-5 and primary thyroid cells was coincident with loss of tissue organization and follicularization at one or more doses and time points. Several pKC isoforms increased post-irradiation, which coincided with modulated integrin expression; fibronectin, laminin and collagen were also altered (p<0.05 vs. 0 Gy). Modulation of thyroid cells in culture with 12-O-tetradecanoylphorbol-13 acetate (TPA)+/-calphostin C supported a direct role of pKC in these altered properties. Thyroid tissue from irradiated rats had significantly more fibrotic lesions and increases in several pKC isoforms, integrins and fibronectin compared to 0-Gy (p<0.05). CONCLUSION: pKC is a likely contributor to alteration of key players associated with radiation-induced fibrosis. PMID- 25792645 TI - Expression and roles of CCN2 in dental epithelial cells. AB - Connective tissue growth factor (CCN2) regulates diverse cellular functions, including tooth development. In order to delineate the precise role of CCN2 in the epithelium during odontogenesis, we investigated how it is expressed and what roles it may have in primary cultures of epithelial cells derived from developing tooth germ of the bovine fetus. Ccn2 mRNA and protein were strongly expressed in the inner dental epithelium, which is consistent with the expression of transforming growth factor-beta2 mRNA and proliferating cell nuclear antigen. Bone morphogenetic protein 4 (BMP4) and fibroblast growth factor 2 (FGF2) were also expressed in the inner dental epithelium, indicating that CCN2 functionally interacts with these factors in the epithelium. The stimulatory effects of FGF2 on cell proliferation and BMP4 on cell differentiation were additively up regulated by CCN2 in a newly-established dental epithelium cell culture. Taken together, our data provide clear evidence that CCN2 is synthesized by inner dental epithelial cells, and appears to act as an autocrine factor, which regulates dental epithelial cell proliferation and differentiation in concert with growth factors. PMID- 25792646 TI - Anti-inflammatory activity of the artificial antioxidants 2-tert-butyl-4 methoxyphenol (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT) and 2,4,6-tri-tert butylphenol (TBP), and their various combinations. AB - BACKGROUND/AIM: The artificial complex phenols, 2-tert-butyl-4-methoxyphenol (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT) and 2,4,6-tri-tert-butylphenol (TBP) exert efficient antioxidant activity; however, they are considerable toxic and potentially tumor-promoting. These phenols, particularly in combinations, have enhanced antioxidant activity due to synergistic interactions and produce bioactive intermediates such as quinone methide. We investigated the anti inflammatory activity of BHA, BHT and TBP, and combinations of BHT/BHA (in molar ratios of 1:1, 1:2, 1:3 and 2:1), BHT/TBP (1:1), and BHA/TBP (1:1), using gene expression systems for cyclooxygenase-2 (Cox2) and tumor necrosis facto-alpha (Tnfa) in RAW264.7 cells. MATERIALS AND METHODS: The inhibitory effects of BHA, BHT and TBP on expression of Cox2 and Tnfa genes upon stimulation with Escherichia coli lipopolysaccharide (LPS) or Porphyomonas gingivalis (Pg) fimbriae were determined using real-time polymerase chain reaction. RESULTS: The inhibitory effect on expression of Cox2 and Tnfa genes upon stimulation with LPS and fimbriae was greatly enhanced by the combination of two antioxidants (molar ratio 1:1), BHT/BHA. In addition, that of the Cox2 gene, but not of Tnfa gene was slightly enhanced by a combination of equimolar BHT/TBP and BHA/TBP. None of the antioxidants alone exerted any anti-inflammatory activity upon stimulation with LPS, but a slight anti-inflammatory activity was observed upon stimulation with Pg fimbriae. The inhibitory effect of the BHT/BHA combination on expression of Cox2 mRNA upon stimulation with LPS was investigated at afferent molar ratios, and a molar ratio of 1:1 was found to have considerably less effect than a molar ratio of 1:2 or 2:1. The 1:3 combination had no effect. CONCLUSION: The combination of BHT and BHA at a molar ratio of 0.5-2 exerts potent anti inflammatory activity. This anti-inflammatory activity on the generation of inflammatory mediators in LPS-activated RAW264.7 cells may be attributable to complex synergistic antioxidant activity of the combination of BHT and BHA. Our results suggest the potential usefulness of the BHT/BHA combination at an appropriate molar ratio as an antioxidant in foods and pharmaceuticals, whereas either antioxidant alone is unlikely to be effective. PMID- 25792647 TI - No changes in cerebral microcirculatory parameters in rat during local cortex exposure to microwaves. AB - The aim of this study was to determine whether cerebral microcirculatory parameters in rats were modified during local cortex exposure to a radiofrequency electromagnetic field (RF) under non-thermal conditions. The cortex tissue targeted was locally exposed to 1439 MHz RF using a figure-8 loop antenna at an averaged specific absorption rate of 2.0 W/kg in the target area for 50 min. Three microcirculatory parameters related to cerebral inflammation were measured by the cranial window method in real-time under RF exposure. No extravasation of intravenously injected fluorescent dye was observed during RF exposure. There was no significant difference either in pial venule blood flow velocity or diameter between exposed and sham-exposed rats. Histological evaluation for the brain immediately after RF exposure did not reveal any serum albumin leakage sites or degenerate neurons. These findings suggest that no dynamic changes occurred in cerebral microcirculation even during local cortex exposure under these conditions. PMID- 25792648 TI - Small leucine rich proteoglycans are differently distributed in normal and pathological endometrium. AB - BACKGROUND: During the woman's fertile period, the non-pregnant uterus is subject to constant cyclic changes. The complex mechanisms that control the balance among proliferation, differentiation, cell death and the structural remodeling of the extracellular matrix can contribute to the benign or malignant endometrial pathological state. The small leucine-rich proteoglycans (SLRPs) are important components of cell surface and extracellular matrices. MATERIALS AND METHODS: Using immunohistochemistry, we showed that the distribution patterns of SLRPs were completely modified in the pathological compared to normal endometrium. RESULTS: The expression of SLRPs was low/absent in all endometrial pathologies examined compared to normal endometrium. We observed an increase of lumican from proliferative to secretory phase of the endometrium and a decrease of fibromodulin, biglycan and decorin. In menopause endometrial tissue, the level of expression of fibromodulin, biglycan, decorin and lumican dramatically decreased. CONCLUSION: The results revealed the prominence and importance of proteoglycans in the tissue architecture and extracellular matrix organization. PMID- 25792649 TI - Epidemiological and clinical study of diabetes in immigrants from Bangladesh in Athens versus Greek patients. AB - BACKGROUND/AIM: Greece has experienced a large wave of immigration from Bangladesh. The purpose of this study was to determine whether Bangladeshi immigrants with diabetes have poorer preventive follow-up and diabetes self-care compared to Greek patients. PATIENTS AND METHODS: A total of 166 patients from Bangladesh and 123 patients from Greece were recruited. Interviews were conducted, a physical examination followed and blood and urine samples were collected. RESULTS: Patients from Bangladesh had worse glycemic control (A1C=7.74+/-1.6 vs. 7.55+/-1.7%; p=0.3), and lower high-density lipoprotein levels (33.99+/-9.4 vs. 44.05+/-10.43 mg/dl; p=0.037). They were less likely to regularly take their medication for diabetes mellitus, or to follow dietary recommendations. However, fewer of them smoked, and had a significantly lower body mass index than Greek patients. CONCLUSION: Bangladeshi immigrants are less likely to engage self-care behaviors and have worse glycemic control and less access to medication, laboratory test and healthcare Units. PMID- 25792650 TI - Gene expression levels of elastin and fibulin-5 according to differences between carotid plaque regions. AB - AIM: The purpose of this study was to investigate the gene expression levels of elastin and fibulin-5 according to differences between carotid plaque regions and to correlate it with clinical features of plaque destabilization. MATERIALS AND METHODS: The study included 44 endarterectomy specimens available from operated symptomatic carotid artery stenoses. The specimens were separated according to anatomic location: internal carotid artery (ICA), external carotid artery (ECA) and common carotid artery (CCA), and then stored in liquid nitrogen. The amounts of cDNA for elastin and fibulin-5 were determined by Quantitative real-time PCR (Q-RT-PCR). Target gene copy numbers were normalized using hypoxanthine-guanine phosphoribosyltransferase (HPRT1) gene. The delta-delta CT method was applied for relative quantification. RESULTS: Q-RT-PCR data showed that relative fibulin-5 gene expression was increased in ICA plaque regions when compared to CCA regions but not reaching significance (p=0.061). At the same time, no differences were observed in elastin mRNA level between different anatomic plaque regions (p>0.05). Moreover, elastin and fibulin-5 mRNA expression and clinical parameters were compared in ICA plaques versus CCA and ECA regions, respectively. Up regulation of elastin and fibulin-5 mRNA levels in ICA were strongly correlated with family history of cardiovascular disease when compared to CCA (p<0.05). Up regulation of fibulin-5 in ICA was significantly associated with diabetes, and elevated triglycerides and very low density lipoprotein (VLDL) when compared to ECA (p<0.05). CONCLUSION: The clinical significance is the differences between the proximal and distal regions of the lesion, associated with the ICA, CCA and ECA respectively, with increased fibulin-5 in the ICA region. PMID- 25792651 TI - Hypoacetylation in association with histone 3 modulation in human hepatocellular carcinoma. AB - BACKGROUND: Aberrant histone deacetylase expression may cause imbalance between acetylation and deacetylation of histone and play roles in tumor transformation. We found that histone 3 was modulated in human hepatocellular carcinoma. We determined if histone 3 modulation is related to the aberrant expression of histone deacetylase. MATERIALS AND METHODS: We analyzed human liver and hepatocellular carcinoma tissues and fibroblast and fibrosarcoma cell lines for the expression of histone 3, histone deacetylase 1 and acetylated histone 3 using immunohistochemistry, western blot and immunofluorescence. RESULTS: Histone deacetylase 1 and histone 3 were more strongly detected in hepatocellular carcinoma tissue and fibrosarcoma cells than in liver tissues and fibroblast cells, respectively. However, acetylated histone 3 was more strongly expressed in normal liver and fibroblast cells and less expressed in hepatocellular carcinoma and fibrosarcoma cells. CONCLUSION: Histone deacetylase 1 overexpression and hypoacetylation of histone 3 might play critical roles in the modulation of histone 3 in human hepatocellular carcinoma. PMID- 25792652 TI - The effects of PON1 gene Q192R variant on the development of uterine leiomyoma in Turkish patients. AB - AIM: This study aimed to analyze the relation between uterine leiomyoma (ULM) patients and p.Q192R polymorphism. MATERIALS AND METHODS: ULM patients (n=76) and healthy women (n=103) were recruited from the Yeditepe University, Department of Gynecology and Obstetrics. The genotype and allele distribution of p.Q192R was analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. Genotype and allele frequencies between study groups were calculated by the chi-square (chi(2)) and Fischer's exact test. RESULTS: The frequency of the B allele was lower in patients (p<0.001) and the AB genotype showed a decreased risk for ULM development (p<0.001). The variation was unrelated to ULM size and number. There was no significant difference between p.Q192R genotype frequencies and fibroid size and number. CONCLUSION: The heterogeneous AB genotype of PON1 p.Q192R variation could be recognized as a low risk parameter for the development of ULM in Turkish women. PMID- 25792654 TI - Crude extract of Polygonum cuspidatum promotes immune responses in leukemic mice through enhancing phagocytosis of macrophage and natural killer cell activities in vivo. AB - Polygonum cuspidatum is a traditional Chinese herbal medicine used in the treatment of various diseases. In the present study, we investigated whether the crude extract of Polygonum cuspidatum (CEPC) could affect immune responses of murine leukemia cells in vivo. Normal BALB/c mice were i.p. injected with WEHI-3 cells to generate leukemic mice and then were treated orally with CEPC at 0, 50, 100 and 200 mg/kg for three weeks. Animals were weighed and blood, liver, spleen samples were collected for further analyses. Results indicated that CEPC did not significantly affect the body and liver weight of animals, but reduced the weight of spleen when compared to control groups. Flow cytometric assay demonstrated that CEPC increased the percentage of CD3- (T-cell marker) and CD19- (B-cell marker) positive cells, but reduced that of CD11b-positive ones (monocytes). However, it did not significantly affect the proportion of Mac-3-positive cells (macrophages), compared to control groups. Results indicated that CEPC promoted phagocytosis by macrophages from blood samples at all examined doses but did not affect that of macrophages from the peritoneal cavity. CEPC also promoted natural killer cell activity of splenocytes at 200 mg/kg of CEPC. CEPC promoted B-cell proliferation at 200 mg/kg treatment when cells were stimulated with lipopolysaccharides but did not promote T-cell proliferation at three doses of CEPC treatment on concanavalin A stimulation. PMID- 25792653 TI - Purmorphamine and oxysterols accelerate and promote osteogenic differentiation of mesenchymal stem cells in vitro. AB - AIM: The purpose of the present study was to find inexpensive and non-toxic additives enhancing and accelerating the osteogenesis of mesenchymal stem cells in vitro, which can be used for tissue engineering of bone material. MATERIALS AND METHODS: Osteogenic differentiation of rat mesenchymal stem cells was carried out using classic differentiation medium containing or lacking purmorphamine, statins or oxysterols, respectively. Cell proliferation, alkaline phosphatase activity, calcium sedimentation and expression of bone matrix protein genes were measured to monitor differentiation. RESULTS: Purmorphamine substantially suppressed proliferation, enhanced and accelerated alkaline phosphatase activity and calcium sedimentation and increased the expression of osteopontin and osteocalcin in rat mesenchymal stem cells in vitro. A similar osteogenesis promoting effect was observed for oxysterols but not for the two statins. CONCLUSION: Purmorphamine and oxysterols promote and accelerate osteogenesis of mesenchymal stem cells in vitro suggesting their potential application for tissue engineering of bone material. PMID- 25792655 TI - Evaluation of Hirsutella sinensis mycelium for antifatigue effect. AB - The aim of this study was to investigate whether Hirsutella sinensis mycelium (HSM) has any antifatigue effect, using a forced swimming model in rats. Forty rats were randomly divided into five groups, each containing eight animals. The control group received 2 ml/kg body weight of distilled water and a positive control group was administered 1.13 ml/kg Quaker Essence of Chicken. The treated swimming groups were administered HSM powder manufactured by Chang Gung Biotechnology Corporation, Ltd., at doses of 63 mg/kg, 189 mg/kg or 378 mg/kg body weight/day, respectively for a period of six weeks. The above experiment was repeated with another 40 rats but for a period of eight weeks. At the end of the experiments, rats were placed in a swimming apparatus and the total swimming time until exhaustion was recorded. Pre-/post-exercise concentrations of serum urea nitrogen (BUN) and lactic acid were also determined. There were no deaths during the study. Physical and behavioral examinations did not reveal any treatment related adverse effects after dosing. Changes in lactate levels were dose dependent for the 8- but not the 6-week treatment. BUN levels were more affected by the 8-week treatment of HSM but not significantly altered in the 6-week treatment groups. The 8-week treatment groups showed a significant increase in swimming time to exhaustion compared to the control groups, which was not dose dependent. For the 6-week treatment, only the middle and high doses increased swimming time to exhaustion. Conjugated diene contents were significantly higher in rats treated at any HSM dose for 8-weeks than the control groups. Swimming did not alter levels of liver glycogen when compared to the control sub-groups. Results of this study demonstrate that HSM improves physical endurance, which may be beneficial in treating conditions where fatigue is a factor and other antifatigue treatments are contraindicated. PMID- 25792657 TI - Fractal dimension as a new tool to analyze optic nerve head vasculature in primary open angle glaucoma. AB - AIM: To investigate the features of optic nerve head (ONH) microvasculature in primary open angle glaucoma using fractal geometry analysis. PATIENTS AND METHOD: ONH blood flow was analyzed at the level of the lamina cribrosa by means of confocal scanning laser Heidelberg Doppler flowmetry (HRF) in medically controlled early and advanced glaucoma. Fractal dimension D of vasculature map was calculated using the Box Counting. RESULTS: Our data demonstrated that, in patients with advanced glaucoma, fractal dimension D was significantly lower than in controls, whereas, in the early stage of disease, its value was similar. Fractal dimension D of microcirculation was significantly and negatively correlated with the cup-disk area ratio in both early and advanced glaucoma groups, whereas linear cup-disk ratio of the disk, cup shape measure and nerve fiber layer thickness, where correlated only in advanced stage of the disease. CONCLUSION: These findings demonstrate that fractal dimension D of ONH appeared significantly reduced in advanced glaucoma and correlated with the optic disc damage. PMID- 25792656 TI - Importance of Wells score and Geneva score for the evaluation of patients suspected of pulmonary embolism. AB - AIM: The European Society of Cardiology guidelines for pulmonary embolism (PE) published in 2008 and updated in 2014 recommend a risk stratification including risk scores like Wells and the Geneva score. The utility and practicability of these scores are controversially discussed. Recently, in a trauma cohort and in spinal surgery patients, no correlation between Wells Score and PE diagnosis was found. The aim of the study was the evaluation of Wells and Geneva scores in patients presenting with chest pain, dyspnoea or syncope in an emergency department. PATIENTS AND METHODS: We retrospectively examined 326 patients suspected of PE, including assessment, according to Wells and Geneva scores. RESULTS: PE was detected in 13.5 %. The average Wells score was 1.0, the average Geneva score 3.9. The receiver operating characteristic (ROC) curve analyses showed for both scores a high significant area under the curve (Wells score 0.68; Geneva score 0.64). The association between the scores and the diagnosis of PE was calculated with logistic regression analysis and showed high significant odds ratios (OR) for both scores (Wells score 1.38; Geneva score 1.24). There was no significant difference between the area under the curve (AUC) of Wells score and Geneva score. CONCLUSION: The utility of Wells and Geneva scores for the evaluation of patients suspected of PE in an emergency patient cohort. PMID- 25792658 TI - Nasal speech associated with hyperaeration of the sphenoid sinus. AB - The sinus sphenoidalis is the paranasal sinus most centrally located in the skull base and known to vary extremely in dimensions. A very large volume of the sinus visible on skull radiographs is called sinus 'hyperaeration'. This finding has been described many times in the literature, but is generally rare. The term 'pneumosinus dilatans' is synonymously used to address an unexpectedly large paranasal sinus. In the majority of cases, sphenoid sinus hyperaeration is not associated with any clinical symptoms. On the other hand, different complaints have been described in cases of extensive sphenoid sinus volume, such as headache, inflammation or neoplasia. This is a report of an adult patient with nasal speech who was thoroughly investigated for alterations of the upper airway in order to clarify the reason for the speech anomaly. After extensive diagnostics, the patient was found to have normal anatomy and no functional alteration of the velo-pharyngeal complex. However, an impressively large sphenoid sinus was shown on computed tomograms. This is likely the first report detailing a patient with nasal speech and hyperaeration of the sinus. PMID- 25792659 TI - Molecular evidence of apoptotic pathway activation in semen samples with high DNA fragmentation. AB - BACKGROUND/AIM: Male infertility is diagnosed by semen parameters, such as concentration, motility and morphology; however, these are not sufficient for the prediction of male fertility capacity. In the clinical routine, several other sperm functions have been introduced, including the sperm DNA fragmentation test. The objective of the present study was to evaluate sperm chromatin integrity in semen samples. MATERIALS AND METHODS: Sperm chromatin dispersion test (SCD) was used in ejaculates from men divided into five groups: normozoospermic, oligozoospermic, asthenozoospermic, oligoasthenozoospermic and cryptozoospermic. RESULTS: The data obtained showed that the SCD percentage appeared to be significantly associated with oligozoospermia diagnosis. We also evaluated total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and inhibin B serum hormonal levels in all samples examined, in order to assess whether DNA fragmentation increase could correlate with abnormal hormonal values. Finally we selected certain samples with an increasing DNA fragmentation and analyzed the molecular activated apoptotic pathways. CONCLUSION: A significant relationship was found between caspase-3 activation and increased DNA fragmentation. PMID- 25792660 TI - Outcomes of laparoscopic and open surgery for colorectal cancer in the emergency setting. AB - AIM: To evaluate the short-term and oncological outcomes of laparoscopy compared to open procedures for colorectal cancer in the emergency setting. PATIENTS AND METHODS: Forty-nine consecutive patients undergoing emergency open (n=38) or laparoscopic (n=11) major resection were analyzed. RESULTS: There were no significant differences in age, gender, American Society of Anesthesiologists (ASA) score, body mass index (BMI), history of previous abdominal surgery and tumor location between the open and laparoscopy groups. Pathological T4 tumors were more commonly observed in the open-surgery group than the laparoscopy group (47% vs. 9%; p=0.022). Obstruction (45% vs. 27%) and perforation (42% vs. 27%) were also more common in the open-surgery group. Bleeding or anemia was more common in the laparoscopy group (8% vs. 45%; p=0.028). There were no open conversions in the laparoscopy group. Regarding the type of surgery, Hartmann's operation was more common in the open-surgery group (32%) and right hemicolectomy was more common in the laparoscopy group (36%; p=0.058). There was no difference in the 30-day complication rate of open surgery (34%) and laparoscopy (36%) (p=0.895). Mean time to tolerable diet (8 days vs. 6 days, p=0.035) and mean length of hospital stay (17 days vs. 13 days, p=0.041) were shorter in the laparoscopy group. Overall recurrence and cancer-specific death did not differ between the two groups. CONCLUSION: In selected colorectal cancer patients, emergency laparoscopy confers benefits in terms of short-term and oncological outcomes. Therefore, experienced laparoscopic surgeons may more actively consider the use of laparoscopy in the emergency setting. PMID- 25792661 TI - Clopidogrel resistance after renal transplantation. AB - BACKGROUND: Leading causes of mortality and morbidity after kidney transplantation are cardiovascular diseases. One of the fundamentals of their prevention is the inhibition of platelet aggregation. Resistance to anti-platelet agents is a well-established phenomenon; however, its causes are yet to be clarified. PATIENTS AND METHODS: Forty post-transplant patients, who received 75 mg clopidogrel q.d. as a prophylactic measure, were examined using optical aggregometry. Subsequently, logistic regression analysis was performed with 24 variables in order to expose possible causes of resistance. RESULTS: Sixty percent of patients (24) were resistant to clopidogrel therapy; effective thrombocyte inhibition could only be shown in 40% of them (16). Significant correspondence between resistance and variables could not be found. CONCLUSION: Clopidogrel resistance is expected to occur on a large scale in patients who underwent kidney transplant surgery. Thus, a key component of preventive therapy, which stresses the importance of discovering the cause of resistance so as to decrease mortality rates, is missing. PMID- 25792663 TI - Increased risk of dementia among patients with pulmonary tuberculosis: a retrospective population-based cohort study. AB - OBJECTIVE: We investigated and compared the risk of dementia development in a cohort of patients with tuberculosis (TB). METHODS: The study involved 6473 patient with newly diagnosed TB, and each patient was randomly frequency matched with 4 people without TB based on age, sex, and index year. The risk of dementia development was analyzed using Cox proportional hazards regression. RESULTS: Among the patients with TB, the overall risk of developing dementia was 1.21-fold significantly higher than the non-TB cohort. In the stratified analysis of dementia risks, only the patients with TB who were male or 50 to 64 years of age exhibited a significantly higher risk of dementia development compared with those without TB. An analysis of the follow-up duration revealed that patients with TB had a 1.78-fold increased risk within 1 year of follow-up. CONCLUSION: Patients with TB have a significantly higher risk of developing dementia than that of the general population. PMID- 25792662 TI - Does serum lactate combined with soluble endothelial selectins at ICU admission predict sepsis development? AB - AIM: We sought to determine for serum lactate its specificity and sensitivity in sepsis development prognosis in critically-ill, non-septic patients. Additionally, we evaluated whether sE-selectin or sP-selectin add prognostic value to lactate in sepsis. PATIENTS AND METHODS: Using a cohort previously studied in another context, in this retrospective investigation we plotted receiver operating characteristic (ROC) curves using sepsis development as the classification variable and serum lactate levels and their linear combinations with soluble sE-selectin and/or sP-selectin levels at intensive care unit (ICU) admission, as prognostic variables. RESULTS: Lactate levels combined with sE- and sP-selectin levels have the best prognostic accuracy showing a sensitivity and specificity of 76% and 84%, respectively, and an area under the curve (AUC) at 0.854 (95% confidence interval (CI)=0.775-0.932; p<0.001). CONCLUSION: In our patient cohort, combining sE- and sP-selectin with serum lactate offers better prognostic value for sepsis development during ICU hospitalization. PMID- 25792664 TI - The Italian validation of the Anosognosia Questionnaire for Dementia in Alzheimer's disease. AB - Although the Anosognosia Questionnaire-Dementia (AQ-D) is one of the main instruments for assessing awareness in Alzheimer's disease (AD), the normative data were until now limited to people from Argentina and Japan. This study aims to validate this instrument in an European context, in particular in an Italian sample. In a multicenter project (Verona, Padova, and Trapani), 130 patients with AD and their caregivers participated in the study. Psychometric characteristics of AQ-D are confirmed indicating that the scale permits the early identification of anosognosia and the correct care management of patients. Indeed, anosognosia results to be present also in patients with very mild AD (moderate: 44.44%; mild: 47.17%; and very mild: 23.73%). Moreover, the results indicate that deficits in awareness may vary in severity and that different types of anosognosia may be identified. PMID- 25792667 TI - Mutations in the MYO15A gene are a significant cause of nonsyndromic hearing loss: massively parallel DNA sequencing-based analysis. AB - OBJECTIVES: Screening for MYO15A mutations was carried out using a large cohort to clarify the frequency and clinical characteristics of patients with MYO15A (DFNB3) mutations in a hearing loss population. METHODS: Genetic analysis of 63 previously reported deafness genes based on massively parallel DNA sequencing (MPS) in 1120 Japanese hearing loss patients from 53 otorhinolaryngology departments was performed. Detailed clinical features of the patients with MYO15A mutations were then collected and analyzed. RESULTS: Eleven patients from 10 families were found to have compound heterozygosity for MYO15A. Audiograms showed profound or high frequency hearing loss, with some patients showing progressive hearing loss. Age at onset was found to vary from 0 to 14 years, which seemed to be associated with the mutation. Four children underwent bilateral cochlear implantation for congenital hearing loss, with all showing good results. CONCLUSION: Mutations in the MYO15A gene are a notable cause of nonsyndromic hearing loss. MPS technology successfully detected mutations in relatively rare deafness genes such as MYO15A. PMID- 25792670 TI - A Study of Human Killer Cell Immunoglobulin-Like Receptor and Multidrug Resistance Gene Polymorphisms in Children With Immune Thrombocytopenia. AB - THE OBJECTIVE: This study was undertaken to detect characterization of the different gene polymorphisms in Human killer cell immunoglobulin-like receptor (KIR2) gene and multi-drug resistance (MDR1) gene, among childhood ITP Egyptian patients. In addition to assess the potential role of these polymorphisms in relation to types of ITP and response to different treatment modalities. PATIENTS AND METHODS: A total of 48 pediatric patients with immune thrombocytopenia (ITP; 24 newly diagnosed and 24 chronic) and 35 healthy controls were investigated via polymerase chain reaction-restriction fragment length polymorphism analysis for multidrug resistance (MDR) 1 and killer cell immunoglobulin-like receptor (KIR) 2 genes. RESULTS: The frequency of MDR1 gene in patients and control was not significant (P = .090). The CT genotype was the highest distribution among all ITP cases (62.50%, n = 30) and control (48.60%, n = 17). There was a significant difference in age at diagnosis of MDR1 gene with the CC genotype had the eldest age and lowest initial platelets count (P = .029 and P = .004). The distribution of KIR2 gene among all patients with ITP and controls was significant (P = .026) with (KIRDL2-/KIRDS2-) genotype was the most prevalent among patients. CONCLUSION: The frequency of MDR1 polymorphisms was not associated with susceptibility to the development and clinical progression of the disease. However, KIR2 gene polymorphisms were independently associated with childhood ITP in Egyptian patients with highest prevalence among (KIRDL2-/KIRDS2-) genotypes. PMID- 25792668 TI - Mutational spectrum and clinical features of patients with ACTG1 mutations identified by massively parallel DNA sequencing. AB - OBJECTIVES: ACTG1 has been reported to be a causative gene for autosomal dominant sensorineural hearing loss, DFNA20/26. In this study we sought to clarify the detailed mutational spectrum, clinical features, and genotype-phenotype correlations. METHODS: Massively parallel DNA sequencing (MPS) of 63 target candidate genes was used to screen 1120 Japanese hearing loss patients. RESULTS: MPS screening successfully identified 4 ACTG1 mutations in 5 families. The majority of patients showed high frequency-involved progressive hearing loss, with the age of onset mostly in the first or second decade. One patient received electric acoustic stimulation (EAS), which showed a good outcome. CONCLUSIONS: Target exon-sequencing using MPS was proven to be a powerful new clinical diagnostic tool for the identification of rare causative genes such as ACTG1. The present clinical findings not only confirmed those previous reports but also provided important new clinical information. PMID- 25792666 TI - De novo mutation in X-linked hearing loss-associated POU3F4 in a sporadic case of congenital hearing loss. AB - OBJECTIVES: In this report, we present a male patient with no family history of hearing loss, in whom we identified a novel de novo mutation in the POU3F4 gene. METHODS: One hundred ninety-four (194) Japanese subjects from unrelated and nonconsanguineous families were enrolled in this study. We used targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes for identifying the genetic causes of hearing loss. RESULTS: A novel de novo frameshift mutation of POU3F4 to c.727_728insA (p.N244KfsX26) was identified. The patient was a 7-year-old male with congenital progressive hearing loss and inner ear deformity. Although the patient had received a cochlear implant, auditory skills were still limited. The patient also exhibited developmental delays similar to those previously associated with POU3F4 mutation. CONCLUSION: This is the first report of a mutation in POU3F4 causing hearing loss in a Japanese patient without a family history of hearing loss. This study underscores the importance of comprehensive genetic testing of patients with hearing loss for providing accurate prognostic information and guiding the optimal management of patient rehabilitation. PMID- 25792671 TI - Wild birds most likely source of UK avian influenza cases. PMID- 25792669 TI - Mutations in LOXHD1 gene cause various types and severities of hearing loss. AB - OBJECTIVE: We present 2 families that were identified with novel mutations in LOXHD1 as a cause of nonprogressive hearing loss. METHODS: One thousand three hundred fourteen (1314) Japanese subjects with sensorineural hearing loss from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic cause of hearing loss. RESULTS: Two patients in 1 family affected with homozygous mutation c.879+1G>A in LOXHD1 showed profound congenital hearing loss, whereas 2 patients in another family with compound heterozygous mutations, c.5869G>T (p.E1957X) and c.4480C>T (p.R1494X), showed moderate to severe hearing loss. CONCLUSION: Mutations in LOXHD1 are extremely rare, and these cases are the first identified in a Japanese population. The genotype-phenotype correlation in LOXHD1 is still unclear. The differences in phenotypes in each patient might be the result of the nature of the mutations or the location on the gene, or be influenced by a genetic modifier. PMID- 25792673 TI - Programme to take an in-depth look at veterinary profession. PMID- 25792674 TI - Seal deaths: possible cause of 'corkscrew seals' identified. PMID- 25792672 TI - Marathon effort in aid of mental health. PMID- 25792675 TI - Developing the next generation of vaccines. PMID- 25792665 TI - Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. AB - Cigarette smoke (CS)-induced cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The molecular mechanism by which CS induces cellular senescence is unknown. Here, we show that CS stress (exposure of primary lung cells to CS extract 0.2-0.75% with a half-maximal inhibitory concentration of ~0.5%) led to impaired mitophagy and perinuclear accumulation of damaged mitochondria associated with cellular senescence in both human lung fibroblasts and small airway epithelial cells (SAECs). Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, which was due to CS-induced cytoplasmic p53 accumulation and its interaction with Parkin. Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m(3)) as well as in lungs of chronic smokers and patients with COPD. Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling. Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells. In conclusion, defective mitophagy leads to CS stress-induced lung cellular senescence, and restoring mitophagy delays cellular senescence, which provides a promising therapeutic intervention in chronic airway diseases. PMID- 25792676 TI - '24/7 practices' to help clients manage their schedules. PMID- 25792677 TI - RCVS Council considers its future. AB - Reviewing the size and structure of the RCVS Council. Time for clearer guidance on what can be counted as CPD? Use of the courtesy title 'Dr'. Addressing a shortage of veterinary nurses. These were among matters discussed by the RCVS Council at its meeting on March 5. The RCVS President, Stuart Reid, chaired the meeting, which was held at Belgravia House, London SW1P. PMID- 25792678 TI - Erysipelas in turkeys, sheep and pigs. AB - Erysipelas diagnosed in turkeys, sheep and pigs. Parasitic gastroenteritis reported in cattle on several farms. Unusual presentation of Actinobacillus suis causing spinal abscesses in pigs on a breeder-finisher unit. First APHA diagnosis of oedema disease in pigs in East Anglia for many years. Infectious coryza confirmed in a hobby breeding flock. These are among matters discussed in the Animal and Plant Health Agency's (APHA's) disease surveillance report for November 2014. PMID- 25792680 TI - Translational research: putting the right price on innovation. AB - The animal health sector makes a substantial contribution to innovation in the field of human health, but this is undervalued, says Lloyd Reeve-Johnson. He argues that this contribution needs to be recognised and quantified if the benefits of One Health, and the potential of the veterinary profession, are to be realised. PMID- 25792679 TI - Using infrared radiation to detect local inflammation in cattle. PMID- 25792682 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 25792681 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 25792683 TI - Inherited pathology and pet trading. PMID- 25792685 TI - Delivering OV training. AB - Sue Hay wanted to be a vet from her early teens - 'no other career path stood a chance' - but her determination was tested. After qualifying, she worked in practice, raised her family and then joined the State Veterinary Service. More recently she joined Improve International as Head of Practical Skills, delivering training and revalidation of Official Veterinarians. PMID- 25792684 TI - Role of vets in abattoirs. PMID- 25792686 TI - Diary of a poultry intern. AB - William Garton, intern at Minster Vets, has been on an intensive two-week poultry health course where he gained lots of new knowledge as well as a sense of direction and purpose. PMID- 25792687 TI - Resistance training: not all programs are created equal. PMID- 25792688 TI - Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) receptor antagonism is an approach to migraine therapy. The locus of action of antimigraine treatment is not resolved. The objective was to investigate CGRP receptors in the ventrolateral periaqueductal gray (vlPAG) involved in the modulation of trigeminovascular nociception by descending influences on neurotransmission. METHODS: The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), which form functional CGRP receptors, was investigated. CGRP and its receptor antagonists, olcegepant and CGRP (8-37), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored. RESULTS: Immunoreactivity indicated the presence of functional CGRP receptor components in the vlPAG and adjacent mesencephalic trigeminal nucleus. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP (8-37) decreased them. CONCLUSIONS: CGRP and its receptor antagonists act on neurons in the region of vlPAG to influence nociceptive transmission in the TCC. This suggests CGRP receptor antagonists may act at loci outside of the TCC and reinforces the concept of migraine as a disorder of the brain. PMID- 25792690 TI - Erratum. PMID- 25792689 TI - The reliability and validity of cervical auscultation in the diagnosis of dysphagia: a systematic review. AB - OBJECTIVE: To systematically review the available evidence for the reliability and validity of cervical auscultation in diagnosing the several aspects of dysphagia in adults and children suffering from dysphagia. DATA SOURCES: Medline (PubMed), Embase and the Cochrane Library databases. REVIEW METHODS: The systematic review was carried out applying the steps of the PRISMA-statement. The methodological quality of the included studies were evaluated using the Dutch 'Cochrane checklist for diagnostic accuracy studies'. RESULTS: A total of 90 articles were identified through the search strategy, and after applying the inclusion and exclusion criteria, six articles were included in this review. In the six studies, 197 patients were assessed with cervical auscultation. Two of the six articles were considered to be of 'good' quality and three studies were of 'moderate' quality. One article was excluded because of a 'poor' methodological quality. Sensitivity ranges from 23%-94% and specificity ranges from 50%-74%. Inter-rater reliability was 'poor' or 'fair' in all studies. The intra-rater reliability shows a wide variance among speech language therapists. CONCLUSION: In this systematic review, conflicting evidence is found for the validity of cervical auscultation. The reliability of cervical auscultation is insufficient when used as a stand-alone tool in the diagnosis of dysphagia in adults. There is no available evidence for the validity and reliability of cervical auscultation in children. Cervical auscultation should not be used as a stand-alone instrument to diagnose dysphagia. PMID- 25792691 TI - DRD3 gene and striatum in autism spectrum disorder. AB - A single-nucleotide polymorphism (SNP) of the DRD3 gene (rs167771) was recently associated with autism spectrum disorders (ASD). Different polymorphisms of rs167771 corresponded to varying degrees of stereotyped behaviour. As DRD3 receptors are relatively overexpressed in the striatum, we investigated whether striatal volume was related to these polymorphisms in autism. We assessed volumes of caudate nucleus and putamen in 86 participants with ASD (mean age 15.3 years). MANCOVA showed an association between alleles of the rs167771 SNP and the volume of striatal structures. Furthermore, greater caudate nucleus volume correlated with stereotyped behaviour. These findings support a relationship between DRD3 gene SNPs, striatum and stereotyped behaviour in ASD. PMID- 25792693 TI - Predictive validity of the Trauma Screening Questionnaire in detecting post traumatic stress disorder in patients with psychotic disorders. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is highly prevalent in patients with a psychotic disorder. Because a PTSD diagnosis is often missed in patients with psychosis in routine care, a valid screening instrument could be helpful. AIMS: To determine the validity of the Trauma Screening Questionnaire (TSQ) as a screening tool for PTSD among individuals with psychotic disorders. METHOD: Among 2608 patients with a psychotic disorder, the rate of trauma exposure was determined and the TSQ was administered to screen for PTSD. PTSD status was verified in 455 patients using the Clinician-Administered PTSD Scale (trial registration: ISRCTN 79584912). RESULTS: Trauma exposure was reported by 78.2% of the 2608 patients. PTSD prevalence was estimated at 16% (95% CI 14.6-17.4%) compared with 0.5% reported in the patients' clinical charts. A TSQ cut-off score of six predicted PTSD with 78.8% sensitivity, 75.6% specificity, 44.5% correct positives and 93.6% correct negatives. CONCLUSIONS: The TSQ seems to be a valid screening tool for PTSD in patients with a psychotic disorder. PMID- 25792694 TI - Training-induced plasticity of the social brain in autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is linked to social brain activity and facial affect recognition (FAR). AIMS: To examine social brain plasticity in ASD. METHOD: Using FAR tests and functional magnetic resonance imaging tasks for FAR, we compared 32 individuals with ASD and 25 controls. Subsequently, the participants with ASD were assigned to FAR computer-aided cognitive training or a control group. RESULTS: The ASD group performed more poorly than controls on explicit behavioural FAR tests. In the scanner, during implicit FAR, the amygdala, fusiform gyrus and other regions of the social brain were less activated bilaterally. The training group improved on behavioural FAR tests, and cerebral response to implicit affect processing tasks increased bilaterally post training in the social brain. CONCLUSIONS: Individuals with ASD show FAR impairments associated with hypoactivation of the social brain. Computer-based training improves explicit FAR and neuronal responses during implicit FAR, indicating neuroplasticity in the social brain in ASD. PMID- 25792692 TI - Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure. AB - BACKGROUND: Fragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals. AIMS: To examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability. METHOD: We used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30). RESULTS: Individuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. CONCLUSIONS: The genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders. PMID- 25792695 TI - Collaborative care for patients with bipolar disorder: randomised controlled trial. AB - BACKGROUND: A substantial number of people with bipolar disorder show a suboptimal response to treatment. AIMS: To study the effectiveness of a collaborative care programme on symptoms and medication adherence in patients with bipolar disorder, compared with care as usual. METHOD: A two-armed, cluster randomised clinical trial was carried out in 16 out-patient mental health clinics in The Netherlands, in which 138 patients were randomised. Patient outcomes included duration and severity of symptoms and medication adherence, and were measured at baseline, 6 months and 12 months. Collaborative care comprised contracting, psychoeducation, problem-solving treatment, systematic relapse prevention and monitoring of outcomes. Mental health nurses functioned as care managers in this programme. The trial was registered with The Netherlands Trial Registry (NTR2600). RESULTS: Collaborative care had a significant and clinically relevant effect on number of months with depressive symptoms, both at 6 months (z = -2.6, P = 0.01, d = 0.5) and at 12 months (z = -3.1, P = 0.002, d = 0.7), as well as on severity of depressive symptoms at 12 months (z = -2.9, P = 0.004, d = 0.4). There was no effect on symptoms of mania or on treatment adherence. CONCLUSIONS: When compared with treatment as usual, collaborative care substantially reduced the time participants with bipolar disorder experienced depressive symptoms. Also, depressive symptom severity decreased significantly. As persistent depressive symptoms are difficult to treat and contribute to both disability and impaired quality of life in bipolar disorder, collaborative care may be an important form of treatment for people with this disorder. PMID- 25792696 TI - Socioeconomic gradients and mental health: implications for public health. AB - BACKGROUND: Research on mental well-being is relatively new and studies of its determinants are rare. AIMS: To investigate whether the socioeconomic correlates of mental well-being mirror those for mental illness. METHOD: Using logistic regression analyses, the independent odds ratios of high and low mental well being, compared with middle-range mental well-being, were estimated for a number of sociodemographic variables known to be associated with mental illness from 13 983 participants in the 2010 and 2011 Health Surveys for England. RESULTS: Independent odds ratios for low mental well-being were as expected from studies of mental illness with increased odds for the unemployed (OR = 1.46, 95% CI 1.01 2.10) and those aged 35-54 years (OR = 1.58, 95% CI 1.35-1.84) and reduced odds for the married (OR = 0.78, 95% CI 0.62-0.97). A linear trend was observed with education and equivalised income. Odds ratios for high mental well-being differed from those for low mental well-being with regard to age (55+ years: OR = 1.48, 95% CI 1.23-1.79); employment status where there was an association only with retirement (OR = 1.35, 95% CI 1.09-1.69); education where there was no association; and equivalised income for which the association was non-linear. CONCLUSIONS: Odds ratios for low mental well-being mirrored those for mental illness, but not those for high mental well-being, suggesting that the socioeconomic factors associated with positive mental health are different from those associated with mental illness. PMID- 25792697 TI - Incidence and 12-month outcome of childhood non-affective psychoses: British national surveillance study. AB - The schizophrenias are uncommon before the age of 14 but incidence/prevalence figures are lacking. The 1-year incidence, clinical features and short-term outcomes in childhood-onset schizophrenia spectrum disorder were evaluated via the Child and Adolescent Psychiatry Surveillance System. Fifteen children with a provisional diagnosis were reported. Outcome data were obtained for 12 individuals, 8 of whom met the diagnostic criteria, equating to an estimated incidence of 0.21/100 000 (95% CI 0.08-0.34). Delusions and thought disorder were a more consistent predictor of 'caseness' than hallucinations. Illness outcomes at 1 year were generally poor. Childhood-onset schizophrenia appears to be a rare but serious disorder. PMID- 25792704 TI - Graphical display of diagnostic test results in electronic health records: a comparison of 8 systems. AB - Accurate display and interpretation of clinical laboratory test results is essential for safe and effective diagnosis and treatment. In an attempt to ascertain how well current electronic health records (EHRs) facilitated these processes, we evaluated the graphical displays of laboratory test results in eight EHRs using objective criteria for optimal graphs based on literature and expert opinion. None of the EHRs met all 11 criteria; the magnitude of deficiency ranged from one EHR meeting 10 of 11 criteria to three EHRs meeting only 5 of 11 criteria. One criterion (i.e., the EHR has a graph with y-axis labels that display both the name of the measured variable and the units of measure) was absent from all EHRs. One EHR system graphed results in reverse chronological order. One EHR system plotted data collected at unequally-spaced points in time using equally-spaced data points, which had the effect of erroneously depicting the visual slope perception between data points. This deficiency could have a significant, negative impact on patient safety. Only two EHR systems allowed users to see, hover-over, or click on a data point to see the precise values of the x-y coordinates. Our study suggests that many current EHR-generated graphs do not meet evidence-based criteria aimed at improving laboratory data comprehension. PMID- 25792705 TI - Screening and surveillance CT abdomen/pelvis for metastases in patients with soft tissue sarcoma of the extremity. AB - OBJECTIVES: The clinical utility of routine cross sectional imaging of the abdomen and pelvis in the screening and surveillance of patients with primary soft-tissue sarcoma of the extremities for metastatic disease is controversial, based on its questionable yield paired with concerns regarding the risks of radiation exposure, cost, and morbidity resulting from false positive findings. METHODS: Through retrospective review of 140 patients of all ages (mean 53 years; 2 to 88) diagnosed with soft-tissue sarcoma of the extremity with a mean follow up of 33 months (0 to 291), we sought to determine the overall incidence of isolated abdominopelvic metastases, their temporal relationship to chest involvement, the rate of false positives, and to identify disparate rates of metastases based on sarcoma subtype. RESULTS: A total of four patients (2.9%) exhibited isolated abdominopelvic metastatic disease during the surveillance period. In all cases of concomitant chest and abdominopelvic disease, chest involvement preceded abominopelvic involvement. There was a significant false positive rate requiring invasive workup. CONCLUSIONS: In the setting of a relative paucity of evidence concerning a rare disease process and in difference to recently published investigations, we add a clinical cohort not supportive of routine cross sectional imaging of the abdomen and pelvis. Cite this article: Bone Joint Res 2015;4:45-9. PMID- 25792706 TI - Reduced expression of the oligosaccharyltransferase exacerbates protein hypoglycosylation in cells lacking the fully assembled oligosaccharide donor. AB - A defect in the assembly of the oligosaccharide donor (Dol-PP GlcNAc(2)Man(9)Glc(3)) for N-linked glycosylation causes hypoglycosylation of proteins by the oligosaccharyltransferase (OST). Mammalian cells express two OST complexes that have different catalytic subunits (STT3A or STT3B). We monitored glycosylation of proteins in asparagine-linked glycosylation 6 (ALG6) deficient cell lines that assemble Dol-PP-GlcNAc(2)Man(9) as the largest oligosaccharide donor. Based upon pulse labeling experiments, 30-40% of STT3A-dependent glycosylation sites and 20% of STT3B-dependent sites are skipped in ALG6 congenital disorders of glycosylation fibroblasts supporting previous evidence that the STT3B complex has a relaxed preference for the fully assembled oligosaccharide donor. Glycosylation of STT3B-dependent sites was more severely reduced in the ALG6 deficient MI8-5 cell line. Protein immunoblot analysis and RT PCR revealed that MI8-5 cells express 2-fold lower levels of STT3B than the parental Chinese hamster ovary cells. The combination of reduced expression of STT3B and the lack of the optimal Dol-PP-GlcNAc(2)Man(9)Glc(3) donor synergize to cause very severe hypoglycosylation of proteins in MI8-5 cells. Thus, differences in OST subunit expression can modify the severity of hypoglycosylation displayed by cells with a primary defect in the dolichol oligosaccharide assembly pathway. PMID- 25792707 TI - An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. AB - BACKGROUND AND AIM: Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. METHODS: The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. RESULTS: 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was -13.0% for CXB+DFMO and -1.0% for CXB (p=0.69). Mean % change in adenoma burden was -40% (CXB+DFMO) vs -27% (CXB) (p=0.13). Video-based global polyp change was -0.80 for CXB+DFMO vs -0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). CONCLUSIONS: CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number N01-CN95040. PMID- 25792708 TI - A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis. AB - OBJECTIVE: To investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE). DESIGN: Adults with active EoE (n=76) randomly received 14 days' treatment with either BET 2*1 mg/day (BET1, n=19) or BET 2*2 mg/day (BET2, n=19), or BVS 2*5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm(2 )hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation. RESULTS: Histological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients. CONCLUSIONS: BET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation. CLINICALTRIALSGOV NUMBER: NCT02280616; EudraCT number, 2009-016692-29. PMID- 25792710 TI - Commentaries on Viewpoint: Why do some patients stop breathing after taking narcotics? Ventilatory chemosensitivity as a predictor of opioid-induced respiratory depression. PMID- 25792709 TI - Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin mutations. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the beta-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by beta-catenin, potentially involved in liver tumorigenesis. DESIGN: We used a mouse model, in which beta-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC. RESULTS: We found that miR-34a was regulated by beta-catenin, and significantly induced by the overactivation of beta-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4alpha, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying beta-catenin activation together with an activation of caspases 2 and 3. CONCLUSIONS: This work demonstrates the key oncogenic role of miR-34a in liver tumours with beta-catenin gene mutations. We suggest that patients diagnosed with HCC with beta-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4alpha, which targets cyclin D1, and the induction of a proapoptotic programme. PMID- 25792711 TI - Mechanism of action of antiplatelet drugs on decompression sickness in rats: a protective effect of anti-GPIIbIIIa therapy. AB - Literature highlights the involvement of disseminated thrombosis in the pathophysiology of decompression sickness (DCS). We examined the effect of several antithrombotic treatments targeting various pathways on DCS outcome: acetyl salicylate, prasugrel, abciximab, and enoxaparin. Rats were randomly assigned to six groups. Groups 1 and 2 were a control nondiving group (C; n = 10) and a control diving group (CD; n = 30). Animals in Groups 3 to 6 were treated before hyperbaric exposure (HBE) with either prasugrel (n = 10), acetyl salicylate (n = 10), enoxaparin (n = 10), or abciximab (n = 10). Blood samples were taken for platelet factor 4 (PF4), thiobarbituric acid reactive substances (TBARS), and von Willebrand factor analysis. Onset of DCS symptoms and death were recorded during a 60-min observation period after HBE. Although we observed fewer outcomes of DCS in all treated groups compared with the CD, statistical significance was reached in abciximab only (20% vs. 73%, respectively, P = 0.007). We also observed significantly higher levels of plasmatic PF4 in abciximab (8.14 +/- 1.40 ng/ml; P = 0.004) and enoxaparin groups (8.01 +/- 0.80 ng/ml; P = 0.021) compared with the C group (6.45 +/- 1.90 ng/ml) but not CD group (8.14 +/- 1.40 ng/ml). Plasmatic levels of TBARS were significantly higher in the CD group than the C group (49.04 +/- 11.20 MUM vs. 34.44 +/- 5.70 MUM, P = 0.002). This effect was prevented by all treatments. Our results suggest that abciximab pretreatment, a powerful glycoprotein IIb/IIIa receptor antagonist, has a strong protective effect on decompression risk by significantly improving DCS outcome. Besides its powerful inhibitory action on platelet aggregation, we suggest that abciximab could also act through its effects on vascular function, oxidative stress, and/or inflammation. PMID- 25792712 TI - Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice. AB - We tested the hypothesis that endogenous brain Epo is a respiratory stimulant. Adult (3 mo) and newborn (10 days) male and female mice received an intracisternal (cisterna magna) injection of soluble Epo receptor (sEpoR; competes with EpoR to bind Epo; 50 MUg/ml) or vehicle (0.1% BSA in PBS). Twenty four hours after injection, we used whole body plethysmography to record minute ventilation (Ve) tidal volume (VT), respiratory frequency (fR), O2 consumption (Vo2), and CO2 production (Vco2) under normoxia and progressive exposure to hypoxia (12-10-6% O2; 10 min each). In adult male and female mice sEpoR decreased normoxic Ve (-25%), due to a decrease of VT in males and fR in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O2, assessed as Ve/Vo2 or Ve/Vco2, in male but not in female mice. In newborn male and female mice sEpoR decreased Ve (-37% in males, -59% in females) and VT (-38% in males, -47% in females) in normoxia and fR in females. During hypoxia, sEpoR decreased Ve/Vo2 and Ve/Vco2 in mice of both sexes. Upon extreme hypoxia (6% O2), the newborn mice treated with sEpoR showed respiratory depression, signs of asphyxia (gasping) and a high mortality rate in males and females. We concluded that endogenous brain Epo is a potent respiratory stimulant under normoxia and hypoxia in adult and newborn mice. Because sex-specific effects are different in newborn male and female, sex steroids secreted at different ages mice appear to modulate the effects of Epo on respiratory regulation in normoxia and in response to hypoxia. PMID- 25792714 TI - Aerobic physical training increases contractile response and reduces cardiac fibrosis in rats subjected to early ovarian hormone deprivation. AB - We investigated the effects of early ovarian hormone deprivation on the heart and the role of physical training in this condition using different approaches: cardiac autonomic tone, contractility, morphology and function, and cardiac fibrosis. Female Wistar rats (n = 48) were assigned into two groups: ovariectomized (Ovx; 10-wk-old) and control rats (Sham; 10-wk-old). Each group was further divided into two subgroups, sedentary and trained (aerobic training by swimming for 10 wk). The sedentary groups showed similar cardiac autonomic tone values; however, only the Sham group had an increase in vagal participation for the determination of the basal heart rate after physical training. The contractile responses to cardiac beta-agonists of the sedentary groups were similar, including an increased response to a beta1-agonist (dobutamine) observed after physical training. The Ovx sedentary group presented changes in cardiac morphology, which resulted in decreases in the ejection fraction, fractional shortening, and cardiac index compared with the Sham sedentary group. Physical training did little to alter these findings. Moreover, histology analysis showed a significant increase in cardiac fibrosis in the sedentary Ovx group, which was not observed in the trained Ovx group. We conclude that early ovarian hormone deprivation in rats impairs autonomic control, cardiac morphology, and cardiac function and increases cardiac fibrosis; however, it does not affect the contractility induced by dobutamine and salbutamol. Furthermore, this model of physical training prevented an increase in fibrosis and promoted an increase in the cardiac contractile response but had little effect on cardiac autonomic control or morphological and functional parameters. PMID- 25792713 TI - Voluntary exercise improves metabolic profile in high-fat fed glucocorticoid treated rats. AB - Diabetes is rapidly induced in young male Sprague-Dawley rats following treatment with exogenous corticosterone (CORT) and a high-fat diet (HFD). Regular exercise alleviates insulin insensitivity and improves pancreatic beta-cell function in insulin-resistant/diabetic rodents, but its effect in an animal model of elevated glucocorticoids is unknown. We examined the effect of voluntary exercise (EX) on diabetes development in CORT-HFD-treated male Sprague-Dawley rats (~6 wk old). Animals were acclimatized to running wheels for 2 wk, then given a HFD, either wax (placebo) or CORT pellets, and split into 4 groups: placebo-sedentary (SED) or -EX and CORT-SED or -EX. After 2 wk of running combined with treatment, CORT EX animals had reduced visceral adiposity, and increased skeletal muscle type IIb/x fiber area, oxidative capacity, capillary-to-fiber ratio and insulin sensitivity compared with CORT-SED animals (all P < 0.05). Although CORT-EX animals still had fasting hyperglycemia, these values were significantly improved compared with CORT-SED animals (14.3 +/- 1.6 vs. 18.8 +/- 0.9 mM). In addition, acute in vivo insulin response to an oral glucose challenge was enhanced ~2-fold in CORT-EX vs. CORT-SED (P < 0.05) which was further demonstrated ex vivo in isolated islets. We conclude that voluntary wheel running in rats improves, but does not fully normalize, the metabolic profile and skeletal muscle composition of animals administered CORT and HFD. PMID- 25792718 TI - MRI and the exercise blood pressure response in dilated cardiomyopathy. PMID- 25792717 TI - LC-MS-MS Analysis of N,alpha-Diethylphenethylamine (N,alpha-ETH) and Its Positional Isomer N,beta-Diethylphenethylamine (N,beta-ETH) in Dietary Supplements. AB - In a previous publication, we reported on the analysis of several dietary supplement/exercise formulas and the quantitation of N,alpha diethylphenethylamine (N,alpha-ETH, 3: ). In this article we report on the reanalysis of these products using LC-MS-MS and GC-MS methods capable of clearly separating the N,alpha-isomer ( 3: ) from its N,beta-isomer (N,beta-ETH, 4: ). The reanalysis, by both methods, showed that all samples previously reported as containing N,alpha-ETH ( 3: ) do contain only that isomer with no detectable concentrations of the N,beta-ETH ( 4: ). PMID- 25792716 TI - Contribution of epoxyeicosatrienoic acids to the cerebral blood flow response to hypoxemia. AB - Adenosine A2A receptors and ATP-activated K(+) (KATP) channels contribute to part of the cerebral vasodilatory response to systemic hypoxia, but other mediators are likely involved. Epoxyeicosatrienoic acids (EETs) are cerebral vasodilators and are released from astrocytes exposed to hypoxia. Moreover, stimulation of metabotropic glutamate receptors (mGluR) produces vasodilation by an EET dependent mechanism. Here, we tested the hypothesis that EET signaling and mGluR activation contribute to hypoxic vasodilation. Laser-Doppler flow was measured over cerebral cortex of anesthetized rats subjected to stepwise reductions in arterial oxygen saturation to 50-70%. Hypoxic reactivity was calculated as the slope of the change in laser-Doppler flow vs. the reciprocal of arterial oxygen content. Hypoxic reactivity significantly decreased from 9.2 +/- 1.9 (+/-95% confidence interval) in controls with vehicle treatment to 2.6 +/- 1.4 with the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid, to 3.0 +/- 1.5 with the EET synthesis inhibitor MS-PPOH, to 1.9 +/- 2.3 with the combined mGluR subtype 1 and 5 antagonists 2-methyl-6-(phenylethynyl)pyridine and LY367385, to 5.6 +/- 1.2 with the KATP channel inhibitor glibenclamide, and to 5.8 +/- 2.3 with the A2A receptor antagonist SCH58261. However, reactivity was not significantly altered by the A2B receptor antagonist MRS1754 (6.7 +/- 1.8; P = 0.28 Dunnett's test) or by the 20-hydroxyeicosatetraenoic acid synthesis inhibitor HET0016 (7.5 +/- 2.3; P = 0.6). These data indicate that, in addition to the known contributions of A2A receptors and KATP channels to the increase in cerebral blood flow during hypoxia, EETs and mGluRs make a major contribution, possibly by mGluR stimulation and hypoxia-induced release of EETs. In contrast, A2B receptors do not make a major contribution, and 20-hydroxyeicosatetraenoic acid does not significantly limit hypoxic vasodilation. PMID- 25792715 TI - Redox regulation of muscle adaptations to contractile activity and aging. AB - Superoxide and nitric oxide are generated by skeletal muscle, and these species are increased by contractile activity. Mitochondria have long been assumed to play the primary role in generation of superoxide in muscle, but recent studies indicate that, during contractile activity, membrane-localized NADPH oxidase(s) rapidly generate(s) superoxide that plays a role in redox signaling. This process is important in upregulation of rapid and specific cytoprotective responses that aid maintenance of cell viability following contractile activity, but the overall extent to which redox signaling contributes to regulation of muscle metabolism and homeostasis following contractile activity is currently unclear, as is identification of key redox-sensitive protein targets involved in these processes. Reactive oxygen and nitrogen species have also been implicated in the loss of muscle mass and function that occurs with aging, although recent work has questioned whether oxidative damage plays a key role in these processes. A failure of redox signaling occurs in muscle during aging and may contribute to the age-related loss of muscle fibers. Whether such changes in redox signaling reflect primary age-related changes or are secondary to the fundamental mechanisms is unclear. For instance, denervated muscle fibers within muscles from aged rodents or humans appear to generate large amounts of mitochondrial hydrogen peroxide that could influence adjacent innervated fibers. Thus, in this instance, a "secondary" source of reactive oxygen species may be potentially generated as a result of a primary age-related pathology (loss of neurons), but, nevertheless, may contribute to loss of muscle mass and function during aging. PMID- 25792719 TI - The different clinical presentations of vasovagal syncope. AB - For some decades, after the introduction of the head-up tilt test into clinical practice, the clinical presentation of vasovagal syncope (VVS) has been classified as typical (or classical) and atypical (or non-classical). Some clinical features and recent data suggest that even unexplained falls and syncope during sleeping hours may be possible clinical presentations of VVS. In recent studies, tilt testing and carotid sinus massage by means of the 'method of symptoms' were performed in one group of patients with unexplained falls and in another group with unexplained syncope (presence of prodromal symptoms). Overall, tilt testing and carotid sinus massage displayed a high positivity rate in the group of patients with unexplained falls (about 60%), which was similar to that of the unexplained syncope group. These new data seem to indicate that some unexplained falls could be cases of atypical VVS/carotid sinus syncope with retrograde amnesia. Some clinical features suggest that syncope during sleeping hours is a form of VVS with a different clinical presentation: high prevalence of autonomic prodromes, of diurnal episodes of typical VVS and specific phobias, and of positive tilt testing with severe cardioinhibition. PMID- 25792720 TI - What can rhythm control therapy contribute to prognosis in atrial fibrillation? AB - Atrial fibrillation (AF) is a global healthcare problem of growing prevalence and major significance. The consequences of AF include an increased rate of death, stroke and heart failure. Theoretically, a therapeutic strategy aiming at restoration and maintenance of sinus rhythm should offset the prognosis impairment associated with AF. However, these expectations were disproven in large randomised controlled trials comparing conventional antiarrhythmic drugs for rhythm control with conventional rate control. These apparently contradictory findings suggest that rhythm control strategies require better therapeutic instruments. These improvements may involve drugs and/or interventions with optimised risk-benefit profile and which also appreciate the specific atrial pathology and the patient's comorbidities. This article addresses important aspects of rhythm control strategies, which may have the potential of a beneficial contribution to the prognosis of AF patients. PMID- 25792721 TI - Paradoxical low-flow, low-gradient severe aortic stenosis: a distinct disease entity. PMID- 25792722 TI - Editorial: Innovative practice. PMID- 25792728 TI - Mogamulizumab: 2 birds, 1 stone. AB - In this issue of Blood, Duvic et al demonstrate that mogamulizumab, a humanized monoclonal antibody targeting the chemokine receptor CCR4, is well tolerated and has significant clinical activity (overall response rate 36.8%, median duration of response 10.4 months) in heavily pretreated patients with mycosis fungoides (MF) and Sezary syndrome (SS). PMID- 25792726 TI - Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5-10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp 43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology. PMID- 25792729 TI - DNA methylation in lymphoma: an opportunity? AB - Epigenetic mechanisms, including DNA methylation, play an important role in not only the development and maturation of normal cells, but also the development and progression of malignant cells. In this edition of Blood, Arribas et al show that DNA methylation profiling identifies 2 subtypes of splenic marginal zone lymphoma with different clinical and genetic features. These findings provide an opportunity to better understand the biology of marginal zone lymphoma and optimize therapy by using demethylating agents to reverse the high-methylation phenotype and thereby target malignant B cells. PMID- 25792730 TI - Speaking a common language in MDS/MPNs. AB - In this issue of Blood, Savona and an international consortium of clinical investigators propose uniform response criteria for treatment trials enrolling adult patients with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Such a proposal is needed because new drugs are finally being tested in these rare "overlap" syndromes that have both dysplastic and proliferative pathological features, and neither the International Working Group (IWG) response criteria for myelodysplastic syndromes nor the IWG Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) response criteria for myelofibrosis or for other myeloproliferative neoplasms fit such patients well. PMID- 25792727 TI - Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53 dependent apoptosis in a Drosophila cardiomyopathy model. AB - The heart is a muscle with high energy demands. Hence, most patients with mitochondrial disease produced by defects in the oxidative phosphorylation (OXPHOS) system are susceptible to cardiac involvement. The presentation of mitochondrial cardiomyopathy includes hypertrophic, dilated and left ventricular noncompaction, but the molecular mechanisms involved in cardiac impairment are unknown. One of the most frequent OXPHOS defects in humans frequently associated with cardiomyopathy is cytochrome c oxidase (COX) deficiency caused by mutations in COX assembly factors such as Sco1 and Sco2. To investigate the molecular mechanisms that underlie the cardiomyopathy associated with Sco deficiency, we have heart specifically interfered scox expression, the single Drosophila Sco orthologue. Cardiac-specific knockdown of scox reduces fly lifespan, and it severely compromises heart function and structure, producing dilated cardiomyopathy. Cardiomyocytes with low levels of scox have a significant reduction in COX activity and they undergo a metabolic switch from OXPHOS to glycolysis, mimicking the clinical features found in patients harbouring Sco mutations. The major cardiac defects observed are produced by a significant increase in apoptosis, which is dp53-dependent. Genetic and molecular evidence strongly suggest that dp53 is directly involved in the development of the cardiomyopathy induced by scox deficiency. Remarkably, apoptosis is enhanced in the muscle and liver of Sco2 knock-out mice, clearly suggesting that cell death is a key feature of the COX deficiencies produced by mutations in Sco genes in humans. PMID- 25792731 TI - ADAMTS13, lucky to have a hydrophobic pocket. AB - In this issue of Blood, de Groot et al identify a hydrophobic pocket in the Cys rich domain of ADAMTS13 that appears to interact with the hydrophobic pocket in the central A2 domain of von Willebrand factor (VWF) for its proteolysis. PMID- 25792732 TI - PARtitioning protease signaling. AB - In this issue of Blood, Aisiku et al describe a novel class of protease-activated receptor-1 (PAR1) inhibitors that block proinflammatory pathways but spare cytoprotective signaling in endothelial cells. These compounds, parmodulins, target the cytoplasmic face of PAR1, where they selectively interfere with Galphaq, but not Galpha12/13. This strategy of blocking specific pathways provides the ability to modulate the activity of receptors with multiple functions (such as PAR1) and may have therapeutic advantages. PMID- 25792733 TI - You've got to be kindlin! AB - In this issue of Blood, Liao et al report that kindlin-2 is necessary for angiogenic sprouting in vitro and for developmental and tumor angiogenesis in vivo. The process of blood vessel sprouting is known to involve the alphaVbeta3 vitronectin integrin on endothelium. Kindlin-2 linkage to the C-terminal tail of beta3 completed the outside-in circuit necessary for integrin signaling that is critical for navigation of new vessel sprouts. PMID- 25792735 TI - Structural basis for competitive inhibition of 3,4-dihydroxy-2-butanone-4 phosphate synthase from Vibrio cholerae. AB - The riboflavin biosynthesis pathway has been shown to be essential in many pathogens and is absent in humans. Therefore, enzymes involved in riboflavin synthesis are considered as potential antibacterial drug targets. The enzyme 3,4 dihydroxy-2-butanone-4-phosphate synthase (DHBPS) catalyzes one of the two committed steps in the riboflavin pathway and converts d-ribulose 5-phosphate (Ru5P) to l-3,4-dihydroxy-2-butanone 4-phosphate and formate. Moreover, DHBPS is shown to be indispensable for Mycobacterium, Salmonella, and Helicobacter species. Despite the essentiality of this enzyme in bacteria, no inhibitor has been identified hitherto. Here, we describe kinetic and crystal structure characterization of DHBPS from Vibrio cholerae (vDHBPS) with a competitive inhibitor 4-phospho-d-erythronohydroxamic acid (4PEH) at 1.86-A resolution. In addition, we also report the structural characterization of vDHBPS in its apo form and in complex with its substrate and substrate plus metal ions at 1.96-, 1.59-, and 2.04-A resolution, respectively. Comparison of these crystal structures suggests that 4PEH inhibits the catalytic activity of DHBPS as it is unable to form a proposed intermediate that is crucial for DHBPS activity. Furthermore, vDHBPS structures complexed with substrate and metal ions reveal that, unlike Candida albicans, binding of substrate to vDHBPS induces a conformational change from an open to closed conformation. Interestingly, the position of second metal ion, which is different from that of Methanococcus jannaschii, strongly supports an active role in the catalytic mechanism. Thus, the kinetic and structural characterization of vDHBPS reveals the molecular mechanism of inhibition shown by 4PEH and that it can be explored further for designing novel antibiotics. PMID- 25792737 TI - The recruitment of AMP-activated protein kinase to glycogen is regulated by autophosphorylation. AB - The mammalian AMP-activated protein kinase (AMPK) is an obligatory alphabetagamma heterotrimeric complex carrying a carbohydrate-binding module (CBM) in the beta subunit (AMPKbeta) capable of attaching AMPK to glycogen. Nonetheless, AMPK localizes at many different cellular compartments, implying the existence of mechanisms that prevent AMPK from glycogen binding. Cell-free carbohydrate binding assays revealed that AMPK autophosphorylation abolished its carbohydrate binding capacity. X-ray structural data of the CBM displays the central positioning of threonine 148 within the binding pocket. Substitution of Thr-148 for a phospho-mimicking aspartate (T148D) prevents AMPK from binding to carbohydrate. Overexpression of isolated CBM or beta1-containing AMPK in cellular models revealed that wild type (WT) localizes to glycogen particles, whereas T148D shows a diffuse pattern. Pharmacological AMPK activation and glycogen degradation by glucose deprivation but not forskolin enhanced cellular Thr-148 phosphorylation. Cellular glycogen content was higher if pharmacological AMPK activation was combined with overexpression of T148D mutant relative to WT AMPK. In summary, these data show that glycogen-binding capacity of AMPKbeta is regulated by Thr-148 autophosphorylation with likely implications in the regulation of glycogen turnover. The findings further raise the possibility of regulated carbohydrate-binding function in a wider variety of CBM-containing proteins. PMID- 25792736 TI - Mitochondrial heat shock protein (Hsp) 70 and Hsp10 cooperate in the formation of Hsp60 complexes. AB - Mitochondrial Hsp70 (mtHsp70) mediates essential functions for mitochondrial biogenesis, like import and folding of proteins. In these processes, the chaperone cooperates with cochaperones, the presequence translocase, and other chaperone systems. The chaperonin Hsp60, together with its cofactor Hsp10, catalyzes folding of a subset of mtHsp70 client proteins. Hsp60 forms heptameric ring structures that provide a cavity for protein folding. How the Hsp60 rings are assembled is poorly understood. In a comprehensive interaction study, we found that mtHsp70 associates with Hsp60 and Hsp10. Surprisingly, mtHsp70 interacts with Hsp10 independently of Hsp60. The mtHsp70-Hsp10 complex binds to the unassembled Hsp60 precursor to promote its assembly into mature Hsp60 complexes. We conclude that coupling to Hsp10 recruits mtHsp70 to mediate the biogenesis of the heptameric Hsp60 rings. PMID- 25792738 TI - Mutagenesis of the aquaporin 4 extracellular domains defines restricted binding patterns of pathogenic neuromyelitis optica IgG. AB - Neuromyelitis optica-immunoglobulin G (NMO-IgG) binds to aquaporin-4 (AQP4) water channels in the central nervous system leading to immune-mediated injury. We have previously demonstrated that a high proportion of CSF plasma cells of NMO patients produce antibody to the extracellular domains of the AQP4 protein and that recombinant IgG (rAb) derived from these cells recapitulate pathogenic features of disease. We performed a comprehensive mutational analysis of the three extracellular loops of the M23 isoform of human AQP4 using both serial and single point mutations, and we evaluated the effects on binding of NMO AQP4 reactive rAbs by quantitative immunofluorescence. Whereas all NMO rAbs required conserved loop C ((137)TP(138) and Val(150)) and loop E ((230)HW(231)) amino acids for binding, two broad patterns of NMO-IgG recognition could be distinguished based on differential sensitivity to loop A amino acid changes. Pattern 1 NMO rAbs were insensitive to loop A mutations and could be further discriminated by differential sensitivity to amino acid changes in loop C ((148)TM(149) and His(151)) and loop E (Asn(226) and Glu(228)). Alternatively, pattern 2 NMO rAbs showed significantly reduced binding following amino acid changes in loop A ((63)EKP(65) and Asp(69)) and loop C (Val(141), His(151), and Leu(154)). Amino acid substitutions at (137)TP(138) altered loop C conformation and abolished the binding of all NMO rAbs and NMO-IgG, indicating the global importance of loop C conformation to the recognition of AQP4 by pathogenic NMO Abs. The generation of human NMO rAbs has allowed the first high resolution mapping of extracellular loop amino acids critical for NMO-IgG binding and identified regions of AQP4 extracellular structure that may represent prime targets for drug therapy. PMID- 25792739 TI - UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1). AB - The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID- 25792740 TI - Structural basis for the phosphorylation-regulated interaction between the cytoplasmic tail of cell polarity protein crumbs and the actin-binding protein moesin. AB - The type I transmembrane protein crumbs (Crb) plays critical roles in the establishment and maintenance of cell polarities in diverse tissues. As such, mutations of Crb can cause different forms of cancers. The cell intrinsic role of Crb in cell polarity is governed by its conserved, 37-residue cytoplasmic tail (Crb-CT) via binding to moesin and protein associated with Lin7-1 (PALS1). However, the detailed mechanism governing the Crb.moesin interaction and the balance of Crb in binding to moesin and PALS1 are not well understood. Here we report the 1.5 A resolution crystal structure of the moesin protein 4.1/ezrin/radixin/moesin (FERM).Crb-CT complex, revealing that both the canonical FERM binding motif and the postsynaptic density protein-95/Disc large-1/Zonula occludens-1 (PDZ) binding motif of Crb contribute to the Crb.moesin interaction. We further demonstrate that phosphorylation of Crb-CT by atypical protein kinase C (aPKC) disrupts the Crb.moesin association but has no impact on the Crb.PALS1 interaction. The above results indicate that, upon the establishment of the apical-basal polarity in epithelia, apical-localized aPKC can actively prevent the Crb.moesin complex formation and thereby shift Crb to form complex with PALS1 at apical junctions. Therefore, Crb may serve as an aPKC-mediated sensor in coordinating contact-dependent cell growth inhibition in epithelial tissues. PMID- 25792742 TI - Recruitment of the 40S ribosome subunit to the 3'-untranslated region (UTR) of a viral mRNA, via the eIF4 complex, facilitates cap-independent translation. AB - Barley yellow dwarf virus mRNA, which lacks both cap and poly(A) tail, has a translation element (3'-BTE) in its 3'-UTR essential for efficient translation initiation at the 5'-proximal AUG. This mechanism requires eukaryotic initiation factor 4G (eIF4G), subunit of heterodimer eIF4F (plant eIF4F lacks eIF4A), and 3' BTE-5'-UTR interaction. Using fluorescence anisotropy, SHAPE (selective 2' hydroxyl acylation analyzed by primer extension) analysis, and toeprinting, we found that (i) 40S subunits bind to BTE (Kd = 350 +/- 30 nm), (ii) the helicase complex eIF4F-eIF4A-eIF4B-ATP increases 40S subunit binding (Kd = 120 +/- 10 nm) to the conserved stem-loop I of the 3'-BTE by exposing more unpaired bases, and (iii) long distance base pairing transfers this complex to the 5'-end of the mRNA, where translation initiates. Although 3'-5' interactions have been recognized as important in mRNA translation, barley yellow dwarf virus employs a novel mechanism utilizing the 3'-UTR as the primary site of ribosome recruitment. PMID- 25792743 TI - Crystal structure of barley limit dextrinase-limit dextrinase inhibitor (LD-LDI) complex reveals insights into mechanism and diversity of cereal type inhibitors. AB - Molecular details underlying regulation of starch mobilization in cereal seed endosperm remain unknown despite the paramount role of this process in plant growth. The structure of the complex between the starch debranching enzyme barley limit dextrinase (LD), hydrolyzing alpha-1,6-glucosidic linkages, and its endogenous inhibitor (LDI) was solved at 2.7 A. The structure reveals an entirely new and unexpected binding mode of LDI as compared with previously solved complex structures of related cereal type family inhibitors (CTIs) bound to glycoside hydrolases but is structurally analogous to binding of dual specificity CTIs to proteases. Site-directed mutagenesis establishes that a hydrophobic cluster flanked by ionic interactions in the protein-protein interface is vital for the picomolar affinity of LDI to LD as assessed by analysis of binding by using surface plasmon resonance and also supported by LDI inhibition of the enzyme activity. A phylogenetic analysis identified four LDI-like proteins in cereals among the 45 sequences from monocot databases that could be classified as unique CTI sequences. The unprecedented binding mechanism shown here for LDI has likely evolved in cereals from a need for effective inhibition of debranching enzymes having characteristic open active site architecture. The findings give a mechanistic rationale for the potency of LD activity regulation and provide a molecular understanding of the debranching events associated with optimal starch mobilization and utilization during germination. This study unveils a hitherto not recognized structural basis for the features endowing diversity to CTIs. PMID- 25792741 TI - Variability of Potassium Channel Blockers in Mesobuthus eupeus Scorpion Venom with Focus on Kv1.1: AN INTEGRATED TRANSCRIPTOMIC AND PROTEOMIC STUDY. AB - The lesser Asian scorpion Mesobuthus eupeus (Buthidae) is one of the most widely spread and dispersed species of the Mesobuthus genus, and its venom is actively studied. Nevertheless, a considerable amount of active compounds is still under investigated due to the high complexity of this venom. Here, we report a comprehensive analysis of putative potassium channel toxins (KTxs) from the cDNA library of M. eupeus venom glands, and we compare the deduced KTx structures with peptides purified from the venom. For the transcriptome analysis, we used conventional tools as well as a search for structural motifs characteristic of scorpion venom components in the form of regular expressions. We found 59 candidate KTxs distributed in 30 subfamilies and presenting the cysteine stabilized alpha/beta and inhibitor cystine knot types of fold. M. eupeus venom was then separated to individual components by multistage chromatography. A facile fluorescent system based on the expression of the KcsA-Kv1.1 hybrid channels in Escherichia coli and utilization of a labeled scorpion toxin was elaborated and applied to follow Kv1.1 pore binding activity during venom separation. As a result, eight high affinity Kv1.1 channel blockers were identified, including five novel peptides, which extend the panel of potential pharmacologically important Kv1 ligands. Activity of the new peptides against rat Kv1.1 channel was confirmed (IC50 in the range of 1-780 nm) by the two-electrode voltage clamp technique using a standard Xenopus oocyte system. Our integrated approach is of general utility and efficiency to mine natural venoms for KTxs. PMID- 25792744 TI - Cytosolic accumulation of small nucleolar RNAs (snoRNAs) is dynamically regulated by NADPH oxidase. AB - Small nucleolar RNAs (snoRNAs) guide nucleotide modifications of cellular RNAs in the nucleus. We previously showed that box C/D snoRNAs from the Rpl13a locus are unexpected mediators of physiologic oxidative stress, independent of their predicted ribosomal RNA modifications. Here we demonstrate that oxidative stress induced by doxorubicin causes rapid cytoplasmic accumulation of the Rpl13a snoRNAs through a mechanism that requires superoxide and a nuclear splice variant of NADPH oxidase. RNA-sequencing analysis reveals that box C/D snoRNAs as a class are present in the cytoplasm, where their levels are dynamically regulated by NADPH oxidase. These findings suggest that snoRNAs may orchestrate the response to environmental stress through molecular interactions outside of the nucleus. PMID- 25792745 TI - Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes. AB - Astrocytes contain glycogen, an energy buffer, which can bridge local short term energy requirements in the brain. Glycogen levels reflect a dynamic equilibrium between glycogen synthesis and glycogenolysis. Many factors that include hormones and neuropeptides, such as insulin and insulin-like growth factor 1 (IGF-1) likely modulate glycogen stores in astrocytes, but detailed mechanisms at the cellular level are sparse. We used a glucose nanosensor based on Forster resonance energy transfer to monitor cytosolic glucose concentration with high temporal resolution and a cytochemical approach to determine glycogen stores in single cells. The results show that after glucose depletion, glycogen stores are replenished. Insulin and IGF-1 boost the process of glycogen formation. Although astrocytes appear to express glucose transporter GLUT4, glucose entry across the astrocyte plasma membrane is not affected by insulin. Stimulation of cells with insulin and IGF-1 decreased cytosolic glucose concentration, likely because of elevated glucose utilization for glycogen synthesis. PMID- 25792746 TI - Opposite cross-talk by oleate and palmitate on insulin signaling in hepatocytes through macrophage activation. AB - Chronic low grade inflammation in adipose tissue during obesity is associated with an impairment of the insulin signaling cascade. In this study, we have evaluated the impact of palmitate or oleate overload of macrophage/Kupffer cells in triggering stress-mediated signaling pathways, in lipoapoptosis, and in the cross-talk with insulin signaling in hepatocytes. RAW 264.7 macrophages or Kupffer cells were stimulated with oleate or palmitate, and levels of M1/M2 polarization markers and the lipidomic profile of eicosanoids were analyzed. Whereas proinflammatory cytokines and total eicosanoids were elevated in macrophages/Kupffer cells stimulated with palmitate, enhanced arginase 1 and lower leukotriene B4 (LTB4) levels were detected in macrophages stimulated with oleate. When hepatocytes were pretreated with conditioned medium (CM) from RAW 264.7 or Kupffer cells loaded with palmitate (CM-P), phosphorylation of stress kinases and endoplasmic reticulum stress signaling was increased, insulin signaling was impaired, and lipoapoptosis was detected. Conversely, enhanced insulin receptor-mediated signaling and reduced levels of the phosphatases protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homolog (PTEN) were found in hepatocytes treated with CM from macrophages stimulated with oleate (CM-O). Supplementation of CM-O with LTB4 suppressed insulin sensitization and increased PTP1B and PTEN. Furthermore, LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes, activated the NFkappaB pathway, and up-regulated PTP1B and PTEN, these effects being mediated by LTB4 receptor BTL1. In conclusion, oleate and palmitate elicit an opposite cross-talk between macrophages/Kupffer cells and hepatocytes. Whereas CM-P interferes at the early steps of insulin signaling, CM-O increases insulin sensitization, possibly by reducing LTB4. PMID- 25792747 TI - Carboxyl terminus of HSC70-interacting protein (CHIP) down-regulates NF-kappaB inducing kinase (NIK) and suppresses NIK-induced liver injury. AB - Ser/Thr kinase NIK (NF-kappaB-inducing kinase) mediates the activation of the noncanonical NF-kappaB2 pathway, and it plays an important role in regulating immune cell development and liver homeostasis. NIK levels are extremely low in quiescent cells due to ubiquitin/proteasome-mediated degradation, and cytokines stimulate NIK activation through increasing NIK stability; however, regulation of NIK stability is not fully understood. Here we identified CHIP (carboxyl terminus of HSC70-interacting protein) as a new negative regulator of NIK. CHIP contains three N-terminal tetratricopeptide repeats (TPRs), a middle dimerization domain, and a C-terminal U-box. The U-box domain contains ubiquitin E3 ligase activity that promotes ubiquitination of CHIP-bound partners. We observed that CHIP bound to NIK via its TPR domain. In both HEK293 and primary hepatocytes, overexpression of CHIP markedly decreased NIK levels at least in part through increasing ubiquitination and degradation of NIK. Accordingly, CHIP suppressed NIK-induced activation of the noncanonical NF-kappaB2 pathway. CHIP also bound to TRAF3, and CHIP and TRAF3 acted coordinately to efficiently promote NIK degradation. The TPR but not the U-box domain was required for CHIP to promote NIK degradation. In mice, hepatocyte-specific overexpression of NIK resulted in liver inflammation and injury, leading to death, and liver-specific expression of CHIP reversed the detrimental effects of hepatic NIK. Our data suggest that CHIP/TRAF3/NIK interactions recruit NIK to E3 ligase complexes for ubiquitination and degradation, thus maintaining NIK at low levels. Defects in CHIP regulation of NIK may result in aberrant NIK activation in the liver, contributing to live injury, inflammation, and disease. PMID- 25792750 TI - The N-terminal domain of the tomato immune protein Prf contains multiple homotypic and Pto kinase interaction sites. AB - Resistance to Pseudomonas syringae bacteria in tomato (Solanum lycopersicum) is conferred by the Prf recognition complex, composed of the nucleotide-binding leucine-rich repeats protein Prf and the protein kinase Pto. The complex is activated by recognition of the P. syringae effectors AvrPto and AvrPtoB. The N terminal domain is responsible for Prf homodimerization, which brings two Pto kinases into close proximity and holds them in inactive conformation in the absence of either effector. Negative regulation is lost by effector binding to the catalytic cleft of Pto, leading to disruption of its P+1 loop within the activation segment. This change is translated through Prf to a second Pto molecule in the complex. Here we describe a schematic model of the unique Prf N terminal domain dimer and its interaction with the effector binding determinant Pto. Using heterologous expression in Nicotiana benthamiana, we define multiple sites of N domain homotypic interaction and infer that it forms a parallel dimer folded centrally to enable contact between the N and C termini. Furthermore, we found independent binding sites for Pto at either end of the N-terminal domain. Using the constitutively active mutant ptoL205D, we identify a potential repression site for Pto in the first ~100 amino acids of Prf. Finally, we find that the Prf leucine-rich repeats domain also binds the N-terminal region, highlighting a possible mechanism for transfer of the effector binding signal to the NB-LRR regulatory unit (consisting of a central nucleotide binding and C terminal leucine-rich repeats). PMID- 25792748 TI - The calcium-binding proteins S100A8 and S100A9 initiate the early inflammatory program in injured peripheral nerves. AB - To shed light on the early immune response processes in severed peripheral nerves, we performed genome-wide transcriptional profiling and bioinformatics analyses of the proximal (P, regenerating) and distal (D, degenerating) nerve stumps on day 1 in the sciatic nerve axotomy model in rats. Multiple cell death related pathways were activated in the degenerating D stump, whereas activation of the cytoskeletal motility and gluconeogenesis/glycolysis pathways was most prominent in the P stump of the axotomized nerve. Our bioinformatics analyses also identified the specific immunomodulatory genes of the chemokine, IL, TNF, MHC, immunoglobulin-binding Fc receptor, calcium-binding S100, matrix metalloproteinase, tissue inhibitor of metalloproteinase, and ion channel families affected in both the P and D segments. S100a8 and S100a9 were the top up regulated genes in both the P and D segments. Stimulation of cultured Schwann cells using the purified S100A8/A9 heterodimer recapitulated activation of the myeloid cell and phagocyte chemotactic genes and pathways, which we initially observed in injured nerves. S100A8/A9 heterodimer injection into the intact nerve stimulated macrophage infiltration. We conclude that, following peripheral nerve injury, an immediate acute immune response occurs both distal and proximal to the lesion site and that the rapid transcriptional activation of the S100a8 and S100a9 genes results in S100A8/A9 hetero- and homodimers, which stimulate the release of chemokines and cytokines by activated Schwann cells and generate the initial chemotactic gradient that guides the transmigration of hematogenous immune cells into the injured nerve. PMID- 25792751 TI - Variation between specialist uropatholgists in reporting extraprostatic extension after radical prostatectomy. AB - AIMS: Extraprostatic extension of prostate cancer in radical prostatectomy specimens significantly affects patient management. We evaluated the degree of interobserver variation between uropathologists at a tertiary referral teaching hospital in assessing the extraprostatic extension of prostate cancer in radical prostatectomy specimens. METHODS: Histopathological data from a consecutive series of 293 radical prostatectomy specimens (January 2007-December 2012) were reviewed. A subset of 50 consecutive radical prostatectomy cases originally staged as tumours confined to the prostate (pT2) or tumours extending into periprostatic tissue (pT3a) during this period were reviewed by four specialist uropathologists. RESULTS: Five consultant histopathologists reported these specimens with significant differences in the reported stage (p=0.0164) between pathologists. Double-blind review by 4 uropathologists of 50 consecutive radical prostatectomy cases showed a lack of consensus in 16/50 (32%) cases (kappa score 0.58, moderate agreement). A consensus meeting was held, but consensus could still not be reached in 9/16 cases. CONCLUSIONS: Our findings highlight variability in the reporting of pT stage in radical prostatectomy specimens even by specialist uropathologists. Assessment of extraprostatic extension has important implications for patient management and there is a need for more precise guidance. PMID- 25792752 TI - Race/ethnicity and the risk of childhood leukaemia: a case-control study in California. AB - BACKGROUND: We conducted a large registry-based study in California to investigate the association between race/ethnicity and childhood leukaemia focusing on two subtypes: acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). METHODS: We obtained information on 5788 cases and 5788 controls by linking California cancer and birth registries. We evaluated relative risk of childhood leukaemia by race and ethnicity of the child and their parents using conditional logistic regression, with adjustment for potential confounders. RESULTS: Compared with Whites, Black children had lower risk of ALL (OR=0.54, 95% CI 0.45 to 0.66) as well as children of Black/Asian parents (OR=0.31, 95% CI 0.10 to 0.94). Asian race was associated with increased risk of AML with OR=1.643, 95% CI 1.10 to 2.46 for Asian vs Whites; and OR=1.67, 95% CI 1.04 to 2.70 for Asian/Asian vs White/White. Hispanic ethnicity was associated with increased risk of ALL (OR=1.37, 95% CI 1.22 to 1.52). A gradient in risk of ALL was observed while comparing Hispanic children with both parents Hispanic, one parent Hispanic and non-Hispanic children (p Value for trend <0.0001). The highest risk of ALL was observed for children with a combination of Hispanic ethnicity and White race compared with non-Hispanic whites (OR=1.27, 95% CI 1.12 to 1.44). The lowest risk was observed for non-Hispanic blacks (OR=0.46, 95% CI 0.36 to 0.60). Associations for total childhood leukaemia were similar to ALL. CONCLUSIONS: Our results confirm that there are ethnic and racial differences in the incidence of childhood leukaemia. These differences indicate that some genetic and/or environmental/cultural factors are involved in aetiology of childhood leukaemia. PMID- 25792754 TI - High capacity for extracellular acid-base regulation in the air-breathing fish Pangasianodon hypophthalmus. AB - The evolution of accessory air-breathing structures is typically associated with reduction of the gills, although branchial ion transport remains pivotal for acid base and ion regulation. Therefore, air-breathing fishes are believed to have a low capacity for extracellular pH regulation during a respiratory acidosis. In the present study, we investigated acid-base regulation during hypercapnia in the air-breathing fish Pangasianodon hypophthalmus in normoxic and hypoxic water at 28-30 degrees C. Contrary to previous studies, we show that this air-breathing fish has a pronounced ability to regulate extracellular pH (pHe) during hypercapnia, with complete metabolic compensation of pHe within 72 h of exposure to hypoxic hypercapnia with CO2 levels above 34 mmHg. The high capacity for pHe regulation relies on a pronounced ability to increase levels of HCO3(-) in the plasma. Our study illustrates the diversity in the physiology of air-breathing fishes, such that generalizations across phylogenies may be difficult. PMID- 25792755 TI - Erratum for Fu et al., Activation of p90 ribosomal S6 kinases by ORF45 of Kaposi's sarcoma-associated herpesvirus is critical for optimal production of infectious viruses. PMID- 25792753 TI - Whole-field visual motion drives swimming in larval zebrafish via a stochastic process. AB - Caudo-rostral whole-field visual motion elicits forward locomotion in many organisms, including larval zebrafish. Here, we investigate the dependence on the latency to initiate this forward swimming as a function of the speed of the visual motion. We show that latency is highly dependent on speed for slow speeds (<10 mm s(-1)) and then plateaus for higher values. Typical latencies are >1.5 s, which is much longer than neuronal transduction processes. What mechanisms underlie these long latencies? We propose two alternative, biologically inspired models that could account for this latency to initiate swimming: an integrate and fire model, which is history dependent, and a stochastic Poisson model, which has no history dependence. We use these models to predict the behavior of larvae when presented with whole-field motion of varying speed and find that the stochastic process shows better agreement with the experimental data. Finally, we discuss possible neuronal implementations of these models. PMID- 25792756 TI - Correction for Joseph et al., Adaptation of pandemic H2N2 influenza A viruses in humans. PMID- 25792749 TI - Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain. AB - Regulators of G protein signaling control the duration and extent of signaling via G protein-coupled receptor (GPCR) pathways by accelerating the GTP hydrolysis on G protein alpha subunits thereby promoting termination of GPCR signaling. A member of this family, RGS7, plays a critical role in the nervous system where it regulates multiple neurotransmitter GPCRs that mediate vision, memory, and the action of addictive drugs. Previous studies have established that in vivo RGS7 forms mutually exclusive complexes with the membrane protein RGS7-binding protein or the orphan receptor GPR158. In this study, we examine the impact of GPR158 on RGS7 in the brain. We report that knock-out of GPR158 in mice results in marked post-transcriptional destabilization of RGS7 and substantial loss of its association with membranes in several brain regions. We further identified the RGS7-binding site in the C terminus of GPR158 and found that it shares significant homology with the RGS7-binding protein. The proximal portion of the GPR158 C terminus additionally contained a conserved sequence that was capable of enhancing RGS7 GTPase-activating protein activity in solution by an allosteric mechanism acting in conjunction with the regulators of the G protein signaling binding domain. The distal portion of the GPR158 C terminus contained several phosphodiesterase E gamma-like motifs and selectively recruited G proteins in their activated state. The results of this study establish GPR158 as an essential regulator of RGS7 in the native nervous system with a critical role in controlling its expression, membrane localization, and catalytic activity. PMID- 25792759 TI - Trisomy of chromosome R confers resistance to triazoles in Candida albicans. AB - Genome plasticity is a hallmark of Candida albicans, and it has been suggested that it generates numerical and structural genomic variations as a means of adaptation. In this study, we used array based comparative genomic hybridization technology and the quantitative real time PCR to investigate the mechanisms by which the following strains obtained by genetic manipulation, CaLY188, CaLY350, CaLY190 and CaLY191, were resistant to antifungal azoles. All four showed trisomy of chromosome R and resistance to azoles. Serial passage of CaLY188 in drug-free medium resulted in chromosome loss, causing chromosome R disomy and loss of azole resistance. Thus we proposed that trisomy of chromosome R contributes to azole resistance. PMID- 25792758 TI - A profiling approach of the natural variability of foliar N remobilization at the rosette stage gives clues to understand the limiting processes involved in the low N use efficiency of winter oilseed rape. AB - Oilseed rape, a crop requiring a high level of nitogen (N) fertilizers, is characterized by low N use efficiency. To identify the limiting factors involved in the N use efficiency of winter oilseed rape, the response to low N supply was investigated at the vegetative stage in 10 genotypes by using long-term pulse chase (15)N labelling and studying the physiological processes of leaf N remobilization. Analysis of growth and components of N use efficiency allowed four profiles to be defined. Group 1 was characterized by an efficient N remobilization under low and high N conditions but by a decrease of leaf growth under N limitation. Group 2 showed a decrease in leaf growth under low N supply that was associated with a low N remobilization efficiency under both N supplies despite a high remobilization of soluble proteins. In response to N limitation, Group 3 is characterized by an increase in N use efficiency and leaf N remobilization compared with high N that is not sufficient to sustain the leaf biomass production at a similar level to non-limited plants. Genotypes of Group 4 subjected to low nitrate were able to maintain leaf growth to the same level as under high N. The profiling approach indicated that enhancement of amino acid export and soluble protein degradation was crucial for N remobilization improvement. At the whole-plant level, N fluxes revealed that Group 4 showed a high N remobilization in source leaves combined with a better N utilization in young leaves. Consequently, an enhanced N remobilization limits N loss in fallen leaves, but this remobilized N needs to be efficiently utilized in young leaves to improve N use efficiency. PMID- 25792762 TI - On the Effects of Thermal History on the Development and Relaxation of Thermo Mechanical Stress in Cryopreservation. AB - This study investigates the effects of the thermal protocol on the development and relaxation of thermo-mechanical stress in cryopreservation by means of glass formation, also known as vitrification. The cryopreserved medium is modeled as a homogeneous viscoelastic domain, constrained within either a stiff cylindrical container or a highly compliant bag. Annealing effects during the cooling phase of the cryopreservation protocol are analyzed. Results demonstrate that an intermediate temperature-hold period can significantly reduce the maximum tensile stress, thereby decreasing the potential for structural damage. It is also demonstrated that annealing at temperatures close to glass transition significantly weakens the dependency of thermo-mechanical stress on the cooling rate. Furthermore, a slower initial rewarming rate after cryogenic storage may drastically reduce the maximum tensile stress in the material, which supports previous experimental observations on the likelihood of fracture at this stage. This study discusses the dependency of the various stress components on the storage temperature. Finally, it is demonstrated that the stiffness of the container wall can affect the location of maximum stress, with implications on the development of cryopreservation protocols. PMID- 25792761 TI - Brain Oscillations, Hypnosis, and Hypnotizability. AB - In this article, we summarize the state-of-science knowledge regarding the associations between hypnosis and brain oscillations. Brain oscillations represent the combined electrical activity of neuronal assemblies, and are usually measured as specific frequencies representing slower (delta, theta, alpha) and faster (beta, gamma) oscillations. Hypnosis has been most closely linked to power in the theta band and changes in gamma activity. These oscillations are thought to play a critical role in both the recording and recall of declarative memory and emotional limbic circuits. Here we propose that it is this role that may be the mechanistic link between theta (and perhaps gamma) oscillations and hypnosis; specifically that theta oscillations may facilitate, and that changes in gamma activity observed with hypnosis may underlie, some hypnotic responses. If these hypotheses are supported, they have important implications for both understanding the effects of hypnosis, and for enhancing response to hypnotic treatments. PMID- 25792763 TI - Investigation of the Effect of Finite Pulse Errors on BABA Pulse Sequence Using Floquet-Magnus Expansion Approach. AB - This paper presents the study of finite pulse widths for the BABA pulse sequence using the Floquet-Magnus expansion (FME) approach. In the FME scheme, the first order F1 is identical to its counterparts in average Hamiltonian theory (AHT) and Floquet theory (FT). However, the timing part in the FME approach is introduced via the Lambda1 (t) function not present in other schemes. This function provides an easy way for evaluating the spin evolution during "the time in between" through the Magnus expansion of the operator connected to the timing part of the evolution. The evaluation of Lambda1 (t) is useful especially for the analysis of the non-stroboscopic evolution. Here, the importance of the boundary conditions, which provides a natural choice of Lambda1 (0) is ignored. This work uses the Lambda1 (t) function to compare the efficiency of the BABA pulse sequence with delta - pulses and the BABA pulse sequence with finite pulses. Calculations of Lambda1 (t) and F1 are presented. PMID- 25792764 TI - SAVINGS BY AND FOR THE POOR: A RESEARCH REVIEW AND AGENDA. AB - The poor can and do save, but often use formal or informal instruments that have high risk, high cost, and limited functionality. This could lead to undersaving compared to a world without market or behavioral frictions. Undersaving can have important welfare consequences: variable consumption, low resilience to shocks, and foregone profitable investments. We lay out five sets of constraints that may hinder the adoption and effective usage of savings products and services by the poor: transaction costs, lack of trust and regulatory barriers, information and knowledge gaps, social constraints, and behavioral biases. We discuss each in theory, and then summarize related empirical evidence, with a focus on recent field experiments. We then put forward key open areas for research and practice. JEL Codes: D12, D91, G21, O16. PMID- 25792765 TI - Developments of the theory of spin fluctuations and spin fluctuation-induced superconductivity. AB - Theory of spin fluctuations as developed in the past 30 years have played important roles in the theory of magnetism in metals, particularly in elucidating the properties around the magnetic instability or quantum critical points. Recently the theory has been extended to deal with the spin fluctuaion-mediated superconductivity with anisotropic order parameters in strongly correlated electron systems. These theoretical developments are briefly reviewed and the high temperature superconductivity of cuprates and organic and heavy electron superconductors are discussed in the light of these theories. PMID- 25792766 TI - Endothelin and endothelial dysfunction. AB - Nitric oxide (NO) and endothelin (ET) produced in endothelial cells are leading molecules which regulate vascular function. Failure of the physiological balance between these two molecules is usually referred to as endothelial dysfunction. ET was initially identified as a potent vasoconstrictive peptide. Three ET isoforms and two ET receptors have been identified. One of the isoforms, ET-1, plays a significant role in many cardiovascular diseases. On the other hand, oxidized low density lipoprotein (oxLDL) is known to induce endothelial dysfunction. The endothelial receptor for oxLDL was cloned, and named lectin-like oxidized receptor-1 (LOX-1). Activation of LOX-1 generates reactive oxygen species (ROS), and acivates a transcriptional factor, nuclear factor kappaB (NFkappaB), resulting in down-regulation of NO and up-regulation of ET-1. LOX-1 might be a key molecule in the generation of endothelial dysfunction. In endothelial dysfunction, ET-1 is an aggravating factor of cardiovascular diseases. PMID- 25792767 TI - Guadalupian (Middle Permian) giant bivalve Alatoconchidae from a mid-Panthalassan paleo-atoll complex in Kyushu, Japan: A unique community associated with Tethyan fusulines and corals. AB - Unique new fossil assemblages containing the large bivalve family Alatoconchidae are recorded from the Guadalupian (Middle Permian) shallow marine limestone in Kamura, Kyushu. The large bivalves occur in the Neoschwagerina Zone and Lepidolina Zone. This discovery establishes that the biostratigraphic range of the family Alatoconchidae extends up to the top of the Lepidolina Zone (upper Capitanian of upper Guadalupian) i.e., to the end-Guadalupian extinction level. The largest Alatoconchidae in Kamura occurs in the Neoschwagerina Zone, the size of which is up to 50 cm long and 5 cm thick. Although details are still unknown, their morphology with a wing-like side projection of their valves appears very similar to that of Alatoconchidae that includes the well-known genus Shikamaia Ozaki. The bivalve-bearing Iwato Formation was derived from a mid-oceanic shallow marine carbonate build-up formed on a mid-oceanic paleo-seamount. The close association among the Alatoconchidae, typical Tethyan fusulines (Verbeekinidae) and rugose corals (Waagenophyllidae), plus their common extinction pattern suggests that the Alatoconchidae flourished in warm, shallow (photic) marine environments in low latitude areas in Panthalassa as well as Tethys. The extra large size and double-layered shell with a translucent outer layer composed of prismatic calcite suggests that these bivalves may have hosted abundant photosynthetic algal symbionts to support their large-body metabolism. PMID- 25792768 TI - A SELEX study of the DNA-binding specificity of archaeal FFRPs: 2. FL4 (pot1613368). AB - The DNA-binding specificity of a transcription factor, the FFRP FL4 (pot1613368) from Pyrococcus sp. OT3, was studied. Using SELEX (systematic evolution of ligands by exponential environment) experiments, from a set of fragments, ~150 bps, of the genomic DNA of P. OT3, seven were selected as containing binding sites. Thirteen bases identified as shared by the seven selected fragments with the least mismatches, 2.71 on average, was ATGAA AAAGTCAT. This sequence was closely related with another sequence, ATGAA[AAA/TTT]TTCAT, in the 5-3-5 arrangement, i.e. NANBNCNDNE [AAA/TTT]NENDNCNBNA , where, e.g. NA was the base complementary to NA. The average number of mismatches found between this sequence and the seven fragments was 3.14. A sequence, TTGAA ATT TACAA, resembling the sequence ATGAA[AAA/TTT]TTCAT and also another 5-3-5 sequence, TTGAA[AAA/TTT]TTCAA, was found upstream of the fl4 gene, which is potentially recognized by FL4 for auto-regulation. Thus it is likely that an ideal binding site of FL4 is ATGAA[AAA/TTT]TTCAT or TTGAA[AAA/TTT]TTCAA. In this abstract, the sequences were highlighted in Italic at 3, and with bold characters at 5 and 5. When two sequences compared were the same at some positions, there they were underlined. PMID- 25792769 TI - Phylogenetic studies of dogs with emphasis on Japanese and Asian breeds. AB - The first domestication of the dog occurred in East Asia, and major ancestor of the dog was a wolf subspecies, Canis lupus chanco. This finding derives from data on the nucleotide sequences of mtDNA and the frequency of genes controlling blood protein polymorphisms in various subspecies of wolves and dog breeds around the world. The results of the allele frequency distribution of genes controlling 16 blood protein polymorphisms, and the incidence of dogs possessing erythrocytes with high potassium (HK) in Japan, East Asia and Europe allowed us to posturate the following hypothesis about the origins of Japanese dogs and the history of their development. In the Jomon period the first dogs entered the Japanese archipelago from southern or northern continental Asia. These dogs eventually spread throughout Japan. Then, during the Yayoi and Kofun periods, other dogs were brought over via the Korean Peninsula, and crossbreeding occurred with the original dogs. The resulted offspring can be assumed to be the ancestors of most of the Japanese breeds that exist today. Ethological studies have revealed a significant breed difference in behavioral traits among canine breeds with Japanese dogs, showing more aggressive dispositions than most of European dogs. PMID- 25792772 TI - The Aharonov-Bohm effect and its applications to electron phase microscopy. AB - The Aharonov-Bohm effect was conclusively established by a series of our electron interference experiments, with the help of some advanced techniques, such as coherent field-emission electron beams and microlithography. Using this fundamental principle behind the interaction of an electron wave with electromagnetic fields, new observation techniques were developed to directly observe microscopic objects and quantum phenomena previously unobservable. PMID- 25792771 TI - Our research on proton pumping ATPases over three decades: their biochemistry, molecular biology and cell biology. AB - ATP is synthesized by F-type proton-translocating ATPases (F-ATPases) coupled with an electrochemical proton gradient established by an electron transfer chain. This mechanism is ubiquitously found in mitochondria, chloroplasts and bacteria. Vacuolar-type ATPases (V-ATPases) are found in endomembrane organelles, including lysosomes, endosomes, synaptic vesicles, etc., of animal and plant cells. These two physiologically different proton pumps exhibit similarities in subunit assembly, catalysis and the coupling mechanism from chemistry to proton transport through subunit rotation. We mostly discuss our own studies on the two proton pumps over the last three decades, including ones on purification, kinetic analysis, rotational catalysis and the diverse roles of acidic luminal organelles. The diversity of organellar proton pumps and their stochastic fluctuation are the important concepts derived recently from our studies. PMID- 25792773 TI - Kawasaki disease. AB - Short history of Kawasaki disease, clinical features (principal symptoms and other significant symptoms or findings), diagnosis, cardiovascular involvement, epidemiology. Pathological features (lesion of vessels and lesion of organs exclusive of vessels), comparison between infantile periarteritis nodosa (IPN)/Kawasaki disease and classic periarteritis nodosa (CPN), etiology, treatment and management of Kawasaki disease are described. PMID- 25792770 TI - The catecholamine system in health and disease -Relation to tyrosine 3 monooxygenase and other catecholamine-synthesizing enzymes. AB - Catecholamines [dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine); CAs] are neurotransmitters in the central and peripheral nervous systems as well as hormones in the endocrine system. CAs in the brain play a central role in versatile functions as slow-acting neurotransmitters functioning in synaptic neurotransmission, modulating the effects of fast-acting neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA). In this review, I focus on recent advances in the biochemistry and molecular biology of the CA system in humans in health and disease, especially in neuropsychiatric diseases such as Parkinson's disease (PD), in relation to the biosynthesis of CAs regulated by a pteridine-dependent monooxygenase, tyrosine 3-monooxygenase (tyrosine hydroxylase, TH) and its pteridine cofactor, tetrahydrobiopterin (BH4). PMID- 25792775 TI - What happened before the last five strong earthquakes in Greece: Facts and open questions. AB - During the period October 2005 - January 2006, five strong earthquakes occurred in Greece as follows: three magnitude 6.0 consecutive earthquakes with almost the same epicenter in the Aegean Sea close to the western coast of Turkey, one magnitude 6.1 in western Greece and one magnitude 6.9 in southern Greece. In March 2005 and September 2005, intense anomalous geoelectric changes were observed at two different stations respectively: one in the Aegean Sea and the other in western Greece. These changes were immediately reported to international journals well in advance of earthquake occurrences. Natural time analysis of seismicity subsequent to the September changes around the epicenter of the last 6.9 earthquake is made. The results indicate that the occurrence time of the 6.9 earthquake can be specified with a narrow range around two days. PMID- 25792774 TI - Chiral poly-rare earth metal complexes in asymmetric catalysis. AB - Asymmetric catalysis is a powerful component of modern synthetic organic chemistry. To further broaden the scope and utility of asymmetric catalysis, new basic concepts for the design of asymmetric catalysts are crucial. Because most chemical reactions involve bond-formation between two substrates or moieties, high enantioselectivity and catalyst activity should be realized if an asymmetric catalyst can activate two reacting substrates simultaneously at defined positions. Thus, we proposed the concept of bifunctional asymmetric catalysis, which led us to the design of new asymmetric catalysts containing two functionalities (e.g. a Lewis acid and a Bronsted base or a Lewis acid and a Lewis base). These catalysts demonstrated broad reaction applicability with excellent substrate generality. Using our catalytic asymmetric reactions as keys steps, efficient total syntheses of pharmaceuticals and their biologically active lead natural products were achieved. PMID- 25792777 TI - Blue metal complex pigments involved in blue flower color. AB - The blue pigment of cornflower, protocyanin, has been investigated for a long time, but its precise structure was not entirely explained until recently. The molecular structure of the pigment was recently shown to be a metal complex of six molecules each of anthocyanin and flavone glycoside, with one ferric iron, one magnesium and two calcium ions by X-ray crystallographic analysis. The studies provided the answer to the question posed in the early part of the last century, "why is the cornflower blue and rose red when both flowers contain the same anthocyanin?" This work was achieved on the basis of the results of long years of the studies made by many researchers. In this review, the author focuses on the investigations of the blue metal complex pigments involved in the bluing of flowers, commelinin from Commelina commusis, protocyanin from Centaurea cyanus, protodelphin from Salvia patens and hydrangea blue pigment. PMID- 25792776 TI - 8-Hydroxyguanine: From its discovery in 1983 to the present status. AB - 8-Hydroxyguanine (8-OH-G) was discovered in 1983 in our laboratory at the National Cancer Center Research Institute, Tokyo. Since it could be formed in DNA not only in vitro but also in vivo by oxygen radical forming agents, we immediately hypothesized the importance of this discovery in connection with its biological consequence. Further intensive efforts by us from 1983 to 1990 confirmed that 8-OH-G is a highly significant oxidated DNA lesion involved in mutation and/or carcinogenesis in mammals, including humans. With the subsequent entry of many investigators to this research field the number of publications on 8-OH-G increased exponentially, reaching more than several thousands by the end of 2005. In this article, a summary is given of the important works carried out in the early days, and further notable contributions by many investigators are reviewed, focusing on 8-OH-G in the mammalian system. A special emphasis is given to research on knockout mice that are deficient in genes involved in the repair systems of the 8-OH-G lesion. Lastly, our own recent work is summarized involving a one-year carcinogenesis study of Ogg1 (the gene for 8-OH-G specific glycosylase/AP lyase) knockout mice that have been exposed to oxidative stress. PMID- 25792778 TI - Hepatic stellate cells: Three-dimensional structure, localization, heterogeneity and development. AB - Hepatic stellate cells (HSCs) are vitamin-A storing collagen-producing cells in hepatic lobules. The three-dimensional structure of HSCs has been demonstrated with the Golgi method, the maceration method for scanning electron microscopy, and confocal laser scanning microscopy. Many thorn-like microprojections or spines extend from the subendothelial processes and make contacts with hepatocytes. One HSC entwines two or more sinusoids and about 20-40 hepatocytes to create a cellular unit, 'the stellate cell unit' or 'stellon'. The Space of Disse is defined as the space between stellate cell-endothelial cell complex and hepatocytes. Intralobular heterogeneity of HSCs is assessed. HSCs develop from mesenchymal cells in the septum transversum. The developmental process of HSCs is reproduced partly in culture. In the lamprey abundant vitamin A is stored not only in HSCs, but in the fibroblast-like cells in the various other splanchnic organs. In vertebrates, the existence of both conventional fibroblast system in somatic tissues and vitamin A-storing cell system in splanchnic organs is suggested. PMID- 25792780 TI - Time variation of the electromagnetic transfer function of the earth estimated by using wavelet transform. AB - In order to accurately estimate the geomagnetic transfer functions in the area of the volcano Mt. Iwate (IWT), we applied the interstation transfer function (ISTF) method to the three-component geomagnetic field data observed at Mt. Iwate station (IWT), using the Kakioka Magnetic Observatory, JMA (KAK) as remote reference station. Instead of the conventional Fourier transform, in which temporary transient noises badly degrade the accuracy of long term properties, continuous wavelet transform has been used. The accuracy of the results was as high as that of robust estimations of transfer functions obtained by the Fourier transform method. This would provide us with possibilities for routinely monitoring the transfer functions, without sophisticated statistical procedures, to detect changes in the underground electrical conductivity structure. PMID- 25792779 TI - Confirmation of sable QTL that modifies the effects of the A(y) allele on yellow coat color on mouse chromosome 1. AB - F1-A(y) mice between RR (aabbCC) and C57BL/6J-A(y) (A(y)aBBCC) have a much darker yellow coat color than do C57BL/6J-A(y) . Quantitative trait locus (QTL) analysis was carried out to identify genes responsible for the darker modification of the yellow coat color (this has been traditionally termed "sable"). A significant sable QTL was identified on chromosome 1 (Dmyaq4, LOD score 15.5 for lightness, and 13.4 for color difference), in a chromosomal position similar to that of Dmyaq2, a sable QTL previously identified in C3H/HeJ. Another significant sable QTL was identified on chromosome 4 (Dmyaq5, LOD score 5.6 for lightness, and 4.3 for color difference) near the tyrosinase-related protein 1 (Tyrp1) locus. The effect of Dmyaq5 was significant only in the presence of the RR allele at Dmyaq4, suggesting that the Dmyaq4 (as well as Dmyaq2) is a novel coat color gene that may act up-stream of Tyrp1 signaling to increase eumelanin production. PMID- 25792781 TI - The analysis of N-glycolylneuraminic acid(NeuGc) of hepatoma tissue and K562 cell ferritins using HPLC and mass spectrometry. AB - Ferritin is an iron-storage protein and its serum level is known to increase in the patient of with inflammation and malignant tumor. To further elucidate the difference between ferritins from normal human liver tissue and that of cancer cells, their sialic acids were analyzed. The Western blot analysis and the cytochemical staining using anti-NeuGc antiserum indicated that ferritins from the human hepatocarcinoma tissue and malignant K562 cells contain NeuGc, but that from the normal liver does not. The result was also confirmed by HPLC analysis and MALDI-TOF/MS analysis of sialic acids which were derivatized by the DMB method. It was also shown that the sialic acid content in hepatocarcinoma ferritin was much higher than that in the normal liver ferritin. These results suggest that normal and cancerous liver ferritins are qualitatively and quantitatively different in sialylation. In addition, K562 cells were shown to express NeuGc even if the cells were cultured in serum-free media which lack NeuGc. This is of interest from the current concept that expression of NeuGc in human cells is due to uptake and utilization of exogenous NeuGc. PMID- 25792782 TI - GD3- and O-acetylated GD3-gangliosides in the GM2 synthase-deficient mouse brain and their immunohistochemical localization. AB - Gangliosides in the brain of the knockout mouse deficient in the activity of beta1,4 N-acetylgalactosaminyl transferase (beta1,4 GalNAc-T)(GM2 synthase) consisted of nearly exclusively of GM3- and GD3-gangliosides as expected from the known substrate specificity of the enzyme and in confirmation of the initial reports from two laboratories that generated the mutant mouse experimentally. The total molar amount of gangliosides was approximately 30% higher in the mutant mouse brain than that in the wild-type brain. However, contrary to the initial reports, one-fourth of total GD3-ganglioside was O-acetylated. It reacted positively with an anti-O-acetylated GD3 monoclonal antibody and disappeared with a corresponding increase in GD3-ganglioside after mild alkaline treatment. The absence of O-acetylated GD3 in the initial reports can be explained by the saponification step included in their analytical procedures. Although quantitatively much less and identification tentative, we also detected GT3 and O acetylated GT3. Anti-GD3 and anti-O-acetylated GD3 monoclonal antibodies gave positive reactions in the brain of mutant mouse as expected from the analytical results. Either antibody barely stained wild-type brain except for immunoreactivity of GD3 in the cerebellar Purkinje cells. The distributions of GD3 and O-acetylated GD3 in the brain of mutant mouse were similar but differential localization was noted in the cerebellar Purkinje cells and cerebral cortex. PMID- 25792785 TI - Mesorbitolina (Cretaceous larger foraminifera) from the Yezo Group in Hokkaido, Japan and its stratigraphic and paleobiogeographic significance. AB - In this paper, we describe an Aptian (Early Cretaceous) larger foraminiferal species Orbitolina (Mesorbitolina) parva from the limestone olistoliths in the lower part of the Yezo Group in the Yubari-Ashibetsu area, central Hokkaido and from limestone pebbles in the lowermost part of the Yezo Group in the Nakagawa area, northern Hokkaido. This is the first report of this species from the circum North Pacific regions. Based on its occurrences, the shallow-marine carbonates, re-deposited in the lower part of the Yezo Group, are precisely assigned in age to the Late Aptian. Comparison of the lower part of the Yezo Group in central and northern Hokkaido indicates differences of the Aptian-Albian depositional history between the two areas. This study reveals that after Late Aptian, Mesogean key taxa (typical Cretaceous Tethyan biota) demised in the Northwest Pacific. PMID- 25792784 TI - Prevention of carcinogenesis and cancer metastasis by bovine lactoferrin. AB - Increasing attention is being paid to chemopreventive agents for individuals at high risk of cancer. We have concentrated on bovine lactoferrin (bLF), an 80 kDa iron-binding glycoprotein known to have anti-microbial and immunoprotective effects. Lactoferrin is particularly abundant in colostrum, and is also present in tears, saliva and seminal and uterine secretions. However, only little is known regarding its influence on carcinogenesis. We have shown preventive effects of bLF and its fragment peptide, lactoferricin (bLFcin), consisting of a 25 amino acid sequence without iron binding capacity, on chemically-induced colon carcinogenesis in the rat and transplanted carcinoma cell metastasis in the mouse. The mechanisms are wide-spectrum, including elevation of caspase-1 and IL 18 in the small intestine, enhancement of the cell killing activity of cytotoxic T and natural killer (NK) cells, and anti-inflammatory and anti-angiogenic effects. It also inhibits the induction of liver CYP1A2, a carcinogen activating enzyme, and induces apoptosis in the colon epithelium of carcinogen treated rats. Thus, bLF possesses multi-functional potential to suppress carcinogenesis and is a good candidate for practical application in humans. PMID- 25792783 TI - In Vitro organogenesis using amphibian pluripotent cells. AB - Mesoderm induction as a result of the interaction between endoderm and ectoderm is one of the most crucial events in vertebrate development. We identified activin as a strong mesoderm-inducing factor in an animal cap assay, an in vitro assay system using amphibian pluripotential cell mass. Activin induces mesodermal tisswes including most dorsal mesodermal tissue, notochord (which has important roles in neural induction, somite segmentation, and endodermal organogenesis), and its effects are concentration-dependent. Animal cap cells treated with high concentrations of activin differentiate into anterior endoderm, which can act as an organizer, or center of body patterning. We have established an in vitro induction system for 22 different organs and tissues using animal cap cells, and have isolated many organ-specific genes. With these useful methods, and analysis of newly isolated tissue- and organ-specific genes, the molecular biological "road map" for organogenesis is being established. PMID- 25792786 TI - Recovery and regularization of initial temperature distribution in a two-layer cylinder with perfect thermal contact at the interface. AB - We investigate the inverse problem associated with the heat equation involving recovery of initial temperature distribution in a two-layer cylinder with perfect thermal contact at the interface. The heat equation is solved backward in time to obtain a relationship between the final temperature distribution and the initial temperature profile. An integral representation for the problem is found, from which a formula for initial temperature is derived using Picard's criterion and the singular system of the associated operators. The known final temperature profile can be used to recover the initial temperature distribution from the formula derived in this paper. A robust method to regularize the outcome by introducing a small parameter in the governing equation is also presented. It is demonstrated with the help of a numerical example that the hyperbolic model gives better results as compared to the parabolic heat conduction model. PMID- 25792787 TI - Establishment of hybrid-derived offspring populations in the Ohomopterus ground beetles through unidirectional hybridization. AB - An approach to deduce the mechanism of stabilization of the hybrid-derived populations in the Ohomopterus ground beetles has been made by comparative studies on the phylogenetic trees of the mitochondrial and nuclear DNA. A phylogenetic tree based on the internal transcribed spacer (ITS) of nuclear ribosomal gene roughly reflects the relations of morphological species group, while mitochondrial NADH dehydrogenase subunit 5 (ND5) gene shows a considerable different topology on the tree; there exist several geographically-linked lineages, most of which consist of more than one species. These results suggest that the replacement of mitochondria has occurred widely in the Ohomopterus species. In most cases, hybridization is unidirectional, i.e., the species A (?) hybridized with another species B (?) and not vice versa, with accompanied replacement of mitochondria of A by those of B. The results also suggest that partial or complete occupation of the distribution territory by a hybrid-derived morphological species. The morphological appearance of the resultant hybrid derivatives are recognized as that of the original species A. Emergence of a morphological new species from a hybrid-derived population has been exemplified. PMID- 25792788 TI - Azurocidin induces elastinolytic activity of medullasin. AB - Addition of azurocidin, a protein in granulocytes similar to serine proteases but has no protease activity because of replacement of the active serine residue by glycine, to the incubation mixture containing medullasin induced elastinolytic activity of medullasin. Both medullasin and human leukocyte elastase were already shown to have negligible elastinolytic activity (Aoki, Y. et al. J. Biochem. 114, 122, 1993). Elastinolytic activity of medullasin was induced dose-dependently by the addition of azurocidin. Medullasin activity determined by using apo-ornithine transaminase or casein as substrates or that by N-methoxy-succinyl-(Ala)2-Pro-Val p-nitroanilide as substrate remained unchanged when azurocidin was added to the tube containing medullasin. Therefore, azurocidin is considered to cause an appearance of elastinolytic activity of medullasin without affecting the protease activity of it. PMID- 25792789 TI - Amphiphilic polysilane-methacrylate block copolymers - Formation and interesting properties. AB - Several polysilane block copolymers have been prepared by the newly developed method, anionic polymerization of masked disilenes. Especially amphiphilic block copolymers of poly(1,1-dimethyl-2,2-dihexyldisilene) and poly methacrylate are focused. Poly(1,1-dimethyl-2,2-dihexyldisilene)-b-poly(2-hydroxyethyl methacrylate) (PMHS-b-PHEMA) is the first example of the amphiphilic polysilane copolymer that can form micelles in polar solvents. Poly(1,1-dimethyl-2,2 dihexyldisilene)-b-poly(methacrylic acid) (PMHS-b-PMAA) is more polar than (PMHS b-PHEMA), soluble in water to form micelles. The cross-linking reaction of (PMHS b-PMAA) with 1,10-diaza-4,7-dioxadecane and 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride afforded the first shell cross linked micelles (SCM) of polysilane. In addition to interesting properties, SCM is indicated to be able to form hollow sphere particles (hollow shell cross linked micelles, HSCM) by a photochemical process. Reversible encapsulation of guest molecules by SCM and HSCM is demonstrated. Finally, SCM can be used as the template for the synthesis of metal nanoparticles, which may be used as catalysts. PMID- 25792790 TI - Spherophylon, the concept of life at a level higher than that of the individual. AB - A new term, spherophylon, indicates a unit of life higher than the individual level. To define this term, critical notes are given on the meaning of age in terms of life, the interrelationships among the elements of biodiversity, and an analogy of development between the multicellular body of an individual and the spherophylon. Life is compared at various levels; at the level of the cell, the individual as a multicellular organism, and the spherophylon. The biology of the spherophylon is discussed in the context of integrative biology. PMID- 25792791 TI - Molecular devices for high fidelity of DNA replication and gene expression. AB - Certain types of DNA lesions, produced through cellular metabolic processes and also by external environmental stresses, are responsible for the induction of mutations as well as of cancer. Most of these lesions can be eliminated by DNA repair enzymes, and cells carrying the remaining DNA lesions are subjected to apoptosis. The persistence of damaged bases in RNA can cause errors in gene expression, and the cells appear to possess a mechanism which can prevent damaged RNA molecules from entering the translation process. We have investigated these processes for high fidelity of DNA replication and gene expression, by using both biochemical and genetic means. We herein describe (1) the molecular mechanisms for accurate DNA synthesis, (2) mammalian proteins for sanitizing the DNA precursor pool, (3) error avoidance mechanisms for gene expression under oxidative stress, and (4) the roles of DNA repair and apoptosis in the prevention of cancer. PMID- 25792793 TI - Formation of black hole and emission of gravitational waves. AB - Numerical simulations were performed for the formation process of rotating black holes. It is suggested that Kerr black holes are formed for wide ranges of initial parameters. The nature of gravitational waves from a test particle falling into a Kerr black hole as well as the development of 3D numerical relativity for the coalescing binary neutron stars are discussed. PMID- 25792792 TI - Nanoanalysis of the arthropod neuro-toxins. AB - Many kinds of venomous principles modulate physiological responses of mammalian signal transduction systems, on which they act selectively as enhancers, inhibitors or some other kind of effectors. These toxins become useful tools for physiological research. We have employed and characterized paralyzing toxins from the venom of spiders, insects and scorpions with a limited supply. We have developed rapid and sensitive mass spectrometric technology and applied for the identification of these toxins. Venom profiles are screened by MALDI-TOF fingerprinting analysis prior to purification of venomous components, then marked target toxins of small molecular mass (1000-5000) are characterized directly by means of mass spectrometric techniques such as Frit-FAB MS/MS, CID/PSD-TOF MS, Capil.-HPLC/Q-TOF MS/MS etc. PMID- 25792794 TI - Resistance minimum and heavy fermions. AB - The phenomenon of the resistance minimum in dilute magnetic alloys is explained in terms of the s-d interaction which takes account of scattering of the conduction electron off the magnetic impurities in metals. Some of the intermetallic compounds which involve rare earth elements or uranium show a very large electronic specific heat and remain non-magnetic even though they show a Curie-like susceptibility at higher temperatures. These phenomena are also explained based on the s-d interaction model. PMID- 25792795 TI - Mechanisms of a tumor marker, glutathione transferase P, expression during hepatocarcinogenesis of the rat. AB - The molecular mechanism of any tumor marker expression may shed a light on the mechanism of the particular tumorigenesis. This idea in mind, we have been pursuing the mechanism of specific induction of the placental type glutathione transferase (GST-P) gene during hepatocarcinogenesis of the rat. Making use of advanced technologies of molecular biology including proteomic analysis, gene cloning and production of specific transgenic rats etc., we were able to identify the enhancer and the activator proteins responsible for this tumor marker expression. Negative regulatory regions and modulatory proteins were also found. The overview of this long range study and the future outlook of the problem will be discussed. PMID- 25792796 TI - GaP Raman Terahertz high accuracy spectrometer and its application to detect organic and inorganic crystalline defects. AB - One of the most important uses of THz spectrometry is to detect defects in molecular structure or in crystals efficiently. We applied GaP Raman THz (GRT) spectrometer to detect and evaluate defects in inorganic and organic materials. High THz-wave absorption due to high defect density of GaSe crystal lowered the efficiency of THz wave generation, when the crystal is used as nonlinear material for DFG (Difference Frequency Generation). Defects in organic molecules could be observed as changes in frequency, intensities of the absorption, and broadenings of the spectra. PMID- 25792797 TI - Molecular systematics and ultrastructural characterization of a forgotten species: Chattonidium setense (Ciliophora, Heterotrichea). AB - In the present paper we redescribe the ciliate Chattonidium setense Villeneuve 1937 combining morphological observations (live, stained, scanning, and transmission electron microscope) with behavioral notes and molecular data. Ultrastructural analysis revealed remarkable similarities between Chattonidium and representative members of the class Heterotrichea in cortical structure and cytoplasmic organization. The most similar genus for these aspects appears to be Condylostoma. To verify this relatedness, 18S rRNA genes from Chattonidium and from one Condylostoma species were sequenced. Phylogenetic analysis indicates Chattonidium belongs to the class Heterotrichea defined according to the modern taxonomy, and confirms its relatedness with Condylostoma already hypothesized by Villeneuve-Brachon (1940). The presence of the aboral cavity complex, a unique feature never described in other ciliates, and its peculiar organization revealed by ultrastructural analysis fully justify, in our opinion, the maintenance of Chattonidium in the separate family Chattonidiidae, established by Villeneuve Brachon in 1940. PMID- 25792798 TI - Extensive superior limbic keratoconjunctivitis in Graves' disease: case report and mini-review of the literature. AB - BACKGROUND: Superior limbic keratoconjunctivitis (SLK) is characterized as an inflammation of the superior bulbar conjunctiva with predominant involvement of the superior limbus and adjacent epithelial keratitis. METHODS: A 51-year-old woman, with a history of medically controlled Graves' disease was seen with an extensive SLK involving 5 mm of the superior cornea. RESULTS: Total remission was observed with topical steroids (DXM). Recurrence was observed 1 week after steroid discontinuation, and steroidal treatment was reintroduced with tapering over 1 month. Total remission was then observed for 1 year. CONCLUSION: Extensive keratitis and vascular pannus in SLK is rarely reported. This form could be treated with topical steroids. Tapering treatment remains essential for long-term success. PMID- 25792799 TI - Nasolacrimal system aeration on computed tomographic imaging: effects of patient positioning and scan orientation. AB - PURPOSE: To determine the impact of patient positioning and scan orientation on the appearance of air in the nasolacrimal drainage system on computed tomography (CT) imaging, and the repeatability of the observations. METHODS: This was a retrospective analysis of CT images for 92 patients. RESULTS: Air was found to be present more fully in the upright-position group as compared with the supine position group. Comparing axial and coronal scan orientation, no difference in aeration was found, except for the nasolacrimal duct in the upright-position group. CONCLUSION: Patient position should be accounted for in diagnostic conclusions and treatment decisions based on CT. PMID- 25792800 TI - Efficiency, safety, and patient preference of switching from dorzolamide 1%/timolol 0.5% to brinzolamide 1%/timolol 0.5% while maintaining the prostaglandin F2alpha analog. AB - BACKGROUND: We investigated the efficiency, safety and patient preference of switching from dorzolamide 1%/timolol 0.5% to brinzolamide 1%/timolol 0.5% while maintaining the prostaglandin F2alpha analog. METHODS: We initially enrolled 44 eyes from 44 primary open angle glaucoma patients, and a total of 42 patients completed the study. All patients were under treatment with various prostaglandin F2alpha analogs and dorzolamide 1%/timolol 0.5%. While maintaining the prostaglandin F2alpha analog, dorzolamide 1%/timolol 0.5% was switched to brinzolamide 1%/timolol 0.5%. Conjunctival hyperemia, superficial punctate keratopathy, and intraocular pressure (IOP) were evaluated at baseline and at 4, 12, and 24 weeks. Adverse events and patient preferences, measured using a questionnaire at study initiation and at 24 weeks, were also noted. RESULTS: The IOP was 17.7+/-1.7, 16.8+/-2.6, 16.7+/-2.2, and 16.7+/-2.4 mmHg at baseline and at 4, 12, and 24 weeks, respectively, with no significant differences in IOP values at any time point (P=0.117, one-way analysis of variance). In addition, no significant differences were found in the incidence of conjunctival hyperemia or SPK score at any time point (all P>0.5, by Kruskal-Wallis test). Based on the evaluation of side effects using the questionnaire, stinging/burning was less common (P=0.042), while blurred vision was more common (P=0.003), after switching to brinzolamide 1%/timolol 0.5%. Regarding patient preferences, 13 patients (31%) preferred dorzolamide 1%/timolol 0.5%, 12 patients (29%) preferred brinzolamide 1%/timolol 0.5%, and 17 patients (40%) preferred neither. CONCLUSION: When switching from dorzolamide 1%/timolol 0.5% to brinzolamide 1%/timolol 0.5%, the IOP values and incidence of superficial punctate keratopathy and conjunctival hyperemia were sustained throughout the 24-week observation period, and the patient preferences were similar for the two regimens. However, differences were observed in the ocular sensations of stinging/burning with dorzolamide 1%/timolol 0.5% and blurred vision with brinzolamide 1%/timolol 0.5%. PMID- 25792801 TI - A comparative study of a modified filtering trabeculotomy and conventional trabeculectomy. AB - PURPOSE: The objective of the study reported here was to evaluate the outcome of a modified filtering trabeculotomy (FTO) without iridectomy in open-angle glaucoma compared with that of conventional trabeculectomy (trab). PATIENTS AND METHODS: Thirty eyes of 30 patients who underwent modified FTO were prospectively followed for 1 year and were compared with 87 conventional trab patients (87 eyes), matched for age and preoperative intraocular pressure (IOP). The FTO procedure consisted of a deep sclerectomy and trabeculotomy preserving the trabeculo-Descemet membrane, without iridectomy. Main outcome measures were complete success (IOP <18 mmHg and >/=30% IOP reduction, without medication), IOP, visual acuity, medication, complications, and subsequent surgeries. RESULTS: In the conventional trab group, the median preoperative IOP was 23.0 mmHg (interquartile range 20.0-27.0) with 3.0 (2.0-3.0) medications, compared with 23.0 mmHg (20.0-27.0) and 3.0 (2.8-4.0) in the modified FTO group. Median postoperative IOP at 12 months was 12.0 mmHg (10.0-13.0) in the conventional trab and 11.0 mmHg (8.0-14.0) in the modified FTO group (P=0.3). The complete success rate at 1 year was 83.1% and 79.3% in the conventional trab group and modified FTO group, respectively (P=0.8). The complications hypotony (20.7%, 24.1%), choroidal detachment (2.3%, 10.3%), and bleb scarring (17.2%, 13.8%), were present in the conventional trab group and modified FTO group, respectively. CONCLUSION: The outcomes of reduced IOP and medications in the FTO group were not different to those in the conventional trab group over 1 year, but some complications were more often seen with the modified FTO technique. The new filtration trabeculotomy, however, has the advantage of avoiding iridectomy, thus reducing the risk of cataract formation, and may result in the development of more favorable blebs by controlling the flow over two resistance levels. PMID- 25792802 TI - Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers. AB - BACKGROUND: Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer's disease. The aim of this randomized, single-blind, placebo controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. METHODS: Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), or 175 mg/50 cm(2). Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. RESULTS: The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74-76 hours (~2-4 hours after patch removal), and mean t1/2beta was ~63.77-93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%-86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. CONCLUSION: The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. PMID- 25792803 TI - Improved corneal bioavailability of ofloxacin: biodegradable microsphere-loaded ion-activated in situ gel delivery system. AB - The aim of the study was to improve corneal penetration and bioavailability of ofloxacin (OFX) eye preparations. OFX was incorporated in poly (lactide-co glycolide) as biodegradable microspheres using oil in oil emulsion solvent evaporation technique. The prepared OFX microspheres were then incorporated in Gelrite((r)) in situ gel preparation. In addition, OFX Gelrite-based in situ gel formulations were prepared. OFX formulations were characterized for gelling capacity, viscosity, and rheological properties. Release studies for OFX microspheres, OFX in situ gel, and OFX-loaded microspheres in situ gel formulations were carried out to investigate release characteristics of the drug. The prepared OFX formulations were then investigated in vivo compared with commercially available OFX eyedrops. Results showed that the optimum Gelrite concentration was at 0.4%-0.7% w/v; the prepared formulations were viscous liquid transformed into a pourable gel immediately after the addition of simulated tear fluid with a gelling factor of 27-35. Incorporation of OFX-loaded microspheres in Gelrite solution (0.4% w/v) significantly altered the release profiles of OFX loaded microspheres in situ gel formula compared with the corresponding OFX gels and OFX microspheres. In vivo results in rabbits showed that OFX-loaded microspheres in situ gel formula improved the relative bioavailability by 11.7 fold compared with the commercially available OFX eyedrops. In addition, the longer duration of action of OFX-loaded microspheres in situ gel formula preparations is thought to avoid frequent instillations, which improves patient tolerability and compliance. PMID- 25792804 TI - Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression. AB - Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 MUM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression of the CAOV-3 cell cycle in S phase. These findings indicate that liriodenine could be considered as a promising anticancer agent. PMID- 25792805 TI - Cryo-ablation improves anti-tumor immunity through recovering tumor educated dendritic cells in tumor-draining lymph nodes. AB - BACKGROUND: In addition to minimally invasive destruction of tumors, cryo ablation of tumors to some extent modulated anti-tumor immunity. Cryo-ablated tumors in glioma mice models induced anti-tumor cellular immunologic response which increases the percentage of CD3(+) and CD4(+)T cells in blood as well as natural killer cells. As a crucial role in triggering anti-tumor immunity, dendritic cells (DCs) were educated by tumors to adopt a tolerance phenotype which helps the tumor escape from immune monitoring. This study aims to study whether cryo-ablation could influence the tolerogenic DCs, and influence anti tumor immunity in tumor-draining lymph nodes (TDLNs). METHODS: Using the GL261 subcutaneous glioma mouse model, we created a tumor bearing group, cryo-ablation group, and surgery group. We analyzed alteration in phenotype and function of tolerogenic DCs, and evaluated the factors of anti-tumor immunity inhibition. RESULTS: DCs in TDLNs in GL261 subcutaneous glioma mouse model expressed tolerogenic phenotype. In contrast to surgery, cryo-ablation improved the quantity and quality of these tolerogenic DCs. Moreover, the DCs decreased the expression of intracellular interleukin-10 (IL-10) and extra-cellular IL-10. In vitro, DCs from the cryo-ablation group recovered their specific function and induced potent anti-tumor immunity through triggering T cells. In vivo, cryo ablation showed weak anti-tumor immunity, only inhibiting the growth of rechallenged tumors. But many IL-10-low DCs, rather than IL-10-high DCs, infiltrated the tumors. More importantly, Tregs inhibited the performance of these DCs; and depletion of Tregs greatly improved anti-tumor immunity in vivo. CONCLUSION: Cryo-ablation could recover function of tumor induced tolerogenic DCs in vitro; and depletion of Tregs could improve this anti-tumor effect in vivo. The Tregs/CD4(+)T and Tregs/CD25(+)T cells in TDLNs inhibit DCs' activity and function. PMID- 25792806 TI - Design, synthesis, and antifungal activities of novel triazole derivatives containing the benzyl group. AB - In previous studies undertaken by our group, a series of 1-(1H-1,2,4-triazole-1 yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a-r), which were analogs of fluconazole, was designed and synthesized by click chemistry. In the study reported here, the in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi. Compounds 1a, 1q, and 1r showed the more antifungal activity than the others. PMID- 25792807 TI - Neuroprotective therapies for glaucoma. AB - Glaucoma is the second leading cause for blindness worldwide. It is mainly caused by glaucomatous optic neuropathy (GON) characterized by retinal ganglion cell loss, which leads to visual field defect and blindness. Up to now, the main purpose of antiglaucomatous therapies has been to lower intraocular pressure (IOP) through surgeries and medications. However, it has been found that progressive GON is still present in some patients with effective IOP decrease. Therefore, risk factors other than IOP elevation, like neurotrophin deprivation and excitotoxicity, contribute to progressive GON. Novel approaches of neuroprotection may be more effective for preserving the function of the optic nerve. PMID- 25792808 TI - Positive effects on hematological and biochemical imbalances in patients with metastatic breast cancer stage IV, of BP-C1, a new anticancer substance. AB - A benzene-poly-carboxylic acid complex with cis-diammineplatinum(II) dihydrocholride, BP-C1 is currently used in clinical trials in treating metastatic breast cancer. BP-C1 controls tumor growth with a few mild side effects, improving quality of life. METHODS: The data consisted of prospectively collected laboratory results from 47 patients in two controlled clinical trials of daily intramuscular injections of BP-C1 for 32 days. Study I was performed as an open, nonrandomized, Phase I dose-response, multicenter study with a three level, between-patient, response surface pathway design. The second study was a randomized, double-blind, and placebo-controlled, multicenter study with a stratified semi-crossover design. RESULTS: Hemoglobin (Hb) and hematocrit (Hct) increased significantly (P<0.01) during BP-C1 treatment, while red blood cell (RBC) count increased but not significantly. The most pronounced increase in Hb, RBC, Hct, and white blood cell (WBC) was in anemic patients (P<=0.01). WBC count and neutrophils increased significantly (P=0.01) in the overall data. WBCs and neutrophils (P<0.01), eosinophils (P=0.05) and monocytes (P<0.01) increased significantly and markedly in patients with lowest baseline levels. Additionally, low levels of thrombocytes significantly increased. No changes in liver parameters, amylase, glucose, creatinine, or albumin, were detected except for albumin in the subgroup with low baseline levels, where levels increased significantly (P=0.04). An increase in K(+), Ca(2+), and PO4 (3-) was most pronounced in patients with low baseline levels (P<=0.02). A similar pattern detected for Mg(2+), prothrombin time (PT), coagulation factors II, VII, X (KFNT), and C-reactive protein (CRP), which increased significantly (P<=0.05) in the groups with the lowest values. CONCLUSION: Our findings support the safety profile of BP-C1 use in cancer patients. BP-C1 did not induce anemia, infection, bleeding, hepatic insufficiency or electrolyte imbalances. In contrast, BP-C1 corrected abnormalities. No hematological and biochemical toxicity was observed. PMID- 25792809 TI - Effect of a topical copper indomethacin gel on inflammatory parameters in a rat model of osteoarthritis. AB - OBJECTIVE: We aimed to investigate the effect of topical application of a Copper indomethacin (Cu-Indo) gel preparation on monosodium iodoacetate (MIA) induced arthritis of the knee joint of rats and to test our hypothesis that copper complex of indomethacin could be a more potent anti-inflammatory agent than its parent compound. METHODS: After induction of osteoarthritis by the intracapsular injection of 50 MUL with 40 mg/mL MIA, we compared the anti-inflammatory efficacy and safety of a topical application of 1% indomethacin gel in a dose of 1 g/kg of the gel (equivalent to 10 mg/kg of the active substance) daily for 3 weeks versus three decremental dose levels of Cu-Indo gel: an equivalent dose, half the dose, and 25% of the dose of indomethacin. Anti-inflammatory efficacy was assessed in all treated groups by measurement of serum inflammatory cytokines: interleukin 6, interleukin 8, and tumor necrosis factor alpha; and by the weekly assessment of knee joint swelling. Joint mobility and motor coordination were also assessed once weekly by the accelerating rotarod apparatus; histopathological examination of affected joints was also performed. Safety of topical application of Cu-Indo (0.25, 0.5, and 1 g/kg) for up to 3 months to rats' skin was determined by the estimation of a complete blood count, liver and kidney functions, and histopathologic examination for target tissues. RESULTS: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation. The lowest tested dose of Cu-Indo, corresponding to 25% of the parent substance indomethacin, exhibited the highest efficacy in reducing the elevated serum tested interleukins and in increasing the time of duration on the rotarod test, whereas its effect on reduction of edema and tumor necrosis factor alpha was comparable to that of the others. After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose. CONCLUSION: Cu-Indo gel has potent anti-inflammatory activity against joint inflammation in the MIA treated rat model of osteoarthritis at doses of 0.25, 0.5, and 1 g/kg. The lowest studied dose was better on both safety and efficacy parameters. PMID- 25792810 TI - Em08red, a dual functional antiproliferative emodin analogue, is a downregulator of ErbB2 expression and inducer of intracellular oxidative stress. AB - Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death. PMID- 25792813 TI - Knowledge about missed contraceptive pills among married women at King Abdulaziz University Hospital. AB - BACKGROUND: Oral contraceptive pills (OCPs) are one of the most reliable methods of contraception. However, lack of knowledge about oral contraceptive use and inconsistent pill-taking might result in decreased efficacy. The study reported here aimed to explore women's knowledge about oral contraceptive use and assess the factors associated with knowledge about OCPs among users. METHODS: This cross sectional survey was conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between April and June 2014. We included married, non-pregnant women >18 years old who had used a combined 21-day OCP for at least 3 months prior to recruitment. A questionnaire was used to collect the participants' demographic information. It also assessed their knowledge about OCPs. Data were entered into and analyzed using SPSS software. RESULTS: A total of 357 women were recruited. Of these, 57.7% reported they knew what to do after missing one or two pills, but only 18.3% knew exactly what to do after missing more than two pills consecutively. Postgraduate women had a significantly higher knowledge score than illiterate women (P=0.002) and those who had completed at least primary education (P=0.001). Conversely, there was no difference in knowledge scores between Saudi and expatriate women (P=0.2). Monthly incomes (P=0.2) and mode of OCP selection (P=0.2) were also not significantly associated with knowledge scores. CONCLUSION: Women had poor knowledge about OCP use. Appropriate measures should be taken to educate women about proper oral contraceptive use. PMID- 25792811 TI - Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. AB - Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U 2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy. PMID- 25792812 TI - The application of click chemistry in the synthesis of agents with anticancer activity. AB - The copper(I)-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry) to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents. PMID- 25792814 TI - Patients' beliefs about adherence to oral antidiabetic treatment: a qualitative study. AB - PURPOSE: The purpose of this study was to elicit patients' beliefs about taking their oral antidiabetic drugs (OADs) as prescribed to inform the development of sound adherence-enhancing interventions. METHODS: A qualitative study was performed. Adults with type 2 diabetes who had been taking an OAD for >3 months were solicited to participate in one of six focus groups. Discussions were facilitated using a structured guide designed to gather beliefs related to important constructs of the theory of planned behavior. Four coders using this theory as the theoretical framework analyzed the videotaped discussions. RESULTS: Forty-five adults participated. The most frequently mentioned advantages for OAD taking as prescribed were to avoid long-term complications and to control glycemia. Family members were perceived as positively influential. Carrying the OAD at all times, having the OAD in sight, and having a routine were important facilitating factors. Being away from home, not accepting the disease, and not having confidence in the physician's prescription were major barriers to OAD taking. CONCLUSION: This study elicited several beliefs regarding OAD-taking behavior. Awareness of these beliefs may help clinicians adjust their interventions in view of their patients' beliefs. Moreover, this knowledge is crucial to the planning, development, and evaluation of interventions that aim to improve medication adherence. PMID- 25792815 TI - Antidepressant medication treatment patterns in Asian patients with major depressive disorder. AB - PURPOSE: To describe pharmacological treatment patterns in Asian patients with major depressive disorder (MDD), including duration of treatment, reasons for medication discontinuation, rate of medication nonadherence, factors associated with medication nonadherence, and impact of medication nonadherence on depression outcomes. PATIENTS AND METHODS: Data were from a prospective, observational 3 month study of East Asian MDD inpatients from 40 sites in six East Asian countries who initiated antidepressant treatment at baseline (n=569). Assessments included the Clinical Global Impression-Severity scale (CGI-S), 17-item Hamilton Depression Rating Scale (HAMD-17), painful physical symptoms, response and remission, employment status, quality of life (QoL) (EuroQOL Questionnaire-5 Dimensions [EQ-5D]) and health state using the visual analog scale, adherence by clinician opinion, and patient self-report. Cox proportional hazards modeling, Kaplan-Meier survival analysis, and regression modeling were employed. RESULTS: Median time to discontinuation for any reason was 70 days (95% confidence interval: 47; 95). Reasons for discontinuation were inadequate response in 64.1%, nonadherence in 6.2%, and adverse events in 4.1%; 25.6% who discontinued experienced an adequate response to treatment. In those patients who had an adequate response, age and country were significantly associated with time to medication discontinuation. Patient-reported nonadherence was 57.5% and clinician reported nonadherence was 14.6% (62/426). At 3 months, nonadherent patients had significantly higher disease severity (CGI-S, P=0.0001; HAMD-17, P<0.0001), lower QoL ratings (EQ-5D tariff, P=0.0007; EQ-5D visual analog scale, P=0.0024), and lower response and remission rates (both P<0.0001) compared with adherent patients. The odds of response and remission were greater among adherent patients. CONCLUSION: Early discontinuation of antidepressants among Asian MDD patients was high. A total of 25.6% who discontinued prematurely were experiencing an adequate response to treatment. Nonadherent patients had significantly higher disease severity, lower QoL ratings, and lower response and remission rates compared with adherent patients. PMID- 25792816 TI - Desire for prenatal gender disclosure among primigravidae in Enugu, Nigeria. AB - BACKGROUND: Prenatal gender disclosure is a nonmedical fetal ultrasonography view, which is considered ethically unjustified but has continued to grow in demand due to pregnant women's requests. OBJECTIVE: The aim of this study was to determine the proportion of primigravidae who want prenatal gender disclosure and the reasons for it. METHODS: This was a descriptive cross-sectional study of randomly selected primigravidae seen at Enugu Scan Centre. The women were randomly selected using a table of random numbers. RESULTS: Ninety percent (225/250) of 250 primigravidae who fulfilled the criteria for inclusion in this study wanted to know the gender of their unborn baby, while 10% (25/250) declined gender disclosure. Furthermore, 62% (155/250) of primigravidae had preference for male children. There was statistically significant desire for male gender (P=0.0001). Statistically significant number of primigravidae who wanted gender disclosure did so to plan for the new baby (P=0.0001), and those that declined gender disclosure "leave it to the will of GOD" (P=0.014). CONCLUSION: Ninety percent of primigravidae wanted gender disclosure because of plans for the new baby, personal curiosity, partner and in-laws' curiosity; moreover, some women wanted to test the accuracy of the findings at delivery and 62% of primigravidae had preference for male children. In view of these results, gender disclosure could be beneficial in this environment. PMID- 25792817 TI - Impact of patient programs on adherence and persistence in inflammatory and immunologic diseases: a meta-analysis. AB - OBJECTIVES: Patient adherence and persistence is important to improve outcomes in chronic conditions, including inflammatory and immunologic (I&I) diseases. Patient programs that aim at improving medication adherence or persistence play an essential role in optimizing care. This meta-analysis assessed the effectiveness of patient programs in the therapeutic area of I&I diseases. METHODS: A global systematic literature review was conducted with inclusion criteria of: patient programs in I&I diseases; published in English language between January 2008 and September 2013; and reporting measures of adherence or persistence, including medication possession ratio >80% and persistence rate. A meta-analysis was performed using a random effects model. Subgroup analyses based on the type of program was performed whenever feasible. RESULTS: Of 67 studies reviewed for eligibility, a total of 17 studies qualified for inclusion in the meta-analysis. Overall, patient programs increased adherence (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.68-3.64, P<0.00001) as compared with standard of care. Combination patient programs that used both informational and behavioral strategies were superior in improving adherence (OR=3.68, 95% CI=2.20 6.16, P<0.00001) compared with programs that used only informational (OR=2.16, 95% CI=1.36-3.44, P=0.001) or only behavioral approaches (OR=1.85, 95% CI=1.00 3.45, P=0.05). Additionally, patients were more likely to be persistent (OR=2.26, 95% CI=1.16-4.39, P=0.02) in the intervention group as compared with the control group. Persistence (in days) was significantly (P=0.007) longer, by 42 additional days, in the intervention group than in the control group. CONCLUSIONS: Patient programs can significantly improve adherence as well as persistence in the therapeutic area of I&I diseases. Programs employing a multimodal approach are more effective in improving adherence than programs with informational or behavioral strategies alone. This in turn may improve patient outcomes. PMID- 25792819 TI - Factors associated with prolonged hospitalization, readmission, and death in elderly heart failure patients in western Romania. AB - PURPOSE: The purpose of this prospective study was to identify factors associated with prolonged hospitalization, readmission, and death in elderly patients presenting heart failure with reduced ejection fraction. PATIENTS AND METHODS: All consecutive patients aged >=65 years discharged with a diagnosis of acute new onset heart failure and a left ventricular ejection fraction (LVEF) <=45% were included and followed up for 1 year. The variables associated with outcomes were analyzed in univariate and multivariate logistic regression. For the independent predictors identified by multivariate analysis, receiver operating characteristic (ROC) analysis was performed. RESULTS: A total of 71 patients were included in the study. The patient mean age was 72.5 years, 50% were female, and the mean LVEF was 31.25%+/-5.76%. In all, 34 (48%) patients experienced prolonged hospitalization, and this was independently associated with patients who were living in a rural area (P=0.005), those with a New York Heart Association functional class of 4 (P<0.001), the presence of comorbidities (P=0.023), chronic obstructive pulmonary disease (COPD) infectious exacerbation (P<0.001), and chronic kidney disease (P=0.025). In the multivariate analysis, only COPD infectious exacerbation was independently associated with prolonged hospitalization (P=0.003). A total 19 patients (27%) experienced readmissions during the 1-year follow up, of which 12 (17%) had cardiovascular causes and seven (10%) had noncardiovascular causes. The following independent variables associated with rehospitalizations were outlined in the univariate analysis: infections (P<0.020); COPD infectious exacerbation (P=0.015); one or more comorbidity (P<0.0001); and prolonged baseline hospitalization (P<0.0001). During the multivariate analysis, it was found that the independent predictors of readmissions were the presence of comorbidities (P<0.001) and prolonged baseline hospitalization (P<0.01). The 1-year mortality rate was 9.8%, with no significant difference between cardiovascular (5.6%) and noncardiovascular (4.2%) deaths. The only independent predictive variable for mortality was a New York Heart Association NYHA functional class 4 at baseline hospitalization (P=0.001). CONCLUSION: Elderly patients are at high risk for prolonged hospitalization, readmission, and death following a first hospitalization for heart failure with reduced ejection fraction. The most powerful predictors for outcomes are the severity of heart failure, the presence of comorbidities, and prolonged hospitalization at baseline. PMID- 25792818 TI - Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment. AB - The aim of this paper is to provide a comprehensive review of the epidemiological evidence linking type 2 diabetes mellitus and its related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, to Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link; however, our focus is on insulin resistance and deficiency. Studies have shown that insulin resistance and deficiency can interact with amyloid-beta protein and tau protein phosphorylation, each leading to the onset and development of AD. Based on those epidemiological data and basic research, it was recently proposed that AD can be considered as "type 3 diabetes". Special attention has been paid to determining whether antidiabetic agents might be effective in treating AD. There has been much research both experimental and clinical on this topic. We mainly discuss the clinical trials on insulin, metformin, thiazolidinediones, glucagon-like peptide 1 receptor agonists, and dipeptidyl peptidase-4 inhibitors in the treatment of AD. Although the results of these trials seem to be contradictory, this approach is also full of promise. It is worth mentioning that the therapeutic effects of these drugs are influenced by the apolipoprotein E (APOE)-epsilon4 genotype. Patients without the APOE-epsilon4 allele showed better treatment effects than those with this allele. PMID- 25792820 TI - Do frequent moderate exacerbations contribute to progression of chronic obstructive pulmonary disease in patients who are ex-smokers? AB - BACKGROUND: In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD). However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory. The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1) and impairment of functional and clinical outcomes in ex-smoking COPD patients. METHODS: A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition. Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance) index, and quality of life (St George's Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire). Severity of exacerbation was graded as moderate or severe according to health care utilization. Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year. Random effects modeling, within hierarchical linear modeling, was used for analysis. RESULTS: During follow-up, 419 (96% moderate) acute exacerbations were registered. At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation, 6-minute walking test, and quality of life. However, no significant difference in FEV1 decline over time was found between the two groups (54.7+/-13 mL/year versus 85.4+/-15.9 mL/year in frequent exacerbators and infrequent exacerbators, respectively). This was also the case for all other measurements. CONCLUSION: Our results suggest that frequent moderate exacerbations do not contribute to accelerated clinical and functional decline in COPD patients who are ex-smokers. PMID- 25792821 TI - Misidentification of airflow obstruction: prevalence and clinical significance in an epidemiological study. AB - BACKGROUND: The fixed threshold criterion for the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) <0.7 is widely applied for diagnosis of airflow obstruction (AO). However, this fixed threshold criterion may misidentify AO, because thresholds below the fifth percentile of normal FEV1/FVC (lower limit of normal; LLN) vary with age. This study aims to identify the prevalence of AO misidentification and its clinical significance. MATERIALS AND METHODS: A cross-sectional population-based study was conducted to identify the prevalence of chronic respiratory diseases in adults older than 40 years of age who live in municipal areas of Chiang Mai province, Thailand. All randomly selected subjects underwent face-to-face interviews and examinations by pulmonologists, and received chest radiographs and post-bronchodilator spirometry. AO misidentification was classified into under- or overestimated AO subgroups. Underestimated AO was defined as ratio of FEV1/FVC greater than the fixed threshold, but below the LLN criteria. Overestimated AO was defined as the ratio of FEV1/FVC below the fixed threshold but greater than the LLN criteria. The clinical significance of each misidentified subject was then explored. RESULTS: There were 554 subjects with a mean age of 52.9+/-10.1 years and a percent predicted FEV1 of 85.5%+/-15.4%. The prevalence of AO misidentification was 5.6% (31/554), and all subjects belonged to the underestimated subgroup. Clinical significance of underestimated subjects included clinical AO disease of 22.6% (7/31) (three subjects with chronic obstructive pulmonary disease [COPD] and four subjects with asthma); chronic respiratory symptoms of 54.8% (17/31) (mostly associated with chronic rhinitis, 70.6% [12/17]); and only 12.9% (4/31) were identified as non-ill subjects. CONCLUSION: The prevalence of AO misidentification in this population was significant, and all were underestimated subjects. Most underestimated subjects had clinical significance as related to obstructive airway diseases and chronic respiratory symptoms, mostly associated with rhinitis. PMID- 25792822 TI - Dialectal influence on chronic pulmonary disease assessment test: the reliability and validity study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients living in many countries are familiar with local dialects rather than the official language. We, therefore, compare the reliability and validity of the COPD Assessment Test (CAT) in Thai and northern Thai dialect versions, in stable COPD patients living in the northern part of Thailand. METHODS: A total of 160 COPD patients were randomly selected for the evaluation of each dialect version of CAT (n=80). The internal consistency of all eight items and test-retest reliability were investigated by using Cronbach's alpha coefficient and intraclass correlation coefficient (ICCC), respectively. The validity was evaluated by the degree of correlation with St George's Respiratory Questionnaire (SGRQ) using Pearson's correlation. The correlations of CAT with clinical parameters such as forced expiratory volume in the first second (FEV1), modified Medical Research Council scale (mMRC) dyspnea score, and 6-minute walk distance (6-MWD) were also evaluated. RESULTS: The two versions of CAT showed high internal consistency reliability (Cronbach's alpha coefficient of 0.82 and 0.76) as well as a high test-retest reliability (ICCC of 0.82 and 0.84) for Thai and northern Thai dialect versions, respectively. The test results revealed that the northern Thai dialect version had good correlation with SGRQ whereas the Thai version correlated only moderately. CONCLUSION: The two Thai versions of CAT were proven to be good clinical tools with high reliability and acceptable validity for assessing the quality of life of Thai COPD patients. However, the northern Thai dialect version is more suitable for evaluating COPD patients living in the northern part of Thailand. PMID- 25792824 TI - In vitro percutaneous penetration and characterization of silver from silver containing textiles. AB - The objective of this study was to determine the in vitro percutaneous penetration of silver and characterize the silver species released from textiles in different layers of full thickness human skin. For this purpose, two different wound dressings and a garment soaked in artificial sweat were placed in the donor compartments of Franz cells for 24 hours. The concentration of silver in the donor phase and in the skin was determined by an electrothermal atomic absorption spectrometer (ET-AAS) and by inductively coupled plasma mass spectrometer (ICP MS). The characterization of silver species in the textiles and in the skin layers was made by scanning electron microscopy with integrated energy dispersive X-ray spectroscopy (SEM-EDX). Additionally, the size distribution of silver nanoparticles in the textiles was performed by atomic force microscopy (AFM). On the surface of all investigated materials, silver nanoparticles of different size and morphology were found. Released silver concentrations in the soaking solutions (ie, exposure concentration) ranged from 0.7 to 4.7 MUg/mL (0.6-4.0 MUg/cm(2)), fitting the bactericidal range. Silver and silver chloride aggregates at sizes of up to 1 MUm were identified both in the epidermis and dermis. The large size of these particles suggests that the aggregation occurred in the skin. The formation of these aggregates likely slowed down the systemic absorption of silver. Conversely, these aggregates may form a reservoir enabling prolonged release of silver ions, which might lead to local effects. PMID- 25792823 TI - Peptide gH625 enters into neuron and astrocyte cell lines and crosses the blood brain barrier in rats. AB - Peptide gH625, derived from glycoprotein H of herpes simplex virus type 1, can enter cells efficiently and deliver a cargo. Nanoparticles armed with gH625 are able to cross an in vitro model of the blood-brain barrier (BBB). In the present study, in vitro experiments were performed to investigate whether gH625 can enter and accumulate in neuron and astrocyte cell lines. The ability of gH625 to cross the BBB in vivo was also evaluated. gH625 was administered in vivo to rats and its presence in the liver and in the brain was detected. Within 3.5 hours of intravenous administration, gH625 can be found beyond the BBB in proximity to cell neurites. gH625 has no toxic effects in vivo, since it does not affect the maximal oxidative capacity of the brain or the mitochondrial respiration rate. Our data suggest that gH625, with its ability to cross the BBB, represents a novel nanocarrier system for drug delivery to the central nervous system. These results open up new possibilities for direct delivery of drugs into patients in the field of theranostics and might address the treatment of several human diseases. PMID- 25792825 TI - Efficient delivery of ursolic acid by poly(N-vinylpyrrolidone)-block-poly (epsilon-caprolactone) nanoparticles for inhibiting the growth of hepatocellular carcinoma in vitro and in vivo. AB - Previous reports have shown that ursolic acid (UA), a pentacyclic triterpenoid derived from Catharanthus trichophyllus roots, could inhibit the growth of a series of cancer cells. However, the potential for clinical application of UA is greatly hampered by its poor solubility, whereas the hydrophobicity of UA renders it a promising model drug for nanosized delivery systems. In the current study, we loaded UA into amphiphilic poly(N-vinylpyrrolidone)-block-poly (epsilon caprolactone) nanoparticles and performed physiochemical characterization as well as analysis of the releasing capacity. In vitro experiments indicated that UA-NPs inhibited the growth of liver cancer cells and induced cellular apoptosis more efficiently than did free UA. Moreover, UA-NPs significantly delayed tumor growth and localized to the tumor site when compared with the equivalent dose of UA. In addition, both Western blotting and immunohistochemistry suggested that the possible mechanism of the superior efficiency of UA-NPs is mediation by the regulation of apoptosis-related proteins. Therefore, UA-NPs show potential as a promising nanosized drug system for liver cancer therapy. PMID- 25792826 TI - Therapeutic antitumor efficacy of tumor-derived autophagosome (DRibble) vaccine on head and neck cancer. AB - PURPOSE: Vaccines play important roles in antitumor biotherapy. Autophagy in tumor cells plays a critical role in depredating proteins, including tumor specific antigens and tumor-associated antigens. We aimed to induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as a novel antitumor vaccine by inhibiting the functions of proteasomes and lysosomes. MATERIALS AND METHODS: DRibbles were prepared and their morphological and autophagic properties characterized. Dendritic cells (DCs) generated from the bone marrow monocytes of mice were cocultured with DRibbles, then surface molecules of DCs and B cells, as well as apoptosis of DCs, were determined by flow cytometry. Meanwhile, functional properties of the DRibble-DCs were examined by mixed lymphocyte reactions and animal experiments. RESULTS: The diameter of autophagic nanoparticles with spherical and double-membrane structure was between 200 nm and 500 nm. DRibbles resulted in the upregulation of costimulatory molecules CD40 and CD86 as well as major histocompatibility complex (MHC)-I molecules on DCs, but not MHC-II. The expressions of CD40, CD80, and CD86 and that of MHC-II molecules on B cells were also upregulated. Moreover, suppression of tumor growth and lifetime prolongation was observed in DRibble-DC-vaccinated tumor-bearing mice. CONCLUSION: Our results demonstrate that naive T cells can be activated effectively by DC cross-presenting antigens on upregulated MHC-I, suggesting that DRibbles be deployed as an effective antitumor vaccine for head and neck cancer immunotherapy in clinical trials. PMID- 25792827 TI - Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors. AB - Magnetically induced heating of magnetic nanoparticles (MNP) in an alternating magnetic field (AMF) is a promising minimal invasive tool for localized tumor treatment that eradicates tumor cells by applying thermal stress. While temperatures between 42 degrees C and 45 degrees C induce apoptosis and sensitize the cells for chemo- and radiation therapies when applied for at least 30 minutes, temperatures above 50 degrees C, so-called thermoablative temperatures, rapidly induce irreversible cell damage resulting in necrosis. Since only little is known concerning the protein expression of anti-apoptotic B-cell lymphoma 2 (BCL2), fibroblast growth factor receptor 1 (FGF-R1), and heat shock protein (HSP70) after short-time magnetic thermoablative tumor treatment, these relevant tumor proteins were investigated by immunohistochemistry (IHC) in a human BT474 breast cancer mouse xenograft model. In the investigated sample groups, the application of thermoablative temperatures (<2 minutes) led to a downregulation of BCL2 and FGF-R1 on the protein level while the level of HSP70 remained unchanged. Coincidently, the tumor tissue was damaged by heat, resulting in large apoptotic and necrotic areas in regions with high MNP concentration. Taken together, thermoablative heating induced via magnetic methods can reduce the expression of tumor-related proteins and locally inactivate tumor tissue, leading to a prospectively reduced tumorigenicity of cancerous tissues. The presented data allow a deeper insight into the molecular mechanisms in relation to magnetic thermoablative tumor treatments with the aim of further improvements. PMID- 25792828 TI - Preparation of poly(beta-L-malic acid)-based charge-conversional nanoconjugates for tumor-specific uptake and cellular delivery. AB - In this study, a multifunctional poly(beta-L-malic acid)-based nanoconjugate with a pH-dependent charge conversional characteristic was developed for tumor specific drug delivery. The short branched polyethylenimine-modified poly(beta-L malic acid) (PEPM) was first synthesized. Then, the fragment HAb18 F(ab')2 and 2,3-dimethylmaleic anhydride were covalently attached to the PEPM to form the nanoconjugate, HDPEPM. In this nanoconjugate, the 2,3-dimethylmaleic anhydride, the shielding group, could shield the positive charge of the conjugate at pH 7.4, while it was selectively hydrolyzed in the tumor extracellular space (pH 6.8) to expose the previously-shielded positive charge. To study the anticancer activity, the anticancer drug, doxorubicin, was covalently attached to the nanoconjugate. The doxorubicin-loaded HDPEPM nanoconjugate was able to efficiently undergo a quick charge conversion from -11.62 mV to 9.04 mV in response to the tumor extracellular pH. The electrostatic interaction between the positively charged HDPEPM nanoconjugates and the negatively charged cell membrane significantly enhanced their cellular uptake, resulting in the enhanced anticancer activity. Also, the tumor targetability of the nanoconjugates could be further improved via the fragment HAb18 F(ab')2 ligand-receptor-mediated tumor cell-specific endocytosis. PMID- 25792829 TI - Anticoccidial and antioxidant activities of zinc oxide nanoparticles on Eimeria papillata-induced infection in the jejunum. AB - Nanomedicine has recently emerged as a better option for the treatment of various diseases. Here, we investigated the in vivo anticoccidial properties of zinc oxide nanoparticles (ZNPs). ZNPs were crystalline in nature, with a smooth and spherical surface and a diameter in the range of ~10-15 nm. The X-ray diffraction pattern was utilized to identify the crystalline property of the grown ZNPs, whereas field emission scanning electron microscopy was employed to check the size and morphology of the ZNPs. The data showed that mice infected with Eimeria papillata produced 29.7*10(3)+/-1,500 oocysts/g feces on day 5 postinfection. This output was significantly decreased, to 12.5*10(3)+/-1,000 oocysts, in mice treated with ZNPs. Infection also induced inflammation and injury of the jejunum. This was evidenced (1) through an increase in the inflammatory histological score, (2) through increased production of nitric oxide and malondialdehyde, and (3) through a decrease in both the glutathione level and goblet cell number in mice jejuna. All these infection-induced parameters were significantly altered during treatment with ZNPs. Our results indicate, therefore, that ZNPs have protective effects against E. papillata-induced coccidiosis. PMID- 25792830 TI - Phase II trial of weekly nab-paclitaxel and carboplatin treatment with or without trastuzumab as nonanthracycline neoadjuvant chemotherapy for locally advanced breast cancer. AB - BACKGROUND: Neoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer. The aim of this study was to compare the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) versus paclitaxel combined with carboplatin. METHODS: Thirty patients were treated with neoadjuvant nab-paclitaxel (125 mg/m(2), days 1, 8, and 15) and carboplatin (area under the curve =2; days 1, 8, and 15) every 21 days for four cycles. Ninety matched patients received paclitaxel (80 mg/m(2), days 1, 8, and 15) and carboplatin every 21 days for four cycles. Weekly trastuzumab is recommended for overexpression of human epidermal receptor-2. The primary endpoint was pathologic complete response (defined as ypT0/is ypN0). Matching was conducted according to six variables: body mass index, clinical tumor stage, clinical lymph node status, estrogen receptor status, HER2 status, and trastuzumab receiving rate. RESULTS: Ninety percent of patients in the nab-paclitaxel group and 80% of patients in the paclitaxel group experienced a clinical objective response (complete response or partial response; P=0.450). Eight patients in the nab-paclitaxel group and 23 patients in the paclitaxel group had a pathologic complete response in the breast and axillary nodes (26.7% versus 25.6%; P=0.904). Nab-paclitaxel showed a beneficial effective trend on clinical tumor stage II (36.8% versus 15.8%; P=0.051). When trastuzumab was added to nab-paclitaxel, the pathologic complete response rate was not significantly improved more than with trastuzumab and paclitaxel (43.6% versus 39.6%; P=0.769). Carboplatin plus nab-paclitaxel or paclitaxel had similarly low pathologic complete response rates (7.7% versus 10.5%) for the luminal molecular subtype. One (50%) triple-negative patient achieved a pathologic complete response. The nab-paclitaxel regimen caused more grade 4 neutropenia than the paclitaxel regimen (56.7% versus 21.1%; P<0.001). CONCLUSION: Our study shows that weekly nab-paclitaxel and carboplatin with or without trastuzumab resulted in a pathologic complete response rate that was not superior to the matched cohorts. Future, larger trials are needed to validate that nab-paclitaxel is beneficial for clinical tumor stage II and the triple negative subgroup. PMID- 25792831 TI - Sunroot mediated synthesis and characterization of silver nanoparticles and evaluation of its antibacterial and rat splenocyte cytotoxic effects. AB - A rapid, green phytosynthesis of silver nanoparticles (AgNPs) using the aqueous extract of Helianthus tuberosus (sunroot tuber) was reported in this study. The morphology of the AgNPs was determined by transmission electron microscopy (TEM). Scanning electron microscopy-energy-dispersive spectroscopy (SEM-EDS) and X-ray powder diffraction (XRD) analysis confirmed the presence of AgNPs. Fourier transform infrared spectroscopy (FTIR) analysis revealed that biomolecules in the tuber extract were involved in the reduction and capping of AgNPs. The energy dispersive spectroscopy (EDS) analysis of the AgNPs, using an energy range of 2-4 keV, confirmed the presence of elemental silver without any contamination. Further, the synthesized AgNPs were evaluated against phytopathogens such as Ralstonia solanacearum and Xanthomonas axonopodis. The AgNPs (1-4 mM) extensively reduced the growth rate of the phytopathogens. In addition, the cytotoxic effect of the synthesized AgNPs was analyzed using rat splenocytes. The cell viability was decreased according to the increasing concentration of AgNPs and 67% of cell death was observed at 100 MUg/mL. PMID- 25792832 TI - Oxcarbazepine-loaded polymeric nanoparticles: development and permeability studies across in vitro models of the blood-brain barrier and human placental trophoblast. AB - Encapsulation of antiepileptic drugs (AEDs) into nanoparticles may offer promise for treating pregnant women with epilepsy by improving brain delivery and limiting the transplacental permeability of AEDs to avoid fetal exposure and its consequent undesirable adverse effects. Oxcarbazepine-loaded nanoparticles were prepared by a modified solvent displacement method from biocompatible polymers (poly(lactic-co-glycolic acid) [PLGA] with or without surfactant and PEGylated PLGA [Resomer((r)) RGPd5055]). The physical properties of the developed nanoparticles were determined with subsequent evaluation of their permeability across in vitro models of the blood-brain barrier (hCMEC/D3 cells) and human placental trophoblast cells (BeWo b30 cells). Oxcarbazepine-loaded nanoparticles with encapsulation efficiency above 69% were prepared with sizes ranging from 140 170 nm, polydispersity indices below 0.3, and zeta potential values below -34 mV. Differential scanning calorimetry and X-ray diffraction studies confirmed the amorphous state of the nanoencapsulated drug. The apparent permeability (Pe ) values of the free and nanoencapsulated oxcarbazepine were comparable across both cell types, likely due to rapid drug release kinetics. Transport studies using fluorescently-labeled nanoparticles (loaded with coumarin-6) demonstrated increased permeability of surfactant-coated nanoparticles. Future developments in enzyme-prodrug therapy and targeted delivery are expected to provide improved options for pregnant patients with epilepsy. PMID- 25792833 TI - Optimizing stem cell functions and antibacterial properties of TiO2 nanotubes incorporated with ZnO nanoparticles: experiments and modeling. AB - To optimize mesenchymal stem cell differentiation and antibacterial properties of titanium (Ti), nano-sized zinc oxide (ZnO) particles with tunable concentrations were incorporated into TiO2 nanotubes (TNTs) using a facile hydrothermal strategy. It is revealed here for the first time that the TNTs incorporated with ZnO nanoparticles exhibited better biocompatibility compared with pure Ti samples (controls) and that the amount of ZnO (tailored by the concentration of Zn(NO3)2 in the precursor) introduced into TNTs played a crucial role on their osteogenic properties. Not only was the alkaline phosphatase activity improved to about 13.8 U/g protein, but the osterix, collagen-I, and osteocalcin gene expressions was improved from mesenchymal stem cells compared to controls. To further explore the mechanism of TNTs decorated with ZnO on cell functions, a response surface mathematical model was used to optimize the concentration of ZnO incorporation into the Ti nanotubes for stem cell differentiation and antibacterial properties for the first time. Both experimental and modeling results confirmed (R (2) values of 0.8873-0.9138 and 0.9596-0.9941, respectively) that Ti incorporated with appropriate concentrations (with an initial concentration of Zn(NO3)2 at 0.015 M) of ZnO can provide exceptional osteogenic properties for stem cell differentiation in bone cells with strong antibacterial effects, properties important for improving dental and orthopedic implant efficacy. PMID- 25792834 TI - New findings about iron oxide nanoparticles and their different effects on murine primary brain cells. AB - The physicochemical properties of superparamagnetic iron oxide nanoparticles (SPIOs) enable their application in the diagnostics and therapy of central nervous system diseases. However, since crucial information regarding side effects of particle-cell interactions within the central nervous system is still lacking, we investigated the influence of novel very small iron oxide particles or the clinically approved ferucarbotran or ferumoxytol on the vitality and morphology of brain cells. We exposed primary cell cultures of microglia and hippocampal neurons, as well as neuron-glia cocultures to varying concentrations of SPIOs for 6 and/or 24 hours, respectively. Here, we show that SPIO accumulation by microglia and subsequent morphological alterations strongly depend on the respective nanoparticle type. Microglial viability was severely compromised by high SPIO concentrations, except in the case of ferumoxytol. While ferumoxytol did not cause immediate microglial death, it induced severe morphological alterations and increased degeneration of primary neurons. Additionally, primary neurons clearly degenerated after very small iron oxide particle and ferucarbotran exposure. In neuron-glia cocultures, SPIOs rather stimulated the outgrowth of neuronal processes in a concentration- and particle dependent manner. We conclude that the influence of SPIOs on brain cells not only depends on the particle type but also on the physiological system they are applied to. PMID- 25792835 TI - Efficacy, safety, and impact on hospitalizations of paliperidone palmitate in recent-onset schizophrenia. AB - OBJECTIVE: To evaluate the efficacy, safety, and impact on hospitalizations of long-acting injectable paliperidone palmitate (PP) treatment, in patients with recent-onset schizophrenia who had not responded satisfactorily to oral antipsychotics. METHODS: In this 18-month, open-label, Phase-IIIb study from Asia Pacific region, patients (18-50 years) with recent-onset (<=5 years) schizophrenia unsatisfactorily treated with previous oral antipsychotics were initiated on PP 150 mg eq on day 1, 100 mg eq on day 8, followed by flexible once monthly maintenance doses of 50-150 mg eq. The number and duration of hospitalizations were compared using a mirror analysis method between two periods: retrospective (12 months before PP initiation) and prospective (12 and 18 months after PP treatment) periods. RESULTS: A total of 303 out of 521 (58%) patients (mean age, 28.7 years; 65.5% men, 92.5% Asian) completed the study. Positive and Negative Syndrome Scale (PANSS) total score improved significantly from baseline to month 18 (mean [standard deviation, SD] change: -11.3 [21.38], P<0.0001, primary endpoint). Subgroup analysis revealed greater improvements among patients with worse disease severity at baseline: PANSS >=70 versus <70 (mean [SD] change: -23.1 [24.62] vs -4.7 [15.98], P<0.0001 each). Secondary efficacy endpoints such as Clinical Global Impression of Schizophrenia (CGI-SCH), Medication Satisfaction Questionnaire (MSQ) scores showed significant improvements (P<0.0001) from baseline; 33.3% patients achieved symptom remission. In mirror analyses set (N=474), PP significantly (P<0.0001) reduced mean number of hospitalization days/person/year (12-month: 74.3 vs 19.7; 18-month: 74.3 vs 18.9) as well as percentage of patients requiring hospitalization in past 12 months (12-month: 39.7% vs 24.6%; 18-month: 39.7% vs 25%), and PP treatment increased the proportion of patients not requiring hospitalization (12-month: 60.3% vs 75.4%; 18-month: 60.3% vs 75%) from retrospective to prospective period. Adverse events (>=15%) were extrapyramidal symptoms-related (31.3%), injection site pain (18.6%), and insomnia (15.2%). CONCLUSION: PP was efficacious and generally tolerable with significant reductions observed in both number of hospitalizations and days spent in hospital. PMID- 25792836 TI - Impact of incarceration in Nazi concentration camps on multimorbidity of former prisoners. AB - OBJECTIVE: To show the extent to which the health of former prisoners was affected by incarceration in extermination camps after 5 and 30 years of leaving the camp, and to determine the etiological factors underlying particular dysfunctions. METHODS: Medical records of former prisoners developed in 1950 (n=250) and 1975 (n=120) were then, after several decades, retrospectively analyzed and compared with the control group, randomized and matched according to age, sex, occupation, and environment. None of the subjects in the control group was a prisoner either at a concentration camp or at any other prison or detention facility. RESULTS: Multimorbidity affected mainly the central nervous system (CNS). Five years after leaving a camp, CNS dysfunctions were observed in 66% of former prisoners. Skeletal (42.4%) and cardiovascular system (34.4%) dysfunctions were the second and third most frequent dysfunctions. Thirty years after leaving a camp, the most prevalent coexisting conditions were also found within the CNS (80%), cardiovascular system (58.33%), and skeletal system (55%). Five and 30 years after leaving a camp, multiorgan lesions were found in 21.6% and 60% of survivors, respectively. Multimorbidity was more frequent in a group of prisoners who underwent the state of apathy and depression or who had been incarcerated longer than 24 months. The rate of CNS diseases was four times higher, and the rate of cardiovascular diseases or skeletal system dysfunctions was two times higher, in the study group after 30 years of leaving a camp compared with the control group. CONCLUSION: The consequences of incarceration in concentration camps manifesting as multimorbidity, premature aging, and dramatic increase in mortality rate are observed in the majority of former prisoners. The multimorbidity mostly affected older prisoners who stayed at a camp for a longer time period. PMID- 25792837 TI - Association between pain severity, depression severity, and use of health care services in Japan: results of a nationwide survey. AB - BACKGROUND: Depression is often associated with painful physical symptoms. Previous research has seldom assessed the relationship between the severity of physical symptoms and the severity of mental and emotional symptoms of depression or other health outcomes, and no such studies have been conducted previously among individuals with depression in Japan. The aim of this study was to assess the relationship between the severity of physical pain and depression and other outcomes among individuals in Japan diagnosed with depression. METHODS: Data for individuals aged 18 and older in Japan who reported being diagnosed with depression and also reported physical pain were obtained from the Japan National Health and Wellness Survey. These respondents were characterized on sociodemographics and health characteristics, and the relationship between ratings of severity on pain in the last week and health outcomes were assessed using bivariate correlations and generalized linear models. Measures included the Patient Health Questionnaire for depression severity, Medical Outcomes Study 12 Item Short Form Survey Instrument for health-related quality of life, the Work Productivity and Activity Impairment for work and activity impairment, and 6 month report of health care use. RESULTS: More severe physical pain in the past week was correlated with more severe depression, worse health-related quality of life, lower health utility, greater impairment at work, and more health care provider visits. These relationships remained significant after incorporating sociodemographics and health characteristics in the statistical models. CONCLUSION: Individuals whose depression is accompanied by more severe physical pain have a higher burden of illness than those whose depression includes less severe pain, suggesting that even partially ameliorating painful physical symptoms may significantly benefit patients with depression. Clinicians should take the presence and severity of physical pain into account and consider treating both the physical and emotional symptoms of these patients. PMID- 25792838 TI - Effects of switching from olanzapine to aripiprazole on the metabolic profiles of patients with schizophrenia and metabolic syndrome: a double-blind, randomized, open-label study. AB - BACKGROUND: Patients with schizophrenia suffer high rates of metabolic derangements on some antipsychotic medications that predispose them to cardiovascular diseases. Keeping this fact in mind, we planned this open-label study to see the effect on various metabolic parameters after switching stable schizophrenia subjects, who had developed metabolic syndrome on olanzapine, to aripiprazole. METHODS: Sixty-two patients with schizophrenia who were stable on olanzapine and were fulfilling modified National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III) criteria for the presence of metabolic syndrome were enrolled on the study. Patients were randomly assigned either to switch to aripiprazole or to stay on olanzapine, on a 1:1 basis. Cross-tapering over a period of 1 month was done while switching patients to aripiprazole. Laboratory assessment for metabolic parameters was done at baseline, 8 weeks, and 24 weeks after enrollment; efficacy assessment was done using the Positive and Negative Syndrome Scale (PANSS) at baseline and 24 weeks, the Clinical Global Impressions severity subscale (CGI-S) at baseline, and the Clinical Global Impressions improvement subscale (CGI-I) at 24 weeks. RESULTS: All parameters of metabolic syndrome (waist circumference, blood pressure, triglyceride level, fasting blood glucose, and high-density lipoprotein cholesterol) kept deteriorating in the stay group, compared with a continuous improvement in the switch group over time. At the end of the study, 26 patients (100%) from the stay group and 15 patients (42.8%) from switch group met the modified NCEP ATP-III criteria for presence of metabolic syndrome (P<0.001). There were no statistically significant differences between groups in psychopathology changes as measured by the PANSS total score and CGI-I scores. CONCLUSION: Clinically stable patients with schizophrenia who are taking olanzapine and who have evidence of metabolic syndrome can be successfully switched to aripiprazole, with improvement in various parameters of metabolic syndrome and without any significant change in efficacy measures. PMID- 25792840 TI - Genotypic resistance profiles in Chinese patients with chronic hepatitis B virus infection and the efficacy of nucleoside analog rescue therapy. AB - BACKGROUND AND AIMS: The aims of this study were to explore the correlation between chronic hepatitis B virus (HBV) drug-resistant mutation profiles and the efficacy of nucleoside analog rescue therapy in patients with initial antiviral treatment failure. PATIENTS AND METHODS: Patients with initial antiviral therapy failure were recruited between January 2011 and January 2013 from the Division of Infectious Disease, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Following drug-resistant mutation testing, eligible patients received nucleoside analog rescue therapy for 24 weeks. The primary endpoint was rescue therapy efficacy, and the secondary endpoint was adverse events. RESULTS: We recruited 168 patients with chronic HBV infection who had initial antiviral treatment failure. Eighty-nine patients (52.98%) experienced virological breakthrough (group A); 79 patients (47.02%) had partial/null response (group B). Among the patients, 102 (102/168, 60.7%) carried at least one HBV drug resistance mutation. The prevalence of genotypic resistance was significantly higher in group A than in group B (P<0.001). In addition, 118 patients (118/168, 70.2%) achieved undetectable serum HBV DNA with the nucleoside analog rescue therapy. Rescue therapy (P=0.002) and no evidence of genotypic resistance (P=0.001) were related to a higher rate of virological response. CONCLUSION: These data indicate that patients with chronic HBV infection who have initial antiviral therapy failure with or without signs of genotypic resistance may still stand a chance of gaining therapeutic benefit with nucleoside analog rescue therapy. PMID- 25792839 TI - Long-term safety and efficacy of tobramycin in the management of cystic fibrosis. AB - Cystic fibrosis (CF) is a fatal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene whose mortality is conditioned by a progressive decline in lung function. Bacterial infections play a key role in this decline. Chronic bacterial infection in CF patients varies over time and the presence of Pseudomonas aeruginosa in sputum is a marker of poor prognosis. P. aeruginosa is eradicated from the airways using inhaled antibiotics administered in various formulations and devices. Antipseudomonal antibiotics have extended the survival of CF patients to 40 years. Tobramycin is a bactericidal aminoglycoside antibiotic with demonstrated activity against gram-negative microorganisms. Initially, the drug was administered as an inhaled parenteral solution. Subsequently, a specific tobramycin inhalation solution was developed. PulmoSphereTM technology enables dry tobramycin powder to be formulated for inhalation (tobramycin inhalation powder) using a small and portable capsule based breath-activated device (T-326). Chronic colonization by P. aeruginosa is the main indication for aerosol antibiotic therapy. The American Cystic Fibrosis Foundation, European guidelines, and Spanish consensus guidelines provide different recommendations for eradication. PMID- 25792841 TI - Virtual reality simulation for the optimization of endovascular procedures: current perspectives. AB - Endovascular technologies are rapidly evolving, often requiring coordination and cooperation between clinicians and technicians from diverse specialties. These multidisciplinary interactions lead to challenges that are reflected in the high rate of errors occurring during endovascular procedures. Endovascular virtual reality (VR) simulation has evolved from simple benchtop devices to full physic simulators with advanced haptics and dynamic imaging and physiological controls. The latest developments in this field include the use of fully immersive simulated hybrid angiosuites to train whole endovascular teams in crisis resource management and novel technologies that enable practitioners to build VR simulations based on patient-specific anatomy. As our understanding of the skills, both technical and nontechnical, required for optimal endovascular performance improves, the requisite tools for objective assessment of these skills are being developed and will further enable the use of VR simulation in the training and assessment of endovascular interventionalists and their entire teams. Simulation training that allows deliberate practice without danger to patients may be key to bridging the gap between new endovascular technology and improved patient outcomes. PMID- 25792842 TI - Erratum: Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era [Corrigendum]. AB - [This corrects the article on p. 1409 in vol. 7, PMID: 25143745.]. PMID- 25792843 TI - Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer. AB - BACKGROUND: The aim of this study was to determine the therapeutic efficacy and safety of transarterial chemoembolization (TACE) with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer (BTC). METHODS: We retrospectively analyzed the outcomes for 65 patients with advanced BTC treated by TACE with gemcitabine 1,000 mg/m(2) and oxaliplatin 100 mg/m(2). Follow-up laboratory tests and computed tomography or magnetic resonance imaging were performed routinely to evaluate the response of the tumor to treatment. All patients were assessed for adverse effects. RESULTS: Of the 65 patients, 19 (29.2%) achieved a partial response, 36 (55.4%) showed stable disease, and ten (15.4%) showed progressive disease. The overall response rate was 29.2%. At the end of this study, five patients were still alive. The median overall survival was 12.0 months (95% confidence interval 8.5-15.5). There were no serious complications after TACE. CONCLUSION: The disease control rate and overall survival in this retrospective study were consistent with those in previous reports. TACE with gemcitabine and oxaliplatin was well tolerated and highly effective in patients with advanced BTC. PMID- 25792844 TI - The association between the migration inhibitory factor -173G/C polymorphism and cancer risk: a meta-analysis. AB - Previous studies have suggested that macrophage migration inhibitory factor (MIF) -173G/C polymorphism may be associated with cancer risk. However, previous research has demonstrated conflicting results. Therefore, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and the meta-analysis on genetic association studies checklist, and performed a meta-analysis to investigate the association between MIF -173G/C polymorphisms and the risk of cancer. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between MIF promoter polymorphisms and cancer risk. The pooled ORs were performed for the dominant model, recessive model, allelic model, homozygote comparison, and heterozygote comparison. The publication bias was examined by Begg's funnel plots and Egger's test. A total of ten studies enrolling 2,203 cases and 2,805 controls met the inclusion criteria. MIF (-173G/C) polymorphism was significantly associated with increased cancer risk under the dominant model (OR=1.32, 95%, CI=1.00-1.74, P=0.01) and the heterozygote comparison (OR=1.38, CI=1.01-1.87, P=0.04). In subgroup analysis, MIF polymorphism and prostate were related to increased risk of prostate and non-solid cancer. In conclusion, MIF polymorphism was significantly associated with cancer risk in heterozygote comparison. The MIF -173G/C polymorphism may be associated with increased cancer risk. PMID- 25792845 TI - Expression and clinical significance of fibroblast growth factor 1 in gastric adenocarcinoma. AB - BACKGROUND: The clinical significance of fibroblast growth factor 1 (FGF1) has been revealed in several cancers, including ovarian cancer, breast cancer, and bladder cancer. However, the clinical significance of FGF1 in gastric adenocarcinoma has not been explored. PATIENTS AND METHODS: In our experiments, we systematically evaluated FGF1 expression in 178 cases of gastric adenocarcinoma with immunohistochemistry, and subsequently analyzed the correlation between FGF1 expression and clinicopathologic features. Moreover, FGF1 expression in tumor tissue and corresponding adjacent tissue was detected and compared by real-time polymerase chain reaction. The Kaplan-Meier method and the Cox-regression model were used with univariate and multivariate analysis, respectively, to evaluate the prognostic value of FGF1 in gastric adenocarcinoma. RESULTS: Higher FGF1 expression rate is 56.7% (101/178) in gastric adenocarcinoma. FGF1 expression in gastric adenocarcinoma was significantly higher than adjacent tissue (P<0.0001). Expression of FGF1 is significantly associated with lymph node invasion (P<0.001), distant metastasis (P=0.013), and differentiation (P=0.015). Moreover, FGF1 overexpression was closely related to unfavorable overall survival rate (P=0.021), and can be identified to be an independent unfavorable prognostic factor (P=0.004). CONCLUSION: FGF1 is an independent prognostic factor, indicating that FGF1 could be a potential molecular drug target in gastric adenocarcinoma. PMID- 25792846 TI - Early enteral and parenteral nutritional support after hepatectomy in patients with hepatic carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: This study sought to conduct a systematic review providing a comparative analysis of enteral nutrition (EN) and parenteral nutrition (PN) after hepatectomy. METHODS: PubMed, Embase, and the China National Knowledge Infrastructure databases were searched for publications describing randomized controlled trials that compared early EN and PN after hepatectomy. The time period for this search was from January 1990 to December 2013. In accordance with the inclusion criteria of this study, two researchers independently screened the retrieved literature, extracted data, and assessed methodological quality. A meta analysis of the included publications was then performed using RevMan 5.2 software. RESULTS: The meta-analysis results indicated statistically significant differences between the group that received EN and the group that received PN during the early stages after hepatectomy with respect to average total bilirubin and alanine aminotransferase levels after nutrition, pre-albumin levels, incidence of diarrhea and abdominal bloating, time to flatus, and average cost of nutrition. To varying degrees, better results were observed in the EN group than in the PN group for these metrics. CONCLUSION: During the early stages after hepatectomy, EN has obvious advantages relative to PN; thus, EN merits more widespread promotion and application in this clinical context. PMID- 25792847 TI - Elevated expression of NEDD9 is associated with metastatic activity in gastric cancer. AB - OBJECTIVE: To investigate the protein and mRNA expression of NEDD9 in gastric cancer (GC) tissues, adjacent atypical hyperplasia tissues, and normal gastric mucosa tissues, and analyze its relationship with the pathological features and prognosis of GC. METHODS: Forty cases of GC tissues, 20 cases of adjacent atypical hyperplasia tissues, and 40 cases of normal gastric mucous tissues were collected. Immunohistochemistry and Western blot were used to examine the expression of NEDD9 protein in various tissues. Situ hybridization and reverse transcription polymerase chain reaction were applied to detect the expression of NEDD9 mRNA in various tissues. The correlation of NEDD9 expression with invasion and metastasis of GC was analyzed. RESULTS: The protein expression level of NEDD9 was significantly higher in GC tissues than in adjacent atypical hyperplasia tissues and normal gastric mucous tissues (P<0.05). The protein expression level of NEDD9 was positively related to the invasion depth of carcinoma and tumor lymph node metastasis (P<0.05), but unrelated to age, sex, tumor size, and clinical classification of cancer (P<0.05). The mRNA expression level of NEDD9 was also significantly higher in GC tissues than in adjacent atypical hyperplasia tissues and normal gastric mucous tissues (P<0.05), and positively related with the tumor lymph node metastasis and invasion depth of carcinoma (P<0.05). CONCLUSION: NEDD9 is involved in the occurrence and development of GC, and it may be an important biological marker of GC metastasis and infiltration. PMID- 25792849 TI - Role of high-mobility group box 1 in patients with acute obstructive suppurative cholangitis-induced sepsis. AB - BACKGROUND: High-mobility group box 1 (HMGB1) is a proinflammatory cytokine that plays an active role during the pathogenesis of inflammatory processes. The primary aim of this study was to detect whether HMGB1 is involved in the pathogenesis of acute obstructive suppurative cholangitis (AOSC). METHODS: We collected peripheral blood samples from 23 patients with AOSC and 23 healthy volunteers who served as normal controls. All participants were tested for HMGB1 mRNA level, HMGB1 protein, tumor necrosis factor alpha (TNF-alpha), and interleukin 10 (IL-10). HMGB1 mRNA levels were tested using real-time polymerase chain reaction. HMGB1 protein expression was measured using Western blot. TNF alpha and IL-10 were tested using enzyme-linked immunosorbent assay. RESULTS: The expression of HMGB1 mRNA and HMGB1 protein was higher in the AOSC group than in the normal controls (P<0.01), and the levels gradually decreased to normal after treatment of the disease (P<0.01). The content of TNF-alpha and IL-10 in peripheral blood of patients with AOSC was significantly higher than that of normal controls (P<0.01) but decreased to normal levels after the necessary treatment (P<0.01). CONCLUSION: The levels of HMGB1 mRNA and HMGB1 protein were elevated in patients with AOSC, which may play an important role in the inflammation of the bile duct and appears to be associated with the development of sepsis. This suggests the importance of monitoring HMGB1 levels in the management of AOSC-induced sepsis. PMID- 25792848 TI - Factors affecting high-sensitivity cardiac troponin T elevation in Japanese metabolic syndrome patients. AB - PURPOSE: The blood concentration of cardiac troponin T (ie, high-sensitivity cardiac troponin T [hs-cTnT]), measured using a highly sensitive assay, represents a useful biomarker for evaluating the pathogenesis of heart failure or predicting cardiovascular events. However, little is known about the clinical significance of hs-cTnT in metabolic syndrome. The aim of this study was to examine the factors affecting hs-cTnT elevation in Japanese metabolic syndrome patients. PATIENTS AND METHODS: We enrolled 258 metabolic syndrome patients who were middle-aged males without a history of cardiovascular events. We examined relationships between hs-cTnT and various clinical parameters, including diagnostic parameters of metabolic syndrome. RESULTS: There were no significant correlations between hs-cTnT and diagnostic parameters of metabolic syndrome. However, hs-cTnT was significantly correlated with age (P<0.01), blood concentrations of brain natriuretic peptide (P<0.01), reactive oxygen metabolites (markers of oxidative stress, P<0.001), and the cardio-ankle vascular index (marker of arterial function, P<0.01). Furthermore, multiple regression analysis revealed that these factors were independent variables for hs-cTnT as a subordinate factor. CONCLUSION: The findings of this study indicate that in vivo oxidative stress and abnormality of arterial function are closely associated with an increase in hs-cTnT concentrations in Japanese metabolic syndrome patients. PMID- 25792850 TI - A fresh look into the pathophysiology of ischemia-induced complications in patients with chronic kidney disease undergoing hemodialysis. AB - Recent case reports of acute esophageal necrosis in patients with chronic kidney disease (CKD) undergoing hemodialysis encouraged us to look beyond hypoperfusion/ischemia as a sole explanation for this dramatic complication. At least three intriguing pathways, ie, accumulation of protein-bound toxins, endotoxin translocation, and altered mucosal defense mechanisms, have been proposed to explain the inherent susceptibility of CKD patients to developing ischemia-related and cardiovascular events. Interestingly, all the proposed pathways can be potentially antagonized or attenuated. At present, however, it is not known whether one pathway predominates or if any interaction exists between these pathways. More solid experimental and clinical data are warranted to acquire a better insight into the complex pathogenesis of CKD-associated ischemia. PMID- 25792851 TI - Strategies to improve physical activity by exercise training in patients with chronic kidney disease. AB - Decreased physical activity resulting in muscle loss is often observed in patients with chronic kidney disease and is one of the main predictors of mortality in these patients. Exercise training may improve physical activity and prevent muscle loss in patients with chronic kidney disease. Efforts to introduce exercise training to these patients may be clinically beneficial by reducing their mortality rates. PMID- 25792853 TI - Stimulation of proinflammatory cytokines by volatile sulfur compounds in endodontically treated teeth. AB - Persistent microorganisms in endodontically treated teeth produce volatile sulfur compounds (VSC) such as methyl mercaptan, hydrogen sulfide, and thioether. In this retrospective study, we evaluated the ex vivo immune response of peripheral blood mononuclear cells to sulfur compounds in 354 patients with systemic diseases. These systemic findings are correlated with semiquantitative values of a VSC indicator applied directly on endodontically treated teeth. Data elucidate the role of VSC in patients with immunologic diseases and the role of a semiquantitative chairside test, like the VSC indicator presented here, in correlation to IFNg and IL-10 sensitization in peripheral blood mononuclear cells. The association between ex vivo-stimulated cytokines and endodontically derived sulfur components is supported by the fact that the number of interferon gamma- and/or interleukin-10-positive sensitized patients declined significantly 3-8 months after extraction of the corresponding teeth. PMID- 25792852 TI - Comparative seroprevalence of measles virus immunoglobulin M antibodies in children aged 0-8 months and a control population aged 9-23 months presenting with measles-like symptoms in selected hospitals in Kaduna State. AB - BACKGROUND: Measles remains the leading cause of vaccine-preventable childhood mortality in developing countries, with its greatest incidence in children younger than 2 years of age. The aim of this study was to determine the seroprevalence of measles virus in children (aged 0-8 months) and older children (aged 9-23 months) presenting with measles-like symptoms. METHODS: A total of 273 blood samples comprising 200 from children aged 0-8 months and 73 from children aged 9-23 months were collected and analyzed for measles virus IgM antibodies by enzyme-linked immunosorbent assay. RESULTS: An overall prevalence of 21.2% was obtained, with a prevalence of 6.5% in children aged 0-8 months and 61.6% in children aged 9-23 months. The prevalence of measles virus increased with age in children aged 0-8 months and decreased with age in older children (aged 9-23 months), showing a significant association between measles virus and age of the child (P=0.000). A higher prevalence was found in females (27.5%) than in males (16.3%) and this difference was significant (odds ratio 1.942, P=0.025). There was no significant association with the level of parental education, parental occupation, or number of children in the family (P>0.05). With respect to children's vaccination status and breastfeeding, there was a significant association (P<0.05). The marital status of the family, place of residence, and household size showed no significant association with the prevalence of measles virus. However, a significant association was observed in relation to maternal measles history (odds ratio 2.535, P=0.005) and maternal vaccination status (odds ratio 1.791, P=0.049), as well as between measles virus infection and all presenting symptoms, except for vomiting, malaria, typhoid, and pneumonia, which showed no significant association (P>0.05). CONCLUSION: The findings of this study confirm the presence of measles virus infection in children aged 0-8 months. PMID- 25792854 TI - Methods to improve rehabilitation of patients following breast cancer surgery: a review of systematic reviews. AB - CONTEXT: Breast cancer is the most prevalent cancer amongst women but it has the highest survival rates amongst all cancer. Rehabilitation therapy of post treatment effects from cancer and its treatment is needed to improve functioning and quality of life. This review investigated the range of methods for improving physical, psychosocial, occupational, and social wellbeing in women with breast cancer after receiving breast cancer surgery. METHOD: A search for articles published in English between the years 2009 and 2014 was carried out using The Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, PubMed, and ScienceDirect. Search terms included: 'breast cancer', 'breast carcinoma', 'surgery', 'mastectomy', 'lumpectomy', 'breast conservation', 'axillary lymph node dissection', 'rehabilitation', 'therapy', 'physiotherapy', 'occupational therapy', 'psychological', 'psychosocial', 'psychotherapy', 'exercise', 'physical activity', 'cognitive', 'occupational', 'alternative', 'complementary', and 'systematic review'. STUDY SELECTION: Systematic reviews on the effectiveness of rehabilitation methods in improving post-operative physical, and psychological outcomes for breast cancer were selected. Sixteen articles met all the eligibility criteria and were included in the review. DATA EXTRACTION: Included review year, study aim, total number of participants included, and results. DATA SYNTHESIS: Evidence for exercise rehabilitation is predominantly in the improvement of shoulder mobility and limb strength. Inconclusive results exist for a range of rehabilitation methods (physical, psycho-education, nutritional, alternative-complementary methods) for addressing the domains of psychosocial, cognitive, and occupational outcomes. CONCLUSION: There is good evidence for narrowly-focused exercise rehabilitation in improving physical outcome particularly for shoulder mobility and lymphedema. There were inconclusive results for methods to improve psychosocial, cognitive, and occupational outcomes. There were no reviews on broader performance areas and lifestyle factors to enable effective living after treatment. The review suggests that comprehensiveness and effectiveness of post-operative breast cancer rehabilitation should consider patients' self-management approaches towards lifestyle redesign, and incorporate health promotion aspects, in light of the fact that breast cancer is now taking the form of a chronic illness with longer survivorship years. PMID- 25792855 TI - Guided bone augmentation using ceramic space-maintaining devices: the impact of chemistry. AB - The purpose of the study was to evaluate histologically, whether vertical bone augmentation can be achieved using a hollow ceramic space maintaining device in a rabbit calvaria model. Furthermore, the chemistry of microporous hydroxyapatite and zirconia were tested to determine which of these two ceramics are most suitable for guided bone generation. 24 hollow domes in two different ceramic materials were placed subperiosteal on rabbit skull bone. The rabbits were sacrificed after 12 weeks and the histology results were analyzed regarding bone to-material contact and volume of newly formed bone. The results suggest that the effect of the microporous structure of hydroxyapatite seems to facilitate for the bone cells to adhere to the material and that zirconia enhance a slightly larger volume of newly formed bone. In conclusion, the results of the current study demonstrated that ceramic space maintaining devices permits new bone formation and osteoconduction within the dome. PMID- 25792856 TI - Assessment of adherence to highly active antiretroviral therapy and associated factors among people living with HIV at Debrebrihan Referral Hospital and Health Center, Northeast Ethiopia: a cross-sectional study. AB - Patient adherence to antiretroviral combination therapy is a critical component to successful treatment outcome. Nonadherence to antiretroviral therapy (ART) is a major challenge to AIDS care, and the risks associated with it are extensive. The intention of this study was to determine prevalence and associated factors with adherence to highly active ART among people living with HIV/AIDS (PLWHA) at the Debrebrihan Referral Hospital and Health Center, Northeast Ethiopia. A cross sectional study design with systematic random sampling conducted by the use of a structured, pretested self-rating adherence questionnaire was used to conduct the study among 422 respondents from the Debrebrihan Referral Hospital and Health Center. A single population proportion formula at 95% CI with 5% of marginal error at 50% of prevalence of occurrence was used to determine sample size. Adherence was defined as not missing a single ART dose during the 30-day period prior to filling out the self-report. Adherence was measured by self-reports by the patients. These results were then used in binary logistic regression analysis. Covariates were analyzed by bivariate and multivariate logistic regression with SPSS statistical software. The total number of respondents in this study was 422; their median age was 35 years. Among the participants, 95.5% were taking their medication without missing a dose. Factors such as having emotional or practical support positively encouraged ART adherence (adjusted odds ratio 0.16 [95% CI 0.05-0.49]). However, users of traditional, complementary, and alternative medicine (TCAM) (adjusted odds ratio 4.7 [95% CI 1.06-21.22]) had nearly a five times higher risk for ART nonadherence (P<0.05) than those not using TCAM. Adherence to ART among PLWA is imperative and standard. But, there is still a need to boost psychological support and practical support for the clients, and there is also a need to create a more integrative approach with TCAM in order to increase adherence to ART. Strengthening emotional and practical support for PLWHA and integrating TCAM with the proper use of ART are mandatory to enhance ART adherence. PMID- 25792857 TI - Characterization of symptoms and edema distribution in premenstrual syndrome. AB - BACKGROUND: Premenstrual syndrome is a group of symptoms linked to the menstrual cycle, and edema is among these symptoms. Physiotherapy is often sought by many patients for the treatment of edema; however, for an adequate prescription of physiotherapeutic procedures, the distribution of edema throughout the body has yet to be characterized. OBJECTIVE: To determine the most frequent symptoms and body regions that present with edema in women during the premenstrual period. SUBJECTS AND METHODS: Sixty women with a mean age of 24.6+/-4.7 years were evaluated during their premenstrual (between days 21 and 28) and menstrual period (between days 1 and 3), and the collected data included body mass, height, biotype (body-fat distribution), face, breast, limb-circumference measurements, and limb-volume estimate, and an adapted version of the Premenstrual Symptoms Screening Tool was used. Statistical analysis was performed using Student's t test and the test for equality of two proportions (P<=0.05). RESULTS: Premenstrual syndrome was identified in 91.7% of the women, and the most frequent symptoms were irritability (73.33%) and physical symptoms, including swelling (65%), and anxiety (58.3%). Edema was detected in the following areas: facial, epigastric, mammary, umbilical, and pubic, the mid-third of the arms, distal forearm, in both thighs and in the mid-third of the legs determined by circumference measurements, and in both upper and lower limbs, according to the estimated volume. CONCLUSION: In this study population, the most frequent symptoms were irritability, physical symptoms, and anxiety, with distribution of edema in the face, breast, abdomen, pubic area, distal upper limb, and proximal lower limb. PMID- 25792858 TI - Acute vertigo in an anesthesia provider during exposure to a 3T MRI scanner. AB - Vertigo induced by exposure to the magnetic field of a magnetic resonance imaging (MRI) scanner is a well-known phenomenon within the radiology community but is not widely appreciated by other clinical specialists. Here, we describe a case of an anesthetist experiencing acute vertigo while providing sedation to a patient undergoing a 3 Tesla MRI scan. After discussing previous reports, and the evidence surrounding MRI-induced vertigo, we review potential etiologies that include the effects of both static and time-varying magnetic fields on the vestibular apparatus. We conclude our review by discussing the occupational standards that exist for MRI exposure and methods to minimize the risks of MRI induced vertigo for clinicians working in the MRI environment. PMID- 25792859 TI - Tendinopathy of the long head of the biceps tendon: histopathologic analysis of the extra-articular biceps tendon and tenosynovium. AB - BACKGROUND: Bicipital tendinitis is a common cause of anterior shoulder pain, but there is no evidence that acute inflammation of the extra-articular long head of the biceps (LHB) tendon is the root cause of this condition. We evaluated the histologic findings of the extra-articular portion of the LHB tendon and synovial sheath in order to compare those findings to known histologic changes seen in other tendinopathies. METHODS: Twenty-six consecutive patients (mean age 45.4+/ 13.7 years) underwent an open subpectoral biceps tenodesis for anterior shoulder pain localized to the bicipital groove. Excised tendons were sent for histologic analysis. Specimens were graded using a semiquantitative scoring system to evaluate tenocyte morphology, the presence of ground substance, collagen bundle characteristics, and vascular changes. RESULTS: Chronic inflammation was noted in only two of 26 specimens, and no specimen demonstrated acute inflammation. Tenocyte enlargement and proliferation, characterized by increased roundness and size of the cell and nucleus with proteoglycan matrix expansion and myxoid degenerative changes, was found in all 26 specimens. Abundant ground substance, collagen bundle changes, and increased vascularization were visualized in all samples. CONCLUSION: Anterior shoulder pain attributed to the biceps tendon does not appear to be due to an inflammatory process in most cases. The histologic findings of the extra-articular portion of the LHB tendon and synovial sheath are similar to the pathologic findings in de Quervain tenosynovitis at the wrist, and may be due to a chronic degenerative process similar to this and other tendinopathies of the body. PMID- 25792860 TI - Are curriculum changes the ideal method for increasing undergraduate exposure to tomorrow's specialties? PMID- 25792861 TI - Service and its association with matching into a primary care residency. AB - BACKGROUND AND OBJECTIVES: There is a shortfall in the primary care workforce, and an effort is needed in learning more about what motivates students to work as generalists. There is enthusiasm about service as a potential motivator. The objective is to determine whether there is an association between high participation in service and selection of a primary care residency. METHODS: This is a retrospective cohort analysis. The service award was used to delineate two groups, recipients and non-recipients, with the recipients considered high service participators. This was associated with residency match data using test of proportions to examine relationships between service and selection of a primary care residency and other secondary factors. RESULTS: Of award recipients, 57.3% matched in primary care, compared to 52.8%, though this did not reach statistical significance. Service was linked with induction into Alpha Omega Alpha honor society (23.3% versus 14.6%) and induction into the Gold Humanism Honor Society (22.6%. versus 10.4%), with statistical significance. CONCLUSION: This was an unsuccessful attempt to find a link between service and a primary care career choice, though there is a trend in the direction. The association with induction into the humanism honor society suggests that service is linked with development and/or retention of positively viewed qualities in medical students. PMID- 25792862 TI - The value of postmortem experience in undergraduate medical education: current perspectives. AB - The autopsy has traditionally been used as a tool in undergraduate medical education, but recent decades have seen a sharp decline in their use for teaching. This study reviewed the current status of the autopsy as a teaching tool by means of systematic review of the medical literature, and a questionnaire study involving UK medical schools. Teachers and students are in agreement that autopsy-based teaching has many potential benefits, including a deeper knowledge of basic clinical sciences, medical fallibility, end of life issues, audit and the "hidden curriculum". The reasons underlying the decline in teaching are complex, but include the decreasing autopsy rate, increasing demands on teachers' time, and confusion regarding the law in some jurisdictions. Maximal use of autopsies for teaching may be achieved by involvement of anatomical pathology technologists and trainee pathologists in teaching, the development of alternative teaching methods using the principles of the autopsy, and clarification of the law. Students gain most benefit from repeated attendance at autopsies, being taught by enthusiastic teachers, when they have been effectively prepared for the esthetic of dissection and the mortuary environment. PMID- 25792863 TI - Web-based teaching in point-of-care ultrasound: an alternative to the classroom? AB - OBJECTIVES: To evaluate two educational methods for point-of-care ultrasound (POC US) in order to: 1) determine participant test performance and attitudes in using POC US and 2) compare cost and preparation time to run the courses. METHODS: This was a pilot study conducted at a county teaching hospital. Subjects were assigned to participate in either a large group course with live classroom lectures (Group A) or a group asked to watch 4.5 hours of online prerecorded lectures (Group B). Both groups participated in small-group hands-on training after watching the lectures. Both groups took a pre- and post-course exam, and completed course surveys. Cost and time spent running the courses were also compared. RESULTS: Forty-seven physicians participated in the study. The pre-test and post-test scores between the two groups did not differ significantly. Of those with prior ultrasound experience, the majority of both groups preferred to continue classroom-based teaching for future courses. Interestingly, in the groups who had no ultrasound experience prior to their course participation, there was a higher percentage who preferred web-based teaching. Lastly, Group B was shown to have the potential to take less preparatory time when compared to Group A. CONCLUSION: A web-based curriculum in POC US appears to be a promising and potentially time saving alternative to live classroom lectures and seems to offer similar educational benefits for the postgraduate learner. PMID- 25792864 TI - Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key? AB - ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism. PMID- 25792865 TI - A Critical Role of GIT1 in Vertebrate and Invertebrate Brain Development. AB - GIT1, a multifunctional signaling adaptor protein, is implicated in the development of dendritic spines and neuronal synapses. GIT1 forms a signaling complex with PIX, RAC, and PAK proteins that is known to play important roles in brain development. Here we found that Git1-knockout (Git1(-/-) ) mice show a microcephaly-like small brain phenotype, which appears to be caused by reduced neuronal size rather than number. Git1(-/-) mice also show decreased dendritic spine number without morphological alterations in the hippocampus. Behaviorally, Git1(-/-) mice show impaired motor coordination and learning and memory. In addition, adult dGit Drosophila mutants show decreased brain size and abnormal morphology of the mushroom body. These results suggest that GIT1 is important for brain development in both rodents and flies. PMID- 25792866 TI - Ca(2+) Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte. AB - Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca(2+) oscillations. ATP is known to be released from astrocytes by Ca(2+)-dependent manner. However, the precise source of Ca(2+), whether it is Ca(2+) entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca(2+) was released from intracellular stores by activation of Galphaq coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca(2+) was omitted. Our results suggest that Ca(2+) entry, but not release from intracellular Ca(2+) store, is critical for MS-induced ATP release from astrocyte. PMID- 25792867 TI - Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model. AB - We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA pretreated group was higher than in the saline-pretreated group. The up regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level. PMID- 25792868 TI - Amelioration of Cerebral Ischemic Injury by a Synthetic Seco-nucleoside LMT497. AB - Recently, we reported that the A3 adenosine receptor (A3AR) agonist LJ529 (2 chloro-N(6)-(3-iodobnzyl)-5'-N-methylcarbamoyl-4'-thioadenosine) reduces cerebral ischemic injury via inhibition of recruitment of peripheral inflammatory cells into ischemic brain lesion. A3AR agonists, however, are known to possess anti platelet activity, which may deter the combination therapy with tissue plasminogen activator for the therapy of cerebral ischemic stroke. Thus, the present study investigates the neuroprotective/anti-ischemic effect of a synthetic seco-nucleoside, LMT497 ((S)-2-((R)-1-(2-chloro-6-(3-iodobenzylamino) 9H-purin-9-yl)-2-hydroxyethoxy)-3-hydroxy-N-methylpropanamide) with little anti platelet activity. LMT497 neither showed A3AR binding activity nor anti-platelet activity. In our present study LMT497 significantly attenuated the injury/death of cortical neurons exposed to oxygen-glucose deprivation (OGD) followed by re oxygenation (R). LMT497 significantly reduced the ascending cellular level of reactive oxygen species under ischemic conditions by increasing the superoxide dismutase (SOD) levels. LMT497 also inhibited the migration of microglia which mediates inflammatory responses in ischemia. In rats subjected to middle cerebral artery occlusion (MCAO, 1.5 h) followed by reperfusion, LMT497 largely reduced brain infarction volume, and edema, and improved neurological score. Therapeutic efficacy of LMT497 was obtained by twice treatments even at 10 h and 18 h after the onset of ischemia. Collectively, LMT497 could be a therapeutic drug candidate with a wide therapeutic time window for the treatment of cerebral ischemic stroke. PMID- 25792869 TI - Dehydroascorbic Acid Attenuates Ischemic Brain Edema and Neurotoxicity in Cerebral Ischemia: An in vivo Study. AB - Ischemic stroke results in the diverse phathophysiologies including blood brain barrier (BBB) disruption, brain edema, neuronal cell death, and synaptic loss in brain. Vitamin C has known as the potent anti-oxidant having multiple functions in various organs, as well as in brain. Dehydroascorbic acid (DHA) as the oxidized form of ascorbic acid (AA) acts as a cellular protector against oxidative stress and easily enters into the brain compared to AA. To determine the role of DHA on edema formation, neuronal cell death, and synaptic dysfunction following cerebral ischemia, we investigated the infarct size of ischemic brain tissue and measured the expression of aquaporin 1 (AQP-1) as the water channel protein. We also examined the expression of claudin 5 for confirming the BBB breakdown, and the expression of bcl 2 associated X protein (Bax), caspase-3, inducible nitric oxide synthase (iNOS) for checking the effect of DHA on the neurotoxicity. Finally, we examined postsynaptic density protein-95 (PSD-95) expression to confirm the effect of DHA on synaptic dysfunction following ischemic stroke. Based on our findings, we propose that DHA might alleviate the pathogenesis of ischemic brain injury by attenuating edema, neuronal loss, and by improving synaptic connection. PMID- 25792870 TI - COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway. AB - Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2 FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins alphanubeta3, alpha4, beta1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1alpha to induce angiogenesis. Taken together, it is concluded that COMP Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy. PMID- 25792872 TI - Development of a touch-screen-based paradigm for assessing working memory in the mouse. AB - Assessing the working memory of the rodent by using a touch-screen system has several advantages (e.g., allowing highly accurate data collection and flexibility in memory task design). However, there is currently no available testing paradigm utilizing touch-screen systems that can assess working memory in the mouse. In this study, we developed a touch-screen testing paradigm in which mice were trained to choose a location that is matched to a sample location after a time delay. Consistent with previous studies, this study showed that mice could not only learn the rule in the delayed matched to position (DMTP), but also could retain a transitory memory of the sample position during delay. This indicates that a touch-screen system can provide a DMTP testing platform to assess working memory in the mouse. PMID- 25792871 TI - Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency. AB - Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders. PMID- 25792873 TI - Asymmetry of Dopamine D2/3 Receptor Availability in Dorsal Putamen and Body Mass Index in Non-obese Healthy Males. AB - The dopaminergic system is involved in the regulation of food intake, which is crucial for the maintenance of body weight. We examined the relationship between striatal dopamine (DA) D2/3 receptor availability and body mass index (BMI) in 25 non-obese healthy male subjects using [(11)C]raclopride and positron emission tomography. None of [(11)C]raclopride binding potential (BP) values (measures of DA D2/3 receptor availability) in striatal subregions (dorsal caudate, dorsal putamen, and ventral striatum) in the left and right hemispheres was significantly correlated with BMI. However, there was a positive correlation between the right-left asymmetry index of [(11)C]raclopride BP in the dorsal putamen and BMI (r=0.43, p<0.05), suggesting that greater BMI is linked with higher receptor availability in the right dorsal putamen relative to the left in non-obese individuals. The present results, combined with previous findings, may also suggest neurochemical mechanisms underlying the regulation of food intake in non-obese individuals. PMID- 25792875 TI - Effects on Performance of Interpolated Tasks During the KR Delay or the Post-KR Delay Interval. AB - The present study was designed to investigate the nature of motor information processing in the intertrial intervals of a discrete motor task. In Experiment 1, the subjects were given the task of grasping the dynamometer with an intensity yielding a value as close as possible to the target value (40% of the subject's maximum grasping power). The exercise session consisted of 5 trials without Knowledge of Results (NO-KR phase), and 30 trials with Knowledge of Results (KR phase). In the KR phase, one of the two interpolated tasks, one was a verbal task and the other was a motor task, was given during the KR delay interval or the post-KR delay interval. Performance level in the exercise session was measured by constant error and variable error. In Experiment 2, the degrees of difficulty in the two types of interpolated tasks used in Experiment 1 were measured. The main results of our experiments were as follows; (1) Although the results of Experiment 2 showed that the difficulty of the verbal interpolated task was exceeded that of the motor interpolated task, only variable errors of the groups which had executed the motor interpolated task were increased. If the kinetic sense was changed by executing the motor interpolated task, constant error should have increased. The results of Experiment 1, however, showed no difference in constant error, suggesting that the occurrence of interference by the motor interpolated task is related to the capacity of the motor short term memory space. (2) In the latter period of the KR phase, variable error of the group in which the motor task was interpolated during the KR delay interval was at the same level as that of the control group. Whereas variable error of the group in which the motor task was interpolated during the post-KR delay interval exceeded that of the control group over the whole of the KR phase. These results suggest information processing during the post-KR delay interval has more influence on performance than that during the KR delay interval. PMID- 25792874 TI - Longitudinal change in the physical performance of older adults in the community. AB - The primary purposes of this study were 1) to confirm age-related deterioration of physical performance in older adults longitudinally, and 2) to predict future functional status and mortality by initial level of physical performances. The subjects were 517 older adults examined both in 1992 and 1996 in the Tokyo Metropolitan Institute of Gerontology, Longitudinal Interdisciplinary Study on Aging. The same battery consisting of muscle strength, balance, walking, and manual speed was administered to the subjects in the baseline and follow-up examinations. A significant longitudinal decline was observed in all physical performances except for grip strength. The age-related decline accelerated with aging for preferred walking velocity. Inter-subject variability in walking velocity significantly increased for 4 years period. Maximum walking velocity was a common predictor for functional status and mortality. The results suggest that physical performance measures, especially maximum walking velocity, is a valid means for physical therapy to evaluate physical functioning of community-living older persons. PMID- 25792876 TI - The effects of posture on the ventilatory responses during exercise. AB - This study was undertaken to evaluate the postural effect on ventilatory responses during both supine and sitting exercise. Seven healthy men performed two exercise tests utilizing the ramp protocol (20 watts/min) with a cycle ergometer in each position. The results were as follows: The oxygen uptake and the oxygen pulse measured at 180 watts and at anaerobic threshold in the sitting were significantly higher compared with those in the supine position. The average of carbon-dioxide output, minute ventilation and tidal volume at lower exercise intensities showed higher values in the sitting compared with those in the supine position, whereas there were no significant differences for respiratory rate. There was significant difference in the slope of the minute ventilation to carbon dioxide output plot between sitting and supine position. In conclusion, the higher minute ventilation in the sitting position was mainly performed by higher tidal volume which may counteract the effects of an increase in physiological dead space. The lower slope of the minute ventilation to carbon-dioxide output plot which shows more effective ventilation in the supine position may be due to decreased physiological dead space and higher diffusion capacity. PMID- 25792878 TI - The effects of cervical traction on the soleus h reflex in stroke patients. AB - The purpose of this study was to investigate the effects of cervical traction on the soleus H reflex amplitude in stroke patients. Cervical traction with intensity of 3 kgw was performed on six stroke patients. The soleus H reflex was evoked before, during, and after the cervical traction. All subjects showed smaller H reflex amplitudes in the second and third minutes after traction than before the traction. The results suggested that cervical traction with intensity of 3 kgw inhibited the soleus H reflex amplitude several minutes after traction in stroke patients. PMID- 25792877 TI - Effects of weight bearing intervals on disuse atrophy of rat soleus muscle. AB - The purpose of this study was to investigate the effects of weight bearing at varying intervals in suppressing the progression of disuse muscle atrophy, while setting the total daily weight bearing time constant. Disuse muscle atrophy was induced by 2-week hindlimb suspension. Thirty male Wistar rats ( weight : 215 +/- 8 g ) were divided into 6 groups ( 5 rats/group ) : control (CON), suspension alone (SUS), two sessions of 30-minute weight bearing at intervals of 4, 8, and 12 hours during suspension, and one session of 60-minute weight bearing at intervals of 24 hours during suspension. Weight bearing was done each day during the daytime. Histochemical staining, followed by morphometrical analysis using NIH Image, demonstrated that the cross-sectional area of type I fiber in SUS was 44% of that in CON, while in the weight bearing groups ranged from 62 to 70%. The proportion of type I fibers was lower in SUS and tended to increase as the interval of weight bearing become longer, indicating the effects of weight bearing at intervals of 12 and 24 hours. For both types I and II, the distribution of muscle fiber size indicated that weight bearing at longer intervals was more effective in keeping the cross-sectional areas of muscle fibers closed to that in CON. In conclusion, when suppressing the progression of disuse atrophy of rat soleus muscle by weight bearing of one hour per day, the results suggest that the weight bearing intervals is important factor. PMID- 25792879 TI - Repairing process in the transected muscle fibers of the mouse tibialis anterior. AB - Repairing process at the injury site in the transected muscle fibers of the mouse tibialis anterior was studied by light and electron microscopy. Immediately after the transection, the cut end (approximately 10 um) was filled with dense network of disorganized myofilaments, in which disrupted membranous structures and degraded mitochondria were scattered. In the portion next to the portion exhibiting sudden necrotic changes, morphological features of the myofilaments, mitochondria and membranous structures appeared to be almost normal. The degradation of disorganized myofilaments at the cut end began within 1 hour after the transection, and at 1hour after the transection, the degenerating areas were noted in most of muscle fibers up to 150-250 um from the cut end. Following the degradation, accumulation of mitochondria occurred between the necrotic and myofilament-predominant living portions, and several transverse tubules (T tubules) and sarcoplasmic reticula were found between the mitochondria accumulated and myofilament-predominant areas. In most cases, demarcation membrane formed between the mitochondria-accumulated and myofilament-predominant areas, and the fusion of T-tubules and sarcoplasmic reticula was encountered in these areas, suggesting that at least some parts of the demarcation membranes formed through fusion of T-tubules and sarcoplasmic reticula. This repairing process was completed in a number of muscle fibers within 6 hours after the transection. Macrophages were first found in the injured portions at 6 hours after the transection, increased in number with time, and several macrophages were distributed at 1 to 3 days after the transection. Some spindle-shaped cells were first found in the degenerating portions of the muscle fibers at 1 day after the transection. Since they were located along the basal lamina of the muscle fiber, and had a long oval pale nucleus and relatively abundant cytoplasm, they can be regarded as activated satellite cells. They gradually increased in number with time, and became larger and longer. On and after 5 days, thin regenerating muscle fibers exhibiting centrally located nuclei were observed, and they became gradually thicker with time. These findings indicate that the muscle regeneration was actively occurring during these periods. The repairing process is followed by the invasion of macrophages, and then the occurrence of muscle regeneration in the sequential order. These findings suggest that there might be close chronological relationship among these events. PMID- 25792880 TI - Clinical Characteristics of Swallowing Disorders Caused by Cerebrovascular Disease: A Study Using Newly-developed Indices for the Basic Elements of Swallowing Movement and Neck Range of Motion. AB - The objective of this study was to elucidate the characteristics of swallowing disorder in cerebrovascular disease (CVD) patients in terms of newly developed indices for the basic elements of swallowing movement and muscle tone in the neck. A total of 133 patients participated in our study, 116 patients with CVD and 17 elderly patients who had no history of dysphagia and CVD. These patients were divided into 5 groups according to the existence of swallowing disorder and interval from onset. The effects of CVD and swallowing disorder were elucidated by two-group comparison. Measurement items consisted of and passive neck ROM in 4 directions (flexion, extension, lateral flexion, and rotation.) 5 newly developed indices: distance from the genion to the upper end of thyroid cartilage (GT), distance from the upper end of thyroid cartilage to the upper end of sternum (TS), length of the suprahyoid and infrahyoid muscles on neck extension (GT+TS), relative larynx position (GT/(GT+TS)), and strength of the suprahyoid muscles (GS grade). Patients with CVD of less than 90 days' duration exhibited GT shortening, decline in GS grade, and limitations in neck extension and rotation ROM. In the chronic phase, TS shortening, laryngeal lowering, and limitations in neck flexion and lateral flexion ROM were observed. Physical therapists should aim to improve the factors that might impede laryngeal movement and to conduct preparatory exercises that facilitate swallowing movements. PMID- 25792881 TI - The Effect of Vertical Oscillatory Pressure (VOP) on Youths and Elderly Adult Low Back Pain (LBP) Intensity and Lumbo-Sacral Mobility. AB - The effect of Vertical Oscillatory Pressure (VOP) on Low Back Pain (LBP) intensity and lumbo-sacral mobility in youths compared to elders was examined. Eighty five male (56) and female (29) subjects comprising 45 youths (18-28 years old) and 42 elders (65-75 years old), including LBP (40) and pain-free individuals participated in the study. Subjects with LBP received VOP on each vertebra from the first lumbar to the sacrum, 10 oscillations in one minute repeated at each vertebra. Pain intensity (measured using Borg's 10 point scale) and mobility were measured at the start, after VOP and five minutes after cryotherapy. Control subjects did not receive VOP and cryotherapy but had their sensory perception and spinal mobility measured at the start, after 15 and 26 minutes respectively. Pain intensity decreased significantly [elders, p<0.01; youths, p<0.05] while the range of forward and side flexions increased significantly (p<0.05) only in elders after VOP. Cryotherapy after VOP therapy did not add any significant effect on pain intensity and trunk mobility. Mobility and perceptual levels of the control subjects did not alter significantly. Pain intensity and flexion (forward and side flexions in elders only) are improved by VOP and should be preferred spinal mobilization therapy outcome measures in youths and elders with LBP respectively. PMID- 25792882 TI - Understanding and prevention of low back pain in care workers. AB - The aim of this study was to investigate the actual situation of low back pain (LBP) prevention in care workers with questionnaires, and this data were used to clarify and decrease LBP factors. Subjects were 52 care workers (30.7 +/- 10.0 years old) in a nursing home who filled out two kinds of questionnaires about LBP, one about the prevalence of LBP (QN1) and the other about LBP control measures (QN2). They had either license of certified care worker, 1st or 2nd class care worker. The data were collected for the purpose of finding differences in age and career (QN1) and differences in LBP control measures (QN2) between subjects with and without LBP. The average career of the subjects was 19.1 +/- 12.5 months, and the prevalence of LBP among them was 46.2% (24 care workers), of which 66.7% began having LBP after starting work as care workers. Moreover, 75.0% of these subjects began having LBP within a year after starting work. Further, of the 24 care workers with LBP, 66.7% reported constantly experiencing LBP. The major risk factors given for LBP in care work were transfer, the replacement of diapers, and movement in a half-sitting posture. Compared with LBP subjects, rates of taking preventative steps in the non-LBP group were low. More than 80% of the subjects with LBP engaged in prevention methods such as using body mechanics, learning the proper way to perform care activities, using LBP support belts, and increasing their skills and knowledge with regard to their job responsibilities. Most subjects began to engage in such prevention methods after the onset of LBP. The results of this investigation indicated that most subjects did not engage in measures to counter their LBP until after it had already started, and that they selected prevention methods which were easy to perform and effective. It is important for care workers to learn the best ways to inhibit pain and prevent the occurrence, or recurrence, of LBP. It is necessary for physical therapists to grasp the actual situation of LBP prevention as an occupational disease and to educate this. PMID- 25792883 TI - Effect of Immobilization on Insoluble Collagen Concentration and Type I and Type III Collagen Isoforms of Rat Soleus Muscle. AB - Immobilization is often associated with decreased muscle elasticity. This condition is known as muscle contracture; however, the mechanism remains unclear. The purpose of this study was to clarify the mechanism governing muscle contracture in rat soleus muscle by identifying changes in ankle joint mobility, insoluble collagen concentration and type I and type III collagen isoforms following 1- and 3-week immobilizations. Following a 1-week immobilization, range of motion (ROM) of dorsiflexion declined to 90% of the control value; additionally, ROM dropped to 67.5% of the control value after a 3-week immobilization. This finding suggested that ankle joint mobility decreases in conjunction with extended periods of immobilization. Insoluble collagen concentration in soleus muscles, which was unchanged after 1 week of immobilization, increased 3 weeks after immobilization. These results may be indicative of collagen fibers with strong intermolecular cross-links contained in the muscle was made increased relatively by 3 weeks of immobilization. Therefore, the change in intermolecular cross-links may be significant in terms of progress of muscle contracture with longer periods of immobilization. On the other hand, the ratio of type III to type I collagen isoforms in muscular tissue increased following a 1-week immobilization; moreover, this ratio remained constant after 3 weeks of immobilization. These data suggested that muscle immobilization may induce type III collagen isoform expression. The increase in the ratio of type III to type I collagen isoforms do not change in parallel with the increase in the limitation in ROM; however, this phenomenon probably is not closely related to the progress of muscle contracture. The change of collagen isoform in immobilized muscle may be involved in the mechanism governing the progression of muscle fibrosis. PMID- 25792884 TI - The effects of comprehensive exercise program on the adjustments of standing balance in community-dwelling elderly persons. AB - The objective of this study was to assess the effect of comprehensive exercise program widely accepted as a community-based physical intervention for the prevention of falling in the elderly persons on their controlling standing balance. Twenty-six community-dwelling elderly persons (13 males and females; 69.8 +/- 2.8 years old) participated in this study. Daily exercise was comprised of walking for more than 30 min, stretching, muscle strengthening and balance exercise without exercise equipments. The intervention was continued for three months. Indicators of standing balance related to static balance, dynamic balance and postural response were measured before and after the intervention. As an effect of the intervention on static balance, the sway of center of pressure (COP) in the static stance significantly increased. In the dynamic balance, significant improvements were observed in one leg standing time, the 10-m gait time, functional reach. Additionally, the maximal movable length of COP which subjects can move voluntarily to right and left significantly increased. In the postural response, the integrated electromyography (IEMG) induced by postural response for sudden postural perturbation significantly decreased in the lower leg muscles. Since less muscular activities were sufficient to maintain posture, it was suggested that postural response was elicited more efficiently following the intervention. This study suggested that the comprehensive exercise program, which has been widely introduced as community-based interventions for the prevention of falling, have extensive effects on the control of standing balance covering static balance, dynamic balance and postural response in the elderly persons. PMID- 25792885 TI - Crying and behavioral characteristics in premature infants. AB - The aims of this study were to analyze 1) whether there was the relationship between the neonatal behavioral characteristics and amount of crying in premature infants at term age, and 2) what kind of difference between infants with high levels of crying and cry less on neonatal behavioral characteristics using the Neonatal Behavioral Assessment Scale (NBAS). The study participants consisted of 69 healthy low birth-weight infants who were admitted to the NICU at the Nagasaki University Hospital, Nagasaki, Japan. This study analyzed the relationship between NBAS scores measured neonatal behavioral performance and crying at term age. This study results indicate that there was significant statistical negative correlation between the amount of total daily crying and Habituation, Range of state, Regulation of state, and Autonomic stability cluster scores and some individual items scores (Response decrement to light, Response decrement to tactile of foot, Alert responsiveness, Examiner persistence, Motor maturity, Irritability, General irritability, Cuddliness, Consolability, Self-quieting activity, and State regulation). The high levels crying group also showed higher responsivity than less crying group in the items of Peak of excitement, Rapidity of build-up, Irritability and General irritability. In conclusion, neonatal behavioral characteristics such as poor inhibit discrete stimuli while asleep, hyper-responsivity and poor state regulation abilities were risk factors of high levels of crying. PMID- 25792887 TI - The Relationship between Age and Change in Physical Functions after Exercise Intervention. Trainability of Japanese Community-Dwelling Older Elderly. AB - The purposes of this study were to evaluate the relationship between age and changes in physical measurements after exercise intervention and to investigate the trainability of the older elderly. Two hundred seventy-six community-dwelling people aged 60 years and older practiced exercise intervention for 3 months. The measurements of physical functions were one-legged standing with eyes open and closed (OLS-O, OLS-C), functional reach test (FR), timed up and go test (TUG), maximum walking velocity, flexibility, and muscle strength. We evaluated the associations between age and the changes in these physical measurements. All measurements except for OLS-C significantly improved after intervention. The magnitude of the changes in hand-grip strength and FR after the intervention showed weak negative correlations with the subject's age, but other measurements showed no correlations. In addition, there were no differences between younger elderly persons and older elderly persons with regard to changes in any measurements. These results suggested that the exercise intervention we applied could improve physical fitness in community-dwelling older people, regardless of their age. The older elderly were comparable to the younger elderly in trainability to improve physical fitness. PMID- 25792886 TI - The Change of Grip Strength in a Patient with Congenital Myotonic Dystrophy Over a 4-year Period. AB - Myotonic dystrophy (MyD) is a neuromuscular disease that is autosomal dominant and the most common form of muscular dystrophy affecting adults. The clinical features of MyD include a multisystemic disorder characterized by myotonia, progressive muscle weakness and wasting, cataracts, premature balding and mental retardation. The most severe type of MyD is classified as congenital MyD (CMyD). The muscle weakness in CMyD is very severe, but muscle development can be observed in the period of growth. However, no clinical case of this type has been reported yet. Therefore, we report on a girl with CMyD who had an increase in muscle strength over a four-year period. The girl with CMyD participated in this study from the age of 9 to the age of 12. The measurement of muscle strength was recorded as the maximum score of grip strength with the use of dynamometers. Grip strength was assessed once a year by the same two physical therapists. Grip strength of CMyD for each year was markedly weak when compared with the normal controls, but muscle strength changed within some specific growth areas. The muscle weakness in CMyD was remarkable, but the result showed that specific muscle strength of CMyD in childhood was actually increased. PMID- 25792888 TI - The weight-bearing rate on the paretic limb of cerebrovascular hemiplegic patients necessary for an independent obstacle negotiation gait. AB - PURPOSE: The obstacle negotiation gait (ONG) is a fundamental activity of daily living. In cerebrovascular hemiplegic patients (stroke patients), the weight bearing rate (WBR) on the paretic limb necessary for an independent ONG was studied. METHODS: One hundred and seventeen stroke patients were involved. The patients' average age at the time of the study was 67 years, and the average time from stroke onset was 102 days. There were 68 men and 49 women. Seventy patients were right hemiplegics, and 47 were left hemiplegics. The correlations between ONG and age, sex, body mass index (BMI), time from stroke onset, muscle strength of both the paretic and non-paretic limbs, Brunnstrom stage of the lower limbs, deep sensation, and the WBR on both the paretic and non-paretic limbs were studied. Patients who could perform ONG independently and safely were categorized as the independent group (IG), and those who needed observation or any assistance were categorized as the dependent group (DG). RESULTS: The BMI, muscle strength of both the paretic and non-paretic limbs, Brunnstrom stage of the lower limbs, deep sensation and the WBR for both the paretic and non-paretic limbs were significantly different between the IG and DG groups. In particular, the WBR on the paretic limb was found to correlate significantly with the ONG, and a WBR value of 80.5% on the paretic limb gave a clear cut-off value. CONCLUSION: Although multiple factors influenced the ONG of stroke patients, the WBR on the paretic limb was the most influential. PMID- 25792889 TI - Effects of combined stretching and clenbuterol on disuse atrophy in rat soleus muscle. AB - BACKGROUND AND PURPOSE: Clinically, disuse muscle atrophy is often seen among patients who are severely debilited and are on prolonged bed rest. Common physical therapy interventions are not successful in preventing disuse muscle atrophy early in the medical treatment of critically ill patients. In situations such as this, the use of a beta 2-adrenergic agonist such as clenbuterol (Cb) may be of benefit in preventing atrophy. Also, recent studies have suggested that stretching is possible in preventing disuse muscle atrophy and the decline in muscle strength. The objective of this study was to evaluate the effects of Cb medication combined with stretching (ST) on rat soleus muscle (SOL) during the progression of disuse muscle atrophy. SUBJECTS: Thirty-five male Wistar rats were used in this study. METHODS: The rats were divided into five groups: control (CON), hindlimb-unweighting (HU) only, HU+ST, HU+Cb medication, and HU+ST+Cb groups. The right SOL in stretching groups was maintained a stretched position for one hour daily by passively dorsiflexing the ankle joint under non anesthesia. The experimental period was 2 weeks. RESULTS: In the ST group, peak twitch tension per cross-sectional area in soleus muscle was significantly larger than in the Cb group, while there was no significant difference between the CON and ST groups. The conversion of type I to type II fibers that was observed in the Cb group was not recognized in the combined ST and Cb group. DISCUSSION AND CONCLUSION: Distinct effect of combined stretching and Cb medication was not recognized statistically. The results indicate that Cb affects muscle morphological characteristics while stretching affects contractile properties. These data suggest that a combined ST and Cb intervention considered the type specificity of muscle fiber may be need more consideration for preventing disuse muscle atrophy and the decline in muscle strength. PMID- 25792890 TI - Aging effects on the structure underlying balance abilities tests. AB - Balance impairment is one of the biggest risk factors for falls reducing inactivity, resulting in nursing care. Therefore, balance ability is crucial to maintain the activities of independent daily living of older adults. Many tests to assess balance ability have been developed. However, few reports reveal the structure underlying results of balance performance tests comparing young and older adults. Covariance structure analysis is a tool that is used to test statistically whether factorial structure fits data. This study examined aging effects on the factorial structure underlying balance performance tests. Participants comprised 60 healthy young women aged 22 +/- 3 years (young group) and 60 community-dwelling older women aged 69 +/- 5 years (older group). Six balance tests: postural sway, one-leg standing, functional reach, timed up and go (TUG), gait, and the EquiTest were employed. Exploratory factor analysis revealed that three clearly interpretable factors were extracted in the young group. The first factor had high loadings on the EquiTest, and was interpreted as 'Reactive'. The second factor had high loadings on the postural sway test, and was interpreted as 'Static'. The third factor had high loadings on TUG and gait test, and was interpreted as 'Dynamic'. Similarly, three interpretable factors were extracted in the older group. The first factor had high loadings on the postural sway test and the EquiTest and therefore was interpreted as 'Static and Reactive'. The second factor, which had high loadings on the EquiTest, was interpreted as 'Reactive'. The third factor, which had high loadings on TUG and the gait test, was interpreted as 'Dynamic'. A covariance structure model was applied to the test data: the second-order factor was balance ability, and the first-order factors were static, dynamic and reactive factors which were assumed to be measured based on the six balance tests. Goodness-of-fit index (GFI) of the models were acceptable (young group, GFI=0.931; older group, GFI=0.923). Static, dynamic and reactive factors relating to balance ability had loadings 0.21, 0.24, and 0.76 in the young group and 0.71, 0.28, and 0.43 in the older group, respectively. It is suggested that the common factorial structure of balance abilities were static, dynamic and reactive, and that for young people reactive balance ability was characterized and explained by balance ability, whereas for older people it was static balance ability. PMID- 25792891 TI - Comparison of four physiotherapy regimens in the treatment of long-term mechanical low back pain. AB - OBJECTIVE: This study compared efficacy of combinations of Back Muscles Endurance Exercise (BMEE) and McKenzie Exercise (ME) and McKenzie Back Care Education (MBE) in the management of long term mechanical Low Back Pain (LBP). SUBJECTS AND METHODS: A single-blind randomized controlled comparative trial was employed. Seventy three participants mean age 45.3 +/- 8.1 years were recruited for the study but only 53 completed the study. Participants in group A were treated with a combination of BMEE, ME and MBE. Group B: A combination BMEE and MBE. Group C: A combination of ME and MBE. Group D: MBE only. Participants were seen thrice weekly for 8 weeks. They were measured for pain intensity, lumbar flexibility, activities limitation and self esteem. Data were analysed using descriptive and inferential statistics of F-test. Significance was set at 0.05 alpha-level. RESULTS: At the end of the study, the four treatment groups had significant reduction in pain intensity p<0.05. Post hoc analysis showed groups A, B, and C had significantly greater reduction than D, and groups A and C had significantly greater reduction than B. Groups A, B and C also had significant improvement in activities limitation p<0.05. Post hoc analysis showed groups A, B and C had significantly greater improvement than D, and group B significantly greater improvement than C. CONCLUSION: Combination physiotherapy regimens proved effective in the management of long- term mechanical LBP. Regimen A is recommended in managing long-term mechanical LBP. PMID- 25792892 TI - Factors Related to Continuation of Health Behaviours among Stroke Survivors. AB - PURPOSE: This study investigated stroke survivors' perspectives of health behaviours after stroke. We aimed to explore the actual process by which stroke survivors changed their health behaviours. METHOD: Semi-structured interviews were conducted with 40 people in a 1-year prospective study in the regional city of Chiba, Japan. Interviews covered views of health behaviours in order to explore why patients change their risk factors. Data were analysed using the principles of modified grounded theory. RESULTS: Six categories related to practising health behaviours were identified: cause of stroke, antithetic thinking, awareness of the body, fear of disease progression, view of health, and psychological meaning of practise. Stroke survivors constructed a meaning of practise for each health behaviour. The recognition of previous lifestyle as cause of stroke, hope for recovery, and fear of future progression influenced health behaviours. CONCLUSIONS: The key finding of this study is that when cognitive behavioural therapy principles are enforced, an important aspect is that stroke survivors recognize the possibility that previous lifestyle was a cause of stroke and appreciate the necessity of preventing a new stroke. PMID- 25792893 TI - Regional chest wall volume changes during various breathing maneuvers in normal men. AB - PURPOSE: The purpose of this study is to investigate the regional chest wall volume changes during various breathing maneuvers in normal men with an optical reflectance system (OR), which tracks reflective markers in three dimensions. METHODS: Chest wall volume was measured by the OR system [VL(CW)], and lung volume was measured by hot wire spirometry [VL(SP)] in 15 healthy men during quiet breathing (QB), during breathing at a rate of 50 tidal breaths/min paced using a metronome (MT: metronome-paced tachypnea), and during a maximal forced inspiratory and expiratory maneuver (MFIE maneuver). RESULTS: There were few discrepancies between VL(CW) and VL(SP) for QB and MT. In the MFIE maneuver, however VL(CW) was often underestimated compared with VL(SP), particularly during forced maximal expiration, because of pulmonary rib cage volume changes. Furthermore, the regional chest wall volume changes were affected by breathing maneuver alternation. In the pulmonary and abdominal rib cage, inspiratory reserve volume was larger than expiratory reserve volume, respectively, and in the abdomen, expiratory reserve volume was larger than inspiratory reserve volume. CONCLUSION: Alternation of breathing maneuvers affects regional chest wall volume changes. PMID- 25792894 TI - Isokinetic trunk and knee muscle strengths and gait performance in walking patients with T-cell lymphotropic virus type 1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). AB - The aim of this study was to investigate the isokinetic trunk and knee muscle strengths, and examine the clinical relevance of dynamic muscle strengths and gait performance in walking patients with human T-cell lymphotropic virus type 1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). Thirteen patients with HAM/TSP (8 females and 5 males, aged 38-76) and 13 sex- and age-matched healthy control subjects participated in the study. We assessed gait speed, stride length, cadence; and maximal isokinetic torque of trunk and knee extensors and flexors at 30 degrees /s, 60 degrees /s and 90 degrees /s using a Biodex System 3 dynamometer. Furthermore, we calculated the isokinetic trunk extensor/flexor (E/F) and hamstrings/quadriceps (H/Q) strength ratios (parameter of the muscle strength balance about the trunk and knee joint). Compared with the age-matched controls, the patients with HAM/TSP had significantly reduced gait speed, stride length and cadence (P < 0.05). Peak torque values related to body weight (PTBW) were significantly reduced, especially for the knee flexors (P < 0.05). For the knee extensors, the PTBW values were significantly reduced at an increased angular velocity (P < 0.05). The PTBW of knee flexors was positively correlated with gait speed and cadence in the patients with HAM/TSP. The H/Q ratio but not E/F ratio was significantly decreased compared with the control. Our results indicated that the isokinetic trunk and knee muscle performance had reduced from the ambulatory stage, and suggested the deterioration in knee muscle performance to be associated with gait disturbance in walking HAM/TSP patients. PMID- 25792895 TI - The Effect of Reloading on Disuse Muscle Atrophy: Time Course of Hypertrophy and Regeneration Focusing on the Myofiber Cross-sectional Area and Myonuclear Change. AB - The purpose of this study was to investigate the effect of reloading on atrophied muscle and the time course of hypertrophy and regeneration. Forty-nine male Wistar rats were randomly assigned to groups for hindlimb suspension (HS), hindlimb suspension and reloading (R), or control (C0). Rats in the HS group were suspended for 14 days. Rats in the R group were randomly divided into five subgroups for different post-hindlimb-suspension recovery times. Briefly, each subgroup was suspended for 14 days and given 1 day of reloading (R1), 3 days of reloading (R3), 7 days of reloading (R7), 10 days of reloading (R10), or 14 days of reloading (R14). Myonuclear numbers were significantly decreased in the groups with hindlimb suspension and 1 day and 3 days of reloading compared with that in the control group. We focused on the processes of change of mean myofiber cross sectional area and myonuclear domain size; the degrees of increase of both indexes were limited until 3 days of reloading, and significantly increased after 7 days of reloading. An important finding of the current study was that the processes of muscle hypertrophy and regeneration did not show uniform change. In addition, there were differences in the ratio of increase among the stages of hypertrophy and regeneration. Therefore, consideration of the duration and method of physiotherapeutic intervention for atrophied muscle on the basis of the process of hypertrophy and regeneration is needed to provide more effective physiotherapy. PMID- 25792896 TI - Influence of passive stretching on inhibition of disuse atrophy and hemodynamics of rat soleus muscle. AB - The purpose of this study was to determine the influence of passive stretching on inhibition of disuse atrophy and hemodynamics among longitudinal regions of the rat soleus muscle. Disuse muscle atrophy was induced by hindlimb suspension for two weeks. Muscle blood flow was evaluated using thallium-201 ((201)Tl) which is a radiotracer that has been reported to be useful to assess blood perfusion in skeletal muscle. Thirty-nine male Wistar rats were divided randomly into 5 groups: control (C: n = 10), a group with hindlimb suspension (HS: n = 7), a group with hindlimb suspension and stretching (ST: n = 7), a group receiving only a single session of stretching after the hindlimb suspension period that was killed just after stretching (HSB: n = 7), and a group receiving only a single session of stretching hindlimb suspension and stretching period that was killed just after stretching (STB: n = 8). From the results of the cross-sectional area (CSA) and the capillary-to-fiber ratio (C/F), muscle atrophy and inhibition of atrophy were shown more in proximal than in distal regions of experimental groups. These results suggest that the alterations of the C/F and CSA were different among muscle regions in experimental groups. These differences may depend on the level of stretching. Moreover, alteration of blood flow resulting from alteration of the mechanical environment had little influence on muscle atrophy or inhibition of atrophy. PMID- 25792897 TI - Functional Changes in the Care-needing Elderly after Surface Electrical Stimulation to the Abdomen. AB - BACKGROUND: Strength of the trunk muscles is a key component of motor control, but it declines easily with the process of aging and/or disuse. OBJECTIVES: To investigate the effects of surface electrical stimulation (ES) to the abdominal muscles and the motor performance for care-needing elderly. DESIGN: Controlled trial. PARTICIPANTS: Twenty-one elderly people (60-90 years) with care-needing, who were admitted to a nursing home or hospital for daily care and their score of Barthel Index had been stable from 55.3 +/- 19.4 to 55.3 +/- 19.8 during 3 months before intervention. INTERVENTION: Common physical/occupational therapy was performed for all of the subjects during the study period. ES was applied to the abdomen of 15 subjects (ES group) twice a day for 8 weeks. MEASUREMENTS: Functional measurements were performed before and after beginning of the study with some parameters as follows: grip strength; movement time for sitting up (MSU); maximum walking speed (WS). RESULTS: No significant differences between two groups were noted for characteristics at baseline. In the ES group, MSU (from 21.1 +/- 21.4 to 10.4 +/- 8.3 sec) significantly improved (p < 0.05) after 8weeks. WS (from 17.7 +/- 12.1 to 24.3 +/- 15.3 m/min) were also improved (p < 0.05) after 8 weeks. LIMITATIONS: A limitation of this study was the small sample size. CONCLUSIONS: ES to the abdominal area has the potential to improve motor function in the care-needing elderly through reinforcement of the abdominal muscles. PMID- 25792898 TI - Mirror observation of finger action enhances activity in anterior intraparietal sulcus: a functional magnetic resonance imaging study. AB - Mirror therapy can be used to promote recovery from paralysis in patients with post-stroke hemiplegia, There are a lot of reports that mirror-image observation of the unilateral moving hand enhanced the excitability of the primary motor area (M1) ipsilateral to the moving hand in healthy subjects. but the neural mechanisms underlying its therapeutic effects are currently unclear. To investigate this issue, we used functional magnetic resonance imaging to measure activity in brain regions related to visual information processing during mirror image movement observation. Thirteen healthy subjects performed a finger-thumb opposition task with the left and right hands separately, with or without access to mirror observation. In the mirror condition, one hand was reflected in a mirror placed above the abdomen in the MRI scanner. In the masked mirror condition, subjects performed the same task but with the mirror obscured. In both conditions, the other hand was held at rest behind the mirror. A between-task comparison (mirror versus masked mirror) revealed significant activation in the ipsilateral hemisphere in the anterior intraparietal sulcus (aIP) while performing all tasks, regardless of which hand was used. The right aIP was significantly activated while moving the right hand. In contrast, in the left aIP, a small number of voxels showed a tendency toward activation during both left and right hand movement. The enhancement of ipsilateral aIP activity by the mirror image observation of finger action suggests that bimodal aIP neurons can be activated by visual information. We propose that activation in the M1 ipsilateral to the moving hand can be induced by information passing through the ventral premotor area from the aIP. PMID- 25792900 TI - Changes in hip and knee muscle strength in patients following total hip arthroplasty. AB - OBJECTIVE: To investigate changes in hip and knee muscle strength in patients before and after total hip arthroplasty (THA) in comparison with that in healthy adults. METHODS: The study included 21 women who underwent unilateral THA (THA group) and 21 age-matched healthy women (healthy group). Maximal isometric strengths of hip flexors, extensors, and abductors, and knee extensors and flexors were measured before surgery and at 4 weeks and 6 months after surgery. RESULTS: Before surgery, muscle strength on both sides, except for hip flexors on the uninvolved side, was significantly lower in the THA group than the corresponding muscle strength in the healthy group. Up to 6 months after THA, strength of all muscle groups on both sides was significantly improved compared with their preoperative status, although the knee extensor strength on the involved side temporarily worsened at 4 weeks. However, the strength of hip extensors and knee extensors on the involved side, and hip abductors on both sides in the THA group remained below that in the healthy group. CONCLUSIONS: Our results suggest that rehabilitation specialists should consider increasing the focus on the uninvolved side and encourage patients to continue strength training beyond 6 months after surgery. PMID- 25792899 TI - Evidence of Improvement in Various Impairments by Exercise Interventions in Patients with Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Clinical Trials. AB - PURPOSE: To investigate improvement in various impairments by exercise interventions in patients with knee osteoarthritis (OA). METHODS: We collected data on randomized controlled trials (RCTs) comparing the effects of exercise intervention with those of either nonintervention or psychoeducational intervention in patients with knee OA. Data on pain, stiffness, muscle strength, range of motion, flexibility, maximal oxygen uptake, and position sense were synthesized. The Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the quality of the evidence. RESULTS: Thirty-three RCTs involving 3,192 participants were identified. Meta-analysis provided highquality evidence that exercise intervention improves maximal oxygen uptake, and moderate-quality evidence that exercise intervention also improves pain, stiffness, knee extensor and flexor muscle strength, and position sense. The evidence that exercise intervention improves knee extension and flexion range of motion was deemed as undetermined-quality. CONCLUSION: In patients with knee OA, improvement in pain, stiffness, muscle strength, maximal oxygen uptake, and position sense with the use of exercise intervention can be expected. Although the quality of evidence of the effect of exercise intervention on range of motion was inconclusive, exercise intervention should be recommended for patients with knee OA to improve various impairments. PMID- 25792901 TI - Effect of Body Weight-supported Walking on Exercise Capacity and Walking Speed in Patients with Knee Osteoarthritis: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the effect of body-weight-supported treadmill training (BWSTT) and full-body-weight treadmill training (FBWTT) on patients with knee osteoarthritis (OA). METHODS: Design was Randomized controlled trial. Patients with knee osteoarthritis (n = 30; mean age, 76.0+/-7.5 y) were randomly assigned to BWSTT or FBWTT group. All patients performed 20 min walking exercise twice a week for 6 weeks under the supervision of the therapist. Main measures were 10 meter walking test (10MWT), functional reach test (FRT), timed get up and go test (TUG), one-leg standing test, 6-minute walking test (6MWT), the parameters set on the treadmill, MOS Short-Form 36-Item Health Survey (SF36), Japanese Knee Osteoarthritis Measure (JKOM). RESULTS: Twenty-five patients (10 men, 15 women; mean age, 76.5 +/- 8.0 y) completed the experiment. Exercise capacity, indicated by the heart rate, was similar in both groups. After 3 weeks of BWSTT, the patients performed significantly better in the 10-m and 6-min walking tests. This was not the case with FBWTT even after 6 weeks training. Pain levels assessed were significantly improved after 3 weeks of BWSTT and 6 weeks of FBWTT. There were no significant improvements in either group assessed by the FRT, one-leg standing time test, TUG, or SF -36 questionnaire. CONCLUSIONS: BWSTT enhanced exercise capacity in terms of walking speed and pain reduction after 3 weeks; however, there was no significant improvement in patients' functional abilities or quality of life. PMID- 25792902 TI - Effects of therapeutic ultrasound on intramuscular blood circulation and oxygen dynamics. AB - PURPOSE: This study aimed to clarify the effects of therapeutic ultrasound on intramuscular local blood circulation (and oxygen dynamics) using near-infrared spectroscopy (NIRS). PARTICIPANTS: The participants were 11 healthy males. METHODS: All participants performed all three trials; (1) the ultrasound (US group), (2) without powered ultrasound (placebo group), and (3) rest (control group). Ultrasound was applied at 3 MHz, 1.0 W/cm(2), and 100% duty cycle for 10 minutes. Evaluation index were oxygenated, deoxygenated, and total hemoglobin (Hb) concentrations in the intramuscular and skin surface temperature (SST). The experimental protocol was a total of 40 minutes, that is, 10 minutes before trial (rest), 10 minutes during the trial (ultrasound, placebo, and control), and 20 minutes after trial (rest). The NIRS and SST data collected before and after the trial were divided into 5 minutes intervals for further analysis. RESULTS: Oxygenated and total hemoglobin levels were significantly higher in the US group than in the placebo and control groups for the 20 minutes after ultrasound (p < 0.01). The SST was significantly higher in the US group than in the control for 15 minutes after ultrasound (p < 0.05), while it was significantly lower in the placebo group than in the US and control groups for 20 minutes after the trials (p < 0.01). CONCLUSION: The effects of ultrasound were maintained for 20 minutes after the trial on intramuscular blood circulation and oxygen dynamics. These effects were caused by a combination of thermal and mechanical effects of the ultrasound. PMID- 25792903 TI - Interference of Different Types of Mastication on Static Balance in Individuals without Temporomandibular Disorder. AB - PURPOSE: This study was to determine whether non-habitual (isotonic) bilateral and unilateral mastication with eyes open and eyes closed exerts an influence on static balance in individuals without temporomandibular disorder (TMD). METHOD: An observational, cross-sectional study was conducted involving 20 volunteers aged 20 to 40 years without temporomandibular disorder. Static balance was assessed with the individuals in a quiet standing position on a force plate performing different types of mastication under six separate conditions. RESULTS: Significant differences (p < .05) were found in the area of oscillation during bilateral mastication (eyes open) and the right unilateral mastication, significant differences were only found for oscillation area with eyes open and mediolateral center of pressure with eyes closed (p < .05). CONCLUSIONS: The findings of the present study reveal that the stomatognathic system (bilateral and unilateral mastication) promote changes in some variables of static balance. PMID- 25792904 TI - Effects of the thermal environment on articular chondrocyte metabolism: a fundamental study to facilitate establishment of an effective thermotherapy for osteoarthritis. AB - AIM: To facilitate establishment of an effective thermotherapy for osteoarthritis (OA), we investigated the effects of the thermal environment on articular chondrocyte metabolism in vitro. METHODS: Chondrocytes were isolated from porcine knee joints, and cultured at 32 degrees C, 37 degrees C and 41 degrees C. Cell proliferation and viability were assessed at Days 2, 4 and 8. In addition, TdT mediated dUTP nick end labeling (TUNEL) assay was performed at Day 3 to determine the proportion of apoptotic chondrocytes. Analysis of genes specific for factors related to the cartilage extracellular matrix (ECM), cartilage destruction, and cartilage protection was performed at Day 2. Furthermore, evaluation of heat stress tolerance, and heat shock protein 70 (HSP70) mRNA expression and protein synthesis was performed at Day 2 and 3, respectively. RESULTS: Cell proliferation was more at 37 degrees C than at 32 degrees C and 41 degrees C. Cell viability and the number of TUNEL-positive cells were not affected until Day 8 and 3, respectively. The expression of the ECM-related genes was up-regulated at higher temperature. The expression of MMP13, a type II collagen destructive enzyme, and that of TIMP1 and TIMP2, which are MMP inhibitors, were up-regulated at higher temperatures. Finally, the chondrocytes cultured at 41 degrees C may acquire heat stress tolerance, in part, due to the up-regulation of HSP70, and may inhibit apoptosis induced by various stresses, which is observed in OA. CONCLUSIONS: The thermal environment affects articular chondrocyte metabolism, and a heat stimulus of approximately 41 degrees C could enhance chondrocyte anabolism and induce heat stress tolerance. PMID- 25792906 TI - Effectiveness of Physical Therapy in Patients with Tension-type Headache: Literature Review. AB - BACKGROUND: Tension-type headache (TTH) is a disease with a great incidence on quality of life and with a significant socioeconomic impact. OBJECTIVES: The aim of this review is to determine the effectiveness of physical therapy by using manual therapy (MT) for the relief of TTH. DATA SOURCES: A review was done identifying randomized controlled trials through searches in MEDLINE, PEDro, Cochrane and CINAHL (January 2002 - April 2012). STUDY SELECTION: English language studies, with adult patients and number of subjects not under 11, diagnosed with episodic tension-type headache (ETTH) and chronic tension-type headache (CTTH) were included. DATA EXTRACTION: Initial search was undertaken with the words Effectiveness, Tension-type headache, and Manual therapy (39 studies). In addition, a search which included terms related to treatments such as physiotherapy, physical therapy, spinal manipulation was performed (25 studies). RESULTS: From the two searches 9 studies met the inclusion criteria and were analysed finding statistically significant results: 1) myofascial release, cervical traction, neck muscles trigger points in cervical thoracic muscles and stretching; 2) Superficial heat and massage, connective tissue manipulation and vertebral Cyriax mobilization; 3) cervical or thoracic spinal manipulation and cervical chin-occipital manual traction; 4) massage, progressive relaxation and gentle stretching, program of active exercises of shoulder, neck and pericranial muscles; 5) massage, passive rhythmic mobilization techniques, cervical, thoracic and lumbopelvic postural correction and cranio-cervical exercises; 6) progressive muscular relaxation combined with joint mobilization, functional, muscle energy, and strain/counterstrain techniques, and cranial osteopathic treatment; 7) massage focused on relieving myofascial trigger point activity; 8) pressure release and muscle energy in suboccipital muscles; 9) combination of mobilizations of the cervical and thoracic spine, exercises and postural correction. All studies used a combination of different techniques and none analyzed treatments separately, also all the studies have assessed aspects related to TTH beyond frequency and intensity of pain. CONCLUSIONS: The findings from these studies showed evidence that physiotherapy with articulatory MT, combined with cervical muscle stretching and massage are effective for this disease in different aspects related with TTH. No evidence was found of the effectiveness of the techniques applied separately. PMID- 25792905 TI - Differences in Cartilage Repair between Loading and Unloading Environments in the Rat Knee. AB - We investigated the histopathological and immunohistochemical effects of loading on cartilage repair in rat full-thickness articular cartilage defects. A total of 40 male 9-week-old Wistar rats were studied. Full-thickness articular cartilage defects were created over the capsule at the loading portion in the medial condyle of the femur. Twenty rats were randomly allocated into each of the 2 groups: a loading group and a unloading group. Twenty rats from these 2 groups were later randomly allocated to each of the 2 groups for evaluation at 1 and 2 weeks after surgery. At the end of each period, knee joints were examined histopathologically and immunohistochemically. In both groups at 1 and 2 weeks, the defects were filled with a mixture of granulation tissue and some remnants of hyaline cartilage. The repair tissue was not stained with toluidine blue in both groups. Strong staining of type I collagen was observed in the repair tissue of both groups. The area stained with type I collagen was smaller in the unloading group than in the loading groups, and the stained area was smaller at 2 weeks than at 1 week. In the staining for type II collagen, apparent staining of type II collagen was observed in the repair tissue of both groups at 1 week. At 2 weeks, there was a tendency toward a higher degree of apparent staining in the loading group than in the unloading group. Accordingly, these results indicated that loading and unloading in the early phase of cartilage repair have both merits and demerits. PMID- 25792907 TI - Fair as a percentage of normal using manual muscle testing of knee extensor strength. AB - We explored the extent to which fair knee extensors might be judged to be weaker than the normal knee extensors of healthy young adults. To obtain quantitative data for normal strength of knee extensors, we recorded knee torque in 20 healthy young subjects using an isokinetic dynamometer, and calculated muscle strength equivalent to fair, including the effect of inertial force, using a rigid body model. The results showed that fair torque as a percentage of actual normal torque at 60 degrees per second was 4.8 +/- 1.2% (mean +/- standard deviation) among the men and 4.6 +/- 1.0% among the women. This difference in per cent strength was not statistically significant between men and women. In manual muscle testing, the grade of fair for knee extensors is thus very far below the midpoint of the scale from no activity to normal. This means that the good range between grade fair and normal is too wide to connote one particular state of strength. We believe that other methods are needed, for example using a dynamometer, to evaluate intermediate muscle weakness in detail. PMID- 25792909 TI - Correlation Between Working Capacity and APDL in Middle-Aged and Elderly People with Intellectual Impairment. AB - In this study we investigated the correlation between working capacity and APDL of middle-aged and elderly residents of welfare homes for the intellectually retarded. The subjects were 313 intellectually retarded people over 35 years old. The subjects were chosen from residents of four welfare institutions and job placement centers for intellectually retarded people in Otaru, Hokkaido. Personal attributes, working capacity, and APDL were investigated in each subject. The items of personal attributes were: gender, chronological age, severity of intellectual impairment, and presence/absence of Down's syndrome. Working capacity was evaluated according to the 6 items. APDL was evaluated according to the 51 items. For statistical analysis of the working capacity of the subjects, the variables were summarized using principal component analysis and scored. Next, a search was made for the common factors in the 51 items of APDL using the principal component method. Finally, the correlation between working capacity and APDL was investigated by multiple regression analysis, with the obtained composite scores as dependent variables and the scores of APDL factors extracted by principal component analysis as independent variables. The following three factors were selected for the subjects: health management, outdoor movement and social activity. The multiple correlation coefficient using these three factors was R=0.63 (F=55.20, p<0.01). This indicates the necessity, from the viewpoints of prevention of senility, to focus not only on the decrease in working capacity of aging residents with intellectual impairment in welfare institutions but to establish various countermeasures based on the interrelationship between working capacity and APDL. PMID- 25792908 TI - Assessment of anteroposterior instability of the knee during gait. AB - A noninvasive kinematic recording technique involving geometric modeling of the knee joint was employed to determine anteroposterior displacements of the knee during walking. The model estimated how much the femoral condyles slid and rolled on the tibial plateau. Movement not due to sliding or rolling was attributed to horizontal translation of the tibia with respect to the femur. Thirty normal adults participated in this study. A three-dimensional analysis system with noninvasive skin markers was employed to collect kinematic data of the femur and tibia during walking. Within-session and between-session reliabilities were high in the tested subjects. Normal subjects had an average of 5.5 mm of maximum anterior displacement of the tibia during stance phase of walking. These results differed neither between left and right knees, nor between men and women. Dynamic instability of the knee during walking can be reasonably measured by the proposed method in normal subjects. PMID- 25792910 TI - Effect of immobilization on solubility of soleus and gastrocnemius muscle collagen: -biochemical studies on collagen from soleus and gastrocnemius muscles of rat. AB - We have been studying mainly the changes in collagen fiber solubility with respect to its influence on immobilization of the soleus muscle and Achilles tendon of rats. We decided to investigate also the change of the collagen fiber solubility in the gastrocnemius muscle which, like the soleus muscle, is assumed to influence the range of motion of the ankle joints. The purpose of this study, therefore, was to investigate the effects of a 7-week immobilization on the solubility of the gastrocnemius muscle and soleus muscle collagen fiber of rats. The results were that in a 7-week immobilization period, hydroxyproline concentration in tissue was increased and salt and pepsin soluble collagen was decreased in both the soleus and the gastrocnemius muscles. The results suggest an increase in the collagen concentration in tissue and an increase in the intermolecular cross-link with a stronger molecular structure. As far as the amount of collagen and solubility were concerned, the immobilization had a similar influence on the collagen fiber in both muscles. PMID- 25792911 TI - Cardiopulmonary responses at various angles of cycle backrest inclination. AB - The purpose of this study was to evaluate cardiopulmonary responses during submaximal cycle exercise at various angles of backrest inclination. Ten healthy Japanese men of mean age 25.9 yrs, height 170.6 cm, and body mass 66.1 kg, performed cycle exercises at a constant workload which reached the anaerobic threshold, at 20 degrees, 40 degrees, and 60 degrees of backrest inclination from the vertical plane, but the angle between the seat and back rest was kept at 110 degrees. The results were as follows: 1) Both cardiac output and stroke volume showed a higher value at the resting control state and during exercise as the backrest angle increased. 2) Oxygen consumption, carbon dioxide output, heart rate, gas exchange ratio, and oxygen pulse were not affected by the angle of backrest inclination. 3) Tidal volume at 20 degrees of backrest inclination was higher than at 60 degrees. 4) No significant differences were found in minute ventilation between each backrest angle. These findings suggest that changes in the backrest angle significantly alter cardiopulmonary parameters at rest and during exercise; in particular, an angle difference of 40 degrees may be enough to alter tidal volume, cardiac output and stroke volume, but not the minute ventilation. PMID- 25792912 TI - Difference in Effect of Muscle Weakness versus Obesity on Stability of Knee Joint. AB - This research examines a question about which is worse to the knee joint: increasing body weight or decreasing muscle force. We simulated unilateral weight bearing and analyzed the extent to which each had a deleterious effect on the knee joint. We used a rigid body model in which body weight was increased and quadriceps muscle force decreased. Also, to account for differences between men and women, the model reflected difference in pelvic width. In this simulation, decreasing muscle strength by 30% of its initial normal value had a stronger unfavorable effect than that of increasing body weight to the same relative degree. The effect of differences in body proportion between men and women did not appreciably influence the results, as long as masses and linear dimensions were average values of the respective sexes. Our results suggest that a patient with osteoarthritis in the knee should pay particular attention to problems of muscle weakness. PMID- 25792913 TI - Analysis of Compression Force in the Hip Joint during Impulsive Exercises: A Preliminary Study for Developing Exercise Protocol for Osteoporosis. AB - Past intervention studies on bone remodeling for preventing osteoporosis in elderly women often lack sufficient description of the intensity of the exercise, though bone remodeling is dependent on applied force at specific sites. The effectiveness of exercise in increasing bone density cannot be defined without sufficient description of the intensity and targeted site of the exercise. We conducted kinetic and kinematic analyses of the lower extremities in order to categorize exercise in terms of compression force applied at the proximal end of the femur, to formulate guidelines for prescribing exercise to elderly women. Thirty healthy women aged 18-24 participated in the study. Joint compression force at the proximal end of the femur was measured with the aid of motion analysis devices under several conditions of impulsive loading. Joint compression force at the proximal end of the femur was estimated for twenty-two exercise regimes varying from low to high-impact exercises, including jumping off, stepping down, vertical jumping, and dropping down after heel raises. Some exercises appear to be inappropriate for exercise intervention, because the variability for these exercises is high. Most of the jumping exercises, with coefficients exceeding 0.36, were excluded from further analysis. Of the remaining exercises, four were categorized as statistically different loads, as determined by a posthoc test of one-way analysis of variance of joint compression force. These included jumping off a 10 cm platform, stepping down from a 20 cm platform with the knees in the extended position, stepping down from a 20 cm platform with the knees in a relaxed position, and heel dropping at 80 cycles per minute with the knees in a relaxed position. The joint compression forces during these exercises were 2.32 +/- .81, 1.81 +/- .59, 1.45 +/- .59, and 1.00 +/- .27 times as much as the subject's body weight, respectively. PMID- 25792914 TI - The effect of low calcium diet on bone in ovariectomized mice. AB - This study investigates the effects of Ca on bone in the ovariectomized mice. Twenty-six female ICR mice aged 5 weeks were used. They were ovariectomized (OVX) or sham-operated (SHAM) and fed standard mouse diet (SF) or special low calcium diet (L.Ca), respectively. All animals were sacrificed at day 100 after operation. Mechanical strength of the left femur and tibia was measured by the three-point bending strength test. The bones were dried, weighed and burned to ash. Correlation between mechanical strength and ash content was found. A specimen of the right tibia was prepared. Mechanical strength, ash content and ratio of dry bone weight to body weight of the femur and tibia in OVX and L.Ca mice were significantly less than in SHAM and SF mice. SHAM/SF mice and OVX/L.Ca group showed highest and lowest values in all cases. The values for the femur and tibia in OVX/SF mice were lower than in SHAM/SF group and in OVX/L.Ca group were less than in OVX/SF mice. Correlation coefficients for mechanical strength and ash content were 0.704 and 0.776 for the femur and tibia. Ca is thus related to inhibition of bone loss and maintenance of bone mass and effective prevention of osteoporosis. PMID- 25792915 TI - Effects of Changes of Foot Position on Romberg's Quotient of Postural Sway and Leg Muscles Electromyographic Activities in Standing. AB - Changing of standing position and visual blocking methods have been used as a convenient evaluation of standing balance by physical therapists. The purpose of this study was to investigate the effects of changes of foot positions on Romberg's quotient of postural sway and the tibialis anterior and gastrocnemius muscles activities in standing for normal men. Subjects were 45 college students. For the measurement of muscles activities, 15 subjects were selected at random from among the 45 students. The standing positions were standing with legs 10 cm apart, standing with legs together, tandem standing, standing on tiptoes, and standing on one leg with the eyes open and closed. Measurements were made using a center of foot pressure recorder and surface electromyography for 30 seconds. Romberg's quotient and the relative muscle activities of the leg were both found to be in the order standing with legs apart, standing with legs together, tandem standing, standing on tiptoes, standing on one leg. It has conventionally been considered that the instability of postural sway is increased when vision is blocked. The present results suggested that postural regulation by the physiological subsystem is indirectly affected by vision and somatosensory input. PMID- 25792916 TI - Modification of postural response caused by footwear conditions. AB - The purpose of this study was to clarify the effect of changing footwear conditions on postural response against postural perturbation. Twenty-three healthy subjects participated in this study. Postural response was induced by moving a platform forward, hereafter referred to as forward-perturbation of a platform. The center of pressure (COP) from the force plate and the electromyograms (EMG) of the tibialis anterior (TA) and quadriceps femoris (QUAD), which are both agonists of the response, were measured. The effect of plantar material and shape of footwear on postural response was examined as footwear condition. Changing plantar materials had an effect on integrated EMG of the agonists (IEMG) but not on the response pattern. On the other hand, the shape of footwear had an effect on the response pattern but not on IEMG. It was supposed from this result that changes in somatosensory input, caused by coupling of plantar material and shape of footwear, modifies postural response variously. PMID- 25792917 TI - The Effects of Stride Walking on Cardiovascular and Electromyographic Responses under Different Conditions in Velocity or Grade in Healthy Young Women. AB - This study was conducted to investigate the effects of stride walking on cardiovascular and electromyographical responses on a treadmill in healthy young female (mean age of 23.0 yrs, height of 156.2 cm and weight of 50.6 kg). The subjects performed initial 6 minutes walking based on a heart rate of anaerobic threshold minus 10 beats per minute under two conditions of treadmill walking, on increased velocity with horizontal inclination (A) and on a constant velocity (2.0 mph) with increased grade (B). Consequently, the subjects performed stride walking which was made by 10% reduction of steps under each condition. The results were as follows: 1) Under A condition, the values of leg fatigue by Borg's 20 numeric scale in stride walking was significantly higher than in non stride walking, while no difference under B condition. 2) Under A condition, the mean values in oxygen uptake and heart rate during stride walking were significantly higher than during non-stride walking, while no difference under B condition. 3) Under A condition, total amount of integrated electromyogram in gastrocnemius, vastus medialis and tibialis anterior were higher during stride walking than during non-stride walking. Under B condition, gastrocnemius and gluteus maximus showed higher values during stride walking than in non-stride walking. These findings suggest that stride walking manipulated on a high velocity tends to alter cardiovascular and electromyographical parameters than on a lower velocity with higher inclination on treadmill walking in healthy young adults. PMID- 25792918 TI - Effects of short duration stretching on disuse muscle atrophy in immobilized rat soleus muscles. AB - The purpose of this study was to determine whether short duration stretching is ameliorating for disuse muscle atrophy in immobilized rat soleus muscles. Eighteen male Wistar rats (age, 8 weeks; weight, 311.0 +/- 35.6 g) were divided randomly into control (n=3) and experimental (n=15) groups. Bilateral ankles of each rat in the experimental group were fixed in full planter flexion with a plaster cast. After the experimental groups rats were immobilized for 4 weeks, animals were divided into three groups: immobilization alone (group I, n=3), stretch training for 30 min/day for 1 or 3 weeks after remobilization (group S, n=6), and spontaneous recovery (non stretch training) for 1 or 3 weeks after remobilization (group NS, n=6). At the end of the experimental periods, the soleus muscle was extracted from hindlimb, and the frozen sections were stained with myofibrillar adenosine triphosphatase. After 1 week of remobilization, the means of the muscle fiber diameters for type I fibers in group S had increased significantly compared with group NS, but those for type II fibers in group S did not significantly differ from that for group NS. After 3 weeks of remobilization, the means of the muscle fiber diameters for types I and II fibers in group S had increased significantly compared with group NS. No difference in the fiber type distribution were observed between the experimental group. Our findings suggest that short duration stretching induces recovery from disuse muscle atrophy after joint fixation. PMID- 25792919 TI - Relationship between Respiratory Movements and Energy Efficiency in the Post Exercise Recovery Phase. AB - The breathing movement is highly automated but it can be voluntarily controlled in some situations. Compared with period of exercise and post-exercise, subjects could control breathing more voluntarily in the post-exercise recovery phase. So, we analyzed relationship between the strategy for controlling the breathing movement pattern and energy efficiency in this phase. Fifteen healthy men (mean age, 22.1 years) were subjected to exercise with a bicycle ergometer at 100 W for 5 minutes, then respiratory pattern was measured four times for 5 minutes after exercise. The measurement items were 1) chest expansion, 2) abdomen expansion, 3) tidal volume, 4) respiration rate, 5) minute ventilation, 6) oxygen intake, and 7) heart rate. The items 1) and 2) were measured by a three-dimensional motion analysis system, and the items 3) through 7) were measured by a respiratory gas analyzer. As for the breathing movement pattern, there were differences among the subjects in terms of the rates of increase in chest expansion and in respiration rate after exercise. The subjects were classified into 4 groups according to these differences. The group, in which respiration rate was increased, showed the marked increase in minute ventilation and oxygen intake, and the rapid recovery of heart rate. The group, in which chest expansion rate was increased, on the other hand, showed small increase in minute ventilation and oxygen intake, and the slow recovery of heart rate. The breathing strategies which are beneficial to energy efficiency exist, however, healthy men do not always select the beneficial strategies. PMID- 25792920 TI - Influence of the time when weight bearing is started on disuse atrophy in rat soleus muscle. AB - Prevention of disuse muscle atrophy is an important problem in physical therapy. Although several reports have been published concerning the effect of weight bearing on the prevention of disuse atrophy of lower extremity muscles, few basic clinical data are available. The present study was undertaken to examine differences in the progression of disuse muscle atrophy in terms of the time when weight bearing is started. The experimental materials consisted of the soleus muscles of 30 male Wistar rats (weight: 220 +/- 6 g). The rats were divided into the control group (CON) and the experimental group, and disuse muscle atrophy caused by non-weight bearing was induced by hindlimb suspension for two weeks in the latter group. The experimental group was subdivided into four groups: no weight bearing permitted (SUS), and daily weight bearing permitted from 1, 4 and 7 days after the start of suspension (1-D, 4-D and 7-D). The relative weight of the soleus muscles did not differ for CON and 1-D or for 7-D and SUS. The mean cross-sectional area of type I fibers was 68% of that of CON for 1-D, 61% for 4 D, 52% for 7-D and 52% for SUS. This parameter showed significant differences any two groups, except for between 7-D and SUS. The results were regarded as normal in view of differences in the total time of weight bearing. The data also suggested that disuse muscle atrophy can be prevented quantitatively if weight bearing is initiated from the day following the start of suspension, and that early start of weight bearing is more effective for controlling atrophy progression. PMID- 25792921 TI - Time course of influence by ovariectomy and calcium diet on bone properties in mice. AB - This study was investigated the influence by ovariectomy (OVX) and calcium diet on bone properties in eighty-one female ICR strain mice with age of 5 weeks. The animals were randomly assigned to sham operation (SHAM), OVX, SHAM+low Ca intake (L.Ca) and OVX+L.Ca group. They were euthanized with lethal dose of pentobarbital sodium at day 50, 100 and 140 post-operatively. For determining the bone properties, both femur and tibial bones were excised from the hind limb, and removed off surrounding tissues. Thereafter, bone length, bone dry weight, and also mechanical strength and ash content of the bones were determined. The bone length on both femur and tibia was significantly longer in OVX group than in the other groups after 50 day of experiment, this situation was continued to the end of the experiment. Bone dry weight, mechanical strength, and ash content were significantly decreased by OVX and L.Ca over the time of the experiment, and those of OVX+L.Ca group were the lowest in all groups. OVX and L.Ca have a great potential for weakening the mechanical strength and have an additive effect when combined. OVX and L.Ca block the gain of bone mass. PMID- 25792922 TI - Effects of treadmill exercise on muscle fibers in mice with steroid myopathy. AB - We studied the effect of treadmill exercise on muscle fibers in mice with experimental steroid myopathy. Frozen sections of the extensor digitorum longus (EDL) and soleus (SOL) muscles were stained with hematoxylin-eosin, and the muscle fiber diameters measured. In the EDL, muscle fiber diameters in the steroid groups decreased significantly compared with those in the control groups; moreover, muscle fiber diameters in the exercise groups increased significantly compared with those in the non-exercise groups, whereas the diameters in the SOL did not differ. We speculate that treadmill exercise may prevent corticosteroid induced muscle fiber atrophy. PMID- 25792924 TI - Effects of ultrasound therapy on calcificated tendinitis of the shoulder. AB - In general, surgery is recommended for calcificated tendinitis of the shoulder if the patients have symptoms after conservative treatments, including needle aspiration and physical therapy. Many researchers agree about the need for adequate physical therapy consisting of range of motion exercise, muscle strengthening exercises and electrophysical agents. Some researchers report that ultrasound (u/s) promotes angiogenesis and calcium uptake to fibroblasts, but there are few studies about u/s effects on calcificated tendinitis of the shoulder. The purpose of this study was to evaluate the u/s therapy effect on calcification, pain during active movement, and to identify factors related to improvement in a randomized controlled fashion. We used the stratified random allocation method to assign 40 consecutive patients to experimental and control groups, so each group consisted of 20 patients. The experimental group was treated by u/s therapy and therapeutic exercises, and the control group was treated with therapeutic exercises only. All patients in both groups came to our department 3 times per week and u/s therapy was performed 3 times per week until the end of the study. First, we classified the calcifications as type I (clearly circumscribed and with dense appearance on radiography), type II (dense or clearly circumscribed appearance) and type III (translucent or cloudy appearance without clear circumscription) according to the classification of Gartner and Heyer. Radiography was performed every one month, and the main outcome measure was the change from the base-line of the calcification on radiography at the end of the treatment. The three point scale of Gartner and Heyer was used, in which a score of 1 indicates no change or a worsening of the condition, a score of 2 a decrease of at least 50 percent in the area and density of the calcification, and a score of 3 a complete resolution of the calcification. We also examined the affected shoulders for presence or absence of pain in active movement at the start and at the end of the study. The calcifications improved significantly and fewer patients had pain during active movement in the experimental group. There was a statistical significant disease duration difference from the first clinical presentation between scores 2 and 3 in the experimental group. The results of this study suggest that u/s therapy helps to resolve calcifications of shorter disease duration. Calcifications of longer disease duration tended to persist in spite of u/s therapy, but we thought treatment of 27-38 times (95% CI), until score 2 was attained, was a desirable strategy. PMID- 25792923 TI - EEG gamma band is asymmetrically activated by location and shape memory tasks in humans. AB - From the viewpoint of psychology, it is thought that perception analysis of the visual world includes two information processes: global (whole) and local (part) processes. It is assumed that the global process is carried out in the right hemisphere, and the local process, in the left hemisphere. In the present study, gamma EEG band activities during location memory (LM) task, as a global form, and shape memory (SM) task, as a local form, were calculated from the temporal, parietal and occipital areas using stimuli consisting of categorical patterns of small shapes. Gamma band activity during the SM task was greater than that during the LM task. It was assumed that the SM task requires a higher memory load condition than the LM task. In terms of the laterality ratio obtained from the whole electrode array, the gamma band was significantly activated in the right hemisphere during the LM task, and in the left hemisphere during the SM task. The gamma activation in the occipital area was significantly high in the right hemisphere for both tasks. High gamma band activation was observed in the right parietal area during the LM task and in the left temporal area during the SM task. It was concluded that global and local information processes occur in the left temporal areas and in the right occipitoparietal areas, respectively. The results of this study are useful in the assessment of visual cognition deficits in patients with cerebral hemispheric lesions in the physical therapy. PMID- 25792925 TI - The effect of short duration static stretching and reinnervation on the recovery of denervated soleus muscle in the rat. AB - Denervation elicits profound alterations in the morphometry of the skeletal muscle. There is evidence that the increased mechanical load placed upon the muscle via rhythmic stretching attenuates denervation induced alterations in muscle morphology. To investigate the effect of short duration static stretching (40 min/day) for denervated and reinnervated muscle, a histochemical study was performed on the soleus muscle of the rat. Twenty-one eight-week-old female Wistar rats were used. Partial denervation was carried out by locally freezing the proximal root of the sciatic nerve innervating the soleus muscle. Contralateral hindlimbs were untreated and served as control. Axonal degeneration was evident within the sciatic nerve following freezing, although variable amounts of damage were observed and thin nerve fibers were observed at 3 weeks. No clear difference of morphological change of the sciatic nerve was observed in the short duration static stretching groups (group S) or the non-stretching groups (group D). The wet weight of the denervated soleus muscles progressively declined to a minimum at 2 weeks after injury (group D, 50.8 +/- 8.9%; group S, 61.3 +/- 4.2%) and began to reverse in the following 3 weeks. Muscle wet weight for short duration static stretching groups similarly decreased and began to reverse in the following 3 weeks. The muscle fiber cross-sectional area also similarly changed with the muscle wet weight. The type II fiber ratios of the denervated sides were consistently higher than the control levels. In non stretching groups, type II fibers had increased by 3 weeks after denervation (49.4%), whereas type II fiber ratios of the short duration static stretching groups decreased after 3 weeks (31.3%). These data suggests that mechanical stimuli provided by short duration static stretching can prevent the atrophy of the denervated muscle over a short period. In addition, it was indicated that short duration static stretching affected the reinnervated muscle fiber type composition. However, the reinnervation took the crucial role of recovering from the atrophy and composing the integrity of the soleus muscles. PMID- 25792926 TI - Effect of physical therapy on the sense of perceived fatigue in persons with residual type schizophrenia: report of two cases. AB - Some schizophrenics experience difficulty in explaining precisely their physical condition because of their blunted senses of fatigue and malaise. In this case presentation, using Borg's scale, we examined the effect of a physical therapy program on the sense of perceived fatigue in two male outpatient cases with residual schizophrenia over 6 years. Case 1 showed that the HR and the RPE linearly increased as the exercise strength increased after year 2. On the other hand, case 2's changes in RPE were not parallel to linear increases in HR, and consistently expressed a certain range of exercise as "light" and ended with "very, very hard" which continued over 6 years. These results suggested that the long period of continuing repetitive physical therapy in case 1 caused habituation to the exercise and he became aware of physical responses, and these resulted in an improvement of RPE. We suggest that awareness of the degree of a patient's ability of expression through the observation of changes in RPE could provide a useful clue for advancing various therapeutic programs for patients with residual schizophrenia. PMID- 25792927 TI - Influence of hindlimb unweighting and intermittent weight bearing on dynamics of nuclei in rat soleus muscle. AB - The purpose of this study was to examine differences in the inhibitory effect of disuse atrophy as a result of intermittent weight bearing in terms of the dynamics of nuclei in rat soleus muscle. Disuse muscle atrophy was induced by hindlimb suspension for two weeks. Forty-nine male Wistar rats (body weight: 190 228 g) were divided into the control group (CON) and the experimental group. The experimental group was subdivided into four groups: hindlimb suspension alone (HS), weight bearing for 10 minutes * 4 times/day (W10), weight bearing for 20 minutes * 2 times/day (W20), and weight bearing for 40 minutes * one time/day (W40). In addition to histochemical examination, this study examined both cell proliferation and apoptosis in terms of the dynamics of myonuclei immuno histochemically. The mean cross-sectional area of muscle fibers demonstrated the effect of weight bearing. The number of proliferating myonuclei per 100 muscle fibers was decreased in the experimental groups as compared with CON. Proliferating myonuclei in W10 and W40 were more than HS, indicating the effect of weight bearing. Apoptotic myonuclei was increased in the experimental groups as compared with CON. This parameter in W10 and W40 were statistically not significantly different from CON, suggesting that these weight bearing methods can prevent the loss of myonuclei by apoptosis. However, W20 was not significantly different from HS in terms of the dynamics of myonuclei. This suggests that weight bearing for W20 was ineffective. The results in this study indicated the possibility of inducing different effects by the frequency of weight bearing. PMID- 25792928 TI - Test-retest reliability and inter-tester reliability of kinematic data from a three-dimensional gait analysis system. AB - This study aimed to determine the test-retest reliability and inter-tester reliability of kinematic measures in a three-dimensional gait analysis system. Using a VICON 140TM three-dimensional motion analysis system, kinematic data for lower extremities during walking were collected by 2 testers (senior physical therapists) for 6 unimpaired adults (age = 20 to 52; mean = 35.2 +/- 6.2). The study was conducted using a repeated measures design consisting of two testing sessions per day on two separate testing days. The reliability of joint angle data collected by two different testers on two different days was compared for 2 sessions (days) * 2 testers * 5 trials. Skin markers were placed on 15 defined pelvis and lower body locations in accordance with the VICON Clinical Manager model. Prior to the study commencing, the two physical therapists practiced marker placement for a 3 month period. The first measurements (T1) were carried out by two testers on the same day. The second measurement session (T2) was performed within two weeks using an identical procedure. Coefficients of multiple correlation (CMC) were calculated to evaluate the consistency between the kinematic variables across testers and sessions. Both test-retest and inter tester reliability were high for motion in the sagittal plane (R a= 0.971 to 0.994), the frontal plane (R a= 0.759 to 0.977), and the transverse plane (R a= 0.729 to 0.899), excluding pelvic tilt. Reduction of variability of marker placement appears possible with standardization and understanding of the placement method. These findings provide evidence of the reliability of using three-dimensional motion analysis for measuring human gait. PMID- 25792929 TI - Relationship between the oxygen uptake during cardiopulmonary exercise testing and left ventricular function in patients with acute myocardial infarction. AB - The relationship between exercise capacity and left ventricular function has been evaluated in 35 patients with acute myocardial infarction (34 males and 1 female; mean age 55.5 +/- 7.1 years). Single photon emission computed tomography (SPECT) was used to measure left ventricular function in the acute phase (4.9 +/- 2.2 days after onset) and the chronic phase (188.5 +/- 22.9 days after onset). More than 10% left ventricular dilatation from the acute phase to the chronic phase was defined as remodeling (RM) and the subjects were divided into 2 groups: RM and non-RM. Cardiopulmonary exercise testing was performed at 1 month (1M), 3 months (3M) and 6 months (6M) after onset. In the RM group, anaerobic threshold (AT) and peak oxygen uptake (Peak ) did not change significantly. In the non-RM group, AT was 15 +/- 1 (ml/min/Kg) at 1M, 16 +/- 2 at 3M and 18 +/- 4 at 6M. Peak was 26 +/- 3 (ml/min/Kg) at 1M, 30 +/- 2 at 3M and 32 +/- 3 at 6M. Both parameters in the chronic phase increased significantly compared with those at 1M (p<0.002 and p<0.0001). Thus, change in exercise capacity would correlate with change in left ventricular function. PMID- 25792931 TI - Kinematic and kinetic analysis of rolling motion in normal adults. AB - The purpose of this study was to describe a rolling motion, which is common in normal adults and patients with motor disorder, and to try to understand the mechanism of the motion. Ten healthy young adults participated in the experiment and were requested to roll from supine to side-lying by pressing the floor with their contra-lateral foot. Their motions in the task were measured with a 3-D analysis system and a force platform. The hip abduction-adduction angle was at around the neutral position and was approximately constant throughout the rolling motion. The hip rotation angle was at a neutral or slightly internally rotated position at the beginning of the motion, and it externally rotated linearly toward the end of the rolling motion. These patterns were thought to be mechanically the most effective for the subjects to perform the motion as was also indicated by the kinetic analysis. PMID- 25792930 TI - Gender and age-related differences in axial alignment of the lower limb among healthy Japanese volunteers: comparative and correlation study. AB - A cross-sectional study was designed for this investigation using a healthy Japanese population. The objectives of this study were to confirm gender and age related differences in axial alignment of the lower limb, and to investigate the correlation between femorotibial angle and axial alignment of the lower limb among a healthy Japanese population. Although axial alignment of the lower limb has been defined as one of the associating factors for osteoarthritis of the knee along with varus and valgus deformity, the results in the literature are inconsistent. Since there is gender difference in femorotibial angle, axial alignment of the lower limb should show the difference if it is an associating factor for osteoarthritis of the knee. Few studies have been conducted to investigate gender difference in axial alignment of the lower limb. One hundred and forty four healthy Japanese subjects took part in the study. Reliable clinical methods of measuring femoral torsion, tibiofibular torsion, rotational range of motion of the hip and knee joints, and femorotibial angle were employed utilizing a digital inclinometer. Two way ANOVA and Pearson product-moment correlation analysis were used for statistical analyses. Axial alignment of the lower limb was different between genders (p<0.05). An age-related difference was also shown in hip rotation (p<0.05). Further, the femorotibial angle was significantly correlated with hip and knee joint rotation (p<0.05) in older males and younger females. This study implied that axial alignment of the lower limb may be related to deformity of the knee joint. PMID- 25792932 TI - The Relationship between Postural Deformation and Standing Balance in Elderly Person. AB - Falling due to unstable standing balance is considered to be the main cause of bone fractures, which lead elderly persons to becoming bedridden. Thus, the standing balance of elderly persons is being given increasingly greater attention. On the other hand, postural deformation caused by deformation in the spine and lower leg joints is considered to have an effect on standing balance. The objective of this study is to clarify the effect of postural deformation on the following three categories of standing balance; 1) the ability to immobilize Center of Gravity (COG) in standing statically, 2) the ability to control COG during movement and 3) the postural response induced by postural sway. Fifty elderly persons (age:77.7 +/- 6.4 years old, fifty females) participated in this study. Postural deformation was measured using a Spinal Mouse, a device for non invasive measurement of spinal curvature and photographic image in sagittal plane. In line with to Nakata's classification of postural deformation, subjects were classified by extension type, S-character deformation type, flexion type, hands on the knee type and normal group. In order to assess the ability to immobilize COG in static standing, Center of Pressure (COP) in static standing was measured for 30 sec. In order to assess the ability to control COG during movement, functional reach, maximal length of stride and the period of 10 m gait were measured. Postural response was induced by fore-aft perturbation of the platform on which the subjects stood. Postural responses were assessed by measuring both COP, and electromyography (EMG) of muscles in the lower legs. There was little significant difference among the five groups concerning postural deformation in every measured item, neither in the ability to immobilize COP in static standing, nor in the postural response induced by postural sway. However, the results of measured items concerning the ability to control COG during movement were significantly worse in flexion type and hands on the knee type compared with the normal group. It was suggested that postural deformation in elderly persons effects exclusively on the ability to control COG during movement in standing balance. PMID- 25792933 TI - Task dependent motor strategy of human triceps surae muscle. AB - Even though many investigators have analyzed the functional difference of the three heads of triceps surae in human, none of them succeeded to clarify the distinctive functional difference of those three muscles. The aim of this study was to investigate whether the integrated EMGs (IEMGs) of the triceps surae muscle, gastrocnemius and soleus, were task dependent. IEMGs of the medial head of the gastrocnemius (GM), lateral head of the gastrocnemius (GL), and soleus (SO) were investigated at three different knee joint angles, at four different duration of ramp contraction, with the generation of a single ongoing force, from 0 to the maximum voluntary contraction (MVC). Three-way ANOVAs for repeated measures were used to estimate differences in IEMG values in each of the GM, GL, and SO, taken at four different durations of ramp contraction (5, 10, 15 and 20 s), at three different knee joint angles (0 deg, 30 deg and 90 deg), across ankle plantar flexion levels of force (10, 20, 30, 40, 50, 60 and 70% MVC). According to three-way ANOVAs for repeated measures, IEMG of the GM muscle showed a first order interaction between force and knee joint angle. In addition, IEMG of the GL muscle showed first-order interactions between the level of force and knee joint angle, and between the level of force and duration of ramp contraction. Furthermore, IEMG of the SO showed a main effect only on level of force. These results suggest that the each head of the triceps surae may work task dependently. PMID- 25792934 TI - Intra-tester and inter-tester reliability of chest expansion measurement in clients with ankylosing spondylitis and healthy individuals. AB - The purpose of this study was to examine the intra-tester and inter-tester reliability of chest expansion (CE) using a tape measure, in people with ankylosing spondylitis (AS) and healthy subjects. Twenty-two subjects with AS with a mean age of 41.4 years and 25 healthy subjects with a mean age of 41.0 years were tested in two arm positions: hands on head and arms at the sides, the tape measure being placed at the level of xiphisternum. There were three testers for subjects with AS and two testers for healthy subjects. Three trials in both arm positions were recorded by each tester on two separate occasions which were 10 minutes apart. Results showed intraclass correlation coefficients (ICC) for intra-tester reliability good (0.85 to 0.97) across the occasions. Intraclass correlation coefficients for inter-tester reliability were also very good (0.93 to 0.97). As reliability is good it is suggested that CE can be used for monitoring disease progression and efficacy of intervention with confidence within tester and between testers. PMID- 25792935 TI - Oxygen Saturation and Hemoglobin Level in the Muscles of Hypertensive Patients during Exercise in Water. AB - To clarify whether exercise therapy in a water environment is appropriate therapy for hypertensive patients, we investigated oxygen saturation and hemoglobin level in the vastus medialis muscle using a laser tissue blood oxygen monitor. Seven hypertensive patients (52 to 77 years of age, hypertensive group) and five healthy volunteers (44 to 69 years of aged, control group) participated in this study. Subjects maintained resting postures for about 5 minutes each in a standing position, a sitting position on a chair, a lying position out of water, and a position in water below the navel and to the chest level. Subjects performed flexion/extension movement of the knee joint (30 times/min) in and out of water. Oxygen saturation level (SaO2), oxygenated hemoglobin level (HbO2), deoxygenated hemoglobin level (HbD), and total tissue hemoglobin level (HbT) were measured in the muscle tissue. Blood pressure (BP) and pulse rate (PR) were monitored simultaneously. In the hypertensive group, SaO2 in muscle tissue in water was significantly increased compared with that in a standing position out of water (p<0.05), and returned to the level in the control group. HbD in the hypertensive group was significantly reduced in the position in water to the chest level compared to that in a standing position (p<0.05). In both groups, the ratios of HbD and HbO2 (O2/D ratio) was significantly increased in water environment compared with that out of water (p<0.05). The O2 /D ratio, which indicates oxygenation within the tissue, increased during exercise in water in the hypertensive group. This study demonstrated that oxygen saturation in the muscles of the hypertensive group was lower than that in controls out of water, but the level was increased in water. Our findings suggest that water provides a good exercise environment for hypertensive patients from the perspective of oxygen saturation in hypertensive muscle tissue. PMID- 25792936 TI - Literature review of evidence based physiotherapy in patients with facial nerve paresis. AB - A variety of physiotherapeutic approaches have been tried out during the past 25 years to alleviate the plight of patients with peripheral facial nerve paresis. The objective of this review was to assess the effectiveness of physiotherapy in patients with facial nerve paresis. Trials were identified by computerised searches of biomedical databases, reference lists, and by contacting investigators. Selection criteria were randomised controlled trials of physiotherapy for the improvement of sequelae of facial nerve paresis, comparing the treatment with either another intervention or no intervention. Two reviewers independently assessed the trials using the PEDro scale. Two physiotherapy randomised controlled studies were identified. Interventions used for treatment of patients with facial nerve paresis in the included studies were relaxation, biofeedback and exercise therapy. Neither of the two randomised controlled studies showed scientific evidence of a physiotherapeutic approach in comparison with a control group. Both studies described benefits of the interventions. Further randomised controlled studies are required to determine the effectiveness of physiotherapy in patients with facial nerve paresis. PMID- 25792937 TI - Does fear of falling relate to low physical function in frail elderly persons?: associations of fear of falling, balance, and gait. AB - Falls are a major public health problem for older people. Recent research suggests that fear of falling may be a more pervasive and serious problem than falls among the elderly. The present study was conducted to determine whether frail elderly persons with fear of falling have lower physical function. A total of 47 subjects (aged 73 to 95) were recruited from a geriatric health services facility in Osaka. Physical function including balance, mobility, and muscular strength were measured using the following tests: Timed up & go test (TUG), functional reach test, single limb stance with eyes open, ten-meter walk, and knee extensor strength. Twenty-nine subjects (62%) had fear of falling and 18 (38%) had no fear of falling. There was no significant difference in age, sex, or the proportion using assistive devices. Results from the statistical tests showed that there were no differences in physical function, except in the functional reach test. The ratio of TUG to 10 m walk was used to determine the association between balance and mobility. In frail elderly persons with fear of falling and in those without fear of falling, the means of the ratios were 1.20 (SD=0.27) and 1.03 (SD=0.16), respectively. The ratios for frail elderly persons with fear of falling were higher (p=0.024) than the frail elderly without fear of falling. Our study suggests that even if frail elderly individuals walk slowly, they are not afraid of falling if there is a feasible balance function. We conclude that, in low-functioning frail elderly, fear of falling is associated with a combination of balance function and gait speed. PMID- 25792938 TI - Shoulder impingement syndromes: implications on physical therapy examination and intervention. AB - A painful shoulder presents challenges in examination, diagnosis and intervention for the physical therapist because of the complexity of the structures involved. A common cause of shoulder pain is shoulder impingement syndrome. This was first described as a condition in which the soft tissues of the subacromial space were chronically entrapped and compressed between the humeral head and the subacromial arch. This definition does not account for the myriad potential causes of shoulder impingement conditions, as forms of impingement other than subacromial soft tissue compression may explain different symptomatic shoulder injuries. This paper describes shoulder impingement syndromes that have been hypothesized, identified and analyzed in the literature. Physical Therapy examination and intervention for these syndromes are also discussed. PMID- 25792939 TI - Effects of intermittent weight-bearing and clenbuterol on disuse atrophy of rat hindlimb muscles. AB - The present study was undertaken to evaluate the effects of intermittent weight bearing (IWB) combined with beta 2-agonist clenbuterol (Cb) medication for suppressing muscle atrophy during progressive disuse atrophy. Male Wistar rats (age: 8weeks, body weight: 232 +/- 14 g) were divided into a control group (CON) and an experimental group. The experimental group was further subdivided into a Cb medication group under normal conditions and a hindlimb unweighting (HU) treatment group. The HU treatment group was composed of four groups: HU treatment only, HU treatment + IWB, HU treatment + Cb medication and HU treatment + IWB + Cb medication. IWB was performed by temporarily removing the suspension device for one hour daily. On Day 14, bilateral soleus muscle (SOL) and extensor digitorum longus muscle (EDL) were extracted. Muscles from the right side were used for the measurement of contractile properties (physiological functional evaluations). Muscles from the left side were used for histochemical and biochemical analysis. During HU, IWB combined with Cb medication worked to preserve the wet weight and relative weight of SOL as compared to CON. Its contractile properties were affected by weight-bearing, while the cross-sectional area of type I fiber and protein concentration were affected by Cb. This combined therapy had marked effects on the morphology of EDL, particularly on the cross sectional area of type II fiber. The protein concentration and contractile properties of EDL were unaffected by this combined therapy. The effect of a combination of IWB and Cb medication was specific to fiber-type and region. The data suggested that 1) IWB was effective on functional aspects such as contractile properties and useful for physical therapy, 2) Cb medication exerted the atrophy-suppressive effect in morphological parameters and manifested less effect on functional aspects. The results in this study indicated the possibility of elevating the efficacy of IWB by Cb medication in SOL. PMID- 25792941 TI - Effects of inspiratory and expiratory muscle training in normal subjects. AB - The present study aimed to clarify the effects of inspiratory muscle training (IMT) and expiratory muscle training (EMT) on ventilatory muscle strength, pulmonary function and responses during exercise testing. Young healthy women were randomly assigned to 3 groups: IMT (n=16); EMT (n=16); or untrained normal controls (NC, n=8). Subjects in the IMT and EMT groups trained for 15 minutes twice daily over 2 weeks at loads of 30% maximal inspiratory and expiratory muscle strength, respectively. Ventilatory muscle strength (maximal inspiratory and expiratory muscle strength; PImax and PEmax, respectively), pulmonary function and progressive exercise testing was performed. Both PImax and PEmax increased in the IMT group, and PEmax increased in the EMT group. Neither trained group demonstrated any change in pulmonary function or peak values during exercise testing. In the IMT group, exercise-induced increases in heart rate, oxygen uptake (VO2/kg) and rating of perceived exertion (RPE) decreased with training, as did increases in VO2/kg and RPE in the EMT group. The increased ventilatory muscle strength in both IMT and EMT groups might improve ventilatory efficacy during exercise, and increased inspiratory muscle strength might facilitate oxygen delivery through improved circulatory responses. PMID- 25792940 TI - Physiological and health-related quality of life outcomes following cardiac rehabilitation after cardiac surgery. AB - We investigated the changes of an 8-week cardiac rehabilitation (CR) program on physiological outcomes and health-related quality of life (HRQL) in Japanese cardiac surgery patients. Subjects were 47 consecutive outpatients (32 men, 15 women; mean age 59.4 +/- 12.6 years) recovering from cardiac surgery. Patients performed both aerobic exercise on a treadmill at anaerobic threshold intensity and moderate resistance training 2 days per week, 60 min per session, from 1 to 3 months after cardiac surgery. Differences in the eight SF-36 subscale scores and physiological outcomes within the patient group at 1 month and at 3 months after cardiac surgery were analyzed. Peak oxygen uptake, handgrip strength, and knee extension strength were used as physiological outcome measures. HRQL was assessed with the Japanese version Medical Outcome Study Short Form 36 (SF-36). Significant change in overall physiological outcome from 1 month to 3 months was observed. There was also significant change in seven of the eight SF-36 health status subscale scores (physical functioning, role-physical, bodily pain, general health, vitality, role-emotional, and mental health). However, with the exception of physical functioning and mental health scores, values did not reach those of the average healthy Japanese. In conclusion, we found that CR exercise training for Japanese cardiac surgery patients during the recovery phase changes not only physiological outcomes but also HRQL as assessed by the SF-36. PMID- 25792942 TI - Health-related quality of life in relation to different levels of disease severity in patients with chronic heart failure. AB - The purpose of the present study was to compare differences in physiological outcomes and health-related quality of life (HRQOL) in relation to degree of illness in patients with chronic heart failure (CHF) and to compare HRQOL in CHF patients with that of a normal Japanese population. One hundred and twenty-five patients with stable CHF (93 men, 32 women, mean age 63.3 +/- 12.4 years) with left ventricular ejection fraction (LVEF) of less than 40% were enrolled in the present study. We used New York Heart Association (NYHA) functional class as an index of degree of illness. In 64 of the 125 patients, physiological outcome measures included peak oxygen uptake (peak O2) and E/CO2 slope. HRQOL was assessed with the medical outcome study short form-36 (SF-36) Japanese version. In addition, SF-36 scores of CHF patients were compared against Japanese standard values. Age and LVEF did not differ according to NYHA functional class. The eight SF-36 subscale scores and peak O2 decreased with increases in the NYHA functional classes, whereas E/CO2 slope increased with increases in NYHA functional class (p<0.05). Of the 8 SF-36 subscales measured in CHF patients, only the bodily pain score attained that of the normal Japanese population. These findings suggest that HRQOL decreases as NYHA functional class increases and other physiological measures worsen. In addition, HRQOL values of CHF patients were low in comparison with standard values of a normal Japanese population. PMID- 25792943 TI - Intralimb and Interlimb Incoordination: Comparative Study between Patients with Parkinsonism and with Cerebellar Ataxia. AB - Dysfunction of limb coordination may be divided into two categories; intra and inter-limb incoordination. To make clear differential character in these two limb incoordination, we measured 13 patients mainly with cerebellar ataxia and 27 patients mainly with parkinsonism during pedaling of an ergometer with left and right pedals that can be rotated independently. As a result, interlimb incoordination was predominantly observed in patients with parkinsonism, while patients with cerebellar ataxia showed relatively preserved interlimb coordination but intralimb incoordination. We concluded that impairment of intralimb coordination was a character in patients with cerebellar ataxia, while impairment of interlimb coordination was a character in patients with parkinsonism. PMID- 25792944 TI - The effects of unsupervised exercise training on physical activity and physiological factors after supervised cardiac rehabilitation. AB - Exercise maintenance after supervised cardiac rehabilitation is important in maintaining both physical activity and physiological factors, such as peak and muscle strength (MS), associated with reduced mortality. However, there is no evidence of the effects of unsupervised exercise training and MS training on physical activity and physiological factors after supervised cardiac rehabilitation of Japanese cardiac patients. We conducted a randomized, controlled trial to evaluate the effect of unsupervised exercise training on physical activity and selected physiological factors after supervised cardiac rehabilitation. Eighteen myocardial infarction (MI) patients (16 men, 2 women; mean age 66.3 years) were recruited following completion of a supervised recovery phase cardiac rehabilitation program. Patients were randomly assigned to a MS training (n=10) or control group (n=8). Baseline measurements of physical activity, peak , and MS were performed at the end of supervised recovery-phase cardiac rehabilitation (6 months after the onset of MI: T1). Six months later, after going through an unsupervised exercise program (12 months after the onset of MI: T2) exercise maintenance, peak , MS, and physical activity were remeasured. The MS training group performed low-intensity MS training and walking over the second 6-month period; the control group performed walking exercise only. All patients maintained their exercise training. At T2, there were no significant differences in peak values between the MS training and control groups. There was also no significant difference in physical activity (mean number of steps per week) between the MS training and control groups. However, MS was significantly higher in the MS training group than in the control group. We concluded that unsupervised exercise training and low-level MS training performed after supervised cardiac rehabilitation may effectively maintain not only physical activity and peak but increase MS. PMID- 25792945 TI - Prediction on affected upper extremity function in hemiplegic patients after thalamic hemorrhage using somatosensory evoked magnetic fields. AB - The aim of the present study was to investigate the prognostic value of somatosensory evoked magnetic fields (SEFs) at an acute stage on recovery of an affected upper extremity (UE) function as practicality in hemiplegic patients after thalamic hemorrhage. Nine hemiplegic patients after thalamic hemorrhage were enrolled in this study. Median nerve SEFs, evoked by electrical stimulation at the wrist of the affected UE, were measured using a 204 channel whole-head magnetoencephalography system within 72 hours after the onset of thalamic hemorrhage (acute stage). Assessments on the affected UE, which included the motor palsies of the UE and fingers (Brunnstrom's motor recovery stage: BS), sensory disturbance (the thumb localizing test) and UE function (the UE ability test), were performed at both the acute stage and 3 months after the onset of thalamic hemorrhage (chronic stage). Almost all the patients showing any median nerve SEF components that originated from the somatosensory cortex in the affected hemisphere and occurred between about 20 ms and 100 ms post-stimulus at the acute stage demonstrated good outcomes in the motor palsies (BSV), sensory disturbance (normal) and affected UE function (practical hand) at the chronic stage. In contrast, majority of patients not showing them at all demonstrated poor outcomes in the motor palsies (BSIII or less), sensory disturbance (severely impaired) and affected UE function (disabled hand) at the chronic stage. These results suggest that the findings of the median nerve SEFs at the acute stage would contribute to the early outcome prediction on the affected UE function in hemiplegic patients after thalamic hemorrhage. PMID- 25792946 TI - Excitability of Spinal Motor Neuron Function after the Transcutaneous Electrical Stimulation (TES) in Healthy Subjects -F-wave Study. AB - To clarify the excitability of spinal motor neuron function after transcutaneous electrical stimulation (TES), we investigated the F-wave before and after TES. Fourteen healthy volunteers with a mean age of 23.4 years were studied. TES was applied to the flexor hallucis brevis (FHB) for 15 minutes. F-wave and M-wave were recorded from the FHB after tibial nerve stimulation at the ankle before TES, just after TES, 10, 20 and 30 minutes after TES. TES evoked full flexion of the great toe. F-wave was analyzed for the amplitude ratio of F/M, latency and duration. The amplitude ratio of F/ M was 3.1% before TES, 1.4% just after TES, 1.6% 10 minutes after, 1.9% 20 minutes after and 1.7% 30 minutes after TES. Each amplitude ratio of F/M after TES was significantly lower than that before TES (p<0.05). There was no statistically significant difference in the latency and the duration. These results suggest that the excitability of spinal motor neuron function after TES to muscles under this condition was reduced in healthy subjects. PMID- 25792947 TI - EMG Analysis of Lower Extremity Muscles in Three Different Squat Exercises. AB - The purpose of this study was to come across an exercise that increases the Hamstring contraction levels so that it may protect the anterior cruciate ligament (ACL). Previous studies have postulated that changing the projection of the center of gravity behind the feet will decrease the translation of the tibia, therefore protect the ACL. Muscle activity of the quadriceps, hamstring and soleus muscles in healthy subjects was measured with an EMG during three different squat tasks with differences of support of body weight and the center of gravity. The subjects were nine healthy female recreational athletes with no history of any pathological knee condition or musculoskeletal system disorder. There was no significant difference in the activities of the four muscles (Vastus Medialis; Hamstring: Semitendinosus and Biceps Femoris; and Soleus); and there was a similar pattern in the activity between those muscles in the exercises. In addition, VM values were considerably higher than the Hamstring and soleus activity levels. There was no significant difference between one squat from another and among the phases (0-30 degrees , 30-60 degrees or 60-90 degrees ) of knee flexion. These results suggest that even when changing the projection of the center of gravity, the activity of the quadriceps is high compared to the hamstring and soleus muscles. PMID- 25792948 TI - Stability analysis and simulations of coupled bulk-surface reaction-diffusion systems. AB - In this article, we formulate new models for coupled systems of bulk-surface reaction-diffusion equations on stationary volumes. The bulk reaction-diffusion equations are coupled to the surface reaction-diffusion equations through linear Robin-type boundary conditions. We then state and prove the necessary conditions for diffusion-driven instability for the coupled system. Owing to the nature of the coupling between bulk and surface dynamics, we are able to decouple the stability analysis of the bulk and surface dynamics. Under a suitable choice of model parameter values, the bulk reaction-diffusion system can induce patterning on the surface independent of whether the surface reaction-diffusion system produces or not, patterning. On the other hand, the surface reaction-diffusion system cannot generate patterns everywhere in the bulk in the absence of patterning from the bulk reaction-diffusion system. For this case, patterns can be induced only in regions close to the surface membrane. Various numerical experiments are presented to support our theoretical findings. Our most revealing numerical result is that, Robin-type boundary conditions seem to introduce a boundary layer coupling the bulk and surface dynamics. PMID- 25792950 TI - Well-posedness and qualitative behaviour of a semi-linear parabolic Cauchy problem arising from a generic model for fractional-order autocatalysis. AB - In this paper, we examine a semi-linear parabolic Cauchy problem with non Lipschitz nonlinearity which arises as a generic form in a significant number of applications. Specifically, we obtain a well-posedness result and examine the qualitative structure of the solution in detail. The standard classical approach to establishing well-posedness is precluded owing to the lack of Lipschitz continuity for the nonlinearity. Here, existence and uniqueness of solutions is established via the recently developed generic approach to this class of problem (Meyer & Needham 2015 The Cauchy problem for non-Lipschitz semi-linear parabolic partial differential equations. London Mathematical Society Lecture Note Series, vol. 419) which examines the difference of the maximal and minimal solutions to the problem. From this uniqueness result, the approach of Meyer & Needham allows for development of a comparison result which is then used to exhibit global continuous dependence of solutions to the problem on a suitable initial dataset. The comparison and continuous dependence results obtained here are novel to this class of problem. This class of problem arises specifically in the study of a one step autocatalytic reaction, which is schematically given by A->B at rate apbq (where a and b are the concentrations of A and B, respectively, with 0=8/27pi2~0.03. In the case of free boundaries, analytical approaches permit direct treatment of the role played by the Prandtl number [Formula: see text], which-in contrast to the classical stationary scenario-can impact on oscillatory modes significantly owing to the non-zero frequency of convection. Numerical investigation indicates that the behaviour found analytically for free boundaries applies in a qualitatively similar fashion for fixed boundaries, while the threshold Cattaneo number CT is computed as a function of [Formula: see text] for both boundary regimes. PMID- 25792961 TI - Mechanisms for mechanical trapping of geologically sequestered carbon dioxide. AB - Carbon dioxide (CO2) sequestration in subsurface reservoirs is important for limiting atmospheric CO2 concentrations. However, a complete physical picture able to predict the structure developing within the porous medium is lacking. We investigate theoretically reactive transport in the long-time evolution of carbon in the brine-rock environment. As CO2 is injected into a brine-rock environment, a carbonate-rich region is created amid brine. Within the carbonate-rich region minerals dissolve and migrate from regions of high-to-low concentration, along with other dissolved carbonate species. This causes mineral precipitation at the interface between the two regions. We argue that precipitation in a small layer reduces diffusivity, and eventually causes mechanical trapping of the CO2. Consequently, only a small fraction of the CO2 is converted to solid mineral; the remainder either dissolves in water or is trapped in its original form. We also study the case of a pure CO2 bubble surrounded by brine and suggest a mechanism that may lead to a carbonate-encrusted bubble owing to structural diffusion. PMID- 25792962 TI - On the duality of resilience and privacy?. AB - Protecting information has long been an important problem. We would like to protect ourselves from the risk of loss: think of the library of Alexandria; and from unauthorized access: consider the very business of the 'Scandal Sheets', going back centuries. This has never been more true than today when vast quantities of data (dare one say lesser quantities of information) are stored on computer systems, and routinely moved around the Internet, at almost no cost. Computer and communication systems are both fragile and vulnerable, and so the risk of catastrophic loss or theft is potentially much higher. A single keystroke can delete a public database, or expose a private dataset to the world. In this paper, I consider the problems of providing resilience against loss, and against unacceptable access as a dual. Here, we see that two apparently different solutions to different technical problems may be transformed into one another, and hence give better insight into both problems. PMID- 25792963 TI - Size-dependent energy in crystal plasticity and continuum dislocation models. AB - In the light of recent progress in coarsening the discrete dislocation mechanics, we consider two questions relevant for the development of a mesoscale, size dependent plasticity: (i) can the phenomenological expression for size-dependent energy, as quadratic form of Nye's dislocation density tensor, be justified from the point of view of dislocation mechanics and under what conditions? (ii) how can physical or phenomenological expressions for size-dependent energy be computed from dislocation mechanics in the general case of elastically anisotropic crystal? The analysis based on material and slip system symmetries implies the negative answer to the first question. However, the coarsening method developed in response to the second question, and based on the physical interpretation of the size-dependent energy as the coarsening error in dislocation interaction energy, introduces additional symmetries. The result is that the equivalence between the phenomenological and the physical expressions is possible, but only if the multiplicity of characteristic lengths associated with different slip systems, is sacrificed. Finally, we discuss the consequences of the assumption that a single length scale governs the plasticity of a crystal, and note that the plastic dissipation at interfaces has a strong dependence on the length scale embedded in the energy expression. PMID- 25792964 TI - The evolution of air resonance power efficiency in the violin and its ancestors. AB - The fact that acoustic radiation from a violin at air-cavity resonance is monopolar and can be determined by pure volume change is used to help explain related aspects of violin design evolution. By determining the acoustic conductance of arbitrarily shaped sound holes, it is found that air flow at the perimeter rather than the broader sound-hole area dominates acoustic conductance, and coupling between compressible air within the violin and its elastic structure lowers the Helmholtz resonance frequency from that found for a corresponding rigid instrument by roughly a semitone. As a result of the former, it is found that as sound-hole geometry of the violin's ancestors slowly evolved over centuries from simple circles to complex f-holes, the ratio of inefficient, acoustically inactive to total sound-hole area was decimated, roughly doubling air-resonance power efficiency. F-hole length then slowly increased by roughly 30% across two centuries in the renowned workshops of Amati, Stradivari and Guarneri, favouring instruments with higher air-resonance power, through a corresponding power increase of roughly 60%. By evolution-rate analysis, these changes are found to be consistent with mutations arising within the range of accidental replication fluctuations from craftsmanship limitations with subsequent selection favouring instruments with higher air-resonance power. PMID- 25792965 TI - Bending a beam by a generalized ideal elastomeric gel. AB - A hybrid beam with a gel layer bonded on the top of an elastic non-swellable substrate has been commonly adopted to make various sensors and actuators. Usually, different models need to be developed for the hybrid beam when different gels are used in the system. In this article, based on the generalized ideal elastomeric gel model, we formulate a unified relationship between the swelling of hydrogels and the bending curvature of the elastic beam, which is independent of specific swelling mechanisms of gels. We further illustrate that the equations derived in the article can be used to validate the ideal elastomeric gel model and measure the elasticity of polymer networks of the gels. PMID- 25792966 TI - Heat kernel asymptotic expansions for the Heisenberg sub-Laplacian and the Grushin operator. AB - The sub-Laplacian on the Heisenberg group and the Grushin operator are typical examples of sub-elliptic operators. Their heat kernels are both given in the form of Laplace-type integrals. By using Laplace's method, the method of stationary phase and the method of steepest descent, we derive the small-time asymptotic expansions for these heat kernels, which are related to the geodesic structure of the induced geometries. PMID- 25792967 TI - A fractional Fourier transform analysis of the scattering of ultrasonic waves. AB - Many safety critical structures, such as those found in nuclear plants, oil pipelines and in the aerospace industry, rely on key components that are constructed from heterogeneous materials. Ultrasonic non-destructive testing (NDT) uses high-frequency mechanical waves to inspect these parts, ensuring they operate reliably without compromising their integrity. It is possible to employ mathematical models to develop a deeper understanding of the acquired ultrasonic data and enhance defect imaging algorithms. In this paper, a model for the scattering of ultrasonic waves by a crack is derived in the time-frequency domain. The fractional Fourier transform (FrFT) is applied to an inhomogeneous wave equation where the forcing function is prescribed as a linear chirp, modulated by a Gaussian envelope. The homogeneous solution is found via the Born approximation which encapsulates information regarding the flaw geometry. The inhomogeneous solution is obtained via the inverse Fourier transform of a Gaussian-windowed linear chirp excitation. It is observed that, although the scattering profile of the flaw does not change, it is amplified. Thus, the theory demonstrates the enhanced signal-to-noise ratio permitted by the use of coded excitation, as well as establishing a time-frequency domain framework to assist in flaw identification and classification. PMID- 25792968 TI - Implicit constitutive relations for nonlinear magnetoelastic bodies. AB - Implicit constitutive relations that characterize the response of elastic bodies have greatly enhanced the arsenal available at the disposal of the analyst working in the field of elasticity. This class of models were recently extended to describe electroelastic bodies by the present authors. In this paper, we extend the development of implicit constitutive relations to describe the behaviour of elastic bodies that respond to magnetic stimuli. The models that are developed provide a rational way to describe phenomena that have hitherto not been adequately described by the classical models that are in place. After developing implicit constitutive relations for magnetoelastic bodies undergoing large deformations, we consider the linearization of the models within the context of small displacement gradients. We then use the linearized model to describe experimentally observed phenomena which the classical linearized magnetoelastic models are incapable of doing. We also solve several boundary value problems within the context of the models that are developed: extension and shear of a slab, and radial inflation and extension of a cylinder. PMID- 25792969 TI - Acute respiratory distress syndrome: we can't miss regional lung perfusion! AB - In adult respiratory distress syndrome (ARDS), life-threatening hypoxemia may occur, dictating the need for differentiated ventilator strategies. Pronounced consolidation and/or atelectasis have been well documented in ARDS, but the contribution of regional perfusion to oxygenation has been poorly addressed. Evidence has accumulated that, in ARDS, regional perfusion is extremely variable and may affect oxygenation, independently from the amount of atelectatic consolidated lung regions. Thus, the response in oxygenation to different ventilatory settings, both during controlled and assisted mechanical ventilation, should be interpreted with caution. In fact, gas exchange may be not determined solely by changes in aeration, but also redistribution of perfusion. Furthermore, regional perfusion can play an important role in worsening of lung injury due to increased transmural pressures. In addition, distribution of perfusion in lungs might affect the delivery of drugs through the pulmonary circulation, including antibiotics. In recent years, several techniques have been developed to determine pulmonary blood flow with increasing level of spatial resolution, allowing a better understanding of normal physiology and various pathophysiological conditions, but most of them are restricted to experimental or clinical research. Lung ultrasound and novel algorithms for electrical impedance tomography represent new promising techniques that could enable physicians to assess the distribution of pulmonary blood flow at the bedside. In ARDS, we cannot afford missing regional lung perfusion! Please see related article: http://dx.doi.org/10.1186/s12871-015-0013-0. PMID- 25792970 TI - Light cupula of the horizontal semicircular canal occurring alternately on both sides: a case report. AB - BACKGROUND: The light cupula is a condition wherein the cupula of the semicircular canal has a lower specific gravity than its surrounding endolymph. It is characterized by a persistent geotropic direction-changing positional nystagmus in the supine head-roll test, and the identification of a null plane with slight head-turning to either side. CASE PRESENTATION: This study describes a case of recurring light cupula that occurred alternately on both sides. At the first episode, a null plane was identified on the right side, which led to the diagnosis of a light cupula on the right side. At the second episode, a null plane was identified on the left side, leading to the diagnosis of a light cupula on the left side. CONCLUSION: This is the first case report of recurring light cupula alternately involving both sides. Although the pathophysiology is not entirely understood yet, the light cupula should be considered as one of causes of recurrent positional vertigo. PMID- 25792971 TI - Trends in receiving chemotherapy for advanced cancer patients at the end of life. AB - BACKGROUND: The use of chemotherapy in advanced cancer patients has increased with the development of novel, high-efficacy anticancer therapeutic agents. In the current study, we analyzed the 10-year trends in patients receiving chemotherapy at the end of life. METHOD: We retrospectively reviewed mortality data for advanced cancer patients who died in 2000, 2005, and 2010 at a single institution. The trends of receiving palliative chemotherapy at the end of life were assessed for each year. In addition, logistic regression analysis was performed to determine the factors associated with receiving chemotherapy. RESULTS: We analyzed the records of 2,345 patients who died of cancer. Patients with less responsive tumors were less likely to receive chemotherapy than patients with responsive tumors at the time of death. Patients who were >= 65 years were less likely to receive chemotherapy compared with patients who were < 65 years at the end of life. However, the proportion of older patients receiving chemotherapy in the last month of life increased in 2010 (44.2%) compared with 2005 (32.7%) and 2000 (25.7%). Compared with the year 2000, the likelihood of receiving chemotherapy during the last 1 month of life increased in 2005 (odds ratio [OR], 2.05; 95% confidence interval [CI], 1.60-2.62) and 2010 (OR, 4.42; 95% CI, 3.51-5.57). CONCLUSIONS: The proportion of patients receiving chemotherapy at the end of life increased successively from 2000 to 2005 to 2010. Physicians should consider whether to continue chemotherapy at the end of life. PMID- 25792972 TI - A Delphi survey of leadership attributes necessary for national nurse leaders' participation in health policy development: an East African perspective. AB - BACKGROUND: Nurses' involvement in health policy development ensures that health services are: safe, effective, available and inexpensive. Nursing history reveals several legendary nurse leaders who have influenced policy and the course of nursing and health care. In the recent times there have been concerns regarding the availability of effective leaders physically, symbolically and functionally at clinical, organizational and national levels, who can effectively influence health policy. Exerting influence in the policy arena requires that nurse leaders acquire attributes that enable them to be effective in policy development activity. This paper reports part of a larger study whose purpose included: "build consensus on leadership attributes necessary for nurse leaders' participation in health policy development in East Africa". METHOD: A Delphi survey was utilized and included the following criteria: expert panelists, three iterative rounds, qualitative and quantitative analysis, and building consensus. The study included purposively selected sample of national nurse leaders (expert panelists) from the three East African countries of Kenya, Tanzania and Uganda. The study was conducted in three iterative rounds. Seventy eight (78) expert panelists were invited to participate in the study and 37 (47%) participated in the first round of these; 24 (64.8%) participated in the second round and all invited in the third round 24 (100%) participated. Data collection was done using questionnaires and collected qualitative and quantitative data. Data analysis was done utilizing the principles of qualitative analysis in the first round and descriptive statistics in the second and third rounds. RESULTS: The study achieved consensus on the essential leadership attributes for nurse leaders' participation in health policy and include being able to: influence; communicate effectively; build relationships; feel empowered and demonstrate professional credibility. CONCLUSIONS: For nursing to participate in influencing the health policy and the health of the population, it will need to develop nurses with leadership attributes who are able to inspire change and influence the policy development process within the context where it exists. The leadership attributes identified in this study can be utilized to develop programmes geared to support nurses' participation in health policy activity. PMID- 25792973 TI - The association between Salt-inducible kinase 2 (SIK2) and gamma isoform of the regulatory subunit B55 of PP2A (B55gamma) contributes to the survival of glioma cells under glucose depletion through inhibiting the phosphorylation of S6K. AB - BACKGROUND: PPP2R2C encodes a gamma isoform of the regulatory subunit B55 subfamily consisting PP2A heterotrimeric with A and C subunits. Currently, the precise functions of B55gamma in cancer are still under investigating. In this project, we reported a novel function of B55gamma in the regulation of glucose metabolism in Glioma cells. METHODS: Western blot and immunoprecipitation were performed to determine protein expression and interaction. Cell viability was measured by Typan Blue staining and direct cell counting using hematocytometer. siRNA technology was used to down regulate protein expression. RESULTS: Glucose uptake and lactate product were suppressed by overexpression of B55gamma in Glioma cells. In addition, cancer cells with larger amount of B55gamma showed higher survival advantages in response to glucose starvation through the dephosphorylation of S6K. From proteomic analysis, we found B55gamma binds with and up regulates SIK2 through the stabilization of SIK2 protein which is required for the B55gamma-mediated suppression of S6K pathway. Knocking down of SIK2 in B55gamma over expressing cells recovered the phosphorylation of S6K. CONCLUSION: In summary, our project will provide novel insight into the design and development of therapeutic strategies to target the B55gamma-mediated glucose metabolism for the treatment of human brain tumor patients. PMID- 25792974 TI - Downregulated lincRNA HOTAIR expression in ovarian cancer stem cells decreases its tumorgeniesis and metastasis by inhibiting epithelial-mesenchymal transition. AB - BACKGROUND: Emerging evidence indicates that dysregulated long intervening non coding RNA (lincRNA) HOTAIR correlates highly with tumor invasion and metastasis but a link between the high expression of HOTAIR and the metastatic cascade of cancer stem cells (CSCs) needs to be further studied. The purpose of this study was to investigate the effect of down-regulated HOTAIR expression on tumorgeniesis and metastasis of epithelial ovarian cancer (EOC) CSCs. CD117(+)CD44(+)CSCs were isolated from human EOC SKOV3 cell line by using a magnetic-activated cell sorting system, and were then transfected with the expression vector-based small hairpin RNA targeting HOTAIR; the stably transfected cells were selected for the study. Colony-forming, wound-healing, cellular metastasis and tumorigenicity assays were performed. RESULTS: The results demonstrated that the HOTAIR expression in clinical EOC tissues and SKOV3 CD117(+)CD44(+)CSCs was higher than in SKOV3 tumor tissues and non CD117(+)CD44(+)CSCs. The CD117(+)CD44(+)-shHOTAIR showed an inhibited HOTAIR expression, reduced cell migration and invasion than CD117(+)CD44(+)- scramble, suggesting the inhibition of an epithelial-mesenchymal transition. Moreover, the downregulated HOTAIR expression in CD117(+)CD44(+) CSCs significantly decreased the tumor growth and lung metastasis in xenograft mice. CONCLUSION: Our findings demonstrated the shHOTAIR-mediated down-regulation of the HOTAIR expression in CD117(+)CD44(+) CSCs can be a promising new opportunity for future clinical trials. PMID- 25792975 TI - Expression of the immune regulation antigen CD70 in osteosarcoma. AB - Osteosarcoma is the most frequent bone cancer in children and young adults. The outcome of patients with advanced disease is dismal. Exploitation of tumor-immune cell interactions may provide novel therapeutic approaches. CD70-CD27 interactions are important for the regulation of adaptive immunity. CD70 expression has been reported in some solid cancers and implicated in tumor escape from immunosurveillance. In this study, expression of CD70 and CD27 was analyzed in osteosarcoma cell lines and tumor specimens. CD70 protein was expressed on most osteosarcoma cell lines (5/7) and patient-derived primary osteosarcoma cultures (4/6) as measured by flow cytometry. In contrast, CD70 was detected on few Ewing sarcoma cell lines (5/15) and was virtually absent from neuroblastoma (1/7) and rhabdomyosarcoma cell lines (0/5). CD70(+) primary cultures were derived from CD70(+) osteosarcoma lesions. CD70 expression in osteosarcoma cryosections was heterogeneous, restricted to tumor cells and not attributed to infiltrating CD3(+) T cells as assessed by immunohistochemistry/immunofluorescence. CD70 was detected in primary (1/5) but also recurrent (2/4) and metastatic (1/3) tumors. CD27, the receptor for CD70, was neither detected on tumor cells nor on T cells in CD70(+) or CD70(-) tumors, suggesting that CD70 on tumor cells is not involved in CD27-dependent tumor immune cell interactions in osteosarcoma. CD70 gene expression in diagnostic biopsies of osteosarcoma patients did not correlate with the occurrence of metastasis and survival (n = 70). Our data illustrate that CD70 is expressed in a subset of osteosarcoma patients. In patients with CD70(+) tumors, CD70 may represent a novel candidate for antibody-based targeted immunotherapy. PMID- 25792977 TI - Sex, Math and Scientific Achievement: Why do men dominate the fields of science, engineering and mathematics? PMID- 25792976 TI - Effects of protein type and composition on postprandial markers of skeletal muscle anabolism, adipose tissue lipolysis, and hypothalamic gene expression. AB - BACKGROUND: We examined the acute effects of different dietary protein sources (0.19 g, dissolved in 1 ml of water) on skeletal muscle, adipose tissue and hypothalamic satiety-related markers in fasted, male Wistar rats (~250 g). METHODS: Oral gavage treatments included: a) whey protein concentrate (WPC, n = 15); b) 70:30 hydrolyzed whey-to-hydrolyzed egg albumin (70 W/30E, n = 15); c) 50 W/50E (n = 15); d) 30 W/70E (n = 15); and e) 1 ml of water with no protein as a fasting control (CTL, n = 14). RESULTS: Skeletal muscle analyses revealed that compared to CTL: a) phosphorylated (p) markers of mTOR signaling [p-mTOR (Ser2481) and p-rps6 (Ser235/236)] were elevated 2-4-fold in all protein groups 90 min post-treatment (p < 0.05); b) WPC and 70 W/30E increased muscle protein synthesis (MPS) 104% and 74% 180 min post-treatment, respectively (p < 0.05); and c) 70 W/30E increased p-AMPKalpha (Thr172) 90 and 180-min post-treatment as well as PGC-1alpha mRNA 90 min post-treatment. Subcutaneous (SQ) and omental fat (OMAT) analyses revealed: a) 70 W/30 W increased SQ fat phosphorylated hormone sensitive lipase [p-HSL (Ser563)] 3.1-fold versus CTL and a 1.9-4.4-fold change versus all other test proteins 180 min post-treatment (p < 0.05); and b) WPC, 70 W/30E and 50 W/50E increased OMAT p-HSL 3.8-6.5-fold 180 min post-treatment versus CTL (p < 0.05). 70 W/30E and 30 W/70E increased hypothalamic POMC mRNA 90 min post-treatment versus CTL rats suggesting a satiety-related response may have occurred in the former groups. However, there was a compensatory increase in orexigenic AGRP mRNA in the 70 W/30E group 90 min post-treatment versus CTL rats, and there was a compensatory increase in orexigenic NPY mRNA in the 30 W/70E group 90 min post-treatment versus CTL rats. CONCLUSIONS: Higher amounts of whey versus egg protein stimulate the greatest post-treatment anabolic skeletal muscle response, though test proteins with higher amounts of WPH more favorably affected post-treatment markers related to adipose tissue lipolysis. PMID- 25792978 TI - The Effectiveness of Short Message Service to Assure the Preparation-to Colonoscopy Interval before Bowel Preparation for Colonoscopy. AB - Background/Aims. The preparation-to-colonoscopy (PC) interval is one of several important factors for the bowel preparation. Short message service (SMS) reminder from a cellular phone has been suggested to improve compliance in various medical situations. We evaluated the effectiveness of SMS reminders to assure the PC interval for colonoscopy. Methodology. This prospective randomized study was investigator blinded. In the No-SMS group, patients took the first 2 L polyethylene glycol (PEG) between 6 and 8 PM on the day before colonoscopy and the second 2 L PEG approximately 6 hours before the colonoscopy without SMS. In the SMS group, patients took first 2 L PEG in the same manner as the No-SMS group and the second 2 L PEG after receiving an SMS 6 hours before the colonoscopy. Results. The SMS group had a lower score than the No-SMS group, according to the Ottawa Bowel Preparation Scale (P < 0.001). Multivariate logistic regression analysis showed that compliance with diet instructions (odds ratio (OR) 2.109; 95% confidence interval (CI), 1.11-3.99, P = 0.022) and intervention using SMS ((OR) 2.329; 95% (CI), 1.34-4.02, P = 0.002) were the independent significant factors for satisfactory bowel preparation. Conclusions. An SMS reminder to assure PC interval improved the bowel preparation quality for colonoscopy with bowel preparation. PMID- 25792979 TI - Beneficial effects of combining computed tomography enteroclysis/enterography with capsule endoscopy for screening tumor lesions in the small intestine. AB - Aim. To compare the efficacy of using computed tomography enteroclysis/enterography (CTE), capsule endoscopy (CE), and CTE with CE for diagnosing tumor lesions in the small intestine. Materials and Methods. We included 98 patients who underwent CE during the observation period and were subjected to CTE at our hospital from April 2008 to May 2014. Results. CTE had a significantly higher sensitivity than CE (84.6% versus 46.2%, P = 0.039), but there were no significant differences in specificity, positive or negative predictive values, or diagnostic accuracy rates. The sensitivity of CTE/CE was 100%, again significantly higher than that of CE (P = 0.002). The difference in specificity between CTE/CE and CE was not significant, but there were significant differences in positive predictive values (100% for CTE/CE versus 66.7% for CE, P = 0.012), negative predictive values (100% versus 92.1%, P = 0.008), and diagnostic accuracy rate (100% versus 89.8%, P = 0.001). The diagnostic accuracy rate was also significantly higher in CTE/CE versus CTE (100% versus 95.9%, P = 0.043). Conclusion. Our findings suggested that a combination of CTE and CE was useful for screening tumor lesions in the small intestine. This trial is registered with number UMIN000016154. PMID- 25792981 TI - The "lipid accumulation product" is associated with 2-hour postload glucose outcomes in overweight/obese subjects with nondiabetic fasting glucose. AB - "Lipid accumulation product" (LAP) is a continuous variable based on waist circumference and triglyceride concentration previously associated with insulin resistance. We investigated the accuracy of LAP in identifying oral glucose tolerance test (OGTT) abnormalities and compared it to the homeostasis model assessment of insulin resistance (HOMA-IR) in a population of overweight/obese outpatients presenting with nondiabetic fasting glucose. We studied 381 (male: 23%) adult (age: 18-70 years) overweight/obese Caucasians (body mass index: 36.9 +/- 5.4 Kg/m(2)) having fasting plasma glucose < 7.0 mmol/L. OGTT was used to diagnose unknown glucose tolerance abnormalities: impaired glucose tolerance (IGT) and type-2 diabetes mellitus (T2-DM). According to OGTT 92, subjects had an IGT and 33 were diagnosed T2-DM. Logistic regression analysis detected a significant association for both LAP and HOMA-IR with single (IGT and T2-DM) and composite (IGT + T2-DM) abnormal glucose tolerance conditions. However, while the association with diabetes was similar between LAP and HOMA-IR, the relationship with IGT and composite outcomes by models including LAP was significantly superior to those including HOMA-IR (P = 0.006 and P = 0.007, resp.). LAP seems to be an accurate index, performing better than HOMA-IR, for identifying 2-hour postload OGTT outcomes in overweight/obese patients with nondiabetic fasting glucose. PMID- 25792980 TI - Insulin Increases Sestrin 2 Content by Reducing Its Degradation through the PI 3 K/mTOR Signaling Pathway. AB - Sestrin (SESN) is known as a cysteine sulfinic acid reductase. Recently, nonredox functions of SESN in metabolic regulation and antitumor property have been recognized. While mechanisms underlying the expression of SESN are not fully understood. Here we report that insulin markedly increased SESN2 level in HepG2 cells through mTOR activation. To determine whether insulin affects SESN2 degradation, we assessed SESN2 turnover by applying the protein synthesis inhibitor, cycloheximide (CHX), and found that following insulin treatment SESN2 protein levels were reduced significantly slower than non-insulin-treated cells. Furthermore, the proteasomal inhibitor, MG132, dramatically increased SESN2 protein and its ubiquitination level while in the presence of MG132 insulin did not further increase SESN2 content, suggesting that insulin increases SESN2 content mainly via inhibiting its proteasomal degradation. We then explored the potential feedback role of SESN2 in insulin signaling by SESN2 siRNA knockdown in HepG2 cells. Following SESN2 knockdown insulin-stimulated PKB phosphorylation was enhanced and accompanied by reduced PTEN content. Taken together, our study suggests that insulin upregulates SESN2 content via the PI3K/mTOR signaling pathway and this effect is attributed to decreased SESN2 degradation. Furthermore, SESN2 via modulating PTEN plays a negative feedback role in insulin signaling. PMID- 25792983 TI - Rapid Screening and Structural Characterization of Antioxidants from the Extract of Selaginella doederleinii Hieron with DPPH-UPLC-Q-TOF/MS Method. AB - 2,2-Diphenyl-1-picrylhydrazyl-ultra-high performance liquid chromatography-Q-time of-flight mass spectrometry (DPPH-UPLC-Q-TOF/MS), as a rapid and efficient means, now was used for the first time to screen antioxidants from Selaginella doederleinii. The nine biflavone compounds were screened as potential antioxidants. The biflavones were structurally identified and divided into the three types, that is, amentoflavone-type, robustaflavone-type, and hinokiflavone type biflavonoids. Among the compounds bilobetin (3) and putraflavone (8) were found from Selaginella doederleinii for the first time and others including amentoflavone (1), robustaflavone (2), 4'-methoxy robustaflavone (4), podocarpusflavone A (5), hinokiflavone (6), ginkgetin (7), and heveaflavone (9) were identified previously in the plant. Moreover, nine biflavones possessed a good antioxidant activity via their DPPH free radical scavenging. It demonstrates that DPPH-UPLC-Q-TOF/MS exhibits strong capacity in separation and identification for small molecule. The method is suitable for rapid screening of antioxidants without the need for complicated systems and additional instruments. PMID- 25792982 TI - Effects of beta-Hydroxy-beta-methylbutyrate Free Acid Ingestion and Resistance Exercise on the Acute Endocrine Response. AB - Objective. To examine the endocrine response to a bout of heavy resistance exercise following acute beta-hydroxy-beta-methylbutyrate free acid (HMB-FA) ingestion. Design. Twenty resistance trained men were randomized and consumed either 1 g of HMB-FA (BetaTor) or placebo (PL) 30 min prior to performing an acute heavy resistance exercise protocol. Blood was obtained before (PRE), immediately after (IP), and 30 min after exercise (30P). Circulating concentrations of testosterone, growth hormone (GH), insulin-like growth factor (IGF-1), and insulin were assayed. Data were analyzed with a repeated measures ANOVA and area under the curve (AUC) was analyzed by the trapezoidal rule. Results. The resistance exercise protocol resulted in significant elevations from PRE in testosterone (P < 0.01), GH (P < 0.01), and insulin (P = 0.05) at IP, with GH (P < 0.01) and insulin (P < 0.01) remaining elevated at 30P. A significant interaction was noted between groups in the plasma GH response at IP, which was significantly higher following HMB-FA compared to PL (P < 0.01). AUC analysis revealed an elevated GH and IGF-1 response in the HMB-FA group compared to PL. Conclusion. HMB-FA prior to resistance exercise augments the GH response to high volume resistance exercise compared to PL. These findings provide further support for the potential anabolic benefits associated with HMB supplementation. PMID- 25792984 TI - Impact of Educational Program on the Management of Chronic Suppurative Otitis Media among Children. AB - Background. Chronic suppurative otitis media (CSOM) remains one of the most common childhood chronic infectious diseases worldwide, affecting diverse racial and cultural groups in both developing and industrialized countries. Aim of the Study. This study aimed to assess the impact of educational program on the management of children with CSOM. Subjects and Methods. An experimental study design was used. This study included 100 children of both sexes of 2 years and less of age with CSOM. Those children were divided into 3 groups: group I: it involved 50 children with CSOM (naive) who received the designed educational program; control group: it involved 50 children who were under the traditional treatment and failed to respond; group II: those children in the control group were given the educational program and followed up in the same way as group I and considered as group II. Tools of the Study. Tool I is a structured questionnaire interview sheet for mothers. It consists of four parts: (1) personal and sociodemographic characteristics of child and (2) data about risk factors of otitis media (3) assessment of maternal practice about care of children with suppurative otitis medi (4) diagnostic criteria for suppurative otitis media. Tool II is the educational program: an educational program was developed by the researchers based on the knowledge and practices needs. This study was carried out through a period of 9 months starting from September 2013 to May 2014. The educational program was implemented for mothers of children with CSOM in the form of 5 scheduled sessions at the time of diagnosis, after one week, 1, 3, and 6 months. Results. There were significant differences between children who received the educational program and control group regarding the response to treatment after one and 3 months. The percentages of complete cure increased progressively 32%, 60%, and 84% after 1, 3, and 6 months in group I while they were 24%, 44%, and 64% in group II, respectively. Cure (dry perforation) was 64%, 36%, and 12% among children of group I after 1, 3, and 6 months while it was 64%, 44%, and 24% in group II, respectively. The percentages of compliance to the educational program improved with time in both groups: 44%, 64%, and 80% in group I and 32%, 48%, and 56% in group II after 1, 3, and 6 months, respectively. The percentages of cure were statistically significantly higher among children with complete compliance with the educational program in both groups in comparison to those with incomplete compliance (P = 0.000 for both). Conclusions. From this study we can conclude that the majority of children with CSOM had one or more risk factors for occurrence of the disease; the educational program is effective for management of CSOM (whether cure or complete cure); the higher the compliance of mothers with the program the higher the response rate; regular followup and explanation of the importance of the program played an important role in the compliance with the program. PMID- 25792985 TI - Daisaikoto for menstrual pain: a lesson from a case with menstrual pain successfully treated with daisaikoto. AB - Menstrual pain is one of the common symptoms among women. It is estimated that 5 14% of women are sometimes absent from school or work because of pain. Usually gynecologists prescribe analgesics and/or low-dose oral contraceptives. However, such treatment is not always effective and sometimes causes an adverse effect, such as stomach pain or low body temperature. Kampo medicine is one of the choices for the menstrual pain in Japan. Tokishakuyakusan, kamishoyosan, or keishibukuryogan is commonly used for the treatment of menstrual pain. Here we report a case of menstrual pain successfully treated with daisaikoto which is not commonly used for such a case. Twenty-five-year-old woman suffered from severe menstrual pain and stress at company. She also had constipation and abdominal distension. We prescribed daisaikoto extract 7.5 g per day. Not only menstrual pain but also constipation and abdominal distension improved within 6 months. Here we propose that daisaikoto is one of the choices for the treatment of menstrual pain with mental stress. PMID- 25792986 TI - The Relationship between Emotional Intelligence and Marital Satisfaction: 10-Year Outcome of Partners from Three Different Economic Levels. AB - BACK GROUND: Emotional communication and economic factors play an important role in having a satisfying relationship and a more successful marriage. In this regard, we investigated the 10-year outcome of partners from three different economic levels regarding the relationship between emotional intelligence (EI) and marital satisfaction. OBJECTIVE: The research was designed as a descriptive correlative survey and data were analyzed using Pearson correlation test and stepwise regression. METHODS AND MATERIAL: Participants were 159 couples (N = 318) who were randomly selected through clustered sampling. The questionnaires included: Bar-on Emotional Intelligence (1997) and Enrich Marital satisfaction (1989). RESULTS: The findings revealed that the average values of emotional intelligence (m = 333.1) and marital satisfaction (m = 300.77) were high in the under-rich region (p<0.05). Moreover, there was no significant relationship between interpersonal and marital satisfaction within the under-rich region. On average, emotional intelligence accounted for 40.8% of marital satisfaction within those three regions (p<0.01). CONCLUSION: The results of the regression analysis showed that general mood is the most effective factor changing marital satisfaction in the three studied regions (R2= 0.34), rich (R2= 0.42) and semi rich (R2= 0.52) regions (p<0.01). The most influential factor changing marital satisfaction in the under-rich (R2= 0.28) region was found to be stress management (p<0.01). PMID- 25792987 TI - Neurocognitive Profile of Children with Attention Deficit Hyperactivity Disorders (ADHD): A comparison between subtypes. AB - OBJECTIVE: The aim of this study was to examine the differences between ADHD subtypes in executive function tasks compared to themselves and normal controls. METHOD: In this study, 45 school aged children with Attention Deficit Hyperactivity Disorder (ADHD) and 30 normal children who were matched based on age and IQ score in Wechsler Intelligence Scale for Children-Revised (WISC-R) were compared in terms of executive function. We used Wisconsin Sorting Card Test to assess executive function in both groups. We also used children's scores in Children Symptom Inventory-4 (CSI-4) for diagnosing ADHD and specifying ADHD subtypes. Data were entered in SPSS-17 and analyzed by T-test and ANOVA static tests to clarify the differences between ADHD and controls and between ADHD subtypes. Scheffe's test was also used to identify which groups were different from one another. The mean and standard divisions (SD) were used for descriptive analysis. RESULTS: ADHD subtypes are significantly different in terms of perseverative responses (p<= 0/01) and perseverative errors (p<= 0/001). Based on Scheffe's test, Attention Deficit Hyperactivity Disorders-Hyperactive type (ADHD H) is not that different from Attention Deficit Hyperactivity Disorders Inattention type (ADHD-I) and Attention Deficit Hyperactivity Disorders-Combined type (ADHD-C), but there are significant responses and perseverative differences between ADHD-I and ADHD-C in terms of perseverative errors. ADHD-C shows more perseverative responses and perseverative errors than ADHD-I. CONCLUSION: The findings of this study revealed that executive function patterns are different in children with ADHD compared to normal children. In this study it was also found that ADHD subtypes are also different in terms of perseveration and response inhibition domains; ADHD-C has more deficits in these domains. PMID- 25792988 TI - The high prevalence of obsessive-compulsive disorder in patients with chronic pain. AB - OBJECTIVE: Chronic pain is a common disorder with a high prevalence of psychiatric disorder that imposes a worse prognosis on both conditions. Obsessive compulsive disorder (OCD) is estimated to be the fourth most prevalent life time psychiatric disorder, but yet has gained less attention in chronic pain comorbidity researches. METHODS: Ninety three heterogeneous chronic pain patients who attended a pain clinic in Tehran (Iran) in an outpatient setting during three months were included in this study. Diagnosis was made by Structured Clinical Interview for DSM-IV (SCID). RESULTS: The mean age of the patients was 46.37 (SD 15.005) years; of the patients, 66.7% were female and 33.3% were male. The mean duration of pain was 34.43 (SD 51.422) months. The mean pain severity on numerical pain scale was 5.82 (SD 1.950) from 10. The mean pain site number was 3.68 (SD 3.401) from the maximum of 27 places. Furthermore, 61.3% of the participants were diagnosed with lifetime OCD, 25.8% with subclinical OCD and 61.5 % with major depressive disorder (MDD). OCD diagnosis was not correlated with MDD or pain intensity. Female gender was associated with OCD (OD; 4.182, 95% CL (1.655-10.568)). Pain intensity was correlated with MDD (P < 0.05). CONCLUSIONS: The high prevalence of OCD was comorbidity, independent of MDD and most pain characteristics. The high prevalence of OCD may be explained by the high rate of undiagnosed cause of pain as well as cultural and local factors. Using screening tests is suggested for tackling under diagnosis and under treatment of OCD and MDD. PMID- 25792989 TI - Quantitative electroencephalogram (QEEG) Spectrum Analysis of Patients with Schizoaffective Disorder Compared to Normal Subjects. AB - OBJECTIVE: The aim of this study was to achieve a better understanding of schizoaffective disorder. Therefore, we obtained electroencephalogram (EEG) signals from patients with schizoaffective disorder and analyzed them in comparison to normal subjects. METHOD: Forty patients with schizoaffective disorder and 40 normal subjects were selected randomly and their electroencephalogram signals were recorded based on 10-20 international system by 23 electrodes in open- and closed-eyes while they were sitting on a chair comfortably. After preprocessing for noise removal and artifact reduction, we took 60- second segments from each recorded signals. Then, the absolute and relative powers of these segments were evaluated in all channels and in 4 frequency bands (i.e., delta, theta, alpha and beta waves). Finally, Data were analyzed by independent t-test using SPSS software. RESULTS: A significant decrease in relative power in the alpha band, a significant decrease in power spectra in the alpha band and a significant increase in power spectra in the beta band were found in patients compared to normal subjects (P < 0.05). The predominant wave in the centro-parietal region was the beta wave in patients, but it was the alpha band in normal subjects (P = 0.048). Also, the predominant wave of the occipital region in patients was the delta wave, while it was the alpha wave in normal subjects (P = 0.038). CONCLUSION: Considering the findings, particularly based on the significant decrease of the alpha waves in schizoaffective patients, it can be concluded that schizoaffective disorder can be seen in schizophrenia spectrum. PMID- 25792990 TI - Comparing the drawings of children with attention deficit hyperactivity disorder with normal children. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is the most common behavioral problem during childhood and in school-aged children. Various projection drawings have been designed for assessing children's personality and psychological disorders including the tests of draw a person (DAP) and draw a family (DAF). We aimed to compare the differences between typically developing children and children with ADHD using these tests. METHODS: In this case-control study, all the 9-10 year-old boy students studying at the third and fourth grades were enrolled from schools in the 2nd educational district of Shiraz, south of Iran. Eighty students were then selected and enrolled into the ADHD group and the control group. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition- text Revised (DSM-IV-TR), and the Child Symptoms Inventory were used to diagnose the children with ADHD. We evaluated and analyzed impulsiveness, non impulsiveness, emotional problems and incompatibility indices in the DAP and DAF tests in each group. RESULTS: A significant difference was found in the indices of incompatibility and emotional problems, impulsiveness, non-impulsiveness and DAF between typically developing children and those with ADHD. The mean (+/-SD) total scores of the above mentioned indices in the ADHD group were 19.79(+/ 2.94), 12.31(+/-1.84), 5.26(+/-2.29) and 5.89(+/-2.13), respectively (P<0.001). The corresponding figures for these indices in the normal group were 12.11(+/ 4.74), 5.63(+/-2), 10.36+/- (2.33) and 2.88(+/-2.13), respectively (P<0.001). CONCLUSION: Significant differences were obtained between the control group and children with ADHD using these two drawing tests. The rate of impulsivity and emotional problems indices in drawings of children with ADHD was markedly more common than those of the typically developing children. This suggests the need for further assessment to screen ADHD. PMID- 25792991 TI - The Effectiveness of Mindfulness Training in Improving the Quality of Life of the War Victims with Post Traumatic stress disorder (PTSD). AB - OBJECTIVE: Those veterans suffering from Post Traumatic stress disorder (PTSD) experience a low quality of life. This study investigated how the quality of life of warfare victims with PTSD was influenced by mindfulness training (MT). METHOD: This study followed a randomized controlled trial and included a pre-test, post test and delayed post- and was conducted in 2012 at Shahid Rajaee Hospital in Isfahan, Iran. The participants were 28 randomly selected male warfare victims with PTSD who were assigned into control and experimental groups. Data were collected using World Health Organization Quality of Life Questionnaire-26 (WHOQOL-26). Repeated measures ANOVA was run to analyze the data. RESULTS: The findings of this study indicated a statistically significant decrease in the mean score of the experimental group in both post-test and delayed post-test. Also, in comparison with the control group, there was a statistically significant increase in the mean scores of the physical and psychiatric health, social relationship and social setting and condition of the experimental group in the post-test and delayed post-test (p< 0.01). CONCLUSION: The findings of this study lend support to the effectiveness of MT in improving the quality of life of those veterans with PTSD and have significant implications for drawing our attention to mindfulness-based treatments as a way to enhance the quality of life of warfare victims suffering from PTSD. PMID- 25792992 TI - The effect of isotretinoin (roaccutane) therapy on depression and quality of life of patients with severe acne. AB - OBJECTIVE: Acne is the most common skin disease and isotretinoin is the most powerful drug among the various drugs used for its treatment, but it has some adverse effects. The aim of this study was to evaluate the effect of isotretinoin on depression and quality of life of a group of patients undergoing isotretinoin therapy before and after the treatment course. METHODS: In this prospective study, 98 patients with severe acne were enrolled consecutively and underwent isotretinoin therapy receiving 0.5 mg/kg/d of isotretinoin for 16 weeks. Isotretinoin effects on quality of life and depression were evaluated using Dermatology Life Quality Index (DLQI) and Beck Depression Inventory (BDI) questionnaires, respectively. RESULTS: In this study, 98 patients suffering from severe acne (38 males and 60 females) were enrolled. Treatment of acne was associated with improvement of quality of life scores in both male and female patients (p = 0.001). Considering the cutoff value of 13 for mild depressive mood in the BDI score, in total, 48 (49%) of the enrolled patients (21 males and 33 females) had a mild depressive mood before the commencement of the treatment in this study. The analysis of before and after treatment BDI scores showed that the number of patients and also the mean score of BDI were increased in both male and female patients after the treatment (p<0.05). CONCLUSION: Isotretinoin therapy improved the quality of life of patients suffering from acne, but depression was accentuated in the patients to some extent. PMID- 25792993 TI - Mental health priorities in Iranian women: overview of social determinants of mental health. AB - OBJECTIVE: Mental health is an essential component for positive adaptation that enables people to cope with adversity to achieve their full potential and humanity. In this study, using a community based approach, the social determinants of mental health in Iranian women were extracted; and in addition, priority setting for interventional programs according to analytical framework of WHO was implemented. METHOD: This study was a community based participatory research (CBPR) in district 22 of Tehran (Iran). The target group was married females with age range of 18-65 years. In this study, mental health priorities were extracted by qualitative methods according to Essential National Health Research model (ENHR) and the analytical framework of WHO. Data analysis was done based on content analysis by the open code 3.6 software. RESULTS: In the quantitative phase, according to secondary data, 1144 individuals (560 females and 584 males) were selected, of whom 41 percent had impaired mental health based on General Health Questionnaire (GHQ) (P<0.05). According to the qualitative phase, the first mental health priority in socioeconomic level was lack of insurance for unattended families, it was unemployment in differential exposure level and it was lack of knowledge and skills related to dealing with stress in the differential vulnerability level; in differential outcome and consequence levels, the priorities were lack of free counseling centers in the study area and lack of facilities for mental health rehabilitation. CONCLUSION: Providing training courses to improve the skills to deal with stress is considered one of the most important interventions for mental health promotion in women. PMID- 25792995 TI - Herb-drug interactions: systematic review, mechanisms, and therapies. PMID- 25792994 TI - Validation of the Persian Version of the Problematic Internet Use Questionnaire (PIUQ). AB - OBJECTIVE: The most commonly used instrument for the research and treatment of excessive internet use is Young's Internet Addiction Test (IAT). While the IAT has been translated to several languages (including Persian) and has demonstrated good psychometric properties across several independent studies, there is still a room for alternative assessment instruments. This study reports a validation of the Persian version of the Problematic Internet Use Questionnaire (PIUQ). METHOD: A sample (n = 296) from Kerman, Iran was administered the translated Persian version of the PIUQ as well as the Persian version of the University of California, Los Angeles (UCLA) Loneliness scale, Satisfaction With Life scale, and questions related to use of technology and the internet. RESULTS: Analyses using confirmatory and exploratory factor analyses demonstrated that the Persian version of the PIUQ had good internal reliability and concurrent validity (with loneliness and satisfaction with life), but they also had an alternative factor structure that did not support the original factor structure. CONCLUSION: The Persian version of the PIUQ produced adequate psychometric properties (internal reliability and concurrent validity), but care should be taken in the interpretation of the factor structure. PMID- 25792996 TI - Traditional Chinese Medicine, the Zishen Yutai Pill, Ameliorates Precocious Endometrial Maturation Induced by Controlled Ovarian Hyperstimulation and Improves Uterine Receptivity via Upregulation of HOXA10. AB - Controlled ovarian hyperstimulation (COH) is widely used in assisted reproductive technology (ART), but it often leads to precocious maturation of the endometrium such that it impairs embryonic implantation and limits pregnancy rates. Previous studies have shown the traditional Chinese medicine, the Zishen Yutai pill (ZYP), to be effective in treatment of threatened as well as recurrent miscarriages, and it can improve embryonic implantation rates in patients undergoing IVF treatment. In the present study, the ZYP has been found to ameliorate precocious endometrial maturation in a mouse model of different COH. Molecular evaluations, real-time PCR, relative RT-PCR, Western blotting, and immunohistochemistry have indicated that the ZYP increased the expression of HOXA10, an important marker of uterine receptivity. Elevation of HOXA10 led to further upregulation of its target gene, integrin beta3, and downregulation of EMX2, two additional markers of uterine receptivity. In this way, the ZYP may mitigate COH-induced precocious maturation of the endometrium and improve uterine receptivity by upregulating HOXA10. PMID- 25792997 TI - Safety evaluation of chinese medicine injections with a cell imaging-based multiparametric assay revealed a critical involvement of mitochondrial function in hepatotoxicity. AB - The safety of herbal medicine products has been a widespread concern due to their complex chemical nature and lack of proper evaluation methods. We have adapted a sensitive and reproducible multiparametric cell-based high-content analysis assay to evaluate the hepatic-safety of four Chinese medicine injections and validated it with classical animal-based toxicity assays. Our results suggested that the reported hepatotoxicity by one of the drugs, Fufangkushen injection, could be attributed at least in part to the interference of mitochondrial function in human HepG2 cells by some of its constituents. This method should be useful for both preclinical screen in a drug discovery program and postclinical evaluation of herbal medicine preparations. PMID- 25792998 TI - Gray matter volumes in patients with chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a debilitating and complex disorder characterized by profound fatigue with uncertain pathologic mechanism. Neuroimage may be an important key to unveil the central nervous system (CNS) mechanism in CFS. Although most of the studies found gray matter (GM) volumes reduced in some brain regions in CFS, there are many factors that could affect GM volumes in CFS, including chronic pain, stress, psychiatric disorder, physical activity, and insomnia, which may bias the results. In this paper, through reviewing recent literatures, we discussed these interferential factors, which overlap with the symptoms of CFS. PMID- 25792999 TI - Factors Affecting Definitions of and Approaches to Integrative Medicine: A Mixed Methods Study Examining China's Integrative Medicine Development. AB - Aim. This study identifies existing definitions and approaches among China's integrative medicine (IM) experts and examines relationships with key characteristics distinguishing individual experts. Methods. Snowball sampling was used to select 73 IM experts for semistructured interviews. In this mixed methods study, we first identified definitions and approaches through analyzing core statements. Four key factors, including age, education, practice type, and working environment, were then chosen to evaluate the associations with the definitions. Results. Four unique definitions were identified, including IM as a "new medicine" (D1), as a combination of western medicine (WM) and Chinese medicine (CM) (D2), as a modernization of CM (D3), and as a westernization of CM (D4). D4 was mostly supported by those working in WM organizations, while D3 was more prominent from individuals working in CM organizations (P = 0.00004). More than 64% clinicians had D2 while only 1 (5.9%) nonclinician had D2. Only 1 clinician (1.8%) had D4 while almost 30% nonclinicians had D4 (P = 0.0001). Among nonclinicians working in WM organizations, 83.3% of them had D4 (P = 0.001). Conclusion. Findings indicate that institutional structure and practice type are factors affecting IM approaches. These results carry implications for the ways in which western countries move forward with the definition and implementation of IM. PMID- 25793000 TI - Tai chi chuan exercise for patients with breast cancer: a systematic review and meta-analysis. AB - Objective. Tai Chi Chuan (TCC) is a form of aerobic exercise that may be an effective therapy for improving psychosomatic capacity among breast cancer survivors. This meta-analysis analyzed the available randomized controlled trials (RCTs) on the effects of TCC in relieving treatment-related side effects and quality of life in women with breast cancer. Methods. RCTs were searched in PubMed, Embase, Web of Science, and Cochrane Library through April 2014. Data were analyzed on pathology (pain, interleukin-6, and insulin-like growth factor 1), physical capacity (handgrip, limb physical fitness, and BMI), and well-being (physical, social, emotional, and general quality of life). Results. Nine RCTs, including a total of 322 breast cancer patients, were examined. Compared with control therapies, the pooled results suggested that TCC showed significant effects in improving handgrip dynamometer strength, limb elbow flexion (elbow extension, abduction, and horizontal adduction). No significant differences were observed in pain, interleukin-6, insulin-like growth factor, BMI, physical well being, social or emotional well-being, or general health-related quality of life. Conclusion. The short-term effects of TCC may have potential benefits in upper limb functional mobility in patients with breast cancer. Additional randomized controlled trials with longer follow-up are needed to provide more reliable evidence. PMID- 25793001 TI - Effects of green tea extracts on the pharmacokinetics of quetiapine in rats. AB - Quetiapine is an atypical antipsychotic, used clinically in the treatment of schizophrenia, acute mania in bipolar disorders, and bipolar depression in adults. In this study, the effect of green tea extracts (GTE) on the pharmacokinetics of quetiapine (substrate of CYP3A4) was investigated in rats. Male Wistar albino rats received GTE (175 mg/kg) or saline (control) by oral gavage for 7 days before a single intragastric administration of 25 mg/kg quetiapine. Plasma concentrations of quetiapine were measured up to 12 h after its administration by a validated ultraperformance liquid chromatography-tandem mass spectroscopy. Pretreatment with GTE produced significant reductions in the maximum plasma concentration and area under the curve of quetiapine by 45% and 35%, respectively, compared to quetiapine alone. However, GTE did not produce significant change in elimination half-life and oral clearance of quetiapine. This study concluded that GTE may decrease the bioavailability of quetiapine when coadministered. PMID- 25793003 TI - Effect of keishibukuryogan on genetic and dietary obesity models. AB - Obesity has been recognized as one of the most important risk factors for a variety of chronic diseases, such as diabetes, hypertension/cardiovascular diseases, steatosis/hepatitis, and cancer. Keishibukuryogan (KBG, Gui Zhi Fu Ling Wan in Chinese) is a traditional Chinese/Japanese (Kampo) medicine that has been known to improve blood circulation and is also known for its anti-inflammatory or scavenging effect. In this study, we evaluated the effect of KBG in two distinct rodent models of obesity driven by either a genetic (SHR/NDmcr-cp rat model) or dietary (high-fat diet-induced mouse obesity model) mechanism. Although there was no significant effect on the body composition in either the SHR rat or the DIO mouse models, KBG treatment significantly decreased the serum level of leptin and liver TG level in the DIO mouse, but not in the SHR rat model. Furthermore, a lower fat deposition in liver and a smaller size of adipocytes in white adipose tissue were observed in the DIO mice treated with KBG. Importantly, we further found downregulation of genes involved in lipid metabolism in the KBG-treated liver, along with decreased liver TG and cholesterol level. Our present data experimentally support in fact that KBG can be an attractive Kampo medicine to improve obese status through a regulation of systemic leptin level and/or lipid metabolism. PMID- 25793005 TI - Beneficial effects and safety of corticosteroids combined with traditional chinese medicine for pemphigus: a systematic review. AB - Objective. To evaluate the beneficial effects and safety of corticosteroids combined with traditional Chinese medicine (TCM) for pemphigus. Methods. Seven electronic databases were searched to identify any potential randomized controlled trials (RCTs) or clinical controlled trials (CCTs) that compared corticosteroids with and without TCM for the treatment of pemphigus, published in any language. Remission of the mucocutaneous lesions, therapeutic duration, dosage of corticosteroids, and specific antibody titers were employed as the main outcome measures. The methodological quality of the included studies was assessed using the Cochrane Handbook for Systematic Review of Interventions and Rev Man 5.1.0 software. Results. Four RCTs with a total of 199 patients were included in the present review. Management with corticosteroids combined with TCM seemed to benefit pemphigus patients in terms of healing of lesions, prevention of complications and relapse, and reduced interferon-gamma (IFN-gamma) level. The trials were not of high methodological quality. No study mentioned allocation concealment and blinding. Only one trial reported adverse events, and it indicated that the safety of corticosteroids combined with TCM was uncertain. Conclusion. There is some, albeit weak, evidence to show that combined treatment with corticosteroids with TCM could be of benefit for some patients with pemphigus. The efficacy and safety of this combined treatment should be evaluated further in better designed, fully powered, and confirmatory RCTs. PMID- 25793004 TI - Effects of shenque moxibustion on behavioral changes and brain oxidative state in apolipoprotein e-deficient mice. AB - Purpose. To determine whether moxibustion influences the learning and memory behavior of ApoE-/- male mice, and investigate the mechanism of moxibustion on the alteration of oxidized proteins (glial fibrillary acidic protein, beta amyloid) in hippocampus. Methods. Thirty-three ApoE-/- mice were randomly divided into 3 groups (n = 11/group): moxibustion, sham moxibustion, and no treatment control. Wild-type C57BL/6 mice (n = 13) were used for normal control. Moxibustion was performed with Shenque (RN8) moxibustion for 20 minutes per day, 6 days/week for 12 weeks. In sham control, the procedure was similar except burning of the moxa stick. Behavioral tests (step-down test and Morris water maze task) were conducted in the 13th week. The mice were then sacrificed and the tissues were harvested for immune-histochemical staining. Results. In the step down test, the moxibustion group had shorter reaction time in training record and committed less mistakes compared to sham control. In immune-histochemical study, the moxibustion group expressed lower level of GFAP and less aggregation of beta amyloid in the hippocampus than the sham control. Conclusion. Our findings suggest that moxibustion may enhance learning capability of ApoE-/- mice. The mechanism may be via inhibiting oxidized proteins (GFAP and beta-amyloid) in astrocytes. PMID- 25793002 TI - Antimicrobial activity of oleanolic and ursolic acids: an update. AB - Triterpenoids are the most representative group of phytochemicals, as they comprise more than 20,000 recognized molecules. These compounds are biosynthesized in plants via squalene cyclization, a C30 hydrocarbon that is considered to be the precursor of all steroids. Due to their low hydrophilicity, triterpenes were considered to be inactive for a long period of time; however, evidence regarding their wide range of pharmacological activities is emerging, and elegant studies have highlighted these activities. Several triterpenic skeletons have been described, including some that have presented with pentacyclic features, such as oleanolic and ursolic acids. These compounds have displayed incontestable biological activity, such as antibacterial, antiviral, and antiprotozoal effects, which were not included in a single review until now. Thus, the present review investigates the potential use of these triterpenes against human pathogens, including their mechanisms of action, via in vivo studies, and the future perspectives about the use of compounds for human or even animal health are also discussed. PMID- 25793006 TI - Suan zao ren tang in combination with zhi zi chi tang as a treatment protocol for insomniacs with anxiety: a randomized parallel-controlled trial. AB - Insomnia is a serious worldwide health problem that is often comorbid with anxiety. The purpose of the present study was to evaluate the efficacy of a Chinese formula containing Suan Zao Ren Tang (SZRT) and Zhi Zi Chi Tang (ZZCT; SZR-ZZC) for improving sleep quality and anxiety states with four indices of Polysomnography (PSG), the Insomnia Severity Index (ISI), the Pittsburgh Sleep Quality Index (PSQI), and the Self Rating Anxiety Scale (SAS). Methods. A randomized, parallel-controlled trial compared SZR-ZZC to lorazepam tablet in insomniacs with anxiety. Patients were randomized to the SZR-ZZC treatment group (n = 60) and the lorazepam tablet treatment group (n = 59). Results. SZR-ZZC significantly improved scores on all four treatment indices. Compared with lorazepam, treatment with SZR-ZZC resulted in a significant reduction in the ISI (P = 0.029), the PSQI (P = 0.017), and wake after sleep onset (WASO; P = 0.008) scores and improved sleep architecture (P = 0.000-0.003) after a 4-week treatment period. Only one subject in the SZR-ZZC group experienced adverse side effects. Conclusion. Treatment with SZR-ZZC for 4 weeks appears to be a relatively safe and effective complementary therapeutic option when aiming to improve sleep quality and anxiety in insomniacs with anxiety. PMID- 25793007 TI - The APOB insertion/deletion polymorphism (rs17240441) influences postprandial lipaemia in healthy adults. AB - BACKGROUND: Apolipoprotein (apo)B is the structural apoprotein of intestinally- and liver- derived lipoproteins and plays an important role in the transport of triacylglycerol (TAG) and cholesterol. Previous studies have examined the association between the APOB insertion/deletion (ins/del) polymorphism (rs17240441) and postprandial lipaemia in response to a single meal; however the findings have been inconsistent with studies often underpowered to detect genotype-lipaemia associations, focused mainly on men, or with limited postprandial characterisation of participants. In the present study, using a novel sequential test meal protocol which more closely mimics habitual eating patterns, we investigated the impact of APOB ins/del polymorphism on postprandial TAG, non-esterified fatty acids, glucose and insulin levels in healthy adults. FINDINGS: Healthy participants (n = 147) consumed a standard test breakfast (0 min; 49 g fat) and lunch (330 min; 29 g fat), with blood samples collected before (fasting) and on 11 subsequent occasions until 480 min after the test breakfast. The ins/ins homozygotes had higher fasting total cholesterol, LDL-cholesterol, TAG, insulin and HOMA-IR and lower HDL-cholesterol than del/del homozygotes (P < 0.017). A higher area under the time response curve (AUC) was evident for the postprandial TAG (P < 0.001) and insulin (P = 0.032) responses in the ins/ins homozygotes relative to the del/del homozygotes, where the genotype explained 35% and 7% of the variation in the TAG and insulin AUCs, respectively. CONCLUSIONS: In summary, our findings indicate that the APOB ins/del polymorphism is likely to be an important genetic determinant of the large inter-individual variability in the postprandial TAG and insulin responses to dietary fat intake. PMID- 25793008 TI - Remote, aerial phenotyping of maize traits with a mobile multi-sensor approach. AB - BACKGROUND: Field-based high throughput phenotyping is a bottleneck for crop breeding research. We present a novel method for repeated remote phenotyping of maize genotypes using the Zeppelin NT aircraft as an experimental sensor platform. The system has the advantage of a low altitude and cruising speed compared to many drones or airplanes, thus enhancing image resolution while reducing blurring effects. Additionally there was no restriction in sensor weight. Using the platform, red, green and blue colour space (RGB), normalized difference vegetation index (NDVI) and thermal images were acquired throughout the growing season and compared with traits measured on the ground. Ground control points were used to co-register the images and to overlay them with a plot map. RESULTS: NDVI images were better suited than RGB images to segment plants from soil background leading to two separate traits: the canopy cover (CC) and its NDVI value (NDVIPlant). Remotely sensed CC correlated well with plant density, early vigour, leaf size, and radiation interception. NDVIPlant was less well related to ground truth data. However, it related well to the vigour rating, leaf area index (LAI) and leaf biomass around flowering and to very late senescence rating. Unexpectedly, NDVIPlant correlated negatively with chlorophyll meter measurements. This could be explained, at least partially, by methodical differences between the used devices and effects imposed by the population structure. Thermal images revealed information about the combination of radiation interception, early vigour, biomass, plant height and LAI. Based on repeatability values, we consider two row plots as best choice to balance between precision and available field space. However, for thermography, more than two rows improve the precision. CONCLUSIONS: We made important steps towards automated processing of remotely sensed data, and demonstrated the value of several procedural steps, facilitating the application in plant genetics and breeding. Important developments are: the ability to monitor throughout the season, robust image segmentation and the identification of individual plots in images from different sensor types at different dates. Remaining bottlenecks are: sufficient ground resolution, particularly for thermal imaging, as well as a deeper understanding of the relatedness of remotely sensed data and basic crop characteristics. PMID- 25793009 TI - A novel clinical decision support system using improved adaptive genetic algorithm for the assessment of fetal well-being. AB - A novel clinical decision support system is proposed in this paper for evaluating the fetal well-being from the cardiotocogram (CTG) dataset through an Improved Adaptive Genetic Algorithm (IAGA) and Extreme Learning Machine (ELM). IAGA employs a new scaling technique (called sigma scaling) to avoid premature convergence and applies adaptive crossover and mutation techniques with masking concepts to enhance population diversity. Also, this search algorithm utilizes three different fitness functions (two single objective fitness functions and multi-objective fitness function) to assess its performance. The classification results unfold that promising classification accuracy of 94% is obtained with an optimal feature subset using IAGA. Also, the classification results are compared with those of other Feature Reduction techniques to substantiate its exhaustive search towards the global optimum. Besides, five other benchmark datasets are used to gauge the strength of the proposed IAGA algorithm. PMID- 25793011 TI - Comment on "Impact of dose and sensitivity heterogeneity on TCP". PMID- 25793010 TI - Adaptive localization of focus point regions via random patch probabilistic density from whole-slide, Ki-67-stained brain tumor tissue. AB - Analysis of whole-slide tissue for digital pathology images has been clinically approved to provide a second opinion to pathologists. Localization of focus points from Ki-67-stained histopathology whole-slide tissue microscopic images is considered the first step in the process of proliferation rate estimation. Pathologists use eye pooling or eagle-view techniques to localize the highly stained cell-concentrated regions from the whole slide under microscope, which is called focus-point regions. This procedure leads to a high variety of interpersonal observations and time consuming, tedious work and causes inaccurate findings. The localization of focus-point regions can be addressed as a clustering problem. This paper aims to automate the localization of focus-point regions from whole-slide images using the random patch probabilistic density method. Unlike other clustering methods, random patch probabilistic density method can adaptively localize focus-point regions without predetermining the number of clusters. The proposed method was compared with the k-means and fuzzy c means clustering methods. Our proposed method achieves a good performance, when the results were evaluated by three expert pathologists. The proposed method achieves an average false-positive rate of 0.84% for the focus-point region localization error. Moreover, regarding RPPD used to localize tissue from whole slide images, 228 whole-slide images have been tested; 97.3% localization accuracy was achieved. PMID- 25793012 TI - Comparative study of retinal vessel segmentation based on global thresholding techniques. AB - Due to noise from uneven contrast and illumination during acquisition process of retinal fundus images, the use of efficient preprocessing techniques is highly desirable to produce good retinal vessel segmentation results. This paper develops and compares the performance of different vessel segmentation techniques based on global thresholding using phase congruency and contrast limited adaptive histogram equalization (CLAHE) for the preprocessing of the retinal images. The results obtained show that the combination of preprocessing technique, global thresholding, and postprocessing techniques must be carefully chosen to achieve a good segmentation performance. PMID- 25793013 TI - Is IORT ready for roll-out? AB - Two large randomised controlled trials of intraoperative radiotherapy (IORT) in breast-conserving surgery (TARGIT-A and ELIOT) have been published 14 years after their launch. Neither the TARGIT-A trial nor the ELIOT trial results have changed the current clinical practice for the use of IORT. The in-breast local recurrence rate (LRR) after IORT met the pre-specified non-inferiority margins in both trials and was 3.3% in TARGIT-A and 4.4% in the ELIOT trial. In both trials, the pre-specified estimates for local recurrence (LR) with external beam radiation therapy (EBRT) significantly overestimated actual LRR. In the TARGIT-A trial, LR with EBRT was estimated at the outset to be 6%, and in the ELIOT trial, it was estimated to be 3%. Surprisingly, LRR in the EBRT groups has been found to be significantly lower, 1.3% in the EBRT arm of the TARGIT-A and 0.4% in the EBRT arm of the ELIOT trial, respectively. Median follow-up was 2.4 years for the TARGIT-A trial and 5.8 years for the ELIOT trial. However, the initial cohort of patients in the TARGIT-A trial (reported in 2010) now have a median follow-up of 3.8 years and data on LR were available at 5 years follow-up on 35% of patients (18% who received IORT). Although further follow-up will increase confidence with the data, it will also further delay clinical implementation. By carefully weighing the risks and benefits of a single-fraction radiation treatment with patients, IORT should be offered within agreed and strict protocols. Patients deemed at low risk of LR or those deemed suitable for partial breast irradiation, according to the GEC-ESTRO and ASTRO recommendations, could be considered as candidates for IORT. These guidelines apply to all partial breast irradiation techniques, and more specific guidelines for IORT would assist clinicians. PMID- 25793014 TI - Genotyping and clinical factors in pediatric diarrhea caused by rotaviruses: one year surveillance in Surabaya, Indonesia. AB - BACKGROUND: Rotavirus infections are a major cause of diarrhea in children in both developed and developing countries. Rotavirus genetics, patient immunity, and environmental factors are thought to be related to the severity of acute diarrhea due to rotavirus in infants and young children. The objective of this study was to provide a correlation between rotavirus genotypes, clinical factors and degree of severity of acute diarrhea in children under 5 years old in Surabaya, Indonesia. METHODS: A cross-sectional study was conducted in children aged 1-60 months with acute diarrhea hospitalized in Soetomo Hospital, Surabaya, Indonesia from April to December 2013. Rotavirus in stool specimens was identified by ELISA and genotyping (G-type and P-type) using multiplex reverse transcription PCR. Severity was measured using the Ruuska and Vesikari scoring system. The clinical factors were investigated included patient's age (months), hydration, antibiotic administration, nutritional state, co-bacterial infection and co-viral infection. RESULTS: A total of 88 children met the criteria; 80.7% were aged 6-24 months, watery diarrhea was the most common type (77.3%) and 73.6% of the subjects were co-infected with bacteria, of which pathogenic Escherichia coli was the most common (42.5%). The predominant VP7 genotyping (G-type) was G2 (31.8%) and that of VP4 genotyping (P-type) was P[4] (31.8%). The predominant rotavirus genotype was G2P[4] (19.3%); G1P[4] and G9P[4] were uncommon with a prevalence of 4.5%. There were significant differences between the common genotype and uncommon genotype with respect to the total severity score of diarrhea (p <0.05). G3, G4 and G9 were significantly correlated with severe diarrhea (p = 0.009) in multivariate analyses and with frequency of diarrhea (>10 times a day) (p = 0.045) in univariate analyses, but there was no significant correlation between P typing and severity of diarrhea. For combination genotyping of G and P, G2P[4] was significantly correlated with severe diarrhea in multivariate analyses (p = 0.029). CONCLUSIONS: There is a correlation between rotavirus genotype and severity of acute diarrhea in children. Genotype G2P[4] has the highest prevalence. G3, G4, G9 and G2P[4] combination genotype were found to be associated with severe diarrhea. PMID- 25793016 TI - Few-cycle, broadband, mid-infrared optical parametric oscillator pumped by a 20 fs Ti:sapphire laser. AB - A few-cycle, broadband, singly-resonant optical parametric oscillator (OPO) for the mid-infrared based on MgO-doped periodically-poled LiNbO3 (MgO:PPLN), synchronously pumped by a 20-fs Ti:sapphire laser is reported. By using crystal interaction lengths as short as 250 um, and careful dispersion management of input pump pulses and the OPO resonator, near-transform-limited, few-cycle idler pulses tunable across the mid-infrared have been generated, with as few as 3.7 optical cycles at 2682 nm. The OPO can be continuously tuned over 2179-3732 nm (4589-2680 cm-1) by cavity delay tuning, providing up to 33 mW of output power at 3723 nm. The idler spectra exhibit stable broadband profiles with bandwidths spanning over 422 nm (FWHM) recorded at 3732 nm. The effect of crystal length on spectral bandwidth and pulse duration is investigated at a fixed wavelength, confirming near-transform-limited idler pulses for all grating interaction lengths. By locking the repetition frequency of the pump laser to a radio frequency reference, and without active stabilization of the OPO cavity length, an idler power stability better than 1.6% rms over >2.75 hours is obtained when operating at maximum output power, in excellent spatial beam quality with TEM00 mode profile. Photograph shows a multigrating MgO:PPLN crystal used as a nonlinear gain medium in the few-cycle femtosecond mid-IR OPO. The visible light is the result of non-phase-matched sum-frequency mixing between the interacting beams. PMID- 25793015 TI - Coherent fluorescence emission by using hybrid photonic-plasmonic crystals. AB - The spatial and temporal coherence of the fluorescence emission controlled by a quasi-two-dimensional hybrid photonic-plasmonic crystal structure covered with a thin fluorescent-molecular-doped dielectric film is investigated experimentally. A simple theoretical model to describe how a confined quasi-two-dimensional optical mode may induce coherent fluorescence emission is also presented. Concerning the spatial coherence, it is experimentally observed that the coherence area in the plane of the light source is in excess of 49 MUm2, which results in enhanced directional fluorescence emission. Concerning temporal coherence, the obtained coherence time is 4 times longer than that of the normal fluorescence emission in vacuum. Moreover, a Young's double-slit interference experiment is performed to directly confirm the spatially coherent emission. This smoking gun proof of spatial coherence is reported here for the first time for the optical-mode-modified emission. PMID- 25793017 TI - Increased DNA methylation of the SLC30A8 gene promoter is associated with type 2 diabetes in a Malay population. AB - BACKGROUND: Recent studies have demonstrated that DNA polymorphisms in the solute carrier family 30 member 8 (SLC30A8) gene confer the risk susceptibility to type 2 diabetes (T2D). The present study aimed to analyze DNA methylation levels of this gene in T2D and diabetic nephropathy (DN). RESULTS: We confirmed the genetic association study of SLC30A8 in 992 Malay subjects with normal glucose tolerance and T2D patients with and without DN. Genotyping was conducted with TaqMan allelic discrimination. SNP rs11558471(A/G) in the SLC30A8 gene was strongly associated with T2D (P = 0.002, OR = 1.334, 95% CI = 1.110 to 1.602) and moderately associated with DN (P = 0.041, OR = 1.399, 95% CI = 1.013 to 1.932). We further performed DNA methylation analysis of six CpG sites in the SLC30A8 gene promoter with bisulfite pyrosequencing protocol. The average DNA methylation levels of the SLC30A8 gene in all Malay subjects were at approximately 81.4%. DNA methylation levels of the SLC30A8 gene in T2D patients were higher compared to non-diabetic subjects (82.9% vs. 80.1%, P = 0.014). But no significant difference of DNA methylation levels of the SLC30A8 gene between T2D patients with and without DN was observed. CONCLUSION: The present study thus provides the first evidence that increased DNA methylation of the SLC30A8 gene promoter is associated with T2D but not DN in a Malay population. PMID- 25793018 TI - Patients with diabetic retinopathy have high retinal venous pressure. AB - BACKGROUND: The introduction of ophthalmodynamometric measurement of retinal venous pressure (RVP) now permits the quantification, or at least an approximation, of the real pressure in the retinal veins. METHODS: We measured the RVP of healthy control subjects, patients with diabetes without diabetic retinopathy (nonDR) and patients with diabetes and diabetic retinopathy (DR). RESULTS: The mean +/- SD RVP for the control, nonDR and DR groups were 23.4 +/- 7.33, 22.5 +/- 5.78 and 37.7 +/- 10.1 mmHg, respectively. In the diabetes patients with DR, the RVP was markedly and significantly increased, and this result was significantly age dependent. RVP was not increased in the group of diabetes patients without DR. In our tested population, diabetes had a minor influence on intraocular pressure. CONCLUSION: Regardless of the cause, a marked increase in RVP in diabetes patients with DR is clinically relevant, as it reduces perfusion pressure and increases transmural pressure. The reduced perfusion pressure contributes to hypoxia, and the increased transmural pressure can facilitate retinal edema. Diabetes is an increasing burden, and DR is one of its most severe complications. Strategies to recognize the risk for DR and to develop personalized prevention and therapy therefore have major implications. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01771835. PMID- 25793020 TI - Journal editors salute Jerry D. Estep and Matthias Loebe for their contribution to the special issue on mechanical assist devices. PMID- 25793021 TI - Overview of the current benefits and risks of continuous-flow left ventricular assist devices. PMID- 25793019 TI - DNA damage and inhibition of akt pathway in mcf-7 cells and ehrlich tumor in mice treated with 1,4-naphthoquinones in combination with ascorbate. AB - The aim of this study was to enhance the understanding of the antitumor mechanism of 1,4-naphthoquinones and ascorbate. Juglone, phenylaminonaphthoquinone-7, and 9 (Q7/Q9) were evaluated for effects on CT-DNA and DNA of cancer cells. Evaluations in MCF-7 cells are DNA damage, ROS levels, viability, and proliferation. Proteins from MCF-7 lysates were immunoblotted for verifying PARP integrity, gammaH2AX, and pAkt. Antitumor activity was measured in Ehrlich ascites carcinoma-bearing mice. The same markers of molecular toxicity were assessed in vivo. The naphthoquinones intercalate into CT-DNA and caused oxidative cleavage, which is increased in the presence of ascorbate. Treatments caused DNA damage and reduced viability and proliferation of MCF-7 cells. Effects were potentiated by ascorbate. No PARP cleavage was observed. Naphthoquinones, combined with ascorbate, caused phosphorylation of H2AX and inhibited pAkt. ROS were enhanced in MCF-7 cells, particularly by the juglone and Q7 plus ascorbate. Ehrlich carcinoma was inhibited by juglone, Q7, or Q9, but the potentiating effect of ascorbate was reproduced in vivo only in the cases of juglone and Q7, which caused up to 60% inhibition of tumor and the largest extension of survival. Juglone and Q7 plus ascorbate caused enhanced ROS and DNA damage and inhibited pAkt also in Ehrlich carcinoma cells. PMID- 25793022 TI - Treatment strategies for patients with an INTERMACS I profile. AB - Treatment of patients with INTERMACS class I heart failure can be very challenging, and temporary long-term device support may be needed. In this article, we review the currently available temporary support devices in order to support these severely ill patients with decompensated heart failure. Strategies of using a temporary assist as a bridge to long-term device support are also discussed. PMID- 25793023 TI - Ventricular assist devices as destination therapy: psychosocial and ethical implications. AB - One of the candidate evaluation challenges is determining when and how psychosocial domains influence short- and long-term destination therapy ventricular assist device (DT-VAD) outcomes. There are very few DT-VAD studies and no validated instruments to identify psychosocial risk factors. General practice is to borrow from the transplant literature, which may not be applicable to this unique device application. We question the relevance of using transplant psychosocial evaluation for patients who are candidates for DT-VAD only, particularly because these patients require a certain level of cognitive, psychological, and behavioral functioning to ensure proper long-term self-care with the VAD. We may be missing important psychological characteristics in our pre-evaluations by "borrowing" from the transplant literature, thereby underplaying significant factors that are especially relevant for DT-VAD candidates. Conversely, we may be screening out candidates who may benefit greatly from DT-VAD by using transplant criteria as part of the screening process. We use a case study to illustrate some of the challenges of weighing psychosocial risk factors in the DT-VAD population and to emphasize the need for developing distinct psychosocial assessment criteria for DT-VAD patients. PMID- 25793024 TI - Physiological impact of continuous flow on end-organ function: clinical implications in the current era of left ventricular assist devices. AB - The clinical era of continuous-flow left ventricular assist devices has debunked many myths about the dire need of a pulse for human existence. While this therapy has been documented to provide a clear survival benefit in end-stage heart failure patients, we are now faced with certain morbidity challenges that as of yet have no easy mechanistic physiological explanation. The effect of physiological changes on end-organ function in patients supported by continuous flow ventricular assist devices may offer insight into some of these morbidities. We therefore present a review of current evidence documenting the impact of continuous flow on end-organ function. PMID- 25793025 TI - Predictors and management of right heart failure after left ventricular assist device implantation. AB - Newer generation continuous-flow left ventricular assist devices (LVADs) have overall improved outcomes with lower incidences of right ventricular failure (RVF) than their pulsatile predecessors, yet RVF still occurs in 9% to 40% of LVAD recipients. Post-implant, RVF is associated with poor outcomes, end-organ dysfunction, high mortality, and reduced survival to transplant. Therefore, preoperative risk stratification, appropriate patient selection, and optimal timing of implant are of paramount importance. In this article, we review the definition, incidence, pathophysiology, and current risk prediction models for RVF and touch on the contemporary management of RVF perioperatively and post-LVAD implant. PMID- 25793027 TI - A review of infections in patients with left ventricular assist devices: prevention, diagnosis and management. AB - Since the advent of ventricular assist devices with smaller configurations and continuous-flow technology, survival rates for patients with end-stage heart failure have dramatically improved. While the burden of infectious complications is decreased in patients on continuous-flow ventricular assist devices compared to bulkier pulsatile-flow devices, infection remains one of the most common causes of morbidity and mortality. The majority of infections occur at the driveline exit site, beginning with a disruption or trauma to the barrier between the skin and driveline and sometimes spreading deeper. Once infections develop, they can be difficult to eradicate. Depending on the degree of infection, treatment options may include local wound care, antibiotics, or surgical treatment. Preventive strategies and careful surveillance are crucial to improve patient outcomes. PMID- 25793026 TI - Gastrointestinal bleeding after continuous-flow left ventricular device implantation: review of pathophysiology and management. AB - Gastrointestinal bleeding is one of the most common complications in patients with continuous-flow left ventricular assist devices. Though the exact pathophysiology is still unclear, continuous-flow physiology, acquired Von Willebrand disease, and formation of arteriovenous malformations in the gastrointestinal tract are implicated. An individualized plan of endoscopic therapy and anticoagulation management is required when caring for these patients. PMID- 25793028 TI - Continuous flow left ventricular assist devices: shared care goals of monitoring and treating patients. AB - Continuous-flow left ventricular assist devices (CF-LVADs) have been clinically adopted as a long-term standard of care therapy option for patients with end stage heart failure. For many patients, shared care between the care providers at the implanting center and care providers in the community in which the patient resides is a clinical necessity. The aims of this review are to (1) provide a rationale for the outpatient follow-up exam and surveillance testing used at our center to monitor patients supported by the HeartMate II((r)) CF-LVAD (Thoratec Corporation, Pleasanton, CA) and (2) provide the protocol/algorithms we use for blood pressure, driveline exit site, LVAD alarm history, surveillance blood work, and echocardiography monitoring in this patient population. In addition, we define our partnership outpatient follow-up protocol and the "shared care" specific responsibilities we use with referring health care providers to best manage many of our patients. PMID- 25793029 TI - Editorial: an interview with Dr. George P. Noon. PMID- 25793030 TI - Case report: necrosis of the anterolateral papillary muscle--an unusual mechanical complication of myocardial infarction. AB - We report the case of a 66-year-old woman with no significant past medical history who presented to the Emergency Department at Houston Methodist Hospital with 24 hours of chest pain. An electrocardiogram was done, an electrocardiogram confirmed a posterolateral ST elevation myocardial infarction. An immediate and successful percutaneous coronary intervention of a totally occluded ramus intermedius was performed. Six hours later she developed pulmonary edema, cardiogenic shock, severe acidosis, and anuria. Echocardiography showed severe mitral regurgitation due to a ruptured anterolateral papillary muscle, and emergency surgery revealed necrosis of this muscle. A bioprosthetic mitral valve was placed, and extracorporeal membrane oxygenation was needed for 3 days. This is a rare mechanical complication of myocardial infarction, which usually affects the posteromedial papillary muscle. The patient subsequently made a good recovery. One month later, just prior to discharge home, the patient developed pneumonia and sepsis, and she expired from multiorgan failure. PMID- 25793031 TI - Case report: a lead you can't miss: a case of right ventricular perforation. PMID- 25793033 TI - Editorial: Husband-and-wife editorial team at New England J Med. PMID- 25793032 TI - Case report: isolated cardiac amyloidosis: an enigma unravelled. AB - Amyloidosis is a rare, multisystem disease characterized by deposition of fibrils in extracellular tissue involving kidney, liver, heart, autonomic nervous system, and several other organs. This report discusses a 75-year-old male who presented with worsening dyspnea on exertion, orthopnea, and lower-extremity edema. On physical exam, he had elevated jugular venous pressure and lower-extremity edema. Electrocardiogram depicted low voltage in limb leads and a prolonged PR interval. Echocardiogram revealed left ventricular hypertrophy, severe biatrial dilatation, and restrictive filling physiology. Coronary angiography showed absence of significant epicardial coronary artery disease. On right heart catheterization, a "dip-and-plateau sign" was noted on right ventricular pressure tracings. A diagnosis of cardiac amyloidosis was considered, but a complete hematology work up for systemic amyloidosis was negative. Cardiac magnetic resonance imaging was pursued, showing delayed gadolinium enhancement, and this ultimately led to the myocardial biopsy confirming the diagnosis of isolated cardiac amyloidosis. Further genetic analyses confirmed isolated cardiac amyloid caused by mutant transthyretin protein (Val-122-Ile). Isolated cardiac amyloidosis is an extremely rare entity, and diagnosis may be difficult despite the use of multimodality imaging. If the index of suspicion is high, then myocardial biopsy should be considered. PMID- 25793034 TI - Editorial: 59 years of doctoring. PMID- 25793035 TI - Museum image: tricuspid. PMID- 25793036 TI - Points to remember: gastrointestinal pearls for the cardiovascular clinician. PMID- 25793038 TI - Dr. Phil's Art Corner: Tiger Mosaic and Tiger Mosaic Close Up. PMID- 25793040 TI - Risk factors for recurrent respiratory infections in preschool children in china. AB - OBJECTIVE: To identify and compare risk factors for recurrent respiratory infections in preschool children between resident and floating population in Yiwu, China. METHODS: Investigations was conducted in resident and floating population in Yiwu city, Zhejiang province. A structured questionnaire was used to collect information on influence factors. Univariate and multivariate analyses were carried out using the Binary logistic regression. Findings : The study was conducted in Yiwu from June 2009 to September 2010. We recruited 844 participants,resident population 639(75.7%) and floating population 205(24.3%) who were preschool children. Multivariate analysis showed that Childbearing age (OR=0.93, 95%CI: 0.88-0.99), Asthma (OR=3.20, 95%CI: 1.60-6.45), Rickets (OR=5.30, 95%CI: 1.99-14.09), Food preference (OR=1.57, 95%CI: 1.02-2.43), Snack (OR=1.50, 95%CI: 1.07-2.07) were the influence factors for recurrent respiratory infections in resident preschool children. Infant feeding (OR=2.24, 95%CI: 1.31 3.81), Snack (OR=2.06, 95%CI: 1.07-3.98,), Trip mode (OR=2.77, 95%CI: 1.11-6.94) were the influence factors for recurrent respiratory infections in floating preschool children. CONCLUSION: Public health measures against risk factors should be taken to protect against recurrent respiratory infections in resident and floating preschool children respectively. PMID- 25793039 TI - Periodic Fever: a review on clinical, management and guideline for Iranian patients - part I. AB - Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. The first manifestation of these disorders are present in childhood and adolescence, but infrequently it may be presented in young and middle ages. Genetic base has been known for all types of periodic fever syndromes except periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). Common periodic fever disorders are Familial Mediterranean fever (FMF) and PFAPA. In each patient with periodic fever, acquired infection with chronic and periodic nature should be ruled out. It depends on epidemiology of infectious diseases. Some of them such as Familial Mediterranean fever and PFAPA are common in Iran. In Iran and other Middle East countries, brucellosis, malaria and infectious mononucleosis should be considered in differential diagnosis of periodic fever disorders especially with fever and arthritis manifestation. In children, urinary tract infection may be presented as periodic disorder, urine analysis and culture is necessary in each child with periodic symptoms. Some malignancies such as leukemia and tumoral lesions should be excluded in patients with periodic syndrome and weight loss in any age. After excluding infection, malignancy and cyclic neutropenia, FMF and PFAPA are the most common periodic fever disorders. Similar to other countries, Hyper IgD, Chronic Infantile Neurologic Cutaneous and Articular, TRAPS and other auto inflammatory syndromes are rare causes of periodic fever in Iranian system registry. In part 1 of this paper we reviewed the prevalence of FMF and PFAPA in Iran. In part 2, some uncommon auto-inflammatory disorders such as TRAPS, Hyper IgD sydrome and cryopyrin associated periodic syndromes will be reviewed. PMID- 25793041 TI - Relationship between Biochemical Bone Markers and Bone Mineral Density in Patients with Phenylketonuria under Restricted Diet. AB - OBJECTIVE: Most of phenylketonuria (PKU) develops bone turnover impairment and low bone mineral density (BMD). Measurements of BMD reflect only bone mineral status but not the dynamics of bone turnover. Bone markers are a noninvasive tool useful for the assessment of bone formation and bone resorption processes. Our study was to assess the levels of bone markers in PKU in order to select a screen marker and detect the most specific marker which can be combined with BMD for appropriate follow up. METHODS: Thirty three classic PKU patients were studied. BMD and bone mineral content (BMC) were measured. Total alkaline phosphatase (ALP), osteocalcin (OC) and carboxy-terminal propeptide of type I collagen (CICP), osteoprotegerin (OPG), receptor activator of nuclear factor kappabeta ligand (RANKL) and Deoxypyridinoline (DPD) were measured. Findings : Nineteen (57.6%) male and fourteen (42.4 %) female PKU patients were involved in the current study. Their mean age was 8.4+/-4.6 yrs and the age range 3-19 yrs. The control group consisted of twenty two (52.4%) males and twenty (47.6%) females. Their mean age was 8.5+/-3.3 yrs and th age range 2-17 yrs. Using the Z score values, there was a significant decrease of total BMC (TBMC-Z), BMD of the femoral neck BMD-FN-Z, BMD of lumbar vertebrae (BMD-L-Z), BMD-FN and DPD while RANKL increased. There was a negative correlation between CICP and TBMC and between CICP and BMD-L in these patients. Also, a negative correlation between ALP and TBMC and between ALP and BMD-L was observed. It was concluded that the ALP provides a good impression of the new bone formation in the PKU patients and it has a highly significant negative correlation with the many parameters of the bone mineral status beside the wide availability of inexpensive and simple methods. So a screening test and/or follow up for the PKU patients using ALP would be available. Once the level of ALP decrease is detected, one can combine it with BMD to explore the bone mineral status and with specific bone markers (OC, RANKL and DBD), to verify the dynamics of bone turnover. CONCLUSION: This schedule will reduce the risk of exposure of these patients to the risk hazards of DXA and limit its use only to a limited number of the highly suspected cases. PMID- 25793042 TI - Synbiotics in Children with Cow's Milk Allergy: A Randomized Controlled Trial. AB - OBJECTIVE: Cow's milk protein allergy usually occurs in infants within the first months of life. It can affect several organs, but gastrointestinal symptoms are the most clinical symptoms observed. The most effective treatment is restricting the cow 's milk protein in mother and infant's diet. Lactobacillus GG supplementation in infant could be effective through modulation of the immune system and the gut microflora. METHODS: Thirty two breastfed infants with cow's milk protein allergy were enrolled in a double-blinded randomized controlled trial in which they received Synbiotic (n=16) or placebo (n=16) once a day for one month, simultaneously with cow's milk protein restriction in mother and infant's diet. Clinical gastrointestinal symptoms (vomiting, colic, rectal bleeding and diarrhea), head circumference, body length and weight were recorded at the beginning, the end of the first and third month of study. Findings : Percentage of increment in head circumference and weight were statistically more in synbiotic group compared with placebo group at the end of the first and third month of study. There was no significant difference in resolution of clinical gastrointestinal symptoms (vomiting, colic, rectal bleeding or diarrhea) and percentage of increment in body length. CONCLUSION: Synbiotic supplementation in infants may improve increment of head circumference and weight gain, but has no effect on resolution of clinical symptoms. PMID- 25793043 TI - Is supplementation efficacious in maintaining adequate plasma levels of vitamin a and e for thalassemic patients undergoing hematopoietic stem cell transplantation? A cross-sectional study. AB - OBJECTIVE: Thalassemia along with hematopoietic stem cell transplantation (HSCT) can lead to major oxidative stress. Vitamins A and E are antioxidants which protect membrane from lipid peroxidation. We sought to determine for the first time, whether vitamins A and E supplementation is efficacious in maintaining or increasing plasma level of these vitamins in thalassemic children undergoing HSCT. METHODS: A cross-sectional study was performed on 50 children with beta thalassemia major hospitalized for HSCT. Patients took a daily multivitamin. Plasma vitamins A and E levels were measured at four different times: on admission, HSCT day (day 0), day 7 and day 14 after HSCT. Findings : Plasma vitamin A and E were abnormal on admission in most patients (62.0% and 60.0% respectively). Ratio of patient with normal to abnormal plasma level of the vitamins improved from baseline to a peak on day 7 then deteriorated afterward until day 14. There was an increasingly positive correlation between daily oral intake and plasma vitamin A at different times, but plasma vitamin E showed inverse correlation at first which tended towards no correlation subsequently. In multivariate analysis, supplementation significantly changed plasma level of vitamin A at different measurement time (P=0.001) within study subjects. But, plasma level of vitamin E showed no significant difference (P=0.2). CONCLUSION: Our findings suggest that oral supplementation could have beneficial effects due to increasing plasma vitamin A level and preventing plasma vitamin E depletion. PMID- 25793045 TI - Effect of natural-feeding education on successful exclusive breast-feeding and breast-feeding self-efficacy of low-birth-weight infants. AB - OBJECTIVE: The ideal nourishment for newborns with low birth-weight is breast milk. The purpose of the study was to determine the effect of natural-feeding education given to mothers of low-birth-weight infants, on the mothers' breast feeding self-efficacy level, breast-feeding success, and the growth of the infants. METHODS: The study was conducted in a quasi-experimental way. The study group consisted of a total of 85 low-birth-weight infants and their mothers who had been treated in the neonatal clinics of two hospitals. The mothers included in the test group were given breast-feeding education for half an hour per day, during the first 5 days of their hospitalization. Home visits were carried out at the homes of the participants from both the test and control groups, until the infants reached 6 months of age. For collecting data, the following forms were used: Personal Information Form, Breast-feeding Self-Efficacy Form, LATCH Breast feeding Assessment Tool, and Anthropometric Measurements Form. For analyzing the collected data, percentage, arithmetic mean, standard deviation, and chi-square we used, and, in independent groups, t-tests were employed. Findings : It was determined that natural-feeding education given to the mothers increases their breast-feeding self-efficacy levels and success in breast-feeding (P<0.05). It was found that in the test group, the rate of feeding the infants exclusively with breast milk is higher in comparison with the control group (P<0.001). CONCLUSION: Results of the study indicate that natural-feeding education increases breast-feeding self-efficacy levels, breast-feeding success, and the breast-feeding duration. PMID- 25793044 TI - The Association between Patent Ductus Arteriosus and Perinatal Infection in A Group of Low Birth Weight Preterm Infants. AB - OBJECTIVE: Patent ductus arteriosus (PDA) is an extremely common occurrence in very premature infants. Untreated symptomatic PDA may be associated with chronic lung disease. PDA has a major role in neonatal mortality and morbidity. We compared the efficacy and safety of oral versus intravenous ibuprofen for the pharmacological closure of PDA in low birth weight (LBW) preterm infants. METHODS: A randomized, single-blinded, controlled study was performed on premature neonates at the neonatal unit, University Hospital for Obstetrics and Gynecology "Koco Gliozheni", Tirana, Albania from January 2010 to December 2012. The study enrolled 68 preterm infants with a confirmed and significant PDA. The preterm infants received either intravenous or oral ibuprofen randomly as an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h. Findings : 36 patients were treated with oral ibuprofen and 32 with intravenous ibuprofen during this period. After the first course of the treatment, the PDA closed in 30 (83.3%) of the patients assigned to the oral ibuprofen group versus 23 (71.8%) of those enrolled in the intravenous ibuprofen group (P=0.355). 15 patiens needed a second treatment course and they all (100%) had clinical signs of infection and positive blood culture. There was no reopening of the ductus after the closure. CONCLUSION: Our data indicate that, for LBW infants, the rate of early ductal closure was comparable and the adverse effects were fewer with oral ibuprofen in comparison to the intravenous route. Association of PDA with perinatal infection has a negative impact in pharmacological closure of the ductus, increasing the need for a second course of treatment or for surgery. PMID- 25793046 TI - Management of Neonatal Respiratory Distress Syndrome Employing ACoRN Respiratory Sequence Protocol versus Early Nasal Continuous Positive Airway Pressure Protocol. AB - OBJECTIVE: Respiratory distress syndrome (RDS) is a common cause of respiratory distress in premature infants. This study was designed to evaluate two different RDS treatment protocols by comparing the outcomes. METHODS: This study was a double center cross sectional study performed from June to December 2012. During that period, 386 neonates with RDS were hospitalized and treated according to two different therapeutic protocols so-called Acute Care of at-Risk Newborns (ACoRN) respiratory sequence protocol (group I) and Early Nasal Continuous Positive Airway Pressure (E-NCPAP) protocol (group II). The variables and main outcomes of this study were gestational age, birth weight, bronchopulmonary dysplasia (BPD), pulmonary hemorrhage (PH), intraventricular hemorrhage (IVH), air leak and mortality rate (MR). Findings : Out of 386 infants, 202 infants were in group I (male 60.4%, female 39.6%, mean gestational age 31(6/7) weeks, mean birth weight=1688 grams) and group II included 184 infants (male 61.4%, female 38.6%, mean gestational age 32 weeks, mean birth weight 1787 grams), P= 0.07. The ratios of BPD of group I to group II and PH of group I to group two were not significant (P=0.63 and P=0.84, respectively). Air leak ratio in group I was higher than in group II (P=0.001). Although IVH ratio in group II was higher than in group I (P=0.01), grade III and IV IVH was higher in group I (30% vs. 4.6%). In case of MR, it was higher in group I than in group II (P=0.001). CONCLUSION: According to the findings the incidence of air leak, grade III and IV IVH and MR was less common in E-NCPAP protocol, so it may show the effectiveness of this protocol. The authors suggest that more researches are needed for more accurate results. PMID- 25793047 TI - PFAPA and 12 Common MEFV Gene Mutations Our Clinical Experience. AB - OBJECTIVE: Marshall Syndrome or PFAPA is an inflammatory periodic disease characterized by periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Although PFAPA is an auto inflammatory disease, it doesn't have genetic basis such as other periodic fevers. This study evaluates the 12 common MEFV gene mutations in patients with PFAPA syndrome. METHODS: 21 patients with PFAPA syndrome who had diagnostic criteria were enrolled in this study and 12 common MEFV gene mutations i.e. P369S, F479L, M680I (G/C), M680I (G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q evaluated. All the patients were screened for MEFV gene mutations by a reverse hybridization assay (FMF Strip Assay, Vienna lab, Vienna, Austria) according to the instructions provided by the manufacturer. Findings : The age of patients was between 6 months to 14 years, and 15 were males. Seven patients had heterozygote and one had compound heterozygote (K695R, V725A) mutation. There were 4 alleles M694V, 3 alleles V726A, 1 allele E148Q and 1 allele K694R. No significant difference existed between mutated patients with non-mutated in symptoms like aphthous and stomatitis, duration of attacks, episodes of fever and response to treatment. Gaslini score test was not helpful to predict the probability of gene mutations. CONCLUSION: About 30 percent of patients had MEFV gene mutations but these mutations did not play a main role in presentation of PFAPA symptoms. PMID- 25793048 TI - Etiologic and epidemiologic pattern of urolithiasis in north iran;review of 10 year findings. AB - OBJECTIVE: To determine epidemiologic and metabolic characteristics of renal stone in the northern Iran. METHODS: We prospectively analyzed demographic, clinical and metabolic findings in children less than 16 years old with renal stone revealed by ultrasonography from September 2003 to May 2012. Evaluations included serum and urine measurement of main elements predisposing patients to stone formation. Findings : 271 children (160 males) aged 2 months to 16-years (mean 30 months) were evaluated. 91 (33.6%) had a positive family history, abdominal discomfort (18.8%), UTI (11.8%) and hematuria (11.4%) were main presenting features. 45 children were diagnosed accidentally without any specific compliant. Nearly all (99%) stones lay in kidney., 35.1% had metabolic, 10% infective and 4.1% obstructive trends, 110 children had no definable etiology. Hypercalciuria (25.5%) hyperoxaluria (18.4%) and hypocitraturia (18.1%) were more frequent than uricosuria (8.5%) and cystinuria (3.1%) CONCLUSION: Metabolic derangement plays significant role in stone formation in our area. Patients should be carefully evaluated considering this point of view. PMID- 25793049 TI - Treatment of children with advanced-stage lymphoblastic lymphoma with pegaspargase. AB - OBJECTIVE: To evaluate the feasibility of Pegaspargase instead of L-asparaginase to treat children with advanced-stage lymphoblastic lymphoma (LBL) on the Berlin Frankfurt-Munster (BFM)-95 protocol. METHODS: Fifty-four newly diagnosed patients with stage III or IV LBL and without any treatment were enrolled in this study. Pegaspargase took place of L-asparaginase in BFM-95. The complications and treatment responses of patients treated on the BFM-95 protocol and modified BFM 95 protocol were then evaluated respectively. Findings : For LBL patients treated with BFM-95 protocol or modified BFM-95 protocol, the complete response, event free survival, overall survival were similar. Stage 4 myelosuppression was the most common complication in both groups. Besides that, among 31 patients receiving modified BFM-95 protocol, coagulation defects were the most common complication. In contrast, anaphylactic reaction was the most common complication in the other 23 patients receiving BFM-95 protocol. CONCLUSION: Modified BFM-95 protocol is available to children with advanced-stage LBL with an equal outcome and enhances its compliance and decreases the incidence of anaphylactic reaction, compared to BFM-95 protocol. Coagulation defects are the major complication and tolerable in modified one. PMID- 25793050 TI - Renal function in children with cyanotic congenital heart disease: pre- and post cardiac surgery evaluation. AB - OBJECTIVE: Cyanotic congenital heart diseases (CCHDs) are a series of cardiac anomalies that have long been recognized as a potential cause of nephropathy. There have been few reports on renal impairment in patients with CCHD before and after corrective cardiac surgery. The aim of this study was to evaluate the prevalence of renal dysfunction before and after cardiac surgery and the impact of some risk factors on final renal outcome. METHODS: Thirty children with CCHD who had done corrective cardiac surgery in the previous 6 months were enrolled in this study. All data prior to surgery were collected from the charts. Post operation data including blood and spot urine samples were taken simultaneously for CBC, Cr, and uric acid and 24 hour urine was collected for microalbumin and Cr during the follow up visits. Pre- and post-operation parameters were compared to study the impact of cardiac surgery on renal function. Findings : Pre- and post-operative GFRs were not significantly different. Final GFR was significantly and inversely associated with pre- and post-operation age (P=0.008 r=-0.48, P=0.03 r=-0.38). Three (10%) patients had microalbuminuria. The prevalence of microalbuminuria in children older than 10 years was 30%. There was no link between microalbuminuria and age, GFR, and hematocrit (P=0.1, P=0.3, P=0.3, respectively). Patients with preoperation hematocrit >45 had a significantly lower final GFR compared to children with HCT <45 (83.7+/-6.5 vs 111.10.2, P=0.001). The mean uric acid fraction (FEua) excretion was 8.21+/-4.75. Pre operative HCT was inversely associated to FEua (P=0.01, r=-0.44). There was no relationship between FEua and age, serum uric acid, and GFR (P=0.7, P=0.4, P=0.2). CONCLUSION: Children with CCHD are at increased risk of renal injury which is related more to the duration of cyanosis and higher degree of hematocrit level. To lower the risk, corrective cardiac surgery is recommended to be done as soon as possible to improve renal function and stop more renal impairment. PMID- 25793052 TI - The Association between Weight for Gestational Age and Kidney Volume: A Study in Newborns in India. AB - OBJECTIVE: The association of low birth weight (LBW) with adult onset diseases like hypertension is suggested to be partially mediated by a low number of nephrons at birth. Studies have established a relation between LBW and renal volume as the latter is a surrogate marker of total nephron number. Most such studies have considered birth weight or gestational age as separate independent predictors, without taking into consideration the baby's weight with respect to its gestational age. This study aims to investigate the influence of weight for gestational age on kidney volume in newborns. METHODS: Consecutive newborns delivered in the department of neonatology in a tertiary care medical college and hospital, were included in a cross-sectional study. The subjects were classified as appropriate for gestational age (AGA) and small for gestational age (SGA) as per Lubchenco's charts of weight for gestational age (WGA). Bilateral kidney dimensions were measured by a single observer and combined kidney volumes were calculated and compared between the groups. Findings : Four hundred and seventeen newborns (SGA 159; AGA 258) were included. The mean combined kidney volume (CKV) was significantly lower among SGA newborns (13.85+/-4.02 cm(3)) compared to that of AGA (16.88+/-4.53 cm(3)) (P<.001). Univariable and multivariable analyses were done for assessing the effect of demographic, anthropometric and maternal parameters on CKV. WGA, crown heel length, gestational age and postnatal age (hours of life) were independent predictors of mean CKV. An SGA newborn was expected to have a mean CKV 1.57 cm less (95% CI -2.49 cm to -0.65 cm) than that of its AGA counterpart. CONCLUSION: Considering the future implications of being SGA and having low kidney volumes at birth, it is essential to have an objective depiction of the relationship between these two vital parameters. This study from the Indian subcontinent brings forth such an association. PMID- 25793051 TI - Evaluation of physicians' awareness of pediatric diseases in iran. AB - OBJECTIVE: Physicians' awareness about pediatric health problems is very important in health system. This has not been investigated in Iran as yet. Therefore this study was conducted to characterize the knowledge of the Iranian physicians which has direct association with health status of children. METHODS: One hundred and four physicians, mainly pediatric specialists (58.6%) working in the state hospitals (45.1%) were enrolled. They filled a valid and reliable questionnaire, containing 26 questions about basic and important pediatric issues before and after an educational pediatric program (EPP). Findings : Thirty nine (37.5%) physicians answered correctly more than 2/3 of all questions (passed the examination) before EPP, which increased to 42.3% after EEP. Subgroup analysis showed that the total scores of general practitioners (P=0.007) was significantly increased after the EPP. Moreover, physicians with shorter practicing time (P=0.006) and those with shorter time past graduation (P=0.01) had a significant improvement in their total scores after the program. The best scores of educational issues were documented in growth and development (16.0%; P=0.04), followed by dermatology (9.2%, P=0.04), urology (9.1%; P=0.04), and asthma and allergy (9.0%, P=0.04). CONCLUSION: This study revealed that there are gaps in the knowledge of professionals about the pediatric issues. PMID- 25793053 TI - Efficacy of pregabalin in childhood refractory partial seizure. AB - OBJECTIVE: About one third of partial seizures are refractory to treatment. Several anticonvulsant drugs have entered the market in recent decades but concerns about intolerance, drug interactions, and the safety of the drug are notable. One of these new anticonvulsants is pregabalin, a safe drug with almost no interaction with other antiepileptic drugs. METHODS: In this open label clinical trial study, pregabalin was used for evaluation of its efficacy on reducing seizure frequency in 29 children suffering from refractory partial seizures. Average daily and weekly seizure frequency of the patients was recorded during a 6-week period (baseline period). Then, during a period of 2 weeks (titration period), pregabalin was started with a dose of 25-75 mg/d, using method of flexible dose, and was brought to maximum dose of drug that was intended in this study (450 mg/d) based on clinical response of the patients and seizure frequency. Then the patients were given the drug for 12 weeks and the average frequency of daily and weekly seizures were recorded again (treatment period). Findings : Reduction in seizure frequency in this study was 36% and the responder rate or number of patients who gained more than 50% reduction in seizure frequency was 51.7%. CONCLUSION: This study showed that pregabalin can be used with safety and an acceptable efficacy in treatment of childhood refractory partial seizures. PMID- 25793054 TI - Changes in Structure, Interstitial Cajal-like Cells and Apoptosis of Smooth Muscle Cells in Congenital Ureteropelvic Junction Obstruction. AB - OBJECTIVE: The goal of this study is to evaluate some structural changes in muscular, collagenous and neural components as well as expression of Cajal-like cells and apoptosis of smooth muscle cells in congenital ureteropelvic junction obstruction (UPJO). METHODS: Tissue specimens were obtained from 25 patients with UPJO and compared with normal ureteropelvic junction regions of 19 autopsies. In paraffin embedded sections the amount of Cajal-like cells, density of nerve fibers and smooth muscle cell apoptosis (using immunohistochemical staining) were determined. Collagen deposition and muscular components were stained by Trichrome Masson staining and evaluated by image analysis techniques. Arrangement of muscular bundles was also evaluated qualitatively. Findings : The number of Cajal like cells was significantly lower in patients than in controls. The apoptotic score and mean number of nerve fibers were not statistically different for the two groups. Arrangement of muscular fibers was more irregular in patients than in controls (P<0.001). Collagen deposition was significantly higher in patients than in controls (P<0.001). The mean amount of muscular component was lower in patients than in normal ones. (P= 0.09) CONCLUSION: We found significant pathologic changes in congenital ureteropelvic junction obstruction such as decrease in Cajal-like cells, increase in collagen deposition and irregular arrangement of muscle fibers. PMID- 25793055 TI - Prevalence of using complementary and alternative medicine in children and its related factors in East iran. AB - OBJECTIVE: Recently application of complementary and alternative medicine (CAM) is increasing in children worldwide. The present study was conducted to determine the prevalence, related factors, types, the sources of information and knowledge of mothers for the possible side effects. METHODS: This descriptive and analytical study carried out within three months from April-June 2012 through oral interviews and questionnaires with 300 mothers of children referred to pediatric clinic in Vali-Asr Hospital, Birjand (center of South Khorasan province: East of Iran). Findings : 35.6% of mothers had used CAM as medication at least once for their children during the last year. There was a significant and direct correlation between using CAM for children with increased maternal age, decreased level of mother's education, mother being as a housewife and having more than two children. Most (93.3%) common treatments included medicinal herbs, oil rub (26.6 %) and prayer therapy (25.7%). Relative (72%) and neighbors (50%) were the most sources for mother's information while physicians consist only 2% of the information source. Only 1.3% of mothers knew that CAM may also exert some side effects. CONCLUSION: Considering the fact that about one third of mothers used CAM modalities, physicians were the least maternal source of CAM information, nearly all mothers were unaware of the side effects of CAM It is recommended that physicians should learn about the CAM to enable them for providing information to parents regarding its benefits and disadvantages. It is also highly recommended to enhance community knowledge about the proper use of different kinds of CAM. PMID- 25793056 TI - Prevalence of G6PD Deficiency in Neonatal Sepsis in Iran. PMID- 25793057 TI - A case of pneumoscrotum following spontaneous colonic perforation and mimicking strangulated inguinal hernia. PMID- 25793058 TI - Gender-based differences in anthropometry and cord blood insulin levels in term neonates. PMID- 25793059 TI - Native right ventricular outflow tract stenting in a child with tetralogy of fallot and absent left pulmonary artery. PMID- 25793060 TI - Comparison of Children's Oral Health Related Quality Of Life Pre- and Post Dental Treatment Under General Anesthesia Using F-ECOHIS Questionnaire. PMID- 25793061 TI - From Concept to Bedside: What Pediatricians Should Know about Synthesis of Clinical Practice Guidelines? AB - Clinical Practice guidelines (CPGs) have emerged as a potentially effective intervention in delivering a high quality, consistent, safe and evidence-based health care. CPGs can either be developed by de novo synthesis or by adaptation of existing guidelines formed in another organization. Guideline recommendations are formulated based on strength of the evidence, validity, clinical relevance and patient values. Support of the organization leadership, role modeling of senior staff and involvement of stakeholders is a key to the success of implementation of guidelines. This article aims to enhance a practicing pediatrician's understanding of how guidelines are developed, disseminated, and potentially utilized. PMID- 25793062 TI - Metformin and diabetic kidney disease: a mini-review on recent findings. AB - Metformin, an oral anti-diabetic agent in the biguanide class is a widely prescribed drug to treat high blood glucose in patients with type 2 diabetes mellitus. Metformin has three different roles, including blood glucose regulatory effect, protection of kidney tubular cell by acting as an effective antioxidant and finally ameliorative effect on diabetic kidney disease through saving the podocytes. Therefore, diabetic patients may benefit from all of these three distinct ameliorative effects. PMID- 25793063 TI - Risk Factors and Predictors of Mortality in Critically ill Children with Extensively-Drug Resistant Acinetobacter baumannii Infection in a Pediatric Intensive Care Unit. AB - OBJECTIVE: Acinetobacter baumannii is an important emerging cause for extensively drug resistant (XDR) hospital associated infections (HAIs) in pediatric intensive care units (PICU). The study was done to evaluate the risk factors, outcome, antibiotic sensitivity pattern, and predictors of mortality in critically ill children with XDR A. baumannii infection. METHODS: Retrospective case control study, done in the PICU of a tertiary care pediatric hospital of India from April 2010 to March 2012. FINDINGS: Eighty-five children who developed XDR A. baumannii infection matched to 170 controls. Majority (76%) of the organisms were isolated from endotracheal lavage. The mortality rate was 28.2% (24/85). The factors found to be significantly associated with A. baumannii infection were prior use of broad-spectrum antibiotics, major surgeries done, prolonged PICU stay, use of central venous catheters, and mechanical ventilation. The predictors of mortality associated with A. baumannii infection were acute kidney injury, presence of septic shock, and disseminated intravascular coagulopathy. Colistin found to be the single most effective drug against XDR A. baumannii infection. CONCLUSION: XDR A. baumannii infections are associated with high morbidity and mortality in critically ill children. Early diagnosis and treatment are crucial. Implementation of infection control practices and rational use of antibiotics are required to control such infections. PMID- 25793064 TI - Restricted versus Standard Maintenance Fluid Volume in Management of Transient Tachypnea of Newborn: A Clinical Trial. AB - OBJECTIVE: The incidence of Transient Tachypnea of Newborn (TTN) is higher in infants born by cesarean section than with vaginal delivery. Treatment of transient tachypnea of newborn is supportive. The purpose of this study was to assess the effect of restricted fluid volume intake on the course of respiratory distress in patients with TTN. METHODS: This is a quasi-experimental clinical trial of 83 neonates diagnosed with TTN admitted to a neonatal intensive care unit in south west Iran. In this study the effect of restriction of maintenance fluid volume in the course of respiratory distress in newborns with transient tachypnea was assessed. FINDINGS: In the standard fluid volume intake group 18 (42.8%) cases needed nasal continuous positive airway pressure (NCPAP) and one (2.38%) case mechanical ventilation, and in restricted fluid volume intake group 13 (32.5%) cases needed NCPAP and two (5%) cases mechanical ventilation. 54.82% of cases were supported with oxyhood in the standard fluid volume and 62.5% in the restricted fluid volume intake group. Differences in duration of the needed NCPAP and oxygen hood between the two groups were significant. Fluid restriction had no adverse effect on the urine specific gravity or weight loss of the studied newborns. CONCLUSION: Limited fluid administered to newborns with transient tachypnea of newborn is safe and resulted in shorter duration of respiratory support. PMID- 25793065 TI - Motor developmental status of moderately low birth weight preterm infants. AB - OBJECTIVE: Motor development is frequently reported to be impaired in very low birth weight (VLBW) infants, but little is known about the moderately low birth weight (MLBW) infants. The aim of this study was to investigate whether MLBW preterm infants present developmental delay. METHODS: In a historical cohort study, 18+/-2 month-old infants with a history of low birth weight (LBW) were identified. All infants with complications of LBW with negative effects on development were excluded. Healthy infants with normal birth weight (2500-4000 g) were included as controls. All infants were evaluated by the Peabody Developmental Motor Scale II (PDMS-2) test and final scores compared between the two groups. FINDING: 88 infants including 58 MLBW and 30 NBW with a mean birth weight of 1900+/-382.4 g and 3150+/-473.5 g respectively, were studied. In the MLBW group, gross and fine motor skill scores were below average in 6 (6.8%) and 10 (17%) infants, respectively. There were no significant differences between the two groups according to gross motor quotient (102.5+/-5.5 in NBW vs 100.1+/-7.2 in MLBW; P=0.1), but MLBW infants achieved significantly lower scores in fine motor (93.3+/-5.4 vs 99.6+/-5.0; P=0.001) and total motor quotient (97.0+/-5.9 vs 101.53+/-5.0; P=0.001). CONCLUSION: The finding of this study show developmental defects in fine motor skills in MLBW infants. Accurate monitoring of the developmental status of this population should be emphasized for an earlier recognition and intervention. PMID- 25793066 TI - Prevalence of celiac disease in children with idiopathic dilated cardiomyopathy. AB - OBJECTIVE: This study aimed to evaluate the prevalence of celiac disease (CD) in the patients with dilated cardiomyopathy (DCM). Simultaneous presentation of these two diseases has been recently reported in some studies; however, few researches have been done on children. The sooner CD is diagnosed, the better the prognosis will be, especially in the patients with a chronic disease like DCM. METHODS: In this study, 82 cases were screened for CD by measuring the level of anti-body against transglutaminase (anti tTG). These cases included 41 patients with DCM labeled according to clinical evaluation and echocardiography and 41 healthy children who had been referred for routine checkup. All the patients were between 1 and 18 years old. The expired patients and those with previous diagnosis of CD were excluded from the study. Besides, the patients with positive antibody results underwent intestinal biopsy to match the serology findings with histopathology of CD in the intestine. Finally, the data were analyzed by the SPSS statistical software (v. 16) and through t-test and Pearson correlation coefficient. FINDINGS: According to the findings, 1/41 (2.5%) DCM cases had positive tTG antibody level and negative intestinal biopsy which is classified as potential CD in the children with DCM. In addition, 7/41 (17%) patients had borderline anti body level. A direct correlation was observed between age and anti tTG level. CONCLUSION: It is beneficial to assess CD in DCM children with unknown cause. PMID- 25793067 TI - Safety and efficacy of phenylephrine nasal drops in bronchiolitis. AB - OBJECTIVE: Bronchiolitis is a common lower respiratory tract infection in the first year of life. In this disease upper respiratory tract infection is associated with nasal congestion, respiratory distress and hypoxia. We studied the effect of phenylephrine drops as a decongestant in treatment of light and moderately severe cases of acute bronchiolitis. METHODS: This is a double blind randomized trial involving 100 children aged 4 weeks to 12 months. The patients were divided into two groups, the first group received 0.1 ml phenylephrine 0.5% and the second group 0.1 ml sodium chloride (NaCl) 0.9% as placebo in both nostrils. Respiratory rate, heart rate, O2 saturation, dyspnea, retractions and wheezing were assessed before and 30 minutes after medication. FINDINGS: After medication, O2 saturation and respiratory muscles retractions in the phenylephrine group were significantly better than those of the placebo group (P=0.004 and P=0.002, respectively). In the phenylephrine group, O2 saturation, retractions and wheezing were also significantly better before than those after medication (P=0.003 and P<0.0001 respectively). In the placebo group no significant difference before and after intervention was observed. CONCLUSION: Phenylephrine as a topical decongestant is an inexpensive, easily available and suitable means in the treatment of mild to moderately severe bronchiolitis. PMID- 25793068 TI - Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) Syndrome in Iranian Children First Report of Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR). AB - OBJECTIVE: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a nonhereditary idiopathic febrile syndrome belonging to the group of autoinflammatory diseases. No longtime sequel was reported in this disease. Early diagnosis can lead physicians to treatment of this disorder with a short course steroid application and provide satisfaction of the patient's family. METHODS: This study is a prospective review of patients diagnosed with PFAPA syndrome who were registered in Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR) through periodic fever clinic in the Children's Medical Center, Pediatric Center of Excellence in Tehran, Iran from January 2013 to March 2014. FINDINGS: One hundred thirty patients were registered in our databases. Twenty-one (16.1%) patients including 15 males and 6 females had PFAPA. Normal growth was seen in all patients. The median age at onset was 18 months. The mean duration of fever was 4 days and the mean duration of intervals between fever episodes 21 days. Along with fever, all patients had characteristic symptoms. All patients were asymptomatic between fever episodes. Steroid was used in all patients and causing immediate reduction by 84.61%. Two patients received both steroid and colchicine because of their clinical feature and positive laboratory tests for PFAPA and familial Mediterranean fever. No patient received biological therapy or a tonsillectomy. CONCLUSION: The long diagnostic delay of PFAPA gives cause to concern indicating a need for greater awareness of the disease so that the diagnosis may be made timely. PMID- 25793069 TI - Comparison between the Ability of Glasgow Coma Scale and Full Outline of Unresponsiveness Score to Predict the Mortality and Discharge Rate of Pediatric Intensive Care Unit Patients. AB - OBJECTIVE: Prediction of survival and mortality rates in costly environments such as the intensive care unit (ICU) is of great importance for the assessment of new treatments, resource consumption control, and improvement of quality control. This study aimed to determine the ability to predict mortality and discharge rate of patients using the FOUR score in the pediatric ICU (PICU) of Ali Ibn Abitalib Hospital, Zahedan and compare the results with those of Glasgow Coma Scale (GCS). METHODS: This prospective study was conducted on 200 patients admitted to the PICU. Convenience purposive sampling was used. Research data was collected using the Full Outline of Unresponsiveness (FOUR) score and GCS using questionnaires. Obtained data was analyzed with SPSS 16 using descriptive statistics and correlation analyses. FINDINGS: Of the 200 children admitted to the PICU, 71.5% and 28.5% were discharged and died, respectively. The inter-rater reliability for the FOUR score was good to excellent (weighted kappa: eye, 0.72; respiration, 0.82; brainstem, 0.74; motor, 0.78), In terms of mortality and discharge prediction, logistic regression analyses (FOUR score = OR: 0.13; 95% CI: 0.06 0.29; P<0.001; GCS=OR: 2.49; 95% CI: 1.44-4.32; P<0.001) showed that the FOUR score is a good predictor for in-hospital mortality. CONCLUSION: Results indicated that the FOUR score is more capable than GCS in predicting the mortality and discharge of patients admitted to the PICU. PMID- 25793070 TI - Dermatoglyphic patterns in cystic fibrosis children. AB - OBJECTIVE: It is believed that fingerprints and palm patterns may represent genetically determined congenital abnormalities in Cystic Fibrosis (CF). The main idea of this paper was to determine differences of fingerprints and palm patterns in CF and normal children. METHODS: Forty-six CF children (27 males, 19 females) and 341 (113 males, 228 females) healthy individuals were recruited for this study. Fingerprint patterns, Total ridge count (TRC) of each finger, a-b ridge count, and atd angles of all participants were recorded. Asymmetry of the right and left hand for each value was determined and dissimilarity in fingerprint patterns between homologous fingers was compared using Chi-square analysis, Mann Whitney U test and Fisher's exact test. FINDINGS: There were significant differences in the mean TRC of the right digit IV (P=0.009), left digit III (P=0.02), left digit IV (P=0.03), and left digit V (P=0.03). Furthermore, we found significant differences in right atd angel (P=0.001), left atd angel (P=0.002), right a-b ridge (P=0.007) and left a-b ridge (P=0.001). In contrast, we found no significant differences in atd angle asymmetry, a-b ridge count asymmetry and pattern dissimilarity score between both groups (P>0.05). CONCLUSION: Dermatoglyphic characteristics could be used as a supplementary diagnostic method in CF children. PMID- 25793071 TI - Mean platelet volume as a negative marker of inflammation in children with rotavirus gastroenteritis. AB - OBJECTIVE: Mean platelet volume (MPV) is a determinant of inflammation. The aim of the present study was to investigate the MPV levels in children with rotavirus gastroenteritis and to evaluate the possible relationship between MPV and severity of gastroenteritis. METHODS: Children diagnosed with acute rotavirus gastroenteritis and healthy controls were enrolled in this study. Patients were classified into three disease severity groups based on their Vesikari score (<7 mild, 7-10 moderate and >11 severe). Rotavirus was determined in fresh stool samples using ELISA test. Leukocyte and platelet counts, MPV and C-reactive protein (CRP) levels were assessed for all children. FINDINGS: A total of 151 patients with rotavirus gastroenteritis (mean age 2.41+/- 0.14 years) and 80 healthy controls (mean age 2.63+/-0.22 years, P=0.129) were enrolled. MPV levels of children with rotavirus gastroenteritis were significantly lower than those of healthy peers (7.48+/-0.04 vs 7.79+/-0.07 fl, P=0.000). MPV levels were not significantly different among three gastroenteritis groups. Gastroenteritis score was positively correlated with leukocyte (r=0.670, P<0.01) and platelet count (r=0.159, P<0.05) and CRP level (r=0.256, P<0.01) in patients group. MPV was inversely correlated with platelet count. There was no significant correlation between MPV and gastroenteritis score. CONCLUSION: MPV levels were significantly lower in children with rotavirus gastroenteritis compared to controls. MPV can be used as a negative acute phase reactant in children with rotavirus gastroenteritis. PMID- 25793072 TI - Diagnostic value of procalcitonin and apo-e in extrahepatic biliary atresia. AB - OBJECTIVE: Extrahepatic biliary atresia (EHBA) is one of the main causes of neonatal cholestasis. Its early diagnosis could increase the survival of the infants with early surgery. We evaluated the diagnostic accuracy of procalcitonin and apolipoprotein E (Apo-E) levels in infants with and without EHBA. METHODS: This prospective study included 18 infants with EHBA and 15 infants with other causes of cholestasis. Blood samples were taken from each patient and different markers including procalcitonin and Apo-E levels were measured. ROC analysis was used to define sensitivity, specificity, positive and negative predictive value (PPV and NPV) for procalcitonin and Apo-E. Findings : There was a significantly positive correlation between Apo-E and SGOT (r=0.37, P=0.03), SGPT (r=0.38, P=0.02) and GGT (r=0.38, P=0.02), and an inverse correlation between procalcitonin and GGT (r=-0.45, P=0.01). Area under curve (AUC) for procalcitonin was 0.69 (P=0.05) with cut-point of 0.735 ng/ml. The sensitivity, specificity, PPV and NPV was 67%, 61%, 69% and 59%, respectively. AUC for Apo-E was 0.68 (P=0.06) for cut-point of 61.25 ng/ml with sensitivity, specificity, PPV and NPV of 67%, 67%, 71% and 67%, respectively. CONCLUSION: Both PCT and Apo-E have relatively good accuracy in diagnosing EHBA cases; we could not rely on these markers for diagnosis of EHBA, however, combinations of these biomarkers with other markers and imaging tests could improve their accuracy and may help to achieve a rapid and accurate diagnosis of EHBA. PMID- 25793073 TI - Effects of Metoclopramide on Feeding Intolerance among Preterm Neonates; A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the efficacy and safety of metoclopramide in the treatment of feeding intolerance in preterm neonates less than 36 weeks of gestational age. METHODS: A randomized, controlled, masked cross-over study. A block of 4 randomizations was used. The "drug group" received intravenous metoclopramide before feeding and placebo group received placebo at the same time. The time to full enteral feeding and suspected adverse effects of metoclopramide, length of hospital stay or incidence of NEC or septicemia were the main outcome measures. FINDINGS: Mean (standard deviation) of weight and Apgar score among metoclopramide and placebo groups were 1638.3+/-321 gr, 8.9+/-1.4 and 1593.3+/ 318.8 gr, 8.8+/-1.3 respectively. Times to full feeding were significantly shorter in the metoclopramide group than in the control group (12.9+/-5.6 vs 17.0+/-6.3; P<0.0001) and also the numbers of withheld feedings were significantly lower (P<0.0001). According to the regression analysis, lower weight and placebo group were significantly related to increasing of lavage frequency, number of vomits, start time of feeding, number of feeding cessations and decreased feeding completion time (P<0.0001).No adverse effects of this treatment modality were observed in the two groups. CONCLUSION: Intravenous metoclopramide may be considered as an attempt in facilitating and treatment of feeding intolerance in preterm neonates. PMID- 25793074 TI - Perinatal Factors Leading to Birth Asphyxia among Term Newborns in a Tertiary Care Hospital. AB - OBJECTIVE: To determine various perinatal factors leading to birth asphyxia among term newborns in a tertiary care hospital. METHODS: In a cross sectional study, a total of 196 asphyxiated cases were selected through consecutive non-probability sampling technique from neonatal intensive care unit (NICU) of a tertiary care Military Hospital in Pakistan from 1st December 2012 to 1st December 2013. Data obtained was analyzed using SPSS version 15.0. Descriptive statistics were used to calculate means, standard deviations and frequencies. Stratification with respect to maternal age, gestational age, newborns weight, parity and gravidity was done and post stratification chi-square test was applied to find statistical significance. FINDINGS: Out of 196 cases, 125 (64%) were males and 71 females (36%). Mean maternal age was 27.04+4.97 years and gestational age of babies was 39.86+1.24 weeks. Majority (57.14 %) of 112 mothers were 1-3 para and >=4 parity was recorded in 84 (42.86%) cases. Majority (64.80%) of the 127 mothers were 1-3 gravida while 69 (35.20%) had >=4 gravidity, mean of 3.45+0.87. Mode of delivery as a factor leading to birth asphyxia was found in 32.14% (n=63) cesarean section, 44.39% (n=87) spontaneous vertex delivery, and instrumental delivery in 23.47% (n= 46). Prolonged second stage of labor reported in 72% (n=141), 29.08% (n=57) had prolonged rupture of membranes, 7.65% (n=15) had meconium staining, 5.61% (n=11) had multiple births, 21.94% (n=43) had maternal fever, and 58.84% (n=113) had anemia at delivery. CONCLUSION: Birth asphyxia is a preventable problem and long term neurological sequelae almost untreatable. Timely identification of the perinatal risk factors and their prompt solution can prevent and reduce the neonatal morbidity and mortality from birth asphyxia. Early identification of high-risk cases with improved antenatal and perinatal care can further decrease such high mortality. PMID- 25793075 TI - Estimation of macronutrient content in kindergartens meals: food composition tables or chemical analysis? AB - OBJECTIVE: The nutrition of children in kindergartens has a great significance for proper growth and development of children. In order to save time and money, the control of macronutrients content is performed by calculations using food composition tables instead of performing a chemical analysis. METHODS: We examined the macronutrients content of 240 whole day meals using food composition tables and performed chemical analysis of meals to determine adequacy and validity of food composition tables in calculation of macronutrient contents in kindergarten meals. FINDINGS: We established no correlation (P>0.05) between the value of proteins, fats and carbohydrates. Significant difference was established between the average content of proteins (t=2.57; P<0.05), and carbohydrates (t=3.20; P<0.01), but not with the content of fats in the meals (t=1.26; P>0.05) (food composition tables vs chemical analysis). CONCLUSION: Until we establish new food composition tables, chemical analysis remains the only valid method for assessment of macronutrients content and energy value of a meal in kindergarten. PMID- 25793076 TI - Mycoplasma pneumoniae infection with neurologic complications. AB - BACKGROUND: Extrapulmonary complications of Mycoplasma pneumoniae (M. pneumoniae) infection include encephalitis, optic neuritis, acute psychosis, stroke, cranial nerve palsies, aseptic meningitis and also it may be implicated in immune mediated neurological diseases such as acute demyelinating encephalomyelitis, Guillain-Barre syndrome and transverse myelitis. CASE PRESENTATION: We present five cases with acute neurological diseases after M. pneumoniae infection. The clinical presentations were characterized by encephalitis in 2 patients, Gullain Barre syndrome in 2 patients, transverse myelitis in 1 patient. M. pneumoniae infection was detected in serum by serological method. Only two patients had respiratory symptoms preceding M. pneumoniae infection. Brain MRI revealed hyperintensities on corpus striatum and mesencephalon in one patient with encephalitis, the other had front parietal coalescent periventricular white matter lesions on T2 images. The patient with transverse myelitis had cervical, dorsal and lumbar scattered hyperintense lesions on T2 images. Two patients were treated with high dose steroid, the other two patients received treatment with intravenous immune globuline. CONCLUSION: M. pneumoniae may reveal different neurologic complications with different radiologic findings. PMID- 25793077 TI - A case of congenital disorder of glycosylation ia presented with recurrent pericardial effusion. AB - BACKGROUND: Inherited deficiency of phosophomannomutase (PMM2) causes a human glycosylation disorder known as Congenital Disorder of Glycosylation Ia. CASE PRESENTATION: Herein, we describe a case of congenital disorder of glycosylation Ia, presented with recurrent pericardial effusion and unusual findings of inverted nipples, fat pads, reduced deep-tendon reflexes and multisystem involvement. CONCLUSION: Congenital Disorder of Glycosylation Ia should be considered in children with developmental delay, those with multi-system disease involving neurologic, gastrointestinal, ophthalmologic, cardiac or endocrine systems. On the other hand, severe cardiac involvement may also be a feature of Congenital Disorder of Glycosylation Ia and diagnosed patients should also be evaluated in this respect. PMID- 25793078 TI - Langer-giedion syndrome: a distinct phenotype. PMID- 25793079 TI - Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Syndrome in Childhood; A Rare Clinical Entity. PMID- 25793080 TI - Fournier's Gangrene in Children: Report on 7 Cases and Review of Literature. PMID- 25793081 TI - Cystic lymphangioma of the rectus abdominis muscle: an extremely rare clinical entity. PMID- 25793082 TI - Cardiac Tamponade; A rare Presentation of Childhood Hypothyroidism. PMID- 25793083 TI - Metabolic Pattern of Asymptomatic Hip-Prosthesis by 18F-FDG-Positron-Emission Tomography. AB - BACKGROUND: Joint replacement is a procedure with a major impact on the quality of life of patients with joint degenerative disease or traumatic injuries. However, some patients develop symptoms after the intervention caused by mechanical loosening or infection. Metabolic imaging by 18F-FDG-PET investigated in these patients isoften hampered by low specificity for diagnosis of possible septic vs. mechanical loosening. The reason for this shortcoming is to our opinion the unawareness of physiological remodeling processes that could be seen in asymptomatic patients. OBJECTIVES: In order to overcome this drawback, we aimed to find out the physiological metabolic functional pattern in asymptomatic patients with implanted hip prosthesis. PATIENTS AND METHODS: Twelve patients (6 males, 6 females); mean age 73 +/- 7 (range 58 - 91) years were prospectively enrolled in the study. The patients were admitted to our department for oncological referral with implanted hip prostheses. All patients explained no symptoms with regard to their implanted prosthesis. The attenuation corrected images were used for analysis. RESULTS: Fourteen hip prostheses in 12 patients were visually analyzed. Seven out of 14 prostheses among 12 patients showed focal periprosthetic enhanced metabolism, two of which showed two sites of enhanced uptake; whereas, the remaining five prostheses showed singular hypermetabolic areas within the periprosthetic site. The remaining seven prostheses in the other five patients showed no periprosthetic-enhanced uptake. CONCLUSION: Of the asymptomatic patients investigated, 58% showed focal enhanced periprosthetic glucose metabolism. This finding should be taken into consideration as a more probable unspecific metabolic pattern for correct interpretation of 18F-FDG-PET studies in patients with suspected septic loosening of the hip prosthesis. PMID- 25793084 TI - Ultrasonographic diagnosis of lipofibromatous hamartoma of the median nerve. AB - Lipofibromatous hamartoma (LFH) is an extremely rare benign tumor, which is characterized by an excessive infiltration of the epineurium and perineurium by fibroadipose tissues.A 27-year-old woman was diagnosed with left carpal tunnel syndrome (CTS) due to (LFH) of the median nerve. LFH was diagnosed by MRI and sonography; the characteristic ultrasonographic feature of LFH showed a good correlation with pathognomonic MRI findings. The median nerve was involved along its course in the forearm; however, the patient needed carpal tunnel release because of severe compression of the median nerve under the flexor retinaculum.Radiologic evaluation of patient with CTS to evaluate probable secondary CTS is recommended. PMID- 25793085 TI - Clinico-radiologic findings in primary cutaneous extranodal natural killer/t-cell lymphoma, nasal type mimicking cellulitis of the left arm. AB - Extranodal natural killer (NK)/T-cell lymphoma is a very rare and aggressive disease characterized histopathologically by an Epstein-Barr virus (EBV)-positive atypical lymphoid cytotoxic infiltrate, extensive vascular destruction, and prominent tissue necrosis. It commonly shows cutaneous lesions that primarily or secondarily mimic cellulitis at the primary site. We report on a very rare case of extranodal NK/T-cell lymphoma, nasal type of skin/soft tissue, in a 64-year old man, and describe the radiological findings. The condition was misdiagnosed as cellulitis of the left arm based on initial noninvasive clinical and radiologic work-up. PMID- 25793086 TI - The value of prostate MRI with endorectal coil in detecting seminal vesicle involvement in patients with prostate cancer. AB - BACKGROUND: In prostate cancer, detection of seminal vesicle involvement is important because it influences the treatment planning and prognosis of the patients. OBJECTIVES: The objective of this study was to determine the value of prostate MRI with endorectal coil in the detection of seminal vesicle involvement in patients with prostate cancer. PATIENTS AND METHODS: A total number of 238 biopsy-proven prostate cancer patients were examined by 1.5 Tesla MRI with a combination of pelvic and endorectal coils to detect seminal vesicle involvement. After radical prostatectomy, the MRI results were compared with pathology results. RESULTS: Seminal vesicle involvement was detected in 67 (28.1%) patients. Pathology confirmed the involvement of seminal vesicles by prostate cancer in 63 patients. In two patients, seminal vesicle involvement was diagnosed by pathology but not detected by MRI. The sensitivity was 0.97 [95% confidence interval = 0.89-0.99], the specificity was 0.98 [95% confidence interval = 0.94 0.99], the positive predictive value was 0.94 [95% confidence interval = 0.85 0.98], and the negative predictive value was 0.99 [95% confidence interval = 0.96 0.99]. CONCLUSIONS: MRI with endorectal coil is a valuable imaging technique with suitable accuracy in detecting seminal vesicle involvement in prostate cancer. PMID- 25793087 TI - A case of pulmonary artery hydatid cyst observed on endobronchial ultrasound. AB - Hydatid cyst (HC) is a parasitic disease that may involve many organs, especially the lung and the liver. Pulmonary artery location of the hydatid cyst is extremely rare, but it may cause life-threatening complications. We report a case of a hydatid cyst that completely filled the left main pulmonary artery and its distal part without cardiac involvement. Thoracic computed tomography showed filling defects in the pulmonary arteries. Endobronchial ultrasound was performed for differential diagnosis and it showed a cystic lesion. Hydatid cyst-specific IgE and hem agglutination test results were positive. In the literature, cases like this in which the diagnosis of pulmonary hydatid cyst is made by endobronchial ultrasound are not usually seen. Although many imaging modalities such as plain chest radiography, cross-sectional imaging (MDCT and MRI), echocardiography and conventional pulmonary angiography have been used in the diagnostic approach, we recommend endobronchial ultrasound for the differential diagnosis of cases with cystic formation. PMID- 25793088 TI - Liver biopsy versus non-invasive tests in determining liver disease status. PMID- 25793089 TI - Multimodality imaging of left circumflex artery to coronary sinus fistula. AB - Coronary artery fistula (CAF) is a rare anomaly of the coronary artery. Patients with this condition are usually asymptomatic. However, cardiac failure may occur later in life due to progressive enlargement of the fistula. Diagnosis is traditionally made by echocardiogram and conventional angiogram. However with the advantage of new technologies such as computed tomography (CT) coronary angiography, the course and communications of these fistulae can be delineated non-invasively and with greater accuracy. We report a case of a left circumflex artery fistula to the coronary sinus which was suspected on echocardiogram and the diagnosis was clinched on ECG-gated CT. PMID- 25793090 TI - Congenital external carotid-external jugular arteriovenous fistula: diagnosis with contrast-enhanced computed tomography. AB - Arteriovenous fistula (AVF) between the external carotid artery and external jugular vein is extremely rare, with only few cases reported in the literature so far. Most of these AVFs have been either iatrogenic or secondary to previous trauma. Herein, we report a 42-year-old woman with congenital AVF between the external carotid artery and external jugular vein, presenting with palpitation and dyspnea. The patient was suffering from mitral and tricuspid regurgitation. On physical examination, a thrill on the left side of the neck and an audible bruit over the left mandibular angle were detected. The possibility of abnormal AVF was considered and it was confirmed on contrast-enhanced computed tomography (CT), inferring that this modality is not only fast and non-invasive, but also accurate in detecting vascular abnormalities. PMID- 25793091 TI - A review approaches to identify enteric bacterial pathogens. AB - CONTEXT: Diarrhea is a common disease across the world. According to WHO, every year about two billion cases of diarrhea are reported in the world. It occurs mainly in the tropical regions and is a main cause of morbidity and mortality, particularly in young children and adults. EVIDENCE ACQUISITION: One of the major causes of diarrheal diseases is bacteria; detection of pathogenic bacteria is a global key to the prevention and identification of food-borne diseases and enteric infections (like diarrhea). CONCLUSIONS: Therefore, development of rapid diagnostic methods with suitable sensitivity and specificity is very important about this infectious disease. In this review, we will discuss some of the important diagnostic methods. PMID- 25793093 TI - Antibacterial Activity of Some Plant Extracts Against Extended- Spectrum Beta Lactamase Producing Escherichia coli Isolates. AB - BACKGROUND: The extended-spectrum beta-lactamase (ESBL) -producing Escherichia coli isolates make many serious infections, especially urinary tract infections. OBJECTIVES: The purpose of this study was to determine the antibacterial activities of some natural plant extracts against ESBL-producing E. coli isolates, which harbor the TEM gene in urine samples of the patients who have urinary tract infections. MATERIALS AND METHODS: Evaluation has to be exactly determined for both methods of disk diffusion test and polymerase chain reaction (PCR), separately. We evaluated 120 strains of E. coli isolates from the urine culture of the patients in Boo-Ali Hospital (Zahedan, south-eastern Iran) who were suffering from urinary tract infections. The ESBL-producing E. coli isolates were evaluated by disk diffusion test and PCR through TEM gene detection. The minimal inhibitory concentration (MIC) of commonly used antibiotics including ceftazidime, ceftriaxon, amikacin, gentamicin and ciprofloxacin along with the MIC of the alcoholic extract of different natural plants including Myrtus communis L (Myrtaceae), Amaranthus retraflexus (Amaranthaceae), Cyminum cuminum L (Apiaceae), Marrubium vulgare (Laminaceae) and Peganum. harmala (Zygrophyllaceae) against the ESBL-producing E. coli isolates, which harbor the TEM genes, were determined using the microdulition method. RESULTS: Results of this study showed that in disk diffusion method, 80 samples of E. coli produced ESBLs. In PCR method, the TEM gene distribution in the isolated ESBL-producing organisms was 50 (41.6%). Amikacin was the most effective anti-bacterial agent and ciprofloxacin was the least effective against E. coli isolates. All the natural plant extracts mentioned above, especially P. harmala, were effective against the selected isolates of ESBL-producing E. coli. The most frequent ESBL rate producing E. coli isolates (32 out of 50) had MIC of 2.5 mg/mL in ethanol extract of P. harmala. CONCLUSIONS: The alcoholic extract of P. harmala was very effective against the selected ESBL-producing E. coli isolates harboring the TEM gene. Therefore, it could be suggested as an antibacterial agent in the future. More researches are necessary for detecting the mechanism of this plant's behavior and its pharmacological effects. PMID- 25793092 TI - Distribution of hepatitis delta virus genotypes in mashhad, northeast iran. AB - BACKGROUND: Hepatitis delta virus (HDV) is dependent on the hepatitis B virus for transmission and propagation. Based on isolated HDV sequences from different parts of the world, at least three major different genotypes with different geographic distributions are suggested. Studies have shown that genotype 1 is the predominant genotype of HDV in different parts of Iran; however, the genotype distribution of this virus has not been identified in Mashhad, northeast Iran. OBJECTIVES: This current study determines the frequency of HDV major genotypes in Mashhad, Iran. PATIENTS AND METHODS: Twenty-five participants were enrolled in this study. All samples were positive for HBsAg (determined by Enzyme-linked immunosorbent assay (ELISA)) and anti-HDV. RNA extraction and cDNA synthesis was performed. Then, PCR was performed and HDV genotypes were determined by restriction fragment length polymorphism (RFLP). RESULTS: Of 25 patients, 12 (48%) were positive for HDV RNA. Genotype analysis of HDV RNA revealed that the prevalence of HDV genotypes I and II was 83.3% (n = 10) and 16.7% (n = 2), respectively. CONCLUSIONS: This study showed that the most prevalent genotype of HDV in Mashhad was genotype I. It was of interest that in contrast to other provinces of Iran, HDV genotype 2 was observed in Mashhad. Similar studies with larger sample sizes could provide valuable information regarding the molecular epidemiology and geographical distribution. It may also help control and prevent the spread of hepatitis D virus infections. In addition, the genotyping of HDV may predict the severity of the disease. PMID- 25793094 TI - Effects of benzalkonium chloride on planktonic growth and biofilm formation by animal bacterial pathogens. AB - BACKGROUND: Resistance toward quaternary ammonium compounds (QACs) is widespread among a diverse range of microorganisms and is facilitated by several mechanisms such as biofilm formation. OBJECTIVES: In this study, the effects of benzalkonium chloride on planktonic growth and biofilm formation by some field isolates of animal bacterial pathogens were investigated. MATERIALS AND METHODS: Forty clinical isolates of Escherichia coli, Salmonella serotypes, Staphylococcus aureus and Streptococcus agalactiae (10 isolates of each) were examined for effects of benzalkonium chloride on biofilm formation and planktonic growth using microtiter plates. For all the examined strains in the presence of benzalkonium chloride, biofilm development and planktonic growth were affected at the same concentrations of disinfectant. RESULTS: The means of strains growth increase after the minimal inhibitory concentration (MIC) were significant in all the bacteria (except for E. coli in 1/32 and S. agalactiae in of 1/8 MIC). Biofilm formation increased with decrease of antiseptics concentration; a significant increase was found in all the samples. The most turbidity related to S. aureus and the least to Salmonella. CONCLUSIONS: Bacterial resistance against quaternary ammonium compounds is increasing which can increase the bacterial biofilm formation. PMID- 25793095 TI - Designing novel and simple competitive internal amplification control for reliable PCR diagnosis of herpes simplex virus. AB - BACKGROUND: PCR is a molecular technique for herpes simplex virus (HSV) detection that can cause life-threatening infections such as encephalitis and keratitis. However, the main issues, false-negative results causing by PCR inhibitors, of this technique that reduce PCR efficiency. To overcome this problem, a competitive internal amplification control (IAC) was constructed for conventional PCR using the PCR-cloning technique. OBJECTIVES: The purpose of this study is the design of competitive IAC for PCR diagnosis of HSV, which in fact is the main cause of keratitis and viral encephalitis in developed countries. MATERIALS AND METHODS: Composite primers for PCR amplification of Leishmania major kDNA (kinetoplast DNA) were designed and optimized to use as IAC-HSV. IAC-HSV amplified in a non-stringent condition, ligated into pTZ57R plasmid vector, and transformed into Escherichia coli JM207 and then cloned. Resulting IAC was used for 105 CSF and 78 keratitis specimens. RESULTS: PCR amplicons for HSV and IAC HSV were 454-bp and 662-bp, respectively. Detection limit of IAC was determined as 1000 plasmids per PCR reaction. IAC sensitivity for HSV detection was determined as 1000 plasmids per PCR reaction. IAC sensitivity for HSV detection was 500 copies/mL of HSV DNA. Among all specimens, 7 inhibited specimens were detected. CONCLUSIONS: Indeed, using other DNA as an IAC is expected to detect false-negative results and amplification of the DNA is the key tool to examine the accuracy of amplification and detection steps. This internal amplification control is applicable for early reliable diagnosis of HSV in different loads of virus in different specimens. PMID- 25793096 TI - Bacteriological and molecular assessment of staphylococcal enterotoxin e in the blood of patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is the most common chronic inflammatory disease of unknown etiology. In this regard, the role of bacterial superantigens (as an effective agent) were considered. OBJECTIVES: This study aimed to assess staphylococcal enterotoxin E in the blood of patients with rheumatoid arthritis. PATIENTS AND METHODS: A total of 83 blood samples of patients with RA were studied. All of patient's blood samples have been cultured. Polymerase chain reaction (PCR) and ELISA methods have been used to assess the existence of staphylococcal enterotoxin E (entE). The data were analyzed through descriptive statistics. RESULTS: During this study and after sequential sub cultures, only 5 bacterial strains were isolated. Based on the results of biochemical tests, just one case was detected as Staphylococcus aureus. The result of molecular diagnosis of enterotoxin E gene was 13.25%. The results of ELISA were 40.96% positive for staphylococcal enterotoxin E. CONCLUSIONS: In this study, staphylococcal enterotoxin E (superantigen E) was detected in the blood of patients with RA, but its origin is unknown, because no staphylococcus enterotoxin E producer was isolated. This finding could provide a good model for the diagnosis and treatment of RA. However, the results of this study have shown some evidence regarding endogenous origin of involved superantigens in patients with rheumatoid arthritis. PMID- 25793097 TI - Determining major genotypes of hepatitis C virus among transplant recipients by real-time polymerase chain reaction assay. AB - BACKGROUND: Hepatitis C virus (HCV) infection still exists as a health concern among the transplant patients. Because of the severity of the disease, different responses to treatment, and side effects resulting from long therapeutic period, determination of genotypes and viral loads can help choose the best treatment protocols. OBJECTIVES: This study aimed to determine the HCV genotypes and its distribution patterns among liver, kidney, and bone marrow recipient candidates across Iran, referred to Namazi Hospital, southern Iran. PATIENTS AND METHODS: A total of 101 individuals, including 44 (43.6%) liver, 55 (54.5%) kidney, and 2 (2%) bone marrow recipient candidates, with ages ranging between 5 and 74 years (Mean +/-SD: 46.53 +/- 13.73 y) participated in this study. From those, whole blood sample were collected and anti-HCV antibodies, RNA detection, and genotyping were performed on plasma using commercial chromatographic immunoassay, TaqMan one-step real-time polymerase chain reaction (RT-PCR), and genotyping RT PCR kits, respectively. The frequencies of anti-HCV antibodies, RNA, various genotypes, and the viral load were compared with respect to gender, age, and transplant recipient groups. RESULTS: Of 101 individuals, 47 (46.5%) were positive for anti-HCV antibodies and 34 (33.7%) for RNA with a significant difference (P < 0.05). RNA copy number ranged from 4.6 * 103 to 3.11 * 107 copies/mL, median: 2.92 * 106 copies/mL, with no statistical differences in all groups. Analyses revealed no significant differences between the frequencies of anti-HCV antibodies or RNA in different groups. The frequencies of the genotypes 1 (50%) and 3 (35.3%) were higher than those of the genotypes 2 (2.9%), 4 (2.9%), and undetermined one (8.8%). Genotype 1 was significantly more prevalent in liver transplant recipients, those older than 40 years, and male cases (P < 0.05). CONCLUSIONS: Considering the high frequency of genotypes 1 and 3 among the studied groups, it is suggested that before and after transplantation programs be improved to manage and treat the disease efficiently, based on the standard protocols for such genotypes in the region. Accordingly, the occurrence of post transplant complications due to immunosuppression among all the recipients as well as reinfection in HCV infected liver transplant patients can be diminished. PMID- 25793098 TI - Determination of cytomegalovirus prevalence and glycoprotein B genotypes among ulcerative colitis patients in ahvaz, iran. AB - BACKGROUND: The human cytomegalovirus (HCMV) is a common pathogen which usually remains asymptomatic in the healthy adults; however, it can cause a symptomatic disease in the immunocompromised patients. The risk of infection with HCMV increases in ulcerative colitis (UC) patients as a result of receiving immunosuppressive agents. OBJECTIVES: This study aimed to determine the prevalence and the glycoprotein B genotypes of HCMV among the patients with HCMV disease superimposed on an UC flare that required hospitalization in Imam Khomeini Hospital in Ahvaz, Iran, during 2010- 2012. PATIENTS AND METHODS: In this case-control study, formalin-fixed paraffin-embedded intestinal tissue samples were taken from 98 patients with UC disease including 53 males and 45 females (mean age +/- standard deviation, 38.95 +/- 17.93) and 67 control patients with noninflammatory disease who were referred to Imam Khomeini Hospital during 2010-2012. Detection of HCMV genome in intestinal samples was carried out by seminested polymerase chain reaction. Glycoprotein B genotypes were determined by sequencing. RESULTS: Among 98 patients with UC, only 12 (12.2%) patients were positive for HCMV genome, while the HCMV genome was not detected in any of the controls. (P = 0.002). The distribution of HCMV gB genotypes in 12 CMV-positive UC patients was as follow: gB1, 11 (91.7%) and gB3, 1 (8.3%). The most prevalent genotype in CMV-positive UC patients was gB1. CONCLUSIONS: In this study, high prevalence of 91.7% HCMV gB1 genotype was predominant among HCMV-positive UC patients, which suggests that there might be an association between HCMV gB genotype 1 and UC disease. PMID- 25793099 TI - Characterization of indigenous lactobacillus strains for probiotic properties. AB - BACKGROUND: Probiotics are defined as adequate amount of live microorganisms able to confer health benefits on the host. Currently, most commercially available probiotic products in the market belong to genera Lactobacillus. Traditional dairy products are usually rich source of Lactobacillus strains with significant health benefits. In order to evaluate the probiotic potential of these bacteria, it is essential to assess their health benefits, efficacy, and safety. OBJECTIVES: The probiotic efficacy of two Lactobacillus strains namely Lactobacillus pentosus LP05 and L. brevis LB32 was evaluated. They were previously isolated from ewes' milk in a rural area in East Azerbaijan, Iran. MATERIALS AND METHODS: The selected isolates were tested for certain phenotypic characters and identified to genus and species level by 16S rRNA gene sequencing and species specific primers. Further analysis included acid and bile resistance, antagonistic activity, cholesterol removing ability, survival in simulated gastric and upper intestine contents, aggregation and coaggregation properties. Finally, the adhering ability of the selected Lactobacillus strains to epithelial cells was tested using Caco-2 cell lines. RESULTS: The selected isolates tolerated bile salt concentrations ranging from 0.5% to 3%, however their coefficient of inhibition were varied. Both isolates hydrolyzed bile and grew at pH values of 3, 4, and 5, while isolate LP05 was not able to hydrolyze arginine. Based on 16s rRNA gene sequencing and species-specific primers, the isolates were identified as L. brevis LB32 and L. pentosus LP05. In contrast to simulated gastric conditions, the growth rate of the isolates in alkaline conditions of upper intestine increased significantly with the passage of time reaching its maximum in 24 hours. These 2 isolates inhibited the growth of Listeria monocytogenes, Salmonella enteritidis, Shigella dysenteriae, Staphylococcus aureus, and Streptococcus pneumonia. Furthermore, L. brevis LB32 was able to reduce approximately 86% of cholesterol compared to L. pentosus LP05, which showed only 69% of reduction. Higher aggregation and coaggregation percentage and adherence to Caco-2 cell line was observed in L. pentosus LP05 compared to L. brevis LB32. CONCLUSIONS: This research study proved the presence of viable probiotic LAB microflora in the ewe milk with enhanced health benefits. The 2 selected Lactobacillus strains could be exploited in dairy or pharmaceutical industry in future. PMID- 25793100 TI - Antimicrobial activity of seven essential oils from Iranian aromatic plants against common causes of oral infections. AB - BACKGROUND: Over the past two decades, there has been a growing trend in using oral hygienic products originating from natural resources such as essential oils (EOs) and plant extracts. Seven aromatic plants used in this study are among popular traditional Iranian medicinal plants with potential application in modern medicine as anti-oral infectious diseases. OBJECTIVES: This study was conducted to determine the chemical composition and antimicrobial activities of essential oils from seven medicinal plants against pathogens causing oral infections. MATERIALS AND METHODS: The chemical compositions of EOs distilled from seven plants were analyzed by gas chromatography/mass spectrometry (GC/MS). These plants included Satureja khuzestanica, S. bachtiarica, Ocimum sanctum, Artemisia sieberi, Zataria multiflora, Carum copticum and Oliveria decumbens. The antimicrobial activity of the essential oils was evaluated by broth micro dilution in 96 well plates as recommended by the Clinical and Laboratory Standards Institute (CLSI) methods. RESULTS: The tested EOs inhibited the growth of examined oral pathogens at concentrations of 0.015-16 uL/mL. Among the examined oral pathogens, Enterococcus faecalis had the highest Minimum Inhibitory Concentrations (MICs) and Minimum Microbicidal Concentrations (MMCs). Of the examined EOs, S. khuzestanica, Z. multiflora and S. bachtiarica, showed the highest antimicrobial activities, respectively, while Artemisia sieberi exhibited the lowest antimicrobial activity. CONCLUSIONS: The excellent antimicrobial activities of the tested EOs might be due to their major phenolic or alcoholic monoterpenes with known antimicrobial activities. Hence, these EOs can be possibly used as an antimicrobial agent in treatment and control of oral pathogens. PMID- 25793101 TI - Calculating second derivatives of population growth rates for ecology and evolution. AB - 1. Second derivatives of the population growth rate measure the curvature of its response to demographic, physiological or environmental parameters. The second derivatives quantify the response of sensitivity results to perturbations, provide a classification of types of selection and provide one way to calculate sensitivities of the stochastic growth rate. 2. Using matrix calculus, we derive the second derivatives of three population growth rate measures: the discrete time growth rate lambda, the continuous-time growth rate r = log lambda and the net reproductive rate R0, which measures per-generation growth. 3. We present a suite of formulae for the second derivatives of each growth rate and show how to compute these derivatives with respect to projection matrix entries and to lower level parameters affecting those matrix entries. 4. We also illustrate several ecological and evolutionary applications for these second derivative calculations with a case study for the tropical herb Calathea ovandensis. PMID- 25793102 TI - Response of conventional chondrosarcoma to gemcitabine alone: a case report. AB - Conventional skeletal chondrosarcoma is a bone neoplasm, which is poorly sensitive to anthracyclines-based chemotherapy. We report on an 18-month-long tumour response to gemcitabine as single agent in a young patient with an advanced secondary peripheral conventional chondrosarcoma, previously treated unsuccessfully with anthracyclines, ifosfamide, platinum, etoposide. PMID- 25793103 TI - Preventive health behaviors and physician visits: relevance to health inequality. AB - Clear definitions and measurement of preventive health behaviors, as well as the relevant demographic and socioeconomic variables, is important to understanding what factors explain inequalities in health and in the use of health care services. This commentary addresses issues related to the measurement of preventive health behaviors and suggests a distinction between personal life style behaviors and preventive screening practices in order to better explain the associations between these practices and visits to general practitioners. The commentary notes that physician visits are a health-related behavior which is shaped by socioeconomic status: visits to general practitioners are more prevalent among the poor, while visits to specialists are more prevalent among the rich. Therefore, in any analysis of the factors contributing to socioeconomic inequalities in health, physician visits and preventive health behaviors ought to be included as two distinct sets of health-related behaviors. Changing these health-related behaviors is only one of the interventions that are better developed by healthcare services, while the majority of multi-level efforts to reduce inequalities should be outside of the health sector. PMID- 25793104 TI - Speeding the growth of primary mental health prevention. AB - While there is a strong case for primary prevention of mental health problems, relatively little mental health scholarship has been devoted to it in the last decade. Efforts to accelerate prevention scholarship could potentially benefit from strengthening pathways for interdisciplinary research; developing new training and working models for mental health professionals; developing a common language for public, policy, and scientific discussion of prevention; learning how to measure the common outcomes of heterogeneous interventions tailored to diverse communities. PMID- 25793105 TI - Changes in the cerebrospinal fluid circulatory system of the developing rat: quantitative volumetric analysis and effect on blood-CSF permeability interpretation. AB - BACKGROUND: The cerebrospinal fluid (CSF) circulatory system is involved in neuroimmune regulation, cerebral detoxification, and delivery of various endogenous and exogenous substances. In conjunction with the choroid plexuses, which form the main barrier site between blood and CSF, this fluid participates in controlling the environment of the developing brain. The lack of comprehensive data on developmental changes in CSF volume and distribution impairs our understanding of CSF contribution to brain development, and limits the interpretation of blood-CSF permeability data. To address these issues, we describe the evolution of the CSF circulatory system during the perinatal period and have quantified the volume of the different ventricular, cisternal and subarachnoid CSF compartments at three ages in developing rats. METHODS: Immunohistofluorescence was used to visualize tight junctions in parenchymal and meningeal vessels, and in choroid plexus epithelium of 19-day fetal rats. A quantitative method based on serial sectioning of frozen head and surface measurements at the cutting plane was used to determine the volume of twenty different CSF compartments in rat brain on embryonic day 19 (E19), and postnatal days 2 (P2) and 9 (P9). Blood-CSF permeability constants for sucrose were established at P2 and P9, following CSF sampling from the cisterna magna. RESULTS: Claudin-1 and claudin-5 immunohistofluorescence labeling illustrated the barrier phenotype acquired by all blood-brain and blood-CSF interfaces throughout the entire CNS in E19 rats. This should ensure that brain fluid composition is regulated and independent from plasma composition in developing brain. Analysis of the caudo-rostral profiles of CSF distribution and of the volume of twenty CSF compartments indicated that the CSF-to-cranial cavity volume ratio decreases from 30% at E19 to 10% at P9. CSF compartmentalization within the brain changes during this period, with a major decrease in CSF-to-brain volume ratio in the caudal half of the brain. Integrating CSF volume with the measurement of permeability constants, adds to our understanding of the apparent postnatal decrease in blood CSF permeability to sucrose. CONCLUSION: Reference data on CSF compartment volumes throughout development are provided. Such data can be used to refine blood-CSF permeability constants in developing rats, and should help a better understanding of diffusion, bulk flow, and volume transmission in the developing brain. PMID- 25793106 TI - The rise of large-scale imaging studies in psychiatry. AB - From the initial arguments over whether 12 to 20 subjects were sufficient for an fMRI study, sample sizes in psychiatric neuroimaging studies have expanded into the tens of thousands. These large-scale imaging studies fall into several categories, each of which has specific advantages and challenges. The different study types can be grouped based on their level of control: meta-analyses, at one extreme of the spectrum, control nothing about the imaging protocol or subject selection criteria in the datasets they include, On the other hand, planned multi site mega studies pour intense efforts into strictly having the same protocols. However, there are several other combinations possible, each of which is best used to address certain questions. The growing investment of all these studies is delivering on the promises of neuroimaging for psychiatry, and holds incredible potential for impact at the level of the individual patient. However, to realize this potential requires both standardized data-sharing efforts, so that there is more staying power in the datasets for re-use and new applications, as well as training the next generation of neuropsychiatric researchers in "Big Data" techniques in addition to traditional experimental methods. The increased access to thousands of datasets along with the needed informatics demands a new emphasis on integrative scientific methods. PMID- 25793107 TI - Possible confounding factors on cerebral diffusion tensor imaging measurements. AB - BACKGROUND: Diffusion tensor imaging (DTI) is prone to numerous systemic confounding factors that should be acknowledged to avoid false conclusions. PURPOSE: To investigate the possible effects of age, gender, smoking, alcohol consumption, and education on cerebral DTI parameters in a generally healthy homogenous sample with no neurological or psychiatric diseases. MATERIAL AND METHODS: Forty (n = 40) subjects (mean age, 40.3 years; SD, 12.3) underwent brain DTI with 3 T magnetic resonance imaging (MRI). At enrolment, all the subjects were interviewed with respect to general health, education, history of smoking, and alcohol consumption. Studied DTI parameters included: (i) fractional anisotropy (FA); and (ii) apparent diffusion coefficient (ADC). Region-of interest (ROI)-based measurements were estimated at 13 anatomical locations bilaterally on the axial images, except for the corpus callosum in which the ROIs were placed on the sagittal images. Circular ROI measurements were mainly used. Freehand ROI method was used with the forceps minor, uncinate fasciculus, and thalamus. Intra-observer variability and repeatability were assessed. RESULTS: The most consistent finding was that aging decreased FA values in the frontal brain regions. Regarding the other confounding factors, the results were discontinuous and no concrete conclusions could be drawn from these findings. In general, intra-observer repeatability of the DTI measurement was considered relatively good. CONCLUSION: Age should be noted as considerable confounding factors in ROI-based DTI analysis. More research on the effects of gender, smoking, alcohol consumption, and education is needed. PMID- 25793108 TI - Adult onset asynchronous multifocal eosinophilic granuloma of bone: an 11-year follow-up. AB - Multifocal eosinophilic granuloma (EG) is a rare observation within the spectrum of histiocytosis X, generally described in children. We report the case of a 33 year-old man with multifocal EG showing an asynchronous evolution of bone lesions during a follow-up of 11 years. We also present the therapeutic approach chosen for this patient and the repeated magnetic resonance imaging (MRI) examinations used to monitor the disease with a final favorable outcome. PMID- 25793109 TI - Intra-individual comparison of PET/CT with different body weight-adapted FDG dosage regimens. AB - BACKGROUND: 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) imaging demands guidelines to safeguard sufficient image quality at low radiation exposure. Various FDG dose regimes have been investigated; however, body weight-adapted dose regimens and related image quality (IQ) have not yet been compared in the same patient. PURPOSE: To investigate the relationship between FDG dosage and image quality in PET/CT in the same patient and determine prerequisites for low dosage scanning. MATERIAL AND METHODS: This study included 61 patients undergoing a clinically indicated PET/CT imaging study and follow-up with a normal (NDS, 5 MBq/kg body weight [BW]) and low dosage scanning protocol (LDS, 4 MBq/kg BW), respectively, using a Discovery VCT64 scanner. Two blinded and independent readers randomly assessed IQ of PET using a 5-point Likert scale and signal-to-noise ratio (SNR) of the liver. RESULTS: Body mass index (BMI) was significantly lower at LDS (P = 0.021) and represented a significant predictor of SNR at both NDS (P < 0.001) and LDS (P = 0.005). NDS with a mean administered activity of 340 MBq resulted in significantly higher IQ (P < 0.001) and SNR as compared with LDS with a mean of 264 MBq (F-value = 23.5, P < 0.001, mixed model ANOVA adjusted for covariate BMI). Non-diagnostic IQ at LDS was associated with a BMI > 22 kg/m(2). CONCLUSION: FDG dosage significantly predicts IQ and SNR in PET/CT imaging as demonstrated in the same patient with optimal IQ achieved at 5 MBq/kg BM. PET/CT imaging at 4 MBq/kg BW may only be recommended in patients with a BMI <= 22 kg/m(2) to maintain diagnostic IQ. PMID- 25793111 TI - Balloon-occluded retrograde transvenous obliteration successfully performed for a large gastric varix in combination with temporary occlusion of the splenic artery in a child. AB - We encountered a 10-year-old boy with a gastric varix that occurred after long term treatment by Kasai's hepatic portoenterostomy for biliary atresia for which balloon-occluded retrograde transvenous obliteration (B-RTO) was performed. With the standard B-RTO procedure, sufficient distribution in the entire gastric varix could not be obtained. However, the gastric varix was successfully treated by the addition of occlusion of the splenic artery by inflation of a balloon catheter during B-RTO. PMID- 25793110 TI - Comparison of gadoxetic acid and gadopentetate dimeglumine-enhanced MRI for HCC detection: prospective crossover study at 3 T. AB - BACKGROUND: Gadoxetic acid and gadopentetate dimeglumine are gadolinium-based contrast agents (GBCAs) with an established role in HCC detection and characterization. PURPOSE: To compare gadopentetate dimeglumine and gadoxetic acid-enhanced magnetic resonance imaging (MRI) for image quality and hepatocellular carcinoma (HCC) detection/conspicuity. MATERIAL AND METHODS: In this IRB approved cross-over pilot prospective study, 12 patients (all men; mean age, 56 years) with chronic liver disease at risk of HCC underwent two repeat MRI examinations using gadopentetate dimeglumine and gadoxetic acid (mean interval between studies, 5 days). Two independent observers analyzed images for image quality and HCC detection/conspicuity. Per-lesion sensitivity, positive predictive value, quantitative enhancement, and lesion-to-liver contrast ratio were calculated for both contrast agents. RESULTS: There was no significant difference in image quality scores between both GBCAs (P = 0.3). A total of 20 HCCs were identified with reference standard in 12 patients (mean size 2.6 cm, range, 1.0-5.0 cm). Higher sensitivity was seen for observer 1 for gadoxetic acid set in comparison with gadopentetate dimeglumine-set (sensitivity increased from 85.7% to 92.8%), while no difference was noted for observer 2 (sensitivity of 78.5%). Lesion conspicuity was significantly higher on hepatobiliary phase (HBP) images compared to arterial phase images with both GBCAs for both observers (P < 0.05). Lesion-to-liver contrast ratios were significantly higher for HBP compared to all dynamic phases for both agents (P < 0.05). CONCLUSION: Our initial experience suggests that gadoxetic acid-set was superior to gadopentetate dimeglumine-set in terms of HCC detection for one observer, with improved lesion conspicuity and liver-to-lesion contrast on HBP images. PMID- 25793112 TI - Individual patient data meta-analysis of the smoking prevalence in mazandaran province of iran. AB - BACKGROUND: Smoking is regarded as one of the main risk factors and additive to the global burden of diseases in the World. OBJECTIVES: This individual patient data (IPD) meta-analysis aimed to estimate the smoking prevalence in Mazandaran province of Iran. MATERIALS AND METHODS: This study was an IPD meta-analysis. The study data were part of the STEPS Study in Mazandaran province (northern Iran), conducted annually from 2005 to 2009. Sample size was 7759 subjects. Sampling method was census. Data entry was in Epi6 software and the analyses were with stata 11 software. RESULTS: Mean (standard error) age of starting to smoke was 20.21 (0.6) years and females had started smoking 4 years later (P = 0.01). During the study, men smoked cigarettes more than women (total prevalence: 23.2%; 95% CI: 22.5-23.9 vs. 0.9%; 95% CI: 0.7-1.1 respectively). The pooled prevalence of the current smoking was estimated about 12.08 % (95% CI: 11.40-12.81). CONCLUSIONS: Present study showed that the prevalence of Smoking in men is very high in this region of Iran. Therefore to prevent the problem it is necessary that educational and research centres and health providers make suitable policies and strategies . PMID- 25793113 TI - Casein phosphopeptide-amorphous calcium phosphate and shear bond strength of adhesives to primary teeth enamel. AB - BACKGROUND: CPP-ACP (Phosphopeptide-Amorphous Calcium Phosphate) has an important role in caries prevention in pediatric patients. This study was done, because of the great use of CPP-ACP and the need for restoration for teeth treated with CPP ACP as well as the importance of shear bond strength of adhesives in the success of restorations. OBJECTIVES: This study aimed to evaluate the effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on shear bond strength of dental adhesives to enamel of primary teeth molars. MATERIALS AND METHODS: This in vitro study was conducted on 180 extracted primary molars. They were randomly divided into 6 groups and each group was divided into 2 subgroups (treated with CPP-ACP and untreated). In subgroups with CPP-ACP, enamel was treated with CPP ACP paste 1 h/d for 5 days. Types of adhesives that were evaluated in this study were Tetric N-Bond, AdheSE, AdheSE One F, single Bond 2, SE Bond, and Adper Prompt L-Pop. Shear bond strength was tested with a universal testing machine and mode of failure was evaluated under stereomicroscope. Data were analyzed by T test, 2-way analysis of variance (ANOVA), Tukey and Fisher exact test using SPSS18. P < 0.05 was considered as significance level. RESULTS: Shear bond strengths of different adhesive systems to enamel of primary teeth treated and untreated with CPP-ACP showed no significant difference (P > 0.05). Mode of failure in all groups regardless of CPP-ACP administration was mainly adhesive type. Our results indicated that CPP-ACP did not affect shear bond strength of studied adhesives to primary teeth enamel. CONCLUSIONS: To have a successful and durable composite restoration, having a high strength bonding is essential. Considering the wide use of CPP-ACP in preventing tooth decay and the role of adhesive shear bond strength (SBS) in success of composite restoration, we conducted the present study to evaluate the effect of CPP-ACP on the SBS of adhesives to primary teeth enamel. PMID- 25793114 TI - How well establishment of research plans can improve scientific ranking of medical universities. AB - BACKGROUND: As a developing country, Iran has not had a substantial share in global science production activities; however, this country has recently been the forth country in the world regarding research output publications, and biomedical research has played a crucial role in achieving this honorable position. OBJECTIVES: In this paper, we aimed to introduce the strategies employed at Baqiyatallah University of Medical Sciences of Iran, to enhance scientific research output of this university. PATIENTS AND METHODS: The present study used the qualitative content analysis technique. The Research deputies and the head of research centers of Baqiyatallah University of Medical Sciences were the research subjects. The main researcher conducted all the interviews. The participants were all authorities of the university. Sampling continued until data saturation. After speaking with 16 participants, the interviews yielded no new information, and no new categories or subcategories were added to the previous ones. Deep and semi-structured interviews with open-ended questions were used to collect data. RESULTS: Diplomacies employed to promote research, organizing educational classes, and foundation of infrastructural organizations for research and true surveillance of research programs were the main characteristics of Baqiyatallah University of Medical Sciences research strategies. CONCLUSIONS: Baqiyatallah University of Medical Sciences is a military university of limited resources that has won several awards in the recent years, and has been categorized as one of the leading first ranked medical universities in Iran; a position quite higher than several other larger universities of the country. We recommend more enhanced strategies for other universities. PMID- 25793115 TI - Evaluation of auditory brain stems evoked response in newborns with pathologic hyperbilirubinemia in mashhad, iran. AB - BACKGROUND: Neonatal jaundice is a common cause of sensorneural hearing loss in children. OBJECTIVES: We aimed to detect the neurotoxic effects of pathologic hyperbilirubinemia on brain stem and auditory tract by auditory brain stem evoked response (ABR) which could predict early effects of hyperbilirubinemia. PATIENTS AND METHODS: This case-control study was performed on newborns with pathologic hyperbilirubinemia. The inclusion criteria were healthy term and near term (35 - 37 weeks) newborns with pathologic hyperbilirubinemia with serum bilirubin values of >= 7 mg/dL, >= 10 mg/dL and >=14 mg/dL at the first, second and third-day of life, respectively, and with bilirubin concentration >= 18 mg/dL at over 72 hours of life. The exclusion criteria included family history and diseases causing sensorineural hearing loss, use of auto-toxic medications within the preceding five days, convulsion, congenital craniofacial anomalies, birth trauma, preterm newborns < 35 weeks old, birth weight < 1500 g, asphyxia, and mechanical ventilations for five days or more. A total of 48 newborns with hyperbilirubinemia met the enrolment criteria as the case group and 49 healthy newborns as the control group, who were hospitalized in a university educational hospital (22 Bahaman), in a north-eastern city of Iran, Mashhad. ABR was performed on both groups. The evaluated variable factors were latency time, inter peak intervals time, and loss of waves. RESULTS: The mean latencies of waves I, III and V of ABR were significantly higher in the pathologic hyperbilirubinemia group compared with the controls (P < 0.001). In addition, the mean interpeak intervals (IPI) of waves I-III, I-V and III-V of ABR were significantly higher in the pathologic hyperbilirubinemia group compared with the controls (P < 0.001). For example, the mean latencies time of wave I was significantly higher in right ear of the case group than in controls (2.16 +/- 0.26 vs. 1.77 +/- 0.15 milliseconds, respectively) (P < 0.001). CONCLUSIONS: Pathologic hyperbilirubinemia causes acute disorder on brain stem function; therefore, early diagnosis of neonatal jaundice for prevention of bilirubin neurotoxic effects is essential. As national neonatal hearing screening in not yet established in Iran, we recommend performing ABR for screening of bilirubin neurotoxicity in all cases with hyperbilirubinemia. PMID- 25793116 TI - Nurses' creativity: advantage or disadvantage. AB - BACKGROUND: Recently, global nursing experts have been aggressively encouraging nurses to pursue creativity and innovation in nursing to improve nursing outcomes. Nurses' creativity plays a significant role in health and well-being. In most health systems across the world, nurses provide up to 80% of the primary health care; therefore, they are critically positioned to provide creative solutions for current and future global health challenges. OBJECTIVES: The purpose of this study was to explore Iranian nurses' perceptions and experiences toward the expression of creativity in clinical settings and the outcomes of their creativity for health care organizations. PATIENTS AND METHODS: A qualitative approach using content analysis was adopted. Data were collected through in-depth semistructured interviews with 14 nurses who were involved in the creative process in educational hospitals affiliated to Jahrom and Tehran Universities of Medical Sciences in Iran. RESULTS: Four themes emerged from the data analysis, including a) Improvement in quality of patient care, b) Improvement in nurses' quality of work, personal and social life, c) Promotion of organization, and d) Unpleasant outcomes. CONCLUSIONS: The findings indicated that nurses' creativity in health care organizations can lead to major changes of nursing practice, improvement of care and organizational performance. Therefore, policymakers, nurse educators, nursing and hospital managers should provide a nurturing environment that is conducive to creative thinking, giving the nurses opportunity for flexibility, creativity, support for change, and risk taking. PMID- 25793117 TI - Fecal Calprotectin is an Accurate Tool and Correlated to Seo Index in Prediction of Relapse in Iranian Patients With Ulcerative Colitis. AB - BACKGROUND: The natural clinical course of Ulcerative Colitis (UC) is characterized by episodes of relapse and remission. Fecal Calprotectin (FC) is a relatively new marker of intestinal inflammation and is an available, non expensive tool for predicting relapse of quiescent UC. The Seo colitis activity index is a clinical index for assessment of the severity of UC. OBJECTIVES: The present study aimed to evaluate the accuracy of FC and the Seo colitis activity index and their correlation in prediction of UC exacerbation. PATIENTS AND METHODS: In this prospective cohort study, 157 patients with clinical and endoscopic diagnosis of UC selected randomly from 1273 registered patients in Fars province's IBD registry center in Shiraz, Iran, were followed from October 2012 to October 2013 for 12 months or shorter, if they had a relapse. Two patients left the study before completion and one patient had relapse because of discontinuation of drugs. The participants' clinical and serum factors were evaluated every three months. Furthermore, stool samples were collected at the beginning of study and every three months and FC concentration (commercially available enzyme linked immunoassay) and the Seo Index were assessed. Then univariate analysis, multiple variable logistic regression, Receiver Operating Characteristics (ROC) curve analysis, and Pearson's correlation test (r) were used for statistical analysis of data. RESULTS: According to the results, 74 patients (48.1%) relapsed during the follow-up (33 men and 41 women). Mean +/- SD of FC was 862.82 +/- 655.97 MUg/g and 163.19 +/- 215.85 MUg/g in relapsing and non-relapsing patients, respectively (P < 0.001). Multiple logistic regression analysis revealed that age, number of previous relapses, FC and the Seo index were significant predictors of relapse. ROC curve analysis of FC level and Seo activity index for prediction of relapse demonstrated area under the curve of 0.882 (P < 0.001) and 0.92 1(P < 0.001), respectively. Besides, FC level of 341 MUg/g was identified as the cut-off point with 11.2% and 79.7% relapse rate below and above this point, respectively. Additionally, Pearson correlation coefficient (r) between FC and the Seo index was significant in prediction of relapse (r = 0.63, P < 0.001). CONCLUSIONS: As a simple and noninvasive marker, FC is highly accurate and significantly correlated to the Seo activity index in prediction of relapse in the course of quiescent UC in Iranian patients. PMID- 25793118 TI - Monoamine oxidase a gene polymorphisms and bipolar disorder in Iranian population. AB - BACKGROUND: Bipolar disorder (BPD) is a common and severe mood disorder. Although genetic factors have important rolesin the etiology of bipolar disorder, no specific gene has been identified in relation to this disorder. Monoamine oxidase gene is suggested to be associated with bipolar disorder in many studies. OBJECTIVES: This study aimed to investigatethe role of MAOA gene polymorphisms in the etiology of bipolar disorder in Iranian population. PATIENTS AND METHODS: This study is a case-control study, with convenient sampling. Three common polymorphisms, a CA microsatellite, a VNTR, and a RFLP were typed in 156 bipolar patients and 173 healthy controls. Patients were chosen from Imam Hossein General Hospital, Psychiatry Ward (Tehran/Iran). Controlsamples for this study consisted of 173 healthy individuals recruitedby convenient sampling. Allelic distributions of these polymorphisms were analyzed in bipolar and control groups to investigate any association with MAOA gene. RESULTS: Significant associations were observed regarding MAOA-CA (P = 0.016) and MAOA-VNTR (P = 0.004) polymorphisms in the bipolar females. There was no association between MAOA-RFLP and bipolar disorder. CONCLUSIONS: The obtained results confirm some previous studies regardinga gender specific association of MAOA gene with the bipolar disorder. PMID- 25793119 TI - Demographic and clinical differences of aggressive and non-aggressive suicide attempts in the emergency department in the eastern region of Turkey. AB - BACKGROUND: Worldwide, suicide ranks among the three leading causes of death among those aged 15-44 years. An estimated 800000 people die by committing suicide annually. OBJECTIVES: To better understand the association between aggressive suicidal attempt and non-aggressive suicidal attempt in patients with suicide attempt in the emergency department. PATIENTS AND METHODS: A cross sectional observational study was conducted on suicide attempters of eastern region of Turkey between May 2008 and January 2012. Information of all adult suicide attempts was collected prospectively on a form. Suicide attempts were grouped as aggressive and non-aggressive attempts on a specially designed data collection form. The aggressive suicide attempts contained violent suicide methods such as firearm, hanging, jumping, car exhaust or drowning. RESULTS: A total of 533 patients were included. Sixty-four of these patients admitted to ED with aggressive suicide attempt (12%). Non-aggressive suicide attempts were consulted to psychiatry more compared to aggressive ones (%73.6, n = 345 vs. %32.8, n = 21, P < 0.0001). Agitation in ED and being male increased aggressive suicide attempt risk by 3.5 (%95 CI: 1.6-7.6) and 3.2 times (%95 CI: 1.8-5.5), agitated patients in ED group and male group respectively. Patients with aggressive suicide attempt were statistically more frequent among these patients; patients with agitation, those hospitalized in intensive care or surgical services and those whose length of stay in the emergency department was less than one day (P < 0.05 for all). Patients with non-aggressive suicide attempt were statistically more frequent in these patients; patients complained of nausea, vomiting, stomach pain, fatigue, those with confusion, those tending to sleep, those hospitalized in internal services or emergency ward and finally those whose length of stay in the emergency department was more than one day (P < 0.05 for all). CONCLUSIONS: Patients with aggressive suicide attempt who have high risk of dying should be recognized and requested psychiatric consultation even if not in the emergency department. PMID- 25793120 TI - Psychometric Properties of the Coping Self-Efficacy Scale Among HIV-Infected Iranian Patients. AB - BACKGROUND: Self-efficacy is an important predicator of coping with stress. OBJECTIVES: This study aimed to determine the psychometric characteristics of the coping self-efficacy (CSE) scale among HIV-infected Iranian patients. PATIENTS AND METHODS: Psychometric properties of the CSE scale were examined by using a cross-sectional study design. One hundred and twenty HIV-infected Iranian patients that had been referred to the Counseling of Behavioral Diseases Center at Imam Khomeini Hospital in Tehran, Iran in 2014 were selected through simple random sampling method. To determine the Content Validity Index (CVI) and the content validity ratio (CVR), a panel of experts (n = 20) reviewed items of CSE scale. Reliability was estimated through the internal consistency (n = 30) and the conformity factor analysis was performed. RESULTS: Iranian version of the CSE scale contained 16 items, including 7 items on the "use of problem-focused coping" method, 5 items on "stopping unpleasant emotions and thoughts", and 4 items on "getting support from friends and family". CVI and CVR scores were 0.79, 0.42 and more, respectively. Internal consistencies (range, 0.64 to 0.84) of 3 subscales were acceptable. Confirmatory factor analysis showed that comparative indices of the model, including CFI, IFI, GFI, RMSEA, and Chi-square (chi2/df) were 0.96, 0.95, 0.84, 0.83, and 1.82, respectively, which indicated a good fit for the data. CONCLUSIONS: The Iranian version of the CSE scale is a valid instrument to measure the coping self-efficacy among people living with HIV in research and community settings in Iran. PMID- 25793121 TI - Increased interleukin-17 transcripts in peripheral blood mononuclear cells, a link between T-helper 17 and proinflammatory responses in bladder cancer. AB - BACKGROUND: Interleukin (IL)-17-producing CD4+ T helper (Th17) cells thatare known by producing IL-17 have recently been defined as a unique subset of proinflammatory helper cells. IL-17 is an inflammatory cytokine with robust effect on many cells and it can play important roles in pathogenesis of diverse groups of immune-mediated diseases. OBJECTIVES: The aim of this case-control study was to determine the gene expression of IL-6, IL-17, and transforming growth factor beta (TGF-beta) in Iranian patients with bladder cancer. PATIENTS AND METHODS: Blood samples were collected from 37 patients with bladder cancer and 37 healthy individuals with no history of malignancies or autoimmune disorders, based of simple sampling. The expression of IL-6, IL-17, and TGF-beta were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The mean of IL-17 transcripts was significantly higher in patients with bladder cancer compared with healthy individuals (0.33 +/- 0.06 vs. 0.42 +/- 0.14, ) (P = 0.04), but their TGF-beta was lower (12.53 +/- 8.41 vs. 54.94 +/- 17.95, ) (P = 0.04). However, the IL-6 transcripts level was similar in both groups (5.34 +/- 2.40 vs. 8.07 +/- 3.28, ) (P > 0.05) and there was not any significant difference between the noted cytokines expressions among patients with different stages and grades. CONCLUSIONS: As most of the cases studied in this investigation were in stages I and II, IL-17 as a prominent proinflammatory cytokine may play an important role in recruiting and infiltrating of antitumor immune responses in early stages of bladder cancer. Furthermore, it can be used as predictor for the clinical stage and prognosis of cancers such as bladder carcinoma. PMID- 25793123 TI - Resistance to Cotrimoxazole and Other Antimicrobials among Isolates from HIV/AIDS and Non-HIV/AIDS Patients at Bugando Medical Centre, Mwanza, Tanzania. AB - Bacterial resistance has increased in the AIDS era and is attributed to the widespread use of cotrimoxazole prophylaxis against opportunistic infections in HIV/AIDS patients. In Tanzania, cotrimoxazole prophylaxis has been used for more than ten years. Little is known, however, about its impact on the spread of antibiotic resistance in HIV positive patients. This cross-sectional study was done to compare magnitude of bacterial resistance to cotrimoxazole and other antimicrobials among isolates from HIV infected patients on cotrimoxazole prophylaxis and those not on prophylaxis and non-HIV patients attending Bugando Medical Centre (BMC). Susceptibility testing on obtained urine and swab specimens followed Clinical Laboratory Standard Institute, 2010, Guidelines. Of 945 samples collected, 155 had positive bacterial growth after 24 hours of incubation. Of the positive samples (72), 46.4% were from HIV positive patients. The common isolates were E. coli 41.3% (64/155), Klebsiella pneumoniae 17.5% (27/155), and Staphylococcus aureus 16.1% (25/155). Overall, bacterial resistance to cotrimoxazole was 118 (76.1%); among isolates from HIV patients bacterial resistance was 54 (75%), and for isolates from HIV patients on prophylaxis bacterial resistance was 36 (81.3%). HIV seropositivity and cotrimoxazole prophylaxis are not associated with antibiotic resistance observed in bacteria infecting patients attending BMC, Mwanza, Tanzania. PMID- 25793124 TI - Attitudes toward Management of Sickle Cell Disease and Its Complications: A National Survey of Academic Family Physicians. AB - Objective. Sickle cell disease (SCD) is a disease that requires a significant degree of medical intervention, and family physicians are one potential provider of care for patients who do not have access to specialists. The extent to which family physicians are comfortable with the treatment of and concerned about potential complications of SCD among their patients is unclear. Our purpose was to examine family physician's attitudes toward SCD management. Methods. Data was collected as part of the Council of Academic Family Medicine Educational Research Alliance (CERA) survey in the United States and Canada that targeted family physicians who were members of CERA-affiliated organizations. We examined attitudes regarding management of SCD. Results. Overall, 20.4% of respondents felt comfortable with treatment of SCD. There were significant differences in comfort level for treatment of SCD patients depending on whether or not physicians had patients who had SCD, as well as physicians who had more than 10% African American patients. Physicians also felt that clinical decision support (CDS) tools would be useful for treatment (69.4%) and avoiding complications (72.6%) in managing SCD patients. Conclusions. Family physicians are generally uncomfortable with managing SCD patients and recognize the utility of CDS tools in managing patients. PMID- 25793125 TI - Association between Washing Residue on the Feet and Tinea Pedis in Diabetic Patients. AB - Tinea pedis (TP) may lead to the development of foot ulcers in diabetic patients; thus, its prevention in diabetic patients is important. TP occurs after dermatophytes on the skin scales of TP patients attach to the feet. Therefore, it is necessary to remove the scales and dermatophytes, and this can be performed using various methods, including foot washing. This study aimed to objectively examine the association between the presence of TP and foot-washing habits. We included 33 diabetic patients, and, of these, 17 had TP. The presence of washing residue on the feet was determined by applying a fluorescent cream to the participants' feet, and images of the feet were captured under ultraviolet light before and after foot washing. Our results showed that diabetic patients with TP had higher levels of washing residue on their feet than those without TP. The importance of washing feet to prevent TP needs to be emphasized through educational programs for diabetic patients. Furthermore, the development of an effective foot-washing technique is essential. PMID- 25793122 TI - Tourniquet in surgery of the limbs: a review of history, types and complications. AB - CONTEXT: A tourniquet is a device that is used frequently in most orthopaedic surgeries but this routine device can lead to serious complications so we decided to review and declare it for safe instruction and use. EVIDENCE ACQUISITION: We searched the word "tourniquet" in PubMed and Google and reviewed all full text English articles and abstracts of non-English articles. In addition, we read all the reference pages of articles to find the new references. RESULTS: The use of tourniquet in orthopedic surgery can lead to serious but rare complications that can be prevented by its correct knowledge and use. CONCLUSIONS: At present, there is not enough evidence to discontinue the routine uses of tourniquets. PMID- 25793126 TI - Evaluation of a u.s. Public health laboratory service for the molecular detection of drug resistant tuberculosis. AB - Crucial to interrupting the spread of tuberculosis (TB) is prompt implementation of effective treatment regimens. We evaluated satisfaction, comfort with interpretation, and use of molecular results from a public health service provided by the Centers for Disease Control and Prevention (CDC) for the molecular detection of drug resistant Mycobacterium tuberculosis complex (MTBC). An electronic survey instrument was used to collect information anonymously from U.S. Public Health Laboratories (PHL) that submitted at least one isolate of MTBC to CDC from September 2009 through February 2011. Over 97% of those responding expressed satisfaction with the turnaround time for receiving results. Twenty-six PHL (74%) reported molecular results to healthcare providers in less than two business days. When comparing the molecular results from CDC with their own phenotypic drug susceptibility testing, 50% of PHL observed discordance. No respondents found the molecular results difficult to interpret and 82% were comfortably discussing them with TB program officials and healthcare providers. Survey results indicate PHL were satisfied with CDC's ability to rapidly provide interpretable molecular results for isolates of MTBC submitted for determination of drug resistance. To develop educational materials and strategies for service improvement, reasons for discordant results and areas of confusion need to be identified. PMID- 25793127 TI - Thrombus formation in left atrium on dabigatran therapy. AB - Dabigatran is a direct thrombin inhibitor, approved in the United States for stroke prevention in nonvalvular atrial fibrillation and prevention and treatment of thromboembolism. It has been also used in patients with documented left atrial thrombus, where treatment with dabigatran effectively led to thrombus resolution. We present a rare case of left atrial thrombus formation in a patient with chronic atrial fibrillation being treated with dabigatran 150 mg twice a day. The patient presented with multiple embolic strokes. There are only three such cases reported in the literature till date, all of whom had thrombus in the left atrium. The possible mechanisms of dabigatran failure include compensatory increase in upstream coagulation factors due to single level downstream blockade of thrombin, lack of inhibition of all available thrombin, and lack of monitoring measures that can be implemented in common clinical laboratories that lead to failure to assess adherence, which in turn can lead to dabigatran failure. PMID- 25793128 TI - Emergent unilateral renal artery stenting for treatment of flash pulmonary edema: fact or fiction? AB - Flash pulmonary edema is characteristically sudden in onset with rapid resolution once appropriate therapy has been instituted (Messerli et al., 2011). Acute increase of left ventricular (LV) end diastolic pressure is the usual cause of sudden decompensated cardiac failure in this patient population. Presence of bilateral renal artery stenosis or unilateral stenosis in combination with a single functional kidney in the susceptible cohort is usually blamed for this condition. We describe a patient who presented with flash pulmonary edema in the setting of normal coronary arteries. Our case is distinct as our patient developed flash pulmonary edema secondary to unilateral renal artery stenosis in the presence of bilateral functioning kidneys. Percutaneous stent implantation in the affected renal artery resulted in rapid resolution of pulmonary edema. PMID- 25793130 TI - Perianal median raphe cyst: a rare lesion with unusual histology and localization. AB - Median raphe cysts present anywhere between the external urethral meatus and the anus. The cysts can occur at parameatus, glans penis, penile shaft, scrotum, or perineum. Perianal region is an extremely rare location for these lesions. Here we present a 50-year-old male patient who presented with a cystic, fluctuant lesion, located at 12 o'clock in perianal region. Microscopic examination revealed a cystic lesion with keratinized and nonkeratinized stratified squamous epithelium, pseudostratified ciliated epithelium, and scattered goblet cells. The final diagnosis of the lesion was median raphe cyst. Ciliated cells and perianal localization in median raphe cysts are extremely rare characteristics. PMID- 25793129 TI - Unusual transalveolar and transmuco-gingival root avulsion of a fractured primary central incisor: a case with an 8-year follow-up. AB - The purpose of this unique case report is to describe a very unusual dentoalveolar fracture associated with avulsion of the near-complete root. A 3 year-old male patient came for consultation after a dentoalveolar trauma with a "fragment that looks like canine" found in his mouth by his mother. This boy suffered root fracture of the upper primary central right incisor, accompanied by transalveolar and transmuco-gingival avulsion of the tooth root fragment, leaving the crown in its position in the dental arch. Clinical and radiological examinations were performed in order to follow up the case: 15 days, one month, and three months after trauma, the crown had a slight mobility without other clinical or radiological signs. After six months, the upper primary central right incisor's crown was exfoliated. Open bite due to the persistence of the pacifier habit favored the crown retention in the mouth. This case emphasizes the importance of primary diagnosis and follow-up of trauma cases. To the best of our knowledge, this kind of dental injury has not been previously described in the literature nor in the current Dental Trauma guidelines for the management of traumatic dental injuries in the primary dentition. PMID- 25793131 TI - Ovarian hyperstimulation syndrome, the master of disguise? AB - The use of IVF has risen dramatically over the past 10 years and with this the complications of such treatments have also risen. One such complication is ovarian hyperstimulation syndrome with which patients can present acutely to hospital with shortness of breath. On admission, a series of blood tests are routinely performed, including the d-dimer. We present a case of a 41-year-old lady who had recently undergone IVF and presented with chest pain and dyspnoea. In the emergency department, a d-dimer returned as mildly elevated. Consequential admission onto MAU initiated several avoidable investigations for venous thromboembolism. Careful examination elicited a mild ascites and a thorough drug history gave recent low molecular weight heparin usage. Ultrasound scan of the abdomen subsequently confirmed the diagnosis of severe OHSS. The d-dimer should therefore be used to negate and not to substantiate a diagnosis of VTE. This case report aims to highlight the importance of OHSS as an uncommon cause of dyspnoea but whose prevalence is likely to increase in the forthcoming years. We discuss the complications of the misdiagnosis of OHSS, the physiology behind raised d dimers, and the potential harm from incorrect treatment or inappropriate imaging. PMID- 25793132 TI - Unusual Presentation of Meckel's Diverticulum: Gangrene due to Axial Torsion. AB - Meckel's diverticulum is the most common congenital anomaly of the small bowel. The majority of cases are asymptomatic; however, life-threatening complications can also take place. We present a case of a 37-year-old male who was admitted with symptoms of acute, severe abdominal pain in the right iliac fossa. The patient was operated on with the preoperative diagnosis of acute appendicitis but the operative findings were consistent with torted Meckel's diverticulum due to presence of mesodiverticular band and he was treated successfully with surgical resection. PMID- 25793133 TI - Meningioma of foramen magnum causing drop attacks. AB - A 52-year-old female presented with frequent episodes of falls without loss of consciousness. These episodes lasted for brief period followed by full neurological recovery. Magnetic resonance imaging (MRI) of the brain showed foramen magnum meningioma encasing left vertebral artery. The patient had dramatic improvement after excision of the tumor. PMID- 25793134 TI - Revision of a fractured uncemented revision stem using a custom designed punch and retrograde through-knee approach. AB - We report a unique case of a fractured modular cobalt chromium connection taper Revitan (Zimmer, Warsaw, IN) revision prosthesis. Macroscopic examination revealed a fracture at the diaphyseal-metaphyseal junction of this modular component. This report highlights that fractures can still occur with modern modular prostheses. We are not aware of any published failures of the Revitan revision prosthesis. We also describe a unique method of retrieval for a broken well fixed uncemented femoral stem, using a custom designed extraction instrument via a through-knee approach. PMID- 25793135 TI - Pleural mycobacterium avium complex infection in an immunocompetent female with no risk factors. AB - Mycobacterium avium complex (MAC) infections rarely affect the pleura, accounting for 5-15% of pulmonary MAC. We report a case of MAC pleural effusion in an otherwise immunocompetent young patient. A 37-year-old healthy female with no past medical history was admitted to the hospital with two weeks of right sided pleuritic chest pain, productive cough, and fever. She was febrile, tachycardic, and tachypneic with signs of right sided pleural effusion which were confirmed by chest X-ray and chest CT. Thoracentesis revealed lymphocytic predominant exudative fluid. The patient underwent pleural biopsy, bronchoscopy with bronchoalveolar lavage, and video assisted thoracoscopic surgery (VATS), all of which failed to identify the causative organism. Six weeks later, MAC was identified in the pleural fluid and pleural biopsy by DNA hybridization and culture. The patient was started on clarithromycin, ethambutol, and rifampin. After six months of treatment, she was asymptomatic with complete radiological resolution of the effusion. The presence of lymphocytic effusion should raise the suspicion for both tuberculous and nontuberculous mycobacterial disease. Pleural biopsy must be considered to make the diagnosis. Clinicians must maintain a high index of suspicion of MAC infection in an otherwise immunocompetent patient presenting with a unilateral lymphocytic exudative effusion. PMID- 25793137 TI - Delayed total breast reconstruction with brava. AB - Several surgical procedures exist in regard to reconstruction of the breast after mastectomy. The use of Brava a vacuum-based external soft-tissue expansion system in combination with fat transplantation is a less documented but viable option in treating patients after mastectomy. We share our experience in treating a 57-year old patient with mastectomy, describing the complications and pitfalls we experienced when using the Brava system in combination with fat transplantation. PMID- 25793136 TI - Assessing Biological Response to Bevacizumab Using 18F-Fluoromisonidazole PET/MR Imaging in a Patient with Recurrent Anaplastic Astrocytoma. AB - We present our initial experience in using single modality fluoromisonidazole (FMISO) PET/MR imaging to noninvasively evaluate the biological effects induced by bevacizumab therapy in a patient treated for recurrent high grade glioma. In this index patient, bevacizumab therapy resulted in the development of nonenhancing tumor characterized by reduced diffusion and markedly decreased FMISO uptake in the setting of maintained CBF and CBV. These observations suggest that the dynamic biological interplay between tissue hypoxia and vascular normalization occurring within treated recurrent high grade glioma can be captured utilizing FMISO PET/MR imaging. PMID- 25793138 TI - Heterotopic Pancreas within the Proximal Hepatic Duct, Containing Intraductal Papillary Mucinous Neoplasm. AB - We report a unique first case of benign heterotopic pancreas arising within the proximal hepatic bile duct, containing a focus of intraductal papillary mucinous neoplasm (IPMN). The condition was diagnosed on pathological explant after left hepatic lobectomy with total extrahepatic bile duct excision. PMID- 25793139 TI - Hepatocellular carcinoma with osteoclast-like giant cells: report of the seventh case in the literature. AB - Hepatocellular carcinoma with osteoclast-like giant cells is extremely rare, and only six cases have been previously reported. Its histogenesis is at the moment controversial. The authors report a case of hepatocellular carcinoma with osteoclast-like giant cells found in a 74-year-old woman. The patient came with a dull pain in the right upper abdominal quadrants due to a liver neoplasm described at CT scan. A wedge resection of the fifth hepatic segment with appendectomy, omentectomy, and debulking of the major peritoneal implants was performed. Histologically, the diagnosis of hepatocellular carcinoma with high grade differentiation associated with giant osteoclast-like cells was done without any evidence of hepatitis or cirrhosis in the surrounding hepatic parenchyma. Immunohistochemistry was positive for CD10 and CD68 and in situ hybridization revealed the expression of receptor activator of nuclear factor kappa B (RANK) in the giant cells and receptor activator of nuclear factor-kappa B ligand (RANKL) in the tumor cells. PMID- 25793140 TI - Acute hepatocellular drug induced liver injury probably by alfuzosin. AB - Alpha blockers are the drugs that exert their effects by binding to alpha receptors and relaxing smooth muscles and are currently used for treatment of benign prostate hyperplasia (BPH). These drugs are often tolerated well by the patients. However, they also possess some common side effects. Hepatotoxicity, on the other hand, is quite rare. We report herein a case with the rare complication of acute hepatocellular drug induced liver injury (DILI) by administration of Alfuzosin. PMID- 25793141 TI - Bilateral wunderlich syndrome caused by spontaneous rupture of renal angiomyolipomas. AB - Wunderlich syndrome (WS) is a urological emergency characterized by retroperitoneal hemorrhage. In most cases, bleeding occurs from a renal angiomyolipoma (AML) and may be the first manifestation of the disease. We report a female patient with bilateral WS due to the metachronous rupture of renal AMLs. Because the patient was stable and the tumor was not malignant, treatment was conservative. Follow-up revealed the full recovery of kidney function and the resolution of the hematoma. PMID- 25793142 TI - Adaptive immunity and inflammation. PMID- 25793143 TI - Transdermal Rotigotine Improves Sleep Fragmentation in Parkinson's Disease: Results of the Multicenter, Prospective SLEEP-FRAM Study. AB - Sleep disturbances occur frequently in patients with Parkinson's disease (PD). The aim of this study was to investigate the effects of rotigotine on sleep fluctuations in a sample of PD patients with self-reported complaints of nocturnal awakenings. This prospective, open-label, observational, and multicenter study enrolled consecutive outpatients with PD and administered rotigotine (mean dose 8.9 mg/day) for 3 months. The primary endpoint was the change from baseline in sleep fragmentation, assessed using the sleep maintenance subscale score of the Parkinson's Disease Sleep Scale (PDSS). The newly designed Parkinson's Disease Sleep Fragmentation Questionnaire (PD-SFQ) was used to measure other sleep parameters. A total of 62 patients were enrolled (mean age 70.2 years; 66% male). At 3 months, rotigotine significantly improved sleep fragmentation from baseline on the PDSS-2 sleep maintenance subscale (from 3.4 +/ 0.9 to 1.9 +/- 1.4; P < 0.0001). Rotigotine also significantly improved nocturnal motor symptoms (P < 0.0001), restless legs-like symptoms (P < 0.005), and nocturia (P = 0.004). Rotigotine significantly improved self-reported complaints of sleep fragmentation in PD patients and could be a useful treatment to improve this specific sleep problem in PD. However, these results are based on a small and clinically heterogeneous sample so they must be taken cautiously. PMID- 25793144 TI - Instant transport media for biopsied soft tissue specimens: a comparative study. AB - Background. Formalin, a traditionally preferred fixative in the field of pathology, has restricted usage in private settings. Since its toxicity violates the Occupational Safety and Health Administration regulations, an eco-friendly alternative would be the need of the hour. Hence an instant media which is economical and nontoxic and enables easy transport of biopsied soft tissue specimens in its original state is of vital importance. Materials and Methods. Commercially available fresh goat buccal mucosa specimens were sliced into smaller bits of equal dimensions and placed in six different containers containing 20% honey, 30% jaggery, milk, and ice for 1 hr, 6 hours, 12 hours, and 24 hours each with formalin as a positive control. After the set time interval, the specimens were fixed in 10% buffered formalin for 24 hours followed by routine processing and staining. The histologic interpretations were a blinded procedure and evaluated by two experts. Results were statistically analysed. Results. 30% jaggery proved to be an ideal transport media showing high quality preservation after 24 hours. 20% honey and ice showed optimal tissue preservation up to 6 hours following which quality deteriorated. Tissues transported in milk showed poor preservation. Conclusion. 30% jaggery can be endorsed in routine histopathological analysis as a transport media. PMID- 25793145 TI - Myoclonus in ataxia-telangiectasia. AB - BACKGROUND: Various movement disorders can be found in ataxia-telangiectasia (AT), including ataxia, dystonia, chorea, and myoclonus, but myoclonus has rarely been described as the predominant feature in AT. CASE REPORT: We report two AT patients with prominent myoclonus, illustrating an unusual presentation of this disorder. Sequencing of the ATM gene in the first patient revealed a homozygous truncating mutation, c.5908C>T (p.Q1970*) in exon 38 of the ATM gene, which has been previously reported as a founder mutation in the Costa Rican population. DISCUSSION: Myoclonus can be a predominant or presenting feature in AT, even without dystonia. PMID- 25793146 TI - Severity stages in essential tremor: a long-term retrospective study using the glass scale. AB - BACKGROUND: Few prospective studies have attempted to estimate the rate of decline of essential tremor (ET) and these were over a relatively short time period (less than 10 years). We performed a long-term study of severity stages in ET using the Glass Scale scoring system. METHODS: Fifty consecutive patients with severe ET were included. We retrospectively obtained Glass Scale scores throughout the patient's life. Common milestone events were used to help recall changes in tremor severity. RESULTS: According to the Glass Scale, the age distributions were as follows: score I, 40+/-17 years, score II, 55+/-12 years, score III, 64+/-9 years, and score IV, 69+/-7 years. A significant negative correlation between age at first symptom and rate of progression was found (r = 0.669, p<0.001). The rate of progression was significantly different (p<0.001) when the first symptom appeared at a younger age (under 40 years of age) compared with older age (40 years or older). DISCUSSION: Our results support the progressive nature of ET. Age at onset was a prognostic factor. The Glass Scale may be a useful tool to determine severity stages during the course of ET in a manner similar to the Hoehn and Yahr Scale for Parkinson's disease. PMID- 25793147 TI - Diagnosis of brain tumors using dynamic contrast-enhanced perfusion imaging with a short acquisition time. AB - This study sought to determine the diagnostic utility of perfusion parameters derived from dynamic contrast-enhanced (DCE) perfusion MRI with a short acquisition time (approximately 3.5 min) in patients with glioma, brain metastasis, and primary CNS lymphoma (PCNSL). Twenty-six patients with 29 lesions (4 low-grade glioma, 13 high-grade glioma, 7 metastasis, and 5 PCNSL) underwent DCE-MRI in a 3 T scanner. A ROI was placed on the hotspot of each tumor in maps for volume transfer contrast K (trans) , extravascular extracellular volume V e , and fractional plasma volume V p . We analyzed differences in parameters between tumors using the Mann-Whitney U test. We calculated sensitivity and specificity using receiver operating characteristics analysis. Mean K (trans) values of LGG, HGG, metastasis and PCNSL were 0.034, 0.31, 0.38, 0.44, respectively. Mean Ve values of each tumors was 0.036, 0.57, 0.47, 0.96, and mean Vp value of each tumors was 0.070, 0.086, 0.26, 0.17, respectively. Compared with other tumor types, low-grade glioma showed lower K (trans) (P < 0.01, sensitivity = 88%, specificity = 100%) and lower V e (P < 0.01, sensitivity = 96%, specificity = 100%). PCNSL showed higher V e (P < 0.01, sensitivity = 100%, specificity = 88%), but the other perfusion parameters overlapped with those of different histology. Kinetic parameters derived from DCE-MRI with short acquisition time provide useful information for the differential diagnosis of brain tumors. PMID- 25793148 TI - Parasympathetic reactivation after maximal CPET depends on exercise modality and resting vagal activity in healthy men. AB - PURPOSE: The main purpose of this study was to investigate parasympathetic reactivation of the heart [evaluated through heart rate recovery (HRR) and HR variability (HRV)] after maximal cardiopulmonary exercise testing (CPET) using three different exercise modalities. METHODS: Twenty healthy men, aged 17 to 28 yr, performed three maximal CPETs (cycling, walking, and running) separated by 72 h and in a randomized, counter-balanced order. HRR was determined from the absolute differences between HRpeak and HR at 1-3 min after exercise. The root mean square of successive R-R differences calculated for consecutive 30-s windows (rMSSD30s) was calculated to assess the parasympathetic reactivation after maximal CPET. RESULTS: Lower HRpeak, VO2peak and energy expenditure were observed after the cycling CPET than the walking and running CPETs (P < 0.001). Both HRR and rMSSD30s were significantly greater during recovery from the cycling CPET compared to the walking and running CPETs (P < 0.001). Furthermore, Delta rMSSD (i.e. resting minus postexercise rMSSD every 30 s into the recovery period) was positively related to the resting high-frequency component (HF), rMSSD, and standard deviation of all normal R-R intervals (SDNN) (rs = 0.89 to 0.98; P < 0.001), and negatively related to the resting low-frequency component (LF) and sympathovagal balance (LF:HF ratio) after all exercise conditions (rs = -0.73 to 0.79 and -0.86 to -0.90, respectively; P < 0.001). CONCLUSIONS: These findings support that parasympathetic reactivation after maximal CPET (as assessed by HRR and rMSSD30s) depends on exercise modality and cardiac autonomic control at rest. PMID- 25793149 TI - Cardiopulmonary resuscitation outcomes in a cancer center emergency department. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) after cardiac arrest is utilized indiscriminately among unselected populations. Cancer patients have particularly low rates of return of spontaneous circulation (ROSC) and survival to hospital discharge after CPR. Our study determines rates of ROSC and survival to hospital discharge among cancer patients undergoing CPR in our cancer center. We examined whether these rates have changed over the past decade. METHODS: This IRB-approved retrospective observational study was conducted in our cancer center. The ED and cancer center provide medical care for >= 115,000 patients annually. Cases of CPR presenting to the cancer center for years 2003-2012 were identified using Institutional CPR and Administrative Data for Resuscitation and Billing databases. Age, gender, ethnicity, ROSC and Discharge Alive using a modified Utsein template was used to compare proportions achieving ROSC and survival to hospital discharge for two time periods: 2003-2007 (Group 1) and 2008-2012 (Group 2), using traditional Pearson chi-square statistics. RESULTS: One hundred twenty six cancer center patients received CPR from 2003-2012. Group 1 (N = 64) and Group 2 (N = 62) were similar; age (60 vs. 60 years), gender (63% vs. 58% male), and race/ethnicity (67% vs. 56% White). Proportions achieving ROSC were similar in the two time periods (36% Group 1 vs. 45% Group 2, OR = 1.47, 95% CI 0.72 - 3.00) as was survival to hospital discharge (11% Group 1 vs. 10% Group 2, OR 0.87, 95% CI 0.28 - 2.76). CONCLUSIONS: ROSC after CPR in cancer patients and survival to hospital discharge did not change over time. PMID- 25793150 TI - Evaluation of appropriateness of second-generation 320-row computed tomography for coronary artery disease. AB - The influence of newer-generation CT on the clinical indications and appropriateness of cardiac CT has not been adequately surveyed. We aimed to evaluate the distribution of appropriateness ratings and test the outcomes of cardiac CT using second-generation 320-row CT. The 2010 appropriate use criteria (AUC) were applied at the point of service to a consecutive series of patients (N = 309) who were referred for cardiac CT. The CT indication was determined based on interviews and medical records. The proportions of patients within the categories of appropriate (A), uncertain (U), inappropriate (I), and not covered were described. The prevalence of significant coronary artery disease (CAD) was also compared among the categories. The proportions were 49.2%, 25.9%, and 20.7% for appropriate, uncertain, and inappropriate indication, respectively. The indication that was not covered was only 4.2%. Significant CAD was more frequently observed for uncertain- than appropriate indication (42.5% vs 27.6%; P = 0.03), although the number of significant stenosed segments was not different (P = 0.13). The recent advancement of cardiac CT increased the proportion of uncertain scans, which were associated with a high prevalence of significant CAD. PMID- 25793151 TI - Frequency and associated factors of axillary web syndrome in women who had undergone breast cancer surgery: a transversal and retrospective study. AB - BACKGROUND: Breast cancer is the most common malignancy among women. Surgical treatment is an essential part of therapy, which still includes chemotherapy, radiotherapy and hormone therapy. The increase in early cancer detection and less aggressive treatment has made longer survival rates possible for women with this neoplasia. Morbidities after treatment have subsequently aroused particular interest in the scientific community in order to minimize their effects and provide increased quality-of-life for these patients. The present study aimed at investigating one of these morbidities: axillary web syndrome, which occurs after axillary surgical management. METHODS: From December 2011 to September 2012, according to the inclusion and exclusion criteria, 97 patients, who had been surgically treated for breast cancer, were enrolled, interviewed, and submitted to a specific physical exam. An investigation of the axillary cords, characteristic of this syndrome, was performed in all patients. RESULTS: The axillary web syndrome was diagnosed in 28.86% of the women. Higher risk of triggering the syndrome has been associated with younger age (21.7%), longer time between first treatment and data collection (29.3%), greater number of resected lymph nodes (149.7%) and surgical management medical teams (113.2%). CONCLUSIONS: One can conclude that axillary web syndrome was associated with younger age, greater time elapsed since surgery, surgical management of medical staff and number of resected lymph nodes. Further studies are needed to review prior-to surgery and post-operative follow-up, to properly assess the effects of surgery in the axilla on homeostatic balance, not only in the ipsilateral upper limb, but also assess their compensatory consequences throughout the body. PMID- 25793152 TI - Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etanercept in patients with moderately active rheumatoid arthritis despite DMARD therapy. AB - This study evaluated the efficacy and safety of adding etanercept to disease modifying antirheumatic drugs (DMARDs) in patients with moderately active rheumatoid arthritis (RA). This randomized, double-blind, placebo-controlled study (ClinicalTrials.gov #NCT01313208) enrolled RA patients with Disease Activity Score using 28 joints with C-reactive protein (DAS28-CRP) >3.2 and <=5.1 (moderate disease) despite stable DMARD therapy. Patients were randomized to etanercept 50 mg or placebo weekly for 12 weeks; all patients then received etanercept 50 mg weekly through week 24. Primary endpoint was low disease activity (LDA) at week 12; secondary endpoints included DAS28-CRP remission at week 12; Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) LDA; American College of Rheumatology (ACR) responses; change in Health Assessment Questionnaire Disability Index (HAQ-DI), and safety. For 210 patients with moderate disease at screening, (104 placebo; 106 etanercept), only 58% still had moderate disease at baseline. At week 12, 33% on etanercept and 21% on placebo achieved LDA (P = 0.055); remission was achieved in 19% and 12%, respectively (P = 0.14). At week 12, ACR20, ACR50, and ACR70 responses were observed in 29%, 13%, and 1% respectively, in patients on placebo, and 41%, 21%, and 6% of patients on etanercept. Mean (SD) change from baseline in HAQ-DI score was -0.20 (0.43) for placebo patients and -0.39 (0.54) for etanercept patients at week 12. No new safety signals were observed. LDA was achieved by more patients on etanercept than placebo in patients with moderate disease at screening, but the difference was not statistically significant at week 12. PMID- 25793153 TI - Virtual pathology of cervical radiculopathy based on 3D MR/CT fusion images: impingement, flattening or twisted condition of the compressed nerve root in three cases. AB - BACKGROUND: There have been several imaging studies of cervical radiculopathy, but no three-dimensional (3D) images have shown the path, position, and pathological changes of the cervical nerve roots and spinal root ganglion relative to the cervical bony structure. The objective of this study was to introduce a technique that enables the virtual pathology of the nerve root to be assessed using 3D magnetic resonance (MR)/computed tomography (CT) fusion images that show the compression of the proximal portion of the cervical nerve root by both the herniated disc and the preforaminal or foraminal bony spur in patients with cervical radiculopathy. FINDINGS: MR and CT images were obtained from three patients with cervical radiculopathy. 3D MR images were placed onto 3D CT images using a computer workstation. The entire nerve root could be visualized in 3D with or without the vertebrae. The most important characteristic evident on the images was flattening of the nerve root by a bony spur. The affected root was constricted at a pre-ganglion site. In cases of severe deformity, the flattened portion of the root seemed to change the angle of its path, resulting in twisted condition. CONCLUSIONS: The 3D MR/CT fusion imaging technique enhances visualization of pathoanatomy in cervical hidden area that is composed of the root and intervertebral foramen. This technique provides two distinct advantages for diagnosis of cervical radiculopathy. First, the isolation of individual vertebra clarifies the deformities of the whole root groove, including both the uncinate process and superior articular process in the cervical spine. Second, the tortuous or twisted condition of a compressed root can be visualized. The surgeon can identify the narrowest face of the root if they view the MR/CT fusion image from the posterolateral-inferior direction. Surgeons use MR/CT fusion images as a pre-operative map and for intraoperative navigation. The MR/CT fusion images can also be used as educational materials for all hospital staff and for patients and patients' families who provide informed consent for treatments. PMID- 25793154 TI - Modulation of Biointeractions by Electrically Switchable Oligopeptide Surfaces: Structural Requirements and Mechanism. AB - Understanding the dynamic behavior of switchable surfaces is of paramount importance for the development of controllable and tailor-made surface materials. Herein, electrically switchable mixed self-assembled monolayers based on oligopeptides have been investigated in order to elucidate their conformational mechanism and structural requirements for the regulation of biomolecular interactions between proteins and ligands appended to the end of surface tethered oligopeptides. The interaction of the neutravidin protein to a surface appended biotin ligand was chosen as a model system. All the considerable experimental data, taken together with detailed computational work, support a switching mechanism in which biomolecular interactions are controlled by conformational changes between fully extended ("ON" state) and collapsed ("OFF" state) oligopeptide conformer structures. In the fully extended conformation, the biotin appended to the oligopeptide is largely free from steric factors allowing it to efficiently bind to the neutravidin from solution. While under a collapsed conformation, the ligand presented at the surface is partially embedded in the second component of the mixed SAM, and thus sterically shielded and inaccessible for neutravidin binding. Steric hindrances aroused from the neighboring surface confined oligopeptide chains exert a great influence over the conformational behaviour of the oligopeptides, and as a consequence, over the switching efficiency. Our results also highlight the role of oligopeptide length in controlling binding switching efficiency. This study lays the foundation for designing and constructing dynamic surface materials with novel biological functions and capabilities, enabling their utilization in a wide variety of biological and medical applications. PMID- 25793155 TI - Transcriptional profiling of SNAI2 regulated genes in primary human keratinocytes. AB - Epithelial to mesenchymal transition transcription factors (EMT-TFs) such as SNAI2 have been found to be expressed endogenously in epidermal stem and progenitor cells and downregulated upon differentiation. The presence of SNAI2 in progenitor cells is necessary to repress the expression of differentiation genes by binding directly to their promoters. SNAI2 is downregulated upon differentiation which allows expression of differentiation genes. Furthermore overexpression of SNAI2 can block the differentiation process suggesting that the levels of SNAI2 are crucial to epidermal cell fate decisions. To address on a genome wide level the genes that are impacted by changing the levels of SNAI2, we performed microarray analysis on SNAI2 knockdown and overexpressing epidermal progenitor cells. Here we provide a detailed methods and analysis on these microarray data which has been deposited in Gene Expression Omnibus (GEO): GSE55269. PMID- 25793156 TI - Secretion of salivary statherin is compromised in uncontrolled diabetic patients. AB - BACKGROUND: Statherin is an important salivary protein for maintaining oral health. The purpose of the current study was to determine if differences in statherin levels exist between diabetic and healthy subjects. METHODS: A total of 48 diabetic and healthy controls were randomly selected from a community-based database. Diabetic subjects (n=24) had fasting glucose levels >180 mg/dL, while controls (n=24) had levels <110 mg/dL. Parotid saliva (PS) and sublingual/submandibular saliva (SS) were collected and salivary flow rates determined. Salivary statherin levels were determined by densitometry of Western blots. Blood hemoglobin A1c (HbA1c) and total protein in saliva were also obtained. RESULTS: SS, but not PS, salivary flow rate and total protein in diabetics were significantly less than in healthy controls (p=0.021 & p<0.001 respectively). Correlation analysis revealed the existence of a negative correlation between PS statherin levels and HbA1c (p=0.012) and fasting glucose (p=0.021) levels, while no such correlation was found for SS statherin levels. When statherin levels were normalized to total salivary protein, the proportion of PS statherin, but not SS statherin, in diabetics was significantly less than controls (p=0.032). In contrast, the amount of statherin secretion in SS, but not PS, was significantly decreased in diabetics compared to controls (p=0.016). CONCLUSIONS AND GENERAL SIGNIFICANCE: The results show that synthesis and secretion of statherin is reduced in diabetics and this reduction is salivary gland specific. As compromised salivary statherin secretion leads to increased oral health risk, this study indicates that routine oral health assessment of these patients is warranted. PMID- 25793157 TI - Management and prevention of acute and chronic lateral ankle instability in athletic patient populations. AB - Acute and chronic lateral ankle instability are common in high-demand patient populations. If not managed appropriately, patients may experience recurrent instability, chronic pain, osteochondral lesions of the talus, premature osteoarthritis, and other significant long-term disability. Certain populations, including young athletes, military personnel and those involved in frequent running, jumping, and cutting motions, are at increased risk. Proposed risk factors include prior ankle sprain, elevated body weight or body mass index, female gender, neuromuscular deficits, postural imbalance, foot/ankle malalignment, and exposure to at-risk athletic activity. Prompt, accurate diagnosis is crucial, and evidence-based, functional rehabilitation regimens have a proven track record in returning active patients to work and sport. When patients fail to improve with physical therapy and external bracing, multiple surgical techniques have been described with reliable results, including both anatomic and non-anatomic reconstructive methods. Anatomic repair of the lateral ligamentous complex remains the gold standard for recurrent ankle instability, and it effectively restores native ankle anatomy and joint kinematics while preserving physiologic ankle and subtalar motion. Further preventative measures may minimize the risk of ankle instability in athletic cohorts, including prophylactic bracing and combined neuromuscular and proprioceptive training programs. These interventions have demonstrated benefit in patients at heightened risk for lateral ankle sprain and allow active cohorts to return to full activity without adversely affecting athletic performance. PMID- 25793158 TI - Biological response to prosthetic debris. AB - Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is considered absolutely perfect. Generation of wear debris from any part of the prosthesis is unavoidable. Implant loosening secondary to osteolysis is the most common mode of failure of arthroplasty. Osteolysis is the resultant of complex contribution of the generated wear debris and the mechanical instability of the prosthetic components. Roughly speaking, all orthopedic biomaterials may induce a universal biologic host response to generated wear debris with little specific characteristics for each material; but some debris has been shown to be more cytotoxic than others. Prosthetic wear debris induces an extensive biological cascade of adverse cellular responses, where macrophages are the main cellular type involved in this hostile inflammatory process. Macrophages cause osteolysis indirectly by releasing numerous chemotactic inflammatory mediators, and directly by resorbing bone with their membrane microstructures. The bio-reactivity of wear particles depends on two major elements: particle characteristics (size, concentration and composition) and host characteristics. While any particle type may enhance hostile cellular reaction, cytological examination demonstrated that more than 70% of the debris burden is constituted of polyethylene particles. Comprehensive understanding of the intricate process of osteolysis is of utmost importance for future development of therapeutic modalities that may delay or prevent the disease progression. PMID- 25793160 TI - Advanced concepts in knee arthrodesis. AB - The aim is to describe advanced strategies that can be used to diagnose and treat complications after knee arthrodesis and to describe temporary knee arthrodesis to treat infected knee arthroplasty. Potential difficult complications include nonunited knee arthrodesis, limb length discrepancy after knee arthrodesis, and united but infected knee arthrodesis. If a nonunited knee arthrodesis shows evidence of implant loosening or failure, then bone grafting the nonunion site as well as exchange intramedullary nailing and/or supplemental plate fixation are recommended. If symptomatic limb length discrepancy cannot be satisfactorily treated with a shoe lift, then the patient should undergo tibial lengthening over nail with a monolateral fixator or exchange nailing with a femoral internal lengthening device. If a united knee arthrodesis is infected, the nail must be removed. Then the surgeon has the option of replacing it with a long, antibiotic cement-coated nail. The authors also describe temporary knee arthrodesis for infected knee arthroplasty in patients who have the potential to undergo insertion of a new implant. The procedure has two goals: eradication of infection and stabilization of the knee. A temporary knee fusion can be accomplished by inserting both an antibiotic cement-coated knee fusion nail and a static antibiotic cement-coated spacer. These advanced techniques can be helpful when treating difficult complications after knee arthrodesis and treating cases of infected knee arthroplasty. PMID- 25793159 TI - Economic impact of minimally invasive lumbar surgery. AB - Cost effectiveness has been demonstrated for traditional lumbar discectomy, lumbar laminectomy as well as for instrumented and noninstrumented arthrodesis. While emerging evidence suggests that minimally invasive spine surgery reduces morbidity, duration of hospitalization, and accelerates return to activites of daily living, data regarding cost effectiveness of these novel techniques is limited. The current study analyzes all available data on minimally invasive techniques for lumbar discectomy, decompression, short-segment fusion and deformity surgery. In general, minimally invasive spine procedures appear to hold promise in quicker patient recovery times and earlier return to work. Thus, minimally invasive lumbar spine surgery appears to have the potential to be a cost-effective intervention. Moreover, novel less invasive procedures are less destabilizing and may therefore be utilized in certain indications that traditionally required arthrodesis procedures. However, there is a lack of studies analyzing the economic impact of minimally invasive spine surgery. Future studies are necessary to confirm the durability and further define indications for minimally invasive lumbar spine procedures. PMID- 25793161 TI - Factors affecting healing after arthroscopic rotator cuff repair. AB - Rotator cuff repair has been shown to have good long-term results. Unfortunately, a significant proportion of repairs still fail to heal. Many factors, both patient and surgeon related, can influence healing after repair. Older age, larger tear size, worse muscle quality, greater muscle-tendon unit retraction, smoking, osteoporosis, diabetes and hypercholesterolemia have all shown to negatively influence tendon healing. Surgeon related factors that can influence healing include repair construct-single vs double row, rehabilitation, and biologics including platelet rich plasma and mesenchymal stem cells. Double-row repairs are biomechanically stronger and have better healing rates compared with single-row repairs although clinical outcomes are equivalent between both constructs. Slower, less aggressive rehabilitation programs have demonstrated improved healing with no negative effect on final range of motion and are therefore recommended after repair of most full thickness tears. Additionally no definitive evidence supports the use of platelet rich plasma or mesenchymal stem cells regarding improvement of healing rates and clinical outcomes. Further research is needed to identify effective biologically directed augmentations that will improve healing rates and clinical outcomes after rotator cuff repair. PMID- 25793163 TI - Atlanto-occipital dislocation. AB - Atlanto-occipital dislocation (AOD) is being increasingly recognized as a potentially survivable injury as a result of improved prehospital management of polytrauma patients and increased awareness of this entity, leading to earlier diagnosis and more aggressive treatment. However, despite overall improved outcomes, AOD is still associated with significant morbidity and mortality. The purpose of this paper is to review the biomechanical aspects, clinical features, radiologic criteria, and treatment strategies of AOD. Given that the diagnosis of AOD can be very challenging, a high degree of clinical suspicion is essential to ensure timely recognition and treatment, thus preventing neurological decline or death. PMID- 25793164 TI - Use of scoring systems for assessing and reporting the outcome results from shoulder surgery and arthroplasty. AB - To investigate shoulder scoring systems used in Europe and North America and how outcomes might be classified after shoulder joint replacement. All research papers published in four major journals in 2012 and 2013 were reviewed for the shoulder scoring systems used in their published papers. A method of identifying how outcomes after shoulder arthroplasty might be used to categorize patients into fair, good, very good and excellent outcomes was explored using the outcome evaluations from patients treated in our own unit. A total of 174 research articles that were published in the four journals used some form of shoulder scoring system. The outcome from shoulder arthroplasty in our unit has been evaluated using the constant score (CS) and the oxford shoulder score and these scores have been used to evaluate individual patient outcomes. CSs of < 30 = unsatisfactory; 30-39 = fair; 40-59 = good; 60-69 = very good; and 70 and over = excellent. The most popular shoulder scoring systems in North America were Simple Shoulder Test and American shoulder and elbow surgeons standard shoulder assessment form score and in Europe CS, Oxford Shoulder Score and DASH score. PMID- 25793162 TI - Fractal lacunarity of trabecular bone and magnetic resonance imaging: New perspectives for osteoporotic fracture risk assessment. AB - Osteoporosis represents one major health condition for our growing elderly population. It accounts for severe morbidity and increased mortality in postmenopausal women and it is becoming an emerging health concern even in aging men. Screening of the population at risk for bone degeneration and treatment assessment of osteoporotic patients to prevent bone fragility fractures represent useful tools to improve quality of life in the elderly and to lighten the related socio-economic impact. Bone mineral density (BMD) estimate by means of dual energy X-ray absorptiometry is normally used in clinical practice for osteoporosis diagnosis. Nevertheless, BMD alone does not represent a good predictor of fracture risk. From a clinical point of view, bone microarchitecture seems to be an intriguing aspect to characterize bone alteration patterns in aging and pathology. The widening into clinical practice of medical imaging techniques and the impressive advances in information technologies together with enhanced capacity of power calculation have promoted proliferation of new methods to assess changes of trabecular bone architecture (TBA) during aging and osteoporosis. Magnetic resonance imaging (MRI) has recently arisen as a useful tool to measure bone structure in vivo. In particular, high-resolution MRI techniques have introduced new perspectives for TBA characterization by non invasive non-ionizing methods. However, texture analysis methods have not found favor with clinicians as they produce quite a few parameters whose interpretation is difficult. The introduction in biomedical field of paradigms, such as theory of complexity, chaos, and fractals, suggests new approaches and provides innovative tools to develop computerized methods that, by producing a limited number of parameters sensitive to pathology onset and progression, would speed up their application into clinical practice. Complexity of living beings and fractality of several physio-anatomic structures suggest fractal analysis as a promising approach to quantify morpho-functional changes in both aging and pathology. In this particular context, fractal lacunarity seems to be the proper tool to characterize TBA texture as it is able to describe both discontinuity of bone network and sizes of bone marrow spaces, whose changes are an index of bone fracture risk. In this paper, an original method of MRI texture analysis, based on TBA fractal lacunarity is described and discussed in the light of new perspectives for early diagnosis of osteoporotic fractures. PMID- 25793165 TI - Review of evolution of tunnel position in anterior cruciate ligament reconstruction. AB - Anterior cruciate ligament (ACL) rupture is one of the commonest knee sport injuries. The annual incidence of the ACL injury is between 100000-200000 in the United States. Worldwide around 400000 ACL reconstructions are performed in a year. The goal of ACL reconstruction is to restore the normal knee anatomy and kinesiology. The tibial and femoral tunnel placements are of primordial importance in achieving this outcome. Other factors that influence successful reconstruction are types of grafts, surgical techniques and rehabilitation programmes. A comprehensive understanding of ACL anatomy has led to the development of newer techniques supplemented by more robust biological and mechanical concepts. In this review we are mainly focussing on the evolution of tunnel placement in ACL reconstruction, focusing on three main categories, i.e., anatomical, biological and clinical outcomes. The importance of tunnel placement in the success of ACL reconstruction is well researched. Definite clinical and functional data is lacking to establish the superiority of the single or double bundle reconstruction technique. While there is a trend towards the use of anteromedial portals for femoral tunnel placement, their clinical superiority over trans-tibial tunnels is yet to be established. PMID- 25793166 TI - Frozen shoulder: A systematic review of therapeutic options. AB - Frozen shoulder is a common disease which causes significant morbidity. Despite over a hundred years of treating this condition the definition, diagnosis, pathology and most efficacious treatments are still largely unclear. This systematic review of current treatments for frozen shoulder reviews the evidence base behind physiotherapy, both oral and intra articular steroid, hydrodilatation, manipulation under anaesthesia and arthroscopic capsular release. Key areas in which future research could be directed are identified, in particular with regard to the increasing role of arthroscopic capsular release as a treatment. PMID- 25793168 TI - Is non-biological treatment of rheumatoid arthritis as good as biologics? AB - The management of rheumatoid arthritis (RA) in the past three decades has undergone a paradigm shift from symptomatic relief to a "treat-to-target" approach. This has been possible through use of various conventional and biologic disease modifying anti-rheumatic drugs (DMARDs) which target disease pathogenesis at a molecular level. Cost and infection risk preclude regular use of biologics in resource-constrained settings. In the recent years, evidence has emerged that combination therapy with conventional DMARDs is not inferior to biologics in the management of RA and is a feasible cost-effective option. PMID- 25793167 TI - Use of demineralized bone matrix in the extremities. AB - Autologous bone graft is considered as the gold standard for all indications for bone grafting procedures but the limited availability and complications in donor site resulted in seeking other options like allografts and bone graft substitutes. Demineralized bone matrix (DBM) is an allograft product with no quantity limitation. It is an osteoconductive material with osteoinductive capabilities, which vary among different products, depending on donor characteristics and differences in processing of the bone. The purpose of the present review is to provide a critical review of the existing literature concerning the use of DBM products in various procedures in the extremities. Clinical studies describing the use of DBM alone or in combination with other grafting material are available for only a few commercial products. The Level of Evidence of these studies and the resulting Grades of Recommendation are very low. In conclusion, further clinical studies of higher quality are required in order to improve the Recommendation Grades for or against the use of DBM products in bone grafting procedures. PMID- 25793169 TI - Total knee arthroplasty: Effect of obesity and other patients' characteristics on operative duration and outcome. AB - AIM: To examine the effects of patients' characteristics mainly obesity on operative duration and other outcome measures of knee arthroplasty. METHODS: This is a retrospective chart review of 204 patients who had knee arthroplasty within the past five years (2007-2011) at King Abdulaziz Medical City in Riyadh, Kingdom of Saudi Arabia. The data collection form was developed utilizing the literature review to gather all the needed variables. Data were gathered from admission notes, nursing notes, operative reports and discharge summaries. RESULTS: A feasible sample of 204 patients were included in the study. Of those patients, 155 (76%) were females. The mean age was 70.1 years for males (SD +/- 9.4) and 62.7 years (SD +/- 8) for females. Regarding the type of total knee replacement (TKR), 163 (79.9%) patients had unilateral TKR and 41 (20.1%) had bilateral TKR. Nine patients (4.4%) had a normal body mass index (BMI) (18.5 to < 25). Overweight patients (BMI 25 to < 30) represented 18.1%. Obesity class I (BMI 30 to < 35) and obesity class II (BMI from 35 to < 40) were present in 23% and 29.9% of the patients, respectively. Morbid obesity (BMI greater than 40) was present in 24.5%. The mean duration of surgery was 126.3 min (SD +/- 30.8) for unilateral TKR and 216.6 min (SD +/- 55.4) for bilateral TKR.The mean length of stay in the hospital was 12 d (SD +/- 4.9). The complications that patients had after the operation included 2 patients (1%) who developed deep venous thrombosis, 2 patients (1%) developed surgical wound infections and none had pulmonary embolism. Patients' characteristics (including age, gender, BMI and co morbidities) did not have an effect on the operative duration of knee replacement nor the length of hospital stay. CONCLUSION: Our study shows that obesity and other patients' characteristics do not have effect on the operative duration nor the length of hospital stay following TKR. PMID- 25793170 TI - Computerised tomography vs magnetic resonance imaging for modeling of patient specific instrumentation in total knee arthroplasty. AB - AIM: To summarise and compare currently available evidence regarding accuracy of pre-operative imaging, which is one of the key choices for surgeons contemplating patient-specific instrumentation (PSI) surgery. METHODS: The MEDLINE and EMBASE medical literature databases were searched, from January 1990 to December 2013, to identify relevant studies. The data from several clinical studies was assimilated to allow appreciation and comparison of the accuracy of each modality. The overall accuracy of each modality was calculated as proportion of outliers > 3% in the coronal plane of both computerised tomography (CT) or magnetic resonance imaging (MRI). RESULTS: Seven clinical studies matched our inclusion criteria for comparison and were included in our study for statistical analysis. Three of these reported series using MRI and four with CT. Overall percentage of outliers > 3% in patients with CT-based PSI systems was 12.5% vs 16.9% for MRI-based systems. These results were not statistically significant. CONCLUSION: Although many studies have been undertaken to determine the ideal pre operative imaging modality, conclusions remain speculative in the absence of long term data. Ultimately, information regarding accuracy of CT and MRI will be the main determining factor. Increased accuracy of pre-operative imaging could result in longer-term savings, and reduced accumulated dose of radiation by eliminating the need for post-operative imaging and revision surgery. PMID- 25793171 TI - Bone mass in axial spondyloarthritis: A literature review. AB - AIM: To review the published literature reporting bone loss in patients with axial spondyloarthritis (SpA) particularly those studies using dual X-ray absorptiometry (DXA) methods. METHODS: This literature review examines the reported bone mass in patients with ax-SpA, particularly those using the DXA methods. The MEDLINE, Web of Science and Scopus databases were searched for relevant articles published between September 1992 and November 2013. Some of used search terms were ankylosing spondylitis (AS), SpA, spondyloarthropathy, bone loss, bone mass, osteopenia, bone mineral density, osteoporosis (OP), densitometry. Studies in which bone loss was investigated by using DXA in patients with SpA were eligible. Each article was reviewed and the key elements were noted. RESULTS: There were 286 hits on MEDLINE, 200 on Web of Science and 476 on Scopus. After applying inclusion and exclusion criteria, we identified 55 articles in our systematic search. The sample size of the studies varied from 14 to 332 patients with SpA. The reported age range varied from 25 to 56 years in the reviewed studies. The symptom duration of patients with axSpA varied from 1.6 to 49 years. There were more males than females in these studies. Most of the recruited females were premenopausal women. Reported HLA-B27 positivity changed between 19% to 95%. The prevalence of OP and osteopenia in patients with SpA varied from 3%-47% to 5%-88%, respectively, in the included studies. In particular, the prevalence of OP and osteopenia ranged from 2.0%-47.0% and 5.0% 78.3%, respectively, in patients with AS. There are conflicting results regarding the relationship among disease activity, acute phase response and bone mass. Some studies suggest good correlation of bone mass with disease activity and acute phase reactants. CONCLUSION: Bone loss may be determined in patients with axSpA at the lumbar spine or proximal femur even in the early phase of the disease and may be associated with inflammation (bone marrow edema) at the vertebral colon. PMID- 25793172 TI - Impact of osteoporosis in dental implants: A systematic review. AB - AIM: To assess the failure and bone-to-implant contact rate of dental implants placed on osteoporotic subjects. METHODS: Extensive examination strategies were created to classify studies for this systematic review. MEDLINE (via PubMed) and EMBASE database were examined for studies in English up to and including May 2014. The examination presented a combination of the MeSH words described as follow: "osteoporosis" or "osteopenia" or "estrogen deficiency" AND "implant" or "dental implant" or "osseointegration". Assessment of clinical and/or histological peri-implant conditions in osteoporosis subjects treated with titanium dental implants. The examination included a combination of the MeSH terms described as follow: "osteoporosis" or "osteopenia" or "estrogen deficiency" AND "implant" or "dental implant" or "osseointegration". RESULTS: Of 943 potentially eligible articles, 12 were included in the study. A total of 133 subjects with osteoporosis, 73 subjects diagnosed with osteopenia and 708 healthy subjects were assessed in this systematic review. In these subjects were installed 367, 205, 2981 dental implants in osteoporotic, osteopenic and healthy subjects, respectively. The failure rate of dental implant was 10.9% in osteoporotic subjects, 8.29% in osteopenic and 11.43% in healthy ones. Bone-to implant contact obtained from retrieved implants ranged between 49.96% to 47.84%, for osteoporosis and non-osteoporotic subjects. CONCLUSION: Osteoporotic subjects presented higher rates of implant loss, however, there is a lower evidence to strengthen or refute the hypothesis that osteoporosis may have detrimental effects on bone healing. Consequently, final conclusions regarding the effect of osteoporosis in dental implant therapy cannot be made at this time. There are no randomized clinical trial accessible for evaluation and the retrospective nature of the evaluated studies shall be taken in account when interpreting this study. PMID- 25793173 TI - Total hip arthroplasty for surgical management of advanced tuberculous hip arthritis: Case report. AB - Tuberculosis (TB) arthritis of the hip is a debilitating disease that often results in severe cartilage destruction and degeneration of the hip. In advanced cases, arthrodesis of the hip confers benefits to the young, high-demand and active patient. However, many of these patients go on to develop degenerative arthritis of the spine, ipsilateral knee and contralateral hip, necessitating the need for a conversion to total hip arthroplasty. Conversion of a previously fused hip to a total hip arthroplasty presents as a surgical challenge due to altered anatomy, muscle atrophy, previous surgery and implants, neighbouring joint arthritis and limb length discrepancy. We report a case of advanced TB arthritis of the hip joint in a middle-aged Singaporean Chinese gentleman with a significant past medical history of miliary tuberculosis and previous hip arthrodesis. Considerations in pre-operative planning, surgical approaches and potential pitfalls are discussed and the operative technique utilized and post operative rehabilitative regime of this patient is described. This case highlights the necessity of pre-operative planning and the operative technique used in the conversion of a previous hip arthrodesis to a total hip arthroplasty in a case of TB hip arthritis. PMID- 25793174 TI - Advantages of digital subtraction angiography during nerve block. AB - INTRODUCTION: Most pain physicians know that fluoroscopy might improve the safety, accuracy, and efficacy of nerve block; however, it is difficult to distinguish the previously administered contrast medium from the injecting contrast medium, and to identify accurate contrast medium diffusion flow in a case of existing radiodensities such as cement and screw. Digital subtraction angiography (DSA) can improve accuracy of nerve blocks. CASE PRESENTATION: We described our experiences with two successful transforaminal epidural injections and nerve block of two patients with 73 and 68 years of age who were diagnosed as failed back surgery syndrome. CONCLUSIONS: The advantages of DSA in fluoroscopy guided transforaminal epidural block and nerve block are identification of the degree of appropriate contrast flow (epidural and nerve root sleeve) and the intravascular administration without overlapping radiodense structures. PMID- 25793175 TI - "Robo-tripping": dextromethorphan abuse and its anesthetic implications. AB - INTRODUCTION: We describe a patient scheduled for elective surgery who regularly consumed approximately 12 to 15 times the maximum recommended daily dose of dextromethorphan. We describe the clinical pharmacology of dextromethorphan and discuss its anesthetic implications. CASE PRESENTATION: A 30-year-old man with a history of a nasal fracture was scheduled to undergo an elective septorhinoplasty. He reported daily consumption of large quantities (1440 to 1800 mg) of dextromethorphan for six years. He was previously treated for dextromethorphan dependency on several occasions with urine dextromethorphan levels exceeding 2000 ng/mL. He described marked dissociative effects when abusing the drug, but had abstained from use for 48 hours before his elective surgery. Considering that dextromethorphan has a relatively short half-life and that the patient did not suffer major withdrawal symptoms after voluntarily discontinuing the drug, the authors proceeded with the case while recognizing that the drug has significant neuropsychiatric and sympathetic nervous system stimulant effects resulting from its actions as a N-methyl-D-aspartate receptor antagonist. CONCLUSIONS: Anesthesiologists need to be aware of dextromethorphan's clinical pharmacology because recreational abuse of the drug has become increasingly common in adolescents and young adults. PMID- 25793176 TI - Intravenous hypnotic regimens in patients with liver disease; a review article. AB - CONTEXT: The liver as an important organ in the body has many essential functions in physiological processes. One of the major activities of liver is drug metabolism. Hepatic dysfunction affecting hepatic physiological activities, especially drug metabolism can cause many problems during anesthesia and administration of different drugs to patients. EVIDENCE ACQUISITION: Studies on hepatic disorders and hypnotic anesthetics prescribed in hepatic disorders were included in this review. For this purpose, reliable databases were used. RESULTS: Anesthesia should be performed with caution in patients with hepatic dysfunction and drugs with long half-life should be avoided in these patients. CONCLUSIONS: A review of the literature on the use of hypnotic drugs in patients with liver dysfunction showed that some hypnotic drugs used during anesthesia could be safely used in patients with impaired liver function. In these patients, certain drugs should be used with caution. PMID- 25793177 TI - Lateral pterygoid muscle volume and migraine in patients with temporomandibular disorders. AB - PURPOSE: Lateral pterygoid muscle (LPM) plays an important role in jaw movement and has been implicated in Temporomandibular disorders (TMDs). Migraine has been described as a common symptom in patients with TMDs and may be related to muscle hyperactivity. This study aimed to compare LPM volume in individuals with and without migraine, using segmentation of the LPM in magnetic resonance (MR) imaging of the TMJ. MATERIALS AND METHODS: Twenty patients with migraine and 20 volunteers without migraine underwent a clinical examination of the TMJ, according to the Research Diagnostic Criteria for TMDs. MR imaging was performed and the LPM was segmented using the ITK-SNAP 1.4.1 software, which calculates the volume of each segmented structure in voxels per cubic millimeter. The chi squared test and the Fisher's exact test were used to relate the TMD variables obtained from the MR images and clinical examinations to the presence of migraine. Logistic binary regression was used to determine the importance of each factor for predicting the presence of a migraine headache. RESULTS: Patients with TMDs and migraine tended to have hypertrophy of the LPM (58.7%). In addition, abnormal mandibular movements (61.2%) and disc displacement (70.0%) were found to be the most common signs in patients with TMDs and migraine. CONCLUSION: In patients with TMDs and simultaneous migraine, the LPM tends to be hypertrophic. LPM segmentation on MR imaging may be an alternative method to study this muscle in such patients because the hypertrophic LPM is not always palpable. PMID- 25793178 TI - Volumetric quantification of bone-implant contact using micro-computed tomography analysis based on region-based segmentation. AB - PURPOSE: We have developed a new method of segmenting the areas of absorbable implants and bone using region-based segmentation of micro-computed tomography (micro-CT) images, which allowed us to quantify volumetric bone-implant contact (VBIC) and volumetric absorption (VA). MATERIALS AND METHODS: The simple threshold technique generally used in micro-CT analysis cannot be used to segment the areas of absorbable implants and bone. Instead, a region-based segmentation method, a region-labeling method, and subsequent morphological operations were successively applied to micro-CT images. The three-dimensional VBIC and VA of the absorbable implant were then calculated over the entire volume of the implant. Two-dimensional (2D) bone-implant contact (BIC) and bone area (BA) were also measured based on the conventional histomorphometric method. RESULTS: VA and VBIC increased significantly with as the healing period increased (p<0.05). VBIC values were significantly correlated with VA values (p<0.05) and with 2D BIC values (p<0.05). CONCLUSION: It is possible to quantify VBIC and VA for absorbable implants using micro-CT analysis using a region-based segmentation method. PMID- 25793179 TI - Reproducibility of the sella turcica landmark in three dimensions using a sella turcica-specific reference system. AB - PURPOSE: This study was performed to assess the reproducibility of identifying the sella turcica landmark in a three-dimensional (3D) model by using a new sella specific landmark reference system. MATERIALS AND METHODS: Thirty-two cone-beam computed tomographic scans (3D Accuitomo(r) 170, J. Morita, Kyoto, Japan) were retrospectively collected. The 3D data were exported into the Digital Imaging and Communications in Medicine standard and then imported into the Maxilim(r) software (Medicim NV, Sint-Niklaas, Belgium) to create 3D surface models. Five observers identified four osseous landmarks in order to create the reference frame and then identified two sella landmarks. The x, y, and z coordinates of each landmark were exported. The observations were repeated after four weeks. Statistical analysis was performed using the multiple paired t-test with Bonferroni correction (intraobserver precision: p<0.005, interobserver precision: p<0.0011). RESULTS: The intraobserver mean precision of all landmarks was <1 mm. Significant differences were found when comparing the intraobserver precision of each observer (p<0.005). For the sella landmarks, the intraobserver mean precision ranged from 0.43+/-0.34 mm to 0.51+/-0.46 mm. The intraobserver reproducibility was generally good. The overall interobserver mean precision was <1 mm. Significant differences between each pair of observers for all anatomical landmarks were found (p<0.0011). The interobserver reproducibility of sella landmarks was good, with >50% precision in locating the landmark within 1 mm. CONCLUSION: A newly developed reference system offers high precision and reproducibility for sella turcica identification in a 3D model without being based on two-dimensional images derived from 3D data. PMID- 25793180 TI - Accuracy of virtual models in the assessment of maxillary defects. AB - PURPOSE: This study aimed to assess the reliability of measurements performed on three-dimensional (3D) virtual models of maxillary defects obtained using cone beam computed tomography (CBCT) and 3D optical scanning. MATERIALS AND METHODS: Mechanical cavities simulating maxillary defects were prepared on the hard palate of nine cadavers. Images were obtained using a CBCT unit at three different fields-of-views (FOVs) and voxel sizes: 1) 60*60 mm FOV, 0.125 mm(3) (FOV60); 2) 80*80 mm FOV, 0.160 mm(3) (FOV80); and 3) 100*100 mm FOV, 0.250 mm(3) (FOV100). Superimposition of the images was performed using software called VRMesh Design. Automated volume measurements were conducted, and differences between surfaces were demonstrated. Silicon impressions obtained from the defects were also scanned with a 3D optical scanner. Virtual models obtained using VRMesh Design were compared with impressions obtained by scanning silicon models. Gold standard volumes of the impression models were then compared with CBCT and 3D scanner measurements. Further, the general linear model was used, and the significance was set to p=0.05. RESULTS: A comparison of the results obtained by the observers and methods revealed the p values to be smaller than 0.05, suggesting that the measurement variations were caused by both methods and observers along with the different cadaver specimens used. Further, the 3D scanner measurements were closer to the gold standard measurements when compared to the CBCT measurements. CONCLUSION: In the assessment of artificially created maxillary defects, the 3D scanner measurements were more accurate than the CBCT measurements. PMID- 25793181 TI - Intravenous contrast media application using cone-beam computed tomography in a rabbit model. AB - PURPOSE: This study was performed to evaluate the feasibility of visualizing soft tissue lesions and vascular structures using contrast-enhanced cone-beam computed tomography (CE-CBCT) after the intravenous administration of a contrast medium in an animal model. MATERIALS AND METHODS: CBCT was performed on six rabbits after a contrast medium was administered using an injection dose of 2 mL/kg body weight and an injection rate of 1 mL/s via the ear vein or femoral vein under general anesthesia. Artificial soft tissue lesions were created through the transplantation of autologous fatty tissue into the salivary gland. Volume rendering reconstruction, maximum intensity projection, and multiplanar reconstruction images were reconstructed and evaluated in order to visualize soft tissue contrast and vascular structures. RESULTS: The contrast enhancement of soft tissue was possible using all contrast medium injection parameters. An adequate contrast medium injection parameter for facilitating effective CE-CBCT was a 5-mL injection before exposure combined with a continuous 5-mL injection during scanning. Artificial soft tissue lesions were successfully created in the animals. The CE-CBCT images demonstrated adequate opacification of the soft tissues and vascular structures. CONCLUSION: Despite limited soft tissue resolution, the opacification of vascular structures was observed and artificial soft tissue lesions were visualized with sufficient contrast to the surrounding structures. The vascular structures and soft tissue lesions appeared well delineated in the CE-CBCT images, which was probably due to the superior spatial resolution of CE-CBCT compared to other techniques, such as multislice computed tomography. PMID- 25793182 TI - Accuracy and reliability of stitched cone-beam computed tomography images. AB - PURPOSE: This study was performed to evaluate the linear distance accuracy and reliability of stitched small field of view (FOV) cone-beam computed tomography (CBCT) reconstructed images for the fabrication of implant surgical guides. MATERIALS AND METHODS: Three gutta percha points were fixed on the inferior border of a cadaveric mandible to serve as control reference points. Ten additional gutta percha points, representing fiduciary markers, were scattered on the buccal and lingual cortices at the level of the proposed complete denture flange. A digital caliper was used to measure the distance between the reference points and fiduciary markers, which represented the anatomic linear dimension. The mandible was scanned using small FOV CBCT, and the images were then reconstructed and stitched using the manufacturer's imaging software. The same measurements were then taken with the CBCT software. RESULTS: The anatomic linear dimension measurements and stitched small FOV CBCT measurements were statistically evaluated for linear accuracy. The mean difference between the anatomic linear dimension measurements and the stitched small FOV CBCT measurements was found to be 0.34 mm with a 95% confidence interval of +0.24 - +0.44 mm and a mean standard deviation of 0.30 mm. The difference between the control and the stitched small FOV CBCT measurements was insignificant within the parameters defined by this study. CONCLUSION: The proven accuracy of stitched small FOV CBCT data sets may allow image-guided fabrication of implant surgical stents from such data sets. PMID- 25793183 TI - Unusually large erupted complex odontoma: A rare case report. AB - Odontomas are nonaggressive, hamartomatous developmental malformations composed of mature tooth substances and may be compound or complex depending on the extent of morphodifferentiation or on their resemblance to normal teeth. Among them, complex odontomas are relatively rare tumors. They are usually asymptomatic in nature. Occasionally, these tumors become large, causing bone expansion followed by facial asymmetry. Odontoma eruptions are uncommon, and thus far, very few cases of erupted complex odontomas have been reported in the literature. Here, we report the case of an unusually large, painless, complex odontoma located in the right posterior mandible. PMID- 25793184 TI - Multiple myeloma presenting with a maxillary lesion as the first sign. AB - Multiple myeloma is a clonal neoplastic proliferation of terminally differentiated B-lymphocytes involving the skeletal system in a multifocal fashion. Its oral manifestations are less common in the maxilla than in the mandible due to the lower amount of hemopoietic bone marrow in the maxilla. We report the case of a 50-year-old man who presented with a mass in the left maxillary alveolar region with tooth mobility. The mass had become enlarged after the teeth were extracted 15 days previously. Radiographs demonstrated multiple punched-out radiolucent lesions in the skull and pelvic region. Computed tomography images showed a soft tissue density mass in the left maxilla, eroding the floor and walls of the maxillary sinus. Although several analytical techniques were used to characterize the lesion, it was finally confirmed as multiple myeloma through immunohistochemistry. PMID- 25793185 TI - Accessory mental foramen: A rare anatomical variation detected by cone-beam computed tomography. AB - The mental foramen is a bilateral opening in the vestibular portion of the mandible through which nerve endings, such as the mental nerve, emerge. In general, the mental foramen is located between the lower premolars. This region is a common area for the placement of dental implants. It is very important to identify anatomical variations in presurgical imaging exams since damage to neurovascular bundles may have a direct influence on treatment success. In the hemimandible, the mental foramen normally appears as a single structure, but there are some rare reports on the presence and number of anatomical variations; these variations may include accessory foramina. The present report describes the presence of accessory mental foramina in the right mandible, as detected by cone beam computed tomography before dental implant placement. PMID- 25793186 TI - Arrested pneumatization of the sphenoid sinus mimicking intraosseous lesions of the skull base. AB - Arrested pneumatization of the sphenoid sinus is a developmental variant that is not always well recognized and is often confused with other pathologies associated with the skull base. This report describes the case of a patient referred for cone-beam computed tomography (CBCT) imaging for dental implant therapy. CBCT demonstrated a well-defined incidental lesion in the left sphenoid sinus with soft tissue-like density and sclerotic borders with internal curvilinear opacifications. The differential diagnoses included intraosseous lipoma, arrested pneumatization of the sphenoid sinus, chondrosarcoma, chondroid chordoma, and ossifying fibroma. The radiographic diagnosis of arrested pneumatization was based on the location of the lesion, its well-defined nature, the presence of internal opacifications, and lack of expansion. Gray-scale CBCT imaging of the area demonstrated values similar to fatty tissue. This case highlighted the fact that benign developmental variants associated with the skull base share similar radiographic features with more serious pathological entities. PMID- 25793187 TI - Prevalence of human papillomavirus variants and genetic diversity in the L1 gene and long control region of HPV16, HPV31, and HPV58 found in North-East Brazil. AB - This study showed the prevalence of human papillomavirus (HPV) variants as well as nucleotide changes within L1 gene and LCR of the HPV16, HPV31, and HPV58 found in cervical lesions of women from North-East Brazil. PMID- 25793188 TI - Lespedeza davurica (Lax.) Schindl. extract protects against cytokine-induced beta cell damage and streptozotocin-induced diabetes. AB - Lespedeza has been used for the management of diabetes in folklore medicine. The purpose of this study is to investigate the protective effects of the methanol extract of Lespedeza davurica (LD) on cytokine-induced beta-cell damage and streptozotocin- (STZ-) induced diabetes. RINm5F cells were treated with interleukin- (IL-) 1beta and interferon- (IFN-) gamma to induce pancreatic beta cell damage. The exposure of LD extract significantly decreased cell death, nitric oxide (NO) production, nitric oxide synthase (iNOS) expression, and nucleus factor-kappa B (NF-kappaB) p65 activation. Antidiabetic effects of LD extract were observed by oral glucose tolerance test (OGTT) in normal rats and by checking the biochemical, physiological, and histopathological parameters in STZ induced diabetic rats. In OGTT, glucose clearance levels improved by oral treatment of LD extract. The water intake, urine volume, blood glucose, and serum TG, TC, TBARS, and DPP-IV levels were significantly decreased, and liver glycogen content was significantly increased by treatment of LD extract (250 mg/kg BW) in STZ-induced diabetic rats. Also, insulin immunoreactivity of the pancreases was increased in LD extract administrated rats compared with diabetic control rats. These results indicate that LD extract may protect pancreatic beta-cell damage and regulate the blood glucose in STZ-induced diabetic rats. PMID- 25793190 TI - Design and user evaluation of a wheelchair mounted robotic assisted transfer device. AB - PURPOSE: The aim of this study is to describe the robotic assisted transfer device (RATD) and an initial focus group evaluation by end users. The purpose of the device is to aid in the transfers of people with disabilities to and from their electric powered wheelchair (EPW) onto other surfaces. The device can be used for both stand-pivot transfers and fully dependent transfers, where the person being transferred is in a sling and weight is fully on the robot. The RATD is fixed to an EPW to allow for its use in community settings. METHOD: A functional prototype of the RATD was designed and fabricated. The prototype was presented to a group of 16 end users and feedback on the device was obtained via a survey and group discussion. RESULTS: Thirteen out of sixteen (83%) participants agreed that it was important to develop this type of technology. They also indicated that user, caregiver, and robotic controls were important features to be included in the device. CONCLUSIONS: Participants in this study suggested that they would be accepting the use of robotic technology for transfers and a majority did not feel that they would be embarrassed to use this technology. PMID- 25793191 TI - Food bioactive compounds against diseases of the 21st century. PMID- 25793189 TI - The role of enteral nutrition in patients with inflammatory bowel disease: current aspects. AB - Enteral nutrition (EN) is considered to be of great importance in patients with inflammatory bowel disease (IBD) and nutritional problems. This comprehensive review is aiming to provide the reader with an update on the role of EN in IBD patients. EN can reduce Crohn's disease (CD) activity and maintain remission in both adults and children. Nutritional support using liquid formulas should be considered for CD patients and in serious cases of ulcerative colitis (UC), especially for those who may require prolonged cycles of corticosteroids. Given that the ultimate goal in the treatment of CD is mucosal healing, this advantage of EN over corticosteroid treatment is valuable in therapeutic decision-making. EN is indicated in active CD, in cases of steroid intolerance, in patient's refusal of steroids, in combination with steroids in undernourished individuals, and in patients with an inflammatory stenosis of the small intestine. No differences between the efficiency of elemental diets and nonelemental formulas have been noticed. EN must be the first choice compared to TPN. EN has a restricted value in the treatment of patients with large bowel CD. In conclusion, it seems important not to underestimate the role of nutrition as supportive care in patients with IBD. PMID- 25793192 TI - Modified weekly cisplatin-based chemotherapy is acceptable in postoperative concurrent chemoradiotherapy for locally advanced head and neck cancer. AB - BACKGROUND: Triweekly cisplatin-based postoperative concurrent chemoradiotherapy (CCRT) has high intolerance and toxicities in locally advanced head and neck cancer (LAHNC). We evaluated the effect of a modified weekly cisplatin-based chemotherapy in postoperative CCRT. METHODS: A total of 117 patients with LAHNC were enrolled between December 2007 and December 2012. Survival, compliance/adverse events, and independent prognostic factors were analyzed. RESULTS: Median follow-up time was 30.0 (3.1-73.0) months. Most patients completed the entire course of postoperative CCRT (radiotherapy >= 60 Gy, 94.9%; >= 6 times weekly chemotherapy, 75.2%). Only 17.1% patients required hospital admission. The most common adverse effect was grade 3/4 mucositis (28.2%). No patient died due to protocol-related adverse effects. Multivariate analysis revealed the following independent prognostic factors: oropharyngeal cancer, extracapsular spread, and total radiation dose. Two-year progression-free survival and overall survival rates were 70.9% and 79.5%, respectively. CONCLUSION: Modified weekly cisplatin-based chemotherapy is an acceptable regimen in postoperative CCRT for LAHNC. PMID- 25793193 TI - Phlebotomine sand fly fauna and leishmania infection in the vicinity of the Serra do Cipo National Park, a natural Brazilian heritage site. AB - In the New World, the leishmaniases are primarily transmitted to humans through the bites of Leishmania-infected Lutzomyia (Diptera: Psychodidae) phlebotomine sand flies. Any or both of two basic clinical forms of these diseases are endemic to several cities in Brazil--the American cutaneous leishmaniasis (ACL) and the American visceral leishmaniasis (AVL). The present study was conducted in the urban area of a small-sized Brazilian municipality (Jaboticatubas), in which three cases of AVL and nine of ACL have been reported in the last five years. Jaboticatubas is an important tourism hub, as it includes a major part of the Serra do Cipo National Park. Currently, no local data is available on the entomological fauna or circulating Leishmania. During the one-year period of this study, we captured 3,104 phlebotomine sand flies belonging to sixteen Lutzomyia species. In addition to identifying incriminated or suspected vectors of ACL with DNA of the etiological agent of AVL and vice versa, we also detected Leishmania DNA in unexpected Lutzomyia species. The expressive presence of vectors and natural Leishmania infection indicates favorable conditions for the spreading of leishmaniases in the vicinity of the Serra do Cipo National Park. PMID- 25793194 TI - Modulation and predictors of periprosthetic bone mineral density following total knee arthroplasty. AB - Total knee arthroplasty (TKA) leads to a loss of periprosthetic bone mineral density (BMD). Great importance is attached to the prevention of periprosthetic bone loss with a view to ensuring a long service life of the prosthesis. In order to provide appropriate recommendations for preventive movement therapy measures to combat peri-implant bone loss, it is necessary to know the predictors of periprosthetic BMD. The aim of this study was (1) to determine the change of periprosthetic BMD of the femur and tibia and (2) to analyse the effects of different predictors on periprosthetic BMD. Twenty-three patients with primary TKA were evaluated 10 days and 3 months postoperatively. The data analysis comprised (1) the change in periprosthetic BMD from pretest to posttest and (2) the correlations between BMD and the variables isometric maximum voluntary force, lean mass, physical activity (step count), and BMI using multiple linear regression and structural equation modelling (SEM). BMD of the distal femur was significantly reduced by 19.7% (P = 0.008) 3 months after surgery, while no changes were found in BMD of the tibia. The results of SEM demonstrate that 55% of the BMD variance was explained by the model (chi(2) = 0.002; df = 1; P = 0.96; chi(2)/df = 0.002; RMSEA < 0.01; TLI = 1.5; CFI = 1.0). A significant direct effect was only evidenced by the variable lean mass (beta = 0.38; b = 0.15; SE = 0.07; C.R. = 2.0; P = 0.046). It can be assumed that a large muscle mass with accompanying distribution of high mechanical load in the bones can contribute to local changes of periprosthetic BMD. Concrete recommendations for preventing peri implant bone loss therefore include exercises which have the aim of maintaining or building up muscle mass. PMID- 25793195 TI - The draining lymph node in rheumatoid arthritis: current concepts and research perspectives. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of unknown aetiology, leading to progressive damage of bone and cartilage with functional impairment and disability. Whilst the synovial membrane represents the epicentre of the immune-inflammatory process, there is growing evidence indicating the potential involvement of additional anatomical compartments, such as the lung, bone marrow, and secondary lymphoid tissues. Draining lymph nodes represent the elective site for tissue immune-surveillance, for the generation of adaptive immune responses and a candidate compartment for the maintenance of peripheral tolerance. Despite the precise role of the juxta- and extra-articular lymph node stations in the pathogenesis of RA remaining poorly defined, several lines of research exploiting new technological approaches are now focusing on their assessment as a potential new source of pathobiologic information, biomarkers, and complementary therapeutic targets. In this review we present an updated overview of the main concepts driving lymph node research in RA, highlighting the most relevant findings, current hypothesis, and translational perspectives. PMID- 25793196 TI - The effects of Bifidobacterium breve on immune mediators and proteome of HT29 cells monolayers. AB - The use of beneficial microorganisms, the so-called probiotics, to improve human health is gaining popularity. However, not all of the probiotic strains trigger the same responses and they differ in their interaction with the host. In spite of the limited knowledge on mechanisms of action some of the probiotic effects seem to be exerted through maintenance of the gastrointestinal barrier function and modulation of the immune system. In the present work, we have addressed in vitro the response of the intestinal epithelial cell line HT29 to the strain Bifidobacterium breve IPLA20004. In the array of 84 genes involved in inflammation tested, the expression of 12 was modified by the bifidobacteria. The genes of chemokine CXCL6, the chemokine receptor CCR7, and, specially, the complement component C3 were upregulated. Indeed, HT29 cells cocultivated with B. breve produced significantly higher levels of protein C3a. The proteome of HT29 cells showed increased levels of cytokeratin-8 in the presence of B. breve. Altogether, it seems that B. breve IPLA20004 could favor the recruitment of innate immune cells to the mucosa reinforcing, as well as the physical barrier of the intestinal epithelium. PMID- 25793198 TI - Results of surgical treatment of schwannomas arising from extremities. AB - Schwannomas are benign neoplasms derived from Schwann cells. In this work, we present our experience in operative management of schwannomas and analyse results of treatment. Clinical material consisted of 34 patients, in whom 44 schwannomas located in extremities were excised between 1985 and 2013. Thirty-five tumours originated from major peripheral nerves and 9 from small nerve branches. Postoperatively, in the first group of tumours, pain resolved in 100%, paresthesias in 83.3%, and Hoffmann-Tinel sign in 91.6% of the patients. Improvement in motor function was noted in 28.5% of the cases, in sensory function: complete in 70%, and partial in 15%. The most frequently affected major peripheral nerves were the ulnar (11 tumours) and median (5 tumours) nerves. Schwannomas originating from small nerve branches were removed without identification of the site of origin. After their resection, definitive healing was achieved. Conclusions. (1) Schwannomas located in extremities arise predominantly from major peripheral nerves, most commonly the ulnar and median nerves. (2) Gradual tumour growth causes exacerbation of compression neuropathy, creating an indication for surgery. (3) In most cases, improvement in peripheral nerve function after excision of schwannoma is achieved. (4) The risk of new permanent postoperative neurological deficits is low. PMID- 25793197 TI - The role of probiotic lactic acid bacteria and bifidobacteria in the prevention and treatment of inflammatory bowel disease and other related diseases: a systematic review of randomized human clinical trials. AB - Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammation of the small intestine and colon caused by a dysregulated immune response to host intestinal microbiota in genetically susceptible subjects. A number of fermented dairy products contain lactic acid bacteria (LAB) and bifidobacteria, some of which have been characterized as probiotics that can modify the gut microbiota and may be beneficial for the treatment and the prevention of IBD. The objective of this review was to carry out a systematic search of LAB and bifidobacteria probiotics and IBD, using the PubMed and Scopus databases, defined by a specific equation using MeSH terms and limited to human clinical trials. The use of probiotics and/or synbiotics has positive effects in the treatment and maintenance of UC, whereas in CD clear effectiveness has only been shown for synbiotics. Furthermore, in other associated IBD pathologies, such as pouchitis and cholangitis, LAB and bifidobacteria probiotics can provide a benefit through the improvement of clinical symptoms. However, more studies are needed to understand their mechanisms of action and in this way to understand the effect of probiotics prior to their use as coadjuvants in the therapy and prevention of IBD conditions. PMID- 25793199 TI - Application of bladder acellular matrix in urinary bladder regeneration: the state of the art and future directions. AB - Construction of the urinary bladder de novo using tissue engineering technologies is the "holy grail" of reconstructive urology. The search for the ideal biomaterial for urinary bladder reconstruction has been ongoing for decades. One of the most promising biomaterials for this purpose seems to be bladder acellular matrix (BAM). In this review we determine the most important factors, which may affect biological and physical properties of BAM and its regeneration potential in tissue engineered urinary bladder. We also point out the directions in modification of BAM, which include incorporation of exogenous growth factors into the BAM structure. Finally, we discuss the results of the urinary bladder regeneration with cell seeded BAM. PMID- 25793201 TI - Corrigendum to "Presymptomatic treatment with acetylcholinesterase antisense oligonucleotides prolongs survival in ALS (G93A-SOD1) mice". AB - [This corrects the article DOI: 10.1155/2013/845345.]. PMID- 25793200 TI - Trunk and shoulder kinematic and kinetic and electromyographic adaptations to slope increase during motorized treadmill propulsion among manual wheelchair users with a spinal cord injury. AB - The main objective was to quantify the effects of five different slopes on trunk and shoulder kinematics as well as shoulder kinetic and muscular demands during manual wheelchair (MWC) propulsion on a motorized treadmill. Eighteen participants with spinal cord injury propelled their MWC at a self-selected constant speed on a motorized treadmill set at different slopes (0 degrees , 2.7 degrees , 3.6 degrees , 4.8 degrees , and 7.1 degrees ). Trunk and upper limb movements were recorded with a motion analysis system. Net shoulder joint moments were computed with the forces applied to the handrims measured with an instrumented wheel. To quantify muscular demand, the electromyographic activity (EMG) of the pectoralis major (clavicular and sternal portions) and deltoid (anterior and posterior fibers) was recorded during the experimental tasks and normalized against maximum EMG values obtained during static contractions. Overall, forward trunk flexion and shoulder flexion increased as the slope became steeper, whereas shoulder flexion, adduction, and internal rotation moments along with the muscular demand also increased as the slope became steeper. The results confirm that forward trunk flexion and shoulder flexion movement amplitudes, along with shoulder mechanical and muscular demands, generally increase when the slope of the treadmill increases despite some similarities between the 2.7 degrees to 3.6 degrees and 3.6 degrees to 4.8 degrees slope increments. PMID- 25793202 TI - Actual anatomical and dosimetric changes of parotid glands in nasopharyngeal carcinoma patients during intensity modulated radiation therapy. AB - The goal of this study was to evaluate the actual anatomical and dosimetric changes of parotid glands in nasopharyngeal carcinoma patients during intensity modulated radiation therapy. With helical tomotherapy, its planning system, and adaptive software, weekly anatomical and dosimetric changes of parotid glands in 35 NPC patients were evaluated. Interweekly parotid volume varied significantly (P < 0.03). The rate of volume change reached the highest level at the 16th fraction. The average V 1 increased by 32.2 (left) and 28.6 (right), and the average D 50 increased by 33.9 (left) and 24.93 (right), respectively. Repeat data comparison indicated that the V 1 and D 50 varied significantly among different fractions (both with P = 0.000). The variation of parotid volume was inversely correlated with that of the V 1 and D 50 (both with P = 0.000). In conclusion, parotid volume and actual dose vary significantly in NPC patients during IMRT. Replanning at the end of the fourth week of IMRT may have clinical benefits. PMID- 25793203 TI - Binding of carbonic anhydrase IX to 45S rDNA genes is prevented by exportin-1 in hypoxic cells. AB - Carbonic anhydrase IX (CA IX) is a surrogate marker of hypoxia, involved in survival and pH regulation in hypoxic cells. We have recently characterized its interactome, describing a set of proteins interacting with CA IX, mainly in hypoxic cells, including several members of the nucleocytoplasmic shuttling apparatuses. Accordingly, we described complex subcellular localization for this enzyme in human cells, as well as the redistribution of a carbonic anhydrase IX pool to nucleoli during hypoxia. Starting from this evidence, we analyzed the possible contribution of carbonic anhydrase IX to transcription of the 45 S rDNA genes, a process occurring in nucleoli. We highlighted the binding of carbonic anhydrase IX to nucleolar chromatin, which is regulated by oxygen levels. In fact, CA IX was found on 45 S rDNA gene promoters in normoxic cells and less represented on these sites, in hypoxic cells and in cells subjected to acetazolamide-induced acidosis. Both conditions were associated with increased representation of carbonic anhydrase IX/exportin-1 complexes in nucleoli. 45 S rRNA transcript levels were accordingly downrepresented. Inhibition of nuclear export by leptomycin B suggests a model in which exportin-1 acts as a decoy, in hypoxic cells, preventing carbonic anhydrase IX association with 45 S rDNA gene promoters. PMID- 25793204 TI - Isolation and molecular characterization of Brucella isolates in cattle milk in Uganda. AB - Brucellosis is endemic in livestock and humans in Uganda and its transmission involves a multitude of risk factors like consumption of milk from infected cattle. To shed new light on the epidemiology of brucellosis in Uganda the present study used phenotypic and molecular approaches to delineate the Brucella species, biovars, and genotypes shed in cattle milk. Brucella abortus without a biovar designation was isolated from eleven out of 207 milk samples from cattle in Uganda. These isolates had a genomic monomorphism at 16 variable number tandem repeat (VNTR) loci and showed in turn high levels of genetic variation when compared with other African strains or other B. abortus biovars from other parts of the world. This study further highlights the usefulness of MLVA as an epidemiological tool for investigation of Brucella infections. PMID- 25793205 TI - Postnatal administration of allopregnanolone modifies glutamate release but not BDNF content in striatum samples of rats prenatally exposed to ethanol. AB - Ethanol consumption during pregnancy may induce profound changes in fetal CNS development. We postulate that some of the effects of ethanol on striatal glutamatergic transmission and neurotrophin expression could be modulated by allopregnanolone, a neurosteroid modulator of GABAA receptor activity. We describe the acute pharmacological effect of allopregnanolone (65 MUg/kg, s.c.) administered to juvenile male rats (day 21 of age) on the corticostriatal glutamatergic pathway, in both control and prenatally ethanol-exposed rats (two ip injections of 2.9 g/kg in 24% v/v saline solution on gestational day 8). Prenatal ethanol administration decreased the K(+)-induced release of glutamate regarding the control group. Interestingly, this effect was reverted by allopregnanolone. Regarding BDNF, allopregnanolone decreases the content of this neurotrophic factor in the striatum of control groups. However, both ethanol alone and ethanol plus allopregnanolone treated animals did not show any change regarding control values. We suggest that prenatal ethanol exposure may produce an alteration of GABAA receptors which blocks the GABA agonist-like effect of allopregnanolone on rapid glutamate release, thus disturbing normal neural transmission. Furthermore, the reciprocal interactions found between GABAergic neurosteroids and BDNF could underlie mechanisms operating during the neuronal plasticity of fetal development. PMID- 25793206 TI - Comment on "Effectiveness of naltrexone in the prevention of delayed respiratory arrest in opioid-naive methadone-intoxicated patients". PMID- 25793207 TI - The role of androgen receptor expression in the curative treatment of prostate cancer with radiotherapy: a pilot study. AB - The androgen receptor (AR) and its signaling pathway play an important role in the development and progression of prostate cancer (PCa). In the setting of primary treatment of PCa with radiotherapy (RT), where the AR can be expected to be of more importance, studies evaluating the AR expression are lacking. The goal of this research is to evaluate AR protein expression in hormone-naive PCa patients treated by RT and investigate its possible prognostic role. Primary biopsy samples of 18 patients treated with primary RT were analyzed including the corresponding clinical information. AR protein expression of the tumor epithelium (with highest Gleason pattern) and the surrounding stroma was quantified using the Quick score for steroid receptors. The differential expression between epithelium and stroma, respectively, between tumor and normal tissue (DeltaTumor DeltaBenign >2 versus <= 2), was predictive for clinical progression-free survival in the biopsy samples (P = 0.014). Preliminary results of this research show already a promising role of differential AR expression in predicting clinical relapse after PCa treatment with primary EBRT. Further research is needed to validate these findings. Hopefully this can lead to a better understanding of PCa evolution and eventually lead to better therapy strategies. PMID- 25793208 TI - Encapsulation of curcumin in diblock copolymer micelles for cancer therapy. AB - Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (P < 0.05). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (P < 0.05). Average tumor size and weight were significantly lower in PNPC group than control (P < 0.05). PNPC increased proapoptotic Bax protein expression (P < 0.05). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (P < 0.05). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (P < 0.05). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response. PMID- 25793209 TI - Clinical usefulness of the 2010 clinical and laboratory standards institute revised breakpoints for cephalosporin use in the treatment of bacteremia caused by Escherichia coli or Klebsiella spp. AB - We investigated the clinical usefulness of the revised 2010 Clinical and Laboratory Standards Institute (CLSI) breakpoints for Escherichia coli and Klebsiella spp. Of 2,623 patients with bacteremia caused by E. coli or Klebsiella spp., 573 who had been treated appropriately with cephalosporin based on the CLSI 2009 guidelines were enrolled. There were no differences in the rates of treatment failure or mortality between the appropriately and inappropriately treated groups according to the CLSI 2010 guidelines. Additionally, in the matched case-control analysis, the treatment failure rate was higher in bacteremic patients with extended-spectrum beta-lactamase- (ESBL-) producing but cephalosporin-susceptible organisms than in those with ESBL-nonproducing isolates when patients with urinary tract infections were excluded (44% and 0%, resp., P = 0.026). In patients with bacteremia caused by E. coli or Klebsiella spp., the revised CLSI 2010 guidelines did not lead to poorer outcomes. However, ESBL production appeared to be associated with poor clinical outcomes in patients with bacteremia from sources other than the urinary tract. PMID- 25793210 TI - A survey of modulation of gut microbiota by dietary polyphenols. AB - Dietary polyphenols present in a broad range of plant foods have been related to beneficial health effects. This review aims to update the current information about the modulation of the gut microbiota by dietary phenolic compounds, from a perspective based on the experimental approaches used. After referring to general aspects of gut microbiota and dietary polyphenols, studies related to this topic are presented according to their experimental design: batch culture fermentations, gastrointestinal simulators, animal model studies, and human intervention studies. In general, studies evidence that dietary polyphenols may contribute to the maintenance of intestinal health by preserving the gut microbial balance through the stimulation of the growth of beneficial bacteria (i.e., lactobacilli and bifidobacteria) and the inhibition of pathogenic bacteria, exerting prebiotic-like effects. Combination of in vitro and in vivo models could help to understand the underlying mechanisms in the polyphenols microbiota-host triangle and elucidate the implications of polyphenols on human health. From a technological point of view, supplementation with rich polyphenolic stuffs (phenolic extracts, phenolic-enriched fractions, etc.) could be an effective option to improve health benefits of functional foods such as the case of dairy fermented foods. PMID- 25793211 TI - Environmental lead exposure, catalase gene, and markers of antioxidant and oxidative stress relation to hypertension: an analysis based on the EGAT study. AB - Lead has been linked to the development of hypertension via oxidative stress. Catalase plays an important role in the disposal of hydrogen peroxide in erythrocyte and its activity was determined by CAT gene. The aims of this study were to investigate (1) the association between blood levels of antioxidant markers such as catalase, superoxide dismutase, glutathione, glutathione peroxidase, oxidative stress-marker (malondialdehyde), and blood lead level and (2) the influence of genetic polymorphism of CAT gene (rs769217) on change in blood pressure in general population of EGAT study project. This is a cross sectional study of 332 normotensive, 432 prehypertensive, and 222 hypertensive male subjects. Hypertensive subjects had significantly higher blood lead level (5.28 MUg/dL) compared to normotensive (4.41 MUg/dL) and prehypertensive (4.55 MUg/dL) subjects (P < 0.05). These significant findings are also found in MDA levels. Moreover, individuals with TT genotype in hypertensive group had significantly higher blood lead and MDA levels (6.06 MUg/dL and 9.67 MUmol/L) than those with CC genotype (5.32 MUg/dL and 8.31 MUmol/L, P < 0.05). Our findings suggested that decreased blood catalase activity in this polymorphism together with low level lead exposure induced lipid peroxidation may be responsible for hypertension. PMID- 25793212 TI - Impact of different body positions on bioelectrical activity of the pelvic floor muscles in nulliparous continent women. AB - We examined pelvic floor muscles (PFM) activity (%MVC) in twenty nulliparous women by body position during exercise as well as the activation of abdominal muscles and the gluteus maximus during voluntary contractions of the PFMs. Pelvic floor muscle activity was recorded using a vaginal probe during five experimental trials. Activation of transversus abdominis, rectus abdominis, and gluteus maximus during voluntary PFM contractions was also assessed. Significant differences in mean normalized amplitudes of baseline PFM activity were revealed between standing and lying (P < 0.00024) and lying and ball-sitting positions (P < 0.0053). Average peak, average time before peak, and average time after peak did not differ significantly during the voluntary contractions of the PFMs. Baseline PFM activity seemed to depend on the body position and was the highest in standing. Pelvic floor muscles activity during voluntary contractions did not differ by position in continent women. Statistically significant differences between the supine lying and sitting positions were only observed during a sustained 60-second contraction of the PFMs. PMID- 25793213 TI - Joint minimization of uplink and downlink whole-body exposure dose in indoor wireless networks. AB - The total whole-body exposure dose in indoor wireless networks is minimized. For the first time, indoor wireless networks are designed and simulated for a minimal exposure dose, where both uplink and downlink are considered. The impact of the minimization is numerically assessed for four scenarios: two WiFi configurations with different throughputs, a Universal Mobile Telecommunications System (UMTS) configuration for phone call traffic, and a Long-Term Evolution (LTE) configuration with a high data rate. Also, the influence of the uplink usage on the total absorbed dose is characterized. Downlink dose reductions of at least 75% are observed when adding more base stations with a lower transmit power. Total dose reductions decrease with increasing uplink usage for WiFi due to the lack of uplink power control but are maintained for LTE and UMTS. Uplink doses become dominant over downlink doses for usages of only a few seconds for WiFi. For UMTS and LTE, an almost continuous uplink usage is required to have a significant effect on the total dose, thanks to the power control mechanism. PMID- 25793214 TI - Competing role of bioactive constituents in Moringa oleifera extract and conventional nutrition feed on the performance of Cobb 500 broilers. AB - The influence of Moringa oleifera (MO) leaf extract as a dietary supplement on the growth performance and antioxidant parameters was evaluated on broiler meat and the compounds responsible for the corresponding antioxidant activity were identified. 0.5%, 1.0%, and 1.5% w/v of MO leaf aqueous extracts (MOLE) were prepared, and nutritional feed supplemented with 0%, 0.5%, 1.0%, and 1.5% w/w of MO leaf meal (MOLM) extracts were also prepared and analysed for their in vitro antioxidant potential. Furthermore, the treated broiler groups (control (T1) and treatment (T2, T3, and T4)) were evaluated for performance, meat quality, and antioxidant status. The results of this study revealed that, among the broilers fed MOLM, the broilers fed 0.5% w/w MOLM (T2) exhibited enhanced meat quality and antioxidant status (P < 0.05). However, the antioxidant activity of the MOLE is greater than that of the MOLM. The LC-MS/MS analysis of MOLM showed high expression of isoflavones and fatty acids from soy and corn source, which antagonistically inhibit the expression of the flavonoids/phenols in the MO leaves thereby masking its antioxidant effects. Thus, altering the soy and corn gradients in conventional nutrition feed with 0.5% w/w MO leaves supplement would provide an efficient and cost-effective feed supplement. PMID- 25793215 TI - Effects of chronic REM sleep restriction on D1 receptor and related signal pathways in rat prefrontal cortex. AB - The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R' signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (P < 0.01, P < 0.05); the expression of phosphor PKAcalpha was significantly lowered in CSR rats (P < 0.05). The present results suggested that the alteration of neuropathology and D1R expression in PFC may be associated with CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function. PMID- 25793216 TI - Effect of Alcohol Administration on Mg2+ Homeostasis in H9C2 Cells. AB - Alcoholic cardiomyopathy represents one of the main clinical complications in chronic alcoholics. This pathology contrasts the seemingly beneficial effect of small doses of alcohol on the cardiovascular system. Studies carried out in liver cells exposed acutely or chronically to varying doses of EtOH indicate that intrahepatic alcohol metabolism results in a major loss of cellular Mg2+. To investigate whether EtOH administration also induced Mg2+ extrusion in cardiac cells, H9C2 cells were exposed to varying doses of EtOH for short- or ling-term periods of time. The results indicate that H9C2 cells exposed to EtOH doses higher than 0.1% (v/v, or 15 mM) extruded Mg2+ into the extracellular medium on a time- and dose-dependent manner. Consistent with the involvement of cyP4502E1 in metabolizing EtOH, administration of chloro-methiazole (CMZ) as an inhibitor of the cytochrome prevented EtOH-induced Mg2+ loss to a large extent. EtOH-induced Mg2+ extrusion was also prevented by the administration of di-thio-treitol (DTT) and n-acetyl-cysteine (NAC), two agents that prevent the negative effects of ROS formation and free radicals generation associated with EtOH metabolism by cyP4502E1. Taken together, our data indicate that Mg2+ extrusion also occur in cardiac cells exposed to EtOH as a result of alcohol metabolism by cyP4502E1 and associated free radical formation. Interestingly, Mg2+ extrusion only occurs at doses of EtOH higher than 0.1% administered for an extended period of time. The significance of Mg2+ extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated. PMID- 25793217 TI - One-Day Acceptance and Commitment Training Workshops in Medical Populations. AB - Chronic medical illnesses often require a high level of self-management, which can be challenging, particularly over extended periods. The challenge is accentuated by comorbid depression or anxiety, which interfere with motivation and drive. Acceptance and Commitment Therapy is an empirically based behavioral intervention aimed at helping individuals develop greater psychological flexibility in the face of life's challenges. It provides a unified model of behavior change and has shown promise in treating depression and anxiety, as well as chronic medical conditions. Importantly, Acceptance and Commitment Therapy has been effectively implemented in various formats, including 1-day group workshops, well-suited for dissemination into medical settings. The purpose of this review is to provide an overview of studies of 1-day group workshops in medical populations and suggest future directions for further development of this promising area. PMID- 25793218 TI - Spatial and temporal variability of rainfall in eastern Amazon during the rainy season. AB - Empirical orthogonal functions (EOF) and composites analysis were employed on pentad data in order to investigate the tropical atmospheric-ocean patterns over the Atlantic Ocean and the spatial-temporal characteristics of the rainfall in eastern Amazon during the peak of the rainy season (February to April). The EOF results evidenced that the Intertropical Convergence Zone (ITCZ) is the main rainfall-producing system in eastern Amazon during the rainy season. Conditions associated with the southward SST gradient in the intertropical Atlantic formed the dynamic patterns that favored the position of the ITCZ to south of the equator, thus explaining the predominance of positive precipitation anomalies in eastern Amazon, especially in the state of Maranhao and northeastern Para during the February and April months. PMID- 25793219 TI - Performance of size 1 I-gel compared with size 1 ProSeal laryngeal mask in anesthetized infants and neonates. AB - PURPOSE: The size 1 I-gel, recommended for small infants and neonates weighing 2 5 kg, has recently been released. There are no prospective studies available that assess the insertion conditions, sealing pressures, or ventilation quality of it. This study was designed to compare the performance of recently released size 1 I gel with size 1 ProSeal LMA. METHODS: Fifty infants and neonates, ASA I-II were included in this prospective, randomized, and controlled study. Patients were divided into two groups for placing I-gel or ProSeal LMA. The primary outcome was airway leak pressure, and secondary outcomes included insertion time, insertion success and conditions, initial airway quality, fiberoptic view of the larynx, and complications. RESULTS: There were no significant differences in terms of airway leak pressure between the I-gel (27.44 +/- 5.67) and ProSeal LMA (23.52 +/ 8.15) (P = 0.054). The insertion time for the I-gel was shorter (12.6 +/- 2.19 s) than for the ProSeal LMA (24.2 +/- 6.059 s) (P = 0.0001). Insertion success and conditions were similar in groups. We encountered few complications. CONCLUSION: Our study demonstrates that the size 1 I-gel provided an effective and satisfactory airway as the size 1 ProSeal LMA. It may be a good alternative supraglottic airway device for use in small infants and neonates. This trial is registered with: ClinicalTrials.gov NCT01704118. PMID- 25793221 TI - An energy-efficient cluster-based vehicle detection on road network using intention numeration method. AB - The traffic in the road network is progressively increasing at a greater extent. Good knowledge of network traffic can minimize congestions using information pertaining to road network obtained with the aid of communal callers, pavement detectors, and so on. Using these methods, low featured information is generated with respect to the user in the road network. Although the existing schemes obtain urban traffic information, they fail to calculate the energy drain rate of nodes and to locate equilibrium between the overhead and quality of the routing protocol that renders a great challenge. Thus, an energy-efficient cluster-based vehicle detection in road network using the intention numeration method (CVDRN IN) is developed. Initially, sensor nodes that detect a vehicle are grouped into separate clusters. Further, we approximate the strength of the node drain rate for a cluster using polynomial regression function. In addition, the total node energy is estimated by taking the integral over the area. Finally, enhanced data aggregation is performed to reduce the amount of data transmission using digital signature tree. The experimental performance is evaluated with Dodgers loop sensor data set from UCI repository and the performance evaluation outperforms existing work on energy consumption, clustering efficiency, and node drain rate. PMID- 25793220 TI - Improving ammonium and nitrate release from urea using clinoptilolite zeolite and compost produced from agricultural wastes. AB - Improper use of urea may cause environmental pollution through NH3 volatilization and NO3 (-) leaching from urea. Clinoptilolite zeolite and compost could be used to control N loss from urea by controlling NH4 (+) and NO3 (-) release from urea. Soil incubation and leaching experiments were conducted to determine the effects of clinoptilolite zeolite and compost on controlling NH4 (+) and NO3 (-) losses from urea. Bekenu Series soil (Typic Paleudults) was incubated for 30, 60, and 90 days. A soil leaching experiment was conducted for 30 days. Urea amended with clinoptilolite zeolite and compost significantly reduced NH4 (+) and NO3 (-) release from urea (soil incubation study) compared with urea alone, thus reducing leaching of these ions. Ammonium and NO3 (-) leaching losses during the 30 days of the leaching experiment were highest in urea alone compared with urea with clinoptilolite zeolite and compost treatments. At 30 days of the leaching experiment, NH4 (+) retention in soil with urea amended with clinoptilolite zeolite and compost was better than that with urea alone. These observations were because of the high pH, CEC, and other chemical properties of clinoptilolite zeolite and compost. Urea can be amended with clinoptilolite zeolite and compost to improve NH4 (+) and NO3 (-) release from urea. PMID- 25793222 TI - The effect of intraoperative sounds of saw and hammer on psychological condition in patients with total knee arthroplasty: prospective randomized study. AB - PURPOSE: Surgical procedures are likely to be stressful for patients and their families. Total knee arthroplasty (TKA) is a major surgical procedure used in the treatment of osteoarthritis. During this procedure the sounds of the saw and hammer may irritate the patient and adversely affect mood. The present study examines the effect of these intraoperative sounds during TKA on postoperative mood and anxiety, by comparing two different anesthetic procedures. METHODS: A total of 40 patients who underwent TKA for grade IV gonarthrosis participated in the study. Patients were randomly divided into two groups: 20 patients in the general anesthesia group and 20 patients in the spinal anesthesia group. Mood and anxiety changes were evaluated using the Profile of Mood States (POMS) and State Trait Anxiety Inventory (STAI) instruments, respectively. RESULTS: The postoperative POMS value in the spinal anesthesia group was definitively higher than the general anesthesia group, though the difference in preoperative and postoperative POMS and STAI scores between the two groups was not significant. CONCLUSION: It would seem that sounds of hammer and saw have no evident negative effect on patient's mood. Regional anesthesia is advisable for TKA patients and appropriate sedation can be administered during the operation if needed. PMID- 25793224 TI - Some properties of fuzzy soft proximity spaces. AB - We study the fuzzy soft proximity spaces in Katsaras's sense. First, we show how a fuzzy soft topology is derived from a fuzzy soft proximity. Also, we define the notion of fuzzy soft delta-neighborhood in the fuzzy soft proximity space which offers an alternative approach to the study of fuzzy soft proximity spaces. Later, we obtain the initial fuzzy soft proximity determined by a family of fuzzy soft proximities. Finally, we investigate relationship between fuzzy soft proximities and proximities. PMID- 25793223 TI - Evolutionary analysis of structural protein gene VP1 of foot-and-mouth disease virus serotype Asia 1. AB - Foot-and-mouth disease virus (FMDV) serotype Asia 1 was mostly endemic in Asia and then was responsible for economically important viral disease of cloven hoofed animals, but the study on its selection and evolutionary process is comparatively rare. In this study, we characterized 377 isolates from Asia collected up until 2012, including four vaccine strains. Maximum likelihood analysis suggested that the strains circulating in Asia were classified into 8 different groups (groups I-VIII) or were unclassified (viruses collected before 2000). On the basis of divergence time analyses, we infer that the TMRCA of Asia 1 virus existed approximately 86.29 years ago. The result suggested that the virus had a high mutation rate (5.745 * 10(-3) substitutions/site/year) in comparison to the other serotypes of FMDV VP1 gene. Furthermore, the structural protein VP1 was under lower selection pressure and the positive selection occurred at many sites, and four codons (positions 141, 146, 151, and 169) were located in known critical antigenic residues. The remaining sites were not located in known functional regions and were moderately conserved, and the reason for supporting all sites under positive selection remains to be elucidated because the power of these analyses was largely unknown. PMID- 25793225 TI - The cause for the low efficiency of dye sensitized solar cells with a combination of ruthenium dyes and cobalt redox. AB - It has been a concern that the cobalt redox cannot give a good performance for the dye-sensitized solar cells when it is used with ruthenium dyes. The electron dynamics measurements clarified the electron loss processes, and clarified the cause. The result indicated the direct interaction between the ruthenium dyes with the cobalt redox, and it reduced the charge injection from the triplet state of the dyes to the titanium oxide, and also it increased the electron recombination process with the cobalt redox species. Both the problems of injection and recombination were solved by using the ruthenium dye with alkyl chains keeping a distance between the dye and the cobalt redox. PMID- 25793226 TI - Chemistry of the pheromones of mealybug and scale insects. AB - This article comprehensively reviews the syntheses of all known sex pheromones of scales and mealybugs, describes how they were identified, and how the synthetic pheromones are used in insect management. PMID- 25793227 TI - Fingering patterns during droplet impact on heated surfaces. AB - A droplet impinging on a sufficiently heated surface may be cushioned by its own vapor and never touch the surface. In previous work, the transition to this so called Leidenfrost regime was only qualitatively described as an abrupt change between the "contact-boiling" regime, which is characterized by violent boiling behaviors, and the Leidenfrost state. We reveal that the wetted area can be used as a quantity that quantitatively characterizes this transition and it is a continuous function of surface temperature up to the Leidenfrost regime. The wetted area exhibits fingering patterns caused by vapor flow under the liquid. This underlines the crucial role of vapor transport in the Leidenfrost transition and unveils the physical mechanism of the transition to the Leidenfrost regime. PMID- 25793228 TI - Ratiometric detection of oligonucleotide stoichiometry on multifunctional gold nanoparticles by whispering gallery mode biosensing. AB - A label-free method is developed to ratiometrically determine the stoichiometry of oligonucleotides attached to the surface of gold nanoparticle (GNP) by whispering gallery mode biosensing. Utilizing this scheme, it is furthermore shown that the stoichiometric ratio of GNP attached oligonucleotide species can be controlled by varying the concentration ratio of thiolated oligonucleotides that are used to modify the GNP. PMID- 25793229 TI - Self-calibrating highly sensitive dynamic capacitance sensor: towards rapid sensing and counting of particles in laminar flow systems. AB - In this report we propose a sensor architecture and a corresponding read-out technique on silicon for the detection of dynamic capacitance change. This approach can be applied to rapid particle counting and single particle sensing in a fluidic system. The sensing principle is based on capacitance variation of an interdigitated electrode (IDE) structure embedded in an oscillator circuit. The capacitance scaling of the IDE results in frequency modulation of the oscillator. A demodulator architecture is employed to provide a read-out of the frequency modulation caused by the capacitance change. A self-calibrating technique is employed at the read-out amplifier stage. The capacitance variation of the IDE due to particle flow causing frequency modulation and the corresponding demodulator read-out has been analytically modelled. Experimental verification of the established model and the functionality of the sensor chip were shown using a modulating capacitor independent of fluidic integration. The initial results show that the sensor is capable of detecting frequency changes of the order of 100 parts per million (PPM), which translates to a shift of 1.43 MHz at 14.3 GHz operating frequency. It is also shown that a capacitance change every 3 MUs can be accurately detected. PMID- 25793237 TI - Error in the estimation of ablation centration using pachymetric difference maps. PMID- 25793235 TI - Evolution: Polyploid gains. PMID- 25793238 TI - Flap thickness in femtosecond laser. PMID- 25793239 TI - Chemistry: green refill. PMID- 25793240 TI - Reply from the author. PMID- 25793241 TI - Mitochondrial medicine. Preface. PMID- 25793242 TI - "Cup-like" blasts in acute myeloid leukemia with FLT3 and NPM1 mutations. PMID- 25793243 TI - Intraoperative facial nerve monitoring during cochlear implant surgery: an observational study. AB - Iatrogenic facial nerve injury is one of the most severe complications of cochlear implantation (CI) surgery. Intraoperative facial nerve monitoring (IFNM) is used as an adjunctive modality in a variety of neurotologic surgeries. The purpose of this retrospective study was to assess whether the use of IFNM is associated with postoperative facial nerve injury during CI surgery. The medical charts of 645 patients who underwent CI from 1999 to 2014 were reviewed to identify postoperative facial nerve palsy between those who did and did not receive IFNM. Four patients (3 children and 1 adult) were found to have delayed onset facial nerve weakness. IFNM was used in 273 patients, of whom 2 had postoperative facial nerve weakness (incidence of 0.73%). The incidence of facial nerve weakness was 0.54% (2/372) in the patients who did not receive IFNM. IFNM had no significant effect on postoperative delayed facial palsy (P = 1.000). All patients completely recovered within 3 months after surgery. Interestingly, all 4 cases of facial palsy received right CI, which may be because all of the surgeons in this study used their right hand to hold the drill. When right CI surgery is performed by a right-handed surgeon, the shaft of the drill is closer to the inferior angle of the facial recess, and it is easier to place the drilling shaft against the medial boundary (facial nerve) when the facial recess is small. The facial nerve sheaths of another 3 patients were unexpectedly dissected by a diamond burr during the surgery, and the monitor sounded an alarm. None of these 3 patients developed facial palsy postoperatively. This suggests that IFNM could be used as an alarm system for mechanical compression even without current stimulation. Although there appeared to be no relationship between the use of monitoring and delayed facial nerve palsy, IFNM is of great value in the early identification of a dehiscent facial nerve and assisting in the maintenance of its integrity. IFNM can still be used as an additional technique to optimize surgical success. PMID- 25793244 TI - [Why do cancer patients refuse curative radiation therapy?]. PMID- 25793245 TI - [Influence of dose and fractionation in intensity modulated re-irradiation of patients with relapse of nasopharyngeal carcinoma: a randomized phase II study]. PMID- 25793246 TI - [Brain metastases in pulmonary adenocarcinoma with EGFR mutation: how important is therapy with erlotinib compared to radiotherapy?]. PMID- 25793247 TI - Response: "Actually, it's more of a guideline than a rule". PMID- 25793248 TI - With flu numbers among staff increasing, hospitals report challenges, need for vigilance. AB - With a flu vaccine that is largely missing the mark, EDs around the country have their hands full with patients complaining of flu-like symptoms. The flu arrived earlier this year than usual, and by mid-January, it was still not clear whether the virus had peaked. Many EDs are struggling with staffing challenges as more personnel than usual are missing work because they have come down with the flu themselves. As a result, hospital administrators are stepping up infection control practices and urging vigilance with respect to hand hygiene and wearing masks. By mid-January, the Influenza Hospitalization Surveillance Network reported that there had been more than 9,900 hospitalizations related to laboratory-confirmed cases of flu since October 1, translating to an overall rate of more than 36 hospitalizations per 100,000 people. This season's predominant H3N2 viruses have been particularly hard on children, with the CDC reporting that more than 56 children had died from the flu by mid-January. Hospital administrators also report that chronically ill patients are particularly vulnerable to the flu. In some cases, these patients are straining hospital resources as they often require higher-level, inpatient care. PMID- 25793249 TI - Borrowing yet another technique from manufacturing, investigators find that 'operational flexibility' can offer dividends to ED operations. AB - Through the use of a sophisticated modeling technique, investigators at the University of Cincinnati have found that the creation of a so-called "flex track" that includes beds that can be assigned to either high-acuity or Iow-acuity- patients has the potential to lower mean wait times for patients when it is i added to the traditional fast-track and high-acuity areas of a 50-bed ED that sees 85,000 patients per year. Investigators used discrete-event simulation to model the patient flow and characteristics of the ED at the University of Cincinnati Medical Center, and to test out various operational scenarios without disrupting real-world operations. The investigators concluded that patient wait times were lowest when three flex beds were appropriated from the 10-bed fast track area of the EDs. In light of the results, three flex rooms are being incorporated into a newly remodeled ED scheduled for completion laterthis spring. Investigators suggest the modeling technique could be useful to other EDs interested in optimizing their operational plans. Further, they suggest that ED administrators consider ways to introduce flexibility into departments that are now more rigidly divided between high- and low-acuity areas. PMID- 25793250 TI - Researchers offer up a mnemonic tool to guide clinicians who must assess decision making capacity in patients during emergency situations. AB - Clinicians from Johns Hopkins University School of Medicine have developed a mnemonic-driven tool to help clinicians quickly assess whether patients have decision-making capacity during emergency situations. The approach uses the mnemonic "CURVES" to guide physicians to first consider whether patients have decision-making capacity, and then to determine whether treatment can be commenced-without informed consent. The first four letters of the mnemonic "CURVES'" stand for: choose and' communicate, understanding, reason, and value. The authors rote that these four qualities/abilities need to be present to establish decision-making capacity. The last two letters of the pneumonic stand for emergency and surrogate, prompting physicians to consider whether the patient is at immninent risk and whether there is a surrogate decision-maker available. The authors note that while the issues represented by the CURVES pneumonic should be very familiar to clinicians, effective use of the tool requires training and practice. PMID- 25793251 TI - TJC: new reporting changes give hospitals added flexibility on core measures. PMID- 25793252 TI - To avoid misdiagnoses and unnecessary care, take the time to engage patients, listen to their concerns. AB - Despite time constraints and other pressures, emergency personnel can improve both outcomes and patient satisfaction by taking the time to engage patients in decisions about their care, according to Leana Wen, MD, MSc, an emergency medicine physician and the director of Patient-Centered Care Research at George Washington University in Washington, DC. Wen has written a book aimed at helping patients advocate for themselves, but she also notes that many emergency providers could be doing a better job of asking patients about their concerns. Wen advises nurses and other emergency staff to prompt patients to organize their thoughts and preparequestions while they are waiting to see the provider. She also urges providers to explain to patients why they are doing certain tests or procedures. This can help providers avoid unnecessary steps, and to formulate a better plan of care. With respect to patient satisfaction, Wen acknowledges that some patients maynot be happy when they are denied antibiotics or other care thatthey are requesting, but she notes that such concerns are usually assuaged when providers take the time to explain why the requested test or prescription is not advisable. PMID- 25793253 TI - Susceptibility of Helicobacter pylori to Levofloxacin and Rifampicin in Israel. AB - The aim of this study was to assess the resistance level of Helicobacter pylori to levofloxacin and rifampicin from samples collected from pediatric and adult Israeli patients from 2012 to 2013. A total of 117 isolate samples of H. pylori were collected between 2012 and 2013. Isolates were cultured from stomach antrum biopsies and identified by the microbiology laboratory. Isolates were considered susceptible to levofloxacin and rifampicin by an Etest. Out of 117 isolates, 105 were found susceptible and 12 resistant to levofloxacin. For rifampicin, 104 isolates were susceptible and 13 were resistant. Study results estimate an alarming resistance rate, which reiterates the need for prudent use of alternative antibiotics to prevent further spread of resistant strains. Therefore, we suggest subjecting cultures from biopsy samples to susceptibility testing for the purpose of identification of strains resistant to levofloxacin and rifampicin among other antibiotic agents. This will allow for successful monitoring of microbial resistance and will assure prudent use of antimicrobial modalities. PMID- 25793254 TI - Effects of a Multi-Component Behavioral Intervention (MCI) for Insomnia on Depressive and Insomnia Symptoms in Individuals with High and Low Depression. AB - Insomnia and depression are prevalent and co-occurring conditions that are associated with significant impairment of life. Previous research indicates that cognitive-behavioral interventions for insomnia (CBT-I) can improve both insomnia and depressive symptoms. The aim of the authors in this study was to determine whether a multi-component behavioral intervention (MCI) improved both insomnia and depressive symptoms in persons presenting with insomnia and high levels of depression. The sample consisted of 321 individuals with insomnia who participated in a trial of insomnia treatments; 106 participants had high levels of depression (score >= 16 on CES-D) at baseline. Participants either received the MCI or a control treatment (sleep education and hygiene booklet). At post test, participants with high and low levels of depressive symptoms showed significant improvement in insomnia symptoms. Those with high depression also had significant reductions in depressive symptoms. It can be concluded that for individuals with depression and insomnia, CBT-I is a viable intervention for managing depressive symptoms, which complements other approaches for treating depression. PMID- 25793255 TI - Purple chromoprotein gene serves as a new selection marker for transgenesis of the microalga Nannochloropsis oculata. AB - Among the methods used to screen transgenic microalgae, antibiotics selection has raised environmental and food safety concerns, while the observation of fluorescence proteins could be influenced by the endogenous fluorescence of host chloroplasts. As an alternative, this study isolated the purple chromoprotein (CP) from Stichodacyla haddoni (shCP). A plasmid in which shCP cDNA is driven by a heat-inducible promoter was linearized and electroporated into 2.5*10(8) protoplasts of Nannochloropsis oculata. Following regeneration and cultivation on an f/2 medium plate for two weeks, we observed 26 colonies that displayed a slightly dark green coloration. After individually subculturing and performing five hours of heat shock at 42 degrees C, a dark brown color was mosaically displayed in five of these colonies, indicating that both untransformed and transformed cells were mixed together in each colony. To obtain a uniform expression of shCP throughout the whole colony, we continuously isolated each transformed cell that exhibited brown coloration and subcultured it on a fresh plate, resulting in the generation of five transgenic lines of N. oculata which stably harbored the shCP gene for at least 22 months, as confirmed by PCR detection and observation by the naked eye. As shown by Western blot, exogenous shCP protein was expressed in these transgenic microalgae. Since shCP protein is biodegradable and originates from a marine organism, both environmental and food safety concerns have been eliminated, making this novel shCP reporter gene a simple, but effective and ecologically safe, marker for screening and isolating transgenic microalgae. PMID- 25793257 TI - A genome-wide scan reveals important roles of DNA methylation in human longevity by regulating age-related disease genes. AB - It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3)] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2)] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity. PMID- 25793256 TI - Tempol treatment reduces anxiety-like behaviors induced by multiple anxiogenic drugs in rats. AB - We have published that pharmacological induction of oxidative stress (OS) causes anxiety-like behavior in rats. Using animal models, we also have established that psychological stress induces OS and leads to anxiety-like behaviors. All evidence points towards the causal role of OS in anxiety-like behaviors. To fully ascertain the role of OS in anxiety-like behaviors, it is reasonable to test whether the pro-anxiety effects of anxiogenic drugs caffeine or N-methyl-beta carboline-3-carboxamide (FG-7142) can be mitigated using agents that minimize OS. In this study, osmotic pumps were either filled with antioxidant tempol or saline. The pumps were attached to the catheter leading to the brain cannula and inserted into the subcutaneous pocket in the back pocket of the rat. Continuous i.c.v. infusion of saline or tempol in the lateral ventricle of the brain (4.3 mmol/day) was maintained for 1 week. Rats were intraperitoneally injected either with saline or an anxiogenic drug one at a time. Two hours later all groups were subjected to behavioral assessments. Anxiety-like behavior tests (open-field, light-dark and elevated plus maze) suggested that tempol prevented anxiogenic drug-induced anxiety-like behavior in rats. Furthermore, anxiogenic drug-induced increase in stress examined via plasma corticosterone and increased oxidative stress levels assessed via plasma 8-isoprostane were prevented with tempol treatment. Protein carbonylation assay also suggested preventive effect of tempol in the prefrontal cortex brain region of rats. Antioxidant protein expression and pro-inflammatory cytokine levels indicate compromised antioxidant defense as well as an imbalance of inflammatory response. PMID- 25793258 TI - Proteomic analysis of urine exosomes reveals renal tubule response to leptospiral colonization in experimentally infected rats. AB - BACKGROUND: Infectious Leptospira colonize the kidneys of reservoir (e.g. rats) and accidental hosts such as humans. The renal response to persistent leptospiral colonization, as measured by urinary protein biosignatures, has not been systematically studied. Urinary exosomes--bioactive membrane-bound nanovesicles- contain cell-state specific cargo that additively reflect formation all along the nephron. We hypothesized that Leptospira-infection will alter the content of urine exosomes, and further, that these Leptospira-induced alterations will hold clues to unravel novel pathways related to bacterial-host interactions. METHODOLOGY/PRINCIPAL FINDINGS: Exosome protein content from 24 hour urine samples of Leptospira-infected rats was compared with that of uninfected rats using SDS-PAGE and liquid chromatography/tandem mass spectrometry (LC-MS/MS). Statistical models were used to identify significantly dysregulated proteins in Leptospira-infected and uninfected rat urine exosomes. In all, 842 proteins were identified by LC-MS/MS proteomics of total rat urine and 204 proteins associated specifically with exosomes. Multivariate analysis showed that 25 proteins significantly discriminated between uninfected control and infected rats. Alanyl (membrane) aminopeptidase, also known as CD13 topped this list with the highest score, a finding we validated by Western immunoblotting. Whole urine analysis showed Tamm-Horsfall protein level reduction in the infected rat urine. Total urine and exosome proteins were significantly different in male vs. female infected rats. CONCLUSIONS: We identified exosome-associated renal tubule specific responses to Leptospira infection in a rat chronic colonization model. Quantitative differences in infected male and female rat urine exosome proteins vs. uninfected controls suggest that urine exosome analysis identifies important differences in kidney function that may be of clinical and pathological significance. PMID- 25793260 TI - Plasmodium vivax and Plasmodium falciparum at the crossroads of exchange among islands in Vanuatu: implications for malaria elimination strategies. AB - Understanding the transmission and movement of Plasmodium parasites is crucial for malaria elimination and prevention of resurgence. Located at the limit of malaria transmission in the Pacific, Vanuatu is an ideal candidate for elimination programs due to low endemicity and the isolated nature of its island setting. We analyzed the variation in the merozoite surface protein 1 (msp1) and the circumsporozoite protein (csp) of P. falciparum and P. vivax populations to examine the patterns of gene flow and population structures among seven sites on five islands in Vanuatu. Genetic diversity was in general higher in P. vivax than P. falciparum from the same site. In P. vivax, high genetic diversity was likely maintained by greater extent of gene flow among sites and among islands. Consistent with the different patterns of gene flow, the proportion of genetic variance found among islands was substantially higher in P. falciparum (28.81 31.23%) than in P. vivax (-0.53-3.99%). Our data suggest that the current island by-island malaria elimination strategy in Vanuatu, while adequate for P. falciparum elimination, might need to be complemented with more centrally integrated measures to control P. vivax movement across islands. PMID- 25793261 TI - IL22/IL-22R pathway induces cell survival in human glioblastoma cells. AB - Interleukin-22 (IL-22) is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1) and IL-10R2. IL 22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM). Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL 22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells. PMID- 25793259 TI - bacterial infection drives the expression dynamics of microRNAs and their isomiRs. AB - The optimal coordination of the transcriptional response of host cells to infection is essential for establishing appropriate immunological outcomes. In this context, the role of microRNAs (miRNAs)--important epigenetic regulators of gene expression--in regulating mammalian immune systems is increasingly well recognised. However, the expression dynamics of miRNAs, and that of their isoforms, in response to infection remains largely unexplored. Here, we characterized the genome-wide miRNA transcriptional responses of human dendritic cells, over time, to various mycobacteria differing in their virulence as well as to other bacteria outside the genus Mycobacterium, using small RNA-sequencing. We detected the presence of a core temporal response to infection, shared across bacteria, comprising 49 miRNAs, highlighting a set of miRNAs that may play an essential role in the regulation of basic cellular responses to stress. Despite such broadly shared expression dynamics, we identified specific elements of variation in the miRNA response to infection across bacteria, including a virulence-dependent induction of the miR-132/212 family in response to mycobacterial infections. We also found that infection has a strong impact on both the relative abundance of the miRNA hairpin arms and the expression dynamics of miRNA isoforms. That we observed broadly consistent changes in relative arm expression and isomiR distribution across bacteria suggests that this additional, internal layer of variability in miRNA responses represents an additional source of subtle miRNA-mediated regulation upon infection. Collectively, this study increases our understanding of the dynamism and role of miRNAs in response to bacterial infection, revealing novel features of their internal variability and identifying candidate miRNAs that may contribute to differences in the pathogenicity of mycobacterial infections. PMID- 25793262 TI - Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. AB - Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology. PMID- 25793263 TI - Green auctions and reduction of information rents in payments for environmental services: an experimental investigation in Sunan County, northwestern China. AB - Reducing information rents is an important task for government agencies wishing to purchase maximal environmental services with limited budgets. This paper reports on several green auction options for reducing information rents and improving the performance of the "Grain for Green" Payments for environmental services (PES) program implemented in northwestern China. In r experimental auctions and investigations, door-to-door interviews were conducted and bidding envelopes and survey questionnaires were used to determine the offers and the foregone profits of the participants. Three scenarios are analyzed in this paper: a uniform price auction, a discriminatory price auction, and an opportunity-cost system. The results show that compared to the uniform price auction system, the other auction systems can increase the cost-effectiveness of conservation contracting. Competitive bidding can reveal true opportunity costs and can reduce information rents extracted from the government by farmers using private information. The demographics and average bids of these auction types were also analyzed. "Perfect information" in the opportunity-cost offer system has the best performance but is very hard to implement in reality. The results of this research show that the auction is a valuable tool for purchasing conservation contracts in northwestern China, but that in the future, the performance of these auctions should be studied with relaxed model assumptions. PMID- 25793265 TI - A National, Comparative Analysis of Perioperative Outcomes of Open and Minimally Invasive Simple Prostatectomy. AB - PURPOSE: To compare perioperative outcomes of open (OSP) and minimally invasive (MISP) simple prostatectomy for benign prostatic hyperplasia (BPH) in a large national cohort using validated patient safety measures. PATIENTS AND METHODS: We studied patients undergoing simple prostatectomy for BPH in the Nationwide Inpatient Sample (NIS) from 1998 to 2010 and used weighted sampling to estimate national trends. Patient safety indicators (PSI) and multivariable regression were used to generate adjusted odds ratios (ORadj) comparing OSP with MISP. RESULTS: We identified 34,418 and 193 patients undergoing OSP and MISP, respectively. Although the overall frequency of simple prostatectomy cases decreased from 3157 cases in 1998 to 2227 cases in 2010, the annual frequency increased each year from 2008 to 2010. We focused on 2008 to 2010 for the comparative outcome analyses. Among all OSP cases during this period (n=6027), the transfusion prevalence was 21%. MISP patients were more likely to have higher Charlson comorbidity scores (P=0.11) and less likely to undergo transfusion (P=0.13), but these differences did not attain significance. There were no significant differences in median length of stay (LOS) (P=0.19), hospital charges (P=0.15), or unadjusted in-hospital mortality (P=0.73). PSI frequency was low, and did not differ significantly between groups (ORadj 1.59, 95% confidence interval 0.26 to 9.53, P=0.61). CONCLUSIONS: In this, the first national analysis of simple prostatectomy, use of both OSP and MISP rose substantially from 2008 to 2010. Although transfusion prevalence was lower and LOS shorter for MISP, these differences did not attain significance. Further comparative analyses are needed. PMID- 25793264 TI - CoREST1 promotes tumor formation and tumor stroma interactions in a mouse model of breast cancer. AB - Regulators of chromatin structure and gene expression contribute to tumor formation and progression. The co-repressor CoREST1 regulates the localization and activity of associated histone modifying enzymes including lysine specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1). Although several CoREST1 associated proteins have been reported to enhance breast cancer progression, the role of CoREST1 in breast cancer is currently unclear. Here we report that knockdown of CoREST1 in the basal-type breast cancer cell line, MDA-MB-231, led to significantly reduced incidence and diminished size of tumors compared to controls in mouse xenograft studies. Notably, CoREST1-depleted cells gave rise to tumors with a marked decrease in angiogenesis. CoREST1 knockdown led to a decrease in secreted angiogenic and inflammatory factors, and mRNA analysis suggests that CoREST1 promotes expression of genes related to angiogenesis and inflammation including VEGF-A and CCL2. CoREST1 knockdown decreased the ability of MDA-MB-231 conditioned media to promote endothelial cell tube formation and migration. Further, tumors derived from CoREST1-depleted cells had reduced macrophage infiltration and the secretome of CoREST1 knockdown cells was deficient in promoting macrophage migration and macrophage-mediated angiogenesis. Taken together, these findings reveal that the epigenetic regulator CoREST1 promotes tumorigenesis in a breast cancer model at least in part through regulation of gene expression patterns in tumor cells that have profound non-cell autonomous effects on endothelial and inflammatory cells in the tumor microenvironment. PMID- 25793266 TI - Is greater acculturation associated with an increased prevalence of cardiovascular risk factors among Latinos in South Florida? AB - OBJECTIVE: To examine the association of acculturation with various cardiovascular risk factors (CRFs) among Latinos with diabetes in South Florida. METHODS: In a cross-sectional analysis of data collected from 300 Latinos with poorly controlled diabetes we measured acculturation using the Marin Short Acculturation Scale. We examined correlations between acculturation and the following 7 CRFs: hemoglobin A1C, low-density lipoprotein, systolic blood pressure, body mass index, smoking status, physical activity, and fruit and vegetable intake. RESULTS: Cubans made up 38% of our population; no other Latino subgroup represented over 17% of the sample. Of the 8 outcomes examined, only smoking was associated with increased acculturation; 12% of Latinos in the 2 lowest acculturation groups were current smokers versus 25% in the highest acculturation group (P=0.02). Furthermore, Cuban Americans from our sample had over double the prevalence of smoking compared with non-Cubans in both the lowest and highest acculturation groups. CONCLUSIONS: With the exception of smoking, our data does not support a link between increased acculturation and higher prevalence of CRFs in Latinos with diabetes. Smoking prevention and cessation programs targeting Latinos and particularly among Cubans are needed. PMID- 25793267 TI - Patient-centered Medical Home capability and clinical performance in HRSA supported health centers. AB - OBJECTIVES: To evaluate the relationship between Patient-centered Medical Home (PCMH) model adoption in health centers (HCs) and clinical performance measures and to determine if adoption of PCMH characteristics is associated with better clinical performance. RESEARCH DESIGN: Data came from the Health Resources and Services Administration's 2009 Uniform Data System and the 2009 Commonwealth Fund National Survey of Federally Qualified Health Centers. Clinical performance measures included 2 process measures (childhood immunization and cervical cancer screening) and 2 outcome measures (hypertension control and diabetes control). Total and subscale PCMH scores were regressed on the clinical performance measures, adjusting for patient, provider, financial, and institutional characteristics. RESULTS: The findings showed different directional relationships, with some PCMH domains (care management, test/referral tracking, quality improvement, and external coordination) showing little or no effect on outcome measures of interest, 1 domain (access/communication) associated with improved outcomes, and 1 domain (patient tracking/registry) associated with worse outcomes. CONCLUSIONS: This study is among the first to examine the association between PCMH transformation and clinical performance in HCs, providing an understanding of the impact of PCMH adoption within safety-net settings. The mixed results highlight the importance of examining relationships between specific PCMH domains and specific clinical quality measures, in addition to analyzing overall PCMH scores which could yield distorted findings. PMID- 25793268 TI - Cognitive function and the concordance between survey reports and Medicare claims in a nationally representative cohort of older adults. AB - BACKGROUND: While age-related cognitive decline may affect all stages in the response process--comprehension, retrieval, judgment, response selection, and response reporting--the associations between objective cognitive tests and the agreement between self-reports and Medicare claims has not been assessed. We evaluate those associations using the Survey on Assets and Health Dynamics among the Oldest Old (AHEAD). METHODS: Eight waves of reinterviews (1995-2010) were linked to Medicare claims for 3661 self-respondents yielding 12,313 person-period observations. Cognitive function was measured by 2 episodic memory tests (immediate and delayed recall of 10 words) and 1 mental status test (backward counting, dates, and names). Survey reports on 12 diseases and 4 health services were mapped to Medicare claims to derive counts of concordant reports, underreports, and overreports, as were the numbers of hospital episodes and physician visits. GEE negative binomial and logistic regression models were used. RESULTS: Better mental status was associated with more concordant reporting and less underreporting on disease history and the number of hospital episodes. Better mental status and delayed word recall were associated with more concordant reporting and less underreporting on health services use. Better delayed recall was significantly associated with less underreporting on the number of physician visits. These associations were not appreciably altered by adjustment for demographic characteristics, socioeconomic status, self-rated health, or secular trends. CONCLUSION: We recommend that future surveys of older adults include an objective measure of mental status (rather than memory), especially when those survey reports cannot be verified by access to Medicare claims or chart review. PMID- 25793269 TI - Body mass index and health care utilization in diabetic and nondiabetic individuals. AB - BACKGROUND: Although controversial, most studies examining the relationship of body mass index (BMI) with mortality in diabetes suggest a paradox: the lowest risk category is above normal weight, versus normal weight in nondiabetic persons. One proposed explanation is greater morbidity of diabetes in normal weight persons. If this were so, it would suggest a health care utilization paradox in diabetes, paralleling the mortality paradox, yet no studies have examined this issue. OBJECTIVE: To compare the relationship of BMI with health care utilization in diabetic versus nondiabetic persons. DESIGN: Population-based cross-sectional study. SUBJECTS: Adults in the 2000-2011 Medical Expenditures Panel Surveys (N=120,389). MEASURES: Total health care expenditures, hospital utilization (>=1 admission), and emergency department utilization (>=1 visit). BMI (kg/m) categories were: <20 (underweight); 20 to <25 (normal); 25 to <30 (overweight); 30 to <35 (obese); and >=35 (severely obese). Adjustors were age, sex, race/ethnicity, income, health insurance, education, smoking, co-morbidity, urbanicity, region, and year. RESULTS: Among diabetic persons, adjusted mean total health care expenditures were significantly lower in obese versus normal weight persons ($1314, 95% confidence interval [CI], $513-$2115; P=0.001). By contrast, among nondiabetic persons, total expenditures were nonsignificantly higher in obese versus normal weight persons (-$229, 95% CI, -$460 to $2; P=0.052). Findings for hospital and emergency department utilization exhibited similar patterns. CONCLUSIONS: Normal weight diabetic persons used substantially more health care than their overweight and obese counterparts, a difference not observed in nondiabetic persons. These differences support the plausibility of a BMI mortality paradox related to greater morbidity of diabetes in normal weight than in heavier persons. PMID- 25793270 TI - Sociodemographic and health characteristics, rather than primary care supply, are major drivers of geographic variation in preventable hospitalizations in Australia. AB - BACKGROUND: Geographic rates of preventable hospitalization are used internationally as an indicator of accessibility and quality of primary care. Much research has correlated the indicator with the supply of primary care services, yet multiple other factors may influence these admissions. OBJECTIVE: To quantify the relative contributions of the supply of general practitioners (GPs) and personal sociodemographic and health characteristics, to geographic variation in preventable hospitalization. METHODS: Self-reported questionnaire data for 267,091 participants in the 45 and Up Study, Australia, were linked with administrative hospital data to identify preventable hospitalizations. Multilevel Poisson models, with participants clustered in their geographic area of residence, were used to explore factors that explain geographic variation in hospitalization. RESULTS: GP supply, measured as full-time workload equivalents, was not a significant predictor of preventable hospitalization, and explained only a small amount (2.9%) of the geographic variation in hospitalization rates. Conversely, more than one-third (36.9%) of variation was driven by the sociodemographic composition, health, and behaviors of the population. These personal characteristics explained a greater amount of the variation for chronic conditions (37.5%) than acute (15.5%) or vaccine-preventable conditions (2.4%). CONCLUSIONS: Personal sociodemographic and health characteristics, rather than GP supply, are major drivers of preventable hospitalization. Their contribution varies according to condition, and if used for performance comparison purposes, geographic rates of preventable hospitalization should be reported according to individual condition or potential pathways for intervention. PMID- 25793271 TI - Assessing Medicare Part D claim completeness using medication self-reports: the role of veteran status and Generic Drug Discount Programs. AB - OBJECTIVE: Medicare Part D claims are commonly used for research, but missing claims could compromise their validity. This study assessed 2 possible causes of missing claims: veteran status and Generic Drug Discount Programs (GDDP). MATERIALS AND METHODS: We merged medication self-reports from telephone interviews in the Atherosclerosis Risk in Communities (ARIC) Study with Part D claims for 6 medications (3 were commonly in GDDP in 2009). Merged records (4468) were available for 2905 ARIC participants enrolled in Part D. Multinomial logit regression provided estimates of the association of concordance (self-report and Part D, self-report only, or Part D only) with veteran and GDDP status, controlling for participant sociodemographics. RESULTS: Sample participants were 74+/-5 years of age, 68% white and 63% female; 19% were male veterans. Compared with females, male veterans were 11% [95% confidence interval (CI), 7%-16%] less likely to have matched medications in self-report and Part D and 11% (95% CI, 7% 16%) more likely to have self-report only. Records for GDDP versus non-GDDP medications were 4% (95% CI, 1%-7%) more likely to be in self-report and Part D and 3% (95% CI, 1%-5%) less likely to be in Part D only, with no difference in self-report only. CONCLUSIONS: Part D claims were more likely to be missing for veterans, but claims for medications commonly available through GDDP were more likely to match with self-reports. Although researchers should be aware of the possibility of missing claims, GDDP status was associated with a higher rather than lower likelihood of claims being complete in 2009. PMID- 25793272 TI - Broad-spectrum antibiotic or G-CSF as potential countermeasures for impaired control of bacterial infection associated with an SPE exposure during spaceflight. AB - A major risk for astronauts during prolonged space flight is infection as a result of the combined effects of microgravity, situational and confinement stress, alterations in food intake, altered circadian rhythm, and radiation that can significantly impair the immune system and the body's defense systems. We previously reported a massive increase in morbidity with a decrease in the ability to control a bacterial challenge when mice were maintained under hindlimb suspension (HS) conditions and exposed to solar particle event (SPE)-like radiation. HS and SPE-like radiation treatment alone resulted in a borderline significant increase in morbidity. Therefore, development and testing of countermeasures that can be used during extended space missions in the setting of exposure to SPE radiation becomes a serious need. In the present study, we investigated the efficacy of enrofloxacin (an orally bioavailable antibiotic) and Granulocyte colony stimulating factor (G-CSF) (Neulasta) on enhancing resistance to Pseudomonas aeruginosa infection in mice subjected to HS and SPE-like radiation. The results revealed that treatment with enrofloxacin or G-CSF enhanced bacterial clearance and significantly decreased morbidity and mortality in challenged mice exposed to suspension and radiation. These results establish that antibiotics, such as enrofloxacin, and G-CSF could be effective countermeasures to decrease the risk of bacterial infections after exposure to SPE radiation during extended space flight, thereby reducing both the risk to the crew and the danger of mission failure. PMID- 25793273 TI - Muller glia activation in response to inherited retinal degeneration is highly varied and disease-specific. AB - Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Muller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Muller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Delta307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Delta307, but decreased in the Prph2+/Delta307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Muller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Muller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent. PMID- 25793274 TI - Folic acid supplementation during pregnancy induces sex-specific changes in methylation and expression of placental 11beta-hydroxysteroid dehydrogenase 2 in rats. AB - In the placenta, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) limits fetal glucocorticoid exposure and its inhibition has been associated to low birth weight. Its expression, encoded by the HSD11B2 gene is regulated by DNA methylation. We hypothesized that maternal diets supplemented with folic acid (FA) during pregnancy modify the expression of placental HSD11B2 through gene methylation. Wistar rats were fed with high (8 mg/kg) or normal low (1mg/kg, control) levels of FA during pregnancy. Concentrations of mRNA and protein in placentas were determined by qRT-PCR and Western blot respectively. Methylation in five CpG sites of the placental HSD11B2 promoter (-378 to -275) was analyzed by bacterial cloning and subsequent sequencing. In the FA-supplemented group, mRNA and protein levels of 11beta-HSD2 decreased by 58% and increased by 89%, respectively, only in placentas attached to males. In controls, most CpG sites were not methylated except for the CpG2 site which was 80% methylated. CpG2 methylation level increased under the FA treatment; however, only in placentas attached to females was this increase significant (113%). This change was not related to HSD11B2 expression. Fetal weight of females from FA- supplemented mothers was 6% higher than females from control mothers. In conclusion, this is the first study reporting that FA over supplementation during pregnancy modifies the placental HSD11B2 gene expression and methylation in a sex-dependent manner, suggesting that maternal diets with high content of FA can induce early sex specific responses, which may lead to long-term consequences for the offspring. PMID- 25793275 TI - Weighting mean and variability during confidence judgments. AB - Humans can not only perform some visual tasks with great precision, they can also judge how good they are in these tasks. However, it remains unclear how observers produce such metacognitive evaluations, and how these evaluations might be dissociated from the performance in the visual task. Here, we hypothesized that some stimulus variables could affect confidence judgments above and beyond their impact on performance. In a motion categorization task on moving dots, we manipulated the mean and the variance of the motion directions, to obtain a low mean low-variance condition and a high-mean high-variance condition with matched performances. Critically, in terms of confidence, observers were not indifferent between these two conditions. Observers exhibited marked preferences, which were heterogeneous across individuals, but stable within each observer when assessed one week later. Thus, confidence and performance are dissociable and observers' confidence judgments put different weights on the stimulus variables that limit performance. PMID- 25793276 TI - The role of cellular coupling in the spontaneous generation of electrical activity in uterine tissue. AB - The spontaneous emergence of contraction-inducing electrical activity in the uterus at the beginning of labor remains poorly understood, partly due to the seemingly contradictory observation that isolated uterine cells are not spontaneously active. It is known, however, that the expression of gap junctions increases dramatically in the approach to parturition, by more than one order of magnitude, which results in a significant increase in inter-cellular electrical coupling. In this paper, we build upon previous studies of the activity of electrically excitable smooth muscle cells (myocytes) and investigate the mechanism through which the coupling of these cells to electrically passive cells results in the generation of spontaneous activity in the uterus. Using a recently developed, realistic model of uterine muscle cell dynamics, we investigate a system consisting of a myocyte coupled to passive cells. We then extend our analysis to a simple two-dimensional lattice model of the tissue, with each myocyte being coupled to its neighbors, as well as to a random number of passive cells. We observe that different dynamical regimes can be observed over a range of gap junction conductances: at low coupling strength, corresponding to values measured long before delivery, the activity is confined to cell clusters, while the activity for high coupling, compatible with values measured shortly before delivery, may spread across the entire tissue. Additionally, we find that the system supports the spontaneous generation of spiral wave activity. Our results are both qualitatively and quantitatively consistent with observations from in vitro experiments. In particular, we demonstrate that the increase in inter cellular electrical coupling observed experimentally strongly facilitates the appearance of spontaneous action potentials that may eventually lead to parturition. PMID- 25793277 TI - Genetic structure analysis of Spirometra erinaceieuropaei isolates from central and southern China. AB - BACKGROUND: Sparganosis caused by invasion of the plerocercoid larvae (spargana) of Spirometra erinaceieuropaei have increased in recent years in China. However, the population genetic structure regarding this parasite is still unclear. In this study, we used the sequences of two mitochondrial genes cytochrome b (cytb) and cytochrome c oxidase subunit I (cox1) to analyze genetic variation and phylogeographic structure of the S. erinaceieuropaei populations. METHODOLOGY/PRINCIPAL FINDINGS: A total of 88 S. erinaceieuropaei isolates were collected from naturally infected frogs in 14 geographical locations of China. The complete cytb and cox1 genes of each sample was amplified and sequenced. Total 61 haplotypes were found in these 88 concatenated sequences. Each sampled population and the total population have high haplotype diversity (Hd), accompanied by very low nucleotide diversity (Pi). Phylogenetic analyses of haplotypes revealed two distinct clades (HeN+HuN+GZ-AS clade and GX+HN+GZ-GY clade) corresponding two sub-networks yielded by the median-joining network. Pairwise FST values supported great genetic differentiation between S. erinaceieuropaei populations. Both negative Fu's FS value of neutrality tests and unimodal curve of mismatch distribution analyses supported demographic population expansion in the HeN+HuN+GZ-AS clade. The BEAST analysis showed that the divergence time between the two clades took place in the early Pleistocene (1.16 Myr), and by Bayesian skyline plot (BSP) an expansion occurred after about 0.3 Myr ago. CONCLUSIONS: S. erinaceieuropaei from central and southern China has significant phylogeographic structure, and climatic oscillations during glacial periods in the Quaternary may affect the demography and diversification of this species. PMID- 25793278 TI - Physical Routes to Primitive Cells: An Experimental Model Based on the Spontaneous Entrapment of Enzymes inside Micrometer-Sized Liposomes. AB - How did primitive living cells originate? The formation of early cells, which were probably solute-filled vesicles capable of performing a rudimentary metabolism (and possibly self-reproduction), is still one of the big unsolved questions in origin of life. We have recently used lipid vesicles (liposomes) as primitive cell models, aiming at the study of the physical mechanisms for macromolecules encapsulation. We have reported that proteins and ribosomes can be encapsulated very efficiently, against statistical expectations, inside a small number of liposomes. Moreover the transcription-translation mixture, which realistically mimics a sort of minimal metabolic network, can be functionally reconstituted in liposomes owing to a self-concentration mechanism. Here we firstly summarize the recent advancements in this research line, highlighting how these results open a new vista on the phenomena that could have been important for the formation of functional primitive cells. Then, we present new evidences on the non-random entrapment of macromolecules (proteins, dextrans) in phospholipid vesicle, and in particular we show how enzymatic reactions can be accelerated because of the enhancement of their concentration inside liposomes. PMID- 25793279 TI - How close we are to achieving commercially viable large-scale photobiological hydrogen production by cyanobacteria: a review of the biological aspects. AB - Photobiological production of H2 by cyanobacteria is considered to be an ideal source of renewable energy because the inputs, water and sunlight, are abundant. The products of photobiological systems are H2 and O2; the H2 can be used as the energy source of fuel cells, etc., which generate electricity at high efficiencies and minimal pollution, as the waste product is H2O. Overall, production of commercially viable algal fuels in any form, including biomass and biodiesel, is challenging, and the very few systems that are operational have yet to be evaluated. In this paper we will: briefly review some of the necessary conditions for economical production, summarize the reports of photobiological H2 production by cyanobacteria, present our schemes for future production, and discuss the necessity for further progress in the research needed to achieve commercially viable large-scale H2 production. PMID- 25793280 TI - Vancomycin tolerant, methicillin-resistant Staphylococcus aureus reveals the effects of vancomycin on cell wall thickening. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important opportunistic pathogen that causes both healthcare- and community-acquired infections. An increase in the incidence of these infections may lead to a substantial change in the rate of vancomycin usage. Incidence of reduced susceptibility to vancomycin has been increasing worldwide for the last few years, conferring different levels of resistance to vancomycin as well as producing changes in the cell wall structure. The aim of the present study was to determine the effect of vancomycin on cell wall thickening in clinical isolates of vancomycin-tolerant (VT) MRSA obtained from pediatric patients. From a collection of 100 MRSA clinical isolates from pediatric patients, 12% (12/100) were characterized as VT-MRSA, and from them, 41.66% (5/12) exhibited the heterogeneous vancomycin-intermediate S. aureus (hVISA) phenotype. Multiplex-PCR assays revealed 66.66% (8/12), 25% (3/12), and 8.33% (1/12) of the VT-MRSA isolates were associated with agr group II, I, and III polymorphisms, respectively; the II-mec gene was amplified from 83.3% (10/12) of the isolates, and the mecIVa gene was amplified from 16.66% (2/12) of the isolates. Pulsed field electrophoresis (PFGE) fingerprint analysis showed 62% similarity among the VT-MRSA isolates. Thin transverse sections analyzed by transmission electron microscopy (TEM) revealed an average increase of 24 nm (105.55%) in the cell wall thickness of VT-MRSA compared with untreated VT-MRSA isolates. In summary, these data revealed that the thickened cell walls of VT MRSA clinical isolates with agr type II and SCCmec group II polymorphisms are associated with an adaptive resistance to vancomycin. PMID- 25793282 TI - Image quality assessment based on inter-patch and intra-patch similarity. AB - In this paper, we propose a full-reference (FR) image quality assessment (IQA) scheme, which evaluates image fidelity from two aspects: the inter-patch similarity and the intra-patch similarity. The scheme is performed in a patch wise fashion so that a quality map can be obtained. On one hand, we investigate the disparity between one image patch and its adjacent ones. This disparity is visually described by an inter-patch feature, where the hybrid effect of luminance masking and contrast masking is taken into account. The inter-patch similarity is further measured by modifying the normalized correlation coefficient (NCC). On the other hand, we also attach importance to the impact of image contents within one patch on the IQA problem. For the intra-patch feature, we consider image curvature as an important complement of image gradient. According to local image contents, the intra-patch similarity is measured by adaptively comparing image curvature and gradient. Besides, a nonlinear integration of the inter-patch and intra-patch similarity is presented to obtain an overall score of image quality. The experiments conducted on six publicly available image databases show that our scheme achieves better performance in comparison with several state-of-the-art schemes. PMID- 25793281 TI - Primary screening for cervical cancer based on high-risk human papillomavirus (HPV) detection and HPV 16 and HPV 18 genotyping, in comparison to cytology. AB - OBJECTIVES: The objective of the present study is to assess the performance of a high-risk human papillomavirus (HR-HPV) DNA test with individual HPV-16/HPV-18 genotyping as a method for primary cervical cancer screening compared with liquid based cytology (LBC) in a population of Greek women taking part in routine cervical cancer screening. METHODS: The study, conducted by the "HEllenic Real life Multicentric cErvical Screening" (HERMES) study group, involved the recruitment of 4,009 women, aged 25-55, who took part in routine cervical screening at nine Gynecology Departments in Greece. At first visit cervical specimens were collected for LBC and HPV testing using the Roche Cobas 4800 system. Women found positive for either cytology or HPV were referred for colposcopy, whereas women negative for both tests will be retested after three years. The study is ongoing and the results of the first screening round are reported herein. RESULTS: Valid results for cytology and HPV testing were obtained for 3,993 women. The overall prevalence of HR-HPV was 12.7%, of HPV-16 2.7% and of HPV-18 1.4%. Of those referred for colposcopy, cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was detected in 41 women (1.07%). At the threshold of CIN2+, cytology [atypical squamous cells of undetermined significance (ASC-US) or worse] and HPV testing showed a sensitivity of 53.7% and 100% respectively, without change between age groups. Cytology and HPV testing showed specificity of 96.8% and 90.3% respectively, which was increased in older women (>=30) in comparison to younger ones (25-29). Genotyping for HPV16/18 had similar accuracy to cytology for the detection of CIN2+ (sensitivity: 58.5%; specificity 97.5%) as well as for triage to colposcopy (sensitivity: 58.5% vs 53.7% for cytology). CONCLUSION: HPV testing has much better sensitivity than cytology to identify high-grade cervical lesions with slightly lower specificity. HPV testing with individual HPV-16/HPV-18 genotyping could represent a more accurate methodology for primary cervical cancer screening in comparison to liquid-based cytology, especially in older women. PMID- 25793283 TI - Intimacy versus isolation: a qualitative study of sexual practices among sexually active HIV-infected patients in HIV care in Brazil, Thailand, and Zambia. AB - The success of global treatment as prevention (TasP) efforts for individuals living with HIV/AIDS (PLWHA) is dependent on successful implementation, and therefore the appropriate contribution of social and behavioral science to these efforts. Understanding the psychosocial context of condomless sex among PLWHA could shed light on effective points of intervention. HPTN 063 was an observational mixed-methods study of sexually active, in-care PLWHA in Thailand, Zambia, and Brazil as a foundation for integrating secondary HIV prevention into HIV treatment. From 2010-2012, 80 qualitative interviews were conducted with PLWHA receiving HIV care and reported recent sexual risk. Thirty men who have sex with women (MSW) and 30 women who have sex with men (WSM) participated in equal numbers across the sites. Thailand and Brazil also enrolled 20 biologically-born men who have sex with men (MSM). Part of the interview focused on the impact of HIV on sexual practices and relationships. Interviews were recorded, transcribed, translated into English and examined using qualitative descriptive analysis. The mean age was 25 (SD = 3.2). There were numerous similarities in experiences and attitudes between MSM, MSW and WSM across the three settings. Participants had a high degree of HIV transmission risk awareness and practiced some protective sexual behaviors such as reduced sexual activity, increased use of condoms, and external ejaculation. Themes related to risk behavior can be categorized according to struggles for intimacy and fears of isolation, including: fear of infecting a sex partner, guilt about sex, sexual communication difficulty, HIV stigma, and worry about sexual partnerships. Emphasizing sexual health, intimacy and protective practices as components of nonjudgmental sex-positive secondary HIV prevention interventions is recommended. For in-care PLWHA, this approach has the potential to support TasP. The overlap of themes across groups and countries indicates that similar intervention content may be effective for a range of settings. PMID- 25793284 TI - Variable active site loop conformations accommodate the binding of macrocyclic largazole analogues to HDAC8. AB - The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn(2+) ion, as observed in the X-ray crystal structure of the HDAC8-Largazole complex [Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., and Christianson, D. W. (2011) J. Am. Chem. Soc. 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a six-membered pyridine ring is also substituted (with two different orientations) for the five-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn(2+) ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in loops L1 and L2 flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8. PMID- 25793285 TI - Blood meal analysis of culicoides (Diptera: ceratopogonidae) in central Tunisia. AB - To evaluate the host preferences of Culicoides species (Diptera: Ceratopogonidae) in Central Tunisia, we identified the source of blood meals of field collected specimens by sequencing of the cytochrome b (cyt b) mitochondrial locus and Prepronociceptine single copy nuclear gene. The study includes the most common and abundant livestock associated species of biting midges in Tunisia: C. imicola, C. jumineri, C. newsteadi, C. paolae, C. cataneii, C. circumscriptus, C. kingi, C. pseudojumineri, C. submaritimus, C. langeroni, C. jumineri var and some unidentified C. species. Analysis of cyt b PCR products from 182 field collected blood-engorged females' midges revealed that 92% of them fed solely on mammalian species, 1.6% on birds, 2.4% on insects and 0.8% on reptiles. The blast results identified the blood origin of biting midges to the species level with exact or nearly exact matches (>=98%). The results confirm the presence of several Culicoides species, including proven vectors in Central Tunisia. Blood meal analyses show that these species will indeed feed on bigger mammals, thereby highlighting the risk that these viruses will be able to spread in Tunisia. PMID- 25793286 TI - Correction: Correlation of the apparent diffusion coefficient (ADC) with the standardized uptake value (SUV) in lymph node metastases of non-small cell lung cancer (NSCLC) patients using hybrid 18F-FDG PET/MRI. PMID- 25793288 TI - Time-dependent effect of hypoxia on tumor progression and liver progenitor cell markers in primary liver tumors. AB - BACKGROUND & AIMS: Expression of liver progenitor cell (LPC) characteristics has been proposed as a negative prognostic marker in primary liver tumors. Hypoxia has been linked to activation of the Notch pathway which is responsible for activation and proliferation of LPCs and hypoxia-induced LPC activation has been shown in hepatocellular carcinoma. Our aim was to elucidate the time-dependent effects of hypoxia on the LPC niche in hepatocellular carcinoma which could aid in determining a safe time frame for use of hypoxia inducing therapies. METHODS: We used dimethyloxaloylglycine to mimic a hypoxic reaction in mice by stabilizing hypoxia-inducible factor 1 alpha at three distinct time points in diethylnitrosamine induced hepatocarcinogenesis. LPC, metastasis and Notch pathway markers were determined by quantitative PCR and (immune)histochemistry (heamatoxillin-eosin, reticulin, Sirius red and cytokeratin 19 staining). RESULTS: Activating the hypoxia inducible pathway early in hepatocarcinogenesis resulted in an increased incidence of both cholangioma and hepatocellular lesions, associated with high expression of LPC, metastatic and Notch pathway markers. Adversely, activating the hypoxic response during tumor development resulted in decreased incidence of hepatocellular lesions and increased cholangioma incidence, with an unaltered gene expression profile of LPC-, Notch pathway- and metastatic markers. A hypoxic insult at advanced stages of hepatocarcinogenesis severely increased the expression of LPC characteristics, however without increased expression of actors of the Notch pathway and metastatic markers and minor changes in incidence of hepatocellular and cholangioma lesions. CONCLUSION: Our results indicate that increased hypoxia at the onset of tumor development has detrimental effects on tumor progression; patients with HCC developed in a background of fibrosis/cirrhosis might therefore represent a more difficult treatment group. In contrast, hypoxia during tumor development appears to favor tumor outcome, highlighting the importance of early detection. Finally, hypoxia in advanced stages resulted in increased expression of LPC characteristics indicating poor outcome. PMID- 25793289 TI - Conversation electrified: ERP correlates of speech act recognition in underspecified utterances. AB - The ability to recognize speech acts (verbal actions) in conversation is critical for everyday interaction. However, utterances are often underspecified for the speech act they perform, requiring listeners to rely on the context to recognize the action. The goal of this study was to investigate the time-course of auditory speech act recognition in action-underspecified utterances and explore how sequential context (the prior action) impacts this process. We hypothesized that speech acts are recognized early in the utterance to allow for quick transitions between turns in conversation. Event-related potentials (ERPs) were recorded while participants listened to spoken dialogues and performed an action categorization task. The dialogues contained target utterances that each of which could deliver three distinct speech acts depending on the prior turn. The targets were identical across conditions, but differed in the type of speech act performed and how it fit into the larger action sequence. The ERP results show an early effect of action type, reflected by frontal positivities as early as 200 ms after target utterance onset. This indicates that speech act recognition begins early in the turn when the utterance has only been partially processed. Providing further support for early speech act recognition, actions in highly constraining contexts did not elicit an ERP effect to the utterance-final word. We take this to show that listeners can recognize the action before the final word through predictions at the speech act level. However, additional processing based on the complete utterance is required in more complex actions, as reflected by a posterior negativity at the final word when the speech act is in a less constraining context and a new action sequence is initiated. These findings demonstrate that sentence comprehension in conversational contexts crucially involves recognition of verbal action which begins as soon as it can. PMID- 25793287 TI - Surface vulnerability of cerebral cortex to major depressive disorder. AB - Major depressive disorder (MDD) is accompanied by atypical brain structure. This study first presents the alterations in the cortical surface of patients with MDD using multidimensional structural patterns that reflect different neurodevelopment. Sixteen first-episode, untreated patients with MDD and 16 matched healthy controls underwent a magnetic resonance imaging (MRI) scan. The cortical maps of thickness, surface area, and gyrification were examined using the surface-based morphometry (SBM) approach. Increase of cortical thickness was observed in the right posterior cingulate region and the parietal cortex involving the bilateral inferior, left superior parietal and right paracentral regions, while decreased thickness was noted in the parietal cortex including bilateral pars opercularis and left precentral region, as well as the left rostral-middle frontal regions in patients with MDD. Likewise, increased or decreased surface area was found in five sub-regions of the cingulate gyrus, parietal and frontal cortices (e.g., bilateral inferior parietal and superior frontal regions). In addition, MDD patients exhibited a significant hypergyrification in the right precentral and supramarginal region. This integrated structural assessment of cortical surface suggests that MDD patients have cortical alterations of the frontal, parietal and cingulate regions, indicating a vulnerability to MDD during earlier neurodevelopmental process. PMID- 25793290 TI - Frequency of Primary Nonadherence to Acne Treatment. AB - IMPORTANCE: Treatment outcomes depend on adherence to the prescribed regimen. Primary nonadherence refers to not obtaining and starting to take a prescribed medication. The frequency of primary nonadherence to acne treatment has not been well characterized. The complexity of multidrug acne regimens may add to this problem but, to our knowledge, has not been explored. OBJECTIVES: To estimate acne treatment primary nonadherence rates and to determine the relationship between primary nonadherence and the number of acne treatments prescribed. DESIGN, SETTING, AND PARTICIPANTS: A review of medical records from an outpatient university dermatology clinic identified patients with an acne diagnosis at a dermatology visit in the past 3 months who were prescribed 1, 2, or 3 or more treatments. Patients were excluded if they were not English speakers, were not prescribed treatment for their acne, or did not have an active telephone number. Using randomized lists, these patients were queried via telephone regarding which acne treatments they obtained. The results were analyzed using Fisher exact tests and multivariable logistic regression. For patients who were prescribed 1, 2, or 3 or more treatments, 47, 48, and 48 eligible patients were contacted, respectively. MAIN OUTCOMES AND MEASURES: The primary study outcomes were the overall rate of primary nonadherence and the rate for each treatment-number subgroup. Secondary outcomes included the association of sex, age, medication type, and electronic prescription status with primary nonadherence. RESULTS: Overall, 27% of patients did not fill all their prescriptions. Of patients who were given 1, 2, or 3 or more treatments, 9%, 40%, and 31%, respectively, did not fill all their prescriptions. There was no statistically significant difference by sex or age for primary nonadherence in any of the 3 treatment-number groups. Based on multivariable analyses, being prescribed a topical retinoid (odds ratio, 2.9; 95% CI, 1.0-8.0) or an over-the-counter product (odds ratio, 3.6; 95% CI, 1.1-12.3) was associated with primary nonadherence. Based on univariate analysis, there was less primary nonadherence with electronic prescriptions compared with paper prescriptions (P < .001). CONCLUSIONS AND RELEVANCE: Primary adherence to an acne treatment regimen is better when only 1 treatment is prescribed. Some patients may not complete acne treatment because 1 or more of their medications were never obtained. PMID- 25793291 TI - Altered neural basis of the reality processing and its relation to cognitive insight in schizophrenia. AB - It has been reported that reality evaluation and recognition are impaired in patients with schizophrenia and these impairments are related to the severity of psychotic symptoms. The current study aimed to investigate the neural basis of impairments in reality evaluation and recognition and their relationships with cognitive insight in schizophrenia. During functional magnetic resonance imaging, 20 patients with schizophrenia and 20 healthy controls performed a set of reality evaluation and recognition tasks, in which subjects judged whether scenes in a series of drawings were real or unreal and whether they were familiar or novel. During reality evaluation, patients showed decreased activity in various regions including the inferior parietal lobule, retrosplenial cortex and parahippocampal gyrus, compared with controls. Particularly, parahippocampal gyrus activity was correlated with the severity of positive symptoms in patients. During recognition, patients also exhibited decreased activity in various regions, including the dorsolateral prefrontal cortex, inferior parietal lobule and posterior cingulate cortex. Particularly, inferior parietal lobule activity and posterior cingulate cortex activity were correlated with cognitive insight in patients. These findings provide evidence that neural impairments in reality evaluation and recognition are related to psychotic symptoms. Anomalous appraisal of context by dysfunctions in the context network may contribute to impairments in the reality processing in schizophrenia, and abnormal declarative memory processes may be involved in cognitive insight in patients with schizophrenia. PMID- 25793292 TI - Modeling of microvascular permeability changes after electroporation. AB - Vascular endothelium selectively controls the transport of plasma contents across the blood vessel wall. The principal objective of our preliminary study was to quantify the electroporation-induced increase in permeability of blood vessel wall for macromolecules, which do not normally extravasate from blood into skin interstitium in homeostatic conditions. Our study combines mathematical modeling (by employing pharmacokinetic and finite element modeling approach) with in vivo measurements (by intravital fluorescence microscopy). Extravasation of fluorescently labeled dextran molecules of two different sizes (70 kDa and 2000 kDa) following the application of electroporation pulses was investigated in order to simulate extravasation of therapeutic macromolecules with molecular weights comparable to molecular weight of particles such as antibodies and plasmid DNA. The increase in blood vessel permeability due to electroporation and corresponding transvascular transport was quantified by calculating the apparent diffusion coefficients for skin microvessel wall (D [MUm2/s]) for both molecular sizes. The calculated apparent diffusion coefficients were D = 0.0086 MUm2/s and D = 0.0045 MUm2/s for 70 kDa and 2000 kDa dextran molecules, respectively. The results of our preliminary study have important implications in development of realistic mathematical models for prediction of extravasation and delivery of large therapeutic molecules to target tissues by means of electroporation. PMID- 25793294 TI - Trends in the diversity, distribution and life history strategy of Arctic Hydrozoa (Cnidaria). AB - This is the first attempt to compile a comprehensive and updated species list for Hydrozoa in the Arctic, encompassing both hydroid and medusa stages and including Siphonophorae. We address the hypothesis that the presence of a pelagic stage (holo- or meroplanktonic) was not necessary to successfully recolonize the Arctic by Hydrozoa after the Last Glacial Maximum. Presence-absence data of Hydrozoa in the Arctic were prepared on the basis of historical and present-day literature. The Arctic was divided into ecoregions. Species were grouped into distributional categories according to their worldwide occurrences. Each species was classified according to life history strategy. The similarity of species composition among regions was calculated with the Bray-Curtis index. Average and variation in taxonomic distinctness were used to measure diversity at the taxonomic level. A total of 268 species were recorded. Arctic-boreal species were the most common and dominated each studied region. Nineteen percent of species were restricted to the Arctic. There was a predominance of benthic species over holo- and meroplanktonic species. Arctic, Arctic-Boreal and Boreal species were mostly benthic, while widely distributed species more frequently possessed a pelagic stage. Our results support hypothesis that the presence of a pelagic stage (holo- or meroplanktonic) was not necessary to successfully recolonize the Arctic. The predominance of benthic Hydrozoa suggests that the Arctic could have been colonised after the Last Glacial Maximum by hydroids rafting on floating substrata or recolonising from glacial refugia. PMID- 25793293 TI - Characteristic and prognostic implication of venous thromboembolism in ovarian clear cell carcinoma: a 12-year retrospective study. AB - PURPOSE: To profile the characteristic and prognostic implications of venous thromboembolism (VTE) in Chinese ovarian clear cell carcinoma (CCC) patients. METHODS: We identified all of the cases between 2000 and 2012 by searching our institutional Ovarian CCC Database. A comprehensive review of the medical documentation was performed to collect relevant data. Kaplan-Meier models and Cox regression were employed for survival analysis. RESULTS: Of the 227 patients, 33 (14.5%) experienced VTE events. There was no significant difference between VTE and non-VTE group patients regarding age, serum cancer antigen 125 or tumor size. The optimal cytoreduction rate was higher in patients without VTE (70.1%) than in those with VTE (51.5%). VTE events were more likely to occur at presentation (36.4%) and recurrence (33.3%), followed by an adjuvant chemotherapy period (18.2%). VTE was more common in patients with advanced-stage disease than those with early-stage disease (P=0.003), whereas pulmonary embolism (PE) was 10-fold as common in advanced-stage disease as in early-stage disease (8.6% vs. 0.8%, P = 0.012). Patients with advanced disease tended to have thrombi in the proximal veins. Two patients died of PE, as confirmed by autopsy. Patients with VTE had reduced survival compared to those without VTE (median overall survival 54 vs. 140 months, P<0.001; median progression-free survival 17 vs. 43 months, P<0.001). CONCLUSIONS: Overall, 14.5% of the patients with ovarian CCC experienced VTE, mainly before their cancer diagnosis or at a time of recurrence. VTE adversely impacted patient survival. PMID- 25793297 TI - Correction: Intrinsically disordered and pliable starmaker-like protein from medaka (Oryzias latipes) controls the formation of calcium carbonate crystals. PMID- 25793296 TI - The use of a pocket-sized ultrasound device improves physical examination: results of an in- and outpatient cohort study. AB - BACKGROUND: The performance of pocket mobile ultrasound devices (PUDs) is comparable with that of standard ultrasonography, whereas the accuracy of a physical examination is often poor requiring further tests to assess diagnostic hypotheses. Adding the use of PUD to physical examination could lead to an incremental benefit. AIM: We assessed whether the use of PUD in the context of physical examination can reduce the prescription of additional tests when used by physicians in different clinical settings. METHODS: We conducted a cohort impact study in four hospital medical wards, one gastroenterological outpatient clinic, and 90 general practices in the same geographical area. The study involved 135 physicians who used PUD, after a short predefined training course, to examine 1962 consecutive patients with one of 10 diagnostic hypotheses: ascites, pleural effusion, pericardial effusion, urinary retention, urinary stones, gallstones, biliary-duct dilation, splenomegaly, abdominal mass, abdominal aortic aneurysm. According to the physicians' judgment, PUD examination could rule out or in the diagnostic hypothesis or require further testing; the concordance with the final diagnosis was assessed. The main outcome was the proportion of cases in which additional tests were required after PUD. The PUD diagnostic accuracy was assessed in patients submitted to further testing. FINDINGS: The 1962 patients included 37% in-patients, 26% gastroenterology outpatients, 37% from general practices. Further testing after PUD examination was deemed unnecessary in 63%. Only 5% of patients with negative PUD not referred for further testing were classified false negatives with respect to the final diagnosis. In patients undergoing further tests, the sensitivity was 91%, and the specificity 83%. CONCLUSIONS: After a simple and short training course, a PUD examination can be used in addition to a physical examination to improve the answer to ten common clinical questions concerning in- and outpatients, and can reduce the need for further testing. PMID- 25793295 TI - The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model. AB - Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20MUg/kg/day) or high (200MUg/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress. PMID- 25793298 TI - Injury hospitalizations due to unintentional falls among the Aboriginal population of British Columbia, Canada: incidence, changes over time, and ecological analysis of risk markers, 1991-2010. AB - BACKGROUND: Aboriginal people in British Columbia (BC) have higher injury incidence than the general population. Our project describes variability among injury categories, time periods, and geographic, demographic and socio-economic groups. This report focuses on unintentional falls. METHODS: We used BC's universal health care insurance plan as a population registry, linked to hospital separation and vital statistics databases. We identified Aboriginal people by insurance premium group and birth and death record notations. We identified residents of specific Aboriginal communities by postal code. We calculated crude incidence and Standardized Relative Risk (SRR) of hospitalization for unintentional fall injury, standardized for age, gender and Health Service Delivery Area (HSDA), relative to the total population of BC. We tested hypothesized associations of geographic, socio-economic, and employment-related characteristics with community SRR of injury by linear regression. RESULTS: During 1991 through 2010, the crude rate of hospitalization for unintentional fall injury in BC was 33.6 per 10,000 person-years. The Aboriginal rate was 49.9 per 10,000 and SRR was 1.89 (95% confidence interval 1.85-1.94). Among those living on reserves SRR was 2.00 (95% CI 1.93-2.07). Northern and non-urban HSDAs had higher SRRs, within both total and Aboriginal populations. In every age and gender category, the HSDA-standardized SRR was higher among the Aboriginal than among the total population. Between 1991 and 2010, crude rates and SRRs declined substantially, but proportionally more among the Aboriginal population, so the gap between the Aboriginal and total population is narrowing, particularly among females and older adults. These community characteristics were associated with higher risk: lower income, lower educational level, worse housing conditions, and more hazardous types of employment. CONCLUSIONS: Over the years, as socio economic conditions improve, risk of hospitalization due to unintentional fall injury has declined among the Aboriginal population. Women and older adults have benefited more. PMID- 25793300 TI - Capacitive and oxidant generating properties of black-colored TiO2 nanotube array fabricated by electrochemical self-doping. AB - Recently, black-colored TiO2 NTA (denoted as black TiO2 NTA) fabricated by self doping of TiO2 NTA with the amorphous phase led to significant success as a visible-light-active photocatalyst. This enhanced photocatalytic activity is largely attributed to a higher charge carrier density as an effect of electrochemical self-doping resulting in a higher optical absorbance and lower transport resistance. Nevertheless, the potential of black TiO2 NTA for other electrochemical applications, such as a supercapacitor and an oxidant-generating anode, has not been fully investigated. Here, we report the capacitive and oxidant generating properties of black TiO2 NTA. The black TiO2 NTA exhibited significantly a high value for areal capacitance with a good rate capability and novel electrocatalytic activity in generating (*)OHs and Cl2 compared to pristine TiO2 NTA with the anatase phase. This study suggests that the black TiO2 NTA be applied as a supercapacitor and an oxidant generating anode. PMID- 25793299 TI - Impact of intratumoral expression levels of fluoropyrimidine-metabolizing enzymes on treatment outcomes of adjuvant S-1 therapy in gastric cancer. AB - We analyzed the expression levels of fluoropyrimidine-metabolizing enzymes (thymidylate synthase [TS], dihydropyrimidine dehydrogenase [DPD], thymidine phosphorylase [TP] and orotate phosphoribosyltransferase [OPRT]) to identify potential biomarkers related to treatment outcomes in gastric cancer (GC) patients receiving adjuvant S-1 chemotherapy. In this study, 184 patients who received curative gastrectomy (D2 lymph node dissection) and adjuvant S-1 were included. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction were performed to measure the protein and mRNA levels of TS, DPD, TP, and OPRT in tumor tissue. In univariate analysis, low intratumoral DPD protein expression was related to poorer 5-year disease-free survival (DFS; 78% vs. 88%; P = 0.068). Low intratumoral DPD mRNA expression (1st [lowest] quartile) was also related to poorer DFS (69% vs. 90%; P < 0.001) compared to high intratumoral DPD expression (2nd to 4th quartiles). In multivariate analyses, low intratumoral DPD protein or mRNA expression was related to worse DFS (P < 0.05), irrespective of other clinical variables. TS, TP, and OPRT expression levels were not related to treatment outcomes. Severe non-hematologic toxicities (grade >= 3) had a trend towards more frequent development in patients with low intratumoral DPD mRNA expression (29% vs. 16%; P = 0.068). In conclusion, GC patients with high intratumoral DPD expression did not have inferior outcome following adjuvant S-1 therapy compared with those with low DPD expression. Instead, low intratumoral DPD expression was related to poor DFS. PMID- 25793301 TI - Evaluation of the stability of concentrated emulsions for lemon beverages using sequential experimental designs. AB - The study of the stability of concentrated oil-in-water emulsions is imperative to provide a scientific approach for an important problem in the beverage industry, contributing to abolish the empiricism still present nowadays. The use of these emulsions would directly imply a reduction of transportation costs between production and the sales points, where dilution takes place. The goal of this research was to evaluate the influence of the main components of a lemon emulsion on its stability, aiming to maximize the concentration of oil in the beverage and to correlate its physicochemical characteristics to product stability, allowing an increase of shelf life of the final product. For this purpose, analyses of surface and interface tension, electrokinetic potential, particle size and rheological properties of the emulsions were conducted. A 2(4 1) fractional factorial design was performed with the following variables: lemon oil/water ratio (30% to 50%), starch and Arabic gum concentrations (0% to 30%) and dioctyl sodium sulfosuccinate (0 mg/L to 100 mg/L), including an evaluation of the responses at the central conditions of each variable. Sequentially, a full design was prepared to evaluate the two most influential variables obtained in the first plan, in which concentration of starch and gum ranged from 0% to 20%, while concentration of lemon oil/water ratio was fixed at 50%, without dioctyl sodium sulfosuccinate. Concentrated emulsions with stability superior to 15 days were obtained with either starch or Arabic gum and 50% lemon oil. The most stable formulations presented viscosity over 100 cP and ratio between the surface tension of the emulsion and the mucilage of over 1. These two answers were selected, since they better represent the behavior of emulsions in terms of stability and could be used as tools for an initial selection of the most promising formulations. PMID- 25793302 TI - Anticipation and choice heuristics in the dynamic consumption of pain relief. AB - Humans frequently need to allocate resources across multiple time-steps. Economic theory proposes that subjects do so according to a stable set of intertemporal preferences, but the computational demands of such decisions encourage the use of formally less competent heuristics. Few empirical studies have examined dynamic resource allocation decisions systematically. Here we conducted an experiment involving the dynamic consumption over approximately 15 minutes of a limited budget of relief from moderately painful stimuli. We had previously elicited the participants' time preferences for the same painful stimuli in one-off choices, allowing us to assess self-consistency. Participants exhibited three characteristic behaviors: saving relief until the end, spreading relief across time, and early spending, of which the last was markedly less prominent. The likelihood that behavior was heuristic rather than normative is suggested by the weak correspondence between one-off and dynamic choices. We show that the consumption choices are consistent with a combination of simple heuristics involving early-spending, spreading or saving of relief until the end, with subjects predominantly exhibiting the last two. PMID- 25793305 TI - Correction: Allelic richness following population founding events--a stochastic modeling framework incorporating gene flow and genetic drift. PMID- 25793304 TI - Identification of active retinaldehyde dehydrogenase isoforms in the postnatal human eye. AB - BACKGROUND/OBJECTIVES: Retinaldehyde dehydrogenase 2 (RALDH2) has been implicated in regulating all-trans-retinoic acid (atRA) synthesis in response to visual signals in animal models of myopia. To explore the potential role of retinaldehyde dehydrogenase (RALDH) enzymes and atRA in human postnatal ocular growth, RALDH activity, along with the distribution of RALDH1, RALDH2, and RALDH3 in the postnatal eye was determined. METHODOLOGY: Retina, retinal pigment epithelium (RPE), choroid, and sclera were isolated from donor human eyes. RALDH catalytic activity was measured in tissue homogenates using an in vitro atRA synthesis assay together with HPLC quantification of synthesized atRA. Homogenates were compared by western blotting for RALDH1, RALDH2, and RALDH3 protein. Immunohistochemistry was used to determine RALDH1 and RALDH2 localization in posterior fundal layers of the human eye. PRINCIPAL FINDINGS: In the postnatal human eye, RALDH catalytic activity was detected in the choroid (6.84 +/- 1.20 pmol/hr/ug), RPE (5.46 +/- 1.18 pmol/hr/ug), and retina (4.21 +/- 1.55 pmol/hr/ug), indicating the presence of active RALDH enzymes in these tissues. RALDH2 was most abundant in the choroid and RPE, in moderate abundance in the retina, and in relatively low abundance in sclera. RALDH1 was most abundant in the choroid, in moderate abundance in the sclera, and substantially reduced in the retina and RPE. RALDH3 was undetectable in human ocular fundal tissues. In the choroid, RALDH1 and RALDH2 localized to slender cells in the stroma, some of which were closely associated with blood vessels. CONCLUSIONS/SIGNIFICANCE: Results of this study demonstrated that: 1) Catalytically active RALDH is present in postnatal human retina, RPE, and choroid, 2) RALDH1 and RALDH2 isoforms are present in these ocular tissues, and 3) RALDH1 and RALDH2 are relatively abundant in the choroid and/or RPE. Taken together, these results suggest that RALDH1 and 2 may play a role in the regulation of postnatal ocular growth in humans through the synthesis of atRA. PMID- 25793303 TI - Microvesicles derived from human umbilical cord mesenchymal stem cells facilitate tubular epithelial cell dedifferentiation and growth via hepatocyte growth factor induction. AB - During acute kidney injury (AKI), tubular cell dedifferentiation initiates cell regeneration; hepatocyte growth factor (HGF) is involved in modulating cell dedifferentiation. Mesenchymal stem cell (MSC)-derived microvesicles (MVs) deliver RNA into injured tubular cells and alter their gene expression, thus regenerating these cells. We boldly speculated that MVs might induce HGF synthesis via RNA transfer, thereby facilitating tubular cell dedifferentiation and regeneration. In a rat model of unilateral AKI, the administration of MVs promoted kidney recovery. One of the mechanisms of action is the acceleration of tubular cell dedifferentiation and growth. Both in vivo and in vitro, rat HGF expression in damaged rat tubular cells was greatly enhanced by MV treatment. In addition, human HGF mRNA present in MVs was delivered into rat tubular cells and translated into the HGF protein as another mechanism of HGF induction. RNase treatment abrogated all MV effects. In the in vitro experimental setting, the conditioned medium of MV-treated injured tubular cells, which contains a higher concentration of HGF, strongly stimulated cell dedifferentiation and growth, as well as Erk1/2 signaling activation. Intriguingly, these effects were completely abrogated by either c-Met inhibitor or MEK inhibitor, suggesting that HGF induction is a crucial contributor to the acceleration of cell dedifferentiation and growth. All these findings indicate that MV-induced HGF synthesis in damaged tubular cells via RNA transfer facilitates cell dedifferentiation and growth, which are important regenerative mechanisms. PMID- 25793306 TI - The molecular composition of dissolved organic matter in forest soils as a function of pH and temperature. AB - We examined the molecular composition of forest soil water during three different seasons at three different sites, using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS). We examined oxic soils and tested the hypothesis that pH and season correlate with the molecular composition of dissolved organic matter (DOM). We used molecular formulae and their relative intensity from ESI-FT-ICR-MS for statistical analysis. Applying unconstrained and constrained ordination methods, we observed that pH, dissolved organic carbon (DOC) concentration and season were the main factors correlating with DOM molecular composition. This result is consistent with a previous study where pH was a main driver of the molecular differences between DOM from oxic rivers and anoxic bog systems in the Yenisei River catchment. At a higher pH, the molecular formulae had a lower degree of unsaturation and oxygenation, lower molecular size and a higher abundance of nitrogen-containing compounds. These characteristics suggest a higher abundance of tannin connected to lower pH that possibly inhibited biological decomposition. Higher biological activity at a higher pH might also be related to the higher abundance of nitrogen-containing compounds. Comparing the seasons, we observed a decrease in unsaturation, molecular diversity and the number of nitrogen-containing compounds in the course of the year from March to November. Temperature possibly inhibited biological degradation during winter, which could cause the accumulation of a more diverse compound spectrum until the temperature increased again. Our findings suggest that the molecular composition of DOM in soil pore waters is dynamic and a function of ecosystem activity, pH and temperature. PMID- 25793307 TI - Assessment of the hemispheric lateralization of grapheme-color synesthesia with Stroop-type tests. AB - Grapheme-color synesthesia, the idiosyncratic, arbitrary association of colors to letters or numbers, develops in childhood once reading is mastered. Because language processing is strongly left-lateralized in most individuals, we hypothesized that grapheme-color synesthesia could be left-lateralized as well. We used synesthetic versions of the Stroop test with colored letters and numbers presented either in the right or the left visual field of thirty-four synesthetes. Interference by synesthetic colors was stronger for stimuli in the right hemifield (first experiment, color naming task). Synesthetes were also faster in the right hemifield when naming the synesthetic color of graphemes (second experiment). Overall, the lateralization effect was 7 ms (the 95% confidence interval was [1.5 12] ms), a delay compatible with an additional callosal transfer for stimuli presented in the left hemifield. Though weak, this effect suggests that the association of synesthetic colors to graphemes may be preferentially processed in the left hemisphere. We speculate that this left lateralization could be a landmark of synesthetic grapheme-color associations, if not found for color associations learnt by non-synesthete adults. PMID- 25793308 TI - 4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone is a Biologically Active Precursor for the Generation of 2-(omega-Carboxyethyl)pyrrole (CEP) Derivatives of Proteins and Ethanolamine Phospholipids. AB - 2-(omega-Carboxyethyl)pyrrole (CEP) derivatives of proteins were previously shown to have significant pathological and physiological relevance to age-related macular degeneration, cancer and wound healing. Previously, we showed that CEPs are generated in the reaction of epsilon-amino groups of protein lysyl residues with 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphatidylcholine (HOHA-PC), a lipid oxidation product uniquely generated by oxidative truncation of docosahexanenate-containing phosphatidylcholine. More recently, we found that HOHA-PC rapidly releases HOHA-lactone and 2-lyso-PC (t1/2 = 30 min at 37 degrees C) by nonenzymatic transesterification/deacylation. Now we report that HOHA lactone reacts with Ac-Gly-Lys-OMe or human serum albumin to form CEP derivatives in vitro. Incubation of human red blood cell ghosts with HOHA-lactone generates CEP derivatives of membrane proteins and ethanolamine phospholipids. Quantitative analysis of the products generated in the reaction HOHA-PC with Ac-Gly-Lys-OMe showed that HOHA-PC mainly forms CEP-dipeptide that is not esterified to 2 lysophosphatidycholine. Thus, the HOHA-lactone pathway predominates over the direct reaction of HOHA-PC to produce the CEP-PC-dipeptide derivative. Myleoperoxidase/H2O2/NO2(-) promoted in vitro oxidation of either 1-palmityl-2 docosahexaneoyl-sn-glycero-3-phosphatidylcholine (DHA-PC) or docosahexaenoic acid (DHA) generates HOHA-lactone in yields of 0.45% and 0.78%, respectively. Lipid oxidation in human red blood cell ghosts also releases HOHA-lactone. Oxidative injury of ARPE-19 human retinal pigmented epithelial cells by exposure to H2O2 generated CEP derivatives. Treatment of ARPE-19 cells with HOHA-lactone generated CEP-modified proteins. Low (submicromolar), but not high, concentrations of HOHA lactone promote increased vascular endothelial growth factor (VEGF) secretion by ARPE-19 cells. Therefore, HOHA-lactone not only serves as an intermediate for the generation of CEPs but also is a biologically active oxidative truncation product from docosahexaenoate lipids. PMID- 25793309 TI - Improved Biofilm Antimicrobial Activity of Polyethylene Glycol Conjugated Tobramycin Compared to Tobramycin in Pseudomonas aeruginosa Biofilms. AB - The objective of this study was to develop a functionally enhanced antibiotic that would improve the therapeutic activity against bacterial biofilms. Tobramycin was chemically conjugated with polyethylene glycol (PEG) via site specific conjugation to form PEGylated-tobramycin (Tob-PEG). The antibacterial efficacy of Tob-PEG, as compared to tobramycin, was assessed on the planktonic phase and biofilms phase of Pseudomonas aeruginosa. The minimum inhibitory concentration (MIC80) of Tob-PEG was higher (13.9 MUmol/L) than that of tobramycin (1.4 MUmol/L) in the planktonic phases. In contrast, the Tob-PEG was approximately 3.2-fold more effective in eliminating bacterial biofilms than tobramycin. Specifically, Tob-PEG had a MIC80 lower than those exhibited by tobramycin (27.8 MUmol/L vs 89.8 MUmol/L). Both confocal laser scanning microscopy and scanning electron microscopy further confirmed these data. Thus, modification of antimicrobials by PEGylation appears to be a promising approach for overcoming the bacterial resistance in the established biofilms of Pseudomonas aeruginosa. PMID- 25793310 TI - Measurements of single nucleotide electronic states as nanoelectronic fingerprints for identification of DNA nucleobases, their protonated and unprotonated states, isomers, and tautomers. AB - Several nanoelectronic techniques have been explored to distinguish the sequence of nucleic acids in DNA macromolecules. Identification of unique electronic signatures using nanopore conductance, tunneling spectroscopy, or other nanoelectronic techniques depends on electronic states of the DNA nucleotides. While several experimental and computational studies have focused on interaction of nucleobases with different substrates, the effect of nucleic acid biochemistry on its electronic properties has been largely unexplored. Here, we present correlated measurements of frontier molecular orbitals and higher-order electronic states for four DNA nucleobases (adenine, cytosine, thymine, and guanine), and first-principle quantum chemical density functional theoretical (DFT) computations. Using different pH conditions in our experiments, we show that small changes in the biochemical state of these nucleic acids strongly affect the intrinsic electronic structure, measured using scanning tunneling spectroscopy (STS). In our experimental measurements and computations, significant differences were observed between the position of frontier orbitals and higher-energy states between protonated and unprotonated nucleic acids, isomers, and different keto-enol tautomer's formed in these nucleotides, leading to their facile identification. Furthermore, we show unique "electronic fingerprints" for all nucleotides (A, G, T, C) using STS, with most distinct states identified at acidic pH. These results can have important implications for identification of nucleic acid sequences in DNA molecules using a high-throughput nanoelectronic identification technique. PMID- 25793311 TI - Application of C4d Immunohistochemistry on Routinely Processed Tissue Sections for the Diagnosis of Autoimmune Bullous Dermatoses. AB - The diagnosis of autoimmune bullous dermatoses relies greatly on direct immunofluorescence (DIF) examination performed on frozen tissue sections, showing deposits of immunoglobulins and/or C3 on specific cutaneous structures. However, frozen material is not always available for DIF; therefore, alternative techniques are needed in the diagnostic procedure. We therefore tested the usefulness of C4d immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections for the diagnosis of bullous pemphigoid (BP) and pemphigus (P). A retrospective immunohistochemical study was performed on biopsies of BP (n: 29) and P (n: 22, including 19 Pemphigus vulgaris and 3 paraneoplastic), submitted for routine histological examination and compared with DIF on the corresponding frozen sections. Twenty-five BP biopsies (86.2%) showed C4d deposits seen as a linear labeling along the dermal-epidermal junction and on the membrane of basal keratinocytes. Seventeen P biopsies (77.2%) showed C4d deposits in a classical "intercellular" pattern, predominating on the lower epidermal layers. The sensitivity, specificity, positive predictive value, and negative predictive value reached 86%, 98%, 96%, and 92% in BP, respectively and 77%, 98%, 94%, and 92% in P, respectively. Furthermore, in the cases where serological tests were available, the sensitivity of C4d detection was higher than that of enzyme-linked immunosorbent assay/indirect immunofluorescence in both BP (87% vs. 67%) and P (82% vs. 54.5%). We conclude that DIF on frozen sections still remains the gold standard for the immunopathological diagnosis of BP and P; however, in the absence of frozen material, C4d immunohistochemistry performed on routinely processed biopsy material can be of considerable help in confirming the diagnosis. PMID- 25793312 TI - Sleepiness and Motor Vehicle Crashes in a Representative Sample of Portuguese Drivers: The Importance of Epidemiological Representative Surveys. AB - OBJECTIVE: Sleepiness is considered to be a leading cause of crashes. Despite the huge amount of information collected in questionnaire studies, only some are based on representative samples of the population. Specifics of the populations studied hinder the generalization of these previous findings. For the Portuguese population, data from sleep-related car crashes/near misses and sleepiness while driving are missing. The objective of this study is to determine the prevalence of near-miss and nonfatal motor vehicle crashes related to sleepiness in a representative sample of Portuguese drivers. METHODS: Structured phone interviews regarding sleepiness and sleep-related crashes and near misses, driving habits, demographic data, and sleep quality were conducted using the Pittsburgh Sleep Quality Index and sleep apnea risk using the Berlin questionnaire. A multivariate regression analysis was used to determine the associations with sleepy driving (feeling sleepy or falling asleep while driving) and sleep-related near misses and crashes. RESULTS: Nine hundred subjects, representing the Portuguese population of drivers, were included; 3.1% acknowledged falling asleep while driving during the previous year and 0.67% recalled sleepiness-related crashes. Higher education, driving more than 15,000 km/year, driving more frequently between 12:00 a.m. and 6 a.m., fewer years of having a driver's license, less total sleep time per night, and higher scores on the Epworth Sleepiness Scale (ESS) were all independently associated with sleepy driving. Sleepiness-related crashes and near misses were associated only with falling asleep at the wheel in the previous year. Sleep-related crashes occurred more frequently in drivers who had also had sleep-related near misses. CONCLUSION: Portugal has lower self reported sleepiness at the wheel and sleep-related near misses than most other countries where epidemiological data are available. Different population characteristics and cultural, social, and road safety specificities may be involved in these discrepancies. Despite this, Portuguese drivers report sleep related crashes in frequencies similar to those of drivers in other countries. PMID- 25793313 TI - Energy pooling upconversion in organic molecular systems. AB - A combination of molecular quantum electrodynamics, perturbation theory, and ab initio calculations was used to create a computational methodology capable of estimating the rate of three-body singlet upconversion in organic molecular assemblies. The approach was applied to quantify the conditions under which such relaxation rates, known as energy pooling, become meaningful for two test systems, stilbene-fluorescein and hexabenzocoronene-oligothiophene. Both exhibit low intramolecular conversion, but intermolecular configurations exist in which pooling efficiency is at least 90% when placed in competition with more conventional relaxation pathways. For stilbene-fluorescein, the results are consistent with data generated in an earlier experimental investigation. Exercising these model systems facilitated the development of a set of design rules for the optimization of energy pooling. PMID- 25793314 TI - Structural basis for the neutralization of hepatitis E virus by a cross-genotype antibody. AB - Hepatitis E virus (HEV), a non-enveloped, positive-sense, single-stranded RNA virus, is a major cause of enteric hepatitis. Classified into the family Hepeviridae, HEV comprises four genotypes (genotypes 1-4), which belong to a single serotype. We describe a monoclonal antibody (mAb), 8G12, which equally recognizes all four genotypes of HEV, with ~ 2.53-3.45 nM binding affinity. The mAb 8G12 has a protective, neutralizing capacity, which can significantly block virus infection in host cells. Animal studies with genotypes 1, 3 and 4 confirmed the cross-genotype neutralizing capacity of 8G12 and its effective prevention of hepatitis E disease. The complex crystal structures of 8G12 with the HEV E2s domain (the most protruded region of the virus capsid) of the abundant genotypes 1 and 4 were determined at 4.0 and 2.3 A resolution, respectively. These structures revealed that 8G12 recognizes both genotypes through the epitopes in the E2s dimerization region. Structure-based mutagenesis and cell-model assays with virus-like particles identified several conserved residues (Glu549, Lys554 and Gly591) that are essential for 8G12 neutralization. Moreover, the epitope of 8G12 is identified as a key epitope involved in virus-host interactions. These findings will help develop a common strategy for the prevention of the most abundant form of HEV infection. PMID- 25793316 TI - The Impact of Red Light Cameras on Crashes Within Miami-Dade County, Florida. AB - OBJECTIVE: To determine the safety effect of red light camera (RLC) programs, this study attempted to estimate its impact on collisions within Miami-Dade County, Florida Methods: A before-after evaluation using a comparison group along with traffic control correction was employed. Twenty signalized intersections with RLCs that began enforcement on January 1, 2011, were matched to 2 comparison sites located at least 2 miles from camera sites to minimize spillover effect. An empirical Bayes analysis was used to account for potential regression to the mean effects. An index of effectiveness along with 95% confidence intervals were calculated based on the comparison between the estimated and actual number of crashes in the after period. RESULTS: During the first year, RLC sites experienced a marginal decrease in right angle/turn collisions (-3%), a significant increase in rear-end collisions (+40%), and significant decreases in all injury (-19%) and RLR-related injury collisions (-24%). An increase in right angle/turning (+14%) and rear-end (+51%) collisions at the RLC sites was observed after 2 years despite camera enforcement. A significant reduction in RLR-related injury crashes (-17%), however, was still observed after 2 years. A nonsignificant decline in all injury collisions (-12%) was also noted. CONCLUSIONS: RLCs showed a benefit in reducing RLR-related injury collisions at camera sites after enforcement commenced, yet its tradeoff was a large increase in rear-end collisions. There was inconclusive evidence whether RLCs affected right angle/turning and all injury collisions. Statutory changes in crash reporting during the second year of camera enforcement affected the incidence of right angle and rear-end collisions; nevertheless, a "novelty effect" could not be ruled out. Future research should consider events such as low frequencies of severe injury/fatal collisions and changes in crash reporting requirements when conducting RLC analyses. PMID- 25793315 TI - cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. AB - Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions. PMID- 25793317 TI - Betray my trust, shame on me: Shame, dissociation, fear, and betrayal trauma. AB - Recent research suggests that betrayal is a fundamental dimension of trauma that may be a major factor contributing to posttraumatic distress (Freyd & Birrell, 2013). In the current study using a college student sample of female trauma survivors, (N = 124; 79% Caucasian; mean age = 20.40, SD = 3.60), we examined the contribution of high- and low-betrayal trauma history to shame, dissociation, and fear responses to threat. We hypothesized that (a) overall, shame and dissociation would be higher following interpersonal compared with noninterpersonal threat; (b) high- but not low-betrayal trauma history would predict increased shame and dissociation following interpersonal threat; and (c) low- but not high-betrayal trauma history would predict increased fear following noninterpersonal threat. Hypothesis 1 was not supported. There was no difference in overall shame and dissociation following interpersonal compared with noninterpersonal threat. Hypotheses 2 and 3 were supported. History of high- but not low-betrayal trauma predicted increases in shame (R2 = .14) and dissociation (R2 = .23) following interpersonal threat, whereas history of low- but not high betrayal trauma predicted increases in fear (R2 = .07) following noninterpersonal threat. These results contribute to growing evidence that perpetrator closeness matters when considering posttraumatic responses. Shame and dissociation warrant more clinical attention as possible barriers to effective exposure therapy among betrayal trauma survivors. PMID- 25793319 TI - Traumatic events and trauma-related psychopathology in former drug cartel soldiers in Rio de Janeiro: A pilot study. AB - This pilot study investigated the occurrence of traumatic events and trauma related psychopathology in former drug cartel soldiers (FDCS) in Rio de Janeiro. Furthermore, the authors examined the relationship between the number of traumatic events and symptom severity, and compared symptom severity in perpetrators versus victims of traumatic events. They found high exposure rates to traumatic events, with 83.5% of the FDCS (n = 97) and 57.9% of the controls (n = 95) having experienced more than 5 events. FDCS had higher mean scores for trauma exposure, posttraumatic stress (PTS), depressive symptoms, and general mental health problems, compared to controls. More FDCS than controls satisfied DSM-IV symptom criteria for posttraumatic stress disorder (36.4% vs. 15.8%) and reported severe depressive symptoms (25.8% vs. 8.3%). The number of traumatic events was strongly related to PTS among FDCS (r = .48). Furthermore, more FDCS than controls (23.7% vs. 10.5%) identified themselves as a perpetrator of 1 or more traumatic events. Among FDCS, perpetrators reported more PTS than victims. It is concluded that being a (former) drug cartel soldier is associated with elevated trauma exposure and severe trauma-related psychopathology. PMID- 25793318 TI - Evaluating the dimensionality of PTSD in a sample of OIF/OEF veterans. AB - Both categorical and dimensional models of mental disorders, including posttraumatic stress disorder (PTSD), are useful for diagnostic and heuristic purposes; however, few empirical studies have compared categorical and dimensional models of PTSD side-by-side or compared these models to a hybrid (dimensional and categorical) model. In the present study, the dimensionality of PTSD was examined by fitting latent profile analytic, confirmatory factor analytic, and factor mixture models in 271 Operation Iraqi Freedom/Operation Enduring Freedom veterans 6 months after return from deployment. Latent profile analysis was used to identify subgroups of individuals with similar PTSD symptom profiles and predictors of subgroup membership, confirmatory factor analysis was used to identify the underlying continuous structure of PTSD in this sample, and factor mixture modeling was used to test whether a hybrid categorical and continuous model of PTSD best fit our sample. A factor mixture model consisting of a 4-factor dysphoria model of PTSD with 2 classes characterized by low and moderate symptom severity was the best-fitting model. Dissociation and deployment concerns emerged as significant predictors of membership in the moderate symptoms class. Implications for PTSD diagnostic conceptualization and treatment planning are discussed. PMID- 25793322 TI - Enzyme-catalysed deposition of ultrathin silver shells on gold nanorods: a universal and highly efficient signal amplification strategy for translating immunoassay into a litmus-type test. AB - On the basis of enzyme-catalysed reduction of silver ions and consequent deposition of ultrathin silver shells on gold nanorods, a highly efficient signal amplification method for immunoassay is developed. For a model analyte prostate specific antigen, a 10(4)-fold improvement over conventional enzyme-linked immunosorbent assay is accomplished by leveraging on the cumulative nature of the enzymatic reaction and the sensitive response of plasnomic gold nanorods to the deposition the silver shells. PMID- 25793320 TI - Association of parental status and diagnosis of posttraumatic stress disorder among veterans of Operations Iraqi and Enduring Freedom. AB - Research indicates that concerns about disruption of family relationships during military service may be associated with greater posttraumatic stress symptomatology. The current study sought to extend previous findings by examining the relative odds of a posttraumatic stress disorder (PTSD) diagnosis among Operations Enduring and Iraqi Freedom (OEF/OIF) veterans with dependent children versus veterans without dependent children. Administrative databases were queried to identify 36,334 OEF/OIF veterans with dependent children seeking care in the Veterans Health Administration (VA) during fiscal years 2006-2009. These veterans were matched 1:1 on age, gender, and demobilization date to veterans without dependent children (N = 72,668). In unconditional analyses, OEF/OIF veterans with dependent children versus those without were significantly more likely to incur a PTSD diagnosis (44% vs. 28%). After controlling for demographic variables, mental health utilization, and other serious mental illness, OEF/OIF veterans with dependent children were about 40% more likely to carry a diagnosis of PTSD. The association was stronger for men than for women. It may be of value for clinicians to consider parental status when assessing and treating veterans with PTSD. In-depth study of OEF/OIF veterans is needed to determine whether disruption of family relationships leads to increased psychological stress or parents are more likely than nonparents to seek VA mental health services for PTSD symptoms. PMID- 25793323 TI - Prevalence of simultaneously measured interarm systolic blood pressure difference and its clinical and demographic predictors: a systemic review and meta-analysis. AB - Prevalence of interarm systolic blood pressure difference and clinical and demographic characteristics associated with interarm systolic blood pressure difference (IASBPD) have been a matter of debate. We aimed to ascertain the prevalence of IASBPD and clinical and demographic characteristics associated with it. We searched PubMed, EMBASE, and CINAHL, Ovid and Cochrane Library, and Google Scholar. Twenty-seven studies meeting all inclusion criteria were included in the analysis. Weighted average cumulative prevalence of simultaneous IASBPD of 10, 15, and 20 mmHg or greater was 9.49% [95% confidence interval (CI) 7.9-11.1%], 5.3% (95% CI 3.1-7.5%), and 4.4% (95% CI 1.5-7.4%), respectively. The prevalence of IASBPD of 10 mmHg was 9% (95% CI 7-11%), 7.5% (95% CI 5.6-9.4%), and 12.1% (95% CI 8.2-16.1%) in outpatient, community, and hospital-based setting, respectively. The prevalence of IASBPD of 15 mmHg was 4.9% (95% CI 2.7-7.2%) in outpatient and 8% in hospital setting. The prevalence of IASBPD of 20 mmHg was 4.4% (95% CI 2.8-11.6%) in outpatient and 4.4% (95% CI 2.1-6.8%) for the hospital setting. Pairwise meta-analysis of five studies showed that the presence or absence of IASBP was not associated with age, sex, diabetes, hypertension, dyslipidemia, and smoking history. However, participants with IASBPD of 10 mmHg or greater had a higher BMI compared with those with IASBPD of less than 10 mmHg. After BMI, hypertension and dyslipidemia had strongest association with IASBPD, but results were not statistically significant. IASBPD is relatively prevalent, but prevalence is lower than that previously reported. Prevalence is higher when blood pressure is measured in hospital setting compared with outpatient and community setting. PMID- 25793324 TI - Inhibition of chronic ulcerative colitis-associated adenocarcinoma development in mice by VSL#3. AB - BACKGROUND: Colorectal cancer is the most severe complication in inflammatory bowel disease. This study aimed to investigate the effects of the probiotic VSL#3 when administered as either preventive or concurrent treatment in the progression from chronic colitis to colon cancer. METHODS: Mice were exposed to 5, 10, and 15 cycles of dextran sulfate sodium (DSS); each cycle consisted of 0.7% DSS for 1 week followed by distilled water for 10 days. VSL#3 was administered either from 2 weeks before the colitis induction or from the first day of the colitis until being killed. After each period, macroscopic and histological studies, as well as analysis of inflammatory and tumor biomarkers, were performed. RESULTS: Prophylactic or concurrent VSL#3 administration attenuated the disease activity index score and colon inflammation after 5, 10, and 15 cycles of DSS, as well as reduced the histological alterations and the incidence of colonic dysplastic lesions at the 3 periods studied. None of the animals receiving VSL#3 as a concurrent treatment developed carcinoma, which is in contrast to 5% and 20% of the mice following preventive VSL#3 administration, developing carcinoma at the 10th and the 15th cycles of DSS, respectively. In addition, the probiotic reduced the proliferating cell nuclear antigen labeling index, tumor necrosis factor alpha, interleukin-1beta, interleukin-6 production, cyclooxygenase-2 expression, and increased interleukin-10 levels in colon tissue at the 3 periods assayed. CONCLUSIONS: VSL#3 administration reduced chronic inflammation and prevented or delayed the development of dysplasia and carcinoma in a mouse model of chronic colitis-associated cancer. PMID- 25793326 TI - High within-day variability of fecal calprotectin levels in patients with active ulcerative colitis: what is the best timing for stool sampling? AB - BACKGROUND: Fecal calprotectin (FC) is considered the best noninvasive way to assess disease activity in ulcerative colitis (UC). However, it is not known which is the more suitable moment for stool sampling in patients with increased stool frequency. The aims of this study were to assess the intraindividual variation of FC within day and to evaluate if the first bowel movement in the morning is the more suitable sample for FC measurement in patients with acute flares of UC. PATIENTS AND METHODS: Patients admitted because of active UC were invited to collect samples from several bowel movements (including the first in the morning) during the same day providing their ordinal chronology. FC was measured by means of a quantitative rapid point-of-care test based on lateral flow assay immunochromatography. RESULTS: Eighteen patients were included for a total of 56 stool samples. Most patients had extensive UC and severe disease activity. Within-day FC values varied widely, and the median coefficient of variation was 40% (5%-114%) with a median range of variation of FC values of 3887 mg/kg (69-9946). The sample from the first stool in the morning obtained the highest individual FC within-day value in 33.3% of cases and the lowest in 38.9%. CONCLUSIONS: FC values widely vary between motions in patients with active UC. Stool sample collection from the first bowel movement in the morning does not ensure the highest or lowest within-day FC value. In patients with overt active UC, a single FC determination should not be used as the basis for therapeutic strategies. PMID- 25793325 TI - Reducing colorectal anastomotic leakage with tissue adhesive in experimental inflammatory bowel disease. AB - BACKGROUND: Anastomotic leakage after gastrointestinal surgery remains a challenging clinical problem. This study aimed to investigate the effectiveness of TissuCol (fibrin glue), Histoacryl Flex (n-butyl-2-cyanoacrylate), and Duraseal (polyethylene glycol) on colorectal anastomotic healing during experimental colitis. METHODS: We first performed colectomy 7 days after 10 mg trinitrobenzene sulfonic acid (TNBS)-induced colitis to validate a rat TNBS colitis-colectomy model. Subsequently, this TNBS-colitis-colectomy model was used in 73 Wistar rats that were stratified into a colitis group (CG, no adhesive), a TissuCol group (TG), a Histoacryl group (HG), and a Duraseal group (DG). Anastomotic sealant was applied with one adhesive after constructing an end-to end hand-sewn anastomosis. Clinical manifestations, anastomotic bursting pressure, and immunohistochemistry of macrophage type-one (M1) and type-two (M2) was performed on postoperative day (POD)3 or POD7. RESULTS: TNBS-caused mucosal and submucosal colon damage and compromised anastomotic healing (i.e., abscess formation and low anastomotic bursting pressure). On POD3, higher severity of abscesses was seen in CG. Average anastomotic bursting pressure was 53.2 +/- 35.5 mm Hg in CG, which was significantly lower than HG (134.4 +/- 27.5 mm Hg) and DG (95.1 +/- 54.3 mm Hg) but not TG (83.4 +/- 46.7 mm Hg). Furthermore, a significantly higher M2/M1 index was found in HG. On POD7, abscesses were only seen in CG (6/9) but not in other groups; HG had the lowest severity of adhesion. CONCLUSIONS: We describe the first surgical IBD model by performing colectomy in rats with TNBS-induced colitis, which causes intra-abdominal abscess formation and compromises anastomotic healing. Anastomotic sealing with Histoacryl Flex prevents these complications in this model. Alternative activation of macrophages seems to be involved in its influence on anastomotic healing. PMID- 25793327 TI - PedsQL gastrointestinal symptoms scales and gastrointestinal worry scales in pediatric patients with inflammatory bowel disease in comparison with healthy controls. AB - BACKGROUND: Patient-reported outcomes are essential in determining the broad impact of inflammatory bowel disease (IBD) and treatments from the patient's perspective. The primary study objectives were to compare the gastrointestinal symptoms and worry of pediatric patients with IBD with matched healthy controls and to compare Crohn's disease and ulcerative colitis with each other using the Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms and Gastrointestinal Worry Scales. METHODS: PedsQL Gastrointestinal Symptoms and Worry Scales were completed in a 9-site study by 256 pediatric patients with IBD and 259 parents of patients (263 families; Crohn's disease [n = 195], ulcerative colitis [n = 68]). Ten Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were administered along with 2 Gastrointestinal Worry Scales. A matched group of 384 healthy children families completed the PedsQL in an Internet survey. RESULTS: PedsQL Gastrointestinal Symptoms and Worry Scales distinguished between pediatric patients with IBD in comparison with healthy controls (P < 0.001), with larger effect sizes for symptoms indicative of IBD, supporting known-groups validity and clinical interpretability including minimal important difference scores. Patients with Crohn's disease or ulcerative colitis did not demonstrate significantly different gastrointestinal symptoms or worry in comparison with each other. CONCLUSIONS: The PedsQL Gastrointestinal Symptoms and Worry Scales may be used as common metrics across pediatric patients with IBD, including Crohn's disease and ulcerative colitis separately to measure gastrointestinal-specific symptoms in clinical research and practice. PMID- 25793329 TI - A light-driven supramolecular nanowire actuator. AB - A single photomechanical supramolecular nanowire actuator with an azobenzene containing 1,3,5-tricarboxamide derivative is developed by employing a direct writing method. Single nanowires display photoinduced reversible bending and the bending behavior follows first-order kinetics associated with azobenzene photoisomerization. A wireless photomechanical nanowire tweezers that remotely manipulates a single micro-particle is also demonstrated. PMID- 25793330 TI - HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales. AB - HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. The core is well-tested, well-documented, and easy to install across computational platforms. The goal of the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program. PMID- 25793331 TI - Frontlines: digging deeper. PMID- 25793328 TI - Harnessing regulatory T cells for the treatment of inflammatory bowel disease. AB - Regulatory CD4 T (Treg) cells are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. The immunoregulatory function of Treg cells is especially important in the intestine where the mucosa is exposed to a diverse array of foreign antigens including those derived from food and commensal bacteria. Treg cells are enriched in the intestinal lamina propria and provide a crucial function in promoting tolerance to enteric antigens while modulating tissue inflammation. Correspondingly, Treg cell dysfunction is associated with a breakdown in intestinal tolerance and the induction of aberrant immune responses that may contribute to the pathogenesis of inflammatory bowel disease. This review will provide a brief overview of Treg cell biology with a focus on Foxp3 Treg and type 1 regulatory (Tr1) cells and summarize the evidence for defective Treg cells in experimental and human inflammatory bowel disease. The potential application of Treg cells as a treatment for inflammatory bowel disease will also be discussed in the context of Treg infusion therapy and the in vivo induction/expansion of intestinal Treg cells. PMID- 25793334 TI - Ten questions with .... PMID- 25793336 TI - Ask George. PMID- 25793337 TI - Mining for answers from big data. PMID- 25793338 TI - Strategies for success in purchasing medical technology. PMID- 25793339 TI - Building a mobile medical app and understanding FDA regulatory requirements. PMID- 25793340 TI - Using athletics to grow stronger on the job. PMID- 25793341 TI - A roundtable discussion: getting to the heart of the PM debate. PMID- 25793342 TI - FAQs about small-bore connectors: understanding the impact for enteral devices. PMID- 25793343 TI - Anatomist executive talks device development. PMID- 25793344 TI - CE team's collaborative efforts help streamline temperature control monitoring. PMID- 25793346 TI - Are you doing shabby work? PMID- 25793347 TI - Psycho-physiological training approach for amputee rehabilitation. AB - Electromyography (EMG) signals are very noisy and difficult to acquire. Conventional techniques involve amplification and filtering through analog circuits, which makes the system very unstable. The surface EMG signals lie in the frequency range of 6Hz to 600Hz, and the dominant range is between the ranges from 20Hz to 150Hz. 1 Our project aimed to analyze an EMG signal effectively over its complete frequency range. To remove these defects, we designed what we think is an easy, effective, and reliable signal processing technique. We did spectrum analysis, so as to perform all the processing such as amplification, filtering, and thresholding on an Arduino Uno board, hence removing the need for analog amplifiers and filtering circuits, which have stability issues. The conversion of time domain to frequency domain of any signal gives a detailed data of the signal set. Our main aim is to use this useful data for an alternative methodology for rehabilitation called a psychophysiological approach to rehabilitation in prosthesis, which can reduce the cost of the myoelectric arm, as well as increase its efficiency. This method allows the user to gain control over their muscle sets in a less stressful environment. Further, we also have described how our approach is viable and can benefit the rehabilitation process. We used our DSP EMG signals to play an online game and showed how this approach can be used in rehabilitation. PMID- 25793348 TI - Let's ID and nurture systems thinkers. PMID- 25793350 TI - Antenna coupling explains unintended thermal injury caused by common operating room monitoring devices. AB - INTRODUCTION: Unintended thermal injury from patient monitoring devices (eg, electrocardiogram pads, neuromonitoring leads) results in third-degree burns. A mechanism for these injuries is not clear. The monopolar "bovie" emits radiofrequency energy that transfers to nearby, nonelectrically active cables or wires without direct contact by capacitive and antenna coupling. The purpose of this study was to determine if, and to what extent, radiofrequency energy couples to common patient monitoring devices. MATERIALS AND METHODS: In an ex vivo porcine model, monopolar radiofrequency energy was delivered to a handheld "bovie" pencil. Nonelectrically active neuromonitoring and cardiac-monitoring leads were placed in proximity to the monopolar pencil and its cord. Temperature changes of tissue touched by the monitoring lead were measured using a thermal camera immediately after a 5-second activation. The energy-device cords were then separated by 15 cm, the power was reduced from 30 W coag to 15 W coag and different cord angulation was tested. An advanced bipolar device, a plasma-based device, and an ultrasonic device were also tested at standard settings. RESULTS: The neuromonitoring lead increased tissue temperature at the insertion site by 39 +/- 13 degrees C (P<0.001) creating visible char at the skin. The electrocardiogram lead raised tissue temperature by 1.3 +/- 0.5 degrees C (P<0.001). Decreasing generator power from 30 W to 15 W and separating the bovie cord from the neuromonitoring cord by 15 cm significantly reduced the temperature change (39 +/- 13 degrees C vs. 26+/-5 degrees C; P<0.001 and 39 +/- 13 degrees C vs. 10 +/- 5 degrees C; P<0.001, respectively). Lastly, monopolar energy increased tissue temperatures significantly more than argon beam energy (34 +/- 15 degrees C), advanced bipolar energy (0.2 +/- 0.4 degrees C), and ultrasonic energy (0 +/- 0.3 degrees C) (all P<0.001). CONCLUSIONS: Stray energy couples to commonly used patient monitoring devices resulting in potentially significant thermal injury. The handheld bovie cord transfers energy via antenna coupling to neuromonitoring leads that can raise tissue temperatures over 100 degrees F (39 degrees C) using standard settings. The most effective ways to decrease this energy coupling is to reduce generator power, increase the separation between wires, or utilize lower voltage energy devices such as ultrasonic or bipolar energy. PMID- 25793351 TI - Pure Laparoscopic Versus Open Liver Resection in Treatment of Hepatolithiasis Within the Left Lobes: A Randomized Trial Study. AB - OBJECTIVE: The application of laparoscopic technology to liver surgery has been developing rapidly, yet very few studies have been conducted to compare the outcomes between open and laparoscopic liver resections. So little is known about their advantages and disadvantages. The aim of this prospective randomized study was to compare the outcomes between laparoscopic and open liver resection in treatment of hepatolithiasis within the left lateral lobes. PATIENTS AND METHODS: Between January 2010 and May 2013, 98 patients with hepatolithiasis within the left lateral lobes diagnosed by preoperative computed tomography and magnetic resonance cholangiopancreatography were randomized into open group and laparoscopic group. Each group had 49 patients. We compared the operation time, the amount of bleeding, the length of their stay in hospital, and complications. RESULTS: Of the laparoscopic group, 2 patients were converted to open surgery. No fatal complication occurred in either the open group or the laparoscopic group. There was no statistically significant difference in the complications between the 2 groups (4.08% vs. 6.12%, P=0.64), but the operating time, the amount of bleeding, and the length of stay in hospital were significantly shorter in the laparoscopic group than in the open group (P<0.05). CONCLUSIONS: Laparoscopic liver resection displays similar safety and feasibility for hepatolithiasis within the left lateral lobes, and they were also similar with respect to the overall complications, but the laparoscopic group has an advantage in the operating time, the amount of bleeding, and the length of their staying in hospital. It is, however, agreed between the authors of this paper that further studies with larger number of patients and longer follow-up observations are necessary to make a definitive conclusion. PMID- 25793352 TI - Laparoscopic Colorectal Surgery in the Emergency Setting: Trends in the Province of Ontario. AB - BACKGROUND: The purpose of this study was to examine the adoption trends of emergency laparoscopic colorectal surgery in the province of Ontario. STUDY DESIGN: We conducted a retrospective time-series analysis examining rates of emergency colorectal surgery among 10.5 million adults in Ontario, Canada from April 1, 2002 to December 31, 2009. We linked administrative claims databases and the Ontario Cancer Registry to assess procedure rates over time. Procedure trends were assessed using time-series analysis. RESULTS: Over the 8-year period, 29,676 emergency colorectal procedures were identified. A total of 2582 (8.7%) were performed laparoscopically and 27,094 (91.3%) were open. Open and laparoscopic patients were similar with respect age, sex, and Charlson Comorbidity Index. The proportion of surgery for benign (63.8% of open cases vs. 65.6% laparoscopic, standardized difference=0.04) and malignant disease (36.2% open vs. 34.4% laparoscopic, standardized difference=0.04) was equal between groups. The percentage of emergency colorectal surgery performed laparoscopically increased from 5.7% in 2002 to 12.0% in 2009 (P<0.01). The use of laparoscopy increased for both benign and malignant disease. Statistically significant upward trends in laparoscopic surgery were seen for inflammatory bowel disease (P<0.01), obstruction (P<0.01), and colon cancer (P<0.01). From 2002 to 2009, annual procedure rates increased at a greater rate in nonacademic centers (P<0.01). CONCLUSIONS: Laparoscopic emergency colorectal surgery has increased significantly between 2002 and 2009 for both benign and malignant disease and for a wide range of diagnoses. This was driven in part by steadily rising usage of laparoscopy in nonacademic centers. PMID- 25793353 TI - Minimally invasive component separation techniques in complex ventral abdominal hernia repair: a systematic review of the literature. AB - PURPOSE: Open component separation (CS) has traditionally been a popular method for management of complex abdominal wall hernias. However, it has been associated with significant wound complications. The aim of this systematic review was to examine the evidence in the literature on modern CS techniques (endoscopic and minimally invasive) for the management of such hernias. METHODS: A systematic literature search was performed (2000 to 2013) using major electronic databases (PUBMED, EMBASE). The outcomes of interest were hernia recurrence rate and wound morbidity. RESULTS: A total of 33 publications were retrieved. Thirteen studies involving in total 220 patients were included in this analysis. No randomised controlled trials were identified. The overall hernia recurrence and wound complication rates appear similar and in some studies superior to the results of open CS. CONCLUSIONS: The initial results of the 2 more recent component separation techniques appear encouraging. However, better quality studies with longer follow-up are needed. PMID- 25793354 TI - Recollection reduces unitised familiarity effect. AB - Two types of encoding tasks have been employed in previous research to investigate the beneficial effect of unitisation on familiarity-based associative recognition (unitised familiarity effect), namely the compound task and the interactive imagery task. Here we show how these two tasks could differentially engage subsequent recollection-based associative recognition and consequently lead to the turn-on or turn-off of the unitised familiarity effect. In the compound task, participants studied unrelated word pairs as newly learned compounds. In the interactive imagery task, participants studied the same word pairs as interactive images. An associative recognition task was used in combination with the Remember/Know procedure to measure recollection-based and familiarity-based associative recognition. The results showed that the unitised familiarity effect was present in the compound task but was absent in the interactive imagery task. A comparison of the compound and the interactive imagery task revealed a dramatic increase in recollection-based associative recognition for the interactive imagery task. These results suggest that unitisation could benefit familiarity-based associative recognition; however, this effect will be eliminated when the memory trace formed is easily accessed by strong recollection without the need for a familiarity assessment. PMID- 25793355 TI - Long-term trends in California mobile source emissions and ambient concentrations of black carbon and organic aerosol. AB - A fuel-based approach is used to assess long-term trends (1970-2010) in mobile source emissions of black carbon (BC) and organic aerosol (OA, including both primary emissions and secondary formation). The main focus of this analysis is the Los Angeles Basin, where a long record of measurements is available to infer trends in ambient concentrations of BC and organic carbon (OC), with OC used here as a proxy for OA. Mobile source emissions and ambient concentrations have decreased similarly, reflecting the importance of on- and off-road engines as sources of BC and OA in urban areas. In 1970, the on-road sector accounted for ~90% of total mobile source emissions of BC and OA (primary + secondary). Over time, as on-road engine emissions have been controlled, the relative importance of off-road sources has grown. By 2010, off-road engines were estimated to account for 37 +/- 20% and 45 +/- 16% of total mobile source contributions to BC and OA, respectively, in the Los Angeles area. This study highlights both the success of efforts to control on-road emission sources, and the importance of considering off-road engine and other VOC source contributions when assessing long-term emission and ambient air quality trends. PMID- 25793358 TI - Rearranging the toes on my baby. PMID- 25793359 TI - A survey of bereaved family members to assess quality of care on a palliative care unit. AB - BACKGROUND: More U.S. hospitals are adopting palliative care programs, prompting inquiry about the relationship of palliative care to patient and family satisfaction. This study compares the impact of palliative care units, palliative care consultation, and usual care on bereaved families' perceptions of care quality. METHODS: Using the Bereaved Family Survey we conducted interviews with family members of patients who died at Mount Sinai Medical Center between March 2012 and March 2013. RESULTS: Of 108 completed surveys, 31 were in the palliative care unit group, 28 in the consultation service group, and 49 in the usual care group. Family members of patients who died on the palliative care unit were more likely to report that their loved one's end-of-life medical care had been "excellent" as compared to family members of patients who received palliative care consultation or usual care (adjusted OR, 2.06; 95% CI, 1.17-3.61). Family members of palliative care unit patients also reported greater satisfaction with emotional support before the patient's death (adjusted OR, 1.71; 95% CI, 1.01 2.90). We found no significant differences between the consultation service and usual care. CONCLUSION: Family members of patients who died while receiving care in a dedicated palliative care unit report higher overall satisfaction and emotional support before death as compared to the consultation service or usual care. PMID- 25793356 TI - Blood Pressure Changes in Relation to Arsenic Exposure in a U.S. Pregnancy Cohort. AB - BACKGROUND: Inorganic arsenic exposure has been related to the risk of increased blood pressure based largely on cross-sectional studies conducted in highly exposed populations. Pregnancy is a period of particular vulnerability to environmental insults. However, little is known about the cardiovascular impacts of arsenic exposure during pregnancy. OBJECTIVES: We evaluated the association between prenatal arsenic exposure and maternal blood pressure over the course of pregnancy in a U.S. METHODS: The New Hampshire Birth Cohort Study is an ongoing prospective cohort study in which > 10% of participant household wells exceed the arsenic maximum contaminant level of 10 MUg/L established by the U.S. EPA. Total urinary arsenic measured at 24-28 weeks gestation was measured and used as a biomarker of exposure during pregnancy in 514 pregnant women, 18-45 years of age, who used a private well in their household. Outcomes were repeated blood pressure measurements (systolic, diastolic, and pulse pressure) recorded during pregnancy. RESULTS: Using linear mixed effects models, we estimated that, on average, each 5 MUg/L increase in urinary arsenic was associated with a 0.15-mmHg (95% CI: 0.02, 0.29; p = 0.022) increase in systolic blood pressure per month and a 0.14-mmHg (95% CI: 0.02, 0.25; p = 0.021) increase in pulse pressure per month over the course of pregnancy. CONCLUSIONS: In our U.S. cohort of pregnant women, arsenic exposure was associated with greater increases in blood pressure over the course of pregnancy. These findings may have important implications because even modest increases in blood pressure impact cardiovascular disease risk. PMID- 25793363 TI - Early Diagnosis of Subclinical Interferon Alpha-Associated Optic Neuropathy Using Fluorescein Angiography. AB - We report a case of a 57-year-old man who presented with decreased visual acuity in the left eye secondary to nonarteritic anterior ischemic optic neuropathy (NAION) while on therapy with interferon-alpha for hepatitis C. Fundus fluorescein angiography revealed late leakage of both optic discs, consistent with bilateral disease. One week later, the patient developed clinical signs and symptoms consistent with NAION in the fellow eye. Fluorescein angiography may play an important role in identifying subclinical NAION in patients taking interferon-alpha. PMID- 25793362 TI - Bladder cancer detection in patients with gross haematuria: Computed tomography urography with enhancement-triggered scan versus flexible cystoscopy. AB - OBJECTIVE: Computed tomography urography (CTU) can be used to direct further investigation of patients if the bladder tumour detection rate is high. The aim of this study was to compare a CTU protocol including an enhancement-triggered scan and flexible cystoscopy for detecting bladder tumours. MATERIALS AND METHODS: Patients with gross haematuria undergoing CTU during 2005-2008 were included. For patients younger than 50 years the CTU protocol included unenhanced, enhancement-triggered corticomedullary, and excretory phases. Patients older than 50 years followed the same protocol plus a nephrographic phase. The entire urinary tract was examined in all phases. RESULTS: Of 435 patients, 55 patients were diagnosed with bladder tumour. CTU detected bladder tumour in 48 patients (87%). Five CTU examination reports were false positive. With CTU, sensitivity for finding bladder tumour was 0.87, specificity 0.99, positive predictive value (PPV) 0.91 and negative predictive value (NPV) 0.98. Cystoscopy detected bladder tumour in 48 patients (87%) and had one false positive finding, resulting in sensitivity of 0.87, specificity 1.0, PPV 0.98 and NPV 0.98. CONCLUSIONS: The detection rate of bladder tumours for the CTU protocol including an enhancement-triggered scan was high and comparable to flexible cystoscopy. Hence, this protocol could be used to assess the bladder as the primary investigation and direct further investigation of the patient. PMID- 25793364 TI - Can immune thrombocytopenia be cured with medical therapy? AB - Primary immune thrombocytopenia (ITP) in adults often assumes a chronic course that requires persistent monitoring and treatment. Medical therapy has traditionally been viewed as a means of temporarily raising the platelet count with little or no potential to induce long-term platelet responses off treatment. However, several recent studies have tested the hypothesis that intensive medical therapy administered early in the disease course may ameliorate or even cure ITP. In this review, we propose a biological rationale for medical intervention that simultaneously targets the innate and adaptive immune responses administered early in the course of disease. We also critically examine data on long-term outcomes after single-agent and multi-agent medical therapy. Intensive regimens that target inflammation and adaptive immunity (e.g., combination high-dose dexamethasone and rituximab) appear to improve response rates at 6 to 12 months compared with standard first-line therapy (e.g., prednisone, high-dose dexamethasone alone) in newly diagnosed patients. Controlled trials with extended follow-up are needed to determine whether these intensive regimens induce more cures compared with standard treatment or merely delay relapse at the expense of potentially greater toxicity. PMID- 25793365 TI - Occupational Exposure to Chromium of Assembly Workers in Aviation Industries. AB - Aircraft are constructed by modules that are covered by a "primer" layer, which can often contain hexavalent chromium [Cr(VI)], known carcinogen to humans. While the occupational exposure to Cr(VI) during aircraft painting is ascertained, the exposure assessment of assembly workers (assemblers) requires investigations. Three biological monitoring campaigns (BM-I,II,III) were performed in an aviation industry, on homogeneous groups of assemblers (N = 43) and controls (N = 23), by measuring chromium concentrations in end-shift urine collected at the end of the working week and the chromium concentration difference between end- and before shift urines. BM-I was conducted on full-time workers, BM-II was performed on workers after a 3-4 day absence from work, BM-III on workers using ecoprimers with lower Cr(VI) content. Samples were analyzed by atomic absorption spectroscopy and mean values were compared by T-test. Even if Cr concentrations measured during BM-I were lower than Biological Exposure Indices by ACGIH, statistically significant differences were found between urinary Cr concentrations of workers and controls. Despite 3-4 days of absence from work, urinary chromium concentrations measured during BM-II were still higher than references from nonoccupationally exposed populations. In the BM-III campaign, the obtained preliminary results suggested the efficacy of using ecoprimers. The healthcare of workers exposed to carcinogenic agents follows the principle of limiting the exposure to "the minimum technically possible". The obtained results evidence that assemblers of aviation industries, whose task does not involve the direct use of primers containing Cr(VI), show an albeit slight occupational exposure to Cr(VI), that must be carefully taken into consideration in planning suitable prevention measures during risk assessment and management processes. PMID- 25793366 TI - Recent advances in dialkyl carbonates synthesis and applications. AB - Dialkyl carbonates are important organic compounds and chemical intermediates with the label of "green chemicals" due to their moderate toxicity, biodegradability for human health and environment. Indeed, owing to their unique physicochemical properties and versatility as reagents, a variety of phosgene free processes derived from CO or CO2 have been explored for the synthesis of dialkyl carbonates. In this critical review, we highlight the recent achievements (since 1997) in the synthesis of dialkyl carbonates based on CO and CO2 utilization, particularly focusing on the catalyst design and fabrication, structure-function relationship, catalytic mechanisms and process intensification. We also provide an overview regarding the applications of dialkyl carbonates as fuel additives, solvents and reaction intermediates (i.e. alkylating and carbonylating agents). Additionally, this review puts forward the substantial challenges and opportunities for future research associated with dialkyl carbonates. PMID- 25793367 TI - Multiple RNA processing defects and impaired chloroplast function in plants deficient in the organellar protein-only RNase P enzyme. AB - Transfer RNA (tRNA) precursors undergo endoribonucleolytic processing of their 5' and 3' ends. 5' cleavage of the precursor transcript is performed by ribonuclease P (RNase P). While in most organisms RNase P is a ribonucleoprotein that harbors a catalytically active RNA component, human mitochondria and the chloroplasts (plastids) and mitochondria of seed plants possess protein-only RNase P enzymes (PRORPs). The plant organellar PRORP (PRORP1) has been characterized to some extent in vitro and by transient gene silencing, but the molecular, phenotypic and physiological consequences of its down-regulation in stable transgenic plants have not been assessed. Here we have addressed the function of the dually targeted organellar PRORP enzyme in vivo by generating stably transformed Arabidopsis plants in which expression of the PRORP1 gene was suppressed by RNA interference (RNAi). PRORP1 knock-down lines show defects in photosynthesis, while mitochondrial respiration is not appreciably affected. In both plastids and mitochondria, the effects of PRORP1 knock-down on the processing of individual tRNA species are highly variable. The drastic reduction in the levels of mature plastid tRNA-Phe(GAA) and tRNA-Arg(ACG) suggests that these two tRNA species limit plastid gene expression in the PRORP1 mutants and, hence, are causally responsible for the mutant phenotype. PMID- 25793368 TI - The fight-or-flight response is associated with PBMC expression profiles related to immune defence and recovery in swine. AB - Defining phenotypes according to molecular features would promote the knowledge of functional traits like behaviour in both human and animal research. Beside physiological states or environmental factors, an innate predisposition of individual coping strategies was discussed, including the proactive and reactive pattern. According to backtest reactivity, animals assigned as high-resisting (proactive) and low-resisting (reactive) were immune challenged with tetanus toxoid in a time course experiment. Using the Affymetrix platform and qPCR, individual coping characteristics were reflected as gene expression signatures in porcine peripheral blood mononuclear cells (PBMC) at naive state (day 0) and in response to the model antigen (day 14, day 28, and day 140). Further, the blood cell count was analysed at all stages. On the transcriptional level, processes acting on cell communication, vasculogenesis, and blood coagulation were highlighted in high-resisting animals at naive state (day 0), temporarily blurred due to immune challenge (day 14) but subsequently restored and intensified (day 28). Notably, similar amounts of white and red blood cells, platelets and haematocrit between high-resisting and low-resisting samples suggest coping specific expression patterns rather than alterations in blood cell distribution. Taken together, the gene expression patterns indicate that proactive pigs might favour molecular pathways enabling an effective strategy for defence and recovery. This corroborates the previously suggested belief, that proactive animals are prone to an increased number of injuries as an evolutionary inherited mechanism. In contrast to previous assumptions, coping-specific immunity in pigs lacks inherited shifts between cellular and humoral immune responses. PMID- 25793369 TI - Immune neuroendocrine phenotypes in Coturnix coturnix: do avian species show LEWIS/FISCHER-like profiles? AB - Immunoneuroendocrinology studies have identified conserved communicational paths in birds and mammals, e.g. the Hypothalamus-Pituitary-Adrenal axis with anti inflammatory activity mediated by glucocorticoids. Immune neuroendocrine phenotypes (INPs) have been proposed for mammals implying the categorization of a population in subgroups underlying divergent immune-neuroendocrine interactions. These phenotypes were studied in the context of the LEWIS/FISCHER paradigm (rats expressing high or low pro-inflammatory profiles, respectively). Although avian species have some common immunological mechanisms with mammals, they have also evolved some distinct strategies and, until now, it has not been studied whether birds may also share with mammals similar INPs. Based on corticosterone levels we determined the existence of two divergent groups in Coturnix coturnix that also differed in other immune-neuroendocrine responses. Quail with lowest corticosterone showed higher lymphoproliferative and antibody responses, interferon-gamma and interleukin-1beta mRNA expression levels and lower frequencies of leukocyte subpopulations distribution and interleukin-13 levels, than their higher corticosterone counterparts. Results suggest the existence of INPs in birds, comparable to mammalian LEWIS/FISCHER profiles, where basal corticosterone also underlies responses of comparable variables associated to the phenotypes. Concluding, INP may not be a mammalian distinct feature, leading to discuss whether these profiles represent a parallel phenomenon evolved in birds and mammals, or a common feature inherited from a reptilian ancestor millions of years ago. PMID- 25793370 TI - MiR-506 is down-regulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1. AB - BACKGROUND: Some microRNAs (miRNAs) are abnormally expressed in cancer and contribute to tumorigenesis. In the present study, we investigated the role of miR-506 in clear cell renal cell carcinoma (ccRCC). METHODS: miR-506 expression was detected in renal cancer cell lines 786-O, ACHN, Caki-1, and Caki-2 and ccRCC specimens by quantitative real-time-PCR. We assessed the association of miR-506 expression with pathology and prognosis in ccRCC patients. We over-expressed and knocked-down miR-506 expression in two renal cancer cell lines, 786-O and ACHN, and assessed the impact on cell proliferation, migration and invasion. A luciferase reporter assay was conducted to confirm the target gene of miR-506 in renal cancer cell lines. RESULTS: miR-506 was significantly down-regulated in renal cancer cell lines and ccRCC specimens. Low miR-506 expression in ccRCC specimens was associated with an advanced clinical stage and poor prognosis. miR 506 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis. Over-expression of miR-506 in renal cancer cells decreased cell growth and metastasis, In contrast, down-regulation of miR 506 expression promoted renal cancer cell growth and metastasis. FLOT1, a potential target gene of miR-506, was inversely correlated with miR-506 expression in ccRCC tissues. Consistent with the effect of miR-506, knockdown of FLOT1 by siRNA inhibited cell malignant behaviors. Rescue of FLOT1 expression partially restored the effects of miR-506. CONCLUSIONS: miR-506 exerts its anti cancer function by directly targeting FLOT1 in renal cancer, indicating a potential novel therapeutic role in renal cancer treatment. PMID- 25793372 TI - Correction: Recruitment of Rpd3 to the telomere depends on the protein arginine methyltransferase Hmt1. PMID- 25793371 TI - Structural analysis of the synthetic Duffy Binding Protein (DBP) antigen DEKnull relevant for Plasmodium vivax malaria vaccine design. AB - The Plasmodium vivax vaccine candidate Duffy Binding Protein (DBP) is a protein necessary for P. vivax invasion of reticulocytes. The polymorphic nature of DBP induces strain-specific immune responses that pose unique challenges for vaccine development. DEKnull is a synthetic DBP based antigen that has been engineered through mutation to enhance induction of blocking inhibitory antibodies. We determined the x-ray crystal structure of DEKnull to identify if any conformational changes had occurred upon mutation. Computational and experimental analyses assessed immunogenicity differences between DBP and DEKnull epitopes. Functional binding assays with monoclonal antibodies were used to interrogate the available epitopes in DEKnull. We demonstrate that DEKnull is structurally similar to the parental Sal1 DBP. The DEKnull mutations do not cause peptide backbone shifts within the polymorphic loop, or at either the DBP dimerization interface or DARC receptor binding pockets, two important structurally conserved protective epitope motifs. All B-cell epitopes, except for the mutated DEK motif, are conserved between DEKnull and DBP. The DEKnull protein retains binding to conformationally dependent inhibitory antibodies. DEKnull is an iterative improvement of DBP as a vaccine candidate. DEKnull has reduced immunogenicity to polymorphic regions responsible for strain-specific immunity while retaining conserved protein folds necessary for induction of strain-transcending blocking inhibitory antibodies. PMID- 25793373 TI - The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract. AB - Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10( 48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors. PMID- 25793375 TI - Neurospora importin alpha is required for normal heterochromatic formation and DNA methylation. AB - Heterochromatin and associated gene silencing processes play roles in development, genome defense, and chromosome function. In many species, constitutive heterochromatin is decorated with histone H3 tri-methylated at lysine 9 (H3K9me3) and cytosine methylation. In Neurospora crassa, a five-protein complex, DCDC, catalyzes H3K9 methylation, which then directs DNA methylation. Here, we identify and characterize a gene important for DCDC function, dim-3 (defective in methylation-3), which encodes the nuclear import chaperone NUP-6 (Importin alpha). The critical mutation in dim-3 results in a substitution in an ARM repeat of NUP-6 and causes a substantial loss of H3K9me3 and DNA methylation. Surprisingly, nuclear transport of all known proteins involved in histone and DNA methylation, as well as a canonical transport substrate, appear normal in dim-3 strains. Interactions between DCDC members also appear normal, but the nup-6(dim 3) allele causes the DCDC members DIM-5 and DIM-7 to mislocalize from heterochromatin and NUP-6dim-3 itself is mislocalized from the nuclear envelope, at least in conidia. GCN-5, a member of the SAGA histone acetyltransferase complex, also shows altered localization in dim-3, raising the possibility that NUP-6 is necessary to localize multiple chromatin complexes following nucleocytoplasmic transport. PMID- 25793374 TI - Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B. AB - Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a beta-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-beta-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone. PMID- 25793376 TI - Bending of protonema cells in a plastid glycolate/glycerate transporter knockout line of Physcomitrella patens. AB - Arabidopsis LrgB (synonym PLGG1) is a plastid glycolate/glycerate transporter associated with recycling of 2-phosphoglycolate generated via the oxygenase activity of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO). We isolated two homologous genes (PpLrgB1 and B2) from the moss Physcomitrella patens. Phylogenetic tree analysis showed that PpLrgB1 was monophyletic with LrgB proteins of land plants, whereas PpLrgB2 was divergent from the green plant lineage. Experiments with PpLrgB-GFP fusion proteins suggested that both PpLrgB1 and B2 proteins were located in chloroplasts. We generated PpLrgB single (?B1 and ?B2) and double (?B1/?B2)-knockout lines using gene targeting of P. patens. The ?B1 plants showed decreases in growth and photosynthetic activity, and their protonema cells were bent and accumulated glycolate. However, because ?B2 and ?B1/?B2 plants showed no obvious phenotypic change relative to the wild-type or ?B1 plants, respectively, the function of PpLrgB2 remains unclear. Arabidopsis LrgB could complement the ?B1 phenotype, suggesting that the function of PpLrgB1 is the same as that of AtLrgB. When ?B1 was grown under high-CO2 conditions, all novel phenotypes were suppressed. Moreover, protonema cells of wild-type plants exhibited a bending phenotype when cultured on media containing glycolate or glycerate, suggesting that accumulation of photorespiratory metabolites caused P. patens cells to bend. PMID- 25793377 TI - The cricket paralysis virus suppressor inhibits microRNA silencing mediated by the Drosophila Argonaute-2 protein. AB - Small RNAs are potent regulators of gene expression. They also act in defense pathways against invading nucleic acids such as transposable elements or viruses. To counteract these defenses, viruses have evolved viral suppressors of RNA silencing (VSRs). Plant viruses encoded VSRs interfere with siRNAs or miRNAs by targeting common mediators of these two pathways. In contrast, VSRs identified in insect viruses to date only interfere with the siRNA pathway whose effector Argonaute protein is Argonaute-2 (Ago-2). Although a majority of Drosophila miRNAs exerts their silencing activity through their loading into the Argonaute-1 protein, recent studies highlighted that a fraction of miRNAs can be loaded into Ago-2, thus acting as siRNAs. In light of these recent findings, we re-examined the role of insect VSRs on Ago-2-mediated miRNA silencing in Drosophila melanogaster. Using specific reporter systems in cultured Schneider-2 cells and transgenic flies, we showed here that the Cricket Paralysis virus VSR CrPV1-A but not the Flock House virus B2 VSR abolishes silencing by miRNAs loaded into the Ago-2 protein. Thus, our results provide the first evidence that insect VSR have the potential to directly interfere with the miRNA silencing pathway. PMID- 25793378 TI - Identification of proanthocyanidins from litchi (Litchi chinensis Sonn.) pulp by LC-ESI-Q-TOF-MS and their antioxidant activity. AB - Content of total proanthocyanidins as well as total phenolics, flavonoids, antioxidant activities were evaluated for litchi (Litchi chinensis Sonn.) pulp of 32 cultivars. One cultivar, Hemaoli, showed the highest total proanthocyanidins and total phenolics, and DPPH or ABTS radical scavenging activities. ESI-MS and NMR analysis of the Hemaoli pulp crude extracts (HPCE) showed that procyandins composed of (epi)catechin unites with degree of polymerization (DP) of 2-6 were dominant proanthocyanidins in HPCE. After the HPCE was fractionated by a Sephadex LH-20 column, 32 procyanidins were identified by LC-ESI-Q-TOF-MS in litchi pulp for the first time. Quantification of individual procyanidin in HPCE indicated that epicatechin, procyanidin B2, procyanidin C1 and A-type procyanidin trimer were the main procyanidins. The radical scavenging activities of different fractions of HPCE as well as six procyanidins standards were evaluated by both DPPH and ABTS assays. HPCE fractions showed similar antioxidant activities with those of Vc and six individual procyanidins, the IC50 of which ranged from 1.88 +/- 0.01 to 2.82 +/- 0.10 MUg/ml for DPPH assay, and from 1.52 +/- 0.17 to 2.71 +/- 0.15 MUg/ml for ABTS assay. Such results indicate that litchi cultivars rich in proanthocyanidins are good resources of dietary antioxidants and have the potential to contribute to human health. PMID- 25793379 TI - Sepsis induces specific changes in histone modification patterns in human monocytes. AB - BACKGROUND: Sepsis is a global burden and the primary cause of death in intensive care units worldwide. The pathophysiological changes induced by the host's systemic inflammatory response to infection are not yet fully understood. During sepsis, the immune system is confronted with a variety of factors, which are integrated within the individual cells and result in changes of their basal state of responsiveness. Epigenetic mechanisms like histone modifications are known to participate in the control of immune reactions, but so far the situation during sepsis is unknown. METHODS AND FINDINGS: In a pilot approach, we performed combined chromatin immunoprecipitation followed by high-throughput sequencing to assess the genome-wide distribution of the chromatin modifications histone 3 lysine 4 and 27 trimethylation and lysine 9 acetylation in monocytes isolated from healthy donors (n = 4) and patients with sepsis (n = 2). Despite different underlying causes for sepsis, a comparison over promoter regions shows a high correlation between the patients for all chromatin marks. These findings hold true also when comparing patients to healthy controls. Despite the global similarity, differential analysis reveals a set of distinct promoters with significant enrichment or depletion of histone marks. Further analysis of overrepresented GO terms show an enrichment of genes involved in immune function. To the most prominent ones belong different members of the HLA family located within the MHC cluster together with the gene coding for the major regulator of this locus-CIITA. CONCLUSIONS: We are able to show for the first time that sepsis in humans induces selective and precise changes of chromatin modifications in distinct promoter regions of immunologically relevant genes, shedding light on basal regulatory mechanisms that might be contributing to the functional changes occurring in monocytes. PMID- 25793380 TI - Serum lipid levels and dyslipidaemia prevalence among 2-10 year-old Northern Mexican children. AB - BACKGROUND AND AIMS: The increase in overweight and obese children may be linked to increased rates of dyslipidaemia. The aim was to assess the prevalence of dyslipidaemia and associated risk factors among the Northern Mexican child population. METHODS AND RESULTS: Four hundred and fifty-one subjects aged between 2 and 10 (47.5% girls) took part in the Nuevo Leon State Survey of Nutrition and Health 2011-2012. According to the 2011 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, serum lipid levels (mg/dL) were categorized into three subgroups (acceptable, borderline high/low or high/low) as follows: TChol: acceptable <170, borderline-high 170 199, high >=200; LDL-chol: acceptable <110, borderline-high 110-129, high >=130; non-HDL-chol: acceptable <120, borderline-high 120-144, high >=145; HDL-chol: acceptable >45, borderline-low 40-45, low <40; and TG: acceptable <75, borderline high 75-99, high >=100 in <=9 year-old children, and acceptable <90, borderline high 90-129, and high >=130 in 10 year-old children. The overall prevalence of borderline-high + high TG, non-HDL-chol, TChol, and LDL-chol was 63.0%, 44.1%, 43.5%, and 29.9%, respectively. The overall prevalence of borderline-low + low HDL-chol was 46.3%. The overall frequency of dyslipidaemia was 54.3%. Thirteen children (2.9%) had all five symptoms of dyslipidaemia. The most common dyslipidaemia was high TG in combination (26.2%) and in isolation (10.6%). CONCLUSIONS: Half of the children had at least one abnormal lipid concentration. A high TG level was the most frequent dyslipidaemia. Obesity was associated with the occurrence of at least one abnormal lipid level. These findings emphasize the need to pay further attention to the prevention of cardiovascular disease and obesity from an early age. PMID- 25793382 TI - Indications for potential parent-of-origin effects within the FTO gene. AB - Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P<=0.05) depending on parental origin--among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P<=0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings. PMID- 25793381 TI - Mid-embryo patterning and precision in Drosophila segmentation: Kruppel dual regulation of hunchback. AB - In early development, genes are expressed in spatial patterns which later define cellular identities and tissue locations. The mechanisms of such pattern formation have been studied extensively in early Drosophila (fruit fly) embryos. The gap gene hunchback (hb) is one of the earliest genes to be expressed in anterior-posterior (AP) body segmentation. As a transcriptional regulator for a number of downstream genes, the spatial precision of hb expression can have significant effects in the development of the body plan. To investigate the factors contributing to hb precision, we used fine spatial and temporal resolution data to develop a quantitative model for the regulation of hb expression in the mid-embryo. In particular, modelling hb pattern refinement in mid nuclear cleavage cycle 14 (NC14) reveals some of the regulatory contributions of simultaneously-expressed gap genes. Matching the model to recent data from wild-type (WT) embryos and mutants of the gap gene Kruppel (Kr) indicates that a mid-embryo Hb concentration peak important in thoracic development (at parasegment 4, PS4) is regulated in a dual manner by Kr, with low Kr concentration activating hb and high Kr concentration repressing hb. The processes of gene expression (transcription, translation, transport) are intrinsically random. We used stochastic simulations to characterize the noise generated in hb expression. We find that Kr regulation can limit the positional variability of the Hb mid-embryo border. This has been recently corroborated in experimental comparisons of WT and Kr- mutant embryos. Further, Kr regulation can decrease uncertainty in mid-embryo hb expression (i.e. contribute to a smooth Hb boundary) and decrease between-copy transcriptional variability within nuclei. Since many tissue boundaries are first established by interactions between neighbouring gene expression domains, these properties of Hb-Kr dynamics to diminish the effects of intrinsic expression noise may represent a general mechanism contributing to robustness in early development. PMID- 25793383 TI - A longitudinal study: changes in cortical thickness and surface area during pubertal maturation. AB - Sex hormones have been shown to contribute to the organization and function of the brain during puberty and adolescence. Moreover, it has been suggested that distinct hormone changes in girls versus boys may contribute to the emergence of sex differences in internalizing and externalizing behavior during adolescence. In the current longitudinal study, the influence of within-subject changes in puberty (physical and hormonal) on cortical thickness and surface area was examined across a 2-year span, while controlling for age. Greater increases in Tanner Stage predicted less superior frontal thinning and decreases in precuneus surface area in both sexes. Significant Tanner Stage and sex interactions were also seen, with less right superior temporal thinning in girls but not boys, as well as greater decreases in the right bank of the superior temporal sulcus surface area in boys compared to girls. In addition, within-subject changes in testosterone over the 2-year follow-up period were found to relate to decreases in middle superior frontal surface area in boys, but increases in surface area in girls. Lastly, larger increases in estradiol in girls predicted greater middle temporal lobe thinning. These results show that within-subject physical and hormonal markers of puberty relate to region and sex-specific changes in cortical development across adolescence. PMID- 25793384 TI - Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome. AB - Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ~55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials. PMID- 25793385 TI - Association between resistin levels and all-cause and cardiovascular mortality: a new study and a systematic review and meta-analysis. AB - CONTEXT: Studies concerning the association between circulating resistin and mortality risk have reported, so far, conflicting results. OBJECTIVE: To investigate the association between resistin and both all-cause and cardiovascular (CV) mortality risk by 1) analyzing data from the Gargano Heart Study (GHS) prospective design (n=359 patients; 81 and 58 all-cause and CV deaths, respectively); 2) performing meta-analyses of all published studies addressing the above mentioned associations. DATA SOURCE AND STUDY SELECTION: MEDLINE and Web of Science search of studies reporting hazard ratios (HR) of circulating resistin for all-cause or CV mortality. DATA EXTRACTION: Performed independently by two investigators, using a standardized data extraction sheet. DATA SYNTHESIS: In GHS, adjusted HRs per one standard deviation (SD) increment in resistin concentration were 1.28 (95% CI: 1.07-1.54) and 1.32 (95% CI: 1.06-1.64) for all-cause and CV mortality, respectively. The meta-analyses included 7 studies (n=4016; 961 events) for all-cause mortality and 6 studies (n=4,187: 412 events) for CV mortality. Pooled HRs per one SD increment in resistin levels were 1.21 (95% CI: 1.03-1.42, Q-test p for heterogeneity<0.001) and 1.05 (95% CI: 1.01 1.10, Q-test p for heterogeneity=0.199) for all-cause and CV mortality, respectively. At meta-regression analyses, study mean age explained 9.9% of all cause mortality studies heterogeneity. After adjusting for age, HR for all-cause mortality was 1.24 (95% CI: 1.06-1.45). CONCLUSIONS: Our results provide evidence for an association between circulating resistin and mortality risk among high risk patients as are those with diabetes and coronary artery disease. PMID- 25793387 TI - Inversely estimating the vertical profile of the soil CO2 production rate in a deciduous broadleaf forest using a particle filtering method. AB - Carbon dioxide (CO2) efflux from the soil surface, which is a major source of CO2 from terrestrial ecosystems, represents the total CO2 production at all soil depths. Although many studies have estimated the vertical profile of the CO2 production rate, one of the difficulties in estimating the vertical profile is measuring diffusion coefficients of CO2 at all soil depths in a nondestructive manner. In this study, we estimated the temporal variation in the vertical profile of the CO2 production rate using a data assimilation method, the particle filtering method, in which the diffusion coefficients of CO2 were simultaneously estimated. The CO2 concentrations at several soil depths and CO2 efflux from the soil surface (only during the snow-free period) were measured at two points in a broadleaf forest in Japan, and the data were assimilated into a simple model including a diffusion equation. We found that there were large variations in the pattern of the vertical profile of the CO2 production rate between experiment sites: the peak CO2 production rate was at soil depths around 10 cm during the snow-free period at one site, but the peak was at the soil surface at the other site. Using this method to estimate the CO2 production rate during snow-cover periods allowed us to estimate CO2 efflux during that period as well. We estimated that the CO2 efflux during the snow-cover period (about half the year) accounted for around 13% of the annual CO2 efflux at this site. Although the method proposed in this study does not ensure the validity of the estimated diffusion coefficients and CO2 production rates, the method enables us to more closely approach the "actual" values by decreasing the variance of the posterior distribution of the values. PMID- 25793386 TI - MTHFR 677C>T polymorphism increases the male infertility risk: a meta-analysis involving 26 studies. AB - BACKGROUND AND OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) polymorphism may be a risk factor for male infertility. However, the epidemiologic studies showed inconsistent results regarding MTHFR polymorphism and the risk of male infertility. Therefore, we performed a meta-analysis of published case-control studies to re-examine the controversy. METHODS: Electronic searches of PubMed, EMBASE, Google Scholar and China National Knowledge Infrastructure (CNKI) were conducted to select eligible literatures for this meta analysis (updated to June 19, 2014). According to our inclusion criteria and the Newcastle-Ottawa Scale (NOS), only high quality studies that observed the association between MTHFR polymorphism and male infertility risk were included. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the MTHFR polymorphism and male infertility risk. RESULTS: Twenty-six studies involving 5,575 cases and 5,447 controls were recruited. Overall, MTHFR 677C>T polymorphism showed significant associations with male infertility risk in both fixed effects (CT+TT vs. CC: OR = 1.34, 95% CI: 1.23-1.46) and random effects models (CT+TT vs. CC: OR = 1.39, 95% CI: 1.19 1.62). Further, when stratified by ethnicity, sperm concentration and control sources, the similar results were observed in Asians, Caucasians, Azoo or OAT subgroup and both in population-based and hospital-based controls. Nevertheless, no significant association was only observed in oligo subgroup. CONCLUSIONS: Our results indicated that the MTHFR polymorphism is associated with an increased risk of male infertility. Further well-designed analytical studies are necessary to confirm our conclusions and evaluate gene-environment interactions with male infertility risk. PMID- 25793388 TI - Transcriptionally active regions are the preferred targets for chromosomal HPV integration in cervical carcinogenesis. AB - Integration of human papillomavirus (HPV) into the host genome is regarded as a determining event in cervical carcinogenesis. However, the exact mechanism for integration, and the role of integration in stimulating cancer progression, is not fully characterized. Although integration sites are reported to appear randomly distributed over all chromosomes, fragile sites, translocation break points and transcriptionally active regions have all been suggested as being preferred sites for integration. In addition, more recent studies have reported integration events occurring within or surrounding essential cancer-related genes, raising the question whether these may reflect key events in the molecular genesis of HPV induced carcinomas. In a search for possible common denominators of the integration sites, we utilized the chromosomal coordinates of 121 viral cellular fusion transcripts, and examined for statistical overrepresentation of integration sites with various features of ENCODE chromatin information data, using the Genomic HyperBrowser. We find that integration sites coincide with DNA that is transcriptionally active in mucosal epithelium, as judged by the relationship of integration sites to DNase hypersensitivity and H3K4me3 methylation data. Finding an association between integration and transcription is highly informative with regard to the spatio-temporal characteristics of the integration process. These results suggest that integration is an early event in carcinogenesis, more than a late product of chromosomal instability. If the viral integrations were more likely to occur in destabilized regions of the DNA, a completely random distribution of the integration sites would be expected. As a by-product of integration in actively transcribing DNA, a tendency of integration in or close to genes is likely to be observed. This increases the possibility of viral signals to modulate the expression of these genes, potentially contributing to the progression towards cancer. PMID- 25793389 TI - Renal hemodynamic and morphological changes after 7 and 28 days of leptin treatment: the participation of angiotensin II via the AT1 receptor. AB - The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin's action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED 1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-alpha and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-alpha and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects. PMID- 25793390 TI - SIgA binding to mucosal surfaces is mediated by mucin-mucin interactions. AB - The oral mucosal pellicle is a layer of absorbed salivary proteins, including secretory IgA (SIgA), bound onto the surface of oral epithelial cells and is a useful model for all mucosal surfaces. The mechanism by which SIgA concentrates on mucosal surfaces is examined here using a tissue culture model with real saliva. Salivary mucins may initiate the formation of the mucosal pellicle through interactions with membrane-bound mucins on cells. Further protein interactions with mucins may then trigger binding of other pellicle proteins. HT29 colon cell lines, which when treated with methotrexate (HT29-MTX) produce a gel-forming mucin, were used to determine the importance of these mucin-mucin interactions. Binding of SIgA to cells was then compared using whole mouth saliva, parotid (mucin-free) saliva and a source of purified SIgA. Greatest SIgA binding occurred when WMS was incubated with HT29-MTX expressing mucus. Since salivary MUC5B was only able to bind to cells which produced mucus and purified SIgA showed little binding to the same cells we conclude that most SIgA binding to mucosal cells occurs because SIgA forms complexes with salivary mucins which then bind to cells expressing membrane-bound mucins. This work highlights the importance of mucin interactions in the development of the mucosal pellicle. PMID- 25793391 TI - Uptake of fluorescent gentamicin by peripheral vestibular cells after systemic administration. AB - OBJECTIVE: In addition to cochleotoxicity, systemic aminoglycoside pharmacotherapy causes vestibulotoxicity resulting in imbalance and visual dysfunction. The underlying trafficking routes of systemically-administered aminoglycosides from the vasculature to the vestibular sensory hair cells are largely unknown. We investigated the trafficking of systemically-administered gentamicin into the peripheral vestibular system in C56Bl/6 mice using fluorescence-tagged gentamicin (gentamicin-Texas-Red, GTTR) imaged by scanning laser confocal microscopy to determine the cellular distribution and intensity of GTTR fluorescence in the three semicircular canal cristae, utricular, and saccular maculae at 5 time points over 4 hours. RESULTS: Low intensity GTTR fluorescence was detected at 0.5 hours as both discrete puncta and diffuse cytoplasmic fluorescence. The intensity of cytoplasmic fluorescence peaked at 3 hours, while punctate fluorescence was plateaued after 3 hours. At 0.5 and 1 hour, higher levels of diffuse GTTR fluorescence were present in transitional cells compared to hair cells and supporting cells. Sensory hair cells typically exhibited only diffuse cytoplasmic fluorescence at all time-points up to 4 hours in this study. In contrast, non-sensory cells rapidly exhibited both intense fluorescent puncta and weaker, diffuse fluorescence throughout the cytosol. The numbers and size of fluorescent puncta in dark cells and transitional cells increased over time. There is no preferential GTTR uptake by the five peripheral vestibular organs' sensory cells. Control vestibular tissues exposed to Dulbecco's phosphate-buffered saline or hydrolyzed Texas Red had negligible fluorescence. CONCLUSIONS: All peripheral vestibular cells rapidly take up systemically-administered GTTR, reaching peak intensity 3 hours after injection. Sensory hair cells exhibited only diffuse fluorescence, while non-sensory cells displayed both diffuse and punctate fluorescence. Transitional cells may act as a primary pathway for trafficking of systemic GTTR from the vasculature to endolymph prior to entering hair cells. PMID- 25793392 TI - Standard sub-thermoneutral caging temperature influences radiosensitivity of hematopoietic stem and progenitor cells. AB - The production of new blood cells relies on a hierarchical network of hematopoietic stem and progenitor cells (HSPCs). To maintain lifelong hematopoiesis, HSPCs must be protected from ionizing radiation or other cytotoxic agents. For many years, murine models have been a valuable source of information regarding factors that either enhance or reduce the survival of HSPCs after exposure of marrow to ionizing radiation. In a recent series of studies, however, it has become clear that housing-related factors such as the cool room temperature required for laboratory mice can exert a surprising influence on the outcome of experiments. Here we report that the mild, but chronic cold-stress endured by mice housed under these conditions exerts a protective effect on HSPCs after both non-lethal and lethal doses of total body irradiation (TBI). Alleviation of this cold-stress by housing mice at a thermoneutral temperature (30 degrees C) resulted in significantly greater baseline radiosensitivity to a lethal dose of TBI with more HSPCs from mice housed at thermoneutral temperature undergoing apoptosis following non-lethal TBI. Cold-stressed mice have elevated levels of norepinephrine, a key molecule of the sympathetic nervous system that binds to beta-adrenergic receptors. We show that blocking this signaling pathway in vivo through use of the beta-blocker propanolol completely mitigates the protective effect of cold-stress on HSPC apoptosis. Collectively this study demonstrates that chronic stress endured by the standard housing conditions of laboratory mice increases the resistance of HSPCs to TBI-induced apoptosis through a mechanism that depends upon beta-adrenergic signaling. Since beta blockers are commonly prescribed to a wide variety of patients, this information could be important when predicting the clinical impact of HSPC sensitivity to TBI. PMID- 25793393 TI - On the number of neurons and time scale of integration underlying the formation of percepts in the brain. AB - All of our perceptual experiences arise from the activity of neural populations. Here we study the formation of such percepts under the assumption that they emerge from a linear readout, i.e., a weighted sum of the neurons' firing rates. We show that this assumption constrains the trial-to-trial covariance structure of neural activities and animal behavior. The predicted covariance structure depends on the readout parameters, and in particular on the temporal integration window w and typical number of neurons K used in the formation of the percept. Using these predictions, we show how to infer the readout parameters from joint measurements of a subject's behavior and neural activities. We consider three such scenarios: (1) recordings from the complete neural population, (2) recordings of neuronal sub-ensembles whose size exceeds K, and (3) recordings of neuronal sub-ensembles that are smaller than K. Using theoretical arguments and artificially generated data, we show that the first two scenarios allow us to recover the typical spatial and temporal scales of the readout. In the third scenario, we show that the readout parameters can only be recovered by making additional assumptions about the structure of the full population activity. Our work provides the first thorough interpretation of (feed-forward) percept formation from a population of sensory neurons. We discuss applications to experimental recordings in classic sensory decision-making tasks, which will hopefully provide new insights into the nature of perceptual integration. PMID- 25793394 TI - Expression and prognostic value of miR-486-5p in patients with gastric adenocarcinoma. AB - MicroRNA (miR)-486-5p expression is often reduced in human cancers. However, its expression in gastric carcinoma and its relation to clinicopathological features and prognosis are unclear. Tissue microarrays were constructed from 84 patients with gastric adenocarcinoma (GC) who were undergoing radical resection. miR-486 5p expression was detected by miRNA-locked nucleic acid in situ hybridization, and its correlations with clinicopathological features and overall survival were analyzed. Bioinformatic studies predict that fibroblast growth factor 9 (FGF9) is a potential target gene of miR-486-5p. miR-486-5p was mainly located in the cytoplasm of GC cells and neighboring normal tissues. Compared with paracancerous normal tissue, miR-486-5p expression was decreased in 63.1% (53/84) of the GC samples, increased in 32.1% (27/84) and unchanged in 4.8% (4/84). FGF9 expression was decreased in 69.0% (58/84) of GC samples and increased in 31.0% (26/84) compared with normal paracancerous tissues using immunohistochemical analysis. Low or unchanged miR-486-5p expression (P = 0.002), tumor stage (P = 0.001), tumor status (P = 0.001), node status (P = 0.001), tumor size (P = 0.004), and depth of tumor invasion (P = 0.013) were significant negative prognostic predictors for overall survival in patients with GC. After stratification according to American Joint Committee on Cancer (AJCC) stage, low/unchanged miR 486-5p expression remained a significant predictor of poor survival in stage II (P = 0.024) and stage III (P = 0.003). Cox regression analysis identified the following predictors of poor prognosis: tumor status (hazard ratio [HR], 7.19; 95% confidence interval [CI], 1.75-29.6; P = 0.006), stage (HR, 2.62; 95%CI, 1.50 4.59; P = 0.001), lymph node metastasis (HR, 2.52; 95% CI, 1.27-4.99; P = 0.008), low/unchanged miR-486-5p (HR, 2.47; 95% CI, 1.35-4.52; P = 0.003), high level of FGF9 (HR, 2.41; 95% CI, 1.42-4.09; P = 0.001) and tumor size (HR, 2.50; 95% CI, 1.30-4.82; P = 0.006). Low or unchanged expression of miR-486-5p compared with neighboring normal tissues was associated with a poor prognosis, while high expression was associated with a good prognosis in GC. miR-486-5p may thus be useful for evaluating prognosis and may provide a novel target treatment in patients with GC. PMID- 25793396 TI - Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia. AB - INTRODUCTION: MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. METHODS: For this, we performed gene expression profiling after siRNA-mediated repression of MLL AF4, MLL-ENL, and AF4-MLL in MLL-rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. RESULTS: Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples. CONCLUSION: We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias. PMID- 25793395 TI - Elevated serum leptin, adiponectin and leptin to adiponectin ratio is associated with chronic kidney disease in Asian adults. AB - BACKGROUND: Adiponectin and leptin, two of the key cytokines secreted by adipocytes, have been shown to be associated with cardiovascular disease. However, the association of these adipocytokines with chronic kidney disease (CKD) is not clear. We examined the association of serum adiponectin, leptin levels and leptin to adiponectin ratio (LAR) with CKD in a population-based sample of Asian adults. METHODS: We conducted a case-control study (450 CKD cases and 920 controls matched for age, sex and ethnicity) involving Chinese and Indian adults aged 40-80 years who participated in the Singapore Epidemiology of Eye Diseases Study (2007-2011). CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73m2 from serum creatinine. Serum adiponectin and leptin levels were measured using commercially available ELISA. Odds ratio of CKD associated with elevated adiponectin and leptin levels were estimated using logistic regression models adjusted for age, gender, ethnicity, education, smoking, body mass index, diabetes, blood pressure, total and HDL cholesterol. RESULTS: CKD cases had higher levels of leptin (mean [SD] 9.7 [11.5] vs.16.9 [20.2] ng/mL, p<0.0001) and adiponectin (10.4 [7.4] vs. 9.2 [4.2], p = 0.001) compared to controls. In multi-variable models, compared to those in the lowest quartile, the OR (95% confidence interval) of CKD among those in the highest quartile were: 6.46 (3.84, 10.88), 1.94 (1.32-2.85) and 2.88 (1.78-4.64) for leptin, adiponectin and LAR. Similar associations were also observed when adiponectin and leptin were analyzed as continuous variables. This positive association of serum adiponectin, leptin and LAR with CKD was consistently present in subgroups of gender, ethnicity, diabetes, hypertension and overweight status (all P-interaction >0.1). CONCLUSIONS: Higher levels of serum adiponectin, leptin and LAR were positively associated with CKD independent of traditional risk factors in this Asian population. PMID- 25793397 TI - Characterization of a novel mutation in NS1 protein of influenza A virus induced by a chemical substance for the attenuation of pathogenicity. AB - It is generally accepted that live attenuated influenza vaccine (LAIV) has the potential for use as a vaccination against flu. In this study, we demonstrated the nature of an influenza A virus (IAV) mutant induced by treating the IAV with a stable furan derivative, (1R,2R)-1-(5'-methylfur-3'-yl)propane-1,2,3-triol (MFPT), which had been isolated from Streptomyces sp. strain FV60 with the objective of it being an LAIV candidate. The resulting MFPT-resistant (MFPTr) IAVs possessed attenuated pathogenicity in vitro and in vivo when compared with that of the parent virus (H1N1 subtype, NWS strain). Sequencing analysis revealed that a novel mutation, C490U in ns gene (P164S in NS1), was detected in all MFPTr virus clones tested. Therefore, NS1 might be a main target of MFPT, and it was suggested that the P164S mutation contributed to the attenuated pathogenicity of the mutants. Although the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the targets of NS1, the MFPTr virus suppressed the phosphorylation of Akt when compared with the wild-type (WT) virus. It was suggested that this might lead to the subsequent inhibition of the cleavage of PARP-1 and caspase-3, which is important for the progression of apoptosis. At the same time, nucleoprotein (NP) was found to be retained in the nuclei in MFPTr virus-infected cells while nuclear export of NP was detected in WT virus-infected cells. In addition, the expression levels of interferon-beta transcripts were significantly decreased in MFPTr virus-infected cells. From these results it can be shown that the mutation, NS1P164S, might be one of the key residues to control NS1 function concerning the induction of apoptosis. In conclusion, MFPT induced favorable mutation in the ns gene for the attenuation of IAV, and therefore might provide the novel methodology for preparing LAIVs. PMID- 25793398 TI - Narrative characteristics of genocide testimonies predict posttraumatic stress disorder symptoms years later. AB - Cognitive theories of posttraumatic stress disorder (PTSD) suggest that trauma narratives that make greater use of somatosensory, perceptual, and negative emotion words may be indicators of greater risk of PTSD symptoms (Ehlers & Clark, 2000). The purpose of this study was to analyze whether the way that survivors of the 1994 Rwandan Genocide against the Tutsi naturally construct genocide testimonies predicts PTSD symptoms 6 years later. One hundred orphaned heads of household (OHH) who were members of a community association gave testimonies about their genocide experiences in 2002. In 2008, PTSD symptoms of 61 of the original OHH were assessed using a genocide-specific version of the Impact of Events Scale-Revised (Weiss & Marmar, 1997). Experienced genocide events were coded from the genocide testimonies, and the types of words used in the testimonies were analyzed using the Linguistic Inquiry and Word Count program (Pennebaker, Chung, Ireland, Gonzales, & Booth, 2007). Pearson correlations and path analyses assessed the relationships between variables. After accounting for genocide events, touching positively predicted avoidance, and sadness negatively predicted hyperarousal. Sensory descriptions of traumatic experiences in trauma narratives may signify higher risk for mental health problems whereas expressions of sadness may indicate emotional processing and better mental health. Analyzing genocide testimonies may help identify survivors at the highest risk of developing PTSD symptoms, even among a group of survivors who have arguably suffered some of the most severe genocide experiences. PMID- 25793399 TI - DSM-5 posttraumatic stress disorder symptoms associated with suicide behaviors in veterans. AB - A connection between suicidality and posttraumatic stress disorder (PTSD) has been consistently demonstrated; however, the underlying relationship between suicidality and PTSD remains unclear. The aim of this study was to examine patterns of DSM-5 PTSD symptom endorsement that differentiated veteran participants with and without a history of suicide behaviors. We enrolled 95 veterans, 32 of whom reported no suicide ideation (SI) or suicide attempts (SA). The 63 remaining participants reported a history of SI, with 28 of the 63 also reporting a historical SA. Participants completed a standardized diagnostic interview (Structured Clinical Interview for DSM-IV-TR; First, Spitzer, Gibbon, & Williams, 2002), structured interview of suicidal behaviors (Columbia-Suicide Severity Rating Scale; Posner et al., 2011), and selected clinical measures. Veterans who reported SI and/or SA were more likely to meet criteria for PTSD on DSM-5 than were veterans who reported neither SI nor SA. Participants who reported SA were more likely to meet criteria for clusters C and D. Finally, at the symptom level, those who reported SI were more likely to report experiencing feelings of alienation. Those who reported a SA were more likely to report avoidance of thoughts and feelings, inability to recall an important aspect of their trauma, persistent negative beliefs, diminished interest, and feelings of alienation. These findings suggest that targeting specific symptoms of PTSD may aid in treatment of suicidal thoughts and behaviors associated with PTSD. PMID- 25793401 TI - Transmitting the sum of all fears: Iranian nuclear threat salience among offspring of Holocaust survivors. AB - Many Israelis are preoccupied with the prospect of a nuclear-armed Iran, frequently associating it with the danger of annihilation that existed during the Holocaust. The current article examined whether offspring of Holocaust survivors (OHS) are especially preoccupied and sensitive to the Iranian threat, and whether this susceptibility is a part of their increased general image of actual and potential threats, defined as the hostile world scenario (HWS). Study 1 (N = 106) showed that relative to comparisons, OHS reported more preoccupation with the Iranian nuclear threat. Moreover, the positive relationship between the salience of the Iranian threat and symptoms of anxiety was stronger among OHS. Study 2 (N = 450) replicated these findings, while focusing on the Iranian nuclear threat salience and symptoms of psychological distress. It further showed that OHS reported more negative engagement with the HWS (i.e., feeling that surrounding threats decrease one's sense of competence), which in turn mediated their increased preoccupation with the Iranian threat. The results suggest that intergenerational transmission of the Holocaust trauma includes heightened preoccupation with and sensitivity to potential threats of annihilation, and that the specific preoccupation with threats of annihilation reflects a part of a more general preoccupation with surrounding threats. PMID- 25793400 TI - Continuous exposure to life threats among different age groups in different types of communities. AB - The current study compared levels of posttraumatic symptoms (PTS) resulting from continuous exposure to missile attacks among residents of 2 types of communities (urban vs. rural) in 2 different age groups (elderly persons vs. young adults). We also took into account the contribution of individual resources (sociodemographic variables) and community resources (type of community of residence and sense of belonging to the community). The results revealed that, in general, the elderly residents were classified as suffering from more posttraumatic stress disorder (PTSD) and reported more PTS. Nonetheless, type of community of residence as well as individual and social resources contributed more to PTS symptoms than did the participants' age. The results are analyzed in light of the current literature on PTS, and in light of literature dealing with the impact of developmental life stage among populations that are continuously exposed to traumatic events. PMID- 25793403 TI - Mechanism of antibacterial activity of liposomal linolenic acid against Helicobacter pylori. AB - Helicobacter pylori infects approximately half of the world population and is a major cause of gastritis, peptic ulcer, and gastric cancer. Moreover, this bacterium has quickly developed resistance to all major antibiotics. Recently, we developed a novel liposomal linolenic acid (LipoLLA) formulation, which showed potent bactericidal activity against several clinical isolated antibiotic resistant strains of H. pylori including both the spiral and coccoid form. In addition, LipoLLA had superior in vivo efficacy compared to the standard triple therapy. Our data showed that LipoLLA associated with H. pylori cell membrane. Therefore, in this study, we investigated the possible antibacterial mechanism of LipoLLA against H. pylori. The antibacterial activity of LipoLLA (C18:3) was compared to that of liposomal stearic acid (LipoSA, C18:0) and oleic acid (LipoOA, C18:1). LipoLLA showed the most potent bactericidal effect and completely killed H. pylori within 5 min. The permeability of the outer membrane of H. pylori increased when treated with LipoOA and LipoLLA. Moreover, by detecting released adenosine triphosphate (ATP) from bacteria, we found that bacterial plasma membrane of H. pylori treated with LipoLLA exhibited significantly higher permeability than those treated with LipoOA, resulting in bacteria cell death. Furthermore, LipoLLA caused structural changes in the bacterial membrane within 5 min affecting membrane integrity and leading to leakage of cytoplasmic contents, observed by both transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Our findings showing rapid bactericidal effect of LipoLLA suggest it is a very promising new, effective anti-H. pylori agent. PMID- 25793404 TI - HDAC9 Inhibits Osteoclastogenesis via Mutual Suppression of PPARgamma/RANKL Signaling. AB - Recent studies suggest that the class II histone deacetylase (HDAC)9 plays important roles in physiology such as metabolism and immunity. Here, we report that HDAC9 also controls bone turnover by suppressing osteoclast differentiation and bone resorption. HDAC9 expression is down-regulated during osteoclastogenesis. Ex vivo osteoclast differentiation is accelerated by HDAC9 deletion but diminished by HDAC9 overexpression. HDAC9 knockout mice exhibit elevated bone resorption and lower bone mass. Bone marrow transplantation reveal that the osteoclastogenic defects are intrinsic to the hematopoietic lineage, because the excessive bone resorption phenotype can be conferred in wild-type (WT) mice receiving HDAC9-null bone marrow, and rescued in HDAC9-null mice receiving WT bone marrow. Mechanistically, HDAC9 forms a negative regulatory loop with peroxisome proliferator-activated receptor gamma (PPARg) and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. On one hand, PPARgamma and nuclear factor kappaB suppress HDAC9 expression, on the other hand, HDAC9 inhibits PPARgamma activity in synergy with silencing mediator of retinoic acid and thyroid hormone receptors (SMRT)/NCoR corepressors. These findings identify HDAC9 as a novel, important and physiologically relevant modulator of bone remodeling and skeletal homeostasis. PMID- 25793402 TI - Evidence of long-lived founder virus in mother-to-child HIV transmission. AB - Exposure of the infant's gut to cell-associated and cell-free HIV-1 trafficking in breast milk (BM) remains a primary cause of mother-to-child transmission (MTCT). The mammary gland represents a unique environment for HIV-1 replication and host-virus interplay. We aimed to explore the origin of the virus transmitted during breastfeeding, and the link with quasi-species found in acellular and cellular fractions of breast-milk (BM) and in maternal plasma. The C2-V5 region of the env gene was amplified, cloned and sequenced from the RNA and DNA of BM, the RNA from the mother's plasma (PLA) and the DNA from infant's dried blood spot (DBS) in 11 post-natal mother-infant pairs. Sequences were assembled in Geneious, aligned in ClustalX, manually edited in SeAL and phylogenetic reconstruction was undertaken in PhyML and MrBayes. We estimated the timing of transmission (ETT) and reconstructed the time for the most recent common ancestor (TMRCA) of the infant in BEAST. Transmission of single quasi-species was observed in 9 of 11 cases. Phylogenetic analysis illustrated a BM transmission event by cell-free virus in 4 cases, and by cell-associated virus in 2 cases but could not be identified in the remaining 5 cases. Molecular clock estimates, of the infant ETT and TMRCA, corresponded well with the timing of transmission estimated by sequential infant DNA PCR in 10 of 11 children. The TMRCA of BM variants were estimated to emerge during gestation in 8 cases. We hypothesize that in the remaining cases, the breast was seeded with a long-lived lineage latently infecting resting T-cells. Our analysis illustrated the role of DNA and RNA virus in MTCT. We postulate that DNA archived viruses stem from latently infected quiescent T-cells within breast tissue and MTCT can be expected to continue, albeit at low levels, should interventions not effectively target these cells. PMID- 25793405 TI - Minireview: prolactin regulation of adult stem cells. AB - Adult stem/progenitor cells are found in many tissues, where their primary role is to maintain homeostasis. Recent studies have evaluated the regulation of adult stem/progenitor cells by prolactin in various target tissues or cell types, including the mammary gland, the prostate, the brain, the bone marrow, the hair follicle, and colon cancer cells. Depending on the tissue, prolactin can either maintain stem cell quiescence or, in contrast, promote stem/progenitor cell expansion and push their progeny towards differentiation. In many instances, whether these effects are direct or involve paracrine regulators remains debated. This minireview aims to overview the current knowledge in the field. PMID- 25793406 TI - Enhancement of protective efficacy through adenoviral vectored vaccine priming and protein boosting strategy encoding triosephosphate isomerase (SjTPI) against Schistosoma japonicum in mice. AB - BACKGROUND: Schistosomiasis japonica is a zoonotic parasitic disease; developing transmission blocking veterinary vaccines are urgently needed for the prevention and control of schistosomiasis in China. Heterologous prime-boost strategy, a novel vaccination approach, is more effective in enhancing vaccine efficacy against multiple pathogens. In the present study, we established a novel heterologous prime-boost vaccination strategy, the rAdV-SjTPI.opt intramuscular priming and rSjTPI subcutaneous boosting strategy, and evaluated its protective efficacy against Schistosoma japonicum in mice. METHODOLOGY/PRINCIPAL FINDINGS: Adenoviral vectored vaccine (rAdV-SjTPI.opt) and recombinant protein vaccine (rSjTPI) were prepared and used in different combinations as vaccines in a mouse model. The specific immune responses and protective efficacies were evaluated. Furthermore, the longevity of protective efficacy was also determined. Results showed that the rAdV-SjTPI.opt priming-rSjTPI boosting strategy elicited higher levels of specific IgG responses and broad-spectrum specific cellular immune responses. The protective efficacy could reach up to nearly 70% and 50% of protection could be observed at 10 weeks after the last immunization in mice. CONCLUSIONS/SIGNIFICANCE: The rAdV-SjTPI.opt intramuscular priming-rSjTPI subcutaneous boosting vaccination strategy is a novel, highly efficient, and stable approach to developing vaccines against Schistosoma japonicum infections in China. PMID- 25793407 TI - N-glycomic changes in serum proteins in type 2 diabetes mellitus correlate with complications and with metabolic syndrome parameters. AB - BACKGROUND: Glycosylation, i.e the enzymatic addition of oligosaccharides (or glycans) to proteins and lipids, known as glycosylation, is one of the most common co-/posttranslational modifications of proteins. Many important biological roles of glycoproteins are modulated by N-linked oligosaccharides. As glucose levels can affect the pathways leading to glycosylation of proteins, we investigated whether metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), pathological conditions characterized by altered glucose levels, are associated with specific modifications in serum N-glycome. METHODS: We enrolled in the study 562 patients with Type 2 Diabetes Mellitus (T2DM) (mean age 65.6+/-8.2 years) and 599 healthy control subjects (CTRs) (mean age, 58.5+/-12.4 years). N-glycome was evaluated in serum glycoproteins. RESULTS: We found significant changes in N glycan composition in the sera of T2DM patients. In particular, alpha(1,6)-linked arm monogalactosylated, core-fucosylated diantennary N-glycans (NG1(6)A2F) were significantly reduced in T2DM compared with CTR subjects. Importantly, they were equally reduced in diabetic patients with and without complications (P<0.001) compared with CTRs. Macro vascular-complications were found to be related with decreased levels of NG1(6)A2F. In addition, NG1(6)A2F and NG1(3)A2F, identifying, respectively, monogalactosylated N-glycans with alpha(1,6)- and alpha(1,3) antennary galactosylation, resulted strongly correlated with most MS parameters. The plasmatic levels of these two glycans were lower in T2DM as compared to healthy controls, and even lower in patients with complications and MS, that is the extreme "unhealthy" phenotype (T2DM+ with MS). CONCLUSIONS: Imbalance of glycosyltransferases, glycosidases and sugar nucleotide donor levels is able to cause the structural changes evidenced by our findings. Serum N-glycan profiles are thus sensitive to the presence of diabetes and MS. Serum N-glycan levels could therefore provide a non-invasive alternative marker for T2DM and MS. PMID- 25793408 TI - The interaction affinity between vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) analyzed by quantitative FRET. AB - Very late antigen-4 (VLA-4), a member of integrin superfamily, interacts with its major counter ligand vascular cell adhesion molecule-1 (VCAM-1) and plays an important role in leukocyte adhesion to vascular endothelium and immunological synapse formation. However, irregular expressions of these proteins may also lead to several autoimmune diseases and metastasis cancer. Thus, quantifying the interaction affinity of the VCAM-1/VLA-4 interaction is of fundamental importance in further understanding the nature of this interaction and drug discovery. In this study, we report an 'in solution' steady state organic fluorophore based quantitative fluorescence resonance energy transfer (FRET) assay to quantify this interaction in terms of the dissociation constant (Kd). We have used, in our FRET assay, the Alexa Fluor 488-VLA-4 conjugate as the donor, and Alexa Fluor 546-VCAM 1 as the acceptor. From the FRET signal analysis, Kd of this interaction was determined to be 41.82 +/- 2.36 nM. To further confirm our estimation, we have employed surface plasmon resonance (SPR) technique to obtain Kd = 39.60 +/- 1.78 nM, which is in good agreement with the result obtained by FRET. This is the first reported work which applies organic fluorophore based 'in solution' simple quantitative FRET assay to obtain the dissociation constant of the VCAM-1/VLA-4 interaction, and is also the first quantification of this interaction. Moreover, the value of Kd can serve as an indicator of abnormal protein-protein interactions; hence, this assay can potentially be further developed into a drug screening platform of VLA-4/VCAM-1 as well as other protein-ligand interactions. PMID- 25793409 TI - Sex differences in shotgun proteome analyses for chronic oral intake of cadmium in mice. AB - Environmental diseases related to cadmium exposure primarily develop owing to industrial wastewater pollution and/or contaminated food. In regions with high cadmium exposure in Japan, cadmium accumulation occurs primarily in the kidneys of individuals who are exposed to the metal. In contrast, in the itai-itai disease outbreak that occurred in the Jinzu River basin in Toyama Prefecture in Japan, cadmium primarily accumulated in the liver. On the other hand, high concentration of cadmium caused renal tubular disorder and osteomalacia (multiple bone fracture), probably resulting from the renal tubular dysfunction and additional pathology. In this study, we aimed to establish a mouse model of chronic cadmium intake. We administered cadmium-containing drinking water (32 mg/l) to female and male mice ad libitum for 11 weeks. Metal analysis using inductively coupled plasma mass spectrometry revealed that cadmium accumulated in the kidneys (927 x 10 + 185 ng/g in females and 661 x 10 + 101 ng/g in males), liver (397 x 10 + 199 ng/g in females and 238 x 10 + 652 ng/g in males), and thyroid gland (293 + 93.7 ng/g in females and 129 + 72.7 ng/g in males) of mice. Female mice showed higher cadmium accumulation in the kidney, liver, and thyroid gland than males did (p = 0.00345, p = 0.00213, and p = 0.0331, respectively). Shotgun proteome analyses after chronic oral administration of cadmium revealed that protein levels of glutathione S-transferase Mu2, Mu4, and Mu7 decreased in the liver, and those of A1 and A2 decreased in the kidneys in both female and male mice. PMID- 25793410 TI - Suppression of sensitivity to drugs and antibiotics by high external cation concentrations in fission yeast. AB - BACKGROUND: Potassium ion homeostasis plays an important role in regulating membrane potential and therefore resistance to cations, antibiotics and chemotherapeutic agents in Schizosaccharomyces pombe and other yeasts. However, the precise relationship between drug resistance in S. pombe and external potassium concentrations (particularly in its natural habitats) remains unclear. S. pombe can tolerate a wide range of external potassium concentrations which in turn affect plasma membrane polarization. We thus hypothesized that high external potassium concentrations suppress the sensitivity of this yeast to various drugs. METHODS: We have investigated the effect of external KCl concentrations on the sensitivity of S. pombe cells to a wide range of antibiotics, antimicrobial agents and chemotherapeutic drugs. We employed survival assays, immunoblotting and microscopy for these studies. RESULTS: We demonstrate that KCl, and to a lesser extent NaCl and RbCl can suppress the sensitivity of S. pombe to a wide range of antibiotics. Ammonium chloride and potassium hydrogen sulphate also suppressed drug sensitivity. This effect appears to depend in part on changes to membrane polarization and membrane transport proteins. Interestingly, we have found little relationship between the suppressive effect of KCl on sensitivity and the structure, polarity or solubility of the various compounds investigated. CONCLUSIONS: High concentrations of external potassium and other cations suppress sensitivity to a wide range of drugs in S. pombe. Potassium-rich environments may thus provide S. pombe a competitive advantage in nature. Modulating potassium ion homeostasis may sensitize pathogenic fungi to antifungal agents. PMID- 25793411 TI - Risk factors for obesity at age 3 in Alaskan children, including the role of beverage consumption: results from Alaska PRAMS 2005-2006 and its three-year follow-up survey, CUBS, 2008-2009. AB - BACKGROUND: Prenatal and early life risk factors are associated with childhood obesity. Alaska Native children have one of the highest prevalences of childhood obesity of all US racial/ethnic groups. METHODS: Using the Pregnancy Risk Assessment Monitoring System (PRAMS) and the follow-up survey at 3 years of age (CUBS), we evaluated health, behavioral, lifestyle and nutritional variables in relation to obesity (95th percentile for body mass index (BMI)) at 3 years of age. Multivariate logistic regression modeling was conducted using Stata 12.0 to evaluate independent risk factors for obesity in non-Native and Alaska Native children. RESULTS: We found an obesity prevalence of 24.9% in all Alaskan and 42.2% in Alaska Native 3 year olds. Among Alaska Native children, obesity prevalence was highest in the Northern/Southwest part of the state (51.6%, 95%CI (42.6-60.5)). Independent predictive factors for obesity at age 3 years in Alaska non-Native children were low income (<$10,000 in the year before the child was born (OR 3.94, 95%CI 1.22--17.03) and maternal pre-pregnancy obesity (OR 2.01, 95%CI 1.01-4.01) and longer duration of breastfeeding was protective (OR 0.95, 95%CI 0.91-0.995). Among Alaska Native children, predictive factors were witnessing domestic violence/abuse as a 3 year-old (OR 2.28, 95%CI 1.17-7.60). Among obese Alaska Native children, there was an increased daily consumption of energy dense beverages in the Northern/Southwest region of the state, which may explain higher rates of obesity in this part of the state. CONCLUSIONS: The high prevalence of obesity in Alaska Native children may be explained by differences in lifestyle patterns and food consumption in certain parts of the state, specifically the Northern/Southwest region, which have higher consumption of energy dense beverages. PMID- 25793412 TI - Lipid mixtures containing a very high proportion of saturated fatty acids only modestly impair insulin signaling in cultured muscle cells. AB - In vitro examinations of the effect of saturated fatty acids on skeletal muscle insulin action often use only one or two different fatty acid species, which does not resemble the human plasma fatty acid profile. We compared graded concentrations (0.1-0.8 mM) of 3 different lipid mixtures: 1) a physiologic fatty acid mixture (NORM; 40% saturated fatty acids), 2) a physiologic mixture high in saturated fatty acids (HSFA; 60% saturated fatty acids), and 3) 100% palmitate (PALM) on insulin signaling and fatty acid partitioning into triacylglycerol (TAG) and diacylglycerol (DAG) in cultured muscle cells. As expected, PALM readily impaired insulin-stimulated pAktThr308/Akt and markedly increased intracellular DAG content. In contrast, the fatty acid mixtures only modestly impaired insulin-stimulated pAktThr308M/Akt, and we found no differences between NORM and HSFA. Importantly, NORM and HSFA did not increase DAG content, but instead dose-dependently increased TAG accumulation. Therefore, the robust impairment in insulin signaling found with palmitate exposure was attenuated with physiologic mixtures of fatty acids, even with a very high proportion of saturated fatty acids. This may be explained in part by selective partitioning of fatty acids into neutral lipid (i.e., TAG) when muscle cells were exposed to physiologic lipid mixtures. PMID- 25793413 TI - The CYP19 RS4646 polymorphism IS related to the prognosis of stage I-II and operable stage III breast cancer. AB - PURPOSE: Aromatase, encoded by the CYP19 gene, catalyzes the final step of the conversion of androgens to estrogens. Given the critical role of CYP19 in estrogen synthesis, the potential influence of CYP19 rs4646 polymorphism on breast cancer survival, deserves further study. METHODS: Genotyping for CYP19 rs4646 variants was performed on 406 Chinese women with stage I-II and operable stage III breast cancer. Associations were evaluated between CYP19 rs4646 genotypes and disease-free survival (DFS). RESULTS: In premenopausal patients, women who are homozygous for the minor allele (AA) have a longer DFS compared with those carrying the major allele (CC or AC) (87 months versus 48.7 months; Hazard ratio (HR) = 0.56, 95 % CI = 0.318-0.985, P = 0.041). These differences were further demonstrated by a multivariate analysis (HR = 0.456, 95 % CI = 0.249 0.836, P = 0.011). Conversely, the same variant (AA) was estimated to be associated with a poorer DFS in postmenopausal women (AA versus AC or CC: 13.7 months versus 56.3 months; HR = 2.758, 95 % CI = 1.432-5.313, P = 0.002). Furthermore, the differences were confirmed by the COX proportional hazards model (HR = 2.983, 95% CI =1.494-5.955, P = 0.002). CONCLUSIONS: The present study indicates that CYP19 rs4646 polymorphism is related to DFS in early breast cancer and that the prognosis index of the homozygous for the minor allele (AA) may depend on menopause status. The findings are novel, if confirmed, rs4646 genotypes may provide useful information for routine management in breast cancer. PMID- 25793414 TI - Aerobic and anaerobic in vitro testing of feed additives claiming to detoxify deoxynivalenol and zearalenone. AB - Deoxynivalenol (DON) and zearalenone (ZEN) are mycotoxins produced by fungi of the genus Fusarium which frequently contaminate maize and grain cereals. Mycotoxin-contaminated feed endangers animal health and leads to economic losses in animal production. Several mycotoxin elimination strategies, including the use of commercially available DON and ZEN detoxifying agents, have been developed. However, frequently there is no scientific proof of the efficacy of such adsorbents and degrading products. We therefore tested 20 commercially available products claiming to detoxify DON and/or ZEN either by biodegradation (4 products) or a combination of degradation and adsorption (16 products) under aerobic and anaerobic conditions at approx. pH 7. Under the applied conditions, a complete reduction of DON and consequent formation of the known non-toxic metabolite DOM-1 was exclusively observed in samples taken from the anaerobic degradation experiment of one product. For all other products, incubated under aerobic and anaerobic conditions, a maximum DON reduction of 17% after 72 h of incubation was detected. Aerobic and anaerobic incubation of only one tested product resulted in complete ZEN reduction as well as in the formation of the less-toxic metabolites DHZEN and HZEN. With this product, 68-97% of the toxin was metabolised within 3 h. After 24 h, a ZEN reduction >= 60% was obtained with four additional products during aerobic incubation only. Six of the 20 investigated products produced alpha- and/or beta-ZEL, which are metabolites showing similar oestrogenic activity compared to ZEN. Aerobic and anaerobic degradation to unknown metabolites with unidentified toxicity was obtained with 10 and 3 products, respectively. The results of our study demonstrate the importance of in vitro experiments to critically screen agents claiming mycotoxin detoxification. PMID- 25793415 TI - Mechanism-Based Mathematical Model for Gating of Ionotropic Glutamate Receptors. AB - We present a mathematical model for ionotropic glutamate receptors (iGluR's) that is built on mechanistic understanding and yields a number of thermodynamic and kinetic properties of channel gating. iGluR's are ligand-gated ion channels responsible for the vast majority of fast excitatory neurotransmission in the central nervous system. The effects of agonist-induced closure of the ligand binding domain (LBD) are transmitted to the transmembrane channel (TMC) via interdomain linkers. Our model demonstrates that, relative to full agonists, partial agonists may reduce either the degree of LBD closure or the curvature of the LBD free energy basin, leading to less stabilization of the channel open state and hence lower channel open probability. A rigorous relation is derived between the channel closed-to-open free energy difference and the tension within the linker. Finally, by treating LBD closure and TMC opening as diffusive motions, we obtain gating trajectories that resemble stochastic current traces from single-channel recordings and calculate the rate constants for transitions between the channel open and closed states. Our model can be implemented by molecular dynamics simulations to realistically depict iGluR gating and may guide functional experiments in gaining deeper insight into this essential family of channel proteins. PMID- 25793416 TI - Directed evolution of cytochrome P450 enzymes for biocatalysis: exploiting the catalytic versatility of enzymes with relaxed substrate specificity. AB - Cytochrome P450 enzymes are renowned for their ability to insert oxygen into an enormous variety of compounds with a high degree of chemo- and regio-selectivity under mild conditions. This property has been exploited in Nature for an enormous variety of physiological functions, and representatives of this ancient enzyme family have been identified in all kingdoms of life. The catalytic versatility of P450s makes them well suited for repurposing for the synthesis of fine chemicals such as drugs. Although these enzymes have not evolved in Nature to perform the reactions required for modern chemical industries, many P450s show relaxed substrate specificity and exhibit some degree of activity towards non-natural substrates of relevance to applications such as drug development. Directed evolution and other protein engineering methods can be used to improve upon this low level of activity and convert these promiscuous generalist enzymes into specialists capable of mediating reactions of interest with exquisite regio- and stereo-selectivity. Although there are some notable successes in exploiting P450s from natural sources in metabolic engineering, and P450s have been proven repeatedly to be excellent material for engineering, there are few examples to date of practical application of engineered P450s. The purpose of the present review is to illustrate the progress that has been made in altering properties of P450s such as substrate range, cofactor preference and stability, and outline some of the remaining challenges that must be overcome for industrial application of these powerful biocatalysts. PMID- 25793417 TI - Glycosynthesis in a waterworld: new insight into the molecular basis of transglycosylation in retaining glycoside hydrolases. AB - Carbohydrates are ubiquitous in Nature and play vital roles in many biological systems. Therefore the synthesis of carbohydrate-based compounds is of considerable interest for both research and commercial purposes. However, carbohydrates are challenging, due to the large number of sugar subunits and the multiple ways in which these can be linked together. Therefore, to tackle the challenge of glycosynthesis, chemists are increasingly turning their attention towards enzymes, which are exquisitely adapted to the intricacy of these biomolecules. In Nature, glycosidic linkages are mainly synthesized by Leloir glycosyltransferases, but can result from the action of non-Leloir transglycosylases or phosphorylases. Advantageously for chemists, non-Leloir transglycosylases are glycoside hydrolases, enzymes that are readily available and exhibit a wide range of substrate specificities. Nevertheless, non-Leloir transglycosylases are unusual glycoside hydrolases in as much that they efficiently catalyse the formation of glycosidic bonds, whereas most glycoside hydrolases favour the mechanistically related hydrolysis reaction. Unfortunately, because non-Leloir transglycosylases are almost indistinguishable from their hydrolytic counterparts, it is unclear how these enzymes overcome the ubiquity of water, thus avoiding the hydrolytic reaction. Without this knowledge, it is impossible to rationally design non-Leloir transglycosylases using the vast diversity of glycoside hydrolases as protein templates. In this critical review, a careful analysis of literature data describing non-Leloir transglycosylases and their relationship to glycoside hydrolase counterparts is used to clarify the state of the art knowledge and to establish a new rational basis for the engineering of glycoside hydrolases. PMID- 25793418 TI - A stable RNA G-quadruplex within the 5'-UTR of Arabidopsis thaliana ATR mRNA inhibits translation. AB - Guanine quadruplex structures (GQSs) play important roles in the regulation of gene expression and cellular processes. Recent studies provide strong evidence for the formation and function of DNA and RNA GQSs in human cells. However, whether GQSs form and are functional in plants remains essentially unexplored. On the basis of circular dichroism (CD)-detected titration, UV-detected melting, in line probing (ILP) and reporter gene assay studies, we report the first example of a plant RNA GQS that inhibits translation. This GQS is located within the 5' UTR of the ATAXIA TELANGIECTASIA-MUTATED AND RAD3-RELATED (ATR) mRNA of Arabidopsis thaliana (mouse-ear cress). We show that this GQS is highly stable and is thermodynamically favoured over a competing hairpin structure in the 5' UTR at physiological K+ and Mg2+ concentrations. Results from ILP reveal the secondary structure of the RNA and support formation of the GQS in vitro in the context of the complete 5'-UTR. Transient reporter gene assays performed in living plants reveal that the GQS inhibits translation but not transcription, implicating this GQS as a translational repressor in vivo. Our results provide the first complete demonstration of the formation and function of a regulatory RNA GQS in plants and open new avenues to explore potential functional roles of GQS in the plant kingdom. PMID- 25793419 TI - DUBs, the regulation of cell identity and disease. PMID- 25793420 TI - Identification of key binding site residues of MCT1 for AR-C155858 reveals the molecular basis of its isoform selectivity. PMID- 25793421 TI - Four FACTs Spiritual Assessment Tool. AB - The Four FACTs Spiritual Assessment Tool combines the Four Fs and the FACT Spiritual Assessment Tool of LaRocca-Pitts into a single tool. The Four FACTs Tool is specifically designed for beginning students, but can also meet the needs of professional chaplains. Though designed for use in an acute care setting, it can be easily adapted for other settings. The Four FACTs Tool is easy to learn and to use and it gathers and evaluates relevant clinical information that can then be used to develop a plan of care. In its shortened form, as ACT, it informs how the chaplain can be fully present with patients and their families, especially in a time of crisis. PMID- 25793422 TI - A qualitative study of patient and family perceptions of chaplain presence during post-trauma care. AB - Improving the provision of spiritual care to hospitalized patients requires understanding what patients look for from a hospital chaplain, and why. This qualitative study uses grounded theory methodology to analyze data from 25 interviews with adult patients and/or adult family members who received spiritual care in a large tertiary care hospital. Analysis reveals three key themes in chaplaincy care: the attributes valued in the chaplain's presence, the elements necessary to form relationship with the chaplain, and the role of the chaplain in helping patients to discover and express meaning in their experiences. The authors weave these three themes together into a grounded theory and propose an assessment model that incorporates psychological theory about human motivation, faith development, and the development of autonomy. An understanding of the proposed assessment model can guide chaplain interventions and benefit all members of the clinical care team. PMID- 25793424 TI - Improving the quality of wastewater to tackle trace organic contaminants: think before you act! PMID- 25793423 TI - Testing the feasibility and acceptability of a chaplaincy intervention to improving treatment attitudes and self-efficacy of adolescents with cystic fibrosis: a pilot study. AB - Religious factors are known to contribute to treatment adherence in different patient populations, and religious coping has been found to be particularly important to adolescents dealing with chronic diseases. Adherence to prescribed treatments slows disease progression and contributes to desirable outcomes in most patients, and, therefore, adherence-promoting interventions provided by chaplains could be beneficial to various patient populations. The current article describes a pilot study to test the feasibility of a theoretically and empirically based chaplain intervention to promote treatment adherence for adolescents with CF. Cognitive interviews were conducted 24 with adolescents with CF, and content analysis was used to identify themes, which informed revision of the intervention protocol. The authors thought that presenting the methods and results of this pilot study would be helpful for chaplains who want to conduct intervention research. The results indicated that the proposed intervention was acceptable and feasible to deliver in hard copy or an electronic platform. PMID- 25793425 TI - Role of carbon nanotube interlayer in enhancing the electron field emission behavior of ultrananocrystalline diamond coated Si-tip arrays. AB - We improved the electron field emission properties of ultrananocrystalline diamond (UNCD) films grown on Si-tip arrays by using the carbon nanotubes (CNTs) as interlayer and post-treating the films in CH4/Ar/H2 plasma. The use of CNTs interlayer effectively suppresses the presence of amorphous carbon in the diamond to-Si interface that enhances the transport of electrons from Si, across the interface, to diamond. The post-treatment process results in hybrid-granular structured diamond (HiD) films via the induction of the coalescence of the ultrasmall grains in these films that enhanced the conductivity of the films. All these factors contribute toward the enhancement of the electron field emission (EFE) process for the HiDCNT/Si-tip emitters, with low turn-on field of E0 = 2.98 V/MUm and a large current density of 1.68 mA/cm(2) at an applied field of 5.0 V/MUm. The EFE lifetime stability under an operation current of 6.5 MUA was improved substantially to tauHiD/CNT/Si-tip = 365 min. Interestingly, these HiDCNT/Si-tip materials also show enhanced plasma illumination behavior, as well as improved robustness against plasma ion bombardment when they are used as the cathode for microplasma devices. The study concludes that the use of CNT interlayers not only increase the potential of these materials as good EFE emitters, but also prove themselves to be good microplasma devices with improved performance. PMID- 25793426 TI - IL-17, IL-23, and p73 expression in cutaneous melanoma: a pilot study. AB - The incidence of cutaneous malignant melanoma is increasing worldwide, resulting in the demand for clinically useful prognostic biomarkers, especially for invasive and metastatic disease. We studied the immunohistochemical expression of interleukin-17 (IL-17), IL-23, and p73 in 35 malignant melanomas and compared them with benign melanocytic nevi and Spitz nevi, correlating them with clinical pathological variables. A higher and statistically significant difference (P<0.05) in the intensity and percentage of stained cells of IL-17 and IL-23 was found in the melanoma group than in ordinary benign nevi that did not correlate with Breslow thickness nor Clark level. Moreover, p73 staining and percentage of stained cells was significantly higher (P<0.05) in all the melanomas studied, with a peculiar cytoplasmatic distribution. Our findings could suggest a possible IL-17, IL-23, and p73 involvement in cutaneous melanomas with a hypothetical impact on melanoma invasiveness. PMID- 25793427 TI - Mechanistic insight into the elastin degradation process by the metalloprotease myroilysin from the deep-sea bacterium Myroides profundi D25. AB - Elastases have been widely studied because of their important uses as medicine and meat tenderizers. However, there are relatively few studies on marine elastases. Myroilysin, secreted by Myroides profundi D25 from deep-sea sediment, is a novel elastase. In this study, we examined the elastin degradation mechanism of myroilysin. When mixed with insoluble bovine elastin, myroilysin bound hydrophobically, suggesting that this elastase may interact with the hydrophobic domains of elastin. Consistent with this, analysis of the cleavage pattern of myroilysin on bovine elastin and recombinant tropoelastin revealed that myroilysin preferentially cleaves peptide bonds with hydrophobic residues at the P1 and/or P1' positions. Scanning electron microscopy (SEM) of cross-linked recombinant tropoelastin degraded by myroilysin showed preferential damages of spherules over cross-links, as expected for a hydrophobic preference. The degradation process of myroilysin on bovine elastin fibres was followed by light microscopy and SEM, revealing that degradation begins with the formation of crevices and cavities at the fibre surface, with these openings increasing in number and size until the fibre breaks into small pieces, which are subsequently fragmented. Our results are helpful for developing biotechnological applications for myroilysin. PMID- 25793428 TI - Toxic picoplanktonic cyanobacteria--review. AB - Cyanobacteria of a picoplanktonic cell size (0.2 to 2.0 um) are common organisms of both freshwater and marine ecosystems. However, due to their small size and relatively short study history, picoplanktonic cyanobacteria, in contrast to the microplanktonic cyanobacteria, still remains a poorly studied fraction of plankton. So far, only little information on picocyanobacteria toxicity has been reported, while the number of reports concerning their presence in ecosystems is increasing. Thus, the issue of picocyanobacteria toxicity needs more researchers' attention and interest. In this report, we present information on the current knowledge concerning the picocyanobacteria toxicity, as well as their harmfulness and problems they can cause. PMID- 25793429 TI - CE: original research: The efficacy of a nurse-led breathing training program in reducing depressive symptoms in patients on hemodialysis: a randomized controlled trial. AB - BACKGROUND: Depression is common in patients with chronic kidney disease who are on hemodialysis. Available behavioral modalities for treating depression may not be feasible for patients who receive hemodialysis two or three times per week. OBJECTIVES: The purpose of this randomized controlled trial was to examine the efficacy of a nurse-led, in-center breathing training program in reducing depressive symptoms and improving sleep quality and health-related quality of life in patients on maintenance hemodialysis. PARTICIPANTS AND METHODS: Fifty seven patients on hemodialysis were randomly assigned either to an eight-session breathing training group or to a control group. The Beck Depression Inventory II (BDI-II), the Pittsburgh Sleep Quality Index (PSQI), and the Medical Outcome Studies 36-Item Short Form Health Survey (SF-36) were used to assess self reported depressive symptoms, sleep quality, and health-related quality of life, respectively. RESULTS: The intervention group exhibited significantly greater decreases in BDI-II scores than the control group. No significant differences in PSQI change scores were observed between the groups. SF-36 change scores for both the domain of role limitation due to emotional problems and the mental component summary were significantly higher in the breathing training group than in the control group. CONCLUSION: This intervention significantly alleviated depressive symptoms, reduced perceived role limitation due to emotional problems, and improved the overall mental health component of quality of life in patients on maintenance hemodialysis. PMID- 25793430 TI - CE: The potential effects of sleep loss on a nurse's health. AB - OVERVIEW: While much has been written about the effects of extended work hours on quality of nursing care, nurse burnout, and job attrition, the potential adverse effects of acute and chronic sleep loss on the overall health and well-being of nurses has received little attention. The author describes the acute and chronic effects of sleep loss on nurses, strategies nurses can use to increase the quantity and quality of their sleep, and institutional policies that can promote adequate rest and recuperation between work shifts for nursing staff. PMID- 25793431 TI - Studying the Morbidity and Renal Function Outcome of Missed Internal Ureteral Stents: A Matched Pair Analysis. AB - PURPOSE: To investigate the effect of missed internal ureteral stents (IUS) on renal function and to describe different modalities of management and associated morbidity. PATIENTS AND METHODS: A retrospective study included patients with missed IUS (>1 year). The complications of missed IUS were categorized according to the forgotten, encrusted, calcified (FECal) grading system. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation at time of initial stent placement and time of stent removal. An age- and sex-matched group of patients who had IUS and had available follow-up for the same duration of the study group were used as a control. RESULTS: A total of 46 missed IUS in 46 patients were included. Complicated stents were reported in 34 (73.9%) patients. FECal grade 1 was reported in 16 (57.2%) patients followed by grade 2 and 4 in 5 (17.8%) patients each. Retrograde removal, visual cystolitholapaxy, ureteroscopy with laser disintegration of encrustations and combined retrograde and antegrade approach have been used in 21, 5, 10, and 9 patients, respectively. In the missed IUS group, the mean+/-standard deviation (SD) eGFR has declined from 65.5+/-26.3 mL/min/1.73m(2) to 54.3+/-30 mL/min/1.73m(2) (P=0.001). While in the control group, the mean+/-SD eGFR has increased from 57.5+/-30 mL/min/1.73 m(2) to 66.7+/ 27 mL/min/1.73 m(2) (P=0.001). CONCLUSIONS: Missed IUS were associated with significant complications that necessitated more invasive intervention. In addition, IUS had a negative impact on renal function at time of removal. PMID- 25793432 TI - Secondary Behavior of Drivers on Cell Phones. AB - OBJECTIVES: The objective of this study was to determine whether cell phone use by drivers leads to changes in the frequency of other types of potentially distracting behavior. There were 2 main questions of interest: (1) As each driver changes cell phone use, does he or she change the amount of driving time spent on other distracting behavior? (2) As each driver changes cell phone use, does he or she change the amount of driving time spent looking away from the driving task? METHODS: Day-to-day driving behavior of 105 volunteer subjects was monitored over a period of 1 year. The amount of driving time during each trip spent on tasks secondary to driving (or looking away from the driving task) was correlated to the amount of time on a cell phone, taking into account the relationships among trips taken by the same driver. RESULTS: Drivers spent 42% of the time engaging in at least one secondary activity. Drivers were talking on a cell phone 7% of the time, interacting in some other way with a cell phone 5% of the time, and engaging in some other secondary activity (sometimes in conjunction with cell phone use) 33% of the time. Other than cell phone use, the most common secondary activities were interacting with a passenger (12% of driving time), holding but not otherwise interacting with an object (6%), and talking/singing/dancing to oneself (5%). Drivers were looking straight forward 81% of the time, forward left or right 5% of time, in a mirror 4% of the time, and elsewhere (eyes off driving task) 10% of time. On average, for each 1 percentage point increase in cell phone talking, the other secondary behavior rate decreased by 0.28 percentage points (P <.0001), and the rate of eyes off driving task decreased by 0.02 percentage points (P =.0067). For each 1 percentage point increase in the amount of other cell phone interaction per trip, the other secondary behavior rate decreased by 0.08 percentage points (P =.0558), but the rate of eyes off driving task increased by 0.06 percentage points (P <.0001). CONCLUSIONS: Although using a cell phone can be distracting from the driving task, other secondary activities can be equally or more distracting, at least as measured by eye glances away from the road ahead and mirrors. In this group of drivers, dialing, reaching for, and answering the cell phone were associated with increased eyes off driving task, as opposed to the decrease in eyes off driving task associated with talking on the phone. Predictions about the effect of cell phone usage on driver distraction need to consider what other behavior is being displaced by the time spent on the phone. A focus by researchers, policy-makers, and the media on the distraction of using cell phones while driving may lead drivers to disregard the risk of other secondary behavior that is even more distracting. PMID- 25793433 TI - Carotid Intima-Media Thickness and Long-Term Exposure to Traffic-Related Air Pollution in Middle-Aged Residents of Taiwan: A Cross-Sectional Study. AB - BACKGROUND: Associations between long-term exposure to air pollution and carotid intima-media thickness (CIMT) have inconsistent findings. OBJECTIVES: In this study we aimed to evaluate association between 1-year average exposure to traffic related air pollution and CIMT in middle-aged adults in Asia. METHODS: CIMT was measured in Taipei, Taiwan, between 2009 and 2011 in 689 volunteers 35-65 years of age who were recruited as the control subjects of an acute coronary heart disease cohort study. We applied land-use regression models developed by the European Study of Cohorts for Air Pollution Effects (ESCAPE) to estimate each subject's 1-year average exposure to traffic-related air pollutants with particulate matter diameters <= 10 MUm (PM10) and <= 2.5 MUm (PM2.5) and the absorbance levels of PM2.5 (PM2.5abs), nitrogen dioxide (NO2), and nitrogen oxides (NOx) in the urban environment. RESULTS: One-year average air pollution exposures were 44.21 +/- 4.19 MUg/m3 for PM10, 27.34 +/- 5.12 MUg/m3 for PM2.5, and (1.97 +/- 0.36) * 10-5/m for PM2.5abs. Multivariate regression analyses showed average percentage increases in maximum left CIMT of 4.23% (95% CI: 0.32, 8.13) per 1.0 * 10-5/m increase in PM2.5abs; 3.72% (95% CI: 0.32, 7.11) per 10 MUg/m3 increase in PM10; 2.81% (95% CI: 0.32, 5.31) per 20-MUg/m3 increase in NO2; and 0.74% (95% CI: 0.08, 1.41) per 10-MUg/m3 increase in NOx. The associations were not evident for right CIMT, and PM2.5 mass concentration was not associated with the outcomes. CONCLUSIONS: Long-term exposures to traffic related air pollution of PM2.5abs, PM10, NO2, and NOx were positively associated with subclinical atherosclerosis in middle-aged adults. PMID- 25793434 TI - Can a Boxer Engine Reduce Leg Injuries Among Motorcyclists? Analysis of Injury Distributions in Crashes Involving Different Motorcycles Fitted with Antilock Brakes (ABS). AB - OBJECTIVES: Several studies have shown that motorcycle antilock braking systems (ABS) reduce crashes and injuries. However, it has been suggested that the improved stability provided by ABS would make upright crashes more frequent, thus changing the injury distributions among motorcyclists and increasing the risk of leg injuries. The overall motorcycle design can vary across different categories and manufacturers. For instance, some motorcycles are equipped with boxer-twin engines; that is, with protruding cylinder heads. A previous study based on a limited material has suggested that these could provide some leg protection; therefore, the aim of this research was to analyze injury distributions in crashes involving ABS-equipped motorcycles with boxer-twin engines compared to similar ABS-equipped motorcycles with other engine configurations. METHODS: Swedish hospital and police records from 2003-2014 were used. Crashes involving ABS-equipped motorcycles with boxer-twin engines (n = 55) were compared with similar ABS-equipped motorcycles with other engines configurations (n = 127). The distributions of Abbreviated Injury Scale (AIS) 1+ and AIS 2+ were compared. Each subject's injury scores were also converted to the risk for permanent medical impairment (RPMI), which shows the risk of different levels of permanent medical impairment given the severity and location and of injuries. To compare injury severity, the mean RPMI 1+ and RPMI 10+ were analyzed for each body region and in overall for each group of motorcyclists. RESULTS: It was found that AIS 1+, AIS 2+, and PMI 1+ leg injuries were reduced by approximately 50% among riders with boxer engines. These results were statistically significant. The number of injuries to the upper body did not increase; the mean RPMI to the head and upper body were similar across the 2 groups, suggesting that the severity of injuries did not increase either. Indications were found suggesting that the overall mean RPMI 1+ was lower among riders with boxer engines, although this result was not statistically significant. The mean values of the overall RPMI 10+ were similar. CONCLUSIONS: Boxer-twin engines were not originally developed to improve motorcycle crashworthiness. However, the present article indicates that these engines can reduce leg injuries among riders of motorcycles fitted with ABS. Though it is recommended that future research should look deeper into this particular aspect, the present findings suggest that the concept of integrated leg protection is indeed feasible and that further engineering efforts in this area are likely to yield significant savings in health losses among motorcyclists. PMID- 25793435 TI - Homeless Patients in the ICU: An Observational Propensity-Matched Cohort Study. AB - OBJECTIVE: To describe epidemiology and outcome of critically ill homeless patients, as compared with those of nonhomeless patients. DESIGN: Homeless and nonhomeless admissions were matched on the basis of a 1:4 ratio, using a propensity score-based procedure involving age, sex, date, and main diagnosis at ICU admission. SETTING: A 18-bed closed medical ICU of a French tertiary care university hospital. PATIENTS: All consecutive admissions from July 2000 to December 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 421 homeless and 9,353 nonhomeless admissions. Considering homeless admissions, 50% patients had no health insurance, 56% had no financial resource, 91% were socially isolated, and 69% lived in street. In a multivariable analysis of homeless admissions including age, sex, and Simplified Acute Physiology Score II, living in street was significantly associated with hospital mortality (odds ratio=2.94; 95% CI, 1.30-7.10; p=0.012). As compared with nonhomeless, homeless admissions more frequently concerned men (89% vs 57%; p<0.0001) and younger patients (49 yr [43-57] vs 62 yr [46-76]; p<0.0001), whereas Simplified Acute Physiology Score II (37 [24-50] vs 37 [25-52]; p=0.99) and distribution of the number of organ supports (p=0.49) were similar. ICU mortality concerned 19.1% and 18% of matched homeless and nonhomeless admissions, respectively. The corresponding figures for hospital mortality were 20.8% and 20.6%. In multivariable analysis, homeless status was associated with neither ICU (odds ratio=1.27 [0.92-1.73]; p=0.14) nor hospital mortality (odds ratio=1.07 [0.77 1.49]; p=0.68), while it was independently associated with longer ICU (means ratio=1.16 [1.01-1.34]; p=0.035) and hospital (means ratio=1.30 [1.12-1.49]; p=0.0002) stay of survivors. CONCLUSIONS: Critically ill homeless patients benefit from the same level of care and have globally the same prognosis than housed patients but experience longer lengths of stay. Most precarious patients living in street have a higher mortality rate. The study perspective is not ICU centered but also concerns the global organization of healthcare since homeless patients are referred by numerous sources and discharged to different wards. PMID- 25793436 TI - The presence of hypothermia within 24 hours of sepsis diagnosis predicts persistent lymphopenia. AB - OBJECTIVE: To determine whether hypothermia within 24 hours of sepsis diagnosis is associated with development of persistent lymphopenia, a feature of sepsis induced immunosuppression. DESIGN: Retrospective cohort study. SETTING: A 1,200 bed university-affiliated tertiary care hospital. PATIENTS: Adult patients diagnosed with bacteremia and sepsis within 5 days of hospital admission between January 1, 2010, and July 31, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Leukocyte counts were recorded during the first 4 days following sepsis diagnosis. Persistent lymphopenia was defined as an absolute lymphocyte count less than 1.2 cells/MUL*10(3) present on the fourth day after diagnosis. Of the 445 patients with sepsis included, hypothermia developed in 64 patients (14.4%) (defined as a body temperature<36.0 degrees C) within 24 hours of sepsis diagnosis. Hypothermia was a significant independent predictor of persistent lymphopenia (adjusted odds ratio, 2.70 [95% CI, 1.10, 6.60]; p=0.03) after accounting for age, disease severity, comorbidities, source of bacteremia, and type of organism. Compared with the nonhypothermic patients, hypothermic patients had higher 28-day (50.0% vs 24.9%, p<0.001) and 1-year mortality (60.9% vs 47.0%, p=0.001). CONCLUSIONS: Hypothermia is associated with higher mortality and an increased risk of persistent lymphopenia in patients with sepsis, and it may be an early clinical predictor of sepsis-induced immunosuppression. PMID- 25793437 TI - Excess Mortality Associated With Colistin-Tigecycline Compared With Colistin Carbapenem Combination Therapy for Extensively Drug-Resistant Acinetobacter baumannii Bacteremia: A Multicenter Prospective Observational Study. AB - OBJECTIVES: Since few therapeutic options exist for extensively drug resistant Acinetobacter baumannii, an emerging threat in ICUs worldwide, and comparative prospective studies of colistin-based combination therapies are lacking, our objective was to compare the outcomes of patients with extensively drug-resistant A. baumannii bacteremia, treated with colistin-carbapenem and colistin tigecycline combinations. DESIGN: Prospective, observational, multicenter study. SETTING, PATIENTS, AND INTERVENTIONS: Adults with extensively drug-resistant A. baumannii bacteremia were prospectively followed from 2010 to 2013 at three hospitals in Taiwan. Extensively drug-resistant A. baumannii was defined as A. baumannii (genospecies 2) nonsusceptible to all drug classes except for colistin and tigecycline, and standard combination therapy as use of parenteral colistin carbapenem or colistin-tigecycline for at least 48 hours after onset of bacteremia. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was 14-day mortality. Of the 176 episodes of extensively drug-resistant A. baumannii bacteremia evaluated, 55 patients with a median (interquartile range) age of 62 years (44-79 yr) and Sequential Organ Failure Assessment score of 9 (5-13) points received standard combination therapy: colistin-tigecycline in 29 patients and colistin-carbapenem in 26. Crude 14-day and in-hospital mortality rates for patients receiving colistin-tigecycline versus patients receiving colistin carbapenem were 35% versus 15% (p=0.105) and 69% versus 50% (p=0.152), respectively. Breakthrough extensively drug-resistant A. baumannii bacteremia under steady state concentrations of combination therapy for colistin-tigecycline group was 18% and for colistin-carbapenem group was 0% (p=0.059). Eleven patients (20.0%) developed nephrotoxicity. After adjusting for age, sex, comorbidity, initial disease severity, loading colistin dose, polymicrobial infection, and primary infection site, excess 14-day mortality was associated with the use of colistin-tigecycline in the subgroup with tigecycline minimum inhibitory concentration greater than 2 mg/L compared with the use of colistin-carbapenem (hazard ratio, 6.93; 95% CI, 1.61-29.78; p=0.009). CONCLUSIONS: Increased 14-day mortality was associated with colistin-tigecycline therapy given tigecycline minimum inhibitory concentration greater than 2 mg/L compared with colistin carbapenem therapy for extensively drug-resistant A. baumannii bacteremia. PMID- 25793438 TI - Juvenile porcine islets can restore euglycemia in diabetic athymic nude mice after xenotransplantation. AB - BACKGROUND: Porcine islet xenotransplantation has been demonstrated in many animal studies to cure experimentally induced diabetes. However, several issues currently impede the translation of porcine islet xenotransplantation to sustained insulin independence clinically. Although adult pigs have mature islets that secrete insulin in response to a glucose challenge, and are physiologically similar to humans, there are logistical considerations with adult porcine tissue that are not present with juvenile porcine tissue. To circumvent these issues, we have identified 18- to 21-day-old preweaned juvenile pigs as islet donors as we have previously demonstrated superior islet yields and function from juvenile pigs using our islet isolation protocols. METHODS: We evaluated the efficacy of islets isolated from 18- to 24-day-old Yorkshire swine in vitro using a standard glucose-stimulated insulin response assay, and in vivo after xenotransplantation under the kidney capsule of streptozotocin-induced 8- to 10-week-old male athymic nude mice. The mice were monitored for a period of 60 days after transplantation, after which the grafts were explanted and analyzed. RESULTS: Diabetic athymic nude mice transplanted with 1500 to 3000 islet equivalents (IEq) of islets achieved sustained normoglycemia for up to 60 days after islet transplantation. When the grafts were explanted with the kidney, a rapid return to hyperglycemia was observed. CONCLUSIONS: Efficacy and dose-titration studies evaluating these islets in immunocompetent and nonobese diabetic mouse models are underway. The results of these studies will permit application for nonhuman primate and pivotal clinical trials in human diabetic patients in the near future. PMID- 25793439 TI - Pericytes, microvasular dysfunction, and chronic rejection. AB - Chronic rejection of transplanted organs remains the main obstacle in the long term success of organ transplantation. Thus, there is a persistent quest for development of antichronic rejection therapies and identification of novel molecular and cellular targets. One of the potential targets is the pericytes, the mural cells of microvessels, which regulate microvascular permeability, development, and maturation by controlling endothelial cell functions and regulating tissue fibrosis and inflammatory response. In this review, we discuss the potential of targeting pericytes in the development of microvasular dysfunction and the molecular pathways involved in regulation of pericyte activities for antichronic rejection intervention. PMID- 25793443 TI - Large-scale deployment of seed treatments has driven rapid increase in use of neonicotinoid insecticides and preemptive pest management in US field crops. AB - Neonicotinoids are the most widely used class of insecticides worldwide, but patterns of their use in the U.S. are poorly documented, constraining attempts to understand their role in pest management and potential nontarget effects. We synthesized publicly available data to estimate and interpret trends in neonicotinoid use since their introduction in 1994, with a special focus on seed treatments, a major use not captured by the national pesticide-use survey. Neonicotinoid use increased rapidly between 2003 and 2011, as seed-applied products were introduced in field crops, marking an unprecedented shift toward large-scale, preemptive insecticide use: 34-44% of soybeans and 79-100% of maize hectares were treated in 2011. This finding contradicts recent analyses, which concluded that insecticides are used today on fewer maize hectares than a decade or two ago. If current trends continue, neonicotinoid use will increase further through application to more hectares of soybean and other crop species and escalation of per-seed rates. Alternatively, our results, and other recent analyses, suggest that carefully targeted efforts could considerably reduce neonicotinoid use in field crops without yield declines or economic harm to farmers, reducing the potential for pest resistance, nontarget pest outbreaks, environmental contamination, and harm to wildlife, including pollinator species. PMID- 25793440 TI - Range-dependent flexibility in the acoustic field of view of echolocating porpoises (Phocoena phocoena). AB - Toothed whales use sonar to detect, locate, and track prey. They adjust emitted sound intensity, auditory sensitivity and click rate to target range, and terminate prey pursuits with high-repetition-rate, low-intensity buzzes. However, their narrow acoustic field of view (FOV) is considered stable throughout target approach, which could facilitate prey escape at close-range. Here, we show that, like some bats, harbour porpoises can broaden their biosonar beam during the terminal phase of attack but, unlike bats, maintain the ability to change beamwidth within this phase. Based on video, MRI, and acoustic-tag recordings, we propose this flexibility is modulated by the melon and implemented to accommodate dynamic spatial relationships with prey and acoustic complexity of surroundings. Despite independent evolution and different means of sound generation and transmission, whales and bats adaptively change their FOV, suggesting that beamwidth flexibility has been an important driver in the evolution of echolocation for prey tracking. PMID- 25793444 TI - Divergence in the reactivity between amine- and phosphine-catalyzed cycloaddition reactions of allenoates with enynals: one-pot gold-catalyzed synthesis of trisubstituted benzofurans from the [3 + 2] cycloadduct via 1,2-alkyl migration and dehydrogenation. AB - Regioselective synthesis of functionalized dihydropyran derivatives by DABCO catalyzed [2 + 4] cycloaddition of allenoates with enynals or enynones has been developed. Phosphine-catalyzed [3 + 2] cycloaddition of allenoates with enynals provides 1,1-alkyne (aldehyde)-substituted cyclopentenes wherein enynals act as electrophiles. These alkyne-tethered cyclopentenes upon [Au]/[Ag] catalysis lead to substituted benzofurans via 1,2-alkyl migration and dehydrogenation (aromatization). One-pot reaction of allenoates with enynals using sequential phosphine and gold catalysis is also reported. The cyclopentene obtained from the PPh3-catalyzed reaction of allenoate H2C?C?CH(COO-t-Bu) with enynal undergoes decarboxylation under the [Au]/[Ag] catalysis and forms a carboxylate-free benzofuran. The structures of key products are confirmed by single-crystal X-ray analysis. PMID- 25793442 TI - The polarity protein Baz forms a platform for the centrosome orientation during asymmetric stem cell division in the Drosophila male germline. AB - Many stem cells divide asymmetrically in order to balance self-renewal with differentiation. The essence of asymmetric cell division (ACD) is the polarization of cells and subsequent division, leading to unequal compartmentalization of cellular/extracellular components that confer distinct cell fates to daughter cells. Because precocious cell division before establishing cell polarity would lead to failure in ACD, these two processes must be tightly coupled; however, the underlying mechanism is poorly understood. In Drosophila male germline stem cells, ACD is prepared by stereotypical centrosome positioning. The centrosome orientation checkpoint (COC) further serves to ensure ACD by preventing mitosis upon centrosome misorientation. In this study, we show that Bazooka (Baz) provides a platform for the correct centrosome orientation and that Baz-centrosome association is the key event that is monitored by the COC. Our work provides a foundation for understanding how the correct cell polarity may be recognized by the cell to ensure productive ACD. PMID- 25793446 TI - A roundtable discussion: elevating the value and importance of risk management in healthcare technology. PMID- 25793441 TI - Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression. AB - Intracellular pH (pHi) dynamics is increasingly recognized as an important regulator of a range of normal and pathological cell behaviors. Notably, increased pHi is now acknowledged as a conserved characteristic of cancers and in cell models is confirmed to increase proliferation and migration as well as limit apoptosis. However, the significance of increased pHi for cancer in vivo remains unresolved. Using Drosophila melanogaster, we show that increased pHi is sufficient to induce dysplasia in the absence of other transforming cues and potentiates growth and invasion with oncogenic Ras. Using a genetically encoded biosensor we also confirm increased pHi in situ. Moreover, in Drosophila models and clonal human mammary cells we show that limiting H(+) efflux with oncogenic Raf or Ras induces acidosis and synthetic lethality. Further, we show lethality in invasive primary tumor cell lines with inhibiting H(+) efflux. Synthetic lethality with reduced H(+) efflux and activated oncogene expression could be exploited therapeutically to restrain cancer progression while limiting off target effects. PMID- 25793445 TI - A million ways to think about risk management. PMID- 25793447 TI - Eight common myths and misunderstandings about risk management. PMID- 25793448 TI - Best practices in applying medical device risk management terminology. PMID- 25793449 TI - Documenting medical device risk management through the risk traceability summary. PMID- 25793450 TI - Evolution of a risk-based approach to effective healthcare technology management. PMID- 25793451 TI - Medical device risk management and safety cases. PMID- 25793452 TI - Risk management and IEC 60601-1: assessing compliance. PMID- 25793453 TI - Assessing risk in the Kaiser Permanente clinical technology program. PMID- 25793455 TI - Noble metal alloy complex nanostructures: controllable synthesis and their electrochemical property. AB - Noble metal nanocrystals have been extensively utilized as promising catalysts for chemical transformations and energy conversion. One of their significant applications lies in electrode materials in fuel cells (FCs) due to their superior electrocatalytic performance towards the reactions both on anode and cathode. Nowadays, tremendous efforts have been devoted to improve the catalytic performance and minimize the usage of precious metals. Constructing multicomponent noble metal nanocrystals with complex structures provides the opportunity to reach this goal due to their highly tunable compositions and morphologies, leading to the modification of the related electrochemical properties. In this review, we first highlight the recent advances in the controllable synthesis of noble metal alloy complex nanostructures including nanoframes/nanocages, branched structures, concave/convex structures, core-shell structures and ultrathin structures. Then the effects of the well-defined nanocrystals on the modified and improved electrochemical properties are outlined. Finally, we make a conclusion with the points on the challenges and perspectives of the controllable synthesis of noble metal alloy complex nanostructures and their electrocatalytic performance. PMID- 25793456 TI - Unusual 1,2-aryl migration in Pd(ii)-catalyzed aza-Wacker-type cyclization of 2 alkenylanilines. AB - Inspired by the Hegedus aza-Wacker indole synthesis, we were intrigued with the fate of the aminopalladation intermediate if syn beta-hydrogen is made inaccessible or unavailable. In contrast to our previously reported beta-carbon elimination, cyclization of a variety of 2-alkenylaniline substrates under electrophilic palladium conditions unexpectedly afforded C3-substituted indoles. This unusual 1,2-migratory process was found to be operative across a variety of substrates with predictable migratory aptitude. A mechanistic proposal was put forward to rationalize the observed substrate dependence, and this unexpected finding could provide an opportunity for other related processes. PMID- 25793457 TI - Towards optimal seeding for the synthesis of ordered nanoparticle arrays on alumina/Ni3Al(111). AB - The adsorption and the nucleation of different transition metals (Fe, Co, Ni, Cu, Pd, Ag, and Au) on alumina/Ni3Al(111) have been studied to shed light on the first stages of the synthesis of supported nanoparticles, focusing in particular on the possibility of producing ordered arrays. Affinity for oxygen, atomic radii, electronic properties and kinetics have been taken into account to rationalize the different behavior. In agreement with empirical findings, Pd is confirmed to be the best choice for a highly ordered nucleation following the "dot" superstructure of the alumina, due to a remarkable preference for the corresponding adsorption sites (holes) with respect to others, and for a rather strong binding. Atom by atom nucleation of this material has been studied, for seeds up to 6 atoms that offer a stiff anchoring of nanoparticles to the support. PMID- 25793458 TI - Development and Validation of the Athlete Fear Avoidance Questionnaire. AB - CONTEXT: The fear-avoidance model was developed in an attempt to explain the process by which "pain experience" and "pain behavior" become dissociated from the actual pain sensation in individuals who manifest the phenomenon of exaggerated pain perception. High levels of fear avoidance can lead to chronic pain and disability and have successfully predicted rehabilitation time in the work-related-injury population. Existing fear-avoidance questionnaires have all been developed for the general population, but these questionnaires may not be specific enough to fully assess fear avoidance in an athletic population that copes with pain differently than the general population. OBJECTIVE: To develop and validate the Athlete Fear Avoidance Questionnaire (AFAQ). DESIGN: Qualitative research to develop the AFAQ and a cross-sectional study to validate the scale. PATIENTS OR OTHER PARTICIPANTS: For questionnaire development, a total of 8 experts in the fields of athletic therapy, sport psychology, and fear avoidance were called upon to generate and rate items for the AFAQ. For determining concurrent validity, 99 varsity athletes from various sports participated. DATA COLLECTION AND ANALYSIS: A total of 99 varsity athletes completed the AFAQ, the Fear-Avoidance Beliefs Questionnaire, and the Pain Catastrophizing Scale. We used Pearson correlations to establish concurrent validity. RESULTS: Concurrent validity was established with significant correlations between the AFAQ and the Fear Avoidance Beliefs Questionnaire-Physical Activity (r = 0.352, P > .001) as well as with the Pain Catastrophizing Scale (r = 0.587, P > .001). High internal consistency of our questionnaire was established with a Cronbach alpha coefficient of 0.805. The final version of the questionnaire includes 10 items with good internal validity (P < .05). CONCLUSIONS: We developed a questionnaire with good internal and external validity. The AFAQ is a scale that measures sport injury-related fear avoidance in athletes and could be used to identify potential psychological barriers to rehabilitation. PMID- 25793459 TI - Acute stimulant ingestion and neurocognitive performance in healthy participants. AB - CONTEXT: Concussion management has become an area of great concern in athletics, and neurocognitive tests, such as Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), are commonly used as management tools. Given the restrictive nature of current management plans, anecdotal concerns have been raised about athletes trying to cheat the assessments and return to participation sooner. Stimulants have been shown to improve neurocognitive measures similar to those used in ImPACT. Therefore, they could possibly improve performance during baseline and postinjury testing. OBJECTIVE: To examine the effects of a supplement containing stimulants on ImPACT performance. DESIGN: Crossover study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 5 men (age = 20.6 +/- 1.5 years, height = 176.3 +/- 9.6 cm, mass = 76.9 +/- 18.6 kg) and 7 women (age = 20.6 +/- 1.1 years, height = 162.9 +/- 7.8 cm, mass = 60.9 +/- 8.2 kg) with no histories of physician-diagnosed head injury, learning disability, or attention-deficit disorder. INTERVENTION(S): Participants were assessed under supplement (5.5 g of Jacked 3D, which contains caffeine and 1,3 dimethylamylamine), placebo, and control conditions separated by 1 week. MAIN OUTCOME MEASURE(S): I compared ImPACT composite scores for verbal and visual memory, visual motor speed, reaction time, impulse control, and a cognitive efficiency index under each of the 3 conditions and assessed them 30 minutes after ingestion. RESULTS: I observed a difference when comparing reaction times, as the participants reacted faster during the supplement condition (0.53 +/- 0.03 seconds) than during the placebo (0.55 +/- 0.03 seconds) and control (0.55 +/- 0.03 seconds) conditions (F2,22 = 4.31, P = .03). A difference also was observed for the cognitive-efficiency index, as participants scored higher during the supplement condition (0.49 +/- 0.09) than during the placebo (0.41 +/- 0.10) and control (0.41 +/- 0.12) conditions (F2,22 = 4.07, P = .03). CONCLUSIONS: Stimulant ingestion 30 minutes before testing resulted in improved memory, visual processing speed, and reaction time. However, the improvements were relatively nominal, and the question of clinical importance remains. Thus, it is unclear if stimulant ingestion would affect the return-to-participation progression. PMID- 25793460 TI - Preparation of the Professional Athletic Trainer: A Descriptive Study of Undergraduate and Graduate Degree Programs. AB - CONTEXT: The examination of the appropriate professional degree for preparation as an athletic trainer is of interest to the profession. Descriptive information concerning universal outcomes is needed to understand the effect of a degree change. OBJECTIVE: To obtain and compare descriptive information related to professional athletic training programs and a potential degree change and to determine if any of these factors contribute to success on existing universal outcome measures. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: We contacted 364 program directors; 178 (48.9%; 163 undergraduate, 15 postbaccalaureate) responded. INTERVENTION(S): The survey consisted of 46 questions: 45 questions that dealt with 5 themes (institutional demographics [n = 13], program admissions [n = 6], program outcomes [n = 10], program design [n = 9], faculty and staff [n = 7]) and 1 optional question. MAIN OUTCOME MEASURE(S): Descriptive statistics for all programs were calculated. We compared undergraduate and postbaccalaureate programs by examining universal outcome variables. RESULTS: Descriptive statistics demonstrated that 33 programs could not support postbaccalaureate degrees, and a substantial loss of faculty could occur if the degree requirement changed (553 graduate assistants, 642 potentially underqualified instructors). Postbaccalaureate professional programs had higher 2011-2012 first-time Board of Certification (BOC) passing rates (U = 464.5, P = .001), 3-year aggregate first-time BOC passing rates (U = 451.5, P = .001), and employment rates for 2011-2012 graduates employed within athletic training (U = 614.0, P = .01). Linear multiple-regression models demonstrated that program and institution type contributed to the variance of the first-time BOC passing rates and the 3-year aggregate first-time BOC passing rates (P < .05). CONCLUSIONS: Students in postbaccalaureate athletic training programs performed better in universal outcome measures. Our data supported the concerns that this transition could result in the loss of some programs and an additional immediate strain on current staff due to potential staffing changes and the loss of graduate assistant positions. PMID- 25793461 TI - Conformational analysis and chemical reactivity of the multidomain sulfurtransferase, Staphylococcus aureus CstA. AB - The cst operon of the major human pathogen Staphylococcus aureus (S. aureus) is under the transcriptional control of CsoR-like sulfurtransferase repressor (CstR). Expression of this operon is induced by hydrogen sulfide, and two components of the cst operon, cstA and cstB, protect S. aureus from sulfide toxicity. CstA is a three-domain protein, and each domain harbors a single cysteine that is proposed to function in vectorial persulfide shuttling. We show here that single cysteine substitution mutants of CstA fail to protect S. aureus against sulfide toxicity in vivo. The N-terminal domain of CstA exhibits thiosulfate sulfurtransferase (TST; rhodanese) activity, and a Cys66 (34)S persulfide is formed as a catalytic intermediate in both the presence and absence of the adjacent TusA-like domain using (34)S-SO3(2-) as a substrate. Cysteine persulfides can be trapped on both C66 in CstA(Rhod) and on C66 and C128 in CstA(Rhod-TusA) when incubated with thiosulfate, sodium tetrasulfide (Na2S4), and in situ persulfurated SufS. C66A substitution in CstA(Rhod-TusA) abolishes C128 S sulfhydration, consistent with directional persulfide shuttling in CstA. Fully reduced CstA(Rhod-TusA) is predominately monomeric, and high resolution tandem mass spectrometry reveals that Cys66 and Cys128 can form a C66-C128 disulfide bond using a number of oxidants, which leads to a significant change in conformation. A competing intermolecular C128-C128' disulfide bond is also formed. Small-angle X-ray scattering measurements and gel filtration chromatography of reduced CstA(Rhod-TusA) reveal an elongated molecule (Rg ~ 30 A, 21.6 kDa) where the two domains pack "side-by-side" that likely places Cys66 and Cys128 far apart. These studies are consistent with the low yield of C66-C128 cross-link as a mimic of a persulfide transfer intermediate in CstA, and small, but measurable persulfide transfer from Cys66 to Cys128 within the CstA(Rhod TusA) with inorganic sulfur donors. PMID- 25793462 TI - Precedent fluctuation of serum hs-CRP to albumin ratios and mortality risk of clinically stable hemodialysis patients. AB - BACKGROUND: A high sensitivity C-reactive protein to albumin ratio (hs-CRP/Alb) predicts mortality risk in patients with acute kidney injury. However, it varies dynamically. This study was conducted to evaluate whether a variation of this marker was associated with long-term outcome in clinically stable hemodialysis (HD) patients. METHODS: hs-CRP/Alb was checked bimonthly in 284 clinically stable HD outpatients throughout all of 2008. Based on the "slope" of trend equation derived from 5-6 hs-CRP/alb ratios for each patient, the total number of patients was divided into quartiles--Group 1: beta? -0.13, n = 71; group 2: beta> 0.13?0.003; n = 71, group 3: beta>0.003?0.20; and group 4: beta>0.20, n = 71. The observation period was from January 1, 2009 to August 31, 2012. RESULTS: Group 1+4 showed a worse long-term survival (p = 0.04) and a longer 5-year hospitalization stay than Group 2+3 (38.7+/-44.4 vs. 16.7+/-22.4 days, p<0.001). Group 1+4 were associated with older age (OR = 1.03, 95% CI = 1.01-1.05) and a high prevalence of congestive heart failure (OR = 2.02, 95% CI = 1.00-4.11). Standard deviation (SD) of hs-CRP/Alb was associated with male sex (beta = 0.17, p = 0.003), higher Davies co-morbidity score (beta = 0.16, p = 0.03), and baseline hs-CRP (beta = 0.39, p<0.001). Patients with lower baseline and stable trend of hs-CRP/Alb had a better prognosis. By multivariate Cox proportional methods, SD of hs-CRP/alb (HR: 1.05, 95% CI: 1.01-1.08) rather than baseline hs CRP/Alb was an independent predictive factor for long-term mortality after adjusting for sex and HD vintage. CONCLUSION: Clinically stable HD patients with a fluctuating variation of hs-CRP/Alb are characterized by old age, and more co morbidity, and they tend to have longer subsequent hospitalization stay and higher mortality risk. PMID- 25793463 TI - Psychosocial factors at work and obesity among young finnish adults: a cohort study. AB - OBJECTIVE: To examine the associations between occupational psychosocial factors and obesity among 31-year-olds, adjusting for adolescent body mass index, physical strenuousness of work, and adverse health behaviors (ie, stress-related eating/drinking, leisure-time physical inactivity, smoking, and high alcohol consumption). METHODS: The study population comprised 2083 men and 1770 women from the Northern Finland Birth Cohort 1966. Obesity was defined as a body mass index of 30.0 kg/m or more. Psychosocial exposures were defined in terms of demands, control, and social support at work. RESULTS: Among men, high job demands and low worksite social support were independently associated with obesity. Among women, stress-related eating/drinking and physical inactivity seemed to promote obesity. Body mass index at age 14 was an important predictor of obesity for both sexes. CONCLUSIONS: In workplace obesity prevention programs, it might be beneficial to improve the psychosocial work environment and promote healthy behaviors simultaneously. PMID- 25793464 TI - The forgotten role of central volume in low frequency oscillations of heart rate variability. AB - The hypothesis that central volume plays a key role in the source of low frequency (LF) oscillations of heart rate variability (HRV) was tested in a population of end stage renal disease patients undergoing conventional hemodialysis (HD) treatment, and thus subject to large fluid shifts and sympathetic activation. Fluid overload (FO) in 58 chronic HD patients was assessed by whole body bioimpedance measurements before the midweek HD session. Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. Time domain and frequency domain analyses were performed on HRV signals. Patients were retrospectively classified in three groups according to tertiles of FO normalized to the extracellular water (FO/ECW%). These groups were also compared after stratification by diabetes mellitus. Patients with the low to medium hydration status before the treatment (i.e. 1st and 2nd FO/ECW% tertiles) showed a significant increase in LF power during last 30 min of HD compared to dialysis begin, while no significant change in LF power was seen in the third group (i.e. those with high pre-treatment hydration values). In conclusion, several mechanisms can generate LF oscillations in the cardiovascular system, including baroreflex feedback loops and central oscillators. However, the current results emphasize the role played by the central volume in determining the power of LF oscillations. PMID- 25793465 TI - Percutaneous cryoablation of ovarian cancer metastasis to the liver: initial experience in 13 patients. AB - OBJECTIVE: To evaluate the feasibility, safety, and effectiveness of percutaneous cryoablation for the treatment of liver metastases from ovarian cancer. METHODS/MATERIALS: A retrospective review was performed on 13 patients with liver metastases from ovarian cancer who underwent percutaneous cryoablation with computed tomography (CT) guidance. The tumor response was assessed by enhanced computed tomography performed before treatment, 1 month after, and every 3 months after treatment. The Functional Assessment of Cancer Therapy-General quality of life (QOL) was used to assess the patients' QOL before, 1 week, 1 month, and 3 months after cryoablation. RESULTS: A total of 27 procedures of cryoablation were performed on these patients, and 5 patients underwent repeat procedures. Complete ablation was achieved for all lesions. Months are counted from the time of cryoablation, and the median duration of follow-up was 15 months (4-22 months). At the 1-month follow-up, the primary technique effectiveness was 100%. At the 3 month follow-up, local tumor progression was observed in 2 (7.14%) of 28 lesions. The 1-year survival from the time of cryoablation was 92.3%. Two patients died after 9 and 14 months, respectively. The QOL symptoms and functioning scales were preserved in patients alive at 3 months after cryoablation. No major complications such as cryoshock, hepatic bleeding, liver abscess, biliary fistula, and renal insufficiency were encountered. CONCLUSIONS: Our initial experience showed that cryoablation is a safe and effective ablative therapy, providing a high rate of local tumor control in ovarian cancer liver metastases. PMID- 25793466 TI - Time-dependent density functional theory study of the luminescence properties of gold phosphine thiolate complexes. AB - The origin of the emission of the gold phosphine thiolate complex (TPA)AuSCH(CH3)2 (TPA = 1,3,5-triaza-7-phosphaadamantanetriylphosphine) is investigated using time-dependent density functional theory (TDDFT). This system absorbs light at 3.6 eV, which corresponds mostly to a ligand-to-metal transition with some interligand character. The P-Au-S angle decreases upon relaxation in the S1 and T1 states. Our calculations show that these two states are strongly spin-orbit coupled at the ground state geometry. Ligand effects on the optical properties of this complex are also discussed by looking at the simple AuP(CH3)3SCH3 complex. The excitation energies differ by several tenths of an electronvolt. Excited state optimizations show that the excited singlet and triplet of the (TPA)AuSCH(CH3)2 complex are bent. On the other hand, the Au-S bond breaks in the excited state for the simple complex, and TDDFT is no longer an adequate method. The excited state energy landscape of gold phosphine thiolate systems is very complex, with several state crossings. This study also shows that the formation of the [(TPA)AuSCH(CH3)2]2 dimer is favorable in the ground state. The inclusion of dispersion interactions in the calculations affects the optimized geometries of both ground and excited states. Upon excitation, the formation of a Au-Au bond occurs, which results in an increase in energy of the low energy excited states in comparison to the monomer. The experimentally observed emission of the (TPA)AuSCH(CH3)2 complex at 1.86 eV cannot be unambiguously assigned and may originate from several excited states. PMID- 25793467 TI - Long-term outcomes in primary spinal osteochondroma: a multicenter study of 27 patients. AB - OBJECT Clinical outcomes in patients with primary spinal osteochondromas are limited to small series and sporadic case reports. The authors present data on the first long-term investigation of spinal osteochondroma cases. METHODS An international, multicenter ambispective study on primary spinal osteochondroma was performed. Patients were included if they were diagnosed with an osteochondroma of the spine and received surgical treatment between October 1996 and June 2012 with at least 1 follow-up. Perioperative prognostic variables, including patient age, tumor size, spinal level, and resection, were analyzed in reference to long-term local recurrence and survival. Tumor resections were compared using Enneking appropriate (EA) or Enneking inappropriate surgical margins. RESULTS Osteochondromas were diagnosed in 27 patients at an average age of 37 years. Twenty-two lesions were found in the mobile spine (cervical, thoracic, or lumbar) and 5 in the fixed spine (sacrum). Twenty-three cases (88%) were benign tumors (Enneking tumor Stages 1-3), whereas 3 (12%) exhibited malignant changes (Enneking tumor Stages IA-IIB). Sixteen patients (62%) underwent en bloc treatment-that is, wide or marginal resection-and 10 (38%) underwent intralesional resection. Twenty-four operations (92%) followed EA margins. No one received adjuvant therapy. Two patients (8%) experienced recurrences: one in the fixed spine and one in the mobile spine. Both recurrences occurred in latent Stage 1 tumors following en bloc resection. No osteochondroma related deaths were observed. CONCLUSIONS In the present study, most patients underwent en bloc resection and were treated as EA cases. Both recurrences occurred in the Stage 1 tumor cohort. Therefore, although benign in character, osteochondromas still require careful management and thorough follow-up. PMID- 25793468 TI - Cervical compensatory alignment changes following correction of adult thoracic deformity: a multicenter experience in 57 patients with a 2-year follow-up. AB - OBJECT Alignment changes in the cervical spine that occur following surgical correction for thoracic deformity remain poorly understood. The purpose of this study was to evaluate such changes in a cohort of adults with thoracic deformity treated surgically. METHODS The authors conducted a multicenter retrospective analysis of consecutive patients with thoracic deformity. Inclusion criteria for this study were as follows: corrective osteotomy for thoracic deformity, upper most instrumented vertebra (UIV) between T-1 and T-4, lower-most instrumented vertebra (LIV) at or above L-5 (LIV >= L-5) or at the ilium (LIV-ilium), and a minimum radiographic follow-up of 2 years. Sagittal radiographic parameters were assessed preoperatively as well as at 3 months and 2 years postoperatively, including the C-7 sagittal vertical axis (SVA), C2-7 cervical lordosis (CL), C2-7 SVA, T-1 slope (T1S), T1S minus CL (T1S-CL), T2-12 thoracic kyphosis (TK), apical TK, lumbar lordosis (LL), pelvic incidence (PI), PI-LL, pelvic tilt (PT), and sacral slope (SS). RESULTS Fifty-seven patients with a mean age of 49.1 +/- 14.6 years met the study inclusion criteria. The preoperative prevalence of increased CL (CL > 15 degrees ) was 48.9%. Both 3-month and 2-year apical TK improved from baseline (p < 0.05, statistically significant). At the 2-year follow-up, only the C2-7 SVA increased significantly from baseline (p = 0.01), whereas LL decreased from baseline (p < 0.01). The prevalence of increased CL was 35.3% at 3 months and 47.8% at 2 years, which did not represent a significant change. Postoperative cervical alignment changes were not significantly different from preoperative values regardless of the LIV (LIV >= L-5 or LIV-ilium, p > 0.05 for both). In a subset of patients with a maximum TK >= 60 degrees (35 patients) and 3-column osteotomy (38 patients), no significant postoperative cervical changes were seen. CONCLUSION Increased CL is common in adult spinal deformity patients with thoracic deformities and, unlike after lumbar corrective surgery, does not appear to normalize after thoracic corrective surgery. Cervical sagittal malalignment (C2-7 SVA) also increases postoperatively. Surgeons should be aware that spontaneous cervical alignment normalization might not occur following thoracic deformity correction. PMID- 25793469 TI - High self-assessment of disability and the surgeon's recommendation against surgical intervention may negatively impact satisfaction scores in patients with spinal disorders. AB - OBJECT Patient satisfaction scores have become a common metric for health care quality. Because satisfaction scores are right-skewed, even small differences in mean scores can have a large impact. Little information, however, is available on the specific factors that play a role in satisfaction in patients with spinal disorders. The authors investigated whether disability severity and the surgeon's recommendation for or against surgical intervention were associated with patient satisfaction scores. METHODS The authors conducted a retrospective cohort study involving adult patients who were referred to a spine surgeon for an outpatient evaluation of back pain. Patients completed the Oswestry Disability Index (ODI) before their clinic appointment and a Press Ganey patient satisfaction survey after their visit. Patients were grouped by self-assessed disability severity: mild to moderate (ODI < 40%) and severe (>= 40%). Satisfaction scores were graded from 0 (very poor) to 100 (very good). Nonparametric tests were used to evaluate the association between patient satisfaction and current disability self assessment. The authors also investigated whether the surgeon's recommendation against surgery negatively affected patient satisfaction. RESULTS One hundred thirty patients completed the ODI questionnaire before and satisfaction surveys after seeing a spine surgeon for a new outpatient back pain consultation. Of these, 68 patients had severe disability, 62 had mild to moderate disability, 67 received a recommendation for surgery, and 63 received a recommendation against surgery. Composite satisfaction scores were lower among patients who had severe disability than among those with mild to moderate disability (median [interquartile range]: 91.7 [83.7-96.4] vs 95.8 [91.0-99.3], respectively; p = 0.0040). Patients who received a recommendation against surgery reported lower satisfaction scores than those who received a recommendation for surgery (91.7 [83.5-95.8] vs 95.8 [88.5-99.8]; p = 0.0059). CONCLUSIONS High self-assessment of disability and a surgeon's recommendation against surgical intervention are associated with lower satisfaction scores in patients with spinal disorders. PMID- 25793470 TI - Definitive single-stage posterior surgical correction of complete traumatic spondyloptosis at the thoracolumbar junction. AB - Complete dislocation at the thoracolumbar junction is a rare occurrence, with only 4 previously reported cases in 3 separate series. Surgical procedures in the reported cases of spondyloptosis at the thoracolumbar junction have been described using instrumentation, reduction, decompression, and stabilization techniques. In this report the authors' patient presented with spondyloptosis at the thoracolumbar junction, resulting in a T-11 American Spinal Injury Association Grade A injury. The authors corrected the patient's thoracolumbar spondyloptosis with surgical reconstruction without the use of leveraged instrumented reduction. They describe a single-stage, posterior-only spinal realignment, reconstruction, and stabilization. Within months of beginning postoperative therapy, the patient enrolled and attended courses at a local college and regained personal independence by learning to drive a motor vehicle with a hand control. Two-year radiographic and clinical follow-up confirms solid fusion across the reconstruction. PMID- 25793472 TI - Looking forward by looking back: using historical calibration to improve forecasts of human disease vector distributions. AB - Arthropod disease vectors, most notably mosquitoes, ticks, tsetse flies, and sandflies, are strongly influenced by environmental conditions and responsible for the vast majority of global vector-borne human diseases. The most widely used statistical models to predict future vector distributions model species niches and project the models forward under future climate scenarios. Although these methods address variations in vector distributions through space, their capacity to predict changing distributions through time is far less certain. Here, we review modeling methods used to validate and forecast future distributions of arthropod vectors under the effects of climate change and outline the uses or limitations of these techniques. We then suggest a validation approach specific to temporal extrapolation models that is gaining momentum in macroecological modeling and has great potential for epidemiological modeling of disease vectors. We performed systematic searches in the Web of Science, ScienceDirect, and Google Scholar to identify peer-reviewed English journal articles that model arthropod disease vector distributions under future environment scenarios. We included studies published up to and including June, 2014. We identified 29 relevant articles for our review. The majority of these studies predicted current species niches and projected the models forward under future climate scenarios without temporal validation. Historically calibrated forecast models improve predictions of changing vector distributions by tracking known shifts through recently observed time periods. With accelerating climate change, accurate predictions of shifts in disease vectors are crucial to target vector control interventions where needs are greatest. PMID- 25793471 TI - Quantitative proteomic analysis of the rice (Oryza sativa L.) salt response. AB - Salt stress is one of most serious limiting factors for crop growth and production. An isobaric Tags for Relative and Absolute Quantitation (iTRAQ) approach was used to analyze proteomic changes in rice shoots under salt stress in this study. A total of 56 proteins were significantly altered and 16 of them were enriched in the pathways of photosynthesis, antioxidant and oxidative phosphorylation. Among these 16 proteins, peroxiredoxin Q and photosystem I subunit D were up-regulated, while thioredoxin M-like, thioredoxin x, thioredoxin peroxidase, glutathione S-transferase F3, PSI subunit H, light-harvesting antenna complex I subunits, chloroplast chaperonin, vacuolar ATP synthase subunit H, and ATP synthase delta chain were down-regulated. Moreover, physiological data including total antioxidant capacity, peroxiredoxin activity, chlorophyll a/b content, glutathione S-transferase activity, reduced glutathione content and ATPase activity were consistent with changes in the levels of these proteins. The levels of the mRNAs encoding these proteins were also analyzed by real-time quantitative reverse transcription PCR, and approximately 86% of the results were consistent with the iTRAQ data. Importantly, our data suggest the important role of PSI in balancing energy supply and ROS generation under salt stress. This study provides information for an improved understanding of the function of photosynthesis and PSI in the salt-stress response of rice. PMID- 25793473 TI - Emergence of neural angiostrongyliasis in eastern Australia. AB - Despite an apparent increase in cases of angiostrongyliasis in humans and animals in Australia, the epidemiology of infection with the two species of Angiostrongylus that co-exist in this country, namely A. cantonensis and A. mackerrasae, is poorly understood. This knowledge gap is particularly important with respect to A. mackerrasae, a species evidently native to Australia, as its ability to cause disease in humans is unknown. Likewise, there is little information on the roles of native and introduced species of rodents and molluscs as hosts of Angiostrongylus species in Australia. This review focuses on the gaps in the knowledge about the two species, highlighting the need for epidemiological and pathogenesis studies on the native lungworm A. mackerrasae. PMID- 25793474 TI - Seroprevalence of spotted fever group Rickettsiae in dogs in Germany. AB - Tick-transmitted spotted fever group Rickettsiae (SFGR) are considered emerging disease pathogens in Europe. To assess the situation in Germany, a seroepidemiologic survey of dogs (n=605, which have never left Germany) was conducted to determine the prevalence of antibodies to SFGR. For this purpose, a commercially available enzyme-linked immunosorbent assay (ELISA) test for all SFGR was used. A total of 78% of the dogs were positive for antibodies of the SFGR, and there was a positive correlation between age, tick-infestation, and seropositivity. There was no correlation between clinical state, location, and seropositivity, suggesting that infection with rickettsia is neither related to the health condition of the dogs nor to their abode in Germany. According to our results, all of Germany can be considered as an endemic area for SFGR. This should be taken into account when assessing the epidemiology of human rickettsioses and their impact on public health. PMID- 25793475 TI - Epidemiological, diagnostic, clinical, and therapeutic aspects of Brucella bacteremia in children in southern Israel: a 7-year retrospective study (2005 2011). AB - BACKGROUND: Data on the various aspects of brucellosis in children living in southern Israel are missing. OBJECTIVES: Our aim was to study the epidemiological, microbiological, diagnostic, clinical, therapeutic and outcome features of brucellosis in children <19 years of age in southern Israel during 2005-2011. PATIENTS AND METHODS: The study population included all patients hospitalized with a diagnosis of brucellosis, established according to a clinical presentation compatible with brucellosis+presence of Brucella bacteremia (BB). RESULTS: A total of 128 (50.8%) of 252 patients admitted with a diagnosis of brucellosis had BB (all with Brucella melitensis). All patients were of Muslim Bedouin ethnicity. The mean incidence of BB in southern Israel was 16 cases/100,000 Bedouin, with no significant changes during the study period. Overall duration of symptoms before diagnosis was 10.1+/-10.9 days. Fever at diagnosis was recorded in <20% of the patients. The most frequent symptoms were arthralgia (61.7%), weakness (32.8%), gastrointestinal disturbances (27.3%), myalgia (25%), and headache (18.8%). The main clinical findings included monoarthritis (36.7%), hepatosplenomegaly (25%), lymphadenopathy (17.2%), heart murmur (11.7%), and skin rash (9.4%), respectively. Anemia, leukopenia, thrombocytopenia, and pancytopenia were reported in 17.6%, 29.6%, 12.8%, and 2.3% of the patients, respectively. Twenty-nine (30.5%) patients with BB had serum agglutinin titers <=1/160 (13, 13.7%%, had titers <1/160). Twenty-seven (93%) of the 29 patients aged 0-4 years were treated with gentamicin and trimethoprim sulfamethoxazole; a total of 77 (60.2%) patients received gentamicin and doxycycline. CONCLUSIONS: Childhood brucellosis remains an important public health problem in southern Israel. BB was diagnosed in >50% of the children with brucellosis, and B. melitensis was identified in all cases. Arthralgia, weakness, and gastrointestinal complaints were the most common symptoms, and monoarthritis, hepatosplenomegaly, and lymphadenopathy were the most common clinical findings. A considerable number of patients with BB had undetectable/low serum agglutinin titers, suggesting insufficient reliability on serology alone in diagnosis of brucellosis. PMID- 25793477 TI - Prevalence of eastern equine encephalitis virus antibodies among white-tailed deer populations in Maine. AB - During the fall of 2010, 332 deer serum samples were collected from 15 of the 16 (93.8%) Maine counties and screened for eastern equine encephalitis virus (EEEV) antibodies using plaque reduction neutralizing tests (PRNTs). The aim was to detect and map EEEV activity in the state of Maine. Forty-seven of the 332 (14.2%) sera were positive for EEEV antibodies, showing a much wider distribution of EEEV activity in Maine than previously known. The percentage of EEEV antibody positive deer sera was >=10% in six counties-Piscataquis (100%), Somerset (28.6%), Waldo (22.2%), Penobscot (21.7%), Kennebec (13.7%), and Sagadahoc (10%). Positive sera were detected in all the six counties (Somerset, Waldo, Penobscot, Kennebec, Cumberland, and York) that were positive in 2009, suggesting endemic EEEV activity in these counties. EEEV antibodies were not detected in sera collected in five counties-Franklin, Knox, Lincoln, Oxford, and Washington-which was either due to low sample size or lack of EEEV activity in these counties. Our data suggest higher EEEV activity in central Maine compared to southern Maine, whereas EEEV activity in Maine has historically been associated with the southern counties of York and Cumberland. PMID- 25793476 TI - The flagellar protein FLAG1/SMP1 is a candidate for Leishmania-sand fly interaction. AB - Leishmaniasis is a serious problem that affects mostly poor countries. Various species of Leishmania are the agents of the disease, which take different clinical manifestations. The parasite is transmitted by sandflies, predominantly from the Phlebotomus genus in the Old World and Lutzomyia in the New World. During development in the gut, Leishmania must survive various challenges, which include avoiding being expelled with blood remnants after digestion. It is believed that attachment to the gut epithelium is a necessary step for vector infection, and molecules from parasites and sand flies have been implicated in this attachment. In previous work, monoclonal antibodies were produced against Leishmania. Among these an antibody was obtained against Leishmania braziliensis flagella, which blocked the attachment of Leishmania panamensis flagella to Phlebotomus papatasi guts. The protein recognized by this antibody was identified and named FLAG1, and the complete FLAG1 gene sequence was obtained. This protein was later independently identified as a small, myristoylated protein and called SMP1, so from now on it will be denominated FLAG1/SMP1. The FLAG1/SMP1 gene is expressed in all developmental stages of the parasite, but has higher expression in promastigotes. The anti-FLAG1/SMP1 antibody recognized the flagellum of all Leishmania species tested and generated the expected band by western blots. This antibody was used in attachment and infection blocking experiments. Using the New World vector Lutzomyia longipalpis and Leishmania infantum chagasi, no inhibition of attachment ex vivo or infection in vivo was seen. On the other hand, when the Old World vectors P. papatasi and Leishmania major were used, a significant decrease of both attachment and infection were seen in the presence of the antibody. We propose that FLAG1/SMP1 is involved in the attachment/infection of Leishmania in the strict vector P. papatasi and not the permissive vector L. longipalpis. PMID- 25793478 TI - R0 for vector-borne diseases: impact of the assumption for the duration of the extrinsic incubation period. AB - Mathematical modeling and notably the basic reproduction number R0 have become popular tools for the description of vector-borne disease dynamics. We compare two widely used methods to calculate the probability of a vector to survive the extrinsic incubation period. The two methods are based on different assumptions for the duration of the extrinsic incubation period; one method assumes a fixed period and the other method assumes a fixed daily rate of becoming infectious. We conclude that the outcomes differ substantially between the methods when the average life span of the vector is short compared to the extrinsic incubation period. PMID- 25793479 TI - High seroprevelance of West Nile virus antibodies observed in horses from southwestern Nigeria. AB - To investigate exposure of Nigerian horses to West Nile virus (WNV), we determined the seroprevalence rate of anti-WNV antibody in a cohort of 145 horses. Serum samples were collected from three locations in southwestern Nigeria between October, 2011, and July, 2012. The horses were asymptomatic and unvaccinated against WNV at the time of sampling. All sera were tested using a competition enzyme-linked immmunosorbent assay (ELISA) and by an immunoglobulin M (IgM)-specific ELISA. High rates of anti-WNV antibody prevalence were observed in all locations with a mean level of 90.3% (95% confidence interval 84.3-94.6%). None of the horses had detectable anti-WNV IgM. This is the first ELISA-based report of WNV seroprevalence in Nigerian horses and suggests that WNV is enzootic in the study areas, indicating a potential risk of infection in humans and animals. PMID- 25793480 TI - [Issue editorial 1]. PMID- 25793484 TI - Everything should be as simple as possible, but no simpler: towards a protocol for accumulating evidence regarding the active content of health behaviour change interventions. AB - There is a need to consolidate the evidence base underlying our toolbox of methods of behaviour change. Recent efforts to this effect have conducted meta regressions on evaluations of behaviour change interventions, deriving each method's effectiveness from its association to intervention effect size. However, there are a range of issues that raise concern about whether this approach is actually furthering or instead obstructing the advancement of health psychology theories and the quality of health behaviour change interventions. Using examples from theory, the literature and data from previous meta-analyses, these concerns and their implications are explained and illustrated. An iterative protocol for evidence base accumulation is proposed that integrates evidence derived from both experimental and applied behaviour change research, and combines theory development in experimental settings with theory testing in applied real-life settings. As evidence gathered in this manner accumulates, a cumulative science of behaviour change can develop. PMID- 25793485 TI - Dread returns to Mega-Silly One. PMID- 25793483 TI - Sex differences in device therapy for heart failure: utilization, outcomes, and adverse events. AB - BACKGROUND: Multiple studies of heart failure patients demonstrated significant improvement in exercise capacity, quality of life, cardiac left ventricular function, and survival from cardiac resynchronization therapy (CRT), but the underenrollment of women in these studies is notable. Etiological and pathophysiological differences may result in different outcomes in response to this treatment by sex. The observed disproportionate representation of women suggests that many women with heart failure either do not meet current clinical criteria to receive CRT in trials or are not properly recruited and maintained in these studies. METHODS: We performed a systematic literature review through May 2014 of clinical trials and registries of CRT use that stratified outcomes by sex or reported percent women included. One-hundred eighty-three studies contained sex-specific information. RESULTS: Ninety percent of the studies evaluated included <= 35% women. Fifty-six articles included effectiveness data that reported response with regard to specific outcome parameters. When compared with men, women exhibited more dramatic improvement in specific parameters. In the studies reporting hazard ratios for hospitalization or death, women generally had greater benefit from CRT. CONCLUSIONS: Our review confirms women are markedly underrepresented in CRT trials, and when a CRT device is implanted, women have a therapeutic response that is equivalent to or better than in men, while there is no difference in adverse events reported by sex. PMID- 25793486 TI - Towards healthy theorising about health behaviours in the maze of messy reality: a reaction to Peters, de Bruin, and Crutzen. PMID- 25793487 TI - Advancing cumulative evidence on behaviour change techniques and interventions: a comment on Peters, de Bruin, and Crutzen. PMID- 25793488 TI - Changing behaviour, slow and fast: commentary on Peters, de Bruin and Crutzen. PMID- 25793489 TI - We cannot keep firing blanks - yet another appeal for improved RCT reporting: commentary on Peters, de Bruin and Crutzen. PMID- 25793490 TI - Barriers to screening mammography. AB - Breast cancer (BRCA) is the second most commonly diagnosed cancer among women in the USA, and mammography is an effective means for the early detection of BRCA. Identifying the barriers to screening mammography can inform research, policy and practice aiming to increase mammography adherence. A literature review was conducted to determine common barriers to screening mammography adherence. PsycINFO and PubMed databases were searched to identify studies published between 2000 and 2012 that examined barriers associated with reduced mammography adherence. Three thematic groups of barriers, based on social ecology, were identified from the literature: healthcare system-level, social and individual level barriers. Researchers must consider screening behaviour in context and, therefore, should simultaneously consider each level of barriers when attempting to understand screening behaviour and create interventions to increase mammography adherence. PMID- 25793491 TI - Experiences of chronic low back pain: a meta-ethnography of qualitative research. AB - Chronic low back pain (CLBP) is associated with a number of costly disability related outcomes. It has received increasing attention from qualitative researchers studying its consequences for personal, social, and health care experiences. As research questions and methods diversify, there is a growing need to integrate findings emerging from these studies. A meta-ethnography was carried out to synthesise the findings of 38 separate qualitative articles published on the subjective experience of CLBP between 1994 and 2011. Studies were identified following a literature search and quality appraisal. Four themes were proposed after a process of translating the meaning of text extracts from the findings sections across all the articles. The themes referred to the undermining influence of pain, its disempowering impact on all levels, unsatisfying relationships with health care professionals, and learning to live with the pain. The findings are dominated by wide-ranging distress and loss but also acknowledge self-determination and resilience. Implications of the meta-ethnography for clinicians and future qualitative research are outlined, including the need to study relatively unexamined facets of subjective experience such as illness trajectory and social identity. PMID- 25793492 TI - Self-affirmation and motivational interviewing: integrating perspectives to reduce resistance and increase efficacy of alcohol interventions. AB - To promote efforts at reducing problematic alcohol use and improving health outcomes, the present review proposes an integration of a social psychological approach - self-affirmation theory - with a clinical psychology intervention - motivational interviewing. Motivational interviewing (MI) is a popular empirically-designed treatment approach that has shown moderate success at reducing drinking and improving health, especially with resistant drinkers. Experiments informed by self-affirmation theory have found that people exhibit reduced defensiveness to threatening health messages and increased intentions to reduce alcohol consumption when affirmed. This review focuses on the mechanisms by which self-affirmation reduces resistance and how these mechanisms are complementary to the MI approach. Further, the review outlines suggestions for conducting and integrating self-affirmation into a MI intervention and provides recommendations for future empirical research. PMID- 25793493 TI - Acculturation and HIV-related sexual behaviours among international migrants: a systematic review and meta-analysis. AB - This review examines the global literature regarding the relationship between acculturation and HIV-related sexual behaviours among international migrants. Seventy-nine articles published in English-language journals prior to July 2012 met the criteria for inclusion. We conducted a systematic review and subset meta analysis of correlations between acculturation and five types of sexual behaviours including condom use, multiple partnerships, early sexual initiation, sexually transmitted diseases (STDs) and other unsafe sexual practices. Immigrants high in mainstream acculturation were more likely to have multiple partnerships, early sexual initiation, STDs and unsafe sex (rs ranged from 0.10 to 0.16), but acculturation was not associated with condom use (r = 0.02). Gender moderated the relationships between acculturation and multiple partnerships, STDs and unsafe sex. The relationship between acculturation and unsafe sex also varied across ethnicity. These findings suggest that acculturation may serve as a risk factor towards immigrants' HIV-related sexual health. We offered a theoretical framework and suggested applying cross-cultural and longitudinal designs in future research on acculturation and health behaviours. PMID- 25793494 TI - Miniature fiber optic spectrometer-based quantitative fluorescence resonance energy transfer measurement in single living cells. AB - Spectral measurement of fluorescence resonance energy transfer (FRET), spFRET, is a widely used FRET quantification method in living cells today. We set up a spectrometer-microscope platform that consists of a miniature fiber optic spectrometer and a widefield fluorescence microscope for the spectral measurement of absolute FRET efficiency (E) and acceptor-to-donor concentration ratio (R(C)) in single living cells. The microscope was used for guiding cells and the spectra were simultaneously detected by the miniature fiber optic spectrometer. Moreover, our platform has independent excitation and emission controllers, so different excitations can share the same emission channel. In addition, we developed a modified spectral FRET quantification method (mlux-FRET) for the multiple donors and multiple acceptors FRET construct (mD~nA) sample, and we also developed a spectra-based 2-channel acceptor-sensitized FRET quantification method (spE FRET). We implemented these modified FRET quantification methods on our platform to measure the absolute E and R(C) values of tandem constructs with different acceptor/donor stoichiometries in single living Huh-7 cells. PMID- 25793495 TI - Trypanosoma cruzi, etiological agent of Chagas disease, is virulent to its triatomine vector Rhodnius prolixus in a temperature-dependent manner. AB - It is often assumed that parasites are not virulent to their vectors. Nevertheless, parasites commonly exploit their vectors (nutritionally for example) so these can be considered a form of host. Trypanosoma cruzi, a protozoan found in mammals and triatomine bugs in the Americas, is the etiological agent of Chagas disease that affects man and domestic animals. While it has long been considered avirulent to its vectors, a few reports have indicated that it can affect triatomine fecundity. We tested whether infection imposed a temperature-dependent cost on triatomine fitness. We held infected insects at four temperatures between 21 and 30 degrees C and measured T. cruzi growth in vitro at the same temperatures in parallel. Trypanosoma cruzi infection caused a considerable delay in the time the insects took to moult (against a background effect of temperature accelerating moult irrespective of infection status). Trypanosoma cruzi also reduced the insects' survival, but only at the intermediate temperatures of 24 and 27 degrees C (against a background of increased mortality with increasing temperatures). Meanwhile, in vitro growth of T. cruzi increased with temperature. Our results demonstrate virulence of a protozoan agent of human disease to its insect vector under these conditions. It is of particular note that parasite-induced mortality was greatest over the range of temperatures normally preferred by these insects, probably implying adaptation of the parasite to perform well at these temperatures. Therefore we propose that triggering this delay in moulting is adaptive for the parasites, as it will delay the next bloodmeal taken by the bug, thus allowing the parasites time to develop and reach the insect rectum in order to make transmission to a new vertebrate host possible. PMID- 25793496 TI - Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist. AB - Beta cell death caused by endoplasmic reticulum (ER) stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3beta, epsilon, and theta, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide. PMID- 25793497 TI - Systematic review on irrational use of medicines in China and Vietnam. AB - BACKGROUND: Irrational use of medicines has been an issue concerned all over the world and the outlooks in developing countries are more severe. This study aimed to assess the different patterns of irrational use of medicines and its influential factors in China and Vietnam. METHODS: A systematic review was performed on both published and grey literatures in English, Chinese and Vietnamese languages between 1993 and 2013 based on the WHO framework. Quality assessment was conducted on the basis of the Critical Appraisal Skills Programme. Key indicators were analyzed to compare the irrational use of medicines in two countries. RESULTS: A total of 67 published works about China and 29 about Vietnam were included, the majority of which were cross-sectional prescription studies in both China and Vietnam. Irrational use of medicines was found in both the countries but issues with polypharmacy as well as overuse of antibiotics were more severe in Vietnam while overuse of injections was unique to China. Various patterns of irrational use were also indicated between urban and rural areas, and among different levels of hospitals. Rarely does literature focus on the analysis of influential factors of irrational use of medicines. While lack of proper knowledge from both providers and patients were the most recognized influential factors in both countries, economic incentives from pharmaceutical companies in China, and weak control and regulation over prescriptions in Vietnam were the main factors attributed to this issue. CONCLUSION: Severe irrational use of medicines has been abundantly evidenced in both China and Vietnam, highlighting the importance of policy interventions on the issue. However, limited evidence on the appropriateness or its compliance (conformity) to guidelines of prescription has been found. In addition, convincing evidence on the underlying explanation of this issue is lacking, although economic incentives, health insurance coverage, and knowledge of service providers and users have been implied to be factors influencing irrational drug use. PMID- 25793498 TI - Triclabendazole sulfoxide causes stage-dependent embryolethality in zebrafish and mouse in vitro. AB - BACKGROUND: Fascioliasis and paragonimiasis are widespread foodborne trematode diseases, affecting millions of people in more than 75 countries. The treatment of choice for these parasitic diseases is based on triclabendazole, a benzimidazole derivative which has been suggested as a promising drug to treat pregnant women and children. However, at the moment, this drug is not approved for human use in most countries. Its potential adverse effects on embryonic development have been scarcely studied, and it has not been assigned a pregnancy category by the FDA. Thus, to help in the process of risk-benefit decision making upon triclabendazole treatment during pregnancy, a better characterization of its risks during gestation is needed. METHODOLOGY: The zebrafish embryo test, a preimplantation and a postimplantation rodent whole embryo culture were used to investigate the potential embryotoxicity/teratogenicity of triclabendazole and its first metabolite triclabendazole sulfoxide. Albendazole and albendazole sulfoxide were included as positive controls. PRINCIPAL FINDINGS: Triclabendazole was between 10 and 250 times less potent than albendazole in inducing dysmorphogenic effects in zebrafish or postimplantation rodent embryos, respectively. However, during the preimplantation period, both compounds, triclabendazole and triclabendazole sulfoxide, induced a dose-dependent embryolethal effect after only 24 h of exposure in rodent embryos and zebrafish (lowest observed adverse effect concentrations = 10 MUM). CONCLUSIONS/SIGNIFICANCE: In humans, after ingestion of the recommended doses of triclabendazole to treat fascioliasis and paragonimiasis (10 mg/kg), the main compound found in plasma is triclabendazole sulfoxide (maximum concentration 38.6 MUM), while triclabendazole concentrations are approximately 30 times lower (1.16 MUM). From our results it can be concluded that triclabendazole, at concentrations of the same order of magnitude as the clinically relevant ones, does not entail teratogenic potential in vitro during the organogenesis period, but its first metabolite triclabendazole sulfoxide has a high embryotoxic capacity in vitro during the preimplantation stage. PMID- 25793499 TI - Association between childhood strabismus and refractive error in Chinese preschool children. AB - PURPOSE: To investigate the association between concomitant esotropia or concomitant exotropia and refractive error in preschool children. METHODS: A population-based sample of 5831 children aged 3 to 6 years was selected from all kindergartens in a representative county (Yuhuatai District, Nanjing, Jiangsu Province) of Nanjing, China. Clinical examinations including ocular alignment, ocular motility, visual acuity, optometry, stereopsis screening, slit lamp examination and fundus examination were performed by trained ophthalmologists and optometrists. Odd ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the association of refractive error with concomitant esotropia and concomitant exotropia. RESULTS: In multivariate logistic regression analysis, concomitant esotropia was associated independently with spherical equivalent anisometropia (OR, 3.15 for 0.50 to <1.00 diopter (D) of anisometropia, and 7.41 for > = 1.00 D of anisometropia) and hyperopia. There was a severity-dependent association of hyperopia with the development of concomitant esotropia, with ORs increasing from 9.3 for 2.00 to <3.00 D of hyperopia, to 180.82 for > = 5.00 D of hyperopia. Concomitant exotropia was associated with astigmatism (OR, 3.56 for 0.50 to 1.00 D of astigmatism, and 1.9 for <0.00 D of astigmatism), myopia (OR, 40.54 for -1.00 to <0.00 D of myopia, and 18.93 for < 1.00 D of myopia), and hyperopia (OR, 67.78 for 1.00 to <2.00 D of hyperopia, 23.13 for 2.00 to <3.00 D of hyperopia, 25.57 for 3.00 to <4.00 D of hyperopia, and 8.36 for 4.00 to <5.00 D of hyperopia). CONCLUSIONS: This study highlights the close associations between refractive error and the prevalence of concomitant esotropia and concomitant exotropia, which should be considered when managing childhood refractive error. PMID- 25793500 TI - Zinc finger independent genome-wide binding of Sp2 potentiates recruitment of histone-fold protein Nf-y distinguishing it from Sp1 and Sp3. AB - Transcription factors are grouped into families based on sequence similarity within functional domains, particularly DNA-binding domains. The Specificity proteins Sp1, Sp2 and Sp3 are paradigmatic of closely related transcription factors. They share amino-terminal glutamine-rich regions and a conserved carboxy terminal zinc finger domain that can bind to GC rich motifs in vitro. All three Sp proteins are ubiquitously expressed; yet they carry out unique functions in vivo raising the question of how specificity is achieved. Crucially, it is unknown whether they bind to distinct genomic sites and, if so, how binding site selection is accomplished. In this study, we have examined the genomic binding patterns of Sp1, Sp2 and Sp3 in mouse embryonic fibroblasts by ChIP-seq. Sp1 and Sp3 essentially occupy the same promoters and localize to GC boxes. The genomic binding pattern of Sp2 is different; Sp2 primarily localizes at CCAAT motifs. Consistently, re-expression of Sp2 and Sp3 mutants in corresponding knockout MEFs revealed strikingly different modes of genomic binding site selection. Most significantly, while the zinc fingers dictate genomic binding of Sp3, they are completely dispensable for binding of Sp2. Instead, the glutamine-rich amino terminal region is sufficient for recruitment of Sp2 to its target promoters in vivo. We have identified the trimeric histone-fold CCAAT box binding transcription factor Nf-y as the major partner for Sp2-chromatin interaction. Nf y is critical for recruitment of Sp2 to co-occupied regulatory elements. Equally, Sp2 potentiates binding of Nf-y to shared sites indicating the existence of an extensive Sp2-Nf-y interaction network. Our results unveil strikingly different recruitment mechanisms of Sp1/Sp2/Sp3 transcription factor members uncovering an unexpected layer of complexity in their binding to chromatin in vivo. PMID- 25793501 TI - Baseline omega-3 index correlates with aggressive and attention deficit disorder behaviours in adult prisoners. AB - BACKGROUND: There is emerging evidence that the supplementation of omega-3 contributes to a decrease in aggressive behaviour in prison populations. A challenge of such research is achieving statistical power against effect sizes which may be affected by the baseline omega-3 index. There are no published data on the blood omega-3 index with studies of this kind to assess the variability of the blood omega-3 index in conjunction with aggression and attention deficit assessments. OBJECTIVE: To determine if the variance of the omega-3 index is correlated with aggressive and attention deficit behaviour in a prison population. DESIGN: 136 adult male prisoners were recruited from South Coast Correctional Centre (SCCC), NSW Australia. A 7 point categorisation was used to quantify levels of aggressive behaviour (4 weeks) from individual SCCC case notes, whereby higher scores correspond to increasingly aggressive behaviour. Study participants completed the Aggression Questionnaire (AQ) and the Brown's Attention Deficit Disorder Scales (BADDS), provided a blood sample for erythrocyte fatty acid analysis using gas chromatography and the omega-3 index was calculated. RESULTS: The baseline omega-3 index ranged from 2.3% to 10.3%, indicating that some participants already had substantial omega-3 intake, however a median of 4.7% indicated a lower overall omega-3 intake than the general Australian population. Assessment of aggressive and attention deficit behaviour shows that there were negative correlations between baseline omega-3 index and baseline aggression categorisation scores (r = -0.21, P = 0.016); total AQ score (r = -0.234, P = 0.011); Anger (r = -0.222 p = 0.016); Hostility AQ (r = -0.239, P = 0.009); indirect aggression (r = -0.188 p = 0.042); total BADDS (r = -0.263, p = 0.005); Activation (r = -0.224, p = 0.016); Attention (r = -0.192, p = 0.043); Effort (r = -0.253, p = 0.007); Affect (r = -0.330, p = 0.000) and Memory (r = -0.240, p = 0.010). CONCLUSIONS: There is a high variability in omega-3 status of a NSW prison population, and inmates with lower omega-3 index were more aggressive and had higher ADD scores. PMID- 25793502 TI - Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles. AB - Filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. Several vaccine platforms that include multiple virus vectored approaches and virus-like particles (VLPs) have shown efficacy in nonhuman primates. Previous studies have shown protection of cynomolgus macaques against homologous infection for Ebola virus (EBOV) and Marburg virus (MARV) following a three-dose vaccine regimen of EBOV or MARV VLPs, as well as heterologous protection against Ravn Virus (RAVV) following vaccination with MARV VLPs. The objectives of the current studies were to determine the minimum number of vaccine doses required for protection (using EBOV as the test system) and then demonstrate protection against Sudan virus (SUDV) and Tai Forest virus (TAFV). Using the EBOV nonhuman primate model, we show that one or two doses of VLP vaccine can confer protection from lethal infection. VLPs containing the SUDV glycoprotein, nucleoprotein and VP40 matrix protein provide complete protection against lethal SUDV infection in macaques. Finally, we demonstrate protective efficacy mediated by EBOV, but not SUDV, VLPs against TAFV; this is the first demonstration of complete cross-filovirus protection using a single component heterologous vaccine within the Ebolavirus genus. Along with our previous results, this observation provides strong evidence that it will be possible to develop and administer a broad-spectrum VLP-based vaccine that will protect against multiple filoviruses by combining only three EBOV, SUDV and MARV components. PMID- 25793503 TI - Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling. AB - Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS), a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR) proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs) exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS DrmMS-R2 interactions would reflect our structure-activity relationship (SAR) data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue specific signaling existed, which was in line with our SAR data. We identified R. prolixus (Rhp)MS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock, transmission switch, and tyrosine toggle switch being involved in mechanisms underlying TM movement and MS-R activation, and the ability of MS agonists and antagonists to influence physiology. PMID- 25793504 TI - Correction: Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels. PMID- 25793505 TI - Identification of reference genes for quantitative expression analysis of microRNAs and mRNAs in barley under various stress conditions. AB - For accurate and reliable gene expression analysis using quantitative real-time reverse transcription PCR (qPCR), the selection of appropriate reference genes as an internal control for normalization is crucial. We hypothesized that non coding, small nucleolar RNAs (snoRNAs)would be stably expressed in different barley varieties and under different experimental treatments,in different tissues and at different developmental stages of plant growth and therefore might prove to be suitable reference genes for expression analysis of both microRNAs (miRNAs)and mRNAs. In this study, we examined the expression stability of ten candidate reference genes in six barley genotypes under five experimental stresses, drought, fungal infection,boron toxicity, nutrient deficiency and salinity. We compared four commonly used housekeeping genes; Actin (ACT), alpha Tubulin (alpha-TUB), Glycolytic glyceraldehyde-3-phosphate dehydrogenase(GAPDH), ADP-ribosylation factor 1-like protein (ADP), four snoRNAs; (U18,U61, snoR14 and snoR23) and two microRNAs (miR168, miR159) as candidate reference genes. We found that ADP, snoR14 and snoR23 were ranked as the best of these candidates across diverse samples. Additionally, we found that miR168 was a suitable reference gene for expression analysis in barley. Finally, we validated the performance of our stable and unstable candidate reference genes for both mRNA and miRNA qPCR data normalization under different stress conditions and demonstrated the superiority of the stable candidates. Our data demonstrate the suitability of barley snoRNAs and miRNAs as potential reference genes form iRNA and mRNA qPCR data normalization under different stress treatments [corrected]. PMID- 25793506 TI - The management of lower extremity multilevel arterial injuries: a 10-year experience. AB - BACKGROUND: Limb amputation due to lower extremity arterial injury is not uncommon and multilevel arterial injury is even more limb-threatening and easily missed with potentially devastating consequences. There is limited information on multilevel arterial injuries. PURPOSE: We undertook a review of our experience to gain insight on multilevel arterial injury patterns associated with lower extremity trauma and to analyze the results of management of such injuries with a special focus on the influence of initial diagnosis on limb salvage. PATIENTS AND METHODS: Between August 2002 and September 2012, 38 patients with lower extremity multilevel arterial injuries were reviewed, retrospectively. The injury patterns and amputation rates associated with initial diagnosis or misdiagnosis were analyzed. RESULTS: According to their injury levels, three multilevel arterial injury patterns were seen in this series: arterial injuries with the involvement of femoral artery and popliteal artery (pattern A), femoral artery and anterior or (and) posterior artery (pattern B), and popliteal artery and anterior or (and) posterior artery (pattern C). The general missed diagnosis rate was 31.6%. Pattern B had a much higher missed diagnosis rate than the other two patterns. The missed diagnosis rate was significantly correlated with the amputation rates (Odds Ratio =10.7, 95% CI: 2.04-56.61). The definite diagnosis rate was only 14.8% using duplex ultrasonography examination. CONCLUSIONS: Diagnosis of pattern B injury is more prone to be missed. DUS has low specificity in the detection of multilevel arterial injuries. Aggressive intraoperative exploration is considered to be valuable in the definitive diagnosis of highly suspected cases when other diagnostic tools are unavailable. PMID- 25793507 TI - Protein-binding RNA aptamers affect molecular interactions distantly from their binding sites. AB - Nucleic acid aptamer selection is a powerful strategy for the development of regulatory agents for molecular intervention. Accordingly, aptamers have proven their diligence in the intervention with serine protease activities, which play important roles in physiology and pathophysiology. Nonetheless, there are only a few studies on the molecular basis underlying aptamer-protease interactions and the associated mechanisms of inhibition. In the present study, we use site directed mutagenesis to delineate the binding sites of two 2'-fluoropyrimidine RNA aptamers (upanap-12 and upanap-126) with therapeutic potential, both binding to the serine protease urokinase-type plasminogen activator (uPA). We determine the subsequent impact of aptamer binding on the well-established molecular interactions (plasmin, PAI-1, uPAR, and LRP-1A) controlling uPA activities. One of the aptamers (upanap-126) binds to the area around the C-terminal alpha-helix in pro-uPA, while the other aptamer (upanap-12) binds to both the beta-hairpin of the growth factor domain and the kringle domain of uPA. Based on the mapping studies, combined with data from small-angle X-ray scattering analysis, we construct a model for the upanap-12:pro-uPA complex. The results suggest and highlight that the size and shape of an aptamer as well as the domain organization of a multi-domain protein such as uPA, may provide the basis for extensive sterical interference with protein ligand interactions considered distant from the aptamer binding site. PMID- 25793509 TI - The association of methylenetetrahydrofolate reductase genotypes with the risk of childhood leukemia in Taiwan. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations. METHODOLOGY/PRINCIPAL FINDINGS: In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42 0.87 and 0.24-0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32-0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26 0.71, P=0.0016). CONCLUSIONS: Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease. PMID- 25793508 TI - A novel respiratory syncytial virus (RSV) F subunit vaccine adjuvanted with GLA SE elicits robust protective TH1-type humoral and cellular immunity in rodent models. AB - BACKGROUND: Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults. The fusion glycoprotein (F) of RSV, which plays a key role in RSV infection and is a target of neutralizing antibodies, is an attractive vaccine target for inducing RSV specific immunity. METHODOLOGY AND PRINCIPAL FINDINGS: BALB/c mice and cotton rats, two well-characterized rodent models of RSV infection, were used to evaluate the immunogenicity of intramuscularly administered RSV vaccine candidates consisting of purified soluble F (sF) protein formulated with TLR4 agonist glucopyranosyl lipid A (GLA), stable emulsion (SE), GLA-SE, or alum adjuvants. Protection from RSV challenge, serum RSV neutralizing responses, and anti-F IgG responses were induced by all of the tested adjuvanted RSV sF vaccine formulations. However, only RSV sF + GLA-SE induced robust F-specific TH1-biased humoral and cellular responses. In mice, these F-specific cellular responses include both CD4 and CD8 T cells, with F-specific polyfunctional CD8 T cells that traffic to the mouse lung following RSV challenge. This RSV sF + GLA-SE vaccine formulation can also induce robust RSV neutralizing titers and prime IFNgamma producing T cell responses in Sprague Dawley rats. CONCLUSIONS/SIGNIFICANCE: These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism. This vaccine may benefit older populations at risk for RSV disease. PMID- 25793510 TI - Blood-based protein biomarker panel for the detection of colorectal cancer. AB - BACKGROUND: The majority of colorectal cancer (CRC) cases are preventable by early detection and removal of precancerous polyps. Even though CRC is the second most common internal cancer in Australia, only 30 per cent of the population considered to have risk factors participate in stool-based test screening programs. Evidence indicates a robust, blood-based, diagnostic assay would increase screening compliance. A number of potential diagnostic blood-based protein biomarkers for CRC have been reported, but all lack sensitivity or specificity for use as a stand-alone diagnostic. The aim of this study was to identify and validate a panel of protein-based biomarkers in independent cohorts that could be translated to a reliable, non-invasive blood-based screening test. PRINCIPAL FINDINGS: In two independent cohorts (n = 145 and n = 197), we evaluated seven single biomarkers in serum of CRC patients and age/gender matched controls that showed a significant difference between controls and CRC, but individually lack the sensitivity for diagnostic application. Using logistic regression strategies, we identified a panel of three biomarkers that discriminated between controls and CRC with 73% sensitivity at 95% specificity, when applied to either of the two cohorts. This panel comprised of Insulin like growth factor binding protein 2 (IGFBP2), Dickkopf-3 (DKK3), and Pyruvate kinase M2(PKM2). CONCLUSIONS: Due to the heterogeneous nature of CRC, a single biomarker is unlikely to have sufficient sensitivity or specificity for use as a stand alone diagnostic screening test and a panel of markers may be more effective. We have identified a 3 biomarker panel that has higher sensitivity and specificity for early stage (Stage I and -II) disease than the faecal occult blood test, raising the possibility for its use as a non-invasive blood diagnostic or screening test. PMID- 25793513 TI - Core belief challenge and rumination as predictors of PTSD and PTG among adolescent survivors of the Wenchuan earthquake. AB - Middle school students in Wenchuan County (N = 354) were assessed 4.5 years after the Wenchuan earthquake to examine the effects of challenges to core beliefs, intrusive rumination, and deliberate rumination on posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG). The results indicated that intrusive rumination partly mediated the relationship between challenges to core beliefs and PTSD, whereas deliberate rumination partly mediated both the relationship between challenges to core beliefs and PTG, as well as the relationship between intrusive rumination and PTG. These findings suggest that challenges to core beliefs had a direct positive impact on both PTSD and PTG. Moreover, such challenges predicted PTSD through intrusive rumination and predicted PTG through deliberate rumination. Furthermore, intrusive rumination might cue individuals to engage in a more purposive deliberate rumination process. These results indicate that PTSD and PTG are influenced by different mechanisms and that PTSD and PTG represent 2 separate dimensions of experience following adversity. PMID- 25793512 TI - Multi-approaches analysis reveals local adaptation in the emmer wheat (Triticum dicoccoides) at macro- but not micro-geographical scale. AB - Detecting local adaptation and its spatial scale is one of the most important questions of evolutionary biology. However, recognition of the effect of local selection can be challenging when there is considerable environmental variation across the distance at the whole species range. We analyzed patterns of local adaptation in emmer wheat, Triticum dicoccoides, at two spatial scales, small (inter-population distance less than one km) and large (inter-population distance more than 50 km) using several approaches. Plants originating from four distinct habitats at two geographic scales (cold edge, arid edge and two topographically dissimilar core locations) were reciprocally transplanted and their success over time was measured as 1) lifetime fitness in a year of planting, and 2) population growth four years after planting. In addition, we analyzed molecular (SSR) and quantitative trait variation and calculated the QST/FST ratio. No home advantage was detected at the small spatial scale. At the large spatial scale, home advantage was detected for the core population and the cold edge population in the year of introduction via measuring life-time plant performance. However, superior performance of the arid edge population in its own environment was evident only after several generations via measuring experimental population growth rate through genotyping with SSRs allowing counting the number of plants and seeds per introduced genotype per site. These results highlight the importance of multi-generation surveys of population growth rate in local adaptation testing. Despite predominant self-fertilization of T. dicoccoides and the associated high degree of structuring of genetic variation, the results of the QST - FST comparison were in general agreement with the pattern of local adaptation at the two spatial scales detected by reciprocal transplanting. PMID- 25793511 TI - Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. AB - The gut/brain peptide, glucagon like peptide 1 (GLP-1), suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS), GLP-1 receptors (GLP-1R). Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP 1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-beta hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS. PMID- 25793514 TI - Predictors of posttraumatic stress disorder among police officers: A prospective study. AB - This prospective study examined risk and protective factors in the development of posttraumatic stress disorder (PTSD) in a sample of 83 police officers. Structured interviews were conducted in order to assess the most recent work related traumatic event and establish diagnoses of acute stress disorder (ASD) and full or partial PTSD. Police officers were assessed between 5 and 15 days, and at 1 month, 3 months, and 12 months after the event. They also completed self administered questionnaires assessing several potential predictors. Predictive analyses about the onset of PTSD were based on a 4-step nested random-effect linear regression. Overall, results showed that the modulation of PTSD symptomatology was associated with some pretraumatic (i.e., emotional coping strategies and number of children), peritraumatic (i.e., physical and emotional reactions and dissociation), and posttraumatic factors (i.e., ASD, depression symptoms, and seeking psychological help at the employee assistance program and at the police union between the event and Time 1). Clinical implications of these findings are discussed and key directions for future studies are proposed. PMID- 25793515 TI - Posttraumatic growth among combat veterans: A proposed developmental pathway. AB - With the large number of combat veterans returning from war, there is an ever increasing need to understand ways to help soldiers and veterans successfully navigate their return to life after combat. Posttraumatic growth (PTG) offers strong protective elements following combat, including reduction in suicidal ideation (Bush et al., 2011). The purpose of this study was to explore a proposed psychosocial developmental pathway between posttraumatic stress symptoms and PTG among combat veterans of the Afghanistan and Iraq wars. The indirect pathway from posttraumatic symptoms to PTG through negative psychosocial development was found to be significant and positive. It appears that psychosocial development may indeed mediate the process by which combat veterans can make meaning from their experiences, improving overall well-being. PMID- 25793516 TI - Promoting wired links in wireless mesh networks: an efficient engineering solution. AB - Wireless Mesh Networks (WMNs) cannot completely guarantee good performance of traffic sources such as video streaming. To improve the network performance, this study proposes an efficient engineering solution named Wireless-to-Ethernet-Mesh Portal-Passageway (WEMPP) that allows effective use of wired communication in WMNs. WEMPP permits transmitting data through wired and stable paths even when the destination is in the same network as the source (Intra-traffic). Tested with four popular routing protocols (Optimized Link State Routing or OLSR as a proactive protocol, Dynamic MANET On-demand or DYMO as a reactive protocol, DYMO with spanning tree ability and HWMP), WEMPP considerably decreases the end-to-end delay, jitter, contentions and interferences on nodes, even when the network size or density varies. WEMPP is also cost-effective and increases the network throughput. Moreover, in contrast to solutions proposed by previous studies, WEMPP is easily implemented by modifying the firmware of the actual Ethernet hardware without altering the routing protocols and/or the functionality of the IP/MAC/Upper layers. In fact, there is no need for modifying the functionalities of other mesh components in order to work with WEMPPs. The results of this study show that WEMPP significantly increases the performance of all routing protocols, thus leading to better video quality on nodes. PMID- 25793517 TI - Assessment of the quality of reporting of randomised controlled trials in otorhinolaryngologic literature - adherence to the CONSORT statement. AB - BACKGROUND: Randomised Controlled Trials (RCTs) are the preferred study design when comparing therapeutical interventions in medicine. To improve clarity, consistency and transparency of reporting RCTs, the Consolidated Standards of Reporting Trials (CONSORT) statement was developed. OBJECTIVES: (1) To assess the quality of reports and abstracts of RCTs in otorhinolaryngologic literature by using CONSORT checklists, (2) to compare the quality of reports and abstracts of otorhinolaryngologic RCTs between the top 5 general medical journals and top 5 otorhinolaryngologic journals, and (3) to formulate recommendations for authors and editors of otorhinolaryngologic ('ENT') journals. METHODS: Based on 2012 ISI Web of Knowledge impact factors, the top 5 general medical and ENT journals were selected. On 25 June 2014, using a highly sensitive Cochrane RCT filter and ENT filter, possibly relevant articles since January 1st, 2010 were retrieved and relevant RCTs were selected. We assessed how many CONSORT items were reported adequately in reports and abstracts and compared the two journal types. RESULTS: Otorhinolaryngologic RCTs (n = 15) published in general medical journals reported a mean of 92.1% (95% confidence interval: 89.5%-94.7%) of CONSORT items adequately, whereas RCTs (n = 18) published in ENT journals reported a mean of 71.8% (66.7%-76.8%) adequately (p < 0.001). For abstracts, means of 70.0% (63.7% 76.3%) and 32.3% (26.6-38.0%) were found respectively (p < 0.001). Large differences for specific items exist between the two journal types. CONCLUSION: The quality of reporting of RCTs in otorhinolaryngologic journals is suboptimal. RCTs published in general medical journals have a higher quality of reporting than RCTs published in ENT journals. We recommend authors to report their trial according to the CONSORT Statement and advise editors to endorse the CONSORT Statement and implement the CONSORT Statement in the editorial process to ensure more adequate reporting of RCTs and their abstracts. PMID- 25793519 TI - Differences in the predictors of reading comprehension in first graders from low socio-economic status families with either good or poor decoding skills. AB - Based on the assumption that good decoding skills constitute a bootstrapping mechanism for reading comprehension, the present study investigated the relative contribution of the former skill to the latter compared to that of three other predictors of reading comprehension (listening comprehension, vocabulary and phonemic awareness) in 392 French-speaking first graders from low SES families. This large sample was split into three groups according to their level of decoding skills assessed by pseudoword reading. Using a cutoff of 1 SD above or below the mean of the entire population, there were 63 good decoders, 267 average decoders and 62 poor decoders. 58% of the variance in reading comprehension was explained by our four predictors, with decoding skills proving to be the best predictor (12.1%, 7.3% for listening comprehension, 4.6% for vocabulary and 3.3% for phonemic awareness). Interaction between group versus decoding skills, listening comprehension and phonemic awareness accounted for significant additional variance (3.6%, 1.1% and 1.0%, respectively). The effects on reading comprehension of decoding skills and phonemic awareness were higher in poor and average decoders than in good decoders whereas listening comprehension accounted for more variance in good and average decoders than in poor decoders. Furthermore, the percentage of children with impaired reading comprehension skills was higher in the group of poor decoders (55%) than in the two other groups (average decoders: 7%; good decoders: 0%) and only 6 children (1.5%) had impaired reading comprehension skills with unimpaired decoding skills, listening comprehension or vocabulary. These results challenge the outcomes of studies on "poor comprehenders" by showing that, at least in first grade, poor reading comprehension is strongly linked to the level of decoding skills. PMID- 25793518 TI - DICER-ARGONAUTE2 complex in continuous fluorogenic assays of RNA interference enzymes. AB - Mechanistic studies of RNA processing in the RNA-Induced Silencing Complex (RISC) have been hindered by lack of methods for continuous monitoring of enzymatic activity. "Quencherless" fluorogenic substrates of RNAi enzymes enable continuous monitoring of enzymatic reactions for detailed kinetics studies. Recombinant RISC enzymes cleave the fluorogenic substrates targeting human thymidylate synthase (TYMS) and hypoxia-inducible factor 1-alpha subunit (HIF1A). Using fluorogenic dsRNA DICER substrates and fluorogenic siRNA, DICER+ARGONAUTE2 mixtures exhibit synergistic enzymatic activity relative to either enzyme alone, and addition of TRBP does not enhance the apparent activity. Titration of AGO2 and DICER in enzyme assays suggests that AGO2 and DICER form a functional high-affinity complex in equimolar ratio. DICER and DICER+AGO2 exhibit Michaelis-Menten kinetics with DICER substrates. However, AGO2 cannot process the fluorogenic siRNA without DICER enzyme, suggesting that AGO2 cannot self-load siRNA into its active site. The DICER+AGO2 combination processes the fluorogenic siRNA substrate (Km=74 nM) with substrate inhibition kinetics (Ki=105 nM), demonstrating experimentally that siRNA binds two different sites that affect Dicing and AGO2 loading reactions in RISC. This result suggests that siRNA (product of DICER) bound in the active site of DICER may undergo direct transfer (as AGO2 substrate) to the active site of AGO2 in the DICER+AGO2 complex. Competitive substrate assays indicate that DICER+AGO2 cleavage of fluorogenic siRNA is specific, since unlabeled siRNA and DICER substrates serve as competing substrates that cause a concentration-dependent decrease in fluorescent rates. Competitive substrate assays of a series of DICER substrates in vitro were correlated with cell-based assays of HIF1A mRNA knockdown (log-log slope=0.29), suggesting that improved DICER substrate designs with 10-fold greater processing by the DICER+AGO2 complex can provide a strong (~2800-fold) improvement in potency for mRNA knockdown. This study lays the foundation of a systematic biochemical approach to optimize nucleic acid-based therapeutics for Dicing and ARGONAUTE2-loading for improving efficacy. PMID- 25793520 TI - Improved statistical methods enable greater sensitivity in rhythm detection for genome-wide data. AB - Robust methods for identifying patterns of expression in genome-wide data are important for generating hypotheses regarding gene function. To this end, several analytic methods have been developed for detecting periodic patterns. We improve one such method, JTK_CYCLE, by explicitly calculating the null distribution such that it accounts for multiple hypothesis testing and by including non-sinusoidal reference waveforms. We term this method empirical JTK_CYCLE with asymmetry search, and we compare its performance to JTK_CYCLE with Bonferroni and Benjamini Hochberg multiple hypothesis testing correction, as well as to five other methods: cyclohedron test, address reduction, stable persistence, ANOVA, and F24. We find that ANOVA, F24, and JTK_CYCLE consistently outperform the other three methods when data are limited and noisy; empirical JTK_CYCLE with asymmetry search gives the greatest sensitivity while controlling for the false discovery rate. Our analysis also provides insight into experimental design and we find that, for a fixed number of samples, better sensitivity and specificity are achieved with higher numbers of replicates than with higher sampling density. Application of the methods to detecting circadian rhythms in a metadataset of microarrays that quantify time-dependent gene expression in whole heads of Drosophila melanogaster reveals annotations that are enriched among genes with highly asymmetric waveforms. These include a wide range of oxidation reduction and metabolic genes, as well as genes with transcripts that have multiple splice forms. PMID- 25793521 TI - Experimental butchering of a chimpanzee carcass for archaeological purposes. AB - Two archaeological assemblages from the Sierra de Atapuerca sites show evidence of anthropogenic cannibalism. These are the late Early Pleistocene level TD6-2 at Gran Dolina, and the Bronze Age level MIR4 in the Mirador Cave. Despite the chronological distance between these two assemblages, they share the common feature that the human remains exhibit a high frequency of anthropogenic modifications (cut marks, percussion pits and notches and peeling). This frequency could denote special treatment of bodies, or else be the normal result of the butchering process. In order to test these possibilities, we subjected a chimpanzee carcass to a butchering process. The processing was intensive and intended to simulate preparation for consumption. In doing this, we used several simple flakes made from quartzite and chert from quarries in the Sierra de Atapuerca. The skull, long bones, metapodials and phalanges were also fractured in order to remove the brain and bone marrow. As a result, about 40% of the remains showed some kind of human modification. The frequency, distribution and characteristics of these modifications are very similar to those documented on the remains of Homo antecessor from TD6-2. In case of the MIR4 assemblage, the results are similar except in the treatment of skulls. Our results indicate that high frequencies of anthropogenic modifications are common after an intensive butchering process intended to prepare a hominin body for consumption in different contexts (both where there was possible ritual behavior and where this was not the case and the modifications are not the result of special treatment). PMID- 25793522 TI - Expression of dominant-negative thyroid hormone receptor alpha1 in Leydig and Sertoli cells demonstrates no additional defect compared with expression in Sertoli cells only. AB - BACKGROUND: In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial. METHODS: The TRalphaAMI knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRalpha1 (thyroid receptor alpha1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter. FINDINGS: We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRalphaAMI specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRalphaAMI-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRalphaAMI-ARO males showed normal fertility. This phenotype is similar to TRalphaAMI-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRalphaAMI ARO. CONCLUSIONS/SIGNIFICANCE: We concluded that the presence of a mutant TRalphaAMI allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRalpha1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis. PMID- 25793523 TI - The dilemma of choosing a reference character for measuring sexual size dimorphism, sexual body component dimorphism, and character scaling: cryptic dimorphism and allometry in the scorpion Hadrurus arizonensis. AB - Sexual differences in morphology, ranging from subtle to extravagant, occur commonly in many animal species. These differences can encompass overall body size (sexual size dimorphism, SSD) or the size and/or shape of specific body parts (sexual body component dimorphism, SBCD). Interacting forces of natural and sexual selection shape much of the expression of dimorphism we see, though non adaptive processes may be involved. Differential scaling of individual features can result when selection favors either exaggerated (positive allometry) or reduced (negative allometry) size during growth. Studies of sexual dimorphism and character scaling rely on multivariate models that ideally use an unbiased reference character as an overall measure of body size. We explored several candidate reference characters in a cryptically dimorphic taxon, Hadrurus arizonensis. In this scorpion, essentially every body component among the 16 we examined could be interpreted as dimorphic, but identification of SSD and SBCD depended on which character was used as the reference (prosoma length, prosoma area, total length, principal component 1, or metasoma segment 1 width). Of these characters, discriminant function analysis suggested that metasoma segment 1 width was the most appropriate. The pattern of dimorphism in H. arizonensis mirrored that seen in other more obviously dimorphic scorpions, with static allometry trending towards isometry in most characters. Our findings are consistent with the conclusions of others that fecundity selection likely favors a larger prosoma in female scorpions, whereas sexual selection may favor other body parts being larger in males, especially the metasoma, pectines, and possibly the chela. For this scorpion and probably most other organisms, the choice of reference character profoundly affects interpretations of SSD, SBCD, and allometry. Thus, researchers need to broaden their consideration of an appropriate reference and exercise caution in interpreting findings. We highly recommend use of discriminant function analysis to identify the least-biased reference character. PMID- 25793524 TI - Algorithmic mechanisms for reliable crowdsourcing computation under collusion. AB - We consider a computing system where a master processor assigns a task for execution to worker processors that may collude. We model the workers' decision of whether to comply (compute the task) or not (return a bogus result to save the computation cost) as a game among workers. That is, we assume that workers are rational in a game-theoretic sense. We identify analytically the parameter conditions for a unique Nash Equilibrium where the master obtains the correct result. We also evaluate experimentally mixed equilibria aiming to attain better reliability-profit trade-offs. For a wide range of parameter values that may be used in practice, our simulations show that, in fact, both master and workers are better off using a pure equilibrium where no worker cheats, even under collusion, and even for colluding behaviors that involve deviating from the game. PMID- 25793525 TI - Packed red blood cells are an abundant and proximate potential source of nitric oxide synthase inhibition. AB - OBJECTIVE: We determined, for packed red blood cells (PRBC) and fresh frozen plasma, the maximum content, and ability to release the endogenous nitric oxide synthase (NOS) inhibitors asymmetric dimethylarginine (ADMA) and monomethylarginine (LNMMA). BACKGROUND: ADMA and LNMMA are near equipotent NOS inhibitors forming blood's total NOS inhibitory content. The balance between removal from, and addition to plasma determines their free concentrations. Removal from plasma is by well-characterized specific hydrolases while formation is restricted to posttranslational protein methylation. When released into plasma they can readily enter endothelial cells and inhibit NOS. Fresh rat and human whole blood contain substantial protein incorporated ADMA however; the maximum content of ADMA and LNMMA in PRBC and fresh frozen plasma has not been determined. METHODS: We measured total (free and protein incorporated) ADMA and LNMMA content in PRBCs and fresh frozen plasma, as well as their incubation induced release, using HPLC with fluorescence detection. We tested the hypothesis that PRBC and fresh frozen plasma contain substantial inhibitory methylarginines that can be released chemically by complete in vitro acid hydrolysis or physiologically at 37 degrees C by enzymatic blood proteolysis. RESULTS: In vitro strong-acid-hydrolysis revealed a large PRBC reservoir of ADMA (54.5 +/- 9.7 uM) and LNMMA (58.9 +/- 28.9 MUM) that persisted over 42-d at 6 degrees or -80 degrees C. In vitro 5h incubation at 37 degrees C nearly doubled free ADMA and LNMMNA concentration from PRBCs while no change was detected in fresh frozen plasma. CONCLUSION: The compelling physiological ramifications are that regardless of storage age, 1) PRBCs can rapidly release pathologically relevant quantities of ADMA and LNMMA when incubated and 2) PRBCs have a protein incorporated inhibitory methylarginines reservoir 100 times that of normal free inhibitory methylarginines in blood and thus could represent a clinically relevant and proximate risk for iatrogenic NOS inhibition upon transfusion. PMID- 25793526 TI - Colorectal mucus binds DC-SIGN and inhibits HIV-1 trans-infection of CD4+ T lymphocytes. AB - Bodily secretions, including breast milk and semen, contain factors that modulate HIV-1 infection. Since anal intercourse caries one of the highest risks for HIV-1 transmission, our aim was to determine whether colorectal mucus (CM) also contains factors interfering with HIV-1 infection and replication. CM from a number of individuals was collected and tested for the capacity to bind DC-SIGN and inhibit HIV-1 cis- or trans-infection of CD4+ T-lymphocytes. To this end, a DC-SIGN binding ELISA, a gp140 trimer competition ELISA and HIV-1 capture/ transfer assays were utilized. Subsequently we aimed to identify the DC-SIGN binding component through biochemical characterization and mass spectrometry analysis. CM was shown to bind DC-SIGN and competes with HIV-1 gp140 trimer for binding. Pre-incubation of Raji-DC-SIGN cells or immature dendritic cells (iDCs) with CM potently inhibits DC-SIGN mediated trans-infection of CD4+ T-lymphocytes with CCR5 and CXCR4 using HIV-1 strains, while no effect on direct infection is observed. Preliminary biochemical characterization demonstrates that the component seems to be large (>100kDa), heat and proteinase K resistant, binds in a alpha1-3 mannose independent manner and is highly variant between individuals. Immunoprecipitation using DC-SIGN-Fc coated agarose beads followed by mass spectrometry indicated lactoferrin (fragments) and its receptor (intelectin-1) as candidates. Using ELISA we showed that lactoferrin levels within CM correlate with DC-SIGN binding capacity. In conclusion, CM can bind the C-type lectin DC SIGN and block HIV-1 trans-infection of both CCR5 and CXCR4 using HIV-1 strains. Furthermore, our data indicate that lactoferrin is a DC-SIGN binding component of CM. These results indicate that CM has the potential to interfere with pathogen transmission and modulate immune responses at the colorectal mucosa. PMID- 25793527 TI - MiRNAs with apoptosis regulating potential are differentially expressed in chronic exercise-induced physiologically hypertrophied hearts. AB - Physiological cardiac hypertrophy is an adaptive mechanism, induced during chronic exercise. As it is reversible and not associated with cardiomyocyte death, it is considered as a natural tactic to prevent cardiac dysfunction and failure. Though, different studies revealed the importance of microRNAs (miRNAs) in pathological hypertrophy, their role during physiological hypertrophy is largely unexplored. Hence, this study is aimed at revealing the global expression profile of miRNAs during physiological cardiac hypertrophy. Chronic swimming protocol continuously for eight weeks resulted in induction of physiological hypertrophy in rats and histopathology revealed the absence of tissue damage, apoptosis or fibrosis. Subsequently, the total RNA was isolated and small RNA sequencing was executed. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during physiological hypertrophy. The expression profile of the significantly differentially expressed miRNAs was validated by qPCR. In silico prediction of target genes by miRanda, miRdB and TargetScan and subsequent qPCR analysis unraveled that miRNAs including miR-99b, miR-100, miR-19b, miR-10, miR-208a, miR-133, miR-191a, miR-22, miR-30e and miR 181a are targeting the genes that primarily regulate cell proliferation and cell death. Gene ontology and pathway mapping showed that the differentially expressed miRNAs and their target genes were mapped to apoptosis and cell death pathways principally via PI3K/Akt/mTOR and MAPK signaling. In summary, our data indicates that regulation of these miRNAs with apoptosis regulating potential can be one of the major key factors in determining pathological or physiological hypertrophy by controlling fibrosis, apoptosis and cell death mechanisms. PMID- 25793528 TI - Interferon-gamma suppresses intestinal epithelial aquaporin-1 expression via Janus kinase and STAT3 activation. AB - Inflammatory bowel diseases are associated with dysregulated electrolyte and water transport and resultant diarrhea. Aquaporins are transmembrane proteins that function as water channels in intestinal epithelial cells. We investigated the effect of the inflammatory cytokine, interferon-gamma, which is a major player in inflammatory bowel diseases, on aquaporin-1 expression in a mouse colonic epithelial cell line, CMT93. CMT93 monolayers were exposed to 10 ng/mL interferon-gamma and aquaporin-1 mRNA and protein expressions were measured by real-time PCR and western blot, respectively. In other experiments, CMT93 cells were pretreated with inhibitors or were transfected with siRNA to block the effects of Janus kinases, STATs 1 and 3, or interferon regulatory factor 2, prior to treatment with interferon-gamma. Interferon-gamma decreased aquaporin-1 expression in mouse intestinal epithelial cells in a manner that did not depend on the classical STAT1/JAK2/IRF-1 pathway, but rather, on an alternate Janus kinase (likely JAK1) as well as on STAT3. The pro-inflammatory cytokine, interferon-gamma may contribute to diarrhea associated with intestinal inflammation in part through regulation of the epithelial aquaporin-1 water channel via a non-classical JAK/STAT receptor signalling pathway. PMID- 25793529 TI - RNA interference of myocyte enhancer factor 2A accelerates atherosclerosis in apolipoprotein E-deficient mice. AB - OBJECTIVE: Myocyte enhancer factor-2A (MEF 2A) has been shown to be involved in atherosclerotic lesion development, but its role in preexisting lesions is still unclear. In the present study we aim to assess the role of MEF 2A in the progression of pre-existing atherosclerosis. METHODS: Eighty apolipoprotein E deficient mice (APOE KO) were randomly allocated to control, scramble and MEF 2A RNA interference (RNAi) groups, and constrictive collars were used to induce plaque formation. Six weeks after surgery, lentiviral shRNA construct was used to silence the expression of MEF 2A. Carotid plaques were harvested for analysis 4 weeks after viral vector transduction. Inflammatory gene expression in the plasma and carotid plaques was determined by using ELISAs and real-time RT-PCR. RESULTS: The expression level of MEF 2A was significantly reduced in plasma and plaque in the RNAi group, compared to the control and NC groups, whereas the expression level of pro-inflammatory cytokines was markedly increased. Silencing MEF 2A using lentiviral shRNA significantly reduced the plaque collagen content and fibrous cap thickness, as well as increased plaque area. However, silencing MEF 2A had no obvious effect on plaque lipid content. CONCLUSIONS: Lentivirus mediated MEF 2A shRNA accelerates inflammation and atherosclerosis in APOE KO mice, but has no effect on lipoprotein levels in plasma. PMID- 25793530 TI - Evolutionary analysis of mitogenomes from parasitic and free-living flatworms. AB - Mitochondrial genomes (mitogenomes) are useful and relatively accessible sources of molecular data to explore and understand the evolutionary history and relationships of eukaryotic organisms across diverse taxonomic levels. The availability of complete mitogenomes from Platyhelminthes is limited; of the 40 or so published most are from parasitic flatworms (Neodermata). Here, we present the mitogenomes of two free-living flatworms (Tricladida): the complete genome of the freshwater species Crenobia alpina (Planariidae) and a nearly complete genome of the land planarian Obama sp. (Geoplanidae). Moreover, we have reanotated the published mitogenome of the species Dugesia japonica (Dugesiidae). This contribution almost doubles the total number of mtDNAs published for Tricladida, a species-rich group including model organisms and economically important invasive species. We took the opportunity to conduct comparative mitogenomic analyses between available free-living and selected parasitic flatworms in order to gain insights into the putative effect of life cycle on nucleotide composition through mutation and natural selection. Unexpectedly, we did not find any molecular hallmark of a selective relaxation in mitogenomes of parasitic flatworms; on the contrary, three out of the four studied free-living triclad mitogenomes exhibit higher A+T content and selective relaxation levels. Additionally, we provide new and valuable molecular data to develop markers for future phylogenetic studies on planariids and geoplanids. PMID- 25793531 TI - The cost-effectiveness of monitoring strategies for antiretroviral therapy of HIV infected patients in resource-limited settings: software tool. AB - BACKGROUND: The cost-effectiveness of routine viral load (VL) monitoring of HIV infected patients on antiretroviral therapy (ART) depends on various factors that differ between settings and across time. Low-cost point-of-care (POC) tests for VL are in development and may make routine VL monitoring affordable in resource limited settings. We developed a software tool to study the cost-effectiveness of switching to second-line ART with different monitoring strategies, and focused on POC-VL monitoring. METHODS: We used a mathematical model to simulate cohorts of patients from start of ART until death. We modeled 13 strategies (no 2nd-line, clinical, CD4 (with or without targeted VL), POC-VL, and laboratory-based VL monitoring, with different frequencies). We included a scenario with identical failure rates across strategies, and one in which routine VL monitoring reduces the risk of failure. We compared lifetime costs and averted disability-adjusted life-years (DALYs). We calculated incremental cost-effectiveness ratios (ICER). We developed an Excel tool to update the results of the model for varying unit costs and cohort characteristics, and conducted several sensitivity analyses varying the input costs. RESULTS: Introducing 2nd-line ART had an ICER of US$1651 1766/DALY averted. Compared with clinical monitoring, the ICER of CD4 monitoring was US$1896-US$5488/DALY averted and VL monitoring US$951-US$5813/DALY averted. We found no difference between POC- and laboratory-based VL monitoring, except for the highest measurement frequency (every 6 months), where laboratory-based testing was more effective. Targeted VL monitoring was on the cost-effectiveness frontier only if the difference between 1st- and 2nd-line costs remained large, and if we assumed that routine VL monitoring does not prevent failure. CONCLUSION: Compared with the less expensive strategies, the cost-effectiveness of routine VL monitoring essentially depends on the cost of 2nd-line ART. Our Excel tool is useful for determining optimal monitoring strategies for specific settings, with specific sex-and age-distributions and unit costs. PMID- 25793532 TI - Defining immunological impact and therapeutic benefit of mild heating in a murine model of arthritis. AB - Traditional treatments, including a variety of thermal therapies have been known since ancient times to provide relief from rheumatoid arthritis (RA) symptoms. However, a general absence of information on how heating affects molecular or immunological targets relevant to RA has limited heat treatment (HT) to the category of treatments known as "alternative therapies". In this study, we evaluated the effectiveness of mild HT in a collagen-induced arthritis (CIA) model which has been used in many previous studies to evaluate newer pharmacological approaches for the treatment of RA, and tested whether inflammatory immune activity was altered. We also compared the effect of HT to methotrexate, a well characterized pharmacological treatment for RA. CIA mice were treated with either a single HT for several hours or daily 30 minute HT. Disease progression and macrophage infiltration were evaluated. We found that both HT regimens significantly reduced arthritis disease severity and macrophage infiltration into inflamed joints. Surprisingly, HT was as efficient as methotrexate in controlling disease progression. At the molecular level, HT suppressed TNF-alpha while increasing production of IL-10. We also observed an induction of HSP70 and a reduction in both NF-kappaB and HIF-1alpha in inflamed tissues. Additionally, using activated macrophages in vitro, we found that HT reduced production of pro-inflammatory cytokines, an effect which is correlated to induction of HSF-1 and HSP70 and inhibition of NF-kappaB and STAT activation. Our findings demonstrate a significant therapeutic benefit of HT in controlling arthritis progression in a clinically relevant mouse model, with an efficacy similar to methotrexate. Mechanistically, HT targets highly relevant anti inflammatory pathways which strongly support its increased study for use in clinical trials for RA. PMID- 25793533 TI - Excitotoxic insult results in a long-lasting activation of CaMKIIalpha and mitochondrial damage in living hippocampal neurons. AB - Over-activation of excitatory NMDA receptors and the resulting Ca2+ overload is the main cause of neuronal toxicity during stroke. CaMKII becomes misregulated during such events. Biochemical studies show either a dramatic loss of CaMKII activity or its persistent autonomous activation after stroke, with both of these processes being implicated in cell toxicity. To complement the biochemical data, we monitored CaMKII activation in living hippocampal neurons in slice cultures using high spatial/temporal resolution two-photon imaging of the CaMKIIalpha FRET sensor, Camui. CaMKII activation state was estimated by measuring Camui fluorescence lifetime. Short NMDA insult resulted in Camui activation followed by a redistribution of its protein localization: an increase in spines, a decrease in dendritic shafts, and concentration into numerous clusters in the cell soma. Camui activation was either persistent (> 1-3 hours) or transient (~20 min) and, in general, correlated with its protein redistribution. After longer NMDA insult, however, Camui redistribution persisted longer than its activation, suggesting distinct regulation/phases of these processes. Mutational and pharmacological analysis suggested that persistent Camui activation was due to prolonged Ca2+ elevation, with little impact of autonomous states produced by T286 autophosphorylation and/or by C280/M281 oxidation. Cell injury was monitored using expressible mitochondrial marker mito-dsRed. Shortly after Camui activation and clustering, NMDA treatment resulted in mitochondrial swelling, with persistence of the swelling temporarily linked to the persistence of Camui activation. The results suggest that in living neurons excitotoxic insult produces long-lasting Ca2+-dependent active state of CaMKII temporarily linked to cell injury. CaMKII function, however, is to be restricted due to strong clustering. The study provides the first characterization of CaMKII activation dynamics in living neurons during excitotoxic insults. PMID- 25793534 TI - Sulforaphane epigenetically regulates innate immune responses of porcine monocyte derived dendritic cells induced with lipopolysaccharide. AB - Histone acetylation, regulated by histone deacetylases (HDACs) is a key epigenetic mechanism controlling gene expressions. Although dendritic cells (DCs) are playing pivotal roles in host immune responses, the effect of epigenetic modulation of DCs immune responses remains unknown. Sulforaphane (SFN) as a HDAC inhibitor has anti-inflammatory properties, which is used to investigate the epigenetic regulation of LPS-induced immune gene and HDAC family gene expressions in porcine monocyte-derived dendritic cells (moDCs). SFN was found to inhibit the lipopolysaccharide LPS induced HDAC6, HDAC10 and DNA methyltransferase (DNMT3a) gene expression, whereas up-regulated the expression of DNMT1 gene. Additionally, SFN was observed to inhibit the global HDAC activity, and suppressed moDCs differentiation from immature to mature DCs through down-regulating the CD40, CD80 and CD86 expression and led further to enhanced phagocytosis of moDCs. The SFN pre-treated of moDCs directly altered the LPS-induced TLR4 and MD2 gene expression and dynamically regulated the TLR4-induced activity of transcription factor NF-kappaB and TBP. SFN showed a protective role in LPS induced cell apoptosis through suppressing the IRF6 and TGF-beta1 production. SFN impaired the pro-inflammatory cytokine TNF-alpha and IL-1beta secretion into the cell culture supernatants that were induced in moDCs by LPS stimulation, whereas SFN increased the cellular-resident TNF-alpha accumulation. This study demonstrates that through the epigenetic mechanism the HDAC inhibitor SFN could modulate the LPS induced innate immune responses of porcine moDCs. PMID- 25793536 TI - Recent developments in the management of anthelmintic resistance in small ruminants - an Australasian perspective. AB - There have been a number of significant advances in recent years to the theory and practice of managing anthelmintic resistance in sheep in Australasia. The general principles of resistance management are, firstly identification and mitigation of high-risk practices, secondly using effective anthelmintics, and thirdly maintaining a refuge of unselected parasites. The first of these principles has been updated recently with the findings from a series of farm based trials in New Zealand, in which the economic benefits of both short- and long-acting anthelmintic treatments in ewes pre-lambing were found to be inconsistent and not always positive. There have also been significant changes to the second principle, particularly given the introduction of new active families onto the market. Evidence continues to favour the use of combination products to maximise efficacy and delay the onset of treatment-failure. Many farmers have readily accepted the effectiveness of maintaining a refuge of unselected parasites; the challenge for researchers and advisers is now to improve adoption of properly designed and implemented resistance management programmes. A recently completed education programme in New Zealand has demonstrated that when this is achieved, then anthelmintic resistance can be controlled, and in many cases reduced in severity. PMID- 25793537 TI - But Those Who Wait. PMID- 25793535 TI - Quinidine, but not eicosanoid antagonists or dexamethasone, protect the gut from platelet activating factor-induced vasoconstriction, edema and paralysis. AB - Intestinal circulatory disturbances, atony, edema and swelling are of great clinical relevance, but the related mechanisms and possible therapeutic options are poorly characterized, in part because of the difficulties to comprehensively analyze these conditions. To overcome these limitations we have developed a model of the isolated perfused rat small intestine where all of these symptoms can be studied simultaneously. Here we used this model to study the role of eicosanoids, steroids and quinidine in platelet-activating factor (PAF)-induced intestinal disorders. A vascular bolus of PAF (0.5 nmol) triggered release of thromboxane and peptidoleukotrienes into the vascular bed (peak concentration 35 nM and 0.8 nM) and reproduced all symptoms of intestinal failure: mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen and lymphatics, intestinal edema formation, loss of intestinal peristalsis and decreased galactose uptake. All effects of PAF were abolished by the PAF-receptor antagonist ABT491 (2.5 MUM). The COX and LOX inhibitors ASA and AA861 (500 MUM, 10 MUM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 MUM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen. The steroid dexamethasone (10 MUM) showed no barrier-protective properties and failed to prevent edema formation. Quinidine (100 MUM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph. While quinidine by itself reduced peristalsis, it also obviated paralysis, preserved intestinal functions and prevented edema formation. We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine. The therapeutic use of quinidine for intestinal ailments deserves further study. PMID- 25793538 TI - Maternal Exercise Does Not Significantly Alter Adult Rat Offspring Vascular Function. AB - PURPOSE: Research has revealed the role of adverse behaviors during pregnancy on metabolic and cardiovascular health outcomes in offspring. However, minimal attention has been focused on positive prenatal behaviors, such as exercise, and the effect on offspring health outcomes. The objective of this investigation was to test the hypothesis that mothers who voluntarily exercise during pregnancy would improve endothelial function in offspring from exercising compared with sedentary mothers. METHODS: Female Sprague Dawley rats were divided into sedentary (n = 10) or exercise (n = 9) groups with, the exercise group having voluntary access to a running wheel throughout gestation. Litter characteristics (weight and size) were taken 1 d after birth. After weaning, offspring were placed in sedentary cages where they remained until 4 or 8 months of age. Offspring food consumption and cage activity were assessed during a 72-h interval at 2, 4, 6, and 8 months of age. The abdominal aortas of offspring were harvested at 4 or 8 months of age, and vascular function was assessed using cumulative doses of endothelium-dependent (acetylcholine/10(-10)-10(-4) M) and independent (sodium nitroprusside/10(-10)-10(-4) M) vasodilators. RESULTS: There were no significant differences in litter size and litter weight at weaning between the sedentary and exercise groups. Food consumption and wheel running activity did not differ between the sedentary and exercise offspring at 2, 4, 6, or 8 months of age. Vasorelaxation response to acetylcholine or sodium nitroprusside did not differ between the offspring from sedentary and exercise dams. CONCLUSIONS: Maternal voluntary wheel running during pregnancy does not significantly alter behavior or vascular function in adult offspring. PMID- 25793539 TI - Physical Activity and Vascular Events and Mortality in Patients with Vascular Disease. AB - INTRODUCTION: In patients with CAD, moderate levels of leisure time physical activity are associated with lower risk of mortality. However, less is known about the effects in patients with vascular disease other than CAD. In this study, we examined the association between physical activity and risk of future vascular events and all-cause mortality in patients with vascular disease or risk factors and investigated whether these associations were similar across the different manifestations of vascular disease. METHODS: A total of 9942 consecutive patients with various manifestations of vascular disease or risk factors enroled in the Second Manifestations of ARTerial disease study were included. The amount of physical activity was assessed at baseline in MET-hours per week. RESULTS: The study population (mean age, 56.7 yr; male, 67%) had a median level of physical activity of 17.4 MET.h.wk(-1). During a median follow-up of 6.7 yr, 1224 vascular events and 1353 cases of all-cause mortality were recorded. Cox regression analyses adjusted for age, sex, smoking, and current alcohol consumption showed that higher levels of physical activity were associated with reduced risk of vascular events (quartile 4 vs quartile 1; hazard ratio, 0.68 (95% confidence interval, 0.58-0.79)) and all-cause mortality (hazard ratio, 0.61 (95% confidence interval, 0.53-0.71)). This reduced risk was observed both in patients with vascular disease and in patients with risk factors. The associations were similar across the different manifestations of vascular disease. CONCLUSIONS: Higher levels of leisure time physical activity were associated with reduced risk of vascular events and all-cause mortality in patients with CAD and other manifestations of vascular disease, suggesting that physical exercise programs should also be investigated in these other manifestations. PMID- 25793540 TI - The Advantage of a Ureteroscopic Navigation System with Magnetic Tracking in Comparison with Simulated Fluoroscopy in a Phantom Study. AB - PURPOSE: To assess whether our ureteroscopic real-time navigation system has the possibility to reduce radiation exposure and improve performance of ureteroscopic maneuvers in surgeons of various ages and experience levels. MATERIALS AND METHODS: Our novel ureteroscopic navigation system used a magnetic tracking device to detect the position of the ureteroscope and display it on a three dimensional image. We recruited 31 urologists from five institutions to perform two tasks. Task 1 consisted of finding three internal markings on the phantom calices. Task 2 consisted of identifying all calices by ureteroscopy. In both tasks, participants performed with simulated fluoroscopy first, followed by our navigation system. Accuracy rates (AR) for identification, required time (T) for completing the task, migration length (ML), and time exposed to simulated fluoroscopy were recorded. RESULTS: The AR, T, and ML for both tasks were significantly better with the navigation system than without it (Task 1 with simulated fluoroscopy vs with navigation: AR 87.1 % vs 98.9%, P=0.003; T 355 s vs 191 s, P<0.0001; ML 4627 mm vs 2701 mm, P<0.0001. Task 2: AR 88.2% vs 96.7%, P=0.011; T 394 s vs 333 s, P=0.027; ML 5966 mm vs 5299 mm, P=0.0006). In both tasks, the participants used the simulated fluoroscopy about 20% of the total task time. CONCLUSIONS: Our navigation system, while still under development, could help surgeons of all levels to achieve better performances for ureteroscopic maneuvers compared with using fluoroscopic guidance. It also has the potential to reduce radiation exposure during fluoroscopy. PMID- 25793541 TI - Understanding the physicochemical properties of mitragynine, a principal alkaloid of Mitragyna speciosa, for preclinical evaluation. AB - Varied pharmacological responses have been reported for mitragynine in the literature, but no supportive scientific explanations have been given for this. These studies have been undertaken without a sufficient understanding of the physicochemical properties of mitragynine. In this work a UV spectrophotometer approach and HPLC-UV method were employed to ascertain the physicochemical properties of mitragynine. The pKa of mitragynine measured by conventional UV (8.11 +/- 0.11) was in agreement with the microplate reader determination (8.08 +/- 0.04). Mitragynine is a lipophilic alkaloid, as indicated by a logP value of 1.73. Mitragynine had poor solubility in water and basic media, and conversely in acidic environments, but it is acid labile. In an in vitro dissolution the total drug release was higher for the simulated gastric fluid but was prolonged and incomplete for the simulated intestinal fluid. The hydrophobicity, poor water solubility, high variability of drug release in simulated biological fluids and acid degradable characteristics of mitragynine probably explain the large variability of its pharmacological responses reported in the literature. The determined physicochemical properties of mitragynine will provide a basis for developing a suitable formulation to further improve its solubility, stability and oral absorption for better assessment of this compound in preclinical studies. PMID- 25793542 TI - Cysteine specific targeting of the functionally distinct peroxiredoxin and glutaredoxin proteins by the investigational disulfide BNP7787. AB - Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the development and/or progression of human diseases. Grx and Prx are overexpressed in human cancers, including human lung cancers. BNP7787 is a novel investigational agent that has been evaluated in previous clinical studies, including non-small cell lung cancer (NSCLC) studies. Herein, data from activity assays, mass spectrometry analyses, and X-ray crystallographic studies indicate that BNP7787 forms mixed disulfides with select cysteine residues on Grx and Prx and modulates their function. Studies of interactions between BNP7787 and Trx have been conducted and reported separately. Despite the fact that Trx, Grx, and Prx are functionally distinct proteins that impact oxidative stress, cell proliferation and disease processes through different intracellular pathways, BNP7787 can modify each protein and appears to modulate function through mechanisms that are unique to each target protein. Tumor cells are often genomically heterogeneous containing subpopulations of cancer cells that often express different tumor-promoting proteins or that have multiple dysregulated signaling pathways modulating cell proliferation and drug resistance. A multi targeted agent that simultaneously modulates activity of proteins important in mediating cell proliferation by functionally distinct intracellular pathways could have many potentially useful therapeutic applications. PMID- 25793543 TI - Determination of phenolic compounds and antioxidant activity in leaves from wild Rubus L. species. AB - Twenty-six different wild blackberry leaf samples were harvested from various localities throughout southeastern Poland. Leaf samples were assessed regarding their phenolic compound profiles and contents by LC/MS QTOF, and their antioxidant activity by ABTS and FRAP. Thirty-three phenolic compounds were detected (15 flavonols, 13 hydroxycinnamic acids, three ellagic acid derivatives and two flavones). Ellagic acid derivatives were the predominant compounds in the analyzed leaves, especially sanguiin H-6, ellagitannins, lambertianin C, and casuarinin. The content of phenolic compounds was significantly correlated with the antioxidant activity of the analyzed samples. The highest level of phenolic compounds was measured for R. perrobustus, R. wimmerianus, R. pedemontanus and R. grabowskii. The study showed that wild blackberry leaves can be considered a good source of antioxidant compounds. There is clear potential for the utilization of blackberry leaves as a food additive, medicinal source or herbal tea. PMID- 25793544 TI - Synthesis of C-arylnucleoside analogues. AB - Modified nucleoside analogues are of great biological importance as antiviral and antitumoral agents. There is special interest in the preparation of C-aryl nucleosides with an aromatic ring in different positions of the glycone for their biological activity. Different chemical synthesis strategies for these targets are described in this review. PMID- 25793545 TI - Auto-thermal reforming using mixed ion-electronic conducting ceramic membranes for a small-scale H2 production plant. AB - The integration of mixed ionic electronic conducting (MIEC) membranes for air separation in a small-to-medium scale unit for H2 production (in the range of 650 850 Nm3/h) via auto-thermal reforming of methane has been investigated in the present study. Membranes based on mixed ionic electronic conducting oxides such as Ba0.5Sr0.5Co0.8Fe0.2O3-delta (BSCF) give sufficiently high oxygen fluxes at temperatures above 800 degrees C with high purity (higher than 99%). Experimental results of membrane permeation tests are presented and used for the reactor design with a detailed reactor model. The assessment of the H2 plant has been carried out for different operating conditions and reactor geometry and an energy analysis has been carried out with the flowsheeting software Aspen Plus, including also the turbomachines required for a proper thermal integration. A micro-gas turbine is integrated in the system in order to supply part of the electricity required in the system. The analysis of the system shows that the reforming efficiency is in the range of 62%-70% in the case where the temperature at the auto-thermal reforming membrane reactor (ATR-MR) is equal to 900 degrees C. When the electric consumption and the thermal export are included the efficiency of the plant approaches 74%-78%. The design of the reactor has been carried out using a reactor model linked to the Aspen flowsheet and the results show that with a larger reactor volume the performance of the system can be improved, especially because of the reduced electric consumption. From this analysis it has been found that for a production of about 790 Nm3/h pure H2, a reactor with a diameter of 1 m and length of 1.8 m with about 1500 membranes of 2 cm diameter is required. PMID- 25793546 TI - Effect of gold nanorods in an MgO protective layer of AC plasma display panels. AB - We propose a modified MgO protective layer for alternating current plasma display panels. The modified MgO protective layer of the panel tested here has a structure that incorporates silica-coated Au nanorods (NRs), leading to localized surface plasmon resonance (LSPR) in the near-infrared (IR) region. The silica coated Au NRs were synthesized by a simple chemical method and inserted into an MgO protective layer using an air-spray method. The operating voltage of the proposed structure was decreased by 10 V. The luminance and luminous efficacy of the test panel part with the silica-coated Au NRs both increased by about 15%. According to the measured results of the IR response time, the sustain discharge time lag was reduced. In addition, by inserting the silica-coated Au NRs into the MgO protective layer, a decrease of the IR emission proceeding from the plasma discharge was acquired. Finally, we investigated the LSPR effect of the silica coated Au NRs in a simulation with a finite-difference time domain method. PMID- 25793548 TI - Statistical Characteristics of Wrong-Way Driving Crashes on Illinois Freeways. AB - OBJECTIVE: Driving the wrong way on freeways, namely wrong-way driving (WWD), has been found to be a major concern for more than 6 decades. The purpose of this study was to identify characteristics of this type of crash as well as to rank the locations/interchanges according to their vulnerability to WWD entries. METHODS: The WWD crash data on Illinois freeways were statistically analyzed for a 6-year time period (2004 to 2009) from 3 aspects: crash, vehicle, and person. The temporal distributions, geographical distributions, roadway characteristics, and crash locations were analyzed for WWD crashes. The driver demographic information, physical condition, and injury severity were analyzed for wrong-way drivers. The vehicle characteristics, vehicle operation, and collision results were analyzed for WWD vehicles. A method was brought about to identify wrong-way entry points that was then used to develop a relative-importance technique and rank different interchange types in terms of potential WWD incidents. RESULTS: The findings revealed that a large proportion of WWD crashes occurred during the weekend from midnight to 5 a.m. Approximately 80% of WWD crashes were located in urban areas and nearly 70% of wrong-way vehicles were passenger cars. Approximately 58% of wrong-way drivers were driving under the influence (DUI). Of those, nearly 50% were confirmed to be impaired by alcohol, about 4% were impaired by drugs, and more than 3% had been drinking. The analysis of interchange ranking found that compressed diamond interchanges, single point diamond interchanges (SPDIs), partial cloverleaf interchanges, and freeway feeders had the highest wrong-way crash rates (wrong-way crashes per 100 interchanges per year). CONCLUSIONS: The findings of this study call for more attention to WWD crashes from different aspects such as driver age group, time of day, day of week, and DUI drivers. Based on the analysis results of WWD distance, the study explained why a 5-mile radius of WWD crash location should be studied for WWD fatal crashes with unknown entry points. PMID- 25793549 TI - Twist-induced defects of the P-SSP7 genome revealed by modeling the cryo-EM density. AB - We consider the consequences of assuming that DNA inside of phages can be approximated as a strongly nonlinear persistence length polymer. Recent cryo-EM experiments find a hole in the density map of P-SSP7 phage, located in the DNA segment filling the portal channel of the phage. We use experimentally derived structural constraints with coarse-grained simulation techniques to consider contrasting model interpretations of reconstructed density in the portal channel. The coarse-grained DNA models used are designed to capture the effects of torsional strain and electrostatic environment. Our simulation results are consistent with the interpretation that the vacancy or hole in the experimental density map is due to DNA strain leading to strand separation. We further demonstrate that a moderate negative twisting strain is able to account for the strand separation. This effect of nonlinear persistence length may be important in other aspects of phage DNA packing. PMID- 25793550 TI - PTSD Symptoms, Emotion Dysregulation, and Alcohol-Related Consequences Among College Students With a Trauma History. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD), alcohol use, and alcohol-related consequences have been linked to emotion dysregulation. Sex differences exist in both emotion regulation dimensions and alcohol use patterns. This investigation examined facets of emotion dysregulation as potential mediators of the relationship between PTSD symptoms and alcohol-related consequences and whether differences may exist across sexes. METHODS: Participants were 240 college students with a trauma history who reported using alcohol within the past three months and completed measures of PTSD symptoms, emotion dysregulation, alcohol consumption, alcohol-related consequences, and negative affect. The six facets of emotion dysregulation were examined as mediators of the relationship between PTSD symptoms and alcohol-related consequences in the full sample and by sex. RESULTS: There were differences in sexes on several variables, with women reporting higher PTSD scores and lack of emotional awareness. Men reported significantly more drinks per week in a typical week and a heavy week. There were significant associations between the variables for the full sample, with PTSD showing associations with five facets of emotion dysregulation subscales: impulse control difficulties when upset, difficulties engaging in goal-directed behavior, nonacceptance of emotional responses, lack of emotional clarity, and limited access to emotion regulation strategies. Alcohol-related consequences were associated with four aspects of emotion dysregulation: impulse control difficulties when upset, difficulties engaging in goal-directed behavior, nonacceptance of emotional responses, and limited access to emotion regulation strategies. Two aspects of emotion regulation, impulse control difficulties and difficulties engaging in goal directed behavior, mediated the relationship between PTSD symptoms and alcohol-related consequences in the full sample, even after adjusting for the effects of negative affect. When examined separately by gender, impulse control difficulties remained a mediator for men and difficulties engaging in goal directed behavior for women. CONCLUSIONS: These analyses shed light on processes that may underlie "self-medication" of PTSD symptoms. Gender specific interventions targeting emotion dysregulation may be effective in reducing alcohol-related consequences in individuals with PTSD. Women may possibly benefit from interventions that focus on difficulties engaging in goal directed behavior, while men may benefit from interventions that target impulse control difficulties when upset. PMID- 25793552 TI - Construction of beta-mannosidic bonds via gold(I)-catalyzed glycosylations with mannopyranosyl ortho-hexynylbenzoates and its application in synthesis of acremomannolipin A. AB - A mild and convenient protocol for direct synthesis of beta-mannosides has been developed. Glycosylation of 4,6-O-benzylidene-protected mannosyl ortho hexynylbenzoates with various alcohol acceptors catalyzed by gold(I) complex proceeded smoothly at 0 degrees C to room temperature and afforded the corresponding beta-mannoside in high yield and satisfactory stereoselectivity. This reaction was applied to the total synthesis of acremomannolipin A and its analogue. PMID- 25793553 TI - Anion selectivity in ion exchange reactions with surface functionalized ionosilicas. AB - Mesoporous imidazolium functionalized surface functionalized ionosilicas have been investigated as anion exchange materials for the adsorption of oxo-anions in aqueous media. We studied particularly pertechnetate adsorption and could show that solids bearing long chain substituted imidazolium groups are highly efficient anion exchange materials often displaying high distribution coefficients between solid and liquid phases. We observed that the distribution coefficient of pertechnetate is a function of the presence of competing anionic species. As a consequence, our experiments allowed reproducing experimentally Hofmeister's series. However, pertechnetate adsorption on the material can completely be inhibited in the presence of highly fluorinated anions such as bis(trifluoromethylsulfonyl)amide (NTf2). This behaviour indicates a particularly imidazophilic behaviour of these anions, which have a particular importance due to their use in water immiscible ionic liquids. Finally, the adsorption process has been shown to be reversible. This feature is of importance in view of the regeneration of the anion exchange material. PMID- 25793554 TI - Central trends in nursing informatics: students' reflections from International Congress on Nursing Informatics 2014 (Taipei, Taiwan). PMID- 25793551 TI - Epidemiology and Ecology of Opportunistic Premise Plumbing Pathogens: Legionella pneumophila, Mycobacterium avium, and Pseudomonas aeruginosa. AB - BACKGROUND: Legionella pneumophila, Mycobacterium avium, and Pseudomonas aeruginosa are opportunistic premise plumbing pathogens (OPPPs) that persist and grow in household plumbing, habitats they share with humans. Infections caused by these OPPPs involve individuals with preexisting risk factors and frequently require hospitalization. OBJECTIVES: The objectives of this report are to alert professionals of the impact of OPPPs, the fact that 30% of the population may be exposed to OPPPs, and the need to develop means to reduce OPPP exposure. We herein present a review of the epidemiology and ecology of these three bacterial OPPPs, specifically to identify common and unique features. METHODS: A Water Research Foundation-sponsored workshop gathered experts from across the United States to review the characteristics of OPPPs, identify problems, and develop a list of research priorities to address critical knowledge gaps with respect to increasing OPPP-associated disease. DISCUSSION: OPPPs share the common characteristics of disinfectant resistance and growth in biofilms in water distribution systems or premise plumbing. Thus, they share a number of habitats with humans (e.g., showers) that can lead to exposure and infection. The frequency of OPPP-infected individuals is rising and will likely continue to rise as the number of at-risk individuals is increasing. Improved reporting of OPPP disease and increased understanding of the genetic, physiologic, and structural characteristics governing the persistence and growth of OPPPs in drinking water distribution systems and premise plumbing is needed. CONCLUSIONS: Because broadly effective community-level engineering interventions for the control of OPPPs have yet to be identified, and because the number of at-risk individuals will continue to rise, it is likely that OPPP-related infections will continue to increase. However, it is possible that individuals can take measures (e.g., raise hot water heater temperatures and filter water) to reduce home exposures. PMID- 25793555 TI - Nursing leadership in development and implementation of a patient-centered plan of care toolkit in the acute care setting. PMID- 25793557 TI - Unfolding the contents of sub-nm plasmonic gaps using normalising plasmon resonance spectroscopy. AB - Plasmonic coupling of gold nanoparticles to a gold surface creates intense plasmonic hot spots with large electromagnetic field-enhancements within the cavity formed by the two metallic surfaces. The localised field in such structures is extremely sensitive to morphological fluctuations and subtle changes in the dielectric properties of the cavity contents. Here, we present an optical method that pins down the properties of the gap contents with high sensitivity, termed normalising plasmon resonance (NPR) spectroscopy. We use this on a variety of ultrathin molecular spacers such as filled and empty cucurbiturils, and graphene. Clear differences in the spectral positions and intensities of plasmonic modes observed in the scattering spectrum resolve thickness differences of 0.1 nm, and refractive index changes from molecular filling. PMID- 25793559 TI - Resolving Some Paradoxes in the Thermal Decomposition Mechanism of Acetaldehyde. AB - The mechanism for the thermal decomposition of acetaldehyde has been revisited with an analysis of literature kinetics experiments using theoretical kinetics. The present modeling study was motivated by recent observations, with very sensitive diagnostics, of some unexpected products in high temperature microtubular reactor experiments on the thermal decomposition of CH3CHO and its deuterated analogs, CH3CDO, CD3CHO, and CD3CDO. The observations of these products prompted the authors of these studies to suggest that the enol tautomer, CH2CHOH (vinyl alcohol), is a primary intermediate in the thermal decomposition of acetaldehyde. The present modeling efforts on acetaldehyde decomposition incorporate a master equation reanalysis of the CH3CHO potential energy surface (PES). The lowest-energy process on this PES is an isomerization of CH3CHO to CH2CHOH. However, the subsequent product channels for CH2CHOH are substantially higher in energy, and the only unimolecular process that can be thermally accessed is a reisomerization to CH3CHO. The incorporation of these new theoretical kinetics predictions into models for selected literature experiments on CH3CHO thermal decomposition confirms our earlier experiment and theory-based conclusions that the dominant decomposition process in CH3CHO at high temperatures is C-C bond fission with a minor contribution (~10-20%) from the roaming mechanism to form CH4 and CO. The present modeling efforts also incorporate a master-equation analysis of the H + CH2CHOH potential energy surface. This bimolecular reaction is the primary mechanism for removal of CH2CHOH, which can accumulate to minor amounts at high temperatures, T > 1000 K, in most lab-scale experiments that use large initial concentrations of CH3CHO. Our modeling efforts indicate that the observation of ketene, water, and acetylene in the recent microtubular experiments are primarily due to bimolecular reactions of CH3CHO and CH2CHOH with H-atoms and have no bearing on the unimolecular decomposition mechanism of CH3CHO. The present simulations also indicate that experiments using these microtubular reactors when interpreted with the aid of high-level theoretical calculations and kinetics modeling can offer insights into the chemistry of elusive intermediates in the high-temperature pyrolysis of organic molecules. PMID- 25793558 TI - Postconditioning with cyclosporine a reduces early renal dysfunction by inhibiting mitochondrial permeability transition. AB - BACKGROUND: Ischemia-reperfusion (IR) injury leads to mitochondrial permeability transition pore opening, which contributes to cell death. The aim of this study is to determine whether ischemic or pharmacological postconditioning with cyclosporine A (CsA) might protect the kidney from lethal reperfusion injury. METHODS: Male mice underwent a unilateral (right) nephrectomy followed by 30 minutes of contralateral (left) clamping of the renal artery. We studied 4 groups at 20 minutes and 24 hours of reperfusion: a sham group (n = 4), an ischemic group (n = 6), CsA-postconditioned group (postcond-CsA, injection of 3 mg/kg of CsA 5 minutes before the end of ischemia, (n = 6), and an ischemic postconditioning (IPC) group (n = 6), consisting of 3 cycles of 30 seconds of renal ischemia with 30 seconds intervening reperfusion. After 24 hours of reperfusion, we measured plasma creatinine, urea, and histological kidney injury. The kidney mitochondria were isolated to assess the mitochondria calcium retention capacity and oxidative phosphorylation. RESULTS: At 24 hours after reperfusion, serum creatinine decreased in postcond-CsA and IPC compared to ischemic group. The histological score was also significantly improved with postcond-CsA and IPC. At 20 minutes and 24 hours of reperfusion, calcium retention capacity was decreased significantly in the ischemic group. The mitochondrial respiration stay decreased in the ischemic group at 24 hours of reperfusion, whereas the respiration was improved significantly in the postcond CsA and IPC group. Bax and cleaved caspase 3 decreased in PostCsA and IPC group. CONCLUSIONS: Our results suggest that IPC and CsA, administered immediately before reperfusion, protect the kidney from lethal injury. PMID- 25793560 TI - Quantitative assessment of photostability and photostabilisation of Fluvoxamine and its design for actinometry. AB - Despite the numerous concerns that have been raised in relation to considering 0(th), 1(st) and 2(nd)-order kinetic treatments for photodegradation characterisation and assessment of drugs, they still are employed, as they are the only tools available for these types of studies. The recently developed Phi order kinetic models have opened new perspectives in the treatment of photoreaction kinetics and stand as the best known alternative to the classical approach. The Phi-order kinetics have been applied here to Fluvoxamine (Fluvo) with the aim of setting out a detailed and comprehensive procedure capable of rationalising photodegradation/photostability of drugs and proposing a platform for photosafety studies. Our results prove that quantum yields of drugs (0.0016 < Phi(lambdairr)(Fluvo) < 0.43) should a priori be considered wavelength-dependent; their photostabilisation (up to 75% for Fluvo) by means of absorption competitors can explicitly be related to a decrease of the photokinetic factor, and photoreversible drugs can be developed into efficient actinometers (as Fluvoxamine in the 260-290 nm range). A pseudo-rate-constant factor was proposed as a descriptive parameter, circumventing the limitations of overall rate constants and allowing a comparison between kinetic data of drugs obtained under different conditions. PMID- 25793561 TI - Speckle reduction in optical coherence tomography by two-step image registration. AB - The image quality of optical coherence tomography can be severely influenced by speckle noise (i.e., signal-degrading speckle). Averaging multiple B-scans can effectively suppress speckle noise. Because of sample motion, images subject to averaging must be aligned exactly. We propose a two-step image registration scheme that combines global and local registrations for speckle reduction by the averaging of multiple B-scans. The method begins with a global registration to compensate for overall motion, which is estimated based on the rigid transformation model involving translation and rotation. Then each A-scan is aligned by cross-correlation using a graph-based algorithm, followed by a pixel subdivision method to improve smoothness in local registration. The method does not rely on any information about the retinal layer boundaries. We have applied this method to the registration of macular optical coherence tomography images. The results show the reduction of speckle noise and the enhanced visualization of layer structures. A signal-to-noise ratio improvement of nearly the square root of the number of averaged B-scans and a contrast-to-noise ratio improvement of around 11 are achieved through our method. PMID- 25793563 TI - Sensomics analysis of key bitter compounds in the hard resin of hops (Humulus lupulus L.) and their contribution to the bitter profile of Pilsner-type beer. AB - Recent brewing trials indicated the occurrence of valuable bitter compounds in the hard resin fraction of hop. Aiming at the discovery of these compounds, hop's epsilon-resin was separated by means of a sensory guided fractionation approach and the key taste molecules were identified by means of UV/vis, LC-TOF-MS, and 1D/2D-NMR studies as well as synthetic experiments. Besides a series of literature known xanthohumol derivatives, multifidol glucosides, flavon-3-on glycosides, and p-coumaric acid esters, a total of 11 bitter tastants are reported for the first time, namely, 1",2"-dihydroxanthohumol F, 4' hydroxytunicatachalcone, isoxantholupon, 1-methoxy-4-prenylphloroglucinol, dihydrocyclohumulohydrochinone, xanthohumols M, N, and P, and isoxanthohumols M, N, and P, respectively. Human sensory analysis revealed low bitter recognition threshold concentrations ranging from 5 (co-multifidol glucopyranoside) to 198 MUmol/L (trans-p-coumaric acid ethyl ester) depending on their chemical structure. For the first time, LC-MS/MS quantitation of these taste compounds in Pilsner-type beer, followed by taste re-engineering experiments, revealed the additive contribution of iso-alpha-acids and the identified hard resin components to be truly necessary and sufficient for constructing the authentic bitter percept of beer. Finally, brewing trails using the epsilon-resin as the only hop source impressively demonstrated the possibility to produce beverages strongly enriched with prenylated hop flavonoids. PMID- 25793562 TI - Macroscopic-imaging technique for subsurface quantification of near-infrared markers during surgery. AB - Obtaining accurate quantitative information on the concentration and distribution of fluorescent markers lying at a depth below the surface of optically turbid media, such as tissue, is a significant challenge. Here, we introduce a fluorescence reconstruction technique based on a diffusion light transport model that can be used during surgery, including guiding resection of brain tumors, for depth-resolved quantitative imaging of near-infrared fluorescent markers. Hyperspectral fluorescence images are used to compute a topographic map of the fluorophore distribution, which yields structural and optical constraints for a three-dimensional subsequent hyperspectral diffuse fluorescence reconstruction algorithm. Using the model fluorophore Alexa Fluor 647 and brain-like tissue phantoms, the technique yielded estimates of fluorophore concentration within +/ 25% of the true value to depths of 5 to 9 mm, depending on the concentration. The approach is practical for integration into a neurosurgical fluorescence microscope and has potential to further extend fluorescence-guided resection using objective and quantified metrics of the presence of residual tumor tissue. PMID- 25793564 TI - Synthesis, reactivity, and biological activity of gold(I) complexes modified with thiourea-functionalized tyrosine kinase inhibitors. AB - Thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as potential receptor-targeted carrier ligands in linear gold(I) complexes. The molecules mimic the epidermal growth factor receptor (EGFR) tyrosine kinase-targeted inhibitor gefitinib. Thiourea groups were either directly attached to quinazoline-C6 (compounds 4, 5, and 7) or linked to this position via a flexible ethylamino chain (compound 9). Compound 7 acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving the unexpected dinuclear complex [{Au(MU-7-S,N)}2]X2 (X = Cl(-), SCN(-)) (12a,b) (X-ray crystallography, electrospray mass spectrometry). Derivative 9 forms a stable linear complex, [Au(PEt3)(9-S)](NO3) (13). The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. Compound 9 partially overcomes resistance to gefitinib in NCI-H1975, a lung cancer cell line characterized by a L858R/T790M mutation in EGFR (IC50 values of 1.7 and 30 MUM, respectively). The corresponding gold complex (13) maintains activity in the low-micromolar concentration range similar to the metal free carrier. Compound 9 and the corresponding [Au(PEt3)] complex, 13, inhibit EGFR kinase-mediated phosphorylation with sub-micromolar IC50 values similar to those observed for gefitinib under the same assay conditions. Potential mechanisms of action and reactions in biological media of this new type of hybrid agent, as well as shortcomings of the current design are discussed. PMID- 25793565 TI - Molecular dynamics simulations on the interaction of the transmembrane NavAb channel with cholesterol and lipids in the membrane. AB - Increased cholesterol levels are associated with multiple pathological conditions. In this work, molecular dynamics simulations were applied to observe the influence of membrane cholesterol levels on a voltage-gated sodium channel. Different lipid compositions are modeled around the channel to obtain information about the possible effects by which cholesterol influences NavAb channels. Cholesterol was normally not directly interacting with either the closed or inactivated conformation. Cholesterol increased lipid packing implying that it plays a crucial role in restricting lipid movement in the region around 1 nm of the channel in a 1-palmitoyl-2-oeleoyl phosphatidylcholine matrix. Our results provide the first computational indication of an indirect modulation of NavAb channels by membrane cholesterol. PMID- 25793566 TI - Management of distal femur fractures with modern plates and nails: state of the art. AB - Fractures of the distal femur, even those with articular extension, are well suited to surgical fixation with modern precontoured anatomic plates and nails. Numerous adjuvant techniques are available to the treating surgeon to obtain and maintain reduction while preserving fracture biology. Yet despite their proven track record and benefits over older implants, technical errors are common and must be overcome with proper preoperative planning and intraoperative attention to detail. This review summarizes the current state of the art regarding distal femur fractures, with an emphasis on relevant modern plate and nail surgical techniques, tempered by our current understanding of implant biomechanics, fracture healing, and long-term outcomes. PMID- 25793567 TI - Invited commentary related to: A cost analysis of internal fixation versus nonoperative treatment in adult midshaft clavicle fractures using multiple randomized controlled trials. PMID- 25793568 TI - In response. PMID- 25793569 TI - Invited commentary: disability versus impairment. PMID- 25793570 TI - Hydration status affects mood state and pain sensation during ultra-endurance cycling. AB - Laboratory-based studies indicate mild dehydration adversely affects mood. Although ultra-endurance events often result in mild to moderate dehydration, little research has evaluated whether the relationship between hydration status and mood state also exists in these arduous events. Therefore, the purpose of this study was to evaluate how hydration status affected mood state and perceptual measures during a 161 km ultra-endurance cycling event. One hundred and nineteen cyclists (103 males, 16 females; age = 46 +/- 9 years; height = 175.4 +/- 17.9 cm; mass = 82.8 +/- 16.3 kg) from the 2011 and 2013 Hotter'N Hell events participated. Perceived exertion, Thermal, Thirst, and Pain sensations, Brunel Profile of Mood States, and urine specific gravity (USG) were measured pre (~1 h before), mid- (~97 km), and post-ride. Participants were classified at each time point as dehydrated (USG >= 1.022) or euhydrated (USG <= 1.018). Independent of time point, dehydrated participants (USG = 1.027 +/- 0.004) had decreased Vigour and increased Fatigue, Pain, Thirst, and Thermal sensations compared to euhydrated participants (USG = 1.012 +/- 0.004; all P < 0.01). USG significantly correlated with Fatigue (r = 0.36), Vigour (r = -0.27), Thirst (r = 0.15), and Pain (r = 0.22; all P < 0.05). In conclusion, dehydrated participants had greater Fatigue and Pain than euhydrated participants. These findings indicate dehydration may adversely affect mood state and perceptual ratings during ultra-endurance cycling. PMID- 25793571 TI - Surgical management of the patients with chronic subdural haematoma and contralateral subdural effusion: Operation or no-operation? AB - OBJECTIVE: Patients with chronic subdural haematoma and contralateral subdural effusion are rare after head injury. Surgery might reduce clinical progression of subdural effusion, but is not used routinely. This study aimed to investigate the effect of surgery on subdural effusion and clinical outcome. METHODS: A retrospective study was performed, comparing operation and non-operation in the patients with chronic subdural haematoma and contralateral subdural effusion, in a series of 47 patients divided into two groups. The operation group of 21 patients underwent bilateral surgery. The non-operation group of 26 patients underwent surgery on the side with chronic subdural haematoma. Neurological status was assessed by the Glasgow Coma score and Modified Rankin Scale score on admission and at follow-up. All cases underwent pre- and post-operative computed tomography scans. RESULTS: Pre-operative clinical and radiological data were similar in the two groups. The rate of subdural effusion progression was significantly lower in the operation group than in the non-operation group (p < 0.05). Thirteen cases (50%) in the non-operation group and three cases (14.3%) in the operation group had progression of subdural effusion to chronic subdural haematoma (p < 0.05). Chronic subdural haematoma recurrence rate, mortality and neurological recovery were similar, with no significant difference between groups. CONCLUSIONS: The patients benefitted from surgery for subdural effusion when they had chronic subdural haematoma and contralateral subdural effusion. PMID- 25793572 TI - Depressive symptomology management and falls among middle aged and older adults. AB - OBJECTIVES: This study aims to examine the relationship between middle-aged and older adults' depressive symptomology and anti-depressant use and the frequency of falls within the previous 12 months, controlling for sociodemographic variables, health indicators, and health behaviors. METHOD: From the 2010 National Social Life, Health, and Aging Project, 2338 cases were examined. Falls were categorized into a binary variable, comparing zero falls with one or more falls. An unadjusted model was run to examine the relationship between independent and dependent variables. Potential covariates were added into the model, and backward elimination was used among independent variables with a univariate P < 0.05 to identify the covariates with the strongest association with falls. This final adjusted binary logistic regression model was then used to examine the relationship between falls and the independent variables. RESULTS: In the adjusted model, anti-depressant use was positively associated with falls (P = 0.001), as was being female (P < 0.001), having diabetes (P = 0.018), and having increased limitations in daily activities (P < 0.001). The relationship between depressive symptomology and anti-depressant prescription was also significantly associated with falls (P = 0.006). CONCLUSION: While findings confirm that a relationship between depressive symptomology and anti-depressant use are associated with falls among middle-aged and older adults, additional studies are needed that simultaneously examine the influence of these two risk factors. PMID- 25793573 TI - Special issue of Cell Adhesion & Migration on Tenascins: Defining their role in tissue homeostasis and cancer. PMID- 25793575 TI - Tenascins in fibrotic disorders-from bench to bedside. AB - Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in chronic inflammatory diseases, available treatment strategies are limited. Tenascins constitute a family of matricellular proteins, primarily modulating interactions of cells with other matrix components and growth factors. Data obtained from tenascin C deficient mice show important roles of this molecule in several models of fibrosis. Moreover there is growing evidence that tenascin C has a strong impact on chronic inflammation, myofibroblast differentiation and recruitment. Tenascin C as well as tenascin X has furthermore been shown to affect TGF-beta activation and signaling. Taken together these data suggest that these proteins might be important factors in fibrosis development and make them attractive both as biological markers and as targets for therapeutical intervention. So far most clinical research in fibrosis has been focused on tenascin C. This review aims at summarizing our up-to-date knowledge on the involvement of tenascin C in the pathogenesis of fibrotic disorders. PMID- 25793574 TI - Transcriptional regulation of tenascin genes. AB - Extracellular matrix proteins of the tenascin family resemble each other in their domain structure, and also share functions in modulating cell adhesion and cellular responses to growth factors. Despite these common features, the 4 vertebrate tenascins exhibit vastly different expression patterns. Tenascin-R is specific to the central nervous system. Tenascin-C is an "oncofetal" protein controlled by many stimuli (growth factors, cytokines, mechanical stress), but with restricted occurrence in space and time. In contrast, tenascin-X is a constituitive component of connective tissues, and its level is barely affected by external factors. Finally, the expression of tenascin-W is similar to that of tenascin-C but even more limited. In accordance with their highly regulated expression, the promoters of the tenascin-C and -W genes contain TATA boxes, whereas those of the other 2 tenascins do not. This article summarizes what is currently known about the complex transcriptional regulation of the 4 tenascin genes in development and disease. PMID- 25793576 TI - Tenascin-C and integrins in cancer. AB - Tenascin-C (TNC) is highly expressed in cancer tissues. Its cellular sources are cancer and stromal cells, including fibroblasts/myofibroblasts, and also vascular cells. TNC expressed in cancer tissues dominantly contains large splice variants. Deposition of the stroma promotes the epithelial-mesenchymal transition, proliferation, and migration of cancer cells. It also facilitates the formation of cancer stroma including desmoplasia and angiogenesis. Integrin receptors that mediate the signals of TNC have also been discussed. PMID- 25793579 TI - Corrigendum. PMID- 25793577 TI - Tenascin-C and carcinoma cell invasion in oral and urinary bladder cancer. AB - Carcinoma invasion is a complex process regulated by genetic and epigenetic factors as well. A relevant supportive condition for cancer cell migration is the reorganization of the extracellular matrix (ECM), which is realized in an orchestrated multicellular manner including carcinoma cells and stromal fibroblasts. An important key player in the process of ECM reorganization is Tenascin-C (Tn-C). The molecule occurs as different isoforms generated by alternative splicing and de novo glycosylation. Large variants of Tn-C are abundantly re-expressed in the invasive front of many carcinoma types. A special role for initiating migration and accompanied epithelial to mesenchymal transition has been suggested. Here, we review the current knowledge concerning the tumor biological importance of Tn-C, the synthesis and alternative splicing during the invasive process in general, and give an overview on the impact of Tn C in urothelial carcinoma of the urinary bladder (UBC) and oral squamous cell carcinoma (OSCC). PMID- 25793578 TI - Tenascin-X: beyond the architectural function. AB - Tenascin-X is the largest member of the tenascin (TN) family of evolutionary conserved extracellular matrix glycoproteins, which also comprises TN-C, TN-R and TN-W. Among this family, TN-X is the only member described so far to exert a crucial architectural function as evidenced by a connective tissue disorder (a recessive form of Ehlers-Danlos syndrome) resulting from a loss-of-function of this glycoprotein in humans and mice. However, TN-X is more than an architectural protein, as it displays features of a matricellular protein by modulating cell adhesion. However, the cellular functions associated with the anti-adhesive properties of TN-X have not yet been revealed. Recent findings indicate that TN-X is also an extracellular regulator of signaling pathways. Indeed, TN-X has been shown to regulate the bioavailability of the Transforming Growth Factor (TGF) beta and to modulate epithelial cell plasticity. The next challenges will be to unravel whether the signaling functions of TN-X are functionally linked to its matricellular properties. PMID- 25793580 TI - Lithium prescribing during pregnancy: a UK primary care database study. AB - BACKGROUND: Women taking lithium must decide whether to continue the medication if they conceive or plan to conceive. Little is known about the extent of prescribing of lithium during pregnancy. AIMS: To determine: 1) the prevalence of lithium prescribing during pregnancy and 2) to assess whether pregnancy is associated with discontinuation of lithium. METHOD: First, we identified women receiving any lithium prescriptions before and during pregnancy using The Health Improvement Network (THIN) primary care database. Subsequently, we used a Kaplan Meier plot to compare time to last prescription in women prescribed lithium continuously three months before pregnancy and a comparison group of non-pregnant women. Finally, we described the characteristics of the women prescribed lithium in pregnancy. RESULTS: Very few women were prescribed lithium during pregnancy; out of 458,761 pregnancies, we identified 47 (0.01%) in which lithium was prescribed after the 6th week of pregnancy (when the pregnancy was likely to be known). In our study of discontinuation, we found pregnant women were more likely to stop lithium than those who were not pregnant. Of the 52 women who were being continuously prescribed lithium three months before pregnancy, only 17 (33%) continued receiving prescriptions beyond the 6th week of pregnancy. However, most of these 17 women continued treatment throughout pregnancy. CONCLUSIONS: Pregnancy was strongly associated with discontinuation of lithium. Further evidence on the risks of lithium is needed so that women can weight these against the risk of a deterioration in maternal mental health. PMID- 25793581 TI - Optimization and validation of high-performance chromatographic condition for simultaneous determination of adapalene and benzoyl peroxide by response surface methodology. AB - The aim of this study was to develop a simple and reliable high-performance chromatographic (HPLC) method for simultaneous analysis of adapalene and benzoyl peroxide in pharmaceutical formulation by response surface methodology (RSM). An optimized mobile phase composed of acetonitrile, tetrahydrofuran and water containing 0.1% acetic acid at a ratio of 25:50:25 by volume was successfully predicted by using RSM. An isocratic separation was achieved by using the condition. Furthermore, the analytical method was validated in terms of specificity, linearity, accuracy and precision in a range of 80% to 120% of the expected concentration. Finally, the method was successfully applied to the analysis of a commercial product. PMID- 25793582 TI - A meta-analysis of risk factors for combat-related PTSD among military personnel and veterans. AB - Post-traumatic stress disorder (PTSD), a complex and chronic disorder caused by exposure to a traumatic event, is a common psychological result of current military operations. It causes substantial distress and interferes with personal and social functioning. Consequently, identifying the risk factors that make military personnel and veterans more likely to experience PTSD is of academic, clinical, and social importance. Four electronic databases (PubMed, Embase, Web of Science, and PsycINFO) were used to search for observational studies (cross sectional, retrospective, and cohort studies) about PTSD after deployment to combat areas. The literature search, study selection, and data extraction were conducted by two of the authors independently. Thirty-two articles were included in this study. Summary estimates were obtained using random-effects models. Subgroup analyses, sensitivity analyses, and publication bias tests were performed. The prevalence of combat-related PTSD ranged from 1.09% to 34.84%. A total of 18 significant predictors of PTSD among military personnel and veterans were found. Risk factors stemming from before the trauma include female gender, ethnic minority status, low education, non-officer ranks, army service, combat specialization, high numbers of deployments, longer cumulative length of deployments, more adverse life events, prior trauma exposure, and prior psychological problems. Various aspects of the trauma period also constituted risk factors. These include increased combat exposure, discharging a weapon, witnessing someone being wounded or killed, severe trauma, and deployment-related stressors. Lastly, lack of post-deployment support during the post-trauma period also increased the risk of PTSD. The current analysis provides evidence of risk factors for combat-related PTSD in military personnel and veterans. More research is needed to determine how these variables interact and how to best protect against susceptibility to PTSD. PMID- 25793583 TI - Suppression of TGF-beta1/Smad signaling pathway by sesamin contributes to the attenuation of myocardial fibrosis in spontaneously hypertensive rats. AB - This study investigated the effect of sesamin on myocardial fibrosis in spontaneously hypertensive rats (SHRs) and the possible mechanisms involved. Twenty-eight male SHRs were randomly allocated to SHR group, Ses160 group (sesamin 160 mg/kg), Ses80 group (sesamin 80 mg/kg) and Cap30 group (captopril 30 mg/kg). Seven male WKY rats were used as control. Sesamin and captopril were administered intragastrically for 12 weeks. Captopril significantly reduced systolic blood pressure and angiotensin II (Ang II) levels in SHRs, accompanied by a marked attenuation of left ventricular hypertrophy (LVH) and collagen deposition (P <0.05 or P <0.01). Though sesamin had no significant influence on Ang II levels, and the hypotensive effect was also significantly inferior to that of captopril (P <0.05 or P <0.01), however, the improvement of LVH and collagen deposition was similar to that in captopril group. Sesamin markedly reduced transforming growth factor-beta1 (TGF-beta1) content in cardiac tissues, with Smad3 phosphorylation decreased and Smad7 protein expression increased notably (P <0.05 or P <0.01). Protein expression of type I collagen and type III collagen, target genes of Smad3, was down-regulated markedly by sesamin (P <0.05 or P <0.01). In addition, sesamin significantly increased total antioxidant capacity and superoxide dismutase protein in cardiac tissues (P <0.05 or P <0.01), while the expression of NADPH oxidase subunit p47phox and malondialdehyde content were reduced markedly (P <0.05 or P <0.01). In vitro studies also demonstrated that sesamin was able to suppress Ang II induced phosphorylation of Smad3 and secretion of TGF-beta1 and type I and type III collagen in cultured rat cardiac fibroblasts. These data suggest that sesamin is capable of attenuating hypertensive myocardial fibrosis through, at least partly, suppression of TGF beta1/Smad signaling pathway. PMID- 25793584 TI - Identifying and evaluating field indicators of urogenital schistosomiasis-related morbidity in preschool-aged children. AB - BACKGROUND: Several studies have been conducted quantifying the impact of schistosome infections on health and development in school-aged children. In contrast, relatively little is known about morbidity levels in preschool-aged children (<= 5 years) who have been neglected in terms of schistosome research and control. The aim of this study was to compare the utility of available point of-care (POC) morbidity diagnostic tools in preschool versus primary school-aged children (6-10 years) and determine markers which can be used in the field to identify and quantify Schistosoma haematobium-related morbidity. METHODS/PRINCIPAL FINDINGS: A comparative cross-sectional study was conducted to evaluate the performance of currently available POC morbidity diagnostic tools on Zimbabwean children aged 1-5 years (n=104) and 6-10 years (n=194). Morbidity was determined using the POC diagnostics questionnaire-based reporting of haematuria and dysuria, clinical examination, urinalysis by dipsticks, and urine albumin-to creatinine ratio (UACR). Attributable fractions were used to quantify the proportion of morbidity attributable to S. haematobium infection. Based on results of attributable fractions, UACR was identified as the most reliable tool for detecting schistosome-related morbidity, followed by dipsticks, visual urine inspection, questionnaires, and lastly clinical examination. The results of urine dipstick attributes showed that proteinuria and microhaematuria accounted for most differences between schistosome egg-positive and negative children (T=-50.1; p<0.001). These observations were consistent in preschool vs. primary school-aged children. CONCLUSIONS/SIGNIFICANCE: Preschool-aged children in endemic areas can be effectively screened for schistosome-related morbidity using the same currently available diagnostic tools applicable to older children. UACR for detecting albuminuria is recommended as the best choice for rapid assessment of morbidity attributed to S. haematobium infection in children in the field. The use of dipstick microhaematuria and proteinuria as additional indicators of schistosome-related morbidity would improve the estimation of disease burden in young children. PMID- 25793587 TI - How do negative emotions relate to dysfunctional posttrauma cognitions? An examination of interpersonal trauma survivors. AB - In order to broaden theoretical models of adaptation following trauma and inform current diagnostic practices, the goal of the current study was to examine associations between negative emotions and dysfunctional trauma-related cognitions. In a sample of 109 women who were seeking mental health assistance after intimate partner violence (IPV), anxiety, depression, shame, and guilt were explored in association with negative thoughts about the self, negative thoughts about the world, and self-blame. Higher levels of shame and depression were significantly associated with higher levels of negative thoughts about the self. An increased level of guilt was the only significant finding in the analysis involving negative thoughts about the world. Lower levels of depression and higher levels of shame and guilt were significantly associated with increased levels of self-blame. Anxiety did not emerge as a significant predictor in any of these analyses. Implications for current models of posttraumatic stress disorder (PTSD), revisions to diagnostic practices, and treatment of individuals who have experienced interpersonal trauma are discussed. PMID- 25793585 TI - Diagnostic accuracy of 123I-meta-iodobenzylguanidine myocardial scintigraphy in dementia with Lewy bodies: a multicenter study. AB - BACKGROUND AND PURPOSE: Dementia with Lewy bodies (DLB) needs to be distinguished from Alzheimer's disease (AD) because of important differences in patient management and outcome. Severe cardiac sympathetic degeneration occurs in DLB, but not in AD, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the diagnostic accuracy, in the ante-mortem differentiation of probable DLB from probable AD, of cardiac imaging with the ligand 123I-meta-iodobenzylguanidine (MIBG) which binds to the noradrenaline reuptake site, in the first multicenter study. METHODS: We performed a multicenter study in which we used 123I-MIBG scans to assess 133 patients with clinical diagnoses of probable (n = 61) or possible (n = 26) DLB or probable AD (n = 46) established by a consensus panel. Three readers, unaware of the clinical diagnosis, classified the images as either normal or abnormal by visual inspection. The heart-to-mediastinum ratios of 123I-MIBG uptake were also calculated using an automated region-of-interest based system. RESULTS: Using the heart-to-mediastinum ratio calculated with the automated system, the sensitivity was 68.9% and the specificity was 89.1% to differentiate probable DLB from probable AD in both early and delayed images. By visual assessment, the sensitivity and specificity were 68.9% and 87.0%, respectively. In a subpopulation of patients with mild dementia (MMSE >= 22, n = 47), the sensitivity and specificity were 77.4% and 93.8%, respectively, with the delayed heart-to-mediastinum ratio. CONCLUSIONS: Our first multicenter study confirmed the high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from AD, especially in patients with mild dementia. PMID- 25793588 TI - Trauma and event centrality: Valence and incorporation into identity influence well-being more than exposure. AB - Although the association between trauma exposure and posttraumatic stress disorder (PTSD) symptoms is well established, how such trauma is incorporated into identity, or the centrality of the negative event, is also of considerable importance in understanding the development of psychological symptoms. Alternatively, positive event centrality may have positive effects on well-being in the face of trauma. Thus, the current study examined associations between positive and negative event centrality, and both adaptive and maladaptive outcomes, above and beyond the impact of traumatic experience. A sample of 214 college students completed a series of self-report questionnaires. As anticipated, negative event centrality predicted PTSD and other maladaptive measures of functioning, even after controlling for traumatic experience. High levels of positive event centrality predicted adaptive, as opposed to maladaptive, psychological functioning. Results also suggested that both positive and negative event centrality predicted posttraumatic growth, controlling for traumatic experience. These findings suggest that assessing centrality of trauma may also be valuable in the prediction of psychological symptoms. The implications of these findings and proposals for future work are discussed further. PMID- 25793586 TI - Dopamine receptor antagonists as new mode-of-action insecticide leads for control of Aedes and Culex mosquito vectors. AB - BACKGROUND: New mode-of-action insecticides are sought to provide continued control of pesticide resistant arthropod vectors of neglected tropical diseases (NTDs). We previously identified antagonists of the AaDOP2 D1-like dopamine receptor (DAR) from the yellow fever mosquito, Aedes aegypti, with toxicity to Ae. aegypti larvae as leads for novel insecticides. To extend DAR-based insecticide discovery, we evaluated the molecular and pharmacological characteristics of an orthologous DAR target, CqDOP2, from Culex quinquefasciatus, the vector of lymphatic filariasis and West Nile virus. METHODS/RESULTS: CqDOP2 has 94.7% amino acid identity to AaDOP2 and 28.3% identity to the human D1-like DAR, hD1. CqDOP2 and AaDOP2 exhibited similar pharmacological responses to biogenic amines and DAR antagonists in cell-based assays. The antagonists amitriptyline, amperozide, asenapine, chlorpromazine and doxepin were between 35 to 227-fold more selective at inhibiting the response of CqDOP2 and AaDOP2 in comparison to hD1. Antagonists were toxic to both C. quinquefasciatus and Ae. aegypti larvae, with LC50 values ranging from 41 to 208 MUM 72 h post-exposure. Orthologous DOP2 receptors identified from the African malaria mosquito, Anopheles gambiae, the sand fly, Phlebotomus papatasi and the tsetse fly, Glossina morsitans, had high sequence similarity to CqDOP2 and AaDOP2. CONCLUSIONS: DAR antagonists represent a putative new insecticide class with activity against C. quinquefasciatus and Ae. aegypti, the two most important mosquito vectors of NTDs. There has been limited change in the sequence and pharmacological properties of the DOP2 DARs of these species since divergence of the tribes Culicini and Aedini. We identified antagonists selective for mosquito versus human DARs and observed a correlation between DAR pharmacology and the in vivo larval toxicity of antagonists. These data demonstrate that sequence similarity can be predictive of target potential. On this basis, we propose expanded insecticide discovery around orthologous DOP2 targets from additional dipteran vectors. PMID- 25793589 TI - Posttraumatic growth and centrality of event: A longitudinal study in the aftermath of the 2011 Oslo bombing. AB - Previous studies have reported that construing a traumatic event as central to one's life story and identity are associated with posttraumatic growth (PTG). Due to cross-sectional designs, these studies provide only weak evidence of a causal relationship between event centrality and PTG. The main aim in the present study is to examine the longitudinal associations and directionality between centrality of event and PTG in ministerial employees who were present at work during the 2011 Oslo bombing attack (N = 229). By applying a cross-lagged autoregressive model, the present study investigates both stability across time, possible time lagged effects, and the relationship between centrality of event and PTG at 1 and 2 years after the bombing. The results showed that levels of centrality of event and PTG were stable across time. There was a significant association between centrality of event and PTG both 1 and 2 years after the bombing; however, this relationship attenuated over time. No time-lagged effects in either direction were found. The present findings are in line with previous findings indicating that centrality of a traumatic event is related to PTG. However, the present longitudinal data do not support a hypothesis about a long-term causal effect of event centrality on PTG. Rather, the relationship between centrality of event and PTG are concurrent, and attenuates with time. PMID- 25793590 TI - Morally injurious experiences and meaning in Salvadorian teachers exposed to violence. AB - Helping professionals working to alleviate the effects of violence and injustice can confront morally injurious experiences (MIE) that violate deeply held moral values/beliefs, placing them at risk for burnout and trauma-related problems (e.g., posttraumatic stress disorder [PTSD]). Focusing on 257 teachers from educational departments throughout El Salvador, we incorporated structural equation modeling (SEM) to examine (1) whether exposure to MIEs for this population (e.g., betrayal, witnessing harm to an innocent student) are directly linked with higher PTSD symptomatology and work-related burnout and (2) whether MIEs contribute to these outcomes via meaning made of trauma. SEM results revealed that MIEs were in fact uniquely linked with PTSD symptoms and burnout, above and beyond rates of direct victimization and demographic factors. In addition, greater MIEs were indirectly linked with study outcomes via the extent to which teachers were able to make meaning of their identified stressors. These findings support the importance of screening for MIEs among helping professionals and also suggest that meaning making could serve as a central mediating factor for how MIEs contribute to trauma-related problems among persons working to promote peace and justice in the world. PMID- 25793591 TI - Dispositional optimism and self-esteem as competing predictors of acute symptoms of generalized anxiety disorders and dissociative experiences among civilians exposed to war trauma. AB - Although previous studies have rarely examined predictors of acute emotional responses to war trauma, this "natural laboratory" study aimed to examine the role that individual differences in dispositional optimism and self-esteem play in the development of acute symptoms of generalized anxiety disorder (GAD) and dissociative experiences. A sample of 140 female adults exposed to missile and rocket fire during an eruption of violence in the Middle East in November 2012 was assessed during real-time exposure. The results demonstrate inverse associations between dispositional optimism and acute symptoms of GAD and dissociation. The associations were accounted for by individual differences in self-esteem. In addition, individuals with low levels of dispositional optimism demonstrated a higher risk for acute GAD and dissociative experiences, in part because of their low levels of self-esteem. Theoretical and clinical implications of the findings are discussed. PMID- 25793592 TI - Role of trait shame in the association between posttraumatic stress and aggression among men with a history of interpersonal trauma. AB - Given the theoretical and empirical associations among posttraumatic stress, shame, and interpersonal aggression, this study examined whether trait shame accounts for the associations between posttraumatic stress and aggressive behavior in a sample of 103 men with a history of interpersonal trauma. Results indicated that trait shame accounted for the associations of posttraumatic stress with the variety of both physically and psychologically aggressive behavior, as well as with the frequency of physical aggression. This study also examined trait guilt, given its conceptual relationship to both shame and posttraumatic stress; unlike trait shame, trait guilt did not account for the association between posttraumatic stress and the variety of physically aggressive acts. Additionally, although trait guilt reduced the association between posttraumatic stress and the frequency of physical aggression, the indirect path including guilt was nonsignificant. Taken together, the present study supports existing theories suggesting that shame, but not guilt, may contribute to aggressive behavior, especially among individuals with histories of traumatic exposure. PMID- 25793593 TI - Linguistic changes in expressive writing predict psychological outcomes in women with history of childhood sexual abuse and adult sexual dysfunction. AB - An expressive writing treatment was recently reported to reduce depressive symptoms and improve sexual function and satisfaction in a sample of female survivors of childhood sexual abuse (Meston, Lorenz, & Stephenson, 2013). We conducted a linguistic analysis of this data to determine whether pre- to posttreatment changes in participants' language use were associated with the improvements in sexuality and depression. Linguistic Inquiry and Word Count (LIWC), a program that counts the use of word categories within a text, was used to evaluate the impact of several word categories, previously associated with changes in mental health (Frattaroli, 2006), and shown to differ between childhood sexual abuse survivors and nonabused women (Lorenz & Meston, 2012), on treatment outcomes. A reduction in the use of the word "I" and an increase in positive emotion words were associated with decreased depression symptoms. A reduction in the use of "I" and negative emotion words were associated with improvement in sexual function and sexual satisfaction. The findings suggest that, because language may serve as an implicit measure of depression and sexual health, monitoring language changes during treatment may provide a reliable indicator of treatment response free of the biases of traditional self-report assessments. PMID- 25793594 TI - Posttraumatic stress disorder in incarcerated women: A call for evidence-based treatment. AB - The majority of women who enter the criminal justice system, most of whom are poor and women of color, have suffered from significant lifetime trauma exposure that can lead to posttraumatic stress disorder (PTSD). It is essential to identify the prevalence of PTSD among this population in order to identify treatment needs. Most studies on PTSD among incarcerated women have focused on PTSD in jailed populations, including women awaiting trial. Using a cross sectional study design, we estimated the prevalence of PTSD and comorbid physical and mental health conditions in 387 incarcerated women sentenced to a maximum security prison in the United States. Almost half (44%) of our sample met the diagnostic criteria for PTSD. Women with moderate to severe PTSD symptoms were more likely to report several comorbid physical and mental health conditions than were women without PTSD. Women with the most severe symptoms were most likely to report receiving mental health treatment in prison; women with moderate to severe symptoms were less likely to report receiving similar mental health care. Our findings add support to the link between PTSD and comorbid physical and mental health conditions and suggest that many women with PTSD are not receiving mental health treatment that is likely to benefit them. Because prison has become the mental health safety net for some of the nation's most vulnerable women, it is imperative that prisons provide evidence-based PTSD treatment during incarceration. PMID- 25793595 TI - Implicit and explicit memory in survivors of chronic interpersonal violence. AB - We investigated the relationship of implicit and explicit memory to a range of symptoms in a sample of 27 women with exposure to chronic interpersonal violence (IPV). Participants viewed the first 3 letters ("stems") of trauma-related, general threat, and neutral words; valenced words were matched with neutral words with the same stem. Free recall and a word-stem completion task were used to test explicit and implicit memory, respectively. Participants exhibited increased implicit memory for trauma-related words as compared with both general threat words and neutral "match" words. They also showed increased explicit memory for both general threat and trauma-related words. Finally, although neither implicit nor explicit memory was correlated with PTSD symptoms, implicit memory for trauma related words was significantly correlated with symptoms associated with ongoing IPV. Interpersonal sensitivity, hostility, and alexithymia were significantly correlated with implicit, but not explicit, memory for trauma words. Somatization, dissociation, and alexithymia were negatively correlated with explicit, but not implicit, memory for general-threat words. These findings suggest that memory processes in survivors of IPV are closely related to the symptom profile associated with complex trauma. Exploring memory processes in survivors of IPV may lend unique insight into the development and maintenance of the symptom profile associated with IPV. PMID- 25793596 TI - Sleep problems may mediate associations between rumination and PTSD and depressive symptoms among OIF/OEF veterans. AB - Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans have high rates of posttraumatic stress disorder (PTSD), depression, and sleep problems. Identifying potential contributing factors to these mental health problems is crucial for improving treatments in this population. Rumination, or repeated thoughts about negative experiences, is associated with worse PTSD, depression, and sleep problems in nonveterans. Therefore, we hypothesized that rumination would be associated with worse sleep problems, PTSD, and depressive symptoms in OIF/OEF veterans. Additionally, we proposed a novel hypothesis that sleep problems are a mechanism by which rumination contributes to depressive and PTSD symptoms. In this cross-sectional study, 89 OIF/OEF veterans completed measures of trait rumination, sleep problems, and PTSD and depressive symptoms. Analyses confirmed that greater rumination was associated with worse functioning on all mental health measures. Moreover, greater global sleep problems statistically mediated the association between higher rumination and more PTSD and depressive symptoms. Specifically, sleep disturbance and daytime somnolence but not sleep quantity emerged as significant mediators. Although it is impossible with the current nonexperimental data to test causal mediation, these results support the idea that rumination could contribute to impaired sleep, which in turn could contribute to psychological symptoms. We suggest that interventions targeting both rumination and sleep problems may be an effective way to treat OIF/OEF veterans with PTSD or depressive symptoms. PMID- 25793597 TI - The parent ratings of traumatized children with or without PTSD. AB - Two clinical and 2 structured clinical interviews were used to identify children with posttraumatic stress disorder (PTSD), traumatized children without PTSD, and nontraumatized controls. Parents evaluated child conduct by marking the Conners' Parent Rating Scale-48 (CPRS-48; Conners, 1989). Data analysis indicated that the CPRS-48 Total scores and the Anxiety and Psychosomatic subscales scores of the PTSD group significantly exceeded the scores of the comparison groups. Children with PTSD and traumatized children without PTSD did not significantly differ on the Hyperactivity Index. The Hyperactivity Index scores of traumatized children without PTSD and nontraumatized controls were not significantly different. Nonsignificant differences were observed between groups on the CPRS-48 Impulsivity-Hyperactivity, Conduct Problems, and Learning subscales. Overall, PTSD was marked by higher internalizing scores and trauma exposure without PTSD was not associated with increased psychological morbidity. PMID- 25793598 TI - Distinguishing simulated from genuine dissociative identity disorder on the MMPI 2. AB - Due to high elevations on validity and clinical scales on personality and forensic measures, it is challenging to determine if individuals presenting with symptoms of dissociative identity disorder (DID) are genuine or not. Little research has focused on malingering DID, or on the broader issue of the profiles these patients obtain on the Minnesota Multiphasic Personality Inventory (MMPI 2), despite increasing awareness of dissociation. This study sought to characterize the MMPI-2 profiles of DID patients and to determine the utility of the MMPI-2 in distinguishing DID patients from uncoached and coached DID simulators. The analyses revealed that Infrequency, Back Infrequency, and Infrequency-Psychopathology (Fp) distinguished simulators from genuine DID patients. Fp was best able to discriminate simulated DID. Utility statistics and classification functions are provided for classifying individual profiles as indicative of genuine or simulated DID. Despite exposure to information about DID, the simulators were not able to accurately feign DID, which is inconsistent with the iatrogenic/sociocultural model of DID. Given that dissociation was strongly associated with elevations in validity, as well as clinical scales, including Scale 8 (i.e., Schizophrenia), considerable caution should be used in interpreting validity scales as indicative of feigning, and Scale 8 as indicative of schizophrenia, among highly dissociative individuals. PMID- 25793599 TI - Monitoring and evaluating the quality consistency of Compound Bismuth Aluminate tablets by a simple quantified ratio fingerprint method combined with simultaneous determination of five compounds and correlated with antioxidant activities. AB - A combination method of multi-wavelength fingerprinting and multi-component quantification by high performance liquid chromatography (HPLC) coupled with diode array detector (DAD) was developed and validated to monitor and evaluate the quality consistency of herbal medicines (HM) in the classical preparation Compound Bismuth Aluminate tablets (CBAT). The validation results demonstrated that our method met the requirements of fingerprint analysis and quantification analysis with suitable linearity, precision, accuracy, limits of detection (LOD) and limits of quantification (LOQ). In the fingerprint assessments, rather than using conventional qualitative "Similarity" as a criterion, the simple quantified ratio fingerprint method (SQRFM) was recommended, which has an important quantified fingerprint advantage over the "Similarity" approach. SQRFM qualitatively and quantitatively offers the scientific criteria for traditional Chinese medicines (TCM)/HM quality pyramid and warning gate in terms of three parameters. In order to combine the comprehensive characterization of multi wavelength fingerprints, an integrated fingerprint assessment strategy based on information entropy was set up involving a super-information characteristic digitized parameter of fingerprints, which reveals the total entropy value and absolute information amount about the fingerprints and, thus, offers an excellent method for fingerprint integration. The correlation results between quantified fingerprints and quantitative determination of 5 marker compounds, including glycyrrhizic acid (GLY), liquiritin (LQ), isoliquiritigenin (ILG), isoliquiritin (ILQ) and isoliquiritin apioside (ILA), indicated that multi-component quantification could be replaced by quantified fingerprints. The Fenton reaction was employed to determine the antioxidant activities of CBAT samples in vitro, and they were correlated with HPLC fingerprint components using the partial least squares regression (PLSR) method. In summary, the method of multi-wavelength fingerprints combined with antioxidant activities has been proved to be a feasible and scientific procedure for monitoring and evaluating the quality consistency of CBAT. PMID- 25793601 TI - Correction: Mining CK2 in cancer. PMID- 25793600 TI - Stromal expression of heat-shock protein 27 is associated with worse clinical outcome in patients with colorectal cancer lung metastases. AB - BACKGROUND: Pulmonary metastases are common in patients with primary colorectal cancer (CRC). Heat-shock protein 27 (Hsp27) is upregulated in activated fibroblasts during wound healing and systemically elevated in various diseases. Cancer-associated fibroblasts (CAFs) are also thought to play a role as prognostic and predictive markers in various malignancies including CRC. Surprisingly, the expression of Hsp27 has never been assessed in CAFs. Therefore we aimed to investigate the expression level of Hsp27 in CAFs and its clinical implications in patients with CRC lung metastases. METHODS: FFPE tissue samples from 51 pulmonary metastases (PMs) and 33 paired primary tumors were evaluated for alpha-SMA, CD31, Hsp27 and vimentin expression by immunohistochemistry and correlated with clinicopathological variables. 25 liver metastases served as control group. Moreover, serum samples (n=10) before and after pulmonary metastasectomy were assessed for circulating phospho-Hsp27 and total Hsp27 by ELISA. RESULTS: Stromal expression of Hsp27 was observed in all PM and showed strong correlation with alpha-SMA (P<0.001) and vimentin (P<0.001). Strong stromal Hsp27 was associated with higher microvessel density in primary CRC and PM. Moreover, high stromal Hsp27 and alphaSMA expression were associated with decreased recurrence-free survival after pulmonary metastasectomy (P=0.018 and P=0.008, respectively) and overall survival (P=0.031 and P=0.017, respectively). Serum levels of phospho- and total Hsp27 dropped after metastasectomy to levels comparable to healthy controls. CONCLUSIONS: Herein we describe for the first time that Hsp27 is highly expressed in tumor stroma of CRC. Stromal alpha-SMA and Hsp27 expressions correlate with the clinical outcome after pulmonary metastasectomy. Moreover, serum Hsp27 might pose a future marker for metastatic disease in CRC. PMID- 25793602 TI - Regional-scale drivers of forest structure and function in northwestern Amazonia. AB - Field studies in Amazonia have found a relationship at continental scales between soil fertility and broad trends in forest structure and function. Little is known at regional scales, however, about how discrete patterns in forest structure or functional attributes map onto underlying edaphic or geological patterns. We collected airborne LiDAR (Light Detection and Ranging) data and VSWIR (Visible to Shortwave Infrared) imaging spectroscopy measurements over 600 km2 of northwestern Amazonian lowland forests. We also established 83 inventories of plant species composition and soil properties, distributed between two widespread geological formations. Using these data, we mapped forest structure and canopy reflectance, and compared them to patterns in plant species composition, soils, and underlying geology. We found that variations in soils and species composition explained up to 70% of variation in canopy height, and corresponded to profound changes in forest vertical profiles. We further found that soils and plant species composition explained more than 90% of the variation in canopy reflectance as measured by imaging spectroscopy, indicating edaphic and compositional control of canopy chemical properties. We last found that soils explained between 30% and 70% of the variation in gap frequency in these forests, depending on the height threshold used to define gaps. Our findings indicate that a relatively small number of edaphic and compositional variables, corresponding to underlying geology, may be responsible for variations in canopy structure and chemistry over large expanses of Amazonian forest. PMID- 25793603 TI - Insights into the establishment of the Manila clam on a tidal flat at the southern end of an introduced range in Southern California, USA. AB - Coastal ecosystem modifications have contributed to the spread of introduced species through alterations of historic disturbance regimes and resource availability, and increased propagule pressure. Frequency of occurrence of the Manila clam (Venerupis phillipinarum, Veneridae) in Southern California estuaries has increased from absent or sparse to common since the mid-1990s. Potential invasion vectors include seafood sales and aquaculture, and spread from established northern populations over decades. The clam's post-settlement habitat preferences are, however, uncertain in this region. Our project aimed to identify factors associated with established patches of the clam within a bay toward the southern end of this introduced range. During summer 2013, we sampled 10 tidal flat sites in Mission Bay, San Diego; each containing an area with and without hard structure (e.g., riprap, boulders). We measured likely environmental influences (e.g., sediment variables, distance to ocean). Manila clam densities across the bay were most strongly associated with site, where highest densities were located in the northern and/or back halves of the bay; and weakly correlated with lower porewater salinities. Within sites, Manila clam density was enhanced in the presence of hard structure in most sites. Prevailing currents and salinity regimes likely contribute to bay wide distributions, while hard structures may provide suitable microhabitats (refuge from predators and physical stress) and larval entrapment within sites. Results provide insights into decisions about future shoreline management efforts. Finally, we identify directions for future study to better understand and therefore predict patterns of establishment of the Manila clam in the southern portion of its introduced range. PMID- 25793604 TI - MicroRNA-153 inhibits osteosarcoma cells proliferation and invasion by targeting TGF-beta2. AB - Increasing evidence indicates that microRNAs (miRNAs), a class of small noncoding RNAs, participate in almost every step of cellular processes. MiRNAs are aberrantly expressed in human cancers and contribute to cancer development and progression. Study of miRNAs may provide a new clue for understanding the mechanism of carcinogenesis and a new tool for cancer treatment. In the present study, miR-153 was downregulated in human osteosarcoma tissues and cell lines. Introduction of miR-153 mimics into the MG-63 cells inhibited cell proliferation and invasion. Our results further revealed that transforming growth factor beta 2 (TGF-beta2) was negatively regulated by miR-153. Furthermore, overexpression of miR-153 decreased p-SMAD2, p-SMAD3, epidermal growth factor receptor (EGFR) and insulin-like growth factor binding protein-3 (IGFBP-3) expressions, which were the downstream signaling molecules of TGF-beta. Furthermore, miRNA-153 suppressed TGF-beta-mediated MG-63 proliferation and migration. Therefore, our results suggest that miR-153 may act as a tumor suppressor in osteosarcoma through targeting TGF-beta2. PMID- 25793605 TI - Automatic prediction of cardiovascular and cerebrovascular events using heart rate variability analysis. AB - BACKGROUND: There is consensus that Heart Rate Variability is associated with the risk of vascular events. However, Heart Rate Variability predictive value for vascular events is not completely clear. The aim of this study is to develop novel predictive models based on data-mining algorithms to provide an automatic risk stratification tool for hypertensive patients. METHODS: A database of 139 Holter recordings with clinical data of hypertensive patients followed up for at least 12 months were collected ad hoc. Subjects who experienced a vascular event (i.e., myocardial infarction, stroke, syncopal event) were considered as high risk subjects. Several data-mining algorithms (such as support vector machine, tree-based classifier, artificial neural network) were used to develop automatic classifiers and their accuracy was tested by assessing the receiver-operator characteristics curve. Moreover, we tested the echographic parameters, which have been showed as powerful predictors of future vascular events. RESULTS: The best predictive model was based on random forest and enabled to identify high-risk hypertensive patients with sensitivity and specificity rates of 71.4% and 87.8%, respectively. The Heart Rate Variability based classifier showed higher predictive values than the conventional echographic parameters, which are considered as significant cardiovascular risk factors. CONCLUSIONS: Combination of Heart Rate Variability measures, analyzed with data-mining algorithm, could be a reliable tool for identifying hypertensive patients at high risk to develop future vascular events. PMID- 25793606 TI - Effect of the interplay between trauma severity and trait neuroticism on posttraumatic stress disorder symptoms among adolescents exposed to a pipeline explosion. AB - BACKGROUND: While numerous studies have explored relevant factors of posttraumatic stress disorder (PTSD) symptoms, there have been few joint investigations of trauma severity and trait neuroticism on the development of PTSD symptoms. This study aims to assess the involvement and interrelationship of trauma severity and neuroticism in the expression of PTSD symptoms among adolescents exposed to an accidental explosion. METHODS: Six hundred and sixty two adolescents were recruited from a junior middle school closest to the 2013 pipeline explosion site in China and were assessed using the Explosion Exposure Questionnaire, the NEO Five Factor Inventory-Neuroticism Subscale (FFI-N), and the PTSD Checklist-Civilian (PCL-C). A battery of hierarchical multiple regression analyses and two-way ANOVAs were performed to examine the effect of trauma severity and trait neuroticism on adolescent PTSD symptoms. RESULTS: Eighty-seven adolescents (13.1%) showed PTSD symptoms after the pipeline explosion. Correlation analysis showed that all the factors of explosion exposure and trait neuroticism were positively associated with adolescent PTSD symptoms. Being male and younger was linked to lower risk for PTSD symptoms. The regression models identified explosion exposure and neuroticism as independent risk factors for PTSD symptoms, and the interactions between trait neuroticism and trauma exposure (personal casualty, degree of influence, total traumatic severity) were related to PTSD symptoms. CONCLUSIONS: The results highlight the role of trauma exposure and trait neuroticism as risk factors for PTSD symptoms. Therefore, the combination of these two factors should be investigated in clinical settings due to an augmented risk for more severe PTSD symptoms. PMID- 25793607 TI - Benefits of a working memory training program for inattention in daily life: a systematic review and meta-analysis. AB - BACKGROUND: Many common disorders across the lifespan feature impaired working memory (WM). Reported benefits of a WM training program include improving inattention in daily life, but this has not been evaluated in a meta-analysis. This study aimed to evaluate whether one WM training method has benefits for inattention in daily life by conducting a systematic review and meta-analysis. METHODS: We searched Medline and PsycINFO, relevant journals and contacted authors for studies with an intervention and control group reporting post training estimates of inattention in daily life. To reduce the influence of different WM training methods on the findings, the review was restricted to trials evaluating the Cogmed method. A meta-analysis calculated the pooled standardised difference in means (SMD) between intervention and control groups. RESULTS: A total of 622 studies were identified and 12 studies with 13 group comparisons met inclusion criteria. The meta-analysis showed a significant training effect on inattention in daily life, SMD=-0.47, 95% CI -0.65, -0.29, p<.00001. Subgroup analyses showed this significant effect was observed in groups of children and adults as well as users with and without ADHD, and in studies using control groups that were active and non-adaptive, wait-list and passive as well as studies using specific or general measures. Seven of the studies reported follow-up assessment and a meta-analysis showed persisting training benefits for inattention in daily life, SMD=-0.33, 95% CI -0.57 -0.09, p=.006. Additional meta analyses confirmed improvements after training on visuospatial WM, SMD=0.66, 95% CI 0.43, 0.89, p<.00001, and verbal WM tasks, SMD=0.40, 95% CI 0.18, 0.62, p=.0004. CONCLUSIONS: Benefits of a WM training program generalise to improvements in everyday functioning. Initial evidence shows that the Cogmed method has significant benefits for inattention in daily life with a clinically relevant effect size. PMID- 25793608 TI - Trends in socioeconomic inequalities in HIV prevalence among young people in seven countries in eastern and southern Africa. AB - BACKGROUND: In Eastern and Southern Africa, HIV prevalence was highest among higher socioeconomic groups during the 1990s. It has been suggested that this is changing, with HIV prevalence falling among higher-educated groups while stable among lower-educated groups. A multi-country analysis has not been undertaken. METHODS: We analysed data on socio-demographic factors and HIV infection from 14 nationally representative surveys of adults aged 15-24 (seven countries, two surveys each, 4-8 years apart). Sample sizes ranged from 2,408-12,082 (72,135 total). We used logistic regression to assess gender-stratified associations between highest educational level attended and HIV status in each survey, adjusting for age and urban/rural setting. We tested for interactions with urban/rural setting and age. Our primary hypothesis was that higher education became less of a risk factor for HIV over time. We tested for interaction between survey-year and the education-HIV association in each country and all countries pooled. FINDINGS: In Ethiopia and Malawi, HIV prevalence was higher in more educated women in both surveys. In Lesotho, Kenya and Zimbabwe, HIV prevalence was lower in higher educated women in both surveys. In Ethiopia, HIV prevalence fell among no and secondary educated women only (interaction p<0.01). Only among young men in Tanzania there was some evidence that the association between education and HIV changed over time (p=0.07). Pooled analysis found little evidence for an interaction between survey year and the education-HIV association among men (p=0.60) or women (p=0.37). INTERPRETATION: The pattern of prevalent HIV infection among young adults by level of education in different sub-Saharan African countries was heterogeneous. There was little statistical evidence that this pattern changed between 2003-5 and 2008-12. Explanations for the social epidemiology of HIV in Africa will need to account for time-trends and inter country differences. PMID- 25793609 TI - Determining microvascular obstruction and infarct size with steady-state free precession imaging cardiac MRI. AB - PURPOSE: In cardiac MRI (cMRI) injection of contrast medium may be performed prior to the acquisition of cine steady-state free precession (SSFP) imaging to speed up the protocol and avoid delay before late Gadolinium enhancement (LGE) imaging. Aim of this study was to evaluate whether a condensed clinical protocol with contrast cine SSFP imaging is able to detect early microvascular obstruction (MO) and determine the infarct size compared to the findings of LGE inversion recovery sequences. MATERIALS AND METHODS: The study complies with the Declaration of Helsinki and was performed following approval by the ethic committee of the University of Erlangen-Nuremberg. Written informed consent was obtained from every patient. 68 consecutive patients (14 females/54 males) with acute ST-elevation myocardial infarction (STEMI) treated by percutaneous coronary revascularization were included in this study. CMRI was performed 6.6+/-2 days after symptom onset and MO and infarct size in early contrast SSFP cine imaging were compared to LGE imaging. RESULTS: MO was detected in 47/68 (69%) patients on cine SSFP and in 41/68 (60%) patients on LGE imaging. In 6 patients MO was found on cine SSFP imaging but was not detectable on LGE imaging. Infarct size on cine SSFP showed a strong agreement to LGE imaging (intraclass correlation coefficient [ICC] of 0.96 for enddiastolic, p<0.001 and 0.96 for endsystolic, p<0.001 respectively). Significant interobserver agreement was found measuring enddiastolic and endsystolic infarct size on cine SSFP imaging (p<0.01). CONCLUSIONS: In patients after STEMI infarct size and presence of MO can be detected with contrast cine SSFP imaging. This could be an option in patients who are limited in their ability to comply with the demands of a cMRI protocol. PMID- 25793611 TI - Correction: Parallel force assay for protein-protein interactions. PMID- 25793610 TI - Method designed to respect molecular heterogeneity can profoundly correct present data interpretations for genome-wide expression analysis. AB - Although genome-wide expression analysis has become a routine tool for gaining insight into molecular mechanisms, extraction of information remains a major challenge. It has been unclear why standard statistical methods, such as the t test and ANOVA, often lead to low levels of reproducibility, how likely applying fold-change cutoffs to enhance reproducibility is to miss key signals, and how adversely using such methods has affected data interpretations. We broadly examined expression data to investigate the reproducibility problem and discovered that molecular heterogeneity, a biological property of genetically different samples, has been improperly handled by the statistical methods. Here we give a mathematical description of the discovery and report the development of a statistical method, named HTA, for better handling molecular heterogeneity. We broadly demonstrate the improved sensitivity and specificity of HTA over the conventional methods and show that using fold-change cutoffs has lost much information. We illustrate the especial usefulness of HTA for heterogeneous diseases, by applying it to existing data sets of schizophrenia, bipolar disorder and Parkinson's disease, and show it can abundantly and reproducibly uncover disease signatures not previously detectable. Based on 156 biological data sets, we estimate that the methodological issue has affected over 96% of expression studies and that HTA can profoundly correct 86% of the affected data interpretations. The methodological advancement can better facilitate systems understandings of biological processes, render biological inferences that are more reliable than they have hitherto been and engender translational medical applications, such as identifying diagnostic biomarkers and drug prediction, which are more robust. PMID- 25793612 TI - Putting your money where your mouth is: why sustainability reporting based on the triple bottom line can be misleading. AB - In the packaged food industry, Corporate Social Responsibility (CSR) is an informal requirement for which firms account through sustainability reporting. CSR behaviors are often reported and analyzed using the Triple Bottom Line (3BL) framework, which categorizes them as affecting people, planet, or profit. 3BL is useful in determining which of these categories is most elaborated upon by the firm, but has a limited scope and many documented criticisms. This paper aims to address the aforementioned insufficiencies by augmenting the 3BL framework with two important attributes of CSR practices: (1) the presence of change in core firm behavior of the firm itself or of others in the supply chain, and (2) whether the behavior qualifies as being outside of the firm's normal business practice or is something that they might have done anyway. We qualitatively analyze CSR behaviors described in sustainability reports and interviews from major players in the packaged food industry and categorize them using these attributes as a supplement to 3BL. This enables us to separate the behaviors from their framing and analyze them more critically. Our results demonstrate how the visible CSR efforts of a firm can be misleading at first glance. Using only 3BL, we find that the CSR focus of firms in this industry is people. We then discover that the codes focusing on people (as opposed to planet or profit) require the least amount of real structural change from a firm or its supply chain partners, and thus arguably, the least amount of effort. We also find that behaviors that focus on planet require the most effort within the firm itself, but for behaviors involving supply chain partners, effort is required for behaviors in all three categories. Finally, we find that CSR behavior that is related to planet tends to go beyond normal business practice. PMID- 25793613 TI - Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. AB - OBJECTIVE: The aim of the study was to determine the serum levels of CRP, IL-6 and TNF-alpha in elderly diabetic patients with depressive syndrome alone or with coexisting mild cognitive impairment (MCI). METHODS: 276 diabetics elders were screened for depressive symptoms (using Geriatric Depression Scale: GDS-30) and MCI (using the Montreal Cognitive Assessment: MoCA score). Data of HbA1c, blood lipids and inflammatory markers levels were collected. RESULTS: In all groups of patients levels of CRP, IL-6 and TNF-alpha were significantly higher as compared to controls. The highest level of inflammatory markers was detected in group with depressive mood and coexisting MCI, however IL-6 level didn't significantly differ as compared to MCI group. We founded correlations between all inflammatory markers in group of patients with depressive mood and in group of subjects with depressive symptoms and coexisting MCI. GDS-30 score was correlated with levels of inflammatory markers in group with depressive mood, and with levels of CRP and TNF-alpha in group with depressive mood and coexisting MCI. In the group with depressive mood and coexisting MCI we founded that MoCA score was negatively correlated with CRP and TNF-alpha levels; and HbA1c level was positively correlated with all inflammatory markers. The univariate logistic regression models revealed that variables which increased the likelihood of having been diagnosed with MCI in depressed patients were: higher levels of HbA1c, CRP, IL-6 and TNF-alpha, previous CVD or stroke, increased number of co-morbidities and microvascular complications, older age, less years of formal education. The multivariable model showed that previous CVD, higher HbA1c and IL-6 levels are significant factors. CONCLUSIONS: We demonstrated that the presence of depressive syndrome is associated with higher levels of inflammatory markers in elderly patients with diabetes. The presence of MCI in these depressed subjects has additive effect on levels of inflammatory mediators. PMID- 25793614 TI - Diffuse axonal injury at ultra-high field MRI. AB - OBJECTIVE: Diffuse axonal injury (DAI) is a specific type of traumatic brain injury caused by shearing forces leading to widespread tearing of axons and small vessels. Traumatic microbleeds (TMBs) are regarded as a radiological marker for DAI. This study aims to compare DAI-associated TMBs at 3 Tesla (T) and 7 T susceptibility weighted imaging (SWI) to evaluate possible diagnostic benefits of ultra-high field (UHF) MRI. MATERIAL AND METHODS: 10 study participants (4 male, 6 female, age range 20-74 years) with known DAI were included. All MR exams were performed with a 3 T MR system (Magnetom Skyra) and a 7 T MR research system (Magnetom 7 T, Siemens AG, Healthcare Sector, Erlangen, Germany) each in combination with a 32-channel-receive coil. The average time interval between trauma and imaging was 22 months. Location and count of TMBs were independently evaluated by two neuroradiologists on 3 T and 7 T SWI images with similar and additionally increased spatial resolution at 7 T. Inter- and intraobserver reliability was assessed using the interclass correlation coefficient (ICC). Count and diameter of TMB were evaluated with Wilcoxon signed rank test. RESULTS: Susceptibility weighted imaging revealed a total of 485 TMBs (range 1-190, median 25) at 3 T, 584 TMBs (plus 20%, range 1-262, median 30.5) at 7 T with similar spatial resolution, and 684 TMBs (plus 41%, range 1-288, median 39.5) at 7 T with 10-times higher spatial resolution. Hemorrhagic DAI appeared significantly larger at 7 T compared to 3 T (p = 0.005). Inter- and intraobserver correlation regarding the counted TMB was high and almost equal 3 T and 7 T. CONCLUSION: 7 T SWI improves the depiction of small hemorrhagic DAI compared to 3 T and may be supplementary to lower field strengths for diagnostic in inconclusive or medicolegal cases. PMID- 25793617 TI - Exerting control over the helical chirality in the main chain of sergeants-and soldiers-type poly(quinoxaline-2,3-diyl)s by changing from random to block copolymerization protocols. AB - Chiral random poly(quinoxaline-2,3-diyl) polymers of the sergeants-and-soldiers type (sergeant units bearing (S)-3-octyloxymethyl groups) adopt an M- or P helical conformation in the presence of achiral units bearing propoxymethyl or butoxy groups (soldier units), respectively. Unusual bidirectional induction of the helical sense can be observed for a copolymer with butoxy soldier units upon changing the mole fraction of the sergeant units. In the presence of 16-20% of sergeant units, the selective induction of a P-helix was observed, while the selective induction of an M-helix was observed for a mole fraction of sergeant units of more than 60%. This phenomenon could be successfully employed to control the helical chirality of copolymers by applying either random or block copolymerization protocols. Random or block copolymerization of sergeant and soldier monomers in a 18:82 ratio resulted in the formation of 250mers with almost absolute P- or M-helical conformation, respectively (>99% ee). Incorporation of a small amount of coordination sites into the random and block copolymers resulted in chiral macromolecular ligands, which allowed the enantioselective synthesis of both enantiomers in the Pd-catalyzed asymmetric hydrosilylation of beta-methylstyrene. PMID- 25793615 TI - An S-(hydroxymethyl)glutathione dehydrogenase is involved in conidiation and full virulence in the rice blast fungus Magnaporthe oryzae. AB - Magnaporthe oryzae is a hemibiotrophic fungal pathogen that causes rice blast disease. A compatible interaction requires overcoming plant defense responses to initiate colonization during the early infection process. Nitric oxide (NO) plays important roles in defense responses during host-pathogen interactions. Microbes generally protect themselves against NO-induced damage by using enzymes. Here, we characterized an S-(hydroxymethyl)-glutathione dehydrogenase gene in M. oryzae, MoSFA1, the homologs of which are involved in NO metabolism by specifically catalyzing the reduction of S-nitrosoglutathione (GSNO) in yeasts and plants. As expected from the activities of S-(hydroxymethyl)glutathione dehydrogenase in formaldehyde detoxification and GSNO reduction, MoSFA1 deletion mutants were lethal in formaldehyde containing medium, sensitive to exogenous NO and exhibited a higher level of S-nitrosothiols (SNOs) than that of the wild type. Notably, the mutants showed severe reduction of conidiation and appressoria turgor pressure, as well as significantly attenuated the virulence on rice cultivar CO-39. However, the virulence of MoSFA1 deletion mutants on wounded rice leaf was not affected. An infection assay on barley leaf further revealed that MoSFA1 deletion mutants exhibited a lower infection rate, and growth of infectious hyphae of the mutants was retarded not only in primary infected cells but also in expansion from cell to cell. Furthermore, barley leaf cell infected by MoSFA1 deletion mutants exhibited a stronger accumulation of H2O2 at 24 and 36 hpi. MoSFA1 deletion mutants displayed hypersensitivity to different oxidants, reduced activities of superoxide dismutases and peroxidases, and lower glutathione content in cells, compared with the wild type. These results imply that MoSFA1 mediated NO metabolism is important in redox homeostasis in response to development and host infection of M. oryzae. Taken together, this work identifies that MoSFA1 is required for conidiation and contributes to virulence in the penetration and biotrophic phases in M. oryzae. PMID- 25793616 TI - COMT and MAO-A polymorphisms and obsessive-compulsive disorder: a family-based association study. AB - OBJECTIVE: Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric illness. Although a genetic component contributes to its etiology, no single gene or mechanism has been identified to the OCD susceptibility. The catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A) genes have been investigated in previous OCD studies, but the results are still unclear. More recently, Taylor (2013) in a comprehensive meta-analysis of genetic association studies has identified COMT and MAO-A polymorphisms involved with OCD. In an effort to clarify the role of these two genes in OCD vulnerability, a family-based association investigation was performed as an alternative strategy to the classical case-control design. METHODS: Transmission disequilibrium analyses were performed after genotyping 13 single-nucleotide polymorphisms (eight in COMT and five in MAO-A) in 783 OCD trios (probands and their parents). Four different OCD phenotypes (from narrow to broad OCD definitions) and a SNP x SNP epistasis were also analyzed. RESULTS: OCD, broad and narrow phenotypes,were not associated with any of the investigated COMT and MAO-A polymorphisms. In addition, the analyses of gene-gene interaction did not show significant epistatic influences on phenotype between COMT and MAO-A. CONCLUSIONS: The findings do not support an association between DSM-IV OCD and the variants of COMT or MAO-A. However, results from this study cannot exclude the contribution of these genes in the manifestation of OCD. The evaluation of broader spectrum phenotypes could help to understand the role of these and other genes in the pathophysiology of OCD and its spectrum disorders. PMID- 25793619 TI - Variation in pollen-donor composition among pollinators in an entomophilous tree species, Castanea crenata, revealed by single-pollen genotyping. AB - BACKGROUND: In plants, reproductive success is largely determined by the composition of pollen (i.e., self-pollen and outcross-pollen from near and distant pollen-donors) transported as a result of pollinator foraging behavior (e.g., pollen carryover). However, little evidence is available on how and to what extent the pollen carryover affects the pollen-donor composition and on which insect taxa are effective outcross-pollen transporters under field conditions. In this study, we explored roles of foraging behavior of insect pollinators on pollen-donor composition and subsequent reproductive success in a woody plant. METHODS: We performed paternity analyses based on microsatellite genotyping of individual pollen grains found on diurnal pollinators (i.e., bumblebee, small bee, fly, small beetle, and honeybee) visiting Castanea crenata trees. RESULTS: The outcross-pollen rate was highest in bumblebees (66%), followed by small bees (35%), flies (31%), and small beetles (18%). The effective number of pollen donors, representing pollen carryover, was greater in bumblebees (9.71) than in flies (3.40), small bees (3.32), and small beetles (3.06). The high percentages of pollen from outside the plot on bumblebees (65.4%) and flies (71.2%) compared to small bees (35.3%) and small beetles (13.5%) demonstrated their longer pollen dispersal distances. CONCLUSIONS: All of the diurnal insects carried outcross-pollen grains for long distances via pollen carryover. This fact suggests that a wide range of insect taxa are potential outcross-pollen transporters for the self-incompatible C. crenata. PMID- 25793620 TI - In situ synthesis and characterization of silver/polymer nanocomposites by thermal cationic polymerization processes at room temperature: initiating systems based on organosilanes and starch nanocrystals. AB - New methods for the preparation of silver nanoparticles/polymer nanocomposite materials by thermal cationic polymerization of epsilon-caprolactone (epsilon-CL) or alpha-pinene oxide (alpha-PO) at room temperature (RT) and under air were developed. The new initiating systems were based on silanes (Si), starch nanocrystals (StN) and metal salts. Excellent polymerization profiles were revealed. It was shown that silver nanoparticles (Ag(0) NPs) were in situ formed and that the addition of StN improves the polymerization efficiency. The as synthesized nanocomposite materials contained spherical nanoparticles homogeneously dispersed in the polymer matrices. Polymers and nanoparticles were characterized by gel permeation chromatography (GPC), X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and UV-vis spectroscopy. A coherent picture of the involved chemical mechanisms is presented. PMID- 25793618 TI - Alpha-catulin contributes to drug-resistance of melanoma by activating NF-kappaB and AP-1. AB - Melanoma is the most dangerous type of skin cancer accounting for 48,000 deaths worldwide each year and an average survival rate of about 6-10 months with conventional treatment. Tumor metastasis and chemoresistance of melanoma cells are reported as the main reasons for the insufficiency of currently available treatments for late stage melanoma. The cytoskeletal linker protein alpha-catulin (CTNNAL1) has been shown to be important in inflammation, apoptosis and cytoskeletal reorganization. Recently, we found an elevated expression of alpha catulin in melanoma cells. Ectopic expression of alpha-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. In the current study we showed that alpha catulin knockdown reduced NF-kappaB and AP-1 activity in malignant melanoma cells. Further, downregulation of alpha-catulin diminished ERK phosphorylation in malignant melanoma cells and sensitized them to treatment with chemotherapeutic drugs. In particular, cisplatin treatment led to decreased ERK-, JNK- and c-Jun phosphorylation in alpha-catulin knockdown melanoma cells, which was accompanied by enhanced apoptosis compared to control cells. Altogether, these results suggest that targeted inhibition of alpha-catulin may be used as a viable therapeutic strategy to chemosensitize melanoma cells to cisplatin by down regulation of NF-kappaB and MAPK pathways. PMID- 25793622 TI - Hepatic arterial vasodilation is independent of portal hypertension in early stages of cirrhosis. AB - INTRODUCTION: The compensatory increase in hepatic arterial flow with a decrease in portal venous flow is known as the hepatic arterial buffer response. In cirrhosis with elevated portal pressure, the vascular resistance of the hepatic artery is decreased. Whether this lower resistance of the hepatic artery is a consequence of portal hypertension or not remains unknown. STUDY AIM: The aim of the study was to investigate the hepatic arterial resistance and response to vasoconstriction in cirrhosis without portal hypertension (normal portal resistance). METHODS: Cirrhosis was induced by CCl4-inhalation for 8 weeks (8W, normal portal resistance) and for 12-14 weeks (12W, elevated portal resistance). Bivascular liver perfusion was performed at 8W or 12W and dose response curves of methoxamine were obtained in the presence or absence of LNMMA (nitric oxide synthase blocker). Vascular resistances of the hepatic artery (HAR), portal vein (PVR) and sinusoids (SVR) were measured. Western Blot (WB) and Immunohistochemistry (IHC) were done to measure eNOS and HIF 1a expression. RESULTS: HAR in both groups of cirrhotic animals (8W and 12W) were lower compared to controls. Dose response curves to methoxamine revealed lower HAR in both cirrhotic models (8W and 12W) regardless the magnitude of portal resistance. LNMMA corrected the dose response curves in cirrhosis (8W and 12W) to control. WB and IHC show increased protein expression of eNOS and HIF1a in 8W and 12W. CONCLUSION: Hepatic arterial resistance is decreased in cirrhosis independent of portal resistance. Vasodilation of the hepatic artery in cirrhosis seems to be influenced by hypoxia rather than increase in portal resistance. Nitric oxide is the main vasodilator. PMID- 25793621 TI - Spatio-temporal model of endogenous ROS and raft-dependent WNT/beta-catenin signaling driving cell fate commitment in human neural progenitor cells. AB - Canonical WNT/beta-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/beta-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear beta-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of beta-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/beta-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream beta-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/beta-catenin signal or as amplifier during continuous auto /parcrine WNT/beta-catenin signaling. In addition we provide the first stochastic computational model of WNT/beta-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent beta-catenin activation. The model's predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule based language, that facilitates the extension and modification of the model. Thus, our results provide both new insights and means to further our understanding of canonical WNT/beta-catenin signaling and the role of ROS as intracellular signaling mediator. PMID- 25793623 TI - Immune derangements in patients with myelofibrosis: the role of Treg, Th17, and sIL2Ralpha. AB - Myelofibrosis (MF), including primary myelofibrosis, post-essential thrombocythemia MF, and post-polycythemia vera MF, has been reported to be associated with autoimmune phenomena. IMiDs have been reported to be effective in some patients with MF, presumably for their immune-modulator effects. We therefore sought to elucidate the immune derangements in patients with MF. We found no differences in T regulatory cells (Treg) and T helper 17 (Th17) cells in MF patients and normal healthy controls. However, we found significantly elevated soluble interleukin 2 alpha (sIL2Ralpha) in MF patients compared to those with other myeloproliferative neoplasm diseases and normal healthy controls. Our studies with MF patients further revealed that Treg cells were the predominant cells producing sIL2Ralpha. sIL2Ralpha and IL2 complex induced the formation of Treg cells but not the formation of Th1 or Th17 cells. sIL2Ralpha induced CD8+ T cell proliferation in the presence of Treg cells. Monocytes or neutrophils had no effect on the production of sIL2Ralpha by Treg cells. Furthermore, we found plasma sIL2Ralpha levels were correlated to the auto-immune serology in MPN patients and ruxolitinib significantly inhibits the sIL2Ralpha production by the Treg cells in MF patients which may explain the effects of ruxolitinib on the relief of constitutional symptoms. All these findings suggest that sIL2Ralpha likely plays a significant role in autoimmune phenomena seen in patients with MF. Further studies of immune derangement may elucidate the mechanism of IMiD, and exploration of immune modulators may prove to be important for treating myelofibrosis. PMID- 25793624 TI - Adaptation and transcriptome analysis of Aureobasidium pullulans in corncob hydrolysate for increased inhibitor tolerance to malic acid production. AB - Malic acid is a dicarboxylic acid widely used in the food industry, and is also a potential C4 platform chemical. Corncob is a low-cost renewable feedstock from agricultural industry. However, side-reaction products (furfural, 5 hydroxymethylfurfural (HMF), formic acid, and acetic acid) that severely hinder fermentation are formed during corncob pretreatment. The process for producing malic acid from a hydrolysate of corncob was investigated with a polymalic acid (PMA)-producing Aureobasidium pullulans strain. Under the optimal hydrolysate sugar concentration 110 g/L, A. pullulans was further adapted in an aerobic fibrous bed bioreactor (AFBB) by gradually increasing the sugar concentration of hydrolysate. After nine batches of fermentation, the production and productivity of malic acid reached 38.6 g/L and 0.4 g/L h, respectively, which was higher than that in the first batch (27.6 g/L and 0.29 g/L h, respectively). The adapted strain could grow under the stress of 0.5 g/L furfural, 3 g/L HMF, 2g/L acetic acid, and 0.5 g/L formic acid, whereas the wild type did not. Transcriptome analysis revealed that the differentially expressed genes were related to carbohydrate transport and metabolism, lipid transport and metabolism, signal transduction mechanism, redox metabolism, and energy production and conversion under 0.5 g/L furfural and 3 g/L HMF stress conditions. In total, 42 genes in the adapted strain were upregulated by 15-fold or more, and qRT-PCR also confirmed that the expression levels of key genes (i.e. SIR, GSS, CYS, and GSR) involved in sulfur assimilation pathway were upregulated by over 10-fold in adapted strain for cellular protection against oxidative stress. PMID- 25793625 TI - Modification of the susceptibility of gram-negative rods producing ESbetaLS to beta-lactams by the efflux phenomenon. AB - The production of beta-lactamases is the most important mechanism of Gram negative rod resistance to beta-lactams. Resistance to ceftazidime and cefepime in clinical isolates of Enterobacteriaceae (especially ESbetaL-positive E. coli and K. pneumoniae) and P. aeruginosa is life-threatening. However, all strains of the above mentioned species possess chromosomally encoded RND efflux pump systems in addition to beta-lactamase production. The main goal of this study was to assess the role of efflux pump systems in cefepime and/or ceftazidime resistant phenotypes of ESbetaL-positive clinical strains of Enterobacteriaceae and P. aeruginosa. The influence of the efflux pump inhibitor PAbetaN on the minimum inhibitory concentration (MIC) values of tested cephalosporins was species dependent. Generally, a significant reduction (at least four-fold) of beta-lactam MICs was observed in the presence of PAbetaN only in the case of P. aeruginosa clinical isolates as well as the ESbetaL-producing transformant PAO1161 DeltaampC. The usage of this agent resulted in the restoration of susceptibility to cefepime and/or ceftazidime in the majority of the P. aeruginosa ESbetaL positive strains with low and moderate resistance to the above cephalosporins. Moreover, an outer membrane permeabilizing effect in the presence of PAbetaN was identified. Strain-dependent beta-lactamase leakage upon PAbetaN or beta-lactam treatment was demonstrated. The most important observation was the restoration of susceptibility of P. aeruginosa WUM226 to cefepime (MIC decrease from 32 to 4 mg/L) and ceftazidime (MIC decrease from 128 to 4 mg/L) in the presence of PAbetaN, which occurred despite an almost complete lack of beta-lactamase leakage from bacterial cells. In conclusion, these data indicate that RND efflux pumps can modify the susceptibility to beta-lactams in Gram-negative rods producing ESbetaLs. However, this phenomenon occurs only in P. aeruginosa strains and was not observed among E. coli and K. pneumoniae strains, representing the Enterobacteriaceae family. PMID- 25793626 TI - Trueperella pyogenes multispecies infections in domestic animals: a retrospective study of 144 cases (2002 to 2012). AB - BACKGROUND: Formerly, Arcanobacterium pyogenes was recently renamed Trueperella pyogenes. This opportunistic bacterium is related to miscellaneous pyogenic infections in animals. Most studies involving T. pyogenes are case reports, whereas few surveys have focused the major aspects of T. pyogenes infections involving a case series study design. OBJECTIVE: The aim of this study was to retrospectively evaluate selected epidemiological and clinical aspects, as well as the in vitro antimicrobial susceptibility pattern of 144 cases of T. pyogenes infections among domestic animals from 2002 to 2012. ANIMALS AND METHODS: T. pyogenes was isolated from different clinical specimens from cattle, goats, sheep, pigs, horses, dogs, and buffaloes. Correlations were assessed by the Chi square or Fisher's exact tests. RESULTS: Mastitis (45.1%), abscesses (18.0%), pneumonia (11.1%), and lymphadenitis (9.0%) were the most common clinical manifestations. In addition, the organism was also isolated from other miscellaneous clinical specimens from cases of septicemia, encephalitis, pyometra, prostatitis, orchitis, seminal vesiculitis, pericarditis, and omphalitis. No statistical association was observed between T. pyogenes infections and age, gender, or season across the study. The most effective drugs against the pathogen were florfenicol (99.1%), cefoperazone (96.0%), cephalexin (95.0%), and ceftiofur (94.8%). High resistance rates were observed against trimethoprim-sulfamethoxazole (49.3%), followed by norfloxacin (10.9%) and tetracycline (9.2%). CONCLUSIONS: This study highlights the diversity of clinical manifestations and the opportunistic behavior of T. pyogenes infections in domestic animals, with predominance of mastitis, abscesses, pneumonia, and lymphadenitis. It also reinforces the importance of knowing the susceptibility profile before initiating therapy, to improve antimicrobial therapy approaches. PMID- 25793627 TI - Cholesterol Gallstones Larger Than 3 cm Appear to Be Associated With Gallbladder Cancer: Identification of a High Risk Group of Patients That Could Benefit From Preventive Cholecystectomy. PMID- 25793628 TI - An automatic image-based modelling method applied to forensic infography. AB - This paper presents a new method based on 3D reconstruction from images that demonstrates the utility and integration of close-range photogrammetry and computer vision as an efficient alternative to modelling complex objects and scenarios of forensic infography. The results obtained confirm the validity of the method compared to other existing alternatives as it guarantees the following: (i) flexibility, permitting work with any type of camera (calibrated and non-calibrated, smartphone or tablet) and image (visible, infrared, thermal, etc.); (ii) automation, allowing the reconstruction of three-dimensional scenarios in the absence of manual intervention, and (iii) high quality results, sometimes providing higher resolution than modern laser scanning systems. As a result, each ocular inspection of a crime scene with any camera performed by the scientific police can be transformed into a scaled 3d model. PMID- 25793629 TI - Genetic parentage analysis confirms a polygynandrous breeding system in the European grayling (Thymallus thymallus). AB - Knowing the breeding system of a species is important in order to understand individual variation in reproductive success. Large variation in reproductive success and thus reproductive skew strongly impacts on the effective number of breeders and thus the long-term effective population size (Ne). Fishes, in particular species belonging to the salmonid family, exhibit a wide diversity of breeding systems. In general, however, breeding systems are rarely studied in detail in the wild. Here we examine the breeding system of the spring-spawning European grayling Thymallus thymallus from a small Norwegian stream using parentage assignment based on the genotyping of 19 polymorphic microsatellite loci. In total 895 individual grayling fry and 154 mature grayling (57 females and 97 males) were genotyped. A total of 466 offspring were assigned a father, a mother, or a parent pair with a confidence of 90% or higher. Successfully reproducing males had on average 11.9 +/- 13.3 (SD) offspring with on average 2.1 +/- 1.2 partners, whereas successful females had on average 9.5 +/- 12.8 offspring and 2.3 +/- 1.5 partners. Parents with more partners also produced more offspring. Thus the grayling breeding system within this small stream revealed a polygynandrous breeding system, similar to what has been observed for many other salmonid fish species. The present study thus unambiguously corroborates a polygynadrous breeding system in the European grayling. This knowledge is critical for managing populations of this species, which has suffered significant local population declines throughout its range over the last several decades. PMID- 25793630 TI - Endoscopic Valves and Irrigation Devices for Flexible Ureteroscopy: Is There a Difference? AB - BACKGROUND AND PURPOSE: A variety of ureteroscopic irrigation systems are available, ranging from gravity-driven pressure bags to hand-operated pumps. Endoscopic valves maintain a watertight seal during ureteroscopy (URS) while facilitating passage of instruments. The clinical utility and ergonomics of such devices have not been established. We systematically compare the mechanical properties and usability of select valve devices and hand-operated irrigation systems in an in vitro setting. MATERIALS AND METHODS: In vitro testing of four different endoscopic valves: UroSeal adjustable endoscopic valve (US Urology), adjustable biopsy port seal (Gyrus ACMI), Blue Silicone Seal ACMI CS B612 (Gyrus ACMI), and REF ABP Biopsy Port Seal (ACMI Corporation) was performed. Usability was evaluated via insertion/extraction forces and insertion time for instruments, including a straight tip sensor wire, 0.035", (Boston Scientific), a laser fiber (Flexiva 200, Boston Scientific), and an Ngage Nitinol Stone Extractor 1.7F (Cook Urological) through a flexible ureteroscope (Olympus URF P5, Olympus). Flow rate, flow time, and user fatigue were tested for two irrigation systems: The single action pumping system (SAP, Boston Scientific) and the Pathfinder Plus (PP, Utah Medical Products). RESULTS: The US needed the shortest time for both wire insertion and basket insertion (P=0.005, and P<0.001, respectively), while the BSS needed the greatest time for laser fiber insertion (P<0.005). The REF ABP needed the greatest force for withdrawal of the Ngage basket, the laser fiber, and the Captura stone grasper through a closed seal, while the US took the least amount of force for both laser fiber withdrawal and insertion via analysis of variance. Leak point pressure assessment demonstrated that the US was leak free at irrigation pressures up to 200 mm Hg, while the ABP, BSS, and the REF ABP devices demonstrated leaks ranging from 30 to 200 mm Hg. The average and peak flow of the SAP were significantly higher than that of the PP. Mean grip strength decreased significantly after operation of the SAP for 10 minutes, while no loss of grip strength was observed after use of the PP. CONCLUSIONS: The US valve has the advantage of facile manipulation of wires and baskets while maintaining a watertight seal, while other devices may be more cost-effective and secure. The PP has the advantage of less operator hand fatigue and ease of use, but the SAPS may allow for greater on-demand pressures. Further studies are needed to evaluate the effect of these irrigation systems on outcomes. PMID- 25793632 TI - Fish intake during pregnancy and foetal neurodevelopment--a systematic review of the evidence. AB - Fish is a source of several nutrients that are important for healthy foetal development. Guidelines from Australia, Europe and the USA encourage fish consumption during pregnancy. The potential for contamination by heavy metals, as well as risk of listeriosis requires careful consideration of the shaping of dietary messages related to fish intake during pregnancy. This review critically evaluates literature on fish intake in pregnant women, with a focus on the association between neurodevelopmental outcomes in the offspring and maternal fish intake during pregnancy. Peer-reviewed journal articles published between January 2000 and March 2014 were included. Eligible studies included those of healthy pregnant women who had experienced full term births and those that had measured fish or seafood intake and assessed neurodevelopmental outcomes in offspring. Medline, Scopus, Web of Science, ScienceDirect and the Cochrane Library were searched using the search terms: pregnant, neurodevelopment, cognition, fish and seafood. Of 279 papers sourced, eight were included in the final review. Due to heterogeneity in methodology and measured outcomes, a qualitative comparison of study findings was conducted. This review indicates that the benefits of diets providing moderate amounts of fish during pregnancy outweigh potential detrimental effects in regards to offspring neurodevelopment. It is important that the type of fish consumed is low in mercury. PMID- 25793633 TI - Quercetin inhibits the migration and proliferation of astrocytes in wound healing. AB - A previous study showed that quercetin inhibits astrogliosis in a scratch-wound model, but did not identify the underlying mechanisms. Here, we show that quercetin exerts no effect on apoptosis or the viability of astrocytes, but significantly inhibits their proliferation, arresting them in the G1 phase and decreasing the percentage of cells in the S and G2 phase. In addition, we found that quercetin significantly decreased the phosphorylation of ERK1/2 and FAK, a downstream ERK signaling protein. Inhibition of this pathway with U0126, an inhibitor of MAP kinase, retarded wound closure, whereas sustained p-ERK1/2 activation, induced by vanadate, restored astrocyte migration. Our findings thus indicate that quercetin inhibits healing in the scratch-wound model of primary astrocytes in two ways: blockade of the G1 to S phase cell cycle transition and inhibition of the ERK/FAK signaling pathway, which may contribute toward decreasing astroglial scar formation in vivo. PMID- 25793631 TI - Alcohol: a nutrient with multiple salutary effects. AB - Numerous studies have shown that cardiovascular disease is lower among alcohol consumers than among nonconsumers. Many of the metabolic effects of alcohol are mediated by its terminal metabolite, acetate, which has reported insulinemic properties. There have been few rational metabolic targets that underly its cardioprotective effects until it was reported that acetate, the terminal product of alcohol metabolism, is the ligand for G-protein coupled receptor 43 (GPCR43), which is highly expressed in adipose tissue. Here, we recast much of some of the major lipid and lipoprotein effects of alcohol in the context of this newly discovered G-protein and develop a mechanistic model connecting the interaction of acetate with adipose tissue-GPCR43 with these effects. According to our model, ingestions of acetate could replace alcohol as a means of improving plasma lipid risk factors, improving glucose disposal, and reducing cardiovascular disease. Future studies should include biochemical, cell, animal, and human tests of acetate on energy metabolism. PMID- 25793634 TI - Vascular endothelial growth factor-expressing neural stem cell for the treatment of neuropathic pain. AB - Previously, we determined that vascular endothelial growth factor (VEGF) improves the survival of neural stem cells (NSCs) transplanted into an ischemic environment and effectively enhances angiogenesis. Here, we applied NSCs expressing VEGF (SV-VEGF-NSCs) to treat neuropathic pain. In this study, our goal was to verify the therapeutic effect of SV-VEGF-NSCs by transplanting the cells in a sciatic nerve injury model. We compared the amount of VEGF secreted from DsRed-NSCs (control) or SV-VEGF-NSCs and observed that SV-VEGF-NSCs have a much higher expression level of VEGF. We next investigated whether transplantation with SV-VEGF-NSCs aids functional recovery and pain reduction. We confirmed that transplantation with SV-VEGF-NSCs enhances functional recovery, pain reduction, and remyelination as well as the number of blood vessels compared with the control groups. Our results show that VEGF aids functional recovery and pain reduction in a sciatic nerve injury model. PMID- 25793635 TI - Galvanic vestibular stimulation may improve anterior bending posture in Parkinson's disease. AB - This study investigated the effects of binaural monopolar galvanic vestibular stimulation (GVS), which likely stimulates the bilateral vestibular system, on the anterior bending angle in patients with Parkinson's disease (PD) with anterior bending posture in a single-blind, randomized sham-controlled crossover trial. The seven PD patients completed two types of stimulation (binaural monopolar GVS and sham stimulation) applied in a random order 1 week apart. We measured each patient's anterior bending angles while he or she stood with eyes open and eyes closed before/after the stimulations. The anterior bending angles in both the eyes-open and the eyes-closed conditions were significantly reduced after the GVS. The amount of change in the eyes-closed condition post-GVS was significantly larger than that by sham stimulation. The amount of change in anterior bending angles in the GVS condition was not significantly correlated with Unified Parkinson's Disease Rating Scale motor score, disease duration, the duration of the postural deformities, and the anterior bending angles before the GVS. Binaural monopolar GVS might improve anterior bending posture in PD patients, irrespective of the duration and the severity of disease and postural deformities. Binaural monopolar GVS might be a novel treatment strategy to improve anterior bending posture in PD. PMID- 25793636 TI - Boron/nitrogen co-doped helically unzipped multiwalled carbon nanotubes as efficient electrocatalyst for oxygen reduction. AB - Bamboo structured nitrogen doped multiwalled carbon nanotubes have been helically unzipped, and nitrogen doped graphene oxide nanoribbons (CNx-GONRs) with a multifaceted microstructure have been obtained. CNx-GONRs have then been codoped with nitrogen and boron by simultaneous thermal annealing in ammonia and boron oxide atmospheres, respectively. The effects of the codoping time and temperature on the concentration of the dopants and their functional groups have been extensively investigated. X-ray photoelectron spectroscopy results indicate that pyridinic and BC3 are the main nitrogen and boron functional groups, respectively, in the codoped samples. The oxygen reduction reaction (ORR) properties of the samples have been measured in an alkaline electrolyte and compared with the state-of-the-art Pt/C (20%) electrocatalyst. The results show that the nitrogen/boron codoped graphene nanoribbons with helically unzipped structures (CNx/CBx-GNRs) can compete with the Pt/C (20%) electrocatalyst in all of the key ORR properties: onset potential, exchange current density, four electron pathway selectivity, kinetic current density, and stability. The development of such graphene nanoribbon-based electrocatalyst could be a harbinger of precious metal-free carbon-based nanomaterials for ORR applications. PMID- 25793637 TI - Impact of small groups with heterogeneous preference on behavioral evolution in population evacuation. AB - Up to now, there have been a great number of mechanisms to explain the individual behavior and population traits, which seem of particular significance in evolutionary biology and social behavior analysis. Among them, small groups and heterogeneity are two useful frameworks to the above issue. However, vast majority of existing works separately consider both scenarios, which is inconsistent with realistic cases in our life. Here we propose the evolutionary games of heterogeneous small groups (namely, different small groups possess different preferences to dilemma) to study the collective behavior in population evacuation. Importantly, players usually face completely different dilemmas inside and outside the small groups. By means of numerous computation simulations, it is unveiled that the ratio of players in one certain small group directly decides the final behavior of the whole population. Moreover, it can also be concluded that heterogeneous degree of preference for different small groups plays a key role in the behavior traits of the system, which may validate some realistic social observations. The proposed framework is thus universally applicable and may shed new light into the solution of social dilemmas. PMID- 25793638 TI - Road Traffic Suicide in Switzerland. AB - OBJECTIVE: To determine details of road traffic suicides in Switzerland between 2000 and 2010 and to look at our results in relation to studies from other countries. METHODS: Retrospective data analysis of road traffic suicides extracted from the database of all suicides investigated by Swiss institutes of forensic medicine between 2000 and 2010 using a standardized assessment sheet. RESULTS: Out of 4,885 suicides in Switzerland, we identified 76 cases (1.56%) of road traffic suicide. Twenty-three cases had to be excluded because, although the forensic medical experts suspected suicide, they could not establish it for sure. That left 53 cases (1.02% of all suicides), mostly unmarried men, who were on average 9 years younger than the study population as a whole. Most collided with other vehicles, mainly other cars, and usually on main highways or country roads. In most cases, the cause of death was multiple injuries. Other persons were killed 4 times more often than with other suicide methods. Toxicology screening was performed significantly more frequently than with other methods but more often proved negative. Acute psychiatric problems were commonly assumed to be the underlying reasons. Suicide notes were left by only 20%, a lower proportion than in the study population as a whole. CONCLUSIONS: Road traffic suicides account for approximately 1% of all suicide methods used in Switzerland, although unclassifiable cases indicate that the rate might be higher. Every road traffic crash should therefore be routinely investigated by an interdisciplinary team and suicide should be considered as the possible cause. PMID- 25793639 TI - The effects of mycoplasma contamination upon the ability to form bioengineered 3D kidney cysts. AB - Mycoplasma contamination of cell cultures is a pervasive, often undiagnosed and ignored problem in many laboratories that can result in reduced cell proliferation and changes in gene expression. Unless contamination is specifically suspected, it is often undetected in two dimensional (2D) cultures and the resulting effects of mycoplasma contamination are rarely appreciated and can lead to incorrect conclusions. Three dimensional (3D) tissue cultures are increasingly utilized to explore tissue development and phenotype. However, 3D cultures are more complex than 2D cell cultures and require a more controlled cellular environment in order to generate structures necessary to mimic in vivo responses and are often maintained for longer time periods. Changes to the microenvironment are assumed to have a more extreme effect upon the success of 3D tissue cultures than 2D cell cultures, but the effects of mycoplasma have not been studied. To test this hypothesis, we grew 2D cell cultures and 3D tissues from pig kidney epithelial cells (LLC-PK1) that were contaminated with mycoplasma and the same stock of cells after mycoplasma removal. We did not observe an effect of mycoplasma contamination on proliferation in 2D monolayer cell culture. However, cyst formation in 3D tissues was altered, with effects upon the number, size and structure of cysts formed. These data serve to reinforce the necessity of testing cell stocks for mycoplasma contamination. PMID- 25793640 TI - MicroRNA-223 regulates granulopoiesis but is not required for HSC maintenance in mice. AB - MIR233 is genetically or epigenetically silenced in a subset of acute myeloid leukemia (AML). MIR223 is normally expressed throughout myeloid differentiation and highly expressed in hematopoietic stem cells (HSCs). However, the contribution of MIR223 loss to leukemic transformation and HSC function is largely unknown. Herein, we characterize HSC function and myeloid differentiation in Mir223 deficient mice. We show that Mir223 loss results in a modest expansion of myeloid progenitors, but is not sufficient to induce a myeloproliferative disorder. Loss of Mir223 had no discernible effect on HSC quiescence, long-term repopulating activity, or self-renewal capacity. These results suggest that MIR223 loss is likely not an initiating event in AML but may cooperate with other AML associated oncogenes to induce leukemogenesis. PMID- 25793641 TI - RMND5 from Xenopus laevis is an E3 ubiquitin-ligase and functions in early embryonic forebrain development. AB - In Saccharomyces cerevisiae the Gid-complex functions as an ubiquitin-ligase complex that regulates the metabolic switch between glycolysis and gluconeogenesis. In higher organisms six conserved Gid proteins form the CTLH protein-complex with unknown function. Here we show that Rmnd5, the Gid2 orthologue from Xenopus laevis, is an ubiquitin-ligase embedded in a high molecular weight complex. Expression of rmnd5 is strongest in neuronal ectoderm, prospective brain, eyes and ciliated cells of the skin and its suppression results in malformations of the fore- and midbrain. We therefore suggest that Xenopus laevis Rmnd5, as a subunit of the CTLH complex, is a ubiquitin-ligase targeting an unknown factor for polyubiquitination and subsequent proteasomal degradation for proper fore- and midbrain development. PMID- 25793642 TI - First GIS analysis of modern stone tools used by wild chimpanzees (Pan troglodytes verus) in Bossou, Guinea, West Africa. AB - Stone tool use by wild chimpanzees of West Africa offers a unique opportunity to explore the evolutionary roots of technology during human evolution. However, detailed analyses of chimpanzee stone artifacts are still lacking, thus precluding a comparison with the earliest archaeological record. This paper presents the first systematic study of stone tools used by wild chimpanzees to crack open nuts in Bossou (Guinea-Conakry), and applies pioneering analytical techniques to such artifacts. Automatic morphometric GIS classification enabled to create maps of use wear over the stone tools (anvils, hammers, and hammers/ anvils), which were blind tested with GIS spatial analysis of damage patterns identified visually. Our analysis shows that chimpanzee stone tool use wear can be systematized and specific damage patterns discerned, allowing to discriminate between active and passive pounders in lithic assemblages. In summary, our results demonstrate the heuristic potential of combined suites of GIS techniques for the analysis of battered artifacts, and have enabled creating a referential framework of analysis in which wild chimpanzee battered tools can for the first time be directly compared to the early archaeological record. PMID- 25793643 TI - Multimodal secondary prevention behavioral interventions for TIA and stroke: a systematic review and meta-analysis. AB - BACKGROUND: Guidelines recommend implementation of multimodal interventions to help prevent recurrent TIA/stroke. We undertook a systematic review to assess the effectiveness of behavioral secondary prevention interventions. STRATEGY: Searches were conducted in 14 databases, including MEDLINE (1980-January 2014). We included randomized controlled trials (RCTs) testing multimodal interventions against usual care/modified usual care. All review processes were conducted in accordance with Cochrane guidelines. RESULTS: Twenty-three papers reporting 20 RCTs (6,373 participants) of a range of multimodal behavioral interventions were included. Methodological quality was generally low. Meta-analyses were possible for physiological, lifestyle, psychosocial and mortality/recurrence outcomes. Note: all reported confidence intervals are 95%. Systolic blood pressure was reduced by 4.21 mmHg (mean) (-6.24 to -2.18, P = 0.01 I2 = 58%, 1,407 participants); diastolic blood pressure by 2.03 mmHg (mean) (-3.19 to -0.87, P = 0.004, I2 = 52%, 1,407 participants). No significant changes were found for HDL, LDL, total cholesterol, fasting blood glucose, high sensitivity-CR, BMI, weight or waist:hip ratio, although there was a significant reduction in waist circumference (-6.69 cm, -11.44 to -1.93, P = 0.006, I2 = 0%, 96 participants). There was no significant difference in smoking continuance, or improved fruit and vegetable consumption. There was a significant difference in compliance with antithrombotic medication (OR 1.45, 1.21 to 1.75, P<0.0001, I2 = 0%, 2,792 participants) and with statins (OR 2.53, 2.15 to 2.97, P< 0.00001, I2 = 0%, 2,636 participants); however, there was no significant difference in compliance with antihypertensives. There was a significant reduction in anxiety (-1.20, -1.77 to 0.63, P<0.0001, I2 = 85%, 143 participants). Although there was no significant difference in odds of death or recurrent TIA/stroke, there was a significant reduction in the odds of cardiac events (OR 0.38, 0.16 to 0.88, P = 0.02, I2 = 0%, 4,053 participants). CONCLUSIONS: There are benefits to be derived from multimodal secondary prevention interventions. However, the findings are complex and should be interpreted with caution. Further, high quality trials providing comprehensive detail of interventions and outcomes, are required. REVIEW REGISTRATION: PROSPERO CRD42012002538. PMID- 25793644 TI - Temperature and magnetic-field dependence of radiative decay in colloidal germanium quantum dots. AB - We conduct spectroscopic and theoretical studies of photoluminescence (PL) from Ge quantum dots (QDs) fabricated via colloidal synthesis. The dynamics of late time PL exhibit a pronounced dependence on temperature and applied magnetic field, which can be explained by radiative decay involving two closely spaced, slowly emitting exciton states. In 3.5 nm QDs, these states are separated by ~1 meV and are characterized by ~82 MUs and ~18 MUs lifetimes. By using a four-band formalism, we calculate the fine structure of the indirect band-edge exciton arising from the electron-hole exchange interaction and the Coulomb interaction of the Gamma-point hole with the anisotropic charge density of the L-point electron. The calculations suggest that the observed PL dynamics can be explained by phonon-assisted recombination of excitons thermally distributed between the lower-energy "dark" state with the momentum projection J = +/- 2 and a higher energy "bright" state with J = +/- 1. A fairly small difference between lifetimes of these states is due to their mixing induced by the exchange term unique to crystals with a highly symmetric cubic lattice such as Ge. PMID- 25793645 TI - YCZ-18 is a new brassinosteroid biosynthesis inhibitor. AB - Plant hormone brassinosteroids (BRs) are a group of polyhydroxylated steroids that play critical roles in regulating broad aspects of plant growth and development. The structural diversity of BRs is generated by the action of several groups of P450s. Brassinazole is a specific inhibitor of C-22 hydroxylase (CYP90B1) in BR biosynthesis, and the application use of brassinazole has emerged as an effective way of complementing BR-deficient mutants to elucidate the functions of BRs. In this article, we report a new triazole-type BR biosynthesis inhibitor, YCZ-18. Quantitative analysis the endogenous levels of BRs in Arabidopsis indicated that YCZ-18 significantly decreased the BR contents in plant tissues. Assessment of the binding affinity of YCZ-18to purified recombinant CYP90D1 indicated that YCZ-18 induced a typical type II binding spectrum with a Kd value of approximately 0.79 MUM. Analysis of the mechanisms underlying the dwarf phenotype associated with YCZ-18 treatment of Arabidopsis indicated that the chemically induced dwarf phenotype was caused by a failure of cell elongation. Moreover, dissecting the effect of YCZ-18 on the induction or down regulation of genes responsive to BRs indicated that YCZ-18 regulated the expression of genes responsible for BRs deficiency in Arabidopsis. These findings indicate that YCZ-18 is a potent BR biosynthesis inhibitor and has a new target site, C23-hydroxylation in BR biosynthesis. Application of YCZ-18 will be a good starting point for further elucidation of the detailed mechanism of BR biosynthesis and its regulation. PMID- 25793646 TI - Associations between Long-Term Air Pollutant Exposures and Blood Pressure in Elderly Residents of Taipei City: A Cross-Sectional Study. AB - BACKGROUND: Limited information is available regarding long-term effects of air pollution on blood pressure (BP) and hypertension. OBJECTIVE: We studied whether 1-year exposures to particulate matter (PM) and nitrogen oxides (NOx) were correlated with BP and hypertension in the elderly. METHODS: We analyzed cross sectional data from 27,752 Taipei City residents > 65 years of age who participated in a health examination program in 2009. Land-use regression models were used to estimate participants' 1-year exposures to particulate matter with aerodynamic diameter <= 10 MUm (PM10), coarse particles (PM2.5-10), fine particles (<= 2.5 MUm; PM2.5), PM2.5 absorbance, NOx, and nitrogen dioxide (NO2). Generalized linear regressions and logistic regressions were used to examine the association between air pollution and BP and hypertension, respectively. RESULTS: Diastolic BP was associated with 1-year exposures to air pollution, with estimates of 0.73 [95% confidence interval (CI): 0.44, 1.03], 0.46 (95% CI: 0.30, 0.63), 0.62 (95% CI: 0.24, 0.99), 0.34 (95% CI: 0.19, 0.50), and 0.65 (95% CI: 0.44, 0.85) mmHg for PM10 (10 MUg/m3), PM2.5-10 (5 MUg/m3), PM2.5 absorbance (10 5/m), NOx (20 MUg/m3), and NO2 (10 MUg/m3), respectively. PM2.5 was not associated with diastolic BP, and none of the air pollutants was associated with systolic BP. Associations of diastolic BP with PM10 and PM2.5 absorbance were stronger among participants with hypertension, diabetes, or a body mass index >= 25 kg/m2 than among participants without these conditions. One-year air pollution exposures were not associated with hypertension. CONCLUSIONS: One-year exposures to PM10, PM2.5-10, PM2.5 absorbance, and NOx were associated with higher diastolic BP in elderly residents of Taipei. PMID- 25793647 TI - Less is more: the detrimental consequences of immunosuppressive therapy in the treatment of type-1 diabetes. AB - The prevalent current approach to type 1 diabetes (T1D) is the abrogation of pathogenic potential by immunosuppressive therapy, an intuitive approach aiming to slow down disease progression by the reduction of pathogenic burden. In spite of promising initial results in rodent models, there has been little efficacy of most lymphoreductive strategies in human subjects. Our analysis suggests that lymphopenia is the common denominator of ineffective immunosuppressive therapies: Immune rebound from lymphopenia is associated per se with increased susceptibility to immune reactivity, including relapse of autoimmunity. In addition, immune homeostasis and self-tolerance are not restored. These considerations raise the following question: What is the allowed degree of immunosuppressive therapy that does not elicit recurrent autoimmunity. More effective therapeutic strategies include targeted deletion of pathogenic cells, preferably in the pancreatic islets and regional lymphatics using selective T cell activation markers, re-education and remodeling of effector responses. PMID- 25793648 TI - Organocatalytic enantioselective alpha-hydroxymethylation of aldehydes: mechanistic aspects and optimization. AB - Further studies of the direct enantioselective alpha-hydroxymethylation of aldehydes employing the alpha,alpha-diarylprolinol trimethylsilyl ether class of organocatalysts are described. This process has proven efficient for access to beta-hydroxycarboxylic acids and delta-hydroxy-alpha,beta-unsaturated esters from aldehydes in generally good yields, excellent enantioselectivity, and compatibility with a broad range of functional groups in the aldehyde. The goal of these studies was to identify the critical reaction variables that influence the yield and enantioselectivity of the alpha-hydroxymethylation process such as catalyst structure, pH of the medium, purity of the reactants and reagents particularly with respect to the presence of acidic impurities, and the nature of the buffer, along with the standard variables including solvent, time, temperature and mixing efficiency. The previously identified intermediate lactol has been further characterized and its reactivity examined. These studies have led to identification of the most critical variables translating directly into improved substrate scope, reproducibility, enantioselectivity, and yields. PMID- 25793649 TI - Nanohydration of uracil: emergence of three-dimensional structures and proton induced charge transfer. AB - Stepwise hydration of uracil has been theoretically revisited using different methods ranging from classical force fields to quantum chemical approaches. Hydration initially begins within the uracil plane but proceeds at four molecules into three-dimensional configurations or even water clusters next to the nucleobase. The relative stability between the various structures is significantly affected by zero-point energy and finite temperature (entropy) effects and also gives rise to markedly different responses to an excitation by an impinging high-energy proton. In particular, charge transfer to the molecular complex is dramatically altered in collisions toward the coating cluster but barely modified for peripheral hydration patterns. PMID- 25793650 TI - Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride. AB - In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPalpha release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease. PMID- 25793651 TI - Three new families with recurrent male miscarriages and hypercoiled umbilical cord. PMID- 25793652 TI - Unusual appearance of malignant peritoneal mesothelioma. AB - Malignant peritoneal mesothelioma (MPM) is a rare and fatal cancer arising from the mesothelial cells lining the peritoneum. This typically occurs in men in their fifth and sixth decades, but can be seen in women and any age group. Pleural and extrapleural mesothelioma can arise in the setting of asbestos exposure, but other reported causes of MPM include exposure to silicate fibers and radiation therapy. Because it presents with vague symptoms such as abdominal pain, anorexia, and weight loss, it is generally advanced at diagnosis. This is a case of MPM that presented initially at contrast-enhanced computed tomography as a small focal lesion in the lesser sac, ultimately resulting in death from complications of the disease. PMID- 25793653 TI - Texture Analysis of Non-Contrast-Enhanced Computed Tomography for Assessing Angiogenesis and Survival of Soft Tissue Sarcoma. AB - OBJECTIVE: To evaluate the role of computed tomographic (CT) texture analysis in assessing tumor angiogenesis and survival of soft tissue sarcoma (STS). METHODS: In 20 patients with STSs, tumor texture parameters, which were measured on pretherapeutic CT using CT texture analysis software with the spatial scale filter extracting fine to coarse texture, were compared with microvessel density, plasma vascular endothelial growth factor (VEGF), soluble VEGF receptor-1, and overall survival (OS). RESULTS: Mean of positive pixels (MPP) showed a positive correlation with microvessel density (P = 0.02). Entropy at medium texture scales (spatial scale filter = 3, 4, 5) showed positive correlations with VEGF (P = 0.03, P = 0.009, and P = 0.02, respectively), and entropy without filtration showed a positive correlation with soluble VEGF receptor-1 (P = 0.02). In the univariate analysis, kurtosis at a medium texture scale and MPP showed significant correlations with OS (P = 0.04 and P = 0.007), and multivariate analysis demonstrated that MPP was an independent prognostic factor (P = 0.01). CONCLUSION: Texture parameters are associated with tumor angiogenesis and OS in STS. PMID- 25793654 TI - Liposomal hypocrellin B as a potential photosensitizer for age-related macular degeneration: pharmacokinetics, photodynamic efficacy, and skin phototoxicity in vivo. AB - Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clinical use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepared by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new preparation were found to remain nearly constant over 1 year. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 +/- 0.462 h and a very low serum concentration at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg(-1) along with yellow laser irradiation; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD. PMID- 25793655 TI - Self-assembly of microcapsules regulated via the repressilator signaling network. AB - One of the intriguing challenges in designing active matter is devising systems that not only self-organize, but also exhibit self-regulation. Inspired by biological regulatory networks, we design a collection of self-organizing, self regulating microcapsules that move in response to self-generated chemical signals. Three microcapsules act as localized sources of distinct chemicals that diffuse through surrounding fluid. Production rates are modulated by the "repressilator" regulatory network motif: each chemical species represses the production of the next in a cycle. Depending on the maximum production rates and capsule separation distances, we show that immobile capsules either exhibit steady or oscillatory chemical production. We then consider movement of the microcapsules over the substrate, induced by gradients in surface energy due to adsorbed chemicals. We numerically simulate this advection-diffusion-reaction system with solid-fluid interactions by combining lattice Boltzmann, immersed boundary and finite difference methods, and thereby, construct systems where the three capsules spontaneously assemble to form a close-packed triad. Chemical oscillations are shown to be critical to this assembly. By adjusting parameters, the triad can either remain stationary or translate as a cohesive group. Stationary triads can also be made to "turn off", producing chemicals at minimal rates after assembly. These findings provide design rules for creating synthetic material systems that encompass biomimetic feedback loops, which enable dynamic collective behavior. PMID- 25793656 TI - Proteomics, peptidomics, and immunogenic potential of wheat beer (Weissbier). AB - Wheat beer is a traditional light-colored top-fermenting beer brewed with at least 50% malted (e.g., German Weissbier) or unmalted (e.g., Belgian Witbier) wheat (Triticum aestivum) as an adjunct to barley (Hordeum vulgare) malt. For the first time, we explored the proteome of three Weissbier samples, using both 2D electrophoresis (2DE)-based and 2DE-free strategies. Overall, 58 different gene products arising from barley, wheat, and yeast (Saccharomyces spp.) were identified in the protein fraction of a representative Weissbier sample analyzed in detail. Analogous to all-barley-malt beers (BMB), barley and wheat Z-type serpins and nonspecific lipid transfer proteins dominated the proteome of Weissbier. Several alpha-amylase/trypsin inhibitors also survived the harsh brewing conditions. During brewing, hundreds of peptides are released into beer. By liquid chromatography-electrospray tandem mass spectrometry (LC-ESI MS/MS) analysis, we characterized 167 peptides belonging to 44 proteins, including gliadins, hordeins, and high- and low-molecular-weight glutenin subunits. Because of the interference from the overabundant yeast-derived peptides, we identified only a limited number of epitopes potentially triggering celiac disease. However, Weissbier samples contained 374, 372, and 382 ppm gliadin-equivalent peptides, as determined with the competitive G12 ELISA, which is roughly 10-fold higher than a lager BMB (41 ppm), thereby confirming that Weissbier is unsuited for celiacs. Western blot analysis demonstrated that Weissbier also contained large-sized prolamins immunoresponsive to antigliadin IgA antibodies from the pooled sera of celiac patients (n = 4). PMID- 25793658 TI - Polarized light imaging in biomedicine: emerging Mueller matrix methodologies for bulk tissue assessment. AB - Polarized light point measurements and wide-field imaging have been studied for many years in an effort to develop accurate and information-rich tissue diagnostic methods. However, the extensive depolarization of polarized light in thick biological tissues has limited the success of these investigations. Recently, advances in technology and conceptual understanding have led to a significant resurgence of research activity in the promising field of bulk tissue polarimetry. In particular, with the advent of improved measurement, analysis, and interpretation methods, including Mueller matrix decomposition, new diagnostic avenues, such as quantification of microstructural anisotropy in bulk tissues, have been enabled. Further, novel technologies have improved the speed and the accuracy of polarimetric instruments for ex vivo and in vivo diagnostics. In this paper, we review some of the recent progress in tissue polarimetry, provide illustrative application examples, and offer an outlook to the future of polarized light imaging in bulk biological tissues. PMID- 25793657 TI - Combined hormonal versus nonhormonal versus progestin-only contraception in lactation. AB - BACKGROUND: Postpartum contraception improves the health of mothers and children by lengthening birth intervals. For lactating women, contraception choices are limited by concerns about hormonal effects on milk quality and quantity and passage of hormones to the infant. Ideally, the contraceptive chosen should not interfere with lactation or infant growth. Timing of contraception initiation is also important. Immediately postpartum, most women have contact with a health professional, but many do not return for follow-up contraceptive counseling. However, immediate initiation of hormonal methods may disrupt the onset of milk production. OBJECTIVES: To determine the effects of hormonal contraceptives on lactation and infant growth SEARCH METHODS: We searched for eligible trials until 2 March 2015. Sources included the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, POPLINE, Web of Science, LILACS, ClinicalTrials.gov, and ICTRP. We also examined review articles and contacted investigators. SELECTION CRITERIA: We sought randomized controlled trials in any language that compared hormonal contraception versus another form of hormonal contraception, nonhormonal contraception, or placebo during lactation. Hormonal contraception includes combined or progestin-only oral contraceptives, injectable contraceptives, implants, and intrauterine devices.Trials had to have one of our primary outcomes: breast milk quantity or biochemical composition; lactation initiation, maintenance, or duration; infant growth; or timing of contraception initiation and effect on lactation. Secondary outcomes included contraceptive efficacy while breastfeeding and birth interval. DATA COLLECTION AND ANALYSIS: For continuous variables, we calculated the mean difference (MD) with 95% confidence interval (CI). For dichotomous outcomes, we computed the Mantel-Haenszel odds ratio (OR) with 95% CI. Due to differing interventions and outcome measures, we did not aggregate the data in a meta-analysis. MAIN RESULTS: In 2014, we added seven trials for a new total of 11. Five reports were published before 1985 and six from 2005 to 2014. They included 1482 women. Four trials examined combined oral contraceptives (COCs), and three studied a levonorgestrel-releasing intrauterine system (LNG-IUS). We found two trials of progestin-only pills (POPs) and two of the etonogestrel-releasing implant. Older studies often lacked quantified results. Most trials did not report significant differences between the study arms in breastfeeding duration, breast milk composition, or infant growth. Exceptions were seen mainly in older studies with limited information.For breastfeeding duration, two of eight trials indicated a negative effect on lactation. A COC study reported a negative effect on lactation duration compared to placebo but did not quantify results. Another trial showed a lower percentage of the LNG-IUS group breastfeeding at 75 days versus the nonhormonal IUD group (reported P < 0.05) but no significant difference at one year.For breast milk volume, two older studies indicated lower volume for the COC group versus the placebo group. One trial did not quantify results. The other showed lower means (mL) for the COC group, e.g. at 16 weeks (MD -24.00, 95% CI -34.53 to -13.47) and at 24 weeks (MD -24.90, 95% CI -36.01 to -13.79). Another four trials did not report any significant difference between the study groups in milk volume or composition with two POPs, a COC, or the etonogestrel implant.Seven trials studied infant growth; one showed greater weight gain (grams) for the etonogestrel implant versus no method for six weeks (MD 426.00, 95% CI 58.94 to 793.06) but less compared with depot medroxyprogesterone acetate (DMPA) from 6 to 12 weeks (MD -271.00, 95% CI -355.10 to -186.90). The others studied POPs, COCs versus POPs, or an LNG-IUS. AUTHORS' CONCLUSIONS: Results were not consistent across the 11 trials. The evidence was limited for any particular hormonal method. The quality of evidence was moderate overall and low for three of four placebo-controlled trials of COCs or POPs. The sensitivity analysis included six trials with moderate quality evidence and sufficient outcome data. Five trials indicated no significant difference between groups in breastfeeding duration (etonogestrel implant insertion times, COC versus POP, and LNG-IUS). For breast milk volume or composition, a COC study showed a negative effect, while an implant trial showed no significant difference. Of four trials that assessed infant growth, three indicated no significant difference between groups. One showed greater weight gain in the etonogestrel implant group versus no method but less versus DMPA. PMID- 25793659 TI - To remember is not to forget: a reply to Moore and Henderson. PMID- 25793660 TI - Psychometric properties of the simple test for evaluating hand function in patients with stroke. AB - OBJECTIVE: The simple test for evaluating hand function (STEF) is widely used for clinical evaluation of upper extremity function in Japan. However, except for test-re-test reliability, its psychometric properties have not been investigated. The aim of this study is to explore its internal consistency, concurrent validity and responsiveness in patients with sub-acute stroke. DESIGN: This was a prospective longitudinal study. PATIENTS: Thirty-four inpatients who had suffered hemiparetic stroke within 60 days of participation were enrolled. METHODS: To investigate its internal consistency and responsiveness, they were assessed with the STEF and Action Research Arm Test (ARAT) at admission and 3 weeks later. To explore its concurrent validity, the Fugl-Meyer Assessment (FMA), Motor Activity Log (MAL) and Functional Independence Measure (FIMTM) were also evaluated at admission. RESULTS: The Cronbach's alpha for the STEF was 0.98-0.99, indicating excellent internal consistency. The STEF score strongly correlated with the ARAT, FMA and MAL scores and moderately with the FIMTM score. Effect sizes and the standardized response mean were 0.27 and 0.52 for the STEF and 0.30 and 0.95 for the ARAT, respectively. CONCLUSION: This study indicates that the STEF is reliable, valid and sensitive to changes when applied to patients with sub-acute stroke. PMID- 25793661 TI - Match statistics related to winning in the group stage of 2014 Brazil FIFA World Cup. AB - Identifying match statistics that strongly contribute to winning in football matches is a very important step towards a more predictive and prescriptive performance analysis. The current study aimed to determine relationships between 24 match statistics and the match outcome (win, loss and draw) in all games and close games of the group stage of FIFA World Cup (2014, Brazil) by employing the generalised linear model. The cumulative logistic regression was run in the model taking the value of each match statistic as independent variable to predict the logarithm of the odds of winning. Relationships were assessed as effects of a two standard-deviation increase in the value of each variable on the change in the probability of a team winning a match. Non-clinical magnitude-based inferences were employed and were evaluated by using the smallest worthwhile change. Results showed that for all the games, nine match statistics had clearly positive effects on the probability of winning (Shot, Shot on Target, Shot from Counter Attack, Shot from Inside Area, Ball Possession, Short Pass, Average Pass Streak, Aerial Advantage and Tackle), four had clearly negative effects (Shot Blocked, Cross, Dribble and Red Card), other 12 statistics had either trivial or unclear effects. While for the close games, the effects of Aerial Advantage and Yellow Card turned to trivial and clearly negative, respectively. Information from the tactical modelling can provide a more thorough and objective match understanding to coaches and performance analysts for evaluating post-match performances and for scouting upcoming oppositions. PMID- 25793662 TI - Satisfaction with the relationship from the perspectives of family caregivers, older adults and their home care workers. AB - OBJECTIVES: Given the increasing reliance on both formal (paid) and informal (unpaid) assistance for the care of older adults and the close relationships which are often formed with home care workers, the present study evaluated satisfaction with the relationship from the perspectives of the three members that make up the home caregiving triad: older adults, their family members and their home care workers. METHODS: We relied on a representative sample of 223 complete caregiving triads composed of an older adult, a family member and a home care worker. Each of the members rated his or her level of satisfaction with all other members in the unit, using a seven-item self-report satisfaction with the relationship scale (e.g., satisfaction with communication, intimacy). The Social Relations Model (SRM) was used to partial out the specific variance associated with each of the members as either an actor (i.e., the average satisfaction as a rater, unrelated to whom the person rates) or a partner (i.e., the unique satisfaction level elicited by a person, which is consistent across all ratings of this person). RESULTS: The structural equations model yielded acceptable results: chi2(3) = 6.94, p = .07. Our analysis revealed that the variability associated with the worker as partner was significantly greater than the variability associated with the older adult as partner (?chi2 [1] = 9.21, p = .002) or with the family member as partner (?chi2 [1] = 8.46, p = .004). CONCLUSIONS: The study highlights the importance of studying satisfaction with the relationship in the home care setting and calls for further examination of the entire caregiving triad. The home care worker plays a key role in ensuring the overall satisfaction in the caregiving triad. PMID- 25793665 TI - Adaptation within natural variation. PMID- 25793663 TI - Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice. AB - Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (>=0.5 uM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (>=0.5 uM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC. PMID- 25793666 TI - To boost cancer immunotherapy, just add oxygen? PMID- 25793668 TI - Understanding the link between obesity and infertility. PMID- 25793669 TI - A mitochondrial gene product regulates metabolism. PMID- 25793671 TI - Flashy tail, bony antlers. PMID- 25793672 TI - USDA Inspector General's report on oversight of research facilities. PMID- 25793673 TI - Congruence between grants and protocols. PMID- 25793674 TI - Response to protocol review scenario: hole in the system. PMID- 25793675 TI - Response to protocol review scenario: a word from OLAW. PMID- 25793676 TI - Response to protocol review scenario: verify congruence. PMID- 25793677 TI - Response to protocol review scenario: documentation needed. PMID- 25793678 TI - Postoperative multimodal pain management. PMID- 25793679 TI - Assessment of four experimental models of hyperlipidemia. AB - Various animal models of hyperlipidemia are used in research. Four rodent hyperlipidemia experimental models are examined in this study: three chronic hyperlipidemia models based on dietary supplementation with lipid or sucrose for 3 months and one acute hyperlipidemia model based on administration of the nonionic surfactant poloxamer. Neither lipid supplementation nor sucrose supplementation in Wistar rats was effective for establishing hyperlipidemia. Combining both lipid and sucrose supplementation in BALB/c mice induced hypercholesterolemia, as reflected in a considerable increase in blood cholesterol concentration, but did not produce an increase in blood triglyceride concentration. Poloxamer administration in C57BL/J6 mice produced increases in blood cholesterol and triglyceride concentrations. The authors conclude that supplementation of both lipid and sucrose in BALB/c mice was the most effective method for developing chronic hypercholesterolemia. PMID- 25793681 TI - A shift in designing cage-washing operations. AB - Support systems for animal research facilities are often complex and resource intensive operations whose successful design and implementation require substantial experience. The cage-washing center is at the heart of these support spaces and is not only one of the largest spaces found in an animal facility but also one of the greatest consumers of resources, in terms of both utilities and human labor. Certain methodologies and systems for cage-wash operations have become 'go-to' solutions, but alternative approaches have the potential to reduce utility consumption and human labor. The author's firm analyzed cage-washing operations at an academic institution with the goal of reducing consumption of resources, both human labor and utilities such as water, steam and electricity. Here he describes the analysis and design process as a case study and shows that substantial savings can be achieved by using alternative systems in cage-washing systems. He recommends that cage-washing operations can be optimized by thoroughly investigating the anticipated cage-washing throughput and then thoughtfully selecting the most efficient means to handle that workload. PMID- 25793680 TI - The effects of picric acid (2,4,6-trinitrophenol) and a bite-deterrent chemical (denatonium benzoate) on autotomy in rats after peripheral nerve lesion. AB - Denervation of the hind limb is a technique used to study peripheral nerve regeneration. Autotomy or autophagia is an undesirable response to denervation in such studies. Application of a commercially available lotion used to deter nail biting in humans reduced autotomy in rats after denervation but did not completely prevent it. In this study, this authors evaluated the application of picric acid to prevent autotomy in rats in peripheral nerve experiments. They carried out sciatic nerve transection in 41 adult female Wistar rats and then applied either bite-deterrent lotion (n = 26) or saturated picric acid solution (n = 15) topically to the affected hind limb immediately after surgery and every day for 1 month. Autotomy scores were lower for rats treated with picric acid than for rats treated with bite-deterrent lotion 1 week and 2 weeks after surgery but were not different between the two groups 4 weeks after surgery. The authors conclude that application of picric acid could be used as an alternative strategy to prevent autotomy in peripheral nerve studies. PMID- 25793682 TI - Safety training. PMID- 25793683 TI - Us and them. PMID- 25793684 TI - A career with far-reaching effects. PMID- 25793685 TI - Emerging posttraumatic growth: a prospective study with pre- and posttrauma psychological predictors. AB - Posttraumatic growth (PTG) is viewed as a positive psychological change resulting from a struggle with trauma. A number of trauma-related factors have been proven effective in predicting PTG; however, the effects of pretrauma psychological factors on PTG have not been adequately evaluated (e.g., using a prospective design). This prospective study examined the effects of pretrauma psychological factors (e.g., coping styles, prior trauma) on PTG. In total, 810 Taiwanese undergraduate students were recruited for a baseline survey (Time 1), among whom 592 completed a survey 2 months later (Time 2). Data from 110 participants who had experienced trauma between Time1 and Time 2 were used for analysis. Among the pretrauma factors examined at baseline, only rumination and distractive style were positively correlated with PTG. The posttrauma factors based on Calhoun and Tedeschi's model (i.e., core belief challenge, deliberate rumination, and social support) were also positively correlated with PTG. A hierarchical regression analysis showed that pretrauma coping styles had an incremental effect on PTG beyond posttrauma predictors. Deliberate rumination signifciantly mediated the relationship between pretrauma rumination and PTG. These findings highlight the role of pretrauma psychological factors in PTG and present further support for Calhoun and Tedeschi's model of PTG. PMID- 25793687 TI - Loneliness and isolation in life-stories of Israeli veterans of combat and captivity. AB - Loneliness holds detrimental ramifications for health and well-being. Nevertheless, loneliness references in the literature addressing combat-related trauma are few. Consequentially, the qualities and characteristics of such experiences in these posttraumatic realities remain uninvestigated empirically. In the current qualitative study we began filling this gap in the literature. We utilized thematic content analysis of life-stories of 19 combat veterans and 7 ex POWs that have given testimony at the Israel Trauma Center for Victims of Terror and War (NATAL). Our findings suggest that the loneliness in the contexts at hand is primarily characterized by a sense of experiential isolation, rather than social, emotional, or existential. This is the sensation that due to the extraordinary nature of traumatic experiences the fulfillment of needs such as empathy and intersubjectivity may be unattainable. Integrating our findings with existing interdisciplinary literature regarding social sharing, trauma, and loneliness, we discuss implications for clinical interventions and further research. PMID- 25793686 TI - Trajectories of posttraumatic growth and depreciation after two major earthquakes. AB - This study examined trajectories of posttraumatic growth or depreciation (i.e., positive or negative life change) in personal strength and relationships after 2 major earthquakes in Canterbury, New Zealand using group-based trajectory modeling. Participants completed questionnaires regarding posttraumatic growth or depreciation in personal strength and relationship domains 1 month after the first earthquake in September 2010 (N = 185) and 3 months (n = 156) and 12 months (n = 144) after the more severe February 2011 earthquake. Three classes of growth or depreciation patterns were found for both domains. For personal strength, most of the participants were grouped into a "no growth or depreciation" class and smaller proportions were grouped into either a "posttraumatic depreciation" or "posttraumatic growth" class. The 3 classes for relationships all reported posttraumatic growth, differing only in degree. None of the slopes were significant for any of the classes, indicating that levels of growth or depreciation reported after the first earthquake remained stable when assessed at 2 time points after the second earthquake. Multinomial logistic regression analyses examining pre- and postearthquake predictors of trajectory class membership revealed that those in the "posttraumatic growth" personal strength class were significantly younger and had significantly higher pre-earthquake mental health than those in the "posttraumatic depreciation" class. Sex was the only predictor of the relationship classes: No men were assigned to the "high posttraumatic growth" class. Implications and future directions are discussed. PMID- 25793688 TI - Emotion regulation difficulties and posttraumatic stress disorder symptom cluster severity among trauma-exposed college students. AB - The present investigation examined the role of emotion regulation difficulties in predicting severity of the 3 posttraumatic stress disorder (PTSD) symptom clusters (i.e., reexperiencing, hyperarousal, avoidance) in a sample of undergraduates who reported exposure to at least 1 DSM-IV-TR Criterion A traumatic event (n = 297; 77.1% female, Mage = 20.46, SD = 4.64, range = 18-50 years). Results indicated that greater difficulties with emotional acceptance significantly predicted greater avoidance and hyperarousal symptom severity above and beyond the effects of number of trauma types endorsed and negative affect. Emotion regulation difficulties were not significantly predictive of reexperiencing symptom severity. Results from an exploratory analysis indicated that greater difficulties with emotional acceptance and greater difficulties accessing effective emotion regulation strategies when upset significantly predicted the DSM-5 negative alterations in cognitions and mood symptom cluster. These findings suggest that difficulties accepting one's emotional responses, in particular, may heighten emotional responding to and avoidance of trauma-related cues. Thus, individuals who experience such difficulties may be more likely to experience negative outcomes after experiencing a traumatic event. PMID- 25793689 TI - The mediating role of anger in the relationship between PTSD symptoms and impulsivity. AB - Research indicates a significant relationship between posttraumatic stress disorder (PTSD) and anger (Olatunji, Ciesielski, & Tolin, 2010; Orth & Wieland, 2006). Individuals may seek urgent coping to deal with the distress of anger, which is a mobilizing and action-oriented emotion (Novaco & Chemtob, 2002); possibly in the form of impulsive actions consistent with impulsivity's association with anger (Milligan & Waller, 2001; Whiteside & Lynam, 2001). This could be 1 of the explanations for the relationship between PTSD and impulsivity (Kotler, Julian, Efront, & Amir, 2001; Ledgerwood & Petry, 2006). The present study assessed the mediating role of anger between PTSD (overall scores and subscales of arousal and negative alterations in mood/cognitions) and impulsivity, using gender as a covariate of impulsivity. The PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), Dimensions of Anger Reaction scale-5, and the UPPS Impulsivity Scale were administered to a sample of 244 undergraduate students with a trauma history. Results based on 1000 bootstrapped samples indicated significant direct effects of PTSD (overall and 2 subscales) on anger, of anger on impulsivity, and of PTSD (overall and 2 subscales) on impulsivity. Further, anger significantly mediated the relationship between PTSD (overall and 2 subscales) and impulsivity, consistent with the hypothesized models. Results suggest that impulsivity aims at coping with distressing anger, possibly explaining the presence of substance usage, and other impulsive behaviors in people with PTSD. Further, anger probably serves as a mobilizing and action-oriented emotion coupled with PTSD symptoms. PMID- 25793690 TI - The mediating role of anxiety sensitivity in the relation between avoidant coping and posttraumatic stress among trauma-exposed HIV+ individuals. AB - The current study examined the mediating role of anxiety sensitivity in regard to the relation between avoidant coping and posttraumatic stress (PTS) symptoms among trauma-exposed persons living with HIV/AIDS (PLHA). Participants included 103 PLHA (18.4% female, Mage = 48.33, SD = 9.34). Results indicated significant positive indirect effects for avoidant coping through anxiety sensitivity on overall PTS symptoms (point estimate = .27, PB 95% CI [.01, .65]), PTS hyperarousal symptoms (point estimate = .09, PB 95% CI [.01, .21]), and PTS avoidant symptoms (point estimate = .14, PB 95% CI [.03, .30]). The observed findings were statistically significant and evident above and beyond the variance accounted for by CD4 cell count, race, sex, recruitment site, and lifetime number of traumatic events experienced. The results may indicate that avoidant coping affects PTS symptoms through anxiety sensitivity among trauma-exposed PLHA. These findings highlight the importance of anxiety sensitivity in relation to PTS symptoms among PLHA, and the possibility of adapting anxiety sensitivity reduction training for PTS symptoms among PLHA. PMID- 25793691 TI - PTSD personality subtypes in women exposed to intimate-partner violence. AB - There is considerable research implicating posttraumatic stress disorder (PTSD) as a common reaction to intimate-partner violence (IPV; Golding, 1999). PTSD is categorized as a single disorder; however, there is significant heterogeneity in its symptom-presentation patterns (Dickstein, Suvak, Litz, & Adler, 2010). Researchers have posited underlying personality characteristics as potentiating different expressions of PTSD (Miller, Greif, & Smith, 2003). Specifically, a model with 3 personality subtypes (i.e., externalizing, internalizing, and simple) has been proposed to explain PTSD symptom-pattern heterogeneity (Miller, 2003; Miller & Resick, 2007). The current study tested the PTSD personality subtype model in a sample of 129 women exposed to a range of IPV experiences. Temperament patterns of women reporting clinically significant PTSD symptoms replicated the 3 personality-subtype patterns found in previous investigations (i.e., an externalizing subtype group characterized by high negative emotionality and low disinhibition, an internalizing subtype group characterized by high negative emotionality and low positive emotionality, and a simple subtype group characterized by midrange scores across the temperament variables; Miller et al., 2003; Miller, Kaloupek, Dillon, & Keane, 2004; Miller & Resick, 2007). Differences between personality-subtype groups and women without clinically significant PTSD symptoms were found (p < .05), with women reporting personality patterns consistent with the internalizing and externalizing subtype groups exhibiting higher comorbid personality pathology and psychological difficulties. Implications are discussed for personality as a risk or resiliency factor in PTSD and as contributing to explaining PTSD symptom heterogeneity. PMID- 25793692 TI - Sexual assault-characteristics effects on PTSD and psychosocial mediators: a cluster-analysis approach to sexual assault types. AB - Using cluster analysis, we investigated the effects of assault characteristics (i.e., level of violence, subjective distress, alcohol consumption, perpetrator identity) on PTSD symptoms, and whether these effects are mediated by postassault social and psychological reactions. A large community sample of women sexual assault survivors completed 2 mail surveys at a 1-year interval. In line with prior research, cluster analyses revealed the existence of 3 general categories of sexual assault, which we described as "high violence," "alcohol-related," and "moderate sexual severity." Alcohol-related assaults resulted in fewer PTSD symptoms than high-violence assaults at Time 1, but not at Time 2. Alcohol related and violent assaults resulted in more PTSD symptoms than moderate severity assaults at both times. The effect of assault-characteristics clusters on Time 2 PTSD was mediated by Time 1 self-blame and turning against social reactions. The importance of considering effects of violence and alcohol consumption during the assault to better understand postassault PTSD, including implications for theory and practice, are discussed. PMID- 25793693 TI - Correction to peter-hagene and ullman (2014). AB - Reports an error in "Sexual Assault-Characteristics Effects on PTSD and Psychosocial Mediators: A Cluster-Analysis Approach to Sexual Assault Types" by Liana C. Peter-Hagene and Sarah E. Ullman (Psychological Trauma: Theory, Research, Practice, and Policy, Advanced Online Publication, Aug 18, 2014, np). In the article, there was an error in the abstract. The second to last sentence should have read, "The effect of assault-characteristics clusters on Time 2 PTSD was mediated by Time 1 self-blame and turning against social reactions." (The following abstract of the original article appeared in record 2014-33772-001.) Using cluster analysis, we investigated the effects of assault characteristics (i.e., level of violence, subjective distress, alcohol consumption, perpetrator identity) on PTSD symptoms, and whether these effects are mediated by postassault social and psychological reactions. A large community sample of women sexual assault survivors completed 2 mail surveys at a 1-year interval. In line with prior research, cluster analyses revealed the existence of 3 general categories of sexual assault, which we described as "high violence," "alcohol-related," and "moderate sexual severity." Alcohol-related assaults resulted in fewer PTSD symptoms than high-violence assaults at Time 1, but not at Time 2. Alcohol related and violent assaults resulted in more PTSD symptoms than moderate severity assaults at both times. The effect of assault-characteristics clusters on Time 2 PTSD was mediated by Time 1 self-blame and turning against social reactions. The importance of considering effects of violence and alcohol consumption during the assault to better understand postassault PTSD, including implications for theory and practice, are discussed. (PsycINFO Database Record PMID- 25793694 TI - Tonic immobility among survivors of sexual assault. AB - While tonic immobility (TI) is a phenomenon well known and documented in the animal world, far less is known about its manifestation in humans. Available literature demonstrates that TI is significantly associated with less hopeful prognoses when compared with survivors who did not experience TI (Fiszman et al., 2008; Heidt et al., 2005). If survivors who experience TI are at increased risk for "depression, anxiety, posttraumatic stress disorder (PTSD), and peritraumatic dissociation" (Heidt et al., 2005, p. 1166) and respond more poorly "to standard pharmacological treatment for PTSD" (Fiszman et al., 2008, p. 196), the implications for treatment are significant, suggesting that TI "should be routinely assessed in traumatized patients" (Fiszman et al., 2008, p. 193). Literature indicates that "TI is thought to be particularly relevant to survivors of rape and other sexual assault" and that "sexual assault is a trauma that appears to entail virtually all of the salient elements associated with the induction of TI in nonhuman animals, namely, fear, contact, and restraint" (Marx et al., 2008, p. 79). Describing the phenomenon as it is experienced by survivors is especially important because the ability to accurately understand and describe the nature of the phenomenon is the first step toward accurately identifying, diagnosing, and treating the sequelae of such a response. This study examines the experience of TI from the perspective of 7 women who survived a sexual assault accompanied by tonic immobility using qualitative phenomenological methodology, and yields a description of the core defining themes of the experience of TI. PMID- 25793695 TI - Persistent grief in the aftermath of mass violence: the predictive roles of posttraumatic stress symptoms, self-efficacy, and disrupted worldview. AB - This study tested a conceptual model merging anxiety buffer disruption and social cognitive theories to predict persistent grief severity among students who lost a close friend, significant other, and/or professor/teacher in tragic university campus shootings. A regression-based path model tested posttraumatic stress (PTS) symptom severity 3 to 4 months postshooting (Time 1) as a predictor of grief severity 1 year postshootings (Time 2), both directly and indirectly through cognitive processes (self-efficacy and disrupted worldview). Results revealed a model that predicted 61% of the variance in Time 2 grief severity. Hypotheses were supported, demonstrating that Time 1 PTS severity indirectly, positively predicted Time 2 grief severity through undermining self-efficacy and more severely disrupting worldview. Findings and theoretical interpretation yield important insights for future research and clinical application. PMID- 25793696 TI - Secondary traumatization among ex-POWs' adult children: the mediating role of differentiation of the self. AB - The aversive impact of combat and parents' combat-induced posttraumatic stress disorder on young children has been examined in a few studies. However, the long term toll of war captivity on secondary traumatization (ST) and the mediating role of differentiation of the self remain unknown. This study examined ST symptoms and differentiation of the self (DS) among adult children of former prisoners of war (ex-POW's children) who were compared with adult children of comparable veterans (controls' children). Furthermore, I examined the mediating role of DS dimensions in the association between exposure to stress and ST symptoms. Participants were Israeli ex-POW's children (n = 98) and controls' children (n = 90), whose fathers fought in the 1973 Yom Kippur War. Results showed that ex-POW's children reported a higher number of ST symptoms and lower levels of emotional cutoff differentiation compared with controls' children. Emotional cutoff was also found to mediate the association between research group and ST symptoms. Among ex-POW's children, emotional cutoff and emotional reactivity dimensions mediated the association between exposure to stress stemming from fathers' behaviors and ST symptoms. Forty years after the war ended, the experience of living with ex-POWs is associated with ex-POW's children ST symptoms. PMID- 25793697 TI - Postdoctoral training in posttraumatic stress disorder research. AB - Postdoctoral training is increasingly common in the field of psychology. Although many individuals pursue postdoctoral training in psychology, guidelines for research training programs at this level do not exist. The rapid advances in the field, particularly with respect to genetics, neuroimaging, and data analytic approaches, require clinical scientists to possess knowledge and expertise across a broad array of areas. Postdoctoral training is often needed to acquire such a skill set. This paper describes a postdoctoral training program designed for individuals pursuing academic careers in traumatic stress disorders research. In this paper, we describe the structure of our training program, challenges we have faced during the 15 years of its existence, and how we have addressed these challenges. We conclude with a presentation of outcome data for the training program and a discussion of how training programs in other settings might be structured. PMID- 25793698 TI - Correction: fish sound production in the presence of harmful algal blooms in the eastern Gulf of Mexico. PMID- 25793699 TI - Testing the relationship between human occupancy in the landscape and tadpole developmental stress. AB - Amphibian population declines are widespread; the main causal factors are human related and include habitat fragmentation due to agriculture, mining, fires, and urban development. Brazil is the richest country in species of amphibians, and the Brazilian regions with the greatest amphibian diversity are experiencing relatively high rates of habitat destruction, but there are presently relatively few reports of amphibian declines. It is thus important to develop research methods that will detect deterioration in population health before severe declines occur. We tested the use of measurements of fluctuating asymmetry (FA) taken on amphibian larvae to detect anthropogenic stress. We hypothesized that greater human occupancy in the landscape might result in more stressful conditions for amphibians. We conducted this study at the Espinhaco mountain range in southeastern Brazil, using as a model an endemic species (Bokermannohyla saxicola, Hylidae). We chose two tadpole denticle rows and eye-nostril distance as traits for FA measurement. We measured percent cover of human-altered habitats in the landscape around tadpole sampling points and measured FA levels in sampled tadpoles. We found FA levels to differ among localities but found no relationship between human modification of the landscape and tadpole FA levels. Levels of FA in the traits we examined may not be strongly affected by environmental conditions, or may be affected by local variables that were not captured by our landscape-scale measures. Alternatively, populations may be genetically differentiated, affecting how FA levels respond to stress and obscuring the effects of anthropogenic disturbance. PMID- 25793700 TI - Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique. AB - INTRODUCTION: We investigated the role of pancreatic stone protein (PSP) in predicting the occurrence of infection in the postoperative course of cardiac surgery patients. Several biomarkers indicating the presence of inflammation and infection are available in the clinical routine; yet, their utility in the postoperative course of patients following cardiac surgery remains uncertain. Moreover, cardiopulmonary bypass, also referred to as "on-pump surgery", increases the susceptibility to an exaggerated inflammatory state. However, the impact of such extracorporeal circulation on circulating PSP levels remains poorly understood. METHODS: In a prospective cohort of unselected patients undergoing cardiac surgery, we set out to elucidate the diagnostic accuracy of serum PSP levels as opposed to canonical biomarkers (CRP, WBC) of inflammation to discriminate between the presence of infection and surgical trauma,. In addition, we investigated whether the biomarkers were influenced by the surgical technique employed, i.e. on-pump vs. off-pump and minimally invasive surgery vs. sternotomy. Levels of circulating PSP and routine inflammatory biomarkers (CRP, WBC) were measured in samples taken from 120 patients at baseline as well as at postoperative day 1-3. RESULTS: Univariate analysis showed that among the biomarkers investigated, only PSP levels had discriminatory power to differentiate infection from surgical trauma in the postoperative course of the entire cohort of patients following cardiac surgery. With regard to cardiac surgical interventions, there was no significant association between the absence or presence of extracorporeal circulation and PSP levels. However, there was a significant difference in the slope of the rise of postoperative PSP between minimally invasive surgery as opposed to patients subjected to sternotomy. CONCLUSION: In an unselected population of cardiac surgery patients, post operative serum PSP levels were significantly associated with the presence of infection in both the on-pump and off-pump setting. Of note, the surgical technique employed (sternotomy vs. minimally invasive approach) had a significant impact on postoperative PSP levels. PMID- 25793701 TI - Intestinal fatty acid-binding protein as a diagnostic marker for complicated and uncomplicated necrotizing enterocolitis: a prospective cohort study. AB - BACKGROUND: Early NEC symptoms are non-specific and diagnostic tests lack discriminative power. Intestinal fatty acid-binding protein (I-FABP), mainly located in small bowel enterocytes, is released into the blood following NEC associated enterocyte disruption. Aim of this prospective cohort trial was to determine the diagnostic value of I-FABP measured in plasma (I-FABPp) and urine (I-FABPu) for the presence of NEC, to evaluate I-FABP levels during NEC development, and to assess its prognostic value for the progression from suspected to complicated disease. METHODS: Between 2010 and 2012 we prospectively enrolled neonates with suspected NEC. We measured I-FABP levels eight-hourly from onset of suspected NEC for at least 48 hours, or until surgery. NEC diagnosis was confirmed radiologically or during operation. We defined NEC as complicated if it resulted in surgery and/or death. We determined disease course and diagnostic I FABP cut-off points. RESULTS: The study comprised 37 neonates (24M, 13F), gestational age 28 (24-36) weeks, birth weight 1190 (570-2,400) grams. We found significantly higher I-FABPp and I-FABPu levels in NEC patients (n = 22) than in patients with other diagnoses (n = 15). Cut-off values for diagnosing NEC were 9 ng/mL I-FABPp and 218 ng/mL I-FABPu, with corresponding likelihood ratios (LRs) of 5.6 (95% CI 0.89-35) and 5.1 (95% CI 0.73-36), respectively. I-FABP levels were highest in the first eight hours after symptom onset and gradually decreased over time. Cut-off values for complicated disease were 19 ng/mL I-FABPp and 232 ng/mL I-FABPu, with LRs of 10 (95% CI 1.6-70) and 11 (95% CI 1.6-81), respectively. CONCLUSIONS: Both plasma and urinary I-FABP levels specifically identify NEC in preterm infants prior to appearance of diagnostic radiological signs suggestive for NEC. Moreover, serial I-FABP measurements accurately predict development of complicated disease. PMID- 25793702 TI - Treponema pallidum subsp. pallidum TP0136 protein is heterogeneous among isolates and binds cellular and plasma fibronectin via its NH2-terminal end. AB - Adherence-mediated colonization plays an important role in pathogenesis of microbial infections, particularly those caused by extracellular pathogens responsible for systemic diseases, such as Treponema pallidum subsp. pallidum (T. pallidum), the agent of syphilis. Among T. pallidum adhesins, TP0136 is known to bind fibronectin (Fn), an important constituent of the host extracellular matrix. To deepen our understanding of the TP0136-Fn interaction dynamics, we used two naturally-occurring sequence variants of the TP0136 protein to investigate which region of the protein is responsible for Fn binding, and whether TP0136 would adhere to human cellular Fn in addition to plasma Fn and super Fn as previously reported. Fn binding assays were performed with recombinant proteins representing the two full-length TP0136 variants and their discrete regions. As a complementary approach, we tested inhibition of T. pallidum binding to Fn by recombinant full-length TP0136 proteins and fragments, as well as by anti-TP0136 immune sera. Our results show that TP0136 adheres more efficiently to cellular Fn than to plasma Fn, that the TP0136 NH2-terminal conserved region of the protein is primarily responsible for binding to plasma Fn but that binding sites for cellular Fn are also present in the protein's central and COOH-terminal regions. Additionally, message quantification studies show that tp0136 is highly transcribed during experimental infection, and that its message level increases in parallel to the host immune pressure on the pathogen, which suggests a possible role for this protein in T. pallidum persistence. In a time where syphilis incidence is high, our data will help in the quest to identify suitable targets for development of a much needed vaccine against this important disease. PMID- 25793704 TI - Characterization of Tunga penetrans antigens in selected epidemic areas in Murang'a county in Kenya. AB - Tunga penetrans are fleas that cause tungiasis, a condition characterized by high transmission rate due to poor housing conditions, social neglect and inadequate health care in economically disadvantaged communities in developing countries. This study therefore aimed at characterizing jiggers antigens to identify immunodominant ones to help understand immunological behavior of the parasite that would otherwise be important in future control of the parasite. Samples were gravid fleas and blood samples from infested individuals in Kahuro and Murang'a East district in Murang'a County. Freeze and thaw was used to extract soluble proteins from the fleas. Ouchterlony Double immunodiffusion was used to assess antigen-antibody reactions between extracted soluble protein and the serum from immunized rats, Rattus norvegicus prior to analysis of human sera. These results were comparable to results of immunoelectrphoresis. Jigger protein isolates were analyzed in Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis technique (SDS-PAGE), against Pharmacia standard protein markers. Further analysis of jigger antigens against pooled human sera from infested victims in Western blot revealed three immunodominant antigens. Using simple regression analysis molecular weights of the three immunodominant antigens were estimated as 51.795, 23.395 and 15.38 kDa respectively. These results are important since they would help understand immunological behavior of the parasites. This would help to create basis for designing and improving approaches against jiggers such as development of immune prophylaxis to complement social science approaches that is mainly concerned with maintenance of high standards of hygiene. PMID- 25793703 TI - Survival, morbidity, growth and developmental delay for babies born preterm in low and middle income countries - a systematic review of outcomes measured. AB - BACKGROUND: Premature birth is the leading cause of neonatal death and second leading in children under 5. Information on outcomes of preterm babies surviving the early neonatal period is sparse although it is considered a major determinant of immediate and long-term morbidity. METHODS: Systematic review of studies reporting outcomes for preterm babies in low and middle income settings was conducted using electronic databases, citation tracking, expert recommendations and "grey literature". Reviewers screened titles, abstracts and articles. Data was extracted using inclusion and exclusion criteria, study site and facilities, assessment methods and outcomes of mortality, morbidity, growth and development. The Child Health Epidemiology Reference Group criteria (CHERG) were used to assess quality. FINDINGS: Of 197 eligible publications, few (10.7%) were high quality (CHERG). The majority (83.3%) report on the outcome of a sample of preterm babies at time of birth or admission. Only 16.0% studies report population-based data using standardised mortality definitions. In 50.5% of studies, gestational age assessment method was unclear. Only 15.8% followed-up infants for 2 years or more. Growth was reported using standardised definitions but recommended morbidity definitions were rarely used. The criteria for assessment of neurodevelopmental outcomes was variable with few standardised tools - Bayley II was used in approximately 33% of studies, few studies undertook sensory assessments. CONCLUSIONS: To determine the relative contribution of preterm birth to the burden of disease in children and to inform the planning of healthcare interventions to address this burden, a renewed understanding of the assessment and documentation of outcomes for babies born preterm is needed. More studies assessing outcomes for preterm babies who survive the immediate newborn period are needed. More consistent use of data is vital with clear and aligned definitions of health outcomes in newborn (preterm or term) and intervention packages aimed to save lives and improve health. PMID- 25793706 TI - Reactions of Co(III)-nitrosyl complexes with superoxide and their mechanistic insights. AB - New Co(III)-nitrosyl complexes bearing N-tetramethylated cyclam (TMC) ligands, [(12-TMC)Co(III)(NO)](2+) (1) and [(13-TMC)Co(III)(NO)](2+) (2), were synthesized via [(TMC)Co(II)(CH3CN)](2+) + NO(g) reactions. Spectroscopic and structural characterization showed that these compounds bind the nitrosyl moiety in a bent end-on fashion. Complexes 1 and 2 reacted with KO2/2.2.2-cryptand to produce [(12 TMC)Co(II)(NO2)](+) (3) and [(13-TMC)Co(II)(NO2)](+) (4), respectively; these possess O,O'-chelated nitrito ligands. Mechanistic studies using (18)O-labeled superoxide ((18)O2(*-)) showed that one O atom in the nitrito ligand is derived from superoxide and the O2 produced comes from the other superoxide O atom. Evidence supporting the formation of a Co-peroxynitrite intermediate is also presented. PMID- 25793705 TI - A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. AB - BACKGROUND: Although myocarditis/pericarditis (MP) has been identified as an adverse event following smallpox vaccine (SPX), the prospective incidence of this reaction and new onset cardiac symptoms, including possible subclinical injury, has not been prospectively defined. PURPOSE: The study's primary objective was to determine the prospective incidence of new onset cardiac symptoms, clinical and possible subclinical MP in temporal association with immunization. METHODS: New onset cardiac symptoms, clinical MP and cardiac specific troponin T (cTnT) elevations following SPX (above individual baseline values) were measured in a multi-center prospective, active surveillance cohort study of healthy subjects receiving either smallpox vaccine or trivalent influenza vaccine (TIV). RESULTS: New onset chest pain, dyspnea, and/or palpitations occurred in 10.6% of SPX vaccinees and 2.6% of TIV-vaccinees within 30 days of immunization (relative risk (RR) 4.0, 95% CI: 1.7-9.3). Among the 1081 SPX-vaccinees with complete follow-up, 4 Caucasian males were diagnosed with probable myocarditis and 1 female with suspected pericarditis. This indicates a post-SPX incidence rate more than 200 times higher than the pre-SPX background population surveillance rate of myocarditis/pericarditis (RR 214, 95% CI 65-558). Additionally, 31 SPX-vaccinees without specific cardiac symptoms were found to have over 2-fold increases in cTnT (>99th percentile) from baseline (pre-SPX) during the window of risk for clinical myocarditis/pericarditis and meeting a proposed case definition for possible subclinical myocarditis. This rate is 60-times higher than the incidence rate of overt clinical cases. No clinical or possible subclinical myocarditis cases were identified in the TIV-vaccinated group. CONCLUSIONS: Passive surveillance significantly underestimates the true incidence of myocarditis/pericarditis after smallpox immunization. Evidence of subclinical transient cardiac muscle injury post-vaccinia immunization is a finding that requires further study to include long-term outcomes surveillance. Active safety surveillance is needed to identify adverse events that are not well understood or previously recognized. PMID- 25793707 TI - Effect of intravenous sodium valproate vs dexamethasone on acute migraine headache: a double blind randomized clinical trial. AB - BACKGROUND: Despite the impact of sodium valproate and dexamethasone on migraine headache, the efficacy of the two drugs has not been properly investigated and compared. This trial compared the effect of the two drugs on acute migraine headache. METHODS: This double blind randomized clinical trial was conducted on patients aged 18 to 65 years with acute migraine headache who referred to the emergency departments of Beasat and Farshchian Hospitals in Hamadan, Iran, from April 2012 to June 2014. Patients were randomly assigned to receive a single-dose of either 400 mg sodium valproate or 16 mg dexamethasone plus 50 ml saline normal solution within 15 min intravenously. The severity of headache in the two groups was evaluated at baseline, 0.5 and 2 hours later using the Visual Analog Scale (VAS) on a scale of 0 to 10. RESULTS: Of 104 patients enrolled, 72 patients remained for analysis. The effect of both sodium valproate and dexamethasone on acute migraine headache was statistically significant at 0.5 and 2 hours post treatment compared to pre-treatment (P=0.001). The severity of headache based on VAS reduced form 8.20 (7.72, 8.68) before treatment to 5.31 (4.74, 5.89) and 3.66 (2.99, 4.33) at 0.5 and 2 hours after treatment, respectively, in patients receiving sodium valproate and from 8.46 (8.05, 8.86) before treatment to 5.46 (4.81, 6.11) and 3.59 (2.84, 4.35) at 0.5 and 2 hours after treatment, respectively, in patients receiving dexamethasone. Both drugs were highly effective in improvement of acute headache in patients without aura. However, sodium valproate significantly improved the acute headache in patients with aura but dexamethasone did not. The severity of headache based on VAS reduced form 8.50 (7.40, 9.60) before treatment to 4.67 (2.40, 6.93) and 3.50 (1.78, 5.22) at 0.5 and 2 hours after treatment, respectively, in patients with aura receiving sodium valproate and from 8.80 (7.76, 9.84) before treatment to 7.20 (4.98, 9.42) and 6.20 (2.43, 9.97) at 0.5 and 2 hours after treatment, respectively, in patients with aura receiving dexamethasone. CONCLUSIONS: This trial indicated that, in overall, intravenous sodium valproate is not superior to intravenous dexamethasone in treatment of acute migraine attacks. However, in patients with aura, only sodium valproate but not dexamethasone is effective in headache relief. This issue needs further investigations. TRIAL REGISTRATION: ClinicalTrials.gov IRCT201202199014N1. PMID- 25793708 TI - Correction: Socio-psychological factors driving adult vaccination: a qualitative study. PMID- 25793709 TI - Interpolymer complexation: comparisons of bulk and interfacial structures. AB - The interactions between the strong polyelectrolyte sodium poly(styrenesulfonate), NaPSS, and the neutral polymer poly(vinylpyrrolidone), PVP, were investigated in bulk and at the silica/solution interface using a combination of diffusion nuclear magnetic resonance spectroscopy (NMR), small angle neutron scattering (SANS), solvent relaxation NMR, and ellipsometry. We show for the first time that complex formation occurs between NaPSS and PVP in solution; the complexes formed were shown not to be influenced by pH variation, whereas increasing the ionic strength increases the complexation of NaPSS but does not influence the PVP directly. The complexes formed contained a large proportion of NaPSS. Study of these interactions at the silica interface demonstrated that complexes also form at the nanoparticle interface where PVP is added in the system prior to NaPSS. For a constant PVP concentration and varying NaPSS concentration, the system remains stable until NaPSS is added in excess, which leads to depletion flocculation. Surface complex formation using the layer by-layer technique was also reported at a planar silica interface. PMID- 25793710 TI - The use of MAGE C1 and flow cytometry to determine the malignant cell type in multiple myeloma. AB - The malignant cell phenotype of Multiple Myeloma (MM) remains unclear with studies proposing it to be either clonotypic B or proliferating plasma cells. Cancer/testis antigen MAGE C1 is being extensively studied in MM and it has been suggested that it is involved in the pathogenesis of the cancer. Therefore, we report on the use of MAGE C1 to determine the malignant cell phenotype in MM using flow cytometry. Bone marrow aspirate (BM) and peripheral blood (PB) was collected from twelve MM patients at diagnosis, as well as three MM disease-free controls. Mononuclear cells were isolated using density-gradient centrifugation, and stabilized in 80% ethanol, before analysis via flow cytometry using relevant antibodies against B cell development cell-surface markers and nuclear MAGE C1. MAGE C1 expression was observed consistently in the early stem cells (CD34+) and early pro-B to pre-B cells (CD34+/-/CD19+), as well as the proliferating plasma cells in both the MM PB and BM, while no expression was observed in the corresponding control samples. Monoclonality indicated a common origin of these cell types suggesting that the CD34+/MAGE C1+ are the primary malignant cell phenotype that sustains the downstream B cell maturation processes. Furthermore, this malignant cell phenotype was not restricted to the BM but also found in the circulating PB cells. PMID- 25793711 TI - Genetic variants in miRNA processing genes and pre-miRNAs are associated with the risk of chronic lymphocytic leukemia. AB - Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in DROSHA, rs1057035 in DICER1, rs17676986 in SND1, rs9611280 in TNRC6B, rs784567 in TRBP and rs11866002 in CNOT1) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings. PMID- 25793712 TI - Genetic diversity of grasspea and its relative species revealed by SSR markers. AB - The study of genetic diversity between Lathyrus sativus L. and its relative species may yield fundamental insights into evolutionary history and provide options to meet the challenge of climate changes. 30 SSR loci were employed to assess the genetic diversity and population structure of 283 individuals from wild and domesticated populations from Africa, Europe, Asia and ICARDA. The allele number per loci ranged from 3 to 14. The average gene diversity index and average polymorphism information content (PIC) was 0.5340 and 0.4817, respectively. A model based population structure analysis divided the germplasm resources into three subgroups: the relative species, the grasspea from Asia, and the grasspea from Europe and Africa. The UPGMA dendrogram and PCA cluster also demonstrated that Asian group was convincingly separated from the other group. The AMOVA result showed that the cultivated species was quite distinct from its relative species, however a low level of differentiation was revealed among their geographic origins. In all, these results provided a molecular basis for understanding genetic diversity of L. sativus and its relatives. PMID- 25793714 TI - Ron Hites: Gas Chromatography/Mass Spectrometry Pioneer and the Great Detector Debate. PMID- 25793713 TI - Overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) correlates with cell aggressiveness and poor survival in gastric cancer. AB - Eukaryotic translation initiation factor 5A2 (EIF5A2) plays an important role in tumor progression and prognosis evaluation. However, little information is available about its potential role in gastric cancer. This study aimed to investigate the function of EIF5A2 in tumor progression and its potential mechanisms. EIF5A2 expression was measured in human gastric cancer cell lines, the immortalized gastric mucosal epithelial cell line (GES-1) and human gastric cancer tissues and knocked down by RNA interference or upregulated by EIF5A2 plasmid transfection. Cell proliferation, migration and invasion were assessed in vitro. The downstream targets of EIF5A2 were examined by western blotting. EIF5A2 and its potential target metastasis-associated protein 1 (MTA1) expression were examined in 160 pairs of human gastric cancer and adjacent non-tumor specimens using immunohistochemistry (IHC) staining, and its correlation with clinicopathological features and survival was investigated. Knockdown of EIF5A2 or MTA1 caused an apparent suppression of HGC27 cell proliferation, migration and invasion. After knockdown of EIF5A2 in HGC27 cells, E-cadherin levels were upregulated and vimentin, cyclin D1, cyclin D3, C-MYC and MTA1 levels were downregulated. Upregulation of EIF5A2 in MKN45 cells resulted in the converse. IHC results showed a positive correlation between EIF5A2 and MTA1 expression in gastric cancers (P<0.001). Both EIF5A2 and MTA1 overexpression were correlated with pT stage (P=0.018 and P=0.042), pN stage (P=0.037 and P=0.020) and lymphovascular invasion (P=0.016 and P=0.044). EIF5A2 or MTA1 overexpression was significantly associated with poor overall survival and disease-free survival (All P<0.05). Multivariate analyses identified EIF5A2 as an independent predictor for both overall survival (P=0.012) and disease-free survival (P=0.008) in gastric cancer patients. Our findings indicate that EIF5A2 upregulation plays an important oncogenic role in gastric cancer. EIF5A2 may represent a new predictor for poor survival and is a potential therapeutic target for gastric cancer. PMID- 25793715 TI - Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. AB - Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham's chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A beta-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control's 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group's 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform movements and elevated antibodies against D2R; 2) the originally reported group with choreiform movements and elevated anti-D2R antibodies, similar to SC. Increased antibody mediated CaMKII activation was found in both groups and requires further study as a potential biomarker. PMID- 25793716 TI - Experimental study on differences in clivus chordoma bone invasion: an iTRAQ based quantitative proteomic analysis. AB - Although a bone tumor, significant differences in the extent of bone invasion exist in skull base chordoma, which directly affect the extent of surgical resection, and have an impact on its prognosis. However, the underlying mechanism of the phenomenon is not clearly understood. Therefore, we used an iTRAQ-based quantitative proteomics strategy to identify potential molecular signatures, and to find predictive markers of discrepancy in bone invasion of clivus chordoma. According to bone invasive classification criteria, 35 specimens of clivus chordoma were calssified to be either endophytic type (Type I) or exophytic type (Type II). An initial screening of six specimens of endophytic type and six of exophytic was performed, and 250 differentially expressed proteins were identified. Through the GO and IPA analysis, we found evidence that the expression of inflammatory activity-associated proteins up-regulated in endophytic type, whereas the expression of cell motility-associated proteins up regulated in exophytic ones. Moreover, TGFbeta1 and mTOR signal pathway seemed to be related with bone invasion. Thus, TGFbeta1, PI3K, Akt, mTOR, and PTEN were validated in the following 23 samples by immune histochemistry and Western blot. The expression levels of TGFbeta1 and PTEN were significantly lower in the endophytic type than in the exophytic ones. It was found that TGFbeta1 may play an important role in its bone invasion. The mechanisms may be related with conducting an increased inflammatory cell response and a decline in cytoskeletal protein expression. PTEN is confirmed to be associated with the degree of bone invasion. The PI3K/AKT/mTOR signaling pathway might be associated with the bone invasion, but still needs a larger sample size to be verified These results, for the first time, not only demonstrate the biological changes that occur in different growth patterns from the perspective of proteomics, but also provide novel markers that may help to reveal the mechanisms behind clivus chordomas. PMID- 25793717 TI - Humoral immunity links Candida albicans infection and celiac disease. AB - OBJECTIVE: The protein Hwp1, expressed on the pathogenic phase of Candida albicans, presents sequence analogy with the gluten protein gliadin and is also a substrate for transglutaminase. This had led to the suggestion that C. albicans infection (CI) may be a triggering factor for Celiac disease (CeD) onset. We investigated cross-immune reactivity between CeD and CI. METHODS: Serum IgG levels against recombinant Hwp1 and serological markers of CeD were measured in 87 CeD patients, 41 CI patients, and 98 healthy controls (HC). IgA and IgG were also measured in 20 individuals from each of these groups using microchips sensitized with 38 peptides designed from the N-terminal of Hwp1. RESULTS: CI and CeD patients had higher levels of anti-Hwp1 (p=0.0005 and p=0.004) and anti gliadin (p=0.002 and p=0.0009) antibodies than HC but there was no significant difference between CeD and CI patients. CeD and CI patients had higher levels of anti-transglutaminase IgA than HC (p=0.0001 and p=0.0039). During CI, the increase in anti-Hwp1 paralleled the increase in anti-gliadin antibodies. Microchip analysis showed that CeD patients were more reactive against some Hwp1 peptides than CI patients, and that some deamidated peptides were more reactive than their native analogs. Binding of IgG from CeD patients to Hwp1 peptides was inhibited by gammaIII gliadin peptides. CONCLUSIONS: Humoral cross-reactivity between Hwp1 and gliadin was observed during CeD and CI. Increased reactivity to Hwp1 deamidated peptide suggests that transglutaminase is involved in this interplay. These results support the hypothesis that CI may trigger CeD onset in genetically-susceptible individuals. PMID- 25793718 TI - Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis. AB - Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis. PMID- 25793719 TI - Patterns of Recurrence After Resection of IPMN: Who, When, and How? AB - OBJECTIVE: To describe the patterns of recurrence after resection of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. BACKGROUND: IPMNs represent an increasing indication for pancreatic resection, but little is known about the actual incidence and the patterns of recurrence after surgical excision. METHODS: Retrospective review of 412 resected IPMNs from 1990 to 2013 who have had near complete follow-up. RESULTS: Median age of the cohort was 68 years, 56% had branch duct (BD)-IPMN and 21% had invasive cancers. Nineteen patients (5%) had distinct pancreatic ductal adenocarcinoma (PDAC) and were excluded from the recurrence analysis. After a median of 58 months, 65 of 381 patients (17%) experienced recurrence of the IPMN, and 5- and 10-year disease-free survival (DFS) was 82% and 78%, respectively. Only 2 patients (0.5%) developed metachronous PDAC. In 33 patients (9%), a residual BD-IPMN was left in the pancreatic remnant, but none of these significantly grew or required reoperation. Invasive component and resection margin positive for IPMN were predictors of recurrence (P < 0.05). Invasive IPMN recurred in 45% of cases, whereas noninvasive in only 9% and later (P < 0.001), but patterns depended on IPMN subtypes. Only 9 patients required reoperation for recurrence, with good long term outcome particularly for oncocytic IPMNs. CONCLUSIONS: Recurrence of noninvasive BD-IPMN is infrequent and surveillance may be avoided in selected cases. In invasive IPMN recurrence depends on N status, pancreatic margin, and invasive type. PMID- 25793721 TI - Correction: establishment of trophoblast stem cells under defined culture conditions in mice. PMID- 25793720 TI - Microporous dermal-mimetic electrospun scaffolds pre-seeded with fibroblasts promote tissue regeneration in full-thickness skin wounds. AB - Electrospun scaffolds serve as promising substrates for tissue repair due to their nanofibrous architecture and amenability to tailoring of chemical composition. In this study, the regenerative potential of a microporous electrospun scaffold pre-seeded with dermal fibroblasts was evaluated. Previously we reported that a 70% collagen I and 30% poly(E-caprolactone) electrospun scaffold (70:30 col/PCL) containing 160 MUm diameter pores had favorable mechanical properties, supported fibroblast infiltration and subsequent cell mediated deposition of extracellular matrix (ECM), and promoted more rapid and effective in vivo skin regeneration when compared to scaffolds lacking micropores. In the current study we tested the hypothesis that the efficacy of the 70:30 col/PCL microporous scaffolds could be further enhanced by seeding scaffolds with dermal fibroblasts prior to implantation into skin wounds. To address this hypothesis, a Fischer 344 (F344) rat syngeneic model was employed. In vitro studies showed that dermal fibroblasts isolated from F344 rat skin were able to adhere and proliferate on 70:30 col/PCL microporous scaffolds, and the cells also filled the 160 MUm pores with native ECM proteins such as collagen I and fibronectin. Additionally, scaffolds seeded with F344 fibroblasts exhibited a low rate of contraction (~14%) over a 21 day time frame. To assess regenerative potential, scaffolds with or without seeded F344 dermal fibroblasts were implanted into full thickness, critical size defects created in F344 hosts. Specifically, we compared: microporous scaffolds containing fibroblasts seeded for 4 days; scaffolds containing fibroblasts seeded for only 1 day; acellular microporous scaffolds; and a sham wound (no scaffold). Scaffolds containing fibroblasts seeded for 4 days had the best response of all treatment groups with respect to accelerated wound healing, a more normal-appearing dermal matrix structure, and hair follicle regeneration. Collectively these results suggest that microporous electrospun scaffolds pre-seeded with fibroblasts promote greater wound-healing than acellular scaffolds. PMID- 25793722 TI - Human outbreak of Salmonella Typhimurium associated with exposure to locally made chicken jerky pet treats, New Hampshire, 2013. AB - Pet treats and pet food can be contaminated with Salmonella and other pathogens, though they are infrequently implicated as the source of human outbreaks. In 2013, the New Hampshire Department of Health and Human Services investigated a cluster of Salmonella Typhimurium infections associated with contaminated locally made pet treats. Case-patients were interviewed with standardized questionnaires to assess food, animal, and social histories. Laboratory and environmental investigations were conducted, including testing of clinical specimens, implicated product, and environmental swabs. Between June and October 2013, a total of 43 ill persons were identified. Sixteen patients (37%) were hospitalized. Among 43 case-patients interviewed, the proportion exposed to dogs (95%) and pet treats (69%) in the 7 days prior to illness was statistically higher than among participants in a U.S. population-based telephone survey (61%, p<0.0001 and 16%, p<0.0001, respectively). On further interview, 38 (88%) reported exposure to Brand X Chicken Jerky, the maker of Brand X chicken jerky, or the facility in which it was made. Product testing isolated the outbreak strain from four of four Brand X Chicken Jerky samples, including an unopened package purchased at retail, opened packages collected from patient households, and unpackaged jerky obtained from the jerky maker. A site visit revealed inadequate processing of the chicken jerky, bare-hand contact with the finished product prior to packaging, and use of vacuum-sealed packaging, which may have enabled facultative anaerobic bacteria to proliferate. Seven (78%) of nine environmental swabs taken during the site visit also yielded the outbreak strain. Brand X Chicken Jerky was voluntarily recalled on September 9, 2013. Consumers should be made aware of the potential for locally made products to be exempt from regulation and for animals and animal food to carry pathogens that cause human illness, and be educated to perform hand hygiene after handling pet food or treats. PMID- 25793723 TI - The importance of lake sediments as a pathway for microcystin dynamics in shallow eutrophic lakes. AB - Microcystins are toxins produced by cyanobacteria. They occur in aquatic systems across the world and their occurrence is expected to increase in frequency and magnitude. As microcystins are hazardous to humans and animals, it is essential to understand their fate in aquatic systems in order to control health risks. While the occurrence of microcystins in sediments has been widely reported, the factors influencing their occurrence, variability, and spatial distribution are not yet well understood. Especially in shallow lakes, which often develop large cyanobacterial blooms, the spatial variability of toxins in the sediments is a complex interplay between the spatial distribution of toxin producing cyanobacteria, local biological, physical and chemical processes, and the re distribution of toxins in sediments through wind mixing. In this study, microcystin occurrence in lake sediment, and their relationship with biological and physicochemical variables were investigated in a shallow, eutrophic lake over five months. We found no significant difference in cyanobacterial biomass, temperature, pH, and salinity between the surface water and the water directly overlying the sediment (hereafter 'overlying water'), indicating that the water column was well mixed. Microcystins were detected in all sediment samples, with concentrations ranging from 0.06 to 0.78 ug equivalent microcystin-LR/g sediments (dry mass). Microcystin concentration and cyanobacterial biomass in the sediment was different between sites in three out of five months, indicating that the spatial distribution was a complex interaction between local and mixing processes. A combination of total microcystins in the water, depth integrated cyanobacterial biomass in the water, cyanobacterial biomass in the sediment, and pH explained only 21.1% of the spatial variability of microcystins in the sediments. A more in-depth analysis that included variables representative of processes on smaller vertical or local scales, such as cyanobacterial biomass in the different layers and the two fractions of microcystins, increased the explained variability to 51.7%. This highlights that even in a well-mixed lake, local processes are important drivers of toxin variability. The present study emphasises the role of the interaction between water and sediments in the distribution of microcystins in aquatic systems as an important pathway which deserves further consideration. PMID- 25793724 TI - A mutational analysis of residues in cholera toxin A1 necessary for interaction with its substrate, the stimulatory G protein Gsalpha. AB - Pathogenesis of cholera diarrhea requires cholera toxin (CT)-mediated adenosine diphosphate (ADP)-ribosylation of stimulatory G protein (Gsalpha) in enterocytes. CT is an AB5 toxin with an inactive CTA1 domain linked via CTA2 to a pentameric receptor-binding B subunit. Allosterically activated CTA1 fragment in complex with NAD+ and GTP-bound ADP-ribosylation factor 6 (ARF6-GTP) differs conformationally from the CTA1 domain in holotoxin. A surface-exposed knob and a short alpha-helix (formed, respectively, by rearranging "active-site" and "activation" loops in inactive CTA1) and an ADP ribosylating turn-turn (ARTT) motif, all located near the CTA1 catalytic site, were evaluated for possible roles in recognizing Gsalpha. CT variants with one, two or three alanine substitutions at surface-exposed residues within these CTA1 motifs were tested for assembly into holotoxin and ADP-ribosylating activity against Gsalpha and diethylamino-(benzylidineamino)-guanidine (DEABAG), a small substrate predicted to fit into the CTA1 active site). Variants with single alanine substitutions at H55, R67, L71, S78, or D109 had nearly wild-type activity with DEABAG but significantly decreased activity with Gsalpha, suggesting that the corresponding residues in native CTA1 participate in recognizing Gsalpha. As several variants with multiple substitutions at these positions retained partial activity against Gsalpha, other residues in CTA1 likely also participate in recognizing Gsalpha. PMID- 25793725 TI - Firing the sting: chemically induced discharge of cnidae reveals novel proteins and peptides from box jellyfish (Chironex fleckeri) venom. AB - Cnidarian venom research has lagged behind other toxinological fields due to technical difficulties in recovery of the complex venom from the microscopic nematocysts. Here we report a newly developed rapid, repeatable and cost effective technique of venom preparation, using ethanol to induce nematocyst discharge and to recover venom contents in one step. Our model species was the Australian box jellyfish (Chironex fleckeri), which has a notable impact on public health. By utilizing scanning electron microscopy and light microscopy, we examined nematocyst external morphology before and after ethanol treatment and verified nematocyst discharge. Further, to investigate nematocyst content or "venom" recovery, we utilized both top-down and bottom-up transcriptomics proteomics approaches and compared the proteome profile of this new ethanol recovery based method to a previously reported high activity and recovery protocol, based upon density purified intact cnidae and pressure induced disruption. In addition to recovering previously characterized box jellyfish toxins, including CfTX-A/B and CfTX-1, we recovered putative metalloproteases and novel expression of a small serine protease inhibitor. This study not only reveals a much more complex toxin profile of Australian box jellyfish venom but also suggests that ethanol extraction method could augment future cnidarian venom proteomics research efforts. PMID- 25793726 TI - A review on bradykinin-related peptides isolated from amphibian skin secretion. AB - Amphibian skin secretion has great potential for drug discovery and contributes hundreds of bioactive peptides including bradykinin-related peptides (BRPs). More than 50 BRPs have been reported in the last two decades arising from the skin secretion of amphibian species. They belong to the families Ascaphidae (1 species), Bombinatoridae (3 species), Hylidae (9 speices) and Ranidae (25 species). This paper presents the diversity of structural characteristics of BRPs with N-terminal, C-terminal extension and amino acid substitution. The further comparison of cDNA-encoded prepropeptides between the different species and families demonstrated that there are various forms of kininogen precursors to release BRPs and they constitute important evidence in amphibian evolution. The pharmacological activities of isolated BRPs exhibited unclear structure-function relationships, and therefore the scope for drug discovery and development is limited. However, their diversity shows new insights into biotechnological applications and, as a result, comprehensive and systematic studies of the physiological and pharmacological activities of BRPs from amphibian skin secretion are needed in the future. PMID- 25793727 TI - MicroRNA-499 expression distinctively correlates to target genes sox6 and rod1 profiles to resolve the skeletal muscle phenotype in Nile tilapia. AB - A class of small non-coding RNAs, the microRNAs (miRNAs), has been shown to be essential for the regulation of specific cell pathways, including skeletal muscle development, maintenance and homeostasis in vertebrates. However, the relative contribution of miRNAs for determining the red and white muscle cell phenotypes is far from being fully comprehended. To better characterize the role of miRNA in skeletal muscle cell biology, we investigated muscle-specific miRNA (myomiR) signatures in Nile tilapia fish. Quantitative (RT-qPCR) and spatial (FISH) expression analyses revealed a highly differential expression (forty-four-fold) of miR-499 in red skeletal muscle compared to white skeletal muscle, whereas the remaining known myomiRs were equally expressed in both muscle cell types. Detailed examination of the miR-499 targets through bioinformatics led us to the sox6 and rod1 genes, which had low expression in red muscle cells according to RT qPCR, FISH, and protein immunofluorescence profiling experiments. Interestingly, we verified that the high expression of miR-499 perfectly correlates with a low expression of sox6 and rod1 target genes, as verified by a distinctive predominance of mRNA destabilization and protein translational decay to these genes, respectively. Through a genome-wide comparative analysis of SOX6 and ROD1 protein domains and through an in silico gene regulatory network, we also demonstrate that both proteins are essentially similar in vertebrate genomes, suggesting their gene regulatory network may also be widely conserved. Overall, our data shed light on the potential regulation of targets by miR-499 associated with the slow-twitch muscle fiber type phenotype. Additionally the results provide novel insights into the evolutionary dynamics of miRNA and target genes enrolled in a putative constrained molecular pathway in the skeletal muscle cells of vertebrates. PMID- 25793729 TI - Auditory brainstem implantation: anatomy and approaches. AB - BACKGROUND: Auditory brainstem implantation at the cochlear nuclei used mainly for neurofibromatosis type 2 patients with bilateral loss of the cochlear nerves has more recently been extended to the inferior colliculus. OBJECTIVE: To examine the microsurgical and endoscopic anatomy of the cochlear nuclei and inferior colliculus as seen through the translabyrinthine and retrosigmoid approaches used for cochlear nuclei and inferior collicular implantation. METHODS: Ten cerebellopontine angles of formalin-fixed adult cadaveric heads were examined with the aid of the surgical microscope and endoscope. The ascending auditory pathways between the cochlear nuclei and inferior colliculi and above were examined by the fiber dissection technique. RESULTS: Both the translabyrinthine and retrosigmoid routes provide sufficient exposure for concurrent tumor removal and implantation at either the cochlear nuclei or inferior colliculus. The position of the inferior colliculus in the auditory pathways and its accessibility in the infratentorial supracerebellar exposure directed through either the translabyrinthine or retrosigmoid approach makes it an alternative site for electrode placement if the cochlear nuclei are not functionally or structurally suitable for implantation. Endoscopic assistance may aid the exposure and electrode placement at either site. CONCLUSION: The translabyrinthine or retrosigmoid approaches provide access to the cochlear nuclei for implantation and also to the inferior colliculus through the translabyrinthine or retrosigmoid infratentorial supracerebellar route. The endoscope may aid in exposing either site. PMID- 25793728 TI - Modest attenuation of HIV-1 Vpu alleles derived from elite controller plasma. AB - In the absence of antiretroviral therapy, infection with human immunodeficiency virus type 1 (HIV-1) can typically not be controlled by the infected host and results in the development of acquired immunodeficiency. In rare cases, however, patients spontaneously control HIV-1 replication. Mechanisms by which such elite controllers (ECs) achieve control of HIV-1 replication include particularly efficient immune responses as well as reduced fitness of the specific virus strains. To address whether polymorphisms in the accessory HIV-1 protein Vpu are associated with EC status we functionally analyzed a panel of plasma-derived vpu alleles from 15 EC and 16 chronic progressor (CP) patients. Antagonism of the HIV particle release restriction by the intrinsic immunity factor CD317/tetherin was well conserved among EC and CP Vpu alleles, underscoring the selective advantage of this Vpu function in HIV-1 infected individuals. In contrast, interference with CD317/tetherin induced NF-kappaB activation was little conserved in both groups. EC Vpus more frequently displayed reduced ability to downregulate cell surface levels of CD4 and MHC class I (MHC-I) molecules as well as of the NK cell ligand NTB-A. Polymorphisms potentially associated with high affinity interactions of the inhibitory killer immunoglobulin-like receptor (KIR) KIR2DL2 were significantly enriched among EC Vpus but did not account for these functional differences. Together these results suggest that in a subgroup of EC patients, some Vpu functions are modestly reduced, possibly as a result of host selection. PMID- 25793730 TI - Distraction, Compression, Extension, and Reduction Combined With Joint Remodeling and Extra-articular Distraction: Description of 2 New Modifications for Its Application in Basilar Invagination and Atlantoaxial Dislocation: Prospective Study in 79 Cases. AB - BACKGROUND: Recent strategies for treatment of basilar invagination (BI) and atlantoaxial dislocation (AAD) are based on simultaneous posterior reduction and fixation. OBJECTIVE: To describe new modifications of the procedure distraction, compression, extension, and reduction (DCER), ie, joint remodeling (JRM) and extra-articular distraction (EAD) in patients with "vertical" joints, and to quantify the improvement in joint indices, ie, sagittal inclination (SI), craniocervical tilt (CCT), and coronal inclination. METHODS: Prospective study (May 2010 to September 2014). Joint indices measured included (normal values): SI (87.15 +/- 5.65 degrees ), CCT (60.2 +/- 9.2 degrees ), and coronal inclination (110.3 +/- 4.23 degrees ). Surgical procedures included DCER alone (performed in SI <100 degrees , group I) or JRM with DCER (in SI: 100-160 degrees , group II), or EAD with DCER in severe BI with almost vertical joints (SI >160 degrees , group III). RESULTS: Seventy-nine patients were selected (mean, 22.5 years of age). All conventional indices improved significantly (P < .001). CCT improved in all groups (P < .01); group I (n = 32): 54 +/- 8.7 degrees (preoperative 80.71 +/- 12.72 degrees ); group II (n = 40): 58 +/- 7.0 degrees (preoperative 86.5 +/ 14 degrees ); group III (n = 7): 62 +/- 10.0 degrees (preoperative 104 +/- 11.2 degrees ). SI improved in both group I and II, P < .01 (cannot be measured in group III). At long-term follow-up (n = 64, 29 +/- 8 months, range 12-39 months), the Nurick grade improved to 1.5 +/- 0.52 (preoperative: 3.4 +/- 0.65; P < .001). CONCLUSION: DCER seems to be an effective technique in reducing both BI and AAD. JRM and EAD with DCER are useful in moderate to severe BI and AAD (with SI >100 degrees ). Joint indices provide useful information for surgical strategy and planning. PMID- 25793731 TI - Significance of T2 Hyperintensity on Magnetic Resonance Imaging After Cervical Cord Injury and Return to Play in Professional Athletes. AB - BACKGROUND: Cervical cord magnetic resonance imaging (MRI) T2 hyperintensity is used as evidence of cord trauma in the evaluation and management of athletes in contact sports. The long-term pathophysiologic and prognostic value of this finding is poorly understood, especially in return to play (RTP). OBJECTIVE: To examine the significance of T2 hyperintensity in the cervical spinal cord of professional athletes. METHODS: Retrospective review of MRI T2 hyperintensity findings between 2007 and 2014 in 5 professional athletes. Pertinent examination and demographics, including mechanism of injury, surgical intervention, radiographs, MRI studies, long-term outcomes, and RTP recommendations were collected. RESULTS: Four National Football League players and 1 professional wrestler had prior traumatic neurapraxia that at the time of initial consultation had resolved. MRIs showed congenitally small cervical canal (1) and multilevel spondylosis/stenosis/disc herniation (4) along with focal cord T2 hyperintensity (5). The signal abnormalities were at C3/C4 (3), C4 mid-vertebral body (1), and C5/C6 (1). Four athletes had single-level anterior cervical discectomy and fusion, and 1 was nonoperative. Serial MRI imaging at 3 months after surgery showed hyperintensity partially resolved (4) and unchanged (1), and at 9-months 3 of the 5 completely resolved. Based on the author's RTP criteria, 4 of 5 were released to return to their sport. Clearance for RTP preceded complete resolution of MRI T2 hyperintensity in 3 of 4 athletes. The 2 athletes that have returned to profession sport have not had any additional episodes of neurapraxia or any cervical spine-related complications. CONCLUSION: MRI T2 hyperintensity in contact sport athletes who are symptom-free with normal examination and no evidence of spinal instability may not be a contraindication to RTP. Additional observations are needed to confirm this observation. PMID- 25793732 TI - Strigolactone regulates anthocyanin accumulation, acid phosphatases production and plant growth under low phosphate condition in Arabidopsis. AB - Phosphate is an essential macronutrient in plant growth and development; however, the concentration of inorganic phosphate (Pi) in soil is often suboptimal for crop performance. Accordingly, plants have developed physiological strategies to adapt to low Pi availability. Here, we report that typical Pi starvation responses in Arabidopsis are partially dependent on the strigolactone (SL) signaling pathway. SL treatment induced root hair elongation, anthocyanin accumulation, activation of acid phosphatase, and reduced plant weight, which are characteristic responses to phosphate starvation. Furthermore, the expression profile of SL-response genes correlated with the expression of genes induced by Pi starvation. These results suggest a potential overlap between SL signaling and Pi starvation signaling pathways in plants. PMID- 25793733 TI - Salt potentiates methylamine counteraction system to offset the deleterious effects of urea on protein stability and function. AB - Cellular methylamines are osmolytes (low molecular weight organic compounds) believed to offset the urea's harmful effects on the stability and function of proteins in mammalian kidney and marine invertebrates. Although urea and methylamines are found at 2:1 molar ratio in tissues, their opposing effects on protein structure and function have been questioned on several grounds including failure to counteraction or partial counteraction. Here we investigated the possible involvement of cellular salt, NaCl, in urea-methylamine counteraction on protein stability and function. We found that NaCl mediates methylamine counteracting system from no or partial counteraction to complete counteraction of urea's effect on protein stability and function. These conclusions were drawn from the systematic thermodynamic stability and functional activity measurements of lysozyme and RNase-A. Our results revealed that salts might be involved in protein interaction with charged osmolytes and hence in the urea-methylamine counteraction. PMID- 25793734 TI - Comparison of prelaminar thickness between primary open angle glaucoma and normal tension glaucoma patients. AB - MAIN OBJECTIVE: The thinning of prelaminar tissue and prelamina cupping is known to occur by ischemia, as we see in anterior ischemic optic neuropathy. Since normal tension glaucoma (NTG) is thought to be more related to vascular factor than in primary open-angle glaucoma (POAG), we hypothesized that prelamina thinning may occur prominently in NTG patients. This study investigated the difference in prelaminar tissue thickness between patients with POAG and NTG and verified the factors related to prelaminar thinning. METHODS: Complete ophthalmic examination including standard automatic perimetry was performed in all patients. The prelaminar tissue thickness was measured in all patients by performing enhanced depth imaging with a Heidelberg Spectralis Optical Coherence Tomography. The retinal nerve fiber layer and optic nerve head parameters were obtained using the Heidelberg Retina Tomography II and Cirrus Optical Coherence Tomography. Various ocular factors and their relationships with prelaminar thickness were analyzed. RESULTS: The mean prelaminar tissue thickness was significantly thinner in patients with POAG than in those with NTG. The difference in the prelaminar thickness between patients with POAG and those with NTG was greater in the early field defect group than in the moderate and severe field groups. In multivariate analysis, the mean prelaminar thickness was related to the intraocular pressure, mean deviation, cup-disc ratio, and cup volume. CONCLUSIONS: The prelaminar tissue was thinner in patients with POAG than in patients with NTG, and intraocular pressure had a strong influence on the prelaminar thickness in both POAG and NTG. This may indicate that mechanical compression is the main pathogenic factor in both POAG and NTG. PMID- 25793735 TI - Selection and validation of reference genes for qRT-PCR expression analysis of candidate genes involved in olfactory communication in the butterfly Bicyclus anynana. AB - Real-time quantitative reverse transcription PCR (qRT-PCR) is a technique widely used to quantify the transcriptional expression level of candidate genes. qRT-PCR requires the selection of one or several suitable reference genes, whose expression profiles remain stable across conditions, to normalize the qRT-PCR expression profiles of candidate genes. Although several butterfly species (Lepidoptera) have become important models in molecular evolutionary ecology, so far no study aimed at identifying reference genes for accurate data normalization for any butterfly is available. The African bush brown butterfly Bicyclus anynana has drawn considerable attention owing to its suitability as a model for evolutionary ecology, and we here provide a maiden extensive study to identify suitable reference gene in this species. We monitored the expression profile of twelve reference genes: eEF-1alpha, FK506, UBQL40, RpS8, RpS18, HSP, GAPDH, VATPase, ACT3, TBP, eIF2 and G6PD. We tested the stability of their expression profiles in three different tissues (wings, brains, antennae), two developmental stages (pupal and adult) and two sexes (male and female), all of which were subjected to two food treatments (food stress and control feeding ad libitum). The expression stability and ranking of twelve reference genes was assessed using two algorithm-based methods, NormFinder and geNorm. Both methods identified RpS8 as the best suitable reference gene for expression data normalization. We also showed that the use of two reference genes is sufficient to effectively normalize the qRT-PCR data under varying tissues and experimental conditions that we used in B. anynana. Finally, we tested the effect of choosing reference genes with different stability on the normalization of the transcript abundance of a candidate gene involved in olfactory communication in B. anynana, the Fatty Acyl Reductase 2, and we confirmed that using an unstable reference gene can drastically alter the expression profile of the target candidate genes. PMID- 25793736 TI - Aberrant expression of PHLPP1 and PHLPP2 correlates with poor prognosis in patients with hypopharyngeal squamous cell carcinoma. AB - The PHLPP (pleckstrin homology [PH] domain leucine rich repeat protein phosphatase) family, which represents a family of novel Ser/Thr protein phosphatases, is composed of 2 members: PHLPP1 and PHLPP2. PHLPPs partake in diverse cellular activities to exhibit their antitumor and metastasis suppressor functions. It is necessary to investigate the expression patterns of PHLPP1 and PHLPP2 in hypopharyngeal squamous cell carcinomas (HSCCs) and clarify their clinical significance. A total of 138 patients with primary HSCC who underwent curative surgical treatment as an initial treatment were enrolled in this study. A total of 138 HSCC specimens and 64 adjacent noncancerous mucosal epithelial tissues were collected. The expression levels of PHLPP1 and PHLPP2 were examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry assays. Correlations between clinicopathological parameters of the patients were further evaluated. PHLPP1 and PHLPP2 mRNA transcript levels were significantly lower in tumor samples than in paired adjacent nontumor mucosae (P<0.0001, both). Positive correlations were observed between the mRNA levels of PHLPP1 and PHLPP2 in HSCC tissues (correlation coefficient r = 0.678, P<0.001) and in adjacent nontumor mucosae (r = 0.460, P<0.001). The majority of the noncancerous tissues showed high expression levels of PHLPP1 (87.5%, 56/64) and PHLPP2 (85.9%, 55/64). However, the expressions of PHLPP1 and PHLPP2 were significantly decreased in 83.3% (115/138) and 82.6% (114/138) of tumor tissues, respectively (P<0.0001, both). The expressions of both PHLPP isoforms were significantly related to the tumor clinical stage, differentiation, and cervical lymph node metastasis (P<0.05, all). It was PHLPP1 but not PHLPP2 that was significantly related to the tumor T stage. Low PHLPP1 and PHLPP2 expressions were associated with poor overall survival (OS) in HSCC patients (P = 0.004, P = 0.008, respectively). Multivariate analysis revealed that PHLPP1 was an independent prognostic factor for OS. This study indicates that, in HSCC, aberrant expressions of PHLPP1 and PHLPP2 are common events, and loss of PHLPPs might identify patients with poor prognostic outcomes. PMID- 25793738 TI - Novel microstructural strategies to enhance the electrochemical performance of La0.8Sr0.2MnO3-delta cathodes. AB - Novel strategies based on spray-pyrolysis deposition are proposed to increase the triple-phase boundary (TPB) of La0.8Sr0.2MnO3-delta (LSM) cathodes in contact with yttria-stabilized zirconia (YSZ) electrolyte: (i) nanocrystalline LSM films deposited on as-prepared YSZ surface; (ii) the addition of poly(methyl methacrylate) microspheres as pore formers to further increase the porosity of the film cathodes; and (iii) the deposition of LSM by spray pyrolysis on backbones of Zr0.84Y0.16O1.92 (YSZ), Ce0.9Gd0.1O1.95 (CGO), and Bi1.5Y0.5O3-delta (BYO) previously fixed onto the YSZ. This last method is an alternative to the classical infiltration process with several advantages for large-scale manufacturing of planar solid oxide fuel cells (SOFCs), including easier industrial implementation, shorter preparation time, and low cost. The morphology and electrochemical performance of the electrodes are investigated by scanning electron microscopy and impedance spectroscopy. Very low values of area specific resistance are obtained, ranging from 1.4 Omega.cm(2) for LSM films deposited on as-prepared YSZ surface to 0.06 Omega-cm(2) for LSM deposited onto BYO backbone at a measured temperature of 650 degrees C. These electrodes exhibit high performance even after annealing at 950 degrees C, making them potentially suitable for applications in SOFCs at intermediate temperatures. PMID- 25793737 TI - Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer. AB - The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID- 25793739 TI - Contrast-enhanced harmonic endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of solid pancreatic lesions: a retrospective study. AB - BACKGROUND: The negative predictive value of endoscopic ultrasonography-guided fine needle aspiration for the diagnosis of solid pancreatic lesions remains low, and the biopsy specimens are sometimes inadequate for appropriate pathological diagnosis. AIMS: To evaluate the usefulness of a novel method of contrast enhanced harmonic endoscopic ultrasonography-guided fine-needle aspiration for the differential diagnosis and adequate sampling of solid pancreatic lesions. METHODS: Patients with a diagnosis of solid pancreatic lesions who underwent fine needle aspiration guided by contrast-enhanced harmonic endoscopic ultrasonography or by endoscopic ultrasonography from October 2010 to July 2013 were retrospectively identified and classified into the CH-EUS or EUS group, respectively. Surgical pathology and/or follow-up results were defined as the final diagnosis. Operating characteristics and adequacy of biopsy specimens by fine-needle aspiration were compared between the two groups. RESULTS: Operating characteristics for contrast-enhanced harmonic endoscopic ultrasonography-guided fine-needle aspiration in solid pancreatic lesions were as follows: area under the curve = 0.908, sensitivity = 81.6%, specificity = 100%, positive predictive value = 100%, negative predictive value = 74.1%, and accuracy = 87.9%. The percentage of adequate biopsy specimens in the CH-EUS group (96.6%) was greater than that in the EUS group (86.7%). CONCLUSION: Simultaneous contrast-enhanced harmonic endoscopic ultrasonography during fine-needle aspiration is useful for improving the diagnostic yield and adequate sampling of solid pancreatic lesions. PMID- 25793740 TI - Occipital nerve stimulation for chronic migraine--a systematic review and meta analysis. AB - BACKGROUND: Chronic migraine is a debilitating headache disorder that has significant impact on quality of life. Stimulation of peripheral nerves is increasingly being used to treat chronic refractory pain including headache disorders. This systematic review examines the effectiveness and adverse effects of occipital nerve stimulation (ONS) for chronic migraine. METHODS: Databases, including the Cochrane Library, MEDLINE, EMBASE, CINAHL and clinical trial registers were searched to September 2014. Randomized controlled trials (RCTs), other controlled and uncontrolled observational studies and case series (n>= 10) were eligible. RCTs were assessed using the Cochrane risk of bias tool. Meta analysis was carried out using a random-effects model. Findings are presented in summary tables and forest plots. RESULTS: Five RCTs (total n=402) and seven case series (total n=115) met the inclusion criteria. Pooled results from three multicenter RCTs show that ONS was associated with a mean reduction of 2.59 days (95% CI 0.91 to 4.27, I2=0%) of prolonged, moderate to severe headache per month at 3 months compared with a sham control. Results for other outcomes generally favour ONS over sham controls but quantitative analysis was hampered by incomplete publication and reporting of trial data. Lead migration and infections are common and often require revision surgery. Open-label follow-up of RCTs and case series suggest long-term effectiveness can be maintained in some patients but evidence is limited. CONCLUSIONS: While the effectiveness of ONS compared to sham control has been shown in multiple RCTs, the average effect size is modest and may be exaggerated by bias as achieving effective blinding remains a methodological challenge. Further measures to reduce the risk of adverse events and revision surgery are needed. SYSTEMATIC REVIEW REGISTRATION: this systematic review is an update and expanded work of part of a broader review registered with PROSPERO. Registration No. CRD42012002633. PMID- 25793741 TI - Optogenetic activation of CA1 pyramidal neurons at the dorsal and ventral hippocampus evokes distinct brain-wide responses revealed by mouse fMRI. AB - The dorsal and ventral hippocampal regions (dHP and vHP) are proposed to have distinct functions. Electrophysiological studies have revealed intra-hippocampal variances along the dorsoventral axis. Nevertheless, the extra-hippocampal influences of dHP and vHP activities remain unclear. In this study, we compared the spatial distribution of brain-wide responses upon dHP or vHP activation and further estimate connection strengths between the dHP and the vHP with corresponding extra-hippocampal areas. To achieve this, we first investigated responses of local field potential (LFP) and multi unit activities (MUA) upon light stimulation in the hippocampus of an anesthetized transgenic mouse, whose CA1 pyramidal neurons expressed a step-function opsin variant of channelrhodopsin 2 (ChR2). Optogenetic stimulation increased hippocampal LFP power at theta, gamma, and ultra-fast frequency bands, and augmented MUA, indicating light induced activation of CA1 pyramidal neurons. Brain-wide responses examined using fMRI revealed that optogenetic activation at the dHP or vHP caused blood oxygenation level-dependent (BOLD) fMRI signals in situ. Although activation at the dHP induced BOLD responses at the vHP, the opposite was not observed. Outside the hippocampal formation, activation at the dHP, but not the vHP, evoked BOLD responses at the retrosplenial cortex (RSP), which is in line with anatomical evidence. In contrast, BOLD responses at the lateral septum (LS) were induced only upon vHP activation, even though both dHP and vHP send axonal fibers to the LS. Our findings suggest that the primary targets of dHP and vHP activation are distinct, which concurs with attributed functions of the dHP and RSP in spatial memory, as well as of the vHP and LS in emotional responses. PMID- 25793744 TI - Mixture models for distance sampling detection functions. AB - We present a new class of models for the detection function in distance sampling surveys of wildlife populations, based on finite mixtures of simple parametric key functions such as the half-normal. The models share many of the features of the widely-used "key function plus series adjustment" (K+A) formulation: they are flexible, produce plausible shapes with a small number of parameters, allow incorporation of covariates in addition to distance and can be fitted using maximum likelihood. One important advantage over the K+A approach is that the mixtures are automatically monotonic non-increasing and non-negative, so constrained optimization is not required to ensure distance sampling assumptions are honoured. We compare the mixture formulation to the K+A approach using simulations to evaluate its applicability in a wide set of challenging situations. We also re-analyze four previously problematic real-world case studies. We find mixtures outperform K+A methods in many cases, particularly spiked line transect data (i.e., where detectability drops rapidly at small distances) and larger sample sizes. We recommend that current standard model selection methods for distance sampling detection functions are extended to include mixture models in the candidate set. PMID- 25793743 TI - Detection of the quarantine species Thrips palmi by loop-mediated isothermal amplification. AB - Thrips palmi (from the order Thysanoptera) is a serious insect pest of various crops, including vegetables, fruits and ornamental plants, causing significant economic losses. Its presence constitutes a double threat; not only does T. palmi feed on the plants, it is also a vector for several plant viruses. T. palmi originated in Asia, but has spread to North and Central America, Africa, Oceania and the Caribbean in recent decades. This species has been sporadically noted in Europe and is under quarantine regulation in the European Union. For non specialists its larval stages are indistinguishable morphologically from another widespread and serious insect pest Frankliniella occidentalis (a non-quarantine species in the European Union) as well as other frequently occurring thrips. In this study, we have developed a loop-mediated isothermal amplification protocol to amplify rDNA regions of T. palmi. The results were consistent whether isolated DNA or crushed insects were used as template, indicating that the DNA isolation step could be omitted. The described method is species-specific and sensitive and provides a rapid diagnostic tool to detect T. palmi in the field. PMID- 25793742 TI - An examination of the association between 5-HTTLPR, combat exposure, and PTSD diagnosis among U.S. veterans. AB - OBJECTIVE: To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans. METHOD: The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat-exposed veterans. Participants were genotyped for the 5-HTTLPR/rs25531 variants of the SLC6A4 gene. A structured clinical interview was used to diagnose PTSD. Combat and civilian trauma exposure were assessed with validated self-report instruments. Logistic regression was used to test for main effects of 5-HTTLPR on PTSD diagnosis as well as gene x environment (GxE) interactions after adjusting for sex, ancestry proportion scores, civilian trauma exposure, and combat exposure. RESULTS: Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S' allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample. In addition, no evidence for combat x 5-HTTLPR effects were observed in either sample. CONCLUSION: The present study suggests that there may be an association between 5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found. PMID- 25793745 TI - Corrections to "A neuro-fuzzy approach for medical image fusion". PMID- 25793746 TI - Demographic and psychological predictors of panel attrition: evidence from the New Zealand attitudes and values study. AB - This study examines attrition rates over the first four years of the New Zealand Attitudes and Values Study, a longitudinal national panel sample of New Zealand adults. We report the base rate and covariates for the following four distinct classes of respondents: explicit withdrawals, lost respondents, intermittent respondents and constant respondents. A multinomial logistic regression examined an extensive range of demographic and socio-psychological covariates (among them the Big-Six personality traits) associated with membership in these classes (N = 5,814). Results indicated that men, Maori and Asian peoples were less likely to be constant respondents. Conscientiousness and Honesty-Humility were also positively associated with membership in the constant respondent class. Notably, the effect sizes for the socio-psychological covariates of panel attrition tended to match or exceed those of standard demographic covariates. This investigation broadens the focus of research on panel attrition beyond demographics by including a comprehensive set of socio-psychological covariates. Our findings show that core psychological covariates convey important information about panel attrition, and are practically important to the management of longitudinal panel samples like the New Zealand Attitudes and Values Study. PMID- 25793747 TI - Relationship of Near-Crash/Crash Risk to Time Spent on a Cell Phone While Driving. AB - OBJECTIVES: The objective of this study was to examine in a naturalistic driving setting the dose-response relationship between cell phone usage while driving and risk of a crash or near crash. How is the increasing use of cell phones by drivers associated with overall near-crash/crash risk (i.e., during driving times both on and off the phone)? METHODS: Day-to-day driving behavior of 105 volunteer subjects was monitored over a period of 1 year. A random sample was selected comprised of 4 trips from each month that each driver was in the study, and in vehicle video was used to classify driver behavior. The proportion of driving time spent using a cell phone was estimated for each 3-month period and correlated with overall crash and near-crash rates for each period. Thus, it was possible to test whether changes in an individual driver's cell phone use over time were associated with changes in overall near-crash/crash risk. RESULTS: Drivers in the study spent 11.7% of their driving time interacting with a cell phone, primarily talking on the phone (6.5%) or simply holding the phone in their hand or lap (3.7%). The risk of a near-crash/crash event was approximately 17% higher when the driver was interacting with a cell phone, due primarily to actions of reaching for/answering/dialing, which nearly triples risk (relative risk = 2.84). However, the amount of driving time spent interacting with a cell phone did not affect a driver's overall near-crash/crash risk. Vehicle speeds within 6 s of the beginning of each call on average were 5-6 mph lower than speeds at other times. CONCLUSIONS: Results of this naturalistic driving study are consistent with the observation that increasing cell phone use in the general driving population has not led to increased crash rates. Although cell phone use can be distracting and crashes have occurred during this distraction, overall crash rates appear unaffected by changes in the rate of cell phone use, even for individual drivers. Drivers compensate somewhat for the distraction by conducting some of the more demanding tasks, such as reaching for or dialing a cell phone, at lower speeds. It is also possible that cell phones and other electronic devices in cars are changing how drivers manage their attention to various tasks and/or changing the kinds of secondary tasks in which they engage. PMID- 25793748 TI - Communication competence, psychological well-being, and the mediating role of coping efforts among women with breast cancer: cross-sectional and longitudinal evidence. AB - Despite existing research identifying psychological benefits of patients' interpersonal competence in various contexts, little longitudinal research has addressed underlying mechanism(s). To address this limitation, we examined both the cross-sectional and longitudinal associations between cancer patients' communication competence in close relationships and psychological well-being, as well as the mediating role of coping efforts. Data came from a larger project with women with breast cancer (N = 661), recruited from April 2005 to May 2007 at three large university-affiliated cancer centers in the U.S. to study the effects of an Internet-based system providing patients and families with a range of services. The present study focused on survey data at baseline, 6 weeks, and 12 weeks after the intervention (controlling for the possible effects of the intervention). Results from both cross-sectional and longitudinal analyses indicated that competence in open communication between patients and their close support persons had a positive association with patients' psychological well being and that approach coping efforts partially mediated this association. We discussed the implications and limitations of the study. PMID- 25793749 TI - Do Web-based and clinic samples of gay men living with HIV differ on self reported physical and psychological symptoms? A comparative analysis. AB - BACKGROUND: Although the Internet is commonly used to recruit samples in studies of human immunodeficiency virus (HIV)-related risk behaviors, it has not been used to measure patient-reported well-being. As the burden of long-term chronic HIV infection rises, the Internet may offer enormous potential for recruitment to research and interventions. OBJECTIVE: This study aimed to compare two samples of gay men living with HIV, one recruited via the Web and the other recruited in outpatient settings, in terms of self-reported physical and psychological symptom burden. METHODS: The Internet sample was recruited from a UK-wide Web-based survey of gay men with diagnosed HIV. Of these, 154 respondents identified themselves as resident in London and were included in this analysis. The HIV clinic sample was recruited from five HIV outpatient clinics. Of these participants, 400 gay men recruited in London clinics were included in this analysis. RESULTS: The Web-based sample was younger than the clinic sample (37.3 years, SD 7.0 vs 40.9 years, SD 8.3), more likely to be in paid employment (72.8%, 99/136 vs 60.1%, 227/378), less likely to be on antiretroviral therapy (ART) (58.4%, 90/154 vs 68.0%, 266/391), and had worse mean psychological symptom burden compared to the clinic sample (mean scores: 1.61, SD 1.09 vs 1.36, SD 0.96) but similar physical symptom burden (mean scores: 0.78, SD 0.65 vs 0.70, SD 0.74). In multivariable logistic regression, for the physical symptom burden model, adjusted for age, ethnicity, employment status, and ART use, the recruitment setting (ie, Web-based vs clinic) was not significantly associated with high physical symptom score. The only variable that remained significantly associated with high physical symptom score was employment status, with those in employment being less likely to report being in the upper (worst) physical symptom tertile versus the other two tertiles (adjusted OR 0.41, 95% CI 0.28 0.62, P<.001). For the psychological symptom burden model, those recruited via the Web were significantly more likely to report being in the upper (worst) tertile (adjusted OR 2.20, 95% CI 1.41-3.44, P=.001). In addition, those in employment were less likely to report being in the upper (worst) psychological symptom tertile compared to those not in employment (adjusted OR 0.32, 95% CI 0.21-0.49, P<.001). CONCLUSIONS: Our data have revealed a number of differences. Compared to the clinic sample, the Web-based sample had worse psychological symptom burden, younger average age, higher prevalence of employment, and a lower proportion on ART. For future research, we recommend that Web-based data collection should include the demographic variables that we note differed between samples. In addition, we recognize that each recruitment method may bring inherent sampling bias, with clinic populations differing by geographical location and reflecting those accessing regular medical care, and Web-based sampling recruiting those with greater Internet access and identifying survey materials through specific searches and contact with specific websites. PMID- 25793750 TI - Distinct Strategies Employed by Dendritic Cells and Macrophages in Restricting Mycobacterium tuberculosis Infection: Different Philosophies but Same Desire. AB - Dendritic cells (DCs) and macrophages (Mphis) are professional antigen-presenting cells (APCs) that can efficiently phagocytose Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). It is quite interesting to mention here that DCs and Mphis use distinct strategies to combat and eliminate Mtb. Similarly, Mtb employs different mechanisms to counteract the action of DCs and Mphis. Mphis are evolved with specialized, innate, defensive machinery to restrict growth of Mtb at the initial phase of infection. However, DCs are more endowed toward initiating adaptive immunity by activating naive T cells. During encounter with Mtb, DCs and Mphis deliver discrete functions via triggering through different pattern recognition receptors (PRRs) expressed by these APCs. Mtb-infected DCs and Mphis show differential expression of genes encoding cytokines, chemokines, costimulatory molecules, and adhesion molecules. Interestingly, Mtb impairs the immune defensive machinery by exploiting various PRRs. Remarkably, selective signaling through PRRs by Mtb abrogates the bactericidal activity of Mphis, but subverts differentiation of monocytes to DCs. In this article, we highlight the role of PRRs in inducing distinct immune response by DCs and Mphis against Mtb. Concurrently, we also discuss smart strategies exploited by Mtb to impair the function of host DCs and Mphis. PMID- 25793752 TI - Direct observation of enhanced plasmon-driven catalytic reaction activity of Au nanoparticles supported on reduced graphene oxides by SERS. AB - Graphene-based nanocomposites have recently attracted tremendous research interest in the field of catalysis due to their unique optical and electronic properties. However, direct observation of enhanced plasmon-driven catalytic activity of Au nanoparticles (NPs) supported on reduced graphene oxides (Au/rGO) has rarely been reported. Herein, based on the reduction from 4-nitrobenzenethiol (4-NBT) to p,p'-dimercaptoazobenzene (DMAB), the catalytic property of Au/rGO nanocomposites was investigated and compared with corresponding Au NP samples with similar size distribution. Our results show that Au/rGO nanocomposites could serve as a good catalytic and analytic platform for plasmon-driven chemical reactions. In addition, systematic comparisons were conducted during power- and time-dependent surface-enhanced Raman scattering (SERS) experiments, which exhibited a lower power threshold and higher catalytic efficiency for Au/rGO as compared to Au NPs toward the reaction. PMID- 25793753 TI - Endurance training-induced increase in circulating irisin levels is associated with reduction of abdominal visceral fat in middle-aged and older adults. AB - To elucidate the effects of endurance training on circulating irisin levels in young and middle-aged/older adults, and to determine the association between endurance training-induced alteration of irisin and reduction in body fat. Twenty five healthy young (age 21 +/- 1 years; 16 men, 9 women) and 28 healthy middle aged/older adults (age 67 +/- 8 years; 12 men, 16 women) participated in the study. Each age cohort was divided into two groups: the endurance-training group (14 young, 14 middle-aged/older) and the control group. Subjects in the training groups completed an 8-week endurance-training program (cycling at 60-70% peak oxygen uptake [VO2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated serum irisin level, VO2peak, and body composition. The increase in VO2peak in the young and middle-aged/older training groups after the intervention period was significantly greater than those in the young and middle aged/older control groups (P < 0.05). Serum irisin level was significantly increased in the middle-aged/older training group after the intervention period (P < 0.01), but not in the young training group. Furthermore, in the middle aged/older training group, the endurance training-induced reduction in visceral adipose tissue area was negatively correlated with the change in serum irisin level (r = -0.54, P < 0.05). These results suggest a possible role for secreted irisin in the exercise-induced alteration of abdominal visceral fat in middle aged and older adults. PMID- 25793751 TI - Sequencing and analysis of globally obtained human respiratory syncytial virus A and B genomes. AB - BACKGROUND: Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in children globally, with nearly all children experiencing at least one infection by the age of two. Partial sequencing of the attachment glycoprotein gene is conducted routinely for genotyping, but relatively few whole genome sequences are available for RSV. The goal of our study was to sequence the genomes of RSV strains collected from multiple countries to further understand the global diversity of RSV at a whole-genome level. METHODS: We collected RSV samples and isolates from Mexico, Argentina, Belgium, Italy, Germany, Australia, South Africa, and the USA from the years 1998 2010. Both Sanger and next-generation sequencing with the Illumina and 454 platforms were used to sequence the whole genomes of RSV A and B. Phylogenetic analyses were performed using the Bayesian and maximum likelihood methods of phylogenetic inference. RESULTS: We sequenced the genomes of 34 RSVA and 23 RSVB viruses. Phylogenetic analysis showed that the RSVA genome evolves at an estimated rate of 6.72 * 10(-4) substitutions/site/year (95% HPD 5.61 * 10(-4) to 7.6 * 10(-4)) and for RSVB the evolutionary rate was 7.69 * 10(-4) substitutions/site/year (95% HPD 6.81 * 10(-4) to 8.62 * 10(-4)). We found multiple clades co-circulating globally for both RSV A and B. The predominant clades were GA2 and GA5 for RSVA and BA for RSVB. CONCLUSIONS: Our analyses showed that RSV circulates on a global scale with the same predominant clades of viruses being found in countries around the world. However, the distribution of clades can change rapidly as new strains emerge. We did not observe a strong spatial structure in our trees, with the same three main clades of RSV co circulating globally, suggesting that the evolution of RSV is not strongly regionalized. PMID- 25793754 TI - Dentary morphological variation in Clevosaurus brasiliensis (Rhynchocephalia, Clevosauridae) from the Upper Triassic of Rio Grande do Sul, Brazil. AB - Clevosaurus was a cosmopolitan rhynchocephalian genus, known from the Late Triassic to the Early Jurassic. In South America this genus is represented by C. brasiliensis, an important component of the Linha Sao Luiz taphocoenosis, on the top of the Norian Santa Maria 2 Sequence of Southern Brazil. The best preserved and most abundant bone elements of C. brasiliensis are dentaries, in which variations of shape and size are observed. The aim of this study is to describe and evaluate the variation, using geometric morphometrics methods. Geometric morphometric analysis of 10 specimens highlights variations in relative size of the dentary. Most of the variation observed for PC1 (83.3%) is likely related to ontogeny, and PC2 (10.0%) is likely related to taphonomic signatures. The development patterns observed, such as the growth of the dentary, consists of differential growth in length between the posterior portion of the dentary, that grows at a higher rate, regarding the anterior portion of the element. This allometric growth is similar to what is observed in other rhynchocephalians and is accompanied by the allometric skull growth, similar to the trend exhibited by clevosaurs. The taphocoenosis is bimodal (juveniles and adults) with a bias towards adult preservation. Some diagenetic influence is reflected in deformed skulls and this is observed in the tangent-plot. Finally, a strong correlation was detected between the taphonomic signatures and the PC2, regarding specially disarticulation and degree of fragmentation. PMID- 25793755 TI - Influence of action-effect associations acquired by ideomotor learning on imitation. AB - According to the ideomotor theory, actions are represented in terms of their perceptual effects, offering a solution for the correspondence problem of imitation (how to translate the observed action into a corresponding motor output). This effect-based coding of action is assumed to be acquired through action-effect learning. Accordingly, performing an action leads to the integration of the perceptual codes of the action effects with the motor commands that brought them about. While ideomotor theory is invoked to account for imitation, the influence of action-effect learning on imitative behavior remains unexplored. In two experiments, imitative performance was measured in a reaction time task following a phase of action-effect acquisition. During action-effect acquisition, participants freely executed a finger movement (index or little finger lifting), and then observed a similar (compatible learning) or a different (incompatible learning) movement. In Experiment 1, finger movements of left and right hands were presented as action-effects during acquisition. In Experiment 2, only right-hand finger movements were presented during action-effect acquisition and in the imitation task the observed hands were oriented orthogonally to participants' hands in order to avoid spatial congruency effects. Experiments 1 and 2 showed that imitative performance was improved after compatible learning, compared to incompatible learning. In Experiment 2, although action-effect learning involved perception of finger movements of right hand only, imitative capabilities of right- and left-hand finger movements were equally affected. These results indicate that an observed movement stimulus processed as the effect of an action can later prime execution of that action, confirming the ideomotor approach to imitation. We further discuss these findings in relation to previous studies of action-effect learning and in the framework of current ideomotor approaches to imitation. PMID- 25793757 TI - Correction: Variable expression of PIK3R3 and PTEN in Ewing sarcoma impacts oncogenic phenotypes. PMID- 25793758 TI - Correction to "Reoxidation of photoreduced polyoxotungstate [PW12O40](4-)) by different oxidants in the presence of a model pollutant. Kinetics and reaction mechanism". PMID- 25793756 TI - Identification and molecular characterization of the homogentisate pathway responsible for pyomelanin production, the major melanin constituents in Aeromonas media WS. AB - The pigmentation of many Aeromonas species has been thought to be due to the production of a L-DOPA (L-3,4-dihydroxyphenylalanine) based melanin. However, in this study we found that although L-DOPA synthesis occurs in the high-melanin yielding Aeromonas media strain WS, it plays a minor, if any, role in pigmentation. Instead, the pigmentation of A. media strain WS is due to the production of pyomelanin through HGA (homogentisate). Gene products of phhA (encodes phenylalanine hydroxylase), tyrB and aspC (both encode aromatic amino acid aminotransferase), and hppD (encodes 4-hydroxyphenylpyruvate dioxygenase) constitute a linear pathway of converting phenylalanine to HGA and disruption of any one of these genes impairs or blocks pigmentation of A. media strain WS. This HGA biosynthesis pathway is widely distributed in Aeromonas, but HGA is only detectable in the cultures of pigmented Aeromonas species. Heterologous expression of HppD from both pigmented and non-pigmented Aeromonas species in E. coli leads to the production of pyomelanin and thus pigmentation, suggesting that most Aeromonas species have the critical enzymes to produce pyomelanin through HGA. Taken together, we have identified a widely conserved biosynthesis pathway of HGA based pyomelanin in Aeromonas that may be responsible for pigmentation of many Aeromonas species. PMID- 25793759 TI - Ultrasound-guided tranversus abdominis plane block for herniorrhaphy in children: what is the optimal dose of levobupivacaine? PMID- 25793760 TI - Survival after long-term isoflurane sedation as opposed to intravenous sedation in critically ill surgical patients: Retrospective analysis. AB - BACKGROUND: Isoflurane has shown better control of intensive care sedation than propofol or midazolam and seems to be a useful alternative. However, its effect on survival remains unclear. OBJECTIVE: The objective of this study is to compare mortality after sedation with either isoflurane or propofol/midazolam. DESIGN: A retrospective analysis of data in a hospital database for a cohort of consecutive patients. SETTING: Sixteen-bed interdisciplinary surgical ICU of a German university hospital. PATIENTS: Consecutive cohort of 369 critically ill surgical patients defined within the database of the hospital information system. All patients were continuously ventilated and sedated for more than 96 h between 1 January 2005 and 31 December 2010. After excluding 169 patients (93 >79 years old, 10 <40 years old, 46 mixed sedation, 20 lost to follow-up), 200 patients were studied, 72 after isoflurane and 128 after propofol/midazolam. INTERVENTIONS: Sedation with isoflurane using the AnaConDa system compared with intravenous sedation with propofol or midazolam. MAIN OUTCOME MEASURES: Hospital mortality (primary) and 365-day mortality (secondary) were compared with the Kaplan-Meier analysis and a log-rank test. Adjusted odds ratios (ORs) [with 95% confidence interval (95% CI)] were calculated by logistic regression analyses to determine the risk of death after isoflurane sedation. RESULTS: After sedation with isoflurane, the in-hospital mortality and 365-day mortality were significantly lower than after propofol/midazolam sedation: 40 versus 63% (P = 0.005) and 50 versus 70% (P = 0.013), respectively. After adjustment for potential confounders (coronary heart disease, chronic obstructive pulmonary disease, acute renal failure, creatinine, age and Simplified Acute Physiology Score II), patients after isoflurane were at a lower risk of death during their hospital stay (OR 0.35; 95% CI 0.18 to 0.68, P = 0.002) and within the first 365 days (OR 0.41; 95% CI 0.21 to 0.81, P = 0.010). CONCLUSION: Compared with propofol/midazolam sedation, long-term sedation with isoflurane seems to be well tolerated in this group of critically ill patients after surgery. PMID- 25793761 TI - Correction: spatially explicit trends in the global conservation status of vertebrates. PMID- 25793762 TI - Recombinant TSH stimulated remnant ablation therapy in thyroid cancer: the success rate depends on the definition of ablation success--an observational study. AB - INTRODUCTION: Patients with differentiated thyroid cancer (DTC) are treated with (near)-total thyroidectomy followed by remnant ablation. Optimal radioiodine-131 (131I) uptake is achieved by withholding thyroid hormone (THW), pretreatment with recombinant human Thyrotropin Stimulating Hormone (rhTSH) is an alternative. Six randomized trials have been published comparing THW and rhTSH, however comparison is difficult because an uniform definition of ablation success is lacking. Using a strict definition, we performed an observational study aiming to determine the efficacy of rhTSH as preparation for remnant ablation. PATIENTS AND METHODS: Adult DTC patients with, tumor stage T1b to T3, Nx, N0 and N1, M0 were included in a prospective multicenter observational study with a fully sequential design, using a stopping rule. All patients received remnant ablation with 131I using rhTSH. Ablation success was defined as no visible uptake in the original thyroid bed on a rhTSH stimulated 150 MBq 131I whole body scan (WBS) 9 months after remnant ablation, or no visible uptake in the original thyroid bed on a post therapeutic WBS when a second high dose was necessary. RESULTS: After interim analysis of the first 8 patients, the failure rate was estimated to be 69% (90% confidence interval (CI) 20-86%) and the inclusion of new patients had to be stopped. Final analysis resulted in an ablation success in 11 out of 17 patients (65%, 95% CI 38-86%). CONCLUSION: According to this study, the efficacy of rhTSH in the preparation of 131I ablation therapy is inferior, when using a strict definition of ablation success. The current lack of agreement as to the definition of successful remnant ablation, makes comparison between different ablation strategies difficult. Our results point to the need for an international consensus on the definition of ablation success, not only in routine patient's care but also for scientific reasons. TRIAL REGISTRATION: Dutch Trial Registration NTR2395. PMID- 25793763 TI - Immunomodulatory cross-talk between conjunctival goblet cells and dendritic cells. AB - Goblet cells are secretory epithelial cells of mucosal tissues that confer protection from environmental agents or pathogens via expression and secretion of soluble mucins. Loss of these cells is associated with several chronic inflammatory disorders of the mucosa. Although demonstrated to transfer antigens from the luminal surface to stromal cells in the intestinal mucosa, it is not known if goblet cells contribute to the regulation of an immune response. In this study we report that similar to intestinal and respiratory mucosal epithelia, mouse ocular surface epithelia predominantly express the TGF-beta2 isoform. Specifically, we demonstrate the ability of goblet cells to express TGF-beta2 and increase it in response to Toll-Like Receptor 4 mediated stimulus in cultures. Goblet cells not only express TGF-beta2, but are also able to activate it in a thrombospondin-1 (TSP-1) dependent manner via their cell surface receptor CD36. Furthermore, goblet cell derived soluble factors that possibly include TGF-beta2, alter dendritic cell (DC) phenotype to a tolerogenic type by downregulating DC expression of MHC class II and co-stimulatory molecules CD80, CD86 and CD40. Thus our study demonstrates goblet cells as a cellular source of active TGF-beta2 in ocular mucosa and implicates their immunomodulatory function in maintaining mucosal immune homeostasis. PMID- 25793764 TI - The basic reproduction number as a predictor for epidemic outbreaks in temporal networks. AB - The basic reproduction number R0--the number of individuals directly infected by an infectious person in an otherwise susceptible population--is arguably the most widely used estimator of how severe an epidemic outbreak can be. This severity can be more directly measured as the fraction of people infected once the outbreak is over, Omega. In traditional mathematical epidemiology and common formulations of static network epidemiology, there is a deterministic relationship between R0 and Omega. However, if one considers disease spreading on a temporal contact network--where one knows when contacts happen, not only between whom--then larger R0 does not necessarily imply larger Omega. In this paper, we numerically investigate the relationship between R0 and Omega for a set of empirical temporal networks of human contacts. Among 31 explanatory descriptors of temporal network structure, we identify those that make R0 an imperfect predictor of Omega. We find that descriptors related to both temporal and topological aspects affect the relationship between R0 and Omega, but in different ways. PMID- 25793765 TI - Hyperglycaemia, insulin therapy and critical penumbral regions for prognosis in acute stroke: further insights from the INSULINFARCT trial. AB - BACKGROUND: Recently, the concept of 'clinically relevant penumbra' was defined as an area saved by arterial recanalization and correlated with stroke outcome. This clinically relevant penumbra was located in the subcortical structures, especially the periventricular white matter. Our aims were to confirm this hypothesis, to investigate the impact of admission hyperglycemia and of insulin treatment on the severity of ischemic damages in this area and to study the respective contributions of infarct volume and ischemic damage severity of the clinically relevant penumbra on 3-month outcome. METHODS: We included 99 patients from the INSULINFARCT trial. Voxel-Based Analysis was carried on the Apparent Diffusion Coefficient (ADC) maps obtained at day one to localize the regions, which were more damaged in patients i) with poor clinical outcomes at three months and ii) without arterial recanalization. We determined the intersection of the detected areas, which represents the clinically relevant penumbra and investigated whether hyperglycemic status and insulin regimen affected the severity of ischemic damages in this area. We performed logistic regression to examine the contribution of infarct volume or early ADC decrease in this strategic area on 3-month outcome. FINDINGS: Lower ADC values were found in the corona radiata in patients with poor prognosis (p< 0.0001) and in those without arterial recanalization (p< 0.0001). The tracking analysis showed that lesions in this area interrupted many important pathways. ADC values in this area were lower in hyperglycemic than in normoglycemic patients (average decrease of 41.6 +/- 20.8 x10(-6) mm2/s) and unaffected by the insulin regimen (p: 0.10). ADC values in the clinically relevant penumbra, but not infarct volumes, were significant predictors of 3-month outcome. CONCLUSION: These results confirm that the deep hemispheric white matter is part of the clinically relevant penumbra and show that hyperglycaemia exacerbates the apparition of irreversible ischemic damage within 24 hours in this area. However, early intensive insulin therapy fails to protect this area from infarction. TRIAL REGISTRATION: ClinicalTrials.gov NCT00472381. PMID- 25793766 TI - Alterations in cerebral white matter and neuropsychology in patients with cirrhosis and falls. AB - BACKGROUND & AIM: Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls. PATIENTS AND METHODS: Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson's Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson's Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients. RESULTS: The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson's Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05). CONCLUSIONS: With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment. PMID- 25793767 TI - The elicitin-like glycoprotein, ELI025, is secreted by the pathogenic oomycete Pythium insidiosum and evades host antibody responses. AB - Pythium insidiosum is a unique oomycete that can infect humans and animals. Patients with a P. insidiosum infection (pythiosis) have high rates of morbidity and mortality. The pathogen resists conventional antifungal drugs. Information on the biology and pathogenesis of P. insidiosum is limited. Many pathogens secrete proteins, known as effectors, which can affect the host response and promote the infection process. Elicitins are secretory proteins and are found only in the oomycetes, primarily in Phytophthora and Pythium species. In plant-pathogenic oomycetes, elicitins function as pathogen-associated molecular pattern molecules, sterol carriers, and plant defense stimulators. Recently, we reported a number of elicitin-encoding genes from the P. insidiosum transcriptome. The function of elicitins during human infections is unknown. One of the P. insidiosum elicitin encoding genes, ELI025, is highly expressed and up-regulated at body temperature. This study aims to characterize the biochemical, immunological, and genetic properties of the elicitin protein, ELI025. A 12.4-kDa recombinant ELI025 protein (rELI025) was expressed in Escherichia coli. Rabbit anti-rELI025 antibodies reacted strongly with the native ELI025 in P. insidiosum's culture medium. The detected ELI025 had two isoforms: glycosylated and non-glycosylated. ELI025 was not immunoreactive with sera from pythiosis patients. The region near the transcriptional start site of ELI025 contained conserved oomycete core promoter elements. In conclusion, ELI025 is a small, abundant, secreted glycoprotein that evades host antibody responses. ELI025 is a promising candidate for development of diagnostic and therapeutic targets for pythiosis. PMID- 25793768 TI - Homing receptor expression is deviated on CD56+ blood lymphocytes during pregnancy in Type 1 diabetic women. AB - Type 1 Diabetes Mellitus (T1DM) is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56bright NK cells, into early decidua basalis and a 2nd trimester shift towards Type 2 immunity. Decidual CD56bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. In vitro studies show that T1DM reduces interactions between blood CD56+ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1+) and Type 2 (IL1RL1+) CD56bright NK, CD56dim NK, NKT and T cells) from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2nd trimester. At this time, these receptors were expressed at very low levels by CD56bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56bright NK cells. This implicates CD56bright NK cells in diabetic pregnancy complications. PMID- 25793769 TI - Cigarette smoke causes caspase-independent apoptosis of bronchial epithelial cells from asthmatic donors. AB - BACKGROUND: Epidemiologic studies have demonstrated important links between air pollution and asthma. Amongst these pollutants, environmental cigarette smoke is a risk factor both for asthma pathogenesis and exacerbation. As the barrier to the inhaled environment, the bronchial epithelium is a key structure that is exposed to cigarette smoke. OBJECTIVES: Since primary bronchial epithelial cells (PBECs) from asthmatic donors are more susceptible to oxidant-induced apoptosis, we hypothesized that they would be susceptible to cigarette smoke-induced cell death. METHODS: PBECs from normal and asthmatic donors were exposed to cigarette smoke extract (CSE); cell survival and apoptosis were assessed by fluorescence activated cell sorting, and protective effects of antioxidants evaluated. The mechanism of cell death was evaluated using caspase inhibitors and immunofluorescent staining for apoptosis-inducing factor (AIF). RESULTS: Exposure of PBEC cultures to CSE resulted in a dose-dependent increase in cell death. At 20% CSE, PBECs from asthmatic donors exhibited significantly more apoptosis than cells from non-asthmatic controls. Reduced glutathione (GSH), but not ascorbic acid (AA), protected against CSE-induced apoptosis. To investigate mechanisms of CSE-induced apoptosis, caspase-3 or -9 inhibitors were tested, but these failed to prevent apoptosis; in contrast, CSE promoted nuclear translocation of AIF from the mitochondria. GSH reduced the number of nuclear-AIF positive cells whereas AA was ineffective. CONCLUSION: Our results show that PBECs from asthmatic donors are more susceptible to CSE-induced apoptosis. This response involves AIF, which has been implicated in DNA damage and ROS-mediated cell-death. Epithelial susceptibility to CSE may contribute to the impact of environmental tobacco smoke in asthma. PMID- 25793770 TI - Achieving body weight adjustments for feeding status and pregnant or non-pregnant condition in beef cows. AB - BACKGROUND: Beef cows herd accounts for 70% of the total energy used in the beef production system. However, there are still limited studies regarding improvement of production efficiency in this category, mainly in developing countries and in tropical areas. One of the limiting factors is the difficulty to obtain reliable estimates of weight variation in mature cows. This occurs due to the interaction of weight of maternal tissues with specific physiological stages such as pregnancy. Moreover, variation in gastrointestinal contents due to feeding status in ruminant animals is a major source of error in body weight measurements. OBJECTIVES: Develop approaches to estimate the individual proportion of weight from maternal tissues and from gestation in pregnant cows, adjusting for feeding status and stage of gestation. METHODS AND FINDINGS: Dataset of 49 multiparous non-lactating Nellore cows (32 pregnant and 17 non-pregnant) were used. To establish the relationships between the body weight, depending on the feeding status of pregnant and non-pregnant cows as a function of days of pregnancy, a set of general equations was tested, based on theoretical suppositions. We proposed the concept of pregnant compound (PREG), which represents the weight that is genuinely related to pregnancy. The PREG includes the gravid uterus minus the non-pregnant uterus plus the accretion in udder related to pregnancy. There was no accretion in udder weight up to 238 days of pregnancy. By subtracting the PREG from live weight of a pregnant cow, we obtained estimates of the weight of only maternal tissues in pregnant cows. Non-linear functions were adjusted to estimate the relationship between fasted, non-fasted and empty body weight, for pregnant and non-pregnant cows. CONCLUSIONS: Our results allow for estimating the actual live weight of pregnant cows and their body constituents, and subsequent comparison as a function of days of gestation and feeding status. PMID- 25793771 TI - High ABCC2 and low ABCG2 gene expression are early events in the colorectal adenoma-carcinoma sequence. AB - Development of colorectal cancer (CRC) may result from a dysfunctional interplay between diet, gut microbes and the immune system. The ABC transport proteins ABCB1 (P-glycoprotein, Multidrug resistance protein 1, MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) are involved in transport of various compounds across the epithelial barrier. Low mRNA level of ABCB1 has previously been identified as an early event in colorectal carcinogenesis (Andersen et al., PLoS One. 2013 Aug 19;8(8):e72119). ABCC2 and ABCG2 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 106 adenoma cases (12 with severe dysplasia, 94 with mild moderate dysplasia) and from 18 controls with normal endoscopy. We found significantly higher level of ABCC2 in adenomas with mild to moderate dysplasia and carcinoma tissue compared to the levels in unaffected tissue from the same individual (P = 0.037, P = 0.037, and P<0.0001) and in carcinoma and distant unaffected tissue from CRC cases compared to the level in the healthy individuals (P = 0.0046 and P = 0.036). Furthermore, ABCG2 mRNA levels were significantly lower in adenomas and carcinomas compared to the level in unaffected tissue from the same individuals and compared to tissue from healthy individuals (P<0.0001 for all). The level of ABCB2 in adjacent normal tissue was significantly higher than in tissue from healthy individuals (P = 0.011). In conclusion, this study found that ABCC2 and ABCG2 expression levels were altered already in mild/moderate dysplasia in carcinogenesis suggesting that these ABC transporters are involved in the early steps of carcinogenesis as previously reported for ABCB1. These results suggest that dysfunctional transport across the epithelial barrier may contribute to colorectal carcinogenesis. PMID- 25793772 TI - Jumping to conclusions style along the continuum of delusions: delusion-prone individuals are not hastier in decision making than healthy individuals. AB - Literature comparing 'jumping to conclusions' (JTC) between patients and healthy controls has demonstrated the importance of the reasoning bias in the development of delusions. When groups that vary along the entire delusional continuum are included, the relationship between JTC and delusionality is less clear. This study compared JTC and delusional dimensions between 28 patients with delusions, 35 delusion-prone individuals and 32 non-delusion-prone individuals. Delusion proneness was defined by an established threshold based on the Peters et al. Delusions Inventory. Two versions of the beads task (85:15 and 60:40) were used to measure JTC. As hypothesized, patients manifested hastier data gathering than the two non-clinical groups on both beads tasks. However, delusion-prone individuals did not manifest a hastier decision making style than non-delusion prone individuals. Instead, non-delusion-prone participants showed more JTC bias than delusion-prone individuals on the easier beads task. There was no evidence for a dose-response relationship between JTC and delusional dimensions, with correlations between JTC and PDI scores found in the non-delusion-prone group only. The present finding confirms the link between an extreme JTC bias and the presence of clinical delusions, and argues against a linear relationship between JTC and delusionality along the symptomatic continuum. PMID- 25793773 TI - Randomized single-blinded non-inferiority trial of 7 mg/kg pentamidine isethionate versus 4 mg/kg pentamidine isethionate for cutaneous leishmaniaisis in Suriname. AB - BACKGROUND: Standard treatment of cutaneous leishmaniasis (CL) in Suriname entails three injections of pentamidine isethionate (PI) 4 mg/kg per injection in 7 days (7 day regimen). Compliance to treatment is low and may contribute to increasing therapy failure. A 3 day regimen, including 2 injections of 7 mg/kg in 3 days may increase compliance. METHODS: In a randomized, single-blinded non inferiority trial conducted in Suriname, 84 CL patients received the 7 day regimen and 79 CL patients received the 3 day regimen. Primary objective was the proportion of patients clinically cured at 6 weeks follow-up. Secondary objectives were clinical cure at 12 weeks follow-up; parasitological cure at 6 and 12 weeks; adverse and drug related toxicity events recorded one week after the end of treatment and health related quality of life. The non-inferiority margin was set at 15%, 1 sided test, alpha = 0.1. RESULTS: At 6 weeks follow-up 31 (39%) patients in the 3 day regimen and 41 (49%) patients in the 7 day regimen were clinically cured. Intention to treat (ITT) analyses showed that the difference in proportion clinically cured was -9.6% (90% Confidence Interval (CI): -22.3% to 3.2%). Per protocol (PP) analysis showed that the difference in proportion clinically cured was 0.2% (90% CI: -14.6% to 15.2%). ITT analysis showed that the difference in proportion parasitological cured at 6 weeks was 15.2% (90% CI:-28.0% to -2.5%). PP analyses showed similar results. Non inferiority could not be concluded for all adverse and toxicological events. CONCLUSION: We cannot conclude that the 3 day regimen is non-inferior to the 7 day regimen regarding proportion clinically and parasitological cured. Therefore there is no evidence to change the current standard practice of the 7 day regimen for the treatment of CL in Suriname. PMID- 25793774 TI - Synthesis of improved lysomotropic autophagy inhibitors. AB - Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of antimalarial agents and found that quinacrine (QN) had 60-fold higher potency of autophagy inhibition than chloroquine (CQ), a well-known autophagy inhibitor that functions by disrupting lysosomal activity. Despite desirable autophagy inhibiting properties, QN showed considerable cytotoxicity. Therefore, we designed and synthesized a novel series of QN analogs and investigated their effects on autophagy inhibition and cell viability. Notably, we found two compounds (33 and 34), bearing a backbone of 1,2,3,4-tetrahydroacridine, had limited cytotoxicity yet strong autophagy inhibition properties. In conclusion, these improved lysomotropic autophagy inhibitors may have use as anticancer agents in combination with conventional therapies. PMID- 25793775 TI - Euros vs. yuan: comparing European and Chinese fishing access in West Africa. AB - We compare the performance of European Union (EU) and Chinese fisheries access agreements with West African countries in terms of illegal and unreported fishing, economic equity, and patterns of exploitation. Bottom-up re-estimations of catch reveal that the EU (1.6 million t*year(-1)) and China (2.3 million t*year(-1)) report only 29% and 8%, respectively, of their estimated total catches (including estimated discards whenever possible) from West African countries between 2000 and 2010. EU catches are declining, while Chinese catches are increasing and are yet to reach the historic maximum level of EU catches (3 million t*year(-1) on average in the 1970s-1980s). The monetary value of EU fishing agreements, correlated in theory with reported catches, is straightforward to access, in contrast to Chinese agreements. However, once quantified, the value of Chinese agreements is readily traceable within the African economy through the different projects they directly cover, in contrast to the funds disbursed [to host governments] by the EU. Overall, China provides resources equivalent to about 4% of the ex-vessel value [value at landing] of the catch taken by Chinese distant-water fleets from West African waters, while the EU pays 8%. We address the difficulties of separating fees directly related to fishing from other economic or political motivations for Chinese fees, which could introduce a bias to the present findings as this operation is not performed for EU access fees officially related to fishing. Our study reveals that the EU and China perform similarly in terms of illegal fishing, patterns of exploitation and sustainability of resource use, while under-reporting by the EU increases and that by China decreases. The EU agreements provide, in theory, room for improving scientific research, monitoring and surveillance, suggesting a better performance than for Chinese agreements, but the end-use of the EU funds are more difficult, and sometime impossible to ascertain. PMID- 25793776 TI - Biomass and abundance biases in European standard gillnet sampling. AB - The European Standard EN 14757 recommends gillnet mesh sizes that range from 5 to 55mm (knot-to-knot) for the standard monitoring of fish assemblages and suggests adding gillnets with larger mesh sizes if necessary. Our research showed that the recommended range of mesh sizes did not provide a representative picture of fish sizes for larger species that commonly occur in continental Europe. We developed a novel, large mesh gillnet which consists of mesh sizes 70, 90, 110 and 135mm (knot to knot, 10m panels) and assessed its added value for monitoring purposes. From selectivity curves obtained by sampling with single mesh size gillnets (11 mesh sizes 6 - 55mm) and large mesh gillnets, we identified the threshold length of bream (Abramis brama) above which this widespread large species was underestimated by European standard gillnet catches. We tested the European Standard gillnet by comparing its size composition with that obtained during concurrent pelagic trawling and purse seining in a cyprinid-dominated reservoir and found that the European Standard underestimated fish larger than 292mm by 26 times. The inclusion of large mesh gillnets in the sampling design removed this underestimation. We analysed the length-age relationship of bream in the Rimov Reservoir, and concluded that catches of bream larger than 292mm and older than five years were seriously underrepresented in European Standard gillnet catches. The Rimov Reservoir is a typical cyprinid-dominated water body where the biomass of bream > 292mm formed 70% of the pelagic trawl and purse seine catch. The species-specific relationships between the large mesh gillnet catch and European Standard catch suggested that the presence of carp (Cyprinus carpio), European catfish (Silurus glanis), tench (Tinca tinca) or bream warrants the use of both gillnet types. We suggest extending the gillnet series in the European Standard to avoid misinterpretation of fish community biomass estimates. PMID- 25793777 TI - Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. AB - We aimed to determine the effect of SGI-110 on methylation and expression of the cancer testis antigens (CTAs) NY-ESO-1 and MAGE-A in epithelial ovarian cancer (EOC) cells in vitro and in vivo and to establish the impact of SGI-110 on expression of major histocompatibility (MHC) class I and Intracellular Adhesion Molecule 1 (ICAM-1) on EOC cells, and on recognition of EOC cells by NY-ESO-1 specific CD8+ T-cells. We also tested the impact of combined SGI-110 and NY-ESO-1 specific CD8+ T-cells on tumor growth and/or murine survival in a xenograft setting. EOC cells were treated with SGI-110 in vitro at various concentrations and as tumor xenografts with 3 distinct dose schedules. Effects on global methylation (using LINE-1), NY-ESO-1 and MAGE-A methylation, mRNA, and protein expression were determined and compared to controls. SGI-110 treated EOC cells were evaluated for expression of immune-modulatory genes using flow cytometry, and were co-cultured with NY-ESO-1 specific T-cell clones to determine immune recognition. In vivo administration of SGI-110 and CD8+ T-cells was performed to determine anti-tumor effects on EOC xenografts. SGI-110 treatment induced hypomethylation and CTA gene expression in a dose dependent manner both in vitro and in vivo, at levels generally superior to azacitidine or decitabine. SGI-110 enhanced the expression of MHC I and ICAM-1, and enhanced recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. Sequential SGI-110 and antigen-specific CD8+ cell treatment restricted EOC tumor growth and enhanced survival in a xenograft setting. SGI-110 is an effective hypomethylating agent and immune modulator and, thus, an attractive candidate for combination with CTA-directed vaccines in EOC. PMID- 25793778 TI - Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress. AB - Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine response to stress. We here show that ELS programs the expression of the GR gene (Nr3c1) by site specific hypermethylation at the CpG island (CGI) shore in hypothalamic neurons that produce corticotropin-releasing hormone (Crh), thus preventing Crh upregulation under conditions of chronic stress. CpGs mapping to the Nr3c1 CGI shore region are dynamically regulated by ELS and underpin methylation-sensitive control of this region's insulation-like function via Ying Yang 1 (YY1) binding. Our results provide new insight into how a genomic element integrates experience dependent epigenetic programming of the composite proximal Nr3c1 promoter, and assigns an insulating role to the CGI shore. PMID- 25793779 TI - Nod-like receptor protein-3 inflammasome plays an important role during early stages of wound healing. AB - The Nod-like receptor protein (NLRP)-3 inflammasome/IL-1beta pathway is involved in the pathogenesis of various inflammatory skin diseases, but its biological role in wound healing remains to be elucidated. Since inflammation is typically thought to impede healing, we hypothesized that loss of NLRP-3 activity would result in a downregulated inflammatory response and accelerated wound healing. NLRP-3 null mice, caspase-1 null mice and C57Bl/6 wild type control mice (WT) received four 8 mm excisional cutaneous wounds; inflammation and healing were assessed during the early stage of wound healing. Consistent with our hypothesis, wounds from NLRP-3 null and caspase-1 null mice contained lower levels of the pro inflammatory cytokines IL-1beta and TNF-alpha compared to WT mice and had reduced neutrophil and macrophage accumulation. Contrary to our hypothesis, re epithelialization, granulation tissue formation, and angiogenesis were delayed in NLRP-3 null mice and caspase-1 null mice compared to WT mice, indicating that NLRP-3 signaling is important for early events in wound healing. Topical treatment of excisional wounds with recombinant IL-1beta partially restored granulation tissue formation in wounds of NLRP-3 null mice, confirming the importance of NLRP-3-dependent IL-1beta production during early wound healing. Despite the improvement in healing, angiogenesis and levels of the pro-angiogenic growth factor VEGF were further reduced in IL-1beta treated wounds, suggesting that IL-1beta has a negative effect on angiogenesis and that NLRP-3 promotes angiogenesis in an IL-1beta-independent manner. These findings indicate that the NLRP-3 inflammasome contributes to the early inflammatory phase following skin wounding and is important for efficient healing. PMID- 25793781 TI - Trabecular architecture of the manual elements reflects locomotor patterns in primates. AB - The morphology of trabecular bone has proven sensitive to loading patterns in the long bones and metacarpal heads of primates. It is expected that we should also see differences in the manual digits of primates that practice different methods of locomotion. Primate proximal and middle phalanges are load-bearing elements that are held in different postures and experience different mechanical strains during suspension, quadrupedalism, and knuckle walking. Micro CT scans of the middle phalanx, proximal phalanx and the metacarpal head of the third ray were used to examine the pattern of trabecular orientation in Pan, Gorilla, Pongo, Hylobates and Macaca. Several zones, i.e., the proximal ends of both phalanges and the metacarpal heads, were capable of distinguishing between knuckle-walking, quadrupedal, and suspensory primates. Orientation and shape seem to be the primary distinguishing factors but differences in bone volume, isotropy index, and degree of anisotropy were seen across included taxa. Suspensory primates show primarily proximodistal alignment in all zones, and quadrupeds more palmar-dorsal orientation in several zones. Knuckle walkers are characterized by having proximodistal alignment in the proximal ends of the phalanges and a palmar-dorsal alignment in the distal ends and metacarpal heads. These structural differences may be used to infer locmotor propensities of extinct primate taxa. PMID- 25793782 TI - Correction: Distinct facial processing related negative cognitive bias in first episode and recurrent major depression: evidence from the N170 ERP component. PMID- 25793780 TI - Impact of renal dysfunction on mid-term outcome after transcatheter aortic valve implantation: a systematic review and meta-analysis. AB - BACKGROUND: There is conflicting evidence regarding the impact of preexisting renal dysfunction (RD) on mid-term outcomes after transcatheter aortic valve implantation (TAVI) in patients with symptomatic aortic stenosis (AS). METHODS AND RESULTS: Forty-seven articles representing 32,131 patients with AS undergoing a TAVI procedure were included in this systematic review and meta-analysis. Pooled analyses were performed with both univariate and multivariate models, using a fixed or random effects method when appropriate. Compared with patients with normal renal function, mid-term mortality was significantly higher in patients with preexisting RD, as defined by the author (univariate hazard ratio [HR]: 1.69; 95% confidence interval [CI]: 1.50-1.90; multivariate HR: 1.47; 95% CI: 1.17-1.84), baseline estimated glomerular filtration rate (eGFR) (univariate HR: 1.65; 95% CI: 1.47-1.86; multivariate HR: 1.46; 95% CI: 1.24-1.71), and serum creatinine (univariate HR: 1.69; 95% CI: 1.48-1.92; multivariate HR: 1.65; 95% CI: 1.36-1.99). Advanced stage of chronic kidney disease (CKD stage 3-5) was strongly related to bleeding (univariate HR in CKD stage 3: 1.30, 95% CI: 1.13 1.49; in CKD stage 4: 1.30, 95% CI: 1.04-1.62), acute kidney injure (AKI) (univariate HR in CKD stage 3: 1.28, 95% CI: 1.03-1.59; in CKD stage 4: 2.27, 95% CI: 1.74-2.96), stroke (univariate HR in CKD stage 4: 3.37, 95% CI: 1.52-7.46), and mid-term mortality (univariate HR in CKD stage 3: 1.57, 95% CI: 1.26-1.95; in CKD stage 4: 2.77, 95% CI: 2.06-3.72; in CKD stage 5: 2.64, 95% CI: 1.91-3.65) compared with CKD stage 1+2. Patients with CKD stage 4 had a higher incidence of AKI (univariate HR: 1.70, 95% CI: 1.34-2.16) and all-cause death (univariate HR: 1.60, 95% CI: 1.28-1.99) compared with those with CKD stage 3. A per unit decrease in serum creatinine was also associated with a higher mortality at mid term follow-up (univariate HR: 1.24, 95% CI: 1.18-1.30; multivariate HR: 1.19, 95% CI: 1.08-1.30). CONCLUSIONS: Preexisting RD was associated with increased mid term mortality after TAVI. Patients with CKD stage 4 had significantly higher incidences of peri-procedural complications and a poorer prognosis, a finding that should be factored into the clinical decision-making process regarding these patients. PMID- 25793784 TI - Effects of fermion exchange on the polarization of exciton condensates. AB - Exchange interaction is responsible for the stability of elementary boson condensates with respect to momentum fragmentation. This remains true for composite bosons when single fermion exchanges are included but spin degrees of freedom are ignored. Here, we show that their inclusion can produce a spin fragmentation of the dark exciton condensate, i.e., an unpolarized condensate with an equal amount of spin (+2) and (-2) excitons not coupled to light. The composite boson many-body formalism allows us to predict that, for spatially indirect excitons, the condensate polarization switches from unpolarized to fully polarized when the distance between the layers confining electrons and holes increases. Importantly, the threshold distance for this switch lies in a regime fully accessible to experiments. PMID- 25793783 TI - Particle statistics affects quantum decay and Fano interference. AB - Quantum mechanical decay, Fano interference, and bound states with energy in the continuum are ubiquitous phenomena in different areas of physics. Here we experimentally demonstrate that particle statistics strongly affects quantum mechanical decay in a multiparticle system. By considering propagation of two photon states in engineered photonic lattices, we simulate quantum decay of two noninteracting particles in a multilevel Fano-Anderson model. Remarkably, when the system sustains a bound state in the continuum, fractional decay is observed for bosonic particles, but not for fermionic ones. Complete decay in the fermionic case arises because of the Pauli exclusion principle, which forbids the bound state to be occupied by the two fermions. Our experiment indicates that particle statistics can tune many-body quantum decay from fractional to complete. PMID- 25793785 TI - Characterizing quantum dynamics with initial system-environment correlations. AB - We fully characterize the reduced dynamics of an open quantum system initially correlated with its environment. Using a photonic qubit coupled to a simulated environment, we tomographically reconstruct a superchannel-a generalized channel that treats preparation procedures as inputs-from measurement of the system alone. We introduce novel quantitative measures for determining the strength of initial correlations, and to allow an experiment to be optimized in regard to its environment. PMID- 25793786 TI - Prediction and retrodiction for a continuously monitored superconducting qubit. AB - The quantum state of a superconducting transmon qubit inside a three-dimensional cavity is monitored by transmission of a microwave field through the cavity. The information inferred from the measurement record is incorporated in a density matrix rho_{t}, which is conditioned on probe results until t, and in an auxiliary matrix E_{t}, which is conditioned on probe results obtained after t. Here, we obtain these matrices from experimental data and we illustrate their application to predict and retrodict the outcome of weak and strong qubit measurements. PMID- 25793787 TI - Emergent supersymmetry at the Ising-Berezinskii-Kosterlitz-Thouless multicritical point. AB - We show that supersymmetry emerges in a large class of models in 1+1 dimensions with both Z_{2} and U(1) symmetry at the multicritical point where the Ising and Berezinskii-Kosterlitz-Thouless transitions coincide. To arrive at this result we perform a detailed renormalization group analysis of the multicritical theory including all perturbations allowed by symmetry. This analysis reveals an intricate flow with a marginally irrelevant direction that preserves part of the supersymmetry of the fixed point. The slow flow along this special line has significant consequences on the physics of the multicritical point. In particular, we show that the scaling of the U(1) gap away from the multicritical point is different from the usual Berezinskii-Kosterlitz-Thouless exponential gap scaling. PMID- 25793788 TI - Long-distance measurement-device-independent multiparty quantum communication. AB - The Greenberger-Horne-Zeilinger (GHZ) entanglement, originally introduced to uncover the extreme violation of local realism against quantum mechanics, is an important resource for multiparty quantum communication tasks. But the low intensity and fragility of the GHZ entanglement source in current conditions have made the practical applications of these multiparty tasks an experimental challenge. Here we propose a feasible scheme for practically distributing the postselected GHZ entanglement over a distance of more than 100 km for experimentally accessible parameter regimes. Combining the decoy-state and measurement-device-independent protocols for quantum key distribution, we anticipate that our proposal suggests an important avenue for practical multiparty quantum communication. PMID- 25793789 TI - Simulating Hamiltonian dynamics with a truncated Taylor series. AB - We describe a simple, efficient method for simulating Hamiltonian dynamics on a quantum computer by approximating the truncated Taylor series of the evolution operator. Our method can simulate the time evolution of a wide variety of physical systems. As in another recent algorithm, the cost of our method depends only logarithmically on the inverse of the desired precision, which is optimal. However, we simplify the algorithm and its analysis by using a method for implementing linear combinations of unitary operations together with a robust form of oblivious amplitude amplification. PMID- 25793790 TI - Superconducting quantum node for entanglement and storage of microwave radiation. AB - Superconducting circuits and microwave signals are good candidates to realize quantum networks, which are the backbone of quantum computers. We have realized a quantum node based on a 3D microwave superconducting cavity parametrically coupled to a transmission line by a Josephson ring modulator. We first demonstrate the time-controlled capture, storage, and retrieval of an optimally shaped propagating microwave field, with an efficiency as high as 80%. We then demonstrate a second essential ability, which is the time-controlled generation of an entangled state distributed between the node and a microwave channel. PMID- 25793791 TI - Minimal model of stochastic athermal systems: origin of non-Gaussian noise. AB - For a wide class of stochastic athermal systems, we derive Langevin-like equations driven by non-Gaussian noise, starting from master equations and developing a new asymptotic expansion. We found an explicit condition whereby the non-Gaussian properties of the athermal noise become dominant for tracer particles associated with both thermal and athermal environments. Furthermore, we derive an inverse formula to infer microscopic properties of the athermal bath from the statistics of the tracer particle. We apply our formulation to a granular motor under viscous friction and analytically obtain the angular velocity distribution function. Our theory demonstrates that the non-Gaussian Langevin equation is the minimal model of athermal systems. PMID- 25793792 TI - Capturing exponential variance using polynomial resources: applying tensor networks to nonequilibrium stochastic processes. AB - Estimating the expected value of an observable appearing in a nonequilibrium stochastic process usually involves sampling. If the observable's variance is high, many samples are required. In contrast, we show that performing the same task without sampling, using tensor network compression, efficiently captures high variances in systems of various geometries and dimensions. We provide examples for which matching the accuracy of our efficient method would require a sample size scaling exponentially with system size. In particular, the high variance observable e^{-betaW}, motivated by Jarzynski's equality, with W the work done quenching from equilibrium at inverse temperature beta, is exactly and efficiently captured by tensor networks. PMID- 25793793 TI - Loophole to the universal photon spectrum in electromagnetic cascades and application to the cosmological lithium problem. AB - The standard theory of electromagnetic cascades onto a photon background predicts a quasiuniversal shape for the resulting nonthermal photon spectrum. This has been applied to very disparate fields, including nonthermal big bang nucleosynthesis (BBN). However, once the energy of the injected photons falls below the pair-production threshold the spectral shape is much harder, a fact that has been overlooked in past literature. This loophole may have important phenomenological consequences, since it generically alters the BBN bounds on nonthermal relics; for instance, it allows us to reopen the possibility of purely electromagnetic solutions to the so-called "cosmological lithium problem," which were thought to be excluded by other cosmological constraints. We show this with a proof-of-principle example and a simple particle physics model, compared with previous literature. PMID- 25793794 TI - Accelerating cosmological expansion from shear and bulk viscosity. AB - The dissipation of energy from local velocity perturbations in the cosmological fluid affects the time evolution of spatially averaged fluid dynamic fields and the cosmological solution of Einstein's field equations. We show how this backreaction effect depends on shear and bulk viscosity and other material properties of the dark sector, as well as the spectrum of perturbations. If sufficiently large, this effect could account for the acceleration of the cosmological expansion. PMID- 25793795 TI - Quanta of geometry: noncommutative aspects. AB - In the construction of spectral manifolds in noncommutative geometry, a higher degree Heisenberg commutation relation involving the Dirac operator and the Feynman slash of real scalar fields naturally appears and implies, by equality with the index formula, the quantization of the volume. We first show that this condition implies that the manifold decomposes into disconnected spheres, which will represent quanta of geometry. We then refine the condition by involving the real structure and two types of geometric quanta, and show that connected spin manifolds with large quantized volume are then obtained as solutions. The two algebras M_{2}(H) and M_{4}(C) are obtained, which are the exact constituents of the standard model. Using the two maps from M_{4} to S^{4} the four-manifold is built out of a very large number of the two kinds of spheres of Planckian volume. We give several physical applications of this scheme such as quantization of the cosmological constant, mimetic dark matter, and area quantization of black holes. PMID- 25793796 TI - Wess-Zumino terms for relativistic fluids, superfluids, solids, and supersolids. AB - We use the coset construction of low-energy effective actions to systematically derive Wess-Zumino (WZ) terms for fluid and isotropic solid systems in two, three, and four spacetime dimensions. We recover the known WZ term for fluids in two dimensions as well as the very recently found WZ term for fluids in three dimensions. We find two new WZ terms for supersolids that have not previously appeared in the literature. In addition, by relaxing certain assumptions about the symmetry group of fluids we find a number of new WZ terms for fluids with and without charge, in all dimensions. We find no WZ terms for solids and superfluids. PMID- 25793797 TI - Spectrum of three-body bound States in a finite volume. AB - The spectrum of a bound state of three identical particles with a mass m in a finite cubic box is studied. It is shown that in the unitary limit, the energy shift of a shallow bound state is given by DeltaE=c(kappa^{2}/m)(kappaL)^{ 3/2}|A|^{2}exp(-2kappaL/sqrt[3]), where kappa is the bound-state momentum, L is the box size, |A|^{2} denotes the three-body analog of the asymptotic normalization coefficient of the bound state wave function, and c is a numerical constant. The formula is valid for kappaL?1. PMID- 25793798 TI - Central charges from the (N)=1 superconformal index. AB - We present prescriptions for obtaining the central charges, a and c, of a four dimensional superconformal quantum field theory from the superconformal index. At infinite N, for holographic theories dual to Sasaki-Einstein 5-manifolds the prescriptions give the O(1) parts of the central charges. This allows us, among other things, to show the exact AdS/CFT matching of a and c for arbitrary toric quiver CFTs without adjoint matter that are dual to smooth Sasaki-Einstein 5 manifolds. In addition, we include evidence from nonholographic theories for the applicability of these results outside of a holographic setting and away from the large-N limit. PMID- 25793799 TI - Lepton flavor violation in B decays? AB - The LHCb Collaboration's measurement of R_{K}=B(B^{+}->K^{+}MU^{+}MU^{-})/B(B^{+} >K^{+}e^{+}e^{-}) lies 2.6sigma below the Standard Model prediction. Several groups suggest this deficit to result from new lepton nonuniversal interactions of muons. But nonuniversal leptonic interactions imply lepton flavor violation in B decays at rates much larger than are expected in the Standard Model. A simple model shows that these rates could lie just below current limits. An interesting consequence of our model, that B(B_{s}->MU^{+}MU^{-})_{exp}/B(B_{s}->MU^{+}MU^{ })_{SM}?R_{K}?0.75, is compatible with recent measurements of these rates. We stress the importance of searches for lepton flavor violations, especially for B >KMUe, KMUtau, and B_{s}->MUe, MUtau. PMID- 25793800 TI - Determination of the strange nucleon form factors. AB - The strange contribution to the electric and magnetic form factors of the nucleon is determined at a range of discrete values of Q^{2} up to 1.4 GeV^{2}. This is done by combining a recent analysis of lattice QCD results for the electromagnetic form factors of the octet baryons with experimental determinations of those quantities. The most precise result is a small negative value for the strange magnetic moment: G_{M}^{s}(Q^{2}=0)=-0.07+/-0.03MU_{N}. At larger values of Q^{2} both the electric and magnetic form factors are consistent with zero to within 2 standard deviations. PMID- 25793802 TI - Dissecting soft radiation with factorization. AB - An essential part of high-energy hadronic collisions is the soft hadronic activity that underlies the primary hard interaction. It includes soft radiation from the primary hard partons, secondary multiple parton interactions (MPI), and factorization-violating effects. The invariant mass spectrum of the leading jet in Z+jet and H+jet events is directly sensitive to these effects, and we use a QCD factorization theorem to predict its dependence on the jet radius R, jet p_{T}, jet rapidity, and partonic process for both the perturbative and nonperturbative components of primary soft radiation. We prove that the nonperturbative contributions involve only odd powers of R, and the linear R term is universal for quark and gluon jets. The hadronization model in Pythia8 agrees well with these properties. The perturbative soft initial state radiation (ISR) has a contribution that depends on the jet area in the same way as the underlying event, but this degeneracy is broken by dependence on the jet p_{T}. The size of this soft ISR contribution is proportional to the color state of the initial partons, yielding the same positive contribution for gg->Hg and gq->Zq, but a negative interference contribution for qq[over -]->Zg. Hence, measuring these dependencies allows one to separate hadronization, soft ISR, and MPI contributions in the data. PMID- 25793803 TI - Jet quenching phenomenology from soft-collinear effective theory with Glauber gluons. AB - We present the first application of a recently developed effective theory of jet propagation in matter, soft-collinear effective theory with Glauber gluons (SCET_{G}), to inclusive hadron suppression in nucleus-nucleus collisions at RHIC and the LHC. SCET_{G}-based splitting kernels allow us to go beyond the traditional energy loss approximation and unify the treatment of vacuum and medium-induced parton showers. In the soft gluon emission limit, we establish a simple analytic relation between the QCD evolution and energy loss approaches to jet quenching. We quantify the uncertainties associated with the implementation of the in-medim modification of hadron production cross sections and show that the coupling between the jet and the medium can be constrained with better than 10% accuracy. PMID- 25793801 TI - Three-body nature of N(*) and Delta(*) resonances from sequential decay chains. AB - The Npi^{0}pi^{0} decays of positive-parity N^{*} and Delta^{*} resonances at about 2 GeV are studied at ELSA by photoproduction of two neutral pions off protons. The data reveal clear evidence for several intermediate resonances: Delta(1232), N(1520)3/2^{-}, and N(1680)5/2^{+}, with spin parities J^{P}=3/2^{+}, 3/2^{-}, and 5/2^{+}. The partial wave analysis (within the Bonn Gatchina approach) identifies N(1440)1/2^{+} and the N(pipi)_{S wave} (abbreviated as Nsigma here) as further isobars and assigns the final states to the formation of nucleon and Delta resonances and to nonresonant contributions. We observe the known Delta(1232)pi decays of Delta(1910)1/2^{+}, Delta(1920)3/2^{+}, Delta(1905)5/2^{+}, Delta(1950)7/2^{+}, and of the corresponding spin-parity series in the nucleon sector, N(1880)1/2^{+}, N(1900)3/2^{+}, N(2000)5/2^{+}, and N(1990)7/2^{+}. For the nucleon resonances, these decay modes are reported here for the first time. Further new decay modes proceed via N(1440)1/2^{+}pi, N(1520)3/2^{-}pi, N(1680)5/2^{+}pi, and Nsigma. The latter decay modes are observed in the decay of N^{*} resonances and at most weakly in Delta^{*} decays. It is argued that these decay modes provide evidence for a 3-quark nature of N^{*} resonances rather than a quark-diquark structure. PMID- 25793805 TI - eta(c) production at the LHC challenges nonrelativistic QCD factorization. AB - We analyze the first measurement of eta_{c} production, performed by the LHCb Collaboration, in the nonrelativistic QCD (NRQCD) factorization framework at next to-leading order (NLO) in the strong-coupling constant alpha_{s} and the relative velocity v of the bound quarks including the feeddown from h_{c} mesons. Converting the long-distance matrix elements extracted by various groups from J/psi yield and polarization data to the eta_{c} case using heavy-quark spin symmetry, we find that the resulting NLO NRQCD predictions greatly overshoot the LHCb data, while the color-singlet model provides an excellent description. PMID- 25793806 TI - eta(c) production at LHC and implications for the understanding of J/psi production. AB - We present a complete evaluation for the prompt eta_{c} production at the LHC at next-to-leading order in alpha_{s} in nonrelativistic QCD. By assuming heavy quark spin symmetry, the recently observed eta_{c} production data by LHCb results in a very strong constraint on the upper bound of the color-octet long distance matrix element ?O^{J/psi}(^{1}S_{0}^{[8]})? of J/psi. We find this upper bound is consistent with our previous study of the J/psi yield and polarization and can give good descriptions for the measurements, but the upper bound is inconsistent with some other theoretical estimates. This may provide important information for understanding the nonrelativistic QCD factorization formalism. PMID- 25793807 TI - Impact of eta(c) hadroproduction data on charmonium production and polarization within the nonrelativistic QCD framework. AB - With the recent LHCb data on eta_{c} production and based on heavy quark spin symmetry, we obtain the long-distance matrix elements for both eta_{c} and J/psi productions, among which, the color-singlet one for eta_{c} is obtained directly by the fit of experiment for the first time. Using our long-distance matrix elements, we can provide good description of the eta_{c} and J/psi hadroproduction measurements. Our predictions on J/psi polarization are in good agreement with the LHCb data, explain most of the CMS data, and pass through the two sets of CDF measurements in the medium p_{t} region. Considering all the possible uncertainties carefully, we obtained quite narrow bands of the J/psi polarization curves. PMID- 25793808 TI - Hyperon puzzle: hints from quantum Monte Carlo calculations. AB - The onset of hyperons in the core of neutron stars and the consequent softening of the equation of state have been questioned for a long time. Controversial theoretical predictions and recent astrophysical observations of neutron stars are the grounds for the so-called hyperon puzzle. We calculate the equation of state and the neutron star mass-radius relation of an infinite systems of neutrons and Lambda particles by using the auxiliary field diffusion Monte Carlo algorithm. We find that the three-body hyperon-nucleon interaction plays a fundamental role in the softening of the equation of state and for the consequent reduction of the predicted maximum mass. We have considered two different models of three-body force that successfully describe the binding energy of medium mass hypernuclei. Our results indicate that they give dramatically different results on the maximum mass of neutron stars, not necessarily incompatible with the recent observation of very massive neutron stars. We conclude that stronger constraints on the hyperon-neutron force are necessary in order to properly assess the role of hyperons in neutron stars. PMID- 25793809 TI - Direct observation of double-core-hole shake-up States in photoemission. AB - Direct measurements of Ar^{+} 1s^{-1}2p^{-1}nl double-core-hole shake-up states are reported using conventional single-channel photoemission, offering a new and relatively easy means to study such species. The high-quality results yield accurate energies and lifetimes of the double-core-hole states. Their photoemission spectrum also can be likened to 1s absorption of an exotic argon ion with a 2p core vacancy, providing new information about the spectroscopy of both this unusual ionic state as well as the neutral atom. PMID- 25793810 TI - Observation of motion-dependent nonlinear dispersion with narrow-linewidth atoms in an optical cavity. AB - As an alternative to state-of-the-art laser frequency stabilization using ultrastable cavities, it has been proposed to exploit the nonlinear effects from coupling of atoms with a narrow transition to an optical cavity. Here, we have constructed such a system and observed nonlinear phase shifts of a narrow optical line by a strong coupling of a sample of strontium-88 atoms to an optical cavity. The sample temperature of a few mK provides a domain where the Doppler energy scale is several orders of magnitude larger than the narrow linewidth of the optical transition. This makes the system sensitive to velocity dependent multiphoton scattering events (Dopplerons) that affect the cavity field transmission and phase. By varying the number of atoms and the intracavity power, we systematically study this nonlinear phase signature which displays roughly the same features as for much lower temperature samples. This demonstration in a relatively simple system opens new possibilities for alternative routes to laser stabilization at the sub-100 mHz level and superradiant laser sources involving narrow-line atoms. The understanding of relevant motional effects obtained here has direct implications for other atomic clocks when used in relation to ultranarrow clock transitions. PMID- 25793811 TI - gamma-Ray spectra and enhancement factors for positron annihilation with core electrons. AB - Many-body theory is developed to calculate the gamma spectra for positron annihilation in noble-gas atoms. Inclusion of electron-positron correlation effects and core annihilation gives spectra in excellent agreement with experiment [K. Iwata et al., Phys. Rev. Lett. 79, 39 (1997)]. The calculated correlation enhancement factors gamma_{nl} for individual electron orbitals nl are found to scale with the ionization energy I_{nl} (in eV), as gamma_{nl}=1+sqrt[A/I_{nl}]+(B/I_{nl})^{beta}, where A~40 eV, B~24 eV, and beta~2.3. PMID- 25793812 TI - Absorption-ablation-excitation mechanism of laser-cluster interactions in a nanoaerosol system. AB - The absorption-ablation-excitation mechanism in laser-cluster interactions is investigated by measuring Rayleigh scattering of aerosol clusters along with atomic emission from phase-selective laser-induced breakdown spectroscopy. For 532 nm excitation, as the laser intensity increases beyond 0.16 GW/cm^{2}, the scattering cross section of TiO_{2} clusters begins to decrease, concurrent with the onset of atomic emission of Ti, indicating a scattering-to-ablation transition and the formation of nanoplasmas. With 1064 nm laser excitation, the atomic emissions are more than one order of magnitude weaker than that at 532 nm, indicating that the thermal effect is not the main mechanism. To better clarify the process, time-resolved measurements of scattering signals are examined for different excitation laser intensities. For increasing laser intensity, the cross section of clusters decreases during a single pulse, evincing the shorter ablation delay time and larger ratios of ablation clusters. Assessment of the electron energy distribution during the ablation process is conducted by nondimensionalizing the Fokker-Planck equation, with analogous Strouhal Sl_{E}, Peclet Pe_{E}, and Damkohler Da_{E} numbers defined to characterize the laser induced aerothermochemical environment. For conditions where Sl_{E}?1, Pe_{E}?1, and Da_{E}?1, the electrons are excited to the conduction band by two-photon absorption, then relax to the bottom of the conduction band by electron energy loss to the lattice, and finally serve as the energy transfer media between laser field and lattice. The relationship between delay time and excitation intensity is well correlated by this simplified model with quasisteady assumption. PMID- 25793813 TI - Optical precursor with four-wave mixing and storage based on a cold-atom ensemble. AB - We observed optical precursors in four-wave mixing based on a cold-atom gas. Optical precursors appear at the edges of pulses of the generated optical field, and propagate through the atomic medium without absorption. Theoretical analysis suggests that these precursors correspond to high-frequency components of the signal pulse, which means the atoms cannot respond quickly to rapid changes in the electromagnetic field. In contrast, the low-frequency signal components are absorbed by the atoms during transmission. We also showed experimentally that the backward precursor can be stored using a Raman transition of the atomic ensemble and retrieved later. PMID- 25793814 TI - Squeezed optomechanics with phase-matched amplification and dissipation. AB - We investigate the nonlinear interaction between a squeezed cavity mode and a mechanical mode in an optomechanical system (OMS) that allows us to selectively obtain either a radiation-pressure coupling or a parametric-amplification process. The squeezing of the cavity mode can enhance the interaction strength into the single-photon strong-coupling regime, even when the OMS is originally in the weak-coupling regime. Moreover, the noise of the squeezed mode can be suppressed completely by introducing a broadband-squeezed vacuum environment that is phase matched with the parametric amplification that squeezes the cavity mode. This proposal offers an alternative approach to control the OMS using a squeezed cavity mode, which should allow single-photon quantum processes to be implemented with currently available optomechanical technology. Potential applications range from engineering single-photon sources to nonclassical phonon states. PMID- 25793815 TI - Higher-order nonlinearities revisited and their effect on harmonic generation. AB - We report on harmonic generation experiments and calculations in air to investigate the theoretical prediction of Kolesik et al. [Opt. Lett. 35, 2550 (2010)] for testing the recently proposed higher-order Kerr effect model. Our observations show that although the fifth-order nonlinearity is non-negligible, the overall defocusing effect via the higher-order nonlinearities is sufficiently small that plasma formation should be a main defocusing mechanism in high power filamentation. We also explore cross-phase modulation via the optical Kerr effect, and find that the higher-order nonlinearities can significantly alter the phase matching of harmonic generation. PMID- 25793816 TI - Optimally coherent Kerr combs generated with crystalline whispering gallery mode resonators for ultrahigh capacity fiber communications. AB - Optical Kerr frequency combs are known to be effective coherent multiwavelength sources for ultrahigh capacity fiber communications. These combs are the frequency-domain counterparts of a wide variety of spatiotemporal dissipative structures, such as cavity solitons, chaos, or Turing patterns (rolls). In this Letter, we demonstrate that Turing patterns, which correspond to the so-called primary combs in the spectral domain, are optimally coherent in the sense that for the same pump power they provide the most robust carriers for coherent data transmission in fiber communications using advanced modulation formats. Our model is based on a stochastic Lugiato-Lefever equation which accounts for laser pump frequency jitter and amplified spontaneous emission noise induced by the erbium doped fiber amplifier. Using crystalline whispering-gallery-mode resonators with quality factor Q~10^{9} for the comb generation, we show that when the noise is accounted for, the coherence of a primary comb is significantly higher than the coherence of their solitonic or chaotic counterparts for the same pump power. In order to confirm this theoretical finding, we perform an optical fiber transmission experiment using advanced modulation formats, and we show that the coherence of the primary comb is high enough to enable data transmission of up to 144 Gbit/s per comb line, the highest value achieved with a Kerr comb so far. This performance evidences that compact crystalline photonic systems have the potential to play a key role in a new generation of coherent fiber communication networks, alongside fully integrated systems. PMID- 25793817 TI - Time-ordering effects in the generation of entangled photons using nonlinear optical processes. AB - We study the effects of time ordering in photon generation processes such as spontaneous parametric down-conversion (SPDC) and four wave mixing (SFWM). The results presented here are used to construct an intuitive picture that allows us to predict when time-ordering effects significantly modify the joint spectral amplitude (JSA) of the photons generated in SPDC and SFWM. These effects become important only when the photons being generated lie with the pump beam that travels through the nonlinear material for a significant amount of time. Thus sources of spectrally separable photons are ideal candidates for the observation of modifications of the JSA due to time ordering. PMID- 25793818 TI - Classical and quantum chaotic angular-momentum pumps. AB - We study directed transport of charge and intrinsic angular momentum by periodically driven scattering in the regime of fast and strong driving. A spin orbit coupling through a kicked magnetic field confined to a compact region in space leads to irregular scattering and triggers spin flips in a spatially asymmetric manner which allows us to generate polarized currents. The dynamical mechanisms responsible for the spin separation carry over to the quantum level and give rise to spin pumping. Our theory based on the Floquet formalism is confirmed by numerical solutions of the time-dependent inhomogeneous Schrodinger equation with a continuous source term. PMID- 25793819 TI - Extreme degree of ionization in homogenous micro-capillary plasma columns heated by ultrafast current pulses. AB - Homogeneous plasma columns with ionization levels typical of megaampere discharges are created by rapidly heating gas-filled 520-MUm-diameter channels with nanosecond rise time current pulses of 40 kA. Current densities of up to 0.3 GA cm^{-2} greatly increase Joule heating with respect to conventional capillary discharge Z pinches, reaching unprecedented degrees of ionization for a high-Z plasma column heated by a current pulse of remarkably low amplitude. Dense xenon plasmas are ionized to Xe^{28+}, while xenon impurities in hydrogen discharges reach Xe^{30+}. The unique characteristics of these hot, ~300:1 length-to diameter aspect ratio plasmas allow the observation of unexpected spectroscopic phenomena. Axial spectra show the unusual dominance of the intercombination line over the resonance line of He-like Al by nearly an order of magnitude, caused by differences in opacities in the axial and radial directions. These plasma columns could enable the development of sub-10-nm x-ray lasers. PMID- 25793820 TI - Scaling of magnetic reconnection in relativistic collisionless pair plasmas. AB - Using fully kinetic simulations, we study the scaling of the inflow speed of collisionless magnetic reconnection in electron-positron plasmas from the nonrelativistic to ultrarelativistic limit. In the antiparallel configuration, the inflow speed increases with the upstream magnetization parameter sigma and approaches the speed of light when sigma>O(100), leading to an enhanced reconnection rate. In all regimes, the divergence of the pressure tensor is the dominant term responsible for breaking the frozen-in condition at the x line. The observed scaling agrees well with a simple model that accounts for the Lorentz contraction of the plasma passing through the diffusion region. The results demonstrate that the aspect ratio of the diffusion region, modified by the compression factor of proper density, remains ~0.1 in both the nonrelativistic and relativistic limits. PMID- 25793821 TI - Universal instability for wavelengths below the ion Larmor scale. AB - We demonstrate that the universal mode driven by the density gradient in a plasma slab can be absolutely unstable even in the presence of reasonable magnetic shear. Previous studies from the 1970s that reached the opposite conclusion used an eigenmode equation limited to L_{x}?rho_{i}, where L_{x} is the scale length of the mode in the radial direction, and rho_{i} is the ion Larmor radius. Here we instead use a gyrokinetic approach which does not have this same limitation. Instability is found for perpendicular wave numbers k_{y} in the range 0.7?k_{y}rho_{i}?100, and for sufficiently weak magnetic shear: L_{s}/L_{n}?17, where L_{s} and L_{n} are the scale lengths of magnetic shear and density. Thus, the plasma drift wave in a sheared magnetic field may be unstable even with no temperature gradients, no trapped particles, and no magnetic curvature. PMID- 25793804 TI - Study of e(+)e(-)->omegachi(cJ) at center of mass energies from 4.21 to 4.42 GeV. AB - Based on data samples collected with the BESIII detector at the BEPCII collider at nine center of mass energies from 4.21 to 4.42 GeV, we search for the production of e^{+}e^{-}->omegachi_{cJ} (J=0, 1, 2). The process e^{+}e^{-} >omegachi_{c0} is observed for the first time, and the Born cross sections at sqrt[s]=4.23 and 4.26 GeV are measured to be (55.4+/-6.0+/-5.9) and (23.7+/-5.3+/ 3.5) pb, respectively, where the first uncertainties are statistical and the second are systematic. The omegachi_{c0} signals at the other seven energies and the e^{+}e^{-}->omegachi_{c1} and omegachi_{c2} signals are not significant, and the upper limits on the cross sections are determined. By examining the omegachi_{c0} cross section as a function of center of mass energy, we find that it is inconsistent with the line shape of the Y(4260) observed in e^{+}e^{-} >pi^{+}pi^{-}J/psi. Assuming the omegachi_{c0} signals come from a single resonance, we extract the mass and width of the resonance to be (4230+/-8+/-6) MeV/c^{2} and (38+/-12+/-2) MeV, respectively, and the statistical significance is more than 9sigma. PMID- 25793823 TI - Critical velocity in the BEC-BCS crossover. AB - We map out the critical velocity in the crossover from Bose-Einstein condensation to Bardeen-Cooper-Schrieffer superfluidity with ultracold ^{6}Li gases. A small attractive potential is dragged along lines of constant column density. The rate of the induced heating increases steeply above a critical velocity v_{c}. In the same samples, we measure the speed of sound v_{s} by exciting density waves and compare the results to the measured values of v_{c}. We perform numerical simulations in the Bose-Einstein condensation regime and find very good agreement, validating the approach. In the strongly correlated regime our measurements of v_{c} provide a testing ground for theoretical approaches. PMID- 25793822 TI - Enhanced relativistic-electron-beam energy loss in warm dense aluminum. AB - Energy loss in the transport of a beam of relativistic electrons in warm dense aluminum is measured in the regime of ultrahigh electron beam current density over 2*10^{11} A/cm^{2} (time averaged). The samples are heated by shock compression. Comparing to undriven cold solid targets, the roles of the different initial resistivity and of the transient resistivity (upon target heating during electron transport) are directly observable in the experimental data, and are reproduced by a comprehensive set of simulations describing the hydrodynamics of the shock compression and electron beam generation and transport. We measured a 19% increase in electron resistive energy loss in warm dense compared to cold solid samples of identical areal mass. PMID- 25793824 TI - Impact of rattlers on thermal conductivity of a thermoelectric clathrate: a first principles study. AB - We investigate the role of rattling guest atoms on the lattice thermal conductivity of a type-I clathrate Ba_{8}Ga_{16}Ge_{30} by first-principles lattice dynamics. Comparing phonon properties of filled and empty clathrates, we show that rattlers cause tenfold reductions in the relaxation time of phonons by increasing the phonon-phonon scattering probability. Contrary to the resonant scattering scenario, the reduction in the relaxation time occurs in a wide frequency range, which is crucial for explaining the unusually low thermal conductivities of clathrates. We also find that the impact of rattlers on the group velocity of phonons is secondary because the flattening of phonon dispersion occurs only in a limited phase space in the Brillouin zone. PMID- 25793826 TI - Functional metamirrors using bianisotropic elements. AB - Conventional mirrors obey the simple reflection law that a plane wave is reflected as a plane wave, at the same angle. To engineer spatial distributions of fields reflected from a mirror, one can either shape the reflector or position some phase-correcting elements on top of a mirror surface. Here we show, both theoretically and experimentally, that full-power reflection with general control over the reflected wave phase is possible with a single-layer array of deeply subwavelength inclusions. These proposed artificial surfaces, metamirrors, provide various functions of shaped or nonuniform reflectors without utilizing any mirror. This can be achieved only if the forward and backward scattering of the inclusions in the array can be engineered independently, and we prove that it is possible using electrically and magnetically polarizable inclusions. The proposed subwavelength inclusions possess desired reflecting properties at the operational frequency band, while at other frequencies the array is practically transparent. The metamirror concept leads to a variety of applications over the entire electromagnetic spectrum, such as optically transparent focusing antennas for satellites, multifrequency reflector antennas for radio astronomy, low profile conformal antennas for telecommunications, and nanoreflectarray antennas for integrated optics. PMID- 25793825 TI - Stick-slip control in nanoscale boundary lubrication by surface wettability. AB - We study the effect of atomic-scale surface-lubricant interactions on nanoscale boundary-lubricated friction by considering two example surfaces-hydrophilic mica and hydrophobic graphene-confining thin layers of water in molecular dynamics simulations. We observe stick-slip dynamics for thin water films confined by mica sheets, involving periodic breaking-reforming transitions of atomic-scale capillary water bridges formed around the potassium ions of mica. However, only smooth sliding without stick-slip events is observed for water confined by graphene, as well as for thicker water layers confined by mica. Thus, our results illustrate how atomic-scale details affect the wettability of the confining surfaces and consequently control the presence or absence of stick-slip dynamics in nanoscale friction. PMID- 25793827 TI - Rate dependent response of nanoscale structures having a multiwell energy landscape. AB - A stochastic and rate-dependent response originating from thermal fluctuations over a highly nonconvex energy landscape is a prevailing aspect of the mechanical behavior of nanoscale structures. The overdamped dynamics of a bistable chain subjected to thermal fluctuations is prototypical of such behavior. Based on this approach, we find a new nondimensional quantity, similar in its mathematical structure to Boltzmann's factor, which captures the intricate competition between rate, temperature, and energy barriers underlying the system dynamics. In turn, we obtain simple universal laws for predicting statistical properties of the mechanical response. PMID- 25793828 TI - Spin glass in a field: a new zero-temperature fixed point in finite dimensions. AB - By using real-space renormalization group (RG) methods, we show that spin glasses in a field display a new kind of transition in high dimensions. The corresponding critical properties and the spin-glass phase are governed by two nonperturbative zero-temperature fixed points of the RG flow. We compute the critical exponents and discuss the RG flow and its relevance for three-dimensional systems. The new spin-glass phase we discovered has unusual properties, which are intermediate between the ones conjectured by droplet and full replica symmetry-breaking theories. These results provide a new perspective on the long-standing debate about the behavior of spin glasses in a field. PMID- 25793829 TI - Sliding mechanisms in multilayered hexagonal boron nitride and graphene: the effects of directionality, thickness, and sliding constraints. AB - The interlayer sliding potential of multilayered hexagonal boron nitride (h-BN) and graphene is investigated using density-functional theory including many-body van der Waals (vdW) interactions. We find that interlayer sliding constraints can be employed to tune the contribution of electrostatic interactions and dispersive forces to the sliding energy profile, ultimately leading to different sliding pathways in these two materials. In this context, vdW interactions are found to contribute more to the interlayer sliding potential of polar h-BN than they do in nonpolar graphene. In particular, the binding energy, the interlayer distance, and the friction force are found to depend sensitively on the number of layers. By comparing with the experimental findings, we identify sliding pathways which rationalize the observed reduced friction for thicker multilayers and provide quantitative explanation for the anisotropy of the friction force. PMID- 25793830 TI - Unveiling the orbital angular momentum and acceleration of electron beams. AB - New forms of electron beams have been intensively investigated recently, including vortex beams carrying orbital angular momentum, as well as Airy beams propagating along a parabolic trajectory. Their traits may be harnessed for applications in materials science, electron microscopy, and interferometry, and so it is important to measure their properties with ease. Here, we show how one may immediately quantify these beams' parameters without need for additional fabrication or nonstandard microscopic tools. Our experimental results are backed by numerical simulations and analytic derivation. PMID- 25793831 TI - Adiabatic pumping of Chern-Simons axion coupling. AB - We study the adiabatic pumping of the Chern-Simons axion (CSA) coupling along a parametric loop characterized by a nonzero second Chern number C^{(2)} from the viewpoint of the hybrid Wannier representation, in which the Wannier charge centers are visualized as sheets defined over a projected 2D Brillouin zone. We derive a new formula for the CSA coupling, expressing it as an integral involving Berry curvatures and potentials defined on the Wannier charge center sheets. We show that a loop characterized by a nonzero C^{(2)} requires a series of sheet touching events at which 2pi quanta of Berry curvature are passed from sheet to sheet, in such a way that e^{2}/h units of CSA coupling are pumped by a lattice vector by the end of the cycle. We illustrate these behaviors via explicit calculations on a model tight-binding Hamiltonian and discuss their implications. PMID- 25793832 TI - Orbital control of effective dimensionality: from spin-orbital fractionalization to confinement in the anisotropic ladder system CaCu(2)O(3). AB - Fractionalization of an electronic quasiparticle into spin, charge, and orbital parts is a fundamental and characteristic property of interacting electrons in one dimension. However, real materials are never strictly one dimensional and the fractionalization phenomena are hard to observe. Here we studied the spin and orbital excitations of the anisotropic ladder material CaCu_{2}O_{3}, whose electronic structure is not one dimensional. Combining high-resolution resonant inelastic x-ray scattering experiments with theoretical model calculations, we show that (i) spin-orbital fractionalization occurs in CaCu_{2}O_{3} along the leg direction x through the xz orbital channel as in a 1D system, and (ii) no fractionalization is observed for the xy orbital, which extends in both leg and rung direction, contrary to a 1D system. We conclude that the directional character of the orbital hopping can select different degrees of dimensionality. Using additional model calculations, we show that spin-orbital separation is generally far more robust than the spin-charge separation. This is not only due to the already mentioned selection realized by the orbital hopping, but also due to the fact that spinons are faster than the orbitons. PMID- 25793833 TI - J(eff)=1/2 Mott-insulating state in Rh and Ir fluorides. AB - Discovery of new transition metal compounds with large spin orbit coupling coexisting with strong electron-electron correlation among the d electrons is essential for understanding the physics that emerges from the interplay of these two effects. In this study, we predict a novel class of J_{eff}=1/2 Mott insulators in a family of fluoride compounds that are previously synthesized, but not characterized extensively. First principles calculations in the level of all electron density functional theory+dynamical mean field theory indicate that these compounds have large Mott gaps and some of them exhibit unprecedented proximity to the ideal, SU(2) symmetric J_{eff}=1/2 limit. PMID- 25793834 TI - Structural distortion-induced magnetoelastic locking in Sr(2)IrO(4) revealed through nonlinear optical harmonic generation. AB - We report a global structural distortion in Sr_{2}IrO_{4} using spatially resolved optical second and third harmonic generation rotational anisotropy measurements. A symmetry lowering from an I4_{1}/acd to I4_{1}/a space group is observed both above and below the Neel temperature that arises from a staggered tetragonal distortion of the oxygen octahedra. By studying an effective superexchange Hamiltonian that accounts for this lowered symmetry, we find that perfect locking between the octahedral rotation and magnetic moment canting angles can persist even in the presence of large noncubic local distortions. Our results explain the origin of the forbidden Bragg peaks recently observed in neutron diffraction experiments and reconcile the observations of strong tetragonal distortion and perfect magnetoelastic locking in Sr_{2}IrO_{4}. PMID- 25793835 TI - Molecular dynamics with on-the-fly machine learning of quantum-mechanical forces. AB - We present a molecular dynamics scheme which combines first-principles and machine-learning (ML) techniques in a single information-efficient approach. Forces on atoms are either predicted by Bayesian inference or, if necessary, computed by on-the-fly quantum-mechanical (QM) calculations and added to a growing ML database, whose completeness is, thus, never required. As a result, the scheme is accurate and general, while progressively fewer QM calls are needed when a new chemical process is encountered for the second and subsequent times, as demonstrated by tests on crystalline and molten silicon. PMID- 25793836 TI - Tuning bulk and surface conduction in the proposed topological Kondo insulator SmB(6). AB - Bulk and surface state contributions to the electrical resistance of single crystal samples of the topological Kondo-insulator compound SmB_{6} are investigated as a function of crystal thickness and surface charge density, the latter tuned by ionic liquid gating with electrodes patterned in a Corbino disk geometry on a single (100) surface. By separately tuning bulk and surface conduction channels, we show conclusive evidence for a model with an insulating bulk and metallic surface states, with a crossover temperature that depends solely on the relative contributions of each conduction channel. The surface conductance, on the order of 100 e^{2}/h, exhibits a field-effect mobility of 133 cm^{2}/Vs and a large carrier density of ~2*10^{14} cm^{-2}, in good agreement with recent photoemission results. With the ability to gate modulate surface conduction by more than 25%, this approach provides promise for both fundamental and applied studies of gate-tuned devices structured on bulk crystal samples. PMID- 25793837 TI - Cooper pair splitting by means of graphene quantum dots. AB - A split Cooper pair is a natural source for entangled electrons which is a basic ingredient for quantum information in the solid state. We report an experiment on a superconductor-graphene double quantum dot (QD) system, in which we observe Cooper pair splitting (CPS) up to a CPS efficiency of ~10%. With bias on both QDs, we are able to detect a positive conductance correlation across the two distinctly decoupled QDs. Furthermore, with bias only on one QD, CPS and elastic cotunneling can be distinguished by tuning the energy levels of the QDs to be asymmetric or symmetric with respect to the Fermi level in the superconductor. PMID- 25793838 TI - Current-induced forces and hot spots in biased nanojunctions. AB - We investigate theoretically the interplay of current-induced forces (CIFs), Joule heating, and heat transport inside a current-carrying nanoconductor. We find that the CIFs, due to the electron-phonon coherence, can control the spatial heat dissipation in the conductor. This yields a significant asymmetric concentration of excess heating (hot spot) even for a symmetric conductor. When coupled to the electrode phonons, CIFs drive different phonon heat flux into the two electrodes. First-principles calculations on realistic biased nanojunctions illustrate the importance of the effect. PMID- 25793839 TI - Robust helical edge transport in gated InAs/GaSb bilayers. AB - We have engineered electron-hole bilayers of inverted InAs/GaSb quantum wells, using dilute silicon impurity doping to suppress residual bulk conductance. We have observed robust helical edge states with wide conductance plateaus precisely quantized to 2e^{2}/h in mesoscopic Hall samples. On the other hand, in larger samples the edge conductance is found to be inversely proportional to the edge length. These characteristics persist in a wide temperature range and show essentially no temperature dependence. The quantized plateaus persist to a 12 T applied in-plane field; the conductance increases from 2e^{2}/h in strong perpendicular fields manifesting chiral edge transport. Our study presents a compelling case for exotic properties of a one-dimensional helical liquid on the edge of InAs/GaSb bilayers. PMID- 25793840 TI - Band of critical States in anderson localization in a strong magnetic field with random spin-orbit scattering. AB - The Anderson localization problem for a noninteracting two-dimensional electron gas subject to a strong magnetic field, disordered potential, and spin-orbit coupling is studied numerically on a square lattice. The nature of the corresponding localization-delocalization transition and the properties of the pertinent extended states depend on whether the spin-orbit coupling is uniform or fully random. For uniform spin-orbit coupling (such as Rashba coupling due to a uniform electric field), there is a band of metallic extended states in the center of a Landau band as in a "standard" Anderson metal-insulator transition. However, for fully random spin-orbit coupling, the familiar pattern of Landau bands disappears. Instead, there is a central band of critical states with definite fractal structure separated at two critical energies from two side bands of localized states. Moreover, finite size scaling analysis suggests that for this novel transition, on the localized side of a critical energy E_{c}, the localization length diverges as xi(E)?exp(alpha/sqrt[|E-E_{c}|]), a behavior which, together with the emergence of a band of critical states, is reminiscent of a Berezinskii-Kosterlitz-Thouless transition. PMID- 25793841 TI - Crossed surface flat bands of Weyl semimetal superconductors. AB - It has been noted that certain surfaces of Weyl semimetals have bound states forming open Fermi arcs, which are never seen in typical metallic states. We show that the Fermi arcs enable them to support an even more exotic surface state with crossed flat bands in the superconducting state. We clarify the topological origin of the crossed flat bands and the relevant symmetry that stabilizes the cross point. Our symmetry analysis is applicable to known candidate materials of time-reversal breaking Weyl semimetals. We also discuss their possible experimental verification by tunneling spectroscopy. PMID- 25793842 TI - Enhancement of superconductivity near a nematic quantum critical point. AB - We consider a low T_{c} metallic superconductor weakly coupled to the soft fluctuations associated with proximity to a nematic quantum critical point (NQCP). We show that (1) a BCS-Eliashberg treatment remains valid outside of a parametrically narrow interval about the NQCP, (2) the symmetry of the superconducting state (d wave, s wave, p wave) is typically determined by the noncritical interactions, but T_{c} is enhanced by the nematic fluctuations in all channels, and (3) in 2D, this enhancement grows upon approach to criticality up to the point at which the weak coupling approach breaks down, but in 3D, the enhancement is much weaker. PMID- 25793843 TI - Ambient pressure structural quantum critical point in the phase diagram of (Ca(x)Sr(1-x))(3)Rh(4)Sn(13). AB - The quasiskutterudite superconductor Sr_{3}Rh_{4}Sn_{13} features a pronounced anomaly in electrical resistivity at T^{*}~138 K. We show that the anomaly is caused by a second-order structural transition, which can be tuned to 0 K by applying physical pressure and chemical pressure via the substitution of Ca for Sr. A broad superconducting dome is centered around the structural quantum critical point. Detailed analysis of the tuning parameter dependence of T^{*} as well as insights from lattice dynamics calculations strongly support the existence of a structural quantum critical point at ambient pressure when the fraction of Ca is 0.9 (i.e., x_{c}=0.9). This establishes the (Ca_{x}Sr_{1 x})_{3}Rh_{4}Sn_{13} series as an important system for exploring the physics of structural quantum criticality without the need of applying high pressures. PMID- 25793844 TI - Effects of Lifshitz transition on charge transport in magnetic phases of Fe-based superconductors. AB - The unusual temperature dependence of the resistivity and its in-plane anisotropy observed in the Fe-based superconducting materials, particularly Ba(Fe_{1 x}Co_{x})_{2}As_{2}, has been a long-standing puzzle. Here, we consider the effect of impurity scattering on the temperature dependence of the average resistivity within a simple two-band model of a dirty spin density wave metal. The sharp drop in resistivity below the Neel temperature T_{N} in the parent compound can only be understood in terms of a Lifshitz transition following Fermi surface reconstruction upon magnetic ordering. We show that the observed resistivity anisotropy in this phase, arising from nematic defect structures, is affected by the Lifshitz transition as well. PMID- 25793845 TI - Phase diagram of a three-dimensional antiferromagnet with random magnetic anisotropy. AB - Three-dimensional antiferromagnets with random magnetic anisotropy (RMA) that have been experimentally studied to date have competing two-dimensional and three dimensional exchange interactions which can obscure the authentic effects of RMA. The magnetic phase diagram of Fe_{x}Ni_{1-x}F_{2} epitaxial thin films with true random single-ion anisotropy was deduced from magnetometry and neutron scattering measurements and analyzed using mean-field theory. Regions with uniaxial, oblique, and easy-plane anisotropies were identified. A RMA-induced glass region was discovered where a Griffiths-like breakdown of long-range spin order occurs. PMID- 25793846 TI - Exchange-bias phenomenon: the role of the ferromagnetic spin structure. AB - The exchange bias of antiferromagnetic-ferromagnetic (AFM-FM) bilayers is found to be strongly dependent on the ferromagnetic spin configuration. The widely accepted inverse proportionality of the exchange bias field with the ferromagnetic thickness is broken in FM layers thinner than the FM correlation length. Moreover, an anomalous thermal dependence of both exchange bias field and coercivity is also found. A model based on springlike domain walls parallel to the AFM-FM interface quantitatively accounts for the experimental results and, in particular, for the deviation from the inverse proportionality law. These results reveal the active role the ferromagnetic spin structure plays in AFM-FM hybrids which leads to a new paradigm of the exchange bias phenomenon. PMID- 25793848 TI - Momentum-resolved spin dynamics of bulk and surface excited States in the topological insulator Bi(2)Se(3). AB - The prospect of optically inducing and controlling a spin-polarized current in spintronic devices has generated wide interest in the out-of-equilibrium electronic and spin structure of topological insulators. In this Letter we show that only measuring the spin intensity signal over several orders of magnitude by spin-, time-, and angle-resolved photoemission spectroscopy can provide a comprehensive description of the optically excited electronic states in Bi_{2}Se_{3}. Our experiments reveal the existence of a surface resonance state in the second bulk band gap that is benchmarked by fully relativistic ab initio spin-resolved photoemission calculations. We propose that the newly reported state plays a major role in the ultrafast dynamics of the system, acting as a bottleneck for the interaction between the topologically protected surface state and the bulk conduction band. In fact, the spin-polarization dynamics in momentum space show that these states display macroscopically different temperatures and, more importantly, different cooling rates over several picoseconds. PMID- 25793847 TI - Magnetic polarization of the americium J=0 ground state in AmFe(2). AB - Trivalent americium has a nonmagnetic (J=0) ground state arising from the cancellation of the orbital and spin moments. However, magnetism can be induced by a large molecular field if Am^{3+} is embedded in a ferromagnetic matrix. Using the technique of x-ray magnetic circular dichroism, we show that this is the case in AmFe_{2}. Since ?J_{z}?=0, the spin component is exactly twice as large as the orbital one, the total Am moment is opposite to that of Fe, and the magnetic dipole operator ?T_{z}? can be determined directly; we discuss the progression of the latter across the actinide series. PMID- 25793849 TI - Dynamically controlled resonance fluorescence spectra from a doubly dressed single InGaAs quantum dot. AB - We report the first experimental demonstration of the interference-induced spectral line elimination predicted by Zhu and Scully [Phys. Rev. Lett. 76, 388 (1996)] and Ficek and Rudolph [Phys. Rev. A 60, R4245 (1999)]. We drive an exciton transition of a self-assembled quantum dot in order to realize a two level system exposed to a bichromatic laser field and observe the nearly complete elimination of the resonance fluorescence spectral line at the driving laser frequency. This is caused by quantum interference between coupled transitions among the doubly dressed excitonic states, without population trapping. We also demonstrate a multiphoton ac Stark effect with shifted subharmonic resonances and dynamical modifications of resonance fluorescence spectra by using double dressing. PMID- 25793850 TI - Giant enhancement of the optical second-harmonic emission of WSe(2) monolayers by laser excitation at exciton resonances. AB - We show that the light-matter interaction in monolayer WSe_{2} is strongly enhanced when the incoming electromagnetic wave is in resonance with the energy of the exciton states of strongly Coulomb bound electron-hole pairs below the electronic band gap. We perform second harmonic generation (SHG) spectroscopy as a function of laser energy and polarization at T=4 K. At the exciton resonance energies we record an enhancement by up to 3 orders of magnitude of the SHG efficiency, due to the unusual combination of electric dipole and magnetic dipole transitions. The energy and parity of the exciton states showing the strong resonance effects are identified in 1- and 2-photon photoluminescence excitation experiments, corroborated by first principles calculations. Targeting the identified exciton states in resonant 2-photon excitation allows us to maximize k valley coherence and polarization. PMID- 25793851 TI - Time-resolved X-ray diffraction reveals the hidden mechanism of high piezoelectric activity in a uniaxial ferroelectric. AB - High piezoelectric activity of many ferroelectrics has been the focus of numerous recent studies. The structural origin of this activity remains poorly understood due to a lack of appropriate experimental techniques and mixing of different mechanisms related to ferroelectricity and ferroelasticity. Our work reports on the study of a uniaxial Sr_{0.5}Ba_{0.5}Nb_{2}O_{6} ferroelectric where the formation of regions with different spontaneous strains is ruled out by the symmetry and where the interrelation between piezoelectricity and ferroelectricity can be inspected in an isolated fashion. We performed x-ray diffraction experiments on a single crystalline sample under alternating electric field and observed an unknown hidden-in-the-bulk mechanism, which suggests that the highest piezoelectric activity is realized in the volumes where nucleation of small ferroelectric domains takes place. This new mechanism creates a novel roadmap for designing materials with enhanced piezoelectric properties. PMID- 25793852 TI - Membrane composition variation and underdamped mechanics near transmembrane proteins and coats. AB - We study the effect of transmembrane proteins on the shape, composition, and thermodynamic stability of the surrounding membrane. When the coupling between membrane composition and curvature is strong enough, the nearby membrane composition and shape both undergo a transition from overdamped to underdamped spatial variation, well before the membrane becomes unstable in the bulk. This transition is associated with a change in the sign of the thermodynamic energy and, hence, favors the early stages of coat assembly necessary for vesiculation (budding) and may suppress the activity of mechanosensitive membrane channels and transporters. Our results suggest an approach to obtain physical parameters of the membrane that are otherwise difficult to measure. PMID- 25793853 TI - Three-dimensional reconstruction of the giant mimivirus particle with an x-ray free-electron laser. AB - We present a proof-of-concept three-dimensional reconstruction of the giant mimivirus particle from experimentally measured diffraction patterns from an x ray free-electron laser. Three-dimensional imaging requires the assembly of many two-dimensional patterns into an internally consistent Fourier volume. Since each particle is randomly oriented when exposed to the x-ray pulse, relative orientations have to be retrieved from the diffraction data alone. We achieve this with a modified version of the expand, maximize and compress algorithm and validate our result using new methods. PMID- 25793854 TI - Variational scheme to compute protein reaction pathways using atomistic force fields with explicit solvent. AB - We introduce a variational approximation to the microscopic dynamics of rare conformational transitions of macromolecules. Within this framework it is possible to simulate on a small computer cluster reactions as complex as protein folding, using state of the art all-atom force fields in explicit solvent. We test this method against MD simulations of the folding of an alpha and a beta protein performed with the same all-atom force field on the Anton supercomputer. We find that our approach yields results consistent with those of MD simulations, at a computational cost orders of magnitude smaller. PMID- 25793855 TI - Anomalous discontinuity at the percolation critical point of active gels. AB - We develop a percolation model motivated by recent experimental studies of gels with active network remodeling by molecular motors. This remodeling was found to lead to a critical state reminiscent of random percolation (RP), but with a cluster distribution inconsistent with RP. Our model not only can account for these experiments, but also exhibits an unusual type of mixed phase transition: We find that the transition is characterized by signatures of criticality, but with a discontinuity in the order parameter. PMID- 25793856 TI - Magnetic flattening of stem-cell spheroids indicates a size-dependent elastocapillary transition. AB - Cellular aggregates (spheroids) are widely used in biophysics and tissue engineering as model systems for biological tissues. In this Letter we propose novel methods for molding stem-cell spheroids, deforming them, and measuring their interfacial and elastic properties with a single method based on cell tagging with magnetic nanoparticles and application of a magnetic field gradient. Magnetic molding yields spheroids of unprecedented sizes (up to a few mm in diameter) and preserves tissue integrity. On subjecting these spheroids to magnetic flattening (over 150g), we observed a size-dependent elastocapillary transition with two modes of deformation: liquid-drop-like behavior for small spheroids, and elastic-sphere-like behavior for larger spheroids, followed by relaxation to a liquidlike drop. PMID- 25793857 TI - Macroscopic discontinuous shear thickening versus local shear jamming in cornstarch. AB - We study the emergence of discontinuous shear thickening (DST) in cornstarch by combining macroscopic rheometry with local magnetic resonance imaging measurements. We bring evidence that macroscopic DST is observed only when the flow separates into a low-density flowing and a high-density jammed region. In the shear-thickened steady state, the local rheology in the flowing region is not DST but, strikingly, is often shear thinning. Our data thus show that the stress jump measured during DST, in cornstarch, does not capture a secondary, high viscosity branch of the local steady rheology but results from the existence of a shear jamming limit at volume fractions quite significantly below random close packing. PMID- 25793859 TI - Impact of single-particle compressibility on the fluid-solid phase transition for ionic microgel suspensions. AB - We study ionic microgel suspensions composed of swollen particles for various single-particle stiffnesses. We measure the osmotic pressure pi of these suspensions and show that it is dominated by the contribution of free ions in solution. As this ionic osmotic pressure depends on the volume fraction of the suspension phi, we can determine phi from pi, even at volume fractions so high that the microgel particles are compressed. We find that the width of the fluid solid phase coexistence, measured using phi, is larger than its hard-sphere value for the stiffer microgels that we study and progressively decreases for softer microgels. For sufficiently soft microgels, the suspensions are fluidlike, irrespective of volume fraction. By calculating the dependence on phi of the mean volume of a microgel particle, we show that the behavior of the phase-coexistence width correlates with whether or not the microgel particles are compressed at the volume fractions corresponding to fluid-solid phase coexistence. PMID- 25793858 TI - Active viscoelastic matter: from bacterial drag reduction to turbulent solids. AB - A paradigm for internally driven matter is the active nematic liquid crystal, whereby the equations of a conventional nematic are supplemented by a minimal active stress that violates time-reversal symmetry. In practice, active fluids may have not only liquid-crystalline but also viscoelastic polymer degrees of freedom. Here we explore the resulting interplay by coupling an active nematic to a minimal model of polymer rheology. We find that adding a polymer can greatly increase the complexity of spontaneous flow, but can also have calming effects, thereby increasing the net throughput of spontaneous flow along a pipe (a "drag reduction" effect). Remarkably, active turbulence can also arise after switching on activity in a sufficiently soft elastomeric solid. PMID- 25793860 TI - Comment on "d+id' chiral superconductivity in bilayer silicene". PMID- 25793861 TI - Liu et al. reply. PMID- 25793862 TI - Comment on "superspin glass mediated giant spontaneous exchange bias in a nanocomposite of BiFeO(3)-Bi(2)Fe(4)O(9)". PMID- 25793863 TI - Maity et al. reply. PMID- 25793864 TI - Restoration of responsiveness of phospholipase Cgamma2-deficient platelets by enforced expression of phospholipase Cgamma1. AB - Receptor-mediated platelet activation requires phospholipase C (PLC) activity to elevate intracellular calcium and induce actin cytoskeleton reorganization. PLCs are classified into structurally distinct beta, gamma, delta, epsilon, zeta, and eta isoforms. There are two PLCgamma isoforms (PLCgamma1, PLCgamma2), which are critical for activation by tyrosine kinase-dependent receptors. Platelets express both PLCgamma1 and PLCgamma2. Although PLCgamma2 has been shown to play a dominant role in platelet activation, the extent to which PLCgamma1 contributes has not been evaluated. To ascertain the relative contributions of PLCgamma1 and PLCgamma2 to platelet activation, we generated conditionally PLCgamma1-deficient, wild-type (WT), PLCgamma2-deficient, and PLCgamma1/PLCgamma2 double-deficient mice and measured the ability of platelets to respond to different agonists. We found that PLCgamma2 deficiency abrogated alphaIIbbeta3-dependent platelet spreading, GPVI-dependent platelet aggregation, and thrombus formation on collagen-coated surfaces under shear conditions, which is dependent on both GPVI and alphaIIbbeta3. Addition of exogenous ADP overcame defective spreading of PLCgamma2-deficient platelets on immobilized fibrinogen, suggesting that PLCgamma2 is required for granule secretion in response to alphaIIbbeta3 ligation. Consistently, alphaIIbbeta3-mediated release of granule contents was impaired in the absence of PLCgamma2. In contrast, PLCgamma1-deficient platelets spread and released granule contents normally on fibrinogen, exhibited normal levels of GPVI-dependent aggregation, and formed thrombi normally on collagen coated surfaces. Interestingly, enforced expression of PLCgamma1 fully restored GPVI-dependent aggregation and alphaIIbbeta3-dependent spreading of PLCgamma2 deficient platelets. We conclude that platelet activation through GPVI and alphaIIbbeta3 utilizes PLCgamma2 because PLCgamma1 levels are insufficient to support responsiveness, but that PLCgamma1 can restore responsiveness if expressed at levels normally achieved by PLCgamma2. PMID- 25793865 TI - GhWRKY68 reduces resistance to salt and drought in transgenic Nicotiana benthamiana. AB - The WRKY transcription factors modulate numerous physiological processes, including plant growth, development and responses to various environmental stresses. Currently, our understanding of the functions of the majority of the WRKY family members and their possible roles in signalling crosstalk is limited. In particular, very few WRKYs have been identified and characterised from an economically important crop, cotton. In this study, we characterised a novel group IIc WRKY gene, GhWRKY68, which is induced by different abiotic stresses and multiple defence-related signalling molecules. The beta-glucuronidase activity driven by the GhWRKY68 promoter was enhanced after exposure to drought, salt, abscisic acid (ABA) and H2O2. The overexpression of GhWRKY68 in Nicotiana benthamiana reduced resistance to drought and salt and affected several physiological indices. GhWRKY68 may mediate salt and drought responses by modulating ABA content and enhancing the transcript levels of ABA-responsive genes. GhWRKY68-overexpressing plants exhibited reduced tolerance to oxidative stress after drought and salt stress treatments, which correlated with the accumulation of reactive oxygen species (ROS), reduced enzyme activities, elevated malondialdehyde (MDA) content and altered ROS-related gene expression. These results indicate that GhWRKY68 is a transcription factor that responds to drought and salt stresses by regulating ABA signalling and modulating cellular ROS. PMID- 25793866 TI - Individual and facility-level determinants of iron and folic acid receipt and adequate consumption among pregnant women in rural Bihar, India. AB - BACKGROUND: In Bihar, India, high maternal anemia prevalence and low iron and folic acid supplement (IFA) receipt and consumption have continued over time despite universal IFA distribution and counseling during pregnancy. PURPOSE: To examine individual and facility-level determinants of IFA receipt and consumption among pregnant women in rural Bihar, India. METHODS: Using District Level Household Survey (2007-08) data, multilevel modeling was conducted to examine the determinants of two outcomes: IFA receipt (any IFA receipt vs. none) and IFA consumption (>=90 days vs. <90 days). Individual-level and facility-level factors were included. Factor analysis was utilized to construct antenatal care (ANC) quality and health sub-center (HSC) capacity variables. RESULTS: Overall, 37% of women received any IFA during their last pregnancy. Of those, 24% consumed IFA for 90 or more days. Women were more likely to receive any IFA when they received additional ANC services and counseling, and attended ANC earlier and more frequently. Significant interactions were found between ANC quality factors (odds ratio (OR): 0.37, 95% confidence interval (CI): 0.25, 0.56) and between ANC services and ANC timing and frequency (OR: 0.68, 95% CI: 0.56, 0.82). No HSC factors were significantly associated with IFA receipt. Women were more likely to consume IFA for >=90 days if they attended at least 4 ANC check-ups and received more ANC services. IFA supply at the HSC (OR: 1.37, 95% CI: 1.04, 1.82) was also significantly associated with IFA consumption. CONCLUSIONS: Our findings indicate that individual and ANC factors (timing, frequency, and quality) play a key role in facilitating IFA receipt and consumption. Although HSC capacity factors were not found to influence our outcomes, significant variation at the facility level indicates unmeasured factors that could be important to address in future interventions. PMID- 25793867 TI - Increasing patient engagement in rehabilitation exercises using computer-based citizen science. AB - Patient motivation is an important factor to consider when developing rehabilitation programs. Here, we explore the effectiveness of active participation in web-based citizen science activities as a means of increasing participant engagement in rehabilitation exercises, through the use of a low-cost haptic joystick interfaced with a laptop computer. Using the joystick, patients navigate a virtual environment representing the site of a citizen science project situated in a polluted canal. Participants are tasked with following a path on a laptop screen representing the canal. The experiment consists of two conditions: in one condition, a citizen science component where participants classify images from the canal is included; and in the other, the citizen science component is absent. Both conditions are tested on a group of young patients undergoing rehabilitation treatments and a group of healthy subjects. A survey administered at the end of both tasks reveals that participants prefer performing the scientific task, and are more likely to choose to repeat it, even at the cost of increasing the time of their rehabilitation exercise. Furthermore, performance indices based on data collected from the joystick indicate significant differences in the trajectories created by patients and healthy subjects, suggesting that the low-cost device can be used in a rehabilitation setting for gauging patient recovery. PMID- 25793868 TI - ADCY5 gene expression in adipose tissue is related to obesity in men and mice. AB - Genome wide association studies revealed an association of the single nucleotide polymorphism rs11708067 within the ADCY5 gene--encoding adenylate cyclase 5--with increased type 2 diabetes (T2D) risk and higher fasting glucose. However, it remains unclear whether the association between ADCY5 variants and glycemic traits may involve adipose tissue (AT) related mechanisms. We therefore tested the hypothesis that ADCY5 mRNA expression in human and mouse AT is related to obesity, fat distribution, T2D in humans and high fat diet (HFD) in mice. We measured ADCY5 mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 244 individuals with a wide range of body weight and parameters of hyperglycemia, which have been genotyped for rs11708067. In addition, AT ADCY5 mRNA was assessed in C57BL/6NTac which underwent a 10 weeks standard chow (n = 6) or high fat diet (HFD, n = 6). In humans, visceral ADCY5 expression is significantly higher in obese compared to lean individuals. ADCY5 expression correlates with BMI, body fat mass, circulating leptin, fat distribution, waist and hip circumference, but not with fasting plasma glucose and HbA1c. Adcy5 expression in mouse AT is significantly higher after a HFD compared to chow (p<0.05). Importantly, rs11708067 is not associated with ADCY5 mRNA expression levels in either fat depot in any of the genetic models tested. Our results suggest that changes in AT ADCY5 expression are related to obesity and fat distribution, but not with impaired glucose metabolism and T2D. However, altered ADCY5 expression in AT does not seem to be the mechanism underlying the association between rs11708067 and increased T2D risk. PMID- 25793869 TI - Gender differences in sleep deprivation effects on risk and inequality aversion: evidence from an economic experiment. AB - Excessive working hours--even at night--are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects' risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females' reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making. PMID- 25793870 TI - The transcription factor optomotor-blind antagonizes Drosophila haltere growth by repressing decapentaplegic and hedgehog targets. AB - In Drosophila, decapentaplegic, which codes for a secreted signaling molecule, is activated by the Hedgehog signaling pathway at the anteroposterior compartment border of the two dorsal primordia; the wing and the haltere imaginal discs. In the wing disc, Decapentaplegic and Hedgehog signaling targets are implicated in cell proliferation and cell survival. However, most of their known targets in the wing disc are not expressed in the haltere disc due to their repression by the Hox gene Ultrabithorax. The T-box gene optomotor-blind escapes this repression in the haltere disc, and therefore is expressed in both the haltere and wing discs. Optomotor-blind is a major player during wing development and its function has been intensely investigated in this tissue, however, its role in haltere development has not been reported so far. Here we show that Optomotor-blind function in the haltere disc differs from that in the wing disc. Unlike its role in the wing, Optomotor-blind does not prevent apoptosis in the haltere but rather limits growth by repressing several Decapentaplegic and Hedgehog targets involved both in wing proliferation and in modulating the spread of morphogens similar to Ultrabithorax function but without disturbing Ultrabithorax expression. PMID- 25793871 TI - Using lidar data to analyse sinkhole characteristics relevant for understory vegetation under forest cover-case study of a high karst area in the dinaric mountains. AB - In this article, we investigate the potential for detection and characterization of sinkholes under dense forest cover by using airborne laser scanning data. Laser pulse returns from the ground provide important data for the estimation of digital elevation model (DEM), which can be used for further processing. The main objectives of this study were to map and determine the geomorphometric characteristics of a large number of sinkholes and to investigate the correlations between geomorphology and vegetation in areas with such characteristics. The selected study area has very low anthropogenic influences and is particularly suitable for studying undisturbed karst sinkholes. The information extracted from this study regarding the shapes and depths of sinkholes show significant directionality for both orientation of sinkholes and their distribution over the area. Furthermore, significant differences in vegetation diversity and composition occur inside and outside the sinkholes, which indicates their presence has important ecological impacts. PMID- 25793873 TI - Crystallisation-driven self-assembly of poly(2-isopropyl-2-oxazoline)-block poly(2-methyl-2-oxazoline) above the LCST. AB - The solution behaviour in water of a polyoxazoline-type block copolymer, namely poly(2-isopropyl-2-oxazoline)-block-poly(2-methyl-2-oxazoline), denoted as P(iPrOx-b-MeOx), above the lower critical solution temperature (LCST) of the PiPrOx block was exploited to induce a temporary or permanent self-assembly. Spherical micelles were first obtained and could be disassembled in a reversible manner when kept for a short period of time (i.e. t < 90 min) above the LCST, and cooled down to room temperature. In contrast, annealing the copolymer solution for more than 90 min at 65 degrees C induced the crystallisation of the PiPrOx block, as evidenced by wide angle X-ray scattering (WAXS) experiments. This crystallisation-driven self-assembly phenomenon resulted in different morphologies, including spherical and distorted crystallised micelles and micron size fibers, their relative proportion varies with the annealing time. Formation of micron-size range fiber-like structures might be explained by the re organization of parent crystallised micelles. The crystal structure, as determined by WAXS, appeared to be identical to that of the PiPrOx homopolymer. PMID- 25793872 TI - A comparison of the effects of estrogen and Cimicifuga racemosa on the lacrimal gland and submandibular gland in ovariectomized rats. AB - This study aims to observe the effects of estradiol and Cimicifuga racemosa on the lacrimal gland and submandibular gland of ovariectomized rats. We randomly divided 20 adult female SD rats into four groups-a sham-operated group (SHAM), ovariectomized (OVX) group, ovariectomized group treated with estradiol (OVX+ E), and ovariectomized group treated with the isopropanolic extract of Cimicifuga racemosa (OVX+ iCR). The SHAM group and OVX group used distilled water to instead the drugs. Two weeks after ovariectomy, the estradiol and iCR were administered for 4 weeks. Next, we used H&E staining and electron microscopy to observe any histological changes in the lacrimal and submandibular glands and immunohistochemical staining to observe the expressions of cleaved caspase-3 (Casp-3) and Cu-Zn SOD (superoxide dismutase). The H&E staining find that both drugs can prevent the cells of area from shrinkage in the two kinds of gland. But under the electron microscopy, estradiol and iCR have different efficacy. Estradiol is more effective at protecting mitochondria in lacrimal gland acinar cells than iCR, and iCR is more effective at suppressing endoplasmic reticulum expansion than estradiol. Both estradiol and iCR have a similar protective function on mitochondria in the submandibular gland. The protective function of the two glands may inhibit apoptosis by suppressing the expression of Casp-3. In addition, iCR increases the expression of Cu-Zn SOD in duct system of submandibular gland. The results suggest that both estradiol and iCR confer a protective effect on the lacrimal and submandibular glands of ovariectomized rats via different mechanisms. PMID- 25793875 TI - Correction: primary reasons for osteopathic consultation: a prospective survey in quebec. PMID- 25793874 TI - Primer-dependent and primer-independent initiation of double stranded RNA synthesis by purified Arabidopsis RNA-dependent RNA polymerases RDR2 and RDR6. AB - Cellular RNA-dependent RNA polymerases (RDRs) are fundamental components of RNA silencing in plants and many other eukaryotes. In Arabidopsis thaliana genetic studies have demonstrated that RDR2 and RDR6 are involved in the synthesis of double stranded RNA (dsRNA) from single stranded RNA (ssRNA) targeted by RNA silencing. The dsRNA is subsequently cleaved by the ribonuclease DICER-like into secondary small interfering RNAs (siRNAs) that reinforce and/or maintain the silenced state of the target RNA. Models of RNA silencing propose that RDRs could use primer-independent and primer-dependent initiation to generate dsRNA from a transcript targeted by primary siRNA or microRNA (miRNA). However, the biochemical activities of RDR proteins are still partly understood. Here, we obtained active recombinant RDR2 and RDR6 in a purified form. We demonstrate that RDR2 and RDR6 have primer-independent and primer-dependent RNA polymerase activities with different efficiencies. We further show that RDR2 and RDR6 can initiate dsRNA synthesis either by elongation of 21- to 24- nucleotides RNAs hybridized to complementary RNA template or by elongation of self-primed RNA template. These findings provide new insights into our understanding of the molecular mechanisms of RNA silencing in plants. PMID- 25793876 TI - Magnolol administration in normotensive young spontaneously hypertensive rats postpones the development of hypertension: role of increased PPAR gamma, reduced TRB3 and resultant alleviative vascular insulin resistance. AB - Patients with prehypertension are more likely to progress to manifest hypertension than those with optimal or normal blood pressure. However, the mechanisms underlying the development from prehypertension to hypertension still remain largely elusive and the drugs for antihypertensive treatment in prehypertension are absent. Here we determined the effects of magnolol (MAG) on blood pressure and aortic vasodilatation to insulin, and investigated the underlying mechanisms. Four-week-old male spontaneous hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) control rats were used. Our results shown that treatment of young SHRs with MAG (100 mg/kg/day, o.g.) for 3 weeks decreased blood pressure, improved insulin-induced aorta vasodilation, restored Akt and eNOS activation stimulated by insulin, and increased PPARgamma and decreased TRB3 expressions. In cultured human umbilical vein endothelial cells (HUVECs), MAG incubation increased PPARgamma, decreased TRB3 expressions, and restored insulin-induced phosphorylated Akt and eNOS levels and NO production, which was blocked by both PPARgamma antagonist and siRNA targeting PPARgamma. Improved insulin signaling in HUVECs by MAG was abolished by upregulating TRB3 expression. In conclusion, treatment of young SHRs with MAG beginning at the prehypertensive stage decreases blood pressure via improving vascular insulin resistance that is at least partly attributable to upregulated PPARgamma, downregulated TRB3 and consequently increased Akt and eNOS activations in blood vessels in SHRs. PMID- 25793877 TI - Transcriptome assembly, gene annotation and tissue gene expression atlas of the rainbow trout. AB - Efforts to obtain a comprehensive genome sequence for rainbow trout are ongoing and will be complemented by transcriptome information that will enhance genome assembly and annotation. Previously, transcriptome reference sequences were reported using data from different sources. Although the previous work added a great wealth of sequences, a complete and well-annotated transcriptome is still needed. In addition, gene expression in different tissues was not completely addressed in the previous studies. In this study, non-normalized cDNA libraries were sequenced from 13 different tissues of a single doubled haploid rainbow trout from the same source used for the rainbow trout genome sequence. A total of ~1.167 billion paired-end reads were de novo assembled using the Trinity RNA-Seq assembler yielding 474,524 contigs > 500 base-pairs. Of them, 287,593 had homologies to the NCBI non-redundant protein database. The longest contig of each cluster was selected as a reference, yielding 44,990 representative contigs. A total of 4,146 contigs (9.2%), including 710 full-length sequences, did not match any mRNA sequences in the current rainbow trout genome reference. Mapping reads to the reference genome identified an additional 11,843 transcripts not annotated in the genome. A digital gene expression atlas revealed 7,678 housekeeping and 4,021 tissue-specific genes. Expression of about 16,000-32,000 genes (35-71% of the identified genes) accounted for basic and specialized functions of each tissue. White muscle and stomach had the least complex transcriptomes, with high percentages of their total mRNA contributed by a small number of genes. Brain, testis and intestine, in contrast, had complex transcriptomes, with a large numbers of genes involved in their expression patterns. This study provides comprehensive de novo transcriptome information that is suitable for functional and comparative genomics studies in rainbow trout, including annotation of the genome. PMID- 25793879 TI - Correction: Biological responses of three-dimensional cultured fibroblasts by sustained compressive loading include apoptosis and survival activity. PMID- 25793878 TI - An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging. AB - Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups. PMID- 25793880 TI - Factors affecting the duration of nestling period and fledging order in Tengmalm's owl (Aegolius funereus): effect of wing length and hatching sequence. AB - In altricial birds, the nestling period is an important part of the breeding phase because the juveniles may spend quite a long time in the nest, with associated high energy costs for the parents. The length of the nestling period can be variable and its duration may be influenced by both biotic and abiotic factors; however, studies of this have mostly been undertaken on passerine birds. We studied individual duration of nestling period of 98 Tengmalm's owl chicks (Aegolius funereus) at 27 nests during five breeding seasons using a camera and chip system and radio-telemetry. We found the nestlings stayed in the nest box for 27 - 38 days from hatching (mean +/- SD, 32.4 +/- 2.2 days). The individual duration of nestling period was negatively related to wing length, but no formally significant effect was found for body weight, sex, prey availability and/or weather conditions. The fledging sequence of individual nestlings was primarily related to hatching order; no relationship with wing length and/or other factors was found in this case. We suggest the length of wing is the most important measure of body condition and individual quality in Tengmalm's owl young determining the duration of the nestling period. Other differences from passerines (e.g., the lack of effect of weather or prey availability on nestling period) are considered likely to be due to different life-history traits, in particular different food habits and nesting sites and greater risk of nest predation among passerines. PMID- 25793881 TI - Correction: Implications of an absolute simultaneity theory for cosmology and universe acceleration. PMID- 25793882 TI - Antiretroviral therapy and reasons for not taking it among men having sex with men (MSM)--results from the European MSM Internet Survey (EMIS). AB - BACKGROUND: The preventive effects of antiretroviral treatment (ART) on onward transmission of HIV are a major reason for broadening eligibility for ART. In the WHO European Region, surveillance reveals substantial differences in access to ART across regions and sub-populations. We analysed self-reported data on ART and reasons for not taking ART from EMIS, a large Pan-European Internet survey among men-who-have-sex-with-men (MSM). METHODS: Respondents from 38 European countries reported their last HIV test result and, if diagnosed with HIV, their treatment status, and reasons for not taking or having stopped ART from a 7 item multiple choice list and/ or answered an open-ended question to give other reasons. Responses were classified as fear of consequences, perceived lack of need, and ART inaccessibility based on factor analysis. Associations between not taking ART because of fear of consequences, and demographic, behavioural and contextual indicators were identified in a multivariable regression model. RESULTS: 13,353 (7.7%) of 174,209 respondents had been diagnosed with HIV. Among them 3,391 (25.4%) had never received ART, and 278 (2.1%) had stopped taking ART. Perceived lack of need was by far the most common reason for not taking or stopping ART (mentioned by 3259 (88.8%) respondents), followed by fear of consequences (428 (11.7%)), and ART inaccessibility (86 (2.3%)). For all reasons, an East-West gradient could be seen, with larger proportions of men living in Central and Eastern Europe reporting reasons other than medical advice for not taking ART. A minority of men were reluctant to start ART independent of medical advice and this was associated with experiences of discrimination in health care systems. CONCLUSIONS: ART is widely available for MSM diagnosed with HIV across Europe. Not being on treatment is predominantly due to treatment not being recommended by their physician and/or not perceived to be needed by the respondent. PMID- 25793883 TI - The subcortical cocktail problem; mixed signals from the subthalamic nucleus and substantia nigra. AB - The subthalamic nucleus and the directly adjacent substantia nigra are small and important structures in the basal ganglia. Functional magnetic resonance imaging studies have shown that the subthalamic nucleus and substantia nigra are selectively involved in response inhibition, conflict processing, and adjusting global and selective response thresholds. However, imaging these nuclei is complex, because they are in such close proximity, they can vary in location, and are very small relative to the resolution of most fMRI sequences. Here, we investigated the consistency in localization of these nuclei in BOLD fMRI studies, comparing reported coordinates with probabilistic atlas maps of young human participants derived from ultra-high resolution 7T MRI scanning. We show that the fMRI signal reported in previous studies is likely not unequivocally arising from the subthalamic nucleus but represents a mixture of subthalamic nucleus, substantia nigra, and surrounding tissue. Using a simulation study, we also tested to what extent spatial smoothing, often used in fMRI preprocessing pipelines, influences the mixture of BOLD signals. We propose concrete steps how to analyze fMRI BOLD data to allow inferences about the functional role of small subcortical nuclei like the subthalamic nucleus and substantia nigra. PMID- 25793885 TI - Calcium alginate gels as stem cell matrix-making paracrine stem cell activity available for enhanced healing after surgery. AB - Regeneration after surgery can be improved by the administration of anabolic growth factors. However, to locally maintain these factors at the site of regeneration is problematic. The aim of this study was to develop a matrix system containing human mesenchymal stem cells (MSCs) which can be applied to the surgical site and allows the secretion of endogenous healing factors from the cells. Calcium alginate gels were prepared by a combination of internal and external gelation. The gelling behaviour, mechanical stability, surface adhesive properties and injectability of the gels were investigated. The permeability of the gels for growth factors was analysed using bovine serum albumin and lysozyme as model proteins. Human MSCs were isolated, cultivated and seeded into the alginate gels. Cell viability was determined by AlamarBlue assay and fluorescence microscopy. The release of human VEGF and bFGF from the cells was determined using an enzyme-linked immunoassay. Gels with sufficient mechanical properties were prepared which remained injectable through a syringe and solidified in a sufficient time frame after application. Surface adhesion was improved by the addition of polyethylene glycol 300,000 and hyaluronic acid. Humans MSCs remained viable for the duration of 6 weeks within the gels. Human VEGF and bFGF was found in quantifiable concentrations in cell culture supernatants of gels loaded with MSCs and incubated for a period of 6 weeks. This work shows that calcium alginate gels can function as immobilization matrices for human MSCs. PMID- 25793884 TI - Red cell distribution width and inappropriateness of left ventricular mass in patients with untreated essential hypertension. AB - BACKGROUND: Left ventricular hypertrophy (LVH) was suggested to be an important risk factor for hypertensive vascular complications. Previous studies had also shown that red cell distribution width (RDW) was associated with morbidity and mortality of cardiovascular disease. However, few have yet investigated possible association between RDW and LVH. The aim of the present study was to evaluate the relationship between LVH and RDW levels in hypertensive patients. METHODS: Physical examination, laboratory tests and echocardiography were conducted in 330 untreated newly diagnosed hypertensive patients attending the cardiology consultation unit at the Anzhen Hospital of Beijing. The multivariate logistic regression model was used to verify the independent association between RDW and LVH. RESULTS: 174 patients without LVH and 156 patients with LVH were rolled in the study. The patients with LVH had higher mean SBP, albumin to creatinine ratio, total cholesterol, RDW and fasting glucose compared with non-LVH group. The mean HDL-cholesterol level was significantly lower in patients with LVH than patients without LVH. The multiple logistic regression model suggested that patients with a higher RDW level were more likely to be LVH (OR=2.187, 95%CI: 1.447-3.307, P<0.001). Other predictive factors for LVH were mean SBP, serum creatinine, glucose level. The receiver operating characteristics (ROC) curves indicated area under the curve was 0.688(95%CI: 0.635-0.737, P<0.001) with a cut off value of 12.9, the RDW predicted LVH status among hypertensive patients with a sensitivity of 72.4% and a specificity of 60.3%. CONCLUSIONS: The higher RDW level was observed in the LVH group compared with the non-LVH group. RDW might be associated with LVH in hypertensive patients. These data highlight the role of RDW as a predictor of organ damage in essential hypertensive patients. PMID- 25793886 TI - A model of lipid-free apolipoprotein A-I revealed by iterative molecular dynamics simulation. AB - Apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, has been proven inversely correlated to cardiovascular risk in past decades. The lipid-free state of apo A-I is the initial stage which binds to lipids forming high-density lipoprotein. Molecular models of lipid-free apo A-I have been reported by methods like X-ray crystallography and chemical cross linking/mass spectrometry (CCL/MS). Through structural analysis we found that those current models had limited consistency with other experimental results, such as those from hydrogen exchange with mass spectrometry. Through molecular dynamics simulations, we also found those models could not reach a stable equilibrium state. Therefore, by integrating various experimental results, we proposed a new structural model for lipid-free apo A-I, which contains a bundled four-helix N-terminal domain (1-192) that forms a variable hydrophobic groove and a mobile short hairpin C-terminal domain (193-243). This model exhibits an equilibrium state through molecular dynamics simulation and is consistent with most of the experimental results known from CCL/MS on lysine pairs, fluorescence resonance energy transfer and hydrogen exchange. This solution-state lipid-free apo A-I model may elucidate the possible conformational transitions of apo A-I binding with lipids in high-density lipoprotein formation. PMID- 25793887 TI - Validation of a rapid and sensitive LC-MS/MS method for determination of exemestane and its metabolites, 17beta-hydroxyexemestane and 17beta hydroxyexemestane-17-O-beta-D-glucuronide: application to human pharmacokinetics study. AB - A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC MS/MS) method was developed and validated for the evaluation of exemestane pharmacokinetics and its metabolites, 17beta-dihydroexemestane (active metabolite) and 17beta-dihydroexemestane-17-O-beta-D-glucuronide (inactive metabolite) in human plasma. Their respective D3 isotopes were used as internal standards. Chromatographic separation of analytes was achieved using Thermo Fisher BDS Hypersil C18 analytic HPLC column (100 * 2.1 mm, 5 MUm). The mobile phase was delivered at a rate of 0.5 mL/min by gradient elution with 0.1% aqueous formic acid and acetonitrile. The column effluents were detected by API 4000 triple quadrupole mass spectrometer using electrospray ionisation (ESI) and monitored by multiple reaction monitoring (MRM) in positive mode. Mass transitions 297 > 121 m/z, 300 > 121 m/z, 299 > 135 m/z, 302 > 135 m/z, 475 > 281 m/z, and 478 > 284 m/z were monitored for exemestane, exemestane-d3, 17beta dihydroexemestane, 17beta-dihydroexemestane-d3, 17beta-dihydroexemestane-17-O beta-D-glucuronide, and 17beta-dihydroexemestane-17-O-beta-D-glucuronide-d3 respectively. The assay demonstrated linear ranges of 0.4-40.0 ng/mL, for exemestane; and 0.2-15.0 ng/mL, for 17beta-dihydroexemestane and 17beta dihydroexemestane-17-O-beta-D-glucuronide, with coefficient of determination (r2) of > 0.998. The precision (coefficient of variation) were <=10.7%, 7.7% and 9.5% and the accuracies ranged from 88.8 to 103.1% for exemestane, 98.5 to 106.1% for 17beta-dihydroexemestane and 92.0 to 103.2% for 17beta-dihydroexemestane-17-O beta-D-glucuronide. The method was successfully applied to a pharmacokinetics/dynamics study in breast cancer patients receiving exemestane 25 mg daily orally. For a representative patient, 20.7% of exemestane in plasma was converted into 17beta-dihydroexemestane and 29.0% of 17beta-dihydroexemestane was inactivated as 17beta-dihydroexemestane-17-O-beta-D-glucuronide 24 hours after ingestion of exemestane, suggesting that altered 17-dihydroexemestane glucuronidation may play an important role in determining effect of exemestane against breast cancer cells. PMID- 25793888 TI - Cooling reduces cAMP-stimulated exocytosis and adiponectin secretion at a Ca2+ dependent step in 3T3-L1 adipocytes. AB - We investigated the effects of temperature on white adipocyte exocytosis (measured as increase in membrane capacitance) and short-term adiponectin secretion with the aim to elucidate mechanisms important in regulation of white adipocyte stimulus-secretion coupling. Exocytosis stimulated by cAMP (included in the pipette solution together with 3 mM ATP) in the absence of Ca2+ (10 mM intracellular EGTA) was equal at all investigated temperatures (23 degrees C, 27 degrees C, 32 degrees C and 37 degrees C). However, the augmentation of exocytosis induced by an elevation of the free cytosolic [Ca2+] to ~1.5 MUM (9 mM Ca2+ + 10 mM EGTA) was potent at 32 degrees C or 37 degrees C but less distinct at 27 degrees C and abolished at 23 degrees C. Adiponectin secretion stimulated by 30 min incubations with the membrane permeable cAMP analogue 8-Br-cAMP (1 mM) or a combination of 10 MUM forskolin and 200 MUM IBMX was unaffected by a reduction of temperature from 32 degrees C to 23 degrees C. At 32 degrees C, cAMP stimulated secretion was 2-fold amplified by inclusion of the Ca2+ ionophore ionomycin (1MUM), an effect that was not observed at 23 degrees C. We suggest that cooling affects adipocyte exocytosis/adiponectin secretion at a Ca2+ dependent step, likely involving ATP-dependent processes, important for augmentation of cAMP-stimulated adiponectin release. PMID- 25793889 TI - When can species abundance data reveal non-neutrality? AB - Species abundance distributions (SAD) are probably ecology's most well-known empirical pattern, and over the last decades many models have been proposed to explain their shape. There is no consensus over which model is correct, because the degree to which different processes can be discerned from SAD patterns has not yet been rigorously quantified. We present a power calculation to quantify our ability to detect deviations from neutrality using species abundance data. We study non-neutral stochastic community models, and show that the presence of non neutral processes is detectable if sample size is large enough and/or the amplitude of the effect is strong enough. Our framework can be used for any candidate community model that can be simulated on a computer, and determines both the sampling effort required to distinguish between alternative processes, and a range for the strength of non-neutral processes in communities whose patterns are statistically consistent with neutral theory. We find that even data sets of the scale of the 50 Ha forest plot on Barro Colorado Island, Panama, are unlikely to be large enough to detect deviations from neutrality caused by competitive interactions alone, though the presence of multiple non-neutral processes with contrasting effects on abundance distributions may be detectable. PMID- 25793890 TI - Glycans flanking the hypervariable connecting peptide between the A and B strands of the V1/V2 domain of HIV-1 gp120 confer resistance to antibodies that neutralize CRF01_AE viruses. AB - Understanding the molecular determinants of sensitivity and resistance to neutralizing antibodies is critical for the development of vaccines designed to prevent HIV infection. In this study, we used a genetic approach to characterize naturally occurring polymorphisms in the HIV envelope protein that conferred neutralization sensitivity or resistance. Libraries of closely related envelope genes, derived from virus quasi-species, were constructed from individuals infected with CRF01_AE viruses. The libraries were screened with plasma containing broadly neutralizing antibodies, and neutralization sensitive and resistant variants were selected for sequence analysis. In vitro mutagenesis allowed us to identify single amino acid changes in three individuals that conferred resistance to neutralization by these antibodies. All three mutations created N-linked glycosylation sites (two at N136 and one at N149) proximal to the hypervariable connecting peptide between the C-terminus of the A strand and the N-terminus of the B strand in the four-stranded V1/V2 domain beta-sheet structure. Although N136 has previously been implicated in the binding of broadly neutralizing monoclonal antibodies, this glycosylation site appears to inhibit the binding of neutralizing antibodies in plasma from HIV-1 infected subjects. Previous studies have reported that the length of the V1/V2 domain in transmitted founder viruses is shorter and possesses fewer glycosylation sites compared to viruses isolated from chronic infections. Our results suggest that vaccine immunogens based on recombinant envelope proteins from clade CRF01_AE viruses might be improved by inclusion of envelope proteins that lack these glycosylation sites. This strategy might improve the efficacy of the vaccines used in the partially successful RV144 HIV vaccine trial, where the two CRF01_AE immunogens (derived from the A244 and TH023 isolates) both possessed glycosylation sites at N136 and N149. PMID- 25793891 TI - Patient Protection and Affordable Care Act of 2010 and children and youth with special health care needs. AB - The Patient Protection and Affordable Care Act (ACA) was designed to (1) decrease the number of uninsured Americans, (2) make health insurance and health care affordable, and (3) improve health outcomes and performance of the health care system. During the design of ACA, children in general and children and youth with special health care needs and disabilities (CYSHCN) were not a priority because before ACA, a higher proportion of children than adults had insurance coverage through private family plans, Medicaid, or the State Children's Health Insurance Programs (CHIP). ACA benefits CYSHCN through provisions designed to make health insurance coverage universal and continuous, affordable, and adequate. Among the limitations of ACA for CYSHCN are the exemption of plans that had been in existence before ACA, lack of national standards for insurance benefits, possible elimination or reductions in funding for CHIP, and limited experience with new delivery models for improving care while reducing costs. Advocacy efforts on behalf of CYSHCN must track implementation of ACA at the federal and the state levels. Systems and payment reforms must emphasize access and quality improvements for CYSHCN over cost savings. Developmental-behavioral pediatrics must be represented at the policy level and in the design of new delivery models to assure high quality and cost-effective care for CYSHCN. PMID- 25793892 TI - Structured telephone training improves telephone competence in prelingually deafened children with a cochlear implant. AB - OBJECTIVE: The aim of the study is to assess the efficacy of a 6-month telephone use training programme in prelingually deafened children with a cochlear implant (CI). METHODS: Eleven children with a CI aged between 3.5 and 8 years participated in a step-by-step telephone training programme. After completion of 3 months of formal training provided by a special education professional, parents continued telephone training at home for 3 months and kept records. The outcomes of the entire 6-month telephone training were measured at three intervals using the Telephone Profile, the Iowa closed-set sentence test (Level A), and a parent questionnaire. RESULTS: The scores on the Telephone Profile and Iowa closed-set sentence test significantly increased between the pre-training assessment and the assessments at 3 and 6 months. The results on the Iowa closed-set sentence test significantly decreased between the 3- and the 6-month-post training assessments. The majority of parents reported 'slight improvement' in telephone skills after telephone training. No improvement was reported by the majority of parents in the use of repair strategies during telephone conversations. DISCUSSION: Telephone training provided by a special education professional appears effective in prelingually deafened children with a CI. Home training provided by parents is less effective, but helps maintain the skills acquired in the professional telephone training. CONCLUSION: Structured telephone training provided by a professional improves telephone skills in children with a CI. Repair strategies for telephone use should be incorporated into rehabilitation programmes for CI users. PMID- 25793893 TI - Pyrosequencing reveals changes in soil bacterial communities after conversion of Yungas forests to agriculture. AB - The Southern Andean Yungas in Northwest Argentina constitute one of the main biodiversity hotspots in the world. Considerable changes in land use have taken place in this ecoregion, predominantly related to forest conversion to croplands, inducing losses in above-ground biodiversity and with potential impact on soil microbial communities. In this study, we used high-throughput pyrosequencing of the 16S ribosomal RNA gene to assess whether land-use change and time under agriculture affect the composition and diversity of soil bacterial communities. We selected two areas dedicated to sugarcane and soybean production, comprising both short- and long-term agricultural sites, and used the adjacent native forest soils as a reference. Land-use change altered the composition of bacterial communities, with differences between productive areas despite the similarities between both forests. At the phylum level, only Verrucomicrobia and Firmicutes changed in abundance after deforestation for sugarcane and soybean cropping, respectively. In cultivated soils, Verrucomicrobia decreased sharply (~80%), while Firmicutes were more abundant. Despite the fact that local diversity was increased in sugarcane systems and was not altered by soybean cropping, phylogenetic beta diversity declined along both chronosequences, evidencing a homogenization of soil bacterial communities over time. In spite of the detected alteration in composition and diversity, we found a core microbiome resistant to the disturbances caused by the conversion of forests to cultivated lands and few or none exclusive OTUs for each land-use type. The overall changes in the relative abundance of copiotrophic and oligotrophic taxa may have an impact in soil ecosystem functionality. However, communities with many taxa in common may also share many functional attributes, allowing to maintain at least some soil ecosystem services after forest conversion to croplands. PMID- 25793894 TI - Chondroitin / dermatan sulfate modification enzymes in zebrafish development. AB - Chondroitin/dermatan sulfate (CS/DS) proteoglycans consist of unbranched sulfated polysaccharide chains of repeating GalNAc-GlcA/IdoA disaccharide units, attached to serine residues on specific proteins. The CS/DS proteoglycans are abundant in the extracellular matrix where they have essential functions in tissue development and homeostasis. In this report a phylogenetic analysis of vertebrate genes coding for the enzymes that modify CS/DS is presented. We identify single orthologous genes in the zebrafish genome for the sulfotransferases chst7, chst11, chst13, chst14, chst15 and ust and the epimerase dse. In contrast, two copies were found for mammalian sulfotransferases CHST3 and CHST12 and the epimerase DSEL, named chst3a and chst3b, chst12a and chst12b, dsela and dselb, respectively. Expression of CS/DS modification enzymes is spatially and temporally regulated with a large variation between different genes. We found that CS/DS 4-O-sulfotransferases and 6-O-sulfotransferases as well as CS/DS epimerases show a strong and partly overlapping expression, whereas the expression is restricted for enzymes with ability to synthesize di-sulfated disaccharides. A structural analysis further showed that CS/DS sulfation increases during embryonic development mainly due to synthesis of 4-O-sulfated GalNAc while the proportion of 6-O-sulfated GalNAc increases in later developmental stages. Di-sulfated GalNAc synthesized by Chst15 and 2-O-sulfated GlcA/IdoA synthesized by Ust are rare, in accordance with the restricted expression of these enzymes. We also compared CS/DS composition with that of heparan sulfate (HS). Notably, CS/DS biosynthesis in early zebrafish development is more dynamic than HS biosynthesis. Furthermore, HS contains disaccharides with more than one sulfate group, which are virtually absent in CS/DS. PMID- 25793895 TI - The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation. AB - The pathologic liver changes in chronic heart failure have been characterized mostly based on autopsy series and include sinusoidal dilation and congestion progressing to pericellular fibrosis, bridging fibrosis, and ultimately to cardiac cirrhosis or sclerosis. Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes. We report the pathologic and clinical findings in liver explants from six patients who underwent combined heart-liver transplantation. We also report preoperative liver biopsy findings from 21 patients who underwent heart transplantation without simultaneous liver transplantation. We staged the changes related to chronic passive congestion as follows: stage 0-no fibrosis; stage I pericellular fibrosis; stage II-bridging fibrosis; and stage III-regenerative nodules. Nineteen biopsies showed fibrosis with bridging fibrosis in 13 and regenerative nodules in 6. Fifteen patients were alive at 1 year post transplant. Only three patients had a post-operative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these patients all showed at least stage II fibrosis. These patients survived for 3, 6, and 10 months after cardiac transplant. The presence of bridging fibrosis was not significantly associated with post-operative survival (P=0.336) or post-operative liver failure (P=0.257). We conclude that patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation. Because the pattern of fibrosis due to passive congestion is highly variable throughout the liver, a diagnosis of cirrhosis, which implies fibrosis and regenerative nodules throughout the liver, should be made with great caution on biopsy. PMID- 25793896 TI - Multi-functional regulation of 4E-BP gene expression by the Ccr4-Not complex. AB - The mechanistic target of rapamycin (mTOR) signaling pathway is highly conserved from yeast to humans. It senses various environmental cues to regulate cellular growth and homeostasis. Deregulation of the pathway has been implicated in many pathological conditions including cancer. Phosphorylation cascades through the pathway have been extensively studied but not much is known about the regulation of gene expression of the pathway components. Here, we report that the mRNA level of eukaryotic translation initiation factor (eIF) subunit 4E-binding protein (4E BP) gene, one of the key mTOR signaling components, is regulated by the highly conserved Ccr4-Not complex. RNAi knockdown of Not1, a putative scaffold protein of this protein complex, increases the mRNA level of 4E-BP in Drosophila Kc cells. Examination of the gene expression mechanism using reporter swap constructs reveals that Not1 depletion increases reporter mRNAs with the 3'UTR of 4E-BP gene, but decreases the ones with the 4E-BP promoter region, suggesting that Ccr4-Not complex regulates both degradation and transcription of 4E-BP mRNA. These results indicate that the Ccr4-Not complex controls expression of a single gene at multiple levels and adjusts the magnitude of the total effect. Thus, our study reveals a novel regulatory mechanism of a key component of the mTOR signaling pathway at the level of gene expression. PMID- 25793897 TI - Effect of landscape pattern on insect species density within urban green spaces in Beijing, China. AB - Urban green space is an important refuge of biodiversity in urban areas. Therefore, it is crucial to understand the relationship between the landscape pattern of green spaces and biodiversity to mitigate the negative effects of urbanization. In this study, we collected insects from 45 green patches in Beijing during July 2012 using suction sampling. The green patches were dominated by managed lawns, mixed with scattered trees and shrubs. We examined the effects of landscape pattern on insect species density using hierarchical partitioning analysis and partial least squares regression. The results of the hierarchical partitioning analysis indicated that five explanatory variables, i.e., patch area (with 19.9% independent effects), connectivity (13.9%), distance to nearest patch (13.8%), diversity for patch types (11.0%), and patch shape (8.3%), significantly contributed to insect species density. With the partial least squares regression model, we found species density was negatively related to patch area, shape, connectivity, diversity for patch types and proportion of impervious surface at the significance level of p < 0.05 and positively related to proportion of vegetated land. Regression tree analysis further showed that the highest species density was found in green patches with an area <500 m2. Our results indicated that improvement in habitat quality, such as patch area and connectivity that are typically thought to be important for conservation, did not actually increase species density. However, increasing compactness (low-edge) of patch shape and landscape composition did have the expected effect. Therefore, it is recommended that the composition of the surrounding landscape should be considered simultaneously with planned improvements in local habitat quality. PMID- 25793898 TI - The Red Queen race between parasitic chytrids and their host, Planktothrix: a test using a time series reconstructed from sediment DNA. AB - Parasitic chytrid fungi (phylum Chytridiomycota) are known to infect specific phytoplankton, including the filamentous cyanobacterium Planktothrix. Subspecies, or chemotypes of Planktothrix can be identified by the presence of characteristic oligopeptides. Some of these oligopeptides can be associated with important health concerns due to their potential for toxin production. However, the relationship between chytrid parasite and Planktothrix host is not clearly understood and more research is needed. To test the parasite-host relationship over time, we used a sediment core extracted from a Norwegian lake known to contain both multiple Planktothrix chemotype hosts and their parasitic chytrid. Sediment DNA of chytrids and Planktothrix was amplified and a 35-year coexistence was found. It is important to understand how these two antagonistic species can coexistence in a lake. Reconstruction of the time series showed that between 1979 1990 at least 2 strains of Planktothrix were present and parasitic pressure exerted by chytrids was low. After this period one chemotype became dominant and yet showed continued low susceptibility to chytrid parasitism. Either environmental conditions or intrinsic characteristics of Planktothrix could have been responsible for this continued dominance. One possible explanation could be found in the shift of Planktothrix to the metalimnion, an environment that typically consists of low light and decreased temperatures. Planktothrix are capable of growth under these conditions while the chytrid parasites are constrained. Another potential explanation could be due to the differences between cellular oligopeptide variations found between Planktothrix chemotypes. These oligopeptides can function as defense systems against chytrids. Our findings suggest that chytrid driven diversity was not maintained over time, but that the combination of environmental constraints and multiple oligopeptide production to combat chytrids could have allowed one Planktothrix chemotype to have dominance despite chytrid presence. PMID- 25793899 TI - Conformational dependence of the circular dichroism spectra of single amino acids from plane-waves-based density functional theory calculations. AB - We study the conformational dependence of circular dichroism (CD) spectra of amino acid molecules by means of an efficient ab initio DFT approach which is free from the typical gauge invariance issues arising with the use of localized basis sets and/or real-space grids. We analyze the dependence of the chiroptical spectra on the backbone dihedrals in the specific case of alanine and consider the role of side chain degrees of freedom at the examples of leucine, phenylalanine, and serine, whose side chains have different physicochemical properties. The results allow one to identify the most diagnostic regions of the CD spectra and to critically compare the conformations which match the experimental CD data with conformations extracted from the rotamer library. The inclusion of a solvation shell of explicit water molecules and its effect on the CD spectrum are analyzed at the example of alanine. PMID- 25793900 TI - Effect of common comparators in indirect comparison analysis of the effectiveness of different inhaled corticosteroids in the treatment of asthma. AB - PURPOSE: Indirect comparison (IC) and direct comparison (DC) of four inhaled corticosteroid (CS) treatments for asthma were conducted, and the factors that may influence the results of IC were investigated. Among those factors, we focused on the effect of common comparator selection in the treatment of asthma, where little control group bias or placebo effect is expected. METHOD: IC and DC were conducted using the change from baseline in forced expiratory volume in 1 s (FEV1(L)) as an outcome parameter. Differences between inhaled CS were evaluated to compare the results of IC and DC. As a common comparator for IC, placebo (PLB) or mometasone (MOM) was selected. Whether the results of IC are affected by the selection of a common comparator and whether the results of IC and DC are consistent were examined. RESULTS: 23 articles were identified by a literature search. Our results showed that ICs yielded results similar to DCs in the change from baseline of FEV1(L). No statistically significant difference was observed in inconsistency analysis between ICs and DCs. It was clinically and statistically confirmed that ICs with PLB and those with MOM did not differ in terms of the results of FEV1(L) analysis in this dataset. CONCLUSION: This study demonstrated that ICs among inhaled CS can deliver results consistent with those of DCs when using the change from baseline in FEV1(L) as an outcome parameter in asthma patients. It was also shown that using an active comparator has similar results if there is no effect of control group bias. It should be emphasized that the investigation of control group bias is a key factor in conducting relevant ICs so that an appropriate common comparator can be selected. PMID- 25793902 TI - Pilot Development of an Electronic Pediatric Inflammatory Bowel Disease Quiz Game. AB - OBJECTIVES: Data suggest physicians poorly assess disease-specific literacy and transition readiness in pediatric patients with inflammatory bowel disease (IBD). We piloted an electronic, interactive iPad quiz game that could be used in a clinical setting, with the aims of measuring IBD-related knowledge, and concomitant mood and quality of life (QOL) in a pediatric population. METHODS: Two pediatric IBD clinics developed and tested 2 versions of "Emma." Patients between 10 and 18 years of age played Emma during an office visit. Each patient answered 12 randomly selected disease-related questions and 4 mood-related questions. RESULTS: Sites 1 and 2 tested Emma v1 between May and August 2013. Emma v2 was tested from November 2013 to January 2014 and from September 2013 to January 2014. A total of 56 patients played Emma v1, whereas 60 played Emma v2. In Emma v2, 73.1% of questions were answered correctly. Patients recognized signs of IBD (88%), causes of diarrhea in addition to IBD (79.4%), and could define lactose intolerance (95.8%), but fewer patients understood serological testing used for disease monitoring (68%) or knew that magnetic resonance enterography did not involve radiation (22.9%). Patients tended to report good functioning in the areas of energy, mood, anxiety, and school-related QOL. Patients with Crohn disease, however, reported higher stress levels compared with patients with ulcerative colitis; older patients reported lower energy levels, and postsurgical patients reported lower QOL. CONCLUSIONS: The Emma iPad game has the potential to evaluate gaps in IBD knowledge, assess emotional functioning, and increase patient engagement as a transition tool in the clinical setting. PMID- 25793901 TI - Na+/K+-ATPase alpha-subunit (nkaalpha) isoforms and their mRNA expression levels, overall Nkaalpha protein abundance, and kinetic properties of Nka in the skeletal muscle and three electric organs of the electric eel, Electrophorus electricus. AB - This study aimed to obtain the coding cDNA sequences of Na+/K+-ATPase alpha (nkaalpha) isoforms from, and to quantify their mRNA expression in, the skeletal muscle (SM), the main electric organ (EO), the Hunter's EO and the Sach's EO of the electric eel, Electrophorus electricus. Four nkaalpha isoforms (nkaalpha1c1, nkaalpha1c2, nkaalpha2 and nkaalpha3) were obtained from the SM and the EOs of E. electricus. Based on mRNA expression levels, the major nkaalpha expressed in the SM and the three EOs of juvenile and adult E. electricus were nkaalpha1c1 and nkaalpha2, respectively. Molecular characterization of the deduced Nkaalpha1c1 and Nkaalpha2 sequences indicates that they probably have different affinities to Na+ and K+. Western blotting demonstrated that the protein abundance of Nkaalpha was barely detectable in the SM, but strongly detected in the main and Hunter's EOs and weakly in the Sach's EO of juvenile and adult E. electricus. These results corroborate the fact that the main EO and Hunter's EO have high densities of Na+ channels and produce high voltage discharges while the Sach's EO produces low voltage discharges. More importantly, there were significant differences in kinetic properties of Nka among the three EOs of juvenile E. electricus. The highest and lowest Vmax of Nka were detected in the main EO and the Sach's EO, respectively, with the Hunter's EO having a Vmax value intermediate between the two, indicating that the metabolic costs of EO discharge could be the highest in the main EO. Furthermore, the Nka from the main EO had the lowest Km (or highest affinity) for Na+ and K+ among the three EOs, suggesting that the Nka of the main EO was more effective than those of the other two EOs in maintaining intracellular Na+ and K+ homeostasis and in clearing extracellular K+ after EO discharge. PMID- 25793903 TI - Improving Nonattendance at Outpatient Pediatric Endoscopy Unit of a Tertiary Center. AB - BACKGROUND AND OBJECTIVES: Failure to attend pediatric outpatient endoscopic procedures leads to inefficient use of resources, longer wait-list times, and delay in diagnoses. The causes for pediatric endoscopy nonattendance are not well studied. The aim of the study was to identify factors associated with failure to attend endoscopic procedures and to assess the value of quality improvement (QI) interventions implemented to improve pediatric endoscopy attendance. METHODS: This was a continuous QI project. We collected nonattendance data from November 2011 to November 2013. Information collected included procedure type, age, sex, time on the waiting list, history of previous procedures, and reason for nonattendance. The following QI interventions were implemented sequentially: an appointment reminder letter, a telephone call 1 week before procedure, and creation of an electronic medical note dedicated to endoscopy appointment. Pareto charts and statistical process control charts were used for analysis. RESULTS: From November 2011 to November 2013, we were able to decrease nonattendance from 17% to 11% (P = 0.005). No-show rate was reduced from 5% to 0.9% (P = 0.00001). There was no significant difference between attendees and nonattendees in relation to sex, age, or having a previous procedure. Longer waiting time (33 vs 26 days) was associated with increased risk for nonattendance (P = 0.0007). The most common causes for nonattendance were illness (31.5%), followed by caregiver/patients who no longer wanted the procedure (17.7%), and patients who improved (12.9%). CONCLUSIONS: Applying QI methods and tools improved pediatric endoscopy attendance. Longer wait time for endoscopic procedures is associated with nonattendance. Given the increased pediatric endoscopy demand, strategies should be implemented to reduce wait time for pediatric endoscopy. PMID- 25793904 TI - Usefulness of Gastric Biopsy-Based Real-Time Polymerase Chain Reaction for the Diagnosis of Helicobacter pylori Infection in Children. AB - OBJECTIVES: The aim of the study was to assess the usefulness of gastric biopsy based quantitative real-time polymerase chain reaction (qPCR) for the detection of Helicobacter pylori infection and the identification of clarithromycin resistant strains in children. METHODS: A gastric biopsy-based qPCR for the detection of H pylori infection and the identification of clarithromycin resistant strains in children was evaluated in 62 children with infection and 341 children without infection. H pylori infection was considered by the "reference method" when culture was positive for both histology and rapid urease test (RUT). Results were compared with those obtained using the qPCR. RESULTS: The reference method versus H pylori qPCR positivity showed 95% confidence interval sensitivity 100% versus 100%, specificity 93.2% (86.9-99.4) versus 100%, positive predictive value 59.7% (47.4-71.9) versus 100%, negative predictive value 100% versus 100%, and, finally, test accuracy of 59.6% (47.3-71.8) versus 100%. Sixty-two children were found to be H pylori positive, based on the qPCR results. Among those, 31 children had both positive qPCR and culture with concordant antimicrobial susceptibility testing results, whereas 31 children had negative culture and positive qPCR. The qPCR showed a bacterial load >=10 copies per milliliter when culture, histology, and RUT were all positive (29/31 children) versus <10 copies per milliliter when culture, histology, and RUT were all negative (25/31 children). Grades 2 and 3 histological gastritis were associated with a bacterial load >=10 copies per milliliter for 28/35 of children versus 27/27 of grade 0 to 1 <10 copies per milliliter. CONCLUSIONS: H pylori qPCR positivity is a more precise test than the routine culture, histology, RUT alone and allows detecting low bacterial loads. PMID- 25793905 TI - Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development. AB - OBJECTIVES: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). METHODS: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. RESULTS: The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohn's Disease Activity Index (CDAI) and Harvey-Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration-approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers' input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. CONCLUSIONS: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed. PMID- 25793907 TI - Vomiting in a 2-Year-Old With A Twist: Undiagnosed Gastric Volvulus. PMID- 25793906 TI - Onset of Thrombin Generation Occurs More Rapidly in Pediatric Patients With Celiac Disease. AB - OBJECTIVE: Celiac disease (CD) is a risk factor for venous thromboembolism (VTE) and stroke, but the mechanisms are unclear. Continuous measurement of thrombin generation in plasma is a feasible way to detect hypercoagulable changes. The aim of this pilot study was to investigate thrombin generation in pediatric patients with CD compared with pediatric controls. METHODS: Plasma samples were collected from 19 pediatric patients with CD and 20 healthy controls. In each patient diagnosed as having CD, thrombin generation was determined twice by means of calibrated automated thrombography. The first measurement was undertaken when CD was diagnosed; the second measurement was undertaken after normalization of their IgA antitissue transglutaminase antibody (tTG-Ab) titers following a gluten-free diet. In the controls, measurement for TTG-Ab and thrombin generation was undertaken once during recruitment. RESULTS: Patients with CD at diagnosis showed a significantly shorter lag time compared with controls (P < 0.001) and a shorter time-to-peak compared with controls (P < 0.02). These differences were no longer detectable after normalization of TTG-Ab values. The overall amount of generated thrombin, represented by the endogenous thrombin potential (ETP), showed no significant difference between the study groups. CONCLUSIONS: Our results show that alterations in coagulation can be found in untreated CD that may help to explain the described increased risk of stroke or VTE. A shorter lag time in patients with untreated CD indicates a more rapid onset of thrombin generation as a sign of hypercoagulability. ETP, the best predictive parameter for thromboembolic disease, however, was not altered. PMID- 25793908 TI - Low-dose mannitol (0.3 g kg(-1)) improves the pulsatility index and minimum diastolic blood flow velocity in traumatic brain injury. AB - OBJECTIVE: The aim of the study was to investigate the effects of using low-dose mannitol (0.3 g kg(-1)) on the pulsatility index (PI) and minimum diastolic blood flow velocity (FV-min) of the middle cerebral artery in a traumatic brain injury (TBI). METHODS: Low-dose mannitol (0.3 g kg(-1)) was administered to a group of 20 patients with a TBI. Transcranial Doppler (TCD) ultrasonography was used to monitor the PI and FV-min. The study included patients with a diffuse traumatic brain injury and Glasgow coma score < 8. The initial TCD ultrasonography values were pathological (PI > 1.4 and FV-min < 20 cm s(-1)). TCD ultrasonography examinations were carried out before mannitol administration, immediately after administration and 1, 2 and 3 hours after the administration of mannitol. RESULTS: A one-way analysis of variance revealed significant changes in the PI (F = 8.392; p < 0.001) and FV-min (F = 8.291; p = 0.001) after the use of mannitol. CONCLUSIONS: Low-dose mannitol administration appears to be efficacious for improving the indicators of disturbed circulation in a TBI (FV-min increase, PI decrease). The maximum decrease in the PI was recorded 1 hour after the administration of mannitol and was 10.9% of the initial value. The maximum increase in the FV-min was recorded 1 hour after administration and was 29.7% of the initial value. These changes were significant ~ 2 hours later. PMID- 25793909 TI - Self-assembly of mesogenic bent-core DNA nanoduplexes. AB - Short cylinder-like DNA duplexes, comprising 6 to 20 base pairs, self-assemble into semi-flexible chains, due to coaxial stacking interactions between their blunt ends. The mutual alignment of these chains gives rise to macroscopically orientationally ordered liquid crystal phases. Interestingly, experiments show that the isotropic-nematic phase boundary is sequence-dependent. We perform all atom simulations of several sequences to gain insights into the structural properties of the duplex and correlate the resulting geometric properties with the observed location of the isotropic-nematic phase boundary. We identify in the duplex bending the key parameter for explaining the sequence dependence, suggesting that DNA duplexes can be assimilated to bent-core mesogens. We also develop a coarse-grained model for the different DNA duplexes to evaluate in detail how bending affects the persistence length and excluded volume of the aggregates. This information is fed into a recently developed formalism to predict the isotropic-nematic phase boundary for bent-core mesogens. The theoretical results agree with the experimental observations. PMID- 25793910 TI - Self-assembly and emulsification properties of hydrophobically modified inulin. AB - A series of alkenylated inulin samples were synthesized in aqueous solution using alkenyl succinic anhydrides with varying alkenyl chain lengths (C8-C18). The inulin derivatives (ASA-inulins) were characterized using NMR and FTIR and their degree of substitution determined. The solution properties of ASA-inulins were investigated using dye solubilization, surface tension, and dynamic light scattering, and all three techniques confirmed that the molecules aggregated in solution above a critical concentration (critical aggregation concentration, CAC). The value of the CAC was found to be reasonably consistent between the different techniques and was shown to decrease with increasing alkenyl chain length, from 0.08% for the octenyl succinylated sample to 0.005% for the octadecenyl succinylated sample. The hydrodynamic diameter of ASA-inulins above the CAC was determined from dynamic light scattering studies and was shown to increase with alkenyl chain length, from 4 nm for the octenyl derivative to 55 nm for the hexadecenyl derivative. All ASA-inulins were shown to be able to produce oil-in-water emulsions with a droplet size similar to that of emulsions prepared using Tween 20 on storing for 21 days. The fact that the derivatives are able to form micellarlike aggregates and stabilize emulsions makes them suitable candidates for the encapsulation and delivery of water-insoluble active compounds, with potential application in food, cosmetic, personal care, and pharmaceutical formulations. PMID- 25793911 TI - Selection of di(meth)acrylate monomers for low pollution of fluorinated mold surfaces in ultraviolet nanoimprint lithography. AB - We used fluorescence microscopy to show that low adsorption of resin components by a mold surface was necessary for continuous ultraviolet (UV) nanoimprinting, as well as generation of a low release energy on detachment of a cured resin from a template mold. This is because with low mold pollution, fracture on demolding occurred at the interface between the mold and cured resin surfaces rather than at the outermost part of the cured resin. To achieve low mold pollution, we investigated the radical photopolymerization behaviors of fluorescent UV-curable resins and the mechanical properties (fracture toughness, surface hardness, and release energy) of the cured resin films for six types of di(meth)acrylate-based monomers with similar chemical structures, in which polar hydroxy and aromatic bulky bisphenol moieties and methacryloyl or acryloyl reactive groups were present or absent. As a result, we selected bisphenol A glycerolate dimethacrylate (BPAGDM), which contains hydroxy, bisphenol, and methacryloyl moieties, which give good mechanical properties, monomer bulkiness, and mild reactivity, respectively, as a suitable base monomer for UV nanoimprinting under an easily condensable alternative chlorofluorocarbon (HFC-245fa) atmosphere. The fluorescent UV-curable BPAGDM resin was used for UV nanoimprinting and lithographic reactive ion etching of a silicon surface with 32 nm line-and-space patterns without a hard metal layer. PMID- 25793912 TI - Fabrication and characterization of polysaccharide ion gels with ionic liquids and their further conversion into value-added sustainable materials. AB - A review of the fabrication of polysaccharide ion gels with ionic liquids is presented. From various polysaccharides, the corresponding ion gels were fabricated through the dissolution with ionic liquids. As ionic liquids, in the most cases, 1-butyl-3-methylimidazolium chloride has been used, whereas 1-allyl 3methylimidazolium acetate was specifically used for chitin. The resulting ion gels have been characterized by suitable analytical measurements. Characterization of a pregel state by viscoelastic measurement provided the molecular weight information. Furthermore, the polysaccharide ion gels have been converted into value-added sustainable materials by appropriate procedures, such as exchange with other disperse media and regeneration. PMID- 25793913 TI - Propofol protects against high glucose-induced endothelial apoptosis and dysfunction in human umbilical vein endothelial cells. AB - BACKGROUND: Perioperative hyperglycemia is a common clinical metabolic disorder. Hyperglycemia could induce endothelial apoptosis and dysfunction. Propofol is a widely used IV anesthetic drug in clinical settings. In the present study, we examined whether and how propofol reduced high glucose-induced endothelial apoptosis and dysfunction in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were cultured with different concentrations (5, 10, 15, and 25 mM) of glucose for different times (4, 8, 12, and 24 hours). To study the effect of propofol, cells were incubated with different concentrations (0.2, 1, 5, and 25 MUM) of propofol for 2 hours. In parallel experiments, cells were incubated in 5 mM glucose as control. Nitric oxide (NO) production was measured with a nitrate reductase assay. Cell viability was determined with a Cell Counting Kit-8. Protein expression of active caspase 3, cytochrome c, endothelial NO synthase (eNOS), p-eNOS-Thr, p66, protein kinase C betaII (PKCbetaII), and p-PKCbetaII-Ser was measured by Western blot analysis. Accumulation of superoxide anion (O2) was measured with the reduction of ferricytochrome c. Cell apoptosis was determined with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. RESULTS: Compared with control, high glucose decreased NO production (P < 0.0001) and reduced cells viability (P < 0.0001) in HUVECs. Compared with high glucose treatment, pretreatment of cells with propofol (5 MUM, 2 hours) reduced high glucose-induced inhibitory p-eNOS-Thr phosphorylation (P < 0.0001), increasing NO production (P = 0.0007), decreased high glucose-induced p66 expression (P < 0.0001) and p66 mitochondrial translocation (P < 0.0001), O2 accumulation (P < 0.0001), mitochondrial cytochrome c release (P < 0.0001), active caspase 3 expression (P < 0.0001), and enhancing endothelial viability (P < 0.0001). Furthermore, propofol inhibited high glucose-induced PKCbetaII expression (P = 0.0002) and p-PKCbetaII-Ser phosphorylation (P < 0.0001). Moreover, the observed protective effect of propofol was quite similar to that of PKCbetaII inhibitor. CONCLUSIONS: Propofol, by a mechanism of decreasing high glucose-induced PKCbetaII expression and p-PKCbetaII-Ser phosphorylation, inhibits high glucose-induced p66 mitochondrial translocation, therefore protecting HUVECs from high glucose-induced endothelial dysfunction and apoptosis. PMID- 25793914 TI - The 2014 American College of Nutrition micronutrient symposium summaries of the pro/con presentations on chromium, vitamin D, zinc, and copper. PMID- 25793915 TI - Pathway to the piezoelectronic transduction logic device. AB - The piezoelectronic transistor (PET) has been proposed as a transduction device not subject to the voltage limits of field-effect transistors. The PET transduces voltage to stress, activating a facile insulator-metal transition, thereby achieving multigigahertz switching speeds, as predicted by modeling, at lower power than the comparable generation field effect transistor (FET). Here, the fabrication and measurement of the first physical PET devices are reported, showing both on/off switching and cycling. The results demonstrate the realization of a stress-based transduction principle, representing the early steps on a developmental pathway to PET technology with potential to contribute to the IT industry. PMID- 25793916 TI - Prevalence of gastric precancerous lesions among chronic dyspeptic patients and related common risk factors. AB - Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Progression of gastric cancer follows several steps from gastritis to atrophy, intestinal metaplasia, dysplasia, and finally cancer. The aim of this study was to determine the prevalence of gastric precancerous lesions and related common risk factors in a group of chronic dyspeptic patients. A total of 688 chronic dyspeptic patients older than 40 years of age were consecutively enrolled. The exclusion criteria were pregnancy, and a history of gastric cancer and gastric surgery. A questionnaire including demographic and clinical data, smoking habits, alcohol use, NSAIDs, and regular aspirin use was completed for all patients. Upper endoscopy and gastric biopsy were performed for all of the participants according to the standard protocols. Upper endoscopy was performed for all of the participants and biopsies were taken according to the biopsy protocol. The specimens were examined in a blinded manner by two expert gastrointestinal pathologists. The mean age of the participants was 57.87+/-9.10 years; there were 361 (52.5%) women. The prevalence of intestinal metaplasia, gastric atrophy, dysplasia, and positive Helicobacter pylori infection was 19.8, 12.8, 3.2%, and 64.5%, respectively. Age and H. pylori infection showed a significant association with pathological findings (odds ratio=3.10, 95% confidence interval: 1.91-4.72 and odds ratio=3.56, 95% confidence interval: 2.30-5.53, respectively). According to the high prevalence of precancerous lesions in patients with chronic dyspepsia who were older than 40 years of age, upper endoscopy and gastric mapping sampling for the detection of these lesions is recommended in intermediate-risk to high risk areas. PMID- 25793917 TI - Association of serum cytokines with colorectal polyp number and type in adult males. AB - Chronic inflammation contributes to colorectal carcinogenesis. To determine whether serum cytokines are associated with colon polyps, 126 asymptomatic men (48-65 years) were recruited during colonoscopy. Serum cytokine concentrations were measured. Odds ratios were determined using polytomous logistic regression for polyp number and type. Men with serum monocyte chemotactic protein-3 (MCP-3) or soluble interleukin-4 receptor (sIL-4R) concentrations in the highest tertile were 0.2 times less likely to have three or more polyps relative to no polyps. For each increase in serum MCP-3 or sIL-4R tertile a man was about 0.4 times less likely to have three or more polyps than to have no polyps. Men with serum concentrations of interferon-alpha2 (IFN-alpha2) or interleukin (IL)-7 in the highest tertile were three times more likely to have an adenoma than no polyps. Those with serum IL-8 concentrations in the highest tertile were four times more likely to have an adenoma than no polyps. For each increase in serum IFN-alpha2, IL-7, or IL-8 tertile an individual was 1.8 times more likely to have an adenoma than to have no polyps. Serum concentrations of MCP-3, sIL-4R, IFN-alpha2, IL-7, and IL-8 may indicate which men are more likely to have colorectal polyps. PMID- 25793918 TI - Type 2 diabetes and the risk of non-Hodgkin's lymphoma: a report from two population-based cohort studies in China. AB - Coinciding with the increased incidence of non-Hodgkin's lymphoma (NHL) during the past decades, there has been a significant increase in the prevalence of diabetes mellitus in mainland China. We therefore evaluated whether type 2 diabetes (T2D) is associated with the risk of NHL using data from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). The SMHS and SWHS are two on-going, prospective, population-based cohorts of more than 130 000 Chinese adults in urban Shanghai. Self-reported diabetes was recorded on the baseline questionnaire and updated in follow-up surveys. Cox regression models with T2D as a time-varying exposure were used to estimate hazard ratios and 95% confidence intervals, adjusting for covariates. After a median follow-up of 12.9 years for SWHS and 7.4 years for SMHS, 172 NHL cases were identified. Patients with T2D have a higher risk of incident NHL with a hazard ratio of 2.00 (95% confidence interval: 1.32-3.03) compared with those without diabetes. This positive association remained when the analysis was restricted to untreated diabetes or after excluding NHL cases that occurred within 3 years after the onset of diabetes. No interaction effect was found in the development of NHL between T2D and other potential risk factors. A linear inverse association was found between T2D duration and the risk of NHL in both men and women (Pfor linearity<0.01), with a highest risk of incident NHL in the first 5 years after the diagnosis of diabetes. Our study suggested that T2D might be associated with an increased risk of NHL. PMID- 25793919 TI - Prelabor cesarean delivery and early-onset acute childhood leukemia risk. AB - The long-term impact of cesarean delivery (CD) on the health of the offspring is being explored methodically. We sought to investigate the effect of birth by (a) prelabor and (b) during-labor CD on the risk of early-onset (<=3 years) acute lymphoblastic leukemia (ALL), specifically of its prevailing precursor B (B-ALL) subtype. A total of 1099 incident cases of ALL (957 B-ALL), 131 of acute myeloid leukemia (AML), and their 1 : 1 age-matched and sex-matched controls, derived from the Nationwide Registry for Childhood Hematological Malignancies (1996 2013), were analyzed using multivariate regression models. A null association was found between prelabor and/or during labor CD and either ALL (B-ALL) or AML in the 0-14 age range. By contrast, birth by CD increased significantly the risk of early-onset ALL [odds ratioCD (ORCD)=1.57, 95% confidence interval (CI): 1.10 2.24] mainly on account of prelabor CD (ORprelaborCD=1.66, 95% CI: 1.13-2.43). The respective figures were even higher for the early-onset precursor B-ALL (ORCD=1.66, 95% CI: 1.15-2.40 and ORprelaborCD=1.79, 95% CI: 1.21-2.66), whereas no association emerged for early-onset AML. Prelabor CD, which deprives exposure of the fetus/infant to the presumably beneficial effect of stress hormones released in both vaginal labor and during labor CD, was associated exclusively with an increased risk of early-onset ALL, particularly the precursor B-ALL subtype. If confirmed, these adverse long-term outcomes of CD may point to re evaluation of prelabor CD practices and prompt scientific discussion on the best ways to simulate the effects of vaginal delivery, such as a precesarean induction of labor. PMID- 25793920 TI - Primary prevention and early diagnosis of prostate cancer: recommendations from the prevention and early diagnosis working group of the Spanish Society of Medical Oncology (SEOM). AB - Prostate cancer is the most common neoplasm in men in western countries. The use of strategies for primary prevention and early diagnosis is a usual procedure, but there is considerable controversy on their benefits. Recent data from several remarkable studies have contributed more uncertainty toward this issue. We review the available evidence and suggest some general recommendations for prostate cancer primary prevention and screening. PMID- 25793921 TI - Overweight, obesity, and breast cancer screening: results from the 2012 Swiss Health Survey. AB - Obesity is associated with poor breast cancer (BC) prognosis. Larger tumor size and more advanced disease stage at diagnosis could partly explain this outcome and nonadherence of obese women to BC screening may play a role. We examined the relationship between BMI (kg/m) and the use of mammography in Switzerland as well as separately in the German-speaking part with mainly opportunistic screening and in the French-speaking part with organized programs. We analyzed the data of 50 69-year-old women (n=3121) of the Swiss Health Survey 2012. Study participants were classified as underweight (BMI<18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-29), or obese (BMI>=30). Outcome measures were dichotomized into 2 years or less since most recent mammography versus more than 2 years or never. We carried out multivariable logistic regression analyses, adjusting for sociodemographics, lifestyle, and self-perceived health. In Switzerland, 47% of women aged 50-69 years had had BC screening within the last 2 years, 35% of women in the German-speaking and 78% of women in the French-speaking part. In the total group, mammography use was higher in overweight than in normal-weight women (adjusted odds ratio 1.21, 95% confidence interval 0.98-1.49). Stratified by region, this effect was only maintained in women of the German-speaking part (adjusted odds ratio 1.41, 95% confidence interval 1.08-1.85; P interaction<0.001). There were no differences in mammography attendance between normal-weight and obese and underweight women. In the 2012 Swiss Health Survey, overweight, obesity, and underweight were no barriers to mammography. In the German-speaking part, overweight women even attended mammography screening more often than normal-weight women. PMID- 25793923 TI - 3D printing of a multifunctional nanocomposite helical liquid sensor. AB - A multifunctional 3D liquid sensor made of a PLA/MWCNT nanocomposite and shaped as a freeform helical structure was fabricated by solvent-cast 3D printing. The 3D liquid sensor featured a relatively high electrical conductivity, the functionality of liquid trapping due to its helical configuration, and an excellent sensitivity and selectivity even for a short immersion into solvents. PMID- 25793922 TI - White matter hyperintensities among older adults are associated with futile increase in frontal activation and functional connectivity during spatial search. AB - The mechanisms by which aging and other processes can affect the structure and function of brain networks are important to understanding normal age-related cognitive decline. Advancing age is known to be associated with various disease processes, including clinically asymptomatic vascular and inflammation processes that contribute to white matter structural alteration and potential injury. The effects of these processes on the function of distributed cognitive networks, however, are poorly understood. We hypothesized that the extent of magnetic resonance imaging white matter hyperintensities would be associated with visual attentional control in healthy aging, measured using a functional magnetic resonance imaging search task. We assessed cognitively healthy older adults with search tasks indexing processing speed and attentional control. Expanding upon previous research, older adults demonstrate activation across a frontal-parietal attentional control network. Further, greater white matter hyperintensity volume was associated with increased activation of a frontal network node independent of chronological age. Also consistent with previous research, greater white matter hyperintensity volume was associated with anatomically specific reductions in functional magnetic resonance imaging functional connectivity during search among attentional control regions. White matter hyperintensities may lead to subtle attentional network dysfunction, potentially through impaired frontal-parietal and frontal interhemispheric connectivity, suggesting that clinically silent white matter biomarkers of vascular and inflammatory injury can contribute to differences in search performance and brain function in aging, and likely contribute to advanced age-related impairments in cognitive control. PMID- 25793924 TI - Aqueous and alcoholic extracts of Triphala and their active compounds chebulagic acid and chebulinic acid prevented epithelial to mesenchymal transition in retinal pigment epithelial cells, by inhibiting SMAD-3 phosphorylation. AB - Epithelial to Mesenchymal Transition (EMT) of the retinal pigment epithelium is involved in the pathogenesis of proliferative vitreoretinopathy (PVR) that often leads to retinal detachment. In this study, Triphala, an ayurvedic formulation and two of its active ingredients, namely chebulagic acid and chebulinic acid were evaluated for anti-EMT properties based on in vitro experiments in human retinal pigment epithelial cell line (ARPE-19) under TGFbeta1 induced conditions. ARPE-19 cells were treated with TGFbeta1 alone or co-treated with various concentrations of aqueous extract (AqE) (30-300 MUg/ml); alcoholic extract (AlE) (50-500 MUg/ml) of triphala and the active principles chebulagic acid (CA) and chebulinic acid (CI) (CA,CI: 50-200 MUM). The expression of EMT markers namely MMP-2, alphaSMA, vimentin and the tight junction protein ZO-1 were evaluated by qPCR, western blot and immunofluorescence. The functional implications of EMT, namely migration and proliferation of cells were assessed by proliferation assay, scratch assay and transwell migration assay. AqE, AlE, CA and CI reduced the expression and activity of MMP-2 at an ED50 value of 100 MUg/ml, 50 MUg/ml, 100 MUM and 100 MUM, respectively. At these concentrations, a significant down regulation of the expression of alphaSMA, vimentin and up-regulation of the expression of ZO-1 altered by TGFbeta1 were observed. These concentrations also inhibited proliferation and migration of ARPE-19 cells induced by TGFbeta1. EMT was found to be induced in ARPE-19 cells, through SMAD-3 phosphorylation and it was inhibited by AqE, AlE, CA and CI. Further studies in experimental animals are required to attribute therapeutic potential of these extracts and their active compounds, as an adjuvant therapy in the disease management of PVR. PMID- 25793925 TI - Polybrominated diphenyl ethers (PBDEs) in PM2.5, PM10, TSP and gas phase in office environment in Shanghai, China: occurrence and human exposure. AB - To evaluate risk via inhalation exposure of polybrominated diphenyl ethers (PBDEs) in office environment, thirty-six pairs air samples including PM2.5 (particles with aerodynamic diameter less than 2.5 MUm), PM10 (particles with aerodynamic diameter less than 10 MUm), total suspended particles (TSP) with matching gas phase were collected in office environment in Shanghai, China. The average concentrations of PM2.5, PM10 and TSP were 20.4, 27.2 and 50.3 MUg/m3, respectively. Sigma15PBDEs mean concentrations in PM2.5, PM10, TSP and gas phase were 51.8, 110.7, 148 and 59.6 pg/m3, respectively. Much more PBDEs distributed in fine fractions than coarse ones. PBDEs congener profiles found in PM2.5, PM10 and TSP (dominated by BDE-209) were different from that in gas phase (dominated by the tri- to penta-BDEs). Approximately 3.20 pg/kg/d PM2.5 bound PBDEs can be inhaled into the lung; 3.62 pg/kg/d PM10-PM2.5(particles with aerodynamic diameter of 2.5-10 MUm) bound PBDEs tended to be deposited in the upper part of respiratory system, and the intake of PBDEs via gas-phase was 2.74 pg/kg/d. The exposure of PBDEs was far below the minimal risk levels (MRLs), indicating lower risk from PBDEs via inhalation in the studied office in Shanghai. PMID- 25793926 TI - Application of a Rule-Based Approach in Real-Time Crash Risk Prediction Model Development Using Loop Detector Data. AB - OBJECTIVES: There is a growing trend in development and application of real-time crash risk prediction models within dynamic safety management systems. These real time crash risk prediction models are constructed by associating crash data with the real-time traffic surveillance data (e.g., collected by loop detectors). The main objective of this article is to develop a real-time risk model that will potentially be utilized within traffic management systems. This model aims to predict the likelihood of crash occurrence on motorways. METHODS: In this study, the potential prediction variables are confined to traffic-related characteristics. Given that the dependent variable (i.e., traffic safety condition) is dichotomous (i.e., "no-crash" or "crash"), a rule-based approach is considered for model development. The performance of rule-based classifiers is further compared with the more conventional techniques like binary logistic regression and decision trees. The crash and traffic data used in this study were collected between June 2009 and December 2011 on a part of the E313 motorway in Belgium between Geel-East and Antwerp-East exits, on the direction toward Antwerp. RESULTS: The results of analysis show that several traffic flow characteristics such as traffic volume, average speed, and standard deviation of speed at the upstream loop detector station and the difference in average speed on upstream and downstream loop detector stations significantly contribute to the crash occurrence prediction. The final chosen classifier is able to predict 70% of crash occasions accurately, and it correctly predicts 90% of no-crash instances, indicating a 10% false alarm rate. CONCLUSIONS: The findings of this study can be used to predict the likelihood of crash occurrence on motorways within dynamic safety management systems. PMID- 25793927 TI - Keeping it Natural: Does Persuasive Magazine Content Have an Effect on Young Women's Intentions for Birth? AB - Information in the popular media tends to be biased toward promoting the benefits of medicalized birth for low-risk pregnancies. We aimed to assess the effect of communicating the benefits of non-medicalized birth in magazine articles on women's birth intentions and to identify the mechanisms by which social communication messages affected women's intentions for birth. A convenience sample of 180 nulliparous Australian women aged 18-35 years were randomly exposed to a magazine article endorsing non-medicalized birth (using either celebrity or non-celebrity endorsement) or organic eating (control) throughout June-July 2011. Magazine articles that endorsed non-medicalized birth targeted perceived risk of birth, expectations for labor and birth, and attitudes toward birth. These variables and intention for birth were assessed by self-report before and after exposure. Exposure to a magazine article that endorsed non-medicalized birth significantly reduced women's intentions for a medicalized birth, regardless of whether the endorsement was by celebrities or non-celebrities. Changes in perceived risk of birth mediated the effect of magazine article exposure on women's intentions for a medicalized birth. Persuasive communication that endorses non-medicalized birth could be delivered at the population level and may reduce women's intentions for a medicalized birth. PMID- 25793928 TI - Low-dose radioiodine ablation in differentiated thyroid cancer with macroscopic extrathyroidal extension and low level of preablative-stimulated thyroglobulin. AB - OBJECTIVE: High-dose radioactive iodine (RAI) is recommended for patients with nonmetastatic differentiated thyroid cancer with macroscopic extrathyroidal extension (MAEE). It is unclear whether these patients can be treated with low dose RAI when preablative-stimulated thyroglobulin (ps-Tg) is low. This randomized study aims to evaluate the clinical outcome and ablative efficacy of low-dose radioiodine in patients with MAEE but with low ps-Tg level. MATERIALS AND METHODS: Differentiated thyroid cancer patients with complete thyroidal resection, MAEE, any N stage, ps-Tg less than or equal to 5 ng/ml when thyroglobulin antibodies are less than or equal to 46 IU/ml, and no evidence of distant metastasis were included in the study. Patients were randomly allocated to receive low-dose (1110 MBq) or high-dose RAI (3700 MBq). Follow-up was generally performed 6 months after ablation. Successful ablation was identified as (i) stimulated thyroglobulin 1.0 ng/ml or less when thyroglobulin antibodies 46 IU/ml or less; (ii) negative Dx-WBS; and (iii) negative neck ultrasonography. Clinical recurrence was defined as the reappearance of disease confirmed by cytology or pathology. RESULTS: A total of 102 patients were analyzed: 51 in the low-dose group and 51 in the high-dose group. There was no significant difference in clinicopathological characters between the two groups. No patient had clinical recurrences during the mean 6.8 months of follow-up. Ablation was successful in 43 of 51 (84.3%) patients in the low-dose group and in 44 of 51 (86.27%) patients in the high-dose group, and thus no significant difference was noted (P=0.7798). CONCLUSION: Ablation with low-dose RAI has been proven to be noninferior to high dose RAI in nonmetastatic patients with MAEE when ps-Tg level is less than 5 ng/ml. PMID- 25793929 TI - Respiratory-gated imaging in metabolic evaluation of small solitary pulmonary nodules: 18F-FDG PET/CT and correlation with histology. AB - OBJECTIVE: The aim of the study was to evaluate the effect of 2-((18)F)-fluoro-2 deoxy-D-glucose ((18)F-FDG)-PET/computed tomography (CT) respiratory-gated imaging [four-dimensional (4D)] in the metabolic evaluation of small solitary pulmonary nodules and analyze the cutoff maximum standardized uptake value (SUV(max)) of 2.5 in classifying and distinguishing benign/malignant pulmonary pathologies in 4D studies. MATERIALS AND METHODS: Thirty-two patients with pulmonary lesions measuring 2 cm or less were included during their scheduled (18)F-FDG PET/CT examinations. The whole-body PET/CT acquisition (3D) was followed by a chest-centered PET/CT (4D) study synchronized with the respiratory cycle. The SUV(max) percentage difference (%Diff SUV(max)) was calculated. The nodule size, localization, and relationships with histological/cytological findings were studied. RESULTS: Fifteen nodules were 10 mm or smaller and 17 were larger than 10 mm [mean size = 12 mm (7-20)]. The mean 3D-SUV(max) was 2.5 (0.7 6.1) and the mean 4D-SUV(max) 3.2 (0.9-7.2) (P < 0.001). The mean %Diff SUV(max) was 38% for all patients (7-90), 45% in subcentimetric (7-90%) and 31% (7-75%) in supracentimetric lesions (P = NS). Histology was obtained in 23/32 (72%) cases and the pathologic benign/malignant ratio was 4/19. Malignancies were diagnosed as lung adenocarcinoma, solitary metastases, large cell lung carcinoma, and sarcoma in 13 (41%), 3 (9%), 2 (6%), and 1 (3%) case, respectively. Malignant lesions showed mean 4D-SUV(max) of 3.8 (1.2-7.2). The cutoff SUV(max) of 2.5 did not classify and distinguish between benign/malignant pulmonary pathologies, neither in 3D nor in 4D studies. CONCLUSION: Respiratory gating improves the detectability and metabolic evaluation of solitary pulmonary nodules, mostly those that are subcentimetric. However, as expected, the cutoff SUV(max) of 2.5 does not distinguish between benign/malignant lesions in either 4D or 3D studies. PMID- 25793930 TI - Does plant species richness guarantee the resilience of local medical systems? A perspective from utilitarian redundancy. AB - Resilience is related to the ability of a system to adjust to disturbances. The Utilitarian Redundancy Model has emerged as a tool for investigating the resilience of local medical systems. The model determines the use of species richness for the same therapeutic function as a facilitator of the maintenance of these systems. However, predictions generated from this model have not yet been tested, and a lack of variables exists for deeper analyses of resilience. This study aims to address gaps in the Utilitarian Redundancy Model and to investigate the resilience of two medical systems in the Brazilian semi-arid zone. As a local illness is not always perceived in the same way that biomedicine recognizes, the term "therapeutic targets" is used for perceived illnesses. Semi-structured interviews with local experts were conducted using the free-listing technique to collect data on known medicinal plants, usage preferences, use of redundant species, characteristics of therapeutic targets, and the perceived severity for each target. Additionally, participatory workshops were conducted to determine the frequency of targets. The medical systems showed high species richness but low levels of species redundancy. However, if redundancy was present, it was the primary factor responsible for the maintenance of system functions. Species richness was positively associated with therapeutic target frequencies and negatively related to target severity. Moreover, information about redundant species seems to be largely idiosyncratic; this finding raises questions about the importance of redundancy for resilience. We stress the Utilitarian Redundancy Model as an interesting tool to be used in studies of resilience, but we emphasize that it must consider the distribution of redundancy in terms of the treatment of important illnesses and the sharing of information. This study has identified aspects of the higher and lower vulnerabilities of medical systems, adding variables that should be considered along with richness and redundancy. PMID- 25793931 TI - Molecular Serotyping and Pathogenic Potential of Listeria monocytogenes Isolated from Milk and Milk Products in Tamil Nadu, India. AB - Listeria monocytogenes, an important bacterial pathogen, is responsible for foodborne illnesses worldwide. Examination of food samples for the presence of L. monocytogenes and assessment of their pathogenicity is usually an effective strategy in the prevention of listeriosis. In the present study, we have tested 307 samples of milk and milk products from various places in Tamil Nadu, India for the presence of L. monocytogenes using ISO 11290 and U.S. Food and Drug Administration Bacteriological Analytical Manual methods. 16S rDNA sequencing and duplex polymerase chain reaction (PCR) analysis for prs and iap genes were used to identify L. monocytogenes at the species level. Fifteen of the 307 samples screen tested positive for L. monocytogenes. Molecular serotyping of the L. monocytogenes isolates by multiplex PCR revealed the predominance of the serogroups 1/2a and 4b. Fourteen of the 15 isolates contained all the virulence genes (inlA, inlB, hlyA, and plcA) screened for using multiplex PCR. Only one isolate of L. monocytogenes was negative for the plcA gene and in vitro phosphatidylinositol-phospholipase C activity. L. monocytogenes strains that belong to the serogroup 4b exhibited higher nematocidal activity against Caenorhabditis elegans than the serogroup 1/2a. Worms infected with L. monocytogenes were symptomatic with aberrant contraction of body muscles, loss of pharyngeal pumping, and decreased locomotion, which highlights the pathogenic potential of the L. monocytogenes isolates. PMID- 25793932 TI - Temporal stability and the effects of training on saccade latency in "express saccade makers". AB - The temporal stability of saccade latency, and the effects of training, particularly in "express saccade makers" (ESMs), has received little attention. ESMs are healthy, naive, adults, who persist in executing very many low latency "express saccades" (ES; saccades with latency of 80 ms to 130 ms), in conditions designed to suppress such responses. We investigated the stability of ES production (%ES) in 59 ESM and 54 non-ESM participants in overlap tasks. Within a single session, the intraclass correlation coefficient (ICC) for %ES in two runs of 200 trials was 0.97 (p<0.001); participants in whom >30% of saccades over the two runs were ES, were classified as ESMs. For 60 participants tested over two sessions 12 weeks apart, and 30 participants tested in three sessions over approximately six months, the ICC for %ES was uniformly high (0.95, p<0.001 and 0.97, p<0.001 respectively) and participants behaved consistently with their initial classification. Fourteen participants (7 ESMs) were then exposed to training consisting of either gap or overlap tasks. Training increased %ES in both groups. However, when tested in overlap tasks, it was not sufficient to transform Normal participants into ESMs. We conclude that the pattern of saccade behaviour exhibited by ESMs constitutes a stable and distinct oculomotor phenotype. PMID- 25793933 TI - Treatment of W. bancrofti (Wb) in HIV/Wb coinfections in South India. AB - BACKGROUND: The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coincident infections. METHODOLOGY/PRINCIPAL FINDINGS: To assess the influence of pre-existing Wuchereria bancrofti infection on HIV progression, we performed a case-controlled treatment study of HIV positive individuals with (FIL+) or without (FIL-) W. bancrofti infection. Twenty-eight HIV+/FIL+ and 51 matched HIV+/FIL- subjects were treated with a single dose of diethylcarbamazine and albendazole (DEC/Alb) and followed for a year at regular intervals. Sixteen of the HIV+/FIL+ subjects (54%) and 28 of the HIV+/FIL- controls (57%) were on antiretroviral therapy (ART) during the study. Following treatment, no differences were noted in clinical outcomes between the 2 groups. There also was no significant difference between the groups in the HIV viral load at 12 months as a percentage of baseline viral load (HIV+/FIL+ group had on average 0.97 times the response of the HIV+/FIL- group, 95% CI 0.88, 1.07) between the groups. Furthermore, there were no significant differences found in either the change in viral load at 1, 3, or 6 months or in the change in CD4 count at 3, 6, or 12 months between the 2 groups. CONCLUSIONS/SIGNIFICANCE: We were unable to find a significant effect of W. bancrofti infection or its treatment on HIV clinical course or surrogate markers of HIV disease progression though we recognized that our study was limited by the smaller than predicted sample size and by the use of ART in half of the patients. Treatment of W. bancrofti coinfection in HIV positive subjects (as is usual in mass drug administration campaigns) did not represent an increased risk to the subjects, and should therefore be considered for PLWHA living in W. bancrofti endemic areas. TRIAL REGISTRATION: ClinicalTrials.gov NCT00344279. PMID- 25793934 TI - Ultrastructure of Wax-Producing Structures on the Integument of the Melaleuca Psyllid Boreioglycaspis melaleucae (Hemiptera: Psyllidae), with Honeydew Excretion Behavior in Males and Females. AB - The melaleuca psyllid, Boreioglycaspis melaleucae (Hemiptera: Psyllidae), was introduced to Florida as a biological control agent against Melaleuca quinquenervia, an invasive evergreen tree that has invaded large areas of Florida Everglades. Colonies of B. melaleucae nymphs are normally covered by white waxy secretions, and nymphs of various instars produce long bundles of white waxy filaments extending laterally and posteriorly from their abdomen. Scanning electron microscopy of 'naturally waxed' and 'dewaxed' nymphs (cleaned from wax) revealed two types of wax pore plates located dorsally and laterally on the integument of posterior abdominal segments starting with the 4th segment. Type-1 wax pore plates, with raised rim, peripheral groove, slits and pits, produce long ribbons and filaments of waxy secretions that are wound together forming long wax bundles, whereas type-2 wax pore plates, with slits only, produce shorter wax curls. Additionally, in both nymphs and adult females, the circumanal ring contained ornate rows of wax pores that produce wax filaments covering their honeydew excretions. Video recordings with stereomicroscopy showed that adult females produce whitish honeydew balls, powerfully propelled away from their body, probably to get these sticky excretions away from their eggs and newly hatched nymphs. Adult males, however, produce clear droplets of honeydew immediately behind them, simply by bending the posterior end of the abdomen downward. The possible role(s) of waxy secretions by nymphs and adults of B. melaleucae in reducing contamination of their colonies with honeydew, among other possibilities, are discussed. PMID- 25793936 TI - The effect of breast support and breast pain on upper-extremity kinematics during running: implications for females with large breasts. AB - The relationship between inappropriate breast support and upper-extremity kinematics for female runners is unclear. The purpose of this study was to investigate the effect of breast support and breast pain on upper-extremity kinematics during running. Eleven female recreational runners with larger breasts (UK D and E cup) completed a 7 min 20 s treadmill run (2.58 m . s(-1)) in a high and low breast support condition. Multi-planar breast and upper-extremity kinematic data were captured in each breast support condition by eight infrared cameras for 30 s towards the end of the run. Breast pain was rated at the end of each treadmill run using a numeric analogue scale. The high support bra reduced breast kinematics and decreased breast pain (P < 0.05). Upper-extremity kinematics did not differ between breast support conditions (P > 0.05), although some moderate positive correlations were found between thorax range of motion and breast kinematics (r = 0.54 to 0.73). Thorax and arm kinematics do not appear to be influenced by breast support level in female runners with large breasts. A high support bra that offers good multi-planar breast support is recommended for female runners with larger breasts to reduce breast pain. PMID- 25793935 TI - The Ras GTPase-activating protein Rasal3 supports survival of naive T cells. AB - The Ras-mitogen-activated protein kinase (MAPK) pathway is crucial for T cell receptor (TCR) signaling in the development and function of T cells. The significance of various modulators of the Ras-MAPK pathway in T cells, however, remains to be fully understood. Ras-activating protein-like 3 (Rasal3) is an uncharacterized member of the SynGAP family that contains a conserved Ras GTPase activating protein (GAP) domain, and is predominantly expressed in the T cell lineage. In the current study, we investigated the function and physiological roles of Rasal3. Our results showed that Rasal3 possesses RasGAP activity, but not Rap1GAP activity, and represses TCR-stimulated ERK phosphorylation in a T cell line. In systemic Rasal3-deficient mice, T cell development in the thymus including positive selection, negative selection, and beta-selection was unaffected. However, the number of naive, but not effector memory CD4 and CD8 T cell in the periphery was significantly reduced in Rasal3-deficient mice, and associated with a marked increase in apoptosis of these cells. Indeed, survival of Rasal3 deficient naive CD4 T cells in vivo by adoptive transfer was significantly impaired, whereas IL-7-dependent survival of naive CD4 T cells in vitro was unaltered. Collectively, Rasal3 is required for in vivo survival of peripheral naive T cells, contributing to the maintenance of optimal T cell numbers. PMID- 25793937 TI - Fast "Wittig-like" reactions as a consequence of the inorganic enamine effect. AB - The tungsten alkylidyne [CF3-ONO]W=CC(CH3)3(THF)2 (3) {where CF3-ONO = (MeC6H3[C(CF3)2O])2N(3-)} supported by a trianionic pincer-type ligand demonstrates enhanced nucleophilicity in unusually fast "Wittig-like" reactions. Experiments are designed to provide support for an inorganic enamine effect that is the origin of the enhanced nucleophilicity. Treating complex 3 with various carbonyl-containing substrates provides tungsten-oxo-vinyl complexes upon oxygen atom transfer. The rates of reactivity of 3 are compared with the known alkylidyne (DIPP)3W=CC(CH3)3 (DIPP = 2,6-diisopropylphenoxide). In all cases (except acetone), complex 3 exhibits significantly faster overall rates than (DIPP)3W=CC(CH3)3. New oxo-vinyl complexes are characterized by NMR, combustion analysis and single crystal X-ray diffraction. Treating 3 with acid chlorides provides the tungsten oxo chloride species [CF3-ONO]W(O)Cl (4) and disubstituted alkynes. In the case of acetone the oxo-vinyl complex results in two rotational isomers 10syn and 10anti. The rate of isomerization was determined for the forward and reverse directions and was complimented with DFT calculations. PMID- 25793938 TI - Exquisitely specific bisubstrate inhibitors of c-Src kinase. AB - We have developed a modular approach to bisubstrate inhibition of protein kinases. We apply our methodology to c-Src and identify a highly selective bisubstrate inhibitor for this target. Our approach has yielded the most selective c-Src inhibitor to date, and the methodology to render the bisubstrate inhibitor cell-permeable provides a highly valuable tool for the study of c-Src signaling. In addition, we have applied our bisubstrate inhibitor to develop a novel screening methodology to identify non-ATP-competitive inhibitors of c-Src. Using this methodology, we have discovered the most potent non-ATP-competitive inhibitor reported to date. Our methodology is designed to be general and could be applicable to additional kinases inhibited by the promiscuous ATP-competitive fragment used in our studies. PMID- 25793939 TI - Peptide/protein stapling and unstapling: introduction of s-tetrazine, photochemical release, and regeneration of the peptide/protein. AB - Protocols have been achieved that permit facile introduction of s-tetrazine into unprotected peptides and the protein, thioredoxin, between two cysteine sulfhydryl groups (i.e., staple), followed by photochemical release (i.e., unstaple) and regeneration of the peptide/protein upon removal of the cyano groups from the derived bisthiocyanate. The S,S-tetrazine macrocycles in turn provide a convenient handle for probe introduction by exploiting the inverse electron demand Diels-Alder reactivity of the tetrazine. PMID- 25793940 TI - Field efficacy and transmission of fast- and slow-killing nucleopolyhedroviruses that are infectious to Adoxophyes honmai (Lepidoptera: Tortricidae). AB - The smaller tea tortrix, Adoxophyes honmai (Lepidoptera: Tortricidae), is an economically important pest of tea in Japan. Previous work showed that a fast killing nucleopolyhedrovirus (NPV) isolated from A. orana (AdorNPV) and a slow killing NPV isolated from A. honmai (AdhoNPV) are both infectious to A. honmai larvae. Field application of these different NPVs was conducted against an A. honmai larval population in tea plants, and the control efficacy and transmission rate of the two NPVs were compared. The slow-killing AdhoNPV showed lower field efficacy, in terms of preventing damage caused by A. honmai larvae against the tea plants, than the fast-killing AdorNPV. However, AdhoNPV had a significantly higher horizontal transmission rate than AdorNPV. These results show that AdorNPV is suitable as an inundative agent, while AdhoNPV is an appropriate inoculative agent. PMID- 25793941 TI - Correction: DNA methylation analysis of the macrosatellite repeat associated with FSHD muscular dystrophy at single nucleotide level. PMID- 25793943 TI - Long interspersed retrotransposable elements and susceptibility to schizophrenia. PMID- 25793942 TI - Estimation of canine Leishmania infection prevalence in six cities of the Algerian littoral zone using a Bayesian approach. AB - A large-scale study on canine Leishmania infection (CanL) was conducted in six localities along a west-east transect in the Algerian littoral zone (Tlemcen, Mostaganem, Tipaza, Boumerdes, Bejaia, Jijel) and covering two sampling periods. In total 2,184 dogs were tested with an indirect fluorescent antibody test (IFAT) and a direct agglutination test (DAT). Combined multiple-testing and several statistical methods were compared to estimate the CanL true prevalence and tests characteristics (sensitivity and specificity). The Bayesian full model showed the best fit and yielded prevalence estimates between 11% (Mostaganem, first period) and 38% (Bejaia, second period). Sensitivity of IFAT varied (in function of locality) between 86% and 88% while its specificity varied between 65% and 87%. DAT was less sensitive than IFAT but showed a higher specificity (between 80% and 95% in function of locality or/and season). A general increasing trend of the CanL prevalence was noted from west to east. A concordance between the present results and the incidence of human cases of visceral leishmaniasis was observed, where also a maximum was recorded for Bejaia. The results of the present study highlight the dangers when using IFAT as a gold standard. PMID- 25793944 TI - Phosphorylation of lamins determine their structural properties and signaling functions. AB - Lamin A/C is part of the nuclear lamina, a meshwork of intermediate filaments underlying the inner nuclear membrane. The lamin network is anchoring a complex set of structural and linker proteins and is either directly or through partner proteins also associated or interacting with a number of signaling protein and transcription factors. During mitosis the nuclear lamina is dissociated by well established phosphorylation- dependent mechanisms. A-type lamins are, however, also phosphorylated during interphase. A recent study identified 20 interphase phosphorylation sites on lamin A/C and explored their functions related to lamin dynamics; movements, localization and solubility. Here we discuss these findings in the light of lamin functions in health and disease. PMID- 25793945 TI - The effect of technology-based interventions on pain, depression, and quality of life in patients with cancer: a systematic review of randomized controlled trials. AB - BACKGROUND: The burden of cancer is increasing; projections over the next 2 decades suggest that the annual cases of cancer will rise from 14 million in 2012 to 22 million. However, cancer patients in the 21st century are living longer due to the availability of novel therapeutic regimens, which has prompted a growing focus on maintaining patients' health-related quality of life. Telehealth is increasingly being used to connect with patients outside of traditional clinical settings, and early work has shown its importance in improving quality of life and other clinical outcomes in cancer care. OBJECTIVE: The aim of this study was to systematically assess the literature for the effect of supportive telehealth interventions on pain, depression, and quality of life in cancer patients via a systematic review of clinical trials. METHODS: We searched PubMed, EMBASE, Google Scholar, CINAHL, and PsycINFO in July 2013 and updated the literature search again in January 2015 for prospective randomized trials evaluating the effect of telehealth interventions in cancer care with pain, depression, and quality of life as main outcomes. Two of the authors independently reviewed and extracted data from eligible randomized controlled trials, based on pre-determined selection criteria. Methodological quality of studies was assessed by the Cochrane Collaboration risk of bias tool. RESULTS: Of the 4929 articles retrieved from databases and relevant bibliographies, a total of 20 RCTs were included in the final review. The studies were largely heterogeneous in the type and duration of the intervention as well as in outcome assessments. A majority of the studies were telephone-based interventions that remotely connected patients with their health care provider or health coach. The intervention times ranged from 1 week to 12 months. In general, most of the studies had low risk of bias across the domains of the Cochrane Collaboration risk of bias tool, but most of the studies had insufficient information about the allocation concealment domain. Two of the three studies focused on pain control reported significant effects of the intervention; four of the nine studies focus on depression reported significant effects, while only the studies that were focused on quality of life reported significant effects. CONCLUSIONS: This systematic review demonstrates the potential of telehealth interventions in improving outcomes in cancer care. However, more high-quality large-sized trials are needed to demonstrate cogent evidence of its effectiveness. PMID- 25793947 TI - Is a new sonic toothbrush more effective in plaque removal than a manual toothbrush? AB - AIM: Powered or manual toothbrushes are daily-used instrument in the Western area for the control and removal of bacterial biofilm. Among powered-toothbrushes, sonic technology has shown to produce fluid turbulent activity that might assist in plaque removal; however, limited knowledge is available in-vivo. The objectives of this study were to compare the plaque removal efficacy of two different toothbrushes in a population not familiar with sonic technology, and to collect and analyse data regarding oral hygiene habits. The null-hypothesis was that a sonic toothbrush is able to remove a superior amount of plaque compared to the manual type. MATERIALS AND METHODS: Forty young adult patients were enrolled in the study. A single-cohort crossover clinical trial was designed. For each patient, three appointments were scheduled: the first (T0) was used for oral care education and explanations of toothbrushes techniques, for a preliminary professional hygiene session, and for delivery of a questionnaire; at one week (T1), plaque evaluation was performed (Turesky modification of the Quigley and Hein index) at baseline and after asking patients to brush with the randomly selected manual or sonic device. At the last appointment (week 3, T2), the same plaque evaluations of T1 were repeated asking patients to brush with the other toothbrush. Entire mouth indexes were calculated and mean reductions in whole mouth plaque scores were obtained (pre-brushing minus post-brushing values) for the two tested toothbrushes. Multiple ANOVA tests (p = 0.05 ) were used 1) to compare plaque levels between male and female subjects at baseline and post brushing, regardless the type of toothbrush, and 2) to differentiate between mean reductions in whole mouth plaque scores according to the type of toothbrush (manual versus sonic). The study population was subjected to descriptive statistical analysis; potential relationships between socio-demographic variables and obtained plaque scores were evaluated (Mann-Whitney and Kruskal-Wallis tests). RESULTS: Full-mouth plaque levels were reduced at post-brushing sessions, regardless the device, by approximately 62% (p<0.0001). Mean plaque index reductions for manual and sonic toothbrush were of 1.05 +/- 0.22 and 1.19 +/- 0.37, respectively. A statistically significant difference was found between the two devices (p = 0.0342). The powered sonic toothbrush removed about 10% more plaque than the manual type. From the collected questionnaire financial data, willingness to pay (WTP) values expressing economic efforts of patients for the purchase of toothbrushes were of Euros 4.83 +/- 3.86 and of Euros 54.75 +/- 36, for the manual and sonic devices, respectively. CONCLUSION: Within the limitations of the study, in subjects without any previous experience of a similar technology, the single use of the sonic toothbrush showed a significantly greater plaque reduction compared to the manual traditional toothbrush (null hypothesis accepted). PMID- 25793946 TI - Association between the number of early carious lesions and diet in children with a high prevalence of caries. AB - AIM: An investigation was conducted in a population of paediatric patients with a high risk of caries in order to assess the association between caries history (CH) and the number of early carious lesions (ECLs) and the frequency and timing of cariogenic food and beverage intake, sugar-containing medication, the frequency and efficacy of tooth brushing, and the use of topical fluorides. MATERIALS AND METHODS: Study design: descriptive study. One hundred children aged 6-15 years with>= ECL of a permanent tooth and not enrolled in any dental health educational or preventive programme were selected. For diagnosis it was used an explorer according to the ICDAS II criteria. The participants completed a closed list questionnaire on the frequency and timing of cariogenic food intake. RESULTS: There was a nonsignificant tendency to present more ECLs and a greater CH among patients who consumed cariogenic foods and beverages. A significant relationship (p<0.05) was observed between cariogenic beverages and the number of ECL or CH. Using the number of ECLs as dependent variable, regular fluoridated rinses (p=0.003), frequent sugar-containing medication (p=0.007), and cariogenic beverage consumption (p=0.024) were identified as explanatory parameters in the linear regression model. STATISTICS: The Student t-test was used to compare ECL and CH with dietetic factors, fluoridated rinses, sugar- containing medicines, and the frequency and efficacy of tooth brushing. Linear regression analysis correlated the number of ECLs to the mentioned explanatory variables. CONCLUSION: The frequent consumption of sugary beverages and medications, and failure to regularly use fluoridated rinses, were positively correlated to an increased number of ECLs in patients with a high prevalence of caries. PMID- 25793948 TI - Study of the frequency, localisation and morphology of supernumerary teeth in 1960 Spanish non-syndromic paediatric patients. AB - AIM: The main objective was to study supernumerary teeth diagnosed during the routine checkups at the Paediatric Dentistry Service of Hospital de Nens, Barcelona (Spain), for four months. MATERIALS AND METHODS: A transversal, descriptive study, was performed in 1,960 patients, aged 1 to 17 years, visited during routine oral checkups. An intraoral exploration (with intraoral mirror and probe) was performed to all patients, and subjects older than 5 years also underwent panoramic x-ray examination. RESULTS: A total of 33 patients showed supernumerary teeth (1.68%), 22 boys and 11 girls. A total of 10 patients (8 boys/2 girls) had supernumerary teeth in the temporary dentition, 20 patients (12 boys/8 girls) in the permanent dentition and 3 patients (2 boys/1girls) in both temporary and permanent dentition. A total of 46 supernumerary teeth were diagnosed. CONCLUSION: Any alteration in the number of teeth in patients younger than 5 years are difficult to diagnose, as x-rays are usually not taken. We believe that starting at 5 years old, a radiological exploration (panoramic x ray) has to be carried out as a complement to the clinical examination. PMID- 25793949 TI - Management of paediatric maxillofacial fractures: conventional methods and resorbable materials. AB - AIM: To compare the outcomes between the use of resorbable plates and screws and the conventional methods in children with paediatric maxillofacial fractures. MATERIALS AND METHODS: STUDY DESIGN: a retrospective observational study was designed reviewing the clinical records from June 2007 and June 2011. Data collected included aepidemiological data, type of treatment, outcome and satisfaction questionnaire. Descriptive statistics and bivariate analysis were performed. RESULTS: A total of 1122 children (0-17 years old) were studied. Children treated by conventional methods were 912, while children treated by resorbable materials were 210. The frequency of complications during recovery was similar and no statistically significant difference was noted. The satisfaction questionnaire revealed similar percentages of satisfaction, with a high degree of satisfaction. CONCLUSION: Our experience suggests that resorbable devices should be considered as a treatment option, which avoids the need of further surgery to remove metallic fixation, limits hospital spending and increases children's quality of life. PMID- 25793950 TI - Are behaviour risk factors for traumatic dental injuries in childhood different between males and females? AB - AIM: Examination of the risk factors for childhood traumatic dental injuries for male and female patients have been elusive. The present study aimed to examine whether males and females are differentially vulnerable to Traumatic Dental Injuries in relation to emotion regulation, attention deficiency hyperactive disorder symptomatology and behaviour problems. MATERIALS AND METHODS: An institutional ethical review board approved the case-control study carried out at the Gazi University, Faculty of Dentistry, Turkey. A total of 80 patients with traumatic dental injuries and 80 patients with other dental problems participated in the study. Patients' parents filled in two scales: Conners' Rating Scales Revised Attention Deficiency Hyperactive Disorder-Index, Oppositional Behavior, Hyperactivity, Anxious-Shy, Social Problems, Inattentive and Hyperactive Impulsive subscales; and Emotion Regulation Checklist, with two subscales of Emotional Lability and Emotion Regulation. Multiple logistic regression analyses were performed separately for male and female patients. RESULTS: Oppositional behaviour, hyperactivity and social problems were found to be risk factors for male patients. Being anxious/shy was the protective factor for both males and females. Classification accuracy for males and females were calculated to be 79.2% and 85.2% respectively. CONCLUSION: Several risk factors for childhood traumatic dental injuries were found to differ for male and female patients. PMID- 25793951 TI - Effect of different surface pre-treatment methods on the microleakage of two different self-adhesive composites in Class V cavities. AB - AIM: To evaluate the effect of different surface pre-treatment methods on the microleakage of self-adhesive flowable composites (SAFCs) in comparison with a conventional flowable composite applied with an etch-and-rinse adhesive system. MATERIALS AND METHODS: One hundred and thirty-five standardised Class V cavities were randomly divided into nine groups: (1) three-step etch-and-rinse adhesive (Optibond FL - Kerr, Orange, USA)/flowable composite (Clearfil Majesty Flow - Kuraray, Tokyo, Japan) (E&Ra/flowC); (2) Fusio Liquid Dentin (Pentron Clinical, Orange, USA); (3) Er:YAG Laser/Fusio Liquid Dentin (Er&Las/Fusio Liquid Dentin); (4) Phosphoric Acid/Fusio Liquid Dentin (PhosA/Fusio Liquid Dentin); (5) Polyacrylic Acid/Fusio Liquid Dentin (PolyA/Fusio Liquid Dentin); (6) Vertise Flow (Kerr, Orange, USA); (7) Er:YAG Laser/Vertise Flow (Er&Las/Vertise Flow); (8) Phosphoric Acid/Vertise Flow (PhosA/Vertise Flow); (9) Polyacrylic Acid/Vertise Flow (PolyA/Vertise Flow). After thermocycling and immersion in a 0.5% basic fuchsin, the restorations were evaluated under a stereomicroscope (n = 30). The data were statistically analysed (alpha = 0.05). RESULTS: Both SAFCs showed higher leakage scores than E&Ra/flowC in enamel and dentin (p < 0.05). Vertise Flow showed lower leakage than Fusio Liquid Dentin in dentin (p < 0.05). Pre-phosphoric acid etching reduced the microleakage scores of Fusio Liquid Dentin in both enamel and dentin (p < 0.05), while all surface pre-treatment methods led to a significant reduction in the microleakage scores of Vertise Flow at the enamel margin (p < 0.05). CONCLUSION: Pre-etching of enamel and dentin by phosphoric acid may be satisfactory in improving the sealing ability of Fusio Liquid Dentin, while phosphoric acid or polyacrylic acid etching or laser irradiation may be used to improve the adhesion of Vertise Flow to enamel. PMID- 25793952 TI - Appraisal of the difference between the mesiodistal diameters of deciduous incisors and molars and permanent teeth. AB - AIM: Difference in tooth size between deciduous and permanent teeth can resolve space problems during development of the dentition. AIM: To determine the difference in size between deciduous and permanent teeth in the anterior and posterior areas of the mouth in a group of school-age children from Medellin, Colombia. MATERIALS AND METHODS: DESIGN: this longitudinal prospective, descriptive investigation was carried out in 139 skeletal Class I dental stone casts from school-age children from Medellin. Patients were followed annually from 6 to 12 years of age. The final sample consisted of 53 children (35 girls and 18 boys). Leeway space and the incisor liability were determined. RESULTS: A higher positive leeway space was found in the mandible than in the maxilla (3.622 mm and 1.556 mm, respectively). Incisor liability was negatively higher in the maxilla than in the mandible (-7.884mm and -5.386mm, respectively). Six patients showed a negative leeway space between -1.582 mm and -3.184 mm for the mandible and the maxilla, respectively. No statistical significant differences were found by gender; girls showed higher leeway space and incisor liability than boys. CONCLUSION: Normal values for one ethnic group should not be considered normal for another and each group must be treated according to its own characteristics. PMID- 25793953 TI - Association between mesially displaced maxillary first premolars and early displaced maxillary canines. AB - AIM: To evaluate the association between the mesially displaced maxillary first premolar (MDP) and the early displacement of the adjacent permanent canine (EDC) before their eruption. MATERIALS AND METHODS: A sample of 1247 subjects in the intermediate mixed dentition stage was assessed for the presence of MDP and EDC. All subjects were divided into two groups: MDP group and noMDP group. For each subject two angular measurements (premolar-occlusal plane eta and l premolar midline angles) were analysed on panoramic radiographs. The chi-square test with Yates correction was performed to compare the prevalence rate of EDC in MDP (MDP EDC) and noMDP groups. The statistical comparisons for the values of eta and l angles between MDP vs noMDP, MDP vs MDP-EDC, and noMDP vs MDP-EDC groups were performed by means of ANOVA with Bonferroni correction. RESULTS: The prevalence rate of EDC in the MDP group was significantly greater than in the noMDP group (66% vs. 12.1%). MDP-EDC group showed a significantly larger l angle than in the MDP group resulting in an increased mesial inclination of displaced premolars. CONCLUSION: MDP can be considered a dental anomaly associated to maxillary canine displacement. PMID- 25793954 TI - Use of the ICDAS system and two fluorescence-based intraoral devices for examination of occlusal surfaces. AB - AIM: The aims of this study were to assess the inter-examiner reliability of ICDAS and Soprolife intra-oral camera ex vivo using 5 examiners and to compare in vivo the validity of two fluorescence-based intra-oral devices in examining occlusal surfaces with early carious lesions. MATERIALS AND METHODS: Thirty-seven occlusal surfaces of posterior primary and permanent teeth of 20 children were examined using Diagnodent pen (KaVo, Biberach/Ribeta, Germany) and Soprolife (Acteon Group, La Ciotat, France) fluorescence intra-oral camera. The white light photos, made by Soprolife camera, were evaluated using ICDAS scores and the Soprolife fluorescence photos were scored as sound, enamel caries and dentine caries by 5 experienced dentists. The dentists were trained for the use of ICDAS system with a short online training programme (ICDAS.org) and for the scoring of caries on the fluorescence images with example images. STATISTICS: cut-offs were made for ICDAS, Soprolife and Diagnodent to distinguish sound surfaces and enamel caries from dentinal caries. The inter-examiner reliability was calculated using intra-class correlation coefficient. RESULTS: On white light images the examiners found 16 enamel caries and 21 dentine caries with the ICDAS system. On the Soprolife fluorescent images 24 enamel lesions, 9 dentine lesions and 4 sound surfaces were observed. The inter-examiner reliability (ICC) of the ICDAS system on white light photographs and of Soprolife on the fluorescent images for average measures was 0.70 and 0.72, respectively. The sensitivity and specificity of Soprolife (95%CI) was 0.43 and 1.0 respectively, using ICDAS as a reference standard. The sensitivity and specificity of Diagnodent (95%CI) was 0.62 and 0.81 respectively. CONCLUSION: A short training of dentists in the use the ICDAS system resulted in satisfactory inter-examiner reliability for the analysis of occlusal lesions on white light images. Soprolife and Diagnodent do not contribute to a better detection of early carious lesions. PMID- 25793955 TI - Probiotics and their effect on oral bacteria count in children: a pilot study. AB - AIM: To assess the effect of the daily ingestion of a mixture of probiotics on the amount of Streptococcus mutans in the oral cavity of preschool-age patients with a high risk of caries. MATERIALS AND METHODS: Forty patients, aged between 4 and 6 years, with a high risk of dental caries were included in this pilot study. Patients were randomly assigned to two study groups: the Experimental Group (A) included patients who brushed their teeth and used fluoridated toothpaste in addition to consuming probiotics daily, and the Control Group (B) inclused patients who brushed their teeth and used fluoridated toothpaste but did not consume probiotics. Using the CariScreen, the microorganism count was determined at different times: baseline, 7, 14, 21 and 30 days. To identify the differences between both groups, a Mann-Whitney U test was performed, with a significance level of 0.05. RESULTS: It was observed that both groups showed similar microbial counts at the beginning of the trial (p>0.05), and a significant decrease in the count at the end of the study was found in the experimental group (p<0.05) 15 days after suspending ingestion. CONCLUSION: We found a significant reduction of RLU values in preschool children who ingested the tested probiotics in relation to the baseline values and 15 days after ceasing consumption. PMID- 25793956 TI - Determination of vertical dimension in prosthodontic rehabilitation of a growing patient with severe oligodontia. AB - CASE REPORT: This report describes the oral rehabilitation of a young boy with severe oligodontia of primary dentition and complete anodontia of permanent dentition, treated by complete maxillary and partial mandibular removable dentures. Since the determination of a proper occlusal vertical dimension in paediatric patients is often difficult, treatment was achieved by means of a multidisciplinary approach involving conventional prosthodontic principles combined with cephalometric analysis and growth prediction. After a follow-up of two years a second lateral cephalogram was taken to evaluate the developmental changes in craniofacial morphology and the superimpositions method was performed, showing an improvement of both sagittal and vertical relationship between basal bones. In this case, the early prosthetic treatment resulted in enhanced aesthetics and masticatory function as well as skeletal growth changes. PMID- 25793957 TI - Impact of early childhood caries on oral health-related quality of life of preschool children. AB - AIM: Child oral health-related quality of life (COHRQoL) has been assessed in developed areas; however, it remains unstudied in mainland China. Studies on COHRQoL would benefit a large number of children in China suffering from oral health problems such as dental caries. This study explored the relationship between COHRQoL and early childhood caries, adjusted by socioeconomic factors, in 3- to 4-year-old children in a region of southern China. MATERIALS AND METHODS: In this study, 1062 children aged 3-4 years were recruited by cluster sampling and their oral health statuses were examined by a trained dentist. The Chinese version of the Early Childhood Oral Health Impact Scale (ECOHIS) and questions about the children's socioeconomic conditions were completed by the children's parents. A negative binomial regression analysis was used to assess the prevalence of early childhood caries among the children and its influence on COHRQoL. RESULTS: The total ECOHIS scores of the returned scale sets ranged from 0 to 31, and their average scores was 3.1+/-5.1. The negative binomial analysis showed that the dmfs indices were significantly associated with the ECOHIS score and subscale scores (P<0.05). The multivariate adjusted model showed that a higher dmft index was associated with greater negative impact on COHRQoL (RR = 1.10; 95% CI = 1.07, 1.13; P < 0.05). However, demographic and socioeconomic factors were not associated with COHRQoL (P>0.05). CONCLUSION: The severity of early childhood caries has a negative impact on the oral health-related quality of life of preschool children and their parents. PMID- 25793958 TI - Correlation between aerosol therapy in early childhood and Molar Incisor Hypomineralisation. AB - AIM: To evaluate the correlation between the use of aerosol therapy in early childhood and the presence of Molar Incisor Hypomineralisation (MIH). MATERIALS AND METHODS: STUDY DESIGN: a retrospective case-control study in which a group (cases) consisted of children from 6 to 13 years with MIH visited at the unit of Pediatric Dentistry of the Policlinico Tor Vergata (Rome, Italy), and a group (controls) consisted of an equal number of children of the same age without MIH. Data about the aerosol therapy and the presence of MIH were obtained respectively by medical history and intraoral clinical examination. Collected data underwent statistical analysis using mainly non-parametric tests (p < 0.05). RESULTS: In the study were included 182 patients, of which 91 (46 males, 51%) were children with MIH (cases), and 91 (46 males, 51%) were children without MIH (controls). In the group of patients with MIH, in the early childhood, 12 (13.1%) never had aerosol therapy, 6 (6.6%) underwent aerosol therapy less than 7 days per year, 22 (24.2%) from 8 to 15 days per year, 22 (24.2%) from 16 to 45 days a year, and 29 (31.9%) more than 45 days per year. In the control group, in the early childhood, 9 (9.9%) never had aerosol therapy, 29 (31.9%) underwent aerosol therapy less than 7 days per year, 26 (28.6%) from 8 to 15 days per year, 20 (22.0%) from 16 to 45 days a year and 7 (7.6%) more than 45 days per year. STATISTICS: the risk of developing MIH in children undergoing intensive use of aerosol therapy with respect to those receiving a less intensive use resulted in an odds ratio of 3.19 (p <0.001) in the general population, 4.83 (p < 0.001) in males and was not statistically significant in females (p = 0.132). The Spearman correlation between aerosol therapy and MIH was 0.278 (p < 0.001) in the general population, 0.372 (p < 0.001) in male, and it was not statistically significant (p = 0.08) in female subjects. CONCLUSION: Aerosol therapy carried out in early childhood appears to be a risk factor for the development of MIH, particularly in male subjects. PMID- 25793959 TI - A study of primary teeth restored by intracoronal restorations in children participating in an undergraduate teaching programme at Cork University Dental School and Hospital, Ireland. AB - AIM: To study the outcomes for restored primary molar teeth; to examine outcomes in relation to tooth type involved, intracoronal restoration complexity and to the material used. MATERIALS AND METHODS: DESIGN: Retrospective study of primary molar teeth restored by intracoronal restorations. A series of restored primary molar teeth for children aged 6-12 years was studied. The principal outcome measure was failure of initial restoration (re-restoration or extraction). Three hundred patient records were studied to include three equal groups of primary molar teeth restored with amalgam, composite or glass ionomer, respectively. Restorative materials, the restoration type, simple (single surface) or complex (multi-surface) restoration, and tooth notation were recorded. Subsequent interventions were examined. Data were coded and entered into a Microsoft Excel database and analysis undertaken using SPSS v.18. Statistical differences were tested using the Chi square test of statistical significance. RESULTS: Of the 300 teeth studied, 61 restoration failures were recorded with 11 of those extracted. No significant differences were found between outcomes for upper first, upper second, lower first or lower second primary molars. Outcomes for simple primary teeth restored by intracoronal restorations were significantly better than those for complex intracoronal restorations (P = 0.042). Teeth originally restored with amalgam accounted for 19.7% of the 61 failures, composite for 29.5%, while teeth restored with glass ionomer represented 50.8% of all restoration failures. The differences were significant (P = 0.012). CONCLUSIONS: The majority (79.7%) of the 300 restored primary teeth studied were successful, and 3.7% teeth were extracted. Restorations involving more than one surface had almost twice the failure rate of single surface restorations. The difference was significant. Significant differences in failure rates for the three dental materials studied were recorded. Amalgam had the lowest failure rate while the failure rate with glass ionomer was the highest. PMID- 25793960 TI - Quality of life, safety and efficacy profile of thermostable flolan in pulmonary arterial hypertension. AB - BACKGROUND: Flolan (epoprostenol sodium) is most commonly prescribed to patients with severe pulmonary arterial hypertension (PAH) owing to the requirement that the drug be delivered by continuous intravenous infusion and the reconstituted solution may only be administered up to 24 hours when it is maintained between a temperature of 2 degrees C and 8 degrees C. The aim of this single-arm, open label study was to describe the effects of the new thermostable formulation of Flolan on health-related quality of life (HRQoL) and ease of administration in subjects switching from the currently marketed Flolan to the reformulated product. METHODS: Following a 4-week run-in period and after 4 weeks of treatment with the reformulated product, patients completed the SF-36 HRQoL questionnaire and a study-specific questionnaire evaluating ease of administration, along with World Health Organization (WHO) functional class, six-minute walked distance (6MWD) and N-terminal-pro B-type natriuretic peptide (NT-proBNP) assessment. RESULTS: 16 participants completed the study. The SF-36 scores remained unchanged from baseline to Week 4. Conversely, there were small improvements for the majority of the study-specific questionnaire items and 14 (88%) subjects preferred the reformulated product to the currently marketed Flolan. There was no significant change in the dose of reformulated product, 6MWD, Borg dyspnoea index, WHO functional class and mean NT-proBNP levels. No significant changes in haemodynamic parameters were seen from baseline to 2 hours post transition in a subset of patients undergoing catheterization. CONCLUSION: The reformulated product was not associated with significant improvement in HRQoL compared with the currently marketed Flolan as measured by the SF-36. However, most subjects preferred the reformulated product to the currently marketed Flolan. Moreover, the 2 formulations of Flolan had similar safety and efficacy profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT01462565. PMID- 25793963 TI - Versatility of global transcriptional regulators in alpha-Proteobacteria: from essential cell cycle control to ancillary functions. AB - Recent data indicate that cell cycle transcription in many alpha-Proteobacteria is executed by at least three conserved functional modules in which pairs of antagonistic regulators act jointly, rather than in isolation, to control transcription in S-, G2- or G1-phase. Inactivation of module components often results in pleiotropic defects, ranging from cell death and impaired cell division to fairly benign deficiencies in motility. Expression of module components can follow systemic (cell cycle) or external (nutritional/cell density) cues and may be implemented by auto-regulation, ancillary regulators or other (unknown) mechanisms. Here, we highlight the recent progress in understanding the molecular events and the genetic relationships of the module components in environmental, pathogenic and/or symbiotic alpha-proteobacterial genera. Additionally, we take advantage of the recent genome-wide transcriptional analyses performed in the model alpha-Proteobacterium Caulobacter crescentus to illustrate the complexity of the interactions of the global regulators at selected cell cycle-regulated promoters and we detail the consequences of (mis )expression when the regulators are absent. This review thus provides the first detailed mechanistic framework for understanding orthologous operational principles acting on cell cycle-regulated promoters in other alpha Proteobacteria. PMID- 25793964 TI - Regulatory B Cells and Mechanisms. AB - Regulatory B cells have gained prominence in their role as modulators of the immune response against tumors, infectious diseases, and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, among others. The concept of regulatory B cells has been strongly associated with interleukin (IL)-10 production; however, there is growing evidence that supports the existence of other regulatory mechanisms, such as the production of transforming growth factor beta (TGF-beta), induced cell death of effector T cells, and the induction of CD4(+)CD25(-)Foxp3(+) regulatory T cells. The regulatory function of B cells has been associated with the presence and activation of molecules such as CD40, CD19, CD1d, and BCR. Alterations in signaling by any of these pathways leads to a marked defect in regulatory B cells and to increased clinical symptoms and proinflammatory signs, both in murine models and in autoimmune diseases in humans. B cells mainly exert their regulatory effect through the inhibition of proliferation and production of proinflammatory mediators, such as TNF-alpha, IFN-gamma, and IL-17 by CD4(+) T cells. A better understanding of how regulatory B cells function will offer new perspectives with regard to the treatment of various human diseases. PMID- 25793965 TI - Scopadulciol, Isolated from Scoparia dulcis, Induces beta-Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells. AB - Scopadulciol (1), a scopadulan-type diterpenoid, was isolated from Scoparia dulcis along with three other compounds (2-4) by an activity-guided approach using the TCF reporter (TOP) luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound 1 was cytotoxic to AGS human gastric adenocarcinoma cells. The treatment of AGS cells with 1 decreased beta-catenin levels and also inhibited its nuclear localization. The pretreatment of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin, protected against the degradation of beta-catenin induced by 1. The 1 induced degradation of beta-catenin was also abrogated in the presence of pifithrin-alpha, an inhibitor of p53 transcriptional activity. Compound 1 inhibited TOP activity in AGS cells and downregulated the protein levels of cyclin D1, c-myc, and survivin. Compound 1 also sensitized AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced apoptosis by increasing the levels of the death receptors, DR4 and DR5, and decreasing the level of the antiapoptotic protein Bcl-2. Collectively, our results demonstrated that 1 induced the p53- and proteasome-dependent degradation of beta-catenin, which resulted in the inhibition of TCF/beta-catenin transcription in AGS cells. Furthermore, 1 enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL. PMID- 25793961 TI - Exceptionally widespread nanomachines composed of type IV pilins: the prokaryotic Swiss Army knives. AB - Prokaryotes have engineered sophisticated surface nanomachines that have allowed them to colonize Earth and thrive even in extreme environments. Filamentous machineries composed of type IV pilins, which are associated with an amazing array of properties ranging from motility to electric conductance, are arguably the most widespread since distinctive proteins dedicated to their biogenesis are found in most known species of prokaryotes. Several decades of investigations, starting with type IV pili and then a variety of related systems both in bacteria and archaea, have outlined common molecular and structural bases for these nanomachines. Using type IV pili as a paradigm, we will highlight in this review common aspects and key biological differences of this group of filamentous structures. PMID- 25793967 TI - Capitalizing on synergies-a discourse analysis of the process of collaboration among providers of integrative health care. AB - BACKGROUND: Integrative health care (IHC) combines therapies and providers from complementary and conventional health care. Previous studies on IHC have shown power relations between providers but few studies have explored how the interaction develops over time. The objective of this study was to explore the development of IHC collaboration and interaction among participating providers during a series of consensus case conferences for managing patients with back and neck pain. METHODS: This qualitative study was conducted within a pragmatic randomized controlled clinical trial in primary care. Patients' treatment plans were developed based on IHC provider consensus conferences (n = 26) of which 15 (5 of the first, 5 in the middle, and 5 of the last in the clinical trial) were selected for analysis. Findings were derived by means of discourse analysis, focusing on the participants' use of subject positions during the conferences. FINDINGS: The IHC team in this study gradually formed a group identity, moving their subject positions from individual treating subjects to members of a team and were able to make consensus-based decisions about patients' individual treatment plans. In the discourse, the IHC team identified collaborative shortcomings and problematized the provision of IHC. They were able to capitalize on the synergies in their collaboration and developed a shared vision of IHC provision. CONCLUSIONS: The process of IHC collaboration involved the gradual formation of an IHC team identity, which facilitated interdisciplinary, non hierarchical consensus-based decision-making in the team. The discourse further suggests that a reform of some legal and organizational health sector barriers might be needed to realize sustainable implementation of IHC services in Sweden. PMID- 25793966 TI - Association of Anaplasma marginale strain superinfection with infection prevalence within tropical regions. AB - Strain superinfection occurs when a second strain infects a host already infected with and having mounted an immune response to a primary strain. The incidence of superinfection with Anaplasma marginale, a tick-borne rickettsial pathogen of domestic and wild ruminants, has been shown to be higher in tropical versus temperate regions. This has been attributed to the higher prevalence of infection, with consequent immunity against primary strains and thus greater selective pressure for superinfection with antigenically distinct strains. However an alternative explanation would be the differences in the transmitting vector, Dermacentor andersoni in the studied temperate regions and Rhipicephalus microplus in the studied tropical regions. To address this question, we examined two tropical populations sharing the same vector, R. microplus, but with significantly different infection prevalence. Using two separate markers, msp1alpha (one allele per genome) and msp2 (multiple alleles per genome), there were higher levels of multiple strain infections in the high infection prevalence as compared to the low prevalence population. The association of higher strain diversity with infection prevalence supports the hypothesis that high levels of infection prevalence and consequent population immunity is the predominant driver of strain superinfection. PMID- 25793962 TI - Editorial. PMID- 25793968 TI - Health behaviors: is there any distinction for teachers? A cross-sectional nationwide study. AB - BACKGROUND: Health behaviors, as important modifiable determinants of health, are consistently targeted by prevention messages. Teachers, as educators and role models, may play a key-role in bringing such messages to children and adolescents. It is not clear which areas of prevention could be improved in collaboration with teachers to promote healthy behaviors at the population level through health education in schools. METHODS: to evaluate teacher's health awareness, we compared their health/risk behaviors to those of non-teachers, taking into account demographic and socioeconomic factors that could confound crude differences. We used data from the 2010 Health Barometer, a cross-sectional nationally-representative French survey conducted by telephone among 27,653 persons aged 15-85. Adjusting sequentially for potential confounders, we compared six indicators of lifestyle and risky conducts (at-risk drinking, current smoking, cannabis use, gambling, corpulence, sleep duration) between teachers (n = 725) and two comparison groups: other occupations (n = 12,483) on the one hand, and other intermediate and managerial/professional occupations (n = 6,026) on the other. RESULTS: In the fully-adjusted models, teachers were less likely than other occupations to smoke, to have used cannabis in the last 12 months, to gamble regularly and to be overweight or obese. When restricting the comparison group to other occupations belonging to the same socio-professional category, differences were attenuated, but remain highly significant for tobacco, cannabis and gambling. No significant differences were observed between teachers and non teachers regarding alcohol use and sleep duration, once important confounders had been adjusted for. CONCLUSIONS: Our results suggest that teachers behave on the whole more healthily than other adults with a similar demographic and socioeconomic profile. The absence of a teacher distinction toward at-risk drinking needs to be examined in more detail. PMID- 25793969 TI - Modes of interaction between individuals dominate the topologies of real world networks. AB - We find that the topologies of real world networks, such as those formed within human societies, by the Internet, or among cellular proteins, are dominated by the mode of the interactions considered among the individuals. Specifically, a major dichotomy in previously studied networks arises from modeling networks in terms of pairwise versus group tasks. The former often intrinsically give rise to scale-free, disassortative, hierarchical networks, whereas the latter often give rise to single- or broad-scale, assortative, nonhierarchical networks. These dependencies explain contrasting observations among previous topological analyses of real world complex systems. We also observe this trend in systems with natural hierarchies, in which alternate representations of the same networks, but which capture different levels of the hierarchy, manifest these signature topological differences. For example, in both the Internet and cellular proteomes, networks of lower-level system components (routers within domains or proteins within biological processes) are assortative and nonhierarchical, whereas networks of upper-level system components (internet domains or biological processes) are disassortative and hierarchical. Our results demonstrate that network topologies of complex systems must be interpreted in light of their hierarchical natures and interaction types. PMID- 25793970 TI - Depsides: lichen metabolites active against hepatitis C virus. AB - A thorough phytochemical study of Stereocaulon evolutum was conducted, for the isolation of structurally related atranorin derivatives. Indeed, pilot experiments suggested that atranorin (1), the main metabolite of this lichen, would interfere with the lifecycle of hepatitis C virus (HCV). Eight compounds, including one reported for the first time (2), were isolated and characterized. Two analogs (5, 6) were also synthesized, to enlarge the panel of atranorin related structures. Most of these compounds were active against HCV, with a half maximal inhibitory concentration of about 10 to 70 uM, with depsides more potent than monoaromatic phenols. The most effective inhibitors (1, 5 and 6) were then added at different steps of the HCV lifecycle. Interestingly, atranorin (1), bearing an aldehyde function at C-3, inhibited only viral entry, whereas the synthetic compounds 5 and 6, bearing a hydroxymethyl and a methyl function, respectively, at C-3 interfered with viral replication. PMID- 25793971 TI - Proteomics urine analysis of pregnant women suffering from multiple sclerosis. AB - Multiple sclerosis (MScl) frequently is remitted during the third trimester of pregnancy but exacerbated in the first postpartum period. In this context, we investigated protein identification, its abundance, and its change in urine related to these two periods. Using mass spectrometry (LTQ Orbitrap), we identified 1699 tryptic peptides (related to 402 proteins) in urine from 31 MScl and 8 control at these two periods. Pregnancy-related peptides were significantly elevated (p < 0.01) in MScl patients compared with controls (Analysis 1: 531 peptides in MScl and 36 peptides in controls higher abundant in the third trimester compared to postpartum). When comparing the longitudinal differences (Analysis 2), we identified 43 (related to 35 proteins) MScl disease-associated peptides (p < 0.01) with increased or decreased difference ratio in MScl compared with controls. The most discriminating peptides identified were trefoil factor 3 and lysosomal-associated membrane protein 2. Both proteins have a role in the innate immune system. Three proteins with a significant decreased ratio were plasma glutamate carboxypeptidase, Ig mu chain C region, and osteoclast associated immune like receptor. Our results indicate that the protein expression pattern in urine of MScl patients contains information about remote CNS and brain disease processes. PMID- 25793972 TI - Add-back therapy with GnRH analogues for uterine fibroids. AB - BACKGROUND: Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects. OBJECTIVES: To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms. SEARCH METHODS: We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) 0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm(3), 95% CI 77.58 to 606.80, 2 studies, 32 women, I(2) = 0%, low quality evidence).Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I(2) = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm(3), 95% CI= 8.13 to 39.66, 6 studies, 365 women, I(2) = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm(3), 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm(3), 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings. AUTHORS' CONCLUSIONS: There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive. PMID- 25793973 TI - Surface morphology control of cross-linked polymer particles via dispersion polymerization. AB - Cross-linked polymer colloids (poly(methyl methacrylate) and polystyrene) with diverse shapes were prepared in polar solvents (ethanol, methanol and water) via dispersion polymerization, in which a linear addition of the cross-linker was used during reaction. Apart from spherical particles we found dented spheres or particles covered with nodules, or a combination of both. A comprehensive investigation was carried out, mainly concentrating on the effect of the experimental conditions (e.g., the addition start time and total addition time, cross-linker density and the solvency of the solvents) on particle morphologies. Consequently, we suggest a number of effective ways for the synthesis of regular (spherical) colloidal particles through maintaining a relatively low concentration of the cross-linker during the entire reaction, or forcing the co polymerization (of monomer and cross-linker) locus to the continuous medium, or using a high quality or quantity of the stabilizer. Moreover, the size of the particles was also precisely manipulated by varying the polarity of the solvents, the concentration of the cross-linker, and the amount and average molecular weight of the stabilizer. In addition, the formation of the heavily dented particles with a very rough surface prepared under a pure or oxygen 'contaminated' nitrogen environment was monitored over time. The results accumulated in this article are of use for a better understanding of the mechanism of the polymerization and control over the structure and property of polymer particles. PMID- 25793975 TI - The Mediterranean and Black Sea fisheries at risk from overexploitation. AB - The status of the Mediterranean and Black Sea fisheries was evaluated for the period 1970-2010 on a subarea basis, using various indicators including the temporal variability of total landings, the number of recorded stocks, the mean trophic level of the catch, the fishing-in-balance index and the catch-based method of stock classification. All indicators confirmed that the fisheries resources of the Mediterranean and Black Sea are at risk from overexploitation. The pattern of exploitation and the state of stocks differed among the western (W), central (C) and eastern (E) Mediterranean subareas and the Black Sea (BS), with the E Mediterranean and BS fisheries being in a worst shape. Indeed, in the E Mediterranean and the BS, total landings, mean trophic level of the catch and fishing-in-balance index were declining, the cumulative percentage of overexploited and collapsed stocks was higher, and the percentage of developing stocks was lower, compared to the W and C Mediterranean. Our results confirm the need for detailed and extensive stock assessments across species that will eventually lead to stocks recovering through conservation and management measures. PMID- 25793974 TI - Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. AB - In the present study, prior to the establishment of a method for the clinical diagnosis of chronic fatigue in humans, we validated the utility of plasma metabolomic analysis in a rat model of fatigue using capillary electrophoresis mass spectrometry (CE-MS). In order to obtain a fatigued animal group, rats were placed in a cage filled with water to a height of 2.2 cm for 5 days. A food restricted group, in which rats were limited to 10 g/d of food (around 50% of the control group), was also assessed. The food-restricted group exhibited weight reduction similar to that of the fatigued group. CE-MS measurements were performed to evaluate the profile of food intake-dependent metabolic changes, as well as the profile in fatigue loading, resulting in the identification of 48 metabolites in plasma. Multivariate analyses using hierarchical clustering and principal component analysis revealed that the plasma metabolome in the fatigued group showed clear differences from those in the control and food-restricted groups. In the fatigued group, we found distinctive changes in metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism. Specifically, the fatigued group exhibited significant increases in valine, leucine, isoleucine, and 2-oxoisopentanoate, and significant decreases in citrulline and hydroxyproline compared with the control and food-restricted groups. Plasma levels of total nitric oxide were increased in the fatigued group, indicating systemic oxidative stress. Further, plasma metabolites involved in the citrate cycle, such as cis-aconitate and isocitrate, were reduced in the fatigued group. The levels of ATP were significantly decreased in the liver and skeletal muscle, indicative of a deterioration in energy metabolism in these organs. Thus, this comprehensive metabolic analysis furthered our understanding of the pathophysiology of fatigue, and identified potential diagnostic biomarkers based on fatigue pathophysiology. PMID- 25793976 TI - Effects of trophy hunting leftovers on the ranging behaviour of large carnivores: a case study on spotted hyenas. AB - Human-related food resources such as garbage dumps and feeding sites have been shown to significantly influence space use, breeding success and population dynamics in a variety of animal species. In contrast, relatively little is known on the effects of unpredictable sources of food, such as carcasses discarded by hunters, on carnivore species. We evaluated the effect of elephant carcasses, mainly deriving from trophy hunting, on the ranging and feeding behavior of spotted hyenas (Crocuta crocuta) in the Okavango Delta, Botswana. Using data from hyenas monitored before and during carcass availability via GPS radio-collars and camera traps, we investigated changes in ranging and feeding behavior over time. Carcass availability influenced hyenas' ranging behavior for an average of 10-12 days, after which their movements returned to patterns observed before carcass availability. In particular, we observed an increased spatial clustering of locations and reduced speeds (up to 15% less) between successive locations with carcass availability. Consistent feeding at carcasses during the first two weeks was typical, and some individuals fed from elephant carcasses for as long as 50 days. The impact and conservation value of hunting are often assessed based solely on the effects on the hunted species. Our results show that hunting remains can influence other species and suggest that such extra food could have important effects on critical life history processes and ultimately population dynamics. We recommend conservationists and wildlife managers evaluate management strategies and hunting practices regarding carcass disposal in order to incorporate the potential collateral impacts of hunting on non-hunted species in the same community. PMID- 25793978 TI - Cardiovascular disease rates, outcomes, and quality of care in Ontario Metis: a population-based cohort study. AB - BACKGROUND: The burden of cardiovascular disease in the Metis, Canada's fastest growing Aboriginal group, is not well studied. We determined rates of five cardiovascular diseases and associated outcomes in Ontario Metis, compared to the general Ontario population. METHODS: Metis persons were identified using the Metis Nation of Ontario Citizenship Registry. Metis citizens aged 20-105 were linked to Ontario health databases for the period of April 2006 to March 2011. Age- and sex-standardized prevalence and incidence of acute coronary syndromes (ACS), congestive heart failure (CHF), cerebrovascular disease (stroke), atrial fibrillation, and hypertension were compared between the Metis and the general population. Secondary outcome measures included one-year hospitalizations and mortality following the incident cardiovascular diagnosis, as well as quality-of care measures. RESULTS: There were 12,550 eligible Metis persons and 10,144,002 in the general population. The adjusted prevalence of each disease was higher (p<0.05) among the Metis compared to the general population: ACS 5.3% vs. 3.0%; CHF 5.1% vs. 3.9%; stroke 1.4% vs. 1.1%; atrial fibrillation 2.1% vs. 1.4%; hypertension 34.9% vs. 29.8%. Incident ACS, stroke, and atrial fibrillation were also higher (p<0.05) among the Metis: ACS 2.4% vs. 1.5%; stroke 0.8% vs. 0.6%; atrial fibrillation 0.6% vs. 0.3%. One-year all-cause and cardiovascular-related mortality were not significantly different. Hospitalizations were higher for Metis persons with CHF (OR 1.93; 95% CI 1.34-2.78) and hypertension (OR 2.27; 95% CI 1.88-2.74). Metis with CHF made more emergency department (ED) visits in the year after diagnosis compared to non-Metis with CHF, while Metis aged >=65 with ACS were more likely to be on beta-blockers following diagnosis. CONCLUSIONS: The burden of cardiovascular disease was markedly higher in the Metis compared to the general population: prevalence rates for five cardiovascular conditions were 25% to 77% higher. Metis persons with CHF had more frequent hospitalizations and ED visits following their diagnosis. PMID- 25793977 TI - Nontypeable Haemophilus influenzae induces sustained lung oxidative stress and protease expression. AB - Nontypeable Haemophilus influenzae (NTHi) is a prevalent bacterium found in a variety of chronic respiratory diseases. The role of this bacterium in the pathogenesis of lung inflammation is not well defined. In this study we examined the effect of NTHi on two important lung inflammatory processes 1), oxidative stress and 2), protease expression. Bronchoalveolar macrophages were obtained from 121 human subjects, blood neutrophils from 15 subjects, and human-lung fibroblast and epithelial cell lines from 16 subjects. Cells were stimulated with NTHi to measure the effect on reactive oxygen species (ROS) production and extracellular trap formation. We also measured the production of the oxidant, 3 nitrotyrosine (3-NT) in the lungs of mice infected with this bacterium. NTHi induced widespread production of 3-NT in mouse lungs. This bacterium induced significantly increased ROS production in human fibroblasts, epithelial cells, macrophages and neutrophils; with the highest levels in the phagocytic cells. In human macrophages NTHi caused a sustained, extracellular production of ROS that increased over time. The production of ROS was associated with the formation of macrophage extracellular trap-like structures which co-expressed the protease metalloproteinase-12. The formation of the macrophage extracellular trap-like structures was markedly inhibited by the addition of DNase. In this study we have demonstrated that NTHi induces lung oxidative stress with macrophage extracellular trap formation and associated protease expression. DNase inhibited the formation of extracellular traps. PMID- 25793980 TI - Correction: The collaborative image of the city: mapping the inequality of urban perception. PMID- 25793979 TI - Paracoccidioides brasiliensis interferes on dendritic cells maturation by inhibiting PGE2 production. AB - Paracoccidioidomycosis (PCM) is a systemic mycosis, endemic in most Latin American countries, especially in Brazil, whose etiologic agent is the thermodimorphic fungus of the genus Paracoccidioides, comprising cryptic species of Paracoccidioides brasiliensis, S1, PS2, PS3 and Paracoccidioides lutzii. The mechanisms involved in the initial interaction of the fungus with cells of the innate immune response, as dendritic cells (DCs), deserve to be studied. Prostaglandins (PGs) are eicosanoids that play an important role in modulating functions of immune cells including DCs. Here we found that human immature DCs derived from the differentiation of monocytes cultured with GM-CSF and IL-4 release substantial concentrations of PGE2, which, however, were significantly inhibited after challenge with P. brasiliensis. In vitro blocking of pattern recognition receptors (PRRs) by monoclonal antibodies showed the involvement of mannose receptor (MR) in PGE2 inhibition by the fungus. In addition, phenotyping assays showed that after challenge with the fungus, DCs do not change their phenotype of immature cells to mature ones, as well as do not produce IL-12 p70 or adequate concentrations of TNF-alpha. Assays using exogenous PGE2 confirmed an association between PGE2 inhibition and failure of cells to phenotypically mature in response to P. brasiliensis. We conclude that a P. brasiliensis evasion mechanism exists associated to a dysregulation on DC maturation. These findings may provide novel information for the understanding of the complex interplay between the host and this fungus. PMID- 25793982 TI - Correction: Effects of diets high in unsaturated fatty acids on socially induced stress responses in guinea pigs. PMID- 25793981 TI - Cell-free propagation of Coxiella burnetii does not affect its relative virulence. AB - Q fever is caused by the obligate intracellular bacterium Coxiella burnetii. In vitro growth of the bacterium is usually limited to viable eukaryotic host cells imposing experimental constraints for molecular studies, such as the identification and characterisation of major virulence factors. Studies of pathogenicity may benefit from the recent development of an extracellular growth medium for C. burnetii. However, it is crucial to investigate the consistency of the virulence phenotype of strains propagated by the two fundamentally different culturing systems. In the present study, we assessed the viability of C. burnetii and the lipopolysaccaride (LPS) encoding region of the bacteria in both culture systems as indirect but key parameters to the infection potential of C. burnetii. Propidium monoazide (PMA) treatment-based real-time PCR was used for enumeration of viable C. burnetii which were validated by fluorescent infectious focus forming unit counting assays. Furthermore, RNA isolated from C. burnetiipropagated in both the culture systems was examined for LPS-related gene expression. All thus far known LPS-related genes were found to be expressed in early passages in both culturing systems indicating the presence of predominantly the phase I form of C. burnetii. Finally, we used immune-competent mice to provide direct evidence, that the relative virulence of different C. burnetii strains is essentially the same for both axenic and cell-based methods of propagation. PMID- 25793983 TI - Hepatocyte nuclear factor 1A (HNF1A) as a possible tumor suppressor in pancreatic cancer. AB - BACKGROUND: HNF1A (Hepatocyte nuclear factor 1 alpha) is a transcription factor that is known to regulate pancreatic differentiation and maintain homeostasis of endocrine pancreas. Recently, genome-wide association studies have implicated HNF1A as a susceptibility gene for pancreatic cancer. However, the functional significance and molecular mechanism of HNF1A in pancreatic carcinogenesis remains unclear. METHODS: Using RT-PCR, Western blot and immunohistochemistry methods, we examined HNF1A gene expression in eight pancreatic carcinoma cell lines and in paired tumor and normal tissue samples from patients with resected pancreatic ductal adenocarcinoma. We knocked down the HNF1A gene expression in two cancer cell lines using three siRNA sequences. The impacts on cell proliferation, apoptosis, and cell cycle as well as the phosphorylation of Akt signaling transduction proteins were examined using ATP assay, flow cytometry and Western blot. RESULTS: HNF1A was expressed in three out of eight pancreatic adenocarcinoma cell lines and the level of HNF1A mRNA and protein expression was significantly lower in tumors than in normal adjacent tissues by both RT-PCR and Western Blot analyses. Immunohistochemistry revealed that the level of HNF1A expression was significantly lower in tumor tissues than in non-tumor tissues. Selective blocking of HNF1A by specific siRNA conferred a 2-fold higher rate of cell proliferation, 20% increased S phase and G2 phase cells, and 30-40% reduced apoptosis in pancreatic cancer cell lines. We further demonstrated that HNF1A knockdown activated Akt and its downstream target, the mammalian target of rapamycin (mTOR) in pancreatic cancer cells. CONCLUSION: These observations provide experimental evidence supporting a possible tumor suppressor role of HNF1A in pancreatic cancer. PMID- 25793984 TI - Low shear stress induced HMGB1 translocation and release via PECAM-1/PARP-1 pathway to induce inflammation response. AB - Low shear stress (LSS) plays a critical role in the site predilection of atherosclerosis through activation of cellular mechanosensors, such as platelet endothelial cell adhesion molecule 1 (PECAM-1). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that regulates the expression of various inflammatory cytokines. The nuclear enzyme high mobility group box 1 (HMGB1) can induce inflammation response by binding to toll-like receptor 4 (TLR4). In the present study, we aimed to investigate the role and mechanism of HMGB1 in LSS induced inflammation in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated by undisturbed shear stress (USS, 1 Pa) and LSS (0.4 Pa) in our experiments. Gene expression was inhibited by small interfering RNA (siRNA). ICAM 1 expression was regulated by LSS in a time dependent manner. LSS can induce HMGB1 translocation from nucleus to cytoplasm and release. Compared with the USS, LSS could increase the protein expression of PECAM-1 and PARP-1 as well as the secretion of TNF-alpha and IL-1beta. LSS induced the translocation of HMGB1 from nucleus to cytoplasm. Inhibition of HGMB1 reduced LSS-induced inflammatory response. Inhibition of PARP-1 suppressed inflammatory response through inhibiting TLR4 expression and HMGB1 translocation. PECAM-1 inhibition reduced LSS-induced ICAM-1 expression, TNF-alpha and IL-1beta secretion, and monocytes adhesion. LSS can induce inflammatory response via PECAM-1/PARP-1/HMGB1 pathway. PARP-1 plays a fundamental role in HMGB1 translocation and TLR4 expression. Inhibition of PARP-1 may shed light on the treatment of HMGB1 involved inflammation during atherosclerosis. PMID- 25793985 TI - Short term minimum water temperatures determine levels of infection by the amphibian chytrid fungus in Alytes obstetricans tadpoles. AB - Amphibians are one of the groups of wildlife most seriously threatened by emerging infectious disease. In particular, chytridiomycosis, caused by the aquatic fungus Batrachochytrium dendrobatidis, is responsible for amphibian species declines on a worldwide scale. Population-level outcomes following the introduction of the pathogen are context dependent and mediated by a large suite of abiotic and biotic variables. In particular, studies have shown that temperature has a key role in determining infection dynamics owing to the ectothermic nature of the amphibian host and temperature-dependency of pathogen growth rates. To assess the temperature-dependent seasonality of infectious burdens in a susceptible host species, we monitored lowland populations of larval midwife toads, Alytes obstetricians, in Central Spain throughout the year. We found that infections were highly seasonal, and inversely correlated against water temperature, with the highest burdens of infection seen during the colder months. Short-term impacts of water-temperature were found, with the minimum temperatures occurring before sampling being more highly predictive of infectious burdens than were longer-term spans of temperature. Our results will be useful for selecting the optimal time for disease surveys and, more broadly, for determining the key periods to undertake disease mitigation. PMID- 25793986 TI - Critical cooperation range to improve spatial network robustness. AB - A robust worldwide air-transportation network (WAN) is one that minimizes the number of stranded passengers under a sequence of airport closures. Building on top of this realistic example, here we address how spatial network robustness can profit from cooperation between local actors. We swap a series of links within a certain distance, a cooperation range, while following typical constraints of spatially embedded networks. We find that the network robustness is only improved above a critical cooperation range. Such improvement can be described in the framework of a continuum transition, where the critical exponents depend on the spatial correlation of connected nodes. For the WAN we show that, except for Australia, all continental networks fall into the same universality class. Practical implications of this result are also discussed. PMID- 25793987 TI - Cytology and human papillomavirus co-test results preceding incident high-grade cervical intraepithelial neoplasia. AB - OBJECTIVE: High-risk HPV (hrHPV) and cytology co-testing is utilized for primary cervical cancer screening and for enhanced follow-up of women who are hrHPV positive, cytology negative. However, data are lacking on the utility of this method to detect pre-cancer or cancer in community-based clinical practice. This study describes cytology and hrHPV results preceding high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer (i.e., CIN2+) in an integrated health system employing routine co-testing among women aged 30 years and older. METHODS: We conducted a cross-sectional analysis of adult female members of Kaiser Permanente Northern California (KPNC) with incident CIN2+ between July 2008 and June 2009. The primary outcome was the proportions of cytologic diagnoses and hrHPV co-test results preceding a diagnosis of CIN2+. Cervical cytology and hrHPV testing results were abstracted from electronic medical records. RESULTS: Of 1283 CIN2+ cases among adult women, 880 (68.5%) were among women aged 30 years and older and 145/880 (16.5%, 95% CI 14.1-19.1) had only normal cytology during the 12 months prior to diagnosis. Furthermore, 133/880 (15.1%, 95% 12.9-17.7) were preceded by only normal cytology and persistent hrHPV infection (at least 2 positive hrHPV tests) during the 6-36 months preceding CIN2+ diagnosis. CONCLUSIONS: Incident CIN2+ is frequently preceded by normal cytology and persistent hrHPV infection among women aged 30 years and older; screening strategies that employ HPV testing and cytology may improve the detection of CIN2+ compared with cytology alone. PMID- 25793988 TI - The immediate effect of sildenafil on right ventricular function in patients with heart failure measured by cardiac magnetic resonance: a randomized control trial. AB - BACKGROUND: Studies have demonstrated that phosphodiesterase 5 (PDE5) inhibition is associated with right ventricle (RV) functional improvement in patients with primary pulmonary hypertension. This study aims to demonstrate the immediate impact of Sildenafil, a PDE5 inhibitor, on RV function, measured by cardiovascular magnetic resonance (CMR), in patients with heart failure (HF). METHODS: We conducted a randomized double-blind controlled trial. INCLUSION CRITERIA: diagnosis of HF functional class I-III; left ventricle ejection fraction < 35%. Patients underwent CMR evaluation and were then equally randomly assigned to either 50 mg of Sildenafil or Placebo groups. One hour following drug administration, they were submitted to a second scan examination. RESULTS: 26 patients were recruited from a tertiary reference center in Brazil and 13 were allocated to each study group. The median age was 61.5 years (50-66.5 years). Except for the increase in RV fractional area change following the administration of sildenafil (Sildenafil [before vs. after]: 34.3 [25.2-43.6]% vs. 42.9 [28.5 46.7]%, p = 0.04; Placebo [before vs. after]: 28.1 [9.2-34.8]% vs. 29.2 [22.5 38.8]%, p = 0.86), there was no statistically significant change in parameters. There was no improvement in left ventricular parameters or in the fractional area change of the pulmonary artery. CONCLUSION: This study demonstrated that a single dose of Sildenafil did not significantly improve RV function as measured by the CMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01936350. PMID- 25793989 TI - Gaze behavior in one-handed catching and its relation with interceptive performance: what the eyes can't tell. AB - In ball sports, it is usually acknowledged that expert athletes track the ball more accurately than novices. However, there is also evidence that keeping the eyes on the ball is not always necessary for interception. Here we aimed at gaining new insights on the extent to which ocular pursuit performance is related to catching performance. To this end, we analyzed eye and head movements of nine subjects catching a ball projected by an actuated launching apparatus. Four different ball flight durations and two different ball arrival heights were tested and the quality of ocular pursuit was characterized by means of several timing and accuracy parameters. Catching performance differed across subjects and depended on ball flight characteristics. All subjects showed a similar sequence of eye movement events and a similar modulation of the timing of these events in relation to the characteristics of the ball trajectory. On a trial-by-trial basis there was a significant relationship only between pursuit duration and catching performance, confirming that keeping the eyes on the ball longer increases catching success probability. Ocular pursuit parameters values and their dependence on flight conditions as well as the eye and head contributions to gaze shift differed across subjects. However, the observed average individual ocular behavior and the eye-head coordination patterns were not directly related to the individual catching performance. These results suggest that several oculomotor strategies may be used to gather information on ball motion, and that factors unrelated to eye movements may underlie the observed differences in interceptive performance. PMID- 25793990 TI - Detection and discrimination of cotton foreign matter using push-broom based hyperspectral imaging: system design and capability. AB - Cotton quality, a major factor determining both cotton profitability and marketability, is affected by not only the overall quantity of but also the type of the foreign matter. Although current commercial instruments can measure the overall amount of the foreign matter, no instrument can differentiate various types of foreign matter. The goal of this study was to develop a hyperspectral imaging system to discriminate major types of foreign matter in cotton lint. A push-broom based hyperspectral imaging system with a custom-built multi-thread software was developed to acquire hyperspectral images of cotton fiber with 15 types of foreign matter commonly found in the U.S. cotton lint. A total of 450 (30 replicates for each foreign matter) foreign matter samples were cut into 1 by 1 cm2 pieces and imaged on the lint surface using reflectance mode in the spectral range from 400-1000 nm. The mean spectra of the foreign matter and lint were extracted from the user-defined region-of-interests in the hyperspectral images. The principal component analysis was performed on the mean spectra to reduce the feature dimension from the original 256 bands to the top 3 principal components. The score plots of the 3 principal components were used to examine clusterization patterns for classifying the foreign matter. These patterns were further validated by statistical tests. The experimental results showed that the mean spectra of all 15 types of cotton foreign matter were different from that of the lint. Nine types of cotton foreign matter formed distinct clusters in the score plots. Additionally, all of them were significantly different from each other at the significance level of 0.05 except brown leaf and bract. The developed hyperspectral imaging system is effective to detect and classify cotton foreign matter on the lint surface and has the potential to be implemented in commercial cotton classing offices. PMID- 25793992 TI - Oral, nasal and pharyngeal exposure to lipopolysaccharide causes a fetal inflammatory response in sheep. AB - BACKGROUND: A fetal inflammatory response (FIR) in sheep can be induced by intraamniotic or selective exposure of the fetal lung or gut to lipopolysaccharide (LPS). The oral, nasal, and pharyngeal cavities (ONP) contain lymphoid tissue and epithelium that are in contact with the amniotic fluid. The ability of the ONP epithelium and lymphoid tissue to initiate a FIR is unknown. OBJECTIVE: To determine if FIR occurs after selective ONP exposure to LPS in fetal sheep. METHODS: Using fetal recovery surgery, we isolated ONP from the fetal lung, GI tract, and amniotic fluid by tracheal and esophageal ligation and with an occlusive glove fitted over the snout. LPS (5 mg) or saline was infused with 24 h Alzet pumps secured in the oral cavity (n = 7-8/group). Animals were delivered 1 or 6 days after initiation of the LPS or saline infusions. RESULTS: The ONP exposure to LPS had time-dependent systemic inflammatory effects with changes in WBC in cord blood, an increase in posterior mediastinal lymph node weight at 6 days, and pro-inflammatory mRNA responses in the fetal plasma, lung, and liver. Compared to controls, the expression of surfactant protein A mRNA increased 1 and 6 days after ONP exposure to LPS. CONCLUSION: ONP exposure to LPS alone can induce a mild FIR with time-dependent inflammatory responses in remote fetal tissues not directly exposed to LPS. PMID- 25793993 TI - The impact of prior information on estimates of disease transmissibility using Bayesian tools. AB - The basic reproductive number (R0) and the distribution of the serial interval (SI) are often used to quantify transmission during an infectious disease outbreak. In this paper, we present estimates of R0 and SI from the 2003 SARS outbreak in Hong Kong and Singapore, and the 2009 pandemic influenza A(H1N1) outbreak in South Africa using methods that expand upon an existing Bayesian framework. This expanded framework allows for the incorporation of additional information, such as contact tracing or household data, through prior distributions. The results for the R0 and the SI from the influenza outbreak in South Africa were similar regardless of the prior information (R0 = 1.36-1.46, MU = 2.0-2.7, MU = mean of the SI). The estimates of R0 and MU for the SARS outbreak ranged from 2.0-4.4 and 7.4-11.3, respectively, and were shown to vary depending on the use of contact tracing data. The impact of the contact tracing data was likely due to the small number of SARS cases relative to the size of the contact tracing sample. PMID- 25793991 TI - Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates. AB - BACKGROUND: We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). METHODS: Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. RESULTS: Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6 3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. CONCLUSION: hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly. PMID- 25793995 TI - SIRT1 is a regulator in high glucose-induced inflammatory response in RAW264.7 cells. AB - Sepsis is defined as a systemic inflammatory response syndrome that disorders the functions of host immune system, including the imbalance between pro- and anti inflammatory responses mediated by immune macrophages. Sepsis could also induce acute hyperglycemia. Studies have shown that the silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent deacetylase, mediates NF-kappab deacetylation and inhibits its function. Therefore, SIRT1 is likely to play an important role in high glucose-mediated inflammatory signalings. Here we demonstrate that high glucose significantly downregulates both the mRNA and protein levels of SIRT1 and upregulates the mRNA level and the release of two pro inflammatory cytokines, IL-1beta and TNF-alpha, in RAW264.7 macrophages. Interestingly, the reduced level of SIRT1 by high glucose is remarkably upregulated by SIRT1 activator SRT1720, while the level and the release of IL 1beta and TNF-alpha significantly decrease with the use of SRT1720. However, when the function of SIRT1 is inhibited by EX527 or its expression is suppressed by RNAi, the upregulated level and release of IL-1beta and TNF-alpha by high glucose are further increased. Taken together, these findings collectively suggest that SIRT1 is an important regulator in many high glucose-related inflammatory diseases such as sepsis. PMID- 25793996 TI - Numerical analysis of granular flows in a silo bed on flow regime characterization. AB - The flow characteristics of a gravity-driven dense granular flow in a granular bed with a contracted drainage orifice are studied by using discrete element method and quantitative analysis. Three values of discharging rates, ranging from fast to slow dense flows, are investigated. Time variations and derivatives of mean forces and velocities, as well as their respective correlations, are analyzed to quantitatively depict the characteristics of granular flow as well as flow regime categorization. The auto-correlation functions, as well as their Fourier spectrums, are utilized to characterize the differences between the mechanisms of slow and fast granular flows. Finally, it is suggested that the flow regimes of slow and fast flows can be characterized by the kinetic and kinematic flow properties of particles. PMID- 25793994 TI - Lithothamnion muelleri treatment ameliorates inflammatory and hypernociceptive responses in antigen-induced arthritis in mice. AB - Rheumatoid Arthritis (RA) is a chronic disease characterized by persistent inflammation and pain. Alternative therapies to reduce these symptoms are needed. Marine algae are valuable sources of diverse bioactive compounds. Lithothamnion muelleri (Hapalidiaceae) is a marine algae with anti-inflammatory, antitumor, and immunomodulatory properties. Here, we investigated the potential anti inflammatory and analgesic activities of L. muelleri in a murine model of antigen induced arthritis (AIA) in mice. Our results demonstrate that treatment with L. muelleri prevented inflammation and hypernociception in arthritic mice. Mechanistically, the crude extract and the polysaccharide-rich fractions of L. muelleri may act impairing the production of the chemokines CXCL1 and CXCL2, and consequently inhibit neutrophil influx to the knee joint by dampening the adhesion step of leukocyte recruitment in the knee microvessels. Altogether our results suggest that treatment with L.muelleri has a potential therapeutic application in arthritis treatment. PMID- 25793997 TI - Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate. AB - The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in "non-syndromic" orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug. PMID- 25793998 TI - Asymmetric genome organization in an RNA virus revealed via graph-theoretical analysis of tomographic data. AB - Cryo-electron microscopy permits 3-D structures of viral pathogens to be determined in remarkable detail. In particular, the protein containers encapsulating viral genomes have been determined to high resolution using symmetry averaging techniques that exploit the icosahedral architecture seen in many viruses. By contrast, structure determination of asymmetric components remains a challenge, and novel analysis methods are required to reveal such features and characterize their functional roles during infection. Motivated by the important, cooperative roles of viral genomes in the assembly of single stranded RNA viruses, we have developed a new analysis method that reveals the asymmetric structural organization of viral genomes in proximity to the capsid in such viruses. The method uses geometric constraints on genome organization, formulated based on knowledge of icosahedrally-averaged reconstructions and the roles of the RNA-capsid protein contacts, to analyse cryo-electron tomographic data. We apply this method to the low-resolution tomographic data of a model virus and infer the unique asymmetric organization of its genome in contact with the protein shell of the capsid. This opens unprecedented opportunities to analyse viral genomes, revealing conserved structural features and mechanisms that can be targeted in antiviral drug design. PMID- 25793999 TI - Referred pain patterns provoked on intra-pelvic structures among women with and without chronic pelvic pain: a descriptive study. AB - OBJECTIVES: To describe referred pain patterns provoked from intra-pelvic structures in women with chronic pelvic pain (CPP) persisting after childbirth with the purpose to improve diagnostics and give implications for treatment. MATERIALS AND METHODS: In this descriptive and comparative study 36 parous women with CPP were recruited from a physiotherapy department waiting list and by advertisements in newspapers. A control group of 29 parous women without CPP was consecutively assessed for eligibility from a midwifery surgery. Inclusion criterion for CPP was: moderate pain in the sacral region persisting at least six months after childbirth confirmed by pelvic pain provocation tests. Exclusion criteria in groups with and without CPP were: persistent back or pelvic pain with onset prior to pregnancy, previous back surgery and positive neurological signs. Pain was provoked by palpation of 13 predetermined intra-pelvic anatomical landmarks. The referred pain distribution was expressed in pain drawings and described in pain maps and calculated referred pain areas. RESULTS: Pain provoked by palpation of the posterior intra-pelvic landmarks was mostly referred to the sacral region and pain provoked by palpation of the ischial and pubic bones was mostly referred to the groin and pubic regions, with or without pain referred down the ipsilateral leg. The average pain distribution area provoked by palpation of all 13 anatomical landmarks was 30.3 mm2 (19.2 to 53.7) in women with CPP as compared to 3.2 mm2 (1.0 to 5.1) in women without CPP, p< 0.0001. CONCLUSIONS: Referred pain patterns provoked from intra-pelvic landmarks in women with CPP are consistent with sclerotomal sensory innervation. Magnification of referred pain patterns indicates allodynia and central sensitization. The results suggest that pain mapping can be used to evaluate and confirm the pain experience among women with CPP and contribute to diagnosis. PMID- 25794000 TI - Scanning the landscape of genome architecture of non-O1 and non-O139 Vibrio cholerae by whole genome mapping reveals extensive population genetic diversity. AB - Historically, cholera outbreaks have been linked to V. cholerae O1 serogroup strains or its derivatives of the O37 and O139 serogroups. A genomic study on the 2010 Haiti cholera outbreak strains highlighted the putative role of non O1/non O139 V. cholerae in causing cholera and the lack of genomic sequences of such strains from around the world. Here we address these gaps by scanning a global collection of V. cholerae strains as a first step towards understanding the population genetic diversity and epidemic potential of non O1/non-O139 strains. Whole Genome Mapping (Optical Mapping) based bar coding produces a high resolution, ordered restriction map, depicting a complete view of the unique chromosomal architecture of an organism. To assess the genomic diversity of non O1/non-O139 V. cholerae, we applied a Whole Genome Mapping strategy on a well defined and geographically and temporally diverse strain collection, the Sakazaki serogroup type strains. Whole Genome Map data on 91 of the 206 serogroup type strains support the hypothesis that V. cholerae has an unprecedented genetic and genomic structural diversity. Interestingly, we discovered chromosomal fusions in two unusual strains that possess a single chromosome instead of the two chromosomes usually found in V. cholerae. We also found pervasive chromosomal rearrangements such as duplications and indels in many strains. The majority of Vibrio genome sequences currently in public databases are unfinished draft sequences. The Whole Genome Mapping approach presented here enables rapid screening of large strain collections to capture genomic complexities that would not have been otherwise revealed by unfinished draft genome sequencing and thus aids in assembling and finishing draft sequences of complex genomes. Furthermore, Whole Genome Mapping allows for prediction of novel V. cholerae non-O1/non-O139 strains that may have the potential to cause future cholera outbreaks. PMID- 25794001 TI - Clinical and prognostic implications of Roundabout 4 (robo4) in adult patients with acute myeloid leukemia. AB - BACKGROUND: Robo4 is involved in hematopoietic stem/progenitor cell homeostasis and essential for tumor angiogenesis. Expression of Robo4 was recently found in solid tumors and leukemia stem cells. However, the clinical implications of Robo4 expression in patients with acute myeloid leukemia (AML) remain unclear. METHODS: We investigated the clinical and prognostic relevance of mRNA expression of Robo4 in bone marrow (BM) mononuclear cells from 218 adult patients with de novo AML. We also performed immunohistochemical staining to assess the Robo4 protein expression in the BM biopsy specimens from 30 selected AML patients in the cohort. RESULTS: Higher Robo4 expression was closely associated with lower white blood cell counts, expression of HLA-DR, CD13, CD34 and CD56 on leukemia cells, t(8;21) and ASXL1 mutation, but negatively correlated with t(15;17) and CEBPA mutation. Compared to patients with lower Robo4 expression, those with higher expression had significantly shorter disease-free survival (DFS) and overall survival (OS). This result was confirmed in an independent validation cohort. Furthermore, multivariate analyses showed that higher Robo4 expression was an independent poor prognostic factor for DFS and OS in total cohort and patients with intermediate-risk cytogenetics, irrespective of age, WBC count, karyotype, and mutation status of NPM1/FLT3-ITD, and CEBPA. CONCLUSIONS: BM Robo4 expression can serve as a new biomarker to predict clinical outcomes in AML patients and Robo4 may serve as a potential therapeutic target in patients with higher Robo4 expression. PMID- 25794002 TI - Relationship between tobacco, cagA and vacA i1 virulence factors and bacterial load in patients infected by Helicobacter pylori. AB - BACKGROUND AND AIM: Several biological and epidemiological studies support a relationship between smoking and Helicobacter pylori (H. pylori) to increase the risk of pathology. However, there have been few studies on the potential synergistic association between specific cagA and vacA virulence factors and smoking in patients infected by Helicobacter pylori. We studied the relationship between smoking and cagA, vacA i1 virulence factors and bacterial load in H. pylori infected patients. METHODS: Biopsies of the gastric corpus and antrum from 155 consecutive patients in whom there was clinical suspicion of infection by H. pylori were processed. In 106 patients H. pylori infection was detected. Molecular methods were used to quantify the number of microorganisms and presence of cagA and vacA i1 genes. A standardized questionnaire was used to obtain patients' clinical data and lifestyle variables, including tobacco and alcohol consumption. Adjusted Odds Ratios (ORadjusted) were estimated by unconditional logistic regression. RESULTS: cagA was significantly associated with active smoking at endoscope: ORadjusted 4.52. Evidence of association was found for vacA i1 (ORadjusted 3.15). Bacterial load was higher in active-smokers, although these differences did not yield statistical significance (median of 262.2 versus 79.4 copies of H. pylori per cell). CONCLUSIONS: The association between smoking and a higher risk of being infected by a virulent bacterial population and with higher bacterial load, support a complex interaction between H. pylori infection and environmental factors. PMID- 25794003 TI - The mediating role of resilience in the relationship between big five personality and anxiety among Chinese medical students: a cross-sectional study. AB - BACKGROUNDS: The psychological distress of medical students is a major concern of public health worldwide. However, few studies have been conducted to evaluate anxiety symptoms of medical students in China. The purpose of this study was to investigate the anxiety symptoms among Chinese medical students, to examine the relationships between big five personality traits and anxiety symptoms among medical students, and to explore the mediating role of resilience in these relationships. METHODS: This multicenter cross-sectional study was conducted in June 2014. Self-reported questionnaires consisting of the Zung Self-Rating Anxiety Scale (SAS), Big Five Inventory (BFI), Wagnild and Young Resilience Scale (RS-14) and demographic section were distributed to the subjects. A stratified random cluster sampling method was used to select 2925 medical students (effective response rate: 83.57%) at four medical colleges and universities in Liaoning province, China. Asymptotic and resampling strategies were used to explore the mediating role of resilience. RESULTS: The prevalence of anxiety symptoms was 47.3% (SAS index score>=50) among Chinese medical students. After adjusting for the demographic factors, the traits of agreeableness, conscientiousness and openness were all negatively associated with anxiety whereas neuroticism was positively associated with it. Resilience functioned as a mediator in the relationships between agreeableness/conscientiousness/openness and anxiety symptoms. CONCLUSIONS: Among Chinese medical students, the prevalence of anxiety symptoms was high and resilience mediated the relationships between big five personality traits and anxiety symptoms. Identifying at-risk individuals and undertaking appropriate intervention strategies that focus on both personality traits and resilience might be more effective to prevent and reduce anxiety symptoms. PMID- 25794004 TI - Vascular pattern analysis for the prediction of clinical behaviour in pheochromocytomas and paragangliomas. AB - Pheochromocytomas (PCCs) are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla. Related tumors that arise from the paraganglia outside the adrenal medulla are called paragangliomas (PGLs). PCC/PGLs are usually benign, but approximately 17% of these tumors are malignant, as defined by the development of metastases. Currently, there are no generally accepted markers for identifying a primary PCC or PGL as malignant. In 2002, Favier et al. described the use of vascular architecture for the distinction between benign and malignant primary PCC/PGLs. The aim of this study was to validate the use of vascular pattern analysis as a test for malignancy in a large series of primary PCC/PGLs. Six independent observers scored a series of 184 genetically well-characterized PCCs and PGLs for the CD34 immunolabeled vascular pattern and these findings were correlated to the clinical outcome. Tumors were scored as malignant if an irregular vascular pattern was observed, including vascular arcs, parallels and networks, while tumors with a regular pattern of short straight capillaries were scored as benign. Mean sensitivity and specificity of vascular architecture, as a predictor of malignancy was 59.7% and 72.9%, respectively. There was significant agreement between the 6 observers (mean kappa = 0.796). Mean sensitivity of vascular pattern analysis was higher in tumors >5 cm (63.2%) and in genotype cluster 2 tumors (100%). In conclusion, vascular pattern analysis cannot be used in a stand-alone manner as a prognostic tool for the distinction between benign and malignant PCC, but could be used as an indicator of malignancy and might be a useful tool in combination with other morphological characteristics. PMID- 25794006 TI - Correction: Caco-2 cell acquisition of dietary iron(III) invokes a nanoparticulate endocytic pathway. PMID- 25794005 TI - Quantifying the evidence for the risk of metabolic syndrome and its components following androgen deprivation therapy for prostate cancer: a meta-analysis. AB - BACKGROUND: No meta-analysis is yet available for the risk of metabolic syndrome (MetS) following androgen deprivation therapy (ADT) for men with prostate cancer. To summarize the evidence for the link between ADT and MetS or its components quantitatively with a meta-analysis including all studies published to date. METHODS: PubMed and Embase were searched using predefined inclusion criteria to perform meta-analyses on the association between metabolic syndrome, hyperglycemia, diabetes, hypertension, dyslipidemia or obesity and androgen deprivation therapy in patients with prostate cancer. Random effects methods were used to estimate pooled relative risks (RRs) and 95% confidence intervals (CI). RESULTS: A total of nine studies was included. There was a positive association between ADT and risk of MetS (RR: 1.75 (95% CI: 1.27-2.41)). Diabetes was the only MetS component present in more than 3 studies, and also showed an increased risk following ADT (RR: 1.36 (95% CI: 1.17-1.58)). CONCLUSION: This is the first quantitative summary addressing the potential risk of MetS following ADT in men with PCa. The positive RRs indicate that there is a need to further elucidate how type and duration of ADT affect these increased risks of MetS and diabetes as the number of men with PCa treated with ADT is increasing. PMID- 25794007 TI - An O antigen capsule modulates bacterial pathogenesis in Shigella sonnei. AB - Shigella is the leading cause for dysentery worldwide. Together with several virulence factors employed for invasion, the presence and length of the O antigen (OAg) of the lipopolysaccharide (LPS) plays a key role in pathogenesis. S. flexneri 2a has a bimodal OAg chain length distribution regulated in a growth dependent manner, whereas S. sonnei LPS comprises a monomodal OAg. Here we reveal that S. sonnei, but not S. flexneri 2a, possesses a high molecular weight, immunogenic group 4 capsule, characterized by structural similarity to LPS OAg. We found that a galU mutant of S. sonnei, that is unable to produce a complete LPS with OAg attached, can still assemble OAg material on the cell surface, but a galU mutant of S. flexneri 2a cannot. High molecular weight material not linked to the LPS was purified from S. sonnei and confirmed by NMR to contain the specific sugars of the S. sonnei OAg. Deletion of genes homologous to the group 4 capsule synthesis cluster, previously described in Escherichia coli, abolished the generation of the high molecular weight OAg material. This OAg capsule strongly affects the virulence of S. sonnei. Uncapsulated knockout bacteria were highly invasive in vitro and strongly inflammatory in the rabbit intestine. But, the lack of capsule reduced the ability of S. sonnei to resist complement mediated killing and to spread from the gut to peripheral organs. In contrast, overexpression of the capsule decreased invasiveness in vitro and inflammation in vivo compared to the wild type. In conclusion, the data indicate that in S. sonnei expression of the capsule modulates bacterial pathogenesis resulting in balanced capabilities to invade and persist in the host environment. PMID- 25794008 TI - The TALE transcription factor homothorax functions to assemble heterochromatin during Drosophila embryogenesis. AB - We have previously identified Homothorax (Hth) as an important factor for the correct assembly of the pericentromeric heterochromatin during the first fast syncytial divisions of the Drosophila embryo. Here we have extended our studies to later stages of embryonic development. We were able to show that hth mutants exhibit a drastic overall reduction in the tri-methylation of H3 in Lys9, with no reduction of the previous di-methylation. One phenotypic outcome of such a reduction is a genome instability visualized by the many DNA breaks observed in the mutant nuclei. Moreover, loss of Hth leads to the opening of closed heterochromatic regions, including the rDNA genomic region. Our data show that the satellite repeats get transcribed in wild type embryos and that this transcription depends on the presence of Hth, which binds to them as well as to the rDNA region. This work indicates that there is an important role of transcription of non-coding RNAs for constitutive heterochromatin assembly in the Drosophila embryo, and suggests that Hth plays an important role in this process. PMID- 25794009 TI - Epidemiology of Japanese encephalitis in the Philippines: a systematic review. AB - BACKGROUND: Japanese encephalitis virus (JEV) is an important cause of encephalitis in most of Asia, with high case fatality rates and often significant neurologic sequelae among survivors. The epidemiology of JE in the Philippines is not well defined. To support consideration of JE vaccine for introduction into the national schedule in the Philippines, we conducted a systematic literature review and summarized JE surveillance data from 2011 to 2014. METHODS: We conducted searches on Japanese encephalitis and the Philippines in four databases and one library. Data from acute encephalitis syndrome (AES) and JE surveillance and from the national reference laboratory from January 2011 to March 2014 were tabulated and mapped. RESULTS: We identified 29 published reports and presentations on JE in the Philippines, including 5 serologic surveys, 18 reports of clinical cases, and 8 animal studies (including two with both clinical cases and animal data). The 18 clinical studies reported 257 cases of laboratory confirmed JE from 1972 to 2013. JE virus (JEV) was the causative agent in 7% to 18% of cases of clinical meningitis and encephalitis combined, and 16% to 40% of clinical encephalitis cases. JE predominantly affected children under 15 years of age and 6% to 7% of cases resulted in death. Surveillance data from January 2011 to March 2014 identified 73 (15%) laboratory-confirmed JE cases out of 497 cases tested. SUMMARY: This comprehensive review demonstrates the endemicity and extensive geographic range of JE in the Philippines, and supports the use of JE vaccine in the country. Continued and improved surveillance with laboratory confirmation is needed to systematically quantify the burden of JE, to provide information that can guide prioritization of high risk areas in the country and determination of appropriate age and schedule of vaccine introduction, and to measure the impact of preventive measures including immunization against this important public health threat. PMID- 25794010 TI - ENTPD5 induces apoptosis in lung cancer cells via regulating caspase 3 expression. AB - This study is to investigate the relationship between ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) expression and lung cancer clinicopathological factors, and the impact of ENTPD5 on lung cancer cell functions. Lung cancer specimens and matched adjacent normal tissues were obtained from patients without any preoperative radiotherapy or chemotherapy. Knockdown of ETNPD5 expression led to significantly decreased lung cancer cell growth rate, markedly increased apoptosis and the ability to repair, and significantly reduced invasion. Gene chip tests showed that knockdown of ENTPD5 expression caused more Caspase expression. Quantitative real-time polymerase chain reaction showed that the Caspase 3 expression was significantly increased after the knockdown of ENTPD5. In addition, immunohistochemistry showed that the tumor growth marker, proliferating cell nuclear antigen, was significantly reduced in the knockdown model. Tumorigenicity assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay showed that the apoptosis of lung cancer cells was increased in the knockdown model. Our results suggest that ENTPD5 affects lung cancer apoptosis via Caspase 3 pathway, and can be potentially used to monitor prognosis or to guide appropriate therapeutic regimens. PMID- 25794011 TI - Predictors of negotiated NIH indirect rates at US institutions. AB - BACKGROUND: The United States (US) Department of Health and Human Services and the Office of Naval Research negotiate institutional rates for payments of overhead costs associated with administration and space usage, commonly known as indirect rates. Such payments account for a large proportion of spending by the National Institutes of Health (NIH). Little has been published about differences in rates and their predictors. METHODS: Negotiated indirect rates for on-campus research grants were requested from the Council on Governmental Relations for the 100 institutions with greatest NIH funding in 2010. NIH funding, cost of living (ACCRA Index for 2008), public vs. private status, negotiating governmental organization (Department of Health and Human Services or Office of Naval Research), US Census Region, and year were assessed as predictors of institutional indirect rates using generalized estimating equations with all variables included in the model. RESULTS: Overall, 72 institutions participated, with 207 reported indirect rates for the years 2006, 2008, and 2010. Indirect rates ranged from 36.3% to 78%, with an average of 54.5%. Mean rates increased from 53.6% in 2006 to 55.4% in 2010 (p<0.001). In multivariable models, private institutions had 6.2% (95% CI 3.7%-8.7%; p<0.001) higher indirect rates than public institutions. Rates in the Northeast were highest (Midwest 4.0% lower; West 4.9% lower; South 5.2% lower). Greater NIH funding (p = 0.025) and cost of living (p = 0.034) also predicted indirect rates while negotiating governmental organization did not (p = 0.414). CONCLUSIONS: Negotiated indirect rates for governmental research grants to academic centers vary widely. Although the association between indirect rates and cost of living may be justified, the cause of variation in rates by region, public-private status, and NIH funding levels is unclear. PMID- 25794012 TI - Oleic acid metabolism via a conserved cytochrome P450 system-mediated omega hydroxylation in the bark beetle-associated fungus Grosmannia clavigera. AB - The bark beetle-associated fungus Grosmannia clavigera participates in the large scale destruction of pine forests. In the tree, it must tolerate saturating levels of toxic conifer defense chemicals (e.g. monoterpenes). The fungus can metabolize some of these compounds through the beta-oxidation pathway and use them as a source of carbon. It also uses carbon from pine triglycerides, where oleic acid is the most common fatty acid. High levels of free fatty acids, however, are toxic and can cause additional stress during host colonization. Fatty acids induce expression of neighboring genes encoding a cytochrome P450 (CYP630B18) and its redox partner, cytochrome P450 reductase (CPR2). The aim of this work was to study the function of this novel P450 system. Using LC/MS, we biochemically characterized CYP630 as a highly specific oleic acid omega hydroxylase. We explain oleic acid specificity using protein interaction modeling. Our results underscore the importance of omega-oxidation when the main beta-oxidation pathway may be overwhelmed by other substrates such as host terpenoid compounds. Because this CYP-CPR gene cluster is evolutionarily conserved, our work has implications for metabolism studies in other fungi. PMID- 25794013 TI - Second-hand cigarette smoke impairs bacterial phagocytosis in macrophages by modulating CFTR dependent lipid-rafts. AB - INTRODUCTION: First/Second-hand cigarette-smoke (FHS/SHS) exposure weakens immune defenses inducing chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are not fully understood. Hence, we evaluated if SHS induced changes in membrane/lipid-raft (m-/r)-CFTR (cystic fibrosis transmembrane conductance regulator) expression/activity is a potential mechanism for impaired bacterial phagocytosis in COPD. METHODS: RAW264.7 murine macrophages were exposed to freshly prepared CS-extract (CSE) containing culture media and/or Pseudomonas aeruginosa-PA01-GFP for phagocytosis (fluorescence-microscopy), bacterial survival (colony-forming-units-CFU), and immunoblotting assays. The CFTR expression/activity and lipid-rafts were modulated by transient-transfection or inhibitors/inducers. Next, mice were exposed to acute/sub-chronic-SHS or room-air (5-days/3-weeks) and infected with PA01-GFP, followed by quantification of bacterial survival by CFU-assay. RESULTS: We investigated the effect of CSE treatment on RAW264.7 cells infected by PA01-GFP and observed that CSE treatment significantly (p<0.01) inhibits PA01-GFP phagocytosis as compared to the controls. We also verified this in murine model, exposed to acute/sub-chronic-SHS and found significant (p<0.05, p<0.02) increase in bacterial survival in the SHS exposed lungs as compared to the room-air controls. Next, we examined the effect of impaired CFTR ion-channel-activity on PA01-GFP infection of RAW264.7 cells using CFTR172-inhibitor and found no significant change in phagocytosis. We also similarly evaluated the effect of a CFTR corrector-potentiator compound, VRT-532, and observed no significant rescue of CSE impaired PA01-GFP phagocytosis although it significantly (p<0.05) decreases CSE induced bacterial survival. Moreover, induction of CFTR expression in macrophages significantly (p<0.03) improves CSE impaired PA01-GFP phagocytosis as compared to the control. Next, we verified the link between m-/r-CFTR expression and phagocytosis using methyl-beta-cyclodextran (CD), as it is known to deplete CFTR from membrane lipid-rafts. We observed that CD treatment significantly (p<0.01) inhibits bacterial phagocytosis in RAW264.7 cells and adding CSE further impairs phagocytosis suggesting synergistic effect on CFTR dependent lipid-rafts. CONCLUSION: Our data suggest that SHS impairs bacterial phagocytosis by modulating CFTR dependent lipid-rafts. PMID- 25794015 TI - Obstructive Sleep Apnea Following Pharyngeal Flap Surgery for Velopharyngeal Insufficiency: A Prospective Polysomnographic and Aerodynamic Study in Middle Aged Adults. AB - OBJECTIVE: To compare the frequency and severity of obstructive sleep apnea (OSA) in middle-aged adults who underwent pharyngeal flap surgery for velopharyngeal insufficiency (VPI) with matched subjects who did not undergo pharyngeal flap surgery and to verify the relationship between OSA severity and internal pharyngeal dimensions. SETTING: National referral care center for cleft lip and palate. METHOD: Prospective study on 42 nonsyndromic subjects with repaired cleft palate with flap (F group, n = 22) and without flap (NF group, n = 20), aged 40 to 58 years. The main outcome measure was the apnea-hypopnea index (AHI), measured by in-lab nocturnal polysomnography (PSG). The OSA-related symptoms were investigated by Pittsburgh, Epworth, and Berlin questionnaires. The nasopharyngeal or velopharyngeal (NP/VP) cross-sectional area was measured by modified anterior rhinomanometry in subgroups of the F (n = 14) and NF (n = 10) groups at rest and during speech. Differences were considered significant at P < .05. RESULTS: Questionnaire scores and frequency of self-reported symptoms of snoring, nasal obstruction, and breathing interruptions during sleep did not differ between groups. OSA was diagnosed by PSG in 60% and 77% of the NF and F subjects, respectively. The difference was not significant. No cases of severe OSA were observed. There was no correlation between AHI and NP/VP area. CONCLUSION: A significant number of middle-aged adults with repaired cleft palate had OSA and related symptoms, regardless of the presence of a pharyngeal flap. Results suggest that VPI treatment with a flap may not cause sleep-disordered breathing in the cleft population. Besides advancing age, congenital upper airway abnormalities may be involved. PMID- 25794014 TI - Evaluation of a Three-Dimensional Stereophotogrammetric Method to Identify and Measure the Palatal Surface Area in Children With Unilateral Cleft Lip and Palate. AB - OBJECTIVE: To assess a three-dimensional (3D) stereophotogrammetric method for area delimitation and evaluation of the dental arches of children with unilateral cleft lip and palate (UCLP). Obtained data were also used to assess the 3D changes occurring in the maxillary arch with the use of orthopedic therapy prior to rhinocheiloplasty and before the first year of life. DESIGN: Within the collaboration between the Universita degli Studi di Milano (Italy) and the University CES of Medellin (Colombia), 96 palatal cast models obtained from neonatal patients with UCLP were analyzed using a 3D stereophotogrammetric imaging system. MAIN OUTCOME MEASURES: The area of the minor and greater cleft segments on the digital dental cast surface were delineated by the visualization tool of the stereophotogrammetric software and then examined. "Trueness" of the measurements, as well as systematic and random errors between operators' tracings ("precision") were calculated. RESULTS: The method gave area measurements close to true values (errors lower than 2%), without systematic measurement errors for tracings by both interoperators and intraoperators (P > .05). Statistically significant differences (P < .05) were noted for alveolar segment and time. CONCLUSIONS: Maxillary segments have the potential for growth during presurgical orthopedic treatment in the early neonatal period. The cleft segment delimitation on digital dental casts and area measurements by the 3D stereophotogrammetric system revealed an accurate (true and precise) method for evaluating the stone casts of newborn patients with UCLP. PMID- 25794016 TI - Risk and Protective Factors at Age 10: Psychological Adjustment in Children With a Cleft Lip and/or Palate. AB - Objective To explore psychological functioning in children with a cleft at age 10 from a broad perspective, including cognitive, emotional, behavioral, appearance related, and social adjustment. High-risk groups were identified within each area of adjustment to investigate whether vulnerable children were found across domains or whether risk was limited to specific areas of adjustment. Methods Retrospective chart review from psychological assessments at age 10 (N = 845). The effects of gender, cleft visibility, and the presence of an additional condition were investigated. Results were compared with large national samples. Measures Personality Inventory for Children, Child Experience Questionnaire, Strengths and Difficulties Questionnaire, Satisfaction With Appearance scale. Results The factor affecting psychological adjustment on most domains was the presence of an associated condition in addition to the cleft. As expected, no support was found for cleft visibility as a risk factor, while there were some gender differences related to emotional difficulties and attention. Correlation analyses of risk groups pointed to an association between social experiences and emotional adjustment and between social and behavioral adjustment; whereas, dissatisfaction with appearance was not related to any other domains of risk at age 10. Conclusions The results point to the importance of early screening and assessment of children born with a cleft to identify possible associated conditions and offer adapted and appropriate treatment and care. Future research should investigate how protective factors could counteract potential risk in children with a cleft. PMID- 25794017 TI - The Nasality Severity Index 2.0: Revision of an Objective Multiparametric Approach to Hypernasality. AB - OBJECTIVE: Due to the multidimensional nature of resonance disorders, multivariate diagnostic assessment is advisable. The nasality severity index (NSI) is based on this point of view. Because of the influence of personal and environmental variables on the current NSI, this study aims to refine this index. DESIGN: Prospective case-control study. SETTING: Tertiary university hospital. PATIENTS: Forty-two patients with cleft lip and palate and 50 children without resonance disorders were tested. INTERVENTIONS: Resonance was investigated by perceptual as well as objective measurements. A Nasometer was used to score nasalance, and spectral speech characteristics of a sustained sound /i:/ were determined, among which the voice low tone to high tone ratio (VLHR). Binary logistic regression analysis was performed to calculate the optimal index to discriminate patients from control children. Additionally, the validity of the index was determined based on data from an independent patient and control group. RESULTS: The NSI 2.0, a weighted linear combination of three variables, can be obtained using the equation NSI 2.0 = 13.20 - (.0824 * nasalance /u:/ [%]) - (.260 * nasalance oral text [%]) - (.242 * VLHR 4.47*F0 [dB]). The NSI has a sensitivity of 92% and a specificity of 100%. Moreover, it has excellent validity (sensitivity 88%, specificity 89%). CONCLUSIONS: The NSI 2.0 discriminates patients from control children with high sensitivity, specificity, and validity. This multiparametric method can offer a more powerful approach in the assessment and treatment planning of individuals with hypernasality. PMID- 25794018 TI - Upward Advancement of the Nasolabial Components at Unilateral Cleft Lip Repair Prevents Postoperative Long Lip. AB - OBJECTIVE: To prevent the occurrence of postoperative long lip, longitudinal postoperative changes in nasolabial forms of patients with unilateral cleft lip who underwent primary lip repair with or without upward advancement of the nasolabial components were compared. PATIENTS: Forty-three subjects (24 unilateral cleft lip and palate [UCLP] and 19 unilateral cleft lip solely, and cleft lip and alveolus [UCL/UCLA]) who underwent primary lip repair with upward advancement of the nasolabial components (NA group) and 30 subjects (16 UCLP and 14 UCL/UCLA) without upward advancement (LA group) were enrolled. OUTCOME MEASURES: Postoperative photos taken at 1 and 6 months and at 1, 2, and 3 years were used for measuring the heights of the nasal alar base (NBH), the columellar base (CBH), Cupid's peak (CPH), and the upper lip (ULH). The ratios of these measurements between the affected and unaffected sides were calculated in both groups. RESULTS: In the LA group, the 3-year postoperative all-items ratios of UCLP were significantly larger than those at 1 month postoperatively, demonstrating drooping of the nasolabial tissues in the affected side (all P < .01). Furthermore, the 3-year postoperative CPH and ULH ratio of UCL/UCLA was significantly larger than that at 1 month postoperatively, demonstrating the long lip (P < .01). In the NA group, the NBH, CBH, and CPH ratios of both UCLP and UCL/UCLA did not show significant differences between 1 month and 3 years postoperatively. CONCLUSION: Upward advancement of the nasolabial components prevents postoperative long lip. PMID- 25794019 TI - Ocular Findings in Alemtuzumab (Campath-1H)-induced Thyroid Eye Disease. AB - Alemtuzumab (Campath-1H) is a humanized anti-CD52 monoclonal antibody used in the treatment of multiple sclerosis (MS). Studies demonstrate significant reduction in relapse risk and the risk of accumulating sustained disability. Adverse events include infusion-associated reactions, infections, and secondary autoimmunity. Systemic thyroid disease is the most common secondary autoimmune event and affects up to approximately 30% of treated patients. This is the first description of the ocular findings and management in a case of thyroid eye disease (Graves' Ophthalmopathy [GO]) following alemtuzumab therapy. The ocular disease was managed conservatively while the systemic Graves' was managed with thyroidectomy. PMID- 25794020 TI - Surgical Management of Cicatricial Ectropion in Pityriasis Rubra Pilaris. AB - Pityriasis rubra pilaris is an idiopathic, papulosquamous dermatological disease. It is clinically and histologically distinct from, but may resemble, psoriasis. Pityriasis rubra pilaris can be self-limiting but may also run a protracted, relapsing course. Medical treatment may involve topical emollients, systemic retinoids, methotrexate, and/or tumor necrosis factor antagonists. Ocular complications include cicatricial ectropion. The authors describe the surgical management of 3 patients with cicatricial ectropion secondary to pityriasis rubra pilaris. All patients had procedures involving skin grafts; 1 patient required multiple operations. The management principles are discussed, including the role and timing of surgery, within the context of emerging treatments for pityriasis rubra pilaris. Patients with pityriasis rubra pilaris and cicatricial ectropion should be closely managed by both ophthalmologist and dermatologist. The eyelid position may improve with conservative or surgical measures. If surgery is required, the limitations of skin grafting under these circumstances should be anticipated and patients counseled appropriately. PMID- 25794021 TI - Thymic Origin Neuroendocrine Carcinoma Metastasizing to the Orbit in an Otherwise Asymptomatic Patient. AB - A 39-year-old man without a significant medical history developed headaches, OS swelling, and limited left-sided ocular motility. An ultrasound of the left orbit and head MRI revealed a retro-orbital mass. A partial left anterior orbitotomy with partial resection was performed, and histopathologic examination of the resected tumor portion was suggestive of a neuroendocrine carcinoma. A large, anterior mediastinal mass was found on chest imaging, and the patient was diagnosed with a primary thymic neuroendocrine tumor. To the authors' knowledge, this is the first report of an otherwise healthy patient presenting with the mass effects of a thymic neuroendocrine carcinoma metastasis to the orbital tissues before detection of the primary thymic malignancy. PMID- 25794022 TI - A Vector Force Model of Upper Eyelid Position in the Setting of a Trabeculectomy Bleb. AB - PURPOSE: A vector force model for the determination of upper eyelid position in the setting of a trabeculectomy bleb is presented. The model is used to explain the clinical courses of 5 patients with bleb-induced upper eyelid malposition and the efficacy of modalities previously described for the treatment of bleb-induced upper eyelid retraction. The novel use of botulinum toxin in the treatment of bleb-induced eyelid retraction and unique surgical considerations in patients with trabeculectomy blebs undergoing upper eyelid surgery are discussed. METHODS: A vector force analysis was conducted and a force diagram constructed. The clinical and surgical courses of 5 patients with trabeculectomy blebs and upper eyelid malposition were reviewed. The vector force model was applied to these cases and the previously described treatment modalities for bleb-induced upper eyelid retraction. RESULTS: Vector force analysis demonstrates that in the case of trabeculectomy bleb-induced upper eyelid retraction, the net force vector, which represents the sum of all the individual forces acting on the eyelid, has a positive vertical component resulting in superior displacement of the eyelid. In contrast, bleb-induced ptosis results when the net force vector has a negative vertical component. In 3 patients, alterations in the bleb resulted in resolution of upper eyelid malposition. Botulinum toxin was used to achieve a normal upper eyelid position in 1 patient with lateral canthal tendon disinsertion and unilateral eyelid retraction and 1 patient with bilateral eyelid retraction. One patient developed unilateral ptosis in concert with the emergence of a large Tenon cyst that resolved with the treatment of the cyst via eyelid massage. One patient with unilateral ptosis and an ipsilateral bleb underwent external levator advancement but was unable to achieve the desired upper eyelid height as retraction over the bleb occurred with any attempt to elevate the eyelid above a marginal reflex distance of 1.5 mm. The efficacy of previously reported modalities for the treatment of trabeculectomy bleb-induced upper eyelid retraction can be explained by either a reduction in the positive vertical component of the net force vector or augmentation of the negative vertical component. CONCLUSIONS: A vector force model systematically accounts for the multiple determinants of upper eyelid position in the setting of a trabeculectomy bleb. This model provides a framework for the evaluation of bleb-induced upper eyelid malposition and offers a logical, mathematical explanation for the occurrence of bleb-induced upper eyelid retraction and the usefulness of previously reported treatment modalities for this clinical entity. PMID- 25794023 TI - Accuracy of Biopsy in Subtyping Periocular Basal Cell Carcinoma. AB - PURPOSE: To determine the accuracy of initial biopsy in the diagnosis of basal cell carcinoma (BCC) histologic subtype. METHODS: Retrospective histopathologic review of patients with a diagnosis of primary periocular BCC from 2006 to 2013 inclusive. RESULTS: A total of 174 primary BCCs were identified. BCCs were classified as nodular, superficial, or aggressive (including mixed cases with an aggressive component). Punch biopsies were used in 41% of cases, while the remaining patients underwent shave or incision biopsies. The final histologic subtypes at excision were nodular (59%), superficial (7%), nodular and superficial (7%), and aggressive (51%). The overall concordance between the BCC subtype identified in the biopsy specimen and the subsequent excision specimen was 54%. In total, there were 51 cases (29%) of BCC, which included aggressive subtypes, of which 52% of initial biopsies failed to detect an aggressive component. There were 45 cases (26%) of mixed BCC, and an aggressive histologic subtype was present in 73% of these cases. CONCLUSIONS: The accuracy of initial biopsy for BCC histologic subtype at excision is highest for nodular BCC. For aggressive BCC, biopsy was able to detect the aggressive component in only 48% of cases. This may have implications for choice of treatment modality. PMID- 25794024 TI - Intraorbital Irrigation of Amphotericin B in the Treatment of Rhino-Orbital Mucormycosis. AB - The aim of this study was to describe a modified technique of intraorbital irrigation of amphotericin B in the treatment of rhino-orbital mucormycosis. A 38 year-old man was diagnosed with rhino-orbital mucormycosis and subsequently underwent orbital and sinus debridement with postoperative intraorbital irrigation of amphotericin B. Daily irrigation of amphotericin B was infused in the orbit with measures taken to avoid iatrogenic toxicity to the ocular surface and gastrointestinal tract. The use of local amphotericin B irrigation directly in the orbit allowed for local control of infection without orbital exenteration, a good cosmetic outcome and excellent postoperative visual acuity. The published reports on the use of intraorbital irrigation with amphotericin B in mucormycosis infections were reviewed and the technique used at the institution was outlined. PMID- 25794025 TI - Proprioceptive Phenomenon With Involutional Ptosis: Evidential Findings in Anophthalmic Ptosis. AB - PURPOSE: To determine the effect of ptosis on compensatory frontalis contraction in patients without visual input and to identify if a sensory stimulus contributes to brow elevation. METHODS: A prospective study. Clinical photographs were measured by 2 masked oculoplastic surgeons to determine brow height in 8 patients with unilateral ocular prosthesis in 3 conditions: at baseline, after a gold weight was applied to the upper eyelid inducing acute ptosis, and with the gold weight plus topical anesthetic. The measured brow height was then compared between the 3 scenarios. RESULTS: Mean brow height increased after application of the gold weight when compared with baseline, and this difference reached significance (p = 0.012). After topical anesthetic was applied, the mean brow height decreased but not back to baseline. When mean brow height during the gold weight with topical anesthesia was compared with baseline and with the gold weight only scenarios, the difference was not significant (p > 0.05). CONCLUSIONS: Frontalis contraction is observed when acute ptosis is simulated in anophthalmic patients, confirming that a contracted visual field cannot be the only stimulus for compensatory brow elevation. A sensory or proprioceptive mechanism is suggested but not confirmed by the trend of reduction in brow elevation with topical anesthesia. PMID- 25794026 TI - Regional Variations in Orbicularis Oculi Histology. AB - PURPOSE: To investigate and compare the histologic compositions of the pretarsal, preseptal, and orbital orbicularis oculi muscle (OOM) using nonpreserved, fresh frozen, human cadavers. METHODS: The OOM was exposed using sharp and blunt dissection. A metric ruler was used to measure and mark 0.5 cm * 1 cm samples from each portion of the right, superior OOM. Samples were excised, fixed in formalin, and completely embedded in paraffin. Five-micrometer-thick, hematoxylin and eosin-stained sections were generated for each sample and analyzed by an anatomical pathologist. The relative percentages of the 4 main tissue types (skeletal muscle, fibrous tissue, adipose tissue, and neurovascular tissue) were quantified. RESULTS: Forty-two samples were obtained from 14 Caucasian cadavers. On average, the pretarsal samples were composed of 83.5% skeletal muscle, 0.0% adipose, 5.0% neurovascular, and 11.5% fibrous tissue. Average preseptal OOM was 46.5% skeletal muscle, 12.7% adipose, 9.2% neurovascular, and 31.5% fibrous tissue. The orbital OOM was, on average, 42.7% skeletal muscle, 32.7% adipose tissue, 6.9% neurovascular, and 17.7% fibrous tissue. CONCLUSIONS: The OOM represents a histologically heterogeneous structure. PMID- 25794027 TI - Use of Direct Otoscope for Intranasal Examination After Dacryocystorhinostomy. AB - PURPOSE: To evaluate whether the use of a direct otoscope in the nose is an effective method to observe the nasolacrimal anastomosis site after dacryocystorhinostomy. METHODS: In 75 eyes undergoing external dacryocystorhinostomy, the lacrimal irrigation test was performed and fluorescein solution was instilled in the conjunctival sac. After applying topical anesthetics and decongestant, a direct otoscope was inserted in the middle meatus and directed toward the medial canthus. RESULTS: In 69 eyes (92%), intranasal lacrimal examination with the otoscope could be performed. In 6 eyes (8%), the otoscope could not be adequately advanced in the nose because of middle meatal stenosis (n = 5 eyes) or intolerance to the intranasal examination (n = 1). In 66 (96%) of 69 eyes, concordant with the results of the lacrimal irrigation test, the presence or absence of fluorescein dye flow in the nose was observed. In this examination, the main features that were useful in locating the anastomotic area were (1) the use of fluorescein dye, (2) motility of the nasal mucosa that was synchronized with eyelid movements, (3) appearance of mucosal hole or internal orifice in the nasal wall, and (4) dye or air-fluid bubble emergence upon blinking or finger pressure over the sac region. CONCLUSIONS: Direct otoscope can be effectively used in the nose for examining the nasolacrimal anastomosis in patients undergoing dacryocystorhinostomy. PMID- 25794028 TI - Peripheral Nerve Sheath Tumors of the Eyelid Dermis: A Clinicopathologic and Immunohistochemical Analysis. AB - PURPOSE: To determine the incidences, clinical features, and detailed histopathologic and immunohistochemical findings of 10 peripheral nerve tumors (isolated neurofibromas, solitary circumscribed neuromas [SCNs], and schwannomas) localized to the eyelid dermis. METHODS: In this retrospective clinicopathologic study, clinical records and paraffin sections subjected to hematoxylin and eosin, Masson trichrome, periodic acid-Schiff, reticulin, and Alcian blue staining were critically reviewed from each case. Additional paraffin sections were immunoreacted for S100, neurofilament, CD34, epithelial membrane antigen (EMA), glucose transporter-1 (glut-1), and calretinin. RESULTS: Ten patients with a median age of 57 years had solitary, small, flesh-colored papules, 70% at the eyelid margin. Microscopically, they were diagnosed either as a SCN or an isolated neurofibroma. SCN was diffusely S100-positive (and sometimes diffusely calretinin-positive) with myriad neurofilaments. Fascicles of cells were separated by CD34-positive septa, and the lesions were surrounded by a glut-1/EMA positive capsule. Neurofibromas were calretinin-negative and had a moderate number of S100-positive cells, with widely scattered neurofilaments, many CD34 postive intermixed cells, and no capsule. No schwannomas were diagnosed. CONCLUSIONS: Peripheral nerve tumors of the eyelid have a distinct clinical presentation at the eyelid margin. Careful histopathologic and immunohistochemical studies can reliably separate the entities in the categories of isolated neurofibroma, SCN, and schwannoma when the last occurs. These distinctions can have important systemic implications. PMID- 25794029 TI - Arteriovenous Malformation of the Eyelid: Surgical Management and Histologic Study. AB - A raised erythematous eyelid lesion that appeared in a 31-year-old man was diagnosed as an arteriovenous malformation (AVM), with confirmatory Doppler ultrasound demonstrating high arterial flow. Surgical excision, aided by electrocautery for extensive hemorrhage, resulted in an acceptable cosmetic result. Histopathology of the excised lesion showed collapsed capillary channels lined by endothelium. AVM is rarely encountered in the eyelid. PMID- 25794030 TI - Rethinking the Role of Nitroglycerin Ointment in Ischemic Vascular Filler Complications: An Animal Model With ICG Imaging. AB - PURPOSE: Soft tissue dermal fillers, both temporary and permanent, are used frequently in facial rejuvenation. As the use of fillers increases, ischemic complications including skin necrosis are becoming more prevalent. In the literature, topical nitroglycerin paste has been recommended in the early treatment of patients presenting with ischemia. The purpose of this study was to evaluate the vascular perfusion effects of topical nitroglycerin paste in an animal model using indocyanine green (ICG) imaging. METHODS: After Animal Research Committee approval, a rabbit ear model was used to create filler associated skin ischemia. Ischemia was confirmed to occur after intra-arterial occlusion. Four commonly used soft tissue fillers were injected intra-arterially: Radiesse (Merz USA, Greensboro NC), Restylane (Galderma, Ft. Worth, TX), Juvederm Ultra (Allergan, Irvine CA), Belotero (Merz USA, Greensboro NC) (0.1 ml). A total of 15 ears were used, 1 control and 4 experimental per product. Thirty minutes after occlusion, nitroglycerin ointment USP, 2%(Nitro-Bid) was applied topically to the experimental ears. Vascular perfusion was evaluated with the SPY System (Novadaq Inc.) using ICG imaging. Perfusion images were obtained at baseline, immediately after, and 30 minutes after intra-arterial filler injection, and at 30, 60, 90, and 120 minutes after application of topical nitroglycerin ointment. RESULTS: In this rabbit ear model, no statistically significant improvement in perfusion was noted after topical application of nitroglycerin paste with ICG imaging. In addition, the skin of the rabbit ear post-nitroglycerin ointment appeared to have more of a congested appearance than the controls. CONCLUSIONS: Ischemic filler complications are becoming increasingly prevalent. Practitioners often treat these complications with topical nitroglycerin paste based on the knowledge that topical nitroglycerin causes vasodilation. In filler-induced tissue ischemia, however, filler product is present within arterioles. Theoretically, applying nitroglycerin paste, at least early, may not improve perfusion and could worsen ischemia with dilation of vessels and further propagation of product into the smaller arterioles and capillaries. In addition, nitroglycerin paste has systemic effects, including hypotension and dizziness, which may not be tolerated by some patients. Therefore, the authors caution the use of topical nitroglycerin paste in patients presenting with filler-associated ischemia. Further studies in the best treatment algorithms for patients presenting with ischemic complications need to be performed. PMID- 25794031 TI - Pigmented Caruncular Apocrine Hidrocystoma With Oncocytic Features. AB - An unprecedented pigmented caruncular apocrine hidrocystoma with the additional feature of an oncocytic transformation of the cyst's lining cells is reported. Over a year, a 79-year-old woman developed a centrally pigmented lesion of her right caruncle with translucent borders. Because of concern about a melanoma, a carunculectomy with adjunctive cryotherapy and placement of an amniotic membrane graft were performed, and the excised specimen was evaluated microscopically. A large cyst dominated the caruncle and was lined by an inner layer of columnar eosinophilic and granular cells with an outer, interrupted layer of flattened myoepithelial cells. Phosphotungstic acid hematoxylin staining disclosed myriad cytoplasmic, dot-like mitochondria signifying an oncocytic change. Immunohistochemistry revealed gross cystic fluid disease protein-15 and cytokeratin 7-positivity indicative of apocrine differentiation. Oncocytic change is characteristically encountered in lacrimal ductal cysts and tumors. PMID- 25794032 TI - Increased Incidence of Rhino-Orbital-Cerebral Mucormycosis After Colorado Flooding. AB - In September 2013, central Colorado experienced a record amount of rainfall resulting in widespread flooding. Within 1 month of the flooding, 4 patients presented to the authors' institution with rhino-orbital-cerebral mucormycosis. This represents the largest number of cases ever recorded over a 1-month period. The authors hypothesize that the combination of immunocompromised status and environmental exposure resulted in the increased incidence. PMID- 25794033 TI - Nasal Floor Mucosa: New Donor Site for Mucous Membrane Grafts. AB - PURPOSE: Mucous membrane grafts are used for various indications in oculoplastics. The authors report the use of nasal floor mucosa as a new donor site for mucous membrane grafts. METHODS: Following adequate anesthesia and vasoconstriction, the nasal floor is visualized with a 30 degrees endoscope. Next, the interior turbinate is medialized, and the nasolacrimal duct is identified and preserved. Anterior, posterior, medial, and lateral incisions are made through the nasal mucosa to the nasal bone. The mucosa is dissected off the nasal bone with a periosteal elevator. Nasal saline irrigation is used postoperatively to aid healing. Histologic analysis of the harvested graft and mucosa from the inferior and middle turbinates were analyzed histologically for the number of mucin-producing cells per high power field and compared. RESULTS: Nasal floor mucosa provides ample tissue for grafting with little donor site morbidity. The surgery is technically easy to learn and perform. There is less risk for blood loss compared with harvesting tissue from the turbinates and less postoperative discomfort compared with buccal mucosal grafts. The grafts have been used in 9 different patients for a variety of ocular indications. Histologically, the nasal floor mucosa contains statistically more mucin secreting cells than other nasal site, which can be helpful especially in cases of ocular surface disease. In 1 case, biopsy of the grafted tissue at postoperative year 2 showed survival of the respiratory mucin-secreting cells under histologic examination. CONCLUSIONS: Nasal floor mucosa should be considered a donor site when a mucous membrane graft is needed. The surgery is safe, easy to perform, and has less morbidity than either a nasal turbinate graft or a buccal mucosal graft. PMID- 25794034 TI - Participation in a social and recreational day programme increases community integration and reduces family burden of persons with acquired brain injury. AB - PRIMARY OBJECTIVE: To describe and evaluate a new day programme for persons living with an acquired brain injury (ABI), including persons exhibiting challenging behaviours. Activities were designed to reduce participants' social isolation, increase participation in community activities and increase social and leisure skills. It was expected that community integration would increase and challenging behaviours and family burden would decrease for day programme participants. METHODS AND PROCEDURES: Pre-post convenience sample design. Sixty one participants and family members completed questionnaires before starting the day programme and after 6-month participation. MEASURES: Community Integration Questionnaire, Overt Behaviour Scale, Burden Assessment Scale, Goal Attainment Scaling. RESULTS: Participants had increased community integration (p = 0.000) and decreased family burden (p = 0.006). There was a trend to decreased severity of challenging behaviour. Participants and family members were very satisfied. Results suggest that the programme was effective in reducing participants' social isolation and increasing appropriate interpersonal behaviours. CONCLUSIONS: Participation increased community integration and reduced burden on family caregivers. ABI day programmes help fill the void left after other rehabilitation services end and provide survivors with opportunities to engage in a variety of activities. Persons living with ABI have need for ongoing social, recreational and life skill coaching services after formal rehabilitation has been completed. PMID- 25794035 TI - Three-dimensional hotspots in evaporating nanoparticle sols for ultrahigh Raman scattering: solid-liquid interface effects. AB - Three-dimensional (3D) hotspots for ultrahigh surface-enhanced Raman scattering (SERS) has been experimentally demonstrated by evaporating a droplet of citrate Ag sols on both hydrophobic and hydrophilic flat surfaces. Interestingly, the hydrophobic surface increased the Raman enhancement by two orders of magnitude and exhibits a better signal stability than the hydrophilic one. This study highlights the differences between hydrophilic and hydrophobic surfaces in enhanced Raman scattering by the use of extremely diluted rhodamine 6G (R6G) as the SERS reporter. In situ synchrotron-radiation small-angle X-ray scattering (SR SAXS) was employed to explore the evolution of the 3D geometry of Ag nanoparticles in a single droplet and verify the influence mechanism of these two kinds of surface. The ideal situation of 3D self-assembly of nanoparticles in the evaporation process is a collaborative behaviour, but our results evidenced that a progressive 3D self-assembly of nanoparticles was more preferred due to the interface effects. Our experimental data derived from in situ SR-SAXS reveals that a truly distinct 3D geometry of the Ag particles develops during the evaporation process on both hydrophilic and hydrophobic surfaces. In this type of 3D geometry, the increased uniformity of the interparticle distance induced a sharp peak of the SR-SAXS signal, differing significantly from the dry state. In particular, the fluorosilylated surface reduces the interaction with particles and decreases the electrostatic adsorption on the flat surface, which helps to control the interparticle distance to remain within a small range, produce a larger number of hotspots in 3D space, and amplify the SERS enhancement accordingly. PMID- 25794036 TI - The association between metabolic syndrome or chronic kidney disease and hearing thresholds in Koreans: the Korean National Health and Nutrition Examination Survey 2009-2012. AB - BACKGROUND: The aim of this study was to determine whether metabolic syndrome (MetS) or chronic kidney disease (CKD) is associated with hearing thresholds in the general Korean population. PATIENTS AND METHODS: A total of 16,554 participants were included in this study. MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III guidelines, and CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 or a dipstick proteinuria result of >=1+. The hearing thresholds were measured at 0.5, 1, 2, 3, 4, and 6 kHz. Low-frequency (Freq) was defined as pure-tone averages at 0.5 and 1 kHz, while Mid-Freq and High-Freq were defined as the average thresholds at mid-frequency (2 and 3 kHz) and high frequency (4 and 6 kHz), respectively. RESULTS: In men, the hearing thresholds were 15.1 +/- 14.5 dB, 22.2 +/- 21.3 dB, and 37.3 +/- 26.5 dB for Low-, Mid-, and High-Freq, respectively. In women, the hearing thresholds were 14.9 +/- 15.3 dB, 16.6 +/- 18.0 dB, and 26.1 +/- 21.5 dB for Low-, Mid-, and High-Freq, respectively. The hearing thresholds for men were significantly higher than the hearing thresholds for women in all 3 threshold categories. Male and female subjects with MetS or CKD had higher hearing thresholds than the subjects that did not have these disorders. In the multivariate analysis, MetS was associated with increased hearing thresholds in women, and CKD was associated with increased hearing thresholds in men and women. CONCLUSION: MetS is associated with hearing thresholds in women, and CKD is associated with hearing thresholds in men and women. Therefore, patients with MetS or CKD should be closely monitored for hearing impairment. PMID- 25794038 TI - Correction: Nanomiemgel--a novel drug delivery system for topical application--in vitro and in vivo evaluation. PMID- 25794037 TI - Microbial communities associated with healthy and White syndrome-affected Echinopora lamellosa in aquaria and experimental treatment with the antibiotic ampicillin. AB - Prokaryotic and ciliate communities of healthy and aquarium White Syndrome (WS) affected coral fragments were screened using denaturing gradient gel electrophoresis (DGGE). A significant difference (R = 0.907, p < 0.001) in 16S rRNA prokaryotic diversity was found between healthy (H), sloughed tissue (ST), WS-affected (WSU) and antibiotic treated (WST) samples. Although 3 Vibrio spp were found in WS-affected samples, two of these species were eliminated following ampicillin treatment, yet lesions continued to advance, suggesting they play a minor or secondary role in the pathogenesis. The third Vibrio sp increased slightly in relative abundance in diseased samples and was abundant in non diseased samples. Interestingly, a Tenacibaculum sp showed the greatest increase in relative abundance between healthy and WS-affected samples, demonstrating consistently high abundance across all WS-affected and treated samples, suggesting Tenacibaculum sp could be a more likely candidate for pathogenesis in this instance. In contrast to previous studies bacterial abundance did not vary significantly (ANOVA, F2, 6 = 1.000, p = 0.422) between H, ST, WSU or WST. Antimicrobial activity (assessed on Vibrio harveyi cultures) was limited in both H and WSU samples (8.1% +/-8.2 and 8.0% +/-2.5, respectively) and did not differ significantly (Kruskal-Wallis, chi2 (2) = 3.842, p = 0.146). A Philaster sp, a Cohnilembus sp and a Pseudokeronopsis sp. were present in all WS-affected samples, but not in healthy samples. The exact role of ciliates in WS is yet to be determined, but it is proposed that they are at least responsible for the neat lesion boundary observed in the disease. PMID- 25794039 TI - Consumption of Oxidized and Partially Hydrogenated Oils Differentially Induces Trans-Fatty Acids Incorporation in Rats' Heart and Dyslipidemia. AB - OBJECTIVES: A direct effect of process-induced trans-fatty acids (TFAs) on nonalcoholic fatty liver disease (NAFLD) as a cardiovascular disease (CVD) risk factor has previously been shown. We hypothesized that TFAs directly induced CVD. This article describes an investigation of the association between TFAs, provided by the consumption of oxidized soybean oil and margarine, and plasma lipid profiles, coronary artery lesions, and coronary fatty acids distribution in rats. Male rats were fed a standard chow or high-fat diet containing different TFA levels ranging from <1%, <2%, and >2% of total fat in fresh soybean oil, oxidized soybean oil, and margarine, respectively, for 4 weeks. RESULTS: The results indicated that the high-fat diets differently changed the plasma lipid profiles by significantlt increasing triglycerides, total cholesterol, low-density lipoprotein cholesterol, and the ratio of low-density to high-density lipoprotein cholesterol compared to control rats. Compared to fresh soybean oil, oxidized oil further increased plasma lipid markers. The strongest inflammatory effect was induced by margarine, which contains the highest level of TFAs, or 2% of total fat. Total TFAs in the heart of the margarine-fed group were increased by 4.7 regarding to control and by 2.17 and 2.6 relative to groups receiving oxidized and fresh oil, respectively. Increased TFAs consumption was associated with increased histological aspects of atherosclerotic lesions in a dose-dependent manner. CONCLUSION: In conclusion, process-induced TFAs cause changes including proatherogenic plasma lipid markers, heart fatty acid profiles, and coronary artery histology depending on the TFA level in the supplemented fat and therefore on the type of technological process used. PMID- 25794040 TI - Generic Role of Polymer Supports in the Fine Adjustment of Interfacial Interactions between Solid Substrates and Model Cell Membranes. AB - To understand the generic role of soft, hydrated biopolymers in adjusting interfacial interactions at biological interfaces, we designed a defined model of the cell-extracellular matrix contacts based on planar lipid membranes deposited on polymer supports (polymer-supported membranes). Highly uniform polymer supports made out of regenerated cellulose allow for the control of film thickness without changing the surface roughness and without osmotic dehydration. The complementary combination of specular neutron reflectivity and high-energy specular X-ray reflectivity yields the equilibrium membrane-substrate distances, which can quantitatively be modeled by computing the interplay of van der Waals interaction, hydration repulsion, and repulsion caused by the thermal undulation of membranes. The obtained results help to understand the role of a biopolymer in the interfacial interactions of cell membranes from a physical point of view and also open a large potential to generally bridge soft, biological matter and hard inorganic materials. PMID- 25794041 TI - High throughput measurement of gammaH2AX DSB repair kinetics in a healthy human population. AB - The Columbia University RABiT (Rapid Automated Biodosimetry Tool) quantifies DNA damage using fingerstick volumes of blood. One RABiT protocol quantifies the total gamma-H2AX fluorescence per nucleus, a measure of DNA double strand breaks (DSB) by an immunofluorescent assay at a single time point. Using the recently extended RABiT system, that assays the gamma-H2AX repair kinetics at multiple time points, the present small scale study followed its kinetics post irradiation at 0.5 h, 2 h, 4 h, 7 h and 24 h in lymphocytes from 94 healthy adults. The lymphocytes were irradiated ex vivo with 4 Gy gamma rays using an external Cs-137 source. The effect of age, gender, race, ethnicity, alcohol use on the endogenous and post irradiation total gamma-H2AX protein yields at various time points were statistically analyzed. The endogenous gamma-H2AX levels were influenced by age, race and alcohol use within Hispanics. In response to radiation, induction of gamma-H2AX yields at 0.5 h and peak formation at 2 h were independent of age, gender, ethnicity except for race and alcohol use that delayed the peak to 4 h time point. Despite the shift in the peak observed, the gamma-H2AX yields reached close to baseline at 24 h for all groups. Age and race affected the rate of progression of the DSB repair soon after the yields reached maximum. Finally we show a positive correlation between endogenous gamma-H2AX levels with radiation induced gamma-H2AX yields (RIY) (r=0.257, P=0.02) and a negative correlation with residuals (r=-0.521, P=<0.0001). A positive correlation was also observed between RIY and DNA repair rate (r=0.634, P<0.0001). Our findings suggest age, race, ethnicity and alcohol use influence DSB gamma-H2AX repair kinetics as measured by RABiT immunofluorescent assay. PMID- 25794042 TI - Endoscopic Cycloplasty (ECPL) and Lens Extraction in the Treatment of Severe Plateau Iris Syndrome. AB - PURPOSE: To describe the anatomic and clinical results of the treatment of severe plateau iris syndrome with lens extraction and endoscopic cycloplasty (ECPL). A secondary aim was to describe 4 novel ultrasound biomicroscopy (UBM) measurements for plateau iris syndrome. DESIGN: Prospective case series with UBM evaluation. METHODS: Included were 12 eyes of 6 patients with plateau iris refractory to laser iridotomy and iridoplasty, miotic and other glaucoma medical treatment, with appositional angle closure in at least 3 quadrants. Treatment consisted of lens extraction and ECPL, an endoscopic diode laser treatment of the ciliary processes in the superior, nasal, and inferior quadrants. UBM measurements were taken in all quadrants before and after surgery. The untreated temporal quadrants were used as controls. Measurement parameters included: anterior chamber depth (ACD), angle opening distance (AOD 500), trabecular ciliary process distance (TCPD), iris ciliary process distance (ICPD), iris depth (ID), iridocorneal angle (ICA), and sulcus angle (SA). Four novel measurements included: ciliary process thickness (CPT), ciliary process width (CPW), ciliary process area (CPA), and iris ciliary process contact length (ICPCL). Visual acuity, intraocular pressure, glaucoma medications, and complications were also followed. RESULTS: The ACD, AOD 500, and ICA all increased significantly (P<0.001). ICPD, CPT, CPW, CPA, and ICPL all decreased significantly (P<0.01). Parameters remaining unchanged were: TCPD, ID, and SA. The untreated quadrants showed similar measurements to the preoperative measurements. There were no serious complications noted. DISCUSSION: Treating the ciliary processes with diode laser using an endoscopic approach (ECPL) and lens extraction, results in opening of the anterior chamber angle and shrinkage of the ciliary processes in the treated areas. This effect seems to be primarily a result of the laser treatment in combination rather than the lens extraction alone. This effectively reverses the anatomic cause and angle closure of plateau iris syndrome. PMID- 25794043 TI - How does predation affect the bioaccumulation of hydrophobic organic compounds in aquatic organisms? AB - It is well-known that the body burden of hydrophobic organic compounds (HOCs) increases with the trophic level of aquatic organisms. However, the mechanism of HOC biomagnification is not fully understood. To fill this gap, this study investigated the effect of predation on the bioaccumulation of polycyclic aromatic hydrocarbons (PAHs), one type of HOC, in low-to-high aquatic trophic levels under constant freely dissolved PAH concentrations (1, 5, or 10 MUg L(-1)) maintained by passive dosing systems. The tested PAHs included phenanthrene, anthracene, fluoranthene, and pyrene. The test organisms included zebrafish, which prey on Daphnia magna, and cichlids, which prey on zebrafish. The results revealed that for both zebrafish and cichlids, predation elevated the uptake and elimination rates of PAHs. The increase of uptake rate constant ranged from 20.8% to 39.4% in zebrafish with the amount of predation of 5 daphnids per fish per day, and the PAH uptake rate constant increased with the amount of predation. However, predation did not change the final bioaccumulation equilibrium; the equilibrium concentrations of PAHs in fish only depended on the freely dissolved concentration in water. Furthermore, the lipid-normalized water-based bioaccumulation factor of each PAH was constant for fish at different trophic levels. These findings infer that the final bioaccumulation equilibrium of PAHs is related to a partition between water and lipids in aquatic organisms, and predation between trophic levels does not change bioaccumulation equilibrium but bioaccumulation kinetics at stable freely dissolved PAH concentrations. This study suggests that if HOCs have not reached bioaccumulation equilibrium, biomagnification occurs due to enhanced uptake rates caused by predation in addition to higher lipid contents in higher trophic organisms. Otherwise, it is only due to the higher lipid contents in higher trophic organisms. PMID- 25794044 TI - High-volume resistance training reduces postprandial lipaemia in postmenopausal women. AB - The aim of this study was to compare the effects of 11 weeks of low-volume resistance training (LVRT) and high-volume resistance training (HVRT) on muscle strength, muscle thickness (MT), and postprandial lipaemia (PPL) in postmenopausal women. Thirty-six healthy and untrained postmenopausal women (age, 58.9 +/- 5.8 years; 68.6 +/- 10.3 kg; and BMI, 26.9 +/- 4.8 kg . m(-2)) participated in resistance training 3* per week for 11 weeks (HVRT = 12; LVRT = 13; and control group = 11). Biochemical variables, both pretraining and post training, were evaluated 16 h after the administration of an oral fat tolerance test (OFTT) and metabolic variable during [energy expenditure (EE)] and after training session [excess postexercise oxygen consumption (EPOC)]. Muscle strength (1 RM) and MT were also calculated, and no significant differences were observed between the groups for PPL (mmol . L(-1) per 5 h) as measured by glucose, high density lipoprotein, low-density lipoprotein, and total cholesterol. EE total (EE + EPOC; 6.12 +/- 1.21 MJ vs. 2.26 +/- 0.85 MJ), resting fat oxidation (5.52 +/- 1.69 g . h(-1) vs. 4.11 +/- 1.12 g . h(-1)); MT (vastus medialis, 21.4 +/- 1.8 mm vs. 18.4 +/- 1.2 mm and vastus lateralis 22.3 +/- 1.2 mm vs. 20.8 +/- 1.3 mm); triacylglycerol (TAG) 0, 1, 2, 4; and 5 h after OFTT, TAG area under the curve (AUC) (5.79 +/- 0.42 vs. 7.78 +/- 0.68), and incremental AUC (-46.21 +/- 14.42% vs. 7.78 +/- 4.68%) were all significantly different post-training for HVRT versus LVRT, respectively (P < 0.05). The results of this investigation suggest that HVRT reduces PPL in postmenopausal women. PMID- 25794045 TI - Cost-effectiveness of adding bedaquiline to drug regimens for the treatment of multidrug-resistant tuberculosis in the UK. AB - OBJECTIVE: To evaluate the cost-effectiveness of adding bedaquiline to a background regimen (BR) of drugs for multidrug-resistant tuberculosis (MDR-TB) in the United Kingdom (UK). METHODS: A cohort-based Markov model was developed to estimate the incremental cost-effectiveness ratio of bedaquiline plus BR (BBR) versus BR alone (BR) in the treatment of MDR-TB, over a 10-year time horizon. A National Health Service (NHS) and personal social services perspective was considered. Cost-effectiveness was evaluated in terms of Quality-Adjusted Life Years (QALYs) and Disability-Adjusted Life Years (DALYs). Data were sourced from a phase II, placebo-controlled trial, NHS reference costs, and the literature; the US list price of bedaquiline was used and converted to pounds (L18,800). Costs and effectiveness were discounted at a rate of 3.5% per annum. Probabilistic and deterministic sensitivity analysis was conducted. RESULTS: The total discounted cost per patient (pp) on BBR was L106,487, compared with L117,922 for BR. The total discounted QALYs pp were 5.16 for BBR and 4.01 for BR. The addition of bedaquiline to a BR resulted in a cost-saving of L11,434 and an additional 1.14 QALYs pp over a 10-year period, and is therefore considered to be the dominant (less costly and more effective) strategy over BR. BBR remained dominant in the majority of sensitivity analyses, with a 81% probability of being dominant versus BR in the probabilistic analysis. CONCLUSIONS: In the UK, bedaquiline is likely to be cost-effective and cost-saving, compared with the current MDR-TB standard of care under a range of scenarios. Cost-savings over a 10-year period were realized from reductions in length of hospitalization, which offset the bedaquiline drug costs. The cost-benefit conclusions held after several sensitivity analyses, thus validating assumptions made, and suggesting that the results would hold even if the actual price of bedaquiline in the UK were higher than in the US. PMID- 25794046 TI - Mineral elements of subtropical tree seedlings in response to elevated carbon dioxide and nitrogen addition. AB - Mineral elements in plants have been strongly affected by increased atmospheric carbon dioxide (CO2) concentrations and nitrogen (N) deposition due to human activities. However, such understanding is largely limited to N and phosphorus in grassland. Using open-top chambers, we examined the concentrations of potassium (K), calcium (Ca), magnesium (Mg), aluminum (Al), copper (Cu) and manganese (Mn) in the leaves and roots of the seedlings of five subtropical tree species in response to elevated CO2 (ca. 700 MUmol CO2 mol(-1)) and N addition (100 kg N ha( 1) yr(-1)) from 2005 to 2009. These mineral elements in the roots responded more strongly to elevated CO2 and N addition than those in the leaves. Elevated CO2 did not consistently decrease the concentrations of plant mineral elements, with increases in K, Al, Cu and Mn in some tree species. N addition decreased K and had no influence on Cu in the five tree species. Given the shifts in plant mineral elements, Schima superba and Castanopsis hystrix were less responsive to elevated CO2 and N addition alone, respectively. Our results indicate that plant stoichiometry would be altered by increasing CO2 and N deposition, and K would likely become a limiting nutrient under increasing N deposition in subtropics. PMID- 25794047 TI - Biomantling and bioturbation by colonies of the Florida harvester ant, Pogonomyrmex badius. AB - In much of the world, soil-nesting ants are among the leading agents of biomantling and bioturbation, depositing excavated soil on the surface or in underground chambers. Colonies of the Florida harvester ant, Pogonomyrmex badius excavate a new nest once a year on average, depositing 0.1 to 12 L (3 L average) of soil on the surface. Repeated surveys of a population of about 400 colonies yielded the frequency of moves (approximately once per year), the distance moved (mean 4 m), and the direction moved (random). The area of the soil disc correlated well with the volume and maximum depth of the nest, as determined by excavation and mapping of chambers. The population-wide frequency distribution of disc areas thus yielded the frequency distribution of nest volumes and maximum depths. For each surveyed colony, the volume of soil excavated from six specified depth ranges and deposited on the surface was estimated. These parameters were used in a simulation to estimate the amount of soil mantled over time by the observed population of P. badius colonies. Spread evenly, P. badius mantling would create a soil layer averaging 0.43 cm thick in a millennium, with 10-15% of the soil deriving from depths greater than 1 m. Biomantling by P. badius is discussed in the context of the ant community of which it is a part, and in relation to literature reports of ant biomantling. PMID- 25794048 TI - Poroelastic mechanical effects of hemicelluloses on cellulosic hydrogels under compression. AB - Hemicelluloses exhibit a range of interactions with cellulose, the mechanical consequences of which in plant cell walls are incompletely understood. We report the mechanical properties of cell wall analogues based on cellulose hydrogels to elucidate the contribution of xyloglucan or arabinoxylan as examples of two hemicelluloses displaying different interactions with cellulose. We subjected the hydrogels to mechanical pressures to emulate the compressive stresses experienced by cell walls in planta. Our results revealed that the presence of either hemicellulose increased the resistance to compression at fast strain rates. However, at slow strain rates, only xyloglucan increased composite strength. This behaviour could be explained considering the microstructure and the flow of water through the composites confirming their poroelastic nature. In contrast, small deformation oscillatory rheology showed that only xyloglucan decreased the elastic moduli. These results provide evidence for contrasting roles of different hemicelluloses in plant cell wall mechanics and man-made cellulose-based composite materials. PMID- 25794049 TI - Effects of Alpha Particle and Proton Beam Irradiation as Putative Cross-Talk between A549 Cancer Cells and the Endothelial Cells in a Co-Culture System. AB - BACKGROUND: High-LET ion irradiation is being more and more often used to control tumors in patients. Given that tumors are now considered as complex organs composed of multiple cell types that can influence radiosensitivity, we investigated the effects of proton and alpha particle irradiation on the possible radioprotective cross-talk between cancer and endothelial cells. MATERIALS AND METHODS: We designed new irradiation chambers that allow co-culture study of cells irradiated with a particle beam. A549 lung carcinoma cells and endothelial cells (EC) were exposed to 1.5 Gy of proton beam or 1 and 2 Gy of alpha particles. Cell responses were studied by clonogenic assays and cell cycle was analyzed by flow cytometry. Gene expression studies were performed using Taqman low density array and by RT-qPCR. RESULTS: A549 cells and EC displayed similar survival fraction and they had similar cell cycle distribution when irradiated alone or in co-culture. Both types of irradiation induced the overexpression of genes involved in cell growth, inflammation and angiogenesis. CONCLUSIONS: We set up new irradiation chamber in which two cell types were irradiated together with a particle beam. We could not show that tumor cells and endothelial cells were able to protect each other from particle irradiation. Gene expression changes were observed after particle irradiation that could suggest a possible radioprotective inter-cellular communication between the two cell types but further investigations are needed to confirm these results. PMID- 25794050 TI - Correction: Hypoxia inducible factor 3alpha plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development. PMID- 25794051 TI - Polarized Macrophages Have Distinct Roles in the Differentiation and Migration of Embryonic Spinal-cord-derived Neural Stem Cells After Grafting to Injured Sites of Spinal Cord. AB - Spinal cord injury (SCI) frequently provokes serious detrimental outcomes because neuronal regeneration is limited in the central nervous system (CNS). Thus, the creation of a permissive environment for transplantation therapy with neural stem/progenitor cells (NS/PCs) is a promising strategy to replace lost neuronal cells, promote repair, and stimulate functional plasticity after SCI. Macrophages are important SCI-associated inflammatory cells and a major source of secreted factors that modify the lesion milieu. Here, we used conditional medium (CM) from bone marrow-derived M1 or M2 polarized macrophages to culture murine NS/PCs. The NS/PCs showed enhanced astrocytic versus neuronal/oligodendrocytic differentiation in the presence of M1- versus M2-CM. Similarly, cotransplantation of NS/PCs with M1 and M2 macrophages into intact or injured murine spinal cord increased the number of engrafted NS/PC-derived astrocytes and neurons/oligodendrocytes, respectively. Furthermore, when cotransplantated with M2 macrophages, the NS/PC-derived neurons integrated into the local circuitry and enhanced locomotor recovery following SCI. Interesting, engrafted M1 macrophages promoted long-distance rostral migration of NS/PC-derived cells in a chemokine (C X-C motif) receptor 4 (CXCR4)-dependent manner, while engrafted M2 macrophages resulted in limited cell migration of NS/PC-derived cells. Altogether, these findings suggest that the cotransplantation of NS/PCs together with polarized macrophages could constitute a promising therapeutic approach for SCI repair. PMID- 25794053 TI - Zinc supplementation for the treatment of measles in children. AB - BACKGROUND: Measles is still an important cause of childhood morbidity and mortality globally, despite increasing vaccine coverage. Zinc plays a significant role in the maintenance of normal immunological functions, therefore supplements given to zinc-deficient children will increase the availability of zinc and could reduce measles-related morbidity and mortality. OBJECTIVES: To assess the effects of zinc supplementation in reducing morbidity and mortality in children with measles. SEARCH METHODS: We searched CENTRAL (2014, Issue 5), MEDLINE (1946 to June week 3, 2014), EMBASE (1974 to June 2014), CINAHL (1981 to June 2014), LILACS (1982 to June 2014), Web of Science (1985 to June 2014) and BIOSIS Previews (1985 to June 2014). We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) to identify unpublished and ongoing studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of zinc in reducing morbidity and mortality in children with measles. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion and extracted data on outcomes, details of the interventions and other study characteristics using a standardised data extraction form. We used the risk ratio (RR) and hazard ratio as measures of effect with 95% confidence intervals (CI). We included only one study and we did not conduct any meta-analysis. MAIN RESULTS: One RCT met our inclusion criteria. The study was conducted in India and included 85 children diagnosed with measles and pneumonia. The trial showed that there was no significant difference in mortality between the two groups (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.01 to 8.14). Also, there was no significant difference in time to absence of fever between the two groups (hazard ratio (HR) 1.08, 95% CI 0.67 to 1.74). No treatment-related side effects were reported in either group. The overall quality of the evidence can be described as very low. AUTHORS' CONCLUSIONS: We cannot draw any definite conclusions from this review about the effects of zinc supplementation on clinical outcomes of children with measles due to the very low quality of the evidence available. There is insufficient evidence to confirm or refute the effect of zinc supplementation in measles. PMID- 25794052 TI - Air pollution and stillbirth risk: exposure to airborne particulate matter during pregnancy is associated with fetal death. AB - OBJECTIVE: To test the hypothesis that exposure to fine particulate air pollution (PM2.5) is associated with stillbirth. STUDY DESIGN: Geo-spatial population-based cohort study using Ohio birth records (2006-2010) and local measures of PM2.5, recorded by the EPA (2005-2010) via 57 monitoring stations across Ohio. Geographic coordinates of the mother's residence for each birth were linked to the nearest PM2.5 monitoring station and monthly exposure averages calculated. The association between stillbirth and increased PM2.5 levels was estimated, with adjustment for maternal age, race, education level, quantity of prenatal care, smoking, and season of conception. RESULTS: There were 349,188 live births and 1,848 stillbirths of non-anomalous singletons (20-42 weeks) with residence <=10 km of a monitor station in Ohio during the study period. The mean PM2.5 level in Ohio was 13.3 MUg/m3 [+/-1.8 SD, IQR(Q1: 12.1, Q3: 14.4, IQR: 2.3)], higher than the current EPA standard of 12 MUg/m3. High average PM2.5 exposure through pregnancy was not associated with a significant increase in stillbirth risk, adjOR 1.21(95% CI 0.96,1.53), nor was it increased with high exposure in the 1st or 2nd trimester. However, exposure to high levels of PM2.5 in the third trimester of pregnancy was associated with 42% increased stillbirth risk, adjOR 1.42(1.06,1.91). CONCLUSIONS: Exposure to high levels of fine particulate air pollution in the third trimester of pregnancy is associated with increased stillbirth risk. Although the risk increase associated with high PM2.5 levels is modest, the potential impact on overall stillbirth rates could be robust as all pregnant women are potentially at risk. PMID- 25794054 TI - Exploring the nature of cellulose microfibrils. AB - Ultrathin cellulose microfibril fractions were extracted from spruce wood powder using combined delignification, TEMPO-catalyzed oxidation, and sonication processes. Small-angle X-ray scattering of these microfibril fractions in a "dilute" aqueous suspension (concentration 0.077 wt %) revealed that their shape was in the form of nanostrip with 4 nm width and only about 0.5 nm thicknesses. These dimensions were further confirmed by TEM and AFM measurements. The 0.5 nm thickness implied that the nanostrip could contain only a single layer of cellulose chains. At a higher concentration (0.15 wt %), SAXS analysis indicated that these nanostrips aggregated into a layered structure. The X-ray diffraction of samples collected at different preparation stages suggested that microfibrils were delaminated along the (110) planes from the Ibeta cellulose crystals. The degree of oxidation and solid-state (13)C NMR characterizations indicated that, in addition to the surface molecules, some inner molecules of microfibrils were also oxidized, facilitating the delamination into cellulose nanostrips. PMID- 25794055 TI - Patient-centered prenatal counseling: aligning obstetric healthcare professionals with needs of pregnant women. AB - The first trimester aneuploidy screen (FTS) continues to be a leading approach to identify the risk of fetal aneuploidy. This study evaluated how obstetric (OB) professionals counsel women about FTS as one of a growing number of options to assess fetal health. A survey was completed by OB professionals (board-certified obstetrician/gynecologists and certified nurse midwives) between February and March 2011: (1) to identify knowledge and practice patterns with regard to FTS, and (2) to compare pregnant women's educational needs and decision-making preferences with clinicians' perceptions of these factors. A total of 216 surveys (11 percent) were completed by OB professionals and analyzed. Several barriers to effective patient counseling were identified, including gaps in obstetric professionals' mastery of the screening test characteristics and variable approaches to discuss concepts of aneuploidy risk. OB participants reported limited confidence in discussing patient-valued topics, specifically post-screen options and pregnancy termination. Discordance was identified between OB professionals' perceptions of pregnant women's educational needs and decision making preferences specific to FTS and historical data recently collected from 139 pregnant women who underwent the FTS. Study findings illustrate the need for clinician-targeted strategies to support pregnant women as they formulate informed decisions about the tests that may have a salient impact on their prenatal care decisions. PMID- 25794056 TI - The Figley Fellowship: an entrance to fundamentals of excellent radiology journalism through the lens of editorship and publishing. PMID- 25794057 TI - Medical education research for radiologists: a road map for developing a project. AB - OBJECTIVE: Medical education research is challenging to do well, but researchers can develop a robust project with knowledge of basic principles. Thoughtful creation of a study question, development of a conceptual framework, and attention to study design are crucial to developing a successful project. CONCLUSION: A thorough understanding of research methods and elements of survey design is necessary. Projects that result in changes to behavior, clinical practice, and patient outcomes have the most potential for success. PMID- 25794058 TI - Journal Club: Prevalence of flawed multiple-choice questions in continuing medical education activities of major radiology journals. AB - OBJECTIVE: The purpose of this study was to assess whether the continuing medical education (CME) multiple-choice questions (MCQs) in three major radiology journals adhere to standard question-writing principles. MATERIALS AND METHODS: All CME MCQs (total of 181) in the January 2013 editions of the AJR, RadioGraphics, and Radiology composed the test sample. Each question was evaluated by three reviewers for compliance with seven MCQ-writing guidelines that have been documented in the medical education literature as associated with frequent flaws in medical CME. RESULTS: Seventy-eight of the 181 (43%) questions contained one to four flaws. CONCLUSION: A large fraction of radiology CME questions violate standard question-writing principles. PMID- 25794059 TI - Assessment of rates of acute adverse reactions to gadobenate dimeglumine: review of more than 130,000 administrations in 7.5 years. AB - OBJECTIVE: The purpose of this study was to determine the incidence of adverse events associated with gadobenate dimeglumine over 7.5 years in a major hospital system consisting of both academic and community hospitals. SUBJECTS AND METHODS: As part of a regular and continuous prospective quality assurance project, MRI technologists contemporaneously recorded all gadolinium-based contrast administrations and any associated adverse reactions, including type of reaction and treatment rendered, between August 1, 2005, and March 14, 2013. Weekly data review was performed by the director of MRI services, who evaluated data both by individual site and by comparison among the participating hospitals and sites within the hospital system. Comparison between reaction rates at different sites was performed with a chi-square test. RESULTS: Over 7.5 years, 132,252 doses of gadobenate dimeglumine were administered, and 236 reactions were recorded (0.18% of contrast-enhanced examinations). Of these, 133 (56.4% of all adverse reactions) required treatment and 12 (5.1%) qualified as serious. Reaction rates were significantly different between academic (0.23%) and community (0.07%) hospitals (p<0.001). Reaction rates were higher in the initial years of the study, tapering to a lower baseline rate, which was maintained over more than 5 years. The findings were consistent with the Weber and Lalli effects reported in the literature on other pharmaceutical agents. CONCLUSION: Rates of adverse reactions to gadobenate dimeglumine recorded over 7.5 years were comparable to those reported for other gadolinium-based contrast agents examined over smaller time ranges and populations. The findings reinforce the relatively robust safety profile of this agent. PMID- 25794060 TI - Imaging of cosmetic plastic procedures and implants in the body and their potential complications. AB - OBJECTIVE: Cosmetic plastic surgery procedures, as well as implants, are increasingly being performed. These implants are often encountered on routine imaging examinations, and radiologists are often asked to evaluate for complications or evidence of failure. Pectoral augmentation, gluteal augmentation, body lift and abdominoplasty, and penile and testicular prostheses are reviewed in this article. CONCLUSION: The typical appearance of common cosmetic implants and cosmetic techniques used in the human body is presented, along with the imaging spectrum of their potential complications. PMID- 25794061 TI - Rethinking radiology informatics. AB - OBJECTIVE: Informatics innovations of the past 30 years have improved radiology quality and efficiency immensely. Radiologists are groundbreaking leaders in clinical information technology (IT), and often radiologists and imaging informaticists created, specified, and implemented these technologies, while also carrying the ongoing burdens of training, maintenance, support, and operation of these IT solutions. Being pioneers of clinical IT had advantages of local radiology control and radiology-centric products and services. As health care businesses become more clinically IT savvy, however, they are standardizing IT products and procedures across the enterprise, resulting in the loss of radiologists' local control and flexibility. Although this inevitable consequence may provide new opportunities in the long run, several questions arise. CONCLUSION: What will happen to the informatics expertise within the radiology domain? Will radiology's current and future concerns be heard and their needs addressed? What should radiologists do to understand, obtain, and use informatics products to maximize efficiency and provide the most value and quality for patients and the greater health care community? This article will propose some insights and considerations as we rethink radiology informatics. PMID- 25794062 TI - Lung nodule detection by microdose CT versus chest radiography (standard and dual energy subtracted). AB - OBJECTIVE: The purpose of this study was to investigate the feasibility of microdose CT using a comparable dose as for conventional chest radiographs in two planes including dual-energy subtraction for lung nodule assessment. MATERIALS AND METHODS: We investigated 65 chest phantoms with 141 lung nodules, using an anthropomorphic chest phantom with artificial lung nodules. Microdose CT parameters were 80 kV and 6 mAs, with pitch of 2.2. Iterative reconstruction algorithms and an integrated circuit detector system (Stellar, Siemens Healthcare) were applied for maximum dose reduction. Maximum intensity projections (MIPs) were reconstructed. Chest radiographs were acquired in two projections with bone suppression. Four blinded radiologists interpreted the images in random order. RESULTS: A soft-tissue CT kernel (I30f) delivered better sensitivities in a pilot study than a hard kernel (I70f), with respective mean (SD) sensitivities of 91.1%+/-2.2% versus 85.6%+/-5.6% (p=0.041). Nodule size was measured accurately for all kernels. Mean clustered nodule sensitivity with chest radiography was 45.7%+/-8.1% (with bone suppression, 46.1%+/-8%; p=0.94); for microdose CT, nodule sensitivity was 83.6%+/-9% without MIP (with additional MIP, 92.5%+/-6%; p<10(-3)). Individual sensitivities of microdose CT for readers 1, 2, 3, and 4 were 84.3%, 90.7%, 68.6%, and 45.0%, respectively. Sensitivities with chest radiography for readers 1, 2, 3, and 4 were 42.9%, 58.6%, 36.4%, and 90.7%, respectively. In the per-phantom analysis, respective sensitivities of microdose CT versus chest radiography were 96.2% and 75% (p<10(-6)). The effective dose for chest radiography including dual-energy subtraction was 0.242 mSv; for microdose CT, the applied dose was 0.1323 mSv. CONCLUSION: Microdose CT is better than the combination of chest radiography and dual-energy subtraction for the detection of solid nodules between 5 and 12 mm at a lower dose level of 0.13 mSv. Soft-tissue kernels allow better sensitivities. These preliminary results indicate that microdose CT has the potential to replace conventional chest radiography for lung nodule detection. PMID- 25794063 TI - Ultralow-radiation-dose chest CT: accuracy for lung densitometry and emphysema detection. AB - OBJECTIVE: The purpose of this study was to determine whether ultralow-radiation dose chest CT can be used for quantification of lung density and for emphysema detection in participants undergoing lung cancer screening. SUBJECTS AND METHODS: Fifty-two patients were prospectively enrolled and underwent scanning twice with low-dose CT (reference parameters, 120 kV, 50 effective mAs) and ultralow-dose CT (reference parameters, 80 kV, 4-5 effective mAs). Images were reconstructed by filtered back projection (FBP) for low-dose CT and FBP and iterative reconstruction (IR) for ultralow-dose CT. Radiation dose was recorded. Image noise, mean lung attenuation, 15th percentile of lung attenuation, and emphysema index were measured in each image series and compared. Test characteristics of ultralow-dose CT in detecting more than subtle emphysema (emphysema index>=3%) were calculated. RESULTS: The effective dose of low-dose CT was 2.1+/-0.5 mSv, and that of ultralow-dose CT was 0.13+/-0.04 mSv. Compared with the findings for low-dose CT, absolute overestimation of emphysema index was 7% on ultralow-dose CT images reconstructed with FBP and 2% on those processed with IR. The 15th percentile of lung attenuation was underestimated by 21.3 HU on ultralow-dose FBP images and by 5.8 HU on IR images. No relevant bias was observed for mean lung attenuation. Four patients (8%) had more than subtle emphysema. The emphysema index measured at ultralow-dose CT with FBP and IR had 100% and 100% sensitivity and 92% and 96% specificity in identifying patients with more than subtle emphysema at a cutoff of greater than 12.1% for FBP and greater than 6.7% for IR. CONCLUSION: Ultralow-dose chest CT performed for lung cancer screening can be used for quantification of lung density and for emphysema detection. IR improves the accuracy of ultralow-dose CT in this setting. PMID- 25794064 TI - Nononcologic applications of diffusion-weighted imaging in the gastrointestinal system. AB - OBJECTIVE: The purpose of this article is to review infectious, inflammatory, and auto-immune-mediated processes in the gastrointestinal system where diffusion weighted imaging can be helpful as well as pitfalls associated with its use. CONCLUSION: Diffusion-weighted imaging has become an important and widely used tool in abdominal and pelvic MRI, but it has been used primarily for oncologic applications. As more body MRI protocols are routinely including diffusion weighted imaging, this sequence can be useful in evaluating an increasing number of nononcologic processes. PMID- 25794065 TI - Dysphagia secondary to anterior cervical fusion: radiologic evaluation and findings in 74 patients. AB - OBJECTIVE: The objective of our study was to assess the frequency, cause, and time course of dysphagia after anterior cervical fusion (ACF). MATERIALS AND METHODS: A review of the surgical database revealed that 1789 patients underwent ACF procedures during the 8-year study period. A radiologic database review indicated that 80 of the 1789 patients underwent radiologic evaluation for the assessment of dysphagia after ACF. Three patients were excluded from the study because they had a history of dysphagia before ACF, and three additional patients were excluded because they had more recently undergone Nissen fundoplication, intubation, and radiation therapy, respectively. Modified barium swallow (MBS) studies and esophagrams of the 74 remaining patients were collected and analyzed to determine the cause of dysphagia and time course of dysphagia onset after surgery. RESULTS: Dysphagia was evaluated radiologically in 74 of the 1789 ACF patients (4.1%) using video MBS studies (n=66) and esophagography (n=26). Patients underwent radiologic evaluation from 1 to 1150 days after surgery (mean, 120 days after surgery); 76% of the patients presented more than 2 weeks after surgery. The location of the ACF in the study group was the upper, mid, and lower cervical spine in 5.4% (n=4), 55.4% (n=41), and 39.2% (n=29) of patients, respectively. Soft-tissue swelling with displacement of the pharynx or esophagus was identified in 91% of patients (n=67). More serious complications of ACF that resulted in dysphagia included surgical hardware displacement or bone graft displacement (n=18), esophageal perforation (n=3), and a retropharyngeal abscess (n=3). Pharyngeal functional abnormalities were detected in 50 patients, with penetration, aspiration, or both seen in 32. CONCLUSION: Dysphagia is an underrecognized but significant complication of ACF. After ACF, 4.1% of patients presented for radiologic evaluation of dysphagia. Although ACF procedures are most frequently performed in the lower cervical spine, dysphagia is a more common clinical problem after ACF in the mid cervical spine. Radiologic examinations should be specifically tailored to evaluate ACF patients. PMID- 25794066 TI - Measuring treatment response to systemic therapy and predicting outcome in biliary tract cancer: comparing tumor size, volume, density, and metabolism. AB - OBJECTIVE: The purpose of this study was to evaluate the response of biliary tract cancer treated with multidrug chemotherapy using FDG PET in comparison with morphologic and density changes. MATERIALS AND METHODS: In this phase II clinical trial, 28 patients with unresectable or metastatic biliary tract cancers treated with gemcitabine and oxaliplatin combined with bevacizumab (GEMOX-B) underwent FDG PET and contrast-enhanced CT at baseline and after the second cycle of the therapy (8 weeks). A single reviewer recorded tumor maximum standardized uptake value (SUVmax) along with size, volume (3D-sphere), and density. The percentage changes of the parameters were compared with progression-free survival at 7 months. Overall survival was compared with the percentage change of SUVmax. RESULTS: After 8 weeks, measurable reductions (+/-SD) in size (7.05+/-4.19 to 5.52+/-3.28 cm, -21.70%), volume (411.38+/-540.08 to 212.41+/-293.45 cm3, 48.36%), and density (60.76+/-20.65 to 50.68+/-16.89 HU, -15.59%) were noted along with a substantial drop in SUVmax (5.95+/-1.95 to 3.36+/-1.28, -43.52%). The SUVmax change showed positive correlations with tumor size change (R2=0.39, p=0.0004) and volumetric change (R2=0.34, p=0.001). Patients who showed a larger drop in SUVmax at 8 weeks correlated with favorable progression-free survival (p=0.02). ROC analysis showed that a 45% reduction in SUVmax was the best cutoff value to detect favorable progression-free survival patients. When we used this cutoff value, Kaplan-Meier analysis showed that patients with tumors showing greater reduction in SUVmax had favorable progression-free survival and overall survival (p=0.0009, p=0.03). CONCLUSION: In biliary tract cancers treated with GEMOX-B, the reduction of SUVmax after therapy is a better predictor for survival than morphologic and density changes. PMID- 25794067 TI - Imaging of perihilar cholangiocarcinoma. AB - OBJECTIVE: The purpose of this article is to review imaging workup of perihilar cholangiocarcinoma, including MDCT and MRI protocols, imaging findings, differential diagnosis, and staging. A reporting template is included. CONCLUSION: Imaging plays a central role in the detection, differential diagnosis, and staging of perihilar cholangiocarcinoma. PMID- 25794068 TI - T categorization of urothelial carcinomas of the ureter with CT: preliminary study of new diagnostic criteria proposed for differentiating T2 or lower from T3 or higher. AB - OBJECTIVE: The purposes of this study were to propose and evaluate new diagnostic criteria for the differentiation of category T2 or lower from T3 or higher ureteral urothelial carcinomas on contrast-enhanced CT (CECT) images and to investigate the diagnostic applicability of the criteria. MATERIALS AND METHODS: The study included 30 patients with ureteral urothelial carcinoma who underwent CECT before surgery. For all patients, unenhanced and contrast-enhanced images (nephrographic and excretory phases) were acquired with a 16- or 64-MDCT scanner. The slice thickness of axial images was 5 mm. A grading system was devised that focused on spiculation and mass formation along the ureter on CECT images to differentiate T2 or lower from T3 or higher tumors. Three radiologists not specialized in abdominal radiology participated in an observer performance study to investigate the diagnostic utility of the criteria. Jackknife ROC analysis was used to compare the radiologists' diagnostic performance without and with the proposed diagnostic criteria. In addition, two board-certified radiologists used consensus to determine the CT grade, and the correlation between CT and pathologic findings was assessed. RESULTS: The mean AUCs for the three radiologists without and with the proposed criteria were 0.54 (SD, 0.09) and 0.73 (SD, 0.08), indicating a statistically significant difference (p<0.01). For the CT-pathologic correlation, the diagnostic sensitivity and specificity of the proposed criteria with respect to pT3 and higher tumors were 87.5% (14/16) and 92.9% (13/14). CONCLUSION: The proposed CT grading system was accurate for differentiating T2 or lower from T3 or higher ureteral urothelial carcinoma. PMID- 25794069 TI - MRI features of renal cell carcinoma that predict favorable clinicopathologic outcomes. AB - OBJECTIVE: The purpose of this article is to determine whether MRI features of renal cell carcinoma (RCC), such as enhancing solid component and T1 signal intensity, are associated with clinicopathologic outcomes. MATERIALS AND METHODS: This retrospective study included 241 RCCs in 230 patients who underwent preoperative MRI, had pathologic analysis results available, and were monitored for at least 3 months. A radiologist assessed tumor features on MRI, including unenhanced T1 signal relative to renal cortex and the percentage of solid enhancing components. The electronic medical record or follow-up images were reviewed to assess for the development of local recurrence or metastases. Statistical analysis was performed to correlate imaging features at MRI with pathologic and clinical outcome. RESULTS: The following tumor features were observed: predominantly cystic morphologic features (defined as solid component<=25%, n=33), solid component greater than 25% (n=208), T1 hypointensity (n=97), and T1 intermediate intensity or hyperintensity (n=144). Local recurrence or metastases were observed in 14 patients. Compared with T1-intermediate or hyperintense lesions, T1-hypointense RCCs were more likely to be low stage (90.7% vs 74.3%; p=0.001) and low grade (78.9% vs 41.8%; p<0.001) and had a lower rate of recurrence or metastases (3.3% vs 8%; p=0.167). Compared with lesions with greater than 25% solid enhancement, predominantly cystic RCCs were more likely to be lower stage (93.9% vs 78.8%; p=0.053) and lower grade (94.7 vs 56.5%; p<0.001) and to have no incidence of recurrence or metastasis (0% vs 6.9%; p=0.227). RCCs that were both cystic and T1 hypointense (n=14) were lower stage (100% vs 79.6%; p=0.047) and lower grade (92.9% vs 58.1%; p=0.01) and had no recurrence or metastases on follow-up. CONCLUSION: Cystic and T1-hypointense RCC show less aggressive pathologic features and favorable clinical behavior. PMID- 25794070 TI - Location of core diagnostic information across various sequences in brain MRI and implications for efficiency of MRI scanner utilization. AB - OBJECTIVE: Targeting redundancy within MRI can improve its cost-effective utilization. We sought to quantify potential redundancy in our brain MRI protocols. MATERIALS AND METHODS: In this retrospective review, we aggregated 207 consecutive adults who underwent brain MRI and reviewed their medical records to document clinical indication, core diagnostic information provided by MRI, and its clinical impact. Contributory imaging abnormalities constituted positive core diagnostic information whereas absence of imaging abnormalities constituted negative core diagnostic information. The senior author selected core sequences deemed sufficient for extraction of core diagnostic information. For validating core sequences selection, four readers assessed the relative ease of extracting core diagnostic information from the core sequences. Potential redundancy was calculated by comparing the average number of core sequences to the average number of sequences obtained. RESULTS: Scanning had been performed using 9.4+/ 2.8 sequences over 37.3+/-12.3 minutes. Core diagnostic information was deemed extractable from 2.1+/-1.1 core sequences, with an assumed scanning time of 8.6+/ 4.8 minutes, reflecting a potential redundancy of 74.5%+/-19.1%. Potential redundancy was least in scans obtained for treatment planning (14.9%+/-25.7%) and highest in scans obtained for follow-up of benign diseases (81.4%+/-12.6%). In 97.4% of cases, all four readers considered core diagnostic information to be either easily extractable from core sequences or the ease to be equivalent to that from the entire study. With only one MRI lacking clinical impact (0.48%), overutilization did not seem to contribute to potential redundancy. CONCLUSION: High potential redundancy that can be targeted for more efficient scanner utilization exists in brain MRI protocols. PMID- 25794071 TI - Radiologist compliance with California CT dose reporting requirements: a single center review of pediatric chest CT. AB - OBJECTIVE: Effective July 1, 2012, CT dose reporting became mandatory in California. We sought to assess radiologist compliance with this legislation and to determine areas for improvement. MATERIALS AND METHODS: We retrospectively reviewed reports from all chest CT examinations performed at our institution from July 1, 2012, through June 30, 2013, for errors in documentation of volume CT dose index (CTDIvol), dose-length product (DLP), and phantom size. Reports were considered as legally compliant if both CTDIvol and DLP were documented accurately and as institutionally compliant if phantom size was also documented accurately. Additionally, we tracked reports that did not document dose in our standard format (phantom size, CTDIvol for each series, and total DLP). RESULTS: Radiologists omitted CTDIvol, DLP, or both in nine of 664 examinations (1.4%) and inaccurately reported one or both of them in 56 of the remaining 655 examinations (8.5%). Radiologists omitted phantom size in 11 of 664 examinations (1.7%) and inaccurately documented it in 20 of the remaining 653 examinations (3.1%). Of 664 examinations, 599 (90.2%) met legal reporting requirements, and 583 (87.8%) met institutional requirements. In reporting dose, radiologists variably used less decimal precision than available, summed CTDIvol, included only series-level DLP, and specified dose information from the scout topogram or a nonchest series for combination examinations. CONCLUSION: Our institutional processes, which primarily rely on correct human performance, do not ensure accurate dose reporting and are prone to variation in dose reporting format. In view of this finding, we are exploring higher-reliability processes, including better-defined standards and automated dose reporting systems, to improve compliance. PMID- 25794072 TI - From tumor to trauma: etiologically deconstructing a unique differential diagnosis of musculoskeletal entities with high signal intensity on T1-weighted MRI. AB - OBJECTIVE: This article reviews the neoplastic and nonneoplastic abnormalities of the musculoskeletal system that contain high signal intensity on T1-weighted MRI. The physical properties accounting for the increased signal intensity as well as the key clinical and imaging characteristics of each entity are discussed. CONCLUSION: Recognition of high signal intensity within musculoskeletal lesions on T1-weighted MRI can limit the differential diagnosis and can also have important clinical implications. PMID- 25794073 TI - Histogram analysis of apparent diffusion coefficient maps for differentiating primary CNS lymphomas from tumefactive demyelinating lesions. AB - OBJECTIVE: This study intended to investigate the usefulness of histogram analysis of apparent diffusion coefficient (ADC) maps for discriminating primary CNS lymphomas (PCNSLs), especially atypical PCNSLs, from tumefactive demyelinating lesions (TDLs). MATERIALS AND METHODS: Forty-seven patients with PCNSLs and 18 with TDLs were enrolled in our study. Hyperintense lesions seen on T2-weighted images were defined as ROIs after ADC maps were registered to the corresponding T2-weighted image. ADC histograms were calculated from the ROIs containing the entire lesion on every section and on a voxel-by-voxel basis. The ADC histogram parameters were compared among all PCNSLs and TDLs as well as between the subgroup of atypical PCNSLs and TDLs. ROC curves were constructed to evaluate the diagnostic performance of the histogram parameters and to determine the optimum thresholds. RESULTS: The differences between the PCNSLs and TDLs were found in the minimum ADC values (ADCmin) and in the 5th and 10th percentiles (ADC5% and ADC10%) of the cumulative ADC histograms. However, no statistical significance was found in the mean ADC value or in the ADC value concerning the mode, kurtosis, and skewness. The ADCmin, ADC5%, and ADC10% were also lower in atypical PCNSLs than in TDLs. ADCmin was the best indicator for discriminating atypical PCNSLs from TDLs, with a threshold of 556*10(-6) mm2/s (sensitivity, 81.3 %; specificity, 88.9%). CONCLUSION: Histogram analysis of ADC maps may help to discriminate PCNSLs from TDLs and may be particularly useful in differentiating atypical PCNSLs from TDLs. PMID- 25794074 TI - Demographic confounders in volumetric MRI analysis: is the posterior fossa really small in the adult Chiari 1 malformation? AB - OBJECTIVE: Measurement of posterior fossa volume has been proposed to have diagnostic utility and physiologic significance in the Chiari malformation type 1. This study evaluated the effects of demographics on posterior fossa volume and total intracranial volume in adult control subjects, adult patients with Chiari malformation type 1, and adult patients with idiopathic intracranial hypertension, who may share some imaging features of patients with Chiari malformation type 1. MATERIALS AND METHODS: Twenty-eight patients with Chiari malformation type 1, 21 patients with idiopathic intracranial hypertension, and 113 control subjects underwent brain MRI including contrast-enhanced 3D gradient recalled echo (GRE) T1-weighted imaging. Linear measurements of the posterior fossa and intracranial space were obtained. Manual segmentation of the posterior fossa and intracranial space was performed to yield posterior fossa volume and total intracranial volume. Age, sex, race, and body mass index (weight in kilograms divided by the square of height in meters; BMI) were controlled for when comparing cohorts. RESULTS: Three of the 12 linear measurements significantly predicted total intracranial volume (accounting for 74% of variance), and four predicted posterior fossa volume (54% of variance). Age, race, sex, and BMI each statistically significantly influenced posterior fossa volume and total intracranial volume. No statistically significant differences in posterior fossa volume, total intracranial volume, or ratio of posterior fossa volume to total intracranial volume were seen between the Chiari malformation type 1 group and control group after controlling for demographics. Patients with idiopathic intracranial hypertension were more likely than control subjects to have smaller posterior fossa volumes (odds ratio [OR]=1.81; p=0.01) and larger total intracranial volumes (OR=1.24; p=0.06). CONCLUSION: Linear measurements of the posterior fossa are not strong predictors of posterior fossa volume. Age, race, sex, and BMI have statistically significant effects on intracranial measurements that must be considered, particularly with respect to posterior fossa volume in Chiari malformation type 1. Even when these demographic variables are appropriately accounted for, other similarly presenting diseases may show small posterior fossa volumes. PMID- 25794075 TI - PET/MRI for the evaluation of patients with lymphoma: initial observations. AB - OBJECTIVE: The objective of our study was to assess the role of recently introduced hybrid PET/MRI in the evaluation of lymphoma patients using PET/CT as a reference standard. SUBJECTS AND METHODS: In this prospective study 28 consecutive lymphoma patients (18 men, 10 women; mean age, 53.6 years) undergoing clinically indicated PET/ CT were subsequently imaged with PET/MRI using residual FDG activity from the PET/ CT study. Blinded readers evaluated PET/CT (reference standard), PET/MRI, and diffusion-weighted imaging (DWI) studies separately; for each study, they assessed nodal and extranodal involvement. Each FDG-avid nodal station was marked and compared on DWI, PET/MRI, and PET/CT. Modified Ann Arbor staging was performed and compared between PET/MRI and PET/CT. The maximum standardized uptake value (SUVmax) on PET/MRI for FDG-avid nodal lesions was compared with the SUVmax on PET/CT. The apparent diffusion coefficient (ADC) for FDG-avid nodal lesions was compared to SUVmax on PET/MRI. RESULTS: Fifty-one FDG avid nodal groups were identified on PET/CT in 13 patients. PET/MRI identified 51 of these nodal groups with a sensitivity of 100%. DWI identified 32 nodal groups for a sensitivity of 62.7%. PET/MRI staging and PET/CT staging were concordant in 96.4% of patients. For the one patient with discordant staging results, disease was correctly upstaged to stage IV on the basis of the PET/MRI finding of bone marrow involvement, which was missed on PET/CT. DWI staging was concordant with PET/CT staging in 64.3% of the patients. The increased staging accuracy of PET/MRI relative to DWI was significant (p=0.004). SUVmax measured on PET/MRI and PET/CT showed excellent statistically significant correlation (r=0.98, p<0.001). There was a poor negative correlation between ADC and SUVmax (r=-0.036, p=0.847). CONCLUSION: PET/MRI can be used to assess disease burden in lymphoma with sensitivity similar to PET/CT and can be a viable alternative for lymphoma staging and follow-up. PMID- 25794076 TI - Improvement in diagnostic accuracy of ultrasound of the pediatric appendix through the use of equivocal interpretive categories. AB - OBJECTIVE: The purpose of this article is to evaluate the diagnostic performance of ultrasound of the pediatric appendix using standardized structured reports that incorporate equivocal interpretive categories. MATERIALS AND METHODS: Standardized structured appendix ultrasound reports using a five-category interpretive scheme were reviewed. Interpretive categories were positive, intermediate likelihood, or negative when the appendix was visualized, and secondary signs or no secondary signs when the appendix was not visualized. Interpretations were compared with clinical and pathologic follow-up. Diagnostic accuracy was compared with the accuracy of a simulated binary interpretive scheme based on the same data. RESULTS: One thousand three hundred fifty-seven examinations were included, with appendicitis present in 16.9% (230/1357) of cases. The appendix was visualized in 47.2% (641/1357) of cases, with interpretations as follows: positive, 27.5% (176/641); intermediate likelihood, 9.7% (62/641); and normal, 62.9% (403/641). The appendicitis rate in each group was 92.6% (163/176), 25.8% (16/62), and 0.5% (2/403), respectively. The appendix was not visualized in 52.8% (716/1357) of cases, with secondary findings identified in 8.5% (61/716) and no secondary findings in 91.5% (655/716) of cases. The appendicitis rate was 39.3% (24/61) and 3.8% (25/655) in these groups, respectively. Appendicitis was present in 32.5% of equivocal (intermediate likelihood and not visualized, secondary findings) cases and 2.6% of negative (normal and not visualized, no secondary findings) cases. Diagnostic accuracy of a five-category scheme was 96.8% versus 94.1% for a binary scheme. CONCLUSION: Appendix ultrasound examinations interpreted according to a scheme that incorporates equivocal categories better convey diagnostic certainty and increase diagnostic accuracy compared with a binary interpretive scheme. PMID- 25794077 TI - Performance of CT examinations in children with suspected acute appendicitis in the community setting: a need for more education. AB - OBJECTIVE: Despite a recent focus on the preferential use of ultrasound over CT for pediatric appendicitis, most children transferred from community hospitals still undergo diagnostic CT scans. The purpose of this study was to evaluate CT techniques performed for children with acute appendicitis at nonpediatric treatment centers. MATERIALS AND METHODS: All patients treated for acute appendicitis at our tertiary-care pediatric hospital from July 1, 2011, through June 30, 2012, were identified. Patient demographics, imaging modality used to diagnoses appendicitis (CT or ultrasound), location (home or referral institution), and CT technique parameters were collected. The estimated mean organ radiation dose, number of imaging phases, and use of contrast media were evaluated at home and referral institutions. RESULTS: During the study period, 1215 patients underwent appendectomies after imaging, with 442 (36.4%) imaged at referral facilities. Most referral patients received a diagnosis by CT (n=384, 87%), compared with 73 of 773 (9.4%) who received a diagnosis by CT at the home institution. The estimated mean (+/-SD) organ radiation dose was not statistically significantly different between home and referral institutions (13.5+/-7.3 vs 12.9+/-6.4 mGy; p=0.58) for single-phase examinations. Of 384 referral patients, 344 had images available for review. In total, 40% (138/344) of patients from referral centers were imaged with suboptimal CT techniques: 50 delayed phase only, 52 dual phase (eight of which were imaged twice in delayed phase), eight triple phase, and 36 without IV contrast agent. CONCLUSION: CT parameters and radiation doses from single-phase examinations in children with appendicitis were similar at nonpediatric treatment centers and a tertiary care children's hospital. Future educational outreach should focus on optimizing other technical parameters. PMID- 25794078 TI - Effect of body size on dose reduction with longitudinal tube current modulation in pediatric patients. AB - OBJECTIVE: The purpose of the study was to evaluate whether dose reduction by tube current modulation in pediatric abdominal CT depends on patient body size. MATERIALS AND METHODS: A 12-month (February 2012 through January 2013) retrospective evaluation of consecutive abdominal 128-MDCT examinations was performed. All studies were performed with longitudinal (z-axis) tube current modulation. Dose reduction from tube current modulation in every CT acquisition was recorded and compared with body weight. In addition, 100 randomized CT abdominal scans were evaluated for average and SD of the water-equivalent diameter along the z-axis. RESULTS: The results include 466 abdominal CT scans of 369 children (172 girls, 197 boys; age range, 3 weeks-18 years; average, 9.2 years; body weight range, 3.5-130 kg; average, 31 kg). The average tube current time reduction was 19%. Dose reduction was least effective (p<0.05; average, 11%) for body weight less than 20 kg. The least variability (SD/average) of water equivalent diameter along the z-axis was found for body weights greater than 20 kg (5.0%) and 20-40 kg (5.9%) (p<0.05). Dose reduction was most effective (p<0.05; average, 30%) at the body weight range of 60-100 kg. CONCLUSION: Dose reduction with automated tube modulation depends on body weight and is less effective in children with a small body size. One of the reasons for this phenomenon could be a closer to uniform water-equivalent diameter along the z axis in children with a small body size. PMID- 25794079 TI - Hydrodissection-assisted image-guided percutaneous biopsy of abdominal and pelvic lesions: experience with seven patients. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of retroperitoneal organ displacement for image-guided percutaneous biopsy. CONCLUSION: Organ displacement using 0.9% saline or 5% dextrose in water (D5W) can create safe access routes for targeted abdominal and pelvic biopsies. PMID- 25794080 TI - Primary creation of an externally constrained TIPS: a technique to control reduction of the portosystemic gradient. AB - OBJECTIVE: Transjugular intrahepatic portosystemic shunt (TIPS) creation increases the risk of hepatic encephalopathy due to overshunting. Techniques exist to secondarily reduce the shunt for refractory encephalopathy. The purpose of this article is to describe a technique for primary TIPS restriction using a balloon-expandable stent within the transvenous hepatic track followed by deployment of a self-expanding polytetrafluoroethylene-lined stent-graft within the balloon-expandable stent to create the TIPS. CONCLUSION: This technique enables control over the degree of portosystemic shunting in elective TIPS creation. PMID- 25794081 TI - Radioactive seed localization versus wire localization for lumpectomies: a comparison of outcomes. AB - OBJECTIVE: The purpose of this study was to compare outcomes of radioactive seed localization (RSL) versus wire localization using surgical margin size, reexcision and reoperation rates, specimen size, radiology resource utilization, and cosmesis as measures. MATERIALS AND METHODS: Patients who underwent RSL before segmental mastectomy from April 1, 2011, to March 1, 2012, for biopsy proven cancer were selected. Each was matched using tumor size, type, and surgeon to a wire localization control case, resulting in 232 cases. Width of the closest surgical margin, reexcision rate, and reoperation rate were compared as were the ratios of tumor volume to initial surgical specimen volume and tumor volume to all surgically excised volume (including reexcisions and reoperations). Cosmetic outcome was analyzed by comparison of Harvard scores and specimen volume with breast volume. Radiology resource utilization was compared before and after RSL implementation. RESULTS: No significant differences between methods were found in closest surgical margin (RSL mean, 0.45 cm; wire localization mean, 0.45 cm; p=0.972), reexcision rate (RSL mean, 21.1%; wire localization mean, 26.3%; p=0.360), reoperation rate (RSL, 11.4%; wire localization, 12.7%; p=0.841), ratio of the tumor volume to initial surgical specimen volume (RSL mean, 0.027; wire localization mean, 0.028; p=0.886), ratio of the tumor volume to total volume resected (RSL mean, 0.024; wire localization mean, 0.024; p=0.997), or in clinical or computed cosmesis scores (clinical p=0.5; calculated p=0.060). There was a 34% increase in scheduled biopsy slot utilization, 50% savings in time spent scheduling, and a 4.1-day average decrease in biopsy wait time after RSL institution. CONCLUSION: RSL is an acceptable alternative to wire localization and offers significant improvements in workflow. PMID- 25794082 TI - Correlation between sonographic findings and clinicopathologic and biologic features of pure ductal carcinoma in situ in 691 patients. AB - OBJECTIVE: The objective of our study was to compare the sonographic features of pure ductal carcinoma in situ (DCIS) lesions with the initial clinical presentation and histopathologic findings. MATERIALS AND METHODS: The images and records of 691 patients with pure DCIS who underwent preoperative mammography and whole-breast sonography as part of staging workup in a single institution from January 1, 1996, through July 31, 2009, were reviewed. The BI-RADS sonography lexicon was used when reviewing the sonographic studies. Histopathologic features recorded included estrogen receptor (ER) status, nuclear grade, and presence or absence of comedonecrosis. Statistical comparisons were made using the Student t test, chi-square test, Fisher exact test, Kruskal-Wallis or Wilcoxon rank sum test, multiple logistic regression analysis, and Pearson correlation coefficient. RESULTS: A total of 304 (44%) tumors were visible on mammography and sonography; 315 (46%), on mammography only; 58 (8%), on sonography only; and 14 (2%), on neither mammography nor sonography. The most common sonographic appearance of DCIS was an irregular hypoechoic mass with indistinct margins and normal posterior features that was indistinguishable from invasive carcinoma. Patients with symptomatic high-nuclear-grade DCIS, dense breasts, and comedonecrosis were younger and had larger tumors on sonography than asymptomatic women with nondense breasts and low-nuclear-grade and noncomedo DCIS. Women with ER-negative DCIS were older and had larger tumors on sonography than women with ER-positive DCIS. ER-negative tumors were more frequently visible on sonography than ER-positive tumors (p=0.007). High-grade DCIS (p<0.0001) and comedo DCIS (p<0.0001) presented more frequently as microcalcifications, architectural distortion, and ductal changes on sonography than low-grade DCIS or noncomedo DCIS. CONCLUSION: Of the 691 pure DCIS lesions, 362 (52%) were visible on sonography and presented most commonly as a mass. Lesion visibility of DCIS on sonography was not related to nuclear grade or the presence of comedonecrosis. PMID- 25794083 TI - Breast MRI as an adjunct to mammography for breast cancer screening in high-risk patients: retrospective review. AB - OBJECTIVE: In July 2011, the provincial government of Ontario, Canada, approved funding for the addition of annual breast MRI to mammography screening for all women 30-69 years old considered to be at high risk for breast cancer. The purpose of this study was to evaluate the diagnostic performance of screening breast MRI as compared with mammography in a population-based high-risk screening program. MATERIALS AND METHODS: A retrospective review identified 650 eligible high-risk women who underwent screening breast MRI and mammography between July 2011 and January 2013 at one institution. Results of 806 screening rounds (comprising both MRI and mammography) were reviewed. RESULTS: Malignancy was diagnosed in 13 patients (invasive cancer in nine, ductal carcinoma in situ in three [one with microinvasion], and chest wall metastasis in one). Of the 13 cancers, 12 (92.3%) were detected by MRI and four (30.8%) by mammography. In nine of these patients, the cancer was diagnosed by MRI only, resulting in an incremental cancer detection rate of 10 cancers per 1000 women screened. MRI screening had significantly higher sensitivity than mammography (92.3% vs 30.8%) but lower specificity (85.9% vs 96.8%). MRI also resulted in a higher callback rate for a 6-month follow-up study (BI-RADS category 3 assessment) than mammography (119 [14.8%] vs 13 [1.6%]) and more image-guided biopsies than mammography (95 [11.8%] vs 19 [2.4%]). CONCLUSION: MRI is a useful adjunct to mammography for screening in high-risk women, resulting in a significantly higher rate of cancer detection. However, this was found to be at the cost of more imaging and biopsies for lesions that ultimately proved to be benign. PMID- 25794084 TI - All-cause mortality is decreased in women undergoing annual mammography before breast cancer diagnosis. AB - OBJECTIVE: The value of annual mammography remains an area of debate because of concerns regarding risk versus benefit. The potential for harm due to overdiagnosis and treatment of clinically insignificant cancers may not be captured by breast cancer-specific mortality. Instead, we examined all-cause mortality as a function of missed annual mammography examinations before breast cancer diagnosis. MATERIALS AND METHODS: Primary breast cancer cases diagnosed in the Marsh-field Clinic Health System from 2002 through 2008 were identified for retrospective review, and whether annual mammography examinations had been performed in the 5 years before diagnosis was assessed. RESULTS: Analyses were performed on 1421 women with breast cancer. After adjustment of data for age, comorbidity status, a family history of breast cancer, insurance status, medical encounter frequency, and the calendar year, women who had missed any of the previous five annual mammography examinations had a 2.3-fold increased risk of all-cause mortality compared with subjects with no missed mammography examinations (hazard ratio=2.28; 95% CI, 1.58-3.30; p<0.0001). Additionally, an analysis by the number of missed annual mammography examinations showed a progressive increase in hazard as the number of missed mammography studies increased. CONCLUSION: These results suggest that annual mammography before breast cancer diagnosis is predictive of increased overall survival. A stepwise decline in overall survival was noted for each additional missed mammography examination. These results are similar to findings in the literature for breast cancer-specific mortality and illustrate the importance of recommending annual mammography to all eligible women. PMID- 25794085 TI - Do mammographic technologists affect radiologists' diagnostic mammography interpretative performance? AB - OBJECTIVE: The purpose of this study was to determine whether the technologist has an effect on the radiologists' interpretative performance of diagnostic mammography. MATERIALS AND METHODS: Using data from a community-based mammography registry from 1994 to 2009, we identified 162,755 diagnostic mammograms interpreted by 286 radiologists and performed by 303 mammographic technologists. We calculated sensitivity, false-positive rate, and positive predictive value (PPV) of the recommendation for biopsy from mammography for examinations performed (i.e., images acquired) by each mammographic technologist, separately for conventional (film-screen) and digital modalities. We assessed the variability of these performance measures among mammographic technologists, using mixed effects logistic regression and taking into account the clustering of examinations within women, radiologists, and radiology practices. RESULTS: Among the 291 technologists performing conventional examinations, mean sensitivity of the examinations performed was 83.0% (95% CI, 80.8-85.2%), mean false-positive rate was 8.5% (95% CI, 8.0-9.0%), and mean PPV of the recommendation for biopsy from mammography was 27.1% (95% CI, 24.8-29.4%). For the 45 technologists performing digital examinations, mean sensitivity of the examinations they performed was 79.6% (95% CI, 73.1-86.2%), mean false-positive rate was 8.8% (95% CI, 7.5-10.0%), and mean PPV of the recommendation for biopsy from mammography was 23.6% (95% CI, 18.8-28.4%). We found significant variation by technologist in the sensitivity, false-positive rate, and PPV of the recommendation for biopsy from mammography for conventional but not digital mammography (p < 0.0001 for all three interpretive performance measures). CONCLUSION: Our results suggest that the technologist has an influence on radiologists' interpretive performance for diagnostic conventional but not digital mammography. Future studies should examine why this difference between modalities exists and determine if similar patterns are observed for screening mammography. PMID- 25794086 TI - Simulation center training as a means to improve resident performance in percutaneous noncontinuous CT-guided fluoroscopic procedures with dose reduction. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of a multifaceted simulation-based resident training for CT-guided fluoroscopic procedures by measuring procedural and technical skills, radiation dose, and procedure times before and after simulation training. SUBJECTS AND METHODS: A prospective analysis included 40 radiology residents and eight staff radiologists. Residents took an online pretest to assess baseline procedural knowledge. Second-through fourth-year residents' baseline technical skills with a procedural phantom were evaluated. First-through third-year residents then underwent formal didactic and simulation-based procedural and technical training with one of two interventional radiologists and followed the training with 1 month of supervised phantom-based practice. Thereafter, residents underwent final written and practical examinations. The practical examination included essential items from a 20-point checklist, including site and side marking, consent, time out, and sterile technique along with a technical skills portion assessing pedal steps, radiation dose, needle redirects, and procedure time. RESULTS: The results indicated statistically significant improvement in procedural and technical skills after simulation training. For residents, the median number of pedal steps decreased by three (p=0.001), median dose decreased by 15.4 mGy (p<0.001), median procedure time decreased by 4.0 minutes (p<0.001), median number of needle redirects decreased by 1.0 (p=0.005), and median number of 20-point checklist items successfully completed increased by three (p<0.001). The results suggest that procedural skills can be acquired and improved by simulation-based training of residents, regardless of experience. CONCLUSION: CT simulation training decreases procedural time, decreases radiation dose, and improves resident efficiency and confidence, which may transfer to clinical practice with improved patient care and safety. PMID- 25794087 TI - CT radiation dose and iterative reconstruction techniques. AB - 1. CT radiation dose optimization is one of the major concerns for the scientific community. 2. CT image quality is dependent on the selected image reconstruction algorithm. 3. Iterative reconstruction algorithms have reemerged with the potential of radiation dose optimization by lowering image noise. 4. Tube current is the most common parameter used to reduce radiation dose along with iterative reconstruction. 5. Tube potential (kV) is also used for dose optimization with iterative reconstruction in CT angiography protocols and small patients. PMID- 25794088 TI - X-ray-based medical imaging and resolution. PMID- 25794089 TI - Tumor thrombus as a rare presentation of lymphoma: a case series of 14 patients. AB - OBJECTIVE: We present a case series of 14 patients with lymphoma presenting with tumor thrombus to highlight this rare but important manifestation of lymphoma. CONCLUSION: The dominant mass leading to tumor thrombus formation was nodal disease in nine patients and extranodal disease in five patients. Lymphoma should be considered in the differential diagnosis in the setting of tumor thrombus with solid organ involvement when there are other imaging features suggestive of lymphoma. PMID- 25794090 TI - Images of imaging: how to process and display imaging utilization for large populations. AB - OBJECTIVE: We propose a method of processing and displaying imaging utilization data for large populations. CONCLUSION: The comprehensive and finely grained picture of imaging utilization yielded by our methods is a first step toward population-based imaging utilization management. We believe that our methods for the categorization and display of imaging utilization will prove to be widely useful. PMID- 25794091 TI - Breast dose reduction options during thoracic CT: influence of breast thickness. AB - OBJECTIVE: Little is known about the effectiveness of dose reduction options according to breast thickness. The purpose of this phantom study was to compare the effects on dose and noise of bismuth shielding versus a low kilovoltage for different breast thicknesses. MATERIALS AND METHODS: CT acquisitions were performed first at 120 kVp (reference acquisition), then at 120 kVp with shielding and at 100 kVp without shielding on a phantom with three different prosthetic breast thicknesses, corresponding to the minimum, median, and maximum values first measured in a sample of 30 female thoracic CT examinations, which were randomly selected. Breast doses were measured with optically stimulated luminescence dosimeters placed on and beneath the prosthetic breast. For noise evaluation, the CT number SDs were measured within six ROIs at increasing depths. RESULTS: Taking into account all breast thicknesses, the average breast dose was reduced by 42.1% with shielding and by 33.0% at 100 kVp (p=0.009). In-depth noise increased less with shielding (19.0% vs 32.1%, p<0.0001). For 1-cm breast thickness, the breast dose fell by 46.5% and 29.7% with shielding and 100 kVp, respectively (p=0.01), and in-depth noise increased by 19.5% and 33.9% (p=0.01). The corresponding values for 2-cm breast thickness were -38.5% and -30.1%, (p=0.02) and 16.5% and 33.5% (p=0.001), whereas those for 4-cm thickness were 40.6% and -40.5% (p=0.95) and 20.7 and 29.2% (p=0.02). CONCLUSION: Greater breast dose reduction is achieved by shielding for breast thicknesses less than 4 cm. Regardless of breast thickness, shielding leads to a smaller increase in in-depth noise. PMID- 25794092 TI - Simethicone to prevent colonic bubbles during CT colonography performed with polyethylene glycol lavage and iohexol tagging: a randomized clinical trial. AB - OBJECTIVE: The purpose of this study was to determine whether the occurrence of numerous colonic bubbles during CT colonography (CTC) performed with polyethylene glycol cleansing and oral iohexol fecal/fluid tagging could be prevented by use of simethicone. SUBJECTS AND METHODS: Adults with suspected colonic neoplasia who had been randomly assigned to control and simethicone intervention groups underwent CTC after cleansing with 4 L of polyethylene glycol, tagging with 50 mL of 350 mg I/mL oral iohexol, and without (control) or with (intervention) oral administration of 200 mg of simethicone. Colonic segments in the control and intervention groups were evaluated for amount of colonic bubbles during CTC. A 6 point grading system was used in which 0 indicated no bubbles and 5 indicated that more than three fourths of the air-distended mucosa was covered with bubbles. The primary endpoint was a per-patient colonic bubble grade, derived as an average of the segmental grades. RESULTS: Eighty adults with suspected colonic neoplasia were randomly assigned to the control (40 patients) and simethicone intervention (40 patients) groups. A total of 659 colonic segments in the control group and 689 segments in the intervention group were evaluated for amount of colonic bubbles during CTC. The per-patient colonic bubble score was significantly lower in the simethicone intervention group than in the control group. The mean score was 0.0+/-0.1 (SD) versus 1.2+/-0.8 (p<0.001; 95% CI for the mean difference, -1.4 to -1.0). In the intervention group, 673 (97.7%) segments were grade 0, and 16 (2.3%) were grade 1. In contrast, in the control group, 226 (34.3%) segments were grade 0; 173 (26.3%), grade 1; 175 (26.6%), grade 2; 45 (6.8%), grade 3; 23 (3.5%), grade 4; and 17 (2.6%), grade 5. CONCLUSION: The colonic bubbles associated with fecal/fluid tagging with iohexol can be successfully prevented by adding simethicone to the colonic preparation. PMID- 25794093 TI - Dynamic contrast-enhanced MRI for the detection of prostate cancer: meta analysis. AB - OBJECTIVE: The purpose of this study was to systematically review and meta analyze dynamic contrast-enhanced MRI (DCE-MRI) for the detection of prostate cancer in comparison with standard evaluation with T2-weighted imaging. MATERIALS AND METHODS: A PubMed electronic database search for the terms "dynamic contrast enhanced," "prostate," and "MRI" was completed for articles up to September 17, 2013. All included studies had histopathologic correlation. Two by two contingency data were constructed for each study. A binormal bayesian ROC model was used to estimate and compare sensitivity, specificity, and AUC among eligible modalities. RESULTS: Both DCE-MRI (0.82-0.86) and diffusion-weighted MRI (DWI) (0.84-0.88) yielded significantly better AUC than T2-weighted imaging (0.68 0.77). Moreover, partial AUC for the combination of DCE-MRI, DWI, and T2-weighted imaging was improved significantly (0.111; 0.103-0.119) when compared with DCE MRI alone (0.079; 0.072-0.085) and T2-weighted imaging alone (0.079; 0.074-0.084) but not DWI alone (0.099; 0.091-0.108). Sensitivity and specificity were similar among the four modalities. CONCLUSION: DCE-MRI improves AUC of tumor detection overall compared with T2-weighted imaging alone. Methods for DCE-MRI analysis require standardization, but visual analysis performs similar to semiquantitative methods. A two-parameter approach using DCE-MRI and T2-weighted imaging or DWI and T2-weighted imaging may be sufficient, and the latter may be more favorable for most routine prostate cancer imaging. PMID- 25794094 TI - Prostate cancer: top places where tumors hide on multiparametric MRI. AB - OBJECTIVE: Prostate tumors occasionally have unusual manifestations on multiparametric MR images that can present a diagnostic dilemma and result in a false-negative interpretation. This article presents examples of such "hiding places" of prostate tumors, four in the peripheral zone and four in the central gland. CONCLUSION: The provided pointers in multiparametric MRI assessment can aid the radiologist in achieving an accurate diagnosis of tumor in the eight scenarios described. PMID- 25794095 TI - Correlation of cystoscopically confirmed periureterally located hunner lesion with vesicoureteral reflux: preliminary study in patients with interstitial cystitis. AB - OBJECTIVE: The purpose of this study is to evaluate the incidence of vesicoureteral reflux (VUR) in patients with interstitial cystitis (IC) and to explore the correlation between periureterally located Hunner lesions and ipsilateral VUR. MATERIALS AND METHODS: We evaluated 344 patients with IC who underwent cystoscopy (March 2012 to July 2013). Among these patients, 25 underwent voiding cystourethrography (VCUG) to check for the presence of VUR. We reviewed the cystoscopy findings (grade and location of Hunner lesions) and the results of VCUG (presence and grade of VUR). The relationship between VUR and periureterally located Hunner lesions and the association between cystoscopic grading of IC and VUR were evaluated. RESULTS: Of the 25 patients with IC, seven (28%) had VUR (two bilateral and five unilateral). Among nine separate ureters with VUR, seven (78%) had associated periureterally located Hunner lesions, as evaluated cystoscopically. The median bladder capacity was 200 mL for patients with VUR and 230 mL for patients without VUR, with no statistically significant difference between the two groups (p>0.05). There was a strong correlation between the presence of VUR and ipsilateral periureterally located Hunner lesions (p<0.05). However, there was no association between the severity of cystoscopy grading and the presence of VUR (p>0.05). CONCLUSION: According to our study, VUR is not an uncommon complication in patients with IC, and there is a statistically significant correlation between VUR and periureterally located Hunner lesions. We assume that, along with the decrease in bladder capacity, a periureterally located Hunner lesion may be an important factor in the development of VUR. PMID- 25794096 TI - Functional radiography in examination of spondylolisthesis. AB - OBJECTIVE: Despite the predominant use of standing flexion-extension radiography for quantifying instability in isthmic and degenerative spondylolisthesis, other functional radio-graphic techniques have been presented in the literature. CONCLUSION: The current evidence reported in the literature is insufficient to influence how the results of these other functional radiographic techniques should affect clinical management; however, it does raise doubts regarding the accuracy and reliability of standing flexion-extension radiography in this setting. Based on the currently available evidence and until randomized studies are performed to assess the efficacy of functional radiographic techniques in directing clinical decision making, positioning schemes other than traditional standing flexion-extension may be considered as options in the evaluation of patients with symptomatic isthmic and degenerative spondylolisthesis in which standard flexion-extension radiographs fail to show pathologic instability. PMID- 25794097 TI - Marginal impaction in posterior wall fractures of the acetabulum. AB - OBJECTIVE: The purposes of this study were to describe the CT features of isolated posterior acetabular wall fractures with associated marginal impaction and to discuss the potential therapeutic implications of recognizing this type of fracture. CONCLUSION: Marginal impaction is an important cause of articular incongruity that adversely affects prognosis. Radiologists should be capable of identifying posterior acetabular wall fracture patterns because they may be the first to suggest diagnoses. PMID- 25794099 TI - A large display is a powerful tool to reduce radiation exposure during single plane fluoroscopically guided procedures. AB - OBJECTIVE: Magnification is a well-known, but often overlooked, factor impacting radiation exposure. Modern angiography units are commonly offered with single large monitors that allow multiple configurations, including wide display setting in addition to standard display setting similar to a classic arrangement of multiple monitors. CONCLUSION: By reducing the need for magnification, the wide display mode of large angiography monitors is a simple but extremely efficient tool to decrease radiation exposure to patients and care providers during single plane procedures. PMID- 25794098 TI - Radiographic screening of infants and young children with genetic predisposition for rare malignancies: DICER1 mutations and pleuropulmonary blastoma. AB - OBJECTIVE: The purpose of this study was to compare the risks of radiation in screening strategies using chest radiographs and CT to detect a rare cancer in a genetically predisposed population against the risks of undetected disease. MATERIALS AND METHODS: A decision analytic model of diagnostic imaging screening strategies was built to predict outcomes and cumulative radiation doses for children with DICER1 mutations screened for pleuropulmonary blastoma. Screening strategies compared were chest radiographs followed by chest CT for a positive radiographic result and CT alone. Screening frequencies ranged from once in 3 years to once every 3 months. BEIR VII (model VII proposed by the Committee on the Biological Effects of Ionizing Radiation) risk tables were used to predict excess cancer mortality for each strategy, and the corresponding loss of life expectancy was calculated using Surveillance Epidemiologic and End Results (SEER) statistics. Loss of life expectancy owing to undetected progressive pleuropulmonary blastoma was estimated on the basis of data from the International Pleuropulmonary Blastoma Registry. Sensitivity analysis was performed for all model parameters. RESULTS: Loss of life expectancy owing to undetected disease in an unscreened population exceeded that owing to radiation induced cancer for all screening scenarios investigated. Increases in imaging frequency decreased loss of life expectancy for the combined (chest radiographs and CT) screening strategy but increased that for the CT-only strategy. This was because loss of life expectancy for combined screening is dominated by undetected disease, whereas loss of life expectancy for CT screening is dominated by radiation-induced cancers. CONCLUSION: Even for a rare disease such as pleuropulmonary blastoma, radiographic screening of infants and young children with cancer-predisposing mutations may result in improved life expectancy compared with the unscreened population. The benefit of screening will be greater for diseases with a higher screening yield. PMID- 25794100 TI - Criteria for identifying radiologists with acceptable screening mammography interpretive performance on basis of multiple performance measures. AB - OBJECTIVE: Using a combination of performance measures, we updated previously proposed criteria for identifying physicians whose performance interpreting screening mammography may indicate suboptimal interpretation skills. MATERIALS AND METHODS: In this study, six expert breast imagers used a method based on the Angoff approach to update criteria for acceptable mammography performance on the basis of two sets of combined performance measures: set 1, sensitivity and specificity for facilities with complete capture of false-negative cancers; and set 2, cancer detection rate (CDR), recall rate, and positive predictive value of a recall (PPV1) for facilities that cannot capture false-negative cancers but have reliable cancer follow-up information for positive mammography results. Decisions were informed by normative data from the Breast Cancer Surveillance Consortium (BCSC). RESULTS: Updated combined ranges for acceptable sensitivity and specificity of screening mammography are sensitivity>=80% and specificity>=85% or sensitivity 75-79% and specificity 88-97%. Updated ranges for CDR, recall rate, and PPV1 are: CDR>=6 per 1000, recall rate 3-20%, and any PPV1; CDR 4-6 per 1000, recall rate 3-15%, and PPV1>=3%; or CDR 2.5-4.0 per 1000, recall rate 5-12%, and PPV1 3-8%. Using the original criteria, 51% of BCSC radiologists had acceptable sensitivity and specificity; 40% had acceptable CDR, recall rate, and PPV1. Using the combined criteria, 69% had acceptable sensitivity and specificity and 62% had acceptable CDR, recall rate, and PPV1. CONCLUSION: The combined criteria improve previous criteria by considering the interrelationships of multiple performance measures and broaden the acceptable performance ranges compared with previous criteria based on individual measures. PMID- 25794101 TI - Medicolegal--malpractice and ethical issues in radiology. Must all monitors meet DICOM standards? PMID- 25794102 TI - Spinal instability neoplastic scale: methodologic issues to avoid misinterpretation. PMID- 25794103 TI - Differential diagnosis of anterior mediastinal masses. PMID- 25794105 TI - Identification of a recombinant inulin fructotransferase (difructose dianhydride III forming) from Arthrobacter sp. 161MFSha2.1 with high specific activity and remarkable thermostability. AB - Difructose dianhydride III (DFA III) is a functional carbohydrate produced from inulin by inulin fructotransferase (IFTase, EC 4.2.2.18). In this work, an IFTase gene from Arthrobacter sp. 161MFSha2.1 was cloned and expressed in Escherachia coli. The recombinant enzyme was purified by metal affinity chromatography. It showed significant inulin hydrolysis activity, and the produced main product from inulin was determined as DFA III by nuclear magnetic resonance analysis. The molecular mass of the purified protein was calculated to be 43 and 125 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration, respectively, suggesting the native enzyme might be a homotrimer. The recombinant enzyme showed maximal activity as 2391 units/mg at pH 6.5 and 55 degrees C. It displayed the highest thermostability among previously reported IFTases (DFA III forming) and was stable up to 80 degrees C for 4 h of incubation. The smallest substrate was determined as nystose. The conversion ratio of inulin to DFA III reached 81% when 100 g/L inulin was catalyzed by 80 nM recombinant enzyme for 20 min at pH 6.5 and 55 degrees C. All of these data indicated that the IFTase (DFA III forming) from Arthrobacter sp. 161MFSha2.1 had great potential for industrial DFA III production. PMID- 25794104 TI - Interleukin-19 acts as a negative autocrine regulator of activated microglia. AB - Activated microglia can exert either neurotoxic or neuroprotective effects, and they play pivotal roles in the pathogenesis and progression of various neurological diseases. In this study, we used cDNA microarrays to show that interleukin-19 (IL-19), an IL-10 family cytokine, is markedly upregulated in activated microglia. Furthermore, we found that microglia are the only cells in the nervous system that express the IL-19 receptor, a heterodimer of the IL 20Ralpha and IL-20Rbeta subunits. IL-19 deficiency increased the production of such pro-inflammatory cytokines as IL-6 and tumor necrosis factor-alpha in activated microglia, and IL-19 treatment suppressed this effect. Moreover, in a mouse model of Alzheimer's disease, we observed upregulation of IL-19 in affected areas in association with disease progression. Our findings demonstrate that IL 19 is an anti-inflammatory cytokine, produced by activated microglia, that acts negatively on microglia in an autocrine manner. Thus, microglia may self-limit their inflammatory response by producing the negative regulator IL-19. PMID- 25794106 TI - Accurate prediction of severe allergic reactions by a small set of environmental parameters (NDVI, temperature). AB - Severe allergic reactions of unknown etiology,necessitating a hospital visit, have an important impact in the life of affected individuals and impose a major economic burden to societies. The prediction of clinically severe allergic reactions would be of great importance, but current attempts have been limited by the lack of a well-founded applicable methodology and the wide spatiotemporal distribution of allergic reactions. The valid prediction of severe allergies (and especially those needing hospital treatment) in a region, could alert health authorities and implicated individuals to take appropriate preemptive measures. In the present report we have collecterd visits for serious allergic reactions of unknown etiology from two major hospitals in the island of Crete, for two distinct time periods (validation and test sets). We have used the Normalized Difference Vegetation Index (NDVI), a satellite-based, freely available measurement, which is an indicator of live green vegetation at a given geographic area, and a set of meteorological data to develop a model capable of describing and predicting severe allergic reaction frequency. Our analysis has retained NDVI and temperature as accurate identifiers and predictors of increased hospital severe allergic reactions visits. Our approach may contribute towards the development of satellite-based modules, for the prediction of severe allergic reactions in specific, well-defined geographical areas. It could also probably be used for the prediction of other environment related diseases and conditions. PMID- 25794108 TI - Dynamics of the Active Sites of Dimeric Seryl tRNA Synthetase from Methanopyrus kandleri. AB - Aminoacyl tRNA synthetases (aaRSs) carry out the first step of protein biosynthesis. Several aaRSs are multimeric, and coordination between the dynamics of active sites present in each monomer is a prerequisite for the fast and accurate aminoacylation. However, important lacunae of understanding exist concerning the conformational dynamics of multimeric aaRSs. Questions remained unanswered pertaining to the dynamics of the active site. Little is known concerning the conformational dynamics of the active sites in response to the substrate binding, reorganization of the catalytic residues around reactants, time-dependent changes at the reaction center, which are essential for facilitating the nucleophilic attack, and interactions at the interface of neighboring monomers. In the present work, we carried out all-atom molecular dynamics simulation of dimeric (mk)SerRS from Methanopyrus kandleri bound with tRNA using an explicit solvent system. Two dimeric states of seryl tRNA synthetase (open, substrate bound, and adenylate bound) and two monomeric states (open and substrate bound) are simulated with bound tRNA. The aim is to understand the conformational dynamics of (mk)SerRS during its reaction cycle. While the present results provide a clear dynamical perspective of the active sites of (mk)SerRS, they corroborate with the results from the time-averaged experimental data such as crystallographic and mutation analysis of methanogenic SerRS from M. kandleri and M. barkeri. It is observed from the present simulation that the motif 2 loop gates the active site and its Glu351 and Arg360 stabilizes ATP in a bent state favorable for nucleophilic attack. The flexibility of the walls of the active site gradually reduces near reaction center, which is a more organized region compared to the lid region. The motif 2 loop anchors Ser and ATP using Arg349 in a hydrogen bonded geometry crucial for nucleophilic attack and favorably influences the electrostatic potential at the reaction center. Synchronously, Arg366 of the beta sheet at the base holds the syn oxygen of the attacking carboxylic group so that the attack by the anti oxygen is feasible. This residue also contributes to the reduction of the unfavorable electrostatic potential at the reaction center. Present simulation clearly shows the catalytic role of the residues at reaction center. A precise and stable geometry of hydrogen bonded network develops within the active site, which is essential for the development of an optimum transition state geometry. All loops move away from the platform of active site in the open or adenylate bound state and the network of hydrogen bond disappears. The serine binding site is most rigid among all three subsites. The Ser is held here in a highly organized geometry bound by Zn(2+) and Cys residues. Present simulation further suggests that the helix-turn helix motif connecting the monomers might have important role in coordinating the functional dynamics of the two active sites. The N-terminal domain is involved in long-range electrostatic interaction and specific hydrogen bond interaction (both direct and water mediated) with tRNA. Overall conformational fluctuation is less in the N terminal compared to the catalytic domain due to the presence of a motif 2 loop, loop f, and serine ordering loop, which change conformation in the later domain during the reaction cycle. The dynamic perspective of the active site of (mk)SerRS with the mobile loop acting as the gate and dynamically silent beta sheets performing as the base has similarity with the perception of the active site in various other enzymes. PMID- 25794107 TI - Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A. AB - Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK) in response to endoplasmic reticulum (ER) stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A). Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2), to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling. PMID- 25794109 TI - Use of a Web-based physical activity record system to analyze behavior in a large population: cross-sectional study. AB - BACKGROUND: The use of Web-based physical activity systems has been proposed as an easy method for collecting physical activity data. We have developed a system that has exhibited high accuracy as assessed by the doubly labeled water method. OBJECTIVE: The purpose of this study was to collect behavioral data from a large population using our Web-based physical activity record system and assess the physical activity of the population based on these data. In this paper, we address the difference in physical activity for each urban scale. METHODS: In total, 2046 participants (aged 30-59 years; 1105 men and 941 women) participated in the study. They were asked to complete data entry before bedtime using their personal computer on 1 weekday and 1 weekend day. Their residential information was categorized as urban, urban-rural, or rural. Participant responses expressed the intensity of each activity at 15-minute increments and were recorded on a Web server. Residential areas were compared and multiple regression analysis was performed. RESULTS: Most participants had a metabolic equivalent (MET) ranging from 1.4 to 1.8, and the mean MET was 1.60 (SD 0.28). The median value of moderate-to-vigorous physical activity (MVPA, >=3 MET) was 7.92 MET-hours/day. A 1-way ANCOVA showed that total physical activity differed depending on the type of residential area (F2,2027=5.19, P=.006). The urban areas (n=950) had the lowest MET-hours/day (mean 37.8, SD, 6.0), followed by urban-rural areas (n=432; mean 38.6, SD 6.5; P=.04), and rural areas (n=664; mean 38.8, SD 7.4; P=.002). Two-way ANCOVA showed a significant interaction between sex and area of residence on the urban scale (F2,2036=4.53, P=.01). Men in urban areas had the lowest MET hours/day (MVPA, >=3 MET) at mean 7.9 (SD 8.7); men in rural areas had a MET hours/day (MVPA, >=3 MET) of mean 10.8 (SD 12.1, P=.002). No significant difference was noted in women among the 3 residential areas. Multiple regression analysis showed that physical activity consisting of standing while working was the highest contributor to MVPA, regardless of sex. CONCLUSIONS: We were able to compile a detailed comparison of physical activity because our Web-based physical activity record system allowed for the simultaneous evaluation of physical activity from 2046 Japanese people. We found that rural residents had greater total physical activity than urban residents and that working and transportation behaviors differed depending on region type. Multiple regression analysis showed that the behaviors affected MVPA. People are less physically active while working, and sports and active transportation might be effective ways of increasing physical activity levels. PMID- 25794110 TI - Use of formate salts as a hydride and a co2 source in PGeP-palladium complex catalyzed hydrocarboxylation of allenes. AB - Use of formate salts as a hydride as well as a CO2 source was achieved in a PGeP palladium complex-catalyzed hydrocarboxylation of allenes through a highly efficient decarboxylation-carboxylation process. This reaction proceeds under mild conditions and provides an alternative strategy for utilizing formate salts as a C1 source. PMID- 25794111 TI - Anesthesia Care Transitions and Risk of Postoperative Complications. AB - BACKGROUND: A patient undergoing surgery may receive anesthesia care from several anesthesia providers. The safety of anesthesia care transitions has not been evaluated. Using unconditional and conditional multivariable logistic regression models, we tested whether the number of attending anesthesiologists involved in an operation was associated with postoperative complications. METHODS: In a cohort of patients undergoing elective colorectal surgical in an academic tertiary care center with a stable anesthesia care team model participating in the American College of Surgeons National Surgical Quality Improvement Program, using unconditional and conditional multivariable logistic regression models, we tested adjusted associations between numbers of attending anesthesiologists and occurrence of death or a major complication (acute renal failure, bleeding that required a transfusion of 4 units or more of red blood cells within 72 hours after surgery, cardiac arrest requiring cardiopulmonary resuscitation, coma of 24 hours or longer, myocardial infarction, unplanned intubation, ventilator use for 48 hours or more, pneumonia, stroke, wound disruption, deep or organ-space surgical-site infection, superficial surgical-site infection, sepsis, septic shock, systemic inflammatory response syndrome). RESULTS: We identified 927 patients who underwent elective colectomy of comparable surgical intensity. In all, 71 (7.7%) patients had major nonfatal complications or death. One anesthesiologist provided care for 530 (57%) patients, 2 anesthesiologists for 287 (31%), and 3 or more for 110 (12%). The number of attending anesthesiologists was associated with increased odds of postoperative complication (unadjusted odds ratio [OR] = 1.52, 95% confidence interval [CI] 1.18-1.96, P = 0.0013; adjusted OR = 1.44, 95% CI 1.09-1.91, P = 0.0106). In sensitivity analyses, occurrence of a complication was significantly associated with the number of in-room providers, defined as anesthesia residents and nurse anesthetists (adjusted OR = 1.39, 95% CI 1.01-1.92, P = 0.0446) and for all anesthesia providers (adjusted OR = 1.58, 95%CI 1.20-2.08, P = 0.0012). Findings persisted across multiple, alternative adjustments, sensitivity analyses, and conditional logistic regression with matching on operative duration. CONCLUSIONS: In our study, care by additional attending anesthesiologists and in-room providers was independently associated with an increased odds of postoperative complications. These findings challenge the assumption that anesthesia transitions are care neutral and not contributory to surgical outcomes. PMID- 25794112 TI - The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval. AB - BACKGROUND: Therapeutic hypothermia is the standard of care after perinatal asphyxia. Preclinical studies show 50% xenon improves outcome, if started early. METHODS: During a 32-patient study randomized between hypothermia only and hypothermia with xenon, 5 neonates were given xenon during retrieval using a closed-circuit incubator-mounted system. RESULTS: Without xenon availability during retrieval, 50% of eligible infants exceeded the 5-hour treatment window. With the transportable system, 100% were recruited. Xenon delivery lasted 55 to 120 minutes, using 174 mL/h (117.5-193.2) (median [interquartile range]), after circuit priming (1300 mL). CONCLUSIONS: Xenon delivery during ambulance retrieval was feasible, reduced starting delays, and used very little gas. PMID- 25794113 TI - Labor Analgesia Consumption and Time to Neuraxial Catheter Placement in Women with a History of Surgical Correction for Scoliosis: A Case-Matched Study. AB - BACKGROUND: Neuraxial analgesic techniques are the most effective form of labor analgesia. Small studies (9-21 patients), conducted 10 to 20 years ago, demonstrated successful neuraxial labor analgesia in only 50% to 66% of patients with surgical correction for scoliosis. Newer surgical techniques for scoliosis correction make the epidural space more accessible, but postsurgical changes may still alter the efficacy of neuraxial labor analgesia. The purpose of this prospective case-matched study was to compare hourly bupivacaine consumption and time to placement of neuraxial technique in laboring women with spinal instrumentation compared with women without previous back surgery. METHODS: All women with previous spinal instrumentation surgery for scoliosis correction who requested neuraxial labor analgesia at Prentice Women's Hospital during the study period were approached. Control subjects were matched for anesthesiologist level of experience. The primary outcomes were bupivacaine consumption per hour of labor analgesia and time to placement of the neuraxial technique. Secondary outcomes included supplemental analgesia requirements and neuraxial analgesia failures and complications. RESULTS: Data from 41 women with surgical correction for scoliosis and 41 control subjects requesting neuraxial labor analgesia were analyzed. Obstetric and demographic characteristics of study participants were not different between groups. Median (interquartile range) hourly bupivacaine consumption was 15.2 mg/h (12.5-18.7) in the spinal instrumentation group and 14.2 mg/h (11.8-16.0) in the control group; the difference in medians was 1 mg/h (95% confidence interval [CI], -1.3 to 3.0; P = 0.38). The total bupivacaine consumption, number of manual reboluses, and number of subjects requiring greater bupivacaine concentrations did not differ between groups. Neuraxial analgesia failure occurred in 5 (12%) of women in the spinal instrumentation group but in none of the control patients (difference [95% CI], 12% [-0.3% to 25%]; P = 0.06). The mean time required to complete the neuraxial technique was 41% (95% CI, 7% 108%; P = 0.01) longer in the spinal instrumentation group than in the control group. The spinal instrumentation group also required a greater number of needle redirections, attempted interspaces, and need to switch to a more experienced provider than matched controls. CONCLUSIONS: The findings of this investigation suggest that previous surgery for scoliosis repair does not affect neuraxial labor analgesia consumption, but performance of the neuraxial technique is more difficult. Our findings suggest that neuraxial labor analgesia should be offered to parturients with previous surgery for scoliosis repair although informed consent should include a discussion of the possibility of technical difficulties and surgical anesthesia failure. PMID- 25794114 TI - Patient satisfaction in out-of-hospital emergency care: a multicentre survey. AB - BACKGROUND: There is only limited information on patient satisfaction with emergency medical services (EMS). The aim of this multicentre survey was to evaluate patient satisfaction in five out-of-hospital physician-based EMS in Austria and Switzerland. METHODS: The psychometrically tested and standardized questionnaire 'patient satisfaction in out-of-hospital emergency care' was used for this survey. The recruitment of the patients was carried out on the basis of inclusion and exclusion criteria. All questionnaires were sent together with an invitation letter and a prepaid return envelope, followed by a reminder 2 weeks later. The descriptive statistical analysis was carried out by an external organization to maintain anonymity. RESULTS: The response rate of all EMS was 46.7%. High satisfaction rates were achieved for the four quality scales 'emergency call, emergency treatment, transport and hospital admission'. A significant difference was found between the Swiss and the Austrian dispatch centres in the judgement of the call takers' social skills. Patient satisfaction with the emergency treatment, for example, reduction of pain, was high in all EMS, independent of whether the EMS is physician (Austria) or physician and emergency medical assistant based (Switzerland). Lowest satisfaction rates were found for items of social skills. CONCLUSION: Patient satisfaction in out-of hospital physician-based EMS is generally high. There is room for improvement in areas such as the social skills of dispatchers and EMS-team members and the comfort of the patients during transport. A checklist should be developed for basic articles that patients should take along to hospital and for questions on responsibilities for children, dependent people or pets. PMID- 25794115 TI - Distal femoral derotational osteotomy with external fixation for correction of excessive femoral anteversion in patients with cerebral palsy. AB - Patients with cerebral palsy (CP) disorder often develop rotational hip deformity. Increasing deformities impair already diminished walking abilities; femoral osteotomies are often performed to maintain and improve walking abilities. Fixation of osteotomies with condylar plates has been used successfully, but does not often enable immediate postoperative full weight bearing. To avoid considerable postoperative rehabilitation deficit and additional bone loss because of inactivity, a postoperative treatment with full weight-bearing, is therefore, desirable. Self-tapping Schanz screws with a unilateral external fixator crossing the knee joint providing stronger anchoring in osteopenic bone might fulfill these demands. A retrospective study was carried out on 27 ambulatory CP patients, mean age 17.5 years (range 9-22 years); 11 patients with bilateral severe intoeing deformities underwent a supracondylar femoral osteotomy between September 2008 and April 2012. All patients were allowed to bear their full weight postoperatively. The aim of this study was to describe the technique, the results of this technique, to evaluate the time required for bone healing, and the type of complications associated with a distal derotational femoral osteotomy fixed with a uniaxial external fixator crossing the knee joint. A total of 27 patients were studied [mean weight 48.8 kg (range 29.8-75 kg)]. The mean preoperative rotation included internal rotation of 69 degrees and external rotation of 17 degrees . All patients were evaluated clinically and radiographically for a minimum of 1 year after surgery. There was a significant decrease in the mean medial rotation from 69 degrees to 32 degrees (P=0.00034). The lateral rotation increased significantly from preoperative 17 degrees to postoperative 45 degrees (P=0.0011). The femoral anteversion decreased significantly from a mean of 55 degrees preoperatively to a mean 17 degrees postoperatively (P=0.030). All patients, except one, achieved solid fusion uneventfully. One patient was a 16-year-old female who had sustained a knee flexion contracture of 30 degrees because of a delay in the physiotherapy program. One 13-year-old female patient with a bilateral osteotomy had a nondisplaced fracture in her right femur after a direct trauma 2 weeks after removal of an external fixator, and was treated by a cast. Another 17-year-old male patient developed a nonunion because of loosening of two pins and achieved solid union after revision by dynamic compression plate plating. Besides four cases with superficial pin-tract infection, no other complications were documented. Minimally invasive supracondylar femoral derotational osteotomy fixed with a unilateral external fixators crossing the knee joint is a reliable procedure in CP patients. Most patients can be treated with early postoperative full weight-bearing. However, removal of the knee joint crossing fixator should be performed as early as possible to achieve a full range of motion. PMID- 25794120 TI - What is your diagnosis? Hepatic neoplasia. PMID- 25794116 TI - Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures. AB - Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders. PMID- 25794121 TI - What is your diagnosis? Cecocolic intussusception. PMID- 25794122 TI - ECG of the month. Right atrial hemangiosarcoma and intracardial thrombus. PMID- 25794123 TI - Animal behavior case of the month. Fear-induced behavior (alarm call), seasonally induced mating behavior, contact calling, boredom or lack of stimulation, and attention-seeking behavior. PMID- 25794124 TI - Pathology in practice. Moderate, chronic-active, locally extensive, proliferative, erosive, and eosinophilic dermatitis, with parakeratotic hyperkeratosis and superficial spirochetal and rod-shaped bacteria. PMID- 25794125 TI - Hemodynamic influence of acepromazine or dexmedetomidine premedication in isoflurane-anesthetized dogs. AB - OBJECTIVE: To investigate hemodynamic effects of acepromazine and dexmedetomidine premedication in dogs undergoing general anesthesia induced with propofol and maintained with isoflurane in oxygen and assess the influence of these drugs on oxygen-carrying capacity and PCV. DESIGN: Prospective, randomized crossover study. ANIMALS: 6 healthy adult dogs. PROCEDURES: Dogs received acepromazine (0.05 mg/kg [0.023 mg/lb]) or dexmedetomidine (15.0 MUg/kg [6.82 MUg/lb]) IM. Fifteen minutes later, anesthesia was induced with propofol and maintained at end tidal isoflurane concentration of 1.28% (1 minimum alveolar concentration) for 30 minutes. Hemodynamic variables were recorded at predetermined times. The experiment was repeated 48 hours later with the alternate premedication. Results were analyzed by repeated-measures ANOVA with a mixed-models procedure. RESULTS: Bradycardia, hypertension, and significant cardiac output (CO) reduction developed after dexmedetomidine premedication but improved during isoflurane anesthesia. Hypotension developed after acepromazine administration and persisted throughout the isoflurane maintenance period, but CO was maintained throughout the anesthetic period when dogs received this treatment. Oxygen delivery and consumption were not different between treatments at most time points, whereas arterial oxygen content was lower with acepromazine premedication owing to lower PCV during isoflurane anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Acepromazine exacerbated hypotension, but CO did not change in dogs anesthetized with propofol and isoflurane. Dexmedetomidine reduced CO but prevented propofol isoflurane-induced hypotension. In general, oxygen-carrying capacity and PCV were higher in dexmedetomidine-treated than in acepromazine-treated dogs anesthetized with propofol and isoflurane. PMID- 25794126 TI - Comparison of 2- and 3-category histologic grading systems for predicting the presence of metastasis at the time of initial evaluation in dogs with cutaneous mast cell tumors: 386 cases (2009-2014). AB - OBJECTIVE: To compare the Kiupel (2 categories) and Patnaik (3 categories) histologic grading systems for predicting the presence of metastasis at the time of initial examination in dogs with cutaneous mast cell tumors (MCTs). DESIGN: Retrospective case series. ANIMALS: 386 client-owned dogs with cutaneous MCTs. PROCEDURES: Medical records of dogs with newly diagnosed, histologically confirmed cutaneous MCTs that had undergone complete clinical staging were reviewed for clinical and histopathologic data. RESULTS: All Patnaik grade 1 MCTs (n = 52) were classified as Kiupel low-grade MCTs, and all Patnaik grade 3 MCTs (43) were classified as Kiupel high-grade MCTs. Of the 291 Patnaik grade 2 MCTs, 243 (83.5%) were classified as Kiupel low-grade tumors, and 48 (16.5%) were classified as Kiupel high-grade MCTs. Dogs with Patnaik grade 3 MCTs were significantly more likely to have metastases at the time of initial examination than were dogs with grade 1 or 2 MCTs (OR, 5.46), and dogs with Kiupel high-grade MCTs were significantly more likely to have metastases than were dogs with Kiupel low-grade MCTs (OR, 2.54). However, 3 of 52 (5.8%) dogs with Patnaik grade 1 tumors, 48 of 291 (16.5%) dogs with Patnaik grade 2 tumors, and 44 of 295 (14.9%) dogs with Kiupel low-grade tumors had metastatic disease. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that in dogs with cutaneous MCTs, prognostication should not rely on histologic grade alone, regardless of grading system used, but should take into account results of clinical staging. PMID- 25794127 TI - Antemortem diagnosis of hydrocephalus in two Congo African grey parrots (Psittacus erithacus erithacus) by means of computed tomography. AB - CASE DESCRIPTION: A 7-year-old and a 10-year-old Congo African grey parrot (Psittacus erithacus erithacus; parrots 1 and 2, respectively) were evaluated because of neurologic deficits. CLINICAL FINDINGS: Parrot 1 had an 8- to 9-month history of lethargy and anorexia, with a recent history of a suspected seizure. Parrot 2 had a 6-month history of decreased activity and vocalizing, with an extended history of excessive water intake; a water deprivation test ruled out diabetes insipidus, and psychogenic polydipsia was suspected. Both birds had ophthalmologic asymmetry, with anisocoria detected in parrot 1 and unilateral blindness in parrot 2. Metal gastrointestinal foreign bodies were observed on whole-body radiographs of both birds, but blood lead concentrations were below the range indicated for lead toxicosis. Findings on CT of the head were consistent with hydrocephalus in both cases. TREATMENT AND OUTCOME: Parrot 1 received supportive care and died 3 months after the diagnosis of hydrocephalus. Parrot 2 was treated with omeprazole and prednisolone for 10 days without any improvement in neurologic deficits; euthanasia was elected, and hydrocephalus was confirmed on necropsy. No underlying or concurrent disease was identified. CLINICAL RELEVANCE: Hydrocephalus should be considered a differential diagnosis for parrots evaluated because of CNS signs. Computed tomography was an excellent screening tool to diagnose hydrocephalus in these patients. Compared with MRI, CT is more frequently available and offers reduced scanning times, reduced cost, and less concern for interference from metallic foreign bodies. PMID- 25794128 TI - Cryptorchidectomy in equids: 604 cases (1977-2010). AB - OBJECTIVE: To evaluate the management of equids undergoing cryptorchidectomy at a referral hospital. DESIGN: Retrospective case series. ANIMALS: 604 client-owned equids. PROCEDURES: Medical records of all equids undergoing surgical treatment of cryptorchidism from 1977 to 2010 were retrospectively reviewed. Analyses of breed, location of retained testes, accuracy of palpation per rectum for determining the location of retained testes, surgical technique, and postoperative complications were performed. RESULTS: The most frequently affected breed was the Quarter Horse (282/604 [47%]), which was significantly overrepresented. Of the 604 equids, 90 (15%) had undergone previous surgical attempts at castration. Preoperative palpation per rectum was performed in 395/604 (65.4%) patients, and was accurate in predicting the location of the retained testes in 354/395 (89.6%). Surgeons were significantly more likely to be incorrect in determining the location of the retained testis by means of palpation per rectum in patients that had undergone a prior attempt at castration. For equids with abdominal cryptorchidism (360/604 [59.6%]), the most common surgical technique was noninvasive cryptorchidectomy (298/360 [82.8%]). In unilateral cryptorchids (521/604 [86.3%]), the 2 most common sites were left abdominal (184/521 [35.3%]) and right inguinal (148/521 [28.4%]). For bilateral retention (80/604 [13.2%]), abdominal cryptorchidism was most common (48/80 [60%]). Fever was present in 138/324 (43%) equids on the first day after surgery. Postoperative fever was not significantly associated with any variables evaluated. Including postoperative (<= 24 hours) fever, 150 of 604 (25%) patients developed postoperative complications. Excluding postoperative fever, 18 of 604 (3%) patients developed major postoperative complications; complications in 10 of 604 patients were deemed surgically related, and 3 of 604 patients died. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that cryptorchidectomy in equids performed with a variety of surgical approaches was associated with minimal postoperative complications. A history of previous attempts at castration decreased the ability to accurately predict the location of the retained testis. PMID- 25794129 TI - Bacterial isolates, antimicrobial susceptibility patterns, and factors associated with infection and outcome in foals with septic arthritis: 83 cases (1998-2013). AB - OBJECTIVE: To determine clinical characteristics, clinicopathologic data, and bacterial culture and antimicrobial susceptibility results associated with septic arthritis in foals <= 180 days old. DESIGN: Retrospective case series. ANIMALS: 83 foals with septic arthritis. PROCEDURES: Medical records at 2 teaching hospitals between 1998 and 2013 were searched to identify those for foals <= 180 days old with confirmed infection of >= 1 synovial structure. Data extracted from the records included signalment, clinicopathologic information, bacteriologic culture and antimicrobial susceptibility results, and outcome. Data were analyzed for all foals as a single population and for foals stratified into 3 age groups (<= 7 days, 8 to 30 days, and 31 to 180 days). RESULTS: Mean +/- SD age of all foals was 18.2 +/- 25 days (range, 0 to 180 days). The median number of joints affected per foal was 2 (range, 1 to 10 joints). Forty-seven of 83 (56.6%) foals survived to discharge from the hospital. Seventy antemortem synovial fluid samples underwent bacteriologic culture, of which 60 (85.7%) yielded growth. Of the 72 bacterial isolates identified, 45 (62.5%) were gram negative and 27 (375%) were gram positive. Survival rate was positively associated with plasma fibrinogen concentration and negatively associated with number of affected joints. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated the frequency with which certain bacterial agents were isolated from septic joints, which may be beneficial for the empirical treatment of septic arthritis in foals. Also, the positive association between survival rate and plasma fibrinogen concentration may have prognostic value in a clinical setting. PMID- 25794130 TI - Phase I/II study of melphalan, prednisone and lenalidomide combination for patients with newly diagnosed multiple myeloma who are not candidates for stem cell transplantation. PMID- 25794131 TI - Frequent CALR exon 9 alterations in JAK2 V617F-mutated essential thrombocythemia detected by high-resolution melting analysis. PMID- 25794133 TI - A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia. AB - Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rgammac(null) mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies. PMID- 25794132 TI - Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma. AB - Renal impairment (RI) is seen in over a quarter of patients with newly diagnosed multiple myeloma (NDMM). It is not clear if reversal of RI improves the outcome to that expected for NDMM patients without RI. We evaluated 1135 consecutive patients with NDMM seen at the Mayo Clinic between January 2003 and December 2012. RI was defined as having a creatinine clearance (CrCl) <40ml/min. The median overall survival (OS) for patients with RI at diagnosis receiving and not receiving novel agent induction therapy was not reached vs 46 months (P<0.001). The median OS for patients with CrCl ?40 ml/min at diagnosis, CrCl <40 ml/min at diagnosis but improved to ?40 ml/min and CrCl <40 ml/min at diagnosis and remained <40 ml/min, were 112, 56 and 33 months, respectively (P<0.001). The complete renal response rate for patients with RI at diagnosis receiving novel agent induction therapy compared to the rest was 40 vs 16% (P<0.001). In conclusion, patients with reversal of RI have improved outcomes, but it remains inferior to patients with normal renal function at diagnosis. These results have implications for identifying early treatment strategies for patients at risk of developing renal insufficiency. PMID- 25794134 TI - Efficacy of bortezomib and thalidomide in the recrudescent form of multicentric mixed-type Castleman's disease. PMID- 25794135 TI - BRAF V600E mutation in early-stage multiple myeloma: good response to broad acting drugs and no relation to prognosis. AB - In this study, we analyzed the prevalence and clone size of BRAF V600E mutation in 209 patients with multiple myeloma and related the results to clinical phenotype, response and survival. Biopsies were screened for BRAF V600E by allele specific real-time PCR (AS-PCR). Positive results were confirmed by immunohistochemistry, Sanger sequencing and, in three patients from whom we had stored purified myeloma cells, whole-exome sequencing. Eleven patients (5.3%) were BRAF V600E mutation positive by AS-PCR and at least one other method. The fraction of mutated cells varied from 4 to 100%. BRAF V600E-positive patients had no characteristic clinical phenotype except for significantly higher levels of serum creatinine (125 versus 86 MUmol/l) Seven of eleven patients responded with at least very good partial response to alkylators, immunomodulatory agents or proteasome inhibitors. Progression-free and overall survival were similar in patients with and without the mutation. By this integrated approach, we found that patients with BRAF V600E mutation responded very well to broad acting drugs and there was no relation to prognosis in early-stage myeloma. In particular, a large mutated cell fraction did not correlate with aggressive disease. PMID- 25794136 TI - Capgras syndrome in a very late onset, treatment resistant schizophrenia. AB - We report a Malay man, with underlying chronic medical illnesses, presenting with positive symptoms of schizophrenia, including Capgras syndrome (CS) at the age of 73. Physical examination and blood investigations were normal and brain CT scan showed age-related cerebral atrophy. Neuropsychological assessment showed probable right hemisphere lesions but relatively intact memory and intellectual functions. Several neuroleptics including depot injections were tried but ineffective. Positive symptoms including CS eventually improved with clozapine before his death from myocardial infarction. This case report highlights the uncommon occurrence of CS in treatment resistant schizophrenia (TRS) of very late onset and its treatment challenges. PMID- 25794137 TI - A New Panel of Blood Biomarkers for the Diagnosis of Mild Traumatic Brain Injury/Concussion in Adults. AB - No routine tests currently exist to objectively diagnose mild traumatic brain injury (mTBI)/concussion. Previously reported biomarkers for mTBI represented proteins released from damaged neurons or glia. However, low levels of these proteins, and/or the complexity of assays used for their detection, limits implementation of these biomarkers in routine practice. Here, we sought to identify proteins whose synthesis is altered post-mTBI and whose blood levels could be measured using standard immunoassays. Adult patients sustaining a concussion within the past 24 h were enrolled. Controls were uninjured subjects and patients with orthopedic injury (OI). Four candidate biomarkers were identified: copeptin; galectin 3 (LGALS3); matrix metalloproteinase 9 (MMP9); and occludin (OCLN). A 3.4-fold decrease (p<0.0001) in plasma concentration of copeptin was found in mTBI patients within 8 h after accident, compared to uninjured controls. Plasma levels of LGALS3, MMP9, and OCLN increased 3.6- to 4.5 fold (p<0.0001) within the same time frame postinjury. Levels of at least two biomarkers were altered beyond their respective cut-off values in 90% of mTBI patients, whereas in none of uninjured controls were levels of two biomarkers simultaneously changed. A positive correlation (r=0.681; p<0.001) between plasma levels of LGALS3 and OCLN was also found in mTBI patients, whereas in OI patients or uninjured subjects, these variables did not correlate. This panel of biomarkers discerns, with high accuracy, patients with isolated concussion from uninjured individuals within the first 8 h after accident. These biomarkers can also aid in diagnosing concussion in the presence of OI. PMID- 25794138 TI - Correlates and Barriers Associated with Motorcycle Helmet Use in Wa, Ghana. AB - OBJECTIVE: This study was conducted to investigate the correlates and barriers to helmet use among motorcycle riders in Wa, a motorcycle-predominant town in Ghana. An additional objective was to determine the association between helmet use and riders' knowledge, attitudes, and beliefs toward helmets. METHODS: Cross sectional surveys including both observation of helmet use and interviews were conducted among motorcycle riders at 6 randomly selected fuel stations and 4 motorcycle service centers within and outside the Central Business District of Wa. Questions covered riders' sociodemographic and riding characteristics, helmet use, reasons for use or nonuse of helmets, and knowledge, attitudes, and beliefs about helmets. Analyses were based on frequencies and testing of strength of association using adjusted odds ratios (with 95% confidence intervals) in binary logistic regression. RESULTS: The prevalence of helmet use among the 271 sampled riders was 46% (95% confidence interval [CI], 40.2-52.0). Gender, age, marital status, and occupation were significant sociodemographic correlates of helmet use in Wa. Compared to currently married riders, unmarried riders were 5 times less likely to use a helmet. No significant association existed between riders' educational attainment and helmet use. Helmet use was also positively correlated with helmet ownership and license holding. The leading reasons stated for helmet nonuse among nonusers were not traveling a long distance and helmets block vision and hearing. Protection from injury, legal requirement, and coping with the police for fear of being accosted for helmet nonuse were identified as common reasons for helmet use. Positive attitudes and beliefs were also significantly correlated with helmet use. CONCLUSIONS: Despite the existence of a legislation mandating the use of helmets on all roads as well as the high level of awareness among riders on this legislation and the benefits of helmets, the incidence of helmet use among motorists continue to be low in Wa, Ghana. This means that efforts to identify strategies to increase helmet use need to continue. The evidence provided by this study suggests that stakeholders in road safety need to put in interventions to ensure a rigorous enforcement of the helmet use legislation and improvement in helmet design. These should be combined with the development of targeted educational programs with the aim of changing unfavorable attitudes and beliefs toward helmet use. PMID- 25794139 TI - CAPER 3.0: A Scalable Cloud-Based System for Data-Intensive Analysis of Chromosome-Centric Human Proteome Project Data Sets. AB - The Chromosome-centric Human Proteome Project (C-HPP) aims to catalog genome encoded proteins using a chromosome-by-chromosome strategy. As the C-HPP proceeds, the increasing requirement for data-intensive analysis of the MS/MS data poses a challenge to the proteomic community, especially small laboratories lacking computational infrastructure. To address this challenge, we have updated the previous CAPER browser into a higher version, CAPER 3.0, which is a scalable cloud-based system for data-intensive analysis of C-HPP data sets. CAPER 3.0 uses cloud computing technology to facilitate MS/MS-based peptide identification. In particular, it can use both public and private cloud, facilitating the analysis of C-HPP data sets. CAPER 3.0 provides a graphical user interface (GUI) to help users transfer data, configure jobs, track progress, and visualize the results comprehensively. These features enable users without programming expertise to easily conduct data-intensive analysis using CAPER 3.0. Here, we illustrate the usage of CAPER 3.0 with four specific mass spectral data-intensive problems: detecting novel peptides, identifying single amino acid variants (SAVs) derived from known missense mutations, identifying sample-specific SAVs, and identifying exon-skipping events. CAPER 3.0 is available at http://prodigy.bprc.ac.cn/caper3. PMID- 25794140 TI - ASR1 transcription factor and its role in metabolism. AB - Asr1 (ABA, stress, ripening) is a plant gene widely distributed in many species which was discovered by differential induction levels in tomato plants subjected to drought stress conditions. ASR1 also regulates the expression of a hexose transporter in grape and is involved in sugar and amino acid accumulation in some species like maize and potato. The control that ASR1 exerts on hexose transport is interesting from a biotechnological perspective because both sugar partitioning and content in specific organs affect the yield and the quality of many agronomically important crops. ASR1 affect plant metabolism by its dual activity as a transcription factor and as a chaperone-like protein. In this paper, we review possible mechanisms by which ASR1 affects metabolism, the differences observed among tissues and species, and the possible physiological implications of its role in metabolism. PMID- 25794142 TI - Comparison of sample types and analytical methods for the detection of highly campylobacter-colonized broiler flocks at different stages in the poultry meat production chain. AB - Exclusion of broiler batches, highly colonized with Campylobacter (>7.5 log10 colony-forming units/g), from the fresh poultry meat market might decrease the risk of human campylobacteriosis. The objective of this study was to compare different sample types (both at the farm and the slaughterhouse) and methods (direct culture, quantitative real-time polymerase chain reaction [qPCR], propidium monoazide [PMA]-qPCR) applied for the quantification of the Campylobacter colonization level. In addition, the applicability of the lateral flow-based immunoassay, Singlepath((r)) Direct Campy Poultry test (Singlepath((r)) test), was evaluated as a rapid method for the qualitative detection of Campylobacter in highly colonized broiler batches. Campylobacter counts differed significantly between sample types collected at farm level (cecal droppings, feces, boot swabs) and at slaughterhouse level (cecal content, fecal material from crates). Furthermore, comparison of Campylobacter counts obtained by different methods (direct culture, qPCR, PMA-qPCR) in cecal droppings revealed significant differences, although this was not observed for cecal-content samples. Evaluation of the Singlepath((r)) test on cecal droppings and cecal content samples revealed an acceptable level of sensitivity and specificity. In conclusion, cecal droppings and cecal content are proposed as the most representative sample types for quantification of Campylobacter colonization level of broilers at farm and slaughterhouse, respectively. Direct culture and qPCR are equally sensitive for quantification of Campylobacter in fresh cecal content samples. PMA treatment before qPCR inhibits the signal from dead Campylobacter cells. Consequently, when samples are extensively stored and/or transported, qPCR is preferred to direct culture and PMA-qPCR. Furthermore, the Singlepath((r)) test offers a convenient alternative method for rapid detection of Campylobacter in highly colonized broiler batches. PMID- 25794141 TI - Monoaminylation of Fibrinogen and Glia-Derived Proteins: Indication for Similar Mechanisms in Posttranslational Protein Modification in Blood and Brain. AB - Distinct proteins have been demonstrated to be posttranslationally modified by covalent transamidation of serotonin (5-hydropxytryptamin) to glutamine residues of the target proteins. This process is mediated by transglutaminase (TGase) and has been termed "serotonylation." It has also been shown that other biogenic amines, including the neurotransmitters dopamine and norepinephrine, can substitute for serotonin, implying a more general mechanism of "monoaminylation" for this kind of protein modification. Here we transamidated the autofluorescent monoamine monodansylcadaverine (MDC) to purified plasma fibrinogen and to proteins from a primary glia cell culture. Electrophoretic separation of MDC conjugated proteins followed by mass spectrometry identified three fibrinogen subunits (Aalpha, Bbeta, gamma), a homomeric Aalpha2 dimer, and adducts of >250 kDa molecular weight, as well as several glial proteins. TGase-mediated MDC incorporation was strongly reduced by serotonin, underlining the general mechanism of monoaminylation. PMID- 25794143 TI - Photoactivatable BODIPYs designed to monitor the dynamics of supramolecular nanocarriers. AB - Self-assembling nanoparticles of amphiphilic polymers can transport hydrophobic molecules across hydrophilic media and, as a result, can be valuable delivery vehicles for a diversity of biomedical applications. Strategies to monitor their dynamics noninvasively and in real time are, therefore, essential to investigate their translocation within soft matrices and, possibly, rationalize the mechanisms responsible for their diffusion in biological media. In this context, we designed molecular guests with photoactivatable fluorescence for these supramolecular hosts and demonstrated that the activation of the fluorescent cargo, under optical control, permits the tracking of the nanocarrier translocation across hydrogel matrices with the sequential acquisition of fluorescence images. In addition, the mild illumination conditions sufficient to implement these operating principles permit fluorescence activation within developing Drosophila melanogaster embryos and enable the monitoring of the loaded nanocarriers for long periods of time with no cytotoxic effects and no noticeable influence on embryogenesis. These photoresponsive compounds combine a borondipyrromethene (BODIPY) chromophore and a photocleavable oxazine within their covalent skeleton. Under illumination at an appropriate activation wavelength, the oxazine ring cleaves irreversibly to bring the adjacent BODIPY fragment in conjugation with an indole heterocycle. This structural transformation shifts bathochromically the BODIPY absorption and permits the selective excitation of the photochemical product with concomitant fluorescence. In fact, these operating principles allow the photoactivation of BODIPY fluorescence with large brightness and infinite contrast. Thus, our innovative structural design translates into activatable fluorophores with excellent photochemical and photophysical properties as well as provides access to a general mechanism for the real-time tracking of supramolecular nanocarriers in hydrophilic matrices. PMID- 25794144 TI - Carbapenem-nonsusceptible Enterobacteriaceae in Taiwan. AB - A total of 1135 carbapenem-resistant (nonsusceptible) Enterobacteriaceae (CRE) isolates were recovered between November 2010 and July 2012 (517 from 2010-2011 and 618 from 2012) from 4 hospitals in Taiwan. Carbapenemase-producing Enterobacteriaceae (CPE) comprised 5.0% (57 isolates), including 17 KPC-2 (16 Klebsiella pneumoniae and 1 Escherichia coli), 1 NDM-1 (K. oxytoca), 37 IMP-8 (26 Enterobacter cloacae, 4 Citrobacter freundii, 4 Raoultella planticola, 1 K. pneumoniae, 1 E. coli and 1 K. oxytoca), and 2 VIM-1 (1 E. cloacae, 1 E. coli). The KPC-2-positive K. pneumoniae were highly clonal even in isolates from different hospitals, and all were ST11. IMP-8 positive E. cloacae from the same hospitals showed higher similarity in PFGE pattern than those from different hospitals. A total of 518 CRE isolates (45.6%) were positive for blaESBL, while 704 (62.0%) isolates were blaAmpC-positive, 382 (33.6% overall) of which carried both blaESBL and blaAmpC. CTX-M (414, 80.0%) was the most common blaESBL, while DHA (497, 70.6%) and CMY (157, 22.3%) were the most common blaAmpC. Co-carriage of blaESBL and blaAmpC was detected in 31 (54.4%) and 15 (26.3%) of the 57 CPE, respectively. KPC-2 was the most common carbapenemase detected in K. pneumoniae (2.8%), while IMP-8 was the most common in E. cloacae (9.7%). All KPC-2-positive CRE were resistant to all three tested carbapenems. However, fourteen of the 37 IMP-8-positive CRE were susceptible to both imipenem and meropenem in vitro. Intra- and inter-hospital spread of KPC-2-producing K. pneumoniae and IMP-8 producing E. cloacae likely occurred. Although the prevalence of CPE is still low, careful monitoring is urgently needed. Non-susceptibility to ertapenem might need to be considered as one criterion of definition for CRE in areas where IMP type carbapenemase is prevalent. PMID- 25794145 TI - Enrichment of Genetic Variants for Rheumatoid Arthritis within T-Cell and NK-Cell Enhancer Regions. AB - To identify disease-causative variants, we intersected the published results of a metaanalysis of genome-wide association studies (GWAS) for rheumatoid arthritis (RA) with the set of enhancer regions for 71 primary cell types that was provided by the FANTOM consortium. We first retrieved all single nucleotide polymorphisms (SNPs) that are associated (P < 5 * 10(8)) with RA in the GWAS meta-analysis and that are located in any of these enhancer regions. After excluding the major histocompatibility complex (MHC) region, we identified 50 such RA-associated SNPs that are located in enhancer regions. Enhancer sets from different cell types were then compared with each other for their number of RA-associated SNPs by permutation analysis. This analysis showed that RA-associated SNPs are preferentially located in enhancers from several immunological cell types. In particular, we see a strong relative enrichment in enhancer regions that are active in T cells (P < 0.001) and NK cells (P < 0.001). Several loci display multiple RA-associated SNPs in tight linkage disequilibrium that are located within the same or neighboring enhancers. These haplotypes may have a greater likelihood to influence enhancer activity than any SNP on its own. Taken together, these results support the hypothesis that RA-causative variants often act through altering the activity of immune cell enhancers. The enrichment in T cell and NK-cell enhancer regions indicates that expression changes in these cell types are particularly relevant for the pathogenesis of RA. The specific SNPs that account for this enrichment can be used as a basis for focused genotype phenotype studies of these cell types. PMID- 25794146 TI - Phylogenomic analyses of Echinodermata support the sister groups of Asterozoa and Echinozoa. AB - Echinoderms (sea urchins, sea stars, brittle stars, sea lilies and sea cucumbers) are a group of diverse organisms, second in number within deuterostome species to only the chordates. Echinoderms serve as excellent model systems for developmental biology due to their diverse developmental mechanisms, tractable laboratory use, and close phylogenetic distance to chordates. In addition, echinoderms are very well represented in the fossil record, including some larval features, making echinoderms a valuable system for studying evolutionary development. The internal relationships of Echinodermata have not been consistently supported across phylogenetic analyses, however, and this has hindered the study of other aspects of their biology. In order to test echinoderm phylogenetic relationships, we sequenced 23 de novo transcriptomes from all five clades of echinoderms. Using multiple phylogenetic methods at a variety of sampling depths we have constructed a well-supported phylogenetic tree of Echinodermata, including support for the sister groups of Asterozoa (sea stars and brittle stars) and Echinozoa (sea urchins and sea cucumbers). These results will help inform developmental and evolutionary studies specifically in echinoderms and deuterostomes in general. PMID- 25794147 TI - Association between free testosterone levels and anal human papillomavirus types 16/18 infections in a cohort of men who have sex with men. AB - BACKGROUND: Human papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown. METHODS: Free testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing. RESULTS: Participants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence=17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/18 infection in unadjusted and adjusted analyses. CONCLUSIONS: Higher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study. PMID- 25794148 TI - Intentional weight loss and all-cause mortality: a meta-analysis of randomized clinical trials. AB - BACKGROUND: Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality. METHODS: 2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of >=18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials. RESULTS: Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5+/-4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73-1.00). There was no evidence for heterogeneity of effect (Cochran's Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization >=55 years (RR = 0.84; 95% CI 0.71-0.99) and a follow-up time of >=4 years (RR = 0.85; 95% CI 0.72-1.00). CONCLUSIONS: In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality. PMID- 25794149 TI - Heat-modified citrus pectin induces apoptosis-like cell death and autophagy in HepG2 and A549 cancer cells. AB - Cancer is still one of the leading causes of death worldwide, and finding new treatments remains a major challenge. Previous studies showed that modified forms of pectin, a complex polysaccharide present in the primary plant cell wall, possess anticancer properties. Nevertheless, the mechanism of action of modified pectin and the pathways involved are unclear. Here, we show that citrus pectin modified by heat treatment induced cell death in HepG2 and A549 cells. The induced cell death differs from classical apoptosis because no DNA cleavage was observed. In addition, Z-VAD-fmk, a pan-caspase inhibitor, did not influence the observed cell death in HepG2 cells but appeared to be partly protective in A549 cells, indicating that heat-modified citrus pectin might induce caspase independent cell death. An increase in the abundance of the phosphatidylethanolamine-conjugated Light Chain 3 (LC3) protein and a decrease in p62 protein abundance were observed in both cell types when incubated in the presence of heat-modified citrus pectin. These results indicate the activation of autophagy. To our knowledge, this is the first time that autophagy has been revealed in cells incubated in the presence of a modified form of pectin. This autophagy activation appears to be protective, at least for A549 cells, because its inhibition with 3-methyladenine increased the observed modified pectin induced cytotoxicity. This study confirms the potential of modified pectin to improve chemotherapeutic cancer treatments. PMID- 25794150 TI - Accounting for limited detection efficiency and localization precision in cluster analysis in single molecule localization microscopy. AB - Single Molecule Localization Microscopy techniques like PhotoActivated Localization Microscopy, with their sub-diffraction limit spatial resolution, have been popularly used to characterize the spatial organization of membrane proteins, by means of quantitative cluster analysis. However, such quantitative studies remain challenged by the techniques' inherent sources of errors such as a limited detection efficiency of less than 60%, due to incomplete photo conversion, and a limited localization precision in the range of 10-30 nm, varying across the detected molecules, mainly depending on the number of photons collected from each. We provide analytical methods to estimate the effect of these errors in cluster analysis and to correct for them. These methods, based on the Ripley's L(r) - r or Pair Correlation Function popularly used by the community, can facilitate potentially breakthrough results in quantitative biology by providing a more accurate and precise quantification of protein spatial organization. PMID- 25794152 TI - A census of nuclear cyanobacterial recruits in the plant kingdom. AB - The plastids and mitochondria of the eukaryotic cell are of endosymbiotic origin. These events occurred ~2 billion years ago and produced significant changes in the genomes of the host and the endosymbiont. Previous studies demonstrated that the invasion of land affected plastids and mitochondria differently and that the paths of mitochondrial integration differed between animals and plants. Other studies examined the reasons why a set of proteins remained encoded in the organelles and were not transferred to the nuclear genome. However, our understanding of the functional relations of the transferred genes is insufficient. In this paper, we report a high-throughput phylogenetic analysis to identify genes of cyanobacterial origin for plants of different levels of complexity: Arabidopsis thaliana, Chlamydomonas reinhardtii, Physcomitrella patens, Populus trichocarpa, Selaginella moellendorffii, Sorghum bicolor, Oryza sativa, and Ostreococcus tauri. Thus, a census of cyanobacterial gene recruits and a study of their function are presented to better understand the functional aspects of plastid symbiogenesis. From algae to angiosperms, the GO terms demonstrated a gradual expansion over functionally related genes in the nuclear genome, beginning with genes related to thylakoids and photosynthesis, followed by genes involved in metabolism, and finally with regulation-related genes, primarily in angiosperms. The results demonstrate that DNA is supplied to the nuclear genome on a permanent basis with no regard to function, and only what is needed is kept, which thereby expands on the GO space along the related genes. PMID- 25794151 TI - Association between the ENPP1 K121Q polymorphism and risk of diabetic kidney disease: a systematic review and meta-analysis. AB - The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I2 < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27 2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations. PMID- 25794153 TI - Structure determination of feline calicivirus virus-like particles in the context of a pseudo-octahedral arrangement. AB - The vesivirus feline calicivirus (FCV) is a positive strand RNA virus encapsidated by an icosahedral T=3 shell formed by the viral VP1 protein. Upon its expression in the insect cell - baculovirus system in the context of vaccine development, two types of virus-like particles (VLPs) were formed, a majority built of 60 subunits (T=1) and a minority probably built of 180 subunits (T=3). The structure of the small particles was determined by x-ray crystallography at 0.8 nm resolution helped by cryo-electron microscopy in order to understand their formation. Cubic crystals belonged to space group P213. Their self-rotation function showed the presence of an octahedral pseudo-symmetry similar to the one described previously by Agerbandje and co-workers for human parvovirus VLPs. The crystal structure could be solved starting from the published VP1 structure in the context of the T=3 viral capsid. In contrast to viral capsids, where the capsomers are interlocked by the exchange of the N-terminal arm (NTA) domain, this domain is disordered in the T=1 capsid of the VLPs. Furthermore it is prone to proteolytic cleavage. The relative orientation of P (protrusion) and S (shell) domains is alerted so as to fit VP1 to the smaller T=1 particle whereas the intermolecular contacts around 2-fold, 3-fold and 5-fold axes are conserved. By consequence the surface of the VLP is very similar compared to the viral capsid and suggests a similar antigenicity. The knowledge of the structure of the VLPs will help to improve their stability, in respect to a use for vaccination. PMID- 25794155 TI - Fire in the Plio-Pleistocene: the functions of hominin fire use, and the mechanistic, developmental and evolutionary consequences. AB - Fire is a powerful natural force that can change landscapes extremely quickly. Hominins have harnessed this resource for their own purposes, with mechanistic and developmental physiological consequences. In addition, the use of fire has niche constructive effects, altering selective environments for genetic and cultural evolution. We review the record for hominin fire use in the Plio Pleistocene, before considering the various functions for its use, and the resultant mechanistic and developmental consequences. We also adopt the niche construction framework to consider how the use of fire can modify selective environments, and thus have evolutionary consequences at genetic and cultural levels. The light that fire produces may influence photoperiodicity and alter hormonally-controlled bodily rhythms. Fire used for cooking could have extended the range of foods hominins were able to consume, and reduced digestion costs. This may have contributed to the expansion of the hominin brain and facial anatomy, influenced by a higher quality cooked diet. Fire may also have allowed dispersal into northern areas with much cooler climates than the hominin African origin, posing novel problems that affected diet and social behaviour. PMID- 25794154 TI - Protein domain-level landscape of cancer-type-specific somatic mutations. AB - Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level. PMID- 25794156 TI - Serum uric acid and subsequent cognitive performance in patients with pre existing cardiovascular disease. AB - High serum uric acid (UA) levels are associated with numerous vascular risk factors, and vascular disease, that predispose patients to cognitive impairment, yet UA is also a major natural antioxidant and higher levels have been linked to slower progression of several neurodegenerative disease. In-order to test the association between UA and subsequent cognitive performance among patients that carry a high vascular burden, UA levels were determined by calorimetric enzymatic tests in a sub-cohort of patients with chronic cardiovascular disease who previously participating in a secondary prevention trial. After an average of 9.8+/-1.7 years, we assessed cognitive performance (Neurotrax Computerized Cognitive Battery) as well as cerebrovascular reactivity (CVR) and common carotid intima-media thickness (IMT). Among 446 men (mean age 62.3+/-6.4 yrs) mean UA levels were 5.8+/-1.1 mg/dL. Adjusted linear regression models revealed that low UA levels (bottom quintile) were associated with poorer cognitive performance. Adjusted differences between the bottom quintile and grouped top UA quintiles were (B coefficient+/-SE) -4.23+/-1.28 for global cognitive scores (p = 0.001), 4.69+/-1.81 for memory scores (p = 0.010), -3.32+/-1.43 for executive scores (p = 0.020) and -3.43+/-1.97 for visual spatial scores (p = 0.082). Significant difference was also found for attention scores (p = 0.015). Additional adjustment for impaired CVR and high common carotid IMT slightly attenuated the relationship. Stronger UA effect on cognitive performance was found for older (age>65) patients with significant age interaction for global cognitive score (p = 0.016) and for executive (p = 0.018) and attention domains (p<0.001). In conclusion, we demonstrate that low UA levels in patients with preexisting cardiovascular disease are associated with poorer cognitive function a decade later. These findings lend support to the hypothesis that oxidative stress may be involved in the pathogenesis of age-associated cognitive impairment. PMID- 25794158 TI - Transponder-aided joint calibration and synchronization compensation for distributed radar systems. AB - High-precision radiometric calibration and synchronization compensation must be provided for distributed radar system due to separate transmitters and receivers. This paper proposes a transponder-aided joint radiometric calibration, motion compensation and synchronization for distributed radar remote sensing. As the transponder signal can be separated from the normal radar returns, it is used to calibrate the distributed radar for radiometry. Meanwhile, the distributed radar motion compensation and synchronization compensation algorithms are presented by utilizing the transponder signals. This method requires no hardware modifications to both the normal radar transmitter and receiver and no change to the operating pulse repetition frequency (PRF). The distributed radar radiometric calibration and synchronization compensation require only one transponder, but the motion compensation requires six transponders because there are six independent variables in the distributed radar geometry. Furthermore, a maximum likelihood method is used to estimate the transponder signal parameters. The proposed methods are verified by simulation results. PMID- 25794157 TI - Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells. AB - WT1 is a transcription factor expressed in hematopoietic stem cells and in most cases of myeloid leukemia. We investigated the roles of hypoxia and epigenetics in the regulation of WT1 expression in myeloid leukemia cells. WT1 expression correlates with hypomethylation of the CpG island in Intron 1, and pharmacologic demethylation of this CpG island induces WT1 mRNA expression. Hypoxia causes decreases in DNMT expression and activity and increased expression and activity of TET2 and TET3, resulting in demethylation of this CpG island and expression of WT1 mRNA. Demethylation of the CpG island, either from pharmacologic treatment or induction of hypoxia, results in transcription of an antisense-oriented lncRNA, and inhibiting lncRNA expression with shRNA blocks WT1 mRNA expression. These results reveal a novel model of hypoxia-mediated epigenetic gene regulation. In addition, this is the first report that TET2 and TET3, increasingly recognized as important epigenetic regulators of gene expression in stem cells and in cancer cells, can be regulated by hypoxia, providing a solid mechanistic link between hypoxia and epigenetic regulation of gene expression with important implications for the role of hypoxia in stem cell function. PMID- 25794159 TI - Isometric arm strength and subjective rating of upper limb fatigue in two-handed carrying tasks. AB - Sustained carrying could result in muscular fatigue of the upper limb. Ten male and ten female subjects were recruited for measurements of isometric arm strength before and during carrying a load for a period of 4 minutes. Two levels of load of carrying were tested for each of the male and female subjects. Exponential function based predictive equations for the isometric arm strength were established. The mean absolute deviations of these models in predicting the isometric arm strength were in the range of 3.24 to 17.34 N. Regression analyses between the subjective ratings of upper limb fatigue and force change index (FCI) for the carrying were also performed. The results indicated that the subjective rating of muscular fatigue may be estimated by multiplying the FCI with a constant. The FCI may, therefore, be adopted as an index to assess muscular fatigue for two-handed carrying tasks. PMID- 25794160 TI - AP-1 Transcription Factors c-FOS and c-JUN Mediate GnRH-Induced Cadherin-11 Expression and Trophoblast Cell Invasion. AB - GnRH is expressed in first-trimester human placenta and increases cell invasion in extravillous cytotrophoblasts (EVTs). Invasive phenotypes have been reported to be regulated by transcription factor activator protein 1 (AP-1) and mesenchymal cadherin-11. The aim of our study was to investigate the roles of AP 1 components (c-FOS/c-JUN) and cadherin-11 in GnRH-induced cell invasion in human EVT cells. Phosphorylated c-FOS and phosphorylated c-JUN were detected in the cell column regions of human first-trimester placental villi by immunohistochemistry. GnRH treatment increased c-FOS, c-JUN, and cadherin-11 mRNA and protein levels in immortalized EVT (HTR-8/SVneo) cells. Moreover, GnRH treatment induced c-FOS and c-JUN protein phosphorylation and nuclear accumulation. Pretreatment with antide, a GnRH antagonist, attenuated GnRH induced cadherin-11 expression. Importantly, basal and GnRH-induced cadherin-11 expression and cell invasion were reduced by small interfering RNA-mediated knockdown of c-FOS, c-JUN, and cadherin-11 in HTR-8/SVneo cells. Our results suggest that GnRH induces the expression and phosphorylation of the AP-1 transcription factors c-FOS and c-JUN in trophoblast cells, which contributes to GnRH-induced elevation of cadherin-11 expression and cell invasion. PMID- 25794162 TI - The Cw6 and late-cornified envelope genotype plays a significant role in anti tumor necrosis factor response among psoriatic patients. AB - Our aim was to determine whether the HLA-Cw6 and late-cornified envelope (LCE) deletion polymorphisms were related to disease improvement among psoriasis patients treated with anti-tumor necrosis factor (TNF) antibodies. The study included a total of 116 patients. Positive response (68%) was defined as a reduction of at least 75% of the Psoriasis Area and Severity Index (PASI) after 24 weeks of starting the anti-TNF therapy. We found a trend toward a better response among Cw6-positive patients. The frequency of patients who did not reach the PASI75 was higher among the LCE-DD patients (P=0.028; odds ratio=2.45, 95% confidence interval=1.09-5.52). Patients who were Cw6-positive and LCE-I carriers (ID/II) were significantly more likely to reach PASI75 than those who were Cw6 negative and LCE-DD (P=0.034; odds ratio=3.14, 95% confidence interval=1.07 9.24). In conclusion, we found an interaction between the HLA-Cw6 and LCE genotypes on disease improvement among psoriatic patients treated with anti-TNFs. PMID- 25794161 TI - Genetic and phenotypic variation in UGT2B17, a testosterone-metabolizing enzyme, is associated with BMI in males. AB - OBJECTIVE: A number of candidate gene and genome-wide association studies have identified significant associations between single nucleotide polymorphisms, particularly in FTO and MC4R, and body weight. However, the association between copy number variation and body weight is less understood. Anabolic androgenic steroids, such as testosterone, can regulate body weight. In humans, UDP glucuronosyltransferase 2B17 (UGT2B17) metabolizes testosterone to a metabolite, which is readily excreted in urine. We investigate the association between genetic and phenotypic variation in UGT2B17 and body weight. MATERIALS AND METHODS: UGT2B17 deletion was genotyped and in-vivo UGT2B17 enzymatic activity (as measured by the 3-hydroxycotinine glucuronide to free 3-hydroxycotinine ratio) was measured in 400 Alaska Native individuals and 540 African Americans. RESULTS: In Alaska Native people, UGT2B17 deletion was strongly associated with lower BMI in male individuals (P<0.001), but not in female individuals, consistent with testosterone being a male dominant steroid. The sex-specific association between UGT2B17 deletion and lower BMI was also observed in African Americans (P=0.01 in male individuals). In both populations, UGT2B17 deletion was significantly associated with lower measured in-vivo UGT2B17 activity. In male individuals, lower in-vivo UGT2B17 activity was associated with lower BMI, as observed in the sex-specific genotypic association. CONCLUSION: These data suggest that UGT2B17 deletion leads to reduced UGT2B17 activity, and lower BMI in male individuals. This is consistent with the hypothesis that reduced UGT2B17 mediated testosterone excretion results in higher testosterone levels. Future studies could confirm this hypothesis by directly measuring serum testosterone levels. PMID- 25794163 TI - Effect of cytomegalovirus co-infection on normalization of selected T-cell subsets in children with perinatally acquired HIV infection treated with combination antiretroviral therapy. AB - BACKGROUND: We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children >= 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART) algorithm study. METHODS: Participants were categorized as CMV-naive, CMV positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naive (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28 ) CD4+ and CD8+ T-cells were measured by flow cytometry. RESULTS: Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naive. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naive status was significantly associated with faster recovery of CD8+CD62L+CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T cell subsets. CONCLUSIONS: In this cohort of PHIV+ children, the normalization of naive and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system. PMID- 25794164 TI - Characterization of monoclonal gammopathy of undetermined significance by calorimetric analysis of blood serum proteome. AB - Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant proliferative disorder that may progress to multiple myeloma, a malignant plasma cell neoplasia. We evaluated differential scanning calorimetry (DSC) as an experimental tool for differentiating serum samples of MGUS patients from healthy individuals. DSC thermograms can be used for monitoring changes in the serum proteome associated with MGUS. MGUS patients showed great variability in serum thermogram characteristics, which depended on the IgG, IgA or IgM isotypes and/or the kappa or lambda light chains. Thermogram feature parameters distinguished patients with MGUS from healthy people. Serum samples, named as non-MGUS, were also collected from patients with subjacent immunological pathologies who were discarded of having MGUS through serum immunofixation. They were used to verify the sensitivity of DSC for discriminating MGUS from related blood dyscrasias. Only some DSC thermogram feature parameters differentiated, to a lesser extent, between MGUS and non-MGUS individuals. We contemplate DSC as a tool for early diagnosis and monitoring of MGUS. PMID- 25794166 TI - Manganite-based memristive heterojunction with tunable non-linear I-V characteristics. AB - A resistive random access memory (ReRAM) based on the memristive effect allows high-density integration through a cross-point array (CPA) structure. However, a significant common drawback of the CPA configuration is the crosstalk between cells. Here, we introduce a solution based on a novel heterojunction stack solely made of members of the perovskite manganite family Pr(1-x)Ca(x)MnO3 (PCMO) and CaMnO(3-delta) (CMO) which show electroforming-free bipolar resistive switching. The heterojunction consists of rectifying interfaces and shows a symmetrical and tunable non-linear current-voltage curve. The spectromicroscopic measurements support the scenario of specialized roles, with the memristive effect taking place at the active Al-PCMO interface via a redox mechanism, while non-linearity was achieved by adopting a rectifying double interface PCMO-CMO-PCMO. PMID- 25794165 TI - Activation of AMPK improves lipopolysaccharide-induced dysfunction of the blood brain barrier in mice. AB - PRIMARY OBJECTIVE: Lipopolysaccharide (LPS) is known to alter the integrity of the blood-brain barrier (BBB) in sepsis, although the underlying mechanism remains unknown. The aim of this study was to elucidate the molecular mechanisms underlying disruption of the BBB in LPS-induced sepsis. RESEARCH DESIGN: Both in vitro and in vivo experiments were designed to test the role of AMP-activated protein kinase (AMPK) in LPS-induced BBB dysfunction. METHODS AND PROCEDURES: Human brain microvascular endothelial cells (HBMECs) were cultured. The protein expressions were detected by western blot. BBB integrity was determined by Evans Blue. MAIN OUTCOMES AND RESULTS: LPS (1 MUg ml(-1)) dramatically increased the permeability of the BBB and the ROS productions, as well as reducing the expression levels of occludin and claudin-5 in cultured HBMECs. Inhibition of NAD(P)H oxidase by apocynin or up-regulation of AMPK reversed the LPS-induced abnormities in HBMECs. In LPS-induced sepsis in mice, it was found that LPS dramatically increased NAD(P)H oxidase protein expressions and ROS productions in the brain and disrupted BBB function assayed by Evans blue staining, which were abolished by AICAR treatment. CONCLUSIONS: It is concluded that AMPK activation improves the functions of the BBB impaired by LPS through suppression of NAD(P)H oxidase-derived ROS in mice. PMID- 25794167 TI - TLR7 influences germinal center selection in murine SLE. AB - TLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain transgene 3H9 that encodes for the TLR7 regulated anti-CL response. To create a physiologic setting in which autoreactive B cells compete for survival with non-autoreactive B cells, we generated bone marrow chimeras in which disease onset occurred with similar kinetics and the transferred 3H9+ female non-Yaa, male Yaa or male TLR7( /Yaa) cells could be easily identified by positivity for GFP. Deletion of 3H9 B cells occurred in the bone marrow and the remaining 3H9 follicular B cells manifested a decrease in surface IgM. Although there were differences in the naive repertoire between the chimeras it was not possible to distinguish a clear pattern of selection against lupus related autoreactivity in TLR7(-/Yaa) or female chimeras. By contrast, preferential expansion of 3H9+ B cells occurred in the germinal centers of male Yaa chimeras. In addition, although all chimeras preferentially selected 3H9/Vkappa5 encoded B cells into the germinal center and plasma cell compartments, 3H9 male Yaa chimeras had a more diverse repertoire and positively selected the 3H9/Vkappa5-48/Jkappa4 pair that confers high affinity anti-cardiolipin activity. We were unable to demonstrate a consistent effect of Tlr7 dose or Yaa on somatic mutations. Our data show that TLR7 excess influences the selection, expansion and diversification of B cells in the germinal center, independent of other genes in the Yaa locus. PMID- 25794169 TI - Innovative training with virtual patients in transcultural psychiatry: the impact on resident psychiatrists' confidence. AB - BACKGROUND: Virtual patients are now widely accepted as efficient and safe training tools in medical education, but very little is known about their implementation in psychiatry, especially in transcultural clinical care of traumatized refugee patients. OBJECTIVE: This study aimed at assessing the impact of training with a virtual patient on confidence in providing clinical care for traumatized refugee patients. METHODS: The authors developed an educational tool based on virtual patient methodology portraying the case of "Mrs. K", a traumatized refugee woman with symptoms of PTSD and depression. A group (N=32) of resident psychiatrists tested the system and their confidence in different aspects of providing clinical care for this patient group was evaluated pre- and post-test by using a validated confidence questionnaire. Cronbach's alpha was calculated for all clusters. Changes between pre- and post-test were compared by using the matched-pair t-test, binomial distribution for exact significance test and a calculation of effect sizes (Cohen's d). RESULTS: A statistically significant improvement was exhibited in overall confidence (mean Delta: 0.34; p<0.0001; d: 0.89) as well as in four more specific domains of clinical care, with the area of identifying and evaluating trauma-related diagnoses and disability showing the most prominent improvement (mean Delta: 0.47; p<0.0001; d: 1.00). CONCLUSIONS: This VP-system can lead to physicians' improvement of confidence in providing transcultural clinical care for traumatized refugee patients. Further research is required to investigate improvement in actual performance and cognitive outcomes with several VPs and in a long-term effect perspective. PMID- 25794168 TI - The complete mitochondrial genome of the geophilomorph centipede Strigamia maritima. AB - Strigamia maritima (Myriapoda; Chilopoda) is a species from the soil-living order of geophilomorph centipedes. The Geophilomorpha is the most speciose order of centipedes with over a 1000 species described. They are notable for their large number of appendage bearing segments and are being used as a laboratory model to study the embryological process of segmentation within the myriapods. Using a scaffold derived from the recently published genome of Strigamia maritima that contained multiple mitochondrial protein-coding genes, here we report the complete mitochondrial genome of Strigamia, the first from any geophilomorph centipede. The mitochondrial genome of S. maritima is a circular molecule of 14,938 base pairs, within which we could identify the typical mitochondrial genome complement of 13 protein-coding genes and 2 ribosomal RNA genes. Sequences resembling 16 of the 22 transfer RNA genes typical of metazoan mitochondrial genomes could be identified, many of which have clear deviations from the standard 'cloverleaf' secondary structures of tRNA. Phylogenetic trees derived from the concatenated alignment of protein-coding genes of S. maritima and >50 other metazoans were unable to resolve the Myriapoda as monophyletic, but did support a monophyletic group of chilopods: Strigamia was resolved as the sister group of the scolopendromorph Scolopocryptos sp. and these two (Geophilomorpha and Scolopendromorpha), along with the Lithobiomorpha, formed a monophyletic group the Pleurostigmomorpha. Gene order within the S. maritima mitochondrial genome is unique compared to any other arthropod or metazoan mitochondrial genome to which it has been compared. The highly unusual organisation of the mitochondrial genome of Strigamia maritima is in striking contrast with the conservatively evolving nuclear genome: sampling of more members of this order of centipedes will be required to see whether this unusual organization is typical of the Geophilomorpha or results from a more recent reorganisation in the lineage leading to Strigamia. PMID- 25794170 TI - The TP73 gene polymorphism (rs4648551, A>G) is associated with diminished ovarian reserve. AB - It's known that the members of the TP53 family are involved in the regulation of female reproduction. Studies in mice showed that the TP73 gene (member of this family) plays a role in the size of follicular pool, ovulation rate and maintenance of genomic stability. In the present study we analyzed data from 605 patients with <= 37 years attending their first intracytoplasmic sperm injection (ICSI). The association between the TP73 polymorphism (rs4648551, A>G) and the following parameters related to ovarian reserve, like age, antral follicular count (AFC), anti-Mullerian hormone levels (AMH) and ovarian response prediction index (ORPI) was evaluated. Our results showed an association of the AA genotype with diminished ovarian reserve (AMH <1, AFC <=9). Women presenting the AA genotype had a 2.0-fold increased risk for having AMH <1 and AFC <=9 (OR 2.0, 95% CI 1.23-3.31, P = 0.005). Patients presenting AA genotype had the lowest levels of AMH (P = 0.02), the lowest number of antral follicles (P = 0.01) and the lowest ORPI (P = 0.007). Analyzing the alleles, we can see an enrichment of the A allele in the group of diminished ovarian reserve (OR 1.4, 95%CI 1.02-1.83, P = 0.04). To the best of our knowledge, the present study is the first to analyze this polymorphism in humans for assessing the numbers of ovarian follicles and AMH levels and, therefore, the ovarian reserve. Our findings can contribute to the use of this polymorphism as a potential marker of diminished ovarian reserve. PMID- 25794172 TI - Towards semantically sensitive text clustering: a feature space modeling technology based on dimension extension. AB - The objective of text clustering is to divide document collections into clusters based on the similarity between documents. In this paper, an extension-based feature modeling approach towards semantically sensitive text clustering is proposed along with the corresponding feature space construction and similarity computation method. By combining the similarity in traditional feature space and that in extension space, the adverse effects of the complexity and diversity of natural language can be addressed and clustering semantic sensitivity can be improved correspondingly. The generated clusters can be organized using different granularities. The experimental evaluations on well-known clustering algorithms and datasets have verified the effectiveness of our approach. PMID- 25794171 TI - A method for combining RNAscope in situ hybridization with immunohistochemistry in thick free-floating brain sections and primary neuronal cultures. AB - In situ hybridization (ISH) is an extremely useful tool for localizing gene expression and changes in expression to specific cell populations in tissue samples across numerous research fields. Typically, a research group will put forth significant effort to design, generate, validate and then utilize in situ probes in thin or ultrathin paraffin embedded tissue sections. While combining ISH and IHC is an established technique, the combination of RNAscope ISH, a commercially available ISH assay with single transcript sensitivity, and IHC in thick free-floating tissue sections has not been described. Here, we provide a protocol that combines RNAscope ISH with IHC in thick free-floating tissue sections from the brain and allows simultaneous co-localization of genes and proteins in individual cells. This approach works well with a number of ISH probes (e.g. small proline-rich repeat 1a, betaIII-tubulin, tau, and beta-actin) and IHC antibody stains (e.g. tyrosine hydroxylase, betaIII-tubulin, NeuN, and glial fibrillary acidic protein) in rat brain sections. In addition, we provide examples of combining ISH-IHC dual staining in primary neuron cultures and double ISH labeling in thick free-floating tissue sections from the brain. Finally, we highlight the ability of RNAscope to detect ectopic DNA in neurons transduced with viral vectors. RNAscope ISH is a commercially available technology that utilizes a branched or "tree" in situ method to obtain ultrasensitive, single transcript detection. Immunohistochemistry is a tried and true method for identifying specific protein in cell populations. The combination of a sensitive and versatile oligonucleotide detection method with an established and versatile protein assay is a significant advancement in studies using free-floating tissue sections. PMID- 25794173 TI - Identifying the field of health communication. AB - This empirical investigation addresses four paradigmatically framed research questions to illuminate the epistemological status of the field of health communication, systematically addressing the limitations of existing disciplinary introspections. A content analysis of published health communication research indicated that the millennium marked a new stage of health communication research with a visible shift onto macro-level communication of health information among nonhealth professionals. The analysis also revealed the emergence of a paradigm around this particular topic area, with its contributing scholars predominantly sharing postpositivistic thought traditions and cross-sectional survey-analytic methodologies. More interdisciplinary collaborations and meta-theoretical assessments are needed to facilitate a continued growth of this evolving paradigm, which may advance health communication scholars in their search for a disciplinary identity. PMID- 25794174 TI - No association of maternal gestational weight gain with offspring blood pressure and hypertension at age 18 years in male sibling-pairs: a prospective register based cohort study. AB - BACKGROUND: Maternal gestational weight gain (GWG) is associated with birth weight, obesity, and possibly blood pressure (BP) and hypertension in the offspring. These associations may however be confounded by genetic and/or shared environmental factors. In contrast to previous studies based on non-siblings and self-reported data, we investigated whether GWG is associated with offspring BP and hypertension, in a register-based cohort of full brothers while controlling for fixed shared effects. METHODS: By using Swedish nation-wide record-linkage data, we identified women with at least two male children (full brothers) born 1982-1989. Their BP was obtained from the mandatory military conscription induction tests. We adopted linear and Poisson regression models with robust variance, using generalized estimating equations to analyze associations between GWG and BP, as well as with hypertension, within and between offspring sibling pairs. RESULTS: Complete data on the mothers' GWG and offspring BP was obtained for 9,816 brothers (4,908 brother-pairs). Adjusted regression models showed no significant associations between GWG and SBP (beta = 0.03 mmHg per 1-kg GWG difference, [95% CI -0.08, 0.14], or DBP (beta = -0.03 mmHg per 1-kg GWG difference [95% CI -0.11, 0.05]), or between GWG and offspring's risk of hypertension (relative risk = 1.0 [95% CI 0.99, 1.02], neither within nor between siblings. CONCLUSIONS: In this large sibling-pair study, we did not find any significant association between GWG and offspring BP or the risk of hypertension at 18y, when taking genetic and environmental factors shared within sibling pairs into account. Further large sibling studies are required to confirm a null association between GWG and other cardiovascular risk factors. PMID- 25794176 TI - Solution-processed MoO3:PEDOT:PSS hybrid hole transporting layer for inverted polymer solar cells. AB - Solution-processed organic-inorganic hybrids composing of MoO3 nanoparticles and PEDOT:PSS were developed for use in inverted organic solar cells as hole transporting layer (HTL). The hybrid MoO3:PEDOT:PSS inks were prepared by simply mixing PEDOT:PSS aqueous and MoO3 ethanol suspension together. A core-shell structure was proposed in the MoO3:PEDOT:PSS hybrid ink, where PEDOT chains act as the core and MoO3 nanoparticles connected with PSS chains act as the composite shell. The mixing with PEDOT:PSS suppressed the aggregation of MoO3 nanoparticles, which led to a smoother surface. In addition, since the hydrophilic PSS chains were passivated through preferentially connection with MoO3, the stronger adhesion between MoO3 nanoparticles and the photoactive layer improved the film forming ability of the MoO3:PEDOT:PSS hybrid ink. The MoO3:PEDOT:PSS hybrid HTL can therefore be feasibly deposited onto the hydrophobic photoactive polymer layer without any surface treatment. The use of the MoO3:PEDOT:PSS hybrid HTL resulted in the optimized P3HT:PC61BM- and PTB7:PC61BM-based inverted organic solar cells reaching highest power conversion efficiencies of 3.29% and 5.92%, respectively, which were comparable with that of the control devices using thermally evaporated MoO3 HTL (3.05% and 6.01%, respectively). Furthermore, less HTL thickness dependence of device performance was found for the hybrid HTL-based devices, which makes it more compatible with roll-to-roll printing process. In the end, influence of the blend ratio of MoO3 to PEDOT:PSS on photovoltaic performance and device stability was studied carefully, results indicated that the device performance would decrease with the increase of MoO3 blended ratio, whereas the long-term stability was improved. PMID- 25794175 TI - Protective effect of leaf essential oil from Cinnamomum osmophloeum Kanehira on endotoxin-induced intestinal injury in mice associated with suppressed local expression of molecules in the signaling pathways of TLR4 and NLRP3. AB - Endotoxin is a potent microbial mediator implicated in sepsis. We investigated the anti-inflammatory effect of leaf essential oil from Cinnamomum osmophloeum Kanehira (CO) of the linalool chemotype on endotoxin-injected mice. Mice were administered CO or vehicle by gavage before endotoxin injection and were killed 12 h after injection. Neither growth nor the organ weight or tissue weight to body weight ratio was affected by CO treatment. CO significantly lowered peripheral levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-18, interferon-gamma, and nitric oxide and inhibited the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene (88), myeloid differentiation factor 2, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1, and Nod-like receptor family, pyrin domain containing 3 (NLRP3). CO also inhibited the activation of nuclear factor KB, inhibited the activity of caspase-1 in small intestine, and ameliorated intestinal edema. Our data provide strong evidence for a protective effect of CO of the linalool chemotype in the endotoxin-induced systemic inflammatory response in close association with suppression of the TLR4 and NLRP3 signaling pathways in intestine. PMID- 25794177 TI - Evaluation of the national Notifiable Diseases Surveillance System for dengue fever in Taiwan, 2010-2012. AB - BACKGROUND: In Taiwan, around 1,500 cases of dengue fever are reported annually and incidence has been increasing over time. A national web-based Notifiable Diseases Surveillance System (NDSS) has been in operation since 1997 to monitor incidence and trends and support case and outbreak management. We present the findings of an evaluation of the NDSS to ascertain the extent to which dengue fever surveillance objectives are being achieved. METHODOLOGY: We extracted the NDSS data on all laboratory-confirmed dengue fever cases reported during 1 January 2010 to 31 December 2012 to assess and describe key system attributes based on the Centers for Disease Control and Prevention surveillance evaluation guidelines. The system's structure and processes were delineated and operational staff interviewed using a semi-structured questionnaire. Crude and age-adjusted incidence rates were calculated and key demographic variables were summarised to describe reporting activity. Data completeness and validity were described across several variables. PRINCIPAL FINDINGS: Of 5,072 laboratory-confirmed dengue fever cases reported during 2010-2012, 4,740 (93%) were reported during July to December. The system was judged to be simple due to its minimal reporting steps. Data collected on key variables were correctly formatted and usable in > 90% of cases, demonstrating good data completeness and validity. The information collected was considered relevant by users with high acceptability. Adherence to guidelines for 24-hour reporting was 99%. Of 720 cases (14%) recorded as travel related, 111 (15%) had an onset >14 days after return, highlighting the potential for misclassification. Information on hospitalization was missing for 22% of cases. The calculated PVP was 43%. CONCLUSIONS/SIGNIFICANCE: The NDSS for dengue fever surveillance is a robust, well maintained and acceptable system that supports the collection of complete and valid data needed to achieve the surveillance objectives. The simplicity of the system engenders compliance leading to timely and accurate reporting. Completeness of hospitalization information could be further improved to allow assessment of severity of illness. To minimize misclassification, an algorithm to accurately classify travel cases should be established. PMID- 25794178 TI - Indoor emissions as a primary source of airborne allergenic fungal particles in classrooms. AB - This study quantifies the influence of ventilation and indoor emissions on concentrations and particle sizes of airborne indoor allergenic fungal taxa and further examines geographical variability, each of which may affect personal exposures to allergenic fungi. Quantitative PCR and multiplexed DNA sequencing were employed to count and identify allergenic fungal aerosol particles indoors and outdoors in seven school classrooms in four different countries. Quantitative diversity analysis was combined with building characterization and mass balance modeling to apportion source contributions of indoor allergenic airborne fungal particles. Mass balance calculations indicate that 70% of indoor fungal aerosol particles and 80% of airborne allergenic fungal taxa were associated with indoor emissions; on average, 81% of allergenic fungi from indoor sources originated from occupant-generated emissions. Principal coordinate analysis revealed geographical variations in fungal communities among sites in China, Europe, and North America (p < 0.05, analysis of similarity), demonstrating that geography may also affect personal exposures to allergenic fungi. Indoor emissions including those released with occupancy contribute more substantially to allergenic fungal exposures in classrooms sampled than do outdoor contributions from ventilation. The results suggest that design and maintenance of buildings to control indoor emissions may enable reduced indoor inhalation exposures to fungal allergens. PMID- 25794179 TI - Selection of reference genes for gene expression studies related to intramuscular fat deposition in Capra hircus skeletal muscle. AB - The identification of suitable reference genes is critical for obtaining reliable results from gene expression studies using quantitative real-time PCR (qPCR) because the expression of reference genes may vary considerably under different experimental conditions. In most cases, however, commonly used reference genes are employed in data normalization without proper validation, which may lead to incorrect data interpretation. Here, we aim to select a set of optimal reference genes for the accurate normalization of gene expression associated with intramuscular fat (IMF) deposition during development. In the present study, eight reference genes (PPIB, HMBS, RPLP0, B2M, YWHAZ, 18S, GAPDH and ACTB) were evaluated by three different algorithms (geNorm, NormFinder and BestKeeper) in two types of muscle tissues (longissimus dorsi muscle and biceps femoris muscle) across different developmental stages. All three algorithms gave similar results. PPIB and HMBS were identified as the most stable reference genes, while the commonly used reference genes 18S and GAPDH were the most variably expressed, with expression varying dramatically across different developmental stages. Furthermore, to reveal the crucial role of appropriate reference genes in obtaining a reliable result, analysis of PPARG expression was performed by normalization to the most and the least stable reference genes. The relative expression levels of PPARG normalized to the most stable reference genes greatly differed from those normalized to the least stable one. Therefore, evaluation of reference genes must be performed for a given experimental condition before the reference genes are used. PPIB and HMBS are the optimal reference genes for analysis of gene expression associated with IMF deposition in skeletal muscle during development. PMID- 25794180 TI - Maximizing the wildlife conservation value of road right-of-ways in an agriculturally dominated landscape. AB - There has been a growing recognition that the narrow linear strips of uncultivated vegetation that lie between roads and agricultural crops, referred to as roadside right-of-ways or verges, can serve as areas for the conservation of wildlife. The features of right-of-ways that should influence the composition of wildlife communities vary considerably. Our goal was to determine what features of right-of-ways increased the conservation potential of right-of-ways for wildlife in a grassland system dominated by agricultural production. We sampled 100 right-of-ways for birds and 92 right-of-ways for small mammals in McDonough and Warren Counties in west-central Illinois. We found that the sizes of right-of-ways and the amount of traffic on the adjacent roads synergistically worked to influence wildlife communities. On roads with low traffic, avian species richness increased rapidly with increased right-of-way width, while on roads with high traffic, avian richness increased only slightly with increasing right-of-way widths. We found that wider roadside right-of-ways (preferably across the road from equally wide right-of-ways) with thicker and taller vegetation had the greatest conservation value for birds and small mammals. The features that enhanced the conservation value of right-of-ways in our study area were uncommon. Efforts to create or enhance these features for the benefit of wildlife would likely face numerous obstacles. Nonetheless, from a grassland conservation perspective, working with stakeholders to implement specific strategies to enhance these often neglected areas may be an effective complement to purchasing and restoring conservation lands away from roads. PMID- 25794181 TI - Prediction of the damage-associated non-synonymous single nucleotide polymorphisms in the human MC1R gene. AB - The melanocortin 1 receptor (MC1R) is involved in the control of melanogenesis. Polymorphisms in this gene have been associated with variation in skin and hair color and with elevated risk for the development of melanoma. Here we used 11 computational tools based on different approaches to predict the damage associated non-synonymous single nucleotide polymorphisms (nsSNPs) in the coding region of the human MC1R gene. Among the 92 nsSNPs arranged according to the predictions 62% were classified as damaging in more than five tools. The classification was significantly correlated with the scores of two consensus programs. Alleles associated with the red hair color (RHC) phenotype and with the risk of melanoma were examined. The R variants D84E, R142H, R151C, I155T, R160W and D294H were classified as damaging by the majority of the tools while the r variants V60L, V92M and R163Q have been predicted as neutral in most of the programs The combination of the prediction tools results in 14 nsSNPs indicated as the most damaging mutations in MC1R (L48P, R67W, H70Y, P72L, S83P, R151H, S172I, L206P, T242I, G255R, P256S, C273Y, C289R and R306H); C273Y showed to be highly damaging in SIFT, Polyphen-2, MutPred, PANTHER and PROVEAN scores. The computational analysis proved capable of identifying the potentially damaging nsSNPs in MC1R, which are candidates for further laboratory studies of the functional and pharmacological significance of the alterations in the receptor and the phenotypic outcomes. PMID- 25794183 TI - Mass density and water content of saturated never-dried calcium silicate hydrates. AB - Calcium silicate hydrates (C-S-H) are the most abundant hydration products in ordinary Portland cement paste. Yet, despite the critical role they play in determining mechanical and transport properties, there is still a debate about their density and exact composition. Here, the site-specific mass density and composition of C-S-H in hydrated cement paste are determined with nanoscale resolution in a nondestructive approach. We used ptychographic X-ray computed tomography in order to determine spatially resolved mass density and water content of the C-S-H within the microstructure of the cement paste. Our findings indicate that the C-S-H at the border of hydrated alite particles possibly have a higher density than the apparent inner-product C-S-H, which is contrary to the common expectations from previous works on hydrated cement paste. PMID- 25794182 TI - Comparative value of four measures of retention in expert care in predicting clinical outcomes and health care utilization in HIV patients. AB - This study compared the ability of four measures of patient retention in HIV expert care to predict clinical outcomes. This retrospective study examined Veterans Health Administration (VHA) beneficiaries with HIV (ICD-9-CM codes 042 or V08) receiving expert care (defined as HIV-1 RNA viral load and CD4 cell count tests occurring within one week of each other) at VHA facilities from October 1, 2006, to September 30, 2008. Patients were >=18 years old and continuous VHA users for at least 24 months after entry into expert care. Retention measures included: Annual Appointments (>=2 appointments annually at least 60 days apart), Missed Appointments (missed >=25% of appointments), Infrequent Appointments (>6 months without an appointment), and Missed or Infrequent Appointments (missed >=25% of appointments or >6 months without an appointment). Multivariable nominal logistic regression models were used to determine associations between retention measures and outcomes. Overall, 8,845 patients met study criteria. At baseline, 64% of patients were virologically suppressed and 37% had a CD4 cell count >500 cells/mm3. At 24 months, 82% were virologically suppressed and 46% had a CD4 cell count >500 cells/mm3. During follow-up, 13% progressed to AIDS, 48% visited the emergency department (ED), 28% were hospitalized, and 0.3% died. All four retention measures were associated with virologic suppression and antiretroviral therapy initiation at 24 months follow-up. Annual Appointments correlated positively with CD4 cell count >500 cells/mm3. Missed Appointments was predictive of all primary and secondary outcomes, including CD4 cell count <=500 cells/mm3, progression to AIDS, ED visit, and hospitalization. Missed Appointments was the only measure to predict all primary and secondary outcomes. This finding could be useful to health care providers and public health organizations as they seek ways to optimize the health of HIV patients. PMID- 25794185 TI - Males and females gain differentially from sociality in a promiscuous fruit bat Cynopterus sphinx. AB - Sociality emerges when the benefits of group living outweigh its costs. While both males and females are capable of strong social ties, the evolutionary drivers for sociality and the benefits accrued maybe different for each sex. In this study, we investigate the differential reproductive success benefits of group membership that males and females might obtain in the promiscuous fruit bat Cynopterus sphinx. Individuals of this species live in flexible social groups called colonies. These colonies are labile and there is high turnover of individuals. However, colony males sire more offspring within the colony suggesting that being part of a colony may result in reproductive benefits for males. This also raises the possibility that long-term loyalty towards the colony may confer additional advantage in terms of higher reproductive success. We used ten seasons of genetic parentage data to estimate reproductive success and relatedness of individuals in the colony. We used recapture data to identify long and short-term residents in the colony as well as to obtain rates of recapture for males and females. Our results reveal that males have a significantly higher chance of becoming long-term residents (than females), and these long-term resident males gain twice the reproductive success compared to short-term resident males. We also observed that long-term resident females are related to each other and also achieve higher reproductive success than short-term resident females. In contrast, long-term resident males do not differ from short-term resident males in their levels of relatedness. Our results re-iterate the benefits of sociality even in species that are promiscuous and socially labile and possible benefits of maintaining a colony. PMID- 25794184 TI - In or out-of-Madagascar?--Colonization patterns for large-bodied diving beetles (Coleoptera: Dytiscidae). AB - High species diversity and endemism within Madagascar is mainly the result of species radiations following colonization from nearby continents or islands. Most of the endemic taxa are thought to be descendants of a single or small number of colonizers that arrived from Africa sometime during the Cenozoic and gave rise to highly diverse groups. This pattern is largely based on vertebrates and a small number of invertebrate groups. Knowledge of the evolutionary history of aquatic beetles on Madagascar is lacking, even though this species-rich group is often a dominant part of invertebrate freshwater communities in both standing and running water. Here we focus on large bodied diving beetles of the tribes Hydaticini and Cybistrini. Our aims with this study were to answer the following questions 1) How many colonization events does the present Malagasy fauna originate from? 2) Did any colonization event lead to a species radiation? 3) Where did the colonizers come from--Africa or Asia--and has there been any out-of-Madagascar event? 4) When did these events occur and were they concentrated to any particular time interval? Our results suggest that neither in Hydaticini nor in Cybistrini was there a single case of two or more endemic species forming a monophyletic group. The biogeographical analysis indicated different colonization histories for the two tribes. Cybistrini required at least eight separate colonization events, including the non-endemic species, all comparatively recent except the only lotic (running water) living Cybister operosus with an inferred colonization at 29 Ma. In Hydaticini the Madagascan endemics were spread out across the tree, often occupying basal positions in different species groups. The biogeographical analyses therefore postulated the very bold hypothesis of a Madagascan origin at a very deep basal node within Hydaticus and multiple out-of Madagascar dispersal events. This hypothesis needs to be tested with equally intense taxon sampling of mainland Africa as for Madagascar. PMID- 25794186 TI - Early formation of bilirubin isomers during phototherapy for neonatal jaundice: effects of single vs. double fluorescent lamps vs. photodiodes. AB - BACKGROUND: In neonatal jaundice, phototherapy converts bilirubin to more polar photoisomers which can be excreted without conjugation. We measured changes in the concentration of bilirubin Z,E-photoisomer during the first 4 h of intensive phototherapy using single fluorescent lights as a reference, compared to double fluorescent lights, and a single unit of photodiodes. METHODS: Neonates (N = 42; birth weight: 1,200-4,690 g; gestational age: 28-42 wk) were studied during phototherapy. Infants were randomized to: (i) single, or (ii) double fluorescent phototherapy; or (iii) single unit photodiodes. Irradiance was measured. Serum bilirubin (by cooximetry) and Z,E bilirubin (by high-pressure liquid chromatography) were measured at 0,15, 30, 60, 120, and 240 min after the start of phototherapy. Data were analyzed with a linear mixed model. RESULTS: There was a highly significant increase of Z,E-bilirubin over time (P < 0.0001), starting at 15 min. Photoisomers reached ~25% of total bilirubin concentration after 4 h. However, there were no significant differences between the three randomized groups in spite of significantly higher irradiance using double fluorescent lights vs. single fluorescent or photodiodes. CONCLUSION: Formation of bilirubin photoisomers is rapid, and occurs early during intensive phototherapy for neonatal jaundice. The rate and level of photoisomerization was not influenced by irradiance and light source. PMID- 25794187 TI - Demographic differences in sun protection beliefs and behavior: a community-based study in Shanghai, China. AB - OBJECTIVE: We want to know the attitudes and behaviors towards UV protection and we want to analyze the difference between different Chinese demographic groups in this study. METHODS: A community-based study was undertaken in Shanghai from October 2009 to January 2010. The participants, ages 20-60 years old, were screened by cluster sampling and were investigated through interviews at their own homes. Personal basic information and questions pertaining to their knowledge and attitudes towards sunlight and sun protective activities were included in the questionnaire. RESULTS: We completed 5964 questionnaires (2794 men and 3170 women). Eighty-six percent of the respondents belonged to Fitzpatrick skin type IV. Knowledge about UV-induced risks was known by more than half of the participants. However, only one-third of the participants thought they needed sun protection in winter and indoors or in vehicles, and 27% of the participants acknowledged tanning was not favorable. The attitudes towards sun exposure varied greatly, showing significant differences based on gender, age, socioeconomic groups and skin type groups (p<0.05). Fifty-five percent of the participants never use an umbrella under sunlight, only 26.5% of the respondents wear hats, and 21.3% of the participants applied sunscreen. Females and individuals of a younger age and higher education level were more likely to perform sun-protective behaviors than males and those of an older age and lower education level (p<0.001). CONCLUSION: There is a deficit in the use of sun protection existing in our surveyed Chinese population, especially in males and lower socioeconomic population, which could allow for planning prevention campaigns and exploring sun preventive products. PMID- 25794188 TI - City dweller responses to multiple stressors intruding into their homes: noise, light, odour, and vibration. AB - Urban densification increases exposure to noise, light, odour, and vibration in urban dwellings. Exposure from combined environmental stressors intruding into the home could increase the risk of adverse effects on wellbeing, even when the exposure is at a relatively low level. This study assesses the prevalence of annoyance with a combination of potential environmental stressors common in urban areas and the association with wellbeing. A questionnaire was sent by mail to residents in five areas in Halmstad (Sweden) with similar socioeconomic and housing characteristics but different exposure (response rate 56%; n=385). Of the respondents, 50% were annoyed to some degree by at least one of the suggested stressors, most commonly by noise and vibration from local traffic. Structural equation modelling showed that annoyance led to lowered quality of life via the mediating construct residential satisfaction, which in turn was influenced by place attachment and perceived restoration possibilities in the dwelling. Stress had a negative impact on quality of life, but was not directly correlated to annoyance. Stress was however correlated with sensitivity. The findings suggest that dose-response relationships for environmental stressors should be studied in a broader context of environmental and individual factors. Also relatively low levels of exposure should be mitigated, especially if several stressors are present. PMID- 25794189 TI - On the road to HIV/AIDS competence in the household: building a health-enabling environment for people living with HIV/AIDS. AB - When aiming to provide chronic disease care within the context of human resource shortages, we should not only consider the responsibility of the individual person living with HIV/AIDS (PLWHA) but also the capacity of the social environment to actively encourage a lifestyle that fosters health. In this social environment, extensive efforts are thus required to increase HIV/AIDS knowledge, reduce stigma, stimulate HIV testing, improve health care-seeking behavior, and encourage safe sexual practices-described in the literature as the need for AIDS competence. In accordance with socio-ecological theory, one cannot restrict the research focus to communities, as AIDS competence studies should also incorporate the intermediate household level. In responding to this research need, the aim of this article is to conceptualize an "HIV/AIDS competent household" based on qualitative interviews and focus group discussions conducted in a township on the outskirts of Cape Town, South Africa. Our results show that a household's supportive response to disclosure allows a patient to live openly as HIV positive in the household concerned. This may mark the start of the road to HIV/AIDS competence in the household, meaning the PLWHA receives sustainable support throughout the care continuum and positive living becomes the norm for the PLWHA and his or her household. A feedback loop might also be created in which other household members are encouraged to be tested and to disclose their status, which is an important step towards a sustainable response to HIV/AIDS-related challenges. Despite the fact that this road to HIV/AIDS competence at the household level is fragile and prone to various barriers, this article shows that the household has the potential to be a health-enabling environment for PLWHA. PMID- 25794190 TI - Awareness and the arguments for and against the International Classification of Functioning, Disability and Health among representatives of disability organisations. AB - Disability organisations have not been engaged in the debate about the International Classification of Functioning, Disability and Health (ICF) in Sweden. We wanted to know representatives' attitudes about the ICF. The aim of the study was to elucidate the arguments for and against the ICF among representatives of disability organisations. The study consisted of eighteen representatives (from six disability organisations) that answered electronic questionnaires. The questionnaires involved ten open questions about the arguments for and against the ICF. The answers of the questionnaires have been categorized according to qualitative content analysis. Our results indicated four themes: awareness, arguments for and against, influence and the future. More than half of the representatives had very limited awareness of the ICF. There was an explicit criticism of individual classification but more positive comments about classification on an aggregated level. The most important issue for representatives was influencing social policy in society, not learning and spreading information about the ICF. PMID- 25794191 TI - Treating Major Depression with Physical Activity: A Systematic Overview with Recommendations. AB - The purpose of this systematic overview was to determine the most effective mode and dose of physical activity (PA) for treating major depressive disorder (MDD), and to suggest guidelines and recommendations for clinicians. The selection process consisted of a comprehensive search that was conducted up until April 2014 in the following databases: PsycINFO, Medline, PubMed and Scopus. The inclusion criteria were: (1) a randomized controlled trial (RCT) design, (2) complete description of intensity, duration and frequency of the PA, (3) the participants had to be diagnosed with MDD according to Diagnostic Statistical Manual 4 th edition (DSM-IV) or International Classification of Disease tenth Revision (ICD-10) criteria (4) if the controls received any treatment, it had to be specified, (5) published after 1990, (6) consist of aerobic or anaerobic treatment PA, and (7) not be a pilotor preliminary study. A quality assessment of each study was conducted independently by two reviewers; this stringent selection process resulted in 12 reviewed studies. CONCLUSION: individually customized PA, for at least 30 minutes, preferably performed under supervision and with a frequency of at least three times per week is recommended when treating MDD. These recommendations must be viewed in light of the relatively few studies matching the inclusion criteria. PMID- 25794192 TI - No effect of insecticide treated curtain deployment on aedes infestation in a cluster randomized trial in a setting of low dengue transmission in Guantanamo, Cuba. AB - OBJECTIVE & METHODOLOGY: The current study evaluated the effectiveness and cost effectiveness of Insecticide Treated Curtain (ITC) deployment for reducing dengue vector infestation levels in the Cuban context with intensive routine control activities. A cluster randomized controlled trial took place in Guantanamo city, east Cuba. Twelve neighborhoods (about 500 households each) were selected among the ones with the highest Aedes infestation levels in the previous two years, and were randomly allocated to the intervention and control arms. Long lasting ITC (PermaNet) were distributed in the intervention clusters in March 2009. Routine control activities were continued in the whole study area. In both study arms, we monitored monthly pre- and post-intervention House Index (HI, number of houses with at least 1 container with Aedes immature stages/100 houses inspected), during 12 and 18 months respectively. We evaluated the effect of ITC deployment on HI by fitting a generalized linear regression model with a negative binomial link function to these data. PRINCIPAL FINDINGS: At distribution, the ITC coverage (% of households using >=1 ITC) reached 98.4%, with a median of 3 ITC distributed/household. After 18 months, the coverage remained 97.4%. The local Aedes species was susceptible to deltamethrin (mosquito mortality rate of 99.7%) and the residual deltamethrin activity in the ITC was within acceptable levels (mosquito mortality rate of 73.1%) after one year of curtain use. Over the 18 month observation period after ITC distribution, the adjusted HI rate ratio, intervention versus control clusters, was 1.15 (95% CI 0.57 to 2.34). The annualized cost per household of ITC implementation was 3.8 USD, against 16.8 USD for all routine ACP activities. CONCLUSION: Deployment of ITC in a setting with already intensive routine Aedes control actions does not lead to reductions in Aedes infestation levels. PMID- 25794193 TI - DISIS: prediction of drug response through an iterative sure independence screening. AB - Prediction of drug response based on genomic alterations is an important task in the research of personalized medicine. Current elastic net model utilized a sure independence screening to select relevant genomic features with drug response, but it may neglect the combination effect of some marginally weak features. In this work, we applied an iterative sure independence screening scheme to select drug response relevant features from the Cancer Cell Line Encyclopedia (CCLE) dataset. For each drug in CCLE, we selected up to 40 features including gene expressions, mutation and copy number alterations of cancer-related genes, and some of them are significantly strong features but showing weak marginal correlation with drug response vector. Lasso regression based on the selected features showed that our prediction accuracies are higher than those by elastic net regression for most drugs. PMID- 25794195 TI - Society for Maternal Fetal Medicine 2015 Annual Pregnancy Meeting supplemental episode 7: Post-Meeting Round-Up (Part 3 of 3). PMID- 25794194 TI - Protein kinase C activation of a blebbistatin sensitive contractile component in the wall of hypertrophying mouse urinary bladder. AB - AIM: To examine the role of protein kinase C (PKC) and non-muscle myosin in regulation of wall tension in the hypertrophied urinary bladder. METHODS: A partial urinary outflow obstruction was induced in the mouse. Tissue strips from sham operated controls and obstructed bladders were examined in vitro with quantitative gel electrophoresis, immunohistochemistry, and in vitro force recordings. RESULTS: Outlet obstruction (14-18 days) induced a significant growth of the bladder, 73 +/- 6.13 mg compared to 19 +/- 1 13 mg in sham operated controls. The hypertrophying bladder tissue had increased expression of non muscle myosin B (SMemb) mainly localized to serosa and suburothelium. Direct activation of PKC with PDBu did not alter force in the control urinary bladder. In contrast, PDBu initiated a prominent and sustained contraction which had an increased sensitivity to the myosin type II inhibitor blebbistatin. CONCLUSIONS: PKC activates a significant contractile response in the wall of the hypertrophying urinary bladder, possibly supported by non-muscle myosin. This contractile component is not contributing to the physiological response to muscarinic stimulation, but might be separately regulated by other, yet unknown, mechanisms. PMID- 25794196 TI - Protein corona of nanoparticles: distinct proteins regulate the cellular uptake. AB - Understanding nanoparticle-protein interactions is a crucial issue in the development of targeted nanomaterial delivery. Besides unraveling the composition of the nanoparticle's protein coronas, distinct proteins thereof could control nanoparticle uptake into specific cell types. Here we differentially analyzed the protein corona composition on four polymeric differently functionalized nanoparticles by label-free quantitative mass spectrometry. Next, we correlated the relative abundance of identified proteins in the corona with enhanced or decreased cellular uptake of nanoparticles into human cancer and bone marrow stem cells to identify key candidates. Finally, we verified these candidate proteins by artificially decorating nanoparticles with individual proteins showing that nanoparticles precoated with the apolipoproteins ApoA4 or ApoC3 significantly decreased the cellular uptake, whereas precoating with ApoH increased the cellular uptake. PMID- 25794197 TI - Everyday exposure to benevolent sexism and condom use among college women. AB - Understanding factors related to condom use is critical in reducing the spread of sexually transmitted infections (STIs), especially for women, who are disproportionately affected by many STIs. Extant work has shown that perceived sexism is one such factor associated with lower levels of condom use among women, but has yet to explore whether benevolent sexism in particular-a subtle form of sexism that often goes unnoticed and increases cognitions and behaviors consistent with traditional female gender roles (e.g., sexual submissiveness) relates negatively to this safer-sex practice. The present research tested this possibility and, in addition, examined whether relational sex motives, which reflect a desire to engage in sex as a means to foster partners' sexual satisfaction, mediated the relation between benevolent sexism and condom use. During the spring of 2011, female college students (N = 158) reported how often they experienced benevolent sexism in their daily lives and, 2 weeks later, their relational sex motives and condom use. Supporting hypotheses results indicated that greater exposure to benevolent sexism was associated significantly with lower condom use, and that relational sex motives mediated this relationship. We discuss implications for women's well-being, including ways to promote safer sex in the face of sexism. PMID- 25794198 TI - Lipid partitioning in maize (Zea mays L.) endosperm highlights relationships among starch lipids, amylose, and vitreousness. AB - Content and composition of maize endosperm lipids and their partition in the floury and vitreous regions were determined for a set of inbred lines. Neutral lipids, i.e., triglycerides and free fatty acids, accounted for more than 80% of endosperm lipids and are almost 2 times higher in the floury than in the vitreous regions. The composition of endosperm lipids, including their fatty acid unsaturation levels, as well as their distribution may be related to metabolic specificities of the floury and vitreous regions in carbon and nitrogen storage and to the management of stress responses during endosperm cell development. Remarkably, the highest contents of starch lipids were observed systematically within the vitreous endosperm. These high amounts of starch lipids were mainly due to lysophosphatidylcholine and were tightly linked to the highest amylose content. Consequently, the formation of amylose-lysophosphatidylcholine complexes has to be considered as an outstanding mechanism affecting endosperm vitreousness. PMID- 25794199 TI - Systematic review of radiofrequency ablation and pulsed radiofrequency for management of cervicogenic headache. AB - BACKGROUND: Cervicogenic headache is a secondary headache that has a source in the upper cervical spine. There is a small but growing body of evidence to establish effectiveness of radiofrequency (RF) neurotomy, and the pulsed RF (PRF) procedure for management of cervicogenic headache. OBJECTIVE: To investigate the clinical utility of RF neurotomy, and PRF ablation for the management of cervicogenic headache. STUDY DESIGN: Systematic review. METHODS: The review included relevant literature identified through searches of PubMed, Cochrane, Clinical trials, U.S. National Guideline Clearinghouse and EMBASE from 1960 to January 2014.The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria for randomized control trials and the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, and poor based on the quality of evidence. OUTCOMES MEASURED: The primary outcome measures were reduction in pain scores and improvement in quality of life. RESULTS: The primary outcome measures were headache relief and improved quality of life. Twenty five studies were identified for full text review of these, 9 studies met inclusion criteria. There were 5 non randomized, among them 4/5 were of moderate quality, 3/5 showed RF ablation and 1/5 showed PRF as an effective intervention for cervicogenic headache. There were 4 randomized trials among them 2/4 were of high quality, 3/4 investigated RF ablation as an intervention for CHA, 1/4 investigated PRF ablation as an intervention for CHA and none of the randomized studies showed strong evidence for RF and PRF ablation as an effective intervention for CHA. LIMITATIONS: In the selected studies there were inconsistencies between randomized trials, flaws in trial design, and gaps in the chain of evidence. CONCLUSION: There is limited evidence to support RF ablation for management of CHA as there are no high quality RCTs and/ or multiple consistent non-RCTs without methodological flaws. There is poor evidence to support PRF for CHA as there are no high quality RCTs or Non-RCTs. PMID- 25794200 TI - The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain: a systematic review and meta-analysis. AB - BACKGROUND: Individual response to opioid analgesics varies among patients. OBJECTIVE: This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain. STUDY DESIGN: A systematic review and meta-analysis of associations between genetic single-nucleotide polymorphisms (SNPs) and opioids used for acute postoperative pain. SETTING: This meta-analysis examined all studies involving an association between genetic polymorphisms and the analgesic efficacy or clinical outcome of opioid analgesics for postoperative pain. METHODS: A literature search was performed up to January 31, 2014, using the PubMed, EMBase, ISI Web of Science, and Cochrane Library databases. RESULTS: Fifty-nine studies were included in this systematic review, and 23 studies (a total of 5,902 patients) were included in the final meta-analysis. The results showed that human MU-opioid receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = -0.17, 95% CI = [-0.25, -0.10], P < 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative period. Moreover, CYP3A4*1G carriers consumed less opioids than homozygous CYP3A4*1/*1 patients during the first 24 hours postoperative period (MD = 45.12, 95% CI = [36.17, 54.06], P < 0.00001). No significant differences were found in CYP3A5*3, ABCB1 C3435T, and G2477T/A genetic polymorphisms. LIMITATIONS: Some potential non-genetic factors can modify the effects of gene SNP on pain and opioid consumption during the postoperative period, such as age, gender, mood, anxiety, and drug-drug interactions. But further analyses could not be performed in the present meta-analysis due to limited information. CONCLUSION: The results indicate that among the genetic SNPs we studied which include those affecting analgesic drug metabolism, transport of analgesic agents across the blood-brain barrier, and their activity at target receptors and ion channels and in the modulation of neurotransmitter pathways, the A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians to properly manage the analgesic use of opioids individually for better pain management. PMID- 25794202 TI - Piriformis syndrome: comparison of the effectiveness of local anesthetic and corticosteroid injections: a double-blinded, randomized controlled study. AB - BACKGROUND: Piriformis syndrome (PS), which is characterized by pain radiating to the gluteal region and posterior leg, is accepted as one of the causes of sciatalgia. Although the importance of local piriformis muscle injections whenever PS is clinically suspected has been shown in many studies, there are not enough studies considering the clinical efficacy of these injections. OBJECTIVE: To investigate the differences between local anesthetic (LA) and LA + corticosteroid (CS) injections in the treatment of PS. STUDY DESIGN: A prospective, double-blinded, randomized controlled trial. SETTING: Physical medicine and rehabilitation department of a university hospital. METHODS: Fifty seven patients having unilateral hip and/or leg pain with positive FAIR test and tenderness and/or trigger point at the piriformis muscle were evaluated. Out of 50 patients randomly assigned to 2 groups, 47 patients whose pain resolved at least 50% from the baseline after the injection were diagnosed as having PS. The first group (n = 22) received 5 mL of lidocaine 2% while the second group (n = 25) received 4 mL of lidocaine 2% + 1 mL of betametazone under the guidance of ultrasound. OUTCOME ASSESSMENT: Numeric Rating Scale (NRS) and Likert Analogue Scale (LAS). RESULTS: No statistically significant difference (P > 0.05) was detected between the groups in NRS score values at resting (P = 0.814), night (P = 0.830), and in motion (P = 0.145), and LAS values with long duration of sitting (P = 0.547), standing (P = 0.898), and lying (P = 0.326) with evaluations at baseline, first week, and first and third months after the injection. A statistically highly significant (P < 0.005) reduction of pain was evaluated through NRS scores at resting (P = 0.001), in motion (P = 0.001), and at night (P = 0.001) and LAS values with long duration of sitting (P = 0.001), standing (P = 0.001), and lying (P = 0.001) in both of the groups. LIMITATIONS: Presumed limitations of this study include having a relatively small sample. CONCLUSION: LA injections for the PS were found to be clinically effective. However, addition of CS to LA did not give an additional benefit. This gives us the idea that PS is mostly muscular in origin and responds well to both LA and LA+CS injections. PMID- 25794201 TI - Ultrasound-guided greater occipital nerve block: an efficient technique in chronic refractory migraine without aura? AB - BACKGROUND: The effectiveness of greater occipital nerve block (GONB) in patients with primary headache syndromes is controversial. Few studies have been evaluated the usefulness of GONB in patients with migraine without aura (MWOA). OBJECTIVE: To compare the effectiveness of ultrasound-guided GONB using bupivacaine 0.5% and placebo on clinical improvement in patients with refractory MWOA in a randomized, double-blinded clinical trial. STUDY DESIGN: A prospective, randomized, placebo controlled, double-blind pilot trial. SETTING: Physical medicine and rehabilitation and neurology departments of a University Hospital. METHODS: Thirty-two patients with a diagnosis of MWOA according to the International Classification of Headache Disorders-II criteria were included in the study. Twenty-three patients (2 men, 21 women) completed the study. They were randomly assigned to receive either GONB with local anesthetic (bupivacaine 0.5% 1.5 mL) or greater occipital nerve (GON) injection with normal saline (0.9% 1.5 mL). Ultrasound-guided GONB was performed to more accurately locate the nerve. All procedures were performed using a 7 - 13 MHz high-resolution linear ultrasound transducer. The treatment group was comprised of 11 patients and the placebo group was comprised of 12 patients. The primary outcome measure was the change in the headache severity score during the one-month post-intervention period. Headache severity was assessed with a visual analogue scale (VAS) from 0 (no pain) to 10 (intense pain). RESULTS: In both groups, a decrease in headache intensity on the injection side was observed during the first post-injection week and continued until the second week. After the second week, the improvement continued in the treatment group, and the VAS score reached 0.97 at the end of the fourth week. In the placebo group after the second week, the VAS values increased again and nearly reached the pre-injection levels. The decrease in the monthly average pain intensity score on the injected side was statistically significant in the treatment group (P = 0.003), but not in the placebo group (P = 0.110). No statistically significant difference in the monthly average pain intensity score was observed on the uninjected side in either group (treatment group, P = 0.994; placebo group, P = 0.987). No serious side effect was observed after the treatment in either group. Only one patient had a self-limited vaso vagal syncope during the procedure. LIMITATIONS: This trial included a relatively small sample. This may have been the result of the inclusion of only those patients who correctly completed their pain diaries. Another major limitation is the short follow-up duration. Patients were followed for one month after the injection, thus relatively long-term effects of the injection have not been observed. CONCLUSIONS: Ultrasound guided GONB with 1.5 mL of 0.5% bupivacaine for the treatment of migraine patients is a safe, simple, and effective technique without severe adverse effects. To increase the effectiveness of the injection, and to implement the isolated GONB, ultrasonography guidance could be suggested. PMID- 25794203 TI - Effects of stellate ganglion block on sedation as assessed by bispectral index in normal healthy volunteers. AB - BACKGROUND: The sympathetic nervous system plays an important role in the arousal response. Recently, the stellate ganglion block (SGB) was found to effectively treat anxiety and night awakening in humans and decrease electroencephalogram (EEG) indices of arousal responses in rat. But, the role of the sympathetic block in human arousal responses has not yet been studied. OBJECTIVE: We performed this prospective, double-blinded, controlled volunteer study to investigate the sedative effects and bispectral index (BIS) changes of SGB. STUDY DESIGN: A randomized, double-blind trial. SETTING: Single academic medical center. METHODS: This study was approved by the Ethics Committee of Kyungpook National University Hospital (ref: KNUH-10-1081) and registered with CRiS (Clinical Research Information Service, http://cris.cdc.go.kr, ref: KCT0000036, 2010. 9.24). Twenty healthy volunteers were enrolled in this study. The volunteers were randomly assigned to one of 2 groups: the SGB group (n = 10) and the sham group (n =10). Volunteers in SGB group received SGB and volunteers in the sham group received a sham procedure. BIS value, heart rate, and blood pressure were measured before and 5, 10, 20, and 30 minutes after the procedure. Observer's Assessment of Alertness/Sedation (OAA/S) scores were assessed before and 10 and 30 minutes after the intervention. RESULTS: In the SGB group, BIS values and OAA/S scores significantly decreased after the intervention as compared to baseline (P < 0.05). The values were also significantly decreased in the SGB group when compared to the values in sham group after the intervention (P < 0.05). There was a significant change of mean blood pressure 10 to 30 minutes after SGB (P < 0.05). There were no differences in heart rate during study period between groups. LIMITATIONS: This study is limited by a relatively small sample size. CONCLUSIONS: This study showed that SGB has a sedative effect in normal healthy volunteers, as evidenced by decreased OAA/S scores and BIS values. PMID- 25794204 TI - Transforaminal endoscopic treatment of lumbar radiculopathy after instrumented lumbar spine fusion. AB - BACKGROUND: Transforaminal endoscopic discectomy and foraminotomy is a well described minimally invasive technique for surgically treating lumbar radiculopathy caused by a herniated disc and foraminal narrowing. OBJECTIVE: To describe the technique and feasibility of transforaminal foraminoplasty for the treatment of lumbar radiculopathy in patients who have already undergone instrumented spinal fusion. STUDY DESIGN: Retrospective study. SETTING: Hospital and ambulatory surgery center METHODS: After Institutional Review Board approval, charts from 18 consecutive patients with lumbar radiculopathy and instrumented spinal fusions who underwent endoscopic procedures between 2008 and 2013 were reviewed. RESULTS: The average pain relief one year postoperatively was reported to be 67.0%, good results as defined by MacNab. The average preoperative VAS score was 9.14, indicated in our questionnaire as severe and constant pain. The average one year postoperative VAS score was 3.00, indicated in our questionnaire as mild and intermittent pain. LIMITATIONS: This is a retrospective study and only offers one year follow-up data for patients with instrumented fusions who have undergone endoscopic spine surgery. CONCLUSION: Transforaminal endoscopic discectomy and foraminotomy could be used as a safe, yet, minimally invasive and innovative technique for the treatment of lumbar radiculopathy in the setting of previous instrumented lumbar fusion. IRB approval: Meridian Health: IRB Study # 201206071J PMID- 25794205 TI - Event-related cortical processing in neuropathic pain under long-term spinal cord stimulation. AB - BACKGROUND: Several mechanisms were suggested in the past to explain the beneficial effect of spinal cord stimulation (SCS) in patients suffering from neuropathic pain. Little is known about potential supraspinal mechanisms. OBJECTIVE: In this study cortical signaling of patients with neuropathic pain and successful long-term treatment with SCS was analyzed. STUDY DESIGN: Observational study. SETTING: University hospital, neurosurgical department, outpatient clinic for movement disorders and pain, institute for cognitive and clinical neuroscience. METHODS: Nine patients with neuropathic pain of a lower extremity with a lasting response to chronic SCS were included. Cortical activity was analyzed using event-related potentials of the electroencephalogram after non painful and painful stimulation. Each patient was tested under the effect of long term SCS and 24 hours after cessation of SCS. Cortical areas involved in the peaks of evoked potentials were localized using a source localization method based on a fixed dipole model. RESULTS: Detection threshold and intensity of non painful stimulation did not differ significantly on both sides. Pain threshold was significantly lower on the neuropathic side under the effect of SCS (P = 0.03). Bilateral pain thresholds were significantly lower (P = 0.03 healthy side, P = 0.003 neuropathic side) in 5 patients with increased pain after cessation of SCS. Under the effect of SCS cortical negativities (N1, N2, N3) and positivities (P1) demonstrated bilaterally comparable amplitudes. After cessation of SCS, decreased threshold for peripheral stimulation resulted in lowered negativities on both sides. The positivity P1 was differentially regulated and was reduced more contralateral to the unaffected side. N2 was localized at the sensory representation of the leg within the homunculus. The main vector of P1 was localized within the cingular cortex (CC) and moved more anteriorly under the effect of SCS. LIMITATIONS: The exact time span that SCS continues to have an effect is not known. However, due to patient discomfort discontinuation of SCS therapy was not prolonged over a 24 hour period. Further limitations were the low number of patients who agreed to discontinue SCS therapy for research purposes. CONCLUSIONS: Long-term SCS for treatment of neuropathic pain influenced both pain thresholds and cortical signalling. Source localization of P1 suggests involvement of regions involved in cognitive/associative processing of pain. PMID- 25794206 TI - Different analgesic effects of intrathecal endomorphin-2 on thermal hyperalgesia and evoked inflammatory pain in ovariectomized rats. AB - Hormone replacement remains one of the common therapies for menopause-related pain but is associated with risk of orofacial or back pain. Spinal endomorphin-2 (EM-2) is involved in varied pain and its release is steroid-dependent, but whether increasing spinal EM-2 can inhibit thermal hyperalgesia and inflammatory pain in ovariectomized (OVX) female rats, an animal model mimicking menopause, is not clear, nor is the potential involvement of spinal mu-opioid receptor (MOR). In the current study, we revealed that the temporal decrease of spinal EM-2 is accompanied with OVX-induced thermal hyperalgesia that was dose-dependently attenuated by intrathecal (IT) delivery of EM-2. The subcutaneous injection of formalin-induced inflammatory pain in OVX rats was exacerbated and IT delivery of EM-2 dose-dependently inhibited the inflammatory pain. However, the ED50 for IT delivery of EM-2 on thermal hyperalgesia is smaller than that on inflammatory pain in OVX rats, suggesting different contributions of the EM-2 system to these 2 pain modalities in OVX rats. IT pretreatment with MOR antagonist, beta funaltrexamine (beta-FNA), attenuated IT EM-2 analgesia on both thermal hyperalgesia and inflammatory pain in OVX rats. Furthermore, IT delivery of EM-2 did not affect the animals' locomotion or anxiety status. Our findings suggested that IT EM-2 might be a safer analgesia strategy than hormone replacement therapy in reducing risk of orofacial or back pain. However, a long-lasting form of EM-2 with less tolerance is needed to induce sustained analgesia. PMID- 25794208 TI - Elusive "Doc Fix": Groundhog Day 2015 for sustainable growth rate (SGR). AB - In summary, the SGR continues to hang like Damocles sword over physicians. To understand health care needs, we need to separate basic health care needs from economic mandates, and health insurance from health care coverage. The SGR flux represents another meaningful uncertainty to this health care conundrum. PMID- 25794209 TI - First, do no harm by adopting evidence-based policy initiatives: the overselling of ICD-10 by congress with high expectations. AB - While it appears to be beneficial to apply a detailed disease classification system, the costs, cash flow disruptions, and increased investments with physician time incorporated into learning these processes, patient care might unfortunately suffer. This is essentially an unfunded mandate with much of the burden of transitioning to ICD-10 falling on health care providers,especially small independent practices. This will impact interventional pain management practices substantially.Further, as we have shown in previous manuscripts,the so called advantages of multiple codes with specificity and granularity does not translate into reality where some specificity is actually lost for various codes. As Grimsley and O'Shea (1) have described in clinical practices, doctors do not treat codes, but they treat patients according to the individual clinical condition.A doctor will be losing valuable time and also will not be able to obtain meaningful information due to burdensome regulations of meaningful use, PQRS,value-based reimbursement, electronic prescribing,and now a major impact with change to ICD-10. Thus,very little benefit will be seen by practitioners, which cannot be said for the health care information industry.With overwhelming regulatory atmosphere created by numerous federal regulations and those including under the Affordable Care Act (15), there is no evidence that ICD-10 is needed, there is no evidence that it will be effective, and, finally, there is preponderance of evidence of adverse consequences. Thus, Congress should be cautious in imposing further regulations on already strained independent practices with ongoing regulations and imposing yet another unfunded mandate on the medical profession. PMID- 25794210 TI - An updated assessment of utilization of interventional pain management techniques in the Medicare population: 2000 - 2013. AB - BACKGROUND: The rapid increase in the prevalence of chronic pain and disability, and the explosion of interventional pain management associated health care costs are a major concern for our community. Further, the increasing utilization of numerous modalities of treatments in managing chronic pain, continue to escalate at a pace which may not be sustainable. There are multiple regulations in place to control the growth of health care expenditures which seem to have been largely ineffective. Among the various modalities utilized in managing chronic pain, interventional techniques have shown a significant increase in their utilization in the face of continued debate with respect to the accuracy of diagnostic interventions and the efficacy of therapeutic interventions. OBJECTIVE: To update and assess the utilization of interventional techniques in chronic pain management in fee-for-service Medicare population. STUDY DESIGN: An updated analysis of the growth of interventional techniques in managing chronic pain in fee-for-service Medicare beneficiaries from 2000 through 2013. METHODS: The data were derived and analyzed utilizing the Centers for Medicare and Medicaid Services (CMS) Physician Supplier Procedure Summary Master Data from 2000 through 2013. RESULTS: From 2000 through 2013, in fee-for-service Medicare beneficiaries, the overall utilization of interventional techniques services increased 236% at an annual average growth of 9.8%, whereas the per 100,000 Medicare population utilization increased 156% with an annual average growth of 7.5%. During this period, the US population increased 12% with an annual average increase of 0.9%, whereas those above 65 years of age increased 27% with an annual average increase of 1.9%. Total Medicare beneficiaries increased 31% with an annual average increase of 2.1%, with an overall increase of 64% for those above 65 years of age, an increase of 26%, constituting 17% of the US population in 2013. The overall increases in epidural and adhesiolysis procedures were 165% compared to 102% per 100,000 fee-for-service population with annual average increases of 7.8% and 5.6%. Facet joint and sacroiliac joint injections increased 417% for services with an annual average increase of 13.5%, whereas the rate per 100,000 fee-for service Medicare beneficiaries increased 295% with an annual average increase of 11.1%. LIMITATIONS: Limitations of this assessment include the lack of inclusion of participants from Medicare Advantage plans, lack of appropriate available data for state-wide utilization, and potential errors in documentation, coding, and billing. CONCLUSION: This update once again shows a significant increase in interventional techniques in fee-for-service Medicare beneficiaries from 2000 through 2013 with an increase of 156% per 100,000 Medicare population with an annual average increase of 7.5%. During this period the Medicare population increased 31% with an annual average increase of 2.1%. PMID- 25794211 TI - Safeguards to prevent neurologic complications after epidural steroid injections: analysis of evidence and lack of applicability of controversial policies. PMID- 25794212 TI - Perioperative lidocaine infusion reduces the incidence of post-mastectomy chronic pain: a double-blind, placebo-controlled randomized trial. AB - BACKGROUND: Chronic post-surgical pain (CPSP) is a not uncommon complication after mastectomy, with a reported incidence between 20% and 68%. Careful dissection, the use of minimally invasive surgical techniques, and attempts to reduce the associated inflammatory and hyperalgesic responses are suggested methods to prevent CPSP. OBJECTIVE: To determine if the use of perioperative lidocaine infusion is associated with decreased incidence of CPSP after mastectomy. STUDY DESIGN: Double-blind, placebo-controlled randomized trial. METHODS: This is a secondary analysis of data from 61 out of 71 patients who underwent mastectomy for breast cancer. Patients were randomized to either placebo (Group P; n = 27) or intravenous lidocaine (Group L; n = 34, bolus 1.5 mg/kg at induction, then infusion at 2 mg/kg/hr, up to 2 hours after the end of surgery) in a prospective double-blind design. CPSP was assessed at 6 months after surgery. Stepwise logistic regression analysis was performed to assess the efficacy of lidocaine. RESULTS: Overall 12 (20%) patients developed CPSP, 8 (30%) in the placebo group and 4 (12%) in the lidocaine group. Predictive factors for CPSP that remained significant after multivariate analysis included lidocaine (associated with a 20-fold decrease in CPSP, P = 0.013), breast implant placement (associated with a 16-fold increase in CPSP, P = 0.034), and radiotherapy (associated with a 29-fold increase in CPSP, P = 0.008). LIMITATIONS: Small sample size. CONCLUSION: Perioperative lidocaine administration was associated with a decreased incidence of CPSP, while breast implant placement and radiotherapy were associated with an increased incidence. These findings suggest a protective effect of lidocaine on CPSP development in mastectomy patients. PMID- 25794213 TI - Pulsed radiofrequency for chronic inguinal neuralgia. AB - BACKGROUND: Chronic inguinal neuralgia has been reported after inguinal herniorrhaphy, caesarean section, appendectomy, and trauma to the lower quadrant of the abdomen or inguinal region. OBJECTIVES: This study was designed to evaluate the efficacy of pulsed radiofrequency in management of chronic inguinal neuralgia. STUDY DESIGN: Randomized, double-blind controlled trial. SETTING: Hospital outpatient setting. METHODS: Twenty-one patients were allocated into 2 groups. Group 1 received 2 cycles of pulsed radiofrequency (PRF) for each nerve root. In Group 2, after stimulation, we spent the same time to mimic PRF. Both groups received bupivacaine 0.25% +' 4 mg dexamethasone in 2 mL for each nerve root. Visual Analogue Scale (VAS) was assessed. Duration of the first block effective pain relief was reported. Repeated PRF blockade was allowed for any patient who reported a VAS > 30 mm in both groups during the one year follow-up period. The number and duration of blocks were reported and adverse effects were also reported. RESULTS: Significantly longer duration of pain relief was noticed in Group 1 (P = 0.005) after the first block, while the durations of pain relief of the second block were comparable (P = 0.59). In Group 1 the second PRF produced pain relief from the twenty-fourth week until the tenth month while in Group 2, pain relief was reported from the sixteenth week until the eighth month after the use of PRF. All patients in Group 2 received 3 blocks (the first was a sham PRF) during the one year follow-up period. Meanwhile, 2 PRF blocks were sufficient to achieve pain relief for patients in Group 1 except 4 patients who needed a third PRF block. No adverse events were reported. LIMITATIONS: Small sample size. CONCLUSION: For intractable chronic inguinal pain, PRF for the dorsal root ganglion represents a promising treatment modality. PMID- 25794214 TI - Blood testing in chronic pain management. AB - Blood testing is quickly becoming a useful laboratory tool for opioid prescribers who wish to document and assess patient tolerance, more objectively monitor patient safety, and evaluate patient compliance using information that is not available with traditional urine drug testing (UDT). Blood testing does not need to be performed as frequently as UDT but provides extremely valuable information which can be used to more accurately evaluate patient compliance and assist with interpreting blood toxicology results commonly used in impairment or overdose cases. This narrative review presents the current evidence supporting the use of blood testing within the chronic pain management setting. In addition, this review aims to introduce and discuss the role of routine blood testing within the chronic pain management setting. Blood testing for the purpose of documenting opioid tolerance is a relatively novel tool for pain physicians and as such this review is not intended to be a comprehensive or exhaustive review of the scientific or medical literature. Prescribers must also be aware that this type of laboratory testing need only be administered to chronic pain patients receiving daily opioid therapy. Patients taking infrequent, low dose, or as needed medications are not anticipated to benefit from this type of test. Based on the complexity of both achieving acceptable outcomes with opioid treatment and the legal and societal issues at hand, we feel that the addition of blood concentration levels will become the standard of care in the near future. PMID- 25794215 TI - Assessment of clinical outcomes of cervical epidural neuroplasty using a Racz catheter and predictive factors of efficacy in patients with cervical spinal pain. AB - BACKGROUND: Epidural neuroplasty using the Racz catheter has a therapeutic effect in patients with cervical disc herniation and central stenosis who do not respond to fluoroscopically guided epidural injections. OBJECTIVE: To evaluate the clinical outcomes of cervical epidural neuroplasty in patients with posterior neck and upper extremity pain and to demonstrate correlations between predictive factors and unsuccessful results of cervical epidural neuroplasty. STUDY DESIGN: Observational study. SETTING: An interventional pain management practice in a university hospital. METHODS: Outcome measures were obtained using the numeric rating scale (NRS) for total pain, neck pain, arm pain, and sleep disturbance; and the neck pain and disability scale (NPDS); as well as opioid consumption at preprocedure, one month, 3, 6, and 12 months after procedure. Successful epidural neuroplasty was defined as 50% or greater reduction from the preprocedure NRS for total pain, and at least a 40% reduction in the NPDS. We obtained clinical data and radiologic findings to evaluate correlations between predictive factors and efficacy of epidural neuroplasty. RESULTS: Of the 169 patients, successful outcomes were observed in 108 patients (63.9%) at one month following the procedure, in 109 patients (64.5%) at 3 months, in 96 patients (56.8%) at 6 months, and in 89 patients (52.7%) at 12 months. Previous surgery, spondylolisthesis, and ossification of the posterior longitudinal ligament were significantly associated with unsuccessful outcomes as measured by NRS and NPDS (P < 0.05). LIMITATIONS: Limitations of this evaluation include the lack of a placebo group. CONCLUSIONS: Cervical epidural neuroplasty may be an effective treatment for pain reduction and functional improvement in patients with cervical spinal pain who did not respond to conservative treatment, and may decrease surgical demand. Previous surgery, spondylolisthesis, and ossification of the posterior longitudinal ligament are associated with unsuccessful outcomes of epidural neuroplasty. PMID- 25794216 TI - Patients with refractory back pain treated in the emergency department: is immediate interlaminar epidural steroid injection superior to hospital admission and standard medical pain management? AB - BACKGROUND: Hospital admissions for back pain are prolonged, costly, and common. Epidural steroid injections are frequently performed in an outpatient setting with an excellent safety and efficacy profile. OBJECTIVES: The purpose was to review data from patients with severe pain that did not respond to aggressive medical treatment in the emergency department (ED) and determine the effectiveness of an interlaminar epidural steroid injection (ESI) in this patient population. STUDY DESIGN: Retrospective matched cohort design. SETTING: Single urban emergency department at a tertiary referral center. METHODS: A retrospective cohort comparison pairing 2 groups that both failed aggressive pain control in the ED was performed. The epidural injection group (1ESI) received an interlaminar ESI while in the ED. The standard therapy group (2ST) was admitted for medical pain management. Groups were matched for pain intensity, age, and symptom duration. RESULTS: Thirty-five patients in 1ESI (NRS 8.8, 5 - 10, 0.35), and 28 patients in 2ST (NRS 8.9, 4 - 10, 1.7). Pain score after ESI 0.33 (0 - 2, 0.6); all were discharged. Pain score on day 1 of hospital admission for 2ST was 8.7 (7 - 10, 1.5). Total ED time was 8 hours for 1ESI and 13 hours for 2ST (P < 0.002). 1ESI patients received less narcotics while in the ED (P < 0.002) and were discharged home with less narcotics than 2ST (< 0.002). Average inpatient length of stay (LOS) for 2ST was 5 (1.5 - 15, 3.3) days. Cost of care was over 6 times greater for those patients admitted for pain management (P < 0.001). LIMITATIONS: Retrospective design, non-randomized sample, and a small patient population. CONCLUSION: An ED patient cohort with severe refractory pain was treated with an interlaminar ESI after failing maximal medical pain management while in the ED. Complete pain relief was achieved safely and rapidly. The need for inpatient admission was eliminated after injection. Costs were lower in the group that received an epidural injection. Narcotic requirements upon discharge were decreased as well. PMID- 25794217 TI - Clinical evaluation of transforaminal epidural steroid injection in patients with gadolinium enhancing spinal nerves associated with disc herniation. AB - BACKGROUND: Transforaminal epidural steroid injection (TFESI) of corticosteroid is frequently employed to mitigate the painful and disabling symptoms of lumbar disc herniation. However, the treatment outcome of TFESI in patients with radicular pain and inflamed neural structures as assessed by contrast-enhanced magnetic resonance imaging (MRI) has not been forthcoming. OBJECTIVES: To investigate functional improvement and pain reduction following TFESI in patients found to have nerve inflammation as evidenced by gadolinium-enhanced (MRI). STUDY DESIGN: Retrospective assessment. SETTING: Tertiary spinal intervention center, Daegu, Korea. METHODS: Thirty-seven patients were selected by strict inclusion criteria. Patients were classified into enhancing and non-enhancing groups as evidenced by gadolinium-enhanced MRI. The enhancing group was further divided into pre-dorsal roog ganglion (DRG) only enhanced group and pre-DRG and post-DRG enhanced group. Clinical outcomes were evidenced by numeric rating scale (NRS) and Oswestry disability index (ODI) at pretreatment, one week, and 4 weeks after treatment. RESULTS: The improvement of NRS and ODI in the enhanced group was greater than those of the non-enhanced group, at one week and 4 weeks after TFESI (P < 0.05). However there was no significant difference in improvement of NRS and ODI between pre-DRG only enhanced group and pre-DRG and post-DRG enhanced group at one week and 4 weeks after TFESI. LIMITATIONS: Retrospective chart review with a small sample size. CONCLUSION: The improvement of NRS and ODI in the enhanced group was significantly greater than those of the non-enhanced group after TFESI. Radicular pain and functional impairment in the presence of gadolinium enhancing spinal neural structures and lumbar disc herniation may be more responsive to TFESI than patients without enhancing neural structures. PMID- 25794218 TI - Comparison of high-viscosity cement vertebroplasty and balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures. AB - BACKGROUND: Percutaneous vertebroplasty is a widely used vertebral augmentation procedure for treating osteoporotic vertebral compression fractures (OVCFs). But high cement leakage rate caused by a low-viscosity cement and high injection pressure has limited its general use. Balloon kyphoplasty (BKP) and high viscosity cement vertebroplasty (HVCV) are 2 modifications of vertebroplasty designed to decrease cement leakage. OBJECTIVE: To assess the safety and efficacy of HVCV compared with BKP. STUDY DESIGN: A prospective cohort study. SETTING: Department of Spine Surgery, an affiliated hospital of a medical university. METHOD: One hundred seven patients suffering from painful OVCFs were randomly assigned into HVCV or BKP groups. Visual Analog Scale (VAS), Oswestry Disability Index (ODI), cement leakage, and vertebral height restoration were evaluated. All occurring complications and injected cement volumes were recorded. The follow-up time was one year. RESULTS: VAS and ODI scores improved in both groups, and did not differ significantly between the 2 groups. More cement was used in the BKP group than in HVCV group (4.22 vs. 3.31 mL, P < 0.0001). The incidence of cement leakage in the HVCV group was lower than that of the BKP group (13.24% vs 30.56%, P < 0.05). No symptomatic cement leakages occurred in the HVCV group. In the BKP group, one patient experienced discogenic back pain related to a disc leak, and another patient had asymptomatic cement emboli in the lung related to venous leakage. The mean compression rate before the procedure was 29.98% in the HVCV group and 28.67% in the BKP group (P = 0.94). The vertebral height was improved significantly and maintained at one-year follow-up in both groups. BKP was more effective in vertebral height restoration than HVCV (44.87% vs. 23.93%, P < 0.0001). There was one case of a new adjacent vertebral fracture in the HVCV group (2%), and 4 cases of new nonadjacent vertebral fractures in the BKP group (7.84%) (P = 0.18). LIMITATIONS: A single-center and relatively small-sample size study. CONCLUSION: HVCV and BKP are safe and effective in improving quality of life and relieving pain. HVCV has a lower cement leakage rate, whereas BKP is more effective in vertebral height restoration. Subsequent fractures are not different between the 2 groups. PMID- 25794219 TI - Pain relief scale is more highly correlated with numerical rating scale than with visual analogue scale in chronic pain patients. AB - The pain relief scale (PRS) is a method that measures the magnitude of change in pain intensity after treatment. The present study aimed to evaluate the correlation between PRS and changes in pain determined by the visual analogue scale (VAS) and numerical rating scale (NRS), to confirm the evidence supporting the use of PRS. Sixty patients with chronic spinal pain that had a VAS and NRS recorded during an initial examination were enrolled in the study. One week later, the patients received an epidural nerve block, then VAS, NRS, and PRS assessments were performed. Differences between VAS and NRS were compared to the PRS and scatter plots and correlation coefficient were generated. The differences and magnitude of decrease in the VAS and NRS raw data were converted to percentile values, and compared to the PRS. Both VAS and NRS values exhibited strong correlations (> 0.8) with PRS. Further, the differences between the VAS PRS R (0.859) and NRS-PRS R (0.915) were statistically significant, (P = 0.0259). Compared to PRS, the VAS and NRS percentile scores exhibited higher correlation coefficients than scores based on the raw data differences. Furthermore, even when converted to a percentile, the NRS%-PRS R (0.968) was higher than the VAS% PRS R (0.904), P = 0.0001. The results indicated that using the PRS together with NRS in pain assessment increased the objectivity of the assessment compared to using only VAS or NRS, and may have offset the limitations of VAS or NRS alone. PMID- 25794220 TI - Pressure pain and isometric strength of neck flexors are related in chronic tension-type headache. AB - BACKGROUND: In patients with chronic tension-type headache (CTTH) changes in pressure pain in the cervical region are associated with peripheral or central sensitization. It is hypothesized that an increase of isometric strength of neck flexors would lead to a decrease of pressure pain in CTTH, as an expression of reduced peripheral or central sensitization OBJECTIVE: In this study we aimed to analyze the correlation between change in isometric strength of the neck flexors and change in pressure pain scores (PPS) in patients with CTTH. STUDY DESIGN: Comparative analysis of data from previous study. SETTING: Primary healthcare center. METHODS: Data from 145 patients with CTTH who underwent a manual therapy program including isometric strength training of the neck flexors were analyzed at 8 and 26 weeks post-treatment. PPS were measured as a total of pain scores on a numeric rating scale (score 0 to 10) on application of a pressure stimulus of 3kg/cm at 8 cervical- and suboccipital muscles. Isometric strength of the neck flexors was measured in seconds. Correlations were computed between changes in PPS and isometric neck flexor strength. RESULTS: Isometric strength of neck flexors scored significantly different compared to baseline measurement (mean 30.0 seconds, sd:25.2), and increased with a mean difference of 17.33 seconds (95%CI: 20.61 to 14.05) at 8 weeks and 19.18 seconds (95%CI: 23.48 to 14.87) at 26 weeks. Similarly, compared to PPS baseline measurement (31.6 points, sd:18.6), mean difference in PPS was significantly decreased at 8 and 26 weeks: -11.3 points (95%CI: -8.77 to -13.83) and -11.15 points (95%CI: -8.31 to -13.99). There is a negative correlation between changes in PPS and changes in isometric strength of neck flexors which is weak at 8 weeks (r = -0.243, P = 0.004) and moderate at 26 weeks (r = -0.318, P < 0.000). LIMITATIONS: Correlational analysis. CONCLUSION: Decrease in PPS correlates with increases in isometric strength of neck flexors in patients with CTTH in short- and long-term. PMID- 25794221 TI - Trigeminal neuralgia induced by cobra venom in the rat leads to deficits in abilities of spatial learning and memory. AB - BACKGROUND: Patients with chronic pain usually suffer from cognitive impairment, with memory deterioration being the most common deficit that affects daily functioning and quality of life. The causes for this impairment are not clear despite intensive clinical studies. Few studies have evaluated impaired learning using animal models of persistent pain. OBJECTIVE: In this study, a new trigeminal neuralgia model induced by cobra venom was adopted to explore effects of chronic pain on spatial learning and memory in rats. STUDY DESIGN: Controlled animal study. SETTING: Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University. METHODS: Thirty adult male Sprague-Dawley rats were randomly divided into 2 groups (n = 15): NS control group and cobra venom group, 0.9% sterile saline or cobra venom solution was injected into the sheath of the infraorbital nerve (ION), respectively. The development of trigeminal neuralgia was accessed by changes in free behavioral activity 3 days before the surgery and 3, 7, 12, 20, and 30 days after the surgery to identify whether the model was successful or not. Morris water maze test determined the abilities of spatial learning and memory at the time points before the surgery, and 2 weeks and 5 weeks after the surgery. We also observed the ultrastructure of the ION and medulla oblongata of rats following 8 weeks of chronic trigeminal neuropathic pain. RESULTS: Rats with the cobra venom injection displayed significantly more face grooming and fewer exploratory activities compared to the NS control group or baseline (P < 0.01). Both groups improved their latency to reach the platform with the largest difference on the first day (P < 0.01), but without memory deficits in a probe trial for the second water maze protocol. For the third water maze testing, the rats in the cobra venom group experienced decreased abilities of spatial learning and memory, a longer latency with spatial memory deficits during the probe trial (P < 0.05). At the ultrastructural level, we found changes in the medulla oblongata after cobra venom injection resulting in severe demyelination and loss of axons that might be implicated in the causes of cognitive deficits. LIMITATIONS: Limitations include partial vision loss in the eye on the lesion side of the rats that might be missed and the absence of evaluating the ultrastructural changes in other parts of the brain. CONCLUSIONS: The results of this study suggest that trigeminal neuralgia induced by cobra venom in adult rats can impair spatial learning and memory function over time and results in demonstrable changes in the ultrastructure of the medulla oblongata. This new animal model may be useful for future studies on the effect of chronic pain on learning and cognition. PMID- 25794222 TI - Intervertebral disc temperature mapping during disc biacuplasty in the human cadaver. AB - BACKGROUND: Intradiscal biacuplasty (IDB) is a novel heating therapy using cooled radiofrequency (RF), which may offer relief for discogenic pain. Effective neuroablation may be achieved intradiscally at higher lesion temperatures. The safety of intradiscal heating at elevated temperatures using cooled RF has never been reported. OBJECTIVE: The purpose of this study is to map the intradiscal and peridiscal temperatures when IDB is performed at increased temperature using a modified lesion approach. The resulting temperature profiles are used to assess the safety and theoretical efficacy of this approach to ablate nociceptors in the posterior annulus. STUDY DESIGN: Research article. METHODS: Eleven lumbar discs in a non-perfused human cadaver were treated by IDB. Temperature profiles in the disc during bipolar lesion at 50 degrees C followed by 2 monopolar lesions at 60 degrees C were mapped using custom thermocouples. Temperatures inside the disc, at the nerve roots, and in the midline ventral epidural space were monitored in real-time using a data-collection system with custom RF filters. SETTING: Human research laboratory. RESULTS: Higher maximum temperature was reached intradiscally, and a larger volume of tissue was exposed to neuroablative temperature (> 45 degrees C). Temperature at the nerve roots and in the epidural space increased by 2.4 degrees C +/- 2.6 degrees C and 4.9 degrees C +/- 1.9 degrees C (mean +/- SD), respectively, during bipolar lesion. Similarly, temperature increased by 2.2 degrees C +/- 1.9 degrees C and 0.8 degrees C +/- 1.3 degrees C at the nerve roots and in the epidural space, respectively, during monopolar lesion. LIMITATIONS: Limitations include the ex vivo setting which lacks perfusion and may not reproduce in vivo conditions such as cerebrospinal fluid dynamics. CONCLUSIONS: The modified treatment paradigm showed intradiscal heating is achieved and is concentrated in the posterior annulus, suggesting minimal risk of thermal damage to the neighboring neural structures. Clinical benefits should be evaluated. PMID- 25794223 TI - Occult spinal dysraphism: a challenge in pain management. AB - Spina bifida is a common birth defect affecting the central nervous system and represents a group of neural tube defects caused by congenital dysraphic malformations of the vertebral column and/or spinal cord. The anatomy in these patients is challenging and includes structural and vascular abnormalities including arteriovenous malformation or fistulae, and fatty substitution of paravertebral tissues. A magnetic resonance image (MRI) is needed for management of patients with lumbar radiculopathy and clinical features suspicious of occult spinal dysraphism. Risks and benefits of lumbar epidural steroids should be discussed comprehensively with those patients and in the best case scenario be avoided. Occult spinal dysraphism poses a clinical dilemma for interventional pain specialists managing those patients with lumbar radiculopathy. We report a case of occult spinal dysraphism discovered following the development of post traumatic radicular symptoms. PMID- 25794224 TI - Management of pain secondary to temporomandibular joint syndrome with peripheral nerve stimulation. AB - BACKGROUND: Temporomandibular joint syndrome, or Costen syndrome, is a clinically diagnosed disorder whose most common symptoms include joint pain and clicking, difficulty opening the mouth, and temporomandibular joint discomfort. The temporomandibular joint (TMJ) is supplied by the auriculotemporal nerve, a collateral branch of the mandibular nerve (the V3 branch of the trigeminal nerve). OBJECTIVES: The aim of this study is to assess the effectiveness and safety of permanent peripheral nerve stimulation to relieve TMJ pain. STUDY DESIGN: This case series is a prospective study. SETTING: Pain Unit of a regional universitary hospital. METHODS: The study included 6 female patients with temporomandibular pain lasting from 2 to 8 years that did not respond to intraarticular local anesthetic and corticoid injections. After a positive diagnostic block test, the patients were implanted with quadripolar or octapolar leads in the affected preauricular region for a 2-week stimulation test phase, after which the leads were connected to a permanent implanted pulse generator. Results of the visual analog scale, SF-12 Health Survey, Brief Pain Inventory, and drug intake were recorded at baseline and at 4, 12, and 24 weeks after the permanent implant. RESULTS: Five out of 6 patients experienced pain relief exceeding 80% (average 72%) and received a permanent implant. The SF-12 Health Survey results were very positive for all specific questions, especially items concerning the physical component. Patients reported returning to normal physical activity and rest at night. Four patients discontinued their analgesic medication and 1 patient reduced their gabapentin dose by 50%. LIMITATIONS: Sample size; impossibility of placebo control. CONCLUSION: Patients affected with TMJ syndrome who do not respond to conservative treatments may find a solution in peripheral nerve stimulation, a simple technique with a relatively low level of complications. PMID- 25794225 TI - Intrapelvic obturator internus muscle injections: a novel fluoroscopic technique. AB - The obturator internus (OI) muscle is important in adult chronic noninfectious pelvic, perineal, gluteal, and retrotrochanteric pain syndromes. Evaluation and management of these patients' pain can be challenging because of the complex anatomy of this region, broad differential diagnosis, and lack of specific physical examination findings. Consequently, several clinicians have advocated the use of image guided injections to assist in the accurate diagnosis of OI related symptoms and provide symptomatic relief to affected patients. We present 2 case series describing a novel fluoroscopically guided contrast controlled transpectineal approach to intrapelvic OI injections. Unlike prior fluoroscopically guided OI injection techniques, the approach described in the present 2 cases utilized multiple standard pelvic views, thus facilitating optimal needle positioning in three-dimensional space. This technique utilized standard fluoroscopic pelvic views to accurately measure needle depth within the pelvic cavity permitting the bulk of the OI to be injected in a controlled and safe fashion. The first patient underwent a left intrapelvic OI muscle injection with bupivacaine 0.25% and 40 mg methylprednisolone. The average pre- and postprocedural visual analog pain scale scores were 5 out of 10 and 2 out of 10, respectively, with a self-reported 75% pain reduction. The second patient underwent a right intrapelvic OI muscle injection with bupivacaine 0.25% and 40 mg methylprednisolone. The average pre- and postprocedural visual analog scale scores were 8 out of 10 and 1 out of 10, respectively, with a self-reported 90% pain reduction. Larger scale studies should be undertaken to evaluate the therapeutic efficacy and generalized accuracy of this technique. PMID- 25794226 TI - Spontaneous muscle contraction with extreme pain after thoracotomy treated by pulsed radiofrequency. AB - BACKGROUND: Chronic post thoracotomy pain (CPTP) was a common complication after thoracotomy, while spontaneous muscle contraction (SMC) was very rare. Neuropathic pain components appeared in some CPTP patients. The patients with neuropathic pain (NPP) often suffered from more severe pain. OBJECTIVE: We presented a case of a 57 year- old Chinese male, suffering from SMC with extreme chronic pain after thoracotomy for 2 years. The patient was treated by pulsed radiofrequency (PRF). Then we reviewed the related progresses including recent view on NPP in CPTP, the possible mechanism of SMC, treatments for CTPT, and peripheral nerve treatments in NPP. STUDY DESIGN: Case report and review of the literature. METHODS: The patient was diagnosed as CPTP with SMC. After the experimental intercostal nerve block provided short-term analgesia, we performed PRF through the angulus costae on intercostal nerves under x-ray guidance. We performed PRF for 3 times in all, at an interval of 2 weeks. Then we had followed up the pain intensity, frequency and amplitude of SMC of this patient during the 2 years. RESULTS: The pain intensity decreased from 8 to 2 on the visual analogue scale (VAS). The frequency of muscle contraction was decreased by 90%, and the amplitude was decreased by 60%. The treatment also improved the patient's sleep quality. These improvements were stable in 2 years' follow-up. In our review of the literature, the SMC may be based on the pain-spasm-pain model. LIMITATION: Single case report. CONCLUSION: Pulsed radiofrequency provided good efficacy in CPTP with SMC in this case. PMID- 25794227 TI - The results of scaphoid avascular necrosis can be more than just wrist [corrected] pain in patients with spinal cord injury. PMID- 25794228 TI - Lumbar disc herniation with contralateral radiculopathy: do we neglect the epidural fat? AB - Lumbar disc herniation (LDH) is the most common cause of radiculopathy, whose pathological entity underlying nerve root compression is usually on the same side as the symptoms. However, LDH causing contralateral radiculopathy are sometimes encountered by pain physicians. There have been tremendous developments in the treatment options for LDH; the situation of LDH causing contralateral radiculopathy is indeed a dilemma for some pain physicians. We will report a case of a patient with a L4-5 disc herniation whose left herniated disc caused radiculopathy on the right side. After a percutaneous lumbar endoscopic discectomy via the side ipsilateral to the symptomatic side, this case obtained a significant symptom remission. The migrated epidural fat is discussed as a cause of associated contralateral neurological deficit. Only via a surgical approach ipsilateral to the herniated side, could there be a clinical improvement postoperatively. PMID- 25794229 TI - Early onset of syringomyelia presenting with hyperhidrosis and neuropathic pain in upper limbs in a paraplegic patient. PMID- 25794230 TI - Is hip originated pain misdiagnosed? PMID- 25794231 TI - Effect of buprenorphine on total intravenous anesthetic requirements during spine surgery. AB - Buprenorphine is a partial mu receptor agonist and kappa/delta antagonist commonly used for the treatment of opioid dependence or as an analgesic. It has a long plasma half-life and a high binding affinity for opioid receptors. This affinity is so high, that the effects are not easily antagonized by competitive antagonists, such as naloxone. The high affinity also prevents binding of other opioids, at commonly used clinical doses, to receptor sites - preventing their analgesic and likely minimum alveolar concentration (MAC) reducing benefits. This case report contrasts the anesthetic requirements of a patient undergoing emergency cervical spine surgery while taking buprenorphine with anesthetic requirements of the same patient undergoing a similar procedure after weaning of buprenorphine. Use of intraoperative neurophysiological monitoring prevented use of paralytics and inhalational anesthetics during both cases, therefore total intravenous anesthesia (TIVA) was maintained with propofol and remifentanil infusions. During the initial surgery, intraoperative patient movement could not be controlled with very high doses of propofol and remifentanil. The patient stopped moving in response to surgical stimulation only after the addition of a ketamine. Buprenorphine-naloxone was discontinued postoperatively. Five days later the patient underwent a similar cervical spine surgery. She had drastically reduced anesthetic requirements during this case, suggesting buprenorphine's profound effect on anesthetic dosing. This case report elegantly illustrates that discontinuation of buprenorphine is likely warranted for patients who present for major spine surgery, which necessitates the avoidance of volatile anesthetic and paralytic agents. The addition of ketamine may be necessary in patients maintained on buprenorphine in order to ensure a motionless surgical field. PMID- 25794232 TI - Steroid effects on upper limb functions in a patient with cervical spinal cord injury. PMID- 25794233 TI - Sacroiliac fascial lipocele could be a neglected cause of lumbosacral pain: case study of percutaneous endoscopic treatment. AB - The pathological entities commonly associated with lumbosacral pain are the intervertebral discs, facet joints or surrounding muscle. However, in the absence of diagnostic confirmation of the aforementioned structures, the diagnosis may become confusing and intractable. Sacroiliac fascial lipocele (SFL), namely, pannicular hernia, could be a neglected cause. First reported by Ficarra et al in 1952, it was highlighted by the formation of lipocele in the sacroiliac fascia. Mostly, it could be spontaneously eliminated under conservative therapy. However, for intractable pain, surgical intervention may be the only choice. We will first present a typical case of SFL which was treated by percutaneous endoscopic surgery. Ultimately, a satisfactory outcome was achieved and maintained at 12 months follow-up. It is important to distinguish SFL some cases with lumbosacral back pain. Detailed physical examination, superficial ultrasonography and diagnostic nerve block are extremely valuable for acquiring a precise diagnosis. Overall, when considering the clinical outcome of such cases and the foregoing benefits, percutaneous endoscopic treatment could be an efficacious alternative treatment for SFL-related lumboscral back pain. PMID- 25794234 TI - Spinal anesthesia and not pneumorrhachis as cause for temporary paraplegia. PMID- 25794235 TI - Response to letter to the editor. PMID- 25794236 TI - Recovery facilitation with Montmorency cherries following high-intensity, metabolically challenging exercise. AB - The impact of Montmorency tart cherry (Prunus cerasus L.) concentrate (MC) on physiological indices and functional performance was examined following a bout of high-intensity stochastic cycling. Trained cyclists (n = 16) were equally divided into 2 groups (MC or isoenergetic placebo (PLA)) and consumed 30 mL of supplement, twice per day for 8 consecutive days. On the fifth day of supplementation, participants completed a 109-min cycling trial designed to replicate road race demands. Functional performance (maximum voluntary isometric contraction (MVIC), cycling efficiency, 6-s peak cycling power) and delayed onset muscle soreness were assessed at baseline, 24, 48, and 72 h post-trial. Blood samples collected at baseline, immediately pre- and post-trial, and at 1, 3, 5, 24, 48, and 72 h post-trial were analysed for indices of inflammation (interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, high sensitivity C-reactive protein (hsCRP)), oxidative stress (lipid hydroperoxides), and muscle damage (creatine kinase). MVIC (P < 0.05) did not decline in the MC group (vs. PLA) across the 72-h post-trial period and economy (P < 0.05) was improved in the MC group at 24 h. IL-6 (P < 0.001) and hsCRP (P < 0.05) responses to the trial were attenuated with MC (vs. PLA). No other blood markers were significantly different between MC and PLA groups. The results of the study suggest that Montmorency cherry concentrate can be an efficacious functional food for accelerating recovery and reducing exercise-induced inflammation following strenuous cycling exercise. PMID- 25794237 TI - Chewing gum increases energy expenditure before and after controlled breakfasts. AB - Chewing has been associated with improved satiation and satiety, but little is known about the metabolic impact of gum chewing. We tested the hypothesis that gum chewing would increase energy expenditure (EE) and reduce respiratory exchange ratio (RER) before and after a controlled test meal. Seventeen males and 13 females (age 21.5 +/- 6.6 years, body mass index 23.9 +/- 2.8 kg/m(2)) participated in a randomized crossover study in which subjects chewed sugar-free gum for a total of 1 h (3 sessions of 20 min) on the test day (GC) and did not chew gum on a control day (NG). EE and RER were measured by indirect calorimetry after an overnight fast. Subjects consumed a breakfast shake containing 30% of their measured energy needs, and then postprandial EE and RER were measured for 3 h. Blood glucose (GLC) was measured in the fasting and postprandial states at regular intervals. Fasting EE was higher during GC (1.23 +/- 0.04 kcal/min; 1 kcal = 4.2 kJ) than during NG (1.17 +/- 0.04 kcal/min; p = 0.016). Postprandial EE was also higher during GC (1.46 +/- 0.05 kcal/min) than during NG (1.42 +/- 0.05 kcal/min; p = 0.037). Fasting and postprandial RER and GLC did not differ between GC and NG. The findings demonstrate that GC is associated with higher fasting and postprandial EE without altering blood glucose or substrate oxidation as measured by RER. These data suggest that gum chewing potentially could influence short-term energy balance in this population; however, longer-term research is needed. PMID- 25794238 TI - Linking cardiorespiratory fitness classification criteria to early subclinical atherosclerosis in children. AB - It is unclear if cardiorespiratory fitness (CRF) can be used as a screening tool for premature changes in carotid intima-media thickness (cIMT) in paediatric populations. The purpose of this cross-sectional study was 3-fold: (i) to determine if CRF can be used to screen increased cIMT; (ii) to determine an optimal CRF cut-off to predict increased cIMT; and (iii) to evaluate its ability to predict increased cIMT among children in comparison with existent CRF cut offs. cIMT was assessed with high-resolution ultrasonography and CRF was determined using a maximal cycle test. Receiver operating characteristic analyses were conducted in boys (n = 211) and girls (n = 202) aged 11-12 years to define the optimal sex-specific CRF cut-off to classify increased cIMT (>=75th percentile). Logistic regression was used to examine the association between the CRF cut-offs with the risk of having an increased cIMT. The optimal CRF cut-offs to predict increased cIMT were 45.81 and 34.46 mL.kg(-1).min(-1) for boys and girls, respectively. The odds-ratios for having increased cIMT among children who were unfit was up to 2.8 times the odds among those who were fit (95% confidence interval: 1.40-5.53). Considering current CRF cut-offs, only those suggested by Adegboye et al. 2011. (Br. J. Sports Med. 45(9): 722-728) and Boddy et al. 2012 (PLoS One, 7(9): e45755) were significant in predicting increased cIMT. In conclusion, CRF cut-offs (boys: <= 45.8; girls: <= 34.5 mL.kg(-1).min(-1)) are associated with thickening of the arterial wall in 11- to 12-year-old children. Low CRF is an important cardiovascular risk factor in children and our data highlight the importance of obtaining an adequate CRF. PMID- 25794241 TI - Water-Mediated Differential Binding of Strontium and Cesium Cations in Fulvic Acid. AB - The migration of potentially harmful radionuclides, such as cesium ((137)Cs) and strontium ((90)Sr), in soil is governed by the chemical and biological reactivity of soil components. Soil organic matter (SOM) that can be modeled through fulvic acid (FA) is known to alter the mobility of radionuclide cations, Cs(+) and Sr(2+). Shedding light on the possible interaction mechanisms at the atomic level of these two ions with FA is thus vital to explain their transport behavior and for the design of new ligands for the efficient extraction of radionuclides. Here we have performed molecular dynamics, metadynamics simulations, and density functional-theory-based calculations to understand the binding mechanism of Sr(2+) and Cs(+) cations with FA. Our studies predict that interaction of Cs(+) to FA is very weak as compared with Sr(2+). While the water-FA interaction is largely responsible for the weak binding of Cs(+) to FA, leading to the outer sphere complexation of the ion with FA, the interaction between Sr(2+) and FA is stronger and thus can surpass the existing secondary nonbonding interaction between coordinated waters and FA, leading to inner sphere complexation of the ion with FA. We also find that entropy plays a dominant role for Cs(+) binding to FA, whereas Sr(2+) binding is an enthalpy-driven process. Our predicted results are found to be in excellent agreement with the available experimental data on complexation of Cs(+) and Sr(2+) with SOM. PMID- 25794239 TI - Increased skeletal muscle glucose uptake by rosemary extract through AMPK activation. AB - Stimulation of the energy sensor AMP-activated kinase (AMPK) has been viewed as a targeted approach to increase glucose uptake by skeletal muscle and control blood glucose homeostasis. Rosemary extract (RE) has been reported to activate AMPK in hepatocytes and reduce blood glucose levels in vivo but its effects on skeletal muscle are not known. In the present study, we examined the effects of RE and the mechanism of regulation of glucose uptake in muscle cells. RE stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 5 MUg/mL of RE for 4 h (184% +/- 5.07% of control, p < 0.001), a response comparable to maximum insulin (207% +/- 5.26%, p < 0.001) and metformin (216% +/- 8.77%, p < 0.001) stimulation. RE did not affect insulin receptor substrate 1 and Akt phosphorylation but significantly increased AMPK and acetyl CoA carboxylase phosphorylation. Furthermore, the RE-stimulated glucose uptake was significantly reduced by the AMPK inhibitor compound C, but remained unchanged by the PI3K inhibitor, wortmannin. RE did not affect GLUT4 or GLUT1 glucose transporter translocation in contrast with a significant translocation of both transporters seen with insulin or metformin treatment. Our study is the first to show a direct effect of RE on muscle cell glucose uptake by a mechanism that involves AMPK activation. PMID- 25794242 TI - Synthesis of polysubstituted iodobenzene derivatives from alkynylsilanes and 1,3 dienes via diels-alder/oxidation/iodination reaction sequence. AB - The cobalt-catalyzed Diels-Alder reaction of trimethylsilyl-substituted alkynes with 1,3-dienes led to dihydroaromatic intermediates which were transformed into iodobenzene derivatives. For this transformation, the dihydroaromatic intermediates had to be oxidized and the trimethylsilyl-substituted arene had to undergo a silicon-iodine exchange reaction. For this purpose, a number of oxidizing agents and iodonium sources were tested in order to realize the desired two transformations in a single step. Eventually, the combination of tert-butyl hydroperoxide (TBHP), zinc iodide, and potassium carbonate led to the desired oxidation/iodination in good to excellent yields in a short reaction time at ambient temperatures. PMID- 25794240 TI - Cooking enhances beneficial effects of pea seed coat consumption on glucose tolerance, incretin, and pancreatic hormones in high-fat-diet-fed rats. AB - Pulses, including dried peas, are nutrient- and fibre-rich foods that improve glucose control in diabetic subjects compared with other fibre sources. We hypothesized feeding cooked pea seed coats to insulin-resistant rats would improve glucose tolerance by modifying gut responses to glucose and reducing stress on pancreatic islets. Glucose intolerance induced in male Sprague-Dawley rats with high-fat diet (HFD; 10% cellulose as fibre) was followed by 3 weeks of HFD with fibre (10%) provided by cellulose, raw-pea seed coat (RP), or cooked-pea seed coat (CP). A fourth group consumed low-fat diet with 10% cellulose. Oral and intraperitoneal glucose tolerance tests (oGTT, ipGTT) were done. CP rats had 30% and 50% lower glucose and insulin responses in oGTT, respectively, compared with the HFD group (P < 0.05) but ipGTT was not different. Plasma islet and incretin hormone concentrations were measured. alpha- and beta-cell areas in the pancreas and density of K- and L-cells in jejunum and ileum were quantified. Jejunal expression of hexose transporters was measured. CP feeding increased fasting glucagon-like peptide 1 and glucose-stimulated gastric inhibitory polypeptide responses (P < 0.05), but K- and L-cells densities were comparable to HFD, as was abundance of SGLT1 and GLUT2 mRNA. No significant difference in beta-cell area between diet groups was observed. alpha-cell area was significantly smaller in CP compared with RP rats (P < 0.05). Overall, our results demonstrate that CP feeding can reverse adverse effects of HFD on glucose homeostasis and is associated with enhanced incretin secretion and reduced alpha-cell abundance. PMID- 25794244 TI - Tetrabenzocircumpyrene: a nanographene fragment with an embedded peripentacene core. AB - A new disc-shaped highly symmetric C54H20 nanographene fragment, tetrabenzocircumpyrene, has been synthesized and characterized by scanning tunnelling microscopy, demonstrating the potential of this technique for identifying highly insoluble graphenic molecules. PMID- 25794243 TI - The Mobile Insulin Titration Intervention (MITI) for Insulin Glargine Titration in an Urban, Low-Income Population: Randomized Controlled Trial Protocol. AB - BACKGROUND: Patients on insulin glargine typically visit a clinician to obtain advice on how to adjust their insulin dose. These multiple clinic visits can be costly and time-consuming, particularly for low-income patients. It may be feasible to achieve insulin titration through text messages and phone calls with patients instead of face-to-face clinic visits. OBJECTIVE: The objectives of this study are to (1) evaluate if the Mobile Insulin Titration Intervention (MITI) is clinically effective by helping patients reach their optimal dose of insulin glargine, (2) determine if the intervention is feasible within the setting and population, (3) assess patient satisfaction with the intervention, and (4) measure the costs associated with this intervention. METHODS: This is a pilot study evaluating an approach to insulin titration using text messages and phone calls among patients with insulin-dependent type 2 diabetes in the outpatient medical clinic of Bellevue Hospital Center, a safety-net hospital in New York City. Patients will be randomized in a 1:1 ratio to either the MITI arm (texting/phone call intervention) or the usual-care arm (in-person clinic visits). Using a Web-based platform, weekday text messages will be sent to patients in the MITI arm, asking them to text back their fasting blood glucose values. In addition to daily reviews for alarm values, a clinician will rereview the texted values weekly, consult our physician-approved titration algorithm, and call the patients with advice on how to adjust their insulin dose. The primary outcome will be whether or not a patient reaches his/her optimal dose of insulin glargine within 12 weeks. RESULTS: Recruitment for this study occurred between June 2013 and December 2014. We are continuing to collect intervention and follow up data from our patients who are currently enrolled. The results of our data analysis are expected to be available in 2015. CONCLUSIONS: This study explores the use of widely-available text messaging and voice technologies for insulin titration. We aim to show that remote insulin titration is clinically effective, feasible, satisfactory, and cost saving for low-income patients in a busy, urban clinic. TRIAL REGISTRATION: Clinicaltrials.gov NCT01879579; http://clinicaltrials.gov/ct2/show/NCT01879579 (Archived by WebCite at http://www.webcitation.org/6WUEgjZUO). PMID- 25794245 TI - Survival Benefits of Treatment Access Among Underserved Breast Cancer Patients Diagnosed Through the Texas Breast and Cervical Cancer Services Program. AB - PURPOSE: The Texas Breast and Cervical Cancer Services (BCCS) program was established to address socioeconomic disparities in breast and cervical cancer screening and survival. This study examined the impact of the program on treatment and survival of breast cancer patients. METHODS: A retrospective analysis was performed using the Texas Cancer Registry data linked to the BCCS program data. The sample consisted of 40- to 64-year-old women screened and diagnosed with breast cancer through the BCCS program (participants) and similar women living in low socioeconomic status census tracts and diagnosed outside the program (comparison group) during 1995-2008. Regular screeners among the participants were also compared with the comparison group. RESULTS: Participants had lower rates of breast surgery and higher rates of chemotherapy as compared with the comparison group. Participants undergoing surgery had higher rates of mastectomy (as compared with breast-conserving surgery) and lower rates of adjuvant radiation therapy. Unadjusted survival rates were similar between the participants and the comparison group, and higher among regular screeners, which was primarily driven by stage at diagnosis. Adjusted survival rates were similar between the 3 groups. CONCLUSIONS: Although there are differences in the types of treatment provided to the participants and the comparison group, there is no evidence of guideline noncompliance or stage-inappropriate treatment provision in either of the groups. Despite being diagnosed with a more advanced stage, the participants had similar unadjusted and adjusted survival rates as the comparison group. Access to timely treatment improved survival and brought the underserved participants on par with the comparison group. PMID- 25794246 TI - Is Continuous Flow Superior to Pulsatile Flow in Single Ventricle Mechanical Support? Results from a Large Animal Pilot Study. AB - Durable mechanical support in situations of physiologic single ventricle has been met with little success so far, particularly in small children. We created an animal model to investigate whether pulsatile or continuous flow would be superior. Three 1 month old sheep (10-16 kg) were instrumented. Via sternotomy and with cardiopulmonary bypass, a large ventricular septal defect and atrial septal defect were created. The left ventricle was cannulated using a Berlin Heart inflow cannula. This was connected sequentially to a continuous flow device (Thoratec HeartMate X, Pleasanton, CA) and to a pulsatile device (Berlin Heart Excor, The Woodlands, TX). Outflow was via a Y-graft to both aorta and pulmonary artery, striving for equal flow to both. Atrial filling pressures were controlled with volume infusions over a wide range. Under comparable loading conditions, significantly higher maximum flow was obtained by HeartMate X than by Excor (4.95 +/- 1.27 L/min [range, 3.84-6.34 L/min] for HeartMate X vs. 1.80 +/- 0.85 L/min [range, 1.01-2.7 L/min] for Excor; p < 0.05). Judging from this limited animal study, in single ventricle scenarios, continuous flow devices may achieve higher pump flows than pulsatile devices when provided with similar filling pressures. Their clinical use should be investigated. More extensive experimental studies are needed. PMID- 25794247 TI - Treatment of Severe Metabolic Alkalosis with Continuous Renal Replacement Therapy: Bicarbonate Kinetic Equations of Clinical Value. AB - Concomitant severe metabolic alkalosis, hypernatremia, and kidney failure pose a therapeutic challenge. Hemodialysis to correct azotemia and abnormal electrolytes results in rapid correction of serum sodium, bicarbonate, and urea but presents a risk for dialysis disequilibrium and brain edema. We describe a patient with Zollinger-Ellison syndrome with persistent encephalopathy, severe metabolic alkalosis (highest bicarbonate 81 mEq/L), hypernatremia (sodium 157 mEq/L), and kidney failure despite 30 hours of intravenous crystalloids and proton pump inhibitor. We used continuous renal replacement therapy (RRT) with delivered hourly urea clearance of ~3 L/hour (24 hour sustained low efficiency dialysis with regional citrate anticoagulation protocol at blood flow rate 60 ml/min and dialysate flow rate 400 ml/min). To mitigate a pronounced decrease in plasma osmolality while removing urea from this hypernatremic patient, dialysate sodium was set to start at 155 mEq/L then at 150 mEq/L after 6 hours. Serum bicarbonate, urea, and sodium were slowly corrected over 26 hours. This case demonstrates how to regulate and predict the systemic bicarbonate level using single pool kinetic modeling during convective or diffusive RRT. Kinetic modeling provides a valuable tool for systemic blood pH control in future combined use of extracorporeal CO2 removal and continuous RRT systems. PMID- 25794248 TI - Factors influencing utilization of the primary prevention implantable defibrillator. AB - BACKGROUND: A growing literature suggests underutilization of the primary prevention implantable cardioverter-defibrillator (ICD); thus, factors influencing utilization need to be understood. We performed a comprehensive assessment of patient characteristics and health insurance status among subjects eligible for primary prevention ICD in a tertiary care center. METHODS: From among a group of patients who met criteria for primary prevention ICD based on left ventricular dysfunction (LVEF <= 35%), ICD recipients (n = 110) were compared to ICD non-recipients (n = 110) to identify determinants of ICD implantation. We evaluated demographics, clinical profile including Charlson Comorbidity Index [CCI, categorized as low (<=3) or high (>3)] and health insurance status. RESULTS: ICD recipients were younger (62.1+/-15.0 vs. 68.0+/ 18.2; P = 0.01), with more males (80% vs. 65.5%; P = 0.01), higher NYHA class (II/III: 75.5% vs. 40.2%; P<0.001) and more likely to have supplemental private health insurance (61.8% vs. 46.4%; P = 0.02). CCI was not significantly different between the two groups (low CCI 61.8% vs. 62.7%; P = 0.89). In multivariable analysis, factors independently associated with ICD implantation were male sex (OR, 2.77, [1.31-5.85]; P = 0.01), age<75 (OR, 2.68, [1.30-5.50]; P = 0.01), private insurance (OR, 2.17, [1.08-4.36], P = 0.03) and NYHA Class II/III (OR, 5.91, [2.91-12.01]; P<0.001). Documentation of discussion about primary prevention ICD was absent in the majority (57.2%) of non-recipients. CONCLUSION: In a contemporary urban tertiary care setting, age, sex and heart failure symptom class were associated with ICD utilization, with socioeconomic/insurance status also potentially playing a role. These findings have implications for optimizing appropriate utilization of the prophylactic ICD and warrant follow-up in larger, more diverse populations. PMID- 25794252 TI - Physicians Poster SessionsPoster Session / Day 1. PMID- 25794249 TI - Glycoxidized HDL, HDL enriched with oxidized phospholipids and HDL from diabetic patients inhibit platelet function. AB - CONTEXT: High-density lipoproteins (HDL) possess atheroprotective properties including anti-thrombotic and antioxidant effects. Very few studies relate to the functional effects of oxidized HDL on platelets in type 2 diabetes (T2D). OBJECTIVE: The objective of our study was to investigate the effects of in vitro glycoxidized HDL and HDL from patients with T2D on platelet aggregation and arachidonic acid signaling cascade. At the same time, the contents of hydroxylated fatty acids were assessed in HDL. RESULTS: Compared with control HDL, in vitro glycoxidized HDL had decreased proportions of linoleic (LA) and arachidonic (AA) acids in phospholipids and cholesteryl esters, and increased concentrations of hydroxy-octadecadienoic acids (9-HODE and 13-HODE) and 15 hydroxy-eicosatetraenoic acid (15-HETE), derived from LA and AA respectively, especially hydroxy derivatives esterified in phospholipids. Glycoxidized HDL dose dependently decreased collagen-induced platelet aggregation by binding to scavenger receptor BI (SR-BI). Glycoxidized HDL prevented collagen-induced increased phosphorylation of platelet p38 MAPK and cytosolic phospholipase A2, as well as intracellular calcium mobilization. HDL enriched with oxidized phosphatidylcholine (PC), namely PC(16:0/13-HODE) dose-dependently inhibited platelet aggregation. Increased concentrations of 9-HODE, 13-HODE, and 15-HETE in phospholipids (2.1-, 2.1-, and 2.4-fold increase, respectively) were found in HDL from patients with T2D, and these HDL also inhibited platelet aggregation via SR BI. CONCLUSIONS: Our results suggest that in vitro glycoxidized HDL as well as HDL from patients with T2D inhibit platelet aggregation, and suggest that oxidized LA-containing phospholipids may contribute to the anti-aggregatory effects of glycoxidized HDL and HDL from patients with T2D. PMID- 25794251 TI - Physicians abstracts. PMID- 25794253 TI - Physicians Poster SessionsPoster session / Day 2. PMID- 25794255 TI - The nurses group poster session. PMID- 25794254 TI - The nurses group oral sessions. PMID- 25794256 TI - The data management group. PMID- 25794257 TI - The quality management group oral session. PMID- 25794258 TI - The quality management group poster session. PMID- 25794259 TI - Statistical symposium oral presentations. PMID- 25794260 TI - Publication only. PMID- 25794262 TI - Working parties. PMID- 25794263 TI - An FMRI-compatible Symbol Search task. AB - Our objective was to determine whether a Symbol Search paradigm developed for functional magnetic resonance imaging (FMRI) is a reliable and valid measure of cognitive processing speed (CPS) in healthy older adults. As all older adults are expected to experience cognitive declines due to aging, and CPS is one of the domains most affected by age, establishing a reliable and valid measure of CPS that can be administered inside an MR scanner may prove invaluable in future clinical and research settings. We evaluated the reliability and construct validity of a newly developed FMRI Symbol Search task by comparing participants' performance in and outside of the scanner and to the widely used and standardized Symbol Search subtest of the Wechsler Adult Intelligence Scale (WAIS). A brief battery of neuropsychological measures was also administered to assess the convergent and discriminant validity of the FMRI Symbol Search task. The FMRI Symbol Search task demonstrated high test-retest reliability when compared to performance on the same task administered out of the scanner (r=.791; p<.001). The criterion validity of the new task was supported, as it exhibited a strong positive correlation with the WAIS Symbol Search (r=.717; p<.001). Predicted convergent and discriminant validity patterns of the FMRI Symbol Search task were also observed. The FMRI Symbol Search task is a reliable and valid measure of CPS in healthy older adults and exhibits expected sensitivity to the effects of age on CPS performance. PMID- 25794264 TI - Illicit Use of Prescription Opiates among Graduate Students. AB - Through this study the authors assessed the prevalence rate, reasons for use, and poly-substance use of prescription opiates among graduate students. The authors employed a cross-sectional survey research design using an online, self administered questionnaire to assess the prevalence rates of prescription opiate use among graduate students (N = 1,033), reasons for use, and their likelihood for poly-substance use. The survey was e-mailed to 5,000 graduate students. Graduate students (19.7%) reported illicit use of prescription opiates in their lifetime and 6.6% reported past-year illicit use. Those who indicated illicitly using prescription opiates did so for self-medication reasons; a few respondents indicated recreational use. Students using prescription opiates were 75% less likely to use marijuana; 79% less likely to use cocaine; and 75% less likely to use ecstasy. Graduate students are illicitly using prescription opiates, but primarily for self-medication, and, while doing so, are less likely to use other substances. PMID- 25794265 TI - Dual Therapeutic Effects of C-10068, a Dextromethorphan Derivative, Against Post Traumatic Nonconvulsive Seizures and Neuroinflammation in a Rat Model of Penetrating Ballistic-Like Brain Injury. AB - Post-traumatic seizures can exacerbate injurious outcomes of severe brain trauma, yet effective treatments are limited owing to the complexity of the pathology underlying the concomitant occurrence of both events. In this study, we tested C 10068, a novel deuterium-containing analog of (+)-N-methyl-3-ethoxymorphinan, in a rat model of penetrating ballistic-like brain injury (PBBI) and evaluated the effects of C-10068 on PBBI-induced nonconvulsive seizures (NCS), acute neuroinflammation, and neurofunctional outcomes. NCS were detected by electroencephalographic monitoring. Neuroinflammation was evaluated by immunohistochemical markers, for example, glial fibrillary acidic protein and major histocompatibility complex class I, for activation of astrocytes and microglia, respectively. Neurofunction was tested using rotarod and Morris water maze tasks. Three infusion doses of C-10068 (1.0, 2.5, and 5.0 mg/kg/h * 72 h) were tested in the antiseizure study. Neuroinflammation and neurofunction were evaluated in animals treated with 5.0 mg/kg/h * 72 h C-10068. Compared to vehicle treatment, C-10068 dose dependently reduced PBBI-induced NCS incidence (40-50%), frequency (20-70%), and duration (30-82%). The most effective antiseizure dose of C-10068 (5.0 mg/kg/h * 72 h) also significantly attenuated hippocampal astrocyte activation and perilesional microglial reactivity post-PBBI. Within C-10068 treated animals, a positive correlation was observed in reduction in NCS frequency and reduction in hippocampal astrocyte activation. Further, C-10068 treatment significantly attenuated astrocyte activation in seizure-free animals. However, C-10068 failed to improve PBBI-induced motor and cognitive functions with the dosing regimen used in this study. Overall, the results indicating that C-10068 exerts both potent antiseizure and antiinflammatory effects are promising and warrant further investigation. PMID- 25794266 TI - Predicting Motor Vehicle Collisions in a Driving Simulator in Young Adults Using the Useful Field of View Assessment. AB - OBJECTIVE: Being involved in motor vehicle collisions is the leading cause of death in 1- to 34-year-olds, and risk is particularly high in young adults. The Useful Field of View (UFOV) task, a cognitive measure of processing speed, divided attention, and selective attention, has been shown to be predictive of motor vehicle collisions in older adults, but its use as a predictor of driving performance in a young adult population has not been investigated. The present study examined whether UFOV was a predictive measure of motor vehicle collisions in a driving simulator in a young adult population. METHOD: The 3-subtest version of UFOV (lower scores measured in milliseconds indicate better performance) was administered to 60 college students. Participants also completed an 11-mile simulated drive to provide driving performance metrics. RESULTS: Findings suggested that subtests 1 and 2 suffered from a ceiling effect. UFOV subtest 3 significantly predicted collisions in the simulated drive. Each 30 ms slower on the subtest was associated with nearly a 10% increase in the risk of a simulated collision. Post hoc analyses revealed a small partially mediating effect of subtest 3 on the relationship between driving experience and collisions. CONCLUSION: The selective attention component of UFOV subtest 3 may be a predictive measure of crash involvement in a young adult population. Improvements in selective attention may be the underlying mechanism in how driving experience improves driving performance. PMID- 25794267 TI - Organic arsenicals as efficient and highly specific linkers for protein/peptide polymer conjugation. AB - The entropy-driven affinity of trivalent (in)organic arsenicals for closely spaced dithiols has been exploited to develop a novel route to peptide/protein polymer conjugation. A trivalent arsenous acid (As(III)) derivative (1) obtained from p-arsanilic acid (As(V)) was shown to readily undergo conjugation to the therapeutic peptide salmon calcitonin (sCT) via bridging of the Cys(1)-Cys(7) disulfide, which was verified by RP-HPLC and MALDI-ToF-MS. Conjugation was shown to proceed rapidly (t < 2 min) in situ and stoichiometrically through sequential reduction-conjugation protocols, therefore exhibiting conjugation efficiencies equivalent to those reported for the current leading disulfide-bond targeting strategies. Furthermore, using bovine serum albumin as a model protein, the trivalent organic arsenical 1 was found to demonstrate enhanced specificity for disulfide-bond bridging in the presence of free cysteine residues relative to established maleimide functional reagents. This specificity represents a shift toward potential orthogonality, by clearly distinguishing between the reactivity of mono- and disulfide-derived (vicinal or neighbors-through-space) dithiols. Finally, p-arsanilic acid was transformed into an initiator for aqueous single electron-transfer living radical polymerization, allowing the synthesis of hydrophilic arsenic-functional polymers which were shown to exhibit negligible cytotoxicity relative to a small molecule organic arsenical, and an unfunctionalized polymer control. Poly(poly[ethylene glycol] methyl ether acrylate) (PPEGA480, DPn = 10, Mn,NMR = 4900 g.mol(-1), D = 1.07) possessing a pentavalent arsenic acid (As(V)) alpha-chain end was transformed into trivalent As(III) post-polymerization via initial reduction by biological reducing agent glutathione (GSH), followed by binding of GSH. Conjugation of the resulting As(III)-functional polymer to sCT was realized within 35 min as indicated by RP HPLC and verified later by thermodynamically driven release of sCT, from the conjugate, in the presence of strong chelating reagent ethanedithiol. PMID- 25794268 TI - Low interobserver agreement among endoscopists in differentiating dysplastic from non-dysplastic lesions during inflammatory bowel disease colitis surveillance. AB - OBJECTIVES: During endoscopic surveillance in patients with longstanding colitis, a variety of lesions can be encountered. Differentiation between dysplastic and non-dysplastic lesions can be challenging. The accuracy of visual endoscopic differentiation and interobserver agreement (IOA) has never been objectified. MATERIAL AND METHODS: We assessed the accuracy of expert and nonexpert endoscopists in differentiating (low-grade) dysplastic from non-dysplastic lesions and the IOA among and between them. An online questionnaire was constructed containing 30 cases including a short medical history and an endoscopic image of a lesion found during surveillance employing chromoendoscopy. RESULTS: A total of 17 endoscopists, 8 experts, and 9 nonexperts assessed all 30 cases. The overall sensitivity and specificity for correctly identifying dysplasia were 73.8% (95% confidence interval (CI) 62.1-85.4) and 53.8% (95% CI 42.6-64.7), respectively. Experts showed a sensitivity of 76.0% (95% CI 63.3 88.6) versus 71.8% (95% CI 58.5-85.1, p = 0.434) for nonexperts, the specificity 61.0% (95% CI 49.3-72.7) versus 47.1% (95% CI 34.6-59.5, p = 0.008). The overall IOA in differentiating between dysplastic and non-dysplastic lesions was fair 0.24 (95% CI 0.21-0.27); for experts 0.28 (95% CI 0.21-0.35) and for nonexperts 0.22 (95% CI 0.17-0.28). The overall IOA for differentiating between subtypes was fair 0.21 (95% CI 0.20-0.22); for experts 0.19 (95% CI 0.16-0.22) and nonexpert 0.23 (95% CI 0.20-0.26). CONCLUSION: In this image-based study, both expert and nonexpert endoscopists cannot reliably differentiate between dysplastic and non dysplastic lesions. This emphasizes that all lesions encountered during colitis surveillance with a slight suspicion of containing dysplasia should be removed and sent for pathological assessment. PMID- 25794269 TI - Neurodevelopmental Animal Models Reveal the Convergent Role of Neurotransmitter Systems, Inflammation, and Oxidative Stress as Biomarkers of Schizophrenia: Implications for Novel Drug Development. AB - Schizophrenia is a life altering disease with a complex etiology and pathophysiology, and although antipsychotics are valuable in treating the disorder, certain symptoms and/or sufferers remain resistant to treatment. Our poor understanding of the underlying neuropathological mechanisms of schizophrenia hinders the discovery and development of improved pharmacological treatment, so that filling these gaps is of utmost importance for an improved outcome. A vast amount of clinical data has strongly implicated the role of inflammation and oxidative insults in the pathophysiology of schizophrenia. Preclinical studies using animal models are fundamental in our understanding of disease development and pathology as well as the discovery and development of novel treatment options. In particular, social isolation rearing (SIR) and pre- or postnatal inflammation (PPNI) have shown great promise in mimicking the biobehavioral manifestations of schizophrenia. Furthermore, the "dual-hit" hypothesis of schizophrenia states that a first adverse event such as genetic predisposition or a prenatal insult renders an individual susceptible to develop the disease, while a second insult (e.g., postnatal inflammation, environmental adversity, or drug abuse) may be necessary to precipitate the full-blown syndrome. Animal models that emphasize the "dual-hit" hypothesis therefore provide valuable insight into understanding disease progression. In this Review, we will discuss SIR, PPNI, as well as possible "dual-hit" animal models within the context of the redox-immune-inflammatory hypothesis of schizophrenia, correlating such changes with the recognized monoamine and behavioral alterations of schizophrenia. Finally, based on these models, we will review new therapeutic options, especially those targeting immune-inflammatory and redox pathways. PMID- 25794270 TI - Backbone hydration determines the folding signature of amino acid residues. AB - The relation between the sequence of a protein and its three-dimensional structure remains largely unknown. A lasting dream is to elucidate the side-chain dependent driving forces that govern the folding process. Different structural data suggest that aromatic amino acids play a particular role in the stabilization of protein structures. To better understand the underlying mechanism, we studied peptides of the sequence EGAAXAASS (X = Gly, Ile, Tyr, Trp) through comparison of molecular dynamics (MD) trajectories and NMR residual dipolar coupling (RDC) measurements. The RDC data for aromatic substitutions provide evidence for a kink in the peptide backbone. Analysis of the MD simulations shows that the formation of internal hydrogen bonds underlying a helical turn is key to reproduce the experimental RDC values. The simulations further reveal that the driving force leading to such helical-turn conformations arises from the lack of hydration of the peptide chain on either side of the bulky aromatic side chain, which can potentially act as a nucleation point initiating the folding process. PMID- 25794275 TI - NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-kappaB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies. PMID- 25794276 TI - Comparison of normal saline, hypertonic saline albumin and terlipressin plus hypertonic saline albumin in an infant animal model of hypovolemic shock. AB - INTRODUCTION: In series of cases and animal models suffering hemorrhagic shock, the use of vasopressors has shown potential benefits regarding hemodynamics and tissue perfusion. Terlipressin is an analogue of vasopressin with a longer half life that can be administered by bolus injection. We have previously observed that hypertonic albumin improves resuscitation following controlled hemorrhage in piglets. The aim of the present study was to analyze whether the treatment with the combination of terlipressin and hypertonic albumin can produce better hemodynamic and tissular perfusion parameters than normal saline or hypertonic albumin alone at early stages of hemorrhagic shock in an infant animal model. METHODS: Experimental, randomized animal study including 39 2-to-3-month-old piglets. Thirty minutes after controlled 30 ml/kg bleed, pigs were randomized to receive either normal saline (NS) 30 ml/kg (n = 13), 5% albumin plus 3% hypertonic saline (AHS) 15 ml/kg (n = 13) or single bolus of terlipressin 15 MUg/kg i.v. plus 5% albumin plus 3% hypertonic saline 15 ml/kg (TAHS) (n = 13) over 30 minutes. Global hemodynamic and tissular perfusion parameters were compared. RESULTS: After controlled bleed a significant decrease of blood pressure, cardiac index, central venous saturation, carotid and peripheral blood flow, brain saturation and an increase of heart rate, gastric PCO2 and lactate was observed. After treatment no significant differences in most hemodynamic (cardiac index, mean arterial pressure) and perfusion parameters (lactate, gastric PCO2, brain saturation, cutaneous blood flow) were observed between the three therapeutic groups. AHS and TAHS produced higher increase in stroke volume index and carotid blood flow than NS. CONCLUSIONS: In this pediatric animal model of hypovolemic shock, albumin plus hypertonic saline with or without terlipressin achieved similar hemodynamics and perfusion parameters than twice the volume of NS. Addition of terlipressin did not produce better results than AHS. PMID- 25794277 TI - GRYFUN: a web application for GO term annotation visualization and analysis in protein sets. AB - Functional context for biological sequence is provided in the form of annotations. However, within a group of similar sequences there can be annotation heterogeneity in terms of coverage and specificity. This in turn can introduce issues regarding the interpretation of actual functional similarity and overall functional coherence of such a group. One way to mitigate such issues is through the use of visualization and statistical techniques. Therefore, in order to help interpret this annotation heterogeneity we created a web application that generates Gene Ontology annotation graphs for protein sets and their associated statistics from simple frequencies to enrichment values and Information Content based metrics. The publicly accessible website http://xldb.di.fc.ul.pt/gryfun/ currently accepts lists of UniProt accession numbers in order to create user defined protein sets for subsequent annotation visualization and statistical assessment. GRYFUN is a freely available web application that allows GO annotation visualization of protein sets and which can be used for annotation coherence and cohesiveness analysis and annotation extension assessments within under-annotated protein sets. PMID- 25794278 TI - Prevalence of mental distress and associated factors among undergraduate students of University of Gondar, Northwest Ethiopia: a cross-sectional institutional based study. AB - BACKGROUND: Mental health problems affect society as a whole and no group is immune to mental disorders; however, students have significantly high level of mental distress than their community peers. OBJECTIVES: The purpose of this study was to assess the prevalence and associated factors of mental distress among undergraduate students of University of Gondar, Northwest Ethiopia. METHODS: Institution based cross sectional study was conducted among 836 students from April 9-11/2014. Stratified multistage sampling technique was used to select the study participants. Data were collected using pretested and structured self administered questionnaire. Bivariate and multivariate logistic regression model was fitted to identify factors associated with mental distress among students. An adjusted odds ratio with 95% confidence interval was computed to determine the level of significance. RESULTS: Prevalence of mental distress among students was found to be 40.9%. Female sex (AOR = 1.65; 95% CI 1.17-2.30), lack of interest towards their field of study (AOR = 2.28; 95% CI 1.49-3.50), not having close friends (AOR = 1.48; 95% CI 1.03-2.14), never attend religious programs (AOR = 1.58; 95% CI 1.02-2.46), conflict with friends (AOR = 1.93; 95% CI 1.41-2.65), having financial distress (AOR1.49 = 95% CI 1.05, 2.10), family history of mental illness (AOR = 2.12; 95% CI 1.31-3.45), Ever use of Khat (AOR = 1.71; 95% CI 1.12 2.59), lower grade than anticipated(AOR = 2.07; 95% CI 1.51-2.83), lack of vacation or break (AOR = 1.46; 95% CI 1.06-2.02), and low social support(AOR = 2.58; 95% CI 1.58-4.22) were significantly associated with mental distress. CONCLUSION: The overall prevalence of mental distress among students was found to be high. Therefore, it is recommended that mental distress needs due attention and remedial action from policy makers, college officials, non-governmental organizations, parents, students and other concerned bodies. PMID- 25794279 TI - Melting curve analysis after T allele enrichment (MelcaTle) as a highly sensitive and reliable method for detecting the JAK2V617F mutation. AB - Detection of the JAK2V617F mutation is essential for diagnosing patients with classical myeloproliferative neoplasms (MPNs). However, detection of the low frequency JAK2V617F mutation is a challenging task due to the necessity of discriminating between true-positive and false-positive results. Here, we have developed a highly sensitive and accurate assay for the detection of JAK2V617F and named it melting curve analysis after T allele enrichment (MelcaTle). MelcaTle comprises three steps: 1) two cycles of JAK2V617F allele enrichment by PCR amplification followed by BsaXI digestion, 2) selective amplification of the JAK2V617F allele in the presence of a bridged nucleic acid (BNA) probe, and 3) a melting curve assay using a BODIPY-FL-labeled oligonucleotide. Using this assay, we successfully detected nearly a single copy of the JAK2V617F allele, without false-positive signals, using 10 ng of genomic DNA standard. Furthermore, MelcaTle showed no positive signals in 90 assays screening healthy individuals for JAK2V617F. When applying MelcaTle to 27 patients who were initially classified as JAK2V617F-positive on the basis of allele-specific PCR analysis and were thus suspected as having MPNs, we found that two of the patients were actually JAK2V617F-negative. A more careful clinical data analysis revealed that these two patients had developed transient erythrocytosis of unknown etiology but not polycythemia vera, a subtype of MPNs. These findings indicate that the newly developed MelcaTle assay should markedly improve the diagnosis of JAK2V617F positive MPNs. PMID- 25794280 TI - Epibatidine blocks eye-specific segregation in ferret dorsal lateral geniculate nucleus during stage III retinal waves. AB - The segregation and maintenance of eye-specific inputs in the dorsal lateral geniculate nucleus (dLGN) during early postnatal development requires the patterned spontaneous activity of retinal waves. In contrast to the development of the mouse, ferret eye-specific segregation is not complete at the start of stage III glutamatergic retinal waves, and the remaining overlap is limited to the C/C1 lamina of the dLGN. To investigate the role of patterned spontaneous activity in this late segregation, we disrupted retinal waves pharmacologically for 5 day windows from postnatal day (P) 10 to P25. Multi-electrode array recordings of the retina in vitro reveal that the cholinergic agonist epibatidine disrupts correlated retinal activity during stage III waves. Epibatidine also prevents the segregation of eye-specific inputs in vivo during that period. Our results reveal a novel role for cholinergic influence on stage III retinal waves as an instructive signal for the continued segregation of eye-specific inputs in the ferret dLGN. PMID- 25794282 TI - Energy landscape reveals that the budding yeast cell cycle is a robust and adaptive multi-stage process. AB - Quantitatively understanding the robustness, adaptivity and efficiency of cell cycle dynamics under the influence of noise is a fundamental but difficult question to answer for most eukaryotic organisms. Using a simplified budding yeast cell cycle model perturbed by intrinsic noise, we systematically explore these issues from an energy landscape point of view by constructing an energy landscape for the considered system based on large deviation theory. Analysis shows that the cell cycle trajectory is sharply confined by the ambient energy barrier, and the landscape along this trajectory exhibits a generally flat shape. We explain the evolution of the system on this flat path by incorporating its non gradient nature. Furthermore, we illustrate how this global landscape changes in response to external signals, observing a nice transformation of the landscapes as the excitable system approaches a limit cycle system when nutrients are sufficient, as well as the formation of additional energy wells when the DNA replication checkpoint is activated. By taking into account the finite volume effect, we find additional pits along the flat cycle path in the landscape associated with the checkpoint mechanism of the cell cycle. The difference between the landscapes induced by intrinsic and extrinsic noise is also discussed. In our opinion, this meticulous structure of the energy landscape for our simplified model is of general interest to other cell cycle dynamics, and the proposed methods can be applied to study similar biological systems. PMID- 25794281 TI - A single parS sequence from the cluster of four sites closest to oriC is necessary and sufficient for proper chromosome segregation in Pseudomonas aeruginosa. AB - Among the mechanisms that control chromosome segregation in bacteria are highly conserved partitioning systems comprising three components: ParA protein (a deviant Walker-type ATPase), ParB protein (a DNA-binding element) and multiple cis-acting palindromic centromere-like sequences, designated parS. Ten putative parS sites have been identified in the P. aeruginosa PAO1 genome, four localized in close proximity of oriC and six, diverged by more than one nucleotide from a perfect palindromic sequence, dispersed along the chromosome. Here, we constructed and analyzed P. aeruginosa mutants deprived of each single parS sequence and their different combinations. The analysis included evaluation of a set of phenotypic features, chromosome segregation, and ParB localization in the cells. It was found that ParB binds specifically to all ten parS sites, although with different affinities. The P. aeruginosa parS mutant with all ten parS sites modified (parSnull) is viable however it demonstrates the phenotype characteristic for parAnull or parBnull mutants: slightly slower growth rate, high frequency of anucleate cells, and defects in motility. The genomic position and sequence of parS determine its role in P. aeruginosa biology. It transpired that any one of the four parS sites proximal to oriC (parS1 to parS4), which are bound by ParB with the highest affinity, is necessary and sufficient for the parABS role in chromosome partitioning. When all these four sites are mutated simultaneously, the strain shows the parSnull phenotype, which indicates that none of the remaining six parS sites can substitute for these four oriC-proximal sites in this function. A single ectopic parS2 (inserted opposite oriC in the parSnull mutant) facilitates ParB organization into regularly spaced condensed foci and reverses some of the mutant phenotypes but is not sufficient for accurate chromosome segregation. PMID- 25794283 TI - Molecular dynamics simulations of acylpeptide hydrolase bound to chlorpyrifosmethyl oxon and dichlorvos. AB - Acylpeptide hydrolases (APHs) catalyze the removal of N-acylated amino acids from blocked peptides. Like other prolyloligopeptidase (POP) family members, APHs are believed to be important targets for drug design. To date, the binding pose of organophosphorus (OP) compounds of APH, as well as the different OP compounds binding and inducing conformational changes in two domains, namely, alpha/beta hydrolase and beta-propeller, remain poorly understood. We report a computational study of APH bound to chlorpyrifosmethyl oxon and dichlorvos. In our docking study, Val471 and Gly368 are important residues for chlorpyrifosmethyl oxon and dichlorvos binding. Molecular dynamics simulations were also performed to explore the conformational changes between the chlorpyrifosmethyl oxon and dichlorvos bound to APH, which indicated that the structural feature of chlorpyrifosmethyl oxon binding in APH permitted partial opening of the beta-propeller fold and allowed the chlorpyrifosmethyl oxon to easily enter the catalytic site. These results may facilitate the design of APH-targeting drugs with improved efficacy. PMID- 25794284 TI - Abortive infection of snakehead fish vesiculovirus in ZF4 cells was associated with the RLRs pathway activation by viral replicative intermediates. AB - Snakehead fish vesiculovirus (SHVV) is a negative strand RNA virus which can cause great economic losses in fish culture. To facilitate the study of SHVV-host interactions, the susceptibility of zebrafish embryonic fibroblast cell line (ZF4) to the SHVV was investigated in this report. The results showed that high amount of viral mRNAs and cRNAs were detected at the 3 h post-infection. However, the expressions of the viral mRNAs and cRNA were decreased dramatically after 6 h post-infection. In addition, the expressions of interferon (IFN) and interferon induced GTP-binding protein Mx were all up regulated significantly at the late stage of the infection. Meanwhile, the expressions of Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated gene 5 (MDA5) were also all up-regulated significantly during the infection. Two isoforms of DrLGP2 from zebrafish were also cloned and analyzed. Interestingly, the expression of DrLGP2a but not DrLGP2b was significantly up-regulated at both mRNA and protein levels, indicating that the two DrLGP2 isoforms might play different roles during the SHVV infection. Transfection experiment showed that viral replicative intermediates were required for the activation of IFN-alpha expression. Taken together, the abortive infection of SHVV in ZF4 cells was associated with the activation of RLRs pathway, which was activated by viral replicative intermediates. PMID- 25794285 TI - Prediction of long-term treatment response to selective serotonin reuptake inhibitors (SSRIs) using scalp and source loudness dependence of auditory evoked potentials (LDAEP) analysis in patients with major depressive disorder. AB - BACKGROUND: Animal and clinical studies have demonstrated that the loudness dependence of auditory evoked potentials (LDAEP) is inversely related to central serotonergic activity, with a high LDAEP reflecting weak serotonergic neurotransmission and vice versa, though the findings in humans have been less consistent. In addition, a high pretreatment LDAEP appears to predict a favorable response to antidepressant treatments that augment the actions of serotonin. The aim of this study was to test whether the baseline LDAEP is correlated with response to long-term maintenance treatment in patients with major depressive disorder (MDD). METHODS: Scalp N1, P2 and N1/P2 LDAEP and standardized low resolution brain electromagnetic tomography-localized N1, P2, and N1/P2 LDAEP were evaluated in 41 MDD patients before and after they received antidepressant treatment (escitalopram (n = 32, 10.0 +/- 4.0 mg/day), sertraline (n = 7, 78.6 +/ 26.7 mg/day), and paroxetine controlled-release formulation (n = 2, 18.8 +/- 8.8 mg/day)) for more than 12 weeks. A treatment response was defined as a reduction in the Beck Depression Inventory (BDI) score of >50% between baseline and follow up. RESULTS: The responders had higher baseline scalp P2 and N1/P2 LDAEP than nonresponders (p = 0.017; p = 0.036). In addition, changes in total BDI score between baseline and follow-up were larger in subjects with a high baseline N1/P2 LDAEP than those with a low baseline N1/P2 LDAEP (p = 0.009). There were significantly more responders in the high-LDAEP group than in the low-LDAEP group (p = 0.041). CONCLUSIONS: The findings of this study reveal that a high baseline LDAEP is associated with a clinical response to long-term antidepressant treatment. PMID- 25794286 TI - DNA synthesis during endomitosis is stimulated by insulin via the PI3K/Akt and TOR signaling pathways in the silk gland cells of Bombyx mori. AB - Silk gland cells undergo multiple endomitotic cell cycles during silkworm larval ontogeny. Our previous study demonstrated that feeding is required for continued endomitosis in the silk gland cells of silkworm larvae. Furthermore, the insulin signaling pathway is closely related to nutritional signals. To investigate whether the insulin signaling pathway is involved in endomitosis in silk gland cells, in this study, we initially analyzed the effects of bovine insulin on DNA synthesis in endomitotic silk gland cells using 5-bromo-2'-deoxyuridine (BrdU) labeling technology, and found that bovine insulin can stimulate DNA synthesis. Insulin signal transduction is mainly mediated via phosphoinositide 3-kinase (PI3K)/Akt, the target of rapamycin (TOR) and the extracellular signal-regulated kinase (ERK) pathways in vertebrates. We ascertained that these three pathways are involved in DNA synthesis in endomitotic silk gland cells using specific inhibitors against each pathway. Moreover, we investigated whether these three pathways are involved in insulin-stimulated DNA synthesis in endomitotic silk gland cells, and found that the PI3K/Akt and TOR pathways, but not the ERK pathway, are involved in this process. These results provide an important theoretical foundation for the further investigations of the mechanism underlying efficient endomitosis in silk gland cells. PMID- 25794288 TI - Professionalism: one size does not fit all. AB - When a child is born with or acquires special needs, the parents may find some parental tasks more difficult. They may not know how to make their tasks easier, or that some parents find it exceptionally rewarding and meaningful to raise their children with special needs. This piece explores how clinicians might share this potentially life-altering information. It also explores when and why clinicians might want to make one-of-a-kind exceptions to their usual professional practices. PMID- 25794287 TI - Role of pancreatic transcription factors in maintenance of mature beta-cell function. AB - A variety of pancreatic transcription factors including PDX-1 and MafA play crucial roles in the pancreas and function for the maintenance of mature beta cell function. However, when beta-cells are chronically exposed to hyperglycemia, expression and/or activities of such transcription factors are reduced, which leads to deterioration of b-cell function. These phenomena are well known as beta cell glucose toxicity in practical medicine as well as in the islet biology research area. Here we describe the possible mechanism for beta-cell glucose toxicity found in type 2 diabetes. It is likely that reduced expression levels of PDX-1 and MafA lead to suppression of insulin biosynthesis and secretion. In addition, expression levels of incretin receptors (GLP-1 and GIP receptors) in beta-cells are decreased, which likely contributes to the impaired incretin effects found in diabetes. Taken together, down-regulation of insulin gene transcription factors and incretin receptors explains, at least in part, the molecular mechanism for beta-cell glucose toxicity. PMID- 25794289 TI - A quality of life quandary: a framework for navigating parental refusal of treatment for co-morbidities in infants with underlying medical conditions. AB - Parental refusal of a recommended treatment is not an uncommon scenario in the neonatal intensive care unit. These refusals may be based upon the parents' perceptions of their child's projected quality of life. The inherent subjectivity of quality of life assessments, however, can exacerbate disagreement between parents and healthcare providers. We present a case of parental refusal of surgical intervention for necrotizing enterocolitis in an infant with Bartter syndrome and develop an ethical framework in which to consider the appropriateness of parental refusal based upon an infant's projected quality of life. PMID- 25794290 TI - Witnesses to mute suffering: quality of life, intellectual disability, and the harm standard. AB - Decisions to override a parental request to withhold or withdraw treatment in the neonatal intensive care unit are often made based on the harm standard, with death being cast as the ultimate harm. However, often the treatment itself is not without harm, and the suffering engendered is undergone by an infant who is neither able to understand it nor express its presence. We can draw upon anticipated future quality of life to justify the present suffering, but are in a quandary when that future is not guaranteed or is likely to hold little but further suffering. I propose that conflicts over continuing treatment are based both on disagreements about the desirability of possible futures, and on differing perceptions of the infant's current level of suffering. Those of us who witness the suffering of these tiny, mute infants all bear some responsibility to insure that their suffering is not without purpose. PMID- 25794291 TI - Home birth of infants with congenital anomalies: a case study and ethical analysis of careproviders' obligations. AB - This article presents the case of a mother who is planning a home birth with a midwife with the shared knowledge that the fetus would have congenital anomalies of unknown severity. We discuss the right of women to choose home birth, the caregivers' duty to the infant, and the careproviders' dilemma about how to respond to this request. The ethical duties of concerned careproviders are explored and reframed as professional obligations to the mother, infant, and their profession at large. Recommendations are offered based on this case in order to clarify the considerations surrounding not only home birth of a fetus with anticipated anomalies, but also to address the ethical obligations of caregivers who must navigate the unique tension between respecting the mother's wishes and the duty of the careproviders to deliver optimal care. PMID- 25794292 TI - Of missing voices and the obstetric imaginary: commentary on Jankowski and Burcher. AB - In this commentary, I respond to an ethical analysis of a case study, reported by Jankowski and Burcher, in which a woman gives birth to an infant with a known heart anomaly of unknown severity, at home, attended by a midwife. Jankowski and Burcher argue that the midwife who attended this family acted unethically because she knowingly operated outside of her scope of practice. While I agree that the authors' conclusions are well supported by the portion of the story they were able to gather, the fact that the midwife and mother declined to engage in the ethics consult that informs their piece means that critical segments of the narrative are left untold. Some important additional considerations emerge from these silences. I explore the implicit assumptions of the biotechnical embrace, the roles of the political economy of hope and the obstetric imaginary in driving prenatal testing, and institutional blame for the divisiveness of the home hospital divide in the United States. The value of Jankowski and Burcher's case study lies in its ability to highlight the intersections and potential conflicts between the principles of beneficence, patients' autonomy, and professional ethics, and to begin to chart a course for us through them. PMID- 25794293 TI - Hinduism and death with dignity: historic and contemporary case examples. AB - An estimated 1.2 to 2.3 million Hindus live in the United States. End-of-life care choices for a subset of these patients may be driven by religious beliefs. In this article, we present Hindu beliefs that could strongly influence a devout person's decisions about medical care, including end-of-life care. We provide four case examples (one sacred epic, one historical example, and two cases from current practice) that illustrate Hindu notions surrounding pain and suffering at the end of life. Chief among those is the principle of karma, through which one reaps the benefits and penalties for past deeds. Deference to one's spouse or family is another important Hindu value, especially among Hindu women, which can impact the decision-making process and challenge the Western emphasis on autonomy. In addition, the Hindu embrace of astrology can lead to a desire to control the exact time of death. Confounding any generalizations, a Hindu patient may reject or accept treatments based on the individual patient's or family's interpretation of any given tradition. Through an awareness of some of the fundamental practices in Hinduism and the role of individual interpretation within the tradition, clinicians will be better able to support their Hindu patients and families at the end of life. PMID- 25794294 TI - Medical professionalism in China and the United States: a transcultural interpretation. AB - As in other societies, medical professionalism in the Peoples' Republic of China has been rapidly evolving. One of the major events in this process was the endorsement in 2005 of the document, "Medical Professionalism in the New Millennium: A Physician Charter," by the Chinese Medical Doctor Association (hereafter, the Charter)(1). More recently, a national survey, the first on such a large scale, was conducted on Chinese physicians' attitudes toward the fundamental principles and core commitments put forward in the Charter. Based on empirical findings from that study and comparing them to the published results of a similar American survey, the authors offer an in-depth interpretation of significant cross-cultural differences and important transcultural commonalities. The broader historical, socio-economic, and ethical issues relating to salient Chinese cultural practices such as family consent, familism (the custom of deferring decisions to family members), and the withholding of medical information, as well as controversial topics such as not respecting patients' autonomy, are examined. The Chinese Survey found that Chinese physicians supported the principles of the Charter in general. Here we argue that Chinese culture and traditional medical ethics are broadly compatible with the moral commitments demanded by modern medical professionalism. Methodologically and theoretically-recognizing the problems inherent in the hoary but still popular habit of dichotomizing cultures and in relativism-a transcultural approach is adopted that gives greater (due) weight to the internal moral diversity present within every culture, the common ground shared by different cultures, and the primacy of morality. Genuine cross-cultural dialogue, including a constructive Chinese-American dialogue in the area of medical professionalism, is not only possible, but necessary. PMID- 25794295 TI - Re-evaluating ethical concerns in planned emergency research involving critically ill patients: an interpretation of the guidance document from the United States Food and Drug Administration. AB - BACKGROUND: U.S. federal regulations require that certain ethical elements be followed to protect human research subjects. The location and clinical circumstances of a proposed research study can differ substantially and can have significant implications for these ethical considerations. Both the location and clinical circumstances are particularly relevant for research in intensive care units (ICUs), where patients are often unable to provide informed consent to participate in a proposed research intervention. PURPOSE: Our goal is to elaborate on the updated 2013 U.S. Food and Drug Administration (FDA) guidance document regarding an exemption from the requirement of obtaining informed consent from patients or their surrogates and to address certain elements within that document, thereby assisting clinicians in developing a framework for emergency research in accordance with the regulatory bodies at their own institutions and in the United States. METHODS: Review of the 2011 and updated FDA guidance document on exemption from informed consent. RESULTS: The current process of obtaining informed consent within ICUs needs to be revisited, especially for research in which timely informed consent is not likely. In particular, the process of obtaining informed consent may not be appropriate or even ethical for critically ill patients in extremis who require an intervention for which there is no current acceptable standard of care and clinical equipoise exists. We provide clinicians with a viewpoint that further elaborates on the FDA guidance document. LIMITATIONS: The viewpoints provided herein are those of the authors and are therefore inherently limited by the personal views of a selected few. Other clinicians or researchers may not interpret the FDA guidelines in a similar manner. Moreover, the discussion of a guideline document is a limitation in and of itself. The guidelines set forth by the FDA are precisely that guidelines. Therefore, they may not be followed as outlined in the guidance document within one's own institution. Our goal is that, by elaborating on the guidelines for planned research involving human subjects in the ICU, institutional regulatory bodies may gain a better understanding in drafting their own document when faced with a clinician or a researcher who wishes to conduct planned research in an ICU. CONCLUSIONS: We believe that the interpretations provided will allow clinicians to safely undertake planned research in ICUs without endangering the main tenets of ethical research involving human participants. This research is needed for the advancement of care in the critically ill. PMID- 25794296 TI - The ethics of physicians' web searches for patients' information. AB - When physicians search the web for personal information about their patients, others have argued that this undermines patients' trust, and the physician patient relationship in general. We add that this practice also places other relationships at risk, and could jeopardize a physician's career. Yet there are also reports of web searches that have unambiguously helped in the care of patients, suggesting circumstances in which a routine search of the web could be beneficial. We advance the notion that, just as nonverbal cues and unsolicited information can be useful in clinical decision making, so too can online information from patients. As electronic records grow more voluminous and span more types of data, searching these resources will become a clinical skill, to be used judiciously and with care--just as evaluating the literature is, today. But to proscribe web searches of patients' information altogether is as nonsensical as disregarding findings from physical exams-instead, what's needed are guidelines for when to look and how to evaluate what's uncovered, online. PMID- 25794297 TI - Legal briefing: coerced treatment and involuntary confinement for contagious disease. AB - This issue's "Legal Briefing" column covers recent legal developments involving coerced treatment and involuntary confinement for contagious disease. Recent high profile court cases involving measles, tuberculosis, human immunodeficiency virus, and especially Ebola, have thrust this topic back into the bioethics and public spotlights. This has reignited debates over how best to balance individual liberty and public health. For example, the Presidential Commission for the Study of Bioethical Issues has officially requested public comments, held open hearings, and published a 90-page report on "ethical considerations and implications" raised by "U.S. public policies that restrict association or movement (such as quarantine)." Broadly related articles have been published in previous issues of The Journal of Clinical Ethics. We categorize recent legal developments on coerced treatment and involuntary confinement into the following six categories: 1. Most Public Health Confinement Is Voluntary 2. Legal Requirements for Involuntary Confinement 3. New State Laws Authorizing Involuntary Confinement 4. Quarantine Must Be as Least Restrictive as Necessary 5. Isolation Is Justified Only as a Last Resort 6. Coerced Treatment after Persistent Noncompliance. PMID- 25794299 TI - Methylphenidate reduces mental fatigue and improves processing speed in persons suffered a traumatic brain injury. AB - OBJECTIVE: Post-traumatic brain injury symptoms, such as mental fatigue, have considerable negative impacts on quality-of-life. In the present study the effects of methylphenidate in two different dosages were assessed with regard to mental fatigue, pain and cognitive functions in persons who had suffered a traumatic brain injury. METHODS: Fifty-one subjects were included and 44 completed the study. The treatment continued for 12 weeks, including three treatment periods with no medication for 4 weeks, administration of low dose methylphenidate (up to 5 mg * 3) for 4 weeks and normal dose methylphenidate (up to 20 mg * 3) for a further 4 weeks. The patients were randomized into three groups where all groups were given all treatments. RESULTS: Significantly reduced mental fatigue, assessed with the Mental Fatigue Scale (MFS) and increased information processing speed (coding, WAIS-III), were detected. The SF-36 vitality and social functioning scales were also improved significantly. Pain was not reduced by methylphenidate. The positive effects of treatment were dose dependent, with the most prominent effects being at 60 mg methylphenidate/day spread over three doses. Observed side-effects were increased blood pressure and increased heart rate. CONCLUSIONS: Methylphenidate was generally well-tolerated and it improved long-lasting mental fatigue and processing speed after traumatic brain injury. PMID- 25794298 TI - Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System. AB - There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts. PMID- 25794300 TI - Chemical characterization of unburned carbon in coal fly ashes by use of TPD/TPO and LRS methods. AB - Functional forms of the unburned carbon present in six kinds of coal fly ashes have been examined mainly by the temperature-programmed desorption (TPD)/temperature-programmed oxidation (TPO) and laser Raman spectroscopy (LRS) methods. The carbon contents of the ash samples range from 0.4 to 4.1 mass%. The LRS analysis shows that the C consists of both amorphous and crystallized forms, and the proportion of the former is as large as 50-65 C%. Further, the TPD measurement exhibits that the C contains several types of surface oxygen species, such as carboxyl and lactone/acid anhydride groups, which can readily be decomposed into CO2 up to 700 degrees C to provide active carbon sites. The results of the TPD also indicate that the ashes have surface CaCO3, and most of this species can be converted to CaO and CO2 around 600-700 degrees C. Interestingly, there is a significant correlation between organic fluorine concentrations and carboxyl/lactone/acid anhydride groups or surface CaCO3 contents in the ash samples. It might thus be possible that the formation of organic F forms proceeds through gas-solid-solid interactions among HF (and/or F2) in flue gas, active carbon sites and surface Ca species produced around 600 700 degrees C downstream of coal-fired boilers. PMID- 25794301 TI - Open Labware: 3-D printing your own lab equipment. AB - The introduction of affordable, consumer-oriented 3-D printers is a milestone in the current "maker movement," which has been heralded as the next industrial revolution. Combined with free and open sharing of detailed design blueprints and accessible development tools, rapid prototypes of complex products can now be assembled in one's own garage--a game-changer reminiscent of the early days of personal computing. At the same time, 3-D printing has also allowed the scientific and engineering community to build the "little things" that help a lab get up and running much faster and easier than ever before. PMID- 25794302 TI - Pharmacophore based 3DQSAR of phenothiazines as specific human butyrylcholinesterase inhibitors for treatment of Alzheimer's disease. AB - Quantitative three dimensional structure activity relationship (3D-QSAR) studies were performed on phenothiazine derivatives as Butyrylcholinesterase (BuChE) inhibitors. Pharmacophore Alignment and Scoring Engine (PHASE) was used to develop predictive Common Pharmacophore Hypotheses (CPHs). The alignment thus obtained was used for Comparative Molecular Field Analysis (CoMFA)/Comparative Molecular Similarity Indices Analysis (CoMSIA) model development. A fourpoint common pharmacophore hypothesis, comprising of one acceptor, one hydrophobic region and two aromatic ring centres was generated. A structurally diverse set of 80 molecules was used of which 56 were grouped into training set to develop the model and the rest 24 molecules into test set to validate the CoMFA/CoMSIA models. The models so developed showed a good r(2)predictive of 0.7587 for CoMFA and 0.7737 for CoMSIA. CoMFA and CoMSIA models had excellent Q(2) (cross validated coefficient) of 0.7125 and 0.7093, respectively which showed high correlative and predictive abilities of the models. The 3-D contour maps of CoMFA/CoMSIA provided interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects on the phenothiazine derivatives. The outcomes of the study would help in the rational design of novel and potent therapeutic agents as specific BuChE inhibitors for symptomatic or disease modifying treatment of AD. PMID- 25794303 TI - Characteristics of influenza HA-NA interdependence determined through a graphical technique. AB - Influenza viruses are characterized by two surface proteins - the hemagglutinin (HA) of which there are 16 varieties, and the neuraminidase (NA) of which there are 9, each subtype characterized by its antigenic properties. Although theoretically 16 x 9 combinations are possible, only a few like the H1N1, H3N2, etc are seen to occur more frequently. Numerous studies with select subtypes like H1N1, H5N1, etc., have explained this phenomena by indicating that viral viability necessitates functional balance between the NA and HA so that only some combinations are favored. However, the reasons for this balance or its characteristics and whether this is universal for influenza subtypes are not yet known. Using novel graphical techniques and hypothesizing a coupling between the HA and NA, we devised a coupling factor to estimate the interdependence, if any, between HA and NA sequences covering a global sample of 10 subtypes and 164 sequences. We found that (a) the coupling we hypothesized between HAs and NAs is characteristic of each subtype, (b) within each subtype the coupling value is significantly different for human infecting strains and those that infect avians, and (c) artificial strains made up by mixing and matching HAs and NAs from different subtypes produce coupling factors that are far from the characteristic values for the parent subtype indicating possibly non-viable viruses, a result that matches with experimental evidence of Zhang et al. [1]. We also show that some natural strains that did not fit the characteristic values for its subtype could have been possible mismatches during viral packaging. Our observations have important consequences for drug and vaccine design and for monitoring of influenza virus reassortments and possible evolution of human pandemics. PMID- 25794304 TI - Communication Strategies in Direct-to-Consumer Prescription Drug Advertising (DTCA): Application of the Six Segment Message Strategy Wheel. AB - This study addresses a void in the literature on direct-to-consumer prescription drug advertising (DTCA) with a theory-based content analysis. The findings indicate that Taylor's communication strategy wheel provides insight into what and how pharmaceutical marketers communicate with consumers by means of DTCA. Major findings are summarized as follows: (a) In most DTC ads, informational and transformational message themes and creative approaches were simultaneously used, indicating a combination strategy; (b) DTCA message themes were associated with creative strategies in alignment with Taylor's framework; and (c) message themes and creative strategies varied across therapeutic categories and DTCA categories with different levels of ad spending. Theoretical and practical implications of the findings are discussed. PMID- 25794305 TI - Indomethacin co-crystals and their parent mixtures: does the intestinal barrier recognize them differently? AB - Co-crystals are crystalline complexes of two or more molecules bound together in crystal lattices through noncovalent interactions. The solubility and dissolution properties of co-crystals can allow to increase the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). It is currently believed that the co-crystallization strategy should not induce changes on the pharmacological profile of the APIs, even if it is not yet clear whether a co crystal would be defined as a physical mixture or as a new chemical entity. In order to clarify these aspects, we chose indomethacin as guest poorly aqueous soluble molecule and compared its properties with those of its co-crystals obtained with 2-hydroxy-4-methylpyridine (co-crystal 1), 2-methoxy-5-nitroaniline (co-crystal 2), and saccharine (co-crystal 3). In particular, we performed a systematic comparison among indomethacin, its co-crystals, and their parent physical mixtures by evaluating via HPLC analysis the API dissolution profile, its ability to permeate across intestinal cell monolayers (NCM460), and its oral bioavailability in rat. The indomethacin dissolution profile was not altered by the presence of co-crystallizing agents as physical mixtures, whereas significant changes were observed by the dissolution of the co-crystals. Furthermore, there was a qualitative concordance between the API dissolution patterns and the relative oral bioavailabilities in rats. Co-crystal 1 induced a drastic decrease of the transepithelial electrical resistance (TEER) value of NCM460 cell monolayers, whereas its parent mixture did not evidence any effect. The saccharin indomethacin mixture induced a drastic decrease of the TEER value of monolayers, whereas its parent co-crystal 3 did not induce any effects on their integrity, being anyway able to increase the permeation of indomethacin. Taken together, these results demonstrate for the first time different effects induced by co crystals and their parent physical mixtures on a biologic system, findings that could raise serious concerns about the use of co-crystal strategy to improve API bioavailability without performing appropriate investigations. PMID- 25794306 TI - Does Footwear Matter When Performing Spatiotemporal Gait Analysis Among Older Women? AB - BACKGROUND AND PURPOSE: Although shoe type may influence gait performance and is considered to be an extrinsic fall risk factor, little or no attention is paid to it when conducting research in this field. Therefore, this study aimed to assess the effect of various types of footwear under single- and dual-task conditions on spatiotemporal gait characteristics in older women. METHODS: Fifty-seven community-dwelling women (68.0 +/- 4.6 years) were enrolled in this study. Spatiotemporal gait analysis using the GAITRite walkway was performed under 4 footwear conditions (barefoot, slippers, high heels, and standard shoes) and 3 task conditions (single-task, motor dual-task, and cognitive dual-task). Two factor repeated-measures analysis of variance was conducted. Primary outcomes were velocity, cadence, stride time, stride length, and stride length variability. RESULTS: Irrespective of task condition, walking barefoot resulted in a significantly slower gait pattern with decreased cadence and stride length and increased stride time and stride length variability compared with walking with the standard shoe. These significant gait alterations were also observed when adding a cognitive task to normal walking. The effects of footwear were most obvious during the cognitive dual-task condition and for the spatiotemporal parameters velocity and stride length. CONCLUSIONS: Footwear matters when analyzing gait in older women. It should be described in greater detail by gait researchers. Footwear should also be considered by clinicians in light of the study findings and its effects on gait. Older women are strongly discouraged to walk barefoot because barefoot walking adversely affects gait patterns. A well fitting standard shoe with laces, a low and wide heel, firm heel collar and a grooved, moderately hard sole is recommended in research, rehabilitation, and daily use. PMID- 25794307 TI - Efficacy of Deep Dry Needling on Latent Myofascial Trigger Points in Older Adults With Nonspecific Shoulder Pain: A Randomized, Controlled Clinical Trial Pilot Study. AB - BACKGROUND: Nonspecific shoulder pain has a high prevalence in older adults and causes functional alterations. Furthermore, there are difficulties in establishing a clinical diagnosis, effective treatments are lacking, and little evidence has been found regarding the use of invasive physical therapy techniques in this age group. PURPOSE: To determine the efficacy of a single physical therapy intervention with deep dry needling (DDN) on latent and active myofascial trigger points (MTrPs) in older adults with nonspecific shoulder pain. METHODS: This pilot study is a single-blind, randomized, controlled clinical trial that included 20 participants, aged 65 years and older, who were diagnosed with nonspecific shoulder pain. The study was approved by the Clinical Research Ethics Committee of the area. Participants were recruited at their homes or at a care center and were randomly assigned into either an experimental group (n = 10), which received a session of DDN on 1 active and 1 latent MTrP of the infraspinatus muscle, or a control group (n = 10), which received a session of DDN on only 1 active MTrP. A blind examiner assessed the pain intensity, pain pressure threshold on the anterior deltoid, and extensor carpi radialis brevis muscles and grip strength before, immediately after, and 1 week after the intervention. RESULTS: Statistically significant differences (P < .05) in the pressure pain thresholds (PPTs) of the extensor carpi radialis brevis were found in the experimental group in both posttreatment assessments. Moreover, the effect size values (d Cohen) varied from small for grip strength (0.017-0.36) to moderate for the pain intensity (0.46-0.78) and PPT in the anterior deltoid (0.49 0.66) and to large for the PPT in the extensor carpi radialis brevis (1.06-1.58). CONCLUSIONS: A single physical therapy intervention with DDN on 1 latent MTrP, in conjunction with 1 active MTrP, in the infraspinatus muscle may increase the PPT of the extensor carpi radialis brevis muscle area immediately following and 1 week after the intervention in older adults with nonspecific shoulder pain. PMID- 25794308 TI - The Mini-Balance Evaluation Systems Test (Mini-BESTest) Demonstrates Higher Accuracy in Identifying Older Adult Participants With History of Falls Than Do the BESTest, Berg Balance Scale, or Timed Up and Go Test. AB - BACKGROUND AND PURPOSE: Balance deficits a significant predictor of falls in older adults. The Balance Evaluation Systems Test (BESTest) and the Mini-Balance Evaluation Systems Test (Mini-BESTest) are tools that may predict the likelihood of a fall, but their capabilities and accuracies have not been adequately addressed. Therefore, this study aimed at examining the capabilities of the BESTest and Mini-BESTest for identifying older adult with history of falls and comparing the participants with history of falls identification accuracy of the BESTest, Mini-BESTest, Berg Balance Scale (BBS), and the Timed Up and Go Test (TUG) for identifying participants with a history of falls. METHODS: Two hundred healthy older adults with a mean age of 70 years were classified into participants with and without history of fall groups on the basis of their 12 month fall history. Their balance abilities were assessed using the BESTest, Mini BESTest, BBS, and TUG. An analysis of the resulting receiver operating characteristic curves was performed to calculate the area under the curve (AUC), sensitivity, specificity, cutoff score, and posttest accuracy of each. RESULTS: The Mini-BESTest showed the highest AUC (0.84) compared with the BESTest (0.74), BBS (0.69), and TUG (0.35), suggesting that the Mini-BESTest had the highest accuracy in identifying older adult with history of falls. At the cutoff score of 16 (out of 28), the Mini-BESTest demonstrated a posttest accuracy of 85% with a sensitivity of 85% and specificity of 75%. The Mini-BESTest had the highest posttest accuracy, with the others having results of 76% (BESTest), 60% (BBS), and 65% (TUG). CONCLUSION: The Mini-BESTest is the most accurate tool for identifying older adult with history of falls compared with the BESTest, BBS, and TUG. PMID- 25794309 TI - Physical Activity, Central Adiposity, and Functional Limitations in Community Dwelling Older Adults. AB - BACKGROUND AND PURPOSE: Obesity and physical inactivity are independently associated with physical and functional limitations in older adults. The current study examines the impact of physical activity on odds of physical and functional limitations in older adults with central and general obesity. METHODS: Data from 6279 community-dwelling adults aged 60 years or more from the Health and Retirement Study 2006 and 2008 waves were used to calculate prevalence and odds of physical and functional limitation among obese older adults with high waist circumference (waist circumference >=88 cm in females and >=102 cm in males) who were physically active versus inactive (engaging in moderate/vigorous activity less than once per week). Logistic regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and number of comorbidities. RESULTS: Physical activity was associated with lower odds of physical and functional limitations among older adults with high waist circumference (odds ratio [OR], 0.59; confidence interval [CI], 0.52-0.68, for physical limitations; OR, 0.52; CI, 0.44-0.62, for activities of daily living; and OR, 0.44; CI, 0.39-0.50, for instrumental activities of daily living). CONCLUSIONS: Physical activity is associated with significantly lower odds of physical and functional limitations in obese older adults regardless of how obesity is classified. Additional research is needed to determine whether physical activity moderates long-term physical and functional limitations. PMID- 25794310 TI - Anodic WO3 mesosponge @ carbon: a novel binder-less electrode for advanced energy storage devices. AB - A novel design for an anodic WO3 mesosponge @ carbon has been introduced as a highly stable and long cyclic life Li-ion battery electrode. The nanocomposite was successfully synthesized via single-step electrochemical anodization and subsequent heat treatment in an acetylene and argon gas environment. Morphological and compositional characterization of the resultant materials revealed that the composite consisted of a three-dimensional interconnected network of WO3 mesosponge layers conformally coated with a 5 nm thick carbon layer and grown directly on top of tungsten metal. The results demonstrated that the carbon-coated mesosponge WO3 layers exhibit a capacity retention of 87% after completion of 100 charge/discharge cycles, which is significantly higher than the values of 25% for the crystalline (without carbon coating) or 40% for the as prepared mesosponge WO3 layers. The improved electrochemical response was attributed to the higher stability and enhanced electrical conductivity offered by the carbon coating layer. PMID- 25794312 TI - Influence of fluorination on protein-engineered coiled-coil fibers. AB - We describe the design and characterization of fluorinated coiled-coil proteins able to assemble into robust nano- and microfibers. Fluorination is achieved biosynthetically by residue-specific incorporation of 5,5,5-trifluoroleucine (TFL). The fluorinated proteins C+TFL and Q+TFL are highly alpha-helical as confirmed via circular dichroism (CD) and more resistant to thermal denaturation compared to their nonfluorinated counterparts, C and Q. The fluorinated proteins demonstrate enhanced fiber assembly at pH 8.0 with higher order structure in contrast to nonfluorinated proteins, which are unable to form fibers under the same conditions. Ionic strength dependent fiber assembly is observed for fluorinated as well as wild-type proteins in which the fluorinated proteins exhibited more stable, thicker fibers. The fluorinated and nonfluorinated proteins reveal metal ion-dependent small molecule recognition and supramolecular assemblies. In the presence of Zn (II), enhanced thermal stability and fiber assembly is observed for the fluorinated proteins and their nonfluorinated counterparts. Whereas Ni (II) promotes aggregation with no fiber assembly, the stabilization of alpha-helix by Zn (II) results in enhanced binding to curcumin by the fluorinated proteins. Surprisingly, the nonfluorinated proteins exhibit multiple-fold increase in curcumin binding in the presence of Zn (II). In the context of the growing number of protein-based fiber assemblies, these fluorinated coiled-coil proteins introduce a new paradigm in the development of highly stable, robust self-assembling fibers under more physiologically relevant pH conditions that promotes the binding and release of small molecules in response to external cues. PMID- 25794311 TI - Magic angle spinning NMR spectroscopy: a versatile technique for structural and dynamic analysis of solid-phase systems. AB - Magic Angle Spinning (MAS) NMR spectroscopy is a powerful method for analysis of a broad range of systems, including inorganic materials, pharmaceuticals, and biomacromolecules. The recent developments in MAS NMR instrumentation and methodologies opened new vistas to atomic-level characterization of a plethora of chemical environments previously inaccessible to analysis, with unprecedented sensitivity and resolution. PMID- 25794313 TI - TACkling NKB's role in puberty. PMID- 25794316 TI - Euestrogenemia and the mineralocorticoid receptor. PMID- 25794317 TI - [Creativity and mental disorder]. PMID- 25794318 TI - [Somatoform vertigo syndromes]. AB - About 30 % of patients presenting to general practitioners complain of episodic or chronic vertigo or dizziness symptoms mostly with substantial impact on their daily living and activities. 30 to 50 % of the dizziness disorders are organically not sufficiently explained and are caused by mental or psychosomatic diseases. Somatoform dizziness syndromes can occur without a preceding vestibular disorder (e. g., primary somatoform dizziness) or they can develop in consequence of an organic vestibular disorder (secondary somatoform dizziness). However, it often takes months or even years until the correct diagnosis is made and an appropriate psychosomatic therapy can be initiated. Therefore, it is essential for the course of the disease that at an early stage not only careful interdisciplinary organic but also psychosomatic diagnostics are applied. PMID- 25794319 TI - [Acute pharmacotherapy for anxiety symptoms in patients with depression]. AB - Patients with depression often also present symptoms of anxiety. First-line pharmacotherapy of comorbid symptoms of depression and anxiety is often a combination therapy of an antidepressant agent, which is combined with benzodiazepines. However, benzodiazepines pose the drawbacks of being associated with cognitive and motor impairments and hold a significant risk for dependence. For some patients, benzodiazepines are contraindicated or patients refuse to take them. Therefore, alternative therapy strategies for the acute treatment of anxiety symptoms in depressed patients are urgently needed. A selective Medline/Pubmed search with focus on acute pharmacological treatment strategies for anxiety and agitation in depressed patients was undertaken. In the light of the paucity of studies in this field, positive effects could be assumed for quetiapine, olanzapine, olanzapine-fluoxetine combination, pregabaline and silexan. PMID- 25794320 TI - [Optimising pain therapy for neurological inpatients]. AB - BACKGROUND: The Department of Neurology at the Medical University Graz has implemented a multiprofessional pain management concept and evaluated the outcome by means of a patient survey. METHODS: Standard operating procedures for standardised pain measurement, documentation and therapy were developed. All engaged professional participants were trained before implementation. RESULTS: 88.7 % of the surveyed 63 patients reported pain during the hospitalisation. During the night and in the morning, the occurrence of severe pain was most likely. The position or activity most likely triggering severe pain was mobilisation (19 %). Patients with degenerative diseases of the spine without radiculopathy reported the highest levels of pain. CONCLUSIONS: Pain is an important problem for neurological inpatients. Nocturnal pain, pain induced by mobilisation, and pain therapy for patients with degenerative diseases of the spine without radiculopathy require particular attention. PMID- 25794321 TI - [Convergent validity of SCID-II and TCI: categorical vs. dimensional diagnostics of personality disorders using the example of short-term prisoners]. AB - In order to objectify the diagnostics of personality disorders, questionnaires and structured interviews are used. Nevertheless, due to different methodological approaches even those instruments arrive at different results very often. Therefore, this study aimed to check the convergent validity of two frequently used instruments - the Structured Clinical Interview for DSM IV Axis II Disorders (SCID-II) and the Temperament and Character Inventory (TCI) - the first one representing the categorical and the latter one the dimensional approach for diagnosing personality disorders. The diagnostic concordances were statistically described with Cohen's Kappa, Yule's Y, and correlations. The results indicate that there are striking differences in diagnoses and that the SCID-II rather tends to diagnose a personality disorder earlier than the TCI. PMID- 25794322 TI - [Association between the MAOA-uVNTR polymorphism and antisocial personality traits in alcoholic men]. AB - AIMS: We have analysed the MAOA-uVNTR polymorphism in the promoter region of the X-chromosomal monoamine oxidase A (MAOA) gene. The first aim was to examine the association between the MAOA genotype and the alcoholic phenotype. In the second part of the paper we have analysed the association of the MAOA genotype with impulsive and aggressive behaviour. Genotypes with 3 or 5-repeat alleles (MAOA-L genotype) were reported to be associated with impulsive and aggressive traits. METHODS: The MAOA genotype was determined in 371 male alcohol-dependent subjects and 236 male controls all of German descent. Behavioural and personality traits were evaluated using the self-report questionnaires Barratt Impulsiveness Scale (BIS), Buss Durkee Hostility Inventory (BDHI), Temperament and Character Inventory (TCI) and NEO-Five Factor Inventory (NEO-FFI). A median split in BIS, Buss Durkee Physical Assault, Buss Durkee Irritability, TCI and NEO-FFI was conducted. RESULTS: No association could be detected between the MAOA genotype and the alcoholic phenotype. Based on the results of the BIS questionnaire, we were able to make out an association between the MAOA-L genotype and higher levels of impulsivity (p = 0.043). Furthermore - without reaching statistical significance - we detected a very slight association between the MAOA-L genotype and higher scores in the BDHI subcategory physical aggression (p = 0.058). CONCLUSION: Taken together, these findings suggest that the MAOA-L genotype is to some extent associated with impulsive and antisocial personality traits in alcoholic men. Further studies on that question are needed. PMID- 25794323 TI - [Tizanidine withdrawal symptoms in stress cardiomyopathy]. AB - INTRODUCTION: An acute discontinuation of tizanidine, an alpha-2-agonistic muscle relaxant, is associated with reflex tachycardia, hypertension, tremor, hypertonicity and anxiety. CASE REPORT: We describe a 53-year-old patient with broken-heart syndrome, who developed serious tizanidine withdrawal symptoms after high-dosed long-term treatment within the framework of stress cardiomyopathy. CONCLUSION: Central muscle relaxants like tizanidine might have an impact on the development of delirium. Tizanidine withdrawal should be considered in patients who manifest signs and symptoms of withdrawal from medications. The drug should be gradually reduced in dosage under observation by a psychiatrist. When prescribing tizanidine, the possible pharmacological side effects and interactions should be taken into careful account. PMID- 25794324 TI - [New therapeutic options in multiple sclerosis]. AB - Therapeutic options in the treatment of multiple sclerosis (MS) have broadened notably over the past years, especially for relapsing-remitting forms of MS. The revision of the diagnostic criteria simplified and accelerated MS diagnosis, definitions of disease courses were operationalized focussing on disease activity and progression as major determinants. The paradigm of an early treatment initiation is accepted and evidence-based. All these aspects have led to an increasing complexity of therapeutic decision making. Besides a benefit-risk evaluation for each substance, individual patient-related factors have to be considered, e.g. life and family planning. This article reviews new and established disease-modifying drugs in the context of disease courses and stages and benefit-risk-considerations. PMID- 25794325 TI - Expeditious low-temperature sintering of copper nanoparticles with thin defective carbon shells. AB - The realization of air-stable nanoparticles, well-formulated nanoinks, and conductive patterns based on copper is a great challenge in low-cost and large area flexible printed electronics. This work reports the synthesis of a conductively interconnected copper structure via thermal sintering of copper inks at a low temperature for a short period of time, with the help of thin defective carbon shells coated onto the copper nanoparticles. Air-stable copper/carbon core/shell nanoparticles (typical size ~23 nm, shell thickness ~1.0 nm) are prepared by means of an electric explosion of wires. Gaseous oxidation of the carbon shells with a defective structure occurs at 180 degrees C, impacting the choice of organic solvents as well as the sintering conditions to create a crucial neck formation. Isothermal oxidation and reduction treatment at 200 degrees C for only about 10 min yields an oxide-free copper network structure with an electrical resistivity of 25.1 MUOmega cm (14.0 MUOmega cm at 250 degrees C). Finally, conductive copper line patterns are achieved down to a 50 MUm width with an excellent printing resolution (standard deviation ~4.0%) onto a polyimide substrate using screen printing of the optimized inks. PMID- 25794327 TI - A turn-on fluorescence probe for imaging iodide in living cells based on an elimination reaction. AB - Based on a unique elimination reaction prompted by the iodide ion, a novel turn on fluorescence probe (HCy-OMe-Br) has been developed for the first time. The probe emits in the near infrared region with a large Stokes shift, and can respond rapidly to iodide with high selectivity and sensitivity. PMID- 25794326 TI - Twin displacive phase transitions in amino acid quasiracemates. AB - Three quasiracemates, L-norleucine:D-methionine, L-norvaline:D-norleucine, and L norvaline:D-methionine, were crystallized to see how they differ from regular racemates in terms of crystal structure (studied by single-crystal X-ray diffraction) and of thermally induced phase transitions (studied by differential scanning calorimetry). Two types of transitions are detected between 100 and 450 K and structurally characterized: (1) displacive transitions of the molecular bilayers that form the crystal and (2) continuous or discontinuous disordering transitions in the amino acid side chains. Uniquely for the quasiracemates, the displacive transition proceeds in two close steps as only one surface of each molecular bilayer slides at first, upon forming an intermediate phase, while the other surface follows at a slightly higher temperature. Altogether, 18 new single crystal structure-refinement data sets are reported for these three quasiracemates. PMID- 25794328 TI - Alternaria is an Infrequent Cause of Keratitis: A Case Report and Review of the Literature. AB - OBJECTIVE: To report a case of fungal keratitis caused by Alternaria in a 49-year old female who developed an acute onset of eye infection after ocular trauma caused by an olive leaf. METHODS: The clinical presentation, microbiological diagnosis, and therapeutic approaches are reported. RESULTS: The patient was referred to our university hospital clinic with corneal abscess in her left eye. Before the start of an empirical antibacterial therapy (both topical and systemic), a swab of the cornea was obtained which at microscopic examination revealed a few fragments of hyphal elements, probably for the paucity of material collected. After one week, the corneal abscess had increased in size, and the corneal stroma was filled with filamentous structures similar to fungal hyphae. Oral and topical voriconazole was administered because of the clinical picture and the response of microbiological laboratory whose examination of the material removed from the anterior chamber showed numerous hyphal fragments identified by culture as Alternaria spp. The corneal abscess healed in two weeks, but the patient now has a corneal scar and is awaiting a corneal transplant. CONCLUSIONS: Ophthalmologists and microbiologists must take fungi into greater consideration as a possible cause of keratitis as they are emerging as the cause of this infectious disease in many countries. Voriconazole spreads well in the eye and is effective in the cure of fungal keratitis including those caused by Alternaria. PMID- 25794329 TI - Impact of Collagen Cross-linking on Psychological Distress and Vision and Health Related Quality of Life in Patients With Keratoconus. AB - OBJECTIVE: To evaluate the changes in psychological distress level and quality of life (QoL) scores of keratoconus (KC) patients 1 year after corneal collagen cross-linking (CXL). METHODS: Observational cross-sectional study. Thirty-three, consecutive progressive KC patients who received CXL treatment were enrolled in the study. All patients were evaluated before and 1 year after CXL ophthalmologically and psychologically. Main outcome measures were the visual, refractive, and topographic changes and the Beck Depression Inventory, State Trait Anxiety Inventory (STAI), Short Form-36 (SF-36), and The National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). RESULTS: There were significant improvements in the keratometric readings at flat axis, steep axis, the mean keratometric reading, the corneal astigmatism (Kast), and the maximum keratometric reading. State-Trait Anxiety Inventory-II scores, QoL dimensions, such as physical role difficulty, general health, mental health, ocular pain, near activities, distance activities, peripheral vision, and mental health scores, and the composite score of NEI-VFQ-25, were higher after surgery. There was a positive correlation between the changes observed in Kast and mental health; a negative correlation between the changes in Kast and STAI-II, and a negative correlation between the changes in mental health and STAI-II. Change in STAI-II has significantly predicted the improvement observed in general health. CONCLUSIONS: Our results suggested lower trait anxiety and better vision-related and health-related QoL in KC patients 1 year after successful CXL treatment. Better QoL in these patients seems to be related not only with the visual and refractive results but also improvement observed in trait anxiety. PMID- 25794330 TI - Corneal involvement in systemic inflammatory diseases. AB - Corneal involvement in patients with systemic inflammatory disorders may be sight threatening, and it may be associated with a life-threatening disease. Significant systemic inflammatory diseases in this context are autoimmune connective tissue diseases, systemic autoimmune dermatological disorders, and autoimmune diseases of the lacrimal system. Keratoconjunctivitis sicca is usually the most common ocular finding in these patients. Peripheral ulcerative keratitis is a rare condition usually associated with increased ocular morbidity and also mortality, as it might act as an indicator of a more widespread vasculitis. Corneal biomechanical properties may also be altered in connective tissue diseases. Although recent studies suggest that the risk for corneal complications after ocular surgery in patients with quiescent autoimmune disease is minimal, caution is still recommended, as the knowledge about the corneal wound-healing process and the corneal biomechanical properties in these patients is not yet fully understood. This article reviews corneal abnormalities and characteristics in the setting of systemic inflammatory diseases. PMID- 25794331 TI - The Influence of Synthetic Cannabinoid UR-144 on Human Psychomotor Performance--A Case Report Demonstrating Road Traffic Risks. AB - OBJECTIVE: UR-144 [(1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl) methanone] is a synthetic cannabinoid, which has been detected in many "legal highs" seized from the global drug market since the beginning of 2012. It gained popularity as a "legal" alternative to classic cannabis in countries where it was not controlled. The popularity of UR-144 means that this substance is also abused by individuals driving motor vehicles. This article describes a case of driving under the influence (DUI) of UR-144. The aim of the undertaken case analysis and presenting description of pharmacological similarity of THC and UR-144 is to answer the question whether UR-144 can produce effects incompatible with safe driving. METHODS: Blood from the driver was obtained by a physician approximately 2 h after the collision and 4.5 h after self-reported dosing. Police from the crash site provided behavioral observations, and the physician performed medical examination. Blood was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The developed method was described in detail. The method was linear in the range of 0.5-50 ng/mL; the precision and accuracy values obtained were less than 15%. The symptoms observed by police and physician who collected the blood sample were described. RESULTS: In the blood sample collected from the driver, UR-144 and its major pyrolysis product [1-(1-pentyl-1H-indol-3-yl)-3 methyl-2-(propan-2-yl)but-3-en-1-one] were detected. Whole-blood concentration of UR-144 was 14.6 ng/mL. The result of blood analysis and observed symptoms clearly indicated that the driver was under the influence of UR-144. CONCLUSIONS: UR-144 produces effects and impairment similar to or even more dangerous than delta-9 tetrahydrocannabinol (Delta(9)-THC), making it unsafe for driving. Therefore, UR 144 should be treated as a potentially dangerous substance in traffic safety. PMID- 25794332 TI - Continuous infusion of the alpha7 nicotinic acetylcholine receptor agonist EVP 6124 produces no signs of tolerance at memory-enhancing doses in rats: a pharmacokinetic and behavioral study. AB - We investigated whether the effects of acutely administered EVP-6124, an alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonist, on cognition were maintained after 6-day continuous minipump administration. Performance in a delay dependent forgetting test was measured in the object recognition task after single-oral doses of 0.3 or 1 mg/kg, or at plasma steady-state concentrations (Css) of 0.6 or 2 ng/ml, which were similar to the efficacious plasma concentrations after single-oral dosing. The 0.3 mg/kg acute dose enhanced memory at a total plasma concentration of ~0.3 ng/ml at 1-4 h after dosing. Continuous treatment produced total plasma Css values of 0.48 and 1.93 ng/ml on day 6 and enhanced memory. At EVP-6124 plasma concentrations that optimally enhance memory in the object recognition task, tolerance did not develop after 6 days of continuous treatment. PMID- 25794333 TI - Methylone-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. AB - Methylone (2-methylamino-1-[3,4-methylenedioxy-phenyl]propan-1-one), an amphetamine analog, has emerged as a popular drug of abuse worldwide. Methylone induces hyperthermia, which is thought to contribute toward the lethal consequences of methylone overdose. Methylone has been assumed to induce hyperthermic effects through inhibition of serotonin and/or dopamine transporters (SERT and DAT, respectively). To examine the roles of each of these proteins in methylone-induced toxic effects, we used SERT and DAT knockout (KO) mice and assessed the hyperthermic and lethal effects caused by a single administration of methylone. Methylone produced higher rates of lethal toxicity compared with other amphetamine analogs in wild-type mice. Compared with wild-type mice, lethality was significantly lower in DAT KO mice, but not in SERT KO mice. By contrast, only a slight diminution in the hyperthermic effects of methylone was observed in DAT KO mice, whereas a slight enhancement of these effects was observed in SERT KO mice. Administration of the selective D1 receptor antagonist SCH 23390 and the D2 receptor antagonist raclopride reduced methylone-induced hyperthermia, but these drugs also had hypothermic effects in saline-treated mice, albeit to a smaller extent than the effects observed in methylone-treated mice. In contradistinction to 3,4-methylenedioxymethamphetamine, which induces its toxicity through SERT and DAT, these data indicate that DAT, but not SERT, is strongly associated with the lethal toxicity produced by methylone, which did not seem to be dependent on the hyperthermic effects of methylone. DAT is therefore a strong candidate molecule for interventions aimed at preventing acute neurotoxic and lethal effects of methylone. PMID- 25794335 TI - Dicarabrones A and B, a pair of new epimers dimerized from sesquiterpene lactones via a [3 + 2] cycloaddition from Carpesium abrotanoides. AB - Dicarabrones A and B, a pair of epimers possessing a new skeleton featuring a cyclopentane ring connecting two sesquiterpene lactone units, were isolated from the whole plant of Carpesium abrotanoides L. Their full structures were established on the basis of spectroscopic data and were further confirmed by single-crystal X-ray crystallography. They were presumably biosynthesized from two sesquiterpenoid monomers through a [3 + 2] cycloaddition. Dicarabrones A and B showed moderate effects on HL-60 cells with IC50 values of 9.1 and 8.2 MUM, respectively. PMID- 25794337 TI - In response to 'Pancreatic neuroendocrine tumors in von Hippel-Lindau disease', by Louis de Mestier & Pascal Hammel. PMID- 25794338 TI - Endovascular transvenous cure for ruptured brain arteriovenous malformations in complex cases with high Spetzler-Martin grades. AB - OBJECT: Ruptured cerebral arteriovenous malformations (AVMs) with deep localization and high Spetzler-Martin grades are associated with considerable challenges regarding nidus eradication treatment. The authors report their experience with curative endovascular transvenous embolization in a series of patients harboring "untreatable" lesions. METHODS: Between January 2008 and June 2013, a transvenous endovascular embolization protocol was implemented at the authors' institution for consecutive patients with ruptured brain AVMs that were considered incurable by classic endovascular and surgical techniques. Therapeutic decision making was based on Spetzler-Martin grades, AVM location, type of venous drainage, and angioarchitectural evaluation. Complete exclusion of the nidus was the objective of treatment. RESULTS: Twenty patients (10 male and 10 female, mean age 36.7 +/- 17.7 years) were included. Initial Spetzler-Martin grades were III-V for 90.0% of the patients. The lesions were deeply seated in 80% and in eloquent locations in 90% of cases. The preprocedural modified Rankin Scale score was 0-2 for 12 of the 20 patients (60.0%), 3 for 2 patients (10.0%), and 4 for 6 patients (30.0%). The postprocedural clinical status was unchanged for all patients. The procedure was technically feasible in all cases. Procedure-related mortality was 0%. Ninety percent of the patients were independent in their everyday lives (modified Rankin Scale Scores 0-2) at the 6-month follow-up. In all cases but one (95%) the embolization was curative, confirmed by selective DSA at 6 months and 18 months postintervention. CONCLUSIONS: Single-session endovascular transvenous embolization seems to be a safe and effective curative treatment for patients harboring complex brain AVMs with high Spetzler-Martin grade. PMID- 25794339 TI - Isolated cortical vein thrombosis: case series. AB - OBJECT: Isolated cortical vein thrombosis (ICVT) accounts for less than 1% of all cerebral infarctions. ICVT may cause irreversible parenchymal damage, rendering early and accurate diagnosis critical. This case series and literature review presents the clinical and radiological findings in 7 patients with ICVT, and highlights risk factors and imaging modalities that may be most beneficial in rendering an accurate and timely diagnosis. METHODS: Patients with CT and MRI findings consistent with ICVT examined between January 2011 and June 2014 were included in this retrospective review. RESULTS: Seven patients (5 females, 2 males), ranging in age from 11 months to 34 years, met the inclusion criteria. The most common clinical presentations were headaches (n = 4) and seizures (n = 3). The most common comorbidities noted in these patients were hypercoagulable states (n = 4) and intracranial hypotension (n = 3). Five patients had intraparenchymal involvement. CT suggested the correct diagnosis in 4 patients, and MRI confirmed the diagnosis in all 7 patients. All patients who received anticoagulation therapy (n = 5) experienced complete resolution of their symptoms. CONCLUSIONS: The majority of these patients were adult females, consistent with published data. Seizures and headaches were the most common presenting symptoms. Hypercoagulable state and intracranial hypotension, both known risk factors for thrombosis, were the most commonly noted ICVT risk factors. Intraparenchymal involvement was prevalent in nearly all ICVT cases and presented as vasogenic edema, early intraparenchymal hemorrhage, or hemorrhagic venous infarction. Susceptibility-weighted imaging was the most sensitive imaging technique in diagnosing ICVT. PMID- 25794340 TI - Clinical and radiographic outcomes following traumatic Grade 1 and 2 carotid artery injuries: a 10-year retrospective analysis from a Level I trauma center. The Parkland Carotid and Vertebral Artery Injury Survey. AB - OBJECT: Proper screening, management, and follow-up of Grade 1 and 2 blunt carotid artery injuries (BCIs) remains controversial. These low-grade BCIs were analyzed to define their natural history and establish a rational management plan based on lesion progression and cerebral infarction. METHODS: A retrospective review of a prospectively maintained database of all blunt traumatic carotid and vertebral artery injuries treated between August 2003 and April 2013 was performed and Grade 1 and 2 BCIs were identified. Grade 1 injuries are defined as a vessel lumen stenosis of less than 25%, and Grade 2 injuries are defined as a stenosis of the vessel lumen between 25% and 50%. Demographic information, radiographic imaging, number of imaging sessions performed per individual, length of radiographic follow-up, radiographic outcome at end of follow-up, treatment(s) provided, and documentation of ischemic stroke or transient ischemic attack were recorded. RESULTS: One hundred seventeen Grade 1 and 2 BCIs in 100 patients were identified and available for follow-up. The mean follow-up duration was 60 days. Final imaging of Grade 1 and 2 BCIs demonstrated that 64% of cases had resolved, 13% of cases were radiographically stable, and 9% were improved, whereas 14% radiographically worsened. Of the treatments received, 54% of cases were treated with acetylsalicylic acid (ASA), 31% received no treatment, and 15% received various medications and treatments, including endovascular stenting. There was 1 cerebral infarction that was thought to be related to bilateral Grade 2 BCI, which developed soon after hospital admission. CONCLUSIONS: The majority of Grade 1 and 2 BCIs remained stable or improved at final follow-up. Despite a 14% rate of radiographic worsening in the Grade 1 and 2 BCIs cohort, there were no adverse clinical outcomes associated with these radiographic changes. The stroke rate was 1% in this low-grade BCIs cohort, which may be an overestimate. The use of ASA or other antiplatelet or anticoagulant medications in these low-grade BCIs did not appear to correlate with radiographic injury stability, nor with a decreased rate of cerebral infarction. Although these data suggest that these Grade 1 and 2 BCIs may require less intensive radiographic follow-up, future prospective studies are needed to make conclusive changes related to treatment and management. PMID- 25794341 TI - Pallidal stimulation for Holmes tremor: clinical outcomes and single-unit recordings in 4 cases. AB - OBJECT: Holmes tremor (HT) is characterized by irregular, low-frequency (< 4.5 Hz) tremor occurring at rest, with posture, and with certain actions, often affecting proximal muscles. Previous reports have tended to highlight the use of thalamic deep brain stimulation (DBS) in cases of medication-refractory HT. In this study, the authors report the clinical outcome and analysis of single-unit recordings in patients with medication-refractory HT treated with globus pallidus internus (GPi) DBS. METHODS: The authors retrospectively reviewed the medical charts of 4 patients treated with pallidal DBS for medication-refractory HT at the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center. Clinical outcomes were measured at baseline and after surgery using an abbreviated motor-severity Fahn-Tolosa-Marin (FTM) tremor rating scale. Intraoperative microelectrode recordings were performed with patients in the awake state. The neurophysiological characteristics identified in HT were then also compared with characteristics previously described in Parkinson's disease (PD) studied at the authors' institution. RESULTS: The mean percentage improvement in tremor motor severity was 78.87% (range 59.9%-94.4%) as measured using the FTM tremor rating scale, with an average length of follow-up of 33.75 months (range 18-52 months). Twenty-eight GPi neurons were recorded intraoperatively in the resting state and 13 of these were also recorded during contralateral voluntary arm movement. The mean firing rate at rest in HT was 56.2 +/- 28.5 Hz, and 63.5 +/- 19.4 Hz with action, much lower than the GPi recordings in PD. GPi unit oscillations of 2-8 Hz were prominent in both patients with HT and those with PD, but in HT, unlike PD, these oscillations were not suppressed by voluntary movement. CONCLUSIONS: The efficacy of GPi DBS exceeded that reported in prior studies of ventrolateral thalamus DBS and suggest GPi may be a better target for treating HT. These clinical and neurophysiological findings help illuminate evolving models of HT and highlight the importance of cerebellar basal ganglia interactions. PMID- 25794342 TI - Actual and projected incidence rates for chronic subdural hematomas in United States Veterans Administration and civilian populations. AB - OBJECT: Chronic subdural hematomas (SDHs) are more common among veterans and elderly persons than among members of the general population; however, precise incidence rates are unknown. The purposes of this study were 1) to determine the current incidence of chronic SDH in a US Veterans Administration (VA) population and 2) to create a mathematical model for determining the current and future incidence of chronic SDH as a function of population age, sex, and comorbidity in the United States VA and civilian populations. METHODS: To determine the actual number of veterans who received a radiographic diagnosis and surgical treatment for SDH during 2000-2012, the authors used the VISN03 VA database. On the basis of this result and data from outside the United States, they then created a mathematical model accounting for age, sex, and alcohol consumption to predict the incidence of SDH in the VA and civilian populations during 2012-2040. RESULTS: Of 875,842 unique (different patient) visits to a VA hospital during the study period, 695 new SDHs were identified on CT images. Of these 695 SDHs, 203 (29%) required surgical drainage. The incidence rate was 79.4 SDHs per 100,000 persons, and the age-standardized rate was 39.1+/-4.74 SDHs per 100,000 persons. The authors' model predicts that incidence rates of chronic SDH in aging United States VA and civilian populations will reach 121.4 and 17.4 cases per 100,000 persons, respectively, by 2030, at which time, approximately 60,000 cases of chronic SDH will occur each year in the United States. CONCLUSIONS: The incidence of chronic SDH is rising; SDH is projected to become the most common cranial neurosurgical condition among adults by the year 2030. PMID- 25794343 TI - No additional protection against ventriculitis with prolonged systemic antibiotic prophylaxis for patients treated with antibiotic-coated external ventricular drains. AB - OBJECT External ventricular drains (EVDs) are commonly used for CSF diversion but pose a risk of ventriculitis, with rates varying in frequency from 2% to 45%. Results of studies examining the utility of prolonged systemic antibiotic therapy for the prevention of EVD-related infection have been contradictory, and no study to date has examined whether this approach confers additional benefit in preventing ventriculitis when used in conjunction with antibiotic-coated EVDs (ac EVDs). METHODS A prospective performance analysis was conducted over 4 years to examine the impact of discontinuing systemic antibiotic prophylaxis after insertion of an ac-EVD on rates of catheter-related ventriculitis. Ventriculitis and other nosocomial infections were ascertained by a qualified infection disease nurse using definitions based on published standards from the Centers for Disease Control and Prevention, comparing the period when patients received systemic antibiotic therapy for the duration of EVD treatment (Period 1) compared with only for the peri-insertion period (Period 2). Costs were analyzed and compared across the 2 time periods. RESULTS Over the 4-year study period, 866 patients were treated with ac-EVDs for a total of 7016 catheter days. There were 8 cases of ventriculitis, for an overall incidence of 0.92%. Rates of ventriculitis did not differ significantly between Period 1 and Period 2 (1.1% vs 0.4%, p = 0.22). The rate of nosocomial infections, however, was significantly higher in Period 1 (2.0% vs 0.0% in Period 2, p = 0.026). Cost savings of $162,516 were realized in Period 2 due to decreased drug costs and savings associated with the reduction in nosocomial infections. CONCLUSIONS Prolonged systemic antibiotic therapy following placement of ac-EVDs does not seem to reduce the incidence of catheter related ventriculitis and was associated with a higher rate of nosocomial infections and increased cost. PMID- 25794345 TI - Editorial: Mild narrowing of the cervical carotid is noted. PMID- 25794344 TI - Impact of surgical methodology on the complication rate and functional outcome of patients with a single brain metastasis. AB - OBJECT Brain metastases are the most common intracranial neoplasms and are on the increase. As radiation side effects are increasingly better understood, more patients are being treated with surgery alone with varying outcomes. The authors previously reported that en bloc resection of a single brain metastasis was associated with decreased incidences of leptomeningeal disease and local recurrence compared with piecemeal resection. However, en bloc resection is often feared to cause an increased incidence of postoperative complications. This study aimed to answer this question. METHODS The authors reviewed data from patients with a previously untreated single brain metastasis, who were treated with resection at The University of Texas M.D. Anderson Cancer Center (1993-2012). Data related to the patient, tumor, and methods of resection were obtained. Discharge Karnofsky Performance Scale (KPS) scores and 30-day postoperative complications were noted. Complications were considered major when they persisted for longer than 30 days, resulted in hospitalization or prolongation of hospital stay, required aggressive treatment, and/or were life threatening. RESULTS During the study period, 1033 eligible patients were identified. The median age was 58 years, 83% had a KPS score greater than 70, and 81% were symptomatic at surgery. Sixty-two percent of the patients underwent en bloc resection of their tumor, and 38% underwent piecemeal resection. There were significant differences between the 2 groups in terms of preoperative tumor volume, tumor functional grade, and symptoms at presentation, among others. The overall complication rates were 13% for patients undergoing en bloc resection and 19% for patients undergoing piecemeal resection (p = 0.007). The incidences of major complications and neurological complications were also significantly different. There was a trend in the same direction for major neurological complications, although it was not significant. Among patients undergoing piecemeal resection of tumors in eloquent cortex, 24% had complications (13% had major, 18% had neurological, 9% had major neurological, and 13% had select neurological complications; 4% died within 1 month of surgery). Among those undergoing en bloc resection of such tumors, 11% had complications (6% had major, 8% had neurological, 4% had major neurological, and 4% had select neurological; 2% died within 1 month of surgery). The differences in overall, major, neurological, and select neurological complications were statistically significant, but 1-month mortality and major neurological complications were not. In addition, within subcategories of tumor volume, the incidence of various complications was generally higher for patients undergoing piecemeal resection than for those undergoing en bloc resection. CONCLUSIONS The authors' results indicate that postoperative complication rates are not increased by en bloc resection, including for lesions in eloquent brain regions or for large tumors. This gives credence to the idea that en bloc resection of brain metastases, when feasible, is at least as safe as piecemeal resection. PMID- 25794346 TI - Combined fragment molecular orbital cluster in molecule approach to massively parallel electron correlation calculations for large systems. AB - The local correlation "cluster-in-molecule" (CIM) method is combined with the fragment molecular orbital (FMO) method, providing a flexible, massively parallel, and near-linear scaling approach to the calculation of electron correlation energies for large molecular systems. Although the computational scaling of the CIM algorithm is already formally linear, previous knowledge of the Hartree-Fock (HF) reference wave function and subsequent localized orbitals is required; therefore, extending the CIM method to arbitrarily large systems requires the aid of low-scaling/linear-scaling approaches to HF and orbital localization. Through fragmentation, the combined FMO-CIM method linearizes the scaling, with respect to system size, of the HF reference and orbital localization calculations, achieving near-linear scaling at both the reference and electron correlation levels. For the 20-residue alanine alpha helix, the preliminary implementation of the FMO-CIM method captures 99.6% of the MP2 correlation energy, requiring 21% of the MP2 wall time. The new method is also applied to solvated adamantine to illustrate the multilevel capability of the FMO CIM method. PMID- 25794347 TI - Simultaneous determination of sweeteners in beverages by LC-MS/MS. AB - A new method was established for the simultaneous determination of 10 sweeteners and a degradation product in beverages by using LC-MS/MS. An ACQUITY UPLC BEH C18 (2.1 * 100 mm, 1.7 MUm) was used as the LC column and 0.1% each of aqueous formic acid and formic acid in acetonitrile were used as the mobile phase. A simple and rapid determination of sweeteners was possible by diluting with a solvent, and in the case of some samples containing a large amount of foreign matter, after pre treatment by diluting with solvent and clean-up of the sample using an Oasis HLB cartridge. All the validation results were satisfactory. As the regulations and standards for sweeteners vary from country to country, a field survey of 58 beverages marketed in Japan was performed using the present method. No issues concerning the labelling or food sanitation law were found in the tested samples. PMID- 25794348 TI - High throughput protein nanocrystal fractionation in a microfluidic sorter. AB - Protein crystallography is transitioning into a new generation with the introduction of the X-ray free electron laser, which can be used to solve the structures of complex proteins via serial femtosecond crystallography. Sample characteristics play a critical role in successful implementation of this new technology, whereby a small, narrow protein crystal size distribution is desired to provide high quality diffraction data. To provide such a sample, we developed a microfluidic device that facilitates dielectrophoretic sorting of heterogeneous particle mixtures into various size fractions. The first generation device demonstrated great potential and success toward this endeavor; thus, in this work, we present a comprehensive optimization study to improve throughput and control over sorting outcomes. First, device geometry was designed considering a variety of criteria, and applied potentials were modeled to determine the scheme achieving the largest sorting efficiency for isolating nanoparticles from microparticles. Further, to investigate sorting efficiency within the nanoparticle regime, critical geometrical dimensions and input parameters were optimized to achieve high sorting efficiencies. Experiments revealed fractionation of nanobeads from microbeads in the optimized device with high sorting efficiencies, and protein crystals were sorted into submicrometer size fractions as desired for future serial femtosecond crystallography experiments. PMID- 25794349 TI - Risk and protective factors among preschool children: integrating research and practice. AB - In this article the authors present a review of previous reviews and meta analyses, identifying and summarizing the empirical research base on risk and protective factors for future psychosocial problems-specifically externalizing and internalizing problems-among preschool children. The authors also discuss risk and protective factors in the framework of concepts such as evidence-based practice, risk-focused prevention and treatment, and the Risk, Need, and Responsivity principles. They conclude that there is an extensive amount of research on risk and protective factors for preschool children that could and should be used by well educated professionals to help children to a better life. PMID- 25794350 TI - Influence of implant surface topography on primary stability in a standardized osteoporosis rabbit model study. AB - Evaluating primary stability is important to predict the prognosis of dental implant treatment. Primary stability is decreased in a low bone density site such as osteoporosis. However, it is difficult to apply in small animal and the effect of the different implant surface topography for the primary stability at low bone density site has not yet fully been investigated. The purpose of the present study was to evaluate the influence of implant surface topography on primary stability in a standardized osteoporosis animal model. Six rabbits underwent ovariectomy and administrated glucocorticoid to induce an osteoporosis model. Sham-operations were performed in additional six rabbits. Implants with machined or oxidized-surfaces were inserted into the femur epiphyses and insertion torque (IT) and implant stability quotient (ISQ) were measured. In sham model, the IT and ISQ did not differ significantly between the both implant. However, the IT value of oxidized-surface implant was significantly higher than that of the machined implant in the osteoporosis model. Meanwhile, ISQ did not significantly differ between the machined and oxidized-surfaced implants. In conclusion, the IT of implants is higher with rough than with smooth surfaces but that there are no differences in ISQ value between different surfaces in a standardized osteoporosis bone reduced rabbit model. PMID- 25794352 TI - RELB Alters Proliferation of Human Pluripotent Stem Cells via IMP3- and LIN28 Mediated Modulation of the Expression of IGF2 and Other Cell-Cycle Regulators. AB - The molecular mechanisms that orchestrate the exit from pluripotency, cell cycle progression, and lineage-specific differentiation in human pluripotent stem cells (hPSCs) are poorly understood. RELB, a key protein in the noncanonical nuclear factor-kappaB (NFkappaB) signaling pathway, was previously implicated in controlling the switch between human embryonic stem cell (hESC) proliferation and differentiation. Here, we show that RELB enhances the proliferation of hESCs and human-induced pluripotent stem cells (hiPSCs) without affecting their pluripotency. We demonstrate that RELB does this by interacting with two RNA binding proteins LIN28A and IMP3 (IGF2 mRNA-binding protein 3); further, these interactions control mRNA levels and protein expression of insulin-like growth factor 2 (IGF2) and key cell-cycle genes. Finally, after stress, these proteins co-localize in stress granules in hESCs and iPSCs. Our data identify RELB as a novel regulator of hPSC proliferation, and suggest a new function for RELB, in addition to its widely accepted role as a transcription factor, that involves recruitment of IMP3 and LIN28 to the cytosolic mRNA translation-control domains for post-transcriptional modulation of IGF2 and cell-cycle gene expression. PMID- 25794351 TI - Molecular Dynamics Simulations of KirBac1.1 Mutants Reveal Global Gating Changes of Kir Channels. AB - Prokaryotic inwardly rectifying (KirBac) potassium channels are homologous to mammalian Kir channels. Their activity is controlled by dynamical conformational changes that regulate ion flow through a central pore. Understanding the dynamical rearrangements of Kir channels during gating requires high-resolution structure information from channels crystallized in different conformations and insight into the transition steps, which are difficult to access experimentally. In this study, we use MD simulations on wild type KirBac1.1 and an activatory mutant to investigate activation gating of KirBac channels. Full atomistic MD simulations revealed that introducing glutamate in position 143 causes significant widening at the helix bundle crossing gate, enabling water flux into the cavity. Further, global rearrangements including a twisting motion as well as local rearrangements at the subunit interface in the cytoplasmic domain were observed. These structural rearrangements are similar to recently reported KirBac3.1 crystal structures in closed and open conformation, suggesting that our simulations capture major conformational changes during KirBac1.1 opening. In addition, an important role of protein-lipid interactions during gating was observed. Slide-helix and C-linker interactions with lipids were strengthened during activation gating. PMID- 25794353 TI - [German Version of the Social Impact Scale (SIS-D)--Pilot Testing of an Instrument for Measuring Experienced Stigmatization in a Sample of Cancer Patients]. AB - PURPOSE: PURPOSE of this study was to investigate the psychometric properties of the newly adapted German Version of the Social Impact Scale (SIS), a multidimensional questionnaire measuring perceived stigmatization. METHODS: The SIS was translated into the German language following state-of-the-art criteria and completed in a sample of 139 outpatients with mixed tumor entities. In addition to the SIS-D, participants answered questions about their experience of discrimination and perceived visibility of their disease as well as about illness beliefs and perceptions of cancer control. RESULTS: Comparably to the original scale, exploratory factor analysis resulted in a 4-factor solution and the following dimensions: "social isolation" (Cronbachs alpha=0.89), "social rejection" (alpha=0.81), "internalized shame" (alpha=0.81) and "financial insecurity" (alpha=0.81). DISCUSSION: Considering the results of this pilot study, it can be concluded that the German version of the SIS is an instrument measuring perceived stigmatization in cancer patients with very good psychometric properties. However, further validation studies are considered necessary. PMID- 25794355 TI - The 5-4-3-2-1 go! Brand to promote nutrition and physical activity: a case of positive behavior change but negative change in beliefs. AB - In recent years, community-based obesity prevention programs have taken an ecological approach and addressed social determinants of obesity. The branded 5-4 3-2-1 Go! obesity prevention program aims to change obesity risk behaviors in low income neighborhoods in Chicago with a multilevel approach. This study follows a previous evaluation, which showed 5-4-3-2-1 Go! exposure to be associated with increased fruit and vegetable consumption. The authors examined whether increased positive beliefs about fruit and vegetable consumption were associated with exposure to program messages. Exploratory factor analysis identified a fresh fruit/vegetable availability satisfaction factor. The authors compared outcome measures between baseline and follow-up samples and between exposure and control conditions. Multivariable logistic regression models were estimated to evaluate the effects of program exposure on changes in nutrition beliefs. The study found that participants' (n = 246) beliefs about fruit and vegetable consumption were negatively associated with exposure to the program and that demographic factors, social environment, and physical environment were strongly associated with beliefs about fruit and vegetable consumption. These findings merit further research and may indicate the environmental factors that are associated with attitude formation among those reached by obesity prevention interventions, especially when many participants live in neighborhoods lacking convenient fruit and vegetable shopping options. PMID- 25794354 TI - [Integrated Peer Teaching of Communication and Clinical Skills: How to Train Student Tutors?]. AB - AIM: This paper describes the theory-based development of a standardized training model for peer tutors. The aim is to qualify tutors to teach communication skills integrated with practical clinical skills, to medical students in the pre clinical curriculum. As a result, students are encouraged to form a basic understanding of the biopsychosocial model of diseases early in their studies. METHOD: The training model's design is based on the Kern model for curriculum development as adapted by McLean et al., who outlined the following steps: planning, implementation, and evaluation/feedback. Our focus is on development, review of feasibility, and evaluation as measured by the subjectively perceived effectiveness of the implemented training model. 2 target groups were considered: the peer tutors and the student tutees. RESULTS: In 2009, a 3-step training model consisting of 12 units was developed, based on the theory of patient-centered communication and the biopsychosocial model. The training was rated very positively on a 5-point Likert scale by all tutors at 2 points in time: t1 (directly after training) and t2 (after conducting 2 tutorials) (t1: M=1.67; SD=+/-0.86; t2: M=1.75; SD=+/-0.71). On a 6-point Likert scale, the tutees also evaluated their communication and clinical skills as being significantly better after completing the 10 tutorials (t2: scale for interaction and communication: M=4.81; SD: 1.09; scale for clinical examination: M=4.99; SD: 0.85) than before the tutorials (t0: scale for communication and interaction: M=3.18; SD=1.15; scale for clinical examination: M=2.88; SD: 1.09). CONCLUSIONS: By implementing a standardized tutor training model, one can qualify peer tutors to teach communication skills integrated with practical clinical skills during the pre clinical phase. Practice teaching of the curricular material via role playing, tutorial simulation and an extensive feedback session, along with the definition of clinical standards for recording case histories and performing examinations, have proven themselves to be core elements of effective tutor training. PMID- 25794360 TI - Tobacco alkaloids and tobacco-specific nitrosamines in dust from homes of smokeless tobacco users, active smokers, and nontobacco users. AB - Smokeless tobacco products, such as moist snuff or chewing tobacco, contain many of the same carcinogens as tobacco smoke; however, the impact on children of indirect exposure to tobacco constituents via parental smokeless tobacco use is unknown. As part of the California Childhood Leukemia Study, dust samples were collected from 6 homes occupied by smokeless tobacco users, 6 homes occupied by active smokers, and 20 tobacco-free homes. To assess children's potential for exposure to tobacco constituents, vacuum-dust concentrations of five tobacco specific nitrosamines, including N'-nitrosonornicotine [NNN] and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], as well as six tobacco alkaloids, including nicotine and myosmine, were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used generalized estimating equations derived from a multivariable marginal model to compare levels of tobacco constituents between groups, after adjusting for a history of parental smoking, income, home construction date, and mother's age and race/ethnicity. The ratio of myosmine/nicotine was used as a novel indicator of the source of tobacco contamination, distinguishing between smokeless tobacco products and tobacco smoke. Median dust concentrations of NNN and NNK were significantly greater in homes with smokeless tobacco users compared to tobacco free homes. In multivariable models, concentrations of NNN and NNK were 4.8- and 6.9-fold higher, respectively, in homes with smokeless tobacco users compared to tobacco-free homes. Median myosmine/nicotine ratios were lower in homes with smokeless tobacco users (1.8%) compared to homes of active smokers (7.7%), confirming that cigarette smoke was not the predominant source of tobacco constituents in homes with smokeless tobacco users. Children living with smokeless tobacco users may be exposed to carcinogenic tobacco-specific nitrosamines via contact with contaminated dust and household surfaces. PMID- 25794361 TI - Carbon-coated Fe3O4 microspheres with a porous multideck-cage structure for highly reversible lithium storage. AB - A novel H3PO4 etching strategy together with subsequent carbon coating has been developed for the synthesis of carbon-coated Fe3O4 microspheres with a porous multideck-cage structure. These carbon-coated Fe3O4 microspheres manifest high specific capacity (~1100 m h g(-1) at 200 mA g(-1)) and excellent cycling stability for lithium storage. PMID- 25794362 TI - EPR spectroscopy shows that the blood carrier protein, human serum albumin, closely interacts with the N-terminal domain of the copper transporter, Ctr1. AB - Copper is an essential metal whose localization within the cells must be carefully controlled to avoid copper dependent redox cycling. Although most of the key proteins involved in cellular copper transfer have been identified, fundamental questions regarding the copper transfer mechanism have yet to be resolved. One of the blood carrier proteins believed to be involved in copper transfer to the cell is human serum albumin (HSA). However, direct evidence for close interaction between HSA and the extracellular domain of the copper transporter Ctr1 has not yet been found. By utilizing EPR spectroscopy, we show here that HSA closely interacts with the first 14 amino acids of the Ctr1, even without the presence of copper ions. PMID- 25794363 TI - Correction: a bioenergetic basis for membrane divergence in archaea and bacteria. PMID- 25794364 TI - Determination and quantification of the emetic toxin cereulide from Bacillus cereus in pasta, rice and cream with liquid chromatography-tandem mass spectrometry. AB - A rapid and sensitive method has been developed for determination and quantification of cereulide in cream, rice and pasta. Samples are homogenised after addition of amylase to cooked rice and pasta, and cereulide is extracted with methanol. After the removal of water with methyl-tert butyl ether/hexane and evaporation until dryness, no further purification was required before analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Recently, both cereulide and (13)C6-cereulide has become commercially available at high purities; hence, this method offers a more reliable quantification of positive samples than previous methods using valinomycin or in-house produced and purified cereulide as calibration standard. The introduction of amylase in the sample preparation improves both the extraction yield of cereulide from positive samples of starch-rich matrices such as pasta and rice, and the within-laboratory reproducibility of the analytical method. The LoQ of the method is 1.1 ng/g cereulide with RSDs ranging from 2.6% to 10%. The method is fully validated based on Commission Decision 2002/657/EC, suitable for routine analysis, and has been used to analyse samples from a cereulide food poisoning outbreak in a kindergarten in Norway. Cereulide production in different rice and pasta samples was investigated, showing that cereulide was unexpectedly produced by emetic Bacillus cereus in all eight pasta and rice samples. PMID- 25794367 TI - Do Technology-Based Support Groups Reduce Care Burden Among Dementia Caregivers? A Review. AB - Technology-based support groups for caregivers are often more accessible and convenient than attending face-to-face support groups. In this review the author examines the effectiveness of technology-based social support groups on reducing care burden among caregivers of individuals with dementia. Studies were identified through 10 online bibliographic databases. INCLUSION CRITERIA: (a) published before June 2013, (b) rigorous study design, (c) English language, (d) peer-reviewed journals, (e) home-based care, (f) telephone and/or Internet support group utilized at home, and (g) outcome measure of care burden or caregiver stress. Technology-based social support groups enjoy a modest level of positive outcomes, appear to be low cost, and pose little risk of harmful effects while reducing care burden in caregivers. Based on the five studies reviewed, technology-based support group services have demonstrated a positive impact on reducing care burden among dementia caregivers; and improve support networks similarly to the way face-to-face support groups connect participants. PMID- 25794366 TI - Topography compensation for haptization of a mesh object and its stiffness distribution. AB - This work was motivated by the need for perceptualizing nano-scale scientific data, e.g., those acquired by a scanning probe microscope, where collocated topography and stiffness distribution of a surface can be measured. Previous research showed that when the topography of a surface with spatially varying stiffness is rendered using the conventional penalty-based haptic rendering method, the topography perceived by the user could be significantly distorted from its original model. In the worst case, a higher region with a smaller stiffness value can be perceived to be lower than a lower region with a larger stiffness value. This problem was explained by the theory of force constancy: the user tends to maintain an invariant contact force when s/he strokes the surface to perceive its topography. In this paper, we present a haptization algorithm that can render the shape of a mesh surface and its stiffness distribution with high perceptual accuracy. Our algorithm adaptively changes the surface topography on the basis of the force constancy theory to deliver adequate shape information to the user while preserving the stiffness perception. We also evaluated the performance of the proposed haptization algorithm in comparison to the constraint based algorithm by examining relevant proximal stimuli and carrying out a user experiment. Results demonstrated that our algorithm could improve the perceptual accuracy of shape and reduce the exploration time, thereby leading to more accurate and efficient haptization. PMID- 25794368 TI - Pagetoid dyskeratosis in dermatopathology. AB - Pagetoid dyskeratosis (PD) is an incidental pathologic finding that appears in several skin conditions. In an attempt to better understand PD and its incidence in dermatopathology, the authors have analyzed all skin biopsies performed over the period of 1 year in our Department of Dermatology and examined their clinical and dermatopathological variables. The criteria used for a keratinocyte to be considered a PD cell were: (1) a size larger than normal, (2) the presence of pycnotic nucleus, (3) a clear halo surrounding the nucleus, and (4) a pale eosinophilic cytoplasm. A total of 3565 biopsies were analyzed, PD cells being found in 80 cases (2.24%). Melanocytic nevi were the commonest skin lesions in which PD was observed, followed by soft fibromas, angiofibromas, and acrochordons. Most lesions were located on the head, neck, and trunk. Most cases displayed fewer than 15 PD cells per field. PD cells were normally located in the mid epidermis (frequently in clusters). The biopsies usually revealed indirect signs of rubbing, although PD cells were also found in places where rubbing was unlikely. Here, the authors report the largest series of PD analyzed to date, expanding our understanding of this striking pathological observation. PMID- 25794369 TI - Cutaneous manifestations of angioimmunoblastic T-cell lymphoma: clinical and pathological characteristics. AB - Angioimmunoblastic T-cell lymphoma (AITL), an uncommon variant of peripheral T cell lymphoma, affects the skin in approximately 50% of cases. Its protean clinical and histopathological cutaneous manifestations pose a challenge in diagnosis, particularly when these precede the diagnosis of AITL on a lymph node biopsy. In this retrospective study, we compared 11 cases of AITL with cutaneous manifestations (mean age 67 years; male:female ratio 1:0.8; 24 skin biopsies) with 20 control cases of inflammatory and non-AITL lymphomatous diseases (mean age 52 years; male:female ratio 1:1.5; 26 skin biopsies). Clinical, histopathological, immunohistochemical, and molecular data were documented. New insights into the clinical evolution of cutaneous involvement by AITL (C-AITL), from early macular, through papular to nodular stages, were observed. Microscopically, a parallel increment in the density of the dermal infiltrate and in the detection of lymphocyte cytological atypia was noted over time. Identification and quantification of follicular T-helper cells (Tfh), the neoplastic lineage, by immunohistochemistry helped to separate cases of C-AITL from inflammatory controls, offering promise as a useful diagnostic adjunct. The presence of T-cell clonality did not have discriminatory value between the 2 groups. Our work suggests that the early maculopapular phase of C-AITL eludes identification on pathological grounds alone and that features such as cytological atypia and high endothelial venules lack diagnostic specificity. In the context of (1) a rash that simulates a drug/viral exanthem or an acute manifestation of a connective tissue disorder, but proves recalcitrant, (2) constitutional abnormalities and/or lymphadenopathy that persist, and (3) a Tfh cell-rich perivascular dermatitis, the diagnosis of early C-AITL can be suspected, but not confirmed, without the benefit of a lymph node biopsy. The later nodular phase of C-AITL occurring in a similar constitutional background, can usually be discerned as lymphomatous, clinically and pathologically. Here a Tfh cell-rich infiltrate is a clue to the specific diagnosis, but confirmation by a nodal evaluation remains mandatory. Despite the difficulty in establishing a diagnosis of C-AITL in its early stages, and speculation that the initial eruptions might be reactive in nature, our sequential data support the concept that these are lymphomatous ab initio. To address the diagnostic challenge presented by this disease, meaningful integration of clinical and pathological data is imperative. PMID- 25794370 TI - Enlarging ulcers in the mouth and on the back. Granulomatosis with polyangiitis. PMID- 25794371 TI - Primary cutaneous malignant granular cell tumor: an immunohistochemical study and review of the literature. AB - Granular cell tumors (GCTs) are uncommon soft tissue tumors characterized by cytoplasmic granular appearance of the neoplastic cells. Malignant granular cell tumors (MGCTs) comprise less than 2% of GCTs and are mostly found in the subcutaneous soft tissues of the lower extremities, especially the thighs. Very few cases have been reported in the skin. The uncommon occurrence of cutaneous MGCTs and their histopathologic similarities with their benign counterpart make difficult the diagnosis of this particular malignancy. We describe a primary cutaneous MGCT that presented as a left posterior chest wall mass in a 51-year old woman. Local excision was performed for the primary tumor, which was first interpreted as an atypical GCT, but 3 months later a left axillary mass appeared, and subsequent axillary lymph node dissection demonstrated metastatic disease in 4 of 12 excised lymph nodes. We report the immunophenotype of this primary cutaneous MGCT, which was studied with an ample panel of antibodies and compare our results with those of the few previously reported cases in the skin and subcutaneous soft tissues. PMID- 25794374 TI - Quaternion-valued echo state networks. AB - Quaternion-valued echo state networks (QESNs) are introduced to cater for 3-D and 4-D processes, such as those observed in the context of renewable energy (3-D wind modeling) and human centered computing (3-D inertial body sensors). The introduction of QESNs is made possible by the recent emergence of quaternion nonlinear activation functions with local analytic properties, required by nonlinear gradient descent training algorithms. To make QENSs second-order optimal for the generality of quaternion signals (both circular and noncircular), we employ augmented quaternion statistics to introduce widely linear QESNs. To that end, the standard widely linear model is modified so as to suit the properties of dynamical reservoir, typically realized by recurrent neural networks. This allows for a full exploitation of second-order information in the data, contained both in the covariance and pseudocovariances, and a rigorous account of second-order noncircularity (improperness), and the corresponding power mismatch and coupling between the data components. Simulations in the prediction setting on both benchmark circular and noncircular signals and on noncircular real-world 3-D body motion data support the analysis. PMID- 25794373 TI - Steroid-responsive atypical marginal zone hyperplasia of the lip in a child. AB - Atypical marginal zone hyperplasia (AMZH) is a recently described disease entity seen mainly in children. AMZH most commonly affects tonsils and appendices. Cutaneous AMZH is rare. The authors report here a recurrent AMZH in the lip of a 9-year-old child who presented originally with a lip swelling for approximately 3 months. The lip lesion recurred after each incomplete excision for 4 times. Pathologically, the lesion demonstrated marginal zone B-cell hyperplasia with kappa monoclonality by flow cytometry and immunohistochemistry studies. Lymphoepithelial lesions were noted with involvement of minor salivary glands. Polymerase chain reaction for immunoglobulin heavy-chain gene rearrangement has been repeatedly negative. Polymerase chain reaction for Borrelia species DNA was negative on both paraffin-embedded tissue and plasma. Serum antibodies IgG and IgM for Helicobacter Pylori were positive. A diagnosis of AMZH was made. Two courses of anti H. Pylori therapy did not improve the lip lesion, which completely regressed after a course of prednisone therapy. With differential diagnosis of cutaneous marginal zone lymphoma, the case illustrated diagnostic challenges, especially with recurrent lesions. This is the first case of recurrent cutaneous AMZH that has uncharacteristic kappa light-chain restriction. AMZH should be considered in children with mucocutaneous lesions with features of marginal zone lymphoma. PMID- 25794375 TI - Adaptive optimal control of highly dissipative nonlinear spatially distributed processes with neuro-dynamic programming. AB - Highly dissipative nonlinear partial differential equations (PDEs) are widely employed to describe the system dynamics of industrial spatially distributed processes (SDPs). In this paper, we consider the optimal control problem of the general highly dissipative SDPs, and propose an adaptive optimal control approach based on neuro-dynamic programming (NDP). Initially, Karhunen-Loeve decomposition is employed to compute empirical eigenfunctions (EEFs) of the SDP based on the method of snapshots. These EEFs together with singular perturbation technique are then used to obtain a finite-dimensional slow subsystem of ordinary differential equations that accurately describes the dominant dynamics of the PDE system. Subsequently, the optimal control problem is reformulated on the basis of the slow subsystem, which is further converted to solve a Hamilton-Jacobi-Bellman (HJB) equation. HJB equation is a nonlinear PDE that has proven to be impossible to solve analytically. Thus, an adaptive optimal control method is developed via NDP that solves the HJB equation online using neural network (NN) for approximating the value function; and an online NN weight tuning law is proposed without requiring an initial stabilizing control policy. Moreover, by involving the NN estimation error, we prove that the original closed-loop PDE system with the adaptive optimal control policy is semiglobally uniformly ultimately bounded. Finally, the developed method is tested on a nonlinear diffusion-convection reaction process and applied to a temperature cooling fin of high-speed aerospace vehicle, and the achieved results show its effectiveness. PMID- 25794376 TI - Convolutive bounded component analysis algorithms for independent and dependent source separation. AB - Bounded component analysis (BCA) is a framework that can be considered as a more general framework than independent component analysis (ICA) under the boundedness constraint on sources. Using this framework, it is possible to separate dependent as well as independent components from their mixtures. In this paper, as an extension of a recently introduced instantaneous BCA approach, we introduce a family of convolutive BCA criteria and corresponding algorithms. We prove that the global optima of the proposed criteria, under generic BCA assumptions, are equivalent to a set of perfect separators. The algorithms introduced in this paper are capable of separating not only the independent sources but also the sources that are dependent/correlated in both component (space) and sample (time) dimensions. Therefore, under the condition that the sources are bounded, they can be considered as extended convolutive ICA algorithms with additional dependent/correlated source separation capability. Furthermore, they have potential to provide improvement in separation performance, especially for short data records. This paper offers examples to illustrate the space-time correlated source separation capability through a copula distribution-based example. In addition, a frequency-selective Multiple Input Multiple Output equalization example demonstrates the clear performance advantage of the proposed BCA approach over the state-of-the-art ICA-based approaches in setups involving convolutive mixtures of digital communication sources. PMID- 25794377 TI - Gaussian kernel width optimization for sparse Bayesian learning. AB - Sparse kernel methods have been widely used in regression and classification applications. The performance and the sparsity of these methods are dependent on the appropriate choice of the corresponding kernel functions and their parameters. Typically, the kernel parameters are selected using a cross validation approach. In this paper, a learning method that is an extension of the relevance vector machine (RVM) is presented. The proposed method can find the optimal values of the kernel parameters during the training procedure. This algorithm uses an expectation-maximization approach for updating kernel parameters as well as other model parameters; therefore, the speed of convergence and computational complexity of the proposed method are the same as the standard RVM. To control the convergence of this fully parameterized model, the optimization with respect to the kernel parameters is performed using a constraint on these parameters. The proposed method is compared with the typical RVM and other competing methods to analyze the performance. The experimental results on the commonly used synthetic data, as well as benchmark data sets, demonstrate the effectiveness of the proposed method in reducing the performance dependency on the initial choice of the kernel parameters. PMID- 25794378 TI - Multiclass semisupervised learning based upon kernel spectral clustering. AB - This paper proposes a multiclass semisupervised learning algorithm by using kernel spectral clustering (KSC) as a core model. A regularized KSC is formulated to estimate the class memberships of data points in a semisupervised setting using the one-versus-all strategy while both labeled and unlabeled data points are present in the learning process. The propagation of the labels to a large amount of unlabeled data points is achieved by adding the regularization terms to the cost function of the KSC formulation. In other words, imposing the regularization term enforces certain desired memberships. The model is then obtained by solving a linear system in the dual. Furthermore, the optimal embedding dimension is designed for semisupervised clustering. This plays a key role when one deals with a large number of clusters. PMID- 25794379 TI - Impulsive stabilization and impulsive synchronization of discrete-time delayed neural networks. AB - This paper investigates the problems of impulsive stabilization and impulsive synchronization of discrete-time delayed neural networks (DDNNs). Two types of DDNNs with stabilizing impulses are studied. By introducing the time-varying Lyapunov functional to capture the dynamical characteristics of discrete-time impulsive delayed neural networks (DIDNNs) and by using a convex combination technique, new exponential stability criteria are derived in terms of linear matrix inequalities. The stability criteria for DIDNNs are independent of the size of time delay but rely on the lengths of impulsive intervals. With the newly obtained stability results, sufficient conditions on the existence of linear state feedback impulsive controllers are derived. Moreover, a novel impulsive synchronization scheme for two identical DDNNs is proposed. The novel impulsive synchronization scheme allows synchronizing two identical DDNNs with unknown delays. Simulation results are given to validate the effectiveness of the proposed criteria of impulsive stabilization and impulsive synchronization of DDNNs. Finally, an application of the obtained impulsive synchronization result for two identical chaotic DDNNs to a secure communication scheme is presented. PMID- 25794380 TI - A universal concept based on cellular neural networks for ultrafast and flexible solving of differential equations. AB - This paper develops and validates a comprehensive and universally applicable computational concept for solving nonlinear differential equations (NDEs) through a neurocomputing concept based on cellular neural networks (CNNs). High precision, stability, convergence, and lowest-possible memory requirements are ensured by the CNN processor architecture. A significant challenge solved in this paper is that all these cited computing features are ensured in all system-states (regular or chaotic ones) and in all bifurcation conditions that may be experienced by NDEs.One particular quintessence of this paper is to develop and demonstrate a solver concept that shows and ensures that CNN processors (realized either in hardware or in software) are universal solvers of NDE models. The solving logic or algorithm of given NDEs (possible examples are: Duffing, Mathieu, Van der Pol, Jerk, Chua, Rossler, Lorenz, Burgers, and the transport equations) through a CNN processor system is provided by a set of templates that are computed by our comprehensive templates calculation technique that we call nonlinear adaptive optimization. This paper is therefore a significant contribution and represents a cutting-edge real-time computational engineering approach, especially while considering the various scientific and engineering applications of this ultrafast, energy-and-memory-efficient, and high-precise NDE solver concept. For illustration purposes, three NDE models are demonstratively solved, and related CNN templates are derived and used: the periodically excited Duffing equation, the Mathieu equation, and the transport equation. PMID- 25794381 TI - On learning navigation behaviors for small mobile robots with reservoir computing architectures. AB - This paper proposes a general reservoir computing (RC) learning framework that can be used to learn navigation behaviors for mobile robots in simple and complex unknown partially observable environments. RC provides an efficient way to train recurrent neural networks by letting the recurrent part of the network (called reservoir) be fixed while only a linear readout output layer is trained. The proposed RC framework builds upon the notion of navigation attractor or behavior that can be embedded in the high-dimensional space of the reservoir after learning. The learning of multiple behaviors is possible because the dynamic robot behavior, consisting of a sensory-motor sequence, can be linearly discriminated in the high-dimensional nonlinear space of the dynamic reservoir. Three learning approaches for navigation behaviors are shown in this paper. The first approach learns multiple behaviors based on the examples of navigation behaviors generated by a supervisor, while the second approach learns goal directed navigation behaviors based only on rewards. The third approach learns complex goal-directed behaviors, in a supervised way, using a hierarchical architecture whose internal predictions of contextual switches guide the sequence of basic navigation behaviors toward the goal. PMID- 25794382 TI - Coupled attribute similarity learning on categorical data. AB - Attribute independence has been taken as a major assumption in the limited research that has been conducted on similarity analysis for categorical data, especially unsupervised learning. However, in real-world data sources, attributes are more or less associated with each other in terms of certain coupling relationships. Accordingly, recent works on attribute dependency aggregation have introduced the co-occurrence of attribute values to explore attribute coupling, but they only present a local picture in analyzing categorical data similarity. This is inadequate for deep analysis, and the computational complexity grows exponentially when the data scale increases. This paper proposes an efficient data-driven similarity learning approach that generates a coupled attribute similarity measure for nominal objects with attribute couplings to capture a global picture of attribute similarity. It involves the frequency-based intra coupled similarity within an attribute and the inter-coupled similarity upon value co-occurrences between attributes, as well as their integration on the object level. In particular, four measures are designed for the inter-coupled similarity to calculate the similarity between two categorical values by considering their relationships with other attributes in terms of power set, universal set, joint set, and intersection set. The theoretical analysis reveals the equivalent accuracy and superior efficiency of the measure based on the intersection set, particularly for large-scale data sets. Intensive experiments of data structure and clustering algorithms incorporating the coupled dissimilarity metric achieve a significant performance improvement on state-of the-art measures and algorithms on 13 UCI data sets, which is confirmed by the statistical analysis. The experiment results show that the proposed coupled attribute similarity is generic, and can effectively and efficiently capture the intrinsic and global interactions within and between attributes for especially large-scale categorical data sets. In addition, two new coupled categorical clustering algorithms, i.e., CROCK and CLIMBO are proposed, and they both outperform the original ones in terms of clustering quality on UCI data sets and bibliographic data. PMID- 25794383 TI - Robust consensus tracking control for multiagent systems with initial state shifts, disturbances, and switching topologies. AB - This paper deals with the consensus tracking control issues of multiagent systems and aims to solve them as accurately as possible over a finite time interval through an iterative learning approach. Based on the iterative rule, distributed algorithms are proposed for every agent using its nearest neighbor knowledge, for which the robustness problem is addressed against initial state shifts, disturbances, and switching topologies. These uncertainties are dynamically changing not only along the time axis but also the iteration axis. It is shown that the matrix norm conditions can be developed to achieve the convergence of the considered consensus tracking objectives, for which necessary and sufficient conditions are presented in terms of linear matrix inequalities to guarantee their feasibility in the sense of the spectral norm. Furthermore, simulation examples are given to illustrate the effectiveness and robustness of the obtained consensus tracking results. PMID- 25794384 TI - A bootstrap based Neyman-Pearson test for identifying variable importance. AB - Selection of most informative features that leads to a small loss on future data are arguably one of the most important steps in classification, data analysis and model selection. Several feature selection (FS) algorithms are available; however, due to noise present in any data set, FS algorithms are typically accompanied by an appropriate cross-validation scheme. In this brief, we propose a statistical hypothesis test derived from the Neyman-Pearson lemma for determining if a feature is statistically relevant. The proposed approach can be applied as a wrapper to any FS algorithm, regardless of the FS criteria used by that algorithm, to determine whether a feature belongs in the relevant set. Perhaps more importantly, this procedure efficiently determines the number of relevant features given an initial starting point. We provide freely available software implementations of the proposed methodology. PMID- 25794385 TI - A Directional Interstitial Antenna for Microwave Tissue Ablation: Theoretical and Experimental Investigation. AB - Microwave ablation (MWA) is a minimally invasive thermal therapy modality increasingly employed for the treatment of tumors and benign disease. For successful treatment, complete thermal coverage of the tumor and margin of surrounding healthy tissue must be achieved. Currently available interstitial antennas for MWA have cylindrically symmetric radiation patterns. Thus, when treating targets in proximity to critical structures, caution must be taken to prevent unintended thermal damage. A novel coaxial antenna design for MWA with an asymmetrical cylindrical heating pattern is presented in this paper. This radiation pattern is achieved by employing a hemicylindrical reflector positioned at a critical distance from a conventional coaxial monopole antenna. Finite element method simulations were employed to optimize the geometric dimensions of the antenna with the objective of minimizing the antenna reflection coefficient at the 2.45-GHz operating frequency, and maximizing volume of the ablation zone. Prototype antennas were fabricated and experimentally evaluated. Simulations indicated an optimal S11 of -32 dB at 2.45 GHz in close agreement with experimental measurements of -29 dB. Ex vivo experiments were performed to validate simulations and observe effects to the antennas' heating pattern with the varying input power and geometry of the reflector. Ablation zones up to 20 mm radially were observed in the forward direction, with minimal heating (less than 4 mm) behind the reflector. PMID- 25794386 TI - Energy Window Optimization for X-Ray K-Edge Tomographic Imaging. AB - GOAL: In K-edge tomographic imaging with photon counting detectors, the energy window width of photon counting detectors significantly affects the signal-to noise ratio (SNR) of measured intensity data and the contrast-to-noise ratio (CNR) of reconstructed images. In this paper, we present an optimization method to determine an optimal window width around a K-edge for optimal SNR and CNR. METHODS: An objective function is designed to describe SNR of the projection data based on the Poisson distribution of detected X-ray photons. Then, a univariate optimization method is applied to obtain an X-ray energy window width. RESULTS: Numerical simulations are performed to evaluate the proposed method, and the results show that the optimal energy window width obtained from the proposed method produces not only optimal SNR data in the projection domain but also optimal CNR values in the image domain. CONCLUSION: The proposed method in the projection domain can determine an optimal energy window width for X-ray photon counting imaging, and achieve optimality in both projection and image domains. SIGNIFICANCE: Our study provides a practical way to determine the optimal energy window width of photon counting detectors, which helps improve contrast resolution for X-ray K-edge tomographic imaging. PMID- 25794387 TI - Automatic Coronary Calcium Scoring in Non-Contrast-Enhanced ECG-Triggered Cardiac CT With Ambiguity Detection. AB - The amount of coronary artery calcification (CAC) is a strong and independent predictor of cardiovascular events. We present a system that automatically quantifies total patient and per coronary artery CAC in non-contrast-enhanced, ECG-triggered cardiac CT. The system identifies candidate calcifications that cannot be automatically labeled with high certainty and optionally presents these to an expert for review. Candidates were extracted by intensity-based thresholding and described by location features derived from estimated coronary artery positions, as well as size, shape and intensity features. Next, a two class classifier distinguished between coronary calcifications and negatives or a multiclass classifier labeled CAC per coronary artery. Candidates that could not be labeled with high certainty were identified by entropy-based ambiguity detection and presented to an expert for review and possible relabeling. The system was evaluated with 530 test images. Using the two-class classifier, the intra-class correlation coefficient (ICC) between reference and automatically determined total patient CAC volume was 0.95. Using the multiclass classifier, the ICC between reference and automatically determined per artery CAC volume was 0.98 (LAD), 0.69 (LCX), and 0.95 (RCA). In 49% of CTs, no ambiguous candidates were identified, while review of the remaining CTs increased the ICC for total patient CAC volume to 1.00, and per artery CAC volume to 1.00 (LAD), 0.95 (LCX), and 0.99 (RCA). In conclusion, CAC can be automatically identified in non contrast-enhanced ECG-triggered cardiac CT. Ambiguity detection with expert review may enable the application of automatic CAC scoring in the clinic with a performance comparable to that of a human expert. PMID- 25794388 TI - Evaluation and Comparison of Anatomical Landmark Detection Methods for Cephalometric X-Ray Images: A Grand Challenge. AB - Cephalometric analysis is an essential clinical and research tool in orthodontics for the orthodontic analysis and treatment planning. This paper presents the evaluation of the methods submitted to the Automatic Cephalometric X-Ray Landmark Detection Challenge, held at the IEEE International Symposium on Biomedical Imaging 2014 with an on-site competition. The challenge was set to explore and compare automatic landmark detection methods in application to cephalometric X ray images. Methods were evaluated on a common database including cephalograms of 300 patients aged six to 60 years, collected from the Dental Department, Tri Service General Hospital, Taiwan, and manually marked anatomical landmarks as the ground truth data, generated by two experienced medical doctors. Quantitative evaluation was performed to compare the results of a representative selection of current methods submitted to the challenge. Experimental results show that three methods are able to achieve detection rates greater than 80% using the 4 mm precision range, but only one method achieves a detection rate greater than 70% using the 2 mm precision range, which is the acceptable precision range in clinical practice. The study provides insights into the performance of different landmark detection approaches under real-world conditions and highlights achievements and limitations of current image analysis techniques. PMID- 25794389 TI - Beyond perspective dual photography with illumination masks. AB - Scene appearance from the point of view of a light source is called a reciprocal or dual view. Since there exists a large diversity in illumination, these virtual views may be nonperspective and multiviewpoint in nature. In this paper, we demonstrate the use of occluding masks to recover these dual views, which we term shadow cameras. We first show how to render a single reciprocal scene view by swapping the camera and light source positions. We then extend this technique for multiple views by both building a virtual shadow camera array and by exploiting area sources. We also capture nonperspective views such as orthographic, cross slit and a pushbroom variant, while introducing novel applications such as converting between camera projections and removing refractive and catadioptric distortions. Finally, since a shadow camera is artificial, we can manipulate any of its intrinsic parameters, such as camera skew, to create perspective distortions. We demonstrate a variety of indoor and outdoor results and show a rendering application for capturing the light-field of a light-source. PMID- 25794390 TI - Event oriented dictionary learning for complex event detection. AB - Complex event detection is a retrieval task with the goal of finding videos of a particular event in a large-scale unconstrained Internet video archive, given example videos and text descriptions. Nowadays, different multimodal fusion schemes of low-level and high-level features are extensively investigated and evaluated for the complex event detection task. However, how to effectively select the high-level semantic meaningful concepts from a large pool to assist complex event detection is rarely studied in the literature. In this paper, we propose a novel strategy to automatically select semantic meaningful concepts for the event detection task based on both the events-kit text descriptions and the concepts high-level feature descriptions. Moreover, we introduce a novel event oriented dictionary representation based on the selected semantic concepts. Toward this goal, we leverage training images (frames) of selected concepts from the semantic indexing dataset with a pool of 346 concepts, into a novel supervised multitask lp -norm dictionary learning framework. Extensive experimental results on TRECVID multimedia event detection dataset demonstrate the efficacy of our proposed method. PMID- 25794391 TI - Fractal analysis for reduced reference image quality assessment. AB - In this paper, multifractal analysis is adapted to reduced-reference image quality assessment (RR-IQA). A novel RR-QA approach is proposed, which measures the difference of spatial arrangement between the reference image and the distorted image in terms of spatial regularity measured by fractal dimension. An image is first expressed in Log-Gabor domain. Then, fractal dimensions are computed on each Log-Gabor subband and concatenated as a feature vector. Finally, the extracted features are pooled as the quality score of the distorted image using l1 distance. Compared with existing approaches, the proposed method measures image quality from the perspective of the spatial distribution of image patterns. The proposed method was evaluated on seven public benchmark data sets. Experimental results have demonstrated the excellent performance of the proposed method in comparison with state-of-the-art approaches. PMID- 25794392 TI - A Classification Method for User-Independent Intent Recognition for Transfemoral Amputees Using Powered Lower Limb Prostheses. AB - Powered lower limb prosthesis technologies hold the promise of providing greater ability and mobility to transfemoral amputees. Intent recognition systems for these devices may allow amputees to perform automatic, seamless transitions between locomotion modes. Prior studies in which pattern recognition algorithms have been trained to recognize subject-specific patterns within device-mounted sensor data have shown the feasibility of such systems. While effective, these strategies require substantial training regimens. To reduce this training burden, we developed and evaluated user-independent intent recognition systems. A novel mode-specific classification system was developed that allowed each locomotion transition to be statistically considered its own class. Various pattern recognition algorithms were trained with sensor data from a pool of eight lower limb amputees and performance was tested using data on a novel subject. For both user-dependent and user-independent classification, mode-specific classification reduced error ( ) on transitional steps by ~ 50% without affecting steady-state classification. Incorporating sensor time history and level-ground walking data from the novel subject into the training data resulted in decreasing errors ( ) on steady-state classification by over 60% without affecting transitional error. These strategies were combined to demonstrate significant overall system improvements from baseline conditions presented in prior research. PMID- 25794393 TI - Grouped Automatic Relevance Determination and Its Application in Channel Selection for P300 BCIs. AB - During the development of a brain-computer interface, it is beneficial to exploit information in multiple electrode signals. However, a small channel subset is favored for not only machine learning feasibility, but also practicality in commercial and clinical BCI applications. An embedded channel selection approach based on grouped automatic relevance determination is proposed. The proposed Gaussian conjugate group-sparse prior and the embedded nature of the concerned Bayesian linear model enable simultaneous channel selection and feature classification. Moreover, with the marginal likelihood (evidence) maximization technique, hyper-parameters that determine the sparsity of the model are directly estimated from the training set, avoiding time-consuming cross-validation. Experiments have been conducted on P300 speller BCIs. The results for both public and in-house datasets show that the channels selected by our techniques yield competitive classification performance with the state-of-the-art and are biologically relevant to P300. PMID- 25794394 TI - Flexible, Polarization-Diverse UWB Antennas for Implantable Neural Recording Systems. AB - Implanted antennas for implant-to-air data communications must be composed of material compatible with biological tissues. We design single and dual polarization antennas for wireless ultra-wideband neural recording systems using an inhomogeneous multi-layer model of the human head. Antennas made from flexible materials are more easily adapted to implantation; we investigate both flexible and rigid materials and examine performance trade-offs. The proposed antennas are designed to operate in a frequency range of 2-11 GHz (having S11 below -10 dB) covering both the 2.45 GHz (ISM) band and the 3.1-10.6 GHz UWB band. Measurements confirm simulation results showing flexible antennas have little performance degradation due to bending effects (in terms of impedance matching). Our miniaturized flexible antennas are 12 mm*12 mm and 10 mm*9 mm for single- and dual-polarizations, respectively. Finally, a comparison is made of four implantable antennas covering the 2-11 GHz range: 1) rigid, single polarization, 2) rigid, dual polarization, 3) flexible, single polarization and 4) flexible, dual polarization. In all cases a rigid antenna is used outside the body, with an appropriate polarization. Several advantages were confirmed for dual polarization antennas: 1) smaller size, 2) lower sensitivity to angular misalignments, and 3) higher fidelity. PMID- 25794395 TI - A Baseline Wander Tracking System for Artifact Rejection in Long-Term Electrocardiography. AB - Long-term electrocardiogram (ECG) signals might suffer from relevant baseline disturbances during physical activity. Motion artifacts in particular are more pronounced with dry surface or esophageal electrodes which are dedicated to prolonged ECG recording. In this paper we present a method called baseline wander tracking (BWT) that tracks and rejects strong baseline disturbances and avoids concurrent saturation of the analog front-end. The proposed algorithm shifts the baseline level of the ECG signal to the middle of the dynamic input range. Due to the fast offset shifts, that produce much steeper signal portions than the normal ECG waves, the true ECG signal can be reconstructed offline and filtered using computationally intensive algorithms. Based on Monte Carlo simulations we observed reconstruction errors mainly caused by the non-linearity inaccuracies of the DAC. However, the signal to error ratio of the BWT is higher compared to an analog front-end featuring a dynamic input ranges above 15 mV if a synthetic ECG signal was used. The BWT is additionally able to suppress (electrode) offset potentials without introducing long transients. Due to its structural simplicity, memory efficiency and the DC coupling capability, the BWT is dedicated to high integration required in long-term and low-power ECG recording systems. PMID- 25794396 TI - Ambient and Unobtrusive Cardiorespiratory Monitoring Techniques. AB - Monitoring vital signs through unobtrusive means is a goal which has attracted a lot of attention in the past decade. This review provides a systematic and comprehensive review over the current state of the field of ambient and unobtrusive cardiorespiratory monitoring. To this end, nine different sensing modalities which have been in the focus of current research activities are covered: capacitive electrocardiography, seismo- and ballistocardiography, reflective photoplethysmography (PPG) and PPG imaging, thermography, methods relying on laser or radar for distance-based measurements, video motion analysis, as well as methods using high-frequency electromagnetic fields. Current trends in these subfields are reviewed. Moreover, we systematically analyze similarities and differences between these methods with respect to the physiological and physical effects they sense as well as the resulting implications. Finally, future research trends for the field as a whole are identified. PMID- 25794397 TI - Material Roughness Modulation via Electrotactile Augmentation. AB - Tactile exploration of a material's texture using a bare finger pad is a daily human activity. However, modern tactile displays do not allow users to experience the natural sensations of a material when artificial sensations are presented. We propose an electrotactile augmentation technique capable of superimposing vibrotactile sensations in a finger pad, thereby allowing the texture modulation of real materials. Users attach two stimulus electrodes to the middle phalanx of a finger and a grounded electrode at the base of the finger in order to evoke nerve activity. This paper evaluates the proposed electrotactile augmentation for roughness modulation of real materials. First, we introduce the principle of the electrotactile display, which presents artificial sensations at the finger pad. We then confirm that the perceived frequency of mechanical vibration at the finger pad can be shifted using electrotactile augmentation. Finally, we discuss a user study, wherein participants rated the roughness of real materials explored using the proposed system. Experimental results indicate that fine- and macro roughness perceptions of real materials can be altered using electrotactile augmentation. PMID- 25794398 TI - Decentralized Output Feedback Adaptive NN Tracking Control for Time-Delay Stochastic Nonlinear Systems With Prescribed Performance. AB - This paper studies the dynamic output feedback tracking control problem for stochastic interconnected time-delay systems with the prescribed performance. The subsystems are in the form of triangular structure. First, we design a reduced order observer independent of time delay to estimate the unmeasured state variables online instead of the traditional full-order observer. Then, a new state transformation is proposed in consideration of the prescribed performance requirement. Using neural network to approximate the composite unknown nonlinear function, the corresponding decentralized output tracking controller is designed. It is strictly proved that the resulting closed-loop system is stable in probability in the sense of uniformly ultimately boundedness and that both transient-state and steady-state performances are preserved. Finally, a simulation example is given, and the result shows the effectiveness of the proposed control design method. PMID- 25794399 TI - An Asynchronous Neuromorphic Event-Driven Visual Part-Based Shape Tracking. AB - Object tracking is an important step in many artificial vision tasks. The current state-of-the-art implementations remain too computationally demanding for the problem to be solved in real time with high dynamics. This paper presents a novel real-time method for visual part-based tracking of complex objects from the output of an asynchronous event-based camera. This paper extends the pictorial structures model introduced by Fischler and Elschlager 40 years ago and introduces a new formulation of the problem, allowing the dynamic processing of visual input in real time at high temporal resolution using a conventional PC. It relies on the concept of representing an object as a set of basic elements linked by springs. These basic elements consist of simple trackers capable of successfully tracking a target with an ellipse-like shape at several kilohertz on a conventional computer. For each incoming event, the method updates the elastic connections established between the trackers and guarantees a desired geometric structure corresponding to the tracked object in real time. This introduces a high temporal elasticity to adapt to projective deformations of the tracked object in the focal plane. The elastic energy of this virtual mechanical system provides a quality criterion for tracking and can be used to determine whether the measured deformations are caused by the perspective projection of the perceived object or by occlusions. Experiments on real-world data show the robustness of the method in the context of dynamic face tracking. PMID- 25794400 TI - Peaking-Free Output-Feedback Adaptive Neural Control Under a Nonseparation Principle. AB - High-gain observers have been extensively applied to construct output-feedback adaptive neural control (ANC) for a class of feedback linearizable uncertain nonlinear systems under a nonlinear separation principle. Yet due to static-gain and linear properties, high-gain observers are usually subject to peaking responses and noise sensitivity. Existing adaptive neural network (NN) observers cannot effectively relax the limitations of high-gain observers. This paper presents an output-feedback indirect ANC strategy under a nonseparation principle, where a hybrid estimation scheme that integrates an adaptive NN observer with state variable filters is proposed to estimate plant states. By applying a single Lyapunov function candidate to the entire system, it is proved that the closed-loop system achieves practical asymptotic stability under a relatively low observer gain dominated by controller parameters. Our approach can completely avoid peaking responses without control saturation while keeping favourable noise rejection ability. Simulation results have shown effectiveness and superiority of this approach. PMID- 25794401 TI - DL-ReSuMe: A Delay Learning-Based Remote Supervised Method for Spiking Neurons. AB - Recent research has shown the potential capability of spiking neural networks (SNNs) to model complex information processing in the brain. There is biological evidence to prove the use of the precise timing of spikes for information coding. However, the exact learning mechanism in which the neuron is trained to fire at precise times remains an open problem. The majority of the existing learning methods for SNNs are based on weight adjustment. However, there is also biological evidence that the synaptic delay is not constant. In this paper, a learning method for spiking neurons, called delay learning remote supervised method (DL-ReSuMe), is proposed to merge the delay shift approach and ReSuMe based weight adjustment to enhance the learning performance. DL-ReSuMe uses more biologically plausible properties, such as delay learning, and needs less weight adjustment than ReSuMe. Simulation results have shown that the proposed DL-ReSuMe approach achieves learning accuracy and learning speed improvements compared with ReSuMe. PMID- 25794402 TI - Adaptive Position/Attitude Tracking Control of Aerial Robot With Unknown Inertial Matrix Based on a New Robust Neural Identifier. AB - This paper presents a novel adaptive controller for controlling an autonomous helicopter with unknown inertial matrix to asymptotically track the desired trajectory. To identify the unknown inertial matrix included in the attitude dynamic model, this paper proposes a new structural identifier that differs from those previously proposed in that it additionally contains a neural networks (NNs) mechanism and a robust adaptive mechanism, respectively. Using the NNs to compensate the unknown aerodynamic forces online and the robust adaptive mechanism to cancel the combination of the overlarge NNs compensation error and the external disturbances, the new robust neural identifier exhibits a better identification performance in the complex flight environment. Moreover, an optimized algorithm is included in the NNs mechanism to alleviate the burdensome online computation. By the strict Lyapunov argument, the asymptotic convergence of the inertial matrix identification error, position tracking error, and attitude tracking error to arbitrarily small neighborhood of the origin is proved. The simulation and implementation results are provided to evaluate the performance of the proposed controller. PMID- 25794403 TI - Finite-Horizon Near-Optimal Output Feedback Neural Network Control of Quantized Nonlinear Discrete-Time Systems With Input Constraint. AB - The output feedback-based near-optimal regulation of uncertain and quantized nonlinear discrete-time systems in affine form with control constraint over finite horizon is addressed in this paper. First, the effect of input constraint is handled using a nonquadratic cost functional. Next, a neural network (NN) based Luenberger observer is proposed to reconstruct both the system states and the control coefficient matrix so that a separate identifier is not needed. Then, approximate dynamic programming-based actor-critic framework is utilized to approximate the time-varying solution of the Hamilton-Jacobi-Bellman using NNs with constant weights and time-dependent activation functions. A new error term is defined and incorporated in the NN update law so that the terminal constraint error is also minimized over time. Finally, a novel dynamic quantizer for the control inputs with adaptive step size is designed to eliminate the quantization error overtime, thus overcoming the drawback of the traditional uniform quantizer. The proposed scheme functions in a forward-in-time manner without offline training phase. Lyapunov analysis is used to investigate the stability. Simulation results are given to show the effectiveness and feasibility of the proposed method. PMID- 25794404 TI - Automated Video Analysis of Handwashing Behavior as a Potential Marker of Cognitive Health in Older Adults. AB - The identification of different stages of cognitive impairment can allow older adults to receive timely care and plan for the level of caregiving. People with existing diagnosis of cognitive impairment go through episodic phases of dementia requiring different levels of care at different times. Monitoring the cognitive status of existing patients is, thus, critical to deciding the level of care required by older adults. In this paper, we present a system to assess the cognitive status of older adults by monitoring a common activity of daily living, namely handwashing. Specifically, we extract features from handwashing trials of participants diagnosed with different levels of dementia ranging from cognitively intact to severe cognitive impairment, as assessed by the mini-mental state exam (MMSE). Based on videos of handwashing trials, we extract two classes of features: one characterizing the occupancy of different sink regions by the participant, and the other capturing the path tortuosity of the motion trajectory of participant's hands. We perform correlation analysis to assess univariate capacity of individual features to predict MMSE scores. To assess multivariate performance, we use machine learning methods to train models that predict the cognitive status (aware, mild, moderate, severe), as well as the MMSE scores. We present results demonstrating that features derived from hand washing behavior can be potential surrogate markers of a person's dementia, which can be instrumental in developing automated tools for continuously monitoring the cognitive status of older adults. PMID- 25794405 TI - A Beamformer-Particle Filter Framework for Localization of Correlated EEG Sources. AB - Electroencephalography (EEG)-based brain computer interface (BCI) is the most studied noninvasive interface to build a direct communication pathway between the brain and an external device. However, correlated noises in EEG measurements still constitute a significant challenge. Alternatively, building BCIs based on filtered brain activity source signals instead of using their surface projections, obtained from the noisy EEG signals, is a promising and not well explored direction. In this context, finding the locations and waveforms of inner brain sources represents a crucial task for advancing source-based noninvasive BCI technologies. In this paper, we propose a novel multicore beamformer particle filter (multicore BPF) to estimate the EEG brain source spatial locations and their corresponding waveforms. In contrast to conventional (single-core) beamforming spatial filters, the developed multicore BPF considers explicitly temporal correlation among the estimated brain sources by suppressing activation from regions with interfering coherent sources. The hybrid multicore BPF brings together the advantages of both deterministic and Bayesian inverse problem algorithms in order to improve the estimation accuracy. It solves the brain activity localization problem without prior information about approximate areas of source locations. Moreover, the multicore BPF reduces the dimensionality of the problem to half compared with the PF solution, thus alleviating the curse of dimensionality problem. The results, based on generated and real EEG data, show that the proposed framework recovers correctly the dominant sources of brain activity. PMID- 25794406 TI - Consensus Control With Failure--Wait or Abandon? AB - This paper introduces and solves a decision-making problem under the context of consensus control with failure. We study an optimal consensus control problem in which n autonomous agents try to arrive at a target at the same time. One of the agents suddenly fails and the rest n - 1 agents can either wait or abandon the failed agent. If they wait, they must slow down and delay the consensus time. If they abandon the failed agent, they can reach consensus earlier at the cost of losing one agent at consensus. This cost is an added delay to the consensus time. The decision problem is to decide whether to wait or abandon and, if abandon, when? To solve this problem, we derive analytical expressions and establish structural properties for target distance functions. We use numerical examples and simulation examples to demonstrate the applications of the derived formulas and results. PMID- 25794407 TI - Large-Scale Aerial Image Categorization Using a Multitask Topological Codebook. AB - Fast and accurately categorizing the millions of aerial images on Google Maps is a useful technique in pattern recognition. Existing methods cannot handle this task successfully due to two reasons: 1) the aerial images' topologies are the key feature to distinguish their categories, but they cannot be effectively encoded by a conventional visual codebook and 2) it is challenging to build a realtime image categorization system, as some geo-aware Apps update over 20 aerial images per second. To solve these problems, we propose an efficient aerial image categorization algorithm. It focuses on learning a discriminative topological codebook of aerial images under a multitask learning framework. The pipeline can be summarized as follows. We first construct a region adjacency graph (RAG) that describes the topology of each aerial image. Naturally, aerial image categorization can be formulated as RAG-to-RAG matching. According to graph theory, RAG-to-RAG matching is conducted by enumeratively comparing all their respective graphlets (i.e., small subgraphs). To alleviate the high time consumption, we propose to learn a codebook containing topologies jointly discriminative to multiple categories. The learned topological codebook guides the extraction of the discriminative graphlets. Finally, these graphlets are integrated into an AdaBoost model for predicting aerial image categories. Experimental results show that our approach is competitive to several existing recognition models. Furthermore, over 24 aerial images are processed per second, demonstrating that our approach is ready for real-world applications. PMID- 25794408 TI - Multiobjective Vehicle Routing Problems With Simultaneous Delivery and Pickup and Time Windows: Formulation, Instances, and Algorithms. AB - This paper investigates a practical variant of the vehicle routing problem (VRP), called VRP with simultaneous delivery and pickup and time windows (VRPSDPTW), in the logistics industry. VRPSDPTW is an important logistics problem in closed-loop supply chain network optimization. VRPSDPTW exhibits multiobjective properties in real-world applications. In this paper, a general multiobjective VRPSDPTW (MO VRPSDPTW) with five objectives is first defined, and then a set of MO-VRPSDPTW instances based on data from the real-world are introduced. These instances represent more realistic multiobjective nature and more challenging MO-VRPSDPTW cases. Finally, two algorithms, multiobjective local search (MOLS) and multiobjective memetic algorithm (MOMA), are designed, implemented and compared for solving MO-VRPSDPTW. The simulation results on the proposed real-world instances and traditional instances show that MOLS outperforms MOMA in most of instances. However, the superiority of MOLS over MOMA in real-world instances is not so obvious as in traditional instances. PMID- 25794409 TI - Multivariate Discretization Based on Evolutionary Cut Points Selection for Classification. AB - Discretization is one of the most relevant techniques for data preprocessing. The main goal of discretization is to transform numerical attributes into discrete ones to help the experts to understand the data more easily, and it also provides the possibility to use some learning algorithms which require discrete data as input, such as Bayesian or rule learning. We focus our attention on handling multivariate classification problems, where high interactions among multiple attributes exist. In this paper, we propose the use of evolutionary algorithms to select a subset of cut points that defines the best possible discretization scheme of a data set using a wrapper fitness function. We also incorporate a reduction mechanism to successfully manage the multivariate approach on large data sets. Our method has been compared with the best state-of-the-art discretizers on 45 real datasets. The experiments show that our proposed algorithm overcomes the rest of the methods producing competitive discretization schemes in terms of accuracy, for C4.5, Naive Bayes, PART, and PrUning and BuiLding Integrated in Classification classifiers; and obtained far simpler solutions. PMID- 25794410 TI - Assessment of Short- and Long-Term Mortality Displacement in Heat-Related Deaths in Brisbane, Australia, 1996-2004. AB - BACKGROUND: Mortality displacement (or "harvesting") has been identified as a key issue in the assessment of the temperature-mortality relationship. However, only a few studies have addressed the "harvesting" issue and findings have not been consistent. OBJECTIVES: We examined the potential impact of both short- and long term harvesting effects on heat-related deaths in Brisbane, Australia. METHODS: We collected data on daily counts of deaths (nonaccidental, cardiovascular, and respiratory), weather, and air pollution in Brisbane from 1 January 1996 to 30 November 2004. We estimated heat-related deaths, identified potential short-term mortality displacement, and assessed how and to what extent the impact of summer temperature on mortality was modified by mortality in the previous winter using a Poisson time-series regression combined with distributed lag nonlinear model (DLNM). RESULTS: There were significant associations between temperature and each mortality outcome in summer. We found evidence of short-term mortality displacement for respiratory mortality, and evidence of longer-term mortality displacement for nonaccidental and cardiovascular mortality when the preceding winter's mortality was low. The estimated heat effect on mortality was generally stronger when the preceding winter mortality level was low. For example, we estimated a 22% increase in nonaccidental mortality (95% CI: 14, 30) with a 1 degrees C increase in mean temperature above a 28 degrees C threshold in summers that followed a winter with low mortality, compared with 12% (95% CI: 7, 17) following a winter with high mortality. The short- and long-term mortality displacement appeared to jointly influence the assessment of heat-related deaths. CONCLUSIONS: We found evidence of both short- and long-term harvesting effects on heat-related mortality in Brisbane, Australia. Our finding may clarify temperature-related health risks and inform effective public health interventions to manage the health impacts of climate change. PMID- 25794411 TI - Forest Fire Smoke Exposures and Out-of-Hospital Cardiac Arrests in Melbourne, Australia: A Case-Crossover Study. AB - BACKGROUND: Millions of people can potentially be exposed to smoke from forest fires, making this an important public health problem in many countries. OBJECTIVE: In this study we aimed to measure the association between out-of hospital cardiac arrest (OHCA) and forest fire smoke exposures in a large city during a severe forest fire season, and estimate the number of excess OHCAs due to the fire smoke. METHODS: We investigated the association between particulate matter (PM) and other air pollutants and OHCA using a case-crossover study of adults (>= 35 years of age) in Melbourne, Australia. Conditional logistic regression models were used to derive estimates of the percent change in the rate of OHCA associated with an interquartile range (IQR) increase in exposure. From July 2006 through June 2007, OHCA data were collected from the Victorian Ambulance Cardiac Arrest Registry. Hourly air pollution concentrations and meteorological data were obtained from a central monitoring site. RESULTS: There were 2,046 OHCAs with presumed cardiac etiology during our study period. Among men during the fire season, greater increases in OHCA were observed with IQR increases in the 48-hr lagged PM with diameter <= 2.5 MUm (PM2.5) (8.05%; 95% CI: 2.30, 14.13%; IQR = 6.1 MUg/m(3)) or <= 10 MUm (PM10) (11.1%; 95% CI: 1.55, 21.48%; IQR = 13.7 MUg/m(3)) and carbon monoxide (35.7%; 95% CI: 8.98, 68.92%; IQR = 0.3 ppm). There was no significant association between the rate of OHCA and air pollutants among women. One hundred seventy-four "fire-hours" (i.e., hours in which Melbourne's air quality was affected by forest fire smoke) were identified during 12 days of the 2006/2007 fire season, and 23.9 (95% CI: 3.1, 40.2) excess OHCAs were estimated to occur due to elevations in PM2.5 during these fire-hours. CONCLUSIONS: This study found an association between exposure to forest fire smoke and an increase in the rate of OHCA. These findings have implications for public health messages to raise community awareness and for planning of emergency services during forest fire seasons. PMID- 25794413 TI - Anesthetic management of labor and delivery in patients with elevated intracranial pressure. AB - The anesthetic management of labor and delivery in patients with elevated intracranial pressure is complex. This review discusses the etiologies of diffuse and focal pathologies which lead to elevated intracranial pressure in pregnancy. The role of neuraxial and general anesthesia in the management of labor and delivery is also examined. Finally, a comprehensive review of strategies to minimize increases in intracranial pressure during general anesthesia for cesarean delivery is presented. PMID- 25794412 TI - Association of Atmospheric Particulate Matter and Ozone with Gestational Diabetes Mellitus. AB - BACKGROUND: Ambient air pollution has been linked to the development of gestational diabetes mellitus (GDM). However, evidence of the association is very limited, and no study has estimated the effects of ozone. OBJECTIVE: Our aim was to determine the association of prenatal exposures to particulate matter <= 2.5 MUm (PM2.5) and ozone (O3) with GDM. METHODS: We used Florida birth vital statistics records to investigate the association between the risk of GDM and two air pollutants (PM2.5 and O3) among 410,267 women who gave birth in Florida between 2004 and 2005. Individual air pollution exposure was assessed at the woman's home address at time of delivery using the hierarchical Bayesian space time statistical model. We further estimated associations between air pollution exposures during different trimesters and GDM. RESULTS: After controlling for nine covariates, we observed increased odds of GDM with per 5-MUg/m3 increase in PM2.5 (ORTrimester1 = 1.16; 95% CI: 1.11, 1.21; ORTrimester2 = 1.15; 95% CI: 1.10, 1.20; ORPregnancy = 1.20; 95% CI: 1.13, 1.26) and per 5-ppb increase in O3 (ORTrimester1 = 1.09; 95% CI: 1.07, 1.11; ORTrimester2 = 1.12; 95% CI: 1.10, 1.14; ORPregnancy = 1.18; 95% CI: 1.15, 1.21) during both the first trimester and second trimester as well as the full pregnancy in single-pollutant models. Compared with the single-pollutant model, the ORs for O3 were almost identical in the co-pollutant model. However, the ORs for PM2.5 during the first trimester and the full pregnancy were attenuated, and no association was observed for PM2.5 during the second trimester in the co-pollutant model (OR = 1.02; 95% CI: 0.98, 1.07). CONCLUSION: This population-based study suggests that exposure to air pollution during pregnancy is associated with increased risk of GDM in Florida, USA. CITATION: Hu H, Ha S, Henderson BH, Warner TD, Roth J, Kan H, Xu X. 2015. Association of atmospheric particulate matter and ozone with gestational diabetes mellitus. Environ Health Perspect 123:853-859; http://dx.doi.org/10.1289/ehp.1408456. PMID- 25794415 TI - Video laryngoscopes and the obstetric airway. AB - The pitfalls surrounding securing the airway in the obstetric patient are well documented. From Tunstall's original failed intubation drill onwards, there has been progress both in recognition of the difficulties of airway management in the pregnant patient and development of algorithms to enhance patient safety. Current trends in obstetric anaesthesia have resulted in a significant decrease in exposure of anaesthetists, especially trainees, to caesarean section under general anaesthesia, compounding the difficulties in safely managing the airway. Video laryngoscopes have recently appeared in airway algorithms. They improve glottic visualisation and are useful in the management of the difficult non obstetric airway, including those in morbidly obese patients and in the setting of a rapid-sequence induction. There is growing interest in the potential use of video laryngoscopes in the obstetric population and as a teaching tool to maximise training opportunities. PMID- 25794414 TI - Pulmonary embolism in the setting of HELLP syndrome. AB - HELLP syndrome (hemolysis, elevated liver enzymes and low platelets) complicates 0.5-0.9% of pregnancies and is frequently associated with multiorgan dysfunction. Treatment relies on prompt diagnosis, delivery and supportive care. The clinical presentation may make the concurrent diagnosis and management of other disease entities challenging. This case report describes a patient with postpartum HELLP syndrome complicated by severe multiorgan dysfunction and pulmonary embolism. PMID- 25794416 TI - Rectus sheath haematoma: a rare cause of abdominal pain in pregnancy. PMID- 25794417 TI - Introduction of enhanced recovery for elective caesarean section enabling next day discharge: a tertiary centre experience. AB - BACKGROUND: The widespread adoption of enhanced recovery programmes in various surgical specialties has resulted in patient benefits including reduced morbidity, reduced length of stay and an earlier return to normal activities. This evidence, along with the increased financial pressures in the UK National Health Service, has led many units to consider introducing such a programme for obstetric surgery. We report our experience in setting up an enhanced recovery programme for women undergoing elective caesarean section and a prospective analysis of factors that influence length of stay. METHODS: An enhanced recovery pathway was designed by a multidisciplinary team and introduced in March 2012. Factors influencing length of stay were determined using a log normal model. RESULTS: The proportion of women discharged on Day 1 increased from 1.6% in the first quarter of 2012 to 25.2% in the first quarter of 2014. The 30-day readmission rate was 4.4% for those discharged on Day 1 and 5.6% for Day 2. Earlier gestation, multiple birth, intention to breast feed, longer surgery and more time in the post-anaesthesia recovery unit were all independently associated with a longer postoperative stay. Women presenting for obstetric surgery with the indication "one previous caesarean section" were more likely to leave hospital earlier compared to most other indications. CONCLUSION: An enhanced recovery programme was successfully introduced into our unit. Many of the interventions were straightforward and could be adopted easily elsewhere. PMID- 25794418 TI - Chronotropic variation in the incidence of unintentional dural puncture in parturients undergoing epidural placement. PMID- 25794419 TI - Anaphylaxis-induced hyperfibrinolysis in pregnancy. AB - Anaphylaxis during pregnancy is rare but life threatening to both mother and fetus. The anaesthetist may be unexpectedly faced with an obstructing airway, severe bronchospasm and cardiac arrest requiring perimortem caesarean delivery to relieve aortocaval compression. We present a case of anaphylaxis-induced hyperfibrinolysis, an infrequently discussed complication that could exacerbate postpartum haemorrhage and hamper resuscitative efforts. PMID- 25794421 TI - Sedation in critically-ill obstetric patients. PMID- 25794420 TI - Fetal bradycardia following maternal administration of low-molecular-weight intravenous iron. PMID- 25794422 TI - Nanoscale magnetization reversal caused by electric field-induced ion migration and redistribution in cobalt ferrite thin films. AB - Reversible nanoscale magnetization reversal controlled merely by electric fields is still challenging at the moment. In this report, first-principles calculation indicates that electric field-induced magnetization reversal can be achieved by the appearance of unidirectional magnetic anisotropy along the (110) direction in Fe-deficient cobalt ferrite (CoFe(2-x)O4, CFO), as a result of the migration and local redistribution of the Co(2+) ions adjacent to the B-site Fe vacancies. In good agreement with the theoretical model, we experimentally observed that in the CFO thin films the nanoscale magnetization can be reversibly and nonvolatilely reversed at room temperature via an electrical ion-manipulation approach, wherein the application of electric fields with appropriate polarity and amplitude can modulate the size of magnetic domains with different magnetizations up to 70%. With the low power consumption (subpicojoule) characteristics and the elimination of external magnetic field, the observed electric field-induced magnetization reversal can be used for the construction of energy-efficient spintronic devices, e.g., low-power electric-write and magnetic-read memories. PMID- 25794423 TI - Phosphatidylinositol-3-kinase as a putative target for anticancer action of clotrimazole. AB - Clotrimazole (CTZ) has been proposed as an antitumoral agent because of its properties that inhibit glycolytic enzymes and detach them from the cytoskeleton. However, the broad effects of the drug, e.g., acting on different enzymes and pathways, indicate that CTZ might also affect several signaling pathways. In this study, we show that CTZ interferes with the human breast cancer cell line MCF-7 after a short incubation period (4 h), thereby diminishing cell viability, promoting apoptosis, depolarizing mitochondria, inhibiting key glycolytic regulatory enzymes, decreasing the intracellular ATP content, and permeating plasma membranes. CTZ treatment also interferes with autophagy. Moreover, when the incubation is performed under hypoxic conditions, certain effects of CTZ are enhanced, such as phosphatidylinositol-3-phosphate kinase (PI3K), which is inhibited upon CTZ treatment; this inhibition is potentiated under hypoxia. CTZ induced PI3K inhibition is not caused by upstream effects of CTZ because the drug does not affect the interaction of the PI3K regulatory subunit and the insulin receptor substrate (IRS)-1. Additionally, CTZ directly inhibits human purified PI3K in a dose-dependent and reversible manner. Pharmacologic and in silico results suggest that CTZ may bind to the PI3K catalytic site. Therefore, we conclude that PI3K is a novel, putative target for the antitumoral effects of CTZ, interfering with autophagy, apoptosis, cell division and viability. PMID- 25794424 TI - Functional and structural interaction of (-)-lobeline with human alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptor subtypes. AB - To determine the pharmacologic activity of (-)-lobeline between human (h)alpha4beta2 and halpha4beta4 nicotinic acetylcholine receptors (AChRs), functional and structural experiments were performed. The Ca(2+) influx results established that (-)-lobeline neither actives nor enhances the function of the studied AChR subtypes, but competitively inhibits halpha4beta4 AChRs with potency ~10-fold higher than that for halpha4beta2 AChRs. This difference is due to a higher binding affinity for the [(3)H]cytisine sites at halpha4beta4 compared to halpha4beta2 AChRs, which, in turn, can be explained by our molecular dynamics (MD) results: (1) higher stability of (-)-lobeline and its hydrogen bonds within the alpha4beta4 pocket compared to the alpha4beta2 pocket, (2) (-)-lobeline promotes Loop C to cap the binding site at the alpha4beta4 pocket, but forces Loop C to get apart from the alpha4beta2 pocket, precluding the gating process elicited by agonists, and (3) the orientation of (-)-lobeline within the alpha4beta4, but not the alpha4beta2, subpocket, promoted by the t- (or t+) rotameric state of alpha4-Tyr98, remains unchanged during the whole MD simulation. This study gives a detailed view of the molecular and dynamics events evoked by (-)-lobeline supporting the differential binding affinity and subsequent inhibitory potency between halpha4beta2 and halpha4beta4 AChRs, and supports the possibility that the latter subtype is also involved in its activity. PMID- 25794425 TI - CCN4/WISP1 (WNT1 inducible signaling pathway protein 1): a focus on its role in cancer. AB - The matricellular protein WISP1 is a member of the CCN protein family. It is induced by WNT1 and is a downstream target of beta-catenin. WISP1 is expressed during embryonic development, wound healing and tissue repair. Aberrant WISP1 expression is associated with various pathologies including osteoarthritis, fibrosis and cancer. Its role in tumor progression and clinical outcome makes WISP1 an emerging candidate for the detection and treatment of tumors. PMID- 25794426 TI - Gut region-specific accumulation of reactive oxygen species leads to regionally distinct activation of antioxidant and apoptotic marker molecules in rats with STZ-induced diabetes. AB - The aim of this study was to seek possible links between the regionality along the digestive tract and the accumulation of reactive oxygen species, the effectiveness of the antioxidant defense system and the sensitivity to the types of demise in different gut regions of rats with streptozotocin-induced diabetes. Significant changes were observed in the oxidative status and in the activity of the antioxidant defense system in the diabetic colon; the peroxynitrite production was doubled, the level of hemoxygenase-2 protein was increased 11-fold and the expression of anti-apoptotic bcl-2 was also increased. The segment specific vulnerability of the gastrointestinal tract induced by hyperglycemia was also confirmed by electron microscopy, demonstrating the presence of severe necrosis in the colon of the diabetic rats. No remarkable histopathological alterations were seen in the duodenum of the diabetic animals and there were likewise no significant changes in the production of peroxynitrite in their duodenum, whereas the level of the free radical scavenger metallothionein-2 was increased ~300-fold. CONCLUSION: The spatially restricted vulnerability observed along the digestive tract could originate from a high level of oxidative stress via peroxynitrite production. PMID- 25794427 TI - Flank-free Modified Supine Percutaneous Nephrolithotomy in Pediatric Age Group. AB - OBJECTIVE: To evaluate the safety and efficacy of pediatric percutaneous nephrolithotomy (PCNL) in the flank-free modified supine position (FFMSP). PCNL in the supine position is increasingly and successfully used in pediatric age group. Different modifications of supine positions have been described; however, the best supine position is not well established and remains a matter of debate. PATIENTS AND METHODS: This prospective study included 22 children presenting with single renal pelvis stone (2-3 cm) in the period between May 2012 and April 2014. Diagnosis was set by plain x-ray and computed tomography in all patients. PCNL was performed with the patients placed in the FFMSP. The operative time and hospital stay were estimated. The outcome and any perioperative complications or conflicts were recorded. RESULTS: The study included 22 children (15 boys and 7 girls) with a solitary renal pelvis stone. Mean +/- standard deviation age of the patients was 9.5 +/- 3.2 years (range, 3-15.5 years). Stone length, operative time, and hospital stay had mean +/- standard deviation of 2.4 +/- 0.23 cm, 65.1 +/- 18.7 minutes, and 4.4 +/- 0.9 days. Stone-free rate was 90.9% after 1 session of PCNL. One patient (4.5%) needed a second-look PCNL. Shock wave lithotripsy was performed for another patient. Postoperative fever occurred in 4 patients (18.2%). One patient received postoperative blood transfusion. Postoperative transient urinoma occurred in 2 patients (9.1%). CONCLUSION: PCNL in pediatric age group via FFMSP was proved to be safe and effective in management of renal pelvis stones of size 2-3 cm. It provides stone clearance rate comparable with that reported of conventional PCNL in the prone position. PMID- 25794428 TI - Choice of the best equation for plasma osmolality calculation: Comparison of fourteen formulae. AB - BACKGROUND: Many different equations have been previously described to estimate plasma osmolality. The aim of this study is to compare 14 of these equations, in order to determine which results agree best with measured osmolality. OBJECTIVES: Our aim is to elucidate which is the most accurate equation for osmolality calculation among the fourteen that were previously described. METHODS: We measured osmolality by the freezing point depression method, and glucose, urea, sodium, potassium, calcium and magnesium concentrations with Unicell DXC 800 analyzer. Goodness-of-fit rates were calculated using the Passing-Bablok regression model and the t-paired sample test. In addition, we used survival curves in order to find the percentage of cases in which the difference between measured and calculated osmolality was under 10 mOsm/kg. Data were plotted using the Bland-Altman graphical approach. RESULTS: The equation that provides the best fit between measured and calculated osmolality is 1.86(Na+K)+1.15(Glu/18)+(Urea/6)+14, followed by 2Na+1.15(Glu/18)+(Urea/6). CONCLUSIONS: According to our results, the Dorwart-Chalmer's equation should not be used for osmolality calculations. The equation 1.86(Na+K)+1.15(Glu/18)+(Urea/6)+14 is the most accurate. The widespread use of the equation 2(Na+K)+(Glu/18)+(Urea/6) is also acceptable. PMID- 25794429 TI - The association of PLA2G2A single nucleotide polymorphisms with type IIa secretory phospholipase A2 level but not its activity in patients with stable coronary heart disease. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) of the secretory phospholipase A2 type IIa (sPLA-IIa) gene (PLA2G2A) affect sPLA2-IIa level and activity in patients with diabetes mellitus, acute coronary syndrome or recent cardiovascular surgical interventions. Our study examined the effects of PLA2G2A SNPs on sPLA2 IIa levels and activity in patients with stable CHD. METHODS AND RESULTS: The study included a total of 396 patients (30% women). Six SNPs of PLA2G2A: rs1774131, rs11573156, rs3753827, rs2236771, rs876018, and rs3767221, sPLA2-IIa level and activity were determined for all patients. Four SNPs (rs1774131, rs11573156, rs3753827, rs3767221) correlated with sPLA2-IIa level but not activity with the strongest correlation observed for rs11573156 (r=0.49, p=3.7.10(-13)). All partial correlations controlling for rs11573156 became insignificant, whereas, the partial correlation of rs11573156 with sPLA2-IIa level controlling for other SNPs remained significant. Only rs11573156 showed association with sPLA2-IIa level in multiple regression analysis. Haplotype CGGGTT was associated with a significantly higher sPLA2-IIa level but not activity compared with all other haplotypes after adjustment for gender, age, diabetes mellitus and statin use (p=0.0023). CONCLUSIONS: According to our results the examined SNPs affect the sPLA2-IIa level to a greater extent than its activity in patients with stable CHD. It seems that, the impact of these SNPs on sPLA2-IIa level is caused by their linkage to rs11573156 whose minor alleles were associated with higher sPLA2-IIa level. At the same time haplotype CGGGTT, which includes the minor allele of rs11573156, was the dominant haplotype and was associated with the highest sPLA2-IIa level. PMID- 25794430 TI - A novel compound WISP3 mutation in a Chinese family with progressive pseudorheumatoid dysplasia. AB - BACKGROUND: Progressive pseudorheumatoid dysplasia (PPD) is an extremely rare autosomal recessive genetic disease caused by mutation of the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. Here, we characterize the clinical manifestations and features of PPD and screen for WISP3 mutations. MATERIALS AND METHODS: We performed genetic testing for PPD in a Chinese family, after investigating the clinical particulars and family history, in addition to 200 healthy individuals, who served as the controls for this study. All 5 exons and the exon-intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) and sequenced directly. RESULTS: We identified a missense mutation (c.667T>G, p.C223G) in the maternal allele and a nonsense mutation (c.756C>A, p.C252X) in the paternal allele in the two affected individuals. To our knowledge, the mutation c.756C>A has not been reported previously. In these patients, there was a specific period when their condition markedly improved after having been very serious. Moreover, severe compression of lumbar spinal cord led to conspicuous spinal disorders in the proband. CONCLUSIONS: Our study suggests that novel C223G and C252X mutations in exon 4 of the WISP3 gene are responsible for PPD in Chinese patients. Furthermore, we report certain unique phenotypic characteristics in our patients. PMID- 25794431 TI - The sterile male technique: irradiation negatively affects male fertility but not male courtship. AB - The sterile male technique is a common method to assign paternity, widely adopted due to its relative simplicity and low cost. Male sterility is induced by exposure to sub lethal doses of chemosterilants or irradiation, the dosage of which has to be calibrated for every species to provide successful male sterilisation, without affecting male physiology and behaviour. While the physiological effects of sterilisation are usually assessed for each study, the behavioural ones are rarely analysed in detail. Using the orb web spider Argiope keyserlingi as a model we first tested (1) the validity of the thread assay, which simulates male courtship behaviour in a standardised context, as a proxy representing courtship on a female web. We then investigated (2) the effectiveness of male sterilisation via irradiation and (3) its consequences on male courtship behaviour. Our results validate the thread assay and the sterile male technique as legitimate tools for the study of male courtship behaviour and fertilisation success. We show that these techniques are time and cost effective and reduce undesirable variation, thereby creating opportunities to study and understand the mechanisms underlying sexual selection. PMID- 25794432 TI - Chemical proteomics versus leishmaniasis. AB - In this issue of Chemistry & Biology, Wright et al. (2015) describe an elegant approach to evaluating substrates and the drug target potential of Leishmania donovani N-myristoyltransferase (NMT) using a technically simple and straightforward chemical proteomics approach. PMID- 25794433 TI - Fueling up skeletal muscle to reduce obesity: A TrkB story. AB - Targeting TrkB signaling could represent a good therapeutic strategy to prevent obesity. In this issue of Chemistry & Biology, Chan et al. report the efficacy of 7,8-DHT, a TrkB agonist, in preventing obesity in female mice. The underlying molecular mechanisms behind this activity seem to involve increased energy expenditure in skeletal muscle. PMID- 25794434 TI - A trojan horse for human immunodeficiency virus. AB - In this issue of Chemistry & Biology, Zhou et al. demonstrate the possibility of effective multiple targeting of HIV infection by using a multifunctional molecule in which an anti-CCR5 receptor aptamer (G-3) is conjugated to an anti-TNPO3 siRNA. PMID- 25794435 TI - Weighing the proteasome for covalent modifications. AB - Posttranslational modifications (PTMs) control protein function, but established peptide-based proteomic methods often fail to provide a comprehensive view of PTMs. In this issue of Chemistry & Biology, Gersch et al. describe an efficient combination of chromatographic separation and top-down mass spectrometry that together with an intuitive visualization tool allowed them to screen the proteasome for PTMs and covalently binding inhibitors. PMID- 25794436 TI - Biosynthetic manipulation of tryptophan in bacteria: pathways and mechanisms. AB - Tryptophan, the most chemically complex and the least abundant of the 20 common proteinogenic amino acids, is a biosynthetic precursor to a large number of complex microbial natural products. Many of these molecules are promising scaffolds for drug discovery and development. The chemical features of tryptophan, including its ability to undergo enzymatic modifications at almost every atom in its structure and its propensity to undergo spontaneous, non-enzyme catalyzed chemistry, make it a unique biological precursor for the generation of chemical complexity. Here, we review the pathways that enable incorporation of tryptophan into complex metabolites in bacteria, with a focus on recently discovered, unusual metabolic transformations. PMID- 25794437 TI - Quantitative analysis of proteome and lipidome dynamics reveals functional regulation of global lipid metabolism. AB - Elucidating how and to what extent lipid metabolism is remodeled under changing conditions is essential for understanding cellular physiology. Here, we analyzed proteome and lipidome dynamics to investigate how regulation of lipid metabolism at the global scale supports remodeling of cellular architecture and processes during physiological adaptations in yeast. Our results reveal that activation of cardiolipin synthesis and remodeling supports mitochondrial biogenesis in the transition from fermentative to respiratory metabolism, that down-regulation of de novo sterol synthesis machinery prompts differential turnover of lipid droplet associated triacylglycerols and sterol esters during respiratory growth, that sphingolipid metabolism is regulated in a previously unrecognized growth stage specific manner, and that endogenous synthesis of unsaturated fatty acids constitutes an in vivo upstream activator of peroxisomal biogenesis, via the heterodimeric Oaf1/Pip2 transcription factor. Our work demonstrates the pivotal role of lipid metabolism in adaptive processes and provides a resource to investigate its regulation at the cellular level. PMID- 25794438 TI - Prevalence and management of colorectal neoplasia in surgically treated esophageal cancer patients. AB - AIMS: The existence of other primary tumors during the treatment of esophageal cancer patients has been an important issue. Our aim is to investigate the prevalence and management of colorectal neoplasia (CRN) in surgically treated esophageal cancer patients. METHODS: Between 2002 and 2008, 93 patients with esophageal cancer were surgically treated. Seventy-three patients underwent subtotal esophagectomy and 20 underwent lower esophagectomy for esophageal cancer. Colonoscopy was available for detecting CRN before and after surgery. RESULTS: Eighty-nine (95.7%) of the 93 patients were screened by colonoscopy preoperatively or within a year from the operation. Thirty-nine patients (43.8%) with CRN were synchronously identified: adenoma in 34 (38.2%) and adenocarcinoma in 5 patients (5.6%). Eleven adenomas with high grade-dysplasia and 8 adenomas with low grade-dysplasia were removed endoscopically. Three superficial adenocarcinomas were endoscopically removed before surgery, and 2 adenocarcinomas were surgically removed. Seventy-four patients (83.1%) were followed using colonoscopy, and 11 subsequent CRN, including 2 superficial adenocarcinomas, were endoscopically detected in 8 patients (10.8%). The size of esophageal cancer was larger in the patients with than without CRN (p = 0.036). The body mass index in esophageal cancer patients with CRN tended to be higher than in those without CRN (p = 0.065). CONCLUSIONS: We noted that esophageal cancer is frequently associated with synchronous and/or metachronous colorectal cancer and adenomas. Colonoscopy is useful to detect and manage CRN before and after esophagectomy, although a few limitations exist. PMID- 25794440 TI - Nasal photodisinfection and chlorhexidine: post hoc ergo propter hoc? PMID- 25794441 TI - Adenosine tri-phosphate (ATP)-based cleaning monitoring in health care: how rapidly does environmental ATP deteriorate? AB - BACKGROUND: Ensuring cleaning compliance of housekeeping staff is critical to ensure adequate application of surface disinfectants. Adenosine triphosphate (ATP) testing has been recommended as a way to monitor cleaning compliance; however, little is known about the stability of ATP on environmental surfaces. AIM: To assess the stability of ATP from various sources to determine if it is stable for sufficient time to be an effective means of assessing environmental cleaning and disinfection in health care. METHODS: Purified ATP, ATP derived from ATS-T (blood-based test soil) and ATP derived from 10(7) colony-forming units/site of micro-organisms (Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans) were evaluated in liquid suspension and dried on to surfaces to assess stability over 29 days. Cleaners and disinfectants were sprayed on to surface-dried material with no wiping to determine their effect on microbial viability and ATP stability. FINDINGS: Surface-dried P. aeruginosa, E. faecalis and C. albicans retained 65-96% of their original ATP level on Day 29, despite reduced or no viability. Surface-dried ATS-T had 100% and 3% of its original ATP on Days 4 and 29, respectively. Deterioration of the ATP signal was most pronounced for suspensions. Purified ATP was stable over 29 days in suspension or dried on to a surface. CONCLUSIONS: ATP residuals from organic material and micro organisms (dead or alive) are stable when dried on to surfaces. In the absence of cleaning and disinfection, the relative light unit signal will not deteriorate rapidly, making ATP a good marker to monitor cleaning. PMID- 25794439 TI - Effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women: A randomised controlled clinical trial. AB - BACKGROUND & AIMS: Low levels of serum 25-hydroxy vitamin D (25(OH)D) are common in type 2 diabetic patients and cause several complications particularly, in postmenopausal women due to their senile and physiological conditions. This study aimed to assess the effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women. METHODS: In a randomized, placebo-controlled, double-blind parallel-group clinical trial, 59 postmenopausal women with type 2 diabetes received fortified yogurt (FY; 2000 IU vitamin D in 100 g/day) or plain yogurt (PY) for 12 weeks. Glycemic markers, anthropometric indexes, inflammatory, and bone turnover markers were assessed at baseline and after 12 weeks. RESULTS: After intervention, in FY group (vs PY group), were observed: significant increase in serum 25(OH)D and decrease of PTH (stable values in PY); significant improvement in serum fasting insulin, HOMA-IR, HOMA-B, QUICKI, and no changes in serum fasting glucose and HbA1c (significant worsening of all indexes in PY); significant improvement in WC, WHR, FM, and no change in weight and BMI (stable values in PY); significant increase of omentin (stable in PY) and decrease of sNTX (significant increase in PY). Final values of glycemic markers (except HbA1c), omentin, and bone turnover markers significantly improved in FY group compared to PY group. Regarding final values of serum 25(OH)D in FY group, subjects were classified in insufficient and sufficient categories. Glycemic status improved more significantly in the insufficient rather than sufficient category; whereas the other parameters had more amelioration in the sufficient category. CONCLUSIONS: Daily consumption of 2000 IU vitamin D-fortified yogurt for 12 weeks improved glycemic markers (except HbA1c), anthropometric indexes, inflammation, and bone turnover markers in postmenopausal women with type 2 diabetes. TRIAL REGISTRATION: www.irct.ir (IRCT2013110515294N1). PMID- 25794442 TI - Effect of siloxane spacer length on organosilicon bi-quaternary ammonium amphiphiles. AB - A series of organosilicon Bola-form bi-quaternary ammonium amphiphiles, [OH5C3(C2H5)2N+-(CH2)3-Si(CH2)3-O-(Si(CH3)2O)n-Si(CH2)3?(CH2)3-N+(C2H5)2C3H5O]Cl2 (SinN2Cl2, n=0, 4, 6, 8), with the same headgroups and different length of hydrophobic linkage has been synthesized. The critical micelle concentration (CMC) of each amphiphiles was determined by equilibrium surface tension. With the increased length of hydrophobic siloxane spacer, the CMC values follow the order of Si8N2Cl2=9.0 h/day) sleep duration [(OR (95% CI): 1.59 (1.17-2.17)] had an increased risk of breast cancer. In addition, daytime napping was associated with a reduced risk of breast cancer among night-shift workers [OR (95% CI): 0.57 (0.36-0.90)], but no association was found among women who never had night-shift work [OR (95% CI): 1.01 (0.75-1.35)] (P for interaction = 0.054). Night-shift work and longer sleep duration also synergistically increased breast cancer risk [OR (95% CI): 3.69 (1.94-7.02)] (P for interaction = 0.009). CONCLUSIONS: Sleep problems, including night-shift work, and shorter and longer sleep duration, are associated with an increased breast cancer risk. In particular, the combined effects of night-shift work with no daytime napping or longer sleep duration are greater than the independent effects. PMID- 25794455 TI - Downhill oesophageal variceal bleeding: A rare complication in Behcet's disease related superior vena cava syndrome. AB - Behcet's disease (BD) is a multisystemic disorder that involves vessels of all sizes. Superior vena cava (SVC) thrombosis is a rare complication that can lead to the development of various collateral pathways. A 31-year-old man presented with SVC syndrome. He had a history of recurrent genital aphthosis. Computed tomography revealed extensive thrombosis of the right internal jugular, axillary, and subclavian veins with collateral circulation. The patient was diagnosed with BD, and he was started on anticoagulation and immunosuppressive therapy. One week later, he presented with haematemesis. Upper gastrointestinal endoscopy disclosed varices in the upper third of the oesophagus with stigmata of recent bleeding. Portal hypertension was ruled out. Anticoagulation therapy was discontinued. He was discharged on immunosuppressive therapy. Bleeding from downhill oesophageal varices should be suspected in any patient presenting with upper gastrointestinal bleeding and a history of SVC syndrome due to BD. PMID- 25794456 TI - Renal Ischemia During Partial Nephrectomy: Does Every Minute Still Count? PMID- 25794457 TI - Maintenance Therapy with 3-monthly Bacillus Calmette-Guerin for 3 Years is Not Superior to Standard Induction Therapy in High-risk Non-muscle-invasive Urothelial Bladder Carcinoma: Final Results of Randomised CUETO Study 98013. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) maintenance therapy for 3 yr following BCG induction can reduce the progression of urothelial bladder carcinoma versus BCG induction alone, but is associated with high toxicity. OBJECTIVE: To investigate whether a modified 3-yr BCG maintenance regimen following induction therapy is more effective than standard BCG induction therapy alone and exhibits a low toxicity profile. DESIGN, SETTING, AND PARTICIPANTS: Patients from the outpatient clinics of the participating centres with high-risk non-muscle invasive bladder carcinoma (NMIBC) were randomised between October 1999 and April 2007. INTERVENTION: Participants received BCG induction once-weekly for 6 wk (no maintenance arm) or BCG induction followed by one BCG instillation every 3 mo for 3 yr (maintenance arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were disease-free interval (DFI) and time to progression (TTP). Secondary endpoints included survival duration and toxicity. Differences between treatment arms were tested using Student's t test and chi(2) and log-rank tests. RESULTS AND LIMITATIONS: A total of 397 patients were randomised, 195 to the no maintenance and 202 to the maintenance arm. A median time to recurrence was not reached in either treatment arm. DFI was similar between the arms (hazard ration [HR] 0.83; 95% CI 0.61-1.13; p=0.2) with disease relapse at 5 yr of 33.5% and 38.5%, respectively. TTP was also similar between the treatment arms (HR 0.79; 95% CI 0.50-1.26; p=0.3), with a progression rate at 5 yr of 16% and 19.5%, respectively. There were no significant differences between the treatment groups for overall survival and cancer-specific survival at 5 yr. Twenty and five patients in the maintenance and no-maintenance arms, respectively, stopped treatment because of toxicity. The most common local side effects were frequency (65% of patients), dysuria (63%), and haematuria (43%); the most frequent systemic side effects were general malaise (7.2%) and fever (34%). CONCLUSIONS: In NMIBC patients treated with maintenance therapy comprising a single BCG instillation every 3 mo for 3 yr following standard induction BCG, we did not observe a decrease in recurrence and progression rates versus induction therapy alone. PATIENT SUMMARY: Patients who undergo surgery to remove bladder cancer are usually treated with bacillus Calmette-Guerin (BCG) for 6 wk if there is a high risk of disease recurrence. Extending BCG therapy by 3 yr can further minimise disease recurrence and progression, but is associated with more side effects. We report that a modified 3-yr BCG treatment regimen showed low toxicity, but seemed to be no more effective than 6-wk treatment. TRIAL REGISTRATION: CUETO 98013. PMID- 25794459 TI - Doing it right: how, not whether, to perform prostate-specific antigen screening. PMID- 25794458 TI - Anthropometric Measures at Multiple Times Throughout Life and Prostate Cancer Diagnosis, Metastasis, and Death. AB - BACKGROUND: Previous studies of prostate cancer (PCa) risk and anthropometrics (ie, body measurements) were based on single measurements or obtained over limited time spans. OBJECTIVE: To study the association between anthropometrics measured at multiple time points in life and their relation to later diagnosis, metastasis, or death from PCa. DESIGN, SETTING, AND PARTICIPANTS: This case control study includes 27 167 Swedish men enrolled in two population-based projects from 1974 to 1996. PCa diagnosis up to December 31, 2006, disease information, gestation time, and anthropometrics at birth, military conscript testing, and adulthood were collected. A total of 1355 PCa cases were matched with 5271 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariate conditional logistic regression was used to determine whether clinical diagnosis, metastasis, or PCa death was associated with low birth weight (weight <2500 g); with small size for gestational age; or with weight, length, or body mass index (BMI) at birth, adolescence (aged 16-22 yr), or early middle age (aged 44-50 yr). RESULTS AND LIMITATIONS: Apart from weight at adolescence, which was associated with an increased risk of PCa diagnosis (odds ratio [OR] per 5 kg: 1.05; 95% confidence interval [CI], 1.01-1.09; p=0.026), preadulthood measurements were not associated with any PCa end point. Adulthood parameters were not associated with diagnosis. In contrast, weight and BMI at early middle age were significantly associated with metastasis (OR per 5 kg: 1.13; 95% CI, 1.06-1.20; p<0.0001, and OR: 1.09; 95% CI, 1.05-1.14; p<0.0001) and death (OR per 5 kg: 1.11 (95% CI, 1.03 1.19; p=0.005, and OR: 1.08; 95% CI, 1.03-1.13; p=0.003), respectively. It remains unclear whether these results apply to men of nonwhite origin, to populations with active PCa screening programs, or to countries without socialized health care. CONCLUSIONS: The analyses of these large data sets demonstrate that significant effects of body characteristics (with links to metabolic syndrome) measured at early middle age are associated with PCa disease severity, metastatic progression, and outcome. Conversely, measurements at birth and adolescence are not associated with PCa prevalence or outcome. PATIENT SUMMARY: Increased weight and body mass index in adults is associated with a higher risk of prostate cancer metastasis and death. PMID- 25794460 TI - A novel device for studying weight supported, quadrupedal overground locomotion in spinal cord injured rats. AB - BACKGROUND: Providing weight support facilitates locomotion in spinal cord injured animals. To control weight support, robotic systems have been developed for treadmill stepping and more recently for overground walking. NEW METHOD: We developed a novel device, the body weight supported ambulatory rodent trainer (i.e. BART). It has a small pneumatic cylinder that moves along a linear track above the rat. When air is supplied to the cylinder, the rats are lifted as they perform overground walking. We tested the BART device in rats that received a moderate spinal cord contusion injury and in normal rats. Locomotor training with the BART device was not performed. RESULTS: All of the rats learned to walk in the BART device. In the contused rats, significantly greater paw dragging and dorsal stepping occurred in the hindlimbs compared to normal. Providing weight support significantly raised hip position and significantly reduced locomotor deficits. Hindlimb stepping was tightly coupled to forelimb stepping but only when the contused rats stepped without weight support. Three weeks after the contused rats received a complete spinal cord transection, significantly fewer hindlimb steps were performed. COMPARISON WITH EXISTING METHODS: Relative to rodent robotic systems, the BART device is a simpler system for studying overground locomotion. The BART device lacks sophisticated control and sensing capability, but it can be assembled relatively easily and cheaply. CONCLUSIONS: These findings suggest that the BART device is a useful tool for assessing quadrupedal, overground locomotion which is a more natural form of locomotion relative to treadmill locomotion. PMID- 25794461 TI - Wavelet methodology to improve single unit isolation in primary motor cortex cells. AB - The proper isolation of action potentials recorded extracellularly from neural tissue is an active area of research in the fields of neuroscience and biomedical signal processing. This paper presents an isolation methodology for neural recordings using the wavelet transform (WT), a statistical thresholding scheme, and the principal component analysis (PCA) algorithm. The effectiveness of five different mother wavelets was investigated: biorthogonal, Daubachies, discrete Meyer, symmetric, and Coifman; along with three different wavelet coefficient thresholding schemes: fixed form threshold, Stein's unbiased estimate of risk, and minimax; and two different thresholding rules: soft and hard thresholding. The signal quality was evaluated using three different statistical measures: mean squared error, root-mean squared, and signal to noise ratio. The clustering quality was evaluated using two different statistical measures: isolation distance, and L-ratio. This research shows that the selection of the mother wavelet has a strong influence on the clustering and isolation of single unit neural activity, with the Daubachies 4 wavelet and minimax thresholding scheme performing the best. PMID- 25794463 TI - Cyclotron production of high purity (44m,44)Sc with deuterons from (44)CaCO3 targets. AB - INTRODUCTION: Due to its longer half-life, (44)Sc (T1/2 = 3.97 h) as a positron emitter can be an interesting alternative to (68)Ga (T1/2 = 67.71 min). It has been already proposed as a PET radionuclide for scouting bone disease and is already available as a (44)Ti/(44)Sc generator. (44)Sc has an isomeric state, (44 m)Sc (T1/2 = 58.6 h), which can be co-produced with (44)Sc and that has been proved to be considered as an in-vivo PET generator (44 m)Sc/(44)Sc. This work presents the production route of (44 m)Sc/(44)Sc generator from (44)Ca(d,2n), its extraction/purification process and the evaluation of its performances. METHODS: Irradiation was performed in a low activity target station using a deuteron beam of 16 MeV, which favors the number of (44 m)Sc atoms produced simultaneously to (44)Sc. Typical irradiation conditions were 60 min at 0.2 MUA producing 44 MBq of (44)Sc with a (44)Sc/(44 m)Sc activity ratio of 50 at end of irradiation. Separations of the radionuclides were performed by means of cation exchange chromatography using a DGA(r) resin (Triskem). Then, the developed process was applied with bigger targets, and could be used for preclinical studies. RESULTS: The extraction/purification process leads to a radionucleidic purity higher than 99.99% ((43)Sc, (46)Sc, (48)Sc < DL). (44 m)Sc/(44)Sc labeling towards DOTA moiety was performed in order to get an evaluation of the specific activities that could be reached with regard to all metallic impurities from the resulting source. Reaction parameters of radiolabeling were optimized, reaching yields over 95%, and leading to a specific activity of about 10-20 MBq/nmol for DOTA. A recycling process for the enriched (44)Ca target was developed and optimized. CONCLUSION: The quality of the final batch with regard to radionucleidic purity, specific activity and metal impurities allowed a right away use for further radiopharmaceutical evaluation. This radionucleidic pair of (44 m)Sc/(44)Sc offers a quite interesting PET radionuclide for being further evaluated as an in vivo generator. PMID- 25794464 TI - Enhanced photodynamic therapy efficacy of methylene blue-loaded calcium phosphate nanoparticles. AB - Although methylene blue (MB) is the most inexpensive photosensitizer with promising applications in the photodynamic therapy (PDT) for its high quantum yield of singlet oxygen generation, the clinical use of MB has been limited by its rapid enzymatic reduction in the biological environment. To enhance PDT efficacy of MB by preventing the enzymatic reduction, we have developed a new mineralization method to produce highly biocompatible MB-loaded calcium phosphate (CaP-MB) nanoparticles in the presence of polymer templates. The resulting CaP-MB nanoparticles exhibited spherical shape with a size of under 50 nm. Fourier transform infrared (FT-IR) and zeta-potential analyses confirmed the insertion of MB into the CaP-MB nanoparticles. The encapsulation of MB in CaP nanoparticles could effectively protect MB from the enzymatic reduction. In addition, the CaP MB nanoparticles exhibited a good biocompatibility in the dark condition and significantly enhanced PDT efficacy due to apoptotic cell death against human breast cancer cells as compared with free MB, implying that CaP-MB nanoparticle system might be potentially applicable in PDT. PMID- 25794465 TI - The effect of fine bubble aeration intensity on membrane bioreactor sludge characteristics and fouling. AB - While most membrane bioreactor (MBR) research focuses on improving membrane filtration through air scour, backwashing and chemical cleaning to physically counteract fouling, relatively few studies have dealt with fouling prevention, e.g. minimizing the impact of operational settings that negatively impact sludge filterability. To evaluate the importance of those settings, the effects of bioreactor aeration intensity variations on membrane fouling have been studied in a lab-scale MBR setup while simultaneously monitoring a unique set of key sludge parameters. In particular, this paper focuses on the impact of shear dynamics resulting from fine air bubbles on the activated sludge quality and flocculation state, impacting membrane fouling. When augmenting the fine bubble aeration intensity both the total and irreversible fouling rate increased. Major indications for sludge filterability deterioration were found to be a shift in the particle size distribution (PSD) in the 3-300 MUm range towards smaller sludge flocs, and increasing concentrations of submicron particles (10-1000 nm), soluble microbial products and biopolymers. When lowering the aeration intensity, both the sludge characteristics and fouling either went back to background values or stabilized, respectively indicating a temporary or more permanent effect, with or without time delay. The shift in PSD to smaller flocs and fragments likely increased the total fouling through the formation of a less permeable cake layer, while high concentrations of submicron particles were likely causing increased irreversible fouling through pore blocking. The insights from the performed fouling experiments can be used to optimize system operation with respect to influent dynamics. PMID- 25794466 TI - Characteristics of pollutant gas releases from swine, dairy, beef, and layer manure, and municipal wastewater. AB - Knowledge about characteristics of gas releases from various types of organic wastes can assist in developing gas pollution reduction technologies and establishing environmental regulations. Five different organic wastes, i.e., four types of animal manure (swine, beef, dairy, and layer hen) and municipal wastewater, were studied for their characteristics of ammonia (NH3), carbon dioxide (CO2), hydrogen sulfide (H2S), and sulfur dioxide (SO2) releases for 38 or 43 days in reactors under laboratory conditions. Weekly waste additions and continuous reactor headspace ventilation were supplied to simulate waste storage conditions. Results demonstrated that among the five waste types, layer hen manure and municipal wastewater had the highest and lowest NH3 release potentials, respectively. Layer manure had the highest and dairy manure had the lowest CO2 release potentials. Dairy manure and layer manure had the highest and lowest H2S release potentials, respectively. Beef manure and layer manure had the highest and lowest SO2 releases, respectively. The physicochemical characteristics of the different types of wastes, especially the total nitrogen, total ammoniacal nitrogen, dry matter, and pH, had strong influence on the releases of the four gases. Even for the same type of waste, the variation in physicochemical characteristics affected the gas releases remarkably. PMID- 25794467 TI - Epilepsy and eating disorders during pregnancy: Prevalence, complications and birth outcome. AB - PURPOSE: The aim was to investigate the prevalence of eating disorders and its relation to pregnancy and delivery complications in childbearing women with epilepsy (WWE). METHOD: This study is based on The Norwegian Mother and Child Cohort Study (MoBa) linked to the Medical Birth Registry of Norway. Epilepsy was reported in 706 pregnancies. The remaining cohort (n=106,511) served as the reference group. Eating disorders were diagnosed using DSM-IV criteria adjusted for pregnancy. The risk of preeclampsia, gestational hypertension, diabetes and weight gain during pregnancy as well as delivery outcome (small for gestational age, large for gestational age, ponderal index, low APGAR score, small head circumference) were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for maternal age, smoking, parity and socioeconomic factors. RESULTS: Pregnant WWE were significantly more likely to have binge eating disorder (6.5% vs. 4.7%, p<0.05). WWE and comorbid eating disorders had significantly more preeclampsia (7.9% vs. 3.7%, p<0.05), peripartum depression and/or anxiety (40.4% vs. 17.8%, p<0.001) and operative delivery (38.2% vs. 23.5%, p<0.001) than the reference group without epilepsy or eating disorders. After adjustment for confounders, a significantly increased risk of operative delivery (OR 1.96, CI 1.26-3.05) and peripartum depression and/or anxiety (OR 2.17, CI 1.40-3.36) was demonstrated. CONCLUSION: Eating disorders in WWE contribute to the increased risk of pregnancy and delivery complications. Health personnel should be aware of eating disorders in WWE and refer them for treatment before pregnancy. PMID- 25794468 TI - Patient preference for monthly bisphosphonate versus weekly bisphosphonate in a cluster-randomized, open-label, crossover trial: Minodroate Alendronate/Risedronate Trial in Osteoporosis (MARTO). AB - Minodronate is a potent nitrogen-containing bisphosphonate that can be administered according to a monthly (every 4 weeks) dosing regimen. A 6-month, cluster-randomized, open-label, multicenter, crossover trial was conducted to test the preference of Japanese patients with osteoporosis for monthly bisphosphonate versus weekly bisphosphonate. One hundred and forty-seven patients (postmenopausal women and men) with primary osteoporosis were recruited at eight outpatient clinics. The clinics were randomized into two groups according to the dosing protocol-monthly minodronate followed by weekly alendronate or risedronate for a total of 24 weeks, or weekly alendronate or risedronate followed by monthly minodronate for 24 weeks. Patient preference for either the monthly or weekly bisphosphonate regimen was evaluated using a preference questionnaire. One hundred and fifteen patients (78.2 %) who completed the trial were processed for the analyses. Significantly more patients preferred the monthly bisphosphonate regimen (65.2 %) than the weekly bisphosphonate regimen (15.7 %) (P = 0.007). 'Dosing schedule fits lifestyle better' was the most common reason given for the patient preference for both the monthly (32.0 %) and weekly bisphosphonate (33.3 %) regimens. Significantly more patients found the monthly bisphosphonate regimen to be more convenient (73.0 %) than the weekly bisphosphonate regimen (13.9 %) (P < 0.0001). The safety profiles of the two regimens were similar. The present trial demonstrated a strong patient preference for and the convenience of the monthly bisphosphonate regimen over the weekly bisphosphonate regimen in Japanese patients with osteoporosis. PMID- 25794469 TI - Tuberculosis infection in a late-medieval Hungarian population. AB - The AD 16-17(th) century skeletal series from Bacsalmas-Oalmas (southern Hungary) has already been the subject of previous paleopathological studies concerning TB related bone lesions. Due to recent development of macroscopic and molecular diagnostic methods in paleopathology and paleomicrobiology, a five-year international research program was recently started in order to re-evaluate the TB-related lesions in the complete series, comprising 481 skeletons. The skeletal material of these individuals was examined using macromorphological methods focusing on both classical/advanced stage skeletal TB alterations and atypical/early-stage TB lesions. Paleomicrobial analysis was used to study the presence of Mycobacterium tuberculosis complex (MTBC) DNA both in morphologically positive and negative cases. Samples were tested for the repetitive element IS6110 and further characterized by spoligotyping. In the whole series, 283 possible cases of TB infections were identified based on morphological alterations. Skeletal samples of eighteen individuals, morphologically positive as well as negative cases, were selected for further biomolecular examinations. Among them, seven individuals were PCR positive for the repetitive IS6110 sequence of the MTBC genome. Compared to the few cases of TB from the Bacsalmas Oalmas series previously described, a much higher prevalence of MTBC infected skeletons was revealed in this study. The atypical/early stage skeletal lesions occurred significantly more frequently than the so-called classical alterations. Paleomicrobial analysis confirmed a prevalence of MTBC infection nearing 40% among the selected sample. Preliminary results also indicated better preservation of bacterial DNA in the compact layer of long bones and teeth, while spoligotyping suggested infection by different MTBC pathogens. PMID- 25794470 TI - Childhood BCG vaccination does not influence control of Mycobacterium tuberculosis growth by human bronchoalveolar lavage cells. AB - BACKGROUND: Childhood vaccination with Mycobacterium bovis Bacille Calmette Guerin (BCG) reduces the risk of infection with Mycobacterium tuberculosis and the risk of severe forms of tuberculosis in children. The protection of adults from pulmonary tuberculosis is doubtful. This study evaluated the effect of the vaccination on the growth of M. tuberculosis human bronchoalveolar mononuclear cells (BALMC). METHODS: Healthy, adult healthcare workers who were regularly exposed to M. tuberculosis, household tuberculosis contacts, and cured tuberculosis patients were recruited in a multicentre study conducted in Germany. BALMC were co-cultured with different strains of M. tuberculosis in growth inhibition assays (MGIAs). RESULTS: MGIAs on BALMC were conducted in 90 contact persons (known vaccination status, n = 75) and 62 former tuberculosis patients (known status, n = 22). Growth rates for M. tuberculosis H37Rv in BALMC were independent of the vaccination status, both in healthy contacts and in cured tuberculosis patients. This finding was validated in growth inhibition assays using two different Haarlem M. tuberculosis outbreak strains. Subgroup analyses based on the Interferon-gamma release assay status found no impact of the vaccination on mycobacterial growth. CONCLUSIONS: This study suggests that M. bovis BCG vaccination does not alter the anti-mycobacterial capacity of BALMC as assessed in ex-vivo growth inhibition assays. PMID- 25794471 TI - Suicide in U.S. Workplaces, 2003-2010: a comparison with non-workplace suicides. AB - INTRODUCTION: Suicide rates have risen considerably in recent years. National workplace suicide trends have not been well documented. The aim of this study is to describe suicides occurring in U.S. workplaces and compare them to suicides occurring outside of the workplace between 2003 and 2010. METHODS: Suicide data originated from the Census of Fatal Occupational Injury database and the Web Based Injury Statistics Query and Reporting System. Suicide rates were calculated using denominators from the 2013 Current Population Survey and 2000 U.S. population census. Suicide rates were compared among demographic groups with rate ratios and 95% CIs. Suicide rates were calculated and compared among occupations. Linear regression, adjusting for serial correlation, was used to analyze temporal trends. Analyses were conducted in 2013-2014. RESULTS: Between 2003 and 2010, a total of 1,719 people died by suicide in the workplace. Workplace suicide rates generally decreased until 2007 and then sharply increased (p=0.035). This is in contrast with non-workplace suicides, which increased over the study period (p=0.025). Workplace suicide rates were highest for men (2.7 per 1,000,000); workers aged 65-74 years (2.4 per 1,000,000); those in protective service occupations (5.3 per 1,000,000); and those in farming, fishing, and forestry (5.1 per 1,000,000). CONCLUSIONS: The upward trend of suicides in the workplace underscores the need for additional research to understand occupation-specific risk factors and develop evidence-based programs that can be implemented in the workplace. PMID- 25794472 TI - Predictive modeling: potential application in prevention services. AB - INTRODUCTION: In 2012, the New Zealand Government announced a proposal to introduce predictive risk models (PRMs) to help professionals identify and assess children at risk of abuse or neglect as part of a preventive early intervention strategy, subject to further feasibility study and trialing. The purpose of this study is to examine technical feasibility and predictive validity of the proposal, focusing on a PRM that would draw on population-wide linked administrative data to identify newborn children who are at high priority for intensive preventive services. METHODS: Data analysis was conducted in 2013 based on data collected in 2000-2012. A PRM was developed using data for children born in 2010 and externally validated for children born in 2007, examining outcomes to age 5 years. RESULTS: Performance of the PRM in predicting administratively recorded substantiations of maltreatment was good compared to the performance of other tools reviewed in the literature, both overall, and for indigenous Maori children. CONCLUSIONS: Some, but not all, of the children who go on to have recorded substantiations of maltreatment could be identified early using PRMs. PRMs should be considered as a potential complement to, rather than a replacement for, professional judgment. Trials are needed to establish whether risks can be mitigated and PRMs can make a positive contribution to frontline practice, engagement in preventive services, and outcomes for children. Deciding whether to proceed to trial requires balancing a range of considerations, including ethical and privacy risks and the risk of compounding surveillance bias. PMID- 25794475 TI - Reversible posterior leukoencephalopathy syndrome after withdrawal of antipsychotic medication in the context of lithium intoxication. AB - OBJECTIVE: To report a case of reversible posterior leukoencephalopathy syndrome (RPLS) after withdrawal of antipsychotic medication in a patient with acute lithium intoxication. METHODS: Case report. RESULTS: A patient with schizoaffective disorder was admitted with lithium intoxication, rhabdomyolysis and acute renal failure. After withdrawal of psychotropic medication, she developed a significant increase in blood pressure - though to moderately hypertensive levels - and prolonged disturbance of consciousness with profound agitation. MRI revealed RPLS. Resumption of antipsychotic treatment resulted in significant drop of blood pressure and improvement. CONCLUSION: Acute withdrawal of antipsychotic medication may lead to rebound hypertension and development of RPLS, especially in the presence of lithium intoxication and renal dysfunction. PMID- 25794474 TI - Continued Impact of SunSmart Advertising on Youth and Adults' Behaviors. AB - INTRODUCTION: Televised advertising campaigns play a central role in public education for skin cancer prevention in Australia. Continued impact on behavior is crucial to optimize these investments. This study examines whether exposure to increased intensity of summer campaigns in the past decade has continued to influence sun protection behaviors and to examine behavioral impact across age groups. METHODS: Cross-sectional weekly telephone surveys of Melbourne residents were conducted over summers from 1987-1988 to 2010-2011, and analyzed in 2012 2014. Respondents' sun-related attitudes and their sun protection and sunburn on the weekend prior to interview were assessed. Population exposure to campaign TV advertising was measured as cumulated weekly target audience rating points (TARPs) for 4 weeks prior to interviews. Multiple logistic and linear regression models examined the relationship of campaign advertising with tanning preference and behavioral outcomes (N=11,881). RESULTS: Respondents' attitudes and behaviors in 1987-2011 were associated with TARPs. Increasing TARPs were related to increased preference for no tan (OR=1.12, 95% CI=1.07, 1.17); sunscreen use (OR=1.09, 95% CI=1.02, 1.17); and overall reduced mean percentage of skin exposed to the sun (B=-0.01, 95% CI=-0.01, 0.00). These effects had limited interaction with time period, age group, gender, or skin type. There was evidence of diminishing returns at the highest TARP quartile for tan preference but not for behavioral outcomes. CONCLUSIONS: Sustained youth-focused advertising campaigns (for adolescents and young adults), when broadcast with sufficient TARPs during the summer months, continue to provide consistent beneficial impact on sun protection behaviors population-wide. PMID- 25794473 TI - Nicotine and the Developing Human: A Neglected Element in the Electronic Cigarette Debate. AB - The elimination of cigarettes and other combusted tobacco products in the U.S. would prevent tens of millions of tobacco-related deaths. It has been suggested that the introduction of less harmful nicotine delivery devices, such as electronic cigarettes or other electronic nicotine delivery systems, will accelerate progress toward ending combustible cigarette use. However, careful consideration of the potential adverse health effects from nicotine itself is often absent from public health debates. Human and animal data support that nicotine exposure during periods of developmental vulnerability (fetal through adolescent stages) has multiple adverse health consequences, including impaired fetal brain and lung development, and altered development of cerebral cortex and hippocampus in adolescents. Measures to protect the health of pregnant women and children are needed and could include (1) strong prohibitions on marketing that increase youth uptake; (2) youth access laws similar to those in effect for other tobacco products; (3) appropriate health warnings for vulnerable populations; (4) packaging to prevent accidental poisonings; (5) protection of non-users from exposure to secondhand electronic cigarette aerosol; (6) pricing that helps minimize youth initiation and use; (7) regulations to reduce product addiction potential and appeal for youth; and (8) the age of legal sale. PMID- 25794476 TI - Partition coefficient vs. binding constant: How best to assess molecular lipophilicity. AB - Partition coefficient, P, is the preferred descriptor of molecular lipo- or hydrophilicity, and thus of relationships between a solute (S, e.g., a drug), a polar medium (W, e.g., an aqueous buffer), and an essentially apolar, organic, medium or a drug carrier (O). The coefficient is commonly identified with the linear ratio of solute quantities in the two media, P=nSO/nSW, even to characterise solute association with or binding to a surface (e.g., of a HPLC column or a drug carrier). To check the latter practice correctness-and credibility of the prevailing P definition-this paper compares an ideal solute distribution between two separate homogeneous fluid media (i.e., partitioning) to solute association with a uniform surface immersed in one such medium (i.e., binding). This reveals that solute partitioning and binding fundamentally differ and can only exceptionally be described, or analysed, with similar equations. Nonlinearised formulae that describe partitioning (Eq. (9)) and binding (Eq. (11)) can yield similar lipophilicity descriptor values only if solute preparation is relatively dilute; employing a large organic medium fraction is helpful in this respect. Additional prerequisites for partitioning and binding models match are: 1:1 stoichiometry at the association maximum and identical interfacial area of solute and organic medium molecules. If these requirements are not met, binding model yields different, potentially somewhat higher, but more often up to >10 times lower results than partitioning model. The main reason is saturation of organic medium with solute molecules. Partitioning model excludes this phenomenon, which cannot always be prevented by focussing on dilute solute preparations. The current practice of using a linear model and approximate equations to study partitioning or binding can cause large errors (>10(3)*), and is one possible reason for the notoriously high experimental logP values scattering. The latter makes logP predictions more difficult and less reliable than they could be if the measured data were evaluated with non-linearised partitioning or binding equations, as appropriate. PMID- 25794477 TI - Curcumin loaded PLGA-poloxamer blend nanoparticles induce cell cycle arrest in mesothelioma cells. AB - The pharmacological potential of curcumin (CURC) is severely restricted because of its low water solubility/absorption, short half-life and poor bioavailability. To overcome these issues, CURC-loaded nanoparticles (NPs) were produced by a double emulsion technique. In particular, NPs were made up of an amphiphilic blend of poloxamers and PLGA to confer stealth properties to the NPs to take advantage of the enhanced permeability and retention (EPR) effect. Different surface properties of NPs made up of bare PLGA and PLGA/poloxamer blend were confirmed by the different interactions of these NPs with serum proteins and also by their ability to be internalized by mesothelioma cell line. The uptake of PLGA/poloxamer NPs induces a persistent block in G0/G1 phase of the cell cycle up to 72 h, thus overcoming the drug tolerance phenomenon, normally evidenced with free CURC. PMID- 25794478 TI - Interactions between distal speech rate, linguistic knowledge, and speech environment. AB - During lexical access, listeners use both signal-based and knowledge-based cues, and information from the linguistic context can affect the perception of acoustic speech information. Recent findings suggest that the various cues used in lexical access are implemented with flexibility and may be affected by information from the larger speech context. We conducted 2 experiments to examine effects of a signal-based cue (distal speech rate) and a knowledge-based cue (linguistic structure) on lexical perception. In Experiment 1, we manipulated distal speech rate in utterances where an acoustically ambiguous critical word was either obligatory for the utterance to be syntactically well formed (e.g., Conner knew that bread and butter (are) both in the pantry) or optional (e.g., Don must see the harbor (or) boats). In Experiment 2, we examined identical target utterances as in Experiment 1 but changed the distribution of linguistic structures in the fillers. The results of the 2 experiments demonstrate that speech rate and linguistic knowledge about critical word obligatoriness can both influence speech perception. In addition, it is possible to alter the strength of a signal-based cue by changing information in the speech environment. These results provide support for models of word segmentation that include flexible weighting of signal based and knowledge-based cues. PMID- 25794479 TI - The relationship of eating until 80% full with types and energy values of food consumed. AB - OBJECTIVE: Eating until one is 80% full is considered a healthy dietary practice in Japan. This study examined the relationship between this behavior and energy intake and types and quantities of foods consumed to examine its beneficial effects. METHODS: This study relied on dietary records and self-administered questionnaires completed by 330 users of a health-management website in November 2012. ANOVA was performed to examine the relationship between eating until one is 80% full and intake. RESULTS: Men who always ate until they were 80% full consumed less energy than those who did not (mean [SD]; always: 1997.3 [356.7] kcal; rarely/never: 2448.9 [637.1] kcal; p<0.05). Moreover, men who ate until they were 80% full consumed fewer servings of grain dishes (always: 3.7 [0.9] servings; rarely/never: 5.1 [1.9] servings; p<0.05) and more servings of vegetable dishes (always: 5.9 [2.2] servings; rarely/never: 4.0 [2.3] servings, p<0.05) than those who did not. CONCLUSION: Men who ate until they were 80% full consumed less energy and more vegetable dishes than those who did not, suggesting that eating until one is 80% full is associated with healthy dietary habits among men. PMID- 25794480 TI - Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models. AB - The use of in silico tools within the drug development process to predict a wide range of properties including absorption, distribution, metabolism, elimination and toxicity has become increasingly important due to changes in legislation and both ethical and economic drivers to reduce animal testing. Whilst in silico tools have been used for decades there remains reluctance to accept predictions based on these methods particularly in regulatory settings. This apprehension arises in part due to lack of confidence in the reliability, robustness and applicability of the models. To address this issue we propose a scheme for the verification of in silico models that enables end users and modellers to assess the scientific validity of models in accordance with the principles of good computer modelling practice. We report here the implementation of the scheme within the Innovative Medicines Initiative project "eTOX" (electronic toxicity) and its application to the in silico models developed within the frame of this project. PMID- 25794481 TI - Paenibacillus alba nov., isolated from peat soil. AB - A white-colored bacterial strain designated J20-6(T) was isolated from peat soil collected in Russia. Based on the 16S rRNA gene sequence similarities, the strain J20-6(T) belonged to the genus Paenibacillus, and the closest relatives were Paenibacillus frigoriresistens YIM 016(T) (98.2 %), Paenibacillus alginolyticus DSM 5050T(T) (97.9 %), Paenibacillus chondroitinus DSM 5051(T) (97.4 %), Paenibacillus pocheonensis Gsoil 1138(T) (96.9 %), and Paenibacillus pectinilyticus RCB-08(T) (96.6 %). Cells are gram-positive, motile, facultative aerobic, endospore forming, and rod shaped. The cell wall contains MK-7 as the predominant menaquinone and meso-diaminopimelic acid as the diagnostic diamino acid. The major fatty acid is anteiso-C15:0, and the major polar lipids are diphosphatidylglycerol and phosphatidyl-ethanolamine. The DNA G+C content of the strain J20-6(T) was 49.9 mol %. The phenotypic, chemotaxonomic, and phylogenetic data clearly suggest that the strain J20-6(T) belongs to the novel member of the genus Paenibacillus, for which the name Paenibacillus alba sp. nov., is proposed. The type strain is J20-6(T) (=KEMC 7302-005(T) = JCM 18165(T)). PMID- 25794482 TI - A comparative study of McFarland turbidity standards and the Densimat photometer to determine bacterial cell density. AB - McFarland Turbidity Standards and the Densimat photometer were compared for their accuracy to adjust bacterial suspensions. Six bacterial species were tested with both methods. Statistical analyses showed that adjusting bacterial suspensions with the Densimat photometer results in less variation within assays and in a more accurate determination of bacterial inocula. PMID- 25794483 TI - Hydrostatic pressure promotes the proliferation and osteogenic/chondrogenic differentiation of mesenchymal stem cells: The roles of RhoA and Rac1. AB - Our previous studies have shown that hydrostatic pressure can serve as an active regulator for bone marrow mesenchymal stem cells (BMSCs). The current work further investigates the roles of cytoskeletal regulatory proteins Ras homolog gene family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac1) in hydrostatic pressure-related effects on BMSCs. Flow cytometry assays showed that the hydrostatic pressure promoted cell cycle initiation in a RhoA- and Rac1 dependent manner. Furthermore, fluorescence assays confirmed that RhoA played a positive and Rac1 displayed a negative role in the hydrostatic pressure-induced F actin stress fiber assembly. Western blots suggested that RhoA and Rac1 play central roles in the pressure-inhibited ERK phosphorylation, and Rac1 but not RhoA was involved in the pressure-promoted JNK phosphorylation. Finally, real time polymerase chain reaction (PCR) experiments showed that pressure promoted the expression of osteogenic marker genes in BMSCs at an early stage of osteogenic differentiation through the up-regulation of RhoA activity. Additionally, the PCR results showed that pressure enhanced the expression of chondrogenic marker genes in BMSCs during chondrogenic differentiation via the up regulation of Rac1 activity. Collectively, our results suggested that RhoA and Rac1 are critical to the pressure-induced proliferation and differentiation, the stress fiber assembly, and MAPK activation in BMSCs. PMID- 25794484 TI - Trends in Hospital Volume and Failure to Rescue for Pancreatic Surgery. AB - BACKGROUND: We sought to evaluate trends in selection of high volume (HV) hospitals for pancreatic surgery, as well as examine trends in preoperative complications, mortality, and failure to rescue (FTR). METHOD: Patients who underwent pancreatic resection between 2000 and 2011 were identified from the Nationwide Inpatient Sample (NIS). Preoperative morbidity, mortality, and FTR were examined over time. Hospital volume was stratified into tertiles based on the number of pancreatic resections per year for each time period. Logistic regression models were used to assess the effect of hospital volume on risk of complication, postoperative mortality, and FTR over time. RESULT: A total of 35,986 patients were identified. Median hospital volume increased from 13 in 2000 2003 to 55 procedures/year in 2008-2011 (P < 0.001). Morbidity remained relatively the same over time at low volume (LV), intermediate volume (IV), and HV hospitals (all P > 0.05). Overall postoperative mortality was 5%, and it decreased over time across all hospital volumes (P < 0.05). FTR was more common at LV (12.0%) and IV (8.5%) volume hospitals compared with HV hospitals (6.4%). The improvement in FTR over time was most pronounced at LV and IV hospitals versus HV hospitals (P = 0.001). CONCLUSION: Median hospital volume for pancreatic surgery has increased over the past decade. While the morbidity remained relatively stable over time, mortality improved especially in LV and IV hospitals. This improvement in mortality seems to be related to a decreased FTR. PMID- 25794485 TI - Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA). AB - In 2011 Shoenfeld and Agmon-Levin proposed a new syndrome as a way of grouping together a range of emerging autoimmune diseases with possible adjuvant associated causes, Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants (ASIA). At present, there is no evidence to suggest that ASIA syndrome is a viable explanation for unusual autoimmune diseases. Since the initial paper, over 80 publications have discussed ASIA. This systematic review examines the research that has been done to investigate whether ASIA is a broad umbrella term with little clinical significance, or whether there is some underlying mechanism which could be utilised to reduce the occurrence of adjuvant mediated disease. Twenty seven animal, epidemiological and case studies were reviewed. Unfortunately, a robust animal model of ASIA using biologically relevant doses of adjuvants has yet to be defined. It is also apparent that the broadness of the current ASIA criteria lack stringency and, as a result, very few cases of autoimmune disease could be excluded from a diagnosis of ASIA. The current studies involving human cases are so diverse, in both external stimuli and in resulting conditions, that there is currently a lack of reproducible evidence for any consistent relationship between adjuvant and autoimmune condition. The addition of a mandatory criterion requiring temporal association and clinically relevant adjuvant dose would allow better definition of what constitutes a diagnosis of ASIA. PMID- 25794487 TI - Erratum to: Imaging of spinal injury in abusive head trauma: a retrospective study. PMID- 25794486 TI - Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas? AB - BACKGROUND: There is a paucity of literature describing and comparing the imaging features of adrenocortical adenomas and carcinomas in children and adolescents. OBJECTIVE: To document the CT and MRI features of adrenocortical neoplasms in a pediatric population and to determine whether imaging findings (other than metastatic disease) can distinguish adenomas from carcinomas. MATERIALS AND METHODS: We searched institutional medical records to identify pediatric patients with adrenocortical neoplasms. Pre-treatment CT and MRI examinations were reviewed by two radiologists in consensus, and pertinent imaging findings were documented. We also recorded relevant histopathological, demographic, clinical follow-up and survival data. We used the Student's t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We used receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performances of tumor diameter and volume for discriminating carcinoma from adenoma. A P-value <=0.05 was considered statistically significant. RESULTS: Among the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant potential. There were no differences in mean age, gender or sidedness between adenomas and carcinomas. Carcinomas were significantly larger than adenomas based on mean estimated volume (581 ml, range 16-2,101 vs. 54 ml, range 3-197 ml; P-value = 0.003; ROC area under the curve = 0.92) and mean maximum transverse plane diameter (9.9 cm, range 3.0-14.9 vs. 4.4 cm, range 1.9-8.2 cm; P-value = 0.0001; ROC area under the curve = 0.92). Carcinomas also were more heterogeneous than adenomas on post-contrast imaging (13/14 vs. 2/9; odds ratio [OR] = 45.5; P-value = 0.001). Six of 13 carcinomas and 1 of 8 adenomas contained calcification at CT (OR = 6.0; P-value = 0.17). Seven of 15 children with carcinomas exhibited metastatic disease at diagnosis, and three had inferior vena cava invasion. Median survival for carcinomas was 27 months. CONCLUSION: In our experience, pediatric adrenocortical carcinomas are larger, more heterogeneous, and more often calcified than adenomas, although there is overlap in their imaging appearances. PMID- 25794488 TI - Fibre type composition of female longus capitis and longus colli muscles. AB - Effective management of neck pain requires detailed knowledge of cervical muscle structure and function. Information on muscle fibre type assists in determining function; few data exist on the fibre type composition of many cervical muscles. The purpose of this study was to investigate the fibre type composition of longus capitis (LCa) and longus colli (LCo) to provide a better understanding of their function. Muscle sections were harvested unilaterally from LCa (C2-C7) and LCo (C3, C6, T1) in seven female cadavers (mean age 86 +/- 9 years). Immunohistochemistry was used to identify type I and type II fibres, and stereology (random systematic sampling) used to determine fibre numbers. Data were assessed using descriptive statistics and one-way ANOVA (significance P < 0.05). Fifty-two sections were assessed (82,785 fibres; mean 1,592 +/- 927 per section). LCa had a significantly greater proportion of type I fibres than LCo (64.3 % vs 55.7 %, P = 0.011). The percentage of fibre types varied significantly between individuals in LCa, but not LCo. No significant difference was found in the proportion of type I fibres between cervical levels for either LCa or LCo. LCa and LCo appear functionally different in elderly females, with LCa potentially having a more postural role (higher type I fibre proportion). Fibre types were homogenous throughout each muscle, indicating that contractile function is similar across the length of individual muscles. Further studies across a larger age-span and in males are required to determine whether results are representative of other populations. PMID- 25794489 TI - Cetuximab in patients with esophageal cancer: a systematic review and meta analysis of randomized controlled trials. AB - Esophageal cancer is one cause of the most common cancer death and diagnosed in approximately half a million people annually worldwide, as well as has resulted in worse status, which is responsible for an estimated 482,300 new cases and 406,800 deaths in 2008, and is the fifth highest in the mortality rate among tumor sites. Esophageal cancer mainly occurred in southern and eastern Africa, eastern Asia and some areas of China. The results of meta-analysis suggested that survival rate can be improved [relative risk (RR) 1.6; 95 % confidence interval (CI) 1.17-2.18]; objective response rate (RR 1.47; 95 % CI 1.05-2.06) and disease control rate (RR 1.21; 95 % CI 1.03-1.43) in combination group are superior to that of the control group; however, the higher incidence of acne-like rash was caused (RR 9.03; 95 % CI 1.64-49.63) . Moreover, collated differences in overall survival rate and progression-free survival remained the most common grade 3/4/5 toxicities, and quality of life after intervention revealed no evidence of a difference between the two groups. With the present evidence, there is no role for cetuximab combined with standard approaches for esophageal cancer. PMID- 25794491 TI - A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer. AB - AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD. PMID- 25794490 TI - Suppression of the nuclear transporter-KPNbeta1 expression inhibits tumor proliferation in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the malignant tumors and leads to the highly death in the solid tumors, but its mechanism remains unclear. KPNbeta1 is one of the soluble nuclear transport receptors, has been reported to act as an important role in the occurrence and development of tumor, such as cervical cancer, head and neck and lung cancer. However, the expression mechanisms and physiological significance of KPNbeta1 in HCC is still unclear. AIM: The expression of KPNbeta1 and its involvement in HCC was studied. METHODS: The expression of KPNbeta1 protein was measured by Western blot and immunohistochemistry in HCC. We analyzed the effects of growth and interference of KPNbeta1 in the cell cycle process by CCK8 and flow cytometrical analysis. RESULTS: KPNbeta1 protein level was up-regulated in HCC tissue samples. The KPNbeta1 expression was significantly associated with histological differentiation. The levels of KPNbeta1 were significantly correlated with histological grade (P = 0.03), metastasis (P = 0.01), vein invasion (P = 0.04) and tumor size (P = 0.01) in HCC samples. Serum starvation assay proved that KPNbeta1 was arrested in G1 phase and was gradually reduced by refeeding serum. Moreover, the knockdown of KPNbeta1 induced cell proliferation arrest in HepG2 cell. Western blot analyses showed that KPNbeta1 was correlated with NF-kB signaling pathway. CONCLUSIONS: Our datum showed that KPNbeta1 expression was up regulated in HCC tissue samples and increasing HCC cells growth and the KPNbeta1 expression was associated with poor survival. KPNbeta1 may take part in the pathogenesis of hepatocellular carcinoma via NF-kB signaling pathway and serve as an independent prognostic indicator and a novel therapeutic target for HCC. PMID- 25794492 TI - Construction, expression, and function of 6B11ScFv-mIL-12, a fusion protein that attacks human ovarian carcinoma. AB - We previously produced an anti-idiotypic monoclonal antibody, 6B11, which mimics ovarian cancer antigen CA166-9 and induces cellular and humoral immunity. Here, to enhance the immunogenicity of 6B11, we constructed the 6B11ScFv-mIL-12 fusion protein (FP), by fusing single-chain fragment of 6B11 variable region (6B11ScFv) with mouse interleukin-12 (mIL-12), which was expressed in eukaryotic 293EBNA cells transfected with pSBI vectors. A binding activity assay showed 6B11ScFv-mIL 12 to have activities of both 6B11 and mIL-12-it specifically bound both ovarian monoclonal antibody COC166-9 and rabbit anti-mouse IL-12 antibody. The immune activity assay showed 6B11ScFv-mIL-12 to promote proliferation of lymphocytes stimulated by phytohemagglutinin, increase the absolute numbers and percentages of CD3(-)/CD56(+) natural killer cells and CD3(+)/CD56(+) natural killer T cells among peripheral lymphocytes, and increase interferon-gamma. The FP was specifically cytotoxic to the CA166-9(+) ovarian cancer cell lines HOC1A and SKOV3 and inhibited growth of ID8 subcutaneous tumors in C57BL/6J mice. This study provides an experimental basis for clinical use of 6B11ScFv-mIL-12 in ovarian cancer therapy. To our knowledge, this is the first report of a fusion protein from an anti-idiotypic antibody and IL-12. PMID- 25794493 TI - A preliminary health survey of the hermit crab, Pagurus bernhardus, on the southwest coast of Ireland. AB - During October and November of 2011 and 2012, 229 hermit crabs, Pagurus bernhardus, were randomly collected from the intertidal shore at three locations along the southwest coast of Ireland. This is the first survey to assess the health status of this crustacean in Ireland. Carapace length and the sex of each crab were recorded. Crabs were screened for parasites by histology and the intensity and prevalence of infection was determined. Crabs of varying carapace length were screened. The only parasite observed in the crabs was Microphallus sp., the first record of this digenetic trematode in P. bernhardus in Europe. PMID- 25794495 TI - Incremental Sentence Processing in Japanese: A Maze Investigation into Scrambled and Control Sentences. AB - This study investigates preverbal structural and semantic processing in Japanese, a head-final language, using the maze task. Two sentence types were tested-simple scrambled sentences (Experiment 1) and control sentences (Experiment 2). Experiment 1 showed that even for simple, mono-clausal Japanese sentences, (1) there are online processing costs associated with parsing noncanonical word orders and (2) these costs are incurred during the incremental integration of constituents into developing sentence representations. Experiment 2 indicated (1) that antecedents are provisionally assigned to empty subjects in Japanese control sentences before verb information becomes available and (2) that this process is guided by an object control bias. Taken together, these findings are interpreted to suggest an important role for preverbal analysis in the processing of displaced constituents and of referential properties for empty elements in head final languages. PMID- 25794496 TI - Biafine topical emulsion accelerates excisional and burn wound healing in mice. AB - Macrophages play a fundamental role in wound healing; therefore, employing a strategy that enhances macrophage recruitment would be ideal. It was previously suggested that the mechanism by which Biafine topical emulsion improves wound healing is via enhanced macrophage infiltration into the wound bed. The purpose of this study was to confirm this observation through gross and histologic assessments of wound healing using murine full-thickness excisional and burn wound models, and compare to common standards, Vaseline and silver sulfadiazine (SSD). Full-thickness excisional and burn wounds were created on two groups of 60 mice. In the excisional arm, mice were divided into untreated control, Biafine, and Vaseline groups. In the burn arm, mice were divided into untreated control, Biafine, and SSD groups. Daily treatments were administered and healing was measured over time. Wound tissue was excised and stained to appropriately visualize morphology, collagen, macrophages, and neutrophils. Collagen deposition was measured and cell counts were performed. Biafine enhanced wound healing in murine full-thickness excisional and burn wounds compared to control, and surpassed Vaseline and SSD in respective wound types. Biafine treatment accelerated wound closure clinically, with greater epidermal/dermal maturity, granulation tissue formation, and collagen quality and arrangement compared to other groups histologically. Biafine application was associated with greater macrophage and lower neutrophil infiltration at earlier stages of healing when compared to other study groups. In conclusion, Biafine can be considered an alternative topical therapy for full-thickness excisional and burn wounds, owing to its advantageous biologically based wound healing properties. PMID- 25794494 TI - Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors. AB - The human thymus supports the production of self-tolerant T cells with competent and regulatory functions. Various cellular components of the thymic microenvironment such as thymic epithelial cells (TEC) and dendritic cells play essential roles in thymic T cell differentiation. The multiple cellular events occurring during thymic T cell and TEC differentiation involve proteins regulating cell cycle and apoptosis. Dysregulation of the cell cycle and apoptosis networks is involved in the pathogenesis of thymic epithelial tumors (TET) which are divided into two broad categories, thymomas and thymic carcinomas. The present review focuses on the usefulness of the analysis of the expression patterns of major cell cycle and apoptosis regulators in order to gain insight in the histophysiology of thymus and the histopathology, the clinical behavior and the biology of TET. PMID- 25794498 TI - Role of sodium fluoride PET imaging for identification of bony metastases in prostate cancer patients. AB - Sodium fluoride (Na-F) PET/CT is an imaging technique which allows radiolabeled fluoride to help detect areas of bone turnover. Detecting metastatic prostate cancer earlier than is currently possible with standard imaging may help prevent unnecessary morbidity for patients and improve staging in an effort to more accurately select the appropriate therapy at an appropriate time. Na-F PET/CT has been investigated as a means to help detect osseous metastatic disease in prostate cancer. It is still unclear which clinical circumstances are beneficial for a patient to undergo Na-F PET/CT in addition to, or instead of, the current standard imaging. This review examines the most recent publications related to this topic. PMID- 25794497 TI - Observational clinical study on the effects of different dosing regimens on vancomycin target levels in critically ill patients: Continuous versus intermittent application. AB - Different dosing regimens for vancomycin are in clinical use: intermittent infusion and continuous administration. The intention of using these different dosing regimens is to reduce toxicity, to achieve target levels faster and to avoid treatment failure. The aim of this phase IV study was to compare safety and effectiveness in both administration regimens. The study was conducted in 2010 and 2011 in three postoperative intensive care units (ICUs) in a tertiary care university hospital in Berlin, Germany. Adult patients with vancomycin therapy and therapeutic drug monitoring were included. Out of 675 patients screened, 125 received vancomycin therapy, 39% with intermittent and 61% with continuous administration. Patients with continuous administration achieved target serum levels significantly earlier (median day 3 versus 4, p=0.022) and showed fewer sub-therapeutic serum levels (41% versus 11%, p<0.001). ICU mortality rate, duration of ICU stay and duration of ventilation did not differ between groups. Acute renal failure during the ICU stay occurred in 35% of patients with intermittent infusion versus 26% of patients with continuous application (p=0.324). In conclusion, continuous administration of vancomycin allowed more rapid achievement of targeted drug levels with fewer sub-therapeutic vancomycin levels observed. This might indicate that patients with more severe infections or higher variability in renal function could benefit from this form of administration. PMID- 25794499 TI - Transurethral endoscopic treatment of seminal vesicle cysts (report of seven cases). AB - OBJECTIVE: Seminal vesicle cysts are a rare disorder of the male reproductive system. The goal of this report was to summarize the radiological manifestations and transurethral endoscopic treatment of large seminal vesicle cysts. MATERIALS AND METHODS: The clinical data of seven cases of giant seminal vesicle cysts, including their symptoms, radiological images, transurethral endoscopic treatment, and postoperative follow-up, were retrospectively reviewed. RESULTS: Computerized tomography and magnetic resonance imaging (MRI) demonstrated the cysts behind the bladder, above the prostate, and away from the midline. The lesions ranged in size from 8.26 cm * 7.98 cm * 4.85 cm to 9.27 cm * 8.95 cm * 8.15 cm. Two cases were associated with ipsilateral renal and ureteral agenesis and were classified as congenital malformations. The other five cases were simple seminal vesicle cysts thought to be secondary to acquired ejaculatory duct obstruction. All seven cases were successfully treated using transurethral endoscopic unroofing with cautery of the mucosa. All the seminal vesicle cysts were confirmed by pathologic examination. No malignant disease was found. All preoperative symptoms resolved after surgery. No complications were observed. No patient developed abnormalities of erection, ejaculation, or orgasm. No bladder or rectal injuries were noted. The seminal vesicle cysts were significantly decreased in size or absent 3-6 months after treatment. CONCLUSION: MRI best characterized seminal vesical cysts and their cause. Transurethral unroofing with cautery of the mucosa is an extension of well-accepted cystoscopic techniques. It is safe, easy to perform, and effective. It is the preferred method for the treatment of large seminal vesicle cysts. PMID- 25794500 TI - Biological potential of carbazole derivatives. AB - Carbazole skeleton is the key structural motif of many biologically active compounds including synthetic and natural products. Over the past several years, a large number of research highlighting the significance of carbazole derivatives has been reported in the literature. The present review focuses on the recent progress, from 2010 until now, in knowledge on various biological properties of classical, tricyclic carbazole derivatives. PMID- 25794501 TI - Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites. AB - BACKGROUND AND OBJECTIVE: Systemic therapy for metastatic cancer is currently determined exclusively by the site of tumor origin. Yet, there is increasing evidence that the molecular characteristics of metastases significantly differ from the primary tumor. We define the evolutionary dynamics of metastases that govern this molecular divergence and examine their potential contribution to variations in response to targeted therapies. METHODOLOGY: Darwinian interactions of transformed cells with the tissue microenvironments at primary and metastatic sites are analyzed using evolutionary game theory. Computational models simulate responses to targeted therapies in different organs within the same patient. RESULTS: Tumor cells, although maximally fit at their primary site, typically have lower fitness on the adaptive landscapes offered by the metastatic sites due to organ-specific variations in mesenchymal properties and signaling pathways. Clinically evident metastases usually exhibit time-dependent divergence from the phenotypic mean of the primary population as the tumor cells evolve and adapt to their new circumstances. In contrast, tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence. Thus, metastases in the liver from different primary tumors and even in different hosts will evolve toward similar adaptive phenotypes. The combination of evolutionary divergence from the primary cancer phenotype and convergence towards similar adaptive strategies in the same tissue cause significant variations in treatment responses particularly for highly targeted therapies. CONCLUSION AND IMPLICATIONS: The results suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ. PMID- 25794502 TI - The capsule biosynthesis locus of Haemophilus influenzae shows conspicuous similarity to the corresponding locus in Haemophilus sputorum and may have been recruited from this species by horizontal gene transfer. AB - The newly described species Haemophilus sputorum has been cultured from the upper respiratory tract of humans and appears to have little pathogenic potential. The species encodes a capsular biosynthesis locus of approximately 12 kb composed of three distinct regions. Region I and III genes, involved in export and processing of the capsular material, show high similarity to the corresponding genes in capsulate lineages of the pathogenic species Haemophilus influenzae; indeed, standard bexA and bexB PCRs for detection of capsulated strains of H. influenzae give positive results with strains of H. sputorum. Three ORFs are present in region II of the sequenced strain of H. sputorum, of which a putative phosphotransferase showed homology with corresponding genes from H. influenzae serotype c and f. Phylogenetic analysis of housekeeping genes from 24 Pasteurellaceae species showed that H. sputorum was only distantly related to H. influenzae. In contrast to H. influenzae, the capsule locus in H. sputorum is not associated with transposases or other transposable elements. Our data suggest that the capsule locus of capsulate lineages of H. influenzae may have been recruited relatively recently from the commensal species H. sputorum by horizontal gene transfer. PMID- 25794503 TI - Insulin has never become a cheap generic drug in the US because of companies' small changes to "evergreen" the patent. PMID- 25794505 TI - Perioperative fluid management: science, art or random chaos? PMID- 25794508 TI - Use of double stiff wire allows successful transfemoral transcatheter aortic valve implantation through extreme thoracic aorta tortuosity. PMID- 25794507 TI - Temperature as a risk factor for hospitalisations among young children in the Mekong Delta area, Vietnam. AB - BACKGROUND: The Mekong Delta is the most vulnerable region to climate change in South-East Asia; however, the association between climate and children's health has rarely been studied in this region. OBJECTIVE: We examined the short-term association between daily temperature and hospital admissions for all causes, gastrointestinal and respiratory infection, among young children in the Mekong Delta area in Vietnam. METHODS: Daily paediatric hospital admissions and meteorological data were obtained from January 2008 to December 2012. A time series approach was used with a combination of a Poisson regression and constrained distributed lag models to analyse the data. The long-term and seasonal trends, as well as other time-varying covariates, were adjusted using spline functions. Temperature--pediatric admission relationship was evaluated by age-specific (0-2 and 3-5-year-olds) and cause of admission groupings. RESULTS: A 1 degrees C increase in the 2-day moving average temperature was significantly associated with a 3.4% (95% CI 1.2% to 5.5%), 4.6% (95% CI 2.2% to 7.3%), 2.6% (95% CI 0.6% to 4.6%), 4.4% (95% CI 0.6% to 8.2%) and 3.8%(95% CI 0.4% to 7.2%) increase in hospital admissions with 0-2-year-old children, 3-5-year-old children, all causes, gastrointestinal infection and respiratory infection, respectively. The cumulative effects from 1-day to 6-day moving average temperature on hospital admissions were greater for 3-5-year-old children and gastrointestinal infection than for 0-2-year-old children and other causes. CONCLUSIONS: Temperature was found to be significantly associated with hospital admissions in young children with the highest association between temperature and gastrointestinal infection. The government agencies of Mekong Delta should implement measures to protect children from the changing temperature conditions related to climate change. PMID- 25794506 TI - Prevalence and correlates of latent tuberculosis infection among employees of a high security prison in Malaysia. AB - OBJECTIVES: Although prison employees share the same tuberculosis (TB) risk environment with prisoners, the magnitude of TB problems among prison employees is unknown in most resource-limited prisons. This survey was conducted to investigate the prevalence and correlates of tuberculin skin test (TST) positivity among employees in Malaysia's largest prison. METHODS: Consented, full time prison employees were interviewed using a structured questionnaire that included sociodemographic data, history of working in the correctional system and TB-related risk. TST was placed intradermally and read after 48-72 h. Induration size of >=10 mm was considered positive. Logistic regression analyses were conducted to explore associations with TST positivity. RESULTS: Of the 445 recruited prison employees, 420 (94.4%) had complete data. Most were young (median=30.0 years) men (88.8%) who had only worked at this prison (76.4%) for a median total employment period of 60 months (IQR 34.5-132.0). The majority were correctional officers, while civilian employees represented only 7.6% of the sample. Only 26 (6.2%) reported having ever been screened for TB since employment. Prevalence of TST positivity was 81% and was independently associated with longer (>=12 months) prison employment (AOR 4.9; 95% CI 1.5 to 15.9) and current tobacco smoking (AOR=1.9, 95% CI 1.2 to 3.2). CONCLUSIONS: Latent TB prevalence was high in this sample, approximating that of prisoners in this setting, perhaps suggesting within prison TB transmission in this facility. Formal TB control programmes for personnel and prisoners alike are urgently needed within the Malaysian correctional system. PMID- 25794509 TI - Magnetic resonance imaging of bioresorbable vascular scaffolds: potential approach for noninvasive evaluation of coronary patency. PMID- 25794510 TI - Alzheimer's disease and the elderly in Israel: are we paying enough attention to the topic in the Arab population? AB - With the continuing rise in the elderly population, Alzheimer's disease (AD) and dementia represent an increasing public health concern worldwide. In recent years, research has focused on the relationship between AD and ethnicity. Israel, a multiethnic society, provides a natural laboratory for research on ethnicity and health. The largest ethnic group is that of Israeli Jews, followed by Arab citizens, mostly Arab Muslims, with smaller numbers of Arab Christians in addition to Druze, Circassians, and others. The aim of this review is to clarify ethnic differences in prevalence and risk factors for Alzheimer's disease. We review available literature on ethnic differences in epidemiologic and risk factors for Alzheimer's disease, including genetic differences as well as disparities in health access and quality of health services. We will conclude with research and policy implications. PMID- 25794504 TI - A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation. AB - Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. PMID- 25794511 TI - Cognitive screening in persons with chronic diseases in primary care: challenges and recommendations for practice. AB - An integrative literature review was performed to identify the challenges in current cognitive screening. The aim of the review was to serve as an evaluative resource to guide clinicians in the selection of the best available cognitive screening measures for early assessment of mild cognitive impairment (MCI) in people with chronic diseases. The review classified the available cognitive screening measures according to purpose, time to administer, and cognitive domains assessed as: 1) simple/ brief cognitive screening measures, 2) disease specific screening measures, 3) domain specific screening measures, 4) self administered screening measures, and 5) technology-based screening measures. There is no single optimal cognitive measure for all patient populations and settings. Although disease specific cognitive screening measures are optimal, there is a lack of validated screening measures for many chronic diseases. Technology-based screening measure is a promising avenue for increasing the accessibility of cognitive screening. Future work should focus on translating available screening measures to mobile technology format to enhance the utility in busy primary care settings. Early cognitive screening in persons with chronic disease should enhance appropriate referrals for detailed neurocognitive examination and cognitive interventions to preserve and or minimize cognitive decline. PMID- 25794512 TI - Waiting to return to normal: an exploration of family systems intervention in childhood cancer. AB - The illness suffering of families in childhood cancer is characterized in part by a loss of family normalcy. Hermeneutic phenomenology and family process research methods were used to analyze videotaped family intervention sessions and post intervention family/clinician interviews. Within this article, some of the findings from the larger doctoral study that focused on the illness suffering of family members and relational, family systems intervention based on the Illness Beliefs Model are described. Although the larger study included findings of family interventions that addressed several aspects of the illness suffering experienced, this article details specific findings related to the theme of the loss of family normalcy and a longing to return home. Family systems intervention practices which facilitated a lessening of illness suffering included the following: offering new interpretations of suffering within a reflecting team, articulating family strength, sensitively acknowledging the illness suffering, and eliciting the experiences of family members in a shared therapeutic conversation. PMID- 25794513 TI - Families living with chronic illness: beliefs about illness, family, and health care. AB - Beliefs can be described as the lenses through which we view the world. With emerging illness, beliefs about the illness experience become important for nurses to understand to enhance well-being and healing. The aim of this study was to illuminate illness beliefs of families living with chronic illness. A qualitative design was chosen, including repeated narrative research interviews with seven Swedish families living with chronic illness. Hermeneutic analysis was used to interpret the transcribed family interviews. The result described beliefs in families, both within and across families. Both core beliefs and secondary beliefs about illness, family, and health care were revealed. Illness beliefs have importance for how families respond to and manage situations that arise from their encounters with illness. Nurses have to make space for and listen to families' stories of illness to become aware of what beliefs may support and encourage family well-being and healing. The Illness Beliefs Model provides a touchstone whereby nurses can distinguish both individual and shared beliefs within families living with chronic illness and provide ideas for family intervention if needed. PMID- 25794514 TI - Comparative effectiveness of screening strategies for Lynch syndrome. AB - BACKGROUND: Colorectal cancer is the second leading cause of cancer death in the United States. Approximately 3% of colorectal cancers are associated with Lynch Syndrome. Controversy exists regarding the optimal screening strategy for Lynch Syndrome. METHODS: Using an individual level microsimulation of a population affected by Lynch syndrome over several years, effectiveness and cost effectiveness of 21 screening strategies were compared. Modeling assumptions were based upon published literature, and sensitivity analyses were performed for key assumptions. In a two-step process, the number of Lynch syndrome diagnoses (Step 1) and life-years gained as a result of foreknowledge of Lynch syndrome in otherwise healthy carriers (Step 2) were measured. RESULTS: The optimal strategy was sequential screening for probands starting with a predictive model, then immunohistochemistry for mismatch repair protein expression (IHC), followed by germline mutation testing (incremental cost-effectiveness ratio [ICER] of $35 143 per life-year gained). The strategies of IHC + BRAF, germline testing and universal germline testing of colon cancer probands had ICERs of $144 117 and $996 878, respectively. CONCLUSIONS: This analysis suggests that the initial step in screening for Lynch Syndrome should be the use of predictive models in probands. Universal tumor testing and general population screening strategies are not cost-effective. When family history is unavailable, alternate strategies are appropriate. Documentation of family history and screening for Lynch Syndrome using a predictive model may be considered a quality-of-care measure for patients with colorectal cancer. PMID- 25794515 TI - Family matters in lynch syndrome. PMID- 25794516 TI - Development of paradoxical low-flow, low-gradient severe aortic stenosis. AB - OBJECTIVE: Among patients with severe aortic stenosis (sAS) and preserved LVEF, those with low-flow, low-gradient sAS (LFLG-sAS) have an adverse prognosis. It has been proposed that LFLG-sAS represents an end-stage point of sAS, but longitudinal information has not been described. The aim was to determine whether LFLG-sAS represents an end-stage consequence of normal-flow, high-gradient sAS (NFHG-sAS) or a different entity. METHODS: From our transthoracic echocardiogram (TTE) database, we identified patients with sAS (aortic valve area <1 cm(2)) and preserved LVEF (>=50%), and from these, patients with LFLG-sAS (stroke volume index <35 mL/m(2) and mean transvalvular gradient <40 mm Hg) who had >=1 additional TTE within five years prior to the index TTE. Patients were age/sex/date matched 2:1 with patients with NFHG-sAS and normal-flow, low gradient (NFLG)-sAS who also had >=1 TTE. Included were 1203 TTEs (383 index studies and 820 preceding studies). RESULTS: In 78 patients with LFLG-sAS, an HG stage preceded the index TTE in only 4 (5%). During the five years preceding the index TTE, patients with LFLG-sAS developed increasing relative wall thickness (0.42 to 0.49; p<0.001) without change in LV mass index. Patients with NFHG-sAS had a marked increase in LV mass index (87 to 115 g/m(2); p<0.001). Patients with LFLG-sAS demonstrated the greatest reduction in LV end-diastolic diameters (-3 vs -1 for NFLG-sAS vs +2 mm for NFHG-sAS; p=0.001), deceleration time (-55 vs -3 vs +3 ms, respectively; p<0.01) and LVEF (-4 vs 0 vs 0%, respectively; p=0.01). CONCLUSIONS: LFLG-sAS is a distinct presentation of sAS preceded by a unique remodelling pathway and is uncommonly preceded by an HG stage. PMID- 25794517 TI - Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland. AB - OBJECTIVE: To assess safety up to 1 year of follow-up associated with prasugrel and clopidogrel use in a prospective cohort of patients with acute coronary syndromes (ACS). METHODS: Between 2009 and 2012, 2286 patients invasively managed for ACS were enrolled in the multicentre Swiss ACS Bleeding Cohort, among whom 2148 patients received either prasugrel or clopidogrel according to current guidelines. Patients with ST-elevation myocardial infarction (STEMI) preferentially received prasugrel, while those with non-STEMI, a history of stroke or transient ischaemic attack, age >=75 years, or weight <60 kg received clopidogrel or reduced dose of prasugrel to comply with the prasugrel label. RESULTS: After adjustment using propensity scores, the primary end point of clinically relevant bleeding events (defined as the composite of Bleeding Academic Research Consortium, BARC, type 3, 4 or 5 bleeding) at 1 year, occurred at a similar rate in both patient groups (prasugrel/clopidogrel: 3.8%/5.5%). Stratified analyses in subgroups including patients with STEMI yielded a similar safety profile. After adjusting for baseline variables, no relevant differences in major adverse cardiovascular and cerebrovascular events were observed at 1 year (prasugrel/clopidogrel: cardiac death 2.6%/4.2%, myocardial infarction 2.7%/3.8%, revascularisation 5.9%/6.7%, stroke 1.0%/1.6%). Of note, this study was not designed to compare efficacy between prasugrel and clopidogrel. CONCLUSIONS: In this large prospective ACS cohort, patients treated with prasugrel according to current guidelines (ie, in patients without cerebrovascular disease, old age or underweight) had a similar safety profile compared with patients treated with clopidogrel. CLINICAL TRIAL REGISTRATION NUMBER: SPUM-ACS: NCT01000701; COMFORTABLE AMI: NCT00962416. PMID- 25794518 TI - The Feasibility of Reducing Sitting Time in Overweight and Obese Older Adults. AB - BACKGROUND: Overweight and obese older adults have high sedentary time. We tested the feasibility and preliminary effects of a sedentary time reduction intervention among adults over age 60 with a body mass index over 27 kg/m2 using a nonrandomized one-arm design. METHODS: Participants (N = 25, mean age = 71.4, mean body mass index = 34) completed an 8-week theory-based intervention targeting reduced total sitting time and increased sit-to-stand transitions. An inclinometer (activPAL) measured the primary outcomes, change in total sitting time and sit-to-stand transitions. Secondary outcomes included physical activity (ActiGraph GT3X+ accelerometer), self-reported sedentary behaviors, physical function (Short Physical Performance Battery), depressive symptoms (8-item Patient Health Questionnaire), quality of life (PROMIS), and study satisfaction. Paired t tests examined pre-post test changes in sitting time, sit-to-stand transitions, and secondary outcomes. RESULTS: Inclinometer measured sitting time decreased by 27 min/day (p < .05) and sit-to-stand transitions increased by 2 per day (p > .05), while standing time increased by 25 min/day (p < .05). Accelerometer measured sedentary time, light-intensity, and moderate-to-vigorous physical activity improved (all p values <= .05). Self-reported sitting time, gait speed, and depressive symptoms also improved (all p values < .05). Effect sizes were small. Study satisfaction was high. CONCLUSIONS: Reducing sitting time is feasible, and the intervention shows preliminary evidence of effectiveness among older adults with overweight and obesity. Randomized trials of sedentary behavior reduction in overweight and obese older adults, most of whom have multiple chronic conditions, may be promising. PMID- 25794519 TI - Disparities in the Population Distribution of African American and Non-Hispanic White Smokers Along the Quitting Continuum. AB - PURPOSE: To examine disparities and changes over time in the population-level distribution of smokers along a cigarette quitting continuum among African American smokers compared with non-Hispanic Whites. METHODS: Secondary data analyses of the 1999, 2002, 2005, and 2008 California Tobacco Surveys (CTS). The CTS are large, random-digit-dialed, population-based surveys designed to assess changes in tobacco use in California. The number of survey respondents ranged from n = 6,744 to n = 12,876 across CTS years. Current smoking behavior (daily or nondaily smoking), number of cigarettes smoked per day, intention to quit in the next 6 months, length of most recent quit attempt among current smokers, and total length of time quit among former smokers were assessed and used to recreate the quitting continuum model. RESULTS: While current smoking rates were significantly higher among African Americans compared with non-Hispanic Whites across all years, cigarette consumption rates were lower among African Americans in all years. There were significant increases in the proportion of former smokers who had been quit for at least 12 months from 1999 (African Americans, 26.8% +/- 5.5%; non-Hispanic Whites, 36.8% +/- 1.6%) to 2008 (African Americans, 43.6% +/- 4.1%; non-Hispanic Whites, 57.4% +/- 2.9%). The proportion of African American former smokers in each CTS year was significantly lower than that of non Hispanic Whites. CONCLUSIONS: Despite positive progression along the quitting continuum for both African American and non-Hispanic White smokers, the overall distribution was less favorable for African Americans. The lower smoking consumption levels among African Americans, combined with the lower rates of successful smoking cessation, suggest that cigarette addiction and the quitting process may be different for African American smokers. PMID- 25794520 TI - Sugar-Sweetened Beverage Consumption by Adult Caregivers and Their Children: The Role of Drink Features and Advertising Exposure. AB - OBJECTIVE: To examine how parents' beliefs about beverage attributes and exposure to sugar-sweetened beverage (SSB) advertising are associated with parents' and their children's SSB consumption. DESIGN: Cross-sectional representative telephone survey of Philadelphia parents in households with children between the ages of 3 and 16 years. PARTICIPANTS: Three hundred and seventy-one randomly selected survey respondents. The response rate was 27% using the American Association for Public Opinion Research RR3 formula. MAIN OUTCOME MEASURES: SSB consumption, health ratings of SSBs, exposure to SSB ads, and exposure to anti SSB public service advertisements. ANALYSIS: Seemingly unrelated regression was used to correct for Type I error and significance levels were set at .05 or less. RESULTS: Assessment of SSB "healthiness" was associated with the increased adult consumption of SSBs for three of the five SSBs and associated with children's consumption for all four SSBs with child consumption data. For both groups, ratings of SSB sugar and caloric content were not related to consumption. Adult exposure to SSB-specific advertising was related to consumption for three of five SSBs and two of four SSBs consumed by children. CONCLUSIONS AND IMPLICATIONS: These results suggest that sugar and calories are not relevant to consumption, absent an explicit connection to a healthiness evaluation of SSBs. PMID- 25794521 TI - Piezoelectric-driven self-charging supercapacitor power cell. AB - In this work, we have fabricated a piezoelectric-driven self-charging supercapacitor power cell (SCSPC) using MnO2 nanowires as positive and negative electrodes and a polyvinylidene difluoride (PVDF)-ZnO film as a separator (as well as a piezoelectric), which directly converts mechanical energy into electrochemical energy. Such a SCSPC consists of a nanogenerator, a supercapacitor, and a power-management system, which can be directly used as a power source. The self-charging capability of SCSPC was demonstrated by mechanical deformation under human palm impact. The SCSPC can be charged to 110 mV (aluminum foil) in 300 s under palm impact. In addition, the green light emitting diode glowed using serially connected SCSPC as the power source. This finding opens up the possibility of making self-powered flexible hybrid electronic devices. PMID- 25794522 TI - Feelings and Intersubjectivity in Qualitative Suicide Research. AB - In this article, we explore how feelings permeated our qualitative research on suicide. Drawing on phenomenological theory, we argue for the epistemic and ethical importance of the feelings that emerge through research encounters, considering them to be embodied, intersubjective, and multilayered, and requiring careful interpretation through a "reflexivity of feelings." We sketch a tentative framework of the ways that we experienced feelings in our research and give three in-depth examples to illustrate some of the different layers and types of feelings we identified. We reflexively interpret these feelings and their role in our analysis and then discuss some of the ethical and methodological issues related to examining feelings in suicide research, and research more generally. PMID- 25794523 TI - Using Sandelowski and Barroso's Meta-Synthesis Method in Advancing Qualitative Evidence. AB - The purpose of this article was to iteratively account for and discuss the handling of methodological challenges in two qualitative research syntheses concerning patients' experiences of hospital transition. We applied Sandelowski and Barroso's guidelines for synthesizing qualitative research, and to our knowledge, this is the first time researchers discuss their methodological steps. In the process, we identified a need for prolonged discussions to determine mutual understandings of the methodology. We discussed how to identify the appropriate qualitative research literature and how to best conduct exhaustive literature searches on our target phenomena. Another finding concerned our status as third-order interpreters of participants' experiences and what this meant for synthesizing the primary findings. Finally, we discussed whether our studies could be classified as metasummaries or metasyntheses. Although we have some concerns regarding the applicability of the methodology, we conclude that following Sandelowski and Barroso's guidelines contributed to valid syntheses of our studies. PMID- 25794524 TI - A Grounded Theory of Students' Long-Distance Coping With a Family Member's Cancer. AB - In this study, we explore how family members cope with one source of stress cancer diagnosis and treatment. We suggest that coping away from one's family is characterized by constraints that are not common to proximal coping. We conducted six focus groups with college students (N = 21) at a university in the United States to investigate their long-distance coping experiences and used grounded theory methods to develop a model of college students' long-distance coping. Negotiating the tension between being here (at school) and being there (at home) was central to their experiences. Participants described four manifestations of their negotiation between here and there (i.e., expressing/hiding emotion, longing to care for the patient there/avoiding responsibility here, feeling shock at degeneration there/escaping degeneration by being here, and lacking information from there) and three strategies they used to cope (i.e., being here and withdrawing, being here and doing school, and seeking/not seeking support). PMID- 25794525 TI - Photovoice: Assessing the Long-Term Impact of a Disaster on a Community's Quality of Life. AB - Photovoice is a qualitative method of inquiry whereby individuals can document their lived experiences, particularly individuals whose voices are not typically heard in regard to promoting social change and policy development. We used photovoice to elicit major themes regarding community members' perceptions of the long-term impact on their quality of life as a deadly technological disaster hit a small, rural town in South Carolina. Overall, participants photographed more negative images than positive. Overarching themes included residential and business vacancies, economic decline, the need for clean-up and modernization, attention to wellness or rehabilitation, and concerns for safety. Emergency response agencies should consider the themes elicited from these community residents to help identify where to focus disaster response efforts both in the immediate aftermath and during the long-term recovery period of technological disasters, particularly in underserved, rural communities. PMID- 25794526 TI - Proximity of couples to parents: influences of gender, labor market, and family. AB - We use household survey data from the UK to study how close middle-aged men and women in partnerships live to their parents and their partner's parents. We find a slight tendency for couples to live closer to the woman's parents than the man's. This tendency is more pronounced among couples in which neither partner has a college degree and in which there is a child. In other respects, proximity to parents is gender-neutral, with the two partners having equal influence on intergenerational proximity. Better-educated couples live farther from their parents. And although certain family characteristics matter, intergenerational proximity is primarily driven by factors affecting mobility over long distances, which are mainly associated with the labor market, as opposed to gender or family circumstances. PMID- 25794527 TI - On-demand delivery of single DNA molecules using nanopipets. AB - Understanding the behavioral properties of single molecules or larger scale populations interacting with single molecules is currently a hotly pursued topic in nanotechnology. This arises from the potential such techniques have in relation to applications such as targeted drug delivery, early stage detection of disease, and drug screening. Although label and label-free single molecule detection strategies have existed for a number of years, currently lacking are efficient methods for the controllable delivery of single molecules in aqueous environments. In this article we show both experimentally and from simulations that nanopipets in conjunction with asymmetric voltage pulses can be used for label-free detection and delivery of single molecules through the tip of a nanopipet with "on-demand" timing resolution. This was demonstrated by controllable delivery of 5 kbp and 10 kbp DNA molecules from solutions with concentrations as low as 3 pM. PMID- 25794528 TI - Pre-cultivation of adipose tissue-derived microvascular fragments in porous scaffolds does not improve their in vivo vascularisation potential. AB - Adipose tissue-derived microvascular fragments represent promising vascularisation units for implanted tissue constructs. However, their reassembly into functional microvascular networks takes several days, during which the cells inside the implants are exposed to hypoxia. In the present study, we analysed whether this critical phase may be overcome by pre-cultivation of fragment-seeded scaffolds prior to their implantation. Green fluorescent protein (GFP)-positive microvascular fragments were isolated from epididymal fat pads of male C57BL/6 TgN (ACTB-EGFP) 1Osb/J mice. Nano-size hydroxyapatite particles/poly (ester urethane) scaffolds were seeded with these fragments and cultivated for 28 days. Subsequently, these scaffolds or control scaffolds, which were freshly seeded with GFP-positive microvascular fragments, were implanted into the dorsal skinfold chamber of C57BL/6 wild-type mice to study their vascularisation and incorporation by means of intravital fluorescence microscopy, histology and immunohistochemistry over 2 weeks. Pre-cultivation of microvascular fragments resulted in the loss of their native vessel morphology. Accordingly, pre cultivated scaffolds contained a network of individual CD31/GFP-positive endothelial cells with filigrane cell protuberances. After implantation into the dorsal skinfold chamber, these scaffolds exhibited an impaired vascularisation, as indicated by a significantly reduced functional microvessel density and lower fraction of GFP-positive microvessels in their centre when compared to freshly seeded control implants. This was associated with a deteriorated incorporation into the surrounding host tissue. These findings indicate that freshly isolated, non-cultivated microvascular fragments should be preferred as vascularisation units. This would also facilitate their use in clinical practice during intra operative one-step procedures. PMID- 25794529 TI - Intervertebral disc repair with activated nucleus pulposus cell transplantation: a three-year, prospective clinical study of its safety. AB - Degeneration of the lumbar intervertebral discs is irreversible, with no treatment currently available. Building upon experimental studies that demonstrated the importance of the nucleus pulposus (NP) in preserving disc structure, we demonstrated that reinsertion of NP cells slowed further disc degeneration and that direct cell-to-cell contact co-culture with mesenchymal stromal cells (MSCs) significantly upregulated the viability of NP cells in basic and pre-clinical studies in vitro and in vivo using animal models and human cells. Here, we report a 3-year result of a prospective clinical study, aimed to assess the safety and efficacy of activated NP cell transplantation in the degenerate lumbar intervertebral disc. Candidates were 9 patients aged 20-29 years who had Pfirrmann's grade III disc degeneration at the level adjacent to the level scheduled for posterior lumbar intervertebral fusion. Viable NP cells from the fused disc were co-cultured in direct contact with autologous bone marrow-derived MSCs. One million activated NP cells were transplanted into the degenerated disc adjacent to the fused level at 7 d after the first fusion surgery. No adverse effects were observed during the 3-year follow-up period. Magnetic resonance imaging did not show any detrimental effects to the transplanted discs and revealed a mild improvement in 1 case. No cases reported any low back pain. Our clinical study confirmed the safety of activated NP cell transplantation, and the findings suggest the minimal efficacy of this treatment to slow the further degeneration of human intervertebral discs. PMID- 25794530 TI - Investigation of orofacial stem cell niches and their innervation through microfluidic devices. AB - Stem cell-based mediated therapies represent very promising approaches for tissue regeneration and are already applied with success in clinics. These therapeutic approaches consist of the in vitro manipulation of stem cells and their consequent administration to patients as living and dynamic biological agents. Nevertheless, the deregulation of stem cells function might result in the generation of pathologies such as tumours or accelerated senescence. Moreover, different stem cells sources are needed for regeneration of specific tissues. It is thus fundamental to understand the mechanisms regulating the physiology of stem cells. Microfluidic technology can be used to mimic in vivo scenarios and allow the study of stem cell physiology at both single cell and whole stem cell niche levels.This review focuses on the potential sources of stem and progenitor cells for orofacial regeneration and the use of microfluidic technologies for the study of stem cells behaviour and stem cell niches, in the light of regenerative medicine. PMID- 25794531 TI - In vitro effect of sodium trimetaphosphate additives to conventional toothpastes on enamel demineralization. AB - OBJECTIVE: The aim of this study was to evaluate the ability of conventional toothpastes (1100 ppm F) supplemented with sodium trimetaphosphate (TMP) in demineralization. MATERIAL AND METHODS: Blocks of enamel were selected and then divided into seven experimental groups of 12: toothpaste without F and TMP (placebo), toothpaste with 1100 ppm F (1100), and toothpaste with 1100 ppm F supplemented with TMP-1 % (1100 1 % TMP), 3 % (1100 3 % TMP), 4.5 % (1100 4.5 % TMP), 6 % (1100 6 % TMP), and 9 % (1100 9 % TMP). Blocks were subjected to five pH cycles (demineralizing/remineralizing solutions) at 37 degrees C and treated with toothpaste slurries twice daily, after which the blocks were maintained for 2 days in fresh remineralizing solution. Following treatments, surface hardness (SHf) and cross-sectional hardness were determined for calculating the integrated loss of subsurface hardness (DeltaKHN). The fluoride present in the enamel was also measured. RESULTS: The SHf and DeltaKHN measurements showed that supplementation with 3 % TMP was the most effective (p < 0.001) and showed greater concentration of F in the enamel (p < 0.001). CONCLUSION: Addition of 3 % TMP to a conventional toothpaste (1100 ppm F) showed greater efficacy in reducing enamel demineralization. CLINICAL RELEVANCE: Fluoride toothpastes containing trimetaphosphate possess good anticaries potential required to reduce the prevalence of dental caries in high-risk patients. PMID- 25794532 TI - [Blister beetle dermatitis: Dermatitis linearis]. AB - Several families of beetles cause toxic reactions on exposed human skin. Cantharidin provokes nearly asymptomatic vesicles and blisters, while pederin leads to itching and burning erythema with vesicles and small pustules, later crusts. Paederi are attracted by fluorescent light especially after rain showers and cause outbreaks in regions with moderate climate. Clinical findings and patient history lead to the diagnosis: dermatitis linearis. PMID- 25794533 TI - [Recruitment problems]. PMID- 25794534 TI - Erratum to: Internalization and retrograde axonal trafficking of tetanus toxin in motor neurons and trans-synaptic propagation at central synapses exceed those of its C-terminal-binding fragments. PMID- 25794535 TI - Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity. AB - BACKGROUND: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). METHODS: Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4 AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. RESULTS: The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. CONCLUSIONS: Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors. PMID- 25794537 TI - Capsule Commentary on Andrade et al., Clinical Benefit of American College of Chest Physicians versus European Society of Cardiology Guidelines for Stroke Prophylaxis in Atrial Fibrillation. PMID- 25794536 TI - Percutaneous reconstruction of chronic total occlusion of brachiocephalic vein using transseptal needle in dialysis-dependent patient. AB - Placement of a dialysis catheter substantially increases the risk of central vein stenosis. 52-year-old female with end-stage renal disease and a right brachial cephalic hemodialysis access presented with right arm swelling. The chronic total occlusion of right brachiocephalic vein was refractory to wire traversal. Sharp recanalization of the central venous occlusion was done with transseptal needle retrogradely. The track was balloon dilated and stented. When the conventional catheters and guide wires options fail, sharp recanalization technique may be used to salvage a precious dialysis access. PMID- 25794538 TI - A Case of Subacute Ataxia in the Summertime: Tick Paralysis. AB - Tick paralysis is caused by a neurotoxin secreted in the saliva of a gravid female tick, and manifests with ataxia, areflexia, ascending paralysis, bulbar palsy, and ophthalmoparesis. An 84-year-old man presented in June in coastal Mississippi with several days of subacute ataxia, bulbar palsy, unilateral weakness, and absent deep tendon reflexes. MRI/MRA and extensive serum and cerebrospinal fluid investigations were unrevealing. His symptoms progressed over several days, until his nurse discovered and removed an engorged tick from his gluteal fold. Within hours of tick removal, his subacute symptoms completely resolved. While tick paralysis is rare in adults, it is a condition that internists should be familiar with, particularly in seasons and areas with high prevalence of disease. This case also highlights the importance of performing a thorough skin exam on patients with the aforementioned neurologic abnormalities. PMID- 25794539 TI - Immigration Policies and the U.S. Medical Education System: A Diverse Physician Workforce to Reduce Health Disparities. PMID- 25794540 TI - Transcriptional repression caused by Dof5.8 is involved in proper vein network formation in Arabidopsis thaliana leaves. AB - Vascular plants have a network of vasculature in their leaves, which supplies water and nutrients and exports photoassimilates to other tissues. The vascular network is patterned during the development of leaf primordia through the induction of provascular differentiation by auxin. Arabidopsis thaliana Dof5.8, encoding a Dof-type transcription factor, is expressed early in provascular cells under the control of the MONOPTEROS transcription factor, also known as auxin response factor 5 (ARF5). Here, we report the effect of overexpressing Dof5.8 in provascular cells on the formation of the vascular network. Overexpression of Dof5.8 inhibited the formation of higher-order veins in cotyledons and leaves, probably through transcriptional repression by Dof5.8. The expression of auxin associated transcription factor genes, DORNRoSCHEN and SHI-RELATED SEQUENCE 5, was downregulated in the Dof5.8 overexpressors, and overexpression of these genes partially rescued the impaired formation of higher-order veins in Dof5.8 overexpressing lines, suggesting that the overexpression of Dof5.8 modulates the auxin response and leads to impaired vein formation in A. thaliana. PMID- 25794542 TI - Adverse histopathological findings in glottic cancer with anterior commissure involvement. AB - Open partial horizontal laryngectomy (OPHL) specimens include cartilage and lymph nodes. Pathological adverse findings (PAF): perichondrium, cartilage, perineural invasion, microvessel spread and prelaryngeal metastases can be detected histologically. We aimed at examining PAF in OPHL specimens and examining the interdependence with oncological outcomes. Prospective analysis of 254 glottis cancers: 87-T2a, 77-T2b and 90-T3 with anterior commissure (AC) involvement treated by OPHL at tertiary referral centre between 2001 and 2008. In 38/254 patients (15 %) PAF were found (16 prelaryngeal metastases, 22 other); more often in stage T2b/T3 versus T2a (p = 0.008). PAF other than prelaryngeal metastases were found more often in T2b than T2a tumours (p = 0.005). Outcomes revealed that out of 36 patients with local recurrence, 19 had PAF. Comparison of 216 patients with no PAF and 16 patients with prelaryngeal metastases revealed, respectively: 7.9 versus 81.3 % local recurrences (p = 0.034), 3.2 versus 68.8 % nodal recurrences (p = 0.011), 90.7 versus 43.8 % of 5-year organ preservation (p = 0.021) and 92.6 versus 75 % 5-year overall survival (p = 0.022). Out of 10 patients with close margins, 1 developed the local recurrence; impact for organ preservation and overall survival was not significant. In 22/254 cases including the cartilage into the operating specimen were therapeutically meaningful; in 16/254 with prelaryngeal metastases, the impact for larynx preservation and overall survival was significant. T2b patients had higher probability of PAF than T2a. PAF significantly influenced higher local recurrence rate. This finding ensures the authors, that OPHL type II is not the "overtreatment" compared to the TLM. PMID- 25794541 TI - Peritonsillar abscess: remember to always think twice. AB - Peritonsillar abscess (PTA) is the most common complication of acute tonsillitis resulting in fever, unilateral sore throat, odynophagia and trismus. This retrospective study was undertaken to analyze the clinical courses of 775 patients with two different methods of the first-line treatment. Abscess tonsillectomy (TAC) including contralateral tonsillectomy was preferably performed between 2007 und 2010 (group A; n = 443). After that, incisional drainage (ID) was chosen as first-line treatment between 2010 and 2013 (group B; n = 332). The data of the patients were pooled from the individual charts to evaluate the prevalence of smoking habits, the incidence of the recurrence/complication rates and the number/types of surgical procedures associated with each therapy modality. Replacing TAC by ID as first-line treatment of PTA resulted in a significant decrease of days of inpatient treatment (4 vs. 7 days) and hemorrhage rate (0.3 vs. 5.1 %). A second, third and fourth surgical revision procedure was performed with comparable rates in group A (21.6; 2.4; 0.5 %) and B (21; 4.9; 0.3 %). Smoking habits were reported by almost every second patient. ID as first-line treatment of PTA is capable to reduce the hemorrhage rate and length of inpatient observation significantly. To suggest ID as first-line PTA treatment mandates a close follow-up to indicate repeated drainage of residual pus at an early stage. Further analysis is warranted to verify whether a better surveillance in an academic teaching hospital or surgical modification of the ID is followed by a higher success rate. Smoking habits are overrepresented in PTA patients. PMID- 25794543 TI - Reduced dosage of bevacizumab in treatment of vestibular schwannomas in patients with neurofibromatosis type 2. AB - Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas and other benign tumors of the central nervous system. Bevacizumab is used for treatment of progressive vestibular schwannomas, with the intent to reduce tumor size or preserve/improve hearing. Prolonged treatment can cause side effects such as hypertension and proteinuria, which can be cause for discontinuation of therapy. We report on 3 patients who were treated with bevacizumab for 66-76 months, with dose reductions that minimized side effects while sustaining the clinical effect of the antiangiogenic therapy. After dose reduction from 5 mg/kg bi- or tri-weekly to 2.5 mg bi- or tri-weekly, all patients appeared clinically stable and radiographic and audiologic follow-up showed sustained response. In conclusion, in some NF2 patients, dose reduction of bevacizumab seems to be an effective option for managing side effects. PMID- 25794544 TI - Theories on possible temporal relationships between sleep bruxism and obstructive sleep apnea events. An expert opinion. AB - BACKGROUND: Sleep bruxism (SB) is a term covering different motor phenomena with various risk and etiological factors and potentially different clinical relevance, especially as far as its possible protective role against obstructive sleep apnea (OSA) is concerned. The present expert opinion discusses the possible temporal relationships between the two phenomena. METHODS: Four hypothetical scenarios for a temporal relationship may be identified: (1) the two phenomena are unrelated; (2) the onset of the OSA event precedes the onset of the SB event within a limited time span, with SB having a potential OSA-protective role; (3) the onset of the SB event precedes the onset of the OSA event within a limited time span, with SB having an OSA-inducing effect; and (4) the onset of the OSA and SB event occurs at the same moment. RESULTS: Literature findings on the SB OSA temporal relationship are inconclusive. The most plausible hypothesis is that the above scenarios are all actually possible and that the relative predominance of one specific sequence of events varies at the individual level. SB activity may be protective against OSA by protruding the mandible and restoring airway patency in those subjects who benefit from mandibular advancement strategies or may even be related to OSA induction, as a consequence of airways' mucosae swelling resulting from a SB-induced trigeminal cardiac reflex. CONCLUSIONS: Clinicians should keep in mind that the SB-OSA relationship is complex and that interindividual differences may explain the possible different SB-OSA relationships, with particular regard to the anatomical site of obstruction. PMID- 25794546 TI - Help for Heroes: PTSD, Warrior Recovery, and the Liturgy. AB - The incidence of PTSD is on a steady rise in combative countries around the world, and civilian churches are increasingly like to encounter persons suffering from PTSD. This article will consider the ancient rituals for the purification of warriors after battle to demonstrate the responsibility of the church toward returning warriors and explore how the liturgy can function as a place for recovery. I will demonstrate how the sacraments of Reconciliation, the Eucharist, and the Anointing of the Sick function as sites of re-integration into the world the warriors have fought for, recovery from trauma, and purification after battle. PMID- 25794545 TI - Depressed Affect and Dimensions of Religiosity in Family Caregivers of Individuals with Dementia. AB - Religiosity and mood have long been recognized as associated, but some patterns of associations suggest complex relationships. Using a multidimensional measure of religiosity, we explored the possibility that dimensions of religiosity may have (1) different strengths of association and (2) directions of association with depressed mood. We measured five dimensions of religiosity in 1227 family caregivers of persons with dementia, testing associations of each dimension to caregivers' depressive symptoms. In zero-order associations, higher scores on each religiosity dimension were associated with lower depression. Yet in hierarchical multiple regressions models, adjusting for other religiosity dimensions, different dimensions showed either no independent association, an independent association, or an inverse association with depressed mood. Frequency of prayer reversed directions of association-showing higher depression in caregivers who prayed more. Findings underscore the complex and sometimes bidirectional association between depressed mood and religiosity and argue for recognition of distinct dimensions of religiosity. PMID- 25794547 TI - Shadows Along the Spiritual Pathway. AB - Contemporary spirituality discourses tend to assume that a canopy of light and love overarches all spiritual pathways. Unfortunately, the dark side of humanity cannot be spirited away so easily, and aberrations of personal spiritual development, interpersonal spiritual relationships and new spiritual movements can often be traced to the denial, repression and return of our dark side. Transpersonal psychology offers a way of approaching, reframing and redeeming the unconscious depths of our psyche, with its metaphors of shadows and daimons on the one hand, and its therapeutic practices for symbolically containing and transcending polarities on the other. In its absence, any spirituality which eulogises holistic growth is likely to engender the reverse effect. PMID- 25794548 TI - Biodegradation of the phytoestrogen luteolin by the endophytic fungus Phomopsis liquidambari. AB - Phytoestrogens are plant-derived hormonally-active compounds known to cause varied reproductive, immunosuppressive and behavioral effects in vertebrates. In this study, biodegradation of luteolin, a common phytoestrogen, was investigated during incubation with endophytic fungus Phomopsis liquidambari. The optimum concentration of luteolin as sole carbon source supplied in culture was 200 mg L( 1), which allowed 97 and 99 % degradation of luteolin by P. liquidambari in liquid culture and soil conditions, respectively. The investigation of the fungal metabolic pathway showed that luteolin was first decomposed to caffeic acid and phloroglucinol. These intermediate products were degraded to protocatechuic acid and hydroxyquinol, respectively, and then rings were opened by ring-cleavage dioxygenases. Two novel genes encoding the protocatechuate 3,4-dioxygenase and hydroxyquinol 1,2-dioxygenase were successfully cloned. Reverse-transcription quantitative polymerase chain reaction demonstrated that expression levels of mRNA of these two genes increased significantly after P. liquidambari was induced by the intermediate products caffeic acid and phloroglucinol, respectively. These results revealed that P. liquidambari can biodegrade luteolin efficiently and could potentially be used to bioremediate phytoestrogen contamination. PMID- 25794549 TI - The impact of small kidneys. AB - BACKGROUND: Small kidneys due to renal hypodysplasia (RHD) result from a decrease in nephron number. The objectives of this study were to identify clinical variables that determine long-term renal outcome in children with RHD and to define the role of kidney size as a predictor of developing end-stage renal disease (ESRD). METHODS: This was a single-center retrospective cohort analysis. The primary outcome was development of ESRD. We identified 202 RHD cases, with 25 (12%) reaching ESRD at mean age of 8.9 (+/-6.6) years. RESULTS: Children with RHD with a known genetic syndrome had the smallest kidneys while those with posterior urethral valves (PUV) had the largest kidneys at diagnosis. Cases with bilateral RHD were most likely to develop ESRD. Younger gestational age (OR 0.8, CI 0.69 0.99, p = 0.05), smaller kidney size at diagnosis (OR 0.13, CI 0.03-0.47, p = 0.002), lower best-estimated glomerular filtration rate (eGFR) (OR 0.74, CI 0.58 0.93, p = 0.01), proteinuria (OR 1.03, CI 1.01-1.05, p < 0.001) and high blood pressure (OR 1.02, CI 1.01-1.04, p = 0.01) were associated with development of ESRD, while kidney size at diagnosis was independently associated with ESRD (HR 0.03, CI 0.01-0.72, p = 0.043). CONCLUSIONS: In children with RHD, kidney size at diagnosis predicts the likelihood of developing ESRD. PMID- 25794551 TI - Reply to Hall J: "Use of the Fluocinolone Acetonide Intravitreal Implant for the Treatment of Noninfectious Posterior Uveitis: 3-Year Results of a Randomized Clinical Trial in a Predominantly Asian Population" : Virender S. Sangwan, P. Andrew Pearson, Hemanth Paul, Timothy L. Comstock. PMID- 25794550 TI - Interferon gamma, interleukin-6, and -17a levels were correlated with minimal hepatic encephalopathy in HBV patients. AB - BACKGROUND AND OBJECTIVE: Cytokines have been reported to be involved in the cirrhosis and hepatic encephalopathy (HE). Many aspects on the correlation between minimal HE (MHE) and cytokine levels were still unclear. METHODS: Two hundred eighty-nine HBV-infected cirrhotic patients were grouped: non MHE (n = 156), MHE (n = 98) and clinical HE (CHE, n = 213). Another 88 healthy volunteers were included as controls. Clinical and laboratory findings and levels of ten serum cytokines were analyzed. RESULTS: All tested cytokines were significantly elevated in cirrhotic patients and patients with CHE compared with controls. Statistical analysis showed only IL-6, IFNgamma and IL-17a were correlated MHE (all three p < 0.001). Multivariate regression analysis indicated that serum IL-6 and IL-17a levels were independent risk factors for MHE. Moreover, all patients with MHE had IL-17a levels higher than 49 pg/mL, whereas those without MHE had IL 17a levels lower than 49 pg/mL. CONCLUSIONS: IL-6, IFNgamma, and IL-17a were correlated with MHE in HBV-infected patients. Two independent risk factors (IL-6, IL-17a) for MHE were identified. Our findings pointed out the crucial roles of cytokines in MHE in HBV-infected patients. PMID- 25794552 TI - Monolayer-precision synthesis of molybdenum sulfide nanoparticles and their nanoscale size effects in the hydrogen evolution reaction. AB - Metal sulfide-based nanostructured materials have emerged as promising catalysts for hydrogen evolution reaction (HER), and significant progress has been achieved in enhancing their activity and durability for the HER. The understanding of nanoscale size-dependent catalytic activities can suggest critical information regarding catalytic reactivity, providing the scientific basis for the design of advanced catalysts. However, nanoscale size effects in metal sulfide-based HER catalysts have not yet been established fully, due to the synthetic difficulty in precisely size-controlled metal sulfide nanoparticles. Here we report the preparation of molybdenum sulfide (MoS2) nanoparticles with monolayer precision from one to four layers with the nearly constant basal plane size of 5 nm, and their size-dependent catalytic activity in the HER. Using density functional theory (DFT) calculations, we identified the most favorable single-, double-, and triple-layer MoS2 model structures for the HER, and calculated elementary step energetics of the HER over these three model structures. Combining HER activity measurements and the DFT calculation results, we establish that the turnover frequency of MoS2 nanoparticles in the HER increases in a quasi-linear manner with decreased layer numbers. Cobalt-promoted MoS2 nanoparticles also exhibited similar HER activity trend. We attribute the higher HER activity of smaller metal sulfide nanoparticles to the higher degree of oxidation, higher Mo-S coordination number, formation of the 1T phase, and lower activation energy required to overcome transition state. This insight into the nanoscale size-dependent HER activity trend will facilitate the design of advanced HER catalysts as well as other hydrotreating catalysts. PMID- 25794553 TI - Recovery of dengue virus from urine samples by real-time RT-PCR. AB - Recently, reverse transcription polymerase chain reaction (RT-PCR) for dengue virus (DENV) has been reported to test positive in urine samples for a longer time frame than in serum. We evaluated two RNA extraction procedures from urine and investigated the stability of DENV RNA in urine and serum up to 1 year at different storage temperatures. In addition, 24 urine samples collected from patients with a recent infection were tested with DENV real-time RT-PCR and compared to the RT-PCR results on serum. Five patients with an acute DENV infection were followed up for 6 months by RT-PCR on urine. The automated extraction method with the MagNA Pure LC 2.0 device had a higher yield of DENV RNA compared to the manual QIAGEN method, explained by the higher volume used in the former method. DENV RNA in both serum and urine was stable at room temperature up to 1 month and at 4 degrees C and -20 degrees C for at least 1 year. The detection rate by RT-PCR on urine was 50 % (4/8) until day 7, 100 % (6/6) between 1 and 3 weeks after symptom onset, and 25 % (2/8) thereafter. Generally, DENV RNA concentrations are higher in serum than in urine up till day 7, switching to lower concentrations in serum thereafter. Peak concentrations in urine are reached around day 10, and RNA becomes undetectable 3 to 4 weeks following disease onset. This diagnostic tool is of added value in clinical settings by extending the period during which DENV infections are diagnosed by RT PCR. PMID- 25794554 TI - [Comments on: Cervical myelopathy after mild whiplash injury to the cervical spine]. PMID- 25794556 TI - Intermittent haemodialysis and sustained low-efficiency dialysis (SLED) for acute theophylline toxicity. AB - INTRODUCTION: Theophylline overdose can result in significant cardiovascular and neurologic toxicity and is potentially fatal. Clearance of theophylline can be enhanced by the administration of multiple-dose activated charcoal (MDAC) and extracorporeal elimination techniques. We report a case of severe theophylline toxicity initially treated with MDAC and intermittent haemodialysis. Subsequent to this, sustained low-efficiency dialysis (SLED) was undertaken. This is a prolonged renal replacement therapy that uses blood and dialysate flow rates between those of intermittent haemodialysis and continuous renal replacement therapy. CASE REPORT: A 61-year-old man presented following ingestion of 24 g of theophylline SR (300 mg/kg), 240 mg of diazepam and 2 g of gabapentin. He required intubation and developed a supraventricular tachycardia treated with esmolol, but suffered no seizures. Serum theophylline concentration peaked at 636 MUmol/L (55-110) at 9.5 h post-ingestion. Intermittent haemodialysis was performed for 4 h and resulted in a theophylline extraction ratio of 0.57 with elimination half-life of 2.3 h. SLED was subsequently performed on two occasions for 7 h. Theophylline extraction ratio ranged from 0.46 (half-life 5.3 h during the first cycle) to 0.61 (half-life 10.6 h during the second cycle). After cessation of SLED, elimination half-life was 26 h. The patient made an uneventful recovery. DISCUSSION: Intermittent haemodialysis is the current recommended extracorporeal technique for enhancing theophylline elimination in the absence of charcoal haemoperfusion. However, SLED produced similar apparent extraction ratios with longer associated elimination half-life for theophylline than for intermittent haemodialysis. SLED is undertaken by intensive care unit (ICU) staff and may be a useful extracorporeal elimination technique in cases where access to intermittent haemodialysis, requiring specialist dialysis nursing staff, is limited or may be delayed. PMID- 25794557 TI - Regulatory mechanism of protein metabolic pathway during the differentiation process of chicken male germ cell. AB - We explored the regulatory mechanism of protein metabolism during the differentiation process of chicken male germ cells and provide a basis for improving the induction system of embryonic stem cell differentiation to male germ cells in vitro. We sequenced the transcriptome of embryonic stem cells, primordial germ cells, and spermatogonial stem cells with RNA sequencing (RNA Seq), bioinformatics analysis methods, and detection of the key genes by quantitative reverse transcription PCR (qRT-PCR). Finally, we found 16 amino acid metabolic pathways enriched in the biological metabolism during the differentiation process of embryonic stem cells to primordial germ cells and 15 amino acid metabolic pathways enriched in the differentiation stage of primordial germ cells to spermatogonial stem cells. We found three pathways, arginine proline metabolic pathway, tyrosine metabolic pathway, and tryptophan metabolic pathway, significantly enriched in the whole differentiation process of embryonic stem cells to spermatogonial stem cells. Moreover, for these three pathways, we screened key genes such as NOS2, ADC, FAH, and IDO. qRT-PCR results showed that the expression trend of these genes were the same to RNA-Seq. Our findings showed that the three pathways and these key genes play an important role in the differentiation process of embryonic stem cells to male germ cells. These results provide basic information for improving the induction system of embryonic stem cell differentiation to male germ cells in vitro. PMID- 25794555 TI - Exploiting viral natural history for vaccine development. AB - The partial successes of the Phase 2 gB-based vaccine trials for HCMV highlight the very real likelihood that vaccine-mediated induction of antibodies that neutralize the fusion pathway of fibroblast infection is not sufficient as a singular strategy to confer protective efficacy against primary HCMV infection. Alternative strategies that serve as adjuncts to gB-based vaccines are likely required to target different aspects of the complex lifecycle of HCMV infection. There has been considerable recent interest in targeting the gH/gL/UL128/UL130/UL131 pentamer complex (gH/gL-PC) to neutralize the endocytic pathway of HCMV infection of epithelial and endothelial cells. Since both cell types are critical during primary mucosal infection, intrahost spread, and shedding of HCMV in an infected host, the gH/gL-PC represents a high-value target for vaccination to interrupt the HCMV lifecycle. The natural history of HCMV is exceedingly complex and incompletely resolved, and the protective efficacy generated by gH/gL-PC remains to be validated in clinical trials. Yet, there are salient aspects of its lifecycle that offer clues about how other novel vaccine strategies can be targeted to especially susceptible parts of the viral proteome to significantly disrupt HCMV's ability to infect susceptible hosts. In particular, the protracted evolution of Herpesvirales has endowed HCMV with two remarkable properties of its natural history: (1) lifelong persistence within immune hosts that develop extraordinarily large antiviral immune responses and (2) the ability to reinfect those with prior immunity. The latter phenotype strongly implies that, if HCMV can overcome prior immunity to initiate a new infection, it is likely irrelevant whether prior immunity derives from prior infection or prior vaccination. Both phenotypes are unified by the extensive devotion of the HCMV coding repertoire (~50%) to viral proteins that modulate host cell signaling, trafficking, activation, antigen presentation, and resistance to apoptosis. Collectively, these viral proteins are the likely reason for the high barrier to success for the 4-decade effort to design an HCMV vaccine, and they represent the viral proteins that make HCMV be the virus that it is. James Hanshaw wrote in 1971 that, based on a 15-year retrospective of congenital HCMV cases, "... any thoughtful program designed at prevention or treatment deserves consideration". Drawing upon natural history data from the nonhuman primate model of HCMV persistence and pathogenesis, a "thoughtful program" is put forth that HCMV immune-modulating proteins should be considered as vaccine candidates. PMID- 25794558 TI - Level of UV-B radiation influences the effects of glyphosate-based herbicide on the spotted salamander. AB - Glyphosate-based herbicides are the number one pesticide in the United States and are used commonly around the world. Understanding the affects of glyphosate-based herbicides on non-target wildlife, for example amphibians, is critical for evaluation of regulations pertaining to the use of such herbicides. Additionally, it is important to understand how variation in biotic and abiotic environmental conditions, such as UV-B light regime, could potentially affect how glyphosate based herbicides interact with non-target species. This study used artificial pond mesocosms to identify the effects of generic glyphosate-based herbicide (GLY 4 Plus) on mortality, cellular immune response, body size, and morphological plasticity of larvae of the spotted salamander (Ambystoma maculatum) under conditions that reflect moderate (UV(M)) and low (UV(L)) UV-B light regimes. Survival within a given UV-B level was unaffected by herbicide presence or absence. However, when herbicide was present, survival varied between UV-B levels with higher survival in UV(M) conditions. Herbicide presence in the UV(M) treatments also decreased body size and reduced cellular immune response. In the UV(L) treatments, the presence of herbicide increased body size and affected tail morphology. Finally, in the absence of herbicide, body size and cellular immune response were higher in UV(M) treatments compared to UV(L) treatments. Thus, the effects of herbicide on salamander fitness were dependent on UV-B level. As anthropogenic habitat modifications continue to alter landscapes that contain amphibian breeding ponds, salamanders may increasingly find themselves in locations with reduced canopy cover and increased levels of UV light. Our findings suggest that the probability of surviving exposure to the glyphosate based herbicide used in this study may be elevated in more open canopy ponds, but the effects on other components of fitness may be varied and unexpected. PMID- 25794559 TI - Migrating Tundra Peregrine Falcons accumulate polycyclic aromatic hydrocarbons along Gulf of Mexico following Deepwater Horizon oil spill. AB - Monitoring internal crude oil exposure can assist the understanding of associated risks and impacts, as well as the effectiveness of restoration efforts. Under the auspices of a long-term monitoring program of Tundra Peregrine Falcons (Falco peregrinus tundrius) at Assateague (Maryland) and South Padre Islands (Texas), we measured the 16 parent (unsubstituted) polycyclic aromatic hydrocarbons (PAHs), priority pollutants identified by the United States Environmental Protection Agency and components of crude oil, in peripheral blood cells of migrating Peregrine Falcons from 2009 to 2011. The study was designed to assess the spatial and temporal trends of crude oil exposure associated with the 2010 Deepwater Horizon (DWH) oil spill which started 20 April 2010 and was capped on 15 July of that year. Basal PAH blood distributions were determined from pre-DWH oil spill (2009) and unaffected reference area sampling. This sentinel species, a predator of shorebirds and seabirds during migration, was potentially exposed to residual oil from the spill in the northern Gulf of Mexico. Results demonstrate an increased incidence (frequency of PAH detection and blood concentrations) of PAH contamination in 2010 fall migrants sampled along the Texas Gulf Coast, declining to near basal levels in 2011. Kaplan-Meier peak mean ?PAH blood concentration estimates varied with age (Juveniles-16.28 +/- 1.25, Adults-5.41 +/- 1.10 ng/g, wet weight) and PAHs detected, likely attributed to the discussed Tundra Peregrine natural history traits. Increased incidence of fluorene, pyrene and anthracene, with the presence of alkylated PAHs in peregrine blood suggests an additional crude oil source after DWH oil spill. The analyses of PAHs in Peregrine Falcon blood provide a convenient repeatable method, in conjunction with ongoing banding efforts, to monitoring crude oil contamination in this avian predator. PMID- 25794560 TI - Successful treatment of refractory cold hemagglutinemia in MYD88 L265P mutation negative Waldenstrom's macroglobulinemia with bortezomib. AB - We report here the successful treatment of cold agglutinin-associated refractory hemolysis with bortezomib in a patient with Waldenstrom's macroglobulinemia (WM). A 78-year-old man was referred to our hospital with cold hemagglutinemia of unknown cause. Laboratory examination revealed a hemoglobin concentration of 6.9 g/dL, serum IgM concentration of 1904 mg/dL, and a titer of cold hemagglutinin of over *8192. Serum immunoelectrophoresis demonstrated monoclonal protein of the IgM-kappa type. A bone marrow aspirate showed many lymphoplasmacytic cells, which were positive for CD19, CD20, CD38, and cytoplasmic MU and kappa light chains. A diagnosis of WM-associated cold hemagglutinemia was made. Because of red blood cell transfusion-dependency, we treated him with intravenous fludarabine, oral melphalan-prednisolone, cyclophosphamide, and melphalan, and two courses of R CHOP in sequence with a marked decrease of serum IgM (928 mg). We then started weekly bortezomib plus dexamethasone (BD) therapy, as he was still transfusion dependent. Soon after the initiation of BD, he achieved transfusion independence, with a further decrease in serum levels of IgM and marked improvement of anemia. Interestingly, his marrow abnormal lymphocytes were later found not to carry the MYD88 L265P mutation. The successful treatment with bortezomib for WM lacking this mutation is discussed. PMID- 25794561 TI - Is multiculturalism bad for health care? The case for re-virgination. AB - Hymenoplasty is a surgical procedure requested by women who are expected to remain virgins until marriage. In this article, I assess the ethical and legal challenges raised by this request, both for the individual physician and for the health care system. I argue that performing hymenoplasty is not always an unethical practice and that, under certain conditions, it should be provided by the health care system. PMID- 25794564 TI - [MUV researcher of the month, March 2015]. PMID- 25794562 TI - Improvement in prehospital time in acute coronary syndrome between 1985 and 2013 in the south-eastern area of Hungary. AB - Acute coronary syndrome (ACS) is a life-threatening condition and the time-period from the onset of symptoms to the patients' arrival into the hospital has crucial importance. The authors investigated retrospectively the patients' decision time (time from the onset of the symptoms to seeking medical help) and the transport time to hospital arrival. In Hungary, it is unique of its kind that the present data can be compared to those obtained in the same area almost three decades ago.One-hundred forty-two patients (106 males and 36 females) were involved in the study, the mean age +/- SD was 62.4 +/- 11.3 years. The median decision time was 40 min; the median hospital arrival time was 2 h and 13 min. These were significantly shorter than in 1985-1986. These time parameters were influenced neither by gender, age, the number of inhabitants in the patients' city, the patients' education level, the occurrence of any former coronary event in the family and nor by the fact that the type of ACS was myocardial infarction with or without ST segment elevation.During the last two and half decades both the decision and the hospital arrival time decreased significantly (by 39 and 28 %, respectively) probably due to greater knowledge of general practitioners and the better organized ambulance service. Further improvement is needed; this can be expected by consistent education of the patients. PMID- 25794565 TI - [MUV researcher of the month, March 2015]. PMID- 25794568 TI - Kinetics of microRNA Expression in Bronchoalveolar Lavage Fluid Samples. AB - Levels of microRNAs (miRNAs) are increasingly assessed in biological fluids, for example, in samples obtained by bronchoalveolar lavage (BAL). "Post-collection kinetics" of miRNA expression levels, however, have not been investigated to date. In these experiments, we analyzed the dynamic expression profile of 5 different miRNAs (miR-17, miR-19b, miR-20b, miR-125a, and miR-223-3p) in BAL within the first 24 h following collection by routine bronchoscopy. miRNAs were quantified 0, 1, 4, 8, and 24 h after collection in samples that were kept at 4 degrees C or at room temperature. The expression of all five miRNAs was found to remain stable between the first 8 h after collection. 24 h after collection miRNAs faced substantial alterations in their expression profile. These data emphasize that BAL samples intended for further miRNA analysis can be handled at room temperature within the first 8 h after bronchoscopy. PMID- 25794567 TI - Gene and Protein Expression of Fibronectin and Tenascin-C in Lung Samples from COPD Patients. AB - PURPOSE: Fibronectin (Fn) and tenascin-C (TnC) are two extracellular matrix proteins associated with remodeling changes. Fn and TnC gene and protein expression in lung tissue, including their predominant location in bronchial and pulmonary artery structures, have not yet been fully evaluated. The aim of the present study was to assess: (1) gene expression of Fn and TnC in lung samples from chronic obstructive pulmonary disease (COPD) and non-COPD subjects; and (2) protein content and location of Fn and TnC in both groups. METHODS: Consecutive subjects requiring lung resection due to lung cancer surgery were included. Lung specimens were examined for gene expression by quantitative real-time PCR (values expressed as fold change ratio). The analysis of their protein content and location was performed by western blot and immunohistochemical studies, respectively. Patients were divided into two cohorts according to COPD status. RESULTS: A total of 41 patients (20 with COPD and 21 without COPD) were included. An enhanced Fn gene expression was observed in the COPD group compared to the non COPD group (4.73 +/- 0.54 vs. 2.65 +/- 0.57; P = 0.012), whereas no differences in gene TnC expression were observed (2.91 +/- 0.44 vs. 2.60 +/- 0.48; P = 0.633). No differences in lung protein content and location were found between groups. Immunohistochemical evaluation showed a predominantly vascular and bronchial location of Fn and TnC in both groups. CONCLUSIONS: An enhanced lung gene expression of Fn was observed in COPD subjects compared to non-COPD subjects. No differences were found in Fn protein expression or in TnC gene or protein expression among groups. PMID- 25794566 TI - Survival and susceptibility of Burkholderia cepacia complex in chlorhexidine gluconate and benzalkonium chloride. AB - The Burkholderia cepacia complex (BCC) includes opportunistic pathogenic bacteria that have occasionally been recovered from various pharmaceutical products, including antiseptics and disinfectants. Plausible reasons for the contamination include intrinsic sources, such as inadequate process controls, especially for water or equipment used during product manufacture, or extrinsic sources, such as improper handling and dilution or distribution in contaminated containers. Because the survival of BCC in antiseptics is a concern to the public health and pharmaceutical industry, we determined minimum inhibitory concentrations (MICs) of 36 BCC strains against the antiseptics, following exposure to chlorhexidine gluconate (CHX) and benzalkonium chloride (BZK) solutions (1-500 ug/ml for each chemical). Susceptibility to CHX and BZK varied across the BCC strains and was recorded as mean 90.3 and 111.1 ug/ml, respectively, at initial inoculation, which was significantly higher than the 46.4 and 61.1 ug/ml levels measured for BCC incubated in water for 40 days. After determining antiseptic MICs of individual BCC strains, BCC recovery was measured on Tryptic Soy Agar (TSA), Reasoner's Second Agar (R2A) and diluted preparations of these media under their sub-MICs. The survival of BCC was monitored for 14 days (336 h) in sub-MICs diluted to less than their antiseptic susceptible concentration value. Diluted TSA and R2A media exhibited greater efficiency of recovery for most BCC strains from the CHX and BZK solutions than full strength TSA or R2A. For BCC survival in antiseptic solutions, the cell number of BCC decreased rapidly within the first 20 min in both antiseptics, but after this, recovery remained constant in CHX and increased in BZK over the 14 day incubation period. The results indicate that BCC in water can remain viable with low susceptibility to antiseptics for 14 days, which suggests the necessity for improved detection methods and control measures to monitor BCC contamination in pharmaceutical products. PMID- 25794570 TI - Meat consumption and gout: Friend, foe or neither? PMID- 25794569 TI - Cost-utility analysis of tocilizumab monotherapy in first line versus standard of care for the treatment of rheumatoid arthritis in Greece. AB - The study aims to evaluate the cost-effectiveness of adding tocilizumab (TCZ) first line to a treatment sequence for patients with active rheumatoid arthritis (RA), who had an inadequate response to one or more traditional synthetic disease modifying antirheumatic drugs (DMARDs) and are intolerant to methotrexate (MTX), or in whom continued treatment with MTX is considered inappropriate. An individual simulation model was applied to project lifetime costs and outcomes for 10,000 patients from a payer's perspective. The analysis compared the standard treatment pathway (STP) with a similar pathway, where treatment was initiated with TCZ. QALYs were used as primary efficacy outcomes. Efficacy data were obtained from the ADACTA trial and a network meta-analysis. Clinical practice standards were derived from an expert panel of Greek rheumatologists. Results indicate that a treatment sequence starting with TCZ yields 1.17 more QALYs (9.38 vs. 8.21) at an additional cost of ?3,744 (?119,840 vs. ?86,096) compared with the STP. The incremental cost-effectiveness ratio was ?28,837/QALY gained. Probabilistic sensitivity analysis confirms robustness of these findings as consistently below a threshold of ?45,000. The results of the analysis suggest that TCZ, when used as a first-line biologic monotherapy, can be a cost-effective treatment option for the management of active RA in patients in need of biologic monotherapy. PMID- 25794571 TI - A patient-reported outcome measures-based composite index (RAPID3) for the assessment of disease activity in ankylosing spondylitis. AB - A single questionnaire regarding to disease activity for all rheumatic diseases may present advantages to introduce quantitative measurement into routine care. The aim of this study was to evaluate the correlation of routine assessment of patient index data 3 (RAPID3) with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). A total of 341 consecutive AS patients who met the modified New York classification criteria were included. All patients completed BASDAI and RAPID3 at each visit, and their physicians completed physician global assessment. ASDASs were calculated using defined formulas. Proposed RAPID3 severity categories were compared to BASDAI and ASDAS categories. Spearman's rho correlation test and kappa statistics were used to analyze statistical significance. The median age of AS patients was 34.0 (21.0-69.0) years and the median disease duration 10.0 (2.0 35.0) years. Median scores for RAPID3, BASDAI, ASDAS-CRP, and ASDAS-ESR were 13.0 (0.0-27.3), 4.7 (0.0-9.7), 3.0 (0.4-5.8), and 2.5 (0.5-6.3), respectively. RAPID3 was strongly correlated with BASDAI and ASDAS-ESR (r = 0.842, r = 0.815; p < 0.001, respectively). Among the 209 patients with high disease activity according to BASDAI, 83.3 % had high or moderate severity according to RAPID3 (kappa 0.693; p < 0.001). Among the 133 patients with moderate, high, and very high disease activity on ASDAS-CRP, 91.7 % had high or moderate severity according to RAPID3 (kappa 0.548; p < 0.001). RAPID3 is as informative as BASDAI and ASDAS in our cohort of AS patients. We therefore suggest that RAPID3 may be used to assess the patient status quantitatively in AS patients, as part of routine care. PMID- 25794573 TI - Corrigendum. PMID- 25794572 TI - New medical treatment strategies for nonalcoholic steatohepatitis. AB - OPINION STATEMENT: Nonalcoholic steatohepatitis (NASH) is a severe form of fatty liver disease unrelated to chronic alcohol consumption. As nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and is becoming the most common cause for chronic liver disease, NASH likely will replace chronic hepatitis C as leading indication for liver cirrhosis and liver transplantation in this decade. Despite this alarming trend, effective treatment is lacking and continues to rely on dietary interventions and physical exercise, known to be of limited effect. Hence, there is an urgent need for safe pharmacologic therapy that successfully reverses or prevents progression of liver injury and fibrosis in patients with NASH. Employing emerging concepts of disease development and progression that involve in parallel ongoing events originating from the liver, adipose tissue, and intestine will ultimately promote the development of effective agents for targeted therapies for NASH. Novel agents must be safe, optimally dosed, and finally pass clinical trials providing proof of concept and efficacy. In the case of NASH, trial design is not necessarily straightforward as surrogate end points to predict clinical benefits are not yet established. The level of unmet needs for NASH goes however even beyond therapeutic agents and also includes patient and physician awareness. This article focuses on identifying potential pathophysiology-guided targets for medical therapy of NASH. PMID- 25794574 TI - Fate of phthalates and BPA in agricultural and non-agricultural soils of the Paris area (France). AB - This study (i) investigated the concentration levels of nine phthalates and bisphenol A (BPA) in sludge samples originating from a French wastewater treatment plant (WWTP), (ii) studied the distribution of target compounds according to soil depth and calculated their half-lives, and (iii) compared the contamination level of the agricultural soil with those of soils with other land uses. The sludge contamination levels varied from a few hundred nanograms per gram dry weight (dw) for diethyl phthalate (DEP), di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and butyl-benzyl phthalate (BBP) to a few micrograms per gram dw for diethylhexyl phthalate (DEHP), di-iso-nonyl phthalate (DiNP), and di-iso-decyl phthalate (DiDP). After sludge application, an 8-fold increase for DEHP level and a 3-fold increase for BPA level occurred in the surface horizon of the soil. The mean distribution of phthalates according to the depth showed a positive gradient for the low molecular weight compounds and inversely, a negative gradient for the highest ones. The half-lives in the 0-20-cm soil horizon were 64 days for DEHP and 36 days for BPA. A predictive environmental concentration (PEC) of 0.3 MUg g(-1) dw was estimated for DEHP, while the experimental value was 0.16 MUg g(-1) dw, suggesting degradation processes in soil and/or formation of non-extractable residues. Comparisons of contamination levels for soils from different origins (urban, rural, agricultural, and forest) showed that the urban soil remained the most contaminated one, prior to the agricultural soil after treatment. PMID- 25794575 TI - Mitigating heavy metal accumulation into rice (Oryza sativa L.) using biochar amendment--a field experiment in Hunan, China. AB - A field experiment was conducted to investigate the effect of bean stalk (BBC) and rice straw (RBC) biochars on the bioavailability of metal(loid)s in soil and their accumulation into rice plants. Phytoavailability of Cd was most dramatically influenced by biochars addition. Both biochars significantly decreased Cd concentrations in iron plaque (35-81 %), roots (30-75 %), shoots (43 79 %) and rice grain (26-71 %). Following biochars addition, Zinc concentrations in roots and shoots decreased by 25.0-44.1 and 19.9-44.2 %, respectively, although no significant decreases were observed in iron plaque and rice grain. Only RBC significantly reduced Pb concentrations in iron plaque (65.0 %) and roots (40.7 %). However, neither biochar significantly changed Pb concentrations in rice shoots and grain. Arsenic phytoavailability was not significantly altered by biochars addition. Calculation of hazard quotients (HQ) associated with rice consumption revealed RBC to represent a promising candidate to mitigate hazards associated with metal(loid) bioaccumulation. RBC reduced Cd HQ from a 5.5 to 1.6. A dynamic factor's way was also used to evaluate the changes in metal(loid) plant uptake process after the soil amendment with two types of biochar. In conclusion, these results highlight the potential for biochar to mitigate the phytoaccumulation of metal(loid)s and to thereby reduce metal(loid) exposure associated with rice consumption. PMID- 25794576 TI - Risk assessment of heavy metals in air, water, vegetables, grains, and related soils irrigated with biogas slurry in Taihu Basin, China. AB - Metal contamination in farmlands irrigated with biogas slurry is of great concern because of its potential health risks to local inhabitants. Health risks that depend heavily on multi-pathway exposure to heavy metals (e.g., Pb, Cd, Cr, Zn, Cu, and As) in water, soil, air, and local food were studied through field sampling in Taihu Basin, China. Results show that Zn, Pb, and Cd in soils irrigated with biogas slurry exceed the soil quality standard values, and grown vegetables and grains contaminated with Pb and Cd exceed the permissible limits. Food ingestion plays an important role in the total average daily dose of metals, especially for Cu and Zn, which account for 94 and 91%, respectively. Non carcinogenic risks posed to adults mainly result from Cu, Zn, Pb, Cd, and As through food ingestion and from Cr through soil ingestion. The highest non carcinogenic risk was determined from food ingestion, followed by soil ingestion, air inhalation, air ingestion, and dermal contact with air. Carcinogenic risks to adults are 6.68 to 7.00 times higher than the safe level and can be attributed to Cr, As, and Cd pollution. The estimated risks mainly result from As and Cd through food ingestion and from Cr through soil ingestion. Both cancer and non cancer risks through dermal contact can be ignored. Therefore, attention should be paid to health risks imposed by adults' multi-pathway exposure to heavy metals in vegetables, grains, and related soils irrigated with biogas slurry in Taihu Basin. Effective measures should be implemented to control heavy metal pollution and protect potentially exposed adults. PMID- 25794577 TI - Vermistabilization of sugar beet (Beta vulgaris L) waste produced from sugar factory using earthworm Eisenia fetida: Genotoxic assessment by Allium cepa test. AB - In the present study, sugar beet mud (SBM) and pulp (SBP) produced as a waste by products of the sugar industry were mixed with cattle dung (CD) at different ratios on dry weight basis for vermicomposting with Eisenia fetida. Minimum mortality and highest population of worms were observed in 20:80 (SBM20) mixture of SBM and 10:90 (SBP10) ratios. However, increased percentages of wastes significantly affected the growth and fecundity of worms. Nutrients like nitrogen, phosphorus, sodium, increased from initial feed mixture to final products (i.e., vermicompost), while organic carbon (OC), C:N ratio and electrical conductivity (EC) declined in all the products of vermicomposting. Although there was an increase in the contents of all the heavy metals except copper, chromium, and iron in SBM, the contents were less than the international standards for compost which indicates that the vermicompost can be used in the fields without any ill effects on the soil. Allium cepa root chromosomal aberration assay was used to evaluate the genotoxicity of pre- and post vermicomposted SBM to understand the effect of vermicomposting on the reduction of toxicity. Genotoxicity analysis of post-vermicomposted samples of SBM revealed 18-75% decline in the aberration frequencies. Scanning electron microscopy (SEM) was recorded to identify the changes in texture in the control and vermicomposted samples. The vermicomposted mixtures in the presence of earthworms confirm more numerous surface irregularities that prove to be good manure. PMID- 25794578 TI - Phase ratio variation approach for the study of partitioning behavior of volatile organic compounds in polymer sample bags: Nalophan case study. AB - Sorption of volatile organic compounds on the inner surface of polymer sampling bags leads to important underestimations of the real headspace concentration. Introducing a wide range of volatiles in a two-phase system containing Nalophan revealed that recoveries decreased down to 57 % in a period of 22 h. In this work, a phase ratio variation approach is investigated to quantify the degree of scalping, and thus enabling to compensate for sorption phenomena. This method requires limited measurements, without the need for time-consuming calibrations. By spiking identical amounts of volatiles in three two-phase systems, each having unique polymer volume/mass ratios beta (beta 1 = 0, beta 2 = 80.9, beta 3 = 161.9), individual partitioning coefficients could be experimentally determined for a wide range of compounds. Additionally, a correlation was found between these partitioning coefficients and the liquid molar volume for a number of aliphatic, aromatic, and oxygenated compounds. PMID- 25794579 TI - Environmental geochemistry of dissolved and biogenic silicon and its nutrient limitation effects in an inland lake, China. AB - Silicon (Si) processing and retention play a key role in nutrients biogeochemistry cycling in aquatic environment. In order to interpret the possibility of Si limitation, multivariate analysis was performed based on stoichiometric nutrients balance, distribution characteristics of dissolved silicon (DSi) and biogenic silica (BSi), adsorption behavior, and response relation of BSi with paleoenvironment in water-sediment system of Lake Daihai. The spatial distributions of DSi and BSi in the water-sediment system indicated that terrigenous inputs (such as the weathering of rock and soil in the drainage basin) was the main sources of Si. Meanwhile, grain sizes of sediments, water hydrogeochemistry, and space competition between diatoms and submergent or emerging plants also played important roles in regulating BSi spatial distributions. The sediments from the lake presented obvious releasing trend of Si at low initial concentrations (<= 3 mg/L) in adsorption experiments, indicating that the sediments were the source of Si to the overlying water. Furthermore, the good response relation between BSi and paleoenvironment observed in the sediment profiles from Lake Daihai indicated that the main reasons for Si limitation to siliceous plankton were different during different periods. The multi-evidences of distribution characteristics, stoichiometric nutrient balance, adsorption behaviors, and response to paleoenvironment were jointly indicative of Si limitation on the primary production of siliceous plankton in Lake Daihai. PMID- 25794580 TI - Phytotoxicity of ZnO nanoparticles and the released Zn(II) ion to corn (Zea mays L.) and cucumber (Cucumis sativus L.) during germination. AB - Toxicity of engineered nanoparticles on organisms is of concern worldwide due to their extensive use and unique properties. The impacts of ZnO nanoparticles (ZnO NPs) on seed germination and root elongation of corn (Zea mays L.) and cucumber (Cucumis sativus L.) were investigated in this study. The role of seed coats of corn in the mitigation toxicity of nanoparticles was also evaluated. ZnO NPs (1,000 mg L(-1)) reduced root length of corn and cucumber by 17 % (p < 0.05) and 51 % (p < 0.05), respectively, but exhibited no effects on germination. In comparison with Zn(2+), toxicity of ZnO NPs on the root elongation of corn could be attributed to the nanoparticulate ZnO, while released Zn ion from ZnO could solely contribute to the inhibition of root elongation of cucumber. Zn uptake in corn exposed to ZnO NPs during germination was much higher than that in corn exposed to Zn(2+), whereas Zn uptake in cucumber was significantly correlated with soluble Zn in suspension. It could be inferred that Zn was taken up by corn and cucumber mainly in the form of ZnO NPs and soluble Zn, respectively. Transmission electron microscope confirmed the uptake of ZnO NPs into root of corn. Although isolation of the seed coats might not be the principal factor that achieved avoidance from toxicity on germination, seed coats of corn were found to mitigate the toxicity of ZnO NPs on root elongation and prevent approximately half of the Zn from entering into root and endosperm. PMID- 25794581 TI - Impact of multi-metals (Cd, Pb and Zn) exposure on the physiology of the yeast Pichia kudriavzevii. AB - Metal contamination of the environment is frequently associated to the presence of two or more metals. This work aimed to study the impact of a mixture of metals (Cd, Pb and Zn) on the physiology of the non-conventional yeast Pichia kudriavzevii. The incubation of yeast cells with 5 mg/l Cd, 10 mg/l Pb and 5 mg/l Zn, for 6 h, induced a loss of metabolic activity (assessed by FUN-1 staining) and proliferation capacity (evaluated by a clonogenic assay), with a small loss of membrane integrity (measured by trypan blue exclusion assay). The staining of yeast cells with calcofluor white revealed that no modification of chitin deposition pattern occurred during the exposure to metal mixture. Extending for 24 h, the exposure of yeast cells to metal mixture provoked a loss of membrane integrity, which was accompanied by the leakage of intracellular components. A marked loss of the metabolic activity and the loss of proliferation capacity were also observed. The analysis of the impact of a single metal has shown that, under the conditions studied, Pb was the metal responsible for the toxic effect observed in the metal mixture. Intracellular accumulation of Pb seems to be correlated with the metals' toxic effects observed. PMID- 25794582 TI - Improvement of oxygen-containing functional groups on olive stones activated carbon by ozone and nitric acid for heavy metals removal from aqueous phase. AB - Recently, modification of surface structure of activated carbons in order to improve their adsorption performance toward especial pollutants has gained great interest. Oxygen-containing functional groups have been devoted as the main responsible for heavy metal binding on the activated carbon surface; their introduction or enhancement needs specific modification and impregnation methods. In the present work, olive stones activated carbon (COSAC) undergoes surface modifications in gaseous phase using ozone (O3) and in liquid phase using nitric acid (HNO3). The activated carbon samples were characterized using N2 adsorption desorption isotherm, SEM, pHpzc, FTIR, and Boehm titration. The activated carbon parent (COSAC) has a high surface area of 1194 m(2)/g and shows a predominantly microporous structure. Oxidation treatments with nitric acid and ozone show a decrease in both specific surface area and micropore volumes, whereas these acidic treatments have led to a fixation of high amount of surface oxygen functional groups, thus making the carbon surface more hydrophilic. Activated carbon samples were used as an adsorbent matrix for the removal of Co(II), Ni(II), and Cu(II) heavy metal ions from aqueous solutions. Adsorption isotherms were obtained at 30 degrees C, and the data are well fitted to the Redlich Peterson and Langmuir equation. Results show that oxidized COSACs, especially COSAC(HNO3), are capable to remove more Co(II), Cu(II), and Ni(II) from aqueous solution. Nitric acid-oxidized olive stones activated carbon was tested in its ability to remove metal ions from binary systems and results show an important maximum adsorbed amount as compared to single systems. PMID- 25794583 TI - Effects of selenite and selenate application on growth and shoot selenium accumulation of pak choi (Brassica chinensis L.) during successive planting conditions. AB - Selenate and selenite are two main kinds of inorganic selenium (Se) sources in soil, but these substances can pose threats to the environment. Phytoextraction is an emerging technology to remove Se from polluted soils by using a hyper accumulator. In this study, a pot experiment was conducted to investigate Se phytoextraction potential of pak choi (Brassica chinensis L.) and to determine the effects of Se on growth and Se accumulation of pak choi under successive planting conditions (four crops). Results showed that Se concentration in pak choi shoots significantly increased as selenate and selenite rates increased. Se concentration increased in successive crops on soil treated with selenite; by contrast, Se concentration decreased in crops on soil treated with selenate. Se concentrations of pak choi on soil treated with selenate were higher than those on soil treated with selenite. The maximum Se accumulations amount in crops on selenite- and selenate-treated soil were 7818 and 8828 MUg . pot(-1), respectively. High bioconcentration factor (BCF) values indicated that pak choi could accumulate more Se from Se-contaminated soil. The Se phytoextraction efficiency of pak choi increased under successive planting conditions in selenite and selenate treatments; the maximum Se phytoextraction efficiencies of four successive crops of pak choi on selenite- and selenate-treated soil were 4.91 and 31.90 %, respectively. These differences between selenate and selenite treatments were attributed to the differences in Se forms in soil. Total and available Se contents in soil decreased significantly during repeated planting crops on soil treated with selenate; conversely, total and available Se contents decreased slightly in crops on soil treated with selenite. These results suggested that pak choi could highly tolerate and accumulate Se. Thus, pak choi may remove Se from contaminated soil; indeed, pak choi can be used in the phytoextraction of Se in polluted soil. PMID- 25794584 TI - Valorization of treated olive mill wastewater in fertigation practice. AB - Olive mill wastewater (OMW) brings about a major environmental problem in Tunisia as well as in the other Mediterranean countries. Its strong organic load and its toxicity due to the presence of complex phenolic compounds have dire effects when applied to soil. To overcome this difficulty, the OMW pretreatment was investigated in the present work using the Fenton oxidation reaction with zero valent iron. Then, this pretreated wastewater was valorized in fertigation practice. The effects of the addition of different concentrations of both treated and raw OMW on soil and cropping system were investigated. The treatment by Fenton oxidation with zero-valent iron could reduce 50 % of COD and decrease 53 % of phenolic compounds. OMW application had a temporary effect on the soil pH and EC. The results showed that the evolution of soil pH and EC was related to the organic matter of the soil which depends on the spread concentrations of raw or treated OMW. After 15-day incubation period, the soil pH and EC tended to stabilize and return to the control level. Moreover, this stabilization is faster in treated OMW than that in raw OMW especially for concentrations as high as 3 and 4 %. Plants cultivated with treated OMW showed an increase in their germination. The results pointed an improvement in the stem length of plants which is almost similar to that of the control for both pea and tomato, especially for high concentrations of 3 and 4 %. PMID- 25794585 TI - Cytotoxicity of aluminum oxide nanoparticles on Allium cepa root tip--effects of oxidative stress generation and biouptake. AB - The commercial usage of Al2O3 nanoparticles (Al2O3 NPs) has gone up significantly in the recent times, enhancing the risk of environmental contamination with these agents and their consequent adverse effects on living systems. The current study has been designed to evaluate the cytogenetic potential of Al2O3 NPs in Allium cepa (root tip cells) at a range of exposure concentrations (0.01, 0.1, 1, 10, and 100 MUg/mL), their uptake/internalization profile, and the oxidative stress generated. We noted a dose-dependent decrease in the mitotic index (42 to 28 %) and an increase in the number of chromosomal aberrations. Various chromosomal aberrations, e.g. sticky, multipolar and laggard chromosomes, chromosomal breaks, and the formation of binucleate cells, were observed by optical, fluorescence, and confocal laser scanning microscopy. FT-IR analysis demonstrated the surface chemical interaction between the nanoparticles and root tip cells. The biouptake of Al2O3 in particulate form led to reactive oxygen species generation, which in turn probably contributed to the induction of chromosomal aberrations. PMID- 25794586 TI - Seasonal variations of dissolved organic carbon in precipitation over urban and forest sites in central Poland. AB - Spatial and temporal variability of carbon species in rainwater (bulk deposition) was studied for the first time at two sites located in urban area of Poznan City and protected woodland area (Jeziory), in central Poland, between April and December 2013. The mean concentration of total carbon (TC) for the first site was 5.86 mg L(-1), whereas for the second, 5.21 mg L(-1). Dissolved organic carbon (DOC) concentration accounted for, on average, 87 and 91 % of total carbon in precipitation at urban and non-urban sites, respectively. Significant changes in TC concentrations in rainwater were observed at both sites, indicating that atmospheric transformation, transport, and removal mechanisms of carbonaceous particles were affected by seasonal fluctuations in biogenic/anthropogenic emission and meteorological conditions (i.e., precipitation height and type, atmospheric transport). During the warm season, the DOC concentration in rainwater was mostly influenced by mixed natural and anthropogenic sources. In contrast, during the cold season, the DOC concentration significantly increased mainly as a result of anthropogenic activities, i.e., intensive coal combustion, domestic wood burning, high-temperature processes, etc. In addition, during the winter measurements, significant differences in mean DOC concentration (Kruskal Wallis test, p < 0.05) were determined for rain, mixed rain-snow, and snow samples. It was found that rainwater TOC concentration measured in Poznan and Jeziory reflected a combination of local, regional, and distant sources. Backward trajectory analysis showed that air masses advected from polluted regions in western Europe largely affect the DOC amount in rainwater, both at urban and non urban sites. These data imply that carbonaceous compounds are of crucial importance in atmospheric chemistry and should be considered as an important parameter while considering wet deposition, reactions with different substances, especially over polluted environments. PMID- 25794587 TI - [Value of perineal HistoScanningTM template-guided prostate biopsy]. AB - BACKGROUND: Modern imaging modalities improve prostate diagnostics. OBJECTIVES: This study was performed to determine the outcome characteristics of biopsy procedures using the results of HistoScanning(TM) analysis (HS) for identifying prostate cancer (PCa) in patients with perineal template-guided prostate biopsy. PATIENTS AND METHODS: A total of 104 consecutive men (mean age 69 years, mean PSA 9.9 ng/ml) underwent HS prior to the extended prostate biopsy procedure. Patients received a targeted transperineal (template-assisted) as well as a targeted transrectal prostate biopsy using HS projection reports supplemented by a standardized 14-core systematic transrectal prostate biopsy (Bx). The cancer detection rate was analyzed on the sector level and HS targeted results were correlated to biopsy outcome, sensitivity, specificity, predictive accuracy, negative predictive value (NPV) and positive predictive value (PPV). RESULTS: Of 104 patients, 44 patients (42%) were found to have PCa. Histology detected atypical small acinar proliferation in 3 patients (2.9%), high-grade prostatic intraepithelial neoplasia in 16 (15.4%), and chronic active inflammation in 74 (71.1%), respectively. The detection rate for each region was significantly higher in HS-targeted biopsies compared to Bx. The detection rate per patient was not significantly different, although a smaller number of regions were biopsied with the targeted approach. The overall sensitivity, specificity, predictive accuracy, NPV, and PPV on the sector level were 37.2, 85.6, 78.6, 88.7 and 30.8%, respectively. CONCLUSION: The use of HS analysis results in a higher detection rate of prostate cancer compared to common transrectal ultrasonography (TRUS) guided Bx. This technique increases the informative value of TRUS imaging and improves the diagnostic impact at least in the targeted biopsy setting. PMID- 25794588 TI - [Treatment of bladder cancer in the elderly]. AB - BACKGROUND: In Germany, bladder cancer is the fourth most common malignancy in males, while it occupies the 14th place in females. About 75% of cases occur in patients aged 65 or more years. OBJECTIVES: Elderly patients with nonmuscle invasive bladder cancer appear to harbor a higher risk of disease recurrence and progression and should undergo the same treatment and careful surveillance as their younger counterparts. Elderly patients with muscle-invasive bladder cancer undergoing radical cystectomy are at an increased risk of perioperative morbidity and mortality and should be referred to experienced high-volume centers. CONCLUSION: Beside radical cystectomy as standard treatment, several bladder sparing approaches (transurethral resection, chemotherapy, radiotherapy, chemoradiotherapy) are available which may be treatment alternatives in carefully selected cases. Valid randomized comparisons between these approaches and radical cystectomy are, however, still lacking. PMID- 25794589 TI - [Superficial bladder cancer: Transurethral resection and instillation therapy]. AB - Bladder cancer is the fifth most common tumor in men with the incidence of bladder tumors continuing to rise in industrialized and developed countries. Because 80% of all bladder tumors grow on the surface, endoscopic transurethral resection (TUR-B) can be used for complete removal. Due to continuous technical developments and improvements of endoscopic equipment, video imaging and bipolar resection (TUR-IS) offers a high level of safety. Despite optimal equipment, intra- and postoperative complications in transurethral electrosurgery of bladder tumors may occur. PMID- 25794590 TI - Palladium-catalyzed C-H functionalization of acyldiazomethane and tandem cross coupling reactions. AB - Palladium-catalyzed C-H functionalization of acyldiazomethanes with aryl iodides has been developed. This reaction is featured by the retention of the diazo functionality in the transformation, thus constituting a novel method for the introduction of diazo functionality to organic molecules. Consistent with the experimental results, the density functional theory (DFT) calculation indicates that the formation of Pd-carbene species in the catalytic cycle through dinitrogen extrusion from the palladium ethyl diazoacetate (Pd-EDA) complex is less favorable. The reaction instead proceeds through Ag2CO3 assisted deprotonation and subsequently reductive elimination to afford the products with diazo functionality remained. This C-H functionalization transformation can be further combined with the recently evolved palladium-catalyzed cross-coupling reaction of diazo compounds with aryl iodides to develop a tandem coupling process for the synthesis of alpha,alpha-diaryl esters. DFT calculation supports the involvement of Pd-carbene as reactive intermediate in the catalytic cycle, which goes through facile carbene migratory insertion with a low energy barrier (3.8 kcal/mol). PMID- 25794591 TI - Correlation between METAVIR scores and Raman spectroscopy in liver lesions induced by hepatitis C virus: a preliminary study. AB - The viral hepatitis C is one of the most important causes of chronic hepatic illness worldwide, affecting around 3 % of the world population. Raman spectroscopy has been employed to distinguish normal from hepatic lesions through differences in the spectral features related to the METAVIR score system. This preliminary study evaluated 11 patients with diagnoses of chronic hepatitis C who underwent hepatic biopsies; the biopsies were submitted to near-infrared Raman spectroscopy using a dispersive spectrometer (830-nm wavelength, 300-mW laser power, and 20-s exposure time). The METAVIR was further scored, and the spectra were submitted to principal component analysis (PCA). The results show a good correlation between the Raman spectroscopy features and the stage of hepatic inflammation and fibrosis. PCA showed that samples with a higher degree of fibrosis presented a higher amount of protein features (collagen), whereas samples with a higher degree of inflammation presented higher features of hemoglobin, in accordance to the expected evolution of chronic hepatitis. Quinone was found to be an important biomarker in early hepatic lesions with a spectral feature at 1595 cm(-1). This study demonstrates that Raman spectroscopy may become an important tool for diagnosing liver disease. PMID- 25794592 TI - Nanoparticle-loaded macrophage-mediated photothermal therapy: potential for glioma treatment. AB - Gold-based nanoparticles have been used in a number of therapeutic and diagnostic applications. The purpose of this study was to investigate the efficacy of gold silica nanoshells (AuNS) in photothermal therapy (PTT) of rat gliomas. Rat alveolar macrophages (Ma) were used as nanoparticle delivery vectors. Uptake of AuNS (bare and PEGylated) was investigated in Ma. AuNS were incubated with Ma for 24 h. Phase contrast microscopy was used to visualize the distribution of loaded Ma in three-dimensional glioma spheroids. PTT efficacy was evaluated for both empty (Ma) and AuNS-loaded Ma (Ma(NS)) in both monolayers and spheroids consisting of C6 rat glioma cells and Ma. Monolayers/spheroids were irradiated for 5 min with light from an 810-nm diode laser at irradiances ranging from 7 to 28 W cm(-2). Monolayer survival was evaluated using a 3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay while PTT efficacy in spheroids was determined from growth kinetics and live/dead fluorescence microscopy. PTT efficacy was investigated in vivo using a Sprague Dawley rat glioma model. Five rats received direct intracranial injection of a mixture of 10(4) C6 glioma cells and, 2 days later, an equal number of Ma(NS). Three rats received laser treatment (810 nm; 10 min; 1 W) while the remaining two served as controls (no laser treatment). The uptake ratio of bare to PEGylated AuNS by Ma was 4:1. A significant photothermal effect was observed in vitro, albeit at relatively high radiant exposures (2.1-4.2 kJ cm(-2)). PTT proved effective in vivo in preventing or delaying tumor development in the PTT-treated animals. PMID- 25794594 TI - [Report by the editor]. PMID- 25794593 TI - Seasonal Variation of Honeybee Pathogens and its Association with Pollen Diversity in Uruguay. AB - Honeybees are susceptible to a wide range of pathogens, which have been related to the occurrence of colony loss episodes reported mainly in north hemisphere countries. Their ability to resist those infections is compromised if they are malnourished or exposed to pesticides. The aim of the present study was to carry out an epidemiological study in Uruguay, South America, in order to evaluate the dynamics and interaction of honeybee pathogens and evaluate their association with the presence of external stress factors such as restricted pollen diversity and presence of agrochemicals. We monitored 40 colonies in two apiaries over 24 months, regularly quantifying colony strength, parasite and pathogen status, and pollen diversity. Chlorinated pesticides, phosphorus, pyrethroid, fipronil, or sulfas were not found in stored pollen in any colony or season. Varroa destructor was widespread in March (end of summer-beginning of autumn), decreasing after acaricide treatments. Viruses ABPV, DWV, and SBV presented a similar trend, while IAPV and KBV were not detected. Nosema ceranae was detected along the year while Nosema apis was detected only in one sample. Fifteen percent of the colonies died, being associated to high V. destructor mite load in March and high N. ceranae spore loads in September. Although similar results have been reported in north hemisphere countries, this is the first study of these characteristics in Uruguay, highlighting the regional importance. On the other side, colonies with pollen of diverse botanical origins showed reduced viral infection levels, suggesting that an adequate nutrition is important for the development of healthy colonies. PMID- 25794595 TI - Magnetic resonance imaging of sellar and juxtasellar abnormalities in the paediatric population: an imaging review. AB - The sellar and juxtasellar regions in the paediatric population are complex both anatomically and pathologically, with magnetic resonance imaging (MRI) being the "gold standard" imaging modality due to the high contrast of detail. Assessment requires a detailed understanding of the anatomy, embryology, pathophysiology and normal signal characteristics of the pituitary gland and surrounding structures in order to appropriately characterise abnormalities. This article aims to provide an overview of the imaging characteristics of developmental/congenital and acquired disease processes which affect the sellar and juxtasellar region in the paediatric population. Main Messages * The sellar region is anatomically complex and covers a wide pathology spectrum. * MRI is the key imaging modality to assess sellar and juxtasellar pathology. * Numerous developmental anomalies may not be discovered until adulthood. * Knowledge of pathology alerts and guides the clinician towards appropriate management. PMID- 25794596 TI - The role of biochar, natural iron oxides, and nanomaterials as soil amendments for immobilizing metals in shooting range soil. AB - High concentration of toxic metals in military shooting range soils poses a significant environmental concern due to the potential release of metals, such as Pb, Cu, and Sb, and hence requires remediation. The current study examined the effectiveness of buffalo weed (Ambrosia trifida L.) biomass and its derived biochars at pyrolytic temperatures of 300 and 700 degrees C, natural iron oxides (NRE), gibbsite, and silver nanoparticles on metal immobilization together with soil quality after 1-year soil incubation. Destructive (e.g., chemical extractions) and non-destructive (e.g., molecular spectroscopy) methods were used to investigate the immobilization efficacy of each amendment on Pb, Cu, and Sb, and to explore the possible immobilization mechanisms. The highest immobilization efficacy was observed with biochar produced at 300 degrees C, showing the maximum decreases of bioavailability by 94 and 70% for Pb and Cu, respectively, which were attributed to the abundance of functional groups in the biochar. Biochar significantly increased the soil pH, cation exchange capacity, and P contents. Indeed, the scanning electron microscopic elemental dot mapping and X ray absorption fine structure spectroscopic (EXAFS) studies revealed associations of Pb with P (i.e., the formation of stable chloropyromorphite [Pb5(PO4)3Cl]) in the biomass- or biochar-amended soils. However, no amendment was effective on Sb immobilization. PMID- 25794597 TI - DNA repair gene XRCC3 Thr241Met polymorphisms and lung cancer risk: a meta analysis. AB - BACKGROUND: The X-ray repair cross-complementing group 3 (XRCC3) is a highly suspected candidate gene for cancer susceptibility, and a large amount studies have examined the association of the rs861539 in XRCC3 (Thr241Met) with lung cancer risk in various populations. However, the results remain inconclusive. METHODS: The electronic database of PubMed, Medline, Embase and CNKI (China National Knowledge Infrastructure) were searched for case-control studies published up to December 05, 2013. A systematic review and meta-analysis was performed to evaluate the relationship between XRCC3 Thr241Met polymorphism and lung cancer risk. Data were extracted and pooled odds ratio (OR) with its 95% confidence intervals (CI) were calculated. RESULTS: Total 21 studies, including 6880 lung cancer cases and 8329 controls, were available for meta-analysis. Overall, our results showed that the XRCC3 Thr241Met polymorphism was not associated with risk of lung cancer in all genetic contrast models (P>0.05). Stratified analyses by ethnicity (Asians, Caucasians and mixed population) showed similar results. Additionally, no evidence of publication bias was observed by using the funnel plot. CONCLUSIONS: There is no clear evidence showing a significant correlation between XRCC3 Thr241Met polymorphism and lung cancer risk in total population and stratified analysis by ethnicity. However, studies assessing the gene-gene interactions should be considered to further estimate this gene variant in lung cancer risk. PMID- 25794598 TI - Overexpression of signal transducers and activators of transcription in embryos derived from vitrified oocytes negatively affect E-cadherin expression and embryo development. AB - Vitrification apart from all drawbacks on oocyte ultra-structure can affect the oocyte mRNA content. Among those evaluated transcripts, no data is available regarding the effect of vitrification on signal transducer and activator of transcription (STAT3) expression in oocytes and the resulting preimplantation embryos. Considering the bidirectional relationship between E-cadherin (CDH1) and STAT3 and the adverse effect of cryopreservation on adherent junctions, we aimed to ascertain to what extent STAT3 and CDH1 genes expression is affected by vitrification in oocytes and the resulting embryos. The ovine vitrified-warmed and fresh GV oocytes were separately subjected to in vitro maturation and fertilization and cultured up to the blastocyst stage. The relative abundance of STAT3 and CDH1 transcripts were analysed by RT-PCR in both classes of fresh and vitrified GV and MII oocytes and the resulting embryos at 2-7 cells, 8-16 cells, morula, and blastocyst stages. Vitrified oocytes showed lower cleavage (37.8% vs. 95.9%, P<0.001) and blastocyst (8.1% vs. 52.7%, P<0.001) rates compared to control. The relative mRNA abundance of both genes was increased after oocyte maturation indicating their expression was started earlier than expected time proposed for embryonic genomic activation. In embryos derived from both fresh and vitrified oocytes, the maximum concentrations of STAT3 and CDH1 transcripts were observed at 2-7 cells and morula stages, respectively. Moreover, in contrast to CDH1 the relative expression of STAT3 in vitrified derived embryos was higher than embryos derived from fresh oocytes. The overexpression of STAT3 in embryos derived from vitrified oocytes might be the reason for the lower CDH1 expression and in turn the lower developmental competence of the resulting embryos. PMID- 25794599 TI - Predicting clinical response in people at ultra-high risk of psychosis: a systematic and quantitative review. AB - People at ultra-high risk (UHR) of psychosis have ~30% chance of developing the illness within two years. A range of pharmacological and psychosocial interventions are now available but there is great individual variation in clinical response. Here we examine the evidence for clinically applicable predictors of clinical response in people at UHR of psychosis. We report that currently there are no reliable predictive markers that can be used to optimise treatment. We argue that there is an urgent need for a better understanding of why some people at UHR of psychosis benefit from a certain treatment whereas others do not. This information will help clinicians make more-effective treatment decisions, and improve long-term clinical outcomes in this population. PMID- 25794601 TI - Cancer Research UK Centre for Drug Development: translating 21st-century science into the cancer medicines of tomorrow. AB - The Cancer Research UK Centre (CRUK) for Drug Development (CDD) can trace its origins back to the Cancer Research Campaign Phase I/II Committee (created in 1980) and to date has tested over 120 potential cancer medicines in early-phase clinical trials. Five drugs are now registered, providing benefit to thousands of patients with cancer as part of their routine standard of care. In recent years, the CDD has established several different business and operating models that provide it with access to the pipelines of pharmaceutical and biotechnology companies. This has enabled potential new treatments to be taken into clinical development that might have otherwise languished on companies' shelves and has increased the number of drug combinations being explored in early-phase clinical trials. PMID- 25794600 TI - Pragmatic randomized trials in drug development pose new ethical questions: a systematic review. AB - Implementation of pragmatic design elements in drug development could bridge the evidence gap that currently exists between the knowledge we have regarding the efficacy of a drug versus its true, comparative effectiveness in real life. We performed a review of the literature to identify the ethical challenges thus far related to pragmatic trials. The three central ethical questions identified for pragmatic trials are: (i) what level of oversight should pragmatic trials require; (ii) do randomized patients face additional risks; and (iii) is a waiver of informed consent ethically defensible? Despite the fact all reviewed publications dealt with post-launch pragmatic trials, these results could serve as an important starting point for conceptualizing which challenges could potentially arise in the pre-launch setting. PMID- 25794602 TI - Molecular basis for nonspecificity of nonsteroidal anti-inflammatory drugs (NSAIDs). AB - Inhibition of the production of inflammatory mediators by the action of nonsteroidal anti-inflammatory drugs (NSAIDs) is highly accredited to their recognition of cyclooxygenase enzymes. Along with inflammation relief, however, NSAIDs also cause adverse effects. Although NSAIDs strongly inhibit enzymes of the prostaglandin synthesis pathways, several other proteins also serve as fairly potent targets for these drugs. Based on their recognition pattern, these receptors are categorised as enzymes modifying NSAIDs, noncatalytic proteins binding to NSAIDs and enzymes with catalytic functions that are inhibited by NSAIDs. The extensive binding of NSAIDs is responsible for their limited in vivo efficacy as well as the large spectrum of their effects. The biochemical nature of drugs binding to multiple protein targets and its implications on physiology are discussed. PMID- 25794603 TI - Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. AB - AIM: To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination. METHODS: HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms. RESULTS: Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy. CONCLUSION: This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648). PMID- 25794604 TI - Early tumour shrinkage as a prognostic factor and surrogate end-point in colorectal cancer: a systematic review and pooled-analysis. AB - PURPOSE: Early tumour shrinkage (ETS), defined as a reduction of at least 20% in tumour size at first reassessment, has been recently investigated retrospectively in first-line trials of metastatic colorectal cancer (CRC), and appears to be associated with better outcomes. We have performed a systematic review and meta analysis of published trials to evaluate the prognostic value of ETS in CRC in terms of overall survival (OS) and progression-free survival (PFS). MATERIAL AND METHODS: An electronic search of the PubMed, SCOPUS, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trial databases identified trials that compared outcomes of patients with or without ETS during first-line chemotherapy for metastatic CRC. The OS, reported as a hazard ratio (HR) with a 95% confidence interval (CI), was the primary outcome measure; the correlation coefficient (R) between ETS with median OS was also estimated. RESULTS: Twenty one trials from 10 publications were analysed. Overall, patients with ETS were associated with a better OS (HR, 0.58; 95% CI, 0.53 to 0.64; P<0.00001) and PFS (HR, 0.57; 95% CI, 0.47-0.69; P<0.00001) compared with patients who were early non-responders. However, ETS was poorly correlated with OS in terms of surrogacy (R=0.37; 95% CI - 0.31-0.78; P=0.28). CONCLUSIONS: ETS is a good prognostic factor but an inappropriate surrogate for predicting outcome in CRC patients. These findings support ETS as prognostic tool in ascertaining earlier non responders; however, its role as a surrogate end-point deserves further evaluation. PMID- 25794605 TI - Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study. AB - BACKGROUND: The optimal timing to start androgen deprivation therapy (ADT) in prostate cancer patients with rising prostate-specific antigen (PSA) as the only sign of relapse is unknown. METHODS: We identified men with prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) study who would have been eligible (? cT3aN0M0, primary radical prostatectomy or radiotherapy, PSA relapse as the only evidence of recurrence) for a randomised trial comparing 'immediate' versus 'deferred' ADT initiation. We emulated such trial by assigning patients to the 'immediate' strategy if they initiated ADT within 3 months of PSA relapse and to the 'deferred' strategy if they initiated ADT when they presented with metastasis, symptoms or a short PSA doubling time. We censored patients when they deviated from the assigned strategy and adjusted for this censoring via inverse probability weighting. RESULTS: Of 2096 eligible patients (median age 69, interquartile range 63-75 years), 88% were white, 35% had a Gleason score ? 7, 69% were treated with radical prostatectomy and 31% received radiotherapy only as primary treatment. The mean time from primary treatment to PSA relapse was 37.4 (standard deviation [SD] 34.2) months. Mean follow-up from primary treatment was 91.4 (SD 48.4) months. The adjusted mortality hazard ratio for immediate versus deferred ADT was 0.91 (95% confidence interval (CI), 0.52-1.60), which would be translated into a similar 5-year survival (difference between groups: -2.0% (95% CI: -10.0 to 5.9%). CONCLUSION: Our analysis suggests that prostate cancer patients undergoing immediate ADT initiation within three months after PSA-only relapse had similar survival to those who deferred ADT initiation within 3 months after clinical progression. PMID- 25794606 TI - 443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011. AB - BACKGROUND: Malignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents. METHODS: 443 patients ? 18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan-Meier method. RESULTS: Age of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182). CONCLUSION: Patient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used. PMID- 25794607 TI - Protective roles of selenium and zinc against postnatal protein-undernutrition induced alterations in Ca(2+)-homeostasis leading to cognitive deficits in Wistar rats. AB - Postnatal protein-undernutrition impacts on mental development and cognition in children and can lead to problem with attention and unresponsiveness which compromise children's ability to learn. These behavioral disorders might be due to alteration in calcium homeostasis as calcium plays critical roles in fundamental functions of neuron. The role of low protein diet as well as Se and Zn supplementation on intracellular calcium concentration ([Ca(2+)]i), Ca(2+) ATPase, Na(+)-K(+)-ATPase, calpain and caspase-3 activities from rat cortex and cerebellum were investigated. Well-fed (WF) and low protein diet-fed (LPDF) rats were given diets containing 16% and 5% casein, respectively, for a period of 10 weeks. Then, the rats were supplemented with Se and Zn at a concentration of 0.15 mgL(-1) and 227 mgL(-1), respectively, in drinking water for 3 weeks. The results obtained from the study showed a significant increase in [Ca(2+)]i; calpain and caspase-3 activities as well as increase transfer latency in water maze study and reductions in Ca(2+)-ATPase and Na(+)-K(+)-ATPase activities for LPDF rats compared to WF rats. Se and Zn supplementation to LPDF rats reversed the elevation in [Ca(2+)]i, calpain and caspase-3 activities and restored the cognitive deficits and the activities of Ca(2+)-ATPase and Na(+)-K(+)-ATPase. Conclusively, protein-undernutrition results in the accumulation of synaptosomal calcium and inhibition of calcium transporters presumably via free radical generations and results in cognitive impairment which also probably results from neuronal death in rats through calpain activation and the caspase cascade mechanisms. However, Se and Zn supplementations ameliorated the anomalies observed. PMID- 25794608 TI - Preparation and characterization of azithromycin--Aerosil 200 solid dispersions with enhanced physical stability. AB - The main purpose of this study was to investigate the feasibility of azithromycin (AZI)--Aerosil 200 solid dispersions specifically with high stability under accelerated condition (40 degrees C/75% RH). Ball milling (BM) and hot-melt extrusion (HME) were used to prepare AZI solid dispersions. The physical properties of solid dispersions were evaluated by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA). For solid dispersions prepared with both methods, no crystalline of AZI was detected (except for AZI: Aerosil 200=75:25) by DSC or PXRD, indicating the amorphous state of AZI in solid dispersions. The FT-IR results demonstrated the loss of crystallization water and the formation of hydrogen bonds between Aerosil 200 and AZI during the preparation of solid dispersions. After 4 weeks storage under accelerated condition, the degree of crystallinity of AZI increased in solid dispersions prepared by BM, whereas for solid dispersions containing AZI, Aerosil 200 and glyceryl behenate (GB) prepared by HME, no crystalline of AZI was identified. This high stability can be attributed to the hydrophobic properties of GB and the presence of hydrogen bonds. Based on the above results, it is inferred the protection of hydrogen bonds between AZI and Aerosil 200 formed during preparation process effectively inhibited the recrystallization of AZI and improved the physical stability of amorphous AZI in the presence of Aerosil 200. PMID- 25794609 TI - Design and preclinical characterization of a novel vaccine adjuvant formulation consisting of a synthetic TLR4 agonist in a thermoreversible squalene emulsion. AB - We describe the development, analytical characterization, stability and preclinical efficacy of AF04, a combination adjuvant comprising the synthetic toll-like receptor 4 (TLR4) agonist, E6020, formulated in AF03, a thermoreversible squalene emulsion. By using AF04 with the recombinant major outer membrane protein of Chlamydia trachomatis (Ct-MOMP) and with the recombinant surface glycoprotein gB from human cytomegalovirus (CMV-gB) as model antigens, we show that AF03 and E6020 can synergize to augment specific antibody and Th-1 cellular immune responses in mice. In terms of formulation, we observe that the method used to incorporate E6020 into AF03 affects its partition between the oil and water phases of the emulsion which in turn has a significant impact on the tolerability (IV pyrogenicity test in rabbits) of this novel adjuvant combination. PMID- 25794610 TI - Use of Oral Contrast for Abdominal Computed Tomography in Children With Blunt Torso Trauma. AB - STUDY OBJECTIVE: We compare test characteristics of abdominal computed tomography (CT) with and without oral contrast for identifying intra-abdominal injuries. METHODS: This was a planned subanalysis of a prospective, multicenter study of children (<18 years) with blunt torso trauma. Children imaged in the emergency department with abdominal CT using intravenous contrast were eligible. Oral contrast use was based on the participating centers' guidelines and discretions. Clinical courses were followed to identify patients with intra-abdominal injuries. Abdominal CTs were considered positive for intra-abdominal injury if a specific intra-abdominal injury was identified and considered abnormal if any findings suggestive of intra-abdominal injury were identified on the CT. RESULTS: A total of 12,044 patients were enrolled, with 5,276 undergoing abdominal CT with intravenous contrast. Of the 4,987 CTs (95%) with documented use or nonuse of oral contrast, 1,010 (20%) were with and 3,977 (80%) were without oral contrast; 686 patients (14%) had intra-abdominal injuries, including 127 CTs (19%) with and 559 (81%) without oral contrast. The sensitivity in the detection of any intra abdominal injury in the oral contrast versus no oral contrast groups was sensitivitycontrast 99.2% (95% confidence interval [CI] 95.7% to 100.0%) versus sensitivityno contrast 97.7% (95% CI 96.1% to 98.8%), difference 1.5% (95% CI 0.4% to 3.5%). The specificity of the oral contrast versus no oral contrast groups was specificitycontrast 84.7% (95% CI 82.2% to 87.0%) versus specificityno contrast 80.8% (95% CI 79.4% to 82.1%), difference 4.0% (95% CI 1.3% to 6.7%). CONCLUSION: Oral contrast is still used in a substantial portion of children undergoing abdominal CT after blunt torso trauma. With the exception of a slightly better specificity, test characteristics for detecting intra-abdominal injury were similar between CT with and without oral contrast. PMID- 25794611 TI - Molecular toggle switch of histone demethylase LSD1. AB - In this issue of Molecular Cell, Laurent et al. (2015) demonstrated that a neuron enriched isoform of LSD1 (LSD1+8a) within a SVIL-containing complex exhibits H3K9me1/2-specific demethylation activity. Such activity was crucial for gene activation during mammalian neurogenesis. PMID- 25794612 TI - Tuberculosis: hey there, lonely guy! AB - In this issue of Molecular Cell,Samanovic et al. (2015) identify that the mycobacterial proteasomal substrate encoded by Rv1205, which appears to code for a homolog of the plant-like enzyme LONELY GUY, is responsible for proteasome mediated nitric oxide resistance. PMID- 25794613 TI - All in the family: a portrait of a nuclear receptor co-activator complex. AB - In this issue of Molecular Cell, Yi et al. (2015) use biochemical assays and cryo EM to determine the molecular architecture of an estrogen receptor (ERalpha) co activator complex bound to DNA. PMID- 25794614 TI - TopBP1 stabilizes BLM protein to suppress sister chromatid exchange. PMID- 25794616 TI - Multiple mechanisms of reinitiation on bicistronic calicivirus mRNAs. AB - Reinitiation is a strategy used by viruses to express several cistrons from one mRNA. Although extremely weak after translation of long open reading frames (ORFs) on cellular mRNAs, reinitiation occurs efficiently on subgenomic bicistronic calicivirus mRNAs, enabling synthesis of minor capsid proteins. The process is governed by a short element upstream of the restart AUG, designated "termination upstream ribosomal binding site" (TURBS). It contains the conserved Motif 1 complementary to h26 of 18S rRNA, displayed in the loop of a hairpin formed by species-specific Motifs 2/2(*). To determine the advantages conferred on reinitiation by TURBS, we reconstituted this process in vitro on two model bicistronic calicivirus mRNAs. We found that post-termination ribosomal tethering of mRNA by TURBS allows reinitiation by post-termination 80S ribosomes and diminishes dependence on eukaryotic initiation factor 3 (eIF3) of reinitiation by recycled 40S subunits, which can be mediated either by eIFs 2/1/1A or by Ligatin following ABCE1-dependent or -independent splitting of post-termination complexes. PMID- 25794615 TI - The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain. AB - DNA binding by numerous transcription factors including the p53 tumor suppressor protein constitutes a vital early step in transcriptional activation. While the role of the central core DNA binding domain (DBD) of p53 in site-specific DNA binding has been established, the contribution of the sequence-independent C terminal domain (CTD) is still not well understood. We investigated the DNA binding properties of a series of p53 CTD variants using a combination of in vitro biochemical analyses and in vivo binding experiments. Our results provide several unanticipated and interconnected findings. First, the CTD enables DNA binding in a sequence-dependent manner that is drastically altered by either its modification or deletion. Second, dependence on the CTD correlates with the extent to which the p53 binding site deviates from the canonical consensus sequence. Third, the CTD enables stable formation of p53-DNA complexes to divergent binding sites via DNA-induced conformational changes within the DBD itself. PMID- 25794617 TI - Bacterial riboswitches cooperatively bind Ni(2+) or Co(2+) ions and control expression of heavy metal transporters. AB - Bacteria regularly encounter widely varying metal concentrations in their surrounding environment. As metals become depleted or, conversely, accrue to toxicity, microbes will activate cellular responses that act to maintain metal homeostasis. A suite of metal-sensing regulatory ("metalloregulatory") proteins orchestrate these responses by allosterically coupling the selective binding of target metals to the activity of DNA-binding domains. However, we report here the discovery, validation, and structural details of a widespread class of riboswitch RNAs, whose members selectively and tightly bind the low-abundance transition metals, Ni(2+) and Co(2+). These riboswitches bind metal cooperatively, and with affinities in the low micromolar range. The structure of a Co(2+)-bound RNA reveals a network of molecular contacts that explains how it achieves cooperative binding between adjacent sites. These findings reveal that bacteria have evolved to utilize highly selective metalloregulatory riboswitches, in addition to metalloregulatory proteins, for detecting and responding to toxic levels of heavy metals. PMID- 25794618 TI - The ubiquitous yybP-ykoY riboswitch is a manganese-responsive regulatory element. AB - The highly structured, cis-encoded RNA elements known as riboswitches modify gene expression upon binding a wide range of molecules. The yybP-ykoY motif was one of the most broadly distributed and numerous bacterial riboswitches for which the cognate ligand was unknown. Using a combination of in vivo reporter and in vitro expression assays, equilibrium dialysis, and northern analysis, we show that the yybP-ykoY motif responds directly to manganese ions in both Escherichia coli and Bacillus subtilis. The identification of the yybP-ykoY motif as a manganese ion sensor suggests that the genes that are preceded by this motif and encode a diverse set of poorly characterized membrane proteins have roles in metal homeostasis. PMID- 25794619 TI - Mn(2+)-sensing mechanisms of yybP-ykoY orphan riboswitches. AB - Gene regulation in cis by riboswitches is prevalent in bacteria. The yybP-ykoY riboswitch family is quite widespread, yet its ligand and function remained unknown. Here, we characterize the Lactococcus lactis yybP-ykoY orphan riboswitch as a Mn(2+)-dependent transcription-ON riboswitch, with a ~30-40 MUM affinity for Mn(2+). We further determined its crystal structure at 2.7 A to elucidate the metal sensing mechanism. The riboswitch resembles a hairpin, with two coaxially stacked helices tethered by a four-way junction and a tertiary docking interface. The Mn(2+)-sensing region, strategically located at the highly conserved docking interface, has two metal binding sites. Whereas one site tolerates the binding of either Mg(2+) or Mn(2+), the other site strongly prefers Mn(2+) due to a direct contact from the N7 of an invariable adenosine. Mutagenesis and a Mn(2+)-free E. coli yybP-ykoY structure further reveal that Mn(2+) binding is coupled with stabilization of the Mn(2+)-sensing region and the aptamer domain. PMID- 25794621 TI - Non-invasive quantitative pulmonary V/Q imaging using Fourier decomposition MRI at 1.5T. AB - OBJECTIVES: Techniques for quantitative pulmonary perfusion and ventilation using the Fourier Decomposition method were recently demonstrated. We combine these two techniques and show that ventilation-perfusion (V/Q) imaging is possible using only a single MR acquisition of less than thirty seconds. METHODS: The Fourier Decomposition method is used in combination with two quantification techniques, which extract baselines from within the images themselves and thus allows quantification. For the perfusion, a region assumed to consist of 100% blood is utilized, while for the ventilation the zero-frequency component is used. V/Q imaging is then done by dividing the quantified ventilation map with the quantified perfusion map. The techniques were used on ten healthy volunteers and fifteen patients diagnosed with lung cancer. RESULTS: A mean V/Q-ratio of 1.15 +/ 0.22 was found for the healthy volunteers and a mean V/Q-ratio of 1.93 +/- 0.83 for the non-afflicted lung in the patients. Mean V/Q-ratio in the afflicted (tumor-bearing) lung was found to be 1.61 +/- 1.06. Functional defects were clearly visible in many of the patient images, but 5 of 15 patient images had to be excluded due to artifacts or low SNR, indicating a lack of robustness. CONCLUSION: Non-invasive, quantitative V/Q-imaging is possible using Fourier Decomposition MRI. The method requires only a single acquisition of less than 30 seconds, but robustness in patients remains an issue. PMID- 25794620 TI - TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation. AB - The Bloom syndrome helicase BLM and topoisomerase-IIbeta-binding protein 1 (TopBP1) are key regulators of genome stability. It was recently proposed that BLM phosphorylation on Ser338 mediates its interaction with TopBP1, to protect BLM from ubiquitylation and degradation (Wang et al., 2013). Here, we show that the BLM-TopBP1 interaction does not involve Ser338 but instead requires BLM phosphorylation on Ser304. Furthermore, we establish that disrupting this interaction does not markedly affect BLM stability. However, BLM-TopBP1 binding is important for maintaining genome integrity, because in its absence cells display increased sister chromatid exchanges, replication origin firing and chromosomal aberrations. Therefore, the BLM-TopBP1 interaction maintains genome stability not by controlling BLM protein levels, but via another as-yet undetermined mechanism. Finally, we identify critical residues that mediate interactions between TopBP1 and MDC1, and between BLM and TOP3A/RMI1/RMI2. Taken together, our findings provide molecular insights into a key tumor suppressor and genome stability network. PMID- 25794622 TI - In Vitro, Pharmacokinetic, Pharmacodynamic, and Safety Comparisons of Single and Combined Administration of Tiotropium and Salmeterol in COPD Patients Using Different Dry Powder Inhalers. AB - In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 MUm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 MUg tiotropium/25 MUg salmeterol (TSHH) were similar (within +/-15%) to reference products containing 18 MUg of tiotropium (Spiriva(r) HandiHaler(r)) (TioHH) and 50 MUg of salmeterol (Serevent(r) Diskus(r)) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, four-way crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and Cmax,ss. No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product. PMID- 25794623 TI - Developing and Assessing Nutrition Education Handouts (DANEH): Testing the Validity and Reliability of the New Tool. PMID- 25794624 TI - Why the Collaboration With the World Health Organization (WHO) Is Important for Specialists in Physical and Rehabilitation Medicine. PMID- 25794625 TI - Rehabilitation Management of Hemicorporectomy. AB - This is a case report of a 55-year-old woman who was treated with a hemicorporectomy consequent to an invasive undifferentiated sacral chordoma. We describe the clinical course and rehabilitation process in an amputee outpatient clinic and report outcome measures such as the modified Functional Reach Test, the Amputee Mobility Predictor, the Functional Independence Measure, and the Short-Form Health Survey after 9 months of rehabilitation. PMID- 25794626 TI - Clinicopathological factors and long-term outcome comparing between lung and peritoneal metastasectomy after hepatectomy for hepatocellular carcinoma in a tertiary institution. AB - BACKGROUND: Recurrence after liver resection for hepatocellular carcinoma (HCC) is common. Resection of extrahepatic recurrences such as lung metastasectomy (LM) has been well documented. Conversely, reports on the long-term outcomes of peritoneal metastasectomy (PM) are lacking. In this study, we compared the outcome of lung and peritoneal metastasectomy after hepatectomies for HCC in a tertiary institution. METHODS: We reviewed retrospectively the data of 1,222 patients who underwent hepatectomies for HCC in Samsung Medical Center in Korea from January 2006 to August 2010. We studied the clinicopathologic factors between resected lung metastasis (LM) and peritoneal metastases (PM) and the long term outcome of patient survival. Kaplan-Meier analysis was used to study the survival outcome. RESULTS: The recurrence rate of resected HCC in this cohort was 41.6% (n = 508). Thirty-two patients with lung metastasis (23% of all lung metastasis) underwent LM whereas 13 patients (36% of all peritoneal metastasis) with peritoneal metastasis underwent PM. Two patients underwent PM and LM sequentially. Demographic and clinical data between the LM and PM groups were comparable. The mean prehepatectomy PIVKA-II level was greater in the LM group compared with the PM group (P = .029). On univariate analysis of pathologic factors, the median tumor size (P = .005), proportion of patients with tumor >75 mm (P = .005) and rate of microvascular invasion (P = .047) were greater in the LM group. The median time-to-recurrence in the LM group was 12 (4-45) months compared with 18 (1-102) months in the PM group (P = .896). The 1-year, 3-year, and 5-year overall survival of patients in the LM group was 92%, 55%, 55% (4 year) whereas that in the PM group was 90%, 75%, and 75%, respectively. The mean overall survival in the LM was comparable with that in the PM group (P = .578). CONCLUSION: Twenty-three percent of patients with lung metastasis and 36.1% of patients with peritoneal metastasis could be considered for metastasectomy. The long-term survival of patients with PM and LM was comparable in this study. Although resection of LM improves survival in patients with resected HCC, we demonstrated favorable outcomes for PM as well, which in the past would have been considered palliative. PMID- 25794627 TI - A systematic review to identify the factors that affect failure to rescue and escalation of care in surgery. AB - BACKGROUND: The relationship between the ability to recognize and respond to patient deterioration (escalate care) and its role in preventing failure to rescue (FTR; mortality after a surgical complication) has not been explored. The aim of this systematic review was to determine the incidence of, and factors contributing to, FTR and delayed escalation of care for surgical patients. METHODS: A search of MEDLINE, EMBASE PsycINFO, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials was conducted to identify articles exploring FTR, escalation of care, and interventions that influence outcomes. Screening of 19,887 citations led to inclusion of 42 articles. RESULTS: The reported incidence of FTR varied between 8.0 and 16.9%. FTR was inversely related to hospital volume and nurse staffing levels. Delayed escalation occurred in 20.7-47.1% of patients and was associated with greater mortality rates in 4 studies (P < .05). Causes of delayed escalation included hierarchy and failures in communication. Of five interventional studies, two reported a significant decrease in intensive care admissions (P < .01) after introduction of escalation protocols; only 1 study reported an improvement in mortality. CONCLUSION: This systematic review explored factors linking FTR and escalation of care in surgery. Important factors that contribute to the avoidance of preventable harm include the recognition and communication of serious deterioration to implement definitive treatment. Targeted interventions aiming to improve these factors may contribute to enhanced patient outcome. PMID- 25794628 TI - The GoMo study: a randomized clinical trial assessing neonatal pain with Gomco vs Mogen clamp circumcision. AB - OBJECTIVE: Our objective was to compare the pain/stress levels of newborns among the 2 most common circumcision techniques after resident-wide education. STUDY DESIGN: The study period of this randomized control trial was October 2012 through March 2014. Following informed consent, full-term males from uncomplicated singleton pregnancies were randomized to Gomco (n=137) or Mogen (n=137) devices. Resident-wide education for an obstetrics and gynecology residency program at a single institution was performed to ensure standardized training. All infants received a subcutaneous ring block before the procedure and oral sucrose intraoperatively. The primary outcome was neonatal pain assessed physiologically by salivary cortisol levels (enzyme-linked immunosorbent assay) and clinically by a validated neonatal pain score (crying, requires increased oxygen administration, increased vital signs, expression, sleeplessness [CRIES]). Secondary outcomes were immediate complications, duration of procedure, and short term outcomes as reported by mothers and pediatricians. A sample size of 274 (accounting for 20% loss of follow-up) was determined sufficient to detect a mean difference of 1.22 MUg/dL in cortisol levels (Gomco, SD+/-3.34; Mogen, SD+/-0.81) with 80% power, P=.05 level of significance. RESULTS: A total of 251 infants completed the protocol. There were no significant differences in maternal or neonatal demographics including preoperative heart rate and mean arterial pressure. In the Mogen circumcision, the percentage change of cortisol was significantly lower than Gomco (279.1+/-498.15 vs 167.75+/-272.22; P=.049). There were no differences in postoperative CRIES scores. Postoperative heart rate was higher in infants undergoing Gomco circumcision than Mogen circumcision (138.7+/ 16.5 vs 133.4+/-17.5; P=.015) as was mean arterial blood pressure (63.3+/-9.2 vs 60.4+/-8.6; P=.012). Mogen circumcisions were shorter (7.00+/-2.97 vs 3.65+/-1.84 minutes; P<.001). There were no significant differences in bleeding complications. A total of 168 maternal surveys were completed, with 98.7% maternal satisfaction in Gomco vs 98.9% in Mogen. There were no reports of bleeding after discharge or circumcision revisions in either group to date. CONCLUSION: Mogen clamp is associated with less neonatal pain physiologically by significantly lower percentage change in salivary cortisol, lower heart rate, and mean arterial blood pressure. There was no difference in CRIES scores. Mogen clamp circumcision duration is significantly shorter than Gomco clamp. Both methods demonstrate satisfactory maternal and pediatrician short-term follow-up. PMID- 25794629 TI - Does the number of forceps deliveries performed in residency predict use in practice? AB - OBJECTIVE: We aimed to determine whether a threshold number of forceps deliveries in residency predicts use of forceps in independent practice. STUDY DESIGN: We surveyed obstetrics and gynecology residency graduates of 2 academic programs from 2008 through 2012 regarding the use of operative vaginal delivery in practice. At these programs, residents are trained in both forceps and vacuums. Individual case log data were obtained with the number of forceps deliveries performed by each respondent during residency. Respondents were grouped as currently using any forceps or vacuums alone. A logistic regression model estimated the probability of forceps use, predicted by the number of residency forceps deliveries. From the resulting receiver-operating characteristic curve, we assessed sensitivity, specificity, positive predictive value, and area under the curve. RESULTS: The response rate was 85% (n = 58) and 90% (n = 52) practice obstetrics. Seventy-nine percent (n = 41) use forceps in practice. The mean number of forceps performed during residency was 22.3 +/- 1.3 (mean +/- SE) in the any-forceps group and 18.5 +/- 2.1 in the vacuums-only group (P = .14). Although the model performed only moderately (area under the curve, 0.61, 95% confidence interval [CI], 0.42-0.81), more than 13 residency forceps deliveries corresponded to a 95% sensitivity (95% CI, 84-99) and a positive predictive value of 83% (95% CI, 69-92) for using forceps in practice. The specificity of this threshold is 27% (95% CI, 6-61). CONCLUSION: Although exceeding 13 forceps deliveries made it highly likely that obstetricians would use them in practice, further study is necessary to set goals for a number of resident forceps deliveries that translate into use in practice. PMID- 25794630 TI - Considerations about retirement from clinical practice by obstetrician gynecologists. AB - Retirement of obstetrician-gynecologists is becoming a matter of increasing concern in light of an expected shortage of practicing physicians. Determining a retirement age is often complex. We address what constitutes a usual retirement age range from general clinical practice for an obstetrician-gynecologist, compare this with practitioners in other specialties, and suggest factors of importance to obstetrician-gynecologists before retirement. Although the proportion of obstetrician-gynecologists >=55 years old is similar to other specialists, obstetrician-gynecologists retire at younger ages than male or female physicians in other specialties. A customary age range of retirement from obstetrician-gynecologist practice would be 59-69 years (median, 64 years). Women, who constitute a growing proportion of obstetrician-gynecologists in practice, retire earlier than men. The large cohort of "baby boomer" physicians who are approaching retirement (approximately 15,000 obstetrician-gynecologists) deserves tracking while an investigation of integrated women's health care delivery models is conducted. Relevant considerations would include strategies to extend the work longevity of those who are considering early retirement or desiring part-time employment. Likewise volunteer work in underserved community clinics or teaching medical students and residents offers continuing personal satisfaction for many retirees and preservation of self-esteem and medical knowledge. PMID- 25794632 TI - Hepatitis B virus (HBV) infection and multiple sclerosis: One more reason to undergo vaccination? PMID- 25794631 TI - The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsia. AB - Preeclampsia is a syndrome occurring only in pregnancy characterized by systemic maternal inflammation and associated with the presence of the placenta. How these 2 aspects of the disease are linked has been the subject of numerous theories and ideas. Recently, there has been increasing interest in DNA shed from the placenta into the maternal circulation as a potential agent initiating the inflammatory response. This review will discuss the current evidence and future directions for placental DNA as the linking factor in preeclampsia in the context of other hypotheses. PMID- 25794634 TI - Peyer's patch innate lymphoid cells regulate commensal bacteria expansion. AB - Anatomical containment of commensal bacteria in the intestinal mucosa is promoted by innate lymphoid cells (ILCs). However, the mechanism by which ILCs regulate bacterial localization to specific regions remains unknown. Here we show that Peyer's patch (PP) ILCs robustly produce IL-22 and IFN-gamma in the absence of exogenous stimuli. Antibiotic treatment of mice decreased both IL-22+ and IFN gamma+ cells in PPs. Blockade of both IL-2 and IL-23 signaling in vitro lowered IL-22 and IFN-gamma production. PP ILCs induced mRNA expression of the antibacterial proteins RegIIIbeta and RegIIIgamma in intestinal epithelial cells. Furthermore, in vivo depletion of ILCs rather than T cells altered bacterial composition and allowed bacterial proliferation in PPs. Collectively, our results show that ILCs regulate the expansion of commensal bacteria in PPs. PMID- 25794633 TI - Lipopolysaccharide directly stimulates Th17 differentiation in vitro modulating phosphorylation of RelB and NF-kappaB1. AB - Toll-like receptors (TLRs) recognize a wide range of pathogen-associated molecular patterns (PAMP) and are preferentially expressed in innate immune cells. TLR-mediated activation of these cells activates the adaptive immune system. However, it has become clear that TLRs are not only expressed but also functionally active in CD4 T cells. The intestines are continuously exposed to TLR ligands, including lipopolysaccharide (LPS), a TLR4 ligand, and TLR4 is expressed higher in Th17 cells than Th1 and Th2 cells. In addition, development of Th17 cells in the gut mucosa is more dependent on gut microbiota than Th1, Th2, and Treg. Thus, we examined whether LPS directly regulates Th17 differentiation. LPS directly stimulated Th17 differentiation in vitro. In Th17 cells, LPS increased phosphorylation of NF-kappaB1, resulting in an increase of p50, the processed form of NF-kappaB1, whereas it decreased phosphorylation of RelB, leading to the up-regulation of RelB. Subcutaneous injection of LPS increased the frequency of IL-17 producing cells in inguinal lymph nodes, worsening experimental autoimmune encephalomyelitis (EAE). Additionally, expression of TLR1, TLR2, TLR4, and TLR5 was reduced upon T cell activation and LPS showed modest effect on TLR4 expression. These findings provide the first evidence that TLR4 activation directly regulate Th17 differentiation. PMID- 25794635 TI - Sleep Quality and Risk of Dementia Among Older Male Veterans. AB - OBJECTIVE: To determine whether a diagnosis of sleep disturbance is associated with dementia in older veterans. METHODS: For this retrospective cohort study, we obtained medical record data from the Department of Veterans Affairs National Patient Care Database for 200,000 randomly selected veterans aged 55 years and older. Prevalent cases of dementia from the baseline period (2000-2003) were excluded, leaving an analytic sample of 179,738 male veterans. Follow-up took place from 2004 to 2011. The primary outcome was all-cause dementia, ascertained using International Classification of Disease, Ninth Revision codes. Sleep disturbance, the primary predictor, was also ascertained using these codes. RESULTS: After adjusting for potential confounders, those with sleep disturbance had a 27% increased risk of dementia (hazard ratio: 1.27; 95% confidence interval: 1.20-1.34). CONCLUSION: Sleep disturbance was associated with increased risk of dementia among a large cohort of older, primarily male veterans. PMID- 25794636 TI - Clinical Case Management versus Case Management with Problem-Solving Therapy in Low-Income, Disabled Elders with Major Depression: A Randomized Clinical Trial. AB - OBJECTIVE: To test the hypotheses that (1) clinical case management integrated with problem-solving therapy (CM-PST) is more effective than clinical case management alone (CM) in reducing depressive symptoms of depressed, disabled, impoverished patients and that (2) development of problem-solving skills mediates improvement of depression. METHODS: This randomized clinical trial with a parallel design allocated participants to CM or CM-PST at 1:1 ratio. Raters were blind to patients' assignments. Two hundred seventy-one individuals were screened and 171 were randomized to 12 weekly sessions of either CM or CM-PST. Participants were at least 60 years old with major depression measured with the 24-item Hamilton Depression Rating Scale (HAM-D), had at least one disability, were eligible for home-based meals services, and had income no more than 30% of their counties' median. RESULTS: CM and CM-PST led to similar declines in HAM-D over 12 weeks (t = 0.37, df = 547, p = 0.71); CM was noninferior to CM-PST. The entire study group (CM plus CM-PST) had a 9.6-point decline in HAM-D (t = 18.7, df = 547, p <0.0001). The response (42.5% versus 33.3%) and remission (37.9% versus 31.0%) rates were similar (chi(2) = 1.5, df = 1, p = 0.22 and chi(2) = 0.9, df = 1, p = 0.34, respectively). Development of problem-solving skills did not mediate treatment outcomes. There was no significant increase in depression between the end of interventions and 12 weeks later (0.7 HAM-D point increase) (t = 1.36, df = 719, p = 0.17). CONCLUSION: Organizations offering CM are available across the nation. With training in CM, their social workers can serve the many depressed, disabled, low-income patients, most of whom have poor response to antidepressants even when combined with psychotherapy. PMID- 25794637 TI - Immunoreactivity of neurogenic factor in the guinea pig brain after prenatal hypoxia. AB - Chronic prenatal hypoxia is considered to cause perinatal brain injury. It can result in neurological disorders such as cerebral palsy or learning disabilities. These neurological problems are related to chronic placental insufficiency (CPI), which leads to chronic hypoxemia and hypoglycemia. The effects of hypoxia on neurogenesis during development have been a matter of controversy. We therefore investigated the effect of chronic prenatal hypoxia in the brain of the fetal guinea pig using the guinea pig CPI model. Chronic placental insufficiency was induced by unilateral uterine artery ligation at 30-32 days of gestation (dg: with term defined as ~67dg). At 50 and 60dg, fetuses were sacrificed and assigned to either the growth-restricted (GR) or control (no ligation) group. Immunohistochemistry was performed with HIF-1alpha, PCNA, NeuN and BDNF antibodies in the cerebral cortex and dentate gyrus. The number of NeuN-IR and BDNF-IR cells was lesser in GR fetuses than in controls in the cerebral cortex and dentate gyrus at 60dg (p<0.05). The growth of the developing brain is dependent upon the availability of growth factors such as BDNF. The reduction in the number of neuronal cells observed in our GR group was associated with the observed reduction in BDNF protein found at 60dg. There was no significant difference between control and GR fetuses in the densities of PCNA-IR cells in the subventricular zone and subgranular zone at 50 and 60dg. These findings suggest that the survival of neurons in the cerebral cortex is decreased by chronic prenatal hypoxia at 60dg. PMID- 25794638 TI - Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide. AB - Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination. PMID- 25794639 TI - The State and Sustainability of Telepsychiatry Programs. AB - Telepsychiatry, or the provision of psychiatric care across a distance using communication technologies, has become widespread and has been used successfully for treating a variety of mental illnesses. Little is known, however, about the sustainability of telepsychiatry programs and their long-term success. The goal of this study was to determine current trends in telepsychiatry by completing an extensive literature review and to follow-up with the authors of telepsychiatry research to examine the current status of their programs and success factors or barriers associated with their experiences. Results indicated that modern telepsychiatry programs often target veteran/military or child populations and that many rely on either federal or internal funding. Interestingly, several researchers indicated that they wished to improve current funding mechanisms, while others wished for improvements in the technology used. Implications of these findings for behavioral health researchers are discussed, along with suggestions for improving future telepsychiatry programs. PMID- 25794640 TI - Elevated expression of HABP1 is a novel prognostic indicator in triple-negative breast cancers. AB - Hyaluronan-binding protein 1 (HABP1) has been documented to overexpress in several malignancies. The aim of our study is to investigate the expression of HABP1 protein in triple-negative breast cancer (TNBC) and its clinical significance. Using immunohistochemistry, HABP1 expression was evaluated in 139 TNBC specimens. The association between HABP1 expression with clinicopathological parameters was assessed using chi-square test. The survival status of patients was analyzed using the Kaplan-Meier and log-rank tests. Cox regression was used for the multivariate analysis of prognostic factors. The results showed that HABP1 overexpression correlated with higher histological grade (P = 0.004), advanced TNM stage (P = 0.008), greater tumor size (P = 0.016), metastasis of lymph node (P < 0.001), and recurrence (P = 0.040). Furthermore, it indicated that patients with HABP1 overexpression had significantly poorer overall survival (OS) and disease-free survival (DFS) compared with patients (P < 0.001 for both). Multivariate Cox regression analysis revealed that elevated HABP1 expression was an independent prognostic factor for both OS (P = 0.035) and DFS (P = 0.013). In contrast to the effect of HABP1 in TNBCs with lymph node metastasis, HABP1 overexpression significantly affects prognosis (OS, P = 0.002; DFS, P = 0.003) in TNBCs without lymph node metastasis. In conclusion, HABP1 protein high expression may contribute to the tumor progression and poor prognosis of TNBC, especially in predicting prognosis in TNBCs without lymph node metastasis. PMID- 25794641 TI - Expression/localization patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells. AB - Sirtuins belong to the family of class III histone deacetylases; its role in neoplasia is controversial as both tumor-suppressive and promoting functions have been reported. There are very few reports available, where expressions of sirtuin isoforms are comprehensively analyzed during neoplasia. Therefore, in the present study, the expression of SIRT1, SIRT2, and SIRT7 during different stages of cervical cancer progression was analyzed. The normal cervical epithelium showed feeble expression of sirtuin isoforms, SIRT1, SIRT2, and SIRT7. A significant increase in SIRT1 expression was noted in the cytoplasm as well as in the nucleus of proliferative layers of cervical epithelium in squamous intraepithelial lesions (SIL); however, in the squamous cell carcinomas (SCC), a heterogeneous pattern of SIRT1 expression varying from low to high was noted. A progressive increase in the expression of both SIRT2 and SIRT7 was noted during cancer progression in the following order: normal < preneoplasia < cancer. Cervical cancer cell lines, HeLa and SiHa, showed higher levels of SIRT1 and SIRT2 in comparison to the immortalized cell counterpart, HaCaT. Specific inhibitors of SIRT1 (Ex527) and SIRT2 (AGK2) impaired the growth of the cervical cancer cells, SiHa, but not of the HaCaT cells. SIRT1 inhibition caused cell death, while SIRT2 inhibition resulted in cell cycle arrest. In conclusion, we report the overexpression of SIRT2 and SIRT7 proteins in cervical cancer and suggest probable application of sirtuin inhibitors as therapeutic targets. Further, a specific increase in the levels of SIRT1 in intraepithelial lesion makes it a promising candidate for identification of preneoplastic changes. PMID- 25794642 TI - Comparative efficacy of postoperative transarterial chemoembolization with or without antiviral therapy for hepatitis B virus-related hepatocellular carcinoma. AB - This study aims to investigate the efficacy of adjuvant transarterial chemoembolization (TACE) with or without antiviral therapy for patients with hepatocellular carcinoma (HCC) after radical hepatectomy. This retrospective study examined 176 patients after radical hepatectomy, 118 of whom were treated using TACE alone and 58 using TACE combined with antiviral therapy. To reduce confounding bias due to baseline differences, propensity score matching was used to generate 51 pairs of patients from both treatment groups. Overall survival (OS) and disease-free survival (DFS) were analyzed for both groups before and after propensity score matching. Analysis of all patients showed that OS was better in the combination therapy group than in the TACE-only group (P = 0.048), while DFS was similar between the two groups (P = 0.322). Analysis of only propensity score-matched pairs confirmed the significantly better 5-year OS in the combination therapy group (64.6 vs. 37.5 %, P = 0.033) and also suggested better 5-year DFS (37.9 vs. 14.6 %, P = 0.048). Among patients experiencing HCC recurrence, radical surgery was the treatment choice for a significantly larger proportion of patients from the combination therapy group than from the TACE-only group (P = 0.018). Our results suggest that combining antiviral therapy with TACE significantly improves OS and potentially DFS relative to TACE alone in patients with HCC. Combination therapy also appears to leave patients with greater remnant liver function, increasing the possibility of curative resection in the event of recurrence. Combination therapy may be useful for preventing HCC recurrence after radical hepatectomy. PMID- 25794643 TI - Pharyngeal airway changes after mono- and bimaxillary surgery in skeletal class III patients: Cone-beam computed tomography evaluation. AB - The aim of this study was to evaluate the two-dimensional (2D) and three dimensional (3D) changes in the pharyngeal airway space (PAS) in 20 class III patients who underwent mono- or bimaxillary surgery using cone-beam computed tomography (CBCT). CBCT examination was obtained before surgery (T1) and at least 3 months after surgery (T2). The pharyngeal airway of each patient was studied at three levels: the level of the posterior nasal spine, the level of the most inferior point of the soft palate, and the level of the top of the epiglottis. At each of these levels, the anteroposterior and lateral dimension as well as cross sectional area were measured. The volume of the whole PAS and volume between each cross section were also measured. The area and anteroposterior dimensions at the level of the most inferior point of the soft palate significantly decreased in patients who underwent monomaxillary surgery. The volume of the PAS decreased in both groups, but decreased significantly only in the monomaxillary group. The upper volume decreased in the mono- and increased in the bimaxillary group. The lower volume significantly decreased in the monomaxillary group. However, results showed that PAS decreased more after mono-than after bimaxillary surgery. PMID- 25794644 TI - Extra-oral defect augmentation using autologous, bovine and equine bone blocks: A preclinical histomorphometrical comparative study. AB - OBJECTIVES: This study aimed to compare autologous bone (AB), bovine bone (BB), and equine bone (EB) blocks with regard to de novo bone formation, connective tissue, and residual bone substitute material portions in a standardized defect animal model. MATERIAL AND METHODS: In the frontal skull of 20 pigs, 106 standardized cylindrical "critical size defects" were prepared. Defects were randomly filled with AB, BB, and EB blocks. After a healing period of 30 and 60 days, de novo bone formation, residual bone substitute material, and connective tissue portion was assessed by means of histomorphometry (Toluidine blue O staining). Mann-Whitney U-tests were used to evaluate differences between the groups. RESULTS: The de novo bone formation was significantly higher in the AB group in comparison to the xenogeneic groups (p < 0.05). After 30 days, EB showed significantly (p < 0.05) more newly formed bone compared to the BB group. The soft tissue formation was significantly higher in the BB and EB group. Defects augmented with BB showed significantly (p < 0.05) higher portions of bone substitute materials compared to sides augmented with EB after 30 days. CONCLUSION: In the extra-oral model, AB blocks were superior concerning de novo bone formation. No clinical advantages of EB blocks could be observed. PMID- 25794645 TI - Atorvastatin promotes human monocyte differentiation toward alternative M2 macrophages through p38 mitogen-activated protein kinase-dependent peroxisome proliferator-activated receptor gamma activation. AB - M1 and M2 macrophages are detectable in human atherosclerotic lesions, and M2 macrophages are present at locations distant from the lipid core in more stable zones of the plaque and appear to exert anti-inflammatory properties on M1 macrophages. Peroxisome proliferator-activated receptor (PPAR) gamma promotes the differentiation of monocytes into anti-inflammatory M2 macrophages. Although both statins and PPARgamma ligands have been reported to protect against the progression of atherosclerosis, no data are currently available regarding the implication of statins in the alternative differentiation of human monocytes. In the present study, we hypothesized that atorvastatin may exert novel effects to prime human monocytes toward an anti-inflammatory alternative M2 phenotype. To this aim, we first found that abundant M2 markers were expressed in human circulating monocytes after atorvastatin treatment. Moreover, atorvastatin was able to induce PPARgamma expression and activation in human monocytes in vivo and in vitro, resulting in priming primary human monocytes differentiation into M2 macrophages with a more pronounced paracrine anti-inflammatory activity in M1 macrophages. Additional data with molecular approaches revealed that p38 mitogen activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) 1/2 activation was involved in atorvastatin-mediated PPARgamma activation and enhanced alternative M2 macrophage phenotype. Collectively, our data demonstrated that atorvastatin promotes human monocyte differentiation toward alternative M2 macrophages via p38 MAPK-dependent PPARgamma activation. PMID- 25794646 TI - Effects of topically applied rapamycin and mycophenolic acid on TNCB-induced atopic dermatitis-like skin lesions in NC/Nga mice. AB - Rapamycin (RPM) and mycophenolic acid (MPA) are immunosuppressive drugs approved for use in preventing transplant rejection. These drugs have also been used in the field of dermatology as glucocorticoid sparing agents for autoimmune and inflammatory disorders such as atopic dermatitis (AD). The aim of this study was to investigate the therapeutic effect of topically applied RPM and/or MPA on AD like skin lesions in NC/Nga mice. RPM (0.04% - 4%), MPA (0.2% - 5%), and formulations of both agents at various ratios were administrated topically to NC/Nga mice with 2-chloro-1,3,5-trinitrobenzene (TNCB)-induced AD-like skin lesions. The therapeutic effects of topical RPM, MPA, and the mixed formulations in TNCB-treated NC/Nga mice were assessed by measuring skin severity scores, ear thickness, and histological changes in the lesioned skin including mast cell count and total serum IgE levels. Expression of interleukin (IL)-4, and interferon (IFN)-gamma was also assessed. Topical 4% RPM and/or 1% MPA treatment significantly improved clinical signs of AD such as erythema, edema, excoriation, and dryness on day 29 (P<0.05). In addition, 4% RPM, 1% MPA, and the mixed formulations significantly decreased epidermal thickening, dermal edema, and cellular infiltration into the dermis compared with the vehicle. RPM (4%) and/or MPA (1%) significantly reduced the expression of IL-4 and IFN-gamma mRNA and protein levels compared with the vehicle (P<0.05). No significant change in the levels of total serum IgE was induced by topical 4% RPM and/or 1% MPA. The present results demonstrated that topical 4% RPM and/or 1% MPA improved TNCB induced AD-like lesions of NC/Nga mice by suppressing expression of Th2-related cytokines (IL-4) and Th1-related cytokines (IFN-gamma). These findings suggest that RPM and/or MPA may be promising topical therapeutic candidates for the treatment of AD. PMID- 25794647 TI - Membrane-type matrix metalloproteinases: Their functions and regulations. AB - Membrane-type matrix metalloproteinases (MT-MMPs) form a subgroup of the matrix metalloproteinase (MMP) family, and there are 6 MT-MMPs in humans. MT-MMPs are further sub-classified into type I transmembrane-type (MT1, -MT2-, MT3- and MT5 MMPs) and glycosylphosphatidylinositol (GPI)-anchored type (MT4- and MT6-MMPs). In either case MT-MMPs are tethered to the plasma membrane, and this cell surface expression provides those enzymes with unique functionalities affecting various cellular behaviours. Among the 6 MT-MMPs, MT1-MMP is the most investigated enzyme and many of its roles and regulations have been revealed to date, but the potential roles and regulatory mechanisms of other MT-MMPs are gradually getting clearer as well. Further investigations of MT-MMPs are likely to reveal novel pathophysiological mechanisms and potential therapeutic strategies for different diseases in the future. PMID- 25794648 TI - Evaluation of semi-generic PBTK modeling for emergency risk assessment after acute inhalation exposure to volatile hazardous chemicals. AB - BACKGROUND: Physiologically Based Toxicokinetic Models (PBTK) may facilitate emergency risk assessment after chemical incidents with inhalation exposure, but they are rarely used due to their relative complexity and skill requirements. We aimed to tackle this problem by evaluating a semi-generic PBTK model built in MS Excel for nine chemicals that are widely-used and often released in a chemical incident. MATERIAL & METHODS: The semi-generic PBTK model was used to predict blood concentration-time curves using inhalation exposure scenarios from human volunteer studies, case reports and hypothetical exposures at Emergency Response Planning Guideline, Level 3 (ERPG-3) levels.(2) Predictions using this model were compared with measured blood concentrations from volunteer studies or case reports, as well as blood concentrations predicted by chemical-specific models. The performances of the semi-generic model were evaluated on biological rationale, accuracy, and ease of use and range of application. RESULTS: Our results indicate that the semi-generic model can be easily used to predict blood levels for eight out of nine parent chemicals (dichloromethane, benzene, xylene, styrene, toluene, isopropanol trichloroethylene and tetrachloroethylene). However, for methanol, 2-propanol and dichloromethane the semi-generic model could not cope with the endogenous production of methanol and of acetone (being a metabolite of 2-propanol) nor could it simulate the formation of HbCO, which is one of the toxic end-points of dichloromethane. The model is easy and intuitive to use by people who are not so familiar with toxicokinetic models. CONCLUSION: A semi-generic PBTK modeling approach can be used as a 'quick-and-dirty' method to get a crude estimate of the exposure dose. PMID- 25794649 TI - Defining "global health ethics" : offering a research agenda for more bioethics and multidisciplinary contributions-from the global south and beyond the health sciences-to enrich global health and global health ethics initiatives. PMID- 25794650 TI - Editorial note: "remembering Stephanie" by Charlee Brodsky. PMID- 25794651 TI - What games support the evolution of an ingroup bias? AB - There is an increasing wealth of models trying to explain the evolution of group discrimination and an ingroup bias. This paper sets out to systematically investigate the most fundamental assumption in these models: in what kind of situations do the interactions take place? What strategic structures - games - support the evolution of an ingroup bias? More specifically, the aim here is to find the prerequisites for when a bias also with respect to minimal groups - arbitrarily defined groups void of group-specific qualities - is selected for, and which cannot be ascribed to kin selection. Through analyses and simulations of minimal models of two-person games, this paper indicates that only some games are conducive to the evolution of ingroup favouritism. In particular, this class does not contain the prisoners' dilemma, but it does contain anti-co-ordination and co-ordination games. Contrasting to the prisoners' dilemma, these are games where it is not a matter of whether to behave altruistically, but rather one of predicting what the other person will be doing, and where I would benefit from you knowing my intentions. In anti-co-ordination games, on average, not only will agents discriminate between groups, but also in such a way that their choices maximise the sum of the available payoffs towards the ingroup more often than towards the outgroup. And in co-ordination games, even if agents do manage to co ordinate with the whole population, they are more likely to co-ordinate on the socially optimal equilibrium within their group. Simulations show that this occurs most often in games where there is a component of risk-taking, and thus trust, involved. A typical such game is the stag hunt or assurance game. PMID- 25794652 TI - "Cargo-mooring" as an operating principle for molecular motors. AB - Navigating through an ever-changing and unsteady environment, and utilizing chemical energy, molecular motors transport the cell's crucial components, such as organelles and vesicles filled with neurotransmitter. They generate force and pull cargo, as they literally walk along the polymeric tracks, e.g. microtubules. What we suggest in this paper is that the motor protein is not really pulling its load. The load is subject to diffusion and the motor may be doing little else than rectifying the fluctuations, i.e. ratcheting the load's diffusion. Below we present a detailed model to show how such ratcheting can quantitatively account for observed data. The consequence of such a mechanism is the dependence of the transport's speed and efficacy not only on the motor, but also on the cargo (especially its size) and on the environment (i.e. its viscosity and structure). Current experimental works rarely provide this type of information for in vivo studies. We suggest that even small differences between assays can impact the outcome. Our results agree with those obtained in wet laboratories and provide novel insight in a molecular motor's functioning. PMID- 25794653 TI - Pediatric cochlear implantation: role of language, income, and ethnicity. AB - OBJECTIVE: To compare post-cochlear implantation (CI) early speech perception (ESP) outcomes between a non-English speaking, ethnic minority study group and an English speaking, ethnic majority control group. STUDY DESIGN/METHODS: We performed a retrospective case-control study at an academic tertiary care children's hospital. Records were reviewed of 49 children who underwent CI from February 2005 to September 2011. Children with abnormal cognitive function (n=12), post-surgical complications (n=1), or incomplete SP testing (n=24) were excluded. The remaining 12 cases (mean implant age 4.3 y) were reviewed for language, income, ethnicity, and ESP scores. Their scores were compared to a subset of patients (n=18; mean implant age 2.2 y) serving as control from the Childhood Development after Cochlear Implantation (CDaCI) study at 1 year follow up where standard ESP testing was performed. Briefly, CDaCI includes a demographically balanced and multicenter-based pediatric cohort from which publications are beginning to define normative post-CI SP outcomes. RESULTS: Of our 12 children, 7 were Hispanic, 2 Caucasian, 2 multi-ethnicity and 1 Russian. 4 were non-English speaking, 5 spoke English as a second language, and 7 were bilingual. Three received bilateral CI. Mean early speech perception (ESP) scores (reported on a scale of 1-4) collected at 6 and 12 months in the study group were 1.71 and 1.75, respectively; in the control group, 3.83 and 3.92. At both follow up intervals the study group performed significantly worse than the control group (6 mo P=0.048, 12 mo P=0.01). CONCLUSIONS: This study suggests that among pediatric CI recipients, those from predominantly non-English speaking, socioeconomically disadvantaged backgrounds develop SP at slower than normal rates. Future interventions should be directed at overcoming these obstacles. PMID- 25794654 TI - Pre-operative simulation of pediatric mastoid surgery with 3D-printed temporal bone models. AB - OBJECTIVES: As the process of additive manufacturing, or three-dimensional (3D) printing, has become more practical and affordable, a number of applications for the technology in the field of pediatric otolaryngology have been considered. One area of promise is temporal bone surgical simulation. Having previously developed a model for temporal bone surgical training using 3D printing, we sought to produce a patient-specific model for pre-operative simulation in pediatric otologic surgery. Our hypothesis was that the creation and pre-operative dissection of such a model was possible, and would demonstrate potential benefits in cases of abnormal temporal bone anatomy. METHODS: In the case presented, an 11 year-old boy underwent a planned canal-wall-down (CWD) tympano-mastoidectomy for recurrent cholesteatoma preceded by a pre-operative surgical simulation using 3D printed models of the temporal bone. The models were based on the child's pre operative clinical CT scan and printed using multiple materials to simulate both bone and soft tissue structures. To help confirm the models as accurate representations of the child's anatomy, distances between various anatomic landmarks were measured and compared to the temporal bone CT scan and the 3D model. RESULTS: The simulation allowed the surgical team to appreciate the child's unusual temporal bone anatomy as well as any challenges that might arise in the safety of the temporal bone laboratory, prior to actual surgery in the operating room (OR). There was minimal variability, in terms of absolute distance (mm) and relative distance (%), in measurements between anatomic landmarks obtained from the patient intra-operatively, the pre-operative CT scan and the 3D printed models. CONCLUSIONS: Accurate 3D temporal bone models can be rapidly produced based on clinical CT scans for pre-operative simulation of specific challenging otologic cases in children, potentially reducing medical errors and improving patient safety. PMID- 25794655 TI - The epithelial to mesenchymal transition in pancreatic cancer: A systematic review. AB - BACKGROUND/OBJECTIVES: The present article summarizes and analyzes the current knowledge about the role of the epithelial to mesenchymal transition (EMT) in the systemic invasiveness of pancreatic cancer. METHOD: An electronic search of PubMed/MEDLINE, EMBASE, and the Web of Science was used to identify relevant original articles and reviews. RESULTS: The EMT represents a key step during normal embryogenesis. However, increasing evidence reveals its essential role in the local progression and metastasis of pancreatic cancer. Areas of interest are the cross-linking between cells undergoing the EMT and pancreatic cancer stem cells, and the correlation between the EMT and chemoresistance to standard therapies. During carcinogenesis, malignant pancreatic cells at the primary site acquire the ability to undergo the EMT, a transformation associated with increased mobility. The reverse process at secondary sites, the mesenchymal to epithelial transition (MET), has devastating consequences, allowing neoplastic epithelial cells to invade surrounding tissues and spread to distant sites. Consequences of the EMT are the loss of E-cadherin expression and the acquisition of mesenchymal markers including fibronectin or vimentin. Detailed knowledge of the molecular processes underlying the EMT has opened possibilities for new therapeutic agents. These include an EMT approach for patients with early cancers, to prevent invasion and dissemination, and anti-MET therapy for patients with established metastasis. CONCLUSIONS: The current literature shows a strong correlation between the EMT and the systemic aggressiveness of pancreatic tumors. Individualized therapy, targeting the process of EMT and its cross-linking with cancer stem cells, may increase survival of patients with pancreatic cancer. PMID- 25794657 TI - International prevalence rates of asthma and allergy are associated with income inequality. PMID- 25794656 TI - A new case of Fas-associated death domain protein deficiency and update on treatment outcomes. PMID- 25794659 TI - The effect of geographic access on severe health outcomes for pediatric asthma. AB - BACKGROUND: Access to medical care and severe pediatric asthma outcomes vary with geography, but the relationship between them has not been studied. OBJECTIVE: We sought to evaluate the relationship between geographic access and health outcomes for pediatric asthma. METHODS: The severe outcome measures include emergency department (ED) visits and hospitalizations for children with an asthma diagnosis in Georgia and North Carolina. We quantify asthma prevalence, outcome measures, and factors included in the statistical model using multiple data sources. We calculate geographic access to primary and asthma specialist care using optimization models. We estimate the association between outcomes and geographic access in the presence of other factors using logistic regression. The model is used to project the reduction in severe outcomes with improvement in access. RESULTS: The association between access and outcomes for pediatric asthma depends on the type of outcome measure, type of care, and variations in other factors. The expression of this association is also different for the 2 states. Access to primary care plays a larger role than access to specialist care in explaining Georgia ED visits, whereas the reverse applies for hospitalizations. In North Carolina access to both primary and specialist care are statistically significant in explaining the variability in ED visits. CONCLUSIONS: The variation in the association between estimated access and outcomes affects the projected reductions of severe outcomes with access improvement. Thus applying one intervention would not have the same level of improvement across geography. Interventions must be tailored to target regions with the potential to deliver the highest effect to gain maximum benefit. PMID- 25794660 TI - Evaluation of endothelial biomarkers as predictors of organ failures in septic shock patients. AB - BACKGROUND: Endothelial injury is recognized to trigger organ failures during the first 48h of septic shock. We evaluate endothelial biomarkers at ICU admission in their ability to predict severity, outcome, and organ failures in septic shock patients. METHODS: This prospective observational pilot study was conducted in a medical intensive care unit of a university hospital. Plasma levels of endothelial biomarkers as angiopoietin-2, sE-selectin or endocan were measured at ICU admission of 20 patients presenting with septic shock. Clinical and biological data were recorded at inclusion and each day during the first week. RESULTS: Significant correlations were found between angiopoietin-2 and severity scores at Day 1: SAPS2 (r(2)=0.620; p=0.004) and LOD score (r(2)=0.681; p=0.001). The angiopoietin-2 level was significantly higher in patients presenting with organ failure such as hemodynamic, renal or hepatic failure. It correlated with catecholamine infusion dose and was higher in non survivors compared with survivors (33.5 [28.9-51.4] vs. 12.4 [6.4-14.7]ng/ml; p=0.001). In contrast, in that population presenting with septic shock, endocan level at inclusion was not related to any organ failure at inclusion or Day 1 but appeared lower in patients presenting with respiratory failure at Day 3 compared to those who do not (1.9 [0.99-3.1] vs 5.2 [3.1-17.2]ng/ml; p=0.032). The endocan level at inclusion was correlated with the decrease in PaO2/FiO2 ratio at Day 2 (r(2)=0.628; p=0.0004) and Day 3 (r(2)=0.645; p=0.005). Endocan level <2.54ng/ml at admission is predictive of a respiratory failure presence at Day 3. CONCLUSION: In septic shock patients, angiopoietine-2 is related with clinical severity during the first 24h but only endocan is able to predict the presence of respiratory failure at Day 3. PMID- 25794658 TI - Seasonal risk factors for asthma exacerbations among inner-city children. AB - BACKGROUND: Asthma exacerbations remain common, even in children and adolescents, despite optimal medical management. Identification of host risk factors for exacerbations is incomplete, particularly for seasonal episodes. OBJECTIVE: We sought to define host risk factors for asthma exacerbations unique to their season of occurrence. METHODS: This is a retrospective analysis of patients aged 6 to 20 years who comprised the control groups of the Asthma Control Evaluation study and the Inner City Anti-IgE Therapy for Asthma study. Univariate and multivariate models were constructed to determine whether patients' demographic and historical factors, allergic sensitization, fraction of exhaled nitric oxide values, spirometric measurements, asthma control, and treatment requirements were associated with seasonal exacerbations. RESULTS: The analysis included 400 patients (54.5% male; 59.0% African American; median age, 13 years). Exacerbations occurred in 37.5% of participants over the periods of observation and were most common in the fall (28.8% of participants). In univariate analysis impaired pulmonary function was significantly associated with greater odds of exacerbations for all seasons, as was an exacerbation in the previous season for all seasons except spring. In multivariate analysis exacerbation in the previous season was the strongest predictor in fall and winter, whereas a higher requirement for inhaled corticosteroids was the strongest predictor in spring and summer. The multivariate models had the best predictive power for fall exacerbations (30.5% variance attributed). CONCLUSIONS: Among a large cohort of inner-city children with asthma, patients' risk factors for exacerbation vary by season. Thus information on individual patients might be beneficial in strategies to prevent these seasonal events. PMID- 25794661 TI - Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas. AB - TGF-beta1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-beta1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-beta signaling, and through these pathways it is able to enhance TGF-beta induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-beta1 combination on cell growth and on TGF-beta and mTOR signalling events in lymphoma cells. Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-beta1 induced apoptosis and restored TGF-beta1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF beta sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-beta1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-beta1 induced apoptosis was not completely eliminated by a caspase inhibitor. These results suggest that high mTOR activity contributes to TGF-beta resistance and lowering mTORC1 kinase activity may provide a tool in high grade B cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-beta1. PMID- 25794662 TI - Tonsil-derived mesenchymal stromal cells produce CXCR2-binding chemokines and acquire follicular dendritic cell-like phenotypes under TLR3 stimulation. AB - We previously isolated mesenchymal stromal cells from human tonsils (T-MSCs) and showed the potential of these cells to differentiate into the mesodermal lineage and acquire a follicular dendritic cell (FDC) phenotype under cytokine stimulation. Because these T-MSCs were originally isolated from inflamed tonsillar tissues, we were curious about their activation status in response to innate immune stimuli, such as Toll-like receptors (TLRs). Therefore, we analyzed the expression profile of TLRs in T-MSCs and stimulated the T-MSCs with TLR agonists. TLR3 stimuli induced C-C chemokine receptor type 6 expression in T-MSCs after 24h. Furthermore, results from cytokine arrays showed increases in epithelial neutrophil-activating peptide-78/C-X-C motif chemokine (CXCL) 5, granulocyte chemotactic protein-2/CXCL6, growth-related oncogene-alpha/CXCL1, interleukin-8/CXCL8, and interferon gamma-induced protein-10/CXCL10. CD54 expression was also increased after TLR3 stimulation. However, co-culturing T MSCs with human B cells did not induce B-cell proliferation. This suggests that TLR3 stimulates the differentiation of T-MSCs into FDC-like cells and induces chemokine secretion, possibly by recruiting C-X-C chemokine receptor 2-expressing immune cells. In addition, T-MSCs also appeared to exert immunomodulatory effects by inhibiting B-cell proliferation, possibly by down-regulating CD18. PMID- 25794664 TI - Follow-up of recurrences of limb soft tissue sarcomas in patients with localized disease: performance of ultrasound. AB - OBJECTIVES: To evaluate diagnostic performance of ultrasound in the detection of local recurrences in patients with localized soft tissue sarcomas of the limb. METHODS: An analysis of patients treated for soft tissue sarcomas between 2005 and April 2014 was performed. Sixty-eight patients (men/women, 36:32; age range, 18-84 years) were evaluated. Sensitivity, specificity with 95% confidence intervals (CIs), positive predictive value (PPV), pre-test probability (the prevalence), negative predictive value (NPV), likelihood ratio for positive results (LH+), accuracy and post-test probability (post-P) of ultrasound were reported on a per patient basis using surgical findings and clinical follow-up as reference standard. Effects of independent variables (US equipment, age and sex, body mass index, radiologist) were considered. Comparison with MR was also performed. RESULTS: The overall sensitivity and specificity were 0.88 (0.60-0.94) and 0.94 (0.86-0.98). PPV, pre-test probability, NPV, LH+, accuracy and post-P: 0.83/0.25/0.96/14.9/0.92/0.83. There were two false negative cases both graded as G3 and deeply located and three false positive US cases. Diagnostic accuracy was not dependent by US machine (p = 0.08), age and sex (p = 0.16), body mass index (p = 0.07) and radiologists (p = 0.07). CONCLUSIONS: Diagnostic accuracy of ultrasound was relatively high. Negative US results excluded the presence of a local recurrence with acceptable accuracy. KEY POINTS: * US accuracy is relatively high in sarcoma follow-up. * Negative US results exclude the presence of local recurrence with acceptable accuracy. * US may miss a small proportion of lesions. * False positive US cases are rare. PMID- 25794665 TI - Death and taxes. PMID- 25794663 TI - Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10. AB - The cytokines IL-6 and IL-10 are produced by cells of the adaptive and innate arms of the immune system and they appear to play key roles in genetically diverse autoimmune diseases such as relapsing remitting multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Whereas previous intense investigations focused on the generation of autoantibodies and their contribution to immune-mediated pathogenesis in these diseases; more recent attention has focused on the roles of cytokines such as IL-6 and IL-10. In response to pathogens, antigen presenting cells (APC), including B cells, produce IL-6 and IL-10 in order to up-or down-regulate immune cell activation and effector responses. Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases. Our recent studies suggest that MS peripheral blood B cells secrete higher quantities of IL-6 and less IL-10 than B cells from healthy controls. Persistent production of IL-6, in turn, contributes to T cell expansion and the functional hyperactivity of APC such as MS B cells. Altered B cell activity can have a profound impact on resultant T cell effector functions. Enhanced signaling through the IL-6 receptor can effectively inhibit cytolytic activity, induce T cell resistance to IL-10-mediated immunosuppression and increase skewing of autoreactive T cells to a pathogenic Th17 phenotype. Our recent findings and studies by others support a role for the indirect attenuation of B cell responses by Glatiramer acetate (GA) therapy. Our studies suggest that GA therapy temporarily permits homeostatic regulatory mechanisms to be reinstated. Future studies of mechanisms underlying dysregulated B cell cytokine production could lead to the identification of novel targets for improved immunoregulatory therapies for autoimmune diseases. PMID- 25794666 TI - Life course consequences of breastfeeding. PMID- 25794667 TI - Scaling up multidrug-resistant tuberculosis care in China. PMID- 25794668 TI - The changing context of overnutrition and undernutrition in Pakistan. PMID- 25794669 TI - Alcohol and related health issues in China: action needed. PMID- 25794670 TI - Comparing the incomparable: studies of echocardiographic rheumatic heart disease prevalence. PMID- 25794671 TI - Comparing the incomparable: studies of echocardiographic rheumatic heart disease prevalence - authors' reply. PMID- 25794672 TI - Visceral leishmaniasis research: operational focus needed. PMID- 25794673 TI - Diagnostics for hepatitis C: an urgent need for action. PMID- 25794674 TI - Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil. AB - BACKGROUND: Breastfeeding has clear short-term benefits, but its long-term consequences on human capital are yet to be established. We aimed to assess whether breastfeeding duration was associated with intelligence quotient (IQ), years of schooling, and income at the age of 30 years, in a setting where no strong social patterning of breastfeeding exists. METHODS: A prospective, population-based birth cohort study of neonates was launched in 1982 in Pelotas, Brazil. Information about breastfeeding was recorded in early childhood. At 30 years of age, we studied the IQ (Wechsler Adult Intelligence Scale, 3rd version), educational attainment, and income of the participants. For the analyses, we used multiple linear regression with adjustment for ten confounding variables and the G-formula. FINDINGS: From June 4, 2012, to Feb 28, 2013, of the 5914 neonates enrolled, information about IQ and breastfeeding duration was available for 3493 participants. In the crude and adjusted analyses, the durations of total breastfeeding and predominant breastfeeding (breastfeeding as the main form of nutrition with some other foods) were positively associated with IQ, educational attainment, and income. We identified dose-response associations with breastfeeding duration for IQ and educational attainment. In the confounder adjusted analysis, participants who were breastfed for 12 months or more had higher IQ scores (difference of 3.76 points, 95% CI 2.20-5.33), more years of education (0.91 years, 0.42-1.40), and higher monthly incomes (341.0 Brazilian reals, 93.8-588.3) than did those who were breastfed for less than 1 month. The results of our mediation analysis suggested that IQ was responsible for 72% of the effect on income. INTERPRETATION: Breastfeeding is associated with improved performance in intelligence tests 30 years later, and might have an important effect in real life, by increasing educational attainment and income in adulthood. FUNDING: Wellcome Trust, International Development Research Center (Canada), CNPq, FAPERGS, and the Brazilian Ministry of Health. PMID- 25794675 TI - Effect of a comprehensive programme to provide universal access to care for sputum-smear-positive multidrug-resistant tuberculosis in China: a before-and after study. AB - BACKGROUND: China has a quarter of all patients with multidrug-resistant tuberculosis (MDRTB) worldwide, but less than 5% are in quality treatment programmes. In a before-and-after study we aimed to assess the effect of a comprehensive programme to provide universal access to diagnosis, treatment, and follow-up for MDRTB in four Chinese cities (population 18 million). METHODS: We designated city-level hospitals in each city to diagnose and treat MDRTB. All patients with smear-positive pulmonary tuberculosis diagnosed in Center for Disease Control (CDC) clinics and hospitals were tested for MDRTB with molecular and conventional drug susceptibility tests. Patients were treated with a 24 month treatment package for MDRTB based on WHO guidelines. Outpatients were referred to the CDC for directly observed therapy. We capped total treatment package cost at US$4644. Insurance reimbursement and project subsidies limited patients' expenses to 10% of charges for services within the package. We compared data from a 12 month programme period (2011) to those from a retrospective survey of all patients with MDRTB diagnosed in the same cities during a baseline period (2006 09). FINDINGS: 243 patients were diagnosed with MDRTB or rifampicin-resistant tuberculosis during the 12 month programme period compared with 92 patients (equivalent to 24 per year) during the baseline period. 172 (71%) of 243 individuals were enrolled in the programme. Time from specimen collection for resistance testing to treatment initiation decreased by 90% (from median 139 days [IQR 69-207] to 14 days [10-21]), the proportion of patients who started on appropriate drug regimen increased 2.7 times (from nine [35%] of 26 patients treated to 166 [97%] of 172), and follow-up by the CDC after initial hospitalisation increased 24 times (from one [4%] of 23 patients to 163 [99%] of 164 patients). 6 months after starting treatment, the proportion of patients remaining on treatment increased ten times (from two [8%] of 26 patients to 137 [80%] of 172), and 116 (67%) of 172 patients in the programme period had negative cultures or clinical-radiographic improvement. Patients' expenses for hospital admission after MDRTB diagnosis decreased by 78% (from $796 to $174), reducing the ratio of patients' expenses to annual household income from 17.6% to 3.5% (p<0.0001 for all comparisons between baseline and programme periods). However, 36 (15%) patients did not start or had to discontinue treatment in the programme period because of financial difficulties. INTERPRETATION: This comprehensive programme substantially increased access to diagnosis, quality treatment, and affordable treatment for MDRTB. The programme could help China to achieve universal access to MDRTB care but greater financial risk protection for patients is needed. FUNDING: Bill & Melinda Gates Foundation. PMID- 25794676 TI - Geographical and socioeconomic inequalities in women and children's nutritional status in Pakistan in 2011: an analysis of data from a nationally representative survey. AB - BACKGROUND: Pakistan has one of the highest levels of child and maternal undernutrition worldwide, but little information about geographical and socioeconomic inequalities is available. We aimed to analyse anthropometric indicators for childhood and maternal nutrition at a district level in Pakistan and assess the association of nutritional status with food security and maternal and household socioeconomic factors. METHODS: We used data from the 2011 Pakistan National Nutrition Survey, which included anthropometric measurements for 33 638 children younger than 5 years and 24 826 women of childbearing age. We estimated the prevalences of stunting, wasting, and underweight among children and of underweight, overweight, and obesity in women for all 143 districts of Pakistan using a Bayesian spatial technique. We used a mixed-effect linear model to analyse the association of nutritional status with individual and household sociodemographic factors and food security. FINDINGS: Stunting prevalence in Pakistan's districts ranged between 22% (95% credible interval 19-26) and 76% (69 83); the lowest figures for wasting and underweight were both less than 2.5% and the highest were 42% (34-50) for wasting and 54% (49-59) for underweight. In 106 districts, more women were overweight than were underweight; in 49 of these districts more women were obese than were underweight. Children were better nourished if their mothers were taller or had higher weight, if they lived in wealthier households, and if their mothers had 10 or more years of education. Severe food insecurity was associated with worse nutritional outcomes for both children and women. INTERPRETATION: We noted large social and geographical inequalities in child and maternal nutrition in Pakistan, masked by national and provincial averages. Pakistan is also beginning to face the concurrent challenge of high burden of childhood undernutrition and overweight and obesity among women of reproductive age. Planning, implementation, and evaluation of programmes for food and nutrition should be based on district-level needs and outcomes. FUNDING: Bill & Melinda Gates Foundation, Grand Challenges Canada, UK Medical Research Council. PMID- 25794677 TI - Onecut1 and Onecut2 transcription factors operate downstream of Pax6 to regulate horizontal cell development. AB - Genetic studies of the last decades strongly indicated that generation of particular retinal cell types is governed by gene regulatory networks of transcription factors and their target genes. The paired and homeodomain transcription factor Pax6 plays a pivotal role in retinal development as its inactivation in the retinal progenitor cell population leads to abolished differentiation of all retinal cell types. However, until now, only a few transcription factors operating downstream of Pax6 responsible for generation of individual retinal cell types have been identified. In this study, we identified two transcription factors of the Onecut family, Onecut1 and Onecut2, as Pax6 downstream-acting factors. Onecut1 and Onecut2 were previously shown to be expressed in developing horizontal cells, retinal ganglion cells and cone photoreceptors; however, their role in differentiation of these cell types is poorly understood. In this study, we show that the horizontal cell genesis is severely disturbed in Onecut-deficient retinae. In single Onecut1 and Onecut2 mutants, the number of horizontal cells is dramatically reduced while horizontal cells are completely missing in the Onecut1/Onecut2 compound mutant. Analysis of genes involved in the horizontal cell genesis such as Foxn4, Ptf1a, Prox1 and Lim1 showed that although horizontal cells are initially formed, they are not maintained in Onecut-deficient retinae. Taken together, this study suggests the model in which Pax6 regulates the maintenance of horizontal cells through the activation of Onecut1 and Onecut2 transcription factors. PMID- 25794678 TI - Mef2c-F10N enhancer driven beta-galactosidase (LacZ) and Cre recombinase mice facilitate analyses of gene function and lineage fate in neural crest cells. AB - Neural crest cells (NCC) comprise a multipotent, migratory stem cell and progenitor population that gives rise to numerous cell and tissue types within a developing embryo, including craniofacial bone and cartilage, neurons and glia of the peripheral nervous system, and melanocytes within the skin. Here we describe two novel stable transgenic mouse lines suitable for lineage tracing and analysis of gene function in NCC. Firstly, using the F10N enhancer of the Mef2c gene (Mef2c-F10N) linked to LacZ, we generated transgenic mice (Mef2c-F10N-LacZ) that express LacZ in the majority, if not all migrating NCC that delaminate from the neural tube. Mef2c-F10N-LacZ then continues to be expressed primarily in neurogenic, gliogenic and melanocytic NCC and their derivatives, but not in ectomesenchymal derivatives. Secondly, we used the same Mef2c-F10N enhancer together with Cre recombinase to generate transgenic mice (Mef2c-F10N-Cre) that can be used to indelibly label, or alter gene function in, migrating NCC and their derivatives. At early stages of development, Mef2c-F10N-LacZ and Mef2c-F10N Cre label NCC in a pattern similar to Wnt1-Cre mice, with the exception that Mef2c-F10N-LacZ and Mef2c-F10N-Cre specifically label NCC that have delaminated from the neural plate, while premigratory NCC are not labeled. Thus, our Mef2c F10N-LacZ and Mef2c-F10N-Cre transgenic mice provide new resources for tracing migratory NCC and analyzing gene function in migrating and differentiating NCC independently of NCC formation. PMID- 25794679 TI - Heterogeneous activation of a slow myosin gene in proliferating myoblasts and differentiated single myofibers. AB - Each skeletal muscle contains a fixed ratio of fast and slow myofibers that are distributed in a stereotyped pattern to achieve a specific motor function. How myofibers are specified during development and regeneration is poorly understood. Here we address this question using transgenic reporter mice that indelibly mark the myofiber lineages based on activation of fast or slow myosin. Lineage tracing indicates that during development all muscles have activated the fast myosin gene Myl1, but not the slow myosin gene Myh7, which is activated in all slow but a subset of fast myofibers. Similarly, most nascent myofibers do not activate Myh7 during fast muscle regeneration, but the ratio and pattern of fast and slow myofibers are restored at the completion of regeneration. At the single myofiber level, most mature fast myofibers are heterogeneous in nuclear composition, manifested by mosaic activation of Myh7. Strikingly, Myh7 is activated in a subpopulation of proliferating myoblasts that co-express the myogenic progenitor marker Pax7. When induced to differentiate, the Myh7-activated myoblasts differentiate more readily than the non-activated myoblasts, and have a higher tendency, but not restricted, to become slow myotubes. Together, our data reveal significant nuclear heterogeneity within a single myofiber, and challenge the conventional view that myosin genes are only expressed after myogenic differentiation. These results provide novel insights into the regulation of muscle fiber type specification. PMID- 25794680 TI - A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma. AB - Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here, we show that the transcriptional regulators YAP (YAP1) and TAZ (WWTR1), which are key effectors of the Hippo pathway, drive protumorigenic signals in OSCC. Regions of premalignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro, and is required for OSCC tumor growth and metastasis in vivo. Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in protumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by The Cancer Genome Atlas (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology. IMPLICATIONS: This study defines a YAP/TAZ-regulated transcriptional program in OSCC and reveals novel roles for nuclear YAP/TAZ activity in the onset and progression of this cancer. PMID- 25794681 TI - Employability among people with uncontrolled seizures: An interpretative phenomenological approach. AB - PURPOSE: This study aimed to explore positive and negative factors affecting the employability in patients with uncontrolled seizures. METHOD: Semistructured interviews with 21 patients with uncontrolled seizures were analyzed using interpretative phenomenological analysis. RESULT: Eleven (52.4%) of the participants interviewed were employed; 7 were holding full-time position with more than 4years of working experience. The mean age was 34.6years, 71.4% were female, 38% were married, 71.4% had at least 11years of education, 38% had a driving license, 19% received government monetary aid, 66.7% had seizure onset before reaching 17years of age, 66.7% experienced monthly seizures, and 76% were on polytherapy. A total of 6 main themes were found to be affecting the employability among people with uncontrolled seizures: (a) ability to work; (b) intention to work; (c) support and stigma at workplace; (d) family support, overdependence, and protection; (e) life event; and (f) government and welfare support. Subthemes under the main theme ability to work included education, cognitive and physical functions, ability to continue working after seizures, ability to travel to work, self-perceived ability to work, and ability to cope with stress. Many shared the same idea that employment is important, but their intention to work varied. The employed group tended to work for a future goal and self-satisfaction, and the unemployed group tended to have no or lack intention to work. Positive factors were noted in the following themes: ability to work; intention to work; support and stigma at workplace; and family support, overdependence, and protection. CONCLUSION: There were internal and external factors affecting the employability among people with uncontrolled seizures both positively and negatively. Positive internal factors such as ability and intention to work require further exploration. PMID- 25794682 TI - Cause-specific mortality among children and young adults with epilepsy: Results from the U.S. National Child Death Review Case Reporting System. AB - We investigated causes of death in children and young adults with epilepsy by using data from the U.S. National Child Death Review Case Reporting System (NCDR CRS), a passive surveillance system composed of comprehensive information related to deaths reviewed by local child death review teams. Information on a total of 48,697 deaths in children and young adults 28days to 24years of age, including 551 deaths with epilepsy and 48,146 deaths without epilepsy, was collected from 2004 through 2012 in 32 states. In a proportionate mortality analysis by official manner of death, decedents with epilepsy had a significantly higher percentage of natural deaths but significantly lower percentages of deaths due to accidents, homicide, and undetermined causes compared with persons without epilepsy. With respect to underlying causes of death, decedents with epilepsy had significantly higher percentages of deaths due to drowning and most medical conditions including pneumonia and congenital anomalies but lower percentages of deaths due to asphyxia, weapon use, and unknown causes compared with decedents without epilepsy. The increased percentages of deaths due to pneumonia and drowning in children and young adults with epilepsy suggest preventive interventions including immunization and better instruction and monitoring before or during swimming. State-specific and national population-based mortality studies of children and young adults with epilepsy are recommended. PMID- 25794683 TI - Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau induced toxicity. AB - The gene mapt codes for the microtubule-associated protein Tau. The R406W amino acid substitution in Tau is associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) characterized by Tau-positive filamentous inclusions. These filamentous Tau inclusions are present in a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To gain more insights into the pathomechanism of tauopathies, we performed an RNAi-based large-scale screen in Drosophila melanogaster to identify genetic modifiers of Tau[R406W]-induced toxicity. A collection of RNAi lines, putatively silencing more than 7000 genes, was screened for the ability to modify Tau[R406W] induced toxicity in vivo. This collection covered more than 50% of all protein coding fly genes and more than 90% of all fly genes known to have a human ortholog. Hereby, we identified 62 genes that, when silenced by RNAi, modified Tau-induced toxicity specifically. Among these 62 modifiers were three subunits of the Dynein/Dynactin complex. Analysis on segmental nerves of fly larvae showed that pan neural Tau[R406W] expression and concomitant silencing of Dynein/Dynactin complex members synergistically caused strong pathological changes within the axonal compartment, but only minor changes at synapses. At the larval stage, these alterations did not cause locomotion deficits, but became evident in adult flies. Our data suggest that Tau-induced detrimental effects most likely originate from axonal rather than synaptic dysfunction and that impaired retrograde transport intensifies detrimental effects of Tau in axons. In conclusion, our findings contribute to the elucidation of disease mechanisms in tauopathies like FTDP-17 or AD. PMID- 25794684 TI - Meat traditions. The co-evolution of humans and meat. AB - The debate on the future of meat centres on recent environmental, economical, ethical, and health issues, whereas historical dimensions are all too often overlooked. The fiery discussions are nevertheless affected by an underlying legacy of "meat traditions" and accompanying hunting, slaughtering, eating, and sharing activities, rituals, and rites. Eating meat is a biocultural activity. Therefore, a closer inspection of the evolutionary, collective, and semiotic aspects of meat in human societies is required. This study ventures such an exploration based on a heuristic model inspired by Maslow's pyramid of needs, distinguishing between physiological, security, community, value, and holistic levels. Besides the potential relevance of an innate craving, it is argued that meat has interfered with the development of fundamental human characteristics, both as a physical and conceptual resource. This relates, amongst others, to elements of gender differentiation, cooperation and reciprocity, social stratification and power, religion, cultural expression, and identity. As such, meat traditions provide a basis for evolutionary and long-term social processes, on which more recent and shallow courses of action are superposed, affecting contemporary behaviour. Several research questions were identified to further explore and anticipate the impact of meat on human populations and their societal and economic functioning. PMID- 25794685 TI - Healthy food consumption in young women. The influence of others' eating behavior and body weight appearance. AB - People's eating behaviors tend to be influenced by the behaviors of others. In the present studies, we investigated the effect of another person's eating behavior and body weight appearance on healthy food consumption of young women. In Study 1, participants watched a short film fragment together with a confederate who appeared normal weight or overweight and consumed either 3 or 10 cucumber slices. In Study 2, a confederate who appeared underweight, normal weight, or overweight consumed no or 4 cucumber slices. The number of cucumber slices eaten by participants was registered. Results showed that participants' healthy eating behavior was influenced by the confederate's eating behavior when the confederate was underweight, normal weight, and overweight. Participants ate more cucumber slices when the confederate ate a higher amount of cucumber slices compared with a lower (or no) amount of cucumber slices (Studies 1 and 2). The food intake effect was stronger for the underweight compared with the overweight model (Study 2). PMID- 25794686 TI - New treatment approach shows promise for relapsed Hodgkin's lymphoma. PMID- 25794687 TI - Probabilistic graphical models to deal with age estimation of living persons. AB - Due to the rise of criminal, civil and administrative judicial situations involving people lacking valid identity documents, age estimation of living persons has become an important operational procedure for numerous forensic and medicolegal services worldwide. The chronological age of a given person is generally estimated from the observed degree of maturity of some selected physical attributes by means of statistical methods. However, their application in the forensic framework suffers from some conceptual and practical drawbacks, as recently claimed in the specialised literature. The aim of this paper is therefore to offer an alternative solution for overcoming these limits, by reiterating the utility of a probabilistic Bayesian approach for age estimation. This approach allows one to deal in a transparent way with the uncertainty surrounding the age estimation process and to produce all the relevant information in the form of posterior probability distribution about the chronological age of the person under investigation. Furthermore, this probability distribution can also be used for evaluating in a coherent way the possibility that the examined individual is younger or older than a given legal age threshold having a particular legal interest. The main novelty introduced by this work is the development of a probabilistic graphical model, i.e. a Bayesian network, for dealing with the problem at hand. The use of this kind of probabilistic tool can significantly facilitate the application of the proposed methodology: examples are presented based on data related to the ossification status of the medial clavicular epiphysis. The reliability and the advantages of this probabilistic tool are presented and discussed. PMID- 25794688 TI - The auditory ossicles as a DNA source for genetic identification of highly putrefied cadavers. AB - Genetic identification of putrefied bodies is a common task in forensic medicine. With advancing putrefaction, however, DNA integrity is rapidly decreasing and genetic typing of tissue might be impaired or impossible. Since DNA stability is generally higher in hard tissues, bones or teeth are frequently used as DNA source in such cases. However, isolation of DNA from hard tissues is usually very time-consuming and labor-intensive. This can be especially important in (forensic) cases where time is short and identification has to be carried out as fast as possible. Here, we present the identification of dead bodies by analyzing DNA from the auditory ossicles. These minuscule bones provided DNA of sufficient quality and quantity for identification purposes in all 40 investigated cases. Additionally, processing of the bones proved to be amazingly easy and fast, and a successful extraction is possible using a variety of different methods. We present a detailed protocol, results, and cases in which this new method has been successfully applied. PMID- 25794689 TI - Comparative Investigation of Postoperative Complications in Patients With Gastroesophageal Junction Cancer Treated With Preoperative Chemotherapy or Surgery Alone. AB - BACKGROUND AND AIM: Gastroesophageal junction cancer is one of the leading causes to cancer-related death and the prognosis is poor. However, progress has been made over the last couple of decades with the introduction of multimodality treatment and optimized surgery. Three-year survival rates have improved to 50% in patients receiving neoadjuvant therapy. Only a few studies have focused on the difference of postoperative complications in patients receiving neoadjuvant therapy in relation to a comparative surgery-only group. The aim of this study was to compare the prevalence of postoperative complications of patients with cancer at the gastroesophageal junction treated with either neoadjuvant chemotherapy or surgery alone in patients from "The Danish Clinical Registry of Carcinomas of the Esophagus, the Gastro-Esophageal Junction and the Stomach." MATERIALS AND METHODS: A historical follow-up study, comparing postoperative complications between two cohorts before and after implementation of chemotherapy was completed. RESULTS: In all, 180 consecutive patients treated with perioperative chemotherapy and a comparative surgery-only group of patients were identified from The Danish Clinical Registry of Carcinomas of the Esophagus, the Gastro-Esophageal Junction and the Stomach. No difference was found in demographics between the two groups, except for alcohol consumption and a lower T and N stage in the surgery-only group, and no difference in complication rates was found. Furthermore, no variable in the multivariate analysis was significantly associated with anastomotic leakage which was considered the most severe complication. CONCLUSION: Since perioperative chemotherapy does not appear to increase surgical complications, the future challenges include defining the optimal combination of chemo- and/or radiotherapy, but more importantly also to select the patients who will benefit the most from the different neoadjuvant strategies. PMID- 25794690 TI - Editorial. PMID- 25794691 TI - Topical use of autologous platelet rich plasma in myringoplasty. AB - OBJECTIVE: The aim of this study was to assess the topical use of autologous platelet rich plasma (PRP) to improve success rate of myringoplasty. METHODS: This study was carried out on 64 patients with large dry central tympanic membrane perforations. Myringoplasty was performed through postauricular approach by underlay graft using conchal perichondrial graft. Patients were classified into two groups: case group included 32 patients who had undergone myringoplasty with use of autologous PRP and control group included 32 patients who had undergone myringoplasty without use of autologous PRP. RESULTS: Both groups were statistically matched with regard to age and sex. At 6 months postoperatively, success rate (graft taking) in case group (100%) was significantly higher than in control group (81.25%) (P=0.02). Success in terms of hearing gain (>=10dB) was achieved in 21 patients (65.6%) in case group and 11 patients (34.4%) in control group with statistically non-significant difference (P=0.079). Infection rate in control group (12.5%) was found to be significantly higher than in case group (P<0.0001). CONCLUSION: Topical autologous PRP application during myringoplasty is safe and highly efficient and successful with no reported complication. PRP not only enhances healing of chronic TM perforations but also avoids infection and obviates the need for inner EAC pack. PMID- 25794692 TI - Can Health Trainers Make a Difference With Difficult-to-Engage Clients? A Multisite Case Study. AB - A political attempt in the United Kingdom to address health inequalities in the past decade has been the government's initiative to employ local health trainers (HTs) or health trainer champions (HTCs) to support disadvantaged individuals with aspects of their health-related behaviors. HT/HTCs provide health-related information and support to individuals with healthy eating, physical activity, and smoking cessation. They undertake community engagement and direct individuals to relevant health services. They differ in that HTs are trained to provide health interventions to individuals or groups and to make referrals to specialist health care services when necessary. This article provides an evaluation of HT/HTCs interventions across three sites, including one prison, one probation service (three teams), and one mental health center. An evaluation framework combining process and outcome measures was employed that used mixed methods to capture data relating to the implementation of the service, including the context of the HT/HTCs interventions, the reactions of their clients, and the outcomes reported. It was found that HT/HTCs interventions were more effective in the prison and mental health center compared with the probation site largely as a result of contextual factors. PMID- 25794693 TI - Effect of acidic and basic pH on Thioflavin T absorbance and fluorescence. AB - Thioflavin T (ThT) is a fluorescent dye able to enhance significantly its fluorescence quantum yield upon binding to protein amyloids. ThT assay is widely used to detect and quantify amyloids in a variety of conditions, including solutions with different pH levels. In the present work, the effect of acidic and basic pH on the conformation of the ThT molecule and its absorption and fluorescence properties was studied. The results show that both acidic and basic pH decrease significantly the intensity of ThT absorption in the visible region and fluorescence emission intensity. Low pHs induce an immediate "all-or-nothing" decrease in the ThT signal, while in alkaline solutions the ThT signal decreases gradually over time. pH-induced signal quenching is less in the presence of glycerol or protein aggregates. Two different mechanisms are responsible for the ThT signal quenching-the ThT hydroxylation at basic pH and protonation of the nitrogen atom of the dimethylamino group at acidic pH. ThT assays should be carefully carried out at basic or acidic pH as strong pH dependence of ThT could be responsible for misinterpretation and false positive/negative experimental results. The potential unsuitability of ThT as a probe in solutions with high pH (>9) has been shown. PMID- 25794694 TI - [Rough erythemato-squamous dermatosis with orange palms]. PMID- 25794695 TI - [How to relieve a dyspneic patient at the end of life?]. AB - Dyspnea is a very common symptom that particularly worries the patient and his relatives. In terminally ill patients, there is no correlation between dyspnea and hypoxaemia. Although a specific cause may require an appropriate treatment, most of the time the treatment is symptomatic. This approach is based on oral or parenteral administration of opioids but with a narrower safety margin than in chronic pain patients. The use of an anxiolytic is indicated in stressful circumstances or when opioids fail. Oxygen administration should be discussed on an individual basis and not conditioned to the achievement of full arterial blood saturation. The airstream effect may improve patient's condition as well as oxygen itself. Facial masks impair communication with the relatives and are poorly tolerated over a long period of time. Accumulation of respiratory tract secretions occurs during the last days of life in half of the patients, due to excessive production, impaired swallowing, pulmonary edema and ineffective coughing. PMID- 25794696 TI - Ulnar nerve lesion at the wrist and sport: A report of 8 cases compared with 45 non-sport cases. AB - OBJECTIVE: Reporting clinical and electrodiagnostic characteristics of sport related ulnar neuropathies at the wrist. PATIENTS AND METHODS: Eight sport related and 45 non-sport-related cases from 53 ulnar neuropathies at the wrist cases over 14 years. RESULTS: Sport-related ulnar neuropathies at the wrist cases were due to cycling (5 cases), kayaking (2 cases), and big-game fishing (1 case). No patient had sensory complaints in ulnar digits, and all had motor impairment. Conduction across the wrist with recording on the first dorsal interosseous muscle was impaired in all cases, with conduction block in 5. Two cyclists showed bilateral ulnar neuropathies at the wrist. All cases recovered within 2 to 6 months with sport discontinuation. Distal lesions of the deep motor branch were more frequent in sport- than non-sport-related cases. CONCLUSIONS: The 8 sport related ulnar neuropathies at the wrist cases involved the deep motor branch. Conduction study to the first dorsal interosseous muscle across the wrist is the key to electrodiagnostics. Bilateral cases in cyclists does not require wrist imaging. PMID- 25794697 TI - The effect of selected factors on the survival of Bacillus cereus in the human gastrointestinal tract. AB - Bacillus cereus is a Gram-positive bacterium widely distributed in soil and vegetation. This bacterial species can also contaminate raw or processed foods. Pathogenic B. cereus strains can cause a range of infections in humans, as well as food poisoning of an emetic (intoxication) or diarrheal type (toxico infection). Toxico-infections are due to the action of the Hbl toxin, Nhe toxin, and cytotoxin K produced by the microorganism in the gastrointestinal tract. This occurs once the spores or vegetative B. cereus cells survive the pH barrier of the stomach and reach the small intestine where they produce toxins in sufficient amounts. This article discusses the effect of various factors on the survival of B. cereus in the gastrointestinal tract, including low pH and the presence of digestive enzymes in the stomach, bile salts in the small intestine, and indigenous microflora in the lower parts of the gastrointestinal tract. Additional aspects also reported to affect B. cereus survival and virulence in the gastrointestinal tract include the interaction of the spores and vegetative cells with enterocytes. In vitro studies revealed that both vegetative B. cereus and spores can survive in the gastrointestinal tract suggesting that the biological form of the microorganism may have less influence on the occurrence of the symptoms of infection than was once believed. It is most likely the interaction between the pathogen and enterocytes that is necessary for the diarrheal form of B. cereus food poisoning to develop. The adhesion of B. cereus to the intestinal epithelium allows the bacterium to grow and produce enterotoxins in the proximity of the epithelium. Recent studies suggest that the human intestinal microbiota inhibits the growth of vegetative B. cereus cells considerably. PMID- 25794698 TI - Lumbar total disc replacement by less invasive lateral approach: a report of results from two centers in the US IDE clinical trial of the XL TDR(r) device. AB - PURPOSE: To evaluate the clinical and radiographic outcomes following total disc arthroplasty using the XL TDR((r)) Lumbar Disc in the treatment of patients with symptomatic degenerative disc disease at one level between L1-2 and L4-5. METHODS: Data were compiled from two centers participating in a prospective, multi-center Food and Drug Administration-approved investigational device exemption clinical trial enrolling patients with single-level lumbar degenerative disc disease unresponsive to non-operative treatment. Longitudinal outcomes were evaluated through 3-year follow-up and included patient-reported pain, function, and general health, as well as radiographic measures such as maintenance of disc height and range of motion. RESULTS: The two-center cohort included 64 treated patients, 42 % female, averaging 45.3 years of age (range 26-67). The majority of procedures were performed at the L4-5 level (75 %), uncomplicated, with minimal blood loss (88 % 0-50 cc), and in an outpatient setting (93.8 %). Postoperative events included 10 patients (15.6 %) with new hip flexion weakness, 7 (10.9 %) with new lower extremity weakness, and 10 (15.6 %) with new lower extremity sensory deficits, all resolved by 3 months in all but two patients whose deficits were prolonged but eventually resolved. Average disc height increased postoperatively from 7.2 to 12.1 mm (69 %), and was 10.7 mm (49 % increase from preoperative) at 3 years. Flexion/extension range of motion averaged 5.9 degrees (SD 4.8 degrees ) at 3 years, and was not statistically different from preoperative (p = 0.471). Heterotopic ossification interfering with segmental motion was noted in 3 patients (10.3 %) at 3 years, none ankylosed (Grade IV). Postoperative improvement in patient-reported outcomes was significant (p < 0.01 for all measures) and maintained through 3-year follow-up. Satisfaction with results was reported by 85 % (51/60) of patients at 2 years and 93 % (28/30) at 3 years. There were no revisions through 3 years postoperative. CONCLUSIONS: The results following XL TDR show good clinical and radiographic outcomes out to 3 years postoperative, with clinically significant improvements in pain, function, and general health, few complications, and high patient satisfaction. PMID- 25794699 TI - Medication reconciliation for patients undergoing spinal surgery. AB - PURPOSE: In recent years, a marked increase of spinal operations prompted a debate on quality issues. Besides obvious factors, such as the surgical technique, medication safety has been identified as one of the major risk factors for patients undergoing anesthesia and surgery. While the issue has already been addressed by hospital pharmacist and anesthesiologists, the prescription of correct medication remains within the surgeons' responsibility. We, therefore, investigated medication-related errors in spinal instrumentation patients and applied current medication reconciliation strategies. METHODS: We performed a data survey on all patients undergoing spinal instrumentation in 2011. Risk factors for medication safety were identified and prioritized. Specific counter measures were introduced in 2012 and evaluated in 2013. RESULTS: 147 patients were included in the 2011 and 162 in the 2013 survey. As top five risk factors we identified the preoperative stopping of medication, recording the medication history, prescription process of postoperative analgetics and anticoagulants and the medication list at discharge. Specific counter-measures included standardization of preparations, doses and the prescription process and improving access to this information (online and via a smartphone application). In elective patients, recording the medication histories was delegated to a hospital pharmacist and informative flyers and posters were used to integrate the patients themselves into the process. Counter-measures directed against the first four risk factors resulted in a significant reduction of medication errors. The last risk factor was targeted by instructing the responsible staff only, which proved to be a rather ineffective measure. CONCLUSIONS: Medication safety could be significantly improved by implementation of counter-measures specific to the identified risk factors. PMID- 25794701 TI - Scoliosis in patients with multiple hereditary exostoses. AB - PURPOSE: To investigate the prevalence of and to identify independent predictors associated with scoliosis in patients with multiple hereditary exostoses (MHE). METHODS: Fifty patients with MHE were clinically examined, and the diagnosis of scoliosis was made based on radiographs. To classify disease severity, three classes based on the presence of deformities and functional limitations were defined. Significant independent predictors of scoliosis in MHE were statistically analyzed. RESULTS: Scoliosis was present in 36 patients (MHE scoliosis) (72 %). In the MHE-scoliosis group, the mean primary curve was 15.3 degrees +/- 5.7 degrees (range 10 degrees -34 degrees ) and the mean minor curve was 10.6 degrees +/- 7 degrees (range 6 degrees -32 degrees ). Left curve was predominant (72 %), and the apex was located in the thoracolumbar or lumbar spine in 64 % of patients. Univariable and multivariable analyses confirmed that MHE severity was a significant predictor of moderate scoliosis (>=20 degrees ). CONCLUSIONS: Our study confirmed that scoliosis is a common feature of MHE and disease severity is a predictor of moderate scoliosis (>=20 degrees ). PMID- 25794702 TI - Letter to the Editor regarding: "Cell transplantation in lumbar spine disc degeneration disease" (by C. Hohaus, T.M. Ganey, Y. Minkus and H.J. Meisel: Eur Spine J; 17, Suppl 4:492-503, December 2008). PMID- 25794700 TI - Occipitocervical stabilization using bilateral laminar C2 screws in children with mucopolysaccharidosis IVA. AB - PURPOSE: Mucopolysaccharidosis IVA (MPS IVA) is a multisystemic storage disorder. Patient's disability and life expectancy depends upon skeletal complications, including cervical myelopathy due to upper cervical compression or instability. Posterior decompression followed by occipitocervical fixation or C1-2 fusion are the most frequently recommended surgical interventions. The bony elements of C1 and C2 are often inadequately developed making routine screw insertion difficult. The main purpose of this work was to present novel technique of occipitocervical fixation using two C2 laminar screws. METHODS: Four children with MPS IVA underwent decompression and C0-C2 instrumented fusion using two C2 bilateral laminar screws. The dimensions of the C2 lamina were measured. Clinical and radiological results were monitored prospectively for a minimum 3 years. RESULTS: The mean laminar length was 24 +/- 1.15 mm, width 6.15 +/- 0.55 mm and height 7.4 +/- 0.6 mm. Patients remained in a stable neurological condition. The mean antero posterior diameter of the spinal canal on the pre-operative MR was 6.2 +/- 0.74 mm and it was enlarged to 11.4 +/- 0.8 mm after 3 years. All screws were placed adequately. In all patients, the control CT scan 2 years post-operatively revealed a stable position of the treated segments, but solid bony fusion was not registered in any patient. CONCLUSIONS: Decompression and fusion of the upper cervical spine is a generally accepted approach to treat upper cervical spine instability and myelopathy in MPS IVA patients. The feasibility and the suitability of the technique of C0-C2 stabilization using bilateral C2 laminar screws have been presented. PMID- 25794703 TI - Antidiabetic agents: Potential anti-inflammatory activity beyond glucose control. AB - A growing body of evidence is emerging to show that abdominal obesity, the metabolic syndrome, type 2 diabetes, cardiovascular disease and microvascular diabetic complications are intimately related to chronic inflammation. These observations pave the way to the development of new pharmacological strategies that aim to reduce silent inflammation. However, besides specific anti inflammatory agents, glucose-lowering medications may also exert anti inflammatory effects that could contribute to improved outcomes in diabetic patients. Most studies have used metformin, an AMP-activated protein kinase (AMPK) activator, and thiazolidinediones (TZDs), which act as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists. Both pharmacological classes (considered insulin-sparing agents or insulin sensitizers) appear to have greater anti-inflammatory activity than insulin-secreting agents such as sulphonylureas or glinides. In particular, TZDs have shown the widest range of evidence of lowered tissue (visceral fat and liver) and serum inflammation. In contrast, despite reducing postprandial hyperglycaemia, the effect of alpha glucosidase inhibitors on inflammatory markers appears rather modest, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and glucagon-like peptide-1 (GLP-1) receptor agonists appear more promising in this respect. These incretin based therapies exert pleiotropic effects, including reports of anti-inflammatory activity. No human data are available so far regarding sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Although they may have indirect effects due to reduced glucotoxicity, their specific mode of action in the kidneys does not suggest systemic anti-inflammatory activity. Also, in spite of the complex relationship between insulin and atherosclerosis, exogenous insulin may also exert anti-inflammatory effects. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and potential anti-inflammatory effects related to intrinsic actions of the pharmacological class. Finally, it would also be of major clinical interest to define what role the anti-inflammatory effects of these glucose-lowering agents may play in the prevention of macrovascular and microvascular diabetic complications. PMID- 25794704 TI - Nonclassical resident macrophages are important determinants in the development of myocardial fibrosis. AB - Macrophages are increasingly recognized as a potential therapeutic target in myocardial fibrosis via interactions with fibroblasts. We have characterized macrophage depletion and inhibition of nonclassical macrophage migration, in addition to direct interactions between nonclassical macrophages and fibroblasts in angiotensin II (AngII)-mediated, hypertensive myocardial fibrosis. Macrophage depletion was achieved by daily i.v. clodronate liposomes (-1 day to +3 days) during AngII infusion. Cx3cr1(-/-) mice were used to inhibit nonclassical macrophage migration. Macrophage phenotype (F4/80, CD11b, Ly6C) was characterized by immunofluorescence and flow cytometry. Collagen was assessed by Sirius Red/Fast Green. Quantitative real-time RT-PCR was performed for transcript levels. AngII/wild-type (WT) mice displayed significant infiltrate and fibrosis compared with saline/WT, which was virtually ablated by clodronate liposomes independent of hypertension. In vitro data supported M2 macrophages promoting fibroblast differentiation and collagen production. AngII/Cx3cr1(-/-) mice, however, significantly increased macrophage infiltrate and fibrosis relative to AngII/WT. AngII/Cx3cr1(-/-) mice also showed an M1 phenotypic shift relative to WT mice in, which the predominant phenotype was Ly6C(low), CD206(+) (M2). Myocardial IL-1beta was significantly up-regulated, whereas transforming growth factor beta down-regulated with this M1 shift. We demonstrated that infiltrating macrophages are critical to AngII-mediated myocardial fibrosis by preventing the development of fibrosis after liposomal depletion of circulating monocytes. Our findings also suggest that some macrophages, namely M2, may confer a protective myocardial environment that may prevent excessive tissue injury. PMID- 25794705 TI - Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl 1. AB - Fas-induced apoptosis is involved in diverse liver diseases. Herein, we investigated the effect of Mir155 deletion on Fas-induced liver injury. Wild-type (WT) mice and Mir155 knockout (KO) mice were i.p. administered with the anti-Fas antibody (Jo2) to determine animal survival and the extent of liver injury. After Jo2 injection, the Mir155 KO mice exhibited prolonged survival versus the WT mice (P < 0.01). The Mir155 KO mice showed lower alanine aminotransferase and aspartate aminotransferase levels, less liver tissue damage, fewer apoptotic hepatocytes, and lower liver tissue caspase 3/7, 8, and 9 activities compared with the WT mice, indicating that Mir155 deletion prevents Fas-induced hepatocyte apoptosis and liver injury. Hepatocytes isolated from Mir155 KO mice also showed resistance to Fas-induced apoptosis, in vitro. Higher protein level of myeloid cell leukemia-1 (Mcl-1) was also observed in Mir155 KO hepatocytes compared to WT hepatocytes. A miR-155 binding site was identified in the 3'-untranslated region of Mcl-1 mRNA; Mcl1 was identified as a direct target of miR-155 in hepatocytes. Consistently, pretreatment with a siRNA specific for Mcl1 reversed Mir155 deletion-mediated protection against Jo2-induced liver tissue damage. Finally, restoration of Mir155 expression in Mir155 KO mice abolished the protection against Fas-induced hepatocyte apoptosis. Taken together, these findings demonstrate that deletion of Mir155 prevents Fas-induced hepatocyte apoptosis and liver injury through the up-regulation of Mcl1. PMID- 25794707 TI - FOXO1 deletion reduces dendritic cell function and enhances susceptibility to periodontitis. AB - The host response plays both protective and destructive roles in periodontitis. FOXO1 is a transcription factor that is activated in dendritic cells (DCs), but its function in vivo has not been examined. We investigated the role of FOXO1 in activating DCs in experimental (CD11c.Cre(+).FOXO1(L/L)) compared with matched control mice (CD11c.Cre(-).FOXO1(L/L)) in response to oral pathogens. Lineage specific FOXO1 deletion reduced the recruitment of DCs to oral mucosal epithelium by approximately 40%. FOXO1 was needed for expression of genes that regulate migration, including integrins alphanu and beta3 and matrix metalloproteinase-2. Ablation of FOXO1 in DCs significantly decreased IL-12 produced by DCs in mucosal surfaces. Moreover, FOXO1 deletion reduced migration of DCs to lymph nodes, reduced capacity of DCs to induce formation of plasma cells, and reduced production of bacteria-specific antibody. The decrease in DC function in the experimental mice led to increased susceptibility to periodontitis through a mechanism that involved a compensatory increase in osteoclastogenic factors, IL 1beta, IL-17, and RANKL. Thus, we reveal a critical role for FOXO1 in DC recruitment to oral mucosal epithelium and activation of adaptive immunity induced by oral inoculation of bacteria. PMID- 25794706 TI - Gonadotropin-releasing hormone stimulates biliary proliferation by paracrine/autocrine mechanisms. AB - During cholestatic liver disease, there is dysregulation in the balance between biliary growth and loss in bile duct-ligated (BDL) rats modulated by neuroendocrine peptides via autocrine/paracrine pathways. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone that modulates reproductive function and proliferation in many cell types. We evaluated the autocrine role of GnRH in the regulation of cholangiocyte proliferation. The expression of GnRH receptors was assessed in a normal mouse cholangiocyte cell line (NMC), sham, and BDL rats. The effect of GnRH administration was evaluated in normal rats and in NMC. GnRH induced biliary proliferation was evaluated by changes in intrahepatic bile duct mass and the expression of proliferation and function markers. The expression and secretion of GnRH in NMC and isolated cholangiocytes was assessed. GnRH receptor subtypes GnRHR1 and GnRHR2 were expressed in cholangiocytes. Treatment with GnRH increased intrahepatic bile duct mass as well as proliferation and function markers in cholangiocytes. Transient knockdown and pharmacologic inhibition of GnRHR1 in NMC decreased proliferation. BDL cholangiocytes had increased expression of GnRH compared with normal rats, accompanied by increased GnRH secretion. In vivo and in vitro knockdown of GnRH decreased intrahepatic bile duct mass/cholangiocyte proliferation and fibrosis. GnRH secreted by cholangiocytes promotes biliary proliferation via an autocrine pathway. Disruption of GnRH/GnRHR signaling may be important for the management of cholestatic liver diseases. PMID- 25794708 TI - Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia. AB - Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-ErbB negative regulator and intestinal stem cell marker down-regulated in many malignancies. We previously reported that 14 of 16 Lrig1-CreERT2/CreERT2 (Lrig1( /-)) mice developed duodenal adenomas, providing the first in vivo evidence that Lrig1 acts as a tumor suppressor. We extended this study to a larger cohort and found that 49 of 54 Lrig1(-/-) mice develop duodenal adenomas beginning at 3 months. Most adenomas were histologically low grade and overlaid expanded Brunner glands. There was morphologic and biochemical blurring of the boundary between the epithelium and Brunner glands with glandular coexpression of ErbB2, which is normally restricted to the epithelium, and the Brunner gland marker Mucin6. Some adenomas were high grade with reduced Brunner glands. At age 4 to 5 weeks, before adenoma formation, we observed enhanced proliferation in Brunner glands and, at 2 months, an increase in the size of the Brunner gland compartment. Elevated expression of the epidermal growth factor receptor (Egfr) ligands amphiregulin and beta-cellulin, as well as Egfr and phosphorylated Egfr, was detected in adenomas compared with adjacent normal tissue. These adenomas expressed the gastric-specific genes gastrokine1 and mucin5ac, indicating gastric metaplasia. Moreover, we found that a subset of human duodenal tumors exhibited features of LRIG1(-/-) adenomas, including loss of LRIG1, gastric metaplasia (MUCIN5AC and MUCIN6), and increased amphiregulin and Egfr activity. PMID- 25794710 TI - Lack of evidence that HACE1 is not a tumor suppressor gene in NKTCL: to the editor-in-chief. PMID- 25794709 TI - Methionine adenosyltransferase 2B-GIT1 complex serves as a scaffold to regulate Ras/Raf/MEK1/2 activity in human liver and colon cancer cells. AB - Methionine adenosyltransferase 2B (MAT2B) encodes for variant proteins V1 and V2 that interact with GIT1 to increase ERK activity and growth in human liver and colon cancer cells. MAT2B or GIT1 overexpression activates MEK. This study explores the mechanism for MEK activation. We examined protein-protein interactions by co-immunoprecipitation and verified by confocal microscopy and pull-down assay using recombinant or in vitro translated proteins. Results were confirmed in an orthotopic liver cancer model. We found that MAT2B and GIT1 mediated MEK1/2 activation was not mediated by PAK1 or Src in HepG2 or RKO cells. Instead, MAT2B and GIT1 interact with B-Raf and c-Raf and enhance recruitment of Raf proteins to MEK1/2. MAT2B-GIT1 activates c-Raf, which is the key mediator for MEK/12 activation, because this still occurred in RKO cells that express constitutively active B-Raf mutant. The mechanism lies with the ability of MAT2B GIT1 to activate Ras and promote B-Raf/c-Raf heterodimerization. Interestingly, MAT2B but not GIT1 can directly interact with Ras, which increases protein stability. Finally, increased Ras-Raf-MEK signaling occurred in phenotypically more aggressive liver cancers overexpressing MAT2B variants and GIT1. In conclusion, interaction between MAT2B and GIT1 serves as a scaffold and facilitates signaling in multiple steps of the Ras/Raf/MEK/ERK pathway, further emphasizing the importance of MAT2B/GIT1 interaction in cancer growth. PMID- 25794711 TI - Lack of evidence that HACE1 is not a tumor suppressor gene in NKTCL: to the editor-in-chief. Authors' reply. PMID- 25794712 TI - Determination of parabens in human milk and other food samples by capillary electrophoresis after dispersive liquid-liquid microextraction with back extraction. AB - Dispersive liquid-liquid microextraction (DLLME) with back-extraction was used prior to capillary electrophoresis (CE) for the extraction of four parabens. Optimum extraction conditions were: 200 MUL chloroform (extraction solvent), 1.0 mL acetonitrile (disperser solvent) and 1 min extraction time. Back-extraction of parabens from chloroform into a 50mM sodium hydroxide solution within 10s facilitated their direct injection into CE. The analytes were separated at 12 degrees C and 25 kV with a background electrolyte of 25 mM borate buffer containing 5.0% (v/v) acetonitrile. Enrichment factors were in the range of 4.3 10.7 and limits of detection ranged from 0.1 to 0.2 MUg mL(-1). Calibration graphs showed good linearity with coefficients of determination (R(2)) higher than 0.9957 and relative standard deviations (%RSDs) lower than 3.5%. DLLME-CE was demonstrated to be a simple and rapid method for the determination of parabens in human milk and food with relative recoveries in the range of 86.7 103.3%. PMID- 25794713 TI - Direct saponification preparation and analysis of free and conjugated phytosterols in sugarcane (Saccharum officinarum L.) by reversed-phase high performance liquid chromatography. AB - A simple method based on direct saponification followed by RP-HPLC analysis was developed for quantification of free and conjugated sterols in sugarcane. Acid hydrolysis prior to alkaline saponification was used to determined acylated steryl glycoside and steryl glycoside in sugarcane. The applicability and generality of this method were improved with intensive investigation. Compared to traditional solvent extraction method, this method was more time saving and appropriate for characterization of sterol fractions in sugarcane. This method was successfully applied for determination of free and conjugated sterols in different sugarcane samples. The results exhibited that stigmasterol (varied from 883.3 +/- 23.5 to 1823.9 +/- 24.5 MUg/g dry weigh) and beta-sitosterol (varied from 117.6 +/- 19.9 to 801.4 +/- 33.5 MUg/g dry weight) were major phytosterols in the sugarcane sample, and their glycosylated forms accounted for almost 87.0% of stigmasterol and 87.5% of beta-sitosterol in sugarcane, respectively. In addition, among other parts of sugarcane, tips contained the greatest amount of phytosterols. PMID- 25794714 TI - Preparation and characterisation of the oligosaccharides derived from Chinese water chestnut polysaccharides. AB - Hydrogen peroxide (H2O2) is a strong oxidant that cleaves glycosidic bonds in polysaccharides. In this study, the oligosaccharides were prepared by removing the starch from Chinese water chestnuts through hydrolysis using alpha-amylase and then hydrolysing the remaining polysaccharides with H2O2, during which the oligosaccharide yield was monitored. The yield of oligosaccharide was affected by reaction time, temperature, and H2O2 concentration. Extended reaction times, high temperatures, and high H2O2 concentrations decreased oligosaccharide yield. Under optimum conditions (i.e., reaction time of 4h, reaction temperature of 80 degrees C, and 2.5% H2O2 concentration), the maximum oligosaccharide yield was 3.91%. The oligosaccharides derived from Chinese water chestnuts polysaccharides exhibited strong hydroxyl and 2,2-diphenyl-beta-picrylhydrazyl radical scavenging activity when applied at a concentration of 100 MUg/mL. The results indicate that the oligosaccharides derived from Chinese water chestnuts polysaccharides possessed good antioxidant properties and can be developed as a new dietary supplement and functional food. PMID- 25794715 TI - Optimization of conditions for the single step IMAC purification of miraculin from Synsepalum dulcificum. AB - In this study, the methods for extraction and purification of miraculin from Synsepalum dulcificum were investigated. For extraction, the effect of different extraction buffers (phosphate buffer saline, Tris-HCl and NaCl) on the extraction efficiency of total protein was evaluated. Immobilized metal ion affinity chromatography (IMAC) with nickel-NTA was used for the purification of the extracted protein, where the influence of binding buffer pH, crude extract pH and imidazole concentration in elution buffer upon the purification performance was explored. The total amount of protein extracted from miracle fruit was found to be 4 times higher using 0.5M NaCl as compared to Tris-HCl and phosphate buffer saline. On the other hand, the use of Tris-HCl as binding buffer gave higher purification performance than sodium phosphate and citrate-phosphate buffers in IMAC system. The optimum purification condition of miraculin using IMAC was achieved with crude extract at pH 7, Tris-HCl binding buffer at pH 7 and the use of 300 mM imidazole as elution buffer, which gave the overall yield of 80.3% and purity of 97.5%. IMAC with nickel-NTA was successfully used as a single step process for the purification of miraculin from crude extract of S. dulcificum. PMID- 25794716 TI - Rapid detection of authenticity and adulteration of walnut oil by FTIR and fluorescence spectroscopy: a comparative study. AB - Fourier transform infrared (FTIR) and fluorescence spectroscopy combined with soft independent modeling of class analogies (SIMCA) and partial least square (PLS) were used to detect the authenticity of walnut oil and adulteration amount of soybean oil in walnut oil. A SIMCA model of FTIR spectra could differentiate walnut oil and other oils into separate categories; the classification limit of soybean oil in walnut oil was 10%. Fluorescence spectroscopy could differentiate oil composition by the peak position and intensity of emission spectrum without multivariate analysis. The classification limit of soybean oil adulterated in walnut oil by fluorescence spectroscopy was below 5%. The deviation of the prediction model for fluorescence spectra was lower than that for FTIR spectra. Fluorescence spectroscopy was more applicable than FTIR in the adulteration detection of walnut oil, both from the determination limit and prediction deviation. PMID- 25794717 TI - Development and analytical validation of a screening method for simultaneous detection of five adulterants in raw milk using mid-infrared spectroscopy and PLS DA. AB - This paper proposed a new screening method for the simultaneous detection of five common adulterants in raw cow milk by using attenuated total reflectance (ATR) mid infrared spectroscopy and multivariate supervised classification (partial least squares discrimination analysis - PLSDA). The method was able to detect the presence of the adulterants water, starch, sodium citrate, formaldehyde and sucrose in milk samples containing from one up to five of these analytes, in the range of 0.5-10% w/v. A multivariate qualitative validation was performed, estimating specific figures of merit, such as false positive and false negative rates, selectivity, specificity and efficiency rates, accordance and concordance. The proposed method does not need any sample pretreatment, requires a small amount of sample (30 MUL), is fast and simple, being suitable for the control of raw milk in a dairy industry or for the quality inspection of commercialized milk. PMID- 25794718 TI - Highly sensitive and selective determination of fluorine ion by graphene oxide/nanogold resonance Rayleigh scattering-energy transfer analytical platform. AB - In pH 4.0 acetate buffer solution, fluorine ions react with fluorine reagent (FR) and La(III) to generate blue ternary complex that exhibited strong absorption at about 370 nm. Upon addition of graphene oxide/nanogold (GO/NG) as resonance Rayleigh scattering (RRS) spectral probe with strong RRS peak at 370 nm, the color changed to gray, and the RRS intensity decreased with the increase of fluorine ion concentration due to the RRS energy transfer (RRSET) from GO/NG to the complex. Under the selected condition, the decreased RRS peak DeltaI370 nm was linear to fluorine ion concentration in the range of 6.0 * 10(-8)-1.3 * 10( 5)mol/L, with a detection limit of 3.0 * 10(-8)mol/L F(-). This RRSET method was applied to the analysis of fluorine in toothpaste and water samples, with satisfactory results. PMID- 25794719 TI - Molecular order and functional properties of starches from three waxy wheat varieties grown in China. AB - Molecular order and functional properties of starch from three waxy wheat varieties grown in China were investigated by a combination of various technical analyses. The total starch content of the waxy wheat ranged between 54.1% and 55.0%, and the amylose content of the starch was between 0.71% and 1.63%. Average particle diameter of the three starches varied between 16.5 and 17.4 MUm. Three waxy wheat starches presented the typical A-type X-ray diffraction pattern, with relative crystallinity between 38.7% and 40.0%. No significant differences were observed in relative crystallinity, IR ratios of 1047/1022 cm(-1) and 1022/995 cm(-1), and FWHH of the band at 480 cm(-1), indicating the similarity in long range order of crystallites and short-range order of double helices of three starch granules. Small differences were observed in swelling power, gelatinization parameters, pasting viscosities, and in vitro enzymatic digestibility of three waxy wheat starches. Under the stored condition, no retrogradation occurred for three waxy wheat starches. PMID- 25794720 TI - Enzymatic production of HMO mimics by the sialylation of galacto oligosaccharides. AB - Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycans that exhibit a wide range of biological activities. In this report, we describe an efficient, Multi-Enzyme One-Pot strategy to produce HMO mimics by the sialylation of galacto-oligosaccharides (GOSs), which are often added to infant formula as an inexpensive alternative to HMOs. In this system, the sialyltransferase donor, cytidine-5'-monophospho-N-acetylneuraminic acid (CMP Neu5Ac), was generated in situ using a CMP-sialic acid synthetase. The sialylated GOSs were obtained by one-step purification after digesting CMP using the alkaline phosphatase PhoA to cytidine and inorganic phosphate. Although the synthesized alpha2,3-, alpha2,6- and alpha2,3/8-sialyl-GOSs exhibit different sialylation levels and patterns, all of these mixtures can be fermented by Bifidobacterium longum subsp. infantis ATCC 15697 but not by Bifidobacterium adolescentis ATCC 15703. The sialidase NanH2, which is unique to the former strain, hydrolyzed all of the synthesized HMO mimics. PMID- 25794721 TI - Determination of avermectins: a QuEChERS approach to the analysis of food samples. AB - We present a simple method for extracting avermectines from meat, based on a QuEChERS approach followed by liquid chromatography (LC) coupled to triple quadrupole (QqQ) tandem mass spectrometry (MS/MS). The compounds considered are ivermectin, abamectin, emamectin, eprinomectin, doramectin and moxidectin. The new method has been fully validated according to the requirements of European Decision 657/2002/CE (EU, 2002). The method is suitable for the analysis of avermectins at concentration as low as 2.5 MUg kg(-1), and allows high sample throughput. In addition, the detection of avermectins by high resolution mass spectrometry using a quadrupole-Orbritrap (Q-Orbitrap) hybrid instrument has been explored, and the target Selected Ion Monitoring data dependent MS/MS (t-SIM-dd MS/MS) mode has been found to provide excellent performance for residue determination of target analytes. PMID- 25794722 TI - Determination of pesticides in lettuce using solid-liquid extraction with low temperature partitioning. AB - This work describes the optimization and validation of a method employing solid liquid extraction with low temperature partitioning (SLE/LTP) together with analysis by gas chromatography with electron capture detection (GC/ECD) for the determination of nine pesticides (chlorothalonil, methyl parathion, procymidone, endosulfan, iprodione, lambda-cyhalothrin, permethrin, cypermethrin, and deltamethrin) in lettuce. The method was found to be selective, accurate, and precise, with means recovery values in the range of 72.3-103.2%, coefficients of variation ? 12%, and detection limits in the range 0.4-37 MUg kg(-1). The matrix components significantly influence the chromatographic response of the analytes (above 10%). The optimized and validated method was applied to determine the residual concentrations of the fungicides iprodione and procymidone that had been applied to field crops of lettuce. The maximum residual concentrations of the pesticides in the lettuce samples were 13.6 +/- 0.4 mg kg(-1) (iprodione) and 1.00 +/- 0.01 mg kg(-1) (procymidone), on the day after application of the products. PMID- 25794723 TI - Determination of furfural and hydroxymethylfurfural from baby formula using headspace solid phase microextraction based on nanostructured polypyrrole fiber coupled with ion mobility spectrometry. AB - Furfural (Fu) and hydroxymethylfurfural (HMFu) are extracted using a dodecylbenzenesulfonate-doped polypyrrole coating as a fiber for headspace solid phase microextraction (HS-SPME) method in baby formula samples and detected using ion mobility spectrometry (IMS). Sample pH, salt effect, extraction time and temperature were investigated and optimized as effective parameters in HS-SPME. The calibration curves were linear in the range of 20-300 ng g(-1) (R(2)>0.99). Limits of detection for Fu and HMFu were 6 ng g(-1) and 5 ng g(-1), respectively. The RSD% of Fu and HMFu for five analyses was 4.4 and 4.9, respectively. The proposed method was successfully applied to determine of Fu and HMFu in the different baby formula samples with satisfactory result. The results were in agreement with those obtained using HPLC analysis. The HS-SPME-IMS is precise, selective and sensitive analytical method for determination of Fu and HMFu in baby formula samples, without any derivatization process. PMID- 25794724 TI - In-house validation of a method for determination of silver nanoparticles in chicken meat based on asymmetric flow field-flow fractionation and inductively coupled plasma mass spectrometric detection. AB - Nanomaterials are increasingly used in food production and packaging, and validated methods for detection of nanoparticles (NPs) in foodstuffs need to be developed both for regulatory purposes and product development. Asymmetric flow field-flow fractionation with inductively coupled plasma mass spectrometric detection (AF(4)-ICP-MS) was applied for quantitative analysis of silver nanoparticles (AgNPs) in a chicken meat matrix following enzymatic sample preparation. For the first time an analytical validation of nanoparticle detection in a food matrix by AF(4)-ICP-MS has been carried out and the results showed repeatable and intermediately reproducible determination of AgNP mass fraction and size. The findings demonstrated the potential of AF(4)-ICP-MS for quantitative analysis of NPs in complex food matrices for use in food monitoring and control. The accurate determination of AgNP size distribution remained challenging due to the lack of certified size standards. PMID- 25794725 TI - High pressure intensification of cassava resistant starch (RS3) yields. AB - Cassava starch, typically, has resistant starch type 3 (RS3) content of 2.4%. This paper shows that the RS3 yields can be substantially enhanced by debranching cassava starch using pullulanase followed by high pressure or cyclic high pressure annealing. RS3 yield of 41.3% was obtained when annealing was carried out at 400MPa/60 degrees C for 15 min, whereas it took nearly 8h to obtain the same yield under conventional atmospheric annealing at 60 degrees C. The yield of RS3 could be further significantly increased by annealing under 400 MPa/60 degrees C pressure for 15 min followed by resting at atmospheric pressure for 3h 45 min, and repeating this cycle for up to six times. Microstructural surface analysis of the product under a scanning electron microscope showed an increasingly rigid density of the crystalline structure formed, confirming higher RS3 content. PMID- 25794726 TI - Influences of organically and conventionally grown strawberry cultivars on anthocyanins content and color in purees and low-sugar jams. AB - The objective of this study was to detect influences of cultivar, cultivation and processing on anthocyanin content and color in purees and low-sugar jams produced from strawberry cultivars (Elsanta, Maya, Marmolada, Queen Elisa), grown under conventional and organic cultivation. Color was determined by CIELab values while anthocyanins were quantified by HPLC-UV/VIS-PDA. Queen Elisa was the best cultivar for processing as it had highest total anthocyanin content (TAC) that was well preserved in processing. On average, processing purees to jams decreased TAC for 28% where pelargonidin-3-glucoside revealed most noticeable loss (53%) and cyanidin-3-rutinoside was best preserved in processing. Obtained results indicated that measurement of colorimetric parameters are strongly correlated with content of anthocyanins. In other words, loss of anthocyanins during processing was accompanied by noticeable decrease in lightness, red/yellow color and total color change. Results showed that change of color is useful predictor for estimating anthocyanins in strawberry purees and jams. PMID- 25794727 TI - Fast and simultaneous determination of eleven synthetic color additives in flour and meat products by liquid chromatography coupled with diode-array detector and tandem mass spectrometry. AB - In this study, an efficient, fast and sensitive method for the simultaneous determination of eleven synthetic color additives (Allura red, Amaranth, Azo rubine, Brilliant blue, Erythrosine, Indigotine, Ponceau 4R, New red, Sunset yellow, Quinoline yellow and Tartrazine) in flour and meat foodstuffs is developed and validated using HPLC coupled with DAD and MS/MS. The color additives were extracted with ammonia-methanol and was further purified with SPE procedure using Strata-AW column in order to reduce matrix interference. This HPLC-DAD method is intended for a comprehensive survey of color additives in foods. HPLC-MS/MS method was used as the further confirmation and identification. Validation data showed the good recoveries in the range of 75.2-113.8%, with relative standard deviations less than 15%. These methods are suitable for the routine monitoring analysis of eleven synthetic color additives due to its sensitivity, reasonable time and cost. PMID- 25794728 TI - Effect of calcium chloride addition and draining pH on the microstructure and texture of full fat Cheddar cheese during ripening. AB - Calcium chloride is commonly added to cheese-milk to improve coagulum formation and to increase cheese yield but high concentrations of calcium ions can have adverse effects. In this study, confocal laser scanning microscopy and cryo scanning electron microscopy were coupled with textural and chemical analyses to observe microstructural and biochemical changes that occur in cheese during ripening when calcium chloride is added or the draining pH altered. For the cheese prepared with no additional calcium at a draining pH of 6.0, the cheese porosity increased with ripening time and the number of protein vertices in the microscopy images declined, indicative of protein solubilisation. As the amount of CaCl2 added was increased, however, these changes became less significant. Our findings show that calcium chloride addition can be used, together with a lower draining pH, to alter the manufacturing process without significantly impacting on the quality of the mature cheese. PMID- 25794729 TI - Simultaneous determination of 38 veterinary antibiotic residues in raw milk by UPLC-MS/MS. AB - A selective and rapid method has been developed to determine, simultaneously, 38 veterinary antibiotic residues in raw milk by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). One milliliter of raw milk was diluted with 0.5 mL water and 3 mL acetonitrile, then purified using an Oasis HLB cartridge. The eluates were evaporated by nitrogen drying and then reconstituted to 4 mL with water/acetonitrile (8:1) before being injected into the UPLC-MS/MS system. The results indicated recoveries of 68-118% for 14 beta lactams, 79-118% for eight quinolones, 71-106% for eight sulfonamides, 76-116% for four tetracyclines, 78-106% for three macrolides, and 88-103% for one lincosamides, with coefficients of variation less than 15% for intraday and interday precisions. The limit of quantification for all antibiotics was 0.03-10 MUg kg(-1). This methodology was then applied to field-collected real raw milk samples and trace levels of four antibiotics were detected. PMID- 25794730 TI - Sensitive determination of quinoline yellow using poly (diallyldimethylammonium chloride) functionalized reduced graphene oxide modified grassy carbon electrode. AB - A novel poly (diallyldimethylammonium chloride) functionalized reduced graphene oxide (PDDA-RGO) nanocomposite modified electrode was fabricated, and applied for the electrochemical determination of quinoline yellow (QY). The formation of PDDA RGO nanocomposite was confirmed by SEM, FTIR and Raman spectroscopy. The electrocatalytic activity of PDDA-RGO nanocomposite to the oxidation of QY was evaluated using cyclic voltammetry and differential pulse voltammetry. Under the optimal conditions, the proposed sensor exhibited excellent electrochemical performance towards detection of QY. The linear range is from 0.01 to 10 MUM, and the detection limit is down to 0.002 MUM (S/N=3). The proposed sensor also exhibited excellent anti-interference property, repeatability and stability. In addition, the proposed electrochemical sensor was successfully applied to determination of QY in soft drink. PMID- 25794731 TI - Modification of porous starch for the adsorption of heavy metal ions from aqueous solution. AB - Porous starch xanthate (PSX) and porous starch citrate (PSC) were prepared in anticipation of the attached xanthate and carboxylate groups respectively forming chelation and electrostatic interactions with heavy metal ions in the subsequent adsorption process. The lead(II) ion was selected as the model metal and its adsorption by PSX and PSC was characterized. The adsorption capacity was highly dependent on the carbon disulfide/starch and citric acid/starch mole ratios used during preparation. The adsorption behaviors of lead(II) ion on PSXs and PSCs fit both the pseudo-second-order kinetic model and the Langmuir isotherm model. The maximum adsorption capacity from the Langmuir isotherm equation reached 109.1 and 57.6 mg/g for PSX and PSC when preparation conditions were optimized, and the adsorption times were just 20 and 60 min, respectively. PSX and PSC may be used as effective adsorbents for removal of heavy metals from contaminated liquid. PMID- 25794732 TI - A monoclonal antibody-based enzyme-linked immunosorbent assay for detection of ustiloxin A in rice false smut balls and rice samples. AB - Ustiloxin A, a cyclopeptide mycotoxin, was isolated from the pathogenic fungus Villosiclava virens that causes rice false smut, a worldwide devastating rice disease. A monoclonal antibody (mAb) 2D3G5 was generated with ustiloxin A-bovine serum albumin conjugate. A highly sensitive and specific indirect competitive enzyme-linked immunosorbent assay (icELISA) was then developed. It possessed a median inhibition concentration (IC50) of 13.8 ng/mL and a working range of 2.8 72 ng/mL. The mAb 2D3G5 recognized ustiloxin B with the cross-reactivity as 4%. The average recoveries of ustiloxin A from rice false smut balls and peeled rice samples ranged from 92% to 117% and from 92% to 107%, respectively. Comparison of the concentrations of ustiloxin A in rice false smut balls detected by both icELISA and high performance liquid chromatography-photodiode array detection indicated that the developed icELISA was suitable for detection of ustiloxin A in rice food and feed samples. PMID- 25794733 TI - Identification of phenolic compounds in red wine extract samples and zebrafish embryos by HPLC-ESI-LTQ-Orbitrap-MS. AB - The zebrafish embryo is a highly interesting biological model with applications in different scientific fields, such as biomedicine, pharmacology and toxicology. In this study, we used liquid chromatography/electrospray ionisation-linear ion trap quadrupole-Orbitrap-mass spectrometry (HPLC/ESI-LTQ-Orbitrap-MS) to identify the polyphenol compounds in a red wine extract and zebrafish embryos. Phenolic compounds and anthocyanin metabolites were determined in zebrafish embryos previously exposed to the red wine extract. Compounds were identified by injection in a high-resolution system (LTQ-Orbitrap) using accurate mass measurements in MS, MS(2) and MS(3) modes. To our knowledge, this research constitutes the first comprehensive identification of phenolic compounds in zebrafish by HPLC coupled to high-resolution mass spectrometry. PMID- 25794734 TI - Fast and neat--determination of biochemical quality parameters in cocoa using near infrared spectroscopy. AB - The qualitative heterogeneity and increasing consumption of cocoa products require fast and efficient methods for quality assessment of fermented cocoa with regard to fermentation quality and flavor potential. To date, quality control is achieved by visual inspection (e.g., "cut test") and sensory testing. Chromatographic methods for quantification of flavor relevant substances are limited in their applicability in standard quality control due to laborious isolation and purification steps. Therefore, the aim of this study was the development of a near infrared spectroscopic (NIRS) method for routine analytical prediction of biochemical quality parameters. Different compound classes like phenolic substances (R(2)=0.93) or organic acids (R(2)=0.88) as well as individual substances like epicatechin (R(2)=0.93) or lactic acid (R(2)=0.87) could be precisely determined just as fermentation time (R(2)=0.92) and pH value (R(2)=0.94) presenting NIRS as fast and reliable alternative in routine quality assessment. PMID- 25794735 TI - Winery by-products: extraction optimization, phenolic composition and cytotoxic evaluation to act as a new source of scavenging of reactive oxygen species. AB - Nearly 20 million tons of winery by-products, with many biological activities, are discarded each year in the world. The extraction of bioactive compounds from Chenin Blanc, Petit Verdot, and Syrah grape by-products, produced in the semi arid region in Brazil, was optimized by a Central Composite Rotatable Design. The phenolic compounds profile, antioxidant capacity against synthetic free radicals (DPPH and ABTS), reactive oxygen species (ROS; peroxyl radical, superoxide radical, hypochlorous acid), cytotoxicity assay (MTT) and quantification of TNF alpha production in RAW 264.7 cells were conducted. Gallic acid, syringic acid, procyanidins B1 and B2, catechin, epicatechin, epicatechin gallate, quercetin 3 beta-d-glucoside, delfinidin 3-glucoside, peonidin 3-O-glucoside, and malvidin 3 glucoside were the main phenolic compounds identified. In general, rachis showed higher antioxidant capacity than pomace extract, especially for Chenin Blanc. All extracts showed low cytotoxicity against RAW 264.7 cells and Petit Verdot pomace suppressed TNF-alpha liberation in vitro. Therefore, these winery by-products can be considered good sources of bioactive compounds, with great potential for application in the food and pharmaceutical industries. PMID- 25794736 TI - Stereoselective interaction of cinchona alkaloid isomers with bovine serum albumin. AB - The dependence of the interaction between bovine serum albumin (BSA) and two cinchona alkaloids, quinine (QN) and quinidine (QD), on the absolute configuration of these stereoisomers has been comprehensively studied. The FTIR spectra showed that QN and QD interacted with both CO and C-N groups of BSA, resulting in changes to the secondary structure of the protein. Fluorescence quenching of BSA by the stereoisomers revealed lower efficiency for QD in quenching the Trp emission of BSA when compared to QN. Further analysis accurately described the different binding behaviors and recognition discrepancies of QN and QD towards BSA, which was reflected through binding affinities, driving forces, energy changes and conformational changes during the ligand-protein interactions. Synchronous fluorescence further proved that QD was farther from Trp and Tyr than that of QN. This work could provide basic data for clarifying the binding interaction, metabolism and distribution of cinchona alkaloid stereoisomers in vivo. PMID- 25794737 TI - Solubilization of proteins in extracted oil bodies by SDS: a simple and efficient protein sample preparation method for Tricine-SDS-PAGE. AB - A simple and efficient method for preparing Tricine-SDS-PAGE protein sample of extracted oil bodies (OBs) was supplied: OB suspension was vortexed with SDS buffer (pH 6.8) for 2 min at room temperature with SDS/protein of 1.52/1(w/w), which could be analyzed by Tricine-SDS-PAGE after simple treatments (dilution and 2-mercaptoethanol). At SDS/protein of 1.52/1, about 95% of proteins in soybean OB suspension were solubilized, whereas residual 5% of proteins were weakly bound to SDS-destroyed OBs; proteins in destroyed OBs might be further solubilized by SDS in the gel and cathode buffer of Tricine-SDS-PAGE, causing about 99% of proteins in soybean OB suspension recover on Tricine-SDS-PAGE gel, which was better than acetone (89%) and diethyl ether (96%) harvested protein samples. Higher or lower SDS/protein was unbeneficial for protein solubilization from OBs. Additionally, the above method was also better than organic solvent method for peanut, sesame, and rapeseed OB suspensions. PMID- 25794738 TI - Analysis of bakery products by laser-induced breakdown spectroscopy. AB - In this study, we focused on the detection of Na in bakery products by using laser-induced breakdown spectroscopy (LIBS) as a quick and simple method. LIBS experiments were performed to examine the Na at 589 nm to quantify NaCl. A series of standard bread sample pellets containing various concentrations of NaCl (0.025 3.5%) were used to construct the calibration curves and to determine the detection limits of the measurements. Calibration graphs were drawn to indicate functions of NaCl and Na concentrations, which showed good linearity in the range of 0.025-3.5% NaCl and 0.01-1.4% Na concentrations with correlation coefficients (R(2)) values greater than 0.98 and 0.96. The obtained detection limits for NaCl and Na were 175 and 69 ppm, respectively. Performed experimental studies showed that LIBS is a convenient method for commercial bakery products to quantify NaCl concentrations as a rapid and in situ technique. PMID- 25794740 TI - Effect of training systems on fatty acids and their derived volatiles in Cabernet Sauvignon grapes and wines of the north foot of Mt. Tianshan. AB - C6 and C9 volatiles, originated from fatty acids, are important volatiles for 'Cabernet Sauvignon' grapes and wines. This study evaluated the influence of different training systems including Modified Vertical Shoot Positioned, (M-VSP); Fan training system with two trunks (F-TT); Fan training system with multiple trunks (F-MT) on these volatiles and the long-chain fatty acids (>C12) of grape berries and wines in the northwest of China. The expression profiles of genes from associated metabolic pathway were also analyzed. F-MT training resulted in lower vine vigor, larger yield, higher content of unsaturated fatty acids in grapes and lower C6 esters in wines in comparison with M-VSP and F-TT. M-VSP and F-TT enhanced C6 volatiles in grape berries. The concentrations of C6 volatiles were positively correlated with the expression of VvLOXA and VvHPL1. The results expanded the knowledge of the influence of training systems on fatty acids and their derived volatiles of grapes and wines. PMID- 25794739 TI - Preparation of magnetic metal organic frameworks adsorbent modified with mercapto groups for the extraction and analysis of lead in food samples by flame atomic absorption spectrometry. AB - A novel magnetic metal organic frameworks adsorbent modified with mercapto groups was synthesized and developed for extraction and spectrophotometric determination of trace lead. The adsorbent was characterized by Fourier transforms infrared spectrometer, X-ray diffraction, scanning electron microscopy and vibrating sample magnetometry. The results indicated the adsorbents exhibited high adsorption capacities for lead due to the chelation mechanism between metal cations and mercapto groups. Meanwhile, the lead sorption onto the adsorbents could be easily separated from aqueous solution using a magnetic separation method. Under the optimal conditions, a linear calibration curve in the range from 1 to 20 MUg L(-1) was achieved with an enrichment factor of 100. The limits of detection and quantitation for lead were found to be 0.29 and 0.97 MUg L(-1), respectively. The developed method was successfully applied to the determination of trace amounts of lead in food samples and certified reference material with satisfactory results. PMID- 25794741 TI - Simultaneous determination of ten preservatives in ten kinds of foods by micellar electrokinetic chromatography. AB - An improved micellar electrokinetic capillary chromatography method (MEKC) for the simultaneous determination of ten preservatives in ten different kinds of food samples was reported. An uncoated fused-silica capillary with 50 MUm i.d. and 70 cm total length was used. Under the optimized conditions, the linear response was observed in the range of 1.2-200mg/L for the analytes. The limits of detection (LOD, S/N=3) and limits of quantitation (LOQ, S/N=10) ranging from 0.4 to 0.5mg/L and 1.2 to 1.5mg/L, respectively were obtained. The method was used for the determination of sorbic and benzoic acids in two FAPAS(r) (Food Analysis Performance Assessment Scheme) proficiency test samples (jam and chocolate cake). The results showed that the current method with simple sample pretreatment and small reagent consumption could meet the needs for routine analysis of the ten preservatives in ten types of food products. PMID- 25794742 TI - Fatty acids profile of Sacha Inchi oil and blends by 1H NMR and GC-FID. AB - This study aimed at the characterization of blends of Sacha Inchi oil (SIO) with different ratios of SO (soybean oil) and CO (corn oil) by nuclear magnetic resonance ((1)H NMR), compared with the data obtained by gas chromatography with a flame ionization detector (GC-FID). The (1)H NMR and GC-FID data from different ratios of SIO were adjusted by a second order polynomial equation. The two techniques were highly correlated (R(2) values ranged from 0.995 to 0.999), revealing that (1)H NMR is an efficient methodology for the quantification of omega-3 fatty acids in oils rich in omega-6 fatty acids or vice versa such as SO and CO and, on the other hand, can be used to quantify omega-6 in oils rich in omega-3, such as SIO. PMID- 25794743 TI - Sorption of 4-ethylphenol and 4-ethylguaiacol by suberin from cork. AB - Cork shows an active role in the sorption of volatile phenols from wine. The sorption properties of 4-ethylphenol and 4-ethylguaiacol phenols in hydro alcoholic medium placed in contact with suberin extracted from cork were especially investigated. To that purpose, suberin was immersed in model wine solutions containing several concentrations of each phenol and the amount of the compound remaining in the liquid phase was determined by SPME-GC-MS. Sorption isotherms of 4-ethylguaiacol and 4-ethylphenol by suberin followed the Henry's model. The solid/liquid partition coefficients (KSL) between the suberin and the model wine were also determined for several other volatile phenols. Suberin displayed rather high sorption capacity, which was positively correlated to the hydrophobicity of the volatile. Finally, the capacity of suberin to decrease the concentration of 4-ethylphenol and 4-ethylguaiacol was also tested in real wines affected by a Brettanomyces character. It also lead to a significant reduction of their concentration in wine. PMID- 25794744 TI - Effect of seasonal variation on some physical properties and heat stability of milk subjected to ultra-high temperature and in-container sterilisation. AB - Heat stability was evaluated in bulk raw milk, collected throughout the year and subjected to ultra-high temperature (UHT) or in-container sterilisation, with and without added calcium chloride (2mM), disodium hydrogen phosphate (DSHP, 10mM) and trisodium citrate (TSC, 10mM). More sediment was observed following in container sterilisation (0.24%) compared with UHT (0.19%). Adding CaCl2 made the milk more unstable to UHT than to in-container sterilisation, while adding DSHP and TSC made the milk more unstable during in-container sterilisation than to UHT processing, although TSC addition increased the sediment formed by UHT processing. Better heat stability was observed in autumn and winter than in spring and summer following UHT. However, following in-container sterilisation, samples with added stabilising salts showed significantly improved heat stability in autumn, whereas with added CaCl2, the best heat stability was observed in spring. No correlation was found between urea and heat stability. PMID- 25794745 TI - Raman spectroscopy of white wines. AB - The feasibility of exploiting Raman scattering to analyze white wines has been investigated using 3 different wavelengths of the incoming laser radiation in the near-UV (325 nm), visible (532 nm) and near infrared (785 nm). To help in the interpretation of the Raman spectra, the absorption properties in the UV-visible range of two wine samples as well as their laser induced fluorescence have also been investigated. Thanks to the strong intensity enhancement of the Raman scattered light due to electronic resonance with 325 nm laser excitation, hydroxycinnamic acids may be detected and analyzed selectively. Fructose and glucose may also be easily detected below ca. 1000 cm(-1). This feasibility study demonstrates the potential of the Raman spectroscopic technique for the analysis of white wines. PMID- 25794746 TI - Physiological and biochemical changes relating to postharvest splitting of sweet cherries affected by calcium application in hydrocooling water. AB - Hydrocooling sweet cherries shortly after harvest (4h) and then transporting fruit in cold flume water during packing are used to maximize postharvest quality, but can cause fruit splitting. This study demonstrated that cherry fruit (two splitting-susceptible cultivars) absorbed Ca in a quadratic polynomial manner with increasing CaCl2 concentration from 0.2% to 2.0% in cold water (0 degrees C) for 5 min, but did not take up Cl. The enhanced tissue Ca content reduced splitting potential by decreasing fruit soluble pectin release and increasing the splitting threshold. In contrast, depleting Ca from fruit tissue by EDTA or low pH, increased soluble pectin release and splitting potential. In a simulated commercial procedure, hydrocooling cherry fruit in appropriate CaCl2 solutions (i.e., 0.2-0.5%) for 5 min and then passing the fruit in cold flume water for 15 min increased fruit firmness, retarded losses in ascorbic acid, titratable acidity, and skin color, and reduced splitting and decay following 4 weeks of cold storage. PMID- 25794747 TI - Phytochemicals and antioxidant capacities of Mao-Luang (Antidesma bunius L.) cultivars from Northeastern Thailand. AB - Phenolic compounds extracted from fourteen Mao-Luang (Antidesma bunius) cultivars grown in Northeastern Thailand were quantified using HPLC analysis and the antioxidant capacity of the extracts was determined by ABTS(+), DPPH radical, and FRAP assays. This study showed that there were differences (p<0.05) in phenolic compounds and antioxidant activities among Mao-Luang cultivars. Gallic acid, (-) epicatechin, (+)-catechin, and cyanidin-3-O-glucoside were the major polyphenolic components in all Mao-Luang cultivars. The highest contents were found in 'Kumlai' with values of 281.30, 949.73, 127.60 and 54.67 mg/100g DW, respectively. 'Kumlai' also exhibited the highest antioxidant activity with the values of 103.04 mmol VCEAC/gDW (DPPH assay), 35.35 mmol Fe(II)/gDW (FRAP assay), and 46.37 mmol TE/gDW (ABTS(+) assay). Correlation analyses revealed that gallic acid, ferulic acid and some anthocyanins, mainly cyanidin-3-O-glucoside, were responsible for the antioxidant capacity of Mao-Luang fruits. PMID- 25794748 TI - Amino acid sequence of Japanese quail (Coturnix japonica) and northern bobwhite (Colinus virginianus) myoglobin. AB - Myoglobin has an important physiological role in vertebrates, and as the primary sarcoplasmic pigment in meat, influences quality perception and consumer acceptability. In this study, the amino acid sequences of Japanese quail and northern bobwhite myoglobin were deduced by cDNA cloning of the coding sequence from mRNA. Japanese quail myoglobin was isolated from quail cardiac muscles, purified using ammonium sulphate precipitation and gel-filtration, and subjected to multiple enzymatic digestions. Mass spectrometry corroborated the deduced protein amino acid sequence at the protein level. Sequence analysis revealed both species' myoglobin structures consist of 153 amino acids, differing at only three positions. When compared with chicken myoglobin, Japanese quail showed 98% sequence identity, and northern bobwhite 97% sequence identity. The myoglobin in both quail species contained eight histidine residues instead of the nine present in chicken and turkey. PMID- 25794749 TI - Development and validation of a LC-MS/MS method to determine sulforaphane in honey. AB - A new method was developed to determine sulforaphane (SFN) in honey using liquid chromatography tandem mass spectrometry (LC-MS/MS) with electrospray ionization (ESI). An efficient extraction procedure was proposed (average analyte recoveries were between 92% and 99%); this involved a solid phase extraction (SPE) with a polymeric sorbent. Chromatography was performed on a SynergiTM Hydro analytical column with a mobile phase of 0.02 M ammonium formate in water and acetonitrile, at a flow rate of 0.5 mL/min. The method was fully validated in terms of selectivity, limits of detection (LOD) and quantification (LOQ), linearity, carry over effect, reinjection reproducibility, precision and accuracy. The LOD and LOQ values were below 0.8 MUg/kg and 2.6 MUg/kg, respectively. The proposed method was applied to analyze SFN in honey from different botanical origins (rosemary, multifloral, orange blossom and heather), and SFN was detected at trace levels in some of the honey samples examined. PMID- 25794750 TI - The embryo and the endosperm contribute equally to argan seed oil yield but confer distinct lipid features to argan oil. AB - In the perspective of studying lipid biosynthesis in the argan seed, the anatomy, ploidy level and lipid composition of mature seed tissues were investigated using an experimental design including two locations in Algeria and four years of study. Using flow cytometry, we determined that mature argan seeds consist of two well-developed tissues, the embryo and the endosperm. The lipid content of the embryo was higher than that of the endosperm, but the dry weight of the endosperm was higher. Consequently, both tissues contribute equally to seed oil yield. Considerable differences in fatty acid composition were observed between the two tissues. In particular, the endosperm 18:2 percentage was twofold higher than that of the embryo. The tocopherol content of the endosperm was also markedly higher than that of the embryo. In contrast, the endosperm and the embryo had similar sterol and triterpene alcohol contents and compositions. PMID- 25794751 TI - Construction of novel xanthine biosensor by using polymeric mediator/MWCNT nanocomposite layer for fish freshness detection. AB - A novel nanocomposite host matrix for enzyme immobilization of xanthine oxidase was developed by incorporating MWCNT in poly(GMA-co-VFc) copolymer film. In the food industry fish is a product with a very low commercial life, and a high variability as well elevated level of xanthine is an important biomarker as a sign of spoilage. The fabricated process was characterized by scanning electron microscopy (SEM), and the electrochemical behaviors of the biosensor were characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The prepared enzyme electrodes exhibited maximum response at pH 7.0 and 45 degrees C +0.35 V and reached 95% of steady-state current in about ~ 4 s and its sensitivity was 16 mAM(-1). Linear ranges (2-28 MUM, 28-46 and 46 86 MUM), analytical performance and a low detection limit 0.12 MUM obtained from the xanthine biosensor gives reliable results in measuring xanthine concentration in the fish meat. All the results indicating that the resulting biosensor exhibited a good response to xanthine that was related to the addition of MWCNT in the polymeric mediator film which played an important role in the biosensor performance. In addition, the biosensor exhibited high good storage stability and satisfactory anti-interference ability. PMID- 25794752 TI - Olive oil phenolic compounds affect the release of aroma compounds. AB - Twelve aroma compounds were monitored and quantified by dynamic headspace analysis after their addition in refined olive oil model systems with extra virgin olive oil (EVOO) biophenols to simulate EVOO aroma. The influence of polyphenols on aroma release was studied under simulated mouth conditions by using human saliva, and SPME-GC/MS analysis. While few differences were observed in orthonasal assay (without saliva), interesting results were obtained for retronasal aroma. Biophenols caused generally the lowest headspace release of almost all volatile compounds. However, only ethyl esters and linalool concentrations were significantly lower in retronasal than orthonasal assay. Saliva also caused higher concentration of hexanal, probably due to hydroperoxide lyase (HPL) action on linoleyl hydroperoxides. Epicatechin was compared to EVOO phenolics and the behaviour was dramatically different, likely to be due to salivary protein-tannin binding interactions, which influenced aroma headspace release. These results were also confirmed using two extra virgin olive oils. PMID- 25794753 TI - Antioxidant and cryoprotective effects of Amur sturgeon skin gelatin hydrolysate in unwashed fish mince. AB - Antioxidant and cryoprotective effects of Amur sturgeon skin gelatin hydrolysates prepared using different commercial proteases in unwashed fish mince were investigated. Gelatin hydrolysates prepared using either Alcalase or Flavourzyme, were effective in preventing lipid oxidation as evidenced by the lower thiobarbituric acid-reactive substances formation. Gelatin hydrolysates were able to retard protein oxidation as indicated by the retarded protein carbonyl formation and lower loss in sulfhydryl content. In the presence of gelatin hydrolysates, unwashed mince had higher transition temperature of myosin and higher enthalpy of myosin and actin as determined by differential scanning calorimetry. Based on low field proton nuclear magnetic resonance analysis, gelatin hydrolysates prevented the displacement of water molecules between the different compartments, thus stabilizing the water associated with myofibrils in unwashed mince induced by repeated freeze-thawing. Oligopeptides in gelatin hydrolysates more likely contributed to the cryoprotective effect. Thus, gelatin hydrolysate could act as both antioxidant and cryoprotectant in unwashed fish mince. PMID- 25794754 TI - Does boiling affect the bioaccessibility of selenium from cabbage? AB - The bioaccessible selenium species from cabbage were studied using an in vitro physiologically-based extraction test (PBET) which establishes conditions that simulate the gastric and gastrointestinal phases of human digestion. Samples of cabbage (Brassica oleracea) grown in peat fortified with different concentrations of Se(IV) and Se(VI) were analysed, and several enzymes (pepsin, pancreatin and amylase) were used in the PBET. The effect of boiling before extraction was also assayed. Selenium speciation in the PBET extracts was determined using anionic exchange and LC-ICP/MS. The selenocompounds in the extracts were Se(IV), SeMet and, mostly, Se(VI) species. The results show that the activity of the enzymes increased the concentration of the selenocompounds slightly, although the use of amylase had no effect on the results. The PBET showed the concentration of inorganic selenium in the extracts from boiled cabbage decreased as much as 4 fold while the release of SeMet and its concentration increased (up to 6-fold), with respect to raw cabbage. PMID- 25794755 TI - Development of an enzyme-linked immunosorbent assay system for detecting beta' component (Onk k 5), a major IgE-binding protein in salmon roe. AB - A novel enzyme-linked immunosorbent assay (ELISA) system has been established for selective detection of chum salmon (Oncorhynchus keta) yolk protein (SYP). Rabbit and rat polyclonal Immunoglobulin G antibodies to beta'-component (the major allergic protein in fish roe; anti-beta) were applied for designing the ELISA system. The sandwich ELISA using rabbit anti-beta for the capture antibody and horseradish peroxidase-labeled F(ab')2 fragment of rat anti-beta for the detection antibody obtained high sensitivity and narrow specificity for SYP. Protein extraction using sodium dodecyl sulfate and 2-mercaptoethanol ensured strict specificity of the ELISA, and components of three popular processed foods had no effect on the ELISA response. The limits of determination and quantification of SYP were estimated to be 0.78 MUg/g and 2.60 MUg/g of food sample, respectively. In conclusion, the developed ELISA system has a probability to be applied for the detection of contaminated chum salmon roe in processed food. PMID- 25794756 TI - Metabolomics approach of infant formula for the evaluation of contamination and degradation using hydrophilic interaction liquid chromatography coupled with mass spectrometry. AB - In this study including the field of metabolomics approach for food, the evaluation of untargeted compounds using HILIC-ESI/TOF/MS and multivariate statistical analysis method is proposed for the assessment of classification, contamination and degradation of infant formula. HILIC mode is used to monitor more detected numbers in infant formulas in the ESI-positive scan mode than the reversed phase. The repeatability of the non-targeted contents from 4 kinds of infant formulas based on PCA was less than the relative standard deviation of 15% in all groups. The PCA pattern showed that significant differences in the classification of types and origins, the contamination of melamine and the degradations for one week were evaluated using HILIC-ESI/TOF/MS. In the S-plot from the degradation test, we could identify two markers by comparison to standards as nicotinic acid and nicotinamide. With this strategy, the differences from the untargeted compounds could be utilized for quality and safety assessment of infant formula. PMID- 25794757 TI - The effect of ripening, heat processing and frozen storage on the in vitro bioaccessibility of capsaicin and dihydrocapsaicin from Jalapeno peppers in absence and presence of two dietary fat types. AB - To date, there is no information in the literature regarding the bioaccessibility of capsaicinoids from natural sources. The effect of ripening and heat-processing on the in vitro bioaccessibility of capsaicin and dihydrocapsaicin was studied in the absence and presence of two dietary fat types. The capsaicinoid bioaccessibility was also studied during the frozen storage of peppers for 6 months. Fresh green peppers showed the highest capsaicinoid bioaccessibility, as compared with that of other experimental groups. The bioaccessibility of capsaicinoids from green peppers decreased as the intensity of heat treatment increased. The dietary fat increased the bioaccessibility of capsaicin and dihydrocapsaicin in digestions with red peppers, especially that of dihydrocapsaicin. The bioaccessibility of capsaicinoids was altered by frozen storage. The Caco-2 cells incorporated capsaicin and dihydrocapsaicin (8.4% and 10.9%, respectively) but they were probably metabolized by cells. PMID- 25794758 TI - Activity of carbohydrate oxidases as influenced by wheat flour dough components. AB - The carbohydrate oxidase (COXMn) from Microdochium nivale may well have desired functionalities as a dough and bread improver, similarly to Aspergillus niger glucose oxidase (GOX). COXMn catalyses the oxidation of various monosaccharides as well as maltooligosaccharides for which the best activity is obtained towards the maltooligosaccharides of polymerisation degrees 3 and 4. For the same activity towards glucose under air saturation, we show that COXMn exhibits a similar efficiency towards maltose as GOX towards glucose whatever the oxygen supply. Assays with COXMn show that no competition exists between carbohydrates naturally present in the wheat flour. We show that reaction products (d-glucono delta-lactone and hydrogen peroxide) and the wheat flour dough component, ferulic acid, have no noticeable specific effect on the COXMn activity. The demonstrated differences in kinetics between COXMn and GOX allow predicting of differences in the functional behaviours of those enzymes during wheat flour dough formation. PMID- 25794759 TI - Effect of food preservatives on the hydration properties and taste behavior of amino acids: a volumetric and viscometric approach. AB - Thermodynamic and transport properties of aqueous solutions are very useful in the elucidation of solute-solvent and solute-solute interactions, which help to understand the hydration and taste behavior of solutes. The densities and viscosities of L-glycine, beta-alanine and L-leucine have been determined in water and in aqueous solutions of sodium propionate (NaP) and calcium propionate (CaP) at temperatures 298.15 and 308.15K. From these data, apparent molar volumes (V2,phi), viscosity B-coefficients and corresponding transfer parameters (DeltatrV2,phio and DeltatrB) have been calculated. The dB/dT values suggest that L-glycine and beta-alanine act as structure-breaker, while L-leucine acts as structure-maker both in water and in aqueous solutions of NaP and CaP. The decrease in hydration number and change in taste behavior have also been observed with increasing concentration of the cosolute. PMID- 25794760 TI - Simultaneous determination of four organotins in food packaging by high performance liquid chromatography-tandem mass spectrometry. AB - A simple method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the simultaneous determination of organotins-tri-n-butyltin chloride (TBT), triphenyltin chloride (TPT), dibutyltin dichloride (DBT), and diphenyltin dichloride (DPT)-in plastic food packaging. Samples were prepared by ultrasonic extraction with dichloromethane, followed by dissolution in acetonitrile containing 0.1% formic acid, and purification by an MCX column. The extracts were analyzed by LC-MS/MS in multiple reaction monitoring and positive modes with a C18 column; elution was carried out with a gradient of 0.1% formic acid and methanol containing 0.1% formic acid. The limits of detection for TBT, TPT, DBT, and DPT were 0.1, 0.6, 0.8, and 0.3 MUg kg(-1), respectively. The recovery of organotins in spiked samples ranged from 68% to 113% (relative standard deviation: 0.4-4.2%). The proposed method was successfully employed to identify the target analytes in plastic packaging used for milk and cake. PMID- 25794761 TI - Physicochemical properties and aroma volatile profiles in a diverse collection of California-grown pomegranate (Punica granatum L.) germplasm. AB - Colorful antioxidant-rich fruits often convey astringency and sourness that juice consumers may not appreciate. We assessed properties in juices from a collection of California-grown pomegranate from the National Clonal Germplasm Repository. The goal was to evaluate overall differences in germplasm with quality traits classified as sweet, sweet-sour and sour. Previous relationships noted in sweet and sour cultivar attributes were observed. Wonderful generally clustered with sweet-sour and sour cultivars. Sweet low acid cultivars occasionally clustered closely with Wonderful which is hard to rationalize. The dominant compounds were 3-hexenol and 1-hexanol which allowed separation of Kara Gul, Haku-botan and Wonderful. Aldehyde and terpene content can be used to characterize cultivars. The study represents the first data on variation in juice qualities in different sweet, sweet-sour and sour cultivars, grown in California, compared with Wonderful. Data may help the juice industry better select raw juice materials in order to ultimately satisfy consumers. PMID- 25794762 TI - Melanins as biomarkers of ovarian follicular atresia in the catfish Heteropneustes fossilis: biochemical and histochemical characterization, seasonal variation and hormone effects. AB - Follicular atresia is a common feature of the vertebrate ovary that occurs at different stages of folliculogenesis and ovarian regression. It has physiological significance to maintain homeostasis and control fecundity, and ensure removal of post-ovulatory follicular remnants for preparing the ovary for the next cycle. Pigments appear late in the atretic process as indigestible waste formed out of the degradation of the oocytes, follicle wall and granulocytes. In the present study, pigment accumulation was demonstrated by Schmorl's and Perls' staining methods in the atretic ovarian follicles of Heteropneustes fossilis during follicular development and regression. Melanins were characterized spectrophotometrically for the first time in fish ovary. The predominant form is eumelanin, followed by pheomelanin and alkali-soluble melanin. Melanins showed significant seasonal variations with levels low in gonad resting phase, increasing to the peak in the post-spawning phase. The concentration of melanins increased time-dependently in post-ovulated ovary after human chorionic gonadotropin treatment. In the spawning phase, in vitro incubation of ovary slices with estradiol-17beta or dexamethasone for 8 or 16 h decreased both eumelanin and pheomelanin levels time-dependently. The alkali-soluble melanin showed a significant decrease only in the dexamethasone group at 16 h. The results show that melanin assay can be used as a biomarker of follicular atresia in fish ovary, natural or induced by environmental toxicants. PMID- 25794764 TI - A population-based prospective birth cohort study of childhood neurocognitive and psychological functioning in healthy survivors of early life meningitis. AB - PURPOSE: To determine neurocognitive, educational, and psychological functioning during childhood and early adolescence among survivors of early life meningitis who are apparently healthy. METHODS: In the general population-based Avon Longitudinal Study of Parents and Children birth cohort, meningitis exposure was determined at age of 18 months. The outcomes of intelligence quotient, short-term memory, working memory, reading and spelling abilities, psychological and behavioral problems, depressive and anxiety symptoms, and psychotic experiences at ages 9 to 13 years were compared between those exposed and unexposed to meningitis. Individuals with special educational needs were excluded. RESULTS: By age of 18 months, 67 of 11,035 children were reported to have suffered from meningitis (0.61%). These children, compared with the unexposed, performed worse on all neurocognitive and educational measures; mean difference in total intelligence quotient 7.36 (95% confidence interval, 1.60-13.11). Meningitis was associated with higher depressive and anxiety symptoms (P = .02), psychological and behavioral problems (P = .09), and increased risk of psychotic experiences; risk ratio 2.22 (95% confidence interval, 1.12-4.38). CONCLUSIONS: Exposure to meningitis in the early life is associated with neurocognitive, educational, and psychological difficulties during childhood and early adolescence among survivors who are apparently healthy. Therefore, focusing only on serious neurologic disabilities may underestimate the true impact of early life meningitis. PMID- 25794765 TI - Sociodemographic predictors of delayed- versus early-stage cervical cancer in California. AB - PURPOSE: We sought to evaluate and distinguish roles of sociodemographic predictors for delayed- versus early-stage cervical cancer. METHODS: Demographic variables for 13,624 cervical cancers having complete data for age at diagnosis (4 categories), race and ethnicity (4 categories), socioeconomic status (SES) quintiles, and marital status (3 categories) were extracted from the California Cancer Registry database for the period 1996 to 2005 and analyzed using multiple logistic regression as predictors of delayed- versus early-stage diagnosis. RESULTS: Fifty-eight percent of cervical cancers were among women younger than 50 years, compared with 46% of delayed-stage cases. Independent odds of delayed- versus early-stage cervical cancer were higher for older age categories within each race and ethnic group. Declining odds of delayed- versus early-stage diagnosis were evident for increasing SES quintiles among Asian or other (trend P = .015), non-Hispanic black (P = .024), Hispanic (P = .001), and non-Hispanic white (P = .001) women. Odds of delayed- versus early-stage cervical cancer were highest among unmarried compared with married women. CONCLUSIONS: Our findings support evidence that older age, low SES, and unmarried status predict delayed stage cervical cancer diagnosis in each of the four major race and ethic groups. The two lowest SES quintiles independently identified larger percentages of delayed-stage cervical cancers in each of the race and ethnicity groups assessed, particularly among Hispanic and non-Hispanic black women. PMID- 25794766 TI - A critical review of the epidemiology of Agent Orange or 2,3,7,8 tetrachlorodibenzo-p-dioxin and lymphoid malignancies. AB - PURPOSE: Establishing a causal relationship between 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) and risk of specific lymphoid cancers, including non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM), would be useful for risk assessment. METHODS: This article systematically and critically reviews epidemiologic studies of the association between exposure to TCDD or TCDD contaminated herbicides and risk of lymphoid malignancies. These include studies of military, industrial, accidental environmental, and general environmental exposure to Agent Orange or TCDD. RESULTS: Collectively, the epidemiologic evidence from industrial cohorts suggests a positive association with NHL mortality, but results are not consistent across other studies, a clear exposure response gradient is not evident, and data are insufficient to conclude that the association is causal. Furthermore, available studies provide little information on NHL incidence or specific NHL subtypes. Epidemiologic studies do not show an association of TCDD exposure with HL, whereas the indication of a positive association with MM in a limited number of studies, but not others, remains to be confirmed in additional research. Exposure classification error and small numbers are important limitations of the available epidemiologic studies. CONCLUSIONS: Overall, a causal effect of TCDD on NHL, HL, MM, or subtypes of these lymphoid malignancies has not been established. PMID- 25794767 TI - Development of a claims-based algorithm to identify colorectal cancer recurrence. AB - PURPOSE: To examine the validity of claims data to identify colorectal cancer (CRC) recurrence and determine the extent to which misclassification of recurrence status affects estimates of its association with overall survival in a population-based administrative database. METHODS: We calculated the accuracy of claims data relative to medical records from one large tertiary hospital to identify CRC recurrence. We estimated the effect of misclassifying recurrence on survival by applying these findings to the linked Surveillance, Epidemiology, and End Results-Medicare data. RESULTS: Of 174 eligible CRC patients identified through medical records, 32 (18.4%) had a recurrence. A claims-based algorithm of secondary malignancy codes yielded a sensitivity of 81% and specificity of 99% for identifying recurrence. Agreement between data sources was almost perfect (kappa: 0.86). In a model unadjusted for misclassification, CRC patients with recurrence were 3.04 times (95% confidence interval: 2.92-3.17) more likely to die of any cause than those without recurrence. In the corrected model, CRC patients with recurrence were 3.47 times (95% confidence interval: 3.06-4.14) more likely to die than those without recurrence. CONCLUSIONS: Identifying recurrence in CRC patients using claims data is feasible with moderate sensitivity and high specificity. Future studies can use this algorithm with Surveillance, Epidemiology, and End Results-Medicare data to study treatment patterns and outcomes of CRC patients with recurrence. PMID- 25794769 TI - [Occupational semicircular lipoatrophy associated with serum adipokine abnormalities]. AB - OBJECTIVES: The aim of this study was to examine the relationship between semicircular lipoatrophy (SL), inflammation marker (high sensibility C-reactive protein [hs-CRP]), adipokines (leptine, chemerine and vaspine) and autoimmune markers (rheumatoid factor [RF], C3 and C4 complement fractions, antinuclear antibodies [ANA], HLA DR3, and DR4). Chemerine is an adipokine, but also is an immunity marker. METHODS: A case-control study was performed in May 2013; 21 cases were included. The closest healthy coworker to each case was used as a control. We calculated Kruskal-Wallis nonparametric test. RESULTS: We found statistical significance (P<.05) between SL and raised hs-CRP, raised leptine and low chemerine. CONCLUSIONS: i) There seems to be an underlying inflammatory component (raised hs-CRP) in SL; ii) adipokine alteration (raised leptine and low chemerine) supports the idea that adipocytic differentiation is affected in SL, and iii) we have not found any immune marker associated with SL, except chemerine itself, which could explain a possible association between SL and immunity. PMID- 25794768 TI - Recellularization of rat liver scaffolds by human liver stem cells. AB - In the present study, rat liver acellular scaffolds were used as biological support to guide the differentiation of human liver stem-like cells (HLSC) to hepatocytes. Once recellularized, the scaffolds were maintained for 21 days in different culture conditions to evaluate hepatocyte differentiation. HLSC lost the embryonic markers (alpha-fetoprotein, nestin, nanog, sox2, Musashi1, Oct 3/4, and pax2), increased the expression of albumin, and acquired the expression of lactate dehydrogenase and three subtypes of cytochrome P450. The presence of urea nitrogen in the culture medium confirmed their metabolic activity. In addition, cells attached to tubular remnant matrix structures expressed cytokeratin 19, CD31, and vimentin. The rat extracellular matrix (ECM) provides not only a favorable environment for differentiation of HLSC in functional hepatocytes (hepatocyte like) but also promoted the generation of some epithelial-like and endothelial-like cells. When fibroblast growth factor-epidermal growth factor or HLSC-derived conditioned medium was added to the perfusate, an improvement of survival rate was observed. The conditioned medium from HLSC potentiated also the metabolic activity of hepatocyte-like cells repopulating the acellular liver. In conclusion, HLSC have the potential, in association with the natural ECM, to generate in vitro a functional "humanized liver-like tissue." PMID- 25794770 TI - [Comparative study of concordance and costs between tuberculin skin test and QuantiFERON((r))-TB Gold In-Tube in the diagnosis of latent tuberculosis infection among contacts of patients with pulmonary tuberculosis]. AB - INTRODUCTION: Recently diagnosis of latent tuberculosis infection (LTBI) can be made using the tuberculin skin test (TST) or by techniques known as interferon gamma release assays (IGRAS), being QuantiFERON((r))-TB Gold In-Tube (QF-G-IT) the most used. The IGRAS avoid some drawbacks of the TST, especially cross reaction with bacillus Calmette-Guerin (BCG) vaccine, but also present some problems such as those arising from cost and the need of having an adequate infrastructure and experience. There is no clear consensus on which technique should be preferentially used for the diagnosis of LTBI. METHODS: This is a comparative study between the TST and QT-G-IT in a cohort of contacts of patients with pulmonary tuberculosis during the study period. An analysis of global agreement and groups was performed according to whether the contacts were vaccinated with BCG or not. A study of costs of both techniques and diagnostic strategies based on these techniques was performed. RESULTS: The agreement between TST and QF-G-IT was acceptable in the whole sample yet it was very good in the unvaccinated group. Few cases of indeterminate values were recorded. The cost study showed that TST was cheaper than QF-G-IT; however when we analyzed the cost of the strategies according to each technique, the QF-G-IT showed a better cost-benefit. CONCLUSION: We suggest considering QF-G-IT as the only preferred technique for the diagnosis of LTBI in household contacts, based on good overall agreement between the 2 techniques (even if we eliminate the effect of the vaccine) and a cost analysis favorable to QF-G-IT. PMID- 25794771 TI - [Reply]. PMID- 25794772 TI - Differential effects of superoxide dismutase and superoxide dismutase/catalase mimetics on human breast cancer cells. AB - Reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H2O2) have been implicated in development and progression of breast cancer. In the present study, we have evaluated the effects of the superoxide dismutase (SOD) mimetic MnTmPyP and the SOD/catalase mimetic EUK 134 on superoxide and H2O2 formation as well as proliferation, adhesion, and migration of MCF-7 and MDA-MB 231 cells. Superoxide and H2O2 production was examined using dihydroethidium and Amplex red assays, respectively. Cell viability and adhesion were measured using a tetrazolium-based MTT assay. Cell proliferation was determined using trypan blue assay. Cell cycle progression was analyzed using flow cytometry. Clonal expansion of a single cell was performed using a colony formation assay. Cell migration was measured using transwell migration assay. Dual luciferase assay was used to determine NF-kappaB reporter activity. EUK 134 effectively reduced both superoxide and H2O2, whereas MnTmPyP removed superoxide but enhanced H2O2 formation. EUK 134 effectively attenuated viability, proliferation, clonal expansion, adhesion, and migration of MCF-7 and MDA-MB-231 cells. In contrast, MnTmPyP only reduced clonal expansion of MCF-7 and MDA-MB-231 cells but had no effect on adhesion and cell cycle progression. Tumor necrosis factor-alpha induced NF-kappaB activity was reduced by EUK 134, whereas MnTmPyP enhanced this activity. These data indicate that the SOD mimetic MnTmPyP and the SOD/catalase mimetic EUK 134 exert differential effects on breast cancer cell growth. Inhibition of H2O2 signaling using EUK 134-like compound might be a promising approach to breast cancer therapy. PMID- 25794774 TI - Prevalence of PALB2 mutations in the Creighton University Breast Cancer Family Registry. AB - The purpose of this study is to determine the prevalence of PALB2 mutations among breast cancer families from the United States. The PALB2 gene was screened for mutations in 90 familial breast cancer patients from the Creighton University Breast Cancer Family Registry. These patients had previously tested negative for mutations in BRCA1 and BRCA2. Two of 90 breast cancer patients (2.2 %) were found to carry a truncating mutation in PALB2 (c.2411_2412delCT and c.2053delC). Both probands were diagnosed with breast cancer before age 35 and each had three relatives with breast cancer. Mutations in PALB2 are less common than BRCA1 and BRCA2 in familial breast cancer patients. However, testing for PALB2 mutations is a useful adjunct for patients undergoing testing for BRCA1 and BRCA2. PMID- 25794773 TI - MiR-153 inhibits epithelial-mesenchymal transition by targeting metadherin in human breast cancer. AB - Epithelial-mesenchymal transition (EMT) is a crucial step in epithelial cancer invasion and metastasis. miR-153 has been identified as a key EMT suppressor. Accordingly, this study aimed to determine the possible relation of miR-153 downregulation to EMT through MTDH modulation. The miR-153 and MTDH expression profiles of human breast cancer specimen were determined by qPCR and evaluated by correlation analysis. Cell viability and clonogenic assays were applied to explore the impact of miR-153 on suppression of proliferation and oncogenic potential of breast cancer cells. Cell migration and invasion assays were used for the functional analysis of miR-153 in MCF-7 and MDA-MB-231 cells. Luciferase assay was adopted to identify MTDH as a new direct target of miR-153. Ectopic expression of miR-153 could significantly inhibit tumor growth and impair the migration and invasion of breast cancer cells. Overexpression of miR-153 simultaneously increased E-cadherin, decreased vimentin expression, and downmodulated EMT-associated transcription factors. miR-153 was negatively correlated with MTDH in cell lines and clinical samples. Overexpression of miR 153 significantly suppressed MTDH, as demonstrated by in vitro MTDH 3' untranslated region luciferase report assay. MTDH is a direct downstream target of miR-153 and is involved in the miR-153-induced suppression of the migration and invasion of breast cancer cells. Our findings indicate that miR-153 functions as a tumor suppressor and miR-153/MTDH link is a promising therapeutic target for breast cancer. PMID- 25794775 TI - Prognostic and biological significance of peroxisome proliferator-activated receptor-gamma in luminal breast cancer. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an adopted orphan receptor that belongs to the nuclear receptor superfamily of transcription factors. PPARgamma is regarded as a differentiation factor and it plays an important role in regulating adipogenesis, cell growth, proliferation and tumour progression. In breast cancer (BC), PPARgamma agonists were reported to inhibit proliferation and growth invasion and promote phenotypic changes associated with a less malignant and more differentiated status. This study aims to assess the prognostic and biological roles of PPARgamma protein expression in a large cohort of BC patients (n = 1100) with emphasis on the luminal oestrogen receptor (ER) positive class. Immunohistochemistry was used to assess the levels of PPARgamma expression in BC series prepared as tissue microarrays (TMAs). PPARgamma antibody specificity was confirmed using Western blotting. PPARgamma nuclear expression was detected in 79 % of the cases and its expression was positively correlated with the hormonal receptors (ER, progesterone receptor and androgen receptor). PPARgamma levels were significantly higher in tumours with lobular subtype, smaller size and lower grade, while HER2-positive, ductal or medullary tumours were associated with lower PPARgamma levels. Survival analysis showed that PPARgamma is associated with better outcome in the whole series as well as in luminal ER-positive class. Cox regression model showed that PPARgamma is an independent predictor of outcome. Higher PPARgamma was associated with longer survival in patients with ER-positive tumours who did not receive hormone therapy. PPARgamma is a good prognostic marker associated with hormone receptors. In patients with luminal BCs, PPARgamma is a marker of better prognosis and is associated with longer survival. PMID- 25794776 TI - [Initial results of robotic esophagectomy for esophageal cancer]. AB - INTRODUCTION: There is scant experience with robot-assisted esophagectomy in cases of esophageal and gastro-esophageal junction cancer. Our aim is to report our current experience. PATIENTS AND METHODS: Observational cohort study of the first 32 patients who underwent minimally invasive esophagectomy for esophageal cancer from September 2011 to June 2014. The gastric tube was created laparoscopically. In the thoracic field, a robot-assisted thoracoscopic approach was performed in the prone position with intrathoracic robotic hand-sewn anastomosis. Patient and tumour characteristics, surgical technique, short-term outcomes (morbidity and mortality) and oncological results (radicality and number of removed nodes) were evaluated. RESULTS: Thirty-two patients, with a mean age of 58 years (34-74) were treated by a totally minimally invasive esophagectomy: robotic laparoscopy and thoracoscopy (11 McKeown and 21 Ivor-Lewis). Twenty-nine received neoadjuvant chemoradiotherapy. There were no conversions to open surgery. Console time was 218minutes (190-285). Blood loss was 170ml (40-255). One patient died from cardiac disease. Nine patients had a major complication (Dindo-Clavien grade II or higher). There was no case of respiratory complication or recurrent laryngeal nerve palsy. Five patients had intrathoracic fistula, 4 radiological and one clinical. Three had chylothorax, 2 cervical fistula and one gastric tube necrosis. The median hospital stay was 12 days (8-50). All the resections were R0 and the median of removed lymph nodes was 16 (2-23). CONCLUSIONS: Our results suggest that minimally invasive esophagectomy with robot assisted thoracoscopy is safe and achieves oncological standards. PMID- 25794777 TI - Therapeutic management of severe relapses in multiple sclerosis. AB - OPINION STATEMENT: While not all multiple sclerosis (MS) relapses require treatment, relapses that are bothersome or that impair function should prompt consideration of timely treatment to restore function and minimize disability. Patients with suspected MS relapses should be evaluated to confirm the diagnosis, exclude other causes of neurological dysfunction, and identify potential triggers for relapse or pseudo-relapse, such as urinary tract infections, fever, or metabolic derangements. The diagnosis of an MS relapse is clinical, but MRI may be useful for confirmation and to evaluate for multifocal disease activity. High dose oral or intravenous glucocorticoids, with or without an oral taper, are first-line therapy for MS relapses. Adrenocorticotropic hormone (ACTH) provides an alternative to glucocorticoid treatment but is currently much more expensive and does not have proven superiority. If the acute neurological deficits remain severe after steroid treatment, and particularly if there is persistent abnormal contrast-enhancement of the symptomatic lesion on repeat MRI, plasma exchange (PLEX) should be considered as an acute rescue therapy for relapse. In exceptional cases, particularly fulminant or tumefactive disease that fails to improve following treatment with steroids and PLEX, cytoxic agents such as cyclophosphamide or B cell-depleting regimens such as rituximab may be considered, although risk must be carefully weighed and the kinetics of such regimens indicate that they probably serve more to accelerate remission of disease activity than as an immediate relapse remedy. A single dose of natalizumab given as acute therapy for MS relapse was shown not to improve clinical outcomes in a randomized controlled trial. Attention to symptom management and promotion of neurorehabilitation are important aspects of MS relapse care. Neuroprotective and neuroreparative therapies remain under investigation, but are likely to become important complementary elements of relapse therapy in the future. Relapses serve as important indicators of MS disease activity. In the context of the emerging treatment paradigm of targeting freedom from evidence of MS disease activity, relapses should prompt consideration of transitioning to a disease-modifying treatment that may offer better efficacy. PMID- 25794778 TI - Response to the letter: Limited mouth opening of unknown cause cured by diagnostic coronoidectomy: a new clinical entity? PMID- 25794779 TI - Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. AB - We investigated the effect of antibiotic prophylaxis on postoperative inflammatory complications after operations for impacted mandibular third molars in Chinese patients. A total of 207 patients had their bilateral third molars removed in a split-mouth, double-blind, self-controlled, clinical trial in two visits. For one side amoxicillin (or clindamycin) was given (antibiotic group) from one hour before operation until 3 days postoperatively. For the other side a placebo was given (placebo group) at the same time. The outcome, including alveolar osteitis, surgical wound infection, prebuccal infection, and infection of the anterior isthmus of fauces, was assessed 2 and 10 days postoperatively. A total of 192 patients completed the study, and there was no difference between the groups in the incidence of inflammatory complications. In the treatment group, there were 4 cases of alveolar osteitis (2%), 2 infections of the wound (1%), and 14 other reactions (gastrointestinal (n=4), bleeding (n=2), ulcer (n=2), and fever (n=6)). In the placebo group, there were 6 cases of alveolar osteitis (3%), 2 wound infections (1%), and 22 other reactions (bleeding (n=6), ulcer (n=2) and fever (n=14)). There was no significant difference in the extraction time and postoperative reactions, except the pain score on day 10 (p=0.005). Prophylactic amoxicillin (or clindamycin) is not effective for the prevention or reduction of postoperative inflammatory complications after the removal of impacted mandibular third molars in Chinese patients. PMID- 25794780 TI - Predicting risk of severe hypoglycaemia in type 2 diabetes. AB - For many, the extent to which blood glucose control can be lowered is limited by risk of hypoglycaemia. Hypoglycaemia is feared and carries fiscal, social and medical costs, with risk of death being associated with severe hypoglycaemia in patients with type 2 diabetes at high cardiovascular risk. In this issue of Diabetologia, Chow et al (DOI: 10.1007/s00125-015-3512-0 ) report that patients with type 2 diabetes who suffered severe hypoglycaemia during attempts to lower blood glucose intensively were more likely to be insulin deficient and/or carry markers of autoimmunity more usually associated with type 1 diabetes. This opens the question of whether biomarkers might help clinicians identify those patients at greater or lower risk of treatment-induced hypoglycaemia, allowing therapeutic targets to be modified accordingly. PMID- 25794781 TI - Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes. AB - Viruses are considered to be potential key modulators of type 1 diabetes mellitus, with several possible mechanisms proposed for their modes of action. Here we discuss the evidence for virus involvement, including pancreatic infection and the induction of T cell-mediated molecular mimicry. A particular focus of this review is the further possibility that virus infection triggers bystander activation of pre-existing autoreactive lymphocytes. In this scenario, the virus triggers dendritic cell maturation and proinflammatory cytokine secretion by engaging pattern recognition receptors. These proinflammatory cytokines provoke bystander autoreactive lymphocyte activation in the presence of cognate autoantigen, which leads to enhanced beta cell destruction. Importantly, this mechanism does not necessarily involve pancreatic virus infection, and its virally non-specific nature suggests that it might represent a means commonly employed by multiple viruses. The ability of viruses specifically associated with type 1 diabetes, including group B coxsackievirus, rotavirus and influenza A virus, to induce these responses is also examined. The elucidation of a mechanism shared amongst several viruses for accelerating progression to type 1 diabetes would facilitate the identification of important targets for disease intervention. PMID- 25794782 TI - PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRbeta mAb therapy. AB - AIMS/HYPOTHESIS: T cells play a major role in the pathogenesis of type 1 diabetes, and there is great interest in developing curative immunotherapies targeting these cells. In this study, a monoclonal antibody (mAb) targeting the T cell receptor beta-chain (TCRbeta) was investigated for its ability to prevent and reverse disease in mouse models of diabetes. METHODS: RIP-OVA(hi) (C57BL/6 Tg(Ins2-OVA)59Wehi/WehiJ) mice adoptively transferred with ovalbumin-specific T cells (an induced model of diabetes) and NOD mice (a spontaneous model of diabetes) were used to test anti-TCRbeta mAb therapy as a means of preventing and reversing type 1 diabetes. RESULTS: A single dose of anti-TCRbeta completely prevented disease in RIP-OVA(hi) mice without inducing the release of inflammatory cytokines. Transient anti-TCRbeta therapy prevented diabetes in 90% of NOD mice and reversed the disease after its onset in 73% of NOD mice. Long after the remission of type 1 diabetes, the anti-TCRbeta treated mice were able to reject BALB/c skin allografts with normal kinetics while maintaining normoglycaemia. Treatment did not cause significant reductions in lymphocyte numbers in the spleen or pancreatic lymph nodes, but did result in a decreased percentage of chemokine receptor 9 (CCR9) positive, CD8(+) T cells. Notably, anti TCRbeta therapy increased the expression of programmed death 1 (PD-1) on the surface of the T cells; PD-1 expression is important for maintaining anti-TCRbeta induced self-tolerance, as type 1 diabetes recurs in mice following a blockade of PD-1 signalling. CONCLUSIONS/INTERPRETATION: Anti-TCRbeta mAb is a safe and effective immunotherapy that results in reduced numbers of CCR9(+) T cells, an increased expression of PD-1 on T cells and the restoration of self-tolerance in NOD mice. PMID- 25794783 TI - Novel approaches for two and three dimensional multiplexed imaging of osteocytes. AB - Although osteocytes have historically been viewed as quiescent cells, it is now clear that they are highly active cells in bone and play key regulatory roles in diverse skeletal functions, including mechanotransduction, phosphate homeostasis and regulation of osteoblast and osteoclast activity. Three dimensional imaging of embedded osteocytes and their dendritic connections within intact bone specimens can be quite challenging and many of the currently available methods are actually imaging the lacunocanalicular network rather than the osteocytes themselves. With the explosion of interest in the field of osteocyte biology, there is an increased need for reliable ways to image these cells in live and fixed bone specimens. Here we report the development of reproducible methods for 2D and 3D imaging of osteocytes in situ using multiplexed imaging approaches in which the osteocyte cell membrane, nucleus, cytoskeleton and extracellular matrix can be imaged simultaneously in various combinations. We also present a new transgenic mouse line expressing a membrane targeted-GFP variant selectively in osteocytes as a novel tool for in situ imaging of osteocytes and their dendrites in fixed or living bone specimens. These methods have been multiplexed with a novel method for labeling of the lacunocanalicular network using fixable dextran, which enables aspects of the osteocyte cell structure and lacunocanalicular system to be simultaneously imaged. The application of these comprehensive approaches for imaging of osteocytes in situ should advance research into osteocyte biology and function in health and disease. PMID- 25794784 TI - No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever. AB - OBJECTIVE: To evaluate whether cosmetically relevant dental effects occurred among children who had received doxycycline for treatment of suspected Rocky Mountain spotted fever (RMSF). STUDY DESIGN: Children who lived on an American Indian reservation with high incidence of RMSF were classified as exposed or unexposed to doxycycline, based on medical and pharmacy record abstraction. Licensed, trained dentists examined each child's teeth and evaluated visible staining patterns and enamel hypoplasia. Objective tooth color was evaluated with a spectrophotometer. RESULTS: Fifty-eight children who received an average of 1.8 courses of doxycycline before 8 years of age and who now had exposed permanent teeth erupted were compared with 213 children who had never received doxycycline. No tetracycline-like staining was observed in any of the exposed children's teeth (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or hypoplasia (P=1.0) was found between the 2 groups. CONCLUSIONS: This study failed to demonstrate dental staining, enamel hypoplasia, or tooth color differences among children who received short-term courses of doxycycline at <8 years of age. Healthcare provider confidence in use of doxycycline for suspected RMSF in children may be improved by modifying the drug's label. PMID- 25794785 TI - The impact of using RUSH protocol for diagnosing the type of unknown shock in the emergency department. AB - Clinical assessment and classification of shock is extremely difficult to conduct on critically ill patients especially upon arrival at the emergency department. Resuscitative point-of-care ultrasound could be used for rapid initial diagnosis and better management. In this study, the results of using the RUSH (Rapid Ultrasound in Shock) exam to determine the type of shock in the emergency department are compared to the final diagnosis of patients. This was a single center prospective study in which all patients with an unknown type of shock and no prior treatment were included. Parallel to the standard resuscitative management and diagnosis of the emergency team, the RUSH exam was performed blindly on the patient by an emergency medicine staff who was not part of the patient's caregiving team. The results of the RUSH exam were then compared to the final diagnosis of the patients and the 48-h outcome. Twenty-five patients were enrolled in this study. The overall kappa correlation of the RUSH exam compared with the final diagnosis was 0.84 which is an almost perfect agreement. The overall sensitivity of the RUSH exam was 88 % and the specificity was 96 %. Although the mortality rate was 64 %, there was not a significant relationship between mortality and the protocol used for diagnosis. The RUSH exam could be used in emergency wards to detect types of shock. PMID- 25794786 TI - Relationship between obesity, diabetes and the risk of thyroid cancer. AB - PURPOSE: Analyze the relationship between obesity and type-2 diabetes mellitus (DM) and the development of differentiated thyroid cancer (DTC). MATERIALS AND METHODS: A randomized case-controlled retrospective chart review of outpatient clinic patients at an academic medical center between January 2005 and December 2012. DTC patients were compared to two control groups: primary hyperparathyroidism (PHPTH) patients with euthyroid state and Internal Medicine (IM) patients. Exposure variables included historical body-mass-index (BMI), most recent BMI within 6 months and DM. Multivariate logistic regressions adjusting for gender, age, and year of BMI assessed the adjusted Odds Ratio (OR) of DTC with both BMI and DM. RESULTS: Comparison of means showed a statistically significant higher BMI in DTC (BMI=37.83) than PHPTH, IM, and pooled controls, BMI=30.36 p=<0.0001, BMI=28.96 p=<0.0001, BMI=29.53 p=<0.0001, respectively. When compared to PHPTH, DM was more frequent in DTC (29% vs. 16%) and prevalence trended towards significance (p=0.0829, 95% CI =0.902-5.407). BMI adjusted OR was significant when compared to PHPTH, IM and pooled controls: 1.125 (p=0.0001), 1.154 (p=<0.0001), and 1.113 (p=<0.0001), respectively. DM adjusted OR was significant when compared to PHPTH and pooled controls at 3.178 (95% 1.202,8.404, p=0.0198) and 2.237 (95% 1.033,4.844, p=0.0410), respectively. CONCLUSION: Our results show that obesity and, to a lesser degree, DM are significantly associated with DTC. BMI in particular was a strong predictive variable for DTC (C=0.82 bivariate, C=0.84 multivariate). PMID- 25794787 TI - Acromegaly: otolaryngic manifestations following pituitary surgery. AB - OBJECTIVES: Acromegalics present with a wide range of otolaryngic symptoms, including rhinosinusitis, changes in facial appearance, obstructive sleep apnea (OSA), and voice disturbances. Treatment typically involves transnasal transsphenoidal (TNTS) resection of the offending pituitary adenoma. In this study, we identify the prevalence of otolaryngic symptoms of acromegalic patients, and evaluate Sinonasal Outcome Test (SNOT-22) scores preceding and following pituitary resection. DESIGN: Retrospective chart review. SETTING: Tertiary academic medical center. PARTICIPANTS: Patients diagnosed with acromegaly who underwent surgical resection of a growth-hormone secreting pituitary adenoma between August 2010 and September 2013. MAIN OUTCOME MEASURES: Subjects were asked to complete questionnaires detailing otolaryngic symptoms as well as SNOT-22 surveys before and after TNTS surgery. A Student's t-test was used to compare preoperative and postoperative SNOT-22 scores. RESULTS: Twenty five patients underwent pituitary surgery for acromegaly. Acromegalic patients were found to have macroglossia (60%), OSA or sleep-disordered breathing (52%), thyroid neoplasia (20%), hearing loss/tinnitus (20%), sinonasal symptoms (16%), and parathyroid pathology (8%). Differences in preoperative and postoperative SNOT-22 scores were not statistically significant. CONCLUSION: Acromegalics present with assorted otolaryngic complaints. Routine screening of all acromegalics with sleep evaluations (for both surgical and perioperative planning), thyroid ultrasound, and audiologic testing should be strongly considered. PMID- 25794788 TI - A natural product based DOS library of hybrid systems. AB - Here we described a natural product inspired modular DOS strategy for the synthesis of a library of hybrid systems that are structurally and stereochemically disparate. The main scaffold is a pyrroloisoquinoline motif, that is synthesized from tandem Pictet-Spengler lactamization. The structural diversity is generated via "privileged scaffolds" that are attached at the appropriate site of the motif. Screening of the library compounds for their antiplasmodial activity against chloroquine sensitive 3D7 cells indicated few compounds with moderate activity (20-50 MUM). A systematic comparison of structural intricacy between the library members and a natural product dataset obtained from ZINC((r)) revealed comparable complexity. PMID- 25794789 TI - Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole benzimidazole derivatives. AB - In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by (1)H NMR, (13)C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4 methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1 b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti tubercular activity with a MIC of 3.125 MUg/mL. A p-substituted phenyl group (p tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line. PMID- 25794790 TI - Pentacyclic triterpene derivatives possessing polyhydroxyl ring A inhibit gram positive bacteria growth by regulating metabolism and virulence genes expression. AB - The hydroxyl group in ring A of pentacyclic triterpene is essential for antibacterial activity. Pentacyclic triterpenes bearing three hydroxyl groups in ring A were mainly found in plants and displayed significant antibacterial activity. However, no study reported how to obtain this type of compounds by chemical modification. In this study, twenty-five new pentacyclic triterpenes bearing polyhydroxyl ring A were synthesized from parental compounds ursolic acid (UA) and oleanolic acid (OA). Here, we showed that most of these derivatives displayed a significantly increased activity against Gram-positive bacteria compared to parental compounds in vitro. Some of these compounds exhibited minimum inhibitory concentration values of 1-3-fold more potent than the positive controls. The structure-activity relationship studies demonstrated that introducing two hydroxyl groups at positions C-1 and C-2 together with a small alkyl ester group at C-17 of UA and OA strongly enhanced growth-inhibiting activity against Gram-positive bacteria. The antibacterial mechanism of the active derivatives was shown to be involved in regulating the expression of genes associated with peptidoglycan and respiratory metabolisms, as well as virulence factor in bacteria. The enhanced potency and unique mechanism of action of these new pentacyclic triterpenes make them a promising antibacterial agent for further studies. PMID- 25794791 TI - Recent advances in the chemistry and biology of pyridopyrimidines. AB - The interest in pyridopyrimidine cores for pharmaceutical products makes this scaffold a highly useful building block for organic chemistry. These derivatives have found applications in various areas of medicine such as anticancer, CNS, fungicidal, antiviral, anti-inflammatory, antimicrobial, and antibacterial therapies. This review mainly focuses on the progress achieved since 2004 in the chemistry and biological activity of pyridopyrimidines. PMID- 25794793 TI - Psychometric properties of the Glaucoma Treatment Compliance Assessment Tool in a multicenter trial. AB - PURPOSE: To assess the psychometric properties of a new version of the Glaucoma Treatment Compliance Assessment Tool, a survey evaluating health behavior and glaucoma adherence using constructs from the Health Belief Model. DESIGN: Psychometric analysis. METHODS: We administered the 47-statement Glaucoma Treatment Compliance Assessment Tool to 201 participants who were using a single bottle of an ocular hypotensive agent, and objectively measured adherence with medication event monitoring system devices over 60 days. Adherence was the percentage of days with correctly timed bottle openings. We used principal components analysis to determine construct validity, Cronbach's alpha for internal consistency reliability, frequency analysis for floor and ceiling effects, and Spearman rho for test-retest reliability. We determined predictive validity using univariate and multiple regression. RESULTS: The mean (+/-SD, range) adherence percentage was 79.9% (+/-18.5%, 20.3%-100.0%). Principal component analysis loaded 24 questions into 6 components that were consistent with the Health Belief Model. All 6 components had Cronbach's alpha reliability between 0.601 and 0.797. No statements had floor or ceiling effects, and all statements had acceptable test-retest reliability. Multiple regression analysis showed 4 Health Belief Model statements, white race, older age, and married marital status to be associated with higher adherence (adjusted R(2) = 0.27, P < .001). CONCLUSIONS: The newest version of the Glaucoma Treatment Compliance Assessment Tool showed acceptable psychometric properties. With further refinement, clinicians and researchers could use it to examine factors related to adherence and measure improvement in adherence with a change in health behavior attitudes. PMID- 25794792 TI - P-selectin Plasma Levels and Genetic Variant Associated With Diabetic Retinopathy in African Americans. AB - PURPOSE: To report the prevalence and risk factors for retinopathy in African Americans with impaired fasting glucose (IFG) and type 2 diabetes in the Jackson Heart Study and to determine if P-selectin plasma levels are independently associated with retinopathy in this population. DESIGN: Prospective, cross sectional observational study. METHODS: setting: Community-based epidemiologic study. STUDY POPULATION: Total of 629 patients with type 2 diabetes and 266 participants with impaired fasting glucose. OBSERVATION PROCEDURES: Bilateral, 7 field fundus photographs were scored by masked readers for diabetic retinopathy (DR) level. Covariate data including P-selectin plasma levels and genotypes were collected in a standardized fashion. MAIN OUTCOME MEASURES: Association between risk factors, including P-selectin plasma levels and genotypes, and retinopathy. RESULTS: The prevalences of any retinopathy among participants with IFG and type 2 diabetes were 9.4% and 32.4%, respectively. Among those with type 2 diabetes, in multivariate models adjusted for age, sex, and other traditional risk factors, higher P-selectin levels were associated with any DR (odds ratio = 1.11, 95% confidence interval = 1.02-1.21, P = .02) and proliferative DR (odds ratio = 1.23, 95% confidence interval = 1.03-1.46, P = .02). To further investigate the relationship between P-selectin and DR, we examined the association between P selectin genotype and DR. Minor allele homozygotes for the variant rs6128 were less likely to develop DR (P after Bonferroni correction = 0.03). CONCLUSIONS: Both serologic and genetic data show an association between P-selectin and DR in the Jackson Heart Study. If confirmed in other studies, this association may provide insight into the pathogenesis of retinopathy. PMID- 25794794 TI - Is histological examination necessary when excising a pilonidal cyst? AB - BACKGROUND: Pilonidal disease is a common inflammatory condition mostly affecting young males. Malignant degeneration of a pilonidal cyst is rare, with incidence estimated at 0.1%. The most common type is squamous cell carcinoma and the treatment of choice remains en block resection of the lesion. CASE REPORT: We present the case of a patient with locally advanced squamous cell carcinoma arising in a pilonidal cyst, due to misdiagnosis of the disease during his first treatment. CONCLUSIONS: Detailed histological examination of all excised pilonidal cyst lesions is essential and any histological suspicion should prompt a wider excision. PMID- 25794795 TI - Primary mandibular xanthoma: case report. AB - Xanthoma is a very rare bone tumor, especially in the mandible, that can be associated with metabolic diseases such as hyperlipidemia. A 14-year-old girl presented with a non-corticated unilocular radiolucent lesion observed on panoramic radiography. The lesion was located between the roots of the left first and second premolar teeth, extending from the cervical to the apical region, measuring approximately 1 cm in greatest dimension. An excisional biopsy revealed foam cells and occasional nonfoamy mononuclear macrophage-like cells spread among a discrete fibrous stroma. Immunohistochemically, the xanthomatous cells were CD68 and vimentin positive, focally positive for S100, CD1a, and CD3 and negative for AE1/AE3, CD20, CD117, and HMB45. Hematologic and biochemical investigations ruled out systemic disease. PMID- 25794796 TI - A new quantitative PCR for human parvovirus B19 genotypes. AB - Parvovirus B19 (B19V) is a minute ssDNA virus associated with a wide range of diseases from childhood erythema to fetal death. After primary infection, the viral genomes persist lifelong in solid tissues of most types. Quantification of the viral DNA is important in the timing of primary infection, assessment of tissue persistence and screening of blood donor plasma. In this study, we present a new PCR assay for detection and quantification as well as for differentiation of all three B19V genotypes. A new B19V qPCR was designed to target a 154-bp region of the NS1 area. Serum, plasma and solid tissue samples were suitable for testing in the assay. The WHO International Reference Panel for Parvovirus B19 Genotypes was utilized to validate the assay for detection of different genotypes of B19V in clinical material. Each panel member yielded, by the new qPCR, a quantity similar to the one reported by National Institute for Biological Standards and Control (NIBSC). The qPCR was specific for B19V and amplified and quantified all three genotypes with detection sensitivities of <=10 copies/reaction. The differentiation of B19V genotypes was performed by Sanger sequencing of the amplified products. PMID- 25794797 TI - Development of a novel PCR-RFLP assay for improved detection and typing of bovine papillomaviruses. AB - A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was developed to detect and type bovine papillomaviruses (BPVs) from tumors in cattle. Two degenerate primer sets targeting the BPV L1 gene, subAup/subAdw and subBup/subBdw, and one restriction enzyme RsaI were used in this assay. In silico analyses of the restriction enzyme sites in the PCR fragments of 13 BPV sequences (BPV-1 to -13) revealed that all known BPVs are differentiated by the PCR-RFLP assay. Analyses of 63 previously typed clinical samples, that included teat papillomas and both esophageal and urinary bladder cancer biopsies, show that the assay clearly differentiates between eight clinically important BPV types (BPV-1 to -6, -9, -10), and discriminates between single and multiple infections. To further assess the reliability of the PCR-RFLP method amplified fragments were sequenced. A high correlation (95%) was observed when the results of the PCR-RFLP method were compared with PCR-sequencing. Differences in typing occurred for 3 of 63 specimens; PCR-RFLP identified additional BPV types in these specimens, while the PCR-sequencing identified only one. These results indicate that the PCR-RFLP method reported here is simpler and more reliable in the detection and typing of BPVs from bovine tumor samples than PCR-sequencing. PMID- 25794798 TI - Effects of chitosan nanoparticle-mediated BRAF siRNA interference on invasion and metastasis of gastric cancer cells. AB - To observe the changes in invasion capacity of gastric cancer BGC823 cells after being treated with chitosan-encapsulated BRAF siRNA nanoparticles, and to evaluate the effects of the nanoparticle-mediated BRAF siRNA interference on cell invasion and metastasis, BRAF siRNA was encapsulated with chitosan into nanoparticles sized 350 nm to treat gastric cancer cells. Silencing of BRAF was detected by Western blot and PCR, and cell invasion was observed by the Transwell assay. The nanoparticles significantly downregulated BRAF expression in BGC823 cells (P < 0.01) and inhibited their invasion (P < 0.001). Chitosan nanoparticle mediated BRAF siRNA interference evidently reduced the invasion capacity of gastric cancers. PMID- 25794799 TI - Distribution and diversity of bacterioplankton communities in subtropical seawater around Xiamen Island, China. AB - Marine bacterioplankton communities have profound impact on global biogeochemical cycles and ecological balances. However, relatively little is known about the bacterioplankton communities and the factors shaping their spatial distribution in subtropical island. Here, the bacterioplankton communities around a typical subtropical island, Xiamen Island, were revealed by analyzing bacterial 16S rRNA gene through quantitative PCR (qPCR) and 454 pyrosequencing methods. The qPCR results indicated that the abundance of 16S rRNA gene ranged from 2.07 * 10(7) to 2.13 * 10(8)copies mL(-1) in surface seawater among eight sampling sites (S1-S8) around Xiamen Island, and the nitrogen and phosphorus-rich sites (S5 and S8) were detected with higher 16S rRNA gene abundance. Pyrosequencing evidenced that a total of 267 genera of 47 classes in 26 different phyla (or candidate phyla) and some unclassified bacteria were obtained from seawater around Xiamen Island. The most dominant phylum was Proteobacteria (49.62-76.84% among sites), followed by Bacteroidetes (6.64-20.88%), Actinobacteria (2.58-9.20%), Firmicutes (0.03 13.30%), Verrucomicrobia (0.23-2.67%) and Planctomycetes (0.14-2.20%). Among eight sites, the nitrogen and phosphorus-rich sites (S5 and S8) exhibited higher proportions of Gammaproteobacteria, Epsilonproteobacteria, Firmicutes and lower proportions of Alphaproteobacteria and Planctomycetes than other sites. S5 and S8 also had more similar beta-diversity, and sampling site near the estuary (S8) showed the highest bacterial diversity. Redundancy analysis (RDA) confirmed that total nitrogen and total phosphorus significantly (P<0.05 and P<0.01, respectively) influenced the bacterioplankton communities around Xiamen Island. These results will provide insights into bacterial abundance, diversity and distribution patterns, as well as their controlling factors, in subtropical marine ecosystems. PMID- 25794800 TI - Pitfalls in RECIST Data Extraction for Clinical Trials: Beyond the Basics. AB - Response Evaluation Criteria in Solid Tumors (RECIST) is a standardized methodology for determining therapeutic response to anticancer therapy using changes in lesion appearance on imaging studies. Many radiologists are now using RECIST in their routine clinical workflow, as part of consultative arrangements, or within dedicated imaging core laboratories. Although basic RECIST methodology is well described in published articles and online resources, inexperienced readers may encounter difficulties with certain nuances and subtleties of RECIST. This article illustrates a set of pitfalls in RECIST assessment considered to be "beyond the basics." These pitfalls were uncovered during a quality improvement review of a recently established cancer imaging core laboratory staffed by radiologists with limited prior RECIST experience. Pitfalls are presented in four categories: (1) baseline selection of lesions, (2) reassessment of target lesions, (3) reassessment of nontarget lesions, and (4) identification of new lesions. Educational and operational strategies for addressing these pitfalls are suggested. Attention to these pitfalls and strategies may improve the overall quality of RECIST assessments performed by radiologists. PMID- 25794801 TI - Modulating prime molecular expressions and in vitro wound healing rate in keratinocyte (HaCaT) population under characteristic honey dilutions. AB - ETHNOPHARMACOLOGY RELEVANCE: In traditional medicines honey is known for healing efficacy and vividly used as "Anupan" in Ayurvedic medicines appreciating roles in dilutions. Validating efficacy of physico-chemically characterized honey in dilutions, studies on in vitro wound healing and attainment of cellular confluence epithelial cells including expressions of cardinal genes is crucial. To evaluate effects of characterized honey in varied dilutions on cellular viability, in vitro wound healing and modulation of prime epithelial gene expressions. MATERIALS AND METHODS: Six Indian honey-samples from different sources were physico-chemically characterized and optimal one was explored in dilutions (v/v%) through in vitro studies on human epithelial (HaCaT) cells for viability, wound healing and expressions of genes p63, E-cadherin, beta-catenin, GnT-III and GnT-V. RESULTS: Studied honey samples (i.e. A-F) depicted range of pH (2-4), water (12.48-23.95), electrical conductivity (2.57-14.34), carbohydrate (68.73-98.65), protein (.316-5.36) and antioxidant potential. Though sample A and F showed physico-chemical proximity, but overall bio-impact of the earlier was better, thus studied in 8-.1% (v/v) dilution range. Four dilutions (.01, .04, .1, .25 v/v%) augmented cellular viability but in vitro wound healing was fastest (p<.05) under .1%. Such efficacy was further documented for p63 up-regulation by immunocytochemistry and mRNA studies. The E-cadherin and beta-catenin mRNA expressions were also up-regulated and their proteins were predominantly cytoplasmic. E-cadherin up-regulation was corroborative with down-regulation and up-regulation of GnT-III and GnT-V respectively. CONCLUSION: Present study illustrated efficacy of particular honey dilution (.1%) with characteristic free radical scavenging activity in facilitating cell proliferation and attainment of confluence towards faster wound healing and modulation of cardinal epithelial genes (viz. p63, E-cadherin, beta-catenin, Gnt-III and V). PMID- 25794802 TI - Herbs and herbal combinations used to treat suspected malaria in Bo, Sierra Leone. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Most adults in West Africa treat acute febrile illnesses with local herbs, but the patterns of herbs used for malaria have not been recently described in Sierra Leone. MATERIALS AND METHODS: We used a population-based cross-sectional approach to interview 810 randomly-sampled rural and urban adult residents of Bo, Sierra Leone, in December 2013 and January 2014 about their use of herbal remedies when they suspect they have malaria. RESULTS: In total, 55% of the participants reported taking one or more of seven herbs to treat symptoms of malaria. Among herb users, the most commonly used anti-malarial herbs were Moringa oleifera (moringa, 52%) and Sarcocephalus latifolius (yumbuyambay, 50%). The other herbs used included Senna siamea (shekutoure, 18%), Cassia sieberiana (gbangba, 18%), Uvaria afzelii (gone-botai, 14%), Morinda chrysorhiza (njasui, 14%), and Craterispermum laurinum (nyelleh, 7%). Combination herbal therapy was common, with 37% of herb users taking two or more herbs together when ill with suspected malaria. CONCLUSIONS: Indigenous medical knowledge about herbal remedies and combinations of local herbs remains an integral part of malaria case management in Sierra Leone. PMID- 25794803 TI - Urinary metabonomics elucidate the therapeutic mechanism of Orthosiphon stamineus in mouse crystal-induced kidney injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Orthosiphon stamineus (OS), a traditional Chinese herb, is often used for promoting urination and treating nephrolithiasis. AIM OF THE STUDY: Urolithiasis is a major worldwide public health burden due to its high incidence of recurrence and damage to renal function. However, the etiology for urolithiasis is not well understood. Metabonomics, the systematic study of small molecule metabolites present in biological samples, has become a valid and powerful tool for understanding disease phenotypes. In this study, a urinary metabolic profiling analysis was performed in a mouse model of renal calcium oxalate crystal deposition to identify potential biomarkers for crystal-induced renal damage and the anti-crystal mechanism of OS. MATERIALS AND METHODS: Thirty six mice were randomly divided into six groups including Saline, Crystal, Cystone and OS at dosages of 0.5g/kg, 1g/kg, and 2g/kg. A metabonomics approach using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was developed to perform the urinary metabolic profiling analysis. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were utilized to identify differences between the metabolic profiles of mice in the saline control group and crystal group. RESULTS: Using partial least squares-discriminant analysis, 30 metabolites were identified as potential biomarkers of crystal-induced renal damage. Most of them were primarily involved in amino acid metabolism, taurine and hypotaurine metabolism, purine metabolism, and the citrate cycle (TCA). After the treatment with OS, the levels of 20 biomarkers had returned to the levels of the control samples. CONCLUSIONS: Our results suggest that OS has a protective effect for mice with crystal-induced kidney injury via the regulation of multiple metabolic pathways primarily involving amino acid, energy and choline metabolism. PMID- 25794804 TI - Lysimachia christinae Hance regresses preestablished cholesterol gallstone in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Whole herb of Lysimachia christinae has long been used as a remedy for cholelithiasis extensively in China. This study was aimed to validate the effect of L. christinae on eliminating preestablished cholesterol gallstone (CGS) in model animals. MATERIALS AND METHODS: Acute toxicity of aqueous extract of L. christinae (LCAE) was estimated in male C57BL/6 mice, so was the efficiency of LCAE on preformed CGS induced by lithogenic diet. The effects of LCAE were also examined on bile secretion rate, the lipid profiles of bile and serum, body weight, main visceral organ indexes, and histomorphology of main visceral organs. RESULTS: Single dose of LCAE did not lead to death and changes on body weight gain, main visceral organ indexes, histomorphology of main visceral organs, and blood hemogram and biochemical indexes, even at dose of 50g material/kg body weight. Preestablished CGSs were almost entirely eliminated after administration of LCAE for 2wk at high dose or for 4wk at low dose. LCAE promoted bile secretion and lowered cholesterol levels in either cystic bile or hepatic bile. LCAE also decreased serum cholesterol content, especially LDL-C content, tremendously, reduced the levels of serum HDL-C, phospholipid, and triglycerine a little, and lowered body weight and liver index significantly. After medication of LCAE for 8wk , neither visceral indexes nor histomorphology of heart, kidney, and spleen were influenced, but fatty degeneration of liver induced by high fat and high cholesterol diet was reverted. CONCLUSION: L. christinae can be considered as non-toxic. It showed prominent efficiency of eliminating preexisted CGS in mice and indicated a hypolipidaemic effect. PMID- 25794805 TI - Comparative pharmacokinetics and tissue distribution profiles of lignan components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Huayu recipe (FZHY) is formulated on the basis of Chinese medicine theory in treating liver fibrosis. AIM OF THE STUDY: To illuminate the influence of the pathological state of liver fibrosis on the pharmacokinetics and tissue distribution profiles of lignan components from FZHY. MATERIALS AND METHODS: Male Wistar rats were randomly divided into normal group and Hepatic fibrosis group (induced by dimethylnitrosamine). Six lignan components were detected and quantified by ultrahigh performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)in the plasma and tissue of normal and hepatic fibrosis rats. RESULTS: A rapid, sensitive and convenient UHPLC-MS/MS method has been developed for the simultaneous determination of six lignan components in different rat biological samples successfully. After oral administration of FZHY at a dose of 15g/kg, the pharmacokinetic behaviors of schizandrin A (SIA), schizandrin B (SIB), schizandrin C (SIC), schisandrol A (SOA), Schisandrol B (SOB) and schisantherin A (STA) have been significantly changed in hepatic fibrosis rats compared with the normal rats, and their AUC(0 t) values were increased by 235.09%, 388.44%, 223.30%, 669.30%, 295.08% and 267.63% orderly (P<0.05). Tissue distribution results showed the amount of SIA, SIB, SOA and SOB were significant increased in heart, lung, spleen and kidney of hepatic fibrosis rats compared with normal rats at most of the time point (P<0.05). Meanwhile, the result also reveals that the hepatic fibrosis could delay the peak time of lignans in liver. CONCLUSION: The results proved that the established UHPLC-MS/MS method could be applied to the comparative study on pharmacokinetics and tissue distribution of lignan components in normal and hepatic fibrosis rats. The hepatic fibrosis could alter the pharmacokinetics and tissue distribution properties of lignan components in rats after administration of FZHY. The results might be helpful for guide the clinical application of this medicine. PMID- 25794807 TI - Ethnomedicinal plants used by traditional healers of North Tripura district, Tripura, North East India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Information about ethnomedicinal plants used by traditional healers in Tripura, India is very much limited. As there is rapid erosion of traditional knowledge in the state, needs has arisen to document the diversity of medicinal plants, their preparation and associated diseases. AIM OF THE STUDY: Attempts have been made to explore the herbal medicines used by the traditional healers belonging to the various communities in North Tripura district of Tripura, India and document the associated traditional knowledge on the utilisation of medicinal plants. MATERIALS AND METHODS: The study was based on ethnomedicinal field survey covering a period of 1 year from February 2012 to February 2013. The ethnomedicinal information was collected by using semi structured questionnaires from different healers and knowledge holders. Collected data were analysed through informant consensus factor, Index of Specialisation and Relative frequency of citation to determine culturally significant plants. RESULTS: A total of 75 species of plants under 68 genera belonging to 43 families were collected during the study for the treatment of 15 disease categories. Leaves were the most frequently used plant parts and most of the medicines were prepared in the form of extract and administered orally. FIC values of the present study indicated that there was a high agreement in the use of plants in the treatment of digestive system disorders and respiratory system disorders among the healers. Plants having high ISu are Justicia adhatoda, Pajanelia longifolia, Catharanthus roseus etc. CONCLUSION: The present study highlighted certain species having higher priority indices for further phytochemical investigation. Counselling of traditional health practitioners should be taken into consideration in order to smooth continuation and extension of traditional medical knowledge and practice for ensuring safe and effective therapy. PMID- 25794806 TI - Antihyperlipidemic effect of Cyclocarya paliurus (Batal.) Iljinskaja extract and inhibition of apolipoprotein B48 overproduction in hyperlipidemic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cyclocarya paliurus (CP) Batal., the sole species in its genus, is a native plant to China. As a traditional Chinese folk medicine, the tree leaves have been widely used for the treatment of metabolic disorders, including hyperlipidemia, obesity, diabetes and hypertension. AIM OF THE STUDY: The study aimed to evaluate the antihyperlipidemic effect of CP ethanol extract, as well as its inhibitory activity on apolipoproteinB48 (apoB48), in normal and hyperlipidemic mice. MATERIALS AND METHODS: The antihyperlipidemic effect of CP was evaluated in hyperlipidemic mice induced by high-fat diet for 4 weeks. CP ethanol extract (0.37, 0.75 and 1.5g/kg/day) was orally administrated once daily. Lipids and antioxidant profiles, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), together with the indices of hepatic and renal functions were examined. RT-qPCR and western blotting were used to analysis the expression levels of tumor necrosis factor (TNF-alpha), total- and triglyceride rich apoB48 (TRL-apoB48), as well as the phosphorylation of the mitogen activatein kinase (MAPK). RESULTS: CP as well as simvastatin remarkably lowered the levels of TC, TG, LDL-C and MDA, and at the same time, elevated the HDL-C, SOD and GSH-Px in high-fat diet mice. It also decreased the serum concentration of total- and TRL-apoB48 in the fasting state. CP inhibited TNF-alpha expression and phosphorylation level of MAPK. Furthermore, the HE staining of liver and kidney, together with hepatic and renal function analysis showed hepato- and renoprotective activities of CP. CONCLUSIONS: These results suggested that CP possesses beneficial potentials for use in treating hyperlipidemia and the underlying lipid-lowering mechanism might associate with a down-regulation of the intestinal-associated lipoprotein apoB48, which may provide evidence about its practical application for treating hyperlipidemia and its complications. PMID- 25794809 TI - Start-up of simultaneous partial nitrification, anammox and denitrification (SNAD) process in sequencing batch biofilm reactor using novel biomass carriers. AB - Simultaneous partial nitrification, anammox and denitrification (SNAD) process was started-up in a 2.5L sequencing batch biofilm reactor (SBBR) using novel biomass carriers. The SNAD process took only 51d for start-up at nitrogen loading rate (NLR) and organic loading rate (OLR) of 120 and 60g/m(3)-d, respectively. Long-term stable operation of SNAD process was observed at NLR and OLR of 360 and 180g/m(3)-d with average total nitrogen and COD removal efficiencies of >88% and >90%, respectively. The values of conversion ratio [Formula: see text] remained below 0.11 after the start-up period, which further confirmed the long-term stability of SNAD process. Results of polymerase chain reaction (PCR), qualitative PCR, and scanning electron microscopic (SEM) analysis of sludge samples confirmed the co-existence and enrichment of AOB, anammox bacteria and denitrifying bacteria in the reactor and biofilm formation on to the carriers. PMID- 25794810 TI - Contribution of acetic acid to the hydrolysis of lignocellulosic biomass under abiotic conditions. AB - Acetic acid was used in abiotic experiments to adjust the solution pH and investigate its influence on the chemical hydrolysis of the Organic Fraction of Municipal Solid Waste (OFMSW). Soluble chemical oxygen demand (SCOD) was used to measure the hydrolysis under oxidative conditions (positive oxidation-reduction potential values), and pH 4 allowed for 20% (+/-2%) of the COD added to be solubilized, whereas only 12% (+/-1%) was solubilized at pH7. Under reducing conditions (negative oxidation-reduction potential values) and pH 4, 32.3% (+/ 3%) of the OFMSW was solubilized which shows that acidogenesis at pH 4 during the anaerobic digestion of solid waste can result in chemical hydrolysis. In comparison, bacterial hydrolysis resulted in 54% (+/-6%) solubilization. PMID- 25794808 TI - Banxia xiexin decoction protects against dextran sulfate sodium-induced chronic ulcerative colitis in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD), one of a traditional Chinese medicine chronicled in Shang Han Lun, is commonly used to treat gastroenteritis, ulcerative colitis and diarrhea. In our study, we used current biomedical approaches to investigate the therapeutic efficacy of BXD and possible protective mechanism involved in inhibiting dextran sulfate sodium (DSS) induced chronic ulcerative colitis model. MATERIALS AND METHODS: Chronic DSS colitis was induced in C57BL/6 male mice by three cycles of 5 days of 2% DSS in drinking water, alternating with 5 days of normal water, totaling 30 days. In BXD group, the mice were administered at a dose of 8.7g/kg BXD for 5 days before and during DSS treatment via oral gavage per day. Mice in vehicle group and DSS group were given orally the same volume of drinking water, instead. Body weight, stool characters and hematochezia were observed everyday. The colorectal tissues were used to detect levels of TNF-alpha, IL-4, IL-10, IL-1beta, IL-17, IL-23 and MPO by ELISA or qRT-PCR. The expression of COX-2, 8-Oxoguanine and Nrf2 were examined by IHC, and p-p65 was examined by western blotting. ThOD and the content of MDA were measured according to kits respectively. RESULTS: BXD significantly protected against DSS-induced chronic ulcerative colitis by amelioration of body weight loss, DAI and histology score. The level of TNF-alpha, IL-1beta, IL-17, IL 23, COX-2 and p-p65 were decreased significantly, while the level of IL-10 improved with the treatment of BXD. MDA, MPO and 8-Oxoguanine were decreased, meanwhile SOD activity and Nrf2 expression were elevated significantly by BXD. CONCLUSIONS: BXD possesses the potential of anti-inflammation and anti-oxidation to treat colitis. The protective mechanism of BXD may involve in inhibition of NF kappaBp65 activation and increasement of Nrf2 expression in colorectums of mice. PMID- 25794811 TI - Optimization and characterization of bio-oil produced by microwave assisted pyrolysis of oil palm shell waste biomass with microwave absorber. AB - In this study, solid oil palm shell (OPS) waste biomass was subjected to microwave pyrolysis conditions with uniformly distributed coconut activated carbon (CAC) microwave absorber. The effects of CAC loading (wt%), microwave power (W) and N2 flow rate (LPM) were investigated on heating profile, bio-oil yield and its composition. Response surface methodology based on central composite design was used to study the significance of process parameters on bio oil yield. The coefficient of determination (R(2)) for the bio-oil yield is 0.89017 indicating 89.017% of data variability is accounted to the model. The largest effect on bio-oil yield is from linear and quadratic terms of N2 flow rate. The phenol content in bio-oil is 32.24-58.09% GC-MS area. The bio-oil also contain 1,1-dimethyl hydrazine of 10.54-21.20% GC-MS area. The presence of phenol and 1,1-dimethyl hydrazine implies that the microwave pyrolysis of OPS with carbon absorber has the potential to produce valuable fuel products. PMID- 25794812 TI - Trabectedin: Supportive care strategies and safety profile. AB - Trabectedin is an approved antineoplastic agent for the treatment of adult patients with advanced soft tissue sarcomas or in combination with pegylated liposomal doxorubicin (PLD) in patients with relapsed platinum sensitive ovarian cancer. The mechanism of action is still not fully understood but many typical side effects seen with other chemotherapy drugs are less common, mild or unreported. Although this apparent favorable safety profile suggests a well tolerated and manageable therapeutic option in the palliative care setting, trabectedin does have specific adverse side effects which can be hazardous for individual patients. The most commonly observed toxicities with trabectedin include neutropenia, nausea, vomiting, and increases in liver transaminases, anemia, fatigue, thrombocytopenia, anorexia and diarrhea. However, for most patients the appropriate use of supportive care strategies can reduce or overcome these side effects. We present a concise review of the safety data of trabectedin with the corresponding overview of the supportive care strategies. PMID- 25794813 TI - Advances in the treatment of prostate cancer with radiotherapy. AB - INTRODUCTION: Prognosis of prostate cancer has improved as a result of the combination with androgen deprivation therapy and the increase of radiation dose. However, a high number of prostate cancer patients will develop biochemical recurrence; therefore a research effort to increase the control of the tumour in these patients is necessary. METHODS: To increase the therapeutic ratio (the index between cytotoxic effects and normal tissue complications with a certain dose of radiation), different new strategies described in the literature have been reviewed. RESULTS: There are several strategies that may increase the efficacy of radiotherapy to treat prostate cancer. First is based on physics and technology, and second based on biology. DISCUSSION: Technical advances in radiotherapy allow intensification of radiation through escalation of the dose or in combination with chemotherapy. Furthermore, targeting specific molecular dysregulated pathways in the tumour will increase the effects of radiation specifically in tumour cells. Hopefully, these strategies will result in increased rates of tumour control in all prognostic groups, especially in high risk tumours and a subgroup of patients with intermediate risk tumours, minimizing treatment morbidity and increasing the therapeutic ratio of radiotherapy. PMID- 25794814 TI - Amazon dams and waterways: Brazil's Tapajos Basin plans. AB - Brazil plans to build 43 "large" dams (>30 MW) in the Tapajos Basin, ten of which are priorities for completion by 2022. Impacts include flooding indigenous lands and conservation units. The Tapajos River and two tributaries (the Juruena and Teles Pires Rivers) are also the focus of plans for waterways to transport soybeans from Mato Grosso to ports on the Amazon River. Dams would allow barges to pass rapids and waterfalls. The waterway plans require dams in a continuous chain, including the Chacorao Dam that would flood 18,700 ha of the Munduruku Indigenous Land. Protections in Brazil's constitution and legislation and in international conventions are easily neutralized through application of "security suspensions," as has already occurred during licensing of several dams currently under construction in the Tapajos Basin. Few are aware of "security suspensions," resulting in little impetus to change these laws. PMID- 25794816 TI - First report of external ophthalmomyiasis caused by Lucilia sericata Meigen in a healthy patient without predisposing risk factors. AB - A 72-year-old man with no medical history initially presented to the emergency room with severe tearing, redness, foreign body sensation, and pain in the left eye. He reported no previous history of any periocular trauma, malignancy, surgery, or systemic illness. On presentation, the patient only showed left periorbital edema and erythema in the left eyelid with no evidence of any skin malignancy. On slit lamp examination, multiple small whitish motile organisms were observed on the left conjunctival fornices. The organisms were removed, preserved, and identified as the third-stage larvae of Lucilia sericata (green bottle fly). The patient was treated with topical antibiotic and steroid eye drops and the inflammation resolved 1 week after treatment initiation. This is the first report of external ophthalmomyiasis caused by facultative parasite, L. sericata maggots in a healthy patient without any predisposing factors. PMID- 25794815 TI - Isolated Ficus trees deliver dual conservation and development benefits in a rural landscape. AB - Many of the world's rural populations are dependent on the local provision of economically and medicinally important plant resources. However, increasing land use intensity is depleting these resources, reducing human welfare, and thereby constraining development. Here we investigate a low cost strategy to manage the availability of valuable plant resources, facilitated by the use of isolated Ficus trees as restoration nuclei. We surveyed the plants growing under 207 isolated trees in Assam, India, and categorized them according to their local human-uses. We found that Ficus trees were associated with double the density of important high-grade timber, firewood, human food, livestock fodder, and medicinal plants compared to non-Ficus trees. Management practices were also important in determining the density of valuable plants, with grazing pressure and land-use intensity significantly affecting densities in most categories. Community management practices that conserve isolated Ficus trees, and restrict livestock grazing and high-intensity land-use in their vicinity, can promote plant growth and the provision of important local resources. PMID- 25794817 TI - Chemical constituents isolated from Juncus effusus induce cytotoxicity in HT22 cells. AB - Effususol A (1), a new 9,10-dihydrophenanthrene, has been isolated from the medullae of Juncus effusus along with ten known compounds, effusol (2), dehydroeffusol (3), juncusol (4), dehydrojuncusol (5), juncuenin B (6), dehydrojuncuenin B (7), juncuenin D (8), luteolin (9), luteolin 5-methyl ether (10), and 4-hydroxy-2,3-dimethyl-2-nonen-4-olide (11). The structure of 1 was elucidated on the basis of spectroscopic data. 2, 4, 6, 7, and 8 have induced caspase-3-mediated cytotoxicity in HT22 cells. PMID- 25794818 TI - Pelvic and right ovarian mature teratomas with malignant mixed germ cell tumors of the anterior abdominal wall. PMID- 25794819 TI - Pregnancy outcome according to pre-pregnancy body mass index and gestational weight gain. AB - OBJECTIVE: To assess birth weight in relation to gestational weight gain (GWG) among women who were and were not obese before pregnancy. METHODS: For a retrospective cohort study, data were obtained for women with a pre-pregnancy body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) of at least 30 who had a singleton delivery at a center in Denmark in 2010-2011. Data were also obtained for 455 non-obese women (BMI 20.0 24.9). GWG was expressed in absolute terms and relative to published recommendations (11-16kg in non-obese women; 5-9kg in obese women). RESULTS: A total of 231 obese women were included in analyses. In non-obese and obese women, fetal weight was highest when GWG was above the recommended amount. Among women who had a GWG in line with the recommendations, mean birth weight was higher among those with a pre-pregnancy BMI of 35.0-39.9 (3758+/-410g) or at least 40 (3671+/-374g) than among non-obese women (3394+/-453g; P=0.0058). CONCLUSION: Birth weight is related to both maternal BMI and GWG. In obese women, adherence to GWG recommendations does not seem to prevent increased birth weights. PMID- 25794820 TI - Curative surgery for placental site trophoblastic tumors. PMID- 25794821 TI - Meta-analysis of Foley catheter plus misoprostol versus misoprostol alone for cervical ripening. AB - BACKGROUND: The effectiveness of Foley catheter plus misoprostol for cervical ripening has not been convincingly shown in trials. OBJECTIVES: To summarize the evidence comparing Foley catheter plus misoprostol versus misoprostol alone for cervical ripening. SEARCH STRATEGY: Embase, Medline, and Cochrane Collaboration databases were searched with the terms "Foley catheter," "misoprostol," "cervical ripening," and "labor induction." SELECTION CRITERIA: Randomized controlled trials comparing the methods of cervical ripening for delivery of a viable fetus were included. DATA COLLECTION AND ANALYSIS: Study characteristics, quality, and outcomes were recorded. Random-effects models were used to combine data. MAIN RESULTS: Eight trials were included, with 1153 patients overall. In a pooled analysis of seven high-quality studies, the combination group had a decreased time to delivery (mean difference -2.36 hours, 95% confidence interval [CI] -4.07 to -0.66; P=0.007). Risk of chorioamnionitis was significantly increased in the combination group (risk ratio [RR] 2.07, 95% CI 1.04-4.13; P=0.04), and that of tachysystole with fetal heart rate changes was decreased (RR 0.58, 95% CI 0.38 0.91; P=0.02). Frequency of cesarean did not differ (P=0.77). CONCLUSIONS: The combined use of Foley catheter and misoprostol results in a reduced time to delivery, a reduced frequency tachysystole with fetal heart rate changes, and an increased incidence of chorioamnionitis. PMID- 25794822 TI - Imaging of radiation damage using complementary field ion microscopy and atom probe tomography. AB - Radiation damage in tungsten and a tungsten-tantalum alloy, both of relevance to nuclear fusion research, has been characterized using a combination of field ion microscopy (FIM) imaging and atom probe tomography (APT). While APT provides 3D analytical imaging with sub-nanometer resolution, FIM is capable of imaging the arrangements of single atoms on a crystal lattice and has the potential to provide insights into radiation induced crystal damage, all the way down to its smallest manifestation--a single vacancy. This paper demonstrates the strength of combining these characterization techniques. In ion implanted tungsten, it was found that atomic scale lattice damage is best imaged using FIM. In certain cases, APT reveals an identifiable imprint in the data via the segregation of solute and impurities and trajectory aberrations. In a W-5at%Ta alloy, a combined APT-FIM study was able to determine the atomic distribution of tantalum inside the tungsten matrix. An indirect method was implemented to identify tantalum atoms inside the tungsten matrix in FIM images. By tracing irregularities in the evaporation sequence of atoms imaged with FIM, this method enables the benefit of FIM's atomic resolution in chemical distinction between the two species. PMID- 25794823 TI - IL-17 and neutrophils: unexpected players in the type 2 immune response. AB - The study of immunity to helminth infection has been central to understanding the function of type 2 cytokines and their targets. Although type 2 cytokines are considered anti-inflammatory and promote tissue repair, they also contribute to allergy and fibrosis. Here, we utilise data from helminth infection models, to illustrate that IL-17 and neutrophils, typically associated with pro-inflammatory responses, are intimately linked with type 2 immunity. Neutrophils work with IL 4Ralpha-activated macrophages to control incoming larvae but this comes at a cost of enhanced tissue damage. Chitinase like proteins (CLPs) bridge these diverse outcomes, inducing both protective IL-17 and reparative Th2 responses. Dysregulation of CLPs, IL-17 and neutrophils likely contribute to disease severity and pathology associated with type 2 immunity. PMID- 25794825 TI - Shaping of the tumor microenvironment: Stromal cells and vessels. AB - Lymphomas develop and progress in a specialized tissue microenvironment such as bone marrow as well as secondary lymphoid organs such as lymph node and spleen. The lymphoma microenvironment is characterized by a heterogeneous population of stromal cells, including fibroblastic reticular cells, nurse-like cells, mesenchymal stem cells, follicular dendritic cells, and inflammatory cells such as macrophages, T- and B-cells. These cell populations interact with the lymphoma cells to promote lymphoma growth, survival and drug resistance through multiple mechanisms. Angiogenesis is also recognized as an important factor associated with lymphoma progression. In recent years, we have learned that the interaction between the malignant and non-malignant cells is bidirectional and resembles, at least in part, the pattern seen between non-neoplastic lymphoid cells and the normal microenvironment of lymphoid organs. A summary of the current knowledge of lymphoma microenvironment focusing on the cellular components will be reviewed here. PMID- 25794826 TI - Response to "Does bariatric surgery influence diabetic retinopathy". PMID- 25794824 TI - Endoplasmic reticulum quality control in cancer: Friend or foe. AB - Quality control systems in the endoplasmic reticulum (ER) mediated by unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) ensure cellular function and organismal survival. Recent studies have suggested that ER quality-control systems in cancer cells may serve as a double-edged sword that aids progression as well as prevention of tumor growth in a context dependent manner. Here we review recent advances in our understanding of the complex relationship between ER proteostasis and cancer pathology, with a focus on the two most conserved ER quality-control mechanisms--the IRE1alpha-XBP1 pathway of the UPR and SEL1L-HRD1 complex of the ERAD. PMID- 25794827 TI - Prevalence and predictors of intimate partner violence among women attending infertility clinic in south-western Nigeria. AB - OBJECTIVE: The study evaluated the prevalence and predictors of intimate partner violence among infertile women attending infertility clinic of Ekiti State University Teaching Hospital, Ado-Ekiti. STUDY DESIGN: A cross sectional study of infertile women presenting at the clinic between 1st November 2012 and 31st October 2013 was done. A semi-structured questionnaire on violence was administered to 170 consecutive women who consented to participate. The data were analysed using SPSS 17 and significances test were performed on variables associated with violence with Student's t test and Chi square test. Logistic regression was done to determine predictive factors associated with intimate partner violence. RESULTS: The prevalence of intimate partner violence associated with infertility among the women was 31.2%. There were no significant differences in the age of the women, duration of marriage and duration of infertility between the women who had experienced violence and those who had not experienced it; p>0.05. Unemployment, polygamous marriage, husbands' social habits, primary infertility and prolonged duration of infertility were associated with violence in these women; p<0.05. Education of the women and their husbands, their religion and ethnicity were not significantly associated with violence; p>0.05. However with logistic regression, the unemployment status of the women and prolonged duration of infertility were the predictors of violence against women with infertility in this study, p value<0.05. More than 50% of the women reported psychological violence as the commonest form of violence experienced by them ever, since the diagnosis of infertility was made and in the past one year. All forms of violence experienced were aggravated by infertility in these women. CONCLUSION: Women with infertility are prone to intimate partner violence and this would further aggravate the challenges of infertility being faced by these women. PMID- 25794828 TI - Peritoneal Tumorigenesis and Inflammation are Ameliorated by Humidified-Warm Carbon Dioxide Insufflation in the Mouse. AB - BACKGROUND: Conventional laparoscopic surgery uses CO2 that is dry and cold, which can damage peritoneal surfaces. It is speculated that disseminated cancer cells may adhere to such damaged peritoneum and metastasize. We hypothesized that insufflation using humidified-warm CO2, which has been shown to reduce mesothelial damage, will also ameliorate peritoneal inflammation and tumor cell implantation compared to conventional dry-cold CO2. METHODS: Laparoscopic insufflation was modeled in mice along with anesthesia and ventilation. Entry and exit ports were introduced to maintain insufflation using dry-cold or humidified warm CO2 with a constant flow and pressure for 1 h; then 1000 or 1 million fluorescent-tagged murine colorectal cancer cells (CT26) were delivered into the peritoneal cavity. The peritoneum was collected at intervals up to 10 days after the procedure to measure inflammation, mesothelial damage, and tumor burden using fluorescent detection, immunohistochemistry, and scanning electron microscopy. RESULTS: Rapid temperature control was achieved only in the humidified-warm group. Port-site tumors were present in all mice. At 10 days, significantly fewer tumors on the peritoneum were counted in mice insufflated with humidified-warm compared to dry-cold CO2 (p < 0.03). The inflammatory marker COX-2 was significantly increased in the dry-cold compared to the humidified-warm cohort (p < 0.01), while VEGFA expression was suppressed only in the humidified-warm cohort. Significantly less mesothelial damage and tumor cell implantation was evident from 2 h after the procedure in the humidified-warm cohort. CONCLUSIONS: Mesothelial cell damage and inflammation are reduced by using humidified-warm CO2 for laparoscopic oncologic surgery and may translate to reduce patients' risk of developing peritoneal metastasis. PMID- 25794829 TI - Should Surgery Referral be Standard Practice in Metastatic Inflammatory Breast Cancer? PMID- 25794830 TI - Predicting three-dimensional conformations of peptides constructed of only glycine, alanine, aspartic acid, and valine. AB - The GADV hypothesis is a form of the protein world hypothesis, which suggests that life originated from proteins (Lacey et al. 1999; Ikehara 2002; Andras 2006). In the GADV hypothesis, life is thought to have originated from primitive proteins constructed of only glycine, alanine, aspartic acid, and valine ([GADV] proteins). In this study, the three-dimensional (3D) conformations of randomly generated short [GADV]-peptides were computationally investigated using replica exchange molecular dynamics (REMD) simulations (Sugita and Okamoto 1999). Because the peptides used in this study consisted of only 20 residues each, they could not form certain 3D structures. However, the conformational tendencies of the peptides were elucidated by analyzing the conformational ensembles generated by REMD simulations. The results indicate that secondary structures can be formed in several randomly generated [GADV]-peptides. A long helical structure was found in one of the hydrophobic peptides, supporting the conjecture of the GADV hypothesis that many peptides aggregated to form peptide multimers with enzymatic activity in the primordial soup. In addition, these results indicate that REMD simulations can be used for the structural investigation of short peptides. PMID- 25794831 TI - Silica aerogel for capturing intact interplanetary dust particles for the Tanpopo experiment. AB - In this paper, we report the progress in developing a silica-aerogel-based cosmic dust capture panel for use in the Tanpopo experiment on the International Space Station (ISS). Previous studies revealed that ultralow-density silica aerogel tiles, comprising two layers with densities of 0.01 and 0.03 g/cm(3) developed using our production technique, were suitable for achieving the scientific objectives of the astrobiological mission. A special density configuration (i.e., box framing) aerogel with a holder was designed to construct the capture panels. Qualification tests for an engineering model of the capture panel as an instrument aboard the ISS were successful. Sixty box-framing aerogel tiles were manufactured in a contamination-controlled environment. PMID- 25794832 TI - Peer review at its finest. PMID- 25794833 TI - Uncovering the metabolic complications of androgen deprivation therapy in patients with prostate cancer--where do we take it next? PMID- 25794835 TI - Screening for bladder cancer in individuals with spinal cord injury. PMID- 25794836 TI - Inhibition of water absorption and selective damage to human colonic mucosa induced by Shiga toxin-2 are enhanced by Escherichia coli O157:H7 infection. AB - Shiga toxin-producing Escherichia coli (STEC) strains are responsible for a variety of clinical syndromes including bloody and non-bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Although multiple serotypes of STEC have been isolated from hemorrhagic colitis cases, E. coli O157:H7 is by far the most prevalent serotype associated with HUS. Shiga toxin is the major virulence factor of E. coli O157:H7 and is responsible for the more severe symptoms of the infection. However, the mechanisms involved in the pathogenesis of diarrhea mediated by Stx2 are not well known. In this study, we have determined the effects of E. coli O157:H7 strain 125/99 wild type (wt) on the human colonic mucosa mounted in an Ussing chamber. In response to 125/99wt, an inhibition of water absorption across human colonic mucosa was observed. Histological sections showed severe necrosis with detachment of the surface epithelium, mononuclear inflammatory infiltrate and loss of goblet cells after 1h of incubation with 125/99wt. These alterations were not observed with the isogenic mutant strain lacking stx2 or with the filter-sterilized culture supernatant from the 125/99wt strain. These results indicate that the cell damages in human colon are induced by Stx2, and that Stx2 production is increased by the interaction with bacterial cells. Identification of host cell-derived factors responsible for increasing Stx2 can lead to new strategies for modulating STEC infections. PMID- 25794837 TI - Long term trends of methane, non methane hydrocarbons, and carbon monoxide in urban atmosphere. AB - The concentrations of methane (CH4), non-methane hydrocarbons (NMHC), and carbon monoxide (CO) were measured at two urban locations (Guro (GR) and Nowon (NW)) in Seoul, Korea between 2004 and 2013. The mean amount fractions of CH4, NMHC, and CO, measured at GR over this period were 2.06+/-0.02, 0.32+/-0.03, and 0.61+/ 0.05 ppm, respectively, while at NW they were 2.08+/-0.06, 0.33+/-0.05, and 0.54+/-0.06 ppm, respectively. The ratio of CH4 to the total hydrocarbon amount fraction remained constant across the study years: 0.82 to 0.90 at GR and 0.81 to 0.89 at NW. Similarly, stable ratios were also observed between NMHC and THC at the two sites. In contrast, the annual mean ratios for CH4/NMHC showed a larger variation: between 4.55 to 8.67 at GR and 4.25 to 8.45 at NW. The seasonality of CO was characterized by wintertime maxima, while for CH4 and NMHC the highest amount fractions were found in fall. The analysis of their long-term trends based on Mann-Kendall and Sen's methods showed an overall increase of THC and CH4, whereas a decreasing trend was observed for NMHC and CO. PMID- 25794838 TI - Bayesian estimation of the accuracy of the calf respiratory scoring chart and ultrasonography for the diagnosis of bovine respiratory disease in pre-weaned dairy calves. AB - There is currently no gold standard method for the diagnosis of bovine respiratory disease (BRD) complex in Holstein pre-weaned dairy calves. Systematic thoracic ultrasonography (TUS) has been used as a proxy for BRD, but cannot be directly used by producers. The Wisconsin calf respiratory scoring chart (CRSC) is a simpler alternative, but with unknown accuracy. Our objective was to estimate the accuracy of CRSC, while adjusting for the lack of a gold standard. Two cross sectional study populations with a high BRD prevalence (n=106 pre weaned Holstein calves) and an average BRD prevalence (n=85 pre-weaned Holstein calves) from North America were studied. All calves were simultaneously assessed using CRSC (cutoff used >= 5) and TUS (cutoff used >= 1cm of lung consolidation). Bayesian latent class models allowing for conditional dependence were used with informative priors for BRD prevalence and TUS accuracy (sensitivity (Se) and specificity (Sp)) and non-informative priors for CRSC accuracies. Robustness of the model was tested by relaxing priors for prevalence or TUS accuracy. The SeCRSC (95% credible interval (CI)) and SpCRSC were 62.4% (47.9-75.8) and 74.1% (64.9-82.8) respectively. The SeTUS was 79.4% (66.4-90.9) and SpTUS was 93.9% (88.0-97.6). The imperfect accuracy of CRSC and TUS should be taken into account when using those tools to assess BRD status. PMID- 25794839 TI - Expression of hypoxia-inducible factors and vascular endothelial growth factor during pregnancy in the feline uterus. AB - Hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) have critical roles during the development of the fetomaternal unit. The HIFs regulate placentation and vascularization by stimulation of VEGF gene expression. This study aimed to investigate the expression profiles of HIF gene family and VEGF in the cat uterus during pregnancy. Tissue samples of the whole uterine wall were collected after ovariohysterectomy and allocated to the following groups: embryo positive (group 1 [G1], n = 7, 7 days after mating), early pregnancy (group 2 [G2], n = 7, 20 days after mating), mid-pregnancy (group 3 [G3], n = 7, 24 days after mating), late pregnancy (group 4 [G4], n = 7, 30-45 days after mating), and oocyte positive groups (group 5 [G5], n = 7, 7 days after induction of ovulation with GnRH analog). Relative mRNA levels were determined by real-time polymerase chain reaction. As housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase was used. The relative gene expression of HIF1A in G5 was found to be significantly higher than that of other groups (G1, G2, G3, and G4) (P < 0.05). In addition, the expression of HIF2A in G5 was higher than that of G1 and HIF2A gene expression at placentation sites of G4 was higher than in G1, G2, and G3 (P < 0.05). Immunohistochemistry indicated that HIF1A, HIF2A, and VEGF expressions were observed in different cell types of uterine and placental tissues in late pregnancy and oocyte groups. The expression of HIF3A did not change significantly in any group investigated. These observations suggest that HIFs and VEGF may play a role in the establishment and development of pregnancy. PMID- 25794840 TI - Increased cortisol release and transport stress do not influence semen quality and testosterone release in pony stallions. AB - The use of breeding stallions for equestrian competitions requires that fertility is not negatively affected by competition or transport to the competition site. In this study, effects of cortisol release induced by road transport (600 km), adrenocorticotropic hormone (ACTH) administration (3 * 0.5 mg synthetic ACTH) and placebo treatment on semen quality and testosterone release were investigated in Shetland stallions (N = 13) using a crossover design. Saliva for cortisol and blood for testosterone analysis were collected for 10 weeks after treatments. Semen was collected daily for 5 days directly after treatments and twice weekly for another 9 weeks. Total sperm count, sperm morphology, motility, and membrane integrity were analyzed. We hypothesized that elevated cortisol decreases testosterone concentration and semen quality. Cortisol concentrations increased in response to transport and ACTH (P < 0.001) but not control treatments (peak concentration, transport: 7.6 +/- 2.4, ACTH: 13.7 +/- 1.5, control: 3.8 +/- 0.9 ng/mL). No treatment effects on testosterone existed. Total sperm count decreased with daily semen collections in week 1 (P < 0.01) but did not differ between the treatments. The percentage of motile, progressively motile, membrane-intact, and morphologically defective spermatozoa did not change over time from Days 2 to 6, and there existed no differences between the treatments. In conclusion, road transport evoked a stress response which was mimicked by ACTH treatment. Both treatments had no effect on testosterone release and semen quality. Testicular function in stallions is apparently well protected against transiently elevated cortisol concentrations, and stallions can be transported over longer distances without negatively affecting their fertility. PMID- 25794841 TI - Motility initiation of sterlet sturgeon (Acipenser ruthenus) spermatozoa: Describing the propagation of the first flagellar waves. AB - In the present study, for the first time in fish spermatozoa, we describe the precise chronology of motility initiation of sterlet (sturgeon) sperm from completely immotile flagella to regular full wave propagation. The successive activation steps were investigated by high-speed video microscopy, using specific experimental situation, where sperm motility initiation was delayed in time up to several seconds (10 +/- 2.68 seconds). Starting from fully immotile, the flagellum shows some trembling for a brief period, soon followed by appearance of the first real bend (so-called "principal bend") with a large wave amplitude 4.28 +/- 0.65 MUm, then by the "reverse bend," the latter presenting a lower (P < 0.05) wave amplitude (1.14 +/- 0.32 MUm). This couple of first bends formed at the basal region begins to propagate toward the flagellar tip but gradually fades when reaching the midflagellum, wherein consequently the sperm cell remains nonprogressive. This behavior repeats several times until a stage where the amplitude of the reverse bend gradually reaches a value similar that of the principal bend: The larger amplitude of this couple of bends finally leads to sustain a real "takeoff" of the sperm cell characterized by a full flagellar wave propagation generating an active forward displacement similar to that occurring during regular steady state motility (several seconds after activation). Starting from the earliest stages of motility initiation, the wave propagation along the flagellum and formation of new waves proceeded in a helical manner leading to a 3 dimensional rotation of the whole spermatozoon. Eventually, we estimated that the time period needed from the activation signal (contact with fresh water) to full wave propagation ranges from 0.4 to 1.2 seconds. PMID- 25794842 TI - Insomnia research--Time for "fine-tuning". PMID- 25794843 TI - Nitrogen metabolism, acid-base regulation, and molecular responses to ammonia and acid infusions in the spiny dogfish shark (Squalus acanthias). AB - Although they are ureotelic, marine elasmobranchs express Rh glycoproteins, putative ammonia channels. To address questions raised by a recent study on high environmental ammonia (HEA) exposure, dogfish were intravascularly infused for 24 h at 3 ml kg(-1) h(-1) with isosmotic NaCl (500 mmol l(-1), control), NH4HCO3 (500 mmol l(-1)), NH4Cl (500 mmol l(-1)), or HCl (as 125 mmol l(-1) HCl + 375 mmol l(-1) NaCl). While NaCl had no effect on arterial acid-base status, NH4HCO3 caused mild alkalosis, NH4Cl caused strong acidosis, and HCl caused lesser acidosis, all predominantly metabolic in nature. Total plasma ammonia (T(Amm)) and excretion rates of ammonia (J(Amm)) and urea-N (J(Urea-N)) were unaffected by NaCl or HCl. However, despite equal loading rates, plasma T(Amm) increased to a greater extent with NH4Cl, while J(Amm) increased to a greater extent with NH4HCO3 due to much greater increases in blood-to-water PNH3 gradients. As with HEA, both treatments caused large (90%) elevations of J(Urea-N), indicating that urea-N synthesis by the ornithine-urea cycle (OUC) is driven primarily by ammonia rather than HCO3(-). Branchial mRNA expressions of Rhbg and Rhp2 were unaffected by NH4HCO3 or NH4Cl, but v-type H(+)-ATPase was down-regulated by both treatments, and Rhbg and Na(+)/H(+) exchanger NHE2 were up-regulated by HCl. In the kidney, Rhbg was unresponsive to all treatments, but Rhp2 was up-regulated by HCl, and the urea transporter UT was up-regulated by HCl and NH4Cl. These responses are discussed in the context of current ideas about branchial, renal, and OUC function in this nitrogen-limited predator. PMID- 25794844 TI - Carvacrol modulates voltage-gated sodium channels kinetics in dorsal root ganglia. AB - Recent studies have shown that many of plant-derived compounds interact with specific ion channels and thereby modulate many sensing mechanisms, such as nociception. The monoterpenoid carvacrol (5-isopropyl-2-methylphenol) has an anti nociceptive effect related to a reduction in neuronal excitability and voltage gated Na(+) channels (NaV) inhibition in peripheral neurons. However, the detailed mechanisms of carvacrol-induced inhibition of neuronal NaV remain elusive. This study explores the interaction between carvacrol and NaV in isolated dorsal root ganglia neurons. Carvacrol reduced the total voltage-gated Na(+) current and tetrodotoxin-resistant (TTX-R) Na(+) current component in a concentration-dependent manner. Carvacrol accelerates current inactivation and induced a negative-shift in voltage-dependence of steady-state fast inactivation in total and TTX-R Na(+) current. Furthermore, carvacrol slowed the recovery from inactivation. Carvacrol provoked a leftward shift in both the voltage-dependence of steady-state inactivation and activation of the TTX-R Na(+) current component. In addition, carvacrol-induced inhibition of TTX-R Na(+) current was enhanced by an increase in stimulation frequency and when neurons were pre-conditioned with long depolarization pulse (5s at -50 mV). Taken all results together, we herein demonstrated that carvacrol affects NaV gating properties. The present findings would help to explain the mechanisms underlying the analgesic activity of carvacrol. PMID- 25794845 TI - Rutaecarpine prevented dysfunction of endothelial gap junction induced by Ox-LDL via activation of TRPV1. AB - Gap junctions, which is formed by connexins, has been proved to play an important role in the atherogenesis development. Rutaecarpine was reported to inhibited monocyte migration, which indicates its potential for anti-atherosclerosis activity. This study evaluated the effect of rutaecarpine on endothelial dysfunction, and focused on the regulation of connexin expression in endothelial cells by rutaecarpine. Endothelia damage was induced by exposing HUVEC-12 to Ox LDL (100mg/l) for 24h, which decreased the expression of protective proteins Cx37 and Cx40, but induced atherogenic Cx43 expression, in both mRNA and protein levels, concomitant with the impaired propidium iodide diffusion through the gap junctions. Pretreatment with rutaecarpine effectively recovered the expression of Cx37 and Cx40, but inhibited Cx43 expression, thereby improving gap junction communication and significantly prevented the endothelial dysfunction. Consequently, the cell viability and nitric oxide production were increased, lactate dehydrogenase production was decreased and monocyte adhesion was inhibited. These protective effects of rutaecarpine were remarkably attenuated by pretreatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid subtype 1 (TRPV1). In summary, this study is the first to report that rutaecarpine prevents endothelial injury and gap junction dysfunction induced by Ox-LDL in vitro, which is related to regulation of connexin expression patterns via TRPV1 activation. These results suggest that rutaecarpine has the potential for use as an anti-atherosclerosis agent with a novel mechanism. PMID- 25794846 TI - Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms. AB - The activities of 2-phthalimidethyl nitrate (PTD-NO) and 2-phthalimidethanol (PTD OH) were recently demonstrated in models of pain and inflammation. We expanded our investigation by evaluating their activities in models of nociceptive and inflammatory pain and inflammatory edema, the preliminary pharmacokinetic parameter for PTD-NO and the role of opioid and cannabinoid pathways in the activity of analogs. Per os (p.o.) administration of PTD-NO or PTD-OH, 1h before intraplantar injection of formaldehyde, inhibited both phases of the nociceptive response (500 and 750 mg/kg) and paw edema (125, 250, 500 and 750 mg/kg). After p.o. administration of PTD-NO, peak plasma concentrations of PTD-NO and PTD-OH were found 0.92 and 1.13 h, respectively. The plasma concentrations of PTD-NO were higher than those of PTD-OH. Intraperitoneal (i.p.) administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists (4 or 8 mg/kg, -30 min) or opioid antagonist naltrexone (5 or 10mg/kg, -30 min) did not affect the antinociceptive activities of the analogs. AM251 (8 mg/kg, i.p., -30 min) attenuated the antiedematogenic activity of both analogs, while naltrexone (10mg/kg, i.p., -30 min) only attenuated the antiedematogenic activity of PTD-NO. The antiedematogenic activities of both analogs were not affected by the CB2 cannabinoid antagonist AM630 (4 or 8 mg/kg, i.p., -30 min). Concluding, we expanded the knowledge on the activities of PTD-NO and PTD-OH by showing that these phthalimide analogs also exhibit marked activity in models of nociceptive and inflammatory pain and inflammatory edema. Opioid and cannabinoid mechanisms partially mediate the anti-inflammatory, but not the antinociceptive activity. PMID- 25794848 TI - Trends in children's exposure to second-hand smoke in the INMA-Granada cohort: an evaluation of the Spanish anti-smoking law. AB - The smoke-free legislation implemented in Spain in 2006 imposed a partial ban on smoking in public and work places, but the result did not meet expectations. Therefore, a more restrictive anti-smoking law was passed five years later in 2011 prohibiting smoking in all public places, on public transport, and the workplace. With the objective of assessing the impact of the latter anti-smoking legislation on children's exposure to second-hand smoke (SHS), we assessed parent's smoking habits and children's urine cotinine (UC) concentrations in 118 boys before (2005-2006) and after (2011-2012) the introduction of this law. Repeated cross-sectional follow-ups of the "Environment and Childhood Research Network" (INMA-Granada), a Spanish population-based birth cohort study, at 4-5 years old (2005-2006) and 10-11 years old (2011-2012), were designed. Data were gathered by ad-hoc questionnaire, and median UC levels recorded as an objective indicator of overall SHS exposure. Multivariable logistic regression was used to examine the association between parent's smoking habits at home and SHS exposure, among other potential predictors. An increase was observed in the prevalence of families with at least one smoker (39.0% vs. 50.8%) and in the prevalence of smoking mothers (20.3% vs. 29.7%) and fathers (33.9% vs. 39.0%). Median UC concentration was 8.0ng/mL (interquartile range [IQR]: 2.0-21.8) before legislation onset and 8.7ng/mL (IQR: 2.0-24.3) afterwards. In the multivariable analysis, the smoking status of parents and smoking habits at home were statistically associated with the risk of SHS exposure and with UC concentrations in children. These findings indicate that the recent prohibition of smoking in enclosed public and workplaces in Spain has not been accompanied by a decline in the exposure to SHS among children, who continue to be adversely affected. There is a need to target smoking at home in order to avoid future adverse health effects in a population that has no choice in the acceptance or not of SHS exposure-derived risk. PMID- 25794849 TI - Increased renal cyst density on abdominal CT at 100-kVp compared with 120-kVp: a preliminary evaluation. AB - OBJECTIVE: To compare the radiographic density of renal cysts on contrast enhanced computed tomography (CT) scans performed at tube voltages of 100 versus 120 kVp. METHODS: Thirty-six renal cysts from contrast-enhanced CT performed on 21 subjects at both 120 kVp and 100 kVp were compared by Kolmogorov-Smirnov statistical testing. RESULTS: The radiographic density (mean+/-standard deviation in Hounsfield units) of cysts was greater on 100-kVp than on 120-kVp CT scans for both 5-mm and 2-mm reconstructed slice thicknesses: 16.6+/-5.6 versus 10.9+/-4.9 and 14.1+/-5.6 versus 8.5+/-3.9, respectively. CONCLUSIONS: Decrease in tube voltage significantly increases measured radiographic density of renal cysts on CT. Further studies are indicated to assess the clinical impact of lower-tube voltage CT. PMID- 25794847 TI - Gestational urinary bisphenol A and maternal and newborn thyroid hormone concentrations: the HOME Study. AB - Bisphenol A (BPA), an endocrine disruptor used in consumer products, may perturb thyroid function. Prenatal BPA exposure may have sex-specific effects on thyroid hormones (THs). Our objectives were to investigate whether maternal urinary BPA concentrations during pregnancy were associated with THs in maternal or cord serum, and whether these associations differed by newborn sex or maternal iodine status. We measured urinary BPA concentrations at 16 and 26 weeks gestation among pregnant women in the HOME Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine (T4) and triiodothyronine (T3) were measured in maternal serum at 16 weeks (n=181) and cord serum at delivery (n=249). Associations between BPA concentrations and maternal or cord serum TH levels were estimated by multivariable linear regression. Mean maternal urinary BPA was not associated with cord THs in all newborns, but a 10-fold increase in mean BPA was associated with lower cord TSH in girls (percent change= 36.0%; 95% confidence interval (CI): -58.4, -1.7%), but not boys (7.8%; 95% CI: 28.5, 62.7%; p-for-effect modification=0.09). We observed no significant associations between 16-week BPA and THs in maternal or cord serum, but 26-week maternal BPA was inversely associated with TSH in girls (-42.9%; 95% CI: -59.9, 18.5%), but not boys (7.6%; 95% CI: -17.3, 40.2%; p-for-effect modification=0.005) at birth. The inverse BPA-TSH relation among girls was stronger, but less precise, among iodine deficient versus sufficient mothers. Prenatal BPA exposure may reduce TSH among newborn girls, particularly when exposure occurs later in gestation. PMID- 25794850 TI - Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke. AB - BACKGROUND: Poststroke angiogenesis contributes to long-term recovery after stroke. Signal transducer and activator of transcription-3 (Stat3) is a key regulator for various inflammatory signals and angiogenesis. It was the aim of this study to determine its function in poststroke outcome. METHODS AND RESULTS: We generated a tamoxifen-inducible and endothelial-specific Stat3 knockout mouse model by crossbreeding Stat3(floxed/KO) and Tie2-Cre(ERT2) mice. Cerebral ischemia was induced by 30 minutes of middle cerebral artery occlusion. We demonstrated that endothelial Stat3 ablation did not alter lesion size 2 days after ischemia but did worsen functional outcome at 14 days and increase lesion size at 28 days. At this late time point vascular Stat3 expression and phosphorylation were still increased in wild-type mice. Gene array analysis of a CD31-enriched cell population of the neurovascular niche showed that endothelial Stat3 ablation led to a shift toward an antiangiogenic and axon growth-inhibiting micromilieu after stroke, with an increased expression of Adamts9. Remodeling and glycosylation of the extracellular matrix and microglia proliferation were increased, whereas angiogenesis was reduced. CONCLUSIONS: Endothelial Stat3 regulates angiogenesis, axon growth, and extracellular matrix remodeling and is essential for long-term recovery after stroke. It might serve as a potent target for stroke treatment after the acute phase by fostering angiogenesis and neuroregeneration. PMID- 25794852 TI - Soluble elastin peptides in cardiovascular homeostasis: Foe or ally. AB - Elastin peptides, also known as elastin-derived peptides or elastokines, are soluble polypeptides in blood and tissue. The blood levels of elastin peptides are usually low but can increase during cardiovascular diseases, such as atherosclerosis, aortic aneurysm and diabetes with vascular complications. Generally, elastin peptides are derived from the degradation of insoluble elastic polymers. The biological activities of elastin peptides are bidirectional, e.g., a pro-inflammatory effect on monocyte migration induction vs. a protective effect on vasodilation promotion. However, recent in vivo studies have demonstrated that elastin peptides promote the formation of atherosclerotic plaques in hypercholesterolemic mice and induce hyperglycemia and elevations in plasma lipid levels in fasted mice. More important, the detrimental effects induced by elastin peptides can be largely inhibited by genetic or pharmacological blockade of the elastin receptor complex or by neutralization of an antibody against elastin peptides. These studies indicate new therapeutic strategies for the treatment of cardiovascular diseases by targeting elastin peptide metabolism. Therefore, the goal of this review is to summarize current knowledge about elastin peptides relevant to cardiovascular pathologies to further delineate their potential application in cardiovascular disease. PMID- 25794853 TI - Host-defense peptides of the skin with therapeutic potential: From hagfish to human. AB - It is now well established that peptides that were first identified on the basis of their ability to inhibit growth of bacteria and fungi are multifunctional and so are more informatively described as host-defense peptides. In some cases, their role in protecting the organism against pathogenic microorganisms, although of importance, may be secondary. A previous article in the journal (Peptides 2014; 57:67-77) assessed the potential of peptides present in the skin secretions of frogs for development into anticancer, antiviral, immunomodulatory and antidiabetic drugs. This review aims to extend the scope of this earlier article by focusing upon therapeutic applications of host-defense peptides present in skin secretions and/or skin extracts of species belonging to other vertebrate classes (Agnatha, Elasmobranchii, Teleostei, Reptilia, and Mammalia as represented by the human) that supplement their potential role as anti-infectives for use against multidrug-resistant microorganisms. PMID- 25794851 TI - Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor alpha and gamma, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive. METHODS AND RESULTS: The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E(-/-) mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-) mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2. CONCLUSIONS: FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels. PMID- 25794854 TI - Vanillic acid prevents altered ion pumps, ions, inhibits Fas-receptor and caspase mediated apoptosis-signaling pathway and cardiomyocyte death in myocardial infarcted rats. AB - The present study aims to evaluate the preventive effects of vanillic acid on altered ion pumps, ions and Fas-receptor and caspase mediated apoptosis-signaling pathway and cardiomyocyte death in isoproterenol induced myocardial infarcted rats. Male albino Wistar rats were pretreated with vanillic acid (5 mg/kg and 10 mg/kg body weight) daily for 10 days. After the pretreatment, isoproterenol (100 mg/kg body weight) was injected into rats at an interval of 24h for 2 days to induce myocardial infarction. Isoproterenol induced rats significantly increased activities/levels of serum cardiac markers, plasma lipid peroxidation products, serum uric acid and significantly decreased plasma non-enzymatic antioxidants. Furthermore, isoproterenol significantly altered the activities/levels of ion pumps and ions in the heart. The myocardial expressions of apoptotic genes such as Fas-receptor, caspases-8, -9, and -3 were increased in isoproterenol induced rats. There was a significant increase in cardiomyocyte apoptosis observed in isoproterenol induced rats. Pretreatment with vanillic acid (5 mg/kg and 10 mg/kg body weight) to isoproterenol induced rats showed significant effects on all the biochemical and molecular parameters evaluated. Isolated cardiomyocyte viability by trypan blue exclusion staining also correlated with these biochemical findings. Thus, vanillic acid prevented altered ion pumps, ions and inhibited Fas receptor and caspase mediated apoptosis-signaling pathway and cardiomyocyte death in isoproterenol induced myocardial infarcted rats. Our study also revealed that pretreatment with vanillic acid at the dose of 10 mg/kg body weight was more effective than 5 mg/kg body weight. The cardioprotective effects of vanillic acid are associated with its antioxidant mechanisms. PMID- 25794855 TI - Ischemic preconditioning and postconditioning alleviates hippocampal tissue damage through abrogation of apoptosis modulated by oxidative stress and inflammation during transient global cerebral ischemia-reperfusion in rats. AB - INTRODUCTION: It has been argued recently that ischemic preconditioning (IPre) and postconditioning (IPost) have beneficial effects in many ischemic disorders however; their effects on global ischemia/reperfusion (I/R) are poorly understood. Thus, the present work aimed to study the possible mechanisms underlying the neuroprotective effects of IPre and IPost. METHODS: Animals were randomly allocated into 4 groups (n = 30): (1) Sham operated (SO); (2) I/R group, animals were subjected to 15 min global ischemia followed by 60 min reperfusion; (3) IPre, animals were subjected to 3 episodes of 5 min ischemia followed by 10 min reperfusion before I/R; (4) IPost, animals were subjected to three episodes of 10s of ischemia and 10s of reperfusion after the period of ischemia followed by a 60 min reperfusion period. Lactate dehydrogenase activity, oxidative stress, inflammatory and apoptotic biomarkers, as well as neurotransmitters, infarct size and histopathological examination were assessed. RESULTS: I/R induced hippocampal damage through increasing oxidative stress, inflammatory, excitotoxic and apoptotic markers as well as lactate dehydrogenase activity and infarct size. Both, IPre and IPost attenuated most markers induced by I/R. CONCLUSIONS: IPre and IPost neuroprotective effects can be explained through their anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. PMID- 25794856 TI - A therapeutically relevant, 3,3'-diindolylmethane derivative NGD16 attenuates angiogenesis by targeting glucose regulated protein, 78kDa (GRP78). AB - Angiogenesis remain a critical procedure for tumor progression and malignancy. Anticancer agents targeting angiogenic cascades have been proved to be an effective strategy in the field of cancer therapeutics. The current study aims to explore the mechanistic prevention of angiogenesis and cancer cell proliferation by 1,1'-beta-d-glucopyranosyl-3,3'-bis(5-bromoindolyl)-octyl methane (NGD16), a novel N-glycosylated derivative of 3,3'-diindolylmethane (DIM). NGD16 suppressed the viability of prostate cancer (PC-3), pancreatic adenocarcinoma (MiaPaca-2), colorectal cancer (COLO-205) and human umbilical vein endothelial cells (HUVECs) effectively with IC50 values 0.8 MUM, 2.8 MUM, 5.3 MUM and 2.5 MUM respectively. Abrogation of angiogenesis by NGD16 was promising in in vivo mouse Matrigel plug assay as well as in ex vivo sprouting of rat thoracic aorta. At the molecular level, NGD16 inhibited the expression of glucose regulated protein, 78 kDa (GRP78), vascular endothelial growth factor receptor-2 (VEGFR2) and matrix metalloproteinase-9 (MMP-9) expression, the main mediators of angiogenesis and neovessel formation. Overexpression of GRP78 upregulated the expression of MMP-9 and VEGFR2 in PC-3 and HUVECs. Antibody blocking of GRP78 further potentiated NGD16 in attenuating angiogenesis through inhibition of MMP-9. NGD16 depicted its promising biodistribution profile in a pharmacokinetic study with 46.9% intraperitoneal bioavailability. Our findings suggest NGD16 is a potent inhibitor of neo-angiogenesis with a desirable pharmacokinetic profile, which can be taken forward in its development as an anticancer drug. PMID- 25794857 TI - Functional neuroimaging findings in patients with lateral and mesio-lateral temporal lobe epilepsy; FDG-PET and ictal SPECT studies. AB - The differentiation of combined mesial and lateral temporal onset of seizures (mesio-lateral TLE, MLTLE) from lateral TLE (LTLE) is critical to achieve good surgical outcomes. However, the functional neuroimaging features in LTLE patients based on the ictal onset zone utilizing intracranial EEG (iEEG) in a large series have not been investigated. We enrolled patients diagnosed with MLTLE (n = 35) and LTLE (n = 53) based on the site of ictal onset zone from iEEG monitoring. MLTLE is defined when ictal discharges originate from the mesial and lateral temporal cortices independently, whereas seizures of LTLE arise exclusively from the lateral temporal cortex. Compared to patients with LTLE, patients with MLTLE were more likely to have 18F- fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism and hyperperfusion on ictal single-photon emission computed tomography (SPECT) restricted to the temporal areas. MLTLE patients had more frequent aura or secondarily generalized seizures than LTLE patients. No significant differences were found in scalp EEG, MRI, and Wada asymmetry between groups. The overall seizure-free rate was good (73.8%, mean follow-up = 9.7 years), which was not different (Engel class I, 74.3% in MLTLE vs. 73.6% in LTLE). Postsurgical memory function was spared in LTLE patients, while visual memory was impaired in MLTLE patients when their mesial temporal structures were sufficiently resected. It suggests that functional neuroimaging (interictal PET and ictal and interictal SPECT) may play a crucial role to differentiate between MLTLE and LTLE. PMID- 25794858 TI - Distributed abnormalities of brain white matter architecture in patients with dominant optic atrophy and OPA1 mutations. AB - Using advanced MRI techniques, we investigated the presence and topographical distribution of brain grey matter (GM) and white matter (WM) alterations in dominant optic atrophy (DOA) patients with genetically proven OPA1 mutation as well as their correlation with clinical and neuro-ophthalmologic findings. Nineteen DOA patients underwent neurological, neuro-ophthalmologic and brainstem auditory evoked potentials (BAEP) evaluations. Voxel-wise methods were applied to assess regional GM and WM abnormalities in patients compared to 20 healthy controls. Visual acuity was reduced in 16 patients. Six DOA patients (4 with missense mutations) had an abnormal I peripheral component (auditory nerve) at BAEP. Compared to controls, DOA patients had significant atrophy of the optic nerves (p < 0.0001). Voxel-based morphometry (VBM) analysis showed that, compared to controls, DOA patients had significant WM atrophy of the chiasm and optic tracts; whereas no areas of GM atrophy were found. Tract-based spatial statistics (TBSS) analysis showed that compared to controls, DOA patients had significantly lower mean diffusivity, axial and radial diffusivity in the WM of the cerebellum, brainstem, thalamus, fronto-occipital-temporal lobes, including the cingulum, corpus callosum, corticospinal tract and optic radiation bilaterally. No abnormalities of fractional anisotropy were detected. No correlations were found between volumetric and diffusivity abnormalities quantified with MRI and clinical and neuro-ophthalmologic measures of disease severity. Consistently with pathological studies, tissue loss in DOA patients is limited to anterior optic pathways reflecting retinal ganglion cell degeneration. Distributed abnormalities of diffusivity indexes might reflect abnormal intracellular mitochondrial morphology as well as alteration of protein levels due to OPA1 mutations. PMID- 25794859 TI - Prevalence of vestibular dysfunction in patients with vestibular schwannoma using video head-impulses and vestibular-evoked potentials. AB - We sought to investigate the utility of new non-invasive tests of semicircular canal and otolith function that are usable in the neuro-otology office practice in patients with vestibular schwannoma. Fifty patients with vestibular schwannoma were assessed using a 5-item battery consisting of air-conducted cervical- and bone conducted ocular-vestibular-evoked myogenic potentials (AC cVEMPs and BC oVEMPs) and video head impulse testing (vHIT) in all three canal planes. VEMP asymmetry ratios, latencies, and vHIT gains were used to determine the test sensitivity, relationship with tumour size and the pattern of vestibular nerve involvement. The percentage of abnormalities for each of the five tests for the entire sample ranged between 36.2-61.7%. In 58.3 % of patients, test abnormalities were referable to both superior and inferior vestibular nerve divisions. Selective inferior nerve dysfunction was identified in 10.4% and superior nerve dysfunction in 12.5%. The remaining 18.8% of patients demonstrated a normal test profile. The sensitivity of the 5-item battery increased with tumour size and all patients with medium to large (>14 mm) schwannoma had at least two abnormal vestibular test result. Our results indicate that dysfunction of the superior and inferior vestibular nerve evolves in parallel for most patients with schwannoma. Unexplained vHIT and VEMP asymmetry should alert otologists and neurologists to undertake imaging in patients presenting with non specific disequilibrium or vertigo. PMID- 25794860 TI - Progress in Huntington's disease: the search for markers of disease onset and progression. AB - Unlike most neurodegenerative disorders, individuals at risk from Huntington's disease can be identified prior to the onset of clinical signs of the disease by virtue of it being an autosomal dominant condition. This provides the hypothetical opportunity to delay disease onset and/or slow down the progression of the disease in the very early stages ahead of overt features of disease. To help prepare for therapeutic trials of disease-modifying compounds, extensive work has gone into (1) finding ways of better predicting the onset of disease in pre-manifest HD gene carriers (PMGC), (2) defining the extent of non-motor features of HD and (3) identifying robust and reliable tests by which to measure disease progression. In this short review, we summarise some of the major findings in this area of clinical research. PMID- 25794861 TI - Brain structural abnormalities in patients with major depression with or without generalized anxiety disorder comorbidity. AB - An overlap frequently occurs between major depression disorder (MDD) and generalized anxiety disorder (GAD). Aim of this study was to assess cortical and white matter (WM) alterations in MDD patients with or without GAD comorbidity. Seventy-one MDD patients and 71 controls were recruited. All subjects underwent T1-weighted and diffusion tensor (DT)/MRI. MRI metrics of cortical thickness and WM integrity were obtained from atlas-based cortical regions and the interhemispheric and major long association WM tracts. Between-group MRI comparisons and multiple regressions with clinical scale scores were performed. Compared to controls, both MDD and MDD-GAD patients showed a cortical thinning of the middle frontal cortex bilaterally, left medial frontal gyrus and frontal pole. Compared to controls and MDD patients, MDD-GAD cases also showed a thinning of the right medial orbitofrontal and fusiform gyri, and left temporal pole and lateral occipital cortices. Compared to controls, MDD patients showed DT MRI abnormalities of the right parahippocampal tract and superior longitudinal fasciculus bilaterally, while no WM alterations were found in MDD-GAD. In all patients, brain abnormalities were related with symptom severity. MDD and MDD-GAD share a common pattern of cortical alterations located in the frontal regions. However, while both the cortex and WM integrity are affected in MDD, only the former is affected in MDD-GAD. These findings support the notion of MDD-GAD as a distinct clinical entity, providing insights into patient vulnerability for specific networks as well as into patient resilience factors reflected by the integrity of other cerebral circuits. PMID- 25794862 TI - Use of a telestroke service for evaluation of non-stroke neurological cases. AB - Telemedicine is a growing field in many medical specialties. Within clinical neurosciences one of its largest applications is in acute stroke care. However, little is known about its value and effect in general neurology, despite stroke. In a retrospective survey of 1500 teleconsultations over a time period of 12 months from October 2008 to September 2009, from a large telestroke network in Germany, we evaluated 352 cases with a non-stroke diagnosis. Duration and methods of teleconsultation as well as neurological consultations at bedside and discharge diagnosis were analyzed and compared to stroke cases. Discharge diagnosis was not identical to teleconsultation diagnosis in 48.9% of all non stroke cases compared to 12.5% of all stroke cases. Duration of teleconsultation was 26.5 min in non-stroke cases compared to 14.3 min for stroke cases. In non stroke cases other parts of the neurological examination were added to the pure administration of a stroke scale. There were no significant differences between non-stroke cases with correct and incorrect consultation diagnoses concerning in hospital mortality (4.6 vs. 5.0%) and length of hospital stay (8.3 vs. 7.6 days). We conclude that diagnostic accuracy and protocol routine is not as exact in non stroke cases compared to acute stroke cases. Other neurologic conditions may need different algorithms for a telemedicine service. Thus experience from a telestroke service cannot be transferred to other neurologic conditions on a routine basis. PMID- 25794863 TI - Reduced duration of breastfeeding is associated with a higher risk of multiple sclerosis in both Italian and Norwegian adult males: the EnvIMS study. AB - Breastfeeding for at least 4 months has been found to be associated with a reduced risk of immune-mediated diseases including multiple sclerosis (MS). Using data from a large multinational case-control study (EnvIMS), the association between MS and breastfeeding was investigated in two distinct populations. A questionnaire (EnvIMS-Q) which included a section on feeding during the first year of life was administered to MS cases and to age and sex frequency-matched controls from Italy and Norway. Logistic regression was used to estimate the odds ratio (ORs) and 95% confidence intervals (95% CIs) as a measure of the association between MS and exposure to prolonged breastfeeding (4 months or more, used as the reference category), vs. no breastfeeding or breastfeeding for less than 4 months (reduced exposure). Education, smoking habits, smoking in mother's pregnancy, and other types of milk used in infant feeding were included as covariates. A total of 547 cases and 1039 controls in Italy, and 737 cases and 1335 controls in Norway were studied. The distribution of prolonged (reference) breastfeeding differed between the Norwegian (65.4%) and the Italian (48.9%) study participants. A significant association between MS and reduced/no exposure to breastfeeding was found overall for Italy (OR(adj) = 1.37; 95% CI 1.09, 1.73), but not for Norway (OR(adj) = 1.14; 95% CI 0.92, 1.40). However, only in men, significant associations were observed for both populations (OR(Italy) = 2.33; 95% CI 1.50, 3.65, OR(Norway) = 2.13; 95% CI 1.37, 3.30). Reduced exposure to breastfeeding in males was found to be associated with increased risk of MS in Italy and in Norway. PMID- 25794864 TI - Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. AB - Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) have been identified in families with early-onset spinocerebellar ataxia type 29 (SCA29) and late-onset SCA15, but have not been found in sporadic infantile-onset cerebellar ataxia. We examined if mutations of ITPR1 are also involved in sporadic infantile-onset SCA. Sixty patients with childhood-onset cerebellar atrophy of unknown etiology and their families were examined by whole-exome sequencing. We found de novo heterozygous ITPR1 missense mutations in four unrelated patients with sporadic infantile-onset, nonprogressive cerebellar ataxia. Patients displayed nystagmus, tremor, and hypotonia from very early infancy. Nonprogressive ataxia, motor delay, and mild cognitive deficits were common clinical findings. Brain magnetic resonance imaging revealed slowly progressive cerebellar atrophy. ITPR1 missense mutations cause infantile-onset cerebellar ataxia. ITPR1-related SCA includes sporadic infantile-onset cerebellar ataxia as well as SCA15 and SCA29. PMID- 25794865 TI - Breaking the vicious circle: Onabotulinum toxin A in children with therapy refractory dysfunctional voiding. AB - INTRODUCTION: An increased activity of the external urethral sphincter or pelvic floor muscles during voluntary voiding leads to dysfunctional voiding. Frequently reported symptoms are urinary incontinence, urinary tract infections and high post-void residuals. Dysfunctional voiding is a common problem in school-aged children and despite various treatment options, 10-40% of the children remain therapy-refractory. OBJECTIVE: The aim of this study is to evaluate the effectiveness of Onabotulinum toxin-A (BTX-A) injections in the external urethral sphincter in children with therapy-refractory dysfunctional voiding. PATIENTS AND METHODS: Patients with therapy-refractory dysfunctional voiding who have received BTX-A injections in the external urethral sphincter from 2010 to 2013 were analysed. Children with known neuropsychiatric disorders were excluded. All children had abnormal flow patterns and increased pelvic floor tone during uroflowmetry/EMG studies. They had received at least five sessions of urotherapy and two sessions of pelvic floor physical therapy prior to treatment. A total of 100 IU of BTX-A was injected in the external urethral sphincter at the 3, 9 and 12 o'clock positions. Our main outcome measures were urinary incontinence, recurrent urinary tract infections and post-void residual. RESULTS: A total of twenty patients, of whom 16 girls, with a median age of 9 years (range 5-14) were treated with BTX-A. The median follow-up was 13 months (range 5-34). Post-void residual decreased by 75% after BTX-A, from a median of 47.5 ml (16.3-88.5 ml) to 0 ml (0.0-28.0 ml) (p = 0.001) Six patients had a post-void residual < 20 ml prior to treatment. After BTX-A sixteen patients had a post-void residual <20 ml (Figure). No significant changes in uroflowmetry results was seen. Sixteen children are no longer daily incontinent, of whom 9 became completely dry (p = 0.0001). Eleven patients suffered from recurrent urinary tract infections prior to treatment. After BTX-A five children remained infection free, while the other six experienced only one urinary tract infection during follow-up (p = 0.003). Fourteen patients received additional urotherapy after BTX-A. Repeat injections were necessary in four patients after initial satisfactory results, with repeated good clinical responses. Two children showed no improvement after first BTX-A injection. No serious adverse events were reported. DISCUSSION: The results in this homogenous group of patients confirm the conclusions of previous studies in opting BTX-A in the external urethral sphincter to be a viable treatment option for the therapy-refractory group of patients with dysfunctional voiding. What is new, is that in most of our patients post-injection urotherapy was used to amplify the BTX-A effect. During our long-term follow-up the satisfactory results were sustained, similar to the results of the long-term follow-up presented by Vricella et al. [1]. The retrospective character and relative small sample size are limitations of this study. CONCLUSIONS: This study shows safe and persistent satisfactory results during our average 13-month follow-up in 90% of our patients with therapy-refractory dysfunctional voiding. A prospective study using validated and standardized measurements will be performed to affirm our results and evaluate the exact role of post-injection urotherapy. PMID- 25794866 TI - Hydronephrosis: Comparison of extrinsic vessel versus intrinsic ureteropelvic junction obstruction groups and a plea against the vascular hitch procedure. AB - INTRODUCTION: Pediatric ureteropelvic junction obstruction (UPJO) due to an extrinsic crossing vessel (CV) is rare and often remains undiagnosed preoperatively. Vascular hitch procedures are often performed as associated intrinsic obstruction is not expected. We compared data and intravenous urography (IVU) findings of patients with aberrant CV versus those with intrinsic UPJO, all undergoing open dismembered pyeloplasty. OBJECTIVE: PRIMARY OBJECTIVE: Is accurate pre-operative diagnosis of aberrant CV causing extrinsic UPJO possible? SECONDARY OBJECTIVE: To assess differences in the demographic, clinical, radiological, intra-operative features and postoperative improvement after pyeloplasty between patients with a CV and those with only intrinsic UPJO. PATIENTS AND METHODS: Prospective study of all children below 12 years with UPJO presenting to a tertiary referral centre and who underwent open Anderson - Hynes dismembered pyeloplasty between 2003 and 2013 was conducted. Pre-operative investigations included serial ultrasonography, renal dynamic [ethylene di cysteine (EC)] scan and IVU. These were repeated 3 months after pyeloplasty. Pre operative IVUs of children with CV were compared with the IVUs of an equal number of similar aged children, randomly selected from the intrinsic obstruction group. RESULTS: Pyeloplasty was performed in 643 children during the study period. Data of 33 children with aberrant CVs (mean age 6.99 years) were compared with the remaining 610 children (mean age 3.27 years) with only intrinsic obstruction. Highly significant associations of those with CV included age above 2 years, female gender, associated anomalies, abdominal pain in those above 2 years and poor preoperative function on IVU. Specific IVU features which were statistically highly significant in favor of presence of CV were small, intrarenal and globular flat bottomed pelvis. (Figure) Calyceal dilatation was also more prominent in the CV group. A funnel shaped, extrarenal pelvis was highly significant in favor of intrinsic obstruction. There was associated intrinsic obstruction in addition to CV obstruction in 8 children. All children symptomatically improved after pyeloplasty and did well on long term follow up. The majority showed improvement or stabilization of function on EC scan. DISCUSSION: With the advent of antenatal ultrasonography, most children with UPJO are detected early. Children with CV tend to present later. This is often detected during surgery. Color Doppler is useful but is operator dependant and not performed routinely. In this study, IVU showed the presence of obstruction and loss of function unlike color Doppler, but also revealed specific diagnostic features not previously reported in literature. This can help in accurate preoperative prediction and avoid endopyelotomy, or a dorsal lumbotomy/retroperitoneal approach. Renal function in CVs is expected to be good as the obstruction is thought to be intermittent. However, we noted delayed contrast uptake on IVU in 60.6% and differential renal function on EC scan below 40% in 17 patients (56.6%). These indicate the effect of the obstruction on the renal parenchyma and the importance of early detection. Higher association with other anomalies and higher incidence in females has also not been emphasized in the literature so far. We noted associated intrinsic obstruction in 24.24% patients which is highly significant. This category of patients is likely to be missed and inappropriately treated if a "vascular hitch procedure" is performed. None of our patients had postoperative complications. CONCLUSIONS: Characteristic features were seen on IVU helping in preoperative diagnosis which can be extrapolated to magnetic resonance urography. There is a higher association of CV in age above 2 years, females, associated congenital anomalies, delayed uptake on IVU and differential renal function below 40% compared to intrinsic obstruction. Associated intrinsic obstruction in 24% with no postoperative complications indicates the superiority of dismembered pyeloplasty over vasculopexy procedures. PMID- 25794867 TI - [Analysis of the anatomical sites of 172 lower-limb venous thromboses occurring in a hormonal context in 996 young women; impact of the duplex-Doppler exploration]. AB - AIM: To analyze localizations of duplex ultrasonography-diagnosed lower-limb venous thrombosis in young women in hormonal periods in order to optimize the ultrasound exploration. PATIENTS AND METHODS: From 42,018 standardized ultrasonography report forms, incremented in a database (January 2001 - July 2013), those performed for a first diagnosis of venous thrombosis in women <= 45 years were selected (n = 996). Among those, diagnosed venous thrombosis (n = 172) were classified into three groups: oral contraception (n = 74), pregnancy (n = 39) and post-partum period (n = 59). Clinical symptoms and thrombosis distribution were analyzed. RESULTS: In the contraception group, pulmonary symptoms at presentation were much more frequent than in the obstetrical group: 69% vs 20% (P < 0.001). The thrombosis was limited to the iliac veins in 31% (23/74) and to the left internal iliac vein in six patients. During pregnancy, the thrombosis was limited to the iliac veins in 28% (11/39), and to the left internal iliac vein in two patients. In the post-partum period, superficial venous thromboses were found more frequently (37/59). Among the 22 deep venous thromboses, nine were limited to the proximal segment, including four in the vena cava coming from a right ovarian vein thrombosis. CONCLUSION: Duplex ultrasonography in young women taking oral contraception, as during pregnancy, must target iliac venous segments, especially on the left side, otherwise one thrombosis out of three may be missed; in the post-partum period, the inferior vena cava and superficial veins are to be explored too. PMID- 25794868 TI - The preventive effect of the nordic hamstring exercise on hamstring injuries in amateur soccer players: a randomized controlled trial. AB - BACKGROUND: Hamstring injuries are the most common muscle injuries in soccer, and they have a high rate of recurrence. Eccentric hamstrings strength is recognized as an important modifiable risk factor. This led to the development of prevention exercises such as the nordic hamstring exercise (NHE). The effectiveness of the NHE on hamstring injury prevention has never been investigated in amateur soccer. PURPOSE: To investigate the preventive effect of the NHE on the incidence and severity of hamstring injuries in male amateur soccer players. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Male amateur soccer players (age, mean +/- SD, 24.5 +/- 3.8 years) from 40 teams were randomly allocated to an intervention (n = 20 teams, 292 players) or control group (n = 20 teams, 287 players). The intervention group was instructed to perform 25 sessions of NHE in a 13-week period. Both the intervention and control groups performed regular soccer training and were followed for hamstring injury incidence and severity during the 2013 calendar year. At baseline, personal characteristics (eg, age, injury history, field position) were gathered from all participants via a questionnaire. Primary outcome was injury incidence. Secondary outcomes were injury severity and compliance with the intervention protocol. RESULTS: A total of 38 hamstring injuries were recorded, affecting 36 of 579 players (6.2%). The overall injury incidence rate was 0.7 (95% CI, 0.6-0.8) per 1000 player hours, 0.33 (95% CI, 0.25-0.46) in training, and 1.2 (95% CI, 0.82-1.94) in matches. Injury incidence rates were significantly different between the intervention (0.25; 95% CI, 0.19-0.35) and control groups (0.8; 95% CI, 0.61-1.15), chi(2)(1, n = 579) = 7.865; P = .005. The risk for hamstring injuries was reduced in the intervention group compared with the control group (odds ratio, 0.282; 95% CI, 0.110-0.721) and was statistically significant (P = .005). No statistically significant differences were identified between the intervention and control groups regarding injury severity. Compliance with the intervention protocol was 91%. CONCLUSION: Incorporating the NHE protocol in regular amateur training significantly reduces hamstring injury incidence, but it does not reduce hamstring injury severity. Compliance with the intervention was excellent. PMID- 25794869 TI - The effect of a combined glenoid and Hill-Sachs defect on glenohumeral stability: a biomechanical cadaveric study using 3-dimensional modeling of 142 patients. AB - BACKGROUND: Bone loss in anterior glenohumeral instability occurs on both the glenoid and the humerus; however, existing biomechanical studies have evaluated glenoid and humeral head defects in isolation. Thus, little is known about the combined effect of these bony lesions in a clinically relevant model on glenohumeral stability. HYPOTHESIS/PURPOSE: The purpose of this study was to determine the biomechanical efficacy of a Bankart repair in the setting of bipolar (glenoid and humeral head) bone defects determined via computer-generated 3-dimensional (3D) modeling of 142 patients with recurrent anterior shoulder instability. The null hypothesis was that adding a bipolar bone defect will have no effect on glenohumeral stability after soft tissue Bankart repair. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 142 consecutive patients with recurrent anterior instability were analyzed with 3D computed tomography scans. Two Hill-Sachs lesions were selected on the basis of volumetric size representing the 25th percentile (0.87 cm(3); small) and 50th percentile (1.47 cm(3); medium) and printed in plastic resin with a 3D printer. A total of 21 cadaveric shoulders were evaluated on a custom shoulder-testing device permitting 6 degrees of freedom, and the force required to translate the humeral head anteriorly 10 mm at a rate of 2.0 mm/s with a compressive load of 50 N was determined at 60 degrees of glenohumeral abduction and 60 degrees of external rotation. All Bankart lesions were made sharply from the 2- to 6-o'clock positions for a right shoulder. Subsequent Bankart repair with transosseous tunnels using high-strength suture was performed. Hill-Sachs lesions were made in the cadaver utilizing a plastic mold from the exact replica off the 3D printer. Testing was conducted in the following sequence for each specimen: (1) intact, (2) posterior capsulotomy, (3) Bankart lesion, (4) Bankart repair, (5) Bankart lesion with 2-mm glenoid defect, (6) Bankart repair, (7) Bankart lesion with 2-mm glenoid defect and Hill-Sachs lesion, (8) Bankart repair, (9) Bankart lesion with 4-mm glenoid defect and Hill-Sachs lesion, (10) Bankart repair, (11) Bankart lesion with 6-mm glenoid defect and Hill-Sachs lesion, and (12) Bankart repair. All sequences were used first for a medium Hill-Sachs lesion (10 specimens) and then repeated for a small Hill-Sachs lesion (11 specimens). Three trials were performed in each condition, and the mean value was used for data analysis. RESULTS: A statistically significant and progressive reduction in load to translation was observed after a Bankart lesion was created and with the addition of progressive glenoid defects for each humeral head defect. For medium (50th percentile) Hill-Sachs lesions, there was a 22%, 43%, and 58% reduction in stability with a 2-, 4-, and 6-mm glenoid defect, respectively. For small (25th percentile) Hill-Sachs lesions, there was an 18%, 27%, and 42% reduction in stability with a 2-, 4-, and 6-mm glenoid defect, respectively. With a >=2-mm glenoid defect, the medium Hill-Sachs group demonstrated significant reduction in translation force after Bankart repair (P < .01), and for the small Hill-Sachs group, a >=4-mm glenoid defect was required to produce a statistical decrease (P < .01) in reduction force after repair. CONCLUSION: Combined glenoid and humeral head defects have an additive and negative effect on glenohumeral stability. As little as a 2-mm glenoid defect with a medium-sized Hill-Sachs lesion demonstrated a compromise in soft tissue Bankart repair, while small-sized Hill Sachs lesions showed compromise of soft tissue repair with >=4-mm glenoid bone loss. CLINICAL RELEVANCE: Bipolar bony lesions of the glenoid and humeral head occur frequently together in clinical practice. Surgeons should be aware that the combined defects and glenoid bone loss of 2 to 4 mm or approximately 8% to 15% of the glenoid could compromise Bankart repair and thus may require surgical strategies in addition to traditional Bankart repair alone to optimize stability. PMID- 25794871 TI - Improving Palliative Care Team Meetings: Structure, Inclusion, and "Team Care". AB - Increasing demands on palliative care teams point to the need for continuous improvement to ensure teams are working collaboratively and efficiently. This quality improvement initiative focused on improving interprofessional team meeting efficiency and subsequently patient care. Meeting start and end times improved from a mean of approximately 9 and 6 minutes late in the baseline period, respectively, to a mean of 4.4 minutes late (start time) and ending early in our sustainability phase. Mean team satisfaction improved from 2.4 to 4.5 on a 5-point Likert-type scale. The improvement initiative clarified communication about patients' plans of care, thus positively impacting team members' ability to articulate goals to other professionals, patients, and families. We propose several recommendations in the form of a team meeting "toolkit." PMID- 25794870 TI - The Prevalence of Neuropathic Pain in Terminally Ill Patients With Cancer Admitted to a Palliative Care Unit: A Prospective Observational Study. AB - OBJECTIVE: The primary aim of this study was to determine the prevalence of neuropathic pain (NP) in patients with cancer receiving palliative care. METHODS: In this prospective observational study, terminally ill patients with cancer having NP were identified by a pain management clinician using the diagnostic algorithm of NP from the International Association for the Study of Pain on the day of admission. RESULTS: A total of 220 patients who were hospitalized in the palliative care unit were enrolled in this study. The median survival times were 21.5 days (range, 0-173 days), and 57.7% of patients were male. Among the 220 patients, 41 (18.6%; 95% confidence interval, 13.5%-23.8%) developed NP. CONCLUSION: The prevalence of NP in terminally ill patients with cancer in Japanese palliative care units was 18.6%. PMID- 25794872 TI - Molecular basis of ventilatory disorders. PMID- 25794874 TI - Recombinant Mycobacterium bovis BCG for immunotherapy in nonmuscle invasive bladder cancer. AB - In the past three decades, intravesical instillation of Mycobacterium bovis bacille Calmette-Guerin (BCG) has been used for treating bladder cancer and it still remains at the forefront of immunotherapy for cancer patients. Although BCG based therapy is the most effective intravesical therapy for this kind of tumor and represents the only agent known to reduce progression into muscle invasive bladder cancer, BCG is ineffective in approximately 30-40 % of cases and disease recurs in up to 50 % of patients. Since that BCG is considered an effective vehicle for delivery of antigens due to its unique characteristics, the genetic manipulation of these mycobacteria has been appealing in the search for less toxic and more potent therapeutic agents for bladder cancer immunotherapy. Herein, we discuss current advances in recombinant BCG construction, research, concerns, and future directions to promote the development of this promising immunotherapeutic approach for bladder cancer. PMID- 25794873 TI - Analysis and application of a neutralizing linear epitope on liable toxin B of enterotoxin Escherichia coli. AB - Heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli (ETEC) is one of the major virulence factors for causing diarrhea in piglets, and LT is a strong immunogen. Thus, LT represents an important target for development of vaccines and diagnostic tests. In this study, bioinformatic tools were used to predict six antigenic B cell epitopes in the B subunit of LT protein (LTB) of ETEC strains. Then, seven antigenic B cell epitopes of LTB were identified by polyclonal antisera (polyclonal antibody (PAb)) using a set of LTB-derived peptides expressed as maltose-binding protein (MBP) fusion protein. In addition, one LTB specific monoclonal antibody (MAb) was generated and defined its corresponding epitope as mentioned above. This MAb was able to specifically bind with native LT toxin and has no cross-reaction with LT-II (type II heat-labile enterotoxin), Stx1 (Shiga toxin I), Stx2 (Shiga toxin II), STa (heat-stable enterotoxin I), and STb (heat-stable enterotoxin II) toxins. Further, this MAb was able to interrupt LT toxin specific binding to GM1 receptor, indicating that the corresponding epitope is the specific binding region to GM1 receptor. Moreover, in vitro and in vivo assay showed that the MAb was able to neutralize the native LT toxin. Diarrheal suckling pigs challenged with LT-positive ETEC strain recovered when an enema with this purified MAb was administered. This study will provide the foundation for further studies about the interaction between LT toxin and GM1 receptor and about the developing of epitope-based vaccines and specific therapeutic agent. PMID- 25794875 TI - Acetate is a superior substrate for microbial fuel cell initiation preceding bioethanol effluent utilization. AB - This study assessed cell voltage development, electricity recovery, and microbial community composition in response to initial substrate including acetate, xylose, acetate/xylose 1:1 mixture (ace/xyl), and bioethanol effluent (BE) during microbial fuel cell (MFC) operation at 1000 Omega external resistance. The BE mainly contained 20.5 g/L xylose, 1.8 g/L arabinose, and 2.5 g/L propionic acid. The MFCs initially fed with acetate showed shorter initiation time (1 day), higher average cell voltage (634 +/- 9 mV), and higher coulombic efficiency (31.5 +/- 0.5 %) than those initially fed with ace/xyl or xylose. However, BE-initiated MFCs only generated 162 +/- 1 mV. The acetate-initiated MFCs exhibited longer adaptation time (21 h) and lower cell voltage (645 +/- 10 mV) when the substrate was switched to xylose, whereas substrate switching to BE produced the highest voltage (656 mV), maximum power density (362 +/- 27 mW/m(2)), maximum current density (709 +/- 27 mA/m(2)), and coulombic efficiency (25 +/- 0.5 %) in the acetate-initiated MFCs. The microbial community in acetate-initiated MFCs was less diverse and contained more electrogenic bacteria (13.9 +/- 0.4 %) including Geobacter sulfurreducens and Desulfuromonas acetexigen than the MFCs initially fed with ace/xyl, xylose, and BE. After switching the substrate to xylose and subsequently to BE, the microbial community in the acetate-initiated MFCs became more diverse, while no significant changes were observed in ace/xyl-, xylose-, and BE-initiated MFCs. The results showed that initial substrate affected the power generation and the capability to adapt to the substrate alteration in MFCs. Acetate-initiated MFCs showed best performance in utilizing BE. PMID- 25794876 TI - Marine lectins and their medicinal applications. AB - Marine organisms have been extensively explored for the last several decades as potential sources of novel biologically active compounds, and extensive research has been conducted on lectins. Lectins derived from marine organisms are structurally diverse and also differ from those identified from terrestrial organisms. Marine lectins appear to be particularly useful in some biological applications. They seem to induce negligible immunogenicity because they have a relatively small size, are more stable due to extensive disulfide bridge formation, and have high specificity for complex glyco-conjugates and carbohydrates instead of simple sugars. It is clear that many of them have not yet been extensively studied when compared with their terrestrial counterparts. Marine lectins can be used to design and develop new potentially useful therapeutic agents. This review encompasses recent research on the isolation and identification of marine lectins with potential value in medicinal applications. PMID- 25794877 TI - [Place of limited resections and prognostic factors in non-small lung cancer]. AB - INTRODUCTION: Results of surgery for non-small-cell lung cancer (NSCLC) are poorer after limited resection, wedge and segmentectomy, than after lobectomy. Guidelines recommend avoiding wedge-resection, which new techniques (radiofrequency ablation and cyberknife) tend to replace. This work aimed to study the wedge-resection carcinological value. PATIENTS AND METHODS: NSCLC without previous other cancer history and neoadjuvant therapy measuring less than 31 millimetres and operated from 1980 to 2009 were reviewed. Analyzed variables were: location, gender, age, FEVS, type of resection, histology, pT and pN. RESULTS: There were 66 wedge-resections (10.9%), 32 segmentectomies (5.3%), 507 lobectomies (83.8%), nine postoperative deaths (1.5%), 136 complications (22.5%), 557 complete resections (R0=92%); 72.2% of NSCLC upper lobe location (437/605). Age was more advanced in wedge-resection and segmentectomy, FEVS lower and NSCLC most often a squamous cell pN0 and pStage I carcinoma than in lobectomy. Lymphadenectomy was not performed in half the wedge-resections. Five-year survival rates were poorer after wedge-resection: 50% versus segmentectomy 59.8% (P=0.09), and lobectomy 66% (P=0.0035), but the number of recurrences was similar. Multivariate analysis demonstrated that age, FEVS, type of surgery and lymphadenectomy, pN in pTNM were the only prognosis factors. CONCLUSION: Wedge resection is less carcinological than segmentectomy when the patient-status and NSCLC location allow performing the latter, but more than the new techniques, because of its pathological yield, when the patient-status and nodule peripheral location allow wedging. PMID- 25794878 TI - Non-thyroid cancer in Northern Ukraine in the post-Chernobyl period: Short report. AB - The Chernobyl nuclear power plant accident in Ukraine in 1986 led to widespread radioactive releases into the environment - primarily of radioiodines and cesium heavily affecting the northern portions of the country, with settlement-averaged thyroid doses estimated to range from 10 mGy to more than 10 Gy. The increased risk of thyroid cancer among exposed children and adolescents is well established but the impact of radioactive contamination on the risk of other types of cancer is much less certain. To provide data on a public health issue of major importance, we have analyzed the incidence of non-thyroid cancers during the post Chernobyl period in a well-defined cohort of 13,203 individuals who were <18 years of age at the time of the accident. The report is based on standardized incidence ratio (SIR) analysis of 43 non-thyroid cancers identified through linkage with the National Cancer Registry of Ukraine for the period 1998 through 2009. We compared the observed and expected number of cases in three cancer groupings: all solid cancers excluding thyroid, leukemia, and lymphoma. Our analyses found no evidence of a statistically significant elevation in cancer risks in this cohort exposed at radiosensitive ages, although the cancer trends, particularly for leukemia (SIR=1.92, 95% confidence interval: 0.69; 4.13), should continue to be monitored. PMID- 25794880 TI - Glycemic control and clinic attendance of emerging adults with type 1 diabetes at a transition care clinic. AB - BACKGROUND: Emerging adulthood is a challenging period for diabetes management. Our aim was to determine whether a dedicated transition clinic for emerging adults with type 1 diabetes can improve glycemic control and visit attendance. METHODS: An observational study of 53 emerging adults (30 males) treated during 2010-2014 in a newly established transition clinic. The clinic was operated jointly by pediatric and adult endocrinologists and included a transition coordinator. Data collected included the source of referral, HbA1c levels, frequency of visit attendance, and acute complications. For 27 patients who had attended the pediatric clinic at the same medical center, data from up to 2 years preceding the transition were also collected. Patients filled the Diabetes Quality of Life-Youth questionnaire at the transition and 1 year later. RESULTS: Mean +/- SD age at the transfer to the transition clinic was 22.1 +/- 2.7 years; mean disease duration was 8.4 +/- 5.0 years. Follow-up duration at the transition clinic was 1.2 +/- 1.1 years. Mean HbA1c levels decreased from 67 mmol/mol (95 % CI 63-72) [8.3 % (95 % CI 7.9-8.7)] at transfer to 57 mmol/mol (95 % CI 52-63) [7.4 % (95 % CI 6.9-7.9)] after 1 year (p < 0.001). Thirty-six patients (68 %) attended three or more visits during their first year in the transition clinic. The impact of diabetes on quality of life, disease-related worries, and life satisfaction did not change significantly during 1-year attendance in the transition clinic. CONCLUSIONS: A dedicated transition clinic for emerging adults, with tailored support according to the developmental needs of emerging adulthood, showed improved glycemic control and visit attendance. PMID- 25794879 TI - Cut-off points of homeostasis model assessment of insulin resistance, beta-cell function, and fasting serum insulin to identify future type 2 diabetes: Tehran Lipid and Glucose Study. AB - AIMS: To determine cut-off points of homeostasis model assessment of insulin resistance (HOMA-IR), beta-cell function (HOMA-B), insulin sensitivity (HOMA-S), and fasting insulin for identifying the subjects with type 2 diabetes mellitus (T2DM) in Iranian adults using data from a prospective population-based study. METHODS: From participants of Tehran Lipid and Glucose Study, 4942 Iranian subjects, aged 20-86 years, were followed for incident T2DM. Fasting serum insulin was determined by the electrochemiluminescence immunoasaay. The associations between HOMA-IR, HOMA-B, HOMA-S, and fasting insulin and incident T2DM were evaluated using Cox proportional hazards models. The receiver operator characteristic curve analysis was used to determine the cut-off points of HOMA IR, HOMA-B, HOMA-S, and fasting insulin. RESULTS: After 9.2 year follow-up, 346 (7.0 %) incident cases of T2DM were identified; the risk-factor-adjusted hazard ratios for HOMA1-IR, HOMA2-IR, HOMA1-B, HOMA2-B, HOMA1-S, HOMA2-S, and insulin were 1.15, 1.70, 0.732, 0.997, 0.974, 0.986, and 1.01 in women and 1.37, 1.67, 0.588, 0.993, 0.986, 0.991, and 1.06 in men, respectively (all p < 0.05 except for HOMA2-B in women). Optimal cut-off points for HOMA1-IR, HOMA2-IR, HOMA1-B, HOMA2-B, HOMA1-S, HOMA2-S, and insulin were 1.85, 1.41, 86.2, 72.5, 54.1, 63.7, and 11.13 uU/ml in women and 2.17, 1.18, 67.1, 74.6, 46.1, 74.1, and 9.16 uU/ml in men, respectively. CONCLUSIONS: HOMA-IR, HOMA-B (except for HOMA2-B in women), HOMA-S, and fasting insulin were independent predictors of T2DM. Optimal cut-off points of HOMA-IR, HOMA-B, HOMA-S, and fasting serum insulin were determined from a population-based study for identifying incident T2DM. PMID- 25794881 TI - The mRNA expressions and immunohistochemistry of factors involved in angiogenesis and lymphangiogenesis in the early stage of rat skin incision wounds. AB - Wound healing evaluation is important in forensic pathology, in which angiogenesis plays an important role. We have already shown that vascular endothelial growth factor A (VEGF) is produced in the rat skin incision wounds by neutrophils, endothelial cells, and fibroblasts. In this study, we assessed the changes in the mRNA expressions of various factors possibly involved in angiogenesis including angiopoietin (ANGPT) 1 and 2, cadherin 5 (CDH5), granulocyte-macrophage colony stimulating factor (CSF2/GM-CSF), granulocyte colony stimulating factor (CSF3/G-CSF), chemokine (C-X-C motif) ligand 2 (CXCL2), chemokine (C-X-C motif) ligand12 (CXCL12/SDF1), endothelin 1 (ET1), fibroblast growth factor 1 (FGF 1), hepatocyte growth factor (HGF), hypoxia inducible factor 1 alpha (HIF1a), leptin, matrix metallopepitidase 9 (MMP9), serpine/plasminogen activator inhibitor1 (PAI1), platelet-derived growth factor-A (PDGF-A), transforming growth factor alpha and beta 1 (TGFa and b1), tenomodulin (TNMD), and troponin I type 2 (TNNI2) in the early stage of the rat skin incision wounds by real time RT-PCR. Factors reported to be involved in lymphangiogenesis such as fibroblast growth factor 2 (FGF 2), c-fos induced growth factor (FIGF/VEGF-D), forkhead box C2 (FOXC2), and prospero homeobox 1 (PROX1) were also studied. One and 3 days after the dorsal skin incisions, wounds on male Sprague-Dawley rats showed the statistically significant increases in the mRNA expressions for CXCL2, CSF3, MMP9, PAI1, and CSF2, whereas TGFa, TNNI2, FGF1, TNMD, leptin, and CXCL12 showed the statistically significant decreases. Interestingly, lymphgangiogenic factors FOXC2, PROX1, and FGF2 also showed the statistically significant decreases. In situ hybridization and immunohistochemistry showed the mRNA and protein positivity in endothelial cells, fibroblasts, and some leukocytes at the bottom of the wound tissue for PAI1, CSF3, and MMP9, 1 day after the skin incisions. Our novel findings show the possible involvement of several factors involved in angiogenesis and lymphangiogenesis in the early stage of wound healing process, which may be useful for forensic wound evaluations. PMID- 25794882 TI - Anonymising and sharing individual patient data. PMID- 25794883 TI - Multiple frailty model for clustered interval-censored data with frailty selection. AB - Interval-censored time-to-event data often occur in studies of diseases where the symptoms of interest are not directly observable but require lab examinations for detection. Furthermore, the independence assumption among observations may not be valid if they are from clusters. Some methods have been developed for analysing clustered interval-censored data with a shared frailty to account for overall heterogeneity. In this paper, we propose a multiple frailty proportional hazards model, where we not only account for the baseline heterogeneity and effect variation across clusters for predictors, but also quantify the probabilities of the existence of such frailties. This proposed model will be especially useful for analysing multi-center randomised clinical trials for HIV, infections or progression-free survival in oncology studies. PMID- 25794884 TI - Precision medicine initiative in the offing. PMID- 25794885 TI - Corrigendum on. Total wrist arthroplasty: a systematic review of the evidence from the last 5 years. PMID- 25794886 TI - A valuable surgical technique to remove a loose fragment Kirschner wire from the carpal bones. PMID- 25794887 TI - Outcome of two types of surgical correction of the extra phalanx in triphalangeal thumb: is there a difference? AB - The surgical strategy of treatment of the opposable triphalangeal thumb is correction of the radio-ulnar deviation, reduction of the additional length and joint stabilization. The commonest procedures are: (1) removal of the extra phalanx and stabilization of the remaining joint; and (2) a combined reduction osteotomy with resection of the distal joint followed by arthrodesis. We treated 20 patients (33 hands). In 17 hands the extra phalanx was removed, and in 16 hands we used the combined osteotomy procedure of distal joint removal and arthrodesis. None of the patients in either group had an unstable interphalangeal joint. The mean radial or ulnar deviation in the interphalangeal joint was 5 degrees degrees and 9 degrees , respectively. Mean active flexion in the interphalangeal joint was 35 degrees and 46 degrees , respectively, in the two groups. Results for both procedures are similar, for both objective measures and self-rated function and activities of daily living. Either surgical approach seems reliable.Therapeutic, Level of evidence: Level III. PMID- 25794888 TI - Cancer-specific mortality of Asian Americans diagnosed with cancer: a nationwide population-based assessment. AB - BACKGROUND: Racial disparities in cancer survival outcomes have been primarily attributed to underlying biologic mechanisms and the quality of cancer care received. Because prior literature shows little difference exists in the socioeconomic status of non-Hispanic whites and Asian Americans, any difference in cancer survival is less likely to be attributable to inequalities of care. We sought to examine differences in cancer-specific survival between whites and Asian Americans. METHODS: The Surveillance, Epidemiology, and End Results Program was used to identify patients with lung (n = 130 852 [16.9%]), breast (n = 313 977 [40.4%]), prostate (n = 166 529 [21.4%]), or colorectal (n = 165 140 [21.3%]) cancer (the three leading causes of cancer-related mortality within each sex) diagnosed between 1991 and 2007. Fine and Gray's competing risks regression compared the cancer-specific mortality (CSM) of eight Asian American groups (Chinese, Filipino, Hawaiian/Pacific Islander, Japanese, Korean, other Asian, South Asian [Indian/Pakistani], and Vietnamese) to non-Hispanic white patients. All P values were two-sided. RESULTS: In competing risks regression, the receipt of definitive treatment was an independent predictor of CSM (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.35 to 0.40; HR = 0.55, 95% CI = 0.53 to 0.58; HR = 0.61, 95% CI = 0.60 to 0.62; and HR = 0.27, 95% CI = 0.25 to 0.29) for prostate, breast, lung, and colorectal cancers respectively, all P < .001). In adjusted analyses, most Asian subgroups (except Hawaiians and Koreans) had lower CSM relative to white patients, with hazard ratios ranging from 0.54 (95% CI = 0.38 to 0.78) to 0.88 (95% CI = 0.84 to 0.93) for Japanese patients with prostate and Chinese patients with lung cancer, respectively. CONCLUSIONS: Despite adjustment for potential confounders, including the receipt of definitive treatment and tumor characteristics, most Asian subgroups had better CSM than non Hispanic white patients. These findings suggest that underlying genetic/biological differences, along with potential cultural variations, may impact survival in Asian American cancer patients. PMID- 25794889 TI - miR-Test: a blood test for lung cancer early detection. AB - Lung cancer is the leading cause of cancer death worldwide. Low-dose computed tomography screening (LDCT) was recently shown to anticipate the time of diagnosis, thus reducing lung cancer mortality. However, concerns persist about the feasibility and costs of large-scale LDCT programs. Such concerns may be addressed by clearly defining the target "high-risk" population that needs to be screened by LDCT. We recently identified a serum microRNA signature (the miR Test) that could identify the optimal target population. Here, we performed a large-scale validation study of the miR-Test in high-risk individuals (n = 1115) enrolled in the Continuous Observation of Smoking Subjects (COSMOS) lung cancer screening program. The overall accuracy, sensitivity, and specificity of the miR Test are 74.9% (95% confidence interval [CI] = 72.2% to 77.6%), 77.8% (95% CI = 64.2% to 91.4%), and 74.8% (95% CI = 72.1% to 77.5%), respectively; the area under the curve is 0.85 (95% CI = 0.78 to 0.92). These results argue that the miR Test might represent a useful tool for lung cancer screening in high-risk individuals. PMID- 25794891 TI - Developing an Evaluation Tool for Assessing Clinical Ethics Consultation Skills in Simulation Based Education: The ACES Project. AB - The American Society for Bioethics and Humanities has created a quality attestation (QA) process for clinical ethics consultants; the pilot phase of reviewing portfolios has begun. One aspect of the QA process which is particularly challenging is assessing the interpersonal skills of individual clinical ethics consultants. We propose that using case simulation to evaluate clinical ethics consultants is an approach that can meet this need provided clear standards for assessment are identified. To this end, we developed the Assessing Clinical Ethics Skills (ACES) tool, which identifies and specifies specific behaviors that a clinical ethics consultant should demonstrate in an ethics case simulation. The aim is for the clinical ethics consultant or student to use a videotaped case simulation, along with the ACES tool scored by a trained rater, to demonstrate their competence as part of their QA portfolio. The development and piloting of the tool is described. PMID- 25794890 TI - Timing of adjuvant surgical oophorectomy in the menstrual cycle and disease-free and overall survival in premenopausal women with operable breast cancer. AB - BACKGROUND: For women with hormone receptor-positive, operable breast cancer, surgical oophorectomy plus tamoxifen is an effective adjuvant therapy. We conducted a phase III randomized clinical trial to test the hypothesis that oophorectomy surgery performed during the luteal phase of the menstrual cycle was associated with better outcomes. METHODS: Seven hundred forty premenopausal women entered a clinical trial in which those women estimated not to be in the luteal phase of their menstrual cycle for the next one to six days (n = 509) were randomly assigned to receive treatment with surgical oophorectomy either delayed to be during a five-day window in the history-estimated midluteal phase of the menstrual cycles, or in the next one to six days. Women who were estimated to be in the luteal phase of the menstrual cycle for the next one to six days (n = 231) were excluded from random assignment and received immediate surgical treatments. All patients began tamoxifen within 6 days of surgery and continued this for 5 years. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess differences in five-year disease-free survival (DFS) between the groups. All statistical tests were two-sided. RESULTS: The randomized midluteal phase surgery group had a five-year DFS of 64%, compared with 71% for the immediate surgery random assignment group (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 0.91 to 1.68, P = .18). Multivariable Cox regression models, which included important prognostic variables, gave similar results (aHR = 1.28, 95% CI = 0.94 to 1.76, P = .12). For overall survival, the univariate hazard ratio was 1.33 (95% CI = 0.94 to 1.89, P = .11) and the multivariable aHR was 1.43 (95% CI = 1.00 to 2.06, P = .05). Better DFS for follicular phase surgery, which was unanticipated, proved consistent across multiple exploratory analyses. CONCLUSIONS: The hypothesized benefit of adjuvant luteal phase oophorectomy was not shown in this large trial. PMID- 25794893 TI - RNAi construct of a cytochrome P450 gene CYP82D109 blocks an early step in the biosynthesis of hemigossypolone and gossypol in transgenic cotton plants. AB - Naturally occurring terpenoid aldehydes from cotton, such as hemigossypol, gossypol, hemigossypolone, and the heliocides, are important components of disease and herbivory resistance in cotton. These terpenoids are predominantly found in the glands. Differential screening identified a cytochrome P450 cDNA clone (CYP82D109) from a Gossypium hirsutum cultivar that hybridized to mRNA from glanded cotton but not glandless cotton. Both the D genome cotton Gossypium raimondii and A genome cotton Gossypium arboreum possessed three additional paralogs of the gene. G. hirsutum was transformed with a RNAi construct specific to this gene family and eight transgenic plants were generated stemming from at least five independent transformation events. HPLC analysis showed that RNAi plants, when compared to wild-type Coker 312 (WT) plants, had a 90% reduction in hemigossypolone and heliocides levels, and a 70% reduction in gossypol levels in the terminal leaves, respectively. Analysis of volatile terpenes by GC-MS established presence of an additional terpene (MW: 218) from the RNAi leaf extracts. The (1)H and (13)C NMR spectroscopic analyses showed this compound was delta-cadinen-2-one. Double bond rearrangement of this compound gives 7 hydroxycalamenene, a lacinilene C pathway intermediate. delta-Cadinen-2-one could be derived from delta-cadinene via a yet to be identified intermediate, delta cadinen-2-ol. The RNAi construct of CYP82D109 blocks the synthesis of desoxyhemigossypol and increases the induction of lacinilene C pathway, showing that these pathways are interconnected. Lacinilene C precursors are not constitutively expressed in cotton leaves, and blocking the gossypol pathway by the RNAi construct resulted in a greater induction of the lacinilene C pathway compounds when challenged by pathogens. PMID- 25794894 TI - Sterols from Hericium erinaceum and their inhibition of TNF-alpha and NO production in lipopolysaccharide-induced RAW 264.7 cells. AB - Erinarols G-J and 10 known ergostane-type sterols were isolated from a methanol extract of the dried fruiting bodies of Hericium erinaceum. Their chemical structures were elucidated using extensive spectroscopic analyses including 1D and 2D NMR experiments and HR-ESI-MS analysis, as well as through comparison with previously reported data. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cells. The results showed that erinarols H and J, as well as 2 of the ergostane-type sterols exhibited inhibitory activity against TNF-alpha secretion, with inhibition values ranging from 33.7% to 43.3% at 10 MUM. Erinarols J and three ergostane-type sterols exhibited significant inhibitory effects against NO production, with inhibition values ranging from 38.4% to 71.5% at 10 MUM. PMID- 25794892 TI - Inosculation of blood vessels allows early perfusion and vitality of bladder grafts--implications for bioengineered bladder wall. AB - Bioengineered bladder tissue is needed for patients with neurogenic bladder disease as well as for cancer. Current technologies in bladder tissue engineering have been hampered by an inability to efficiently initiate blood supply to the graft, ultimately leading to complications that include graft contraction, ischemia, and perforation. To date, the biological mechanisms of vascularization on transplant have not been suitably investigated for urologic tissues. To better understand the mechanisms of neovascularization on bladder wall transplant, a chimeric mouse model was generated such that angiogenesis and vasculogenesis could be independently assessed in vivo. Green fluorescence protein (GFP) transgenic mice received bone marrow transplants from beta-galactosidase (LacZ) transgenic animals and then subsequent bladder wall transplants from wild-type donor mice. Before euthanization, the aorta was infused with fluorescent microbeads (fluorospheres) to identify perfused vessels. The contributions of GFP (angiogenesis) and LacZ (vasculogenesis) to the formation of CD31-expressing blood vessels within the wild-type graft were evaluated by immunohistochemistry at different time points and locations within the graft (proximal, middle, and distal) to provide a spatiotemporal analysis of neovascularization. The GFP index, a measure of angiogenic host ingrowth, was significantly higher at proximal versus mid or distal regions in animals 2-16 weeks post-transplant. However, GFP index did not increase over time in any area. Within 7 days post transplant, perfusion of primarily wild-type, donor blood vessels in the most distal areas of the graft was observed by intraluminal fluorospheres. In addition, chimeric host-donor (GFP-wild type) blood vessels were evident in proximal areas. The contribution of vasculogenesis to vascularization of the graft was limited, as LacZ cells were not specifically associated with the endothelial cells of blood vessels, but rather found primarily in areas of inflammation. The data suggest that angiogenesis of host blood vessels into the proximal region leads to inosculation between host and donor vessels and subsequent perfusion of the graft via pre-existing graft vessels within the first week after transplant. As such, the engineering of graft blood vessels and the promotion of inosculation might prevent graft contraction, thereby potentiating the use of bioengineered bladder tissue for transplantation. PMID- 25794895 TI - Sphingolipid metabolism is strikingly different between pollen and leaf in Arabidopsis as revealed by compositional and gene expression profiling. AB - Although sphingolipids are essential for male gametophytic development in Arabidopsis thaliana, sphingolipid composition and biosynthetic gene expression have not been previously examined in pollen. In this report, electrospray ionization (ESI)-MS/MS was applied to characterization of sphingolipid compositional profiles in pollen isolated from wild type Arabidopsis Col-0 and a long-chain base (LCB) Delta4 desaturase mutant. Pollen fractions were highly enriched in glucosylceramides (GlcCer) relative to levels previously reported in leaves. Accompanying the loss of the Delta4 unsaturated LCB sphingadiene (d18:2) in the Delta4 desaturase mutant was a 50% reduction in GlcCer concentrations. In addition, pollen glycosylinositolphosphoceramides (GIPCs) were found to have a complex array of N-acetyl-glycosylated GIPCs, including species with up to three pentose units that were absent from leaf GIPCs. Underlying the distinct sphingolipid composition of pollen, genes for key biosynthetic enzymes for GlcCer and d18:2 synthesis and metabolism were more highly expressed in pollen than in leaves or seedlings, including genes for GlcCer synthase (GCS), sphingoid base C 4 hydroxylase 2 (SBH2), LCB Delta8 desaturases (SLD1 and SLD2), and LOH2 ceramide synthase (LOH2). Overall, these findings indicate strikingly divergent sphingolipid metabolism between pollen and leaves in Arabidopsis, the significance of which remains to be determined. PMID- 25794896 TI - From 2000years of Ganoderma lucidum to recent developments in nutraceuticals. AB - Medicinal mushrooms have been used for centuries as nutraceuticals to improve health and to treat numerous chronic and infectious diseases. One such mushroom is Ganoderma lucidum, commonly known as Lingzhi, a species revered as a medicinal mushroom for treating assorted diseases and prolonging life. The fungus is found in diverse locations, and this may have contributed to confusion regarding the correct taxonomic classification of the genus Ganoderma. G. lucidum was first used to name a specimen found in England and thereafter was naively applied to a different Ganoderma species found in Asia, commonly known as Chinese Lingzhi. Despite the taxonomic confusion, which has largely been uncorrected, the popularity of Lingzhi has escalated across the globe. The current taxonomic situation is now discussed accurately in this Special Issue on Ganoderma. Today it is a multi-billion dollar industry wherein Lingzhi is cultivated or collected from the wild and consumed as a tea, in alcoholic beverages, and as a nutraceutical to confer numerous health benefits. Consumption of nutraceuticals has grown in popularity, and it is becoming increasingly important that active ingredients be identified and that suppliers make substantiated health claims about their products. The objective of this article is to present a review of G. lucidum over the past 2000 years from prized ancient "herbal" remedy to its use in nutraceuticals and to the establishment of a 2.5 billion $ (US) industry. PMID- 25794897 TI - Provider management of equivocal cervical cancer screening results among underserved women, 2009-2011: follow-up of atypical squamous cells of undetermined significance. AB - PURPOSE: Reflex human papillomavirus (HPV) testing is the preferred triage option for most women diagnosed with atypical squamous cells of undetermined significance (ASC-US). This study was conducted to describe follow-up results of women with ASC-US Pap test results in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), focusing on HPV test use. METHODS: We examined the follow-up of 45,049 women in the NBCCEDP with ASC-US Pap tests during 2009 2011. Data on demographic characteristics, diagnostic procedures, and clinical outcomes were analyzed. RESULTS: NBCCEDP providers diagnosed 45,049 women (4.5 % of all Pap tests) with an ASC-US result. Of those, 28,271 (62.8 %) were followed with an HPV test, 3,883 (8.6 %) with a repeat Pap test, 6,592 (14.6 %) with colposcopy, and 6,303 were lost to follow-up (14.0 %). Women aged 40 and older were followed more often with an HPV test. White, black, and Asian/Pacific Islander women were followed more often with an HPV test after an ASC-US Pap compared to Hispanic and American Indian/Alaska Native (AI/AN) women. Among women with a positive HPV test on follow-up, almost 90 % continued with colposcopy as recommended. AI/AN women had the highest rates of HPV positivity (55.2 %) and of no follow-up (25.0 %). CONCLUSION: This is the first analysis describing follow up of ASC-US Pap test results in the NBCCEDP, providing a window into current management of ASC-US results. Findings raise concerns about persistent disparities among AI/AN women. During 2009-2011, nearly two-thirds of women with an ASC-US Pap test result were followed with an HPV reflex test. PMID- 25794898 TI - Forward. The reach and health impacts of the national breast and cervical cancer early detection program. PMID- 25794900 TI - Chinese Academic Assessment and Incentive System. AB - The Chinese academic assessment and incentive system drew mixed responses from academia. In the essay the author tried to explain why the current assessment system is appropriate in China and an opportunistic behavior in Chinese academia is exposed. PMID- 25794899 TI - Variability of the pullout strength of cancellous bone screws with cement augmentation. AB - BACKGROUND: Orthopaedic surgeons often face clinical situations where improved screw holding power in cancellous bone is needed. Injectable calcium phosphate cements are one option to enhance fixation. METHODS: Paired screw pullout tests were undertaken in which human cadaver bone was augmented with calcium phosphate cement. A finite element model was used to investigate sensitivity to screw positional placement. FINDINGS: Statistical analysis of the data concluded that the pullout strength was generally increased by cement augmentation in the in vitro human cadaver tests. However, when comparing the individual paired samples there were surprising results with lower strength than anticipated after augmentation, in apparent contradiction to the generally expected conclusion. Investigation using the finite element model showed that these strength reductions could be accounted for by small screw positional changes. A change of 0.5mm might result in predicted pullout force changes of up to 28%. INTERPRETATION: Small changes in screw position might lead to significant changes in pullout strength sufficient to explain the lower than expected individual pullout values in augmented cancellous bone. Consequently whilst the addition of cement at a position of low strength would increase the pullout strength at that point, it might not reach the pullout strength of the un-augmented paired test site. However, the overall effect of cement augmentation produces a significant improvement at whatever point in the bone the screw is placed. The use of polymeric bone-substitute materials for tests may not reveal the natural variation encountered in tests using real bone structures. PMID- 25794901 TI - Different antimicrobial susceptibility testing methods to detect ertapenem resistance in Enterobacteriaceae: VITEK2, MicroScan, Etest, disk diffusion, and broth microdilution. AB - We investigated different antimicrobial susceptibility testing methods to detect ertapenem resistance in Enterobacteriaceae. A total of 72 Enterobacteriaceae isolates were collected from a clinical microbiology laboratory of a tertiary university hospital, all of which were detected ertapenem resistance by the VITEK2 system. Bacterial identification and antimicrobial susceptibility were determined using the VITEK2. Ertapenem susceptibility test was performed using the MicroScan, Etest and a disk diffusion test. Ertapenem MICs were confirmed using the broth microdilution (BMD). Sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) of each method for the detection of ertapenem resistance were calculated. Carbapenemases and AmpC beta lactamase were screened using phenotypic methods. Among the 72 isolates, 20 isolates (27.8%) were resistant to ertapenem. Etest showed high sensitivity and specificity (85.0% and 88.5%, respectively) and excellent concordance with BMD. The disk diffusion test had the lowest sensitivity of 50.0%. The VITEK2 showed the lowest essential and categorical agreement (30.5% and 27.8%, respectively). The MicroScan showed relatively good agreement with BMD compared to the VITEK2. Most category disagreements were minor errors. There were 3 very major errors in both the MicroScan and disk diffusion test. Only 1 isolate was positive for carbapenemase screening test and all of the isolates were positive for AmpC screening test. In conclusion, the detection of ertapenem resistance in Enterobacteriaceae has limitations using routine testing such as an automated system or disk diffusion. Confirmation of results by an additional MIC test is recommended for accurate resistance results of ertapenem. PMID- 25794902 TI - Rapid real-time PCR methods to distinguish Salmonella Enteritidis wildtype field isolates from vaccine strains Salmovac SE/Gallivac SE and AviPro SALMONELLA VAC E. AB - Salmonella enterica serovar Enteritidis is a major non-typhoid Salmonella serovar causing human salmonellosis mainly associated with the consumption of poultry and products thereof. To reduce infections in poultry, S. Enteritidis live vaccine strains AviPro SALMONELLA VAC E and Salmovac SE/Gallivac SE have been licensed and used in several countries worldwide. To definitively diagnose a S. Enteritidis contamination in vaccinated herds a reliable and fast method for the differentiation between vaccine and wildtype field isolates is required. In this study, we developed and validated real-time PCR (qPCR) assays to distinguish those variants genetically. Suitable target sequences were identified by whole genome sequencing (WGS) using the Illumina MiSeq system. SNP regions in kdpA and nhaA proved to be most useful for differentiation of AviPro SALMONELLA VAC E and Salmovac SE/Gallivac SE, respectively, from wildtype strains. For each vaccine strain one TaqMan-qPCR assay and one alternative approach using High Resolution Melting (HRM) analysis was designed. All 30 Salmovac SE and 7 AviPro SALMONELLA VAC E vaccine strain reisolates tested were correctly identified by both approaches (100% inclusivity). Furthermore, all 137 (TaqMan) and 97 (HRM) Salmonella non-vaccine and related Enterobacteriaceae strains tested were excluded (100% exclusivity). The analytical detection limits were determined to be approx. 10(2) genome copies/reaction for the TaqMan and 10(4) genome copies/reaction for the HRM approach. The real-time PCR assays proved to be a reliable and fast alternative to the cultural vaccine strain identification tests helping decision makers in control measurements to take action within a shorter period of time. PMID- 25794903 TI - Determination of NAT2 acetylation status in the Greenlandic population. AB - N-acetyltransferase 2 (NAT2) is a well-studied phase II xenobiotic metabolizing enzyme relevant in drug metabolism and cancerogenesis. NAT2 activity is largely determined by genetic polymorphisms in the coding region of the corresponding gene. We investigated NAT2 acetylation status in 1556 individuals from Greenland based on four different single nucleotide polymorphism (SNP) panels and the tagging SNP rs1495741. There was good concordance between the NAT2 status inferred by the different SNP combinations. Overall, the fraction of slow acetylators was low with 17.5 % and varied depending on the degree of Inuit ancestry; in individuals with <50 % Inuit ancestry, we observed more than 25 % slow acetylators reflecting European ancestry. Greenland has a high incidence of tuberculosis, and individual dosing of isoniazid according to NAT2 status has been shown to improve treatment and reduce side effects. Our findings could be a first step in pharmacogenetics-based tuberculosis therapy in Greenland. PMID- 25794904 TI - Serum levels of HGF, IL-6, and TGF-alpha after benign liver tumor resection. AB - PURPOSE: Literature is void of data on the relationship between pre- and postoperative levels of hepatocyte growth factor (HGF), interleukin 6 (IL-6), and tumor growth factor alpha (TGF-alpha) after liver resection performed for particular benign liver tumors. The purpose of this study was to assess whether there is a different degree of liver regeneration through the kinetics of HGF, IL 6, and TGF-alpha in 2 particular types of benign liver lesions. MATERIAL/METHODS: The study included 9 patients diagnosed with hepatic hemangioma and 13 patients with focal nodular hyperplasia (FNH) who underwent liver resection. HGF, IL-6, and TGF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) from blood serum drawn at 6 time points during an 8-day period. Statistical analysis was based on two-factor variance analysis with replicate measurements. RESULTS: The HGF, IL-6, and TGF-alpha levels in patients who underwent FNH resection were not significantly different from the levels observed in hemangioma resection patients. Significant increases in HGF, IL-6, and TGF-alpha concentrations were observed only during the first 24h after resection in both groups of patients. CONCLUSIONS: Obtained results suggest that the pre- and post-operative levels of HGF, IL-6, and TGF-alpha do not depend on the particular type of benign tumor. After resection of FNH and hemangioma tumors, the serum levels of HGF, IL-6, and TGF-alpha increased at similar rates during the first 24h, followed by significant declines back to pre-operative levels. PMID- 25794905 TI - Comments regarding Namratha N, Shett V. A technique to evaluate custom tray border extensions before peripheral molding. J Prosthet Dent 2014;112:1603-4. PMID- 25794906 TI - A prospective evaluation of zirconia anterior partial fixed dental prostheses: Clinical results after seven years. AB - STATEMENT OF PROBLEM: Because of the high mechanical strength of zirconium dioxide, the metal in fixed partial prostheses can now be replaced. However, the material is susceptible to aging or hydrothermal degradation and to chipping of the feldspathic veneer. PURPOSE: The purpose of this prospective study was to evaluate the survival (without failure) and success (survival without any complication or failure) rate and clinical efficacy of anterior zirconia partial fixed dental prostheses. MATERIAL AND METHODS: Twenty-seven anterior partial fixed dental prostheses of 3 to 6 units were fabricated. All participants were examined after 1 month and 6 months, then annually for 7 years. RESULTS: Three partial fixed dental prostheses failed and had to be removed: 2 because of secondary caries, which increased failure significantly (P=.001) and 1 because of severe chipping. Six partial fixed dental prostheses had complications: 2 debonded, 3 had chipping, and 1 had periapical pathology. All veneer porcelain fractures occurred in 6-unit fixed partial prostheses (P=.002). The clinical success rate was 88.8% after the 7-year follow-up. CONCLUSIONS: The clinical behavior of partial fixed dental prostheses with a zirconium dioxide core in the anterior region provides an adequate medium-term survival rate. The main cause of failure was secondary caries. The most frequent complication was chipping, which was directly related to the number of units of the prosthesis. PMID- 25794908 TI - Factors involved in the spectrophotometric measurement of soft tissue: A clinical study of interrater and intrarater reliability. AB - STATEMENT OF PROBLEM: The reliability of spectrophotometric measurements of gingival color has not been tested. PURPOSE: The purpose of this study was to evaluate the repeatability and reproducibility of gingival color measurements with a digital spectrophotometer. Measurement error was estimated by determining the interrater agreement and by repeating measurements in different illumination environments with and without contact of the device with the gingiva. MATERIAL AND METHODS: Two trained examiners measured the gingival shade around 30 central incisors with a spectrophotometer with and without external illumination and with and without contact of the device with the gingiva. Color data obtained (CIELab color coordinates; L*, c*, h*, a*, b*) were analyzed with the intraclass correlation coefficient (ICC) and the Student t test for paired samples. RESULTS: Mean L*, c*, a*, and b* values differed significantly between measurements made with and without contact of the device with the tissue, but no difference was found in h* values. An ICC of >0.9 was obtained for interrater and intrarater agreements in all cases. Shade measurements did not differ between the presence and absence of stable ambient light. CONCLUSIONS: The repeatability and reproducibility of soft tissue shade measurements were almost perfect (ICC >0.9) under the examination conditions tested. The measurements were affected by pressure but not by ambient light. PMID- 25794907 TI - Effect of ferrule location on the fracture resistance of crowned mandibular premolars: An in vitro study. AB - STATEMENT OF PROBLEM: How the location of a ferrule affects the fracture resistance of endodontically treated mandibular premolars is unclear. PURPOSE: The purpose of this in vitro study was to compare the effect of ferrule location on the fracture resistance of endodontically treated mandibular premolars. MATERIAL AND METHODS: Seventy-two extracted human mandibular premolars were selected and divided into 6 test groups (n = 12) according to ferrule location: control group, GHT; endodontically treated teeth without endodontic posts and crowns, GCF; teeth with a 2 mm circumferential ferrule, GBF; teeth with a 2 mm buccal ferrule; GLF, teeth with a 2 mm lingual ferrule; GBLF, teeth with a 2 mm buccal and lingual ferrule; and teeth without ferrule, GWF. After glass fiber posts were cemented with a self-adhesive resin cement and foundation restorations were placed, NiCr crowns were luted to each prepared tooth. All specimens were quasistatically loaded at 30 degrees in a universal testing machine until fractured. Data were then analyzed with 1-way ANOVA, followed by multiple comparisons using the Tukey honestly significant difference test (alpha=.05). RESULTS: Mean +/- SD failure loads for groups ranged from 791.1 +/- 177.5 N to 1086.1 +/- 181.1 N. One-way ANOVA revealed a statistically significant difference between the groups (P <= .05). However, no statistically significant differences were observed among groups (P > .05), except between GHT (control group) and groups GBLF and GWF (P = .025, P = .022). CONCLUSIONS: Within the limitations of this study, the location of the ferrule had no significant effect on the fracture resistance of endodontically treated mandibular premolars. PMID- 25794909 TI - Study and characterization of the crest module design: A 3D finite element analysis. AB - STATEMENT OF PROBLEM: The importance of the crest module design in the cortical bone region triggered a need to understand its geometry and its influence on stress management and bone stimulation. PURPOSE: The purpose of this study was to determine the effect of different crest module designs in the cortical bone region in terms of critical stress distribution and bone stimulation. MATERIAL AND METHODS: Several 3-dimensional finite element analyses were conducted of a mandibular cross section with osseointegrated dental implants. For the numerical models, different crest module designs (cylindrical, divergent, convergent, and cup shaped) were analyzed. An average value of a maximum occlusal load of 250 N was applied to each dental implant design, 30 degrees from the top surface. The concentration and distribution patterns of principal and maximum shear stresses and strains were obtained and analyzed. RESULTS: According to the comparative finite element analyses, the most pathologic stress and strain peaks around the implant collar in the cortical bone region were found in divergent crest modules with angles 14 degrees or larger. Nevertheless, the highest physiologic peaks of passive bone stimulation through compression, and the lowest tensile and shear stresses and strains in the cortical bone region were promoted by extended divergent crest module designs. CONCLUSIONS: A slightly divergent and smooth crest module design extended to the cancellous bone increases the surface area available. This results in the dissipation of critical stresses expressed around the collar of the cortical bone region, not only promoting a higher bone-implant contact area and a physiologic bone stimulation but also boosting a healthy and strong bone-implant interface. PMID- 25794910 TI - Use of an obturator with nCPAP in a premature infant with a cleft lip and palate. AB - Premature infants have underdeveloped lungs and their care involves the use of nasal continuous positive airway pressure (nCPAP). For an adequate amount of oxygen to enter the lungs, the palate needs to be intact. Premature infants with a cleft lip and palate remain intubated for extended periods of time with the risks inherent in long-term intubation because of the inability to maintain nCPAP. This paper describes the fabrication of a custom-designed obturator attached to nCPAP variable flow generator tubing for a premature infant with a unilateral cleft lip and palate. PMID- 25794911 TI - Effect of thermocycling with or without 1 year of water storage on retentive strengths of luting cements for zirconia crowns. AB - STATEMENT OF PROBLEM: Bond stability between zirconia crowns and luting cement and between cement and dentin is a main concern; however, only limited evidence is available as to its longevity. PURPOSE: The purpose of this in vitro study was to measure the retentive strengths of 7 self-adhesive cements (RelyX Unicem Aplicap, RelyX Unicem Clicker, RelyX Unicem 2 Automix, iCEM, Maxcem Elite, Bifix SE, SpeedCem), 2 adhesive cements with self-etch primers (Panavia 21, SEcure), 1 glass ionomer cement (Ketac Cem), 1 resin-modified glass ionomer cement (Meron Plus), and 1 zinc phosphate cement for luting zirconia crowns (LAVA) to extracted teeth after thermocycling with or without 1 year of water storage. MATERIAL AND METHODS: Two-hundred-forty extracted human molars (2 treatments; n=10 per cement) were prepared in a standardized manner. All cements were used according to the manufacturers' recommendations. The intaglios of the crowns were treated with airborne-particle abrasion. After thermocycling (*5000, 5 degrees C/55 degrees C) with or without 1 year of water storage, the cemented ceramic crowns were removed by using a Zwick universal testing device. Statistical analyses were done with the Wilcoxon rank sum and the 2-independent-samples Kolmogorov-Smirnov test. RESULTS: Median retentive strengths [MPa] for specimens thermocycled only/thermocycled with 1 year of water storage were as follows: Panavia 21: 1.7/2.5, SEcure: 3.0/3.0, RelyX Unicem Aplicap: 3.1/3.4, RelyX Unicem Clicker: 4.1/4.2, RelyX Unicem 2 Automix: 3.8/3.1, iCEM: 2.3/2.7, Maxcem Elite: 3.0/3.2, Bifix SE: 1.7/1.7, SpeedCem: 1.3/1.6, Meron Plus: 3.1/2.7, Ketac Cem: 1.4/1.4, and zinc phosphate cement: 1.1/1.6. Statistically significant differences were found only among specimens thermocycled only or thermocycled with 1-year water storage (P<.001). CONCLUSIONS: Significant differences in retentive strengths were observed among cements after thermocycling only or thermocycling with 1 year of water storage, but not for the effect of the additional 1 year of water storage. PMID- 25794912 TI - Effects of glass fiber mesh with different fiber content and structures on the compressive properties of complete dentures. AB - STATEMENT OF PROBLEM: No study has yet evaluated the strength of complete dentures reinforced with glass fiber meshes with different content and structures. PURPOSE: The purpose of this study was to compare the reinforcing effects of glass fiber mesh with different content and structures with that of metal mesh in complete dentures. MATERIAL AND METHODS: Two types of glass fiber mesh were used: SES mesh (SES) and glass cloth (GC2, GC3, and GC4). A metal mesh was used for comparison. The complete dentures were made by placing the reinforcement 1 mm away from the tissue surface. A control group was prepared without any reinforcement (n=10). The compressive properties were measured by a universal testing machine at a crosshead speed of 5 mm/min. The results were analyzed with the Kruskal-Wallis test and the Duncan multiple range test (alpha=.05). RESULTS: The fracture resistance of the SES group was significantly higher than that of the control, GC4, and metal groups (asymptotic P=.004), but not significantly different from the GC2 and GC3 groups. The toughness of the SES and GC3 groups was significantly higher than that of the others (asymptotic P<.001), but not significantly different from that of the GC4 group. CONCLUSIONS: SES and GC3, which have different structures but similar volume content, were the most effective in reinforcing complete dentures. The content of the glass fiber mesh seemed more important than the structures. PMID- 25794913 TI - Comparative study of torque resistance and microgaps between a combined Octatorx cone connection and an internal hexagon implant-abutment connection. AB - STATEMENT OF PROBLEM: Although the implant-abutment connection may prevent crestal bone loss around dental implants, its failure often leads to treatment failure. Microgap and micromovement of the implant-abutment connection could be causes of bone resorption around dental implant neck. PURPOSE: The purpose of this study was to compare torque resistance and microgaps between a new cone and index connection (Octatorx) and an internal hexagon implant-abutment connection (Internal hex). MATERIAL AND METHODS: Twenty Octatorx and 20 internal hexagon connections were attached with retaining screws at 30 Ncm. In a torsion resistance test, 10 of each type of connection were attached to a universal testing machine. Torque resistance with 90 degrees per minute rotation speed was recorded. For microgap measurement, each of 10 connections was embedded in clear acrylic resin. The blocks were cut longitudinally. Twenty specimens of each connection were evaluated. Twelve measurements of microgaps (6 on each side of specimen) were recorded under scanning electron microscopy. RESULTS: The average torsion resistance of Octatorx (203.6 +/-17.4 Ncm) was significantly greater than that of the internal hexagon (146.4 +/-16.1 Ncm, P<.05). For the microgap, there was a significant difference (P=.001) between the median values of Octatorx (1.19 MUm) and the internal hexagon (3.80 MUm). CONCLUSIONS: In this study, the new connection, Octatorx, had a smaller microgap and greater torque resistance than the internal hexagon connection. PMID- 25794914 TI - Adjusting dental ceramics: An in vitro evaluation of the ability of various ceramic polishing kits to mimic glazed dental ceramic surface. AB - STATEMENT OF PROBLEM: During the insertion appointment, the practitioner is often faced with the need to adjust ceramic surfaces to fit a restoration to the adjacent or opposing dentition and soft tissues. PURPOSE: The purpose of this study was to assess the ceramic surface smoothness achieved with various commercially available ceramic polishing kits on different commonly used ceramic systems. The reliability of the cost of a polishing kit as an indicator of improved surface smoothness was assessed. MATERIAL AND METHODS: A total of 350 ceramic surfaces representing 5 commonly available ceramic systems (IPS Empress Esthetic, IPS e.max Press, Cergo Kiss, Vita PM 9, Imagine PressX) were treated with 5 types of ceramic polishing systems (Cerapreshine, 94006C, Ceramiste, Optrafine, Zenostar) by following the manufacturers' guidelines. The surface roughness was measured with a profilometer (Taylor Hobson; Precision Taylor Hobson Ltd). The effects of ceramic systems and polishing kits of interest on surface roughness were analyzed by 2-way ANOVA, paired t test, and Bonferroni corrected significance level. RESULTS: The ceramic systems and polishing kits statistically affected surface roughness (P<.001).The polishing kit Zenostar on IPS e.max Press created the smoothest ceramic surface. No correlation could be established between the high cost of the polishing kit and low surface roughness. None of the commonly used ceramic polishing kits could create a surface smoother than that of glazed ceramic (P<.001). CONCLUSIONS: The inclusion of a diamond polishing paste step is recommended to improve surface smoothness (P<.001). The cost of ceramic polishing kits is not recommended as a reliable indicator of better performance of ceramic polishing kits (P>.30). PMID- 25794915 TI - Die spacer thickness reproduction for central incisor crown fabrication with combined computer-aided design and 3D printing technology: an in vitro study. AB - STATEMENT OF PROBLEM: The inability to control die spacer thickness has been reported. However, little information is available on the congruency between the computer-aided design parameters for die spacer thickness and the actual printout. PURPOSE: The purpose of this study was to evaluate the accuracy and precision of the die spacer thickness achieved by combining computer-aided design and 3-dimensional printing technology. MATERIAL AND METHODS: An ivorine maxillary central incisor was prepared for a ceramic crown. The prepared tooth was duplicated by using polyvinyl siloxane duplicating silicone, and 80 die-stone models were produced from Type IV dental stone. The dies were randomly divided into 5 groups with assigned die spacer thicknesses of 25 MUm, 45 MUm, 65 MUm, 85 MUm, and 105 MUm (n=16). The printed resin copings, obtained from a printer (ProJet DP 3000; 3D Systems), were cemented onto their respective die-stone models with self-adhesive resin cement and stored at room temperature until sectioning into halves in a buccolingual direction. The internal gap was measured at 5 defined locations per side of the sectioned die. Images of the printed resin coping/die-stone model internal gap dimensions were obtained with an inverted bright field metallurgical microscope at *100 magnification. The acquired digital image was calibrated, and measurements were made using image analysis software. Mixed models (alpha=.05) were used to evaluate accuracy. A false discovery rate at 5% was used to adjust for multiple testing. Coefficient of variation was used to determine the precision for each group and was evaluated statistically with the Wald test (alpha=.05). RESULTS: The accuracy, expressed in terms of the mean differences between the prescribed die spacer thickness and the measured internal gap (standard deviation), was 50 MUm (11) for the 25 MUm group simulated die spacer thickness, 30 MUm (10) for the 45 MUm group, 15 MUm (14) for the 65 MUm group, 3 MUm (23) for the 85 MUm group, and -10 MUm (32) for the 105 MUm group. The precision mean of the measurements, expressed as a coefficient of variation, ranged between 14% and 33% for the 5 groups. CONCLUSIONS: For the accuracy evaluation, statistically significant differences were found for all the groups, except the group of 85 MUm. For the precision assessment, the coefficient of variation was above 10% for all groups, showing the printer's inability to reproduce the uniform internal gap within the same group. PMID- 25794916 TI - Maxillofacial prosthetic rehabilitation for esophageal and laryngeal laxity due to the hypermobility syndrome: A clinical report. AB - Laryngeal and esophageal laxity resulting from a connective tissue disease can lead to severe pain and functional impairment. This clinical report describes a patient with such significant neck pain that it prevented her from speaking; it also caused pain with deglutition. Maxillofacial prosthetic rehabilitation with an external laryngeal and esophageal support significantly reduced the patient's pain and restored normal speaking and deglutition functions. This clinical report describes the design and fabrication of a support to stabilize the patient's laryngeal and esophageal structures to her midline. PMID- 25794917 TI - Effect of increased crown height on stress distribution in short dental implant components and their surrounding bone: A finite element analysis. AB - STATEMENT OF PROBLEM: Implants in posterior regions of the jaw require short dental implants with long crown heights, leading to increased crown-to-implant ratios and mechanical stress. This can lead to fracture and screw loosening. PURPOSE: The purpose of this study was to investigate the dynamic nature and behavior of prosthetic components and preimplant bone and evaluate the effect of increased crown height space (CHS) and crown-to-implant ratio on stress concentrations under external oblique forces. MATERIAL AND METHODS: The severely resorbed bone of a posterior mandible site was modeled with Mimics and Catia software. A second mandibular premolar tooth was modeled with CHS values of 8.8, 11.2, 13.6, and 16 mm. A Straumann implant (4.1*8 mm), a directly attached crown, and an abutment screw were modeled with geometric data and designed by using SolidWorks software. Abaqus software was used for the dynamic simulation of screw tightening and the application of an external load to the buccal cusp at a 75.8 degree angle with the occlusal plane. The distribution of screw load and member load at each step was compared, and the stress values were calculated within the dental implant complex and surrounding bone. RESULTS: During tightening, the magnitude and distribution of the preload and clamp load were uniform and equal at the cross section of all CHSs. Under an external load, the screw load decreased and member load increased. An increase in the CHS caused the corresponding distribution to become more nonuniform and increased the maximum compressive and tensile stresses in the preimplant bone. Additionally, the von Mises stress decreased at the abutment screw and increased at the abutment and fixture. CONCLUSIONS: Under nonaxial forces, increased CHS does not influence the decrease in screw load or increase in member load. However, it contributes to screw loosening and fatigue fracture by skewing the stress distribution to the transverse section of the implant. PMID- 25794918 TI - Clinical marginal and internal fit of metal ceramic crowns fabricated with a selective laser melting technology. AB - STATEMENT OF PROBLEM: Selective laser melting (SLM) technology has been introduced to fabricate dental restorations. However, the fit of these restorations still needs further study. PURPOSE: The purpose of this in vivo investigation was to compare the marginal and internal fit of SLM metal ceramic crowns with 2 lost-wax cast metal ceramic crowns and to evaluate the influence of tooth type on the marginal and internal fit of these crowns. MATERIAL AND METHODS: A total of 330 metal ceramic crowns were evaluated. The metal copings were fabricated with SLM Co-Cr, cast Au-Pt, and cast Co-Cr alloy (n=110). The marginal and internal gaps of crowns were recorded by using a replica technique. The anterior and premolar replicas were sectioned 2 times, and molar replicas were sectioned 4 times. The marginal and internal gap width of each cross section was examined by stereomicroscope at *30 magnification. Two-way analysis of variance was performed to identify the statistical difference among the groups. RESULTS: The marginal fit of the SLM Co-Cr group (75.6 +/-32.6 MUm) was not different from the cast Au-Pt group (76.8 +/-32.1 MUm) (P>.05) but was better than the cast Co-Cr group (91.0 +/-36.3 MUm) (P<.01). No significant difference was found among the SLM Co-Cr group (127.3 +/-45.8 MUm), cast Au-Pt group (129.9 +/-61.1 MUm). and cast Co-Cr group (142.5 +/-63.7 MUm) (P>.05). The mean occlusal gap width of the SLM Co-Cr group (309.8 +/-106.6 MUm) was significantly higher than that of the cast Au-Pt group (254.6 +/-109.6 MUm) and the cast Co-Cr group (249.6 +/-110.4 MUm) (P<.005). No significant difference was found in the marginal fit among the anterior group (84.4 +/-35.1 MUm), the premolar group (80.6 +/-26.3 MUm), and the molar group (82.7 +/-38.0 MUm) (P>.05). Also, no significant difference was found in the axial fit among the anterior group (138.3 +/-52.5 MUm), the premolar group (132.9 +/-50.4 MUm), and the molar group (134.4 +/-52.5 MUm) (P>.05). The anterior group (267.6 +/-110.2 MUm) did not differ from the premolar group (270.2 +/-112.8 MUm) and the molar group (268.6 +/-110.5 MUm) in occlusal fit (P>.05). CONCLUSIONS: The marginal fit of SLM Co-Cr metal ceramic crowns was similar to that of the cast Au-Pt metal ceramic crowns and was better than that of the cast Co-Cr metal ceramic crowns. The SLM Co-Cr metal ceramic crowns were not significantly different from the 2 cast metal ceramic crowns in axial fit but were less accurate in occlusal fit. Tooth type did not influence the marginal and internal fit of the metal ceramic crowns. PMID- 25794919 TI - Dynamic Abutment: A method of redirecting screw access for implant-supported restorations: Technical details and a clinical report. AB - The esthetic outcome of implant-supported restorations is affected by the implant position. A well-placed implant will allow appropriate contours of the restoration and together with an adequate volume of soft tissue will result in a functional and esthetic restoration. When a screw-retained restoration is anticipated, an implant that is angled too far facially would be esthetically unacceptable. In 2004, an abutment called the Dynamic Abutment (Talladium International Implantology) became commercially available. This abutment can allow a deviation of the restoration screw access angle to the implant angle of up to 28 degrees while allowing a screw-retained restoration to be connected directly to the platform of the implant. The purpose of this article was to describe the components, technique, and clinical use of this abutment. PMID- 25794920 TI - Fluorodeoxyglucose positron emission tomography/computed tomography for diagnosis of upper urinary tract urothelial carcinoma. AB - BACKGROUND: The purpose of this study was to assess the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to detect upper urinary tract urothelial carcinomas (UTUC) compared with pathological examination of tissues obtained by ureteroscopic biopsy and split cytologic analysis of urine obtained after retrograde pyelography. METHODS: Clinicopathological records of patients at our institution were retrospectively reviewed. Fifty patients with clinically suspected UTUC, who were histologically diagnosed by nephroureterectomy, partial ureterectomy, or endoscopic biopsy, were included. The patient cohort included 42 men and 8 women, with a median age of 73 (range 54-92) years. RESULTS: Only 27 % of 49 patients with UTUC had positive voided urine cytology, and 33 % of 40 patients had positive split urine cytology. In addition, 40 % of 10 patients had a positive endoscopic biopsy. However, 83 % of 48 patients with UTUC had positive results from FDG-PET/CT examination. The positive predictive value of FDG-PET/CT was 95 %. There were no correlations between sensitivity and tumor stage or tumor grade. Sensitivity of FDG-PET/CT for patients with and without diabetes mellitus was 60 and 89 %, respectively. CONCLUSIONS: These preliminary results from a small number of patients revealed that FDG-PET/CT enabled effective detection of UTUC. PMID- 25794921 TI - Analysis of pedestrian accident costs in Sudan using the willingness-to-pay method. AB - The willingness-to-pay (WTP) with contingent valuation (CV) method has been proven to be a valid tool for the valuation of non-market goods or socio-economic costs of road traffic accidents among communities in developed and developing countries. Research on accident costing tends to estimate the value of statistical life (VOSL) for all road users by providing a principle for the evaluation of road safety interventions in cost-benefit analysis. As in many other developing countries, the economic loss of traffic accidents in Sudan is noticeable; however, analytical research to estimate the magnitude and impact of that loss is lacking. Reports have shown that pedestrians account for more than 40% of the total number of fatalities. In this study, the WTP-CV approach was used to determine the amount of money that pedestrians in Sudan are willing to pay to reduce the risk of their own death. The impact of the socioeconomic factors, risk levels, and walking behaviors of pedestrians on their WTP for fatality risk reduction was also evaluated. Data were collected from two cities Khartoum and Nyala-using a survey questionnaire that included 1400 respondents. The WTP-CV Payment Card Questionnaire was designed to ensure that Sudan pedestrians can easily determine the amount of money that would be required to reduce the fatality risk from a pedestrian-related accident. The analysis results show that the estimated VOSL for Sudanese pedestrians ranges from US$0.019 to US$0.101 million. In addition, the willingness-to-pay by Sudanese pedestrians to reduce their fatality risk tends to increase with age, household income, educational level, safety perception, and average time spent on social activities with family and community. PMID- 25794922 TI - What determines the take-over time? An integrated model approach of driver take over after automated driving. AB - In recent years the automation level of driver assistance systems has increased continuously. One of the major challenges for highly automated driving is to ensure a safe driver take-over of the vehicle guidance. This must be ensured especially when the driver is engaged in non-driving related secondary tasks. For this purpose it is essential to find indicators of the driver's readiness to take over and to gain more knowledge about the take-over process in general. A simulator study was conducted to explore how drivers' allocation of visual attention during highly automated driving influences a take-over action in response to an emergency situation. Therefore we recorded drivers' gaze behavior during automated driving while simultaneously engaging in a visually demanding secondary task, and measured their reaction times in a take-over situation. According to their gaze behavior the drivers were categorized into "high", "medium" and "low-risk". The gaze parameters were found to be suitable for predicting the readiness to take-over the vehicle, in such a way that high-risk drivers reacted late and more often inappropriately in the take-over situation. However, there was no difference among the driver groups in the time required by the drivers to establish motor readiness to intervene after the take-over request. An integrated model approach of driver behavior in emergency take-over situations during automated driving is presented. It is argued that primarily cognitive and not motor processes determine the take-over time. Given this, insights can be derived for further research and the development of automated systems. PMID- 25794924 TI - Radionuclide, scintillation cocktail and chemical/color quench influence on discriminator setting in gross alpha/beta measurements by LSC. AB - Gross alpha/beta measurements in drinking waters enable radiochemical composition analysis in environmental studies providing efficient screening method that can indicate whether water contains elevated levels of any radionuclide. Routine gross alpha/beta activity monitoring in drinking waters has been carried out for a few years in laboratory for low-level radioactivity measurements in Novi Sad according to ASTM method, performing measurements on liquid scintillation counter Quantulus 1220 which can simultaneously generate alpha/beta spectra of samples by Pulse Shape Analysis (PSA circuit). In this paper, PSA discriminator impact was investigated to ensure obtaining of accurate and reliable alpha/beta activities. One novelty of presented work is PSA parameter setup with two combinations of radionuclides ((241)Am, (226)Ra and (90)Sr/(90)Y) with varying activity concentrations. Performed experiments also make contribution to investigations on the manner in which chemical and color quench affect optimal PSA parameter setting and further on, their altogether influence on gross alpha/beta activity measurements. Nitromethane, 15.8 M nitric acid and water, as well as yellow and yellow-orange dye, were used as quenching agents in order to test PSA/interference factor behavior in the presence of quenchers with different quenching strengths. Variation of PSA setting in quenched samples with two different commercially available cocktails (Ultima Gold LLT and OptiPhase HiSafe 3) was also tested. Lastly, application i.e. assessment of obtained PSA-SQP(E) correlation on the obtained results of activity concentrations of few artesian well water samples and colored spiked samples, based on the measured SQP(E) value of samples, has been demonstrated. PMID- 25794923 TI - Understanding infection prevention and control in nursing homes: A qualitative study. AB - Infections have been identified as a priority issue in nursing homes (NHs). We conducted a qualitative study purposively sampling 10 NHs across the country where 6-8 employees were recruited (N = 73). Semi-structured, open-ended guides were used to conduct in-depth interviews. Data were audiotaped, transcribed and a content analysis was performed. Five themes emerged: 'Residents' Needs', 'Roles and Training' 'Using Infection Data,' 'External Resources' and 'Focus on Hand Hygiene.' Infection prevention was a priority in the NHs visited. While all sites had hand hygiene programs, other recommended areas were not a focus and many sites were not aware of available resources. Developing ways to ensure effective, efficient and standardized infection prevention and control in NHs continues to be a national priority. PMID- 25794925 TI - Mussels (Mytilus galloprovincialis) as a bio-indicator species in radioactivity monitoring of Eastern Adriatic coastal waters. AB - Croatian Adriatic coastal waters are systematically monitored within the Mediterranean Mussel Watch Project using mussels (Mytilus galloprovincialis) as a bio-indicator species. The study includes determination of naturally occurring ((7)Be, (40)K, (232)Th, (226)Ra and (238)U), as well as anthropogenic (137)Cs radionuclides. Activity concentrations in dry weight of mussels' soft tissue along the Croatian Adriatic coast are presented, with spatial and seasonal variations given and discussed. Samples were collected in spring and autumn for the period between 2009 and 2013. Radionuclides were determined by gamma-ray spectrometry. Activity concentrations of (7)Be were the highest in spring periods, especially in the areas with significant fresh water discharges. Activity concentrations of (40)K did not vary significantly with season or location. (137)Cs activities were low, while (232)Th, (226)Ra and (238)U activities were mostly below the detection limit of performed gamma-spectrometric measurement. PMID- 25794926 TI - Alternative methods for the efficient construction of short hairpin RNA expression vectors. AB - Short hairpin RNA (shRNA)-mediated RNA interference has become a basic technique in modern molecular biology and biochemistry for studying gene function and biological pathways. Here, we report two alternative and efficient methods to construct shRNA expression vectors based respectively on multiple-step sequential PCR and primer extension-homologous recombination (PE-HR). Neither method requires synthesizing long oligonucleotides containing hairpin sequences as used in traditional approaches. The hairpin sequences may produce mutations during oligo synthesis, pose problems in annealing, and lead to inefficient cloning. The PE-HR method further provides rapid and economical construction of shRNA expression vectors without needing the ligation procedure. PMID- 25794927 TI - Chemical components from the leaves of Ardisia insularis and their cytotoxic activity. AB - One new oleanane triterpene glycoside, ardinsuloside (1), and twelve known compounds, demethoxybergenin (2), norbergenin (3), bergenin (4), 4-O galloylbergenin (5), quercitrin (6), myricitrin (7), myricetin 3-O-(3''-O galloyl)-alpha-L-rhamnopyranoside (8), desmanthine-2 (9), epicatechin 3-O-galloyl ester (10), 3'-methoxyepicatechin 3-O-galloyl ester (11), gallic acid (12), and methyl galloate (13) were isolated from the leaves of Ardisia insularis. Their structures were established on the basis of spectral and chemical evidence, which were in agreement with those reported in literature. The cytotoxic activities of these compounds were evaluated on three cancer cell lines namely A-549 (human lung cancer), HT-29 (Human colon adenocarcinoma), and OVCAR (human ovarian carcinoma). The results revealed that compound 1 inhibited A-549, HT-29, and OVCAR cell lines with IC50 values of 8.5 +/- 1.2, 16.4 +/- 3.1, and 13.6 +/- 2.4 MUM, respectively. The remaining compound showed weak cytotoxic activity. This result indicated that compound 1 could be useful in the treatment of cancer disease. PMID- 25794929 TI - Country in Focus: health disparities in Indigenous Canadians. PMID- 25794928 TI - Serum and synovial fluid levels of CCL18 are correlated with radiographic grading of knee osteoarthritis. AB - BACKGROUND: Chemokines are involved in the pathogenesis of osteoarthritis (OA). CCL18, a member of the chemokines family, is observed in synovial fluid (SF) of OA patients. The aim of this study was to determine the association between CCL18 levels in serum and SF with radiographic knee OA. MATERIAL AND METHODS: This study was conducted in a population of 308 patients with knee OA. The radiological knee OA was graded by the Kellgren-Lawrence grading system. RESULTS: Serum levels of CCL18 in knee OA patients were markedly higher than those in healthy controls. Serum and SF levels of CCL18 increased with the severity of KL grades and were correlated with disease severity. CONCLUSIONS: The CCL18 levels in serum and SF are correlated with the severity of OA. PMID- 25794930 TI - Bifidobacteria modulate cognitive processes in an anxious mouse strain. AB - Increasing evidence suggests that a brain-gut-microbiome axis exists, which has the potential to play a major role in modulating behaviour. However, the role of this axis in cognition remains relatively unexplored. Probiotics, which are commensal bacteria offering potential health benefit, have been shown to decrease anxiety, depression and visceral pain-related behaviours. In this study, we investigate the potential of two Bifidobacteria strains to modulate cognitive processes and visceral pain sensitivity. Adult male BALB/c mice were fed daily for 11 weeks with B. longum 1714, B. breve 1205 or vehicle treatment. Starting at week 4, animals were behaviourally assessed in a battery of tests relevant to different aspects of cognition, as well as locomotor activity and visceral pain. In the object recognition test, B. longum 1714-fed mice discriminated between the two objects faster than all other groups and B. breve 1205-fed mice discriminated faster than vehicle animals. In the Barnes maze, B. longum 1714-treated mice made fewer errors than other groups, suggesting a better learning. In the fear conditioning, B. longum 1714-treated group also showed better learning and memory, yet presenting the same extinction learning profile as controls. None of the treatments affected visceral sensitivity. Altogether, these data suggest that B. longum 1714 had a positive impact on cognition and also that the effects of individual Bifidobacteria strains do not generalise across the species. Clinical validation of the effects of probiotics on cognition is now warranted. PMID- 25794931 TI - [The matrix-gla protein awakening may lead to the demise of vascular calcification]. AB - Matrix-gla-protein (MGP) is mainly secreted by chondrocytes and smooth vascular muscle cells. This potent inhibitor of vascular calcification need to undergo 2 post-transcriptional steps to be fully active: one phosphorylation of 3 serine residues (on 5) and a carboxylation of 5 glutamate residues (on 9). Like other "Gla" proteins, this carboxylation is vitamin K dependant. Several forms of MGP thus circulate in the plasma, some of them being totally inactive (the unphosphorylated and uncarboxylated MGP), some others being partially or fully active, according to the number of phosphorylated or carboxylated sites. A theoretical link exists between MGP, vitamin K, vascular calcifications and cardiovascular diseases. This link is even more evident in patients suffering from chronic kidney diseases (CKD), and notably hemodialysis patients. If this link has been demonstrated in different experimental studies, clinical studies are mainly observational and their results must be interpreted accordingly. MGP concentrations are definitely not yet a surrogate to estimate the levels of vascular calcification, but could allow the monitoring of vitamin K treatment. Modulation of MGP concentrations may reduce vascular calcification in hemodialyzed patients, if the large ongoing trials show an efficiency of this treatment. In this review, we will summarize the role of MGP in the vascular calcifications process, describe the problems linked to the analytical determination of MGP in plasma and finally describe the different clinical studies on MGP and vascular calcifications in the general population and in CKD patients. PMID- 25794932 TI - [Role of protein carbamylation in chronic kidney disease complications]. AB - Carbamylation corresponds to the non-enzymatic binding of isocyanic acid, mainly derived from urea decomposition, on amino groups of proteins, and participates in their molecular aging. This process is increased during chronic kidney disease (CKD) because of hyperuremia, and in other pathologies like atherosclerosis, where isocyanic may be formed from thiocyanate by myeloperoxidase in atheroma plates. Carbamylation triggers structural and functional modifications of proteins, thus impairing their biological roles and their interactions with cells. Much experimental evidence in vitro has shown the potential deleterious effects of carbamylated proteins on cell and tissue functions. Carbamylation derived products (CDPs), and especially their major component homocitrulline, accumulate in organism in long half-life proteins, and may participate in the development of different complications of CKD, especially cardiovascular diseases, renal fibrosis, or nutritional and metabolic troubles. Recent clinical studies have confirmed the link between serum protein carbamylation and morbi mortality in patients suffering from CKD or undergoing hemodialysis. Some CDPs could be used as biomarkers in these pathologies. PMID- 25794933 TI - The bHLH transcription factor bHLH104 interacts with IAA-LEUCINE RESISTANT3 and modulates iron homeostasis in Arabidopsis. AB - Iron (Fe) is an indispensable micronutrient for plant growth and development. The regulation of Fe homeostasis in plants is complex and involves a number of transcription factors. Here, we demonstrate that a basic helix-loop-helix (bHLH) transcription factor, bHLH104, belonging to the IVc subgroup of bHLH family, acts as a key component positively regulating Fe deficiency responses. Knockout of bHLH104 in Arabidopsis thaliana greatly reduced tolerance to Fe deficiency, whereas overexpression of bHLH104 had the opposite effect and led to accumulation of excess Fe in soil-grown conditions. The activation of Fe deficiency-inducible genes was substantially suppressed by loss of bHLH104. Further investigation showed that bHLH104 interacted with another IVc subgroup bHLH protein, IAA LEUCINE RESISTANT3 (ILR3), which also plays an important role in Fe homeostasis. Moreover, bHLH104 and ILR3 could bind directly to the promoters of Ib subgroup bHLH genes and POPEYE (PYE) functioning in the regulation of Fe deficiency responses. Interestingly, genetic analysis showed that loss of bHLH104 could decrease the tolerance to Fe deficiency conferred by the lesion of BRUTUS, which encodes an E3 ligase and interacts with bHLH104. Collectively, our data support that bHLH104 and ILR3 play pivotal roles in the regulation of Fe deficiency responses via targeting Ib subgroup bHLH genes and PYE expression. PMID- 25794934 TI - The small GTPase ROP10 of Medicago truncatula is required for both tip growth of root hairs and nod factor-induced root hair deformation. AB - Rhizobia preferentially enter legume root hairs via infection threads, after which root hairs undergo tip swelling, branching, and curling. However, the mechanisms underlying such root hair deformation are poorly understood. Here, we showed that a type II small GTPase, ROP10, of Medicago truncatula is localized at the plasma membrane (PM) of root hair tips to regulate root hair tip growth. Overexpression of ROP10 and a constitutively active mutant (ROP10CA) generated depolarized growth of root hairs, whereas a dominant negative mutant (ROP10DN) inhibited root hair elongation. Inoculated with Sinorhizobium meliloti, the depolarized swollen and ballooning root hairs exhibited extensive root hair deformation and aberrant infection symptoms. Upon treatment with rhizobia secreted nodulation factors (NFs), ROP10 was transiently upregulated in root hairs, and ROP10 fused to green fluorescent protein was ectopically localized at the PM of NF-induced outgrowths and curls around rhizobia. ROP10 interacted with the kinase domain of the NF receptor NFP in a GTP-dependent manner. Moreover, NF induced expression of the early nodulin gene ENOD11 was enhanced by the overexpression of ROP10 and ROP10CA. These data suggest that NFs spatiotemporally regulate ROP10 localization and activity at the PM of root hair tips and that interactions between ROP10 and NF receptors are required for root hair deformation and continuous curling during rhizobial infection. PMID- 25794936 TI - A cascade of sequentially expressed sucrose transporters in the seed coat and endosperm provides nutrition for the Arabidopsis embryo. AB - Developing plant embryos depend on nutrition from maternal tissues via the seed coat and endosperm, but the mechanisms that supply nutrients to plant embryos have remained elusive. Sucrose, the major transport form of carbohydrate in plants, is delivered via the phloem to the maternal seed coat and then secreted from the seed coat to feed the embryo. Here, we show that seed filling in Arabidopsis thaliana requires the three sucrose transporters SWEET11, 12, and 15. SWEET11, 12, and 15 exhibit specific spatiotemporal expression patterns in developing seeds, but only a sweet11;12;15 triple mutant showed severe seed defects, which include retarded embryo development, reduced seed weight, and reduced starch and lipid content, causing a "wrinkled" seed phenotype. In sweet11;12;15 triple mutants, starch accumulated in the seed coat but not the embryo, implicating SWEET-mediated sucrose efflux in the transfer of sugars from seed coat to embryo. This cascade of sequentially expressed SWEETs provides the feeding pathway for the plant embryo, an important feature for yield potential. PMID- 25794937 TI - Age-related differences in corticomotor facilitation indicate dedifferentiation in motor planning. AB - Efficient motor control requires motor planning. Age-related changes in motor control are well described, e.g. increased movement variability and greater antagonistic muscle co-activation, as well as less functional and less regional specific brain activation. However, less is known about age-related changes in motor planning. By use of transcranial magnetic stimulation we investigated differences in corticomotor facilitation during motor planning in 17 young (25+/ 3years) and 17 older healthy adults (70+/-13years) in a delayed movement paradigm for wrist movements. Motor evoked potentials (MEPs) were recorded for the flexor and extensor carpi radialis during movement preparation of wrist flexion and extension as well as during rest. We found that MEPs were less specifically facilitated during planning in older as compared to younger adults, as indicated by an Age*Condition*Muscle interaction. Young participants showed significantly facilitated MEPs in the respective muscle needed for wrist flexion or extension. By contrast MEPs in older participants were less specifically modulated. We conclude that age relates to dedifferentiated activation of the primary motor cortex already during preparation of distinct movements which might contribute to less efficient motor control in older adults. PMID- 25794935 TI - Cleavage of INDOLE-3-ACETIC ACID INDUCIBLE28 mRNA by microRNA847 upregulates auxin signaling to modulate cell proliferation and lateral organ growth in Arabidopsis. AB - MicroRNAs function in a range of developmental processes. Here, we demonstrate that miR847 targets the mRNA of the auxin/indole acetic acid (Aux/IAA) repressor encoding gene IAA28 for cleavage. The rapidly increased accumulation of miR847 in Arabidopsis thaliana coincided with reduced IAA28 mRNA levels upon auxin treatment. This induction of miR847 by auxin was abolished in auxin receptor tir1 1 and auxin-resistant axr1-3 mutants. Further analysis demonstrates that miR847 functions as a positive regulator of auxin-mediated lateral organ development by cleaving IAA28 mRNA. Importantly, the ectopic expression of miR847 increases the expression of cell cycle genes as well as the neoplastic activity of leaf cells, prolonging later-stage rosette leaf growth and producing leaves with serrated margins. Moreover, both miR847 and IAA28 mRNAs are specifically expressed in marginal meristems of rosette leaves and lateral root initiation sites. Our data indicate that auxin-dependent induction of miR847 positively regulates meristematic competence by clearing IAA28 mRNA to upregulate auxin signaling, thereby determining the duration of cell proliferation and lateral organ growth in Arabidopsis. IAA28 mRNA encodes an Aux/IAA repressor protein, which is degraded through the proteasome in response to auxin. Altered signal sensitization to IAA28 mRNA levels, together with targeted IAA28 degradation, ensures a robust signal derepression. PMID- 25794938 TI - Evaluation of (acyloxy)alkyl ester linkers for antibiotic release from siderophore-antibiotic conjugates. AB - The syntheses of five ciprofloxacin-modified (acyloxyl)alkyl esters and two siderophore-ciprofloxacin conjugates based on enterobactin that harbor such hydrolyzable linkages are reported. The hydrolytic stabilities of ciprofloxacin modified (acyloxy)alkyl esters, evaluated at pH 7.5 and 30 degrees C, vary by >370-fold depending on the substituents in the vicinity of the ester linkage. PMID- 25794940 TI - The Spectrum of Motor Neuron Diseases: From Childhood Spinal Muscular Atrophy to Adult Amyotrophic Lateral Sclerosis. PMID- 25794941 TI - Postdural puncture headache: impact of needle type, a randomized trial. AB - BACKGROUND CONTEXT: The most common adverse event after a lumbar puncture (LP) is a headache: In anaesthesiology, well studied is the protective effect of atraumatic spinal needles, and they are routinely used. However, this is less well known in diagnostic LP, and neurologists use atraumatic needles in less than 2% of times. PURPOSE: The purpose of this study was to define the impact of needle type, atraumatic (Sprotte [S]) versus traumatic (Quincke [Q]) on postdural puncture headache (PDPH) incidence. STUDY DESIGN: The study is based on a prospective, randomized, and simple-blinded clinical trial. PATIENT SAMPLE: Patients older than 14 years were scheduled for a diagnostic or therapeutic LP. OUTCOME MEASURES: The outcome measure included the development of PDPH according to the International Headache Association criteria. METHODS: Patients fulfilling eligibility criteria were randomly allocated to one of two kinds of spinal needle: atraumatic or S-type or traumatic or Q-type. They were interviewed on days 2 and 7 about the development of PDPH. RESULTS: The incidence of PDPH was 22.43% with Q-type needle and 8.51% with S-type needle, p=.04. The duration of PDPH in patients in the S-type was 1 day or less, compared with a median of 4.14 days in the Q-type (p=.00). In the logistic regression model, the S-type needle together with the age of the patient were the only two statistically significant factors in the development of postlumbar puncture headache (PLPH), both of them being protective. CONCLUSIONS: We found a lower incidence of PDPH with atraumatic needles, and it was statistically significant compared with the traumatic needles. Our study confirms the effectiveness of the atraumatic needles to prevent PDPH. PMID- 25794939 TI - LGP2 synergy with MDA5 in RLR-mediated RNA recognition and antiviral signaling. AB - Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition receptor proteins detect molecular signatures of virus infection and activate antiviral signaling. The RIG I-like receptor (RLR) proteins are expressed in the cytoplasm of nearly all cells and specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RLR family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All RLRs have the ability to detect virus-derived dsRNA and hydrolyze ATP, but display individual differences in enzymatic activity, intrinsic ability to recognize RNA, and mechanisms of activation. Emerging evidence suggests that MDA5 and RIG-I utilize distinct mechanisms to form oligomeric complexes along dsRNA. Aligning of their signaling domains creates a platform capable of propagating and amplifying antiviral signaling responses. LGP2 with intact ATP hydrolysis is critical for the MDA5 mediated antiviral response, but LGP2 lacks the domains essential for activation of antiviral signaling, leaving the role of LGP2 in antiviral signaling unclear. Recent studies revealed a mechanistic basis of synergy between LGP2 and MDA5 leading to enhanced antiviral signaling. This review briefly summarizes the RLR system, and focuses on the relationship between LGP2 and MDA5, describing in detail how these two proteins work together to detect foreign RNA and generate a fully functional antiviral response. PMID- 25794942 TI - Efficacy of alphacypermethrin-treated high density polyethylene mesh applied to jet stalls housing horses against Culicoides biting midges in South Africa. AB - The efficacy of alphacypermethrin-treated high density polyethylene (HDPE) mesh applied to jet stalls against Culicoides biting midges (Diptera: Ceratopogonidae) was determined by mechanical aspiration of midges from horses and using Onderstepoort 220 V downdraught black light traps in four blocks of a 3 * 2 randomised design under South African field conditions. The alphacypermethrin treated HDPE mesh applied to the stall significantly (P = 0.008) reduced the number of Culicoides midges, predominantly Culicoides (Avaritia) imicola Kieffer, mechanically aspirated from horses housed in the stall. The mesh reduced the Culicoides midge attack rate in the treated stall compared to the untreated stall and a sentinel horse by 6 times and 14 times, respectively. The number of Culicoides midges and C. imicola collected in light traps from the untreated and alphacypermethrin HDPE mesh-treated stalls did not differ significantly (P = 0.82). Alphacypermethrin-treated HDPE mesh could be used to reduce exposure of horses in jet stalls to Culicoides midges, specifically C. imicola, and the risk of midge-borne Orbivirus transmission. PMID- 25794943 TI - Molecular identification of Cryptosporidium spp. and Giardia duodenalis in grazing horses from Xinjiang, China. AB - A total of 262 fecal specimens collected from grazing horses at five locations in Xinjiang, China were examined by PCR for Cryptosporidium spp. and Giardia duodenalis. The Cryptosporidium and G. duodenalis infection rates were 2.7% and 1.5%, respectively. Seven Cryptosporidium-positive specimens were found in foals (16.3%), and four G. duodenalis-positive specimens were found in mares (2.5%). Sequence analyses of 18S rRNA and gp60 genes revealed that seven animals were positive for the subtype VIaA15G4 of Cryptosporidium horse genotype. G. duodenalis assemblages A and B were identified by molecular characterization of the 16S rRNA and tpi genes. This is the first report of Cryptosporidium horse genotype and G. duodenalis in grazing horses from China. PMID- 25794944 TI - Molecular mechanisms of dietary restriction in aging-insights from Caenorhabditis elegans research. AB - Dietary restriction (DR) is one of the most robust environmental manipulations that not only extend life span but also delay the onset of age-related diseases in almost every species examined. Caenorhabditis elegans plays an important role in aging studies due to its simple life cycle, easy genetic manipulations and highly conserved genome. Recent studies have demonstrated that the beneficial effects of DR are mediated by the highly conserved transcription factors and signaling pathways in C. elegans. Here we review recent progress in the methodology and molecular mechanisms of DR using C. elegans as a model, as well as prospects for future research. PMID- 25794945 TI - Transcriptional regulatory circuits controlling muscle fiber type switching. AB - Skeletal muscle fitness plays vital roles in human health and disease and is determined by developmental as well as physiological inputs. These inputs control and coordinate muscle fiber programs, including capacity for fuel burning, mitochondrial ATP production, and contraction. Recent studies have demonstrated crucial roles for nuclear receptors and their co-activators, and microRNAs (miRNAs) in the regulation of skeletal muscle energy metabolism and fiber type determination. In this review, we present recent progress in the study of nuclear receptor signaling and miRNA networks in muscle fiber type switching. We also discuss the therapeutic potential of nuclear receptors and miRNAs in disease states that are associated with loss of muscle fitness. PMID- 25794946 TI - Unfinished nursing care, missed care, and implicitly rationed care: State of the science review. AB - OBJECTIVES: The purposes of this review of unfinished care were to: (1) compare conceptual definitions and frameworks associated with unfinished care and related synonyms (i.e. missed care, implicitly rationed care; and care left undone); (2) compare and contrast approaches to instrumentation; (3) describe prevalence and patterns; (4) identify antecedents and outcomes; and (5) describe mitigating interventions. METHODS: A literature search in CINAHL and MEDLINE identified 1828 articles; 54 met inclusion criteria. Search terms included: implicit ration*, miss* care, ration* care, task* undone, and unfinish*care. Analysis was performed in three phases: initial screening and sorting, comprehensive review for data extraction (first author), and confirmatory review to validate groupings, major themes, and interpretations (second author). RESULTS: Reviewed literature included 42 quantitative reports; 7 qualitative reports; 1 mixed method report; and 4 scientific reviews. With one exception, quantitative studies involved observational cross-sectional survey designs. A total of 22 primary samples were identified; 5 involved systematic sampling. The response rate was >60% in over half of the samples. Unfinished care was measured with 14 self-report instruments. Most nursing personnel (55-98%) reported leaving at least 1 task undone. Estimates increased with survey length, recall period, scope of response referent, and scope of resource scarcity considered. Patterns of unfinished care were consistent with the subordination of teaching and emotional support activities to those related to physiologic needs and organizational audits. Predictors of unfinished care included perceived team interactions, adequacy of resources, safety climate, and nurse staffing. Unfinished care is a predictor of: decreased nurse-reported care quality, decreased patient satisfaction; increased adverse events; increased turnover; decreased job and occupational satisfaction; and increased intent to leave. DISCUSSION & CONCLUSIONS: Unfinished care is a significant problem in acute care hospitals internationally. Prioritization strategies of nurses leave patients vulnerable to unmet educational, emotional, and psychological needs. Key limitations of the science include the threat of common method/source bias, a lack of transparency regarding the use of combined samples and secondary analysis, inconsistency in the reporting format for unfinished care prevalence, and a paucity of intervention studies. PMID- 25794947 TI - Talking about persons--thinking about patients: An ethnographic study in critical care. AB - BACKGROUND: Nursing involves caring for the 'whole person' and it is considered inappropriate for nurses to think or talk about patients in objectifying or dehumanising ways. Objectifying discourses can dominate within the arena of critical care, and critical care nurses can experience moral distress as they struggle to think about patients as persons. No previous study has examined the role played by 'impersonal' talk in the delivery of nursing care. This paper reports a study which examined the relationship between nursing practice and the way(s) in which critical care nurses think and talk about patients. OBJECTIVES: The study objectives were to (1) identify and characterise the ways in which critical care nurses think and talk about patients; and (2) describe patterns of nursing practice associated with these different ways of thinking. STUDY DESIGN: An ethnographic study was undertaken within one critical care unit in the United Kingdom. Data were collected over 8 months through 92h of participant observation and 13 interviews. Seven critical care nurses participated in the study. Data analysis adopted the perspective of linguistic ethnography. FINDINGS: Analysis of these data led to the identification of seven Discourses, each of which was characterised by a particular way of talking about patients, a particular way of thinking about patients, and a particular pattern of practice. Four of these seven Discourses were of particular significance because participants characterised it as 'impersonal' to think and talk about patients as 'routine work', as a 'body', as '(un)stable' or as a 'medical case'. Although participants frequently offered apologies or excuses for doing so, these 'impersonal' ways of thinking and talking were associated with practice that was essential to delivering safe effective care. CONCLUSIONS: Critical care practice requires nurses to think and talk about patients in many different ways, yet nurses are socialised to an ideal that they should always think and talk about patients as whole persons. This means that nurses can struggle to articulate and reflect upon aspects of their practice which require them to think and talk about patients in impersonal ways. This may be an important source of distress to critical care nurses and emotional exhaustion and burnout can arise from such dissonance between ideals and the reality of practice. Nursing leaders, scholars and policy makers need to recognise and legitimise the fact that nurses must think about patients in many ways, some of which may be considered impersonal. PMID- 25794948 TI - Ensuring the reporting quality of publications in nursing journals: A shared responsibility? PMID- 25794949 TI - Mass spectrometry based proteomics for absolute quantification of proteins from tumor cells. AB - In-depth quantitative profiling of the proteome and sub-proteomes of tumor cells has relevance to tumor classification, the development of novel therapeutics, and of prognostic and predictive markers and to disease monitoring. In particular the tumor cell surface represents a highly relevant compartment for the development of targeted therapeutics and immunotherapy. We have developed a proteomic platform to profile tumor cells that encompasses enrichment of surface membrane proteins, intact protein fractionation and label-free mass spectrometry based absolute quantification. Here we describe the methodology for capture, identification and quantification of cell surface proteins using biotinylation for labeling of the cell surface, avidin for capture of biotinylated proteins and ion mobility mass spectrometry for protein identification and quantification. PMID- 25794950 TI - Fabrication of tissue engineered osteochondral grafts for restoring the articular surface of diarthrodial joints. AB - Osteochondral allograft implantation is an effective cartilage restoration technique for large defects (>10 cm(2)), though the demand far exceeds the supply of available quality donor tissue. Large bilayered engineered cartilage tissue constructs with accurate anatomical features (i.e. contours, thickness, architecture) could be beneficial in replacing damaged tissue. When creating these osteochondral constructs, however, it is pertinent to maintain biofidelity to restore functionality. Here, we describe a step-by-step framework for the fabrication of a large osteochondral construct with correct anatomical architecture and topology through a combination of high-resolution imaging, rapid prototyping, impression molding, and injection molding. PMID- 25794951 TI - Vagal modulation of hypertension. AB - Resistant hypertension despite compliance with pharmacologic therapies continues to hamper optimal blood pressure control. Vagal modulation via direct stimulation of the body's parasympathetic nervous system is proving a promising therapeutic modality to help patients achieve their blood pressure goals. In this article, we review some of the key concepts of different vagal modulations for resistant hypertension including baroreflex activation therapy, renal sympathetic denervation, and direct vagal nerve stimulation. PMID- 25794952 TI - The relationship between currently recommended ambulatory systolic blood pressure measures and left ventricular mass index in pediatric hypertension. AB - This study aims to explore the relationship between currently recommended ambulatory blood pressure (ABP) measures used to classify pediatric hypertension and left ventricular mass index (LVMI) in children with true ambulatory hypertension. We performed a cross-sectional survey among 94 children who were consecutively referred for suspected hypertension. The calculated ABP measures were average 24-h systolic blood pressure (24-h aSBP) and 24-h SBP load. The LVMI was estimated by M-mode echocardiography using Devereux's formula and indexed by height(2,7). A total of 35 children fulfilled the criteria for true ambulatory hypertension (elevated office blood pressure, 24-h SBP load >25 %, and 24-h aSBP >95th percentile). Compared with children not fulfilling these criteria, those with true ambulatory hypertension had significantly higher values of 24-h aSBP, 24-h SBP load, and LVMI, as well as body mass index (BMI; P < 0.0001). In a separate analysis of both groups, none of the examined ABP measures adjusted for age, sex, and BMI correlated with LVMI. In those with true hypertension, only BMI was significantly associated with increased LVMI (F = 9.651; P = 0.004; adjusted R (2) = 0.203). The results of our study suggest that pediatric hypertension, as determined by currently recommended ABP (SBP) measures, is not associated with subclinical end-organ damage as defined by the increased left ventricular mass. Therefore, additional factors associated with BMI increase must be considered as risk factors for the development of end-organ damage in hypertensive children. PMID- 25794953 TI - Relative roles of principal and intercalated cells in the regulation of sodium balance and blood pressure. AB - The kidney continuously adapts daily renal excretion of NaCl to match dietary intakes in order to maintain the NaCl content of the body, and keep vascular volume constant. Any situation that leads to NaCl retention favors a rise in blood pressure. The aldosterone-sensitive distal nephron, which contains two main types of cells, principal (PC) and intercalated (IC) cells, is an important site for the final regulation of urinary Na(+) excretion. Research over the past 20 years established a paradigm in which PCs are the exclusive site of Na(+) absorption while ICs are solely dedicated to acid-base transport. Recent studies have revealed the unexpected importance of ICs for NaCl reabsorption. Here, we review the mechanisms of Na(+) and Cl(-) transport in the aldosterone-sensitive distal nephron, with emphasis on the role of ICs in maintaining NaCl balance and normal blood pressure. PMID- 25794954 TI - Obesity and left ventricular hypertrophy: the hypertension connection. AB - The detection of left ventricular hypertrophy (LVH) is recommended for risk prediction, and changes in LV geometry may provide further prognostic information. Obesity is a major determinant of LVH, but the approach to LVH detection in obese hypertensives remains a challenge. In the present review, we discuss evidence leading to the recent acceptance of the use of LV mass indexed to height(2.7) or height(1.7) rather than body surface area, for LVH detection and its regression in obesity. We also review recent findings which indicate that obesity-induced LVH may be associated with concentric LV remodeling, and hence, that the presence of concentric LVH in obesity should not be assumed to indicate a cause of LVH other than obesity. We also discuss recent evidence for obesity and blood pressure producing additive and interactive effects on LV mass, and hence, that weight loss and blood pressure reduction are required to achieve appropriate regression. PMID- 25794956 TI - Personalizing the diuretic treatment of hypertension: the need for more clinical and research attention. AB - Neither randomized controlled trials nor efforts to identify genetic markers have been helpful with regard to the goal of individualizing diuretic therapy in the treatment of hypertension, a goal that receives little clinical or research attention. This review will examine, and bring attention to, the considerable yet overlooked information relevant to individualizing diuretic therapy. It will bring attention to clinical, biochemical, and pharmacological clues that can be helpful in identifying who is likely to respond to a diuretic, who needs a stronger diuretic regimen, which diuretic to prescribe, and how to minimize adverse effects. New directions for clinical research aimed at individualizing use in hypertension will be explored. Research and clinical attention to the goal of individualizing diuretic treatment in hypertension need to be renewed, to help us achieve greater hypertension control with fewer adverse effects and lower costs. PMID- 25794957 TI - A carbon nanofiber-based label free immunosensor for high sensitive detection of recombinant bovine somatotropin. AB - A carbon nanofiber-based label free electrochemical immunosensor for sensitive detection of recombinant bovine somatotropin (rbST) was developed. In this immunosensor design, a mild site-directed antibody immobilization via interaction of boronic acid and oligosaccharide moiety found on Fc region of an antibody was performed to preserve the biological activity of antibody and improve the sensor's sensitivity. Electrochemical characterization of the immunosensor fabrication was carried out by differential pulse voltammetry (DPV) in Fe(CN)6(3 )/Fe(CN)6(4-) probe. A comparison study between different transducer platforms showed carbon nanofiber gave higher current signal response than single-walled carbon nanotube. In this work, calibration curve was obtained from the decrease of DPV peak current of Fe(CN)6(3-)/Fe(CN)6(4-) after immunocomplexed was formed. A linear relationship between DPV current change signal response and rbST concentrations from 1 pg/mL to 10 ng/mL (correlation coefficient of 0.9721) was achieved with detection limit of 1 pg/mL. Our developed immunosensor demonstrated high selectivity in cross-reactivity studies and a good percentage recovery in spiked bovine serum sample. PMID- 25794959 TI - Giant magnetoresistive-based biosensing probe station system for multiplex protein assays. AB - In this study, a sensitive immune-biosensing system capable of multiplexed, real time electrical readout was developed based on giant magnetoresistive (GMR) sensor array to detect a panel of protein biomarkers simultaneously. PAPP-A, PCSK9, and ST2 have been regarded as promising candidate biomarkers for cardiovascular diseases. Early detection of multiple biomarkers for a disease could enable accurate prediction of a disease risk. 64 nano-size GMR sensors were assembled onto one 16 mm * 16 mm chip with a reaction well, and they could work independently and be monitored simultaneously. A detect limit of 40 pg/mL for ST2 antigen had been achieved, and the dynamic ranges for the three proteins detection were up to four orders of magnitude. The GMR sensing platform was also selective enough to be directly used in serum samples. In addition, a lab-based probe station has been designed to implement quick lab-on-a-chip experiments instead of wire bonding. It has a potential application in clinical biomarkers identification and screening, and can be extended to fit other biosensing schemes. PMID- 25794958 TI - A highly sensitive electrochemiluminescence assay for protein kinase based on double-quenching of graphene quantum dots by G-quadruplex-hemin and gold nanoparticles. AB - A highly sensitive electrochemiluminescence (ECL) strategy was developed for the protein kinase A (PKA) activity and inhibition assay based on double-quenching of graphene quantum dots (GQDs) ECL by G-quadruplex-hemin DNAzyme and gold nanoparticles (AuNPs). In this strategy, the GQDs were modified onto the indium tin oxide (ITO) electrode and further assembled with substrate peptide of target protein kinase through covalent coupling, which can exhibit high and stable ECL signal. The AuNPs, functionalized with the phosphorylated DNA and G-quadruplex hemin DNAzyme via Au-S chemistry, were selected as quenching probes. In the presence of PKA, the peptide on the electrode was phosphorylated and the AuNPs functionalized with the phosphorylated DNA and G-quadruplex-hemin DNAzyme were subsequently integrated onto the phosphorylated peptide by Zr(4+). Owing to the reduction of coreactant H2O2 resulting from G-quadruplex-hemin DNAzyme catalytic reaction and the ECL energy transfer (ECL-RET) between AuNPs and GQDs, the ECL intensity of GQDs was significantly decreased. By taking advantage of the double quenching effect, this assay can detect PKA with a linear range of 0.05 to 5 U mL(-1) and a detection limit of 0.04 U mL(-1). In addition, the PKA inhibition assay and interferences experiments of CK2 and T4 PNK have been studied respectively. This assay was also successfully applied to PKA assay in serum samples and cell lysates, indicating that the developed method have the potential applications in protein kinase-related biochemical fundamental research and clinical diagnosis. PMID- 25794955 TI - Coronary heart disease risk factors and outcomes in the twenty-first century: findings from the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. AB - REasons for Geographic and Racial Differences in Stroke (REGARDS) is a longitudinal study supported by the National Institutes of Health to determine the disparities in stroke-related mortality across USA. REGARDS has published a body of work designed to understand the disparities in prevalence, awareness, treatment, and control of coronary heart disease (CHD) and its risk factors in a biracial national cohort. REGARDS has focused on racial and geographical disparities in the quality and access to health care, the influence of lack of medical insurance, and has attempted to contrast current guidelines in lipid lowering for secondary prevention in a nationwide cohort. It has described CHD risk from nontraditional risk factors such as chronic kidney disease, atrial fibrillation, and inflammation (i.e., high-sensitivity C-reactive protein) and has also assessed the role of depression, psychosocial, environmental, and lifestyle factors in CHD risk with emphasis on risk factor modification and ideal lifestyle factors. REGARDS has examined the utility of various methodologies, e.g., the process of medical record adjudication, proxy-based cause of death, and use of claim-based algorithms to determine CHD risk. Some valuable insight into less well-studied concepts such as the reliability of current troponin assays to identify "microsize infarcts," caregiving stress, and CHD, heart failure, and cognitive decline have also emerged. In this review, we discuss some of the most important findings from REGARDS in the context of the existing literature in an effort to identify gaps and directions for further research. PMID- 25794960 TI - A novel graphene oxide-based fluorescent nanosensor for selective detection of Fe(3+) with a wide linear concentration and its application in logic gate. AB - A graphene oxide-based fluorescent nanosensor AGO has been designed and synthesized by covalent grafting allylamine onto GO surface. In aqueous media, AGO displays a highly selective and sensitive discrimination of Fe(3+) from Fe(2+) and other metal ions through electron transfer-induced fluorescence quenching. The quenching of AGO fluorescence is linearly proportional to Fe(3+) concentration in a wide range of 0-120 MUM (correlation coefficient R(2)=0.9994). Moreover, AGO can be used to construct a combinational three-input logic gate to discriminate Fe(3+) and Fe(2+). The logic gate works well in intracellular fluorescence imaging, which shows a potential as a promising platform for biosensing analysis. PMID- 25794961 TI - Impedimetric cell-based biosensor for real-time monitoring of cytopathic effects induced by dengue viruses. AB - We describe an impedimetric cell-based biosensor constructed from poly-l-lysine (PLL)-modified screen-printed carbon electrode for real-time monitoring of dengue virus (DENV) infection of surface-immobilized baby hamster kidney (BHK-21) fibroblast cells. Cytopathic effects (CPE) induced by DENV-2 New Guinea C strain (including degenerative morphological changes, detachment, membrane degradation and death of host cells), were reflected by drastic decrease in impedance signal response detected as early as ~30 hours post-infection (hpi). In contrast, distinct CPE by conventional microscopy was evident only at ~72 hpi at the corresponding multiplicity of infection (MOI) of 10. A parameter that describes the kinetics of cytopathogenesis, CIT50, which refers to the time taken for 50% reduction in impedance signal response, revealed an inverse linear relationship with virus titer and MOI. CIT50 values were also delayed by 31.5h for each order of magnitude decrease in MOI. Therefore, based on the analysis of CIT50, the virus titer of a given sample can be determined from the measured impedance signal response. Furthermore, consistent impedance results were also obtained with clinical isolates of the four DENV serotypes verified by RT-PCR and cycle sequencing. This impedimetric cell-based biosensor represents a label-free and continuous approach for the dynamic measurement of cellular responses toward DENV infection, and for detecting the presence of infectious viral particles. PMID- 25794962 TI - A systematic assessment of the use of platelet-rich plasma in spinal fusion. AB - Spinal fusion is one of the most commonly performed procedures for the treatment of spinal instability caused by a multitude of pathologies. However, despite significant advances in spinal instrumentation, failed fusion, or pseudoarthrosis, remains a significant challenge. Therefore, other additives such as bone graft extenders and growth factors have been explored as a method to augment fusion rates. Platelet-rich plasma (PRP) represents an additional approach, as it has shown some promise in bone regeneration. While the general use of PRP in orthopedic applications has been reviewed previously, its use in spinal fusion has not been systematically analyzed. The objective of this review is to systematically discuss the role of PRP in augmentation of bone regeneration for the purpose of spinal fusion. Background information on PRP, including a discussion of its preparation, activation, and growth factors, is included. Additionally, data from in vitro studies utilizing PRP in bone tissue engineering strategies is analyzed, and the available animal and clinical studies are systematically reviewed in order to provide guidance on future research pathways as well as the potential role of PRP in spinal fusion surgery. PMID- 25794963 TI - Erratum to: Pulsatile Perfusion Bioreactor System for Durability Testing and Compliance Estimation of Tissue Engineered Vascular Grafts. PMID- 25794964 TI - Minimizing impacts of land use change on ecosystem services using multi-criteria heuristic analysis. AB - Development of natural landscapes to support human activities impacts the capacity of the landscape to provide ecosystem services. Typically, several ecosystem services are impacted at a single development site and various footprint scenarios are possible, thus a multi-criteria analysis is needed. Restoration potential should also be considered for the area surrounding the permanent impact site. The primary objective of this research was to develop a heuristic approach to analyze multiple criteria (e.g. impacts to various ecosystem services) in a spatial configuration with many potential development sites. The approach was to: (1) quantify the magnitude of terrestrial ecosystem service (biodiversity, carbon sequestration, nutrient and sediment retention, and pollination) impacts associated with a suite of land use change scenarios using the InVEST model; (2) normalize results across categories of ecosystem services to allow cross-service comparison; (3) apply the multi-criteria heuristic algorithm to select sites with the least impact to ecosystem services, including a spatial criterion (separation between sites). As a case study, the multi criteria impact minimization algorithm was applied to InVEST output to select 25 potential development sites out of 204 possible locations (selected by other criteria) within a 24,000 ha property. This study advanced a generally applicable spatial multi-criteria approach for 1) considering many land use footprint scenarios, 2) balancing impact decisions across a suite of ecosystem services, and 3) determining the restoration potential of ecosystem services after impacts. PMID- 25794965 TI - Evaluation of the accuracy of land-use based ecosystem service assessments for different thematic resolutions. AB - The demand for pragmatic tools for mapping ecosystem services (ES) has led to the widespread application of land-use based proxy methods, mostly using coarse thematic resolution classification systems. Although various studies have demonstrated the limited reliability of land use as an indicator of service delivery, this does not prevent the method from being frequently applied on different institutional levels. It has recently been argued that a more detailed land use classification system may increase the accuracy of this approach. This research statistically compares maps of predicted ES delivery based on land use scoring for three different thematic resolutions (number of classes) with maps of ES delivery produced by biophysical models. Our results demonstrate that using a more detailed land use classification system does not significantly increase the accuracy of land-use based ES assessments for the majority of the considered ES. Correlations between land-use based assessments and biophysical model outcomes are relatively strong for provisioning services, independent of the classification system. However, large discrepancies occur frequently between the score and the model-based estimate. We conclude that land use, as a simple indicator, is not effective enough to be used in environmental management as it cannot capture differences in abiotic conditions and ecological processes that explain differences in service delivery. Using land use as a simple indicator will therefore result in inappropriate management decisions, even if a highly detailed land use classification system is used. PMID- 25794966 TI - Relationship between levels of polycyclic aromatic hydrocarbons in pine needles and socio-geographic parameters. AB - The ability of pine needles to capture polycyclic aromatic hydrocarbons (PAHs) from the surrounding air is well known. In this work the current knowledge of this affinity will be enhanced, investigating the plausible links between the concentrations of PAHs found in pine needles collected in different sites in Portugal, and several socio-geographic variables with environmental relevance. Canonical correlation analysis (CCA) has proven to be a suitable and innovative technique to look for relationships within environmental datasets. In the current work, CCA will simultaneously include chemical information (concentration of PAHs found in pine needles) and socio-geographic information associated to the sampling areas. In order to be more robust in these conclusions, Pinus pinea and Pinus pinaster species were considered separately, allowing an accurate direct comparison between them. The information concerning the different seasons and land occupation was also taken into account. Our results demonstrate how CCA can be a useful tool in environmental impact assessment, and highlight the importance of pine needles as trustful biomonitors of the influence of socio-geographic parameters on the levels of PAHs in a given area. PMID- 25794967 TI - Vaginal Microbicide Film Combinations of Two Reverse Transcriptase Inhibitors, EFdA and CSIC, for the Prevention of HIV-1 Sexual Transmission. AB - PURPOSE: EFdA is a potent nucleoside reverse transcriptase inhibitor (NRTI) with activity against a wide spectrum of wild-type and drug resistant HIV-1 variants. CSIC is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with demonstrated anti-HIV properties important for use in topical prevention of HIV transmission. The objective of this study was to develop and characterize film-formulated EFdA and CSIC for use as a female-controlled vaginal microbicide to prevent sexual transmission of HIV. METHODS: Assessments of EFdA- and CSIC loaded films included physicochemical characteristics, in vitro cytotoxicity, epithelia integrity studies, compatibility with the normal vaginal Lactobacillus flora and anti-HIV bioactivity evaluations. RESULTS: No significant change in physicochemical properties or biological activity of the combination films were noted during 3 months storage. In vitro cytotoxicity and bioactivity testing showed that 50% cytotoxic concentration (CC50) of either EFdA or CSIC was several orders of magnitude higher than the 50% effective concentration (EC50) values. Film-formulated EFdA and CSIC combination showed additive inhibitory activity against wild type and drug-resistant variants of HIV. Epithelial integrity studies demonstrated that the combination vaginal film had a much lower toxicity to HEC-1A monolayers compared to that of VCF(r), a commercial vaginal film product containing nonoxynol-9. Polarized ectocervical explants showed films with drug alone or in combination were effective at preventing HIV infection. CONCLUSIONS: Our data suggest that vaginal microbicide films containing a combination of the NRTI EFdA and the NNRTI CSIC have potential to prevent HIV-1 sexual transmission. PMID- 25794968 TI - New insights into systemic sclerosis related microcirculatory dysfunction by assessment of sublingual micr?ocirculation and vascular glycocalyx layer. Results from a preliminary study. AB - BACKGROUND: Initial morphological and functional markers of systemic sclerosis (SSc) are evidenced in microvascular structural damage. However, nailfold videocapillaroscopy (NVC) explores only morphological abnormalities. Sidestream Dark Field (SDF) imaging of sublingual microcirculation enables assessment of both morphological and functional capillary impairment and allows measurement of the glycocalyx layer, which is an indicator of endothelial dysfunction. OBJECTIVE: To describe and validate sublingual abnormalities assessed by SDF device in comparison with NVC findings and to measure the thickness of the glycocalyx layer. METHODS: From February to May 2014, 26 subjects (16 SSc patients and 10 healthy controls) underwent standardised NVC and SDF imaging of sublingual microcirculation. Glycocalyx thickness was also measured. RESULTS: Capillary density and percentage of perfused vessels were significantly reduced in patients with SSc (n = 13) compared to controls. Correlation between nailfold capillary density assessed by NVC and sublingual capillary density assessed by SDF was observed (r(2) = 0.59; P = 0.023). According to the NVC pattern, patients with "active" disease experienced greater reduction in capillary density than patients with "late" disease as suggested by the de Backer score (9.17 +/- 0.81 vs 10.86 +/- 1.19; P = 0.03). Additionally, the decrease in glycocalyx thickness was measured in SSc patients (n = 13) compared to controls (n = 10) (0.41 +/- 0.03 versus 0.76 +/- 0.29 P = 0.003). CONCLUSION: Our results suggest for the first time in SSc, that sublingual microcirculation and glycocalyx are impaired and that SDF imaging findings correlate with those of NVC. Nevertheless, further studies are required for the validation of our preliminary results. PMID- 25794969 TI - Lumbar load in adolescent fast bowlers: A prospective injury study. AB - OBJECTIVES: This study aimed to identify modifiable mechanisms associated with low back injury in adolescent cricket fast bowlers. DESIGN: A prospective study design examined the association between intrinsic risk factors, workload, bowling kinematics, lumbar load and low back injury incidence. METHODS: Twenty-five injury free fast bowlers, aged 14-19 years, were assessed prior to the start of a cricket season and observed during the season for low back injuries. RESULTS: The twelve bowlers who suffered a low back injury displayed; decreased hip flexion at front foot contact (46+/-6 degrees vs 51+/-6 degrees ), increased pelvis rotation (287+/-11 degrees vs 277+/-11 degrees ) increased thorax lateral flexion (50+/-6 degrees vs 40+/-8 degrees ) at ball release, and larger peak lumbar flexion (10.5+/-4.9Nmkg(-1)m(-1) vs 6.9+/-2.5Nmkg(-1)m(-1)) and lateral flexion moments (12.5+/-2.6Nmkg(-1)m(-1) vs 10.6+/-1.9Nmkg(-1)m(-1)). They also exhibited reduced muscular endurance of the back extensors (103+/-33s vs 132+/ 33s) and increased knee valgus angle during a single leg decline squat on the dominant (9+/-3 degrees vs 5+/-4 degrees ) and non-dominant leg (9+/-4 degrees vs 6+/-3 degrees ) in comparison to uninjured bowlers. CONCLUSIONS: Bowlers who experience greater lumbar loads during bowling, have reduced back extensor muscle endurance, and demonstrate impaired control of the lumbo-pelvic-hip complex, are at increased risk of low back injury. This combination of strength, control and biomechanical factors may be key mechanical elements of low back injury causation in adolescent fast bowlers. PMID- 25794970 TI - Multimedia fate modeling and risk assessment of a commonly used azole fungicide climbazole at the river basin scale in China. AB - Climbazole is an antidandruff active ingredient commonly used in personal care products, but little is known about its environmental fate. The aim of this study was to evaluate the fate of climbazole in water, sediment, soil and air compartments of the whole China by using a level III multimedia fugacity model. The usage of climbazole was calculated to be 345 t in the whole China according to the market research data, and after wastewater treatment a total emission of 245 t was discharged into the receiving environment with approximately 93% into the water compartment and 7% into the soil compartment. The developed fugacity model was successfully applied to estimate the contamination levels and mass inventories of climbazole in various environmental compartments of the river basins in China. The predicted environmental concentration ranges of climbazole were: 0.20-367 ng/L in water, and 0.009-25.2 ng/g dry weight in sediment. The highest concentration was mainly found in Haihe River basin and the lowest was in basins of Tibet and Xinjiang regions. The mass inventory of climbazole in the whole China was estimated to be 294 t, with 6.79% in water, 83.7% in sediment, 9.49% in soil, and 0.002% in air. Preliminary risk assessment showed high risks in sediment posed by climbazole in 2 out of 58 basins in China. The medium risks in water and sediment were mostly concentrated in north China. To the best of our knowledge, it is the first report on the emissions and multimedia fate of climbazole in the river basins of the whole China. PMID- 25794971 TI - Estimating greenhouse gas emissions of European cities--modeling emissions with only one spatial and one socioeconomic variable. AB - Substantive and concerted action is needed to mitigate climate change. However, international negotiations struggle to adopt ambitious legislation and to anticipate more climate-friendly developments. Thus, stronger actions are needed from other players. Cities, being greenhouse gas emission centers, play a key role in promoting the climate change mitigation movement by becoming hubs for smart and low-carbon lifestyles. In this context, a stronger linkage between greenhouse gas emissions and urban development and policy-making seems promising. Therefore, simple approaches are needed to objectively identify crucial emission drivers for deriving appropriate emission reduction strategies. In analyzing 44 European cities, the authors investigate possible socioeconomic and spatial determinants of urban greenhouse gas emissions. Multiple statistical analyses reveal that the average household size and the edge density of discontinuous dense urban fabric explain up to 86% of the total variance of greenhouse gas emissions of EU cities (when controlled for varying electricity carbon intensities). Finally, based on these findings, a multiple regression model is presented to determine greenhouse gas emissions. It is independently evaluated with ten further EU cities. The reliance on only two indicators shows that the model can be easily applied in addressing important greenhouse gas emission sources of European urbanites, when varying power generations are considered. This knowledge can help cities develop adequate climate change mitigation strategies and promote respective policies on the EU or the regional level. The results can further be used to derive first estimates of urban greenhouse gas emissions, if no other analyses are available. PMID- 25794972 TI - Patterns and predictors of recurrence after radical resection of thymoma. AB - BACKGROUND: Recurrence of thymomas even after complete resection is common, but the relapse patterns remain controversial. This study aimed to define the patterns and predictors of relapse after complete resection of thymoma. METHODS: A single-institution retrospective study was performed with 331 patients who underwent radical resection of thymoma between 1991 and 2012. RESULTS: After a median follow-up of 59 months, the recurrence rate was 6.9% (23/331). Relapse occurred in 23 patients with the pleura (14) and tumor bed (6) as the most common sites of recurrence. According to the definitions of the International Thymic Malignancy Interest Group, 10 (43.5%) patients had local relapse, 15 (65.2%) had regional relapse, 10 (43.5%) had distant relapse. The difference in survival following relapse between lung and regional relapse was statistically significant (P=0.027) but that between lung and distant relapse was not (P=0.808). The recurrence rates correlated with the initial Masaoka stage. Further, recurrence also correlated with World Health Organization (WHO) tumor type. The recurrence free survival rates in patients with tumor size ?8 cm were worse than those of patients with tumor size <8 cm (P=0.007). Tumor size was also correlated with stage (r=0.110). As tumor becomes larger, the stage is more advanced (P=0.023). Multivariate analysis showed that Masaoka stage (P=0.005), tumor size (P=0.033), and WHO histological type (P=0.046) were predictive factors of relapse. CONCLUSION: Regional recurrence is the most common relapse pattern but local and distant relapse are also common. Advanced Masaoka stage, larger tumor size, and type B3 are risk factors of recurrence. Lung relapse should be considered distant relapse. Further, tumor size was correlated with Masaoka stage and therefore should be considered in the staging system. PMID- 25794973 TI - In reply to M. Witte: Commenting 'Multi-modality functional image guided dose escalation in the presence of uncertainties'. PMID- 25794975 TI - WITHDRAWN: Investigating the link of ceramide synthases (CerSes) 4 and 5 in endometrial and colon cancers. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.yexmp.2015.03.023. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25794974 TI - HDAC1 overexpression independently predicts biochemical recurrence and is associated with rapid tumor cell proliferation and genomic instability in prostate cancer. AB - Histone deacetylases (HDACs) play an important role in tumor development and progression by modifying histone and non-histone proteins. In the current study we analyzed prevalence and prognostic impact of HDAC1 in prostate cancer. HDAC1 expression was analyzed by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancer specimens. Results were compared to tumor phenotype, biochemical recurrence, and molecular subtypes defined by ERG status as well as genomic deletions of 3p, 5q, 6q and PTEN. HDAC1 immunostaining was detectable in 75.4% of 9744 interpretable cancers and considered strong in 15.4%, moderate in 39.4% and weak in 20.7% of cases. High HDAC1 expression was associated with high Gleason grade (p<0.0001), advanced pathological tumor stage (p<0.0001), positive nodal status (p=0.0010), elevated preoperative PSA-level (p=0.0127), early PSA recurrence (p<0.0001) and increased cell proliferation (p<0.0001). Moreover, high-level HDAC1 staining was associated with TMPRSS2:ERG rearrangement and ERG expression in prostate cancers (p<0.0001) and was linked to deletions of PTEN (p<0.0001), 6q (p<0.0001) and 5q (p=0.0028) in ERG-negative cancers. The prognostic impact of HDAC1 was independent of established clinicopathological parameters and was mostly driven by ERG-negative cancers as revealed by subgroup analyses. HDAC1 has strong prognostic impact in prostate cancer and might contribute to the development of a fraction of genetically instable and particularly aggressive prostate cancers. HDAC1 measurement might therefore be of clinical value for risk stratification of prostate cancer and should be further evaluated in this regard. PMID- 25794976 TI - Pyruvate dehydrogenase kinase 4 (PDK4) could be involved in a regulatory role in apoptosis and a link between apoptosis and insulin resistance. AB - Pyruvate dehydrogenase kinase 4 (PDK4), a mammalian mitochondrial serine kinase has emerged as an interesting candidate for diabetes therapy. Due to the high prevalence of this disease especially type 2 diabetes (T2D) and the health complications associated with it, there is extensive effort to find the appropriate treatment. Understanding the regulation of PDK4 activity would therefore contribute significantly to the development of therapeutic agents. This research outlines the utilization of bioinformatics tools such as Interweaver, ClustalW and Protein Structure Visualizer, in order to predict proteins that potentially interact with PDK4 and possibly regulate its activity. Interweaver database identified 96 proteins that have possible interaction sites for PDK4. Protein p100/p49, containing a death domain that is known to have a role in suppressing apoptosis, was identified as a potential partner for PDK4. The alignment between p100/p49 primary sequence and that of PDK4 using ClustalW demonstrated sequence similarity between the two proteins. Swiss PDB Viewer then located the positions of the amino acids that are in the hypothetical protein binding motif of p100/p49 within the 3D structure of hPDK4. These amino acids were found to be located in the region of PDK4 which is known to bind protein substrates of PDK4 and may be accessible to other proteins as well. These findings were very interesting as PDK4 has not previously been associated with apoptosis and this could be the link between apoptosis and insulin resistance. Cell biology studies were then performed to verify the relationship between PDK4 and apoptosis. In this regard, HeLa and HepG2 cells were treated with apoptosis inducing agents such as TNFalpha, C2-ceramide, and linoleic acid. These cells were then monitored for apoptosis and PDK4 mRNA expression using a DNA laddering assay as well as Real Time PCR. The results showed that these factors induced apoptosis in a concentration dependent manner and suppressed PDK4 mRNA levels. These findings suggested a relationship between PDK4 and apoptosis. PMID- 25794977 TI - Hot topics: thermal injury in the emergency department. PMID- 25794978 TI - The geriatric bookworm: resources for those interested in the geriatric population. PMID- 25794979 TI - ED Greeter Nurse: Transforming Triage and Improving Patient Care Outcomes. PMID- 25794980 TI - Meet Me in Computed Tomography Suite: Decreasing Tissue Plasminogen Activator Door-to-Needle Time for Acute Ischemic Stroke Patients. PMID- 25794981 TI - Welcome new nurses to the wonderful world of emergency nursing! PMID- 25794982 TI - Using Ways of Knowing to Guide Emergency Nursing Practice. PMID- 25794983 TI - Late gadolinium enhancement in cardiac amyloidosis: attributable both to interstitial amyloid deposition and subendocardial fibrosis caused by ischemia. AB - Gadolinium contrast agents used for late gadolinium enhancement (LGE) distribute in the extracellular space. Global diffuse myocardial LGE pronounced in the subendocardial layers is common in cardiac amyloidosis. However, the pathophysiological basis of these findings has not been sufficiently explained. A 64-year-old man was admitted to our hospital with leg edema and nocturnal dyspnea. Bence Jones protein was positive in the urine, and an endomyocardial and skin biopsy showed light-chain (AL) amyloidosis. He died of ventricular fibrillation 3 months later. 9 days before death, the patient was examined by cardiac magnetic resonance (CMR) imaging on a 3-T system. We acquired LGE data at 2, 5, 10, and 20 min after the injection of gadolinium contrast agents, with a fixed inversion time of 350 ms. Myocardial LGE developed sequentially. The myocardium was diffusely enhanced at 2 min, except for the subendocardium, but LGE had extended to almost the entire left ventricle at 5 min and predominantly localized to the subendocardial region at 10 and 20 min. An autopsy revealed massive and diffused amyloid deposits in perimyocytes throughout the myocardium. Old and recent ischemic findings, such as replacement fibrosis and coagulative myocyte necrosis, were evident in the subendocardium. In the intramural coronary arteries, mild amyloid deposits were present within the subepicardial to the mid layer of the left ventricle, but no stenotic lesions were evident. However, capillaries were obstructed by amyloid deposits in the subendocardium. In conclusion, the late phase of dynamic LGE (at 10 and 20 min) visualized in the subendocardium corresponded to the interstitial amyloid deposition and subendocardial fibrosis caused by ischemia in our patient. PMID- 25794984 TI - Effects of sitagliptin on coronary atherosclerosis evaluated using integrated backscatter intravascular ultrasound in patients with type 2 diabetes: rationale and design of the TRUST study. AB - Patients with diabetes mellitus are at high risk for developing coronary artery disease (CAD), even if they are treated with statins. Several studies have shown the beneficial effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the cardiovascular system in an animal model. However, recent clinical trials using DPP-4 inhibitors have shown that these inhibitors fail to reduce the occurrence of cardiovascular events. Therefore, this study will be performed to evaluate the effects of sitagliptin, a DPP-4 inhibitor, on coronary atherosclerosis in patients with type 2 diabetes. This study will be a prospective, open-label, randomized multicenter trial performed in 6 centers in Japan. Stable CAD patients with type 2 diabetes who have undergone successful percutaneous coronary intervention under integrated backscatter (IB)-intravascular ultrasound (IVUS) guidance will be studied. They will be randomly assigned to either the sitagliptin group or a control group. After 48 weeks' treatment, the IVUS examination will be repeated in the same coronary artery as at baseline. The primary end point will be the percentage change in plaque volume measured using grayscale IVUS from baseline to the 48-week follow-up. This study will be the first multicenter trial to evaluate the effects of a DPP-4 inhibitor on coronary atherosclerosis evaluated using IB-IVUS, and the findings will clarify the anti atherogenic effects of sitagliptin. PMID- 25794985 TI - Effect of phytochemical intervention on dibenzo[a,l]pyrene-induced DNA adduct formation. AB - Dibenzo[a,l]pyrene (DBP) has been found to be the most potent carcinogen of the polycyclic aromatic hydrocarbons (PAHs). Primary sources for DBP in the environment are combustion of wood and coal burning, gasoline and diesel exhaust, and tires. Given the likelihood of environmental exposure to DBP and strong experimental evidence of its potency, it is likely to contribute to lung cancer development. Intervention with compounds of natural origin ("phytochemicals") is considered an effective means to prevent cancer development and favorably modulate the underlying mechanisms, including DNA adduct formation. In this study, several agents have been identified that inhibit environmental carcinogen induced DNA adduct formation using a cell-free microsomal system. Of the ten agents tested, resveratrol (648 +/- 26 adducts/10(9) nucleotides), oltipraz (1007 +/- 348 adducts/10(9) nucleotides), delphinidin (1252 +/- 142 adducts/10(9) nucleotides), tanshinone I (1981 +/- 213 adducts/10(9) nucleotides), tanshinone IIA (2606 +/- 478 adducts/10(9) nucleotides) and diindoylmethane (3643 +/- 469 adducts/10(9) nucleotides) were the most effective compared to vehicle treatment (14,062 +/- 1097 adducts/10(9) nucleotides). DBP is metabolized by phase I metabolizing enzymes CYP1A1, CYP1A2, and CYP1B1. DBP-induced DNA adducts can be inhibited by several mechanisms. We found that all the test agents inhibited DNA adducts by inhibiting one or more of these enzymes. Oltipraz inhibited DNA adducts entirely by inhibiting the CYP450s, while resveratrol and delphinidin inhibited DNA adducts by also interacting directly with the carcinogenic metabolite, anti-dibenzo(a,l)pyrene-11,12-dihydrodiol-13,14-epoxide. PMID- 25794986 TI - Correlation between depth and area of retinal nerve fiber layer defect as measured by spectral domain optical coherence tomography. AB - BACKGROUND: To evaluate the correlation between the depth and area of retinal nerve fiber layer (RNFL) defect, as measured on an RNFL map of spectral-domain optical coherence tomography (SD-OCT). METHODS: The RNFL of 472 glaucoma subjects and of 217 healthy subjects was imaged by an SD-OCT. RNFL defect depth and area on the RNFL map were expressed as an RNFL defect depth percentage index (RDPI) and an RNFL defect area index (RDAI), respectively, according to the following two formulas: 100*[1-{summation of thicknesses of RNFL defects/summation of thicknesses of upper 95th percentile range of age-matched healthy subjects in areas corresponding to defects}]; 100*[number of superpixels of RNFL defects/(46 * 46-superpixels inside optic disc or beta zone parapapillary atrophy)]. The best fitting model describing the relationship between the two parameters was derived by fractional polynomial analysis. RESULTS: Logarithmic fit was determined to be the best-fitting model in describing the relationship of the RDPI against the RDAI (y = 53.4 + 3.7 ln(x) and y = 50.9 + 5.9 ln(x) in superior and inferior hemifields, respectively). The expected RDAIs at the point where the RDPI and RDAI rates of change were the same were 3.7 and 5.9 %; the corresponding upper 95 % confidence interval limits of the RDPI 59.0 and 61.8 % in the superior and inferior hemifields, respectively. CONCLUSIONS: The correlation between the RNFL defect depth and area, as derived from the RNFL map, was best described by the logarithmic fit. Changes were more marked in depth than in area, especially for mild localized defects. PMID- 25794987 TI - Treatment of stage 3 Coats' disease by endolaser photocoagulation via a two-port pars plana nonvitrectomy approach. AB - BACKGROUND: To evaluate the effectiveness of endolaser photocoagulation by a two port pars plana nonvitrectomy approach for treating Coats' disease with shallow exudative retinal detachment. METHODS: This study included 24 patients (23 boys with an age range of 2-17 years, and one girl, age 6 years) with stage 3 Coats' disease (25 eyes) from December 2012 and May 2014 at a single center. All of the 25 eyes were complicated with serous or total retinal detachment and received none-vitrectomized endolaser: two (23- or 25-gauge) incisions were routinely made 3 mm posterior to the corneal limbus and a laser was applied directly on the abnormal blood vessels. Additional treatments included subretinal fluid drainage (five eyes), intravitreal triamcinolone injection (seven eyes), and intravitreal anti-vascular endothelial growth factor (VEGF) injection (17 eyes). Best corrected visual acuity, intraocular pressure, and fundus and abnormal vascular changes were recorded to determine therapeutic effects. RESULTS: Twenty-four out of the 25 treated eyes (96 %) had retina reattached. The number of treatment sessions differed case by case (1-5 sessions, average 1.96) and the time to full treatment of retinal reattachment was 4 months in average. One patient (4 %) presented with retinal redetachment. Five (20 %) eyes received further laser treatment with indirect ophthalmoscope and four eyes (16 %) presented with total retinal detachment at their first visits received consecutive treatments. At the end of the follow-up period (mean, 10.08 months), telangiectasias of 24 (96 %) eyes were resolved and no severe complications occurred. CONCLUSIONS: Endolaser photocoagulation by a two-port pars plana nonvitrectomy approach is an effective treatment for advanced Coats' disease with serous retinal detachment. The long term safety of the approach needs further investigation. PMID- 25794988 TI - Oral Rifampin treatment for longstanding chronic central serous chorioretinopathy. AB - PURPOSE: To investigate the effect of oral Rifampin in patients with chronic central serous chorioretinoapthy (CSCR). METHODS: This was a prospective pilot study of patients with chronic CSCR with persistent subretinal fluid (SRF) for at least 3 months, who were treated with oral Rifampin 300 mg twice per day for 3 months and had 6 months of follow-up. All patients underwent a complete ocular examination and a spectral domain optical coherence tomography (SD-OCT) scan monthly from baseline until month 4, and then at month 6. Fluorescein angiography (FA) was performed at baseline and at the end of the study. RESULTS: Fourteen eyes of 12 patients were included in the study, nine men and three women. Mean age was 58.5 years (range 32-80). Mean duration of SRF prior to study entry was 28.4 months. Forty-two percent of eyes were treated previously for CSR with thermal laser, PDT, or intravitreal bevacizumab. Mean best corrected visual acuity (BCVA) at presentation was 20/60 and improved to a mean of 20/50 at month 3 (P > 0.05). Retinal thickness was reduced by 25.3 %, 21.2 %, and 21 % on months 1, 2, 3, respectively (P < 0.05). Mean choroidal thickness at presentation was 476 MU (SD 188 MU) decreasing to 427 MU (SD 125 MU) after 3 months of treatment (P > 0.05). SRF was reduced in nine eyes (64 %) and completely resolved in six eyes (42.8 %) at month 3 following 3 months of treatment, and four out of these six eyes remained fluid free at month 6. Two patients stopped the treatment after 2 months due to adverse events. CONCLUSIONS: Oral Rifampin may be a therapeutic option in patients with longstanding chronic CSCR. PMID- 25794989 TI - For whom the endocannabinoid tolls: Modulation of innate immune function and implications for psychiatric disorders. AB - Toll-like receptors (TLRs) mediate the innate immune response to pathogens and are critical in the host defence, homeostasis and response to injury. However, uncontrolled and aberrant TLR activation can elicit potent effects on neurotransmission and neurodegenerative cascades and has been proposed to trigger the onset of certain neurodegenerative disorders and elicit detrimental effects on the progression and outcome of established disease. Over the past decade, there has been increasing evidence demonstrating that the endocannabinoid system can elicit potent modulatory effects on inflammatory processes, with clinical and preclinical evidence demonstrating beneficial effects on disease severity and symptoms in several inflammatory conditions. This review examines the evidence supporting a modulatory effect of endocannabinoids on TLR-mediated immune responses both peripherally and centrally, and the implications for psychiatric disorders such as depression and schizophrenia. PMID- 25794990 TI - A comparison of Theory of Planned Behavior beliefs and healthy eating between couples without children and first-time parents. AB - OBJECTIVE: To examine the relationship between Theory of Planned Behavior (TPB) beliefs and eating behavior, explore which beliefs have the greatest association with eating behavior, and explore differences between adults without children and first-time parents. DESIGN: Longitudinal evaluation via questionnaires and food records at baseline and 6 and 12 months. PARTICIPANTS: Couples without children (n = 72) and first-time parents (n = 100). MAIN OUTCOME MEASURES: DEPENDENT VARIABLES: fruit and vegetable consumption and fat consumption. INDEPENDENT VARIABLES: TPB beliefs. ANALYSIS: Pearson correlations between TPB beliefs and eating behavior; exploratory data reduction via linear regression. RESULTS: Control beliefs were associated with eating behavior (r = .26-.46; P < .05). After controlling for past behavior, control beliefs were associated with eating behavior for first-time parents only. Control beliefs regarding preparation and time had the strongest associations with fruit and vegetable consumption for mothers (beta = .26; P < .05) and fathers (beta = .38; P < .01). The absence of a ceiling effect for control beliefs suggests room for improvement via intervention. CONCLUSIONS AND IMPLICATIONS: Interventions guided by TPB should target control beliefs to enhance healthy eating among new parents. Strategies (eg, individual, environmental, policy) to enhance control beliefs regarding healthy eating despite limited time and opportunity for preparation may be particularly valuable. PMID- 25794992 TI - How the rheumatologist can guide the patient with rheumatoid arthritis on sexual function. AB - Sexuality, an integral part of human life and quality of life, is one of those responsible for our individual welfare. Sexual dysfunction can be defined as a change in any component of sexual activity, which may cause frustration, pain and decreased sexual intercourse. Although it is known that chronic diseases, such as rheumatoid arthritis (RA), influence the quality of sexual life, sexual dysfunction is still underdiagnosed, due to two reasons: both patients fail to report the complaint because of shame or frustration, and this subject is rarely called into question by doctors. Rheumatologists are increasingly willing to discuss areas which are not directly related to drug treatment of joint diseases, such as quality of life, fatigue, and education of patients; however, sexuality is rarely addressed. The aim of this review is to present some useful concepts to Rheumatologists for orientation of their patients with RA with respect to sexual function/dysfunction, some considerations concerning the role of these professionals in order to instruct the patient, general notions about sexual function, including practical concepts about the more appropriate sexual positions for patients with RA, and a multidisciplinary approach to sexual dysfunction. PMID- 25794991 TI - Food- and health-related correlates of self-reported body mass index among low income mothers of young children. AB - OBJECTIVE: To examine how income-related challenges regarding food and health are associated with variation in self-reported maternal body weight among low-income mothers. DESIGN: Cross-sectional design. SETTING: Two Northeastern cities. Seven day care centers and a Supplemental Nutrition Assistance Program outreach project. PARTICIPANTS: Sample of 166 mothers; 67% were overweight or obese, 55% were Hispanic, and 42% reported household food insecurity (HFI). MAIN OUTCOME MEASURES: Maternal self-reported height and weight to calculate body mass index (BMI). Independent variables were food program participation, supermarket use, 8 item food shopping practices scale, HFI, maternal depressive symptoms, and self rated health. ANALYSIS: Hierarchical multiple regression analysis tested relationships between maternal BMI with the independent variables of interest, adjusting for demographic confounds. RESULTS: Shopping practices to stretch food dollars (P = .04), using community food assistance programs (P < .05), and HFI (P < .04) correlated with heavier maternal BMIs; higher self-rated health corresponded to lower BMIs (P = .004). CONCLUSIONS AND IMPLICATIONS: Some strategies low-income mothers use to manage food resources are associated with heavier BMIs. Nutrition educators, public health practitioners, and researchers need to collaboratively address the associations between these strategies, food insecurity, poor health, and unhealthy weight. PMID- 25794993 TI - Endometrial vs. cervical cancer: development and pilot testing of a magnetic resonance imaging (MRI) scoring system for predicting tumor origin of uterine carcinomas of indeterminate histology. AB - PURPOSE: To report discriminant MRI features between cervical and endometrial carcinomas and to design an MRI- scoring system, with the potential to predict the origin of uterine cancer (cervix or endometrium) in histologically indeterminate cases. MATERIALS AND METHODS: Dedicated pelvic MRIs of 77 patients with uterine tumors involving both cervix and corpus were retrospectively analyzed by two experts in female imaging. Seven MRI tumor characteristics were statistically tested for their discriminant ability for tumor origin compared to final histology: tumor location, perfusion pattern, rim enhancement, depth of myometrial invasion, cervical stromal integrity, intracavitary mass, and retained endometrial secretions. Kappa values were estimated to assess the levels of inter rater reliability. On the basis of positive likelihood ratio values, an MRI-score was assigned. RESULTS: K value was excellent for most of the imaging criteria. Using ROC curve analysis, the estimated optimal cut-off for the MRI-scoring system was 4 with 96.6% sensitivity and 100% specificity. Using a >=4 cut-off for cervical cancers and <4 for endometrial cancers, 97.4% of the patients were correctly classified. 2/58 patients with cervical cancer had MRI score <4 and none of the patients with endometrial cancer had MRI score >4. The area under curve of the MRI-scoring system was 0.99 (95% CI 0.98-1.00). When the MRI-score was applied to 20/77 patients with indeterminate initial biopsy and to 5/26 surgically treated patients with erroneous pre-op histology, all cases were correctly classified. CONCLUSION: The produced MRI-scoring system may be a reliable problem-solving tool for the differential diagnosis of cervical vs. endometrial cancer in cases of equivocal histology. PMID- 25794994 TI - Value of magnetic resonance imaging in evaluating the pancreatic allograft transplant complications. AB - PURPOSE: To retrospectively investigate the value of magnetic resonance imaging (MRI) in detecting complications following pancreas transplant. MATERIALS AND METHODS: Institutional review board approved this retrospective HIPAA-compliant study and waived informed patient consent. We identified all allograft pancreas transplant patients at our institution from 2001 to January 2014 who had all pertinent post-transplant imaging and clinical data available. Transplant type was documented. Patients were divided into two groups according to post transplant period (group A; <12 months, group B; >=12 months). We evaluated the parenchymal enhancement using contrast-enhanced MRI of the allograft and determined the mean percentage of parenchymal enhancement (MPPE) overall and in various abnormalities, the vessel patency, any peripancreatic fluid collection, and the ductal anatomy. We correlated these with clinical results using t test, chi (2), and Fisher's exact test; p < 0.05 was considered significant. RESULTS: 51 patients (34 male, mean age 43.7 years) were identified, 28 (55%) of whom had abnormal imaging findings; transplant rejection-related necrosis (n = 7), fluid collections (n = 7), vascular stenosis (n = 4), isolated venous thromboses (n = 3), acute pancreatitis (n = 3), pancreatic and peripancreatic abscesses (n = 2), pseudoaneurysm (n = 1), and small-bowel obstruction (n = 1). Pre vs. post contrast pancreatic MPPE at 1 min was 120% in the normal allografts and 115% in the allografts with pancreatitis and without necrosis (p > 0.05). MPPE at 1 min was only 9% in the allografts rejections with necrosis/infarction. More complications were found in group A than group B (p < 0.05). CONCLUSIONS: Contrast-enhanced MRI is useful for the non-invasive assessment of pancreas transplant complications. PMID- 25794995 TI - Significance of the mucinous component in the histopathological classification of colon cancer. AB - PURPOSE: Mucinous carcinoma is often independently classified as a histological type of colon cancer, but there are currently no established diagnostic criteria. The relationship between the proportions of mucinous components to the oncological outcomes was examined to determine whether mucinous carcinoma should be classified as an independent histological type. METHODS: The study group comprised 1,038 patients with colon cancer. The relationships between the survival rates and recurrence patterns with the mucinous component area ratio (MC area ratio) and clinical variables were evaluated. RESULTS: Tumors were classified into three groups: Group 1 (MC area ratio, 0 %), Group 2 (1-49 %), and Group 3 (>=50 %). Of the 1038 tumors studied, 877 (84 %) were classified as Group 1, 123 (12 %) as Group 2, and 38 (4 %) as Group 3. The tumor size was significantly larger in Group 3, and an increased MC area ratio was significantly related to a higher proportion of right-sided tumors. Among patients with stage II or III disease, stage III disease, poorly differentiated adenocarcinoma, and no adjuvant chemotherapy were poor prognostic factors. There was no relationship between the MC area ratio and the survival or recurrence pattern. CONCLUSION: Mucinous carcinoma does not need to be classified as a separate histological type from ordinary differentiated adenocarcinoma. PMID- 25794996 TI - [Role of the Sonic Hedgehog pathway in thoracic cancers]. AB - INTRODUCTION: Sonic Hedgehog (Shh) pathway is physiologically activated during embryogenesis and development. It plays a role in idiopathic lung fibrosis and is also activated in several solid cancers. STATE OF THE ART: Shh pathway is reactivated in thoracic cancers, as small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma. Shh pathway is associated with cancer stem cells and seems to have a crucial role in tumor proliferation, aggressiveness and chemoresistance in these cancers. This review describes the activation mode of Shh pathway in thoracic cancers and its role in small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma, using in vitro and in vivo models. Notably, data from literature show that inhibition of Shh pathway has an antitumor action and sensitizes to chemotherapy. PERSPECTIVES: These results incite to develop targeted therapies against Shh pathway in the treatment of thoracic cancers. PMID- 25794997 TI - [Miliary cerebral carcinomatosis secondary to EGFR mutation-positive lung adenocarcinoma]. AB - INTRODUCTION: Miliary brain metastases are a rare form of brain metastatic lesions. CASE REPORT: We report the case of a 58-year-old patient with lung adenocarcinoma and an EGFR mutation, who had metastatic lesions in the bones, pleura and pericardia at the time of diagnosis. The patient was treated with tyrosine kinase inhibitor. A few months later, he presented with progressive neuropsychiatric symptoms, which were attributed to miliary brain metastases based on the radiological pattern (micronodules, some of which were calcified) and the elimination of alternative possible diagnoses. Despite tumour stability in the thorax and metastatic sites other than the brain, his neurological condition deteriorated, even after cerebral radiotherapy, leading to his death eight months after the diagnosis of lung cancer. CONCLUSION: Miliary brain metastases are a rare form of brain metastases with unusual clinical presentation. The diagnosis is based on the radiological pattern of cerebral miliary dissemination, with sometimes calcified tumor nodules. Despite its rarity, several cases have been reported in lung adenocarcinoma in the presence of EGFR mutations. PMID- 25794999 TI - Effects of various factors of ultrasonic treatment on the extraction recovery of drugs from fish tissues. AB - In the present research, a combined extraction method of ultrasound-assisted extraction (UAE) in conjunction with solid phase extraction (SPE) was applied to isolation and enrichment of selected drugs (metoprolol, ticlopidine, propranolol, carbamazepine, naproxen, acenocumarol, diclofenac, ibuprofen) from fish tissues. The extracted analytes were separated and determined by ultra-high performance liquid chromatography with UV detection (UHPLC-UV) technique. The selectivity of the developed UHPLC-UV method was confirmed by comparison with ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The important parameters, such as composition of type and pH of extraction solvent, solid/liquid rate volume of extraction solvent and number of extraction cycles were studied. The ultrasonic parameters, such as time, power and temperature of the process were optimized by using a half-fraction factorial central composite design (CCD). The mixture of 10 mL of methanol and 7 mL of water (pH 2.2) (three times) was chosen for the extraction of selected drug from fish tissues. The results showed that the highest recoveries of analytes were obtained with an extraction temperature of 40 degrees C, ultrasonic power of 300 W, extraction time of 30 min. Under the optimal conditions, the linearity of method was 0.12-5.00 MUg/g. The determination coefficients (R(2)) were from 0.979 to 0.998. The limits of detection (LODs) and limits of quantification (LOQs) for the extracted compounds were 0.04-0.17 MUg/g and 0.12-0.50 MUg/g, respectively. The recoveries were between 85.5% and 115.8%. PMID- 25794998 TI - [Genetic and environmental factors of asthma and allergy: Results of the EGEA study]. AB - INTRODUCTION AND METHODS: The EGEA study (epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), which combines a case-control and a family-based study of asthma case (n=2120 subjects) with three surveys over 20 years, aims to identify environmental and genetic factors associated with asthma and asthma-related phenotypes. We summarize the results of the phenotypic characterization and the investigation of environmental and genetic factors of asthma and asthma-related phenotypes obtained since 2007 in the EGEA study (42 articles). RESULTS: Both epidemiological and genetic results confirm the heterogeneity of asthma. These results strengthen the role of the age of disease onset, the allergic status and the level of disease activity in the identification of the different phenotypes of asthma. The deleterious role of active smoking, exposure to air pollution, occupational asthmogenic agents and cleaning products on the prevalence and/or activity of asthma has been confirmed. Accounting for gene-environment interactions allowed the identification of new genetic factors underlying asthma and asthma-related traits and better understanding of their mode of action. CONCLUSION: The EGEA study is contributing to the advances in respiratory research at the international level. The new phenotypic, environmental and biological data available in EGEA study will help characterizing the long-term evolution of asthma and the factors associated to this evolution. PMID- 25795000 TI - Pulsed ultrasound assisted dehydration of waste oil. AB - A method to aid the separation of the oil phase from waste oil emulsion of refineries had been developed by using a pulsed ultrasonic irradiation technology. Compared with conventional continuous ultrasonic irradiation, it is found that pulsed ultrasonic irradiation is much better to make water drop coalescence and hence dehydration of waste oil. The effects of ultrasonic irradiation parameters on waste oil dehydration are further discussed. The orthogonal experiment is also designed to investigate the degrees of influence of ultrasonic parameters and the optimal technological conditions. Under the optimal experimental conditions, the water content of waste oil is decreased from 65% to 8%, which thereby satisfies the requirements of refineries on the water content of waste oil after treatment (<10%). PMID- 25795001 TI - [The epidemiology of type 1 diabetes: helping to fit the puzzle pieces]. PMID- 25795003 TI - Perspectives in Biological Monitoring of Inhaled Nanosized Particles. AB - Given the results of experimental studies, occupational or environmental exposures to manufactured nanoparticles or to unintentionally produced ultrafine particles may result in health effects or diseases in humans. In this review, we synthesize published data of experimental studies on the distribution of inhaled nanoparticles and the first case reports to discuss the potential usefulness of their biological monitoring for clinical purposes. Toxicokinetic studies suggest that nanoparticles may be absorbed predominantly by respiratory and oral routes with possible systemic translocation, leading to accumulation in the peripheral organs or excretion in feces or urine. Some methods used in these studies may be applied successfully in retrospective evaluation of exposure or in follow-up of occupational exposure in the workplace. Biological monitoring of nanoparticles should be based on imaging methods that are essential to confirm their presence and to characterize them in tissue associated with analytical quantitative methods. The first case reports reviewed emphasize the urgent need for the development of standardized procedures for the preparation and analysis of biological samples with a view to characterizing and quantifying nanoparticles. PMID- 25795002 TI - Statin treatment in multiple sclerosis: a systematic review and meta-analysis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease that leads to progressive disability. Statins [hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors] are widely prescribed drugs in hypercholesterolemia. They exert immunomodulatory and neurotrophic effects and are attractive candidates for MS treatment due to reliable safety profiles and favorable costs. Studies of statins in a murine MS model and in open-label trials in MS have shown decreased disease severity. OBJECTIVE: Our objective was to assess current evidence to support statin treatment in MS and clinically isolated syndrome (CIS). METHODS: We conducted a systematic literature review of EMBASE, PubMed, and CINAHL databases, clinical trials registries, and unpublished conference meeting abstracts as well as reference lists between 1 and 8 June 2014 and repeated it on 1 December 2014. Randomized controlled trials (RCTs) of statins, in any form or dosage, as monotherapy or add-on to established therapy in relapsing-remitting MS (RRMS), progressive MS, and CIS were included. Data were extracted using pre-defined fields to measure study quality. Meta-analysis was performed with regards to pre defined outcome measures of relapse activity, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) progression, and adverse events using a fixed-effects model due to low heterogeneity between studies. RESULTS: Eight trials were included in the review [five of statin add-on to interferon (IFN)-beta treatment in RRMS, one of statin monotherapy in CIS, one of statin monotherapy in optic neuritis (ON)/CIS, and one of statin monotherapy in secondary progressive MS (SPMS)]. Three trials with eligible characteristics had not been published in peer-reviewed journals and were therefore not included. Due to the low number of trials in CIS and SPMS, meta-analysis of primary outcomes was only performed for RRMS studies. Meta-analysis showed no significant effect of statin add-on to IFNbeta therapy. Indeed, a trend towards an increase in disease activity was shown in the statin group with regards to new T2 lesions, proportion of patients with relapse, and whole brain atrophy but not for EDSS progression. In SPMS, statin monotherapy showed significant reduction in brain atrophy and disability progression but no effect on relapse rate. In CIS, a phase II trial showed no difference in relapse activity, MRI activity or risk of MS between statin monotherapy and placebo. In acute ON, statin monotherapy produced better visual outcome but no difference in relapse activity, MRI activity, or risk of MS. CONCLUSIONS: The pleiotropic effects and effects in the murine model of MS could not be converted to a proven effect in relapsing MS and hence statin therapy either as a monotherapy or in combination with IFNbeta treatment for RRMS, and statin monotherapy for CIS cannot at present be recommended. However, indications are that statins may be beneficial in SPMS. The benefit thereof and whether this is due to a direct immunomodulatory and neuroprotective effect warrant further studies. PMID- 25795004 TI - A clinical decision rule identifies risk factors associated with antimicrobial resistant urinary pathogens in the emergency department: a retrospective validation study. AB - BACKGROUND: Identifying patients at high risk for multidrug-resistant urinary tract infections (UTIs) is important for guiding empirical antimicrobial therapy. Clinical risk factors associated with antimicrobial-resistant urinary pathogens and the derivation of a simple clinical decision rule could help define health care-associated UTI. OBJECTIVE: To derive a simple clinical decision rule to identify clinical risk factors associated with antimicrobial-resistant urinary pathogens. METHODS: This was a retrospective case-control study of all emergency department (ED) patients from July 1, 2011, to July 1, 2012, who presented to the ED with UTI and a positive urine culture. Candidate risk factors were collected retrospectively from medical record review. We compared differences in patient characteristics stratified by the presence of an antimicrobial-resistant urinary pathogen. RESULTS: A total of 360 patients with UTI had a positive, noncontaminated urine culture during the study period. About 6.7% of patients (n = 24) had a multidrug-resistant (MDR) urinary infection. Logistic regression modeling identified 3 clinical factors associated with the identification of a MDR pathogen: male sex, chronic hemodialysis, and nursing home residence. A scoring system was created to identify patients with MDR pathogens. Test characteristics were calculated using bootstrapping for internal validation, with a sensitivity of 74.7% (95% CI = 55.1%-91.3%) and specificity of 85.1% (95% CI = 77.8%-86.2%), positive likelihood ratio of 4.3, and a negative likelihood ratio of 0.3. CONCLUSIONS: Clinical factors can be used to identify UTI patients at high risk of MDR urinary pathogens. PMID- 25795005 TI - Buccal micronucleus cytome assay: results of an intra- and inter-laboratory scoring comparison. AB - The buccal micronucleus cytome (BMCyt) assay is a minimally invasive approach for measuring DNA damage, cell proliferation, cell differentiation and cell death in exfoliated buccal cells. The main limitation for its use is the lack of knowledge about inter- and intra-laboratory variability in scoring micronuclei and other end points included in the cytome approach. In order to identify the main sources of variability across the BMCyt biomarkers, a scoring exercise was carried out between three experienced laboratories using the same set of slides and an identical set of detailed scoring criteria and associated images for the different end points. Single batches of slides were prepared from pooled samples of four groups of subjects characterised by different frequencies of cell types and micronuclei, namely Down syndrome patients, head and neck cancer patients undergoing radiotherapy and two age- and gender-matched control groups. A good agreement among the laboratories in the identification of normal differentiated cells and of micronuclei was obtained. A 3-fold and 20-fold increase in the frequency of micronucleated cells and micronuclei in differentiated cells of Down syndrome patients and in cancer patients, respectively, compared to matched controls, was a consistent result in the three laboratories. The scores of other cell types and nuclear anomalies, such as basal, binucleated, condensed chromatin and karyorrhectic cells showed significant disagreement between and within laboratories indicating that their evaluation using the current visual scoring protocol does not yield robust results for these parameters. The guidelines for BMCyt assay application could be improved by combining the anomalies associated with cell death (condensed chromatin and karyorrhectic cells) in a single category and by defining more stringent criteria in classifying basal cell, binucleated cells and buds. PMID- 25795006 TI - Coronal T2 weighted image of the right iliac fossa from a magnetic resonance enteroclysis study. PMID- 25795008 TI - Factors Influencing the Intent to Migrate in Nursing Students in South Korea. AB - PURPOSE: To identify Korean nursing students' level of intent to migrate and the factors influencing their intention to migrate. METHOD: Using a cross-sectional correlational design, data were collected from 886 nursing students in two nursing schools. Data were analyzed using descriptive statistics, chi-square tests, and hierarchical multiple regressions with SPSS version 18. RESULTS: Nursing students had moderate levels of intent to migrate. Variables that were independently associated with intention to migrate were class year and having previously considered the possibility of overseas employment on admission to nursing school. The full model accounted for 45.1% of the variance in intention to migrate. CONCLUSION: The most significant predictor of intent to migrate by nursing students was the possibility of overseas employment on admission to nursing school. To more positively manage the intent to migrate, appropriate strategies to enhance the nursing work environment should be investigated. PMID- 25795007 TI - BRAFV600E Co-opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8+ T-cell Recognition of Melanoma. AB - Oncogene activation in tumor cells induces broad and complex cellular changes that contribute significantly to disease initiation and progression. In melanoma, oncogenic BRAF(V600E) has been shown to drive the transcription of a specific gene signature that can promote multiple mechanisms of immune suppression within the tumor microenvironment. We show here that BRAF(V600E) also induces rapid internalization of MHC class I (MHC-I) from the melanoma cell surface and its intracellular sequestration within endolysosomal compartments. Importantly, MAPK inhibitor treatment quickly restored MHC-I surface expression in tumor cells, thereby enhancing melanoma antigen-specific T-cell recognition and effector function. MAPK pathway-driven relocalization of HLA-A*0201 required a highly conserved cytoplasmic serine phosphorylation site previously implicated in rapid MHC-I internalization and recycling by activated immune cells. Collectively, these data suggest that oncogenic activation of BRAF allows tumor cells to co-opt an evolutionarily conserved MHC-I trafficking pathway as a strategy to facilitate immune evasion. This link between MAPK pathway activation and the MHC-I cytoplasmic tail has direct implications for immunologic recognition of tumor cells and provides further evidence to support testing therapeutic strategies combining MAPK pathway inhibition with immunotherapies in the clinical setting. PMID- 25795009 TI - Identification of novel biomarkers for Parkinson's disease by metabolomic technologies. AB - OBJECTIVE: The pathogenesis of Parkinson's disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD. METHODS: Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS). RESULTS: The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies. CONCLUSIONS: Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts. PMID- 25795010 TI - Microcentrifuge or Automated Hematological Analyzer to Assess Hematocrit in Exercise? Effect on Plasma Volume Loss Calculations. AB - The assessment of plasma volume loss (?PV) induced by exercise can be estimated from changes in hematocrit (Htc) and hemoglobin (Hb), and it is essential when investigating the metabolic or biologic response to exercise of circulating biomarkers. We aimed to ascertain whether the estimation of ?PV may differ when Hb and Htc are determined by automated hematological analyzer (AHA) versus manual methods. Twenty-five healthy male subjects performed a maximal running incremental exercise. Blood samples were taken before exercise, immediately after exercise, and after a 30-min recovery. Hb and Htc (Htc-AHA) were determined by an AHA. Htc was also determined by microcentrifugation (Htc-M). The ?PV immediately after exercise and after recovery was calculated. The serum concentrations of several specimens were determined and corrected for ?PV derived from Htc-AHA (?PVAHA) and from Htc-M (?PVM). Htc-M was found to be higher than Htc-AHA at all time points (p < 0.001). However, no differences were observed between ?PVM and ?PVAHA either post exercise (?PVM -12.43% versus ?PVAHA -12.41%, p = 0.929) or after recovery (?PVM 1.47% versus ?PVAHA 1.97%, p = 0.171). No significant differences were found between both ?PV corrected concentrations of any biomarker (p >= 0.076). In conclusion, both AHA and the microcentrifuge may be reliably used to estimate ?PV during exercise. PMID- 25795011 TI - Erratum to: Toddlers' temperament profiles: stability and relations to negative and positive parenting. AB - Erratum to: J Abnorm Child Psychol (2010) 38:485-495 DOI 10.1007/s10802-009-9379 0. The authors would like to note an error in the method section of this paper. The error is on page 487 in the description of the ages of the children in the study. At T2 and T3 the children's mean ages were 31 months (SD=6.5, range=19 44), and 36 months (SD=6.4, range=24-49) respectively, and not 36 months (SD=6.5, range=26-49) and 39 months (SD=6.5, range=27-51), as originally described in the paper. For T4, the mean age of the children was correct (42 months), but the standard deviation was 6.3, and the range was 30-55 months (rather than SD=6.5, range = 40-55). This error has no implications for the analysis of the reported results, as the loadings of the T2 and T3 assessments in the growth curves were freely estimated to allow for non-linearity of change. The PMID- 25795012 TI - The Social, Behavioral, and Emotional Correlates of Bullying and Victimization in a School-Based Sample. AB - Bullying is a prevalent problem in schools that is associated with a number of negative outcomes for both the child who bullies and his or her victims. In a community sample of 284 ethnically diverse school-children (54.2 % girls) between the ages of 9 and 14 years (M = 11.28, SD = 1.82), the current study examined whether the level of victimization moderated the association between bullying and several behavioral, social, and emotional characteristics. These characteristics were specifically chosen to integrate research on distinct developmental pathways to conduct problems with research on the characteristics shown by children who bully others. Results indicated that both bullying and victimization were independently associated with conduct problems. However, there was an interaction between bullying and victimization in the prediction of callous-unemotional (CU) traits, such that the association between bullying and CU traits was stronger for those lower on victimization. Further, bullying was positively associated with positive attitudes towards bullying and anger expression and neither of these associations were moderated by the level of victimization. In contrast, bullying was not associated with the child's perceived problems regulating anger, suggesting that children with higher levels of bullying admit to expressing anger but consider this emotional expression as being under their control. PMID- 25795013 TI - Effects of Adolescent Universal Substance Misuse Preventive Interventions on Young Adult Depression Symptoms: Mediational Modeling. AB - Depression symptoms are associated with impairments in functioning and have substantial health and economic consequences. Universal substance misuse prevention programs have shown effects on non-targeted mental health-related symptoms, but long-term effects are understudied. This cluster randomized controlled trial examined effects of both the LifeSkills Training (LST) and Strengthening Families Program: For Parents and Youth 10-14 (SFP 10-14) interventions, delivered during seventh grade, on age 22 young adult depression symptoms. The study was conducted in US rural Midwestern communities with a randomly-selected sample from a larger study (N = 670). Experimental conditions were LST+SFP 10-14, LST-only, and a control condition. Effects on age 22 depression symptoms were hypothesized as mediated through effects on age 21 relationship problems and illicit use of substances. Structural equation modeling with manifest and latent variables was conducted to test hypotheses; the intervention conditions were combined and compared with the control condition because analyses indicated a comparable pattern of effects between intervention conditions. Significant indirect intervention effects were found on age 22 depression symptoms via effects on the mediating variables (indirect effect: beta = -0.06, 95 % CI [-0.10, -0.01], p = 0.011). Effect sizes for the young adult variables were between d = 0.17 and 0.29, which can be considered small, but nontrivial, especially in the context of public health benefits. Results support scaled-up implementation of school-based and family-focused universal substance misuse preventive interventions. PMID- 25795014 TI - Symptom Trajectories Among Child Survivors of Maltreatment: Findings from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). AB - Very few studies have investigated the longitudinal trajectory of depression and anxiety related symptomatology among child victims of maltreatment or among those at risk for maltreatment. The current study examined latent class trajectories of anxiety/depression symptoms in a sample of 1354 (n = 657 boys, n = 697 girls) victimized or at risk children using data collected from the Longtitudinal Studies of Child Abuse and Neglect (LONGSCAN). Four trajectory groups were identified labeled low-stable, moderate-stable, moderate-increasing, and high decreasing. This study also sought to investigate predictors of group membership. Relative to the low-stable group, membership in the three more pathological groups (i.e., moderate-stable, moderate-increasing, and high-decreasing) was predicted by a greater number of maltreatment allegations, more visits to a primary care physician for psychological issues, less perceived support by primary maternal caregiver, and lower rated popularity of the child. Implications for early identification of child maltreatment victims in primary health care settings was discussed. PMID- 25795015 TI - Tuberculosis report among injection drug users and their partners in Kazakhstan. AB - OBJECTIVES: Tuberculosis (TB) is a major threat to global public health. Kazakhstan has the second highest percentage of multidrug-resistant tuberculosis (MDR-TB) cases among incident tuberculosis cases in the world (WHO 2013). A high burden of MDR-TB suggests TB prevention, control, and treatment programs are failing. This study provides an epidemiologic profile of TB among injection drug users (IDUs), a high-risk and chronically underserved population, in Kazakhstan. STUDY DESIGN: Cross-sectional study. METHODS: The authors studied the characteristics and risk environment of IDUs with self-reported previous active TB and their primary sexual partners in Almaty, Kazakhstan. 728 individuals (364 couples) participated in a couple-based study in 2009. RESULTS: 16.75% of participants reported at least one positive TB test (x-ray) in their lifetime. In a multivariable logistic regression adjusting for couple-based sampling, persons with positive TB test were significantly more likely to be older (odds ratio (OR) 7.26, 95% confidence interval (CI): 1.73, 30.43), male (OR 5.53, 95% CI: 2.74, 11.16), have a shorter duration of injection drug use (OR 0.17, 95% CI: 0.04, 0.65), have received high social support from their significant other (OR 2.13, 95% CI: 1.03, 4.40) and more likely (non-significantly) to have been incarcerated (OR 7.03, 95% CI: 0.64, 77.30). CONCLUSIONS: Older men with a history of incarceration and recent injection drug use were more likely to have positive TB test in Kazakhstan. Social network support, while potentially positive for many aspects of population health, may increase risk of TB among IDUs in this context. Public health policies that target high-risk populations and their at-risk networks may be necessary to stem the rise of MDR-TB in Central Asia. PMID- 25795016 TI - Predictors of medication use in the Roma population in Spain: a population-based national study. AB - OBJECTIVES: To describe the prevalence of prescribed and self-medicated use of medication in the Spanish Roma population, and identify the associated factors. STUDY DESIGN: Descriptive cross-sectional study. METHODS: Data from the first National Health Survey conducted on the Roma population in Spain were used. The sample comprised 1000 Spanish Roma adults of both sexes aged >=16 years. Answers (yes/no) to the question, 'In the last two weeks have you taken the following medicines [in reference to a list of medicines that might be used by the population] and were they prescribed for you by a doctor?' were used to ascertain 'medication use'. 'Self-medication' referred to use of these medicines without medical prescription. Using multivariate logistic regression models, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to identify associated factors. RESULTS: The overall prevalence of medication use in the Roma population for both sexes was 69.1%, and 38.7% was self-medicated. Females reported higher use of medication than males (75.1% vs 62.3%); however, self-medication was higher among males. Analgesics and antipyretics were used most often (35.8%). Among males, the variables that were independently and significantly associated with a higher probability of medication use were: age; negative perception of health; presence of chronic disease (OR 2.81; 95% CI 1.67-4.73); and medical visits (OR 4.51; 95% CI 2.54-8.01). The variables were the same among females, except for age. CONCLUSION: A high percentage of the Spanish Roma population use medication, and a significant proportion of them self-medicate. The presence of chronic diseases, a negative perception of health and medical consultations were associated with increased use of medication in the study population. PMID- 25795017 TI - Assessment of timeliness, representativeness and quality of data reported to Italy's national integrated surveillance system for acute viral hepatitis (SEIEVA). AB - OBJECTIVES: Periodic assessment of surveillance systems is recommended to verify whether they are appropriately monitoring the public health problem under surveillance. The aim of this study was to evaluate timeliness, data quality and representativeness of data reported to the Italian Integrated Epidemiological System for Acute Viral Hepatitis (SEIEVA). STUDY DESIGN: Cross-sectional analysis of surveillance data. METHODS: Quantitative indicators were used to evaluate representativeness of reported cases, data quality, and timeliness between surveillance steps, for reports of acute viral hepatitis cases with date of onset of symptoms from 2009 to 2012 (N = 4516). RESULTS: Representativeness was 75%. Over 95% of records reported information on age, sex, city of residence, risk factors for hepatitis A and vaccination status. Information on risk factors for hepatitis B and C were reported less consistently (83%), as was information on early outcome (60%). Wide delays were found between surveillance steps. CONCLUSIONS: The system collects high quality data on acute viral hepatitis cases in Italy. Timeliness was found to be the main limit and needs to be improved by optimizing web-based reporting procedures, increasing communication with participating centres, improving feedback and increasing dissemination of surveillance results. The study highlights the importance of reporting timeliness to detect outbreaks of acute viral hepatitis. PMID- 25795018 TI - Accessing evidence to inform public health policy: a study to enhance advocacy. AB - OBJECTIVES: Improving population health often involves policy changes that are the result of complex advocacy efforts. Information exchanges among researchers, advocates, and policymakers is paramount to policy interventions to improve health outcomes. This information may include evidence on what works well for whom and cost-effective strategies to improve outcomes of interest. However, this information is not always readily available or easily communicated. The purposes of this paper are to describe ways advocates seek information for health policy advocacy and to compare advocate demographics. STUDY DESIGN: Cross-sectional telephone survey. METHODS: Seventy-seven state-level advocates were asked about the desirable characteristics of policy-relevant information including methods of obtaining information, what makes it useful, and what sources make evidence most reliable/trustworthy. Responses were explored for the full sample and variety of subsamples (i.e. gender, age, and position on social and fiscal issues). Differences between groups were tested using t-tests and one-way analysis of variance. RESULTS: On average, advocates rated frequency of seeking research information as 4.3 out of five. Overall, advocates rated the Internet as the top source, rated unbiased research and research with relevancy to their organization as the most important characteristics, and considered information from their organization as most reliable/believable. When ratings were examined by subgroup, the two characteristics most important for each question in the total sample (listed above) emerged as most important for nearly all subgroups. CONCLUSIONS: Advocates are a resource to policymakers on health topics in the policy process. This study, among the first of its kind, found that advocates seek research information, but have a need for evidence that is unbiased and relevant to their organizations and report that university-based information is reliable. Researchers and advocates should partner so research is useful in advocating for evidence-based policy change. PMID- 25795019 TI - Comparative reactivity of the myeloperoxidase-derived oxidants HOCl and HOSCN with low-density lipoprotein (LDL): Implications for foam cell formation in atherosclerosis. AB - Atherosclerosis is characterised by the accumulation of lipids within macrophages in the artery wall. Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces oxidants that are implicated in atherosclerosis. Modification of LDL by the MPO oxidant hypochlorous acid (HOCl), results in extensive lipid accumulation by macrophages. However, the reactivity of the other major MPO oxidant, hypothiocyanous acid (HOSCN) with LDL is poorly characterised, which is significant given that thiocyanate is the favoured substrate for MPO. In this study, we comprehensively compare the reactivity of HOCl and HOSCN with LDL, and show key differences in the profile of oxidative damage observed. HOSCN selectively modifies Cys residues on apolipoprotein B100, and oxidises cholesteryl esters resulting in formation of lipid hydroperoxides, 9-hydroxy-10,12-octadecadienoic acid (9-HODE) and F2 isoprostanes. The modification of LDL by HOSCN results macrophage lipid accumulation, though generally to a lesser extent than HOCl-modified LDL. This suggests that a change in the ratio of HOSCN:HOCl formation by MPO from variations in plasma thiocyanate levels, will influence the nature of LDL oxidation in vivo, and has implications for the progression of atherosclerosis. PMID- 25795020 TI - (-)-Epicatechin in the prevention of tumor necrosis alpha-induced loss of Caco-2 cell barrier integrity. AB - An increased permeability of the intestinal barrier is proposed as a major event in the pathophysiology of inflammatory bowel diseases (IBD). Tumor necrosis alpha (TNFalpha) plays a central role in IBD pathogenesis, in part promoting tight function (TJ) barrier dysfunction. Food extracts enriched in (-)-epicatechin (EC) prevent the development or improve the progression of IBD in animal models. This study investigated the capacity of EC to inhibit TNFalpha-induced permeabilization of Caco-2 cell monolayers, characterizing the underlying mechanisms. Caco-2 cells differentiated into intestinal epithelial cells were incubated in the absence/presence of TNFalpha, with or without the addition of 0.5-5 MUM EC. TNFalpha triggered cell monolayer permeabilization, decreasing transepithelial electrical resistance (TEER) and increasing the paracellular transport of fluorescein sulfonic acid. The permeabilizing effects of TNFalpha were not due to Caco-2 cell apoptosis as evaluated by DNA fragmentation, caspase 3 and 9 activation, and cell morphology. EC prevented TNFalpha-triggered Caco-2 monolayer permeabilization and acted inhibiting the associated: (i) NADPH oxidase (NOX)-mediated increased oxidant production, (ii) NF-kappaB (IkappaBalpha phosphorylation, p50 and RelA nuclear transport, and nuclear NF-kappaB-DNA binding) and ERK1/2 activation, (iii) increased myosin light kinase expression, and decreased TJ protein ZO-1 levels. In summary, EC prevented TNFalpha-mediated Caco-2 cell barrier permeabilization in part through the inhibition of NOX/NF kappaB activation and downstream TJ disruption. Diets rich in EC could contribute to ameliorate IBD-associated increased intestinal permeability. PMID- 25795021 TI - Targeted agents for cancer treatment during pregnancy. AB - The last decade has witnessed important advances in the field of managing cancer during pregnancy. However, still limited data is available on the safety of administering targeted agents in pregnant cancer patients. Given the increasing use of targeted agents in clinical practice, it is becoming vital to properly understand how far they can be used in a pregnant patient without compromising the outcome of the fetus. Unlike chemotherapy, monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus. On the other hand, similarly to chemotherapy, small molecules like tyrosine kinase inhibitors (TKIs) can cross the placenta throughout the pregnancy period. The majority of targeted agents have worrying preclinical data discouraging their use during pregnancy. Multi-TKIs are of particular concern given their potential interference with other vital physiological functions that could be necessary in fetal development. Yet this does not mean that all targeted agents should be avoided completely during pregnancy. The current review provides a critical evaluation on all targeted agents that are currently in clinical use and provides a guide in order to help clinicians counseling their pregnant cancer patients. PMID- 25795023 TI - Complete genome sequence of vB_DshP-R2C, a N4-like lytic roseophage. AB - vB_DshP-R2C, a lytic phage that infects the marine bacterium Dinoroseobacter shibae DFL12(T), one of the model organisms of the Roseobacter clade, was isolated. Here we report the overall genome architecture of R2C. Genome analysis revealed that R2C is an N4-like phage with a 74.8 kb genome that contains 85 putative gene products. PMID- 25795022 TI - Complete genome sequence of Bacillus sp. YP1, a polyethylene-degrading bacterium from waxworm's gut. AB - Bacillus sp. strain YP1, isolated from the gut of waxworm (the larvae of Plodia interpunctella) which ate polyethylene (PE) plastic, is capable of degrading PE and utilizing PE as sole carbon source. Here we report the complete genome sequence of strain YP1, which is relevant to polyethylene depolymerization and biodegradation. PMID- 25795024 TI - In-depth transcriptome analysis of Coilia ectenes, an important fish resource in the Yangtze River: de novo assembly, gene annotation. AB - Coilia ectenes is an important teleost species in the Yangtze River and a model organism that can be used to study the protection of fish resources. In this report, we performed de novo transcriptome sequencing of ten cDNA libraries from the brain, gill, heart, intestine, kidney, liver, muscle, stomach, ovary, and testis tissues. A total of 352 million raw reads of 100 base pairs were generated, and 130,113 transcripts, corresponding to 65,350 non-redundant transcripts, with a mean length of 1520 bp, were assembled. BLASTx-based gene annotation (E-value<1 * 10(-5)) allowed the identification of 73,900 transcripts against at least one of four databases, including the NCBI non-redundant database, the GO database, the COG database, and the KEGG database. Our study provides a valuable resource for C. ectenes genomic and transcriptomic data that will facilitate future functional studies of C. ectenes. PMID- 25795025 TI - Age related diastolic function in amateur athletes. AB - Diastolic function get worse with increasing age. Aim of this study was to investigate the impact of aerobic training on diastolic function with increasing age with speckle tracking echocardiography. We enrolled 125 amateur swimmers (AG), divided in three groups at increasing age: young athletes, adult athletes (AG2), old athletes (AG3). We enrolled 95 sedentary controls (SG) age-matched with athletes and divided into three groups: young sedentary group, adult sedentary group (SG2) and old sedentary group (SG3). AG had better diastolic function than SG. AG showed lower left ventricular twist than controls. E/A ratio got worse at increasing of age in all population (r = -0.34; p < 0.001); particularly in SG2 and SG3 there was a worsening of diastolic function respect to diastolic function of AG2 and AG3; in fact E/A ratio decreased with aging. Furthermore in SG E/A ratio showed a linear correlation with age (r = -0.54; p < 0.001); in AG this correlation was lost. Therefore the training and age were independent predictor of E/A (respectively beta = -0.27; p = 0.004; beta = -0.24, p = 0.008). Regular and aerobic training may minimize aging changes of diastolic function. This training-effect may play a key role to preserve diastolic filling in older athletes. PMID- 25795026 TI - An automated high-throughput SPE micro-elution method for perfluoroalkyl substances in human serum. AB - An automated high-throughput solid phase extraction (SPE) micro-elution method for 8 perfluorosulfonic acids, 11 perfluorocarboxylic acids and fluorooctane sulfonamide in human serum was developed. Importance was attached to the application of small volumes of reagents and solvents in addition to low sample volumes (50 MUL) in order to save the highly valuable sample material for follow up and other studies. Instrumental analysis was performed by ultra high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC MS/MS). The recoveries of perfluoroalkyl substances (PFASs) were satisfactory and between 70 and 120% for most of the compounds at the three investigated spike concentrations. Perfluorobutane sulfonate (PFBS) was slightly underestimated at high concentrations (20 ng/mL; 67%), whereas perfluoropentanoate (PFPA), perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) were overestimated with 134, 131 and 133% respectively, at low spike concentrations (0.2 ng/mL). The precision of the method was below 20% coefficient of variation (CV%) for all target compounds with the only exception of PFOS (22%) at low spike concentrations. Method detection limits ranged from 0.006 to 0.34 ng/mL. High sensitivity, accuracy, repeatability and robustness have been demonstrated for an appropriate concentration range. The applicability for real samples was satisfactory demonstrated by analysis of 40 sera samples from the general population from Tromso, Norway. PMID- 25795027 TI - An optimized approach to the rapid assessment and detection of sequence variants in recombinant protein products. AB - The development of sensitive techniques to detect sequence variants (SVs), which naturally arise due to DNA mutations and errors in transcription/translation (amino acid misincorporations), has resulted in increased attention to their potential presence in protein-based biologic drugs in recent years. Often, these SVs may be below 0.1%, adding challenges for consistent and accurate detection. Furthermore, the presence of false-positive (FP) signals, a hallmark of SV analysis, requires time-consuming analyst inspection of the data to sort true from erroneous signal. Consequently, gaps in information about the prevalence, type, and impact of SVs in marketed and in-development products are significant. Here, we report the results of a simple, straightforward, and sensitive approach to sequence variant analysis. This strategy employs mixing of two samples of an antibody or protein with the same amino acid sequence in a dilution series followed by subsequent sequence variant analysis. Using automated peptide map analysis software, a quantitative assessment of the levels of SVs in each sample can be made based on the signal derived from the mass spectrometric data. We used this strategy to rapidly detect differences in sequence variants in a monoclonal antibody after a change in process scale, and in a comparison of three mAbs as part of a biosimilar program. This approach is powerful, as true signals can be readily distinguished from FP signal, even at a level well below 0.1%, by using a simple linear regression analysis across the data set with none to minimal inspection of the MS/MS data. Additionally, the data produced from these studies can also be used to make a quantitative assessment of relative levels of product quality attributes. The information provided here extends the published knowledge about SVs and provides context for the discussion around the potential impact of these SVs on product heterogeneity and immunogenicity. PMID- 25795028 TI - Erratum to: Evaluation of anterior knee pain in a PS total knee arthroplasty: the role of patella-friendly femoral component and patellar size. PMID- 25795029 TI - Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial. AB - BACKGROUND: Several studies have demonstrated that spironolactone has an anti albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. METHODS: Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr-2000 mg/gCr) treated with renin-angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016). RESULTS: Albuminuria was reduced by 33 % (95 % confidence interval: 22-54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient +/- standard error; 514.4 +/- 137.6 mg/gCr, P < 0.0005). No patient was excluded from the study because of hyperkalemia. CONCLUSIONS: Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations. PMID- 25795030 TI - What factors influence the production of orthopaedic research in East Africa? A qualitative analysis of interviews. AB - BACKGROUND: Research addressing the burden of musculoskeletal disease in low- and middle-income countries does not reflect the magnitude of the epidemic in these countries as only 9% of the world's biomedical resources are devoted to addressing problems that affect the health of 90% of the world's population. Little is known regarding the barriers to and drivers of orthopaedic surgery research in such resource-poor settings, the knowledge of which would help direct specific interventions for increasing research capacity and help surgeons from high-income countries support the efforts of our colleagues in low- and middle income countries. PURPOSE: We sought to identify through surveying academic orthopaedic surgeons in East Africa: (1) barriers impeding research, (2) factors that support or drive research, and (3) factors that were identified by some surgeons as barriers and others as drivers (what we term barrier-driver overlap) as they considered the production of clinical research in resource-poor environments. MATERIALS: Semistructured interviews were conducted with 21 orthopaedic surgeon faculty members at four academic medical centers in Ethiopia, Kenya, Tanzania, and Uganda. Qualitative content analysis of the interviews was conducted using methods based in grounded theory. Grounded theory begins with qualitative data, such as interview transcripts, and analyzes the data for repeated ideas or concepts which then are coded and grouped into categories which allow for identification of subjects or problems that may not have been apparent previously to the interviewer. RESULTS: We identified and quantified 19 barriers to and 21 drivers of orthopaedic surgery research (mentioned n = 1688 and n = 1729, respectively). Resource, research process, and institutional domains were identified to categorize the barriers (n = 7, n = 5, n = 7, respectively) and drivers (n = 7, n = 8, n = 6, respectively). Resource barriers (46%) were discussed more often by interview subjects compared with the research process (26%) and institutional barriers (28%). Drivers of research discussed at least once were proportionally similar across the three domains. Some themes such as research ethics boards, technology, and literature access occurred with similar frequency as barriers to and drivers of orthopaedic surgery research. CONCLUSIONS: The barriers we identified most often among East African academic orthopaedic faculty members focused on resources to accomplish research, followed by institutional barriers, and method or process barriers. Drivers to be fostered included a desire to effect change, collaboration with colleagues, and mentorship opportunities. The identified barriers and drivers of research in East Africa provide a targeted framework for interventions and collaborations with surgeons and organizations from high-resource settings looking to be involved in global health. PMID- 25795031 TI - Writing with the end in mind. PMID- 25795032 TI - "Straddling across boundaries"-thoracoabdominal lesions: spectrum and pattern approach. AB - The thoracoabdominal region consists of the inferior thorax and superior abdomen and is separated by the diaphragm. Although the diaphragm appears to act as a barrier in this region, various lesions can straddle across the diaphragm and lie contiguously in both the thorax and the abdomen. Thoracoabdominal lesions can extend across the diaphragm either through its various natural openings or through abnormal defects. The natural openings lie in the midline and include the hiatuses for the inferior vena cava, the esophagus, and the retrocrural space, which includes the aortic hiatus and the prevertebral and paravertebral spaces. Abnormal defects include congenital defects in fusion, that is, foramina of Morgagni and Bochdalek and acquired diaphragmatic rupture. Very large lesions can also displace the diaphragm, either inferiorly or superiorly, and thus appear to pseudoextend across this region. Using a pattern approach based on the location and route of extension, thoracoabdominal lesions can be classified as central and lateral lesions. Central lesions form a large group, and based on their location, they can be further classified as central anterior, central tendon, inferior vena cava, esophageal, and retrocrural pathologies. Both central and lateral thoracoabdominal lesions form a diverse spectrum and can be congenital, neoplastic, inflammatory, iatrogenic, or traumatic in etiology. Morphologically, these can consist of solid masses, cystic lesions, and ill-defined collections extending across the diaphragm. This article depicts the imaging appearance of the wide spectrum of lesions straddling across the diaphragm. Familiarity with these pathologies can help in better understanding the continuum formed by the thoracoabdominal region and the various routes of transdiaphragmatic extension. PMID- 25795033 TI - Alveolar echinococcosis of liver: a diagnostic problem in a nonendemic area. AB - Alveolar echinococcosis is a parasitic disease primarily invading the liver. Due to its aggressive nature, it invades the adjacent structures and can even metastasize to distant organs. The appearance of hepatic involvement on computed tomographic scan is characteristic, but not specific, with areas of calcification seen within a hypoenhancing mass. Although magnetic resonance imaging may better define the extent of the disease, it often misleads the radiologist, especially if the lesion is devoid of cystic component(s) and if it occurs in nonendemic areas. Knowledge of the imaging appearance may prompt serological evaluation and aid in making an early diagnosis and planning appropriate treatment of this uncommon fatal disease, especially in nonendemic areas. PMID- 25795034 TI - [Social support and cardiovascular health: Adaptation of a social support scale for hypertensive and diabetic patients in primary care, Chile]. AB - GOAL: Validate an instrument to measure the Perceived Social Support in outpatients who are in treatment to hypertension and/or diabetes mellitus ii. DESIGN: Observational and exploratory design with mixed methods, qualitative and quantitative. SETTING: Two community health centers from the municipality of Puente Alto (Santiago, Chile). PARTICIPANTS: Hypertensive and/or diabetic patients between 18 and 65 years old. A purposive sample was undertaken for the qualitative study, and a random sample for the final survey. METHODS: Focus groups and semi-structured interviews were conducted to explore the constructs of social support as perceived by patients. According to expert opinion and literature review, a scale of social support was selected and a pilot study was conducted in 40 patients, then we interviewed in depth to some of those participants. The instrument was modified according the results of this process. The final version was applied to 250 participants. RESULTS: The construct existence was verified in the population. In the adaptation, one item was eliminated. The alpha of Cronbach was 0.89 and the factorial analysis had the same four factors from the original study. Nine new items obtained from the focal groups were added to the instrument, obtaining an alpha of Cronbach of 0.92. CONCLUSION: The final instrument has good psychometric proprieties, and is applicable in our population. The additional items from the qualitative study improve its internal consistency, but don't add new information about Perceived Social Support. This is consistent with other studies, and suggests the application of the original version of the instrument. PMID- 25795036 TI - Association between very long chain fatty acids in the meibomian gland and dry eye resulting from n-3 fatty acid deficiency. AB - In our previously study, we reported lower tear volume in with an n-3 fatty acid deficient mice and that the docosahexaenoic acid and total n-3 fatty acid levels in these mice are significantly reduced in the meibomian gland, which secretes an oily tear product. Furthermore, we noted very long chain fatty acids (>=25 carbons) in the meibomian gland. To verify the detailed mechanism of the low tear volume in the n-3 fatty acid-deficient mice, we identified the very long chain fatty acids in the meibomian gland, measured the fatty acid composition in the tear product. Very long chain fatty acids were found to exist as monoesters. In particular, very long chain fatty acids with 25-29 carbons existed for the most part as iso or anteiso branched-chain fatty acids. n-3 fatty acid deficiency was decreased the amount of meibum secretion from meibomian gland without change of fatty acid composition. These results suggest that the n-3 fatty acid deficiency causes the enhancement of evaporation of tear film by reducing oily tear secretion along with the decrease of meibomian gland function. PMID- 25795035 TI - Identification and response to metals of metallothionein in two ancient fishes: white sturgeon (Acipenser transmontanus) and lake sturgeon (Acipenser fulvescens). AB - White sturgeon (Acipenser transmontanus) are among the most sensitive species of fishes to Cu, Cd, and Zn, but there is no information about sensitivity of lake sturgeon (Acipenser fulvescens). To begin to elucidate molecular mechanism(s) of sensitivity of sturgeons to metals a cDNA encoding metallothionein (MT) was amplified from livers of white sturgeon (WS-MT) and lake sturgeon (LS-MT), and expression in response to Cu, Cd, or Zn was characterized in liver explants from each species. The primary structure of WS-MT and LS-MT contained 20 cysteine residues, which is the same as MTs of teleost fishes. However, the primary structure of WS-MT and LS-MT contained 63 amino acids, which is longer than any MT identified in teleost fishes. Abundance of transcripts of WS-MT in explants exposed to 0.3, 3, 30, or 100 MUg/L of Cu was 1.7-, 1.7-, 2.1-, and 2.6-fold less than in controls, respectively. In contrast, abundances of transcripts of WS-MT were 3.3- and 2.4-fold greater in explants exposed to 30 MUg/L of Cd and 1000 MUg/L of Zn, respectively. Abundance of transcripts of LS-MT was not significantly different at any concentration of Cu, Cd, or Zn. MT is hypothesized to represent a critical mechanism for detoxification of metals. Therefore, results of this study suggest that sensitivity of sturgeons to exposure to Cu, Cd, or Zn might be a result of the relatively lesser maximal response of MT to metals. The study also suggestslake sturgeon might be more sensitive than white sturgeon to metals. PMID- 25795038 TI - White matter microstructure abnormalities in pediatric migraine patients. AB - BACKGROUND: Diffusion tensor (DT) magnetic resonance imaging (MRI) provides several quantities with the potential to disclose white matter (WM) microstructural abnormalities. We explored alterations of WM architecture in pediatric migraine patients using DT MRI and two different methods of analysis. METHODS: Dual-echo and DT MRI scans were acquired from 15 pediatric migraine patients and 15 age-matched controls. Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). A DT probabilistic tractography analysis was also run. RESULTS: Both TBSS and DT tractography analysis showed that, compared to controls, pediatric migraine patients had significant lower mean (MD), axial (AD) and radial (RD) diffusivity of WM tracts located in the brainstem, thalamus and fronto-temporo-occipital lobes, bilaterally. Patients also experienced increased fractional anisotropy (FA) of the optic radiations. No correlation was found between WM tract abnormalities and disease duration and attack frequency. CONCLUSIONS: Pediatric migraine patients harbor diffuse brain WM microstructural abnormalities. High FA and low MD, AD and RD in these patients might be explained by repeated neuronal activation, which may lead to cell swelling and stimulate activity-dependent myelin-modulation, or by increased fiber and dendritic densities. Both these mechanisms might reflect a hyperexcitability of the brain in migraineurs. PMID- 25795037 TI - Palliative care for Parkinson's disease: has the time come? AB - Although Parkinson's disease (PD) is traditionally viewed as a movement disorder which affects quality of life, recent literature has revealed an increased mortality, a high burden of difficult-to-manage non-motor symptoms (e.g., pain, fatigue), high caregiver distress, and a high utilization of medical services especially in the last year of life. Current medical systems have yet to adequately respond to this mounting evidence through the adoption of palliative care practices and through the provision of palliative care services to both PD patients and to affected families. This holistic, interdisciplinary approach to practice would enhance care delivery, identify and address unmet needs, and avoid interventions and hospitalizations especially in the last months of life. As we approach an era of increased life expectancy, increasing comorbidities among patients, and escalating healthcare costs, physicians must be proactive in focusing on quality of life, reducing medical interventions, and respecting patient autonomy. PMID- 25795039 TI - Left perirhinal cortex codes for similarity in meaning between written words: Comparison with auditory word input. AB - Left perirhinal cortex has been previously implicated in associative coding. According to a recent experiment, the similarity of perirhinal fMRI response patterns to written concrete words is higher for words which are more similar in their meaning. If left perirhinal cortex functions as an amodal semantic hub, one would predict that this semantic similarity effect would extend to the spoken modality. We conducted an event-related fMRI experiment and evaluated whether a same semantic similarity effect could be obtained for spoken as for written words. Twenty healthy subjects performed a property verification task in either the written or the spoken modality. Words corresponded to concrete animate entities for which extensive feature generation was available from more than 1000 subjects. From these feature generation data, a concept-feature matrix was derived which formed the basis of a cosine similarity matrix between the entities reflecting their similarity in meaning (called the "semantic cossimilarity matrix"). Independently, we calculated a cosine similarity matrix between the left perirhinal fMRI activity patterns evoked by the words (called the "fMRI cossimilarity matrix"). Next, the similarity was determined between the semantic cossimilarity matrix and the fMRI cossimilarity matrix. This was done for written and spoken words pooled, for written words only, for spoken words only, as well as for crossmodal pairs. Only for written words did the fMRI cossimilarity matrix correlate with the semantic cossimilarity matrix. Contrary to our prediction, we did not find any such effect for auditory word input nor did we find cross-modal effects in perirhinal cortex between written and auditory words. Our findings situate the contribution of left perirhinal cortex to word processing at the top of the visual processing pathway, rather than at an amodal stage where visual and auditory word processing pathways have already converged. PMID- 25795040 TI - Disruption of temporally extended self-memory system following traumatic brain injury. AB - We investigated for the first time the episodic/semantic distinction in remembering the past and imagining the future in traumatic brain injury (TBI), and explored cognitive mechanisms that may underlie their deficits. Fifteen severe TBI patients and 15 control participants performed a battery of neuropsychological tests and a set of verbal fluency tasks designed to assess semantic (personality traits knowledge and general events), and episodic (specific events and details) facets of self-representations according to three time periods (remote/retrograde past, recent/anterograde past, future). Compared to controls, TBI patients showed deficits in both semantic and episodic self representations, regardless of the time period, and controlling for basic cognitive functions. By contrast, a subjective evaluation of self-concept measuring the degree of certitude and the valence of self did not differ between patients and controls. The deficits were mainly predicted by altered executive function (i.e., updating) for past periods, as well as by general semantic and feature binding in working memory for the future period, independently of the injury characteristics. For controls, only episodic self-representation for each time period was mediated by executive or working memory functions, while semantic self-representation was mediated by the certitude of the self. This study highlights the dual role of semantic and episodic representations in temporally extended self, and shows the global disruption of self-representations across extended time in severe TBI. This encourages the extension of past and future thinking research to TBI populations to provide important insights into the nature and origin of these deficits and their role in recovery and to suggest future lines of research on rehabilitation procedures. PMID- 25795041 TI - Next-generation sequencing, cancer and molecular diagnostics: an interview with Elaine Mardis. AB - Elaine Mardis, co-director of the Genome Institute at Washington University (St Louis, MO, USA), is an expert in genome sequencing technologies, having been involved in developing and automating the methods employed in sequencing the human genome. Professor Mardis has made key contributions to the Human Genome Project and more recently, to the field of cancer genomics, including work in The Cancer Genome Atlas. Her current research interests lie in next-generation sequencing and analysis of cancer genomes and the translation of these findings to support therapeutic decision making. PMID- 25795042 TI - Multiplexed testing for HIV and related bacterial and viral co-infections at the point-of-care: quo vadis? AB - Recently, there has been a paradigm shift toward an understanding of the need to screen select sub-populations for several sexually transmitted and blood-borne infections simultaneously, at one time with various rapid point-of-care (POC) technologies, rather than one infection at a time. This is an encouraging and promising change, however many contextual factors need to be considered before implementing such technologies. In this editorial, we highlight some challenges, issues and concerns regarding implementation, integration, and uptake of these technologies across global settings. However, careful planning and well thought out implementation plan that include investments in training health care professionals, improving test and treat algorithms, rapid protocols on communicating actionable results to providers, and timely action, will bring about the desired impact in patient's lives. This is especially true in settings where they stand to achieve the maximum desired public health and social impact. PMID- 25795043 TI - Successful Giant Thymic Cyst Removal: Case Report and Review of the Literature. AB - Giant thymic cysts are a rare clinical entity evolving from smaller benign thymic cysts over many years. Benign thymic cysts account for approximately 3% of all mediastinal masses. There is a paucity of literature regarding benign thymic cyst management, especially when dealing with giant cysts. This can lead to potential confusion amongst clinicians on how to best treat these patients. We report the successful diagnosis and treatment of a 76 year-old female with a giant, benign thymic cyst. This cyst was discovered incidentally and after consultation of the literature it was found management strategies regarding this condition are scarce. After careful consideration of surgical principles, patient preference and potential complications of a conservative approach, the successful surgical removal of a 1.8 kg cyst took place. The patient improved symptomatically with improved exercise tolerance and lung function tests. This case demonstrates the benefits of giant thymic cyst removal thus confirming diagnosis, reducing potential serious complications and improving patient quality of life. PMID- 25795044 TI - Constraint-induced movement therapy early after stroke improves rate of upper limb motor recovery but not long-term motor function. PMID- 25795045 TI - Reflections on the career of Janet Carr--a physiotherapy trailblazer. PMID- 25795047 TI - Outcomes of Therasphere Radioembolization for Colorectal Metastases. AB - INTRODUCTION: The liver is the most common site for colorectal cancer (CRC) metastases. Radioembolization with yttrium-90 (Y90) represents an alternative approach in the management of unresectable hepatic colorectal metastases. The objective of this study was to evaluate outcomes after treatment with Y90. MATERIALS AND METHODS: A retrospective review of patients undergoing Y90 glass microsphere treatment for metastatic CRC from 2009 to 2013 was conducted. Multivariable analysis (MVA) of factors related to overall survival (OS) was performed using the Cox proportional hazard and OS estimates were calculated using the Kaplan-Meier method. RESULTS: We identified 68 patients. Median and 2 year OS were 11.6 months and 34%. For patients with <= 25% hepatic burden of disease (HBD) and 1 chemotherapy regimen, 2-year OS was 63%. Median and 2-year OS for patients with <= 25% versus > 25% HBD were 19.6 months and 42% versus 3.4 months and 0% (P < .0001). Univariate analysis revealed that higher HBD, >= 3 lines of chemotherapy received, and higher carcinoembryonic antigen (CEA) were found to be significant predictors of worse OS. MVA revealed age, > 25% HBD, >= 3 lines of chemotherapy, and higher CEA were independently prognostic for increased mortality, and resected status of the primary tumor was associated with decreased mortality. The presence of extrahepatic metastases was not prognostic. Toxicities were mild and only 5 patients experienced Grade 3/4 biochemical toxicity. CONCLUSION: Yttrium-90 was associated with acceptable OS with minimal morbidity in this series. Minimal exposure to chemotherapy and low HBD were found to be associated with better OS, however, even patients with chemotherapy-refractory disease received a benefit from treatment. PMID- 25795048 TI - Gain Correction for an X-ray Imaging System With a Movable Flat Panel Detector and Intrinsic Localization Crosshair. AB - Gain calibration for X-ray imaging systems with a movable flat panel detector and an intrinsic crosshair is a challenge due to the geometry-dependent heel effect and crosshair artifact. This study aims to develop a gain correction method for such systems by implementing the Multi-Acquisition Gain Image Correction technique. Flood field images containing crosshair and heel effect were acquired in 4 different flat panel detector positions at fixed exposure parameters. The crosshair region was automatically detected using common image processing algorithms and removed by a simple interpolation procedure, resulting in a crosshair-removed image. A large kernel-based correction was then used to remove the heel effect. Mask filters corresponding to each crosshair region were applied to the resultant heel effect-removed images to invalidate the pixels of the original crosshair region. Finally, a seamless gain map was composed with corresponding valid pixels from the processed images either by the sequential replacement or by the selective averaging techniques developed in this study. Quantitative evaluation was performed based on normalized noise power spectrum and detective quantum efficiency improvement factor for the flood field images corrected by the Multi-Acquisition Gain Image Correction-based gain maps. For comparison purposes, a single crosshair-removed gain map was also tested. As a result, it was demonstrated that the Multi-Acquisition Gain Image Correction technique achieved better image quality than the crosshair-removed technique, showing lower normalized noise power spectrum values over most of spatial frequencies. The improvement was more obvious at the priori-crosshair region of the gain map. The mean detective quantum efficiency improvement factor was 1.09 +/- 0.06, 2.46 +/- 0.32, and 3.34 +/- 0.36 in the priori-crosshair region and 2.35 +/- 0.31, 2.33 +/- 0.31, and 3.09 +/- 0.34 in the normal region, for crosshair-removed, Multi-Acquisition Gain Image Correction-sequential replacement, and Multi-Acquisition Gain Image Correction-selective averaging techniques, respectively. Therefore, this study indicates that the introduced Multi-Acquisition Gain Image Correction technique is an appropriate method for gain calibration of an imaging system associated with a moving flat panel detector and an intrinsic crosshair. PMID- 25795049 TI - Erratum to: Treatment of camptocormia with continuous subcutaneous infusions of apomorphine: 1-year prospective pilot study. PMID- 25795050 TI - Investigation of the relationship between facial injuries and traumatic brain injuries using a realistic subject-specific finite element head model. AB - In spite of anatomic proximity of the facial skeleton and cranium, there is lack of information in the literature regarding the relationship between facial and brain injuries. This study aims to correlate brain injuries with facial injuries using finite element method (FEM). Nine common impact scenarios of facial injuries are simulated with their individual stress wave propagation paths in the facial skeleton and the intracranial brain. Fractures of cranio-facial bones and intracranial injuries are evaluated based on the tolerance limits of the biomechanical parameters. General trend of maximum intracranial biomechanical parameters found in nasal bone and zygomaticomaxillary impacts indicates that severity of brain injury is highly associated with the proximity of location of impact to the brain. It is hypothesized that the midface is capable of absorbing considerable energy and protecting the brain from impact. The nasal cartilages dissipate the impact energy in the form of large scale deformation and fracture, with the vomer-ethmoid diverging stress to the "crumpling zone" of air-filled sphenoid and ethmoidal sinuses; in its most natural manner, the face protects the brain. This numerical study hopes to provide surgeons some insight in what possible brain injuries to be expected in various scenarios of facial trauma and to help in better diagnosis of unsuspected brain injury, thereby resulting in decreasing the morbidity and mortality associated with facial trauma. PMID- 25795051 TI - Anticancer efficacy and toxicokinetics of a novel paclitaxel-clofazimine nanoparticulate co-formulation. AB - Contemporary chemotherapy is limited by disseminated, resistant cancer. Targeting nanoparticulate drug delivery systems that encapsulate synergistic drug combinations are a rational means to increase the therapeutic index of chemotherapeutics. A lipopolymeric micelle co-encapsulating an in vitro optimized, synergistic fixed-ratio combination of paclitaxel (PTX) and clofazimine (B663) has been developed and called RiminocellesTM. The present pre clinical study investigated the acute toxicity, systemic exposure, repeat dose toxicity and efficacy of Riminocelles in parallel to Taxol(r) at an equivalent PTX dose of 10 mg/kg. Daily and weekly dosing schedules were evaluated against Pgp-expressing human colon adenocarcinoma (HCT-15) xenografts implanted subcutaneously in athymic mice. Riminocelles produced statistically significant (p < .05) tumor growth delays of 3.2 and 2.7 days for the respective schedules in contrast to Taxol delaying growth by 0.5 and 0.6 days. Using the control tumor doubling time of 4.2 days, tumor-cell-kill values of 0.23 for Riminocelles and 0.04 for Taxol following daily schedules were calculated. A significant weight loss of 5.7% after 14 days (p < 0.05) relative to the control group (n = 8) was observed for the daily Taxol group whereas Riminocelles did not incur significant weight loss neither were blood markers of toxicity elevated after acute administration (n = 3). The safety and efficacy of Riminocelles is statistically superior to Taxol. However, passive tumor targeting was not achieved and the tumor burden progressed quickly. Prior to further animal studies, the in vivo thermodynamic instability of the simple lipopolymeric micellular delivery system requires improvement so as to maintain and selectively deliver the fixed-ratio drug combination. PMID- 25795052 TI - Corneal angiogenesis modulation by cysteine cathepsins: In vitro and in vivo studies. AB - Corneal avascularization is essential for normal vision. Several antiangiogenic factors were identified in cornea such as endostatin and angiostatin. Cathepsin V, which is highly expressed in the cornea, can hydrolyze human plasminogen to release angiostatin fragments. Herein, we describe a detailed investigation of the expression profile of cathepsins B, L, S and V in the human cornea and the role of cysteine peptidases in modulating angiogenesis both in vitro and in vivo. We used various methodological tools for this purpose, including real-time PCR, SDS-PAGE, western blotting, catalytic activity assays, cellular assays and induction of corneal neovascularity in rabbit eyes. Human corneal enzymatic activity assays revealed the presence of cysteine proteases that were capable of processing endogenous corneal plasminogen to produce angiostatin-like fragments. Comparative real-time analysis of cathepsin B, L, S and V expression revealed that cathepsin V was the most highly expressed, followed by cathepsins L, B and S. However, cathepsin V depletion revealed that this enzyme is not the major cysteine protease responsible for plasminogen degradation under non-pathological conditions. Furthermore, western blotting analysis indicated that only cathepsins B and S were present in their enzymatically active forms. In vivo analysis of angiogenesis demonstrated that treatment with the cysteine peptidase inhibitor E64 caused a reduction in neovascularization. Taken together, our results show that human corneal cysteine proteases are critically involved in angiogenesis. PMID- 25795053 TI - Beneficial effect of annexin A1 in a model of experimental allergic conjunctivitis. AB - Annexin A1 (ANXA1), a 37 kDa glucocorticoid-regulated protein, is a potent anti inflammatory mediator effective in terminating acute inflammatory response, and its role in allergic settings has been poorly studied. The aim of this investigation was to evaluate the mechanism of action of ANXA1 in intraocular inflammation using a classical model of ovalbumin (OVA)-induced allergic conjunctivitis (AC). OVA-immunised Balb/c mice, wild-type (WT) and ANXA1 deficient (AnxA1(-/-)), were challenged with eye drops containing OVA on days 14 16 with a subset of WT animals pretreated intraperitoneally with the peptide Ac2 26 (N-terminal region of ANXA1) or dexamethasone (DEX). After 24 h of the last ocular challenge, WT mice treated with Ac2-26 and DEX had significantly reduced clinical signs of conjunctivitis (chemosis, conjunctival hyperaemia, lid oedema and tearing), plasma IgE levels, leukocyte (eosinophil and neutrophil) influx and mast cell degranulation in the conjunctiva compared to WT controls. These anti inflammatory effects of DEX were associated with high endogenous levels of ANXA1 in the ocular tissues as detected by immunohistochemistry. Additionally, Ac2-26 administration was effective to reduce IL-2, IL-4, IL-10, IL-13, eotaxin and RANTES in the eye and lymph nodes compared to untreated WT animals. The lack of ANXA1 produced an exacerbated allergic response as detected by the density of the inflammatory cell influx to the conjunctiva and the cytokine/chemokine release. These different effects observed for Ac2-26 were correlated with diminished level of activated ERK at 24 h in the ocular tissues compared to untreated OVA group. Our findings demonstrate the protective effect of ANXA1 during the inflammatory allergic response suggesting this protein as a potential target for new ocular inflammation therapies. PMID- 25795054 TI - Caffeic acid phenethyl ester lessens disease symptoms in an experimental autoimmune uveoretinitis mouse model. AB - Experimental autoimmune uveoretinitis (EAU) is an autoimmune disease that models human uveitis. Caffeic acid phenethyl ester (CAPE), a phenolic compound isolated from propolis, possesses anti-inflammatory and immunomodulatory properties. CAPE demonstrates therapeutic potential in several animal disease models through its ability to inhibit NF-kappaB activity. To evaluate these therapeutic effects in EAU, we administered CAPE in a model of EAU that develops after immunization with interphotoreceptor retinal-binding protein (IRBP) in B10.RIII and C57BL/6 mice. Importantly, we found that CAPE lessened the severity of EAU symptoms in both mouse strains. Notably, treated mice exhibited a decrease in the ocular infiltration of immune cell populations into the retina; reduced TNF-alpha, IL-6, and IFN-gamma serum levels: and inhibited TNF-alpha mRNA expression in retinal tissues. Although CAPE failed to inhibit IRBP-specific T cell proliferation, it was sufficient to suppress cytokine, chemokine, and IRBP-specific antibody production. In addition, retinal tissues isolated from CAPE-treated EAU mice revealed a decrease in NF-kappaB p65 and phospho-IkappaBalpha. The data identify CAPE as a potential therapeutic agent for autoimmune uveitis that acts by inhibiting cellular infiltration into the retina, reducing the levels of pro inflammatory cytokines, chemokine, and IRBP-specific antibody and blocking NF kappaB pathway activation. PMID- 25795055 TI - Lipases: Valuable catalysts for dynamic kinetic resolutions. AB - Dynamic kinetic resolutions have proven to be a useful method for the preparation of enantiopure compounds from racemates, leading to the formation of a single enantiomer in theoretically 100% yield. Because lipases are ubiquitous, versatile, stereoselective and robust biocatalysts, they have been successfully applied as co-catalysts in these reactions, being mostly combined with metals in the chemoenzymatic dynamic kinetic resolutions of alcohols and amines. PMID- 25795056 TI - Nature-inspired enzymatic cascades to build valuable compounds. AB - Biocatalysis currently is focusing on enzymatic and multi-enzymatic cascade processes instead of single steps imbedded into chemical pathways. Alongside this scientific revolution, this review provides an overview on multi-enzymatic cascades that are responsible for the biosynthesis of some terpenes, alkaloids and polyethers, which are important classes of natural products. Herein, we illustrate the development of studies inspired by multi- and chemo-enzymatic approaches to build the core moieties of polyethers, polypeptide alkaloids, piperidines and pyrrolidines promoted by the joint action of oxidoreductases, hydrolases, cyclases, transaminases and imine reductases. PMID- 25795057 TI - Biocatalytic approaches applied to the synthesis of nucleoside prodrugs. AB - Nucleosides are valuable bioactive molecules, which display antiviral and antitumour activities. Diverse types of prodrugs are designed to enhance their therapeutic efficacy, however this strategy faces the troublesome selectivity issues of nucleoside chemistry. In this context, the aim of this review is to give an overview of the opportunities provided by biocatalytic procedures in the preparation of nucleoside prodrugs. The potential of biocatalysis in this research area will be presented through examples covering the different types of nucleoside prodrugs: nucleoside analogues as prodrugs, nucleoside lipophilic prodrugs and nucleoside hydrophilic prodrugs. PMID- 25795058 TI - Retinal vascular caliber between eyes with asymmetric glaucoma. AB - PURPOSE: To compare differences in retinal arterial and venular caliber (RAC and RVC respectively) between fellow eyes with glaucoma of asymmetric severity. METHODS: We included subjects with bilateral primary glaucoma that had vertical cup-disc ratios (VCDR) >0.2 between both eyes, or visual field (VF) mean deviation (MD) >6.0 decibels (dB) between both eyes. RESULTS: Among 158 subjects, the average RAC in glaucoma eyes was 131.5 +/- 17.8 MUm vs 141.6 +/- 18.8 MUm in fellow eyes with mild disease (p < 0.001). RVCs in glaucoma eyes were 201.0 +/- 21.4 MUm vs 211.7 +/- 25.3 MUm in fellow eyes with mild disease (p < 0.001). This relationship held in clustered linear regression models adjusted for age, gender, vascular risk factors, visual acuity, axial length, and intraocular pressure, with RVCs narrower in eyes with worse disease vs mild disease. Eyes with worse disease had greater VCDR (0.9 +/- 0.1 vs 0.7 +/- 0.1, p < 0.001), and worse VF MD (-18.5 +/- 8.6 vs -6.6 +/- 5.6, p < 0.001). CONCLUSION: In glaucoma with asymmetric severity between fellow eyes, retinal vascular caliber is less in the eye with more severe disease. PMID- 25795060 TI - Erratum to: Optimization of Xylanase Production by Filamentous Fungi in Solid State Fermentation and Scale-up to Horizontal Tube Bioreactor. PMID- 25795059 TI - Canaloplasty versus non-penetrating deep sclerectomy - a prospective, randomised study of the safety and efficacy of combined cataract and glaucoma surgery; 12 month follow-up. AB - PURPOSE: To compare outcomes of phaco-canaloplasty (PC) and phaco-non-penetrating deep sclerectomy (PDS) with a viscoelastic compound. METHODS: This study included 29 eyes after PC and 30 after PDS. Indications were uncontrolled primary open angle glaucoma (POAG) and a cataract. Corrected distance visual acuity (CDVA), intraocular pressure (IOP), and number of medications were evaluated. Follow-up examinations were performed on days 1 and 7, and after 1, 3, 6, and 12 months. Complete and qualified success was an IOP <= 18 mmHg. RESULTS: At the 12-month follow-up, mean IOP decreased in the PC group from 19.0 +/-6.9 mmHg to 12.6 +/ 2.7 mmHg, and in the PDS group, from 19.1 +/-5.8 mmHg to 14.3 +/-3.5 mmHg (P < 0.05). Both groups preoperatively and at 12 months showed no significant differences in IOP (P > 0.05). There was no statistically significant difference between the number of medications used (P > 0.05). Complete and qualified success rates for both groups were 79.0 % and 76.9 % (P = 0.701). The most frequent postoperative PC complication was hyphema (58.0 %); for PDS, bleb fibrosis was most frequent (26.7 %). No PC patients required postoperative management. PDS patients required postoperative interventions 58.7 % of the time, including a 5 fluorouracil (5-FU) injection (58.7 %), suture lysis (48.3 %), and needling (27.6 %). CONCLUSIONS: Both PC and PDS lead to an effective decrease in IOP on a short term follow-up basis and demonstrate similar efficacy and safety profiles. PDS patients required additional procedures including 5-FU injections, suture lysis, or needling. PC patients required no additional procedures. PMID- 25795061 TI - Biochemical Characterization and Molecular Modeling of Pancreatic Lipase from a Cartilaginous Fish, the Common Stingray (Dasyatis pastinaca). AB - In order to identify fish enzymes displaying novel biochemical properties, we have chosen the common stingray (Dasyatis pastinaca), one of the most primitive living jawed aquatic vertebrates as a starting biological material to purify a lipase. A stingray pancreatic lipase (SPL) was purified from delipidated pancreatic powder. The SPL molecular weight was around 55 kDa which is slightly higher than that of known classical pancreatic lipases (50 kDa). This increase in the molecular weight was due to glycosylation. Like classic pancreatic lipases, SPL was found to be much more active on short-chain triacylglycerols than on long chain ones. Natural detergents act as inhibitors of the SPL activity. This inhibition can be reversed by the addition of stingray colipase. Starting from total pancreatic messenger RNAs (mRNAs), partial stingray pancreatic lipase complementary DNA (cDNA) was synthesized by reverse transcriptase-polymerase chain reaction (RT-PCR) and cloned into the PGEM-T vector. Partial amino acid sequence of the SPL was homologous to that of Japanese eel, porcine, and human pancreatic lipases. A 3D structure model of the sequenced part of SPL was built using the 3D structure of porcine pancreatic lipase as template, since both lipases shared an amino acid sequence identity of 60%. PMID- 25795062 TI - Antibacterial Activity of Red Pigment Produced by Halolactibacillus alkaliphilus MSRD1--an Isolate from Seaweed. AB - The present study was carried out with the aim to isolate an antibacterial pigment from seaweed-associated bacterium. The bacterium was identified as Halolactibacillus alkaliphilus MSRD1 by 16S rRNA sequencing. The isolated bacterium was cultured in 50% Luria-Bertani seawater broth (LB-SWB) with 1% glycerol. The pigment was extracted with 99% ethanol and analyzed by UV-Vis spectroscopy at 490 nm. The candidate bacterium was optimized with various NaCl concentrations from 5 to 20%. The results inferred that the bacterium produce maximum pigment at 5% NaCl level. The candidate bacterium H. alkaliphilus MSRD1 was found to be producing the maximum pigment during the 120-h incubation. The protein content of the pigment was found to be maximum of 72% at the end of the 120-h incubation. The extracted pigment was stable up to 80 degrees C, pink at acidic pH (1 to 5) and orange at basic pH (8 to 12). The isolated pigment was fractionated by silica gel column chromatography. Fractionated pigment was characterized by TLC, FT-IR, and SDS-PAGE. In the antibacterial context, the pigment was highly inhibited Staphylococcus aureus and Salmonella typhi with the zone of inhibition 16 and 14 mm, respectively. According to SDS-PAGE, the size of the pigment was approximately 80 kDa. The H. alkaliphilus MSRD1 has high capacity to produce the pigment with antibacterial properties. This could be effectively used in the future. PMID- 25795063 TI - US healthcare: how losing your job can kill you in the world's richest country. PMID- 25795064 TI - Halobacillus andaensis sp. nov., a moderately halophilic bacterium isolated from saline and alkaline soil. AB - A Gram-stain-positive, endospore-forming, moderately halophilic bacterial strain, NEAU-ST10-40T, was isolated from a saline and alkaline soil in Anda City, China. It was strictly aerobic, rod-shaped and motile by peritrichous flagella. It formed light yellow colonies and grew at NaCl concentrations of 3-15 % (w/v) (optimum, 8 %, w/v), at pH 7.0-9.0 (optimum, pH 8.0) and at 4-60 degrees C (optimum, 30 degrees C). It contained meso-diaminopimelic acid in the cell-wall peptidoglycan. Phylogenetic analysis based on 16S rRNA gene sequences indicated that it belonged to the genus Halobacillus. Levels of 16S rRNA gene sequence similarity between strain NEAU-ST10-40T and the type strains of related species of the genus Halobacillus ranged from 98.8 % (Halobacillus alkaliphilus FP5T) to 97.1 % (Halobacillus kuroshimensis IS-Hb7T). DNA-DNA hybridization relatedness values between strain NEAU-ST10-40T and H. alkaliphilus DSM 18525T, Halobacillus campisalis KCTC 13144T, Halobacillus yeomjeoni DSM 17110T, Halobacillus halophilus DSM 2266T, Halobacillus litoralis DSM 10405T, Halobacillus dabanensis DSM 18199T, Halobacillus salinus DSM 18897T, Halobacillus naozhouensis DSM 21183T, Halobacillus trueperi DSM 10404T and Halobacillus salsuginis DSM 21185T were from 43 +/- 1 to 19 +/- 1 % (mean +/- sd). The DNA G+C content was 39.3 mol%. The major fatty acids (>10 %) were anteiso-C15:0, anteiso-C17:0 and iso C16:0, the only respiratory quinone detected was MK-7, and polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unknown phospholipids and three unknown lipids. On the basis of the data presented, strain NEAU-ST10-40T is considered to represent a novel species, for which the name Halobacillus andaensis sp. nov. is proposed. The type strain is NEAU-ST10-40T ( = CGMCC 1.12153T = DSM 25866T). PMID- 25795065 TI - Arenimonas subflava sp. nov., isolated from a drinking water network, and emended description of the genus Arenimonas. AB - A strain designated PYM3-14T was isolated from the drinking water network of Budapest (Hungary) and was studied by polyphasic taxonomic methods. The straight rod-shaped cells stained Gram-negative, were aerobic and non-motile. Phylogenetic analysis of the 16S rRNA gene sequence of strain PYM3-14T revealed a clear affiliation with members of the family Xanthomonadaceae within the class Gammaproteobacteria. The 16S rRNA gene sequence of strain PYM3-14T showed the closest sequence similarities to Arenimonas daechungensis CH15-1T (96.2 %), Arenimonas oryziterrae YC6267T (95.2 %) and Lysobacter brunescens UASM DT (94.4 %). The DNA G+C content of strain PYM3-14T, measured by two different methods (52.0 mol% and 55.9 mol%, respectively), was much lower than that of any member of the genus Arenimonas. The predominant fatty acids (>8 %) were iso-C16:0, iso C15:0, iso-C14:0, iso-C17:1omega9c and C16:1omega7c alcohol. Strain PYM3-14T contained Q-8 as the major ubiquinone and phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidylmonomethylethanolamine as the major polar lipids. According to phenotypic and genotypic data strain PYM3-14T represents a novel species of the genus Arenimonas, for which the name Arenimonas subflava sp. nov. is proposed. The type strain is PYM3-14T ( = NCAIM B 02508T = DSM 25526T). On the basis of new data obtained in this study, an emended description of the genus Arenimonas is also proposed. PMID- 25795066 TI - Luteolibacter arcticus sp. nov., isolated from high Arctic tundra soil, and emended description of the genus Luteolibacter. AB - A pale yellow, Gram-reaction-negative, non-motile, aerobic bacterium, designated MC 3726T, was isolated from a tundra soil near Ny-Alesund, Svalbard Archipelago, Norway (78 degrees N). Growth occurred at 4-37 degrees C (optimum 25-30 degrees C) and at pH 5.0-9.0 (optimum pH 8.0). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain MC 3726T belonged to the genus Luteolibacter in the family Verrucomicrobiaceae. The 16S rRNA gene sequence of this strain showed 93.18, 92.54 and 92.44 % similarity to those of Luteolibacter cuticulihirudinis E100T, Luteolibacter pohnpeiensis A4T-83T and Luteolibacter yonseiensis EBTL01T, respectively. The cell wall of strain MC 3726T contained meso-diaminopimelic acid as the diagnostic amino acid. Strain MC 3726T contained iso-C14:0 (38.28 %), C16:0 (15.89 %), C16:1omega9c (14.24 %), iso-C16:0 (10.42 %) and anteiso-C15:0 (5.75 %) as the predominant cellular fatty acids, MK-9 and MK 10 as the major respiratory quinones, and phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol and diphosphatidylglycerol as the main polar lipids. The DNA G+C content was 60.7 mol %. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain MC 3726T is considered to represent a novel species of the genus Luteolibacter, for which the name Luteolibacter arcticus sp. nov. is proposed. The type strain is MC 3726T ( = CCTCC AB 2014275T = LMG 28638T). An emended description of the genus Luteolibacter is also provided, along with emended descriptions of Luteolibacter cuticulihirudinis, Luteolibacter yonseiensis and Luteolibacter pohnpeiensis. PMID- 25795067 TI - Aestuariicella hydrocarbonica gen. nov., sp. nov., an aliphatic hydrocarbon degrading bacterium isolated from a sea tidal flat. AB - A Gram-staining-negative, strictly aerobic bacterial strain, designated SM-6T, was isolated from a sea tidal flat of the Dangjin bay, South Korea. Strain SM-6T was able to degrade a broad range of aliphatic hydrocarbons. Cells were catalase- and oxidase-positive and non-motile rods. Growth of strain SM-6T was observed at 10-37 degrees C (optimum, 20-25 degrees C), at pH 5.5-9.0 (optimum, pH 6.5-7.5) and in the presence of 0-10 % (w/v) NaCl (optimum, 2-3 %). The only isoprenoid quinone detected was ubiquinone-8 (Q-8). C17:1omega8c, C11:0 3-OH, summed feature 3 (comprising C16:1omega7c and/or C16:1omega6c), C9:0 3-OH and C10:0 3-OH were observed as the major cellular fatty acids and phosphatidylethanolamine, phosphatidylglycerol and four unidentified lipids were detected as polar lipids. The G+C content of the genomic DNA was 47.5 mol%. Strain SM-6T was most closely related to Pseudomaricurvus alkylphenolicus KU41GT (95.5 %), Maricurvus nonylphenolicus KU41ET (94.4 %) and Pseudoteredinibacter isoporae SW-11T (94.3 %), based on 16S rRNA gene sequences, and phylogenetic analyses showed that strain SM-6T formed a phyletic lineage distinct from the closely related genera. On the basis of phenotypic, chemotaxonomic and molecular features, strain SM-6T represents a novel genus and species of the order Alteromonadales in the class Gammaproteobacteria, for which name Aestuariicella hydrocarbonica gen. nov., sp. nov. is proposed. The type strain is SM-6T ( = KACC 18121T = JCM 30134T). PMID- 25795068 TI - Vibrio renipiscarius sp. nov., isolated from cultured gilthead sea bream (Sparus aurata). AB - Two strains of Gram-negative, facultatively anaerobic, slightly halophilic bacteria, isolated from healthy gilthead sea bream (Sparus aurata) cultured in Spanish Mediterranean fish farms, were different from their closest relatives, Vibrio scophthalmi and V. ichthyoenteri, by phenotypic, phylogenetic and genomic standards. The strains were negative for decarboxylase tests and lacked extracellular hydrolytic activities, but were able to ferment d-mannitol, sucrose, cellobiose and d-gluconate, among other carbohydrates. The major cellular fatty acids were C16:1 and C16:0, in agreement with other species of the genus Vibrio. Their 16S rRNA gene sequences were 98.4 and 97.2 % similar to those of the type strains of V. scophthalmi and V. ichthyoenteri, and the similarities using other housekeeping genes (ftsZ, rpoD, recA, mreB and gyrB) and indices of genomic resemblance (average nucleotide identity and estimated DNA-DNA hybridization) between the isolates and those type strains were clearly below intraspecific levels, supporting the recognition of the strains as members of a separate novel species. Thus, we propose the name Vibrio renipiscarius sp. nov., with DCR 1-4-2T ( = CECT 8603T = KCTC 42287T) as the type strain. PMID- 25795069 TI - Reconnaissance of contaminants in larval Pacific lamprey (Entosphenus tridentatus) tissues and habitats in the Columbia River Basin, Oregon and Washington, USA. AB - Pacific lampreys (Entosphenus tridentatus) have resided in the Columbia River Basin for millennia and have great ecological and cultural importance. The role of habitat contamination in the recent decline of the species has rarely been studied and was the main objective of this effort. A wide range of contaminants (115 analytes) was measured in sediments and tissues at 27 sites across a large geographic area of diverse land use. This is the largest dataset of contaminants in habitats and tissues of Pacific lamprey in North America and the first study to compare contaminant bioburden during the larval life stage and the anadromous, adult portion of the life cycle. Bioaccumulation of pesticides, flame retardants, and mercury was observed at many sites. Based on available data, contaminants are accumulating in larval Pacific lamprey at levels that are likely detrimental to organism health and may be contributing to the decline of the species. PMID- 25795070 TI - Assessing the combined influence of TOC and black carbon in soil-air partitioning of PBDEs and DPs from the Indus River Basin, Pakistan. AB - Levels of polybrominated diphenyl ethers (PBDEs) and dechlorane plus (DPs) were investigated in the Indus River Basin from Pakistan. Concentrations of ?PBDEs and ?DPs were ranged between 0.05 and 2.38 and 0.002-0.53 ng g(-1) in the surface soils while 1.43-22.1 and 0.19-7.59 pg m(-3) in the passive air samples, respectively. Black carbon (fBC) and total organic carbon (fTOC) fractions were also measured and ranged between 0.73 and 1.75 and 0.04-0.2%, respectively. The statistical analysis revealed strong influence of fBC than fTOC on the distribution of PBDEs and DPs in the Indus River Basin soils. BDE's congener profile suggested the input of penta-bromodiphenylether (DE-71) commercial formulation in the study area. Soil-air partitioning of PBDEs were investigated by employing octanol-air partition coefficients (KOA) and black carbon-air partition coefficients (KBC-A). The results of both models suggested the combined influence of total organic carbon (absorption) and black carbon (adsorption) in the studied area. PMID- 25795071 TI - "Surgical management of complex multiloculated hydrocephalus in infants and children." Child's Nervous System, February 2015, volume 31, issue 2, pp. 243 249. PMID- 25795072 TI - Seizures in children with dysembryoplastic neuroepithelial tumors of the brain--A review of surgical outcomes across several studies. AB - PURPOSE: In children and adolescents, dysembryoplastic neuroepithelial tumors (DNETs) of the brain present with seizures almost 100% of the time, potentially creating significant long-term morbidity and disability despite the generally indolent course of the lesion. These tumors also tend to be quite resistant to anti-epileptic drugs which, themselves, can be associated with long-term side effects and resultant disability. Many clinicians advocate early surgical resection of these lesions, but how effective this approach is, and how aggressive tumor removal should be, continues to be debated. METHODS: We performed a systematic review of the relevant literature to identify all reports of DNET resections in pediatric patients published over the past 20 years. In all, over 3000 MEDLINE abstracts were reviewed, ultimately resulting in 13 studies with 185 pediatric DNET patients to review. RESULTS: Surgical resection of the lesion was effective at improving seizures in over 98% of patients and at achieving long-term seizure freedom in 86%. Surgical resection of DNETs also appeared to be quite safe, with no reported perioperative deaths and an overall rate of postoperative complications of 12%; the vast majority of these complications were transient. CONCLUSIONS: Total gross resection of the lesion was the only factor statistically correlated with long-term seizure freedom (r = 0.63, p = 0.03). However, data remain lacking regarding whether this translates into more extensive procedures-like brain mapping and partial lobectomies-being any more effective than simple lesionectomies alone. Further research is clearly needed to address this and other crucial questions. PMID- 25795075 TI - How effectively do horizontal and vertical response strategies of long-finned pilot whales reduce sound exposure from naval sonar? AB - The behaviour of a marine mammal near a noise source can modulate the sound exposure it receives. We demonstrate that two long-finned pilot whales both surfaced in synchrony with consecutive arrivals of multiple sonar pulses. We then assess the effect of surfacing and other behavioural response strategies on the received cumulative sound exposure levels and maximum sound pressure levels (SPLs) by modelling realistic spatiotemporal interactions of a pilot whale with an approaching source. Under the propagation conditions of our model, some response strategies observed in the wild were effective in reducing received levels (e.g. movement perpendicular to the source's line of approach), but others were not (e.g. switching from deep to shallow diving; synchronous surfacing after maximum SPLs). Our study exemplifies how simulations of source-whale interactions guided by detailed observational data can improve our understanding about motivations behind behaviour responses observed in the wild (e.g., reducing sound exposure, prey movement). PMID- 25795073 TI - A prospective controlled study of living kidney donors: three-year follow-up. AB - BACKGROUND: There have been few prospective controlled studies of kidney donors. Understanding the pathophysiologic effects of kidney donation is important for judging donor safety and improving our understanding of the consequences of reduced kidney function in chronic kidney disease. STUDY DESIGN: Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS: 3-year follow-up of kidney donors and paired controls suitable for donation at their donor's center. PREDICTOR: Kidney donation. OUTCOMES: Medical history, vital signs, glomerular filtration rate, and other measurements at 6, 12, 24, and 36 months after donation. RESULTS: At 36 months, 182 of 203 (89.7%) original donors and 173 of 201 (86.1%) original controls continue to participate in follow-up visits. The linear slope of the glomerular filtration rate measured by plasma iohexol clearance declined 0.36+/-7.55mL/min per year in 194 controls, but increased 1.47+/-5.02mL/min per year in 198 donors (P=0.005) between 6 and 36 months. Blood pressure was not different between donors and controls at any visit, and at 36 months, all 24-hour ambulatory blood pressure parameters were similar in 126 controls and 135 donors (mean systolic blood pressure, 120.0+/-11.2 [SD] vs 120.7+/-9.7mmHg [P=0.6]; mean diastolic blood pressure, 73.4+/-7.0 vs 74.5+/ 6.5mmHg [P=0.2]). Mean arterial pressure nocturnal dipping was manifest in 11.2% +/- 6.6% of controls and 11.3% +/- 6.1% of donors (P=0.9). Urinary protein creatinine and albumin-creatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower, in donors compared with controls. LIMITATIONS: Possible bias resulting from an inability to select controls screened to be as healthy as donors, short follow-up duration, and dropouts. CONCLUSIONS: Kidney donors manifest several of the findings of mild chronic kidney disease. However, at 36 months after donation, kidney function continues to improve in donors, whereas controls have expected age-related declines in function. PMID- 25795074 TI - Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - BACKGROUND: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. STUDY DESIGN: Cross-sectional and longitudinal observational analysis. SETTING & PARTICIPANTS: Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTOR: Quartiles of plasma CX3CL1 levels at baseline. OUTCOMES: Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. RESULTS: Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1 SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04). LIMITATIONS: Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. CONCLUSIONS: Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes. PMID- 25795077 TI - New effective antituberculosis regimens. PMID- 25795076 TI - Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug resistant pulmonary tuberculosis. AB - BACKGROUND: New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. METHODS: We did this phase 2b study of bactericidal activity- defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419. FINDINGS: Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0 56 (0.155, 95% Bayesian credibility interval 0.133-0.178) was significantly greater than for HRZE (n=54, 0.112, 0.093-0.131). DRMPa200Z (n=9) had bactericidal activity of 0.117 (0.070-0.174). The bactericidal activity on days 7 14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. INTERPRETATION: The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR tuberculosis, with the goal of shortening and simplifying treatment. FUNDING: Global Alliance for TB Drug Development. PMID- 25795078 TI - Anxiety disorders and first alcohol use in the general population. Findings from a nationally representative sample. AB - OBJECTIVE: To examine how early onset anxiety disorders are related to age of first alcohol use in a general population sample. METHOD: Discrete time survival analysis was used to model the odds of first alcohol use among those with, vs without, early onset anxiety disorders. Data came from the 2007 Australian National Survey of Mental Health and Wellbeing. RESULTS: After adjusting for the effects of family history of alcohol/drug use, sex, age cohort and education, people who experienced an early onset anxiety disorder had a 27% increased odds of first alcohol use in any given year, when compared to those with no anxiety disorder. This effect was particularly strong for transitions to first alcohol use that occurred after the age of 13 years. CONCLUSIONS: Early onset anxiety disorders significantly predict first alcohol use in the general population and this relationship appears to be related to change over time. These results point to the need for developmentally appropriate and integrated prevention programs that target anxiety and alcohol use together. PMID- 25795079 TI - Altered phalanx force direction during power grip following stroke. AB - Many stroke survivors with severe impairment can grasp only with a power grip. Yet, little knowledge is available on altered power grip after stroke, other than reduced power grip strength. This study characterized stroke survivors' static power grip during 100 and 50 % maximum grip. Each phalanx force angular deviation from the normal direction and its contribution to total normal force was compared for 11 stroke survivors and 11 age-matched controls. Muscle activities and skin coefficient of friction were additionally compared for another 20 stroke and 13 age-matched control subjects. The main finding was that stroke survivors gripped with a 34 % greater phalanx force angular deviation of 19 degrees +/- 2 degrees compared to controls of 14 degrees +/- 1 degrees (p < .05). Stroke survivors' phalanx force angular deviation was closer to the 23 degrees threshold of slippage between the phalanx and grip surface, which may explain increased likelihood of object dropping in stroke survivors. In addition, this altered phalanx force direction decreases normal grip force by tilting the force vector, indicating a partial role of phalanx force angular deviation in reduced grip strength post-stroke. Greater phalanx force angular deviation may biomechanically result from more severe underactivation of stroke survivors' first dorsal interosseous and extensor digitorum communis muscles compared to their flexor digitorum superficialis or somatosensory deficit. While stroke survivors' maximum power grip strength was approximately half of the controls, the distribution of their remaining strength over the fingers and phalanges did not differ, indicating evenly distributed grip force reduction over the entire hand. PMID- 25795080 TI - Recruitment of muscle synergies is associated with endpoint force fluctuations during multi-directional isometric contractions. AB - It has long been assumed that the human central nervous system uses flexible combinations of several muscle synergies to effortlessly and efficiently control redundant movements. However, whether muscle synergies exist in the neural circuit remains controversial, and it is critical to examine the association between the recruitment pattern of synergies and motor output. In this study, we examined the relationship between the activation of muscle synergies and endpoint force fluctuations in the presence of signal-dependent noise. Subjects performed multi-directional isometric force generations around the right ankle on the sagittal plane. We then extracted muscle synergies from measured electromyogram (EMG) data using nonnegative matrix factorization. As a result, the sum of the activation of muscle synergies was correlated with the endpoint force variability from the desired directions. Furthermore, we determined that the activation trace of each synergy reflected the endpoint force fluctuations using cross-correlation analysis. Therefore, these results suggest that muscle synergies statistically calculated from EMG data should be related to the motor output. PMID- 25795081 TI - Predicting auditory space calibration from recent multisensory experience. AB - Multisensory experience can lead to auditory space recalibration. After exposure to discrepant audiovisual stimulation, sound percepts are displaced in space, in the direction of the previous visual stimulation. This study focuses on identifying the factors in recent sensory experience leading to such auditory space shifts. Sequences of five audiovisual pairs were presented, each randomly congruent or discrepant in space. Each sequence was followed by a single auditory trial and two visual trials. In each trial, participants had to identify the perceived stimuli positions. We found that auditory localization is shifted during audiovisual discrepant trials and during subsequent auditory trials, suggesting a recalibration effect. Time did not lead to greater recalibration effects. The last audiovisual trial affects the subsequent auditory shift the most. The number of discrepant trials in a sequence, and the number of consecutive trials in sequence, also correlated with the subsequent auditory shift. To estimate the individual contribution of previously presented trials to the recalibration effect, a best-fitting model was developed to predict the shift in a linear weighted combination of stimulus features: (1) whether matching or discrepant trials occurred in the sequence, (2) total number of discrepant trials, and (3) maximum number of consecutive discrepant trials, (4) whether the last trial was discrepant or not. The selected model consists of a function including as properties the type of stimulus of the last audiovisual sequence trial and the overall probability of mismatching trials in sequence. PMID- 25795082 TI - Profiling of small RNA cargo of extracellular vesicles shed by Trypanosoma cruzi reveals a specific extracellular signature. AB - Over the last years, an expanding family of small regulatory RNAs (e.g. microRNAs, siRNAs and piRNAs) was recognized as key players in novel forms of post-transcriptional gene regulation in most eukaryotes. However, the machinery associated with Ago/Dicer-dependent small RNA biogenesis was thought to be either entirely lost or extensively simplified in some unicellular organisms including Trypanosoma cruzi, Saccharomyces cerevisiae, Leishmania major and Plasmodium falciparum. Although the biogenesis of small RNAs from non-coding RNAs represent a minor fraction of the normal small RNA transcriptome in eukaryotic cells, they represent the unique small RNA pathways in Trypanosoma cruzi which produce different populations of small RNAs derived from tRNAs, rRNAs, sn/snoRNAs and mRNAs. These small RNAs are secreted included in extracellular vesicles and transferred to other parasites and susceptible mammalian cells. This process represents a novel form of cross-kingdom transfer of genetic material suggesting that secreted vesicles could represent new relevant pieces in life cycle transitions, infectivity and cell-to-cell communication. Here, we provide for the first time a detailed analysis of the small RNA cargo of extracellular vesicles from T. cruzi epimastigotes under nutritional stress conditions compared to the respective intracellular compartment using deep sequencing. Compared with the intracellular compartment, shed extracellular vesicles showed a specific extracellular signature conformed by distinctive patterns of small RNAs derived from rRNA, tRNA, sno/snRNAs and protein coding sequences which evidenced specific secretory small RNA processing pathways. PMID- 25795083 TI - The importance of endophenotypes in schizophrenia research. AB - Endophenotypes provide a powerful neurobiological platform from which we can understand the genomic and neural substrates of schizophrenia and other common complex neuropsychiatric disorders. The Consortium on the Genetics of Schizophrenia (COGS) has conducted multisite studies on carefully selected key neurocognitive and neurophysiological endophenotypes in 300 families (COGS-1) and then in a follow up multisite case-control study of 2471 subjects (COGS-2). Endophenotypes are neurobiologically informed quantitative measures that show deficits in probands and their first degree relatives. They are more amenable to statistical analysis than are "fuzzy" qualitative clinical traits or confoundingly heterogeneous diagnostic categories. Endophenotypes are also viewed as uniquely informative in traditional diagnosis-based as well as emerging NIMH Research Domain (RDoC) contexts, offering a bridge between the two approaches to psychopathology classification and research. Endo- or intermediate phenotypes are heritable, and in the COGS-1 cohort their level of heritability is in the same range as is the heritability of schizophrenia itself, using the same statistical methods and subjects to assess both. Because we can demonstrate endophenotypes link to both gene networks and neural circuits on the one hand and also to real life function, endophenotypes provide a critically important bridge for "connecting the dots" between genes, cells, circuits, information processing, neurocognition and functional impairment and personalized treatment selection in schizophrenia patients. By connecting schizophrenia risk genes with neurobiologically informed endophenotypes, and via the use of association, linkage, sequencing, stem cell and other strategies, we can provide our field with new neurobiologically informed information in our efforts to understand and treat schizophrenia. Evolving views, data and new analytic strategies about schizophrenia risk, pathology and treatment are described in this Viewpoint and in the accompanying Special Issue reports. PMID- 25795084 TI - Evaluation of 42 cytokines, chemokines and growth factors for prediction of cardiovascular outcome in patients with coronary artery disease. PMID- 25795085 TI - Age-related medication adherence in patients with chronic heart failure: A systematic literature review. AB - BACKGROUND: Chronic heart failure (CHF) is prevalent among the elderly and is characterized by high mortality and hospitalization rates. Non-adherence to medications is frequent and related to poor clinical outcomes. It is often assumed that older age is related to poorer medication adherence compared with younger age. We analyzed the existing evidence of age as a determinant of medication adherence in patients with CHF. METHODS: A systematic search of the bibliographic database MEDLINE and all Cochrane databases was performed. Studies were included if they examined medication adherence in adult patients with CHF, evaluated factors contributing to medication adherence, and analyzed the relationship between age and medication adherence. Articles classified as studies with poor quality were excluded. RESULTS: A total of 1565 titles were found, and ultimately, 17 studies, which provide data for a total of 162,727 patients, were analyzed. Seven studies showed a statistically significant relationship between age and medication adherence: six articles demonstrated that increased age is correlated with higher medication adherence, and one study showed that patients in the age range of 57 to 64 years are affected by non-adherence to angiotensin converting enzyme inhibitors. Ten studies found no significant relationship. CONCLUSIONS: The results suggest that older age alone is not related to poorer medication adherence compared with younger patients with CHF. More attention should be paid to younger newly-diagnosed patients with CHF. Future studies are required to explore medication adherence in CHF in different, standardized, and specific age groups and should be sufficiently powered to assess clinical endpoints. PMID- 25795086 TI - Hybrid methods for macromolecular structure determination: experiment with expectations. AB - Studies of large and heterogeneous macromolecules often yield low-resolution data that alone does not suffice to build accurate atomic models. Adding information from molecular simulation or other structure prediction methods can lead to models with significantly better quality. Different strategies are discussed to combine experimental data with results from simulation and prediction. This review describes recent approaches for building atomic models with a focus on X ray diffraction and single-particle cryo-electron microscopy (cryo-EM) data. In addition, both cryo-EM and X-ray diffraction provide information on molecular dynamics. Therefore, the best description of molecular structures is often by an ensemble of models. It furthermore becomes apparent that using raw data for the modeling ensures that all information obtained by the experiment can be fully exploited. It is also important to quantify the errors of both experiment and simulation to correctly weigh their different contributions. PMID- 25795087 TI - The importance of dynamics in integrative modeling of supramolecular assemblies. AB - Revealing the atomistic architecture of supramolecular complexes is a fundamental step toward a deeper understanding of cellular functioning. To date, this formidable task is facilitated by an emerging array of integrative modeling approaches that combine experimental data from different sources. One major challenge these methods have to face is the treatment of the dynamic rearrangements of the individual subunits upon assembly. While this flexibility can be sampled at different levels, integrating native dynamic determinants with available experimental inputs can provide an effective way to reveal the molecular recognition mechanisms at the basis of supramolecular assembly. PMID- 25795089 TI - Engineering of erythropoietin receptor for use as an affinity ligand. AB - Recombinant human erythropoietin receptor (rhEPOR) has applicability as an affinity ligand for purification of recombinant human erythropoietin (rHuEPO) because of its specific binding to rHuEPO. For application of rhEPOR as a ligand for purification of rHuEPO, soluble rhEPOR was expressed in the periplasm of Escherichia coli and engineered by directed evolution through random mutagenesis and integration of mutations. From the screening of random mutagenesis, we identified an amino acid mutation (H114Y) contributing to rHuEPO binding and four amino acid mutations (R76S, A132D, A162D, and C181Y) contributing to expression of soluble rhEPOR. However, the rHuEPO that binds to engineered rhEPOR having H114Y mutation is difficult to dissociate from the engineered rhEPOR. Therefore, H114Y mutation was not suitable for the construction of the rhEPOR ligand. As a rhEPOR ligand, engineered rhEPOR containing four amino acid mutations (EPORm4L) was constructed by integration of mutations except for H114Y. The expression of EPORm4L (127mgl(-1) of culture medium) was markedly increased in comparison with wild-type rhEPOR (2mgl(-1) of culture medium). Small-scale affinity chromatography demonstrated that EPORm4L worked as an affinity ligand for purification of rHuEPO. PMID- 25795091 TI - A Sea Lamprey (Petromyzon marinus) Sex Pheromone Mixture Increases Trap Catch Relative to a Single Synthesized Component in Specific Environments. AB - Spermiating male sea lamprey (Petromyzon marinus) release a sex pheromone, of which a component, 7alpha, 12alpha, 24-trihydoxy-3-one-5alpha-cholan-24-sulfate (3kPZS), has been identified and shown to induce long distance preference responses in ovulated females. However, other pheromone components exist, and when 3kPZS alone was used to control invasive sea lamprey populations in the Laurentian Great Lakes, trap catch increase was significant, but gains were generally marginal. We hypothesized that free-ranging sea lamprey populations discriminate between a partial and complete pheromone while migrating to spawning grounds and searching for mates at spawning grounds. As a means to test our hypothesis, and to test two possible uses of sex pheromones for sea lamprey control, we asked whether the full sex pheromone mixture released by males (spermiating male washings; SMW) is more effective than 3kPZS in capturing animals in traditional traps (1) en route to spawning grounds and (2) at spawning grounds. At locations where traps target sea lampreys en route to spawning grounds, SMW-baited traps captured significantly more sea lampreys than paired 3kPZS-baited traps (~10% increase). At spawning grounds, no difference in trap catch was observed between 3kPZS and SMW-baited traps. The lack of an observed difference at spawning grounds may be attributed to increased pheromone competition and possible involvement of other sensory modalities to locate mates. Because fishes often rely on multiple and sometimes redundant sensory modalities for critical life history events, the addition of sex pheromones to traditionally used traps is not likely to work in all circumstances. In the case of the sea lamprey, sex pheromone application may increase catch when applied to specifically designed traps deployed in streams with low adult density and limited spawning habitat. PMID- 25795090 TI - Novel Set-Up for Low-Disturbance Sampling of Volatile and Non-volatile Compounds from Plant Roots. AB - Most studies on rhizosphere chemicals are carried out in substrate-free set-ups or in artificial substrates using sampling methods that require an air flow and may thus cause disturbance to the rhizosphere. Our study aimed to develop a simplified and inexpensive system that allows analysis of rhizosphere chemicals at experimentally less disturbed conditions. We designed a mesocosm in which volatile rhizosphere chemicals were sampled passively (by diffusion) without air- and water flow on polydimethylsiloxane-(PDMS) tubes. Dandelion (Taraxacum sect. ruderalia) was used as model plant; roots were left undamaged. Fifteen volatiles were retrieved from the sorptive material by thermal desorption for analysis by gas chromatography/mass spectrometry (GC/MS). Furthermore, three sugars were collected from the rhizosphere substrate by aqueous extraction and derivatized prior to GC/MS analysis. In order to study how the quantity of detected rhizosphere compounds depends on the type of soil or substrate, we determined the matrix-dependent recovery of synthetic rhizosphere chemicals. Furthermore, we compared sorption of volatiles on PDMS tubes with and without direct contact to the substrate. The results show that the newly designed mesocosm is suitable for low-invasive extraction of volatile and non-volatile compounds from rhizospheres. We further highlight how strongly the type of substrate and contact of PDMS tubes to the substrate affect the detectability of compounds from rhizospheres. PMID- 25795092 TI - High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior. AB - Depression disorder is a common mental illness, of which the pathogenesis is not well understood. Studies suggest that immunity imbalance and up-regulation of pro inflammatory cytokines may be associated with the pathogenesis of depression. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and an modulating factor in several inflammatory diseases. Here we sought to explore the role of HMGB1 in the development of depression. Depression model was established with low dose of lipopolysaccharide (LPS) administration. Depressive behavior was reflected with increased immobility time in tail suspension test. Accompanying with depressive like behavior, translocation of HMGB1 from nuclei to cytoplasm was observed by immunofluorescence assays. Meanwhile, no significant necrosis was observed evaluated by hematoxylin-eosin staining. These data indicated that HMGB1 was released actively in the central nervous system. In addition, treating the mice with human recombinant HMGB1 (rHMGB1) could induce the development of depressive like behavior. Blockage of HMGB1 with GZA abrogated the depressive-like behavior induced by LPS or rHMGB1. These results implicated that HMGB1 was involved in LPS induced depressive-like behavior. PMID- 25795088 TI - Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model. AB - HIV-associated mortality has been significantly reduced with antiretroviral therapy (ART), and HIV infection has become a chronic disease that frequently coexists with many disorders, including substance abuse (Azar et al. Drug Alcohol Depend 112:178-193, 2010; Phillips et al. J Gen Int Med 16:165, 2001). Alcohol and drugs of abuse may modify host-pathogen interactions at various levels including behavioral, metabolic, and immune consequences of HIV infection, as well as the ability of the virus to integrate into the genome and replicate in host cells. Identifying mechanisms responsible for these interactions is complicated by many factors, such as the tissue specific responses to viral infection, multiple cellular mechanisms involved in inflammatory responses, neuroendocrine and localized responses to infection, and kinetics of viral replication. An integrated physiological analysis of the biomedical consequences of chronic alcohol and drug use or abuse on disease progression is possible using rhesus macaques infected with simian immunodeficiency virus (SIV), a relevant model of HIV infection. This review will provide an overview of the data gathered using this model to show that chronic administration of two of the most commonly abused substances, alcohol and cannabinoids (Delta(9)-Tetrahydrocannabinol; THC), affect host-pathogen interactions. PMID- 25795094 TI - Unhealthy lifestyle may increase later depression via inflammation in older women but not men. AB - Depression and inflammatory markers have a reliable cross-sectional association although less is known about the prospective relationship. The current study investigated whether pro-inflammatory markers are prospectively associated with depression, and whether indicators of unhealthy lifestyle, physical health and psychosocial functioning may drive this association. Participants were drawn from the Hunter Community Study, a community-dwelling cohort of individuals aged 55-85 years (N = 1410). Participants completed baseline physiological assessment, health-related questionnaires, and blood sampling for the analysis of inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6. Participants completed the same depressive symptom questionnaire again after 3.5 5.5 years. Depression outcomes at follow-up were analysed dichotomously using established scale cut-off scores and continuously as a "residual score", representing the variation in follow-up depressive symptoms not explained by baseline symptoms and age. Analyses were conducted on males and females separately. At baseline, indicators of unhealthy lifestyle, physical health and psychosocial functioning were associated with depressive symptoms and inflammatory markers. For males, there were no relationships between inflammatory markers and follow-up depression outcomes. In females, IL-6 was significantly associated with depression outcomes in univariate, but not multivariate analyses. However, IL-6 significantly mediated the association between the predictors of waist-to-hip ratio, smoking and psychological coping at baseline, and follow-up depression outcomes. The results support the inflammatory hypothesis of depression, although females may be more vulnerable to effects. The findings raise the possibility that unhealthy lifestyle and psychosocial stress may drive inflammation and subsequent depressive symptoms. PMID- 25795093 TI - Perceived cannabis use norms and cannabis use among adolescents in the United States. AB - Due to changes in cannabis policies, concerns about cannabis use (CU) in adolescents have increased. The population of nonwhite groups is growing quickly in the United States. We examined perceived CU norms and their association with CU and CU disorder (CUD) for White, Black, Hispanic, Native-American, Asian American, Native Hawaiian/Pacific Islander (NH/PI), and mixed-race adolescents. Data were from adolescents (12-17 years) in the 2004-2012 National Surveys on Drug Use and Health (N = 163,837). Substance use and CUD were assessed by computer-assisted, self-interviewing methods. Blacks, Hispanics, Native Americans, and mixed-race adolescents had greater odds of past-year CU and CUD than Whites. Among past-year cannabis users (CUs), Hispanics and Native-Americans had greater odds of having a CUD than Whites. Asian-Americans had the highest prevalence of perceived parental or close friends' CU disapproval. Native Americans and mixed-race adolescents had lower odds than Whites of perceiving CU disapproval from parents or close friends. In adjusted analyses, adolescent's disapproval of CU, as well as perceived disapproval by parents or close friends, were associated with a decreased odds of CU in each racial/ethnic group, except for NHs/PIs. Adolescent's disapproval of CU was associated with a decreased odds of CUD among CUs for Whites (personal, parental, and close friends' disapproval), Hispanics (personal, parental, and close friends' disapproval), and mixed-race adolescents (personal, close friends' disapproval). Racial/ethnic differences in adolescent CU prevalence were somewhat consistent with adolescents' reports of CU norm patterns. Longitudinal research on CU health effects should oversample nonwhite adolescents to assure an adequate sample for analysis and reporting. PMID- 25795095 TI - Felis catus papillomavirus types 1 and 4 are rarely present in neoplastic and inflammatory oral lesions of cats. AB - Oral squamous cell carcinomas (OSCCs) are common feline cancers. Why OSCCs are so common in cats is unknown; however, 25% of human OSCCs are caused by papillomaviruses (PVs). Two feline oral PVs (FcaPV-1 and 4) are recognized. As PVs are highly host and location specific, if PVs do cause feline OSCCs, FcaPV-1 and 4 are the most likely etiological agents. PCR primers specific for FcaPV-1 amplified DNA from 1 of 36 feline OSCCs and 1 of 16 inflammatory oral lesions. No DNA was amplified by primers specific for FcaPV-4. PV DNA was not amplified from any additional sample using consensus primers. No PV cytopathology was visible in the OSCC that contained FcaPV-1 DNA, but viral cytopathology was present in a focus of epithelial hyperplasia in the non-neoplastic sample. This study does not support a PV etiology of feline OSCCs, but shows that FcaPV-1 can asymptomatically infect the mouth of cats. PMID- 25795096 TI - Induction of immune tolerance to RBC, platelet, and neutrophil antigens and IgA. AB - Antibodies to red blood cell (RBC), platelet, and neutrophil antigens, and IgA may cause serious clinical problems. With a few exceptions, preventing these conditions is a matter of limiting exposure to the foreign antigen while treatment consists of managing the consequences. Might immune tolerance induction (ITI) be possible and beneficial in these situations? Neonatal exposure to antigens is known to induce central tolerance. However central tolerance may not be absolute. Factors that determine whether an antibody will be produced in response to an antigen are not well understood but include the appropriate expression of major histocompatibility complex-class II and/or co-stimulatory molecules on dendritic cells, the presence or absence of adjuvants and whether or not the antigen is presented together with agonists for the toll-like receptor. Modifying these may prevent alloimmunization. Peripheral tolerance, in sensitized individuals, as routinely used in patients with allergic/anaphylactic reactions, those with haemophilia A or B with inhibitors and acquired haemophilia, may also be possible. Briefly, monitored, graded, increasing exposure to the antigen of interest with or without additional immunosuppression is used. Neither central nor peripheral ITI has been tried or suggested for individuals sensitizable or sensitised to RBC, platelet, and neutrophil antigens, or IgA. Theoretically, this is possible and may be of benefit. PMID- 25795097 TI - Limitations of a habituation task to demonstrate discrimination of natural signals in songbirds. AB - The habituation-dishabituation (HDH) paradigm is a common method used to examine animal cognition. Recent studies reported that spontaneous vocalizations could be used as an index of song familiarity and novelty in songbirds. However, these studies assigned only a few stimulus sets for all subjects, which might cause pseudoreplication. Therefore, we examined universality and general applicability of this method in Bengalese finches using a variety of stimulus sets. Seven unfamiliar conspecific songs were collected as a stimulus pool and a habituation song was randomly chosen for each subject. The subject was exposed to the habituation song repeatedly over 2h. During the test phase, the habituation song and a novel song randomly chosen from the stimulus pool were presented. We compared the degree of increase in call production during playback of those two songs. Although the degree was greater for the novel song compared with the habituation song in some birds, the trend was not consistent across all stimulus sets tested in these birds. Our results show that the HDH paradigm is not suitable to test song discrimination in songbirds unless precautions are taken to increase external validity by utilizing a variety of stimulus sets for each subject. PMID- 25795098 TI - Evaluation of growth and foraging in laboratory colonies of Coptotermes gestroi (Isoptera, Rhinotermitidae). AB - Coptotermes gestroi is an exotic species in Brazil that forages on several food items at the same time. Different laboratory tests were performed with 6-year-old colonies of this termite in order to follow the development and displacement of these colonies, considering which castes and instars were transferred or moved from their original chamber. Two bioassays were carried out, one with similar alternative foods (Pinus sp. sawdust), and the other with different alternative foods (large block of Pinus taeda and small block of Pinus elliottii). The colonies of C. gestroi did not show preferences in the allocation of foragers when they had alternative similar foods. However, they were found in the chamber that contained the small block of P. elliottii, when termites had the alternative of different blocks of Pinus, indicating an environment most favorable for the nucleus of the colony (royal cup and brood). Many factors may have influenced this choice as more nutritive alimentary resource for brood or the presentation of the food, which allowed better colony accommodation. C. gestroi did not have difficulties of migration from one chamber to another and this characteristic may be a risk factor in urban infestations of this severe pest. PMID- 25795099 TI - A hypothesis about how early developmental methylmercury exposure disrupts behavior in adulthood. AB - Events that disrupt the early development of the nervous system have lifelong, irreversible behavioral consequences. The environmental contaminant, methylmercury (MeHg), impairs neural development with effects that are manifested well into adulthood and even into aging. Noting the sensitivity of the developing brain to MeHg, the current review advances an argument that one outcome of early MeHg exposure is a distortion in the processing of reinforcing consequences that results in impaired choice, poor inhibition of prepotent responding, and perseveration on discrimination reversals (in the absence of alteration of extradimensional shifts). Neurochemical correlates include increased sensitivity to dopamine agonists and decreased sensitivity to gamma-aminobutyric acid (GABA) agonists. This leads to a hypothesis that the prefrontal cortex or dopamine neurotransmission is especially sensitive to even subtle gestational MeHg exposure and suggests that public health assessments of MeHg based on intellectual performance may underestimate the impact of MeHg in public health. Finally, those interested in modeling neural development may benefit from MeHg as an experimental model. PMID- 25795101 TI - Lenvatinib: first global approval. AB - Lenvatinib (LenvimaTM) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor alpha, RET and KIT. In addition to their role in normal cellular function, these kinases have been implicated in pathogenic angiogenesis, tumour growth and cancer progression. Lenvatinib is being developed by Eisai Co. Ltd for the treatment of solid tumours, primarily for differentiated thyroid cancer, and other malignancies. A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Lenvatinib is in pre registration for this indication in the EU, Australia, Brazil, Canada, Japan, South Korea, Russia, Singapore and Switzerland, and is in phase 3 development in Argentina, Chile and Thailand. Lenvatinib has orphan designation in the EU and Japan for use in differentiated thyroid cancer. In addition, an ongoing global, phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma. This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. PMID- 25795100 TI - An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome. AB - This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D3/D2/D1 dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D3/D2/D1 dopamine receptor agonist in the treatment of PD and RLS. PMID- 25795103 TI - Self-perspective leads to increased activation of pain processing brain regions in fibromyalgia. AB - BACKGROUND: Dysfunction of central nervous pain processing is assumed to play a key role in primary fibromyalgia (FM) syndrome. This pilot study examined differences of pain processing associated with adopting different interpersonal perspectives. METHODS: Eleven FM patients and 11 healthy controls (HC) were scanned with functional magnetic resonance imaging. Participants were trained to take either a self-perspective or another person's perspective when viewing the visual stimuli. Stimuli showed body parts in painful situations of varying intensity (low, medium, and high) and visually similar but neutral situations. RESULTS: Patients with FM showed a higher increase in blood oxygen level dependent (BOLD) response, particularly in the supplementary motor area (SMA). All pain-related regions of interest (anterior insula, somatosensory cortices, anterior cingulate cortex, and SMA) showed stronger modulation of BOLD responses in FM patients in the self-perspective. In contrast to pain processing regions, perspective-related regions (e.g. temporoparietal junction) did not differ between FM and HC. CONCLUSIONS: The stronger response of all four pain processing cerebral regions during self-perspective is discussed in the light of disturbed bottom-up processing. Furthermore, the results confirm earlier reports of augmented pain processing in FM, and provide evidence for sensitization of central nervous pain processing. PMID- 25795104 TI - Statins and cataracts: reverse causality? PMID- 25795102 TI - A literature-based guide to the conservative and surgical management of the acute Charcot foot and ankle. AB - Acute Charcot neuroarthropathy of the foot and ankle presents with the insidious onset of a unilateral acutely edematous, erythematous, and warm lower extremity. The acute stages are typically defined as Eichenholtz Stage 1, or Stage 0, which was first described by Shibata et al. in 1990. The ultimate goal of treatment is maintenance of a stable, plantigrade foot which can be easily shod, minimizing the risk of callus, ulceration, infection, and amputation. The gold standard of treatment is non-weight-bearing immobilization in a total contact cast. Surgical intervention remains controversial. A review of the literature was performed to provide an evidenced-based approach to the conservative and surgical management of acute Charcot neuroarthropathy of the foot and ankle. PMID- 25795105 TI - Spectral contrast-enhanced cardiac computed tomography for diagnosis of acute myocarditis. PMID- 25795106 TI - Global burden of cardiovascular disease and stroke: hypertension at the core. PMID- 25795107 TI - Pro-nociceptive and anti-nociceptive effects of a conditioned pain modulation protocol in participants with chronic low back pain and healthy control subjects. AB - BACKGROUND: People with chronic pain may exhibit pro-nociceptive phenotypes characterised partly by reduced conditioned pain modulation (CPM). Characterising variability in CPM in people with chronic low back pain (CLBP) may inform management. OBJECTIVES: To investigate pro/anti-nociceptive effects of a CPM protocol in age/sex-matched healthy controls (HCs) and people with CLBP. DESIGN: Case-controlled trial (64 participants/group). METHOD: The CPM protocol involved: test stimulus (TS) (noxious pressure applied by algometer to lumbar region); conditioning stimulus (CS) (noxious heat applied by thermode to dorsal hand). CPM recruitment was measured by the change in pain intensity (rated on a numeric rating scale (NRS)) of the TS in the presence and absence of the CS. RESULTS: Responses to this CPM protocol were variable for both groups with measures consistent with either inhibitory or facilitatory effects. A significantly greater proportion of facilitatory responses were seen in the CLBP cohort compared to HCs (73% versus 31%). In response to the CS, participants with CLBP demonstrated a mean increase in NRS scores (mean 1.3 points; p < 0.001), while HCs did not (mean -0.2 points; p = 0.35) and the between-group difference in change scores was significant (mean 1.4 points; p < 0.001; effect size (Hedges' g): 1.03). CONCLUSION: In HCs and participants with CLBP this CPM protocol elicited responses consistent with varying pro/anti-nociceptive effects. The higher proportion of participants with CLBP demonstrating a facilitatory response suggests a pro-nociceptive phenotype may characterise this cohort. PMID- 25795108 TI - Acute effects of static stretching on the hamstrings using shear elastic modulus determined by ultrasound shear wave elastography: Differences in flexibility between hamstring muscle components. AB - BACKGROUND: Static stretching (SS) with hip flexion and knee extension is often used to stretch the hamstrings. However, it is unclear whether there are the differences in the acute effect of this SS maneuver on flexibility between each component of the hamstrings, namely the semitendinosus (ST), semimembranosus (SM), and biceps femoris (BF) muscles. OBJECTIVES: The aims of this study were to investigate the acute effects of SS on the flexibility of the individual muscle components of the hamstrings, and to examine the difference in the acute effect of SS between these components using shear elastic modulus as the index of muscle flexibility. METHOD: Twenty healthy men (age, 23.4 +/- 2.3 years) volunteered for this study. The shear elastic modulus of the ST, SM and BF muscles were measured using ultrasound shear wave elastography before (PRE) and immediately after (POST) 5 min of SS. Measurements of shear elastic modulus were taken with the knee at 90 degrees (slack position) and 45 degrees (extension position) of flexion. RESULTS: In all muscles, the shear elastic modulus at both knee angles decreased significantly after SS. The percentage change in the shear elastic modulus from PRE to POST in the muscles at 45 degrees of knee flexion was greatest in the SM. CONCLUSIONS: These results suggest that SS with hip flexion and knee extension has acute effects on increasing flexibility of the hamstring muscle components, especially the SM muscle. PMID- 25795109 TI - The comparison of scapular upward rotation and scapulohumeral rhythm between dominant and non-dominant shoulder in male overhead athletes and non-athletes. AB - Previous studies have stated that the scapulohumeral rhythm dysfunction can make person prone to glenohumeral joint pathologies. The purpose of this study was to compare scapular upward rotation and scapulohumeral rhythm between dominant and non-dominant shoulder in male overhead athletes and non-athletes. Seventeen overhead athletes and seventeen non-athletes volunteered for this study. Two inclinometers were used to measure humeral abduction and scapular upward rotation in rest position, 45 degrees , 90 degrees and 135 degrees humeral abduction in frontal plane. Findings indicated there was no significant asymmetry in scapular upward rotation and scapulohumeral rhythm in different abduction angles between dominant and non-dominant shoulder in non-athletes. In contrast, overhead athletes' dominant shoulders have more downward rotation in scapular rest position and more upward rotation in 90 degrees and 135 degrees shoulder abduction than non-dominant shoulders. Also, overhead athletes presented scapulohumeral rhythm asymmetry between dominant and non-dominant shoulder in 90 degrees and 135 degrees humeral abduction as dominant shoulders have less scapulohumeral rhythm ratio than non-dominant shoulders. Furthermore, overhead athletes dominant shoulders have more scapular downward rotation in scapular rest position, more scapular upward rotation in 90 degrees and 135 degrees humeral abduction and less scapulohumeral rhythm ratio in 45 degrees , 90 degrees and 135 degrees humeral abduction than non-athletes in dominant shoulders. We suggest that clinicians should be aware that some scapular asymmetry may be common in some athletes. It should not be considered as a pathological sign but rather an adaptation to extensive use of upper limb. PMID- 25795110 TI - Nursing and the future of 'care' in health care systems. PMID- 25795111 TI - The passing of Frederick J. de Serres Jr. PMID- 25795112 TI - Reflections on the development and application of FISH whole chromosome painting. AB - This review describes my personal reflections on the development of whole chromosome painting using fluorescence in situ hybridization and how my laboratory applied the technology in humans and in animal models. The trials and triumphs of the early years are emphasized, along with some of the scientific surprises that were encountered along the way. Scientific issues that my laboratory addressed using chromosome painting technologies are summarized and related to questions in radiation dosimetry, chemical clastogenesis, translocation persistence, and translocation frequencies in unexposed people. A description is provided of scientific controversies that were encountered and how they were resolved. I hope this paper will encourage young scientists to follow their passions and pursue their scientific dreams even if the task seems daunting and the circumstances appear exceedingly difficult. In my case the journey has been challenging, exciting, and richly rewarding on many levels. PMID- 25795113 TI - The Ku heterodimer: function in DNA repair and beyond. AB - Ku is an abundant, highly conserved DNA binding protein found in both prokaryotes and eukaryotes that plays essential roles in the maintenance of genome integrity. In eukaryotes, Ku is a heterodimer comprised of two subunits, Ku70 and Ku80, that is best characterized for its central role as the initial DNA end binding factor in the "classical" non-homologous end joining (C-NHEJ) pathway, the main DNA double-strand break (DSB) repair pathway in mammals. Ku binds double-stranded DNA ends with high affinity in a sequence-independent manner through a central ring formed by the intertwined strands of the Ku70 and Ku80 subunits. At the break, Ku directly and indirectly interacts with several C-NHEJ factors and processing enzymes, serving as the scaffold for the entire DNA repair complex. There is also evidence that Ku is involved in signaling to the DNA damage response (DDR) machinery to modulate the activation of cell cycle checkpoints and the activation of apoptosis. Interestingly, Ku is also associated with telomeres, where, paradoxically to its DNA end-joining functions, it protects the telomere ends from being recognized as DSBs, thereby preventing their recombination and degradation. Ku, together with the silent information regulator (Sir) complex is also required for transcriptional silencing through telomere position effect (TPE). How Ku associates with telomeres, whether it is through direct DNA binding, or through protein-protein interactions with other telomere bound factors remains to be determined. Ku is central to the protection of organisms through its participation in C-NHEJ to repair DSBs generated during V(D)J recombination, a process that is indispensable for the establishment of the immune response. Ku also functions to prevent tumorigenesis and senescence since Ku-deficient mice show increased cancer incidence and early onset of aging. Overall, Ku function is critical to the maintenance of genomic integrity and to proper cellular and organismal development. PMID- 25795114 TI - The history, genotoxicity, and carcinogenicity of carbon-based fuels and their emissions. Part 3: diesel and gasoline. AB - Within this review the genotoxicity of diesel and gasoline fuels and emissions is placed in an historical context. New technologies have changed the composition of transportation methods considerably, reducing emissions of many of the components of health concern. The similarity of modern diesel and gasoline fuels and emissions to other carbonaceous fuels and emissions is striking. Recently an International Agency for Research on Cancer (IARC) Working Group concluded that there was sufficient evidence in humans for the carcinogenicity of diesel exhaust (Group 1). In addition, the Working Group found that diesel exhaust has "a positive association (limited evidence) with an increased risk of bladder cancer." Like most other carbonaceous fuel emissions, diesel and gasoline exhausts contain toxic levels of respirable particles (PM <2.5MUm) and polycyclic aromatic hydrocarbons. However, the level of toxic components in exhausts from diesel and gasoline emissions has declined in certain regions over time because of changes in engine design, the development of better aftertreatment devices (e.g., catalysts), increased fuel economy, changes in the fuels and additives used, and greater regulation. Additional research and better exposure assessments are needed so that decision makers and the public can decide to what extent diesel and gasoline engines should be replaced. PMID- 25795115 TI - The history, genotoxicity and carcinogenicity of carbon-based fuels and their emissions: part 4 - alternative fuels. AB - Much progress has been made in reducing the pollutants emitted from various combustors (including diesel engines and power plants) by the use of alternative fuels; however, much more progress is needed. Not only must researchers improve fuels and combustors, but also there is a need to improve the toxicology testing and analytical chemistry methods associated with these complex mixtures. Emissions from many alternative carbonaceous fuels are mutagenic and carcinogenic. Depending on their source and derivation, alternative carbonaceous fuels before combustion may or may not be genotoxic; however, in order to know their genotoxicity, appropriate chemical analysis and/or bioassay must be performed. Newly developed fuels and combustors must be tested to determine if they provide a public health advantage over existing technologies - including what tradeoffs can be expected (e.g., decreasing levels of PAHs versus increasing levels of NOx and possibly nitroarenes in ambient air). Another need is to improve exposure estimations which presently are a weak link in doing risk analyses. PMID- 25795116 TI - The history, genotoxicity, and carcinogenicity of carbon-based fuels and their emissions: part 5. Summary, comparisons, and conclusions. AB - As seen through the previous reviews, each carbonaceous source of energy is associated with genotoxic and carcinogenic health risks; however, energy use is central to human society and provides many health benefits. These reviews examined the genotoxicity of carbonaceous sources of energy, focusing on the impacts due to the combustion of fuels and biomass. In previous reviews, information and data were used to examine occupational, industrial, household, and general environmental pollution as well as laboratory research. In this final summation, the effort is not only to summarize the previous reviews but to provide additional information to support any final conclusions. Included in the final observations are: (1) emissions from combusted carbonaceous fuels are very likely to include genotoxicants and/or carcinogens, and, as such, they can considerably increase the risk of adverse health effects in exposed humans, (2) environmental transformation is likely to increase genotoxicity of emissions, and (3) the world's poor households have an increased health risk because they have limited access to clean fuels and electricity. Because carbonaceous fuel emissions are highly complex, risk assessments are difficult; however, decision makers have many toxicological approaches for evaluating emissions. Although energy efficiency brings many benefits, it also involves health risks, as do renewable energy systems, if not managed carefully. The reviews do not examine climate change or non-carbonaceous fuels (e.g., nuclear fuels). Because these are not papers about the risk assessment or regulation of pollutants from carbon based fuels, the discussions of regulations were to place research, concerns, and actions into a historical reference for the reader. PMID- 25795117 TI - Comprehensive assessment of the association between miRNA polymorphisms and gastric cancer risk. AB - Single nucleotide polymorphisms (SNPs) in pri- or pre-microRNAs (miRNAs) were found to be associated with gastric cancer risk. The aim of this study was to systematically review with update meta-analysis for the association of miRNA SNPs with gastric cancer risk. We systematically reviewed a total of 31 SNPs in the precursor genes of 29 miRNAs associated with overall cancer risk. Meanwhile, 13 case-control studies with a total of 9044 gastric cancer cases and 11,762 controls were included in a meta-analysis of five highly studied pre-miRNA SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs2292832 and miR-27a rs895819). Our results show both the homozygous miR-27a rs895819 and the miR-149 rs2292832 heterozygote genotype were associated with a decreased risk of gastric cancer when compared with wild type. In the stratified analysis, in some subgroup, heterozygous miR-146a rs2910164 was associated with a decreased risk of gastric cancer; and the variant genotype of miR-196a-2 rs11614913 was associated with an increased risk. No association was found between miR-499 rs3746444 and gastric cancer risk. In summary, miR-27a rs895819 and miR-149 rs2292832 are of potential forewarning ability for gastric cancer risk. PMID- 25795118 TI - Susceptibility variants in the CD58 gene locus point to a role of microRNA-548ac in the pathogenesis of multiple sclerosis. AB - Multiple sclerosis (MS) is a neurological immune-driven disease of unknown etiology. A genetic contribution to MS susceptibility is well established and more than 100 associated genomic regions have been identified. However, there is little understanding of how individual genetic variants are involved in the pathogenesis of MS. Single nucleotide polymorphisms (SNPs) within the first intron of CD58 have been independently confirmed to be related to the risk of MS. We here provide evidence that these SNPs may implicate an altered processing of an intronic microRNA. This microRNA, hsa-mir-548ac, belongs to a huge primate specific family of microRNAs that evolved from a mariner-derived transposable element (Made1). Sequencing data of the 1000 Genomes project revealed a SNP, rs1414273, at the base of the microRNA stem-loop to be in strong linkage disequilibrium with the MS-associated haplotype. This SNP is suspected to affect the recognition of the primary microRNA hairpin by Drosha and its cofactor DGCR8. Future studies on microRNA-548ac and its genetic variant may yield deeper insights into the mechanisms underlying MS. Experimental challenges and open questions are discussed. PMID- 25795120 TI - Assessment of mechanisms driving non-linear dose-response relationships in genotoxicity testing. AB - In genetic toxicology, risk assessment has traditionally adopted linear dose responses for any compound that causes genotoxic effects. Increasing evidence of non-linear dose-responses, however, suggests potential cellular tolerance to low levels of many genotoxicants with diverse modes of action. Such putative non linear dose-responses need to be substantiated by strong mechanistic data that identifies the mechanisms responsible for the tolerance to low doses. This can be achieved by experimental demonstration of cytoprotective mechanisms and by providing experimental support for the existence of tolerance mechanisms against low dose effects. By highlighting key experiments into low dose mechanisms, this review aims to clarify which mechanistic data are required to support the use of non-linear dose-response models in risk assessment. Such key experiments are presented and discussed for alkylating agents, oxidants, particulate matter, nucleoside analogues, topoisomerase inhibitors and aneugens and exemplify the use of gene knockout models or transgenic models as well as chemical modulators of key effectors of relevant pathways and their impact on dose-response relationships. In vitro studies are particularly valuable to elucidate mechanisms of low-dose protection or lack thereof, while in vivo experiments are most appropriate for deriving a safe dose. In order to evaluate the existence of non linear dose-response relationships for genotoxicants, we suggest that careful attention should be given to the mode of genotoxic action, relevant biomarkers of exposure, as well as to the existence and impact of potential cytoprotective mechanisms like detoxifying metabolism and DNA repair. PMID- 25795121 TI - Non-coding RNAs: an emerging player in DNA damage response. AB - Non-coding RNAs play a crucial role in maintaining genomic stability which is essential for cell survival and preventing tumorigenesis. Through an extensive crosstalk between non-coding RNAs and the canonical DNA damage response (DDR) signaling pathway, DDR-induced expression of non-coding RNAs can provide a regulatory mechanism to accurately control the expression of DNA damage responsive genes in a spatio-temporal manner. Mechanistically, DNA damage alters expression of a variety of non-coding RNAs at multiple levels including transcriptional regulation, post-transcriptional regulation, and RNA degradation. In parallel, non-coding RNAs can directly regulate cellular processes involved in DDR by altering expression of their targeting genes, with a particular emphasis on miRNAs and lncRNAs. MiRNAs are required for almost every aspect of cellular responses to DNA damage, including sensing DNA damage, transducing damage signals, repairing damaged DNA, activating cell cycle checkpoints, and inducing apoptosis. As for lncRNAs, they control transcription of DDR relevant gene by four different regulatory models, including signal, decoy, guide, and scaffold. In addition, we also highlight potential clinical applications of non-coding RNAs as biomarkers and therapeutic targets for anti-cancer treatments using DNA damaging agents including radiation and chemotherapy. Although tremendous advances have been made to elucidate the role of non-coding RANs in genome maintenance, many key questions remain to be answered including mechanistically how non-coding RNA pathway and DNA damage response pathway is coordinated in response to genotoxic stress. PMID- 25795122 TI - Oxidatively induced DNA damage and its repair in cancer. AB - Oxidatively induced DNA damage is caused in living organisms by endogenous and exogenous reactive species. DNA lesions resulting from this type of damage are mutagenic and cytotoxic and, if not repaired, can cause genetic instability that may lead to disease processes including carcinogenesis. Living organisms possess DNA repair mechanisms that include a variety of pathways to repair multiple DNA lesions. Mutations and polymorphisms also occur in DNA repair genes adversely affecting DNA repair systems. Cancer tissues overexpress DNA repair proteins and thus develop greater DNA repair capacity than normal tissues. Increased DNA repair in tumors that removes DNA lesions before they become toxic is a major mechanism for development of resistance to therapy, affecting patient survival. Accumulated evidence suggests that DNA repair capacity may be a predictive biomarker for patient response to therapy. Thus, knowledge of DNA protein expressions in normal and cancerous tissues may help predict and guide development of treatments and yield the best therapeutic response. DNA repair proteins constitute targets for inhibitors to overcome the resistance of tumors to therapy. Inhibitors of DNA repair for combination therapy or as single agents for monotherapy may help selectively kill tumors, potentially leading to personalized therapy. Numerous inhibitors have been developed and are being tested in clinical trials. The efficacy of some inhibitors in therapy has been demonstrated in patients. Further development of inhibitors of DNA repair proteins is globally underway to help eradicate cancer. PMID- 25795119 TI - The fork and the kinase: a DNA replication tale from a CHK1 perspective. AB - Replication fork progression is being continuously hampered by exogenously introduced and naturally occurring DNA lesions and other physical obstacles. Checkpoint kinase 1 (Chk1) is activated at replication forks that encounter damaged DNA. Subsequently, Chk1 inhibits the initiation of new replication factories and stimulates the firing of dormant origins (those in the vicinity of stalled forks). Chk1 also avoids fork collapse into DSBs (double strand breaks) and promotes fork elongation. At the molecular level, the current model considers stalled forks as the site of Chk1 activation and the nucleoplasm as the location where Chk1 phosphorylates target proteins. This model certainly serves to explain how Chk1 modulates origin firing, but how Chk1 controls the fate of stalled forks is less clear. Interestingly, recent reports demonstrating that Chk1 phosphorylates chromatin-bound proteins and even holds kinase-independent functions might shed light on how Chk1 contributes to the elongation of damaged DNA. Indeed, such findings have unveiled a puzzling connection between Chk1 and DNA lesion bypass, which might be central to promoting fork elongation and checkpoint attenuation. In summary, Chk1 is a multifaceted and versatile signaling factor that acts at ongoing forks and replication origins to determine the extent and quality of the cellular response to replication stress. PMID- 25795123 TI - Role of DNA repair in host immune response and inflammation. AB - In recent years, the understanding of how DNA repair contributes to the development of innate and acquired immunity has emerged. The DNA damage incurred during the inflammatory response triggers the activation of DNA repair pathways, which are required for host-cell survival. Here, we reviewed current understanding of the mechanism by which DNA repair contributes to protection against the oxidized DNA damage generated during infectious and inflammatory diseases and its involvement in innate and adaptive immunity. We discussed the functional role of DNA repair enzymes in the immune activation and the relevance of these processes to: transcriptional regulation of cytokines and other genes involved in the inflammatory response; V(D)J recombination; class-switch recombination (CSR); and somatic hypermutation (SHM). These three last processes of DNA damage repair are required for effective humoral adaptive immunity, creating genetic diversity in developing T and B cells. Furthermore, viral replication is also dependent on host DNA repair mechanisms. Therefore, the elucidation of the pathways of DNA damage and its repair that activate innate and adaptive immunity will be important for a better understanding of the immune and inflammatory disorders and developing new therapeutic interventions for treatment of these diseases and for improving their outcome. PMID- 25795125 TI - Elg1, a central player in genome stability. AB - ELG1 is a conserved gene uncovered in a number of genetic screens in yeast aimed at identifying factors important in the maintenance of genome stability. Elg1's activity prevents gross chromosomal rearrangements, maintains proper telomere length regulation, helps repairing DNA damage created by a number of genotoxins and participates in sister chromatid cohesion. Elg1 is evolutionarily conserved, and its mammalian ortholog (also known as ATAD5) is embryonic lethal when lost in mice, acts as a tumor suppressor in mice and humans, exhibits physical interactions with components of the human Fanconi Anemia pathway and may be responsible for some of the phenotypes associated with neurofibromatosis. In this review, we summarize the information available on Elg1-related activities in yeast and mammals, and present models to explain how the different phenotypes observed in the absence of Elg1 activity are related. PMID- 25795126 TI - Proteomic overview and perspectives of the radiation-induced bystander effects. AB - Radiation proteomics is a recent, promising and powerful tool to identify protein markers of direct and indirect consequences of ionizing radiation. The main challenges of modern radiobiology is to predict radio-sensitivity of patients and radio-resistance of tumor to be treated, but considerable evidences are now available regarding the significance of a bystander effect at low and high doses. This "radiation-induced bystander effect" (RIBE) is defined as the biological responses of non-irradiated cells that received signals from neighboring irradiated cells. Such intercellular signal is no more considered as a minor side effect of radiotherapy in surrounding healthy tissue and its occurrence should be considered in adapting radiotherapy protocols, to limit the risk for radiation induced secondary cancer. There is no consensus on a precise designation of RIBE, which involves a number of distinct signal-mediated effects within or outside the irradiated volume. Indeed, several cellular mechanisms were proposed, including the secretion of soluble factors by irradiated cells in the extracellular matrix, or the direct communication between irradiated and neighboring non-irradiated cells via gap junctions. This phenomenon is observed in a context of major local inflammation, linked with a global imbalance of oxidative metabolism which makes its analysis challenging using in vitro model systems. In this review article, the authors first define the radiation-induced bystander effect as a function of radiation type, in vitro analysis protocols, and cell type. In a second time, the authors present the current status of protein biomarkers and proteomic-based findings and discuss the capacities, limits and perspectives of such global approaches to explore these complex intercellular mechanisms. PMID- 25795127 TI - Inducible repair of alkylated DNA in microorganisms. AB - Alkylating agents, which are widespread in the environment, also occur endogenously as primary and secondary metabolites. Such compounds have intrinsically extremely cytotoxic and frequently mutagenic effects, to which organisms have developed resistance by evolving multiple repair mechanisms to protect cellular DNA. One such defense against alkylation lesions is an inducible Adaptive (Ada) response. In Escherichia coli, the Ada response enhances cell resistance by the biosynthesis of four proteins: Ada, AlkA, AlkB, and AidB. The glycosidic bonds of the most cytotoxic lesion, N3-methyladenine (3meA), together with N3-methylguanine (3meG), O(2)-methylthymine (O(2)-meT), and O(2) methylcytosine (O(2)-meC), are cleaved by AlkA DNA glycosylase. Lesions such as N1-methyladenine (1meA) and N3-methylcytosine (3meC) are removed from DNA and RNA by AlkB dioxygenase. Cytotoxic and mutagenic O(6)-methylguanine (O(6)meG) is repaired by Ada DNA methyltransferase, which transfers the methyl group onto its own cysteine residue from the methylated oxygen. We review (i) the individual Ada proteins Ada, AlkA, AlkB, AidB, and COG3826, with emphasis on the ubiquitous and versatile AlkB and its prokaryotic and eukaryotic homologs; (ii) the organization of the Ada regulon in several bacterial species; (iii) the mechanisms underlying activation of Ada transcription. In vivo and in silico analysis of various microorganisms shows the widespread existence and versatile organization of Ada regulon genes, including not only ada, alkA, alkB, and aidB but also COG3826, alkD, and other genes whose roles in repair of alkylated DNA remain to be elucidated. This review explores the comparative organization of Ada response and protein functions among bacterial species beyond the classical E. coli model. PMID- 25795128 TI - Overview of xeroderma pigmentosum proteins architecture, mutations and post translational modifications. AB - The xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG, play a critical role in coordinating and promoting global genome and transcription-coupled nucleotide excision repair (GG-NER and TC-NER, respectively) pathways in eukaryotic cells. GG-NER and TC-NER are both required for the repair of bulky DNA lesions, such as those induced by UV radiation. Mutations in genes that encode XPs lead to the clinical condition xeroderma pigmentosum (XP). Although the roles of XPs in the GG-NER/TC-NER subpathways have been extensively studied, complete knowledge of their three-dimensional structure is only beginning to emerge. Hence, this review aims to summarize the current knowledge of mapped mutations and other structural information on XP proteins that influence their function and protein-protein interactions. We also review the possible post-translational modifications for each protein and the impact of these modifications on XP protein functions. PMID- 25795124 TI - Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance. AB - Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell's enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed. PMID- 25795129 TI - Regulation of FATTY ACID ELONGATION1 expression in embryonic and vascular tissues of Brassica napus. AB - The expression of the FATTY ACID ELONGATION1 genes was characterised to provide insight into the regulation of very long chain fatty acid (VLCFA) biosynthesis in Brassica napus embryos. Each of the two rapeseed homoeologous genes (Bn-FAE1.1 and Bn-FAE1.2) encoding isozymes of 3-keto-acylCoA synthase, a subunit of the cytoplasmic acyl-CoA elongase complex that controls the production of elongated fatty acids, are expressed predominantly in developing seeds. The proximal regions of the Bn-FAE1.1 and Bn-FAE1.2 promoters possess strong sequence identity suggesting that transcriptional control of expression is mediated by this region which contains putative cis-elements characteristic of those found in the promoters of genes expressed in embryo and endosperm. Histochemical staining of rapeseed lines expressing Bn-FAE1.1 promoter:reporter gene fusions revealed a strong expression in the embryo cotyledon and axis throughout the maturation phase. Quantitative analyses revealed the region, -331 to -149, exerts a major control on cotyledon specific expression and the level of expression. A second region, -640 to -475, acts positively to enhance expression levels and extends expression of Bn-FAE1.1 into the axis and hypocotyl but also acts negatively to repress expression in the root meristem. The expression of the Bn-FAE1.1 gene was not restricted to the seed but was also detected in the vascular tissues of germinating seedlings and mature plants in the fascicular cambium tissue present in roots, stem and leaf petiole. We propose that Bn-FAE1.1 expression in vascular tissue may contribute VLCFA for barrier lipid synthesis and reflects the ancestral function of FAE1 encoded 3-keto-acylCoA synthase. PMID- 25795130 TI - Efficient expression, purification and characterization of native human cystatin C in Escherichia coli periplasm. AB - Human cystatin C (HCC), encoded by cystatin 3 gene, is a 13.3kDa endogenous cysteine proteinase inhibitor and an important biomarker of renal function. However, expressing recombinant cystatin C is difficult because of low yield and inclusion bodies in Escherichia coli (E. coli). In this study, we cloned HCC gene into pET-22b vector containing PelB leader signal sequence, which could direct the protein to the bacterial periplasm. Large amounts of soluble HCC could be efficiently expressed in the bacterial periplasm at 16 degrees C with 0.1mM IPTG induction. The recombinant HCC was isolated in high purity by cation exchange chromatography and gel filtration chromatography. Furthermore, the HCC was characterized by circular dichroism (CD) and dynamic light scattering (DLS), and displayed biological activity against papain. Here, we provide a method to produce large amounts of soluble mature HCC in E. coli. PMID- 25795131 TI - FoxP3(+) and IL-17(+) cells are correlated with improved prognosis in cervical adenocarcinoma. AB - Cervical adenocarcinoma comprises approximately 15 % of cervical cancer cases. This histological subtype has different characteristics than cervical squamous cell carcinoma, which may influence disease progression. To study whether the infiltration of T cell subpopulations was correlated with cervical adenocarcinoma patient survival, similar to squamous cell carcinoma, the tumor-infiltrating T cells, Tregs, Th17 cells and IL-17(+) cell frequencies were analyzed in a cohort of cervical adenocarcinoma patients (n = 67). Intraepithelial, stromal and total cell frequencies were scored using triple immunofluorescence. The majority of Tregs were present in the tumor stroma, while other T cells and IL-17(+) cells infiltrated the tumor epithelium three times more frequently. A high total number of Tregs were significantly correlated with improved disease-specific and disease free survival (p = 0.010, p = 0.007). Within the tumor epithelium, a high T cell frequency was significantly correlated with improved disease-free survival (p = 0.034). In particular, a low number of both Tregs and IL-17(+) cells were correlated with poor disease-specific survival (p = 0.007). A low number of Tregs combined with Th17 cells present were also correlated with poor survival (p = 0.018). An increased number of IL-17(+) cells were significantly correlated with the absence of vaso-invasion (p = 0.001), smaller tumor size (p = 0.030) and less infiltration depth (p = 0.021). These results suggest that Tregs and IL-17(+) cells represent a beneficial immune response, whereas Th17 cells might represent a poor response in cervical adenocarcinoma. This contrasts with the correlations described in squamous cell carcinoma, suggesting that the local immune response in cervical adenocarcinoma contributes differently to tumor growth than in squamous cell carcinoma. PMID- 25795132 TI - Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma. AB - BACKGROUND: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer. METHODS: Four dose levels (3 * 10(10) to 1 * 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug. RESULTS: Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22 fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration. CONCLUSIONS: AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer. PMID- 25795134 TI - Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells. AB - Transforming growth factor beta (TGF-beta) promotes tumor growth, invasion and metastasis in established tumors. In this study, we analyzed the effect of overexpressing an anti-TGF-beta peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-beta peptide P144 and ApoA-I as control cells. We evaluated in vitro the gene expression profile, cell cycle and anchorage-independent growth. The in vivo tumorigenic potential and immunogenicity were analyzed inoculating the MC38 clones into C57BL/6 mice, recombination-activating gene 1 knockout mice or mice deficient in NK cells either subcutaneously or intrasplenically to generate hepatic metastases. While overexpression of ApoA-I had no effect on the parameters analyzed, ApoA-I fused to P144 markedly diminished the tumorigenic capacity and metastatic potential of MC38 in vitro and in vivo, thus generating a highly immunogenic cell line. MC38 cells transfected with ApoA-I fused to P144 triggered memory T cell responses able to eliminate the parental cell line upon re-challenge. In summary, expression of ApoA-I fused to P144 is a novel strategy to modulate TGF-beta in tumor cells. These results highlight the potential of TGF-beta as a target in the development of new antitumor treatments. PMID- 25795133 TI - Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists. AB - This study investigated whether TNF-alpha, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-alpha, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLA-DR and CD86 expression of AML cells was observed by addition of TNF-alpha, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-alpha, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-gamma release than the medium control in response to autologous AML cells. IFN-gamma release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients. PMID- 25795135 TI - IL-33 inhibits RANKL-induced osteoclast formation through the regulation of Blimp 1 and IRF-8 expression. AB - Interleukin (IL)-33 is a recently discovered proinflammatory cytokine that belongs to the IL-1 family. Several studies have reported that IL-33 inhibits osteoclast differentiation. However, the mechanism of IL-33 regulation of osteoclastogenesis remains unclear. In the present study, we examined the effect of IL-33 on osteoclast formation in vitro. IL-33 suppressed osteoclast formation in both mouse bone marrow cells and monocyte/macrophage cell line RAW264.7 cells induced by receptor activator of NF-kappaB ligand (RANKL) and/or macrophage stimulating factor (M-CSF). IL-33 also inhibited the expression of RANKL-induced nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), thereby decreasing the expression of osteoclastogenesis-related marker genes, including Cathepsin K, Osteoclast stimulatory transmembrane protein (Oc-stamp) and Tartrate-resistant acid phosphatase (Trap). Blockage of IL-33-ST2 binding suppressed the IL-33 mediated inhibition of NFATc1. RANKL-induced B-lymphocyte-induced maturation protein-1 (Blimp-1) expression was also suppressed by IL-33, which was followed by the stimulation of anti-osteoclastic genes such as interferon regulatory factor-8 (IRF-8). These results suggest that IL-33-ST2 interactions down-regulate both RANKL-induced NFATc1 activation and osteoclast differentiation via the regulation of Blimp-1 and IRF-8 expression. PMID- 25795136 TI - MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor gamma dependent Hsp90-eNOS signaling and nitric oxide production. AB - Pulmonary artery endothelial dysfunction is associated with pulmonary arterial hypertension (PAH). Based on recent studies showing that microRNA (miR)-27b is aberrantly expressed in PAH, we hypothesized that miR-27b may contribute to pulmonary endothelial dysfunction and vascular remodeling in PAH. The effect of miR-27b on pulmonary endothelial dysfunction and the underlying mechanism were investigated in human pulmonary artery endothelial cells (HPAECs) in vitro and in a monocrotaline (MCT)-induced model of PAH in vivo. miR-27b expression was upregulated in MCT-induced PAH and inversely correlated with the levels of peroxisome proliferator-activated receptor (PPAR)-gamma, and miR-27b inhibition attenuated MCT-induced endothelial dysfunction and remodeling and prevented PAH associated right ventricular hypertrophy and systolic pressure in rats. PPARgamma was confirmed as a direct target of miR-27b in HPAECs and shown to mediate the effect of miR-27b on the disruption of endothelial nitric oxide synthase (eNOS) coupling to Hsp90 and the suppression of NO production associated with the PAH phenotype. We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90 eNOS and NO signaling by modulating PPARgamma expression, providing potential therapeutic targets for the treatment of PAH. PMID- 25795138 TI - Editorial overview: Viral pathogenesis. PMID- 25795137 TI - Indole-3-carbinol as inhibitors of glucocorticoid-induced apoptosis in osteoblastic cells through blocking ROS-mediated Nrf2 pathway. AB - Apoptosis of osteoblasts induced by glucocorticoid (GC) has been identified as a main cause of osteoporosis, bone loss and fractures, and the oxidative stress was found as an important contributor. Therefore, natural or synthetic agents with antioxidant activities can antagonize GCs-induced apoptosis in osteoblasts, and thus demonstrate the potential application to reverse osteoporosis. In this study, we showed that, indole-3-carbinol (I3C), a natural product found in broadly consumed plants of the Brassica genus, could block the cytotoxic effects of dexamethasone (Dex), and elucidated the underlying molecular mechanisms. Firstly, we showed that, I3C could effectively suppress Dex-induced cytotoxicity and apoptotic cell death in osteoblastic cells, as evidenced by the decrease in Sub-G1 cell population. Treatment of the cells with Dex resulted in activation of caspase-3/-8/-9 and subsequent cleavage of PARP, which was also effectively blocked by co-incubation of I3C. Moreover, exposure to Dex triggered a rapid onset and time-dependent superoxide overproduction in osteoblastic cells, which was effectively suppressed by addition of I3C. Excess intracellular ROS induced by Dex significantly suppressed the expression levels of Nrf2 and the downstream effectors, HO1 and NQO1, but these changes could be reversed by I3C. Knockdown of Nrf2 using siRNA silencing technique significantly reversed the protective effects of I3C against Dex-induced apoptosis and ROS generation. Taken together, I3C can reverse cytotoxicity of Dex through blocking ROS overproduction and enhancement of Nrf2 expression. This study may provide a safe and good strategy for molecular intervention of GCs-induced osteoporosis by using natural products. PMID- 25795139 TI - Response to: Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy. PMID- 25795140 TI - Surgical treatment of obesity in DM1--a case report and a review of the literature. AB - In patients with myotonic dystrophy type 1 overweight and obesity are frequent. When present this has further negative effects on the patients' pulmonary and muscle function as well as social participation. Anesthesia in myotonic dystrophy type 1 patients is associated with increased risks, especially in those who are obese. We describe the outcome of the first patient reported who has undergone gastric bypass surgery. The operation went without complications. Within two years after surgery she has lost 56.5 kg corresponding to 44% of her preoperative body weight (128.5 kg). She has lost muscle mass and muscle strength, but has gained somewhat in functional tests including pulmonary function and has no longer any need for nocturnal ventilation. Surgical treatment of obesity may be feasible in selected myotonic dystrophy type 1 patients but further studies are needed to determine appropriate criteria for surgery including body mass index limits and how pre- and post-operative follow-up should best be made. PMID- 25795141 TI - PRRX1- and PRRX2-positive mesenchymal stem/progenitor cells are involved in vasculogenesis during rat embryonic pituitary development. AB - We have recently shown that cells positive for the paired-related homeobox transcription factors PRRX1 and PRRX2 occur in the rat pituitary, and that they are derived from two different origins: pituitary-derived cells positive for stem cell marker SOX2 and extra-pituitary-derived cells negative for SOX2. In this study, we have further characterized the PRRX1- and PRRX2-positive cells that originate from extra-pituitary cells. Immunohistochemical analyses were performed with specific antibodies against PRRX1 and PRRX2 in order to clarify their roles in pituitary vasculogenesis. PRRX1- and PRRX2-positive cells were found in Atwell's recess and at the periphery of the pituitary on embryonic day 15.5 (E15.5). Several PRRX1-positive cells then invaded the anterior lobe, together with a few PRRX2-positive cells, on E16.5. Some PRRX1-positive cells were also positive for mesenchymal stem cell marker NESTIN. Moreover, some PRRX1/NESTIN double-positive cells showed characteristics of vascular endothelial cells with an Isolectin-B4-binding capacity. PRRX1 co-localized with vascular smooth muscle cell/pericyte marker alpha-smooth muscle actin in the deep area of Atwell's recess. We confirmed the presence of PRRX2/NESTIN double-positive cells at an entry area in Atwell's recess and at the periphery of the pituitary, but PRRX2 did not co-localize with Isolectin B4 or alpha-smooth muscle actin. These data suggest that PRRX1- and PRRX2-positive mesenchymal stem/progenitor cells are present at the periphery of the embryonic pituitary and at the entry from Atwell's recess and participate in pituitary vasculogenesis by differentiation into vascular endothelial cells and pericytes, whereas the presence of PRRX2 indicates much higher stemness than PRRX1. PMID- 25795142 TI - Three-dimensional differentiation of adipose-derived mesenchymal stem cells into insulin-producing cells. AB - The aim of this study is to evaluate the collagen/hyaluronic acid (Col/HA) scaffold effect on the differentiation of insulin-producing cells (IPCs) from adipose-derived mesenchymal stem cells (ASCs). In this experimental study, ASCs were cultured and seeded in a Col/HA scaffold (3D culture) and then treated with induction media. After induction, the presence of IPCs was evaluated using gene expression (PDX-1, GLUT-2 and insulin) analysis and immunocytochemistry, while functional maturity was determined by measuring insulin release in response to low- and high-glucose media. The induced IPCs were morphologically similar to pancreatic islet-like cells. Expression of the islet-associated genes PDX-1, GLUT 2 and insulin genes in 3D-cultured cells was markedly higher than the 2D-cultured cells exposure differentiation media. Compared to the 2D culture of ASCs-derived IPCs, the insulin release from 3D ASCs-derived IPCs showed a nearly 4-fold (p < 0.05) increase when exposed to a high glucose (25 mmol) medium. The percentage of insulin-positive cells in the 3D experimental group showed an approximately 4 fold increase compared to the 2D experimental culture cells. The results of this study demonstrated that the COL/HA scaffold can enhance the differentiation of IPCs from rat ASCs. PMID- 25795144 TI - Needs of caregivers in heart failure management: A qualitative study. AB - OBJECTIVES: To identify the needs of caregivers supporting a person with heart failure and to inform the development of a caregiver resource to be used as part of a home-based self-management programme. METHODS: A qualitative study informed by thematic analysis involving 26 caregivers in individual interviews or a focus group. RESULTS: Three distinct aspects of caregiver support in heart failure management were identified. Firstly, caregivers identified needs about supporting management of heart failure including: coping with the variability of heart failure symptoms, what to do in an emergency, understanding and managing medicines, providing emotional support, promoting exercise and physical activity, providing personal care, living with a cardiac device and supporting depression management. Secondly, as they make the transition to becoming a caregiver, they need to develop skills to undertake difficult discussions about the role; communicate with health professionals; manage their own mental health, well-being and sleep; and manage home and work. Thirdly, caregivers require skills to engage social support, and voluntary and formal services while recognising that the long term future is uncertain. DISCUSSION: The identification of the needs of caregiver has been used to inform the development of a home-based heart failure intervention facilitated by a trained health care practitioner. PMID- 25795145 TI - Promoting pre-quit physical activity to reduce cue reactivity among low-income sedentary smokers: A randomized proof of concept study. AB - BACKGROUND: Smoking and lack of physical activity (PA) contribute to disproportionate rates of disease among low-income adults. Interventions that simultaneously address both risk behaviors have strong potential to reduce health disparities. Existing smoking-PA studies indicate promising results but have limited generalizability to low-income populations. The goal of this study is to assess the effects of an integrated behavioral counseling approach to promote low to-moderate intensity PA (LMPA) and reduce short-term smoking cue reactivity among low-income sedentary smokers. METHODS: This study uses a randomized, 2 group design with 4 measurement time points: baseline, quit day (week 4), 1-week and 1-month follow-up. Participants (sedentary, smoke>6 cigs/day) receive 4 weeks of either (a) standard smoking cessation counseling (SCC control) or (b) our Step Up to Quit (SUTQ) intervention that integrates advice for LMPA with SCC. SUTQ counseling focuses on increasing daily steps (walking) to reach 7500-10,000/day by week 4 (quit day) and explicitly links short bouts of LMPA with smoking urge management. Potential for SUTQ to facilitate urge management will be assessed by comparing between-group differences in the reduction (extinction) of quit day cue reactivity. We will explore group differences in quit rates at 1-week and 1-month follow-up. DISCUSSION: This novel approach overcomes gaps in the PA-smoking intervention literature by promoting a more realistic PA approach for sedentary populations, using an ecologically valid strategy, integrating LMPA with evidence based SCC during a 4-week pre-quit period, and testing the SUTQ counseling model in a high-risk sample. Results will guide future efficacy and dissemination studies. PMID- 25795146 TI - Antioxidant, anti-inflammatory and anticarcinogenic activities of edible red oak (Quercus spp.) infusions in rat colon carcinogenesis induced by 1,2 dimethylhydrazine. AB - Red oak (Quercus spp.) leaves are traditionally used as food in Mexico, and some of their infusions have potential anticarcinogenic and anti-inflammatory effects; however, these properties have not yet been scientifically tested. The aim of this work was to explore the anti-inflammatory activity in HT-29 cells and anticarcinogenic effect in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis of red oak infusions. Quercus infusions were prepared and administered as the sole source of drink to male Sprague-Dawley rats (1% w/v) for the entire 26-week experimental period. On week 4, rats received 8 subcutaneous injections of DMH (21 mg/kg body weight) once a week. The results showed that mean tumor (0.9 +/- 0.2 vs. 2.6 +/- 0.3) and multiplicity (1.2 +/- 0.1 vs. 2.0 +/ 0.23), and beta-catenin protein level (2.2-fold) in adenocarcinomas were significantly lower in Quercus sideroxyla-treated group compared with DMH group. By contrast, Quercus durifolia and Quercus eduardii infusions had no protective effect. Additionally, the experiments in HT-29 cells confirmed that Q. sideroxyla infusion effectively decreased the levels of the inflammatory markers COX-2 and IL-8 by modulating the expression of NF-kappaB. These results highlight some of the molecular mechanisms related to the chemopreventive effect of Q. sideroxyla infusion and its potential value as a source of bioactive compounds. PMID- 25795143 TI - Desmosomes in acquired disease. AB - Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement integrates adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, which occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on the way in which human diseases can inform our understanding of basic desmosome biology and in turn, the means by which fundamental advances in the cell biology of desmosomes might lead to new treatments for acquired diseases of the desmosome. PMID- 25795147 TI - The power of the yeast two-hybrid system in the identification of novel drug targets: building and modulating PPP1 interactomes. AB - Since the description of the yeast two-hybrid (Y2H) method, it has become more and more evident that it is the most commonly used method to identify protein protein interactions (PPIs). The improvements in the original Y2H methodology in parallel with the idea that PPIs are promising drug targets, offer an excellent opportunity to apply the principles of this molecular biology technique to the pharmaceutical field. Additionally, the theoretical developments in the networks field make PPI networks very useful frameworks that facilitate many discoveries in biomedicine. This review highlights the relevance of Y2H in the determination of PPIs, specifically phosphoprotein phosphatase 1 interactions, and its possible outcomes in pharmaceutical research. PMID- 25795148 TI - Proteomics applications in prion biology and structure. AB - Prion diseases are a heterogeneous class of fatal neurodegenerative disorders associated with misfolding of host cellular prion protein (PrP(C)) into a pathological isoform, termed PrP(Sc). Prion diseases affect various mammals, including humans, and effective treatments are not available. Prion diseases are distinguished from other protein misfolding disorders - such as Alzheimer's or Parkinson's disease - in that they are infectious. Prion diseases occur sporadically without any known exposure to infected material, and hereditary cases resulting from rare mutations in the prion protein have also been documented. The mechanistic underpinnings of prion and other neurodegenerative disorders remain poorly understood. Various proteomics techniques have been instrumental in early PrP(Sc) detection, biomarker discovery, elucidation of PrP(Sc) structure and mapping of biochemical pathways affected by pathogenesis. Moving forward, proteomics approaches will likely become more integrated into the clinical and research settings for the rapid diagnosis and characterization of prion pathogenesis. PMID- 25795149 TI - Proteomics studies in inner ear disorders: pathophysiology and biomarkers. AB - Although proteomics has been exploited in a wide range of diseases for identification of biomarkers and pathophysiological mechanisms, there are still biomedical disciplines such as otology where proteomics platforms are underused due to technical challenges and/or complex features of the disease. Thus, in the past few years, healthcare and scientific agencies have advocated the development and adoption of proteomic technologies in otological research. However, few studies have been conducted and limited literature is available in this area. Here, we present the state of the art of proteomics in otology, discussing the substantial evidence from recent experimental models and clinical studies in inner-ear conditions. We also delineate a series of critical issues including minute size of the inner ear, delicacy and poor accessibility of tissue that researchers face while undertaking otology proteomics research. Furthermore, we provide perspective to enhance the impact and lead to the clinical implementation of these proteomics-based strategies. PMID- 25795150 TI - [Meningococcal vaccines. Global epidemiological situation and strategies for prevention by vaccination]. AB - N. meningitidis is a major cause of meningitis and septicemia and a major public health problem in many countries. The disease, that can be fulminant, has a high mortality and may cause serious sequelae, even in cases of apparently optimal medical treatment. Chemoprophylaxis may prevent secondary cases among those in close contact with the ill, but, since secondary cases represent only 1%-2% of all meningococcal disease, chemoprophylaxis has a small impact when fighting most of endemic and epidemic forms. Given that al least 5% -15% of children and young adults are carriers, the fight against meningococcal disease based on chemotherapeutic elimination of nasopharyngeal colonization is virtually impossible. Therefore, immunization is the only rational way to combat this disease. PMID- 25795151 TI - 7beta-Hydroxysitosterol crosses the blood-brain barrier more favored than its substrate sitosterol in ApoE-/- mice. AB - In this study, we compare the distribution of intraperitoneally injected sitosterol, 7beta-hydroxysitosterol or vehicle only (control) for 28days in male ApoE-/- mice. Furthermore we examine its impact on surrogate markers of cholesterol biosynthesis and sterol absorption rate in plasma, brain and liver tissues from these animals. Injection of sitosterol revealed a 32.1% (P=0.013) lower plasma total cholesterol compared with control. Cholesterol corrected plasma and absolute brain and liver levels of sitosterol are 4.1-, 1.7-, and 7.2 fold (P<0.001 for all) higher, respectively. This is in accordance with a reduced plasma campesterol to cholesterol ratio (-16.2%; P=0.018) together with a 24.1% (P=0.047) lower concentration of hepatic lathosterol. After injection of 7beta hydroxysitosterol the concentrations of 7beta-hydroxysitosterol in plasma, brain and liver are 21.0-, 65.8- and 42.7-fold (P<0.001 for all) higher, respectively, compared with control. Injection of 7beta-hydroxysitosterol revealed significantly lower plasma cholesterol corrected cholestanol and campesterol ( 44.2%; P=0.001 and -24.5; P=0.004) as well as lower absolute liver cholestanol levels (-31.9%; P<0.001) compared with control. Intraperitoneally injected sitosterol and 7beta-hydroxysitosterol differently influence cholesterol metabolism in plasma and liver. We conclude that the polar 7beta hydroxysitosterol compound can pass the blood brain barrier with higher efficacy than its substrate, sitosterol. Though present in higher amounts in the brain, both, sitosterol and 7beta-hydroxysitosterol do not influence cholesterol metabolism in the brain as proven by our surrogate markers. PMID- 25795152 TI - 22-Oxocholestanes as plant growth promoters. AB - The spirostanic steroidal side-chain of diosgenin and hecogenin was modified to produce 22-oxocholestane derivatives. This type of side-chain was obtained in good yields through a straightforward four-step pathway. These compounds show potent brassinosteroid-like growth promoting activity evaluated via the rice lamina joint inclination bioassay. This is the first report of steroidal skeletons bearing the 22-oxocholestane side-chain and preserving the basic structure (A-D rings) from their corresponding parent compounds acting as plant growth promoters. PMID- 25795153 TI - Current state of continuous renal replacement therapy for acute kidney injury in Japanese intensive care units in 2011: analysis of a national administrative database. AB - BACKGROUND: Nationwide data for the prevalence and outcomes of patients receiving continuous renal replacement therapy (CRRT) in intensive care units (ICUs) are scarce. This study assessed the status of CRRT in Japanese ICUs using a nationwide administrative claim database. METHODS: Data were extracted from the Japanese Diagnosis Procedure Combination database for 2011. From a cohort of critically ill patients aged 12 years or older who were admitted to ICUs for 3 days or longer, acute kidney injury (AKI) patients treated with CRRT were identified. The period prevalence of CRRT and in-hospital mortality were calculated. Logistic regression analysis identified factors associated with in hospital mortality. RESULTS: Of 165 815 ICU patients, 6478 (3.9%) received CRRT for AKI. The most frequent admission diagnosis category was diseases of the circulatory system (n = 3074). The overall in-hospital mortality rate of the CRRT treated AKI patients was 50.6%. Clustering patients into four groups by background revealed the lowest in-hospital mortality rate of 41.5% for the cardiovascular surgery group (n = 1043) compared with 53.5% for the nonsurgical cardiovascular group (n = 2031), 51.7% for the sepsis group (n = 1863) and 51.6% for other cases (n = 1541). Multiple logistic regression analysis showed a significant association of these four group classifications with in-hospital mortality in addition to age, hospital characteristics (type and volume), time from hospital admission to CRRT initiation and interventions performed on the day of CRRT initiation. CONCLUSIONS: Using a large Japanese nationwide database, this study revealed remarkably high in-hospital mortality of CRRT-treated AKI patients, although the period prevalence of CRRT for AKI in ICUs was low. PMID- 25795154 TI - Neurological complications associated with epidural steroid injections. AB - Multiple case reports of neurological complications resulting from intraarterial injection of corticosteroids have led the Food and Drug Administration (FDA) to issue a warning, requiring label changes, warning of serious neurological events, some resulting in death. The FDA has identified 131 cases of neurological adverse events, including 41 cases of arachnoiditis. A review of the literature reveals an overwhelming proportion of the complications are related to transforaminal epidural injections, of which cervical transforaminal epidural injections constituted the majority of neurological complications. Utilization data of epidural injections in the Medicare population revealed that cervical transforaminal epidural injections constitute only 2.4 % of total epidural injections and <5 % of all transforaminal epidural injections. Multiple theories have been proposed as the cause of neurological injury including particulate steroid, arterial intimal flaps, arterial dissection, dislodgement of plaque causing embolism, arterial muscle spasm, and embolism of a fresh thrombus following disruption of the intima. PMID- 25795155 TI - High-altitude headache. AB - High-altitude headache is one of many neurological symptoms associated with the ascent to high altitudes. Cellular hypoxia due to decreased barometric pressure seems to be the common final pathway for headache as altitude increases. Susceptibility to high-altitude headache depends on genetic factors, history of migraine, and acclimatization, but symptoms of acute mountain sickness are universal at very high altitudes. This review summarizes the pathophysiology of acute mountain sickness and high-altitude headache as well as the evidence for treatment and prevention with different drugs and devices which may be useful for regular and novice mountaineers. This includes an examination of other headache disorders which may mimic high-altitude headache. PMID- 25795156 TI - Cervical facet injections in the management of cervicogenic headaches. AB - Cervicogenic headache is defined as headaches originating from cervical spine structures including cervical facet joints, cervical intervertebral discs, skeletal muscles, connective tissues, and neurovascular structures. Cervical facet injections with steroids have been used to alleviate cervicogenic headache secondary to cervical facet arthropathy. In this article, we will review the cervical spine anatomy, cervical facet injections, and the efficacy of cervical facet injections as a treatment for cervicogenic headache. PMID- 25795158 TI - E. Mugnaini and A. Floris, the unipolar brush cell: a neglected neuron of the mammalian cerebellar cortex, J Comp Neurol, 339:174-180, 1994: elucidating a cell of the cerebellar cortex that largely evaded detection. PMID- 25795157 TI - White matter damage and brain network alterations in concussed patients: a review of recent diffusion tensor imaging and resting-state functional connectivity data. AB - Over 2 million people are diagnosed with concussion each year in the USA, resulting in substantial individual and societal burdens. Although 'routine' clinical neuroimaging is useful for the diagnosis of more severe forms of traumatic brain injury, it is insensitive for detecting pathology associated with concussion. Diffusion tensor imaging (DTI) and blood-oxygenation-level-dependent (BOLD) resting-state functional connectivity magnetic resonance imaging (rs-fMRI) are techniques that allow for investigation of brain structural and functional connectivity patterns. DTI and rs-fMRI may be more sensitive than routine neuroimaging for detecting brain sequelae of concussion. This review summarizes recent DTI and rs-fMRI findings of altered structural and functional connectivity patterns in concussed patients. PMID- 25795159 TI - Provision of survivorship care for patients with haematological malignancy at completion of treatment: A cancer nursing practice survey study. AB - PURPOSE: Many haematological cancer survivors report long-term physiological and psychosocial effects, which persist far beyond treatment completion. Cancer services have been required to extend care to the post-treatment phase to implement survivorship care strategies into routine practice. As key members of the multidisciplinary team, cancer nurses' perspectives are essential to inform future developments in survivorship care provision. METHODS: This is a pilot survey study, involving 119 nurses caring for patients with haematological malignancy in an Australian tertiary cancer care centre. The participants completed an investigator developed survey designed to assess cancer care nurses' perspectives on their attitudes, confidence levels, and practice in relation to post-treatment survivorship care for patients with a haematological malignancy. RESULTS: Overall, the majority of participants agreed that all of the survivorship interventions included in the survey should be within the scope of the nursing role. Nurses reported being least confident in discussing fertility and employment/financial issues with patients and conducting psychosocial distress screening. The interventions performed least often included, discussing fertility, intimacy and sexuality issues and communicating survivorship care with the patient's primary health care providers. Nurses identified lack of time, limited educational resources, lack of dedicated end-of-treatment consultation and insufficient skills/knowledge as the key barriers to survivorship care provision. CONCLUSION: Cancer centres should implement an appropriate model of survivorship care and provide improved training and educational resources for nurses to enable them to deliver quality survivorship care and meet the needs of haematological cancer survivors. PMID- 25795160 TI - Caregiving burden and the quality of life of family caregivers of cancer patients: the relationship and correlates. AB - PURPOSE: Family caregivers of cancer patients become responsible for many elements of cancer care, usually without preparation or training in provision of care. Their efforts of care generate caregiving burden, which could deteriorate caregivers' quality of life (QOL). METHOD: A secondary data analysis of a cross sectional descriptive study was conducted to describe the influence of caregiving burden on the QOL of family caregivers of cancer patients with consideration of correlates (N = 212). The Korean versions of Zarit Burden Interview and the World Health Organization QOL BREF were used. Multiple regression analyses were applied to analyze the relationship between the caregiving burden and QOL. RESULTS: Caregiving burden explained 30.3% of variance of the QOL (beta = -0.534, p < 0.001). Caregivers caring for patients with functional deterioration experienced higher burden. Caregivers providing care for hospitalized patients demonstrated lower QOL. The caregiver's educational level was a positively contributing factor for the QOL. CONCLUSIONS: Caregiving burden was the influential, negatively affecting factor for the QOL. Assessment of caregiving burden with special attention being paid to caregivers caring for patients with functional decline would help to identify caregivers in need of support. Supportive care needs to be sought to alleviate caregiving burden and improve the QOL of caregivers, especially for the caregivers of hospitalized patients. PMID- 25795161 TI - Macrophage subsets in the adipose tissue could be modified by sex and the reproductive age of women. AB - The presence of proinflammatory monocytes/macrophages (CD14+CD16+) has been documented in conditions of inflammation, such as atherosclerosis. We analysed the proportion of proinflammatory monocytes/macrophages in perirenal and perivascular fat in healthy living kidney donors with regard to sex and age reflecting reproductive status in women; therefore, women were further divided to younger and older group (younger and older than 51 years) reflecting potential age of menopause. Monocyte/macrophages were identified as CD14+ mononuclear cells and divided into subpopulations based on the co-expression of CD16. We found no differences in the monocyte/macrophage content between men (n = 15) and women (n = 28). Conversely, we observed a higher proportion of double positive CD14+CD16+ monocytes/macrophages in older women (n = 14) compared to younger women (n = 14). In addition, a strong correlation was found between the monocyte/macrophage content in fat and age only in older women. Therefore, proinflammatory monocytes/macrophages (CD14+CD16+) should be evaluated according to the sex and age. PMID- 25795162 TI - Diffusion tensor imaging--arcuate fasciculus and the importance for the neurosurgeon. AB - OBJECTIVE: Tumors in eloquent areas of the brain like Broca or Wernicke might have disastrous consequences for patients. We intended to visualize the arcuate fasciculus (AF) and to demonstrate his relation with the corticospinal tract and the visual pathway using diffusion tensor imaging (DTI). METHODS: We depicted between 2012 and 2014 the AF in 71 patients. Men and women of all ages were included. Eleven patients had postoperative controls also. We used a 3DT1 sequence for the navigation. Furthermore T2- and DTI-sequences were performed. The FOV was 200 * 200 mm(2), slice thickness 2mm, and an acquisition matrix of 96 * 96 yielding nearly isotropic voxels of 2 * 2 * 2 mm. 3-Tesla-MRI was carried out strictly axial using 32 gradient directions and one b0-image. We used Echo Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. b-Value was 800 s/mm(2). Additional scanning time was less than 9 min. RESULTS: AF was portrayed in 63 patients bilaterally. In one glioblastoma patient it was impossible to visualize the left AF and in seven other patients we could not portray the right one. The lesions affected AF by disrupting or displacing the fibers. CONCLUSIONS: DTI might be a useful tool to portray AF. It is time-saving and can be used to preserve morbidity in patients with lesions in eloquent brain areas. It might give deeper insights of the white matter and the reorganization of AF-fibers postoperatively. PMID- 25795163 TI - Reproducible Matrix Deposition for MALDI MSI Based on Open-Source Software and Hardware. AB - The new open-source software and hardware matrix deposition device named iMatrixSpray was optimized and specified for homogeneity, reproducibility, and sensitivity in MS imaging experiments. The results confirm the design claims, with the device delivering uniform coatings with a constant quality from experiment to experiment. The robustness in combination with the open design allows developing and sharing of matrix deposition and sample preparation protocols between labs. This tool therefore enables researchers to enter the field of MALDI MSI without previous experience in matrix coating. PMID- 25795164 TI - A short-term smoking cessation may increase the risk of developing metabolic syndrome. AB - Smoking cessation is beneficial for health. However, its potential harmful impact on metabolic syndrome has yet to be clarified. Six smokers who attended the smoking cessation clinic were recruited and given the nicotine replacement therapy for 3 months. The values of body weight, BMI, systolic blood pressure, and fasting glycemia were significantly elevated after smoking cessation. We recommend that clinicians should monitor these cardiovascular risk factors in subjects attempting smoking cessation. PMID- 25795165 TI - Association of general and central obesity with diabetes and prediabetes in rural Bangladeshi population. AB - BACKGROUND AND AIMS: Recent data shown that both general and central obesity indices are significantly associated with diabetes (T2DM) and prediabetes (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]). Data regarding association of obesity with T2DM and prediabetes in rural Bangladeshi population is scarce. This study aims to observe the association of general and central obesity with diabetes (T2DM) and prediabetes in rural Bangladeshi population. MATERIALS AND METHODS: A total of 2293 rural Bangladeshi adults aged >=20 years were randomly selected in a population-based, cross-sectional survey which was conducted in 2009. The association of general (defined by body mass index [BMI]) and central obesity (defined by waist circumference [WC] and waist hip ratio [WHR]) with T2DM and prediabetes was assessed by using receiver operating characteristic curve analysis and logistic regression. RESULTS: Subjects with T2DM, IGT and IFG had a higher rate of general and central obesity than normal subjects. WHR was more closely associated with T2DM than WC and BMI. However, all three obesity indices were significantly associated with IGT and IFG. CONCLUSIONS: In rural Bangladeshi population, both general and central obesity showed good association with T2DM and prediabetes. PMID- 25795166 TI - A single-loop recombinant pseudotyped-virus-based assay to detect HIV-1 phenotypic resistance. AB - HIV/AIDS is a leading public health concern throughout the world. Currently, treatment of HIV/AIDS still depends on highly active antiretroviral therapy (HAART); however, there is increasing evidence showing the emergence of resistance to antiretroviral drugs in HIV-1 strains, making ART less effective over time. Intensive monitoring of HIV-1 drug resistance is therefore of great importance to evaluate the current sensitivity of antiretroviral agents and is urgently needed. The aim of this study was to develop a single-loop recombinant pseudotyped-virus-based assay to detect phenotypic resistance in clinical HIV-1 strains. HIV-1 RNA was extracted from HIV-1-infected human plasma samples, and an approximately 3-kb fragment containing p7/p1/p6 cleavage sites and full-length protease (PR), reverse transcriptase (RT), thermonuclease (TNase), and integrase (1-280 aa) genes was amplified by nested RT-PCR. A retroviral vector was constructed using the HIV-1 infectious molecular clone pLWJ to test antiretroviral drug susceptibility. pLWJ-SV40-Luc contained a luciferase expression cassette inserted within a deleted region of the envelope (env) gene as an indicator gene. Resistance test vectors (RTVs) were constructed by incorporating amplified target genes into pLWJ-SV40-Luc by using ApaI or AgeI and AarI restriction sites and conventional cloning methods. The virus stocks used for drug susceptibility test were produced by co-transfecting 293T cells with RTVs and a plasmid that provided vesicular stomatitis virus glycoprotein (VSV-G). Viral replication was monitored by measuring luciferase activity in infected target cells at approximately 48 h postinfection. A total of 35 clinical plasma samples from HIV-1-infected humans were tested, and target fragments were successfully amplified from 34 samples (97.1 %) and 33 RTVs were successfully constructed by directional cloning, with an overall success rate of 94.3 %. A clear-cut dose-dependent relationship was detected between virus production and luciferase activity in the constructed phenotypic resistance testing system. The highest coefficient of determination (R(2)) was found between luciferase activity and drug concentration and viral inhibition at 293T cell concentrations of 5 * 10(4) cells per well. The phenotypic profiles of the viruses from 29 clinical samples almost completely matched the observed genotypes. The results demonstrate that a single-loop recombinant pseudotyped-virus-based assay was successfully developed, and this testing system has high stability and appears to be applicable for testing phenotypic resistance of clinical HIV-1 strains to commonly used antiretroviral agents. PMID- 25795167 TI - NMDA receptor blockade in the developing cortex induces autophagy-mediated death of immature cortical GABAergic interneurons: An ex vivo and in vivo study in Gad67-GFP mice. AB - In neonates, excitotoxicity is a major process involved in hypoxic-ischemic brain lesions, and several research groups have suggested the use of NMDA antagonists for neuroprotection. However, despite their clinical interest, there is more and more evidence suggesting that, in the immature brain, these molecules exert deleterious actions on migrating GABAergic interneurons by suppressing glutamatergic trophic inputs. Consequently, preventing the side effects of NMDA antagonists would be therapeutically useful. Because macroautophagy is involved in the adaptive response to trophic deprivation, the aim of the present study was to investigate the impact of autophagy modulators on the MK801-induced death of immature GABAergic interneurons and to characterize the crosstalk between autophagic and apoptotic mechanisms in this cell type. Ex vivo, using cortical slices from NMRI and Gad67-GFP mice, we show that blockade of the NMDA receptor results in an accumulation of autophagosomes due to the disruption of the autophagic flux. This effect precedes the activation of the mitochondrial apoptotic pathway, and the degeneration of immature GABAergic neurons present in developing cortical layers II-IV and is prevented by 3-MA, an autophagy inhibitor. In contrast, modulators of autophagy (3-MA, rapamycin) do not interfere with the anti-excitotoxic and neuroprotective effect of MK801 observed in deep layers V and VI. In vivo, 3-MA blocks the rapid increase in caspase-3 cleavage induced by the blockade of NMDA receptors and prevents the resulting long-term decrease in Gad67-GFP neurons in layers II-IV. Together, these data suggest that, in the developing cortex, the suppression of glutamatergic inputs through NMDA receptor inhibition results in the impairment of the autophagic flux and the subsequent switch to apoptotic death of immature GABAergic interneurons. The concomitant inhibition of autophagy prevents this pro-apoptotic action of the NMDA blocker and favors the long-term rescue of GABAergic interneurons without interfering with its neuroprotective actions. The use of autophagy modulators in the developing brain would create new opportunities to prevent the side effects of NMDA antagonists used for neuroprotection or anesthesia. PMID- 25795168 TI - Characterization of collagen fibrils after equine suspensory ligament injury: an ultrastructural and biochemical approach. AB - Suspensory ligament (SL) injuries are an important cause of lameness in horses. The mechanical properties of connective tissue in normal and pathological ligaments are mainly related to fibril morphology, as well as collagen content and types. The purpose of this study was to evaluate, using biochemical and ultrastructural approaches, the alterations in collagen fibrils after injury. Eight Warmblood horses with visible signs of injury in only one forelimb SL were selected and specimens were examined by transmission electron microscope (TEM). Collagen types I, III and V were purified by differential salt precipitation after collagen extraction with acetic acid containing pepsin. TEM revealed abnormal organization as well as alterations in the diameter and shape of fibrils after SL injury. The bands corresponding to types I, III and V collagen were assessed by densitometry after sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Densitometric analysis indicated that the proportions of type III and type V collagen were higher (P < 0.001) in damaged tissues compared with normal tissues with a mean increase of 20.9% and 17.3%, respectively. Concurrently, a decrease (P < 0.001) in type I collagen within damaged tissues was recorded with a mean decrease of 15.2%. These alterations could be the hallmark of a decrease in the tissue quality and mechanical properties of the ligament. The findings provide new insight for subsequent research on tissue regeneration that may lead to the development of future treatment strategies for SL injury. PMID- 25795169 TI - Healthy worker survivor analysis in an occupational cohort study of Dutch agricultural workers. AB - OBJECTIVES: High microbial exposures in farmers and agricultural workers are associated with less atopy. Although it has been speculated that healthy worker survival could be an explanation, this has not been studied so far. Therefore, we investigated the presence of healthy worker survival in a five-year follow-up study of an occupational cohort of Dutch farmers and agricultural industry (company) workers. METHODS: We compared baseline demographic characteristics, respiratory health, atopy and endotoxin exposure of 259 workers followed up with 124 workers lost to follow-up. Additionally, baseline health status of 31 participants who had changed to lower exposure jobs at follow-up was compared to those with similar or higher exposure jobs at follow-up. RESULTS: In general, no major healthy worker survival effect was found. Nonetheless, small differences were observed between subjects included in follow-up and those lost to follow-up. Those lost to follow-up were older, had a lower peak expiratory flow, and were less often raised on a farm. Company workers lost to follow-up with a farm childhood had more often self-reported allergy, but this was not observed for subjects with atopic sensitization or other respiratory symptoms. No differences were found for any of the studied characteristics in participants with lower exposure at follow-up compared to participants with similar or higher exposure at follow-up. CONCLUSIONS: No major healthy worker survival is present in this organic dust exposed cohort. Differences between participants lost to follow-up and participants included in follow-up with regard to health characteristics are small and unlikely to explain the previously reported inverse associations between endotoxin exposure and atopy. PMID- 25795170 TI - From association to prediction: statistical methods for the dissection and selection of complex traits in plants. AB - Quantification of genotype-to-phenotype associations is central to many scientific investigations, yet the ability to obtain consistent results may be thwarted without appropriate statistical analyses. Models for association can consider confounding effects in the materials and complex genetic interactions. Selecting optimal models enables accurate evaluation of associations between marker loci and numerous phenotypes including gene expression. Significant improvements in QTL discovery via association mapping and acceleration of breeding cycles through genomic selection are two successful applications of models using genome-wide markers. Given recent advances in genotyping and phenotyping technologies, further refinement of these approaches is needed to model genetic architecture more accurately and run analyses in a computationally efficient manner, all while accounting for false positives and maximizing statistical power. PMID- 25795171 TI - Breeding-assisted genomics. AB - The revolution of inexpensive sequencing has ushered in an unprecedented age of genomics. The promise of using this technology to accelerate plant breeding is being realized with a vision of genomics-assisted breeding that will lead to rapid genetic gain for expensive and difficult traits. The reality is now that robust phenotypic data is an increasing limiting resource to complement the current wealth of genomic information. While genomics has been hailed as the discipline to fundamentally change the scope of plant breeding, a more symbiotic relationship is likely to emerge. In the context of developing and evaluating large populations needed for functional genomics, none excel in this area more than plant breeders. While genetic studies have long relied on dedicated, well structured populations, the resources dedicated to these populations in the context of readily available, inexpensive genotyping is making this philosophy less tractable relative to directly focusing functional genomics on material in breeding programs. Through shifting effort for basic genomic studies from dedicated structured populations, to capturing the entire scope of genetic determinants in breeding lines, we can move towards not only furthering our understanding of functional genomics in plants, but also rapidly improving crops for increased food security, availability and nutrition. PMID- 25795173 TI - Serum Zinc and Haptoglobin in Noncirrhotic Azeri Patients with Chronic Active Hepatitis C: a Case-Control Study. AB - The aim of present study was to compare levels of serum zinc and haptoglobin between patients with chronic active hepatitis C and controls. Two groups including Azeri patients with chronic active hepatitis C (n = 274) and their healthy family members (n = 100) were studied. Serum zinc and haptoglobin were measured using colorimetric and nephelometric methods, respectively. Patients were 156 males (56.9%) and 118 females (43.1%) with the mean age of 40.15 +/- 12.24 years. Controls were 56 males (56%) and 44 females (44%) with the mean age of 39.32 +/- 4.40 (p = 0.87 for sex and 0.51 for age). Both the mean levels of serum zinc (72.04 +/- 19.08 vs. 106.18 +/- 25.52 MUg/dL) and haptoglobin (0.72 +/ 0.45 vs. 1.08 +/- 0.34 g/L) were significantly lower in patients than in controls (p < 0.001 for both comparisons). Serum zinc concentration was significantly higher in males and did not correlate significantly with age, serum glutamic pyruvic transaminase (SGPT), or serum glutamic oxaloacetic transaminase (SGOT). Serum haptoglobin did not differ significantly between males and females, and it correlated significantly with age (r = -0.20), serum SGPT (r = -0.22), and SGOT (r = -0.20). This study showed lower levels of serum zinc and haptoglobin in patients with chronic hepatitis C than in controls. Major confounding factors in previous studies were left out. PMID- 25795172 TI - Exposure to a Low Lead Concentration Impairs Contractile Machinery in Rat Cardiac Muscle. AB - Lead exposure has been considered to be a risk factor for hypertension and cardiovascular disease. Our purpose was to evaluate the effects of low plasma lead concentration on cardiac contractility in isolated papillary muscles. Wistar rats were divided in control group or group treated with 100 ppm of lead acetate in the drinking water for 15 days. Blood pressure (BP) was measured weekly. At the end of the treatment period, the animals were anesthetized and euthanized, and parameters related to isolated papillary muscle contractility were recorded. The lead concentrations in the blood reached 12.3 +/- 2 MUg/dL. The BP was increased in the group treated with 100 ppm of lead acetate. Lead treatment did not alter force and time derivatives of the force of left ventricular papillary muscles. In addition, the inotropic response induced by an increase in the extracellular Ca(2+) concentration was reduced in the Pb(2+) group. However, the uptake of Ca(2+) by the sarcoplasmic reticulum and the protein expression of SERCA and phospholamban remained unchanged. Postrest contraction was similar in the both groups, and tetanic peak and plateau tension were reduced in lead group. These results demonstrated that the reduction in the inotropic response to calcium does not appear to be caused by changes in the trans-sarcolemmal calcium flux but suggest that an impairment of the contractile machinery might be taking place. Our results demonstrate that even at a concentration below the limit considered to be safe, lead exerts deleterious effects on the cardiac contractile machinery. PMID- 25795174 TI - Letter to the editor: Colonic findings in a patient with relapse of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). PMID- 25795175 TI - Particulate matter in rural and urban nursery schools in Portugal. AB - Studies have been showing strong associations between exposures to indoor particulate matter (PM) and health effects on children. Urban and rural nursery schools have different known environmental and social differences which make their study relevant. Thus, this study aimed to evaluate indoor PM concentrations on different microenvironments of three rural nursery schools and one urban nursery school, being the only study comparing urban and rural nursery schools considering the PM1, PM2.5 and PM10 fractions (measured continuously and in terms of mass). Outdoor PM2.5 and PM10 were also obtained and I/O ratios have been determined. Indoor PM mean concentrations were higher in the urban nursery than in rural ones, which might have been related to traffic emissions. However, I/O ratios allowed concluding that the recorded concentrations depended more significantly of indoor sources. WHO guidelines and Portuguese legislation exceedances for PM2.5 and PM10 were observed mainly in the urban nursery school. PMID- 25795176 TI - Using three-dimensional laparoscopy as a novel training tool for novice trainees compared with two-dimensional laparoscopy. AB - BACKGROUND: Laparoscopic skills training is an essential component of general surgery training. This study proposes the use of three-dimensional (3D) laparoscopy as the initial training tool for beginners to shorten the learning curve. METHODS: This study evaluates the surgical performance and subjective experience of junior and senior trainees with 3D versus two-dimensional laparoscopy. Peg transfer task was used as the objective time measurement. A subjective evaluation of the 2 systems using a questionnaire was also used. RESULTS: The mean difference in the juniors was 16.33 seconds, while in the seniors it was only 3.46 seconds (P = .036). The time difference between groups was much smaller in the 3D than the two-dimensional (P = .14 vs .02) laparoscopy. In the subjective evaluation, the novice group also scored significantly higher for the 3D system in the bimanual dexterity category (P = .004, .007). CONCLUSION: Our study demonstrates the feasibility of using 3D laparoscopy for laparoscopic skills training in novices. PMID- 25795177 TI - Scleroderma and the temporomandibular joint: reconstruction in 2 variants. AB - PURPOSE: This article reviews the pathophysiology of scleroderma (systemic sclerosis [SSc]) and its destructive effects on the mandible in general and the temporomandibular joint (TMJ) in particular. It discusses the considerations of operating on patients with devastating chronic disease and presents 2 cases of TMJ reconstruction in patients with the diagnosis. PATIENTS AND METHODS: Two patients with different degrees of SSc involvement underwent TMJ reconstruction with costochondral grafts. The patients represent the surgical considerations pertinent to this disease and different outcomes as determined by the variance in severity of their afflictions. RESULTS: The 2 patients tolerated the surgeries well and exhibited improvement in function in the long-term. One patient thrives and continues to do well despite her SSc approximately 10 years postoperatively; the second patient died of her disease approximately 9 years after her initial surgical care. CONCLUSIONS: The experience with these 2 cases showed that patients with SSc can safely undergo TMJ reconstruction with anticipated good results, but that the overall severity of the disease remains paramount in determining the feasibility of corrective surgery under this diagnosis. PMID- 25795178 TI - Three-dimensional facial simulation in bilateral sagittal split osteotomy: a validation study of 100 patients. AB - PURPOSE: Three-dimensional (3D) virtual planning of orthognathic surgery in combination with 3D soft tissue simulation allows the surgeon and the patient to assess the 3D soft tissue simulation. This study was conducted to validate the predictability of the mass tensor model soft tissue simulation algorithm combined with cone-beam computed tomographic (CBCT) imaging for patients who underwent mandibular advancement using a bilateral sagittal split osteotomy (BSSO). MATERIALS AND METHODS: One hundred patients were treated with a BSSO according to the Hunsuck modification. The pre- and postoperative CBCT scans were matched and the mandible was segmented and aligned. The 3D distance maps and 3D cephalometric analyses were used to calculate the differences between the soft tissue simulation and the actual postoperative results. Other study variables were age, gender, and amount of mandibular advancement or rotation. RESULTS: For the entire face, the mean absolute error was 0.9 +/- 0.3 mm, the mean absolute 90th percentile was 1.9 mm, and for all 100 patients the absolute mean error was less than or equal to 2 mm. The subarea with the least accuracy was the lower lip area, with a mean absolute error of 1.2 +/- 0.5 mm. No correlation could be found between the error of prediction and the amount of advancement or rotation of the mandible or age or gender of the patient. CONCLUSION: Overall, the soft tissue prediction algorithm combined with CBCT imaging is an accurate model for predicting soft tissue changes after mandibular advancement. Future studies will focus on validating the mass tensor model soft tissue algorithm for bimaxillary surgery. PMID- 25795180 TI - Incremental, transcrestal sinus floor elevation with a minimally invasive technique in the rehabilitation of severe maxillary atrophy. Clinical and histological findings from a proof-of-concept case series. AB - In the posterior maxillary sextants, the residual dimensions of the edentulous ridge can considerably limit the insertion of implants with the desired length and diameter. A minimally invasive procedure for transcrestal sinus floor elevation (tSFE), namely the Smart Lift technique, which is based on a standardized sequence of specifically designed drills and osteotomes, was introduced in 2008 and subsequently validated in a series of recent studies. The present technical note describes the use of the technique by a staged approach, called incremental tSFE (i-tSFE), in the augmentation of severely resorbed edentulous ridges. The i-tSFE consists of 2 staged tSFE procedures performed with a transcrestal access, the second of which is performed concomitantly with implant placement. In the present case series, 3 patients with severe bone atrophy (residual bone height, 2 to 3 mm) in the edentulous posterior maxilla were treated with i-tSFE. At the second surgical stage of i-tSFE, implants at least 8 mm long were placed at all sites, and the success of the implant supported restoration was monitored to 6 months (1 patient) or 3 years (2 patients). Histologic findings from an augmented site showed the presence of newly formed bone, bone marrow spaces with numerous vascular canals, and residual graft particles occupying approximately 50%, 15%, and 35% of the total area, respectively. The results of the study showed that i-tSFE can be performed successfully with the Smart Lift technique to rehabilitate atrophic maxillary posterior sextants. PMID- 25795179 TI - How does the close surgical margin impact recurrence and survival when treating oral squamous cell carcinoma? AB - PURPOSE: The surgical margin is the main prognostic factor over which the surgeon has control during resection of oral squamous cell carcinoma (OSCC). This study examined the association between surgical excision margins of patients with OSCC and outcomes of disease-free and overall survival. MATERIALS AND METHODS: The authors implemented a retrospective cohort study. The sample was composed of patients with OSCC having resection as their initial treatment. The predictor variable was the pathologic surgical margin, defined as clear (>5 mm), close (1 to 5 mm), or involved (<1 mm). The outcome variables were disease-free (absence of locoregional recurrence) and overall survival. Data were analyzed using Kaplan Meier survival curves and Cox regression hazard model. RESULTS: The sample was composed of 54 patients with a mean age of 60.5 years (range, 19 to 85 yr) and 26% were women. The 2- and 5-year overall survival rates were 59 and 50%, respectively. The clear surgical margin group showed higher disease-free survival rates than patients with close and involved margins (5-yr probability, 0.78 vs 0.43 and 0.29; P = .014) and a trend toward increased overall survival at 2 and 5 years (P = .093). CONCLUSION: The results suggest that the presence of a close surgical margin (1 to 5 mm) is an adverse risk feature comparable to an involved margin and therefore is associated with decreased disease-free and overall survival. Future studies are needed to replicate these findings before they can be used as a basis for clinical recommendations. PMID- 25795181 TI - Virtual surgical planning for orthognathic surgery using digital data transfer and an intraoral fiducial marker: the charlotte method. AB - PURPOSE: We describe an alternative workup protocol for virtual surgical planning of orthognathic surgery using an intraoral fiducial marker, clinical photography, and the digital transfer of occlusal data. We also discuss our initial experience using this protocol in a series of patients. PATIENTS AND METHODS: A retrospective cohort study was performed of consecutive patients who had undergone combined maxillary and mandibular osteotomies for the correction of dentofacial deformities at 1 center. These patients underwent treatment planning using the modified virtual surgical planning protocol described in the present report. The primary outcome evaluated was the accuracy of the method, which was determined through superimposition of the surgical plan to the postoperative cone beam computed tomography (CBCT) scan. The secondary outcomes included the accuracy of the natural head position readings and the adequacy of the CBCT scanned stone models for the fabrication of occlusal splints. RESULTS: The population included 25 patients. The root mean standard deviation (RMSD) from the preoperative plan to the postoperative scan at the maxillary cephalometric points was 1.2, 1.4, and 2.1 mm in the axial, sagittal, and coronal planes, respectively. The RMSD of the superimposed plan to the postoperative scan at the 3 mandibular cephalometric points was 1.2, 0.8, and 0.7 mm in the axial, sagittal, and coronal planes, respectively. The average variance from the axial, sagittal, and coronal planes for the natural head position was 0.05, 2.22, and 0.69 mm, respectively. All splints fabricated from the CBCT occlusal data fit the stone models and were used intraoperatively. In the subset of patients whose models were both digitally transferred and laser scanned, the superimposition of the laser scan data to the CBCT scanned data was found to have a maximum variation of 0.2 mm at the occlusal level. CONCLUSIONS: The use of an intraoral fiducial marker changed the workflow for the data collection needed for virtual surgical planning of the correction of dentofacial deformities, while still obtaining accurate results. Because the device does not cause lip distortion, the possibility of virtually predicting a more expectant postoperative lip position exists without the need for additional scans. Furthermore, this work flow allows the transfer of data to be isolated to digital media. PMID- 25795182 TI - Comparison of osteoradionecrosis of the jaw after superselective intra-arterial chemoradiotherapy versus conventional concurrent chemoradiotherapy of oral cancer. AB - PURPOSE: The purpose of the present study was to compare the incidence of osteoradionecrosis between superselective intra-arterial chemoradiotherapy and intravenous chemoradiotherapy and to verify the risk factors for osteoradionecrosis. MATERIALS AND METHODS: Of the 79 patients with oral cancer, 40 were treated with intra-venous chemoradiotherapy and 39 were treated with superselective intra-arterial chemoradiotherapy. The incidence of, and risk factors for, osteoradionecrosis were evaluated using statistical analysis. RESULTS: Of the 79 patients, 4 (10%) of 40 in the intravenous chemoradiotherapy and 7 (17.9%) of 39 in the superselective intra-arterial chemoradiotherapy group developed osteoradionecrosis of the jaw. No significant difference was found between the 2 groups. Although the chemoradiotherapy methods, anatomic tumor location, smoking behavior, alcohol consumption, condition of teeth, teeth extraction before radiation, and progression of dental caries were considered predisposing factors for the occurrence of osteoradionecrosis, only progressive dental caries resulted in a significant difference for osteoradionecrosis. CONCLUSIONS: The present study is the first report comparing the incidence of osteoradionecrosis between superselective intra-arterial chemoradiotherapy and intravenous chemoradiotherapy. The administration methods of anticancer drugs were not related to the incidence of osteoradionecrosis in our study. From our study, dental caries is the most important risk factor for osteoradionecrosis; therefore, a radiation caries prevention program is crucial to control osteoradionecrosis. PMID- 25795183 TI - Contemporary update on the treatment of dog bite: injuries to the oral and maxillofacial region. AB - PURPOSE: The purpose of the present retrospective record review was to evaluate the patient demographics, treatment rendered, and long-term outcomes of patients injured in dog bite attacks to the oral and maxillofacial region. MATERIALS AND METHODS: In the present study, a retrospective medical record review was conducted of patients treated by the oral and maxillofacial surgery department at the University of Tennessee Medical Center who had presented with injuries to the head, neck, and face region from dog bite attacks from February 1, 2006 to October 31, 2013. Each patient included had to have had at least 1 follow-up visit. The data obtained from the patients' medical records included patient demographics, event details, injuries sustained, and treatment rendered and analyzed. RESULTS: The medical records from 20 patients were included and reviewed. More than one half (60%) of the patients were younger than 12 years old. The dog was owned by the patient or a relative in 58% of the cases. The children sustained injuries requiring hospital admission and repair in an operating room setting more often than did the adults. Pit bulls were more frequently associated with injuries than other breeds (9 of 20). CONCLUSIONS: Our patients required a total of 28 hospital inpatient days, 29 total procedures, and follow-up treatment for up to 2 years. Our review has shown the complexity of soft tissue injury treatment and the significant financial impact associated with dog bite injuries owing to the multiple hospital admissions, surgical revisions, and lengthy follow-up period required. PMID- 25795184 TI - Temporomandibular joint arthrocentesis: outcomes under intravenous sedation versus general anesthesia. AB - PURPOSE: Although arthrocentesis of the temporomandibular joint (TMJ) has been shown to be an effective, minimally invasive surgical procedure, there is a paucity of literature that has examined its effectiveness under intravenous (IV) sedation compared with general anesthesia (GA) with a secure airway. PATIENTS AND METHODS: A retrospective analysis of patients with TMJ arthrocentesis was performed. Patients were divided into 2 groups based on type of anesthesia (sedation vs general) and location of surgery (office vs hospital). Visual analog scales were used to assess TMJ pain, headaches, jaw function, diet, and disability. Objective examinations were performed for maximum interincisal opening, lateral excursions, and TMJ sounds. RESULTS: Statistical improvements were seen for TMJ pain, headaches, dietary restrictions, jaw function, and disability. Patients reported an 80% satisfaction rate for surgery under IV sedation compared with a 95% satisfaction rate of patients who had surgery under GA. CONCLUSIONS: Arthrocentesis is effective for treatment of TMJ pain and acute closed-lock conditions irrespective of Wilkes classification (grades I to III). Ninety-five percent of patients reported immediate resolution or decrease of pain within the first postoperative week. Although the procedure is effective when performed under IV sedation in an office setup, superior clinical outcomes were noticed when the procedure was performed with a secure airway under GA. PMID- 25795185 TI - Does salivary duct repositioning prevent complications after tumor resection or salivary gland surgery? AB - PURPOSE: Tissue that is resected for the treatment of oral tumors often includes salivary gland ducts. At their institution, the authors conserve and transfer as much of the salivary duct as possible during these procedures to avoid obstructive complications. Differentiating these obstructive complications from a metastatic node can be challenging and can confound subsequent oncologic management. This study compared and examined the effectiveness of salivary duct repositioning in decreasing the incidence of obstructive complications. MATERIALS AND METHODS: Cases of oromandibular disease treated with salivary duct resection at Kobe University Graduate School of Medicine from 2008 to 2013 were retrospectively analyzed. Thirty-two cases (25 patients) of Wharton duct resection and 31 cases (31 patients) of Stensen duct resection were included. The incidence of complications after salivary duct repositioning, duct ligation, and retention of the sublingual gland around the Wharton duct was compared. RESULTS: Wharton ducts were repositioned in 30 cases and ligated in 2 cases. Complications, including oral swelling at the Wharton duct, were observed in 5 cases of repositioning and 2 cases of ligation. Stensen ducts were repositioned in 9 cases and ligated in 22 cases. The only complication reported was a single case of salivary fistula after ligation. CONCLUSIONS: Salivary duct repositioning is performed to prevent blockage of physiologic salivary discharge. Complications were more frequently associated with Wharton ducts than with Stensen ducts because of the unique physiologic and anatomic characteristics of the Wharton duct. Repositioning of the salivary duct is a suitable method for preventing complications associated with the Wharton duct. PMID- 25795186 TI - Linear and volumetric airway changes after maxillomandibular advancement for obstructive sleep apnea. AB - PURPOSE: Maxillomandibular advancement (MMA) surgery is a well-established treatment of obstructive sleep apnea (OSA). Although many studies have assessed the efficacy of MMA in treating OSA, very few studies have quantified the magnitude of its changes to airway morphology. Therefore, the present study investigated the linear and volumetric morphologic changes that occur in the pharyngeal airway after treatment of OSA using MMA. MATERIALS AND METHODS: A retrospective cohort study of patients with OSA treated from May 2010 to February 2014 was performed. Each patient underwent preoperative clinical and fiberoptic nasopharyngoscopic examinations. Pre- and postoperative polysomnograms, lateral cephalograms, and cone-beam computed tomography scans were acquired. The radiographic images were used to determine the linear and volumetric airway measurements. The time and magnitude of skeletal movement were used as the independent variables. The dependent variables included assessment of success or cure, apnea hypopnea index (AHI), cephalometric changes, Epworth score, rapid eye movement sleep, body mass index, and various airway morphologic parameters. RESULTS: A total of 15 patients (13 men and 2 women) participated in the present study. The surgical success and cure rate was 73.33% and 40.00%, respectively. Statistically significant improvements were found in the airway total volume, minimal cross-sectional area, anteroposterior and lateral dimensions, airway index, airway length, posterior airway space morphology, AHI, and Epworth sleepiness score. CONCLUSIONS: MMA is a highly successful surgical treatment of OSA that improves airway morphology and sleep quality. MMA results in a shorter and broader airway and associated improvements in the AHI. PMID- 25795188 TI - The value of early intervention and a multidisciplinary approach in the management of necrotizing fasciitis of the neck and anterior mediastinum of odontogenic origin. AB - Necrotizing fasciitis (NF) is a serious clinical condition, which, if diagnosed late, invariably leads to a fatal outcome. A high index of suspicion of the presenting clinical signs and symptoms, supported by knowledge of the clinicopathologic processes that underlie its aggressive nature, should prompt early surgical intervention. Ultimately, the success of treatment requires a robust clinical pathway in which all members of the health care team are aligned by their skill sets and competencies to manage NF. This report describes the management of a case of a young man with aggressive NF of odontogenic origin affecting the neck and anterior mediastinum. A multidisciplinary approach brought about early recognition of the disease and surgical intervention, the use of frozen section biopsies to determine the extent of fascial spread, and aggressive debridement of the affected tissue. Teamwork, critical thinking, and situational awareness ensured that the patient received optimum care in a timely manner. The psychological, clinical, radiologic, pathologic, and microbiological aspects of the patient's care are presented with a literature review. PMID- 25795187 TI - Facial angioedema and systemic lupus erythematosus: case report. AB - Non-medication-related acquired deficiencies of C1 esterase inhibitor (C1-INH) can cause the facial acquired angioedema (AAE) seen in systemic lupus erythematosus (SLE). The defect can originate from a lymphoproliferative disease (LPD) that catabolizes C1-INH or from circulating antibodies that inactivate C1 INH. This report describes a third and rare variety of facial AAE originating in SLE in which there was no LPD or circulating antibodies to impede C1-INH activity. PMID- 25795189 TI - Head and neck reconstruction using the superiorly based reversed-flow facial artery myomucosal flap. AB - PURPOSE: The use of myomucosal buccinator flaps in the reconstruction of oral cavity defects is well established in the international literature; however, their use for the reconstruction of defects not in the oral cavity has been largely underestimated. The purpose of this report was to describe and review the applications of the superiorly based facial artery myomucosal (FAMM) flap in head and neck reconstruction. MATERIALS AND METHODS: This study was a retrospective evaluation of 12 patients who underwent reconstruction of the palate, lip, nasal septum, and conjunctiva with reversed-flow FAMM flaps. Mouth opening, speech, reconstruction effectiveness, and esthetic outcomes were analyzed. RESULTS: The patient cohort consisted of 7 men and 5 women 33 to 80 years old (mean, 56.2 yr old). No major complication occurred. Cosmetic results were excellent in most patients. Functionally, the best reconstruction results were obtained in the palate, lip, and conjunctiva. Nasal reconstruction led to mild airway obstruction in 2 cases and severe obstruction in 1 case. CONCLUSION: The superiorly based FAMM flap plays an important role in the reconstruction of particular defects involving the oral cavity and other distant sites of the head and neck area. The reliability, low morbidity, and optimal results that can be achieved using this technique make this flap a good option for such reconstructions. PMID- 25795190 TI - Synovial plicae and temporomandibular joint disorders: surgical findings. AB - PURPOSE: Synovial plicae and their relation to pain and disability have been reported in the orthopedic literature in association with the knee and other extremity joints. However, the occurrence of synovial plicae in the temporomandibular joint (TMJ) have rarely been reported. This report describes the surgical appearance, distribution, and histologic findings of synovial plicae in patients with TMJ recurrent dislocation and internal derangement. MATERIALS AND METHODS: Twenty consecutive patients, 16 with recurrent dislocation and 4 with internal derangement, who underwent open TMJ surgery by the same surgeon from 2010 to 2013 were studied retrospectively. RESULTS: Synovial plicae were detected in 18 of 28 joints (64.3%). Synovial plicae were observed in 15 of 24 joints (62.5%) with recurrent dislocation and in 3 of 4 joints (75%) with internal derangement. Histologic findings of these plicae were consistent with dense fibrous or cartilaginous tissues, with some exhibiting a synovial lining. CONCLUSIONS: Although the role of synovial plicae in TMJ disorders is unknown and unstudied, consideration should be given to investigating the possible relation of these structures to the signs and symptoms of TMJ disorders. PMID- 25795191 TI - Three-dimensional computed tomographic evaluation of bilateral sagittal split osteotomy lingual fracture line and le fort I pterygomaxillary separation in orthognathic surgery using cadaver heads: ultrasonic osteotome versus conventional saw. AB - PURPOSE: The purpose of this study was to observe the quality of the fracture line on the lingual side of the mandible after sagittal split osteotomy and the quality of pterygomaxillary separation after Le Fort I osteotomy using the BoneScalpel ultrasonic osteotome. MATERIALS AND METHODS: Bimaxillary procedures, according to the standard protocol, were performed using 10 fresh cadaver heads. The ultrasonic osteotome was used in the study group, and a reciprocating saw was used in the control group. Three-dimensional reconstructions of postoperative computed tomographic scans were obtained. The lingual ramus fracture pattern and the pterygomaxillary separation pattern were observed, classified, and compared. Postoperative dissections of the skulls were performed to assess the integrity of the infra-alveolar nerve and the descending palatine artery. RESULTS: No significant differences were found in the cutting time of bone between the BoneScalpel and the sagittal saw. Of the sagittal split osteotomies in the study group, 90% showed a good pattern (vertical pattern of fracture line extending to the inferior border of the mandible running behind the mandibular canal) compared with 50% of the sagittal split osteotomies in the control group. Ideal separation of the pterygoid plates without fractures was observed in 80% of the Le Fort I osteotomies in the study group compared with 50% of the osteotomies in the control group. High-level fractures occurred in 30% of cases in the control group compared with none in the study group. The integrities of the infra-alveolar nerve and the descending palatine artery were preserved in all cases. CONCLUSION: Use of the ultrasonic BoneScalpel did not require more time than the conventional method. An improved pattern of lingual fracture lines in mandibular sagittal split osteotomy procedures and the pattern of pterygomaxillary separation in Le Fort I osteotomy procedures were observed. PMID- 25795192 TI - Instruments used in American oral and maxillofacial surgery: the person behind the name. AB - Many surgical instruments are used in oral and maxillofacial surgery that bear the name of their creator. However, who these persons really were is generally unknown. The purpose of this report was to identify some of those surgeons who developed instruments during the 19th century that continue to make oral and maxillofacial operations easier for surgeons and patients. PMID- 25795193 TI - Large scale survey of enteric viruses in river and waste water underlines the health status of the local population. AB - Although enteric viruses constitute a major cause of acute waterborne diseases worldwide, environmental data about occurrence and viral load of enteric viruses in water are not often available. In this study, enteric viruses (i.e., adenovirus, aichivirus, astrovirus, cosavirus, enterovirus, hepatitis A and E viruses, norovirus of genogroups I and II, rotavirus A and salivirus) were monitored in the Seine River and the origin of contamination was untangled. A total of 275 water samples were collected, twice a month for one year, from the river Seine, its tributaries and the major WWTP effluents in the Paris agglomeration. All water samples were negative for hepatitis A and E viruses. AdV, NVGI, NVGII and RV-A were the most prevalent and abundant populations in all water samples. The viral load and the detection frequency increased significantly between the samples collected the most upstream and the most downstream of the Paris urban area. The calculated viral fluxes demonstrated clearly the measurable impact of WWTP effluents on the viral contamination of the Seine River. The viral load was seasonal for almost all enteric viruses, in accordance with the gastroenteritis recordings provided by the French medical authorities. These results implied the existence of a close relationship between the health status of inhabitants and the viral contamination of WWTP effluents and consequently surface water contamination. Subsequently, the regular analysis of wastewater could serve as a proxy for the monitoring of the human viruses circulating in both a population and surface water. PMID- 25795194 TI - Quantification of serial changes in cerebral blood volume and metabolism in patients with recurrent glioblastoma undergoing antiangiogenic therapy. AB - OBJECTIVES: To evaluate the usefulness of quantitative advanced magnetic resonance imaging (MRI) methods for assessment of antiangiogenic therapy (AAT) response in recurrent glioblastoma multiforme (GBM). METHODS: Eighteen patients with recurrent GBM received bevacizumab and 18 patients served as control group. Baseline MRI and two follow-up examinations were acquired every 3-5 months using dynamic susceptibility-weighted contrast (DSC) perfusion MRI and (1)H-MR spectroscopic imaging ((1)H-MRSI). Maps of absolute cerebral blood volume (aCBV) were coregistered with choline (Cho) and N-acetyl-aspartate (NAA) concentrations and compared to usually used relative parameters as well as controls. RESULTS: Perfusion significantly decreased in responding and pseudoresponding GBMs but also in normal appearing brain after AAT onset. Cho and NAA concentrations were superior to Cr-ratios in lesion differentiation and showed a clear gap between responding and pseudoresponding lesions. Responders to AAT exceptionally frequently (6 out of 8 patients) showed remote GBM progression. CONCLUSIONS: Quantification of CBV reveals changes in normal brain perfusion due to AAT, which were not described so far. DSC perfusion MRI seems not to be suitable for differentiation between response and pseudoresponse to AAT. However, absolute quantification of brain metabolites may allow for distinction due to a clear gap at 6-9 months after therapy onset. PMID- 25795195 TI - The value of precontrast thoraco-abdominopelvic CT in polytrauma patients. AB - PURPOSE: To evaluate the utility and radiation dose of thoraco-abdominopelvic precontrast CT in polytrauma patients. MATERIALS AND METHODS: We examined retrospectively 125 patients who underwent a thoraco-abdominopelvic CT for trauma. Two radiologists, independently, evaluated precontrast CT acquisition and two other radiologists examined the contrast-enhanced scans. A further two radiologists assessed both the acquisitions. Mean value of sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) were calculated by each group of radiologists. For 104 patients, CTDIvol, DLP data and individual mean size were collected to calculate effective dose. RESULTS: Mean values of SE, SP, PPV and NPV of findings of radiologists who assessed contrast-enhanced acquisitions were respectively: SE=85%, SP=98%, PPV=86%, NPV=88% versus: SE=43%, SP=95%, PPV=69%, NPV=88% of radiologists who examined non-contrast-enhanced scans. Mean values of radiologists who analyzed both acquisitions were: SE=80%, SP=97%, PPV=80%, NPV=88%. Neither the precontrast scans nor the precontrast and postcontrast scans together provided additional useful information compared to the single contrast-enhanced acquisition. Patients received a mean dose of 12 mSv for the precontrast CT. CONCLUSIONS: Precontrast CT acquisition did not provide significant information in trauma patients, exposing them to an unjustified radiation dose. PMID- 25795196 TI - Should abdominal sequences be included in prostate cancer MR staging studies? AB - OBJECTIVES: Prostate cancer staging MR examinations commonly include abdominal sequences to assess for non-regional (common iliac or para-aortic) nodal metastasis. In our experience the diagnostic yield of this is limited, but incidental findings are frequent, often necessitating further investigations. The aim of this study is to assess the diagnostic utility of abdominal sequences in routine prostate cancer MR staging studies. METHODS: Findings on abdominal sequences of consecutive MRI prostate studies performed for staging newly diagnosed prostate cancer between September 2011 and September 2013 were reviewed with respect to adenopathy and additional incidental findings. Results were correlated with Gleason grade and serum prostate-specific antigen (PSA) level in each case. RESULTS: 355 MRI prostate examinations were reviewed. 4 (1.1%) showed enlarged non-regional lymph nodes. Incidental findings were found in 82(23.1%) cases, neccessitating further investigation in 45 (12.7%) cases. Enlarged non regional nodes were associated with higher PSA level and Gleason grade (p=0.007, p=0.005 respectively). With a combined threshold of PSA > 20 ng/mL and/or Gleason grade >= 8 the sensitivity, specificity, PPV and NPV were 100, 60, 3 and 100% respectively for predicting the presence of non-regional adenopathy. CONCLUSIONS: Routine abdominal sequences are of very low yield in routine prostate cancer MR staging, frequently resulting in incidental findings requiring further work-up and should be reserved for high-risk cases. Our experience supports the use of an abdominal staging sequence in high-risk cases only. PMID- 25795197 TI - Altered temporal features of intrinsic connectivity networks in boys with combined type of attention deficit hyperactivity disorder. AB - PURPOSE: Investigating the altered temporal features within and between intrinsic connectivity networks (ICNs) for boys with attention-deficit/hyperactivity disorder (ADHD); and analyzing the relationships between altered temporal features within ICNs and behavior scores. MATERIALS AND METHODS: A cohort of boys with combined type of ADHD and a cohort of age-matched healthy boys were recruited from ADHD-200 Consortium. All resting-state fMRI datasets were preprocessed and normalized into standard brain space. Using general linear regression, 20 ICNs were taken as spatial templates to analyze the time-courses of ICNs for each subject. Amplitude of low frequency fluctuations (ALFFs) were computed as univariate temporal features within ICNs. Pearson correlation coefficients and node strengths were computed as bivariate temporal features between ICNs. Additional correlation analysis was performed between temporal features of ICNs and behavior scores. RESULTS: ADHD exhibited more activated network-wise ALFF than normal controls in attention and default mode-related network. Enhanced functional connectivities between ICNs were found in ADHD. The network-wise ALFF within ICNs might influence the functional connectivity between ICNs. The temporal pattern within posterior default mode network (pDMN) was positively correlated to inattentive scores. The subcortical network, fusiform related DMN and attention-related networks were negatively correlated to Intelligence Quotient (IQ) scores. CONCLUSION: The temporal low frequency oscillations of ICNs in boys with ADHD were more activated than normal controls during resting state; the temporal features within ICNs could provide additional information to investigate the altered network patterns of ADHD. PMID- 25795198 TI - Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib treated patients for metastatic renal cell carcinoma. AB - BACKGROUND: To examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU). METHODS: We retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology. RESULTS: Among 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS [HR = 0.40; 95% CI (0.24-0.66), P < 0.001] and PFS [HR = 0.55 (0.35-0.86), P = 0.009]. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment. CONCLUSION: Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients. PMID- 25795200 TI - Capecitabine plus oxaliplatin (XELOX) compared with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in advanced gastric cancer: meta-analysis of randomized controlled trials. AB - PURPOSE: The study aims to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in patients with advanced gastric cancer. METHODS: Five databases were searched up to June 2014, without language restrictions. The outcomes included overall response rate (ORR), clinical benefit rate (CBR), and toxicity. RESULTS: Twenty six eligible trials were selected from 178 studies that initially were identified. All trials were published in Chinese journals between 2005 and 2014 and included 1585 patients (787 in XELOX group and 798 in FOLFOXs group). The pooled results failed to show statistical significance of XELOX regimen on ORR (OR 1.18, 95% CIs 1.00-1.41, P = 0.057) and CBR (OR 1.10, 95% CIs 0.95-1.28, P = 0.191) as compared with FOLFOXs regimen. None of the 26 clinical trials reported progression-free survival, and only one reported overall survival rate. The meta analysis demonstrated that XELOX regimen was associated with a significant lower risk with nausea, stomatitis, diarrhea and alopecia, and a significant higher risk of hand-foot syndrome. CONCLUSIONS: The evidence is limited to suggest that XELOX may share similar efficacy as FOLFOXs and reduce toxicities of chemotherapy in advanced gastric cancer therapy. However, owing to limited data and potential bias of the included studies, further rigorously controlled trials are required. PMID- 25795201 TI - Axial T1 weighted magnetic resonance image through the upper thorax in a 20 year old woman. PMID- 25795199 TI - Organellar channels and transporters. AB - Decades of intensive research have led to the discovery of most plasma membrane ion channels and transporters and the characterization of their physiological functions. In contrast, although over 80% of transport processes occur inside the cells, the ion flux mechanisms across intracellular membranes (the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, mitochondria, chloroplasts, and vacuoles) are difficult to investigate and remain poorly understood. Recent technical advances in super-resolution microscopy, organellar electrophysiology, organelle-targeted fluorescence imaging, and organelle proteomics have pushed a large step forward in the research of intracellular ion transport. Many new organellar channels are molecularly identified and electrophysiologically characterized. Additionally, molecular identification of many of these ion channels/transporters has made it possible to study their physiological functions by genetic and pharmacological means. For example, organellar channels have been shown to regulate important cellular processes such as programmed cell death and photosynthesis, and are involved in many different pathologies. This special issue (SI) on organellar channels and transporters aims to provide a forum to discuss the recent advances and to define the standard and open questions in this exciting and rapidly developing field. Along this line, a new Gordon Research Conference dedicated to the multidisciplinary study of intracellular membrane transport proteins will be launched this coming summer. PMID- 25795202 TI - Transforming growth factor-beta (TGF-beta) signaling in healthy human fetal skin: a descriptive study. AB - BACKGROUND: TGF-beta plays an important role in growth and development but is also involved in scarring and fibrosis. Differences for this growth factor are known between scarless fetal wound healing and adult wound healing. Nonetheless, most of the data in this area are from animal studies or in vitro studies and, thus, information about the human situation is incomplete and scarce. OBJECTIVE: The aim of this study was to compare the canonical TGF-beta signaling in unwounded human fetal and adult skin. METHODS: Q-PCR, immunohistochemistry, Western Blot and Luminex assays were used to determine gene expression, protein levels and protein localization of components of this pathway in healthy skin. RESULTS: All components of the canonical TGF-beta pathway were present in unwounded fetal skin. Compared to adult skin, fetal skin had differential concentrations of the TGF-beta isoforms, had high levels of phosphorylated receptor-Smads, especially in the epidermis, and had low expression of several fibrosis-associated target genes. Further, the results indicated that the processes of receptor endocytosis might also differ between fetal and adult skin. CONCLUSION: This descriptive study showed that there are differences in gene expression, protein concentrations and protein localization for most components of the canonical TGF-beta pathway between fetal and adult skin. The findings of this study can be a starting point for further research into the role of TGF-beta signaling in scarless healing. PMID- 25795203 TI - Fitbit(r): An accurate and reliable device for wireless physical activity tracking. PMID- 25795204 TI - Unraveling the relation between marital status and prognosis among myocardial infarction survivors: Impact of being widowed on mortality. PMID- 25795205 TI - Transvenous extraction of a left subclavian dialysis catheter: A new challenge in cardiology. PMID- 25795206 TI - Dramatic improvement of clinical and hemodynamic parameters of a heart transplant candidate with sildenafil treatment. PMID- 25795207 TI - Transradial percutaneous coronary intervention with Stentys self-apposing stents and Stentys-Yew technique for angulated and ectatic coronary artery. PMID- 25795208 TI - Adult cor triatriatum and transient ischemic attack. Does this rare congenital heart defect augment embolic risk? PMID- 25795209 TI - Early experience of transradial multivessel percutaneous coronary intervention with new generation STENTYS sirolimus eluting self-apposing stents for ectatic coronary arteries. PMID- 25795210 TI - Subaortic membrane coexisting with systolic anterior motion of the mitral valve. PMID- 25795211 TI - Found in translation: functions and evolution of a recently discovered alternative proteome. AB - A major goal in biology is to map entire proteomes to better understand the biology and evolution of cells. However, our current views of proteomes are conservative and biased against small proteins. Besides serendipitous discoveries of small proteins, it has been largely assumed that eukaryotic mature mRNAs contain a single ORF and that non-coding RNAs are not translated because their ORFs are too short to play a functional role. A flurry of recent studies brought to light an unexplored proteome that is mainly translated from short ORFs in non coding regions and from alternative ORFs (AltORFs) in reference genes. The detection of these small proteins and the elucidation of their functions remain challenging and open a new dimension of eukaryotic proteomes, including the birth of novel genes and proteins. PMID- 25795212 TI - Comparison of risk-based hepatitis C screening and the true seroprevalence in an urban prison system. AB - Hepatitis C virus (HCV) is the most common blood-borne infection in the USA, though seroprevalence is elevated in certain high-risk groups such as inmates. Correctional facility screening protocols vary from universal testing to opt-in risk-based testing. This project assessed the success of a risk-based HCV screening strategy in the Philadelphia Prison System (PPS) by comparing results from current testing practices during 2011-2012 (Risk-Based Screening Group) to a September 2012 blinded seroprevalence study (Philadelphia Department of Public Health (PDPH) Study Cohort). PPS processed 51,562 inmates in 2011-2012; 2,727 were identified as high-risk and screened for HCV, of whom 57 % tested HCV antibody positive. Twelve percent (n = 154) of the 1,289 inmates in the PDPH Study Cohort were anti-HCV positive. Inmates >=30 years of age had higher rates of seropositivity in both groups. Since only 5.3 % of the prison population was included in the Risk-Based Screening Group, an additional 4,877 HCV-positive inmates are projected to have not been identified in 2011-2012. Gaps in case identification exist when risk-based testing is utilized by PPS. A more comprehensive screening model such as opt-out universal testing should be considered to identify HCV-positive inmates. Identification of these individuals is an important opportunity to aid underserved high-risk populations and to provide medical care and secondary prevention. PMID- 25795213 TI - Dimethylglycine Deficiency and the Development of Diabetes. AB - Experimental studies have suggested possible protective effects of dimethylglycine (DMG) on glucose metabolism. DMG is degraded to glycine through a DMG-dehydrogenase (DMGDH)-catalyzed reaction, and this is the only known pathway for the breakdown of DMG in mammals. In this study, we aimed to identify the strongest genetic determinant of circulating DMG concentration and to investigate its associations with metabolic traits and incident diabetes. In the cohort with full metabolomics data (n = 709), low plasma levels of DMG were significantly associated with higher blood glucose levels (P = 3.9E(-4)). In the genome-wide association study (GWAS) of the discovery cohort (n = 5,205), the strongest genetic signal of plasma DMG was conferred by rs2431332 at the DMGDH locus, where the major allele was associated with lower DMG levels (P = 2.5E(-15)). The same genetic variant (major allele of rs2431332) was also significantly associated with higher plasma insulin (P = 0.019), increased HOMA insulin resistance (P = 0.019), and an increased risk of incident diabetes (P = 0.001) in the pooled analysis of the discovery cohort together with the two replication cohorts (n = 20,698 and n = 7,995). These data are consistent with a possible causal role of DMG deficiency in diabetes development and encourage future studies examining if inhibition of DMGDH, or alternatively, supplementation of DMG, might prove useful for the treatment/prevention of diabetes. PMID- 25795214 TI - Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain beta-Cell Function and Glucose Homeostasis. AB - Proinsulin misfolding in the endoplasmic reticulum (ER) initiates a cell death response, although the mechanism(s) remains unknown. To provide insight into how protein misfolding may cause beta-cell failure, we analyzed mice with the deletion of P58(IPK)/DnajC3, an ER luminal co-chaperone. P58(IPK-/-) mice become diabetic as a result of decreased beta-cell function and mass accompanied by induction of oxidative stress and cell death. Treatment with a chemical chaperone, as well as deletion of Chop, improved beta-cell function and ameliorated the diabetic phenotype in P58(IPK-/-) mice, suggesting P58(IPK) deletion causes beta-cell death through ER stress. Significantly, a diet of chow supplemented with antioxidant dramatically and rapidly restored beta-cell function in P58(IPK-/-) mice and corrected abnormal localization of MafA, a critical transcription factor for beta-cell function. Antioxidant feeding also preserved beta-cell function in Akita mice that express mutant misfolded proinsulin. Therefore defective protein folding in the beta-cell causes oxidative stress as an essential proximal signal required for apoptosis in response to ER stress. Remarkably, these findings demonstrate that antioxidant feeding restores cell function upon deletion of an ER molecular chaperone. Therefore antioxidant or chemical chaperone treatment may be a promising therapeutic approach for type 2 diabetes. PMID- 25795216 TI - Allogeneic Transplantation of an Adipose-Derived Stem Cell Sheet Combined With Artificial Skin Accelerates Wound Healing in a Rat Wound Model of Type 2 Diabetes and Obesity. AB - One of the most common complications of diabetes is diabetic foot ulcer. Diabetic ulcers do not heal easily due to diabetic neuropathy and reduced blood flow, and nonhealing ulcers may progress to gangrene, which necessitates amputation of the patient's foot. This study attempted to develop a new cell-based therapy for nonhealing diabetic ulcers using a full-thickness skin defect in a rat model of type 2 diabetes and obesity. Allogeneic adipose-derived stem cells (ASCs) were harvested from the inguinal fat of normal rats, and ASC sheets were created using cell sheet technology and transplanted into full-thickness skin defects in Zucker diabetic fatty rats. The results indicate that the transplantation of ASC sheets combined with artificial skin accelerated wound healing and vascularization, with significant differences observed 2 weeks after treatment. The ASC sheets secreted large amounts of several angiogenic growth factors in vitro, and transplanted ASCs were observed in perivascular regions and incorporated into the newly constructed vessel structures in vivo. These results suggest that ASC sheets accelerate wound healing both directly and indirectly in this diabetic wound healing model. In conclusion, allogeneic ASC sheets exhibit potential as a new therapeutic strategy for the treatment of diabetic ulcers. PMID- 25795215 TI - Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study. AB - Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1 (13)C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 +/- 0.7 vs. 8.4 +/- 0.5 mmol/L), lower PDH flux (0.005 +/- 0.001 vs. 0.017 +/- 0.002 s(-1)), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 +/- 0.8 vs. 20 +/- 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 +/- 0.002 s(-1)), reversed diastolic dysfunction (E/E' 14 +/- 1), and normalized blood glucose levels (7.5 +/- 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy. PMID- 25795217 TI - Large-scale time series microscopy of neovessel growth during angiogenesis. AB - During angiogenesis, growing neovessels must effectively navigate through the tissue space as they elongate and subsequently integrate into a microvascular network. While time series microscopy has provided insight into the cell activities within single growing neovessel sprouts, less is known concerning neovascular dynamics within a large angiogenic tissue bed. Here, we developed a time-lapse imaging technique that allowed visualization and quantification of sprouting neovessels as they form and grow away from adult parent microvessels in three dimensions over cubic millimeters of matrix volume during the course of up to 5 days on the microscope. Using a new image acquisition procedure and novel morphometric analysis tools, we quantified the elongation dynamics of growing neovessels and found an episodic growth pattern accompanied by fluctuations in neovessel diameter. Average elongation rate was 5 MUm/h for individual vessels, but we also observed considerable dynamic variability in growth character including retraction and complete regression of entire neovessels. We observed neovessel-to-neovessel directed growth over tens to hundreds of microns preceding tip-to-tip inosculation. As we have previously described via static 3D imaging at discrete time points, we identified different collagen fibril structures associated with the growing neovessel tip and stalk, and observed the coordinated alignment of growing neovessels in a deforming matrix. Overall analysis of the entire image volumes demonstrated that although individual neovessels exhibited episodic growth and regression, there was a monotonic increase in parameters associated with the entire vascular bed such as total network length and number of branch points. This new time-lapse imaging approach corroborated morphometric changes in individual neovessels described by us and others, as well as captured dynamic neovessel behaviors unique to days-long angiogenesis within the forming neovascular network. PMID- 25795218 TI - Cell-specific impact of nitric oxide-dependent guanylyl cyclase on arteriogenesis and angiogenesis in mice. AB - Nitric oxide (NO) acts as essential regulator of vasculogenesis and angiogenesis and is critical for arteriogenesis. Whether NO's effects in vivo are mediated through NO-sensitive guanylyl cyclase (NO-GC) and thus by cGMP-dependent mechanisms has been only poorly addressed. Mice lacking NO-GC globally or specifically in smooth muscle cells (SMC) or endothelial cells (EC) were subjected to two established models for arteriogenesis and angiogenesis, namely hindlimb ischemia and oxygen-induced retinopathy. Our data clearly show the involvement of NO-GC in the recovery of blood flow after hindlimb ischemia, and this effect could be attributed to NO-GC in SMC. In the retina, global deletion of NO-GC led to reduced oxygen-induced vessel loss and hypoxia-induced capillary regrowth, whereas pathological neovascularization was increased. These effects were also seen in mice with SMC-specific NO-GC deletion but not in animals lacking NO-GC in EC. Intriguingly, NO-GC was found to be strongly expressed in retinal pericytes. Our data prove the involvement of NO-GC in growth and plasticity of hindlimb and retinal vasculature after ischemic/hypoxic insult. PMID- 25795219 TI - Molecular characterization, genomic structure and expressional profiles of a CXC chemokine receptor 4 (CXCR4) from rock bream Oplegnathus fasciatus. AB - The CXC chemokine receptor 4 (CXCR4) is the cognate receptor of the CXC chemokine ligand 12 (CXCL12) and plays a pivotal role under immune-pathophysiological conditions. In the current study, the CXCR4 homolog of Oplegnathus fasciatus (OfCXCR4) was sequenced and the mRNA expression levels were characterized. The genomic structure of the cloned OfCXCR4 coding region (2094 bp) revealed a bi exonic element, where the open reading frame (ORF) appears split by a single intron. Analysis of the ORF (1134 bp) of OfCXCR4 revealed a predicted protein of 42.1 kDa with typical seven transmembrane (TM) domain architecture and several conserved structural features, including two cysteine residues forming a predicted disulfide bond, a characteristic CXC motif (containing CYC) and a G protein-coupled receptor (GPCR) family 1 signature. Furthermore, based on comparative analysis, the structure OfCXCR4 appears well conserved at both the genomic DNA and the amino acid levels. Phylogenic analysis of OfCXCR4 revealed that the greatest homology was with its teleostean relatives. Expression studies showed ubiquitous OfCXCR4 transcription, mainly in immune organs, with the highest levels in the head kidney. Examination of OfCXCR4 transcriptional regulation post injection to different stimuli or pathogens revealed a significant modulation of mRNA expression as detected by reverse transcription quantitative real-time PCR. Evidence of various transcription factor binding sites present in the 5'-flanking region of OfCXCR4 coupled with its observed regulated mRNA expression suggest that it may have an important role in immune surveillance in rock bream. PMID- 25795221 TI - Vicarious resilience and vicarious traumatisation: Experiences of working with refugees and asylum seekers in South Australia. AB - The negative psychological impacts of working with traumatised people are well documented and include vicarious traumatisation (VT): the cumulative effect of identifying with clients' trauma stories that negatively impacts on service providers' memory, emotions, thoughts, and worldviews. More recently, the concept of vicarious resilience (VR) has been also identified: the strength, growth, and empowerment experienced by trauma workers as a consequence of their work. VR includes service providers' awareness and appreciation of their clients' capacity to grow, maintaining hope for change, as well as learning from and reassessing personal problems in the light of clients' stories of perseverance, strength, and growth. This study aimed at exploring the experiences of mental health, physical healthcare, and settlement workers caring for refugees and asylum seekers in South Australia. Using a qualitative method (data-based thematic analysis) to collect and analyse 26 semi-structured face-to-face interviews, we identified four prominent and recurring themes emanating from the data: VT, VR, work satisfaction, and cultural flexibility. These findings-among the first to describe both VT and VR in Australians working with refugee people-have important implications for policy, service quality, service providers' wellbeing, and refugee clients' lives. PMID- 25795220 TI - The structure of feared social situations among race-ethnic minorities and Whites with social anxiety disorder in the United States. AB - We investigated feared social situations in individuals with social anxiety disorder from different racial and ethnic groups in the United States. The sample included 247 African Americans, 158 Latinos, and 533 non-Latino Whites diagnosed with social anxiety disorder within the past 12 months from the integrated Collaborative Psychiatric Epidemiology Studies data set. After randomly splitting the full sample, we conducted an exploratory factor analysis with half of the sample to determine the structure of feared social situations in a more diverse sample than has been used in previous studies. We found evidence for a model consisting of three feared social domains: performance/public speaking, social interaction, and observational. We then conducted a confirmatory factor analysis on the remaining half of the sample to examine whether this factor structure varied significantly between the race-ethnic groups. Analyses revealed an adequate fit of this model across all three race-ethnic groups, suggesting invariance of the factor structure between the study groups. Broader cultural contexts within which these findings are relevant are discussed, along with important implications for comprehensive, culturally sensitive assessment of social anxiety. PMID- 25795222 TI - Self-Rated Health Among Saudi Adults: Findings from a National Survey, 2013. AB - Self-rated health reflects a person's integrated perception of health, including its biological, psychological, and social dimensions. It is a predictor of morbidity and mortality. To assess the current status of self-rated health and associated factors in the Kingdom of Saudi Arabia, we analyzed data from the Saudi Health Interview Survey. We conducted a large national survey of adults aged 15 years or older. A total of 10,735 participants completed a standardized health questionnaire. Respondents rated their health with a five-point scale. Data on socio-demographic characteristics, chronic diseases, health-related habits and behaviors, and anthropometric measurements were collected. Associated factors of self-rated health were analyzed using a backward elimination multivariate logistic regression model. More than 77% of respondents rated their health as excellent/very good. Female sex [odds ratio (OR) 1.52, 95% confidence interval (CI) 1.24-1.88], decades of age (OR 1.35, 95% CI 1.25-1.46), diagnosed diabetes mellitus (OR 1.54, 95 CI 1.22-1.93), diagnosed hypercholesterolemia (OR 1.37, 95% CI 1.06-1.79), diagnosed hypertension (OR 1.55, 95% CI 1.22-1.96), number of other diagnosed chronic diseases (OR 1.69, 95% CI 1.41-2.03), limited vigorous activity (OR 3.59, 95% CI 2.84-4.53), need for special equipment (OR 2.62, 95% CI 1.96-3.51), and more than 3 h of daily television/computer screen time (OR 1.59, 95% CI 1.11-2.29) were positively associated with poor/fair health. Smoking, obesity, and physical inactivity were not associated with self reported health. We found that preventable risk factors are not associated with Saudis' self-rated health. This optimistic perception of health poses a challenge for preventive interventions in the Kingdom and calls for campaigns to educate the public about the harm of unhealthy behaviors. PMID- 25795223 TI - Establishing the SouthWestern Academic Health Network (SWAHN): A Survey Exploring the Needs of Academic and Community Networks in SouthWestern Ontario. AB - With the evolving fields of health research, health professional education and advanced clinical care comes a need to bring researchers, educators and health care providers together to enhance communication, knowledge-sharing and interdisciplinary collaboration. There is also a need for active collaboration between academic institutions and community organizations to improve health care delivery and health outcomes in the community setting. In Canada, an Academic Health Sciences Network model has been proposed to achieve such activities. The SouthWestern Academic Health Network (SWAHN) has been established among three universities, three community colleges, community hospitals, community-based organizations and health care providers and two Local Health Integrated Networks (LHINs) in Southwestern Ontario. A survey was conducted to understand the characteristics, activities, existing partnerships, short- and long-term goals of the academic and community health networks in SouthWestern Ontario to inform the development of SWAHN moving forward. A total of 114 health networks were identified from the two participating LHINs, 103 community health networks and 11 academic health networks. A mailed survey was sent to all networks and responses were analyzed using both quantitative and qualitative approaches. The short- and long-term goals of these networks were categorized into five main themes: Public Health, Education, Research, System Delivery and Special Populations. Overall, this study helped to elicit important information from the academic and community based networks, which will inform the future work of SWAHN. This research has also demonstrated the significance of collecting information from both academic and community partners during the formation of other interdisciplinary health networks. PMID- 25795224 TI - The prospective association between health anxiety and cancer detection: A cohort study linking the Hordaland Health Study (HUSK) with the Norwegian Cancer Registry. AB - OBJECTIVE: Health anxiety is associated with distress and disability, and overutilization of health services, but it is not known whether high levels of health anxiety may lead to increased detection of severe diseases such as cancer. By linking a large population based health study with the national cancer registry, the aim of the study was to investigate a potential prospective association between health anxiety in men and women and later cancer detection and tumour metastasis at the time of diagnosis. METHOD: A longitudinal study with a 13.2 year follow-up linking the population-based Hordaland Health Study (HUSK) and the Cancer Registry of Norway (CRN) was conducted. Health anxiety was measured with the Whiteley Index. Associations were examined through gender stratified Cox regression analyses adjusted for relevant covariates. RESULTS: No association was found between baseline health anxiety and cancer detection for women (adjusted HR: 1.21, 95% CI: 0.42-3.50), but a positive association was found between health anxiety at baseline and cancer detection for men (adjusted HR: 1.76, 95% CI: 1.06-2.91). No statistically significant association was demonstrated between health anxiety and cancer metastasis for either gender. CONCLUSION: An increased level of health anxiety in men may be advantageous, as it may motivate to self-examination and healthcare seeking when disturbing symptoms arise. Research is needed to investigate whether health anxiety has a protective effect on cancer metastasis at the time of detection, or whether health anxiety increases the risk of over-diagnosis and overtreatment. PMID- 25795225 TI - Misery loves company? A meta-regression examining aggregate unemployment rates and the unemployment-mortality association. AB - PURPOSE: Individual-level unemployment has been consistently linked to poor health and higher mortality, but some scholars have suggested that the negative effect of job loss may be lower during times and in places where aggregate unemployment rates are high. We review three logics associated with this moderation hypothesis: health selection, social isolation, and unemployment stigma. We then test whether aggregate unemployment rates moderate the individual level association between unemployment and all-cause mortality. METHODS: We use six meta-regression models (each using a different measure of the aggregate unemployment rate) based on 62 relative all-cause mortality risk estimates from 36 studies (from 15 nations). RESULTS: We find that the magnitude of the individual-level unemployment-mortality association is approximately the same during periods of high and low aggregate-level unemployment. Model coefficients (exponentiated) were 1.01 for the crude unemployment rate (P = .27), 0.94 for the change in unemployment rate from the previous year (P = .46), 1.01 for the deviation of the unemployment rate from the 5-year running average (P = .87), 1.01 for the deviation of the unemployment rate from the 10-year running average (P = .73), 1.01 for the deviation of the unemployment rate from the overall average (measured as a continuous variable; P = .61), and showed no variation across unemployment levels when the deviation of the unemployment rate from the overall average was measured categorically. Heterogeneity between studies was significant (P < .001), supporting the use of the random effects model. CONCLUSIONS: We found no strong evidence to suggest that unemployment experiences change when macroeconomic conditions change. Efforts to ameliorate the negative social and economic consequences of unemployment should continue to focus on the individual and should be maintained regardless of periodic changes in macroeconomic conditions. PMID- 25795226 TI - The socioeconomic gradient in all-cause mortality for women with breast cancer: findings from the 1998 to 2006 National Cancer Data Base with follow-up through 2011. AB - PURPOSE: To analyze the association between socioeconomic status (SES) and all cause mortality among women diagnosed with breast cancer before and after controlling for insurance status, race and ethnicity, stage, treatment modalities, and other demographic and hospital characteristics. METHODS: Data analyzed included follow-up through 2011 for 582,396 patients diagnosed between 1998 and 2006 with ductal carcinoma in situ or invasive (stage I-IV) breast cancer from the National Cancer Data Base. SES was measured by grouping patients into six income and education-level ZIP code categories. Hierarchical Cox regression models were used to analyze SES survival differences. RESULTS: Five- and 10-year survival probabilities for the highest SES group were 87.8% and 71.5%, versus 79.5% and 61.5% for the lowest SES group. Controlling for all covariates reduced the highest-to-lowest SES hazard ratio from 1.69 (95% confidence interval: 1.64-1.74) to 1.27 (95% confidence interval: 1.24-1.31). Results were virtually identical in models that included comorbidity and invasive cancer patients only. CONCLUSIONS: Differences in insurance status, race, and stage at diagnosis are important components of SES disparities and explain about two-thirds of the initial SES survival disparity. The residual SES effect likely mirrors underlying social determinants of health for all American women. PMID- 25795227 TI - Unhealthy weight among children and adults in India: urbanicity and the crossover in underweight and overweight. AB - PURPOSE: Urbanization may promote the rise of dual burdens of underweight and overweight in low- and middle-income countries. We assessed underweight and overweight by urban residence across the lifespan in India. METHODS: Using nationally representative, directly measured height and weight data (2004-2006; n = 236,039), we estimated and compared the prevalence of underweight and overweight (including obesity) at ages 0 to 54 years by urban and rural residence; absolute burdens of underweight, overweight, and combined unhealthy weight were estimated using 2011 Census data. RESULTS: Thirty-eight percent of the urban population and 36% of the rural population of India experienced unhealthy weight, amounting to 378 million underweight or overweight individuals. In urban areas, the unhealthy weight burden was largely underweight in childhood and overweight in adulthood. In rural areas, the unhealthy weight burden was largely underweight at all ages. Urban residents compared with rural residents were more likely to be overweight and less likely to be underweight at nearly all ages. CONCLUSIONS: Combined unhealthy weight was comparable in urban and rural India. Although underweight continues to be the predominant nutritional problem, there is early evidence of an epidemiologic crossover from underweight to overweight. As India experiences urbanization and population aging, low overweight and obesity may be short lived. PMID- 25795228 TI - Downregulation of external death receptor genes FAS and DR5 in colorectal cancer samples positive for human papillomavirus infection. AB - AIM: Human papillomaviruses (HPV) have frequently been detected in colorectal cancer tumor samples, and may play a role in the pathogenesis of colorectal cancer. This study was designed to investigate the presence of DNA and RNA for the high-risk HPV genotypes 16 and 18 in samples of colorectal cancer tumors and adjacent normal tissues. We also investigated the expression of proapoptotic genes in HPV-positive colorectal tumors compared to normal tissue samples. METHODS: Samples of tumoral and adjacent normal tissues were fresh-frozen, and HPV DNA was identified by nested and semiquantitative PCR. Real time PCR was used to quantitatively compare the expression of HPV-18 E6 and nine proapoptotic genes in HPV-positive tumors and samples of adjacent normal tissue. RESULTS: HPV-16 DNA was found in 10.5% of the tumor samples, and HPV-18 DNA was found in 23.6% of the samples. Real time PCR results showed lower expression of the E6 gene in HPV positive tumors than in adjacent normal tissue. The expression of two proapoptotic genes, FAS and DR5, was significantly lower in tumor samples than in adjacent normal tissues. CONCLUSIONS: HPV infection, especially HPV-18, may play a role in colorectal cancer tumorigenesis by downregulating death receptor genes and interfering with the extrinsic pathway of apoptosis. PMID- 25795229 TI - Immunohistochemical analysis of cardiac troponin inhibitor in an experimental model of acute myocardial infarction experimental model and in human tissues. AB - Acute obstruction of coronary arteries leads to acute myocardial infarction (AMI), which causes unexpected death in humans. However, AMI cannot be easily detected in forensic examinations with traditional hematoxylin and eosin (H&E) staining. We analyzed whether cardiac troponin inhibitor (CTnI) could serve as a sensitive and specific early marker for diagnosing AMI in forensic medicine. We established an AMI model in rabbits by ligating the left ventricular branch and observed CTnI expression with immunohistochemistry after different ligation times. We found increased CTnI staining at the 0.5-h time point and depletion of CTnI staining with a 1-h ligation. The areas in which CTnI staining was depleted as seen with immunohistochemical analysis were consistent with the results of H&E staining. Next, human myocardium tissues from 30 persons who died from AMI and were subsequently examined in our forensic center were studied using immunohistochemistry with an antibody to human CTnI. Areas of infarction also showed depletion of CTnI staining. These findings suggested that immunohistochemical detection of CTnI is earlier, more sensitive, and myocardial tissue - specific as compared with H&E staining. CTnI may serve as an ideal marker for diagnosing AMI in forensic investigations. PMID- 25795231 TI - Editorial overview: Cell regulation: cell biology, fueling a renaissance in metabolism. PMID- 25795230 TI - RNA-sequencing studies identify genes differentially regulated during inflammation-driven lung tumorigenesis and targeted by chemopreventive agents. AB - INTRODUCTION: Chronic pulmonary inflammation has been consistently shown to increase the risk of lung cancer. Therefore, assessing the molecular links between the two diseases and identification of chemopreventive agents that inhibit inflammation-driven lung tumorigenesis is indispensable. MATERIALS AND METHODS: Female A/J mice were treated with the tobacco smoke carcinogen 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and lipopolysaccharide (LPS), a potent inflammatory agent and constituent of tobacco smoke, and maintained on control diet or diet supplemented with the chemopreventive agents indole-3 carbinol (I3C) and/or silibinin (Sil). At the end of the study, mice were sacrificed and tumors on the surface of the lung were counted and gene expression levels in lung tissues were determined by RNA sequencing. RESULTS: The mean number of lung tumors induced by NNK and NNK + LPS was 5 and 15 tumors/mouse, respectively. Dietary supplementation with the combination of I3C and Sil significantly reduced the size and multiplicity (by 50 %) of NNK + LPS-induced lung tumors. Also, we found that 330, 2957, and 1143 genes were differentially regulated in mice treated with NNK, LPS, and NNK + LPS, respectively. The inflammatory response of lung tumors to LPS, as determined by the number of proinflammatory genes with altered gene expression or the level of alteration, was markedly less than that of normal lungs. Among 1143 genes differentially regulated in the NNK + LPS group, the expression of 162 genes and associated signaling pathways was significantly modulated by I3C and/or Sil + I3C. These genes include cytokines, chemokines, putative oncogenes and tumor suppressor genes and Ros1, AREG, EREG, Cyp1a1, Arntl, and Npas2. CONCLUSION: To our knowledge, this is the first report that provides insight into genes that are differentially expressed during inflammation-driven lung tumorigenesis and the modulation of these genes by chemopreventive agents. PMID- 25795232 TI - Simulation and matching-based approaches for indirect comparison of treatments. AB - Estimates of the relative effects of competing treatments are rarely available from head-to-head trials. These effects must therefore be derived from indirect comparisons of results from different studies. The feasibility of comparisons relies on the network linking treatments through common comparators; the reliability of these may also be impacted when the studies are heterogeneous or when multiple intermediate comparisons are needed to link two specific treatments of interest. Simulated treatment comparison and matching-adjusted indirect comparison have been developed to address these challenges. These focus on comparisons of outcomes for two specific treatments of interest by using patient level data for one treatment (the index) and published results for the other treatment (the comparator) from compatible studies, taking into account possible confounding due to population differences. This paper provides an overview of how and when these approaches can be used as an alternative or to complement standard MTC approaches. PMID- 25795233 TI - Total Knee Arthroplasty for Osteoarthritis Secondary to Fracture of the Tibial Plateau. A Prospective Matched Cohort Study. AB - A prospective matched cohort study was performed to compare outcomes of total knee arthroplasties (TKA) between 29 patients with posttraumatic osteoarthritis (POA) after a fracture of tibial plateau and 58 patients underwent routine TKA. Mean follow-up was 6.7 years. There were no significant differences in KSS, WOMAC, SF12 scores or range of motion. In the control group there were no complications. In the posttraumatic group, complications occurred in 4 patients (13.7%) (P=0.010) including partial patellar tendon detachment, superficial infection, skin necrosis, and knee stiffness. Only this last patient required revision for manipulation under anesthesia. Also, there was a revision for tibial aseptic loosening in each group. TKA is an effective treatment for POA after tibial plateau fracture. We recommend the prior removal of hardware, as well as tibial tubercle osteotomy when necessary. PMID- 25795234 TI - Tibial Slope is Highly Variable in Patients Undergoing Primary Total Knee Arthroplasty: Analysis of 13,546 Computed Tomography Scans. AB - The purpose of this study was to retrospectively measure with computed tomography (CT) the posterior tibial slope (PTS) to establish the average anatomy and the incidence of outliers in patients undergoing total knee arthroplasty (TKA). Our cohort included 13,546 arthritic patients: 8241 (61%) female; 5305 (39%) male. The average PTS angle was 7.2 degrees +/-3.7 degrees (range, -5 degrees to 25 degrees ). The average of PTS angle of the males was 7.17 degrees +/-3.82 degrees and females was 7.24 degrees +/-3.57 degrees . A significant number of patients 35.0% (4149) were identified outliers in PTS. 1568 (11.6%) patients' PTS angle was less than 4 degrees , 2581 (19.1%) patients' PTS angle was more than 10 degrees . These data can be useful to determine optimum techniques and methodology to perform more accurate TKA. PMID- 25795235 TI - Airborne Exposure of Methyl Methacrylate During Simulated Total Hip Arthroplasty and Fabrication of Antibiotic Beads. AB - As the use of cement remains prevalent in orthopedic surgery, so do concerns over the safety of its active ingredient, methyl methacrylate (MMA). The Occupational Health and Safety Agency (OSHA) limits the airborne exposure to 100 parts per million (ppm) averaged over an 8 hour period. We measured MMA exposure to operating room personnel during simulated total hip arthroplasty (THA), antibiotic bead fabrication and simulated spill of MMA. Cumulative and peak exposures during simulated THA and antibiotic bead fabrication did not exceed OSHA limits of 100ppm. Vacuum mixing and greater distance from the vapor source reduced measured MMA exposure. Spilled MMA led to prolonged and elevated MMA levels. MMA levels returned to a negligible level in all scenarios by 20 minutes after mixing. PMID- 25795236 TI - Association of a characteristic membrane pattern of annexin A2 with high invasiveness and nodal status in colon adenocarcinoma. AB - The identification of tumor cells in lymph nodes is essential for the correct classification of patients with colorectal cancer who may benefit from adjuvant treatments. Proper classification of tumor stage becomes entangled by variables such as an insufficient number of lymph nodes examined, which can result in erroneous or missed diagnosis. The determination of pathologic factors in the primary tumor associated with positive lymph nodes is an area of research that has attempted to provide variables to solve this problem. In the present study, we observed that the localization of annexin A2 (AnxA2) in a cell membrane is the characteristic that distinguishes tumor cells with high invasiveness. Localization of AnxA2 expression was also studied in tissue specimens from 58 patients with invasive colorectal carcinoma (T3-T4), who had undergone colectomy with radical lymph node dissection. Interestingly, the membrane pattern observed in tumor cell lines was also identified in patient's tissue samples and allowed us to distinguish among different cell populations with the tumor. Univariate analysis showed that tumor deposits in pericolic fat, extramural vascular invasion, and amount of cells with AnxA2 membrane pattern in the tumor invasive edge had a significant influence on lymph node metastasis. On the contrary, multivariate analysis revealed that the number of cells with AnxA2 membrane pattern (P < 0.05) and tumor deposits (P < 0.05) was significantly associated with lymph node metastasis. Furthermore, AnxA2 cellular localization was observed in cell clusters that define tumor budding, and a significant association between both variables was detected. PMID- 25795237 TI - Importance of tyrosine phosphorylation in receptor kinase complexes. AB - Tyrosine phosphorylation is an important post-translational modification that is known to regulate receptor kinase (RK)-mediated signaling in animals. Plant RKs are annotated as serine/threonine kinases, but recent work has revealed that tyrosine phosphorylation is also crucial for the activation of RK-mediated signaling in plants. These initial observations have paved the way for subsequent detailed studies on the mechanism of activation of plant RKs and the biological relevance of tyrosine phosphorylation for plant growth and immunity. In this Opinion article we review recent reports on the contribution of RK tyrosine phosphorylation in plant growth and immunity; we propose that tyrosine phosphorylation plays a major regulatory role in the initiation and transduction of RK-mediated signaling in plants. PMID- 25795238 TI - Grand-scale theft: kleptoplasty in parasitic plants? AB - The angiosperm Rafflesia lives as an obligate holoparasite in intimate contact with its hosts, vines in the genus Tetrastigma. The hosts are forced to supply the parasite with all the necessary nutrients. Novel data tentatively suggest that the thievery may happen on a larger scale and include entire organellar genomes. PMID- 25795239 TI - Reply to Biersteker: When methods matter. PMID- 25795240 TI - Links that speak only some languages. PMID- 25795241 TI - Reply to Christ et al.: LQT1 and JLNS phenotypes in hiPSC-derived cardiomyocytes are due to KCNQ1 mutations. PMID- 25795242 TI - LQT1-phenotypes in hiPSC: Are we measuring the right thing? PMID- 25795243 TI - Caveats about interpretation of ancient chicken mtDNAs from northern China. PMID- 25795244 TI - Reply to Peng et al.: Archaeological contexts should not be ignored for early chicken domestication. PMID- 25795246 TI - Outcomes of acute Achilles tendon rupture repair with bone marrow aspirate concentrate augmentation. AB - PURPOSE: Optimal treatment of acute Achilles tendon ruptures remains controversial. Positive results using stem-cell-bearing concentrates have been reported with other soft-tissue repairs, but no studies exist on outcomes of bone marrow aspirate concentrate (BMAC) augmentation in primary Achilles tendon repair. METHODS: We reviewed patients with sport-related Achilles tendon ruptures treated via open repair augmented with BMAC injection from 2009 to 2011. Data on operative complications, strength, range of motion, rerupture, calf circumference and functional improvement through progressive return to sport and the Achilles tendon Total Rupture Score (ATRS) were analysed. RESULTS: A total of 27 patients (28 tendons) treated with open repair and BMAC injection were identified (mean age 38.3 +/- 9.6 years). At mean follow-up of 29.7 +/- 6.1 months, there were no reruptures. Walking without a boot was at 1.8 +/- 0.7 months, participation in light activity was at 3.4 +/- 1.8 months and 92% (25 of 27) of patients returned to their sport at 5.9 +/- 1.8 months. Mean ATRS at final follow-up was 91 (range 72-100) points. One case of superficial wound dehiscence healed with local wound care. No soft-tissue masses, bone formation or tumors were observed in the operative extremity. CONCLUSIONS: Excellent results, including no re-ruptures and early mobilisation, were observed in this small cohort with open Achilles tendon repair augmented by BMAC. No adverse outcomes of biologic treatment were observed with this protocol. The efficacy of BMAC in the operative repair of acute Achilles tendon ruptures warrants further study. LEVEL OF EVIDENCE: IV - Therapeutic. PMID- 25795247 TI - Comparative retrospective study of the direct anterior and transgluteal approaches for primary total hip arthroplasty. AB - PURPOSE: The presented retrospective study compares clinical outcomes five years after total hip arthroplasty performed through a minimally invasive direct anterior approach and a direct transgluteal lateral approach. METHODS: A total of 171 arthroplasties in 167 patients were evaluated utilizing the Harris hip score (HHS), the SF-36, a daily activity questionnaire, and the UCLA activity score. RESULTS: The average HHS showed no significant difference equalling 91.4 points in the anterior group and 92.4 in the lateral group (p = 0.952). The SF-36 physical component scores were 50.7 (anterior) and 50.0 (lateral) while the psychometric properties added up to 48.6 (anterior) and 50.3 (lateral) with no significant differences evident (p = 0.782, p = 0.071). Daily activity was found to result in 4,855 (anterior) and 5,016 (lateral) cycles, respectively (p = 0.364). No difference regarding pain sensation was determined (p = 0.859). A significant difference was found for the UCLA score, which was calculated to be 5.9 in the anterior and 6.4 in the lateral approach group (p = 0.008). CONCLUSION: In summary, our mid-term results show comparable outcomes for both approaches regarding functionality, pain, quality of life and daily activity. PMID- 25795245 TI - Association between vitamin D receptor gene polymorphisms and chronic periodontitis among Libyans. AB - BACKGROUND: Chronic periodontitis (CP) is a common oral disease characterized by inflammation in the supporting tissue of the teeth 'the periodontium', periodontal attachment loss, and alveolar bone loss. The disease has a microbial etiology; however, recent findings suggest that the genetic factors, such as vitamin D receptor (VDR) gene polymorphisms, have also been included. AIM: Investigation of the relationship between VDR gene polymorphisms and CP among Libyans. MATERIALS AND METHODS: In this study, we examined 196 unrelated Libyans between the ages of 25 and 65 years, including 99 patients and 97 controls. An oral examination based on Ramfjord Index was performed at different dental clinics in Tripoli and information were collected using a self-reported questionnaire. DNA was extracted from buccal swabs; the VDR ApaI, BsmI, and FokI polymorphisms were genotyped using polymerase chain reaction and were sequenced using Sanger Method. RESULTS: A significant difference in the newly detected ApaI SNP C/T rs#731236 was found (p=0.022), whereas no significant differences were found in ApaI SNP G/T rs#7975232, BsmI SNP A/G rs#1544410, and FokI SNP A/G rs#2228570 between patients and controls (p=0.939, 0.466, 0.239), respectively. CONCLUSION: VDR ApaI SNP C/T rs#731236 may be related to the risk of CP in the Libyan population. PMID- 25795248 TI - Functional joint line obliquity after kinematic total knee arthroplasty. AB - PURPOSE: Kinematic total knee arthroplasty (TKA) is an emerging technique, but concerns remain around the effect of implanting the prosthesis in more anatomic orientations. Native knees show variation in joint line orientation relative to the tibial mechanical axis but the joint line remains parallel to the floor when standing. This study was undertaken to evaluate joint line obliquity relative to the floor when weight-bearing after kinematic TKA to see if a similar effect occurs. METHODS: Preoperative and postoperative measurements were taken for 55 consecutive kinematically aligned TKAs, including the joint line orientation angle (JLOA), formed between the joint line and a line parallel to the floor. RESULTS: The mean medial proximal tibial angle (MPTA) was 3.4 degrees varus pre operatively (1.7 degrees valgus to 7.9 degrees varus, SD 2.0), and 3.0 degrees varus postoperatively (5.5 degrees valgus to 6.5 degrees varus, SD 2.1). The mean postoperative JLOA was 1.0 degrees varus with a smaller range than the MPTA (2.6 degrees valgus to 6 degrees varus, SD 1.9). The difference between these two measurements was significant (mean 2 degrees , SD 2.5, p < 0.001). CONCLUSIONS: Relative to the mechanical axis, 33 tibial components would be considered at risk outliers, being orientated at more than 3 degrees in varus or valgus. However, only six components were outside this range relative to the vertical, all in varus (mean 4.2 degrees ). This latter measurement may better represent how the prosthesis is functionally loaded and is similar to mechanically aligned TKAs with good survivorship. This may help explain why kinematic alignment does not lead to higher earlier failure rates that may result if similar orientations were seen with mechanically aligned TKA. PMID- 25795249 TI - Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes. AB - PURPOSE: Clinical studies in diabetic patients have demonstrated that there is a high incidence of complications in distal tibia and ankle fracture treatments. One strategy to mitigate issues with wound healing and infection in diabetic patients is to use a percutaneous technique in which autologous, bone marrow derived, concentrated cells are injected at the site of non-unions. METHODS: Eighty-six ankle non-union in diabetic patients were treated with bone marrow mesenchymal stem cells (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes of the 86 diabetic non-union patients treated with BMC were compared with 86 diabetic matched non-unions treated with a standard bone iliac crest autograft. RESULTS: Treatment with BMC promoted non union healing in 70 among 86 diabetic patients (82.1 %) with a low number of complications. Of the 86 diabetic patients treated with iliac bone graft, 53 (62.3 %) had healing; major complications were observed: 5 amputations, 11 osteonecroses of the fracture wound edge and 17 infections. CONCLUSIONS: In diabetic patients with ankle non-unions, treatment with BM-MSCs from bone marrow concentrate may be preferable in view of the high risks of major complications after open surgery and iliac bone grafting, and improved healing rates compared with standard iliac bone autograft treatment. PMID- 25795250 TI - The comparison of measurement accuracy among three different imaging modalities in evaluating elastofibroma dorsi. An analysis of 52 cases. AB - PURPOSE: Elastofibroma dorsi (ED) is a rare soft-tissue tumour. Diagnosis is made using imaging, mainly magnetic resonance due to its higher sensitivity and specificity in soft tissues. No agreement exists when deciding which imaging test must be used. Often multiple tests are made in the same patient, increasing time and costs. The aim of this paper is to compare the usual imaging exams and evaluate which one is the most accurate when diagnosing and measuring ED. METHODS: A retrospective review was made of those patients who were diagnosed and operated for ED since January 2006 to December 2013. Fifty-two ED were included (19 men, 25 women), and eight of them were bilaterally affected. They were divided into three different groups according to the imaging test used: ultrasound (US) computed tomography (CT) and magnetic resonance (MR). After surgery the pieces were sized and compared with the measurements made by imaging exams. RESULTS: Two hundred fourteen measures were analysed (40 US, 33 CT and 34 MR with their pathological equivalent). When CT group and its corresponding AP were analysed, no significant differences between them were founded (p > 0.05). Moreover, we analysed absolute differences between measures. In the US group a mean difference of 2.23 +/- 1.87 cm was obtained. In the CT group, the mean difference was 1.22 +/- 0.97 cm. Likewise, the difference of the MR group was 1.62 +/- 1.15 cm. CONCLUSIONS: This study demonstrates that the CT obtains a higher correlation than MR when determining the size of ED. PMID- 25795251 TI - A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib. AB - Recovery of mitogen activated protein kinase (MAPK) or activation of alternative pathways, such as the PI3K/AKT/mTOR, are involved in acquired resistance to BRAF inhibitors which represent the first-line treatment of BRAF-mutated metastatic melanoma. We recently demonstrated that 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4 yl)thio)hexan-1-ol (NBDHEX) and its water soluble analog 2-(2-(2-((7 nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol (MC3181) trigger apoptosis in BRAF V600E mutated melanoma cells through activation of the MAPK c Jun N-terminal kinase (JNK). Herein, we investigated whether NBDHEX and MC3181 might exert antitumor activity against BRAF V600E mutated human melanoma cells rendered resistant to the BRAF inhibitor vemurafenib. To this aim we generated a subline of A375 melanoma resistant in vitro and in vivo to vemurafenib (A375-VR8) and characterized by NRAS G13R mutation, high basal levels of CRAF protein and phospho-activation of AKT. In these cells ERK phosphorylation was not significantly down-modulated by vemurafenib concentrations capable of abrogating ERK phosphorylation in sensitive A375 cells. Both NBDHEX and MC3181 induced marked antiproliferative and apoptotic effects in A375-VR8 cells and, at equitoxic concentrations, caused a strong phosphorylation of JNK, p38, and of the downstream mediators of apoptosis ATF2 and p53. Drug treatment further increased ERK phosphorylation, which was required for the cellular response to the NBD derivatives, as apoptosis was antagonized by the ERK inhibitor FR180204. Finally, in vivo administration of MC3181 provoked JNK activation at the tumor site and markedly reduced A375-VR8 growth. These evidences strongly suggest that the activation of multiple pro-apoptotic MAPK pathways by MC3181 might represent a new strategy for the treatment of melanoma resistant to BRAF inhibitors. PMID- 25795252 TI - Dose-volume analysis and the temporal nature of toxicity with stereotactic body radiation therapy for prostate cancer. AB - PURPOSE: The purpose of this study was to evaluate the dose-volume relationships of genitourinary toxicity after stereotactic body radiation therapy (SBRT) monotherapy for prostate cancer. METHODS AND MATERIALS: Fifty-six patients diagnosed with low- to intermediate-risk prostate cancer treated with SBRT alone were reviewed retrospectively. All patients received a total dose of 38 Gy in 4 fractions with a planning target volume expansion of 2 mm. Overall, acute, and late genitourinary toxicity were documented according to the Common Terminology Criteria for Adverse Events (version 4) and International Prostate Symptom Scores (IPSS). RESULTS: The median age at treatment was 68 years, and the median prostate volume was 45.5 mL, with a median baseline IPSS of 9.95. The median prescription isodose line was 68%. The median clinical follow-up was 35.49 months. Acute grade 1, 2, and 3 genitourinary toxicities occurred in 41.1%, 35.7%, and 0% of patients. All acute genitourinary toxicities resolved except 1 patient with grade 2 toxicity that progressed to grade 3 late toxicity. No dose volume relationships were associated with acute genitourinary grade 2+ toxicity. Late grade 1, 2, and 3 genitourinary toxicity occurred in 19.6%, 19.6%, and 3.6% of cases, respectively. Of the cases with late toxicities, 16.7% were persistent. Late grade 2+ genitourinary toxicity was associated with prostate volume >=50 mL, lower homogeneity index, and urethral maximum point dose >=47 Gy. The overall risk of any grade 2+ genitourinary toxicity was associated with baseline IPSS >7, prostate volume >=50 mL, urethral volume receiving 44 Gy, and bladder volume receiving 19 Gy. CONCLUSIONS: SBRT for prostate cancer appears well tolerated, with mostly transient low-grade toxicity. Urethral sparing should be used with a maximum point dose <47 Gy, volume receiving 120 Gy <50% of the prostate, and bladder volume receiving 19 Gy <15 mL in 4 fraction treatments. Patients with prostate volumes >=50 mL should be counseled regarding the increased risk of moderate-grade genitourinary toxicity. PMID- 25795253 TI - Species differences in bumblebee immune response predict developmental success of a parasitoid fly. AB - Endoparasitoids develop inside the body of a host organism and, if successful, eventually kill their host in order to reach maturity. Host species can vary in their suitability for a developing endoparasitoid; in particular, the host immune response, which can suppress egg hatching and larval development, has been hypothesized to be one of the most important determinants of parasitoid host range. In this study, we investigated whether three bumblebee host species (Bombus bimaculatus, Bombus griseocollis, and Bombus impatiens) varied in their suitability for the development of a shared parasitoid, the conopid fly (Conopidae, Diptera) and whether the intensity of host encapsulation response, an insect immune defense against invaders, could predict parasitoid success. When surgically implanted with a nylon filament, B. griseocollis exhibited a stronger immune response than both B. impatiens and B. bimaculatus. Similarly, B. griseocollis was more likely to melanize conopid larvae from natural infections and more likely to kill conopids prior to its own death. Our results indicate that variation in the strength of the general immune response of insects may have ecological implications for sympatric species that share parasites. We suggest that, in this system, selection for a stronger immune response may be heightened by the pattern of phenological overlap between local host species and the population peak of their most prominent parasitoid. PMID- 25795255 TI - Vaginal Cuff Dehiscence After Total Laparoscopic Hysterectomy. PMID- 25795254 TI - Cargo adaptors: structures illuminate mechanisms regulating vesicle biogenesis. AB - Cargo adaptors sort transmembrane protein cargos into nascent vesicles by binding directly to their cytosolic domains. Recent studies have revealed previously unappreciated roles for cargo adaptors and regulatory mechanisms governing their function. The adaptor protein (AP)-1 and AP-2 clathrin adaptors switch between open and closed conformations that ensure they function at the right place at the right time. The exomer cargo adaptor has a direct role in remodeling the membrane for vesicle fission. Several different cargo adaptors functioning in distinct trafficking pathways at the Golgi are similarly regulated through bivalent binding to the ADP-ribosylation factor 1 (Arf1) GTPase, potentially enabling regulation by a threshold concentration of Arf1. Taken together, these studies highlight that cargo adaptors do more than just adapt cargos. PMID- 25795256 TI - A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: Results of a phase 2 randomized, controlled trial. AB - BACKGROUND: A meningococcal vaccine protective against all major disease associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM. METHODS: A total of 484 healthy 10-25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters. RESULTS: Seroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90-92% vs. 73%; C: 93-95% vs. 63%; W: 80-84% vs. 65%; and Y: 90-92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported. CONCLUSIONS: Both investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified. PMID- 25795257 TI - C-reactive protein response to influenza vaccination as a model of mild inflammatory stimulation in the Philippines. AB - BACKGROUND: C-reactive protein (CRP) is increasingly measured as a marker of systemic inflammation that predicts elevated risk for cardiovascular disease. Influenza vaccination is a mild pro-inflammatory stimulus, and the CRP response to vaccination may provide additional information on individual differences in inflammatory response and risk for disease. AIM: To document the pattern of CRP response to influenza vaccination among a large sample of older women in the Philippines. The Philippines exemplifies current global trends toward increasing rates of overweight/obesity, but also maintains relatively high rates of infectious disease. The secondary aim of the study is to investigate the impact of infectious symptoms on the pattern of response to vaccination. METHODS: A community-based sample of 934 women (mean age=55.4 years) received the influenza vaccine. CRP was assessed at baseline and 72h post-vaccination. Descriptive, non parametric, and parametric analyses were implemented to assess the magnitude of CRP response, and to investigate whether responses were associated with baseline CRP or the presence of infectious symptoms prior to vaccination. RESULTS: Influenza vaccination resulted in a statistically significant CRP response of 0.35mg/L (p<0.001), representing a 30.2% increase from baseline. For individuals with symptoms of infectious disease at baseline, the CRP response was smaller (12.9%) and not statistically significant (p=0.77). Lower CRP at baseline was associated with larger CRP response to vaccination in the entire sample, and among participants without recent symptoms of infection. CONCLUSIONS: Influenza vaccination produces a mild CRP response in the Philippines. This study extends prior research in US and European populations validating influenza vaccination as an in vivo model for investigating the dynamics of inflammation, but also raises potential complications in settings where rates of infectious disease are elevated. PMID- 25795258 TI - Effectiveness and impact of rotavirus vaccines in Europe, 2006-2014. AB - Prior to the introduction of rotavirus vaccines in 2006, rotavirus was the leading cause of severe gastroenteritis among European children <5 years of age. We conducted a systematic review of the published literature to examine the effectiveness and impact of rotavirus vaccines in Europe following the first eight years of routine use. Four publication databases were searched, yielding 276 unique citations from February 1st, 2006 to July 31st, 2014. Twenty four studies on effectiveness (n=9) and impact (n=15) met the inclusion criteria. Across Europe, vaccine effectiveness against rotavirus-related healthcare utilisation ranged from 68% to 98%, consistent with efficacy data from clinical trials. Reductions in rotavirus hospitalisations ranged from 65% to 84%, consistent with findings from post-marketing studies from the US and Latin America. We confirm the significant public health benefit of rotavirus vaccination in Europe and provide further evidence to support implementation of universal rotavirus vaccination in all European countries. PMID- 25795259 TI - Hydrogen sulphide induces HIF-1alpha and Nrf2 in THP-1 macrophages. AB - The transcription factor HIF-1alpha regulates the adaptive response of cells to hypoxia and oxidative stress. In addition, an important regulatory role for HIF 1alpha in immune reactions and inflammation is suggested. The present study attempts to investigate the effect of the gaseous signalling molecule hydrogen sulphide (H2S) on HIF-1alpha in THP-1 macrophages using the slow H2S releasing donor GYY4137. We found that H2S induced HIF-1alpha protein accumulation in THP-1 macrophages in a concentration-dependent manner. Western blot analysis of cell fractions showed that HIF-1alpha protein translocates into the nucleus and leads to an increase of its target protein glucose transporter-1 (GLUT-1). Activation of nuclear factor-kappaB (NF-kappaB), as well as secretion of the pro inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were reduced in the presence of H2S. These findings indicate that HIF 1alpha accumulation due to H2S was not triggered by the NF-kappaB pathway. The antioxidant pathway Nrf2/HO-1 (nuclear factor erythroid 2-related factor 2/heme oxygenase-1) was activated by H2S. Inhibition of the p38 mitogen-activated protein kinase (MAPK) reversed H2S mediated effects, suggesting that the p38 MAPK pathway may be involved in H2S induced HIF-1alpha/Nrf2 signalling pathways. PMID- 25795260 TI - [Peripheral artery disease and acute coronary syndrome]. AB - Peripheral arterial disease is a common manifestation of systemic atherosclerosis that is associated with increased cardiovascular risk. When presented in the context of an acute coronary syndrome a differential diagnosis with aorta dissection should be made, because peripheral arterial disease may be asymptomatic despite the absence or asymmetry of femoral pulses. PMID- 25795261 TI - [Pregnancy and coronary artery dissection]. AB - Acute myocardial infarction during pregnancy is associated with high maternal and fetal mortality. Coronary atherosclerosis is the most common cause due to an increase in the age of the patients and the association with cardiovascular risk factors such as smoking, hypertension, diabetes mellitus, preeclampsia, and the existence of family history of coronary disease. However, thrombosis, coronary dissection or coronary vasospasms are other causes that may justify it. We report the case of a 33 weeks pregnant first-time mother, without cardiovascular risk factors, who presented an acute coronary event in the context of atherosclerotic disease and coronary dissection after percutaneous coronary intervention. PMID- 25795262 TI - Geographic disparities amongst patients with gynecologic malignancies at an urban NCI-designated cancer center. AB - OBJECTIVE: Women with gynecologic malignancies require specialized care. We hypothesize that a geographic disparity exists amongst patients with gynecologic malignancies and that longer distance and time traveled negatively impact completion of adjuvant therapy. METHODS: Patients with incident gynecologic malignancies at a single, urban NCI-designated cancer center were identified. Distances from the patient's home to the treating facility were calculated in miles and minutes. Demographic variables were evaluated for their impact on treatment outcomes using Chi-squared, ANOVA and Kruskal-Wallis analyses. RESULTS: One hundred and fifty consecutive patients were identified. The median distance traveled to the hospital was 16.9miles with a median travel time of 28min. The distance and time traveled were significantly different between insurance groups, with the uninsured traveling the furthest for care by distance (p=0.04) and time (p=0.03). Race, tumor site, medical comorbidities and median income at zip code were not associated with travel distance or time to the hospital. The majority of patients (87%) completed recommended initial treatment. Treatment completion was related to distance traveled with those patients living at the distance extremes (<10miles or >50miles) least likely to complete care (p<0.01). The presence of medical comorbidities (p<0.01) but not insurance status was correlated to treatment completion. CONCLUSIONS: Geographic disparities exist in women with gynecologic malignancies receiving treatment at an NCI-designated cancer center. Approaches to decreasing these disparities may include improved support for cancer patients needing assistance with travel and additional social work and psychosocial support to patients with medical co-morbidities. PMID- 25795263 TI - Tunable diffusive lateral inhibition in chemical cells. AB - The Belousov-Zhabotinsky (BZ) reaction has become the prototype of nonlinear chemical dynamics. Microfluidic techniques provide a convenient method for emulsifying BZ solutions into monodispersed drops with diameters of tens to hundreds of microns, providing a unique system in which reaction-diffusion theory can be quantitatively tested. In this work, we investigate monolayers of microfluidically generated BZ drops confined in close-packed two-dimensional (2D) arrays through experiments and finite element simulations. We describe the transition from oscillatory to stationary chemical states with increasing coupling strength, controlled by independently varying the reaction chemistry within a drop and diffusive flux between drops. For stationary drops, we studied how the ratio of stationary oxidized to stationary reduced drops varies with coupling strength. In addition, using simulation, we quantified the chemical heterogeneity sufficient to induce mixed stationary and oscillatory patterns. PMID- 25795264 TI - Effect of dynamic seeding methods on the distribution of fibroblasts within human acellular dermis. AB - The purpose of this investigation was to compare different dynamic cell seeding methods regarding their seeding efficiency, homogeneity, infiltration depth and proliferation within a human acellular dermis. In addition, the growth behaviour was observed during a 12-day static in vitro culture. The dynamic methods included orbital-shaker seeding and the use of a plate centrifuge with different rotational speeds, combinations of low-pressure for matrix degassing and centrifugal seeding. Scaffolds were incubated for up to 12 days statically. Cell distribution and infiltration depth were analysed histologically at days 0, 4, 8 and 12. Seeding efficiency and cell proliferation were quantified with the MTT assay at the same time points. Centrifugal seeding with 300g for 5 * 1 min combined with matrix degassing significantly increased the seeding efficiency and homogeneity compared to the other methods. However, following static culture, no cells were detectable after 4 days in the inner matrix zones. Furthermore, none of the degassing+centrifugation groups reached a significantly higher proliferation at day 8 compared to the reference. The use of a single dynamic method resulted in an inefficient cell seeding. We archived the highest seeding efficiency, homogeneity and infiltration depth using a combination of degassing+centrifugation at 300g for 5 * 1 min. PMID- 25795265 TI - Deep brain stimulation for psychiatric diseases: what are the risks? AB - Despite the application of deep brain stimulation (DBS) as an efficient treatment modality for psychiatric disorders, such as obsessive-compulsive disorder (OCD), Gilles de la Tourette Syndrome (GTS), and treatment refractory major depression (TRD), few patients are operated or included in clinical trials, often for fear of the potential risks of an approach deemed too dangerous. To assess the surgical risks, we conducted an analysis of publications on DBS for psychiatric disorders. A PubMed search was conducted on reports on DBS for OCD, GTS, and TRD. Forty-nine articles were included. Only reports on complications related to DBS were selected and analyzed. Two hundred seventy-two patients with a mean follow up of 22 months were included in our analysis. Surgical mortality was nil. The overall mortality was 1.1 %: two suicides were unrelated to DBS and one death was reported to be unlikely due to DBS. The majority of complications were transient and related to stimulation. Long-term morbidity occurred in 16.5 % of cases. Three patients had permanent neurological complications due to intracerebral hemorrhage (2.2 %). Complications reported in DBS for psychiatric diseases appear to be similar to those reported for DBS in movement disorders. But class I evidence is lacking. Our analysis was based mainly on small non-randomized studies. A significant number of patients (approximately 150 patients) who were treated with DBS for psychiatric diseases had to be excluded from our analysis as no data on complications was available. The exact prevalence of complications of DBS in psychiatric diseases could not be established. DBS for psychiatric diseases is promising, but remains an experimental technique in need of further evaluation. A close surveillance of patients undergoing DBS for psychiatric diseases is mandatory. PMID- 25795266 TI - Sexsomnia: sleep sex research and its legal implications. AB - "Sleep sex," also known as sexsomnia, is a sleep disorder characterized by sexual behaviors committed while asleep. There has recently been increased interest in sexsomnia due to controversies arising in legal trials that have been widely publicized in the social and public media. This article attempts to marshal the current information about sexsomnia from the forensic literature and provides an overview of sexsomnia including common features, precipitating factors, prevalence rates, diagnostic procedures, and treatment. As sexsomnia represents a condition in which sexual acts are committed without awareness or intention, this paper also reviews the development of sexsomnia as a legal defense and summarizes Canadian case law on the topic. It provides an overview of the hurdles presented to defense attorneys attempting to utilize the defense and examines popular public notions surrounding the legitimacy of sexsomnia and the possibility of malingering. We conclude that sexsomnia is a legitimate sleep disorder for which case law now exists to support its use in legal defenses based on automatism. The question of whether it is an example of "sane" or "insane" automatism remains to be determined by the courts. Regardless of whether or not sexsomnia is determined to be a mental disorder by the courts, it is now a recognized and well-described sleep disorder that can be safely treated and managed by knowledgeable clinicians. PMID- 25795267 TI - A case of Crohn's disease that developed anti-infliximab and anti-adalimumab antibodies. AB - There are few reports about the rapid appearance of anti-adalimumab antibodies in patients with Crohn's disease positive for anti-infliximab antibodies. We report the case of a 29-year-old female patient with a diagnosis of Crohn's disease who revealed a loss of response to infliximab due to high levels of antibodies to infliximab, and did not respond to the subsequent therapy by adalimumab, with a rapid appearance of antibodies to adalimumab. As one of the possible mechanisms of non-response to adalimumab, immunologic reactivity of infliximab to adalimumab was suspected, since the patient's IgG that was obtained just before the induction of adalimumab reacted with infliximab and adalimumab. We should pay attention to the easy appearance of anti-adalimumab antibodies in association with reactivity of anti-infliximab antibodies to adalimumab in patients with high levels of anti-infliximab antibodies. PMID- 25795268 TI - Quality of antenatal care as a risk factor for early onset neonatal infections in Rio de Janeiro, Brazil. AB - BACKGROUND: Neonatal infection is a serious public health problem. The aim of this study was to assess the influence of the antenatal care on the risk of early onset neonatal healthcare associated infection in two Brazilian maternities. METHODS: Cohort study - Newborns admitted at two public neonatal intensive care units from 2008 to 2009 were included in the study. Data on antenatal and perinatal variables were collected from maternal prenatal cards and medical charts. Newborns were actively surveyed for early-onset neonatal healthcare associated infection, defined as a neonatal infection diagnosed within 48h after birth. Multiple logistic regression was used to assess variables independently associated with early-onset neonatal healthcare associated infection. RESULTS: 561 neonate-mother pairs were included in the study. Early-onset neonatal healthcare associated infection was diagnosed in 283 neonates (51%), an incidence rate of 43.5/1000 live births. Neonates whose mothers had less then six antenatal visits were under risk significantly higher for early-onset neonatal healthcare associated infection (OR=1.69, 95% CI=1.11-2.57), after adjusting for birth weight, membranes ruptured for >18h, maternal complications during delivery, maternal infection at admission, and hospital where patients received care. CONCLUSIONS: The risk of neonatal early-onset neonatal healthcare associated infection was significantly associated with insufficient number of antenatal care visits. Further studies assessing the quality of antenatal care and targeting its improvement are warranted. PMID- 25795269 TI - A multi-scale finite element model for investigation of chondrocyte mechanics in normal and medial meniscectomy human knee joint during walking. AB - Mechanical signals experienced by chondrocytes (articular cartilage cells) modulate cell synthesis and cartilage health. Multi-scale modeling can be used to study how forces are transferred from joint surfaces through tissues to chondrocytes. Therefore, estimation of chondrocyte behavior during certain physical activities, such as walking, could provide information about how cells respond to normal and abnormal loading in joints. In this study, a 3D multi-scale model was developed for evaluating chondrocyte and surrounding peri- and extracellular matrix responses during gait loading within healthy and medial meniscectomy knee joints. The knee joint geometry was based on MRI, whereas the input used for gait loading was obtained from the literature. Femoral and tibial cartilages were modeled as fibril-reinforced poroviscoelastic materials, whereas menisci were considered as transversely isotropic. Fluid pressures in the chondrocyte and cartilage tissue increased up to 2MPa (an increase of 30%) in the meniscectomy joint compared to the normal, healthy joint. The elevated level of fluid pressure was observed during the entire stance phase of gait. A medial meniscectomy caused substantially larger (up to 60%) changes in maximum principal strains in the chondrocyte compared to those in the peri- or extracellular matrices. Chondrocyte volume or morphology did not change substantially due to a medial meniscectomy. Current findings suggest that during walking chondrocyte deformations are not substantially altered due to a medial meniscectomy, while abnormal joint loading exposes chondrocytes to elevated levels of fluid pressure and maximum principal strains (compared to strains in the peri- or extracellular matrices). These might contribute to cell viability and the onset of osteoarthritis. PMID- 25795270 TI - Stem cell comparison: what can we learn clinically from unrelated cord blood transplantation as an alternative stem cell source? AB - Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic option for a variety of malignant and non-malignant disorders (NMD). The use of umbilical cord blood transplantation (UCBT) has made HCT available to many more patients. The increased level of human leukocyte antigen disparity that can be tolerated makes UCBT a very attractive alternative source of hematopoietic stem cells; however, the increased risk of early death observed after UCBT remains an obstacle. Novel strategies such as ex vivo stem cell expansion are now becoming part of the standard clinical approach, and preliminary results are extremely encouraging with suggestion of reduction of early transplant-related mortality. Although there are no randomized studies that compare the risks and benefits of UCBT relative to those observed with related and unrelated donors both for malignant and NMD, several retrospective studies have compared outcomes between UCBT and other stem cell sources. In this review, we aim to describe and summarize the findings of the principal studies in this field. We hope that what we can learn from these studies and how we can use this information will improve the outcomes of HCT for patients with malignant and NMD. PMID- 25795272 TI - Umbilical cord blood-derived cellular products for cancer immunotherapy. AB - Although the vast majority of experience with umbilical cord blood (CB) centers on hematopoietic reconstitution, a recent surge in the knowledge of CB cell subpopulations as well as advances in ex vivo culture technology have expanded the potential of this rich resource. Because CB has the capacity to generate the entire hematopoietic system, we now have a new source for natural killer, dendritic and T cells for therapeutic use against malignancies. This Review will focus on cellular immunotherapies derived from CB. Expansion techniques, ongoing clinical trials and future directions for this new dimension of CB application are also discussed. PMID- 25795271 TI - Placenta-based therapies for the treatment of epidermolysis bullosa. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering skin disease caused by mutations in the COL7A1 gene. These mutations lead to decreased or absent levels of collagen VII at the dermal-epidermal junction. Over the past decade, significant progress has been made in the treatment of RDEB, including the use of hematopoietic cell transplantation, but a cure has been elusive. Patients still experience life-limiting and life-threatening complications as a result of painful and debilitating wounds. The continued suffering of these patients drives the need to improve existing therapies and develop new ones. In this Review, we will discuss how recent advances in placenta-based, umbilical cord blood-based and amniotic membrane-based therapies may play a role in the both the current and future treatment of RDEB. PMID- 25795273 TI - C-peptide immunoreactivity index is associated with improvement of HbA1c: 2-Year follow-up of sitagliptin use in patients with type 2 diabetes. AB - AIMS: This retrospective study aimed to determine the hypoglycaemic effect of 2 years of sitagliptin administration in terms of changes in HbA1c and C-peptide immunoreactivity (CPR) index (plasma CPR [ng/mL]/glucose [mg/dL]*100). METHODS: The inclusion criteria for DPP-4 inhibitor-naive outpatients with type 2 diabetes (n=285) were: continuation of sitagliptin for >=700 days from initial administration and measurement of HbA1c, serum CPR, and plasma glucose levels at 0, 3, 6, 12, 18, and 24 months after sitagliptin initiation. Logistic regression analyses determined the factors contributing to the response to sitagliptin, based on responder (DeltaHbA1c <=-0.4% [<=-4 mmol/mol]) and non-responder (DeltaHbA1c >-0.4% [>-4 mmol/mol]) groups. RESULTS: The HbA1c level decreased and CPR index increased from baseline to 3, 6, 12, 18, and 24 months after the start of sitagliptin administration (HbA1c: 7.4 +/- 0.8% [57 +/- 9 mmol/mol], 7.3 +/- 0.9% [57 +/- 9 mmol/mol], 7.4 +/- 0.9% [58 +/- 10 mmol/mol], 7.1 +/- 0.8% [55 +/- 9 mmol/mol], and 7.3 +/- 0.9% [57 +/- 10 mmol/mol], respectively, all P<0.001 vs. baseline [8.0 +/- 1.0%, 64 +/- 11 mmol/mol] and CPR index: 1.69 +/- 0.96, 1.71 +/ 1.10, 1.62 +/- 0.96, 1.64 +/- 0.92, and 1.66 +/- 0.96, respectively, all P<0.05 vs. baseline [1.47 +/- 0.81]). Higher baseline HbA1c level, shorter diabetes duration, and greater CPR index increase after sitagliptin administration were associated with the response to sitagliptin. CONCLUSIONS: Our results suggest that sitagliptin improves glycaemic control via an improved intrinsic insulin response. PMID- 25795274 TI - Morphological evolution and reconstruction of silver nanoparticles in aquatic environments: the roles of natural organic matter and light irradiation. AB - With the proliferation of silver nanoparticles (AgNPs), their potential entry into the environment has attracted increasing concern. Although photochemical transformation is an important fate of AgNPs in aquatic environments due to their strong light absorption, little is known about the evolution and transformation mechanisms of AgNPs. This study investigated the morphological evolution and reconstruction of AgNPs during photoconversion in the presence of natural organic matter (NOM). In the dark, the AgNPs formed chain-like structures through bridging effects with NOM at concentrations of 0.1 and 1 mg/L, and the proportion of Ag(+) in solution in the presence of 10 mg/L NOM was reduced by roughly half compared with that in the absence of NOM. Under irradiation, NOM participated in the photoreaction of AgNPs and can decelerate the photoreaction of AgNPs via several mechanisms, including light attenuation, the formation of a NOM coating, and competing with Ag for photons. Additionally, NOM can substitute for citrate as a stabilizing agent to compensate for the loss of AgNP stability due to citrate mineralization under extended irradiation, producing stable triangular nanosilver in aquatic environments. This study sheds light on the behavioral differences of AgNPs in different aquatic systems, which create uncertainties and difficulties in assessing the environmental risks of AgNPs. PMID- 25795275 TI - Removal of gas phase low-concentration toluene over Mn, Ag and Ce modified HZSM-5 catalysts by periodical operation of adsorption and non-thermal plasma regeneration. AB - Ag/HZSM-5, Mn/HZSM-5, Ce/HZSM-5, Ag-Mn/HZSM-5 and Ce-Mn/HZSM-5 were prepared by impregnation method. Both their adsorption capacity and catalytic activity were investigated for the removal of gas phase low-concentration toluene by periodical operation of adsorption and non-thermal plasma regeneration. Results show that catalysts loaded with Ag (Ag/HZSM-5 and Ag-Mn/HZSM-5) had larger adsorption capacity for toluene than the other catalysts. And Ag-Mn/HZSM-5 displayed the best catalytic performance for both toluene oxidation by non-thermal plasma and byproducts suppression. On the other hand, the deactivated catalyst can be fully regenerated by calcining in air stream when its adsorption capacity and catalytic activity of the Ag-Mn/HZSM-5 catalyst was found to be decreased after 10 cycles of periodical adsorption and non-thermal regeneration. PMID- 25795276 TI - Verbal and nonverbal predictors of language-mediated anticipatory eye movements. AB - During language comprehension, listeners often anticipate upcoming information. This can draw listeners' overt attention to visually presented objects before the objects are referred to. We investigated to what extent the anticipatory mechanisms involved in such language-mediated attention rely on specific verbal factors and on processes shared with other domains of cognition. Participants listened to sentences ending in a highly predictable word (e.g., "In 1969 Neil Armstrong was the first man to set foot on the moon") while viewing displays containing three unrelated distractor objects and a critical object, which was either the target object (e.g., a moon), an object with a similar shape (e.g., a tomato), or an unrelated control object (e.g., rice). Language-mediated anticipatory eye movements were observed to targets and to shape competitors. Importantly, looks to the shape competitor were systematically related to individual differences in anticipatory attention, as indexed by a spatial cueing task: Participants whose responses were most strongly facilitated by predictive arrow cues also showed the strongest effects of predictive language input on their eye movements. By contrast, looks to the target were related to individual differences in vocabulary size and verbal fluency. The results suggest that verbal and nonverbal factors contribute to different types of language-mediated eye movements. The findings are consistent with multiple-mechanism accounts of predictive language processing. PMID- 25795277 TI - Wildlife forensic science: A review of genetic geographic origin assignment. AB - Wildlife forensic science has become a key means of enforcing legislation surrounding the illegal trade in protected and endangered species. A relatively new dimension to this area of forensic science is to determine the geographic origin of a seized sample. This review focuses on DNA testing, which relies on assignment of an unknown sample to its genetic population of origin. Key examples of this are the trade in timber, fish and ivory and these are used only to illustrate the large number of species for which this type of testing is potentially available. The role of mitochondrial and nuclear DNA markers is discussed, alongside a comparison of neutral markers with those exhibiting signatures of selection, which potentially offer much higher levels of assignment power to address specific questions. A review of assignment tests is presented along with detailed methods for evaluating error rates and considerations for marker selection. The availability and quality of reference data are of paramount importance to support assignment applications and ensure reliability of any conclusions drawn. The genetic methods discussed have been developed initially as investigative tools but comment is made regarding their use in courts. The potential to compliment DNA markers with elemental assays for greater assignment power is considered and finally recommendations are made for the future of this type of testing. PMID- 25795278 TI - Chromosomal localization of 45S rDNA, sex-specific C values, and heterochromatin distribution in Coccinia grandis (L.) Voigt. AB - Coccinia grandis is a widely distributed dioecious cucurbit in India, with heteromorphic sex chromosomes and X-Y sex determination mode. The present study aids in the cytogenetic characterization of four native populations of this plant employing distribution patterns of 45S rDNA on chromosomes and guanine-cytosine (GC)-rich heterochromatin in the genome coupled with flow cytometric determination of genome sizes. Existence of four nucleolar chromosomes could be confirmed by the presence of four telomeric 45S rDNA signals in both male and female plants. All four 45S rDNA sites are rich in heterochromatin evident from the co-localization of telomeric chromomycin A (CMA)(+ve) signals. The size of 45S rDNA signal was found to differ between the homologues of one nucleolar chromosome pair. The distribution of heterochromatin is found to differ among the male and female populations. The average GC-rich heterochromatin content of male and female populations is 23.27 and 29.86 %, respectively. Moreover, the male plants have a genome size of 0.92 pg/2C while the female plants have a size of 0.73 pg/2C, reflecting a huge genomic divergence between the genders. The great variation in genome size is owing to the presence of Y chromosome in the male populations, playing a multifaceted role in sexual divergence in C. grandis. PMID- 25795280 TI - Effectiveness of Platelet-Rich Plasma to Enhance Healing of Diabetic Foot Ulcers in Patients With Concomitant Peripheral Arterial Disease and Critical Limb Ischemia. AB - We sought to investigate the effect of autologous platelet-rich plasma (PRP) on the healing rate of diabetic foot ulcers in patients with diabetes and concomitant peripheral arterial disease (PAD). Diabetic patients with foot ulceration presenting with PAD who were treated with local growth factors in a single center, during a 24-month period from May 2009 to April 2011, were retrospectively reviewed. Based on the severity of PAD, subjects were divided into groups A (Fontaine classification stages I, IIa, and IIb) and B (Fontaine classification stages III and IV), with those included in the latter being considered to suffer from critical limb ischemia (CLI). End points of the analysis were clinical improvement, limb salvage, and amputation rate. Outcome was compared between groups A and B. Overall, 72 patients were evaluated, 30 with CLI. Ulcer area reduction >50% was observed in 58/72 patients while reduction >90% was achieved in 52/72 patients. There were 14 (19%) major and minor amputations, whereas the limb salvage rate was 89%. This variable was significantly different between groups A and B (100% vs. 73%, P < .001), as is rate of reduction in ulcer area >90% (83% vs. 56%, P = .02). Reduction of ulcer area >50% was observed in the majority of patients in both groups (group A 86% vs. group B 73%, P = .23). In conclusion, PRP could serve as a useful adjunct during management of diabetic foot ulcers even in diabetic patients with unreconstructable arterial disease. PMID- 25795279 TI - Effects of the Four-Herb Compound ANBP on Wound Healing Promotion in Diabetic Mice. AB - Wound healing is a troublesome problem in diabetic patients. Besides, there is also an increased risk of postsurgical wound complications for diabetic patient. It has been revealed that traditional Chinese medicine may promote healing and inhibit scar formation, while the changes of morphology and physiology of wounds on such medicine treatment still remain elusive. In this study, we first used the ultralow temperature preparation method to produce mixed superfine powder from Agrimonia pilosa (A), Nelumbo nucifera (N), Boswellia carteri (B), and Pollen typhae (P), named as ANBP. Applying ANBP on 40 streptozotocin (STZ)-induced diabetic C57BL/6 mice (4-6 weeks, 20 +/- 2 g), we observed that the wound healing process was accelerated and the wound healing time was shortened (14 days, P < .05). Pathological observation using hematoxylin-eosin staining indicated that inflammatory cells were reduced (P < .05) while the thickness of granulation tissue and length of epithelial tongue were increased (P < .05). The vascular density was increased on 7 and 14 days after ANBP treatment. Masson and Sirius red staining showed that, at the early stage of trauma, the expressions of Col I and Col III, especially Col III, were increased in the ANBP group (P < .05). Studies in vitro demonstrated that tubular formation was significantly increased after ANBP treatment on human vascular endothelial cells in a dose-dependent way. Taken together, our studies revealed that ANBP treatment could accelerate wound healing, promote vascularization, and inhibit inflammation, suggesting the potential clinic application of ANBP for diabetes mellitus and refractory wounds. PMID- 25795281 TI - Morphological and molecular characterization of Eimeria haematodi, coccidian parasite (Apicomplexa: Eimeriidae) in a rainbow lorikeet (Trichoglossus haematodus). AB - Eimeria haematodi was first described in 1977 from the rainbow lorikeet (Trichoglossus haematodus) in Papua New Guinea. In the present study, we re describe this coccidian species morphologically and molecularly from a rainbow lorikeet bird in Western Australia (WA). The oocysts were ovoid to slightly piriform and measured 28.5-37.8 by 25.8-33.0 um (33.3 by 28.1 um). Oocyst wall was approximately 1.5 um thick and bilayered. Micropyle (5-7 um) and oocyst residuum (8.0-10.0 um) present; polar granule was absent. Sporocysts ellipsoidal, 11.8-13.6 by 8.0-9.6 um (12.2 by 8.3 um), with thin convex Stieda body and granular sporocyst residuum (4.0-5.0 um). Molecular characterization of E. haematodi was conducted at 18S ribosomal RNA and the mitochondrial cytochrome oxidase gene (COI) loci. At the 18S ribosomal RNA locus, E. haematodi shared 98.1% genetic similarity to E. alabamensis from cattle in New South Wales, Australia. At COI locus, E. haematodi was closest (92.3% similarity) to E. praecox from domestic chickens (Gallus gallus domesticus) from Canada and China. PMID- 25795283 TI - Effects of high-fat diet on salivary alpha-amylase, serum parameters and food consumption in rats. AB - Salivary alpha-amylase, a major protein in saliva, has been described as a marker of sympathetic nervous system activity, hence for metabolic energy balance. In this context, its expression in overweight and obesity is of interest. Rats fed with a diet enriched with sunflower oil differentially gained weight yielding two subgroups according to their susceptibility (OP) or resistance (OR) to obesity. Elevated plasmatic levels of leptin in the OP subgroup and altered plasmatic lipid profiles (lower triglycerides and higher total cholesterol/high-density lipoprotein (HDL) ratio compared to controls) in the OR subgroup were observed. Animals from the OP subgroup presented higher alpha-amylase expression and activity even prior to the dietary treatment, suggesting that this salivary protein may constitute a putative indicator of susceptibility for fat tissue accumulation. After 18 weeks of high-fat diet consumption, salivary alpha-amylase levels did not significantly change in the OP subgroup, but increased 3-fold in the OR subgroup. The increase in alpha-amylase levels for the latter might represent an adaptation to lower starch intake. These results suggest that salivary alpha-amylase secretion might be useful to predict susceptibility for weight gain induced by high-fat diet consumption. PMID- 25795282 TI - Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer. AB - Breast cancer metastasis is the leading cause of cancer-related deaths in women worldwide. Collagen in the tumor microenvironment plays a crucial role in regulating tumor progression. We have shown that type III collagen (Col3), a component of tumor stroma, regulates myofibroblast differentiation and scar formation after cutaneous injury. During the course of these wound-healing studies, we noted that tumors developed at a higher frequency in Col3(+/-) mice compared to wild-type littermate controls. We, therefore, examined the effect of Col3 deficiency on tumor behavior, using the murine mammary carcinoma cell line 4T1. Notably, tumor volume and pulmonary metastatic burden after orthotopic injection of 4T1 cells were increased in Col3(+/-) mice compared to Col3(+/+) littermates. By using murine (4T1) and human (MDA-MB-231) breast cancer cells grown in Col3-poor and Col3-enriched microenvironments in vitro, we found that several major events of the metastatic process were suppressed by Col3, including adhesion, invasion, and migration. In addition, Col3 deficiency increased proliferation and decreased apoptosis of 4T1 cells both in vitro and in primary tumors in vivo. Mechanistically, Col3 suppresses the procarcinogenic microenvironment by regulating stromal organization, including density and alignment of fibrillar collagen and myofibroblasts. We propose that Col3 plays an important role in the tumor microenvironment by suppressing metastasis-promoting characteristics of the tumor-associated stroma. PMID- 25795284 TI - Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families. AB - BACKGROUND: Mutations in the gene encoding the alpha subunit of the voltage-gated sodium channel SCN1A are associated with several epilepsy syndromes. These range from severe phenotypes including Dravet syndrome to milder phenotypes such as genetic epilepsy with febrile seizures plus (GEFS+). To date the sequence variants identified have been heterozygous in nature as one would expect for a disorder that occurs de novo or is dominantly inherited. METHODS AND RESULTS: We report the association of two novel homozygous missense mutations of the SCN1A gene in four children with infantile epilepsies from two consanguineous pedigrees. We suggest that the nature and location of the identified amino acid changes allows heterozygous carriers to remain unaffected. However, having such changes on both alleles may have a cumulative and detrimental effect. CONCLUSION: The presented cases illustrate how better understanding of the nature and location of SCN1A missense mutations may aid the interpretation of genotype phenotype associations. SCN1A related epilepsies should be considered in children with infantile onset epilepsies even when an autosomal recessive neurological disorder is suspected. PMID- 25795285 TI - Curcumin supplementation likely attenuates delayed onset muscle soreness (DOMS). AB - INTRODUCTION: Oral curcumin decreases inflammatory cytokines and increases muscle regeneration in mice. PURPOSE: To determine effects of curcumin on muscle damage, inflammation and delayed onset muscle soreness (DOMS) in humans. METHOD: Seventeen men completed a double-blind randomized-controlled crossover trial to estimate the effects of oral curcumin supplementation (2.5 g twice daily) versus placebo on single-leg jump performance and DOMS following unaccustomed heavy eccentric exercise. Curcumin or placebo was taken 2 d before to 3 d after eccentric single-leg press exercise, separated by 14-d washout. Measurements were made at baseline, and 0, 24 and 48-h post-exercise comprising: (a) limb pain (1 10 cm visual analogue scale; VAS), (b) muscle swelling, (c) single-leg jump height, and (d) serum markers of muscle damage and inflammation. Standardized magnitude-based inference was used to define outcomes. RESULTS: At 24 and 48-h post-exercise, curcumin caused moderate-large reductions in pain during single leg squat (VAS scale -1.4 to -1.7; 90 %CL: +/-1.0), gluteal stretch (-1.0 to 1.9; +/-0.9), squat jump (-1.5 to -1.1; +/- 1.2) and small reductions in creatine kinase activity (-22-29 %; +/-21-22 %). Associated with the pain reduction was a small increase in single-leg jump performance (15 %; 90 %CL +/- 12 %). Curcumin increased interleukin-6 concentrations at 0-h (31 %; +/-29 %) and 48-h (32 %; +/ 29 %) relative to baseline, but decreased IL-6 at 24-h relative to post-exercise (-20 %; +/-18 %). CONCLUSIONS: Oral curcumin likely reduces pain associated with DOMS with some evidence for enhanced recovery of muscle performance. Further study is required on mechanisms and translational effects on sport or vocational performance. PMID- 25795288 TI - A tribute to Dr. Edward E. Mason, M.D. PMID- 25795286 TI - Intracellular detection of viral nucleic acids. AB - Successful clearance of a microbial infection depends on the concerted action of both the innate and adaptive arms of the immune system. Accurate recognition of an invading pathogen is the first and most crucial step in eliciting effective antimicrobial defense mechanisms. In recent years, remarkable progress has been made towards understanding the molecular details of how the innate immune system recognizes microbial signatures, commonly called pathogen-associated molecular patterns (PAMPs). For viral pathogens, nucleic acids-both viral genomes and viral replication products-represent a major class of PAMPs that trigger antiviral host responses via activation of germline-encoded innate immune receptors. Here we summarize recent advances in intracellular innate sensing mechanisms of viral RNA and DNA. PMID- 25795289 TI - Classification of lung neuroendocrine tumors: lights and shadows. AB - Neuroendocrine tumors of the lung are classified into low-grade typical and intermediate-grade atypical carcinoids, and high-grade poorly differentiated neuroendocrine carcinomas of the large and small cell types. This scheme is strongly predictive of patients' prognosis but relies on few and scarcely reproducible pathological parameters (namely mitotic count and assessment of the presence of necrosis), which have been demonstrated to affect the inter-observer agreement of the classification. Moreover, tumor and nodal staging schemes are not specific for lung carcinoids, at variance with neuroendocrine tumors of the gastro-entero-pancreatic system, despite these tumors have specific features that strongly differ from conventional lung cancer. Finally, there is no grading for lung neuroendocrine neoplasms and prognostication, as well as the definition of treatment modalities and clinical strategies, which are based on tumor histotypes, only. However, literature data indicate that the evaluation of Ki-67 proliferation index may be a reliable and useful tool to determine the biological and clinical behavior of neuroendocrine tumors, with special reference to carcinoids, both in pre-operative and surgical samples. PMID- 25795291 TI - Systemic nickel allergic syndrome as an immune-mediated disease with an increased risk for thyroid autoimmunity. PMID- 25795290 TI - Comparison of F-18 FDG-PET/CT and Tc-99m MIBI in the preoperative evaluation of cold thyroid nodules in the same patient group. AB - Recent studies have reported that standardized uptake values of FDG-PET imaging might predict malignant thyroid nodules and can be used in the preoperative evaluation of thyroid lesions. The aim of our study was to evaluate FDG-PET imaging in patients with cold thyroid nodules and to compare the imaging findings with Tc-99m MIBI scans and with post-op histopathology results. Twenty-three patients (18F, 5M) with 24 nodules that were suspicious in ultrasound and cold in Tc-99m pertechnetate scan, were included in the study. Each nodule underwent sonographically guided fine-needle aspiration biopsy. FDG-PET and MIBI scans were performed with an interval of 3-5 days. All patients underwent thyroidectomy and their FDG-PET, and MIBI thyroid scan results were compared with post thyroidectomy pathology results. Post-op histopathology results found 7 malignant and 17 benign nodules. Six of the seven malignant nodules had increased uptake, which were positive for malignancy in both PET and MIBI scans. Each imaging method used different radiopharmaceuticals but showed one false-negative result in two different patients. FDG-PET produced false positives in eight nodules and MIBI scans found false positives in four nodules. FDG-PET imaging and MIBI scan showed the same sensitivity in malignant nodule evaluation, but their specificity differed. As a result, we suggest that FDG-PET imaging is not superior to MIBI scanning in differentiating malignant from benign thyroid nodules. MIBI imaging should be the first choice in the preoperative evaluation of patients with cold thyroid nodules as an adjunct procedure to FNAB because of its low cost and availability. This imaging technique can be used routinely in patients who are reluctant to undergo FNAB. PMID- 25795292 TI - Bone mineral content in growth hormone deficient children treated with growth hormone after withdrawal of supplementation with calcium, vitamin D and zinc. PMID- 25795293 TI - The state of personalized treatment for anxiety disorders: A systematic review of treatment moderators. AB - INTRODUCTION: The aim of this review was to synthesize findings for moderators of treatment outcome across adult anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder. METHODS: Twenty-four papers that compared two or more active treatments (at least one of which was a form of cognitive behavioral therapy [CBT]) were identified and organized into five treatment comparison categories (distinct psychotherapy combinations, CBT full package vs. single components, CBT vs. augmented CBT, CBT delivery methods, and CBT vs. pharmacotherapy). Sixty-three distinct baseline moderators were tested across seven categories (symptom severity, comorbid emotional disorders or emotional reactivity, cognitive maintenance factors, behavioral maintenance factors, personality traits and disorders, sociodemographic factors, and biological factors). RESULTS: Few consistent treatment moderators were identified. All studies testing quadratic effects found at least one significant non-linear moderator or predictor effect. In addition, the majority of studies had methodological problems and limitations, demonstrating the need for future methodological improvements. CONCLUSION: Limited conclusions can be drawn about how to match anxiety disorder patients to treatment. A strong need to improve the methodological consistency and rigor of treatment moderator studies was identified. A series of recommendations for moderation analyses are proposed in order to strengthen future studies and facilitate replication efforts. PMID- 25795294 TI - Gender differences in the prevalence of nonsuicidal self-injury: A meta-analysis. AB - Epidemiological research on the prevalence of nonsuicidal self-injury (NSSI) has found inconsistent results in terms of gender differences, with some studies showing a higher prevalence for women compared to men and other studies showing no difference. The goal of the current study was to use meta-analytic techniques to better conceptualize the presence and size of gender differences in the prevalence of NSSI. We also examined two factors proposed to explain gender differences in NSSI prevalence: the gender difference would be larger for clinical samples relative to community samples, and the gender difference would be larger for younger (versus older) samples. The results showed that across studies women were significantly more likely to report a history of NSSI than men. Moderator analyses showed that the gender difference was larger for clinical samples, compared to college/community samples. However, there was not a significant relation between age and effect size. Women were more likely to use some methods of NSSI (e.g., cutting) compared to men, but for other methods there was no significant difference (e.g., punching). These results increase our knowledge of NSSI and fit with a larger literature examining gender, emotion regulation, and psychopathology. PMID- 25795295 TI - Unusual case of pyogenic spondylodiscitis, vertebral osteomyelitis and bilateral psoas abscesses after acupuncture: diagnosis and treatment with interventional management. AB - BACKGROUND: We report, for the first time, a case of pyogenic spondylodiscitis combined with vertebral osteomyelitis and bilateral psoas abscesses after acupuncture. CASE HISTORY: A 60-year-old man was diagnosed with rectal cancer, and radical rectectomy and permanent colostomy were carried out. However, 3 years after the surgery the patient complained of pain in the lower back, and the symptoms worsened after seven sessions of acupuncture. Technetium 99m-labelled methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy (BS) revealed abnormal uptake of (99m)Tc-MDP in the L4 and L5 vertebrae. He was admitted to our hospital because of suspected bone metastases from rectal cancer. He was diagnosed with infection based on a history of acupuncture and the findings of enhanced MRI and CT. Percutaneous lumbar discectomy (PLD), external drainage and irrigation using antibiotics were carried out to treat the L4-5 disc. Pathological analyses and bacterial culture of the resected disc confirmed infection with group C streptococcus. Postoperative antibiotic treatment resulted in significant pain relief on the third day and gradual complete relief. Considerable improvement was seen on CT and MRI at follow-up. CONCLUSIONS: We consider it highly likely that this patient's infection was caused by acupuncture. In patients with malignancy, abnormal uptake of (99m)Tc-MDP in BS may signify bone metastasis but can also be observed in bone infections. PLD can be used to resect diseased discs to relieve pain quickly and to prevent herniation of lumbar discs. After PLD, external drainage can be employed for abscess drainage, decompression and perfusion of antibiotics. PLD may serve as an alternative to open surgery for pyogenic spondylodiscitis. PMID- 25795296 TI - Mechanical prostheses for right ventricular outflow tract reconstruction: a systematic review and meta-analysis. AB - It remains unclear as to whether mechanical valves have a role in pulmonary valve replacement. A systematic review and meta-analysis was performed to answer this question. Nineteen observational studies, including 299 pediatric and adult patients with a mean follow-up of 73 months, were analyzed. Nonstructural valve deterioration and valve thrombosis occurred in 1.5% and 2.2% of patients, respectively. Surgical reintervention was required in 0.9% of cases and thrombolysis was required in 0.5%. Mechanical valves in the pulmonary position are associated with a low incidence of valve deterioration and thrombosis, as well as freedom from reoperation and thrombolysis. PMID- 25795297 TI - The Importance of Continued Quality Improvement Efforts in Monitoring Hospital Acquired Infection Rates: A Cardiac Surgery Experience. AB - BACKGROUND: Hospital-acquired infections have been suggested to affect patients' outcomes and raise health care costs. However, research regarding the change in rates and types of infections over time remains limited. METHODS: All patients who underwent cardiac surgical procedures from 1995 to 2012 at the Queen Elizabeth II Health Sciences Center in Halifax, Canada were identified. The prevalence of superficial surgical site infection (sSSI), deep surgical site infection (dSSI), urinary tract infection, sepsis, pneumonia, and leg site infection was examined to determine trends in infections over time. Nonparsimonious logistic regression models were created to identify independent preoperative predictors of length of stay and infection onset. RESULTS: A total of 19,333 consecutive patients underwent cardiac surgical procedures, of whom 2,726 (14%) contracted at least one postoperative infection. The incidence of infections increased from 8% to 20% during the 17-year span (p < 0.0001). The overall prevalence of infection types, from highest to lowest, was pneumonia (6%), urinary tract infection (6%), sepsis (3%), sSSI (2%), leg infection (2%), and dSSI (1%). After adjusting for clinical differences, postoperative infection was found to be an independent predictor of length of stay longer than 9 days. In turn, independent predictors for contracting a postoperative infection included operative era, advanced age of patients, and complex procedures. CONCLUSIONS: The incidence of infection increased nearly threefold since 1995 independent of patient- or procedure-related variables and was found to affect hospital length of stay significantly. Our findings highlight that efforts to monitor only rates of hospital-acquired infections may not in isolation help affect patient care. PMID- 25795299 TI - CRL4(RBBP7) is required for efficient CENP-A deposition at centromeres. AB - The mitotic spindle drives chromosome movement during mitosis and attaches to chromosomes at dedicated genomic loci named centromeres. Centromeres are epigenetically specified by their histone composition, namely the presence of the histone H3 variant CENP-A, which is regulated during the cell cycle by its dynamic expression and localization. Here, we combined biochemical methods and quantitative imaging approaches to investigate a new function of CUL4-RING E3 ubiquitin ligases (CRL4) in regulating CENP-A dynamics. We found that the core components CUL4 and DDB1 are required for centromeric loading of CENP-A, but do not influence CENP-A maintenance or pre-nucleosomal CENP-A levels. Interestingly, we identified RBBP7 as a substrate-specific CRL4 adaptor required for this process, in addition to its role in binding and stabilizing soluble CENP-A. Our data thus suggest that the CRL4 complex containing RBBP7 (CRL4(RBBP7)) might regulate mitosis by promoting ubiquitin-dependent loading of newly synthesized CENP-A during the G1 phase of the cell cycle. PMID- 25795298 TI - Cadherin-6B undergoes macropinocytosis and clathrin-mediated endocytosis during cranial neural crest cell EMT. AB - The epithelial-to-mesenchymal transition (EMT) is important for the formation of migratory neural crest cells during development and is co-opted in human diseases such as cancer metastasis. Chick premigratory cranial neural crest cells lose intercellular contacts, mediated in part by Cadherin-6B (Cad6B), migrate extensively, and later form a variety of adult derivatives. Importantly, modulation of Cad6B is crucial for proper neural crest cell EMT. Although Cad6B possesses a long half-life, it is rapidly lost from premigratory neural crest cell membranes, suggesting the existence of post-translational mechanisms during EMT. We have identified a motif in the Cad6B cytoplasmic tail that enhances Cad6B internalization and reduces the stability of Cad6B upon its mutation. Furthermore, we demonstrate for the first time that Cad6B is removed from premigratory neural crest cells through cell surface internalization events that include clathrin-mediated endocytosis and macropinocytosis. Both of these processes are dependent upon the function of dynamin, and inhibition of Cad6B internalization abrogates neural crest cell EMT and migration. Collectively, our findings reveal the significance of post-translational events in controlling cadherins during neural crest cell EMT and migration. PMID- 25795300 TI - Rho guanine nucleotide exchange factors involved in cyclic-stretch-induced reorientation of vascular endothelial cells. AB - Cyclic stretch is an artificial model of mechanical force loading, which induces the reorientation of vascular endothelial cells and their stress fibers in a direction perpendicular to the stretch axis. Rho family GTPases are crucial for cyclic-stretch-induced endothelial cell reorientation; however, the mechanism underlying stretch-induced activation of Rho family GTPases is unknown. A screen of short hairpin RNAs targeting 63 Rho guanine nucleotide exchange factors (Rho GEFs) revealed that at least 11 Rho-GEFs - Abr, alsin, ARHGEF10, Bcr, GEF-H1 (also known as ARHGEF2), LARG (also known as ARHGEF12), p190RhoGEF (also known as ARHGEF28), PLEKHG1, P-REX2, Solo (also known as ARHGEF40) and alpha-PIX (also known as ARHGEF6) - which specifically or broadly target RhoA, Rac1 and/or Cdc42, are involved in cyclic-stretch-induced perpendicular reorientation of endothelial cells. Overexpression of Solo induced RhoA activation and F-actin accumulation at cell-cell and cell-substrate adhesion sites. Knockdown of Solo suppressed cyclic stretch- or tensile-force-induced RhoA activation. Moreover, knockdown of Solo significantly reduced cyclic-stretch-induced perpendicular reorientation of endothelial cells when cells were cultured at high density, but not when they were cultured at low density or pretreated with EGTA or VE-cadherin-targeting small interfering RNAs. These results suggest that Solo is involved in cell-cell adhesion-mediated mechanical signal transduction during cyclic-stretch-induced endothelial cell reorientation. PMID- 25795301 TI - SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling. AB - The 5-hydroxytryptamine (5-HT, also known as serotonin) subtype 6 receptor (5 HT6R, also known as HTR6) plays roles in cognition, anxiety and learning and memory disorders, yet new details concerning its regulation remain poorly understood. In this study, we found that 5-HT6R directly interacted with SNX14 and that this interaction dramatically increased internalization and degradation of 5-HT6R. Knockdown of endogenous SNX14 had the opposite effect. SNX14 is highly expressed in the brain and contains a putative regulator of G-protein signaling (RGS) domain. Although its RGS domain was found to be non-functional as a GTPase activator for Galphas, we found that it specifically bound to and sequestered Galphas, thus inhibiting downstream cAMP production. We further found that protein kinase A (PKA)-mediated phosphorylation of SNX14 inhibited its binding to Galphas and diverted SNX14 from Galphas binding to 5-HT6R binding, thus facilitating the endocytic degradation of the receptor. Therefore, our results suggest that SNX14 is a dual endogenous negative regulator in 5-HT6R-mediated signaling pathway, modulating both signaling and trafficking of 5-HT6R. PMID- 25795302 TI - Chaperoning of closed syntaxin-3 through Lys46 and Glu59 in domain 1 of Munc18 proteins is indispensable for mast cell exocytosis. AB - Understanding how Munc18 proteins govern exocytosis is crucial because mutations of this protein cause severe secretion deficits in neuronal and immune cells. Munc18-2 has indispensable roles in the degranulation of mast cell, partly by binding and chaperoning a subset of syntaxin isoforms. However, the key syntaxin that, crucially, participates in the degranulation - whose levels and intracellular localization are regulated by Munc18-2 - remains unknown. Here, we demonstrate that double knockdown of Munc18-1 and Munc-2 in mast cells results in greatly reduced degranulation accompanied with strikingly compromised expression levels and localization of syntaxin-3. This phenotype is fully rescued by wild type Munc18 proteins but not by the K46E, E59K and K46E/E59K mutants of Munc-18 domain 1, each of which exhibits completely abolished binding to 'closed' syntaxin-3. Furthermore, knockdown of syntaxin-3 strongly impairs degranulation. Collectively, our data argue that residues Lys46 and Glu59 of Munc18 proteins are indispensable for mediating the interaction between Munc18 and closed syntaxin-3, which is essential for degranulation by chaperoning syntaxin-3. Our results also indicate that the functional contribution of these residues differs between immune cell degranulation and neuronal secretion. PMID- 25795303 TI - The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis. AB - Centrioles function as core components of centrosomes and as basal bodies for the formation of cilia and flagella. Thus, effective control of centriole numbers is essential for embryogenesis, tissue homeostasis and genome stability. In mammalian cells, the centriole duplication cycle is governed by Polo-like kinase 4 (Plk4). Here, we identify the E3 ubiquitin ligase Mind bomb (Mib1) as a new interaction partner of Plk4. We show that Mib1 localizes to centriolar satellites but redistributes to centrioles in response to conditions that induce centriole amplification. The E3 ligase activity of Mib1 triggers ubiquitylation of Plk4 on multiple sites, causing the formation of Lys11-, Lys29- and Lys48-ubiquitin linkages. These modifications control the abundance of Plk4 and its ability to interact with centrosomal proteins, thus counteracting centriole amplification induced by excess Plk4. Collectively, these results identify the interaction between Mib1 and Plk4 as a new and important element in the control of centriole homeostasis. PMID- 25795305 TI - Fusion genes with ALK as recurrent partner in ependymoma-like gliomas: a new brain tumor entity? AB - BACKGROUND: We have previously characterized 19 ependymal tumors using Giemsa banding and high-resolution comparative genomic hybridization. The aim of this study was to analyze these tumors searching for fusion genes. METHODS: RNA sequencing was performed in 12 samples. Potential fusion transcripts were assessed by seed count and structural chromosomal aberrations. Transcripts of interest were validated using fluorescence in situ hybridization and PCR followed by direct sequencing. RESULTS: RNA sequencing identified rearrangements of the anaplastic lymphoma kinase gene (ALK) in 2 samples. Both tumors harbored structural aberrations involving the ALK locus 2p23. Tumor 1 had an unbalanced t(2;14)(p23;q22) translocation which led to the fusion gene KTN1-ALK. Tumor 2 had an interstitial del(2)(p16p23) deletion causing the fusion of CCDC88A and ALK. In both samples, the breakpoint of ALK was located between exons 19 and 20. Both patients were infants and both tumors were supratentorial. The tumors were well demarcated from surrounding tissue and had both ependymal and astrocytic features but were diagnosed and treated as ependymomas. CONCLUSIONS: By combining karyotyping and RNA sequencing, we identified the 2 first ever reported ALK rearrangements in CNS tumors. Such rearrangements may represent the hallmark of a new entity of pediatric glioma characterized by both ependymal and astrocytic features. Our findings are of particular importance because crizotinib, a selective ALK inhibitor, has demonstrated effect in patients with lung cancer harboring ALK rearrangements. Thus, ALK emerges as an interesting therapeutic target in patients with ependymal tumors carrying ALK fusions. PMID- 25795307 TI - [How to treat fat necrosis after lipofilling into the breast?]. AB - INTRODUCTION: Fat necrosis is a phenomenon that has been known for a long time in surgery. The fat necrosis is produced because of tissue ischemia and it is also known as cytosteatonecrosis. These lesions can appear with different manifestations: indurations or cysts. Fat necrosis develops in breast aesthetic surgery (breast reduction) or reconstructive breast surgery (after abdominal flaps like TRAM or DIEP). In our department we have been using fat grafting into the breast since 1998 and it has really improved the aesthetic results in breast surgery. Also the fat necrosis lesions can appear after fat grafting, and they should be identified in order to avoid worrying the patient and other doctors that are treating her. The purpose of this article is to present different aspects of fat necrosis after surgery and therapeutic approaches to these problems. MATERIAL AND METHODS: The two authors have noticed the frequency of fat necrosis in the breast after fat grafting into the breast in aesthetic surgery (asymmetry, deformity, lipoaugmentation, improvement of aesthetic sequelae) and reconstructive surgery (after total mastectomy or to improve the aspect of sequelae after conservative surgery). A retrospective study was performed including a homogenous series of consecutive cases that needed breast lipofilling, operated by the two authors. Fat was harvested with cannula after infiltration. The adipose tissue was preparated with a short centrifugation. Fat grafting was realized as backward injections. The tolerance of the performed technique has been studied with the discovery of the fat necrosis lesions after surgery up to one-year follow-up evaluation. RESULTS: Between 1998 and 2013, 2236 fat transfers have been performed by the two authors and were included in a series of consecutive homogenous cases treated by using the same surgical technique. The fat necrosis incidence after lipofilling in the breast shows two frequency curves: the first one with a frequency of 15% (the first 50 cases) and then decreases and stabilizes at about 3%. A second frequency curve appears after 500 cases and fat necrosis has a frequency of 10%. The clinical symptoms are variable. The oil cysts are the most frequent and the earliest manifestation. They can be treated in consultation by punction. The cysts with thick yellow filling and the indurate areas of fat necrosis are rare and can be treated by lipofragmentation using a canula. CONCLUSIONS: The fat necrosis lesion is a classic phenomena, and can be a source of inconveniences for the patients and the surgeons after breast surgery. All the efforts should be directed to avoid fat necrosis. However, fat necrosis is not rare and the surgeon should learn to resolve it without worrying the patient or asking for expensive exams. PMID- 25795304 TI - MEI4 - a central player in the regulation of meiotic DNA double-strand break formation in the mouse. AB - The formation of programmed DNA double-strand breaks (DSBs) at the beginning of meiotic prophase marks the initiation of meiotic recombination. Meiotic DSB formation is catalyzed by SPO11 and their repair takes place on meiotic chromosome axes. The evolutionarily conserved MEI4 protein is required for meiotic DSB formation and is localized on chromosome axes. Here, we show that HORMAD1, one of the meiotic chromosome axis components, is required for MEI4 localization. Importantly, the quantitative correlation between the level of axis associated MEI4 and DSB formation suggests that axis-associated MEI4 could be a limiting factor for DSB formation. We also show that MEI1, REC8 and RAD21L are important for proper MEI4 localization. These findings on MEI4 dynamics during meiotic prophase suggest that the association of MEI4 to chromosome axes is required for DSB formation, and that the loss of this association upon DSB repair could contribute to turning off meiotic DSB formation. PMID- 25795306 TI - Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Our previous studies demonstrated that combined inhibition of HDAC and KDM1A increases apoptotic cell death in vitro. However, whether this combination also increases death of the glioma stem cell (GSC) population or has an effect in vivo is yet to be determined. Therefore, we evaluated the translational potential of combined HDAC and KDM1A inhibition on patient-derived GSCs and xenograft GBM mouse models. We also investigated the changes in transcriptional programing induced by the combination in an effort to understand the induced molecular mechanisms of GBM cell death. METHODS: Patient-derived GSCs were treated with the combination of vorinostat, a pan-HDAC inhibitor, and tranylcypromine, a KDM1A inhibitor, and viability was measured. To characterize transcriptional profiles associated with cell death, we used RNA-Seq and validated gene changes by RT-qPCR and protein expression via Western blot. Apoptosis was measured using DNA fragmentation assays. Orthotopic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis and to validate gene changes in vivo. RESULTS: The combination of vorinostat and tranylcypromine reduced GSC viability and displayed efficacy in the U87 xenograft model. Additionally, the combination led to changes in apoptosis-related genes, particularly TP53 and TP73 in vitro and in vivo. CONCLUSIONS: These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment. PMID- 25795308 TI - Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation. AB - An emerging number of diseases and therapeutic approaches with defined involvement of the complement system justify a need for specific markers reflecting activation of particular effector arms of the complement cascade. Measurement of such soluble markers in circulation is a challenge since the specificity of antibodies must be limited to activated complement fragments but not predominant and ubiquitous parental molecules. Existing assays for the measurement of soluble, activated complement proteins are based on the detection of conformational neoepitopes. We tested an alternative approach based on detection of short linear neoepitopes exposed at the cleavage sites after activation of the actual complement component. Obtained antibodies reactive to C4d and C5b fragments enabled us to set up highly specific sandwich ELISAs, which ensured trustful measurements without false positive readouts characteristic for some of the widely used assays. PMID- 25795309 TI - Drug hypersensitivity causing organizing eosinophilic pneumonia in a pediatric patient. AB - OBJECTIVE: To describe a relatively rare hypersentivity reaction with pulmonary manifestations in a pediatric patient. DATA SOURCES: Electronic medical records. STUDY SELECTION: Patient treatment in the pediatric critical care unit. DATA EXTRACTION AND SYNTHESIS: Electronic medical records. CONCLUSIONS: Eosinophilic pneumonias are rare in the pediatric population. Peripheral eosinophilia is not necessary to make the diagnosis. Bronchoalveolar lavage is the diagnostic study of choice. Lung biopsies are rarely needed to make the diagnosis. The treatment of choice is steroids. If steroids fail to improve the patient's condition, consider IVIG, and cyclosporine A. PMID- 25795310 TI - Erratum to: Does Surgically Induced Right Bundle Branch Block Really Effect Ventricular Function in Children After Ventricular Septal Defect Closure? PMID- 25795311 TI - Right Ventricular Mass is Associated with Exercise Capacity in Adults with Repaired Tetralogy of Fallot. AB - The relationship between exercise capacity and right ventricular (RV) structure and function in adult repaired tetralogy of Fallot (TOF) is poorly understood. We therefore aimed to examine the relationships between cardiac MRI and cardiopulmonary exercise test variables in adult repaired TOF patients. In particular, we sought to determine the role of RV mass in determining exercise capacity. Eighty-two adult repaired TOF patients (age at evaluation 26 +/- 10 years; mean age at repair 2.5 +/- 2.8 years; 23.3 +/- 7.9 years since repair; 53 males) (including nine patients with tetralogy-type pulmonary atresia with ventricular septal defect) were prospectively recruited to undergo cardiac MRI and cardiopulmonary exercise testing. As expected, these repaired TOF patients had RV dilatation (indexed RV end-diastolic volume: 153 +/- 43.9 mL/m(2)), moderate-severe pulmonary regurgitation (pulmonary regurgitant fraction: 33 +/- 14 %) and preserved left (LV ejection fraction: 59 +/- 8 %) and RV systolic function (RV ejection fraction: 51 +/- 7 %). Exercise capacity was near-normal (peak work: 88 +/- 17 % predicted; peak oxygen consumption: 84 +/- 17 % predicted). Peak work exhibited a significant positive correlation with RV mass in univariate analysis (r = 0.45, p < 0.001) and (independent of other cardiac MRI variables) in multivariate analyses. For each 10 g higher RV mass, peak work was 8 W higher. Peak work exhibits a significant positive correlation with RV mass, independent of other cardiac MRI variables. RV mass measured on cardiac MRI may provide a novel marker of clinical progress in adult patients with repaired TOF. PMID- 25795312 TI - Expression of the Cydia pomonella granulovirus matrix metalloprotease enhances Autographa californica multiple nucleopolyhedrovirus virulence and can partially substitute for viral cathepsin. AB - The Cydia pomonella granulovirus open reading frame 46 (CpGV-ORF46) contains predicted domains found in matrix metalloproteases (MMPs), a family of zinc dependent endopeptidases that degrade extracellular matrix proteins. We showed that CpGV-MMP was active in vitro. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) expressing CpGV-ORF46 replicated similarly to a control virus lacking CpGV-ORF46 in cultured cells. The effects of AcMNPV expressing CpGV-MMP on virus infection in cultured cells and Trichoplusia ni larvae in the presence or absence of other viral degradative enzymes, cathepsin and chitinase, were evaluated. In the absence of cathepsin and chitinase or cathepsin alone, larval time of death was significantly delayed. This delay was compensated by the expression of CpGV-MMP. CpGV-MMP was also able to promote larvae melanization in the absence of cathepsin and chitinase. In addition, CpGV MMP partially substituted for cathepsin in larvae liquefaction when chitinase, which is usually retained in the endoplasmic reticulum, was engineered to be secreted. PMID- 25795314 TI - ERP correlates of priming in language and stimulus equivalence: evidence of similar N400 effects in absence of semantic content. AB - Semantic priming has been widely observed at both behavioral and electrophysiological levels as reductions in response times and N400 magnitudes respectively. However, the possibility that stimulus relations derived from associative learning elicit N400 priming effects comparable to those found in language has not been properly addressed yet. Equivalence relations emerge after establishing a set of arbitrary and intra-experimentally defined relations through associative learning, thus allowing the study of derived stimulus relations in the absence of semantic content. The present study aimed to compare ERP correlates of priming in semantically related words and pseudowords related through equivalence. We found similar behavioral and N400 effects when comparing unrelated vs related prime-target pairs in language and stimulus equivalence tasks, suggesting that priming engages at least partially overlapping neural mechanisms in both contexts. In addition, we found a posteriorly distributed late positivity in the semantic priming task only, which may be reflecting language specific processing. PMID- 25795315 TI - Antimycobacterial activity of linezolid against multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis in Iran. PMID- 25795313 TI - Varicella-zoster virus (VZV) origin of DNA replication oriS influences origin dependent DNA replication and flanking gene transcription. AB - The VZV genome has two origins of DNA replication (oriS), each of which consists of an AT-rich sequence and three origin binding protein (OBP) sites called Box A, C and B. In these experiments, the mutation in the core sequence CGC of the Box A and C not only inhibited DNA replication but also inhibited both ORF62 and ORF63 expression in reporter gene assays. In contrast the Box B mutation did not influence DNA replication or flanking gene transcription. These results suggest that efficient DNA replication enhances ORF62 and ORF63 transcription. Recombinant viruses carrying these mutations in both sites and one with a deletion of the whole oriS were constructed. Surprisingly, the recombinant virus lacking both copies of oriS retained the capacity to replicate in melanoma and HELF cells suggesting that VZV has another origin of DNA replication. PMID- 25795317 TI - Synergistic interactions between colistin and meropenem against extensively drug resistant and pandrug-resistant Acinetobacter baumannii isolated from ICU patients. PMID- 25795316 TI - Differences in risk factors and drug susceptibility between Mycobacterium avium and Mycobacterium intracellulare lung diseases in China. AB - The aim of this study was to investigate the differences in risk factors and drug susceptibility between Mycobacterium avium and Mycobacterium intracellulare lung diseases in China. In total, 452 nontuberculous mycobacteria (NTM) strains isolated from patients with NTM lung diseases in four specialised TB hospitals were enrolled in this study. The minimum inhibitory concentration (MIC) was used to evaluate the drug susceptibility of M. avium and M. intracellulare isolates. In addition, demographic and clinical characteristics of patients with NTM lung diseases caused by M. avium and M. intracellulare were analysed. Of 452 NTM isolates, M. intracellulare (188; 41.6%) was the most frequently isolated organism. The percentages of moxifloxacin- and linezolid-resistant strains among the M. intracellulare isolates were significantly lower than those among the M. avium group (P=0.003 and P<0.001, respectively). In contrast, M. avium harboured a lower proportion of rifampicin-resistant strains than M. intracellulare (P=0.005). Among patients with M. intracellulare lung diseases, the percentages of patients aged >64 years and patients with chronic obstructive pulmonary disease (COPD) were significantly higher than among patients with M. avium (P=0.008 for age and P=0.001 for COPD). In conclusion, these data demonstrated that M. intracellulare was the most common NTM species in China. This study also revealed that M. intracellulare and M. avium differed in their drug susceptibility profiles. In addition, clinical cases of M. intracellulare lung diseases were more likely to be found in the aged population and among patients with COPD co-morbidity. PMID- 25795318 TI - Patient-specific mathematical neuro-oncology: using a simple proliferation and invasion tumor model to inform clinical practice. AB - Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor associated with a poor median survival of 15-18 months, yet there is wide heterogeneity across and within patients. This heterogeneity has been the source of significant clinical challenges facing patients with GBM and has hampered the drive toward more precision or personalized medicine approaches to treating these challenging tumors. Over the last two decades, the field of Mathematical Neuro oncology has grown out of desire to use (often patient-specific) mathematical modeling to better treat GBMs. Here, we will focus on a series of clinically relevant results using patient-specific mathematical modeling. The core model at the center of these results incorporates two hallmark features of GBM, proliferation [Formula: see text] and invasion (D), as key parameters. Based on routinely obtained magnetic resonance images, each patient's tumor can be characterized using these two parameters. The Proliferation-Invasion (PI) model uses [Formula: see text] and D to create patient-specific growth predictions. The PI model, its predictions, and parameters have been used in a number of ways to derive biological insight. Beyond predicting growth, the PI model has been utilized to identify patients who benefit from different surgery strategies, to prognosticate response to radiation therapy, to develop a treatment response metric, and to connect clinical imaging features and genetic information. Demonstration of the PI model's clinical relevance supports the growing role for it and other mathematical models in routine clinical practice. PMID- 25795319 TI - Laplacian Dynamics with Synthesis and Degradation. AB - Analyzing qualitative behaviors of biochemical reactions using its associated network structure has proven useful in diverse branches of biology. As an extension of our previous work, we introduce a graph-based framework to calculate steady state solutions of biochemical reaction networks with synthesis and degradation. Our approach is based on a labeled directed graph G and the associated system of linear non-homogeneous differential equations with first order degradation and zeroth-order synthesis. We also present a theorem which provides necessary and sufficient conditions for the dynamics to engender a unique stable steady state. Although the dynamics are linear, one can apply this framework to nonlinear systems by encoding nonlinearity into the edge labels. We answer an open question from our previous work concerning the non-positiveness of the elements in the inverse of a perturbed Laplacian matrix. Moreover, we provide a graph theoretical framework for the computation of the inverse of such a matrix. This also completes our previous framework and makes it purely graph theoretical. Lastly, we demonstrate the utility of this framework by applying it to a mathematical model of insulin secretion through ion channels in pancreatic beta-cells. PMID- 25795320 TI - Blood Donor Test-Seeking Motivation and Prior HIV Testing Experiences in Sao Paulo, Brazil. AB - HIV test-seeking behavior among blood donors has been observed worldwide and may pose a threat to the safety of the blood supply. We evaluated current test seeking motivations and prior alternative HIV testing experiences among blood donors in Sao Paulo, Brazil. All candidate or potential blood donors were consecutively approached and recruited to participate in the study upon presentation at Fundacao Pro-Sangue Hemocentro, the largest blood bank in Brazil. Participants were recruited between August 2012 and May 2013 after they were screened for donor eligibility. Questionnaires were administered through audio computer-assisted self-interview. Among 11,867 donors, 38 % previously tested for HIV apart from blood donation, of whom 47.7 % tested at public facilities and 2.7 % acknowledged getting tested for HIV as the primary reason for donating. Dissatisfaction with prior alternative testing experience was reported by 2.5 % of donors. Current test-seeking motivation was associated with dissatisfaction with prior alternative testing experience and testing at a public alternative facility. The most common reasons for dissatisfaction were too long of a wait to get tested and for results, counseling was too long, lack of privacy, and low confidence in the equipment and accuracy of the test. Lack of awareness about the availability of free and confidential public HIV testing services as well as dissatisfaction with past HIV testing and counseling experiences motivate some individuals to test at blood banks. Test-seeking behavior among blood donors may be best addressed by improving alternative testing programs, particularly with respect to time delays, privacy and perceptions about test accuracy. Educational campaigns on safe blood donation and HIV testing for diagnosis, risk counseling and referral to care are also needed for the general public and for health care providers. PMID- 25795321 TI - Fear itself: The effects of distressing economic news on birth outcomes. AB - I use new administrative data on mass layoffs and plant closings to study the effects of distressing economic news. Exposure to stressful events during pregnancy can impair fetal development. I find that announcement of impending job losses leads to a transient decrease in the mean birth weight within the firm's county one to four months before the job losses. A loss of 500 jobs corresponds roughly to a decrease of 15-20g and 16 percent greater risk of low birth weight. Layoffs announced late in pregnancy are most strongly linked to decreased birth outcomes. PMID- 25795322 TI - Multi-class mycotoxins analysis in Angelica sinensis by ultra fast liquid chromatography coupled with tandem mass spectrometry. AB - An ultra fast liquid chromatography coupled with tandem mass spectrometry (UFLC MS/MS) method was developed and validated for simultaneous analysis of multi class mycotoxins including aflatoxins (AFB1, AFB2, AFG1 and AFG2), ochratoxin A (OTA), fumonisins (FB1 and FB2) and zearalanone (ZEN) in 20 batches of Angelica sinensis samples collected from different markets and stores in China. The eight mycotoxins were extracted and cleaned up by using QuEChERS-based procedure, and then were quantified under the multiple reaction monitoring (MRM) together with positive and negative ionization modes. Focusing on the optimization of extraction and clean-up conditions, as well as UFLC separation and MS/MS parameters of targeted analytes, the developed method expressed good linearity for the eight mycotoxins within their respective linear ranges with correlation coefficients all higher than 0.9974. The limits of detection (LODs) and quantification (LOQs) ranged from 0.005 to 0.125 MUg/kg and from 0.0625 to 0.25 MUg/kg, respectively. Recoveries for spiked A. sinensis sample at three different levels were all above 78.9% with relative standard deviations (RSDs) below 6.36% for all analytes. Analysis of real samples demonstrated that two visibly moldy A. sinensis samples were detected with AFB1 of 2.07 and 2.92 MUg/kg, and AFG1 of 2.84 and 1.53 MUg/kg. The proposed quantitative method with significant advantages including simple pretreatment, rapid determination and high sensitivity would be the preferred candidate for the determination and quantification of multi-class mycotoxin contaminants in complex matrixes, which well fulfilled the maximum residue limits (MRLs) from various countries. PMID- 25795324 TI - India's poor sanitation and hygiene practices are linked to stunting in children, study finds. PMID- 25795323 TI - A molecularly imprinted polymer for the selective solid-phase extraction of dimethomorph from ginseng samples. AB - A molecularly imprinted polymer (MIP) was synthesized and evaluated to selectively extract dimethomorph from ginseng samples. Dimethomorph molecularly imprinted polymers with template to monomer molar ratios were contrived and developed via precipitation polymerization employing methacrylic acid as functional monomer, ethylene dimethacrylate as cross-linker and butanone:N heptane (7:3, v:v)as porogen. The LOD (limit of detection) of this method was 0.002 mg kg(-1), and the LOQ (limit of quantification) was 0.005 mg kg(-1). The different spiked level of ginseng was 0.1 mg kg(-1), 1.0 mg kg(-1), 5.0 mg kg( 1), and the average recovery of dimethomrph was 89.2-91.6%. Under the optimized condition, good linearity was obtained from 0.01 to 5 mg kg(-1) (r(2) >= 0.9997) with the relative standard deviations of less than 3.20%. This proposed MISPE-GC procedure eliminated the effect of template leakage on quantitative analysis and could be applied to direct determination of dimethomrph in ginseng samples. PMID- 25795325 TI - Efficient biometric authenticated key agreements based on extended chaotic maps for telecare medicine information systems. AB - Authenticated key agreements for telecare medicine information systems provide patients, doctors, nurses and health visitors with accessing medical information systems and getting remote services efficiently and conveniently through an open network. In order to have higher security, many authenticated key agreement schemes appended biometric keys to realize identification except for using passwords and smartcards. Due to too many transmissions and computational costs, these authenticated key agreement schemes are inefficient in communication and computation. This investigation develops two secure and efficient authenticated key agreement schemes for telecare medicine information systems by using biometric key and extended chaotic maps. One scheme is synchronization-based, while the other nonce-based. Compared to related approaches, the proposed schemes not only retain the same security properties with previous schemes, but also provide users with privacy protection and have fewer transmissions and lower computational cost. PMID- 25795327 TI - 'The institute of sexology'. PMID- 25795328 TI - British infertility counselling association. PMID- 25795329 TI - Human rights and clinical ethics are the right framework to address the probable DMPA-HIV interaction. PMID- 25795331 TI - Correction. PMID- 25795330 TI - Human rights and clinical ethics are the right framework to address the probable DMPA-HIV interaction: authors' response. PMID- 25795332 TI - Incidence of fractured implants. PMID- 25795333 TI - Carl Djerassi: 'father of the pill' and renaissance man. PMID- 25795334 TI - An analysis of the expression of collagen I and III genes in the fascia of obese patients. AB - BACKGROUND: The etiology of incisional hernias in the population of morbidly obese patients remains unclear. Most likely, factors other than purely mechanical are at play; it has been ascertained that nonobese patients suffering from inguinal and incisional hernias display alterations in the architecture of the connective tissue. The goal of this study has been to evaluate and compare the relative expression of collagen type I and III genes in the rectus abdominis muscle sheath (RMS) of obese and nonobese individuals to investigate their possible influence on the quality of the connective tissue. MATERIALS AND METHODS: RMS specimens were harvested in the early stages of either bariatric or non-bariatric laparotomies; total RNA was isolated and enzymatically purified from the tissue samples. The resulting material was subjected to a quantitative and qualitative analysis; reverse transcription reactions were then performed and the resulting complementary DNA was used in real-time reverse transcription polymerase chain reactions. The biopsy specimens were also examined by scanning electron microscopy. RESULTS: The real-time reverse transcription polymerase chain reactions, performed on complementary DNA, provided specific amplicons for individual genes. The efficacy of the reactions was rather low. An almost twofold decrease of the relative expression level for type I and III collagen was observed between the two patient groups; the results did not reach statistical significance. Scanning electron microscope photographs have documented a marked difference in the ultrastructure of the RMS in both groups. CONCLUSIONS: The authors have shown that changes in messenger RNA levels for collagen type I and III genes may be related to the pathogenesis of incisional hernia through alterations in the ultrastructure of the RMS fascia. Our report should be considered preliminary; the results should be verified on a larger group of patients. PMID- 25795335 TI - Mechanisms underlying the cardiac benefits of exercise: Still running in the dark. PMID- 25795336 TI - The role of contrast agents in the diagnosis of renal diseases. AB - The behavior of dynamic enhancement using imaging modalities such as enhanced computed tomography, enhanced magnetic resonance, and contrast-enhanced ultrasound is one of the most important features of imaging characterization of kidney diseases. The enhancement pattern depends on the macrovasculature and microvasculature and is correlated with specific pathologic features. This review focuses on the enhancement pattern of different renal conditions including inflammatory, vascular, and oncologic diseases, with emphasis on the pathophysiological bases of altered perfusion. PMID- 25795338 TI - Late Miocene hominin teeth from the Gona Paleoanthropological Research Project area, Afar, Ethiopia. AB - Since 2000, significant collections of Latest Miocene hominin fossils have been recovered from Chad, Kenya, and Ethiopia. These fossils have provided a better understanding of earliest hominin biology and context. Here, we describe five hominin teeth from two periods (ca. 5.4 Million-years-ago and ca. 6.3 Ma) that were recovered from the Adu-Asa Formation in the Gona Paleoanthropological Research Project area in the Afar, Ethiopia that we assign to either Hominina, gen. et sp. indet. or Ardipithecus kadabba. These specimens are compared with extant African ape and other Latest Miocene and Early Pliocene hominin teeth. The derived morphology of the large, non-sectorial maxillary canine and mandibular third premolar links them with later hominins and they are phenetically distinguishable and thus phyletically distinct from extant apes. PMID- 25795337 TI - The membrane domain of vacuolar H(+)ATPase: a crucial player in neurotransmitter exocytotic release. AB - V-ATPases are multimeric enzymes made of two sectors, a V1 catalytic domain and a V0 membrane domain. They accumulate protons in various intracellular organelles. Acidification of synaptic vesicles by V-ATPase energizes the accumulation of neurotransmitters in these storage organelles and is therefore required for efficient synaptic transmission. In addition to this well-accepted role, functional studies have unraveled additional hidden roles of V0 in neurotransmitter exocytosis that are independent of the transport of protons. V0 interacts with SNAREs and calmodulin, and perturbing these interactions affects neurotransmitter release. Here, we discuss these data in relation with previous results obtained in reconstituted membranes and on yeast vacuole fusion. We propose that V0 could be a sensor of intra-vesicular pH that controls the exocytotic machinery, probably regulating SNARE complex assembly during the synaptic vesicle priming step, and that, during the membrane fusion step, V0 might favor lipid mixing and fusion pore stability. PMID- 25795339 TI - In a sweet mood? Effects of experimental modulation of blood glucose levels on mood-induction during fMRI. AB - Glucose is the primary source of energy for the human brain. Previous literature has shown that varying blood glucose levels may have a strong impact on behaviour, subjective mood, and the intensity of the BOLD signal measured in fMRI. Therefore, blood glucose levels varying even within the normal range may interact with cognitive and emotional processing as well as BOLD signal. Here, in a placebo-controlled, double-blind crossover study on 20 healthy women, we show that overnight fasting, compared to an elevated glucose condition, influences brain activation and the affective state during mood induction. Results indicate that our brain may compensate for low glucose levels during fasting by stronger recruitment of the brain areas relevant to the task at hand. Additionally, we systematically tested the effect of prior cognitive effort on behavioural and neural patterns and found that elevated activation is only associated with maintained performance as long as no prior cognitively challenging task is administered. Prior cognitive effort leads to deteriorated performance and a further increase in emotion-associated brain activation in the pregenual anterior and posterior cingulate, the superior frontal gyrus, and the pre-SMA. These results are in line with the strength model of self-regulation. Our results corroborate the strength model of self-regulation and extend it to affect regulation processes. Additionally, our observations suggest that experimentally controlling for fasting state or glucose levels may be beneficial, especially when studying processes that involve self-regulation. PMID- 25795340 TI - fMRI contrast at high and ultrahigh magnetic fields: insight from complementary methods. AB - This manuscript examines the origins and nature of the function-derived activation detected by magnetic resonance imaging at ultrahigh fields using different encoding methods. A series of preclinical high field (7 T) and ultra high field (17.2 T) fMRI experiments were performed using gradient echo EPI, spin echo EPI and spatio-temporally encoded (SPEN) strategies. The dependencies of the fMRI signal change on the strength of the magnetic field and on different acquisition and sequence parameters were investigated. Artifact-free rat brain images with good resolution in all areas, as well as significant localized activation maps upon forepaw stimulation, were obtained in a single scan using fully refocused SPEN sequences devoid of T2* effects. Our results showed that, besides the normal T2-weighted BOLD contribution that arises in spin-echo sequences, fMRI SPEN signals contain a strong component caused by apparent T1 related effects, demonstrating the potential of such technique for exploring functional activation in rodents and on humans at ultrahigh fields. PMID- 25795341 TI - The relation between functional magnetic resonance imaging activations and single cell selectivity in the macaque intraparietal sulcus. AB - Previous functional magnetic resonance (fMRI) studies in humans and monkeys have demonstrated that the anterior intraparietal sulcus (IPS) is sensitive to the depth structure defined by binocular disparity. However, in the macaque monkey, a single large activation was measured in the anterior lateral bank of the IPS, whereas in human subjects two separate regions were sensitive to depth structure from disparity. We performed fMRI and single-cell experiments in the same animals, in a large number of recording sites in the lateral bank of the IPS. The fMRI interaction effect between the factors curvature (curved or flat) and disparity (stereo or control) correctly predicted the location of higher-order disparity selective neurons that encoded the depth structure of objects. However the large region in the IPS activated by depth structure consisted of two patches of higher-order disparity-selective neurons, one in the anterior IPS and one located more posteriorly, surrounded by regions lacking such selectivity. Thus the IPS region activated by curved surfaces consists of at least two patches of higher-order disparity selective neurons, which may reconcile previous fMRI studies in monkeys and humans. PMID- 25795342 TI - Agreement and repeatability of vascular reactivity estimates based on a breath hold task and a resting state scan. AB - FMRI BOLD responses to changes in neural activity are influenced by the reactivity of the vasculature. By complementing a task-related BOLD acquisition with a vascular reactivity measure obtained through breath-holding or hypercapnia, this unwanted variance can be statistically reduced in the BOLD responses of interest. Recently, it has been suggested that vascular reactivity can also be estimated using a resting state scan. This study aimed to compare three breath-hold based analysis approaches (block design, sine-cosine regressor and CO2 regressor) and a resting state approach (CO2 regressor) to measure vascular reactivity. We tested BOLD variance explained by the model and repeatability of the measures. Fifteen healthy participants underwent a breath hold task and a resting state scan with end-tidal CO2 being recorded during both. Vascular reactivity was defined as CO2-related BOLD percent signal change/mmHg change in CO2. Maps and regional vascular reactivity estimates showed high repeatability when the breath-hold task was used. Repeatability and variance explained by the CO2 trace regressor were lower for the resting state data based approach, which resulted in highly variable measures of vascular reactivity. We conclude that breath-hold based vascular reactivity estimations are more repeatable than resting-based estimates, and that there are limitations with replacing breath-hold scans by resting state scans for vascular reactivity assessment. PMID- 25795344 TI - Serum levels of hydroperoxides and multimorbidity among older patients with mild cognitive impairment or late-onset Alzheimer's disease. AB - BACKGROUND: Oxidative stress (OxS) might be involved in the pathogenesis of late onset Alzheimer disease (LOAD); noteworthy, the presence of multimorbidity is regarded as a common denominator of OxS and dementia. AIM: To evaluate the contribution of multimorbidity to OxS in LOAD and mild cognitive impairment (MCI). METHODS: Serum hydroperoxides and multimorbidity (CIRS-CI scale) were evaluated in 46 Controls, 104 MCI and 75 LOAD. RESULTS: A trend toward an increase of hydroperoxides from Controls to MCI to LOAD was observed (LOAD vs Controls p = 0.01). This OxS marker was positively and significantly correlated with CIRS-CI in Controls (p = 0.002) and patients with MCI (p = 0.005) but not in those with LOAD (p = 0.104). CONCLUSIONS: Multimorbidity is associated with systemic OxS but only in elderly people with either no or mild cognitive impairment. Although OxS is elevated in LOAD patients, its association with multimorbidity seems to be negligible, confirming the existence of strong disease specific pro-oxidant mechanisms. PMID- 25795345 TI - Prospects for a nicotine-reduction strategy in the cigarette endgame: Alternative tobacco harm reduction scenarios. AB - Some major national and international tobacco control organisations favour mandating a reduction in nicotine content of cigarettes to non-addictive levels as a tobacco control tool. Reducing nicotine content, it is argued, will make tobacco smoking less attractive. The 2009 U.S. Food and Drug Administration's regulation of cigarettes appears to have the power to reduce nicotine to non addictive levels provided it is not taken to zero. A consideration of the U.S. context, however, raises doubts about (a) whether this will ever be practicable and (b), if practicable, how long it will take to implement. Current versions of the nicotine-reducing strategy propose the systematic, incentivised use of less harmful nicotine/tobacco products as elements of the mandatory cigarette nicotine reduction strategy. Time will tell if and when mandatory nicotine reduction in tobacco cigarettes will occur and what impact it might have on smoking prevalence. The question posed here is "Why wait?" Resources used in implementing reduction in nicotine content have an opportunity cost. In the meantime, nicotine maintaining harm reduction strategies can have nearer term effects on tobacco use as an individual and a public health issue. PMID- 25795346 TI - Review on Laryngeal Palpation Methods in Muscle Tension Dysphonia: Validity and Reliability Issues. AB - BACKGROUND: Laryngeal palpation is a common clinical method for the assessment of neck and laryngeal muscles in muscle tension dysphonia (MTD). OBJECTIVE: To review the available laryngeal palpation methods used in patients with MTD for the assessment, diagnosis, or document of treatment outcomes. STUDY DESIGN (METHOD): A systematic review of the literature concerning palpatory methods in MTD was conducted using the databases MEDLINE (PubMed), ScienceDirect, Scopus, Web of science, Web of knowledge and Cochrane Library between July and October 2013. Relevant studies were identified by one reviewer based on screened titles/abstracts and full texts. Manual searching was also used to track the source literature. RESULTS: There were five main as well as miscellaneous palpation methods that were different according to target anatomical structures, judgment or grading system, and using tasks. There were only a few scales available, and the majority of the palpatory methods were qualitative. Most of the palpatory methods evaluate the tension at both static and dynamic tasks. There was little information about the validity and reliability of the available methods. CONCLUSION: The literature on the scientific evidence of muscle tension indicators perceived by laryngeal palpation in MTD is scarce. Future studies should be conducted to investigate the validity and reliability of palpation methods. PMID- 25795343 TI - Risky decision-making and ventral striatal dopamine responses to amphetamine: a positron emission tomography [(11)C]raclopride study in healthy adults. AB - Recent functional magnetic resonance imaging (fMRI) studies have provided compelling evidence that corticolimbic brain regions are integrally involved in human decision-making. Although much less is known about molecular mechanisms, there is growing evidence that the mesolimbic dopamine (DA) neurotransmitter system may be an important neural substrate. Thus far, direct examination of DA signaling in human risk-taking has centered on gambling disorder. Findings from several positron emission tomography (PET) studies suggest that dysfunctions in mesolimbic DA circuits may play an important role in gambling behavior. Nevertheless, interpretation of these findings is currently hampered by a need for better understanding of how individual differences in regional DA function influence normative decision-making in humans. To further our understanding of these processes, we used [(11)C]raclopride PET to examine associations between ventral striatal (VS) DA responses to amphetamine (AMPH) and risky decision making in a sample of healthy young adults with no history of psychiatric disorder, Forty-five male and female subjects, ages 18-29 years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second, by intravenous AMPH (0.3mg/kg). Findings of primary analyses showed that less advantageous decision making was associated with greater right VS DA release; the relationship did not differ as a function of gender. No associations were observed between risk-taking and left VS DA release or baseline D2/D3 receptor availability in either hemisphere. Overall, the results support notions that variability in striatal DA function may mediate inter-individual differences in risky decision-making in healthy adults, further suggesting that hypersensitive DA circuits may represent a risk pathway in this population. PMID- 25795347 TI - New Perspective on Psychosocial Distress in Patients with Dysphonia: The Moderating Role of Perceived Control. AB - OBJECTIVES: Although an association between psychosocial distress (depression, anxiety, somatization, and perceived stress) and voice disorders has been observed, little is known about the relationship between distress and patient reported voice handicap. Furthermore, the psychological mechanisms underlying this relationship are poorly understood. Perceived control plays an important role in distress associated with other medical disorders. The objectives of this study were to (1) characterize the relationship between distress and patient reported voice handicap and (2) examine the role of perceived control in this relationship. STUDY DESIGN: This is a cross-sectional study in a tertiary care academic voice clinic. METHODS: Distress, perceived stress, voice handicap, and perceived control were measured using established assessment scales. Association was measured with Pearson correlation coefficients; moderation was assessed using multiple hierarchical regression. RESULTS: A total of 533 patients enrolled. Thirty-four percent of the patients met criteria for clinically significant distress (ie, depression, anxiety, and/or somatization). A weak association (r = 0.13; P = 0.003) was observed between severity of psychosocial distress and vocal handicap. Present perceived control was inversely associated with distress (r = 0.41; P < 0.0001), stress (r = -0.30; P < 0.0001), and voice handicap (r = -0.30; P < 0.0001). The relationship between voice handicap and psychosocial distress was moderated by perceived control (b for interaction term, -0.15; P < 0.001); greater vocal handicap was associated with greater distress in patients with low perceived control. CONCLUSIONS: Severity of distress and vocal handicap were positively related, and the relation between them was moderated by perceived control. Vocal handicap was more related to distress among those with low perceived control; targeting this potential mechanism may facilitate new approaches for improved care. PMID- 25795348 TI - The Effect of Anchors and Training on the Reliability of Voice Quality Ratings for Different Types of Speech Stimuli. AB - OBJECTIVE: The main objective of the present study was to investigate if the type of voice stimuli-sustained vowel, oral reading, and connected speech-results in good intrarater and interrater agreement/reliability. STUDY DESIGN: A short-term panel study was performed. METHODS: Voice samples from 30 native European Portuguese speakers were used in the present study. The speech materials used were (1) the sustained vowel /a/, (2) oral reading of the European Portuguese version of "The Story of Arthur the Rat," and (3) connected speech. After an extensive training with textual and auditory anchors, the judges were asked to rate the severity of dysphonic voice stimuli using the phonation dimensions G, R, and B from the GRBAS scale. The voice samples were judged 6 months and 1 year after the training. RESULTS: Intrarater agreement and reliability were generally very good for all the phonation dimensions and voice stimuli. The highest interrater reliability was obtained using the oral reading stimulus, particularly for phonation dimensions grade (G) and breathiness (B). Roughness (R) was the voice quality that was the most difficult to evaluate, leading to interrater unreliability in all voice quality ratings. CONCLUSIONS: Extensive training using textual and auditory anchors and the use of anchors during the voice evaluations appear to be good methods for auditory-perceptual evaluation of dysphonic voices. The best results of interrater reliability were obtained when the oral reading stimulus was used. Breathiness appears to be a voice quality that is easier to evaluate than roughness. PMID- 25795349 TI - Combined Use of Standard and Throat Microphones for Measurement of Acoustic Voice Parameters and Voice Categorization. AB - OBJECTIVE: The aim of the present study was to evaluate the reliability of the measurements of acoustic voice parameters obtained simultaneously using oral and contact (throat) microphones and to investigate utility of combined use of these microphones for voice categorization. MATERIALS AND METHODS: Voice samples of sustained vowel /a/ obtained from 157 subjects (105 healthy and 52 pathological voices) were recorded in a soundproof booth simultaneously through two microphones: oral AKG Perception 220 microphone (AKG Acoustics, Vienna, Austria) and contact (throat) Triumph PC microphone (Clearer Communications, Inc, Burnaby, Canada) placed on the lamina of thyroid cartilage. Acoustic voice signal data were measured for fundamental frequency, percent of jitter and shimmer, normalized noise energy, signal-to-noise ratio, and harmonic-to-noise ratio using Dr. Speech software (Tiger Electronics, Seattle, WA). RESULTS: The correlations of acoustic voice parameters in vocal performance were statistically significant and strong (r = 0.71-1.0) for the entire functional measurements obtained for the two microphones. When classifying into healthy-pathological voice classes, the oral-shimmer revealed the correct classification rate (CCR) of 75.2% and the throat-jitter revealed CCR of 70.7%. However, combination of both throat and oral microphones allowed identifying a set of three voice parameters: throat-signal-to noise ratio, oral-shimmer, and oral-normalized noise energy, which provided the CCR of 80.3%. CONCLUSIONS: The measurements of acoustic voice parameters using a combination of oral and throat microphones showed to be reliable in clinical settings and demonstrated high CCRs when distinguishing the healthy and pathological voice patient groups. Our study validates the suitability of the throat microphone signal for the task of automatic voice analysis for the purpose of voice screening. PMID- 25795350 TI - Temporal Variables in Voice Therapy. AB - OBJECTIVE: This study analyzed temporal voice therapy data (duration and frequency) as reported in the scientific literature between 1975 and May 2013. METHODS: A PubMed search was conducted using the keywords "voice and therapy" and "therapy and dysphonia," resulting in 93 qualified publications. This information was complemented by data reported in scientific textbooks (47 publications). RESULTS: The results show that voice therapy lasts an average of 9.25 weeks distributed over 10.87 sessions of mostly 30 (36.36%) or 60 minutes (27.27%) and occurs once (34.55%) or twice (28.18%) per week. The total amount of time that a voice therapist spends face-to-face with the patient is 8.17 hours on average. Substantial geographic differences are observed, but only data from North America and Europe are sufficiently represented. For North American patients, more sessions (12.52) are reported over a shorter period (7.62 weeks), resulting in more face-to-face time (12.15 hours) between therapist and patient. However, the opposite trend is true for European patients, who average 10.99 sessions over 10.12 weeks, resulting in 7.68 hours of face-to-face time. The potential impact of diagnosis, clinical practices, prescription habits, health insurance rules, patient compliance, and study design on the representativeness of the data is discussed. CONCLUSIONS: These results offer a frame of reference regarding international practices for temporal variables in voice therapy that may be useful when identifying voice therapy dosage and optimal practice. PMID- 25795351 TI - Impact of Vagal Nerve Stimulation on Objective Vocal Quality, a Pilot Study. AB - OBJECTIVE: The purpose of this study was to determine the impact of vagal nerve stimulation (VNS) on the vocal quality using the dysphonia severity index (DSI). It was hypothesized that the objective vocal quality and other vocal characteristics are disordered in comparison with an age- and gender-matched control group. In addition, the acoustic vocal parameters were compared during three conditions: at rest, during normal stimulation, and raised stimulation. A significant relation between the amount of stimulation and the presence of disturbed acoustic parameters was hypothesized. METHODS: Subjective (auditory perceptual evaluation and voice handicap index) and objective (aerodynamic, vocal range, acoustic measurements and determination of the DSI) measurements were used to determine the vocal quality in 13 subjects with VNS in three different conditions (at rest and during normal and raised stimulation) and the age- and gender-matched control group. RESULTS: The subjects with VNS had a disordered perceptual vocal quality mainly characterized by the presence of a moderate roughness and slight breathiness, and the objective vocal quality by means of the DSI value is -2.4. During stimulation and especially during raised stimulation, the fundamental frequency is significantly increased. However, the subjects experienced no psychosocial handicapping effect of the vocal quality on the quality of life. CONCLUSIONS: Subjects with VNS have typical vocal characteristics. Ear, nose, and throat specialists and voice therapist must be aware of the presence of this vocal pattern at rest and during normal and raised stimulation. Especially, professional voice users and elite vocal performers must be informed before implantation. PMID- 25795352 TI - Longitudinal Voice Outcomes Following Advanced CO2 Laser Cordectomy for Glottic Cancer. AB - OBJECTIVE: CO2 laser cordectomy for glottic carcinoma offers excellent oncologic control on a per stage basis as compared with primary radiotherapy. We aim to further investigate the fluctuations of postoperative vocal outcomes following extended laser cordectomy for glottic cancer. DESIGN: Single center retrospective cohort study. METHODS: Eleven patients with glottic squamous cell carcinoma (SCC) who received CO2 laser cordectomy European Laryngological Society type III-IV with complete datasets at preoperative, immediate postoperative (within 4 months), and delayed (greater than 6 months) time points were included. RESULTS: All patients (n = 11) received cordectomy as their primary treatment. Tumor stage was divided evenly between T1 and T2. One patient was referred for post cordectomy thyroplasty. Mean Voice Handicap Index (VHI) scores increased in the immediate postoperative period (43.3-46.2) but did not reach significance (P > 0.05). Delayed postoperative VHI (23.3) demonstrated substantial improvement from both pre- and immediate postoperative levels (P = 0.047). Objective voice rating significantly declined initially (P = 0.03; Grade, P = 0.01; Breathiness) and recovered to similar preoperative levels. Maximum phonation time (MPT) showed substantial decreases at the initial postoperative period (P = 0.007). Although significant improvement was made at the delayed postoperative point (P = 0.009), MPT remained below the preoperative level (P = 0.028). No significant changes were seen in phonatory subglottic pressures. CONCLUSIONS: Patients undergoing extended CO2 laser cordectomy for glottic cancers can experience initial decline in voice quality; however, vocal function routinely returns to preoperative levels following the initial healing period. A small percentage of extended cordectomy patients may require further vocal interventions. PMID- 25795353 TI - Hoarseness and Risk Factors in University Teachers. AB - PURPOSE: To characterize the presence of hoarseness and the risk factors in male and female university teachers in private institutions in the city of Sao Paulo, Brazil. STUDY DESIGN: Cross-sectional survey. METHODS: Voice self-evaluation forms prepared by the Brazilian Ministry of Labor were administered to 846 university teachers in a private institution in the city of Sao Paulo, Brazil. RESULTS: Prevalence of hoarseness in the sample is 39.6%. Percentage of hoarseness is higher in females (51.8%) than in males (32.6%). Comparing hoarseness and time of teaching, it was observed that the percentage of hoarseness is lower in a time shorter or equal to 1 year, and it is higher in a time between 10 and 20 years. Percentage of hoarseness is lower in the maximum workload of one to three class hours per day compared with the other workloads. Percentage of hoarseness is lower when the maximum number of students per classroom is less than 30 than when it is between 101 and 150 students. Other factors like in terms of noise and sound competition, air pollution, and in terms of causing stress and anxiety, besides habits and style/quality of life are related to the presence of hoarseness. CONCLUSION: University teachers show high percentage of hoarseness. Factors, such as time of teaching, females, work organization, workplace, in terms of noise and sound competition, air pollution, and in terms of causing stress and anxiety, besides habits and style/quality of life, are related to the presence of hoarseness in this group. PMID- 25795354 TI - Results of Voice Rehabilitation With Provox Prosthesis and Factors Affecting the Voice Quality. AB - OBJECTIVES: Voice prosthesis is the standard of care for postlaryngectomy voice rehabilitation. We aimed to assess functional outcomes of Provox voice prosthesis, to study the impact of several clinical factors (timing of Provox insertion, type of pharyngeal closure, requirement of reconstruction, performance of myotomy, and radiotherapy) on the functional outcomes, and to record the complications associated with Provox voice prosthesis. STUDY DESIGN: Prospective nonrandomized cross-sectional observational study. METHODS: Thirty patients with postlaryngectomy speech rehabilitation with Provox prosthesis were studied. After the procedure, the patients were evaluated by a speech-language pathologist and assessed at immediate postoperative period and 6-month and 1-year interval using the parameters of functional outcomes GRBAS scale, maximal phonatory duration (MPD), and words per breath (WPB). SPSS Version 19 was used for statistical analysis. RESULTS: All patients had average good voice at the end of 1 year after Provox insertion with voice quality results improving with time. Number of patients having MPD more than 7 was 21, 29, and 30 at 0 months, 6 months, and 1 year, respectively. At the end of 1 year, 11 patients had WPB score between 15 and 19. Seven patients had complications: periprosthetic leak (4), central leak (1), hypertonic segment (1), and stricture of the neopharynx (1). Primary Provox insertion, nonrequirement of postoperative radiation, cricopharyngeal myotomy, and primary and vertical closure of neopharynx had a better influence on the outcome; however, the results were not statistically significant. CONCLUSIONS: Provox voice prosthesis provides consistent and good voice results, which improve with time. Periprosthetic leak is the most common complication. PMID- 25795355 TI - Automatic Assessment of Acoustic Parameters of the Singing Voice: Application to Professional Western Operatic and Jazz Singers. AB - INTRODUCTION: The obvious perceptual differences between various singing styles like Western operatic and jazz rely on specific dissimilarities in vocal technique. The present study focuses on differences in vibrato acoustics and in singer's formant as analyzed by a novel software tool, named BioVoice, based on robust high-resolution and adaptive techniques that have proven its validity on synthetic voice signals. MATERIAL AND METHODS: A total of 48 professional singers were investigated (29 females; 19 males; 29 Western operatic; and 19 jazz). They were asked to sing "a cappella," but with artistic expression, a well-known musical phrase from Gershwin's Porgy and Bess, in their own style: either operatic or jazz. A specific sustained note was extracted for detailed vibrato analysis. Beside rate (s(-1)) and extent (cents), duration (seconds) and regularity were computed. Two new concepts are introduced: vibrato jitter and vibrato shimmer, by analogy with the traditional jitter and shimmer of voice signals. For the singer's formant, on the same sustained tone, the ratio of the acoustic energy in formants 1-2 to the energy in formants 3, 4, and 5 was automatically computed, providing a quality ratio (QR). RESULTS: Vibrato rates did not differ among groups. Extent was significantly larger in operatic singers, particularly females. Vibrato jitter and vibrato shimmer were significantly smaller in operatic singers. Duration of vibrato was also significantly longer in operatic singers. QR was significantly lower in male operatic singers. CONCLUSIONS: Some vibrato characteristics (extent, regularity, and duration) very clearly differentiate the Western operatic singing style from the jazz singing style. The singer's formant is typical of male operatic singers. The new software tool is well suited to provide useful feedback in a pedagogical context. PMID- 25795356 TI - Vocal Fatigue Index (VFI): Development and Validation. AB - OBJECTIVE: To develop a psychometrically sound self-report questionnaire, the Vocal Fatigue Index (VFI), to help identify individuals with vocal fatigue (VF) and characterize their complaints. STUDY DESIGN: Descriptive research-scale development. METHODS: Four laryngologists and six speech-language pathologists specialized in voice created a beta version of the VFI (version 1), an index of 21 statements they considered to reflect VF. Two hundred patients presenting to two different clinics completed the VFI-1. Two items from VFI-1 were excluded because of poor item-to-total correlations. The final VFI of 19 items (version 2), completed by 105 patients with voice complaints and 70 vocally healthy individuals, was assessed for its psychometric properties. RESULTS: Test-retest reliability for the final VFI was generally strong, as was sensitivity and specificity using the classification table under logistic regression for correctly distinguishing individuals with and without VF. Moreover, factor analysis indicated that VF may be characterized by three factors: (1) factor 1, related to tiredness of voice and voice avoidance, (2) factor 2, related to physical discomfort associated with voicing, and (3) factor 3, related to improvement of symptoms with rest. CONCLUSION: The VFI is a standardized tool that can identify individuals with probable VF with good reliability, validity, sensitivity, and specificity. PMID- 25795357 TI - How do laryngeal and respiratory functions contribute to differentiate actors/actresses and untrained voices? AB - PURPOSE: The present study aimed to compare actors/actresses's voices and vocally trained subjects through aerodynamic and electroglottographic (EGG) analyses. We hypothesized that glottal and breathing functions would reflect technical and physiological differences between vocally trained and untrained subjects. METHODS: Forty participants with normal voices participated in this study (20 professional theater actors and 20 untrained participants). In each group, 10 male and 10 female subjects were assessed. All participants underwent aerodynamic and EGG assessment of voice. From the Phonatory Aerodynamic System, three protocols were used: comfortable sustained phonation with EGG, voice efficiency with EGG, and running speech. Contact quotient was calculated from EGG. All phonatory tasks were produced at three different loudness levels. Mean sound pressure level and fundamental frequency were also assessed. Univariate, multivariate, and correlation statistical analyses were performed. RESULTS: Main differences between vocally trained and untrained participants were found in the following variables: mean sound pressure level, phonatory airflow, subglottic pressure, inspiratory airflow duration, inspiratory airflow, and inspiratory volume. These variables were greater for trained participants. Mean pitch was found to be lower for trained voices. CONCLUSIONS: The glottal source seemed to have a weak contribution when differentiating the training status in speaking voice. More prominent changes between vocally trained and untrained participants are demonstrated in respiratory-related variables. These findings may be related to better management of breathing function (better breath support). PMID- 25795358 TI - Voice disorders in the general Greek population and in patients with laryngopharyngeal reflux. Prevalence and risk factors. AB - OBJECTIVES: To assess the prevalence of voice disorders in the general Greek population and in patients with laryngopharyngeal reflux (LPR) with the use of the reflux symptom index (RSI). STUDY DESIGN: Prospective epidemiological adult participant survey. SETTING: General Greek population. METHOD: The validated Greek version of the RSI was used to assess the prevalence of voice disorders in the general Greek population, as well as in patients with LPR, which were diagnosed using the RSI. The RSI questionnaire was completed by 340 (183 males and 157 females) randomly selected subjects. Subjects with RSI score of >13 were considered to be LPR patients. RESULTS: The prevalence of voice disorders, which was determined by the participants giving a positive response to the field "hoarseness or a problem with your voice," was found to be 38.5% in the general Greek population. In patients with LPR, "hoarseness or a problem with your voice" was present in 90.6%. The number of cigarettes smoked daily and the number of alcoholic drinks consumed daily, each correlated with the presence of voice disorders. No relationship was revealed between voice disorders and coexisting diseases and especially with gastroesophageal reflux disease, which was the most frequent reported disorder among peptic diseases. CONCLUSIONS: The prevalence of voice disorders, determined by a positive response to the question "hoarseness or a problem with your voice," is high (38.5%) in the general population and very high (90.6%) in patients with LPR. The number of tobacco cigarettes smoked daily and the number of alcoholic drinks consumed daily were found to be related to voice disorders. PMID- 25795359 TI - Acquired Glottic Stenosis-The Ongoing Challenge: A Review of Etiology, Pathogenesis, and Surgical Management. AB - OBJECTIVE: To review the etiology and pathogenesis of acquired glottic stenosis, as well as the workup, patient preparation, interventional options, and their changing trends, as described in the literature since the 19th century until the present day. METHODS: Literature from the PubMed search engine and the authors' personal experience were used. The search included up to date studies and historical reports covering different aspects of glottic stenosis, such as basic science, pathogenesis, anesthesia, and surgical techniques. RESULTS: At present, the most common etiology for acquired glottic stenosis is damage to the posterior commissure after intubation. Until less than a century ago, infectious diseases such as diphtheria and syphilis were the most prevalent etiologies. The common pathway of stenosis includes mucosal and cartilaginous ulcers, granulation formation, fibrosis, and tethering scars. Planning of surgical intervention must begin with the matching of expectations with the patient and considering voice versus airway functions. Preoperative tracheotomy should be considered for securing the airway. Anesthesia has to be carefully planned, and both the surgeon and the anesthesiologist have to be familiar with the options for tubeless jet ventilation. Surgical options include a variety of open and endoscopic resection and reconstruction procedures, which are reviewed in this article, followed by images and illustrations based on the authors' experience. CONCLUSION: Acquired glottic stenosis compromises the breathing, voice production, and airway protection. Reconstructing the stenosed glottis is one of the major challenges facing laryngologists in this era. For this reason, the surgeon must be familiar with the variety of treatment options. PMID- 25795360 TI - Vocal Characteristics of Elderly Women Engaged in Aerobics in Private Institutions of Salvador, Bahia. AB - PURPOSE: To characterize the voice of elderly people engaged in aerobics. METHODS: Collection of phonation /a:/ from 58 elderly people engaged in aerobics for perceptual voice analysis (RASATI scale) and computed acoustics (Multi Dimensional Voice Program Advanced, software of Kay Pentax(r), that analyzes up to 33 measures, proposing normal ranges according to sex). The Spearman correlation test was used, with significance level of 5%. RESULTS: The association between auditory-perceptual assessment of voice and acoustic parameters was not statistically significant but showed less vocal quality deviations. The association between acoustic measures and age was only statistically significant result for the measurement of fundamental frequency (f0) and maximum f0 (fhi). There was no correlation between time of aerobics and acoustic measures, but there was correlation of those measurements with age. There was a statistically significant positive correlation between f0 and fhi with minimal roughness and standard deviation of f0 with hoarseness, breathiness, and asthenia; jitter and shimmer measures with hoarseness, breathiness, and asthenia; noise measurements with hoarseness, breathiness, and harshness; measures of breaking voice hoarseness and breathiness; measures of voiceless segments with hoarseness and asthenia; measures of subharmonic with hoarseness; and measures of vocal tremor with breathiness, asthenia, and instability. There was a significant negative correlation between minimum f0 with breathiness; jitter measures with tension; and soft phonation index with roughness and instability. CONCLUSIONS: Elderly women engaged in aerobics showed mostly normal voice, with most values of acoustic measures within normal and positive correlations between perceptual and auditory vocals and acoustic aspects that suggest instability, noise, and vocal tremor. PMID- 25795361 TI - Cepstral Characteristics of Voice in Indian Female Classical Carnatic Singers. AB - BACKGROUND: The cepstral measures are gaining attention in the voice analysis as it is reported to be strong predictor of voice impairments. As singer's voice is reported to be present with more harmonics, it can be hypothesized that there would be an increase in the value of cepstral parameters. Also, little is known about the cepstral characteristics of voices in Indian classical Carnatic singers; and hence, the present study was undertaken with an aim to characterize the singer's voice using cepstral measures. METHODS: Thirty Indian female classical Carnatic singers and 30 nonsingers participated in the study. Phonation of vowel /a/ was recorded at their habitual pitch and loudness. The cepstral peak prominence and smoothened cepstral peak prominence were analyzed using the Hillenbrand algorithm available in Speech Tool software. Mean and standard deviation was calculated for each group. Obtained scores were analyzed using independent t test. RESULTS: Mean raw scores were found to be increased in classical Carnatic singers in comparison with nonsingers. Results of independent t test revealed significant difference between the means of singers and nonsingers for both the cepstral measures at P < 0.05. CONCLUSIONS: The present study investigated the cepstral characteristic of voice in singers and nonsingers. Results revealed that there was a significant difference between the means of singers and nonsingers indicating that cepstral parameters were higher among the singers in comparison with nonsingers. The obtained results were attributed to the harmonic organization in the voices of singers. PMID- 25795362 TI - Prevalence of voice problems in priests and some risk factors contributing to them. AB - OBJECTIVES: The purpose of this questionnaire study was to explore the prevalence and possible risk factors for voice problems in priests. METHODS: About 2044 evangelical Lutheran priests received a link to an electronic questionnaire and 44.1% (n = 901) completed it. Of the participants, 53% were males and 47% were females. RESULTS: The results showed that the prevalence of voice problems in priests was high. Of the participants, 24.5% had sought help for voice problems and 18% reported that they had been diagnosed with a voice disorder by a physician. Twenty-one percent considered themselves as having current voice problems, and 26.7% reported frequently occurring vocal symptoms. Voice-related absenteeism was reported by 11.6%. Significantly, more females than males reported voice problems. There were significant associations between frequently occurring vocal symptoms and several environmental- and health-related risk factors. More than half of the participants considered that they had received less than 5 hours of information on the voice and voice use. The association between frequently occurring vocal symptoms and the number of hours of information on the voice and voice use was significant. CONCLUSIONS: The results of this study indicate that the prevalence of voice problems among priests is high. Prevention of voice problems for priests is recommended. Voice training programs should be included in the curriculum for all those who are studying to become priests. For those already working as priests, practical courses on voice training could be arranged. Additionally, priests should get information on voice related issues from the occupational health care or other health care services. PMID- 25795363 TI - In-Office Excision En Masse of a Vocal Process Granuloma Using the Potassium Titanyl-Phosphate Laser. AB - BACKGROUND: In-office laryngeal surgery is taking on a more commonplace role in the treatment of laryngeal disorders. The potassium-titanyl-phosphate (KTP) laser has been a resourceful adjunct to the management of patients with mucosal lesions of the vocal cords. However, a paucity of data exists for its use in postintubation granulomas treated in-office. CLINICAL CASE: A 43-year-old female presented with voice hoarseness and found to have a large obstructing postintubation granuloma which was treated by in-office KTP laser and en masse excision. CONCLUSIONS: We report the successful case of a patient receiving in office treatment for a large vocal process granuloma using the KTP laser with en masse excision. The combined use of the KTP laser and forceps in-office can be valuable to the surgical management of vocal process granulomas, given their numerous recurrences. New avenues in office-based surgical management of laryngeal disorders can offer accessibility and decreased morbidity to patients. PMID- 25795364 TI - Vocal Performance of Group Fitness Instructors Before and After Instruction: Changes in Acoustic Measures and Self-Ratings. AB - OBJECTIVES: (1) To quantify acute changes in acoustic parameters of the voices of group fitness instructors (GFIs) before and after exercise instruction. (2) To determine whether these changes are discernible perceptually by the instructor. STUDY DESIGN: This is a pilot prospective cohort study. METHODS: Participants were six female GFIs, based in Brisbane, Australia. Participants performed a series of vocal tasks before and after instruction of a 60-minute exercise class. Data were obtained pertaining to fundamental frequency (pitch), intensity (volume), jitter, shimmer, harmonic-to-noise ratio (HNR), maximum duration of sustained phonation (MDSP), and pitch range. Additionally, self-ratings of voice quality were obtained before and after instruction. Data were analyzed using the Wilcoxon signed rank test. RESULTS: Significant increases (P <= 0.05) were found in fundamental frequency and intensity after instruction. No significant changes in jitter, shimmer, HNR, or MDSP were found before and after instruction. For the group, no significant change in self-ratings of voice quality occurred before and after instruction. CONCLUSIONS: Statistically significant changes in pitch and volume were found on acoustic analysis. However, these subtle changes remained within the limits of what is considered normal and representative of the participant's age and gender. Further research into the effects of exercise instruction on the voice is needed. PMID- 25795365 TI - Injection Augmentation for Chronic Cough. AB - OBJECTIVES/HYPOTHESIS: Chronic cough (CC) is a pervasive and expensive health problem in the United States. Almost as diverse as its etiologies are the available therapeutic options. When vocal fold paresis and CC coincide, injection augmentation may provide an alternative to standard medical and behavioral treatments for CC. Our objective was to assess the effect of injection augmentation in a selected group of patients with CC who had failed multiple medical and behavioral treatments. STUDY DESIGN: The study design is a retrospective case review. METHODS: Our study group included six subjects (1 male and 5 females; aged 24-84 y) who presented for laryngologic evaluation with a chief complaint of CC unresponsive to conventional medical and behavioral management. The cough severity index (CSI), reflux symptom index (RSI), dyspnea severity index (DSI), and voice handicap index-10 (VHI-10), as well as subjective evaluation were assessed before and after the injection augmentation of the vocal folds was undertaken. RESULTS: Five of six patients reported subjective improvement in cough. CSI scores improved in all six (average change 7.3, range 2 13). RSI and DSI scores also improved significantly after injection, whereas VHI 10 scores did not significantly change. One patient reported transient hoarseness after injection that completely resolved. One patient received injection augmentation three times, as the material resorbed and symptoms returned. CONCLUSIONS: Injection augmentation effected relief from CC in a select group of patients with CC refractory to previous medical and/or behavioral treatments. This intervention is a novel option for such patients and offers an alternative approach to medical treatment. PMID- 25795366 TI - The Relationship Between Acoustic Signal Typing and Perceptual Evaluation of Tracheoesophageal Voice Quality for Sustained Vowels. AB - OBJECTIVES: To investigate the relationship between acoustic signal typing and perceptual evaluation of sustained vowels produced by tracheoesophageal (TE) speakers and the use of signal typing in the clinical setting. METHODS: Two evaluators independently categorized 1.75-second segments of narrow-band spectrograms according to acoustic signal typing and independently evaluated the recording of the same segments on a visual analog scale according to overall perceptual acoustic voice quality. The relationship between acoustic signal typing and overall voice quality (as a continuous scale and as a four-point ordinal scale) was investigated and the proportion of inter-rater agreement as well as the reliability between the two measures is reported. RESULTS: The agreement between signal type (I-IV) and ordinal voice quality (four-point scale) was low but significant, and there was a significant linear relationship between the variables. Signal type correctly predicted less than half of the voice quality data. There was a significant main effect of signal type on continuous voice quality scores with significant differences in median quality scores between signal types I-IV, I-III, and I-II. CONCLUSIONS: Signal typing can be used as an adjunct to perceptual and acoustic evaluation of the same stimuli for TE speech as part of a multidimensional evaluation protocol. Signal typing in its current form provides limited predictive information on voice quality, and there is significant overlap between signal types II and III and perceptual categories. Future work should consider whether the current four signal types could be refined. PMID- 25795367 TI - An Examination of the Relationship Between Electroglottographic Contact Quotient, Electroglottographic Decontacting Phase Profile, and Acoustical Spectral Moments. AB - OBJECTIVES: To date, only a few studies have examined the possible relationship between electroglottographic (EGG) data and spectral characteristics of the voice. This study examined the possible association between EGG signal data (contact quotient [CQ] and decontacting phase profile) and spectral moments of the acoustic signal (spectral mean, spectral standard deviation (SD), spectral skewness, and spectral kurtosis). Furthermore, the possible effects of gender on these measurements were analyzed. METHODS: Sustained vowel /alpha/ productions were obtained from 48 normophonic individuals (24 adult males and 24 adult females). The central 1-second portions of the acoustic vowel samples were analyzed for spectral moments, and the EGG signal was analyzed for CQ (CQEGG), fundamental frequency (F0), and decontacting phase profile. RESULTS: Across all subjects, the spectral characteristics of the voice (in particular, spectral SD, skewness, and kurtosis) are significantly related to changes in the relative duration of vocal fold contact (as measured via CQEGG). In addition, significant effects of the profile of the EGG decontacting phase (ie, concave down/"knee" vs concave up/"no knee") on spectral SD were also observed, as well as a strong trend for decontacting phase profile to influence the spectral mean. DISCUSSION: Although the degree of vocal fold contact and differences in decontacting phase profile may have an influence on the spectral characteristics of the acoustic voice signal, the strength of correlations between CQEGG values and measures of spectral moments only accounted for approximately 13-16% of the variation in spectral distribution characteristics. These results stress the importance of the transformative role of the supraglottal vocal tract in producing an acoustic output that maintains some of the characteristics of the glottal source, but which modifies the source characteristics in ways not completely accounted for by single parameters such as CQEGG or EGG profile. PMID- 25795368 TI - Formant Frequencies and Bandwidths in Relation to Clinical Variables in an Obstructive Sleep Apnea Population. AB - OBJECTIVES: We investigated whether differences in formants and their bandwidths, previously reported comparing small sample population of healthy individuals and patients with obstructive sleep apnea (OSA), are detected on a larger population representative of a clinical practice scenario. We examine possible indirect or mediated effects of clinical variables, which may shed some light on the connection between speech and OSA. STUDY DESIGN: In a retrospective study, 241 male subjects suspected to suffer from OSA were examined. The apnea-hypopnea index (AHI) was obtained for every subject using overnight polysomnography. Furthermore, the clinical variables usually reported as predictors of OSA, body mass index (BMI), cervical perimeter, height, weight, and age, were collected. Voice samples of sustained phonations of the vowels /a/, /e/, /i/, /o/, and /u/ were recorded. METHODS: Formant frequencies F1, F2, and F3 and bandwidths BW1, BW2, and BW3 of the sustained vowels were determined using spectrographic analysis. Correlations among AHI, clinical parameters, and formants and bandwidths were determined. RESULTS: Correlations between AHI and clinical variables were stronger than those between AHI and voice features. AHI only correlates poorly with BW2 of /a/ and BW3 of /e/. A number of further weak but significant correlations have been detected between voice and clinical variables. Most of them were for height and age, with two higher values for age and F2 of /o/ and F2 of /u/. Only few very weak correlations were detected between voice and BMI, weight and cervical perimeter, wich are the clinical variables more correlated with AHI. CONCLUSIONS: No significant correlations were detected between AHI and formant frequencies and bandwidths. Correlations between voice and other clinical factors characterizing OSA are weak but highlight the importance of considering indirect or mediated effects of such clinical variables in any research on speech and OSA. PMID- 25795369 TI - Effect of Voice Onset Type on Vocal Attack Time. AB - Vocal attack time (VAT) is the time lag between the growth of sound pressure (SP) and electroglottographic (EGG) signals at vocal initiation. The characteristics of voice initiation are associated with issues of vocal hygiene, efficiency, and quality. Vocal onsets have commonly been qualitatively characterized into three types: hard, simultaneous, and breathy. This study examines the effect of voice onset type on VAT values in normal speakers. SP and EGG recordings were obtained for 55 female and 57 male subjects while producing multiple tokens of three tasks (sustained /alpha/ and "always" as unaspirated onsets, and "hallways" as an aspirated onset). Results revealed a significant effect of onset type on VAT, with the mean VAT for the "hallways" (aspirated) task greater than the mean VAT for the sustained /alpha/ and "always" (unaspirated) tasks. There was no significant VAT difference between the sustained /alpha/ and "always" tasks. Findings confirm the sensitivity of the VAT measure to vocal onset type and suggest its potential application as an objective and quantitative clinical measure of the type of vocal onset. PMID- 25795370 TI - An Aerodynamic Study of Phonations in Patients With Parkinson Disease (PD). AB - BACKGROUND: The precise comparison of the voice characteristics of Parkinson disease (PD) patients with age-matched normal subjects is still one of the important research projects. The present study aimed at comparing the voice characteristics in sustained phonations of PD patients with an age-matched control group. METHODS: The subjects were 30 Japanese PD patients (15 males and 15 females). The control group consisted of 30 age-matched normal Japanese subjects (15 males and 15 females). Each subject was required to phonate into a mouthpiece attached to Vocal Function Analyzer (PS-77E; Nagashima Medical Instrumental Corporation, Tokyo, Japan) with the airway interruption system, and expiratory lung pressure, mean flow rate, fundamental frequency and intensity of voice, and pitch range were measured. Maximum phonation time was also assessed. RESULTS: The highest pitch level was significantly lower in the PD group than that of the control group in both sexes, whereas the lowest pitch level was significantly higher in the PD group only in males. In both sexes, the pitch range was significantly narrower in the PD group than in the control group. There was no significant difference in intensity, mean flow rate, expiratory pressure, or maximum phonation time between the two groups, for both males and females. CONCLUSION: Only remarkable difference in the voice characteristics between PD patients and age-matched normal elderlies was limited to the narrowing of the pitch range in PD patients. The restriction in pitch regulation in PD patients was considered to be because of difficulty in reciprocal control of the laryngeal muscles secondary to latent rigidity. PMID- 25795371 TI - Selection of Voice Therapy Methods. Results of an Online Survey. AB - OBJECTIVES: Providing an evidence basis for voice therapy in the German-speaking countries faces the challenge that-for historical reasons-a variety of direct voice therapy methods is available. The aim of this study was to clarify which therapy methods are chosen and the underlying principles for this selection. METHODS: An online survey was implemented to identify to what extent the variety of methods described in theory is also applied in practice. A total of 434 voice therapists in Germany, Austria, and Switzerland were asked, among other things, which methods they prefer. RESULTS: A significant majority of therapists do not apply one specific method but rather work with a unique combination of direct voice therapy methods for individual clients. These results show that the variety of methods described in the literature is also applied in voice therapy practice. The combination of methods becomes apparent during the choice of exercises. The type of voice disorder plays no decisive role in the method selection process, whereas certain patient variables do have an influence on this process. In particular, the patients' movement restrictions, their state of mind or mood on a given day, and aspects of learning theory are taken into account. CONCLUSIONS: The results suggest that a patient-oriented selection of appropriate exercises is of primary importance to voice therapists and that they rarely focus on specific direct voice therapy methods. It becomes clear that an evaluation of single methods does not correspond to practical experience, and therefore, an overall evaluation of voice therapy appears to be more useful. PMID- 25795372 TI - Singers' and Nonsingers' Perception of Vocal Vibrato. AB - Vibrato, a small, nevertheless an important component in the singing voice is known to enrich the overall singing voice quality. However, in the perception of overall performance, it is often neglected. Singing performance is often appreciated by a mixed audience of those who love music, but not necessarily sing and other singers who may or may not be teachers of singing. OBJECTIVES: The objectives of the present study were aimed at investigating singers' and nonsingers' perception of vocal vibrato and its effect on the ratings of singer's overall performance. METHOD: Prerecorded audio samples of the chorus of a hymn (How Great Thou Art) as sung by 10 singers (both men and women) were played via a speaker to two groups of judges which consisted of three experienced singers and three experienced nonsingers. The singer judges (SJs) were vocal instructors in Western classical, music theater, pop, and contemporary styles. Seven parameters (presence of vibrato, rate, extent, conspicuousness, quality, periodicity, and type) related to vibrato were evaluated through auditory perception by these two groups of judges on a rating scale developed specifically for the study, and one parameter evaluated singer's overall performance. RESULTS: Cohen's Kappa statistical analysis was used for inter-rater reliability within groups. Nonsinger judges (NSJs) within the group showed varied ratings as did SJs, yet SJs did have higher agreement than NSJs. Chi-square analysis was used across groups. Both groups were distinct from each other in their perception of vibrato. Ratings of singer's overall performance were not affected for NSJs, but certainly affected for SJ. CONCLUSION: It could not be concluded that ratings on singer's overall performance was affected as a result of vibrato. Since vibrato is often over-ridden by the singer's voice. But a rare occasion can arise where a vibrato may not sound pleasant and can affect the listener's perception of the singer's performance. Often a feedback from listeners would help monitor singers' performance. PMID- 25795373 TI - Growth Factors and COX2 Expression in Canine Perivascular Wall Tumors. AB - Canine perivascular wall tumors (PWTs) are a group of subcutaneous soft tissue sarcomas developing from vascular mural cells. Mural cells are involved in angiogenesis through a complex crosstalk with endothelial cells mediated by several growth factors and their receptors. The evaluation of their expression may have relevance since they may represent a therapeutic target in the control of canine PWTs. The expression of vascular endothelial growth factor (VEGF) and receptors VEGFR-I/II, basic fibroblast growth factor (bFGF) and receptor Flg, platelet-derived growth factor B (PDGFB) and receptor PDGFRbeta, transforming growth factor beta1 (TGFbeta1) and receptors TGFbetaR-I/II, and cyclooxygenase 2 (COX2) was evaluated on frozen sections of 40 PWTs by immunohistochemistry and semiquantitatively scored to identify their potential role in PWT development. Statistical analysis was performed to analyze possible correlations between Ki67 labeling index and the expression of each molecule. Proteins of the VEGF-, PDGFB , and bFGF-mediated pathways were highly expressed in 27 (67.5%), 30 (75%), and 19 (47.5%) of 40 PWTs, respectively. Proteins of the TGFbeta1- and COX2-mediated pathways were highly expressed in 4 (10%) and 14 (35%) of 40 cases. Statistical analysis identified an association between VEGF and VEGFR-I/II (P = .015 and .003, respectively), bFGF and Flg (P = .038), bFGF and PDGFRbeta (P = .003), and between TGFbeta1 and COX2 (P = .006). These findings were consistent with the mechanisms that have been reported to play a role in angiogenesis and in tumor development. No association with Ki67 labeling index was found. VEGF-, PDGFB-, and bFGF-mediated pathways seem to have a key role in PWT development and growth. Blockade of tyrosine kinase receptors after surgery could represent a promising therapy with the aim to reduce the PWT relapse rate and prolong the time to relapse. PMID- 25795374 TI - Re: Haddad et al. Barriers to clinical trial recruitment in head and neck cancer. PMID- 25795375 TI - Reliability of the autoimmune bullous disease quality of life (ABQOL) questionnaire in the USA. AB - PURPOSE: To evaluate the reliability of the autoimmune bullous diseases quality of life (ABQOL) questionnaire in a North American patient cohort. METHODS: Patients attending the dermatology clinics of the University of Pennsylvania with a histological diagnosis of an autoimmune bullous disease (AIBD) and self reported proficiency in English were recruited to participate in the study. Patients completed the ABQOL questionnaire at Day 0 and Day 3. Internal consistency was calculated through Cronbach's alpha. Test-retest reliability was determined by the intraclass correlation coefficient. RESULTS: Of the 45 patients enrolled in the study, 39 patients (87 %) participated to completion. The mean age was 60.7 years with an equal sex distribution observed. Patients had a range of AIBD including pemphigus vulgaris, bullous pemphigoid, pemphigus foliaceus, epidermolysis bullosa acquisita, mucous membrane pemphigoid and linear IgA disease. Cronbach's alpha was calculated to be 0.90. The intraclass correlation coefficient was calculated to be 0.93 (95 % confidence interval 0.88-0.94). CONCLUSION: The ABQOL was found to be reliable tested by internal consistency and test-retest reliability in an American patient cohort. It represents a promising disease-specific outcome measure for patients with AIBD. PMID- 25795376 TI - Effect of the depressor septi nasi muscle modification on nasal tip rotation and projection. AB - BACKGROUND: The nasal tip is an important esthetic feature of the face and surgery on it is the most challenging part of a rhinoplasty. In the present study, we evaluated the effects of modification of the depressor septi nasi muscle on nasal tip rotation and projection. METHODS: Eighty primary rhinoplasty patients who required nasal tip modifications were enrolled in a randomized clinical trial from October 2008 to March 2012. A study group composed of 40 patients underwent rhinoplasty including cutting and repositioning of the depressor septi nasi muscle and another group of 40 patients (control) underwent rhinoplasty without manipulation of the depressor septi nasi muscle. Nasal tip rotation and projection, and patient satisfaction were evaluated before and 6 months after the operation. RESULTS: Following rhinoplasty including cutting of the depressor septi nasi muscle, nasal tip rotation and projection, and patient satisfaction were improved in 70, 57.5, and 85 % of the patients, respectively; and in the control group, they were improved in 82.5, 55, and 67.5 %, respectively (P = 0.089, 0.607, and 0.069). CONCLUSION: Cutting and repositioning of the depressor septi nasi muscle as an adjunct to rhinoplasty is not associated with any additional advantage in terms of nasal tip rotation and projection, or patient satisfaction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25795377 TI - The effects of acute and chronic administration of phosphatidylserine on cell proliferation and survival in the dentate gyrus of adult and middle-aged rats. AB - Phosphatidylserine (PS) is an acidic phospholipid that is widely used as an alternative and/or complementary treatment of cognitive impairments. We hypothesize that these changes may be attributable, at least in part, to alterations in hippocampal neurogenesis. The aim of the present study was to investigate the effects of acute and chronic PS administration on hippocampal cell proliferation and survival in adult (5 months old) and middle-aged (12 months old) male Wistar rats. PS was injected daily (50mg/kg, i.p.) during 7 days (acute experiment) or 21 days (chronic experiment). To label newly generated cells, rats received a single BrdU injection (200mg/kg, i.p.) one day before PS treatment. The object recognition test was performed, and the rats were perfused. The brains were removed and processed with immunohistochemistry techniques for Ki 67 (cell proliferation) and BrdU (cell survival). The acute and chronic regimens were unable to promote cognitive improvement in either age group in the object recognition test. The analysis of cell proliferation showed a significant increase in the number of Ki-67-positive cells after acute and chronic PS administration in both age groups. The analysis of cell survival showed that acute and chronic PS administration increased the number of BrdU-positive cells only in adult animals. PMID- 25795378 TI - SIRP/CD47 signaling in neurological disorders. AB - Microglia play important roles in the process of neuronal injury and recovery. Numeous surface receptors have been described to regulate microglial activation. These receptors tightly mediate normal microglial functions including cell mobility, phagocytosis, and production of inflammatory mediators or trophic factors. In recent years, significant progresses have been achieved for understanding the signaling mechanisms underlying these receptors. Their specific roles in neurological diseases have been documented. This review will focus on the signal regulatory protein (SIRP) and its ligand CD47, two surface receptors expressed on microglia and other cells in the central nervous system (CNS) such as neurons. We will discuss the involvement of SIRP/CD47 signaling in microglial activation and in the interplay between microglia and other CNS cells. Current studies reveal the importance of CD47 and SIRPalpha in the process of neuroinflammation in the CNS disorders. The dual and contradictory role of CD47 suggests that targeting the SIRPalpha/CD47 signaling may achieve different effects depending on disease stage. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25795379 TI - Beyond the "B": a new concept of the surgical staple enabling miniature staplers. AB - BACKGROUND: Surgical staplers currently all rely on the same staple form-the "B" which necessitates a high delivery profile (12 mm). A novel "D" shape staple allows for an extremely low profile of the applicator. The acute and long-term efficacy of a D-shaped staple (Cardica, Redwood City, CA, USA) was compared to conventional B-form staples (Covidien, Norwalk, CN, USA) in an animal model for intestinal transections and anastomoses. METHODS: Jejunojejunal anastomoses (JJ) were performed via mini-laparotomy in a swine model. White & blue D- and B-shaped staples were studied in three groups (planned survival 14-84 days). Intraoperative assessment included completeness of staple line, hemostasis, and need for intervention. Postoperatively, animals were evaluated for complications. At the time of sacrifice, gross pathological and histological assessments were performed. RESULTS: Twenty-three animals had 40 anastomoses (23 "D" and 17 "B" staple anastomoses) with no intraoperative mortalities. One "D" staple application required a manual extension of the cut. Acute hemostasis was 100%. Group 1 (n = 5) compared white staples in JJs (D staple n = 5; B staple n = 5; 14 day survival = 100%). Group 2 (n = 12) compared white staples in JJs (D staple n = 12; B staple n = 6; 34-day survival = 92 %). One animal died on day 4 for a non staple related cause. Group 3 (n = 6) compared blue staples in JJs (D staple n = 6; B staple n = 6; 84 day survival = 84%). One animal died on day 18 due to an obstruction at the B staple JJ caused by stricture. There were no other bleeding, leaks or strictures in any of the groups. Gross pathology and histology were unremarkable in all JJs. CONCLUSIONS: This study showed no difference in intraoperative performance and the chronic healing response in JJs between D- and B-shaped staples. Based on these findings, the D-shaped staple elicits a normal healing response in jejunostomies and offers the possibility of clinical use of this advance in staple design. PMID- 25795380 TI - Erratum to: Update of guidelines on laparoscopic (TAPP) and endoscopic (TEP) treatment of inguinal hernia (International Endohernia Society). PMID- 25795381 TI - Initial experience of laparoscopic pelvic exenteration and comparison with conventional open surgery. AB - BACKGROUND: Generalization of laparoscopic pelvic surgery has brought about profound knowledge of the pelvic anatomy and has encouraged expansion of indications for laparoscopic surgery to extended pelvic surgery. Pelvic exenteration (PE) is still a demanding surgical procedure and remains an essential technique for pelvic surgery although minimally invasive and function preserving surgery is in the mainstream of surgical treatment. However, the techniques of laparoscopic PE (LPE) have been rarely explained nor has its feasibility been fully evaluated. The aim of this study was to describe important technical points and to assess the feasibility of LPE for pelvic malignancies. METHODS: Data on 67 patients with pelvic malignancies, who underwent PE between June 2006 and August 2014, were analyzed retrospectively. LPE has been indicated since 2013. Patients were divided into the LPE group (n = 9) and the conventional open PE (OPE) group (n = 58). RESULTS: Operative time in the LPE and OPE groups was similar (935 vs. 883 min, p = 0.398). Intraoperative blood loss in the LPE group was significantly less than that in the OPE group (830 vs. 2769 ml, p = 0.003). Pathological R0 resection rate was similar in both groups (77.8 vs. 75.9%). Overall incidence of any complication and major complications were much lower in the LPE group (66.7 and 0%) compared to the OPE group (89.7 and 32.8%), although not statistically significant (p = 0.094 and 0.053, respectively). Postoperative hospital stay was significantly shorter in the LPE group than in the OPE group (27 vs. 43 days, p = 0.003). CONCLUSIONS: We confirmed that LPE for pelvic malignancies resulted in less blood loss, a lower complication rate, and shorter postoperative hospital stay compared to OPE. LPE performed by an experienced pelvic surgeon was safe and efficient, and might be a promising option for carefully selected patients. PMID- 25795382 TI - Turkish students' perceptions of professionalism at the beginning and at the end of medical education: a cross-sectional qualitative study. AB - AIM: Medical students' perceptions of professionalism might reflect the impact of the current educational processes on their professional identity development. This study focuses on Ankara University Faculty of Medicine students' perceptions of 'good doctor' along with the factors effective on the formation of these perceptions. METHOD: Six focus groups with 59 medical students from Grade-1 and Grade-6 were held. The transcripts of discussions were analyzed thematically. RESULTS: Results regarding 'being a good physician' mostly mirrored the findings of previous studies framing the medical professionalism concept. The thematic pattern of the discussions on the relation between professional development and medical education suggests that students suffer from a gradual erosion of perception during medical education. That the education cannot either change the person for the better or might downgrade the person instead of improving her/him were shared by participants from both grades. Students consider clinical practice and role models two main variables determining the person's qualification as a professional. CONCLUSIONS: The formal and hidden programs determine the quality and efficacy of the professional education together. Attempts to restructure medical education must recognize the reciprocal dynamics between these two components and, thus, should carefully work out the practical aspect of the educational processes. PMID- 25795383 TI - Discerning applicants' interests in rural medicine: a textual analysis of admission essays. AB - BACKGROUND: Despite efforts to construct targeted medical school admission processes using applicant-level correlates of future practice location, accurately gauging applicants' interests in rural medicine remains an imperfect science. This study explores the usefulness of textual analysis to identify rural oriented themes and values underlying applicants' open-ended responses to admission essays. METHODS: The study population consisted of 75 applicants to the Rural Physician Leadership Program (RPLP) at the University of Kentucky College of Medicine. Using WordStat, a proprietary text analysis program, applicants' American Medical College Application Service personal statement and an admission essay written at the time of interview were searched for predefined keywords and phrases reflecting rural medical values. From these text searches, derived scores were then examined relative to interviewers' subjective ratings of applicants' overall acceptability for admission to the RPLP program and likelihood of practicing in a rural area. RESULTS: The two interviewer-assigned ratings of likelihood of rural practice and overall acceptability were significantly related. A statistically significant relationship was also found between the rural medical values scores and estimated likelihood of rural practice. However, there was no association between rural medical values scores and subjective ratings of applicant acceptability. CONCLUSIONS: That applicants' rural values in admission essays were not related to interviewers' overall acceptability ratings indicates that other factors played a role in the interviewers' assessments of applicants' acceptability for admission. PMID- 25795384 TI - Molecular diagnosis and genotype analysis of Giardia duodenalis in asymptomatic children from a rural area in central Colombia. AB - Giardiasis is a parasitic infection that affects around 200 million people worldwide. This parasite presents a remarkable genetic variability observed in 8 genetic clusters named as 'assemblages' (A-H). These assemblages are host restricted and could be zoonotic where A and B infect humans and animals around the globe. The knowledge of the molecular epidemiology of human giardiasis in South-America is scarce and also the usefulness of PCR to detect this pathogen in fecal samples remains controversial. The aim of this study was to conduct a cross sectional study to compare the molecular targets employed for the molecular diagnosis of Giardia DNA and to discriminate the parasite assemblages circulating in the studied population. We analyzed 181 fecal samples from Children at La Virgen, Cundinamarca, Colombia that were DNA-extracted and analyzed by SSU rDNA, tpi and gdh loci. We observed positivity by microscopy of 13% and by PCR around 76-80% depending on the molecular marker. Additionally, a lack of statistical concordance between microscopy and PCR was detected. Regarding the genetic assemblages, we detected assemblage A (3%), assemblage B (90%) and mixed infections assemblages A+B (7%). Hence, the sub-assemblages were typed as AI, AII, BIII and BIV across the population. This study represents a reliable attempt to understand the molecular epidemiology of giardiasis in Colombia and the use of PCR to detect cryptic infections. The epidemiological implications are herein discussed. PMID- 25795385 TI - Temporal dynamics and subpopulation analysis of Theileria orientalis genotypes in cattle. AB - In Australia, outbreaks of clinical theileriosis caused by Theileria orientalis have been largely associated with the Ikeda genotype which can occur as a sole infection, or more commonly, as a mixture of genotypes. The most prevalent genotype, Chitose, frequently co-occurs with type Ikeda, however the role of this genotype in clinical disease has not been clearly established. Furthermore, the dynamics of individual genotypes in field infection of cattle have not been examined. In this study we developed quantitative PCR (qPCR) and genotyping methods to examine the role of the Chitose genotype in clinical disease and to investigate the temporal dynamics of T. orientalis Ikeda, Chitose and Buffeli genotypes in naive animals introduced to a T. orientalis-endemic area. Analysis of the major piroplasm surface protein (MPSP) genes of Chitose isolates revealed the presence of two distinct phylogenetic clusters, Chitose A and Chitose B. A genotyping assay aimed at determining Chitose A/B allele frequency revealed that the Chitose A phylogenetic cluster is strongly associated with clinical disease but nearly always co-occurs with the Ikeda genotype. qPCR revealed that the Chitose genotype (particularly Chitose A), undergoes temporal switching in conjunction with the Ikeda genotype and contributes substantially to the overall parasite burden. The benign Buffeli genotype can also undergo temporal switching but levels of this genotype appear to remain low relative to the Ikeda and Chitose types. Interplay between vector and host immunological factors is presumed to be critical to the population dynamics observed in this study. Genotypic switching likely contributes to the persistence of T. orientalis in the host. PMID- 25795386 TI - Altered functional connectivity between medial prefrontal cortex and the inferior brainstem in major depression during appraisal of subjective emotional responses: A preliminary study. AB - OBJECTIVE: We tested the hypothesis that reduced rostral anterior cingulate cortex (rACC)-subcortical functional connectivity in depressed subjects might account for depression-related autonomic dysregulation. METHODS: Ten healthy and ten depressed subjects categorized their immediate subjective emotional responses to picture sets while undergoing functional magnetic resonance imaging and electrocardiography. Using an rACC cluster commonly activated in both groups by emotion categorization as a seed region, we then performed voxel-wise functional connectivity analyses to examine rACC connectivity across the brain in depressed and control subjects. RESULTS: rACC had significantly stronger connectivity with a region of the inferior pons in controls than in depressed subjects. Within subjects differences in rACC-pons connectivity also significantly correlated with measures of both heart rate variability and depression severity. CONCLUSIONS: These findings support the hypothesis that autonomic dysregulation in depression may be associated with a functional disconnection between rACC and autonomic brainstem nuclei. PMID- 25795387 TI - [A very misleading vulvar tumor]. PMID- 25795388 TI - Modulation of gene expression and cell cycle by botryosphaeran, a (1->3)(1->6) beta-d-glucan in human lymphocytes. AB - There is growing interest in the anticancer and immunomodulatory potential of fungal beta-d-glucans. In the present study, the modulation of gene expression via RT-qPCR and cell cycle kinetics via flow cytometry were assessed in human normal and tumor (Jurkat) lymphocytes after treatment with botryosphaeran (a fungal (1->3)(1->6)-beta-d-glucan) from Botryosphaeria rhodina MAMB-05. Cell cultures were treated with botryosphaeran either alone, or in combination with doxorubicin (DXR), in a post-treatment protocol. The expression of genes involved in immunomodulatory processes, apoptosis and cell cycle control, as well as beta d-glucans cell receptors were assessed. Flow cytometry analysis identified tetraploid Jurkat cells in G1 phase when treated with botryosphaeran combined with DXR. This antiproliferative effect in G1 may be associated with down regulation of the expression of genes involved in the G1 checkpoint. The repression of the CCR5 gene following botryosphaeran treatment, either alone or in combination with DXR, in tumor lymphocytes indicates a possible affinity of this particular (1->3)(1->6)-beta-d-glucan for the receptor CCR5. Therefore, botryosphaeran action appears to be involved in the repression of genes related to the G1 phase of the cell cycle and possibly in the interaction of the botryosphaeran, either alone, or in combination with DXR, with the CCR5 receptor. PMID- 25795389 TI - Improving the physical and moisture barrier properties of Lepidium perfoliatum seed gum biodegradable film with stearic and palmitic acids. AB - Stearic and palmitic fatty acids (10%, 20% and 30%, W/W gum) were used to improve the barrier properties of Lepidium perfoliatum seed gum (LPSG) film. The impact of the incorporation of fatty acids into the film matrix was studied by investigating the physical, mechanical, and barrier properties of the films. Addition of stearic and palmitic fatty acids to LPSG films reduced their water vapor permeability (WVP), moisture content, water solubility and water adsorption. Increasing fatty acid concentration from 10% to 30%, reduced the elongation at break (EB). Lower values of tensile strength (TS) and elastic modulus (EM) were obtained in the presence of higher fatty acids concentrations. Incorporation of fatty acids led to production of opaque films and the opacity increased as function of fatty acids concentration. Results showed that moisture content, water solubility and WVP decreased as the chain length of fatty acid increased. Therefore, LPSG-fatty acids composite film could be used for packaging in which a low affinity toward water is needed. PMID- 25795390 TI - Molecular mechanism on cadmium-induced activity changes of catalase and superoxide dismutase. AB - Cadmium contributes to adverse effects of organisms probably because of its ability to induce oxidative stress via alterations in activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), but their molecular mechanisms remain unclear. We investigated the molecular mechanism of CAT and SOD response under Cd-induced oxidative stress in the liver of zebrafish. The enzyme activity changes observed in vitro were consistent with those seen in vivo, indicating the direct interaction of CAT and SOD with Cd contributes to their activity change in vivo. Further experiments utilizing multiple spectroscopic methods, isothermal titration calorimetry and a molecular docking study were performed to explore the mechanism of molecular interaction of CAT and SOD with Cd. Different interaction patterns were found that resulted in misfolding and changed the enzyme activities. Taken together, we suggest the misfolding of CAT and SOD contributes to their activity change under Cd-induced oxidative stress in vivo. PMID- 25795391 TI - A cost-utility analysis of ingenol mebutate gel for the treatment of actinic keratosis: a Scottish perspective. AB - BACKGROUND: Actinic keratosis (AK) is a UV-induced, pre-malignant skin condition that is common in adults over 60 years of age with fair skin in Scotland. The most commonly prescribed first-line treatment for AK in Scotland is currently diclofenac gel (3 %). Ingenol mebutate gel is a recently developed topical therapy available in two strengths for the treatment of AK lesions on the face and scalp (150 mcg/g once daily for 3 consecutive days) or trunk and extremities (500 mcg/g once daily for 2 consecutive days). OBJECTIVE: To compare the cost effectiveness of two strengths of ingenol mebutate gel developed to treat AK lesions on the face and scalp (150 mcg/g once daily for 3 consecutive days) or trunk and extremities (500 mcg/g once daily for 2 consecutive days) with other first-line AK therapies including diclofenac gel, 5-FU, 5-FU/salicylic acid, and cryotherapy for the first-line treatment of AK in adult patients, from the perspective of the National Health Service (NHS) in Scotland. METHODS: A cost utility analysis was conducted using a decision-tree approach to calculate the costs and benefits of different treatment strategies for AK on the face and scalp or trunk and limbs over a 12-month time horizon. Data on the relative efficacy of treatments were obtained from a systematic literature review and meta-analysis. Utility scores and resource-use data were obtained from published sources. RESULTS: Over 12 months, ingenol mebutate 150 mcg/g gel and 500 mcg/g gel were cost-effective compared with the most commonly used topical therapy in Scotland, diclofenac (3 %) gel, at a willingness-to-pay threshold of L20,000 per QALY, with a minimal additional cost of L43 and L105, respectively per QALY gained. CONCLUSIONS: Ingenol mebutate gel is a cost-effective therapy for the first-line treatment of AK from a Scottish NHS perspective. PMID- 25795392 TI - Postoperative brain metastases in soft tissue sarcomas. AB - Brain metastases (BMs) from soft tissue sarcoma (STS) are rare but lethal. We reviewed 187 consecutive patients with STS treated with definitive surgery in Nagoya University Hospital from 2004 to 2014. There were 10 patients with neurofibromatosis-1 (NF-1). We investigated estimated brain metastasis free survival (BMFS) after surgery and overall survival (OS) after BMs in STS. The factors that affected BMFS were also investigated. Eight of 187 patients (4.3%) developed BM with a median period of 18.2 (range 8.8-42.6) months after surgery. Seven of 8 BM patients had metastases at other sites. Estimated 5 year BMFS rate after surgery was 95.2%, and 3 month OS rate after BM was 25.0%. NF-1 (p<0.0001), histological subtype of MPNST (p=0.008), and primary tumor size>=5 cm (p=0.021) were significantly associated with increasing incidence of BM. In this study, postoperative BMs were common in patients with NF-1, MPNST, and large tumors. Considering the impact of NF-1 on BMFS, careful follow up for BM is necessary for NF-1 patients with metastases at other sites. PMID- 25795393 TI - Diagnostic and prognostic significance of flow cytometry immunophenotyping in patients with leptomeningeal carcinomatosis. AB - Some patients with epithelial-cell cancers develop leptomeningeal carcinomatosis (LC), a severe complication difficult to diagnose and with an adverse prognosis. This study explores the contribution of flow cytometry immunophenotyping (FCI) to the diagnosis and prognosis of LC. Cerebrospinal fluid (CSF) samples from patients diagnosed with LC were studied using FCI. Expression of the epithelial cell adhesion molecule (EpCAM) was the criterion used to identify the epithelial cells. To test the diagnostic precision, 144 patients (94 diagnosed with LC) were included. The prognostic value of FCI was evaluated in 72 patients diagnosed with LC and eligible for therapy. Compared with cytology, FCI showed greater sensitivity and negative predictive value (79.79 vs. 50%; 68.85 vs. 51.55%, respectively), but lower specificity and positive predictive value (84 vs. 100%; 90.36 vs. 100%, respectively). The multivariate analysis revealed that the percentage of CSF EpCAM+ cells predicted an increased risk of death (HR: 1.012, 95% CI 1.000-1.023; p=0.041). A cut-off value of 8% EpCAM+ cells in the CSF distinguished two groups of patients with statistically significant differences in overall survival (OS) (p=0.018). This cut-off value kept its statistical significance regardless of the absolute CSF cell-count. The FCI study of the CSF improved the sensitivity for diagnosing LC, but refinement of the technique is needed to improve specificity. Furthermore, quantification of CSF EpCAM+ cells was revealed to be an independent prognostic factor for OS in patients with LC eligible for therapy. An 8% cut-off value contributed to predicting clinical evolution before initiation of therapy. PMID- 25795394 TI - Agreements and practical experience of trauma care cooperation in Central Europe: the "Boundless Trauma Care Central Europe" (BTCCE) project. PMID- 25795395 TI - Assessment of RV function using gated blood pool SPECT. PMID- 25795396 TI - Dendrimer-functionalized mesoporous silica as a reversed-phase/anion-exchange mixed-mode sorbent for solid phase extraction of acid drugs in human urine. AB - A new dendrimer-functionalized mesoporous silica material based on large-pore 3D cubic Korea Advanced Institute of Science and Technology-6 (KIT-6) was synthesized by the growing of dendritic branches inside the mesopores of aminopropyl functionalized KIT-6. Detailed physical characterizations using transmission electron microscopy, nitrogen adsorption-desorption measurements, Fourier transform infrared (FTIR) spectroscopy, and elemental analysis reveal that the multifunctional dendrimers have been grown successfully within the confined spaces of mesopores. Although the 3D ordered mesoporous architecture of KIT-6 was well preserved, there was a significant and continuous decrease in pore size, specific surface area (SBET) and pore volume when increasing dendrimer generation up to six. In order to get a compromise between the SBET, pore size and density of functionalities, the dendrimer-functionalized KIT-6 (DF-KIT-6) for generation 2 (SBET, 314.2 m(2) g(-1); pore size, 7.9 nm; carbon and nitrogen contents, 19.80% and 1.92%) was selected for solid phase extraction (SPE) applications. The DF-KIT-6 was then evaluated as a reversed-phase/anion-exchange mixed-mode sorbent for extraction of the selected acidic drugs (ketoprofen, KEP; naproxen, NAP; and ibuprofen, IBU), since the dendrimers contained both hydrocarbonaceous and amine functionalities. The effective parameters on extraction efficiency such as sample pH and volume, type and volume of eluent and wash solvents were optimized. Under the optimized experimental conditions, the DF KIT-6 based SPE coupled with HPLC-UV method demonstrated good sensitivity (0.4 4.6 ng mL(-1) detection of limits) and linearity (R(2)>0.990 for 10-2000 ng mL( 1) of KEP and IBU, and 1-200 ng mL(-1) of NAP). The potential use of DF-KIT-6 sorbent for preconcentration and cleanup of acid drugs in human urine samples was also demonstrated. Satisfactory recoveries at two spiking levels (30 and 300 ng mL(-1) for KEP and IBU, 3 and 30 ng mL(-1) for NAP) were obtained in the range of 85.7-113.9% with RSD values below 9.3% (n=3). PMID- 25795397 TI - Label free targeted detection and quantification of celiac disease immunogenic epitopes by mass spectrometry. AB - Celiac disease (CD) is a food-related disease caused by certain gluten peptides containing T-cell stimulating epitopes from wheat, rye, and barley. CD-patients have to maintain a gluten-free diet and are therefore dependent on reliable testing and labeling of gluten-free products. So far, the R5-ELISA is the approved method to detect if food products can be labeled gluten-free. Because the R5-ELISA detects gluten in general, there is a demand for an improved detection method that quantifies specifically CD-epitopes. Therefore, we developed a new method for detection and quantification of CD-epitopes, based on liquid chromatography (LC) coupled to mass spectrometry (MS) in multiple reaction monitoring (MRM) mode. This method enables targeted label free comparative analysis of the gluten proteins present in different wheat varieties and species, and in wheat-based food products. We have tested our method by analyzing several wheat varieties that vary in CD-epitope content, as was shown before using immunoblotting and specific monoclonal antibodies. The results showed that a modern bread wheat variety Toronto contained the highest amounts of CD immunogenic peptides compared with the older bread wheat variety Minaret and the tetraploid wheat variety Dibillik Sinde. Our developed method can detect quantitatively and simultaneously multiple specific CD-epitopes in a high throughput manner. PMID- 25795398 TI - Polymer-coated sample cup for quantitative analysis of semi-volatile phthalates in polymeric materials by thermal desorption-gas chromatography-mass spectrometry. AB - A new "polymer-coated" sample cup useful for the analysis of phthalates in polymeric materials by thermal desorption (TD)-GC/MS using a temperature programmable furnace type pyrolyzer as a TD device was developed to suppress the emission of semi-volatile phthalates such as dimethyl phthalate (DMP) and diethyl phthalate (DEP) during the measurements. The inner surface of a sample cup was coated by polymers which act as a sorbent for the phthalates. Three polymers, polyvinyl chloride, polystyrene and poly (methyl methacrylate), were chosen as the coating polymers. A mixture of ten phthalates including DMP and DEP was used as the test sample to estimate the performance of the sample cups. When a conventional sample cup without any polymer coating was used, 90 and 50% reductions in the peak areas of DMP and DEP were respectively observed at the waiting time of 200 min. On the contrary, no reduction of peak area of DMP and DEP during the same waiting time was observed with any one of the three coating polymers at the proper polymer film thickness. These results suggest that the polymer-coated sample cup suppresses the emission of semi-volatile phthalates and is effective for the analysis of phthalates containing DMP and DEP by TD-GC/MS. PMID- 25795399 TI - Modeling pH-zone refining countercurrent chromatography: a dynamic approach. AB - A model based on mass transfer resistances and acid-base equilibriums at the liquid-liquid interface was developed for the pH-zone refining mode when it is used in countercurrent chromatography (CCC). The binary separation of catharanthine and vindoline, two alkaloids used as starting material for the semi synthesis of chemotherapy drugs, was chosen for the model validation. Toluene/CH3CN/water (4/1/5, v/v/v) was selected as biphasic solvent system. First, hydrodynamics and mass transfer were studied by using chemical tracers. Trypan blue only present in the aqueous phase allowed the determination of the parameters tauextra and Pe for hydrodynamic characterization whereas acetone, which partitioned between the two phases, allowed the determination of the transfer parameter k0a. It was shown that mass transfer was improved by increasing both flow rate and rotational speed, which is consistent with the observed mobile phase dispersion. Then, the different transfer parameters of the model (i.e. the local transfer coefficient for the different species involved in the process) were determined by fitting experimental concentration profiles. The model accurately predicted both equilibrium and dynamics factors (i.e. local mass transfer coefficients and acid-base equilibrium constant) variation with the CCC operating conditions (cell number, flow rate, rotational speed and thus stationary phase retention). The initial hypotheses (the acid-base reactions occurs instantaneously at the interface and the process is mainly governed by mass transfer) are thus validated. Finally, the model was used as a tool for catharanthine and vindoline separation prediction in the whole experimental domain that corresponded to a flow rate between 20 and 60 mL/min and rotational speeds from 900 and 2100 rotation per minutes. PMID- 25795400 TI - Cell type-specific expression and localization of cytochrome P450 isoforms in tridimensional aggregating rat brain cell cultures. AB - Within the Predict-IV FP7 project a strategy for measurement of in vitro biokinetics was developed, requiring the characterization of the cellular model used, especially regarding biotransformation, which frequently depends on cytochrome P450 (CYP) activity. The extrahepatic in situ CYP-mediated metabolism is especially relevant in target organ toxicity. In this study, the constitutive mRNA levels and protein localization of different CYP isoforms were investigated in 3D aggregating brain cell cultures. CYP1A1, CYP2B1/B2, CYP2D2/4, CYP2E1 and CYP3A were expressed; CYP1A1 and 2B1 represented almost 80% of the total mRNA content. Double-immunolabeling revealed their presence in astrocytes, in neurons, and to a minor extent in oligodendrocytes, confirming the cell-specific localization of CYPs in the brain. These results together with the recently reported formation of an amiodarone metabolite following repeated exposure suggest that this cell culture system possesses some metabolic potential, most likely contributing to its high performance in neurotoxicological studies and support the use of this model in studying brain neurotoxicity involving mechanisms of toxication/detoxication. PMID- 25795401 TI - Inhibitory effects on osteoblast differentiation in vitro by the polychlorinated biphenyl mixture Aroclor 1254 are mainly associated with the dioxin-like constituents. AB - The polychlorinated biphenyl (PCB) mixture Aroclor 1254 alters bone tissue properties. However, the mechanisms responsible for the observed effects have not yet been clarified. This study compared the effect of Aroclor 1254 on the expression of osteoblast differentiation markers in MC3T3-E1 cells with the corresponding effect of the dioxin reference compound 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD), and two PCB congeners belonging to the category of non-dioxin like PCBs. The aim of the study was to quantify the relative influence of dioxin like and non-dioxin-like PCB-components on osteoblast differentiation. Expression of marker genes for AhR activity and osteoblast differentiation were analyzed, and relative potency (REP) values were derived from Benchmark concentration effect curves. Expression of alkaline phosphatase and osteocalcin were decreased by both Aroclor 1254 and TCDD exposure, while the PCB-congeners PCB19 and PCB52 slightly induced the expression. The relative potency of Aroclor 1254 for inhibitory effects on osteoblast differentiation marker genes was within the expected range as estimated from the chemical composition of Aroclor 1254. These results are consistent with previously observed bone modulations following in vivo exposure to Aroclor 1254 and TCDD, and demonstrate that the inhibitory effects of Aroclor 1254 on osteoblast differentiation by the dioxin-like constituents are over-riding the contribution of non-dioxin-like PCBs. PMID- 25795403 TI - Old drugs, new tricks for triple-negative breast cancer. PMID- 25795402 TI - Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial. AB - BACKGROUND: Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS 02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. METHODS: Adults (18 years to physiological age <=70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1.1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. FINDINGS: Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59.6%, 95% CI 44.3-73.6) achieved a partial response and 13 (27.7%, 15.6 42.6) stable disease; 41 (87.2%, 74.3-95.2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3.3%, 95% CI 0.4-11.7) achieved a complete response, 22 (36.1%, 25.0-50.8) had a partial response, and 32 (52.5%, 40.8-67.3) had stable disease; 56 (91.8%, 81.9-97.3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). INTERPRETATION: Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. FUNDING: Pharmamar and Amgen. PMID- 25795404 TI - Nivolumab: another weapon in the growing immunotherapy arsenal. PMID- 25795405 TI - Trabectedin: adding clarification rather than novelty. PMID- 25795406 TI - Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open label, phase 2 study. AB - BACKGROUND: Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma. METHODS: We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1:1) by the minimisation method to receive either trabectedin (1.2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850. FINDINGS: Between July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n=39) or best supportive care (n=37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5.6 months (95% CI 4.1-7.5) and the best supportive care group was 0.9 months (0.7-1.0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0.07 (90% CI 0.03-0.14 and 95% CI 0.03-0.16) by a Cox proportional hazards model (p<0.0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]). INTERPRETATION: Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population. FUNDING: Taiho Pharmaceutical Co., Ltd. PMID- 25795407 TI - Redefining the standard of care in metastatic leiomyosarcoma. PMID- 25795408 TI - Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. AB - BACKGROUND: Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. METHODS: In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. FINDINGS: Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0.94 [95% CI 0.61 1.44]; p=0.77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. INTERPRETATION: Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. FUNDING: Astellas. PMID- 25795409 TI - Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. AB - BACKGROUND: Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. METHODS: For this open label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1.2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. FINDINGS: From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16.3 months (IQR 14.4-26.8) in the cisplatin plus gemcitabine group and 15.9 months (10.7-25.4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0.692 (95% CI 0.523-0.915; pnon-inferiority<0.0001, psuperiority=0.009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7.73 months (95% CI 6.16-9.30) in the cisplatin plus gemcitabine group and 6.47 months (5.76-7.18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. INTERPRETATION: Cisplatin plus gemcitabine could be an alternative or even the preferred first line chemotherapy strategy for patients with metastatic triple-negative breast cancer. FUNDING: Shanghai Natural Science Foundation. PMID- 25795411 TI - Inhibition of IGF-1R in adrenocortical carcinoma. PMID- 25795410 TI - Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open label, phase 3 trial. AB - BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31.7%, 95% CI 23.5-40.8) of the first 120 patients in the nivolumab group versus five (10.6%, 3.5-23.1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment related deaths occurred. INTERPRETATION: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING: Bristol-Myers Squibb. PMID- 25795412 TI - Programmed translational bypassing elements in mitochondria: structure, mobility, and evolutionary origin. AB - Programmed translational bypassing enables ribosomes to 'ignore' a precise mRNA interval of several dozen nucleotides. Well-characterized bypassed sequences include hop and byp elements, present in bacteriophage T4 and mitochondria of the yeast Magnusiomyces capitatus, respectively. The bypassing mechanism of byps is probably similar to that of hop, yet the former appears more effective and less constrained as to sequence context. Furthermore, both elements are mobile but hop moves as part of a cassette including a homing endonuclease, whereas byps seem to spread like miniature DNA transposable elements known as GC clusters. Here, we argue that hop and byps arose independently by convergent evolution, and that byps evolved in magnusiomycete mitochondria due to (as yet unknown) alterations of the mitochondrial translation machinery. PMID- 25795413 TI - Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. AB - OBJECTIVE: Impaired brain insulin action has been linked to obesity, type 2 diabetes, and neurodegenerative diseases. To date, the central nervous effects of insulin in obese humans still remain ill defined, and no study thus far has evaluated the specific brain areas affected by insulin resistance. RESEARCH DESIGN AND METHODS: In 25 healthy lean and 23 overweight/obese participants, we performed magnetic resonance imaging to measure cerebral blood flow (CBF) before and 15 and 30 min after application of intranasal insulin or placebo. Additionally, participants explicitly rated pictures of high-caloric savory and sweet food 60 min after the spray for wanting and liking. RESULTS: In response to insulin compared with placebo, we found a significant CBF decrease in the hypothalamus in both lean and overweight/obese participants. The magnitude of this response correlated with visceral adipose tissue independent of other fat compartments. Furthermore, we observed a differential response in the lean compared with the overweight/obese group in the prefrontal cortex, resulting in an insulin-induced CBF reduction in lean participants only. This prefrontal cortex response significantly correlated with peripheral insulin sensitivity and eating behavior measures such as disinhibition and food craving. Behaviorally, we were able to observe a significant reduction for the wanting of sweet foods after insulin application in lean men only. CONCLUSIONS: Brain insulin action was selectively impaired in the prefrontal cortex in overweight and obese adults and in the hypothalamus in participants with high visceral adipose tissue, potentially promoting an altered homeostatic set point and reduced inhibitory control contributing to overeating behavior. PMID- 25795414 TI - Changes in gene expression in responders and nonresponders to a low-intensity walking intervention. AB - OBJECTIVE: Daily physical activity remains an effective strategy to prevent obesity and type 2 diabetes. However, the metabolic response to exercise training is variable, and the precise clinical and molecular determinants that mark the metabolic improvements remain unknown. We tested the hypothesis that clinical improvements in glucose control after low-intensity exercise in individuals with impaired glucose tolerance (IGT) are coupled to alterations in skeletal muscle gene expression. RESEARCH DESIGN AND METHODS: We investigated 14 overweight individuals with IGT before and after a 4-month low-intensity unsupervised walking exercise intervention. Clinical and anthropometric measurements and glucose tolerance were determined before and after the intervention. Skeletal muscle biopsy specimens were obtained for mRNA expression analysis. RESULTS: Waist circumference and work capacity during cycle ergometry were improved in individuals who achieved normal glucose tolerance (NGT) after exercise training (IGT-NGT; n = 9) but in not individuals who remained IGT (IGT-IGT; n = 5). Pretraining glycemic control was better in IGT-NGT compared with IGT-IGT. mRNA expression of mitochondrial markers and transcription factors was increased in IGT-NGT after exercise intervention and normalized to levels measured in a separate cohort of nonexercised individuals with NGT. Conversely, these markers were unaltered after exercise intervention in IGT-IGT. CONCLUSIONS: Normalization of metabolic control can be achieved after low-intensity exercise in individuals with IGT. This can be tracked with increased mRNA expression of mitochondrial and metabolic genes in skeletal muscle. However, for individuals presenting with a greater derangement in glycemia, the potential for clinical and metabolic improvements after this low-intensity unsupervised exercise protocol appears to be limited. PMID- 25795415 TI - Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal microscopy with intraepidermal nerve fiber density. AB - OBJECTIVE: Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard. RESEARCH DESIGN AND METHODS: Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy. RESULTS: Manual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14). CONCLUSIONS: This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN. PMID- 25795416 TI - Both the autophagy and proteasomal pathways facilitate the Ubp3p-dependent depletion of a subset of translation and RNA turnover factors during nitrogen starvation in Saccharomyces cerevisiae. AB - Protein turnover is an important regulatory mechanism that facilitates cellular adaptation to changing environmental conditions. Previous studies have shown that ribosome abundance is reduced during nitrogen starvation by a selective autophagy mechanism termed ribophagy, which is dependent upon the deubiquitinase Ubp3p. In this study, we asked whether the abundance of various translation and RNA turnover factors are reduced following the onset of nitrogen starvation in Saccharomyces cerevisiae. We found distinct differences in the abundance of the proteins tested following nitrogen starvation: (1) The level of some did not change; (2) others were reduced with kinetics similar to ribophagy, and (3) a few proteins were rapidly depleted. Furthermore, different pathways differentially degraded the various proteins upon nitrogen starvation. The translation factors eRF3 and eIF4GI, and the decapping enhancer Pat1p, required an intact autophagy pathway for their depletion. In contrast, the deadenylase subunit Pop2p and the decapping enzyme Dcp2p were rapidly depleted by a proteasome-dependent mechanism. The proteasome-dependent depletion of Dcp2p and Pop2p was also induced by rapamycin, suggesting that the TOR1 pathway influences this pathway. Like ribophagy, depletion of eIF4GI, eRF3, Dcp2p, and Pop2p was dependent upon Ubp3p to varying extents. Together, our results suggest that the autophagy and proteasomal pathways degrade distinct translation and RNA turnover factors in a Ubp3p-dependent manner during nitrogen starvation. While ribophagy is thought to mediate the reutilization of scarce resources during nutrient limitation, our results suggest that the selective degradation of specific proteins could also facilitate a broader reprogramming of the post-transcriptional control of gene expression. PMID- 25795417 TI - miRBoost: boosting support vector machines for microRNA precursor classification. AB - Identification of microRNAs (miRNAs) is an important step toward understanding post-transcriptional gene regulation and miRNA-related pathology. Difficulties in identifying miRNAs through experimental techniques combined with the huge amount of data from new sequencing technologies have made in silico discrimination of bona fide miRNA precursors from non-miRNA hairpin-like structures an important topic in bioinformatics. Among various techniques developed for this classification problem, machine learning approaches have proved to be the most promising. However these approaches require the use of training data, which is problematic due to an imbalance in the number of miRNAs (positive data) and non miRNAs (negative data), which leads to a degradation of their performance. In order to address this issue, we present an ensemble method that uses a boosting technique with support vector machine components to deal with imbalanced training data. Classification is performed following a feature selection on 187 novel and existing features. The algorithm, miRBoost, performed better in comparison with state-of-the-art methods on imbalanced human and cross-species data. It also showed the highest ability among the tested methods for discovering novel miRNA precursors. In addition, miRBoost was over 1400 times faster than the second most accurate tool tested and was significantly faster than most of the other tools. miRBoost thus provides a good compromise between prediction efficiency and execution time, making it highly suitable for use in genome-wide miRNA precursor prediction. The software miRBoost is available on our web server http://EvryRNA.ibisc.univ-evry.fr. PMID- 25795418 TI - Dietary supplementation with glutamate precursor alpha-ketoglutarate attenuates lipopolysaccharide-induced liver injury in young pigs. AB - There is growing interest in glutamate as a functional amino acid in nutrition and health. This study was conducted to determine whether glutamate precursor alpha-ketoglutarate (AKG) could alleviate lipopolysaccharide (LPS)-induced liver injury in young pigs. Twenty-four piglets were randomly assigned to the control, LPS, or LPS + AKG group. Piglets in the control and LPS groups were fed a basal diet, whereas piglets in the NAC group were fed the basal diet supplemented with 1 % AKG. On days 10, 12, 14, and 16 of the trial, piglets in the LPS and LPS + AKG groups received intraperitoneal administration of LPS (80 MUg/kg BW), whereas piglets in the control group received the same volume of saline. On day 16 of the trial, blood samples were collected 3 h after LPS or saline injection. Twenty four hours post-administration of LPS or saline (on day 17 of the trial), piglets were killed to obtain liver for analysis. Dietary AKG supplementation alleviated LPS-induced histomorphological abnormalities and mitigated LPS-induced increases in aspartate aminotransferase (AST) activity and AST/ALT ratio (P < 0.05). Compared with the LPS group, dietary supplementation with AKG decreased plasma glutamate concentration, while increasing hepatic concentrations of glutamate, glutamine, leucine, asparagine, lysine, alanine, serine, threonine, valine, and phenylalanine (P < 0.05). LPS challenge dramatically increased concentrations of malondialdehyde and decreased glutathione peroxidase activity in the liver. Additionally, LPS challenge enhanced concentrations of AMP and total protein, as well as RNA/DNA and total protein/DNA ratios, while decreasing hepatic ADP concentrations. These adverse effects of LPS challenge were ameliorated by AKG supplementation. Collectively, dietary AKG supplementation provides a new means to ameliorate LPS-induced liver injury by increasing anti-oxidative capacity and improving energy metabolism in young pigs. PMID- 25795419 TI - Utilization of imaging flow cytometry to define intermediates of megakaryopoiesis in vivo and in vitro. AB - Imaging flow cytometry is a particularly powerful analytical approach for the study of megakaryopoiesis. It can utilize well-defined immunophenotypic markers as well as assess maturation of megakaryocytes by their increasing ploidy as they endoreplicate. Imaging flow cytometry can also assess morphometric cell characteristics of size and nuclear to cytoplasmic ratio, which are informative indications of maturation. However, megakaryopoiesis is challenging for flow cytometric analysis, particularly in vivo, because megakaryocytes are very rare in the bone marrow and their odd shape, high DNA content and cell size are similar to clumps of cells. Additionally, both megakaryocytes and immunophenotypically similar platelets are frequently found associated with other cells. Due to these challenges, imaging flow cytometry of megakaryopoiesis exemplifies several strengths of this approach in utilizing fluorescent signal's shape, texture and overlap with other fluorescent signals to distinguish megakaryocytes from a variety of contaminants and to restrict analysis to megakaryocytes, even when associated with other cells. Presented here is a strategy for imaging flow cytometric analysis of rare murine megakaryocytes directly from the bone marrow as well those grown in vitro and analyzed as live cells, or after fixation and permeabilization. PMID- 25795420 TI - Comparison of cell-based and non-cell-based assay platforms for the detection of clinically relevant anti-drug neutralizing antibodies for immunogenicity assessment of therapeutic proteins. AB - Anti-drug neutralizing antibodies (NAbs) formed due to unwanted immunogenicity of a therapeutic protein point towards a mature immune response. NAb detection is important in interpreting the therapeutic's efficacy and safety in vivo. In vitro cell-based NAb assays provide a physiological system for NAb detection, however are complex assays. Non-cell-based competitive ligand binding (CLB) approaches are also employed for NAb detection. Instead of cells, CLB assays use soluble receptor and conjugated reagents and are easier to perform, however have reduced physiological relevance. The aim of this study was to compare the performance of CLB assays to established cell-based assays to determine the former's ability to detect clinically relevant NAbs towards therapeutics that (i) acted as an agonist or (ii) acted as antagonists by binding to a target receptor. We performed a head to-head comparison of the performance of cell-based and CLB NAb assays for erythropoietin (EPO) and two anti-receptor monoclonal antibodies (AMG-X and AMG 317). Clinically relevant NAb-positive samples identified previously by a cell based assay were assessed in the corresponding CLB format(s). A panel of 12 engineered fully human anti-EPO monoclonal antibodies (MAbs) was tested in both EPO NAb assay formats. Our results showed that the CLB format was (i) capable of detecting human anti-EPO MAbs of differing neutralizing capabilities and affinities and (ii) provided similar results as the cell-based assay for detecting NAbs in patient samples. The cell-based and CLB assays also behaved comparably in detecting NAbs in clinical samples for AMG-X. In the case of anti AMG 317 NAbs, the CLB format failed to detect NAbs in more than 50% of the tested samples. We conclude that assay sensitivity, drug tolerance and the selected assay matrix played an important role in the inability of AMG 317 CLB assays to detect clinically relevant NAbs. PMID- 25795421 TI - InFlow microscopy of human leukocytes: A tool for quantitative analysis of actin rearrangements in the immune synapse. AB - The actin cytoskeleton is a main component to preserve the cell shape. It represents a cellular machinery that enables morphological changes and orchestrates important dynamic cellular functions. Thereby, it supports T-cell migration, immune synapse formation, activation and execution of effector functions. The analysis of actin rearrangements in T-cells is therefore an important field of basic and clinical research. Actin reorganization is traditionally performed using flow cytometry or confocal microscopy. However, while flow cytometry lacks spatial and structural information, confocal microscopy is time consuming and not feasible for the characterization of rare events or of un-purified primary cell populations. Here we describe a methodology to analyze actin rearrangements using InFlow microscopy, which is a hybrid technique consisting of flow cytometric and microscopic features. We show that InFlow microscopy is a valuable tool for quantification of the amount and distribution of F-actin in human T-cells after stimulation with chemokines or antigen-presenting cells. PMID- 25795422 TI - Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells. PMID- 25795423 TI - Lunar gravity affects leaf movement of Arabidopsis thaliana in the International Space Station. AB - MAIN CONCLUSION: Cyclic leaf ascent and descent occur in synchrony and phase congruence with the lunisolar tidal force under a broad range of conditions. Digitized records of the vertical leaf movements of Arabidopsis thaliana were collected under space flight conditions in the International Space Station (ISS). Oscillations of leaf movements with periods of 45 and 90 min were found under light-adapted conditions, whereas in darkness, the periods were 45, 90, and 135 min. To demonstrate the close relationship between these oscillations and cyclical variations of the lunisolar gravitational force, we estimated the oscillations of the in-orbit lunisolar tide as they apply to the ISS, with the aid of the Etide software application. In general, in-orbit lunisolar gravitational profiles exhibited a periodicity of 45 min. Alignment of these in orbit oscillations with the oscillations of Arabidopsis leaf movement revealed high degrees of synchrony and a congruence of phase. These data corroborate previous results which suggested a correlative relationship and a possible causal link between leaf movement rhythms obtained on ground and the rhythmic variation of the lunisolar tidal force. PMID- 25795424 TI - Titanium dioxide nanoparticles exacerbate pneumonia in respiratory syncytial virus (RSV)-infected mice. AB - To reveal the effects of TiO2 nanoparticles, used in cosmetics and building materials, on the immune response, a respiratory syncytial virus (RSV) infection mouse model was used. BALB/c mice were exposed once intranasally to TiO2 at 0.5mg/kg and infected intranasally with RSV five days later. The levels of IFN gamma and chemokine CCL5, representative markers of pneumonia, in the bronchoalveolar lavage fluids of RSV-infected mice had increased significantly in TiO2-exposed mice compared with the control on day 5 post-infection, but not in uninfected mice. While pulmonary viral titers were not affected by TiO2 exposure, an increase in the infiltration of lymphocytes into the alveolar septa in lung tissues was observed. Immunohistochemical analysis revealed aggregation of TiO2 nanoparticles near inflammatory cells in the severely affected region. Thus, a single exposure to TiO2 nanoparticles affected the immune system and exacerbated pneumonia in RSV-infected mice. PMID- 25795426 TI - Survival of the project: a case study of ICT innovation in health care. AB - From twenty years of information and communication technology (ICT) projects in the health sector, we have learned one thing: most projects remain projects. The problem of pilotism in e-health and telemedicine is a growing concern, both in medical literature and among policy makers, who now ask for large-scale implementation of ICT in routine health service delivery. In this article, we turn the question of failing projects upside down. Instead of investigating the obstacles to implementing ICT and realising permanent changes in health care routines, we ask what makes the temporary ICT project survive, despite an apparent lack of success. Our empirical material is based on Norwegian telemedicine. Through a case study, we take an in-depth look into the history of one particular telemedical initiative and highlight how ICT projects matter on a managerial level. Our analysis reveals how management tasks were delegated to the ICT project, which thus contributed to four processes of organisational control: allocating resources, generating and managing enthusiasm, system correction and aligning local practice and national policies. We argue that the innovation project in itself can be considered an innovation that has become normalised in health care, not in clinical, but in management work. In everyday management, the ICT project appears to be a convenient tool suited to ease the tensions between state regulatory practices and claims of professional autonomy that arise in the wake of new public management reforms. Separating project management and funding from routine practice handles the conceptualised heterogeneity between innovation and routine within contemporary health care delivery. Whilst this separation eases the execution of both normal routines and innovative projects, it also delays expected diffusion of technology. PMID- 25795427 TI - Metal ions as inflammatory initiators of osteolysis. AB - Osteolysis and aseptic loosening currently contribute 75 % of implant failures. Furthermore, with over four million joint replacements projected to be performed in the United States annually, osteolysis and aseptic loosening may continue to pose a significant morbidity. This paper reviews the osteolysis cascade leading to osteoclast activation and bone resorption at the biochemical level. Additionally, the metal ion release mechanism from metallic implants is elucidated. Even though metal ions are not the predominating initiator of osteolysis, they do increase the concentration of key inflammatory cytokines that stimulate osteoclasts and prove to be a contributor to osteolysis and aseptic loosening. Osteolysis is a competitive mechanism among a number of biological reactions, which includes debris release, macrophage and osteoclast activation, an inflammatory response as well as metal ion release. Pharmacological therapy for component loosening has also been reviewed. A non-surgical treatment of osteolysis has not been found in the literature and thus may become an area of future research. Even though this research is warranted, comprehensively understanding the immune response to orthopedic implants and their metallic ions, and thus, creating improved prostheses appears to be the most cost-effective approach to decrease the morbidity related to osteolysis and to design implants with greater longevity. The ionic forms, cytokines, toxicity, gene expression, biological effects, and hypersensitivity responses of metallic elements from metal implants are summarized as well. PMID- 25795425 TI - The structural basis of XRCC1-mediated DNA repair. AB - Scaffold proteins play a central role in DNA repair by recruiting and organizing sets of enzymes required to perform multi-step repair processes. X-ray cross complementing group 1 protein (XRCC1) forms enzyme complexes optimized for single strand break repair, but participates in other repair pathways as well. Available structural data for XRCC1 interactions is summarized and evaluated in terms of its proposed roles in DNA repair. Mutational approaches related to the abrogation of specific XRCC1 interactions are also discussed. Although substantial progress has been made in elucidating the structural basis for XRCC1 function, the molecular mechanisms of XRCC1 recruitment related to several proposed roles of the XRCC1 DNA repair complex remain undetermined. PMID- 25795428 TI - Pelvic ring reconstruction with a double-barreled free vascularized fibula graft after resection of malignant pelvic bone tumor. AB - INTRODUCTION: In patients undergoing limb-salvage internal hemipelvectomy, pelvic ring reconstruction is mandatory to maintain the stability of the pelvis and the spinal column, which finally expected to achieve a good functional outcome. However, no optimal reconstruction method has been established. In addition, no previous reports have highlighted the long-term complications of pelvic ring reconstruction after internal hemipelvectomy. We aimed to analyze the outcome of pelvic ring reconstruction using a double-barreled free vascularized fibula graft (VFG) after internal hemipelvectomy with special reference to long-term complications. MATERIALS AND METHODS: We conducted a retrospective review of 9 consecutive patients (5 male, 4 female; mean age 31 years) who underwent pelvic ring reconstruction using a double-barreled free VFG after internal hemipelvectomy (P1, n = 4; P1 + 4, n = 3; P1 + 2, n = 2) at our institution between 1998 and 2013. The mean follow-up period was 55 months (range 3-131 months). RESULTS: The mean length of the bone defect was 9 cm. The methods of fixation included a Cotrel-Dubosset rod (n = 4), screw (n = 3), and screw and plate (n = 2). Bone union was achieved in 5 of 8 patients (63 %) over a 1-year follow-up. The mean period required for bone union was 5.4 months (range 3-7 months). There were 3 early postoperative complications: 2 deep infections resulting in graft removal and 1 implant failure resulting in non-union. Among 3 patients, 2 developed scoliosis within 5 years. One patient developed lumbar disc hernia as a result of scoliosis, for which surgical intervention was required. The mean Musculoskeletal Tumor Society score was 57 % at the last follow-up. CONCLUSIONS: In conclusion, this reconstruction method can achieve an early and high rate of bone union and provide good functional outcome. However, follow-up with careful attention to postoperative complications, including deep infection in the early postoperative period and spinal deformity in the long term, is necessary. PMID- 25795429 TI - Editor's note: Past, present, and future work of the American Balint Society. PMID- 25795430 TI - Cardiac troponin testing and myocardial infarction. PMID- 25795431 TI - Delayed presentation of diaphragmatic rupture with stomach herniation and strangulation. PMID- 25795432 TI - Diabetes-Related Composite Quality End Point Attainment: Canagliflozin Versus Sitagliptin Based on a Pooled Analysis of 2 Clinical Trials. AB - PURPOSE: This post hoc analysis evaluated attainment of diabetes-related composite quality measures (CQMs) with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus (T2DM). We used pooled data from two 52-week Phase III clinical trials evaluating the efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg. METHODS: CQMs assessed included the combined attainment of glycosylated hemoglobin (HbA1c), blood pressure (BP), and LDL-C. To assess on-treatment differences at 52 weeks, odds ratios (ORs) and associated 95% CIs were calculated based on a logistic regression model. CQM attainment was assessed in the overall population and for patients with a body mass index >=25 kg/m(2) at baseline. FINDINGS: Overall, baseline demographic and disease characteristics were comparable across treatment groups. Proportions of patients with T2DM meeting the CQMs HbA1c <7.0%, BP <130/80 mm Hg, and LDL-C <100 mg/dL and HbA1c <8.0%, BP <140/90 mm Hg, and LDL-C <100 mg/dL were similar at baseline. After 52 weeks of treatment, the proportion of patients meeting both CQMs was similar for canagliflozin 100 mg and sitagliptin 100 mg, and favored canagliflozin 300 mg versus sitagliptin 100 mg. For canagliflozin 300 mg, the OR was 1.79 (95% CI, 1.25-2.58) for the CQM HbA1c <7.0%, BP <130/80 mm Hg, and LDL-C <100 mg/dL; the OR was 1.49 (95% CI, 1.15-1.92) for the CQM HbA1c <8.0%, BP <140/90 mm Hg, and LDL-C <100 mg/dL. CQM attainments for patients with a body mass index >=25 kg/m(2) were similar to those for the overall population. IMPLICATIONS: At 52 weeks of treatment, this analysis observed comparable CQM attainment for canagliflozin 100 mg, and superior CQM attainment for canagliflozin 300 mg, compared with sitagliptin 100 mg. ClinicalTrials.gov identifiers are NCT01106677 and NCT01137812. PMID- 25795434 TI - JALA special issue: microengineered cell- and tissue-based assays for drug screening and toxicology applications. PMID- 25795433 TI - Salivary extracellular noncoding RNA: emerging biomarkers for molecular diagnostics. AB - Saliva is a complex body fluid that comprises secretions from the major and minor salivary glands, nourished by body's vasculature. Although many circulatory molecules (DNA, RNA, and proteins) can also be present in saliva, saliva harbors unique molecular constituents that can be discriminatory for oral and systemic disease screening and detection. Many studies have reported that salivary constituents can discriminate oral diseases (oral cancer and Sjogren's syndrome) and also systemic diseases (lung cancer, breast cancer, pancreatic cancer, and ovarian cancer). Noncoding RNAs (ncRNAs) are emerging new regulators of diverse biological functions, playing important roles in oncogenesis and tumor progression. Indeed, the short size of these molecules makes them stable in different body fluids such as urine, blood, and saliva, being not as susceptible as mRNAs to degradation by RNases. Here, the current status and clinical implications of the ncRNAs present in human saliva are reviewed for translational applications and basic biological research. The development of noninvasive salivary test (based on ncRNAs profiles) for disease detection could have effective applications into the clinical context with a translational significance as emerging molecular biomarkers for non-invasively disease detection, not only by reducing the cost to the health care system but also by benefitting patients. PMID- 25795437 TI - Continuous psychophysics: Target-tracking to measure visual sensitivity. AB - We introduce a novel framework for estimating visual sensitivity using a continuous target-tracking task in concert with a dynamic internal model of human visual performance. Observers used a mouse cursor to track the center of a two dimensional Gaussian luminance blob as it moved in a random walk in a field of dynamic additive Gaussian luminance noise. To estimate visual sensitivity, we fit a Kalman filter model to the human tracking data under the assumption that humans behave as Bayesian ideal observers. Such observers optimally combine prior information with noisy observations to produce an estimate of target position at each time step. We found that estimates of human sensory noise obtained from the Kalman filter fit were highly correlated with traditional psychophysical measures of human sensitivity (R2 > 97%). Because each frame of the tracking task is effectively a "minitrial," this technique reduces the amount of time required to assess sensitivity compared with traditional psychophysics. Furthermore, because the task is fast, easy, and fun, it could be used to assess children, certain clinical patients, and other populations that may get impatient with traditional psychophysics. Importantly, the modeling framework provides estimates of decision variable variance that are directly comparable with those obtained from traditional psychophysics. Further, we show that easily computed summary statistics of the tracking data can also accurately predict relative sensitivity (i.e., traditional sensitivity to within a scale factor). PMID- 25795438 TI - Lesion location, stability, and pretreatment management: factors affecting outcomes of endovascular treatment for vertebrobasilar atherosclerosis. AB - BACKGROUND AND PURPOSE: The proper role of endovascular treatment of cervicocerebral atherosclerosis is unclear. Posterior circulation disease has not been investigated as extensively as disease in the anterior circulation. In this study, we characterized the rates of technical success, transient ischemic attack, stroke, and death or disability, for both acute and elective endovascular treatment of atherosclerosis in the vertebrobasilar system. METHODS: We identified patients with atherosclerosis of the vertebrobasilar circulation who underwent endovascular intervention at our hospital through retrospective medical record review, and evaluated the association between lesion and treatment features and subsequent stroke, death, or disability at 30 days and 1 year. RESULTS: We identified 136 lesions in 122 patients, including 13 interventions for acute strokes. Technical success was achieved in 123 of 136 cases (90.4%). Elective procedures had higher rates of technical success (6.5% vs 15.4%, p=0.21) and better clinical outcomes. In multivariate analysis, intracranial lesions were associated with more disability (modified Rankin Scale score >2) at 30 days (OR 7.1, p=0.01) and 1 year (OR 10, p=0.03). Patients with non-hypoperfusion related symptoms had fewer strokes at follow-up at 1 year when treated after an asymptomatic interval of >10 days compared with those treated within 10 days of the presenting symptoms (OR 0.2, p=0.03). Statin treatment prior to intervention was associated with favorable outcomes across several examined endpoints. Preoperative antiplatelet treatment was associated with lower rates of disability at 30 days and 1 year (OR 0.1, p<0.01 and OR 0.07, p=0.01, respectively), and preoperative anticoagulation treatment was associated with higher rates of death at 30 days, particularly when prescribed for reasons other than atrial fibrillation (OR 6.4, p=0.01). CONCLUSIONS: Endovascular treatment of symptomatic vertebrobasilar atherosclerosis can be performed safely and with good outcomes. Technical results were better for those with extracranial disease while clinical outcomes were more favorable in those patients with non-progressive symptoms in the subacute period and those receiving statin therapy. PMID- 25795440 TI - Significantly improved thermostability of a reductase CgKR1 from Candida glabrata with a key mutation at Asp 138 for enhancing bioreduction of aromatic alpha-keto esters. AB - The keto ester reductase from Candida glabrata, designated as CgKR1, is a highly versatile biocatalyst with a broad substrate spectrum. Its substrate preference was altered by rational design of the active pocket for bioreduction of aromatic alpha-keto esters in our previous work. However, its practical application is still hindered by its poor thermostability and high biocatalyst loading. In this work, random mutagenesis followed by a saturation mutagenesis was performed aiming to improve its thermostability. Variants M5 (I99Y/D138N/G174A) and M6 (D138N) exhibited an obvious increase in T50(15) from 41.8 degrees C of wild-type to 53.4 degrees C and 48.8 degrees C, respectively, indicating the important role of residue 138 for its thermostability. The homologous three-dimensional structures of the wild-type and variant M6 (D138N) revealed that the increased thermostability might be attributed to the increased hydrogen bonds that asparagine forms with other polar amino acids around it. Combination of the most thermostable variant M5 and the substrate specificity-altered variant M1 (F92L/F94V) yielded variant M7 (F92L/F94V/I99Y/D138N/G174A), with not only higher activity toward aromatic alpha-keto esters, but also an increased T50(15) value of 54.6 degrees C. This variant M7 corresponds to an obvious increase in half life from 2.16min of wild-type to 182min at 50 degrees C. The substrate of methyl ortho-chlorobenzoylformate (CBFM) at 0.5M (100g/L) could be stoichiometrically converted to the product by 1g/L lyophilized cell of variant M7, with 4g/L lyophilized powder of BmGDH for cofactor regeneration within 10h, while the wild type enzyme gave only 84% conversion even the reaction time was extended to 24h. PMID- 25795439 TI - (18)F-FDG-PET/CT findings in pancreatic metastasis. AB - PURPOSE: This study aimed to evaluate the fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings and pattern of FDG uptake in pancreatic metastases. MATERIALS AND METHODS: A total of 19 consecutive patients (26 lesions) with histologically or clinically confirmed pancreatic metastases who had undergone (18)F-FDG-PET/CT were enrolled in this retrospective study. Among the 19 patients, 14 patients underwent abdominal contrast-enhanced CT (ceCT). The location, size and FDG uptake patterns of the pancreatic lesions were recorded. Metabolic activity by means of maximum standardised uptake value (SUVmax) was measured by drawing regions of interest at the site of pancreatic lesions. Twenty pancreatic cancer patients were included in this study as comparative data analysis. The difference of SUVmax between pancreatic metastases and primary pancreatic cancer were compared using the Mann-Whitney U test. P < 0.05 was considered significant. RESULTS: Three different patterns of FDG uptake could be distinguished in the pancreatic metastatic lesions, including focal nodule or mass, multiple foci and segmental lesion with high FDG uptake. The average SUVmax in pancreatic metastases was 7.8 +/- 6.9 versus 7.4 +/- 3.9 in primary pancreatic cancer (P = 0.987 > 0.05). Four intrapancreatic isodense nodules in three patients were undetected on ceCT. CONCLUSION: The described patterns of FDG uptake findings may be helpful for a better characterisation of pancreatic metastases although semiquantitative analysis using SUVmax could not be used as a criterion for differentiating pancreatic metastases from primary pancreatic cancer. FDG-PET/CT has also an advantage in detecting unsuspected pancreatic metastases which cannot be detected by ceCT imaging. Thus, it is a useful adjunct to the described features on CT. PMID- 25795441 TI - Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects. AB - Current available antidepressants exhibit low remission rate with a long response lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant effects. However, a long term use of ketamine tends to elicit its adverse reactions. The present study aimed to investigate the antidepressant-like effects of intermittent and consecutive administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and to determine whether ketamine can redeem the time lag for treatment response of classic antidepressants. The behavioral responses were assessed by the sucrose preference test, forced swimming test, and open field test. In the first stage of experiments, all the four treatment regimens of ketamine (10mg/kg ip, once daily for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days) showed robust antidepressant-like effects, with no significant influence on locomotor activity and stereotype behavior in the CUMS rats. The intermittent administration regimens produced longer antidepressant-like effects than the consecutive administration regimens and the administration every 7 days presented similar antidepressant-like effects with less administration times compared with the administration every 3 days. In the second stage of experiments, the combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg po, once daily) for 21 days caused more rapid and sustained antidepressant-like effects than citalopram administered alone. In summary, repeated sub-anesthestic doses of ketamine can redeem the time lag for the antidepressant-like effects of citalopram, suggesting the combination of ketamine and classic antidepressants is a promising regimen for depression with quick onset time and stable and lasting effects. PMID- 25795442 TI - Sphingobacterium yamdrokense sp. nov., isolated from Lake Yamdrok. AB - A strictly aerobic and facultatively psychrophilic bacterium, strain 3-0-1(T), was isolated from Lake Yamdrok on the Tibetan Plateau, China. Cells were Gram negative and short-rod-shaped. Strain 3-0-1(T) formed circular, opaque, yellow colonies, and grew at 0-5% (w/v) NaCl, pH 5.0-11.0 and 5-35 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences of various species with validly published names showed that strain 3-0-1(T) belongs to the genus Sphingobacterium, family Sphingobacteriaceae, sharing the highest similarity with Sphingobacterim nematocida M-SX103(T) (96.62%) and less than 95% similarity with all the other species in the genus Sphingobactrium. The predominant isoprenoid quinone of strain 3-0-1(T) was identified as menaquinone 7 (MK-7), the major polar lipid was identified as phosphatidylethanolamine and the DNA G+C content was determined to be 42.5 mol%. The predominant cellular fatty acids were identified as summed feature 3 (C(16:1) omega7c and/or C(16:1) omega6c) (>30%), iso-C(15:0) (>20%) and iso-C(17:0) 3-OH (>10%). Based on the variability of phylogenetic and phenotypic characteristics, strain 3-0-1(T) represents a novel species of the genus Sphingobacterium, for which the name Sphingobacterium yamdrokense sp. nov. is proposed. The type strain is 3-0-1(T) (=JCM 19397(T) = CGMCC 1.12560(T)). PMID- 25795443 TI - Erratum to: Negadavirga shengliensis gen. nov., sp. nov., a novel member of the family Cyclobacteriaceae isolated from oil-contaminated saline soil. PMID- 25795444 TI - Aureisphaera galaxeae gen. nov., sp. nov., a marine member of the family Flavobacteriaceae isolated from the hard coral Galaxea fascicularis. AB - A novel Gram-stain negative, spherical, non-motile, strictly aerobic, heterotrophic, yellow pigmented bacterium, designated strain 04OKA003-7(T) was isolated from the hard coral Galaxea fascicularis L. collected at Akajima, Okinawa, Japan. Phylogenetic analysis based on the 16S rRNA gene sequence revealed the novel isolate is affiliated with the family Flavobacteriaceae of the phylum Bacteroidetes and that it showed highest sequence similarity (92.9 %) to Vitellibacter aestuarii JC2436(T) and Aureitalea marina S1-66(T). The strain could be differentiated phenotypically from recognized members of the family Flavobacteriaceae. The major fatty acids of strain 04OKA003-7(T) were identified as iso-C15:0 and iso-C17:0 3-OH as defined by the MIDI system. The DNA G+C content was determined to be 41 mol%, the major respiratory quinone was identified as menaquinone 6 (MK-6) and a polar lipid profile was present consisting of phosphatidylethanolamine, two unidentified aminolipids and an unidentified lipid. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel genus for which the name Aureisphaera galaxeae gen. nov., sp. nov. is proposed. The type strain of A. galaxeae is 04OKA003-7(T) (=KCTC 32993(T) = NBRC 110018(T)). PMID- 25795445 TI - Evaluation of microwave-assisted pretreatment of lignocellulosic biomass immersed in alkaline glycerol for fermentable sugars production. AB - A pretreatment with microwave irradiation was applied to enhance enzyme hydrolysis of corn straw and rice husk immersed in water, aqueous glycerol or alkaline glycerol. Native and pretreated solids underwent enzyme hydrolysis using the extract obtained from the fermentation of Myceliophthora heterothallica, comparing its efficiency with that of the commercial cellulose cocktail Celluclast(r). The highest saccharification yields, for both corn straw and rice husk, were attained when biomass was pretreated in alkaline glycerol, method that has not been previously reported in literature. Moreover, FTIR, TG and SEM analysis revealed a more significant modification in the structure of corn straw subjected to this pretreatment. Highest global yields were attained with the crude enzyme extract, which might be the result of its content in a great variety of hydrolytic enzymes, as revealed zymogram analysis. Moreover, its hydrolysis efficiency can be improved by its supplementation with commercial beta glucosidase. PMID- 25795446 TI - Thermogravimetric analysis and kinetic study of bamboo waste treated by Echinodontium taxodii using a modified three-parallel-reactions model. AB - In this study, the effect of pretreatment with Echinodontium taxodii on thermal decomposition characteristics and kinetics of bamboo wastes was investigated by thermogravimetric analysis. The results showed fungal pretreatment can enhance the thermal degradation of bamboo. The negative effect of extractives in bamboo on the thermal decomposition can be decreased by the pretreatment. A modified three-parallel-reactions model based on isolated lignin was firstly proposed to study pyrolysis kinetics of bamboo lignocellulose. Kinetic analysis showed that with increasing pretreatment time fungal delignification was enhanced to transform the lignin component with high activation energy into that with low activation energy and raise the cellulose content in bamboo, making the thermal decomposition easier. These results demonstrated fungal pretreatment provided a potential way to improve thermal conversion efficiency of bamboo. PMID- 25795447 TI - Implication of composite electrode on the functioning of photo bioelectrocatalytic fuel cell operated with heterotrophic-anoxygenic condition. AB - Electrode materials play a vital role in biofilm formation and electron conduction for efficient functioning of fuel cells. In the present study, graphite polymer composite electrode (GPF) was evaluated as anode for photo bioelectrocatalytic fuel cell (PhFC; biophotovoltaic system) and compared with much studied graphite electrode (Gc) with photosynthetic bacteria as biocatalyst under anoxygenic condition. The electrogenic activity noticed in GPF (584mV; 2.67mA) was slightly lower than Gc (604mV; 2.92mA; OL2/HRT2). Consequently, COD removal observed by GPF (87.3%) was lower than Gc (91.8%). The increase in bacterial chlorophyll pigment showed a positive influence on electrogenic activity for both the electrodes. The polarization resistance (OL2 and HRT2 condition) was significantly higher for GPF (330Omega) as compared to Gc (110Omega). It is interesting to note that the performance of GPF is slightly lower than Gc based PhFC. The findings have opened avenues for composite materials for PhFC. PMID- 25795448 TI - Influence of starch on microalgal biomass recovery, settleability and biogas production. AB - In the context of wastewater treatment with microalgae cultures, coagulation flocculation followed by sedimentation is one of the suitable options for microalgae harvesting. This process is enabled by the addition of chemicals (e.g. iron). However, in a biorefinery perspective, it is important to avoid possible contamination of downstream products caused by chemicals addition. The aim of this study was to evaluate the effect of potato starch as flocculant for microalgal biomass coagulation-flocculation and sedimentation. The optimal flocculant dose (25mg/L) was determined with jar tests. Such a concentration led to more than 95% biomass recovery (turbidity<9NTU). The settleability of flocs was studied using an elutriation apparatus measuring the settling velocities distribution. This test underlined the positive effect of starch on the biomass settling velocity, increasing to >70% the percentage of particles with settling velocities >6.5m/h. Finally, biochemical methane potential tests showed that starch biodegradation increased the biogas production from harvested biomass. PMID- 25795449 TI - Interaction of Cr(VI) reduction and denitrification by strain Pseudomonas aeruginosa PCN-2 under aerobic conditions. AB - Inhibition of efficient denitrification in presence of toxic heavy metals is one of the current problems encountered in municipal wastewater treatment plants. This paper presents how to remove hexavalent chromium (Cr(VI)) and nitrate simultaneously by the novel strain Pseudomonas aeruginosa PCN-2 under aerobic conditions. The capability of strain PCN-2 for Cr(VI) and nitrate reduction was confirmed by PCR analysis of gene ChrR, napA, nirS, cnorB, nosZ, while Cr(VI) reduction was proved via an initial single-electron transfer through Cr(V) detection using electron paramagnetic resonance. Experimental results demonstrated that Cr(VI) and nitrate reduction by strain PCN-2 was much faster at pH 8-9 and higher initial cell concentration. However, increasing Cr(VI) concentration would inhibit aerobic denitrification process and result in an significant delay of nitrate reduction or N2O accumulation, which was attributed to competition between three electron acceptors, i.e., Cr(VI), O2 and nitrate in the electron transport chain. PMID- 25795450 TI - Harvesting of Chlorella sorokiniana by co-culture with the filamentous fungus Isaria fumosorosea: A potential sustainable feedstock for hydrothermal gasification. AB - Despite recent advances in down-stream processing, production of microalgae remains substantially limited because of economical reasons. Harvesting and dewatering are the most energy-intensive processing steps in their production and contribute 20-30% of total operational cost. Bio-flocculation of microalgae by co cultivation with filamentous fungi relies on the development of large structures that facilitate cost effective harvesting. A yet unknown filamentous fungus was isolated as a contaminant from a microalgal culture and identified as Isaria fumosorosea. Blastospores production was optimized in minimal medium and the development of pellets, possibly lichens, was followed when co-cultured with Chlorella sorokiniana under strict autotrophic conditions. Stable pellets (1-2mm) formed rapidly at pH 7-8, clearing the medium of free algal cells. Biomass was harvested with large inexpensive filters, generating wet slurry suitable for hydrothermal gasification. Nutrient rich brine from the aqueous phase of hydrothermal gasification supported growth of the fungus and may increase the process sustainability. PMID- 25795451 TI - Accessible mixotrophic growth of denitrifying sulfide removal consortium. AB - Nitrate, sulfide and organic matters in wastewaters can be removed simultaneously by denitrifying sulfide removal (DSR) process. Complicated interactions between different microbial groups in the DSR medium render the process design and control difficult to implement. A consortium with DSR activity was grown mixotrophically at varying concentrations of nitrate, acetate or ammonium. The kinetic diagram previously proposed was adopted to quantitatively represent DSR performance with accessible regimes of the diagram being identified. Example on the use of the so-yielded accessible regime was provided. PMID- 25795452 TI - Distinct effects of losartan and atenolol on vascular stiffness in Marfan syndrome. AB - We conducted a randomized, double-blind trial of losartan (100 mg QD) versus atenolol (50 mg QD) for 6 months in adults with Marfan syndrome. Carotid-femoral pulse wave velocity (PWV), central augmentation index (AIx), aortic diameter and left ventricular (LV) function were assessed with arterial tonometry and echocardiography. Thirty-four subjects (18 female; median age 35 years, IQR 27, 45) were randomized. Central systolic and diastolic blood pressure decreased comparably with atenolol and losartan (p = 0.64 and 0.31, respectively); heart rate decreased with atenolol (p = 0.02), but not with losartan. PWV decreased in patients treated with atenolol (-1.15 +/- 1.68 m/s; p = 0.01), but not in those treated with losartan (-0.22 +/- 0.59 m/s; p = 0.15; between-group difference p = 0.04). In contrast, AIx decreased in the losartan group (-9.6 +/- 8.6%; p < 0.001) but not in the atenolol group (0.9 +/- 6.2%, p = 0.57; between-group difference p < 0.001). There was no significant change in aortic diameters or LV ejection fraction in either treatment group. In adults with Marfan syndrome, 6 months of treatment with atenolol improves PWV, whereas losartan reduces the AIx. By improving vascular stiffness via distinct mechanisms of action, there is physiologic value to considering the use of both medications in individuals with Marfan syndrome. PMID- 25795454 TI - Differences in Psychiatric Problems and Criminality Between Individuals Treated With Central Stimulants Before and After Adulthood. AB - OBJECTIVE: The evidence for central stimulant (CS) treatment in ADHD is strong in some respects but not with respect to unselected clinical material and long-term effects over the life course cycle. The objective of this study was to explore differences in vocational, psychiatric, and social impairment, including crime and substance abuse, among adults with ADHD, treated or not, with CS drugs before age 18. METHOD: A clinical population of men (N = 343) and women (N = 129) seeking CS treatment as adults was assessed within a specific program for such treatment. Clinical information and data collected by structured instruments were available. RESULTS: Previously CS-treated persons had a lower frequency of problems (alcohol/substance abuse, criminality), and of certain psychiatric disorders (depressive, anxiety and personality ones). Most differences were substantial. CONCLUSION: The study supports the assumption that CS treatment during childhood/adolescence offers some protection against the development of a range of problems known to characterize adult ADHD patients. PMID- 25795453 TI - Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness. AB - Several laboratories, including ours, have reported an overrepresentation of craniofacial (CF) anomalies in schizophrenia (SZ). How might this dysmorphology arise in a brain-based disorder? Because the brain and face derive from shared embryologic primordia and morphogenetic forces, maldevelopmental processes may result in both CF and brain dysmorphology.Our approach is 2-pronged. First, we have employed, for the first time in the study of psychiatric disorders, objective measures of CF morphology that utilize an extensive normative database, permitting computation of standardized scores for each subject. Second, we have rendered these findings biologically interpretable by adopting principles of embryology in the analysis of dysmorphology.Dependent measures in this investigation focused on derivatives of specific embryonic primordia and were contrasted among probands with psychotic disorders, their first-degree relatives, and normal controls (NC). Subject groups included patients with a diagnosis of SZ (N = 39) or bipolar (BP) disorder with psychotic features (N = 32), their clinically unaffected relatives (N = 82 and N = 41, respectively), and NC (N = 95) subjects.Anomalies involving derivatives of frontonasal and mandibular embryonic primordia showed a clear association with psychotic illness, as well as familial aggregation in relatives in both diagnostic groups. In contrast, one class of CF anomalies emerged only among SZ probands and their first-degree relatives: dysmorphology arising along the junction of the frontonasal and maxillary prominence derivatives, manifested as marked asymmetries. This class was not overrepresented among the BP patients nor among their relatives, indicating that this dysmorphology appears to be specific to SZ and not a generalized feature of psychosis. We discuss these findings in light of embryologic models that relate brain regions to specific CF areas. PMID- 25795455 TI - Masticatory muscles of mouse do not undergo atrophy in space. AB - Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 +/- 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12 fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P Akt, and 50-90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle. PMID- 25795456 TI - Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection. AB - We sought to determine the mechanisms by which influenza infection of human epithelial cells decreases cystic fibrosis transmembrane conductance regulator (CFTR) expression and function. We infected human bronchial epithelial (NHBE) cells and murine nasal epithelial (MNE) cells with various strains of influenza A virus. Influenza infection significantly reduced CFTR short circuit currents (Isc) and protein levels at 8 hours postinfection. We then infected CFTR expressing human embryonic kidney (HEK)-293 cells (HEK-293 CFTRwt) with influenza virus encoding a green fluorescent protein (GFP) tag and performed whole-cell and cell-attached patch clamp recordings. Forskolin-stimulated, GlyH-101-sensitive CFTR conductances, and CFTR open probabilities were reduced by 80% in GFP positive cells; Western blots also showed significant reduction in total and plasma membrane CFTR levels. Knockdown of the influenza matrix protein 2 (M2) with siRNA, or inhibition of its activity by amantadine, prevented the decrease in CFTR expression and function. Lysosome inhibition (bafilomycin-A1), but not proteasome inhibition (lactacystin), prevented the reduction in CFTR levels. Western blots of immunoprecipitated CFTR from influenza-infected cells, treated with BafA1, and probed with antibodies against lysine 63-linked (K-63) or lysine 48-linked (K-48) polyubiquitin chains supported lysosomal targeting. These results highlight CFTR damage, leading to early degradation as an important contributing factor to influenza infection-associated ion transport defects. PMID- 25795457 TI - Losartan treating podocyte injury induced by Ang II via downregulation of TRPC6 in podocytes. AB - OBJECTIVE: In this study, we investigated the molecule mechanisms of podocyte injury and proteinuria and the protective effects of losartan. METHODS: This study set up three groups: a control group; an Ang II group (Ang II 10(-6) mol/l, Sigma); and a losartan group (losartan 10(-6) mol/l, Sigma). We used RT-PCR assay to detect TRPC6 mRNA expression, and Western blot to detect TRPC6 protein expression. RESULTS: TRPC6 overexpression was the basic change of podocyte injury and proteinuria occurrence. Losartan can treat podocyte injury and proteinuria induced by Ang II via downregulation of TRPC6 in podocytes. CONCLUSION: These findings maybe provide an ideal drug target for the diagnosis and treatment of acquired glomerular diseases. PMID- 25795458 TI - Activation of renin-angiotensin-aldosterone system (RAAS) in the lung of smoking induced pulmonary arterial hypertension (PAH) rats. AB - OBJECTIVES: To explore the role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of pulmonary arterial hypertension (PAH) induced by chronic exposure to cigarette smoke. METHODS: 48 healthy male SD rats were randomly divided into four groups (12/group): control group (group A); inhibitor alone group (group B); cigarette induction group (group C); cigarette induction + inhibitor group (group D). After the establishment of smoking-induced PAH rat model, the right ventricular systolic pressure (RVSP) was detected using an inserted catheter; western blotting was used to detect the protein expression of angiotensin-converting enzyme-2 (ACE2) and angiotensin-converting enzyme (ACE); expression levels of angiotensin II (AngII) in lung tissue were measured by radioimmunoassay. RESULTS: After six months of cigarette exposure, the RVSP of chronic cigarette induction group was significantly higher than that of the control group; expression levels of AngII and ACE increased in lung tissues, but ACE2 expression levels reduced. Compared with cigarette exposure group, after losartan treatment, RVSP, ACE and AngII obviously decreased (P<0.05), and ACE2 expression levels significantly increased. CONCLUSION: Chronic cigarette exposure may result in PAH and affect the protein expression of ACE2 and ACE in lung tissue, suggesting that ACE2 and ACE play an important role in the pathogenesis of smoking-induced PAH. PMID- 25795459 TI - A feasibility randomised controlled trial of pre-operative occupational therapy to optimise recovery for patients undergoing primary total hip replacement for osteoarthritis (PROOF-THR). AB - OBJECTIVE: To assess the feasibility of a pre-operative occupational therapy intervention for patients undergoing primary total hip replacement. DESIGN: Single blinded feasibility randomised controlled trial, with data collection prior to the intervention, and at 4, 12, and 26 weeks following surgery. SETTING: Recruitment from two NHS orthopaedic outpatient centres in the West Midlands, UK. SUBJECTS: Patients awaiting primary total hip replacement due to osteoarthritis were recruited. Following pre-operative assessment, patients were individually randomised to intervention or control by a computer-generated block randomisation algorithm stratified by age and centre. INTERVENTIONS: The intervention group received a pre-surgery home visit by an occupational therapist who discussed expectations, assessed home safety, and provided appropriate adaptive equipment. The control group received treatment as usual. OUTCOMES: The study assessed the feasibility of recruitment procedures, delivery of the intervention, appropriateness of outcome measures and data collection methods. Health related quality of life and resource use were recorded at 4, 12 and 26 weeks. RESULTS: Forty-four participants were recruited, 21 were randomised to the occupational therapy intervention and 23 to usual care. Analysis of 26 week data included 18 participants in the intervention group and 21 in the control. The intervention was delivered successfully with no withdrawals or crossovers; 5/44 were lost to follow-up with further missing data for participation and resource use. CONCLUSIONS: The feasibility study provided the information required to conduct a definitive trial. Burden of assessment would need to be addressed. A total of 219 patients would be required in an efficacy trial. PMID- 25795460 TI - Isolated unilateral oculomotor paresis in pure midbrain stroke. AB - BACKGROUND AND PURPOSE: Pure midbrain stroke can cause isolated unilateral oculomotor paresis. We attempted to determine whether there is a difference in the oculomotor paresis pattern between pure midbrain infarction and midbrain hemorrhage. METHODS: Pure midbrain stroke patients who presented with isolated unilateral oculomotor paresis were identified from a group of 2447 consecutive patients hospitalized for acute cerebral infarction or hemorrhage during the period May 2008 through April 2014. Detailed oculomotor findings were evaluated in the identified patients per the cause of the stroke. RESULTS: Five patients with infarct and 1 with hemorrhage became our study subjects. Lesions were located in the paramedian area of the midbrain involving the oculomotor fascicles. The pupillary sphincter and inferior rectus muscles were selectively spared in the infarct patients, whereas these muscles were selectively affected in the hemorrhage patient. CONCLUSION: Fibers in the oculomotor fascicle that innervate the levator palpebrae, superior rectus, and inferior oblique muscles appear to be more susceptible to ischemic damage than those that innervate the pupillary sphincter and inferior rectus muscles. Isolated impairment of the pupillary sphincter and inferior rectus muscles may be suggestive of a non ischemic process. PMID- 25795461 TI - Induction of UDP-glucuronosyltransferase 2B15 gene expression by the major active metabolites of tamoxifen, 4-hydroxytamoxifen and endoxifen, in breast cancer cells. AB - We previously reported upregulation of UGT2B15 by 17beta-estradiol in breast cancer MCF7 cells via binding of the estrogen receptor alpha (ERalpha) to an estrogen response unit (ERU) in the proximal UGT2B15 promoter. In the present study, we show that this ERalpha-mediated upregulation was significantly reduced by two ER antagonists (fulvestrant and raloxifene) but was not affected by a third ER antagonist, 4-hydroxytamoxifen (4-OHTAM), a major active tamoxifen (TAM) metabolite. Furthermore, we found that, similar to 17beta-estradiol, 4-OHTAM and endoxifen (another major active TAM metabolite) elevated UGT2B15 mRNA levels, and that this stimulation was significantly abrogated by fulvestrant. Further experiments using 4-OHTAM revealed a critical role for ERalpha in this regulation. Specifically; knockdown of ERalpha expression by anti-ERalpha small interfering RNA reduced the 4-OHTAM-mediated induction of UGT2B15 expression; 4 OHTAM activated the wild-type but not the ERU-mutated UGT2B15 promoter; and chromatin immunoprecipitation assays showed increased ERalpha occupancy at the UGT2B15 ERU in MCF7 cells upon exposure to 4-OHTAM. Together, these data indicate that both 17beta-estradiol and the antiestrogen 4-OHTAM upregulate UGT2B15 in MCF7 cells via the same ERalpha-signaling pathway. This is consistent with previous observations that both 17beta-estradiol and TAM upregulate a common set of genes in MCF7 cells via the ER-signaling pathway. As 4-OHTAM is a UGT2B15 substrate, the upregulation of UGT2B15 by 4-OHTAM in target breast cancer cells is likely to enhance local metabolism and inactivation of 4-OHTAM within the tumor. This represents a potential mechanism that may reduce TAM therapeutic efficacy or even contribute to the development of acquired TAM resistance. PMID- 25795462 TI - Short-term fasting alters cytochrome P450-mediated drug metabolism in humans. AB - Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450 mediated drug metabolism in humans. PMID- 25795464 TI - Targeting the Epidemic: Interventions and Follow-up Are Necessary in the Pediatric Traumatic Brain Injury Clinic. AB - Traumatic brain injury is a major public health problem in the pediatric population. Previously, management was acute emergency department/primary care evaluation with follow-up by primary care. However, persistent symptoms after traumatic brain injury are common, and many do not have access to a specialized traumatic brain injury clinic to manage chronic issues. The goal of this study was to determine the factors related to outcomes, and identify the interventions provided in this subspecialty clinic. Data were extracted from medical records of 151 retrospective and 403 prospective patients. Relationships between sequelae, injury characteristics, and clinical interventions were analyzed. Most patients returning to clinic were not fully recovered from their injury. Headaches were more common after milder injuries, and seizures were more common after severe. The majority of patients received clinical intervention. The presence of persistent sequelae for traumatic brain injury patients can be evaluated and managed by a specialty concussion/traumatic brain injury clinic ensuring that medical needs are met. PMID- 25795463 TI - The winding road to regenerating the human heart. AB - Regenerating the human heart is a challenge that has engaged researchers and clinicians around the globe for nearly a century. From the repair of the first septal defect in 1953, followed by the first successful heart transplant in 1967, and later to the first infusion of bone marrow-derived cells to the human myocardium in 2002, significant progress has been made in heart repair. However, chronic heart failure remains a leading pathological burden worldwide. Why has regenerating the human heart been such a challenge, and how close are we to achieving clinically relevant regeneration? Exciting progress has been made to establish cell transplantation techniques in recent years, and new preclinical studies in large animal models have shed light on the promises and challenges that lie ahead. In this review, we will discuss the history of cell therapy approaches and provide an overview of clinical trials using cell transplantation for heart regeneration. Focusing on the delivery of human stem cell-derived cardiomyocytes, current experimental strategies in the field will be discussed as well as their clinical translation potential. Although the human heart has not been regenerated yet, decades of experimental progress have guided us onto a promising path. SUMMARY: Previous work in clinical cell therapy for heart repair using bone marrow mononuclear cells, mesenchymal stem cells, and cardiac-derived cells have overall demonstrated safety and modest efficacy. Recent advancements using human stem cell-derived cardiomyocytes have established them as a next generation cell type for moving forward, however certain challenges must be overcome for this technique to be successful in the clinics. PMID- 25795465 TI - Teaching Neuroimages: Basal Ganglia Germinoma with Hemiatrophy. PMID- 25795466 TI - Preoperative Evaluation of Patients with Hemifacial Spasm by Three-dimensional Time-of-Flight (3D-TOF) and Three-dimensional Constructive Interference in Steady State (3D-CISS) Sequence. AB - PURPOSE: The purpose of this study was to investigate and evaluate the accuracy and the preoperative diagnostic value of high-resolution magnetic resonance imaging (MRI) techniques, three-dimensional time-of-flight (3D-TOF) and three dimensional constructive interference in steady state (3D-CISS) sequence, solely or in combination for the detection of the relationship between the facial nerve and adjacent vessels in patients with hemifacial spasm (HFS). METHODS: A total of 95 patients with primary HFS were subject to 3D-TOF and 3D-CISS MRI. The MR images were then used to evaluate the anatomical neurovascular relationships, and the results were compared with the surgical findings. We categorized the neurovascular relationship into three types: compression, contact, and neighboring or distant. Compression and/or contacts between root exit zone (REZ) and vessels were defined as positive, whereas neighboring or distant was considered to be negative. RESULTS: 3D-TOF combined with 3D-CISS assessment showed that 94 of 95 patients had artery compression or contact at REZ, whereas the remaining patient had compression at the peripheral branch of the facial nerve but not at REZ. The positive rates and the overall accuracy were 98.95 and 100 %, respectively, for the 3D-TOF combined with 3D-CISS assessment; 92.63 and 93.68 %, respectively, for the 3D-TOF assessment; and 85.26 and 86.32 %, respectively, for the 3D-CISS assessment. The positive rates and overall accuracy for the 3D-TOF combined with 3D-CISS assessment was significantly higher than those for the 3D-TOF or 3D-CISS assessment. CONCLUSIONS: Combination of 3D-TOF with 3D-CISS imaging well delineates the relationship between the facial nerve and adjacent vessels in terms of increased positive rates and accuracy. PMID- 25795467 TI - [Renal extramedullary hematopoietic tumor revealing a hereditary spherocytosis in an adult patient]. AB - INTRODUCTION: Myelolipomas and extramedullary hematopoietic tumors are uncommon benign tumors. They are variably composed of mature adipose tissue and hematopoietic tissue. Myelolipoma is usually observed in the adrenal gland and extramedullary hematopoietic tumors in the liver and spleen but may occasionally be found within solid tumors. CASE REPORT: A 62-year-old man without previous haematological history presented with a voluminous solitary bilateral renal tumor. Contrast-enhanced ultrasound CT-scan and scintigraphy with technetium-99m nanocolloid and indium-111-chloride bone marrow were highly suggestive of extramedullary hematopoietic tumor. CT-guided biopsy suggested a diagnosis of myelolipoma. An atypical hereditary spherocytosis, undiagnosed until now, was demonstrated. CONCLUSION: We report, for the first time to our knowledge, a border form between extramedullary hematopoiesis tumor and myelolipoma of renal localisation revealing a hereditary spherocytosis in an adult patient. PMID- 25795468 TI - The effect of medium selection on adipose-derived stem cell expansion and differentiation: implications for application in regenerative medicine. AB - The use of adipose-derived stem cells is wide-spread in both basic biology and regenerative medicine, due to the abundance of adipose tissue and the multipotent differentiation potential of the cells. However, the methods used to isolate and culture cells vary greatly between different research groups. Identification of medium formulations which provide rapid cell expansion while maintaining cell phenotype would have clear advantages. We compared growth and differentiation potential along the adipogenic lineage in human ADSCs in nine different media. We further assessed induced and spontaneous differentiation along the adipogenic, chondrogenic and osteogenic lineage in three different media. There was significant variation in the rate of growth between different media. All media supported ADSC phenotype and adipogenic differentiation, although there was variation between the different media. Differentiation along the adipogenic, chondrogenic and osteogenic lineages in the three media was confirmed, with some upregulation of specific genes observed when cells were left to spontaneously differentiate. Our study shows a direct comparison of human ADSCs grown in different media, both reported in the literature and commercially available. It indicates that rapid proliferation occurs most often in media which contain 10 % foetal bovine serum and that differentiation along different lineages can be induced but also occurs spontaneously once cells become confluent. These data provide a tool for other researchers to facilitate the choice of medium formulation most appropriate for different applications. PMID- 25795469 TI - Model-based strategy for cell culture seed train layout verified at lab scale. AB - Cell culture seed trains-the generation of a sufficient viable cell number for the inoculation of the production scale bioreactor, starting from incubator scale are time- and cost-intensive. Accordingly, a seed train offers potential for optimization regarding its layout and the corresponding proceedings. A tool has been developed to determine the optimal points in time for cell passaging from one scale into the next and it has been applied to two different cell lines at lab scale, AGE1.HN AAT and CHO-K1. For evaluation, experimental seed train realization has been evaluated in comparison to its layout. In case of the AGE1.HN AAT cell line, the results have also been compared to the formerly manually designed seed train. The tool provides the same seed train layout based on the data of only two batches. PMID- 25795471 TI - The role of physicians in promoting weight loss. AB - There are numerous costs resulting from being overweight or obese. A relevant question is how to effectively reduce rates of obesity. I examine the effect of advice from a physician or heath care provider to lose weight on individual weight outcomes using survey data. I account for selection bias using a control function approach and rely on data restrictions to control for simultaneity. I find robust results indicating that advice has a significant effect on weight loss. Several studies suggest physicians may not adequately advise their patients about weight loss. The results of this paper highlight an important opportunity for physicians to advise at-risk patients. PMID- 25795470 TI - Study of the cytotoxic activity of Styrax camporum extract and its chemical markers, egonol and homoegonol. AB - The benzofuran lignans egonol and homoegonol are found in all species of the genus Styrax. Since natural products are important sources of new anticancer drugs, this study evaluated the cytotoxic activity of a hydroalcoholic extract of the stems of S. camporum (SCHE) and their chemical markers, egonol (EG) and homoegonol (HE), against different tumor cell lines (B16F10, MCF-7, HeLa, HepG2, and MO59J). A normal human cell line (GM07492A) was included. Cytotoxic activity was evaluated at different treatment times (24, 48 and 72 h) using the XTT assay. More effective results were observed after 72 h of treatment. The lowest IC50 values were found for the HepG2 cell line, ranging from 11.2 to 55.0 ug/mL. The combination of EG and HE exerted higher cytotoxic activity than SCHE or treatment with either lignan alone, with the lowest IC50 (13.31 ug/mL) being observed for the MCF-7 line. Furthermore, treatment with these lignans was significantly more cytotoxic for some tumor cell lines compared to the normal cell line, GM07492A, indicating selectivity. These results suggest that these lignans may be used to treat cancer without affecting normal cells. PMID- 25795472 TI - Evaluation of left ventricular function by three-dimensional speckle-tracking echocardiography in patients with myocardial bridging of the left anterior descending coronary artery. AB - BACKGROUND: To understand the influence of myocardial bridging (MB) on left ventricular (LV) function, myocardial function was studied in patients with MB of the left anterior descending coronary artery (LAD) using three-dimensional speckle-tracking echocardiography (STE). METHODS: Left anterior descending coronary artery MB was diagnosed by coronary angiography in 82 subjects. Patients were divided into three groups according to the percentage of systolic narrowing of the compressed segment: 30% to 49% was defined as group I (24 patients), 50% to 74% as group II (28 patients), and >=75% as group III (30 patients). Thirty gender- and age-matched normal subjects were included as controls. Left ventricular myocardial deformation was estimated by three-dimensional STE. RESULTS: Left ventricular ejection fractions were normal in all patients, but diastolic function was impaired in groups II and III (E/E' ratio, 9 +/- 3 and 10 +/- 3, respectively). The amplitudes of longitudinal strain (LS) and area strain (AS) of the LAD territory was significantly reduced in groups II and III compared with controls and group I (LS, -15 +/- 2% and -12 +/- 1% vs -19 +/- 2% and -18 +/ 2%; AS, -22 +/- 2% and -13 +/- 2% vs -33 +/- 4% and -33 +/- 3%; P < .0001), but the amplitudes of circumferential and radial strain showed no intergroup differences. Longitudinal strain and AS were significantly lower in patients with fractional flow reserve < 0.75 than in those with fractional flow reserve >= 0.75 (P < .0001), with relative preservation of circumferential and radial strain. The severity of LAD compression was significantly associated with AS and LS of the LAD territory (r = -0.92 and r = -0.84, respectively, P < .0001), but the correlations with circumferential and radial strain were modest (r = -0.36 and r = -0.32, respectively, P < .05). CONCLUSIONS: With the increasing severity of systolic compression of the mural coronary artery, LV diastolic function and regional systolic deformation (AS and LS) of the MB perfusion territory were reduced. Three-dimensional STE can detect subtle myocardial dysfunction in patients with MB. PMID- 25795473 TI - Anakinra for the treatment of acute severe gout in critically ill patients. AB - OBJECTIVES: To report on the efficacy and safety of anakinra for treatment of acute gouty arthritis in medically complex, critically ill patients. METHODS: Retrospective chart review of 13 critically ill hospitalized patients treated with anakinra for 20 episodes of acute gouty arthritis between 2009 and 2014 at a single health plan and institution (HealthPartners Medical Group and Regions Hospital) in Saint Paul, Minnesota. Data was obtained on baseline characteristics, medical comorbidities, reason for hospitalization, prior gout treatment, reason for choosing anakinra over standard therapy, anakinra dosing, response to treatment, and adverse outcomes. RESULTS: A total of 10 patients were in the Intensive Care Unit, 1 was in the Burn Unit for extensive 3rd degree burns, 1 was critically ill with a new diagnosis of hemophagocytic lymphohistiocytosis, and 1 was critically ill in isolation with active disseminated multidrug-resistant tuberculosis. Of these patients, 85% had active infections and 92% had renal insufficiency. All patients had a significant response to anakinra treatment: 50% (10/20 episodes) within 24h, an additional 40% (8/20 episodes) by 48h, and the remaining 10% (2/20 episodes) by 72h. Anakinra was well tolerated with only 1 case of leukopenia and 1 possible infectious complication. CONCLUSIONS: Anakinra is a safe and efficacious treatment for acute gouty arthritis in medically complex, critically ill patients when standard treatment modalities cannot be used. PMID- 25795474 TI - Retained Short Hook Wires Used for Preoperative Localization of Small Pulmonary Lesions During Video-Assisted Thoracoscopic Surgery: A Report of 2 Cases. PMID- 25795475 TI - Respiratory-Induced Haemodynamic Changes: A Contributing Factor to IVC Filter Penetration. AB - PURPOSE: The purpose of the study is to evaluate the influence of respiratory induced vena caval hemodynamic changes on filter migration/penetration. MATERIALS AND METHODS: After placement of either a Gunther Tulip or Celect IVC filter, 101 consecutive patients scheduled for filter retrieval were prospectively enrolled in this study. Pre-retrieval CT scans were used to assess filter complications and to calculate cross-sectional area in three locations: at level of filter strut fixation, 3 cm above and 3 cm below. A 3D finite element simulation was constructed on these data and direct IVC pressure was recorded during filter retrieval. Cross-sectional areas and pressures of the vena cava were measured during neutral breathing and in Valsalva maneuver and identified filter complications were recorded. A statistical analysis of these variables was then performed. RESULTS: During Valsalva maneuvers, a 60 % decrease of the IVC cross sectional area and a fivefold increase in the IVC pressure were identified (p < 0.001). There was a statistically significant difference in the reduction of the cross-sectional area at the filter strut level (p < 0.001) in patient with filter penetration. Difficulty in filter retrieval was higher in penetrated or tilted filters (p < 0.001; p = 0.005). 3D computational models showed significant IVC deformation around the filter during Valsalva maneuver. CONCLUSION: Caval morphology and hemodynamics are clearly affected by Valsalva maneuvers. A physiological reduction of IVC cross-sectional area is associated with higher risk of filter penetration, despite short dwell times. Physiologic data should be used to improve future filter designs to remain safely implanted over longer dwell times. PMID- 25795476 TI - Spectral-domain optical coherence tomography angiography of choroidal neovascularization. AB - PURPOSE: To describe the characteristics as well as the sensitivity and specificity of detection of choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA) using spectral-domain optical coherence tomography. DESIGN: Observational, retrospective study. PARTICIPANTS: Seventy-two eyes of 61 subjects (48 eyes of 43 subjects with CNV, 24 eyes of 18 subjects without CNV). METHODS: Patients imaged using the prototype AngioVue OCTA system (Optovue, Inc, Fremont, CA) between August 2014 and October 2014 at New England Eye Center were assessed. Patients in whom CNV was identified on OCTA were evaluated to define characteristics of CNV on OCTA: size using greatest linear dimension (small, <1 mm; medium, 1-2 mm; large, >2 mm), appearance (well circumscribed, poorly circumscribed), and presence of subretinal and intraretinal fluid. Concurrently, an overlapping second cohort of patients who underwent same day OCTA and fluorescein angiography (FA) for suspected CNV was evaluated to estimate sensitivity and specificity of OCTA in detecting CNV using FA as ground truth. MAIN OUTCOME MEASURES: Choroidal neovascularization appearance, CNV size, and presence of subretinal and intraretinal fluid. RESULTS: In 48 eyes, CNV was visualized on OCTA. Thirty-one eyes had CNV associated with neovascular age related macular degeneration. Size of CNV was small in 23% (7/31), medium in 42% (13/31), and large in 35% (11/31). Poorly circumscribed vessels, subretinal fluid, and intraretinal fluid each were seen in 71% (22/31). Seven eyes had CNV associated with central serous chorioretinopathy. Size of CNV was small in 71% (5/7) and large in 29% (2/7). Seventy-one percent (5/7) had well-circumscribed vessels, 86% (6/7) had subretinal fluid, and 14% (1/7) had intraretinal fluid. Thirty eyes with OCTA and same-day FA were evaluated to determine sensitivity and specificity of CNV detection on OCTA. Sensitivity was 50% (4/8) and specificity was 91% (20/22). CONCLUSIONS: Using OCTA allows the clinician to visualize CNV noninvasively and may provide a method for identifying and guiding treatment of CNV. The specificity of CNV detection on OCTA compared with FA seems to be high. Future studies with larger sample sizes are needed to elaborate better on the sensitivity and specificity of CNV detection and to illustrate clinical usefulness. PMID- 25795477 TI - Mitomycin-C in corneal surface excimer laser ablation techniques: a report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the published literature assessing the efficacy and safety of mitomycin-C (MMC) as an adjunctive treatment in corneal surface excimer laser ablation procedures. METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted on August 19, 2014, without language or date limitations. The searches retrieved a total of 239 references. Of these, members of the Ophthalmic Technology Assessment Committee Refractive Management/Intervention Panel selected 26 articles that were considered to be of high or medium clinical relevance, and the panel methodologist rated each article according to the strength of evidence. Ten studies were rated as level I evidence, 5 studies were rated as level II evidence, and the remaining 11 studies were rated as level III evidence. RESULTS: The majority of the articles surveyed in this report support the role of MMC as an adjunctive treatment in surface ablation procedures. When MMC is applied in the appropriate concentration and confined to the central cornea, the incidence of post-surface ablation haze is decreased. Although a minority of studies that evaluated endothelial cell density (ECD) reported an MMC-related decrease in ECD, no clinical adverse outcomes were reported. CONCLUSIONS: Over the past 15 years, the use of MMC during surgery in surface ablation has become widespread. There is good evidence of the effectiveness of MMC when used intraoperatively as prophylaxis against haze in higher myopic ablations. Although there are reports of decreased endothelial counts after the administration of MMC during surgery, the clinical significance of this finding remains uncertain, because no adverse outcomes were reported with as much as 5 years of follow-up. Optimal dosage, effectiveness as prophylaxis in lower myopic and hyperopic ablations, and long-term safety, particularly in eyes with reduced corneal endothelial cell counts from prior intraocular surgery, have yet to be established. PMID- 25795478 TI - The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. AB - PURPOSE: To evaluate the clinical characteristics of the 3 classifications of vitreous seeds in retinoblastoma-dust (class 1), spheres (class 2), and clouds (class 3)-and their responses to intravitreal melphalan. DESIGN: Retrospective, bi-institutional cohort study. PARTICIPANTS: A total of 87 patient eyes received 475 intravitreal injections of melphalan (median dose, 30 MUg) given weekly, a median of 5 times (range, 1-12 times). METHODS: At presentation, the vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response to weekly intravitreal melphalan injections and time to regression of vitreous seeds. Kaplan-Meier estimates of time to regression and ocular survival, patient survival, and event-free survival (EFS) were calculated and then compared using the Mantel-Cox test of curve. MAIN OUTCOME MEASURES: Time to regression of vitreous seeds, patient survival, ocular survival, and EFS. RESULTS: The difference in time to regression was significantly different for the 3 seed classes (P < 0.0001): the median time to regression was 0.6, 1.7, and 7.7 months for dust, spheres, and clouds, respectively. Eyes with dust received significantly fewer injections and a lower median and cumulative dose of melphalan, whereas eyes with clouds received significantly more injections and a higher median and cumulative dose of melphalan. Overall, the 2-year Kaplan-Meier estimates for ocular survival, patient survival, and EFS (related to target seeds) were 90.4% (95% confidence interval [CI], 79.7-95.6), 100%, and 98.5% (95% CI, 90-99.7), respectively. CONCLUSIONS: The regression and response of vitreous seeds to intravitreal melphalan are different for each seed classification. The vitreous seed classification can be predictive of time to regression, number, median dose, and cumulative dose of intravitreal melphalan injections required. PMID- 25795479 TI - Six-Year Incidence and Baseline Risk Factors for Pseudoexfoliation in a South Indian Population: The Chennai Eye Disease Incidence Study. AB - OBJECTIVE: To estimate the 6-year incidence of pseudoexfoliation and its risk factors in a South Indian population. DESIGN: Longitudinal population-based study. PARTICIPANTS: Subjects 40 years of age or older without pseudoexfoliation at baseline. METHODS: Participants were examined at baseline and after a 6-year interval. The presence of pseudoexfoliation was looked for after pupillary dilation in either or both eyes at 1 or more locations. Glaucoma was defined using the International Society of Geographical and Epidemiological Ophthalmology Classification. Logistic regression was performed to identify the baseline risk factors that could predict the incident pseudoexfoliation. MAIN OUTCOME MEASURES: Six-year incidence, associated risk factors, and rural-versus-urban differences. RESULTS: From the study cohort of 4228 subjects, 87 subjects (male-to-female ratio, 48:39; rural-to-urban ratio, 69:18) demonstrated incident pseudoexfoliation (2.03%; 95% confidence interval [CI], 1.6-2.5; rural: -2.86%; 95% CI, 1.6-2.5; urban: 0.96%; 95% CI, 0.5-1.4). Pseudoexfoliation was associated with glaucoma in 1 subject (1.1%), with primary angle-closure suspicion in 10 subjects (11.5%), and with ocular hypertension in 2 subjects (2.2%). Significant predictive baseline risk factors were older age (P < 0.001), rural residence (P < 0.001), illiteracy (P = 0.02), pseudophakia (P = 0.04), and nuclear cataract (P = 0.05). With reference to the 40-to-49-year age group, the risk of incidence increased from 4.7 (95% CI, 2.4-9.4) for the 50-to-59-year age group to 12.9 (95% CI, 6.1-27.2) for 70 years of age and older group. CONCLUSIONS: In 6 years, pseudoexfoliation developed in 2.03% of the population. Rural and urban incidence was significantly different. PMID- 25795480 TI - Factors governing particle number emissions in a waste-to-energy plant. AB - Particle number concentration and size distribution measurements were performed on the stack gas of a waste-to-energy plant which co-incinerates municipal solid waste, sewage sludge and clinical waste in two lines. Average total number of particles was found to be 4.0.10(5)cm(-3) and 1.9.10(5)cm(-3) for the line equipped with a wet flue gas cleaning process and a dry cleaning system, respectively. Ultrafine particles (dp<100nm) accounted for about 97% of total number concentration for both lines, whereas the nanoparticle (dp<50nm) contribution differed slightly between the lines (87% and 84%). The experimental data is explored statistically through some multivariate pattern identifying methods such as factor analysis and cluster analysis to help the interpretation of the results regarding the origin of the particles in the flue gas with the objective of determining the factors governing the particle number emissions. The higher moisture of the flue gas in the wet cleaning process was found to increase the particle number emissions on average by a factor of about 2 due to increased secondary formation of nanoparticles through nucleation of gaseous precursors such as sulfuric acid, ammonia and water. The influence of flue gas dilution and cooling monitored through the variation of the sampling conditions also confirms the potential effect of the secondary new particle formation in increasing the particle number emissions. This finding shows the importance of reporting the experimental conditions in detail to enable the comparison and interpretation of particle number emissions. Regarding the fuel characteristics no difference was observed in terms of particle number concentration and size distributions between the clinical waste feed and the municipal solid waste co-incineration with sludge. PMID- 25795481 TI - FTIR-PAS: a powerful tool for characterising the chemical composition and predicting the labile C fraction of various organic waste products. AB - Fourier transform infrared (FT-IR) spectroscopy has been used for several years as a fast, low-cost, reliable technique for characterising a large variety of materials. However, the strong influence of sample particle size and the inability to measure the absorption of very dark and opaque samples have made FTIR unsuitable for many waste materials. FTIR-photoacoustic spectroscopy (FTIR PAS) can eliminate some of the shortcomings of traditional FTIR caused by scattering effects and reflection issues, and recent advances in PAS technology have made commercial instruments available. In this study, FTIR-PAS was used to characterise a wide range of organic waste products and predict their labile carbon fraction, which is normally determined from time-consuming assays. FTIR PAS was found to be capable of predicting the labile fraction of carbon as efficiently as near infrared spectroscopy (NIR) and furthermore of identifying the compounds that are correlated with the predicted parameter, thus facilitating a more mechanistic interpretation. PMID- 25795482 TI - Growth and gas production of a novel obligatory heterofermentative Cheddar cheese nonstarter lactobacilli species on ribose and galactose. AB - An obligatory heterofermentative lactic acid bacterium, Lactobacillus wasatchii sp. nov., isolated from gassy Cheddar cheese was studied for growth, gas formation, salt tolerance, and survival against pasteurization treatments at 63 degrees C and 72 degrees C. Initially, Lb. wasatchii was thought to use only ribose as a sugar source and we were interested in whether it could also utilize galactose. We conducted experiments to determine the rate and extent of growth and gas production in carbohydrate-restricted (CR) de Man, Rogosa, and Sharpe (MRS) medium under anaerobic conditions with various combinations of ribose and galactose at 12, 23, and 37 degrees C, with 23 degrees C being the optimum growth temperature of Lb. wasatchii among the 3 temperatures studied. When Lb. wasatchii was grown on ribose (0.1, 0.5, and 1%), maximum specific growth rates (umax) within each temperature were similar. When galactose was the only sugar, compared with ribose, umax was 2 to 4 times lower. At all temperatures, the highest final cell densities (optical density at 640 nm) of Lb. wasatchii were achieved in CR MRS plus 1% ribose, 0.5% ribose and 0.5% galactose, or 1% ribose and 1% galactose. Similar umax values and final cell densities were achieved when 50% of the ribose in CR-MRS was substituted with galactose. Such enhanced utilization of galactose in the presence of ribose to support bacterial growth has not previously been reported. It appears that Lb. wasatchii co-metabolizes ribose and galactose, utilizing ribose for energy and galactose for other functions such as cell wall biosynthesis. Co-utilization of both sugars could be an adaptation mechanism of Lb. wasatchii to the cheese environment to efficiently ferment available sugars for maximizing metabolism and growth. As expected, gas formation by the heterofermenter was observed only when galactose was present in the medium. Growth experiments with MRS plus 1.5% ribose at pH 5.2 or 6.5 with 0, 1, 2, 3, 4, or 5% NaCl revealed that Lb. wasatchii is able to grow under salt and pH conditions typical of Cheddar cheese (4 to 5% salt-in-moisture, pH ~5.2). Finally, we found that Lb. wasatchii cannot survive low-temperature, long-time pasteurization but survives high-temperature, short-time (HTST) laboratory pasteurization, under which a 4.5 log reduction occurred. The ability of Lb. wasatchii to survive HTST pasteurization and grow under cheese ripening conditions implies that the presence of this nonstarter lactic acid bacterium can be a serious contributor to gas formation and textural defects in Cheddar cheese. PMID- 25795483 TI - Effects of season and herd milk volume on somatic cell counts of Florida dairy farms. AB - Dairy farms in Florida produce less milk and milk with higher somatic cell counts (SCC) in the hot and humid summer. This has consequences for the interpretation of average milk quality. The objectives were to describe the associations of bulk tank SCC (BTSCC) with time of the year and the milk volume per farm. Monthly BTSCC and milk volume records from 84% (in 2012; n=1,308) and 77% (in 2013; n=1,200) of the 130 dairy farms in Florida were used. Data were analyzed separately per year. We calculated arithmetic averages of the BTSCC for each farm (ASCCf), each month (ASCCm), and each year (ASCCy). We used the milk volume to calculate a milk-weighted average for each farm (WSCCf), each month (WSCCm), and each year (WSCCy). Period 1 (P1) was defined as February, March, and April, and period 2 (P2) was defined as August, September, and October. These periods generally had the lowest and highest BTSCC throughout the year, respectively. Seasonality was expressed by the P2/P1 ratios of BTSCC and milk volume in both periods. In 2012 and 2013, 72 and 74% of the monthly milk volume observations were <400,000cells/mL. A clear seasonal pattern with lower milk volume and higher ASCCm during P2 was observed for most farms. The averages of the P2/P1 ratio of milk volume were 0.68 and 0.74 in 2012 and 2013. The averages of the P2/P1 ratio of SCC were 1.30 and 1.65 for 2012 and 2013, respectively. The WSCCy was 297,000 cells/mL in 2012 and 274,000 cells/mL in 2013. These values were 13 and 16% lower than the ASCCy in the respective years. In 2012, 82% of the farms shipped milk with a lower WSCCf than their ASCCf. In 2013, 97% of the farms shipped milk with a lower WSCCf than their ASCCf. The difference between a farm's WSCCf and its ASCCf tended to be greater in more-seasonal farms for BTSCC and milk volume. The WSCCm was lower than the ASCCm in every calendar month in both years. Collectively, these results show that the SCC of pooled milk from Florida was substantially lower than the arithmetic averages of monthly BTSCC values. Therefore, it should be made clear if the SCC is weighted by milk volume when "average" SCC results are reported. Programs to improve milk quality in Florida might be focused on conditions during August, September, and October because the BTSCC is then markedly increased on many farms. PMID- 25795484 TI - The effect of intrauterine infusion of dextrose on clinical endometritis cure rate and reproductive performance of dairy cows. AB - The main objective of this study was to evaluate the intrauterine administration use of 200 mL of 50% dextrose solution as a treatment against clinical endometritis (CE); CE cure rate and reproductive performance were evaluated. Additionally, the association of several relevant risk factors, such as retained placenta (RP), metritis, CE, anovulation, hyperketonemia, and body condition score with reproductive performance, early embryonic mortality, and CE were evaluated. A total of 1,313 Holstein cows housed on 4 commercial dairy farms were enrolled in the study. At 7+/-3 DIM cows were examined for metritis and had blood collected to determine serum beta-hydroxybutyrate concentration. To determine if cows had ovulated at least once before 44+/-3 DIM, the presence of a corpus luteum was evaluated by ovarian ultrasonography at 30+/-3 DIM and at 44+/-3 DIM. At 30+/-3 DIM, CE was diagnosed using the Metricheck device (SimcroTech, Hamilton, New Zealand); cows with purulent or mucopurulent vaginal discharge were diagnosed as having CE. Cows diagnosed with CE (n=175) were randomly allocated into 2 treatment groups: treatment (intrauterine infusion of 200 mL of 50% dextrose) or control (no infusion). Clinical endometritis cows were re-evaluated as described above at 44+/-3 DIM, and cows that were free of purulent or mucopurulent vaginal discharge were considered cured. Intrauterine infusion of dextrose tended to have a detrimental effect on CE cure rate, and treatment did not have an effect on first-service conception rate and early embryonic mortality. A multivariable Cox's proportional hazard model was performed to evaluate the effect of several variables on reproductive performance; the variables RP, CE, parity, anovulation, and the interaction term between parity and anovulation were associated with hazard of pregnancy. Cows that did not have RP or CE were more likely to conceive than cows that were diagnosed with RP or CE. Cows that had RP were at 3.36 times higher odds of losing their pregnancy than cows that did not have RP. In addition, cows diagnosed with CE were at 2.16 higher odds of losing their pregnancy than cows without CE. In conclusion, intrauterine infusion of 200 mL of 50% dextrose solution as a treatment for CE had a strong statistical tendency to decrease CE cure rate, did not improve first service conception rate and early embryonic mortality, and did not decrease calving-to-conception interval. PMID- 25795485 TI - Variations in automatically recorded rumination time as explained by variations in intake of dietary fractions and milk production, and between-cow variation. AB - Individual recording of rumination time (RT) is now possible in commercial dairy herds, through development of a microphone-based sensor, which is able to record RT by the sound of rumination activity. The objectives of this study were to examine the relationship between daily RT and intakes of different dietary fractions, the relationship between RT in minutes per kilogram of dry matter intake (DMI) and milk production, and to examine the variation in RT within and between mid-lactating dairy cows. Data from 3 production trials were used in which a total of 27 different diets were fed. The data contained 761, 290, and 203 daily recordings of RT, milk yield, milk components, DMI, and intake of dietary fractions recorded on 29, 26, and 24 Holstein and Swedish Red cows from trials 1, 2, and 3, respectively. The dietary fractions included forage neutral detergent fiber (NDF), concentrate NDF, crude protein, sugar, starch, and the remaining fraction represented by organic matter--(forage NDF+concentrate NDF+crude protein+sugar+starch). The relationship between the dietary fractions and RT was analyzed in 2 steps. In step 1, the dietary fractions, which were significantly related to RT, were selected and simultaneously checked for multicollinearity between the dietary components; in step 2, a multivariate model, including the effect of repeated measurements, the main effect of the selected dietary fractions from step 1, random effects of cow(trial) and trial, and information on breed, days in milk, and parity was used to analyze the relationship between RT and the selected dietary fractions. Relationships between RT in minutes per kilogram of DMI and milk yield and milk components were analyzed, using the same multivariate model as in step 2. Approximately 32% of the variation in daily RT could be explained by variations in intakes of the dietary fractions, whereas 48% of the total variation in RT was accounted for by individual variations between cows. Intakes of forage NDF and starch were positively related to daily RT, whereas intakes of sugar and the remaining fraction were negatively related to daily RT. Rumination time in minutes per kilogram of DMI was negatively related to milk yield and protein percentage, but positively related to milk fat percentage. PMID- 25795486 TI - The association between occurrence and severity of subclinical and clinical mastitis on pregnancies per artificial insemination at first service of Holstein cows. AB - The objective of this prospective study was to determine associations between occurrence and severity of clinical (CM) and subclinical mastitis (SM) during a defined breeding risk period (BRP, 3d before to 32d after artificial insemination) on pregnancies per artificial insemination at first service (P/AI1). Dairy cows (n=3,144) from 4 Wisconsin herds were categorized based on the occurrence of one or more CM or SM events during and before the BRP: (1) healthy, (2) mastitis before BRP, (3) SM during BRP, (4) chronic SM, (5) CM during BRP, or (6) chronic CM. Clinical mastitis cases were categorized based on etiology (gram-negative, gram-positive, and no growth) and severity (mild, moderate, or severe). Compared with healthy cows, the odds of pregnancy were 0.56, 0.67, and 0.75 for cows experiencing chronic CM, CM, or SM during the BRP, respectively. The occurrence of chronic SM was not associated with reduced probability of P/AI1. Compared with healthy cows, the odds of pregnancy were 0.71 and 0.54 for cows experiencing mild or moderate-severe cases of CM during the BRP, respectively. The odds of pregnancy for cows experiencing CM caused by gram negative or gram-positive bacteria during the BRP were 0.47 and 0.59, respectively. The occurrence of CM that resulted in no growth of bacteria in cultured milk samples was not associated with reductions in P/AI1. Regardless of etiology, microbiologically positive cases of CM with moderate or severe symptoms were associated with substantial reductions in P/AI1. Etiology, severity, and timing of CM were associated with decreases in the probability of pregnancy at first artificial insemination. Severity of the case was more important than etiology; however, regardless of severity, microbiologically negative cases were not associated with reduced probability of pregnancy. PMID- 25795487 TI - Effect of feeding whole compared with cell-free colostrum on calf immune status: The neonatal period. AB - Mortality and decreased weight gain resulting from infection and disease in dairy calves are problems within the dairy industry. The bovine neonate relies solely on colostrum to acquire antibodies through passive transfer. To date, colostrum quality is determined by the concentration of antibodies. However, proteins and cells in the colostrum might also enhance immune development in the neonate. To determine the effect of maternal colostral immune cells on calf health and immune status, maternal colostrum was fed either fresh or after lysis of cells by flash freezing in liquid nitrogen. Thirty-seven female Holstein and Jersey dairy calves were fed 4 quarts total of whole colostrum (WC) or cell-free colostrum (CFC) at birth. Respiratory and fecal scores were measured from birth to d 45 of life. Calf peripheral blood samples were obtained before and after feeding colostrum as well as on d 1, 3, 7, 14, 21, and 28 of life. Peripheral blood mononuclear cells were collected and analyzed for cellular parameters by flow cytometry. Total respiratory scores were greater in CFC-fed calves compared with WC-fed calves on d 38 of life. There were fewer CD4+ T cells and CD4+CD62L+CD45RO- T cells on d 1 and fewer CD4+CD62L+CD45RO+ T cells on d 1 and 3 in CFC-fed calves compared with WC-fed calves. Compared with WC-fed calves, CFC-fed calves had a greater percentage of CD4+CD62L-CD45RO+ T cells on d 0.25, 1, 3, and 7, and a greater percentage of monocytes on d 7. Our data suggest that colostral cells adoptively transfer and enhance neonatal immunity during the first month of life. PMID- 25795488 TI - Bioavailability of the flavonol quercetin in neonatal calves after oral administration of quercetin aglycone or rutin. AB - Polyphenols, such as flavonoids, are secondary plant metabolites with potentially health-promoting properties. In newborn calves flavonoids may improve health status, but little is known about the systemically availability of flavonoids in calves to exert biological effects. The aim of this study was to investigate the oral bioavailability of the flavonol quercetin, applied either as quercetin aglycone (QA) or as its glucorhamnoside rutin (RU), in newborn dairy calves. Twenty-one male newborn German Holstein calves were fed equal amounts of colostrum and milk replacer according to body weight. On d 2 and 29 of life, 9 mg of quercetin equivalents/kg of body weight, either fed as QA or as RU, or no quercetin (control group) were fed together with the morning meal. Blood samples were taken before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24, and 48 h after feed intake. Quercetin and quercetin metabolites with an intact flavonol structure (isorhamnetin, tamarixetin, and kaempferol) were analyzed in blood plasma after treatment with glucuronidase or sulfatase by HPLC with fluorescence detection. Maximum individual plasma concentration was depicted from the concentration-time-curve on d 2 and 29, respectively. Additional blood samples were taken to measure basal plasma concentrations of total protein, albumin, urea, and lactate as well as pre- and postprandial plasma concentrations of glucose, nonesterified fatty acids, insulin, and cortisol. Plasma concentrations of quercetin and its metabolites were significantly higher on d 2 than on d 29 of life, and administration of QA resulted in higher plasma concentrations of quercetin and its metabolites than RU. The relative bioavailability of total flavonols (sum of quercetin and its metabolites isorhamnetin, tamarixetin, and kaempferol) from RU was 72.5% on d 2 and 49.6% on d 29 when compared with QA (100%). Calves fed QA reached maximum plasma concentrations of total flavonols much earlier than did RU-fed calves. Plasma metabolites and hormones were barely affected by QA and RU feeding in this experiment. Taken together, orally administrated QA resulted in a greater bioavailability of quercetin than RU on d 2 and 29, respectively, and quercetin bioavailability of quercetin and its metabolites differed markedly between calves aged 2 and 29 d. PMID- 25795489 TI - Development of an index to rank dairy females on expected lifetime profit. AB - The objective of this study was to develop an index to rank dairy females on expected profit for the remainder of their lifetime, taking cognizance of both additive and nonadditive genetic merit, permanent environmental effects, and current states of the animal including the most recent calving date and cow parity. The cow own worth (COW) index is intended to be used for culling the expected least profitable females in a herd, as well as inform purchase and pricing decisions for trading of females. The framework of the COW index consisted of the profit accruing from (1) the current lactation, (2) future lactations, and (3) net replacement cost differential. The COW index was generated from estimated performance values (sum of additive genetic merit, nonadditive genetic merit, and permanent environmental effects) of traits, their respective net margin values, and transition probability matrices for month of calving, survival, and somatic cell count; the transition matrices were to account for predicted change in a cow's state in the future. Transition matrices were generated from 3,156,109 lactation records from the Irish national database between the years 2010 and 2013. Phenotypic performance records for 162,981 cows in the year 2012 were used to validate the COW index. Genetic and permanent environmental effects (where applicable) were available for these cows from the 2011 national genetic evaluations and used to calculate the COW index and their national breeding index values (includes only additive genetic effects). Cows were stratified per quartile within herd, based on their COW index value and national breeding index value. The correlation between individual animal COW index value and national breeding index value was 0.65. Month of calving of the cow in her current lactation explained 18% of the variation in the COW index, with the parity of the cow explaining an additional 3 percentage units of the variance in the COW index. Females ranking higher on the COW index yielded more milk and milk solids and calved earlier in the calving season than their lower ranking contemporaries. The difference in phenotypic performance between the best and worst quartiles was larger for cows ranked on COW index than cows ranked on the national breeding index. The COW index is useful to rank females before culling or purchasing decisions on expected profit and is complementary to the national breeding index, which identifies the most suitable females for breeding replacements. PMID- 25795490 TI - Bulk tank milk surveillance as a measure to detect Coxiella burnetii shedding dairy goat herds in the Netherlands between 2009 and 2014. AB - In the period from 2005 to 2009, Coxiella burnetii was a cause of abortion waves at 28 dairy goat farms and 2 dairy sheep farms in the Netherlands. Two years after the first abortion waves, a large human Q fever outbreak started mainly in the same region, and aborting small ruminants were regarded as most probable source. To distinguish between infected and noninfected herds, a surveillance program started in October 2009, based on PCR testing of bulk tank milk (BTM) samples, which had never been described before. The aim of this study was to analyze the effectiveness of this surveillance program and to evaluate both the effect of culling of pregnant dairy goats on positive farms and of vaccination on BTM results. Bulk tank milk samples were tested for C. burnetii DNA using a real time PCR, and results were analyzed in relation to vaccination, culling, and notifiable (officially reported to government) C. burnetii abortion records. In spring and autumn, BTM samples were also tested for antibodies using an ELISA, and results were evaluated in relation to the compulsory vaccination campaign. Between October 2009 and April 2014, 1,660 (5.6%) out of 29,875 BTM samples from 401 dairy goat farms tested positive for C. burnetii DNA. The percentage of positive samples dropped from 20.5% in 2009 to 0.3% in 2014. In a multivariable model, significantly higher odds of being PCR positive in the BTM surveillance program were found in farms of which all pregnant dairy goats were culled. Additionally, the risk for C. burnetii BTM PCR positivity significantly decreased after multiple vaccinations. Bulk tank milk ELISA results were significantly higher after vaccination than before. The ELISA results were higher after multiple vaccinations compared with a single vaccination, and ELISA results on officially declared infected farms were significantly higher compared with noninfected farms. In conclusion, BTM surveillance is an effective and useful tool to detect C. burnetii shedding dairy goat herds and to monitor a Q fever outbreak, and thus the effect of implemented measures. PMID- 25795491 TI - Response of lactating cows to live yeast supplementation during summer. AB - Dairy cows experiencing heat stress have reduced intake and increased reliance on glucose, making feeding strategies capable of improving diet digestibility plausible for improving postrumen nutrient flow and performance. The effect of yeast on digestion and performance of lactating cows during the warm summer months of southeastern Brazil was evaluated. Cows were individually fed in tie stalls and temperature-humidity index was above 68 during 75.6% of the experiment. Twenty-eight Holstein cows (207+/-87 d in milk) received a standard diet for 14 d and then a treatment for 70 d, in a covariate-adjusted, randomized block design with repeated measures over time. Treatments were yeast (Saccharomyces cerevisiae) or control. Yeast was top dressed to the diet in the morning, equivalent to 25*10(10) cfu of live cells and 5*10(10) cfu of dead cells. The diet contained corn silage (37.7%), Tifton silage (7.1%), raw soybeans (4.1%), soybean meal (16.5%), finely ground corn (20.7%), and citrus pulp (11.9%). Yeast increased milk (26.7 vs. 25.4 kg/d) and solids yield (3.06 vs. 2.92 kg/d), especially lactose. Response in milk yield was consistent over time and started at d 5. The daily intake of digestible OM, total-tract digestibility of nutrients, urinary allantoin excretion, chewing pattern throughout the day, and dry matter intake did not respond to yeast. A trend was observed for increased plasma glucose with yeast (62.9 vs. 57.3mg/dL), lowered respiratory frequency (48 vs. 56 breaths/min), and increased plasma niacin content (1.31 vs. 1.22 ug/mL), though cows had similar rectal temperature. Ruminal lactate and butyrate as proportions of ruminal organic acids were reduced by yeast, but no effects on other organic acids, ruminal pH, or protozoa content were detected. Plasma urea N over 24h was increased by yeast. On d 72 to 74, citrus pulp was abruptly replaced with finely ground corn to induce acidosis. The increased load of starch increased dry matter intake between 0700 and 1300 h, jugular blood partial pressure of CO2, HCO3-, and base excess, and decreased blood pH for both treatments. The yeast treatment had a higher blood pH compared with the control, 7.34, and 7.31, respectively. Yeast supplementation improved lactation performance of dairy cows under heat stress. Improvement in lactation performance apparently involved the regulation of body homeothermia, rather than improved digestibility. PMID- 25795492 TI - Short communication: Patterns of dairy consumption in free-living children and adolescents. AB - According to national survey data, dairy food consumption has fallen in recent years and declines further with age, especially from childhood to adolescence. Dietary surveys typically rely on retrospective dietary assessment methods and use broad age groupings (4-10 yr; 11-18 yr), making it challenging to differentiate between middle-childhood and adolescence. Consequently, there is a need to assess dairy food consumption during middle-childhood and adolescence using more robust dietary assessment tools. Therefore, the present study aimed to describe and compare patterns of dairy consumption throughout middle-childhood and adolescence. Dairy food consumption was assessed during school term-time over 4 consecutive days, including 2 weekdays and 2 weekend days, in a sample of free living children (9-11 yr, n=40) and adolescents (15-18 yr, n=35). For children, free-living dairy intake was evaluated through parental-weighed food records, and for adolescents, a combined weighed self-reported food record and 24-h dietary recall technique was utilized. Food records were explored to determine types, amounts, and frequency of dairy food consumption, and were analyzed for differences between middle-childhood and adolescence using a between group 2*2 (age*sex) ANOVA. Descriptive data suggested that milk was the most popular dairy product consumed by both children and adolescents. Statistical analysis revealed a main effect for sex on total milk consumption (mL) and number of daily milk portions consumed. No interaction or main effect was present for any other variable. The present study indicates that independent of age, boys consumed greater amounts of milk compared with girls. Contrary to existing literature, findings suggest no difference in milk-based dairy consumption between middle childhood and adolescence. PMID- 25795493 TI - Effect of technical cashew nut shell liquid on rumen methane emission and lactation performance of dairy cows. AB - Technical-grade cashew nut shell liquid (TCNSL) is a by-product of the cashew nut industry in tropical countries, and is known to exhibit a wide range of biological activities, including inhibitory effect against gram-positive bacteria. This study was conducted to investigate the effects of TCNSL (73.3% cardanol, 16.4% cardol, and 3.0% methylcardol) on rumen methane emission, nutrient digestibility, dry matter intake, and milk yield and composition in dairy cows. Eight multiparous Holstein cows were used in a crossover design trial with two 21-d experimental periods. The diet was based on corn silage and alfalfa haylage and was formulated to meet or exceed the energy and metabolizable protein requirements of the cows. Treatments were control (no TCNSL supplementation) or 30 g/cow per day of TCNSL. Rumen carbon dioxide emission was not affected by TCNSL. Treatment had no effect on methane emission (542 vs. 511+/-35.3 g/cow per day, respectively) and methane emission intensity (15.0 vs. 13.9+/-0.58 g/kg of energy-corrected milk, respectively) and tended to decrease methane emission per kilogram of dry matter intake (20.2 vs. 18.6+/-1.04 g/kg, respectively). Dry matter intake (average 26.9+/-1.00 kg/d), milk yield (40.0+/-1.73 kg/d), and milk composition were not different between treatments. The TCNSL had no effect on N losses in urine and feces and total-tract apparent digestibility of nutrients, except digestibility of neutral detergent fiber tended to be increased compared with the control. Plasma urea and glucose concentrations were not affected by TCNSL. Concentration of milk C18:0 tended to be decreased (17%) by TCNSL compared with the control. In this study, TCNSL did not alter absolute methane emission in the rumen, but tended to decrease it by 8% per kilogram of dry matter intake. The TCNSL had no effect on milk yield and composition in dairy cows. PMID- 25795494 TI - Introduction: sepsis-associated AKI. PMID- 25795495 TI - Sepsis-associated acute kidney injury. AB - Acute kidney injury (AKI) is an epidemic problem. Sepsis has long been recognized as a foremost precipitant of AKI. Sepsis-associated AKI (SA-AKI) portends a high burden of morbidity and mortality in both children and adults with critical illness. Although our understanding of its pathophysiology is incomplete, SA-AKI likely represents a distinct subset of AKI contributed to by a unique constellation of hemodynamic, inflammatory, and immune mechanisms. SA-AKI poses significant clinical challenges for clinicians. To date, no singular effective therapy has been developed to alter the natural history of SA-AKI. Rather, current strategies to alleviate poor outcomes focus on clinical risk identification, early detection of injury, modifying clinician behavior to avoid harm, early appropriate antimicrobial therapy, and surveillance among survivors for the longer-term sequelae of kidney damage. Recent evidence has confirmed that patients no longer die with AKI, but from AKI. To improve the care and outcomes for sufferers of SA-AKI, clinicians need a robust appreciation for its epidemiology and current best-evidence strategies for prevention and treatment. PMID- 25795496 TI - Clinical approach to the patient with AKI and sepsis. AB - Sepsis and acute kidney injury (AKI) frequently are combined in critical care patients. They both are associated independently with increased mortality and morbidity. AKI may precede, coincide with, or follow a sepsis diagnosis. Risk factors for sepsis followed by AKI differ from those associated with AKI preceding or coinciding with sepsis, and the pathophysiologic mechanisms may be different. In this article, we review the available clinical, laboratory, and imaging tools available for the recognition of septic AKI. Early identification of high-risk patients and targeted preventive and therapeutic measures are key to reducing the mortality and morbidity of the complex syndrome of septic AKI. PMID- 25795497 TI - Entanglement of sepsis, chronic kidney disease, and other comorbidities in patients who develop acute kidney injury. AB - Acute kidney injury (AKI) is a common and severe complication for patients in the intensive care setting, often occurring in the setting of sepsis. Both sepsis and AKI are complex and heterogeneous syndromes with overlapping risk factors. Comorbidities - such as chronic kidney disease, diabetes mellitus, liver disease, cardiac disease and cancer - may contribute to the development of these syndromes and complicate their management. Recognition of the complex interplay between comorbid conditions, sepsis, and AKI is key to the successful management of these syndromes. PMID- 25795499 TI - Extracorporeal renal replacement therapies in the treatment of sepsis: where are we? AB - Acute kidney injury (AKI) is common among the critically ill, affecting approximately 40% of patients. Sepsis is the cause of AKI in almost 50% of cases of intensive care patients, however, any evidence-based treatment for sepsis associated AKI is lacking. Furthermore, the underlying pathophysiology of septic AKI is inadequately understood given the disparity between severe functional changes and limited tubular injury. What is clear is that within this complex interplay leading to septic AKI, the inflammatory response plays a pivotal role and hence modulation of this response may translate to improved outcomes. We outline the use of extracorporeal therapies in the treatment of sepsis and septic AKI. We consider the classic aspects of extracorporeal renal replacement therapy including indications, timing, and delivered dose. The various techniques that currently are used to try and achieve immune homeostasis also are outlined. As well as discussing the evidence accumulated to date, we also suggest possibilities for the future treatment of our patients. PMID- 25795500 TI - Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation. AB - Traditionally, renal ischemia has been regarded as central to the pathogenesis of sepsis-associated acute kidney injury (SA-AKI). Accordingly, hemodynamic management of SA-AKI has emphasized restoration of renal perfusion, whereas, experimentally, ischemia reperfusion models have been emphasized. However, in human beings, SA-AKI usually is accompanied by hyperdynamic circulation. Moreover, clinical and experimental evidence now suggests the importance of inflammatory mechanisms in the development of AKI and microcirculatory dysfunction more than systemic alteration in renal perfusion. In this review, we examine systemic, regional, and microcirculatory hemodynamics in SA-AKI, and attempt to rationalize the hemodynamic management of this condition. PMID- 25795498 TI - Emerging therapeutic targets of sepsis-associated acute kidney injury. AB - Sepsis-associated acute kidney injury (SA-AKI) is linked to high morbidity and mortality. To date, singular approaches to target specific pathways known to contribute to the pathogenesis of SA-AKI have failed. Because of the complexity of the pathogenesis of SA-AKI, a reassessment necessitates integrative approaches to therapeutics of SA-AKI that include general supportive therapies such as the use of vasopressors, fluids, antimicrobials, and target-specific and time dependent therapeutics. There has been recent progress in our understanding of the pathogenesis and treatment of SA-AKI including the temporal nature of proinflammatory and anti-inflammatory processes. In this review, we discuss the clinical and experimental basis of emerging therapeutic approaches that focus on targeting early proinflammatory and late anti-inflammatory processes, as well as therapeutics that may enhance cellular survival and recovery. Finally, we include ongoing clinical trials in sepsis. PMID- 25795501 TI - The microcirculation of the septic kidney. AB - The renal microcirculation plays a major role in the delivery of blood and oxygen to the kidney. In sepsis, alterations in renal microvascular perfusion, in conjunction with increased oxygen requirements, may contribute to renal failure even when renal macrovascular perfusion is preserved. In this review, we discuss the pathophysiology of the renal microcirculation during sepsis and how it contributes to acute kidney injury. Endothelial dysfunction largely is owing to inflammatory, oxidative, and nitrosative factors. Coagulative disorders and glycocalyx disruption also may contribute to the microcirculatory dysfunction. New technologies in experimental models and human beings are being developed to explore renal microcirculation in vivo. These technologies will allow a better understanding of the pathophysiopathology of the renal microcirculation and will help guide specific therapeutic strategies in sepsis-induced acute kidney injury. PMID- 25795502 TI - Sepsis-associated AKI: epithelial cell dysfunction. AB - Acute kidney injury (AKI) occurs frequently in critically ill patients with sepsis, in whom it doubles the mortality rate and half of the survivors suffer permanent kidney damage or chronic kidney disease. Failure in the development of viable therapies has prompted studies to better elucidate the cellular and molecular etiologies of AKI, which have generated novel theories and paradigms for the mechanisms of this disease. These studies have shown multifaceted origins and elements of AKI that, in addition to/in lieu of ischemia, include the generation of damage-associated molecular patterns and pathogen-associated molecular patterns, the inflammatory response, humoral and cellular immune activation, perturbation of microvascular flow and oxidative stress, bioenergetic alterations, cell-cycle alterations, and cellular de-differentiation/re differentiation. It is becoming clear that a major etiologic effector of all these inputs is the renal tubule epithelial cell (RTEC). This review discusses these elements and their effects on RTECs, and reviews the current hypotheses of how these effects may determine the fate of RTECs during sepsis-induced AKI. PMID- 25795506 TI - Inverse micellar sugar glass (IMSG) nanoparticles for transfollicular vaccination. AB - Transfollicular antigen delivery through the intact skin is an interesting new avenue for needle-free vaccination. The aim of this work was to evaluate the potential of surfactant based inverse micellar sugar glass nanoparticles (IMSG NPs) as a delivery system for such purpose. To this end, we evaluated the strength and type of immune response elicited after administration of IMSG NPs containing the model antigen ovalbumin (OVA) by intranasal, transfollicular or intradermal route. Furthermore, we explored the possibility of improving the immune response elicited by co-encapsulating the adjuvant bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) and OVA within one particulate carrier system. The study showed enhanced stability and encapsulation efficacy of the antigen when encapsulated in IMSG NPs in comparison to polylactic-co-glycolic acid (PLGA) and chitosan-PLGA NPs. Moreover, by transfollicular delivery, IMSG NPs showed enhanced follicular uptake in comparison to OVA solution or OVA-loaded chitosan-PLGA NPs. While the immune response stimulated after intranasal administration was negligible, significant humoral and cellular responses were observed after immunization via transfollicular and intradermal route. This holds particularly true when OVA and c-di-AMP were co-encapsulated in IMSG NPs, as compared to OVA+/-c-di-AMP solution or OVA-loaded IMSG NPs without adjuvantation. The results of this study underscore not only the potential of transfollicular vaccination, but also the need for optimized nanocarriers and adjuvants. PMID- 25795505 TI - An internet based approach to improve general practitioners' knowledge and practices: the development and pilot testing of the "ABC's of vitamin D" program. AB - BACKGROUND: Online continuing medical education (CME) offers a number of advantages for physicians including flexibility with regards to location and timing of use. In order to effect physician practices and improve patient outcomes, it is important that the development of online CME is theory and evidence-based. OBJECTIVES: This paper aims to describe the development of an online CME program for practising general practitioners (GPs) on vitamin D and sun health called "The ABC's of Vitamin D for GPs" using elements of design principles for physician-education web sites as a framework. The paper will also report the program's usability and acceptability pilot test results. METHODS: The ABC's of Vitamin D program was developed following nine principles: needs assessment; evidence-based content development; multimodal program and modularisation; clinical cases; tailoring and interactivity; audit and feedback; credibility of the web site host; patient education materials; ease of use and navigation. Among the 20 GPs invited, acceptability and useability was tested with 12 GPs (60%) who agreed to participate and were interviewed following use of the program. The study was conducted between 2011 and 2013. RESULTS: An online CME program consisting of eight modules was constructed. Of the 12 participating GPs, most (n=11) reported that the program was clear and easy to understand, logical, easy to navigate, and took a reasonable amount of time (estimated between 1 and 3h) to complete. Eleven of 12 participants said they would use the program as an accredited CME activity and all participants indicated that the program was 'very or somewhat' likely to lead to changes in the advice patients are given. CONCLUSION: This study found that a theory and evidence based approach for the development of an online CME program for GPs was acceptable to users. Further research is needed to examine whether the online CME program is effective at changing GP practices and improving patient outcomes. PMID- 25795503 TI - Renal endothelial injury and microvascular dysfunction in acute kidney injury. AB - The kidney is comprised of heterogeneous cell populations that function together to perform a number of tightly controlled, complex and interdependent processes. Renal endothelial cells contribute to vascular tone, regulation of blood flow to local tissue beds, modulation of coagulation and inflammation, and vascular permeability. Both ischemia and sepsis have profound effects on the renal endothelium, resulting in microvascular dysregulation resulting in continued ischemia and further injury. In recent years, the concept of the vascular endothelium as an organ that is both the source of and target for inflammatory injury has become widely appreciated. Here we revisit the renal endothelium in the light of ever evolving molecular advances. PMID- 25795504 TI - Mitochondrial function and disturbances in the septic kidney. AB - Per milligram of tissue, only the heart exceeds the kidney's abundance of mitochondria. Not surprisingly, renal mitochondria are most densely concentrated in the epithelium of the nephron, at sites where the chemical work of moving solutes against electrochemical gradients places large and constant demands for adenosine triphosphate. Derangements of renal epithelial mitochondria appear to be a hallmark for diverse forms of acute kidney injury (AKI). The pathogenesis of multiple-organ dysfunction syndrome in sepsis is complex, but a substantial body of experimental and observational human data supports the twin concepts that mitochondrial dysfunction contributes to impaired filtration and that recovery of mitochondrial structure and function is essential for recovery from sepsis associated AKI. These insights have suggested novel methods to diagnose, stratify, prevent, or even treat this common and deadly complication of critical illness. This review will do the following: (1) describe the structure and functions of healthy mitochondria and how renal energy metabolism relates to solute transport; (2) provide an overview of the evidence linking mitochondrial pathology to renal disease; (3) summarize the mitochondrial lesions observed in septic AKI; (4) analyze the role of mitochondrial processes including fission/fusion, mitophagy, and biogenesis in the development of septic AKI and recovery from this disease; and (5) explore the potential for therapeutically targeting mitochondria to prevent or treat septic AKI. PMID- 25795507 TI - The Post-Myocardial Infarction Pacing Remodeling Prevention Therapy (PRomPT) Trial: Design and Rationale. AB - BACKGROUND: Despite considerable improvements in the medical management of patients with myocardial infarction (MI), patients with large MI still have substantial risk of developing heart failure. In the early post-MI setting, implantable cardioverter defibrillators have reduced arrhythmic deaths but have no impact on overall mortality. Therefore, additional interventions are required to further reduce the overall morbidity and mortality of patients with large MI. METHODS: The Pacing Remodeling Prevention Therapy (PRomPT) trial is designed to study the effects of peri-infarct pacing in preventing adverse post-MI remodeling. Up to 120 subjects with peak creatine phosphokinase >3,000 U/L (or troponin T >10 MUg/L) at time of MI will be randomized to either dual-site or single-site biventricular pacing with the left ventricular lead implanted in a peri-infarct region or to a nonimplanted control group. Those randomized to a device will be blinded to the pacing mode, but randomization to a device or control cannot be blinded. Subjects randomized to pacing will have the device implanted within 10 days of MI. The primary objective is to assess the change in left ventricular end-diastolic volume from baseline to 18 months. Secondary objectives are to assess changes in clinical and mechanistic parameters between the groups, including rates of hospitalization for heart failure and cardiovascular events, the incidence of sudden cardiac death and all-cause mortality, New York Heart Association functional class, 6-minute walking distance, and quality of life. CONCLUSIONS: The PRomPT trial will provide important evidence regarding the potential of peri-infarct pacing to interrupt adverse remodeling in patients with large MI. PMID- 25795508 TI - The Emerging Potential of the Apelin-APJ System in Heart Failure. AB - The apelin-APJ system is a novel neurohormonal pathway, with studies to date suggesting that it may be of pathophysiologic relevance in heart failure and may indeed be a viable therapeutic target in this syndrome. This interest is driven primarily by the demonstration of its vasodilator, inotropic, and aquaretic actions as well as its apparent antagonistic relationship with the renin angiotensin system. However, its promise is heightened further by the observation that, unlike other and more established cardioprotective pathways, it appears to be down-regulated in heart failure, suggesting that augmentation of this axis may have a powerful effect on the heart failure syndrome. We review the literature regarding the apelin-APJ system in heart failure and suggest areas requiring further research. PMID- 25795509 TI - Multilingual part-of-speech tagging with weightless neural networks. AB - Training part-of-speech taggers (POS-taggers) requires iterative time-consuming convergence-dependable steps, which involve either expectation maximization or weight balancing processes, depending on whether the tagger uses stochastic or neural approaches, respectively. Due to the complexity of these steps, multilingual part-of-speech tagging can be an intractable task, where as the number of languages increases so does the time demanded by these steps. WiSARD (Wilkie, Stonham and Aleksander's Recognition Device), a weightless artificial neural network architecture that proved to be both robust and efficient in classification tasks, has been previously used in order to turn the training phase faster. WiSARD is a RAM-based system that requires only one memory writing operation to train each sentence. Additionally, the mechanism is capable of learning new tagged sentences during the classification phase, on an incremental basis. Nevertheless, parameters such as RAM size, context window, and probability bit mapping, make the multilingual part-of-speech tagging task hard. This article proposes mWANN-Tagger (multilingual Weightless Artificial Neural Network tagger), a WiSARD POS-tagger. This tagger is proposed due to its one-pass learning capability. It allows language-specific parameter configurations to be thoroughly searched in quite an agile fashion. Experimental evaluation indicates that mWANN Tagger either outperforms or matches state-of-art methods in accuracy with very low standard deviation, i.e., lower than 0.25%. Experimental results also suggest that the vast majority of the languages can benefit from this architecture. PMID- 25795510 TI - Hierarchical neural networks perform both serial and parallel processing. AB - In this work we study a Hebbian neural network, where neurons are arranged according to a hierarchical architecture such that their couplings scale with their reciprocal distance. As a full statistical mechanics solution is not yet available, after a streamlined introduction to the state of the art via that route, the problem is consistently approached through signal-to-noise technique and extensive numerical simulations. Focusing on the low-storage regime, where the amount of stored patterns grows at most logarithmical with the system size, we prove that these non-mean-field Hopfield-like networks display a richer phase diagram than their classical counterparts. In particular, these networks are able to perform serial processing (i.e. retrieve one pattern at a time through a complete rearrangement of the whole ensemble of neurons) as well as parallel processing (i.e. retrieve several patterns simultaneously, delegating the management of different patterns to diverse communities that build network). The tune between the two regimes is given by the rate of the coupling decay and by the level of noise affecting the system. The price to pay for those remarkable capabilities lies in a network's capacity smaller than the mean field counterpart, thus yielding a new budget principle: the wider the multitasking capabilities, the lower the network load and vice versa. This may have important implications in our understanding of biological complexity. PMID- 25795511 TI - Diversifying customer review rankings. AB - E-commerce Web sites owe much of their popularity to consumer reviews accompanying product descriptions. On-line customers spend hours and hours going through heaps of textual reviews to decide which products to buy. At the same time, each popular product has thousands of user-generated reviews, making it impossible for a buyer to read everything. Current approaches to display reviews to users or recommend an individual review for a product are based on the recency or helpfulness of each review. In this paper, we present a framework to rank product reviews by optimizing the coverage of the ranking with respect to sentiment or aspects, or by summarizing all reviews with the top-K reviews in the ranking. To accomplish this, we make use of the assigned star rating for a product as an indicator for a review's sentiment polarity and compare bag-of words (language model) with topic models (latent Dirichlet allocation) as a mean to represent aspects. Our evaluation on manually annotated review data from a commercial review Web site demonstrates the effectiveness of our approach, outperforming plain recency ranking by 30% and obtaining best results by combining language and topic model representations. PMID- 25795512 TI - Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). AB - Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. Associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) were investigated. Data were available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan 3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Median intake of total flavan-3-ols was 1034mg/d (range: 0-8531mg/d) for men and 970mg/d (0-6695mg/d) for women, median intake of flavan-3-ol monomers was 233mg/d (0 3248mg/d) for men and 217 (0-2712mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow-up, there were 8463 cardiovascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI: 0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk. PMID- 25795513 TI - Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1. AB - Hyperglycemia-induced oxidative stress is implicated in the development of cardiomyopathy in diabetes that is associated with reduced adiponectin (APN) and heme oxygenase-1 (HO-1). Brahma-related gene 1 (Brg1) assists nuclear factor erythroid-2-related factor-2 (Nrf2) to activate HO-1 to increase myocardial antioxidant capacity in response to oxidative stress. We hypothesized that reduced adiponectin (APN) impairs HO-1 induction which contributes to the development of diabetic cardiomyopathy, and that supplementation of APN may ameliorate diabetic cardiomyopathy by activating HO-1 through Nrf2 and Brg1 in diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were untreated or treated with APN adenovirus (1*10(9) pfu) 3 weeks after diabetes induction and examined and terminated 1 week afterward. Rat left ventricular functions were assessed by a pressure-volume conductance system, before the rat hearts were removed to perform histological and biochemical assays. Four weeks after diabetes induction, D rats developed cardiac hypertrophy evidenced as increased ratio of heart weight to body weight, elevated myocardial collagen I content, and larger cardiomyocyte cross-sectional area (all P<0.05 vs C). Diabetes elevated cardiac oxidative stress (increased 15-F2t-isoprostane, 4-hydroxynonenal generation, 8 hydroxy-2'-deoxyguanosine, and superoxide anion generation), increased myocardial apoptosis, and impaired cardiac function (all P<0.05 vs C). In D rats, myocardial HO-1 mRNA and protein expression were reduced which was associated with reduced Brg1 and nuclear Nrf2 protein expression. All these changes were either attenuated or prevented by APN. In primarily cultured cardiomyocytes (CMs) isolated from D rats or in the embryonic rat cardiomyocytes cell line H9C2 cells incubated with high glucose (HG, 25 mM), supplementation of recombined globular APN (gAd, 2MUg/mL) reversed HG-induced reductions of HO-1, Brg1, and nuclear Nrf2 protein expression and attenuated cellular oxidative stress, myocyte size, and apoptotic cells. Inhibition of HO-1 by ZnPP (10MUM) or small interfering RNA (siRNA) canceled all the above gAd beneficial effects. Moreover, inhibition of Nrf2 (either by the Nrf2 inhibitor luteolin or siRNA) or Brg1 (by siRNA) canceled gAd-induced HO-1 induction and cellular protection in CMs and in H9C2 cells incubated with HG. In summary, our present study demonstrated that APN reduced cardiac oxidative stress, ameliorated cardiomyocyte hypertrophy, and prevented left ventricular dysfunction in diabetes by concomitantly activating Nrf2 and Brg1 to facilitate HO-1 induction. PMID- 25795515 TI - Cholesterol under oxidative stress-How lipid membranes sense oxidation as cholesterol is being replaced by oxysterols. AB - The behavior of oxysterols in phospholipid membranes and their effects on membrane properties were investigated by means of dynamic light scattering, fluorescence spectroscopy, NMR, and extensive atomistic simulations. Two families of oxysterols were scrutinized-tail-oxidized sterols, which are mostly produced by enzymatic processes, and ring-oxidized sterols, formed mostly via reactions with free radicals. The former family of sterols was found to behave similar to cholesterol in terms of molecular orientation, roughly parallel to the bilayer normal, leading to increasing membrane stiffness and suppression of its membrane permeability. In contrast, ring-oxidized sterols behave quantitatively differently from cholesterol. They acquire tilted orientations and therefore disrupt the bilayer structure with potential implications for signaling and other biochemical processes in the membranes. PMID- 25795514 TI - Differential involvement of various sources of reactive oxygen species in thyroxin-induced hemodynamic changes and contractile dysfunction of the heart and diaphragm muscles. AB - Thyroid hormones are key regulators of basal metabolic state and oxidative metabolism. Hyperthyroidism has been reported to cause significant alterations in hemodynamics, and in cardiac and diaphragm muscle functions, all of which have been linked to increased oxidative stress. However, the definite source of increased reactive oxygen species (ROS) in each of these phenotypes is still unknown. The goal of the current study was to test the hypothesis that thyroxin (T4) may produce distinct hemodynamic, cardiac, and diaphragm muscle abnormalities by differentially affecting various sources of ROS. Wild-type and T4 mice with and without 2-week treatments with allopurinol (xanthine oxidase inhibitor), apocynin (NADPH oxidase inhibitor), L-NIO (nitric oxide synthase inhibitor), or MitoTEMPO (mitochondria-targeted antioxidant) were studied. Blood pressure and echocardiography were noninvasively evaluated, followed by ex vivo assessments of isolated heart and diaphragm muscle functions. Treatment with L NIO attenuated the T4-induced hypertension in mice. However, apocynin improved the left-ventricular (LV) dysfunction without preventing the cardiac hypertrophy in these mice. Both allopurinol and MitoTEMPO reduced the T4-induced fatigability of the diaphragm muscles. In conclusion, we show here for the first time that T4 exerts differential effects on various sources of ROS to induce distinct cardiovascular and skeletal muscle phenotypes. Additionally, we find that T4 induced LV dysfunction is independent of cardiac hypertrophy and NADPH oxidase is a key player in this process. Furthermore, we prove the significance of both xanthine oxidase and mitochondrial ROS pathways in T4-induced fatigability of diaphragm muscles. Finally, we confirm the importance of the nitric oxide pathway in T4-induced hypertension. PMID- 25795516 TI - Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice. AB - MPS IIIA is an inherited neurodegenerative lysosomal storage disorder characterized by cognitive impairment, sleep-wake cycle disturbance, speech difficulties, eventual mental regression and early death. Neuropathological changes include accumulation of heparan sulfate and glycolipids, neuroinflammation and degeneration. Pre-clinical animal studies indicate that replacement of the deficient enzyme, sulfamidase, via intra-cerebrospinal fluid (CSF) injection is a clinically-relevant treatment approach, reducing neuropathological changes and improving symptoms. Given that there are several routes of administration of enzyme into the CSF (intrathecal lumbar, cisternal and ventricular), determining the effectiveness of each injection strategy is crucial in order to provide the best outcome for patients. We delivered recombinant human sulfamidase (rhSGSH) to a congenic mouse model of MPS IIIA via each of the three routes. Mice were euthanized 24h or one-week post-injection; the distribution of enzyme within the brain and spinal cord parenchyma was investigated, and the impact on primary substrate levels and other pathological lesions determined. Both ventricular and cisternal injection of rhSGSH enable enzyme delivery to brain and spinal cord regions, with the former mediating large, statistically significant decreases in substrate levels and reducing microglial activation. The single lumbar CSF infusion permitted more restricted enzyme delivery, with no reduction in substrate levels and little change in other disease-related lesions in brain tissue. While the ventricular route is the most invasive of the three methods, this strategy may enable the widest distribution of enzyme within the brain, and thus requires further exploration. PMID- 25795517 TI - Detection of vancomycin-resistant Enterococcus faecalis ST6-vanB2 and E. faecium ST915-vanA in faecal samples of wild Rattus rattus in Spain. AB - The detection of vancomycin-resistant-enterococci (VRE) among wild animals represents a worrisome public health concern. The objectives of the study were to determine the possible presence of VRE in faecal samples of wild small mammals in Spain, to characterize the vancomycin resistance mechanisms and genetic lineages of recovered isolates and to know the diversity of enterococcal species in these animals. A total of 155 faecal samples from small mammals were inoculated in Slanetz-Bartley agar supplemented or not with vancomycin (Van-SB/SB plates). The antimicrobial susceptibility profile to 12 antimicrobials and the presence of 20 antimicrobial resistance genes was analyzed. The structure of Tn1546 and the presence of gelE, cylA, asa, esp and hyl genes was studied. Multilocus-sequence typing (MLST) technique was also performed. VRE isolates were recovered in Van-SB plates in 11 samples. Two samples contained vanB2-positive E. faecalis isolates of lineage ST6, which showed a multiresistance phenotype and harboured the virulence genes gelE and asa. One sample contained a vancomycin-resistant E. faecium isolate of the new lineage ST915, with the vanA gene included into Tn1546 (truncated with IS1542 and IS1216 elements). The vanB2 and vanA isolates were obtained from Rattus rattus. The remaining eight VRE-positive samples contained species with intrinsic vancomycin-resistance mechanisms: E. casseliflavus (n=5) and E. gallinarum (n=3). One hundred and forty-seven vancomycin-susceptible enterococcal isolates were obtained in SB plates, and E. faecalis and E. faecium were the most frequent detected species. This is the first report of vanB2 containing enterococci in wild animals. PMID- 25795518 TI - The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat. AB - Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a range of psychostimulants, and other compounds, and may model neuroplastic changes seen in addictive processes and neuropsychiatric disease. The aim of the present study was to investigate the effect of dopamine D1 receptor (D1R) ligands on nicotine-induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically treated (5 days) with vehicle or nicotine (0.4 mg/kg; s.c.) and locomotor activity was measured. Following a 5 day withdrawal period, rats were pretreated with vehicle or the D1R antagonist SCH-23390 (0.03 mg/kg; i.p.) and challenged with nicotine. Either 45 min or 24h post-challenge, the striatum was isolated and ex vivo receptor binding and cAMP accumulation (using LC-MS/MS) were assessed. It was shown that chronic nicotine administration induced the development and expression of locomotor sensitization, of which the latter was blocked by SCH-23390. Nicotine-induced sensitization had no effect on forskolin stimulated cAMP accumulation but increased the efficacy of dopamine for the D1R and decreased the potency of D1R agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. No effect on D1 receptor binding was observed. Moreover, time dependent effects were observed between tissue taken 45 min and 24h post-challenge. The present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the D1R. Together these data suggest that changes in D1R signaling in the dorsal striatum may play an important role in the underlying mechanisms of nicotine-induced behavioral sensitization. PMID- 25795520 TI - Neural correlates of local contextual processing across stimulus modalities and patient populations. AB - The objective of the current review is to integrate information from a series of studies, employing a paradigm that evaluates local contextual processing using electrophysiological measures. Collectively these studies provide an overview of how utilization of predictive context changes as a function of stimulus modality and across different patient populations, as well as the networks that may be critical for this function. The following aspects of local contextual processing will be discussed and reviewed: (i) the correlates associated with contextual processing that have been identified in healthy adults, (ii) stimulus modality effects, (iii) specific alterations and deficits of local contextual processing in aging and across different neurological and psychiatric patient populations, including patients with prefrontal cortex lesions, Parkinson's disease, schizophrenia, and major depressive disorder, (iv) the potential for utilizing the correlates of local context as biomarkers for frontal cognitive dysfunction and (v) the role of frontal networks in the processing of contextual information. Overall findings show that behavioral and neural correlates associated with processing of local context are comparable across stimulus modalities, but show specific alterations in aging and across different neurological and psychiatric disorders. PMID- 25795519 TI - Cluster analysis reveals abnormal hippocampal neurometabolic profiles in young people with mood disorders. AB - While numerous studies have employed magnetic resonance spectroscopy (MRS) to determine in vivo neurometabolite levels associated with mood disorders the findings in both unipolar depression and bipolar disorder have been mixed. Data driven studies may shed new light on this literature by identifying distinct subgroups of patients who may benefit from different treatment strategies. The objective of the present study was to utilize hierarchical cluster analysis in order to generate new hypotheses with respect to neurometabolic profiling of mood disorder. Participants were 165 young persons (18-30 yrs) with a mood disorder and 40 healthy controls. Neurometabolite levels were recorded via proton-MRS ((1)H MRS). The ratios (relative to creatine) of glutamate (GLU), N-acetyl aspartate (NAA) and myo-inositol (MI) measured within the hippocampus. Self reported and clinician rated symptoms as well as cognition were also measured. The unipolar depression (N=90) and bipolar disorder (N=75) groups did not significantly differ (from each other or controls) in their levels of GLU, NAA or MI. Cluster analyses derived four subgroups of patients who were distinguished by all three metabolites. There was a pattern of positive association between NAA and GLU, whereby clusters were abnormally increased (clusters 1, 2) or normal (cluster 4) or abnormally decreased (cluster 3) in these neurometabolites. These findings suggest that there are neurometabolic abnormalities in subgroups of young people with mood disorder, which may occur despite diagnostic similarities. Such evidence highlights that the underlying neurobiology of mood disorder is complex and MRS may have unique utility in delineating underlying neurobiology and targeting treatment strategies. PMID- 25795521 TI - Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review. AB - A frequently proposed mechanism underlying the link between maternal prenatal stress/anxiety and child outcomes is heightened concentrations of maternal cortisol. In this systematic review, empirical findings on associations between maternal prenatal cortisol concentrations and child outcomes (physical/health, cognitive/motor, psychological/behavioral, and cortisol) are summarized. The number of empirical studies that find significant associations between maternal prenatal cortisol and child outcomes is small, but the majority of the studies that do find associations show that maternal cortisol is related to altered child outcomes (e.g. more physical/health problems, lower cognitive/motor development, more psychological/behavioral problems, and higher child cortisol concentrations). Inspection of the studies reveals possible critical gestational periods for maternal cortisol to affect different child outcomes. The heterogeneity in study designs and cortisol assessment methods makes drawing strong conclusions premature. However, the fact that most studies did not find significant associations suggests that maternal cortisol may not to be the sole or even main underlying mechanism in the relation between maternal prenatal stress/anxiety and child outcomes. Limitations of the reviewed studies are discussed, and directions for future research and reporting strategies are provided. PMID- 25795522 TI - Monoclonal paraprotein influences baseline B-cell repertoire diversity and perturbates influenza vaccination-induced B-cell response. AB - Monoclonal gammopathy of undetermined significance (MGUS) arises from a clonal expansion of plasma cells in the bone marrow, secreting monoclonal (M) paraprotein. It is associated with increased susceptibility to infections, which may reflect altered B-cell repertoire. To investigate this, we examined the immunoglobulin (Ig) M, IgG, and IgA B-cell repertoire diversity in MGUS at baseline and after influenza vaccination (n = 16) in comparison with healthy controls (HCs; n = 16). The Complementary Determining Region 3 region of the immunoglobulin heavy chain variable region gene was amplified and B-cell spectratypes analyzed by high-resolution electrophoresis. Spectratype Gaussian distribution, kurtosis, and skewness were quantified to measure repertoire shifts. Both HC and MGUS baseline spectratypes show interindividual variability that is more pronounced in the IGHG and IGHA repertoires. Overall, baseline B cell repertoire is more altered in MGUS, with oligoclonality observed in 50% (p = 0.01). Postvaccination, significant differences emerged in MGUS in relation to M protein levels. High M-protein concentration is associated with a more oligoclonal IgG and IgA response at day 7 postvaccination, and, in contrast to HCs, vaccination also induced significant perturbations in the MGUS IgM repertoire at day 7 (p = 0.005). Monoclonal expansion in MGUS thus has an effect on the baseline B-cell repertoire and influences the recruited repertoire upon vaccination. PMID- 25795523 TI - Digital PCR to assess hematopoietic chimerism after allogeneic stem cell transplantation. AB - Analysis of hematopoietic chimerism after allogeneic stem cell transplantation represents a crucial method to evaluate donor-cell engraftment. Whereas sensitivity of classical approaches for chimerism monitoring is limited to >=1%, quantitative polymerase chain reaction (qPCR)-based techniques readily detect one patient cell in >1,000 donor cells, thus facilitating application of chimerism assessment as a surrogate for minimal residual disease. However, due to methodologic specificities, qPCR combines its high sensitivity with limited resolution power in the state of mixed chimerism (e.g., >10% patient cells). Our aim was to overcome this limitation by employing a further development of qPCR, namely digital PCR (dPCR), for chimerism analysis. For proof-of-principle, we established more than 10 dPCR assays detecting Indel polymorphisms or Y chromosome sequences and tested them on artificial cell mixtures and patient samples. Employing artificial cell mixtures, we found that dPCR allows exact quantification of chimerism over several orders of magnitude. Digital PCR results proved to be highly reproducible (deviation <5%), particularly in the "difficult" range of mixed chimerism. Excellent performance of the new assays was confirmed by analysis of multiple retrospective blood samples from patients after allogeneic stem cell transplantation, in comparison with established qPCR (14 patients) and short-tandem repeat PCR (4 patients) techniques. Finally, dPCR is easy to perform, needs only small amounts of DNA for chimerism assessment (65 ng corresponds to a sensitivity of approximately 0.03%), and does not require the use of standard curves and replicate analysis. In conclusion, dPCR represents a very promising method for routine chimerism monitoring. PMID- 25795524 TI - Affect labeling enhances exposure effectiveness for public speaking anxiety. AB - Exposure is an effective treatment for anxiety but many patients do not respond fully. Affect labeling (labeling emotional experience) attenuates emotional responding. The current project examined whether affect labeling enhances exposure effectiveness in participants with public speaking anxiety. Participants were randomized to exposure with or without affect labeling. Physiological arousal and self-reported fear were assessed before and after exposure and compared between groups. Consistent with hypotheses, participants assigned to Affect Labeling, especially those who used more labels during exposure, showed greater reduction in physiological activation than Control participants. No effect was found for self-report measures. Also, greater emotion regulation deficits at baseline predicted more benefit in physiological arousal from exposure combined with affect labeling than exposure alone. The current research provides evidence that behavioral strategies that target prefrontal-amygdala circuitry can improve treatment effectiveness for anxiety and these effects are particularly pronounced for patients with the greatest deficits in emotion regulation. PMID- 25795525 TI - Laundry pack exposures in children 0-5 years evaluated at a single pediatric institution. AB - BACKGROUND: Case reports and poison center series have highlighted increased safety concerns with laundry packs, especially when compared to traditional laundry detergents. OBJECTIVE: The purpose of this study was to examine the clinical experience with laundry pack exposures at a single institution. METHODS: A retrospective chart review was performed for exposures to laundry packs seen at a single tertiary care children's hospital medical center. Cases were identified by searching the poison center database for exposures to laundry products from March 2012 to October 2013 in children <5 years old. Medical records were reviewed for all identified cases. Data collected included demographics, treatments, laboratory and radiology data, disposition, and length of stay in the emergency department (ED). RESULTS: Forty cases were included. Thirty-two were ingestions and eight were ocular exposures. Nine children were admitted, two of which were admitted to a critical care unit. Seven other children were discharged after 1-night admissions; none received any treatments after initial ED treatment. Of these, four children were admitted for the possibility of central nervous system (CNS) depression, but none showed any progression. Twenty-nine children with ingestions were discharged directly from the ED. No children had progression of CNS symptoms. Children discharged from the ED were observed a mean of 189 min. CONCLUSIONS: Cases of laundry pack exposures seen at our institution were similar to cases described by US poison centers. No child had progression of CNS depression suggesting that prolonged observation is not necessary if the child does not have CNS depression at presentation. PMID- 25795526 TI - An alternative diagnosis for hemoptysis. PMID- 25795527 TI - African tick-bite fever in a returning traveler. AB - BACKGROUND: African tick bite fever (ATBF) is an emerging infection endemic to sub-Saharan Africa and increasingly noted in travelers to the region. CASE REPORT: We present a case of ATBF in a 63-year-old man who presented with complaints of a rash and fever to the emergency department. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Rickettsial diseases are increasingly common and are seen on every continent except Antarctica. Many factors are contributing to their prevalence, and they have become the second most common cause of fever behind malaria in the traveler returning from Africa. Due to the global distribution of rickettsial diseases, as well as increasing international travel, emergency physicians might encounter ill and febrile travelers. A careful travel history and examination will enable the emergency physician to consider spotted fever group rickettsial diseases in their differential diagnosis for single and multiple eschars. PMID- 25795528 TI - Identifying proper agitation interval to prevent floating layers formation of corn stover and improve biogas production in anaerobic digestion. AB - Floating tests were conducted in anaerobic digestion with different OLR of corn stover to investigate formation of floating layers and to find proper agitation interval for preventing floating layer formation. Floating layers were formed in the early stage of no-agitation period. The daily biogas production was decreased by 81.87-87.90% in digesters with no agitation and feeding compared with digesters having agitation. Reduction of biogas production was mainly attributed to poor contact of substrate-microorganisms. Agitation intervals of 10 h, 6 h, and 2 h were found to be proper for eliminating floating layer at OLR of 1.44, 1.78 and 2.11 g(TS) L(-1) d(-1), respectively. The proper agitation interval was further validated by anaerobic experiments. It showed that proper agitation interval could not only prevent floating layer formation and achieve high biogas production but also increase energy efficiency of anaerobic digestion. The finding is useful for operating anaerobic digester with corn stover in a cost effective way. PMID- 25795529 TI - Vulnerability to Sexual Victimization in Female and Male College Students in Brazil: Cross-Sectional and Prospective Evidence. AB - Using both cross-sectional and prospective analyses, this study examined vulnerability factors for sexual victimization in 541 female and male Brazilian college students, of whom a subgroup of 250 took part in two measurements 6 months apart. Risk factors for sexual victimization (alcohol consumption, casual sex, and ambiguous communication) in participants' cognitive scripts for consensual sex were linked to sexual victimization via their translation into risky sexual behavior. Pornography use was indirectly linked to sexual victimization through its influence on risky sexual scripts and sexual behavior. Child sexual abuse predicted sexual victimization in the cross-sectional analysis, and victimization since age 14 predicted revictimization in the six months covered by the prospective period. Few gender differences were found. This study is the first prospective investigation of vulnerability factors for sexual victimization in Brazil, and similarities to evidence from North America are discussed. PMID- 25795530 TI - Behavioral and psychosocial correlates of anal sex among male clients of female sex workers in Tijuana, Mexico. AB - Most studies of heterosexual sex risk practices have focused on condomless vaginal sex despite evidence that condomless anal sex has a significantly higher risk of HIV transmission. The present study focused on male clients' anal sex practices with female sex workers (FSWs) in Tijuana, Mexico, where an HIV epidemic is growing among high-risk groups. Logistic regression analyses were used to identify psychosocial and behavioral correlates of anal sex among male clients. Our sample of HIV-negative men (N = 400) was predominantly Latino (87.5 %), born in Mexico (78.8 %), never married (36.8 %) or in a regular or common-law marriage (31.5 %), and employed (62.8 %), with an average age and education of 37.8 and 9.2 years, respectively. Eighty-nine percent identified as heterosexual and 11 % as bisexual. By design, 50 % of the sample resided in Tijuana and the other 50 % in San Diego County. Nearly half (49 %) reported at least one incident of anal sex with a FSW in Tijuana in the past 4 months; of those participants, 85 % reported that one or more of their anal sex acts with FSWs had been without a condom. In a multivariate model, anal sex with a FSW in the past 4 months was associated with bisexual identification, methamphetamine use with FSWs, repeat visits to the same FSW, higher scores on perceived stigma about being a client of FSWs, and sexual compulsivity. Prevention programs are needed that address the behavioral and psychosocial correlates of heterosexual anal sex in order to reduce HIV/STI transmission risk among male clients, FSWs, and their sexual network members. PMID- 25795531 TI - Sensual, erotic, and sexual behaviors of women from the "kink" community. AB - Unconventional sensual, erotic, and sexual behaviors (herein referred to as kink behaviors) investigated by academia are based largely on clinical and criminal cases, and most published, peer-reviewed, quantitative research on these behaviors is based almost exclusively on male participants. For this study, information was collected and analyzed from 1580 female participants recruited from the kink community, using a non-clinical and non-criminal sample. We explored and described the preferences and diversity of more than 126 sensual, erotic, and sexual behaviors found among these participants, along with recommendations for continued research. Gaining a better understanding of the breadth and depth of activities engaged in by female kink practitioners could benefit educators, counselors, therapists, medical doctors, and other professionals when interacting with members of the kink community. PMID- 25795532 TI - Erratum to: Fusion with the Cross-Gender Group Predicts Genital Sex Reassignment Surgery. PMID- 25795533 TI - Development of screening inventories for bipolar disorder at workplace: a diagnostic accuracy study. AB - BACKGROUND: This study aimed to develop a new instrument for bipolar disorder screening, the Workplace Bipolar Inventory (WBI), and examine its efficiency as compared with Mood Disorder Questionnaire (MDQ) and Bipolar Spectrum Diagnostic Scale (BSDS) among workers on leave of the absence due to their mental health problems. METHODS: Participants were recruited at a psychiatric outpatient clinic for return-to-work in Tokyo, Japan, during September to November 2009. 81 outpatients were recruited, 55 of whom (68%) agreed to participate in this study. Participants answered questionnaires including WBI, MDQ, BSDS, and demographic factors. Their diagnostic information according to the international statistical classification of diseases and related health problems 10th revision (ICD-10) was obtained from their attending psychiatrists. The WBI is a new self-rating 39-item questionnaire which developed with input from occupational mental health specialists and an analysis of WHO Composite International Diagnostic Interview (CIDI) items. The WBI contains 3 subtype scales: WBI-A (5 items), WBI-AB4 (9 items), and WBI-AB (39 items). RESULTS: Reliability of these scales was moderate. In the AUC of these scales, BSDS was the best of them (0.83). In the optimal cut off point of these scales, WBI-AB4 showed good efficiency of screening (sensitivity=0.78, specificity=0.75). Both MDQ and BSDS had high specificity, while low in sensitivity. LIMITATIONS: The well validated diagnostic method (i.e., the structured clinical interview for DSM-IV [SCID] or CIDI) was not applied in this study. CONCLUSIONS: The WBI, especially WBI-AB4 would be a useful workplace screening tool for workers with bipolar disorder. PMID- 25795534 TI - Associations of racial/ethnic identities and religious affiliation with suicidal ideation among lesbian, gay, bisexual, and questioning individuals. AB - BACKGROUND: Our aim was to examine the associations of racial/ethnic identity and religious affiliation with suicidal ideation among lesbian, gay, bisexual, and questioning (LGBQ) and heterosexual college students. An additional aim was to determine the prevalence of passive suicidal ideation (i.e., death ideation) and active suicidal ideation among culturally diverse LGBQ individuals. METHODS: Data from the National Research Consortium probability-based sample of college students from 70 postsecondary institutions (n=24,626) were used to examine active and passive suicidal ideation in the past 12-months and lifetime active suicidal ideation among students by sexual orientation, racial/ethnic identity, and religious affiliation. RESULTS: Across most racial/ethnic groups and religious affiliations, LGBQ students were more likely to report active suicidal ideation than non-LGBQ individuals. Among LGBQ students, Latino individuals had lower odds of reporting both past 12-month passive and active suicidal ideation than their non-Hispanic white LGBQ counterparts. Compared to Christian LGBQ students, Agnostic/Atheist LGBQ individuals had greater odds of reporting past 12 month passive suicidal ideation, and Jewish LGBQ students were less likely to endorse past 12-month passive and active suicidal ideation. LIMITATIONS: Cross sectional design and self-reported data. CONCLUSIONS: Results corroborate previous research showing elevated prevalence of suicidal ideation among LGBQ individuals in comparison to their heterosexual counterparts. These findings are among the first to document prevalence differences within the LGBQ population based on intersectional identities (race/ethnicity and religious affiliation). Providers should recognize that LGBQ individuals might need support in negotiating the complex relationship between multiple identities, especially due to their elevated prevalence of suicidal ideation. PMID- 25795535 TI - Online mindfulness-based intervention for late-stage bipolar disorder: pilot evidence for feasibility and effectiveness. AB - OBJECTIVES: People in the late stage of bipolar disorder (BD) experience elevated relapse rates and poorer quality of life (QoL) compared with those in the early stages. Existing psychological interventions also appear less effective in this group. To address this need, we developed a new online mindfulness-based intervention targeting quality of life (QoL) in late stage BD. Here, we report on an open pilot trial of ORBIT (online, recovery-focused, bipolar individual therapy). METHODS: Inclusion criteria were: self-reported primary diagnosis of BD, six or more episodes of BD, under the care of a medical practitioner, access to the internet, proficient in English, 18-65 years of age. Primary outcome was change (baseline - post-treatment) on the Brief QoL.BD (Michalak and Murray, 2010). Secondary outcomes were depression, anxiety, and stress measured on the DASS scales (Lovibond and Lovibond, 1993). RESULTS: Twenty-six people consented to participate (Age M=46.6 years, SD=12.9, and 75% female). Ten participants were lost to follow-up (38.5% attrition). Statistically significant improvement in QoL was found for the completers, t(15)=2.88, 95% CI:.89-5.98, p=.011, (Cohen's dz=.72, partial eta(2)=.36), and the intent-to-treat sample t(25)=2.65, 95% CI:.47-3.76, (Cohen's dz=.52; partial eta(2)=.22). A non-significant trend towards improvement was found on the DASS anxiety scale (p=.06) in both completer and intent-to-treat samples, but change on depression and stress did not approach significance. LIMITATIONS: This was an open trial with no comparison group, so measured improvements may not be due to specific elements of the intervention. Structured diagnostic assessments were not conducted, and interpretation of effectiveness was limited by substantial attrition. CONCLUSION: Online delivery of mindfulness-based psychological therapy for late stage BD appears feasible and effective, and ORBIT warrants full development. Modifications suggested by the pilot study include increasing the 3 weeks duration of the intervention, adding cautions about the impact of extended meditations, and addition of coaching support/monitoring to optimise engagement. PMID- 25795536 TI - Changes in major depressive and generalized anxiety disorders in the national French working population between 2006 and 2010. AB - BACKGROUND: This study aimed at assessing the changes in mental disorders in the French working population between 2006 and 2010, using nationally representative prospective data and a structured diagnostic interview for major depressive episode (MDE) and generalized anxiety disorder (GAD), and also at exploring the differential changes in mental disorders according to age, origin, occupation, public/private sector, self-employed/employee status and work contract. METHODS: The data came from the prospective national representative Sante et Itineraire Professionnel (SIP) survey, including a sample of 5600 French workers interviewed in 2006 and 2010. The Mini International Neuropsychiatric Interview (MINI) was used to measure MDE and GAD. Analyses were performed using weighted generalized estimation equations, and were stratified by gender. RESULTS: No changes in MDE and GAD were observed for both genders among the working population. No differential changes were observed, except one: the prevalence of GAD increased among women working in the public sector while there was no change among women in the private sector. LIMITATIONS: Two data collections over a 4-year period may not capture the effects of the crisis on mental disorders properly. CONCLUSION: No changes in mental disorders between 2006 and 2010 were found but the increase in the prevalence of anxiety among women in the public sector may be of particular interest for prevention policies. High levels of social protection in France might contribute to explain these non-significant results. PMID- 25795537 TI - Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study. AB - BACKGROUND: Previous cross-sectional studies have suggested a comorbid association between atopic dermatitis (AD) and depressive disorder as well as anxiety disorders, but the temporal relationship was not determined. METHODS: Using the Taiwan National Health Insurance Research Database, 8208 AD patients aged 12 and older without psychiatric history and age-/sex-matched (1:1) controls between 1998 and 2008 were enrolled in our study and followed to the end of 2011. Subjects who developed major depression, any depressive disorder, and anxiety disorders during the follow-up were identified. RESULTS: The Cox regression analysis after adjusting for demographic data and atopic comorbidities demonstrated that patients with AD had an elevated risk of developing major depression (hazard ratio [HR]: 6.56, 95% confidence interval [CI]: 3.64-11.84), any depressive disorder (HR: 5.44, 95% CI: 3.99-7.44), and anxiety disorders (HR: 3.57, 95% CI: 2.55-4.98). Stratified by age group, both adolescents and adults with AD were prone to developing major depression (HR: 4.26, 95% CI: 1.39-13.13; HR: 7.56, 95% CI: 3.75-15.23), any depressive disorder (HR: 4.38, 95% CI: 2.09 9.18; HR: 5.66, 95% CI: 4.01-7.99), and anxiety disorders (HR: 5.40, 95% CI: 2.02 14.39; HR: 3.36, 95% CI: 2.38-4.80). CONCLUSIONS: AD in both adolescence and adulthood increased the risk of developing major depression, any depressive disorder, and anxiety disorders in later life. Further studies would be required to clarify the possible underlying mechanism between AD and depression as well as anxiety disorders. PMID- 25795538 TI - Suicidal ideation and related factors among dementia patients. AB - BACKGROUND: It is generally thought that people with dementia are not able to attempt suicide because of impaired executive function. Little research is available about suicidal ideation among dementia patients. The present study examines 1) the sociodemographic and clinical features of dementia patients with suicidal ideation and 2) the effect of suicidal ideation on caregiver burden. METHODS: A total of 634 dementia outpatients and their family caregivers participated in this study. Comparisons of variables were made among three groups: patients with suicidal ideation, patients with depression without suicidal ideation, and patients with neither suicidal ideation nor depression. Data were collected between April 2007 and July 2013. RESULTS: Suicidal ideation was seen in 64 patients (10.1%). Patients with suicidal ideation had a significantly higher rate of behavioural and psychological symptoms of dementia (BPSD) (P<0.001). Caregivers of patients with suicidal ideation felt a higher caregiver burden, even after adjusting for BPSD score (P<0.01). LIMITATIONS: Suicidal ideation was assessed by interview with caregivers, so we may have overlooked people who had suicidal ideation but did not express it to their caregivers. CONCLUSIONS: Suicidal ideation among dementia patients should receive greater attention. Adequate assessment of suicidal ideation and psychological support for both patients with suicidal ideation and their caregivers are needed. PMID- 25795539 TI - Surface design and engineering 2014. Preface. PMID- 25795540 TI - Transgenerational epigenetic inheritance requires a much deeper analysis. AB - In his article, Szyf [1] has addressed the key challenges in and the controversies surrounding nongenetic inheritance. However, crucial findings that are important to counter two major criticisms held against transgenerational inheritance, especially in mammals--namely epigenetic memory survival across generations, and soma-to-germline transfer of heritable information--need additional discussion. Given the far-reaching implications of nongenetic inheritance on the one hand, and the skepticisms about its existence on the other, it is important that the advances concerned are examined deeply. The following discussion fills the gap left by Szyf [1] and provides an integrated perspective. PMID- 25795541 TI - Analyzing seasonality of tuberculosis across Indian states and union territories. AB - A significant seasonal variation in tuberculosis (TB) is observed in north India during 2006-2011, particularly in states like Himachal Pradesh, Haryana and Rajasthan. To quantify the seasonal variation, we measure average amplitude (peak to trough distance) across seasons in smear positive cases of TB and observe that it is maximum for Himachal Pradesh (40.01%) and minimum for Maharashtra (3.87%). In north India, smear positive cases peak in second quarter (April-June) and reach a trough in fourth quarter (October-December), however low seasonal variation is observed in southern region of the country. The significant correlations as 0.64 (p-value<0.001), 0.54 (p-value<0.01) and 0.42 (p-value<0.05) are observed between minimum temperature and seasonality of TB at lag-1 in north, central and northeast India respectively. However, in south India, this correlation is not significant. PMID- 25795542 TI - School Experiences of Adolescents With Attention-Deficit/Hyperactivity Disorder. AB - This article reports on a qualitative study of the school experiences of adolescents with attention-deficit/hyperactivity disorder (ADHD) in the context of quantitative research on teacher attitudes and practices, adolescent self appraisals, and social and family relationships. Twelve adolescents with ADHD participated in in-depth, semistructured interviews addressing major aspects of school life. Using a modified grounded theory framework, researchers coded these interviews. Three themes emerged: (a) support for a performance deficit, (b) academic and social engagement, and (c) moving from dependence to independence. What is most striking is the low level of agency students demonstrated; that is, rather than acting with purpose on their environments, they seemed to react to things that happened to them. These findings suggest that teachers of adolescents with ADHD know about the nature of the disorder, understand that students' difficulties with organization and academic performance are not typically intentional, use evidence-based interventions to support students, and provide the monitoring and scaffolding needed for academic achievement. The students also provide specific suggestions for parents and peers regarding the supports they need to be successful. PMID- 25795543 TI - Integrated risk index for seafood contaminants (IRISC): Pilot study in five European countries. AB - Consumption of seafood is one of the most relevant pathways of exposure to environmental pollutants present in food. The list of toxic compounds in seafood is very extensive, including heavy metals, polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs). In order to quantify the importance of the problem, tools to combine and simplify large data collections are mandatory for risk managers and decision-makers. In this study, the development of a prioritization setting focusing on chemical hazards taken up through seafood was aimed. For this purpose, the toxicity data of several chemicals was integrated with concentration and seafood consumption data, building an integrated risk index for seafood contaminants (IRISC) able to draw a map of risk for each chemical and family of chemicals. A pilot trial was performed on a sample of 74 pollutants, four seafood species and five European countries (Belgium, Ireland, Italy, Portugal and Spain). The preliminary results revealed that Portugal and Spain presented the highest IRISC, while Belgium was the region with the lowest IRISC. The contribution of each group of contaminants to the IRISC was very similar among countries, with heavy metals being the major contributor, followed by PCBs, PCDD/Fs and endocrine disrupting compounds. When the contribution of different seafood species to the Risk Indexes (RIs) was compared, the results elucidated the high input from sardines, showing the highest rates (54.9-76.1) in the five countries. The IRISC provides a friendly approach to the chemical risk scene in Europe, establishing normalized prioritization criteria considering toxicity and consumption as well as concentration of each chemical. PMID- 25795545 TI - Bioabsorbable interference screw failure in anterior cruciate ligament reconstruction: A case series and review of the literature. AB - BACKGROUND: To report a case series of failures of bioabsorbable interference screws with possible identification of a novel failure mechanism. METHODS: A retrospective review of ACL reconstructions by the senior author utilizing BioCompositeTM Interference Screws (Arthrex, Inc., Naples, FL) was performed. Complications related to screw placement, including fracture, breakage or bending were examined. Our rate and methods of failure were compared to those quoted in the current literature. RESULTS: Eighty-seven patients of average age 23.8 years met inclusion criteria. There were eight screw failures in six patients, with femoral failure in seven and tibial failure in one. The femoral screw fractured halfway between the tip and head in five, while the head of the screw broke in one and the screw bent in another. In the case of tibial interference screw fracture, failure occurred halfway between the tip and head. The insertion device that was used was replaced after recognition of material deformation and considered a potential contributor to the breakage risk as no further screw failures have occurred since. CONCLUSIONS: We demonstrate a unique failure mechanism of bio-absorbable interference screws. In each case, the reconstruction was salvaged. Regular inspection of materials and implants can ensure optimal outcomes and decrease complications intra-operatively. PMID- 25795544 TI - Case series report: Early cement-implant interface fixation failure in total knee replacement. AB - BACKGROUND: Early failure in cemented total knee replacement (TKR) due to aseptic loosening is uncommon. A small number of early failures requiring revision were observed at one hospital due to observed cement-implant fixation failure. The purpose of this case series is to report and identify possible causes for these early failures. METHODS: Between May 2005 and December 2010, 3048 primary TKRs were performed over a five-year period of time by six surgeons. Two total knee systems were used during this period of time. Nine early failures were observed in eight patients. High viscosity cement (HVC) was used in all these cases. RESULTS: Aseptic loosening of the tibial component was observed in all nine early total knee failures. The high viscosity bone cement was noted to be non-adherent to the tibial trays at the time of revision surgery. HVC was used in all these cases. CONCLUSIONS: Properties of HVC may contribute to make it more susceptible to early failure in a small number of TKRs. HVC in total hip replacement (THR) has been associated with cement micro-fractures, cement debris generation and early implant failure. The mechanical properties of HVC may similarly contribute to early failure at the cement-implant interface in a small percentage TKRs. PMID- 25795546 TI - Evaluation of a behind-remnant approach for femoral tunnel creation in remnant preserving double-bundle anterior cruciate ligament reconstruction - Comparison with a standard approach. AB - PURPOSE: To evaluate a novel approach for femoral tunnel creation, a behind remnant approach, in remnant-preserving double-bundle anterior cruciate ligament (ACL) reconstruction through comparison with a standard approach. METHODS: Sixty patients who underwent remnant-preserving double-bundle ACL reconstruction were included. Thirty patients with a standard approach were classified as the standard group, and 30 patients with a behind-remnant approach as the behind remnant (BR) group. The anteromedial bundle (AMB) and posterolateral bundle (PLB) were provisionally fixed at 20 degrees and 45 degrees of flexion to a graft tensioning system during surgery. Bundle tension was recorded during knee flexion extension and in response to anterior or rotatory loads. Femoral tunnel positions were then assessed using the quadrant method. RESULTS: During flexion-extension, the BR group showed equivalent tension curves between AMB and PLB, while the standard group showed reciprocal tension curves. The tension on the PLB was lower than the AMB in response to anterior or rotatory loads in the BR group, while the AMB and PLB shared equivalent loads in the standard group. Tunnel position of the AMB in the BR group was lower and deeper, with smaller variances, than that in the standard group. Tunnel position of the PLB in the BR group was lower than that in the standard group. CONCLUSIONS: In remnant-preserving double-bundle ACL reconstruction, a behind-remnant approach can be achieved without any removal of the remnant tissue, and could create a deeper and lower AMB tunnel and a lower PLB tunnel with higher reproducibility, showing equivalent tension curves between the AMB and PLB. PMID- 25795547 TI - Kinematic analysis of knee varus and rotation movements at the initial stance phase with severe osteoarthritis of the knee. AB - BACKGROUND: The purposes of this study were to understand the kinematics changes in the frontal and horizontal planes with severe medial knee OA at the stance phase and to examine the relationship between varus and rotational movements. METHODS: The OA group comprised 18 knees in 12 subjects (five men, seven women) with a Kellgren-Lawrence grade of three or four in at least one knee. From the results of gait analysis, we calculated Spearman rank-correlation coefficients for the following items: varus angle at initial contact (IC); varus angle at loading response (LR); amount of varus thrust from IC to LR; rotational angle at IC; rotational angle at LR and amount of rotational angle change from IC to LR. RESULTS: The results indicated that, as the external rotation angle at IC and internal rotational movement from IC to LR increased, the maximum varus angle to LR showed a tendency to become large. In addition, varus thrust showed a tendency to become larger as the external rotation angles increased at IC and LR. The subjects with severe knee OA showed a strong correlation between the knee varus angle at IC and at LR. Furthermore, an increase in movement to internal rotation of the knee during the initial stance phase increased the knee varus angle at LR. CONCLUSIONS: The control of the rotational movement according to the extent of varus thrust during the initial stance phase may have possible effects to decrease the load on the medial compartment of the knee. PMID- 25795548 TI - Contribution of geometric design parameters to knee implant performance: Conflicting impact of conformity on kinematics and contact mechanics. AB - BACKGROUND: Articular geometry of knee implant has a competing impact on kinematics and contact mechanics of total knee arthroplasty (TKA) such that geometry with lower contact pressure will impose more constraints on knee kinematics. The geometric parameters that may cause this competing effect have not been well understood. This study aimed to quantify the underlying relationships between implant geometry as input and its performance metrics as output. METHODS: Parametric dimensions of a fixed-bearing cruciate retaining implant were randomized to generate a number of perturbed implant geometries. Performance metrics (i.e., maximum contact pressure, anterior-posterior range of motion [A-P ROM] and internal-external range of motion [I-E ROM]) of each randomized design were calculated using finite element analysis. The relative contributions of individual geometric variables to the performance metrics were then determined in terms of sensitivity indices (SI). RESULTS: The femoral and tibial distal or posterior radii and femoral frontal radius are the key parameters. In the sagittal plane, distal curvature of the femoral and tibial influenced both contact pressure, i.e., SI=0.57; SI=0.65, and A-P ROM, i.e., SI=0.58; SI=0.6, respectively. However, posterior curvature of the femoral and tibial implants had a smaller impact on the contact pressure, i.e., SI=0.31; SI=0.23 and a higher impact on the I-E ROM, i.e., SI=0.72; SI=0.58. It is noteworthy that in the frontal plane, frontal radius of the femoral implant impacted both contact pressure (SI=0.38) and I-E ROM (SI=0.35). CONCLUSION: Findings of this study highlighted how changes in the conformity of the femoral and tibial can impact the performance metrics. PMID- 25795549 TI - Sustained pre-hypertensive blood pressure and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis. AB - The association between sustained pre-hypertension and atrial fibrillation (AF) has not been thoroughly examined. This study included 5311 participants (mean age 62 +/- 10 years; 47% male; 42.9% non-whites) from the Multi-Ethnic Study of Atherosclerosis. Sustained exposure was based on 2 or more visits within the same blood pressure category (optimal, <120/80 mm Hg; pre-hypertension, 120-139/80-89 mm Hg; hypertension, >=140/90 mm Hg or antihypertensive medication use) during visits 1, 2, and 3. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between blood pressure category and AF. Over a median follow-up of 5.3 years, 182 (3.4%) participants developed AF. Pre-hypertension and hypertension were associated with an increased risk of AF compared with participants who had optimal blood pressure (optimal: HR, 1.0; referent; pre-hypertension: HR, 1.8; 95% CI, 1.004-3.2; hypertension: HR, 2.6; 95% CI, 1.6-4.4). Sustained pre-hypertension is associated with an increased risk of AF. PMID- 25795551 TI - Treatment: drug therapy of hypertension. PMID- 25795550 TI - Prevalence and trends of isolated systolic hypertension among untreated adults in the United States. AB - The prevalence and long-term trends of isolated systolic hypertension (ISH) among untreated adults have not been reported. Data from 24,653 participants aged >=18 years were selected from the National Health and Nutrition Examination Survey 1999-2010. The prevalence and 95% confidence intervals (CIs) of untreated ISH were estimated by conducting the independent survey t-test. The prevalence of untreated ISH was 9.4% and decreased from 10.3% in 1999-2004 to 8.5% in 2005-2010 (P = .00248). Old persons, females, and non-Hispanic blacks had higher prevalence of untreated ISH. Compared with 1999-2004, the prevalence of untreated ISH in 2005-2010 decreased among older (33.6%; 95% CI, 30.9%-36.3% vs. 25.1%; 95% CI, 22.7%-27.5%) and female individuals (8.3%; 95% CI, 7.5-9.2% vs. 11.4%; 95% CI, 10.4-12.3%). The stratified prevalence of untreated ISH declined in 2005-2010 (vs. 1999-2004) for older non-Hispanic whites (24.6% vs. 32.8%; P < .0001) and blacks (27.7% vs. 40.8%; P = .0013), non-Hispanic white females (7.5% vs. 10.8%; P < .0001), older individuals with higher education (21.0% vs. 30.6%; P = .0024), and females with lower education (10.1% vs. 13.1%; P = .006). Untreated ISH is more prevalent in older adults and females. Significant decreases in untreated ISH prevalence over time among these groups suggest that public health measures and/or treatment patterns are trending in the right direction. PMID- 25795552 TI - Secondary hypertension: obstructive sleep apnea. PMID- 25795553 TI - Interpretation of coastal sediment quality based on trace metal and PAH analysis, benthic foraminifera, and toxicity tests (Sardinia, Western Mediterranean). AB - An integrated approach for the assessment of coastal sediment quality was utilised in three areas of Sardinia (Western Mediterranean, Italy). Sediments were analysed for trace metals and polycyclic aromatic hydrocarbons (PAHs), while benthic foraminifera were used as bioindicators. Furthermore, the embryo-toxicity test was used to provide ecologically relevant information using rapid and cost effective screening tools. The aim was to evaluate the usefulness of coupling different analytical tools. The results revealed the presence of polluted sediments in areas exposed to petrochemical industries, smelters or military settlements. However, while foraminifera have presented similar indications for chemical analysis of contamination levels in the different areas, the toxicity test exhibited a poor relationship with the contaminants measured individually. The results raise questions concerning the bioavailability of contaminants released by sediments in the water column. Overall, the toxicity rate was significant in many samples in comparison with other sites studied in other Mediterranean regions. PMID- 25795554 TI - Osmotic Stress Modulates the Balance between Exocytosis and Clathrin-Mediated Endocytosis in Arabidopsis thaliana. AB - The sessile life style of plants creates the need to deal with an often adverse environment, in which water availability can change on a daily basis, challenging the cellular physiology and integrity. Changes in osmotic conditions disrupt the equilibrium of the plasma membrane: hypoosmotic conditions increase and hyperosmotic environment decrease the cell volume. Here, we show that short-term extracellular osmotic treatments are closely followed by a shift in the balance between endocytosis and exocytosis in root meristem cells. Acute hyperosmotic treatments (ionic and nonionic) enhance clathrin-mediated endocytosis simultaneously attenuating exocytosis, whereas hypoosmotic treatments have the opposite effects. In addition to clathrin recruitment to the plasma membrane, components of early endocytic trafficking are essential during hyperosmotic stress responses. Consequently, growth of seedlings defective in elements of clathrin or early endocytic machinery is more sensitive to hyperosmotic treatments. We also found that the endocytotic response to a change of osmotic status in the environment is dominant over the presumably evolutionary more recent regulatory effect of plant hormones, such as auxin. These results imply that osmotic perturbation influences the balance between endocytosis and exocytosis acting through clathrin-mediated endocytosis. We propose that tension on the plasma membrane determines the addition or removal of membranes at the cell surface, thus preserving cell integrity. PMID- 25795555 TI - Metabolic determinants of white matter hyperintensity burden in patients with ischemic stroke. AB - OBJECTIVE: Increasing white matter hyperintensity (WMH) burden is linked to risk of stroke and poor post-stroke outcomes. While the biology of WMH remains ill defined, several lines of evidence implicate endothelial dysfunction. In this study, we sought to assess the association between metabolic markers of endothelial dysfunction and WMH severity in patients with acute ischemic stroke (AIS). METHODS: In this retrospective study, consecutive subjects, >=18 years of age, admitted to our ED with AIS, brain MRI, and blood homocysteine (Hcy) and hemoglobin A1c (HgbA1c) measurements were eligible for this analysis. WMH volume (WMHV) was quantified using a validated semi-automated algorithm and log transformed for linear regression analyses. RESULTS: There were 809 AIS subjects included (mean age 65.57+/-14.7, median WMHV 6.25 cm3 (IQR 2.8-13.1)). In univariate analysis, age, female gender, race, ethnicity, systolic blood pressure, history of hypertension, atrial fibrillation, coronary artery disease, prior stroke, and current alcohol and tobacco use (all p<0.05), as well as Hcy (p<0.0001) and HgbA1c levels (p=0.0005) were associated with WMHV. However, only Hcy (beta=0.11, p=0.003) and HgbA1c levels (beta=0.1, p=0.008) independently predicted WMHV in the multivariate model, along with age (beta=0.03, p<0.0001), race (beta=0.39, p=0.01), ethnicity (beta=-0.11, p=0.03), and current alcohol use (beta=0.26, p=0.002). CONCLUSIONS: Elevated levels of Hcy and HgbA1c have been previously linked to endothelial dysfunction related to oxidative stress. The association between Hcy and HgbA1c and WMH burden in AIS suggests that the degree of endothelial dysfunction may be greater in patients with increased WMHV, and may in part explain the relationship between WMHV and poor post-stroke outcomes. PMID- 25795556 TI - Endothelial activation and cardiometabolic profiles of treated and never-treated HIV infected Africans. AB - OBJECTIVE: The role the human immunodeficiency virus (HIV) and antiretroviral treatment on endothelial activation, and the subsequent relationship with cardiovascular disease, is not well understood. We investigated endothelial activation, inflammatory and cardiometabolic profiles, and measures of vascular structure and function of 66 antiretroviral treated (ART), 78 never-treated (no ART) HIV infected and 165 HIV free Africans. METHODS: Blood samples were obtained for biochemical analysis and blood pressure, pulse wave velocity (PWV) and carotid intima-media thickness (IMT) measurements were performed. RESULTS: The HIV infection duration was at least five years and the treatment 2.86+/-0.13 years. The intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) levels were elevated in the HIV infected groups compared to the controls. The odds of higher adhesion molecule levels were increased when HIV infected (especially in the no-ART group); OR no-ART vs. no-HIV: ICAM 3.92 (2.2 7.0); VCAM 16.2 (7.5-35). ICAM and VCAM associated with HIV status and interleukin-6 (IL-6) in the total group (all p<0.01). In both HIV infected groups VCAM associated inversely with CD4 counts (no-ART: beta=-0.28, p=0.01; ART: beta= 0.22, p=0.07) and TC (no-ART: beta=-0.36, p<0.01; ART: beta=-0.27, p=0.03). The ART group had an unfavourable lipid profile compared to the no-ART group. The inflammatory markers (C-reactive protein (CRP) and IL-6), PWV and IMT did not differ between the three groups. CONCLUSION: HIV infected Africans showed endothelial activation when compared to HIV free controls. The endothelial activation was not accompanied by increased inflammation (as measured with CRP and IL-6), arterial stiffness or sub-clinical atherosclerosis. PMID- 25795557 TI - IMPROVE-IT clinical implications. Should the "high-intensity cholesterol-lowering therapy" strategy replace the "high-intensity statin therapy"? PMID- 25795559 TI - The addition of E (Empowerment and Economics) to the ABCD algorithm in diabetes care. AB - The ABCD (Age, Body weight, Complications, Duration of disease) algorithm was proposed as a simple and practical tool to manage patients with type 2 diabetes. Diabetes treatment, as for all chronic diseases, relies on patients' ability to cope with daily problems concerning the management of their disease in accordance with medical recommendations. Thus, it is important that patients learn to manage and cope with their disease and gain greater control over actions and decisions affecting their health. Healthcare professionals should aim to encourage and increase patients' perception about their ability to take informed decisions about disease management and to improve patient self-esteem and feeling of self efficacy to become agents of their own health. E for Empowerment is therefore an additional factor to take into account in the management of patients with type 2 diabetes. E stands also for Economics to be considered in diabetes care. Attention should be paid to public health policies as well as to the physician faced with the dilemma of delivering the best possible care within the problem of limited resources. The financial impact of the new treatment modalities for diabetes represents an issue that needs to be addressed at multiple strata both globally and nationally. PMID- 25795558 TI - GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS. AB - OBJECTIVES: Increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) are associated with type 2 diabetes. However, it remains largely unknown how SFAs interact with LPS to regulate inflammatory responses in microvascular endothelial cells (MIC ECs) that are critically involved in atherosclerosis as a diabetic complication. In this study, we compared the effects of LPS, palmitic acid (PA), the most abundant saturated fatty acid, or the combination of LPS and PA on interleukin (IL)-6 expression by MIC ECs and explored the underlying mechanisms. METHODS: Human cardiac MIC ECs were treated with LPS, PA and LPS plus PA and the regulatory pathways including receptors, signal transduction, transcription and post-transcription, and sphingolipid metabolism for IL-6 expression were investigated. RESULTS: G protein-coupled receptor (GPR)40 or free fatty acid receptor 1 (FFA1), but not toll-like receptor 4, was involved in PA-stimulated IL-6 expression. PA not only stimulated IL-6 expression by itself, but also remarkably enhanced LPS-stimulated IL-6 expression via a cooperative stimulation on mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, and both transcriptional and post transcriptional activation. Furthermore, PA induced a robust neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis that was involved in PA-augmented IL-6 upregulation. CONCLUSION: PA boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase. PMID- 25795560 TI - Perceptions and experiences of nursing students enrolled in a palliative and end of-life nursing elective: A qualitative study. AB - BACKGROUND: The Carnegie Foundation has identified three professional apprenticeships in nursing that are key to helping students acquire a professional identity. These apprenticeships integrate knowledge acquisition (cognitive apprenticeship), practical experience (practical apprenticeship), and an ethical identity (ethical comportment) for guiding conduct. To ensure that patients have a good death, it is important that faculty incorporate diverse teaching strategies from all three apprenticeships into palliative and end-of life nursing education. OBJECTIVE: The purpose of this study was to examine perceptions and experiences of nursing students enrolled in a palliative and end of-life nursing elective that was developed and implemented using the three professional apprenticeships. DESIGN: A qualitative research design was used to obtain data from students who completed the palliative and end-of-life nursing elective. SETTING: The study was implemented at a state supported baccalaureate nursing program located in the south eastern United States. PARTICIPANTS: A purposive sample of 19 students who had completed the palliative and end-of-life nursing elective was included in the study. METHODS: After completing the course, focus groups were conducted with the student participants. Discussion was guided by questions to elicit which experiences were most helpful to student learning. Thematic analysis of the data was conducted by three researchers. FINDINGS: Three themes reflecting the apprenticeships were identified: learning from stories, learning from being there, and learning from caring. Students' understandings about end-of-life care were enhanced by incorporating teaching strategies addressing the apprenticeships. CONCLUSION: In end-of-life nursing education, teaching strategies must provide meaningful connections between the student, course content, practical experience, and the dying patient. PMID- 25795561 TI - Offering personalized health behavior feedback did not increase response rate: a randomized controlled trial. PMID- 25795562 TI - A theoretical framework for modeling dilution enhancement of non-reactive solutes in heterogeneous porous media. AB - Spatial heterogeneity of the hydraulic properties of geological porous formations leads to erratically shaped solute clouds, thus increasing the edge area of the solute body and augmenting the dilution rate. In this study, we provide a theoretical framework to quantify dilution of a non-reactive solute within a steady state flow as affected by the spatial variability of the hydraulic conductivity. Embracing the Lagrangian concentration framework, we obtain explicit semi-analytical expressions for the dilution index as a function of the structural parameters of the random hydraulic conductivity field, under the assumptions of uniform-in-the-average flow, small injection source and weak-to mild heterogeneity. Results show how the dilution enhancement of the solute cloud is strongly dependent on both the statistical anisotropy ratio and the heterogeneity level of the porous medium. The explicit semi-analytical solution also captures the temporal evolution of the dilution rate; for the early- and late-time limits, the proposed solution recovers previous results from the literature, while at intermediate times it reflects the increasing interplay between large-scale advection and local-scale dispersion. The performance of the theoretical framework is verified with high resolution numerical results and successfully tested against the Cape Cod field data. PMID- 25795563 TI - Expression and characterization of a novel human recombinant factor IX molecule with enhanced in vitro and in vivo clotting activity. AB - INTRODUCTION: Hemophilia B is an inherited X-linked recessive bleeding disorder, due to a defect in human factor IX (FIX). The main treatment for hemophilia B is replacement therapy using FIX concentrates. Prophylactic treatment in severe hemophilia B is very effective but is limited by cost issues. Production of a recombinant FIX (rFIX) with enhanced clotting activity, offering the possibility of fewer infusions and fewer costs with similar efficacy, is one of the current challenges for hemophilia B treatment. The present study focused on an important amino acid sequence known to be involved in the interaction of activated FIX (FIXa) with its cofactor, activated factor VIII (FVIIIa). MATERIALS AND METHODS: Using site-directed mutagenesis of glutamate E410 (c240, chymotrypsin numbering), four recombinant FIX-E410 (E410H, A, L and N) mutants were developed and produced by the human hepatoma cell line Huh-7. RESULTS: The in-vitro clotting activity of mutant FIX molecules was 3 to 5-fold higher than wild-type recombinant FIX (FIX WT). FIX-E410H compound showed the highest in-vitro procoagulant activity. Enhanced specific activity was confirmed using thrombin generation assay. FIX E410H induced 5.2-fold higher thrombin generation than FIX-WT. In hemophilia B mice, we observed significantly higher in-vivo clotting activity and thrombin generating capacity with FIX-E410H compared to FIX-WT. We demonstrated that increased procoagulant activity of FIX-E410H was mainly explained by 2.5- fold enhanced affinity of the mutant for human FVIIIa. CONCLUSION: We have engineered and characterized four improved FIX proteins with enhanced in-vitro and in-vivo activity. Future studies are required to evaluate the immunogenicity of FIX-E410. PMID- 25795564 TI - Comparative efficacy and safety of anticoagulants and aspirin for extended treatment of venous thromboembolism: A network meta-analysis. AB - OBJECTIVE: To systematically review the literature and to quantitatively evaluate the efficacy and safety of extended pharmacologic treatment of venous thromboembolism (VTE) through network meta-analysis (NMA). METHODS: A systematic literature search (MEDLINE, Embase, Cochrane CENTRAL, through September 2014) and searching of reference lists of included studies and relevant reviews was conducted to identify randomized controlled trials of patients who completed initial anticoagulant treatment for VTE and then randomized for the extension study; compared extension of anticoagulant treatment to placebo or active control; and reported at least one outcome of interest (VTE or a composite of major bleeding or clinically relevant non-major bleeding). A random-effects Frequentist approach to NMA was used to calculate relative risks with 95% confidence intervals. RESULTS: Ten trials (n=11,079) were included. Risk of bias (assessed with the Cochrane tool) was low in most domains assessed across the included trials. Apixaban (2.5mg and 5mg), dabigatran, rivaroxaban, idraparinux and vitamin K antagonists (VKA) each significantly reduced the risk of VTE recurrence compared to placebo, ranging from a 73% reduction with idraparinux to 86% with VKAs. With exception of idraparinux, all active therapies significantly reduced VTE recurrence risk versus aspirin, ranging from a 73% reduction with either apixaban 2.5mg or rivaroxaban to 80% with VKAs. Apixaban and aspirin were the only therapies that did not increase composite bleeding risk significantly compared to placebo. All active therapies except aspirin increased risk of composite bleeding by 2 to 4-fold compared to apixaban 2.5mg, with no difference found between the two apixaban doses. CONCLUSION: Extended treatment of VTE is a reasonable approach to provide continued protection from VTE recurrence although bleeding risk is variable across therapeutic options. Our results indicate that apixaban, dabigatran, rivaroxaban, idraparinux and VKAs all reduced VTE recurrence when compared to placebo. Apixaban appears to have a more favorable safety profile compared to other therapies. PMID- 25795565 TI - Dosimetric comparison of volume-based and inverse planning simulated annealing based dose optimizations for high-dose rate brachytherapy. AB - The aim of this study was to compare the clinical benefits of inverse planning simulated annealing (IPSA)-based optimization over volume-based optimization for high-dose rate (HDR) cervix interstitial implants. Overall, 10 patients of cervical carcinoma were considered for treatment with HDR interstitial brachytherapy. Oncentra Master Plan brachytherapy planning system was used for generating 3-dimensional HDR treatment planning for all patients. All patient treatments were planned using volume-based optimization and inverse planning optimization (IPSA). The parameters V100, V150, and V200 for the target; D(2 cm3) of bladder, rectum, and sigmoid colon; and V80 and V100 for bladder, rectum, and sigmoid colon were compared using dose-volume histograms (DVHs). The conformity index (CI), relative dose homogeneity index, overdose volume index (ODI), and dose nonuniformity index (DNR) were computed from cumulative DVHs. Good target coverage for prescription dose was achieved with volume-based optimization as compared with IPSA-based dose optimization. Homogeneity was good with the IPSA based technique as compared with the volume-based dose optimization technique. Volume-based optimization resulted in a higher CI (with a mean value of 0.87) compared with the IPSA-based optimization (with a mean value of 0.76). ODI and DNR are better for the IPSA-based plan as compared with the volume-based plan. Mean doses to the bladder, rectum, and sigmoid colon were least with IPSA. IPSA also spared the critical organs but with considerable target conformity as compared with the volume-based plan. IPSA significantly reduces overall treatment planning time with improved reduced doses to the organs at risk compared with the volume-based optimization treatment planning method. PMID- 25795566 TI - High-resolution gene expression profiling using RNA sequencing in patients with inflammatory bowel disease and in mouse models of colitis. AB - BACKGROUND AND AIMS: Proper interpretation of data from preclinical animal studies requires thorough knowledge of the pathophysiology of both the human disease and animal models. In this study, the expression of inflammatory bowel disease [IBD]-associated genes was characterised in mouse models of colitis to examine the underlying molecular pathways and assess the similarity between the experimental models and human disease. METHODS: RNA sequencing was performed on colon biopsies from Crohn's disease [CD] patients, ulcerative colitis [UC] patients and non-IBD controls. Genes shown to be significantly dysregulated in human IBD were used to study gene expression in colons from a piroxicam accelerated colitis interleukin-10 knockout [PAC IL-10 k.o.], an adoptive transfer [AdTr] and a dextran sulfate sodium [DSS] colitis mouse model. RESULTS: Of 115 literature-defined genes linked to IBD, 92 were significantly differentially expressed in inflamed mucosa of CD and/or UC patients compared with non-IBD controls. The most upregulated genes were shared by both diseases, including REG1A, LCN2, NOS2, CXCL1-2, and S100A9. Of those 92 IBD-associated genes, 71 [77%] were significantly dysregulated in PAC IL-10 k.o. mice, whereas 59 [64%] were significantly dysregulated in AdTr mice compared with wild-type controls. Some of the most upregulated genes, including S100a8-9, Nos2, and Lcn2, were shared by the colitis models and correlated with disease activity. CONCLUSIONS: IBD and experimental murine colitis have a high degree of similarity in the colonic transcriptional profile, probably secondary to non-specific inflammatory processes. However, differences do exist between models, emphasising the need for careful selection and interpretation of qualified animal models in preclinical research. PMID- 25795567 TI - Prevalence and significance of isolated T wave inversion in 1755 consecutive American collegiate athletes. AB - BACKGROUND: We evaluated the prevalence of isolated T-wave inversions (TWI) in American athletes using contemporary ECG criteria. Ethnic and gender disparities including the association of isolated TWI with underlying abnormal cardiac structure are evaluated. METHODS: From 2004 to 2014, 1755 collegiate athletes at a single American university underwent prospective collection of medical history, physical examination, 12-lead ECG, and 2-dimensional echocardiography. ECG analysis was performed to evaluate for isolated TWI as per contemporary ECG criteria. RESULTS: The overall prevalence of isolated TWI is 1.3%. Ethnic and gender disparities are not observed in American athletes (black vs. white: 1.7% vs. 1.1%; p=0.41) (women vs. men: 1.5% vs. 1.1; p=0.52). No association was found with underlying cardiomyopathy. CONCLUSION: A lower prevalence of isolated TWI in American athletes than previously reported. Isolated TWI was not associated with an abnormal echocardiogram. No ethnic or gender disparity is seen in American college athletes. PMID- 25795568 TI - RSR' pattern and the risk of mortality in men and women free of cardiovascular disease. AB - This study included 6,398 participants (mean age 55 +/- 0.34 years; 54% female; 49% white; 22% black; 24% Mexican; 4.3% other) free of clinical cardiovascular disease (CVD) and major ECG abnormalities. Cox regression was used to examine the association between the RSR' (incomplete right bundle branch block (RBBB) or right ventricular conduction delay) pattern and CVD and all-cause mortalities. The RSR' pattern was not associated with an increased risk of CVD (HR=1.10; 95%CI=0.63, 1.91) mortality or all-cause (HR=0.95; 95%CI=0.66, 1.35) mortality. The results were similar when the RSR' pattern was further separated into incomplete RBBB and right ventricular conduction delay. In conclusion, the RSR' pattern is a benign finding in older adults free of clinical CVD. PMID- 25795569 TI - Polyphasic characterization of an anaerobic hexachlorobenzene-dechlorinating microbial consortium with a wide dechlorination spectrum for chlorobenzenes. AB - An anaerobic consortium that was capable of reductively dechlorinating hexachlorobenzene (HCB) to benzene was enriched from contaminated sediment. The consortium was capable of dechlorinating all chlorobenzene isomers except 1,4 dichlorobenzene. Singly and doubly flanked chlorines, as well as unflanked meta substituted chlorines, were dechlorinated, although doubly flanked chlorines were preferred. Formate, acetate and lactate (but not ethanol) could be utilized as optimum electron donors for reductive dechlorination. Alternative electron acceptors, including nitrate and sulfate, completely inhibited HCB degradation, whereas amorphous iron oxide (FeOOH) did not suppress dechlorination activity. No degradation was found in chloramphenicol-treated consortium; however, vancomycin, molybdate, and 2-bromoethanesulfonate did not inhibit HCB dechlorination. The results of inhibitory treatments suggested that the dechlorinators were non sulfate-reducing gram-negative or vancomycin resistant gram-positive bacteria. In addition to physiological characterization, analyses of 16S rRNA gene library of the consortium and quantitative PCR of 16S rRNA genes suggested that Dehalococcoides sp. was involved in the reductive dechlorination of HCB, and Geobacter sp. may serve as a dechlorinating candidate. PMID- 25795570 TI - MiR-494-3p induced by compressive force inhibits cell proliferation in MC3T3-E1 cells. AB - Mechanical stimuli regulate fundamental cell processes such as proliferation, differentiation, and morphogenesis. We attempted to identify microRNA (miRNA) whose expression is changed during compressive treatment in MC3T3-E1, a pre osteoblastic cell line. Microarray analysis followed by reverse transcription quantitative polymerase chain reaction revealed that compressive force at 294 Pa for 24 h in MC3T3-E1 cells increased levels of miR-494-3p, miR-146a-5p, miR-210 3p, and miR-1247-3p. Among these miRNAs, miR-494-3p was found to inhibit cell proliferation in MC3T3-E1 cells. Furthermore, cells subjected to compressive force showed slower cell growth compared with control cells. Levels of mRNA for fibroblast growth factor receptor 2 (FGFR2) and Rho-associated coiled-coil kinase 1 (ROCK1), which were predicted to be targets of miR-494-3p, were decreased by compressive force or overexpression of miR-494-3p mimics in MC3T3-E1 cells. Furthermore, binding sites of miR-494-3p within 3'-untranslated regions of Fgfr2 and Rock1 were determined using luciferase reporter assay. In conclusion, compressive force affected expressions of several miRNAs including miR-494-3p in MC3T3-E1 cells. Compressive force might inhibit cell proliferation in osteoblasts by up-regulating miR-494-3p followed by FGFR2 and ROCK1 gene repressions. PMID- 25795571 TI - Culture characteristics of the atmospheric and room temperature plasma-mutated Spirulina platensis mutants in CO2 aeration culture system for biomass production. AB - For biomass production of Spirulina platensis as feedstock of fermentation, the culture characteristics of three typical mutants of 3-A10, 3-B2 and 4-B3 generated by atmospheric and room temperature plasmas (ARTP) mutagenesis were systematically studied by using CO2 aeration culture system and compared with the wild strain. The specific growth rate of wild strain in the pure air aeration culture system exhibited a 76.2% increase compared with static culture, while the specific growth rates of the 3-A10, 3-B2 and 4-B3 in pure air aeration culture system were increased by 114.4%, 95.9% and 88.2% compared with their static cultures. Compared with static culture, the carbohydrate contents of wild strain, 3-A10, 3-B2 and 4-B3 in pure air aeration culture system dropped plainly by 51.0%, 79.3%, 85.5% and 26.1%. Increase of CO2 concentration enhanced carbohydrate content and productivity. Based on the carbohydrate productivity, the optimal inlet of CO2 concentration in aeration culture was determined to be 12% (v/v). Under this condition, 3-B2 exhibited the highest carbohydrate content (30.7%), CO2 fixation rate (0.120gCO2.g(-1).d(-1)) and higher growth rate (0.093 g L(-1).d(-1)), while 3-A10 showed the highest growth rate (0.118 g L(-1).d(-1)) and higher CO2 fixation rate (0.117gCO2.g(-1).d(-1)) but low carbohydrate content (24.5%), and 4-B3 showed the highest chlorophyll (Chl) content (3.82 mg.g(-1)). The most outstanding mutant by static culture in terms of growth rate and carbohydrate productivity (3-B2), was also demonstrated by CO2 aeration culture system. This study revealed that the ARTP mutagenesis could generate the S. platensis mutants suitable for CO2 aeration culture aiming at biomass production. PMID- 25795572 TI - Metabolomic analysis of acid stress response in Saccharomyces cerevisiae. AB - Acid stress has been reported to inhibit cell growth and decrease productivity during bio-production processes. In this study, a metabolomics approach was conducted to understand the effect of lactic acid induced stress on metabolite pools in Saccharomyces cerevisiae. Cells were cultured with lactic acid as the acidulant, with or without initial pH control, i.e., at pH 6 or pH 2.5, respectively. Under conditions of low pH, lactic acid led to a decrease in the intracellular pH and specific growth rate; however, these parameters remained unaltered in the cultures with pH control. Capillary electrophoresis-mass spectrometry followed by a statistical principal component analysis was used to identify the metabolites and measure the increased concentrations of ATP, glutathione and proline during severe acid stress. Addition of proline to the acidified cultures improved the specific growth rates. We hypothesized that addition of proline protected the cells from acid stress by combating acid induced oxidative stress. Lactic acid diffusion into the cell resulted in intracellular acidification, which elicited an oxidative stress response and resulted in increased glutathione levels. PMID- 25795573 TI - Metabolic correlation between polyol and energy-storing carbohydrate under osmotic and oxidative stress condition in Moniliella megachiliensis. AB - Moniliella megachiliensis, the osmo-tolerant basidiomycetous yeast was found to accumulate intracellularly energy-storing carbohydrates (trehalose and glycogen) along with polyols (glycerol and erythritol) up to stationary growth phase. In trehalose-loaded cell, osmotic-stress resulted in the rapid generation of glycerol, and oxidative stress with menadione resulted in the rapid generation of erythritol. Under either of these conditions, the levels of the energy-storing carbohydrates were depleted, while little glucose uptake was observed. These results suggested that the intracellular pools of trehalose and glycogen were rapidly converted to glycerol in response to osmotic stress, and to erythritol in response to oxidative stress and altered redox balance. Expression of tps1 encoding trehalose synthetic enzymes paralleled trehalose accumulation in the cell during the culture in 2% glucose, in contrast, expression of tpp1 or tpp2 encoding trehalose-6-phosphate phosphatase was little increased under the same condition. Expression of tre (tre1/tre2) encoding trehalose hydrolase (trehalase) increased with time associated with depletion of trehalose during oxidative stress. From these results, we concluded that glycerol and erythritol, the compatible solutes in M. megachiliensis were metabolically interrelated to energy storing carbohydrates such as trehalose or glycogen during conditions of osmotic or oxidative stress. PMID- 25795574 TI - A new year, a new hat. PMID- 25795575 TI - Simple CT-based calculations of orbital floor fracture defect size are not sufficiently accurate for clinical use. PMID- 25795576 TI - Reply by the authors. PMID- 25795578 TI - Prevalence and pattern of facial burns: a 5-year assessment of 808 patients. AB - PURPOSE: Retrospective studies on the types and causes of facial burns are important because the patterns might vary in different societies. Our aim was to assess the burn-related factors of significance that might be useful in healthcare planning and implementing preventive strategies, adding to the body of current data on the subject. MATERIALS AND METHODS: A retrospective cross sectional study was conducted to assess the data from a major burns referral center during a 5-year period (2009 to 2013). The data relevant to age, gender, cause, source, location, burn degree, extent (body surface area [BSA]) of the burns, and mortality were gathered from comprehensive patient medical records, recorded, and analyzed using SPSS, version 20, software (SPSS, Chicago, IL). RESULTS: Within the study period, we found 808 documented cases of second- and third-degree facial burns. These burns were more common in men (81.9%) and in the 16- to 35-year age group (42.3%). The mean hospitalization was 9.85 +/- 8.94 days. In 443 patients (54.83%), 10 to 19% of their BSA was burned, and 3.06% had associated inhalation burns. The most common burn was scalding (19%), and the deadliest was burns from acid, with a mortality rate of 7.4%. Accidents accounted for 776 burns (96.03%). Other causes were attempted homicide (16 cases, 1.98%) and suicide attempts (16 cases, 1.98%). The overall mortality was 1.6%. CONCLUSIONS: The key findings were that second- and third-degree facial burns were more common in males aged 16 to 35 years with burns covering 10 to 19% of the BSA. Accidental scalding was commonly responsible for the second-degree burns, and electrical accidents were commonly responsible for third-degree facial burns. Burn accidents occurred more often at the patient's home. PMID- 25795577 TI - A review of general cosmetic surgery training in fellowship programs offered by the American Academy of Cosmetic Surgery. AB - PURPOSE: We sought, first, to evaluate the operative experience of surgeons who have completed postresidency fellowships offered by the American Academy of Cosmetic Surgery (AACS), and second, to compare this cosmetic surgery training to other surgical residency and fellowship programs in the United States. Finally, we suggest how new and existing oral and maxillofacial surgeons can use these programs. MATERIALS AND METHODS: We reviewed the completed case logs from AACS accredited fellowships. The logs were data mined for 7 of the most common cosmetic operations, including the median total number of operations. We then compared the cosmetic case requirements from the different residencies and fellowships. RESULTS: Thirty-nine case logs were reviewed from the 1-year general cosmetic surgery fellowships offered by the AACS from 2007 to 2012. The fellows completed a median of 687 total procedures. The median number of the most common cosmetic procedures performed was 14 rhinoplasties, 31 blepharoplasties, 21 facelifts, 24 abdominoplasties, 28 breast mastopexies, 103 breast augmentations, and 189 liposuctions. The data obtained were compared with the minimum cosmetic surgical requirements in residency and fellowship programs. The minimum residency requirements were as follows: no minimum listed for plastic surgery, 35 for otolaryngology, 20 for oral and maxillofacial surgery, 28 for ophthalmology, 0 for obstetrics and gynecology, and 20 for dermatology. The minimum fellowship requirements were as follows: 300 for the AACS cosmetic surgery fellowship, no minimum listed for facial plastic surgery and reconstruction, no minimum listed for aesthetic surgery, 133 for oculoplastic and reconstructive surgery, and 0 for Mohs dermatology. CONCLUSION: Dedicating one's practice exclusively to cosmetic surgery requires additional postresidency training owing to the breadth of the field. The AACS created comprehensive fellowship programs to fill an essential part in the continuum of cosmetic surgeons' education, training, and experience. This builds on the foundation of their primary board residency program. The AACS fellowships are a valuable option for additional training for qualified surgeons seeking proficiency and competency in cosmetic surgery. PMID- 25795579 TI - Recurrent sublingual ranula or saliva leakage from the submandibular gland? Anatomical consideration of the ductal system of the sublingual gland. AB - PURPOSE: Some believe that the recurrence of sublingual ranula results from incomplete removal of the sublingual gland (SLG), but recurrence remains in some patients who undergo repeated excision of the remnant SLG, and the final solution to the recurrence is to remove the ipsilateral submandibular gland (SMG). In the authors' experience, preoperative aspirate from a sublingual ranula was a thick mucus-like fluid resembling egg white, whereas that from recurrent cyst after removal of the SLG was thin serous fluid. Based on the difference of the aspirated fluids, the authors speculated that the recurrent cystic mass might not be a ranula, but rather iatrogenic saliva leakage from the SMG through the previous surgically damaged excretory duct of the SLG (Bartholin duct) that opens into the SMG duct (Wharton duct). MATERIALS AND METHODS: A gross anatomic study was performed of the ductal system of the SLG and the anatomic communication between the Bartholin duct and Wharton duct. RESULTS: Four anatomic SLG duct variants were found. 1) The SLG has 1 Bartholin duct that seems to fuse with the Wharton duct but does not join the Wharton duct, running parallel to the Wharton duct and opening at its own orifice adjacent to and a short distance from the orifice of the Wharton duct (35.8%). 2) The SLG has 1 Bartholin duct that empties into the middle section of the Wharton duct (32.1%). 3) The SLG has 2 Bartholin ducts, one of which joins the Wharton duct and the other opens at its own orifice near that of the Wharton duct on the floor of the mouth (7.1%). 4) The SLG has many fine ducts (Rivinus ducts) that open at the floor of the mouth with no relation to the Wharton duct (25.0%). Of the 4 anatomic SLG duct variations, types 2 and 3 form immediate anatomic communication between the Bartholin duct and Wharton duct (39.2%). CONCLUSIONS: Several conclusions can be made from the present anatomic findings. 1) A certain proportion of Bartholin ducts open into the Wharton duct, and "recurrent ranula" after removal of the SLG can result from iatrogenic saliva leakage from the SMG through the surgically severed Bartholin duct if the aspirated fluid from the "recurrent cyst" is a thin seriflux. 2) The Bartholin duct emptying into the Wharton duct should be ligated during removal of the SLG to prevent local saliva accumulation from the SMG or even caudal "recurrence" as plunging ranula. 3) The surgical incision for SLG removal should be sutured loosely so that the surgically severed Bartholin duct with communication to the Wharton duct can reopen at the floor of mouth as an outlet for possible saliva leakage from the SMG and saliva accumulation can be avoided. PMID- 25795580 TI - Establishment of a rat model for alveolar cleft with bone wax. AB - PURPOSE: Although treatment of cleft lip and cleft palate is becoming standardized, treatment of alveolar cleft remains controversial. Thus, preclinical animal work remains necessary to improve clinical outcome. This study established an alveolar cleft model in the rat. MATERIALS AND METHODS: Maxillary first molars were extracted to create a 4- * 4- * 3-mm complete alveolar cleft on the right and left sides in 25 8-week-old Sprague-Dawley rats. The left cleft was filled with bone wax and the right side remained untreated. Animals were sacrificed at 0, 4 and 8 weeks after surgery. Harvested alveolar cleft samples were evaluated by micro-computed tomographic and histologic analyses. RESULTS: The healing rate and osteoblast activity of the left cleft were less than those of the right cleft. CONCLUSION: This model of a critical-size alveolar cleft can be used efficiently for the therapeutic evaluation of novel techniques for the treatment of alveolar cleft. PMID- 25795581 TI - A brief history of vascularized free flaps in the oral and maxillofacial region. AB - Vascularized free flaps are now the reference standard for the reconstruction of defects after cancer resection in oral and maxillofacial surgery and other specialties and have an interesting and surprisingly long history. We reviewed the history of free flap use in oral and maxillofacial surgery and show their place in the wider context of surgical progress. An overview is given of both soft tissue and bony reconstruction in the pre-free flap era and the development of vascular anastomosis and microsurgery--one of the main foundations of free flap surgery. The emergence of free flaps from 1959 through to the early 1970s is documented. The history of 19 of the more common free flaps used in oral and maxillofacial surgery is described, from the jejunal flap in 1959 through to the posterior tibial artery flap in 1985. For each, the origin and first reported use in the head and neck are discussed. Free flap surgery has continued to evolve, with developments in perforator and chimeric flaps, and new flaps continue to be described. An appreciation of the surgical history is important in understanding where we are today. Our review should give the practicing surgeon an idea of the origins of the currently used techniques. PMID- 25795582 TI - Periosteal osteosarcoma of the mandible: a case report. AB - This report describes a rare case of a periosteal osteosarcoma of the mandible in a 50-year-old African-American woman who showed no underlying bony changes at panoramic radiography or computed tomography. This report describes the diagnostic workup used to obtain the definitive diagnosis and the surgical treatment and recommended method for subsequent tumor surveillance. Emphasis is placed on distinguishing periosteal osteosarcomas as a separate entity from conventional intraosseous osteosarcomas in the head and neck region. PMID- 25795583 TI - Care assistant experiences of dementia care in long-term nursing and residential care environments. AB - Care assistants have a unique insight into the lives of service users and those factors which may impede or enhance the delivery of high quality dementia oriented care. To address the paucity of research in this area, the present study examined care assistant experiences of dementia care in British long-term residential and nursing environments. Semi-structured interviews were conducted with eight care assistants and transcripts were analysed using interpretive phenomenological analysis. Super-ordinate themes emerging from the data were psychological wellbeing of the care assistant, barriers to effective dementia care, the dementia reality and organisational issues within the care environment. The study revealed important deficiencies in understanding and varying levels of dementia training. Whilst person centred strategies were being implemented, task orientated care remained dominant. Furthermore, care assistants reported taking the perspectives of those with dementia into account, and actively using these to develop relationship centred care. PMID- 25795584 TI - here:now - Conceptual model of the impact of an experiential arts program on persons with dementia and their care partners. AB - Community-based arts programs for persons with dementia and their care partners hold tremendous potential for increasing cognitive, social, and creative engagement and improving quality of life for these dyads. This is a qualitative, grounded theory analysis of here:now, a joint arts engagement program for persons with dementia and their care partners that involves gallery tours and art classes. Twenty-one care partners and 13 persons with dementia completed in depth, semi-structured telephone interviews approximately two weeks following participation in the program. The program was well received by both persons with dementia and care partners as evidenced by high levels of engagement, mindfulness, social connection, and positive interactions. Factors identified as important to the experience included the museum space itself, the facilitation process, and socialization with other participants. Results form the basis for a conceptual model for assessing outcomes of arts programming and highlight the unique position of museums to support persons with dementia and their care partners in the community. PMID- 25795585 TI - Intestinal failure to produce FGF19: A culprit in intestinal failure-associated liver disease? PMID- 25795586 TI - Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir. AB - BACKGROUND & AIMS: New interferon-free anti-HCV regimens are highly efficacious with a favorable safety profile. We assessed health-related quality of life (HRQL) and work productivity in patients with different stages of hepatic fibrosis treated with sofosbuvir+ledipasvir. METHODS: Four questionnaires [Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Short Form-36 (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Index:Specific Health Problem (WPAI:SHP)] were administered at baseline, during, and after treatment with sofosbuvir+ledipasvir+ribavirin or sofosbuvir+ledipasvir (ION-1,2,3 clinical trials). Metavir fibrosis stage was determined from pre-treatment liver biopsies. RESULTS: There were 1005 patients included (stage F0: n=94; F1: n=311; F2: n=301; F3: n=197; F4: n=102). At baseline, patients with more advanced fibrosis had more HRQL impairments, predominantly related to physical functioning (stage 0 vs. stage 4 by up to 0.126 on a normalized 0-1 scale p<0.0001). During and post treatment, HRQL remained lower in patients with advanced fibrosis. After achieving sustained virologic response, significant improvements from baseline in most HRQL domains were observed regardless of fibrosis stage (by 0.024-0.103 on a 0-1 scale; all p>0.05 across fibrosis stages). In multivariate analysis, advanced fibrosis was independently associated with impairment of HRQL and work productivity (beta up to -0.056 in comparison with none-to-mild fibrosis, p<0.05). However, improvement of HRQL and work productivity after viral clearance was not related to the stage of fibrosis (all p>0.05). CONCLUSIONS: Although advanced hepatic fibrosis is associated with HRQL and work productivity impairment, viral eradication with sofosbuvir+ledipasvir leads to HRQL improvement regardless of fibrosis stage. HCV patients with early fibrosis experience similar improvement of patient reported outcomes as those with advanced fibrosis. PMID- 25795587 TI - Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. AB - BACKGROUND & AIMS: The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice. METHODS: Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence. RESULTS: Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-beta, hIFN-beta and hIFN lambda) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling. CONCLUSIONS: Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes. PMID- 25795588 TI - Slow decline of hepatitis B burden in general population: Results from a population-based survey and longitudinal follow-up study in Taiwan. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) infection poses a global public health threat. HBV vaccination has proven highly effective in preventing the infection; however, its long-term impact on the general population has not been addressed. We conducted analysis to determine the total and changing burden of chronic HBV infection and evaluate the serological status between vaccinated and unvaccinated in Taiwan. METHODS: Participants in "The Taiwanese Survey on Prevalence of Hyperglycemia, Hyperlipidemia and Hypertension" in 2002 (n=6602), and 4088 with follow-up survey in 2007 were included. HBsAg (including titers), anti-HBs, anti HBc, HBeAg, anti-HBe, HBV genotypes and viral loads were assayed. Prevalence and evolving patterns of these seromarkers was compared between vaccinated and unvaccinated cohorts and predictors of persistent HBsAg positivity and negativity were examined. RESULTS: The overall prevalence of chronic HBV infection was 13.7% (95% CI, 12.9% to 14.5%) and about two thirds had past exposure (anti-HBc: 68.46%) in 2002. The vaccinated cohort tended to have lower prevalence of HBsAg and anti-HBc, and a higher proportion of anti-HBs and HBeAg positivity, genotype C and high viral load. The majority (85.42%) were consistently HBsAg negative while 12.65% were consistently positive, and 8.98% achieved seroclearance in a five-year period. In the vaccinated cohort, no subjects had acquired new exposure and became HBsAg positive, and only one (0.54%) cleared HBsAg, demonstrating the durability of vaccination through teenage and young adulthood. CONCLUSIONS: This comprehensive, population-representative-survey shows that 20 years after universal vaccination, the backlog still composed a substantial burden of chronic HBV infections in Taiwan. PMID- 25795589 TI - Molecular characterization of methicillin-resistant Staphylococcus aureus: characterization of major clones and emergence of epidemic clones of sequence type (ST) 36 and ST 121 in Tehran, Iran. AB - Information about the molecular structure of MRSA strains provides significant insights into the epidemiology of this important pathogen. To investigate the molecular characteristics of MRSA isolates, MRSA isolates were subjected to molecular typing by means of spa typing, multilocus sequence typing, Staphylococcal Cassette Chromosome mec (SCCmec) grouping and to phenotypic antimicrobial susceptibility testing by means of disk diffusion assay. Then the presence of pvl genes was evaluated. Cluster analysis by eBURSTv3 showed that MRSA isolates belonged to two major clonal complexes (CC); CC8 (ST239, ST585, ST2732, ST1294) and CC30 (ST30, ST36, ST1163) and four singletons. Subsequent analysis of MRSA isolates revealed that the most prevalent SCCmec type was type III (55.8%) followed by type IV (34.9%) and type II (2.3%). Totally 11 different spa types were discriminated among which types t037 and t030 were predominant. The prevalence of Panton-Valentine leukocidin (PVL)-positive MRSA strains was high (20%), which is a matter of great concern, because the PVL is frequently associated with severe and recurrent SSTIs. ST239-III- t037 represented the most predominant MRSA clone. The presence of sequence type (ST) 36 and ST 121 are being reported for the first time in Iran. PMID- 25795590 TI - Characterization of a large novel phage-like plasmid in Salmonella enterica serovar Typhimurium. AB - Salmonella enterica serovar Typhimurium is a food-borne pathogen and a leading cause of gastroenteritis in humans. Recently, we sequenced a phage-type DT108 strain (L945) and found reads with high similarity to both Salmonella typhi strain CT18 plasmid pHCM2 and bacteriophage SSU5. In this study, we completely sequenced the novel phage-like plasmid which was designated as pSTM_Phi. The presence of this phage-like plasmid was examined in a collection of 284 Salmonella Typhimurium isolates using PCR of the parB gene and only one other isolate (L946) was found to carry the phage-like plasmid suggesting that it is infrequently present amongst Salmonella Typhimurium isolates. pSTM_Phi is a circular phage-like plasmid of 107.7 kb encoding 132 coding regions (ORFs) with the majority of the ORFs encoding hypothetical proteins. Comparative analysis with other closely related phage-like plasmids and the SSU5 phage revealed that there were four divergent lineages of phage-like plasmids found in the family of Enterobacteriaceae. In conclusion, pSTM_Phi is a new member of an emerging family of phage-like plasmids. PMID- 25795591 TI - Different patterns of H2S/NO activity and cross-talk in the control of the coronary vascular bed under normotensive or hypertensive conditions. AB - Hydrogen sulfide (H2S) and nitric oxide (NO) play pivotal roles in the cardiovascular system. Conflicting results have been reported about their cross talk. This study investigated their interplays in coronary bed of normotensive (NTRs) and spontaneously hypertensive rats (SHRs). The effects of H2S- (NaHS) and NO-donors (sodium nitroprusside, SNP) on coronary flow (CF) were measured in Langendorff-perfused hearts of NTRs and SHRs, in the absence or in the presence of propargylglycine (PAG, inhibitor of H2S biosynthesis), L-NAME (inhibitor of NO biosynthesis), ODQ (inhibitor of guanylate cyclase), L-Cysteine (substrate for H2S biosynthesis) or L-Arginine (substrate for NO biosynthesis). In NTRs, NaHS and SNP increased CF; their effects were particularly evident in Angiotensin II (AngII)-contracted coronary arteries. The dilatory effects of NaHS were abolished by L-NAME and ODQ; conversely, PAG abolished the effects of SNP. In SHRs, high levels of myocardial ROS production were observed. NaHS and SNP did not reduce the oxidative stress, but produced clear increases of the basal CF. In contrast, in AngII-contracted coronary arteries of SHRs, significant hyporeactivity to NaHS and SNP was observed. In SHRs, the vasodilatory effects of NaHS were only modestly affected by L-NAME and ODQ; PAG poorly influenced the effects of SNP. Then, in NTRs, the vascular actions of H2S required NO and vice versa. By contrast, in SHRs, the H2S-induced actions scarcely depend on NO release; as well, the NO effects are largely H2S-independent. These results represent the first step for understanding pathophysiological mechanisms of NO/H2S interplays under both normotensive and hypertensive conditions. PMID- 25795592 TI - Nitric oxide in marine photosynthetic organisms. AB - Nitric oxide is a versatile and powerful signaling molecule in plants. However, most of our understanding stems from studies on terrestrial plants and very little is known about marine autotrophs. This review summarizes current knowledge about the source of nitric oxide synthesis in marine photosynthetic organisms and its role in various physiological processes under normal and stress conditions. The interactions of nitric oxide with other stress signals and cross talk among secondary messengers are also highlighted. PMID- 25795593 TI - Statistical image reconstruction for low-dose CT using nonlocal means-based regularization. Part II: An adaptive approach. AB - To reduce radiation dose in X-ray computed tomography (CT) imaging, one common strategy is to lower the tube current and exposure time settings during projection data acquisition. However, this strategy would inevitably increase the projection data noise, and the resulting image by the conventional filtered back projection (FBP) method may suffer from excessive noise and streak artifacts. The well-known edge-preserving nonlocal means (NLM) filtering can reduce the noise induced artifacts in the FBP reconstructed image, but it sometimes cannot completely eliminate the artifacts, especially under the very low-dose circumstance when the image is severely degraded. Instead of taking NLM filtering, we proposed a NLM-regularized statistical image reconstruction scheme, which can effectively suppress the noise-induced artifacts and significantly improve the reconstructed image quality. From our previous investigation on NLM based strategy, we noted that using a spatially invariant filtering parameter in the regularization was rarely optimal for the entire field of view (FOV). Therefore, in this study we developed a novel strategy for designing spatially variant filtering parameters which are adaptive to the local characteristics of the image to be reconstructed. This adaptive NLM-regularized statistical image reconstruction method was evaluated with low-contrast phantoms and clinical patient data to show (1) the necessity in introducing the spatial adaptivity and (2) the efficacy of the adaptivity in achieving superiority in reconstructing CT images from low-dose acquisitions. PMID- 25795594 TI - Ethical issues with artificial nutrition of children with degenerative brain diseases. AB - This report highlights viewpoints of the authors and comments from the auditory at a workshop, held during the 14th international Congress on neuronal ceroid lipofuscinoses (NCL) in Cordoba, Argentina, on ethical aspects of artificial nutrition in children with degenerative brain diseases. The discussion centers on what constitutes the best interest of a patient whose personality was immature before the onset of the disease, who has become demented during its course and is unable to communicate his/her own positions and desires. There is wide consensus that in a child with advanced disease who cannot be fed naturally, decisions to withhold nutrition or to institute or stop artificial nutrition, should only be made by parents (or their representatives) who are adequately prepared on an intellectual and emotional level. We try to show that such decisions are highly individual but can be made in a rationally and emotionally acceptable way after a careful and prolonged dialogue between families and professionals. A checklist summarizes important considerations. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". PMID- 25795595 TI - Relationship between white matter microstructure abnormalities and ADHD symptomatology in adolescents. AB - The present study sought to evaluate whether white matter microstructure abnormalities observed in a cohort of adolescents with attention deficit/hyperactivity disorder (ADHD) have specific relationships with either or both Hyperactivity/Impulsivity and Inattentive ADHD symptom domains that would support a dimensional view of ADHD as adopted in the DSM-V. Diffusion tensor imaging (DTI) data were acquired on 22 adolescents diagnosed with ADHD. Multiple regression analyses were performed to determine whether scalar DTI measures in 13 tracts-of-interest demonstrated meaningful associations with Hyperactivity/Impulsivity or Inattentive symptom severity. Fractional anisotropy and radial diffusivity measures of white matter integrity exhibited significant linear relationships with Hyperactivity/Impulsivity and Inattentive symptom severity. However, only radial diffusivity in the right superior longitudinal fasciculus was specifically linked to Inattentive symptom severity and not Hyperactivity/Impulsivity symptom severity. Our results provide preliminary evidence that symptom domains in ADHD are linked to neuroanatomical substrates and confirm the value in examining ADHD from a dimensional perspective. PMID- 25795597 TI - DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications. AB - Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases. PMID- 25795596 TI - Cerebral perfusion differences in women currently with and recovered from anorexia nervosa. AB - Anorexia nervosa is a serious psychiatric disorder characterized by restricted eating, a pursuit of thinness, and altered perceptions of body shape and size. Neuroimaging in anorexia nervosa has revealed morphological and functional alterations in the brain. A better understanding of physiological changes in anorexia nervosa could provide a brain-specific health marker relevant to treatment and outcomes. In this study, we applied several advanced magnetic resonance imaging (MRI) techniques to quantify regional and global cerebral blood flow (CBF) in 25 healthy women (HC), 23 patients currently with anorexia (AN-C) and 19 patients in long-term weight recovery following anorexia (AN-WR). Specifically, CBF was measured with pseudo-continuous arterial spin labeling (pCASL) MRI and then verified by a different technique, phase contrast (PC) MRI. Venous T2 values were determined by T2 relaxation under spin tagging (TRUST) MRI, and were used to corroborate the CBF results. These novel techniques were implemented on a standard 3T MRI scanner without any exogenous tracers, and the total scan duration was less than 10min. Voxel-wise comparison revealed that the AN-WR group showed lower CBF in bilateral temporal and frontal lobes than the AN C group. Compared with the HC group, the AN-C group also showed higher CBF in the right temporal lobe. Whole-brain-averaged CBF was significantly decreased in the AN-WR group compared with the AN-C group, consistent with the PC-MRI results. Venous T2 values were lower in the AN-WR group than in the AN-C group, consistent with the CBF results. A review of prior work examining CBF in anorexia nervosa is included in the discussion. This study identifies several differences in the cerebral physiological alterations in anorexia nervosa, and finds specific differences relevant to the current state of the disorder. PMID- 25795598 TI - Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 suppress chronic cerebral hypoperfusion-induced neuronal apoptosis by inhibiting c-Jun N-terminal kinase signaling. AB - The endocannabinoid system (ECS) has therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced cerebral diseases. This study investigated the protective effects of two ECS compounds, cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase inhibitor URB597 (URB) on CCH induced neuronal apoptosis in vivo. CCH was induced in male Sprague-Dawley rats by bilateral common carotid artery occlusion (BCCAo); the rats were then treated with WIN or URB for 12weeks and their spatial learning and memory abilities were assessed using the Morris water maze. Changes in neuronal number were examined by labeling neurons with an antibody against the neuronal nuclei antigen, and apoptosis of cortical and hippocampal CA1 neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. The expression of B cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), and activated caspase-3 as well as mitogen-activated protein kinases including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, phosphorylated (p-)ERK, p-JNK, and p-P38 was examined by Western blotting. Rats treated with WIN or URB showed better learning and memory performance than controls. The neuroprotective effects of URB were greater than those of WIN, and co-administration of WIN and URB had a synergistic effect. In addition, WIN and URB blocked JNK phosphorylation as well as the decrease in Bcl-2/Bax ratio and caspase-3 activation induced by CCH, implying that these agents modulate neuronal survival. Moreover, the selective JNK inhibitor SP600125 improved mitochondrial membrane dysfunction and blocked neuronal apoptosis induced by JNK-dependent Bcl 2 signaling. WIN and URB enhanced the effects of SP600125, implying that they may exert anti-apoptotic effects in part by inhibiting a non-nuclear JNK pathway. These findings indicate that WIN and URB promote neuronal survival and may potentially be used to protect neurons against chronic ischemic insults. PMID- 25795599 TI - Hippocampal function is compromised in an animal model of multiple sclerosis. AB - Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that is characterized by demyelination and axonal damage in the nervous system. One obvious consequence is a cumulative loss of muscle control. However, cognitive dysfunction affects roughly half of MS sufferers, sometimes already early in the disease course. Although long-term (remote) memory is typically unaffected, the ability to form new declarative memories becomes compromised. A major structure for the encoding of new declarative memories is the hippocampus. Encoding is believed to be mediated by synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength. Here, in an animal model of MS we explored whether disease symptoms are accompanied by a loss of functional neuronal integrity, synaptic plasticity, or hippocampus dependent learning ability. In mice that developed MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), passive properties of CA1 pyramidal neurons were unaffected, although the ability to fire action potentials became reduced in the late phase of EAE. LTP remained normal in the early phase of MOG35-55-induced EAE. However, in the late phase, LTP was impaired and LTP-related spatial memory was impaired. In contrast, LTD and hippocampus-dependent object recognition memory were unaffected. These data suggest that in an animal model of MS hippocampal function becomes compromised as the disease progresses. PMID- 25795600 TI - Chemotactic effect of mono- and disaccharides on the unicellular Tetrahymena pyriformis. AB - Chemotaxis is one of the most essential cell physiological responses, which was developed in parallel the molecular evolution of signal molecules. Previously good correlations were found between chemotactic moieties and physicochemical properties (SEA, solubility, pKa) of peptide type ligands in Tetrahymena model. However, references are rather weak in eukaryotic chemotaxis about significance of simple carbohydrates. In the present work our goal is (i) to investigate the chemotactic effect of 10 mono- and disaccharides in the eukaryotic Tetrahymena pyriformis; (ii) to describe effective ligands with physicochemical parameters; (iii) to test whether sugars are acting via induction of metabolic pathways. Our results are: (i) the tested sugars can trigger both significant attractant (D glucose, D-mannose) and significant repellent (D-glucosamine, D-fructose, N acetyl-D-galactosamine, D-arabinose) effects, while some of the sugars (maltose, lactose, sucrose, D-galactose) had no effect. (ii) Correlations were described between the chemotactic effectiveness of the ligands and their physicochemical characters (TPSA, XLogP), which are supposed to influence the internalization of the sugars. (iii) All ligands proved to have low selection potential, which refers to a 'short-term' receptor moiety or influencing specific metabolic pathways. (iv) Starvation elicited modified, strong chemoattractive responsiveness towards glucose; however, it was independent of concentration while 1 h insulin treatment resulted in an increased and concentration dependent chemotaxis induced by glucose. PMID- 25795601 TI - Gender-specific predictors of retention and opioid abstinence during methadone maintenance treatment. AB - AIMS: Retention in methadone maintenance treatment (MMT) for 1 year is associated with positive outcomes including opioid abstinence, however, most studies have not investigated gender differences. We hypothesized that predictors of retention and opioid abstinence would differ between men and women, and aimed to determine which factors best predict retention and abstinence for each gender. METHODS: Data were available for 290 patients (173 M, 117 F) admitted to outpatient MMT. Regression analyses, stratified by gender, were conducted to identify unique predictors of MMT retention (<1 vs. >1 year) and opioid abstinence rate (proportion of opioid-free urine samples up to 1 year retention). RESULTS: Gender did not significantly predict treatment retention (mean = 231 days, 39% retained > 1 year) or opioid abstinence (49% overall). For males, significant predictors of > 1-year retention were urine samples negative for opioids (odds ratio [OR] = 6.67) and cannabinoids (OR = 5.00) during the first month, and not cocaine dependent (OR = 2.70). Significant predictors of higher long-term opioid abstinence were first-month urine samples negative for opioids and cocaine metabolites. For females, significant predictors of >1-year retention were first month urine samples negative for cocaine metabolites (OR = 4.00) and cannabinoids (OR = 9.26), and no history of sexual victimization (OR = 3.03). The only significant predictor of higher opioid abstinence rate was first-month opioid free urine samples. CONCLUSIONS: These findings indicate gender-specific predictors of MMT retention and opioid abstinence. Future studies on MMT outcomes should examine each gender separately, and consider unique pathways by which females and males adhere to, and benefit from MMT. PMID- 25795602 TI - Maintenance of access as demand for substance use disorder treatment grows. AB - Due to the Affordable Care Act and other recent laws and regulations, funding for substance use disorder (SUD) treatment is on the rise. In the 2000s, the Veterans Health Administration (VA) implemented several initiatives that increased funding for SUD treatment during a period of growth in demand for it. A key question is whether access to and intensity of treatment kept pace or declined. Using VA SUD treatment funding data and patient-level records to construct performance measures, we studied the relationship between funding and access during the VA expansion. Overall, we observed an increase in access to and intensity of VA SUD care associated with increased funding. The VA was able to increase funding for and expand the population to which it offered SUD treatment without diminishing internal access and intensity. PMID- 25795603 TI - Preparation, spectroscopic and antibacterial studies on charge-transfer complexes of 2-hydroxypyridine with picric acid and 7,7',8,8'-tetracyano-p-quinodimethane. AB - The reactions of electron acceptors such as picric acid (HPA) and 7,7',8,8' tetracyano-p-quinodimethane (TCNQ) with 2-hydroxypyridine (HPyO) have been investigated in EtOH at room temperature. Based on elemental analysis and IR spectra of the solid CT-complexes along with the photometric titration curves for the reactions, the data obtained indicate the formation of 1:1 charge transfer complexes [(H2PyO)(PA)] and [(PyO)(HTCNQ)], respectively. The infrared and (1)H NMR spectroscopic data indicate a charge transfer interaction associated with a proton migration from the acceptor to the donor followed by intramolecular hydrogen bonding in [(H2PyO)(PA)] complex. Another charge transfer interaction was observed in [(PyO)(HTCNQ)] complex. The formation constants (KCT) for the CT complexes are shown to be strongly dependent on the type and structure of the electron acceptors. Factors affecting the CT-processes and the kinetics of thermal decomposition of the complexes have been studied. The CT complexes were screened for their antibacterial activities against selected bacterial strains. PMID- 25795604 TI - Binary and ternary new water soluble copper(II) complexes of l-tyrosine and substituted 1,10-phenanthrolines: effect of substitution on DNA interactions and cytotoxicities. AB - Binary and ternary water soluble copper(II) complexes - [Cu(nphen)2(H2O)](NO3)2.H2O (1), [Cu(phen)2(H2O)](NO3)2 (2), [Cu(nphen)(l tyr)(H2O)]NO3.2H2O (3), [Cu(phen)(tyr)(H2O)] NO3.2H2O (4) - and diquarternary salts of nphen and phen (nphen=5-nitro-1,10-phenanthroline, phen=1,10 phenanthroline and tyr=l-tyrosine) have been synthesized and characterized by CHN analysis, (1)H NMR, (13)C NMR and IR spectroscopy, thermal analysis and single crystal X-ray diffraction techniques. The CT-DNA binding properties of these compounds have been investigated by thermal denaturation measurements, absorption and emission spectroscopy. The supercoiled pUC19 plasmid DNA cleavage activity of these compounds has been explored by agarose gel electrophoresis. The cytotoxicity of these compounds against MCF-7, Caco-2, A549 cancer cells and BEAS 2B healthy cells was also studied by using XTT method. The complexes 1-4 exhibit significant high cytotoxicity with low IC50 values in compared with cisplatin. The effect of the substituents of phen and coordinated amino acid in the above complexes are presented and discussed. PMID- 25795605 TI - Absorption, fluorescence and second harmonic generation in Cr3+-doped BiB3O6 glasses. AB - Synthesis, spectral properties and photoinduced nonlinear optical effects of chromium-doped BiB3O6 glass are studied in the present paper. Absorption, excitation and time resolved luminescence spectra are presented and luminescence decay behavior is discussed. Detailed analysis of the obtained spectra (assignment of the most prominent spectral features in terms of the corresponding Cr(3+) energy levels, crystal field strength Dq, Racah parameters B and C) was performed. A weak photostimulated second harmonic generation signal was found to increase drastically due to poling by proton implantation in the investigated sample. PMID- 25795606 TI - Effect of solvents on the bulk growth of 4-aminobenzophenone single crystals: a potential material for blue and green lasers. AB - Although 4-aminobenzophenone (4-ABP) is the best derivative of benzophenone with 260 times higher second harmonic generation (SHG) efficiency than potassium dihydrogen phosphate (KDP), growth of high quality bulk crystal still remains a difficult task. In the present work, the effect of solvents on solubility and growth aspects of 4-ABP was investigated to grow inclusion free 4-ABP crystals. The growth processes were discussed based on solute-solvent interaction in two different growth media of ethyl acetate and ethanol. The growth rate and thereby solvent inclusions are relatively higher in ethyl acetate grown crystal than the crystal grown from ethanol. The structural, thermal and optical properties of 4 ABP crystals were studied. The enthalpy of 4-ABP melting process was estimated from differential thermal analysis. The optical transmission study shows that 4 ABP crystals grown from ethanol has high transparency compared to ethyl acetate grown sample due to solvent inclusion in the later crystal. PMID- 25795607 TI - Synthesis, growth, structural, thermal and optical studies of pyrrolidinium-2 carboxylate-4-nitrophenol single crystals. AB - Organic nonlinear optical material, pyrrolidinium-2-carboxylate-4-nitrophenol (PCN) was synthesized and single crystals were grown by slow evaporation solution growth method. Single crystal X-ray diffraction analysis confirmed the structure and lattice parameters of PCN crystals. Infrared, Raman and NMR spectral analyses were used to elucidate the functional groups present in the compound. The thermal behavior of synthesized compound was studied by thermogravimetric and differential scanning calorimetry (TG-DSC) analyses. The photoluminescence property was studied by exciting the crystal at 360 nm. The relative second harmonic generation (SHG) efficiency of grown crystal was estimated by using Nd:YAG laser with fundamental wavelength of 1,064 nm. PMID- 25795608 TI - Molecular structure, vibrational, electronic and thermal properties of 4 vinylcyclohexene by quantum chemical calculations. AB - The solid phase FT-IR and FT-Raman spectra of 4-vinylcyclohexene (abbreviated as 4-VCH) have been recorded in the region 4000-100cm(-1). The optimized molecular geometry and vibrational frequencies of the fundamental modes of 4-VCH have been precisely assigned and analyzed with the aid of structure optimizations and normal coordinate force field calculations based on density functional theory (DFT) method at 6-311++G(d,p) level basis set. The theoretical frequencies were properly scaled and compared with experimentally obtained FT-IR and FT-Raman spectra. Also, the effect due the substitution of vinyl group on the ring vibrational frequencies was analyzed and a detailed interpretation of the vibrational spectra of this compound has been made on the basis of the calculated total energy distribution (TED). The time dependent DFT (TD-DFT) method was employed to predict its electronic properties, such as electronic transitions by UV-Visible analysis, HOMO and LUMO energies, molecular electrostatic potential (MEP) and various global reactivity and selectivity descriptors (chemical hardness, chemical potential, softness, electrophilicity index). Stability of the molecule arising from hyper conjugative interaction, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. Atomic charges obtained by Mulliken population analysis and NBO analysis are compared. Thermodynamic properties (heat capacity, entropy and enthalpy) of the title compound at different temperatures are also calculated. PMID- 25795609 TI - Multispectral studies of DNA binding, antioxidant and cytotoxic activities of a new pyranochromene derivative. AB - The binding properties of a new pyranochromene derivative, 2-amino-4-(3 hydroxyphenyl)-5-oxo-4H, 5H-pyrano-[3, 2-c] chromene-3-carbonitrile (3-HC) with calf thymus DNA (ctDNA) have been investigated by UV-vis absorption, circular dichroism, fluorescence spectroscopy and viscosity measurement. These results indicated that 3-HC can interact with DNA through non-intercalative mode and the intrinsic binding constant (Kb) for 3-HC with DNA was estimated to be 3.6 * 10(3)M(-1). The antioxidant activity experiments show that 3-HC also exhibit good antioxidant activity in DPPH free radical scavenging and ferric reducing ability methods. Moreover, 3-HC exhibited cytotoxic activity against K562, human chronic myelogenous leukemia cells, with IC50 value of 146 MUM and the cells responded to the treatment with mostly through apoptosis. PMID- 25795610 TI - Two different spectrophotometric determinations of potential anticancer drug and its toxic metabolite. AB - Flutamide is a hormone therapy used for men with advanced prostate cancer. Flutamide is highly susceptible to hydrolysis with the production of 3 (trifluoromethyl)aniline, which is reported to be one of its toxic metabolites, impurities and related substances according to BP and USP. Flutamide was found to be stable when exposed to oxidation by 30% hydrogen peroxide and direct sunlight for up to 4h. Two accurate and sensitive spectrophotometric methods were used for determination of flutamide in bulk and in pharmaceutical formulations. Method (I) is the area under curve (AUC) spectrophotometric method that depends on measuring the AUC in the wavelength ranges of 275-305 nm and 350-380nm and using Cramer's rule. The linearity range was found to be 1-35 MUg/mL and 0.5-16 MUg/mL for the drug and the degradate, respectively. In method (II), combination of the isoabsorptive and dual wavelength spectrophotometric methods was used for resolving the binary mixture. The absorbance at 249.2 nm (lambdaiso) was used for determination of total mixture concentration, while the difference in absorbance between 232 nm and 341.2 nm was used for measuring the drug concentration. By subtraction, the degradate concentration was obtained. Beer's law was obeyed in the range of 2-35 MUg/mL and 0.5-20 MUg/mL for the drug and its degradate, respectively. The two methods were validated according to USP guidelines and were applied for determination of the drug in its pharmaceutical dosage form. Moreover AUC method was used for the kinetic study of the hydrolytic degradation of flutamide. The kinetic degradation of flutamide was found to follow pseudo-first order kinetics and is pH and temperature dependent. Activation energy, kinetic rate constants and t1/2 at different temperatures and pH values were calculated. PMID- 25795611 TI - Inelastic and elastic neutron scattering studies of the vibrational and reorientational dynamics, crystal structure and solid-solid phase transition in [Mn(OS(CH3)2)6](ClO4)2 supported by theoretical (DFT) calculations. AB - The vibrational and reorientational dynamics of CH3 groups from (CH3)2SO ligands in the high- and low-temperature phases of [Mn(OS(CH3)2)6](ClO4)2 were investigated by quasielastic and inelastic incoherent neutron scattering (QENS and IINS) methods. The results show that above the phase transition temperature (detected earlier by differential scanning calorimetry (DSC) at TC5(c)=222.9K on cooling and at TC5(h)=225.4K on heating) the CH3 groups perform fast (tauR~10( 12)-10(-13)s) reorientational motions. These motions start to slow down below TC5(c) Neutron powder diffraction (NPD) measurements, performed simultaneously with QENS and IINS, indicated that this phase transition is associated with a change of the crystal structure, too. Theoretical infrared absorption, Raman and inelastic incoherent neutron scattering spectra were calculated using DFT method (B3LYP functional, LANL2DZ ECP basis set (on Mn atom) and 6-311+G(d,p) basis set (on C, H, S, O atoms) for the isolated equilibrium model (isolated [Mn(DMSO)6](2+) cation and ClO4(-) anion). Calculated spectra show a good agreement with the experimental spectra (FT-IR, RS and IINS). The comparison of the results obtained by these complementary methods was made. PMID- 25795612 TI - Spectroscopic investigation of amber color silicate glasses and factors affecting the amber related absorption bands. AB - The effects of carbon, Fe2O3 and Na2SO4 contents on the amber color of glass with composition (wt%) 64.3 SiO2, 25.7 CaO, 10 Na2O were studied. The effect of some additives that could be found in glass batch or cullets on the amber related absorption band(s) was also studied. An amber related absorption band due to the chromophore Fe(3+)O3S(2-) was recorded at 420 nm with shoulder at 440 nm. A second amber related band recorded at 474 nm with shoulder at 483 nm was assigned to FeS. Increasing melting time at 1400 degrees C up to 6h caused fainting of the amber color, decreases the intensities of the amber related bands and shifted the first band to 406 nm. Addition of ZnO, Cu2O and NaNO3 to the glass produced decolorizing effect and vanishing of the amber related bands. The effects of melting time and these additives were explained on the bases of destruction the amber chromophore and its conversion into Fe(3+) in tetrahedral sites or ZnS. Addition of Se intensifies the amber related bands and may cause dark coloration due to the formation of Se degrees and polyselenide. Amber color can be monitored through measuring the absorption in the range 406-420 nm. PMID- 25795613 TI - Theoretical study of the C-H/O-H stretching vibrations in malonaldehyde. AB - IR and Raman spectra of the malonaldehyde molecule and its deuterated analogues were calculated in the B3LYP/cc-pVQZ approximation. Anharmonicity effects were taken into account both in the context of a standard model of the second order perturbation theory and by constructing the potential energy surfaces (PES) with a limited number of dimensions using the Cartesian coordinates of the hydroxyl hydrogen atom and the stretching coordinates of S-N, C-D, O-H, and O-D bonds. It was shown that in each of the two equivalent forms of the molecule, besides the global minimum, an additional local minimum at the PES is formed with the energy more than 3,000 cm(-1) higher than the energy in the global minimum. Calculations carried out by constructing the 2D and 3D PESs indicate a high anharmonicity level and multiple manifestations of the stretching O-N vibrations, despite the fact that the model used does not take into account the splitting of the ground state and excited vibrational energy levels. In particular, the vibration with the frequency 3,258 cm(-1) may be associated with proton transfer to the region of a local minimum of energy. Comparing the results obtained with the experimental data presented in the literature allowed us to propose a new variant of bands assignments in IR and Raman spectra of the molecule in the spectral region 2,500-3,500 cm(-1). PMID- 25795614 TI - Biotinidase deficiency due to a de novo mutation or gonadal mosaicism in a first child. AB - Biotinidase deficiency (BD), which is caused by BTD genetic lesions, if untreated, can result in neurological and cutaneous manifestations. Biotin supplementation can improve or prevent symptoms. We herewith present a family, which we studied at biochemical and molecular level, after identifying the proband through a newborn screening programme. BTD gene molecular analysis showed the proband to be compound heterozygous for the c.1330G>C p.(Asp444His) mild known variant, and for the c.1475 C>T p.(Thr492Ile) new variant. Bioinformatic analysis allowed us to confirm the pathogenic role of the newly identified variant. The proband's father, who exhibited low biotinidase (BTD) enzyme activity, was homozygous for the mild variant, whereas the proband's mother, who exhibited borderline BTD values, the BTD mutation carrier status could not be detected. This is the first description of a patient with BD harbouring a variant whose origin is either de novo or the consequence of gonadal mosaicism. BTD molecular analysis and bioinformatic tools for the evaluation of pathogenicity of newly identified variants are necessary for diagnostic purposes (i.e., clarifying borderline enzyme assays and the carrier status of parents), and for genetic counselling. PMID- 25795615 TI - Editorial. Advances in biofuels and chemicals from algae. PMID- 25795616 TI - Speaking with one voice: A study of the values of new nursing graduates and the implications for educators. AB - This paper explores the values and meaning of the nursing profession utilising a sample of new nursing graduates just entering the workforce. Nursing practice has shifted over the course of the 20th and 21st Centuries, with varied and shifting positions on the values and philosophy that underpin it. Reported here is data from a cohort of Australian and New Zealand nurse graduates (n = 97) who submitted survey responses to the open-ended question "I love nursing and/or midwifery because ..." as part of the web-based Graduate e-Cohort Study (GeS). Data were analysed relying on qualitative content analysis. Five themes emerged from the complete analysis of the responses. These themes were; self and personal development, immediate reward (intrinsic work values); meaning making and greater good, mobilities and momentum (extrinsic work values); and person-centred care (social work value). The findings suggest that while economic, workplace, organisational and professional influences may have influenced nursing work, when asked about what they value in nursing, the traditional values emerge as central. Nursing curricula and nurse educators would do well to promote these values and meanings leading to the education and recruitment of individuals suited to the work of nursing. PMID- 25795617 TI - Mediation skills for conflict resolution in nursing education. AB - Encountering conflicts among family members in hospital produces burnout among nurses, implying a need for alternative dispute resolution training. However, current nursing education pays more attention to counselling skills training than to mediation. The present report examines the fundamental concepts of mediation, including its nature, basic assumptions and values, and compares those with counselling. Its implications may open a discussion on enhancing contemporary nursing education by providing mediation training in the workplace to nurses so that they can deal more effectively with disputes. PMID- 25795618 TI - The Anopheles stephensi odorant binding protein 1 (AsteObp1) gene: a new molecular marker for biological forms diagnosis. AB - Anopheles (Cellia) stephensi Liston 1901 is known as an Asian malaria vector. Three biological forms, namely "mysorensis", "intermediate", and "type" have been earlier reported in this species. Nevertheless, the present morphological and molecular information is insufficient to diagnose these forms. During this investigation, An. stephensi biological forms were morphologically identified and sequenced for odorant-binding protein 1 (Obp1) gene. Also, intron I sequences were used to construct phylogenetic trees. Despite nucleotide sequence variation in exon of AsteObp1, nearly 100% identity was observed at the amino acid level among the three biological forms. In order to overcome difficulties in using egg morphology characters, intron I sequences of An. stephensi Obp1 opens new molecular way to the identification of the main Asian malaria vector biological forms. However, multidisciplinary studies are needed to establish the taxonomic status of An. stephensi. PMID- 25795619 TI - Occurrence of and risk factors for Strongyloides stercoralis infection in South East Asia. AB - The soil-transmitted nematode, Strongyloides stercoralis is one of the most neglected of all neglected tropical diseases. It is globally distributed, favouring the humid, wet climates of the tropics and subtropics. Inadequate sanitary conditions promote the spread of S. stercoralis infection. In South-East Asia, many countries provide the ideal ecological and economic setting for high S. stercoralis infection rates. Yet, in most of these countries, little is known about the actual prevalence and distribution of S. stercoralis. One reason for this lack of knowledge pertains to the time- and resource-intensive diagnostic methods used to detect S. stercoralis infection. The Koga Agar culture method and the Baermann method are considered to be the best coprological diagnostic methods for field settings today. Both detect the parasite with high sensitivity. This sensitivity can be increased further by examining stool samples for several consecutive days, thereby increasing the chances of detecting low-intensity chronic infections. Diagnostic challenges, however, lead to the omission of S. stercoralis in studies of soil-transmitted helminths and few studies focus on S. stercoralis, specifically. These factors lead to an underreporting of the nematode's prevalence, not only in South-East Asia but worldwide. We have reviewed the scientific literature of the last 25 years and estimated country wide prevalence rates for South-East Asia. We aim to summarise what is known today about the prevalence of S. stercoralis in South-East Asia, as well as to ascertain the risk factors and diagnostic methods most commonly applied. PMID- 25795620 TI - WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 2: breast. AB - The breast section of these Guidelines and Recommendations for Elastography produced under the auspices of the World Federation of Ultrasound in Medicine and Biology (WFUMB) assesses the clinically used applications of all forms of elastography used in breast imaging. The literature on various breast elastography techniques is reviewed, and recommendations are made on evidence based results. Practical advice is given on how to perform and interpret breast elastography for optimal results, with emphasis placed on avoiding pitfalls. Artifacts are reviewed, and the clinical utility of some artifacts is discussed. Both strain and shear wave techniques have been shown to be highly accurate in characterizing breast lesions as benign or malignant. The relationship between the various techniques is discussed, and recommended interpretation based on a BI RADS-like malignancy probability scale is provided. This document is intended to be used as a reference and to guide clinical users in a practical way. PMID- 25795621 TI - Oscillating Square Wave Transcranial Direct Current Stimulation (tDCS) Delivered During Slow Wave Sleep Does Not Improve Declarative Memory More Than Sham: A Randomized Sham Controlled Crossover Study. AB - BACKGROUND: A 2006 trial in healthy medical students found that anodal slow oscillating tDCS delivered bi-frontally during slow wave sleep had an enhancing effect in declarative, but not procedural memory. Although there have been supporting animal studies, and similar findings in pathological groups, this study has not been replicated, or refuted, in the intervening years. We therefore tested these earlier results for replication using similar methods with the exception of current waveform (square in our study, nearly sinusoidal in the original). OBJECTIVE/HYPOTHESIS: Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory. METHODS: Twelve students (mean age 25, 9 women) free of medical problems underwent two testing conditions (active, sham) in a randomized counterbalanced fashion. Active stimulation consisted of oscillating square wave tDCS delivered during early Non-Rapid Eye Movement (NREM) sleep. The sham condition consisted of setting-up the tDCS device and electrodes, but not turning it on during sleep. tDCS was delivered bi-frontally with anodes placed at F3/F4, and cathodes placed at mastoids. Current density was 0.517 mA/cm(2), and oscillated between zero and maximal current at a frequency of 0.75 Hz. Stimulation occurred during five-five minute blocks with 1-min inter-block intervals (25 min total stimulation). The primary outcomes were both declarative memory consolidation measured by a paired word association test (PWA), and non declarative memory, measured by a non-dominant finger-tapping test (FTT). We also recorded and analyzed sleep EEG. RESULTS: There was no difference in the number of paired word associations remembered before compared to after sleep [(active = 3.1 +/- 3.0 SD more associations) (sham = 3.8 +/- 3.1 SD more associations)]. Finger tapping improved, (non-significantly) following active stimulation [(3.6 +/- 2.7 SD correctly typed sequences) compared to sham stimulation (2.3 +/- 2.2 SD correctly typed sequences)]. CONCLUSION: In this study, we failed to find improvements in declarative or performance memory and could not replicate an earlier study using nearly identical settings. Specifically we failed to find a beneficial effect on either overnight declarative or non-declarative memory consolidation via square-wave oscillating tDCS intervention applied bi-frontally during early NREM sleep. It is unclear if the morphology of the tDCS pulse is critical in any memory related improvements. PMID- 25795622 TI - Trigeminal Nerve Stimulation (TNS) for Post-traumatic Stress Disorder: A Case Study. PMID- 25795623 TI - Natural assembly of platelet lysate-loaded nanocarriers into enriched 3D hydrogels for cartilage regeneration. AB - The role of Platelet Lysates (PLs) as a source of growth factors (GFs) and as main element of three-dimensional (3D) hydrogels has been previously described. However, the resulting hydrogels usually suffer from high degree of contraction, limiting their usefulness. This work describes the development of a stable biomimetic 3D hydrogel structure based on PLs, through the spontaneous assembling of a high concentration of chitosan-chondroitin sulfate nanoparticles (CH/CS NPs) with PLs loaded by adsorption. The interactions between the NPs and the lysates resemble the ones observed in the extracellular matrix (ECM) native environment between glycosaminoglycans and ECM proteins. In vitro release studies were carried out focusing on the quantification of PDGF-BB and TGF-beta1 GFs. Human adipose derived stem cells (hASCs) were entrapped in these 3D hydrogels and cultured in vitro under chondrogenic stimulus, in order to assess their potential use for cartilage regeneration. Histological, immunohistological and gene expression analysis demonstrated that the PL-assembled constructs entrapping hASCs exhibited results similar to the positive control (hASCS cultured in pellets), concerning the levels of collagen II expression and immunolocalization of collagen type I and II and aggrecan. Moreover, the deposition of new cartilage ECM was detected by alcian blue and safranin-O positive stainings. This work demonstrates the potential of PLs to act simultaneously as a source/carrier of GFs and as a 3D structure of support, through the application of a "bottom-up" approach involving the assembly of NPs, resulting in an enriched construct for cartilage regeneration applications. PMID- 25795625 TI - Bilateral central serous chorioretinopathy associated with endogenous Cushing's syndrome. PMID- 25795624 TI - Evaluation of the potential of doxorubicin loaded microbubbles as a theranostic modality using a murine tumor model. AB - In this study, a novel phospholipid-based microbubble formulation containing doxorubicin and perfluoropropane gas (DLMB) was developed. The DLMBs were prepared by mechanical agitation of a phospholipid dispersion in the presence of perfluoropropane (PFP) gas. An anionic phospholipid, distearoyl phosphatidylglycerol (DSPG) was selected to load doxorubicin in the microbubbles by means of electrostatic interaction. The particle size, zeta potential, echogenicity and stability of the DLMBs were measured. Drug loading was ? 92%. The potential of the DLMBs for use as a theranostic modality was evaluated in tumor bearing mice. Gas chromatography analysis of PFP showed significant enhancement of PFP retention when doxorubicin was used at concentrations of 10 82% equivalent to DSPG. The inhibitory effects on the proliferation of B16BL6 melanoma murine cells in vitro were enhanced using a combination of ultrasound (US) irradiation and DLMBs. Moreover, in vivo DLMBs in combination with (US) irradiation significantly inhibited the growth of B16BL6 melanoma tumor in mice. Additionally, US echo imaging showed high contrast enhancement of the DLMBs in the tumor vasculature. These results suggest that DLMBs could serve as US triggered carriers of doxorubicin as well as tumor imaging agents in cancer therapy. PMID- 25795626 TI - The 2014 Canadian Diabetes Association-Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes Young Scientist Award recipient is Dr. Robert Screaton. PMID- 25795627 TI - Letter to the editor: Temporomandibular joint disorders' impact, research models, and implications for regenerative approaches. PMID- 25795628 TI - Response to letter to the editor, "Temporomandibular joint disorders' impact, research models, and implications for regenerative approaches". PMID- 25795629 TI - Nrf2 activation attenuates both orthodontic tooth movement and relapse. AB - During orthodontic tooth movement, osteoclasts resorb the alveolar bone at the compress side of periodontium. Reactive oxygen species (ROS) works as intracellular signaling molecules of RANKL during osteoclastogenesis, although ROS has cytotoxicity against cells such as lipid oxidation. To deal with oxidative stress, cells have a defense system that is scavenging ROS by augmented antioxidative stress enzymes via transcriptional regulation with nuclear factor E2-related factor 2 (Nrf2). Previously, we reported that augmented antioxidative stress enzymes by Nrf2-gene transfer inhibited bone destruction. In the present study, we examined the effects of Nrf2 activation on osteoclastogenesis and, thereby, orthodontic tooth movement and orthodontic relapse. Mouse macrophage cell line RAW264.7 cells were used as osteoclast progenitor cells and stimulated with recombinant RANKL (100 ng/mL) with or without Nrf2 activator sulforaphane (SFN) and epigallocatechin gallate (EGCG) or ROS scavenger catechin. Osteoclastogenesis, resorption activity, and osteoclast marker gene expression were examined. Intracellular ROS was analyzed by flow cytometry. Maxillary first molars of C57BL6 male mice were moved palatally with 0.012-inch NiTi wire (100-mN force); SFN or EGCG was injected into the palatal gingiva once a week; and phosphate buffered saline was injected on the contralateral side. Tooth movement was monitored using a stone model with precise impression, and the amount of the tooth movement was compared among groups. SFN and EGCG significantly, but catechin weakly, inhibited RANKL-mediated osteoclastogenesis in vitro. Western blot analysis revealed that SFN and EGCG augmented the nuclear translocation of Nrf2 and the expression of anti-oxidative stress enzymes such as HO-1, although catechin did not. SFN and EGCG significantly, but catechin weakly, attenuated the intracellular ROS. Finally, animal experiment revealed that both SFN and EGCG successfully inhibited the orthodontic tooth movement. Additionally, SFN inhibited the relapse. These results suggest that Nrf2 activation could be therapeutic target for the anchorage enforcement in orthodontic treatment and pharmacologic retention against relapse. PMID- 25795630 TI - Multi-scale textural feature extraction and particle swarm optimization based model selection for false positive reduction in mammography. AB - The high number of false positives and the resulting number of avoidable breast biopsies are the major problems faced by current mammography Computer Aided Detection (CAD) systems. False positive reduction is not only a requirement for mass but also for calcification CAD systems which are currently deployed for clinical use. This paper tackles two problems related to reducing the number of false positives in the detection of all lesions and masses, respectively. Firstly, textural patterns of breast tissue have been analyzed using several multi-scale textural descriptors based on wavelet and gray level co-occurrence matrix. The second problem addressed in this paper is the parameter selection and performance optimization. For this, we adopt a model selection procedure based on Particle Swarm Optimization (PSO) for selecting the most discriminative textural features and for strengthening the generalization capacity of the supervised learning stage based on a Support Vector Machine (SVM) classifier. For evaluating the proposed methods, two sets of suspicious mammogram regions have been used. The first one, obtained from Digital Database for Screening Mammography (DDSM), contains 1494 regions (1000 normal and 494 abnormal samples). The second set of suspicious regions was obtained from database of Mammographic Image Analysis Society (mini-MIAS) and contains 315 (207 normal and 108 abnormal) samples. Results from both datasets demonstrate the efficiency of using PSO based model selection for optimizing both classifier hyper-parameters and parameters, respectively. Furthermore, the obtained results indicate the promising performance of the proposed textural features and more specifically, those based on co-occurrence matrix of wavelet image representation technique. PMID- 25795631 TI - Quick histochemical staining method for measuring lactate dehydrogenase C4 activity in human spermatozoa. AB - The enzyme activity of lactate dehydrogenase C4 (LDH-C4, due to tetrameric nature of C-subunit) has been proposed as an important parameter in evaluating sperm motility and semen quality. A novel histochemical staining method for detecting LDH-C4 activity in human spermatozoa is described in this report. The staining working solution comprises sodium 2-hydroxybutyrate (an affinity substrate of LDH C4), nitrotetrazolium blue chloride (NBT), nicotinamide adenine dinucleotide (NAD) and naphthol blue. The positive products were purple black lumps concentrated in the neck segment of the spermatozoa and weakly in the middle piece. A normal reference range for the integral enzyme activity was constructed from 120 healthy males based upon the scoring criteria. The study further compared the staining method with the routine spectrophotometry technique in terms of the results of 96 cases with infertile status. Moreover, we found the down-regulated LDH-C4 expression was significantly correlated with the lowered enzyme activity (r=0.865, P=0.000). Our data suggest that the histochemical staining method hallmarks a relatively high accuracy and may be a better alternative for measuring LDH-C4 activity in human spermatozoa. PMID- 25795632 TI - In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy? AB - BACKGROUND: The Oncotype DX recurrence score (RS) assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy in patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer. Patients with high RS tumors have substantial benefit, and patients with low RS tumors have minimal if any benefit from chemotherapy. Tumor size is used as a key parameter when selecting patients for neoadjuvant chemotherapy. The aim of this study was to assess the distribution of RS in patients selected for neoadjuvant chemotherapy primarily according to tumor size. PATIENTS AND METHODS: Patients with ER-positive and HER2-negative tumors that were node-negative or had no more than 1 positive node from three trials were included in this study. Oncotype DX was performed at Genomic Health, Inc., blinded to the clinical data. Descriptive statistics were calculated for distribution of RS for all cases. RESULTS: Of 277 patients, 96 met eligibility criteria, and 81 had sufficient material for analysis. Median tumor size was 40 mm (interquartile range [IQR], 30-50 mm). Grade I, II, and III were observed in 13, 49, and 17 cases, respectively. There was a wide distribution of RS with a median of 21.4 (IQR, 16.05-26.75). In total, 23 (28.3%) had high, 28 (34.6%) intermediate, and 30 (37%) low RS results. CONCLUSION: The RS may provide relevant information for neoadjuvant treatment decisions in select patients both in clinical practice and in studies. Inclusion of low RS disease patients in neoadjuvant trials will likely only dilute the ability to look at treatment effects. PMID- 25795633 TI - The anticipated next season of EGFR inhibitors. PMID- 25795634 TI - Perspectives of African Americans on lung cancer: a qualitative analysis. AB - BACKGROUND: Disparities in incidence and mortality for lung cancer in African Americans are well documented; however, the extent to which disparities reflect differences in patient perceptions of tobacco and lung cancer treatment is unclear. The objective of this study was to explore African Americans' knowledge of lung cancer, perceived risk, interest in smoking cessation, attitudes toward lung cancer treatment, and lung cancer diagnosis and treatment experiences. PATIENTS AND METHODS: The cohort comprised 32 African-American current and former smokers without a cancer diagnosis who participated in focus groups and 10 African Americans with lung cancer who participated in in-depth interviews. Transcripts were analyzed using a modified grounded theory approach. RESULTS: Participants without a cancer diagnosis were aware of the link between smoking and lung cancer, the common symptoms of the disease, and its poor prognosis. They desired specific, personalized smoking-cessation information. If diagnosed, the majority reported, they would seek medical care. Most believed that insurance and socioeconomic factors were more likely to affect treatment access than racial discrimination. Participants with a cancer diagnosis were also aware of the relationship between smoking and lung cancer. They felt their treatment plans were appropriate and trusted their physicians. Most did not believe that race affected their care. CONCLUSION: This qualitative study suggests that African American smokers are aware of the relationship between smoking and lung cancer and are interested in smoking-cessation treatment. These data also indicate that lung cancer disparities are unlikely to be associated with differential willingness to receive care but that African Americans may perceive financial and insurance barriers to lung cancer treatment. PMID- 25795635 TI - Gefitinib and erlotinib in metastatic non-small cell lung cancer: a meta-analysis of toxicity and efficacy of randomized clinical trials. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC. METHODS: We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies. RESULTS: We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations. CONCLUSION: Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC. PMID- 25795637 TI - Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors. AB - BACKGROUND: This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS: Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS: Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade <=2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and >=400 mg once daily. CONCLUSION: Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE MRI. Disease stabilization >6 months was observed in 7 of 51 patients. PMID- 25795636 TI - Aprepitant and fosaprepitant: a 10-year review of efficacy and safety. AB - Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with anticancer treatment that can have a significant adverse impact on patient health-related quality of life and that can potentially undermine the effectiveness of chemotherapy. Traditional regimens to prevent CINV generally involved a combination of a corticosteroid plus a 5-hydroxytryptamine (5HT3) receptor antagonist (RA). In the past 10 years, antiemetic treatment has greatly advanced with the availability of the neurokinin-1 receptor antagonist (NK1 RA) aprepitant and its prodrug fosaprepitant. NK1 RAs have a different mechanism of action in CINV than corticosteroids and 5HT3 RAs, thus their use can complement traditional antiemetic drugs and can enhance control of CINV. This review examined accumulated data regarding the safety and efficacy of aprepitant and fosaprepitant over the decade since the first regulatory approval. Data from key studies of aprepitant and fosaprepitant in the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy were explored, as were recommendations in currently available guidelines for their use. In addition, their use as antiemetic therapy in special patient populations was highlighted. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are presented. PMID- 25795638 TI - A novel inactivating mutation of the LH/chorionic gonadotrophin receptor with impaired membrane trafficking leading to Leydig cell hypoplasia type 1. AB - OBJECTIVE: The LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation. METHODS: Five affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed. RESULTS: The five affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C terminal intracellular domain. In vitro studies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin. CONCLUSIONS: This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function. PMID- 25795640 TI - Evaluation of Patient Satisfaction After Using Prefilled Insulin Pen in Real Life in Lithuania. PMID- 25795639 TI - Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies. AB - BACKGROUND: Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme. PATIENTS AND METHODS: We report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a "3+3" dose escalation design. RESULTS: Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints. CONCLUSION: Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy. PMID- 25795641 TI - Safe and Efficacious Use of Automated Bolus Advisors in Individuals Treated With Multiple Daily Insulin Injection (MDI) Therapy: Lessons Learned From the Automated Bolus Advisor Control and Usability Study (ABACUS). AB - Numerous studies have shown that use of integrated automated bolus advisors (BAs) provides significant benefits to individuals using insulin pump devices, including improved glycemic control and greater treatment satisfaction. Within the past few years, BA devices have been developed specifically for individuals treated with multiple daily insulin injection (MDI) therapy; however, many clinicians who treat these individuals may be unfamiliar with insulin pump therapy and, thus, BA use. Findings from the Automated Bolus Advisor Control and Usability Study (ABACUS) revealed that BA use can be efficacious and clinically meaningful in MDI therapy, and that most patients are willing and able to use this technology appropriately when adequate clinical support is provided. The purpose of this article is to review key learnings from ABACUS and provide practical advice for initiating BA use and monitoring therapy. PMID- 25795642 TI - Enhancement of TIA management in primary care with a novel electronic tool. PMID- 25795643 TI - Genetic dosage compensation via co-occurrence of PMP22 duplication and PMP22 deletion. PMID- 25795644 TI - Clinical and electrographic findings in epileptic vertigo and dizziness: a systematic review. AB - OBJECTIVE: Seizures can cause vestibular symptoms, even without obvious epileptic features. We sought to characterize epileptic vertigo or dizziness (EVD) to improve differentiation from nonepileptic causes, particularly when vestibular symptoms are the sole manifestation. METHODS: We conducted a systematic review with electronic (Medline) and manual search for English-language studies (1955 2014). Two independent reviewers selected studies. Study/patient characteristics were abstracted. We defined 3 study population types: (1) seizures, some experiencing vertigo/dizziness (disease cohort); (2) vertigo/dizziness, some due to seizures (symptom cohort); (3) vertigo/dizziness due to seizures in all patients (EVD-only cohort). RESULTS: We identified 84 studies describing 11,354 patients (disease cohort = 8,129; symptom cohort = 2,965; EVD-only cohort = 260). Among 1,055 EVD patients in whom a distinction could be made, non-isolated EVD was present in 8.5%, isolated EVD in 0.8%. Thorough diagnostic workups (ictal EEG, vestibular testing, and brain MRI to exclude other causes) were rare (<0.1%). Ictal EEG was reported in 487 (4.3%), formal neuro-otologic assessment in 1,107 (9.7%). Localized EEG abnormalities (n = 350) were most frequently temporal (79.8%) and uncommonly parietal (11.8%). Duration of episodic vestibular symptoms varied, but was very brief (<30 seconds) in 69.6% of isolated EVD and 6.9% of non-isolated EVD. CONCLUSIONS: Non-isolated EVD is much more prevalent than isolated EVD, which appears to be rare. Diagnostic evaluations for EVD are often incomplete. EVD is primarily associated with temporal lobe seizures; whether this reflects greater epidemiologic prevalence of temporal lobe seizures or a tighter association with dizziness/vertigo presentations than with other brain regions remains unknown. Consistent with clinical wisdom, isolated EVD spells often last just seconds, although many patients experience longer spells. PMID- 25795645 TI - Cluster randomized controlled trial of TIA electronic decision support in primary care. AB - OBJECTIVE: To test if TIA/stroke electronic decision support in primary care improves management. METHODS: Multicenter, single-blind, parallel-group, cluster randomized, controlled trial comparing TIA/stroke electronic decision support guided management with usual care. Main outcomes were guideline adherence and 90 day stroke risk. Secondary outcomes were cerebrovascular/vascular/death/adverse events, cost, and user feedback. Main analysis was logistic regression with a normal random effect for clusters using a generalized linear mixed model. RESULTS: Twenty-nine clinics were randomized to intervention, 27 to control, recruiting 172 and 119 eligible patients. More intervention patients received guideline-adherent care (131/172; 76.2%) than control patients (49/119; 41.2%) (adjusted odds ratio [OR] 4.57; 95% confidence interval [CI] 2.39-8.71; p < 0.001). Ninety-day stroke occurred in 2/172 (1.2%) intervention and 5/119 (4.2%) control patients (OR 0.27; 95% CI 0.05-1.41; p = 0.098). Ninety-day TIA or stroke occurrence was lower in the intervention group, 4/172 (2.3%) compared to 10/119 (8.5%) control (adjusted OR 0.26; 95% CI 0.70-0.97; p = 0.045). Fewer vascular events/deaths occurred in intervention, 6/172 (3.5%), than in control patients, 14/119 (11.9%) (adjusted OR 0.27; 95% CI 0.09-0.78; p = 0.016). Treatment cost ratio of 0.65 (95% CI 0.47-0.91; p = 0.013) favored the intervention without increased adverse events. Clinician feedback was positive. CONCLUSION: Primary care use of the TIA/stroke electronic decision support tool improves guideline adherence, safely reduces treatment cost, achieves positive user feedback, and may reduce cerebrovascular and vascular event risk following TIA/stroke. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a primary care electronic decision support tool improves guideline adherence and might reduce 90-day stroke risk. PMID- 25795646 TI - Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. AB - OBJECTIVE: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population. RESULTS: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. CONCLUSION: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS. PMID- 25795647 TI - DNA methylation slows effects of C9orf72 mutations: An epigenetic brake on genetic inheritance. PMID- 25795649 TI - Understanding shared decision making in pediatric otolaryngology. AB - OBJECTIVE: The aim of this study was to describe the level of decisional conflict experienced by parents considering surgery for their children and to determine if decisional conflict and perceptions of shared decision making are related. STUDY DESIGN: Prospective cohort study. SETTING: Academic pediatric otolaryngology clinic. SUBJECTS AND METHODS: Sixty-five consecutive parents of children who underwent surgical consultation for elective otolaryngological procedures were prospectively enrolled. Participants completed the Shared Decision Making Questionnaire and the Decisional Conflict Scale. Surgeons completed the Shared Decision Making Questionnaire-Physician version. RESULTS: Eleven participants (16.9%) scored over 25 on the Decisional Conflict Scale, a previously defined clinical cutoff indicating significant decisional conflict. Parent years of education and parent ratings of shared decision making were significantly correlated with decisional conflict (positively and negatively correlated, respectively). A logistic regression indicated that shared decision making but not education predicted the presence of significant decisional conflict. Parent and physician ratings of shared decision making were not related, and there was no correlation between physician ratings of shared decision making and parental decisional conflict. CONCLUSIONS: Many parents experienced considerable decisional conflict when making decisions about their child's surgical treatment. Parents who perceived themselves as being more involved in the decision-making process reported less decisional conflict. Parents and physicians had different perceptions of shared decision making. Future research should develop and assess interventions to increase parents' involvement in decision making and explore the impact of significant decisional conflict on health outcomes. PMID- 25795650 TI - Mid- to Long-term Clinical Outcome and Gait Biomechanics After Realignment Surgery in Asymmetric Ankle Osteoarthritis. AB - BACKGROUND: Joint-preserving, realignment surgical procedures have gained increasing popularity as treatment of asymmetric early- and mid-stage ankle osteoarthritis. The aim of the present study was to quantify bilateral gait biomechanics in patients who underwent ankle realignment surgery by supramalleolar osteotomies. METHODS: Eight patients, a minimum of 7 years after realignment surgery, and 8 healthy controls were included in this study. Three dimensional instrumented gait analysis was used to assess spatiotemporal parameters, bilateral joint angles, and moments. Furthermore, a clinical evaluation on pain, ankle function, and quality of life was performed. RESULTS: Compared with the healthy controls, the patients walked more slowly, had a smaller sagittal hindfoot range of motion on their affected leg, and had a lower peak ankle dorsiflexion moment (P < .05). There were no significant differences compared with controls for the ranges of motion in the foot segments of the nonaffected foot and for the knee and hip joint ranges of motion and peak moments of both legs. Additionally, patients and controls did not differ in the quality of life score. However, in the pain subscore, the patients reported significantly more pain than the healthy persons. CONCLUSION: Despite different gait biomechanics of the affected foot after ankle realignment surgery, the quality of life for patients was comparable to that of healthy controls. Therefore, supramalleolar osteotomies should be considered as a promising treatment option in patients with asymmetric non-end-stage ankle osteoarthritis. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 25795648 TI - C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence. AB - OBJECTIVE: To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective. METHODS: Twenty patients with a C9orf72 repeat expansion participating in a high resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing. Regional neuronal loss was measured in an independent autopsy series (n = 35) of C9orf72 repeat expansion patients. RESULTS: GM analysis revealed that hippocampus, frontal cortex, and thalamus are associated with hypermethylation and thus appear to be relatively protected from mutant C9orf72. Neuropathologic analysis demonstrated an association between reduced neuronal loss and hypermethylation in hippocampus and frontal cortex. Longitudinal neuroimaging revealed that hypermethylation is associated with reduced longitudinal decline in GM regions protected by hypermethylation and longitudinal neuropsychological assessment demonstrated that longitudinal decline in verbal recall is protected by hypermethylation. CONCLUSIONS: These cross-sectional and longitudinal neuroimaging studies, along with neuropathologic validation studies, provide converging evidence for neuroprotective properties of C9orf72 promoter hypermethylation. These findings converge with prior postmortem studies suggesting that C9orf72 promoter hypermethylation may be a neuroprotective target for drug discovery. PMID- 25795651 TI - Exogenous tyrosol inhibits planktonic cells and biofilms of Candida species and enhances their susceptibility to antifungals. AB - Tyrosol is a quorum-sensing molecule of Candida albicans able to induce hyphal development in the early and intermediate stages of biofilm growth. In the present study, we evaluated the effect of high concentrations of exogenous tyrosol on planktonic cells and biofilms of C. albicans (n = 10) and C. tropicalis (n = 10), and investigated whether tyrosol could be synergic to antifungals that target cellular ergosterol. Antifungal susceptibility and drug interaction against planktonic cells were investigated by the broth microdilution method. Tyrosol was able to inhibit planktonic cells, with MIC values ranging from 2.5 to 5.0 mM for both species. Synergism was observed between tyrosol/amphotericin B (11/20 strains), tyrosol/itraconazole (18/20 strains) and tyrosol/fluconazole (18/20 strains). Exogenous tyrosol alone or combined with antifungals at both 10 * MIC and 50 * MIC were able to reduce biofilm of both Candida species. Mature biofilms were susceptible to tyrosol alone at 50 * MIC or combined with amphotericin at both 10 * MIC and 50 * MIC. On the other hand, tyrosol plus azoles at both 10 * MIC and 50 * MIC enhanced biofilm growth. PMID- 25795652 TI - Biomarkers for the 21st century: listening to the microbiome. AB - The field of environmental research has benefited greatly from the concept of biomarkers, which originally expanded our thinking by opening the "black box" between environmental exposures and manifestations of disease and dysfunction in exposed populations, as laid out in a highly influential article published in 1987 by an expert committee convened by the National Research Council. Advances in biomedical research now challenge us to revise this concept to include the microbiome as a critical stage in the progression from exposure to outcome. Incorporating the microbiome into the basic 1987 model can spur new advances and understanding in environmental health. The human microbiome as a whole comprises the majority of cells and genes of the super-organism (host and microbiome). Site specific microbiomes are the first to encounter xenobiotics, prior to absorption across gut, skin, or respiratory system. A growing literature indicates that these microbial communities may participate in biotransformation and thus constitute a compartment to add to the original biomarker schematic. In addition, these microbiomes interact with the "niche" in which they are located and thus transduce responses to and from the host organism. Incorporating the microbiome into the environmental health paradigm will enlarge our concepts of susceptibility as well as the interactions between xenobiotics and other factors that influence the status and function of these barrier systems. This article reviews the complexities of host:microbiome responses to xenobiotics in terms of redefining toxicokinetics and susceptibility. Our challenge is to consider these multiple interactions between and within the microbiome, the immune system, and other systems of the host in terms of exposure to exogenous agents, including environmental toxicants. PMID- 25795653 TI - Raising the bar for reproducible science at the U.S. Environmental Protection Agency Office of Research and Development. AB - Considerable concern has been raised regarding research reproducibility both within and outside the scientific community. Several factors possibly contribute to a lack of reproducibility, including a failure to adequately employ statistical considerations during study design, bias in sample selection or subject recruitment, errors in developing data inclusion/exclusion criteria, and flawed statistical analysis. To address some of these issues, several publishers have developed checklists that authors must complete. Others have either enhanced statistical expertise on existing editorial boards, or formed distinct statistics editorial boards. Although the U.S. Environmental Protection Agency, Office of Research and Development, already has a strong Quality Assurance Program, an initiative was undertaken to further strengthen statistics consideration and other factors in study design and also to ensure these same factors are evaluated during the review and approval of study protocols. To raise awareness of the importance of statistical issues and provide a forum for robust discussion, a Community of Practice for Statistics was formed in January 2014. In addition, three working groups were established to develop a series of questions or criteria that should be considered when designing or reviewing experimental, observational, or modeling focused research. This article describes the process used to develop these study design guidance documents, their contents, how they are being employed by the Agency's research enterprise, and expected benefits to Agency science. The process and guidance documents presented here may be of utility for any research enterprise interested in enhancing the reproducibility of its science. PMID- 25795654 TI - Factors affecting school physical education provision in England: a cross sectional analysis. AB - BACKGROUND: Attitudes towards physical activity are largely developed during childhood meaning that school physical education classes can have a strong influence. METHODS: National level data of school pupils (n = 21 515) in England were analysed to examine the association between school provision of physical education with sex, age, geographic and socioeconomic factors. RESULTS: Children attending independent schools had more scheduled physical education time (P < 0.001; 95% confidence interval (CI) 18 to 30 extra min per week). This association was true for males (P = 0.024); schools located in the South (P < 0.001; 95% CI 2 to 3) and rural areas (P < 0.001; 95% CI 3 to 5); or with a higher percentage of pupils eligible for free school meals (P < 0.001; 95% CI 3 to 4). Schools in more affluent areas (P < 0.001; 95% CI -1 to -2) and those with lower percentages of pupils from ethnic minorities (P < 0.001; 95% CI -1 to -2) also had higher minutes of physical education provision per week. Regarding age, 93% of schools met the guidelines in Years 1-9; only 45% did in Years 10-13. CONCLUSION: Differences in physical education were found in relation to school type, socioeconomic status and geographical factors. Age-related differences in compliance with guidelines are of concern; ways to increase provision for older children should be investigated. PMID- 25795655 TI - A health equity impact assessment umbrella program (AAPRISS) to tackle social inequalities in health: program description. AB - BACKGROUND: The failure to simultaneously address two objectives (increasing the average health of the population and reducing health inequalities) may have led to what has been observed in France so far: an overall decrease in mortality and increase in inequality. OBJECTIVE: The Apprendre et Agir pour Reduire les Inegalites Sociales de Sante (AAPRISS) methodology is to analyze and modify interventions that are already underway in terms of their potential impact on health inequalities. It relies on partnership between researchers and actors in the health field, as well as policy makers. In this paper, we describe the program and discuss its feasibility and acceptability. METHODS: This program is not a single intervention, but a process aiming at assessing and reshaping existing health programs, therefore acting as a kind of meta-intervention. The program develops scientific and methodological support stemming from co construction methods aimed at increasing equity within the programs. Stakeholders from prevention policy-making and the health care system, as well as researchers, collaborate in defining interventions, monitoring their progress, and choosing indicators, methods and evaluation procedures. The target population is mainly the population of the greater Toulouse area. The steps of the process are described: (1) establishment of AAPRISS governance and partnerships; (2) inclusion of projects; and (3) the projects' process. DISCUSSION: Many partners have rallied around this program, which has been shown to be feasible and acceptable by partners and health actors. A major challenge is understanding each partner's expectations in terms of temporality of interventions, expected outcomes, assessment methods and indicators. Analyzing the projects has been quite feasible, and some modifications have been implemented in them in order to take inequalities in health into account. PMID- 25795656 TI - La contribucion de los Centros Colaboradores de la OMS/OPS en los avances de la promocion de la salud en America Latina. AB - Los "Centros Colaboradores" de la Organizacion Mundial de la Salud (OMS) son instituciones designadas para prestar apoyo estrategico en el desarrollo de los objetivos y la ejecucion de las actividades de la OMS, y para generar capacidad institucional en paises y regiones. En las Americas existen ocho Centros Colaboradores directamente relacionados a la promocion de la salud. Cuatro centros se ubican en Norteamerica y los otros cuatro en America Latina. El proposito de este articulo es describir los Centros Colaboradores de la Region de America Latina. Los centros han sido importantes en el desarrollo de la agenda de promocion de la salud de la region, la consolidacion de la estrategia de entornos saludables y el fortalecimiento de las redes academicas y profesionales de promocion de la salud. PMID- 25795657 TI - Concise review: optimizing expansion of bone marrow mesenchymal stem/stromal cells for clinical applications. PMID- 25795658 TI - Cross-Cultural Adaptation of a Text Message-Based Program for Smoking Cessation in Buenos Aires, Argentina. AB - INTRODUCTION: Few individual-level nonpharmacological interventions are available in Argentina to support smokers who attempt to quit. METHODS: We conducted a cross-cultural adaptation of Stop Smoking with Mobile Phones, an English text message-based tobacco cessation program, in Buenos Aires. The process included English-Spanish translation and back-translation, face validity checking by two local tobacco cessation experts, and a complete review using a structured questionnaire and discussion groups with potential users (current smokers who want to quit or former smokers who quit in the past 6 months). An editing group was responsible for analyzing information collected and preparing adapted messages. Readability of final messages was assessed. RESULTS: Tobacco cessation experts found translated messages suitable for the local setting, although mention of "mate" (a local infusion which can trigger cravings) was recommended. Review of messages by two potential users confirmed most of the messages would help smokers to quit and resulted in minor edits. Potential users who participated in two discussion groups (n = 17, 64.7% female, age range: 30-73) found the content of messages was relevant for cessation and related to their own experiences, although they suggested adding information regarding the negative consequences of smoking. Participants emphasized that messages should be formatted using voseo and informal style and provided feedback on specific words and expressions. Readability of final messages was easy/very easy (Fernandez Huerta Index: 79.93). CONCLUSION: The cross-cultural adaptation of Stop Smoking with Mobile Phones resulted in relevant revisions for the study population, including tone, wording, and pertinent information (eg, smoking consequences). Local acceptability and effectiveness should be confirmed in future studies. PMID- 25795659 TI - Smokeless Tobacco Supply Chain in South Asia: A Comparative Analysis Using the WHO Framework Convention on Tobacco Control. AB - INTRODUCTION: Most South Asian countries are signatories to the WHO Framework Convention for Tobacco Control (FCTC). However, there is little information on the extent to which FCTC standards are effectively implemented for controlling smokeless tobacco (SLT)-used by over 250 million people in the region. We assessed the feasibility of a novel approach based on interviewing the key actors of SLT supply chain and analyzing its findings using standards set by FCTC. METHODS: Using a snowball-sampling technique, we interviewed point-of-sale vendors, wholesale retailers, manufacturers, raw-tobacco retailers, and farmers involved in the supply chain of SLT in Bangladesh, Nepal, and Pakistan. Using a structured-questionnaire, participants were asked about their customer profiles; product types; marketing practices; suppliers; profit margins, awareness and adherence to legislation. RESULTS: We recruited 72% (130/180) of all supply chain actors approached. Findings indicate several loopholes in the existing taxation, regulatory, and inspection systems. A significant proportion of smuggled and counterfeit SLT products are available in the market. Most SLT products are sold without recommended warnings, information on their ingredients, and manufacturers' details. There appear to be no restrictions on sale of SLT products to minors. On the other hand, there are also several incentives built-in the supply chain that makes tobacco farming, SLT manufacturing, and its sale a profitable business. CONCLUSIONS: Our novel approach to study SLT control was successful in identifying and interviewing actors involved in its supply chain. The analysis using FCTC could provide valuable information to policy makers and enable them to effectively regulate SLT products. PMID- 25795661 TI - Overlapping HIV prevention strategies; case report of pre-exposure and postexposure prophylaxes used for a single risk event between two men. AB - A range of prevention strategies have been considered in an attempt to reduce HIV transmission. The use of continuous antiretrovirals (ARVs) in high-risk HIV negative individuals (pre-exposure prophylaxis or PrEP) and the short-term use of ARVs following a high-risk exposure (postexposure prophylaxis or PEP) are among these strategies. We report a case of the contemporaneous use of PEP and PrEP in a sexual liaison between two men.In an attempt to reduce the number of new cases of HIV infection, a range of prevention strategies have been advocated. Prior to the availability of ARV therapy, the key prevention measure was condom promotion and modifying sexual behaviour such as partner number reduction within high-risk groups. This was followed by: the introduction of PEP, treating all HIV cases with ARVs to reduce the probability of transmission (treatment as prevention) and in the past few years the use of PrEP. Case-control, observational and randomised clinical trial data exist to support these strategies. We describe what we believe is the first reported use of PrEP and PEP in a sexual liaison between two men in Sydney. PMID- 25795660 TI - High-Resolution Metabolomics with Acyl-CoA Profiling Reveals Widespread Remodeling in Response to Diet. AB - The availability of acyl-Coenzyme A (acyl-CoA) thioester compounds affects numerous cellular functions including autophagy, lipid oxidation and synthesis, and post-translational modifications. Consequently, the acyl-CoA level changes tend to be associated with other metabolic alterations that regulate these critical cellular functions. Despite their biological importance, this class of metabolites remains difficult to detect and quantify using current analytical methods. Here we show a universal method for metabolomics that allows for the detection of an expansive set of acyl-CoA compounds and hundreds of other cellular metabolites. We apply this method to profile the dynamics of acyl-CoA compounds and corresponding alterations in metabolism across the metabolic network in response to high fat feeding in mice. We identified targeted metabolites (>50) and untargeted features (>1000) with significant changes (FDR < 0.05) in response to diet. A substantial extent of this metabolic remodeling exhibited correlated changes in acyl-CoA metabolism with acyl-carnitine metabolism and other features of the metabolic network that together can lead to the discovery of biomarkers of acyl-CoA metabolism. These findings show a robust acyl-CoA profiling method and identify coordinated changes of acyl-CoA metabolism in response to nutritional stress. PMID- 25795662 TI - Discs large 5, an Essential Gene in Drosophila, Regulates Egg Chamber Organization. AB - Discs large 5 (Dlg5) is a member of the MAGUK family of proteins that typically serve as molecular scaffolds and mediate signaling complex formation and localization. In vertebrates, Dlg5 has been shown to be responsible for polarization of neural progenitors and to associate with Rab11-positive vesicles in epithelial cells. In Drosophila, however, the function of Dlg5 is not well documented. We have identified dlg5 as an essential gene that shows embryonic lethality. dlg5 embryos display partial loss of primordial germ cells (PGCs) during gonad coalescence between stages 12 and 15 of embryogenesis. Loss of Dlg5 in germline and somatic stem cells in the ovary results in the depletion of both cell lineages. Reduced expression of Dlg5 in the follicle cells of the ovary leads to a number of distinct phenotypes, including defects in egg chamber budding, stalk cell overgrowth, and ectopic polar cell induction. Interestingly, loss of Dlg5 in follicle cells results in abnormal distribution of a critical component of cell adhesion, E-cadherin, shown to be essential for proper organization of egg chambers. PMID- 25795663 TI - The maintenance of single-locus polymorphism by maternal selection. AB - Population geneticists have long been interested in the ability of natural selection to maintain the levels of standing variation observed in natural populations. Here, we study the polymorphism-maintaining properties of maternal selection, in which the fitness of an individual is a function of its own and its mother's genotype. Using a model proposed by Gavrilets, we first estimate the proportion of parameter/state space that preserves allelic variation, before investigating the construction of polymorphism over time through the joint action of mutation and selection. These two methods, the "parameter-space" and "constructionist" approaches, respectively, enable us to draw some general conclusions. We argue that, even though the proportion of parameter-state space allowing multiallele polymorphism is greater under maternal selection than under the standard model of constant viability selection, the former is, in fact, less likely to maintain large numbers of alleles. Nevertheless, variation that is balanced by maternal selection is likely to show elements of heterozygous advantage and be resistant to depletion by genetic drift. We observe that the population mean fitness frequently decreases after the successful invasion of a new mutation, but such declines are usually temporary. PMID- 25795664 TI - Genetic Interaction Landscape Reveals Critical Requirements for Schizosaccharomyces pombe Brc1 in DNA Damage Response Mutants. AB - Brc1, which was first identified as a high-copy, allele-specific suppressor of a mutation impairing the Smc5-Smc6 holocomplex in Schizosaccharomyces pombe, protects genome integrity during normal DNA replication and when cells are exposed to toxic compounds that stall or collapse replication forks. The C terminal tandem BRCT (BRCA1 C-terminus) domain of fission yeast Brc1 docks with phosphorylated histone H2A (gammaH2A)-marked chromatin formed by ATR/Rad3 checkpoint kinase at arrested and damaged replication forks; however, how Brc1 functions in relation to other genome protection modules remains unclear. Here, an epistatic mini-array profile reveals critical requirements for Brc1 in mutants that are defective in multiple DNA damage response pathways, including checkpoint signaling by Rad3-Rad26/ATR-ATRIP kinase, DNA repair by Smc5-Smc6 holocomplex, replication fork stabilization by Mrc1/claspin and Swi1-Swi3/Timeless-Tipin, and control of ubiquitin-regulated proteolysis by the COP9 signalosome (CSN). Exogenous genotoxins enhance these negative genetic interactions. Rad52 and RPA foci are increased in CSN-defective cells, and loss of gammaH2A increases genotoxin sensitivity, indicating a critical role for the gammaH2A-Brc1 module in stabilizing replication forks in CSN-defective cells. A negative genetic interaction with the Nse6 subunit of Smc5-Smc6 holocomplex indicates that the DNA repair functions of Brc1 and Smc5-Smc6 holocomplex are at least partially independent. Rtt107, the Brc1 homolog in Saccharomyces cerevisiae, has a very different pattern of genetic interactions, indicating evolutionary divergence of functions and DNA damage responses. PMID- 25795665 TI - Heterologous Production of Hyaluronic Acid in an epsilon-Poly-L-Lysine Producer, Streptomyces albulus. AB - Hyaluronic acid (HA) is used in a wide range of medical applications, where its performance and therapeutic efficacy are highly dependent on its molecular weight. In the microbial production of HA, it has been suggested that a high level of intracellular ATP enhances the productivity and molecular weight of HA. Here, we report on heterologous HA production in an epsilon-poly-l-lysine producer, Streptomyces albulus, which has the potential to generate ATP at high level. The hasA gene from Streptococcus zooepidemicus, which encodes HA synthase, was refactored and expressed under the control of a late-log growth phase operating promoter. The expression of the refactored hasA gene, along with genes coding for UDP-glucose dehydrogenase, UDP-N-acetylglucosamine pyrophosphorylase, and UDP-glucose pyrophosphorylase, which are involved in HA precursor sugar biosynthesis, resulted in efficient production of HA in the 2.0 MDa range, which is greater than typical bacterial HA, demonstrating that a sufficient amount of ATP was provided to support the biosynthesis of the precursor sugars, which in turn promoted HA production. In addition, unlike in the case of streptococcal HA, S. albulus-derived HA was not cell associated. Based on these findings, our heterologous production system appears to have several advantages for practical HA production. We propose that the present system could be applicable to the heterologous production of a wide variety of molecules other than HA in the case their biosynthesis pathways require ATP in vivo. PMID- 25795666 TI - Fermentation and Cost-Effective 13C/15N Labeling of the Nonribosomal Peptide Gramicidin S for Nuclear Magnetic Resonance Structure Analysis. AB - Gramicidin S (GS) is a nonribosomally synthesized decapeptide from Aneurinibacillus migulanus. Its pronounced antibiotic activity is attributed to amphiphilic structure and enables GS interaction with bacterial membranes. Despite its medical use for over 70 years, the peptide-lipid interactions of GS and its molecular mechanism of action are still not fully understood. Therefore, a comprehensive structural analysis of isotope-labeled GS needs to be performed in its biologically relevant membrane-bound state, using advanced solid-state nuclear magnetic resonance (NMR) spectroscopy. Here, we describe an efficient method for producing the uniformly (13)C/(15)N-labeled peptide in a minimal medium supplemented by selected amino acids. As GS is an intracellular product of A. migulanus, we characterized the producer strain DSM 5759 (rough-convex phenotype) and examined its biosynthetic activity in terms of absolute and biomass-dependent peptide accumulation. We found that the addition of either arginine or ornithine increases the yield only at very high supplementing concentrations (1% and 0.4%, respectively) of these expensive (13)C/(15)N-labeled amino acids. The most cost-effective production of (13)C/(15)N-GS, giving up to 90 mg per gram of dry cell weight, was achieved in a minimal medium containing 1% (13)C-glycerol and 0.5% (15)N-ammonium sulfate, supplemented with only 0.025% of (13)C/(15)N-phenylalanine. The 100% efficiency of labeling is corroborated by mass spectrometry and preliminary solid-state NMR structure analysis of the labeled peptide in the membrane-bound state. PMID- 25795667 TI - Virucidal effect of cold atmospheric gaseous plasma on feline calicivirus, a surrogate for human norovirus. AB - Minimal food-processing methods are not effective against foodborne viruses, such as human norovirus (NV). It is important, therefore, to explore novel nonthermal technologies for decontamination of foods eaten fresh, minimally processed and ready-to-eat foods, and food contact surfaces. We studied the in vitro virucidal activity of cold atmospheric gaseous plasma (CGP) against feline calicivirus (FCV), a surrogate of NV. Factors affecting the virucidal activity of CGP (a so called radio frequency atmospheric pressure plasma jet) were the plasma generation power, the exposure time and distance, the plasma feed gas mixture, and the virus suspension medium. Exposure to 2.5-W argon (Ar) plasma caused a 5.55 log10 unit reduction in the FCV titer within 120 s. The reduction in the virus titer increased with increasing exposure time and decreasing exposure distance. Of the four plasma gas mixtures studied (Ar, Ar plus 1% O2, Ar plus 1% dry air, and Ar plus 0.27% water), Ar plus 1% O2 plasma treatment had the highest virucidal effect: more than 6.0 log10 units of the virus after 15 s of exposure. The lowest virus reduction was observed with Ar plus 0.27% water plasma treatment (5 log10 unit reduction after 120 s). The highest reduction in titer was observed when the virus was suspended in distilled water. Changes in temperature and pH and formation of H2O2 were not responsible for the virucidal effect of plasma. The oxidation of viral capsid proteins by plasma-produced reactive oxygen and nitrogen species in the solution was thought to be responsible for the virucidal effect. In conclusion, CGP exhibits virucidal activity in vitro and has the potential to combat viral contamination in foods and on food preparation surfaces. PMID- 25795668 TI - One-Pot Production of L-threo-3-Hydroxyaspartic Acid Using Asparaginase-Deficient Escherichia coli Expressing Asparagine Hydroxylase of Streptomyces coelicolor A3(2). AB - We developed a novel process for efficient synthesis of L-threo-3-hydroxyaspartic acid (L-THA) using microbial hydroxylase and hydrolase. A well-characterized mutant of asparagine hydroxylase (AsnO-D241N) and its homologous enzyme (SCO2693 D246N) were adaptable to the direct hydroxylation of L-aspartic acid; however, the yields were strictly low. Therefore, the highly stable and efficient wild type asparagine hydroxylases AsnO and SCO2693 were employed to synthesize L-THA. By using these recombinant enzymes, L-THA was obtained by L-asparagine hydroxylation by AsnO followed by amide hydrolysis by asparaginase via 3 hydroxyasparagine. Subsequently, the two-step reaction was adapted to one-pot bioconversion in a test tube. L-THA was obtained in a small amount with a molar yield of 0.076% by using intact Escherichia coli expressing the asnO gene, and thus, two asparaginase-deficient mutants of E. coli were investigated. A remarkably increased L-THA yield of 8.2% was obtained with the asparaginase I deficient mutant. When the expression level of the asnO gene was enhanced by using the T7 promoter in E. coli instead of the lac promoter, the L-THA yield was significantly increased to 92%. By using a combination of the E. coli asparaginase I-deficient mutant and the T7 expression system, a whole-cell reaction in a jar fermentor was conducted, and consequently, L-THA was successfully obtained from L-asparagine with a maximum yield of 96% in less time than with test tube-scale production. These results indicate that asparagine hydroxylation followed by hydrolysis would be applicable to the efficient production of L-THA. PMID- 25795669 TI - Akkermansia muciniphila Adheres to Enterocytes and Strengthens the Integrity of the Epithelial Cell Layer. AB - Akkermansia muciniphila is a Gram-negative mucin-degrading bacterium that resides in the gastrointestinal tracts of humans and animals. A. muciniphila has been linked with intestinal health and improved metabolic status in obese and type 2 diabetic subjects. Specifically, A. muciniphila has been shown to reduce high-fat diet-induced endotoxemia, which develops as a result of an impaired gut barrier. Despite the accumulating evidence of the health-promoting effects of A. muciniphila, the mechanisms of interaction of the bacterium with the host have received little attention. In this study, we used several in vitro models to investigate the adhesion of A. muciniphila to the intestinal epithelium and its interaction with the host mucosa. We found that A. muciniphila adheres strongly to the Caco-2 and HT-29 human colonic cell lines but not to human colonic mucus. In addition, A. muciniphila showed binding to the extracellular matrix protein laminin but not to collagen I or IV, fibronectin, or fetuin. Importantly, A. muciniphila improved enterocyte monolayer integrity, as shown by a significant increase in the transepithelial electrical resistance (TER) of cocultures of Caco 2 cells with the bacterium. Further, A. muciniphila induced interleukin 8 (IL-8) production by enterocytes at cell concentrations 100-fold higher than those for Escherichia coli, suggesting a very low level of proinflammatory activity in the epithelium. In conclusion, our results demonstrate that A. muciniphila adheres to the intestinal epithelium and strengthens enterocyte monolayer integrity in vitro, suggesting an ability to fortify an impaired gut barrier. These results support earlier associative in vivo studies and provide insights into the interaction of A. muciniphila with the host. PMID- 25795670 TI - Houseflies (Musca domestica) as Vectors for Extended-Spectrum beta-Lactamase Producing Escherichia coli on Spanish Broiler Farms. AB - Flies may act as potential vectors for the spread of resistant bacteria to different environments. This study was intended to evaluate the presence of Escherichia coli strains resistant to cephalosporins in flies captured in the areas surrounding five broiler farms. Phenotypic and molecular characterization of the resistant population was performed by different methods: MIC determination, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and phylotyping. The presence of extended-spectrum beta-lactamase (ESBL) genes, their plasmid location, and the mobile genetic elements involved in their mobilization were studied. Additionally, the presence of 35 genes associated with virulence was evaluated. Out of 682 flies captured, 42 yielded ESBL-producing E. coli. Of these isolates, 23 contained bla(CTX-M-1), 18 contained bla(CTX-M-14), and 1 contained bla(CTX-M-9). ESBL genes were associated mainly with the presence of the IncI1 and IncFIB replicons. Additionally, all the strains were multiresistant, and five of them also harbored qnrS. Identical PFGE profiles were found for E. coli isolates obtained from flies at different sampling times, indicating a persistence of the same clones in the farm environment over months. According to their virulence genes, 81% of the isolates were considered avian-pathogenic E. coli (APEC) and 29% were considered extraintestinal pathogenic E. coli (ExPEC). The entrance of flies into broiler houses constitutes a considerable risk for colonization of broilers with multidrug-resistant E. coli. ESBLs in flies reflect the contamination status of the farm environment. Additionally, this study demonstrates the potential contribution of flies to the dissemination of virulence and resistance genes into different ecological niches. PMID- 25795671 TI - Gene Loss and Lineage-Specific Restriction-Modification Systems Associated with Niche Differentiation in the Campylobacter jejuni Sequence Type 403 Clonal Complex. AB - Campylobacter jejuni is a highly diverse species of bacteria commonly associated with infectious intestinal disease of humans and zoonotic carriage in poultry, cattle, pigs, and other animals. The species contains a large number of distinct clonal complexes that vary from host generalist lineages commonly found in poultry, livestock, and human disease cases to host-adapted specialized lineages primarily associated with livestock or poultry. Here, we present novel data on the ST403 clonal complex of C. jejuni, a lineage that has not been reported in avian hosts. Our data show that the lineage exhibits a distinctive pattern of intralineage recombination that is accompanied by the presence of lineage specific restriction-modification systems. Furthermore, we show that the ST403 complex has undergone gene decay at a number of loci. Our data provide a putative link between the lack of association with avian hosts of C. jejuni ST403 and both gene gain and gene loss through nonsense mutations in coding sequences of genes, resulting in pseudogene formation. PMID- 25795672 TI - Acquisition of Iron Is Required for Growth of Salmonella spp. in Tomato Fruit. AB - Salmonella remains a leading cause of bacterial food-borne disease, sickening millions each year. Although outbreaks of salmonellosis have traditionally been associated with contaminated meat products, recent years have seen numerous disease cases caused by the consumption of produce. Tomatoes have been specifically implicated, due to the ability of Salmonella spp. to enter the tomato fruit and proliferate within, making the decontamination of the raw product impossible. To investigate the genetic means by which Salmonella is able to survive and proliferate within tomatoes, we conducted a screen for bacterial genes of Salmonella enterica serovar Montevideo specifically induced after inoculation into ripe tomato fruit. Among these genes, we found 17 members of the previously described anaerobic Fur (ferric uptake regulator) regulon. Fur is a transcriptional and posttranscriptional regulator known to sense iron, suggesting the importance of this mineral to Salmonella within tomatoes. To test whether iron acquisition is essential for Salmonella growth in tomatoes, we tested a DeltafepDGC mutant, which lacks the ability to import iron-associated siderophores. This mutant grew significantly more poorly within tomatoes than did the wild type, but the growth defect of the mutant was fully reversed by the addition of exogenous iron, demonstrating the need for bacterial iron scavenging. Further, dependence upon iron was not apparent for Salmonella growing in filtered tomato juice, implicating the cellular fraction of the fruit as an important mediator of iron acquisition by the bacteria. PMID- 25795673 TI - Genetic Diversity and Pathogenic Potential of Attaching and Effacing Escherichia coli O26:H11 Strains Recovered from Bovine Feces in the United States. AB - Escherichia coli O26 has been identified as the most common non-O157 Shiga toxin producing E. coli (STEC) serogroup to cause human illnesses in the United States and has been implicated in outbreaks around the world. E. coli has high genomic plasticity, which facilitates the loss or acquisition of virulence genes. Attaching and effacing E. coli (AEEC) O26 strains have frequently been isolated from bovine feces, and there is a need to better characterize the relatedness of these strains to defined molecular pathotypes and to describe the extent of their genetic diversity. High-throughput real-time PCR was used to screen 178 E. coli O26 isolates from a single U.S. cattle feedlot, collected from May to July 2011, for the presence or absence of 25 O26 serogroup-specific and virulence-associated markers. The selected markers were capable of distinguishing these strains into molecularly defined groups (yielding 18 unique marker combinations). Analysis of the clustered regularly interspaced short palindromic repeat 1 (CRISPR1) and CRISPR2a loci further discriminated isolates into 24 CRISPR types. The combination of molecular markers and CRISPR typing provided 20.8% diversity. The recent CRISPR PCR target SP_O26-E, which was previously identified only in stx2 positive O26:H11 human clinical strains, was identified in 96.4% (161/167 [95% confidence interval, 99.2 to 93.6%]) of the stx-negative AEEC O26:H11 bovine fecal strains. This supports that these stx-negative strains may have previously contained a prophage carrying stx or could acquire this prophage, thus possibly giving them the potential to become pathogenic to humans. These results show that investigation of specific genetic markers may further elucidate our understanding of the genetic diversity of AEEC O26 strains in bovine feces. PMID- 25795674 TI - Enhanced cutinase-catalyzed hydrolysis of polyethylene terephthalate by covalent fusion to hydrophobins. AB - Cutinases have shown potential for hydrolysis of the recalcitrant synthetic polymer polyethylene terephthalate (PET). We have shown previously that the rate of this hydrolysis can be enhanced by the addition of hydrophobins, small fungal proteins that can alter the physicochemical properties of surfaces. Here we have investigated whether the PET-hydrolyzing activity of a bacterial cutinase from Thermobifida cellulosilytica (Thc_Cut1) would be further enhanced by fusion to one of three Trichoderma hydrophobins, i.e., the class II hydrophobins HFB4 and HFB7 and the pseudo-class I hydrophobin HFB9b. The fusion enzymes exhibited decreased kcat values on soluble substrates (p-nitrophenyl acetate and p nitrophenyl butyrate) and strongly decreased the hydrophilicity of glass but caused only small changes in the hydrophobicity of PET. When the enzyme was fused to HFB4 or HFB7, the hydrolysis of PET was enhanced >16-fold over the level with the free enzyme, while a mixture of the enzyme and the hydrophobins led only to a 4-fold increase at most. Fusion with the non-class II hydrophobin HFB9b did not increase the rate of hydrolysis over that of the enzyme-hydrophobin mixture, but HFB9b performed best when PET was preincubated with the hydrophobins before enzyme treatment. The pattern of hydrolysis by the fusion enzymes differed from that of Thc_Cut1 as the concentration of the product mono(2-hydroxyethyl) terephthalate relative to that of the main product, terephthalic acid, increased. Small-angle X-ray scattering (SAXS) analysis revealed an increased scattering contrast of the fusion proteins over that of the free proteins, suggesting a change in conformation or enhanced protein aggregation. Our data show that the level of hydrolysis of PET by cutinase can be significantly increased by fusion to hydrophobins. The data further suggest that this likely involves binding of the hydrophobins to the cutinase and changes in the conformation of its active center. PMID- 25795675 TI - Hierarchy of Carbon Source Utilization in Soil Bacteria: Hegemonic Preference for Benzoate in Complex Aromatic Compound Mixtures Degraded by Cupriavidus pinatubonensis Strain JMP134. AB - Cupriavidus pinatubonensis JMP134, like many other environmental bacteria, uses a range of aromatic compounds as carbon sources. Previous reports have shown a preference for benzoate when this bacterium grows on binary mixtures composed of this aromatic compound and 4-hydroxybenzoate or phenol. However, this observation has not been extended to other aromatic mixtures resembling a more archetypal context. We carried out a systematic study on the substrate preference of C. pinatubonensis JMP134 growing on representative aromatic compounds channeled through different catabolic pathways described in aerobic bacteria. Growth tests of nearly the entire set of binary combinations and in mixtures composed of 5 or 6 aromatic components showed that benzoate and phenol were always the preferred and deferred growth substrates, respectively. This pattern was supported by kinetic analyses that showed shorter times to initiate consumption of benzoate in aromatic compound mixtures. Gene expression analysis by real-time reverse transcription-PCR (RT-PCR) showed that, in all mixtures, the repression by benzoate over other catabolic pathways was exerted mainly at the transcriptional level. Additionally, inhibition of benzoate catabolism suggests that its multiple repressive actions are not mediated by a sole mechanism, as suggested by dissimilar requirements of benzoate degradation for effective repression in different aromatic compound mixtures. The hegemonic preference for benzoate over multiple aromatic carbon sources is not explained on the basis of growth rate and/or biomass yield on each single substrate or by obvious chemical or metabolic properties of these aromatic compounds. PMID- 25795676 TI - In-Frame and Unmarked Gene Deletions in Burkholderia cenocepacia via an Allelic Exchange System Compatible with Gateway Technology. AB - Burkholderia cenocepacia is an emerging opportunistic pathogen causing life threatening infections in immunocompromised individuals and in patients with cystic fibrosis, which are often difficult, if not impossible, to treat. Understanding the genetic basis of virulence in this emerging pathogen is important for the development of novel treatment regimes. Generation of deletion mutations in genes predicted to encode virulence determinants is fundamental to investigating the mechanisms of pathogenesis. However, there is a lack of appropriate selectable and counterselectable markers for use in B. cenocepacia, making its genetic manipulation problematic. Here we describe a Gateway compatible allelic exchange system based on the counterselectable pheS gene and the I-SceI homing endonuclease. This system provides efficiency in cloning homology regions of target genes and allows the generation of precise and unmarked gene deletions in B. cenocepacia. As a proof of concept, we demonstrate its utility by deleting the Bcam1349 gene, encoding a cyclic di-GMP (c-di-GMP) responsive regulator protein important for biofilm formation. PMID- 25795677 TI - Lantibiotic Reductase LtnJ Substrate Selectivity Assessed with a Collection of Nisin Derivatives as Substrates. AB - Lantibiotics are potent antimicrobial peptides characterized by the presence of dehydrated amino acids, dehydroalanine and dehydrobutyrine, and (methyl)lanthionine rings. In addition to these posttranslational modifications, some lantibiotics exhibit additional modifications that usually confer increased biological activity or stability on the peptide. LtnJ is a reductase responsible for the introduction of D-alanine in the lantibiotic lacticin 3147. The conversion of L-serine into D-alanine requires dehydroalanine as the substrate, which is produced in vivo by the dehydration of serine by a lantibiotic dehydratase, i.e., LanB or LanM. In this work, we probe the substrate specificity of LtnJ using a system that combines the nisin modification machinery (dehydratase, cyclase, and transporter) and the stereospecific reductase LtnJ in Lactococcus lactis. We also describe an improvement in the production yield of this system by inserting a putative attenuator from the nisin biosynthesis gene cluster in front of the ltnJ gene. In order to clarify the sequence selectivity of LtnJ, peptides composed of truncated nisin and different mutated C-terminal tails were designed and coexpressed with LtnJ and the nisin biosynthetic machinery. In these tails, serine was flanked by diverse amino acids to determine the influence of the surrounding residues in the reaction. LtnJ successfully hydrogenated peptides when hydrophobic residues (Leu, Ile, Phe, and Ala) were flanking the intermediate dehydroalanine, while those in which dehydroalanine was flanked by one or two polar residues (Ser, Thr, Glu, Lys, and Asn) or Gly were either less prone to be modified by LtnJ or not modified at all. Moreover, our results showed that dehydrobutyrine cannot serve as a substrate for LtnJ. PMID- 25795678 TI - Glucosylceramide Contained in Koji Mold-Cultured Cereal Confers Membrane and Flavor Modification and Stress Tolerance to Saccharomyces cerevisiae during Coculture Fermentation. AB - In nature, different microorganisms create communities through their physiochemical and metabolic interactions. Many fermenting microbes, such as yeasts, lactic acid bacteria, and acetic acid bacteria, secrete acidic substances and grow faster at acidic pH values. However, on the surface of cereals, the pH is neutral to alkaline. Therefore, in order to grow on cereals, microbes must adapt to the alkaline environment at the initial stage of colonization; such adaptations are also crucial for industrial fermentation. Here, we show that the yeast Saccharomyces cerevisiae, which is incapable of synthesizing glucosylceramide (GlcCer), adapted to alkaline conditions after exposure to GlcCer from koji cereal cultured with Aspergillus kawachii. We also show that various species of GlcCer derived from different plants and fungi similarly conferred alkali tolerance to yeast. Although exogenous ceramide also enhanced the alkali tolerance of yeast, no discernible degradation of GlcCer to ceramide was observed in the yeast culture, suggesting that exogenous GlcCer itself exerted the activity. Exogenous GlcCer also increased ethanol tolerance and modified the flavor profile of the yeast cells by altering the membrane properties. These results indicate that GlcCer from A. kawachii modifies the physiology of the yeast S. cerevisiae and demonstrate a new mechanism for cooperation between microbes in food fermentation. PMID- 25795679 TI - Identification of a New cry1I-Type Gene as a Candidate for Gene Pyramiding in Corn To Control Ostrinia Species Larvae. AB - Pyramiding of diverse cry toxin genes from Bacillus thuringiensis with different modes of action is a desirable strategy to delay the evolution of resistance in the European corn borer (Ostrinia nubilalis). Considering the dependency of susceptibility to Cry toxins on toxin binding to receptors in the midgut of target pests, a diverse mode of action is commonly defined as recognition of unique binding sites in the target insect. In this study, we present a novel cry1Ie toxin gene (cry1Ie2) as a candidate for pyramiding with Cry1Ab or Cry1Fa in corn to control Ostrinia species larvae. The new toxin gene encodes an 81-kDa protein that is processed to a protease-resistant core form of approximately 55 kDa by trypsin digestion. The purified protoxin displayed high toxicity to Ostrinia furnacalis and O. nubilalis larvae but low to no activity against Spodoptera or heliothine species or the coleopteran Tenebrio molitor. Results of binding assays with (125)I-labeled Cry1Ab toxin and brush border membrane vesicles from O. nubilalis larvae demonstrated that Cry1Ie2 does not recognize the Cry1Ab binding sites in that insect. Reciprocal competition binding assays with biotin-labeled Cry1Ie2 confirmed the lack of shared sites with Cry1Ab or Cry1Fa in O. nubilalis brush border membrane vesicles. These data support Cry1Ie2 as a good candidate for pyramiding with Cry1Ab or Cry1Fa in corn to increase the control of O. nubilalis and reduce the risk of resistance evolution. PMID- 25795680 TI - Extracorporeal membrane oxygenation in children with heart disease and del22q11 syndrome: a review of the Extracorporeal Life Support Organization Registry. AB - The study objective was to evaluate outcomes among children with del22q11 (DiGeorge) syndrome supported on ECMO for heart disease. The ELSO registry database was queried to include all children <18 years undergoing heart surgery for either common atrio-ventricular canal, tetralogy of Fallot, truncus arteriosus or transposition of the great vessels and interrupted aortic arch and requiring ECMO, from 1998-2011. The outcomes evaluated included mortality, ECMO duration and length of hospital stay in patients with del22q11 syndrome and with no del22q11 syndrome. Eighty-eight ECMO runs occurred in children with del22q11 syndrome while 2694 ECMO runs occurred in children without del22q11 syndrome. For patients with heart defects receiving ECMO, del22q11 syndrome did not confer a significant mortality risk or an increased risk of infectious complications before or while on ECMO support. Neither the duration of ECMO nor mechanical ventilation prior to ECMO deployment were prolonged in patients with del22q11 syndrome compared to the controls. PMID- 25795681 TI - Predictors and incidence of access site complications in transcatheter aortic valve implantation with the use of new delivery systems. AB - OBJECTIVES: The aim of this single-center study was to assess the incidence and predictors of in-hospital access site complications related to transcatheter aortic valve implantation (TAVI) performed with new delivery systems in our hospital which has the largest case series in Turkey. MATERIALS AND METHOD: We performed successful TAVI with the Edwards Sapien XT valve to 127 (46 male) patients via a transfemoral (121), trans-subclavian (5) and transapical (1) approach. Access site complications were defined according to the Valve Academic Research Consortium (VARC) end-point definitions. RESULTS: Vascular complications occurred in 10.1% of patients. There was negative correlation between vascular complications and diameter of the common femoral artery (r = - 0.301, p=0.004), external iliac artery (r = - 0.327, p=0.004) and common iliac artery (r = - 0.324, p=0.004), but positive correlation between diabetes (r =0.240, p=0.008), sheath to femoral artery ratio (SFAR), sheath to external iliac artery ratio (SEIAR), procedure time, discharge time and the Society of Thoracic Surgeons (STS) score (respectively; r=0.339, 0.001, 0.527, 0.361, 0.289, p=0.003, 0.001, 0.001, 0.001, 0.002). The incidence of vascular complications was significantly higher in patients with diabetes and a high STS score. VARC bleeding complications occurred in 11.7 % of patients. The learning curve pointing out the importance of experience was significantly important in decreasing both bleeding and vascular complications. CONCLUSIONS: In this study, we demonstrated that major vascular complications related to TAVI decrease with the use of smaller delivery systems and experience and increase with high-risk scores (STS) and the presence of diabetes. In addition, VARC major vascular complications, observed mostly in patients with diabete mellitus (DM) and high STS scores, were associated with vascular diameters. These results further underline the importance of experience and a multidisciplinary team in patient selection and management for TAVI. PMID- 25795682 TI - A response to Saviour Siblings: A Relational Approach to the Welfare of the Child in Selective Reproduction. PMID- 25795683 TI - Bronchopleural fistula closed with cellulose patch and fibrin glue. AB - We describe a bronchoscopic technique for closing small postoperative bronchopleural fistulas, using an oxidized regenerated cellulose patch and fibrin glue. The patch is mounted on the end of endoscopic forceps and introduced into the fistula to cover it. Intracavitary and submucosal injections of fibrin glue fill the bronchial stump and achieve apposition of the fistula edges. Closure was obtained in 3 of 4 patients; the 4th had complete bronchial dehiscence and empyema. PMID- 25795684 TI - Sialidases as regulators of bioengineered cellular surfaces. AB - Human sialidases (NEUs) catalyze the removal of N-acetyl neuraminic acids from the glycome of the cell and regulate a diverse repertoire of nominal cellular functions, such as cell signaling and adhesion. A greater understanding of their substrate permissivity is of interest in order to discern their physiological functions in disease states and in the design of specific and effective small molecule inhibitors. Towards this, we have synthesized soluble fluorogenic reporters of mammalian sialidase activity bearing unnatural sialic acids commonly incorporated into the cellular glycocalyx via metabolic glycoengineering. We found cell-surface sialidases in Jurkat capable of cleaving unnatural sialic acids with differential activities toward a variety of R groups on neuraminic acid. In addition, we observed modulated structure-activity relationships when cell-surface sialidases were presented glycans with unnatural bulky, hydrophobic or fluorinated moieties incorporated directly via glycoengineering. Our results confirm the importance of cell-surface sialidases in glycoengineering incorporation data. We demonstrate the flexibility of human NEUs toward derivatized sugars and highlight the importance of native glycan presentation to sialidase binding and activity. These results stand to inform not only metabolic glycoengineering efforts but also inhibitor design. PMID- 25795685 TI - Effectiveness of general preconception care accompanied by a recruitment approach: protocol of a community-based cohort study (the Healthy Pregnancy 4 All study). AB - INTRODUCTION: Promotion of healthy pregnancies has gained high priority in the Netherlands because of the relative unfavourable perinatal outcomes. In response, a nationwide study Healthy Pregnancy 4 All (HP4ALL) has been initiated. One of the substudies within HP4ALL focuses on preconception care (PCC). PCC is an opportunity to detect and eliminate risk factors before conception to optimise health before organogenesis and placentation. The main objectives of the PCC substudy are (1) to assess the effectiveness of a recruitment strategy for the PCC health services and (2) to assess the effectiveness of individual PCC consultations. METHODS/ANALYSIS: Prospective cohort study in neighbourhoods of 14 municipalities with perinatal mortality and morbidity rates exceeding the nation's average. The theoretical framework of the PCC substudy is based on Andersen's model of healthcare utilisation (a model that evaluates the utilisation of healthcare services from a sociological perspective). Women aged 18 up to and including 41 years are targeted for utilisation of the PCC health service by a four armed recruitment strategy. The PCC health service consists of an individual PCC consultation consisting of (1) initial risk assessment and risk management and (2) a follow-up consultation to assess adherence to the management plan. The primary outcomes regarding the effectiveness of consultations is behavioural change regarding folic acid supplementation, smoking cessation, cessation of alcohol consumption and illicit substance use. The primary outcome regarding the effectiveness of the recruitment strategy is the number of women successfully recruited and the outreach in terms of which population is reached in comparison to the approached population. Data collection consists of registration in the database of women that enrol for a visit to the individual PCC consultations (women successfully recruited), and preconsultation and postconsultation measurements among the included study population (by questionnaires, anthropometric measurements and biomarkers). Sample size calculation resulted in a sample size of n=839 women. ETHICS AND DISSEMINATION: Approval for this study has been obtained from the Medical Ethical Committee of the Erasmus Medical Center of Rotterdam (MEC 2012-425). Results will be published and presented at international conferences. PMID- 25795686 TI - Determination of risk factors for drug-related problems: a multidisciplinary triangulation process. AB - INTRODUCTION AND OBJECTIVES: Drug-related problems (DRPs) constitute a frequent safety issue among hospitalised patients leading to patient harm and increased healthcare costs. Because many DRPs are preventable, the specific risk factors that facilitate their occurrence are of considerable interest. The objective of our study was to assess risk factors for the occurrence of DRPs with the intention to identify patients at risk for DRPs to guide and target preventive measures where they are needed most in patients. DESIGN: Triangulation process using a mixed methods approach. METHODS: We conducted an expert panel, using the nominal group technique (NGT) and a qualitative analysis, to gather risk factors for DRPs. The expert panel consisted of two consultant hospital physicians (internal medicine and geriatrics), one emergency physician, one independent general practitioner, one clinical pharmacologist, one clinical pharmacist, one registered nurse, one home care nurse and two independent community pharmacists. The literature was searched for additional risk factors. Gathered factors from the literature search and the NGT were assembled and validated in a two-round Delphi questionnaire. RESULTS: The NGT resulted in the identification of 33 items with 13 additional risk factors from the qualitative analysis of the discussion. The literature search delivered another 39 risk factors. The 85 risk factors were refined to produce 42 statements for the Delphi online questionnaire. Of these, 27 risk factors were judged to be 'important' or 'rather important'. CONCLUSIONS: The gathered risk factors may help to characterise and identify patients at risk for DRPs and may enable clinical pharmacists to guide and target preventive measures in order to limit the occurrence of DRPs. As a further step, these risk factors will serve as the basis for a screening tool to identify patients at risk for DRPs. PMID- 25795687 TI - Remote supervision of medical training via videoconference in northern Australia: a qualitative study of the perspectives of supervisors and trainees. AB - OBJECTIVES: Telemedicine has revolutionised the ability to provide care to patients, relieve professional isolation and provide guidance and supervision to junior medical officers in rural areas. This study evaluated the Townsville teleoncology supervision model for the training of junior medical officers in rural areas of North Queensland, Australia. Specifically, the perspectives of junior and senior medical officers were explored to identify recommendations for future implementation. DESIGN: A qualitative approach incorporating observation and semistructured interviews was used to collect data. Interviews were uploaded into NVivo 10 data management software. Template analysis enabled themes to be tested and developed through consensus between researchers. SETTING: One tertiary level and four secondary level healthcare centres in rural and regional Queensland, Australia. PARTICIPANTS: 10 junior medical officers (Interns, Registrars) and 10 senior medical officers (Senior Medical Officers, Consultants) who participated in the Townsville teleoncology model of remote supervision via videoconference (TTMRS) were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Perspectives on the telemedicine experience, technology, engagement, professional support, satisfaction and limitations were examined. Perspectives on topics raised by participants were also examined as the interviews progressed. RESULTS: Four major themes with several subthemes emerged from the data: learning environment, beginning the learning relationship, stimulus for learning and practicalities of remote supervision via videoconference. While some themes were consistent with the current literature, new themes like increased professional edge, recognising non-verbal cues and physical examination challenges were identified. CONCLUSIONS: Remote supervision via videoconference provides readily available guidance to trainees supporting their delivery of appropriate care to patients. However, resources required for upskilling, training in the use of supervision via videoconference, administration issues and nursing support, as well as physical barriers to examinations, must be addressed to enable more efficient implementation. PMID- 25795688 TI - The effectiveness of self-management support interventions for men with long-term conditions: a systematic review and meta-analysis. AB - OBJECTIVES: To assess the effectiveness of self-management support interventions in men with long-term conditions. METHODS: A quantitative systematic review with meta-analysis. DATA SOURCES: The Cochrane Database of Systematic Reviews was searched to identify published reviews of self-management support interventions. Relevant reviews were screened to identify randomised controlled trials (RCTs) of self-management support interventions conducted in men alone, or which analysed the effects of interventions by sex. REVIEW METHODS: Data on relevant outcomes, patient populations, intervention type and study quality were extracted. Quality appraisal was conducted using the Cochrane Risk of Bias Tool. Meta-analysis was conducted to compare the effects of interventions in men, women, and mixed-sex sub-groups. RESULTS: 40 RCTs of self-management support interventions in men, and 20 eligible RCTs where an analysis by sex was reported, were included in the review. Meta-analysis suggested that physical activity, education, and peer support-based interventions have a positive impact on quality of life in men. However, there is currently insufficient evidence to make strong statements about whether self-management support interventions show larger, similar or smaller effects in men compared with women and mixed-sex groups. CONCLUSIONS: Clinicians may wish to consider whether certain types of self-management support (eg, physical activity, education, peer support) are particularly effective in men, although more research is needed to fully determine and explore this. PMID- 25795689 TI - The feasibility of meeting the WHO guidelines for sodium and potassium: a cross national comparison study. AB - OBJECTIVE: To determine joint compliance with the WHO sodium-potassium goals in four different countries, using data from nationally representative dietary surveys. SETTING: Compared to national and international recommendations and guidelines, the world's population consumes too much sodium and inadequate amounts of potassium. The WHO recommends consuming less than 2000 mg sodium (86 mmol) and at least 3510 mg potassium (90 mmol) per person per day. PARTICIPANTS: Dietary surveillance data were obtained from the National Health and Nutrition Examination Survey (NHANES 2007-2010) for the USA; the Encuesta Nacional de Salud y Nutricion 2012 for Mexico; the Individual and National Study on Food Consumption (INCA2) for France; and the National Diet and Nutrition Survey (NDNS) for the UK. PRIMARY OUTCOME MEASURES: We estimated the proportion of adults meeting the joint WHO sodium-potassium goals in the USA, the UK, France and Mexico. RESULTS: The upper bounds of joint compliance with the WHO sodium potassium goals were estimated at 0.3% in the USA, 0.15% in Mexico, 0.5% in France and 0.1% in the UK. CONCLUSIONS: Given prevailing food consumption patterns and the current food supply, implementing WHO guidelines will be an enormous challenge for global public health. PMID- 25795690 TI - Reasons for smoking cessation attempts among Japanese male smokers vary by nicotine dependence level: a cross-sectional study after the 2010 tobacco tax increase. AB - OBJECTIVES: To examine the association between smoking cessation attempts during the previous 12 months, motivators to quit smoking and nicotine dependence levels among current male smokers after Japan's massive 2010 tobacco tax increase. DESIGN: Cross-sectional study. SETTING: A self-reported questionnaire about smoking habits, nicotine dependence levels and factors identified as motivators to quit smoking was administered to 9378 employees working at a company located in Fukuoka Prefecture in Japan (as of 1 October 2011). PARTICIPANTS: A total of 2251 male current smokers 20-69 years old. PRIMARY AND SECONDARY OUTCOME MEASURES: Nicotine dependence level assessed by Fagerstrom Test for Cigarette Dependence (FTCD), smoking cessation attempts during the previous 12 months and motivators for smoking cessation. RESULTS: The proportion of current smokers who had attempted to quit smoking within the previous 12 months was 40.6%. Nicotine dependence level of current smokers was negatively associated with cessation attempts during the previous 12 months. Motivators for smoking cessation differed by nicotine dependence levels. 'The rise in cigarette prices since October 2010' as a smoking cessation motivator increased significantly at the medium nicotine dependence level (OR 1.44, 95% CI 1.09 to 1.90); however, this association was not statistically significant for individuals with high nicotine dependence (OR 1.24, 95% CI 0.80 to 1.92). 'Feeling unhealthy' was significantly negatively associated for medium (OR 0.42, 95% CI 0.27 to 0.65) and high (OR 0.31, 95% CI 0.14 to 0.71) nicotine dependence levels. Trend associations assessed by assigning ordinal numbers to total FTCD score for those two motivators were statistically significant. CONCLUSIONS: The efficacy of smoking cessation strategies can be improved by considering the target group's nicotine dependence level. For smokers with medium and high nicotine dependence levels, more effective strategies aimed at encouraging smoking cessation, such as policy interventions including increasing tobacco taxes, are needed. PMID- 25795692 TI - 25 mg versus 50 mg dose of rectal diclofenac for prevention of post-ERCP pancreatitis in Japanese patients: a retrospective study. AB - OBJECTIVES: The aim of the present study was to assess the appropriate administration dose of non-steroidal anti-inflammation drugs to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Importantly, the 100 mg dose of diclofenac recommended in Western countries has not been permitted in Japan. DESIGN: A retrospective study. SETTINGS: A single centre in Japan. PARTICIPANTS: This study enrolled patients who underwent ERCP at the Department of Gastroenterology, Osaka Saiseikai Senri Hospital, from April 2011 through June 2013, and who received either a 25 or a 50 mg dose of rectal diclofenac after ERCP. PRIMARY OUTCOME MEASURE: The occurrence of post-ERCP pancreatitis (PEP). A multivariate regression model was used to assess the effect of the 50 mg dose (the 50 mg group) of rectal diclofenac and to compare it to the occurrence of PEP referring to the 25 mg group. RESULTS: A total of 155 eligible patients received either 25 mg (84 patients) or 50 mg (71 patients) doses of rectal diclofenac after ERCP to prevent PEP. The proportion of PEP was significantly lower in the 50 mg group than in the 25 mg group (15.5% (11/71) vs 33.3% (28/84), p=0.018). In a multivariate analysis, the occurrence of PEP was significantly lower in the 50 mg group than in the 25 mg group even after adjusting potential confounding factors (adjusted OR=0.27, 95% CI 0.11 to 0.70). CONCLUSIONS: From this observation, the occurrence of PEP was significantly lower among ERCP patients with the 50 mg dose of rectal diclofenac than among those with the 25 mg dose. PMID- 25795693 TI - Mammograms on-the-go-predictors of repeat visits to mobile mammography vans in St Louis, Missouri, USA: a case-control study. AB - OBJECTIVES: Among women, breast cancer is the most common non-cutaneous cancer and second most common cause of cancer-related death. The purpose of this study was to determine the extent to which women use mobile mammography vans for breast cancer screening and what factors are associated with repeat visits to these vans. DESIGN: A case-control study. Cases are women who had a repeat visit to the mammography van. (n=2134). PARTICIPANTS: Women who received a mammogram as part of Siteman Cancer Center's Breast Health Outreach Program responded to surveys and provided access to their clinical records (N=8450). Only visits from 2006 to 2014 to the mammography van were included. OUTCOME MEASURES: The main outcome is having a repeat visit to the mammography van. Among the participants, 25.3% (N=2134) had multiple visits to the mobile mammography van. Data were analysed using chi(2) tests, logistic regression and negative binomial regression. RESULTS: Women who were aged 50-65, uninsured, or African-American had higher odds of a repeat visit to the mobile mammography van compared with women who were aged 40-50, insured, or Caucasian (OR=1.135, 95% CI 1.013 to 1.271; OR=1.302, 95% CI 1.146 to 1.479; OR=1.281, 95% CI 1.125 to 1.457), respectively. However, the odds of having a repeat visit to the van were lower among women who reported a rural ZIP code or were unemployed compared with women who provided a suburban ZIP code or were employed (OR=0.503, 95% CI 0.411 to 0.616; OR=.868, 95% CI 0.774 to 0.972), respectively. CONCLUSION: This study has identified key characteristics of women who are either more or less likely to use mobile mammography vans as their primary source of medical care for breast cancer screening and have repeat visits. PMID- 25795694 TI - Association of breast feeding with early childhood dental caries: Japanese population-based study. AB - OBJECTIVES: We investigated the association between breastfeeding duration during the first half year of life and the risk of early childhood caries from the age of 30 to 66 months in Japan. DESIGN: Observational study of a longitudinal survey. SETTING: A secondary data analysis of the Japanese Longitudinal Survey of Babies in the 21st Century. PARTICIPANTS: 43,383 infants at the age of 6 months. OUTCOME MEASURES: Early childhood caries--defined as a child's visit to a dentist for treatment of dental caries during the past 12 months--was ascertained from the caregiver from the age of 30 months in the survey. We estimated the risk of dental caries each year according to duration of breast feeding using logistic regression analyses. We controlled for a set of biological factors (birth weight, sex, parity and maternal age at delivery) and socioeconomic factors (maternal educational attainment and smoking status, marital status at delivery, family income and region of birth and residence). RESULTS: We found that infants who had been breast fed for at least 6 or 7 months, both exclusively and partially, were at elevated risk of dental caries at the age of 30 months compared with those who had been exclusively formula fed. Adjusted ORs were 1.78 (95% CI, (1.45 to 2.17)) for the exclusively breastfed group and 1.39 (1.14 to 1.70) for the partially breastfed group. However, the associations became attenuated through the follow up period and were no longer statistically significant beyond the age of 42 months for the partially breastfed group and beyond the age of 54 months for the exclusively breastfed group. CONCLUSIONS: We found an association between breast feeding for at least 6 or 7 months and elevated risk of dental caries at age 30 months. However, the association became attenuated as children grew older. PMID- 25795695 TI - Mental health and functional impairment outcomes following a 6-week intensive treatment programme for UK military veterans with post-traumatic stress disorder (PTSD): a naturalistic study to explore dropout and health outcomes at follow-up. AB - OBJECTIVE: Combat Stress, a UK national charity for veterans with mental health problems, has been funded by the National Health Service (NHS) to provide a national specialist service to deliver treatment for post-traumatic stress disorder (PTSD). This paper reports the efficacy of a PTSD treatment programme for UK veterans at 6 months follow-up. DESIGN: A within subject design. SETTING: UK veterans with a diagnosis of PTSD who accessed Combat Stress. PARTICIPANTS: 246 veterans who received treatment between late 2012 and early 2014. INTERVENTION: An intensive 6-week residential treatment programme, consisting of a mixture of individual and group sessions. Participants were offered a minimum of 15 individual trauma-focused cognitive behavioural therapy sessions. In addition, participants were offered 55 group sessions focusing on psychoeducational material and emotional regulation. MAIN OUTCOME MEASURES: Clinicians completed measures of PTSD and functional impairment and participants completed measures of PTSD, depression, anger and functional impairment. RESULTS: We observed significant reductions in PTSD scores following treatment on both clinician completed measures (PSS-I: -13.0, 95% CI -14.5 to -11.5) and self reported measures (Revised Impact of Events Scale (IES-R): -16.5, 95% CI -19.0 to -14.0). Significant improvements in functional impairment were also observed (eg, Health of the Nation Outcome Scales (HONOS): -6.85, 95% CI -7.98 to -5.72). There were no differences in baseline outcomes between those who completed and those who did not complete the programme, or post-treatment outcomes between those we were able to follow-up at 6 months and those lost to follow-up. CONCLUSIONS: In a naturalistic study we observed a significant reduction in PTSD scores and functional impairment following treatment. These improvements were maintained at 6 month follow-up. Our findings suggest it may be helpful to take a closer look at combining individual trauma-focused cognitive behaviour therapy and group sessions when treating veterans with PTSD. This is the first UK study of its kind, but requires further evaluation. PMID- 25795696 TI - Respiratory health status and its predictors: a cross-sectional study among coal based sponge iron plant workers in Barjora, India. AB - OBJECTIVES: During the past decade, coal-based sponge iron plants, a highly polluted industry, have grown rapidly in Barjora, India. The toxic effects of particulate matters and gaseous pollutants include various respiratory diseases. Understanding workers' perception of respiratory health is essential in people centred healthcare. The aim of the study was to assess their respiratory health status and to determine its predictors. DESIGN: Cross-sectional study. SETTING: Coal-based sponge iron plants in Barjora, India. PARTICIPANTS: 258 coal-based sponge iron plant workers. PRIMARY OUTCOME MEASURE: Respiratory health status was measured using the St. George's respiratory questionnaire (SGRQ) total score. 100 and 0 represent the worst and best possible respiratory health status, respectively. STATISTICAL ANALYSES: The two-part model (frequency (any worse respiratory health status) and severity (amount of worse respiratory health status)) was developed for the score, as the data were positively skewed with many zeros. RESULTS: The mean (SD) SGRQ total score was 7.7 (14.5), the median (IQR) was 0.9 (9.0), and the observed range was 0-86.6. The best possible SGRQ total score was reported by 46.9% of workers. Independent predictors of worse respiratory health status were cleaner domestic cooking fuel (coefficient -0.76, 95% CI -1.46 to -0.06, p=0.034) and personal history of any respiratory disease (1.76, 1.04 to 2.47, p<0.001) in case of frequency; and family history of any respiratory disease (0.43, 0.02 to 0.83, p=0.039) and personal history (1.19, 0.83 to 1.54, p<0.001) in case of severity. CONCLUSIONS: Less than half of the coal-based sponge iron plant workers in Barjora have the best possible respiratory health status. The predictors of worse respiratory health status were identified. The study findings could be taken into consideration in future interventional studies aimed at improving the respiratory health status of these workers. PMID- 25795697 TI - Initial healthcare and coping preferences are associated with outcome 1 year after whiplash trauma: a multicentre 1-year follow-up study. AB - OBJECTIVE: Individuals exposed to whiplash collisions have to cope with the stressful event as well as early physical symptoms. As in other chronic pain conditions, coping has been associated with outcome after whiplash. In this study, our aim was to examine whether initial coping preferences were associated with the development of chronic whiplash. DESIGN: Prospective study. SETTING: Primary care. METHODS: 740 acute whiplash patients were recruited from emergency units and general practitioners after car collisions in Denmark. Within 10 days postinjury, participants were asked what they believed could help them get better. At 12-month follow-up, the level of neck pain and capability to work was obtained. Whether coping preferences (baseline) were associated with outcome was investigated using multiple regression analyses. RESULTS: Persistent neck pain was most strongly associated with preferring medications (mean difference=1.24 (95% CI 0.67 to 1.82)) and sickness absence (mean difference=1.18 (95% CI 0.53 to 1.82)). Reduced work capability was most strongly associated with preferring medications (OR=3.53 (95% CI 2.13 to 5.86)), sickness absence (OR=3.05 (95% CI 1.80 to 5.17)) and being referred to a physiotherapist/chiropractor (OR=3.03 (95% CI 1.33 to 6.91)). Active coping was associated with better outcomes: Participants preferring to change their lifestyle were protected against reduced work capability (OR=0.11 (95% CI 0.01 to 0.78)). Individuals who wanted to keep living as usual only (no other preference reported) were protected against neck pain (mean difference -1.62 (95% CI -2.39 to -0.84)) and reduced work capability (OR=0.09 (95% CI 0.01 to 0.64)). CONCLUSIONS: A simple nine-item measure of coping preferences is associated with the development of chronic neck pain and reduced capability to work following whiplash trauma and may be used to identify individuals at risk of poor recovery. PMID- 25795698 TI - Patient and professional user experiences of simple telehealth for hypertension, medication reminders and smoking cessation: a service evaluation. AB - OBJECTIVES: To establish patient and professional user satisfaction with the Advice & Interactive Messaging (AIM) for Health programme delivered using a mobile phone-based, simple telehealth intervention, 'Florence'. DESIGN: A service evaluation using data extracted from Florence and from a professional user electronic survey. SETTING: 425 primary care practices across 31 Clinical Commissioning Groups in England. PARTICIPANTS: 3381 patients registered on 1 of 10 AIM protocols between March 2013 and January 2014 and 77 professional users. INTERVENTION: The AIM programme offered 10 clinical protocols, in three broad groups: (1) hypertension diagnosis/monitoring, (2) medication reminders and (3) smoking cessation. Florence sent patients prompts to submit clinical information, educational messages and user satisfaction questions. Patient responses were reviewed by their primary healthcare providers. PRIMARY OUTCOME MEASURES: Patients and professional user experiences of using AIM, and within this, Florence. RESULTS: Patient activity using Florence was generally good at month 1 for the hypertension protocols (71-80%), but reduced over 2-3 months (31-60%). For the other protocols, patient activity was 0-39% at 3 months. Minimum target days of texting were met for half the hypertension protocols. 1707/2304 (74%) patients sent evaluative texts responded at least once. Among responders, agreement with the adapted friends and family statement generally exceeded preproject aspirations. Professional responders were generally positive or equivocal about the programme. CONCLUSIONS: Satisfaction with AIM appeared optimal when patients were carefully selected for the protocol; professional users were familiar with the system, the programme addressed a problem with the previous service delivery that was identified by users and users took an active approach to achieve clinical goals. However, there was a significant decrease in patients' use of Florence over time. Future applications may be optimised by identifying and addressing reasons for the waning use of the service and enhancing support during implementation of the service. PMID- 25795691 TI - Nutrition and dietary intake and their association with mortality and hospitalisation in adults with chronic kidney disease treated with haemodialysis: protocol for DIET-HD, a prospective multinational cohort study. AB - INTRODUCTION: Adults with end-stage kidney disease (ESKD) treated with haemodialysis experience mortality of between 15% and 20% each year. Effective interventions that improve health outcomes for long-term dialysis patients remain unproven. Novel and testable determinants of health in dialysis are needed. Nutrition and dietary patterns are potential factors influencing health in other health settings that warrant exploration in multinational studies in men and women treated with dialysis. We report the protocol of the "DIETary intake, death and hospitalisation in adults with end-stage kidney disease treated with HaemoDialysis (DIET-HD) study," a multinational prospective cohort study. DIET-HD will describe associations of nutrition and dietary patterns with major health outcomes for adults treated with dialysis in several countries. METHODS AND ANALYSIS: DIET-HD will recruit approximately 10,000 adults who have ESKD treated by clinics administered by a single dialysis provider in Argentina, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and Turkey. Recruitment will take place between March 2014 and June 2015. The study has currently recruited 8000 participants who have completed baseline data. Nutritional intake and dietary patterns will be measured using the Global Allergy and Asthma European Network (GA(2)LEN) food frequency questionnaire. The primary dietary exposures will be n-3 and n-6 polyunsaturated fatty acid consumption. The primary outcome will be cardiovascular mortality and secondary outcomes will be all-cause mortality, infection-related mortality and hospitalisation. ETHICS AND DISSEMINATION: The study is approved by the relevant Ethics Committees in participating countries. All participants will provide written informed consent and be free to withdraw their data at any time. The findings of the study will be disseminated through peer-reviewed journals, conference presentations and to participants via regular newsletters. We expect that the DIET-HD study will inform large pragmatic trials of nutrition or dietary interventions in the setting of advanced kidney disease. PMID- 25795700 TI - Who speaks for whom? Health humanities and the ethics of representation. AB - The medical or health humanities are in essence a form of advocacy, a means of addressing a problem of underrepresentation. They focus on suffering, rather than pathology, and on sociocultural understandings of illness and disability, rather than a narrow biomedical perspective. The health humanities thus analyse and attempt to recalibrate the power imbalance in healthcare. This article reviews health humanities scholarship that addresses underrepresentation through the analysis of illness and disability narratives. It examines the ethics of representation by exploring how literary representation functions, its aesthetic as well as political dimensions, and how it operates as a relay mechanism for power. The mechanism of representation is further explored through a reading of Eli Clare's narrative Exile and Pride. Donna Haraway's notion of articulations is proposed as a tool for a more ethical approach to representation. The article suggests that transparency about the power health humanities scholars stand to gain through representation may contribute to a more ethical health humanities practice. PMID- 25795699 TI - REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial. AB - INTRODUCTION: Liver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy. METHODS AND ANALYSIS: Patients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 ug/kg body weight daily on days 1-5; group 3 treatment: G-CSF 15 ug/kg body weight daily on days 1-5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2*10(6) cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall alpha=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided alpha=0.05(overall alpha=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total). ETHICS AND DISSEMINATION: The trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335 41). The findings of this trial will be disseminated to patients and through peer reviewed publications and international presentations. PMID- 25795701 TI - Review of 'Palliative care in Amyotrophic Lateral Sclerosis from diagnosis to bereavement' by David Oliver, Gian Domenico Borasio, Wendy Johnson. PMID- 25795702 TI - PET/CT findings for tumors in the base of the skull: comparison of 18 F-FDG with 11 C-methionine. AB - BACKGROUND: Positron emission tomography/computed tomography (PET/CT) using 18 F fluorodeoxyglucose (FDG) has been used to characterize various malignancies. There are few reports regarding the use of 11 C-methionine (MET)-PET/CT to characterize tumors in the skull base. PURPOSE: To compare MET-PET/CT with FDG PET/CT in cases of tumors of the skull base. MATERIAL AND METHODS: Both MET PET/CT and FDG-PET/CT were performed in 27 patients with tumors of the skull base. In all cases, pathology was determined by surgery or biopsy. The images were visually and independently reviewed by two reviewers. For qualitative analysis, the inter-rater agreement between two reviewers was measured. For semi quantitative evaluation, the tumor-to-normal brain uptake ratios (T/N ratios) were calculated by dividing the maximum of standardized uptake value (SUVmax) for the tumor by the SUVmax of the normal contra-lateral cerebellar hemisphere. Difference in T/N ratios between FDG-PET/CT and MET-PET/CT was analyzed for statistical significance. RESULTS: On qualitative evaluation, the inter-rater agreement of MET-PET/CT was superior than that of FDG-PET/CT. MET uptake was interpreted as positive in every tumor by both reviewers. MET-PET/CT had a significantly higher T/N ratio than FDG-PET/CT (2.96 +/- 1.25 vs. 1.02 +/- 0.54, respectively; P < 0.001). CONCLUSION: MET-PET/CT showed superior inter-rater agreement and had higher uptake for tumors at the skull base than FDG-PET/CT. The present study suggests that MET-PET/CT has superior potential for imaging of tumors of the skull base. PMID- 25795703 TI - CT findings after lipiodol marking performed before video-assisted thoracoscopic surgery for small pulmonary nodules. AB - BACKGROUND: In preoperative lipiodol marking for small pulmonary nodules, lipiodol has a potential risk of distribution in the surrounding lung structure. There are no reports about the detailed accumulation and distribution of lipiodol. PURPOSE: To evaluate computed tomography (CT) findings after lipiodol marking before thoracoscopic surgery for pulmonary nodules. MATERIAL AND METHODS: Sixty-four consecutive CT-guided lipiodol markings for 103 nodules were performed in 55 patients. Lipiodol (0.2-0.4 mL) was injected using a 21-gauge needle near the nodule. The appearance of lipiodol spots was classified into the following three types on CT: type 1, dense; type 2, punctate; and type 3, unclear. The distribution of lipiodol was also investigated. Statistical analyses were performed on the accumulation and distribution related to nodule factors. Incidences of complications were also investigated. RESULTS: A total of 110 markings were performed because of seven additional procedures due to insufficient marking. All nodules were successfully resected on the same day. The appearances of the lipiodol spots were type 1 (82%), type 2 (11%), and type 3 (7.3%). The areas of distribution were lung parenchyma (54%), central bronchus (39%), peripheral bronchovascular bundle (24%), needle tract (20%), pleural space (19%), another segment of ipsilateral lung (5.5%), and contralateral lung (0.9%). Distribution into pleural space and central bronchus was frequently seen in the shallow nodules (P < 0.05). Complications were pneumothorax (61%) and pulmonary hemorrhage (35%). There were no serious symptoms. CONCLUSION: The appearance of the lipiodol spot was dense in most cases, despite frequent distribution in the surrounding lung structures without serious complications. PMID- 25795704 TI - Autism: reduced connectivity between cortical areas involved in face expression, theory of mind, and the sense of self. AB - Whole-brain voxel-based unbiased resting state functional connectivity was analysed in 418 subjects with autism and 509 matched typically developing individuals. We identified a key system in the middle temporal gyrus/superior temporal sulcus region that has reduced cortical functional connectivity (and increased with the medial thalamus), which is implicated in face expression processing involved in social behaviour. This system has reduced functional connectivity with the ventromedial prefrontal cortex, which is implicated in emotion and social communication. The middle temporal gyrus system is also implicated in theory of mind processing. We also identified in autism a second key system in the precuneus/superior parietal lobule region with reduced functional connectivity, which is implicated in spatial functions including of oneself, and of the spatial environment. It is proposed that these two types of functionality, face expression-related, and of one's self and the environment, are important components of the computations involved in theory of mind, whether of oneself or of others, and that reduced connectivity within and between these regions may make a major contribution to the symptoms of autism. PMID- 25795705 TI - TLR5 Ligand-Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity. AB - The tumor microenvironment counters antitumor T-cell responses, in part, by blunting their activation and infiltration. Ligands that engage Toll-like receptors (TLR) on T cells and antigen-presenting cells can act as potent immune adjuvants. In this study, we show how tumor-reactive T cells engineered to secrete bacterial flagellin, a TLR5 ligand (TLR5L), can engender a costimulatory signal that augments antitumor activity. Human T cells engineered to express TLR5L along with DMF5, a T-cell receptor that recognizes the melanoma antigen MART-127-35 (DMF5(TLR5L) T cells), displayed increased proliferation, cytokine production, and cytolytic activity against melanoma cells. In a xenogenetic model, adoptive transfer of DMF5(TLR5L) T cells reduced tumor growth kinetics and prolonged mouse survival. In a syngeneic model, similarly engineered melanoma reactive T cells (pmel(TLR5L)) displayed a relative increase in antitumor activity against established tumors, compared with unmodified T cells. In this model, we documented increased T-cell infiltration associated with increased levels of CCR1 and CXCR3 levels on T cells, a reduction in PD-1(+)Lag3(+) T cells and CD11(+)Gr1(+) myeloid-derived suppressor cells, and changes in the chemokine/cytokine profile of tumors. Our findings show how T cell-mediated delivery of a TLR agonist to the tumor site can contribute to antitumor efficacy, in the context of adoptive T-cell immunotherapy. PMID- 25795706 TI - IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia. AB - IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert alpha ketoglutarate (alpha-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of alpha-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM)(+/-) hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc(+) cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy. PMID- 25795709 TI - Nerve-Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression. AB - Recent studies have revealed the essential role played by nerves in tumor progression. Nerves have been shown to infiltrate the tumor microenvironment and actively stimulate cancer cell growth and dissemination. This mechanism involves the release of neurotransmitters, such as catecholamines and acetylcholine, directly into the vicinity of cancer and stromal cells to activate corresponding membrane receptors. Conversely, the secretion of neurotrophic growth factors by cancer cells drives the outgrowth of nerves in solid tumors. This reciprocal interaction between nerves and cancer cells provides new insights into the cellular and molecular bases of tumorigenesis and points to the potential utility of antineurogenic therapies. This review will discuss our evolving understanding of the cross-talk between nerves and cancer cells. PMID- 25795707 TI - Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas. AB - Muscle-invasive urothelial carcinomas of the bladder (MIUCB) exhibit frequent receptor tyrosine kinase alterations, but the precise nature of their contributions to tumor pathophysiology is unclear. Using mutant HRAS (HRAS*) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year. This persistent hyperplastic state appeared to result from an equilibrium between promitogenic factors and compensatory tumor barriers in the p19-MDM2-p53 p21 axis and a prolonged G2 arrest. Conditional inactivation of p53 in urothelial cells of transgenic mice expressing HRAS* resulted in carcinoma in situ and basal subtype MIUCB with focal squamous differentiation resembling the human counterpart. The transcriptome of microdissected MIUCB was enriched in genes that drive epithelial-to-mesenchymal transition, the upregulation of which is associated with urothelial cells expressing multiple progenitor/stem cell markers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker that may inform the progression and treatment of urothelial carcinoma. PMID- 25795710 TI - Atrioventricular plane displacement is the sole mechanism of atrial and ventricular refill. PMID- 25795708 TI - Nitrostyrene Derivatives Act as RXRalpha Ligands to Inhibit TNFalpha Activation of NF-kappaB. AB - Retinoid X receptor alpha (RXRalpha) and its N-terminally truncated version, tRXRalpha, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRalpha and tRXRalpha requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXRalpha by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRalpha are required for binding. The binding results in the potent activation of Gal4-DBD-RXRalpha-LBD transactivation. However, the binding inhibits the transactivation of RXRalpha homodimer, which might be due to the distinct conformation of RXRalpha homodimer induced by these nitrostyrene derivatives. Two RXRalpha point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of autotransactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit the TNFalpha/NFkappaB signaling pathway in a tRXRalpha-dependent manner. tRXRalpha promotes TNFalpha-induced NF-kappaB activation through its interaction with TRAF2 and enhances TNFalpha-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFalpha induced NF-kappaB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFalpha on the induction of cancer cell apoptosis. Together, our results show a new class of RXRalpha modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action. PMID- 25795711 TI - Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction. AB - Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI. PMID- 25795712 TI - Peripheral microvascular function is altered in young individuals at risk for hypertrophic cardiomyopathy and correlates with myocardial diastolic function. AB - Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young. Based on previous reports of functional abnormalities in not only coronary but also peripheral vessels in adults with HCM, we aimed to assess both peripheral vascular and myocardial diastolic function in young individuals with an early stage of HCM and in individuals at risk for HCM. Children, adolescents, and young adults (mean age: 12 yr) with a family history of HCM who either had (HCM group; n = 36) or did not have (HCM-risk group; n = 30) echocardiography documented left ventricular (LV) hypertrophy as well as healthy matched controls (n = 85) and healthy young athletes (n = 12) were included in the study. All underwent assessment with 12-lead electrocardiography, two-dimensional echocardiography, tissue Doppler imaging and laser Doppler with transdermal iontophoresis of ACh and sodium nitroprusside. LV thickness and mass were increased in HCM and athlete groups compared with control and HCM-risk groups. The mitral E-to-e' ratio, measured via tissue Doppler, was increased in HCM (P < 0.0001) and HCM-risk (P < 0.01) groups compared with control and athlete groups, as were microvascular responses to ACh (HCM group: P = 0.045 and HCM-risk group: P = 0.02). Responses to ACh correlated with the E-to-e' ratio (r = 0.5, P = 0.001). Microvascular responses to sodium nitroprusside were similar in all groups (P > 0.2). HCM-causing mutations or its familial history are associated with changes in cardiac diastolic function and peripheral microvascular function even before the onset of myocardial hypertrophy. Tissue Doppler can be used to differentiate HCM from physiological LV hypertrophy in young athletes. PMID- 25795713 TI - A novel pharmacological strategy by PTEN inhibition for improving metabolic resuscitation and survival after mouse cardiac arrest. AB - Sudden cardiac arrest (SCA) is a leading cause of death in the United States. Despite return of spontaneous circulation, patients die due to post-SCA syndrome that includes myocardial dysfunction, brain injury, impaired metabolism, and inflammation. No medications improve SCA survival. Our prior work suggests that optimal Akt activation is critical for cooling protection and SCA recovery. Here, we investigate a small inhibitor of PTEN, an Akt-related phosphatase present in heart and brain, as a potential therapy in improving cardiac and neurological recovery after SCA. Anesthetized adult female wild-type C57BL/6 mice were randomized to pretreatment of VO-OHpic (VO) 30 min before SCA or vehicle control. Mice underwent 8 min of KCl-induced asystolic arrest followed by CPR. Resuscitated animals were hemodynamically monitored for 2 h and observed for 72 h. Outcomes included heart pressure-volume loops, energetics (phosphocreatine and ATP from (31)P NMR), protein phosphorylation of Akt, GSK3beta, pyruvate dehydrogenase (PDH) and phospholamban, circulating inflammatory cytokines, plasma lactate, and glucose as measures of systemic metabolic recovery. VO reduced deterioration of left ventricular maximum pressure, maximum rate of change in the left ventricular pressure, and Petco2 and improved 72 h neurological intact survival (50% vs. 10%; P < 0.05). It reduced plasma lactate, glucose, IL-1beta, and Pre-B cell colony enhancing factor, while increasing IL-10. VO increased phosphorylation of Akt and GSK3beta in both heart and brain, and cardiac phospholamban phosphorylation while reducing p-PDH. Moreover, VO improved cardiac bioenergetic recovery. We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA. PTEN inhibitors may be a novel pharmacologic strategy for treating SCA. PMID- 25795714 TI - The role of cardiac sympathetic innervation and skin thermoreceptors on cardiac responses during heat stress. AB - The mechanism(s) for the changes in cardiac function during heat stress remain unknown. This study tested two unique hypotheses. First, sympathetic innervation to the heart is required for increases in cardiac systolic function during heat stress. This was accomplished by comparing responses during heat stress between paraplegics versus tetraplegics, with tetraplegics having reduced/absent cardiac sympathetic innervation. Second, stimulation of skin thermoreceptors contributes to cardiovascular adjustments that occur during heat stress in humans. This was accomplished by comparing responses during leg only heating between paraplegic versus able-bodied individuals. Nine healthy able-bodied, nine paraplegics, and eight tetraplegics participated in this study. Lower body (i.e., nonsensed area for para/tetraplegics) was heated until esophageal temperature had increased by ~1.0 degrees C. Echocardiographic indexes of diastolic and systolic function were performed before and at the end of heat stress. The heat stress increased cardiac output in all groups, but the magnitude of this increase was attenuated in the tetraplegics relative to the able-bodied (1.3 +/- 0.4 vs. 2.3 +/- 1.0 l/min; P < 0.05). Diastolic function was maintained in all groups. Indexes of left atrial and ventricular systolic function were enhanced in the able-bodied, but did not change in tetraplegics, while these changes in paraplegics were attenuated relative to the able-bodied. These data suggest that the cardiac sympathetic innervation is required to achieve normal increases in cardiac systolic function during heat stress but not required to maintain diastolic function during this exposure. Second, elevated systolic function during heat stress primarily occurs as a result of increases in internal temperature, although stimulation of skin thermoreceptors may contribute. PMID- 25795715 TI - WNT10A promotes an invasive and self-renewing phenotype in esophageal squamous cell carcinoma. AB - Esophageal cells overexpressing epidermal growth factor receptor (EGFR) and TP53 mutation can invade into the extracellular matrix when grown in 3D-organotypic cultures (OTC) and mimic early invasion in esophageal squamous cell carcinoma (ESCC). We have performed laser capture microdissection with RNA microarray analysis on the invasive and non-invasive tumor cells of p53(R175H) overexpressing OTC samples to determine candidate genes facilitating tumor invasion. WNT10A was found to be >4-fold upregulated in the invasive front. Since WNT10A is also prominently upregulated during placode promotion in hair follicle development, a process that requires epithelial cells to thicken and elongate, in order to allow downward growth, we hypothesized that WNT10A may be important in mediating a similar mechanism of tumor cell invasion in ESCC. We have found that WNT10A expression is significantly upregulated in human ESCC, when compared with normal adjacent tissue. Furthermore, high WNT10A expression levels correlate with poor survival. Interestingly, we observe that WNT10A is expressed early in embryogenesis, but is reduced dramatically postnatally. We demonstrate that overexpression of WNT10a promotes migration and invasion, and proliferation of transformed esophageal cells. Lastly, we show that WNT10A overexpression induces a greater CD44(High)/CD24(Low) population, which are putative markers of cancer stem cells, and increases self-renewal capability. Taken together, we propose that WNT10A acts as an oncofetal factor that is highly expressed and may promote proper development of the esophagus. During tumorigenesis, it is aberrantly overexpressed in order to promote ESCC migration and invasion, and may be linked to self-renewal of a subset of ESCC cells. PMID- 25795716 TI - Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern. PMID- 25795717 TI - Risk of bleeding and use of platelet transfusions in patients with hematologic malignancies: recurrent event analysis. AB - A recent randomized trial (TOPPS) compared prophylactic platelet transfusions (for counts <10*10(9)/L) with a strategy of no-prophylaxis in adults with hematologic malignancies. Seventy percent of enrolled patients received an autologous hematopoietic stem cell transplant. Statistical models were developed to explore which patient factors or clinical characteristics are important prognostic factors for bleeding. These models were presented for baseline characteristics and for recurrent analysis of bleeding to assess the risks of World Health Organization grade 2-4 bleeding on any given day. Additional analyses explored the importance of fever. Treatment plan (chemotherapy/allogeneic hematopoietic stem cell transplant), female sex, and treatment arm (no-prophylaxis) were significantly associated with an increased number of days of bleeding. The number of days with a platelet count <10*109/L was significantly associated with a grade 2-4 bleed (P<0.0001). Patients with a temperature of at least 38 degrees C had the highest hazard of a grade 2-4 bleed (hazard ratio: 1.7, 95% confidence interval: 1.3 to 2.4, compared with the risk in patients with a temperature <37.5 degrees C). There was no evidence that minor bleeding predicted a grade 2-4 bleed. The results highlighted the limited role of correction of thrombocytopenia by platelet transfusion in reducing the risk of bleeding. Clinically stable patients undergoing autologous hematopoietic stem cell transplantation had the lowest risk of bleeding and benefited least from prophylactic platelet transfusions. Prospective studies are required to address the usefulness of risk factors to support better targeted platelet transfusions. TOPPS Controlled-Trials.com number ISRCTN08758735. PMID- 25795719 TI - Effect of allogeneic hematopoietic cell transplantation in first complete remission on post-relapse complete remission rate and survival in acute myeloid leukemia. PMID- 25795720 TI - Evidence of long-term disease control with panobinostat maintenance in patients with relapsed multiple myeloma. PMID- 25795718 TI - The heme exporter Flvcr1 regulates expansion and differentiation of committed erythroid progenitors by controlling intracellular heme accumulation. AB - Feline leukemia virus subgroup C receptor 1 (Flvcr1) encodes two heme exporters: FLVCR1a, which localizes to the plasma membrane, and FLVCR1b, which localizes to mitochondria. Here, we investigated the role of the two Flvcr1 isoforms during erythropoiesis. We showed that, in mice and zebrafish, Flvcr1a is required for the expansion of committed erythroid progenitors but cannot drive their terminal differentiation, while Flvcr1b contributes to the expansion phase and is required for differentiation. FLVCR1a-down-regulated K562 cells have defective proliferation, enhanced differentiation, and heme loading in the cytosol, while FLVCR1a/1b-deficient K562 cells show impairment in both proliferation and differentiation, and accumulate heme in mitochondria. These data support a model in which the coordinated expression of Flvcr1a and Flvcr1b contributes to control the size of the cytosolic heme pool required to sustain metabolic activity during the expansion of erythroid progenitors and to allow hemoglobinization during their terminal maturation. Consistently, reduction or increase of the cytosolic heme rescued the erythroid defects in zebrafish deficient in Flvcr1a or Flvcr1b, respectively. Thus, heme export represents a tightly regulated process that controls erythropoiesis. PMID- 25795721 TI - A magnetic resonance imaging-based prognostic scoring system to predict outcome in transplant-eligible patients with multiple myeloma. AB - Diffuse and focal bone marrow infiltration patterns detected by magnetic resonance imaging have been shown to be of prognostic significance in all stages of monoclonal plasma cell disorders and have, therefore, been incorporated into the definition of the disease. The aim of this retrospective analysis was to develop a rapidly evaluable prognostic scoring system, incorporating the most significant information acquired from magnetic resonance imaging. Therefore, the impact of bone marrow infiltration patterns on progression-free and overall survival in 161 transplant-eligible myeloma patients was evaluated. Compared to salt and pepper/minimal diffuse infiltration, moderate/severe diffuse infiltration had a negative prognostic impact on both progression-free survival (P<0.001) and overall survival (P=0.003). More than 25 focal lesions on whole body magnetic resonance imaging or more than seven on axial magnetic resonance imaging were associated with an adverse prognosis (progression-free survival: P=0.001/0.003 and overall survival: P=0.04/0.02). A magnetic resonance imaging based prognostic scoring system, combining grouped diffuse and focal infiltration patterns, was formulated and is applicable to whole-body as well as axial magnetic resonance imaging. The score identified high-risk patients with median progression-free and overall survival of 23.4 and 55.9 months, respectively (whole-body-based). Multivariate analyses demonstrated that the magnetic resonance imaging-based prognostic score stage III (high-risk) and adverse cytogenetics are independent prognostic factors for both progression-free and overall survival (whole-body-based, progression-free survival: hazard ratio=3.65, P<0.001; overall survival: hazard ratio=5.19, P=0.005). In conclusion, we suggest a magnetic resonance imaging-based prognostic scoring system which is a robust, easy to assess and interpret parameter summarizing significant magnetic resonance imaging findings in transplant-eligible patients with multiple myeloma. PMID- 25795723 TI - FDI World Dental Federation: responding to new realities of oral health. PMID- 25795722 TI - Resimmune, an anti-CD3epsilon recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma. AB - Resimmune is a second-generation recombinant immunotoxin composed of the catalytic and translocation domains of diphtheria toxin fused to two single chain antibody fragments reactive with the extracellular domain of CD3epsilon. We gave intravenous infusions of Resimmune 2.5 - 11.25 MUg/kg over 15 minutes to 30 patients (25 with cutaneous T-cell lymphoma, 3 with peripheral T-cell lymphoma, 1 with T-cell large granular lymphocytic leukemia and 1 with T-cell prolymphocytic leukemia) in an inter-patient dose escalation trial. The most common adverse events were fever, chills, hypotension, edema, hypoalbuminemia, hypophosphatemia, and transaminasemia. Among the 25 patients with cutaneous T-cell lymphoma, there were nine responses for a response rate of 36% (95% CI, 18%-57%) including four complete remissions (16%, 95% CI, 5%-36%). The durations of the complete remissions were 72+, 72+, 60+ and 38+ months. There were five partial remissions lasting 3, 3, 3+, 6+ and 14 months. Of 17 patients with a modified skin weighted assessment tool score <50, 17 patients with stage IB/IIB, and 11 patients with both a score <50 and stage IB/IIB, nine (53%), eight (47%), and eight (73%) had responses, respectively. Further studies of Resimmune in patients with low tumor burden, stage IB-IIB cutaneous T-cell lymphoma are warranted. This trial is registered at clinicaltrials.gov as #NCT00611208. PMID- 25795724 TI - Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs. AB - Fragments of the mitochondrial genome released into the systemic circulation after mechanical trauma, termed mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs), are thought to mediate the systemic inflammatory response syndrome. The close association between circulating mtDNA DAMP levels and outcome in sepsis suggests that bacteria also might be a stimulus for mtDNA DAMP release. To test this hypothesis, we measured mtDNA DAMP abundance in medium perfusing isolated rat lungs challenged with an intratracheal instillation of 5 * 10(7) colony-forming units of Pseudomonas aeruginosa (strain 103; PA103). Intratracheal PA103 caused rapid accumulation of selected 200-bp sequences of the mitochondrial genome in rat lung perfusate accompanied by marked increases in both lung tissue oxidative mtDNA damage and in the vascular filtration coefficient (Kf). Increases in lung tissue mtDNA damage, perfusate mtDNA DAMP abundance, and Kf were blocked by addition to the perfusion medium of a fusion protein targeting the DNA repair enzyme Ogg1 to mitochondria. Intra-arterial injection of mtDNA DAMPs prepared from rat liver mimicked the effect of PA103 on both Kf and lung mtDNA integrity. Effects of mtDNA and PA103 on Kf were also attenuated by an oligodeoxynucleotide inhibitor of Toll-like receptor 9 (TLR-9) by mitochondria-targeted Ogg1 and by addition of DNase1 to the perfusion medium. Collectively, these findings are consistent with a model wherein PA103 causes oxidative mtDNA damage leading to a feed-forward cycle of mtDNA DAMP formation and TLR-9-dependent mtDNA damage that culminates in acute lung injury. PMID- 25795725 TI - c-Abl mediated tyrosine phosphorylation of paxillin regulates LPS-induced endothelial dysfunction and lung injury. AB - Paxillin is phosphorylated at multiple residues; however, the role of tyrosine phosphorylation of paxillin in endothelial barrier dysfunction and acute lung injury (ALI) remains unclear. We used siRNA and site-specific nonphosphorylable mutants of paxillin to abrogate the function of paxillin to determine its role in lung endothelial permeability and ALI. In vitro, lipopolysaccharide (LPS) challenge of human lung microvascular endothelial cells (HLMVECs) resulted in enhanced tyrosine phosphorylation of paxillin at Y31 and Y118 with no significant change in Y181 and significant barrier dysfunction. Knockdown of paxillin with siRNA attenuated LPS-induced endothelial barrier dysfunction and destabilization of VE-cadherin. LPS-induced paxillin phosphorylation at Y31 and Y118 was mediated by c-Abl tyrosine kinase, but not by Src and focal adhesion kinase. c-Abl siRNA significantly reduced LPS-induced endothelial barrier dysfunction. Transfection of HLMVECs with paxillin Y31F, Y118F, and Y31/118F double mutants mitigated LPS induced barrier dysfunction and VE-cadherin destabilization. In vivo, the c-Abl inhibitor AG957 attenuated LPS-induced pulmonary permeability in mice. Together, these results suggest that c-Abl mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates LPS-mediated pulmonary vascular permeability and injury. PMID- 25795726 TI - Increased expression of neutrophil-related genes in patients with early sepsis induced ARDS. AB - The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS. PMID- 25795728 TI - Molecular dissection of Mycobacterium tuberculosis integration host factor reveals novel insights into the mode of DNA binding and nucleoid compaction. PMID- 25795727 TI - Roflumilast combined with adenosine increases mucosal hydration in human airway epithelial cultures after cigarette smoke exposure. AB - Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide. Recent studies have shown that cigarette smoke (CS) induces cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, which leads to airway-surface liquid (ASL) dehydration. This in turn contributes to the mucus dehydration and impaired mucociliary clearance that are seen in the chronic bronchitis form of COPD. Roflumilast is a phosphodiesterase 4 inhibitor that may improve lung function and reduce the frequency of exacerbations in patients with COPD. Although roflumilast can affect cAMP metabolism, little is known about the downstream pharmacological effects in the airways. We hypothesized that roflumilast would increase ASL rehydration in human bronchial epithelial cultures (HBECs) after chronic CS exposure. cAMP production was measured by Forster resonance energy transfer in HEK293T cells and by ELISA in HBECs. ASL height was measured by xz-confocal microscopy after air exposure or following HBEC exposure to freshly produced CS. Roflumilast had little effect on cAMP or ASL height when applied on its own; however, roflumilast significantly potentiated adenosine induced increases in cAMP and ASL height in CS-exposed HBECs. Roflumilast increased the rate of ASL height recovery in cultures after CS exposure compared with controls. In contrast, the beta2-adrenergic receptor agonists isoproterenol and salmeterol failed to increase ASL height after CS exposure. Our data suggest that roflumilast can increase ASL hydration in CS-exposed HBECs, which is predicted to be beneficial for the treatment of mucus dehydration/mucus stasis in patients with COPD chronic bronchitis. PMID- 25795729 TI - Identification of a second substrate-binding site in solute-sodium symporters. PMID- 25795730 TI - Detecting collagen VI in Bethlem myopathy. PMID- 25795731 TI - Does the dorsal mesenchymal protrusion act as a temporary pacemaker during heart development? PMID- 25795732 TI - Validity of the Paddington Alcohol Test in an Australian Emergency Department?. AB - AIM: The aim of this study was to validate a modified version of the Paddington Alcohol Test for use in the Australian emergency department (ED) setting. METHODS: A cross sectional survey was used to screen patients attending an Australian tertiary hospital ED. Data were collected over a three-month period at randomly allocated time periods and days. Consenting participants were screened using the Alcohol Use Disorders Identification Test (AUDIT) and a modified-for Australia version of the Paddington Alcohol Test (AusPAT). The association between the two tools was investigated, as well as the sensitivity and specificity of AusPAT at various AUDIT cut-off scores and by gender and age group. RESULTS: The sample comprised 637 ED attendees. Their mean age was 49.9 (SD 20.0) years with a mean AUDIT score of 5.21 (SD 6.58). Most (73.2%) consumed alcohol, and a quarter was AusPAT-positive (n = 153, 24.0%). AusPAT demonstrated a moderate fit with AUDIT at a cut-off score of 8 (Kappa = 0.63, P < 0.001). At this cut-off 23.4% (n = 149) were identified by AUDIT as problematic drinkers. AusPAT sensitivity was 72.5% (95% CI 65.3-79.7) with a specificity of 90.8% (95% CI 88.3-93.4). CONCLUSION: Our results indicate that AusPAT was moderately well associated with AUDIT. When used universally in the ED setting, its sensitivity and specificity were moderate. PMID- 25795733 TI - Expression of p40 and laminin 332 in metaplastic spindle cell carcinoma of the breast compared with other malignant spindle cell tumours. AB - AIMS: To determine the use of p40 and laminin 332 (LN332) immunostains for diagnosing metaplastic carcinoma by studying the expression of these and other routine markers in spindle cell metaplastic carcinomas and other malignant spindle cell tumours. METHODS: We identified cases of spindle cell metaplastic carcinoma (n=36) and other atypical/malignant spindle cell tumours, including 20 phyllodes tumours (14 borderline, six malignant) and 23 spindle cell sarcomas (three primary to breast). Immunohistochemical staining was performed for p40 and two LN332 chains, beta3 (kalinin B1) and gamma2 (lamC2). The expression of these markers was compared with p63 and cytokeratins. RESULTS: p40 and p63 expression was seen in 21 of 36 (58.3%) and 33 of 36 (91.7%) metaplastic carcinomas, respectively. No phyllodes tumours showed stromal expression of p40 or p63. One of 23 (4.3%) sarcomas showed focal weak p63 staining. LamC2 and kalinin B1 expression was seen in 28 of 36 (77.8%) and 26 of 36 (72.2%) metaplastic carcinomas, respectively. LamC2 and kalinin B1 each showed positive stromal cell expression in two of 20 (10%) phyllodes tumours. No sarcomas showed staining with lamC2. Kalinin B1 staining was seen in 17 of 23 (73.9%) sarcomas, including two of three primary breast sarcomas. Cytokeratin expression was seen in 32 of 36 (88.9%) metaplastic carcinomas and diffuse staining was most often seen in 34betaE12 and CK5. CONCLUSIONS: The diagnostic value of relatively novel markers p40 and LN332 was found to be less than that of routinely used markers (p63 and cytokeratins). p40 proved to be a specific marker but lacked the sensitivity of p63, while LN332 showed staining in a significant proportion of phyllodes tumours and sarcomas. PMID- 25795735 TI - The impact of the economic crisis on unmet dental care needs in Spain. AB - OBJECTIVES: To analyse the impact that the economic crisis and the evolution of socioeconomic inequality before (2007) and during (2011) the current crisis have had on unmet dental care needs in Spain. METHODS: The Living Conditions Surveys from the years 2007 and 2011 were used, including 44 138 adults aged under 65 years. A descriptive and stratified analysis was carried out along with the calculation of the concentration index and a multivariate logistic regression jointly and separately by gender. The dependent variable was unmet dental care needs and the independent variables were income, employment status, gender, age, education and chronic disease. A dummy variable was created for the year of survey completion as a proxy measure for the economic crisis. The SPSS V.20 software was used. RESULTS: During the period under analysis, the unmet needs for dental services increased (from 6.2% to 7.2%) along with the concentration index (from -0.1412 to -0.189). The main correlations with unmet needs were: unemployment (OR=1.46), lower income (OR=2.44 for the income quintile) and the year 2011 with respect to 2007 (OR 1.13). For women, the OR is greater according to income level (2.44 compared with 1.77 in men) and the year 2011 (1.21 compared with 1.06), while for men unemployment had a greater effect (OR=1.52 compared with 1.46). CONCLUSIONS: There has been an increase in unmet dental care needs as well as in the social gradient for service access. The most vulnerable groups are those with less purchasing power and the unemployed. The economic crisis has also increased this unmet need. PMID- 25795734 TI - Ethnic differences in risk factors for obesity in New Zealand infants. AB - BACKGROUND: In New Zealand, the burden of childhood obesity is greatest in Maori and Pacific children. METHODS: In 687 infants from an internet-based birth cohort in New Zealand, we investigated ethnic differences in early life risk factors for later obesity, the degree to which these were explained by sociodemographic factors, and the extent to which ethnic differences in weight at age 3 months were explained by measured risk factors. RESULTS: The risk of having an obese mother was double in Maori and Pacific infants compared with NZ European infants (prevalence 24% and 14%, respectively; OR 2.23, 95% CI 1.23 to 4.04). Maori and Pacific infants had higher weights in the first week of life and at 3 months (mean difference 0.19 kg, 95% CI 0.01 to 0.38), and their mothers had higher scores on a 'snacks' dietary pattern and lower scores on 'healthy' and 'sweet' dietary patterns. These inequalities were not explained by maternal education, maternal age or area-based deprivation. No ethnic differences were observed for maternal pre-pregnancy physical activity, hypertension or diabetes in pregnancy, exclusive breastfeeding or early introduction of solid foods. Ethnic inequalities in infant weight at 3 months were not explained by sociodemographic variables, maternal pre-pregnancy body mass index or dietary pattern scores or by other measured risk factors. CONCLUSIONS: This study shows excess prevalence of early life risk factors for obesity in Maori and Pacific infants in New Zealand and suggests an urgent need for early interventions for these groups. PMID- 25795736 TI - Intraspecific metabolic scaling exponent depends on red blood cell size in fishes. AB - The metabolic-level boundaries (MLB) hypothesis and the cell metabolism (CM) hypothesis have been proposed to explain the body mass scaling of metabolic rate. The MLB hypothesis focuses mainly on the influence of the metabolic level on the relative importance of volume and surface area constraints. The CM hypothesis focuses on the variation of cell size as the body grows. The surface area to volume ratio of individual cells may vary among species with different cell sizes, by which surface area constraints on metabolic scaling may change according to the MLB hypothesis. The present study aimed to extend the MLB and the CM hypotheses by proposing that, in addition to metabolic level, the varying cell surface area constraints among species also influence the intraspecific scaling exponents. The red blood cell area (S), and intraspecific scaling exponents for resting (bR) and maximum metabolic rates of four species of cyprinids were assessed. The scaling exponents varied among species, but mass specific resting metabolic rates (RMR) of each species were similar. No significant correlation was found between S and mass-specific RMR among species. As predicted, a significantly negative relationship exists between S and bR among species. The results suggest that the varying bR could be attributed to cell size differences among species, as those with larger cells may face stronger surface boundary limits, as predicted by the MLB hypothesis. This mechanism represents an additional way of relating the MLB and the CM hypotheses and does not exclude another mechanism based on the recent contextual multimodal theory. PMID- 25795737 TI - Evolution of US maize (Zea mays L.) root architectural and anatomical phenes over the past 100 years corresponds to increased tolerance of nitrogen stress. AB - Increasing the nitrogen use efficiency of maize is an important goal for food security and agricultural sustainability. In the past 100 years, maize breeding has focused on yield and above-ground phenes. Over this period, maize cultivation has changed from low fertilizer inputs and low population densities to intensive fertilization and dense populations. The authors hypothesized that through indirect selection the maize root system has evolved phenotypes suited to more intense competition for nitrogen. Sixteen maize varieties representing commercially successful lines over the past century were planted at two nitrogen levels and three planting densities. Root systems of the most recent material were 7 o more shallow, had one less nodal root per whorl, had double the distance from nodal root emergence to lateral branching, and had 14% more metaxylem vessels, but total mextaxylem vessel area remained unchanged because individual metaxylem vessels had 12% less area. Plasticity was also observed in cortical phenes such as aerenchyma, which increased at greater population densities. Simulation modelling with SimRoot demonstrated that even these relatively small changes in root architecture and anatomy could increase maize shoot growth by 16% in a high density and high nitrogen environment. The authors concluded that evolution of maize root phenotypes over the past century is consistent with increasing nitrogen use efficiency. Introgression of more contrasting root phene states into the germplasm of elite maize and determination of the functional utility of these phene states in multiple agronomic conditions could contribute to future yield gains. PMID- 25795739 TI - Use of crop simulation modelling to aid ideotype design of future cereal cultivars. AB - A major challenge of the 21st century is to achieve food supply security under a changing climate and roughly a doubling in food demand by 2050 compared to present, the majority of which needs to be met by the cereals wheat, rice, maize, and barley. Future harvests are expected to be especially threatened through increased frequency and severity of extreme events, such as heat waves and drought, that pose particular challenges to plant breeders and crop scientists. Process-based crop models developed for simulating interactions between genotype, environment, and management are widely applied to assess impacts of environmental change on crop yield potentials, phenology, water use, etc. During the last decades, crop simulation has become important for supporting plant breeding, in particular in designing ideotypes, i.e. 'model plants', for different crops and cultivation environments. In this review we (i) examine the main limitations of crop simulation modelling for supporting ideotype breeding, (ii) describe developments in cultivar traits in response to climate variations, and (iii) present examples of how crop simulation has supported evaluation and design of cereal cultivars for future conditions. An early success story for rice demonstrates the potential of crop simulation modelling for ideotype breeding. Combining conventional crop simulation with new breeding methods and genetic modelling holds promise to accelerate delivery of future cereal cultivars for different environments. Robustness of model-aided ideotype design can further be enhanced through continued improvements of simulation models to better capture effects of extremes and the use of multi-model ensembles. PMID- 25795738 TI - ABI1 regulates carbon/nitrogen-nutrient signal transduction independent of ABA biosynthesis and canonical ABA signalling pathways in Arabidopsis. AB - Plants are able to sense and mediate the balance between carbon (C) and nitrogen (N) nutrient availability to optimize metabolism and growth, described as the C/N response. To clarify the C/N signalling mechanism, C/N-insensitive plants were obtained from an Arabidopsis FOX hunting population, which over-expresses full length cDNAs for individuals. The resulting cni2-D (carbon/nitrogen insensitive 2 dominant) plant was found to overcome the post-germination growth checkpoint and to expand green cotyledons in disrupted high C/low N stress conditions. The CNI2 gene encodes ABI1, a phosphatase type 2C protein, which negatively regulates abscisic acid (ABA) signal transduction. Over-expressors of ABI1 were found to be insensitive to disrupted C/N stress, whereas the loss-of function mutant abi1-2 was hypersensitive, suggesting that ABI1 plays an essential role in the plant C/N response. By contrast, the C/N-dependent growth phenotype observed in wild-type plants was not associated with endogenous ABA content. Accordingly, the ABA insensitive mutant abi1-1, which could not bind to the ABA-ABA receptor complex, was not insensitive and restored normal sensitivity to high C/low N stress. The canonical ABA signalling mutants abi4 and abi5 were also sensitive to disrupted C/N stress. Further gene expression analysis demonstrated that several genes in the SnRK2s and SnRK1s pathways are transcriptionally affected by high C/low N stress in wild-type plants regardless of the lack of increased endogenous ABA contents, whereas the expression of these genes were significantly suppressed in ABI1 over-expressors. Taken together, these results suggest direct cross-talk between C/N and non-canonical ABA signalling pathways, regulated by ABI1, in plants. PMID- 25795740 TI - Genome-wide analysis reveals dynamic changes in expression of microRNAs during vascular cambium development in Chinese fir, Cunninghamia lanceolata. AB - MicroRNAs (miRNAs) are small noncoding regulatory RNAs that play key roles in the process of plant development. To date, extensive studies of miRNAs have been performed in a few model plants, but few efforts have focused on small RNAs (sRNAs) in conifers because of the lack of reference sequences for their enormous genomes. In this study, Solexa sequencing of three sRNA libraries obtained from dormant, reactivating, and active vascular cambium in Chinese fir (Cunninghamia lanceolata) using tangential cryosectioning identified 20 known miRNA families and 18 novel potential miRNAs, of which nine novel miRNA precursors were validated by RT-PCR and sequencing. More than half of these novel miRNAs displayed stage-specific expression patterns in the vascular cambium. Furthermore, analysing the 103 miRNAs and their predicted targets indicated that about 70% appeared to negatively regulate their targets, of which two target genes involved in the regulation of cambial cell division were validated via RNA ligase-mediated rapid amplification of 5'-cDNA ends (RLM 5'-RACE) and transient co-expression in Nicotiana benthamiana leaves. Interestingly, miRNA156 and miRNA172 may regulate the phase transition in vascular cambium from dormancy to active growth. These results provide new insights into the important regulatory functions of miRNAs in vascular cambium development and wood formation in conifers. PMID- 25795741 TI - The Head Injury Retrieval Trial (HIRT): a single-centre randomised controlled trial of physician prehospital management of severe blunt head injury compared with management by paramedics only. AB - BACKGROUND: Advanced prehospital interventions for severe brain injury remains controversial. No previous randomised trial has been conducted to evaluate additional physician intervention compared with paramedic only care. METHODS: Participants in this prospective, randomised controlled trial were adult patients with blunt trauma with either a scene GCS score <9 (original definition), or GCS<13 and an Abbreviated Injury Scale score for the head region >=3 (modified definition). Patients were randomised to either standard ground paramedic treatment or standard treatment plus a physician arriving by helicopter. Patients were evaluated by 30-day mortality and 6-month Glasgow Outcome Scale (GOS) scores. Due to high non-compliance rates, both intention-to-treat and as-treated analyses were preplanned. RESULTS: 375 patients met the original definition, of which 197 was allocated to physician care. Differences in the 6-month GOS scores were not significant on intention-to-treat analysis (OR 1.11, 95% CI 0.74 to 1.66, p=0.62) nor was the 30-day mortality (OR 0.91, 95% CI 0.60 to 1.38, p=0.66). As-treated analysis showed a 16% reduction in 30-day mortality in those receiving additional physician care; 60/195 (29%) versus 81/180 (45%), p<0.01, Number needed to treat =6. 338 patients met the modified definition, of which 182 were allocated to physician care. The 6-month GOS scores were not significantly different on intention-to-treat analysis (OR 1.14, 95% CI 0.73 to 1.75, p=0.56) nor was the 30-day mortality (OR 1.05, 95% CI 0.66 to 1.66, p=0.84). As-treated analyses were also not significantly different. CONCLUSIONS: This trial suggests a potential mortality reduction in patients with blunt trauma with GCS<9 receiving additional physician care (original definition only). Confirmatory studies which also address non-compliance issues are needed. TRIAL REGISTRATION NUMBER: NCT00112398. PMID- 25795742 TI - A rare case of bilateral nasolabial cysts. AB - Nasolabial cysts are rare non-odontogenic cystic lesions representing around 0.7% of all maxillofacial cysts. They usually present as unilateral painless swellings, sometimes with epiphora and dacryocystitis as well as pain in cases of rapid growth or infection. We have reviewed the literature and present an extremely rare case of bilateral nasolabial cysts in a young Afro-Caribbean man presenting with chronic nasal blockage, epiphora and rhinorrhoea. We describe our successful surgical management using a sublabial approach for complete excision, leading to a disease-free outcome at 6 months follow-up. Other modalities have been described, from endoscopic marsupialisation to simple aspiration. However, with the exception of complete surgical excision, all other surgical techniques are associated with a high recurrence rate. We therefore advocate complete surgical excision as described below for optimal results. PMID- 25795743 TI - Cone beam CT assisted re-treatment of class 3 invasive cervical resorption. AB - Invasive cervical root resorption is an uncommon external root resorption which initiates at the cervical aspect of the tooth. This case report involves a case of cervical root resorption which was initially misdiagnosed and managed as cervical root caries. It was later diagnosed with cone beam CT and the lesion microsurgically removed and restored with resin modified glass ionomer cement. The importance of increasing awareness of this uncommon pathology and the role of cone beam CT in mapping the extent of the lesion is emphasised. PMID- 25795744 TI - Large laryngeal vascular malformation in a 5-year-old child. AB - A 5-year-old boy was admitted with stridor, which was initially interpreted as subglottic laryngitis. He had a history of prolonged hoarseness and his voice was deep for his age. The stridor persisted despite treatment with epinephrine inhalations and intravenous glucocorticoids. A direct laryngoscopy and blood work up did not support the suspected diagnosis. A MRI was then carried out, followed by angiography. The latter revealed an arteriovenous malformation (AVM) involving the lingual and superior thyroid arteries bilaterally. Owing to the rareness and extent of such an AVM, the patient was referred to Paris for further treatment. This case presents the difficulties in diagnostics and emphasises the importance of diagnostics and multidisciplinary approaches with regard to treatment of AVMs. PMID- 25795745 TI - Isolated right ventricular cardiomyopathy with autoimmune hypothyroidism: a rare association in an adolescent. AB - A 13-year-old girl presented with progressive dyspnoea and palpitation, diagnosed on echocardiography as primary right ventricular cardiomyopathy with atrial fibrillation. Her thyroid profile was positive for antithyroid microsomal antibody, and antithyroid peroxidase antibodies were suggestive of autoimmune hypothyroidism. She was managed with furosemide, digoxin, acenocoumarol and thyroxine following which she showed significant improvement. This is a rare case of isolated right ventricular cardiomyopathy and its association with autoimmune hypothyroidism presenting at the age of 13. PMID- 25795746 TI - Diagnostic error: what Muir-Torre syndrome has taught us. AB - A low-grade sebaceous carcinoma was excised from a 55-year-old woman's neck. At follow-up, 11 months later, a recent diagnosis of mucinous adenocarcinoma of the colon and history of clear cell endometrial carcinoma were identified. A strong family history of bowel cancer suggested Muir-Torre syndrome. Unexpectedly, hereditary non-polyposis colorectal cancer had previously been genetically confirmed; the results were found loosely filed in the paper chart. The patient had not informed us about her diagnosis; having discussed the case with other physicians she felt the diagnosis would be common knowledge. In 1999, US National Institute of Medicine estimated that preventable medical error resulted in the deaths of 44-98 000 people yearly in US hospitals. Four categories of medical error, including diagnosis, treatment, preventive and 'other' were described, while the reasoning processes that result in these errors are outlined by Reason et al. We utilise this rare case to illustrate these important concepts. PMID- 25795747 TI - Facial extention of ear pathology: infected cholesteatoma causing a parotid abscess. AB - A man in his early 30s presented with right-sided preauricular swelling and facial oedema. He had a history of acid injury to his right ear as a child resulting in pinna deformity and subsequent blind sac closure of the external auditory canal. Imaging showed abnormal ear anatomy and abnormal density of the right parotid gland. Antibiotic therapy prevented progression but did not resolve the symptoms. Therefore, the infected area was surgically drained. This showed an underlying cholesteatoma, a benign but locally destructive condition where keratinising squamous epithelium grows in the middle ear and mastoid. The infected region was drained and the cholesteatoma was excised. This led to full resolution of the infection. The patient is awaiting a follow-up diffusion weighted MRI. This case was unusual as the disease had extended beyond the ear and we therefore wish to alert clinicians to cholesteatoma as a possible cause of facial swelling. PMID- 25795748 TI - Testicular non-Hodgkin's lymphoma presenting in a young adult. AB - We report a case of a 27-year-old man who presented with a slowly growing left testicular swelling associated with mild pain over a period of 3 months. He was evaluated by his family physician with scrotal ultrasound and testicular tumour markers. He was diagnosed and treated as epididymo-orchitis and managed with antibiotics. When he later presented to us, he had an enlarged left testis with normal spermatic cord. Scrotal Doppler evaluation showed a globally enlarged left testis and epididymis with increased vascularity in the left testis, with the right testis being normal. Testicular tumour markers were normal. Fine-needle aspiration cytology of the left testis was suggestive of lymphoma. Exploration through an inguinal approach was carried out and a Chevassu manoeuvre with frozen section study was performed, which was reported as non-Hodgkin's lymphoma. Left radical orchidectomy was performed. Histopathology reported diffuse large B-cell lymphoma, of a germinal centre type. Contrast CT of the abdomen, chest and brain were normal. Sperm cryopreservation was carried out. The patient was started on chemotherapy with cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP) regime. PMID- 25795749 TI - Trigeminal herpes zoster: early recognition and treatment are crucial. AB - Reactivation of varicella zoster virus (VZV) is not uncommon in older patients, particularly in cases of chronic autoimmune disorders and in patients taking immunosuppressant drugs. We present a case of a 57-year-old woman presenting with severe herpes zoster infection, involving the maxillary and ophthalmic branches of the trigeminal nerve. Despite an initial delay in instigating crucial antiviral treatment, the patient achieved an excellent recovery, with only some mild scarring at 2 months postinfection. Trigeminal herpes zoster is a potentially devastating clinical occurrence, and is associated with severe long term neurological sequelae, including encephalitis, vision loss and postherpetic neuralgia. Physicians must be aware of risk factors and treatment modalities. PMID- 25795750 TI - CT findings in Fahr's disease. PMID- 25795751 TI - Ruptured splenic abscess causing pneumoperitoneum: a rare cause revisited. AB - We present a case report of splenic abscess causing pneumoperitoneum in a case of uncontrolled diabetes. The patient presented with chronic pain abdomen and fever which later evolved to acute abdomen during the course of hospital stay. An X-ray showed pneumoperitoneum and exploratory laparotomy was performed under a strong clinical suspicion of hollow viscus perforation. The patient was treated with antibiotics and had an uneventful recovery. PMID- 25795752 TI - The trumpet player with a swelling in the neck. AB - Bilateral neck swelling in patients following valsalva manouveres could lead to a diagnosis of either a pharyngocele or laryngocele. Distinguishing between them can be complicated but is vital given the possibility for an acute airway in patients with laryngoceles. A 20-year-old trumpet player presents with a 5-year history of neck swelling. Clinical suspicion is that of a pharyngocele but imaging introduces some confusion with the diagnosis. Both pharyngoceles and laryngoceles can occur as a result of prolonged positive pressure. Accurate assessment with fibreoptic examination and imaging is needed to confirm the diagnosis. Pharyngoceles are often misdiagnosed as laryngoceles. Though treatment is similar between the two patient groups it is vital that a distinction is made to enable careful observation of the airway in patients with laryngoceles. PMID- 25795753 TI - A sudden pain in the neck: an atypical presentation of cystic lymphangioma. PMID- 25795754 TI - Paroxysmal non-kinesigenic dyskinesia, post-streptococcal syndromes and psychogenic movement disorders: a diagnostic challenge. AB - We report a case of a 15-year-old boy presenting with sudden attacks of hyperkinetic movements of the limbs, trunk and neck. Clinical features were suggestive of paroxysmal non-kinesigenic dyskinesia, but the elevated antistreptolysin O antibody titre and history of recurrent upper airways infection led us to consider a post-streptococcal syndrome as a possible diagnosis. The patient started therapy with benzathine penicillin, sodium valproate and clonazepam without any significant improvement. A successive psychiatric assessment revealed the presence of a psychogenic movement disorder. Psychodynamic psychotherapy and individual counselling were started with progressive improvement of psychological symptoms and gradual resolution of hyperkinetic episodes, without any recurrence recorded during the follow-up (10 months). PMID- 25795755 TI - Silencing IFN-gamma binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity. AB - IFN-gamma, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Thus far, the role of IFN-gamma in EAE has been largely studied through its effects on immune cells, whereas much less is known about its effects on CNS cells, especially in vivo. In this study, we dissected the in vivo effects and mechanisms of IFN-gamma binding/signaling in astrocytes and microglia, and found that IFN-gamma signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-gamma binding/signaling in astrocytes alleviated EAE, whereas in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-gamma signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, whereas blocking IFN-gamma binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-gamma binding/signaling in astrocytes alleviated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-gamma signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-gamma in EAE pathogenesis, and also highlights an opportunity for development of multiple sclerosis therapies directed at CNS cells. PMID- 25795756 TI - Caspase-1-independent IL-1 release mediates blister formation in autoantibody induced tissue injury through modulation of endothelial adhesion molecules. AB - Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1beta in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1alpha and IL-1beta expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R-deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti-IL-1beta. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R-deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1-stimulated, but not on TNF-alpha stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11 deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti-IL-1beta in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs. PMID- 25795757 TI - Cyclin-dependent kinases regulate Ig class switching by controlling access of AID to the switch region. AB - Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ~ 11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border. PMID- 25795758 TI - IFN-alpha/beta receptor signaling promotes regulatory T cell development and function under stress conditions. AB - Type I IFNs are a family of cytokines with antiviral and immunomodulatory properties. Although the antiviral effects of IFNs are well characterized, their immunomodulatory properties are less clear. To specifically address the effects of type I IFNs on T regulatory cells (Tregs), we studied mixed bone marrow chimeras between wild-type and IFN-alpha/beta receptor (IFNAR) knockout (KO) mice, and heterozygous female mice expressing a Treg-specific deletion of the IFNAR. In these two models, IFNAR signaling promotes the development of the Treg lineage in the thymus and their survival in the periphery. IFNAR KO Tregs had a higher expression of the proapoptotic gene Bim and higher frequency of active caspase-positive cells. IFNAR KO Tregs from chimeric mice displayed a more naive phenotype, accompanied by lower levels of CD25 and phosphorylated STAT5. Therefore, in Tregs, IFNAR signaling may directly or indirectly affect phosphorylation of STAT5. In mixed chimeras with Scurfy fetal liver, Tregs derived from IFNAR KO bone marrow were unable to control T effector cell activation and tissue inflammation. Under stress conditions or in a competitive environment, IFNAR signaling may be required to maintain Treg homeostasis and function. PMID- 25795759 TI - Induction of an altered CD40 signaling complex by an antagonistic human monoclonal antibody to CD40. AB - Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes. PMID- 25795760 TI - Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcgamma receptors on macrophages. AB - Trastuzumab has been used for the treatment of HER2-overexpressing breast cancer for more than a decade, but the mechanisms of action for the therapy are still being actively investigated. Ab-dependent cell-mediated cytotoxicity mediated by NK cells is well recognized as one of the key mechanisms of action for trastuzumab, but trastuzumab-mediated Ab-dependent cellular phagocytosis (ADCP) has not been established. In this study, we demonstrate that macrophages, by way of phagocytic engulfment, can mediate ADCP and cancer cell killing in the presence of trastuzumab. Increased infiltration of macrophages in the tumor tissue was associated with enhanced efficacy of trastuzumab whereas depletion of macrophages resulted in reduced antitumor efficacy in mouse xenograft tumor models. Among the four mouse FcgammaRs, FcgammaRIV exhibits the strongest binding affinity to trastuzumab. Knockdown of FcgammaRIV in mouse macrophages reduced cancer cell killing and ADCP activity triggered by trastuzumab. Consistently, an upregulation of FcgammaRIV expression by IFN-gamma triggered an increased ADCP activity by trastuzumab. In an analogous fashion, IFN-gamma priming of human macrophages increased the expression of FcgammaRIII, the ortholog of murine FcgammaRIV, and increased trastuzumab-mediated cancer cell killing. Thus, in two independent systems, the results indicated that activation of macrophages in combination with trastuzumab can serve as a therapeutic strategy for treating high HER2 breast cancer by boosting ADCP killing of cancer cells. PMID- 25795761 TI - Relations between aortic stiffness and left ventricular structure and function in older participants in the Age, Gene/Environment Susceptibility--Reykjavik Study. AB - BACKGROUND: Left ventricular (LV) contraction displaces the aortic annulus and produces a force that stretches the ascending aorta. We hypothesized that aortic stiffening increases this previously ignored component of LV load and may contribute to hypertrophy. Conversely, aortic stretch-related work represents stored energy that may facilitate early diastolic filling. METHODS AND RESULTS: We performed MRI of the aorta and LV in 347 participants (72-91 years old, 189 women) in the Age, Gene/Environment Susceptibility-Reykjavik Study to examine relations of aortic stretch with LV structure and function. Aortic stiffness was evaluated as the product of Young's modulus and aortic wall thickness. Force was computed from Young's modulus and longitudinal aortic strain; work was the integrated product of force and annulus displacement during systole. LV mass and dynamic volume were measured using the area-length method. Filling was assessed from time-resolved LV volume curves. In multivariable models that adjusted for age, sex, height, weight, end-diastolic LV volume, augmentation index, end systolic pressure, and cardiovascular disease risk factors, higher aortic stiffness was associated with increased LV mass (beta=3.0+/-0.8% per SD, P<0.001; sex interaction, P=0.8). Greater stretch-related aortic work was associated with enhanced early filling in men (beta=4.0+/-0.8 mL/SD; P<0.001), but not in women (beta=-0.4+/-0.7 mL/SD; P=0.6). CONCLUSIONS: Higher aortic stiffness was associated with higher LV mass, independently of pressure. Higher stretch-related work was associated with greater early diastolic filling in men only. Impaired diastolic recovery of energy stored by systolic proximal aortic stretch may contribute to increased susceptibility to diastolic dysfunction in women. PMID- 25795767 TI - Conduction of feedback-mediated signal in a computational model of coupled nephrons. AB - The nephron in the kidney regulates its fluid flow by several autoregulatory mechanisms. Two primary mechanisms are the myogenic response and the tubuloglomerular feedback (TGF). The myogenic response is a property of the pre glomerular vasculature in which a rise in intravascular pressure elicits vasoconstriction that generates a compensatory increase in vascular resistance. TGF is a negative feedback response that balances glomerular filtration with tubular reabsorptive capacity. While each nephron has its own autoregulatory response, the responses of the kidney's many nephrons do not act autonomously but are instead coupled through the pre-glomerular vasculature. To better understand the conduction of these signals along the pre-glomerular arterioles and the impacts of internephron coupling on nephron flow dynamics, we developed a mathematical model of renal haemodynamics of two neighbouring nephrons that are coupled in that their afferent arterioles arise from a common cortical radial artery. Simulations were conducted to estimate internephron coupling strength, determine its dependence on vascular properties and to investigate the effect of coupling on TGF-mediated flow oscillations. Simulation results suggest that reduced gap-junctional conductances may yield stronger internephron TGF coupling and highly irregular TGF-mediated oscillations in nephron dynamics, both of which experimentally have been associated with hypertensive rats. PMID- 25795768 TI - A novel tetravalent formulation combining the four aggregated domain III-capsid proteins from dengue viruses induces a functional immune response in mice and monkeys. AB - Our group developed a subunit vaccine candidate against dengue virus based on two different viral regions: the domain III of the envelope protein and the capsid protein. The novel chimeric protein from dengue-2 virus [domain III-capsid (DIIIC 2)], when presented as aggregated incorporating oligodeoxynucleotides, induced anti-viral and neutralizing antibodies, a cellular immune response and conferred significant protection to mice and monkeys. The remaining constructs were already obtained and properly characterized. Based on this evidence, this work was aimed at assessing the immune response in mice of the chimeric proteins DIIIC of each serotype, as monovalent and tetravalent formulations. Here, we demonstrated the immunogenicity of each protein in terms of humoral and cell-mediated immunity, without antigen competition on the mixture forming the formulation tetra DIIIC. Accordingly, significant protection was afforded as measured by the limited viral load in the mouse encephalitis model. The assessment of the tetravalent formulation in non-human primates was also conducted. In this animal model, it was demonstrated that the formulation induced neutralizing antibodies and memory cell-mediated immune response with IFN-gamma-secreting and cytotoxic capacity, regardless the route of immunization used. Taken together, we can assert that the tetravalent formulation of DIIIC proteins constitutes a promising vaccine candidate against dengue virus, and propose it for further efficacy experiments in monkeys or in the dengue human infection model, as it has been recently proposed. PMID- 25795769 TI - Management of anterior cruciate ligament injuries: evidence-based guideline. AB - Management of Anterior Cruciate Ligament Injuries: Evidence-Based Guideline is based on a systematic review of the current scientific and clinical research. This guideline has been endorsed by the National Academy of Sports Medicine, the American Orthopaedic Society for Sports Medicine, the National Athletic Trainers' Association, and the American Academy of Physical Medicine and Rehabilitation. The guideline contains 20 recommendations, including both diagnosis and treatment. In addition, the work group highlighted the need for better research in the treatment of anterior cruciate ligament injuries. PMID- 25795770 TI - AAOS Clinical Practice Guideline: Management of Anterior Cruciate Ligament Injuries: Evidence-Based Guideline. PMID- 25795771 TI - Carbapenemase-producing Salmonella enterica isolates in the UK. PMID- 25795772 TI - Investigation of a possible outbreak of carbapenem-resistant Acinetobacter baumannii in Odense, Denmark using PFGE, MLST and whole-genome-based SNPs. AB - OBJECTIVES: The objectives were to study a possible outbreak of carbapenem resistant Acinetobacter baumannii by comparing three different typing methods (PFGE, MLST and whole-genome SNPs) and to compare the resistance gene profiles of the isolates. METHODS: From December 2012 to October 2013, eight carbapenem resistant A. baumannii were detected at Odense University Hospital, Odense, Denmark. These isolates were typed by PFGE, with ApaI and SmaI, respectively, and subjected to WGS. The WGS data were used for in silico extraction of MLST types using two different schemes, resistance genes and SNPs, to which 31 publicly available A. baumannii genomes were added. RESULTS: Using ApaI, the eight isolates had four different PFGE profiles, which were further differentiated using SmaI, separating one of the profiles into two distinct PFGE types. Five ST2 (Pasteur MLST) OXA-23-producing isolates, two ST1 OXA-72-producing isolates and one ST158 OXA-23-producing isolate were detected. The five ST2 isolates were subdivided into ST195, ST208 and ST218 using the Oxford MLST scheme. The phylogenetic analysis based on the core genome showed that six of the eight Danish A. baumannii isolates were located in three distinct clusters. The two remaining isolates did not cluster with other Danish or international isolates included in the study. Isolates that clustered using PFGE, Oxford MLST and phylogenetic analysis also shared similar resistance gene profiles. CONCLUSIONS: The SNP profile, Oxford MLST, PFGE and resistance gene profiles clearly indicated spread of three different A. baumannii strains. PMID- 25795773 TI - Antimicrobial stewardship: the role of scientists? AB - We continue to be warned about the risk of antibiotic resistance. This campaign has targeted medicine and agriculture, asking these industries to pay attention to the risks of widespread resistance and to cut the use of antibiotics wherever possible. However, there has been little to no mention of the widespread use of antibiotics in the scientific research community. As scientists we use antibiotics and antibiotic resistance as fundamental tools for our research; almost all conventional plasmids use an antibiotic resistance gene as a selectable marker, offering us an easy method of screening. With molecular biology and genetics at the heart of many research disciplines, these tools are ubiquitous. Scientists have a responsibility to monitor and reduce our use of antibiotics. With the growth and fast advancement of synthetic biology, it is timely for us to consider other options and to teach the next generation of researchers by example how to truly value antibiotics by using them more responsibly. PMID- 25795774 TI - Unraveling the specific regulation of the central pathway for anaerobic degradation of 3-methylbenzoate. AB - The mbd cluster encodes the anaerobic degradation of 3-methylbenzoate in the beta proteobacterium Azoarcus sp. CIB. The specific transcriptional regulation circuit that controls the expression of the mbd genes was investigated. The PO, PB 1, and P3 R promoters responsible for the expression of the mbd genes, their cognate MbdR transcriptional repressor, as well as the MbdR operator regions (ATACN10GTAT) have been characterized. The three-dimensional structure of MbdR has been solved revealing a conformation similar to that of other TetR family transcriptional regulators. The first intermediate of the catabolic pathway, i.e. 3-methylbenzoyl-CoA, was shown to act as the inducer molecule. An additional MbdR dependent promoter, PA, which contributes to the expression of the CoA ligase that activates 3-methylbenzoate to 3-methylbenzoyl-CoA, was shown to be necessary for an efficient induction of the mbd genes. Our results suggest that the mbd cluster recruited a regulatory system based on the MbdR regulator and its target promoters to evolve a distinct central catabolic pathway that is only expressed for the anaerobic degradation of aromatic compounds that generate 3-methylbenzoyl CoA as the central metabolite. All these results highlight the importance of the regulatory systems in the evolution and adaptation of bacteria to the anaerobic degradation of aromatic compounds. PMID- 25795775 TI - A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis. AB - The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4 dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer. PMID- 25795776 TI - Characterizing the interactions between a naturally primed immunoglobulin A and its conserved Bacteroides thetaiotaomicron species-specific epitope in gnotobiotic mice. AB - The adaptive immune response to the human gut microbiota consists of a complex repertoire of antibodies interacting with a broad range of taxa. Fusing intestinal lamina propria lymphocytes from mice monocolonized with Bacteroides thetaiotaomicron to a myeloma fusion partner allowed us to recover hybridomas that captured naturally primed, antigen-specific antibody responses representing multiple isotypes, including IgA. One of these hybridomas, 260.8, produced a monoclonal antibody that recognizes an epitope specific for B. thetaiotaomicron isolates in a large panel of hospital- and community-acquired Bacteroides. Whole genome transposon mutagenesis revealed a 19-gene locus, involved in LPS O-antigen polysaccharide synthesis and conserved among multiple B. thetaiotaomicron isolates, that is required for 260.8 epitope expression. Mutants in this locus exhibited marked fitness defects in vitro during growth in rich medium and in gnotobiotic mice colonized with defined communities of human gut symbionts. Expression of the 260.8 epitope was sustained during 10 months of daily passage in vitro and during 14 months of monocolonization of gnotobiotic wild-type, Rag1 /-, or Myd88-/- mice. Comparison of gnotobiotic Rag1-/- mice with and without subcutaneous 260.8 hybridomas disclosed that this IgA did not affect B. thetaiotaomicron population density or suppress 260.8 epitope production but did affect bacterial gene expression in ways emblematic of a diminished host innate immune response. Our study illustrates an approach for (i) generating diagnostic antibodies, (ii) characterizing IgA responses along a continuum of specificity/degeneracy that defines the IgA repertoire to gut symbionts, and (iii) identifying immunogenic epitopes that affect competitiveness and help maintain host-microbe mutualism. PMID- 25795777 TI - DNA topoisomerase I domain interactions impact enzyme activity and sensitivity to camptothecin. AB - During processes such as DNA replication and transcription, DNA topoisomerase I (Top1) catalyzes the relaxation of DNA supercoils. The nuclear enzyme is also the cellular target of camptothecin (CPT) chemotherapeutics. Top1 contains four domains: the highly conserved core and C-terminal domains involved in catalysis, a coiled-coil linker domain of variable length, and a poorly conserved N-terminal domain. Yeast and human Top1 share a common reaction mechanism and domain structure. However, the human Top1 is ~100-fold more sensitive to CPT. Moreover, substitutions of a conserved Gly(717) residue, which alter intrinsic enzyme sensitivity to CPT, induce distinct phenotypes in yeast. To address the structural basis for these differences, reciprocal swaps of yeast and human Top1 domains were engineered in chimeric enzymes. Here we report that intrinsic Top1 sensitivity to CPT is dictated by the composition of the conserved core and C terminal domains. However, independent of CPT, biochemically similar chimeric enzymes produced strikingly distinct phenotypes in yeast. Expression of a human Top1 chimera containing the yeast linker domain proved toxic, even in the context of a catalytically inactive Y723F enzyme. Lethality was suppressed either by splicing the yeast N-terminal domain into the chimera, deleting the human N terminal residues, or in enzymes reconstituted by polypeptide complementation. These data demonstrate a functional interaction between the N-terminal and linker domains, which, when mispaired between yeast and human enzymes, induces cell lethality. Because toxicity was independent of enzyme catalysis, the inappropriate coordination of N-terminal and linker domains may induce aberrant Top1-protein interactions to impair cell growth. PMID- 25795778 TI - Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis. AB - Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis. PMID- 25795779 TI - Fluorescence resonance energy transfer (FRET) and proximity ligation assays reveal functionally relevant homo- and heteromeric complexes among hyaluronan synthases HAS1, HAS2, and HAS3. AB - In vertebrates, hyaluronan is produced in the plasma membrane from cytosolic UDP sugar substrates by hyaluronan synthase 1-3 (HAS1-3) isoenzymes that transfer N acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) in alternative positions in the growing polysaccharide chain during its simultaneous extrusion into the extracellular space. It has been shown that HAS2 immunoprecipitates contain functional HAS2 homomers and also heteromers with HAS3 (Karousou, E., Kamiryo, M., Skandalis, S. S., Ruusala, A., Asteriou, T., Passi, A., Yamashita, H., Hellman, U., Heldin, C. H., and Heldin, P. (2010) The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination. J. Biol. Chem. 285, 23647-23654). Here we have systematically screened in live cells, potential interactions among the HAS isoenzymes using fluorescence resonance energy transfer (FRET) and flow cytometric quantification. We show that all HAS isoenzymes form homomeric and also heteromeric complexes with each other. The same complexes were detected both in Golgi apparatus and plasma membrane by using FRET microscopy and the acceptor photobleaching method. Proximity ligation assays with HAS antibodies confirmed the presence of HAS1-HAS2, HAS2-HAS2, and HAS2-HAS3 complexes between endogenously expressed HASs. C-terminal deletions revealed that the enzymes interact mainly via uncharacterized N-terminal 86-amino acid domain(s), but additional binding site(s) probably exist in their C-terminal parts. Of all the homomeric complexes HAS1 had the lowest and HAS3 the highest synthetic activity. Interestingly, HAS1 transfection reduced the synthesis of hyaluronan obtained by HAS2 and HAS3, suggesting functional cooperation between the isoenzymes. These data indicate a general tendency of HAS isoenzymes to form both homomeric and heteromeric complexes with potentially important functional consequences on hyaluronan synthesis. PMID- 25795780 TI - Effects of membrane mimetics on cytochrome P450-cytochrome b5 interactions characterized by NMR spectroscopy. AB - Mammalian cytochrome P450 (P450) is a membrane-bound monooxygenase whose catalytic activities require two electrons to be sequentially delivered from its redox partners: cytochrome b5 (cytb5) and cytochrome P450 reductase, both of which are membrane proteins. Although P450 functional activities are known to be affected by lipids, experimental evidence to reveal the effect of membrane on P450-cytb5 interactions is still lacking. Here, we present evidence for the influence of phospholipid bilayers on complex formation between rabbit P450 2B4 (CYP2B4) and rabbit cytb5 at the atomic level, utilizing NMR techniques. General line broadening and modest chemical shift perturbations of cytb5 resonances characterize CYP2B4-cytb5 interactions on the intermediate time scale. More significant intensity attenuation and a more specific protein-protein binding interface are observed in bicelles as compared with lipid-free solution, highlighting the importance of the lipid bilayer in stabilizing stronger and more specific interactions between CYP2B4 and cytb5, which may lead to a more efficient electron transfer. Similar results observed for the interactions between CYP2B4 lacking the transmembrane domain (tr-CYP2B4) and cytb5 imply interactions between tr-CYP2B4 and the membrane surface, which might assist in CYP2B4-cytb5 complex formation by orienting tr-CYP2B4 for efficient contact with cytb5. Furthermore, the observation of weak and nonspecific interactions between CYP2B4 and cytb5 in micelles suggests that lipid bilayer structures and low curvature membrane surface are preferable for CYP2B4-cytb5 complex formation. Results presented in this study provide structural insights into the mechanism behind the important role that the lipid bilayer plays in the interactions between P450s and their redox partners. PMID- 25795781 TI - Prostacyclin prevents pericyte loss and demyelination induced by lysophosphatidylcholine in the central nervous system. AB - Pericytes play pivotal roles in physiological and pathophysiological conditions in the central nervous system. As pericytes prevent vascular leakage, they can halt neuronal damage stemming from a compromised blood-brain barrier. Therefore, pericytes may be a good target for the treatment of neurodegenerative disorders, although evidence is lacking. In this study, we show that prostacyclin attenuates lysophosphatidylcholine (LPC)-mediated vascular dysfunction through pericyte protection in the adult mouse spinal cord. LPC decreased the number of pericytes in an in vitro blood-brain barrier model, and this decrease was prevented by iloprost treatment, a prostacyclin analog. Intrathecal administration of iloprost attenuated vascular barrier disruption after LPC injection in the mouse spinal cord. Furthermore, iloprost treatment diminished demyelination and motor function deficits in mice injected with LPC. These results support the notion that prostacyclin acts on pericytes to maintain vascular barrier integrity. PMID- 25795782 TI - Systemic lupus erythematosus-associated neutrophil cytosolic factor 2 mutation affects the structure of NADPH oxidase complex. AB - In a case-control association study with 3716 North Americans of Hispanic descent and 4867 North Americans of European descent, we show that the associations of rs17849502 (NCF2 His-389 -> Gln) and rs13306575 (NCF2 Arg-395 -> Trp) with systemic lupus erythematosus are independent. We have shown that His-389 -> Gln disrupts the binding of NCF2 to the ZF domain of VAV1, resulting in decreased NADPH oxidase activity. With respect to Arg-395 -> Trp, using protein docking and structure analyses, we provide a model for the involvement of this mutation in the structure and function of the NADPH oxidase complex. This model assigns a central role to Arg-395 in the structure and stability of the quaternary NCF2/NCF4/VAV1/RAC1 NADPH oxidase complex. Arg-395 stabilizes the C-terminal tail of NCF4 and the conformation of NCF2 loop 395-402, which in turn stabilize the evolutionarily conserved interactions of NCF2/NCF4 with the DH domain of VAV1 and RAC1 region 120-137. Our findings are consistent with the high levels of conservation of all of the residues involved in these interactions. PMID- 25795783 TI - Factor-induced Reprogramming and Zinc Finger Nuclease-aided Gene Targeting Cause Different Genome Instability in beta-Thalassemia Induced Pluripotent Stem Cells (iPSCs). AB - The generation of personalized induced pluripotent stem cells (iPSCs) followed by targeted genome editing provides an opportunity for developing customized effective cellular therapies for genetic disorders. However, it is critical to ascertain whether edited iPSCs harbor unfavorable genomic variations before their clinical application. To examine the mutation status of the edited iPSC genome and trace the origin of possible mutations at different steps, we have generated virus-free iPSCs from amniotic cells carrying homozygous point mutations in beta hemoglobin gene (HBB) that cause severe beta-thalassemia (beta-Thal), corrected the mutations in both HBB alleles by zinc finger nuclease-aided gene targeting, and obtained the final HBB gene-corrected iPSCs by excising the exogenous drug resistance gene with Cre recombinase. Through comparative genomic hybridization and whole-exome sequencing, we uncovered seven copy number variations, five small insertions/deletions, and 64 single nucleotide variations (SNVs) in beta-Thal iPSCs before the gene targeting step and found a single small copy number variation, 19 insertions/deletions, and 340 single nucleotide variations in the final gene-corrected beta-Thal iPSCs. Our data revealed that substantial but different genomic variations occurred at factor-induced somatic cell reprogramming and zinc finger nuclease-aided gene targeting steps, suggesting that stringent genomic monitoring and selection are needed both at the time of iPSC derivation and after gene targeting. PMID- 25795784 TI - The Functional Maturation of A Disintegrin and Metalloproteinase (ADAM) 9, 10, and 17 Requires Processing at a Newly Identified Proprotein Convertase (PC) Cleavage Site. AB - Proenzyme maturation is a general mechanism to control the activation of enzymes. Catalytically active members of the A Disintegrin And Metalloprotease (ADAM) family of membrane-anchored metalloproteases are synthesized as proenzymes, in which the latency is maintained by their autoinhibitory pro-domains. A proteolytic processing then transforms the proenzyme into a catalytically active form. The removal of the pro-domain of ADAMs is currently thought to depend on processing at a canonical consensus site for the proprotein convertase Furin (RXXR) between the pro- and the catalytic domain. Here, we demonstrate that this previously described canonical site is a secondary cleavage site to a prerequisite cleavage in a newly characterized upstream PC site embedded within the pro-domain sequence. The novel upstream regulatory site is important for the maturation of several ADAM proenzymes. Mutations in the upstream regulatory site of ADAM17, ADAM10, and ADAM9 do not prevent pro-domain processing between the pro and metalloprotease domain, but nevertheless, cause significantly reduced catalytic activity. Thus, our results have uncovered a novel functionally relevant PC processing site in the N-terminal part of the pro-domain that is important for the activation of these ADAMs. These results suggest that the novel PC site is part of a general mechanism underlying proenzyme maturation of ADAMs that is independent of processing at the previously identified canonical Furin cleavage site. PMID- 25795786 TI - T-bet transcendent: unmasking the faces of multifarious immunity. PMID- 25795787 TI - Pillars article: A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000. 100: 655-669. PMID- 25795785 TI - A Proteomic Strategy Identifies Lysine Methylation of Splicing Factor snRNP70 by the SETMAR Enzyme. AB - The lysine methyltransferase (KMT) SETMAR is implicated in the response to and repair of DNA damage, but its molecular function is not clear. SETMAR has been associated with dimethylation of histone H3 lysine 36 (H3K36) at sites of DNA damage. However, SETMAR does not methylate H3K36 in vitro. This and the observation that SETMAR is not active on nucleosomes suggest that H3K36 methylation is not a physiologically relevant activity. To identify potential non histone substrates, we utilized a strategy on the basis of quantitative proteomic analysis of methylated lysine. Our approach identified lysine 130 of the mRNA splicing factor snRNP70 as a SETMAR substrate in vitro, and we show that the enzyme primarily generates monomethylation at this position. Furthermore, we show that SETMAR methylates snRNP70 Lys-130 in cells. Because snRNP70 is a key early regulator of 5' splice site selection, our results suggest a model in which methylation of snRNP70 by SETMAR regulates constitutive and/or alternative splicing. In addition, the proteomic strategy described here is broadly applicable and is a promising route for large-scale mapping of KMT substrates. PMID- 25795788 TI - The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human. AB - The PTPN22 1858T variant was among the first single nucleotide polymorphisms to be associated with multiple autoimmune diseases. Lymphocyte tyrosine phosphatase, a coding variant within the tyrosine phosphatases, is known to participate in AgR signaling; the impact of this variant on the immune response and its role in the development of autoimmunity have been a focus of study. These studies used a series of approaches, including transfected cell lines, animal models, and primary human lymphocytes, and identified multiple alterations in cell signaling and function linked to the PTPN22 variant. Conflicting findings led to questions of how best to study the role of this variant in human autoimmunity. In this review, we discuss these differences and the factors that may account for them, as well as show how an integrated approach can lead to a more complete understanding of the mechanisms that promote autoimmunity in the context of the PTPN22 1858T risk variant. PMID- 25795790 TI - Correction: Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. PMID- 25795789 TI - Tumor-infiltrating dendritic cells in cancer pathogenesis. AB - Dendritic cells (DCs) play a pivotal role in the tumor microenvironment, which is known to affect disease progression in many human malignancies. Infiltration by mature, active DCs into the tumors confers an increase in immune activation and recruitment of disease-fighting immune effector cells and pathways. DCs are the preferential target of infiltrating T cells. However, tumor cells have means of suppressing DC function or of altering the tumor microenvironment in such a way that immune-suppressive DCs are recruited. Advances in understanding these changes have led to promising developments in cancer-therapeutic strategies targeting tumor-infiltrating DCs to subdue their immunosuppressive functions and enhance their immune-stimulatory capacity. PMID- 25795791 TI - High Antibody-Dependent Cellular Cytotoxicity Antibody Titers to H5N1 and H7N9 Avian Influenza A Viruses in Healthy US Adults and Older Children. AB - Human influenza is a highly contagious acute respiratory illness that is responsible for significant morbidity and excess mortality worldwide. In addition to neutralizing antibodies, there are antibodies that bind to influenza virus infected cells and mediate lysis of the infected cells by natural killer (NK) cells (antibody-dependent cellular cytotoxicity [ADCC]) or complement (complement dependent lysis [CDL]). We analyzed sera obtained from 16 healthy adults (18-63 years of age), 52 children (2-17 years of age), and 10 infants (0.75-1 year of age) in the United States, who were unlikely to have been exposed to the avian H7N9 subtype of influenza A virus, by ADCC and CDL assays. As expected, none of these sera had detectable levels of hemagglutination-inhibiting antibodies against the H7N9 virus, but we unexpectedly found high titers of ADCC antibodies to the H7N9 subtype virus in all sera from adults and children aged >=8 years. PMID- 25795792 TI - Bis(monoacylglycero)phosphate: a secondary storage lipid in the gangliosidoses. AB - Bis(monoacylglycero)phosphate (BMP) is a negatively charged glycerophospholipid with an unusual sn-1;sn-1' structural configuration. BMP is primarily enriched in endosomal/lysosomal membranes. BMP is thought to play a role in glycosphingolipid degradation and cholesterol transport. Elevated BMP levels have been found in many lysosomal storage diseases (LSDs), suggesting an association with lysosomal storage material. The gangliosidoses are a group of neurodegenerative LSDs involving the accumulation of either GM1 or GM2 gangliosides resulting from inherited deficiencies in beta-galactosidase or beta-hexosaminidase, respectively. Little information is available on BMP levels in gangliosidosis brain tissue. Our results showed that the content of BMP in brain was significantly greater in humans and in animals (mice, cats, American black bears) with either GM1 or GM2 ganglioside storage diseases, than in brains of normal subjects. The storage of BMP and ganglioside GM2 in brain were reduced similarly following adeno-associated viral-mediated gene therapy in Sandhoff disease mice. We also found that C22:6, C18:0, and C18:1 were the predominant BMP fatty acid species in gangliosidosis brains. The results show that BMP accumulates as a secondary storage material in the brain of a broad range of mammals with gangliosidoses. PMID- 25795793 TI - Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. AB - BACKGROUND: Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. METHODS: A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. RESULTS: We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. CONCLUSIONS: We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome. PMID- 25795794 TI - Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. AB - BACKGROUND: Fabry disease results from deficient alpha-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant alpha-galactosidase A therapy. METHODS: The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. RESULTS: 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were -1.89 mL/min/1.73 m(2)/year and -6.82 mL/min/1.73 m(2)/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age >= 40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. CONCLUSIONS: This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression. PMID- 25795906 TI - CRP and ASDAS are associated with future elevated arterial stiffness, a risk marker of cardiovascular disease, in patients with ankylosing spondylitis: results after 5-year follow-up. AB - OBJECTIVE: To identify factors associated with elevated arterial stiffness in a 5 year follow-up of patients with ankylosing spondylitis (AS). METHODS: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath AS disease activity index (BASDAI) and AS disease activity score (ASDAS) were recorded in 2003, and arterial stiffness (Augmentation Index (AIx) and pulse wave velocity (PWV)) in 2008/2009. Patients were grouped into quartiles according to baseline CRP, ESR and BASDAI and four ASDAS groups. Trend analyses were performed using ANCOVA (AIx/PWV as dependent variable) with separate models for CRP, ESR, BASDAI and ASDAS (age and gender adjusted). Independent predictors of future AIx and PWV levels were identified in multivariate linear regression models. RESULTS: In total, 85 patients participated. Increasing baseline values of CRP, ESR and ASDAS were associated with elevated AIx on follow-up (p(trend) 0.01, 0.05 and 0.04, respectively). Similar non-significant patterns were seen for PWV. In the multivariate analyses, baseline CRP and ASDAS were independently associated with future elevated AIx (p=0.03 and0.02, respectively). In the multivariate PWV model, results for CRP and ASDAS were non-significant. CONCLUSIONS: Baseline CRP and ASDAS were associated with future elevated arterial stiffness measured as AIx, supporting that disease activity is related to future risk of cardiovascular disease in patients with AS. PMID- 25795908 TI - Conventional DMARDs in axial spondyloarthritis: wishful--rather than rational- thinking! PMID- 25795907 TI - The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. AB - OBJECTIVE: To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity. METHODS: We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011-2012 trivalent influenza vaccine. In study A, tofacitinib naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing ('continuous') or interrupting ('withdrawn') tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens). RESULTS: In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (>=1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively). CONCLUSIONS: Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses. TRIAL REGISTRATION NUMBERS: NCT01359150, NCT00413699. PMID- 25795909 TI - Joseph Constantine Carpue and the Bicentennial of the Birth of Modern Plastic Surgery. AB - September 2014 marked the bicentennial of the birth of modern plastic surgery. It was then that Carpue began a prospective observational study of nasal reconstruction that culminated in his 1816 monograph, which caused an explosion of interest in reconstructive surgery throughout Europe. In conducting his study, Carpue demonstrated ethical standards and the power of planning a procedure. His methods to document his results accurately would remain unsurpassed until photography was adopted at the end of the 19th century. Carpue took an apocryphal story of surgery performed in India more than twenty years earlier and transformed it into the beginning of modern plastic surgery. He succeeded in a number of unrecognized tasks that are themselves landmarks not only in plastic surgical history, but surgical history: devising the first prospective observational study, using exclusion criteria, maintaining appropriate patient confidentiality, setting a standard for preoperative disclosure and ethical approval over a century before these measures were codified, having independent documentation of his preoperative and postoperative findings, devising a method to objectively monitor and document the forehead flap, and describing the potential value of tissue expansion. He shared his experience by publishing his results and by lecturing in Europe. His contemporaries recognized him for his contributions and he was honored by election to the Royal Society. Carpue launched the modern era of plastic surgery in an ethical, logical, and objective manner. While plastic surgery has changed in the last two centuries, the principles that Carpue followed remain valid. PMID- 25795910 TI - In vivo mapping of the functional regions of the DEAD-box helicase Vasa. AB - The maternally expressed Drosophila melanogaster DEAD-box helicase Vasa (Vas) is necessary for many cellular and developmental processes, including specification of primordial germ cells (pole cells), posterior patterning of the embryo, piRNA mediated repression of transposon-encoded mRNAs, translational activation of gurken (grk) mRNA, and completion of oogenesis itself. Vas protein accumulates in the perinuclear nuage in nurse cells soon after their specification, and then at stage 10 Vas translocates to the posterior pole plasm of the oocyte. We produced a series of transgenic constructs encoding eGFP-Vas proteins carrying mutations affecting different regions of the protein, and analyzed in vivo which Vas functions each could support. We identified novel domains in the N- and C terminal regions of the protein that are essential for localization, transposon repression, posterior patterning, and pole cell specification. One such functional region, the most C-terminal seven amino acids, is specific to Vas orthologues and is thus critical to distinguishing Vas from other closely related DEAD-box helicases. Surprisingly, we also found that many eGFP-Vas proteins carrying mutations that would be expected to abrogate DEAD-box helicase function localized to the nuage and posterior pole, and retained the capacity to support oogenesis, although they did not function in embryonic patterning, pole cell specification, grk activation, or transposon repression. We conclude from these experiments that Vas, a multifunctional protein, uses different domains and different molecular associations to carry out its various cellular and developmental roles. PMID- 25795911 TI - Differences in the fatty-acid composition of rodent spermatozoa are associated to levels of sperm competition. AB - Sperm competition is a prevalent phenomenon that drives the evolution of sperm function. High levels of sperm competition lead to increased metabolism to fuel higher sperm velocities. This enhanced metabolism can result in oxidative damage (including lipid peroxidation) and damage to the membrane. We hypothesized that in those species experiencing high levels of sperm competition there are changes in the fatty-acid composition of the sperm membrane that makes the membrane more resistant to oxidative damage. Given that polyunsaturated fatty acids (PUFAs) are the most prone to lipid peroxidation, we predicted that higher sperm competition leads to a reduction in the proportion of sperm PUFAs. In contrast, we predicted that levels of sperm competition should not affect the proportion of PUFAs in somatic cells. To test these predictions, we quantified the fatty-acid composition of sperm, testis and liver cells in four mouse species (genus Mus) that differ in their levels of sperm competition. Fatty-acid composition in testis and liver cells was not associated to sperm competition levels. However, in sperm cells, as predicted, an increase in sperm competition levels was associated with an increase in the proportion of saturated fatty-acids (the most resistant to lipid peroxidation) and by a concomitant decrease in the proportion of PUFAs. Two particular fatty acids were most responsible for this pattern (arachidonic acid and palmitic acid). Our findings thus indicate that sperm competition has a pervasive influence in the composition of sperm cells that ultimately may have important effects in sperm function. PMID- 25795912 TI - The small G protein Arl5 contributes to endosome-to-Golgi traffic by aiding the recruitment of the GARP complex to the Golgi. AB - The small G proteins of the Arf family play critical roles in membrane trafficking and cytoskeleton organization. However, the function of some members of the family remains poorly understood including Arl5 which is widely conserved in eukaryotes. Humans have two closely related Arl5 paralogues (Arl5a and Arl5b), and both Arl5a and Arl5b localize to the trans-Golgi with Arl5b being involved in retrograde traffic from endosomes to the Golgi apparatus. To investigate the function of Arl5, we have used Drosophila melanogaster as a model system. We find that the single Arl5 orthologue in Drosophila also localizes to the trans-Golgi, but flies lacking the Arl5 gene are viable and fertile. By using both liposome and column based affinity chromatography methods we find that Arl5 interacts with the Golgi-associated retrograde protein (GARP) complex that acts in the tethering of vesicles moving from endosomes to the trans-Golgi network (TGN). In Drosophila tissues the GARP complex is partially displaced from the Golgi when Arl5 is absent, and the late endosomal compartment is enlarged. In addition, in HeLa cells GARP also becomes cytosolic upon depletion of Arl5b. These phenotypes are consistent with a role in endosome-to-Golgi traffic, but are less severe than loss of GARP itself. Thus it appears that Arl5 is one of the factors that directs the recruitment of the GARP complex to the trans-Golgi, and this function is conserved in both flies and humans. PMID- 25795913 TI - Reticular drusen in eyes with high-risk characteristics for progression to late stage age-related macular degeneration. AB - BACKGROUND/AIMS: To analyse appearance, development over 2 years and characteristic patterns of reticular drusen (RDR) in eyes with high-risk characteristics for progression to late-stage age-related macular degeneration (AMD) (age-related eye disease study stages 3 and 4). METHODS: 98 eyes of 98 patients (median age 73.4 years, IQR [69-78]) participating in the Molecular Diagnostic of Age-related Macular Degeneration study were included. Simultaneous combined confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT) imaging as well as colour-fundus imaging was performed at baseline and at 24 months. Two independent graders determined the presence of different RDR phenotypes (cSLO modalities: 'dot', 'target', 'ribbon'; SD-OCT: 'spike' and 'wave') at both visits. RESULTS: At baseline, RDR were detected in 44% (kappa 0.96). They were always visible in near-infrared reflectance images. Detection rate was 42% using fundus autofluorescence (FAF), 39% on SD-OCT (waves: 100%; spikes: 90%) and 26% on blue reflectance (BR). 'Dots' were more frequently detected in all imaging compared with 'targets'. The 'ribbon' pattern was most frequently observed in colour images, BR images and FAF images. In 8 of the 48 eyes with no signs of RDR in any imaging modality at baseline, the development of RDR lesions was observed at 24 months (16.6%, kappa 0.42). CONCLUSIONS: Careful and meticulous analysis using three-dimensional in vivo imaging reveals distinct characteristic RDR patterns underlying detectable dynamic changes over a period of 2 years. RDR in eyes with early or intermediate AMD are a common observation but appear to be overall less common compared with eyes with geographic atrophy. PMID- 25795914 TI - High-irradiance CXL combined with myopic LASIK: flap and residual stroma biomechanical properties studied ex-vivo. AB - BACKGROUND/AIMS: To evaluate ex vivo biomechanical and enzymatic digestion resistance differences between standard myopic laser in-situ keratomileusis (LASIK) compared with LASIK+CXL, in which high-irradiance cross-linking (CXL) is added. METHODS: Eight human donor corneas were subjected to femtosecond-assisted myopic LASIK. Group A (n=4) served as a control group (no CXL). The corneas in LASIK+CXL group B were subjected to concurrent prophylactic high-irradiance CXL (n=4). Saline-diluted (0.10%) riboflavin was instilled on the stroma, subsequently irradiated with UV-A through the repositioned flap. The cornea stroma and flap specimens were separately subjected to transverse biaxial resistance measurements; biomechanical differences were assessed via stress and Young's shear modulus. Subsequently, the specimens were subjected to enzymatic degradation. RESULTS: For the corneal stroma specimen, stress at 10% strain was 128+/-11 kPa for control group A versus 293+/-20 kPa for the LASIK+CXL group B (relative difference Delta=+129%, p<0.05). The stress in group B was also increased at 20% strain by +68% (p<0.05). Shear modulus in group B was increased at 10% strain by +79%, and at 20% strain by +48% (both statistically significant, p<0.05). The enzymatic degradation time to dissolution was 157.5+/-15.0 min in group A versus 186.25+/-7.5 min in group B (Delta=+18%, p=0.014). For the flaps, both biomechanical, as well as enzymatic degradation tests showed no significant differences. CONCLUSIONS: LASIK+CXL appears to provide significant increase in underlying corneal stromal rigidity, up to +130%. Additionally, there is significant relevant enzymatic digestion resistance confirmatory to the above. LASIK flaps appear unaffected biomechanically by the LASIK+CXL procedure, suggesting effective CXL just under the flap. PMID- 25795915 TI - Do pattern deviation values accurately estimate glaucomatous visual field damage in eyes with glaucoma and cataract? AB - BACKGROUND/AIMS: To study the efficacy of pattern deviation (PD) values in the estimation of visual field compensating the influence of cataract in eyes with glaucoma. METHODS: The study subjects comprised of 48 eyes of 37 glaucoma patients. Mean total deviation value (mTDs) on Humphrey Field Analyzer after cataract surgery was compared with mean PD (mPD) before the surgery. Visual field measurements were carried out <=6 months before (VF(pre)) and following (VF(post)) successful cataract surgery. The difference between the mPD or mTD values in the VF(pre) and mTD values in the VF(post) (denoted as epsilonmPD/DeltamTD) was calculated, and the influence of the extent of 'true' glaucomatous visual field damage or cataract (as represented by epsilonmPD and DeltamTD, respectively) on this difference was also investigated. RESULTS: There was a significant difference between mTD in the VF(pre) and mTD in the VF(post) (p<0.001, repeated measures analysis of variance). There was not a significant difference between mPD in the VF(pre) and mTD in the VF(post) (p=0.06); however, epsilonmPD was significantly correlated with the mTD in VF(post) and also DeltamTD (R(2)=0.56 and 0.27, p<0.001, Pearson's correlation). The accurate prediction of the mTD in the VF(post) can be achieved using the pattern standard deviation (PSD), mTD and also visual acuity before surgery. CONCLUSIONS: Clinicians should be very careful when reviewing the VF of a patient with glaucoma and cataract since PD values may underestimate glaucomatous VF damage in patients with advanced disease and also overestimate glaucomatous VF damage in patients with early to moderate cataract. PMID- 25795916 TI - Calcium channel blockade reduces mechanical strain-induced extracellular matrix gene response in lamina cribrosa cells. AB - PURPOSE: This study examines the effect of the L-type calcium channel blocker verapamil on mechanical strain-induced extracellular matrix genes in optic nerve head lamina cribrosa (LC) cells. METHODS: Changes in LC cell intracellular calcium [Ca(2+)]i following hypotonic cell membrane stretch were measured with the fluorescent probe fura-2/AM. Fluorescence intensity was measured, after labelling, by calcium (Ca2+) imaging confocal microscopy. Confluent human LC cell cultures were serum starved for 24 h prior to exposure to cyclical mechanical strain (1 Hz, 15%) for 24 h in the presence or absence of verapamil (10 mm). Transforming growth factor-beta 1 (TGF-beta1), collagen 6A3 (COL6A3) and chondroitin sulfate proteoglycan 2 (CSPG2) mRNA expression levels were assessed by quantitative RT-PCR. RESULTS: Hypotonic cell membrane stretch of LC cells from normal donors significantly increased [Ca2+]i (p<0.05). Exposure to cyclical mechanical strain (15% strain) produced a statistically significant increase in the three matrix genes that were examined (TGF-beta1, COL6A3 and CSPG2). This response in both cyclical and mechanical stretch was significantly reduced by pretreating LC cells with the L-type calcium channel blocker verapamil (p<0.05). CONCLUSIONS: This study provides evidence of a novel mechanotransduction pathway linking mechanical strain, cation channel function and the induction of LC cell matrix gene transcription. This highlights the potential involvement of calcium influx in the activation of matrix remodelling responses in the optic nerve head and supports the rationale that calcium channel blockers may attenuate disease progression in glaucoma. PMID- 25795917 TI - Combining measurements from three anatomical areas for glaucoma diagnosis using Fourier-domain optical coherence tomography. AB - AIMS: To improve the diagnostic power for glaucoma by combining measurements of peripapillary nerve fibre layer (NFL), macular ganglion cell complex (GCC) and disc variables obtained with Fourier-domain optical coherence tomography (FD-OCT) into the glaucoma structural diagnostic index (GSDI). METHODS: In this observational, cross-sectional study of subjects from the Advanced Imaging of Glaucoma Study, GCC and NFL of healthy and perimetrical glaucoma subjects from four major academic referral centres of the Advanced Imaging of Glaucoma Study were mapped with the RTVue FD-OCT. Global loss volume and focal loss volume parameters were defined using NFL and GCC normative reference maps. Optimal weights for NFL, GCC and disc variables were combined using multivariate logistic regression to build the GSDI. Glaucoma severity was classified using the Enhanced Glaucoma Staging System (GSS2). Diagnostic accuracy was assessed by sensitivity, specificity and the area under the receiver operator characteristic curve (AUC). RESULTS: We analysed 118 normal eyes of 60 subjects, 236 matched eyes of 166 subjects with perimetrical glaucoma, and 105 eyes from a healthy reference group of 61 subjects. The GSDI included composite overall thickness and focal loss volume with weighted NFL and GCC components, as well as the vertical cup-to-disc ratio. The AUC of 0.922 from leave-one-out cross validation was better than the best component variable alone (p=0.047). The partial AUC in the high specificity region was also better (p=0.01), with a sensitivity of 69% at 99% specificity, and a sensitivity of 80.3% at 95% specificity. For GSS2 stages 3-5 the sensitivity was 98% at 99% specificity, and 100% at 95% specificity. CONCLUSIONS: Combining structural measurements of GCC, NFL and disc variables from FD-OCT created a GSDI that improved the accuracy for glaucoma diagnosis. TRIAL REGISTRATION NUMBER: NCT01314326. PMID- 25795918 TI - Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization. AB - Platelet aggregation at sites of vascular injury is not only essential for hemostasis, but may also cause acute ischemic disease states such as myocardial infarction or stroke. The hemi-immunoreceptor tyrosine-based activation motif containing C-type lectinlike receptor 2 (CLEC-2) mediates powerful platelet activation through a Src- and spleen tyrosine kinase (Syk)-dependent tyrosine phosphorylation cascade. Thereby, CLEC-2 not only contributes to thrombus formation and stabilization but also plays a central role in blood-lymphatic vessel development, tumor metastasis, and prevention of inflammatory bleeding, making it a potential pharmacologic target to modulate these processes. We have previously shown that injection of the anti-CLEC-2 antibody, INU1, results in virtually complete immunodepletion of platelet CLEC-2 in mice, which is, however, preceded by a severe transient thrombocytopenia thereby limiting its potential therapeutic use. The mechanisms underlying this targeted CLEC-2 downregulation have remained elusive. Here, we show that INU1-induced CLEC-2 immunodepletion occurs through Src-family kinase-dependent receptor internalization in vitro and in vivo, presumably followed by intracellular degradation. In mice with platelet specific Syk deficiency, INU1-induced CLEC-2 internalization/degradation was fully preserved whereas the associated thrombocytopenia was largely prevented. These results show for the first time that CLEC-2 can be downregulated from the platelet surface through internalization in vitro and in vivo and that this can be mechanistically uncoupled from the associated antibody-induced thrombocytopenia. PMID- 25795919 TI - Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. AB - Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (~30% AML), stable, and behave as a founder genetic lesion. Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)-retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients. Leukemic cells with NPM1 mutation also showed sensibility to ATO in vitro. Here, we explore the mechanisms underlying these observations and show that ATO/ATRA induce proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and primary patients' cells. We also show that PML intracellular distribution is altered in NPM1-mutated AML cells and reverted by arsenic through oxidative stress induction. Interestingly, similarly to what was described for PML, oxidative stress also mediates ATO-induced degradation of the NPM1 mutant oncoprotein. Strikingly, NPM1 mutant downregulation by ATO/ATRA was shown to potentiate response to the anthracyclin daunorubicin. These findings provide experimental evidence for further exploring ATO/ATRA in preclinical NPM1-mutated AML in vivo models and a rationale for exploiting these compounds in chemotherapeutic regimens in clinics. PMID- 25795920 TI - Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality. AB - Graft-versus-host disease (GVHD) is driven by extensive activation and proliferation of alloreactive donor T cells causing significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T (iNKT) cells are a potent immunoregulatory T-cell subset in both humans and mice. Here, we explored the role of adoptively transferred third-party CD4(+) iNKT cells for protection from lethal GVHD in a murine model of allogeneic HCT across major histocompatibility barriers. We found that low numbers of CD4(+) iNKT cells from third-party mice resulted in a significant survival benefit with retained graft-versus-tumor effects. In vivo expansion of alloreactive T cells was diminished while displaying a T helper cell 2-biased phenotype. Notably, CD4(+) iNKT cells from third-party mice were as protective as CD4(+) iNKT cells from donor mice although third-party CD4(+) iNKT cells were rejected early after allogeneic HCT. Adoptive transfer of third-party CD4(+) iNKT cells resulted in a robust expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) that were required for protection from lethal GVHD. However, in vivo depletion of myeloid-derived suppressor cells abrogated both Treg expansion and protection from lethal GVHD. Despite the fact that iNKT cells are a rare cell population, the almost unlimited third-party availability and feasibility of in vitro expansion provide the basis for clinical translation. PMID- 25795922 TI - Impact characteristics of a vehicle population in low speed front to rear collisions. AB - Rear impact collisions are mostly low severity, but carry a very high societal cost due to reported symptoms of whiplash and related soft tissue injuries. Given the difficulty in physiological measurement of damage in whiplash patients, there is a significant need to assess rear impact severity on the basis of vehicle damage. This paper presents fundamental impact equations on the basis of an equivalent single vehicle to rigid barrier collision in order to predict relationships between impact speed, maximum dynamic crush, mean and peak acceleration, time to common velocity and vehicle stiffness. These are then applied in regression analysis of published staged low speed rear impact tests. The equivalent mean and peak accelerations are linear functions of the collision closing speed, while the time to common velocity is independent of the collision closing speed. Furthermore, the time to common velocity can be used as a surrogate measure of the normalized vehicle stiffness, which provides opportunity for future accident reconstruction. PMID- 25795923 TI - The dynamic response characteristics of traumatic brain injury. AB - Traumatic brain injury (TBI) continues to be a leading cause of morbidity and mortality throughout the world. Research has been undertaken in order to better understand the characteristics of the injury event and measure the risk of injury to develop more effective environmental, technological, and clinical management strategies. This research used methods that have limited applications to predicting human responses. This limits the current understanding of the mechanisms of TBI in humans. As a result, the purpose of this research was to examine the characteristics of impact and dynamic response that leads to a high risk of sustaining a TBI in a human population. Twenty TBI events collected from hospital reports and eyewitness accounts were reconstructed in the laboratory using a combination of computational mechanics models and Hybrid III anthropometric dummy systems. All cases were falls, with an average impact velocity of approximately 4.0m/s onto hard impact surfaces. The results of the methodology were consistent with current TBI research, describing TBI to occur in the range of 335-445g linear accelerations and 23.7-51.2krad/s(2) angular accelerations. More significantly, this research demonstrated that lower responses in the antero-posterior direction can cause TBI, with lateral impact responses requiring larger magnitudes for the same types of brain lesions. This suggests an increased likelihood of sustaining TBI for impacts to the front or back of the head, a result that has implications affecting current understanding of the mechanisms of TBI and associated threshold parameters. PMID- 25795921 TI - Secondary mutations as mediators of resistance to targeted therapy in leukemia. AB - The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance. PMID- 25795924 TI - Machine learning approaches to analysing textual injury surveillance data: a systematic review. AB - OBJECTIVE: To synthesise recent research on the use of machine learning approaches to mining textual injury surveillance data. DESIGN: Systematic review. DATA SOURCES: The electronic databases which were searched included PubMed, Cinahl, Medline, Google Scholar, and Proquest. The bibliography of all relevant articles was examined and associated articles were identified using a snowballing technique. SELECTION CRITERIA: For inclusion, articles were required to meet the following criteria: (a) used a health-related database, (b) focused on injury related cases, AND used machine learning approaches to analyse textual data. METHODS: The papers identified through the search were screened resulting in 16 papers selected for review. Articles were reviewed to describe the databases and methodology used, the strength and limitations of different techniques, and quality assurance approaches used. Due to heterogeneity between studies meta analysis was not performed. RESULTS: Occupational injuries were the focus of half of the machine learning studies and the most common methods described were Bayesian probability or Bayesian network based methods to either predict injury categories or extract common injury scenarios. Models were evaluated through either comparison with gold standard data or content expert evaluation or statistical measures of quality. Machine learning was found to provide high precision and accuracy when predicting a small number of categories, was valuable for visualisation of injury patterns and prediction of future outcomes. However, difficulties related to generalizability, source data quality, complexity of models and integration of content and technical knowledge were discussed. CONCLUSIONS: The use of narrative text for injury surveillance has grown in popularity, complexity and quality over recent years. With advances in data mining techniques, increased capacity for analysis of large databases, and involvement of computer scientists in the injury prevention field, along with more comprehensive use and description of quality assurance methods in text mining approaches, it is likely that we will see a continued growth and advancement in knowledge of text mining in the injury field. PMID- 25795925 TI - Chronic lead exposure is epidemic in obligate scavenger populations in eastern North America. AB - Lead is a prominent and highly toxic contaminant with important impacts to wildlife. To understand the degree to which wildlife populations are chronically exposed, we quantified lead levels within American black vultures (Coragyps atratus; BLVU) and turkey vultures (Cathartes aura; TUVU), two species that are useful as environmental sentinels in eastern North America. Every individual sampled (n=108) had bone lead levels indicative of chronic exposure to anthropogenic lead (BLVU: x-=36.99 +/- 55.21 mg Pb/kg tissue (+/-SD); TUVU: x =23.02 +/- 18.77 mg/kg). Only a few showed evidence of recent lead exposure (BLVU liver: x-=0.78 +/- 0.93 mg/kg; TUVU liver: x-=0.55 +/- 0.34 mg/kg). Isotopic ratios suggested multiple potential sources of lead including ammunition, gasoline, coal-fired power plants, and zinc smelting. Black and turkey vultures range across eastern North America, from Quebec to Florida and individuals may traverse thousands of kilometers annually. The extent to which vultures are exposed suggests that anthropogenic lead permeates eastern North American ecosystems to a previously unrecognized degree. Discovery of an epidemic of chronic lead exposure in such widespread and common species and the failure of soft-tissue sampling to diagnose this pattern has dramatic implications for understanding modern wildlife and human health concerns. PMID- 25795927 TI - A randomised controlled trial of group cognitive behavioural therapy for perfectionism. AB - Perfectionism is associated with symptoms of anxiety disorders, eating disorders and mood disorders. Treatments targeting perfectionism may reduce the symptoms of these disorders (Egan, Wade, & Shafran, 2011). This study is the first randomised controlled trial to investigate the efficacy of group cognitive behavioural therapy (CBT) for perfectionism. Forty-two participants with elevated perfectionism and a range of anxiety, eating and mood disorders were randomised to group CBT for perfectionism or a waitlist control. The treatment group reported significantly greater pre-post reductions in perfectionism, symptoms of depression, eating disorders, social anxiety, anxiety sensitivity and rumination, as well as significantly greater pre-post increases in self-esteem and quality of life compared to the waitlist control group. The impact of treatment on most of these outcomes was mediated by pre-post change in perfectionism (Concern over Mistakes). Treatment gains were reliable and clinically significant, and were maintained at 6-month follow-up. Findings support group CBT for perfectionism being an efficacious treatment for perfectionism and related psychopathology, as well as increasing self-esteem and quality of life. PMID- 25795928 TI - The effectiveness of intervention programs in the prevention and control of obesity in infants: a systematic review. AB - OBJECTIVE: This study aims to conduct a literature review to evaluate the effectiveness of intervention programs in the prevention and control of obesity in children and to map the locations where the studies were carried out. METHODS: A systematic review using the PubMed / MEDLINE and LILACS databases to trace the published literature on intervention programs for prevention and control of obesity in the period of January 2004 to October 2013. The initial search was conducted using the terms "body mass index", " Intervention" and "children" or "adolescent" and only articles published in English, Spanish or Portuguese were selected. RESULTS: We found that interventions based only on advice had modest results in identifying changes in the anthropometric indicators of children and adolescents over time, although they appear to be effective in promoting positive changes in the eating habits of this population. Among the studies identified, 77.8 % were conducted in high-income countries, 22.2 % in middle to high income countries and no intervention studies were found in middle to low income countries. CONCLUSION: Intervention programs based only on counseling are effective in promoting changes in dietary patterns, but show poor results in the changes of anthropometric parameters of children and adolescents. PMID- 25795926 TI - Analysing the health effects of simultaneous exposure to physical and chemical properties of airborne particles. AB - BACKGROUND: Airborne particles are a complex mix of organic and inorganic compounds, with a range of physical and chemical properties. Estimation of how simultaneous exposure to air particles affects the risk of adverse health response represents a challenge for scientific research and air quality management. In this paper, we present a Bayesian approach that can tackle this problem within the framework of time series analysis. METHODS: We used Dirichlet process mixture models to cluster time points with similar multipollutant and response profiles, while adjusting for seasonal cycles, trends and temporal components. Inference was carried out via Markov Chain Monte Carlo methods. We illustrated our approach using daily data of a range of particle metrics and respiratory mortality for London (UK) 2002-2005. To better quantify the average health impact of these particles, we measured the same set of metrics in 2012, and we computed and compared the posterior predictive distributions of mortality under the exposure scenario in 2012 vs 2005. RESULTS: The model resulted in a partition of the days into three clusters. We found a relative risk of 1.02 (95% credible intervals (CI): 1.00, 1.04) for respiratory mortality associated with days characterised by high posterior estimates of non-primary particles, especially nitrate and sulphate. We found a consistent reduction in the airborne particles in 2012 vs 2005 and the analysis of the posterior predictive distributions of respiratory mortality suggested an average annual decrease of 3.5% (95% CI: -0.12%, -5.74%). CONCLUSIONS: We proposed an effective approach that enabled the better understanding of hidden structures in multipollutant health effects within time series analysis. It allowed the identification of exposure metrics associated with respiratory mortality and provided a tool to assess the changes in health effects from various policies to control the ambient particle matter mixtures. PMID- 25795929 TI - [Glycemic control through physical exercise in type 2 diabetes systematic review]. AB - INTRODUCTION: In Spain, nearly 14% of the population is diabetic, 95% corresponds to Type 2 Diabetes Mellitus patients. Poor glycemic control increases morbidity and mortality. There are three pillars in the treatment of type 2 diabetes: diet, medication and exercise. However, the potential for prescribing exercise training has not been fully exploited. OBJECTIVE: To analyze the effect of different exercise modalities (AE, RT, Combo, HIIT) on glycemic control in patients with type 2 diabetes mellitus. METHODS: The reserch was performed in 3 electronic databases (Pubmed, Scopus and Proquest), including publications from 2011 to the present, publications undertaking interventions with AE, RT, Combo or HIIT, and those that measured capillary glucose, CGMS or HbA1c. RESULTS: Of the 386 articles found, 14 met the inclusion criteria. These items were classified according to exercise intervention modality (AE, RT, Combo, HIIT) and whether glycemic control was measured as a result of continued training or 24-48h post workout. CONCLUSIONS: EA, RT, Combo and HIIT show efficacy in glycemic control in both the continuous training and 24-48h post-training. To achieve certain benefits in glycemic control, prescribing a structured frequency, volume and intensity training is required. Combo is the modality that gets better results through continued training. PMID- 25795930 TI - Association of excessive GWG with adiposity indicators and metabolic diseases of their offspring: systematic review. AB - INTRODUCTION: It has been reported that excessive gestational weight gain (GWG) during pregnancy is associated with an increase in adiposity indicators and metabolic disorders of the offspring. OBJECTIVE: The objective of this review, using the Institute of Medicine (IOM) criteria, was to analyze the association of excessive GWG in prospective studies with the adiposity indicators and metabolic diseases of the offspring, and the association of excessive GWG with adiposity indicators and metabolic disease of the >= 15 years offspring. METHODS: An electronic search was conducted in the MEDLINE/PubMed, EMBASE, and CINAHL databases of prospective cohort studies published from January 2004 to September 2014. Selection was restricted to prospective cohort studies where the definition of GWG was used according to the IOM-recommendations; and prospective cohort studies including offspring >= 15 years, independent of using the definition for excessive GWG. RESULTS: Nine prospective cohort studies meet the inclusion criteria. Five studies used the IOM-recommendations for assessing GWG, and six studies assessed adiposity or metabolic indicators of their offspring at >= 15 years. In seven of the nine studies, excessive GWG was associated with adiposity and metabolic diseases. Due to the limitations found, the evidence of the association was shown to be low. CONCLUSIONS: The results of this review showed, that independently of the criteria used to diagnose excessive GWG, all the included studies, consistently showed an association of excessive GWG with adiposity indicators or other components of metabolic disease early in life, during adolescence or adulthood. However, due to the limitations of the studies the strength of the evidence was low. Better designed studies are warranted to confirm a stronger evidence. PMID- 25795931 TI - [Sarcopenia intervention with progressive resistance training and protein nutritional supplements]. AB - INTRODUCTION: Aging is accompanied by changes in body composition among which is a progressive reduction in muscle mass, which may contribute to the development of functional limitations in older people, and where the lifestyle plays a particularly important role. OBJECTIVES: To test the effectiveness of progressive resistance training, protein nutritional supplements and both interventions combined in the treatment of sarcopenia. METHODS: Review of literature in Medline, ScienceDirect, CINAHL, ISI WOK and PEDro data by combining the descriptors of Medical Subject Headings (MeSH) concerning sarcopenia, progressive resistance training, protein supplements and seniors. RESULTS: A total of 147 studies were found which resistance exercise performed by sessions 45-60 minutes, 2-3 times a week, and 3-4 sets of 8 repetitions, to an increasing intensity. This exercise resulted in increased muscle mass and strength, and increased skeletal muscle protein synthesis and muscle fiber size. Nutritional supplements such as beta-hydroxy-beta-methylbutyrate, leucine and essential amino acids produced gains in muscle mass. All supplements increased strength, especially when combined with resistance exercise. CONCLUSION: The combination of progressive resistance training and protein included in the diet, either in the form of nutritional supplements, strengthens the impact that each of these interventions can have on the treatment of sarcopenia in the elderly. PMID- 25795932 TI - Vitamin d deficiency is associated with insulin resistance independent of intracellular calcium, dietary calcium and serum levels of parathormone, calcitriol and calcium in premenopausal women. AB - BACKGROUND: There is evidence that vitamin D deficiency is associated with increased risk of cardiovascular disease. However, it is not known if this association is independent of dietary calcium, intracellular calcium and serum levels of parathormone, calcitriol and calcium. OBJECTIVES: To investigate the independent relationship of vitamin D deficiency with insulin resistance, lipid profile, inflammatory status, blood pressure and endothelial function. METHOD: Cross-sectional study conducted with 73 healthy Brazilian premenopausal women aged 18 - 50 years. All participants were evaluated for: 25 hydroxyvitamin D serum levels, anthropometric parameters, body composition, calcium metabolism, insulin resistance, lipoprotein profile, inflammatory status, blood pressure and endothelial function. Endothelial function was assessed by reactive hyperemia index using Endo-PAT 2000(r). Women were stratified in two groups: with vitamin D deficiency (25 hydroxyvitamin D < 20 ng/ml; n=12) and without vitamin D deficiency (25 hydroxyvitamin D >= 20 ng/ml; n=61). RESULTS AND DISCUSSION: Participants with vitamin D deficiency compared with those without deficiency of this vitamin had significantly higher levels of glucose (88.25 +/- 3.24 vs. 80.15 +/- 1.13 mg/dl), greater HOMA-IR (6.43 +/- 0.73 vs. 4.42 +/- 0.25) and lower reactive hyperemia index (1.68 +/- 0.1 vs. 2.17 +/- 0.1). After adjustments for confounding factors including age, body mass index, waist circumference, dietary calcium, intracellular calcium and serum levels of parathormone, calcitriol and calcium differences between groups remained significant, regarding glucose and HOMA-IR. CONCLUSIONS: The findings of the present study suggest that vitamin D deficiency is associated with insulin resistance independent of dietary calcium, intracellular calcium and serum levels of parathormone, calcitriol and calcium in healthy premenopausal women. PMID- 25795933 TI - [Factors affecting oxidative damage in obese children: an exploratory study]. AB - INTRODUCTION: Obesity is a metabolic disorder that creates oxidizing conditions, which can generate high levels of physiological stress as well as a disturbance in the state of redox cell known as Oxidative Stress. OBJECTIVE: To examine the association between the damage on chromosomal DNA and the total antioxidant capacity (TAC) in obese children with severe obesity. METHODS: Participants were 11 children with a mean age and body mass index of 9.5+/-1.2 years and 27.7+/-3.3 kg/m2, respectively, from which venous blood samples were obtained to determine distinctive risk factors of metabolic syndrome, the number of DNA abasic sites (AS) and TAC levels. Biomarkers were quantified from spectrophotometric techniques and ELISA assays. RESULTS: Were identified 4.1+/-4.0x105 AS and TAC of 0.218+/-0.03 mmol/L, and an inverse correlation between AS and TAC (r = -0.63, p=0.038). These results suggest an imbalance in reduction-oxidation status (REDOX) within the cell. CONCLUSION: Increased AS and decreased TAC concentrations in the presence of severe obesity suggest that oxidative stress could be considered as an important risk factor closely linked to the early development of comorbidities associated to obesity. PMID- 25795934 TI - [Bariatric surgery in adults: variables that facilitate and hinder weight loss from pacients perspective]. AB - INTRODUCTION: Obesity has become a public health problem worldwide. Associated with this, bariatric surgeries have progressively increased, given its effectiveness in weight loss in the short term. However, it has been found a high percentage of weight reganancia from third year post surgery, and there are few follow-up studies of these patients. OBJECTIVES: To describe variables that promote and hinder weight loss, from the perspective of adults who have undergone bariatric surgery. METHODS: A qualitative descriptive approach based on Grounded Theory was used. In-depth interviews were conducted and data were analized using open coding. The sample consisted of 11 adults, 8 women and 3 males, who carried on surgery in private clinics. RESULTS: Five categories of analysis were generated: (1) variables that promote weight loss after bariatric surgery (2) variables that hinder weight loss after surgery, (3) evaluation of bariatric surgery results, (4) problematization of obesity and, (5) relationship with food. DISCUSSION: The main findings indicate that failure or success in weight loss after surgery is associated with the possibility of having a network of social and emotional support, as well as the ability to understand and modify the role of food as emotional regulation mechanism. PMID- 25795935 TI - Metabolic syndrome and its components are strongly associated with an inflammatory state and insulin resistance in the pediatric population. AB - INTRODUCTION: Endothelial inflammation and insulin resistance (IR) begin in childhood and constitute the pathophysiological basis of Metabolic Syndrome (MS). The increase levels in plasma of inflammatory markers such as high sensitive PCR (hsPCR), plasminogen activator inhibitor 1 (PAI-1) and tests suggestive of IR such as Insulin (Ins) and alanine aminotransferase (ALT) have been associated with MS in adults, but have not been studied in children. OBJECTIVES: Correlate the presence of MS and its components with the inflammatory and IR markers seen in the pediatric population. METHODS: Cross-sectional study of 337 children (10,9+/-9,7 years) whose levels of hsPCR, PAI-1, Ins and ALT were determined, along with their association with MS and its individual components. RESULTS: 37 children had MS (10,4%). The frequency of MS components was: abdominal obesity 38,5%, hypertension (HTN) 21,3%, hypertriglyceridemia 17,8%, HDL 21,3% and hyperglycemia 1,4%. hsPCR, PAI-1, ALT and Ins were higher in the presence of MS and increased progressively when components were came together. CONCLUSIONS: The pediatric population segment with MS had a higher concentration of hsPCR, PAI-1, Ins and ALT.These levels increase proportionally MS components add up, suggesting that even before diagnosis criteria are fulfilled there is a inflammatory state. PMID- 25795936 TI - [Influence of body composition and acceptance of physical education classes on self-esteem of children aged 14-16 years from Alicante, Spain]. AB - INTRODUCTION: Self-esteem seems to be an important predictor of depressive symptoms in adolescents, especially in females. Some authors suggest that there is a relationship between adolescents with overweight or obesity and lower self esteem. In addition, sports participation has been associated with a higher self esteem. OBJECTIVES: To analyses the relationships between BMI, gender, acceptance for physical education classes and self-esteem in a representative sample of 14 16 years students of the Alicante city. METHODS: Research was conducted with a representative sample of 1,150 students (15.1 +/- 0.8 years) of the Alicante city. Data included their socio-demographic background, anthropometric measurements, self-esteem and acceptance for physical education classes. RESULTS: There is a positive correlation between acceptance for physical education classes and self-esteem (r= .319) and there is a negative correlation between this acceptance and gender (r= -.289), lower scores were shown in a female group. There is a negative correlation between self-esteem and BMI (r= -.083) and gender (r= -.308), lower self-esteem were shown in a female group. CONCLUSIONS: It is necessary to plan actions aimed as reinforcing and increasing self-esteem during the adolescent period, focusing on the group of girls and the group of young adults with overweight and obesity problems and especially in the girl group. PMID- 25795937 TI - [Development and validation of an instrument designed to measure the impact of networks of support for breastfeeding]. AB - BACKGROUND: the hypothesis of this study is that there are not enough validated questionnaires that measure the impact of networks to support breastfeeding for the Spanish speaking population. OBJECTIVE: For this reason, we ask as a general objective of this study, to develop and validate (in terms of content and construct) a quantitative instrument of measure. METHOD: We evaluated the content validity, subjecting the survey to a breastfeeding expert's opinion in the Region of Murcia. The pilot test was conducted between the months of March and April 2014. Surveys were carried out directly by users who attended the breast-feeding support group "Lactando". For construction validity, a factor analysis was conducted, which determined the different dimensions that the survey could measure. A description of each of the items on the statistics was conducted. Through principal component analysis, the total variance explained was obtained, determining the factors that define the elements. RESULTS: Through factor analysis, the questionnaire has a high internal consistency for its five components (satisfaction, consultations, experience, problems and support), obtaining values from 0.942 to 0.632. And a high percentage of total variance explained (11,157% - 5,093%). CONCLUSION: This study has served to create a relevant and valid in terms of content and construction, instrument, capable of measuring the impact of networks of support for breastfeeding through 5 dimensions. PMID- 25795938 TI - [Validation of eating habits subscale in children (sehan: spanish version) from 10 to 12 years]. AB - INTRODUCTION: The vulnerability of children and the current epidemiological situation requires the use of validated instruments to study their eating habits in contexts like home and school. OBJECTIVE: Validating a subscale Eating Habits in Children, aged between 10 and 12 years. METHOD: To study the validity and the internal logic of the instrument, 5 experts rated each item and afterwards, the canonical coefficient concordance (CCC) was calculated. 134 students completed the subscale two times to ensure the study consistency and reliability. The Intraclass Correlation Coefficient (ICC), the Spearman Correlation Coefficient (SCC) and Wilcoxon test were calculated. 187 students were involved for the criterion validity. The SCC between BMI and triceps skinfold (TS) was assessed with the final subscale score. RESULT: The subscale was finally composed by 27 items. The experts score was 3.94 (out of 4 possible points). The CCC was 83.04%. Wilcoxon result was (p<.05) to each item. Result of ICC> .06 was obtained to 81.86% of the subscale. The ICC was (range 467-914)for 25 out of the 27 items. The CCS was (range 350-777)(p <.01) in 25 out of the 27 variables. The SCC for criteria validity of de Subescale with BMI and PLT was in both cases (p<.05). CONCLUSIONS: It is proven that this subscale is a valid instrument, reliable, simple, with fast delivery and easy understanding. PMID- 25795939 TI - Cut-off values of waist circumference to predict metabolic syndrome in obese adolescents. AB - INTRODUCTION: Metabolic syndrome (MetS) is a constellation of metabolic alteration related to abdominal obesity, inflammation and insulin resistance, which increase cardiovascular disease and mortality. The aims of the present study were to identify the prevalence of comorbidities and altered parameters in obese adolescents with and without MetS, and determine cut-off points of waist circumference to predict MetS. METHODS: 195 obese adolescents were recruited and divided according to MetS diagnosis based on IDF criteria. Blood analyses of glucose, lipids, liver enzymes, adiponectin and leptin were measured. Insulin resistance was assessed by HOMA-IR, QUICKI and HOMA-AD. Visceral, subcutaneous and hepatic fat were ultrasonography obtained. Body composition was estimated by BOD POD system. RESULTS: We observed a prevalence of 25% of MetS (n=50). The MetS group presented significant higher body mass, BMI, body fat (kg), free-fat mass (kg), waist circumference, visceral fat, glucose, insulin, insulin resistance, total-cholesterol, LDL-c, VLDL-c, triglycerides, liver enzymes, non-alcoholic fatty liver disease (NAFLD) and blood pressure. Significant lower QUICKI and adiponectin in MetS group were noted. MetS girls presented significant higher leptin/adiponectin ratio compared to Non-MetS girls. Cut-off points of 111.5 cm for boys and 104.6 cm for girls of waist circumference were suggested to predict metabolic syndrome. Moreover, waist circumference was positive correlated with visceral fat and the number of metabolic syndrome parameters. CONCLUSION: MetS group presented significant higher metabolic alterations and inflammation compared to Non-MetS group. Waist circumference is considered an anthropometric measure predictor of metabolic syndrome in obese adolescents, being useful in clinical practice. PMID- 25795940 TI - [Relationship between maternal body mass index, gestational weight gain and birth weight; prospective study in a health department]. AB - OBJECTIVES: To ascertain the relationship between maternal weight gain and birth weight, in every pre-gestational body mass index (BMI) category. MATERIAL AND METHODS: A two-stage sampling observational and descriptive study was carried out in the health department of La Ribera (Valencia, Spain). The sample was divided into four groups according to pre-gestational BMI. FINDINGS: 140 pregnant women were studied. We observed rising pre-gestational weight gain (PWG) and trimestral gradients. There was a higher increase from the first to the second trimester than from the second to the third trimester in every pre-gestational BMI category. According to the international recommendations of Institute of Medicine, 16.4% of women had an inferior gestational weight gain (GWG), 38.6% were within the recommendations and 45% were above them. The pre-gestational BMI, categorized by the WHO, is related to the birth weight, showing a statistical significance (F=6.636 and and p<0.001). Obese mothers with a higher weight gain than the recommended have newborns with higher birth weight (4,353 +/- 821.924 g) and, underweight mothers with a lower weight gain than the recommended, have newborns with lower birth weights (2,900 +/- 381.83 g) than the rest of the groups. CONCLUSIONS: The absolute gestational weight gain did not show a statistical significance compared to the birthweight in any of the pre gestational BMI categories and, as an isolated indicator, is not an added value to the prenatal quality control. PMID- 25795941 TI - [Figures performance of glycemia in type 2 diabetic patients with intake of two breakfast with the same amount of carbohydrates]. AB - Simple Carbohydrates (CHO) in the cardiometabolic risk, lead to the increase of blood glucose and to insulin levels and in the long-term to Diabetes Mellitus type 2( T2DM). OBJECTIVE: To determine the behavior of glycemia figures in T2DM patients with intake of two breakfasts. METHODOLOGY: We evaluated by anthropometry, biochemical and clinical 14 patients with DM2 who were administered 2 breakfasts at different times with 50g of CHO represented in sweet biscuit and white bread. RESULTS: alteration was evident in 92.8% of low-density cholesterol (Ldlc), Total Cholesterol (TC) and high density cholesterol (Hdlc) in 50% and triacylglycerol (TG) in 35.7%. The behavior of blood sugar for breakfast with a sweet biscuit did not show significant difference in the preprandial and postprandial figure at the 2and 3 hours (p = 0.051 and 0.054 respectively) blood glucose 2 hours to 3 hours showed significance (p = 0.012). At breakfast with white bread the preprandial and postprandial blood glucose increased at the 2 hours (p = 0.006), while at the 3 hours, the number reported between 2 and 3 hours did not show significantly difference(p = 0.114 and 0.051 respectively). When comparing each of glycemia of the breakfasts in the preprandial periods at 2 and 3 hours, no statistically significant differences were found (p> 0.05). CONCLUSION: isocaloric amounts of carbohydrates of two eaten breakfasts on different days acted similarly in glycemia figures. Breakfast with cookie favor the diabetic population because of the ingredients used on its preparation given their dyslipidemia. PMID- 25795942 TI - [Effect of fragmentation and quality of carbohydrates diet on metabolic control parameters in insulin treated type 2 diabetic individuals]. AB - INTRODUCTION: Currently there is no consensus regarding fragmentation, quantity and quality of carbohydrates (CHO) that should be followed by insulin treated type 2 diabetic individuals (ITT2D). OBJECTIVE: To determine the relationship between the meal times, quality of available CHO in every meal and the metabolic control parameters in ITT2D individuals with a single or double dose of intermediate-acting insulin. METHODS: 40 ITT2D individuals were evaluated, using food surveys to obtain the quantity of CHO, glycemic index (GI), glycemic load (GL) in every meal and meal times. The metabolic control was determined through lab exams (glycated hemoglobin; HbA1c, venous fasting glycaemia) and fasting (FBG), preprandial (PreG), postprandial (PostG) and bed time (BTG) capilar glycaemia using a glucometer. Statistical analysis were applied considering significant as p<0,05. RESULTS: Individuals recorded an average of 4,9 +/- 1,1 meals a day. It was found an asociation between lunch GL and Post G (r=0,317; p<0,05) and BTG (r=0,321; p<0,05). BTG was inversely correlated with the meals' distribution (r = -0,346; p<0,05) and there was a trend to show lower values of BTG with individuals conducting >=5 meals per day. It was observed that FBG predicts a 65%the variability of HbA1c (r =0,805; r2 =0,648; p<0,001). CONCLUSION: The meal times in ITT2D individuals with s single or double dose of intermediate-acting insulin could improve BTG. PMID- 25795943 TI - [Prevalence of metabolic syndrome and associated risk factors in ecuadorian university students]. AB - INTRODUCTION: Overweight and obesity in in young people especially in children and adolescents is considered as public health problem in the world. Obesity could be the most important cause of insulin resistance. For this reason obese children and adolescents become in a risky group for developing metabolic syndrome (MS). In Ecuador is shocking the low following that is given to the diagnosis of MS for predicting the risk of cardio and cerebral vascular disease and diabetes mellitus. OBJECTIVE: To determine the prevalence of metabolic syndrome and its risk factors in a sample of students from the "Universidad Central del Ecuador" (UCE) in Quito. METHODS: Students form first, second and third semester of Medicine College in UCE were included in the study. The age range was between 17 and 25 years old. All students were measured weight, height, body mass index (BMI, blood pressure, waist circumference and serum levels of total cholesterol, HDL, LDL, triglycerides and glucose. RESULTS: The study shows that the prevalence of MS was 7.58% (IDF). It means that 1 of 13 students had MS. 22.24% has pre obesity and 3.14% has obesity. We found that waist circumference was mainly higher in women than men (33.67% vs. 9.55) of the 31.79% of low values of HDLc, the 24.50% occurred among women and 7.29% among men. , the values of total cholesterol, LDL cholesterol and glucose were normal. CONCLUSION: In the tested sample was found that 1 out of 13 students had MS and 1 out of 2 had at least one risk factor for MS. According with the pre-obesity and obesity result, 1 out of 4 students shows one of these symptoms. In addition, these results show the direct relationship between risk factors and TA. Finally, Healthy lifestyles promotion (includes non-pharmacological treatments such diet and exercise) could be the first goal to prevent metabolic disease, because the large amount of persons with at least one risk factor for MS. PMID- 25795944 TI - [The healthy eating index of new students at an university of Mexico]. AB - INTRODUCTION: The main factor associated with increased prevalence of noncommunicable diseases is the consumption of modern processed foods. OBJECTIVE: Assessing the quality of the diet of freshmen. METHODS: Data from 3550 students aged average 18.65 years of food consumption were collected using a food frequency questionnaire. We evaluated ten variables were graded into three categories: healthy and unhealthy needs changes. Results of health sciences campus with the other were compared. RESULTS: There was a decrease in food intake should be daily as whole grains, vegetables and fruits. Is an increase of food that should be eaten occasionally several a week. Scores of students were 80.2% in the "unhealthy" category, 19.7% in "needs change" and 0.1% in "healthy." CONCLUSIONS: The results are a consequence of decreased food consumption of the traditional diet of Mesoamerica. Can not find effect of selection of campus with the pattern of food consumption. PMID- 25795945 TI - [Waist-height ratio and risk of metabolic syndrome in Chilean adolescent]. AB - OBJECTIVES: the aims of this study are twofold: i) to analyze the prevalence of risk of Metabolic Syndrome (MS) using the waist to height ratio (WHR) in a national representative sample of Chilean adolescents; and ii) to obtain percentile tables of WHR by sex and age for this population. METHODS: cross sectional study with a sample of 23180 adolescents (boys n=11253; girls n=11927) from 13 to 16 years old. It was obtained anthropometric measures of height, weight and waist circumference. Risk of MS was calculated by the WHR with a cutoff of 0.5. Prevalence for risk of MS was calculated for all Chilean regions. Percentile table of WHR was calculated for this population. RESULTS: participants who had a WHR higher than 0.5 was 22.4%. This prevalence was higher in the most extreme regions (both north and south). Girls aged 15 and 16 showed higher WHR than boys. Results of this study shows higher values in WHR than published in previous international studies. CONCLUSION: It has been calculated the risk of MS for Chilean adolescents using WHR and it is associated to sex and region. Additionally percentile tables of WHR for Chilean adolescents aged 13 to 16 have been calculated. PMID- 25795946 TI - [Prevalence of enteral patients with suboptimal feeding at Centro Medico Lic. Adolfo Lopez Mateos]. AB - BACKGROUND AND OBJECTIVE: In Mexico, 64% of hospitalized patients suffer from hospital undernourishment and up to 100% in the elderly patients, the causes have been studied, among the findings are: suboptimal feeding, length of hospital stay, catabolism present in various diseases, lack of interest or time staff working in hospitals among others. The aim of this study was to obtain the prevalence of suboptimal feeding in hospitalized patients with enteral support at the Centro Medico "Lic. Adolfo Lopez Mateos"(CMLALM) during the period August - October 2014. METHODOLOGY: An observational, cross-sectional, descriptive study was designed; with a population of 52 patients with enteral support where the prevalence of patients with a suboptimal feeding from the ministration of enteral nutritional diet and caloric requirement set was analyzed during the period August to October 2014. RESULTS: Measures of central tendency were used to obtain the percentage of patients with suboptimal feeding. The prevalence of suboptimal feeding patients was 71%, with higher prevalence among males (70%) and ranged in age between 51 years and 61 years (43%). The hospital's medical services departments where the highest prevalence of patients met with suboptimal feeding was internal medicine affecting 14 patients (38%), followed by neurosurgery with 7 patients (19%) and intensive care unit (ICU) with 7 patients (19%); being the night shift where he appeared in predominance suboptimal feeding. CONCLUSIONS: Suboptimal feeding affected 37 patients with enteral support which represent 71% of the study population; this figure is consistent with other similar studies. The main cause of the suboptimal feeding was a breach in the subministration of the enteral diet. PMID- 25795947 TI - Whey and soy protein supplements changes body composition in patients with Crohn's disease undergoing azathioprine and anti-TNF-alpha therapy. AB - BACKGROUND: Crohn's disease (CD) is a chronic transmural inflammation of the gastrointestinal tract of unknown cause. Malnutrition associated with active CD has been reduced although obesity has increased. Dietary strategies such as those with high-protein have been proposed to reduce body fat. This study compares the effects of two supplements on the nutritional status of CD patients. MATERIALS AND METHODS: 68 CD patients were randomized in two groups: whey protein group (WP) and soy protein group (SP). Using bioimpedance analysis, anthropometry and albumin and pre-albumin dosages the nutritional status was measured before starting the intervention and after 8 and 16 weeks. The disease activity was determined by Crohn's Disease Activity Index and serum C-reactive protein dosage and dietary intake by 24h dietary recalls. RESULTS: Forty-one patients concluded the study and both supplements changed body composition similarly. Triceps skin fold thickness (p< 0.001) and body fat percentage (p=0.001) decreased, whereas mid-arm muscle circumference (p=0.004), corrected arm muscle area (p=0.005) and body lean percentage (p=0.001) increased. CONCLUSIONS: For Crohn's disease patients undergoing anti TNF-alpha and azatioprine therapies, supplementation with whey and soy proteins changes body composition through reduction of body fat and thus contributes to control inflammation. PMID- 25795948 TI - Cowpea protein reduces LDL-cholesterol and apolipoprotein B concentrations, but does not improve biomarkers of inflammation or endothelial dysfunction in adults with moderate hypercholesterolemia. AB - INTRODUCTION: The risks of cardiovascular diseases, the leading cause of death in the world, can be reduced by diet. Cowpea protein has been shown to significantly reduce total cholesterol, LDL-cholesterol, and liver steatosis in hamsters. OBJECTIVE: The objective of this proof-of-concept study was to verify whether the consumption of cowpea protein improves lipid profile and biomarkers of inflammation and endothelial dysfunction in adults with moderate hypercholesterolemia. METHODS: In a randomized, double-blind, crossover design, 38 hypercholesterolemic subjects (LDL-cholesterol = 182.5 +/- 2.7 mg/dL) consumed 25 g/day of cowpea protein isolate or 25 g/day of casein (control group) for 6 weeks each, separated by a 4-week washout interval. Fasting blood samples were collected at baseline and at the end of each diet period. Lipids (total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol) were determined by enzymatic methods, apolipoproteins (apoA-I and apoB) by standardized immunoassays, inflammatory biomarkers (C-reactive protein) by turbidimetry, and biomarkers of endothelial dysfunction (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) by enzyme-linked immunosorbent assays. RESULTS AND DISCUSSION: Consumption of cowpea protein significantly reduced total cholesterol ( 12 %), LDL cholesterol ( 18.9 %), non HDL-cholesterol ( 16 %) and apoB ( 14 %), and increased HDL cholesterol (+2.7 %). No significant differences between treatment groups were observed for any of the serum inflammatory or endothelial dysfunction biomarkers. CONCLUSION: The present findings demonstrated the favorable effect of cowpea protein consumption on proatherogenic serum lipids and apoB in subjects with moderate hypercholesterolemia, similar to what was observed in a previous studies on animals. PMID- 25795949 TI - [Use of glutamine in total parenteral nutrition of bone marrow transplant patients]. AB - Glutamine is an essential amino acid for nucleotide synthesis and an important energy resource for cellular division. There is contradictory evidence about its benefits as part of parenteral nutrition. More than 75% of bone marrow transplant patients (BMTP) have, during their evolution, digestive tract complications limiting enteral nutrition, for this reason, sometimes total parenteral nutrition (TPN) is required. OBJECTIVE: Our aim was to analyze the relation between the use of glutamine in TPN of BMTP, and the evolution of clinical acute complications as mucositis, graft versus host disease (GVHD) and infections days of stay and days of TPN. MATERIALS AND METHODS: observational retrospective study. All BMTP with total parenteral nutrition during the period 2007-2013 were included. We analyzed days of stay, days of nutrition, glutamine use and acute complications. Results were analyzed in SPSS 15.0. RESULTS: 73 BMTP were divided in two comparable groups depending on glutamine use. The mean age was 36,96 +/- 12,89 years. 47,9% of patients received glutamine in TPN. Patients who received glutamine had a mean stay of 31,49+/-7,41 days with 14,11+/-5,87 days of TPN compared with the non glutamine group with 32,16+/-7,99 and 15,50+/-7,71 days respectively (p=0,71 y 0,39). Mucositis lasted 12,23+/-5,66 days in the glutamine group, and 15,50+/ 7,71 days in the non-glutamine group (p=0,042). Severe grades of GVHD (II,III) was observed in 20,6% of the non glutamine group compared with the 13,7% of the other group (p=0,636). In patients with glutamine suplementation, mucositis last 12,23+/-5,66 days compared with 15,50+/-7,71 days in the non-glutamine group (p=0,042).13,7% of all patients suffered infections while receiving TPN with glutamine compared with 16,4% in patients who did not receive glutamine (p=0,700). CONCLUSION: In our group, a statistically significant reduction in the duration of mucositis was observed in patients who received parenteral glutamine. PMID- 25795950 TI - [Fat-soluble vitamins supplementation in patients with cystic fibrosis: is enough Aquadek's(r)?]. AB - INTRODUCTION AND OBJECTIVE: Evaluate the safety and efficacy of a novel polyvitaminic (Aquadek's(r)) in patients with Cystic Fibrosis (CF). MATERIAL AND METHODS: Prospective, longitudinal and non-randomized study. CF patients with pancreatic insufficiency and clinically stable were given Aquadek's(r) (two chewable tablets) daily for 12 months. Serum levels of retinol, beta-carotene, 25 OH vitamin D and alpha-tocopherol were evaluated twelve months before, at baseline and 12 months after. STATISTICAL ANALYSIS: paired t tests. RESULTS: 28 patients aged 6 to 39 years (median 18.5 years) were included. Aquadek's(r) supplementation led to an increase in vitamin A dose and a decrease in the number of tablets administered. At baseline, 89% had at least one vitamin deficiency (61% pro-Vitamin A and 54% vitamin D). After one year, serum beta-carotene levels were increases 160 (95% CI 98-222) mcg/l (p <0.001) and decreased the percentage of patients with pro-vitamin A deficiency 46% (95% CI 22-64) (p <0.001). The proportion of patients with vitamin D insuficiency increased 18%(95% CI 2-32) (p =0.025). In any case serum levels exceeded the upper limits used to assess the risk of toxicity.Conclusions: Two daily Aquadek's(r) chewable tablets are safe and effective for maintaining vitamin A and E status of CF patients older than 6 years, although it is insufficient to normalize serum 25OHvitaminD according to the current recommendations for this disease. PMID- 25795951 TI - [Prevalence of vitamin d deficiency and insuffiency and associated factors in pregnant women of northern Spain]. AB - BACKGROUND AND OBJECTIVES: The vitamin D deficiency during pregnancy has been associated with adverse events during pregnancy and the postnatal child development. In this study we examined plasma levels of vitamin D [25(OH)D3] and factors associated with plasma deficiency and insufficiency in pregnant women in northern Spain. METHODS: We analyzed data from 453 pregnant women participating in the INMA-Asturias cohort in which was determined 25(OH)D3 by high resolution liquid chromatography.Dietary intake of vitamin D was estimated through a food frequency validated questionnaire. We estimated the prevalence of deficiency [25(OH)D3 <20 ng/ml] and insufficiency [20 to 29.9 ng / ml] of vitamin D and analyzed the distribution of 25(OH)D3 per month extraction and other factors. RESULTS: The mean concentration of 25(OH)D3 was 27.7 ng/ml (range 6.4 to 69.5). 27.4% of pregnant women had deficient levels and 35.3% inssuficient. Levels of 25(OH)D3 were higher in the summer months (median 34.1 ng/ml). There was a higher percentage of deficiency in pregnant women with overweight/obesity (34.5%) and under 25 years (47.8%). The average daily intake of vitamin D was 5.48 mg / day (SD 2.82 range 1.09 to 32.52).Intake during the months of October to May was associated with levels of 25(OH)D3. 8.6% reported taking supplements of vitamin D. CONCLUSIONS: We detected a high proportion of pregnant women with deficient or insufficient vitamin D levels, especially in the months of October to May, in pregnant women with overweight and obesity, and the youngest. PMID- 25795952 TI - Morphologic features of Sancassania berlesei (Acari: Astigmata: Acaridae), a common mite of stored products in China. AB - OBJECTIVE: Sancassania berlesei (S. berlesei) is the leading threatening mite in breeding industry of Eupolyphaga sinensis and public health. METHODS: Living specimens of S. berlesei were obtained from the surface of Eupolyphaga sinensis and purified with double-distilled water. The egg, larva, nymph, hypopus, adult male and female of S. berlesei were screened and picked out under microscope. RESULTS: Morphological variations of S. berlesei, including its legs, setae, external genitalia and accessories, are clearly identified under SEM. The larva has three pairs of legs, with no leaf-like setae, yet its coxal rod is well developed. By nymph stage, four pairs of legs and the fourth dorsal seta arise, whereas the genital area looks still under-developed. At hypopus, the claws and tarsules appear well-built, and leaf-like setae, setae of tibia and setae of genu are seen. The sucker plate totally contains nine suckers and four shell-like dimplings in which there are symmetric distributions with 1 pair of central suckers, 2 pairs of side suckers and 1 pair of anterior suckers, respectively. One pear-like posterior sucker is located at the back of sucker plate. All suckers are smooth except for anterior sucker with radial stripe. The genital sense organ of adults exhibits itself with cordiform external aspect and typical ossification texture; whereas the male is dissimilar with the female regarding seta number on the genital sense organ. CONCLUSION: Description of the morphological structure in great detail for S. berlesei tends to supply the important information for the taxonomy and further study. PMID- 25795953 TI - Serum and liver lipids distributions in streptozotocin induced diabetic rat treated with diet containing yam (Dioscorea bulbifera) flour. AB - INTRODUCTION: Liver disease as a major cause of mortality in patients with diabetes mellitus. There is a interest to investigate the hypolipidemic properties of yam. The goal was assess the role of Brazilian yam (Dioscorea bulbifera) on serum and hepatic levels of triglycerides and cholesterol, in female diabetic rats. METHODS: The rats were divided into three groups: Control (C), Diabetic (DM); Diabetic Yam (DMY), treated with diet containing 25g/100g of yam flour. After 5 weeks of experiment, glucose, insulin, gonadal fat and liver mass were evaluated. Serum and liver concentrations of triglycerides and cholesterol concentrations were quantified. Total liver thiols were determined. RESULTS: After the 5 weeks, experimental groups shower (P < 0.05): Lower body mass; lower serum insulin; higher food intake and higher blood glucose concentration. DMY (vs. DM) group showed (P < 0.05): Lower blood glucose; higher gonadal fat mass; lower serum and hepatic triglycerides; higher hepatic cholesterol and thiols concentrations. DMY (vs. C) group showed: Similar serum and hepatic triglycerides and hepatic thiols. CONCLUSIONS: Brazilian yam (Dioscorea bulbifera) alleviated the consequences of the experimental diabetic disease, suggesting protection to hypertriglyceridemia and lipid peroxidation. PMID- 25795954 TI - Effects of eight months of whole body vibration training on hip bone mass in older women. AB - OBJECTIVE: the aim of this study was to examine the effect of 8 months of whole body vibration training on bone mass in octogenarian women. METHOD: Thirty-seven women (aged 82.4 [SD=5.7] years) voluntarily participated in this study. The vibration group (n=19) trained on a vibration platform twice a week (20 Hz and 2 mm) whereas controls (n=18) did not participate in any training program. Bone mass was measured by dual-energy X-ray absorptiometry at the hip region. General linear repeated measures ANOVA (group by time) was used to examine the effect of whole body vibration on bone mass changes. RESULTS: After the intervention, in all the hip regions (total hip, femoral neck, trochanter, intertrochanter, Ward's area), no statistically significant changes in bone mass were found. CONCLUSION: eight months of whole body vibration training (twice a week) in elderly women do not produce osteogenic effects. PMID- 25795955 TI - [Sarcopenia and functionality in elderly inpatient]. AB - BACKGROUND AND OBJECTIVE: Sarcopenia is a geriatric syndrome associated with adverse events. The aim of the present study was to assess the sarcopenia prevalence and its association with the functionality in elderly inpatient. PATIENTS AND METHODS: A cross sectional study, during 6 months were included elderly inpatients to determine the presence of sarcopenia using the Baumgartner method. The functionality to perform basic activities of daily living (ABVD) was determined by the Katz index. Student's t test or U de Mann-Whitney was used to assess the differences between two groups and one-factor ANOVA or Kruskal Wallis for multiple comparisons; X2 and Fisher's exact test were used to compare the categorical variables and the Pearson correlation was calculated to determine the correlations between variables. RESULTS: 102 patients were included, 41 women and 61 man; subjects had a mean age of 71+/-8.6 years, body mass index 27.8+/-5.2 kg/m2, grip strength 14.9+/-8.3 kg, appendicular skeletal muscle mass (MMEA) 17.6+/-4.3 kg and skeletal muscle mass index (IMME) 7.1+/-1.2 kg/m2. The global prevalence of sarcopenia was 27.5%, was major in men (RR 1.33; CI 95% 1.06-1.67 p<0.05). There was a significant decrease on the grip strength (r=-.341) and MMEA (r=-.231) (p<0.05); sarcopenia was associated to a major dependence in both genders (p<0.05). CONCLUSIONS: Sarcopenia is a frequent condition in the elderly inpatients associated with the functionality's deterioration,identifying it help to perform a primary or secondary prevention and opportunity treatment. PMID- 25795956 TI - [Adherence to the Mediterranean diet and its relation to nutritional status in older people]. AB - INTRODUCTION: the Mediterranean diet (MD) and model quality diet is associated with a reduction in mortality and an improvement in quality of life in elderly. OBJECTIVE: To evaluate the relationship between nutritional status and lifestyles with the degree of adherence to the DM in elderly Methods: Sample consists of 60 subjects who attended the nursing consultation of a scepter health of Alicante with an index greater than 24.9 body mass. The frequency questionnaire food consumption MEDIS-FFQ questionnaire PREDIMED adherence to the Mediterranean diet and anthropometric assessment was used. RESULTS: 83.3% of the population were overweight compared to 16.7% obesity, no significant differences between sexes. The percentage of body fat was 40.3% in women and 29.5% in men (p = 0.001). 65.2% of the women had cardiovascular risk compared with 81.8% of men (p = 0.001). It was observed under compliance with dietary recommendations in whole grains, fruits and nuts. Subjects with low adherence to the DM had higher rates of obesity (OR = 1.46; 95% CI, 0.89-2.40), increased consumption of snuff (OR = 1.65; 95% CI, 1.05-2.60) and alcohol (OR = 1.53; 95% CI, 0.91-2.55), increased waist-hip ratio (OR = 2.57; 95% CI, 1.3-4.9) and higher percentage of body fat (OR = 5.3; 95% CI, 1.02-6.48). CONCLUSION: Subjects with good adherence (DM) had a lower waist-hip ratio and a lower percentage of body fat. PMID- 25795957 TI - Defatted flaxseed meal prevents the appearance of aberrant crypt foci in the colon of mice increasing the gene expression of p53. AB - OBJECTIVE: The goal of this study was to investigate the preventive effects of defatted flaxseed meal on the appearance of aberrant crypt foci (ACF) in mice treated with 1,2-dimethylhydrazine (DMH). MATERIALS AND METHODS: ACF were induced by intraperitoneal administration of 20 mg/kg body weight of DMH for 8 weeks. The animals were divided into three treatments (n=8): AIN93M diet without fibers + DMH (C-); AIN93M diet with defatted flaxseed meal (LIN); and AIN93M diet with defatted flaxseed meal + DMH (LINCA), for 15 weeks. The technique RT-PCR was used to evaluate the expression of p16, p21, p53, cyclin D1, and cyclin E in the distal colon. In addition, flow cytometric analysis of CD4 and CD8 spleen cells, the quantification of short-chain fatty acids (SCFA) in stool, the quantification of Bifidobacterium spp., Clostridium spp. in feces. RESULTS: LIN and LINCA showed increased Bifidobacterium spp. compared with control (C-). In relation to the weight of the organs, the groups LIN and LINCA showed higher values for the liver and kidney compared with control (C-). Regarding ACF, the group LINCA presented fewer ACF in the middle and distal colon compared with control (C-). When we analyzed ACF with more than three crypts the group LIN and LINCA did not present ACF in the middle and distal segments. LINCA presented increased p53 gene expression. CONCLUSION: This finding suggests that defatted flaxseed meal reduces ACF by increasing the expression of p53 and increase Bifidobacterium spp. PMID- 25795958 TI - Antioxidant capacity total in non-melanoma skin cancer and its relationship with food consumption of antioxidant nutrients. AB - The non-melanoma skin cancer is the most common cancer and accounts for more than half of the diagnoses of cancer, and basal cell carcinoma (BCC), the most frequent cutaneous neoplasm, corresponding to 70-80% of cutaneous tumors. Oxidative stress is an important trigger for skin carcinogenesis. Thus, it is important to evaluate oxidative stress, in order to discern effective therapeutic strategies able to stop it or attenuate it, thereby prevent the installation of non-melanoma skin cancer. Cross-sectional study with controls, involving 84 individuals of both sexes aged between 38-84 years, divided into two groups: control group of healthy people(n = 24) and the case group included individuals who presented non-melanoma skin and they have undergoing surgery (n = 60). The blood samples of the individuals were obtained for evaluation of biomarkers of oxidative stress (F2-isoprostane, nitrite, thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity). The usual dietary intake and nutritional status of the subjects were evaluated. The significance level for this study was 5%. Patients in the case group had higher serum concentrations of biomarkers of oxidative stress, F2-isoprostane concentrations were significantly higher compared to controls. The results showed high rates of overweight and obesity in the case and control groups. The dietary concentrations of antioxidant minerals zinc, copper and selenium in the case group were significantly lower compared to controls. The correlation between markers of oxidative stress and dietary concentrations of antioxidant nutrients showed the influence of food intake of vitamins A and E in reducing oxidative stress, since these nutrients behave as important antioxidants, acting as sweepers of RL, by removing of the body the negative effects on the redox balance of the skin. We emphasize the importance of adopting healthy eating habits that optimize the consumption of antioxidant nutrients as a strategy to prevent oxidative damage to the skin. PMID- 25795959 TI - Tissue effects of glutamine in rectal cancer patients treated with preoperative chemoradiotherapy. AB - BACKGROUND: The aim was to evaluate the effects of glutamine on tumor regression and histological damage in patients with rectal patients following chemoradiotherapy previous to surgery. MATERIAL AND METHODS: Ten patients with rectal cancer surgically removed after chemoradiotherapy were included, a subgroup of a randomized trial that compared glutamine and placebo in the prevention of acute radiation enteritis. Samples of neoplasm and healthy tissue were evaluated by an expert pathologist searching for signs of tumor regression, muciphages, and signs of radiation-induced damage. RESULTS: There were no differences in the grade of tumor regression with either glutamine or placebo. All patients who received glutamine presented muciphages, compared with 28.6% of the placebo group (p = 0.038). Histological damage was similar in patients receiving glutamine or placebo, and between those with radiation enteritis or without toxicity. CONCLUSION: Glutamine did not exert a protective effect over chemoradiotherapy in rectal cancer or healthy rectal tissue. PMID- 25795960 TI - Relationship of physical activity and sedentarism with tobacco and alcohol consumption, and Mediterranean diet in Spanish teenagers. AB - BACKGROUND AND OBJECTIVES: This study examined the association of physical activity and sedentarism with tobacco and alcohol consumption, and adherence to the Mediterranean diet in teenagers of both genders. METHODS: A total number of 1897 Spanish teenagers (12-16 year-olds) took part in the present cross-sectional study. The variables were measured by means of questionnaires previously validated for these ages. RESULTS: Physical activity was positively associated to the degree of adherence to the Mediterranean diet for both genders (beta = .144, P < .001 for boys and beta = .066, P< .05 for girls), and inversely associated to smoking for boys (beta = -.135, P = <.001). Sedentary behaviors for leisure purposes (TV and PC) were negatively associated to adherence to the Mediterranean diet for both boys (beta =-.100 and beta = -.104, both P < .05, respectively) and girls (beta= -.148 and beta = -.141, both P <.001), and positively associated to alcohol consumption for girls (beta = .114, P < .01 and beta = .199, P < .001, respectively). CONCLUSION: results suggest that physical activity and sedentary behaviors have an important relationship with the adherence to the Mediterranean diet in teenagers. Also, higher levels of physical activity in boys can lead to reduced tobacco use, while watching TV and PC leisure can lead to increased alcohol consumption in girls. PMID- 25795961 TI - [Validity of the 24-h previous day physical activity recall (PDPAR-24) in Spanish adolescents]. AB - INTRODUCTION: The monitoring of physical activity levels in adolescent population, its determinant factors and susceptibility to change is essential to intervene on the obesity epidemic affecting Spanish society. However, the number of validated questionnaires to assess physical activity in Spanish adolescents is scarce. OBJECTIVES: To assess the validity of the 24h Previous Day Physical Activity Recall (PDPAR-24) questionnaire when it is administered to the Spanish adolescent population. METHODS: The participants of the study were students, aged between 14 and 15 years, from two secondary schools in the north of Galicia. The measurement of physical activity by the accelerometer Actigraph GT3X was used as criterion. Participants were asked to wear the accelerometer during waking hours for one day and the questionnaire was administered the day after. RESULTS: A total of 79 students (15.16 +/- 0.81 years, 36% women) completed the study. Statistically significant positive correlations of high and moderate nature(r=0.50-0.98) were observed for low and moderate intensity physical activity in both sexes. Correlation coefficients were higher as physical activity intensity increased. CONCLUSIONS: The PDPAR-24 can be deemed as a valid tool for the assessment of physical activity in Spanish adolescents. PMID- 25795962 TI - [Psychometric properties of the spanish version of the "Barriers to Being Active Quiz" among university students in Colombia]. AB - OBJECTIVE: The Barriers to Being Active Quiz (BBAQ) measures seven barriers to being physically active. The test was translated into Spanish by the team that developed its original English version, but it lacks of the validity assessment studies. The aim of this study was to evaluate the psychometric properties of BBAQ (21 items version), focusing on the reliability and validity. MATERIAL AND METHODS: A total of 2634 (1462 female and 1172 male; age 18-30 years) university students completed the BBAQ-21 items questionnaire. Cronbach alpha was calculated to assess the internal consistency. Intraclass correlation coefficients (ICC) and degree of agreement were calculated to assess the test-retest reliability, with a period of 7 days between both administrations, as a measure of reproducibility. An exploratory factor analysis (EFA) and confirmatory (CFA) were done to analyze the validity of BBAQ-21 items. RESULTS: The Cronbach alpha coefficient of BBAQ-21 showed between 0,812 and 0,844 and ICC ranged between 0,46 and 0,87. The degree of agreement for all individual items ranged from 45% to 80%. The EFA showed a 4 factor solution that explained 52,90% of the variance and CFA showed moderate factor loadings. CONCLUSION: Results support the use of this questionnaire with populations of university students, considering its reliability and validity. BBAQ-21 is available to assess the barriers to physical activity in Latin America. PMID- 25795963 TI - Comparative analysis between two models of active aging and its influence on body composition, strength levels and quality of life: long-distance runners versus bodybuilders practitioners. AB - AIM: To analyze the body composition, strength level, and the quality of life related to the health (QoL) in veteran sportsmen (>35 years old) in relation to sedentary ones (S), and to compare the result in the mentioned variables between two models of sports practice, long-distance runners (LDR) and bodybuilding practitioners (BBP). METHODS: One hundred forty-eight male participants took part and were distributed into three groups: 47 LDR (age=42.01+/-6.96 years), 49 BBP (age=45.14+/-7.04 years), and 47 S (age=43.71+/-8.75 years). Body composition, upper- and lower-limb strength level, and QoL were assessed. RESULTS: The LDR and BBP obtained better performance in countermovement jump (CMJ) than the S ones (+0.06 m, p<0.001). Significant differences were found in BMI and %fat mass, between BBP and S with relation to LDR (p<0.001). In relation to the effect of aging on body composition, the muscle mass is reduced in all groups controlled (LDR, BBP, and S). Additionally, the %fat mass is increased only in S group (p< 0.05). The CMJ performance is significantly reduced only in S group (-0.07 m, p<0.001). CONCLUSIONS: The results suggested that the LDR as a model of active aging showed healthier values in BMI and %fat mass as well as greater results in QoL than BBP and S groups. Nevertheless, the LDR group showed similar values to S ones in muscle mass. The regression analysis performed showed that the sedentary habit predicts the %fat mass and CMJ performance. PMID- 25795964 TI - Reliability of the maximal oxygen uptake following two consecutive trials by indirect calorimetry. AB - BACKGROUND: The maximal oxygen uptake (VO2max) assessment by indirect calorimetry is the most reliable method to determine VO2max, but when repeated tests are conducted, the results have been controversial. AIM: To determine the reliability of the maximal oxygen uptake (VO2max) in healthy adults following two consecutive trials with 10 min rest between trials using the Bruce protocol. METHODS: Participants were 6 males apparently healthy physically active (Mean age=23,4+/ 1,3 years), who performed twice the Bruce protocol and after reaching their VO2max in the first trial they stepped down the treadmill and rested seated on a chair during 10 min. RESULTS: The data analysis showed high reproducibility values between tests, indicated by the correlation coefficient Pearson product moment and R squared with confidence intervals at 95% (CI95%), the correlation of the maximum oxygen consumption was VO2max =0.907 with a R2=0.823, the maximum heart rate was HRmax=0.786, with R2=0.618 and the rate of ventilation and carbon dioxide elimination was VE/VCO2=0.868, with an R2=754. No adverse effects were reported during the 10 min rest between trials. CONCLUSION: Resting 10 min between consecutive maximal exercise tests using Bruce protocol treadmill tests does not affect VO2max in healthy young adults. It is feasible and reliable to perform maximal treadmill tests in a single session without adverse effects for the participant. PMID- 25795965 TI - [Nutritional risk factors to users in dysmorphia muscular strength of room]. AB - OBJECTIVE: To analyze the prevalence and diet supplements used among gym users with muscle dysmorphia (MD) in the province of Alicante. METHODOLOGY: Several gymnasts weights-lift rooms of the urban area of Alicante were analyzed, collecting measurements of 141 (18-45 years of age) males that pursue an increase in their muscle mass. BMI (kg/m2), type and consume of diet supplements have been checked; and has been determined whether or not the presence of DM through the muscle scale satisfaction. RESULTS: The sample consisted of 141 men, of whom 45 are with MD and 96 not. 89.9% and 71.9% use or have used diet supplements respectively. The consumption of supplements: proteins, carbohydrates and creatine have been significantly higher in MD's users (p=0.007, p=0.016 and p=0.016 respectively). The Kidmed's test results have not been significant according to the Chi-square test, but with a higher percentage of the Mediterranean diet in the group of those with DM. According to multivariate analysis are risk factors consuming supplements with an OR=3.4 (95%CI=1.1-10.9; p=0.041), being overweight with an OR=20.9 (95% CI=2.2-195.6; p =0.008) and obese with an OR=15.5 (95% CI=1.6-145.8; p=0.017). CONCLUSION: The use prevalence of diet supplements among MD and non-MD has relatively higher values compared to most studies. The most consumed diet supplements were protein, creatine and carbohydrates. The risk of suffering MD increases with the obesity degree and supplements consumption. PMID- 25795966 TI - [The effects of 16-weeks pilates mat program on anthropometric variables and body composition in active adult women after a short detraining period]. AB - INTRODUCTION: previous studies have analysed the effect of mat Pilates practice on anthropometric variables and body composition in sedentaries. To date no researchs have investigated the benefits of Pilates on these variables after a short detraining period. OBJETIVE: to determine the effect of a 16-week mat Pilates program on anthropometric variables, body composition and somatotype of women with previous practice experience after three weeks of detraining period. METHOD: twenty-one women underwent a complete anthropometric assessment according with ISAK guidelines before and after a 16 week mat Pilates program (two days, one hour). All women had one to three years of mat Pilates experience and came to three weeks of detraining period (Christmas holiday). RESULTS AND DISCUSSION: women showed significant decreases for body mass, BMI, upper limb (biceps and triceps) and trunk (subscapular, iliac crest, supraspinale and abdominal) individual skinfolds, 6 and 8 skinfold sums, endomorphy and fat mass; and a significant increases for muscle mass. The mean somatotype was classified as mesomorphic endomorph in the pre- (4.91, 4.01, 1.47) and post-test (4.68, 4.16, 1.69). Eight women changed their somatotype clasification after the intervention program. CONCLUSIONS: the practice of mat Pilates for 16 weeks caused changes associated with health state improvements on anthropometric variables, especially on skinfolds which significantly decreased, body composition (fat and muscle masses decreased and increased, respectively) and somatotype (there was a significantly decreased on the endomorph component in experienced women after three week of detraning. PMID- 25795967 TI - [Nutritional status in university students: its relation to the number of daily intakes and macronutrients consumption]. AB - INTRODUCTION: There is increasing scientific evidence that nutrition influence positive and negative on health along life. Many studies have reported that the student population is a particularly vulnerable group from the nutritional point of view, due to it is characterized by meal skipping frequently and nibble between eating occasions. OBJECTIVE: to establish the relationship between the number of daily dietary intakes and nutritional status in male students aged 23 to 33 years of the National Technological University, in the city of Cordoba, in 2013. METHODS: in order to achieve this aim, a prospective, cross-sectional and descriptive correlational design was used. Descriptive and inferential analysis were applied by using multiple logistic regression models. RESULTS: Almost 50% of the sample analyzed presented overweight (OW) and 40% high body fat (BF). In relation to the intakes numbers, the students that take less than 4 and more than 6 had 2 times more chance of presenting overweight and high body fat. It was found that as age increases it also does the Body Fat Storage, whereas diminished physical activity increases the chance of having high Body Mass Index and Body Fat. Moreover, high ingestion of carbohydrates increases the chance of high Body Fat and Overweight, and a high intake of protein and lipids increases the risk of high Body Fat. CONCLUSION: it is recognized that high or low number of daily intakes than recommended, low level of physical activity, high consumption of carbohydrates and having more than 29 years is related to high overweight and body fat. PMID- 25795968 TI - [Prevalence of undernutrition in hospital patients with unbalanced heart failure; subjective global assessment like prognosis sign]. AB - INTRODUCTION: The malnutrition prevalence's studies in patients with heart failure have a great variability. The proportion depends on the used method and the evaluation moment. Malnutrition increases complications, hospital stay, mortality and hospital reentry. It is good idea to diagnose and treat these patients. OBJECTIVES: The objective was determined the prevalence of malnourished heart failure's patients in hospital at our environment and to analyze what used method was a better mortality predictor. METHOD: Observational study. The nutritional status have been evaluated by Subjective Global Assessment and Mini Nutritional Assessment the nutritional status of 377 patients joined in a high complexity hospital with decompensation of chronic heart failure. RESULTS: The mean age was 75+/-10. The 51,5% (n=194) were men . According to the Subjective Global Assessment, 50,7 % (45,6 %-55,7 %) were normal nutrition, 41,9 % (37,0 % 46,9 %) were on risk of malnutrition and 7,4 % (5,2 %-10,5 %) were evident malnutrition. CONCLUSION: The malnutrition prevalence's in hospital chronic heart failure patients by decompensation in our area is high. The Subjective global assessment is a good mortality predictor. PMID- 25795969 TI - [Life style, dietary habits and nutritional evaluation of Hospital de Merida health professionals]. AB - INTRODUCTION AND OBJECTIVES: Living habits, several nutritional aspects and relationship between them were studied of Hospital de Merida health professional of the Extremadura Health Service (SES). METHODS: Forty-three employed workers participates voluntary in this project by submitting a questionary about personal details and life style, and a seven-days-food-intake-dietary. Finally, their anthropometric data were also measured. RESULTS: Men tend to play more physical activities than women. They also were more sedentary. They use to smoke less than women, but they do drink more. Normal-weight subjects tried to practice sport during more time than overweight and obese ones. However, they also remained sitting for longer periods on a weekly basis. The average daily intakes of kilocalories were higher in men, but protein intakes were higher in women. Fat intake was increased in both sexes. The average daily intake of kilocalories was lower in obese subjects than over and normal-weights ones. An increase in the body mass index was accompanied by a bigger waist perimeter, waist to hip ratio, fat mass and body fat percentage. CONCLUSION: The majority of people interviewed in the survey have healthy living and dietary habits. Protein and fat daily intake is slightly higher than the values recommended by the WHO. Carbohydrates intake, by contrast, is lower. PMID- 25795970 TI - Subclinical eating disorders in female medical students in Anhui, China: a cross sectional study. AB - PURPOSE: This cross-sectional study explored the prevalence of eating disorders (EDs) and possible associated factors (depressive symptoms, anxiety and BMI, etc) on EDs in female medical students in China. METHODS: A total of 1,135 students in Wuhu, Anhui Province were sampled to participate in this survey. The survey collected sociodemographic data, depressive symptoms, anxiety and eating behaviors of students. RESULTS: The students at risk for eating disorders were 2.17%. Eating disorder risk was more frequent in students with poor parent's relationship, students with poor relationship with parents, students with high body mass index, students who were excessive focus on slimming propaganda, and students whose relatives have a diet. Also, the mean scores for the psychological factors of depression and anxiety were higher in students with eating disorder risk. A multiple linear regression model was produced depicting that depression, anxiety, high level of BMI, focusing on slimming propaganda, and dieting status among relatives were risk factors of having an eating disorder risk. CONCLUSIONS: A significant fraction of female medical students in Anhui are at high risk of development of eating disorders. A comprehensive intervention focusing on family environment and emotion management should be designed to prevent occurrence of such disorders among medical students that would undoubtedly hamper the availability of dependable medical services in future. PMID- 25795971 TI - [Nutritional status, healthy habits, quality of life and daytime sleepiness in nightlife workers of Cordoba]. AB - This study is aimed to analyze the factors that affect body composition, nutritional status, dietary habits, substance abuse (alcohol and smoking), physical activity, sleepiness disorders and self-rated health status in people working in nightlife in the city of Cordoba. Representative sample of 144 subjects (88 men and 56 women) with a mean age of 26.88 (+/- 4.7) years was studied. Individuals were analized for their body composition. Besides, a personal interview was used to administrate validated questionnaires to get other important data related to the aim of the study. The male group showed higher body mass index (p<0.05), showing overweight in more than half of the sample, and higher levels of body fat in 42% of subjects. Adherence to the Mediterranean diet was low and up to 48.6% presents a risk alcohol consumption, being higher in the male group. 40% of the subjects suffer from disorders of daytime sleepiness, however they spend a big amount of time in physical activities. The sample shows a high obesity and overweight prevalence and a low adherence to the mediterranean diet. Although they are not sedentary, the sample has unhealthy habits such as drinking alcohol and smoking and at the same time they suffer from sleepiness daytime disorders. In spite of they seems to have a high self-awareness about their own health status, 1 from every 5 individuals recognize that they could improve it. PMID- 25795972 TI - [Tap water as a dietary source of exposure to fluoride in Tenerife; risk assessment]. AB - INTRODUCTION: drinking water is the main source of fluoride exposure for the population. According to the Spanish Law RD 140/2003, the fluoride content in drinking water should not exceed the parametric value of 1.5 mg/L. Historically, certain drinking waters in the island of Tenerife have exceeded this value due to the geological/volcanic characteristics of the Canary Islands. Fluoride (F) plays an important role in the prevention of dental caries (tooth decay). However, long exposure to concentrations above 1.5 mg/L in drinking water can cause disorders such as dental fluorosis. OBJECTIVES: To determine the amount of fluoride in the tap waters of the 11 municipalities in the north of the island of Tenerife that, at the time of the study, exceeded the parametric value for fluoride set by the Spanish legislation and to toxicologically estimate and evaluate the fluoride daily intakes from water considering the RDI (Recommended Daily Intake) established in Spain for different population groups. METHOD: 44 samples of tap water collected in the 11 municipalities in the study were analyzed using the fluoride potentiometric determination with an ion selective electrode. RESULTS: 9 of the 11 municipalities presented mean fluoride concentrations in their tap water that exceeded the parametric value set by the Spanish legislation (1.5 mg/L). Considering an average daily water consumption of 2 L, the recommended daily intake (RDI) for women (3mg F/day) is exceeded in 9 of the 11 municipalities and the RDI for men (4 mg F/day) is exceeded in 5 of the 11 municipalities. Considering a daily water consumption of 1.5 L, the RDI for children of 2-3 years (0.7 mg/day) is clearly exceeded in all municipalities. CONCLUSIONS: The results show the existing public health problem on the island of Tenerife and justify the tap water consumption restrictions put in force by the Public Health Authorities of the Canary Islands at the time of the study. Children are the most exposed population group to the risks of fluoride because its RDI is lower. PMID- 25795973 TI - [Proposal of reference values of microbiological environment monitoring in foodservice establishments]. AB - INTRODUCTION: To propose a new reference of microbiological environment monitoring in foodservice establishments. OBJECTIVE: The present work shows the determination and evaluation of the microbiological contamination generated in a foodservice establishment Method: It is based on surface sampling (microbial build-up) using mixed cellulose ester membrane filters and on air sampling (hourly microbial adhesion) using Petri dishes. RESULTS: Limits of contamination are established before and during the food elaboration, by means of the microbiological analysis of the environment, surfaces and equipment systems, until reliable limits and levels of acceptance are established of each selected point. Finally, a program of environmental microbiological monitoring was established including the evaluation of all parameters that compose and are implicit in the area, thus assuring and supporting its continuity with the documentation and registers developed for a safety area. Samples for microbiological examination were collected over a period of one moth on ten different days, at two different times. Twelve selected points having previously been identified as hazardous were monitored. Furthermore, foods though to be of high risk were periodically collected for microbiological analysis. CONCLUSIONS: The possibility to use of an ample range of selective media, well over the limited number used in this study, allows the analysis of many single microbial species. PMID- 25795974 TI - Compliance of nutritional recommendations of Spanish pregnant women according to sociodemographic and lifestyle characteristics: a cohort study. AB - OBJECTIVE: To assess nutrient intakes and compliance with nutritional recommendations in pregnant women according to selected sociodemographic characteristics and lifestyles. METHODS: Cross-sectional study based on data from Spanish INMA cohort which recruited 2,585 pregnant women between 2003 and 2008 from four different regions of Spain. Sociodemographic information and anthropometry was collected and dietary intake was assessed through Food Frequency Questionnaires. The adequacy of food group intake was assessed considering current recommendations and from the Spanish Society of Nutrition. Moreover, intake of vitamin A, vitamin C and vitamin E, were compared with the Dietary Reference Intakes of the US Institute of Medicine. RESULTS: Percentage of women that did not fulfil the recommendations for cereals and legumes (3-4 servings/day) was 70.0%, for fruit intake (2-3 servings/day) it was 39.2%, for vegetables (2-4 servings/day) 47.3% and for dairy (3-4 servings/day) it was 51.6%. Intake of fruit and vegetables increased with age, educational degree and with physical activity (p<0.05). Also non-Spanish achieved better the recommendations. Percentage of pregnant women that did not fulfil the requirements (DRI) of vitamins A and C was 13.2 % and 16.2 respectively. More than 65% of the women did not met the recommended diary intake of vitamin E of 19 mg/day during the lactation period. CONCLUSIONS: Maternal age, education, having healthy habits, as well as country of origin are factors strongly associated with the composition of the diet. Sedentary women and those with a low education are at risk for low vitamin and antioxidant intake and non-optimal food choices during pregnancy. PMID- 25795975 TI - Pharmacology and biochemistry undergraduate students' concern for a healthy diet and nutrition knowledge. AB - OBJECTIVE: To estimate the concern for a healthy diet and the nutrition knowledge of undergraduate students of a pharmacology and biochemistry program and their associations with the variables of interest. METHODS: This cross-sectional study administered the Nutrition Knowledge Scale and the How is your diet? questionnaire to 381 students. The associations between concern for a healthy diet and nutrition knowledge and between these two factors and the demographic variables were measured by the chi-square test (chi2) or Fisher's exact test. The significance level was set at 5%. RESULTS: The mean age of the students was 20.6 (standard deviation [SD] = 2.7) years; 78.2% were female students; their mean body mass index was 22.6 (SD = 3.7) kg/m2; and 73.5% had an appropriate body mass index-related nutritional status. Most students fell within the category "pay attention to your diet" (77.1%) and "moderate nutrition knowledge" (79.7%). Concern for a healthy diet was significantly associated with program year (p = 0.024), socioeconomic class (p = 0.012), and physical activity (p <0.001). Nutrition knowledge was associated only with program year (p < 0.001). Concern for a healthy diet was not associated with nutrition knowledge (p = 0.808). CONCLUSION: Physically inactive, first-year students from socioeconomic class B (US$ 1,046 - 1,872) were less concerned with a healthy diet. Such concern was not related to the students' nutrition knowledge. PMID- 25795976 TI - [Trends in food consumption of university students]. AB - The university students need to consolidate good dietary habits based on an adequate selection of food, which is a factor of fundamental importance to maintain good health and prevent disease. OBJECTIVE: to evaluate the food intake and diet profile of university students from Tucuman and its variation over time. Analyse if they accomplish current dietary recommendations. MATERIAL AND METHOD: Data collection was carried out during the years 1998-1999 (G1) and 2012-2013 (G2); was performed by a self-survey and food frequency questionnaire of food consumption. It was applied to 329 university students selected randomly. The dietary pattern was described by frequency of usual consumption of principal food groups. RESULTS: Students were 25.2% male and 74.8% female, mean age 23 +/- 3 years. In general, in both groups most of the students had a normal BMI, but had a high percentage of men with overweight (18.2%) and obesity (12.1%) and women with underweight (11.6%). According to the groups and sex analysis some significant statistically differences in macronutrient composition of the diet were observed: the G1 was higher carbohydrate intake than proteins and lipids; also differences in the intake of some micronutrients were found, with a higher intake of iron and less intake of vitamins B1, B2, niacin and C in G2. The diet was monotonous for both groups and with differences in the profile of nutrients. The most notable was the gradual increase consumption of sugary products, processed foods, snacks and decrease consumption of dairy, fish, fruits and vegetables in G2. In both groups, adequacy of dietary intake of the university students did not cover the recommendations of iron, calcium and vitamin A. Given the food profile observed in the student population, is warned the need to promote changes to prevent the development of obesity and cardiovascular disease in adulthood; it should be convenient to carrying out food and nutrition education. PMID- 25795977 TI - The association of selenium status with thyroid hormones and anthropometric values in dyslipidemic patients. AB - BACKGROUND: Selenium (Se) is an essential micronutrient that performs physiological functions in the metabolism of thyroid hormone and may have an association with anthropometric variables relevant to cardiovascular disease. AIM: To study the associations between Se status, thyroid hormones and anthropometric variables in dyslipidemic patients. METHODS: Eighty-three patients were assessed in a cross-sectional study. Blood samples were analyzed for Se and thyroid hormones. Anthropometric measurements were taken, and dietary Se intake was investigated. RESULTS: Mean plasma Se concentrations were low in the patients, at 88.7 +/- 16.7 ug/L. Patients with plasma Se >= 95 ug/L were found to have a higher body mass index (BMI) (30.74 +/- 4.31 vs 27.68 +/- 5.63 kg/m2, P = 0.02) and waist-to-height ratio (0.65 +/- 0.05 vs 0.59 +/- 0.07, P = 0.003) when compared to those with concentrations between 80 and 94 ug/L. Se intake associated positively with T3L/T4L ratio (r = 0.273; P= 0.03), BMI (r= 0.257, P= 0.04) and WC (r= 0.299, P= 0.02). CONCLUSION: The patients with the highest normal plasma Se concentrations were found to have increases in the anthropometric variables we investigated. There is a need for further study in order to elucidate these findings. Furthermore, we found a positive association between Se intake and the most metabolically active form of the thyroid hormones. PMID- 25795979 TI - [Cross-sectional study of factors influencing adherence to the Mediterranean diet in pregnancy]. AB - INTRODUCTION: Mediterranean diet is a lifestyle with contrasted beneficial effects on pregnancy, for both the mother and her offspring. However, factors influencing adherence to this diet are unknown. OBJECTIVE: To investigate the factors (educational level, occupation, place of birth, number of previous children and age) that influence adherence to the Mediterranean diet in pregnant women in the region of Pamplona. MATERIAL AND METHODS: Using the data from the Estudio Internacional de Sibilancias en Lactantes (EISL) in the region of Pamplona, associations between food and factors were analysed. A score of Mediterranean diet was established and the scores according to the factors were studied. RESULTS: Significant differences in the Mediterranean diet score by level of education (p=<0,001), occupation (p=0,015) and age (p=<0,001) were found. CONCLUSION: Women with better education, better occupation and older show a greater affinity to the Mediterranean diet during pregnancy. PMID- 25795978 TI - Perception of body image of adolescents and of their parents in relation to the nutritional status and blood pressure. AB - The perception of body image of adolescents is an instrument for nutritional assessment to health conditions. OBJECTIVE: To verify the body image perception of adolescents and their parents in relation to nutritional status and blood pressure levels. METHODS: Population-based study, and cross-sectional model, conducted with parents and adolescents aged 10-19 years old, in rural and urban zones in public schools. There was applied the Scale silhouettes for parents about the perception of the described body image and a question about the concern of the nutritional status of their children. There were verified the blood pressure, weight, height and waist circumference, the BMI (kg/m2) calculation of the adolescents, and the self-perceived body image. The data was expressed as average +/- standard deviation and percentages. RESULTS: The sample consisted of 914 adolescents with a mean age of 13.12 +/- 2.17 years, 56.8% female and 68.9% were eutrophic. As for blood pressure levels, 17.6% were classified in pre hypertensive, 18.8% in stage 1 hypertension and 6% in stage 2. About the self perception, 68% considered themselves being eutrophic and 64.75% of the parents classified their children as eutrophic. There was observed a direct and significant correlation among the body mass index, waist circumference, weight, systemic and diastolic blood pressure with the self-perception of the adolescents and the body image perceptions of the parents (p<0.001). CONCLUSION: The nutritional status was significantly correlated with blood pressure, waist circumference and body image perceptions of the adolescents and their respective parents. PMID- 25795980 TI - [ANDALIES project: consumption, offer and promotion of healthy eating habits within secondary schools in Andalusia]. AB - INTRODUCTION: The school context stands out as one of the factors influencing the food practices of adolescents. Food consumption during the school day, the cafeterias' supply and the promotional activities proposed by the centers are objects of increasing attention to community health services. OBJECTIVES: To describe students' eating habits during the school day; to analyze the food on offer by the cafeterias and surrounding establishments; and to assess whether secondary schools are suitable environments for the promotion of healthy eating habits. DESIGN AND SAMPLE: Cross-sectional study during 2010-2012 courses. Sampling units: public secondary schools (95) and students (8.068). Multistage cluster sampling: random and stratified selection by province and habitat size. Selection of students: systematic sampling of classrooms. RESULTS: 77.5% of students have breakfast at home: cereals and a dairy product (40.9%) or a liquid (29.2%); 70.3% eat something at school and most of them choose a cold meat sandwich. Fruit consumption is infrequent (2.5%) while packed juices are very common (63.3%). 75% eat sweets, the figure increasing significantly in schools with cafeterias. Cafeterias offer a large number of non-recommended products: soft drinks (97,3%), cold meats (91,8%), sweets and chips (89%). Lack of control of the products on offer is common (68.42%); only 28.4% of the managers know the law. 72.5% of the centers undertake isolated activities for the promotion of healthy eating habits. 71.5% of the centers are surrounded by shops that supply the students. DISCUSSION: Low protection of students' food health is evident, resulting from: students' nutritional deficits, the low quality of the food offered by the cafeterias and the lack of activities to encourage healthy habits. For which reason, educational, health and local administrations must accept shared responsibility on this subject. PMID- 25795981 TI - [Relationship between age, body mass index, dependency and quality of life in malnourished patients after hospital discharge]. AB - INTRODUCTION: The quality of life assessment means investigating how patients perceive their disease. Malnutrition-specific characteristics make patients more vulnerable, so it is important to know how these factors impact on patients' daily life. AIM: To assess the quality of life in malnourished patients who have had hospital admission, and to determine the relationship of the quality of life with age, body mass index, diagnosis of malnutrition, and dependency. METHOD: Multicenter transversal descriptive study in 106 malnourished patients after hospital admission. The quality of life (SF-12 questionnaire), BMI, functional independency (Barthel index), morbidity, and a dietary intake evaluation were assessed. The relationship between variables was tested by using the Spearman correlation coefficient. RESULTS: The patients of the present study showed a SF 12 mean of 38.32 points. The age was significantly correlated with the SF-12 (r= 0.320, p= 0.001). The BMI was correlated with the SF-12 (r= 0.251, p= 0.011) and its mental component (r= 0.289, p= 0.03). It was also reported a significant correlation between the Barthel index and the SF-12 (r= 0.370, p< 0.001). CONCLUSIONS: The general health perception in malnourished patients who have had a hospital admission was lower than the Spanish mean. Moreover, the quality of life in these patients is significantly correlated with age, BMI and functional independency. PMID- 25795982 TI - [Efficiency, cost-effectiveness and justification of need for investment in nutrition therapy in a hospital of third level; the role of specialists in endocrinology and nutrition and the coding unit]. AB - Disease Related Malnutrition (DRM) is highly prevalent in Spanish hospitals. WHO estimates that 20-40% of health-associated expenses are lost due to inefficiency. Demonstration that DRM is a component of inefficiency and hiring a specialist physician for its detection and treatment is cost-effective. MATHERIAL AND METHODS: Comparison between nutritional diagnosis and procedures detected and encoded at discharge using McNemar test. Recoding of 55 discharge reports including nutritional diagnoses and procedures. Determine changes on Case-Mix Index (IC), cost of procedure and cost procedure/GRD index. Comparison using Wilcoxon test. RESULTS: Only 2 of 55 diagnoses of malnutrition were coded in delivery statements (p<0,001). After right codification,IC increased in 42,67 GRD points (p<0,05). Consequently, procedure cost/GRD index was reduced in 976,81? (p<0,05). CONCLUSIONS: DRM is underdiagnosed in our hospital. DRM and nutritional procedures detection by a specialist on endocrinology and nutrition led to a reduction in cost procedure/GRD index of 20% of officially established by the Health System. Loss of 20% of health expenses,estimated in 172690? was described. Proper codification would have justified 154581? reimbursement just for nutritional diagnoses and processes. Both expenses were lost due to system's inefficiency. Those amounts are much higher than cost associated of hiring a specialist, so there is no economic reason for denying it. PMID- 25795983 TI - [Chylous asctites post abdominal laparotomy; revision and report of a case]. AB - We describe the case of a 23 year old man who had undergone laparoscopic surgery in order to remove a residual mass secondary to a testicular embryonal carcinoma. 15 days after he attended the emergency department complaining about abdominal bloating and copious drainage via the two laparoscopic surgery incisions. Biochemical analysis was consistent with chylous ascites. Although this is uncommon, it is well known that there is more likely to develop chylous ascites after oncologic surgery if retroperitoneal lymph nodes dissection is performed1. We decide to start with conservative treatment (dietary modifications) but, as it is not enough, then we decide stop any oral intake and treat him with parenteral nutrition, achieving then total resolution of the ascites. PMID- 25795984 TI - Ostomy metastasis after pull endoscopic gastrostomy: a unique favorable outcome. AB - Head and neck cancer (HNC) patients tend to develop dysphagia. In order to preserve the nutritional support, many undergo endoscopic gastrostomy (PEG). In HNC patients, ostomy metastasis is considered a rare complication of PEG, but there are no reports of successful treatment of these metastatic cancers. We report the case of a 65 years old pharyngeal/laryngeal cancer patient who underwent a PEG before the neck surgery. He was considered to be cured, resumed oral intake and the PEG tube was removed. Ten months after, he returned with a metastasis at the ostomy site. A block resection of the stomach and abdominal wall was performed. Two years after the abdominal surgery, he is free of disease. Although usually considered a rare complication of the endoscopic gastrostomy, ostomy metastasis may be more frequent than usually considered and the present case report demonstrates that these patients may have a favourable outcome. PMID- 25795985 TI - Hirschsprung disease associated with Mowat-Wilson syndrome: report of a case. AB - INTRODUCTION: Hirschsprung's disease (HD) or aganglionicmegacolon is a congenital disorder characterized by the absence of ganglion intramural cells of the submucosal myenteric plexus (namely Auerbach and Meissner,respectively) in distal sections of the intestine. This is due to a failure in the migration of the precursors of these cells from the neural chalk during the embryonic development and also due to other abnormalities associated(18 % of cases), in some cases involving specific polymalformation syndromes. OBJECTIVES: The aim of the work is to present the clinical and nutritional evolution of a 14 months aged pediatric patient who was diagnosed with HD since was born associated with Mowat-Wilson syndrome (MWS). In addition,it is also targeted to evaluate the clinical results from this patient. METHODS: Reviewing the medical history of the patient,the evolution of the anthropometric data (weight and height) as well as the analytical parameters for further studies were carried out. In addition, the upcoming issues associated with nutritional support and therapeutic strategies in the multidisciplinary context were evaluated. RESULTS: A male, 14 months aged patient, son of not consanguineous healthy immigrants parents from Colombia went to the emergency department of our hospital suffering abdominal distension and vomiting with no spontaneous bowels. A detailed description of the composition of parenteral nutrition administered within the period of 28 days of hospital admission. CONCLUSION: As observed in this patient, the association of HD and MWS can lead to the need of prolonged parenteral nutrition and frequently present diverting stoma leading to a greater number of postoperative complications in this population. PMID- 25795986 TI - [Combined methylmalonic acidemia and homocystinuria; a case report]. AB - Combined methylmalonic acidemia and homocystinuria is an inborn error of metabolism of vitamin B12 or cobalamin. It's a rare autosomal recessive disease in which there are several variants depending on the pathogenesis of the metabolic disorder (cblC, cblD, cblF and cblJ). The more frequent and more severe is the cblC variant, which usually manifests in the first months of life, although some cases have been reported at the beginning of adulthood. A proper diagnosis and effective therapeutic approach is fundamental. We report the case of a patient of 18 years with a history of epilepsy who consults for acute renal failure requiring renal replacement therapy and diagnosed with combined methylmalonic acidemia and homocystinuria cblC variant. PMID- 25795987 TI - Do children with specific language impairment and autism spectrum disorders benefit from the presence of orthography when learning new spoken words? AB - This experiment investigated whether children with specific language impairment (SLI), children with autism spectrum disorders (ASD), and typically developing children benefit from the incidental presence of orthography when learning new oral vocabulary items. Children with SLI, children with ASD, and typically developing children (n=27 per group) between 8 and 13 years of age were matched in triplets for age and nonverbal reasoning. Participants were taught 12 mappings between novel phonological strings and referents; half of these mappings were trained with orthography present and half were trained with orthography absent. Groups did not differ on the ability to learn new oral vocabulary, although there was some indication that children with ASD were slower than controls to identify newly learned items. During training, the ASD, SLI, and typically developing groups benefited from orthography to the same extent. In supplementary analyses, children with SLI were matched in pairs to an additional control group of younger typically developing children for nonword reading. Compared with younger controls, children with SLI showed equivalent oral vocabulary acquisition and benefit from orthography during training. Our findings are consistent with current theoretical accounts of how lexical entries are acquired and replicate previous studies that have shown orthographic facilitation for vocabulary acquisition in typically developing children and children with ASD. We demonstrate this effect in SLI for the first time. The study provides evidence that the presence of orthographic cues can support oral vocabulary acquisition, motivating intervention approaches (as well as standard classroom teaching) that emphasize the orthographic form. PMID- 25795988 TI - Variation of polycyclic aromatic hydrocarbons in atmospheric PM2.5 during winter haze period around 2014 Chinese Spring Festival at Nanjing: Insights of source changes, air mass direction and firework particle injection. AB - Daily PM2.5 samples were collected at a suburban site of Nanjing around 2014 Chinese Spring Festival (SF) and analyzed for 18 kinds of polycyclic aromatic hydrocarbons (PAHs) by GC-MS. Comparison of PAH concentrations during different periods, with different air mass origins and under different pollution situations was done. Sources were analyzed by diagnostics ratios and principal component analysis (PCA). The threat of PAHs was assessed by BaP equivalent concentrations (BaPeq) and incremental lifetime cancer risk (ILCR). The averaged PAHs for pre SF, SF and after SF periods were 50.6, 17.2 and 29 ng m(-3), indicating the variations of PAH sources, with reduced traffic, industrial and construction activities during SF and gradually re-starting of them after-SF. According to PAH mass concentrations, their relative abundance to particles, ratio of PAHs (3 ring+4-ring)/PAHs(5-ring+6-ring), mass concentrations of combustion-derived and carcinogenic PAHs, fireworks burning is an important source for PAHs during SF. The ILCR values for Chinese New Year day were 0.68 and 3.3 per 100,000 exposed children and adults. It suggested the necessity of controlling fireworks burning during Chinese SF period which was always companied with serious regional haze pollution. PAH concentrations exhibited decreasing trend when air masses coming from the following directions as North China Plain (63.9 ng m(-3))>Central China (53.0 ng m(-3))>Shandong Peninsula (46.6 ng m(-3))>Northwest China (18.8 ng m( 3))>Sea (15.8 ng m(-3)). For different pollution situations, they decreased as haze (44.5 ng m(-3))>fog-haze (28.4 ng m(-3))>clear (12.2 ng m(-3))>fog day (9.2 ng m(-3)). Coal combustion, traffic emission, industrial processes and petroleum (only for non-SF holiday periodss) were the main sources of PM2.5 associated PAHs. Fireworks burning contributed 14.0% of PAHs during SF period. Directly measurement of PAHs from fireworks burning is urgently needed for source apportionment studies in the future. PMID- 25795989 TI - Exposure to runoff from coal-tar-sealed pavement induces genotoxicity and impairment of DNA repair capacity in the RTL-W1 fish liver cell line. AB - Coal-tar-based (CTB) sealcoat, frequently applied to parking lots and driveways in North America, contains elevated concentrations of polycyclic aromatic hydrocarbons (PAHs) and related compounds. The RTL-W1 fish liver cell line was used to investigate two endpoints (genotoxicity and DNA-repair-capacity impairment) associated with exposure to runoff from asphalt pavement with CTB sealcoat or with an asphalt-based sealcoat hypothesized to contain about 7% CTB sealcoat (AS-blend). Genotoxic potential was assessed by the Formamido pyrimidine glycosylase (Fpg)-modified comet assay for 1:10 and 1:100 dilutions of runoff samples collected from 5 h to 36 d following sealcoat application. DNA-repair capacity was assessed by the base excision repair comet assay for 1:10 dilution of samples collected 26 h and 36 d following application. Both assays were run with and without co-exposure to ultraviolet-A radiation (UVA). With co-exposure to UVA, genotoxic effects were significant for both dilutions of CTB runoff for three of four sample times, and for some samples of AS-blend runoff. Base excision repair was significantly impaired for CTB runoff both with and without UVA exposure, and for AS-blend runoff only in the absence of UVA. This study is the first to investigate the effects of exposure to the complex mixture of chemicals in coal tar on DNA repair capacity. The results indicate that co exposure to runoff from CT-sealcoated pavement and UVA as much as a month after sealcoat application has the potential to cause genotoxicity and impair DNA repair capacity. PMID- 25795990 TI - Examining the broader psychosocial effects of mass conflict on PTSD symptoms and functional impairment amongst West Papuan refugees resettled in Papua New Guinea (PNG). AB - Mass conflict and displacement erode the core psychosocial foundations of society, but there is a dearth of quantitative data examining the long-term mental health effects of these macrocosmic changes, particularly in relation to posttraumatic stress disorder (PTSD) symptoms. In 2013, we conducted a cross sectional community study (n = 230) of West Papuan refugees residing in Port Moresby, Papua New Guinea, testing a moderated-mediation structural equation model of PTSD symptoms in which we examined relationships involving the psychosocial effects of mass conflict and displacement based on the Adaptation and Development after Persecution and Trauma (ADAPT) model, a trauma count (TC) of traumatic events (TEs) related to mass conflict, and a count index of current adversity (AC). A direct and an indirect path via AC led to PTSD symptoms. The ADAPT index exerted two effects on PTSD symptoms, an indirect effect via AC, and a moderating effect on TC. PTSD symptoms were directly associated with functional impairment. Although based on cross-sectional data, our findings provide support for a core prediction of the ADAPT model, that is, that undermining of the core psychosocial foundations of society brought about by mass conflict and displacement exerts an indirect and moderating influence on PTSD symptoms. The path model supports the importance of repairing the psychosocial pillars of society as a foundation for addressing trauma-related symptoms and promoting the functioning of refugees. PMID- 25795991 TI - Bioidentical hormones, menopausal women, and the lure of the "natural" in U.S. anti-aging medicine. AB - In 2002, the Women's Health Initiative, a large-scale study of the safety of hormone replacement therapy (HRT) for women conducted in the United States, released results suggesting that use of postmenopausal HRT increased women's risks of stroke and breast cancer. In the years that followed, as rates of HRT prescription fell, another hormonal therapy rose in its wake: bioidentical hormone replacement therapy (BHRT). Anti-aging clinicians, the primary prescribers of BHRT, tout it as a safe and effective alternative to treat menopausal symptoms and, moreover, as a preventative therapy for age-related diseases and ailments. Through in-depth interviews with 31 U.S.-based anti-aging clinicians and 25 female anti-aging patients, we analyze attitudes towards BHRT. We illustrate how these attitudes reveal broader contemporary values, discourses, and discomforts with menopause, aging, and biomedicine. The attraction to and promise of BHRT is rooted in the idea that it is a "natural" therapy. BHRT is given both biomedical and embodied legitimacy by clinicians and patients because of its purported ability to become part of the body's "natural" processes. The normative assumption that "natural" is inherently "good" not only places BHRT beyond reproach, but transforms its use into a health benefit. The clinical approach of anti-aging providers also plays a role by validating patients' embodied experiences and offering a "holistic" solution to their symptoms, which anti-aging patients see as a striking contrast to their experiences with conventional biomedical health care. The perceived virtues of BHRT shed light on the rhetoric of anti-aging medicine and a deeply complicated relationship between conventional biomedicine, hormonal technologies, and women's bodies. PMID- 25795992 TI - Social welfare matters: a realist review of when, how, and why unemployment insurance impacts poverty and health. AB - The recent global recession and concurrent rise in job loss makes unemployment insurance (UI) increasingly important to smooth patterns of consumption and keep households from experiencing extreme material poverty. In this paper, we undertake a realist review to produce a critical understanding of how and why UI policies impact on poverty and health in different welfare state contexts between 2000 and 2013. We relied on literature and expert interviews to generate an initial theory and set of propositions about how UI might alleviate poverty and mental distress. We then systematically located and synthesized peer-review studies to glean supportive or contradictory evidence for our initial propositions. Poverty and psychological distress, among unemployed and even the employed, are impacted by generosity of UI in terms of eligibility, duration and wage replacement levels. Though unemployment benefits are not intended to compensate fully for a loss of earnings, generous UI programs can moderate harmful consequences of unemployment. PMID- 25795993 TI - Sickness and sickness absence of remaining employees in a time of economic crisis: a study among employees of municipalities in Iceland. AB - This article focuses on sickness and sickness absence among employees of 20 municipalities in Iceland who remained at work after the economic crisis in October 2008. The aim was to examine the impact of economic crisis on sickness and sickness absence of "survivors" working within the educational system (primary school teachers and kindergarten teachers) and the care services (elderly care and care of disabled people) operated by the municipalities. The study was based on mixed methods research comprising a balanced panel data set and focus groups. An online survey conducted three times among 2356 employees of 20 municipalities and seven focus group interviews in two municipalities (39 participants). The generalized estimating equations (GEE) were used to analyze the quantitative data, and focused coding was used to analyze the qualitative data. The main finding showed that the economic crisis had negative health implications for the municipal employees. The negative effects grew stronger over time. Employee sickness and sickness absence increased substantially in both downsized and non-downsized workplaces. However, employees of downsized workplaces were more likely to be sick. Sickness and sickness absence were more common among younger than older employees, but no gender differences were observed. The study demonstrates the importance of protecting the health and well being of all employees in the wake of an economic crisis, not only those who lose their jobs or work in downsized workplaces. This is important in the immediate aftermath of a crisis, but also for a significant time thereafter. This is of practical relevance for those responsible for occupational health and safety, as most Western countries periodically go through economic crises, resulting in strains on employees. PMID- 25795994 TI - Effect of hospital referral networks on patient readmissions. AB - Previous studies have shown that referral networks encompass important mechanisms of coordination and integration among hospitals, which enhance numerous organizational-level benefits, such as productivity, efficiency, and quality of care. The present study advances previous research by demonstrating how hospital referral networks influence patient readmissions. Data include 360,697 hospitalization events within a regional community of hospitals in the Italian National Health Service. Multilevel hierarchical regression analysis tests the impacts of referral networks' structural characteristics on patient hospital readmissions. The results demonstrate that organizational centrality in the overall referral network and ego-network density have opposing effects on the likelihood of readmission events within hospitals; greater centrality is negatively associated with readmissions, whereas greater ego-network density increases the likelihood of readmission events. Our findings support the (re)organization of healthcare systems and provide important indications for policymakers and practitioners. PMID- 25795995 TI - Theoretical distribution of load in the radius and ulna carpal joint. AB - PURPOSE: The purpose of this study is to validate a model for the analysis of the load distribution through the wrist joint, subjected to forces on the axes of the metacarpals from distal to proximal for two different mesh densities. METHOD: To this end, the Rigid Body Spring Model (RBSM) method was used on a three dimensional model of the wrist joint, simulating the conditions when making a grip handle. The cartilage and ligaments were simulated as springs acting under compression and tension, respectively, while the bones were considered as rigid bodies. At the proximal end of the ulna the movement was completely restricted, and the radius was allowed to move only in the lateral/medial direction. RESULTS: With these models, we found the load distributions on each carpal articular surface of radius. Additionally, the results show that the percentage of the applied load transmitted through the radius was about 86% for one mesh and 88% for the coarser one; for the ulna it was 21% for one mesh and 18% for the coarser. CONCLUSIONS: The obtained results are comparable with previous outcomes reported in prior studies. The latter allows concluding that, in theory, the methodology can be used to describe the changes in load distribution in the wrist. PMID- 25795996 TI - Efficacy of the hatching event in assessing the embryo toxicity of the nano-sized TiO2 particles in zebrafish: a comparison between two different classes of hatching-derived variables. AB - The aim of the present study was to evaluate the nano-TiO2 toxicity to zebrafish embryos through evaluating the success in hatching in relationship with hours post-exposure instead of considering just the total hatching rate. Zebrafish embryos 4h post-fertilization were exposed to nTiO2 (0, 0.01, 10, and 1000 ug mL( 1)) for 130 h. The hatching rate (HR) was calculated for each concentration (treatment). The HR magnitude was significantly (p<0.001) correlated (using simple regression) to hours post-exposure time interval (hpe; 34, 58, 82, 106, and 130), noted as HR.hpe. The HR descriptive statistics (HRds) and the parameters of the regression models (i.e., constant, x, F, and r(2)) were recruited to define 15 HRds- and 4 h.hpe-derived variables, respectively. The efficacy of the variables was evaluated. Exposure to nTiO2 led to a significant: premature hatching and general decrease in time required for normal hatching; and change in HR and hpe interrelations in a dose-dependent manner. The major change in hatchability between the treatment and control occurred at 58 hpe (62 hpf), when the treatment with nTiO2 induced significant premature hatching compared to only 6% of the hatched embryos in the control at the same time point. EC10 and EC50 values that cause premature hatching at 58 hpe for nTiO2 are 0.073 ug mL(-1) and 107.2 ug mL(-1) respectively. In general(,) this study shows multivariate differences among exposure concentrations of nTiO2 recruiting hatching-derived endpoints. PMID- 25795997 TI - Subcritical water hydrolysis of rice straw for reducing sugar production with focus on degradation by-products and kinetic analysis. AB - The competitive reactions of reducing sugar production and degradation in the subcritical water hydrolysis of rice straw were investigated to optimise reducing sugar yield. The optimised conditions (280 degrees C, 20 MPa, rice straw concentration of 5 wt.% and agitation speed of 200 rpm) resulted in a reducing sugar yield of 0.346 g/g rice straw because of the enhanced reducing sugar production and decreased sugar degradation. The sugar yield increased when the temperature increased from 250 degrees C to 280 degrees C, but it decreased when the temperature further increased to 300 degrees C because of the degradation of monosaccharides (e.g. glucose and xylose) into by-products (e.g. 2 methyltetrahydrofuran and acetic acid). A first-order reaction model was developed to elucidate the competitive reaction kinetics of sugar production and degradation at various temperatures. The highest reducing sugar yield based on the model was achieved at 280 degrees C with the highest production and lowest degradation rates. PMID- 25795998 TI - Enhanced turnover of organic matter fractions by microbial stimulation during lignocellulosic waste composting. AB - Enhanced organic matter turnover was detected in lignocellulosic composting piles inoculated with microorganisms specifically capable of decomposing polymeric compounds. In comparison to uninoculated piles, the following results were obtained in the inoculated piles: degradation of hemicellulose, cellulose and lignin were 28%, 21% and 25% respectively higher. Total organic matter, total sugars and phenolic compounds also decreased more intensely. Greater amounts of soluble organic carbon, reducing sugars and soluble proteins were available to the composting microbiota. Recycling of organic to inorganic nitrogen was improved and humification was more intense and earlier attained. Microbial community structure was also affected by inoculation. It was initially thought that these effects were due to enzymatic capabilities of inoculants, however, microbial counts, especially those corresponding to functional groups, revealed that inoculation induced a true stimulation of microbial growth and activity in the entire composting microbiota which was actually responsible for all the beneficial effects reported here. PMID- 25795999 TI - Photoprotective effect of coumarin and 3-hydroxycoumarin in sea urchin gametes and embryonic cells. AB - Ultraviolet radiation B (UVB) represents 5% of all solar UV radiation and chronic exposure can induce harmful biological responses, including skin cancer. Prospection of new drugs with photoprotective properties and less toxic effects is constant and natural products have been the main options in this field. Coumarins are a group of natural phenolic compounds that shows several pharmacological activities. The aim of present work was to investigate the effect of coumarin and six derivatives in sea urchin gametes and zygotes exposed to UVB. Embryonic development assay was used to monitor UVB embryotoxicity. Firstly, we demonstrated that coumarin inhibited first embryonic cell division from 5 MUM (EC50 = 52.9 MUM) and its derivatives showed an embryotoxic effect ten times higher. Then, gametes or zygotes were treated with coumarin compounds before or after UVB exposure (UVB doses ranged from 0.056 to 0.9 kJm(-2)). Pretreatment of gametes or zygotes with coumarin or 3-hydroxycoumarin (1 MUM, both) decreased UVB embryotoxic effect. Protective effect of the compounds was observed only when cells were treated previous to UVB exposure. Coumarin derivatives 4 hydroxycoumarin, 6-hydroxycoumarin, 7-hydroxycoumarin, 6,7-dihydroxycoumarin and 6-methoxy-7-hydroxycoumarin did not exhibit photoprotective activity. Our data provides evidences that coumarin and 3-hydroxycoumarin can be a promising class of photoprotective drugs. PMID- 25796000 TI - Improved Hilbert phase contrast for transmission electron microscopy. AB - Hilbert phase contrast has been recognized as a means of recording high resolution images with high contrast using a transmission electron microscope. This imaging mode could be used to image typical phase objects such as unstained biological molecules or cryo sections of biological tissue. According to the original proposal by (Danev et al., 2002) the Hilbert phase plate applies a phase shift of pi to approximately half the focal plane (for example the right half excluding the central beam) and an image is recorded at Gaussian focus. After correction for the inbuilt asymmetry of differential phase contrast this image will have an almost perfect contrast transfer function (close to 1) from the lowest spatial frequency up to a maximum resolution determined by the wave length and spherical aberration of the microscope. In this paper I present theory and simulations showing that this maximum spatial frequency can be increased considerably almost without loss of contrast by using a Hilbert phase plate of half the thickness, leading to a phase shift of pi/2, and recording images at Scherzer defocus. The maximum resolution can be improved even more by imaging at extended Scherzer defocus, though at the cost of contrast loss at lower spatial frequencies. PMID- 25796001 TI - Fetuin A adds prognostic value for cardiovascular outcomes among patients with coronary artery disease with moderate calcification. PMID- 25796002 TI - Prognosis of screen-detected heart failure with reduced and preserved ejection fraction in patients with type 2 diabetes. PMID- 25796003 TI - Cardiac arrest saves a patient's procedure. PMID- 25796004 TI - Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intracellular Ca2+ homeostasis. AB - BACKGROUND: We have previously shown that Elatoside C reduces cardiomyocyte apoptosis during ischaemia/reperfusion (I/R). Here, we investigated whether Elatoside C improves heart function in isolated rat hearts subjected to I/R and elucidated the potential mechanisms involved in Elatoside C-induced protection. METHODS AND RESULTS: Isolated rat hearts were subjected to global ischaemia followed by reperfusion in the absence or presence of Elatoside C. We found that Elatoside C significantly attenuated cardiac dysfunction and depressed oxidative stress induced by I/R. Consistently, Elatoside C prevented I/R-induced mitochondrial dysfunction, which was evident by the inhibition of mitochondrial ROS production, mitochondrial permeability transition pore (mPTP) opening, cytochrome c release from the mitochondria and Bax translocation. Moreover, Elatoside C improved abnormal calcium handling during I/R, including increasing sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) activity, alleviating [Ca(2+)]ER depletion, and reducing the expression levels of ER stress protein markers. All of these protective effects of Elatoside C were partially abolished by the PI3K/Akt inhibitor LY294002, ERK1/2 inhibitor PD98059, and JAK2/STAT3 inhibitor AG490. Further assessment in isolated cardiomyocytes showed that Elatoside C maintained the Ca(2+) transients and cell shortening against I/R. CONCLUSIONS: Elatoside C protects against cardiac injury during I/R by attenuating oxidative stress and [Ca(2+)]i overload through the activation of both the reperfusion injury salvage kinase (RISK) pathway (including PI3K/Akt and ERK1/2) and the survivor activating factor enhancement (SAFE) pathway (including JAK2/STAT3) and, subsequently, inhibiting the opening of mPTPs. PMID- 25796005 TI - Biomarkers of cardiomyocyte injury and stress identify left atrial and left ventricular remodelling and dysfunction: A population-based study. AB - BACKGROUND/OBJECTIVES: The validation of effective screening tools for the identification of patients with subclinical myocardial remodelling is a major clinical need. Thus, we explored the associations of circulating biomarkers of cardiomyocyte injury and stress with subclinical cardiac remodelling and dysfunction, and with biomarkers reflecting collagen turnover. METHODS: We randomly recruited 727 subjects from a general population (51.2% women; mean age 51.3 years). Measurements included echocardiographic left atrial (LA) and left ventricular (LV) structure and function, quantification of high sensitivity cardiac Troponin T (hs-cTnT), NT-proBNP, and biomarkers of collagen types I and III turnover. RESULTS: In unadjusted and adjusted analyses, the prevalence of LA enlargement (LAE), LV hypertrophy (LVH) and LV diastolic dysfunction (LVDD) increased with higher hs-cTnT (P <= 0.031). NT-proBNP was independently associated with LVDD (P=0.009). Both biomarkers combined yielded significant integrated discrimination and net reclassification improvements (P <= 0.014 and P <= 0.009, respectively) for LAE, LVH and LVDD, over the conventional risk factors, and were independently and positively associated with biomarkers of collagen type I turnover. In a sensitivity analysis, after excluding participants with previous cardiac diseases, our findings remained consistent. CONCLUSIONS: Our population-based study suggested that subclinical LV and LA remodelling were associated with hs-cTnT, and that, in combination with NT-proBNP, hs-cTnT showed incremental diagnostic utility over the conventional risk factors. Both biomarkers were associated with biomarkers of collagen type I turnover. Thus, biomarkers of cardiomyocyte microinjury and hemodynamic stress may stimulate fibrosis-related mechanisms and facilitate the diagnosis of subclinical LA and LV remodelling and dysfunction in the general population. PMID- 25796006 TI - Trait urgency and gambling problems in young people by age: the mediating role of decision-making processes. AB - Although the personality trait of urgency has been linked to problem gambling, less is known about psychological mechanisms that mediate the relationship between urgency and problem gambling. One individual variable of potential relevance to impulsivity and addictive disorders is age. The aims of this study were to examine: (i) a theoretical model associating urgency and gambling problems, (ii) the mediating effects of decision-making processes (operationalized as preference for small/immediate rewards and lower levels of deliberative decision-making); and (iii) age differences in these relationships. Participants comprised 986 students (64% male; mean age=19.51 years; SD=2.30) divided into three groups: 16-17 years, 18-21 years, and 22-25 years. All participants completed measures of urgency, problem gambling, and a delay discounting questionnaire involving choices between a smaller amount of money received immediately and a larger amount of money received later. Participants were also asked to reflect on their decision-making process. Compared to those aged 16-17 years and 22-25 years, participants aged 18-21 years had a higher level of gambling problems and decreased scores on lower levels of deliberative decision-making. Higher levels of urgency were associated with higher levels of gambling problems. The association was mediated by a lower level of deliberative decision-making and preference for an immediate/small reward. A distinct pathway was observed for lower levels of deliberative decision-making. Young people who tend to act rashly in response to extreme moods, had lower levels of deliberative decision-making, that in turn were positively related to gambling problems. This study highlights unique decision-making pathways through which urgency trait may operate, suggesting that those developing prevention and/or treatment strategies may want to consider the model's variables, including urgency, delay discounting, and deliberative decision-making. PMID- 25796008 TI - Proprioceptive impairments associated with knee osteoarthritis are not generalized to the ankle and elbow joints. AB - The mechanisms for proprioceptive changes associated with knee osteoarthritis (OA) remain elusive. Observations of proprioceptive changes in both affected knees and other joints imply more generalized mechanisms for proprioceptive impairment. However, evidence for a generalized effect remains controversial. This study examined whether joint repositioning proprioceptive deficits are localized to the diseased joint (knee) or generalized across other joints (elbow and ankle) in people with knee OA. Thirty individuals with right knee OA (17 female, 66+/-7 [mean+/-SD] years) of moderate/severe radiographic disease severity and 30 healthy asymptomatic controls of comparable age (17 female, 65+/ 8years) performed active joint repositioning tests of the knee, ankle and elbow in randomised order in supine. Participants with knee OA had a larger relative error for joint repositioning of the knee than the controls (OA: 2.7+/-2.1 degrees , control: 1.6+/-1.7 degrees , p=.03). Relative error did not differ between groups for the ankle (OA: 2.2+/-2.5 degrees , control: 1.9+/-1.3 degrees , p=.50) or elbow (OA: 2.5+/-3.3 degrees , control: 2.9+/-2.8 degrees , p=.58). These results are consistent with a mechanism for proprioceptive change that is localized to the knee joint. This could be mediated by problems with mechanoreceptors, processing/relay of somatosensory input to higher centers, or joint-specific interference with cognitive processes by pain. PMID- 25796007 TI - Adolescent heavy drinkers' amplified brain responses to alcohol cues decrease over one month of abstinence. AB - INTRODUCTION: Heavy drinking during adolescence is associated with increased reactivity to alcohol related stimuli and to differential neural development. Alcohol cue reactivity has been widely studied among adults with alcohol use disorders, but little is known about the neural substrates of cue reactivity in adolescent drinkers. The current study aimed to identify changes in blood-oxygen level dependent (BOLD) signal during a cue reactivity task pre- and post monitored abstinence from alcohol. METHOD: Demographically matched adolescents (16.0-18.9 years, 54% female) with histories of heavy episodic drinking (HD; n=22) and light or non-drinking control teens (CON; n=16) were recruited to participate in a month-long study. All participants completed a functional Magnetic Resonance Imaging (fMRI) scan with an alcohol cue reactivity task and substance use assessments at baseline and after 28 days of monitored abstinence from alcohol and drugs (i.e., urine toxicology testing every 48-72 h). Repeated measure analysis of variance (ANOVA) examined main effects of group, time, and group*time interactions on BOLD signal response in regions of interest defined by functional differences at baseline. RESULTS: The HD group exhibited greater (p<.01) BOLD activation than CON to alcohol cues relative to neutral cues in all regions of interest (ROIs; bilateral striatum/globus pallidus, left anterior cingulate, bilateral cerebellum, and parahippocampal gyrus extending to the thalamus/substantia nigra) across time points. Group*time effects showed that HD exhibited greater BOLD activation to alcohol cues than CON at baseline in left anterior cingulate cortex and in the right cerebellar region, but these decreased to non-significance after one month of monitored abstinence. CONCLUSIONS: In all ROIs examined, HD exhibited greater BOLD response than CON to alcohol relative to neutral beverage picture cues at baseline, indicating heightened cue reactivity to alcohol cues in heavy drinking adolescents prior to the onset of any alcohol use diagnosis. Across the majority of these brain regions, differences in BOLD response were no longer apparent following a month of abstinence, suggesting a decrease in alcohol cue reactivity among adolescent non-dependent heavy drinkers as a consequence of abstaining from alcohol. These results highlight the malleability of adolescent brain function despite no formal intervention targeting cue reactivity. Increased understanding of the neural underpinnings of cue reactivity could have implications for prevention and intervention strategies in adolescent heavy alcohol users. PMID- 25796009 TI - 'Therapeutic landscapes' and the importance of nostalgia, solastalgia, salvage and abandonment for psychiatric hospital design. AB - We examine emotional reactions to changes to medical spaces of care, linked with past experiences. In this paper we draw on findings from a qualitative study of the transfer of psychiatric inpatient care from an old to a newly built facility. We show how the meanings attributed to 'therapeutic landscapes' from one's past can evoke emotions and memories, manifesting in ideas about nostalgia, solastalgia, salvage and abandonment, which can impinge on one's present therapeutic experience. We reflect on how consideration of these ideas might contribute to better future design of psychiatric inpatient facilities and the wellbeing of those using them. PMID- 25796010 TI - Structural and vibrational spectroscopic studies on charge transfer and ionic hydrogen bonding interactions of melaminium benzoate dihydrate. AB - Single crystals of melaminium benzoate dihydrate (MBDH) have been grown from aqueous solution by the slow solvent evaporation method at room temperature. Crystalline nature of the grown crystal has been confirmed by X-ray powder diffraction studies. The optimized geometry, frequency and intensity of the vibrational bands of MBDH were obtained by the Hartree-Fock and density functional theory using B3LYP/cam-B3LYP with 6-311++G(d,p) basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with the experimental FT-IR and FT-Raman spectral values. The obtained vibrational wavenumbers and optimized geometric parameters are found to be in good agreement with the experimental data. UV-Visible spectrum was recorded in the region 200-400 nm and the electronic properties, HOMO-LUMO energies and other related electronic parameters are calculated. The isotropic chemical shifts computed by (1)H and (13)C NMR analysis also show good agreement with experimental observation. Natural bond orbital (NBO) analysis has been performed on MBDH compound to analyze the stability of the molecule arising from hyperconjugative interactions and charge delocalization. Molecular electrostatic potential surface (MEP) has also been performed by DFT/cam-B3LYP method with 6 311++G(d,p) basis set. Differential scanning calorimetric measurements performed on the powder sample indicate the phase transition point approximately at 368 and 358K for heating and cooling, respectively. PMID- 25796011 TI - Dynamic 1H NMR studies of hindered internal rotations in the synthesized particular phosphorus ylide: experimental and theoretical approaches. AB - Dynamic (1)H NMR measurements were performed within the synthesized particular phosphorus ylide involving 4-formylphenyl phenylcarbamate. Four rotational process and thereby parameters were targeted for rotation around the CC, C-C, HCNC and OCNC bonds. The Gibbs free activation energy in CDCl3, DeltaG(?)exp, was found to be 64 +/- 2, 50 +/- 2, 41 +/- 2 and 63 +/- 2, respectively. These findings were compared with related ab initio and DFT results on simulated situation. Theoretical methods tested, were comparable to the present D (1)H NMR data. PMID- 25796012 TI - A combined experimental and quantum chemical analysis to explore the nonlinear optical activity of guanidinium L-monohydrogen tartrate. AB - Single crystal of guanidinium l-monohydrogen tartrate (GuHT) was grown by slow evaporation technique and was characterized by single crystal X-ray diffraction to confirm its crystal structure. UV-vis spectral study reveal that the GuHT crystal is optically transparent and its band gap was estimated from the transmittance data. The laser induced surface damage threshold study was carried out for the grown crystal using Nd:YAG laser. The second harmonic generation (SHG) nonlinearity of the grown crystalline sample was measured by Kurtz and Perry powder technique. The optimized molecular geometry, first order hyperpolarizability, dipole moment and polarizability of GuHT were obtained by density functional theory (DFT) using B3LYP/6-31G (d,p) level of basis set. The thermodynamic functions of the title compound was computed. The HOMO-LUMO energy gap explains the charge transfer interactions that take place within the molecule. PMID- 25796013 TI - Synthesis, spectroscopic properties, molecular docking, anti-colon cancer and anti-microbial studies of some novel metal complexes for 2-amino-4-phenylthiazole derivative. AB - This article describes the synthesis of novel bidentate Schiff base (H2L) from condensation of 2-amino-4-phenylthiazole (APT) with 4,6-diacetylresorcinol (DAR) in the molar ratio 2:1. We studied interaction of ligand (H2L) with transition metal ions such as Cr(III), Fe(III), Cu(II), Zn(II) and Cd(II). The ligand (H2L) has two bidentate sets of (N-O) units which can coordinate with two metal ions to afford novel binuclear metal complexes. The directions of coordinate bonds are from nitrogen atoms of azomethine groups and oxygen atoms of the phenolic groups. Structures of the newly synthesized complexes were confirmed by elemental analysis, IR, UV, (1)H NMR, ESR, TGA and mass spectral data. All of the newly synthesized complexes were evaluated for their antibacterial and anti-fungal activities. They were also evaluated for their in vitro anticancer activity against human colon carcinoma cells (HCT-116) and mammalian cells of African green monkey kidney (VERO). The Cu(II) complex with selectivity index (S.I.)=21.26 exhibited better activity than methotrexate (MTX) as a reference drug with S.I. value=13.30, while Zn(II) complex with S.I. value=10.24 was found to be nearly as active as MTX. Molecular docking studies further helped in understanding the mode of action of the compounds through their various interactions with active sites of dihydrofolate reductase (DHFR) enzyme. The observed activity of Fe(III) and Cu(II) complexes gave rise to the conclusion that they might exert their action through inhibition of the DHFR enzyme. PMID- 25796014 TI - Solid state 13C-NMR, infrared, X-ray powder diffraction and differential thermal studies of the homologous series of some mono-valent metal (Li, Na, K, Ag) n alkanoates: a comparative study. AB - A comparative study of the molecular packing, lattice structures and phase behaviors of the homologous series of some mono-valent metal carboxylates (Li, Na, K and Ag) is carried out via solid state FT-infrared and (13)C-NMR spectroscopes, X-rays powder diffraction, density measurements, differential scanning calorimetry, polarizing light microscopy and variable temperature infrared spectroscopy. It is proposed that, for lithium, sodium and potassium carboxylates, metal-carboxyl coordination is via asymmetric chelating bidentate bonding with extensive intermolecular interactions to form tetrahedral metal centers, irrespective of chain length. However, for silver n-alkanoates, carboxyl moieties are bound to silver ions via syn-syn type bridging bidentate coordination to form dimeric units held together by extensive head group inter molecular interactions. Furthermore, the fully extended hydrocarbon chains which are crystallized in the all-trans conformation are tilted at ca. 30 degrees , 27 degrees , 15 degrees and 31 degrees with respect to a normal to the metal plane, for lithium, sodium, silver and potassium carboxylates, respectively. All compounds are packed as lamellar bilayer structures, however, lithium compounds are crystallized in a triclinic crystal system whilst silver, sodium and potassium n-alkanoates are all monoclinic with possible P1 bravais lattice. Odd even alternation observed in various physical features is associated with different inter-planar spacing between closely packed layers in the bilayer which are not in the same plane; a phenomenon controlled by lattice packing symmetry requirements. All compounds, except silver carboxylates, show partially reversibly first order pre-melting transitions; the number of which increases with increasing chain length. These transitions are associated, for the most part, with lamellar collapse followed by increased gauche-trans isomerism in the methylene group assembly, irrespective of chain length. It is proposed that the absence of mesomorphic transitions in their phase sequences is due to a lack of sufficient balance between attractive and repulsive electrostatic and van der Waals forces during phase change. The evidence presented in this study shows that phase behaviors of mono-valent metal carboxylates are controlled, mainly, by head group bonding. PMID- 25796015 TI - Silver nanoparticles enhanced a novel TCPO-H2O2-safranin O chemiluminescence system for determination of 6-mercaptopurine. AB - The present study deals with first attempt to introduce safranin O as the fluorophore for peroxyoxalate chemiluminescence system. The reaction of bis (2,4,6-trichlorophenyl) oxalate (TCPO) with H2O2 catalyzed by silver nanoparticles can transfer energy to safranin O via the formation of dioxetanedione intermediate and emits orange-red light. The relationship between CL intensity and the concentration of TCPO, fluorophore, hydrogen peroxide and nanocatalyst was investigated. The Ag nanoparticles were synthesized by chemical reduction method and characterized using scanning electron microscopy, particle size analyzer and UV-spectroscopy. Moreover, the system was applied successfully to detect a drug, 6-mercaptopurine (6-MP) in pharmaceuticals. Under optimum conditions, a linear working range for 6-MP concentrations from 5.5 * 10(-7) to 5.5 * 10(-5)mol L(-1) (r>0.9831, n=6) was obtained with a detection limit of 1.6 * 10(-7)mol L(-1). The relative standard deviation for 6 repetitive determinations was less than 3.8% and recoveries of 98% and 103% were obtained. PMID- 25796016 TI - Synthesis, characterization and biological studies of a charge transfer complex: 2-aminopyridinium-4-methylbenzenesulfonate. AB - A single crystal charge transfer (CT) complex, 2-aminopyridinium-4 methylbenzenesulfonate (APTS) was synthesized and recrystallized by slow solvent evaporation solution growth method at room temperature. The complex has been characterized with the elemental analysis, UV-visible, infrared (IR), (1)H and (13)C nuclear magnetic resonance (NMR) spectra. Thermogravimetric (TG) and differential thermal analysis (DTA) were reported the thermal behaviour of the complex. Single crystal XRD studies showed that the orthorhombic nature of the crystal with space group Pbca. The biological activities of CT complex, such as DNA binding and antioxidant activity has been carried out. The results indicated that the compound could interact with DNA through intercalation and show significant capacity of scavenging with 2,2-diphenyl-2-picryl-hydrazyl (DPPH). PMID- 25796017 TI - Time resolved FRET measurement in various heterogeneous media using merocyanine dye as a donor. AB - Ultrafast fluorescence resonance energy transfer (FRET) from a merocyanine dye to a Rhodamine 6G (R6G) molecule in micelles formed by the surfactants SDS and DTAB and also in a catanionic vesicle formed by SDS and DTAB has been studied by picosecond time resolved emission spectroscopy. Here the dye acts as a donor molecule and R6G acts as the acceptor molecule. Multiple timescales of FRET have been detected, namely, an ultrafast component of 100-500 ps and relatively long component (1800-3300 ps). The different time scales are attributed to different donor-acceptor distances. PMID- 25796018 TI - Study of interaction between human serum albumin and three phenanthridine derivatives: fluorescence spectroscopy and computational approach. AB - Over the past decades, phenanthridine derivatives have captured the imagination of many chemists due to their wide applications. In the present work, the interaction between phenanthridine derivatives benzo [4,5]imidazo[1,2 a]thieno[2,3-c]quinoline (BTQ), benzo[4,5]imidazo[1,2-a]furo[2,3-c]quinoline (BFQ), 5,6-dimethylbenzo[4,5]imidazo[1,2-a]furo[2,3-c]quinoline (DFQ) and human serum albumin (HSA) were investigated by molecular modeling techniques and spectroscopic methods. The results of molecular modeling simulations revealed that the phenanthridine derivatives could bind on both site I in HSA. Fluorescence data revealed that the fluorescence quenching of HSA by phenanthridine derivatives were the result of the formation of phenanthridine derivatives-HSA complex, and the binding intensity between three phenanthridine derivatives and HSA was BTQ>BFQ>DFQ. Thermodynamics confirmed that the interaction were entropy driven with predominantly hydrophobic forces. The effects of some biological metal ions and toxic ions on the binding affinity between phenanthridine derivatives and HSA were further examined. PMID- 25796019 TI - Association of chronic thromboembolic pulmonary hypertension with hereditary and acquired risk factors for thromboembolism. AB - Thrombophilia increases the incidence of pulmonary thrombosis significantly. Various hereditary and acquired factors are known for thromboembolism. The hereditary factors are two common genetic autosomal mutations including factor V leidan mutation and prothrombin gene mutation. A descriptive- analytical design was conducted on 60 patients with thromboembolism who met the inclusion criteria. Two groups with hereditary and acquired risk factors for thromboembolism (group A, B, each 30 people) were evaluated. All the patients of two groups were evaluated in terms of emboli associated with hereditary and acquired risk factors. Association of thromboembolism risk factors' with pulmonary hypertension were studied at the beginning of the study and six months after the treatment then the results of two groups were compared. Among participants, 31 (56.4%) were men. The mean age of the patients was 44.4+/-14 years, ranging between 23-75 years. Significant association was observed between the stability of the blood clot in pulmonary vessel, six months after the treatment with genetic risk factors (P=0.03). However, no significant association was between pulmonary hypertension and hereditary and acquired risk factors (P=0.24). Based on the significant association between the hereditary risk factors and pulmonary emboli, by taking special prevention and therapy measurements (e.g. genetic engineering), some pulmonary and mortality complications can be prevented and the patient himself and health care system would benefit from this issue. PMID- 25796020 TI - Effects of combining methylprednisolone with magnesium sulfate on neuropathic pain and functional recovery following spinal cord injury in male rats. AB - Methylprednisolone (MP) has been widely used as a standard therapeutic agent for the treatment of spinal cord injury (SCI). Because of its controversial useful effects, the combination of MP and other pharmacological agents to enhance neuroprotective effects is desirable. Magnesium sulfate (MgSO4) has been shown to have neuroprotective and antihyperalgesic effects. In the present study, we sought to determine the effect of combining MP and MgSO4, on neuropathic pain and functional recovery following spinal cord injury (SCI) in male rats. A total of 48 adult male rats (weight 300-350 g) were used. After laminectomy, complete SCI was achieved by compression of the spinal cord for one minute with aneurysm clips. Single doses of Magnesium sulfate (MgSO4), (600 mg/kg), Methylprednisolone (MP), (30 mg/kg) or combining MgSO4 and MP were injected intraperitoneally. Prior to surgery and during four weeks of study Tail flick latency (TFL) and BBB (Basso Beattie-Bresnahan) score and the acetone drop test were evaluated. In mean values of BBB score, a significant difference was observed in SCI+veh compared with other groups (P<0.05). Mean TFL also was significantly higher in SCI+veh compared with other groups (P<0.05). Mean acetone drop test score and weight were significantly different in MgSO4, MP and combining MgSO4 and MP treated groups compared with SCI+veh group (P<0.05). These findings revealed that MP, MgSO4 and combining MgSO4 and MP treatment can attenuate neuropathic pains following SCI in rats include: thermal hyperalgesia and cold allodynia. They also can yield better improvement in motor function and decrease weight loss after SCI in rats compared with the control group. PMID- 25796021 TI - Ketamine or atropine: which one better prevents oculocardiac reflex during eye surgery? A prospective randomized clinical trial. AB - Profound bradycardia during eye surgery is a potentially serious event. In clinical practice oculo-cardiac reflex (OCR) is most often encountered during squint surgery. The objective of this study was to assess the occurrence of OCR and prove the effect of ketamine as an induction drug and anticholinergic premedication (atropine) to prevent OCR. This study comprised 90 patients (aged 4 10 years) operated for squint surgery under general anesthesia. Patients were divided into three groups. Using block randomization, each patient enrolled in one of the three groups based on organized random table prepared by statistician. Group K received ketamine as an induction drug, Group A was premedicated with intravenous injection of atropine and Group C did not receive any premedication. Patients were monitored during operation for any bradycardia or dysrhythmias. The observed data showed occurrence of 63% OCR in Group C as compared to 43% in group A and only 20% in Group K. Current study showed that induction with ketamine in the patients of squint surgery under general anesthesia definitely obtunds OCR and prevents any untoward effects of dysrhythmias during eye surgery. PMID- 25796022 TI - Folate and homocysteine levels and their association with dietary intakes in Iranian patients infected with Helicobacter pylori: a case-control study. AB - The association between Helicobacter pylori (HP) infection and concentration of folate or homocysteine are still unclear. The aim of the present study was to assess the effect of HP infection on folate and homocysteine concentrations in patients infected with HP and healthy participants. We also assessed dietary intakes of folate, vitamins B6 and B12 in two groups. In this case-control study, 44 participants with HP-infection and 46 healthy controls were studied. Participants were recruited from those referred to the central laboratory of Tabriz University of Medical Sciences. Blood samples were collected to determine serum folate and homocysteine levels. The presence of both IgG and IgA in serum was considered as HP positive. Dietary intakes were assessed in all participants by 24-hour dietary recalls by trained interviewers for three days. The mean concentration of serum folate was significantly lower in HP-positive patients than in controls (8.49 nmol/L vs. 10.95 nmol/L, respectively; P=0.01). Although the mean concentration of serum homocysteine differed between groups, statistical significance was missed (HP infected patients: 9.35 umol/L; healthy participants: 8.96 umol/L; P=0.064). Macro- and micronutrient intakes showed no significant difference between participants with and without HP infection. In logistic regression models, there was a negative correlation between folate concentration and HP infection even after controlling for confounding factors (OR=0.82; CI95%=0.79-0.97). In this study, authors showed that a negative association presents between HP infection and serum folate concentrations, but the homocysteine status was not differed significantly between HP-positive and HP negative participants. PMID- 25796023 TI - Prevalence of parvovirus B19 specific antibody in pregnant women with spontaneous abortion. AB - Human parvovirus B19 is a very common viral infection especially in school-aged children. The infection during pregnancy can affect the fetus due to lack of mother's immunity. Although, there is still no evidence of fetal teratogenic effects with parvovirus B19, but non-immune fetal hydrops and abortion may be caused by vertical transmission of the virus during pregnancy. This study was aimed to assess the prevalence of parvovirus B19-specific antibody (IgM) in pregnant women who had a spontaneous abortion. This cross-sectional study was carried out in all pregnant women who referred due to a spontaneous abortion. All demographic information such as age, occupation, and gestational age, last history of abortion, gravity, and presence of children below the age of six was recorded and a blood sample was provided for all the women. Then, the blood samples were tested to assay parvovirus B19-specific antibody (IgM) by EuroImmune ELISA kit. Among 94 pregnant women with the mean age of 28.4 years who had a spontaneous abortion, parvovirus B19 specific antibody (IgM) was detected in 17 participants (18.1%). Meanwhile, 14 women (14.9%) were suspected for presence of the antibody in their blood sample. There was no significant difference between the presence of antibody and age of pregnant women, occupation, gestational age, number of previous abortion, presence of children below the age of six and number of pregnancy. These findings revealed that a high percentage of pregnant women are probably non-immune against parvovirus B19, and also there might be a number of spontaneous abortions in which parvovirus infection caused fetal death. However, more studies are needed to prove the absolute role of parvovirus B19 in these abortions. PMID- 25796024 TI - Evaluation of effective factors in success rate of intervention on CTO. AB - Chronic total occlusion (CTO) intervention is still a challenging problem. The aim of this study is to determine factors that affect PCI results. METHOD AND RESULTS: The study was conducted on 72 patients in two centers. CTO angioplasty was done by the antegrade approach from the femoral and/or radial approach. The role of age, gender, anatomical variations such as calcification, length of the lesion, proximal bending, retrograde filling and occluded coronary artery (LAD, CCK or RCA), and wires were assessed. The success rate was 79.6%, and presence of calcification was an important factor in CTO PCI. Operator's experience, use of appropriate equipment and calcification are important factors in predicting a successful PCI. PMID- 25796025 TI - Hard ticks (Ixodidae) and Crimean-Congo hemorrhagic fever virus in south west of Iran. AB - Ticks are vectors of some important arthropod-borne diseases in both fields of veterinary and medicine, such as Lyme, tularemia, Rocky Mountain spotted fever, and some types of encephalitis as well as Crimean Congo hemorrhagic fever (CCHF). Iran is known as one of the main foci of CCHF in west of Asia. This study was conducted in DarrehShahr County because of the development of animal husbandry in this area to detect the fauna and viral infection of the hard ticks of livestock. A cross-sectional survey was conducted during 2011-2012 with random sampling in four villages. A sample of ticks was subjected to RT-PCR method for detection of viral infection. During the study period, 592 Ixodidae ticks were collected and identified as seven species of Hyalomma asiaticum, Hy. marginatum, Hy. anatolicum, Hy. dromedarii, Hy. detritum, Rhipicephalus bursa and Rh. sanguineus. More than 20% of these ticks were examined to detect the genome of CCHF virus while 6.6% were positive. All species of Hyalomma were found to be positive. A high rate of livestock was found to be infected with hard ticks, which can act as the vectors of the CCHF disease. Regarding infection of all five Hyalomma species captured in this area, this genus should be considered as the main vector of CCHF. Planning control program can be performed based on the obtained data on seasonal activity of Ixodidae to prevent animal infestation as well as to reduce the risk of CCHF transmission. PMID- 25796026 TI - Predictors of curve flexibility in adolescent idiopathic scoliosis: a retrospective study of 100 patients. AB - Curve flexibility in adolescent idiopathic scoliosis (AIS) was one of the major concerns of spinal surgeons since the evolution of surgical correction techniques. In this respect, many tried to identify which criteria denote more rigid curve. In the present study, we aimed toward determining important factors influencing AIS curve flexibility on supine bending films. We assessed radiographs of 100 patients with AIS for direction of curves, number of involved vertebrae, apical vertebral translation and rotation, magnitude of main thoracic curve and T5-T12 kyphosis. Statistical analysis performed via stepwise linear regression model with these variables plus age and sex against flexibility index. According to regression analysis, there was a clear relationship between flexibility indexes (FI) and magnitude of main thoracic curve at all (P<0.001). When we consider flexible curves (FI>50%) against rigid curves, apical vertebral rotation was a major determinant of curve flexibility also (P<0.001). Adolescent idiopathic scoliosis curves with larger Cobb's angle and apical vertebral rotation show less flexibility on supine bending films. PMID- 25796027 TI - Anemia as a public health issue in Mashhad, Iran: evidence from the first population-based study. AB - Anemia is one of the main conditions that impose an adverse impact on the socioeconomic state of any country; however, evidence on the prevalence of anemia is scant in Northeastern Iran. This study was conducted to determine the overall and age- and sex-specific prevalence of anemia in the city of Mashhad, Iran. In a cross-sectional, population-based survey, 1675 individuals aged 1-90 years (29.1+/-18.5 years) were selected from approximately 2.4 million residents by a multistage cluster sampling method during May to September 2009. Blood samples were evaluated to determine erythrocyte indices and anemia was defined according to hemoglobin (Hb) levels based on World Health Organization (WHO) guidelines. The prevalence of anemia was 9.7% with considerable difference between both sexes; 6.2% and 12.7% in males and females, respectively (P<0.001). The higher prevalence of anemia was detected in females of 15-54 and >= 65 years old (16% and 12.5%, respectively). However, the higher rates were observed in males 65 years and older as well as boys below 5 years old (16.3% and 14.6%, respectively). Current findings show that anemia is a considerable public health problem in the population of Mashhad, Iran, especially among the pre-school children, adult women and the elderly. Great attention should be paid to the pre school boys who are more affected by anemia than what was previously assumed. PMID- 25796028 TI - Sagittal vein thrombosis caused by central vein catheter. AB - Cerebral venous thrombosis, including thrombosis of cerebral veins and major dural sinuses, is an uncommon disorder in the general population. However, it has a higher frequency among patients younger than 40 years of age, patients with thrombophilia, pregnant patients or those receiving hormonal contraceptive therapy or has foreign body such as catheter in their veins or arterial system. In this case report, we described clinical and radiological findings in a patient with protein C-S deficiency and malposition of central vein catheter. PMID- 25796029 TI - Orbital tumor revealing a systemic sarcoidosis. AB - Ocular involvement is seen in approximately 25% of patients with sarcoidosis. Uveitis is the most common ocular manifestation, but sarcoidosis may involve any part of the eye. Orbital manifestations of sarcoidosis are uncommon with few series in the literature. A 65-year-old woman presented with redness of the right eye and painless, unilateral eyelid swelling. Orbital scanning revealed mass infiltrating the soft tissue of the inferior right orbital quadrant. Biopsy results showed nodular, noncaseating granulomas consistent with sarcoidosis. The complete systemic workup revealed systemic manifestations of sarcoidosis at the time of examination with hilar and mediastinal lymphadenopathies noted on CT scan. The orbital surgical treatment was followed by systemic prednisone therapy with good response. Although rare, orbital sarcoidosis must be considered in the evaluation of orbital tumors in elderly patients. A search for systemic findings should be undertaken and appropriate therapy should be instituted. PMID- 25796030 TI - Emotional intelligence of medical residents: further work is required. PMID- 25796031 TI - The beta-barrel membrane protein insertase machinery from Gram-negative bacteria. AB - The outer membranes (OM) of Gram-negative bacteria contain a host of beta-barrel outer membrane proteins (OMPs) which serve many functions for cell survival and virulence. The biogenesis of these OMPs is mediated by the beta-barrel assembly machinery (BAM) complex which is composed of five components including the essential core component called BamA that mediates the insertase function within the OM. The crystal structure of BamA has recently been reported from three different species, including a full-length structure from Neisseria gonorrhoeae. Mutagenesis and functional studies identified several conformational changes within BamA that are required for function, providing a significant advancement towards unraveling exactly how BamA and the BAM complex are able to fold and insert new OMPs in the OM. PMID- 25796032 TI - Protein contact network topology: a natural language for allostery. AB - Protein molecules work as a whole, so that any local perturbation may resonate on the entire structure: allostery deals with this general property of protein molecules. It is worth noting a perturbation does not necessarily involve a conformational change but, more generally, it travels across the structure as an 'energy signal'. The atomic interactions within the network provide the structural support for this 'signaling highway'. Network descriptors, capturing network signaling efficiency, explain allostery in terms of signal transmission. In this review we will survey the key applications of graph theory to protein allostery. The complex network approach introduces a new perspective in biochemistry; as for applications, the development of new drugs relying on allosteric effects (allo-network drugs) represents a promising avenue of contact network formalism. PMID- 25796033 TI - Rotational mechanism of Enterococcus hirae V1-ATPase by crystal-structure and single-molecule analyses. AB - In ion-transporting rotary ATPases, the mechanical rotation of inner rotor subunits against other stator subunits in the complex mediates conversion of chemical free energy from ATP hydrolysis into electrochemical potential by pumping ions across the cell membrane. To fully understand the rotational mechanism of energy conversion, it is essential to analyze a target sample by multiple advanced methods that differ in spatiotemporal resolutions and sample environments. Here, we describe such a strategy applied to the water-soluble V1 moiety of Enterococcus hirae V-ATPase; this strategy involves integration of crystal structure studies and single-molecule analysis of rotary dynamics and torque generation. In addition, we describe our current model of the chemo mechanical coupling scheme obtained by this approach, as well as future prospects. PMID- 25796034 TI - Advancing age increases sperm chromatin damage and impairs fertility in peroxiredoxin 6 null mice. AB - Due to socioeconomic factors, more couples are choosing to delay conception than ever. Increasing average maternal and paternal age in developed countries over the past 40 years has raised the question of how aging affects reproductive success of males and females. Since oxidative stress in the male reproductive tract increases with age, we investigated the impact of advanced paternal age on the integrity of sperm nucleus and reproductive success of males by using a Prdx6(-/-) mouse model. We compared sperm motility, cytoplasmic droplet retention sperm chromatin quality and reproductive outcomes of young (2-month-old), adult (8-month-old), and old (20-month-old) Prdx6(-/-) males with their age-matched wild type (WT) controls. Absence of PRDX6 caused age-dependent impairment of sperm motility and sperm maturation and increased sperm DNA fragmentation and oxidation as well as decreased sperm DNA compaction and protamination. Litter size, total number of litters and total number of pups per male were significantly lower in Prdx6(-/-) males compared to WT controls. These abnormal reproductive outcomes were severely affected by age in Prdx6(-/-) males. In conclusion, the advanced paternal age affects sperm chromatin integrity and fertility more severely in the absence of PRDX6, suggesting a protective role of PRDX6 in age-associated decline in the sperm quality and fertility in mice. PMID- 25796035 TI - Intrafamilial associations of cardiometabolic risk factors--results of the Ulm Birth Cohort Study. AB - BACKGROUND: The identification of genetic, early childhood and lifestyle factors related to cardiometabolic risk factors in childhood is important for the development of preventive strategies against cardiovascular diseases. Intrafamilial associations of cardiometabolic risk factors are rarely studied and the few existing results are inconsistent. AIMS: To study the relationship of cardiometabolic risk factors in parent-offspring pairs (trios) of the prospective Ulm Birth Cohort Study (UBCS). METHODS: At the 8-yr follow-up examination of the UBCS weights, heights, waist circumferences (WC), systolic (sysBP) and diastolic blood pressure (diasBP) of n=304 8 yrs old children and their parents were measured. Fasting plasma samples were collected and concentrations of insulin, glucose, retinol-binding-protein 4 (RBP4), adiponectin, leptin, apolipoprotein A and B (ApoA, ApoB) were analyzed. RESULTS: BMI values and WC were stronger related in father-offspring than in mother-offspring pairs. Adjustment for potential confounders did not change these results. Fasting plasma concentrations of insulin, glucose, RBP4, ApoB, sysBP and diastBP were stronger correlated in mother-offspring than in father-offspring pairs also after adjusting for potential confounders. Offsprings of fathers that have >=3 cardiometabolic risk factors had 0.74 kg/m2 higher BMI values and 2.34 cm higher WC compared to offsprings of the reference group (both parents having <3 cardiometabolic risk factors). There was a trend for higher fasting plasma insulin concentrations in offsprings where the mother had >=3 cardiometabolic risk factors compared to offsprings of the reference group. CONCLUSION: These results might be explained by gender-specific genetic factors as well as by early life programming. PMID- 25796036 TI - Music decreases aortic stiffness and wave reflections. AB - OBJECTIVE: Music has been related to cardiovascular health and used as adjunct therapy in patients with cardiovascular disease. Aortic stiffness and wave reflections are predictors of cardiovascular risk. We investigated the short-term effect of classical and rock music on arterial stiffness and wave reflections. METHODS: Twenty healthy individuals (22.5+/-2.5 years) were studied on three different occasions and listened to a 30-min music track compilation (classical, rock, or no music for the sham procedure). RESULTS: Both classical and rock music resulted in a decrease of carotid-femoral pulse wave velocity (PWV) immediately after the end of music listening (all p<0.01). Augmentation index (AIx) decreased with either classical or rock music in a more sustained way (nadir by 6.0% and 5.8%, respectively, at time zero post-music listening, all p<0.01). When music preference was taken into consideration, both classical and rock music had a more potent effect on PWV in classical aficionados (by 0.20 m/s, p=0.003 and 0.13 m/s, p=0.015, respectively), whereas there was no effect in rock aficionados (all p=NS). Regarding wave reflections, classical music led to a more potent response in classical aficionados (AIx decrease by 9.45%), whereas rock led to a more potent response to rock aficionados (by 10.7%, all p<0.01). CONCLUSIONS: Music, both classical and rock, decreases aortic stiffness and wave reflections. Effect on aortic stiffness lasts for as long as music is listened to, while classical music has a sustained effect on wave reflections. These findings may have important implications, extending the spectrum of lifestyle modifications that can ameliorate arterial function. PMID- 25796037 TI - Increased testosterone levels and cortisol awakening responses in patients with borderline personality disorder: gender and trait aggressiveness matter. AB - BACKGROUND: Borderline personality disorder (BPD) is characterized by antagonism, negative affectivity, disinhibition, and impairments in interpersonal functioning, including enhanced impulsive aggression. Interpersonal dysfunctions may be related to alterations in endocrine systems. The current study investigated alterations in basal activity of the hypothalamus-pituitary-gonadal (HPG) reproductive and the hypothalamus-pituitary-adrenal (HPA) stress system in BPD patients and their association to anger-related aggression with a particular focus on effects of gender and comorbid conditions of depression and posttraumatic stress disorder (PTSD). METHOD: Saliva testosterone levels as well as cortisol awakening responses were assessed in 55 medication-free female and male patients with BPD and compared to 47 gender-, age-, and intelligence-matched healthy volunteers. In addition, analyses controlling for current depression and PSTD and bivariate correlations between testosterone and cortisol levels on the one hand and anger and aggressiveness on the other hand were performed. RESULTS: The results revealed increased saliva testosterone levels in female and male patients with BPD as well as elevated cortisol awakening responses in female, but not male patients with BPD compared to healthy volunteers. Cortisol awakening responses were positively related to anger and aggressiveness in female patients with BPD, but no associations were found with testosterone levels. CONCLUSION: In line with previous reports, the present results suggest endocrine alterations in BPD which may be associated with interpersonal impairments, such as increased anger-related aggressive behavior and could have implications for the development of new (psychopharmaco-) therapeutic interventions that may help to restore the alterations in the HPA and HPG systems. PMID- 25796038 TI - Continuous ozonation treatment of ofloxacin: transformation products, water matrix effect and aquatic toxicity. AB - The continuous ozonation of the antibiotic ofloxacin (OFX) has been performed using a synthetic water matrix and in a sewage treatment plant (STP) effluent. The aim was to study the effect of the water matrix on the ozonation with particular emphasis on the aquatic toxicity of treated water. OFX was completely removed in both water matrices, although the amount of ozone consumed for its depletion was strongly matrix-dependent. The extent of mineralization was limited and a number of intermediate transformation products (TPs) appeared, twelve of which could be identified. OFX reaction pathway includes the degradation of piperazinyl and quinolone moieties. The further oxidation of TPs gave rise to the formation and accumulation of carboxylic acids, aldehydes, nitrogen-containing organic compounds and inorganic ions. Aquatic toxicity of treated mixtures was assessed using four standard species: the bacteria Vibrio fischeri and Pseudomonas putida as target organisms and the algae Pseudokirchneriella subcapitata and the protozoan Tetrahymena thermophila as non-target organisms. OFX was toxic for the bacteria and the microalgae at the spiked concentration in untreated water. However, the continuous ozonation at the upper operational limit removed its toxic effects. T. thermophila was not affected by OFX, but was sensitive to STP effluent. PMID- 25796039 TI - The hyperaccumulator Sedum plumbizincicola harbors metal-resistant endophytic bacteria that improve its phytoextraction capacity in multi-metal contaminated soil. AB - Endophyte-assisted phytoremediation has recently been suggested as a successful approach for ecological restoration of metal contaminated soils, however little information is available on the influence of endophytic bacteria on the phytoextraction capacity of metal hyperaccumulating plants in multi-metal polluted soils. The aims of our study were to isolate and characterize metal resistant and 1-aminocyclopropane-1-carboxylate (ACC) utilizing endophytic bacteria from tissues of the newly discovered Zn/Cd hyperaccumulator Sedum plumbizincicola and to examine if these endophytic bacterial strains could improve the efficiency of phytoextraction of multi-metal contaminated soils. Among a collection of 42 metal resistant bacterial strains isolated from the tissues of S. plumbizincicola grown on Pb/Zn mine tailings, five plant growth promoting endophytic bacterial strains (PGPE) were selected due to their ability to promote plant growth and to utilize ACC as the sole nitrogen source. The five isolates were identified as Bacillus pumilus E2S2, Bacillus sp. E1S2, Bacillus sp. E4S1, Achromobacter sp. E4L5 and Stenotrophomonas sp. E1L and subsequent testing revealed that they all exhibited traits associated with plant growth promotion, such as production of indole-3-acetic acid and siderophores and solubilization of phosphorus. These five strains showed high resistance to heavy metals (Cd, Zn and Pb) and various antibiotics. Further, inoculation of these ACC utilizing strains significantly increased the concentrations of water extractable Cd and Zn in soil. Moreover, a pot experiment was conducted to elucidate the effects of inoculating metal-resistant ACC utilizing strains on the growth of S. plumbizincicola and its uptake of Cd, Zn and Pb in multi-metal contaminated soils. Out of the five strains, B. pumilus E2S2 significantly increased root (146%) and shoot (17%) length, fresh (37%) and dry biomass (32%) of S. plumbizincicola as well as plant Cd uptake (43%), whereas Bacillus sp. E1S2 significantly enhanced the accumulation of Zn (18%) in plants compared with non inoculated controls. The inoculated strains also showed high levels of colonization in rhizosphere and plant tissues. Results demonstrate the potential to improve phytoextraction of soils contaminated with multiple heavy metals by inoculating metal hyperaccumulating plants with their own selected functional endophytic bacterial strains. PMID- 25796041 TI - A signal-on electrochemiluminescence biosensor for detecting Con A using phenoxy dextran-graphite-like carbon nitride as signal probe. AB - A novel signal-on electrochemiluminescence (ECL) biosensor for detecting concanavalin A (Con A) was fabricated with phenoxy dextran-graphite-like carbon nitride (DexP-g-C3N4) as signal probe. In this construction strategy, the nanocomposites of three-dimensional graphene and gold nanoparticles (3D-GR-AuNPs) were used as matrix for high loading of glucose oxidase (GOx), which served as recognition element for bounding Con A. Con A further interacted with DexP-g-C3N4 through a specific carbohydrate-Con A interaction to achieve a sandwiched scheme. With the increase of Con A incubated onto the electrode, the ECL signal resulted from DexP-g-C3N4 would enhance, thus achieving a signal-on ECL biosensor for Con A detection. Due to the integration of the virtues of 3D-GR-AuNPs and the excellent ECL performance of DexP-g-C3N4, the prepared biosensor exhibits a wide linear response range from 0.05 ng/mL to 100 ng/mL and a low detection limit of 17 pg/mL (S/N=3). PMID- 25796040 TI - Smartphone-based portable biosensing system using impedance measurement with printed electrodes for 2,4,6-trinitrotoluene (TNT) detection. AB - Rapid, sensitive, selective and portable detection of 2,4,6-trinitrotoluene (TNT) is in high demand for public safety and environmental monitoring. In this study, we reported a smartphone-based system using impedance monitoring for TNT detection. The screen-printed electrodes modified with TNT-specific peptides were used as disposable a biosensor to produce impedance responses to TNT. The responses could be monitored by a hand-held device and send out to smartphone through Bluetooth. Then, the smartphone was used to display TNT responses in real time and report concentration finally. In the measurement, the system was demonstrated to detect TNT at concentration as low as 10(-6) M and distinguish TNT versus different chemicals in high specificity. Thus, the smartphone-based biosensing platform provided a convenient and efficient approach to design portable instruments for chemical detections such as TNT recognition. PMID- 25796042 TI - Cognitive emotion regulation in children: Reappraisal of emotional faces modulates neural source activity in a frontoparietal network. AB - Emotion regulation has an important role in child development and psychopathology. Reappraisal as cognitive regulation technique can be used effectively by children. Moreover, an ERP component known to reflect emotional processing called late positive potential (LPP) can be modulated by children using reappraisal and this modulation is also related to children's emotional adjustment. The present study seeks to elucidate the neural generators of such LPP effects. To this end, children aged 8-14 years reappraised emotional faces, while neural activity in an LPP time window was estimated using magnetoencephalography-based source localization. Additionally, neural activity was correlated with two indexes of emotional adjustment and age. Reappraisal reduced activity in the left dorsolateral prefrontal cortex during down regulation and enhanced activity in the right parietal cortex during up regulation. Activity in the visual cortex decreased with increasing age, more adaptive emotion regulation and less anxiety. Results demonstrate that reappraisal changed activity within a frontoparietal network in children. Decreasing activity in the visual cortex with increasing age is suggested to reflect neural maturation. A similar decrease with adaptive emotion regulation and less anxiety implies that better emotional adjustment may be associated with an advance in neural maturation. PMID- 25796044 TI - Enhanced semantic priming in synesthetes independent of sensory binding. AB - Synesthesia is the phenomenon in which individuals experience unusual involuntary cross-modal pairings. The evidence to date suggests that synesthetes have access to advantageous item-specific memory cues linked to their synesthetic experience, but whether this emphasis on item-specific memory cues comes at the expense of semantic-level processing has not been unambiguously demonstrated. Here we found that synesthetes produce substantially greater semantic priming magnitudes, unrelated to their specific synesthetic experience. This effect, however, was moderated by whether the synesthetes were projectors (their synesthetic experience occurs in their representation of external space), or associators (their synesthetic experience occurs in their 'mind's eye'). That is, the greater a synesthetes's tendency to project their experience, the weaker their semantic priming when the task did not require them to semantically categorize the stimuli, whereas this trade-off was absent when the task did have that requirement. PMID- 25796043 TI - Organoid development in cancer genome discovery. AB - The tumor response to most therapeutic agents in cancer is highly unpredictable. Cancer models which can adequately represent tumor heterogeneity and predict in vivo drug sensitivity are intense areas of investigation. Cancer cell lines and patient-derived xenograft models are the most frequently used models in cancer research and anticancer drug screening. Recently, cancer 'organoid' culture conditions have been developed to establish in vitro growth of patient-derived samples at higher efficiency and they are very promising for large scale drug screening and fundamental cancer biology research. Here, we leverage our experience in prostate cancer to discuss the advantages and limitations of these cancer models and summarize the development of cancer organoid culture--a development which may provide a new path towards personalized medicine in the future. PMID- 25796045 TI - Masked cross-modal priming turns on a glimpse of the prime. AB - We examined if cross-modal priming (print to speech) was greater for participants who were aware of the presence of letters in the experiment. Experiment 1 determined that word primes displayed at 47ms were adequately masked. In Experiment 2 (a,b) with primes displayed at 47ms masked priming occurred for within-mode printed targets but not for spoken ones. Experiment 3, with spoken targets, presented primes at two different durations (59, 71ms) and priming was found for participants who reported seeing letters but not for those who did not. The results are discussed in terms how the link between prime and target representations might be strengthened even by cursory awareness of the prime and what this tells us about priming. PMID- 25796046 TI - Separation of uncompromised whole blood mixtures for single source STR profiling using fluorescently-labeled human leukocyte antigen (HLA) probes and fluorescence activated cell sorting (FACS). AB - Analysis of biological mixtures is a significant problem for forensic laboratories, particularly when the mixture contains only one cell type. Contributions from multiple individuals to biologic evidence can complicate DNA profile interpretation and often lead to a reduction in the probative value of DNA evidence or worse, its total loss. To address this, we have utilized an analytical technique that exploits the intrinsic immunological variation among individuals to physically separate cells from different sources in a mixture prior to DNA profiling. Specifically, we applied a fluorescently labeled antibody probe to selectively bind to one contributor in a mixture through allele-specific interactions with human leukocyte antigen (HLA) proteins that are expressed on the surfaces of most nucleated cells. Once the contributor's cells were bound to the probe, they were isolated from the mixture using fluorescence activated cell sorting (FACS)-a high throughput technique for separating cell populations based on their optical properties-and then subjected to STR analysis. We tested this approach on two-person and four-person whole blood mixtures where one contributor possessed an HLA allele (A*02) that was not shared by other contributors to the mixture. Results showed that hybridization of the mixture with a fluorescently labeled antibody probe complimentary to the A*02 allele's protein product created a cell population with a distinct optical profile that could be easily differentiated from other cells in the mixture. After sorting the cells with FACS, genetic analysis showed that the STR profile of this cell population was consistent with that of the contributor who possessed the A*02 allele. Minor peaks from the A*02 negative contributor(s) were observed but could be easily distinguished from the profile generated from A*02 positive cells. Overall, this indicates that HLA antibody probes coupled to FACS may be an effective approach for generating STR profiles of individual contributors from forensic mixtures. PMID- 25796047 TI - Genome-wide methylation profiling and a multiplex construction for the identification of body fluids using epigenetic markers. AB - The identification of body fluids found at crime scenes can contribute to solving crimes by providing important insights into crime scene reconstruction. In the present study, body fluid-specific epigenetic marker candidates were identified from genome-wide DNA methylation profiling of 42 body fluid samples including blood, saliva, semen, vaginal fluid and menstrual blood using the Illumina Infinium HumanMethylation450 BeadChip array. A total of 64 CpG sites were selected as body fluid-specific marker candidates by having more than 20% discrepancy in DNA methylation status between a certain type of body fluid and other types of body fluids and to have methylation or unmethylation pattern only in a particular type of body fluid. From further locus-specific methylation analysis in additional samples, 1 to 3 CpG sites were selected for each body fluid. Then, a multiplex methylation SNaPshot reaction was constructed to analyze methylation status of 8 body fluid-specific CpG sites. The developed multiplex reaction positively identifies blood, saliva, semen and the body fluid which originates from female reproductive organ in one reaction, and produces successful DNA methylation profiles in aged or mixed samples. Although it remains to be investigated whether this approach is more sensitive, more practical than RNA- or peptide-based assays and whether it can be successfully applied to forensic casework, the results of the present study will be useful for the forensic investigators dealing with body fluid samples. PMID- 25796048 TI - Forensic utility of the feline mitochondrial control region - A Dutch perspective. AB - Different portions of the feline mitochondrial DNA control region (CR) were evaluated for their informative value in forensic investigations. The 402bp region located between RS2 and RS3 described most extensively in the past is not efficient for distinguishing between the majority of Dutch cats, illustrated by a random match probability (RMP) of 41%. Typing of the whole region between RS2 and RS3, and additional typing of the 5'portion of the feline CR decreases the RMP to 29%, increasing the applicability of such analyses for forensic investigations. The haplotype distribution in Dutch random bred cats (N=113) differs greatly from the distributions reported for other countries, with a single haplotype NL-A1 present in 54% of the population. The three investigated breeds showed haplotype distributions differing from each other and the random bred cats with haplotype NL-A1 accounting for 4%, 29% and 32% of Maine Coon, Norwegian forest cats and Siamese & Oriental cats. These results indicate the necessity of validating haplotype frequencies within continents and regions prior to reporting the value a mtDNA match. In cases where known purebred cats are involved, further investigation of the breed may be valuable. PMID- 25796049 TI - Toxicity effects of profenofos on embryonic and larval development of Zebrafish (Danio rerio). AB - The aim of the present study was to evaluate the developmental toxicity of profenofos to early developing Zebrafish (Danio rerio) embryos (4h post fertilization) in a static system at 1.0 to 2.25mg/L. Median lethal concentrations (LC50) of profenofos at 24-h, 48-h, 72-h and 96-h were determined as 2.04, 1.58, 1.57 and 1.56 mg/L, respectively. The hatching of embryos were recorded at every 12h interval and the median hatching time (HT50) was also calculated for each concentration. In a separate set of experiments, 96-h LC10 (0.74 mg/L) and LC50 (1.56 mg/L) concentrations were used to assess the developmental toxicity in relation to behavior, morphology, and interactions with the targeted enzyme acetylcholinesterase. Live video-microscopy revealed that the profenofos exposed embryos exhibited an abnormal development, skeletal defects and altered heart morphology in a concentration-dependent manner, which leads to alterations in the swimming behavior of hatchlings at 144-h, which indicate that developing zebrafish are sensitive to profenofos. PMID- 25796051 TI - A Nation-Wide Study on the Percentage of Schizophrenia and Bipolar Disorder Patients Who Earn Minimum Wage or Above. AB - OBJECTIVE: Although it is undisputable that patients with severe mental illness have impaired ability to work, the extent of this is unclear. This is a nation wide, cross-sectional survey of patients who have been hospitalized with severe mental illness earning minimum wage or above. METHOD: Data from the Israeli Psychiatric Hospitalization Case Registry were linked with nation-wide data from the National Insurance Institute (the equivalent of US Social Security) on personal income. Hospitalization data were obtained on all consecutive admissions to any psychiatric hospital in the country between 1990-2008 with a diagnosis of schizophrenia, other nonaffective psychotic disorders, or bipolar disorder (N = 35 673). Earning minimum wage or more was defined as earning at least 1000 USD/month, which was equivalent to minimum wage in Israel in December 2010. RESULTS: The percentages of patients with only 1 admission who were earning minimum wage or above in December 2010 were as follows: 10.6% of patients with a diagnosis of schizophrenia; 21.6% of patients with a diagnosis of nonaffective psychotic disorders; and 24.2% of patients with bipolar disorder. The percentages of patients with multiple admissions who were earning minimum wage or above were as follows: 5.8% of patients with schizophrenia; 11.2% of patients with nonaffective psychotic disorders; and 19.9% of patients with bipolar disorder. CONCLUSIONS: Despite potential confounders, the results indicate that patients with schizophrenia, nonaffective psychotic disorders, or bipolar disorder have a poor employment outcome, even if they have only been admitted once. These results emphasize the importance of improving interventions to re-integrate these individuals into the work force. PMID- 25796050 TI - The Effect of Transitions in Caregiving Status and Intensity on Perceived Stress Among 992 Female Caregivers and Noncaregivers. AB - BACKGROUND: Informal caregiving, a chronic stressor, is also a dynamic experience, as caregivers may repeatedly enter and exit the role and alter the amount of care they provide. Changes in caregiving status and intensity influence stress, but few studies have evaluated the simultaneous impact of these changes on perceived stress. METHODS: A total of 1,027 female caregivers and noncaregivers (mean age = 81.7), of which 992 were included in the final sample, were followed for at least two consecutive annual interviews (ie, one interval) and up to five interviews over a 9-year period. Caregiving status was measured by self-report of whether the respondent assisted someone with at least one basic or instrumental activity of daily living; caregiving intensity was dichotomized at the median number of basic or instrumental activity of daily living tasks caregivers performed. The associations between changes in caregiving status and intensity level with Perceived Stress Scale (PSS) score at the end of an interval were estimated using mixed-effects regression models. RESULTS: Respondents contributed 2,832 intervals. High-intensity caregivers reported the highest stress at the end of an interval, whereas noncaregivers reported the lowest (mean PSS = 18.97 vs 15.73, p < .01). Low-intensity caregivers, whose intensity increased, had higher stress than continuing high-intensity caregivers. Those who stopped caregiving, regardless of intensity level, reported the same amount of stress as noncaregivers. CONCLUSIONS: Transitions in caregiving status and intensity affect caregiver perceived stress. Continuing high-intensity caregivers and those who transition from low- to high-intensity caregiving report the highest stress of all transition groups, suggesting that stress-reduction interventions should target high-intensity caregivers. PMID- 25796052 TI - Hazard of Low Salt Intake. PMID- 25796054 TI - Close encounters with errors of the second kind: evaluating risks and benefits of long-term dual antiplatelet therapy. PMID- 25796053 TI - Magnetic resonance imaging safety in pacemaker and implantable cardioverter defibrillator patients: how far have we come? AB - Magnetic resonance imaging (MRI) has long been regarded a general contraindication in patients with cardiovascular implanted electronic devices such as cardiac pacemakers or cardioverter defibrillators (ICDs) due to the risk of severe complications and even deaths caused by interactions of the magnetic resonance (MR) surrounding and the electric devices. Over the last decade, a better understanding of the underlying mechanisms responsible for such potentially life-threatening complications as well as technical advances have allowed an increasing number of pacemaker and ICD patients to safely undergo MRI. This review lists the key findings from basic research and clinical trials over the last 20 years, and discusses the impact on current day clinical practice. With 'MR-conditional' devices being the new standard of care, MRI in pacemaker and ICD patients has been adopted to clinical routine today. However, specific precautions and specifications of these devices should be carefully followed if possible, to avoid patient risks which might appear with new MR technology and further increasing indications and patient numbers. PMID- 25796055 TI - You can detect the trees as well as the forest when adding the leaves: evidence from visual search tasks containing three-level hierarchical stimuli. AB - The present study investigated how multiple levels of hierarchical stimuli (i.e., global, intermediate and local) are processed during a visual search task. Healthy adults participated in a visual search task in which a target was either present or not at one of the three levels of hierarchical stimuli (global geometrical form made by intermediate forms themselves constituted by local forms). By varying the number of distractors, the results showed that targets presented at global and intermediate levels were detected efficiently (i.e., the detection times did not vary with the number of distractors) whereas local targets were processed less efficiently (i.e., the detection times increased with the number of distractors). Additional experiments confirmed that these results were not due to the size of the target elements or to the spatial proximity among the structural levels. Taken together, these results show that the most local level is always processed less efficiently, suggesting that it is disadvantaged during the competition for attentional resources compared to higher structural levels. The present study thus supports the view that the processing occurring in visual search acts dichotomously rather than continuously. Given that pure structuralist and pure space-based models of attention cannot account for the pattern of our findings, we discuss the implication for perception, attentional selection and executive control of target position on hierarchical stimuli. PMID- 25796056 TI - Grounded spatial belief revision. AB - Beliefs frequently undergo revisions, especially when new pieces of information are true but inconsistent with current beliefs. In previous studies, we showed that linguistic asymmetries provided by relational statements, play a crucial role in spatial belief revision. Located objects (LO) are preferably revised compared to reference objects (RO), known as the LO-principle. Here we establish a connection between spatial belief revision and grounded cognition. In three experiments, we explored whether imagined physical object properties influence which object is relocated and which remains at its initial position. Participants mentally revised beliefs about the arrangements of objects which could be envisaged as light and heavy (Experiment 1), small and large (Experiment 2), or movable and immovable (Experiment 3). The results show that intrinsic object properties are differently taken into account during spatial belief revision. Object weight did not alter the LO-principle (Experiment 1), whereas object size was found to influence which object was preferably relocated (Experiment 2). Object movability did not affect relocation preferences but had an effect on relocation durations (Experiment 3). The findings support the simulation hypothesis within the grounded cognition approach and create new connections between the spatial mental model theory of reasoning and the idea of grounded cognition. PMID- 25796057 TI - Impact of osteopathic manipulative therapy on quality of life of patients with deep infiltrating endometriosis with colorectal involvement: results of a pilot study. AB - OBJECTIVE: A prospective pilot study to evaluate the potential role of osteopathic manipulative therapy (OMT) on quality of life (QOL) of patients with Deep Infiltrating Endometriosis (DIE) and colorectal involvement. STUDY DESIGN: Twenty patients with DIE and colorectal infiltration completed the SF-36 QOL questionnaire before and after undergoing OMT. RESULTS: The median age (range) of the patients was 30.4 years (22-39). Thirty-five percent of the patients had undergone previous surgery for endometriosis and 70% were on medical treatment. Fifteen of the 20 patients (75%) completed the protocol. There was no difference in the epidemiological characteristics or in the pre-OMT Physical Component Summary (PCS) and Mental Component Summary (MCS) of the SF-36 questionnaire between patients who completed the protocol or not. After a mean period of 24 days (15-53), a significant improvement in PCS (p=0.03) and MCS (p=0.0009) compared to pre-OMT values was observed giving a success rate of 80% and 60% in intention-to-treat, respectively. CONCLUSION: Our results support that OMT can improve QOL of patients with DIE and colorectal involvement. Moreover, this pilot study can serve to determine power calculations for future randomized trials. PMID- 25796058 TI - Single-port laparoscopically assisted-transumbilical ultraminilaparotomic myomectomy (SPLA-TUM) versus single port laparoscopic myomectomy: a randomized controlled trial. AB - OBJECTIVE: To evaluate whether single-port laparoscopically assisted transumbilical ultraminilaparotomic myomectomy (SPLA-TUM) has a shorter operating time than single port laparoscopic myomectomy (SP-LM), without negatively affecting postoperative pain and cosmesis. STUDY DESIGN: We performed a randomized controlled trial at a University teaching hospital. A total of 92 premenopausal women with symptomatic, superficial intramural or subserosal fibroids were randomized to receive either SPLA-TUM or SP-LM. The primary outcome measured was the operating time. The secondary outcome measures included postoperative pain, as measured by a visual analog scale (VAS) at 2, 6, 12, 24, and 48h after the operation, and cosmetic outcomes, as measured by the Vancouver scar scale (VSS) and patient satisfaction with the scars, using a VAS at 3 postoperative months. RESULTS: There were no differences in the patient demographics or in the clinical characteristics of the resected fibroids between the two groups. The operation results showed no differences in the hemoglobin changes, return of bowel activity, hospital stay, and complication rate between the groups. The mean operating time in the SPLA-TUM group was shorter than that in the SP-LM group (87.0+/-32.7min compared with 102.3+/-32.9min, P=0.026). The patients in each group demonstrated no differences in their postoperative pain levels, VSS scores, and satisfaction with the scars, but the SPLA-TUM group had a longer umbilical wound compared with the SP-LM group. Two (4.3%) patients in the SPLA-TUM group received SP-LM. One (2.2%) patient in the SP-LM group and two (4.3%) patients in the SPLA-TUM group were converted to two or three port laparoscopic myomectomy. CONCLUSIONS: SPLA-TUM has a shorter operating time than SP-LM due to convenient suturing and knotting; the two procedures have comparable postoperative pain levels and cosmetic outcomes. However, further study is needed to evaluate the long-term outcomes of SPLA-TUM. PMID- 25796059 TI - Characterisation of the epithermal neutron irradiation facility at the Portuguese research reactor using MCNP. AB - The radiation field at the epithermal beamline and irradiation chamber installed at the Portuguese Research Reactor (RPI) at the Campus Tecnologico e Nuclear of Instituto Superior Tecnico was characterised in the context of Prompt Gamma Neutron Activation Analysis (PGNAA) applications. Radiographic films, activation foils and thermoluminescence dosimeters were used to measure the neutron fluence and photon dose rates in the irradiation chamber. A fixed-source MCNPX model of the beamline and chamber was developed and compared to measurements in the first step towards planning a new irradiation chamber. The high photon background from the reactor results in the saturation of the detector and the current facility configuration yields an intrinsic insensitivity to various elements of interest for PGNAA. These will be addressed in future developments. PMID- 25796060 TI - Modulation of auditory processing during speech movement planning is limited in adults who stutter. AB - Stuttering is associated with atypical structural and functional connectivity in sensorimotor brain areas, in particular premotor, motor, and auditory regions. It remains unknown, however, which specific mechanisms of speech planning and execution are affected by these neurological abnormalities. To investigate pre movement sensory modulation, we recorded 12 stuttering and 12 nonstuttering adults' auditory evoked potentials in response to probe tones presented prior to speech onset in a delayed-response speaking condition vs. no-speaking control conditions (silent reading; seeing nonlinguistic symbols). Findings indicate that, during speech movement planning, the nonstuttering group showed a statistically significant modulation of auditory processing (reduced N1 amplitude) that was not observed in the stuttering group. Thus, the obtained results provide electrophysiological evidence in support of the hypothesis that stuttering is associated with deficiencies in modulating the cortical auditory system during speech movement planning. This specific sensorimotor integration deficiency may contribute to inefficient feedback monitoring and, consequently, speech dysfluencies. PMID- 25796061 TI - Actinometric and Phi-order photodegradation properties of anti-cancer Sunitinib. AB - The photodegradation reaction of Sunitinib (SUT), occurring via Z-E photoisomerisation, has been evaluated in this study using the recently developed Phi-order kinetics. In ethanol, the forward (Z -> E) photoreaction of SUT was invariant with irradiation (its quantum yield, Phi(E-->Z)(lambda)(irr) ~ 0.019) in contrast to the E -> Z isomerisation whose Phi(E-->Z)(lambda)(irr) undergoes a 30-fold, sigmoid-shaped, increase with increasing irradiation wavelength. This situation limited usefully the extent of Z-SUT photodegradation at the photostationary state to a maximum of c.a. 30% of the initial concentration. Nevertheless, these results support a strong recommendation for a complete protection of SUT from light at all stages. Furthermore, a SUT-actinometer was developed and was proven to be useful for the 320-480 nm spectral range. The latter wavelength interval defined as well SUT photodegradation causative range. The formalism of Phi-order kinetics proves to be a useful investigative tool for drugs' photodegradation studies. PMID- 25796062 TI - Reduction of Salmonella enterica serotype Poona and background microbiota on fresh-cut cantaloupe by electron beam irradiation. AB - The efficacy of electron beam (e-beam) irradiation processing to reduce Salmonella enterica serotype Poona on surfaces of fresh-cut cantaloupe, and the impact of e-beam irradiation processing on the numbers of indigenous microorganisms were determined. Additionally, the D10-value for S. Poona reduction on the cut cantaloupe was also determined. Fresh-cut cantaloupe pieces, inoculated with S. Poona to 7.8 log10 CFU/g, were exposed to 0.0, 0.7, or 1.5 kGy. Surviving S. Poona, lactic acid bacteria (LAB), and fungi (yeasts, molds) were periodically enumerated on appropriate media over 21 days of storage at 5 degrees C. Cantaloupe surface pH was measured for irradiated cantaloupe across the 21 day storage period. To determine the D10-value of S. Poona, cantaloupe discs were inoculated and exposed to increasing radiation dosages between 0 and 1.06 kGy; surviving pathogen cells were selectively enumerated. S. Poona was significantly reduced by irradiation; immediate reductions following exposure to 0.7 and 1.5 kGy were 1.1 and 3.6 log10 CFU/g, respectively. After 21 days, S. Poona numbers were between 4.0 and 5.0 log10 CFU/g less than untreated samples at zero-time. Yeasts were not reduced significantly (p >= 0.05) by e-beam irradiation and grew slowly but steadily during storage. Counts of LAB and molds were initially reduced with 1.5 kGy (p<0.05) but then LAB recovered grew to high numbers, whereas molds slowly declined for irradiated and control samples. Cantaloupe pH declined during storage, with the greatest decrease in untreated control cantaloupe (p<0.05). The D10-value for S. Poona was determined to be 0.211 kGy, and this difference from the reductions observed in the cut cantaloupe studies may be due to the more precise dose distribution obtained in the thin and flat cantaloupe pieces used for the D10-value experiments. The effect of e-beam irradiation at the same doses used in this study was determined in previous studies to have no negative effect in the quality of the cut cantaloupe. Therefore, incorporation of low dosage ionizing irradiation and consistent application of irradiation processing can significantly improve the microbiological safety of fresh-cut cantaloupe. PMID- 25796063 TI - Ral GTPases: crucial mediators of exocytosis and tumourigenesis. AB - The Ral guanosine triphosphatases (GTPases), RalA and RalB, are members of the Ras superfamily of small GTPases. Research on Ral GTPases and their functions over the past 25 years has revealed the essential involvement of these GTPases in unique and diverse cellular processes including exocyst-mediated exocytosis and related cellular activities. Moreover, it is increasingly appreciated that the aberrant activation of Ral GTPases is one of the major causes of human tumourigenesis induced by oncogenic Ras. Recent evidence suggests that Ral signalling pathways may be potential therapeutic targets for the treatment of human cancers. This review summarizes recent advance in the investigation of Ral GTPases. PMID- 25796064 TI - Fugu (Takifugu rubripes) serum GlcNAc-binding lectin is a kalliklectin but has different properties from those of a reported homologue. AB - A 40-kDa lectin with N-acetyl-d-glucosamine-binding ability was purified from the sera of fugu (Takifugu rubripes) by affinity chromatography and subsequent gel filtration. N-terminal amino acid sequencing, in silico cloning using the fugu genome database and cDNA cloning demonstrated that this lectin is a homologue of kalliklectin, a novel lectin that was previously found in the flathead teleost Platycephalus indicus and has structural similarity to mammalian plasma kallikreins and coagulation factor XI. This is the second report of a kalliklectin, but the fugu kalliklectin differs in its sugar-binding spectra, intersubunit association and tissue distribution from the previously identified flathead kalliklectin. These findings indicate that kalliklectins vary in properties among fish species. PMID- 25796065 TI - Influence of phase transformations on dynamical elastic modulus and anelasticity of beta Ti-Nb-Fe alloys for biomedical applications. AB - Recent studies in materials for biomedical applications have focused on beta titanium alloys that are highly biocompatible, free of toxic elements and with an elastic modulus close to that of human bone (10-40 GPa). Beta Ti-xNb-3Fe (x=10, 15, 20 and 25 wt%) alloys were obtained by rapid solidification and characterized by anelastic relaxation measurements at temperatures between 140 K and 770 K, using a free-decay elastometer, as well as analysis by Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD) and Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The observed stabilization of the beta-phase with rising Nb content was linked to the strength of the relaxation peak around 570 K. The phase transformations detected in the anelastic relaxation spectra agreed with those observed in the DSC curves. However, the results from anelastic relaxation spectra provide more detailed information about the kinetics of phase transformations. At temperatures between 140 K and 300 K, there was an indication of a reversible transformation in the alloys studied. The elastic modulus measurements showed a hardening of the material, between 400 K and 620 K, related to the omega-phase precipitation. However, the starting temperature of omega-phase precipitation was clearly influenced by the Nb content, showing a shift to high temperature with increasing percentage of Nb. At temperatures above 620 K, a fall was observed in the dynamical elastic modulus, accompanied by a relaxation peak centered at 660 K, which was attributed to the growing alpha phase arising from the omega-phase, which acts as a nucleation sites or from the decomposition of the metastable beta-phase. XRD patterns confirmed the formation of beta, alpha and omega phases after mechanical relaxation measurements. A predominant beta phase with dendritic morphology was observed, which became more stable with 25 wt% Nb. The lowest elastic modulus was of 65 GPa obtained in the Ti-25Nb-3Fe alloy, representing a good low value for a beta-Ti alloy with a relatively low addition of beta stabilizing elements (Nb and Fe). PMID- 25796066 TI - Evaluating patterns of weight and body composition change among college women. AB - The prevalence of obesity increases as women move from adolescence to young adulthood, and college women have been identified as a population at risk for unhealthy weight gain. Studies of weight gain in college populations have revealed that significant, variable weight change occurs in as few as eight weeks, but few have included participants beyond their freshman year of college or assessed body composition. The aims of the study were to use a repeated measures design to identify patterns of weight change among college women at all grade levels and to evaluate factors that may predict weight change over a one year period. Undergraduate college women (N=131) completed measures of physical activity, dietary restraint, living conditions, and body dissatisfaction at baseline, 6-months, and 12-months. Height, weight, and body composition were collected at all assessment periods. Forty-four percent of participants gained at least 3lb, 23% lost at least 3lb, and 33% maintained weight over one year. Weight change was associated with changes in body fat and was not related to baseline BMI or age. There were no significant differences between grade levels, suggesting that future studies should include women at all grade levels. Baseline physical activity, dietary restraint, living conditions, and body dissatisfaction did not predict weight change at one year, nor did they differentiate between individuals in the three weight change categories. Further research is needed to identify the factors associated with weight gain in young adult women, and such studies should not be limited to college freshmen. PMID- 25796067 TI - Microbial community-based polyhydroxyalkanoates (PHAs) production from wastewater: Techno-economic analysis and ex-ante environmental assessment. AB - This work investigates the potential for polyhydroxybutyrate (PHB) production from wastewater, from a techno-economic and an environmental perspective, examining scale-up opportunities and bottlenecks prior to commercialisation. Conceptual process design, economic, environmental impacts and sensitivity analysis are developed for one fermentation process and three downstream processing routes, based on alkali, surfactant-hypochlorite and solvent treatments. Environmentally and cost-wise, the alkali treatment is the most favourable with production costs of 1.40?/kg PHB, global warming potential of 2.4kgCO2-eq/kg PHB and non-renewable energy use of 106MJ/kg PHB. The solvent based process yields the highest costs and environmental burdens: 1.95?/kg PHB, 4.30kgCO2-eq/kg PHB and 156MJ/kg PHB. The production of PHB from wastewater is identified as an interesting alternative to pure culture-polyhydroxyalkanoates production from sugars. However, these results are not yet competitive with those for the petrochemical counterparts. Additional performance improvements may be possible, through process integration and optimisation. PMID- 25796069 TI - Facial coloration tracks changes in women's estradiol. AB - Red facial coloration is an important social cue in many primate species, including humans. In such species, the vasodilatory effects of estradiol may cause red facial coloration to change systematically during females' ovarian cycle. Although increased red facial coloration during estrus has been observed in female mandrills (Mandrillus sphinx) and rhesus macaques (Macaca mulatta), evidence linking primate facial color changes directly to changes in measured estradiol is lacking. Addressing this issue, we used a longitudinal design to demonstrate that red facial coloration tracks within-subject changes in women's estradiol, but not within-subject changes in women's progesterone or estradiol-to progesterone ratio. Moreover, the relationship between estradiol and facial redness was observed in two independent samples of women (N = 50 and N = 65). Our results suggest that changes in facial coloration may provide cues of women's fertility and present the first evidence for a direct link between estradiol and female facial redness in a primate species. PMID- 25796070 TI - Synthesis and thermal stability of zirconia and yttria-stabilized zirconia microspheres. AB - HYPOTHESIS: Zirconia microparticles produced by sol-gel synthesis have great potential for photonic applications. To this end, identifying synthetic methods that yield reproducible control over size uniformity is important. Phase transformations during thermal cycling can disintegrate the particles. Therefore, understanding the parameters driving these transformations is essential for enabling high-temperature applications. Particle morphology is expected to influence particle processability and stability. Yttria-doping should improve the thermal stability of the particles, as it does in bulk zirconia. EXPERIMENTS: Zirconia and YSZ particles were synthesized by improved sol-gel approaches using fatty acid stabilizers. The particles were heated to 1500 degrees C, and structural and morphological changes were monitored by SEM, ex situ XRD and high energy in situ XRD. FINDINGS: Zirconia particles (0.4-4.3 MUm in diameter, 5-10% standard deviation) synthesized according to the modified sol-gel approaches yielded significantly improved monodispersities. As-synthesized amorphous particles transformed to the tetragonal phase at ~450 degrees C with a volume decrease of up to ~75% and then to monoclinic after heating from ~650 to 850 degrees C. Submicron particles disintegrated at ~850 degrees C and microparticles at ~1200 degrees C due to grain growth. In situ XRD revealed that the transition from the amorphous to tetragonal phase was accompanied by relief in microstrain and the transition from tetragonal to monoclinic was correlated with the tetragonal grain size. Early crystallization and smaller initial grain sizes, which depend on the precursors used for particle synthesis, coincided with higher stability. Yttria-doping reduced grain growth, stabilized the tetragonal phase, and significantly improved the thermal stability of the particles. PMID- 25796068 TI - Longitudinal associations between diurnal cortisol slope and alcohol use across adolescence: a seven-year prospective study. AB - A large body of research has linked hypothalamic-pituitary-adrenal (HPA) axis function and alcohol consumption, including work suggesting that flatter diurnal cortisol slopes are associated with greater alcohol use. A lack of longitudinal studies and a focus on adult and alcoholic populations leaves unclear whether such associations are also present in younger, non-clinical populations and whether flatter diurnal slopes are a consequence of or preexisting risk factor for alcohol use; however, theory suggests such associations may be mutually reinforcing. In a longitudinal, community sample of 200 (55% female) adolescents, the current study demonstrates that flatter diurnal cortisol slope at age 11 predicts higher levels of alcohol use from ages 15-18, and that heavier alcohol use in turn predicts further flattening of diurnal cortisol rhythm at age 18.5. This is the first study to demonstrate a longitudinal chain of associations between diurnal cortisol slope and alcohol use. Findings support contemporary theoretical models of the neurobiological processes underlying alcohol use and can inform future research on risk factors for and consequences of underage drinking. PMID- 25796071 TI - Synthetic methylotrophy: engineering the production of biofuels and chemicals based on the biology of aerobic methanol utilization. AB - Synthetic methylotrophy is the development of non-native methylotrophs that can utilize methane and methanol as sole carbon and energy sources or as co substrates with carbohydrates to produce metabolites as biofuels and chemicals. The availability of methane (from natural gas) and its oxidation product, methanol, has been increasing, while prices have been decreasing, thus rendering them as attractive fermentation substrates. As they are more reduced than most carbohydrates, methane and methanol, as co-substrates, can enhance the yields of biologically produced metabolites. Here we discuss synthetic biology and metabolic engineering strategies based on the native biology of aerobic methylotrophs for developing synthetic strains grown on methanol, with Escherichia coli as the prototype. PMID- 25796072 TI - On how the brain decodes vocal cues about speaker confidence. AB - In speech communication, listeners must accurately decode vocal cues that refer to the speaker's mental state, such as their confidence or 'feeling of knowing'. However, the time course and neural mechanisms associated with online inferences about speaker confidence are unclear. Here, we used event-related potentials (ERPs) to examine the temporal neural dynamics underlying a listener's ability to infer speaker confidence from vocal cues during speech processing. We recorded listeners' real-time brain responses while they evaluated statements wherein the speaker's tone of voice conveyed one of three levels of confidence (confident, close-to-confident, unconfident) or were spoken in a neutral manner. Neural responses time-locked to event onset show that the perceived level of speaker confidence could be differentiated at distinct time points during speech processing: unconfident expressions elicited a weaker P2 than all other expressions of confidence (or neutral-intending utterances), whereas close-to confident expressions elicited a reduced negative response in the 330-500 msec and 550-740 msec time window. Neutral-intending expressions, which were also perceived as relatively confident, elicited a more delayed, larger sustained positivity than all other expressions in the 980-1270 msec window for this task. These findings provide the first piece of evidence of how quickly the brain responds to vocal cues signifying the extent of a speaker's confidence during online speech comprehension; first, a rough dissociation between unconfident and confident voices occurs as early as 200 msec after speech onset. At a later stage, further differentiation of the exact level of speaker confidence (i.e., close-to-confident, very confident) is evaluated via an inferential system to determine the speaker's meaning under current task settings. These findings extend three-stage models of how vocal emotion cues are processed in speech comprehension (e.g., Schirmer & Kotz, 2006) by revealing how a speaker's mental state (i.e., feeling of knowing) is simultaneously inferred from vocal expressions. PMID- 25796073 TI - Does intake of trace elements through urban gardening in Copenhagen pose a risk to human health? AB - This study investigates the potential health risk from urban gardening. The concentrations of the trace elements arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn) in five common garden crops from three garden sites in Copenhagen were measured. Concentrations (mg/kg dw) of As were 0.002-0.21, Cd 0.03-0.25, Cr < 0.09-0.38, Cu 1.8-8.7, Ni < 0.23-0.62, Pb 0.05-1.56, and Zn 10-86. Generally, elemental concentrations in the crops do not reflect soil concentrations, nor exceed legal standards for Cd and Pb in food. Hazard quotients (HQs) were calculated from soil ingestion, vegetable consumption, measured trace element concentrations and tolerable intake levels. The HQs for As, Cd, Cr, Cu, Ni, and Zn do not indicate a health risk through urban gardening in Copenhagen. Exposure to Pb contaminated sites may lead to unacceptable risk not caused by vegetable consumption but by unintentional soil ingestion. PMID- 25796074 TI - Particle doses in the pulmonary lobes of electronic and conventional cigarette users. AB - The main aim of the present study was to estimate size segregated doses from e cigarette aerosols as a function of the airway generation number in lung lobes. After a 2-second puff, 7.7 * 10(10) particles (DTot) with a surface area of 3.6 * 10(3) mm(2) (STot), and 3.3 * 10(10) particles with a surface area of 4.2 * 10(3) mm(2) were deposited in the respiratory system for the electronic and conventional cigarettes, respectively. Alveolar and tracheobronchial deposited doses were compared to the ones received by non-smoking individuals in Western countries, showing a similar order of magnitude. Total regional doses (D(R)), in head and lobar tracheobronchial and alveolar regions, ranged from 2.7 * 10(9) to 1.3 * 10(10) particles and 1.1 * 10(9) to 5.3 * 10(10) particles, for the electronic and conventional cigarettes, respectively. D(R) in the right-upper lung lobe was about twice that found in left-upper lobe and 20% greater in right lower lobe than the left-lower lobe. PMID- 25796075 TI - Determination of the antitubercular drug PA-824 in rat plasma, lung and brain tissues by liquid chromatography tandem mass spectrometry: application to a pharmacokinetic study. AB - A selective, sensitive and high performance liquid chromatography-tandem mass spectrometry (LC-(ESI)MS/MS) method has been developed and validated for the quantification of the potent antitubercular drug candidate, PA-824, in rat plasma, lung and brain tissues. Sample clean-up involved protein precipitation and solid-phase extraction. Chromatographic separation was performed on YMC Triart C18 column (150 mm * 3.0 mm, 3.0 MUm). The method was validated over the concentration range of 75-1500 ng/mL for plasma, 50-1200 ng/g for lungs and 100 1500 ng/g for brain tissue. Evaluation of the pharmacokinetic properties of PA 824 utilized Sprague Dawley rats with a dosage of 20mg/kg at various time points. The new method was applied successfully for the determination of PA-824 with liquid desorption followed by liquid chromatography with ultra-high resolution quadrupole time-of-flight mass spectrometry in the different biological samples. PMID- 25796076 TI - A redox-dependent dimerization switch regulates activity and tolerance for reactive oxygen species of barley seed glutathione peroxidase. AB - Monomeric and dimeric forms of recombinant barley (Hordeum vulgare subsp. vulgare) glutathione peroxidase 2 (HvGpx2) are demonstrated to display distinctly different functional properties in vitro. Monomeric HvGpx2 thus has five fold higher catalytic efficiency than the dimer towards tert-butyl hydroperoxide, but is more sensitive to inactivation by hydrogen peroxide. Treatment of the monomer with hydrogen peroxide results in dimer formation. This observed new behavior of a plant glutathione peroxidase suggests a mechanism involving a switch from a highly catalytically competent monomer to a less active, but more oxidation resistant dimer. PMID- 25796077 TI - Decapping protein 1 phosphorylation modulates IL-8 expression during respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is a negative-strand RNA virus that is an important cause of bronchiolitis and pneumonia. We investigated the effect of RSV infection on the expression patterns of cellular proteins involved in regulating mRNA translation and degradation, and found that a processing-body protein involved in mRNA degradation, decapping protein 1a (DCP1), was phosphorylated rapidly following infection. UV-inactivated and sucrose-purified RSV were sufficient to mediate DCP1 phosphorylation, indicating that it occurs as a consequence of an early event in RSV infection. Analysis using kinase inhibitors showed that RSV-induced DCP1 phosphorylation occurred through the ERK1/2 pathway. The DCP1 phosphorylation sites were limited to serine 315, serine 319, and threonine 321. Overexpression of wt DCP1 led to a decrease in RSV-induced IL-8 production, but this effect was abrogated in cells overexpressing phosphorylation deficient DCP1 mutants. These results suggest that DCP1 phosphorylation modulates the host chemokine response to RSV infection. PMID- 25796078 TI - The pulmonary mesenchyme directs lung development. AB - Each of the steps of respiratory system development relies on intricate interactions and coordinated development of the lung epithelium and mesenchyme. In the past, more attention has been paid to the epithelium than the mesenchyme. The mesenchyme is a source of specification and morphogenetic signals as well as a host of surprisingly complex cell lineages that are crucial for normal lung development and function. This review highlights recent research focusing on the mesenchyme that has revealed genetic and epigenetic mechanisms of its development in the context of other cell layers during respiratory lineage specification, branching morphogenesis, epithelial differentiation, lineage distinction, vascular development, and alveolar maturation. PMID- 25796080 TI - Development of the inner ear. AB - The vertebrate inner ear is a sensory organ of exquisite design and sensitivity. It responds to sound, gravity and movement, serving both auditory (hearing) and vestibular (balance) functions. Almost all cell types of the inner ear, including sensory hair cells, sensory neurons, secretory cells and supporting cells, derive from the otic placode, one of the several ectodermal thickenings that arise around the edge of the anterior neural plate in the early embryo. The developmental patterning mechanisms that underlie formation of the inner ear from the otic placode are varied and complex, involving the reiterative use of familiar signalling pathways, together with roles for transcription factors, transmembrane proteins, and extracellular matrix components. In this review, I have selected highlights that illustrate just a few of the many recent discoveries relating to the development of this fascinating organ system. PMID- 25796079 TI - The tissue mechanics of vertebrate body elongation and segmentation. AB - England's King Richard III, whose skeleton was recently discovered lying ignobly beneath a parking lot, suffered from a lateral curvature of his spinal column called scoliosis. We now know that his scoliosis was not caused by 'imbalanced bodily humors', rather vertebral defects arise from defects in embryonic elongation and segmentation. This review highlights recent advances in our understanding of post-gastrulation biomechanics of the posteriorly advancing tailbud and somite morphogenesis. These processes are beginning to be deciphered from the level of gene networks to a cross-scale physical model incorporating cellular mechanics, the extracellular matrix, and tissue fluidity. PMID- 25796081 TI - Prenatal and early-life polychlorinated biphenyl (PCB) levels and behavior in Inuit preschoolers. AB - BACKGROUND: Whereas it is well established that prenatal exposure to polychlorinated biphenyls (PCBs) can disrupt children's behavior, early postnatal exposure has received relatively little attention in environmental epidemiology. OBJECTIVES: To evaluate prenatal and postnatal exposures to PCB-153, a proxy of total PCB exposure, and their relation to inattention and activity in 5-year-old Inuits from the Cord Blood Monitoring Program. METHODS: Prenatal exposure to PCBs was informed by cord plasma PCB-153 levels. We used a validated pharmacokinetic model to estimate monthly infants' levels across the first year of life. Inattention and activity were assessed by coding of video recordings of children undergoing fine motor testing. We used multivariable linear regression to evaluate the association between prenatal and postnatal PCB-153 levels and inattention (n=97) and activity (n=98) at 5years of age. RESULTS: Cord plasma PCB 153 was not associated with inattention and activity. Each interquartile range (IQR) increase in estimated infant PCB-153 levels at 2months was associated with a 1.02% increase in the duration of inattention (95% CI: 0.04, 2.00). Statistical adjustment for the duration of breastfeeding slightly increased regression coefficients for postnatal level estimates, some of which became statistically significant for inattention (months: 2-4) and activity (months: 2-5). CONCLUSIONS: Our study adds to the growing evidence of postnatal windows of development during which children are more susceptible to neurotoxicants like PCBs. PMID- 25796082 TI - Oesophageal perforation caused by screw displacement 16 months following anterior cervical spine fixation. AB - Anterior cervical spine plating is a standard procedure for fixing unstable vertebral fractures. Following surgery, oesophageal perforation has an incidence of 0.25% and this is usually hours following surgery, due to over prominent screws or friction between the oesophagus and the plate. Instrumentation failure of these plates months or years following surgery is very rare but potentially life-threatening. We report a case of microcytic anaemia which was investigated by oesophagogastroduodenoscopy, and subsequently found that a screw from the anterior plate had lifted off and perforated the oesophagus. This is very rare, but emphasises an important lesson. Anyone presenting with gastrointestinal bleeding or infectious signs, with a history of cervical spine plating should be investigated immediately for instrumentation failure as it brings a high mortality. PMID- 25796083 TI - Influences of Age and Emotion on Source Guessing: Are Older Adults More Likely to Show Fear-Relevant Illusory Correlations? AB - OBJECTIVES: The present study investigates age differences in the vulnerability to illusory correlations between fear-relevant stimuli and threatening information. METHOD: Younger and older adults saw pictures of threatening snakes and nonthreatening fish, paired with threatening and nonthreatening context information ("poisonous" and "nonpoisonous") with a null contingency between animal type and poisonousness. In a source monitoring test, participants were required to remember whether an animal was associated with poisonousness or nonpoisonousness. Illusory correlations were implicitly measured via a multinomial model. One advantage of this approach is that memory and guessing processes can be assessed independently. An illusory correlation would be reflected in a higher probability of guessing that a snake rather than a fish was poisonous if the poisonousness of the animal was not remembered. RESULTS: Older adults showed evidence of illusory correlations in source guessing while younger adults did not; instead they showed evidence of probability matching. Moreover, snake fear was associated with increased vulnerability to illusory correlations in older adults. DISCUSSION: The findings confirm that older adults are more susceptible to fear-relevant illusory correlations than younger adults. PMID- 25796084 TI - Genome-wide association study of rice (Oryza sativa L.) leaf traits with a high throughput leaf scorer. AB - Leaves are the plant's solar panel and food factory, and leaf traits are always key issues to investigate in plant research. Traditional methods for leaf trait measurement are time-consuming. In this work, an engineering prototype has been established for high-throughput leaf scoring (HLS) of a large number of Oryza sativa accessions. The mean absolute per cent of errors in traditional measurements versus HLS were below 5% for leaf number, area, shape, and colour. Moreover, HLS can measure up to 30 leaves per minute. To demonstrate the usefulness of HLS in dissecting the genetic bases of leaf traits, a genome-wide association study (GWAS) was performed for 29 leaf traits related to leaf size, shape, and colour at three growth stages using HLS on a panel of 533 rice accessions. Nine associated loci contained known leaf-related genes, such as Nal1 for controlling the leaf width. In addition, a total of 73, 123, and 177 new loci were detected for traits associated with leaf size, colour, and shape, respectively. In summary, after evaluating the performance with a large number of rice accessions, the combination of GWAS and high-throughput leaf phenotyping (HLS) has proven a valuable strategy to identify the genetic loci controlling rice leaf traits. PMID- 25796086 TI - Novel prognostic markers and treatment options in heart failure: from palliative to regenerative medicine. PMID- 25796085 TI - Combined transcript, proteome, and metabolite analysis of transgenic maize seeds engineered for enhanced carotenoid synthesis reveals pleotropic effects in core metabolism. AB - The aim of this study was to assess whether endosperm-specific carotenoid biosynthesis influenced core metabolic processes in maize embryo and endosperm and how global seed metabolism adapted to this expanded biosynthetic capacity. Although enhancement of carotenoid biosynthesis was targeted to the endosperm of maize kernels, a concurrent up-regulation of sterol and fatty acid biosynthesis in the embryo was measured. Targeted terpenoid analysis, and non-targeted metabolomic, proteomic, and transcriptomic profiling revealed changes especially in carbohydrate metabolism in the transgenic line. In-depth analysis of the data, including changes of metabolite pools and increased enzyme and transcript concentrations, gave a first insight into the metabolic variation precipitated by the higher up-stream metabolite demand by the extended biosynthesis capacities for terpenoids and fatty acids. An integrative model is put forward to explain the metabolic regulation for the increased provision of terpenoid and fatty acid precursors, particularly glyceraldehyde 3-phosphate and pyruvate or acetyl-CoA from imported fructose and glucose. The model was supported by higher activities of fructokinase, glucose 6-phosphate isomerase, and fructose 1,6-bisphosphate aldolase indicating a higher flux through the glycolytic pathway. Although pyruvate and acetyl-CoA utilization was higher in the engineered line, pyruvate kinase activity was lower. A sufficient provision of both metabolites may be supported by a by-pass in a reaction sequence involving phosphoenolpyruvate carboxylase, malate dehydrogenase, and malic enzyme. PMID- 25796088 TI - Rituximab for remission induction in elderly patients with ANCA-associated vasculitis. AB - OBJECTIVES: Advancing age is a risk factor for treatment-related side effects and mortality in AAV patients treated with cyclophosphamide (CYC) and glucocorticoids (GC) for remission induction. The efficacy and safety of rituximab (RTX) in elderly AAV patients has not been well described. METHODS: We performed a single center retrospective review of 31 consecutive AAV patients aged 60 or more at the time of RTX use for remission induction. All patients received RTX with GC for remission induction. Four patients received concomitant CYC for a mean duration of 52 days. We evaluated clinical and laboratory variables at diagnosis, rates of complete remission defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG) = 0 and patient survival, renal survival, infections requiring hospitalization, and vasculitis relapse 24 months following RTX use. RESULTS: Of the 31 patients, 77% were Caucasian, 68% female, mean age was 71 +/- 6 years, 58% were MPO ANCA positive, and 42% had relapsing disease. The mean BVAS/WG score entry was 4.4 +/- 1.5, 71% had glomerulonephritis (GN) and 10% had alveolar hemorrhage. The mean baseline e-GFR was 40 +/- 28ml/min/1.73m(2). Thirty patients achieved remission with a mean time to remission of 57 +/- 27 days. The single patient with refractory vasculitis responded to CYC. The mean prednisone dose at 6 months was 5.6 +/- 4mg. Remission maintenance therapy was started within 12 months of RTX induction in 6 patients (4 with RTX, 1 with azathioprine, and 1 with mycophenolate mofetil). One patient suffered a limited relapse 10 months post RTX use. Among the 22 patients with GN at baseline, 1 developed ESRD. One-year patient survival among 25 patients with at least 1 year of follow-up was 100%. There were no episodes of infusion reaction or leukopenia. There were 3 episodes of bacterial pneumonia, 1 episode of candida pneumonia, and 1 episode of disseminated cutaneous zoster. CONCLUSIONS: This study demonstrates that rituximab is effective for remission induction in elderly patients with AAV. Furthermore, we observed a high incidence of infectious complications. Our experience was limited by its retrospective design, and further studies are needed to evaluate the efficacy and safety of RTX in elderly AAV patients. PMID- 25796089 TI - Re-purposing of histological tissue sections for corroborative western blot analysis of hypothalamic metabolic neuropeptide expression following delineation of transactivated structures by Fos immuno-mapping. AB - Fos immunocytochemistry is a valuable anatomical mapping tool for distinguishing cells within complex tissues that undergo genomic activation, but it is seldom paired with corroborative molecular analytical techniques. Due to preparatory requirements that include protein cross-linking for specimen sectioning, histological tissue sections are regarded as unsuitable for those methods. Our studies show that pharmacological activation of the hindbrain energy sensor AMPK by AICAR elicits estradiol (E)-dependent patterns of Fos immunolabeling of hypothalamic metabolic loci. Here, Western blotting was applied to hypothalamic tissue removed from histological sections of E- versus oil (O)-implanted ovariectomized (OVX) female rat brain to measure levels of metabolic transmitters associated with Fos-positive structures. In both E and O rats, AICAR treatment elicited alterations in pro-opiomelanocortin, neuropeptide Y, SF-1, and orexin-A neuropeptide expression that coincided with patterns of Fos labeling of structures containing neurons that synthesize these neurotransmitters, e.g. arcuate and ventromedial nuclei and lateral hypothalamic area. O, but not E animals also exhibited parallel augmentation of tissue corticotropin-releasing hormone neuropeptide levels and paraventricular nucleus Fos staining. Data demonstrate the utility of immunoblot analysis as a follow-through technique to capitalize on Fos mapping of transactivation sites in the brain. Findings that induction of Fos immunoreactivity coincides with adjustments in hypothalamic metabolic neuropeptide expression affirms that this functional indicator reflects changes in neurotransmission in pathways governing metabolic outflow. PMID- 25796090 TI - Hypoglycemic activity of withanolides and elicitated Withania somnifera. AB - Withania somnifera, known in India as Asghawhanda, is used traditionally to treat many medical problems including diabetes and has demonstrated therapeutic activity in various animal models as well as in diabetic patients. While much of W. somnifera's therapeutic activity is attributed to withanolides, their role in the anti-diabetic activity of W. somnifera has not been adequately studied. In the present study, we evaluated the anti-diabetic activity of W. somnifera extract and purified withanolides, as well as the effect of various elicitors on this activity. W. somnifera leaf and root extracts increased glucose uptake in myotubes and adipocytes in a dose dependent manner, with the leaf extract more active than the root extract. Leaf but not root extract increased insulin secretion in basal pancreatic beta cells but not in stimulated cells. Six withanolides isolated from W. somnifera were tested for anti-diabetic activity based on glucose uptake in skeletal myotubes. Withaferin A was found to increase glucose uptake, with 10MUM producing a 54% increase compared with control, suggesting that withaferin A is at least partially responsible for W. somnifera's anti-diabetic activity. Elicitors applied to the root growing solutions affected the physiological state of the plants, altering membrane leakage or osmotic potential. Methyl salicylate and chitosan increased withaferin A content by 75% and 69% respectively, and extracts from elicited plants increased glucose uptake to a higher extent than non-elicited plants, demonstrating a correlation between increased content of withaferin A and anti-diabetic activity. PMID- 25796091 TI - Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest. AB - PURPOSE: How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects. MATERIALS AND METHODS: We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model. RESULTS: When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition. CONCLUSION: For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation. PMID- 25796092 TI - Gross tumor volume and clinical target volume in prostate cancer: How do satellites relate to the index lesion. AB - PURPOSE: There is an increasing interest for dose differentiation in prostate radiotherapy. The purpose of our study was to analyze the spatial distribution of tumor satellites inside the prostate. METHODS AND MATERIALS: 61 prostatectomy specimens were stained with H&E. Tumor regions were delineated by the uro pathologist. Volumes, distances and cell densities of all delineated tumor regions were measured and further analyzed. RESULTS: Multifocal disease was seen in 84% of the patients. The median number of tumor foci was 3. The median distance between the index lesion and the satellites was 1.0 cm, with a maximum of 4.4 cm. The index lesions accounted for 88% of the total tumor volume. The contribution of tumor foci<0.1 cm(3) to the total tumor volume was 2%. The median cell density of the index lesion and all satellites, regardless of size, were significantly higher than that of the prostate. CONCLUSIONS: Satellites do not appear in a limited margin around the index lesion (GTV). Consequently, a fixed CTV margin would not effectively cover all satellites. Thus if the aim is to treat all tumor foci, the entire prostate gland should be considered CTV. PMID- 25796093 TI - A theoretical model of biochemical control engineering based on the relation between oestrogens/progestagens and prostaglandins. AB - A biological complex organism is involuntarily guided from all sides by measure and regulation systems. The human being is such a complex organism. Many cyclical processes are simultaneously at work, making it unclear how and why which process takes place at which moment. Noticeable examples are the 28-day menstrual cycle and the 40-week pregnancy. The time of activation in the middle of the menstrual is fairly clear. Hormonal changes also occur in this period. Why the hormonal changes occur, and what their relationship is with the activation of the processes is unclear. That is also the case during pregnancies. What is it that determines that a pregnancy should last an average of 40 weeks? What causes the changes in a complicated pregnancy? What are those changes? Prostaglandin concentrations have been found to have some relationship with these changes, but the activation of these changes and how to examine them is unknown. Using an example from practical experience, this article illustrates what Horrobin and Manku already reported in 1977, namely, the properties of prostaglandin E1 and 6 keto pgF1alpha: reversal effect with elevated concentration. The properties described is exceptionally suitable for the time of activation in a biochemically regulated measure and regulation system. These properties can help explain the occurrence of physiological cycles. The known electronic saw-tooth wave has a biochemical analogue with this. This paper describes the presumed relationship between hormones and the accompanying prostaglandins with the hormone effects based on what is known regarding their concentrations progress. This relationship reveals the practical consequences of the experimentally found sensitivity of biochemical effects with regard to the accompanying prostaglandins. This paper shows how the theoretical relationship between effects of oestrogens and progestagens result in a curve that comprise observable aspects of the Basal Body Temperature Curve. The modulating and activating prostaglandins also affect local changes in blood circulation. These changes are visible on specific sites on the abdominal skin via viscerocutaneous reflex pathways. Changes in blood circulation at specific areas of the skin can be representative of pain. Pain that also frequently arises during activation processes. These changes can be seen and measured with non-contactual infrared thermography on the cutaneous surface, and moments of activation and pain can be determined. PMID- 25796094 TI - Effects of isoflurane and sevoflurane on the neutrophil myeloperoxidase system of horses. AB - Volatile anaesthestics have shown to modulate the oxidative response of polymorphonuclear neutrophils (PMNs). We investigated the effects of isoflurane and sevoflurane on the degranulation of total and active myeloperoxidase (MPO) from horse PMNs and their direct interaction with MPO activity. Whole blood from horse was incubated in 1 and 2 minimal alveolar concentrations (MAC) of isoflurane or sevoflurane for 1h and PMNs were stimulated with cytochalasin B (CB) plus N-formyl-methionyl-leucyl-phenylalanine (fMLP). After stimulation, the plasma was collected to measure total and active MPO by enzyme-linked immunosorbent assay (ELISA) and specific immunological extraction followed by enzymatic detection (SIEFED) respectively. The effects of 1 and 2 MAC of isoflurane and sevoflurane on the peroxidase and chlorination activity of pure MPO were assessed by fluorescence using Amplex red and 3'-(p-aminophenyl) fluorescein (APF) respectively and in parallel with a SIEFED assay to estimate the potential interaction of the anaesthetics with the enzyme. Although isoflurane and sevoflurane had inconsistent effects on total MPO release, both volatile agents reduced active MPO release and showed a direct inhibition on the peroxidase and the chlorination activity of the enzyme. A persistent interaction between MPO and anaesthetics was evidenced with isoflurane but not with sevoflurane. PMID- 25796095 TI - Optimizing bowel preparation for colonoscopy: what are the predictors of an inadequate preparation? AB - BACKGROUND: This retrospective study evaluates factors that are associated with an inadequate bowel preparation. METHODS: A chart review was performed on 2,101 patients who underwent colonoscopy. The quality of preparation was classified as adequate or inadequate. Univariate and multivariate regression analyses identified factors associated with inadequate preparations. RESULTS: A total of 91.5% of preparations were adequate. Standard preparations using polyethylene glycol-electrolyte solution and sodium picosulfate alone were 91.1% adequate. Regimens with adjuncts were 91.9% adequate. Factors that predicted an inadequate preparation include the following: stroke/dementia (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.6 to 7.7, P = .002), opioids (OR 2.3, 95% CI 1.1 to 4.6, P = .02), male sex (OR 2.0, 95% CI 1.4 to 2.9, P = .000), calcium channel blockers (OR 1.9, 95% CI 1.1 to 3.3, P = .03), and antidepressants (OR 1.7, 95% CI 1.1 to 2.7, P = .02). CONCLUSIONS: Several factors are associated with inadequate preparations. Adjuncts do not improve preparation quality. The effect of patient education on preparation quality is an area for further research. PMID- 25796096 TI - Axillary reverse lymphatic mapping reduces patient perceived incidence of lymphedema after axillary dissection in breast cancer. AB - BACKGROUND: Lymphedema is a feared complication of many patients following axillary lymph node dissection for breast cancer. Axillary reverse lymphatic mapping (ARM) was adopted to decrease the incidence of lymphedema. METHODS: A retrospective review was conducted on 139 patients with breast cancer who had greater than 10 lymph nodes removed. A survey was sent to patients to identify those with lymphedema. RESULTS: One hundred nine women were contacted via mail survey to determine the presence of lymphedema. Of the 46 surveys returned, the incidence of lymphedema was 39%. Twenty-seven percent of the ARM group identified themselves as having lymphedema compared with 50% in non-ARM group. Eighteen percent of women in the ARM group needed an arm sleeve for treatment compared with 45.8% in the non-ARM group. CONCLUSIONS: The incidence of perceived lymphedema and the need for arm compression sleeve devices were lower in the ARM cohort. ARM should be adopted to decrease patient perception of lymphedema. PMID- 25796097 TI - RNA interference tools for the western flower thrips, Frankliniella occidentalis. AB - The insect order Thysanoptera is exclusively comprised of small insects commonly known as thrips. The western flower thrips, Frankliniella occidentalis, is an economically important pest amongst thysanopterans due to extensive feeding damage and tospovirus transmission to hundreds of plant species worldwide. Geographically-distinct populations of F. occidentalis have developed resistance against many types of traditional chemical insecticides, and as such, management of thrips and tospoviruses are a persistent challenge in agriculture. Molecular methods for defining the role(s) of specific genes in thrips-tospovirus interactions and for assessing their potential as gene targets in thrips management strategies is currently lacking. The goal of this work was to develop an RNA interference (RNAi) tool that enables functional genomic assays and to evaluate RNAi for its potential as a biologically-based approach for controlling F. occidentalis. Using a microinjection system, we delivered double-stranded RNA (dsRNA) directly to the hemocoel of female thrips to target the vacuolar ATP synthase subunit B (V-ATPase-B) gene of F. occidentalis. Gene expression analysis using real-time quantitative reverse transcriptase-PCR (qRT-PCR) revealed significant reductions of V-ATPase-B transcripts at 2 and 3 days post-injection (dpi) with dsRNA of V-ATPase-B compared to injection with dsRNA of GFP. Furthermore, the effect of knockdown of the V-ATPase-B gene in females at these two time points was mirrored by the decreased abundance of V-ATPase-B protein as determined by quantitative analysis of Western blots. Reduction in V-ATPase-B expression in thrips resulted in increased female mortality and reduced fertility, i.e., number of viable offspring produced. Survivorship decreased significantly by six dpi compared to the dsRNA-GFP control group, which continued decreasing significantly until the end of the bioassay. Surviving female thrips injected with dsRNA-V-ATPase-B produced significantly fewer offspring compared to those in the dsRNA-GFP control group. Our findings indicate that an RNAi-based strategy to study gene function in thrips is feasible, can result in quantifiable phenotypes, and provides a much-needed tool for investigating the molecular mechanisms of thrips-tospovirus interactions. To our knowledge, this represents the first report of RNAi for any member of the insect order Thysanoptera and demonstrates the potential for translational research in the area of thrips pest control. PMID- 25796098 TI - Accuracy and reliability of Chile's National Air Quality Information System for measuring particulate matter: Beta attenuation monitoring issue. AB - A critical analysis of Chile's National Air Quality Information System (NAQIS) is presented, focusing on particulate matter (PM) measurement. This paper examines the complexity, availability and reliability of monitoring station information, the implementation of control systems, the quality assurance protocols of the monitoring station data and the reliability of the measurement systems in areas highly polluted by particulate matter. From information available on the NAQIS website, it is possible to confirm that the PM2.5 (PM10) data available on the site correspond to 30.8% (69.2%) of the total information available from the monitoring stations. There is a lack of information regarding the measurement systems used to quantify air pollutants, most of the available data registers contain gaps, almost all of the information is categorized as "preliminary information" and neither standard operating procedures (operational and validation) nor assurance audits or quality control of the measurements are reported. In contrast, events that cause saturation of the monitoring detectors located in northern and southern Chile have been observed using beta attenuation monitoring. In these cases, it can only be concluded that the PM content is equal to or greater than the saturation concentration registered by the monitors and that the air quality indexes obtained from these measurements are underestimated. This occurrence has been observed in 12 (20) public and private stations where PM2.5 (PM10) is measured. The shortcomings of the NAQIS data have important repercussions for the conclusions obtained from the data and for how the data are used. However, these issues represent opportunities for improving the system to widen its use, incorporate comparison protocols between equipment, install new stations and standardize the control system and quality assurance. PMID- 25796099 TI - Are the QRS duration and ST depression cut-points from the Seattle criteria too conservative? AB - BACKGROUND: Screening athletes with ECGs is aimed at identifying "at-risk" individuals who may have a cardiac condition predisposing them to sudden cardiac death. The Seattle criteria highlight QRS duration greater than 140 ms and ST segment depression in two or more leads greater than 50 MUV as two abnormal ECG patterns associated with sudden cardiac death. METHODS: High school, college, and professional athletes underwent 12 lead ECGs as part of routine pre-participation physicals. Prevalence of prolonged QRS duration was measured using cut-points of 120, 125, 130, and 140 ms. ST segment depression was measured in all leads except leads III, aVR, and V1 with cut-points of 25 MUV and 50 MUV. RESULTS: Between June 2010 and November 2013, 1595 participants including 297 (167 male, mean age 16.2) high school athletes, 1016 (541 male, mean age 18.8) college athletes, and 282 (mean age 26.6) male professional athletes underwent screening with an ECG. Only 3 athletes (0.2%) had a QRS duration greater than 125 ms. ST segment depression in two or more leads greater than 50 MUV was uncommon (0.8%), while the prevalence of ST segment depression in two or more leads increased to 4.5% with a cut-point of 25 MUV. CONCLUSION: Changing the QRS duration cut-point to 125 ms would increase the sensitivity of the screening ECG, without a significant increase in false-positives. However, changing the ST segment depression cut point to 25 MUV would lead to a significant increase in false-positives and would therefore not be justified. PMID- 25796100 TI - Simultaneous pulmonary vein cryoablation and cavotricuspid isthmus radiofrequency ablation in patients with combined atrial fibrillation and typical atrial flutter. AB - Pulmonary vein isolation (PVI) using cryoballoon (CB) technique and cavotricuspid isthmus (CTI) ablation using radiofrequency (RF) are established interventions for drug-resistant atrial fibrillation (AF) and typical atrial flutter (AFL). Twelve patients with a mean age of 62 +/- 12 years underwent simultaneous delivery of RF energy at the CTI during CB applications at the PV ostia. Pulmonary vein isolation was achieved in all PVs and sustained bidirectional CTI conduction block obtained in all patients. The reported ablation protocol of combined paroxysmal AF and typical AFL did not result in prolongation of the procedure duration or in prolonged radiation exposure when compared to CB-PVI alone. No interferences between both ablation energy systems were observed. These preliminary results suggest that combined paroxysmal AF and typical AFL can be successfully and safely ablated using hybrid energy sources with simultaneous CTI ablation using RF during CB applications at the PV ostia. PMID- 25796101 TI - Clinical significance of J-wave in elite athletes. AB - The J-wave pattern on 12-lead ECG is traditionally defined as a positive deflection at junction between the end of the QRS and the beginning of the ST segment. This pattern has recently been associated with increased risk for idiopathic ventricular fibrillation in the absence of cardiovascular disease. The interest for the clinical significance of J-wave pattern as a potential ECG hallmark of high risk for cardiac arrest has recently been reinforced by the growing practice of ECG screening, such as occurs in large population of young competitive athletes. The available scientific evidence shows that the J-wave pattern is relatively common in trained athletes (ranging from 14% to 44%) and, differently from subjects who suffered from ventricular fibrillation, commonly localized in lateral leads while it is relatively rare to be found in inferior leads. Furthermore the J-wave pattern has been demonstrated to be a dynamic phenomenon related to the training status, with the larger prominence at the peak of training and with an inverse relation between magnitude of J-wave and heart rate. In addition the J-wave pattern is usually associated with other ECG changes, such as increased QRS voltages and ST-segment elevation, as well as LV remodeling, suggesting that it likely represents another expression of the physiologic athlete's heart. Finally the scientific data available demonstrated that during a medium follow-up period the J-wave pattern does not convey risk for adverse cardiac events, including sudden death or ventricular tachyarrhythmias. PMID- 25796102 TI - Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk. AB - INTRODUCTION: The electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation. METHODS AND RESULTS: We assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 +/- 10 vs. 28 +/- 9 ms/MUg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39 +/- 13 vs. 32 +/- 13 ms/MUg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 +/- 18 vs. 43 +/- 19 ms/MUg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61 +/- 22 vs. 55 +/- 21 ms/MUg/ml, p=0.49). CONCLUSIONS: Women do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation. PMID- 25796104 TI - Is the skeleton still in the hospital closet? A review of hospital malnutrition emphasizing health economic aspects. AB - BACKGROUND: Hospital malnutrition used to be a skeleton, a well hidden secret. Compelling studies in the last four decades revealed the width and depth of the problem. It encompasses not only critically ill hospitalized individuals, but many other vulnerable groups. The aim of this review was to assess the effectiveness of current hospital routines in eradicating this historical scourge. METHODS: Diagnosis used to rely on clinical impression or anthropometrics only. Fortunately well structured questionnaires, complemented by biochemical tests and body composition studies whenever necessary, allow precise and reproducible assessment of nutritional risk, in most age brackets and disease modalities. RESULTS: Near the end of the XIXth century many scientists believed that anatomical studies were doomed. Everything that needed to be discovered was already known: muscles, bones, joints, nerves, cardiovascular structures and other systems. Then in 1893, Wilhelm His in Switzerland discovered the eponimous His bundle. In 1906 Sunao Tawara in Japan was responsible for the concept of the atrioventricular conduction pathway. Combined with the advent of the electrocardiograph by Willem Einthoven in The Netherlands, in 1903, such advances extraordinarily improved the handling of heart arrhythmias. Addressing hospital malnutrition does not depend on new technologies. All the essential tools exist and have been clinically tested, as here analyzed. A simpler breakthrough is desired, namely the wider adoption of available procedures. CONCLUSION: Four decades after a historical report, a barrier still remains in many countries, namely more effectively embedding screening and nutritional therapy tools for hospitalized patients, in the professional routine. PMID- 25796103 TI - The effect of protein intake and resistance training on muscle mass in acutely ill old medical patients - A randomized controlled trial. AB - BACKGROUND & AIM: Stress metabolism is associated with accelerated loss of muscle that has large consequences for the old medical patient. The aim of this study was to investigate if an intervention combining protein and resistance training was more effective in counteracting loss of muscle than standard care. Secondary outcomes were changes in muscle strength, functional ability and body weight. METHODS: 29 acutely admitted old (>65 years) patients were randomly assigned to the intervention (n = 14) or to standard care (n = 15). The Intervention Group received 1.7 g protein/kg/day during admission and a daily protein supplement (18.8 g protein) and resistance training 3 times per week the 12 weeks following discharge. Muscle mass was assessed by Dual-energy X-ray Absorptiometry. Muscle strength was assessed by Hand Grip Strength and Chair Stand Test. Functional ability was assessed by the de Morton Mobility Index, the Functional Recovery Score and the New Mobility Score. Changes in outcomes from time of admission to three-months after discharge were analysed by linear regression analysis. RESULTS: The intention-to-treat analysis showed no significant effect of the intervention on lean mass (unadjusted: beta-coefficient = -1.28 P = 0.32, adjusted for gender: beta-coefficient = -0.02 P = 0.99, adjusted for baseline lean mass: beta-coefficient = -0.31 P = 0.80). The de Morton Mobility Index significantly increased in the Control Group (beta-coefficient = -11.43 CI: 0.72 22.13, P = 0.04). No other differences were found. CONCLUSION: No significant effect on muscle mass was observed in this group of acutely ill old medical patients. High compliance was achieved with the dietary intervention, but resistance training was challenging. Clinical trials identifier NCT02077491. PMID- 25796105 TI - Protein tyrosine kinase 7: a hepatocellular carcinoma-related gene detected by triple-combination array. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. We developed a novel technique to identify cancer-related genes of HCC as follows: triple-combination array analysis, which combines gene expression profiles, single nucleotide polymorphism arrays, and methylation arrays. MATERIALS AND METHODS: Triple-combination array analysis was performed on one HCC sample from a 68-y-old female patient, and one candidate cancer-related gene was selected. Subsequently, we analyzed the identified gene by quantitative real-time reverse-transcriptase polymerase chain reaction (PCR) and methylation-specific PCR in nine HCC cell lines and in samples from 48 HCC patients. Additionally, we evaluated gene expression by immunohistochemistry and Western blotting. RESULTS: Using this method, protein tyrosine kinase 7 (PTK7) was detected as a candidate cancer-related gene. PTK7 was revealed to be hypermethylated (methylation value 0.826, range 0-1.0) in cancer tissue, compared with that of adjacent noncancerous tissues (0.047) by methylation array. Of the 48 clinical samples, 30 HCC samples (62.5%) showed PTK7 promoter hypermethylation. Downregulation of PTK7 (expressions in tumor tissues decreased by >= 50% compared with the noncancerous tissues) was significantly associated with age >60 y (P = 0.030) and elevation in serum protein induced by vitamin K absence or antagonists-II (P = 0.033). Moreover, patients with downregulation were significantly inferior in overall survival (P < 0.001) than the others. CONCLUSIONS: Our data imply that PTK7 acts as a cancer-related gene and may be a potent prognostic marker for HCC. Triple-combination array analysis was once again found to be useful in identifying cancer-related genes. PMID- 25796106 TI - Cost-utility analysis of negative pressure wound therapy in high-risk cesarean section wounds. AB - BACKGROUND: Obese women undergoing cesarean section are at increased risk of postoperative infection. There is growing interest in negative pressure wound therapy (NPWT) to prevent closed surgical incision complications including surgical site infection; however, the evidence on the effectiveness and cost effectiveness of this technology is limited. The objective of this study was to evaluate the cost-effectiveness of NPWT compared with that of standard dressing in preventing surgical site infection in obese women undergoing elective cesarean section based on current evidence and to estimate the value and optimal design of additional research to study this technology. METHODS: The analysis was from the perspective of Queensland Health, Australia, using a decision model. Parameters were obtained from the published literature, a pilot clinical trial, and expert opinion. Monte Carlo simulation was performed to calculate the net monetary benefit, characterize decision uncertainty, and estimate the value of additional research. Comparing the expected monetary benefits and costs of alternative trial sample sizes informed the optimal future study design. RESULTS: The incremental net monetary benefit of NPWT was Australian dollars 70, indicating that NPWT is cost-effective compared with that of standard dressing. The probability of NPWT being cost-effective was 65%. The estimated value of additional research to resolve decision uncertainty would be Australian dollars 2.7 million. The optimal sample size of a future trial investigating the relative effectiveness of NPWT would be 200 patients per arm. CONCLUSIONS: Based on the current evidence, NPWT is cost-effective; however, there is high uncertainty surrounding the decision to adopt this technology. Additional research is worthwhile before implementation. PMID- 25796107 TI - Patient satisfaction: does surgical volume matter? AB - BACKGROUND: Patient satisfaction is an increasing area of interest due to implications of pay for performance and public reporting of results. Although scores are adjusted for patient factors, little is known about the relationship between hospital structure, postoperative outcomes, and patient satisfaction with the hospital experience. METHODS: Hospitals participating in the University HealthSystem Consortium database from 2011-2012 were included. Patients were restricted to those discharged by general surgeons to isolate surgical patients. Hospital data were paired with Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) results from the Hospital Compare website. Postoperative outcomes were dichotomized based on the median for all hospitals and stratified based on surgical volume. The primary outcome of interest was high on overall patient satisfaction, whereas other HCAHPS domains were assessed as secondary outcomes. Chi square and binary logistic regression analyses were performed to evaluate whether postoperative outcomes or surgical volume more significantly influenced high patient satisfaction. RESULTS: The study population consisted of 171 hospitals from the University HealthSystem Consortium database. High surgical volume was a more important predictor of overall patient satisfaction regardless of hospital complication (P < 0.001), readmission (P < 0.001), or mortality rates (P = 0.009). Volume was found to play less of a role in predicting high satisfaction on the other HCAHPS domains. Postoperative outcomes were more predictive of high satisfaction with providers, the hospital experience, and environment. CONCLUSIONS: High surgical volume more strongly predicted overall patient satisfaction on the HCAHPS survey than postoperative outcomes, whereas volume was less predictive in other HCAHPS domains. Patients may require more specific questioning to identify high quality, safe hospitals. PMID- 25796108 TI - Pediatric vascular injury: experience of a level 1 trauma center. AB - BACKGROUND: Our purpose was to analyze modern major vascular injury (MVI) patterns in pediatric trauma, interventions performed, and outcomes at a level 1 trauma center. MATERIALS AND METHODS: From January 2000-December 2012, all pediatric admissions (<=17 y) were reviewed. RESULTS: Of 1928 pediatric admissions, 103 (5.3%) sustained MVI. This cohort was 85% male, age 15 +/- 3 y, 55% black, 58% penetrating, injury severity score of 23 +/- 15, with a length of stay of 8 (5) days. Firearm-related injury (47%) was the most common mechanism. Location of injuries included the extremities (50.5%), abdomen/pelvis (29.1%), and chest/neck (20.4%). Operative procedures included repair/bypass (71.4%), ligation (12.4%), amputation (10.5%), or temporary shunt (2.9%). Only three injuries (2.9%) were treated endovascularly. MVI patients had a mortality rate of 19.4%, higher than the overall pediatric trauma population of 3.5% (P < 0.001). After logistic regression, independent risk factors of mortality were vascular injury to the neck (odds ratio [OR]: 6.5; confidence interval (CI): 1.1-39.3), abdomen/pelvis (OR: 16.3; CI: 3.13-80.2), and chest (OR: 49.0; CI: 3.0-794.5). CONCLUSIONS: MVI in children more commonly results from firearm-related injury. The mortality rate associated with MVI is profoundly higher than that of the overall pediatric trauma population. These findings underscore the major public health concern of firearm-related injury in children. PMID- 25796109 TI - A CD52 antibody impairs mouse-transplanted intestinal tight junctions. AB - BACKGROUND: Induction immunosuppression strategies using a CD52 monoclonal antibody (mAb) have been introduced for small bowel transplantation, resulting in improved outcomes. However, little information is known about the effects of the antibody on the microstructure of the intestinal barrier, which functions to prevent bacterial translocation. In this study, we used a murine orthotopic small bowel transplantation model to investigate the impact of a CD52 mAb on tight junctions (TJs), which are considered a central part of the intestinal barrier, of the transplanted intestine. MATERIALS AND METHODS: C57BL/6 mice were used as recipients. The grafts were harvested from BALB/c mice in allogeneic groups and C57BL/6 mice in syngeneic groups. The anti-mouse CD52 mAb was applied as a surrogate antibody. Transmission electron microscopy was used to evaluate the TJ ultrastructure. The expression of the TJ proteins occludin and ZO-1 was analyzed by Western blot. The distribution of TJ proteins was observed by immunofluorescence, and the permeability of the transplanted intestine was assessed in vivo using FITC-dextran. RESULTS: After CD52 mAb application, a compromised TJ ultrastructure was observed. In addition, TJ protein expression (occludin and ZO-1) decreased and the intestinal permeability increased. CONCLUSIONS: The anti-mouse CD52 mAb impaired the transplanted intestinal TJ and barrier. PMID- 25796111 TI - Flexible ureteroscopic management of symptomatic renal cystic diseases. AB - BACKGROUND: Parapelvic renal cysts are more likely to be symptomatic compared with that of simple peripheral renal cysts, and their treatment remains challenging. This study aimed to assess the feasibility and safety of flexible ureteroscopy in managing symptomatic endogenous renal cystic diseases. MATERIALS AND METHODS: Thirty-five patients with symptomatic endogenous renal cystic diseases were treated by ureteroscopic unroofing and drainage into the collecting system. Surgical procedure, patient's outcome, and postoperative complications were retrospectively evaluated. RESULTS: Ureteroscopic unroofing and drainage were successful in 35 patients without conversion to open surgery. For patients with successful surgery, the mean operation and hospitalization times were 25.38 +/- 3.71 min and 3.01 +/- 0.57 d, respectively, with a curative standard rate of 74.3% (26/35). Three patients experienced Clavien grade I and II complications but no serious perioperative complications occurred. During the follow-up period averaging 36 mo, no cysts were detected in 74.3% of patients (26/35); noticeable relief was observed in four patients showing a simple renal cyst (diameter <2 cm). In five patients who presented with polycystic kidneys, the renal volume was decreased by 93.76 +/- 7.38 mL per side, on average, compared with pretreatment values. Pain was relieved in all 30 patients with renal cysts. Hydronephrosis disappeared in all 15 patients diagnosed with this condition at presentation. No secondary cyst lesions (such as infection, hematoma formation, and solid cystic changes) occurred. CONCLUSIONS: The transurethral flexible ureteroscopic incision and drainage for symptomatic endogenous renal cystic diseases has multiple advantages such as minimal trauma, rapid recovery, and a definite curative effect. PMID- 25796110 TI - Possible role of pannexin 1/P2x7 purinoceptor in neuroprotective mechanism of ischemic postconditioning in mice. AB - BACKGROUND: Previous studies have suggested a significant role of pannexin 1 (Panx1)/P2X7 receptor complex in cardioprotective mechanism of ischemic preconditioning and postconditioning (IPC). The present study has been undertaken to investigate whether Panx1/P2X7 purinoceptors are also involved in the neuroprotective mechanism of IPC in mice. MATERIALS AND METHODS: Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce ischemia-reperfusion-induced cerebral injury in Swiss albino mice. For IPC immediately after BCAO of 12 min, three cycles of 10-s ischemia and reperfusion each were given and then prolonged reperfusion of 24 h was used. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam walking test, and neurologic severity score (NSS) were used to assess motor dysfunction. Acetylcholine esterase levels, brain thiobarbituric acid reactive species, and glutathione level were also estimated. RESULTS: BCAO followed by reperfusion produced a significant increase in cerebral infarct size, NSS along with impairment of memory and motor dysfunction. It also increased brain acetylcholine esterase, thiobarbituric acid reactive species levels, and decreased the glutathione level. IPC produced a significant decrease in the cerebral infarct size and NSS along with reversal of ischemia-reperfusion-induced impairment of memory, motor dysfunction, and altered biochemical levels in the brain. IPC-induced neuroprotective effects were significantly abolished by pretreatment of mefloquine (15.0 mg/kg orally; 30.0 mg/kg orally), blocker of Panx1/P2X7 purinoceptor. CONCLUSIONS: Therefore, activation of Panx1/P2X7 purinoceptors appears to play a significant role in the neuroprotective mechanism of IPC. PMID- 25796112 TI - Vessel ligation training via an adaptive simulation curriculum. AB - BACKGROUND: A cost-effective model for open vessel ligation is currently lacking. We hypothesized that a novel, inexpensive vessel ligation simulator can efficiently impart transferrable surgical skills to novice trainees. MATERIALS AND METHODS: VesselBox was designed to simulate vessel ligation using surgical gloves as surrogate vessels. Fourth-year medical students performed ligations using VesselBox and were evaluated by surgical faculty using the Objective Structured Assessments of Technical Skills global rating scale and a task specific checklist. Subsequently, each student was trained using VesselBox in an adaptive practice session guided by cumulative sum. Posttesting was performed on fresh human cadavers by evaluators blinded to pretest results. RESULTS: Sixteen students completed the study. VesselBox practice sessions averaged 21.8 min per participant (interquartile range 19.5-27.7). Blinded posttests demonstrated increased proficiency, as measured by both Objective Structured Assessments of Technical Skills (3.23 versus 2.29, P < 0.001) and checklist metrics (7.33 versus 4.83, P < 0.001). Median speed improved from 128.2 s to 97.5 s per vessel ligated (P = 0.001). After this adaptive training protocol, practice volume was not associated with posttest performance. CONCLUSIONS: VesselBox is a cost-effective, low-fidelity vessel ligation model suitable for graduating medical students and junior residents. Cumulative sum can facilitate an adaptive, individualized curriculum for simulation training. PMID- 25796113 TI - Increased Expression of Androgen Receptor mRNA in Human Renal Cell Carcinoma Cells is Associated with Poor Prognosis in Patients with Localized Renal Cell Carcinoma. AB - PURPOSE: The role of androgen receptor in renal cell carcinoma is not well understood. In this study the correlation between androgen receptor mRNA expression and clinicopathological features in patients with localized renal cell carcinoma was investigated. Additionally, human renal cell carcinoma cell lines were examined for the presence and effect of androgen receptor. MATERIALS AND METHODS: Androgen receptor mRNA expression was evaluated by quantitative real time polymerase chain reaction in 115 tumor samples from patients with primary pathological stage T1 or T2 (pT1/pT2) renal cell carcinoma and 57 specimens of corresponding normal kidney tissue. Reverse transcriptase-polymerase chain reaction and Western blot were done to examine the expression of androgen receptor in human renal cell carcinoma cell lines. Effects on cellular proliferation were investigated after activating and blocking androgen signaling in tissue culture. RESULTS: Androgen receptor mRNA expression levels were significantly higher in patients with pT2 tumors than in those with pT1 tumors (p = 0.011). Kaplan-Meier estimates revealed significant differences in time to progression and cancer specific survival between low and high androgen receptor mRNA expression groups regardless of gender. Multivariate Cox regression analysis demonstrated that the level of androgen receptor expression was an independent predictor of cancer specific survival (HR 15.546, 95% CI 1.320-183.131, p = 0.029). In tissue culture treatment with dihydrotestosterone caused proliferation in androgen receptor positive cell lines while enzalutamide resulted in reduced cell viability in a dose dependent manner. CONCLUSIONS: In patients with localized renal cell carcinoma the androgen receptor mRNA expression level is associated with prognosis. In addition, cell culture data suggest that enzalutamide may have an effect in limiting the growth of androgen receptor positive renal cell carcinoma. PMID- 25796114 TI - The Efficacy of Postoperative Adjuvant Chemotherapy for Patients with pT3N0M0 Upper Tract Urothelial Carcinoma. AB - PURPOSE: Nephroureterectomy with bladder cuff excision may not be sufficient as monotherapy for patients with pT3N0M0 upper tract urothelial carcinoma. The efficacy of postoperative adjuvant chemotherapy in this setting remains controversial. We evaluated the efficacy of adjuvant chemotherapy for patients with pT3N0M0 upper tract urothelial carcinoma in overall, cancer specific and recurrence-free survival. MATERIALS AND METHODS: We retrospectively reviewed records on 171 consecutive patients with pT3N0M0 upper tract urothelial carcinoma treated with radical nephroureterectomy between 2004 and 2014 at 2 branches of the same institution. Postoperative adjuvant chemotherapy was gemcitabine/cisplatin or cisplatin/fluorouracil/leucovorin. Overall, cancer specific and recurrence-free survival rates were estimated using the Kaplan-Meier method. The values of prognostic factors were evaluated by Cox regression analysis. RESULTS: Postoperative adjuvant chemotherapy was administered in 60 patients vs nonadjuvant therapy in 111 patients. Median followup was 35.8 months. Between the adjuvant and nonadjuvant treatment groups there were statistically significant differences in 5-year cancer specific (80.5% vs 57.6%, p = 0.010) and recurrence-free (74.4% vs 52.9%, p = 0.026) survival rates. Although there was no statistically significant difference in overall survival (71.9% vs 49.0%, p = 0.072), there was a trend of better overall survival in the patients who received postoperative chemotherapy. On multivariable analysis age (p = 0.018), tumor location (p = 0.003) and adjuvant chemotherapy (p = 0.001) were predictors of cancer specific survival. CONCLUSIONS: Adjuvant chemotherapy improves cancer specific and recurrence-free survival in patients with pT3N0M0 upper tract urothelial carcinoma after radical nephroureterectomy. PMID- 25796115 TI - Anatomical Targeting Improves Delivery of Unconjugated Nanoparticles to the Testicle. AB - PURPOSE: Nanoparticles, which are submicroscopic particles typically ranging from 100 to 300 nm, are interesting as potential treatment of testicular disorders because they can be engineered to allow delivery to privileged tissues, such as across the blood-brain barrier or theoretically the blood-testis barrier. We compared the effects of anatomical and/or ligand targeting on testicular nanoparticle uptake in a rat model. MATERIALS AND METHODS: A total of 48 rats were divided into 6 groups, including a control group and groups that received intra-arterial injection of unconjugated nanoparticles with and without saline flush, intravenous injection of unconjugated nanoparticles, intra-arterial injection of follicle stimulating hormone conjugated nanoparticles, intravenous injection of follicle stimulating hormone conjugated nanoparticles and intra arterial injection of transactivating transcriptor conjugated nanoparticles. A dose response curve was assessed for intra-arterially injected unconjugated nanoparticles. Using high performance liquid chromatography and histological analysis we determined nanoparticle uptake by the testicle at 4 hours. RESULTS: Intra-arterial injection resulted in a 5.8-fold increase in uptake compared to intravenous injection at 35 mg/kg of unconjugated nanoparticles (3.7 vs 0.6 MUg nanoparticles per gm testicle, p = 0.04). Anatomical targeting failed to improve testicular uptake in FSH conjugated nanoparticles (intra-arterial vs intravenous injection 0.33 vs 0.38 MUg FSH nanoparticles per gm testicular tissue, p = 0.73). On fluorescence microscopy nanoparticles were noted in the testicular interstitium and seminiferous tubules, and absent from the testicular vasculature. CONCLUSIONS: Arterial injection for anatomical targeting of nanoparticles to the testis is feasible, improves unconjugated nanoparticle delivery to testicular tissue and enables nanoparticles to cross the gonadal vascular endothelium and the blood-testis barrier. PMID- 25796116 TI - Changing roles of population-based cancer registries in Australia. AB - Registries have key roles in cancer incidence, mortality and survival monitoring and in showing disparities across the population. Incidence monitoring began in New South Wales in 1972 and other jurisdictions soon followed. Registry data are used to evaluate outcomes of preventive, screening, treatment and support services. They have shown decreases in cancer incidence following interventions and have been used for workforce and other infrastructure planning. Crude markers of optimal radiotherapy and chemotherapy exist and registry data are used to show shortfalls against these markers. The data are also used to investigate cancer clusters and environmental concerns. Survival data are used to assess service performance and interval cancer data are used in screening accreditation. Registries enable determination of risk of multiple primary cancers. Clinical quality registries are used for clinical quality improvement. Population-based cancer registries and linked administrative data complement clinical registries by providing high-level system-wide data. The USA Commission on Cancer has long used registries for quality assurance and service accreditation. Increasingly population-based registry data in Australia are linked with administrative data on service delivery to assess system performance. Addition oftumour stage and otherprognostic indicators is important forthese analyses and is facilitated by the roll-out of structured pathology reporting. Data linkage with administrative data, following checks on the quality of these data, enables assessment of patterns of care and other performance indicators for health-system monitoring. Australian cancer registries have evolved and increasingly are contributing to broader information networks for health system management. PMID- 25796117 TI - Impact of organizational leadership on physician burnout and satisfaction. AB - OBJECTIVE: To evaluate the impact of organizational leadership on the professional satisfaction and burnout of individual physicians working for a large health care organization. PARTICIPANTS AND METHODS: We surveyed physicians and scientists working for a large health care organization in October 2013. Validated tools were used to assess burnout. Physicians also rated the leadership qualities of their immediate supervisor in 12 specific dimensions on a 5-point Likert scale. All supervisors were themselves physicians/scientists. A composite leadership score was calculated by summing scores for the 12 individual items (range, 12-60; higher scores indicate more effective leadership). RESULTS: Of the 3896 physicians surveyed, 2813 (72.2%) responded. Supervisor scores in each of the 12 leadership dimensions and composite leadership score strongly correlated with the burnout and satisfaction scores of individual physicians (all P<.001). On multivariate analysis adjusting for age, sex, duration of employment at Mayo Clinic, and specialty, each 1-point increase in composite leadership score was associated with a 3.3% decrease in the likelihood of burnout (P<.001) and a 9.0% increase in the likelihood of satisfaction (P<.001) of the physicians supervised. The mean composite leadership rating of each division/department chair (n=128) also correlated with the prevalence of burnout (correlation=-0.330; r(2)=0.11; P<.001) and satisfaction (correlation=0.684; r(2)=0.47; P<.001) at the division/department level. CONCLUSION: The leadership qualities of physician supervisors appear to impact the well-being and satisfaction of individual physicians working in health care organizations. These findings have important implications for the selection and training of physician leaders and provide new insights into organizational factors that affect physician well-being. PMID- 25796118 TI - The engaged physician. PMID- 25796119 TI - Multifunctional network-structured film coating for woven and knitted polyethylene terephthalate against cardiovascular graft-associated infections. AB - Multifunctional network-structured polymeric coat for woven and knitted forms of crimped polyethylene terephthalate PET graft was developed to limit graft associated infections. A newly synthesized antibacterial sulfadimethoxine polyhexylene adipate-b-methoxy polyethylene oxide (SD-PHA-b-MPEO) di-block copolymer was employed. Our figures of merit revealed that the formed coat showed a porous topographic architecture which manifested paramount properties, mostly bacterial anti-adhesion efficiency and biocompatibility with host cells. Compared to untreated grafts, the coat presented marked reduction of adhered Gram-positive Staphylococcus epidermidis previously isolated from a patient's vein catheter by 2.6 and 2.3 folds for woven and knitted grafts, respectively. Similarly, bacterial anti-adhesion effect was observed for Staphylococcus aureus by 2.3 and 2.4 folds, and by 2.9 and 2.7 folds for Gram-negative Escherichia coli for woven and knitted grafts, respectively. Additionally, adhesion and growth characteristics of L929 cells on the modified grafts revealed no significant effect on the biocompatibility. In conclusion, coating of PET with (SD-PHA-b MPEO) is a versatile approach offers the desired bacterial anti-adhesion effect and host biocompatibility. PMID- 25796120 TI - Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (B). Efficiency of pharmacological action. AB - This paper examines a perspective to use newly engineered nanomaterials as effective and safe carriers for gene therapy of cancer. Three different groups of cationic dendrimers (PAMAM, phosphorus, and carbosilane) were complexed with anticancer siRNA and the biophysical properties of the dendriplexes created were analyzed. The potential of the dendrimers as nanocarriers for anticancer Bcl-xl, Bcl-2, Mcl-1 siRNAs and additionally a scrambled sequence siRNA has been explored. Dendrimer/siRNA complexes were characterised by various methods including fluorescence, zeta potential, dynamic light scattering, circular dichroism, gel electrophoresis and transmission electron microscopy. In this part of study, the transfection of complexes in HeLa and HL-60 cells was analyzed using both single apoptotic siRNAs and a mixture (cocktail) of them. Cocktails were more effective than single siRNAs, allowing one to decrease siRNAs concentration in treating cells. The dendrimers were compared as siRNA carriers, the most effective being the phosphorus-based ones. However, they were also the most cytotoxic on their own, so that in this regard the application of all dendrimers in anticancer therapy will be discussed. PMID- 25796121 TI - Optimization of a PGSS (particles from gas saturated solutions) process for a fenofibrate lipid-based solid dispersion formulation. AB - The aim of this study was to develop a formulation containing fenofibrate and Gelucire((r)) 50/13 (Gattefosse, France) in order to improve the oral bioavailability of the drug. Particles from gas saturated solutions (PGSS) process was chosen for investigation as a manufacturing process for producing a solid dispersion. The PGSS process was optimized according to the in vitro drug dissolution profile obtained using a biphasic dissolution test. Using a design of experiments approach, the effects of nine experimental parameters were investigated using a PGSS apparatus provided by Separex((r)) (Champigneulles, France). Within the chosen experimental conditions, the screening results showed that the drug loading level, the autoclave temperature and pressure, the connection temperature and the nozzle diameter had a significant influence on the dissolution profile of fenofibrate. During the optimization step, the three most relevant parameters were optimized using a central composite design, while other factors remained fixed. In this way, we were able to identify the optimal production conditions that would deliver the highest level of fenofibrate in the organic phase at the end of the dissolution test. The closeness between the measured and the predicted optimal dissolution profiles in the organic phase demonstrated the validity of the statistical analyses. PMID- 25796122 TI - Investigating the potential of employing bilosomes as a novel vesicular carrier for transdermal delivery of tenoxicam. AB - Bilosomes represent an evolving vesicular carrier that have been explored for oral vaccines delivery based on its ability to resist enzymes and bile salts in the gastrointestinal tract (GIT). Bilosomes vesicles are formed of bilayer membrane of non-ionic surfactant molecules encompassing bile salts. Although, bilosomes have not been proposed for transdermal drug delivery, this carrier seems to have promising potential in this regard. Accordingly, the aim of this investigation was to assess the capability and safety of utilizing bilosomes for transdermal delivery of tenoxicam (TX) as a model drug. A 3(1)2(2) full factorial design was adopted to study the effects of different formulation parameters on bilosomes properties and select the optimal formulation using Design-Expert((r)) software. The selected formulation displayed nano-sized spherical vesicles (242.5 +/- 6.43nm) with reasonable entrapment efficiency percent (68.33 +/- 2.33%). Confocal laser scanning microscopy confirmed the capability of the flourolabeled bilosomes to penetrate deep within the skin. Both, ex vivo permeation and in vivo skin deposition studies confirmed the superiority of bilosomes over drug solution in delivering TX transdermally. In addition, in vivo histopathological study proved the safety of topically applied bilosomes. In summary, the highlighted results confirmed that bilosomes can be further adopted for delivering drugs transdermally. PMID- 25796123 TI - A comprehensive production method of self-cryoprotected nano-liposome powders. AB - This study provided a convenient approach for large scale production of hydrogenated soya phosphatidylcholine nano-liposome powders using beclometasone dipropionate as a model drug and sucrose as proliposome carrier. Fluid-bed coating was employed to manufacture proliposomes by coating sucrose with the phospholipid (5%, 10%, 15% and 20% weight gains), followed by hydration, size reduction using high pressure homogenization, and freeze-drying to yield stable nano-vesicles. High pressure homogenization was compared with probe-sonication in terms of liposome size, zeta potential and drug entrapment. Furthermore, the effect of freeze-drying on vesicle properties generated using both size reduction methods was evaluated. Results have shown that high-pressure homogenization followed by freeze-drying and rehydration tended to yield liposomes smaller than the corresponding vesicles downsized via probe-sonication, and all size measurements were in the range of 72.64-152.50 nm, indicating that freeze-drying was appropriate, regardless of the size reduction technique. The liposomes, regardless of size reduction technique and freeze drying had slightly negative zeta potential values or were almost neutral in surface charge. The entrapment efficiency of BDP in homogenized liposomes was found to increase following freeze drying, hence the drug entrapment efficiency values in rehydrated liposomes were 64.9%, 57%, 69.5% and 64.5% for 5%, 10%, 15% and 20% weight gains respectively. In this study, we have reported a reliable production method of nano-liposomes based on widely applicable industrial technologies such as fluid-bed coating, high pressure homogenization and freeze-drying. Moreover, sucrose played a dual role as a carrier in the proliposome formulations and as a cryoprotectant during freeze-drying. PMID- 25796124 TI - Specific in vitro binding of a new (99m)Tc-radiolabeled derivative of the C terminal decapeptide of prothymosin alpha on human neutrophils. AB - Prothymosin alpha (ProTalpha) is a conserved mammalian polypeptide with intracellular functions associated with cell proliferation and apoptosis and an extracellular role associated with immunopotentiation. The N-terminal fragment [1 28], which is identical with the immunostimulating peptide thymosin alpha1 (Talpha1), was earlier considered as the immunoactive region of the polypeptide; however, recent data suggest that ProTalpha may exert a discrete immunomodulating action through its central or C-terminal region, via targeting Toll-like receptor 4 (TLR4). In this work, a derivative of the C-terminal fragment ProTalpha[100 109] (ProTalpha-D1) that can be radiolabeled with (99m)Tc was developed. The biological activity of the non-radioactive (185/187)rhenium-complex of this derivative ([(185/187)Re]ProTalpha-D1, structurally similar with [(99m)Tc]ProTalpha-D1) was verified through suitable in vitro bioassays on human neutrophils. Subsequent cell-binding studies revealed specific, time-dependent and saturable binding of [(99m)Tc]ProTalpha-D1 on neutrophils, which was inhibited by intact ProTalpha and ProTalpha[100-109], as well as by a "prototype" TLR4-ligand (lipopolysaccharide from Escherichia coli). Overall, our results support the existence of ProTalpha-binding sites on human neutrophils, recognizing [(99m)Tc]ProTalpha-D1, which might involve TLR4. [(99m)Tc]ProTalpha D1 may be a useful tool for conducting further in vitro and in vivo studies, aiming to elucidate the extracellular mode of action of ProTalpha and, eventually, develop ProTalpha-based immunotherapeutics. PMID- 25796125 TI - Self-assembled filomicelles prepared from polylactide/poly(ethylene glycol) block copolymers for anticancer drug delivery. AB - Bioresorbable filomicelles present many advantageous as drug delivery systems e.g., long circulation time and high loading efficiency. The aim of this study was to develop polylactide/poly(ethylene glycol) (PLA/PEG) filomicelles for drug delivery applications. A series of PLA/PEG diblock copolymers were synthesized using non-toxic initiator, and characterized by means of NMR and GPC. Analysis of morphology of micelles determined by TEM revealed that apart from the weight fraction also the molar mass of PEG and the stereochemistry of PLA block must be considered for tailoring micellar structures. The CMC was found to be dependent on the length and structure of the hydrophobic block. It was observed that the drug loading properties could be improved by selection of appropriate copolymer and encapsulation method. Slower release of paclitaxel was observed for mPEG5000 initiated copolymers than mPEG2000 initiated copolymers. Moreover, the influence of the length of hydrophobic block and its stereoisomeric form on drug release rate was evidenced. Therefore, PLA/PEG filomicelles with good stability, high drug loading capacity and sustained drug release appear most attractive for drug delivery applications. PMID- 25796126 TI - Gastro-resistant characteristics of GRAS-grade enteric coatings for pharmaceutical and nutraceutical products. AB - The use of naturally derived excipients to develop enteric coatings offers significant advantages over conventional synthetic polymers. Unlike synthetic polymers, they are biodegradable, relatively abundant, have no daily intake limits or restrictions on use for dietary and nutraceutical products. However, little information is available on their dissolution properties under different gastrointestinal conditions and in comparison to each other. This work investigated the gastric resistance properties of commercially available GRAS based coating technologies. Three coating systems were evaluated: ethyl cellulose+carboxymethyl cellulose (EC-CMC), ethyl cellulose+sodium alginate (EC Alg) and shellac+sodium alginate (Sh-Alg) combinations. The minimum coating levels were optimized to meet USP pharmacopoeial criteria for delayed release formulations (<10% release after 2h in pH 1.2 followed by >80% release after 45 min of pH change). Theophylline 150 mg tablets were coated with 6.5%, 7%, and 2.75% coating levels of formulations EC-CMC, EC-Alg and Sh-Alg, respectively. In vitro dissolution test revealed a fast release in pH 6.8 for ethyl cellulose based coatings: t80% value of 65 and 45 min for EC-CMC and EC-Alg respectively, while a prolonged drug release from Sh-Alg coating was observed in both pH 6.8 and 7.4 phosphate buffers. However, when more biologically relevant bicarbonate buffer was used, all coatings showed slower drug release. Disintegration test, carried out in both simulated gastric and intestinal fluid, confirmed good mechanical resistance of EC-CMC and EC-Alg coating, and revealed poor durability of the thinner Sh-Alg. Under elevated gastric pH conditions (pH 2, 3 and 4), EC CMC and EC-Alg coatings were broken after 70, 30, 55 min and after 30, 15, 15 min, respectively, while Sh-Alg coated tablets demonstrated gastric resistance at all pH values. In conclusion, none of the GRAS-grade coatings fully complied with the different biological demands of delayed release coating systems. PMID- 25796127 TI - Co-processing of hydroxypropyl methylcellulose (HPMC) for improved aqueous dispersibility. AB - Hydroxypropyl methylcellulose (HPMC), a widely employed film coating polymer, exhibits poor dispersibility in an aqueous medium. Rapid hydration leading to swelling and coherent gel formation is reported to be responsible for this problem. Present study focuses on the use of spray drying based approach for co processing of HPMC to improve its dispersibility. Dispersion behavior of native HPMC showed formation of large lumps that did not dissolve completely for 40min. However, HPMC co-processed with lactose and sodium chloride exhibited improvement in dispersibility with complete dissolution attained within 20min. Mechanistic insights into improved dispersibility were obtained using contact angle studies, confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM) and scanning TEM (STEM) studies. Co-processed products exhibited higher immersional wetting as determined by sessile drop contact angle technique, which indicated spontaneous incursion of water. CLSM study revealed highly swollen and erodible gel in co-processed products. Novel application of TEM and STEM techniques was developed to understand the nature of mixing achieved during co processing. Overall the improvement in dispersibility of co-processed products was predominantly due to the alteration in sub-particulate level properties during co-processing. The effect of excipients on the film properties of HPMC, like tensile strength and hygroscopicity, was also assessed. This study provides the comprehensive understanding of role of co-processing on improvement of dispersion behavior of HPMC and helps in the selection of suitable excipients for the same. PMID- 25796128 TI - Migrability of PVC plasticizers from medical devices into a simulant of infused solutions. AB - Medical devices (MD) for infusion and artificial nutrition are essentially made of plasticized PVC. The plasticizers in the PVC matrix can leach out into the infused solutions and may enter into contact with the patients. In order to assess the risk of patient exposure to these plasticizers we evaluated the migration performance of DEHP, DEHT, DINCH, and TOTM using a model adapted to the clinical use of the MDs. Each PVC tubing sample was immersed in a simulant consisting of a mixture of ethanol/water (50/50v/v) at 40 degrees C and migration tests were carried out after 24h, 72h, and 10 days.DEHP had the highest migration ability, which increased over time. The amount of TOTM released was more than 20 times less than that of DEHP, which makes it an interesting alternative. DEHT is also promising, with a migration level three times smaller than DEHP. However, the migration ability of DINCH was similar to DEHP, with the released amounts equaling 1/8th of the initial amount in the tubing after 24h of contact. Taking into account the available toxicological data, TOTM and DEHT appear to be of particular interest. However, these data should be supplemented and correlated with clinical and toxicological studies on plasticizers and their metabolites. PMID- 25796129 TI - [Lung ultrasound, the new tenant]. PMID- 25796130 TI - Transfusions for anemia in adult and pediatric patients with malignancies. AB - Anemia is present in over two-thirds of patients with malignant hematological disorders. The etiology of anemia predominates from ineffective erythropoiesis from marrow infiltration, cytokine related suppression, erythropoietin suppression, and vitamin deficiency; ineffective erythropoiesis is further exacerbated by accelerated clearance due to antibody mediated hemolysis and thrombotic microangiopathy. As the anemia is chronic in nature, symptoms are generally well tolerated and often non-specific. Transfusion of red blood cells (RBCs) is a balance between providing benefit for patients while avoiding risks of transfusion. Conservative/restrictive RBC transfusion practices have shown equivalent patient outcomes compared to liberal transfusion practices, and meta analysis has shown improved in-hospital mortality, reduced cardiac events, re bleeding, and bacterial infections. The implications for a lower threshold for transfusion in patients with malignancies are therefore increasingly being scrutinized. Alternative management strategies for anemia with IV iron and erythropoietin stimulating agents (ESAs) should be considered in the appropriate settings. PMID- 25796132 TI - Early onset of cognitive impairment is associated with altered synaptic plasticity and enhanced hippocampal GluA1 expression in a mouse model of depression. AB - Memory deficit is a common manifestation of age-related cognitive impairment, of which depression is a frequently occurring comorbidity. Previously, we developed a submissive (Sub) mouse line, validated as a model of depressive-like behavior. Using learning paradigms testing hippocampus-dependent spatial and nonspatial memory, we demonstrate here that Sub mice developed cognitive impairments at earlier age (3 months), compared with wild-type mice. Furthermore, acute hippocampal slices from Sub animals failed to display paired-pulse facilitation, whereas primed burst stimulation elicited significantly enhanced long-term potentiation in region CA1, relative to control mice. Changes in synaptic plasticity were accompanied by markedly reduced hippocampal messenger RNA expression of insulin-like growth factor and brain-derived neurotrophic factor. Finally, we identified markedly elevated protein levels of the alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the hippocampi of Sub mice, which was exacerbated with age. Taken together, the results point to a linkage between depressive-like behavior and the susceptibility to develop age-related cognitive impairment, potentially by hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mediated glutamatergic signaling. PMID- 25796131 TI - Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study. AB - Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD. PMID- 25796133 TI - Characterisation of Dichelobacter nodosus and detection of Fusobacterium necrophorum and Treponema spp. in sheep with different clinical manifestations of footrot. AB - The aim of this study was to determine the proportion of Dichelobacter nodosus, Fusobacterium necrophorum and Treponema spp. in sheep with different clinical manifestations of footrot compared to healthy sheep both at flock and individual level. The second aim was to characterise D. nodosus with respect to virulence, presence of intA gene and the serogroups. Swab samples (n=1000) from footrot affected (n=10) and healthy flocks (n=10) were analysed for the presence of D. nodosus, F. necrophorum and Treponema spp. by real-time PCR and culturing (D. nodosus only). Dichelobacter nodosus isolates (n=78) and positive swabs (n=474) were analysed by real-time PCR for the aprV2/B2 and the intA genes and by PCR for the fimA gene (isolates only). D. nodosus was more commonly found in flocks affected with footrot than in clinically healthy flocks. A significant association was found between feet with severe footrot lesions and the aprV2 gene and between feet with moderate or no lesions and the aprB2 gene, respectively. F. necrophorum was more commonly found in flocks with footrot lesions than in flocks without lesions. No significant association was found between sheep flocks affected with footrot and findings of Treponema spp. or the intA gene. Benign D. nodosus of six different serogroups was detected in twelve flocks and virulent D. nodosus of serogroup G in one. In conclusion, D. nodosus and F. necrophorum were more commonly found in feet with footrot than in healthy feet. The majority of D. nodosus detected was benign, while virulent D. nodosus was only detected in a single flock. PMID- 25796134 TI - Actinobacillus pleuropneumoniae two-component system QseB/QseC regulates the transcription of PilM, an important determinant of bacterial adherence and virulence. AB - QseB/QseC is one of the five predicted two-component systems (TCSs) in Actinobacillus pleuropneumoniae. To understand the roles of this TCS in A. pleuropneumoniae, a markerless gene-deletion mutant DeltaqseBC was constructed. Differentially expressed (DE) genes in DeltaqseBC were filtered by microarray analysis. A total of 44 DE genes were found to be regulated by QseB/QseC system. The transcriptional profile of A. pleuropneumoniae DeltaqseBC was compared with that of DeltaluxS and catecholamine (CA) stimulations, 13 genes regulated by QseB/QseC were found also regulated by LuxS, and 3 Qse-regulons were co-regulated by CA stimulations, respectively. Binding of QseB to the promoters of three regulons (pilM, glpK and hugZ), which were co-regulated by QseB/QseC and LuxS, was evaluated by electrophoretic mobility-shift assay. Results indicated that pilM was directly regulated by phosphorylated-QseB. Then the pilM deletion mutant DeltapilM was constructed and characterized. Data presented here revealed that adherence ability of DeltapilM to St. Jude porcine lung cells was significantly decreased, and DeltapilM exhibited reduced virulence in pigs, suggesting PilM contributes to the process of A. pleuropneumoniae infection. PMID- 25796135 TI - A two-part mixed-effects modeling framework for analyzing whole-brain network data. AB - Whole-brain network analyses remain the vanguard in neuroimaging research, coming to prominence within the last decade. Network science approaches have facilitated these analyses and allowed examining the brain as an integrated system. However, statistical methods for modeling and comparing groups of networks have lagged behind. Fusing multivariate statistical approaches with network science presents the best path to develop these methods. Toward this end, we propose a two-part mixed-effects modeling framework that allows modeling both the probability of a connection (presence/absence of an edge) and the strength of a connection if it exists. Models within this framework enable quantifying the relationship between an outcome (e.g., disease status) and connectivity patterns in the brain while reducing spurious correlations through inclusion of confounding covariates. They also enable prediction about an outcome based on connectivity structure and vice versa, simulating networks to gain a better understanding of normal ranges of topological variability, and thresholding networks leveraging group information. Thus, they provide a comprehensive approach to studying system level brain properties to further our understanding of normal and abnormal brain function. PMID- 25796137 TI - Prevalence and risk factors of abdominal obesity in Polish rural children. AB - Secular trends of body mass index (BMI) and waist circumference indicate greater increase in abdominal obesity compared to general obesity. Determinants of obesity described by BMI are relatively well documented in various populations, unlike abdominal obesity described by waist-to-height ratio (WHtR). The aim of the study was to determine prevalence and abdominal obesity (WHtR) risk factors in a cohort of 3048 rural children aged 7-12 years from southern Poland. Biological, socio-demographic and lifestyle factors were analysed, and odds ratio and 95% confidence interval were calculated using a logistic regression analysis. The prevalence of abdominal obesity in rural boys and girls in the sample was 11% and 9% respectively. Obesity in both parents, irregular breakfasts, irregular meals during the day and regularly consumed tea were significant factors of abdominal obesity risks in rural girls. Being the only child, low number of people in a household, obesity in both parents, high energy-dense food index and no exercise significantly increased the risk of abdominal obesity in rural boys. The study demonstrated tendencies similar to other European countries in the prevalence of abdominal obesity among sexes. Lifestyle behaviours should be changed and adapted to each sex since risk factors differ between the sexes and indicate higher eco-sensitivity in boys. PMID- 25796136 TI - Factors associated with pressure ulcers in individuals with spina bifida. AB - OBJECTIVE: To describe factors associated with pressure ulcers in individuals with spina bifida (SB) enrolled in the National Spina Bifida Patient Registry (NSBPR). DESIGN: Unbalanced longitudinal multicenter cohort study. SETTING: Nineteen SB clinics. PARTICIPANTS: Individuals with SB (N=3153) enrolled in 19 clinic sites that participate in the NSBPR. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pressure ulcer status (yes/no) at the annual visit between 2009 and 2012. RESULTS: Of 3153 total participants, 19% (n=603) reported ulcers at their most recent annual clinic visit. Seven factors-level of lesion, wheelchair use, urinary incontinence, shunt presence, above the knee orthopedic surgery, recent surgery, and male sex-were significantly associated with the presence of pressure ulcers. Of these factors, level of lesion, urinary incontinence, recent surgery, and male sex were included in the final logistic regression model. The 3 adjusting variables-SB type, SB clinic, and age group-were significant in all analyses (all P<.001). CONCLUSIONS: By adjusting for SB type, SB clinic, and age group, we found that 7 factors-level of lesion, wheelchair use, urinary incontinence, shunt presence, above the knee orthopedic surgery, recent surgery, and male sex-were associated with pressure ulcers. Identifying key factors associated with the onset of pressure ulcers can be incorporated into clinical practice in ways that prevent and enhance treatment of pressure ulcers in the population with SB. PMID- 25796138 TI - Egg hatching of two locusts, Schistocerca gregaria and Locusta migratoria, in response to light and temperature cycles. AB - The present study showed that the eggs of the desert locust, Schistocerca gregaria, and the migratory locust, Locusta migratoria, responded to photoperiod by hatching when placed on sand in the laboratory. S. gregaria mainly hatched during the dark phase and L. migratoria during the light phase. The importance of light as a hatching cue depended on the magnitude of the temperature change during the thermoperiod; photoperiod played a more important role in the control of hatching time in both species when the magnitude of the temperature change was small. In addition, the eggs of the two species that were covered with sand did not respond to photoperiod and hatched during both the light and dark phases, indicating that light did not penetrate through the sand. Because locust eggs are normally laid as egg pods and a foam plug is deposited between the egg mass and the ground surface, we tested a possibility that naturally deposited eggs perceived light through the foam plug. The eggs that were deposited and left undisturbed in the sand hatched during the light and dark phases at similar frequencies. These results suggest that the eggs of both locust species responded to light and controlled their hatching timing accordingly but would not use light as a hatching cue in the field. The evolutionary significance of the ability of eggs to respond to light in these locusts was discussed. PMID- 25796141 TI - The natural, peptaibolic peptide SPF-5506-A4 adopts a beta-bend spiral structure, shows low hemolytic activity and targets membranes through formation of large pores. AB - The medium-length fungal peptaibol SPF-5506-A(4) has been shown to inhibit formation of the Abeta peptide involved in Alzheimer''s disease. As Abeta is a cleavage-product from the membrane-bound APP protein, we hypothesized that SPF 5506-A(4)'s activity might be linked to membrane interactions in general. Here we describe the synthesis, structure and membrane interactions of SPF-5506-A4. The challenging synthesis was carried out on solid phase and a detailed conformational analysis in solution revealed a beta-bend ribbon spiral core structure with flexible termini. Investigations of its membrane activity revealed low hemolytic activity, limited inhibition of both Gram-positive and Gram negative cell growth and a preference for an overall negatively charged membrane surface mimicking the bacterial cell surface. SPF-5506-A(4) is the first peptaibol to be shown to facilitate leakage of large (4.6 nm diameter) fluorescence-labeled dextran from vesicles while leaving the vesicles intact. We conclude that SPF-5506-A(4) follows the toroidal pore model in its mode of action. PMID- 25796142 TI - Effects of psoralen on chondrocyte degeneration in lumbar intervertebral disc of rats. AB - Discuss the internal mechanism of delaying degeneration of lumber intervertebral disc. The cartilage of lumbar intervertebral disc of SD rats was selected in vitro, then cultured by tissue explant method, and identified by HE staining, toluidine blue staining and immunofluorescence. The optimal concentration of psoralen was screened by cell proliferation assay and RT-PCR method. The cells in third generation with good growth situation is selected and placed in 6-well plate at concentration of 1*10(5)/well and its expression was tested. Compared to concentration of 0, the mRNA expression of Col2al (Collagen II) secreted by was up regulated chondrocyte of lumbar intervertebral disc at the concentration of 12.5 and 25MUM (P<0.0 or P<0.01). The aggrecan mRNA of psoralen group was higher than blank control group (P<0.01); compared with IL-1beta induced group, the mRNA expression of Col2al was significantly increased but the mRNA expression of ADAMTS-5 was significantly decreased in psoralen group (P<0.01). These findings suggest that, psoralen can remit the degeneration of lumbar intervertebral disc induced by IL-1beta to some extent, and affect the related factors of IL-1beta signaling pathway. PMID- 25796143 TI - The acetylcholinesterase (AChE) inhibition analysis of medaka (Oryzias latipes) in the exposure of three insecticides. AB - The continuous effects on Acetylcholinesterase (AChE) activity of medaka (Oryzias latipes) caused by dichlorvos, methomyl and deltamethrin in vivo were investigated, and the trends of AChE activity inhibition due to the influence of these insecticides were discussed. The LC50-24h of dichlorvos, methomyl and deltamethrin on medaka were 2.3 mg/L, 0.2 mg/L, and 2.9*10(-3) mg/L respectively. The result suggested that at the beginning of the exposure, the AChE activity might increase, and the AChE activity in dead individuals was obviously lower than the live individuals. Though the de novo synthesis of AChE in medaka might help the AChE activity recover, the trends during the exposure in different treatments were downward, and it showed both exposure time and concentration dependent. Meanwhile, higher temperature might cause the AChE inhibition earlier due to the higher metabolic rate. Therefore, as a specific biomarker for organophosphate, carbamate pesticides and pyrethroids, the degree of the AChE inhibition with in vivo conditions is a good tool in continuous monitoring of insecticides, which may induce the nerve conduction disorders. PMID- 25796144 TI - Variability of macroscopic dimensions of Moso bamboo. AB - In order to the macroscopic geometry distributions of vascular bundles in Moso bamboo tubes. The circumference of bamboo tubes was measured, used a simple quadratic diameter formula to analyze the differences between the tubes in bamboo culm, and the arrangement of vascular bundles was investigated by cross sectional images of bamboo tubes. The results shown that the vascular bundles were differently distributed in a bamboo tube. In the outer layer, the vascular bundles had a variety of shapes, and were aligned parallel to each other. In the inner layers, the vascular bundles weren't aligned but uniform in shape. It was concluded that the vascular bundle sections arranged in parallel should be separated from the non-parallel sections for the maximum bamboo utilization. PMID- 25796140 TI - HIF1alpha is necessary for exercise-induced neuroprotection while HIF2alpha is needed for dopaminergic neuron survival in the substantia nigra pars compacta. AB - Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. Hypoxia Inducible Factor (HIF)1alpha and HIF2alpha are transcription factors regulated by cellular oxygen concentration that initiate gene regulation of vascular development, redox homeostasis, and cell cycle control. HIF1alpha and HIF2alpha contribute to important adaptive mechanisms that occur when oxygen and ROS homeostasis become unbalanced. It has been shown that preconditioning by exposure to a stressor prior to a hypoxic event reduces damage that would otherwise occur. Previously we reported that 3 months of exercise protects SNpc dopaminergic (DA) neurons from toxicity caused by Complex I inhibition. Here, we identify the cells in the SNpc that express HIF1alpha and HIF2alpha and show that running exercise produces hypoxia in SNpc DA neurons, and alters the expression of HIF1alpha and HIF2alpha. In mice carrying a conditional knockout of Hif1alpha in postnatal neurons we observe that exercise alone produces SNpc TH+ DA neuron loss. Loss of HIF1alpha also abolishes exercise-induced neuroprotection. In mice lacking Hif2alpha in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but 3months of exercise rescues this loss. We conclude that HIF1alpha is necessary for exercise-induced neuroprotection and both HIF1alpha and HIF2alpha are necessary for the survival and function of adult SNpc DA neurons. PMID- 25796139 TI - Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. AB - In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. PMID- 25796145 TI - Research on green supply chain coordination strategy for uncertain market demand. AB - Based on the status that the green market began to develop (e.g. pharmaceutical industry) in Mainland China, the paper mainly discusses how members of the green supply chain (GSC) cooperate effectively in the process of the supply chain operations. For the uncertainties existing in the market demand of the green products, the GSC coordination strategy is put forward based on the Stackelberg game that the manufacturer is the leader and distributors are the followers. The relationship between the proposed coordination strategy and several factors including the distributor's amount, the distributor's risk aversion and the uncertainties of market demand are analyzed. It indicates that, when there are uncertainties existing in the market demand of the green product, the revenue of each enterprise, the overall revenue and the customer's welfare all decrease; while the increase in the number of distributors and low risk aversion of them are beneficial to the entire GSC and the customer. The conclusions have good guidance for the operational decisions of the green supply chain when the green market is in its initial formation. PMID- 25796147 TI - Nursing and safety of silver needle diathermy treating ankylosing spondylitis. AB - This paper aims to discuss the nursing and safety of silver needle diathermy in the treatment for ankylosing spondylitis. We nursed 46 patients with ankylosing spondylitis treated with silver needle diathermy. Specific nursing was focused on physical condition evaluation and mental nursing before treatment, observation during and after treatment, diet nursing, needle eye nursing, functional training and propaganda and education when discharged. The result suggested that all the patients received mental nursing, diet guide, skin care, health education, functional training and follow-up visit from the nurse and all of them could endure silver needle diathermy as discomfort or drug allergy was barely found, so were slight scald and skin infection nearby the needle eye caused by fainting during acupuncture, accidental puncture or overheat. Follow-up visit showed that no patient suffered obvious untoward effect and the pain, joint range of motion and living condition were distinctly improved a week after discharging. In conclusion, during the treatment for ankylosing spondylitis applying silver needle diathermy, the nursing before, during and after the treatment can obviously reduce the complication, accelerate the recovery, which is highly safe. PMID- 25796146 TI - Curative effect of amlodipine combined with enalapril in curing hypertension of the aged. AB - This paper aims to research the clinical effect and security of using amlodipine and enalapril together to cure hypertension of aged people. Random number table was used to divide clinical data of 114 aged hypertensives into two groups: control group (treat with only amlodipine) and observation group (treat with both amlodipine and enalapril). We formulated evaluation standard and compared the effects in pretherapy and post-treatment of two groups. Results showed that the total effective rate of control group was 59.6% and the total effective rate of observation group was 87.5% and blood pressure was lower. These findings suggest that amlodipine together, with enalapril has outstanding curative effect in hypertension treatment of the aged, they can effectively control the blood pressure, the security is fine and it deserves the popularization and application clinically. PMID- 25796148 TI - Expression of Cripto-1 gene protein and Activin-A in human lung adenocarcinoma tissue. AB - To research the expression in human lung adenocarcinoma tissue of Cripto-1 (teratocarcinoma derived growth factor-1) gene protein and Activin-A gene protein, and explore the relationship and clinical significance between the two gene protein and clinical pathological characteristic of lung adenocarcinoma. This study had applied the immunohistochemical method to detect the 188 cases of lung adenocarcinoma and expression of Cripto-1 protein and Activin-A protein in 100 cases of normal lung tissue. Then, analysis the relationship between these two-gene protein and clinical lung adenocarcinoma histopathological features, and inherent correlation between these two genes. The positive expression rate of Cripto-1 protein in lung adenocarcinoma tissue was significantly higher in normal lung tissue, while, the positive expression rate of Activin-A protein in lung adenocarcinoma tissue was significantly lower than in normal lung tissue. The high expression of Cripto-1 and low expression of Activin-A was closely related (each P<0.05) to the TNM staging of lung adenocarcinoma, lymph node metastasis and the main pathological tissue staging of lung adenocarcinoma. And the correlation analysis showed that it was negative correlation for the expression of Activin-A protein and Cripto-1 protein in lung adenocarcinoma. The over expression of Cripto-1 and the expression lack of Activin-A were correlated with the occurrence, development, metastasis and malignant degree of lung adenocarcinoma. PMID- 25796149 TI - A novel beta-lactam derivative, albactam from the flowers of Albizia lebbeck with platelets anti-aggregatory activity in vitro. AB - A novel beta-lactam derivative, albactam, was isolated from the alcoholic extract of the flowers of Albizia lebbeck. It showed a significant anti-aggregatory activity against adenosine diphosphate and arachidonic acid induced guinea-pigs' platelets aggregation in vitro. Six more known compounds were also isolated and fully characterized by measuring 1D and 2D NMR, two of them are the triterpenes beta-amyrin and 11alpha, 12alpha-oxidotaraxerol, two ceramide derivatives and two flavonoids, kampferol 3-O-rutinoside and rutin. PMID- 25796150 TI - Effect and nursing study of traditional Chinese medicine preparation huayu zhitong powder in the treatment of distal radius fracture. AB - This paper aims to discuss the effect of traditional Chinese medicine preparation Huayu Zhitong powder in the treatment of distal radius fracture. In this paper, 200 patients with distal radius fracture were randomly divided into treatment group and control group. Patients in treatment group orally took Huayu Zhitong powder, while patients in control group were treated with traditional Shangke Jiegu tablets with traditional Chinese medicine composition. After fixed in a cast plaster, patients in the two groups were supervised the disappearance time of pain by adopting NRS (Numerical rating scale) from scale 0 to 10. Besides, they returned at day 5 and day 8 respectively, and then they were observed the swelling affected part. At day 14, day 28, and day 56 after reduction they respectively took an x-ray. Then they would be graded according to the growth of osteotylus and the clinical effects were evaluated based on the grade. Finally, the treatment group worked better in relief effect than the control group. At day 8, the treatment group worked better in detumescence than the control group. At day 28, the recovery effect in treatment group was found to be better than the other. From these, it is shown that the traditional Chinese medicine works much better in the treatment of distal radius fracture than traditional treatment medicine. Thus it is of great worth spreading for use. PMID- 25796151 TI - Biomedical molecular of woody extractives of Cunninghamia Lanceolata biomass. AB - Extractives, important compounds from wood, provide abundant resources for woody medicine. In this study, the three extractives from Cunninghamia lanceolata wood were removed by method of three-stage extraction with alcohol, petroleum ether, and alcohol/petroleum ether and their chemical components were analyzed by gas chromatography-mass spectrometry (GC-MS). Thirteen chemical components were discovered in the first-stage extractives, including: 4-((1e)-3-hydroxy-1 propenyl)-2-methoxyphenol (36.80%), alpha-(2-phenylethenyl)-1 piperidineacetonitrile (15.39%). One-hundred chemical components were discovered in the second-stage extractives, including: [1s-(1alpha,4aalpha,10abeta)]-1, 2,3,4,4a,9,10,10a-octahydro-1,4a- dimethyl-7-(1-methylethyl)-1- phenanthrenecar boxylic acid (15.16%), 1,3-dimethoxy-5-[(1e)-2- phenylethenyl]-benzene (6.99%). Seven chemical components were discovered in the third-stage extractives, including: 1,3-dimethoxy -5-[(1E)-2-phenylethenyl]-benzene (32.88%), stigmasta 4,6,22-trien-3alpha-ol (17.83%). And both the main retention time of the first stage and which of third-stage extractives are 20-30 minutes, and the main retention time of the second-stage extractives is <10 minutes. Besides, the three extractives contained many biomedical molecular, such as [1s (1alpha,4aalpha,10abeta)]-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1 methylethyl)-1-phenanthrenecar-boxylic acid, squalene, stigmast-4-en-3-one and gamma-sitosterol and so on, which means that the three extractives from Cunninghamia lanceolata wood have huge potential in biomedicine. PMID- 25796152 TI - Current trends in treatment of obesity in Karachi and possibilities of cost minimization. AB - Our study finds out drug usage trends in over weight and obese patients without any compelling indications in Karachi, looks for deviations of current practices from evidence based antihypertensive therapeutic guidelines and identifies not only cost minimization opportunities but also communication strategies to improve patients' awareness and compliance to achieve therapeutic goal. In present study two sets were used. Randomized stratified independent surveys were conducted in hospital doctors and family physicians (general practitioners), using pretested questionnaires. Sample size was 100. Statistical analysis was conducted on Statistical Package for Social Science (SPSS). Opportunities of cost minimization were also analyzed. One the basis of doctors' feedback, preference is given to non-pharmacologic management of obesity. Mass media campaign and media usage were recommended to increase patients awareness and patients' education along with strengthening family support systems was recommended for better compliance of the patients to doctor's advice. Local therapeutic guidelines for weight reduction were not found. Feedbacks showed that global therapeutic guidelines were followed by the doctors practicing in the community and hospitals in Karachi. However, high price branded drugs were used instead of low priced generic therapeutic equivalents. Patient's education is required for better awareness and improving patients' compliance. The doctors found preferring brand leaders instead of low cost options. This trend increases cost of therapy by 0.59 to 4.17 times. Therefore, there are great opportunities for cost minimization by using evidence based clinically effective and safe medicines. PMID- 25796153 TI - Influence of Artemisia annua extract derivatives on proliferation, apoptosis and metastasis of osteosarcoma cells. AB - Regarding the Artemisia annua extract derivatives called dihydroarteminin (DHA) as the object, we studied about its influence to the proliferation, apoptosis and metastasis of human osteosarcoma cells. First, we cultured in vitro the osteosarcoma cell strain and divided them into groups, then detected the cell proliferation, apoptosis and cell metastasis, etc by multiple measurement technique. Finally, we observed the influence of DHA to human osteosarcoma cells. Osteosarcoma cells were all sensitive to DHA, and the appropriate concentration range was 10~40MUM. DHA could effectively restrain its protein expression, and there was a significant difference between experimental group and control group. These finding suggest that, the Artemisia annua extract derivatives (DHA) has a biological effect of observably restraining the proliferation and metastasis of human osteosarcoma cells and promoting the tumour cell apoptosis. PMID- 25796154 TI - Influence of local application of glaucoma medications-travoprost eye drops on patients' tear film function. AB - This study discussed about the influence of local application of glaucoma medications -- travoprost eye drops to patients' tear film function. We selected 24 patients, 45 eyes with primary open-angle glaucoma or intraocular hypertension. All of the patients topically used the travoprost eye drops for one time every night. After and before the pharmacy, we proceeded 1, 2, 3 mo lines symptom score and Schirmer's test (St), corneal fluorescein staining (FL), breakup time of tear film (BUT). Average value of symptom score and FL of all the patients before pharmacy were 1.32 +/- 1. 55, 0.42 +/- 0.68, and 1, 2, 3mo after pharmacy were respectively 2.68 +/- 1.59, 0.96 +/- 0.81; 4.97 +/- 1.62, 1.46 +/- 0.62; 6.21 +/- 1.33, 1.88 +/- 0.44. Symptom score and FL of 1, 2, 3 mo patients after pharmacy were all prominent higher than it before pharmacy (P=0.00), and it gradually increased. The average value of patients symptom BUT and St before pharmacy were (7.71 +/- 0.87s), (8.32 +/- 2.63mm /5min) and 1, 2, 3 mo after pharmacy were respectively (6.93 +/- 1.17s), (7.69 +/- 3. 33mm /5min); (5.48 +/- 1.29s), (6.79 +/- 2.94mm /5min); (4.33 +/- 1.83s), (5.98 +/- 3.11mm/5min). BUT and St value after pharmacy were prominent all lower than the level before pharmacy (P=0.00). And it gradually reduced. Short-term use of travoprost eye drops would aggravate the corneal irritation of patients, and decrease the tear film stability and tear secretion. PMID- 25796155 TI - Clinical research on shengjie tongyu granules in the treatment of meteorological cardiovascular disease. AB - This paper aims to study the effect of Shengjie Tongyu granules on the treatment of meteorological cardiovascular disease in clinical treatment. Tongxinluo capsule that is clinically recognized as the effective drug in treating coronary heart disease and angina and was adopted as positive control. The results showed that, angina score and TCM score of two groups were all significantly improved after the treatment (P<0.01), but there was no statistical significance in comparison between groups (P>0.05); total effective rate of angina in the treatment group (77.78%) was superior than the control group (62.52%) after the treatment; but the difference had no statistical significance (P>0.05); total effective rate of TCM syndrome in the treatment group (75%) was superior than the control group (58.62%), and the difference had statistical significance (P<0.05). All these findings suggested that, Shengjie Tongyu granules can effectively improve the clinical symptoms of patients with coronary heart disease and angina, with the curative effect similar to Tongxinluo capsule; meanwhile, it can increase HDL-C and improve abnormal lipid metabolism of angina patient. In the treatment process, there is no significant untoward effect, blood, routine urine test and hepatorenal function have no abnormality, which proves that this drug is safe. PMID- 25796156 TI - Exercise preconditioning reduces ischemia reperfusion-induced focal cerebral infarct volume through up-regulating the expression of HIF-1alpha. AB - To study the effect and mechanism of exercise preconditioning on focal cerebral ischemia reperfusion induced cerebral infarction via rat model; Sixty Sprague Dawley rats were divided into three groups at random: ischemia reperfusion group (IR, n=24), sham group (sham, n=12) and exercise preconditioning group (EP, n=24). Group EP carried out moderate exercise preconditioning for 4 weeks (swimming with non-weight bearing, 60 minutes/day, 6 days/week), Rats in Group EP and IR were established cerebral ischemia reperfusion injury model by Zea Longa's thread method. The cerebral infarct volume in rat of different group was evaluated after 2%TTC staining, expression of HIF-1alpha in rats' brain was detected by real-time RT-PCR, immunohistochmeistry method and western blot. No cerebral infarction and significant expression of HIF-1alpha in Group sham. Compared with Group IR, there was smaller infarct volume and stronger HIF-1alpha expression in Group EP (P<0.05). Moderate exercise preconditioning reduces ischemia reperfusion induced focal cerebral infarct volume through up-regulating the expression of HIF-1alpha. PMID- 25796157 TI - Improvement on solubility of fluticasone propionate with cyclodextrins by mechanochemical activation. AB - To enhance the solubility and in vitro dissolution of fluticasone propionate (FP), a novel approach was developed with mechanochemical treatment. The order of solubilizing effect of beta-CD derivatives was observed as HP-beta-CD-SBE-beta-CD beta-CD-HE-beta-CD, consequently, HP-beta-CD showed the highest stability constant. To further improve FP solubility, FP and HP-beta-CD were grinded using a roll mill, the optimal conditions, determined through single factor experiments, were as follows: rotation frequency of 60 Hz; milling time of 6h. mass ratio of 1: 7. In comparison with pure FP, a 280-fold increase in solubility and a 2.15-fold higher dissolution rate of ground mixture was obtained. The characterization of FP and HP-beta-CD complexes had been analyzed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and fourier transform infrared spectroscopy (FT-IR). The results suggested that the interaction between FP and HP-beta-CD was strengthened and an amorphous ground mixture was gained. After stored for 60 days, the ground mixtures were stable both chemically and physically. PMID- 25796158 TI - Report: Discussion on the development of nano Ag/TiO2 coating bracket and its antibacterial property and biocompatibility in orthodontic treatment. AB - This paper aims to explore the antibacterial property of nano Ag/TiO2 coating bracket for the common bacteria in oral cavity, and discuss its biocompatibility. Micro morphology in the surface of nano Ag/TiO2 coating bracket was detected by scanning electron microscope (SEM), and surface roughness of ordinary mental bracket, nano TiO2 coating bracket and nano Ag/TiO2 coating bracket were measured. First, antibacterial property of nano Ag/TiO2 coating bracket on the common bacteria in oral cavity was studied by sticking membrane method. Secondly, bonding strength of nano TiO2 coating and nano Ag/TiO2 coating bracket in groups were detected by scratching test. The result showed that, the synthetic nano Ag/TiO2 coating was nanogranular films with rigorous organizational structure, presenting as smooth and clean surface, and antibacterial rate of nano Ag/TiO2 coating for the common bacteria in oral cavity for 20 min was more than 79% in the dark. All the findings suggested that, nano Ag/TiO2 coating bracket not only has antibacterial effect but also has good biocompatibility, therefore, it can satisfy the clinical request of orthodontic treatment. PMID- 25796159 TI - Molecular characteristics of extractives of Hylocereus undulates stems. AB - As one of traditional and dominant species of famous fruits in South China, Hylocereus undulates is considered as the important fruit resources, however, the constituent properties of Hylocereus undulates stems have not been known. Therefore, the molecular characteristics of extracts from Hylocereus undulates stems are studied to further utilize the resources. The result showed that there were many toxic substances in the extracts of Hylocereus undulates stems, suggesting that Hylocereus undulates stems should not be used as food. FTIR spectra showed that there were many active groups in the extracts of Hylocereus undulates stems, suggesting that Hylocereus undulates stems contain many bioactive substances. The result indicated that the extracts of H. undulates stems have huge potential resources. PMID- 25796160 TI - Curative effect of lauromacrogol and absolute ethyl alcohol injection guided by ultrasound on simplex hepatic cyst. AB - This research aims to analyze the curative effect and security of lauromacrogol injection and absolute ethyl alcohol treating simplex hepatic cyst respectively. The simplex hepatic cyst patients were divided into lauromacrogol group (86 cases, research group) and absolute ethyl alcohol group (80 cases, control group). Both two groups received sclerotherapy of thoracic drainage under ultrasonic guidance and the curative effect and untoward effect were observed. The result showed there was no hemorrhage or infection within two groups. During the therapeutic process, 45 patients (56.3%) suffered from pain at different degrees and 23 cases were found with symptom of drunkenness in control group, while the patients in the research group were found with no obvious discomfort. A week after treatment, 23 patients (25.0%) in control group still remained to have swelling pain at upper right stomach, while there were only 9 in treatment group (10.5%), and the difference was of statistical significance (X(2)=6.037, P<0.05). through 6 months of follow-up visit after the operation, we found the cure rate of lauromacrogol group was 94.6% and absolute ethyl alcohol was 92.6%, and the difference between these two groups was of no statistical significance (P>0.05). The results showed that, in the treatment of cystosclerosis with absolute ethyl alcohol injection under ultrasonic guidance, some patients suffered pain and the symptom of drunkenness at different degrees, whereas, lauromacrogol was effective with no untoward effects, therefore it is worthy of clinical popularization and application. PMID- 25796161 TI - Clinical study of ganglioside (GM) combined with methylprednisolone (MP) for early acute spinal injury. AB - This paper aims to make an analysis of the effects of ganglioside (GM) combined with methylprednisolone (MP) in early acute spinal injury. Fifty-three patients with acute spinal cord injury were included in this study and they were randomly divided into experimental and control group. Twenty-seven patients in the control group were treated with MP, while the rest 26 patients received more GM based on that. By observing and comparing the clinical responses from patients and recovery time of all indexes, results came out: the curative rates in the experimental and control group were 50.0%, 40.7% respectively, and the total effective rates were 92.3%, 85.2% respectively. There was a remarkable difference between the two groups (P<0.05). Patients in the experimental group took 6.2 +/- 1.9d to restore their sphincter function, 11.2 +/- 2.8d to recover their muscle forces to over grade II, and 13.8 +/- 3.9d to return general activity, while the patients in the other group clearly spent longer time on recovery, that were 12.1 +/- 3.2, 19.2 +/- 4.6 and 23.9 +/- 5.6 respectively. The distinct difference between the two groups was of statistical significance (P<0.05). We conclude that GM has better curative effects than MP, for it is able to promote the recovery of nerve function for patients and greatly improve the prognosis. PMID- 25796162 TI - The effects of intraperitoneal administration of gold nanoparticles size and exposure duration on oxidative and antioxidants levels in various rat organs. AB - As one of the toxic mechanism of nanoparticles (NPs), the reactive oxygen species (ROS) generation which has been widely studied. Nevertheless, the link between GNPs and antioxidant and oxidative stress markers has not been well established. The effects of gold nanoparticles (GNPs) size and exposure duration on antioxidant and oxidative stress markers including reduced glutathione (GSH), super oxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), total antioxidant capacity and malondialdehyde (MDA) were evaluated in different rat organs. Adult male Wistar-Kyoto rats were randomly divided into 6 groups of 5 animals each. One group served as control and received vehicle only. The 10 nm GNPs were used in this study. The GNPs electron density and homogeneity in shape and size was evaluated. Dose of 50 MUl of 10 nm GNPs in aqueous solution were administered to animals via intraperitoneal administration daily for exposure duration of 3 or 7 days. The rats were sacrificed 24 h after the last injection of GNPs. The specimens of liver, lung, kidney and heart were collected for biochemical analyses. The GPx, total antioxidant capacity, GSH and MDA levels significantly increased after administration of 10 nm GNPs for exposure duration of 3 and 7 days in the organs of rats compared with the control while the GR and SOD levels significantly decreased. The GNPs have the potential to interact with the biological system and cause undesirable effects. One of these damaging effects could be the disturbance in the natural balance between oxidative stress and antioxidant defense indices, which in turn can lead to various pathological effects. The changes in antioxidant and oxidative stress markers might be attributed to the production of ROS. PMID- 25796163 TI - The characteristics of acromegalic patients with hyperprolactinemia and the differences with hyperprolactinemia patients. AB - A substantial proportion of acromegalic patients have co-existent hyperprolactinaemia. To compare this group of population (AC+HPRL) to those of patients with merely hyperprolactinemia (HPRL), a retrospective analysis of patients was conducted. Data regarding clinical and immunohistochemical features, and outcome for patients were reviewed throughout the follow-up period. Four hundred and twenty-three patients were enrolled, with 329 in patients with HPRL and 94 in patients with AC+HPRL. Patients in the AC+HPRL group had a younger age at diagnosis (38.13 +/- 13.31 vs. 41.95 +/- 14.70 years; p=0.025) and a higher rate of invasion (p=0.007) than those in the HPRL group. The AC+HPRL group had higher GH levels but relatively lower PRL levels than the HPRL group before and after surgery. The rates of positive staining for GH and PRL in HPRL group were 15.20% and 93.01%, and the rates in AC+HPRL group were 84.04% and 87.23%. Patients with HPRL had a lower recurrence rate compared with patients in AC+HPRL group (p=0.018). Additionally, there were no significant correlations between the mean degree of preoperative GH or PRL and the positive rates of immunostaining (p>0.05, p>0.05). The Ki-67 indexes in HPRL group and AC+HPRL group were 3.07% +/ 2.13 and 2.33% +/- 1.71, respectively (p=0.001). In conclusion, acromegalic patients with hyperprolactinemia need careful and long-term follow-up following an operation. PMID- 25796164 TI - Role of Ki-67 in acromegalic patients with hyperprolactinemia: retrospective analysis in 61 Chinese Patients. AB - To evaluate the specific characteristics in acromegalic patients with hyperprolactinemia by analyzing the differences between patients with different Ki-67 values. Between 2002 and 2010, a set of data on 61 patients undergoing transsphenoidal surgery was available at the Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University. Patients were divided into Ki-67 >3% group and <3% group. A retrospective analysis of clinical, hormonal, immunohistochemical, and imaging was observed in all patients. There were no significant differences in age, gender, tumor size and apoplexy between the two groups. Time interval in Ki-67 >=3% group was longer than <3% group (P=0.037). Patients in Ki-67 >3% group had a higher rate of invasiveness (P=0.048), higher incidences of diabetes mellitus (P=0.036), coarse facial features (P=0.048), large hands and feet (P=0.003), higher GH levels (P<0.05), higher diabetes insipidus rate (P<0.001), and more frequent recurrence (P=0.011) than Ki-67 <3% group. Patients with higher Ki-67 value harbored longer time interval, more aggressive tumors, more acromegaly manifestations, higher GH level, and higher recurrence than patients with lower Ki-67 value. PMID- 25796165 TI - The optimization research of the multi-response problems based on the SUR. AB - In the optimization design of products and processes in the biological medicine, we need to consider multiple characteristics of quality simultaneously, namely multi-response problems, multi-response optimization design can improve the quality of the products effectively, and realize enormous economic benefits and so multi-response optimization design is showing a more and more important role in continuous quality improvement activities. But usually there is no specific set of input variables to make all the response variables be optimal, and the traditional multi-response surface method cannot solve the correlation problem between multi-responses and regression model problem effectively. Because we can make a better fitting model and solve the problem of the correlation between the response variables at the same time with SUR method, this thesis uses the SUR method to model the relationship between each response and control variables, and makes predictions; confirms the satisfaction function of each response and the overall satisfaction function; combines with practical problems of a company in biological medicine field named SX to conduct empirical research, this thesis confirms the optimal factor level combination with the overall satisfaction function in the end, thus solves the multi-response optimization problems. PMID- 25796166 TI - Review: Pediatric nursing status and its application analysis based on high quality nursing theory. AB - children's health concerns the revitalization and future of countries and nations. Pediatric nursing management is always the research hotspot of the international nursing field, and also the weak step in nursing management of China. China is now in a severe situation, i.e., shortage and loss of pediatric nursing staffs. In addition, a huge gap lies in the subject development between China and developed countries. This paper discussed the problems existing in the development of pediatric nursing as well as the application effect of high quality nursing in pediatric nursing, in order to promote the development of pediatric nursing and provide reference for nursing managers. PMID- 25796167 TI - Personality and neuroimaging measures differentiate PTSD from mTBI in veterans. AB - Mild traumatic brain injury (mTBI) is common among recent veterans and often is associated with chronic post-concussive symptoms (PCS). Elevated PCS may also be a consequence of post-traumatic stress disorder (PTSD) which shares symptoms with PCS. Identification of personality, biological, and psychopathology factors that contribute to the relationship between mTBI and PCS could help isolate the sources of chronic post concussive syndrome in veterans. Clinician rated diagnoses (PTSD, Major Depression, Alcohol Dependence), personality characteristics (Multidimensional Personality Questionnaire [MPQ] subscales), white matter brain imaging measures (Mean Diffusivity, Generalized Fractional Anisotropy), and diagnoses of mTBI were collected from 125 American military veterans of Iraq or Afghanistan. Linear and logistic regression models were tested to determine contributions to PCS and whether there were similar contributors to PTSD and mTBI. PCS score was associated with personality characteristics of high Stress Reaction and Traditionalism and low Control as well as mTBI. A diagnosis of PTSD was associated with low Social Closeness, PCS, Alcohol Dependence, and abnormal white matter mean diffusivity. Diagnosis of mTBI was associated with fewer white matter mean diffusivity abnormalities, PCS, and number of deployments. As commonly observed clinically, both PTSD and mTBI were associated with higher rates of PCS, though the contribution of PTSD appears to be secondary to personality traits, particularly Stress Reaction. Furthermore, the observation of factors that are uniquely associated with Blast mTBI (number of deployments) or with PTSD (Lifetime Alcohol Dependence and low Social Closeness), as well as a factor (region of abnormal MD) that had opposite effects on the likelihood of each diagnosis, indicates that the complex relationships between personality, psychopathology, and nature of mTBI need to be considered when interpreting chronic post-concussive symptoms. PMID- 25796168 TI - Serine/Threonine Protein Phosphatase-5 Accelerates Cell Growth and Migration in Human Glioma. AB - Glioma is the most common type of primary central nervous system tumor. Ser/Thr protein phosphatase 5 (PP5) has been shown to regulate multiple signaling cascades that suppress growth and facilitate apoptosis in several human cancer cells. However, the role of PP5 in human gliomas remains unclear. Herein, the relationship between PP5 expression and glioma cell growth was investigated, and the therapeutic value of PP5 in glioma was further evaluated. We employed a short hairpin RNA targeting PPP5C gene to knock down PP5 expression in human glioma cell lines U251 and U373. Depletion of PPP5C via RNAi remarkably inhibited glioma cell proliferation and colony formation, and arrested cell cycle in the G0/G1 phase. Moreover, knockdown of PP5 markedly suppressed glioma cell migration, as determined by Transwell assay. Our findings suggest that PPP5C could be essential for glioma cell growth and serve as a promising therapeutic target in human gliomas. PMID- 25796169 TI - Global metabolic profile identifies choline kinase alpha as a key regulator of glutathione-dependent antioxidant cell defense in ovarian carcinoma. AB - Epithelial Ovarian Cancer (EOC) "cholinic phenotype", characterized by increased intracellular phosphocholine content sustained by over-expression/activity of choline kinase-alpha (ChoKalpha/CHKA), is a metabolic cellular reprogramming involved in chemoresistance with still unknown mechanisms.By stable CHKA silencing and global metabolic profiling here we demonstrate that CHKA knockdown hampers growth capability of EOC cell lines both in vitro and in xenotransplant in vivo models. It also affected antioxidant cellular defenses, decreasing glutathione and cysteine content while increasing intracellular levels of reactive oxygen species, overall sensitizing EOC cells to current chemotherapeutic regimens. Natural recovering of ChoKalpha expression after its transient silencing rescued the wild-type phenotype, restoring intracellular glutathione content and drug resistance. Rescue and phenocopy of siCHKA-related effects were also obtained by artificial modulation of glutathione levels. The direct relationship among CHKA expression, glutathione intracellular content and drug sensitivity was overall demonstrated in six different EOC cell lines but notably, siCHKA did not affect growth capability, glutathione metabolism and/or drug sensitivity of non-tumoral immortalized ovarian cells. The "cholinic phenotype", by recapitulating EOC addiction to glutathione content for the maintenance of the antioxidant defense, can be therefore considered a unique feature of cancer cells and a suitable target to improve chemotherapeutics efficacy. PMID- 25796170 TI - Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice. AB - Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRbeta, IRS-2, Akt, GSK3beta and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRbeta, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. PMID- 25796171 TI - The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina. AB - The neurotoxic effects of N-methyl-N-nitrosourea (MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptor (PR) degeneration. With the helping of MEA (multielectrode array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retina were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PR dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits have been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underlying mechanism of human RP. PMID- 25796172 TI - The calmodulin inhibitor CGS 9343B inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. AB - We investigated the effects of the calmodulin inhibitor CGS 9343B on voltage dependent K(+) (Kv) channels using whole-cell patch clamp technique in freshly isolated rabbit coronary arterial smooth muscle cells. CGS 9343B inhibited Kv currents in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC50) value of 0.81MUM. The decay rate of Kv channel inactivation was accelerated by CGS 9343B. The rate constants of association and dissociation for CGS 9343B were 2.77+/-0.04MUM(-1)s(-1) and 2.55+/-1.50s(-1), respectively. CGS 9343B did not affect the steady-state activation curve, but shifted the inactivation curve toward to a more negative potential. Train pulses (1 or 2Hz) application progressively increased the CGS 9343B-induced Kv channel inhibition. In addition, the inactivation recovery time constant was increased in the presence of CGS 9343B, suggesting that CGS 9343B-induced inhibition of Kv channel was use-dependent. Another calmodulin inhibitor, W-13, did not affect Kv currents, and did not change the inhibitory effect of CGS 9343B on Kv current. Our results demonstrated that CGS 9343B inhibited Kv currents in a state-, time-, and use-dependent manner, independent of calmodulin inhibition. PMID- 25796173 TI - Erratum to: Anti-CarP antibodies as promising marker to measure joint damage and disease activity in patients with rheumatoid arthritis. PMID- 25796174 TI - Overview and future of single particle electron cryomicroscopy. AB - Electron cryomicroscopy (cryoEM) has experienced a quantum leap in its capability in recent years, due to improved microscopes, better detectors and better software. It is now possible to obtain near-atomic resolution 3D density maps of macromolecular assemblies using single particle cryoEM without the need for crystals. Although this recent progress has produced some outstanding achievements, we have still only partly realised the full potential of single particle cryoEM. If one or two remaining problems can be solved, it will become an even more powerful method in structural biology that should closely approach the limit of what is theoretically possible. PMID- 25796175 TI - CYP2J2 rs890293 polymorphism is associated with susceptibility to Alzheimer's disease in the Chinese Han population. AB - Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss. Increasing evidence indicates that inflammation in the brain is a powerful factor in AD progression. Epoxyeicosatrienoic acids, the biologically active derivatives of arachidonic acid, synthesized by cytochrome P450 (CYP) epoxygenases, have been proven to have powerful anti-inflammatory effects. The aim of this study was to examine whether polymorphism in CYP2J2, encoding one of the most common CYP epoxygenase isoforms, is associated with late-onset AD (LOAD). This case-control study genotyped 672 representatives of the Chinese Han population, including 321 LOAD patients and 351 healthy controls matched for age and gender, for the functional rs890293 polymorphism within CYP2J2 by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The CYP2J2 rs890293 T allele and GT+TT genotype were significantly associated with an increased risk of LOAD. Further data stratification according to the presence of the apolipoprotein E (APOE) e4 allele confirmed a strong association between CYP2J2 rs890293 and LOAD, and indicated that the involvement of CYP2J2 in LOAD was independent of ApoE-epsilon4. Our study demonstrated that CYP2J2 rs890293 is a possible predisposing genetic factor for progression of LOAD. PMID- 25796176 TI - Enriched environment increases myelinated fiber volume and length in brain white matter of 18-month female rats. AB - Cognition and memory decline with normal aging, which could be partly attributed to the degeneration of brain white matter. Previous studies demonstrated that exposure to an enriched environment (EE) could protect cognition and memory from aging. However, if or how EE might affect the brain white matter has not been thoroughly investigated. In the current study, 24 middle-aged (14-month-old) female Sprague -Dawley (SD) rats were randomly assigned to EE or standard environment (SE) for 4 months. At the end of the environment intervention, the Morris water maze tests were performed. Then, 5 rats were randomly selected from each group for stereological assessment of the brain white matter and its myelinated fibers. The results revealed that middle-aged rats living in EE displayed better spatial learning than SE controls. The white matter volume was 124.6 +/- 7.8mm(3) in EE rats, which was significantly enlarged compared with 84.8 +/- 3.4mm(3) in SE rats. Likewise, the myelinated fiber volume was markedly increased from 56.6 +/- 1.7 mm(3) in SE rats to 87.2 +/- 9.0mm(3) in EE rats; so was the myelinated fiber length from 83.5 +/- 6.6 km in SE rats to 119.0 +/- 10.0 km in EE rats. Our data suggested that EE could protect brain white matter and its myelinated fibers of female rats at middle age. PMID- 25796177 TI - Inhibition of histone deacetylases enhances the function of serotoninergic neurons in organotypic raphe slice cultures. AB - Inhibition of histone deacetylases (HDACs) is a promising approach for the treatment of mood disorders. However, the effects of HDAC inhibition on the serotonin (5-HT) system, a common target for psychiatric disorders, are poorly understood. Here, we show that a broad-spectrum HDAC inhibitor, trichostatin A (TSA), enhances the function of 5-HT neurons in organotypic raphe slice cultures. Sustained treatment with TSA (1MUM) for 2 or 4 days significantly increased the 5 HT tissue content and tryptophan hydroxylase 2 (TPH2) expression, which were accompanied by hyper-acetylation of histone H3 in the promoter region of the TPH2 gene. TSA treatment for 4 days increased the extracellular 5-HT level, which was significantly suppressed in the presence of the selective AMPA receptor (AMPAR) antagonist NBQX. Moreover, the expression of both the AMPAR subunit GluA2 and Ca(2+)/calmodulin-dependent kinase II alpha (CaMKIIalpha) mRNAs were significantly increased by TSA treatment. Co-treatment with the CaMKII inhibitors KN-62 and KN-93 prevented the TSA-induced increase in 5-HT release, but had no effect on the increases in 5-HT tissue content. These results suggest that inhibition of HDACs increases 5-HT synthesis and release by epigenetic mechanisms, and that 5-HT release is mediated by the enhancement of AMPAR mediated excitatory inputs and CaMKII signaling. PMID- 25796178 TI - Covert effects of "one drink" of alcohol on brain processes related to car driving: an event-related potential study. AB - The effects of a low dose of alcohol on car driving remain controversial. To address this issue, event-related potentials were recorded while subjects performed a simple car-following task in a driving simulator before and after consuming either "one drink" of beer (representing one standard alcoholic beverage containing 14 g of alcohol) or mineral water (control condition). Subjects who had consumed the determined amount of alcohol demonstrated no detectable outward behavioral signs of intoxication while performing the driving task, an observation in agreement with previous findings. However, the parietal P3 elicited by the brake lights of the preceding car was significantly reduced in amplitude, approximately 50% that observed under the control condition, likely indicating alteration of the neural processing of visual information critical for safe driving. The finding suggests that alcohol begins to affect neural processes for driving even at quantities too low to modify behavior. PMID- 25796179 TI - Genetic analysis of FMR1 repeat expansion in essential tremor. AB - We performed an association analysis of Fragile X mental retardation 1 (FMR1) CGG repeats in 321 essential tremor (ET) cases and 296 controls at Columbia University. In addition to analyzing the allele distribution (10-49 CGG repeats) in the entire sample, we also performed a screen for ET cases with the FMR1 premutation allele (55-200 CGG repeats), and evaluated an association between ET and FMR1 alleles that included gray zone alleles (41-54 CGG repeats). CGG premutation alleles and gray zone alleles were rare in ET cases, and we found no evidence for association of premutation or gray zone alleles with ET. These data suggest that FMR1 CGG repeats are not a genetic risk factor for ET. PMID- 25796180 TI - Effects of oxytocin on the fear memory reconsolidation. AB - Oxytoxin (OT) promotes social behavior and reduces anxiety. A great number of studies suggest that OT plays a role in learning and memory processes in animals and humans. Fear memories are rendered labile and prone to modification after reactivation and a restabilization and reconsolidation process is necessary for future memory conservation. This process is crucial for modulation of an existing memory and forms a promising therapeutic target for pathological memory disorders. In this study, we investigated whether a single systemic injection of OT has effects on reconsolidation of fear memories. We found post-reactivation administration of OT impairs reconsolidation of these memories and the impairment effect is reactivation-dependent. Postreactivation short-term fear memories and the learning of new fear memory were unaffected by OT. The study demonstrates the effectiveness of OT in persistently impairing fear memory retention by blocking reconsolidation in rats. OT administration after retrieval of fear memories may open a new avenue to treat pathological memory-related disorders. PMID- 25796181 TI - Lack of effect of Theiler's murine encephalomyelitis virus infection on system xc . AB - Changes in the expression of xCT, the specific subunit of system xc(-) or the cystine/glutamate antiporter, have been associated with several neurological disorders and system xc(-) was recently proposed as a potential target for the development of new treatment strategies for multiple sclerosis (MS). In this study we used Theiler's murine encephalomyelitis virus (TMEV) infection, both in vitro and in vivo, as a model to further evaluate the involvement of system xc(-) in MS. Protein levels of xCT, as well as activity of system xc(-) were unaffected in RAW264.7 macrophages after infection with the demyelinating DA strain of TMEV. Also, protein expression of xCT remained stable in spinal cord and brain of FVB mice 1-2 and 6 weeks after intracranial injection of the DA strain of TMEV. These results demonstrate that TMEV infection of macrophages or FVB mice has no effect on system xc(-) and as such cannot be used as a model to study the involvement of system xc(-) in MS. PMID- 25796182 TI - Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. AB - IMPORTANCE: Spironolactone has been shown to be an effective treatment option for hormonally mediated acne but can cause hyperkalemia. The prevalence of hyperkalemia among healthy young women taking spironolactone for acne is unclear. OBJECTIVE: To measure the rate of hyperkalemia in healthy young women taking spironolactone for acne or for an endocrine disorder with associated acne. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of healthy young women taking spironolactone for acne. Data from December 1, 2000, through March 31, 2014, were obtained from a clinical data repository. Outpatient data were collected from 2 tertiary care centers in the United States. We analyzed rates of hyperkalemia in 974 healthy young women taking spironolactone for acne. We also analyzed 1165 healthy young women taking and not taking spironolactone to obtain a profile for the baseline rate of hyperkalemia in this population. Exclusion criteria were cardiovascular disease, renal failure, and the use of medications that affect the renin-angiotensin-aldosterone system. MAIN OUTCOMES AND MEASURES: The rate of hyperkalemia in healthy young women taking spironolactone for acne was calculated. Secondary measures included spironolactone prescriber profiles and potassium monitoring practices. RESULTS: There were 13 abnormal serum potassium measurements in 1802 measurements obtained among young women receiving spironolactone therapy, yielding a hyperkalemia rate of 0.72%, equivalent to the 0.76% baseline rate of hyperkalemia in this population. Repeat testing in 6 of 13 patients demonstrated normal values, suggesting that these measurements may have been erroneous. In the remaining 7 patients, no action was taken. CONCLUSIONS AND RELEVANCE: The rate of hyperkalemia in healthy young women taking spironolactone for acne is equivalent to the baseline rate of hyperkalemia in this population. Routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. PMID- 25796183 TI - Dynamic and comparative QTL analysis for plant height in different developmental stages of Brassica napus L. AB - KEY MESSAGE: This report describes a dynamic QTL analysis for plant height at various stages using a large doubled haploid population and performs a QTL comparison between different populations in Brassica napus. Plant height (PH) not only plays an important role in determining plant architecture, but is also an important character related to yield. The process of determining PH occurs through a series of steps; however, no studies have focused on developmental behavior factors affecting PH in Brassica napus. In the present study, KN DH, a large doubled haploid population containing 348 lines was used for a dynamic quantitative trait locus (QTL) analysis for PH in six experiments. In all, 20 QTLs were identified at maturity, whereas 50 QTLs were detected by conditional m apping method and the same number was identified by unconditional mapping strategies. Interestingly, five unconditional QTLs ucPH.A2-2, ucPH.A3-2, ucPH.C5 1, ucPH.C6-2 and ucPH.C6-3 were identified that were consistent over the all growth stages of one or two particular experiments, and one conditional QTL cPH.A2-3 was expressed throughout the entire growth process in one experiment. A total of 70 QTLs were obtained after combining QTLs identified at maturity, by conditional and unconditional mapping strategies, in which 25 showed opposite genetic effects in different periods/stages and experiments. A consensus map containing 1357 markers was constructed to compare QTLs identified in the KN population with five previously mapped populations. Alignment of the QTLs detected in different populations onto the consensus map showed that 27 were repeatedly detected in different genetic backgrounds. These findings will enhance our understanding of the genetic control of PH regulation in B. napus, and will be useful for rapeseed genetic manipulation through molecular marker-assisted selection. PMID- 25796184 TI - PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at increased ER PM contacts in TNBC cells. AB - Phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) is known to sequester extracellular signal-regulated kinase (ERK) in the cytoplasm, inhibiting tumorigenesis of human breast cancer cells. Here, we describe how PEA-15 expression affects the dephosphorylation of epidermal growth factor receptor (EGFR) through endoplasmic reticulum (ER)-plasma membrane (PM) contacts in MDA-MB 468, triple-negative breast cancer (TNBC) cells. The increased intracellular calcium concentration resulting from increased cytoplasmic phosphorylated ERK facilitates movement of ER-anchored calcium sensors to the PM. The driving force of trans-localization of calcium-dependent proteins enhances the contact between the activated EGFR and ER-localized phosphatase, PTP1B. Consequently, our findings suggest a mechanism underneath the facilitation of EGFR dephosphorylation by cytoplasmic PEA-15 expression inside TNBC cells, which may be one of the dynamic mechanisms for down-regulation of activated EGFR in cancer cells. PMID- 25796185 TI - A ubiquitin-binding CUE domain in presenilin-1 enables interaction with K63 linked polyubiquitin chains. AB - The presenilins (PS1 and PS2) are the catalytic component of the gamma-secretase intramembrane protease complex, involved in the regulated intramembrane proteolysis of numerous type I transmembrane proteins, including amyloid precursor protein (APP) and Notch. Herein, we describe the identification and characterization of a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD) in PS1, and demonstrate that the CUE domain of PS1 mediates non-covalent binding to Lysine 63-linked polyubiquitin chains. Our results highlight a gamma-secretase-independent function for non-covalent ubiquitin signaling in the regulation of PS1, and add new insights into the structure and function of the presenilin proteins. PMID- 25796187 TI - Images of Percutaneous Closure of Ruptured Sinus of Valsalva. AB - The images of transcatheter closure of ruptured sinus of valsalva are presented. PMID- 25796186 TI - MicroRNA-184 modulates canonical Wnt signaling through the regulation of frizzled 7 expression in the retina with ischemia-induced neovascularization. AB - Aberrant activation of Wnt signaling contributes to ischemia-induced retinal neovascularization in oxygen-induced retinopathy (OIR), although the underlying mechanism is so far unclear. Here, we show that microRNA-184 (miR-184) is significantly down-regulated in the retina of OIR mice, and miR-184 negatively modulates Wnt signaling both in vivo and in vitro. Furthermore, we show that the Wnt receptor, frizzled-7, is a downstream target of miR-184, and delivery of miR 184 mimic inhibits Wnt signaling in the OIR retina. These results suggest that decreased levels of miR-184 are responsible, at least in part, for the aberrant activation of Wnt signaling in ischemia-induced retinal neovascularization. PMID- 25796188 TI - Dynamics of the locomotor-respiratory coupling at different frequencies. AB - The locomotor-respiratory coupling (LRC) is a universal phenomenon reported for various forms of rhythmic exercise. In this study, we investigated the effect of movement and respiratory frequencies on LRC. Participants were instructed to cycle or breath in synchrony with a periodic auditory stimulation at preferred and non-preferred frequencies. LRC stability was assessed by frequency and phase coupling indexes using the theory of nonlinear coupled oscillators through the sine circle map model, and the Farey tree. Results showed a stabilizing effect of sound on LRC for all frequencies and for the two systems paced. The sound-induced effect was more prominent when the rhythm of the stimulation corresponded to the preferred frequencies. The adoption of cycling or respiratory frequencies far off preferential ones led to a loss of stability in LRC. Contrary to previous findings, our results suggest that LRC is not unidirectional-from locomotion onto respiration-but bidirectional between the two systems. They also suggest that auditory information plays an important role in the modulation of LRC. PMID- 25796189 TI - Ultrasound-guided thrombin injection of genicular artery pseudoaneurysm. AB - Pseudoaneurysm is a rare complication after arthroscopic procedures involving the knee. A 38-year-old man presented 1 month after right-knee arthroscopy with a 2 cm pulsating mass on the medial side of the right knee. Duplex ultrasound evaluation revealed 2.5 * 2.1-cm pseudoaneurysm just distal to the patella with arterialized flow communicating with the inferior medial genicular artery. Ultrasound-guided thrombin injection was performed in an office setting, and the resolution of active flow within the pseudoaneurysm was confirmed with duplex ultrasonography. PMID- 25796190 TI - Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic pharmacodynamic relationships. AB - Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3 yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphe serotonergic cells paralleled by plasma sampling showed that there was ~60% inhibition of firing rate indicating significant activation of 5-HT1A receptors-at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic-pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts. PMID- 25796192 TI - Central nervous system infiltrates are characterized by features of ongoing B cell-related immune activity in MP4-induced experimental autoimmune encephalomyelitis. AB - In multiple sclerosis (MS) lymphoid follicle-like aggregates have been reported in the meninges of patients. Here we investigated the functional relevance of B cell infiltration into the central nervous system (CNS) in MP4-induced experimental autoimmune encephalomyelitis (EAE), a B cell-dependent mouse model of MS. In chronic EAE, B cell aggregates were characterized by the presence of CXCL13(+) and germinal center CD10(+) B cells. Germline transcripts were expressed in the CNS and particularly related to TH17-associated isotypes. We also observed B cells with restricted VH gene usage that differed from clones found in the spleen. Finally, we detected CNS-restricted spreading of the antigen specific B cell response towards a myelin and a neuronal autoantigen. These data imply the development of autonomous B cell-mediated autoimmunity in the CNS in EAE - a concept that might also apply to MS itself. PMID- 25796191 TI - Construction of a high-density genetic map and lint percentage and cottonseed nutrient trait QTL identification in upland cotton (Gossypium hirsutum L.). AB - Upland cotton plays a critical role not only in the textile industry, but also in the production of important secondary metabolites, such as oil and proteins. Construction of a high-density linkage map and identifying yield and seed trait quantitative trail loci (QTL) are prerequisites for molecular marker-assisted selective breeding projects. Here, we update a high-density upland cotton genetic map from recombinant inbred lines. A total of 25,313 SSR primer pairs were screened for polymorphism between Yumian 1 and T586, and 1712 SSR primer pairs were used to genotype the mapping population and construct a map. An additional 1166 loci have been added to our previously published map with 509 SSR markers. The updated genetic map spans a total recombinant length of 3338.2 cM and contains 1675 SSR loci and nine morphological markers, with an average interval of 1.98 cM between adjacent markers. Green lint (Lg) mapped on chromosome 15 in a previous report is mapped in an interval of 2.6 cM on chromosome 21. Based on the map and phenotypic data from multiple environments, 79 lint percentage and seed nutrient trait QTL are detected. These include 8 lint percentage, 13 crude protein, 15 crude oil, 8 linoleic, 10 oleic, 13 palmitic, and 12 stearic acid content QTL. They explain 3.5-62.7 % of the phenotypic variation observed. Four morphological markers identified have a major impact on lint percentage and cottonseed nutrients traits. In this study, our genetic map provides new sights into the tetraploid cotton genome. Furthermore, the stable QTL and morphological markers could be used for fine-mapping and map-based cloning. PMID- 25796193 TI - Aminobisphosphonates inhibit dendritic cell-mediated antigen-specific activation of CD1d-restricted iNKT cells. AB - CD1d-restricted invariant natural killer T (iNKT) cells constitute an important immunoregulatory T cell subset that can be activated by the synthetic glycolipid alpha-galactosylceramide (alpha-GalCer) and initiate antitumor immune responses. As cancer patients are frequently treated with aminobisphosphonates (NBP), it is relevant to determine possible effects of NBP on CD1d-restricted glycolipid Ag presentation to iNKT cells. We report a striking reduction of alpha-GalCer induced iNKT cell activation by monocyte derived dendritic cells (moDC) upon their exposure to NBP during maturation. We found that production of apolipoprotein E (apoE), which is a known facilitator of trans-membrane transport of exogenously derived glycolipids, was significantly diminished in moDC exposed to NBP. As the inhibitory effect of NBP on iNKT cell activation was alleviated by exogenous apoE, our data indicate that reduced apoE production by antigen presenting cells (APC) through NBP limits glycolipid-induced iNKT cell activation. This should be taken into account in the design of iNKT cell-based anti-cancer therapies. PMID- 25796194 TI - Changing College Students' Conceptions of Autism: An Online Training to Increase Knowledge and Decrease Stigma. AB - College students with autism may be negatively impacted by lack of understanding about autism on college campuses. Thus, we developed an online training to improve knowledge and decrease stigma associated with autism among college students. Participants (N = 365) completed a pre-test, online training, and post test. Women reported lower stigma towards autism than men. Participation in the training was associated with decreased stigma and increased knowledge about autism. Although participants exhibited relatively high baseline knowledge of autism, misconceptions were common, particularly in open-ended responses. Participants commonly confused autism with other disorders, such as learning disabilities. This study suggests that online training may be a cost-effective way to increase college students' understanding and acceptance of their peers with autism. PMID- 25796195 TI - The Effects of DSM-5 Criteria on Number of Individuals Diagnosed with Autism Spectrum Disorder: A Systematic Review. AB - A growing body of research has raised concerns about the number of individuals diagnosed with autism spectrum disorder (ASD) according to DSM-IV-TR who may no longer qualify for diagnoses under the new DSM-5 criteria, published in May 2013. The current study systematically reviews 25 articles evaluating samples according to both DSM-IV-TR and DSM-5 ASD criteria. Consistent with previous reviews, the majority of included studies indicated between 50 and 75% of individuals will maintain diagnoses. We conducted visual analyses of subgroups using harvest plots and found the greatest decreases among high-functioning populations with IQs over 70 and/or previous diagnoses of PDD-NOS or Asperger's disorder. We discuss the potential research and clinical implications of reduced numbers of individuals diagnosed with ASD. PMID- 25796196 TI - Safety and efficacy study of nasopharyngeal cancer stem cell vaccine. AB - In this trial, nasopharyngeal cancer stem cells (CSCs) were separated and cultured to produce a vaccine; its safety and efficacy were prospectively evaluated in low-, medium-, and high-dose groups. Between April and September 2014, we enrolled 90 patients who met the enrolment criteria, and assigned them to three groups (n=30). Throughout the trial, injection site reaction was the most common reaction (81%), and fever was least common (31%); however, there was no difference among the three groups. When the immune responses pre- and post vaccination were compared, we found that the CSC-specific and -nonspecific response in the medium- and high-dose groups were both significantly enhanced. This study is the first clinical trial of a nasopharyngeal CSC vaccine and preliminarily proves its safety and efficacy. PMID- 25796198 TI - Berberine reduces Toll-like receptor-mediated macrophage migration by suppression of Src enhancement. AB - Berberine is an isoquinoline with anti-inflammatory activity. We previously demonstrated that there was a loop of signal amplification between nuclear factor kappa B and Src for macrophage mobility triggered by the engagement of Toll-like receptors (TLRs). The simultaneous suppression of lipopolysaccharide (LPS) mediated upregulation of inducible nitric oxide synthase, cyclooxygenase 2, and cell mobility in berberine-treated macrophages suggested Src might be a target of berberine. Indeed, th reduced migration, greatly suppressed Src induction in both protein and RNA transcript by berberine were observed in macrophages exposed to LPS, peptidoglycan, polyinosinic-polycytidylic acid, and CpG oligodeoxynucleotides. In addition to Src induction, berberine also inhibited LPS mediated Src activation in Src overexpressing macrophages and S-nitroso-N acetylpenicillamine (a nitric oxide donor) could partly restore it. Moreover, berberine suppressed Src activity in fibronectin-stimulated macrophages and in v Src transformed cells. These results implied that by effectively reducing Src expression and activity, berberine inhibited TLR-mediated cell motility in macrophages. PMID- 25796197 TI - Psychopharmacologic treatment of eating disorders: emerging findings. AB - Psychopharmacologic treatment is playing a greater role in the management of patients with eating disorders. In this paper, we review randomized, placebo controlled trials (RCTs) conducted in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other eating disorders over the past 3 years. Fluoxetine remains the only medication approved for an eating disorder, that being BN. RCTs of antipsychotics in AN have had mixed results; the only agent with some evidence of efficacy is olanzapine. One study suggests dronabinol may induce weight gain in AN. Preliminary studies suggest lack of efficacy of alprazolam, dehydroepiandrosterone, or physiologic estrogen replacement in AN; erythromycin in BN; and the opioid antagonist ALKS-33 in BED. In BED with obesity or overweight, bupropion may cause mild weight loss without seizures, and chromium may improve glucose regulation. Also in BED, three RCTs suggest the stimulant prodrug lisdexamfetamine may reduce binge eating episodes, and another RCT suggests intranasal naloxone may decrease time spent binge eating. There remains a disconnection between the size of eating disorders as a public health problem and the lack of pharmacotherapy research of these conditions. PMID- 25796199 TI - P2X7 receptor antagonists protect against N-methyl-D-aspartic acid-induced neuronal injury in the rat retina. AB - Activation of N-methyl-d-aspartic acid (NMDA) receptors followed by a large Ca(2+) influx is thought to be a mechanism of glaucoma-induced neuronal cell death. It is possible that damage-associated molecular patterns leak from injured cells, such as adenosine triphosphate, causing retinal ganglion cell death in glaucoma. In the present study, we histologically investigated whether antagonists of the P2X7 receptor protected against NMDA-induced retinal injury in the rat in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal injection of NMDA. We used A438079 (3-(5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine) and brilliant blue G as P2X7 receptor antagonists. Upon morphometric evaluation 7 days after an intravitreal injection (200 nmol/eye), NMDA-induced cell loss was apparent in the ganglion cell layer. Intravitreal A438079 (50 pmol/eye) simultaneously injected with NMDA and intraperitoneal brilliant blue G (50 mg/kg) administered just before the NMDA injection as well as 24 and 48h after significantly reduced cell loss. In addition, A438079 decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells 12h after NMDA injection. P2X7 receptors were immunolocalized in the ganglion cell layer and the inner and outer plexiform layers, whereas the immunopositive P2X7 receptor signal was not detected on the Iba1-positive microglial cells that infiltrated the retina 12h after NMDA injection. The present study shows that stimulation of the P2X7 receptor is involved in NMDA-induced histological damage in the rat retina in vivo. P2X7 receptor antagonists may be effective in preventing retinal diseases caused by glutamate excitotoxicity, such as glaucoma and retinal artery occlusion. PMID- 25796200 TI - Therapeutic and immunomodulatory effects of glucosamine in combination with low dose cyclosporine a in a murine model of imiquimod-induced psoriasis. AB - Although cyclosporine A (CsA) is a potent immunomodulating agent and is commonly used as a systemic agent for the management of psoriasis patients, current clinical treatments are not always effective due to the clinical inefficacy of low-doses and numerous harmful effects of higher doses. Currently, the combined use of two other systemic drugs often has better therapeutic efficacy and is safer than low or high dose of a single drug. Glucosamine (Glu) also has immunomodulatory properties for autoimmune diseases. The aims of our study were to investigate the therapeutic efficacy of Glu in combination with low-dose CsA on imiquimod (IMQ)-induced psoriasis-like dermatitis in mice and to determine its immunomodulatory mechanism. We found that combined treatment with Glu (300 mg/kg) and low-dose (10 or 20mg/kg) CsA strongly ameliorated the development of psoriasis-like skin lesions and reduced the levels of Th1 cytokine (TNF-alpha) and Th17 cytokines (IL-17, IL-22, and IL-23) in the serum and dorsal skin. Histological findings also showed that the thickening of epidermis, stratum corneum, and inflammatory cell infiltration. Particularly, these combined treatments increased the number of CD4(+)CD25(+) regulatory T (Treg) cells in splenic. These results suggest that use of a combination of each drug might be used as an efficacious and safe alternative therapeutic strategy, as well as may provide an immunomodulatory approach for T cell-mediated autoimmune diseases, including psoriasis. PMID- 25796201 TI - Genome mining of ascomycetous fungi reveals their genetic potential for ergot alkaloid production. AB - Ergot alkaloids are important as mycotoxins or as drugs. Naturally occurring ergot alkaloids as well as their semisynthetic derivatives have been used as pharmaceuticals in modern medicine for decades. We identified 196 putative ergot alkaloid biosynthetic genes belonging to at least 31 putative gene clusters in 31 fungal species by genome mining of the 360 available genome sequences of ascomycetous fungi with known proteins. Detailed analysis showed that these fungi belong to the families Aspergillaceae, Clavicipitaceae, Arthrodermataceae, Helotiaceae and Thermoascaceae. Within the identified families, only a small number of taxa are represented. Literature search revealed a large diversity of ergot alkaloid structures in different fungi of the phylum Ascomycota. However, ergot alkaloid accumulation was only observed in 15 of the sequenced species. Therefore, this study provides genetic basis for further study on ergot alkaloid production in the sequenced strains. PMID- 25796202 TI - Reciprocal translocation identified in Vigna angularis dominates the wild population in East Japan. AB - Using an F2 population derived from cultivated and wild azuki bean, we previously detected a reciprocal translocation and a seed size QTL near the translocation site. To test the hypothesis that the translocation in the cultivated variety contributed to the larger seed size, we performed further linkage analyses with several cross combinations between cultivated and wild azuki beans. In addition, we visually confirmed the translocation by cytogenetic approach using 25 wild and cultivated accessions. As a result, we found the translocation-type chromosomes in none of the cultivated accessions, but in a number of the wild accessions. Interestingly, all the wild accessions with the translocation were originally collected from East Japan, while all the accessions with normal chromosomes were from West Japan or the Sea of Japan-side region. Such biased geographical distribution could be explained by the glacial refugium hypothesis, and supported narrowing down the domestication origin of cultivated azuki bean. PMID- 25796203 TI - Ground level air convection produces frost damage patterns in turfgrass. AB - Frost injury patterns are commonly observed on the warm-season turfgrass species bermudagrass (Cynodon species Rich.), zoysiagrass (Zoysia species Willd.), and buffalograss [Bouteloua dactyloides (Nutt.) J.T. Columbus] in cool-temperate and subtropical zones. Qualitative observations of these injury patterns are presented and discussed. A model for the formation of such patterns based on thermal instability and convection of air is presented. The characteristic length scale of the observed frost pattern injury requires a temperature profile that decreases with height from the soil to the turfgrass canopy surface followed by an increase in temperature with height above the turfgrass canopy. This is justified by extending the earth temperature theory to include a turf layer with atmosphere above it. Then the theory for a thermally unstable layer beneath a stable region by Ogura and Kondo is adapted to a turf layer to include different parameter values for pure air, as well as for turf, which is treated as a porous medium. The earlier porous medium model of Thompson and Daniels proposed to explain frost injury patterns is modified to give reasonable agreement with observed patterns. PMID- 25796204 TI - Effect of heterogenous and homogenous air gaps on dry heat loss through the garment. AB - In real life conditions, the trapped air between the human body and the garment has uneven shape and vary over the body parts as a consequence of the complex geometry of the human body. However, the existing clothing models assume uniform air layer between the human body and the garment or its full contact, which may cause large error in the output of simulations. Therefore, the aim of this study was to investigate the effect of a heterogeneous vertical air gap with different configuration of folds (size and frequency) on dry heat loss using a heated cylinder (Torso). It was found that the presence of folds in the garment led to an increased heat loss from the body in comparison to a homogeneous air gap of comparable size. Interestingly, the size of folds did not have an influence on the dry heat loss. Additionally, the effect of the contact area on dry heat loss became important when exceeding a threshold of about 42%. The results from this study are useful for modelling of a realistic dry heat loss through the clothing and contribute to the improvement of design of protective and active sport garments. PMID- 25796205 TI - Evaluation of micro-emboli in a patient with ventricular assist device support with hemolysis. AB - The clinical relevance of transcranial Doppler (TCD) detection of micro-embolic signals (MES) in patients with ventricular assist devices (VADs) has been described. However, all of the previous studies concerning TCD in patients with VADs were conducted in patients with old devices; the clinical relevance of TCD in patients with newer devices has not been fully elucidated. We recently encountered a patient with a continuous-flow VAD with hemolysis. TCD monitoring was useful for the direct evaluation of micro-emboli in this patient. A 50-year old male who underwent HeartMate II((r)) VAD (Thoratec Corporation; Pleasanton, CA) implantation with a diagnosis of ischemic cardiomyopathy 15 months prior was admitted to our institution because of findings suggestive of hemolysis, such as elevated lactate dehydrogenase (LDH) and total bilirubin. Unfractionated heparin was started after admission and hemolysis gradually improved. On admission, TCD detected 146 MES during 30 min of monitoring. During the hospital course, the MES count decreased to 20 signals on hospital day 4 and further decreased to 2 signals on hospital day 15 along with decreases in LDH and total bilirubin. Since hemolysis in VAD patients is thought to be associated with thromboembolic outcomes, MES detected by TCD indicate subclinical micro-emboli. TCD monitoring may be useful for assessing the risk of thromboembolic events in newer continuous flow VAD patients through direct visualization of micro-emboli. PMID- 25796206 TI - Development of a Practical Method to Detect Noroviruses Contamination in Composite Meals. AB - Various methods to detect foodborne viruses including norovirus (NoV) in contaminated food have been developed. However, a practical method suitable for routine examination that can be applied for the detection of NoVs in oily, fatty, or emulsive food has not been established. In this study, we developed a new extraction and concentration method for detecting NoVs in contaminated composite meals. We spiked NoV-GI.4 or -GII.4 stool suspension into potato salad and stir fried noodles. The food samples were suspended in homogenizing buffer and centrifuged to obtain a food emulsion. Then, anti-NoV-GI.4 or anti-NoV-GII.4 rabbit serum raised against recombinant virus-like particles or commercially available human gamma globulin and Staphylococcus aureus fixed with formalin as a source of protein A were added to the food emulsion. NoV-IgG-protein A-containing bacterial complexes were collected by centrifugation, and viral RNA was extracted. The detection limits of NoV RNA were 10-35 copies/g food for spiked NoVs in potato salad and stir-fried noodles. Human gamma globulin could also concentrate other NoV genotypes as well as other foodborne viruses, including sapovirus, hepatitis A virus, and adenovirus. This newly developed method can be used as to identify NoV contamination in composite foods and is also possibly applicable to other foodborne viruses. PMID- 25796207 TI - Biofilm formation on tympanostomy tubes depends on methicillin-resistant Staphylococcus aureus genetic lineage. AB - Bacterial biofilm formation has been implicated in the high incidence of persistent otorrhoea after tympanostomy tube insertion. The aim of the study was to investigate whether biofilm formation on tympanostomy tubes depends on the genetic profile of methicillin-resistant Staphylococcus aureus (MRSA) strains. Capacity of biofilm formation on fluoroplastic tympanostomy tubes (TTs) was tested on 30 MRSA strains. Identification and methicillin resistance were confirmed by PCR for nuc and mecA genes. Strains were genotypically characterised (SCCmec, agr and spa typing). Biofilm formation was tested in microtiter plate and on TTs. Tested MRSA strains were classified into SCCmec type I (36.7 %), III (23.3 %), IV (26.7 %) and V (13.3 %), agr type I (50 %), II (36.7 %) and III (13.3 %), and 5 clonal complexes (CCs). All tested MRSA strains showed ability to form biofilm on microtiter plate. Capacity of biofilm formation on TTs was as following: 13.3 % of strains belonged to the category of no biofilm producers, 50 % to the category of weak biofilm producers and 36.7 % to moderate biofilm producers. There was a statistically significant difference between CC, SCCmec and agr types and the category of biofilm production on TTs tubes (p < 0.001): CC5, SCCmecI type and agrII type with a moderate amount of biofilm, and CC8 and agrI type with a low amount of biofilm. Biofilm formation by MRSA on TTs is highly dependent on genetic characteristics of the strains. Therefore, MRSA genotyping may aid the determination of the possibility of biofilm-related post tympanostomy tube otorrhea. PMID- 25796208 TI - The Intergenerational Transmission of Smoking Across Three Cohabitant Generations: A Count Data Approach. AB - This paper examines the extent to which parent and grandparent smoking influences adolescent smoking and its quantitative implications for tobacco control. It extends similar prior studies by investigating the effects on the probability of becoming a smoker and on the number of cigarettes smoked. Count regressions were used to assess the intergenerational transmission of smoking across three cohabitant generations, simultaneously, using data from the 2010 survey "Encuesta Estatal Sobre Uso De Drogas en Estudiantes de Ensenanzas Secundarias". This survey, of 32,234 students, constitutes a representative sample of Spanish students between 14 and 18 years of age. Living with a mother who smokes, a father who smokes, or a grandparent who smokes reduces the odds of being a non smoker by 36.1% (OR 0.639), 26.1% (OR 0.739) and 20.3% (OR 0.797), respectively. Parental smoking increases cigarette consumption levels among adolescents. Having a cohabitant mother who smokes increases the number of cigarettes smoked by children by around 18.7% (IRR 1.187), while having a cohabitant father who smokes increases the number by around 12.1% (IRR 1.121). Estimates support the hypothesis that visibility of smoking among parents and grandparents is a strong predictor of smoking among adolescents. Accordingly, quitting smoking by parents and grandparents before children become adolescents appears to be a powerful means to both reduce smoking rates among adolescents and the number of cigarettes smoked by smokers; such decisions appear to exert a stronger influence on the prevalence of smoking and consumption levels than exposure to smoking prevention campaigns at school. PMID- 25796209 TI - Assimilation and contrast are on the same scale of food anticipated-experienced pleasure divergence. AB - Consumption of a product is preceded by an anticipation of its qualities by the consumer, which can itself modify the consumption experience. Improved knowledge of anticipation would allow better manipulation of it, for example to enhance the acceptance of healthier foods. According to the Assimilation-Contrast theory, the size of anticipation-reality divergence determines how anticipation influences consumers' satisfaction. For small divergences, experienced pleasure is the same as the anticipated pleasure (Assimilation); for large ones, the effect of surprise provokes an even larger discordance with that which was anticipated (Contrast). Few studies have attempted to observe both effects simultaneously, or to consider the anticipation-reality divergence quantitatively rather than qualitatively; these were the study's objectives. A range of 10 flavored drinks was developed to vary progressively in intensity. Ninety healthy young men consumed samples during two separate sessions. In session 1, hedonic and sensory scores of all drinks were recorded during blind tasting. In session 2, three drinks were chosen as references for taste intensity, and associated with neutral symbols that served as labels. Subjects then consumed 36 drink samples, each one bearing a label. For half of the samples drinks did not correspond to labels, creating a range of anticipation-reality divergence. By predicting session 2 scores using linear modeling with session 1 blind ratings as input, it was confirmed that both Assimilation and Contrast effects on hedonic ratings were present (Assimilation (t(89) = 5.645, p < 0.0001) and Contrast (t(89) = 3.186, p = 0.002 or t(89) = 2.494, p = 0.015, depending on the drink-label combination)). This study was the first to position Assimilation and Contrast within a quantitative context using controlled divergence variation rather than products from distinct categories. PMID- 25796210 TI - Measurement and validation of measures for impulsive food choice across obese and healthy-weight individuals. AB - The present study established a brief measure of delay discounting for food, the Food Choice Questionnaire (FCQ), and compared it to another more established measure of food discounting that uses the adjusting amount (AA) procedure. One hundred forty-four undergraduate participants completed either two measures of hypothetical food discounting (a computerized food AA procedure or the FCQ) or two measures of hypothetical money discounting [a computerized monetary AA procedure or the Monetary Choice questionnaire (MCQ)]. The money condition was used as a replication of previous work. Results indicated that the FCQ yielded consistent data that strongly correlated with the AA food discounting task. Moreover, a magnitude effect was found with the FCQ, such that smaller amounts of food were discounted more steeply than larger amounts. In addition, individuals with higher percent body fat (PBF) discounted food more steeply than individuals with lower PBF. The MCQ, which also produced a magnitude effect, and the monetary adjusting amount procedure yielded data that were orderly, consistent, and correlated strongly with one another, replicating previous literature. This study is the first to show that a novel measure of food discounting (the FCQ) yields consistent data strongly correlated with an established measure of food discounting and is sensitive to PBF. Moreover, the FCQ is easier and quicker to administer than the AA procedure, which may interest researchers who use discounting tasks in food-related research. PMID- 25796212 TI - Pathogenicity of three type 2 porcine reproductive and respiratory syndrome virus strains in experimentally inoculated pregnant gilts. AB - Mechanisms of reproductive failure resulting from infection with porcine reproductive and respiratory syndrome virus (PRRSV) are still poorly understood. Presented herein are the results of a side-by-side evaluation of the pathogenicity of three type 2 PRRSV strains in a reproductive model, from a pilot study used to develop experimental conditions and laboratory methods for a larger experiment. Pregnant gilts were experimentally infected with PRRSV at gestation day 85 or served as uninfected negative controls. After 21 days, all gilts and fetuses were necropsied. Clinical signs, litter outcome, viral load, cytokine levels, and pathology were compared from samples collected among pigs exposed to the three PRRSV strains. Based on differences in histologic lesions, and fetal weights, and numeric differences in gilt serum cytokine levels, litter outcome and virus replication in fetal tissues KS06-483 appeared less virulent than NVSL 97-7895 and KS06-72109 isolates. Levels of chemokine ligand 2 (CCL2), interferon alpha (IFNalpha), and interferon gamma (IFNgamma) were increased in PPRRSV infected compared to non-infected gilts (0.01 > P < 0.06). Inoculation with NVSL 97-7895 induced higher levels of all three cytokines. All three PRRSV isolates were able to induce high mean viral load in individual litters, which was closely related to the proportion of PRRSV positive fetuses in the litter. Viral load in fetal samples was also positively associated with viral load at the maternal fetal interface. All but one dead fetus were positive for PRRSV RNA, and higher concentrations of PRRSV RNA in fetal thymus increased the odds of fetal death. Our results suggest that virus replication in fetal tissues and the maternal fetal interface, but not in other gilt tissues, are important for the outcome of reproductive PRRS. Additionally, our data indicate that umbilical lesions decreased corresponding to the use of pentobarbital sedation prior to euthanasia of pregnant gilts by captive bolt. PMID- 25796213 TI - New places and ethical spaces: philosophical considerations for health care ethics outside of the hospital. AB - This paper examines the meaning of space and its relationship to value. In this paper, I draw on Henri Lefebvre to suggest that our ethics produce and are produced by spaces. Space is not simply a passive material container or neutral geographic location. Space includes the ideas on which buildings are modeled, the ordering of objects and movement patterns within the space, and the symbolic meaning of the space and its objects. Although often unrecognized, space itself is value-laden, and its values are suggested as people interact within that space. By reflecting on the spaces of health care, we will see that we not only must attend to the quandaries caused by the delivery of health care in non-acute places, but also to the values that produce and are produced by spaces. These values influence our moral imagination and shape us as people. PMID- 25796211 TI - Multi-step regulation of innate immune signaling by Kaposi's sarcoma-associated herpesvirus. AB - The innate immune system provides an immediate and relatively non-specific response to infection with the aim of eliminating the pathogen before an infection can be fully established. Activation of innate immune response is achieved by production of pro-inflammatory cytokines and type I interferon (IFN). The IFN response in particular is one of the primary defenses utilized by the host innate immune system to control pathogen infection, like virus infection. Hence, viruses have learned to manipulate host immune control mechanisms to facilitate their propagation. Due to this, much work has been dedicated to the elucidation of the Kaposi's sarcoma-associated herpesvirus (KSHV)-mediated immune evasion tactics that antagonize a host's immune system. This review presents our current knowledge of the immune evasion strategies employed by KSHV at distinct stages of its life cycle to control a host's immune system with a focus on interferon signaling. PMID- 25796214 TI - Targeting species D adenoviruses replication to counteract the epidemic keratoconjunctivitis. AB - Human adenoviruses are non-enveloped DNA viruses causing various infections; their pathogenicity varies dependent on virus species and type. Although acute infections can sometimes take severe courses, they are rarely fatal in immune competent individuals. Adenoviral conjunctivitis and epidemic keratoconjunctivitis are hyperacute and highly contagious infections of the eye caused by human adenovirus types within species D. Currently there is no causal treatment available to counteract these diseases effectively. The E2B region of the adenovirus genome encodes for the viral DNA polymerase, which is required for adenoviral DNA replication. Here we propose novel model systems to test this viral key factor, DNA polymerase, as a putative target for the development of efficient antiviral therapy based on RNA interference. Using our model cell lines we found that different small interfering RNAs mediate significant suppression (up to 90%) of expression levels of viral DNA polymerase upon transfection. Moreover, permanent expression of short hairpin RNA based on the most effective small interfering RNA led to a highly significant, more than tenfold reduction in replication for different human group D adenoviruses involved in ocular infections. PMID- 25796215 TI - Effects of proteinase inhibitor from Adenanthera pavonina seeds on short- and long term larval development of Aedes aegypti. AB - Currently, one of the major global public health concerns is related to the transmission of dengue/yellow fever virus by the vector Aedes aegypti. The most abundant digestive enzymes in Ae. aegypti midgut larvae are trypsin and chymotrypsin. Since protease inhibitors have the capacity to bind to and inhibit the action of insect digestive proteinases, we investigated the short- and long term effects of Adenanthera pavonina seed proteinase inhibitor (ApTI) on Ae. aegypti larvae, as well as a possible mechanism of adaptation. ApTI had a significant effect on Ae. aegypti larvae exposed to a non-lethal concentration of ApTI during short- and long-duration assays, decreasing survival, weight and proteinase activities of midgut extracts of larvae. The zymographic profile of ApTI demonstrated seven bands; three bands apparently have trypsin-like activity. Moreover, the peritrophic membrane was not disrupted. The enzymes of ApTI-fed larvae were found to be sensitive to ApTI and to have a normal feedback mechanism; also, the larval digestive enzymes were not able to degrade the inhibitor. In addition, ApTI delayed larval development time. Histological studies demonstrated a degeneration of the microvilli of the posterior midgut region epithelium cells, hypertrophy of the gastric caeca cells and an augmented ectoperitrophic space in larvae. Moreover, Ae. aegypti larvae were incapable of overcoming the negative effects of ApTI, indicating that this inhibitor might be used as a promising agent against Ae. aegypti. In addition, molecular modeling and molecular docking studies were also performed in order to construct three dimensional theoretical models for ApTI, trypsin and chymotrypsin from Ae. aegypti, as well as to predict the possible interactions and affinity values for the complexes ApTI/trypsin and ApTI/chymotrypsin. In this context, this study broadens the base of our understanding about the modes of action of proteinase inhibitors in insects, as well as the way insects adapt to them. PMID- 25796216 TI - Rapid resolution of retinoschisis with acetazolamide. AB - PURPOSE: To report the results of an acetazolamide (Diamox((r))) treatment regimen in a genetically confirmed case of X-linked juvenile retinoschisis (XLRS). METHODS: A patient with XLRS was prescribed acetazolamide (Diamox((r))) at a dose of 500 mg/day, then discontinued the treatment due to non-compliance for 4 days, and finally resumed the course of treatment. Best-corrected visual acuity, retinal structure, and function were monitored with autofluorescence, spectral domain-optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), and full-field electroretinogram (ERG). Full-field ERG was performed using DTL recording electrodes and Ganzfeld stimulation according to ISCEV standards. RESULTS: Serial monitoring of the cysts by SD-OCT revealed a strong association between the effects of acetazolamide administration and the size of the schisis. A reduction in foveal cyst size was significant in as rapid as 6 days after acetazolamide initiation. AOSLO data revealed that the resolution of cone cell images improves as the foveal schisis decreases in size. CONCLUSIONS: Efficacy of acetazolamide in patients with XLRS can be apparent in as rapid as a week of therapy. AOSLO can be a good method to evaluate the cone cells after acetazolamide treatment in the early stages of XLRS. PMID- 25796217 TI - First Trimester Laparoscopic Cerclage. AB - STUDY OBJECTIVE: To review the indications, rationale, and technique for abdominal cerclage, specifically focusing on a laparoscopic approach to this procedure during the first trimester of pregnancy. DESIGN: This is an educational video directed toward gynecologic surgeons. Patient consent was obtained for use of surgical video footage, and Institutional Review Board exemption was granted. A patient case is discussed and a step-by-step description of the technique used to perform laparoscopic cerclage in the first trimester of pregnancy is demonstrated using surgical footage. SETTING: The estimated incidence of cervical insufficiency affecting pregnancy is as high as 1%. Cervical cerclage placement is the treatment for this condition. Although most cerclages are placed transvaginally via the Shirodkar or McDonald technique, abdominal cerclage is necessary in women with a previous failed transvaginal cerclage or in those with minimal cervical tissue accessible vaginally [1,2]. Both laparoscopic and robotic approaches to this procedure have been developed, allowing patients to enjoy a more rapid recovery as well as to avoid an unnecessary laparotomy[3-6]. The observational studies reporting outcomes for laparoscopic-assisted abdominal cerclage quote fetal survival rates of >85%, which is comparable to the rates for abdominal cerclage[7-18]. Complication rates are low, also congruent with the laparotomic approach[12-18]. INTERVENTION: The patient, a 35-year-old gravida 3, para 1, 0, 1, 1, at 11 weeks gestation, had a history of a full-term vaginal delivery followed by an excisional procedure for cervical dysplasia, and then an early second trimester pregnancy loss. She was referred for laparoscopic-assisted abdominal cerclage after a severely shortened cervix was noted on examination. Laparoscopic cerclage placement was uncomplicated, with minimal blood loss encountered. The patient did well in the immediate postoperative period and was discharged home on postoperative day 1. The remainder of the pregnancy was uneventful, and she delivered via scheduled cesarean section at term. CONCLUSION: With proper patient selection and operative planning, the technique of laparoscopic cerclage is both safe and advantageous in terms of faster recovery. Obstetric outcomes are equivalent, if not superior, to an open abdominal approach to this procedure. PMID- 25796218 TI - Laparoscopic Fluorescent Visualization of the Ureter With Intravenous IRDye800CW. AB - OBJECTIVES: Ureter injury is a serious complication of laparoscopic surgery. Current strategies to identify the ureters, such as placement of a ureteral stent, carry additional risks for patients. We hypothesize that the systemically injected near-infrared (NIR) dye IRDye800CW-CA can be used to visualize ureters intraoperatively. METHODS: Adult female mixed-breed pigs weighing 24 to 41 kg (n = 2 per dose) were given a 30, 60, or 120 MUg/kg systemic injection of IRDye800CW CA. Using the Food and Drug Administration-cleared Pinpoint laparoscopic NIR system, images of the ureter and bladder were captured every 10 minutes for 60 minutes after injection. To determine the biodistribution of the dye, tissues were collected for ex vivo analysis with the Pearl Impulse system. ImageJ software was used to quantify fluorescence signal and signal-to-background ratio (SBR) for the intraoperative images. RESULTS: The ureter was identified in all pigs at each dose, with peak intensity reached by 30 minutes and remaining elevated throughout the duration of imaging (60 minutes). The 60 MUg/kg dose was determined to be optimal for differentiating ureters according to absolute fluorescence (>60 counts/pixel) and SBR (3.1). Urine fluorescence was inversely related to plasma fluorescence (R(2) = -0.82). Ex vivo imaging of kidney, ureter, bladder, and abdominal wall tissues revealed low fluorescence. CONCLUSION: Systemic administration of IRDye800CW-CA shows promise in providing ureteral identification with high specificity during laparoscopic surgery. The low dose required, rapid time to visualization, and absence of invasive ureteral instrumentation inherent to this technique may reduce complications related to pelvic surgery. PMID- 25796219 TI - Single-port Access Subtotal Laparoscopic Hysterectomy: A Prospective Case-Control Study. AB - STUDY OBJECTIVE: The objective was to evaluate the perioperative outcomes, safety, and patient acceptance of single-port access laparoscopic subtotal hysterectomy (SPAL-SH) in comparison with conventional multiport access laparoscopic subtotal hysterectomy (MPAL-SH). DESIGN: Case-control study. Canadian Task Force Classification II-2. SETTING: The study was conducted at university hospitals in Cagliari, Italy, and Rouen, France. PATIENTS: Sixty-one women with metrorrhagia, abnormal uterine bleeding with uterine myomas, or symptomatic adenomyosis were included in the study. INTERVENTIONS: Thirty-one patients underwent SPAL-SH, and 30 patients underwent conventional MPAL-SH. MEASUREMENTS AND MAIN RESULTS: We analyzed the data to compare the outcomes of SPAL-SH versus MPAL-SH. Patients in the SPAL-SH group had longer operative times than those in the MPAL-SH group (p < .001) but shorter hospital stays (p < .001). Postoperative pain immediately after surgery, after 6 hours, and after 24 hours were lower in the SPAL-SH group (p < .001). The SPAL-SH group reported significantly higher cosmetic satisfaction at 1, 4, and 24 weeks after surgery (p < .01). CONCLUSION: We conclude that SPAL-SH is a feasible and safe alternative to standard MPAL-SH in selected patients. Ongoing refinement of the surgical technique and instrumentation is likely to expand its role in gynecologic surgery in the future. In addition, SPAL-SH has a definite benefit in relation to body image and cosmesis. PMID- 25796220 TI - Is Cold Loop Hysteroscopic Myomectomy a Safe and Effective Technique for the Treatment of Submucous Myomas With Intramural Development? A Series of 1434 Surgical Procedures. AB - STUDY OBJECTIVE: To assess the safety and efficacy of cold loop hysteroscopic myomectomy in a large series of cases. DESIGN: Retrospective study (Canadian Task Force Classification III). SETTING: Arbor Vitae Center for Endoscopic Gynecology, Rome, Italy. PATIENTS: A total of 1215 patients with 1 or more G1-G2 submucous myomas. INTERVENTION: Cold loop hysteroscopic myomectomy. MEASUREMENT AND MAIN RESULTS: A total of 1690 myomas were removed. A minimum of 1 to a maximum of 5 fibroids for each surgical procedure were totally removed. Out of 1215 patients, 1017 (83.7%) were treated with a single surgical procedure. Twelve intraoperative complications occurred (0.84%). No cases of uterine perforation with the thermal loop or clinical intravasation syndrome were reported. CONCLUSION: Cold loop hysteroscopic myomectomy seems to represent a safe and effective procedure for the removal of submucous myomas with intramural development, while at the same time respecting the anatomic and functional integrity of the myometrium. The use of a cold loop in resectoscopic myomectomy is associated with a low rate of minor intraoperative complications and an absence of major complications. This could be of primary relevance with a view to fertility and future pregnancies. PMID- 25796221 TI - Suggested Method for the Management of Heterotopic Cervical Pregnancy Leading to Term Delivery of the Intrauterine Pregnancy: Case Report and Literature Review. AB - This is a case report and literature review regarding early diagnosis and management of a cervical heterotopic pregnancy. A 41-year-old gravida 2 para 0 with premature ovarian failure was treated successfully in an in vitro fertilization program with donor oocytes. A transvaginal ultrasound scan revealed the presence of a heterotopic pregnancy, with an intrauterine embryo and an intracervical embryo. Both embryos had positive heartbeats. Aspiration of the cervical pregnancy was followed by Foley catheter placement and cervical cerclage suturing. Monitoring of the patient resulted in elective uncomplicated cesarean section delivery at 38 weeks following an uneventful pregnancy. Given the lack of guidelines for the management of heterotopic cervical pregnancy, we reviewed the literature suggesting the most effective method. The value of early diagnosis and management is concluded from the literature, in support of our management principles. PMID- 25796222 TI - Near infrared radiation protects against oxygen-glucose deprivation-induced neurotoxicity by down-regulating neuronal nitric oxide synthase (nNOS) activity in vitro. AB - Near infrared radiation (NIR) has been shown to be neuroprotective against neurological diseases including stroke and brain trauma, but the underlying mechanisms remain poorly understood. In the current study we aimed to investigate the hypothesis that NIR may protect neurons by attenuating oxygen-glucose deprivation (OGD)-induced nitric oxide (NO) production and modulating cell survival/death signaling. Primary mouse cortical neurons were subjected to 4 h OGD and NIR was applied at 2 h reoxygenation. OGD significantly increased NO level in primary neurons compared to normal control, which was significantly ameliorated by NIR at 5 and 30 min post-NIR. Neither OGD nor NIR significantly changed neuronal nitric oxide synthase (nNOS) mRNA or total protein levels compared to control groups. However, OGD significantly increased nNOS activity compared to normal control, and this effect was significantly diminished by NIR. Moreover, NIR significantly ameliorated the neuronal death induced by S-Nitroso-N acetyl-DL-penicillamine (SNAP), a NO donor. Finally, NIR significantly rescued OGD-induced suppression of p-Akt and Bcl-2 expression, and attenuated OGD-induced upregulation of Bax, BAD and caspase-3 activation. These results suggest NIR may protect against OGD at least partially through reducing NO production by down regulating nNOS activity, and modulating cell survival/death signaling. PMID- 25796224 TI - K+larity for Spironolactone: At Last! PMID- 25796223 TI - Increased brain iron deposition is a risk factor for brain atrophy in patients with haemodialysis: a combined study of quantitative susceptibility mapping and whole brain volume analysis. AB - To explore the correlation between increased brain iron deposition and brain atrophy in patients with haemodialysis and their correlation with clinical biomarkers and neuropsychological test. Forty two patients with haemodialysis and forty one age- and gender-matched healthy controls were recruited in this prospective study. 3D whole brain high resolution T1WI and susceptibility weighted imaging were scanned on a 3 T MRI system. The brain volume was analyzed using voxel-based morphometry (VBM) in patients and to compare with that of healthy controls. Quantitative susceptibility mapping was used to measure and compare the susceptibility of different structures between patients and healthy controls. Correlation analysis was used to investigate the relationship between the brain volume, iron deposition and neuropsychological scores. Stepwise multiple regression analysis was used to explore the effect of clinical biomarkers on the brain volumes in patients. Compared with healthy controls, patients with haemodialysis showed decreased volume of bilateral putamen and left insular lobe (All P < 0.05). Susceptibilities of bilateral caudate head, putamen, substantia nigra, red nucleus and dentate nucleus were significantly higher (All P < 0.05). The increased brain iron deposition is negatively correlated with the decreased volume of bilateral putamen (P < 0.01). Neuropsychological scores positively correlated with decreased volume of left insular lobe (P < 0.05). Dialysis duration was negatively associated with decreased volume of bilateral putamen (P < 0.05). Our study indicated increased brain iron deposition and dialysis duration was risk factors for brain atrophy in patients with haemodialysis. The decreased gray matter volume of the left insular lobe was correlated with neurocognitive impairment. PMID- 25796225 TI - Deep proton tunneling in the electronically adiabatic and non-adiabatic limits: comparison of the quantum and classical treatment of donor-acceptor motion in a protein environment. AB - Analytical models describing the temperature dependence of the deep tunneling rate, useful for proton, hydrogen, or hydride transfer in proteins, are developed and compared. Electronically adiabatic and non-adiabatic expressions are presented where the donor-acceptor (D-A) motion is treated either as a quantized vibration or as a classical "gating" distribution. We stress the importance of fitting experimental data on an absolute scale in the electronically adiabatic limit, which normally applies to these reactions, and find that vibrationally enhanced deep tunneling takes place on sub-ns timescales at room temperature for typical H-bonding distances. As noted previously, a small room temperature kinetic isotope effect (KIE) does not eliminate deep tunneling as a major transport channel. The quantum approach focuses on the vibrational sub-space composed of the D-A and hydrogen atom motions, where hydrogen bonding and protein restoring forces quantize the D-A vibration. A Duschinsky rotation is mandated between the normal modes of the reactant and product states and the rotation angle depends on the tunneling particle mass. This tunnel-mass dependent rotation contributes substantially to the KIE and its temperature dependence. The effect of the Duschinsky rotation is solved exactly to find the rate in the electronically non-adiabatic limit and compared to the Born-Oppenheimer (B-O) approximation approach. The B-O approximation is employed to find the rate in the electronically adiabatic limit, where we explore both harmonic and quartic double well potentials for the hydrogen atom bound states. Both the electronically adiabatic and non-adiabatic rates are found to diverge at high temperature unless the proton coupling includes the often neglected quadratic term in the D-A displacement from equilibrium. A new expression is presented for the electronically adiabatic tunnel rate in the classical limit for D-A motion that should be useful to experimentalists working near room temperature. This expression also holds when a broad protein conformational distribution of D-A equilibrium distances dominates the spread of the D-A vibrational wavefunction. PMID- 25796226 TI - Relativistic four-component calculations of indirect nuclear spin-spin couplings with efficient evaluation of the exchange-correlation response kernel. AB - In this work, we report on the development and implementation of a new scheme for efficient calculation of indirect nuclear spin-spin couplings in the framework of four-component matrix Dirac-Kohn-Sham approach termed matrix Dirac-Kohn-Sham restricted magnetic balance resolution of identity for J and K, which takes advantage of the previous restricted magnetic balance formalism and the density fitting approach for the rapid evaluation of density functional theory exchange correlation response kernels. The new approach is aimed to speedup the bottleneck in the solution of the coupled perturbed equations: evaluation of the matrix elements of the kernel of the exchange-correlation potential. The performance of the new scheme has been tested on a representative set of indirect nuclear spin spin couplings. The obtained results have been compared with the corresponding results of the reference method with traditional evaluation of the exchange correlation kernel, i.e., without employing the fitted electron densities. Overall good agreement between both methods was observed, though the new approach tends to give values by about 4%-5% higher than the reference method. On the average, the solution of the coupled perturbed equations with the new scheme is about 8.5 times faster compared to the reference method. PMID- 25796228 TI - One-electron reduced density matrices of strongly correlated harmonium atoms. AB - Explicit asymptotic expressions are derived for the reduced one-electron density matrices (the 1-matrices) of strongly correlated two- and three-electron harmonium atoms in the ground and first excited states. These expressions, which are valid at the limit of small confinement strength omega, yield electron densities and kinetic energies in agreement with the published values. In addition, they reveal the omega(5/6) asymptotic scaling of the exchange components of the electron-electron repulsion energies that differs from the omega(2/3) scaling of their Coulomb and correlation counterparts. The natural orbitals of the totally symmetric ground state of the two-electron harmonium atom are found to possess collective occupancies that follow a mixed power/Gaussian dependence on the angular momentum in variance with the simple power-law prediction of Hill's asymptotics. Providing rigorous constraints on energies as functionals of 1-matrices, these results are expected to facilitate development of approximate implementations of the density matrix functional theory and ensure their proper description of strongly correlated systems. PMID- 25796227 TI - An elementary singularity-free Rotational Brownian Dynamics algorithm for anisotropic particles. AB - Brownian Dynamics is the designated technique to simulate the collective dynamics of colloidal particles suspended in a solution, e.g., the self-assembly of patchy particles. Simulating the rotational dynamics of anisotropic particles by a first order Langevin equation, however, gives rise to a number of complications, ranging from singularities when using a set of three rotational coordinates to subtle metric and drift corrections. Here, we derive and numerically validate a quaternion-based Rotational Brownian Dynamics algorithm that handles these complications in a simple and elegant way. The extension to hydrodynamic interactions is also discussed. PMID- 25796229 TI - The Coulomb, exchange, and correlation components of the electron-electron repulsion in harmonium atoms. AB - Highly accurate Coulomb, exchange, and correlation components of the electron electron repulsion energies of the three-electron harmonium atoms in the (2)P- and (4)P+ states are obtained for 19 values of the confinement strength omega ranging from 10(-3) to 10(3). The computed data are consistent with their omega > 0 and omega -> infinity asymptotics that are given by closed-form algebraic expressions. Robust approximants that accurately reproduce the actual values of the energy components while strictly conforming to these limits are constructed, opening an avenue to stringent tests capable of predicting the performance of electronic structure methods for systems with varying extents of the dynamical and nondynamical electron correlation. The values of the correlation components, paired with the computed 1-matrices are expected to be particularly useful in the context of benchmarking of approximate density matrix functionals. PMID- 25796230 TI - Iterative universal state selective correction for the Brillouin-Wigner multireference coupled-cluster theory. AB - As a further development of the previously introduced a posteriori Universal State-Selective (USS) corrections [K. Kowalski, J. Chem. Phys. 134, 194107 (2011); J. Brabec et al., ibid. 136, 124102 (2012)], we suggest an iterative form of the USS correction by means of correcting effective Hamiltonian matrix elements. We also formulate USS corrections via the left Bloch equations. The convergence of the USS corrections with excitation level towards the full configuration interaction (FCI) limit is also investigated. Various forms of the USS and simplified diagonal USS corrections at the singles and doubles and perturbative triple levels are numerically assessed on several model systems and on the ozone and tetramethyleneethane molecules. It is shown that the iterative USS correction can successfully replace the previously developed a posteriori Brillouin-Wigner coupled cluster size-extensivity correction, while it is not sensitive to intruder states and performs well also in other cases when the a posteriori one fails, like, e.g., for the asymmetric vibration mode of ozone. PMID- 25796231 TI - 3D RISM theory with fast reciprocal-space electrostatics. AB - The calculation of electrostatic solute-solvent interactions in 3D RISM ("three dimensional reference interaction site model") integral equation theory is recast in a form that allows for a computational treatment analogous to the "particle mesh Ewald" formalism as used for molecular simulations. In addition, relations that connect 3D RISM correlation functions and interaction potentials with thermodynamic quantities such as the chemical potential and average solute solvent interaction energy are reformulated in a way that calculations of expensive real-space electrostatic terms on the 3D grid are completely avoided. These methodical enhancements allow for both, a significant speedup particularly for large solute systems and a smoother convergence of predicted thermodynamic quantities with respect to box size, as illustrated for several benchmark systems. PMID- 25796232 TI - Theoretical and numerical investigations of inverse patchy colloids in the fluid phase. AB - We investigate the structural and thermodynamic properties of a new class of patchy colloids, referred to as inverse patchy colloids (IPCs) in their fluid phase via both theoretical methods and simulations. IPCs are nano- or micro- meter sized particles with differently charged surface regions. We extend conventional integral equation schemes to this particular class of systems: our approach is based on the so-called multi-density Ornstein-Zernike equation, supplemented with the associative Percus-Yevick approximation (APY). To validate the accuracy of our framework, we compare the obtained results with data extracted from NpT and NVT Monte Carlo simulations. In addition, other theoretical approaches are used to calculate the properties of the system: the reference hypernetted-chain (RHNC) method and the Barker-Henderson thermodynamic perturbation theory. Both APY and RHNC frameworks provide accurate predictions for the pair distribution functions: APY results are in slightly better agreement with MC data, in particular at lower temperatures where the RHNC solution does not converge. PMID- 25796233 TI - Molecular response properties from a Hermitian eigenvalue equation for a time periodic Hamiltonian. AB - The time-dependent Schrodinger equation for a time-periodic perturbation is recasted into a Hermitian eigenvalue equation, where the quasi-energy is an eigenvalue and the time-periodic regular wave function an eigenstate. From this Hermitian eigenvalue equation, a rigorous and transparent formulation of response function theory is developed where (i) molecular properties are defined as derivatives of the quasi-energy with respect to perturbation strengths, (ii) the quasi-energy can be determined from the time-periodic regular wave function using a variational principle or via projection, and (iii) the parametrization of the unperturbed state can differ from the parametrization of the time evolution of this state. This development brings the definition of molecular properties and their determination on par for static and time-periodic perturbations and removes inaccuracies and inconsistencies of previous response function theory formulations. The development where the parametrization of the unperturbed state and its time evolution may differ also extends the range of the wave function models for which response functions can be determined. The simplicity and universality of the presented formulation is illustrated by applying it to the configuration interaction (CI) and the coupled cluster (CC) wave function models and by introducing a new model-the coupled cluster configuration interaction (CC CI) model-where a coupled cluster exponential parametrization is used for the unperturbed state and a linear parametrization for its time evolution. For static perturbations, the CC-CI response functions are shown to be the analytical analogues of the static molecular properties obtained from finite field equation of-motion coupled cluster (EOMCC) energy calculations. The structural similarities and differences between the CI, CC, and CC-CI response functions are also discussed with emphasis on linear versus non-linear parametrizations and the size-extensivity of the obtained molecular properties. PMID- 25796234 TI - On the convergence of diffusion Monte Carlo in non-Euclidean spaces. I. Free diffusion. AB - We develop a set of diffusion Monte Carlo algorithms for general compactly supported Riemannian manifolds that converge weakly to second order with respect to the time step. The approaches are designed to work for cases that include non orthogonal coordinate systems, nonuniform metric tensors, manifold boundaries, and multiply connected spaces. The methods do not require specially designed coordinate charts and can in principle work with atlases of charts. Several numerical tests for free diffusion in compactly supported Riemannian manifolds are carried out for spaces relevant to the chemical physics community. These include the circle, the 2-sphere, and the ellipsoid of inertia mapped with traditional angles. In all cases, we observe second order convergence, and in the case of the sphere, we gain insight into the function of the advection term that is generated by the curved nature of the space. PMID- 25796235 TI - On the convergence of diffusion Monte Carlo in non-Euclidean spaces. II. Diffusion with sources and sinks. AB - We test the second order Milstein method adapted to simulate diffusion in general compact Riemann manifolds on a number of systems characterized by nonconfining potential energy surfaces of increasing complexity. For the 2-sphere and more complex spaces derived from it, we compare the Milstein method with a number of other first and second order approaches. In each case tested, we find evidence that demonstrate the versatility and relative ease of implementation of the Milstein method derived in Part I. PMID- 25796236 TI - Optimized molecular reconstruction procedure combining hybrid reverse Monte Carlo and molecular dynamics. AB - We report an efficient atom-scale reconstruction method that consists of combining the Hybrid Reverse Monte Carlo algorithm (HRMC) with Molecular Dynamics (MD) in the framework of a simulated annealing technique. In the spirit of the experimentally constrained molecular relaxation technique [Biswas et al., Phys. Rev. B 69, 195207 (2004)], this modified procedure offers a refined strategy in the field of reconstruction techniques, with special interest for heterogeneous and disordered solids such as amorphous porous materials. While the HRMC method generates physical structures, thanks to the use of energy penalties, the combination with MD makes the method at least one order of magnitude faster than HRMC simulations to obtain structures of similar quality. Furthermore, in order to ensure the transferability of this technique, we provide rational arguments to select the various input parameters such as the relative weight omega of the energy penalty with respect to the structure optimization. By applying the method to disordered porous carbons, we show that adsorption properties provide data to test the global texture of the reconstructed sample but are only weakly sensitive to the presence of defects. In contrast, the vibrational properties such as the phonon density of states are found to be very sensitive to the local structure of the sample. PMID- 25796237 TI - Polarizable embedding with a multiconfiguration short-range density functional theory linear response method. AB - We present here the coupling of a polarizable embedding (PE) model to the recently developed multiconfiguration short-range density functional theory method (MC-srDFT), which can treat multiconfigurational systems with a simultaneous account for dynamical and static correlation effects. PE-MC-srDFT is designed to combine efficient treatment of complicated electronic structures with inclusion of effects from the surrounding environment. The environmental effects encompass classical electrostatic interactions as well as polarization of both the quantum region and the environment. Using response theory, molecular properties such as excitation energies and oscillator strengths can be obtained. The PE-MC-srDFT method and the additional terms required for linear response have been implemented in a development version of Dalton. To benchmark the PE-MC-srDFT approach against the literature data, we have investigated the low-lying electronic excitations of acetone and uracil, both immersed in water solution. The PE-MC-srDFT results are consistent and accurate, both in terms of the calculated solvent shift and, unlike regular PE-MCSCF, also with respect to the individual absolute excitation energies. To demonstrate the capabilities of PE-MC srDFT, we also investigated the retinylidene Schiff base chromophore embedded in the channelrhodopsin protein. While using a much more compact reference wave function in terms of active space, our PE-MC-srDFT approach yields excitation energies comparable in quality to CASSCF/CASPT2 benchmarks. PMID- 25796238 TI - Quantum Monte Carlo estimation of complex-time correlations for the study of the ground-state dynamic structure function. AB - We present a method based on the path integral Monte Carlo formalism for the calculation of ground-state time correlation functions in quantum systems. The key point of the method is the consideration of time as a complex variable whose phase delta acts as an adjustable parameter. By using high-order approximations for the quantum propagator, it is possible to obtain Monte Carlo data all the way from purely imaginary time to delta values near the limit of real time. As a consequence, it is possible to infer accurately the spectral functions using simple inversion algorithms. We test this approach in the calculation of the dynamic structure function S(q, omega) of two one-dimensional model systems, harmonic and quartic oscillators, for which S(q, omega) can be exactly calculated. We notice a clear improvement in the calculation of the dynamic response with respect to the common approach based on the inverse Laplace transform of the imaginary-time correlation function. PMID- 25796239 TI - A unified approach to computation of solid and liquid free energy to revisit the solid-fluid equilibrium of Lennard-Jones chains. AB - Liquid free energies are computed by integration along a path from a reference system of known free energy, using a strong localization potential. A particular choice of localization pathway is introduced, convenient for use in molecular dynamics codes, and which achieves accurate results without the need to include the identity-swap or relocation Monte Carlo moves used in previous studies. Moreover, an adaptive timestep is introduced to attain the reference system. Furthermore, a center-of-mass correction that is different from previous studies and phase-independent is incorporated. The resulting scheme allows computation of both solid and liquid free energies with only minor differences in simulation protocol. This is used to re-visit solid-liquid equilibrium in a system of short semi-flexible Lennard-Jones chain molecules. The computed melting curve is demonstrated to be consistent with direct co-existence simulations and computed hysteresis loops, provided that an entropic term arising from unsampled solid states is included. PMID- 25796240 TI - The same number of optimized parameters scheme for determining intermolecular interaction energies. AB - We propose the Same Number Of Optimized Parameters (SNOOP) scheme as an alternative to the counterpoise method for treating basis set superposition errors in calculations of intermolecular interaction energies. The key point of the SNOOP scheme is to enforce that the number of optimized wave function parameters for the noninteracting system is the same as for the interacting system. This ensures a delicate balance between the quality of the monomer and dimer finite basis set calculations. We compare the SNOOP scheme to the uncorrected and counterpoise schemes theoretically as well as numerically. Numerical results for second-order Moller-Plesset perturbation theory (MP2) and coupled-cluster with single, double, and approximate triple excitations (CCSD(T)) show that the SNOOP scheme in general outperforms the uncorrected and counterpoise approaches. Furthermore, we show that SNOOP interaction energies calculated using a given basis set are of similar quality as those determined by basis set extrapolation of counterpoise-corrected results obtained at a similar computational cost. PMID- 25796241 TI - Order and correlation contributions to the entropy of hydrophobic solvation. AB - The entropy of hydrophobic solvation has been explained as the result of ordered solvation structures, of hydrogen bonds, of the small size of the water molecule, of dispersion forces, and of solvent density fluctuations. We report a new approach to the calculation of the entropy of hydrophobic solvation, along with tests of and comparisons to several other methods. The methods are assessed in the light of the available thermodynamic and spectroscopic information on the effects of temperature on hydrophobic solvation. Five model hydrophobes in SPC/E water give benchmark solvation entropies via Widom's test-particle insertion method, and other methods and models are tested against these particle-insertion results. Entropies associated with distributions of tetrahedral order, of electric field, and of solvent dipole orientations are examined. We find these contributions are small compared to the benchmark particle-insertion entropy. Competitive with or better than other theories in accuracy, but with no free parameters, is the new estimate of the entropy contributed by correlations between dipole moments. Dipole correlations account for most of the hydrophobic solvation entropy for all models studied and capture the distinctive temperature dependence seen in thermodynamic and spectroscopic experiments. Entropies based on pair and many-body correlations in number density approach the correct magnitudes but fail to describe temperature and size dependences, respectively. Hydrogen-bond definitions and free energies that best reproduce entropies from simulations are reported, but it is difficult to choose one hydrogen bond model that fits a variety of experiments. The use of information theory, scaled particle theory, and related methods is discussed briefly. Our results provide a test of the Frank-Evans hypothesis that the negative solvation entropy is due to structured water near the solute, complement the spectroscopic detection of that solvation structure by identifying the structural feature responsible for the entropy change, and point to a possible explanation for the observed dependence on length scale. Our key results are that the hydrophobic effect, i.e. the signature, temperature-dependent, solvation entropy of nonpolar molecules in water, is largely due to a dispersion force arising from correlations between rotating permanent dipole moments, that the strength of this force depends on the Kirkwood g-factor, and that the strength of this force may be obtained exactly without simulation. PMID- 25796243 TI - Infrared spectroscopy of the methanol cation and its methylene-oxonium isomer. AB - The carbenium ion with nominal formula [C,H4,O](+) is produced from methanol or ethylene glycol in a pulsed-discharge supersonic expansion source. The ion is mass selected, and its infrared spectrum is measured from 2000 to 4000 cm(-1) using laser photodissociation spectroscopy and the method of rare gas atom tagging. Computational chemistry predicts two isomers, the methanol and methylene oxonium cations. Predicted vibrational spectra based on scaled harmonic and reduced dimensional treatments are compared to the experimental spectra. The methanol cation is the only isomer produced when methanol is used as a precursor. When ethylene glycol is used as the precursor, methylene-oxonium is produced in addition to the methanol cation. Theoretical results at the CCSD(T)/cc-pVTZ level show that methylene-oxonium is lower in energy than methanol cation by 6.4 kcal/mol, and is in fact the global minimum isomer on the [C,H4,O](+) potential surface. Methanol cation is trapped behind an isomerization barrier in our source, providing a convenient method to produce and characterize this transient species. Analysis of the spectrum of the methanol cation provides evidence for strong CH stretch vibration/torsion coupling in this molecular ion. PMID- 25796242 TI - Wavelength dependent resonance Raman band intensity of broadband stimulated Raman spectroscopy of malachite green in ethanol. AB - Resonance broadband stimulated Raman spectroscopy of malachite green in ethanol has been performed. With a tuning picosecond visible laser source and a broadband Raman probe, the Raman gain and loss spectra have been measured simultaneously. By scanning the Raman pump across the first absorption band of the molecule, we found that the resonant Raman bands could be only seen when the pump laser tuned in the range of the red edge of the S1<-S0 transition. Dispersive lineshapes of resonant Raman bands have been observed in the Raman loss spectra, while the line shape is normal (same as spontaneous Raman) in the Raman gain spectra. Although, the resonant bands in the loss spectrum are usually stronger than that in the gain spectrum, the band intensities of both loss and gain linearly increase with the pump energy. The relative magnitude of each corresponding resonant band in the Raman loss and gain varies with the pump wavelength. Mode specified Raman excitation profiles have been obtained through broadband stimulated Raman measurement. PMID- 25796244 TI - High-resolution laser spectroscopy and magnetic effect of the B(2)E(')<-X(2)A2(') transition of the (15)N substituted nitrate radical. AB - Rotationally resolved high-resolution fluorescence excitation spectra of the 0-0 band of the B(2)E(')<-X(2)A2(') transition of the (15)N substituted nitrate radical were observed for the first time, by crossing a jet-cooled molecular beam and a single-mode dye laser beam at right angles. Several thousand rotational lines were detected in the 15 080-15 103 cm(-1) region. We observed the Zeeman splitting of intense lines up to 360 G in order to obtain secure rotational assignment. Two, nine, and seven rotational line pairs with 0.0248 cm(-1) spacing were assigned to the transitions from the X(2)A2(') (upsilon" = 0, k" = 0, N" = 1, J" = 0.5 and 1.5) to the (2)E3/2(') (J' = 1.5), (2)E1/2(') (J' = 0.5), and (2)E1/2(') (J' = 1.5) levels, respectively, based on the ground state combination differences and the Zeeman splitting patterns. The observed spectrum was complicated due to the vibronic coupling between the bright B(2)E(') (upsilon = 0) state and surrounding dark vibronic states. Some series of rotational lines other than those from the X(2)A2(') (J = 0.5 and 1.5) levels were also assigned by the ground state combination differences and the observed Zeeman splitting. The rotational branch structures were identified, and the molecular constants of the B(2)E1/2(') (upsilon = 0) state were estimated by a deperturbed analysis to be T0 = 15 098.20(4) cm(-1), B = 0.4282(7) cm(-1), and DJ = 4 * 10(-4) cm(-1). In the observed region, both the (2)E1/2(') and (2)E3/2(') spin-orbit components were identified, and the spin-orbit interaction constant of the B(2)E(') (upsilon = 0) state was estimated to be -12 cm(-1) as the lower limit. PMID- 25796246 TI - Dissociative recombination and mutual neutralization of heavier molecular ions: C10H8(+), WF5(+), and C(n)F(m)(+). AB - Dissociative recombination (DR) rate coefficients for the naphthalene cation, C10H8(+), and WF5(+), and mutual neutralization (MN) rate coefficients for these species and five CnFm(+) ions, were determined at 300 K using variable electron and neutral density attachment mass spectrometry (VENDAMS). DR proceeds at 9 +/- 3 * 10(-7) cm(3) s(-1) for C10H8(+) and at 6.1 +/- 1.4 * 10(-7) cm(3) s(-1) for WF5(+). Consistent with previous results, MN for the polyatomic cations with the halide anions Cl(-), Br(-), and I(-) exhibits an approximate MU(-1/2) reduced mass dependence of the reactant partners, demonstrating that ion collision velocities influence the rate coefficients. This work is an extension of VENDAMS to systems, where low reactant concentrations are necessary to avoid significant reaction of product ions with the neutral precursor, i.e., conditions not suitable for traditional flowing afterglow measurements, as well as to ions of masses > ~ 100 Da, which are not amenable to the study of DR in magnetic storage rings. Our results expand the sparse literature on DR and MN of heavier ions. PMID- 25796247 TI - Excitonic optical properties of wurtzite ZnS quantum dots under pressure. AB - By means of atomistic empirical pseudopotentials combined with a configuration interaction approach, we have studied the optical properties of wurtzite ZnS quantum dots in the presence of strong quantum confinement effects as a function of pressure. We find the pressure coefficients of quantum dots to be highly size dependent and reduced by as much as 23% in comparison to the bulk value of 63 meV/GPa obtained from density functional theory calculations. The many-body excitonic effects on the quantum dot pressure coefficients are found to be marginal. The absolute gap deformation potential of quantum dots originates mainly from the energy change of the lowest unoccupied molecular orbital state. Finally, we find that the exciton spin-splitting increases nearly linearly as a function of applied pressure. PMID- 25796245 TI - Barrierless proton transfer across weak CH?O hydrogen bonds in dimethyl ether dimer. AB - We present a combined computational and threshold photoelectron photoion coincidence study of two isotopologues of dimethyl ether, (DME - h6)n and (DME - d6)n n = 1 and 2, in the 9-14 eV photon energy range. Multiple isomers of neutral dimethyl ether dimer were considered, all of which may be present, and exhibited varying C-H?O interactions. Results from electronic structure calculations predict that all of them undergo barrierless proton transfer upon photoionization to the ground electronic state of the cation. In fact, all neutral isomers were found to relax to the same radical cation structure. The lowest energy dissociative photoionization channel of the dimer leads to CH3OHCH3 (+) by the loss of CH2OCH3 with a 0 K appearance energy of 9.71 +/- 0.03 eV and 9.73 +/- 0.03 eV for (DME - h6)2 and deuterated (DME - d6)2, respectively. The ground state threshold photoelectron spectrum band of the dimethyl ether dimer is broad and exhibits no vibrational structure. Dimerization results in a 350 meV decrease of the valence band appearance energy, a 140 meV decrease of the band maximum, thus an almost twofold increase in the ground state band width, compared with DME - d6 monomer. PMID- 25796248 TI - Proton transfer in histidine-tryptophan heterodimers embedded in helium droplets. AB - We used cold helium droplets as nano-scale reactors to form and ionize, by electron bombardment and charge transfer, aromatic amino acid heterodimers of histidine with tryptophan, methyl-tryptophan, and indole. The molecular interaction occurring through an N-H...N hydrogen bond leads to a proton transfer from the indole group of tryptophan to the imidazole group of histidine in a radical cationic environment. PMID- 25796249 TI - Effect of solvent on the charging mechanisms of poly(ethylene glycol) in droplets. AB - We examine the effect of solvent on the charging mechanisms of a macromolecule in a droplet by using molecular dynamics simulations. The droplet contains excess charge that is carried by sodium ions. To investigate the principles of the charging mechanisms of a macromolecule in a droplet, we simulate aqueous and methanol droplets that contain a poly(ethylene glycol) (PEG) molecule. We find that the solvent plays a critical role in the charging mechanism and in the manner that the sodiated PEG emerges from a droplet. In the aqueous droplets, the sodiated PEG is released from the droplet while it is being charged at a droplet charge state below the Rayleigh limit. The charging of PEG occurs on the surface of the droplet. In contrast to the aqueous droplets, in the methanol droplet, the sodiated PEG resides in the interior of the droplet and it may become charged at any location in the droplet, interior or surface. The sodiated PEG emerges from the droplet by drying-out of the solvent. Even though these two mechanisms appear to be phenomenologically similar to the widely accepted ion-evaporation and charge-residue mechanisms, they have fundamental differences from those. An integral part of the mechanism that the macromolecular ions emerge from droplets is the droplet morphology. Droplet morphologies give rise to different solvation interactions between the solvent and the macromolecule. In the water-sodiated PEG system, we find the extrusion of the PEG morphology, while in methanol-sodiated droplet, we find the "pearl-on-the-necklace" morphology and the extrusion of the sodiated PEG in the last stage of the desolvation process. These findings provide insight into the mechanisms that macromolecules acquire their charge in droplets produced in electrospray ionization experiments. PMID- 25796250 TI - Rotational study of the NH3-CO complex: millimeter-wave measurements and ab initio calculations. AB - The rotational spectrum of the van der Waals complex NH3-CO has been measured with the intracavity OROTRON jet spectrometer in the frequency range of 112-139 GHz. Newly observed and assigned transitions belong to the K = 0-0, K = 1-1, K = 1-0, and K = 2-1 subbands correlating with the rotationless (jk)NH3 = 00 ground state of free ortho-NH3 and the K = 0-1 and K = 2-1 subbands correlating with the (jk)NH3 = 11 ground state of free para-NH3. The (approximate) quantum number K is the projection of the total angular momentum J on the intermolecular axis. Some of these transitions are continuations to higher J values of transition series observed previously [C. Xia et al., Mol. Phys. 99, 643 (2001)], the other transitions constitute newly detected subbands. The new data were analyzed together with the known millimeter-wave and microwave transitions in order to determine the molecular parameters of the ortho-NH3-CO and para-NH3-CO complexes. Accompanying ab initio calculations of the intermolecular potential energy surface (PES) of NH3-CO has been carried out at the explicitly correlated coupled cluster level of theory with single, double, and perturbative triple excitations and an augmented correlation-consistent triple zeta basis set. The global minimum of the five-dimensional PES corresponds to an approximately T-shaped structure with the N atom closest to the CO subunit and binding energy De = 359.21 cm(-1). The bound rovibrational levels of the NH3-CO complex were calculated for total angular momentum J = 0-6 on this intermolecular potential surface and compared with the experimental results. The calculated dissociation energies D0 are 210.43 and 218.66 cm(-1) for ortho-NH3-CO and para-NH3-CO, respectively. PMID- 25796251 TI - Ultraviolet relaxation dynamics of aniline, N, N-dimethylaniline and 3,5 dimethylaniline at 250 nm. AB - Time-resolved photoelectron imaging was used to investigate the electronic relaxation dynamics of gas-phase aniline, N, N-dimethylaniline, and 3,5 dimethylaniline following ultraviolet excitation at 250 nm. Our analysis was supported by ab initio coupled-cluster calculations evaluating excited state energies and (in aniline) the evolution of a range of excited state physical properties as a function of N-H bond extension. Due to a lack of consistency between several earlier studies undertaken in aniline, the specific aim of this present work was to gain new insight into the previously proposed non-adiabatic coupling interaction between the two lowest lying singlet excited states S1(pipi(*)) and S2(3s/pisigma(*)). The methyl-substituted systems N, N dimethylaniline and 3,5-dimethylaniline were included in order to obtain more detailed dynamical information about the key internal molecular coordinates that drive the S1(pipi(*))/S2(3s/pisigma(*)) coupling mechanism. Our findings suggest that in all three systems, both electronic states are directly populated during the initial excitation, with the S2(3s/pisigma(*)) state then potentially decaying via either direct dissociation along the N-X stretching coordinate (X = H or CH3) or internal conversion to the S1(pipi(*)) state. In aniline and N, N dimethylaniline, both pathways most likely compete in the depletion of S2(3s/pisigma(*)) state population. However, in 3,5-dimethylaniline, only the direct dissociation mechanism appears to be active. This is rationalized in terms of changes in the relative rates of the two decay pathways upon methylation of the aromatic ring system. PMID- 25796252 TI - Formation of ultracold (7)Li(85)Rb molecules in the lowest triplet electronic state by photoassociation and their detection by ionization spectroscopy. AB - We report the formation of ultracold (7)Li(85)Rb molecules in the a(3)Sigma(+) electronic state by photoassociation (PA) and their detection via resonantly enhanced multiphoton ionization (REMPI). With our dual-species Li and Rb magneto optical trap apparatus, we detect PA resonances with binding energies up to ~62 cm(-1) below the (7)Li 2s (2)S1/2 + (85)Rb 5p (2)P1/2 asymptote. In addition, we use REMPI spectroscopy to probe the a(3)Sigma(+) state and excited electronic 3(3)Pi and 4(3)Sigma(+) states and identify a(3)Sigma(+) (v" = 7-13), 3(3)Pi (vPi' = 0-10), and 4(3)Sigma(+) (vSigma' = 0-5) vibrational levels. Our line assignments agree well with ab initio calculations. These preliminary spectroscopic studies on previously unobserved electronic states are crucial to discovering transition pathways for transferring ultracold LiRb molecules created via PA to deeply bound rovibrational levels of the electronic ground state. PMID- 25796253 TI - Application of vibrational correlation formalism to internal conversion rate: case study of Cu(n) (n = 3, 6, and 9) and H2/Cu3. AB - This work reports non-radiative internal conversion (IC) rate constants obtained for Cun with n = 3, 6, and 9 and H2 on Cu3. The Time-Dependent Density Functional Theory (TDDFT) method was employed with three different functionals in order to investigate the electronic structures and the absorption spectra. The performance of the generalized gradient approximation of Perdew, Burke and Ernzerhof (PBE) and the hybrid B3LYP and PBE0 exchange correlation functionals in combination with the SVP and the def2-TZVP basis sets was examined. TDDFT results were used as input data to compute internal conversion rate constants. For this purpose, we have developed a program package. A description of the theoretical background used in our numerical implementation and the program input file is presented. In view of future applications of this program package in photoinduced catalysis, we present the analysis of the IC rate processes for the photodissociation of H2 on Cu3. These results showed the applicability of the method and the computational program to identify the vibrational modes in transition metal clusters giving rise to the largest IC rate constant due to their interactions with the excited electronic states occurring in the hot-electron induced dissociation phenomena. PMID- 25796254 TI - Ab initio calculations of the electronic structure of the low-lying states for the ultracold LiYb molecule. AB - Ab initio techniques have been applied to investigate the electronic structure of the LiYb molecule. The potential energy curves have been computed in the Born Oppenheimer approximation for the ground and 29 low-lying doublet and quartet excited electronic states. Complete active space self-consistent field, multi reference configuration interaction, and Rayleigh Schrodinger perturbation theory to second order calculations have been utilized to investigate these states. The spectroscopic constants, omegae, Re, Be, ..., and the static dipole moment, MU, have been investigated by using the two different techniques of calculation with five different types of basis. The eigenvalues, Ev, the rotational constant, Bv, the centrifugal distortion constant, Dv, and the abscissas of the turning points, Rmin and Rmax, have been calculated by using the canonical functions approach. The comparison between the values of the present work, calculated by different techniques, and those available in the literature for several electronic states shows a very good agreement. Twenty-one new electronic states have been studied here for the first time. PMID- 25796255 TI - Discrete perturbation theory for continuous soft-core potential fluids. AB - In this work, we present an equation of state for an interesting soft-core continuous potential [G. Franzese, J. Mol. Liq. 136, 267 (2007)] which has been successfully used to model the behavior of single component fluids that show some water-type anomalies. This equation has been obtained using discrete perturbation theory. It is an analytical expression given in terms of density, temperature, and the set of parameters that characterize the intermolecular interaction. Theoretical results for the vapor-liquid phase diagram and for supercritical pressures are compared with previous and new simulation data and a good agreement is found. This work also clarifies discrepancies between previous Monte Carlo and molecular dynamics simulation results for this potential. PMID- 25796256 TI - Interpreting the nonlinear dielectric response of glass-formers in terms of the coupling model. AB - Nonlinear dielectric measurements at high electric fields of glass-forming glycerol and propylene carbonate initially were carried out to elucidate the dynamic heterogeneous nature of the structural alpha-relaxation. Recently, the measurements were extended to sufficiently high frequencies to investigate the nonlinear dielectric response of faster processes including the so-called excess wing (EW), appearing as a second power law at high frequencies in the loss spectra of many glass formers without a resolved secondary relaxation. While a strong increase of dielectric constant and loss is found in the nonlinear dielectric response of the alpha-relaxation, there is a lack of significant change in the EW. A surprise to the experimentalists finding it, this difference in the nonlinear dielectric properties between the EW and the alpha-relaxation is explained in the framework of the coupling model by identifying the EW investigated with the nearly constant loss (NCL) of caged molecules, originating from the anharmonicity of the intermolecular potential. The NCL is terminated at longer times (lower frequencies) by the onset of the primitive relaxation, which is followed sequentially by relaxation processes involving increasing number of molecules until the terminal Kohlrausch alpha-relaxation is reached. These intermediate faster relaxations, combined to form the so-called Johari-Goldstein (JG) beta-relaxation, are spatially and dynamically heterogeneous, and hence exhibit nonlinear dielectric effects, as found in glycerol and propylene carbonate, where the JG beta-relaxation is not resolved and in D-sorbitol where it is resolved. Like the linear susceptibility, chi1(f), the frequency dispersion of the third-order dielectric susceptibility, chi3(f), was found to depend primarily on the alpha-relaxation time, and independent of temperature T and pressure P. I show this property of the frequency dispersions of chi1(f) and chi3(f) is the characteristic of the many-body relaxation dynamics of interacting systems which are governed solely by the intermolecular potential, and thermodynamic condition plays no role in this respect. Although linked to chi3(f), dynamic heterogeneity is one of the parallel consequences of the many body dynamics, and it should not be considered as the principal control parameter for the other dynamic properties of glassforming systems. Results same as chi3(f) at elevated pressures had been obtained before by molecular dynamics simulations from the four-points correlation function and the intermediate scattering function. Naturally all properties obtained from the computer experiment, including dynamics heterogeneity, frequency dispersion, the relation between the alpha- and JG beta-relaxation, and the breakdown of the Stokes-Einstein relation, are parallel consequences of the many-body relaxation dynamics governed by the intermolecular potential. PMID- 25796257 TI - Molecular ring rotation in solid ferrocene revisited. AB - We report on quasielastic neutron spectroscopy experiments on ferrocene (bis(eta(5)-cyclopentadienyl)iron) in its three different crystalline phases: the disordered monoclinic crystalline phase (T > 164 K), the metastable triclinic phase (T < 164 K), and the stable orthorhombic phase (T < 250 K). The cyclopentadienyl rings in ferrocene are known to undergo rotational reorientations for which the analysis of our large data set suggests partially a revision of the known picture of the dynamics and allows for an extension and completion of previous studies. In the monoclinic phase, guided by structural information, we propose a model for rotational jumps among non-equivalent sites in contrast to the established 5-fold jump rotation model. The new model takes the dynamical disorder into account and allows the cyclopentadienyl rings to reside in two different configurations which are found to be twisted by an angle of approximately 30 degrees . In the triclinic phase, our analysis demands the use of a 2-ring model accounting for crystallographically independent sites with different barriers to rotation. For the orthorhombic phase of ferrocene, we confirm a significantly increased barrier of rotation using neutron backscattering spectroscopy. Our data analysis includes multiple scattering corrections and presents a novel approach of simultaneous analysis of different neutron scattering data by combining elastic and inelastic fixed window temperature scans with energy spectra, providing a very robust and reliable mean of extracting the individual activation energies of overlapping processes. PMID- 25796258 TI - Revealing and resolving degeneracies in stretching exponents in temporally heterogeneous environments. AB - Supercooled liquids are proposed to be dynamically heterogeneous, with regions exhibiting relaxation time scales that vary in space and time. Measurement of the distribution of such time scales could be an important test of various proposed theories of vitrification. Single molecule fluorescence experiments attempt to uncover this distribution, typically by embedding single molecule probes into these systems and monitoring their individual rotational relaxations from a computed autocorrelation function (ACF). These ACFs may exhibit stretched exponential decays, with the value of the stretching exponent assumed to report the set of dynamical environments explored by the probe. Here, we use simulated trajectories of rotation to investigate how the time scale of dynamic exchange relative to underlying relaxation time scales in the system affects probe ability to report the distribution relaxation of time scales present. We find that dynamically heterogeneous regions must persist for approximately 50 times the median relaxation time scale for a single molecule to accurately report the full distribution of time scales it has experienced. In systems with faster dynamic exchange, single molecule ACFs average over successive environments, limiting the reported heterogeneity of the system. This leads to degeneracies in stretching exponent for systems with different underlying relaxation time distributions. We show that monitoring single molecule median stretching exponent as a function of trajectory length or simultaneously measuring median stretching exponent and measured relaxation time distribution at a given trajectory length can resolve these degeneracies, revealing the underlying set of relaxation times as well as median exchange time. PMID- 25796259 TI - Surface thermodynamics of planar, cylindrical, and spherical vapour-liquid interfaces of water. AB - The test-area (TA) perturbation approach has been gaining popularity as a methodology for the direct computation of the interfacial tension in molecular simulation. Though originally implemented for planar interfaces, the TA approach has also been used to analyze the interfacial properties of curved liquid interfaces. Here, we provide an interpretation of the TA method taking the view that it corresponds to the change in free energy under a transformation of the spatial metric for an affine distortion. By expressing the change in configurational energy of a molecular configuration as a Taylor expansion in the distortion parameter, compact relations are derived for the interfacial tension and its energetic and entropic components for three different geometries: planar, cylindrical, and spherical fluid interfaces. While the tensions of the planar and cylindrical geometries are characterized by first-order changes in the energy, that of the spherical interface depends on second-order contributions. We show that a greater statistical uncertainty is to be expected when calculating the thermodynamic properties of a spherical interface than for the planar and cylindrical cases, and the evaluation of the separate entropic and energetic contributions poses a greater computational challenge than the tension itself. The methodology is employed to determine the vapour-liquid interfacial tension of TIP4P/2005 water at 293 K by molecular dynamics simulation for planar, cylindrical, and spherical geometries. A weak peak in the curvature dependence of the tension is observed in the case of cylindrical threads of condensed liquid at a radius of about 8 A, below which the tension is found to decrease again. In the case of spherical drops, a marked decrease in the tension from the planar limit is found for radii below ~ 15 A; there is no indication of a maximum in the tension with increasing curvature. The vapour-liquid interfacial tension tends towards the planar limit for large system sizes for both the cylindrical and spherical cases. Estimates of the entropic and energetic contributions are also evaluated for the planar and cylindrical geometries and their magnitudes are in line with the expectations of our simple analysis. PMID- 25796261 TI - Chain architecture and micellization: a mean-field coarse-grained model for poly(ethylene oxide) alkyl ether surfactants. AB - Microscopic modeling of surfactant systems is expected to be an important tool to describe, understand, and take full advantage of the micellization process for different molecular architectures. Here, we implement a single chain mean field theory to study the relevant equilibrium properties such as the critical micelle concentration (CMC) and aggregation number for three sets of surfactants with different geometries maintaining constant the number of hydrophobic and hydrophilic monomers. The results demonstrate the direct effect of the block organization for the surfactants under study by means of an analysis of the excess energy and entropy which can be accurately determined from the mean-field scheme. Our analysis reveals that the CMC values are sensitive to branching in the hydrophilic head part of the surfactant and can be observed in the entropy enthalpy balance, while aggregation numbers are also affected by splitting the hydrophobic tail of the surfactant and are manifested by slight changes in the packing entropy. PMID- 25796260 TI - Polymers encapsulated in short single wall carbon nanotubes: pseudo-1D morphologies and induced chirality. AB - Molecular dynamics simulations are performed to investigate the stable morphologies of semi-flexible polymer chains within a single wall carbon nanotube (CNT). We characterize these morphologies with a variety of measures. Due to the different curvature inside the CNT to outside, there are increased numbers of polymer-CNT bead contacts for polymers which reside inside the CNT. A sufficiently long polymer chain first adsorbs on the exterior of the nanotube and subsequently moves inside the cavity of the nanotube. At equilibrium, the polymer configuration consists of a central stem surrounded by helically wrapped layers. Sections of the polymer outside the CNT have helical conformations (for CNTs of small radius) or circular arrangements (for CNTs of larger radius). Polymers encapsulated within the CNT have an increased chirality due to packing of the beads and this chirality is further enhanced for moderately stiff chains. PMID- 25796262 TI - Co-non-solvency: mean-field polymer theory does not describe polymer collapse transition in a mixture of two competing good solvents. AB - Smart polymers are a modern class of polymeric materials that often exhibit unpredictable behavior in mixtures of solvents. One such phenomenon is co-non solvency. Co-non-solvency occurs when two (perfectly) miscible and competing good solvents, for a given polymer, are mixed together. As a result, the same polymer collapses into a compact globule within intermediate mixing ratios. More interestingly, polymer collapses when the solvent quality remains good and even gets increasingly better by the addition of the better cosolvent. This is a puzzling phenomenon that is driven by strong local concentration fluctuations. Because of the discrete particle based nature of the interactions, Flory-Huggins type mean field arguments become unsuitable. In this work, we extend the analysis of the co-non-solvency effect presented earlier [D. Mukherji et al., Nat. Commun. 5, 4882 (2014)]. We explain why co-non-solvency is a generic phenomenon, which can only be understood by the thermodynamic treatment of the competitive displacement of (co)solvent components. This competition can result in a polymer collapse upon improvement of the solvent quality. Specific chemical details are not required to understand these complex conformational transitions. Therefore, a broad range of polymers are expected to exhibit similar reentrant coil-globule coil transitions in competing good solvents. PMID- 25796263 TI - Modeling the effects of pH and ionic strength on swelling of polyelectrolyte gels. AB - A model is developed for the elastic response of a polyelectrolyte gel under unconstrained and constrained swelling in a water bath with an arbitrary pH, where a monovalent salt is dissolved. A gel is treated as a three-phase medium consisting of an equivalent polymer network, solvent (water), and solute (mobile ions). Transport of solvent and solute is thought of as their diffusion through the network accelerated by an electric field formed by mobile and fixed ions and accompanied by chemical reactions (self-ionization of water molecules, dissociation of functional groups attached to polymer chains, and formation of ion pairs between bound charges and mobile counter-ions). Constitutive equations are derived by means of the free energy imbalance inequality for an arbitrary three-dimensional deformation with finite strains. Adjustable parameters in the governing relations are found by fitting equilibrium swelling diagrams on several hydrogels. The effects of pH, ionic strength of solution, and constraints on equilibrium water uptake are studied numerically. PMID- 25796264 TI - Fragmentation and depolymerization of non-covalently bonded filaments. AB - Protein molecules often self-assemble by means of non-covalent physical bonds to form extended filaments, such as amyloids, F-actin, intermediate filaments, and many others. The kinetics of filament growth is limited by the disassembly rate, at which inter-protein bonds break due to the thermal motion. Existing models often assume that the thermal dissociation of subunits occurs uniformly along the filament, or even preferentially in the middle, while the well-known propensity of F-actin to depolymerize from one end is mediated by biochemical factors. Here, we show for a very general (and generic) model, using Brownian dynamics simulations and theory, that the breakup location along the filament is strongly controlled by the asymmetry of the binding force about the minimum, as well as by the bending stiffness of the filament. We provide the basic connection between the features of the interaction potential between subunits and the breakup topology. With central-force (that is, fully flexible) bonds, the breakup rate is always maximum in the middle of the chain, whereas for semiflexible or stiff filaments this rate is either a minimum in the middle or flat. The emerging framework provides a unifying understanding of biopolymer fragmentation and depolymerization and recovers earlier results in its different limits. PMID- 25796265 TI - Water uptake profile in a model ion-exchange membrane: conditions for water-rich channels. AB - Ionic conductivity in a polymeric fuel cell requires water uptake. Previous theoretical studies of water uptake used idealized parameters. We report a parameter-free prediction of the water-swelling behavior of a model fuel cell membrane. The model polymers, poly(methyl-butylene)-block-poly(vinylbenzyl trimethylamine), form lamellar domains that absorb water in humid air. We use the Scheutjens-Fleer methodology to predict the resulting change in lamellar structure and compare with x-ray scattering. The results suggest locally uniform water distributions. However, under conditions where a PVBTMA and water mixture phase-separate, the two phases arrange into stripes with a dilute stripe sandwiched between two concentrated stripes. A small amount of water enhances conductivity most when it is partitioned into such channels, improving fuel-cell performance. PMID- 25796266 TI - Nonlinear vs. linear biasing in Trp-cage folding simulations. AB - Biased simulations have great potential for the study of slow processes, including protein folding. Atomic motions in molecules are nonlinear, which suggests that simulations with enhanced sampling of collective motions traced by nonlinear dimensionality reduction methods may perform better than linear ones. In this study, we compare an unbiased folding simulation of the Trp-cage miniprotein with metadynamics simulations using both linear (principle component analysis) and nonlinear (Isomap) low dimensional embeddings as collective variables. Folding of the mini-protein was successfully simulated in 200 ns simulation with linear biasing and non-linear motion biasing. The folded state was correctly predicted as the free energy minimum in both simulations. We found that the advantage of linear motion biasing is that it can sample a larger conformational space, whereas the advantage of nonlinear motion biasing lies in slightly better resolution of the resulting free energy surface. In terms of sampling efficiency, both methods are comparable. PMID- 25796267 TI - A prospective, double-blind, randomized controlled trial of the angiotensin converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial). AB - AIMS: Angiotensin-converting enzyme (ACE) inhibitors improve left ventricular (LV) remodelling and outcome in heart failure and hypertensive heart disease. They may be similarly beneficial in patients with aortic stenosis (AS), but historical safety concerns have limited their use, and no prospective clinical trials exist. METHODS AND RESULTS: We conducted a prospective, randomized, double blind, placebo-controlled trial in 100 patients with moderate or severe asymptomatic AS to examine the physiological effects of ramipril, particularly LV mass (LVM) regression. Subjects were randomized to ramipril 10 mg daily (n = 50) or placebo (n = 50) for 1 year, and underwent cardiac magnetic resonance, echocardiography, and exercise testing at 0, 6, and 12 months, with follow-up data available in 77 patients. There was a modest but progressive reduction in LVM (the primary end point) in the ramipril group vs. the placebo group (mean change -3.9 vs. +4.5 g, respectively, P = 0.0057). There were also trends towards improvements in myocardial physiology: the ramipril group showed preserved tissue Doppler systolic velocity compared with placebo (+0.0 vs. -0.5 cm/s, P = 0.04), and a slower rate of progression of the AS (valve area 0.0 cm(2) in the ramipril group vs. -0.2 cm(2) in the placebo arm, P = 0.067). There were no significant differences in major adverse cardiac events. CONCLUSION: ACE inhibition leads to a modest, but progressive reduction in LVM in asymptomatic patients with moderate severe AS compared with placebo, with trends towards improvements in myocardial physiology and slower progression of valvular stenosis. A larger clinical outcome trial to confirm these findings and explore their clinical relevance is required. PMID- 25796268 TI - Recovery of activities of daily living among older people one year after hip fracture. AB - This article aims to determine the functional recovery of older people, who were previously independent in activities of daily living (ADLs) and without cognitive impairment, in the year following a fall-related hip fracture. A cohort study was carried out among patients admitted to University General Hospital of Albacete (Spain). Consecutive sampling was performed. Variables included demographic, habitual residence, type of hip fracture, mental status (Short Portable Mental Status Questionnaire [SPMSQ] Pfeiffer), and independence in ADLs (according to the Barthel Index [BI]) prior to the fall and after the fracture. For 205 patients, 1 year after surgery, the mean BI score was 78.09 (SD = 25.13); (vs. 90.02 before the hip fracture), 59% showed urinary continence (vs. 79%), and 65% walked without assistance (vs. 82%). Regarding predictors of recovery, results indicate that patients who are older, who suffer complications after hospital discharge, or who reside in nursing homes experience poorer recovery in ADLs. Only 47.9% of the patients regained prior levels of autonomy 1 year after surgery. PMID- 25796269 TI - Experiences recruiting Indian worksites for an integrated health protection and health promotion randomized control trial in Maharashtra, India. AB - This article provides an overview of the recruitment strategies utilized in the Mumbai Worksites Tobacco Control Study, a cluster randomized trial testing the effectiveness of an integrated tobacco control and occupational safety and health program in Indian manufacturing worksites. From June 2012 to June 2013, 20 companies were recruited. Companies were identified using association lists, referrals, internet searches and visits to industrial areas. Four hundred eighty companies were contacted to validate information, introduce the study and seek an in-person meeting with a company representative. Eighty-three company representatives agreed to meet. Of those 83 companies, 55 agreed to a formal 'pitch meeting' with key decision makers at the company. Seventy-seven recruitment 'pitches' were given, including multiple meetings in the same companies. If the company was interested, we obtained a letter of participation and employee roster. Based on this experience, recommendations are made that can help inform future researchers and practitioners wishing to recruit Indian worksites. When compared with recruitment of US manufacturing worksites, recruitment of Indian worksites lacked current industrial lists of companies to serve as a sampling frame, and required more in-person visits, incentives for control companies and more assurances around confidentiality to allow occupational safety and health experts into their worksite. PMID- 25796270 TI - Hidradenitis Suppurativa: New Opportunities for an Orphan Skin Disease. PMID- 25796271 TI - Lip swelling in an immunocompetent man. PMID- 25796272 TI - Innovative therapeutic strategies for recessive dystrophic epidermolysis bullosa. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is among the most serious rare skin diseases. It is also the rare skin disease for which most effort has been expended in developing advanced therapeutic interventions. RDEB is caused by collagen VII deficiency resulting from COL7A1 mutations. Therapeutic approaches seek to replenish collagen VII and thus restore dermal-epidermal adhesion. Therapeutic options under development include protein therapy and different cell based and gene-based therapies. In addition to treating skin defects, some of these therapies may also target internal mucosa. In the coming years, these novel therapeutic approaches should substantially improve the quality of life of patients with RDEB. PMID- 25796273 TI - Restoration of sensitivity to salinomycin in Eimeria following 5 flocks of broiler chickens reared in floor-pens using drug programs and vaccination to control coccidiosis. AB - Five successive flocks of broilers were reared in floor-pens and given different drug programs or were vaccinated against coccidiosis. Oocysts of Eimeria were isolated from the litter of pens during the fifth flock and their sensitivity to salinomycin (Sal) investigated by measuring new oocyst production following infection of medicated and unmedicated birds. Parasites obtained following 5 flocks given Sal were not well-controlled and it was concluded that they were partially resistant to the drug. Parasites obtained following 4 unmedicated flocks and one medicated flock were better controlled by Sal and it was concluded that in the absence of continuous medication there had been an improvement in drug efficacy. Sal almost completely suppressed oocyst production of isolates from treatments in which medication was followed by vaccination, indicating that when a drug program is followed by vaccination, restoration of sensitivity to Sal had occurred. PMID- 25796274 TI - Effect of partial comb and wattle trim on pullet behavior and thermoregulation,1. AB - The wattles and comb of chickens are important for thermoregulation allowing for heat exchange during high temperatures. These integumentary tissues are sometimes trimmed to prevent tears if caught on cage equipment and to also improve feed efficiency; however, the procedure itself could be painful to chicks. Our objective was to determine the effect of trimming the comb and wattles on behavior, BW, feed usage, and the surface temperature of pullets. The wattles and comb of Leghorns were partially trimmed at 21 d age (n = 6 cages, 13 chicks each) with another 6 cages serving as controls. Behaviors were recorded 3 times daily for 1 h starting at 0800, 1200, and 1500 using instantaneous scan sampling observations conducted every 5 min prior to, on the d of, and after the trim. Group BW at 21, 28, and 36 d age and the amount of feed used for 7 d beginning at 21 and 29 d age were measured per cage. At 1300 h on d before and after the trim, thermal images of the pullet's beak, comb, eye, wattle, and shank were randomly taken on 3 pullets/cage. Smaller proportions of trimmed chicks were eating and greater proportions were sitting on the d of the trim as compared to the controls with the opposite trend occurring on 4 d post-trim (treatment by age interaction, P = 0.03 and 0.0001, respectively). Standing behavior differed only on the d of the trim where smaller proportions of trimmed pullets stood as compared to intact controls (treatment by age interaction, P = 0.0002). Trimming the comb and wattles did not affect preening, running, BW, feed utilization, and the surface temperature of the pullet. The indices of behavior suggest that on the d of the trim, pullets may have experienced temporary distress, but they returned to normal behavior by 5 h post-trim with no long-term effect on BW, feed usage, or surface body temperature. PMID- 25796275 TI - Pseudoaneurysm of the aortic isthmus involving a right aberrant subclavian artery long after multiple coarctation repairs. PMID- 25796276 TI - Extracorporeal life support in patients with refractory cardiogenic shock: keep them awake. AB - OBJECTIVES: Traditionally, patients on extracorporeal life support (ECLS) are sedated and mechanically ventilated and therefore prone to complications related to immobility and ventilation. We adopted this 'Awake ECLS' strategy for the patients with refractory cardiogenic shock (RCS) as a bridge to decision. METHODS: Sixty-eight patients with RCS were supported by ECLS (All veno-arterial) in years 2010-2014. Patients that could not survive 24 h after ECLS implantation (9 patients) were excluded from the study. Study population constituted 59 patients-'Awake' group (n = 18; maintained awake without intubation) and 'Control' group (n = 41; intubated and required mechanical ventilation). RESULTS: Nine (50%) patients were awake at implantation, with 5 of them remaining free of sedation and ventilator support through to explantation. Nine patients were ventilated at the time of implantation but subsequently extubated and remained non-intubated and ventilator free. Post-ECLS survival at 1 month was 78 and 42% while the survival to discharge was 78 and 37% in awake and control group, respectively. CONCLUSIONS: ECLS as a bridge to decision in RCS is effective in restoring adequate systemic perfusion and recovering end-organ function. ECLS can be initiated in awake patients with RCS and patients can be awakened on ECLS. The 'awake ECLS' strategy may avoid complications related to mechanical ventilation, sedation and immobilization. RCS patients supported on ECLS without severe metabolic acidosis, multiorgan failure, intra-aortic balloon pump or uncertain neurological status are more likely to be weaned from the ventilator. Patients that are awake at the time of ECLS implantation are more likely to remain awake during ECLS. PMID- 25796277 TI - [ALR, the multifunctional protein]. AB - ALR is a mystic protein. It has a so called "long" 22 kDa and a "short" 15 kDa forms. It has been described after partial hepatectomy and it has just been considered as a key protein of liver regeneration. At the beginning of the 21st century it has been revealed that the "long" form is localized in the mitochondrial intermembrane space and it is an element of the mitochondrial protein import and disulphide relay system. Several proteins of the substrates of the mitochondrial disulphide relay system are necessary for the proper function of the mitochondria, thus any mutation of the ALR gene leads to mitochondrial diseases. The "short" form of ALR functions as a secreted extracellular growth factor and it promotes the protection, regeneration and proliferation of hepatocytes. The results gained on the recently generated conditional ALR mutant mice suggest that ALR can play an important role in the pathogenesis of alcoholic and non-alcoholic steatosis. Since the serum level of ALR is modified in several liver diseases it can be a promising marker molecule in laboratory diagnostics. PMID- 25796278 TI - [Sulfonylureas in today's blood glucose lowering therapy. New data on advantages and potential barriers of an "old" antidiabetic group]. AB - Sulfonylurea compounds have been basic elements of antidiabetic treatment in type 2 diabetes for a long time. However, with the introduction of incretin type insulin secretagogues it is often arises, whether is still there a place for sulfonylureas in the today's therapy. To answer this question the author overviews general pharmaceutical characteristics of the sulfonylurea compounds as well as individual particularities of the second generation derivatives used at present in Hungary. The author details also the most important differences between incretin type drugs - first of all dipeptidyl peptidase-4 inhibitors - and sulfonylureas. On the basis of available data it can be concluded in accordance with the latest international guidelines, that sulfonylureas have still role in the blood glucose lowering therapy of type 2 diabetes, though they became somewhat pushed back among insulin secretagogue type drugs. If a sulfonylurea compound is the drug of choice, it is important to select the appropriate molecule (in case of normal renal function gliclazide or glimepiride). It is also important to re-educate the patient, as well as to apply the minimal dose providing the desired glycaemic effect. PMID- 25796279 TI - [Cardiovascular side effects of non-steroidal anti-inflammatory drugs in the light of recent recommendations. Diclofenac is not more dangerous]. AB - Among their beneficial effects, non-steroidal anti-inflammatory drugs may also exert several side effects which depend on the dosage and the type of these medications. The most frequent gastrointestinal side effects usually develop shortly after the beginning of their administration, but others such as cardiovascular interactions (which are present much less frequently than gastrointestinal side effects) can also occur after the beginning of drug administration without a latency period. For a long-term treatment, non-steroidal anti-inflammatory drugs are most frequently used in the elderly population where patients typically have high cardiovascular risk and take other medicines, e.g. low dose acetylsalicylic acid that can interact with non-steroidal anti inflammatory drugs; in this aspect diclofenac may cause less side effects. In this review, the authors briefly review cardiovascular side effects of non steroidal anti-inflammatory drugs, the processes which potentially influence them, therapeutic consequences and their interaction with acetylsalicylic acid. PMID- 25796280 TI - [Mechanical circulatory support saves lives -- three years' experience of the newly established assist device program at Semmelweis University, Budapest, Hungary]. AB - INTRODUCTION: Since the celebration of the 20th anniversary of the first heart transplantation in Hungary in 2012 the emerging need for modern heart failure management via mechanical circulatory support has evolved. In May 2012 the opening of a new heart failure and transplant unit with 9 beds together with the procurement of necessary devices at Semmelweis University accomplished this need. AIM: The aim of the authors was to report their initial experience obtained in this new cardiac assist device program. METHOD: Since May, 2012, mechanical circulatory support system was applied in 89 cases in 72 patients. Indication for support were end stage heart failure refractory to medical treatment and acute left or right heart failure. RESULTS: Treatment was initiated for acute graft failure after heart transplantation in 27 cases, for end stage heart failure in 24 cases, for acute myocardial infarction in 21 cases, for acute postcardiotomy heart failure in 14 cases, for severe respiratory insufficiency in 2 cases and for drug intoxication in one case. Among the 30 survivor of the whole program 13 patients were successfully transplanted. CONCLUSIONS: The available devices can cover all modalities of current bridge therapy from short term support through medium support to heart transplantation or long term support and destination therapy. These conditions made possible the successful start of a new cardiac assist device program. PMID- 25796281 TI - [Hemospray: a novel therapeutic option in the management of acute upper gastrointestinal bleeding]. AB - INTRODUCTION: Early endoscopic diagnosis and endoscopic therapy are very important in cases of acute gastrointestinal bleeding. Hemospray is an inorganic powder with hemostatic properties recently proposed for the treatment of acute gastrointestinal bleeding. AIM: The aim of the authors was to report the first Hungarian experience obtained with Hemospray in patients with acute gastrointestinal bleeding. METHOD: During a 14-month period 10 acute upper gastrointestinal bleeder patients were treated endoscopically with Hemospray in 11 settings. In 5 patients previous endoscopic hemostatic methods failed and in the remaining 5 patients Hemospray was administrated as a first-line therapy. RESULTS: Primary hemostasis was achieved in 9 of the 10 patients treated with Hemospray. Two patients died during hospitalization (uncontrolled arterial bleeding in one patient and hepatic encephalopathy in the other one patient). Primary hemostasis and hemodynamic stability were achieved in each of the 4 patients who had thrombopenia. CONCLUSIONS: Hemospray as a rescue therapy may ensure primary hemostasis in severe acute gastrointestinal bleeding even in cases with thrombopenia. PMID- 25796283 TI - Uremic pericarditis: a report of 30 cases and review of the literature. AB - PATIENT: Male, 71 * Male, 69 * . Female, 49. FINAL DIAGNOSIS: Uremic pericarditis. SYMPTOMS: - MEDICATION: - CLINICAL PROCEDURE: Hemodialysis. SPECIALTY: Nephrology. OBJECTIVE: Rare disease. BACKGROUND: Uremic pericarditis, common at one time among dialysis patients, has become a rare entity in recent years. Due to its low incidence, its recognition has gained importance among internists, cardiologists, and nephrologists. It can be seen in predialysis patients and in dialysis patients who are on hemodialysis or peritoneal dialysis. CASE REPORT: We report 3 cases of uremic pericarditis and their presenting manifestations and review 30 cases we have treated. Among these patients, the traditional findings among patients with acute pericarditis such as chest pain, fever, electrocardiographic changes, and leukocytosis are uncommon. Pericardial friction rub has a relatively high incidence but its differentiation by an untrained ear, especially by a non-cardiologist, could be a major problem. Not infrequently, it is complicated by pre-tamponade or tamponade, requiring pericardiocentesis or pericardial surgery. CONCLUSIONS: Uremic pericarditis is a treatable, but not always a preventable, condition. Timely recognition of its presence and its efficient management are essential elements of successful treatment. PMID- 25796284 TI - Bioactivity of ovulation inducing factor (or nerve growth factor) in bovine seminal plasma and its effects on ovarian function in cattle. AB - To understand the role of ovulation-inducing factor (or nerve growth factor) (OIF [NGF]) in bovine seminal plasma, we (1) used an in vivo llama bioassay to test the hypothesis that bovine seminal plasma induces ovulation and CL development in llamas similar to that of llama seminal plasma when the dose of seminal plasma is adjusted to ovulation-inducing factor content (experiment 1) and (2) determined the effect of bovine seminal plasma on the interval to ovulation and luteal development in heifers (experiment 2). Within species, seminal plasma was pooled (n = 160 bulls, n = 4 llamas), and the volume of seminal plasma used for treatment was adjusted to a total dose of 250 MUg of ovulation-inducing factor. In experiment 1, mature female llamas were assigned randomly to four groups and treated intramuscularly with either 10 mL of PBS (negative control, n = 5), 50 MUg GnRH (positive control, n = 5), 6-mL of llama seminal plasma (n = 6), or 12 mL of bull seminal plasma (n = 6). Ovulation and CL development were monitored by transrectal ultrasonography. In experiment 2, beef heifers were given a luteolytic dose of prostaglandin followed by 25-mg porcine LH (pLH) 12 hours later to induce ovulation. Heifers were assigned randomly to three groups and given 12 mL bovine seminal plasma intramuscularly 12 hours after pLH treatment (n = 10), within 4 hours after ovulation (n = 9), or no treatment (control, n = 10). Ovulation was monitored by ultrasonography every 4 hours, and the CL development was monitored daily until the next ovulation. In experiment 1, ovulation was detected in 0/5, 4/5, 4/6, 4/6 llamas in the PBS, GnRH, llama seminal plasma, and bovine seminal plasma groups, respectively (P < 0.05). Luteal development was not different among groups. In experiment 2, the interval to ovulation was more synchronous (range: 4 vs. 22 hours; P < 0.0001) in heifers treated with seminal plasma before ovulation compared with the other groups. Luteal development was not different among groups; however, plasma progesterone concentrations tended to be greater in the postovulation treatment group compared with other groups. In summary, results confirmed the presence of bioactive ovulation-inducing factor in bull seminal plasma and supported the hypothesis that bovine and llama seminal plasma have similar ovulatory effects, using a llama bioassay. Treatment with bovine seminal plasma resulted in greater synchrony of ovulation in heifers pretreated with pLH. Plasma progesterone concentration tended to be higher in heifers given bovine seminal plasma within 4 hours after ovulation, suggesting that bovine ovulation-inducing factor is luteotrophic. PMID- 25796285 TI - Arginine supplementation between 41 and 146 days of pregnancy reduces uterine blood flow in dairy heifers. AB - We hypothesized that arginine (Arg) supplementation during early pregnancy could foster placental vascularization. The objective of this study was to evaluate the effects of Arg supplementation on uterine artery hemodynamics between 40 and 140 days of gestation. At 41 days of gestation, 17 Holstein heifers (448 +/- 73.9 kg) were surgically fitted with a catheter in the peritoneal cavity. After surgery, nine heifers received a daily intraperitoneal infusion of 40 mg of Arg/kg of body weight (BW; ARG), whereas the remaining eight heifers received a daily intraperitoneal infusion of saline solution at equivalent volumes as ARG heifers relative to BW (CTRL). Daily infusions took place every 12 hours until heifers reached 146 days of pregnancy. At 41, 62, 83, 104, 125, and 146 days of pregnancy, all heifers were body weighed, bled, and uterine blood flow volume (FV) and other hemodynamics were determined using Doppler ultrasonography. The measurements included heart rate, FV, pulsatility index, and resistance index. Plasma concentrations of amino acids (AAs), nitric oxide, glucose, insulin growth factor, progesterone (P4), growth hormone, and prolactin were analyzed. In a second experiment, we evaluated Arg metabolism when infused either intravenously or intraperitoneally. Overall, FV did not differ between the treatments, but it increased (P < 0.001) with pregnancy day. Uterine blood FV evolved differently between the treatments, with CTRL heifers having a greater (P < 0.05) FV (1104 +/ 65.42 mL/min) at 146 days of pregnancy than in ARG heifers (806 +/- 65.32 mL/min). Pulsatility index and resistance index decreased throughout pregnancy but did not differ between the treatments. Heart rate was decreased (P < 0.05) in ARG (74 +/- 1.4 beats/min) compared with CTRL heifers (81 +/- 1.5 beats/min). Plasma concentrations of Arg tended (P < 0.09) to be greater in ARG than those in CTRL heifers, but carnitine, valine, isoleucine, leucine, phenylalanine, and tryptophan were lower (P < 0.05) in ARG than those in CTRL heifers. The proportion of essential AAs (with respect to total AAs) in plasma was greater (P < 0.05) in CTRL (73 +/- 2.4%) than that in ARG heifers (65 +/- 2.3%). No differences between the treatments were found in plasma prolactin (P = 0.43), insulin growth factor (P = 0.97), glucose (P = 0.45), growth hormone (P = 0.39), or nitric oxide (P = 0.89) concentrations. However, plasma P4 concentration was greater (P < 0.05) in ARG than in CTRL heifers. Contrary to our hypothesis, Arg supplementation did not increase blood flow to the uterus but did change other parameters that could influence placental and fetal growth such as heart rate, maternal concentration of plasma AAs, or P4 synthesis. Furthermore, infusion sites (blood vs. peritoneum) of Arg render different metabolic responses. PMID- 25796286 TI - Validation of merocyanine 540 staining as a technique for assessing capacitation related membrane destabilization of fresh dog sperm. AB - The aim of this study was to determine whether flow cytometric evaluation of combined merocyanine 540 and Yo-Pro 1 (M540-YP) staining would identify viable dog sperm that had undergone membrane stabilization known to be associated with capacitation in other species, and whether such destabilization is detected earlier than when using the tyrosine phosphorylation and ethidium homodimer (TP EH) stain combination with epifluorescence microscopy. Semen from nine dogs was collected and incubated in parallel in bicarbonate-free modified Tyrode's medium (-BIC), medium containing 15 mM bicarbonate (+BIC), dog prostatic fluid, and in PBS. Aliquots for staining were removed at various time points during incubation of up to 6 hours. Staining with M540-YP allowed the classification of dog sperm as viable without destabilized membranes, viable with destabilized membranes, nonviable without destabilized membranes, or nonviable with destabilized membranes. The percentage of viable sperm detected using EH (83.5 +/- 1.37%; mean +/- SEM) was higher than when using YP (66.7 +/- 1.37%: P < 0.05; n = 54 semen samples). On the other hand, M540-YP identified a higher percentage of viable sperm with destabilized membranes than TP-EH (75 +/- 1.76% vs. 35 +/- 1.70%: P < 0.05; n = 54 semen samples). Staining with M540-YP indicated a rapid increase in the percentage of viable sperm with destabilized membranes, reaching a maximum during the first 30 minutes of incubation in +BIC. For all other treatments (i.e., -BIC, prostatic fluid, and PBS), the peak in the percentage of viable sperm with destabilized membranes was reached as much as 90 to 210 minutes later than incubation in +BIC. The lowest percentage of viable sperm showing signs of capacitation was recorded during incubation in PBS. We conclude that YP identifies sperm committed to cell death earlier than EH, and that the M540-YP stain combination identifies membrane destabilization known to be associated with capacitation in other species earlier than the TP-EH stain combination. PMID- 25796287 TI - The recombinant equine LHbeta subunit combines divergent intracellular traits of human LHbeta and CGbeta subunits. AB - The pituitary LHbeta and placental CGbeta subunits are products of different genes in primates. The major structural difference between the two subunits is in the carboxy-terminal region, where the short carboxyl sequence of hLHbeta is replaced by a longer O-glycosylated carboxy-terminal peptide in hCGbeta. In association with this structural deviation, there are marked differences in the secretion kinetics and polarized routing of the two subunits. In equids, however, the CGbeta and LHbeta subunits are products of the same gene expressed in the placenta and pituitary (LHbeta), and both contain a carboxy-terminal peptide. This unusual expression pattern intrigued us and led to our study of eLHbeta subunit secretion by transfected Chinese hamster ovary and Madin-Darby canine kidney cells. In continuous labeling and pulse-chase experiments, the secretion of the eLHbeta subunit from the transfected Chinese hamster ovary cells was inefficient (medium recovery of 16%-25%) and slow (t1/2 > 6.5 hours). This indicated that, the secretion of the eLHbeta subunit resembles that of hLHbeta rather than hCGbeta. In Madin-Darby canine kidney cells grown on Transwell filters, the eLHbeta subunit was preferentially secreted from the apical side, similar to the hCGbeta subunit secretory route (~65% of the total protein secreted). Taken together, these data suggested that secretion of the eLHbeta subunit integrates features of both hLHbeta and hCGbeta subunits. We propose that the evolution of this intracellular behavior may fulfill the physiological demands for biosynthesis of the LH and CG beta-subunits in the pituitary and placenta, respectively. PMID- 25796288 TI - Sperm quality and fertility of boar seminal doses after 2 days of storage: does the type of extender really matter? AB - The present approach was designed to evaluate the extender effects on sperm quality and fertility of short-term refrigerated seminal doses from Landrace boars lodged in husbandry-controlled conditions. For this purpose, we analyzed the sperm quality of seminal doses diluted in short-term (Beltsville Thawing Solution) and extra-long-term (Duragen) extenders from Days 0 to 2 of storage at 17 degrees C during an 8-month period. Pregnancy rates and litter size were evaluated from double inseminations within an interval of 12 hours (36 and 48 hours of refrigeration) of multiparous females using seminal doses diluted in each extender type. Sperm quality was assessed from the analyses of sperm motility and kinetics, sperm viability, expressed as plasma and acrosome membrane integrity, membrane lipid disorder, intracellular calcium levels, and acrosin activity. Results indicated significant differences between the extenders in the sperm quality of seminal doses. Therefore, the seminal doses diluted in Duragen had higher percentages of progressive motile spermatozoa and membrane-intact spermatozoa than those diluted in Beltsville Thawing Solution throughout all the experimental months. Nevertheless, despite these differences in preserving the sperm quality, pregnancy rates (>90%) and litter sizes (>10 piglets born per litter) were similar between the extenders. Our results had great relevance from a practical point of view because they reported lack of an extender effect on the reproductive performance of seminal doses during short-tem storage. PMID- 25796289 TI - Resilience in a reborn nation: Validation of the Lithuanian Resilience Scale for Adults (RSA). AB - BACKGROUND: Resilience, as an ability to withstand or rebound from crisis or adversity, is becoming an increasingly significant concept in health promotion and well-being. Individuals exhibiting resilience use skills or resources flexibly to solve situational demands. The Resilience Scale for Adults (RSA) may be used to assess protective resources, and the aim of the present study was to validate the Lithuanian translation. METHODS: The translated RSA was administered to a clinical (n=125) and a non clinical sample (n=499) to examine the discriminant validity of the RSA items with a confirmatory factor analysis, the internal consistency as well as construct validity by correlating it with the Quick Psycho-Affective Symptoms Scan (QPASS). RESULTS: The internal consistency, the test-retest stability and the factor structure were replicated as adequate, thus indicating good psychometric properties and support of discriminant validity. Females reported more resilience resources for the domains of social competence, family cohesion and social resources compared to men. The RSA subscales correlated negatively with the QPASS scores, and patients reported significantly less resilience resources than non-patients, thus indicating construct validity. CONCLUSIONS: Valid psychometric tools for research purposes and routine every-day use are urgently needed in Lithuania, a young nation still under numerous challenges due to social, economic and political transitions. The RSA represents a reliable and valid tool for assessing protective factors. Assessing resilience factors may extend the understanding of factors relevant for mental health problems as well as treatment prognosis beyond the capabilities of mere symptom oriented approaches. PMID- 25796290 TI - Analog assessment of frustration tolerance: association with self-reported child abuse risk and physiological reactivity. AB - Although frustration has long been implicated in promoting aggression, the potential for poor frustration tolerance to function as a risk factor for physical child abuse risk has received minimal attention. Instead, much of the extant literature has examined the role of anger in physical abuse risk, relying on self-reports of the experience or expression of anger, despite the fact that this methodology is often acknowledged as vulnerable to bias. Therefore, the present investigation examined whether a more implicit, analog assessment of frustration tolerance specifically relevant to parenting would reveal an association with various markers of elevated physical child abuse risk in a series of samples that varied with regard to age, parenting status, and abuse risk. An analog task was designed to evoke parenting-relevant frustration: the task involved completing an unsolvable task while listening to a crying baby or a toddler's temper tantrum; time scores were generated to gauge participants' persistence in the task when encountering such frustration. Across these studies, low frustration tolerance was associated with increased physical child abuse potential, greater use of parent-child aggression in discipline encounters, dysfunctional disciplinary style, support for physical discipline use and physical discipline escalation, and increased heart rate. Future research directions that could better inform intervention and prevention programs are discussed, including working to clarify the processes underlying frustration intolerance and potential interactive influences that may exacerbate physical child abuse. PMID- 25796291 TI - Playing a role in secondary prevention in the ED: longitudinal study of patients with asymptomatic elevated blood pressures following a brief education intervention: a pilot study. PMID- 25796292 TI - Health-related quality of life and related factors among elderly people in Jinzhou, China: a cross-sectional study. AB - OBJECTIVES: With rapid reductions in fertility and mortality, China has to face the dramatic ageing of its population. Although an ageing population is associated with greater life expectancy, and reflects a huge improvement in people's living standards and health care services, it also means that more elderly people suffer from non-communicable diseases (NCDs). The prolonged course of illness and disability associated with chronic diseases may significantly reduce health-related quality of life (HRQoL) among elderly people. The aims of this study were to evaluate HRQoL of elderly people living in Jinzhou, and to identify the predictors of HRQoL. STUDY DESIGN: Cross-sectional study with stratified sampling. METHODS: A cross-sectional survey was conducted among 1015 elderly people (>=60 years) living in the three administrative regions (Linghe, Guta and Taihe) of Jinzhou. A demographic questionnaire and Short Form-36 were employed to collect demographic variables and evaluate HRQoL, respectively. Multiple stepwise linear regression analysis was performed to estimate factors related to HRQoL of the subjects. RESULTS: Lowest HRQoL scores were obtained in the following dimensions: general health (65.44), role-emotional (69.74) and role physical (70.20). Multiple stepwise regression showed that factors associated with HRQoL of elderly people were medical health checks, age, socio-economic status, NCDs, and various unhealthy lifestyle behaviours such as smoking, excessive drinking and insufficient exercise. CONCLUSIONS: This study described overall HRQoL of elderly people in Jinzhou, and found that medical health checks, age, socio-economic status, NCDs, smoking, excessive drinking and insufficient exercise affected HRQoL. These findings will provide a basis for recommendations regarding health management of elderly people, and will also help local government to devise appropriate health intervention strategies for promoting the health status of elderly people in this region. PMID- 25796293 TI - Improving postoperative tonsillectomy pain management in children--a double blinded randomised control trial of a patient analgesia information sheet. AB - OBJECTIVES: To evaluate paediatric post-tonsillectomy pain management using oxycodone when a specific analgesia information sheet is included with standard postoperative information. METHODS: Oxycodone information sheets were randomly allocated to half the study children's post-tonsillectomy information pack. The trial was double-blinded to the surgeon, anaesthetist, nursing and administrative staff. Parents and children completed the pain assessment on day 3, 5 and 7. On day 10 the parents completed a questionnaire. RESULTS: A postoperative analgesia information sheet provides for higher satisfaction and knowledge for parents using oxycodone (p<0.001) and children have improved postoperative pain control, most significantly at day 5 (p<0.05). Parent assessment of the child's analgesia was superior with the oxycodone information sheet, most significantly at day 3 and 7 post operatively (p<0.05). There is also a positive correlation between the parents' observed pain score and children's self reported pain score, with a low correlation efficient level observed (p<0.001). CONCLUSIONS: Information sheets are useful in education and use of postoperative analgesia. The primary objective to explore the efficacy of the information sheet has proved to be successful in this setting. Given risks of opioid analgesia, it is recommended that postoperative information sheets be given to all parents, to provide for improved analgesia control and safe management of children in the postoperative period. PMID- 25796294 TI - Effectiveness of a parent-implemented intervention program for young children with cleft palate. AB - OBJECTIVE: This study investigated the effectiveness of a parent-implemented intervention on children's speech-language development and parents' interaction styles. METHODS: Seventeen children with cleft palate (CP) and their mothers participated in all sessions of a parent-implemented intervention program. Nine children with CP and their mothers who did not receive the intervention were included to examine the full effectiveness of the program. The intervention program consisted of four phases, pre-intervention test, parent training, parent implemented intervention at children's home for 3 months, and post-intervention test. Children's language and speech measures and maternal measures from pre- and post-intervention tests were compared between groups (intervention vs. no intervention). RESULTS: Children who received a parent-implemented intervention exhibited significant improvement in language measures based on standardized tests and quantitative language and speech measures from spontaneous utterances. The children in the intervention group showed a significantly greater extent of change in expressive vocabulary size, number of total words, and mean length of utterance than did those who did not receive the intervention. Mothers who received the training showed a significantly decreased number of different words, increased responsiveness, and decreased non-contingent utterances for children's communication acts compared to those who did not receive the training. CONCLUSIONS: The results of the study support the effectiveness of parent implemented early intervention on positive changes in children's speech-language development and mothers' use of communication strategies. PMID- 25796295 TI - Investigation of VO-salophen complexes electronic structure. AB - Vanadyl N,N'-bis(salicylidene)-o-phenylenediamine (salophen) complexes have been extensively investigated by cyclic voltammetry, UV-visible spectroscopy and theoretical calculations in MeCN, THF (tetrahydrofuran) and DMF (N,N dimethylformamide), in order to elucidate the overall factors that influence the electronic density of the metal and therefore the properties of these complexes in various applications. Different substituents were introduced into the salophen skeleton to change the vanadium electron density. Results obtained and here presented showed that the substituents influence the metal electronic character in a way that cannot be easily predicted by considering only the electronic effect. Similarly, the solvent polarity or coordination ability affects the metal complex properties in an unpredictable way. Therefore, experimental and theoretical data here collected are a powerful tool to a priori design salophen ligands to obtain vanadyl complexes having the specific electronic properties suitable for desired applications. PMID- 25796296 TI - Examining the Bethesda criteria risk stratification of thyroid nodules. AB - BACKGROUND: The Bethesda criteria are proposed for appropriate stratification of malignancy risk in thyroid nodules, but controversy exists regarding their accuracy and reliability in decision making. Additionally, previous studies have suggested higher rates of both malignancy and false negative fine needle aspiration biopsy (FNA) associated with increasing nodule size. This study aims to determine the accuracy of ultrasound (US)-guided FNA using the current Bethesda criteria in surgical practice. We also aimed to investigate the relationship between nodule size and malignancy. METHODS: A retrospective analysis of US-guided FNAs by a single surgeon during a 4.5 year period. FNA results using Bethesda criteria were compared to final surgical pathology. RESULTS: 611 patients with thyroid nodules underwent US-guided FNA. FNA results in 375 subsequently excised thyroid nodules were recorded according to the Bethesda criteria: 192 (51%) benign, 65 (17%) atypia of unknown significance/follicular lesion of undetermined significance (AUS/FLUS), 42 (11%), suspicious for follicular neoplasm (SFN), 17 (5%) suspicious for malignancy (SM), 28 (8%) malignancy, and 31 (8%) non-diagnostic. Malignancy was confirmed by surgical pathology in 15%, 34%, 50%, 88%, 100%, and 39% of the above groups respectively. Sensitivity, specificity, and false-negative rate were 61%, 99%, and 15% respectively. No correlation existed between the size of nodules with indeterminate FNA results and malignancy rate (p=0.89), or size of nodules with non-diagnostic FNA and malignancy rate (p=0.50). CONCLUSION: The current Bethesda risk stratification system underestimated malignancy rates in benign, indeterminate and non-diagnostic cytopathologic categories in our experience. There was no positive linear correlation between nodule size and malignancy rate in these cytopathologic categories. PMID- 25796297 TI - Infrared neural stimulation fails to evoke neural activity in the deaf guinea pig cochlea. AB - At present there is some debate as to the processes by which infrared neural stimulation (INS) activates neurons in the cochlea, as the lasers used for INS can potentially generate a range of secondary stimuli e.g. an acoustic stimulus is produced when the light is absorbed by water. To clarify whether INS in the cochlea requires functioning hair cells and to explore the potential relevance to cochlear implants, experiments using INS were performed in the cochleae of both normal hearing and profoundly deaf guinea pigs. A response to laser stimulation was readily evoked in normal hearing cochlea. However, no response was evoked in any profoundly deaf cochleae, for either acute or chronic deafening, contrary to previous work where a response was observed after acute deafening with ototoxic drugs. A neural response to electrical stimulation was readily evoked in all cochleae after deafening. The absence of a response from optical stimuli in profoundly deaf cochleae suggests that the response from INS in the cochlea is hair cell mediated. PMID- 25796298 TI - Activity-dependent downregulation of M-Type (Kv7) K+ channels surface expression requires the activation of iGluRs/Ca2+/PKC signaling pathway in hippocampal neuron. AB - M-type (Kv7) K(+) channels, encoded by KCNQ2-KCNQ5 genes, play a pivotal role in controlling neuronal excitability. However, precisely how neuronal activity regulates Kv7 channel translocation has not yet been fully defined. Here we reported activity-dependent changes in Kv7 channel subunits Kv7.2 and Kv7.3 surface expression by glutamate (glu). In the present study, we found that treatment with glutamate rapidly caused a specific decrease in M-current as well as Kv7 channel surface expression in primary cultured hippocampal neurons. The glutamate effects were mimicked by NMDA and AMPA. The glutamate effects on Kv7 channels were partially attenuated by pre-treatment of NMDA receptors antagonist d,l-APV or AMPA-KA receptors antagonist CNQX. The signal required Ca(2+) influx through L-type Ca(2+) channel and intracellular Ca(2+) elevations. PKC activation was involved in the glutamate-induced reduction of Kv7 channel surface expression. Moreover, a significant reduction of Kv7 channel surface expression occurred following glycine-induced "chem"-LTP in vitro and hippocampus-dependent behavioral learning training in vivo. These results demonstrated that activity dependent reduction of Kv7 channel surface expression through activation of ionotropic glutamate receptors (iGluRs)/Ca(2+)/PKC signaling pathway might be an important molecular mechanism for regulation of neuronal excitability and synaptic plasticity. PMID- 25796299 TI - Megalencephalic leukoencephalopathy with subcortical cysts caused by compound heterozygous mutations in MLC1, in patients with and without subcortical cysts in the brain. PMID- 25796300 TI - Altered intrinsic brain activity in patients with familial cortical myoclonic tremor and epilepsy: an amplitude of low-frequency fluctuation study. AB - PURPOSE: To investigate localized cerebral function abnormalities in patients with familial cortical myoclonic tremor and epilepsy (FCMTE) using resting-state functional magnetic resonance imaging (fMRI). METHODS: Seven patients with FCMTE from a Chinese family, seven patients with essential tremor (ET), and ten healthy controls were recruited. Amplitude of low-frequency fluctuation (ALFF) analysis was utilized to reveal the potential functional changes in patients with FCMTE. RESULTS: Significant differences in the bilateral frontal lobe and fusiform gyrus among the three groups were revealed by one-way analysis of variance (ANOVA). The t-tests between groups were performed to compare ALFF in these ROIs. The FCMTE subjects exhibited decreased ALFF in the right fusiform gyrus and posterior cingulate cortex (PCC) with increased ALFF in the frontal lobe, compared with the ET and healthy control groups. Furthermore, the ALFF in the frontal lobe was positively correlated with the duration of tremor in patients with FCMTE and ET. CONCLUSION: These findings suggest that frontal cortex and PCC impairment might be related to the epileptic activity and that the abnormality of the fusiform gyrus may be associated with impairment of visuospatial in FCMTE. Due to the positive correlation between the duration of tremor and ALFF in the frontal lobe, changes in the frontal lobe could be a potential indicator of a candidate causative gene for FCMTE. PMID- 25796301 TI - Analysis of opa1 isoforms expression and apoptosis regulation in autosomal dominant optic atrophy (ADOA) patients with mutations in the opa1 gene. AB - Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy characterized by bilateral symmetrical visual loss, decrease in retinal ganglion cells and a loss of myelin within the optic nerve. ADOA is associated to mutations in Optic atrophy 1 gene (OPA1), which encodes a mitochondrial protein involved in cristae remodeling, maintenance of mitochondrial membrane integrity, mitochondrial fusion and apoptosis regulation. We thus evaluated the rate of apoptosis and the expression levels of OPA1 isoforms in ADOA and control cells. Peripheral blood lymphocytes from eight patients with OPA1 mutation and age matched controls were cultivated both in basal conditions or with 2-deoxy-D ribose, a reducing sugar that induces apoptosis through oxidative stress. Apoptosis was analyzed by flow cytometry, phosphatidylserine translocation, mitochondrial membrane depolarization and caspase 3 activation. We also analyzed the expression levels of OPA1 isoforms in ADOA and control cells cultured with and without 2-deoxy-D-ribose. We showed an increased percentage of apoptotic cells in ADOA patients compared to controls, both in basal culture conditions and after 2-deoxy-D-ribose treatment. This suggested a great susceptibility of ADOA cells to oxidative stress and a strong correlation between OPA1 protein dysfunctions and morphological-functional alterations to mitochondria. Moreover OPA1 protein expression was significantly decreased in lymphocytes from the ADOA patients after 2-deoxy-D-ribose treatment, implying a great sensitivity of the mutated protein to free radical damage. Concluding, we could confirm that oxidative stress-induced apoptosis may play a key role in the pathophysiological process bringing to retinal ganglion cells degeneration in ADOA. PMID- 25796302 TI - Tear and serum vitamin D levels in children with allergic rhinoconjunctivitis. AB - BACKGROUND: Although solid cohort studies confirmed a preventative role for the anti-oxidant vitamin D in allergic asthma, a limited number of studies focused on allergic rhinoconjunctivitis (ARC). Here, we aimed to determine 25 hydroxycholecalciferol levels in tear and serum in young allergic rhinoconjunctivitis patients as compared to their apparently healthy matched controls. METHODS: In total, 22 children with allergic rhinoconjunctivitis and 31 healthy control subjects underwent serum total IgE and 25-hydroxycholecalciferol measurements. Tear levels of 25-hydroxycholecalciferol were also determined in both groups. RESULTS: The mean serum total IgE level in the ARC group (143.6+/ 132.8IU/ml) was significantly higher than that in the control group (54.8+/ 44.1IU/ml; p=0.03). Serum 25(OH)D levels were significantly higher in the ARC group (34.1+/-12.7ng/ml) than in the healthy controls (21.8+/-11.3ng/ml; p=0.001). CONCLUSIONS: To our knowledge, this is the first reported study to show an association between serum 25-hydroxycholecalciferol and ARC in a childhood group. Higher levels of serum 25-hydroxycholecalciferol in children with allergic rhinoconjunctivitis may indicate a possible aetiopathogenic mechanism in the development of allergic rhinoconjunctivitis. This is also the first report to examine tear fluid vitamin D levels in paediatric ARC patients. PMID- 25796304 TI - Exhaled breath condensate annexin A5 levels in exercise-induced bronchoconstriction in asthma: A preliminary study. AB - BACKGROUND AND OBJECTIVE: The pathogenesis of exercise-induced bronchoconstriction (EIB) in asthma is incompletely understood. The role of exhaled breath condensate (EBC) annexin A5, which is an anti-inflammatory mediator, has not been investigated. The purpose of this study is to evaluate EBC annexin A5 levels in EIB in asthmatic children. METHODS: Two groups of children were enrolled in this study: asthmatic children with positive (n=11) and negative (n=7) responses to exercise. The levels of pre- and post-exercise EBC annexin A5 were determined with using enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed significant higher pre-exercise EBC annexin A5 levels in the challenge test negative children than in the challenge test positive children (p<0.05). No significant difference was observed in the post-exercise EBC annexin A5 levels between the groups (p>0.05). Also, no significant difference was observed between pre- and post-exercise EBC annexin A5 levels within each group (p>0.05). There was an inverse correlation between annexin A5 levels and a reduction in forced expiratory volume at one second percent (FEV1%) (p=0.009, r=-0.598). CONCLUSIONS: Our preliminary study showed that EBC annexin A5 may have a possible preventive role in EIB in asthma. Annexin A5 and related compounds may provide novel therapeutic approaches to the treatment of EIB in asthma. PMID- 25796305 TI - Wheezing and risk factors in the first year of life in Cantabria, Spain. The EISL study. AB - OBJECTIVES: To determine the prevalence of wheezing during the first year of life in Cantabria, Spain and its associated risk factors. METHODOLOGY: A cross sectional, multicentre, descriptive epidemiological study was carried out in a representative sample of 958 infants in the first year of life, born in Cantabria. A previously validated and standardised written questionnaire was completed by the parents of infants seen between 12 and 15 months of age in the Primary Care Centres. RESULTS: The prevalence of wheezing was 32.7%. A relationship was found with male gender (OR 1.38, 95%CI [1.05-1.81]), the presence of a sibling (OR 2.43 [1.38-3.98]), attending nursery school (OR 2.40 [1.71-3.35]), exclusive breastfeeding for <3 months (OR 1.47 [1.12-1.93]), a first cold at <=3 months (OR 2.07 [1.56-2.74]), asthma in siblings (OR 2.17 [1.25 3.77]), parental allergic rhinitis (OR 1.62 [1.10-2.37]) and paracetamol use >1 a week (OR 2.49 [1.31-4.73]), and maternal smoking during pregnancy (OR 2.18 [1.51 3.15]). The prevalence of recurrent wheezing (>=3 episodes) was 14.3%. Significant associations were observed with the male gender (OR 1.79 [1.23 2.60]), attending nursery school (OR 2.92 [1.96-4.35]), first cold at <=3 months (OR 2.11 [1.46-3.04]), eczema (OR 1.92 [1.21-3.04]), maternal asthma (OR 1.77 [1.00-3.14]), exclusive breastfeeding for <3 months (OR 1.53 [1.06-2.22]), and maternal smoking during pregnancy (OR 1.53 [1.05-2.22]). CONCLUSIONS: One third of the infants experienced wheezing during the first year of life; those who were less exclusively breastfed, attended nursery school, presented eczema, family asthma or allergic rhinitis, and maternal smoking during pregnancy. PMID- 25796303 TI - Doctors' awareness concerning primary immunodeficiencies in Brazil. AB - BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (+/-16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs. PMID- 25796306 TI - Gender differences in the relationship between body mass index (BMI) changes and the prevalence and severity of wheezing and asthma in the first year of life. AB - BACKGROUND: Rapid weight gain has been recently associated with asthma at school age, but its influence in respiratory symptoms during infancy is still unknown. METHODS: Answers from 6541 parents living in six different cities of Brazil to the International Study of Wheezing in Infants (EISL) questionnaire were analysed. Data from reported weight and height at birth and at one year were used to calculate BMI. Rapid body mass index (BMI) gain was defined by the difference in BMI superior to 1.0z and excessive by the difference superior to 2.0z. RESULTS: Rapid BMI gain was found in 45.8% infants and excessive in 24.4%. Boys showed a significantly higher BMI gain than girls. Girls with rapid BMI gain showed a significantly higher prevalence of hospitalisation for wheezing (8.8% vs. 6.4%; aOR: 1.4, 95%CI: 1.1-1.8), severe wheezing (18.1% vs. 15.0%; aOR: 1.3, 95%CI: 1.0-1.5) and medical diagnosis of asthma (7.5% vs. 5.7%; aOR: 1.3, 95%CI: 1.0-1.7). Girls with excessive BMI gain also had a significantly higher prevalence of hospitalisation for wheezing (9.8% vs. 6.7%; aOR: 1.5, 95%CI: 1.1 2.0) and severe wheezing (18.9% vs. 15.5%; aOR: 1.3, 95%CI: 1.0-1.6). No significant association was found among boys. CONCLUSIONS: The majority of the evaluated infants showed BMI gain above expected in the first year of life. Although more commonly found in boys, rapid and excessive BMI gain in the first year of life was significantly related to more severe patterns of wheezing in infancy among girls. PMID- 25796307 TI - Chronic granulomatous disease: Review of a cohort of Egyptian patients. AB - BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disease that results from a defect in the phagocytic cells of the immune system. It is caused by defects in one of the major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The clinical presentations of CGD patients are heterogeneous. OBJECTIVES: This is the first report from Egypt discussing clinical and laboratory data of twenty-nine patients (from 26 families) with CGD from a single tertiary referral centre. RESULTS: There were twenty male and nine female patients. The consanguinity rate was 76% (19/25). Their age of diagnosis ranged from 2 to 168 months with a mean of 52.8 months +/- 49.6 SD. The most common manifestations were abscesses in 79.3% (deep organ abscesses in 37.9% of patients), followed by pneumonia in 75.8% and gastrointestinal symptoms in 27.5%. Rare but fatal complications were also reported among patients as one patient developed haemophagocytic lymphohistiocytosis (HLH) syndrome. Although X linked CGD universally constitutes the most common pattern of inheritance; only 6 of our patients 6/25 (24%) belonged to this group with a Stimulation Index (SI) of 1-5, and confirmed by carrier pattern of their mothers. Mothers were not available for testing in four male children. Nineteen patients (76%) had autosomal recessive patterns; ten males and nine females patients based on having abnormal SI, positive history of consanguinity and their mothers showing normal SI. CONCLUSION: Increasing the awareness of physicians about symptoms of CGD may lead to earlier diagnosis of the disease, thus enhancing proper management and better quality of life. PMID- 25796308 TI - Methylenetetrahydrofolate Reductase gene polymorphism in children with allergic rhinitis. AB - BACKGROUND: Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms by impairing folate metabolism may influence the development of allergic diseases. The results of studies evaluating the relationship between MTHFR polymorphisms and atopic disease are controversial. The aim of this study was to investigate the association between the polymorphisms of C677T and A1298C for MTHFR gene and allergic rhinitis (AR) in children. METHODS: Ninety patients followed up with diagnosis of allergic rhinitis in our clinic and 30 children with no allergic diseases were included in the study. All participants were genotyped for the MTHFR (C677T) and (A1298C) polymorphisms. Vitamin b12, folate and homocysteine levels were measured. RESULTS: The mean age of patients was 9.2+/-2.9 years; 66.7% of the patients were male. There was no significant difference between patient and control groups regarding gender, age and atopy history of the family (p>0.05). The frequency of homozygotes for MTHFR C677T polymorphism in the patient and control groups was 3.3% and 10%, respectively. The frequency of homozygotes for MTHFR A1298C polymorphism among groups was 26.7% and 16.7%, respectively. The association between allergic rhinitis and polymorphisms of C677T and A1298C for MTHFR gene was not statistically significant in patients compared with controls (p>0.05). There were no statistically significant differences between the patients and the control group in terms of serum vitamin b12, folate and homocysteine levels (p>0.05). CONCLUSION: We found no evidence for an association between allergic rhinitis and polymorphisms of C677T and A1298C for MTHFR gene in children. Further studies investigating the relationship between MTHFR polymorphism and AR are required. PMID- 25796309 TI - A pathophysiological approach for FeNO: A biomarker for asthma. AB - The present review is focused on literature concerning the relevance of fractional exhaled nitric oxide (FeNO) in clinical practice from a pathophysiological point of view. There is increasing evidence that asthma is a heterogeneous pathological condition characterised by different phenotypes/endotypes related to specific biomarkers, including FeNO, helpful to predict therapeutic response in selected asthmatic populations. Nowadays FeNO, a non-invasive biomarker, appears to be useful to foresee asthma developing, to recognise specific asthma phenotypes, like the eosinophilic, to ameliorate asthma diagnosis and management in selected populations and to predict standard corticosteroid and biologic therapy efficacy. In addition, FeNO assessment may also be useful in patients with allergic rhinitis in order to detect the potential involvement of eosinophilic bronchial inflammation in "case finding" subjects at risk of asthma diagnosis. Therefore, it is possible to hypothesise a future with an appropriate use of FeNO by physicians dealing with worrisome clinical issues in specific asthma phenotypes. PMID- 25796311 TI - [Ulcerated nodule on the dorsum of wrist]. PMID- 25796310 TI - Quantitative defects in invariant NKT cells and TLR responses in patients with hyper-IgE syndrome. AB - BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency mainly caused by mutations in STAT3, a signalling molecule implicated in the development of appropriate immune responses. We aimed to characterise the innate immune response in AD-HIES. METHODS: The frequency of innate immune cells in peripheral blood (PB) from seven AD-HIES patients and healthy controls were determined. CD80/CD86 surface expression and cytokine levels in supernatants from PBMC after stimulation with TLR-2, -4 and -9 agonists were also measured by flow cytometry. In addition, several SNPs within these TLR genes in genomic DNA samples from patients and controls were examined. RESULTS: A significantly reduced number of PB iNKT cells was observed in the AD-HIES group. CpG-stimulated pDC and mDC from patients exhibited a lower increase in the expression of the costimulatory molecule CD80. We also observed an increase in the secretion of IL-12p70, TNF-alpha and IL-10 in PBMC from HIES patients after LTA or LPS stimuli. No association was found between the different SNPs detected and the HIES phenotype. CONCLUSIONS: These findings demonstrate that important mediators of the innate immunity responses are affected in AD-HIES. More studies are necessary to investigate how the STAT3 function interferes with development of iNKT cells and TLR-mediated responses. PMID- 25796312 TI - [Cutis verticis gyrata associated with Klinefelter syndrome]. PMID- 25796313 TI - An analysis of reported cases of leishmaniasis in the southern Ecuadorian Amazon region, 1986-2012. AB - An analysis of reported cases of cutaneous leishmaniasis (CL) was performed using the data registered in the southern Ecuadorian Amazon region during 27 years from 1986 to 2012. The cases/subjects with both the suspected CL lesions and the amastigote-positive results were recruited for the analysis. The yearly occurrence of cases showed a markedly higher number during the six years, 1988 and 1993. After 1994 when the insecticide spraying campaign using helicopter in 1993-1994, the number dropped remarkably. Then, the yearly occurrence gradually fluctuated from 101 cases in 1996 to 11 in 2009, maintaining a low number of cases after the campaign. The monthly occurrence of cases showed a markedly high number during March and August, suggesting a correlation to the rainy season (months) in the areas. A statistical significance was found between the monthly average number of the CL case and the average precipitation (p=0.01474). It was suggested that the time of transmission of CL would depend on the rainy seasons at each endemic area of Ecuador, which has a diverse climatic feature depending on the geographic regions. Such information at given leishmaniasis-endemic areas of Ecuador would be important for the future planning of the disease control. Molecular analysis and characterization of clinical samples revealed the presence of Leishmania (Viannia) braziliensis. PMID- 25796314 TI - How real are the health effects of residential energy efficiency programmes? PMID- 25796315 TI - The use of mystery guests by the Dutch Health Inspectorate: Results of a pilot study in long-term intramural elderly care. AB - This paper examines the use of 'mystery guests' as an instrument for monitoring quality and safety in healthcare. The Dutch Health Inspectorate initiated a mystery guest pilot project in elderly care as a response to political and social pressure. An independent evaluation of this project revealed that the primary goal of this approach--to provide a better view of the exigencies of daily practice in elderly care--was not met. Inspectors did not use the information delivered by the mystery guests because how they evaluated quality and reported findings did not align with practices used by the health inspectorate. Additionally, the inspectors felt that other instruments being developed were more appropriate for providing a better view of practice. While political pressure is important for effecting change in general, the specific instruments to be used for formal supervision of health institutions should be developed and implemented within the organization in accordance with existing standards and approaches. The choice to implement a new supervision instrument, including sending mystery guests into care institutions, should be preceded by an ethical analysis that takes into account the specific context of its use. PMID- 25796316 TI - Costs of disposable material in the operating room do not show high correlation with surgical time: Implications for hospital payment. AB - OBJECTIVES: The objectives of this study are to analyze the variation of the surgical time and of disposable costs per surgical procedure and to analyze the association between disposable costs and the surgical time. METHODS: The registration of data was done in an operating room of a 419 bed general hospital, over a period of three months (n = 1556 surgical procedures). Disposable material per procedure used was recorded through a barcode scanning method. RESULTS: The average cost (standard deviation) of disposable material is ?183.66 (?183.44). The mean surgical time (standard deviation) is 96 min (63). Results have shown that the homogeneity of operating time and DM costs was quite good per surgical procedure. The correlation between the surgical time and DM costs is not high (r = 0.65). CONCLUSIONS: In a context of Diagnosis Related Group (DRG) based hospital payment, it is important that costs information systems are able to precisely calculate costs per case. Our results show that the correlation between surgical time and costs of disposable materials is not good. Therefore, empirical data or itemized lists should be used instead of surgical time as a cost driver for the allocation of costs of disposable materials to patients. PMID- 25796317 TI - Ultrasonic vibration-assisted (UV-A) pelleting of wheat straw: a constitutive model for pellet density. AB - Ultrasonic vibration-assisted (UV-A) pelleting can increase cellulosic biomass density and reduce biomass handling and transportation costs in cellulosic biofuel manufacturing. Effects of input variables on pellet density in UV-A pelleting have been studied experimentally. However, there are no reports on modeling of pellet density in UV-A pelleting. Furthermore, in the literature, most reported density models in other pelleting methods of biomass are empirical. This paper presents a constitutive model to predict pellet density in UV-A pelleting. With the predictive model, relations between input variables (ultrasonic power and pelleting pressure) and pellet density are predicted. The predicted relations are compared with those determined experimentally in the literature. Model predictions agree well with reported experimental results. PMID- 25796318 TI - Role of ovarian reserve markers, antimullerian hormone and antral follicle count, as aneuploidy markers in ongoing pregnancies and miscarriages. AB - OBJECTIVE: To assess the role of two ovarian reserve markers, antimullerian hormone (AMH) and antral follicle count (AFC), as markers of the background risk for fetal trisomy. DESIGN: Prospective study. SETTING: Tertiary referral hospital. PATIENT(S): Assessment was carried out either in ongoing pregnancies or miscarriages in our center. INTERVENTION(S): AFC was assessed transvaginally during a routine (11-13 weeks) or referral scan. AMH was determined either during the first-trimester maternal serum markers assessment or in cases referred for chorionic villi sampling after the invasive procedure. MAIN OUTCOME MEASURE(S): AMH reference ranges were constructed according to maternal age, and AMH- and AFC derived ovarian ages were compared among three different cytogenetic groups (normal karyotype, autosomal trisomies, and other chromosomal anomalies) in both ongoing pregnancies and miscarriages. RESULT(S): In autosomal trisomies, the median AFC-derived ovarian age was 3-5 years above the median maternal age. No differences were observed between AMH-derived ovarian age and maternal age. CONCLUSION(S): AFC-derived ovarian biologic age reflects a more precise background risk for fetal aneuploidy that is not observed for AMH-derived age. PMID- 25796319 TI - Prevalence and predictors of major depressive disorder for fertility treatment patients and their partners. AB - OBJECTIVE: To examine the prevalence and predictors of major depressive disorder (MDD) for women and their partners during the course of fertility treatment. DESIGN: Prospective cohort study during an 18-month period. Participants completed interviews and questionnaires at baseline and at 4, 10, and 18 months of follow-up. SETTING: Five community and academic fertility practices. PATIENT(S): A total of 174 women and 144 of their male partners who did not have a successful child-related outcome during the time frame of the study. INTERVENTION(S): No interventions administered. MAIN OUTCOME MEASURE(S): The MDD was assessed using the Composite International Diagnostic Interview Major Depression module, a structured diagnostic interview. Additional variables were assessed with self-report questionnaire measures. RESULT(S): Of the women 39.1% and of the men 15.3% met the criteria for MDD during the 18-month course of the study. A binary logistic covariate-adjusted model showed that, for both women and men, past MDD was a significant predictor of MDD during treatment. Past MDD further predicted significant risk for MDD during treatment after controlling for other well-established risk factors (i.e., baseline levels of depression, anxiety, and partner support). CONCLUSION(S): The MDD was highly prevalent for fertility treatment patients and their partners. Past MDD predicted risk for MDD during treatment, and it contributed to MDD risk more than other commonly assessed risk factors. This suggests that patients and their partners would benefit from being routinely assessed for a history of MDD before the start of treatment to best direct psychosocial support and interventions to those most in need. PMID- 25796320 TI - Extended fertility and longevity: the genetic and epigenetic link. AB - Many women now choose to develop their careers before having children. Thus, it is becoming increasingly important to assess a woman's potential for extended fertility and to understand the health consequences of having children at a late age. In particular, there is a striking positive correlation between extended fertility and longevity in women, which poses important implications for medicine, biology, and evolution. In this article we review the diverse epidemiologic evidence for the link between fertility potential, age of menopause, and women's lifespan. Then we discuss the recent advances using genomic technology to better understand biological mechanisms driving this association. At the genetic level, there are polymorphisms that may be driving both extended fertility and longevity. At the cellular and molecular levels, changes in the genome (both nuclear and mitochondrial), epigenome, and transcriptome during oocyte aging have important implications for fertility. By synthesizing results from diverse domains, we hope to provide a genomic-era conceptual framework in which this important connection can be investigated and understood. PMID- 25796321 TI - Meiotic and sperm aneuploidy studies in three carriers of Robertsonian translocations and small supernumerary marker chromosomes. AB - OBJECTIVE: To study the meiotic behaviour of one carrier of a small supernumerary marker chromosome (sSMC): 47,XY,+mar; one carrier of a Robertsonian translocation (ROB): 45,XY,rob(13;21) (q10;q10); and one carrier of both a sSMC and a ROB: 46,XY,rob(13;21) (q11.1;q11.1),+mar. DESIGN: Case-control study. SETTING: University-affiliated research center and hospital. PATIENT(S): Subfertile men with ROB and sSMC. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The chromosomal origin of the sSMC was assessed by multiplex fluorescence in situ hybridization. The segregation of the ROB and sSMC in sperm and possible interchromosomal effects were examined by fluorescence in situ hybridization. Synapsis, meiotic recombination, and meiotic inactivation were investigated in ejaculate spermatocytes of the 47,XY,+mar and 45,XY,rob(13;21) carriers using immunostaining. RESULT(S): In the 47,XY,+mar and 46,XY,rob(13;21),+mar carriers, the sSMC was found in 13.5% and 11.5 % of sperm, respectively. Analysis of meiotic segregation of chromosome 13 and 21 showed that 91.2% of sperm were normal/balanced in the 46,XY,rob(13;21),+mar case, whereas 88.4% of sperm were normal/balanced in the 45,XY,rob(13;21) case. Interchromosomal effects involving the sex chromosomes were found in both sSMC carriers. Both 47,XY,+mar and 45,XY,rob(13;21) carriers showed decreased global recombination, impaired synapsis, and an association of abnormal chromosomes with the XY body. CONCLUSION(S): Carriers of marker chromosomes produce sperm with markers at frequencies lower than theoretically expected. Carriers of ROB and sSMC showed decreased recombination, impaired synapsis, and association of abnormal chromosomes with the XY body, which may contribute to an interchromosomal effect. Using immunofluorescence techniques to analyze ejaculate-derived spermatocytes from subfertile men provides a novel technique for examining meiosis without the need for a testicular biopsy. PMID- 25796322 TI - [Mindfulness-based stimulation in advanced Alzheimer's disease: A comparative, non-inferiority, clinical pilot study]. AB - INTRODUCTION: A longitudinal study was conducted in order to analyze the feasibility, safety, and effects of the practice of mindfulness, relaxation and cognitive stimulation on the evolution of Alzheimer's disease, with the aim of testing the equivalence of these interventions. MATERIAL AND METHODS: There were a total of 168 participants with probable Alzheimer's disease (AD) treated with donepezil. In the present article, the 21 participants with advanced AD who completed a follow-up period of 24 months are presented. The participants were grouped into three experimental groups (mindfulness, relaxation, and cognitive stimulation) and one control group. Each group carried out three weekly sessions with bi-annual follow-up measurements (cognition: CAMCOG and MMSE; functionality: RDRS; psychopathology: NPI). Non-parametric analyses were performed. RESULTS: The cognitive function and functionality scores showed no significant differences between the groups. However, the scores in cognitive function of the mindfulness group and the cognitive stimulation group did not decrease in an intra-group analysis. In NPI, there were significant differences between the mindfulness group and the control group by the end of the study (P<.017). CONCLUSION: The data showed that the treatment with donepezil in combination with mindfulness or cognitive stimulation presented a better clinical evolution than the pharmacological treatment alone or combined with relaxation. These data suggest that these therapeutic alternatives should be investigated further, and that the non-pharmacological treatments should be recommended in clinical practice in order to control the evolution of AD in the long term. In order to confirm these findings, a larger study is necessary. PMID- 25796323 TI - Effects of sexed semen and interactive effects on commercial in vitro embryo production when oocytes are collected from cows of Bos indicus, and Bos taurus breeding and crossbred cows of these subspecies. AB - A large scale commercial in vitro embryo production and in vitro fertilization record is reported when there was use of oocytes from Bos taurus (BT), Bos indicus (BI), and Bos Taurus/indicus (BT/BI) crossbred subspecies fertilized with sexed (SS) and conventional (CS) semen. The aim of the study was to analyze the impacts of use SS in a commercial embryo production center in Colombia. Non pregnant (n=800), healthy, and estrous cycling BT, BI, and BI/BT crossbred cows were selected to be used as oocyte donors. Viable oocytes from 733 ovum pick up sessions in cows of the BT (4663) and BI (7305), BT/BI (3605) groups were matured and fertilized with frozen thawed semen from commercial sires. Of all cultured oocytes (n=15,573), 52.3% of the embryos (n=8607) underwent cleavage while 3062 (19.7%) developed to the blastocyst stage. For cows of the BT, SS and CS groups, there were similar cleavage rates; however, use of SS decreased blastocyst formation (15.6% versus 18.9%). In the BI group, use of SS increased cleavage rates (59.1% versus 53%, respectively) although there was no effect on blastocyst rate development (22.9% versus 21.9). In the BI/BT groups, use of SS decreased cleavage (44.4% versus 57.1%, respectively) and blastocyst rate development compared with the CS group (15.3% versus 20.1%, respectively). Data from this study indicate embryos from cows of the BT purebred or BI/BT crossbred had less in vitro developmental capacity compared to embryos derived from oocytes of cows that were purebred BI in tropical-subtropical regions. PMID- 25796324 TI - Phylogeny and biogeography of the New World siskins and goldfinches: rapid, recent diversification in the Central Andes. AB - Time-calibrated molecular phylogenies can help us to understand the origins of the diverse and unique Andean avifauna. Previous studies have shown that the tempo of diversification differed between the Andes and adjacent lowland regions of South America. Andean taxa were found to have speciated more recently and to have avoided the decelerated diversification that is typical of Neotropical lowland clades. The South American siskins, a Pleistocene finch radiation, may typify this Andean pattern. We investigated the phylogenetic biogeography of all the New World siskins and goldfinches in new detail. To understand the specific role of the Andes in siskin diversification, we asked: (1) Was diversification faster in Andean siskin lineages relative to non-Andean ones? (2) Did siskin lineages move into and out of the Andes at different rates? We found that siskin lineages in the Andes had higher diversification rates and higher outward dispersal rates than siskin lineages outside the Andes. We conclude that paramo expansion and contraction in response to Pleistocene climatic cycles caused accelerated diversification and outward dispersal in Andean siskins. The younger average age of bird species in the Andes compared to lowland South America may be attributable to bursts of recent diversification in siskins and several other vagile, open-habitat clades. PMID- 25796325 TI - Elucidating the phylogenetic position of Gnathostomulida and first mitochondrial genomes of Gnathostomulida, Gastrotricha and Polycladida (Platyhelminthes). AB - Gnathostomulida is a taxon of small marine worms, which exclusively inhabit the interstitium. The evolution of Gnathostomulida has been discussed for decades. Originally regarded as primitive animals with affinities to flatworms, the phylogenetic position of Gnathostomulida has been debated. Given the lack of an anus a close relationship to Platyhelminthes has been maintained (i.e., Plathelminthomorpha hypothesis). Alternative hypotheses proposed Gnathostomulida as being close to Gastrotricha due to the presence of a monociliary epidermis (i.e., Monokonta/Neotrichozoa hypothesis) or to Syndermata based on the complicated jaw apparatus (i.e., Gnathifera hypothesis). Molecular analyses using only few genes were inconclusive. Recent phylogenomic studies brought some progress by placing Gnathostomulida as sister to Syndermata, but support for this relationship was low and depended on the analytical strategy. Herein we present the first data of complete or nearly complete mitochondrial genomes for two gnathostomulids (Gnathostomula paradoxa &G. armata), one gastrotrich (Lepidodermella squamata) and one polyclad flatworm (Stylochoplana maculata) to address the uncertain phylogenetic affinity of Gnathostomulida. Our analyses found Gnathostomulida as sister to Syndermata (Gnathifera hypothesis). Thorough sensitivity analyses addressing taxon instability, branch length heterogeneity (also known as long branch attraction) and base composition heterogeneity showed that the position of Gnathostomulida is consistent across the different analyses and, hence, independent of potential misleading biases. Moreover, by ameliorating these different biases nodal support values could be increased to maximum values. Thus, our data support the hypothesis that the different jaw apparatuses of Syndermata and Gnathostomulida are indeed homologous structures as proposed by the Gnathifera hypothesis. PMID- 25796326 TI - Sigma-2 receptor binding is decreased in female, but not male, APP/PS1 mice. AB - The sigma-2 receptor is a steroid-binding membrane-associated receptor which has been implicated in cell survival. Sigma-2 has recently been shown to bind amyloid beta (Abeta) oligomers in Alzheimer's disease (AD) brain. Furthermore, blocking this interaction was shown to prevent or reverse the effects of Abeta to cause cognitive impairment in mouse models and synaptic loss in neuronal cultures. In the present work, the density of sigma-2 receptors was measured in a double transgenic mouse model of amyloid-beta deposition (APP/PS1). Comparisons were made between males and females and between transgenic and wt animals. Sigma-2 receptor density was assessed by quantitative autoradiography performed on coronal brain slices using [(3)H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H) yl)butyl]-2-methoxy-5-methyl-benzamide ([(3)H]RHM-1), which has a 300-fold selectivity for the sigma-2 receptor over the sigma-1 receptor. The translocator protein of 18 kDa (TSPO) is expressed on activated microglia and is a marker for neuroinflammation. TSPO has been found to be upregulated in neurodegenerative disorders, including AD. Therefore, in parallel with the sigma-2 autoradiography experiments, we measured TSPO expression using the selective radioligand, [(3)H]PBR28. We also quantified Abeta plaque burden in the same animals using a monoclonal antibody raised against aggregated Abeta. Sigma-2 receptor density was significantly decreased in piriform and motor cortices as well as striata of 16 month old female, but not male, APP/PS1 mice as compared to their wt counterparts. [(3)H]PBR28 binding and immunostaining for Abeta plaques were significantly increased in piriform and motor cortices of both male and female transgenic mice. In striatum however, significant increases were observed only in females. PMID- 25796327 TI - Structural basis for cargo binding and autoinhibition of Bicaudal-D1 by a parallel coiled-coil with homotypic registry. AB - Bicaudal-D1 (BICD1) is an alpha-helical coiled-coil protein mediating the attachment of specific cargo to cytoplasmic dynein. It plays an essential role in minus end-directed intracellular transport along microtubules. The third C terminal coiled-coil region of BICD1 (BICD1 CC3) has an important role in cargo sorting, including intracellular vesicles associating with the small GTPase Rab6 and the nuclear pore complex Ran binding protein 2 (RanBP2), and inhibiting the association with cytoplasmic dynein by binding to the first N-terminal coiled coil region (CC1). The crystal structure of BICD1 CC3 revealed a parallel homodimeric coiled-coil with asymmetry and complementary knobs-into-holes interactions, differing from Drosophila BicD CC3. Furthermore, our binding study indicated that BICD1 CC3 possesses a binding surface for two distinct cargos, Rab6 and RanBP2, and that the CC1-binding site overlaps with the Rab6-binding site. These findings suggest a molecular basis for cargo recognition and autoinhibition of BICD proteins during dynein-dependent intracellular retrograde transport. PMID- 25796328 TI - BIX-01294-induced autophagy regulates elongation of primary cilia. AB - Previously, we showed that BIX-01294 treatment strongly activates autophagy. Although, the interplay between autophagy and ciliogenesis has been suggested, the role of autophagy in ciliogenesis is controversial and largely unknown. In this study, we investigated the effects of autophagy induced by BIX-01294 on the formation of primary cilia in human retinal pigmented epithelial (RPE) cells. Treatment of RPE cells with BIX-01294 caused strong elongation of the primary cilium and increased the number of ciliated cells, as well as autophagy activation. The elongated cilia in serum starved cultured cells were gradually decreased by re-feeding the cells with normal growth medium. However, the disassembly of cilia was blocked in the BIX-01294-treated cells. In addition, both genetic and chemical inhibition of autophagy suppressed BIX-01294-mediated ciliogenesis in RPE cells. Taken together, these results suggest that autophagy induced by BIX-01294 positively regulates the elongation of primary cilium. PMID- 25796329 TI - Salinity-induced expression of HKT may be crucial for Na(+) exclusion in the leaf blade of huckleberry (Solanum scabrum Mill.), but not of eggplant (Solanum melongena L.). AB - Reduced Na(+) accumulation in the leaf blade is an important aspect of salinity tolerance and high affinity K(+) transporters (HKTs) are known to play a significant role in the process. Huckleberry and eggplant have previously been shown to display 'excluder' and 'includer' characteristics, respectively, under salt stress, but the underlying mechanisms have not been investigated. Here, we isolated the cDNA of the HKT homologs, Solanum scabrum HKT (SsHKT) from huckleberry and Solanum melongena HKT (SmHKT) from eggplant, and analyzed their expressions in different tissues under salt stress. SsHKT expression was markedly induced in the root (28-fold) and stem (7-fold), with a corresponding increase in Na(+) accumulation of 52% and 29%, respectively. Conversely, eggplant accumulated 60% total Na(+) in the leaf blade, with a lower SmHKT expression level in the root (3-fold). Huckleberry also maintained a higher K(+)/Na(+) ratio in the leaf blade compared to eggplant, due to the reduction of its Na(+) concentration and unaltered K(+) concentration. Functional analysis demonstrated that SsHKT mediated Na(+) influx inhibited yeast growth under Na(+) stress, and that SsHKT did not complement the growth of the K(+) uptake-deficient CY162 strain under K(+)-limiting conditions. These results suggest that the Na(+) accumulation characteristics of both plants are caused by the differential expression of HKT genes, with SsHKT exerting a greater control over the ability of Na(+) to reach the leaf blade in huckleberry, than SmHKT does in eggplant. PMID- 25796330 TI - Bitter taste receptor T2R1 activities were compatible with behavioral sensitivity to bitterness in chickens. AB - Clarification of the mechanism of the sense of taste in chickens will provide information useful for creating and improving new feedstuffs for chickens, because the character of the taste receptors in oral tissues affects feeding behavior in animals. In this study, we focused on the sensitivity to bitterness in chickens. We cloned one of the bitter taste receptors, T2R1, from the chicken palate, constructed several biosensor-cells expressing chicken T2R1 (cT2R1), and determined a highly sensitive biosensor of cT2R1 among them. By using Ca(2+) imaging methods, we identified two agonists of cT2R1, dextromethorphan (Dex) and diphenidol (Dip). Dex was a new agonist of cT2R1 that was more potent than Dip. In a behavioral drinking study, the intake volumes of solutions of these compounds were significantly lower than that of water in chickens. These aversive concentrations were identical to the concentrations that could activate cT2R1 in a cell-based assay. These results suggest that the cT2R1 activities induced by these agonists are linked to behavioral sensitivity to bitterness in chickens. PMID- 25796331 TI - The elastic free energy of a tandem modular protein under force. AB - Recent studies have provided a theoretical framework for including entropic elasticity in the free energy landscape of proteins under mechanical force. Accounting for entropic elasticity using polymer physics models has helped explain the hopping behavior seen in single molecule experiments in the low force regime. Here, we expand on the construction of the free energy of a single protein domain under force proposed by Berkovich et al. to provide a free energy landscape for N tandem domains along a continuous polypeptide. Calculation of the free energy of individual domains followed by their concatenation provides a continuous free energy landscape whose curvature is dominated by the worm-like chain at forces below 20 pN. We have validated our free energy model using Brownian dynamics and reproduce key features of protein folding. This free energy model can predict the effects of changes in the elastic properties of a multidomain protein as a consequence of biological modifications such as phosphorylation or the formation of disulfide bonds. This work lays the foundations for the modeling of tissue elasticity, which is largely determined by the properties of tandem polyproteins. PMID- 25796333 TI - Involvement of mouse and porcine PLCzeta-induced calcium oscillations in preimplantation development of mouse embryos. AB - In mammals, phospholipase Czeta (PLCzeta) has the ability to trigger calcium (Ca(2+)) oscillations in oocytes, leading to oocyte activation. Although there is a species-specific difference in the PLCzeta-induced Ca(2+) oscillatory pattern, whether PLCzeta-induced Ca(2+) oscillations affect preimplantation embryonic development remains unclear. Here, we show that Ca(2+) oscillations in mouse PLCzeta cRNA-injected oocytes stopped just before pronuclear formation, while that in porcine PLCzeta cRNA-injected oocytes continued for several hours after pronuclei had been formed. This difference of Ca(2+) oscillations in oocytes after pronuclear formation was dependent on the difference in the nuclear localization signal (NLS) sequence of PLCzeta between the mouse and pig. However, mouse and porcine PLCzeta cRNA-injected oocytes parthenogenetically developed to blastocysts regardless of the absence or presence of Ca(2+) oscillations after pronuclear formation. Furthermore, the developmental rate of mouse or porcine PLCzeta-activated oocytes injected with round spermatids to the blastocyst stage was not significantly different from that of strontium-activated oocytes injected with round spermatids. These results suggest that the PLCzeta-induced Ca(2+) oscillatory pattern in mouse oocytes is dependent on the NLS sequence of PLCzeta and injection of PLCzeta may be a useful method for activation of round spermatid injected and somatic nuclear transferred oocytes. PMID- 25796332 TI - ATP-gamma-S-(alpha,beta-CH2) protects against oxidative stress and amyloid beta toxicity in neuronal culture. AB - Amyloid beta (Abeta) oligomers and oxidative stress, typical of Alzheimer's disease, are highly neurotoxic. Previously we identified ATP-gamma-S as a most promising antioxidant and neuroprotectant. To further improve both potency and metabolic stability of ATP-gamma-S, we designed a related analogue, ATP-gamma-S (alpha,beta-CH2). We found that ATP-gamma-S-(alpha,beta-CH2) effectively inhibited ROS formation in PC12 cells subjected to Fe(II)-oxidation, slightly better than ATP-gamma-S (IC50 0.18 and 0.20 MUM, respectively). Moreover, ATP gamma-S-(alpha,beta-CH2) rescued primary neurons from Abeta42 toxicity, 4-fold more potently than ATP-gamma-S, (IC50 0.2 and 0.8 MUM, respectively). In addition, the metabolic stability of ATP-gamma-S-(alpha,beta-CH2) in PC12 cells during 4 h of incubation, was up to 20% greater than that of ATP-gamma-S and ATP. Previously, we found that ATP-gamma-S-(alpha,beta-CH2) resisted hydrolysis by ecto-nucleotidases such as, NPPs and TNAP, and was found to be ~7-fold more potent agonist than ATP at P2Y11 receptor. Therefore, we propose ATP-gamma-S (alpha,beta-CH2) as a promising agent for rescue of neurons from insults typical of Alzheimer's disease. PMID- 25796334 TI - Retinal hypoxia induces vascular endothelial growth factor through induction of estrogen-related receptor gamma. AB - Ischemic retinopathies causing overexpression of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), are the most common cause of blindness. Thus, understanding the pathophysiology of targetable pathways that regulate retinal VEGF is of great interest. A conserved binding site for estrogen related receptor gamma (ERRgamma) has been identified in the promoter of the Vegfa gene. ERRgamma is a constitutively active orphan nuclear receptor and its expression is increased by hypoxic stimuli in metabolically active tissues. This study evaluated the role of ERRgamma in the ischemic retina and the anti-VEGF potential of GSK5182, a selective inverse agonist of ERRgamma. In an oxygen induced retinopathy (OIR) mouse model, immunohistochemistry showed significantly increased ERRgamma expression in the ganglion cell layer at postnatal day (P) 17. In a ganglion cell line (RGC-5), mRNA and protein levels of ERRgamma were increased by desferrioxamine treatment and hypoxic conditions (1% O2). Transient transfection of RGC-5 cells revealed that ERRgamma regulated Vegfa expression and this was inhibited by GSK5182. Intravitreal injection of GSK5182 into the OIR model at P14 inhibited retinal Vegfa mRNA expression at P17. GSK5182 suppresses hypoxia-induced VEGF expression via ERRgamma; therefore, ERRgamma could be a treatment target for ischemic retinopathies. PMID- 25796335 TI - Autonomous production of 1,4-butanediol via a de novo biosynthesis pathway in engineered Escherichia coli. AB - 1,4-Butanediol (BD) is an important chemical that is widely used in industry with an annual demand of one million metric tons. Here we report a modular development of engineered bacteria for successful BD bio-production. Using a systems engineering concept, we partitioned our development into two parts: namely BD biosynthesis and production control. The former was implemented through a de novo pathway that functions as an enzymatic reactor, while the latter was accomplished via synthetic circuits serving as genetic controllers. To facilitate development, the carbon utilizations were also partitioned into two routes. d-xylose was exclusively designated for BD production with other carbon sources utilized for cellular growth. Additionally, a quorum-sensing mechanism was exploited for production control, and the resulting strain was capable of autonomous production of BD. This study represents an example of the synergy between synthetic biology and metabolic engineering, affirming the need for deeper integration of the two fields. PMID- 25796336 TI - The lipopolysaccharide (LPS) of Photorhabdus luminescens TT01 can elicit dose- and time-dependent immune priming in Galleria mellonella larvae. AB - In this work, we primed Galleria mellonella larvae by haemocoel injection of lipopolysaccharide (LPS) extracted from Photorhabdus luminescens TT01 to determine whether bacterial LPS can induce enhanced immune protection (recently called immune priming). We also analyzed the relationship between changes in the levels of innate immune elements and the degree of enhanced immune protection in the larvae at designated time points after priming. The larvae that received experimental doses (20.0, 10.0 and 5.0MUg per larva) of LPS demonstrated increased resistance against lethal challenge with P. luminescens TT01; the degree and period of protection correlated positively with the priming dose. These results indicated that the P. luminescens TT01 LPS could induce typical immune priming in G. mellonella. Moreover, the levels of innate immune parameters (i.e. haemocyte density, phagocytosis, haemocyte encapsulation ability, and antibacterial activity of cell-free haemolymph) and endogenous enzyme activities (i.e. acid phosphatase, ACP; alkaline phosphatase, AKP; superoxide dismutase, SOD and lysozyme, LSZ) were significantly increased following priming of the larvae with LPS, whereas the activities of peroxidase (POD) and catalase (CAT) were significantly decreased. All of the parameters examined changed in a dose- and time-dependent manner. This study demonstrated that G. mellonella larvae could modulate their immune responses based on different doses of LPS used for priming, and that priming phenomenon in G. mellonella larvae elicited by LPS was mediated by the innate immune elements and enzyme activity. PMID- 25796337 TI - M-M-R((r))II manufactured using recombinant human albumin (rHA) and M-M-R((r))II manufactured using human serum albumin (HSA) exhibit similar safety and immunogenicity profiles when administered as a 2-dose regimen to healthy children. AB - Prior to 2006, M-M-R((r))II (measles, mumps, and rubella virus vaccine live) was manufactured using human serum albumin (HSA) and each dose of the vaccine contained a relatively small amount (<=0.3mg) of HSA. Because of specific regulatory requirements and limited suppliers of HSA acceptable for human use, there was a need to replace HSA with recombinant human albumin (rHA) to mitigate any potential risk to the availability of M-M-R((r))II. Two different formulations of M-M-R((r))II manufactured using either rHA or HSA were clinically evaluated for safety and immunogenicity when administered as a 2-dose regimen to healthy children 12-18 months and 3-4 years of age. Adverse events, including those indicative of a possible hypersensitivity reaction, were collected for 42 days after each dose. Antibodies to measles, mumps, and rubella were measured before and approximately 6 weeks after dose 1. Antibodies to rHA were measured before and approximately 6 weeks after dose 1 and dose 2. Antibody seroconversion rates to measles, mumps, and rubella were 97.0%, 99.5%, and 99.7%, respectively, for recipients of M-M-R((r))II with rHA and 97.2%, 97.9%, and 99.6%, respectively, for recipients of M-M-R((r))II with HSA, and geometric mean titers to all 3 vaccine viral antigens were comparable between the 2 vaccination groups. The proportions of subjects who reported adverse events, including those suggestive of hypersensitivity reactions, after each dose of study vaccine were comparable between the 2 vaccination groups. No subject had detectable antibodies to rHA immediately prior to or following receipt of either the first or second dose of study vaccine. Given the comparable immunogenicity and safety profiles of both formulations, rHA is an acceptable replacement for HSA in the manufacture of M-M-R((r))II. PMID- 25796339 TI - Influenza and pertussis vaccination coverage in pregnant women. AB - BACKGROUND: Pregnant women have an increased risk for complications and hospitalizations when infected with the influenza virus in the second or third trimester. Additionally, infants under six months of age are most vulnerable when contracting pertussis. Immunization against influenza and pertussis during pregnancy provides protection for mother and neonate against influenza and for neonates against pertussis pending protection through infant immunization. In Belgium, a gradual increase in pertussis cases over the past decade was observed. This study was undertaken to document vaccination coverage for influenza and pertussis and factors related to vaccination status in pregnant women. METHODS: Two hundred and fifty pregnant women completed a questionnaire during their third trimester. Vaccination data were collected and reasons for non-vaccination were noted as well as socio-demographic data which are known to influence vaccination coverage. RESULTS: A documented vaccination coverage of 42.8% for influenza and 39.2% for pertussis was observed. Taking into account doses which were not documented, but administered according to the expectant mother, coverage for influenza would increase to 62% and for pertussis to 46%. The most important reasons for non-vaccination were the absence of a recommendation by medical staff (9.6%) and delay in vaccination (8.4%). The GP was the most important vaccinator. Pregnant women with a lower education and those with a foreign origin were more vulnerable for non-vaccination. CONCLUSION: Incomplete documentation is the most important barrier in determining the vaccination status of pregnant women. Immunization during pregnancy needs further integration through vaccination campaigns aimed at both health care providers and pregnant women. PMID- 25796338 TI - Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica. AB - The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines. PMID- 25796340 TI - Depressive symptomatology and respiratory sinus arrhythmia in a non-clinical sample of middle-aged African Americans. AB - Decreased heart rate variability and depression are both independent risk factors for cardiac mortality in clinical and non-clinical samples. The purpose of the current study is to examine the hypothesis that severity of depressive symptomatology is inversely associated with respiratory sinus arrhythmia (RSA) in a non-clinical sample of African Americans. The sample included 77 African Americans with a mean age of 48.4 (SD = 11.7). Participants completed the Beck Depression Inventory-II (BDI-II) and a 5-min resting baseline measurement of RSA was collected. The BDI-II total score was positively associated with RSA (beta = .334, p = .008). Given the unexpected direction of the association, we separated the BDI-II into cognitive and somatic affective subscales to identify which construct was driving the relationship. The somatic affective, was related to RSA (beta = .328, p = .010), but not the cognitive subscale. Given this unexpected positive result, future research should further examine the nature of the relationship between depressive symptomatology and RSA in African Americans, as the relationship may vary based on levels of depressive symptomatology. PMID- 25796341 TI - Attentional capture by emotional scenes across episodes in bipolar disorder: Evidence from a free-viewing task. AB - We examined whether the initial orienting, subsequent engagement, and overall allocation of attention are determined exogenously (i.e. by the affective valence of the stimulus) or endogenously (i.e. by the participant's mood) in the manic, depressive and euthymic episodes of bipolar disorder (BD). Participants were asked to compare the affective valence of two pictures (happy/threatening/neutral [emotional] vs. neutral [control]) while their eye movements were recorded in a free-viewing task. Results revealed that the initial orienting was exogenously captured by emotional images relative to control images. Importantly, engagement and overall allocation were endogenously captured by threatening images relative to neutral images in BD patients, regardless of their episode--this effect did not occur in a group of healthy controls. The threat-related bias in BD, which occurs even at the early stages of information processing (i.e. attentional engagement), may reflect a vulnerability marker. PMID- 25796343 TI - Increased TRPM6 expression in atrial fibrillation patients contribute to atrial fibrosis. AB - BACKGROUND: Transient receptor potential (TRP) family plays important roles in cardiovascular system. We investigated the relationship between transient receptor potential channel subfamily M6 (TRPM6) and atrial fibrosis in rheumatic heart disease patients with atrial fibrillation (AF). METHODS: The right atrial tissue samples were obtained from 64 patients with rheumatic heart diseases who underwent heart valve replacement surgery, and composed of 34 sinus rhythm (SR) patients and 30 AF patients. Hematoxylin and Eosin (HE) staining was used to observe cross-sectional area (CSA) of myocardial cell. Masson staining and measurement of connective tissue growth factor (CTGF), transforming growth factor beta 1 (TGF-beta 1), and collagen type I/III (Collagen I/III) were performed to determine atrial fibrosis. The mRNA and protein levels of TRPM6 were detected by real-time quantitative polymerase chain reaction (RT-PCR) and western blotting, respectively. RESULTS: Marked increases were observed in CSA of myocardial cell and myocardial collagen volume fraction in AF group compared with the SR group (all P<0.05). The mRNA levels of myocardial fibrosis markers (CTGF, TGF-beta 1, Collagen I/III) in AF group increased significantly compared to the SR group (all P<0.05). TRPM6 mRNA and protein levels in AF group were elevated markedly in comparison with SR group (P<0.01). CONCLUSION: These findings revealed that increased TRPM6 mRNA and protein levels may contribute to atrial fibrosis, and suggested that TRPM6 might be involved in AF development by promoting fibrogenesis. PMID- 25796342 TI - Manipulating motor performance and memory through real-time fMRI neurofeedback. AB - Task performance depends on ongoing brain activity which can be influenced by attention, arousal, or motivation. However, such modulating factors of cognitive efficiency are unspecific, can be difficult to control, and are not suitable to facilitate neural processing in a regionally specific manner. Here, we non pharmacologically manipulated regionally specific brain activity using technically sophisticated real-time fMRI neurofeedback. This was accomplished by training participants to simultaneously control ongoing brain activity in circumscribed motor and memory-related brain areas, namely the supplementary motor area and the parahippocampal cortex. We found that learned voluntary control over these functionally distinct brain areas caused functionally specific behavioral effects, i.e. shortening of motor reaction times and specific interference with memory encoding. The neurofeedback approach goes beyond improving cognitive efficiency by unspecific psychological factors such as attention, arousal, or motivation. It allows for directly manipulating sustained activity of task-relevant brain regions in order to yield specific behavioral or cognitive effects. PMID- 25796345 TI - The frequency and risk factors for subsequent surgery after a simple elbow dislocation. AB - INTRODUCTION: Simple elbow dislocations treated by closed reduction are thought to result in a satisfactory return of function in most patients. Little, however, is known about how many patients ultimately proceed to subsequent surgical treatment due to the low patient numbers and significant loss to follow-up in the current literature. The purpose of this study was to establish the rate of and risk factors for subsequent surgical treatment after closed reduction of a simple elbow dislocation at a population level. PATIENTS AND METHODS: All patients aged 16 years or older who underwent closed reduction of a simple elbow dislocation between 1994 and 2010 were identified using a population database. Subsequent procedures performed for joint contractures, instability or arthritis were recorded. Outcomes were modelled as a function of age, sex, income quintile, co morbidity, urban/rural status, physician speciality performing the initial reduction and whether orthopaedic consultation and/or post-reduction radiograph was performed within 28 days of the injury, in a time-to-event analysis. RESULTS: We identified 4878 elbow dislocations with a minimum 2-year follow-up: stabilisation surgery was performed in 112 (2.3%) at a median time of 1 month, contracture release in 59 (1.2%) at median 9 months and arthroplasty in seven (0.1%) at median 25 months. Admission to hospital for the initial reduction was associated with an increased risk of undergoing stabilisation (hazard ratio (HR), 2.50; 95% confidence interval (CI), 1.67-3.74) and contracture release (HR, 1.93; CI, 1.08-3.44). Multiple reduction attempts increased the risk of requiring contracture release (HR, 3.71; CI, 1.22-11.29). Survival analysis demonstrated that all subsequent procedures had taken place by 4-5 years. CONCLUSION: Few patients with simple elbow dislocations develop complications requiring surgery, but those that do most commonly undergo soft-tissue stabilisation or contracture release within 4 years of the injury. Contrary to current thinking, surgery for instability is performed more often than joint contracture release, albeit with slightly different time patterns. PMID- 25796346 TI - Why the honey badger don't care: Convergent evolution of venom-targeted nicotinic acetylcholine receptors in mammals that survive venomous snake bites. AB - Honey badgers (Mellivora capensis) prey upon and survive bites from venomous snakes (Family: Elapidae), but the molecular basis of their venom resistance is unknown. The muscular nicotinic cholinergic receptor (nAChR), targeted by snake alpha-neurotoxins, has evolved in some venom-resistant mammals to no longer bind these toxins. Through phylogenetic analysis of mammalian nAChR sequences, we show that honey badgers, hedgehogs, and pigs have independently acquired functionally equivalent amino acid replacements in the toxin-binding site of this receptor. These convergent amino acid changes impede toxin binding by introducing a positively charged amino acid in place of an uncharged aromatic residue. In venom resistant mongooses, different replacements at these same sites are glycosylated, which is thought to disrupt binding through steric effects. Thus, it appears that resistance to snake venom alpha-neurotoxin has evolved at least four times among mammals through two distinct biochemical mechanisms operating at the same sites on the same receptor. PMID- 25796344 TI - Vascular smooth muscle cells contribute to APOL1-induced podocyte injury in HIV milieu. AB - Clinical reports have demonstrated that higher rates of non-diabetic glomerulosclerosis in African Americans can be attributed to two coding sequence variants (G1 and G2) in the APOL1 gene; however, the underlying mechanism is still unknown. Kidney biopsy data suggest enhanced expression of APOL1/APOL1 variants (Vs) in smooth muscle cells (SMCs) of renal vasculature. Since APOL1 is a secretory protein of relatively low molecular weight (41kDa), SMCs may be a contributory endocrine/paracrine source of APOL1 wild type (WT)/APOL1Vs in the glomerular capillary perfusate percolating podocytes. In the present study, we tested the hypothesis that an HIV milieu stimulated secretion of APOL1 and its risk variants by arterial SMCs contributes to podocyte injury. Human umbilical artery smooth muscle cells (HSMCs)-treated with conditioned media (CM) of HIV infected peripheral mononuclear cells (PBMC/HIV-CM), CM of HIV-infected U939 cells, or recombinant IFN-gamma displayed enhanced expression of APOL1. Podocytes co-cultured in trans-wells with HSMCs-over expressing APOL1WT showed induction of injury; however, podocytes co-cultured with HSMC-over expressing either APOL1G1 or APOL1G2 showed several folds greater injury when compared to HSMC-over expressing APOL1WT. Conditioned media collected from HSMC-over-expressing APOL1G1/APOL1G2 (HSMC/APOL1G1-CM or HSMC/APOL1G2-CM) also displayed higher percentages of injured podocytes in the form of swollen cells, leaky lysosomes, loss of viability, and enhanced sensitivity to adverse host factors when compared to HSMC/APOL1WT-CM. Notably, HSMC/APOL1WT-CM promoted podocyte injury only at a significantly higher concentrations compared to HSMC/APOL1G1/G2-CM. We conclude that HSMCs could serve as an endocrine/paracrine source of APOL1Vs, which mediate accelerated podocyte injury in HIV milieu. PMID- 25796347 TI - Selective redox-responsive drug release in tumor cells mediated by chitosan based glycolipid-like nanocarrier. AB - The redox responsive nanocarriers have made a considerable progress in achieving triggered drug release by responding to the endogenous occurring difference between the extra- and intra- cellular redox environments. Despite the promises, this redox difference exists both in normal and tumor tissue. So a non-selective redox responsive drug delivery system may result in an undesired drug release in normal cells and relevant side-effects. To overcome these limitations, we have developed a chitosan based glycolipid-like nanocarrier (CSO-ss-SA) which selectively responded to the reducing environment in tumor cells. The CSO-ss-SA showed an improved reduction-sensitivity which only fast degraded and released drug in 10mM levels of glutathione (GSH). The CSO-ss-SA could transport the drug fast into the human ovarian cancer SKOV-3 cells and human normal liver L-02 cells by internalization, but only fast release drug in SKOV-3 cells. By regulating the intracellular GSH concentration in SKOV-3 cells, it indicated that the cellular inhibition of the PTX-loaded CSO-ss-SA showed a positive correlation with the GSH concentration. The CSO-ss-SA was mainly located in the liver, spleen and tumor in vivo, which evidenced the passive tumor targeting ability. Despite the high uptake of liver and spleen, drug release was mainly occurred in tumor. PTX-loaded CSO-ss-SA achieved a remarkable tumor growth inhibition effect with rather low dose of PTX. This study demonstrates that a smartly designed glycolipid-like nanocarrier with selective redox sensitivity could serve as an excellent platform to achieve minimal toxicity and rapid intracellular drug release in tumor cells. PMID- 25796348 TI - Locally controlled delivery of TNFalpha antibody from a novel glucose-sensitive scaffold enhances alveolar bone healing in diabetic conditions. AB - Diabetic patients are often accompanied with severe alveolar bone destruction and an increased local TNFalpha level. Bone repair is a major challenge in those with poor glycemic control. Herein, we report a glucose-sensitive TNFalpha-antibody delivery system based on quaternized chitosan and collagen for local long-term control of inflammation and improving osteogenesis in diabetes. We demonstrated that the glucose-sensitive delivery system was a honeycomb-shaped scaffold with pores suitable for bone regeneration. It was capable of attenuating inflammatory response of bone marrow stromal cells under the condition of hyperglucose and TNFalpha. Additionally, a special diabetic rat model with fluctuation of blood glucose level was established to investigate biological effects of the scaffold. Our results showed that this TNFalpha-antibody-delivery strategy effectively reduced inflammation by decreasing expression of local TNFalpha and inflammatory factors. More importantly, with the enhancement of osteogenesis-associated proteins, promoted alveolar bone healing was achieved in the diabetic rat model. The data indicate that such a delivery system possibly provides a potential therapeutic strategy for diabetic patients with severe alveolar bone defects. PMID- 25796349 TI - Versatile polyion complex micelles for peptide and siRNA vectorization to engineer tolerogenic dendritic cells. AB - Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in maintaining the balance between immunity and tolerance and, as such are a promising immunotherapy tool to induce immunity or to restore tolerance. The main challenge to harness the tolerogenic properties of DCs is to preserve their immature phenotype. We recently developed polyion complex micelles, formulated with double hydrophilic block copolymers of poly(methacrylic acid) and poly(ethylene oxide) blocks and able to entrap therapeutic molecules, which did not induce DC maturation. In the current study, the intrinsic destabilizing membrane properties of the polymers were used to optimize endosomal escape property of the micelles in order to propose various strategies to restore tolerance. On the first hand, we showed that high molecular weight (Mw) copolymer based micelles were efficient to favor the release of the micelle-entrapped peptide into the endosomes, and thus to improve peptide presentation by immature (i) DCs. On the second hand, we put in evidence that low Mw copolymer-based micelles were able to favor the cytosolic release of micelle-entrapped small interfering RNAs, dampening the DCs immunogenicity. Therefore, we demonstrate the versatile use of polyionic complex micelles to preserve tolerogenic properties of DCs. Altogether, our results underscored the potential of such micelle-loaded iDCs as a therapeutic tool to restore tolerance in autoimmune diseases. PMID- 25796350 TI - Changes in the solid state of anhydrous and hydrated forms of sodium naproxen under different grinding and environmental conditions: Evidence of the formation of new hydrated forms. AB - The aim of the present work was to investigate the solid state change of the anhydrous and hydrate solid forms of sodium naproxen under different grinding and environmental conditions. Grinding was carried out manually in a mortar under the following conditions: at room temperature under air atmosphere (Method A), in the presence of liquid nitrogen under air atmosphere (Method B), at room temperature under nitrogen atmosphere (Method C), and in the presence of liquid nitrogen under nitrogen atmosphere (Method D). Among the hydrates, the following forms were used: a dihydrate form (DSN) obtained by exposing the anhydrous form at 55% RH; a dihydrate form (CSN) obtained by crystallizing sodium naproxen from water; the tetrahydrate form (TSN) obtained by exposing the anhydrous form at 75% RH. The metastable monohydrate form (MSN), previously described in the literature, was not used because of its high physical instability. The chemical stability during grinding was firstly assessed and proven by HPLC. Modification of the particle size and shape, and changes in the solid state under different grinding methods were evaluated by scanning electron microscopy, and X-ray powder diffractometry and thermogravimetry, respectively. The study demonstrated the strong influence of starting form, grinding and environmental conditions on particle size, shape and solid state of recovered sodium naproxen forms. In particular, it was demonstrated that in the absence of liquid nitrogen (Methods A and C), either at air or at nitrogen atmosphere, the monohydrate form (MSN) was obtained from any hydrates, meaning that these grinding conditions favored the dehydration of superior hydrates. The grinding process carried out in the presence of liquid nitrogen (Method B) led to further hydration of the starting materials: new hydrate forms were identified as one pentahydrate form and one hexahydrate form. The hydration was caused by the condensation of the atmospheric water on sodium naproxen particles by liquid nitrogen and by the grinding forces that created a close contact between water and drug. The simultaneous disruption of the crystals, occurring during grinding, and their close contact with water molecules promoted the conversion in higher hydrates. Under the Method D, it was possible to highlight a certain tendency to hydration probably due to a rearrangement of water already present into the hydrates, but results were substantially different from Method B. Thus, summarizing, the different SN forms behave differently under different grinding and environmental conditions. PMID- 25796351 TI - New lignans from the roots of Schisandra sphenanthera. AB - Nine new lignans (1-8, 13) and five known ones (9-12, 14) have been isolated from the roots of Schisandra sphenanthera and were tested for their capacity to scavenge 2,2-diphenyl-1-Picryl-hydrazyl (DPPH). Of these lignans tested, compounds 1, 7, 8 and 13 exhibited noteworthy antioxidant activity with IC50 values of 92, 115, 35 and 48 MUg/mL, respectively. The anti-oxidative haemolysis of human red blood cells (RBCs) activity of the most active compound 8, which is similar to that of vitamin C, was evaluated. PMID- 25796352 TI - Cannabinoid receptor 1 and acute resistance exercise--In vivo and in vitro studies in human skeletal muscle. AB - AIM: This study aimed to determine whether Cannabinoid receptor 1 (CB1) is involved in mammalian target of rapamycin (mTOR) signaling and skeletal muscle protein synthesis. METHODS: This study used human vastus lateralis skeletal muscle biopsies obtained before and after a resistance exercise (RE) bout in young men (n=18). The signaling mechanisms were studied in vitro in human myotubes. Protein expression was determined by Western blot and confocal microscopy, and gene expression by quantitative PCR. Protein synthesis was measured in vitro using puromycin-based SuNSET technique. RESULTS: In human skeletal muscle, an anabolic stimulus in the form of RE down-regulated CB1 expression. The negative change in CB1 expression was associated with increased phosphorylation of mTOR signaling proteins. In vitro, CB1 antagonist AM251 induced phosphorylation of mTOR downstream targets, ribosomal protein S6 kinase (S6K1), S6 and eukaryotic initiation factor 4E binding protein (4E-BP1) in human myotubes. These effects were ERK1/2-dependent and insensitive to mTOR inhibitor, rapamycin. Compared to AM251 treatment alone, inhibition of ERK1/2 by UO126 in the presence of AM251 decreased phosphorylation of S6K1, S6 and and 4E-BP1 at Thr(37/46). AM251 increased protein synthesis in cultured human myotubes, which was not rapamycin-sensitive but was ERK1/2-dependent. CONCLUSIONS: Our results indicate that RE down-regulates CB1 expression. Inhibition of CB1 signaling increases skeletal muscle anabolic signaling down-stream of mTOR and protein synthesis through ERK1/2. Our study may provide base for the development of CB1 blocking drugs to treat or prevent muscle wasting. PMID- 25796353 TI - Micro- and nano-topography to enhance proliferation and sustain functional markers of donor-derived primary human corneal endothelial cells. AB - One of the most common indications for corneal transplantation is corneal endothelium dysfunction, which can lead to corneal blindness. Due to a worldwide donor cornea shortage, alternative treatments are needed, but the development of new treatment strategies relies on the successful in vitro culture of primary human corneal endothelial cells (HCECs) because transformed cell lines and animal derived corneal endothelial cells are not desirable for therapeutic applications. Primary HCECs are non-proliferative in vivo and challenging to expand in vitro while maintaining their characteristic cell morphology and critical markers. Biochemical cues such as growth factors and small molecules have been investigated to enhance the expansion of HCECs with a limited increase in proliferation. In this study, patterned tissue culture polystyrene (TCPS) was shown to significantly enhance the expansion of HCECs. The proliferation of HCECs increased up to 2.9-fold, and the expression amount and localization of cell-cell tight junction protein Zona Occludens-1 (ZO-1) was significantly enhanced when grown on 1 MUm TCPS pillars. 250 nm pillars induced an optimal hexagonal morphology of HCEC cells. Furthermore, we demonstrated that the topographical effect on tight-junction expression and cell morphology could be maintained throughout each passage, and was effectively 'remembered' by the cells. Higher amount of tight-junction protein expression was maintained at cell junctions when topographic cues were removed in the successive seeding. This topographic memory suggested topography-exposed/induced cells would maintain the enhanced functional markers, which would be useful in cell-therapy based approaches to enable the in situ endothelial cell monolayer formation upon delivery. The development of patterned TCPS culture platforms could significantly benefit those researching human corneal endothelial cell cultivation for cell therapy, and tissue engineering applications. PMID- 25796354 TI - Proliferation and differentiation of rat osteoporosis mesenchymal stem cells (MSCs) after telomerase reverse transcriptase (TERT) transfection. AB - BACKGROUND: The aim of this study was to determine whether MSC are excellent materials for MSCs transplantation in the treatment of osteoporosis. MATERIAL AND METHODS: We studied normal, osteoporosis, and TERT-transfected MSC from normal and osteoporosis rats to compare the proliferation and osteogenic differentiation using RT-PCR and Western blot by constructing an ovariectomized rat model of osteoporosis (OVX). The primary MSC from model rats were extracted and cultured to evaluate the proliferation and differentiation characteristics. RESULTS: MSCs of osteoporosis rats obviously decreased in proliferation ability and osteogenic differentiation compared to that of normal rats. In contrast, in TERT-transfected MSC, the proliferation and differentiation ability, and especially the ability of osteogenic differentiation, were significantly higher than in osteoporosis MSC. CONCLUSIONS: TERT-transfected MSCs can help osteoporosis patients in whom MSC proliferation and osteogenic differentiation ability are weak, with an increase in both bone mass and bone density, becoming an effective material for autologous transplantation of MSCs in further treatment of osteoporosis. However, studies are still needed to prove the in vivo effect, biological safety, and molecular mechanism of TERT-osteoporosis treatment. Additionally, because the results are from an animal model, more research is needed in generalizing rat model findings to human osteoporosis patients. PMID- 25796355 TI - Systematic review of risk factors for surgical site infection in pediatric scoliosis surgery. AB - BACKGROUND CONTEXT: Risk factors for surgical site infection (SSI) in children derived from the studies in the adult population are potentially misleading because of differences in pathophysiology and management. PURPOSE: This systematic review addresses the key question: What are the risk factors for SSI in pediatric patients undergoing scoliosis surgery? STUDY DESIGN: This is a qualitative systematic literature review. PATIENT SAMPLE: Retrospective and observational trials of children undergoing scoliosis surgery reported on the occurrence of risk factors for SSI and the occurrence of SSI. METHODS: Pubmed (Medline), Ovid Evidence-Based Medicine Reviews (EBMR), Scopus, and Cumulative Index to Nursing and Allied Health (CINAHL) were searched electronically for relevant articles in all the languages between January 1, 1991 and August 27, 2012, and cross-references were checked. Two independent reviewers identified articles and appraised quality with the Agency for Healthcare Research and Quality (AHRQ) criteria based on a weighted scoring of 0 to 100. RESULTS: Our search identified 135 abstracts and 14 studies meeting the inclusion criteria. The AHRQ grading showed that five articles were high quality with a score of greater than 67, and five articles were moderate quality with a score between 50 and 67. The percent agreement between the two independent reviewers was 84%, and kappa agreement score was 0.91 (95% confidence interval [CI]: 0.78-1.03). There were 76 risk factors identified, of which 22 factors were reported in more than one study. Odds ratios and 95% CIs were reported inconsistently. Pooled p analysis of high- and moderate-quality articles identified five risk factors predictive of SSI: inappropriate antibiotic use (p=.001), neuromuscular scoliosis (p=.014), instrumentation (p=.023), increased hospital stay days (p=.003), and residual postoperative curve (p=.003). CONCLUSIONS: The systematic review identified inappropriate antibiotic use, neuromuscular scoliosis, instrumentation, increased hospital stay days, and residual postoperative curve as risk factors for SSI after pediatric scoliosis surgery. PMID- 25796356 TI - Propidium monoazide reverse transcriptase PCR and RT-qPCR for detecting infectious enterovirus and norovirus. AB - Presently there is no established cell line or small animal model that allows for the detection of infectious human norovirus. Current methods based on RT-PCR and RT-qPCR detect both infectious and non-infectious virus and thus the conclusions that may be drawn regarding the public health significance of positive findings are limited. In this study, PMA RT-PCR and RT-qPCR assays were evaluated for selective detection of infectious poliovirus, murine norovirus (MNV-1), and Norwalk virus. Viruses were inactivated using heat, chlorine, and ultraviolet light (UV). Infectious and non-infectious viruses were treated with PMA before RT PCR and RT-qPCR. PMA RT-PCR was able to differentiate selectively between infectious and heat and chlorine inactivated poliovirus. PMA RT-PCR was able to differentiate selectively between infectious and noninfectious murine norovirus only when inactivated by chlorine. However, PMA RT-PCR could not differentiate infectious Norwalk virus from virus particles rendered non-infectious by any treatment. PMA RT-PCR assay was not able to differentiate between infectious and UV inactivated viruses suggesting that viral capsid damage may be necessary for PMA to enter and bind to the viral genome. PMA RT-PCR on naked MNV-1 and Norwalk virus RNA suggest that PMA RT-PCR can be used to detect intact, potentially infectious MNV-1 and Norwalk viruses and can be used to exclude the detection of free viral RNA by PCR assay. PMID- 25796357 TI - Interpreting atom probe data from chromium oxide scales. AB - Picosecond-pulsed ultraviolet-laser (UV-355 nm) assisted atom probe tomography (APT) was used to analyze protective, thermally grown chromium oxides formed on stainless steel. The influence of analysis parameters on the thermal tail observed in the mass spectra and the chemical composition is investigated. A new parameter termed "laser sensitivity factor" is introduced in order to quantify the effect of laser energy on the extent of the thermal tail. This parameter is used to compare the effect of increasing laser energy on thermal tails in chromia and chromite samples. Also explored is the effect of increasing laser energy on the measured oxygen content and the effect of specimen base temperature and laser pulse frequency on the mass spectrum. Finally, we report a preliminary analysis of molecular ion dissociations in chromia. PMID- 25796358 TI - Whole-genomic analysis of 12 porcine group A rotaviruses isolated from symptomatic piglets in Brazil during the years of 2012-2013. AB - Group A rotaviruses (RVAs) are leading causes of viral diarrhea in children and in the young of many animal species, particularly swine. In the current study, porcine RVAs were found in fecal specimens from symptomatic piglets on 4 farms in Brazil during the years of 2012-2013. Using RT-PCR, Sanger nucleotide sequencing, and phylogenetic analyses, the whole genomes of 12 Brazilian porcine RVA strains were analyzed. Specifically, the full-length open reading frame (ORF) sequences were determined for the NSP2-, NSP3-, and VP6-coding genes, and partial ORF sequences were determined for the VP1-, VP2-, VP3-, VP4-, VP7-, NSP1-, NSP4-, and NSP5/6-coding genes. The results indicate that all 12 strains had an overall porcine-RVA-like backbone with most segments being designated as genotype 1, with the exception of the VP6- and NSP1-coding genes, which were genotypes I5 and A8, respectively. These results add to our growing understanding of porcine RVA genetic diversity and will provide a platform for monitoring the role of animals as genetic reservoirs of emerging human RVAs strains. PMID- 25796359 TI - Characterisation of a novel panel of polymorphic microsatellite loci for the liver fluke, Fasciola hepatica, using a next generation sequencing approach. AB - The liver fluke, Fasciola hepatica is an economically important pathogen of sheep and cattle and has been described by the WHO as a re-emerging zoonosis. Control is heavily reliant on the use of drugs, particularly triclabendazole and as a result resistance has now emerged. The population structure of F. hepatica is not well known, yet it can impact on host-parasite interactions and parasite control with drugs, particularly regarding the spread of triclabendazole resistance. We have identified 2448 potential microsatellites from 83 Mb of F. hepatica genome sequence using msatfinder. Thirty-five loci were developed and optimised for microsatellite PCR, resulting in a panel of 15 polymorphic loci, with a range of three to 15 alleles. This panel was validated on genomic DNA from 46 adult F. hepatica; 38 liver flukes sourced from a Northwest abattoir, UK and 8 liver flukes from an established isolate (Shrewsbury; Ridgeway Research). Evidence for null alleles was found at four loci (Fh_1, Fh_8, Fh_13 and Fh_14), which showed markedly higher levels of homozygosity than the remaining 11 loci. Of the 38 liver flukes isolated from cattle livers (n=10) at the abattoir, 37 genotypes were identified. Using a multiplex approach all 15 loci could be amplified from several life cycle stages that typically yield low amounts of DNA, including metacercariae, the infective life cycle stage present on pasture, highlighting the utility of this multiplex microsatellite panel. This study reports the largest panel of microsatellite markers available to date for population studies of F. hepatica and the first multiplex panel of microsatellite markers that can be used for several life cycle stages. PMID- 25796360 TI - SISPA-Seq for rapid whole genome surveys of bacterial isolates. AB - Whole genome sequencing (WGS) of large isolate collections has many applications, yet sequencing costs are still significant. We sought to develop a rapid and cost efficient WGS method to address fundamental questions in clinical microbiology. We evaluated the performance of SISPA (Sequence-Independent, Single-Primer Amplification) combined with next-generation sequencing (SISPA-Seq) of 75 clinical isolates of Acinetobacter baumannii to establish whether SISPA-Seq resulted in sufficient coverage and quality to (1) determine strain phylogenetic placement and (2) and carriage of known antibiotic resistance (AbR) genes. Strains for which whole genome sequences were available were included for validation. Two libraries for each strain were constructed from separate SISPA reactions with different barcoded primers, using genomic DNA prepared from either high quality or rapid heat-lysis preparations. SISPA-Seq resulted in a median of 65* genome coverage when reads from both primer sets were combined. Coverage and quality were sufficient for detection of AbR genes by comparison of reads to the ARG-ANNOT database and were often sufficient to distinguish between different allelic variants of the same gene. kSNP and RAxML were used to construct a robust phylogeny based on single-nucleotide variants (SNVs) that showed that the SISPA Seq data was sufficient for sensitive and accurate phylogenetic placement. Advantages of the SISPA-Seq method include inexpensive and rapid DNA preparation and a typical total cost less than one-half that of standard genome sequencing. In summary, SISPA-Seq can be used to survey whole genomes of a large strain collection and identify strains that should be targeted for additional sequencing. PMID- 25796361 TI - Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5 Trisphosphate Receptor and Calcium Signaling in Cholangiocytes. AB - BACKGROUND & AIMS: Most cholestatic disorders are caused by defects in cholangiocytes. The type 3 isoform of the inositol 1,4,5-trisphosphate receptor (ITPR3) is the most abundant intracellular calcium release channel in cholangiocytes. ITPR3 is required for bicarbonate secretion by bile ducts, and its expression is reduced in intrahepatic bile ducts of patients with cholestatic disorders. We investigated whether the nuclear factor, erythroid 2-like 2 (NFE2L2 or NRF2), which is sensitive to oxidative stress, regulates expression of ITPR3. METHODS: The activity of the ITPR3 promoter was measured in normal human cholangiocyte (NHC) cells and primary mouse cholangiocytes. Levels of ITPR3 protein and messenger RNA were examined by immunoblot and polymerase chain reaction analyses, respectively. ITPR3 activity was determined by measuring calcium signaling in normal human cholangiocyte cells and secretion in isolated bile duct units. Levels of NRF2 were measured in liver tissues from rats with cholestasis (induced by administration of alpha-napthylisothiocyanate) and from patients with biliary diseases. RESULTS: We identified a musculo-aponeurotic fibrosarcoma recognition element in the promoter of ITPR3 that bound NRF2 directly in NHC cells and mouse cholangiocytes. Increasing binding of NRF2 at this site resulted in chromatin remodeling that reduced promoter activity. Mutant forms of the musculo-aponeurotic fibrosarcoma recognition element did not bind NRF2. Activation of NRF2 with quercetin or by oxidative stress reduced expression of ITPR3 and calcium signaling in NHC cells; quercetin also reduced secretion by bile duct units isolated from rats. Knockdown of NRF2 with small interfering RNAs restored expression and function of ITPR3 in NHC cells incubated with quercetin. Bile ducts from rats with cholestasis and patients with cholangiopathic disorders expressed higher levels of NRF2 and lower levels of ITPR3 than ducts from control rats or patients with other liver disorders. CONCLUSIONS: The transcription factor NRF2 binds to the promoter of ITPR3 to inhibit its expression in cholangiocytes, leading to reduced calcium signaling and bile duct secretion. This could be a mechanism by which oxidative stress inhibits these processes and contributes to cholangiopathies. PMID- 25796363 TI - AGA Strategic Plan 2015-2020: Something that Matters. PMID- 25796364 TI - External cervical resorption associated with the use of bisphosphonates: a case series. AB - Although the pathogenesis and etiology of external cervical resorption (ECR) are not well understood, several predisposing factors have been reported to potentially contribute toward the initiation of ECR. However, a potential link between systemic medication and ECR has not been reported. Bisphosphonates (BSPs) are 1 group of these medications (the amino-containing BSP), which are associated with an acute-phase response and the release of proinflammatory cytokines, which could be associated with the initiation of ECR. Therefore, a possible causal link between BSPs and ECR could be drawn. PMID- 25796365 TI - Comparison of myocardial transmural perfusion gradient by magnetic resonance imaging to fractional flow reserve in patients with suspected coronary artery disease. AB - The goal of this study was to evaluate the diagnostic accuracy of transmural perfusion gradient (TPG) and transmural perfusion gradient reserve (TPGR) with 3.0 T cardiac magnetic resonance (CMR) against invasively determined fractional flow reserve (FFR) to detect coronary artery stenosis. Quantitative analysis of myocardial perfusion with CMR to diagnosis coronary artery disease (CAD) has been widely accepted. However, traditional transmural myocardial perfusion analysis with CMR neglects that endocardium is more vulnerable to ischemia than epicardium. TPG and TPGR can take the inhomogenous perfusion impairment into account and be more sensitive and specific for diagnosis of CAD. In this study, 71 patients (57 men, age 60.1 +/- 6.4 years) with known or suspected CAD referred for invasive angiography study underwent rest and adenosine-induced stress CMR perfusion imaging scan. FFR was attempted to be measured in all major epicardial coronary arteries. FFR <=0.75 was regarded to indicate a hemodynamic significant coronary lesion. A TPG <=0.85 predicted significant CAD with sensitivity and specificity of 74.55% and 83.65%, respectively. Sensitivity and specificity of TPGR <=0.81 were 90.91% and 89.94%, respectively. Area under the receiver operating curve to detect FFR <=0.75 was 0.86 for TPG and 0.95 for TPGR. TPGR yielded significantly better sensitivity and specificity for diagnosis of CAD than traditional myocardial blood flow, myocardial perfusion reserve, and TPG (p < 0.0001). In conclusion, TPG and TPGR analyses with MRI are capable of detecting hemodynamic stenosis of coronary artery and superior to traditional myocardial perfusion analysis. Furthermore, TPGR appears to be superior to TPG in the diagnosis of coronary artery stenosis. PMID- 25796362 TI - Identification of Extracolonic Pathologies by Computed Tomographic Colonography in Colorectal Cancer Symptomatic Patients. AB - BACKGROUND & AIMS: Symptoms suggestive of colorectal cancer may originate outside the colorectum. Computed tomographic colonography (CTC) is used to examine the colorectum and abdominopelvic organs simultaneously. We performed a prospective randomized controlled trial to quantify the frequency, nature, and consequences of extracolonic findings. METHODS: We studied 5384 patients from 21 UK National Health Service hospitals referred by their family doctor for the investigation of colorectal cancer symptoms from March 2004 through December 2007. The patients were assigned randomly to groups that received the requested test (barium enema or colonoscopy, n = 3574) or CTC (n = 1810). We determined the frequency and nature of extracolonic findings, subsequent investigations, ultimate diagnosis, and extracolonic cancer diagnoses 1 and 3 years after testing patients without colorectal cancer. RESULTS: Extracolonic pathologies were detected in 959 patients by CTC (58.7%), in 42 patients by barium enema analysis (1.9%), and in no patients by colonoscopy. Extracolonic findings were investigated in 142 patients (14.2%) and a diagnosis was made for 126 patients (88.1%). Symptoms were explained by extracolonic findings in 4 patients analyzed by barium enema (0.2%) and in 33 patients analyzed by CTC (2.8%). CTC identified 72 extracolonic neoplasms, however, barium enema analysis found only 3 (colonoscopy found none). Overall, CTC diagnosed extracolonic neoplasms in 72 of 1634 patients (4.4%); 26 of these were malignant (1.6%). There were significantly more extracolonic malignancies detected than expected 1 year after examination, but these did not differ between patients evaluated by CTC (22.2/1000 person-years), barium enema (26.5/1000 person-years; P = .43), or colonoscopy (32.0/1000 person-years; P = .88). CONCLUSIONS: More than half of the patients with symptoms of colorectal cancer are found to have extracolonic pathologies by CTC analysis. However, the proportion of patients found to have extracolonic malignancies after 1 year of CTC examination is not significantly greater than after barium enema or colonoscopy examinations. International Standard Randomised Controlled Trials no: 95152621.isrctn.com. PMID- 25796367 TI - Influence of whole wheat feeding on the development of coccidiosis in broilers challenged with Eimeria. AB - A study was conducted to assess the effect of whole wheat (WW) feeding on performance, gizzard development, oocyst yield and intestinal lesion score of broilers challenged with Eimeria species. Diets (ground wheat (GW) and 300 g/kg WW replacing GW before or after pelleting) were offered ad libitum from day 1 or days 7-28 post-hatch. At 21 days of age, each dietary treatment was divided into two groups, one unchallenged control and the other inoculated with mixed species of coccidia (Eimeria acervulina, E. maxima and E. tenella). The results showed that heavier gizzards and higher mortality were observed in WW-fed birds in comparison to GW-fed birds. Interestingly, the pattern of mortality in different dietary treatments paralleled changes in gizzard size. Based on increased mortality, it is concluded that WW feeding exacerbated the severity of coccidiosis infection, possibly via a mechanism involving enhanced gizzard development. PMID- 25796368 TI - Evidence of epithelial-mesenchymal transition in canine prostate cancer metastasis. AB - The epithelial-mesenchymal transition (EMT) is a fundamental event responsible for the invasiveness and metastasis of epithelial tumours. The EMT has been described in many human cancers, but there are few reports of this phenomenon in veterinary oncology. Due to the importance of this process, the current study evaluated mesenchymal and epithelial marker protein expression in prostate lesions from dogs. Our results indicate both a loss of E-cadherin and translocation of beta-catenin from the membrane to the cytoplasm and nucleus in the tumour group. Vimentin expression in the tumour group was higher than in normal tissue. All of the metastases were positive for prostate-specific antigen, pan-cytokeratin and E-cadherin, although fewer positive cells were present than in the primary tumours. The immunohistochemical results showed a loss of epithelial markers and a gain of a mesenchymal marker among metastatic cells, suggesting that the EMT occurs during the metastatic process of canine prostate carcinoma. PMID- 25796366 TI - Structure and function insights into the NuRD chromatin remodeling complex. AB - Transcription regulation through chromatin compaction and decompaction is regulated through various chromatin-remodeling complexes such as nucleosome remodeling and histone deacetylation (NuRD) complex. NuRD is a 1 MDa multi subunit protein complex which comprises many different subunits, among which histone deacetylases HDAC1/2, ATP-dependent remodeling enzymes CHD3/4, histone chaperones RbAp46/48, CpG-binding proteins MBD2/3, the GATAD2a (p66alpha) and/or GATAD2b (p66beta) and specific DNA-binding proteins MTA1/2/3. Here, we review the currently known crystal and NMR structures of these subunits, the functional data and their relevance for biomedical research considering the implication of NuRD subunits in cancer and various other diseases. The complexity of this macromolecular assembly, and its poorly understood mode of interaction with the nucleosome, the repeating unit of chromatin, illustrate that this complex is a major challenge for structure-function relationship studies which will be tackled best by an integrated biology approach. PMID- 25796369 TI - Biliary ochratoxin A as a biomarker of ochratoxin exposure in laying hens: An experimental study after administration of contaminated diets. AB - To evaluate the levels of ochratoxin (OTA) in kidney, liver and bile of laying hens, forty-five laying hens were enrolled in this study and divided into three equal groups: a control group D0, and two experimental groups, D1 fed with 10 ug/kg OTA diet and D2 fed with 200 ug/kg OTA diet for 6 weeks. Kidneys, livers, and bile from all hens were collected and analyzed by HPLC method for the presence of OTA. Eggs collected 2 days before the start of the experiment and 2 days after its end were also analyzed for the presence of OTA. Results show a relevant biliary excretion of the mycotoxin, with high levels of OTA in the bile after administration of the toxin. OTA level in eggs was below the limit of detection (LOD). These results suggest the suitability of using bile as a matrix for screening measurements of OTA in laying hens. PMID- 25796371 TI - Long-term risk of type 2 diabetes mellitus in relation to BMI and weight change among women with a history of gestational diabetes mellitus: a prospective cohort study. AB - AIMS/HYPOTHESIS: Women with a history of gestational diabetes mellitus (GDM) are advised to control their weight after pregnancy. We aimed to examine how adiposity and weight change influence the long-term risk of developing type 2 diabetes after GDM. METHODS: We included 1,695 women who had incident GDM between 1991 and 2001, as part of the Diabetes & Women's Health study, and followed them until the return of the 2009 questionnaire. Body weight and incident type 2 diabetic cases were reported biennially. We defined baseline as the questionnaire period when women reported an incident GDM pregnancy. We estimated HRs and 95% CIs using Cox proportional hazards models. RESULTS: We documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. The adjusted HRs of type 2 diabetes associated with each 1 kg/m(2) increase in BMI were 1.16 (95% CI 1.12, 1.19) for baseline BMI and 1.16 (95% CI 1.13, 1.20) for most recent BMI. Moreover, each 5 kg increment of weight gain after GDM development was associated with a 27% higher risk of type 2 diabetes (adjusted HR 1.27; 95% CI 1.04, 1.54). Jointly, women who had a BMI >=30.0 kg/m(2) at baseline and gained >=5 kg after GDM had an adjusted HR of 43.19 (95% CI 13.60, 137.11), compared with women who had a BMI <25.0 kg/m(2) at baseline and gained <5 kg after GDM. CONCLUSIONS/INTERPRETATION: Baseline BMI, most recent BMI and weight gain after GDM were significantly and positively associated with risk of progression from GDM to type 2 diabetes. PMID- 25796372 TI - Forkhead box O1 mediates defects in palmitate-induced insulin granule exocytosis by downregulation of calcium/calmodulin-dependent serine protein kinase expression in INS-1 cells. AB - AIMS/HYPOTHESIS: The transcription factor forkhead box O1 (FOXO1) induces pancreatic islet beta cell endoplasmic reticulum stress and is involved in fatty acid-induced insulin-secretion defects. Cask is a downstream target gene of FOXO1. Using INS-1 cells with palmitate-induced insulin-release defects, we investigated the relationship between FOXO1 and Cask. METHODS: The expression levels and location of calcium/calmodulin-dependent serine protein kinase (CASK) and FOXO1 were evaluated by real-time PCR, western blotting and immunofluorescence. The regulation of Cask by FOXO1 was examined using chromatin immunoprecipitation (ChIP) and luciferase assays. Potassium-stimulated insulin secretion assays were used to verify the function of INS-1 cells and islets. Electron microscopy was used to establish the anchoring process of the insulin granules after CASK knockdown in islets. RESULTS: Palmitic acid reduced CASK levels and increased FOXO1 levels. ChIP and luciferase assays demonstrated FOXO1 binding with the Cask promoter, which was enhanced by palmitate treatment. CASK knockdown reduced insulin release in INS-1 cells and primary islets, and Cask overexpression reversed the palmitate-induced insulin reduction. CASK knockdown attenuated forskolin-enhanced insulin release, but Cask overexpression did not change the insulin-secretion suppression induced by nifedipine. In pancreatic islet beta cells, CASK knockdown reduced the anchoring of insulin vesicles to cell membranes. CONCLUSIONS/INTERPRETATION: The induction of beta cell insulin secretion defects by fatty acids is mediated, at least in part, by FOXO1 via downregulation of Cask expression. It is characterised mainly as an obstruction of the anchoring of insulin granules to beta cell membranes. PMID- 25796374 TI - Adjusting fracture probability by trabecular bone score. AB - The aim of the present study was to determine the impact of trabecular bone score on the probability of fracture above that provided by the clinical risk factors utilized in FRAX. We performed a retrospective cohort study of 33,352 women aged 40-99 years from the province of Manitoba, Canada, with baseline measurements of lumbar spine trabecular bone score (TBS) and FRAX risk variables. The analysis was cohort-specific rather than based on the Canadian version of FRAX. The associations between trabecular bone score, the FRAX risk factors and the risk of fracture or death were examined using an extension of the Poisson regression model and used to calculate 10-year probabilities of fracture with and without TBS and to derive an algorithm to adjust fracture probability to take account of the independent contribution of TBS to fracture and mortality risk. During a mean follow-up of 4.7 years, 1754 women died and 1639 sustained one or more major osteoporotic fractures excluding hip fracture and 306 women sustained one or more hip fracture. When fully adjusted for FRAX risk variables, TBS remained a statistically significant predictor of major osteoporotic fractures excluding hip fracture (HR/SD 1.18, 95% CI 1.12-1.24), death (HR/SD 1.20, 95% CI 1.14-1.26) and hip fracture (HR/SD 1.23, 95% CI 1.09-1.38). Models adjusting major osteoporotic fracture and hip fracture probability were derived, accounting for age and trabecular bone score with death considered as a competing event. Lumbar spine texture analysis using TBS is a risk factor for osteoporotic fracture and a risk factor for death. The predictive ability of TBS is independent of FRAX clinical risk factors and femoral neck BMD. Adjustment of fracture probability to take account of the independent contribution of TBS to fracture and mortality risk requires validation in independent cohorts. PMID- 25796370 TI - Endocannabinoid signaling at the periphery: 50 years after THC. AB - In 1964, the psychoactive ingredient of Cannabis sativa, Delta(9) tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2 arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes. PMID- 25796375 TI - The role of hyperthermic intraperitoneal intraoperative chemotherapy in ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the fourth most common gynecologic cancer in Europe and is the leading cause of death among women with gynecologic malignancies. This is due to the fact that the majority of the patients are diagnosed with advanced stage disease. In these stages, extensive intraperitoneal metastases are often present, making therapy more difficult. The current standard treatment involves primary or interval cytoreductive surgery and chemotherapy. However, many patients develop intraperitoneal (IP) recurrences despite complete surgery and chemotherapy. Therefore, alternative ways to deliver chemotherapy have been examined. Administration of the chemotherapy directly into the peritoneal cavity allows high doses of the cytotoxic agent at the site of the cancer, while minimizing the occurrence of systemic side effects. Theoretically, IP administration is most beneficial when only microscopic disease is present since penetration of the drug is limited to a few millimeters. IP chemotherapy can be administered during surgery under hyperthermic conditions (HIPEC) or during regular chemotherapy courses through a catheter placed into the abdominal cavity. IP administration results in an improved survival, although catheter related morbidity is reported. Hyperthermia potentiates the cytotoxic effect of chemotherapy and may therefore have an additional positive effect on prognosis. Although recent observational studies show encouraging results with respect to effect on survival and rate of complications, it remains a challenge to identify those patients who would benefit most from adding HIPEC to the standard treatment. In this respect, age and timing of HIPEC during treatment might be important factors, although no convincing evidence is available yet. Currently, a total of 18 clinical trials are open and to answer the above-mentioned questions, it is adamant to complete these trials, especially the randomized phase III trials. Accrual is hampered by the fact that HIPEC is currently offered as standard treatment in some centers even though convincing evidence is not yet available. If these phase III trials show positive results in favor of HIPEC, subsequent trials comparing surgery and postoperative IP chemotherapy with surgery and HIPEC seem a logical next step. PMID- 25796373 TI - Prenatal Maternal Smoking and Tourette Syndrome: A Nationwide Register Study. AB - This is the first nationwide register-based study to examine the relationship between prenatal maternal smoking and Tourette syndrome. A total of 767 children diagnosed with Tourette syndrome were identified from the Finnish Hospital Discharge Register. Each case was matched to four controls. Information on maternal smoking during pregnancy was obtained from the Finnish Medical Birth Register. Conditional logistic regression models were used for statistical analyses. Prenatal maternal smoking was associated with Tourette syndrome when comorbid with ADHD (OR 4.0, 95 % CI 1.2-13.5, p = 0.027 for exposure during first trimester, OR 1.7, 95 % CI, 1.05-2.7, p = 0.031 for exposure for the whole pregnancy). There was no association between maternal smoking during pregnancy and Tourette syndrome without comorbid ADHD (OR 0.5, 95 % CI 0.2-1.3, p = 0.166, OR 0.9, 95 % CI 0.7-1.3, p = 0.567). Further research is needed to elucidate the mechanisms behind the association between prenatal maternal smoking and Tourette syndrome with comorbid ADHD. PMID- 25796376 TI - Treatment of NRAS-mutant melanoma. AB - NRAS mutations in codons 12, 13, and 61 arise in 15-20 % of all melanomas. These alterations have been associated with aggressive clinical behavior and a poor prognosis. Until recently, there has been a paucity of promising genetically targeted therapy approaches for NRAS-mutant melanoma (and RAS-mutant malignancies in general). MEK inhibitors, particularly binimetinib, have shown activity in this cohort. Based on pre-clinical and early clinical studies, combining MEK inhibitors with agents inhibiting the cell cycling and the PI3K-AKT pathway appears to provide additional benefit. In particular, a strategy of MEK inhibition and CDK4/6 inhibition is likely to be a viable treatment option in the future, and is the most promising genetically targeted treatment strategy for NRAS-mutant melanoma developed to date. In addition, immune-based therapies have shown increasing activity in advanced melanoma and may be particularly effective in those with NRAS mutations. Combination strategies of immune and targeted therapies may also play a role in the future although clinical trials testing these approaches are in early stages. PMID- 25796378 TI - Subscapularis management in total shoulder arthroplasty. PMID- 25796377 TI - Breast cancer under age 40: a different approach. AB - Breast cancer (BC) under age 40 is a complex disease to manage due to the additionally fertility-related factors to be taken in consideration. More than 90% of young patients with BC are symptomatic. Women<40 years are more likely to develop BC with worse clinicopathological features and more aggressive subtype. This has been frequently associated with inferior outcomes. Recently, the prognostic significance of age<40 has been shown to differ according to the BC subtype, being associated with worst recurrence-free survival (RFS) and overall survival (OS) for luminal BC. The biology of BC<40 has also been explored through analysis of large genomic data set, and specific pathways overexpressed in these tumors have been identified which can lead to the development of targeted therapy in the future. A multidisciplinary tumor board should determine the optimal locoregional and systemic management strategies for every individual patient with BC before the start of any therapy including surgery. This applies to both early (early breast cancer (EBC)) and advanced (advanced breast cancer (ABC)) disease, before the start of any therapy. Mastectomy even in young patients confers no overall survival advantage when compared to breast-conserving treatment (BCT), followed by radiotherapy. Regarding axillary approach, indications are identical to other age groups. Young age is one of the most important risk factors for local recurrence after both breast-conserving surgery (BCS) and mastectomy, associated with a higher risk of distant metastasis and death. Radiation after BCS reduces local recurrence from 19.5 to 10.2% in BC patients 40 years and younger. The indications for and the choice of systemic treatment for invasive BC (both early and advanced disease) should not be based on age alone but driven by the biological characteristics of the individual tumor (including hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, grade, and proliferative activity), disease stage, and patient's comorbidities. Recommendations regarding the use of genomic profiles such as MammaPrint, Oncotype Dx, and Genomic grade index in young women are similar to the general BC population. Especially in the metastatic setting, patient preferences should always be taken into account, as the disease is incurable. The best strategy for these patients is the inclusion into well-designed, independent, prospective randomized clinical trials. Metastatic disease should always be biopsied whenever feasible for histological confirmation and reassessment of biology. Endocrine therapy is the preferred option for hormone receptor-positive disease (HR+ve), even in presence of visceral metastases, unless there is concern or proof of endocrine resistance or there is a need for rapid disease response and/or symptom control. Recommendations for chemotherapy (CT) should not differ from those for older patients with the same characteristics of the metastatic disease and its extent. Young age by itself should not be an indication to prescribe more intensive and combination CT regimens over the sequential use of monotherapy. Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) represent an important group of promising drugs in managing patients with breast cancer susceptibility gene (BRCA)-1- or BRCA-2-associated BC. Specific age-related side effects of systemic treatment (e.g., menopausal symptoms, change in body image, bone morbidity, cognitive function impairment, fertility damage, sexual dysfunction) and the social impact of diagnosis and treatment (job discrimination, taking care for children) should also be carefully addressed when planning systemic long lasting therapy, such as endocrine therapy. Survivorship concerns for young women are different compared to older women, including issues of fertility, preservation, and pregnancy. PMID- 25796379 TI - Persistent pain after surgery for enthesopathy of the extensor carpi radialis brevis origin. PMID- 25796380 TI - Buyang Huanwu Decoction (BYHWD) Enhances Angiogenic Effect of Mesenchymal Stem Cell by Upregulating VEGF Expression After Focal Cerebral Ischemia. AB - Buyang Huanwu decoction (BYHWD) has been used for centuries to treat paralysis and stroke. Previously, we have demonstrated that BYHWD combined with mesenchymal stem cell (MSC) transplantation attenuates ischemic injury partly by upregulating angiogenesis. However, the mechanisms of this drug for stroke treatment are not completely understood. Here, we aimed to clarify the mechanism of BYHWD on angiogenesis mediated by MSCs. Firstly, we verified microvessels with a size of 50-100 nm produced by either MSCs or MSCs treated by 500 MUg/ml BYHWD. These exosomes were purified and found to be able to activate vascular endothelial growth factor (VEGF) expression in endothelial cells (ECs). Moreover, exosomes from MSCs and MSCs treated by BYHWD induced elevated microRNA (miRNA)-126 expression and reduced miR-221 and miR-222 expression. In MSCs, disruption of dicer, an enzyme responsible for miRNA maturation, by dicer small interfering RNA (siRNA), or RNase pretreatment abolished this ability of the exosomes. Additionally, exosomes from MSCs treated by BYHWD promoted VEGF and Ki-67 expression and augmented vascular density in rat brain after bilateral carotid artery ligation. In conclusion, our study revealed that BYHWD exposure augmented angiogenetic miRNA and VEGF expression in exosomes secreted by MSCs and elevated angiogenesis in rat brain. PMID- 25796381 TI - Estradiol Regulates Dorsal Vagal Complex Signal Transduction Pathway Transcriptional Reactivity to the AMPK Activator 5-Aminoimidazole-4-Carboxamide Riboside (AICAR). AB - The ovarian hormone estradiol (E) regulates effects of hindbrain adenosine 5' monophosphate-activated protein kinase (AMPK) on caudal dorsal vagal complex (cDVC) neuron genomic activation and systemic glucostasis. The present study examined the hypothesis that cDVC signal transduction pathways exhibit distinctive E-dependent reactivity to activation of this sensor. RT-PCR microarray analysis was performed on RNA extracted from the cDVC of E- or oil (O) implanted ovariectomized (OVX) adult female rats injected into the caudal fourth ventricle with the AMP mimetic 5-aminoimidazole-4-carboxamide-riboside (AICAR) (A) or saline (S). Microarray results show that the majority of marker genes differentially expressed in the E/S versus O/S cDVC were upregulated, as only myc (TGFbeta; WNT pathways), bcl2 (Hedgehog pathway), and serpine (hypoxia pathway) mRNA profiles were downregulated by E. Several JAK/STAT and NFkappaB signaling pathway marker gene profiles were upregulated in O/A but unchanged in E/A; additional NFkappaB genes were inhibited by A in E but not O. Hypoxia and p53 pathways contain genes that were inhibited or stimulated in O/A, but unaltered in E/A. Conversely, TGFbeta, p53, and NOTCH pathways each contained marker genes that were correspondingly modified or maintained in E/A versus O/A. Moreover, several oxidative stress pathway genes were suppressed in O/A while elevated or unchanged in E/A. Hedgehog, PPAR, and WNT signaling pathways were characterized by numerous examples of A-induced reversal of E augmentation of marker gene expression coinciding with opposite or no drug effects in O. Data presented here demonstrate that E exerts distinctive effects on cDVC signal transduction pathway marker gene reactivity to activated AMPK. Further research is needed to determine if observed changes in signal pathway marker gene transcription correlate with adjustments in gene product protein expression, and to characterize the role of aforementioned signaling pathways in E-sensitive cellular and systemic responses to hindbrain AMPK activation. PMID- 25796382 TI - Imaging findings in children with proliferative disorders following multivisceral transplantation. AB - BACKGROUND: Multivisceral transplantation represents an important treatment option for children with intestinal failure. The attendant immunosuppression can lead to a spectrum of cellular proliferations including benign and malignant smooth muscle tumors and lymphoproliferative disorders, many related to cellular dysregulation from Epstein-Barr virus infection. OBJECTIVE: The purpose of this study is to investigate the rates of post-transplantation proliferative disorders among children with multivisceral transplantation and to characterize the imaging and pathological features of these disorders. MATERIALS AND METHODS: We identified all consecutive children who underwent multivisceral transplant from August 2004 to October 2011 with at least 27 months of clinical and imaging follow-up. We reviewed medical records to determine the underlying causes of the multivisceral transplant, age at transplantation, onset of neoplasm development, and outcome. Two pediatric radiologists reviewed all imaging studies independently and diagnosis of disease was made by consensus interpretation. Pathological specimens were reviewed for histopathological findings of post transplantation neoplasm in this pediatric patient population. RESULTS: The study population consisted of 14 consecutive pediatric patients (7 boys and 7 girls; mean age 26 months, range 4-113 months). Of these 14 children, 4 (29%) developed histologically confirmed post-transplant neoplasms at a mean time of 2.4 years after multivisceral transplantation. Types of neoplasms included post-transplant lymphoproliferative disorder (PTLD) in three (21%) and Epstein-Barr-virus associated smooth muscle tumor in two (14%). (One child developed both neoplasms following transplantation). Both children with smooth muscle tumor associated with Epstein-Barr virus presented with characteristic hypointense solid masses with peripheral rim enhancement on cross-sectional imaging studies. The mortality rate of children who developed post-transplant neoplasms was higher than that of those who did not develop post-transplant neoplasm (50% vs. 10%, P = 0.17), suggesting a possible risk factor for death. CONCLUSION: Post-transplant neoplasm in children with multivisceral transplantation occurs with high frequency, often presents as Epstein-Barr-virus-associated smooth muscle tumor showing characteristic peripheral rim enhancement on cross-sectional imaging studies. PMID- 25796383 TI - Normal values of spleen stiffness in healthy children assessed by acoustic radiation force impulse imaging (ARFI): comparison between two ultrasound transducers. AB - BACKGROUND: Portal hypertension, a major complication of hepatic fibrosis, can affect the stiffness of the spleen. OBJECTIVE: To suggest normal values of spleen stiffness determined by acoustic radiation force impulse imaging in healthy children and to compare measurements using two different US probes. MATERIALS AND METHODS: In a prospective study, 60 healthy children between 1 day and 14 years of age were assigned to four age groups with 15 children in each. Measurements were performed using two transducers (convex 4C1 and linear 9L4), and 10 measurements were obtained in each child, 5 with each probe. RESULTS: The mean splenic shear wave velocities were 2.17 m/s (SD 0.35, 95% CI 2.08-2.26) with the 4C1 probe and 2.15 m/s (SD 0.23, 95% CI 2.09-2.21) with the 9L4 probe (not significant). CONCLUSION: We found normal values for spleen stiffness with no difference in the mean values obtained using two types of US transducers, but with higher variability using a convex compared to a linear transducer. PMID- 25796384 TI - Upper gastrointestinal fluoroscopic simulator for neonates with bilious emesis. AB - Prompt diagnosis of malrotation and midgut volvulus in infants with bilious emesis is critical. However because of the limited frequency of pediatric upper gastrointestinal (UGI) fluoroscopic procedures in neonates, many diagnostic radiology residents complete their training never having seen or performed a UGI on a baby for evaluation of malrotation and midgut volvulus. A UGI simulation model for infants with bilious emesis was created to supplement the hands-on fluoroscopic experience of residents in training. We are now studying the addition of simulated UGI studies to our pediatric radiology curriculum. PMID- 25796385 TI - Paraventricular or centrum ovale cavernous hemangioma involving the pyramidal tract in children: intraoperative MRI and functional neuronavigation-guided resection. AB - OBJECTIVES: In this study, we investigated whether visualization of the pyramidal tract and intraoperative MRI combined with functional navigation was helpful in the resection of paraventricular or centrum ovale cavernous hemangioma in children. METHODS: Twelve patients with cavernous hemangioma located in the paraventricular area or in the centrum ovale adjacent to the pyramidal tract were prospectively enrolled in the study. The pyramidal tract of all patients was visualized preoperatively, and all patients underwent tailored craniotomy with white matter trajectory to resect the lesion, with the help of intraoperative MRI and microscope-based functional neuronavigation. RESULTS: In our study, of the total of 12 patients (nine males and three females), five patients had lesions on the left side, and seven had lesions located in the right hemisphere. The lesion volume varied from 0.2 to 11.45 cm(3). In seven cases, the distance of the lesion from the pyramidal tract was 0-5 mm (the 0-5 mm group), and five cases were in the 5-10 mm group. The 3D visualization of the lesion and the pyramidal tract helped the surgeon design the optimal surgical approach and trajectory. Intraoperative functional neuronavigation allowed them to obtain access to the lesion accurately and precisely. All lesions had been removed totally at the end of the surgery. Compared with the preoperative level, muscle strength at 2 weeks had decreased in six cases, was unchanged in four cases, and improved in two cases; at 3 months, it was improved in five cases, unchanged in six cases, and decreased in one case. CONCLUSIONS: Pyramidal tract visualization and intraoperative MRI combined with functional neuronavigation can aid in safe removal of paraventricular or centrum ovale cavernous hemangioma involving the pyramidal tract. PMID- 25796386 TI - Viruses in pulp and periapical inflammation: a review. AB - The presence of viruses in endodontic disease has been studied in the last decade. Their presence is associated with periapical radiolucency and with clinical findings, such as pain. The aim of this review is to analyze the scientific evidence currently published about viruses in pulp and periapical inflammation, and its possible clinical implications. A literature review was carried out using the Medline/Pubmed database. The search was performed, in English and Spanish, using the following keyword combinations: virus AND endodontic; virus AND periapical; virus AND pulpitis; herpesvirus AND periapical; papillomavirus AND periapical. We subsequently selected the most relevant studies, which complied with the search criterion. A total of 21 articles were included, of which 18 detected the present of viruses in the samples. In 3 of the studies, viral presence was not found in the samples studied. The Epstein-Barr virus was found in about 41 % of cases compared to controls, in which it was present in about 2 %. The main association between viruses and endodontic pathosis is between Cytomegalovirus and Epstein-Barr virus; these are found in 114 of the 406 samples of different endodontic pathosis. Some evidence supports that the Epstein-Barr virus is present in a significant number of endodontic diseases, without exact knowledge of their action in these diseases. PMID- 25796387 TI - Serum uric acid: an independent predictive marker for coronary artery disease. PMID- 25796388 TI - Laparoscopic versus open fecal diversion: does laparoscopy offer better outcomes in short term? AB - BACKGROUND: Laparoscopic fecal diversion is performed in patients with complicated colon and rectal diseases. We aim to compare operative and short-term outcomes between laparoscopic and open fecal diversion. METHODS: After obtaining institutional review board approval, patients undergoing laparoscopic or open fecal diversion between February 2010 and September 2012 were reviewed. A straight comparison of the open and laparoscopic groups was made initially; then, patients who underwent laparoscopic fecal diversion were case-matched with open counterparts based on stoma type and primary diagnosis. RESULTS: While body mass index (BMI) was higher in the laparoscopy group (p = 0.04), American Society of Anesthesiologists (ASA) score (p = 0.33) and gender (p = 0.74) were comparable between the study groups in the straight comparison. In the case-matched analysis, type of prior operations (p > 0.05), age (p = 0.79), gender (p > 0.99), BMI (p = 0.1), and ASA (p = 0.25) score were comparable between the groups. Open surgery was associated with increased estimated blood loss (p = 0.01), longer hospital stay (p = 0.0002), higher postoperative ileus (p = 0.03), and higher readmission rates (p = 0.002). CONCLUSIONS: Considering the short-term benefits as regards postoperative recovery and morbidity, fecal diversions should be performed laparoscopically when feasible. PMID- 25796390 TI - Precipitation Climatology on Titan-like Exomoons. AB - The availability of liquid water on the surface on Earth's continents in part relies on the precipitation of water. This implies that the habitability of exomoons has to consider not only the surface temperature and atmospheric pressure for the presence of liquid water, but also the global precipitation climatology. This study explores the sensitivity of the precipitation climatology of Titan-like exomoons to these moons' orbital configuration using a global climate model. The precipitation rate primarily depends on latitude and is sensitive to the planet's obliquity and the moon's rotation rate. On slowly rotating moons the precipitation shifts to higher latitudes as obliquity is increased, whereas on quickly rotating moons the latitudinal distribution does not strongly depend on obliquity. Stellar eclipse can cause a longitudinal variation in the mean surface temperature and surface pressure between the subplanetary and antiplanetary side if the planet's obliquity and the moon's orbital distance are small. In this particular condition the antiplanetary side generally receives more precipitation than the subplanetary side. However, precipitation on exomoons with dense atmospheres generally occurs at any longitude in contrast to tidally locked exoplanets. PMID- 25796389 TI - Possibility of production of amino acids by impact reaction using a light-gas gun as a simulation of asteroid impacts. AB - In order to investigate impact production of carbonaceous products by asteroids on Titan and other satellites and planets, simulation experiments were carried out using a 2-stage light gas gun. A small polycarbonate or metal bullet with about 6.5 km/s was injected into a pressurized target chamber filled with 1 atm of nitrogen gas, to collide with a ice + iron target or an iron target or a ice + hexane + iron target. After the impact, black soot including fine particles was deposited on the chamber wall. The soot was carefully collected and analyzed by High Performance Liquid Chromatography (HPLC), Fourier Transform Infrared Spectroscopy (FT-IR), and Laser Desorption Time-of-Flight Mass Spectrometry (LD ToF-MS). As a result of the HPLC analysis, about 0.04-8 pmol of glycine, and a lesser amount of alanine were found in the samples when the ice + hexane + iron target was used. In case of the ice + iron target and the iron target, less amino acids were produced. The identification of the amino acids was also supported by FTIR and LD-ToF-MS analysis. PMID- 25796391 TI - Symmetrical and Thermodynamic Properties of Phenotypic Graphs of Amino Acids Encoded by the Primeval RNY Code. AB - The 12 different types of graphs of the 8 amino acids encoded by the presumably primeval RNY code are derived. The symmetry groups of these graphs are analyzed and coincide with the corresponding values of polar requirement for each amino acid. The symmetry groups at the codon level are partially carried over as a group or subgroup at the amino acid level. Measures of centrality of the 12 graphs indicate that all amino acids were equally relevant irrespective of its chronological order of its appearance. The elimination of any amino acid would be strongly selected against and therefore the genetic code at this stage was already frozen. PMID- 25796392 TI - Energetics of Amino Acid Synthesis in Alkaline Hydrothermal Environments. AB - Alkaline hydrothermal systems have received considerable attention as candidates for the origin and evolution of life on the primitive Earth. Nevertheless, sufficient information has not yet been obtained for the thermodynamic properties of amino acids, which are necessary components for life, at high temperatures and alkaline pH. These properties were estimated using experimental high-temperature volume and heat capacity data reported in the literature for several amino acids, together with correlation algorithms and the revised Helgeson-Kirkham-Flowers (HKF) equations of state. This approach enabled determination of a complete set of the standard molal thermodynamic data and the revised HKF parameters for the 20 protein amino acids in their zwitterionic and ionization states. The obtained dataset was then used to evaluate the energetics of amino acid syntheses from simple inorganic precursors (CO2, H2, NH3 and H2S) in a simulated alkaline hydrothermal system on the Hadean Earth. Results show that mixing between CO2 rich seawater and the H2-rich hydrothermal fluid can produce energetically favorable conditions for amino acid syntheses, particularly in the lower temperature region of such systems. Together with data related to the pH and temperature dependences of the energetics of amino acid polymerizations presented in earlier reports, these results suggest the following. Hadean alkaline hydrothermal settings, where steep pH and temperature gradients may have existed between cool, slightly acidic Hadean ocean water and hot, alkaline hydrothermal fluids at the vent-ocean interface, may be energetically the most suitable environment for the synthesis and polymerization of amino acids. PMID- 25796393 TI - Hydrothermal Systems of Kamchatka are Models of the Prebiotic Environment. AB - The composition of organic matter and fluctuations of thermodynamic parameters were investigated in the hydrothermal systems of the Kamchatka peninsula in the context of the origin of life. Organics were analyzed by gas-chromatography/mass spectrometry, and 111 organic compounds belonging to 14 homologous series (aromatic hydrocarbons, alkanes and isoalkanes, halogenated aromatic hydrocarbons, carboxylic acids, esters, etc.) were found in hot springs inhabited by Archaeal and Bacterial thermophiles. The organics detected in the sterile condensate of water-steam mixture taken from deep boreholes (temperature 108-175 degrees C) consisted of 69 compounds of 11 homologous series, with aromatic hydrocarbons and alkanes being prevalent. The organic material included important prebiotic components such as nitrogen-containing compounds and lipid precursors. A separate organic phase (oil) was discovered in the Uzon Caldera. A biogenic origin is supported by the presence of sterane and hopane biomarkers and the delta(13)C value of the bulk oil; its age determined by (14)C measurements was 1030 +/- 40 years. Multilevel fluctuations of thermodynamic parameters proposed to be required for the origin of life were determined in the Mutnovsky and Pauzhetsky hydrothermal systems. The low-frequency component of the hydrothermal fluid pressure varied by up to 2 bars over periods of hours to days, while mid frequency variations had regular micro-oscillations with periods of about 20 min; the high-frequency component displayed sharp changes of pressure and microfluctuations with periods less than 5 min. The correlation coefficient between pressure and temperature ranges from 0.89 to 0.99 (average 0.96). The natural regimes of pressure and temperature fluctuations in Kamchatka hydrothermal systems can guide future experiments on prebiotic chemistry under oscillating conditions. PMID- 25796394 TI - What properties of life are universal? Substance-free, scale-free life. AB - One approach to answering the question of what properties of life are universal is to try to answer the question of what are the essential properties of biology's best understood model organism, Escherichia coli. One of these properties is competitive coherence whereby E. coli reconciles the generation of a coherent cell state with the generation of a coherent sequence of cell states. The second property is differentiation which occurs ineluctably when E. coli divides. The third property is dualism which is how E. coli navigates between the two main attractors of phenotypes - survival and growth - which are based on quasi-equilibrium and non-equilibrium structures, respectively. The fourth property is complementarity: the interactions between the molecules and macromolecules that constitute E. coli protect them from degradation and confer new properties. The fifth property is multi-scale existence: E. coli exists at levels extending from the bacterium to the global super-organism. The sixth property is maintenance of connectivity; growth alters connectivity and, in the case of E. coli, alters the phenotype. The seventh property is the combination of intensity sensing (the constituents can work no harder) and quantity sensing (too much unused material has been made); this combination is used by E. coli to drive its cell cycle and thereby generate an environmentally adapted population of cells. The eighth property is subjective experience which exists even at the level of a single E. coli but which only becomes important at higher levels of organisation. I propose that the search for life at other times and in other places be based on the above eight universal properties and be independent of both particular substances and spatio-temporal scales. PMID- 25796395 TI - GNAS mutation is a frequent event in pancreatic intraductal papillary mucinous neoplasms and associated adenocarcinomas. AB - In contrast to pancreatic ductal adenocarcinomas (PDAs), intraductal papillary mucinous neoplasms (IPMNs) frequently harbour GNAS mutations. To characterise GNAS-mutated pancreatic carcinomas, we examined mutations of GNAS and KRAS in 290 pancreatic adenocarcinomas and 77 pancreatic intraepithelial neoplasias (PanINs). In 64 % (39/61) of IPMNs and 37 % (11/30) of IPMN-associated adenocarcinomas, a GNAS mutation was found. GNAS mutations were frequent (78 %, 7/9) in mucinous carcinomas, with or without associated IPMN. In contrast, GNAS mutations were rarely observed in PDAs (1 %, 1/88) and PanINs (3 %, 2/77), and not at all in mucinous cystic neoplasms (MCNs) (0/10), neuroendocrine neoplasms (0/52), acinar cell neoplasms (0/16), serous cystadenomas (0/10), and solid-pseudopapillary neoplasms (0/14). We found GNAS mutations in 55/91 IPMNs with or without associated invasive carcinoma, solely in intestinal-type (78 %, 21/27) and gastric-type (62 %, 34/55) IPMNs. Of the IPMN-associated adenocarcinomas, mucinous-subtype tumours harboured GNAS mutations more frequently (83 %, 5/6) than tubular-subtype tumours (25 %, 6/24) (p = 0.02). We separately analysed GNAS in the adenocarcinoma and the IPMN component in the IPMN-associated adenocarcinomas. In all mucinous-subtype tumours, the two components exhibited identical genotypes. In contrast, the two components in 8 of 24 tubular-subtype tumours exhibited different genotypes, indicating intratumour heterogeneity. In conclusion, mucinous carcinomas with or without associated IPMN as well as IPMNs frequently harbour a GNAS mutation, reinforcing the notion that these constitute a spectrum of pancreatic tumours. Clinically and pathologically, these tumours are associated, but GNAS mutation sheds further light on this spectrum. PMID- 25796396 TI - The detection of vector-borne-disease-related DNA in human stool paves the way to large epidemiological studies. AB - The detection of Plasmodium spp. by the molecular analysis of human feces was reported to be comparable to detection in the blood. We believe that for epidemiological studies using molecular tools, it would be simpler to use feces, which are easier to obtain and require no training for their collection. Our aim was to evaluate the usefulness of feces for the detection of these pathogens towards developing a new tool for their surveillance. Between 2008 and 2010, 451 human fecal samples were collected in two Senegalese villages in which malaria and rickettsioses are endemic. Rickettsia and Plasmodium DNA were detected using quantitative PCR targeting Rickettsia of the spotted fever group, R. felis and Plasmodium spp. Two different sequences were systematically targeted for each pathogen. Twenty of the 451 fecal samples (4.4 %) were positive for Rickettsia spp., including 8 for R. felis. Inhabitants of Dielmo were more affected (18/230, 7.8 %; p = 0.0008) compared to those of Ndiop (2/221, 0.9 %). Children under 15 years of age were more often positive (19/285, 6.7 %) than were older children (1/166, 0.6 %; p = 0.005, odds ratio = 11.79). Only one sample was positive for Plasmodium spp. This prevalence is similar to that found in the blood of the Senegalese population reported previously. This preliminary report provides a proof of concept for the use of feces for detecting human pathogens, including microorganisms that do not cause gastroenteritis, in epidemiological studies. PMID- 25796398 TI - Identification and molecular characterization of Orf virus in Argentina. AB - Orf virus (ORFV) is the etiological agent of contagious ecthyma (CE), a pustular dermatitis of sheep and goats. Outbreaks of ORFV have been observed in all geographical regions of the world, including Argentina. The origin and identity of Argentinian ORFVs are unknown, and no comparative or phylogenetic studies of these viruses have been performed. In this study, we described the sequencing and analysis of five ORFV molecular markers: a partial B2L gene (ORF011), VIR (ORF020), an envelope mature protein (ORF109), vIL10 (ORF127), and GIF (ORF117) from two particular Argentinian outbreaks of CE. PMID- 25796399 TI - Functional occlusal patterns during lateral excursions in young adults. AB - STATEMENT OF PROBLEM: A valid system for assessing and classifying functional occlusion has not been established. The prevalence of anterior protected articulation is not known. PURPOSE: The purpose of this study was to quantify the prevalence of various functional occlusal contact patterns, including anterior protected articulation, among dental students. MATERIAL AND METHODS: Occlusal contacts were examined during lateral excursions from the maximal intercuspal position to the canine-to-canine position in 100 young adults. A combination of 3 common clinical methods was used: a visual examination, articulating paper, and feedback from the participants. RESULTS: Data from 3 classification systems were analyzed: (1) Occlusal contacts on the working side only - canine protected articulation was present in 25% of laterotrusions; anterior protected articulation was present in 18.5% of laterotrusions. Group function was present in 56% of laterotrusions. Other schemes were present in 0.5% of laterotrusions. (2) Contacts on both the working and the nonworking side. (3) Contacts on the working and nonworking side during both right and left laterotrusion. Nonworking side contacts were present in 33% of the participants. Nonworking side interference was present in 1 participant. CONCLUSIONS: The prevalence of anterior protected articulation found in this study was high enough to allow anterior protected articulation to be considered one of the fundamental working side occlusal contact patterns. More studies will be necessary to confirm this finding. PMID- 25796397 TI - Meiosis, unreduced gametes, and parthenogenesis: implications for engineering clonal seed formation in crops. AB - KEY MESSAGE: Meiosis and unreduced gametes. Sexual flowering plants produce meiotically derived cells that give rise to the male and female haploid gametophytic phase. In the ovule, usually a single precursor (the megaspore mother cell) undergoes meiosis to form four haploid megaspores; however, numerous mutants result in the formation of unreduced gametes, sometimes showing female specificity, a phenomenon reminiscent of the initiation of gametophytic apomixis. Here, we review the developmental events that occur during female meiosis and megasporogenesis at the light of current possibilities to engineer unreduced gamete formation. We also provide an overview of the current understanding of mechanisms leading to parthenogenesis and discuss some of the conceptual implications for attempting the induction of clonal seed production in cultivated plants. PMID- 25796400 TI - Low gradient aortic stenosis. AB - OPINION STATEMENT: Severe low-gradient (LG) aortic stenosis (AS) [aortic valve area (AVA) <= 1.0 cm(2), mean pressure gradient (MG) < 40 mmHg] represents a frequently encountered and challenging clinical dilemma. A systematic approach, which often requires several imaging modalities, should be undertaken to confirm the hemodynamic findings and rule out measurement error. Low-flow conditions often account for the discrepancy and can be present whether the left ventricular ejection fraction (LVEF) is depressed or normal. In patients with classical low flow (LF), LG AS in which LVEF is reduced (<40-50 %), dobutamine stress echocardiography (DSE) should be used to distinguish patients with true severe AS and pseudo-severe AS, as well as to evaluate for the presence of left ventricular contractile or flow reserve. Surgical or transcatheter aortic valve replacement (AVR) should likely be reserved for those patients with true severe AS. Patient outcome with medical or surgical management generally relates to patient functional capacity, stenosis severity, and left ventricular functional reserve. Patients with severe LG AS with preserved LVEF can have a stroke volume that is either normal (>35 mL/m(2)) or low (<35 mL/m(2)). New data suggest that DSE can identify pseudo-severe AS in up to 30 % of patients with severe LF-LG AS with preserved LVEF. AVR should likely be restricted to those patients with true severe AS, although there is currently little data to support this strategy. Symptomatic patients with severe LG AS with preserved LVEF, whether they have normal or low flow, should be offered AVR. Transcatheter AVR provides an alternative therapeutic option in the high-risk patient. PMID- 25796401 TI - Drug-coated balloons: how should we incorporate into our practice in treating superficial femoral artery lesions? AB - OPINION STATEMENT: Drug-coated balloons (DCBs) provide a novel method to locally deliver paclitaxel into the arterial wall without the need of a chronically implanted delivery system. Following the first positive pilot studies, two large pivotal trials have confirmed superiority of DCBs over plain old balloon angioplasty (POBA) in the treatment of TASC II A and B femoro-popliteal lesions. Even for more complex femoro-popliteal lesions such as long lesions and in-stent restenosis, single-center studies and small randomized studies have shown promising mid-term technical and clinical results. This review article summarizes the current knowledge about DCBs in femoro-popliteal interventions, supplements published guidelines with evidence-based recommendations, and discusses still unresolved needs. PMID- 25796402 TI - Contribution of environmental toxins in the pathogenesis of idiopathic cardiomyopathies. AB - OPINION STATEMENT: The pathogenesis of idiopathic cardiomyopathies is likely highly complex and remains elusive. Environmental toxins have been hypothesized to possibly cause a subset of cardiomyopathies. Epidemiological, preclinical, and small clinical studies have investigated the role of numerous elements and compounds in the pathogenesis of these myocardial disorders. In this review, we present the evidence implicating elements and environmental compounds in myocardial toxicity, including antimony, cobalt, mercury, aluminum, copper, and acrolein. We discuss their sources, toxic effects, and epidemiology, as well as identify groups at risk for toxic exposure. Through our discussion, we highlight areas where further investigation into the clinical effects of these possible toxins is warranted. PMID- 25796404 TI - Improvements in patient care: videoconferencing to improve access to interpreters during clinical consultations for refugee and immigrant patients. AB - OBJECTIVE: To demonstrate the suitability of accessing interpreters via videoconference for medical consultations and to assess doctor and patient perceptions of this compared with either on-site or telephone interpreting. METHODS: We assessed the suitability and acceptability of accessing interpreters via videoconference during out-patient clinical consultations in two situations: (i) when the doctor and patient were in a consulting room at a central hospital and the interpreter sat remotely; and (ii) when the doctor, patient and interpreter were each at separate sites (during a telehealth consultation). The main outcome measures were patient and doctor satisfaction, number of problems recorded and acceptability compared with other methods for accessing an interpreter. RESULTS: Ninety-eight per cent of patients were satisfied overall with the use of an interpreter by video. When comparing videoconference interpreting with telephone interpreting, 82% of patients thought having an interpreter via video was better or much better, 15% thought it was the same and 3% considered it worse. Compared with on-site interpreting, 16% found videoconferencing better or much better, 58% considered it the same and 24% considered it worse or much worse. CONCLUSIONS: The present study has demonstrated that accessing an interpreter via videoconference is well accepted and preferred to telephone interpreting by both doctors and patients. PMID- 25796403 TI - Left ventricular assist devices: a kidney's perspective. AB - The left ventricular assist device (LVAD) has become an established treatment option for patients with refractory heart failure. Many of these patients experience chronic kidney disease (CKD) due to chronic cardiorenal syndrome type II, which is often alleviated quickly following LVAD implantation. Nevertheless, reversibility of CKD remains difficult to predict. Interestingly, initial recovery of GFR appears to be transient, being followed by gradual but significant late decline. Nevertheless, GFR often remains elevated compared to preimplant status. Larger GFR increases are followed by a proportionally larger late decline. Several explanations for this gradual decline in renal function after LVAD therapy have been proposed, yet a definitive answer remains elusive. Mortality predictors of LVAD implantation are the occurrence of either postimplantation acute kidney injury (AKI) or preimplant CKD. However, patient outcomes continue to improve as LVAD therapy becomes more widespread, and adverse events including AKI appear to decline. In light of a growing destination therapy population, it is important to understand the cumulative effects of long-term LVAD support on kidney function. Additional research and passage of time are required to further unravel the intricate relationships between the LVAD and the kidney. PMID- 25796405 TI - Calycosin orchestrates the functions of Danggui Buxue Tang, a Chinese herbal decoction composing of Astragali Radix and Angelica Sinensis Radix: An evaluation by using calycosin-knock out herbal extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue Tang (DBT) is a classical Chinese herbal decoction containing two herbs, Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), which serves as dietary supplement for treating women menopausal syndromes. Pharmacological studies indicate that DBT has estrogenic, erythropoietic and osteogenic properties; however, the action mechanism for this complex herbal decoction is not known. Calycosin, a major flavonoid in AR, shares similar structure with beta-estradiol, and thus which is hypothesized to be the critical compound of DBT. Here, we aim to investigate the role of calycosin in DBT in terms of its biological functions by using a calycosin-depleted DBT decoction (DBT(Deltacal)). The biological functions of DBT(Deltacal) and parental DBT were systematically compared. MATERIALS AND METHODS: In order to standardize DBT decoction, four chemical markers were determined and quantified by HPLC. A semi-preparative HPLC method was utilized to prepare DBT(Deltacal). The authenticity of DBT(Deltacal) was evaluated by LC-QQQ-MS/MS. To reveal the effect of calycosin on DBT functions, several cell assays related to the known properties of DBT were revealed, including estrogenic, erythropoietic and osteogenic functions. RESULTS: As compared to parental DBT, the estrogenic, erythropoietic and osteogenic abilities were markedly reduced in DBT(Deltacal). However, calycosin alone did not show significant responses. CONCLUSIONS: Our results suggest that calycosin is a bioactive chemical in DBT decoction, and which could play a key linker in orchestrating multi-components of DBT as to achieve maximal functions. These discoveries should be invaluable in drug development and in investigating the modernization of traditional Chinese medicine from a new perspective. PMID- 25796406 TI - Plectranthus amboinicus leaves stimulate growth of probiotic L. plantarum: evidence for ethnobotanical use in diarrhea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Plectranthus amboinicus are consumed in India along with buttermilk (a probiotic source) during pathogen induced diarrhea. This treatment is known to reduce the number of episodes as well as duration of diarrhea. AIM OF THE STUDY: In the background of its ethnobotanical use, the present investigation was carried out to determine whether, apart from having an antimicrobial activity on pathogens, the leaves could possibly also have a positive effect on the beneficial microflora of the gut resulting in accelerated microbial ecological balance. MATERIALS AND METHODS: The growth stimulating activity of the hot water extract (HWE) of P. amboinicus leaves on probiotic Lactobacillus plantarum was determined by microbroth dilution technique and viable plate count method in selective medium (MRS) as well as in fermented milk. The ability of the bacteria to utilize the phytoconstituents of HWE primarily phenolic acids and sugars was determined by assaying for phenolic acid decarboxylase by SDS-PAGE and beta-galactosidase activity by beta-gal ONPG assay. RESULTS: HWE of P. amboinicus leaves inhibited growth of pathogens (Escherichia coli and Salmonella typhimurium) while stimulated the growth of L. plantarum. SDS PAGE gel showed the presence of phenolic acid decarboxylase enzyme induced in the presence of HWE in L. plantarum indicating the utilization of polyphenols by the bacteria. Cells grown on HWE also showed beta-galactosidase activity indicating their ability to utilize sugars present in HWE. CONCLUSION: Indian borage leaves have a prebiotic effect on the probiotic bacteria (L. plantarum) which utilizes the phytoconstituents of the leaves by producing necessary metabolic enzymes. This work provides evidence in the traditional use of the leaves in the alleviation of diarrhea by accelerating microbial gut balance during infection. PMID- 25796407 TI - The extract of Hypericum ascyron L. induces bacterial cell death through apoptosis pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum ascyron L. (H. ascyron L.) has been used as a traditional medicine for the treatment of wounds, swelling, headache, nausea, stomach ache, abscesses, dysentery and chronic bronchitis. Pharmacological studies are necessary to provide a scientific basis to substantiate their traditional use. In this study, antimicrobial effect and its mechanism of the H. ascyron L. extract was investigated. MATERIALS AND METHODS: Antimicrobial activity of the H. ascyron L. extract was evaluated by the 3-(4, 5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT). To confirm the antimicrobial mechanism of H. ascyron L. extract on bacterial cells, Annexin V/propidium iodide (PI) double staining, TUNEL, and DNA laddering analysis were performed. RESULTS: Antibacterial effects of the H. ascyron L. extract were tested on Enterobacter cloacae, Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus and Micrococcus luteus, and the results showed that the sensitive bacteria of H. ascyron L. extract mainly included E. coli, S. aureus and M. luteus, especially M. luteus. The MBC value of H. ascyron L. extract on M. luteus was equal to the MIC (20mg/mL). H. ascyron L. extract could induce cells death of M. luteus through apoptosis pathway. CONCLUSIONS: This study provides scientific support for some of the traditional uses and the pharmacological activities of H. ascyron L. Our data provide a rational base for the folkloric use of H. ascyron L. PMID- 25796408 TI - Grafting after sinus lift with anorganic bovine bone alone compared with 50:50 anorganic bovine bone and autologous bone: results of a pilot randomised trial at one year. AB - Our aim was to compare the outcome of implants inserted in maxillary sinuses augmented with anorganic bovine bone grafts compared with those augmented with mixed 50:50 bovine and autologous bone grafts. Twenty sinuses with 1-4mm of residual crestal height below the maxillary sinuses were randomised into two groups according to a parallel group design (n=10 in each). Sinuses were grafted using a lateral approach. In one group the grafts were 50:50 anorganic bovine bone and autologous bone and in the other anorganic bovine bone alone. After 7 months, 32 implants had been inserted. Outcome measures were survival of implants, complications, marginal changes in the height of the bone, and soft tissue variables (pocket probing depth and bleeding on probing). Probabilities of less than 0.05 were accepted as significant. No patient failed to complete the trial and no implant had failed at 1 year. There were some minor complications. After 12 months, the mean (SD) marginal bone loss (mm) was 1.06 (0.61) in the 50:50 group and 1.19 (0.53) in the anorganic bovine group. The mean (SD) values for pocket probing depth (mm) and bleeding on probing (score) were 2.49 (0.38) and 1.59 (0.82) in the 50:50 group and 2.31 (0.64) and 1.36 (0.87) in the anorganic bovine group (neither difference was significant). The present data are consistent with the hypothesis that the outcome of implants inserted in sinuses grafted with either material is comparable. PMID- 25796409 TI - Memory delay and haptic feedback influence the dissociation of tactile cues for perception and action. AB - The somatosensory processing model (SPM) asserts that dissociable cortical processing streams mediate tactile perceptions and actions via relative and absolute cues, respectively (Dijkerman and de Haan, 2007). Accordingly, we sought to determine whether the introduction of a memory delay and/or physically touching a target object (i.e., haptic feedback) differentially influences the cues supporting tactile perceptions and actions. Participants used their right hand to manually estimate (i.e., perceptual task) or grasp (i.e., action task) differently sized objects placed on the palm of their left limb in conditions wherein the target object was available for the duration of the response (i.e., closed-loop condition), or was removed prior to response cuing (i.e., memory guided condition). As well, trials were performed in conditions wherein the physical object was available (i.e., haptic feedback) or unavailable (i.e., no haptic feedback) to touch. Notably, we computed just-noticeable-difference (JND) scores to determine whether the aforementioned tasks and conditions adhered to - or violated - the relative properties of Weber's law. JNDs for manual estimations adhered to Weber's law across each condition - a finding supporting the SPM's contention that an immutable and relative percept supports tactile perceptions. In turn, JNDs for grasping violated Weber's law only when haptic feedback was available. Such a finding indicates that haptic feedback supports the absolute calibration between a tactile defined object and the required motor output. What is more, our study highlights that multiple somatosensory cues (i.e., tactile and haptic) support goal-directed grasping. PMID- 25796410 TI - Enhancing the mirror illusion with transcranial direct current stimulation. AB - Visual feedback has a strong impact on upper-extremity movement production. One compelling example of this phenomena is the mirror illusion (MI), which has been used as a treatment for post-stroke movement deficits (mirror therapy). Previous research indicates that the MI increases primary motor cortex excitability, and this change in excitability is strongly correlated with the mirror's effects on behavioral performance of neurologically-intact controls. Based on evidence that primary motor cortex excitability can also be increased using transcranial direct current stimulation (tDCS), we tested whether bilateral tDCS to the primary motor cortices (anode right-cathode left and anode left-cathode right) would modify the MI. We measured the MI using a previously-developed task in which participants make reaching movements with the unseen arm behind a mirror while viewing the reflection of the other arm. When an offset in the positions of the two limbs relative to the mirror is introduced, reaching errors of the unseen arm are biased by the reflected arm's position. We found that active tDCS in the anode right-cathode left montage increased the magnitude of the MI relative to sham tDCS and anode left-cathode right tDCS. We take these data as a promising indication that tDCS could improve the effect of mirror therapy in patients with hemiparesis. PMID- 25796411 TI - Prosthetic valves and the unending quest for the holy grail. PMID- 25796412 TI - 5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Promotes Phenotypic Switching from Dedifferentiated to Differentiated Phenotype via Reactive Oxygen Species and p38 Mitogen-Activated Protein Kinase in Vascular Smooth Muscle Cells. AB - Sonodynamic therapy (SDT) has been found to inhibit in-stent restenosis in animal models. However, the mechanism is not fully elucidated. Here, we investigated the effects of 5-aminolevulinic acid (ALA)-mediated SDT (ALA-SDT) on vascular smooth muscle cells (VSMCs), a cause of restenosis, with a focus on SDT-induced phenotypic switching. Serum-induced dedifferentiated VSMCs were cultured with ALA (1 mm, 24 h) and exposed to ultrasound (0.8 W/cm(2)) for 5 min. Results indicated that ALA-SDT inhibited the migration and proliferation of VSMCs and enhanced the expression of differentiated phenotypic markers in VSMCs. Additionally, ALA-SDT increased intracellular reactive oxygen species accumulation and phosphorylated p38 mitogen-activated protein kinase in VSMCs. Inhibition of reactive oxygen species elevation or p38 mitogen-activated protein kinase activity abolished the expression of smooth muscle 22alpha (SM22alpha) in VSMCs induced by ALA-SDT. Taken together, these results suggest that ALA-SDT promotes transformation of the VSMC phenotype from the dedifferentiated to differentiated status via reactive oxygen species and activated p38 mitogen-activated protein kinase. PMID- 25796413 TI - Role of ultrasonography in the detection of a subperiosteal abscess secondary to mastoiditis in pediatric patients. AB - The aim of the study described here was to evaluate experience in the diagnosis of a subperiosteal abscess secondary to mastoiditis by means of ultrasound. Ten consecutive cases in which an ultrasound examination of the retro-auricular region was performed for suspected mastoiditis were identified. In nine cases, we found a poorly demarcated, inhomogeneous, irregular, poorly perfused lesion abutting the outer table of the cranial vault, with elevation of the outer periosteum and a clearly delineated defect of the cortical layer. In one case, there was additional invasion of the insertion of the sternocleidomastoid muscle on the mastoid process of the temporal bone, raising the suspicion of Bezold mastoiditis. Ultrasound may help in selecting patients for further imaging and might spare computer tomography, especially in sensitive patient groups such as children and pregnant women, if a defect of the outer cortex of the temporal bone can be excluded with certainty. PMID- 25796414 TI - Continuous Shear Wave Elastography: A New Method to Measure Viscoelastic Properties of Tendons in Vivo. AB - Viscoelastic mechanical properties are frequently altered after tendon injuries and during recovery. Therefore, non-invasive measurements of shear viscoelastic properties may help evaluate tendon recovery and compare the effectiveness of different therapies. The objectives of this study were to describe an elastography method for measuring localized viscoelastic properties of tendons and to discuss the initial results in healthy and injured human Achilles and semitendinosus tendons. The technique used an external actuator to generate the shear waves in the tendon at different frequencies and plane wave imaging to measure shear wave displacements. For each of the excitation frequencies, maps of direction-specific wave speeds were calculated using local frequency estimation. Maps of viscoelastic properties were obtained using a pixel-wise curve fit of wave speed and frequency. The method was validated by comparing measurements of wave speed in agarose gels with those obtained using magnetic resonance elastography. Measurements in human healthy Achilles tendons revealed a pronounced increase in wave speed as a function of frequency, which highlights the importance of tendon viscoelasticity. Additionally, the viscoelastic properties of the Achilles tendon were larger than those reported for other tissues. Measurements in a tendinopathic Achilles tendon indicated that it is feasible to quantify local viscoelastic properties. Similarly, measurement in the semitendinosus tendon revealed substantial differences in viscoelastic properties between the healthy and contralateral tendons. Consequently, this technique has the potential to evaluate localized changes in tendon viscoelastic properties caused by injury and during recovery in a clinical setting. PMID- 25796415 TI - Effects of steatosis on hepatic hemodynamics in patients with metabolic syndrome. AB - The aim of our study was to assess the hemodynamic changes in hepatic and splenic circulation using B-mode ultrasonography and color Doppler ultrasonography, in a population of patients with metabolic syndrome divided with respect to the presence or absence of steatosis diagnosed by ultrasonography. One hundred forty one patients were included in the study. The severity of non-alcoholic fatty liver disease was classified as mild, moderate or severe. Visceral fat thickness, longitudinal diameter of the spleen, diameter of the portal vein, mean maximum portal vein flow velocity, hepatic artery and splenic artery resistivity indexes and hepatic vein flow phasicity were measured. Non-alcoholic fatty liver disease was detected in 114 of 141 patients, with a prevalence of 80.8%. Patients with steatosis had significantly greater diameters of the portal vein, longitudinal diameters of the spleen, visceral fat thickness and hepatic artery and splenic artery resistivity indexes, whereas their portal vein flow velocities were significantly lower. Non-alcoholic fatty liver disease severity correlated positively with diameter of the portal vein, longitudinal diameter of the spleen and visceral fat thickness and negatively with hepatic artery and splenic artery resistivity indexes and reduced hepatic vein flow phasicity. Our patients with metabolic syndrome and non-alcoholic fatty liver disease had a flattened hepatic vein flow phasicity, greater portal vein diameter, reduction in portal vein flow velocity and intrahepatic arterial vasodilation. The vasodilation of the intrahepatic arterial system was likely activated both by the effect of insulin resistance and as a physiologic adaptation to restore hepatic flow. The increase in spleen volume might be related to the organomegaly typical of obese patients. PMID- 25796416 TI - Circumferential esophageal replacement using a tube-shaped tissue-engineered substitute: An experimental study in minipigs. AB - BACKGROUND: Esophageal replacement by the colon or the stomach for malignant and nonmalignant esophageal diseases exposes to significant morbidity and mortality. In this setting, tissue engineering seems to be a seductive alternative. METHODS: In a porcine model, we performed a 5-cm-long circumferential replacement of the cervical esophagus by a tubulized acellular matrix (small intestinal submucosa) cellularized with autologous skeletal myoblasts and covered by a human amniotic membrane seeded with autologous oral epithelial cells. The substitute was grown for 2 weeks in the great omentum before esophageal replacement. Eighteen minipigs (divided into 3 groups: group A [substitute with esophageal endoprothesis; n = 6], group B [substitute alone; n = 6], and group C [endoprothesis alone; n = 6]) were included. The esophageal endoprothesis was removed at 6 months. Animals were killed sequentially over a 12 month-period. Clinical, endoscopic, radiologic and histologic outcomes were analyzed. RESULTS: All animals except 1 of in groups B and C died during the first 2 months owing to refractory esophageal stenosis or endoprothesis extrusion. Nutritional autonomy without endoprothesis was observed in all animals of group A with a follow-up of >6 months (n = 3). A phenotype similar to that of native esophagus, consisting of a mature epithelium, submucosal glands, and a circular muscular layer, was observed after 9 months. CONCLUSION: In this model, the circumferential replacement of the cervical esophagus by a tube-shaped tissue-engineered substitute under the temporary cover of an esophageal endoprothesis allowed nutritional autonomy and tissue remodeling toward an esophageal phenotype. PMID- 25796418 TI - It Took a Village: Good's Syndrome. PMID- 25796417 TI - How to decide to undertake a randomized, controlled trial of stent or surgery in colorectal obstruction. AB - BACKGROUND: Colorectal stents have been available as a management option in obstruction for 23 years, yet there is little randomized evidence of their effectiveness. This study investigated current surgeon-related barriers to conducting a randomized, controlled trial (RCT) of colorectal stent insertion for obstruction in patients with colorectal cancer. METHODS: A binational survey of current members of the Colorectal Surgical Society of Australia and New Zealand was conducted by a mailed questionnaire assessing perceived barriers to adoption of colonic stents and willingness to participate in future multicentre randomized controlled trials, and surgeons' treatment preferences in 16 hypothetical clinical scenarios. RESULTS: Of 148 eligible surgeons, 96 (65%) responded. Colonic stenting was available to 98% of respondents. In the clinical setting of colorectal obstruction, only 29% (95% CI, 20-39%) of surgeons expressed a willingness to participate in a RCT involving colonic stents in the curative setting. More than 70% of surgeons preferred the use of stents in unfit patients for palliation, and preferred surgery in fit patients with curable disease. In the curative setting, most respondents considered colonic stents not cost effective (90%; 95% CI, 82-94%) and believed that their patients would not prefer stents over surgery (80%; 95% CI, 71-87%). CONCLUSION: This study highlights the limitation to conducting a future randomized controlled trial to assess the efficacy of colonic stenting, especially in the curative setting, based on surgeon preference, despite the lack of level I evidence. PMID- 25796419 TI - Silver sucrose octasulfate nasal applications and wound healing after endoscopic sinus surgery: a prospective, randomized, double-blind, placebo-controlled study. AB - OBJECTIVES: The aim of the present prospective, randomized, double-blind, and placebo-controlled investigation (approved by the Ethical Committee of Padova University Hospital [Italy]) was to assess the effect of a nasal gel containing a combination of silver sucrose octasulfate and potassium sucrose octasulfate (Silsos gel(r) [SG]) in wound healing after endoscopic sinus surgery (ESS) for chronic rhinosinusitis in terms of: nasal symptoms (SNOT22), endoscopic appearance of the sinonasal mucosa (Lund-Kennedy score), nasal air flow (anterior active rhinomanometry), evidence of mucosal inflammatory processes (nasal cytology and histology), and microbiological growth. METHODS: Thirty-four patients with chronic rhinosinusitis were randomized on a 1:1 ratio to receive after ESS either SG or placebo (contained only the excipients [carbopol and propylene glycol] in the same concentrations as in SG). RESULTS/CONCLUSIONS: Judging from the present prospective investigation on patients who underwent ESS for chronic rhinosinusitis, treatment with SG seems to enable a significantly faster improvement in specific symptoms (assessed on the validated SNOT22 scale) than placebo. Patients treated with SG also had a quicker improvement in the endoscopic appearance of their nasal mucosa after ESS than patients treated with placebo. These endoscopic improvements in the SG group were also confirmed at the long-term follow-up, while the same did not apply to the placebo-treated group. PMID- 25796420 TI - Detection of nitrifiers and evaluation of partial nitrification for wastewater treatment: A review. AB - Partial nitrification has gained broad interests in the biological nitrogen removal (BNR) from wastewater, since it alleviates carbon limitation issues and acts as a shortcut nitrogen removal system combined with anaerobic ammonium oxidation (Anammox) process. The occurrence and maintenance of partial nitrification relies on various conditions, which favor ammonium oxidizing bacteria (AOB) but inhibit or limit nitrite oxidizing bacteria (NOB). The studies of the AOB and NOB activities have been conducted by state-of-the-art molecular techniques, such as Polymerase Chain Reaction (PCR), Quantitative PCR, denaturing gradient gel electrophoresis (DGGE), Fluorescence in situ hybridization (FISH) technique, Terminal Restriction Fragment Length Polymorphism (T-RFLP), Live/Dead BacLight, and quinone profile. Furthermore, control strategies for obtaining partial nitrification are mainly focused on the pH, temperature, dissolved oxygen concentration, real-time aeration control, sludge retention time, substrate concentration, alternating anoxic and aerobic operation, inhibitor and ultrasonic treatment. Existing problems and further perspectives for the scale-up of partial nitrification are also proposed and suggested. PMID- 25796421 TI - Bayesian modeling approach for characterizing groundwater arsenic contamination in the Mekong River basin. AB - In the Mekong River basin, groundwater from tube-wells is a major drinking water source. However, arsenic (As) contamination in groundwater resources has become a critical issue in the watershed. In this study, As species such as total As (AsTOT), As(III), and As(V), were monitored across the watershed to investigate their characteristics and inter-relationships with water quality parameters, including pH and redox potential (Eh). The data illustrated a dramatic change in the relationship between AsTOT and Eh over a specific Eh range, suggesting the importance of Eh in predicting AsTOT. Thus, a Bayesian change-point model was developed to predict AsTOT concentrations based on Eh and pH, to determine changes in the AsTOT-Eh relationship. The model captured the Eh change-point (~ 100+/-15mV), which was compatible with the data. Importantly, the inclusion of this change-point in the model resulted in improved model fit and prediction accuracy; AsTOT concentrations were strongly negatively related to Eh values higher than the change-point. The process underlying this relationship was subsequently posited to be the reductive dissolution of mineral oxides and As release. Overall, AsTOT showed a weak positive relationship with Eh at a lower range, similar to those commonly observed in the Mekong River basin delta. It is expected that these results would serve as a guide for establishing public health strategies in the Mekong River Basin. PMID- 25796422 TI - Endoscopic submucosal dissection. AB - ESD is an established effective treatment modality for premalignant and early stage malignant lesions of the stomach, esophagus, and colorectum. Compared with EMR, ESD is generally associated with higher rates of en bloc, R0, and curative resections and a lower rate of local recurrence. Oncologic outcomes with ESD compare favorably with competing surgical interventions, and ESD also serves as an excellent T-staging tool to identify noncurative resections that will require further treatment. ESD is technically demanding and has a higher rate of adverse events than most endoscopic procedures including EMR. As such,sufficient training is critical to ensure safe conduct and high-quality resections. A standardized training model for Western endoscopists has not been clearly established,but will be self-directed and include courses, animal model training, and optimally an observership at an expert center.Numerous dedicated ESD devices are now available in the United States from different manufacturers. Although the use of ESD in the United States is increasing, issues related to technical difficulty, limited training opportunities and mentors, risk of adverse events, long procedure duration,and suboptimal reimbursement may limit ESD adoption in the United States to a modest number of academic referral centers for the foreseeable future. PMID- 25796423 TI - Overproduction of altered VLDL in an insulin-resistance rat model: Influence of SREBP-1c and PPAR-alpha. AB - BACKGROUND: In insulin-resistance, VLDL presents alterations that increase its atherogenic potential. The mechanism by which insulin-resistance promotes the production of altered VLDL is still not completely understood. The aim of this study was to evaluate the relationship between the expression of sterol regulatory element binding protein 1c (SREBP-1c) and of peroxisome proliferator activated receptor-alpha (PPAR-alpha), with the features of composition and size of VLDL in an insulin-resistance rat model induced by a sucrose rich diet (SRD). METHODS: The study was conducted on 12 male Wistar rats (180g) receiving SRD (12 weeks) and 12 controls. Lipid profile, free fatty acids, glucose, and insulin were measured. Lipid content in liver and visceral fat were assessed. Isolated VLDL (d<1.006g/ml) was characterized by its chemical composition and size by HPLC. The respective hepatic expression of SREBP-1c and PPAR-alpha was determined (Western blot). RESULTS: As expected, SRD had elevated triglycerides (TG), free fatty acids and insulin levels, and decreased HDL-cholesterol (p<0.05), together with augmented hepatic and visceral fat (p<0.05). SRD showed higher VLDL total mass - with increased TG content - and predominance of large VLDL (p<0.05). SRD showed an increase in SREBP-1c (precursor and mature forms) and decreased PPAR alpha expression (p<0.045). SREBP-1c forms were positively associated with VLDL total mass (p<0.04), VLDL-TG% (p<0.019), and large VLDL% (p<0.002). On the other hand, PPAR-alpha correlated negatively with VLDL total mass (p=0.05), VLDL-TG% (p=0.005), and large VLDL% (p=0.002). CONCLUSIONS: Insulin-resistance, by coordinated activation of SREBP-1c and reduction of PPAR-alpha, could promote the secretion of larger and TG over-enriched VLDL particles, with greater atherogenic capacity. PMID- 25796424 TI - Dynamic perfusion CT in brain tumors. AB - Dynamic perfusion CT (PCT) is an imaging technique for assessing the vascular supply and hemodynamics of brain tumors by measuring blood flow, blood volume, and permeability-surface area product. These PCT parameters provide information complementary to histopathologic assessments and have been used for grading brain tumors, distinguishing high-grade gliomas from other brain lesions, differentiating true progression from post-treatment effects, and predicting prognosis after treatments. In this review, the basic principles of PCT are described, and applications of PCT of brain tumors are discussed. The advantages and current challenges, along with possible solutions, of PCT are presented. PMID- 25796425 TI - Comparison of chest-CT findings of Influenza virus-associated pneumonia in immunocompetent vs. immunocompromised patients. AB - PURPOSE: To retrospectively compare CT-patterns of pulmonary infiltration caused by different Influenza virus types and subtypes in immunocompetent and immunocompromised patients for possible discrimination. MATERIALS AND METHODS: Retrospective database search at our institution yielded 237 patients who were tested positive for Influenza virus type A or type B by bronchoalveolar lavage between January 2009 and April 2014. Fifty-six of these patients (female 26; male 30; median age 55.8 y, range 17-86 y; SD +/- 14.4 y) underwent chest-HRCT due to a more severe clinical course of pulmonary infection. We registered all CT findings compatible with pulmonary infection classifying them as airway predominant (tree-in-bud, centrilobular nodules, bronchial wall thickening +/- peribronchial ground-glass opacity and consolidation) vs. interstitial parenchymal predominant (bilateral, symmetrical GGO, consolidation, crazy paving and/or interlobular septal thickening). Twenty-six patients (46.4%) had follow-up CT-studies (0.78 mean, SD +/- 5.8 scans). RESULTS: Thirty-six patients were immunocompromised (group I) whereas 20 patients were immunocompetent (group II). An airway-centric pattern of infection was found in 15 patients (group I) and 14 patients (group II) whereas an interstitial-parenchymal predominant pattern was found in 14 patients (group I) and 2 patients (group II). Eleven patients had a mixed pattern with no clear assignment to one group. At FU, 12 patients from group I and 3 from group II showed transitional infiltration patterns: in 10 patients from interstitial-parenchymal into airway predominant pattern and in five patients from airway predominant into interstitial-parenchymal. No significant differences in the pattern of pulmonary infection were found between different types and subtypes of Influenza viruses. CONCLUSION: Patterns of pulmonary infiltration caused by Influenza viruses do not significantly differ between immunocompetent and immunocompromised patients or between different types and subtypes of Influenza virus. One possible explanation for this could be the temporarily interchangeable character of pulmonary infiltration in this infection. PMID- 25796426 TI - Dynamic contrast enhanced MRI-derived parameters are potential biomarkers of therapeutic response in bladder carcinoma. AB - OBJECTIVES: To evaluate the performance of dynamic contrast enhanced (DCE) magnetic resonance (MR) imaging to assess the histological response after chemotherapy on bladder carcinoma. METHODS: From 2008 to 2010, 12 patients presenting localized urothelial carcinoma of the bladder were prospectively evaluated by DCE-MR imaging before and after two courses of cisplatin-based neoadjuvant chemotherapy. Size and thickness of tumours were measured. Relative enhancement at the arterial (rSI35s) and venous phases (rSI80s) of each tumour was obtained. Histological response was assessed and outcomes were recorded. RESULTS: Histological examination after neoadjuvant chemotherapy concluded as pathological complete response (pCR) for 6 out of 12 patients. Five patients developed recurrences (4/6 no pCR and 1/6 pCR). Significant differences, between before and after treatment, were found for patients with complete pathological response after chemotherapy for all MR quantitative values. Tumours decreased in size and thickness (both P=0.03). After treatment, rSI80s was significantly different between pCR and non-pCR patients (P=0.04) with a cut-off value of 40%. For this cut-off, sensitivity, specificity and accuracy were 83.33%. Similar recurrence free survivals were obtained if applying the MR cut-off value or the histopathological findings. CONCLUSION: Our results suggest that DCE-MR imaging may be a useful biomarker for patients with localized bladder carcinoma, improving selection before surgery. PMID- 25796427 TI - CEUS of the pancreas: Still research or the standard of care. AB - Contrast-enhanced ultrasonography (CEUS) improves the characterization of pancreatic masses. CEUS is in fact a safe and accurate imaging method to evaluate the vascularity of pancreatic lesions. CEUS should be performed when possible immediately after the ultrasound (US) detection of a pancreatic mass. CEUS is accurate in the characterization of ductal adenocarcinoma. The use of CEUS in studying pancreatic lesions found at US, especially in the same session of ultrasound examination, is therefore recommendable to promote faster diagnosis mainly of pancreatic ductal adenocarcinoma. PMID- 25796428 TI - Response to comment on "is addition of vasodilators to loop diuretics of value in the care of hospitalized acute heart failure patients? Real-world evidence from a retrospective analysis of a large United States hospital database". PMID- 25796429 TI - Bayesian model comparison in genetic association analysis: linear mixed modeling and SNP set testing. AB - We consider the problems of hypothesis testing and model comparison under a flexible Bayesian linear regression model whose formulation is closely connected with the linear mixed effect model and the parametric models for Single Nucleotide Polymorphism (SNP) set analysis in genetic association studies. We derive a class of analytic approximate Bayes factors and illustrate their connections with a variety of frequentist test statistics, including the Wald statistic and the variance component score statistic. Taking advantage of Bayesian model averaging and hierarchical modeling, we demonstrate some distinct advantages and flexibilities in the approaches utilizing the derived Bayes factors in the context of genetic association studies. We demonstrate our proposed methods using real or simulated numerical examples in applications of single SNP association testing, multi-locus fine-mapping and SNP set association testing. PMID- 25796430 TI - Semiparametric likelihood inference for left-truncated and right-censored data. AB - This paper proposes a new estimation procedure for the survival time distribution with left-truncated and right-censored data, where the distribution of the truncation time is known up to a finite-dimensional parameter vector. The paper expands on the Vardis multiplicative censoring model (Vardi, 1989. Multiplicative censoring, renewal processes, deconvolution and decreasing density: non parametric estimation. Biometrika 76: , 751-761), establishes the connection between the likelihood under a generalized multiplicative censoring model and that for left-truncated and right-censored survival time data, and derives an Expectation-Maximization algorithm for model estimation. A formal test for checking the truncation time distribution is constructed based on the semiparametric likelihood ratio test statistic. In particular, testing the stationarity assumption that the underlying truncation time is uniformly distributed is performed by embedding the null uniform truncation time distribution in a smooth alternative (Neyman, 1937. Smooth test for goodness of fit. Skandinavisk Aktuarietidskrift 20: , 150-199). Asymptotic properties of the proposed estimator are established. Simulations are performed to evaluate the finite-sample performance of the proposed methods. The methods and theories are illustrated by analyzing the Canadian Study of Health and Aging and the Channing House data, where the stationarity assumption with respect to disease incidence holds for the former but not the latter. PMID- 25796431 TI - Expression of Hepatitis C Virus Core and E2 antigenic recombinant proteins and their use for development of diagnostic assays. AB - BACKGROUND: Early diagnosis of HCV infection is based on detection of antibodies against HCV proteins using recombinant viral antigens. The present study was designed to select, clone and express the antigenic regions of Core and E2 genes from local HCV-3a genotype and to utilize the antigenic recombinant proteins (Core & E2) to develop highly sensitive, specific and economical diagnostic assays for detection of HCV infection. METHODS: The antigenic sites were determined within Core and E2 genes and were then cloned in pET-28a expression vector. The right orientation of the desired inserted fragments of Core and E2 were confirmed via sequencing prior to expression and were then transformed in BL21 (DE3) pLysS strains of E. coli and induced with 0.5mM Isopropyl-b-D thiogalactopyranoside (IPTG) for the production of antigenic recombinant proteins. The produced truncated antigens were then purified by Nickel affinity chromatography and were confirmed by western blotting, immunoblotting and enzyme linked immunosorbent assay (ELISA). RESULTS: The expressed Core and E2 recombinant antigens were used to develop immunoblotting assay for the detection of anti-HCV antibodies in sera. With immunoblotting, a total of 93-HCV infected sera and 35-HCV negative individuals were tested for the presence of anti-HCV antibodies to the Core and E2 antigens. Recombinant antigen showed 100% reactivity against HCV infected sera, with no cross reactivity against HCV negative sera. The immunoblot assay mixture of recombinant antigens (Core+E2) showed a strong reaction intensity in the test area (TA) as compared to the individual truncated Core and E2 recombinant antigens. In the in-house ELISA assay, mixed Core and E2 recombinant antigens showed 100% reactivity against a standardized panel of 150-HCV-positive sera and non reactivity against a standardized panel of 150 HCV-negative sera while also being non reactive to sera positive for other viral infections. The antigenic recombinant antigens also were tested for the 30 sera of known genotypes. The antigens did not detect antibodies to genotype-3a, but detected antibodies to all genotypes and did not discriminate them genotype wise. A panel of 175 of HCV-suspected serum samples was subjected to comparative analysis with our in-house ELISA assay and with commercial HCV screening assays. After subjecting the results to the formulas for determining the quality parameters, immunoblot assay had 100% sensitivity and specificity, while the ELISA assay had 100% sensitivity and 98.8% specificity as compared to commercially available assays. CONCLUSION: This study indicates that a mixture of Core and E2 antigens are potentially valuable antigens and there is the possibility of developing serological assays for monitoring HCV infection. PMID- 25796432 TI - Molecular epidemiology of enteric viruses and genotyping of rotavirus A, adenovirus and astrovirus among children under 5 years old in Gabon. AB - OBJECTIVES: This study aimed to determine the prevalence of enteric viruses causing gastroenteritis, and the circulating stains, in Gabonese children under five years old who visited health centers between March 2010 and June 2011. METHODS: Stool specimens were collected and sent for analysis to CIRMF (Centre International de Recherches Medicales de Franceville). Stools were screened for six enteric viruses (rotavirus, adenovirus, norovirus I and II, sapovirus, human astrovirus) by means of a multiplex real-time reverse transcription polymerase chain reaction, and Rotavirus A, Adenovirus and Astrovirus were genotyped. RESULTS: Among the 317 specimens analyzed, 193 (60.9%) were positive for at least one enteric virus. Rotavirus A (RVA) (27.1%) was the most frequently detected virus, followed by human Adenovirus (HAdV) (19.6%), Norovirus II (NoVs-II) (13.9%), Norovirus I (NoVs-I) (9.1%), Sapovirus (SaV) (9.5%) and human Astrovirus (HAstV) (6.3%). One-third of the 193 positive samples contained more than one virus. The most common Rotavirus A genotype was G6P[6]. Various HAdV serotypes were found. HAstV-1 was identified. CONCLUSIONS: These findings improve our knowledge of circulating enteric viruses in Gabon. The emergence of unusual G6P[6] strain of rotavirus A, predominant, suggested a particular epidemiological surveillance of circulating rotavirus strains during the introduction of vaccination in Gabon. PMID- 25796433 TI - Genomics in the land of regulatory science. AB - Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making. PMID- 25796434 TI - Postnatal high-protein diet improves learning and memory in premature rats via activation of mTOR signaling. AB - PURPOSE: The present study investigated whether a high-protein diet affects spatial learning and memory in premature rats via modulation of mammalian target of rapamycin (mTOR) signaling. METHODS: Pre- and full-term Sprague-Dawley pups were fed a normal (18% protein) or high-protein (30% protein) diet (HPD) for 6 or 8 weeks after weaning. Spatial learning and memory were tested in the Morris water maze at week 6 and 8. The activation of mTOR signaling pathway components was evaluated by western blotting. RESULTS: Spatial memory performance of premature rats consuming a normal and HPD was lower than that of full-term rats on the same diet at 6 weeks, and was associated with lower levels of ribosomal protein S6 kinase p70 subtype (p70S6K) and initiation factor 4E-binding protein 1 (4EBP1) phosphorylation in the hippocampus. Spatial memory was improved in 8-week old premature rats on an HPD as compared to those on a normal diet. Premature rats on an HPD had p70S6K and 4EBP1 phosphorylation levels in the hippocampus that were comparable to those of full-term rats on an HPD. CONCLUSION: Long-term consumption of a protein-rich diet can restore the impairment in learning and memory in pre-term rats via upregulation of mTOR/p70S6K signaling. PMID- 25796435 TI - Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus. AB - The long lasting antidepressant response seen following acute, i.v. ketamine administration in patients with treatment-resistant depression (TRD) is thought to result from enhanced synaptic plasticity in cortical and hippocampal circuits. Using extracellular field recordings in rat hippocampal slices, we show that a single dose of the non-selective NMDA receptor antagonist ketamine or CP-101,606, a selective antagonist of the NR2B subunit of the NMDA receptor, enhances hippocampal synaptic plasticity induced with high frequency stimulation (HFS) 24h after dosing - a time at which plasma concentrations of the drug are no longer detectable in the animal. These results indicate that acute inhibition of NMDA receptors containing the NR2B subunit can lead to long-lasting changes in hippocampal plasticity. PMID- 25796437 TI - Metabolic regulation of the ultradian oscillator Hes1 by reactive oxygen species. AB - Ultradian oscillators are cyclically expressed genes with a period of less than 24h, found in the major signalling pathways. The Notch effector hairy and enhancer of split Hes genes are ultradian oscillators. The physiological signals that synchronise and entrain Hes oscillators remain poorly understood. We investigated whether cellular metabolism modulates Hes1 cyclic expression. We demonstrated that, in mouse myoblasts (C2C12), Hes1 oscillation depends on reactive oxygen species (ROS), which are generated by the mitochondria electron transport chain and by NADPH oxidases NOXs. In vitro, the regulation of Hes1 by ROS occurs via the calcium-mediated signalling. The modulation of Hes1 by ROS was relevant in vivo, since perturbing ROS homeostasis was sufficient to alter Medaka (Oryzias latipes) somitogenesis, a process that is dependent on Hes1 ultradian oscillation during embryo development. Moreover, in a Medaka model for human microphthalmia with linear skin lesions syndrome, in which mitochondrial ROS homeostasis was impaired, we documented important somitogenesis defects and the deregulation of Hes homologues genes involved in somitogenesis. Notably, both molecular and developmental defects were rescued by antioxidant treatments. Our studies provide the first evidence of a coupling between cellular redox metabolism and an ultradian biological oscillator with important pathophysiological implication for somitogenesis. PMID- 25796438 TI - The regulatory roles of ROCK and MRCK kinases in the plasticity of cancer cell migration. AB - Metastatic cancer cells show great plasticity in their migratory mechanisms. In this review we briefly describe the signal transduction pathways associated with the ROCK and MRCK kinases and their roles in cancer cell migration and in its plasticity. With respect to therapeutic strategies targeting metastatic cancers, selectively blocking a single target, such as ROCK or MRCK, can induce alternate modes of cancer cell migration (i.e. plasticity) making the treatment ineffective. To address the problem of plasticity, we will discuss the strategy of simultaneous targeting of both ROCK and MRCK as an effective anti-metastatic therapeutics. PMID- 25796436 TI - Targeting transporters: promoting blood-brain barrier repair in response to oxidative stress injury. AB - The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., putative membrane transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25796439 TI - Selective targeting of FAK-Pyk2 axis by alpha-naphthoflavone abrogates doxorubicin resistance in breast cancer cells. AB - Despite an initial positive response, breast cancer cells inevitably acquire resistance to doxorubicin (Dox). Alpha-naphthoflavone (ANF) is a well-known chemopreventive agent; however, its anti-cancer properties have not been established. We examined the therapeutic efficacy of ANF in doxorubicin-resistant MCF-7 (MCF-7/Dox) breast cancer cells and investigated its underlying molecular mechanisms of action. MCF-7/Dox cells expressed constitutively active forms of the tyrosine kinases: focal adhesion kinase (FAK-Y397) and protein tyrosine kinase 2 beta (Pyk2- Y579/580) compared with parental MCF-7 cells. ANF significantly enhanced the sensitivity of MCF-7/Dox cells to Dox cytotoxicity in vitro and when co-administered in vivo. This ANF-mediated chemosensitization has dual mechanisms of action: (a) intracellular Dox retention via suppression of P glycoprotein pump activity, and (b) inhibition of clonogenic cell survival via de phosphorylation of FAK, Pyk2, and EGF-induced Akt in MCF-7/Dox cells and tumor xenografts. Because of its strong chemosensitization action, broad safety profile, and health benefits, ANF is an attractive anti-cancer drug with therapeutic implications to circumvent drug resistance in breast cancer patients. PMID- 25796440 TI - Mechanisms regulating glioma invasion. AB - Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM poses several unique challenges to currently available treatments for the disease. For example, GBM cells have the propensity to aggressively infiltrate/invade into the normal brain tissues and along the vascular tracks, which prevents complete resection of all malignant cells and limits the effect of localized radiotherapy while sparing normal tissue. Although anti-angiogenic treatment exerts anti-edematic effect in GBM, unfortunately, tumors progress with acquired increased invasiveness. Therefore, it is an important task to gain a deeper understanding of the intrinsic and post-treatment invasive phenotypes of GBM in hopes that the gained knowledge would lead to novel GBM treatments that are more effective and less toxic. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog GLI1, and microRNAs. The review will also discuss several approaches to cancer therapies potentially altering GBM invasiveness. PMID- 25796441 TI - Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects. AB - Garcinol is the main medicinal component of the dried fruit rind of Garcinia indica (G. indica), which has traditionally been extensively used to treat gastric ailments and skin irritation. In vitro studies of garcinol revealed its potential therapeutic effects, such as its anti-oxidative, anti-inflammatory and anti-cancer properties. Similarly, in vivo studies in animal models also demonstrated the efficacy of garcinol for the treatment of various inflammatory and cancerous conditions. Despite being well tolerated in preclinical studies, the toxicological profile of garcinol remains elusive. More importantly, systematic pharmacokinetics (PK) studies of garcinol to establish an appropriate route of administration and its effective concentration range under physiological conditions have not yet been performed. PK studies play an essential role in translating the preclinical findings of garcinol from cell line models and animal species to humans, thereby facilitating dose selection, the characterization of the therapeutic index, identification of a metabolic pathway, and the determination of garcinol's potency and tolerability. This paper reviews the current studies of garcinol as a potential anti-oxidant, anti-inflammatory and anti-cancer agent and highlights the importance of performing preclinical PK and toxicological studies on garcinol for its development pipeline. PMID- 25796442 TI - PLCepsilon knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor. AB - Phospholipase Cepsilon (PLCepsilon), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCepsilon functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCepsilon expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCepsilon depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCepsilon was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCepsilon mediated oncogenic effects in PCa. Our findings suggest that PLCepsilon is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa. PMID- 25796443 TI - Mathematical modelling of decline in follicle pool during female reproductive ageing. AB - The factors which govern the subtle links between follicle loss and mammalian female reproductive ageing remain unclear despite extensive studies undertaken to understand the critical physiological and biochemical mechanisms that underly the accelerated decline in follicle numbers in women older than 37 years. It is not certain whether there is a sole control by the ovary or whether other factors which affect ageing also intersect with the ovarian effect. There is convincing experimental evidence for an interplay of several processes that seem to influence the follicle loss-female reproductive ageing links, with specific hormones (follicle-stimulating hormone, anti-Mullerian hormone, dehydroepiandrosterone) noted to play important roles in follicular dynamics and ovarian ageing. In this work, we examine the subtle links between the rate of follicular decline with ageing and the role of hormones via a series of non autonomous equations. Simulation results based on the time evolution of the number of ovarian follicles and biochemical changes in the ovarian environment influenced by hormone levels is compared with empirical data based on follicle loss-reproductive ageing correlation studies. PMID- 25796444 TI - Gastric Malignant Peripheral Nerve Sheath Tumor: A Case Report. AB - Gastric malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas arising within a peripheral nerve. Gastric MPNSTs are extremely rare with only a few cases. We herein describe the case of a 48-year-old man with a gastric MPNST for the first time in Korea, which was diagnosed histopathologically after surgery. The patient underwent curative subtotal gastrectomy with D1+ lymph node dissection and Billroth-II reconstruction. The postoperative recovery was uneventful, and he has had no recurrence until now. The ideal adjuvant treatment protocol is yet to be decided due to the relatively limited number of cases of these tumors previously reported. PMID- 25796445 TI - Disappearance of immunoglobulins from persistent renal amyloid deposits following stem cell transplantation for heavy-and light-chain amyloidosis. AB - BACKGROUND: Immunoglobulin (Ig)-related amyloidosis is the most common type of systemic amyloidosis in the developed countries and involves the kidney in most cases. Clinical remission can be achieved with chemotherapy and/or autologous stem cell transplantation (ASCT). Previous case reports have showed persistence of renal amyloid mass in light-chain amyloidosis (AL) even in the setting of hematologic and renal response. METHODS: We report a novel finding in two cases of heavy- and light-chain amyloidosis (AHL) in which monoclonal Ig but not serum amyloid P (SAP), apolipoprotein E (ApoE) or amyloid bulk in the kidney regressed after successful therapy. RESULTS: In the pre-treatment renal biopsies, the amyloid deposits stained for one heavy and one light chains (IgG + lambda in one case and IgA + kappa in one case). Laser microdissection followed by mass spectrometry (LMD/MS) in both cases showed abundant spectra for Ig heavy and light chains, SAP and ApoE. Both patients achieved a hematologic response with disappearance of the monoclonal protein from serum and urine and normalization of serum-free light chain ratio, but renal response occurred in only one patient. Repeat kidney biopsies showed persistence of fibrillar amyloid deposits, but regression of Ig from the amyloid deposits based on immunofluorescence. LMD/MS on the repeat biopsy performed in one case also showed disappearance of Ig but not SAP or ApoE. CONCLUSIONS: Our finding suggests that effective chemotherapy and/or ASCT in some patients with AHL not only eliminates the circulating pathogenic monoclonal Ig but also the Ig component of amyloid deposits, which may translate into renal response. This, however, may not lead to regression of amyloid deposits themselves. The latter may require more time or addition of therapeutic agents that target amyloid-associated proteins such as SAP, which are not commercially available. PMID- 25796447 TI - Structural significance of galectin design: impairment of homodimer stability by linker insertion and partial reversion by ligand presence. AB - Lectins translate information encoded in glycan chains of cellular glycoconjugates into bioeffects. The topological presentation of contact sites for cognate sugar binding is a crucial factor toward this end. To dissect the significance of such phylogenetically conserved properties, the design and engineering of non-natural variants are attractive approaches. Here, a homodimeric human lectin, i.e. adhesion/growth-regulatory galectin-1, is converted into a tandem-repeat display by introducing the 33-amino-acid linker of another family member (i.e. galectin-8). The yield of variant was reduced by about a third. This protein had ~10-fold higher activity in hemagglutination. Nearly complete sequence determination by mass-spectrometric in-source decay and fingerprinting excluded the presence of any modifications. When (1)H-(15)N heteronuclear single-quantum coherence data on the (15)N-labeled variant and wild type protein were compared, changes in chemical shifts, signal intensities and resonance multiplicities revealed reduction of stability of interfacial contacts between the lectin domains and an increase in inter-domain flexibility. When both binding sites in the variant were loaded with ligand, association of the two carbohydrate recognition domains was enhanced, corroborated by gel filtration. Dynamic changes in the spatial presentation of the two lectin domains in the context of a tandem-repeat display can alter counterreceptor targeting relative to the fixed positions found in the proto-type galectin homodimer. PMID- 25796448 TI - Cytotoxicity and DNA interaction of brucine and strychnine-Two alkaloids of semen strychni. AB - The cytotoxicities of the two alkaloids strychnine and brucine from the seed of Strychnos nux-vomica and their interaction with DNA were investigated. A 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrasolium bromide (MTT) assay was used to examine the growth inhibitory effects of these alkaloids on Vero cells after 24, 48 and 72h of incubation. The cytotoxicities of strychnine and brucine were found to be time- and concentration-dependent. Strychnine was determined to be more toxic to Vero cells than brucine. At the same time, the interactions of strychnine and brucine with DNA were investigated using neutral red (NR) dye as a probe by UV-vis spectroscopy, fluorescence spectroscopy, and an examination of the ionic strength effect, and the effects of alkaloids on DNA melting were also examined. The results indicated that a DNA-brucine mixture but not a DNA strychnine mixture could be extracted from Vero cells after treatment with brucine and strychnine, respectively. Brucine competitively intercalated into the DNA double-helix causing fluorescence quenching of the DNA-NR system. UV absorption spectroscopy and the melting temperature (Tm) curve also provided evidence that brucine interacted with DNA through intercalation. Furthermore, the results of the ionic strength effect experiment suggested that electrostatic interactions between brucine and phosphate groups in the DNA backbone might also play an important role in the binding of brucine to DNA. PMID- 25796446 TI - Aerobic glycolysis tunes YAP/TAZ transcriptional activity. AB - Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro-tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth-promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro-tumorigenic activities such as YAP/TAZ. PMID- 25796449 TI - In vitro release of metformin from iron (III) cross-linked alginate-carboxymethyl cellulose hydrogel beads. AB - In the present study, sodium alginate (NaAlg)/sodium carboxymethyl cellulose (NaCMC) blend hydrogel beads were prepared in ferric chloride solution. The developed hydrogel beads exhibited pH sensitive for deliver Metformin hydrochloride (MH). Preparation conditions of the beads (ferric chloride solution) were significantly affected the encapsulation efficiency, swelling and in vitro release profiles of the beads. Swelling studies were accomplished in gastric and intestine stimuli atmosphere at 37 degrees C. The swelling studies reveal that the beads at pH 7.4 showed higher swelling properties compare to pH 1.2. Exterior morphology of beads was analyzed by scanning electron microscope. SEM indicates the surface of the beads is spherical with smooth surface and size of beads drastically reduced with increasing crosslinker concentration. The crosslinking reaction between NaAlg and NaCMC with ferric chloride was confirmed by FTIR analysis. XRD analysis indicates that MH drug molecularly dispersed in the polymer matrix. In vitro release studies of MH loaded beads showed higher release profiles at pH 7.4 compared to pH 1.2. The polymeric matrices followed slightly deviation with Fickian diffusion and fit for experimental co-relation (r(2)) values. PMID- 25796450 TI - Interaction of three new tetradentates Schiff bases containing N2O2 donor atoms with calf thymus DNA. AB - Interaction of 1,3-bis(2-hydroxy-benzylidene)-urea (H2L1), 1,3-bis(2-hydroxy-3 methoxy-benzylidene)-urea (H2L2) and 1,3-bis(2-hydroxy-3-methoxy-benzylidene) urea nickel(II) (NiL2) with calf-thymus DNA were investigated by UV-vis absorption, fluorescence emission and circular dichroism (CD) spectroscopy as well as cyclic voltammetry, viscosity measurements, molecular docking and molecular dynamics simulation. Binding constants were determined using UV-vis absorption and fluorescence spectra. The results indicated that studied Schiff bases bind to DNA in the intercalative mode in which the metal derivative is more effective than non metals. Their interaction trend is further determined by molecular dynamics (MD) simulation. MD results showed that Ni derivative reduces oligonucleotide intermolecular hydrogen bond and increases solvent accessible surface area more than other compounds. PMID- 25796451 TI - Microstructure, rheological and wound healing properties of collagen-based gel from cuttlefish skin. AB - Collagen-based biomaterials are of the utmost importance for tissue engineering and regenerative medicine. The aims of the present investigation were to evaluate structural and rheological properties of collagen-based gel obtained from cuttlefish skin, and to investigate its ability to enhance wound healing. Scanning electron microscopy of resulted gel showed a dense fibrillar microstructure with high interconnection network with a smaller pore size. In addition, the rheological characterization of collagen gel showed an excellent reversibility, when subjected to a temperature variation. Moreover, in the wound healing study, topical application of collagen based gel increased significantly the percentage of wound closure over a period of 12 days, when compared to the untreated and CICAFLORA((r))-treated groups. Wound-healing activity of collagen gel was confirmed by histopathology study. Thus, cuttlefish collagen based gel might be useful as a wound healing agent. PMID- 25796452 TI - Modified hydroxypropyl methyl cellulose: Efficient matrix for controlled release of 5-amino salicylic acid. AB - Hydroxypropyl methyl cellulose has been modified by grafting synthetic polyacrylamide chains [g-HPMC (M)] in presence of microwave irradiation, which has used as carrier for controlled release of 5-amino salicylic acid (5-ASA). The FTIR and UV-vis-NIR studies reveal the excellent compatibility between g-HPMC (M) and 5-ASA. Field emission scanning electron microscopy (FESEM) and UV-vis-NIR analyses suggest that physical interaction predominates between the drug and matrix. % equilibrium swelling ratio (% ESR) of g-HPMC (M) decreased with addition of salt solutions and follow the order: Na(+)>K(+)>Mg(2+)>Ca(2+)>Al(3+). The in vitro 5-ASA release studies indicate that g-HPMC (M) delivers the drug preferentially in colonic region in more sustained way than that of HPMC. The 5 ASA release follows first order kinetics and non-Fickian diffusion mechanism. These favorable features make the graft copolymer a potential matrix for colon specific delivery of 5-ASA. PMID- 25796453 TI - The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis. AB - HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 and OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression. PMID- 25796455 TI - An adaptive case management system to support integrated care services: Lessons learned from the NEXES project. AB - BACKGROUND: Extensive deployment and sustainability of integrated care services (ICS) constitute an unmet need to reduce the burden of chronic conditions. The European Union project NEXES (2008-2013) assessed the deployment of four ICS encompassing the spectrum of severity of chronic patients. OBJECTIVE: The current study aims to (i) describe the open source Adaptive Case Management (ACM) system (Linkcare(r)) developed to support the deployment of ICS at the level of healthcare district; (ii) to evaluate its performance; and, (iii) to identify key challenges for regional deployment of ICS. METHODS: We first defined a conceptual model for ICS management and execution composed of five main stages. We then specified an associated logical model considering the dynamic runtime of ACM. Finally, we implemented the four ICS as a physical model with an ICS editor to allow professionals (case managers) to play active roles in adapting the system to their needs. Instances of ICS were then run in Linkcare(r). Four ICS provided a framework for evaluating the system: Wellness and Rehabilitation (W&R) (number of patients enrolled in the study (n)=173); Enhanced Care (EC) in frail chronic patients to prevent hospital admissions, (n=848); Home Hospitalization and Early Discharge (HH/ED) (n=2314); and, Support to remote diagnosis (Support) (n=7793). The method for assessment of telemedicine applications (MAST) was used for iterative evaluation. RESULTS: Linkcare(r) supports ACM with shared-care plans across healthcare tiers and offers integration with provider-specific electronic health records. Linkcare(r) successfully contributed to the deployment of the four ICS: W&R facilitated long-term sustainability of training effects (p<0.01) and active life style (p<0.03); EC showed significant positive outcomes (p<0.05); HH/ED reduced on average 5 in-hospital days per patient with a 30-d re-admission rate of 10%; and, Support, enhanced community-based quality forced spirometry testing (p<0.01). Key challenges for regional deployment of personalized care were identified. CONCLUSIONS: Linkcare(r) provided the required functionalities to support integrated care adopting an ACM model, and it showed adaptive potential for its implementation in different health scenarios. The research generated strategies that contributed to face the challenges of the transition toward personalized medicine for chronic patients. PMID- 25796454 TI - Comparing hyperbolic, delay-amount sensitivity and present-bias models of delay discounting. AB - Delay discounting is a widely studied phenomenon due to its ubiquity in psychopathological disorders. Several methods are well established to quantify the extent to which a delayed commodity is devalued as a function of the delay to its receipt. The most frequently used method is to fit a hyperbolic function and use an index of the gradient of the function, k, or to calculate the area under the discounting curve. The manuscript examines the behavior of these quantification indices for three different datasets, as well as provides information about potential limitations in their use. The primary limitation examined is the lack of mechanistic specificity provided by either method. Alternative formulations that are thought to provide some mechanistic information are examined for the three separate datasets: two variants of a hyperboloid model (Rachlin, 1989, Judgment, decision and choice. New York: W.H. Freeman) and the quasi-hyperbolic model (Laibson, 1997, Q. J. Econ., 112, 443-477). Examination of the parameters of each formulation suggests that the parameters derived from the quasi-hyperbolic model allows groups and conditions within the three datasets to be reliably distinguished more readily than the hyperboloid models. However, use of the quasi-hyperbolic model is complex and its limitations might offset its ability to discriminate within the datasets. "This article is part of a Special Issue entitled: SQAB 2014". PMID- 25796456 TI - Extracting drug-drug interactions from literature using a rich feature-based linear kernel approach. AB - Identifying unknown drug interactions is of great benefit in the early detection of adverse drug reactions. Despite existence of several resources for drug-drug interaction (DDI) information, the wealth of such information is buried in a body of unstructured medical text which is growing exponentially. This calls for developing text mining techniques for identifying DDIs. The state-of-the-art DDI extraction methods use Support Vector Machines (SVMs) with non-linear composite kernels to explore diverse contexts in literature. While computationally less expensive, linear kernel-based systems have not achieved a comparable performance in DDI extraction tasks. In this work, we propose an efficient and scalable system using a linear kernel to identify DDI information. The proposed approach consists of two steps: identifying DDIs and assigning one of four different DDI types to the predicted drug pairs. We demonstrate that when equipped with a rich set of lexical and syntactic features, a linear SVM classifier is able to achieve a competitive performance in detecting DDIs. In addition, the one-against-one strategy proves vital for addressing an imbalance issue in DDI type classification. Applied to the DDIExtraction 2013 corpus, our system achieves an F1 score of 0.670, as compared to 0.651 and 0.609 reported by the top two participating teams in the DDIExtraction 2013 challenge, both based on non-linear kernel methods. PMID- 25796457 TI - Hodgkin's lymphoma: who needs consolidation treatment? PMID- 25796458 TI - Making sense of health estimates. PMID- 25796460 TI - Prof. Heinz F. R. Prechtl (1927-2014). PMID- 25796459 TI - Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem cell transplantation. METHODS: We did this randomised, double-blind, placebo controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1.8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. FINDINGS: Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0.57, 95% CI 0.40 0.81; p=0.0013). Median progression-free survival by independent review was 42.9 months (95% CI 30.4-42.9) for patients in the brentuximab vedotin group compared with 24.1 months (11.5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. INTERPRETATION: Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. FUNDING: Seattle Genetics and Takeda Pharmaceuticals International. PMID- 25796461 TI - Prof. Fukuyama Yukio (1928-2014). PMID- 25796462 TI - A disintegrin and metalloprotease-10 is correlated with disease activity and mediates monocyte migration and adhesion in rheumatoid arthritis. AB - A disintegrin and metalloproteases (ADAMs) are a family of proteins that have been reported to be involved in several inflammatory conditions. We examined the secretion of ADAM-10 in biological fluids from patients with rheumatoid arthritis (RA) and the role it plays in monocyte migration. ADAM-10 levels were measured using enzyme-linked immunosorbent assays and immunofluorescence. To examine the role of ADAM-10 in RA synovial fluids (SFs), we studied THP-1 (human acute monocyte leukemia cell line) and monocyte chemotaxis. To determine whether ADAM 10 plays a role in cell proliferation in the RA synovium, we assayed the proliferation of ADAM-10 small interfering RNA (siRNA)-transfected RA fibroblast like synoviocytes (FLSs). The ADAM-10 level in RA serum was significantly higher than that in normal serum and was correlated with a disease activity score of 28. ADAM-10-depleted RA SFs showed a decrease in THP-1 and monocyte migratory activity compared with that of sham-depleted controls. ADAM-10 siRNA inhibited monocyte adhesion to RA FLSs. Finally, blocking ADAM-10 secretion in RA FLSs resulted in decreased production of fractalkine/CX3CL1 and vascular endothelial cell growth factor. These data indicate that ADAM-10 plays a role in monocyte migration in RA and suggest that targeting ADAM-10 may provide a method of decreasing inflammation and potentially treating other inflammatory diseases. PMID- 25796463 TI - Atropine overdose mimicking anoxic encephalopathy during cardiopulmonary resuscitation. PMID- 25796464 TI - Fusion of 2 ribs as the cause of deep vein thrombosis in the arm. PMID- 25796466 TI - Burnout in medical residents in two health districts of the same city. PMID- 25796465 TI - Gender related differences in clinical profile and outcome of patients with heart failure. Results of the RICA Registry. AB - HISTORY AND OBJECTIVES: To analyze the differential clinical characteristics according to gender of patients with heart failure in terms of etiology, comorbidity, triggers, treatment, hospital stay and overall mortality at one year. PATIENTS AND METHOD: We employed data from the RICA registry, a multicenter prospective cohort of patients hospitalized in internal medicine departments for heart failure, with a follow-up of one year. We analyzed the differences between the gender in terms of the etiology of the heart disease, comorbidity, triggers, left ventricle ejection fraction, functional state, mental condition, treatment, length of stay and mortality at 1 year. RESULTS: A total of 1772 patients (47.2% men) were included. The women were older than the men (p<.001) and had a higher prevalence of hypertension, obesity, chronic kidney disease, atrial fibrillation and preserved left ventricle ejection fraction (p<.001). The men's medical history had a predominance of myocardial infarction, chronic obstructive pulmonary disease, peripheral arteriopathy (p<.001) and anemia (p=.02). In the women, a hypertensive etiology was predominant, followed by valvular. The main triggers were hypertension and atrial fibrillation. Treatment with beta-blockers, ACEIs and/or ARBs did not differ by sex. The women had poorer functional capacity (p<.001), according to the Barthel index. After adjusting for age and other prognostic factors, the mortality at one year was lower among the women (RR: 0.69; 95% CI 0.53-0.89; p=.004). CONCLUSIONS: HF in women occurs at a later age and with different comorbidities. The hypertensive and valvular etiology is predominant, with preserved left ventricle ejection fraction, and the age adjusted mortality is lower than in men. PMID- 25796467 TI - Abdominal pain and syndrome of inappropriate antidiuretic hormone secretion as clinical presentation of acute intermittent porphyria. AB - Acute intermittent porphyria (AIP) is a rare condition characterized by abdominal pain and a wide range of nonspecific symptoms. We report the case of a woman with abdominal pain and syndrome of inappropriate antidiuretic hormone secretion (SIADH) as clinical presentation of AIP. The diagnosis was achieved through the etiologic study of the SIADH. PMID- 25796469 TI - Senile cardiac amyloidosis in 68 years-old male with ascites. PMID- 25796468 TI - Acute oxalate nephropathy and chronic pancreatitis. PMID- 25796470 TI - Right atrial mass. PMID- 25796472 TI - Glucocorticoid functioning in male combat veterans with posttraumatic stress disorder and mild traumatic brain injury. PMID- 25796471 TI - Estrogen and extinction of fear memories: implications for posttraumatic stress disorder treatment. AB - Posttraumatic stress disorder (PTSD) is a psychiatric illness whose prevalence in women is more than twice the rate as men. Despite a burgeoning literature characterizing sex differences in PTSD incidence and its disproportionate burden on society, there is a dearth of literature describing biological mechanisms underlying these disparities. However, the recent identification of biomarkers of PTSD by translational neuroscientists offers a promising opportunity to explore sex interactions in PTSD phenotypes. A notable observation is that individuals with PTSD show deficits in their ability to inhibit conditioned fear responding after extinction training. Given that extinction procedures, via exposure-based cognitive behavioral therapy, make up one of the predominant modes of treatment in PTSD, there is a critical need for more research on sex interactions in this form of fear regulation. An emerging hypothesis is that fluctuating gonadal hormones, especially estrogen, in the menstrual cycle may play a critical role in fear extinction and, hence, PTSD vulnerability and symptom severity in women. The current review discusses how the study of putative activational effects of estrogen on fear extinction may be harnessed to advance the search for better treatments for PTSD in women. We conclude that estrogen treatment may be a putative pharmacologic adjunct in extinction-based therapies and should be tracked in the menstrual cycle during the course of PTSD treatment. PMID- 25796473 TI - Degradation of sulfonamide antibiotics by Microbacterium sp. strain BR1 - elucidating the downstream pathway. AB - Microbacterium sp. strain BR1 is among the first bacterial isolates which were proven to degrade sulfonamide antibiotics. The degradation is initiated by an ipso-substitution, initiating the decay of the molecule into sulfur dioxide, the substrate specific heterocyclic moiety as a stable metabolite and benzoquinone imine. The latter appears to be instantaneously reduced to p-aminophenol, as that in turn was detected as the first stable intermediate. This study investigated the downstream pathway of sulfonamide antibiotics by testing the strain's ability to degrade suspected intermediates of this pathway. While p-aminophenol was degraded, degradation products could not be identified. Benzoquinone was shown to be degraded to hydroquinone and hydroquinone in turn was shown to be degraded to 1,2,4-trihydroxybenzene. The latter is assumed to be the potential substrate for aromatic ring cleavage. However, no products from the degradation of 1,2,4 trihydroxybenzene could be identified. There are no signs of accumulation of intermediates causing oxidative stress, which makes Microbacterium sp. strain BR1 an interesting candidate for industrial waste water treatment. PMID- 25796474 TI - Trehalolipid biosurfactants from nonpathogenic Rhodococcus actinobacteria with diverse immunomodulatory activities. AB - Actinobacteria of the genus Rhodococcus produce trehalolipid biosurfactants with versatile biochemical properties and low toxicity. In recent years, these biosurfactants are increasingly studied as possible biomedical agents with expressed immunological activities. Applications of trehalolipids from Rhodococcus, predominantly cell-bound, in biomedicine are also attractive because their cost drawback could be less significant for high-value products. The review summarizes recent findings in immunomodulatory activities of trehalolipid biosurfactants from nonpathogenic Rhodococcus and related actinobacteria and compares their biomedical potential with well-known immunomodifying properties of trehalose dimycolates from Mycobacterium tuberculosis. Molecular mechanisms of trehalolipid interactions with immunocompetent cells are also discussed. PMID- 25796475 TI - Optimization of a quantitative PCR based method for plasmid copy number determination in human cell lines. AB - Transient gene expression (TGE) is an essential tool for the production of recombinant proteins, especially in early drug discovery and development phases of biopharmaceuticals. The need for fast production of sufficient recombinant protein for initial tests has dramatically increased with increase in the identification of potential novel pharmaceutical targets. One of the critical factors for transient transfection is plasmid copy number (PCN), for which we here provide an optimized qPCR based protocol. Thereby, we show the loss of PCN during a typical batch process of HEK293 cells after transfection from 606,000 to 4560 copies per cell within 5 days. Finally two novel human kidney cell lines, RS and RPTEC/TERT1 were compared to HEK293 and proved competitive in terms of PCN and specific productivity. In conclusion, since trafficking and degradation of plasmid DNA is not fully understood yet, improved methods for analysis of PCN may contribute to design specific and more stable plasmids for high yield transient gene expression systems. PMID- 25796477 TI - The regulation of Delta11-desaturase gene expression in the pheromone gland of Mamestra brassicae (Lepidoptera; Noctuidae) during pheromonogenesis. AB - Cabbage moth (Mamestra brassicae) females produce sex pheromones to attract conspecific males. In our M. brassicae colony, the pheromone blend is composed of Z11-hexadecenyl acetate (Z11-16Ac) and hexadecyl acetate (16Ac) in a 93:7 ratio. A fatty acyl Delta11-desaturase is involved in the production of the main pheromone component. The release of Pheromone Biosynthesis Activating Neuropeptide (PBAN) regulates the pheromone production in the pheromone gland (PG). We cloned a cDNA encoding the MambrDelta11-desaturase and analyzed its expression profile over time in M. brassicae tissues. Transcript levels of the Delta11-desaturase in larvae, pupal PGs, fat body, brain and muscle tissues were <0.1% of that in female PGs, whereas expression in male genitalia was 2%. In the PGs of virgin females the expression level increased continuously from eclosion to the end of the 1st day when it reached a plateau without further significant fluctuation up to the 8th day. In contrast, we recorded a characteristic daily rhythmicity in pheromone production with a maximum around 200 ng Z11-16Ac/PG. In some experiments, females were decapitated to prevent PBAN release and thereby inhibit pheromone production, which remarkably increased after treatment with Mambr-Pheromonotropin. Further experiments revealed that mating resulted in a significant suppression of pheromone production. However, expression of the Delta11-desaturase was not affected by any of these interventions, suggesting that it's not regulated by PBAN. Fluorescent microscopy was used to study the potential role of lipid droplets during pheromone production, however, no lipid droplets were identified indicating that pheromonogenesis is regulated via de novo fatty acid synthesis. PMID- 25796478 TI - Growth hormone production and role in the reproductive system of female chicken. AB - The expression and role of growth hormone (GH) in the reproductive system of mammals is rather well established. In birds the limited information thus far available suggests that GH is an endocrine or paracrine/autocrine regulator of ovarian and oviductal functions too. GH and its receptors are expressed in all compartments of the ovary and oviduct and change accordingly to physiological state. The intra-ovarian role of GH likely includes the regulation of steroidogenesis, cell proliferation and apoptosis, the modulation of LH action and the synthesis of IGFs (insulin-like growth factors). In the oviduct, GH is also involved in the regulation of oviduct-specific protein expression. The present study provides a review of current knowledge on the presence and action of GH in the female reproduction, in which it is likely that act in endocrine, autocrine or paracrine mechanisms. PMID- 25796476 TI - Is sleep quality related to cognition in individuals with heart failure? AB - OBJECTIVE: To examine how self-reported sleep quality and daytime symptoms are associated with selected domains of cognitive function among individuals with heart failure (HF). BACKGROUND: HF patients suffer from poor sleep quality and cognitive decline. The relationship between sleep and cognition has not been well documented among individuals with HF. METHODS: In this descriptive, cross sectional study, 68 individuals with HF (male: 63%, mean age = 72 years, SD = 11) completed sleep questionnaires and a neuropsychological battery. RESULTS: Participant had mean Pittsburgh Sleep Quality Index score of 5.04 (SD = 2.8). Regression analyses demonstrated neither sleep quality or excessive daytime sleepiness (EDS) were related to cognitive function, but daytime dysfunction was related to lower letter fluency and attention index. CONCLUSION: Contrary to some earlier reports, subjective sleep and EDS in this group of individuals was not associated with cognitive decline. PMID- 25796479 TI - An investigation of binding ability of Ixodes persulcatus Schulze Salp15 with Lyme disease spirochetes. AB - Salp15, a 15-kDa tick salivary gland protein, has several suppressive modes of activity against host immunity and plays a critical role in the transmission of Lyme disease spirochetes in Ixodes scapularis and Ixodes ricinus, major vectors of Lyme disease in North America and Western Europe. Salp15 adheres to Borrelia burgdorferi and specifically interacts with its outer surface protein C (OspC), protecting the spirochete from antibody-mediated cytotoxicity and facilitating infection in the mice. Recently, we identified two Salp15 homologues, IperSalp15 1 and IperSalp15-2, in Ixodes persulcatus, a vector for Lyme disease in Japan. Here we describe the function of IperSalp15 in the transmission of Lyme borreliosis. To investigate the function of IperSalp15, recombinant IperSalp15-1 and IperSalp15-2 were prepared in bacterial and insect cells. Both were identified in the sera of tick-immunized hamsters, indicating that these are secretory proteins in exposed host animals. Solid-phase overlay and indirect fluorescence assays showed that IperSalp15 binds to OspC from B. burgdorferi, Borrelia garinii, and Borrelia afzelii. Importantly, this binding likely protected the spirochete from antibody-mediated cytotoxicity in vitro. In addition, IperSalp15 tended to facilitate infection in mice. Thus, further characterization of tick molecules, including IperSalp15, could lead to the development of new strategies to prevent the transmission of tick-borne diseases. PMID- 25796480 TI - Hepatic encephalopathy treatment and its effect on driving abilities: A continental divide. PMID- 25796481 TI - An autosomal dominant form of non-cirrhotic portal hypertension. PMID- 25796482 TI - Preservation injury of the distal extrahepatic bile duct of donor livers is representative for injury of the intrahepatic bile ducts. PMID- 25796483 TI - [Pain after sternotomy - review]. AB - BACKGROUND AND OBJECTIVE: Adequate analgesia after sternotomy reduces postoperative adverse events. There are various methods of treating pain after heart surgery, such as infiltration with a local anesthetic, nerve block, opioids, non-steroidal anti-inflammatory drugs, alpha-adrenergic agents, intrathecal and epidural techniques, and multimodal analgesia. CONTENT: A review of the epidemiology, pathophysiology, prevention and treatment of pain after sternotomy. We also discuss the various analgesic therapeutic modalities, emphasizing advantages and disadvantages of each technique. CONCLUSIONS: Heart surgery is performed mainly via medium sternotomy, which results in significant postoperative pain and a non-negligible incidence of chronic pain. Effective pain control improves patient satisfaction and clinical outcomes. There is no clearly superior technique. It is believed that a combined multimodal analgesic regimen (using different techniques) is the best approach for treating postoperative pain, maximizing analgesia and reducing side effects. PMID- 25796484 TI - iMem-Seq: A Multi-label Learning Classifier for Predicting Membrane Proteins Types. AB - Predicting membrane protein type is a challenging problem, particularly when the query proteins may simultaneously have two or more different types. Most of the existing methods can only be used to deal with the single-label proteins. Actually, multiple-label proteins should not be ignored because they usually bear some special functions worthy of in-depth studies. By introducing the "multi labeled learning" and hybridizing evolution information through Grey-PSSM, a novel predictor called iMem-Seq is developed that can be used to deal with the systems containing both single and multiple types of membrane proteins. As a demonstration, the jackknife cross-validation was performed with iMem-Seq on a benchmark dataset of membrane proteins classified into the eight types, where some proteins belong to two or there types, but none has >=25% pairwise sequence identity to any other in a same subset. It was demonstrated via the rigorous cross-validations that the new predictor remarkably outperformed all its counterparts. As a user-friendly web-server, iMem-Seq is freely accessible to the public at the website http://www.jci-bioinfo.cn/iMem-Seq . PMID- 25796486 TI - Content Delivery of Lipidic Nanovesicles in Electropermeabilized Cells. AB - Lipidic nanovesicles (the so-called liposomes) were among the one of the earliest forms of nanovectors. One of their limits was our lack of knowledge on the delivery pathway of their content to the target cell cytoplasm. In most models, it appears to be linked to endocytotic transfer. Their direct content delivery can be enhanced by electric field pulses applied to a cell liposomes mixture. The optimal form for liposomes was shown to be large unilamellar vesicles (LUV). The present communication describes an optimization to enhance the delivery. When lipidic nanovesicles (LUVs) are electrostatically brought in contact with electropermeabilized cells by a salt bridge, their content is delivered into the cytoplasm of electropermeabilized cells. The PEF parameters are selected to affect specifically the cells leaving the vesicles unaffected. Cell viability is positively affected by the treatment. High-field short pulses are more efficient than low-field long pulses. A homogeneous cytoplasm labeling is observed under digitized videomicroscopy. The process is a content mixing, not an endocytotic pathway. The lipidic composition of the LUV should contain charged lipids (phosphatidylserine), fusion promoting lipids (phosphatidylethanolamine), and cholesterol. PMID- 25796485 TI - Picosecond and Terahertz Perturbation of Interfacial Water and Electropermeabilization of Biological Membranes. AB - Non-thermal probing and stimulation with subnanosecond electric pulses and terahertz electromagnetic radiation may lead to new, minimally invasive diagnostic and therapeutic procedures and to methods for remote monitoring and analysis of biological systems, including plants, animals, and humans. To effectively engineer these still-emerging tools, we need an understanding of the biophysical mechanisms underlying the responses that have been reported to these novel stimuli. We show here that subnanosecond (<=500 ps) electric pulses induce action potentials in neurons and cause calcium transients in neuroblastoma-glioma hybrid cells, and we report complementary molecular dynamics simulations of phospholipid bilayers in electric fields in which membrane permeabilization occurs in less than 1 ns. Water dipoles in the interior of these model membranes respond in less than 1 ps to permeabilizing electric potentials by aligning in the direction of the field, and they re-orient at terahertz frequencies to field reversals. The mechanism for subnanosecond lipid electropore formation is similar to that observed on longer time scales-energy-minimizing intrusions of interfacial water into the membrane interior and subsequent reorganization of the bilayer into hydrophilic, conductive structures. PMID- 25796487 TI - Solid-binding peptides: smart tools for nanobiotechnology. AB - Over the past decade, solid-binding peptides (SBPs) have been used increasingly as molecular building blocks in nanobiotechnology. These peptides show selectivity and bind with high affinity to the surfaces of a diverse range of solid materials including metals, metal oxides, metal compounds, magnetic materials, semiconductors, carbon materials, polymers, and minerals. They can direct the assembly and functionalisation of materials, and have the ability to mediate the synthesis and construction of nanoparticles and complex nanostructures. As the availability of newly synthesised nanomaterials expands rapidly, so too do the potential applications for SBPs. PMID- 25796489 TI - Increased palatable food intake and response to food cues in intrauterine growth restricted rats are related to tyrosine hydroxylase content in the orbitofrontal cortex and nucleus accumbens. AB - Intrauterine growth restriction (IUGR) is associated with altered food preferences, which may contribute to increased risk of obesity. We evaluated the effects of IUGR on attention to a palatable food cue, as well as tyrosine hydroxylase (TH) content in the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in response to sweet food intake. From day 10 of gestation and through lactation, Sprague-Dawley rats received either an ad libitum (Adlib) or a 50% food-restricted (FR) diet. At birth, pups were cross-fostered, generating four groups (gestation/lactation): Adlib/Adlib (control), FR/Adlib (intrauterine growth-restricted), Adlib/FR, and FR/FR. Adult attention to palatable food cues was measured using the Attentional Set-Shifting Task (ASST), which uses a sweet pellet as reward. TH content in the OFC and NAcc was measured at baseline and in response to palatable food intake. At 90 days of age, FR/Adlib males ate more sweet food than controls, without differences in females. However, when compared to Controls, FR/Adlib females needed fewer trials to reach criterion in the ASST (p=0.04) and exhibited increased TH content in the OFC in response to sweet food (p=0.03). In the NAcc, there was a differential response of TH content after sweet food intake in both FR/Adlib males and females (p<0.05). Fetal programming of adult food preferences involves the central response to palatable food cues and intake, affecting dopamine release in select structures of the brain reward system. PMID- 25796488 TI - Multiscale assembly for tissue engineering and regenerative medicine. AB - Our understanding of cell biology and its integration with materials science has led to technological innovations in the bioengineering of tissue-mimicking grafts that can be utilized in clinical and pharmaceutical applications. Bioengineering of native-like multiscale building blocks provides refined control over the cellular microenvironment, thus enabling functional tissues. In this review, we focus on assembling building blocks from the biomolecular level to the millimeter scale. We also provide an overview of techniques for assembling molecules, cells, spheroids, and microgels and achieving bottom-up tissue engineering. Additionally, we discuss driving mechanisms for self- and guided assembly to create micro-to-macro scale tissue structures. PMID- 25796490 TI - Endogenous testosterone levels are associated with neural activity in men with schizophrenia during facial emotion processing. AB - Growing evidence suggests that testosterone may play a role in the pathophysiology of schizophrenia given that testosterone has been linked to cognition and negative symptoms in schizophrenia. Here, we determine the extent to which serum testosterone levels are related to neural activity in affective processing circuitry in men with schizophrenia. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as 32 healthy controls and 26 people with schizophrenia performed a facial emotion identification task. Whole brain analyses were performed to determine regions of differential activity between groups during processing of angry versus non threatening faces. A follow-up ROI analysis using a regression model in a subset of 16 healthy men and 16 men with schizophrenia was used to determine the extent to which serum testosterone levels were related to neural activity. Healthy controls displayed significantly greater activation than people with schizophrenia in the left inferior frontal gyrus (IFG). There was no significant difference in circulating testosterone levels between healthy men and men with schizophrenia. Regression analyses between activation in the IFG and circulating testosterone levels revealed a significant positive correlation in men with schizophrenia (r=.63, p=.01) and no significant relationship in healthy men. This study provides the first evidence that circulating serum testosterone levels are related to IFG activation during emotion face processing in men with schizophrenia but not in healthy men, which suggests that testosterone levels modulate neural processes relevant to facial emotion processing that may interfere with social functioning in men with schizophrenia. PMID- 25796492 TI - siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery. AB - As the population ages, brain pathologies such as neurodegenerative diseases and brain cancer increase their incidence, being the need to find successful treatments of upmost importance. Drug delivery to the central nervous system (CNS) is required in order to reach diseases causes and treat them. However, biological barriers, mainly blood-brain barrier (BBB), are the key obstacles that prevent the effectiveness of possible treatments due to their ability to strongly limit the perfusion of compounds into the brain. Over the past decades, new approaches towards overcoming BBB and its efflux transporters had been proposed. One of these approaches here reviewed is through small interfering RNA (siRNA), which is capable to specifically target one gene and silence it in a post transcriptional way. There are different possible functional proteins at the BBB, as the ones responsible for transport or just for its tightness, which could be a siRNA target. As important as the effective silence is the way to delivery siRNA to its anatomical site of action. This is where nanotechnology-based systems may help, by protecting siRNA circulation and providing cell/tissue-targeting and intracellular siRNA delivery. After an initial overview on incidence of brain diseases and basic features of the CNS, BBB and its efflux pumps, this review focuses on recent strategies to reach brain based on siRNA, and how to specifically target these approaches in order to treat brain diseases. PMID- 25796491 TI - Associations between the social organization of communities and psychiatric disorders in rural Asia. AB - PURPOSE: We provide rare evidence of factors producing psychiatric variation in a general population sample from rural South Asia. The setting is particularly useful for demonstrating that variations in the social organization of communities, often difficult to observe in rich countries, are associated with important variations in mental health. METHODS: Clinically validated survey measures are used to document variation in psychiatric disorders among 401 adults. This sample is chosen from a systematic sample of the general population of rural Nepal, in a community-level-controlled comparison design. Multilevel logistic regression is used to estimate multivariate models of the association between community-level nonfamily social organization and individual-level psychiatric disorders. RESULTS: Schools, markets, health services and social support groups each substantially reduce the odds of depression, post-traumatic stress disorder (PTSD), intermittent explosive disorder and anxiety disorders. Associations between schools, health services and social support groups and depression are statistically significant and independent of each other. The association between access to markets and PTSD is statistically significant and independent of other social organization and support groups. CONCLUSIONS: Community integration of some nonfamily social organizations promotes mental health in ways that may go unobserved in settings with many such organizations. More research on the mechanisms producing these associations is likely to reveal potential avenues for public policy and programs to improve mental health in the general population. PMID- 25796493 TI - Pattern of rectal cancer recurrence after curative surgery. AB - PURPOSE: After curative rectal cancer surgery, local recurrences manifest in 2.4 10% and distant metastases in 20-50% of patients. The effectiveness of different surveillance regimens is not well established. We evaluated the pattern of recurrence and the utility of different surveillance instruments. Risk factors for recurrence were also recorded. METHODS: This retrospective study comprises 580 consecutive rectal cancer patients operated on at Helsinki University Central Hospital, Finland, during 2005-2011. Data were collected from patient records. After exclusions, 481 patients treated with curative intent remained. Patients were followed up according to an intensive surveillance program. RESULTS: Rectal cancer recurrence was observed in 124 patients (25.8%). Local recurrence manifested in 40 patients (8.3%) and distant metastases in 112 patients (23.3%). Recurrences were observed a median of 1.3 years after surgery. Twelve patients had to be followed up to find one local recurrence and four patients to find one distant metastasis. Recurrences detected during regular follow-up visits were discovered on average earlier than those detected in additional visits arranged because of patient symptoms (p = 0.023 for local recurrence, p = 0.001 for distant metastases). All surveillance instruments were similarly useful in finding recurrence. Curative treatment was possible in 51 (41.1%) of 124 patients with disease recurrence. Follow-up led to a 10.0% chance of detecting recurrence that could be treated with curative intent. CONCLUSIONS: Rectal cancer recurrences are detected earlier within a surveillance program than by symptoms alone. The most intensive follow-up should be focused on patients with known risk factors for recurrence. PMID- 25796494 TI - Osteomyelitis as a complication of a pilonidal sinus. PMID- 25796495 TI - Lethal 5-fluorouracil toxicity in a colorectal patient with severe dihydropyrimidine dehydrogenase (DPD) deficiency. PMID- 25796496 TI - On the correlation between variance in individual susceptibilities and infection prevalence in populations. AB - The hypothesis that infection prevalence in a population correlates negatively with variance in the susceptibility of its individuals has support from experimental, field, and theoretical studies. However, its generality has never been formally demonstrated. Here we formulate an endemic SIS model with individual susceptibility distributed according to a discrete or continuous probability function to assess the generality of such hypothesis. We introduce an ordering among susceptibility distributions with the same mean, analogous to that considered in Katriel (J Math Biol 65:237-262, 2012) to order the attack rates in an epidemic SIR model with heterogeneity. It turns out that if one distribution dominates another in this order then it has greater variance and corresponds to a lower infection prevalence for R0 varying in a suitable maximal interval of the form ]1, R0*]. We show that in both the discrete and continuous frameworks R0* can be finite, so that the expected correlation among variance and prevalence does not always hold. For discrete distributions this fact is demonstrated analytically, and the proof introduces a constructive procedure to find ordered pairs for which R0* is arbitrarily close to 1. For continuous distributions our conclusion is based on numerical studies with the beta distribution. Finally, we present explicit partial orderings among discrete susceptibility distributions and among symmetric beta distributions which guarantee that R0* = +infinity. PMID- 25796497 TI - The use of IMRT in Germany. AB - BACKGROUND: Intensity modulated radiotherapy (IMRT) is frequently used, but there are no data about current frequency regarding specific tumor sites and equipment used for quality assurance (QA). MATERIALS AND METHODS: An online survey about IMRT was executed from April to October 2014 by the collaborative IMRT working group (AK IMRT) of the German Association of Medical Physicists (DGMP). RESULTS: A total of 23 German institutions took part in the survey. Most reports came from users working with Elekta, Varian, and Siemens treatment machines, but also from TomoTherapy and BrainLab. Most frequent IMRT technology was volumetric modulated arc therapy (58.37 %: VMAT/"rapid arc"), followed by step-and-shoot IMRT (14.66 %), dynamic MLC (dMLC: 14.53 %), TomoTherapy (9.25 %), and 3.2 % other techniques. Different commercial hard- and software solutions are available for QA, whereas many institutes still develop their own phantoms. Data of 26,779 patients were included in the survey; 44 % were treated using IMRT techniques. IMRT was most frequently used for anal cancer, (whole) craniospinal irradiation, head and neck cancer, prostate cancer, other tumors in the pelvic region, gynecological tumors (except for breast cancer), and brain tumors. DISCUSSION: An estimated 10 % of all patients treated in 2014 with radiation in Germany were included in the survey. It is representative for the members of the AK IMRT. CONCLUSION: IMRT may be on the way to replace other treatment techniques. However, many scientific questions are still open. In particular, it is unclear when the IMRT technique should not be used. PMID- 25796498 TI - Detection of Pathogenic and Non-pathogenic Bacteria in Drinking Water and Associated Biofilms on the Crow Reservation, Montana, USA. AB - Private residences in rural areas with water systems that are not adequately regulated, monitored, and updated could have drinking water that poses a health risk. To investigate water quality on the Crow Reservation in Montana, water and biofilm samples were collected from 57 public buildings and private residences served by either treated municipal or individual groundwater well systems. Bacteriological quality was assessed including detection of fecal coliform bacteria and heterotrophic plate count (HPC) as well as three potentially pathogenic bacterial genera, Mycobacterium, Legionella, and Helicobacter. All three target genera were detected in drinking water systems on the Crow Reservation. Species detected included the opportunistic and frank pathogens Mycobacterium avium, Mycobacterium gordonae, Mycobacterium flavescens, Legionella pneumophila, and Helicobacter pylori. Additionally, there was an association between HPC bacteria and the presence of Mycobacterium and Legionella but not the presence of Helicobacter. This research has shown that groundwater and municipal drinking water systems on the Crow Reservation can harbor potential bacterial pathogens. PMID- 25796499 TI - Socio-demographic Characteristics of Individuals with History of Crack Cocaine Use in the US General Population. AB - This study explores socio-demographic characteristics of individuals with history of crack cocaine use. Data from the 29th Round of General Social Survey was used. Respondents with history of crack cocaine use were compared to respondents without such history. T test was applied to identify differences between groups. Approximately 6 % of respondents reported lifetime history of crack cocaine use. Groups with and without history of crack cocaine use differed significantly in gender, marital status, education, income distribution, employment, health perception, family and financial satisfaction, criminal history, happiness, sexual history, history of injection drug use, and HIV testing. There were no significant differences for race. The study provides insights that could improve identification and prevention of substance use disorders. PMID- 25796500 TI - Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma. AB - Mitofusin-2 (MFN2) is a mitochondrial protein associated with mitochondrial fusion process. It was initially identified as a hyperplasia suppressor and implicated in Charcot-Marie-Tooth disease. Recent studies showed that MFN2 played important roles in the development of multiple tumors. Here we examined MFN2 expression in 30 lung adenocarcinoma samples and revealed that the expression of MFN2 was significantly higher in lung adenocarcinoma tissues as compared to adjacent normal tissues. We then investigated the impact of MFN2 knockdown on A549 human lung adenocarcinoma cells and showed that cell proliferation, cell cycle and invasion behavior were all deregulated by MFN2 knockdown. And deregulation of cell cycle pathway after MFN2 knockdown was confirmed by microarray analysis. Furthermore, microarray analysis also revealed that different oncogenes such as RAP1A, RALB and ITGA2 were oppositely regulated by MFN2, which provided molecular clues for the paradoxical functions of MFN2 in tumor development. Taken together, our study unraveled the tumor-promoting functions of MFN2 in lung adenocarcinoma and implicated that the role of MFN2 in cancer development might be more complicated than expected and should be explored in detail in the future. PMID- 25796501 TI - Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma. AB - Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is a factor implicating in vascular differentiation and angiogenesis. Several lines of evidence indicate that aberrant expression of AGGF1 is associated with tumor initiation and progression. The aim of this study was to investigate the expression and prognostic value of AGGF1 in hepatocellular carcinoma (HCC), as well as its relationship with clinicopathological factors and tumor angiogenesis. Immunohistochemistry was performed to evaluate the expression of AGGF1 in HCC and paracarcinomatous tissues collected from 70 patients. Vascular endothelial growth factor (VEGF) and CD34 expression levels were examined in the 70 HCC tissues. Prognostic significance of tumoral AGGF1 expression was determined. Notably, AGGF1 expression was significantly higher in HCC than in surrounding non-tumor tissues (65.7 vs. 25.7 %; P < 0.001). AGGF1 expression was significantly correlated with tumoral VEGF expression and CD34-positive microvessel density. Moreover, AGGF1 expression was significantly associated with tumor size, tumor capsule, vascular invasion, Edmondson grade, alpha-fetoprotein level, and TNM stage. Kaplan-Meier survival analysis showed that high AGGF1 was correlated with reduced overall survival (OS) rate (P = 0.001) and disease-free survival (DFS) rate (P < 0.001). Multivariate analysis identified AGGF1 as an independent poor prognostic factor of OS and DFS in HCC patients (P = 0.043 and P = 0.010, respectively). Taken together, increased AGGF1 expression is associated with tumor angiogenesis and serves as an independent unfavorable prognostic factor for OS and DFS in HCC. AGGF1 may represent a potential therapeutic target for HCC. PMID- 25796502 TI - Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study. AB - The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >=2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined. PMID- 25796503 TI - Switch maintenance treatment with oral vinorelbine and bevacizumab after induction chemotherapy with cisplatin, gemcitabine and bevacizumab in patients with advanced non-squamous non-small cell lung cancer: a phase II study. AB - The present study evaluated the efficacy and safety of cisplatin (Cis), gemcitabine (Gem) and bevacizumab (Bev), followed by maintenance treatment with Bev and oral vinorelbine (Vnb), in patients with advanced non-squamous non-small cell lung cancer (NSCLC). The patients were administered six cycles of induction chemotherapy consisting of intravenously (i.v.) Cis 70 mg/m(2) on day 1 plus i.v. Gem 1000 mg/m(2) on days 1 and 8, plus i.v. Bev 7.5 mg/kg on day 1, every 3 weeks. Patients who did not experience tumor progression remained on maintenance treatment with Bev combined with oral Vnb 60 mg/m(2) weekly until occurrence of disease progression or unacceptable toxicity. Thirty-seven patients were enrolled: The median age was 67 years (range 38-81); 22 patients were male, and 30 patients had stage IV tumors. The response rate was 32.4 % (95 % CI 18-49.7). The 9-month disease-control rate was 45.9 %. The median PFS was 8.4 months (95 % CI 4.4-10.7), and the median OS was 18.1 months (95 % CI 15.3-20.8 months). Grade 3-4 neutropenia occurred in 6 (16.2 %) patients and grade 3-4 thrombocytopenia in four (10.8 %) patients during induction chemotherapy. Bev- or Vnb-associated toxicities were mild. Switch maintenance treatment with Bev and oral Vnb after first-line Cis, Gem and Bev is feasible in patients with non-squamous NSCLC and may achieve encouraging results in terms of PFS and OS. PMID- 25796504 TI - Cisplatin-mediated c-myc overexpression and cytochrome c (cyt c) release result in the up-regulation of the death receptors DR4 and DR5 and the activation of caspase 3 and caspase 9, likely responsible for the TRAIL-sensitizing effect of cisplatin. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses multidrug resistance (MDR) and induces apoptosis in MDR gastric carcinoma cells. In our previous study, cisplatin proved to be a sensitizing agent for TRAIL. To study the synergistic effects of cisplatin and TRAIL, we investigated the mechanism by which TRAIL reverses multidrug resistance, the role of c-myc in modulating the death receptors DR4 and DR5 and the relationship between cisplatin and cytochrome c (cyt c) release in SGC7901/VCR and SGC7901/DDP cells. We found that after treatment with TRAIL, the DNA-PKcs/Akt/GSK-3beta pathway, which is positively correlated with the levels of MDR1 and MRP1, was significantly inhibited and that this tendency can be abolished by Z-DEVD-FMK (a specific caspase 3 inhibitor). We also found that suppression of c-myc by siRNA reduced the expression of DR4 and DR5 and that transfection with a pAVV-c-myc expression vector increased the expression of DR4 and DR5. Moreover, cisplatin increased the expression of c-myc in the presence of TRAIL, and there is a clear increase in cyt c release from mitochondria with the increasing concentrations of cisplatin. Meanwhile, the intrinsic death receptor pathway of caspase 9, as well as the common intrinsic and extrinsic downstream target, caspase 3, was potently activated by the release of cyt c. Together, we conclude that in TRAIL-treated MDR gastric carcinoma cells, cisplatin induces the death receptors DR4 and DR5 through the up-regulation of c-myc and strengthens the activation of caspases via promoting the release of cyt c. These effects would then be responsible for the TRAIL sensitization effect of cisplatin. PMID- 25796506 TI - Habituation of LG-mediated tailflip in the crayfish. AB - Crayfish escape from threatening stimuli by tailflipping. If a stimulus is applied to the rear, crayfish escape up and forwards in a summersault maneuver that is mediated by the activation of lateral giant (LG) interneurons. The occurrence probability of LG-mediated tailflip, however, diminishes and habituates if a stimulus is repeatedly applied. Since crayfish have a relatively simple CNS with many identifiable neurons, crayfish represent a good animal to analyze the cellular basis of habituation. A reduction in the amplitude of the EPSP in the LGs, caused by direct chemical synaptic connection from sensory afferents by repetitive stimulations, is essential to bring about an inactivation of the LGs. The spike response of the LGs recovers within several minutes of habituation, but the LGs subsequently fail to spike when an additional stimulus is applied after specific periods following habituation. These results indicate that a decline in synaptic efficacy from the mechanosensory afferents recovers readily after a short delay, but then the excitability of the LGs themselves decreases. Furthermore, the processes underlying habituation are modulated depending on a social status. When two crayfish encounter each other, a winner loser relationship is established. With a short interstimulus interval of 5 s, the rate of habituation of the LG in both socially dominant and subordinate crayfish becomes lower than in socially isolated animals. Serotonin and octopamine affect this social status-dependent modulation of habituation by means of activation of downstream second messenger system of cAMP and IP3 cascades, respectively. PMID- 25796505 TI - Knockdown of HMGN5 suppresses the viability and invasion of human urothelial bladder cancer 5637 cells in vitro and in vivo. AB - The high-mobility group nucleosome-binding domain 5 (HMGN5) is a new and typical member of HMGN protein family. Numerous studies confirmed that HMGN5 was highly expressed in several kinds of malignant tumors, but its role in cancer progression of urothelial bladder cancer (UBC) has not been fully clarified. This study aimed to further investigate the oncogenic role of HMGN5 in UBC 5637 cells employing in vitro and in vivo models and to explore the mechanism [corrected].RNA interference was used to down-regulate HMGN5 expression in 5637 cells by a shRNA expression lentiviral vector. Then cell viability, apoptosis and cell cycle distribution, invasion were detected by MTT assay, flow cytometry and transwell assay, respectively. Tumor growth was also evaluated in nude mice. As a result, successful transfection was confirmed using fluorescence microscopy and HMGN5 was efficiently inhibited. HMGN5 knockdown suppressed invasion, and induced G1/S cell cycle arrestbut not apoptosis and thus contributed to decreased cell viability in UBC 5637 cells [corrected]. Consistent with the cell cycle arrest, the protein expression levels of cyclin D1 were decreased. In vivo study further showed that HMGN5 knockdown affected the tumorigenesis of 5637 cells in nude mice. Western blot also demonstrated that the expression of E-cadherin was enhanced, while the expression of VEGF-C was decreased in 5637 cells depleted of HMGN5 [corrected].In conclusion, we provide both in vivo and in vitro evidence that HMGN5 contribute to the growth and invasion of UBC 5637 cell line and HMGN5 could be exploited as a target for therapy in UBC. PMID- 25796507 TI - Systematic evaluation of combined automated NOE assignment and structure calculation with CYANA. AB - The automated assignment of NOESY cross peaks has become a fundamental technique for NMR protein structure analysis. A widely used algorithm for this purpose is implemented in the program CYANA. It has been used for a large number of structure determinations of proteins in solution but a systematic evaluation of its performance has not yet been reported. In this paper we systematically analyze the reliability of combined automated NOESY assignment and structure calculation with CYANA under a variety of conditions on the basis of the experimental NMR data sets of ten proteins. To evaluate the robustness of the algorithm, the original high-quality experimental data sets were modified in different ways to simulate the effect of data imperfections, i.e. incomplete or erroneous chemical shift assignments, missing NOESY cross peaks, inaccurate peak positions, inaccurate peak intensities, lower dimensionality NOESY spectra, and higher tolerances for the matching of chemical shifts and peak positions. The results show that the algorithm is remarkably robust with regard to imperfections of the NOESY peak lists and the chemical shift tolerances but susceptible to lacking or erroneous resonance assignments, in particular for nuclei that are involved in many NOESY cross peaks. PMID- 25796508 TI - Seroprevalence of Pandemic A(H1N1) pmd09 Virus Antibodies in Mexican Health Care Workers Before and After Vaccination. AB - BACKGROUND AND AIMS: In April 2009, a new strain of influenza A(H1N1) was identified in Mexico and in the U.S. In June 2009, WHO declared this a pandemic. Health care workers constituted a risk group for their close contact with infected individuals. The aim was to estimate seropositivity for A(H1N1)pdm09 in health staff at the Instituto Mexicano del Seguro Social. METHODS: A two-stage cross-sectional study, before and after vaccination in the same workers, was performed on a random sample of health-care workers. A socio-occupational questionnaire was applied and serum antibodies against influenza A(H1N1)pdm09 were determined through neutralization of retroviral pseudotypes; two logistic regression models for both were constructed. RESULTS: The average (median/mean) age of 1378 participants from 13 work centers was 41.7 years and 68.7% (947) were women. Seroprevalence for the first stage was 26.5% (365) (7.4-43%) vs. 20.8% (11) in a control group from the blood bank; for the second stage, the vaccinated group was 33% (215) (18.2-47%) and 27% (196) (11.6-50%) for the unvaccinated group. In regression models, seropositivity was associated with occupational exposure to suspected influenza infected patients, being physicians, and being vaccinated. CONCLUSIONS: Seropositivity against pandemic virus is similar to what was reported, both for vaccinated (2.8-40.9%) and unvaccinated (18.8-64.7%). Low seroprevalence in the vaccinated group indicates that between 67% and 73% were susceptible to infection. Given the relatively low vaccine-induced seropositivity, it is imperative to increase, hygiene and safety for health staff and at-risk populations, and strengthen epidemiological surveillance. PMID- 25796509 TI - Heart coherence: a new tool in the management of stress on professionals and family caregivers of patients with dementia. AB - We describe a stress management intervention intended to reduce the damage and stress impact on the heart physiology and function of a group of caregivers (professional and non-professional) who work with patients with dementia. The intervention consisted in applying heart coherence techniques in a population of 72 caregivers of patients with dementia (42 professional and 29 non-professional caregivers) who had high scores in heart stress and burden tests. Six months after the training they were able to generate appropriate patterns of heart coherence, with a statistically significant decrease in their heart overload. We conclude that training in techniques of heart coherence and positive psychology had effective results on the stress management of the participant caregivers. This was a simple, inexpensive technique with lasting results. To our knowledge this is the first research in Spain studying the application of heart coherence techniques to caregivers of people with dementia. PMID- 25796510 TI - The pharmacokinetics of methamphetamine self-administration in male and female rats. AB - BACKGROUND: Because methamphetamine (METH) pharmacokinetics after single iv doses show significant differences between male and female rats, we hypothesized that pharmacokinetic differences in METH disposition could be a contributing factor to the patterns of METH self-administration behaviors in rats. METHODS: For the studies, we used a passive (non-contingent) METH dosing schedule consisting of 27 METH iv bolus injections (0.048mg/kg) over 2h derived from a previous active (contingent) METH self-administration behavioral study in male rats. After METH dosing of male and female Sprague-Dawley rats (n=5/group), METH and amphetamine serum concentrations were determined by LC-MS/MS. Pharmacokinetic analysis, including predictive mathematical simulations of the data, was then conducted. RESULTS: Male and female rats achieved relatively stable METH serum concentrations within 20min, which remained constant from 20 to 120min. While not statistically different, METH clearance and volume of distribution values for females were 25% and 33% lower (respectively) than males. Linear regression analysis of predicted METH concentrations from pharmacokinetic simulations versus observed concentrations showed a substantially better correlation with male data than female data (r(2)=0.71 vs. 0.56; slope=0.95 vs. 0.45, respectively). At 120min, the time of predicted peak METH serum concentrations, female values were 42% higher than expected, while male values were within 3%. CONCLUSIONS: Unlike METH male pharmacokinetic data, the female data was less predictable during multiple METH administrations and produced overall higher than expected METH concentrations. These findings demonstrate that METH pharmacokinetics could contribute to differences in METH self-administration behaviors in rats. PMID- 25796511 TI - A multiplex ELISA-based protein array for screening diagnostic antigens and diagnosis of Flaviviridae infection. AB - Assays with the ability to detect multiple antibodies in parallel have a wide range of potential applications in epidemiologic research. Here, a multiplex enzyme-linked immunosorbent assay-based protein array (ELISA-array) was developed to simultaneously detect five Flaviviridae infections. The platform was based on an indirect ELISA and 15 antigens were constructed for specific antibody detection against five Flaviviridae viruses (Japanese B, tick-borne encephalitis, West Nile, dengue, and yellow fever viruses) and four serotypes of dengue virus. The specificity was evaluated by calculating the signal value cross-reacting with serum immunized with other viruses, and the sensitivity of antigens was compared with conventional ELISAs using immunized rabbit polyclonal antisera. IgG and IgM calibration curves were constructed to evaluate the reproducibility of the platform. Finally, 24 dengue fever (DF) infection and 15 tick-borne encephalitis (TBE) infection clinical sera were used to compare the advantage of ELISA-array to ELISA. After initial screening, 9 out of 15 antigens were chosen for ELISA array printing. By using different virus-immunized rabbit antiserum, 7 out of 9 antigens showed good specificity in the ELISA-array. Eight out of 9 antigens showed four-fold greater sensitivity in ELISA-array compared to that in conventional ELISAs. The coefficients of determination (r (2)) close to 1 showed high reproducibility, and clinical sera test showed that ELISA-array had higher specificity and sensitivity than traditional ELISA. ELISA-array was a good platform for antigen screening and this multiplexed assay might be a useful and convenient tool for multiple immunological detection of infectious viral antibodies. PMID- 25796512 TI - The influence of maternal BMI and gestational diabetes on pregnancy outcome. AB - AIMS: To evaluate the effect of maternal body mass index (BMI) on gestational diabetes (GDM) and the risk of adverse pregnancy outcomes in women who are overweight or obese. METHODS: A prospective cohort study nested within the LIMIT randomised controlled trial. A total of 1030 women were recruited between 10 and 20 weeks' gestation, with a BMI>=25 kg/m(2), and were grouped into BMI subclasses utilising World Health Organisation criteria. Women underwent a fasting oral glucose tolerance test at 26-28 weeks' gestation, and a diagnosis of GDM was made if fasting blood glucose was >=5.5 mmol/L or >=7.8 mmol/L after 2h. Maternal and neonatal health outcomes were evaluated. RESULTS: The prevalence of GDM increased with increasing maternal BMI (6.74% overweight vs 13.42% obese subclass 1 vs 12.79% obese subclass 2 vs 20.00% obese subclass 3). Women who were diagnosed with GDM were significantly less likely to give birth to an infant with birth weight above 4 kg (RR 0.60; 95% CI 0.36 to 1.00; p=0.05). The need for caesarean delivery (RR 1.27; 95% CI 1.07 to 1.50; p=0.006) and incidence of birth weight >90% (RR 1.38; 95% CI 1.07 to 1.77; p=0.01) was significantly increased in women who were obese, independent of GDM. CONCLUSION: Increasing maternal BMI is a significant risk factor for the development of GDM, and our findings demonstrate a considerably higher prevalence than has been previously described. Raised maternal BMI is a risk factor for high infant birth weight, which may be modified by lifestyle intervention. PMID- 25796513 TI - The role of fibroblast growth factor 21 in diabetes and its complications: A review from clinical perspective. AB - Fibroblast growth factor 21 (FGF21) has been well-recognized as a metabolic hormone and a promising target for treatment of metabolic diseases. The level of endogenous FGF21 is elevated in patients with impaired glucose tolerance and progressively increased from patients with overt type 2 diabetes to those with micro- and macro-vascular complications, presumably as a compensation or response to the deterioration of metabolic imbalance. A few exploratory in vivo studies, including a recent clinical trial, showed that exogenous FGF21 mimetics targeting FGF21 signaling can attain beneficial metabolic effects not with-standing the already elevated ambient FGF21 levels. In addition, some clinically available pharmacologic agents such as fenofibrates and metformin may modulate energy and macronutrients metabolism by acting through FGF21. This review mainly focuses on the role of FGF21 in development, progression and treatment of type 2 diabetes from a clinical perspective. PMID- 25796514 TI - Temperament and character profiles of patients with burning mouth syndrome. AB - OBJECTIVE: Burning mouth syndrome (BMS) is a chronic disease in which patients feel a burning sensation and pain in the oral cavity. Although personality traits have been suggested to influence the development and course of BMS, they have not yet been examined in detail. We therefore investigated the personality traits of BMS patients. METHODS: Sample consisted of 65 BMS patients presenting to the Aichi-Gakuin Dental School Hospital between May 2005 and April 2009. They were also diagnosed as having pain disorder by a psychiatrist. The control group consisted of 116 healthy subjects. The Temperament and Character Inventory (TCI) was used to evaluate personality traits, while the Beck Depression Inventory (BDI) was used to evaluate the depression rate in both groups. RESULTS: In TCI, we found that, in comparison to the control group, the novelty seeking score was significantly lower (p = 0.009), the harm avoidance score was significantly higher (p < 0.001), and the self-directedness score was significantly lower (p = 0.039) in the BMS group. To remove the influence of depression, we performed an analysis of covariance of each TCI item using the BDI score as a covariate. No significant differences were observed in harm avoidance or self-directedness, whereas the differences noted in novelty seeking were significant (p = 0.008). CONCLUSION: The novelty seeking score was low in BMS patients in comparison to the control group. They also had high harm avoidance and low self-directedness tendencies, but these were attributed to the influence of depression. PMID- 25796515 TI - Disruption of Mitotic Progression by Arsenic. AB - Arsenic is an enigmatic xenobiotic that causes a multitude of chronic diseases including cancer and also is a therapeutic with promise in cancer treatment. Arsenic causes mitotic delay and induces aneuploidy in diploid human cells. In contrast, arsenic causes mitotic arrest followed by an apoptotic death in a multitude of virally transformed cells and cancer cells. We have explored the hypothesis that these differential effects of arsenic exposure are related by arsenic disruption of mitosis and are differentiated by the target cell's ability to regulate or modify cell cycle checkpoints. Functional p53/CDKN1A axis has been shown to mitigate the mitotic block and to be essential to induction of aneuploidy. More recent preliminary data suggest that microRNA modulation of chromatid cohesion also may play a role in escape from mitotic block and in generation of chromosomal instability. Other recent studies suggest that arsenic may be useful in treatment of solid tumors when used in combination with other cytotoxic agents such as cisplatin. PMID- 25796516 TI - Plasma Selenium Levels in First Trimester Pregnant Women with Hyperthyroidism and the Relationship with Thyroid Hormone Status. AB - The thyroid gland has the highest selenium (Se) concentration per unit weight among all tissues. The aims of the present study were to evaluate the Se levels in the plasma of hyperthyroidic pregnant women and to investigate the association between maternal plasma Se concentrations and thyroid hormone levels. The study population consisted of 107 pregnant women, 70 healthy pregnant women (group 1) and 37 pregnant women with hyperthyroidism (group 2). The plasma free triiodothyronine (fT3) and free thyroxine (fT4) levels were significantly higher, and the plasma thyroid-stimulating hormone (TSH) and Se levels were significantly lower in group 2 than in group 1 (p < 0.05). A correlation analysis showed a positive correlation between Se and fT4 in group 1 and with TSH in group 2 (p < 0.05). Decreased maternal serum antioxidant trace element Se in hyperthyroidic pregnant women compared with normal pregnant women supported the hypothesis that hyperthyroidism was associated with decreased antioxidant response. PMID- 25796517 TI - A cis-regulatory module activating transcription in the suspensor contains five cis-regulatory elements. AB - Little is known about the molecular mechanisms by which the embryo proper and suspensor of plant embryos activate specific gene sets shortly after fertilization. We analyzed the upstream region of the Scarlet Runner Bean (Phaseolus coccineus) G564 gene in order to understand how genes are activated specifically in the suspensor during early embryo development. Previously, we showed that a 54-bp fragment of the G564 upstream region is sufficient for suspensor transcription and contains at least three required cis-regulatory sequences, including the 10-bp motif (5'-GAAAAGCGAA-3'), the 10 bp-like motif (5' GAAAAACGAA-3'), and Region 2 motif (partial sequence 5'-TTGGT-3'). Here, we use site-directed mutagenesis experiments in transgenic tobacco globular-stage embryos to identify two additional cis-regulatory elements within the 54-bp cis regulatory module that are required for G564 suspensor transcription: the Fifth motif (5'-GAGTTA-3') and a third 10-bp-related sequence (5'-GAAAACCACA-3'). Further deletion of the 54-bp fragment revealed that a 47-bp fragment containing the five motifs (the 10-bp, 10-bp-like, 10-bp-related, Region 2 and Fifth motifs) is sufficient for suspensor transcription, and represents a cis-regulatory module. A consensus sequence for each type of motif was determined by comparing motif sequences shown to activate suspensor transcription. Phylogenetic analyses suggest that the regulation of G564 is evolutionarily conserved. A homologous cis regulatory module was found upstream of the G564 ortholog in the Common Bean (Phaseolus vulgaris), indicating that the regulation of G564 is evolutionarily conserved in closely related bean species. PMID- 25796518 TI - Fungal burden in waste industry: an occupational risk to be solved. AB - High loads of fungi have been reported in different types of waste management plants. This study intends to assess fungal contamination in one waste-sorting plant before and after cleaning procedures in order to analyze their effectiveness. Air samples of 50 L were collected through an impaction method, while surface samples, taken at the same time, were collected by the swabbing method and subject to further macro- and microscopic observations. In addition, we collected air samples of 250 L using the impinger Coriolis MU air sampler (Bertin Technologies) at 300 L/min airflow rate in order to perform real-time quantitative PCR (qPCR) amplification of genes from specific fungal species, namely Aspergillus fumigatus and Aspergillus flavus complexes, as well as Stachybotrys chartarum species. Fungal quantification in the air ranged from 180 to 5,280 CFU m(-3) before cleaning and from 220 to 2,460 CFU m(-3) after cleaning procedures. Surfaces presented results that ranged from 29*10(4) to 109*10(4) CFU m(-2) before cleaning and from 11*10(4) to 89*10(4) CFU m(-2) after cleaning. Statistically significant differences regarding fungal load were not detected between before and after cleaning procedures. Toxigenic strains from A. flavus complex and S. chartarum were not detected by qPCR. Conversely, the A. fumigatus species was successfully detected by qPCR and interestingly it was amplified in two samples where no detection by conventional methods was observed. Overall, these results reveal the inefficacy of the cleaning procedures and that it is important to determine fungal burden in order to carry out risk assessment. PMID- 25796519 TI - Mapping of arsenic pollution with reference to paddy cultivation in the middle Indo-Gangetic Plains. AB - A detailed field study was carried out to monitor (i) the arsenic contents in irrigation groundwater and paddy soil and (ii) the accumulation of arsenic in the roots and grains of different paddy varieties grown in the arsenic-contaminated middle Indo-Gangetic Plains of Northern India. Results showed the highest arsenic contamination in the irrigation groundwater (312 MUg l(-1)) and in paddy soil (35 mg kg(-1)) values that were significantly exceeded the recommended threshold values of 100 MUg l(-1) (EU) and 20 mg kg(-1) (FAO), respectively. The paddy soil arsenic content ranged from 3 to 35 mg kg(-1) with a mean value of 15 mg kg(-1). The soil arsenic content was found to be influenced by the soil texture, carbon, macronutrients, phosphorus, sulfur, hydrolases, and oxidoreductases properties of the paddy soils as revealed in the principal component analyses. Higher root accumulation (>10 mg kg(-1)) of arsenic was observed in 6 of the 17 paddy varieties grown in the study area. The range of arsenic content accumulated in the paddy roots was 4.1 to 16.2 mg kg(-1) dry weight (dw) and in the grains 0.179 to 0.932 mg kg(-1) dw. Out of 17 paddy varieties, eight had 0 > .55 mg kg(-1) grain arsenic content and were found unsafe for subsistence maximum daily tolerable dietary intake (MTDI) by human beings according to the regulatory standards. PMID- 25796520 TI - Estimation of the success rate of anesthetic management for thymectomy in patients with myasthenia gravis treated without muscle relaxants: a retrospective observational cohort study. AB - Although maintaining anesthesia for myasthenia gravis (MG) with minimal muscle relaxants (MR) is common, the success rate of anesthetic management for MG without MR is not clear. We therefore retrospectively examined the success rate of anesthetic management for MG without MR among 66 consecutive cases of thymectomy for MG performed at our hospital between January 2004 and April 2010, before approval of using sugammadex. A total of 60 patients (90.9 %) were treated without MR (N group). Among the 60 cases, 17 (28.3 %) patients were not extubated in the operating room due to postoperative respiratory depression or other reasons. Therefore, the success rate of anesthetic management for thymectomy in patients with MG without treating MR was 71.7 % (43/60) [95 % confident interval (CI): 65.9-77.5 %]. The reasons for using MR included coughing at intubation in one case, bucking during surgery in two cases, and MR was considered to be safer by the attending anesthesiologist in three cases. The number of cases of impossible extubation requiring ventilation on that day was three in the N group and none in the R group. Finally, the success rate of anesthetic management for MG without MR was estimated to be 71.1 % (95 % CI: 65.9-77.5 %). PMID- 25796521 TI - Health Care Access Among Asian American Subgroups: The Role of Residential Segregation. AB - Few studies have examined differences in health care access across Asian American ethnicities and none have considered the effects of residential segregation. The segregation of Asians by neighborhood has been steadily increasing over the past few decades due in part to the settlement patterns of immigrants. Data from the 2009 National Longitudinal Study of Adolescent Health (n = 746) were used. We examined differences in yearly medical checkups between Asian subgroups as well as among foreign-born and US-born Asians. Results showed that immigrant Filipinos and Vietnamese were less likely to get a checkup compared with foreign-born Chinese. The effect of Asian subgroup was modified by the percentage of Asians in a census tract (p < 0.01). Koreans and other Asians had a higher probability of getting a checkup when living in a predominately Asian neighborhood. For Chinese and Vietnamese residential concentration of Asians had a stronger inverse association with having a yearly checkup. PMID- 25796523 TI - Microfluidic aqueous two-phase extraction of bisphenol A using ionic liquid for high-performance liquid chromatography analysis. AB - An aqueous two-phase microfluidics (ATPM) method suitable for selective extraction of bisphenol A (BPA) in aqueous samples was developed, and a functional ionic liquid of N, N, N-trioctyl ammonium propionate (TOAP) was specially employed for the formation of a parallel flow system. Based on the analytical model, we optimized the chip design into branch-connection length pattern to achieve maximum extraction efficiency (phi max) and ensure phase separation. In combining the design flexibility and ideal reaction activity of extractant (TOAP), the developed ATPM enabled a selective and effective extraction of BPA (phi max of 95% within 2 s) from phenol derivatives. Meanwhile, the total operation time and ionic liquid consumption of the microfluidic extraction were only 2.5 min and 5 MUl, respectively. The ATPM can be run at normal pH and room temperature and showed no interferences from components found in tap or beach water. To be noted, this specific extraction system was applied in real water samples; the recoveries of standard addition for all water samples spiked with BPA were from 96 to 110%. Finally, successful reuse of the chip was also realized. In all cases, the developed microfluidic chip was proven to be useful as an effective and low consumption approach in extracting BPA and should be expanded as a "green" preparative method for high-performance liquid chromatography (HPLC) analysis. PMID- 25796524 TI - Assessment of goat milk adulteration with a label-free monolithically integrated optoelectronic biosensor. AB - The label-free detection of bovine milk in goat milk through a miniaturized optical biosensor is presented. The biosensor consists of ten planar silicon nitride waveguide Broad-Band Mach-Zehnder interferometers (BB-MZIs) monolithically integrated and self-aligned with their respective silicon LEDs on the same Si chip. The BB-MZIs were transformed to biosensing transducers by functionalizing their sensing arm with bovine k-casein. Measurements were performed by continuously recording the transmission spectra of each interferometer through an external spectrometer. The amount of bovine milk in goat milk was determined through a competitive immunoassay by passing over the sensor mixtures of anti-k-casein antibodies with the calibrators or the samples. The output spectra of each BB-MZI recorded during the reaction were subjected to Discrete Fourier Transform in order to convert the observed spectral shifts to phase shifts in the wavenumber domain. The method had a detection limit of 0.04 % (v/v) bovine milk in goat milk, dynamic range 0.1-1.0 % (v/v), recoveries 93-110 %, and intra- and inter-assay coefficients of variation less than 12 and 15 %, respectively. The proposed biosensor compared well in terms of analytical performance with a competitive ELISA developed using the same monoclonal antibodies. Nevertheless, the duration of the biosensor assay was 10 min whereas the ELISA required 2 h. Thus, the fast and sensitive determinations along with the small size of the sensor make it ideal for incorporation into portable devices for assessment of goat or ewe's milk adulteration with bovine milk at the point-of-need. PMID- 25796525 TI - Rapid and label-free detection of egg allergen traces in wines by surface plasmon resonance biosensor. AB - The development of a surface plasmon resonance (SPR)-based biosensor tailored to the fast detection of egg-related fining allergens in wines is herein described. Ovalbumin (OVA) was chosen as the target protein to be monitored due to its highest abundance in the egg white powder, a typical fining agent used by the winery industry to promote wine clarification. A direct assay was designed, basing on the use of polyclonal anti-OVA antibody as bio-specific receptor. With the aim of optimizing the assay conditions, different parameters able to influence the final biosensor response were carefully investigated (i.e., pH, ionic strength, and additional surfactant concentration). After the fine tuning of these parameters, the assay was tested in the direct analysis of OVA in commercial wines artificially contaminated with egg white powder at different concentration levels in order to assess the reliability of the biosensor in detecting traces of OVA in complex matrices. The devised assay allowed to trace, in a short analysis time and with a minimal sample pre-treatment required, the presence of egg allergens at the lowest concentration comprised between 0.03 and 0.2 MUg/mL. Finally, the response provided by the developed biosensor was correlated with an established liquid chromatography mass spectrometry (LC-MS) method developed in our laboratories, and performances of both approaches were assessed for the fast monitoring of egg allergen contamination in fined wines. PMID- 25796522 TI - Cell layer-specific distribution of transiently expressed barley ESCRT-III component HvVPS60 in developing barley endosperm. AB - The significance of the endosomal sorting complexes required for transport (ESCRT)-III in cereal endosperm has been shown by the identification of the recessive mutant supernumerary aleurone layer1 (SAL1) in maize. ESCRT-III is indispensable in the final membrane fission step during biogenesis of multivesicular bodies (MVBs), responsible for protein sorting to vacuoles and to the cell surface. Here, we annotated barley ESCRT-III members in the (model) crop Hordeum vulgare and show that all identified members are expressed in developing barley endosperm. We used fluorescently tagged core ESCRT-III members HvSNF7a/CHMP4 and HvVPS24/CHMP3 and the associated ESCRT-III component HvVPS60a/CHMP5 for transient localization studies in barley endosperm. In vivo confocal microscopic analyses show that the localization of recombinantly expressed HvSNF7a, HvVPS24 and HvVPS60a differs within barley endosperm. Whereas HvSNF7a induces large agglomerations, HvVPS24 shows mainly cytosolic localization in aleurone and subaleurone. In contrast, HvVPS60a localizes strongly at the plasma membrane in aleurone. In subaleurone, HvVPS60a was found to a lesser extent at the plasma membrane and at vacuolar membranes. These results indicate that the steady-state association of ESCRT-III may be influenced by cell layer specific protein deposition or trafficking and remodelling of the endomembrane system in endosperm. We show that sorting of an artificially mono-ubiquitinated Arabidopsis plasma membrane protein is inhibited by HvVPS60a in aleurone. The involvement of HvVPS60a in different cell layer-specific trafficking pathways, reflected by localization of HvVPS60a at the plasma membrane in aleurone and at the PSV membrane in subaleurone, is discussed. PMID- 25796526 TI - Determination of succinate-dehydrogenase-inhibitor fungicide residues in fruits and vegetables by liquid chromatography-tandem mass spectrometry. AB - In recent years, a second generation of succinate-dehydrogenase-inhibitor (SDHI) fungicides has been introduced into the market for effective treatment of fruit and vegetable crops, with fluxapyroxad, boscalid, fluopyram, penflufen, bixafen, penthiopyrad, and isopyrazam being some of the members of this new class of agrochemical. We herein report the development of an analytical procedure for the determination of residues of these SDHI fungicides in food samples, based on a modification of the QuEChERS extraction method followed by ultra-performance liquid chromatography coupled to tandem-mass-spectrometry determination. The proposed method reached limits of detection from 0.8 to 2.0 MUg L(-1). Apple, strawberry, tomato, and spinach samples were used as model samples. Spiked samples, from 10 to 1000 MUg kg(-1), were analysed by the proposed method and quantitative recoveries were obtained (from 81 to 115 % for apples, from 84 to 136 % for strawberries, from 84 to 135 % for tomatoes, and from 80 to 136 % for spinach), with precision better than 20 % in all cases. Thus, the proposed method can be used for the analysis of SDHI fungicide residues to efficiently ensure that marketed fruits and vegetables comply with the maximum residue levels established by competent authorities. PMID- 25796527 TI - Revised sample preparation for the analysis of oxysterols by enzyme-assisted derivatisation for sterol analysis (EADSA). AB - Sterols, and specifically oxysterols, play important roles in the biosynthesis of bile acids and steroid hormones as well as possessing biological activities in their own right. Analysis of oxysterols is complicated due to their low abundance in biological systems and poor ionisation characteristics in mass spectrometry. Over the past decade, we have developed a liquid chromatography-mass spectrometry method termed enzyme-assisted derivatisation for sterol analysis (EADSA). Our derivatisation procedure relies on two solid-phase extraction steps to (i) separate cholesterol from oxysterols and (ii) remove excess derivatisation reagents. Recent inter-batch variation in C18 reversed-phase cartridges has led us to experiment with alternative columns. Here, we present our findings and report an improved sample preparation procedure using polymeric hydrophilic lipophilic balanced reversed-phase cartridges. PMID- 25796528 TI - Comparison of sp-ICP-MS and MDG-ICP-MS for the determination of particle number concentration. AB - In 2011, the European Commission introduced new regulations on how nanomaterials are defined. Since then, researchers have emphasized that more complete characterization of nanoparticles (NPs) includes not just mass and size determinations, but also the determination of the particle number concentrations. In this study, two different sample introduction approaches for the analysis of NP suspensions with inductively coupled plasma mass spectrometry (ICP-MS) were investigated: pneumatic nebulization (sp-ICP-MS) and microdroplet generation (MDG ICP-MS). These approaches were compared for the determination of particle number concentrations (PNCs) of gold and silver NP suspensions diluted in either ultra pure water or citrate solution. For accurate sp-ICP-MS analysis, it is crucial to know the transport efficiency of nebulized sample into the plasma. Here, transport efficiencies, measured by the waste collection method, were 11-14 % for Ag suspensions and 9-11 % for Au. In contrast, the droplet transport efficiency of MDG-ICP-MS was 100 %. Analysis by sp-ICP-MS yielded a lower particle number concentration than expected (only 20-40 % of the expected value), whereas MDG-ICP MS had NP recoveries up to 80 %. This study indicates that NP reference materials are of major importance for particle number determination and detailed results on particle number concentrations for different suspensions with respect to storage time are discussed. PMID- 25796529 TI - Screening for petrochemical contamination in seafood by headspace solid-phase microextraction gas chromatography-mass spectrometry. AB - A headspace solid-phase microextraction gas chromatography-mass spectrometry (SPME GC-MS) method is described, to screen seafood for volatile organic compounds (VOCs) associated with petrochemical taint. VOCs are extracted from the headspace of heated sample homogenates by adsorption onto a SPME fiber and desorbed for analysis by GC-MS. Targeted compounds are determined semi quantitatively using representative calibration standards for the various classes (alkanes, alkylbenzenes, indanes/tetralins, and naphthalenes) of VOCs analyzed. Sample preparation is minimal, and the analyses are rapid and automated with a capacity of 50 samples per day. The method was optimized in terms of headspace temperature, sample heating time, extraction time, and desorption time using oyster samples fortified with target compounds. Calibrations for hydrocarbon components were linear in the range of 8.3-167 ng/g; the limit of detection ranged between 0.05 and 0.21 ng/g, and the limit of quantitation between 0.16 and 0.69 ng/g. Good precision (RSD < 10 % at 16.7 ng/g for individual VOCs) and accuracy (recovery range 89-118 % at 25 ng/g) were obtained in oyster, crab, shrimp, and finfish matrices. The trueness of the method was demonstrated by quantifying VOCs at 1-2-ppb levels in oyster fortified with certified reference material NIST SRM 1491a. Following single laboratory validation, the method was employed for the determination of VOCs in seafood exposed to oil contaminated seawater and for the determination of background VOC levels in seafood species from the Gulf of Mexico and local food stores. The method as described can be used to supplement human sensory testing for petrochemical taint in seafood. PMID- 25796530 TI - Chemical tagging of chlorinated phenols for their facile detection and analysis by NMR spectroscopy. AB - A derivatization method that employs diethyl (bromodifluoromethyl) phosphonate (DBDFP) to efficiently tag the endocrine disruptor pentachlorophenol (PCP) and other chlorinated phenols (CPs) along with their reliable detection and analysis by NMR is presented. The method accomplishes the efficient alkylation of the hydroxyl group in CPs with the difluoromethyl (CF2H) moiety in extremely rapid fashion (5 min), at room temperature and in an environmentally benign manner. The approach proved successful in difluoromethylating a panel of 18 chlorinated phenols, yielding derivatives that displayed unique (1)H, (19)F, and (13)C NMR spectra allowing for the clear discrimination between isomerically related CPs. Due to its biphasic nature, the derivatization can be applied to both aqueous and organic mixtures where the analysis of CPs is required. Furthermore, the methodology demonstrates that PCP along with other CPs can be selectively derivatized in the presence of other various aliphatic alcohols, underscoring the superiority of the approach over other general derivatization methods that indiscriminately modify all analytes in a given sample. The present work demonstrates the first application of NMR on the qualitative analysis of these highly toxic and environmentally persistent species. PMID- 25796531 TI - Helicobacter pylori seropositivity and pregnancy-related diseases: a prospective cohort study. AB - The relationship between Helicobacter pylori infection and extragastric disease is well established. This study prospectively investigated whether maternal H. pylori seropositivity, detected during the first half of pregnancy, could be associated with the development of the major pregnancy-related pathological conditions during the late second or third trimester in a general population. Our hypothesis was that H. pylori infection might negatively influence pregnancy development and outcome. A total of 2820 consecutive pregnant women were recruited before 20 weeks' gestation, from October 2008 to August 2010, and blood samples were collected from each subject. IgG antibodies against H. pylori were assayed in maternal serum by a commercial immunoassay. Logistic regression analyses were performed to assess any association between H. pylori seropositivity and adverse pregnancy outcomes. Gestational diabetes mellitus (GDM) was the most common maternal complication (5.7%) and the only pregnancy related disorder with a significantly higher rate of H. pylori-positive women (41.3%) compared with subjects who did not develop the disease (27.7%; P < 0.001; OR = 1.829, 95% CI = 1.320-2.533). The difference observed remained statistically significant after adjusting for potential confounding variables. The presence of antibodies against H. pylori antigens in maternal serum was independently associated with the development of GDM. These findings suggest that H. pylori eradication might play a role in the prevention of gestational diabetes mellitus. PMID- 25796532 TI - Cytokines in the male reproductive tract and their role in infertility disorders. AB - Cell integration between the immune and reproductive systems is the basis for normal male reproductive physiology. Cytokines are a part of the autocrine/paracrine network operating in the male reproductive tract. At the same time, immunological reactions occurring via cytokines appear to be both beneficial and/or risk factors for male fertility. As the cytokines are produced by a whole spectrum of cells in all compartments of the male genital tract, they can also be involved in a variety of andrological disorders. The monitoring of cytokines and other immune factors in seminal plasma may offer a chance to better understand the mechanisms leading to sub-/infertility. In this review, we present insights into cytokine interplay in some of the pathological conditions associated with male reproduction. PMID- 25796533 TI - Oxidation and nitration of mononitrophenols by a DyP-type peroxidase. AB - Substantial conversion of nitrophenols, typical high-redox potential phenolic substrates, by heme peroxidases has only been reported for lignin peroxidase (LiP) so far. But also a dye-decolorizing peroxidase of Auricularia auricula judae (AauDyP) was found to be capable of acting on (i) ortho-nitrophenol (oNP), (ii) meta-nitrophenol (mNP) and (iii) para-nitrophenol (pNP). The pH dependency for pNP oxidation showed an optimum at pH 4.5, which is typical for phenol conversion by DyPs and other heme peroxidases. In the case of oNP and pNP conversion, dinitrophenols (2,4-DNP and 2,6-DNP) were identified as products and for pNP additionally p-benzoquinone. Moreover, indications were found for the formation of random polymerization products originating from initially formed phenoxy radical intermediates. Nitration was examined using (15)N-labeled pNP and Na(14)NO2 as an additional source of nitro-groups. Products were identified by HPLC-MS, and mass-to-charge ratios were evaluated to clarify the origin of nitro groups. The additional nitrogen in DNPs formed during enzymatic conversion was found to originate both from (15)N-pNP and (14)NO2Na. Based on these results, a hypothetical reaction scheme and a catalytically responsible confine of the enzyme's active site are postulated. PMID- 25796534 TI - A step towards evidence-based regulation of health practitioners. AB - In 2010 Australia established a national registration and accreditation scheme, covering more than 620 000 health practitioners. The data held by the Australian Health Practitioner Regulation Agency is a remarkable platform for research aimed at improving health practitioner regulation, health care quality and workforce planning. PMID- 25796535 TI - Novel use of the Wii Balance Board to prospectively predict falls in community dwelling older adults. AB - BACKGROUND: The Wii Balance Board has received increasing attention as a balance measurement tool; however its ability to prospectively predict falls is unknown. This exploratory study investigated the use of the Wii Balance Board and other clinical-based measures for prospectively predicting falls among community dwelling older adults. METHODS: Seventy-three community-dwelling men and women, aged 60-85years were followed-up over a year for falls. Standing balance was indexed by sway velocities measured using the Wii Balance Board interfaced with a laptop. Clinical-based measures included Short Physical Performance Battery, gait speed and Timed-Up-and-Go test. Multivariable regression analyses were used to assess the ability of the Wii Balance Board measure to complement the TUG test in fall screening. FINDINGS: Individually, the study found Wii Balance Board anteroposterior (odds ratio 1.98, 95% CI 1.16 to 3.40, P=0.01) and mediolateral (odds ratio 2.80, 95% CI 1.10 to 7.13, p=0.03) sway velocity measures predictive of prospective falls. However, when each velocity measure was adjusted with body mass index and Timed-Up-and-Go, only anteroposterior sway velocity was predictive of prospective falls (odds ratio 2.21, 95% CI 1.18 to 4.14). A faster anteroposterior velocity was associated with increased odds of falling. Area under-the-curves for Wii Balance Board sway velocities were 0.67 and 0.71 for anteroposterior and mediolateral respectively. INTERPRETATION: The Wii Balance Board-derived anteroposterior sway velocity measure could complement existing clinical-based measures in predicting future falls among community-dwelling older adults. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number: ACTRN12610001099011. PMID- 25796536 TI - Knee motion variability in patients with knee osteoarthritis: The effect of self reported instability. AB - BACKGROUND: Knee osteoarthritis has been previously associated with a stereotypical knee-stiffening gait pattern and reduced knee joint motion variability due to increased antagonist muscle co-contractions and smaller utilized arc of motion during gait. However, episodic self-reported instability may be a sign of excessive motion variability for a large subgroup of patients with knee osteoarthritis. The objective of this work was to evaluate the differences in knee joint motion variability during gait in patients with knee osteoarthritis with and without self-reported instability compared to a control group of older adults with asymptomatic knees. METHODS: Forty-three subjects, 8 with knee osteoarthritis but no reports of instability (stable), 11 with knee osteoarthritis and self-reported instability (unstable), and 24 without knee osteoarthritis or instability (control) underwent Dynamic Stereo X-ray analysis during a decline gait task on a treadmill. Knee motion variability was assessed using parametric phase plots during the loading response phase of decline gait. FINDINGS: The stable group demonstrated decreased sagittal-plane motion variability compared to the control group (p=0.04), while the unstable group demonstrated increased sagittal-plane motion variability compared to the control (p=0.003) and stable groups (p<0.001). The unstable group also demonstrated increased anterior-posterior joint contact point motion variability for the medial tibiofemoral compartment compared to the control (p=0.03) and stable groups (p=0.03). INTERPRETATION: The finding of decreased knee motion variability in patients with knee osteoarthritis without self-reported instability supports previous research. However, presence of self-reported instability is associated with increased knee motion variability in patients with knee osteoarthritis and warrants further investigation. PMID- 25796537 TI - Selective Response to Mammalian Target of Rapamycin Inhibition in a Patient with Metastatic Renal Cell Carcinoma Bearing TSC1 Mutation. PMID- 25796538 TI - Distribution and evolution of cotton fiber development genes in the fibreless Gossypium raimondii genome. AB - Cotton fiber represents the largest single cell in plants and they serve as models to study cell development. This study investigated the distribution and evolution of fiber Unigenes anchored to recombination hotspots between tetraploid cotton (Gossypium hirsutum) At and Dt subgenomes, and within a parental diploid cotton (Gossypium raimondii) D genome. Comparative analysis of At vs D and Dt vs D showed that 1) the D genome provides many fiber genes after its merger with another parental diploid cotton (Gossypium arboreum) A genome although the D genome itself does not produce any spinnable fiber; 2) similarity of fiber genes is higher between At vs D than between Dt vs D genomic hotspots. This is the first report that fiber genes have higher similarity between At and D than between Dt and D. The finding provides new insights into cotton genomic regions that would facilitate genetic improvement of natural fiber properties. PMID- 25796539 TI - Dental eruption in East African wild chimpanzees. AB - Knowledge of chimpanzee development has played an essential role in our understanding of the evolution of human ontogeny. However, recent studies of wild ape dentitions have cast doubt on the use of developmental standards derived from captive individuals. Others have called into question the use of deceased wild individuals to infer normative development. We conducted a high resolution photographic study of living known-age subadults in the Kanyawara community (Kibale National Park, Uganda) to generate a comprehensive three year record of dental eruption (including tooth emergence ages). These non-invasive data allow comparisons of captive and wild chimpanzees, establish accurate developmental standards for relatively healthy wild individuals, and facilitate direct assessments of primate-wide associations between dental development and life history. Emergence ages in the Kanyawara chimpanzees are very similar to living Gombe chimpanzees, and are broadly comparable to deceased Tai Forest chimpanzees. Early-emerging teeth such as the deciduous dentition and first molar (M1) appear during a time of maternal dependence, and are almost indistinguishable from captive chimpanzee emergence ages, while later forming teeth in the Kanyawara population emerge in the latter half of captive age ranges or beyond. Five juveniles whose lower M1s emerged by or before 3.3 years of age continued to nurse for a year or more beyond M1 emergence, and their mothers showed considerable variation in reproductive rates. The third molars of two adolescent females emerged several months to several years prior to the birth of their first offspring. Given that broad primate-wide relationships between molar emergence and life history do not necessarily hold within this population of chimpanzees, particularly for variables that are reported to be coincident with molar emergence, we suggest that further study is required in order to predict life history variables in hominins or hominoids. PMID- 25796540 TI - Validity of linear encoder measurement of sit-to-stand performance power in older people. AB - OBJECTIVE: To investigate construct validity of linear encoder measurement of sit to-stand performance power in older people by showing associations with relevant functional performance and physiological parameters. DESIGN: Cross-sectional study. SETTING: Movement laboratory of a geriatric rehabilitation clinic. PARTICIPANTS: Eighty-eight community-dwelling, cognitively unimpaired older women (mean age 78 years). MAIN OUTCOME MEASURES: Sit-to-stand performance power and leg power were assessed using a linear encoder and the Nottingham Power Rig, respectively. Gait speed was measured on an instrumented walkway. Maximum quadriceps and hand grip strength were assessed using dynamometers. Mid-thigh muscle cross-sectional area of both legs was measured using magnetic resonance imaging. RESULTS: Associations of sit-to-stand performance power with power assessed by the Nottingham Power Rig, maximum gait speed and muscle cross sectional area were r=0.646, r=0.536 and r=0.514, respectively. A linear regression model explained 50% of the variance in sit-to-stand performance power including muscle cross-sectional area (p=0.001), maximum gait speed (p=0.002), and power assessed by the Nottingham Power Rig (p=0.006). CONCLUSIONS: Construct validity of linear encoder measurement of sit-to-stand power was shown at functional level and morphological level for older women. This measure could be used in routine clinical practice as well as in large-scale studies. CLINICAL TRIAL REGISTRATION NUMBER: DRKS00003622. PMID- 25796541 TI - Chemopreventive and therapeutic potentials of thymoquinone in HepG2 cells: mechanistic perspectives. AB - Liver cancer is the fifth commonest malignancy worldwide and the third leading cause of death. Identifying novel curative and preventive therapy may improve its prognosis. In this study, thymoquinone (TQ), the most active biological ingredient of Nigella sativa Linn, was investigated for its antitumor activity. Mechanistic perspectives underlying this antitumor activity were explored by testing its effect on cell cycle, apoptosis, and angiogenesis. In addition, the chemopreventive effect of TQ was carried out by measuring its effect on phase I CYP1A1 and phase II glutathione S-transferase (GST) drug-metabolizing enzymes. The results of the present study revealed the effectiveness of TQ as an antitumor agent against different types of cancer including brain, colon, cervix and liver at both a time- and concentration-dependent manner. In HepG2 cells, it induced G2/M phase cell cycle arrest and a concentration-dependent increase in the percentage of apoptotic cells with an increase in the ratio of Bax/BCL-2. Moreover, the expression of mRNA and protein level of vascular endothelial growth factor decreased as the concentration of TQ increased. Our data showed a significant inhibition of induced phase I CYP1A1 enzyme, and elevation in the content of glutathione and activity of phase II enzyme GST, in HepG2 cells. Our results provide support for the beneficial use of TQ as a therapeutic and chemopreventive agent against liver cancer. PMID- 25796542 TI - Bioaccumulation and ecological risk assessment of heavy metals in the sediments and mullet Liza klunzingeri in the northern part of the Persian Gulf. AB - The concentrations of some heavy metals (Cu, Zn, Pb and Cd) were investigated in the sediments and in the mullet Liza klunzingeri from the northern part of the Persian Gulf. The levels of Cu, Zn and Pb in the sediment varied significantly among the sampling sites (P<0.05). Sediments from the northern part of the Persian Gulf had serious ecological risk when considering PER. The ranges of the average concentrations of Cu, Zn, Pb, and Cd in the tissue of L. klunzingeri were 10.00-16.66 mg/kg, 18.75-32.50 mg/kg, 3.25-14.16 mg/kg and 0.37-3.33 mg/kg, respectively. The health risk analysis of individual heavy metals in the fish tissue indicated dangerous levels of Pb and Cd for the general population at some sampling sites. PMID- 25796543 TI - Metals in Mediterranean aquatic species. AB - Metals such as arsenic (As), cadmium (Cd), copper (Cu), chromium (Cr), nickel (Ni), lead (Pb), vanadium (V), have been determined in species of Mediterranean marine organisms collected from areas supposed to be at background contamination levels. The Inductively Coupled Plasma Mass Spectrometry (ICP-MS) approach was adopted for the determination of all the metals. Arsenic, Cd and Pb determined in the 42 samples, do not exceed the pertinent maximum level except a sample of hake. In wild fish, the concentration range for Cr, Ni, V and Cu was, respectively: 0.07-0.09, 87.6-124, 0.022-0.075 and 0.79-1.74 MUg/g fresh weight (fw). The farmed fish samples show concentration levels below the wild fish ones, except for Cr which range at the same levels. Cadmium and Pb show a high sample number under the quantification limit. The elements do not bio-magnify among the species considered and appear to show low variations in relation to organisms' position in the food chain and at sampling sites. PMID- 25796544 TI - Trace elements distribution in hawksbill turtle (Eretmochelys imbricata) and green turtle (Chelonia mydas) tissues on the northern coast of Bahia, Brazil. AB - Concentrations of elements (As, Al, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sr, V, Zn) were determined in liver, kidneys and bones of Eretmochelys imbricata and Chelonia mydas specimens found stranded along the northern coast of Bahia, Brazil. Results showed that the concentrations of Cd, Cu, Ni and Zn in the liver and kidneys of juvenile C. mydas were the highest found in Brazil. We also observed a significant difference (p<0.05) on the bioaccumulation of trace elements between the two species: Al, Co, Mo, Na and Se in the liver; Al, Cr, Cu, K, Mo, Ni, Pb, Sr and V in the kidneys; and Al, Ba, Ca, Cd, Mn, Ni, Pb, Se, Sr and V in the bones. This study represents the first report on the distribution and concentration of trace elements in E. imbricata in the Brazilian coast. PMID- 25796545 TI - More bang for your monitoring bucks: Detection and reporting of non-indigenous species. AB - 'Collect once, use often' is a frequently cited principle in both national and international efforts to promote the collection, archiving and sharing of marine monitoring data. Since the implementation of the Marine Conservation Zone (MCZ) evidence collection programme, 67 recommended MCZ sites have been visited and a suite of marine data collected. Here we present how this dataset was utilised outside of the MCZ programme to identify occurrences of non-indigenous species (NIS) around the UK coast. One hundred and thirty-five aquatic species from the Non-native Species Information Portal (NNSIP) register were used to produce a standard list of NIS against which, infauna and epifaunal data records from the MCZ project were compared. A total of 20 NIS were identified across 42 of the 67 sites surveyed. This study demonstrates that with sufficient coordination and management data collected for other purposes can be easily utilised to address additional policy requirements. PMID- 25796546 TI - Identification, purification and characterization of furfural transforming enzymes from Clostridium beijerinckii NCIMB 8052. AB - Generation of microbial inhibitory compounds such as furfural and 5 hydroxymethylfurfural (HMF) is a formidable roadblock to fermentation of lignocellulose-derived sugars to butanol. Bioabatement offers a cost effective strategy to circumvent this challenge. Although Clostridium beijerinckii NCIMB 8052 can transform 2-3 g/L of furfural and HMF to their less toxic alcohols, higher concentrations present in biomass hydrolysates are intractable to microbial transformation. To delineate the mechanism by which C. beijerinckii detoxifies furfural and HMF, an aldo/keto reductase (AKR) and a short-chain dehydrogenase/reductase (SDR) found to be over-expressed in furfural-challenged cultures of C. beijerinckii were cloned and over-expressed in Escherichia coli Rosetta-gamiTM B(DE3)pLysS, and purified by histidine tag-assisted immobilized metal affinity chromatography. Protein gel analysis showed that the molecular weights of purified AKR and SDR are close to the predicted values of 37 kDa and 27 kDa, respectively. While AKR has apparent Km and Vmax values of 32.4 mM and 254.2 mM s(-1) respectively, using furfural as substrate, SDR showed lower Km (26.4 mM) and Vmax (22.6 mM s(-1)) values on the same substrate. However, AKR showed 7.1-fold higher specific activity on furfural than SDR. Further, both AKR and SDR were found to be active on HMF, benzaldehyde, and butyraldehyde. Both enzymes require NADPH as a cofactor for aldehydes reduction. Based on these results, it is proposed that AKR and SDR are involved in the biotransformation of furfural and HMF by C. beijerinckii. PMID- 25796547 TI - Ultrastructure of the spermatozoon of the digenean Tergestia acanthocephala (Stossich, 1887) (Gymnophalloidea: Fellodistomidae): An intestinal parasite of Belone belone gracilis (Pisces: Teleostei). AB - The ultrastructural organization of the spermatozoon of the digenean Tergestia acanthocephala (Gymnophalloidea: Fellodistomidae) is described. Live digeneans were collected from Belone belone gracilis (Teleostei: Belonidae), caught off the Gulf of Gabes in Chebba (Tunisia). The mature spermatozoon of T. acanthocephala exhibits the general pattern described in numerous digeneans, characterized by the presence of two axonemes of the different length of the 9+'1' pattern of the Trepaxonemata, a nucleus, two mitochondria, two bundles of parallel cortical microtubules, external ornamentation, spine-like bodies and granules of glycogen. Moreover, the morphology of the posterior spermatozoon extremity in T. acanthocephala corresponds to the fasciolidean type of Quilichini et al. (2010a). PMID- 25796548 TI - "Add-on" effect of phytosterols-enriched fermented milk on lipids and markers of cholesterol metabolism in statin-treated elderly patients. AB - The effect of plant sterol (PS) enriched matrices on lipid profile has been evaluated in statin-treated individuals, with LDL-C concentrations between 3.35mmol/L and 4.90mmol/L, but studies in the elderly are scarce. In this study the additional effect of a low-fat PS-enriched fermented milk (PS-FM) on cholesterol metabolism markers and serum lipids was evaluated in the elderly on stable statin therapy with baseline LDL-C<3.35mmol/L. Thirty-five individuals (88.6% women; 81+/-8years old; BMI 29.9+/-6.0kg/m(2)), living in elderly nursing care facilities were placed on a daily intake of 2g PS-FM for 6weeks, in addition to their statin monotherapy. A fasting blood sample was collected at baseline (t0), after 2 consecutive periods of 3weeks intake (t1 and t2), and after 6weeks of washout (t3), for the analysis of serum lipid profile and cholesterol synthesis (lathosterol, desmosterol) and absorption (sitosterol, campesterol and cholestanol) markers. PS-FM consumption led to a LDL-C reduction of 0.15mmol/L (t1) and 0.27mmol/L (t2) from baseline (P<0.05). Serum campesterol and sitosterol (P<0.001) increased (t0-t1; t0-t2), reflecting PS intake and contributing to the inhibition of cholesterol intestinal absorption, leading to a decrease in cholestanol-to-cholesterol ratio. There was a reciprocal homeostatic rise of serum cholesterol precursors, desmosterol and lathosterol (P<0.001) from baseline, based on the up-regulation of the opposing pathway. Statin-treated elderly individuals, with baseline LDL-C<3.35mmol/L, may still have therapeutic benefit from strategies that reduce cholesterol absorption, such as 2g/day PS-FM. PMID- 25796549 TI - 9,11-Secosteroids with cytotoxic activity from the South China Sea gorgonian coral Subergorgia suberosa. AB - Nine new 9,11-secosterols (1-9), containing the same 3beta,6alpha,11-trihydroxy 9,11-seco-5alpha-cholest-7-en-9-one steroidal nucleus, whereas possessing an array of structurally diverse side chains, along with fourteen known 9,11 secosterol compounds (10-23), were isolated from the South China Sea gorgonian coral Subergorgia suberosa, of which 3/4, 5/6, 7/8, and the known compounds 11/12, 20/21 were five pairs of inseparable C-24 epimers. Their structures were established by the extensive analyses of 1D and 2D NMR spectra, high-resolution chemical ionization mass spectrometry (HRCIMS), and by the comparison with literature data. Cytotoxic effect of these metabolites against the growth of HeLa cell lines was evaluated. The result showed that the inhibitory effect of compounds 1-23 varied considerably depending on the nature of the side chain in spite of sharing the same steroidal nucleus. Compound 19, featuring both the absence of hydroxyl group and the presence of double bond in the stigmasterol side chain, exhibited the most potent cytotoxicity with IC50 being 15.1 MUM. The preliminary structure activity relationship studies identified some important structural features considerably influencing the biological effect deserved, providing valuable information for chemists and pharmacologists to design and synthesize more effective antitumor agents bearing the 9,11-secosteroid framework. PMID- 25796550 TI - Larva migrans in squirrel monkeys experimentally infected with Baylisascaris potosis. AB - Roundworms of the genus Baylisascaris are natural parasites primarily of wild carnivores, and they can occasionally cause infection in humans and animals. Infection results in visceral larva migrans and/or neural larva migrans, which can be severe or fatal in some animals. Recently, Baylisascaris nematodes isolated from kinkajous (Potos flavus) and previously referred to as Baylisascaris procyonis were renamed as Baylisascaris potosis; however, data regarding the pathogenicity of B. potosis towards animals and humans are lacking. In the present study, we experimentally infected squirrel monkeys (Saimiri sciureus) with B. potosis to determine the suitability of the monkey as a primate model. We used embryonated eggs of B. potosis at two different doses (10,000 eggs and 100,000 eggs) and examined the animals at 30 days post-infection. Histopathological examination showed the presence of B. potosis larvae and infiltration of inflammatory cells around a central B. potosis larvae in the brain, intestines, and liver. Nevertheless, the monkeys showed no clinical signs associated with infection. Parasitological examination revealed the presence of B. potosis larvae in the intestines, liver, lung, muscles, brain, kidney, and diaphragm. Our findings extend the range of species that are susceptible to B. potosis and provide evidence for the zoonotic potential of larva migrans in high dose infections. PMID- 25796551 TI - Gonadotrophin-releasing hormone agonists for fertility preservation: unraveling the enigma? AB - STUDY QUESTION: Can gonadotrophin-releasing hormone agonists (GnRH-a) preserve long-term fertility when administered prior to and concomitantly with chemotherapy? SUMMARY ANSWER: GnRH-a display a differential protective effect on fertility, depending upon the specific chemotherapy-induced mechanism of ovarian injury. WHAT IS KNOWN ALREADY: The role of GnRH-a in fertility preservation has been constantly debated and their use is considered experimental due to conflicting clinical evidence and paucity of data regarding their mechanism for ovarian protection. STUDY DESIGN, SIZE, DURATION: In vivo model: 7-8 weeks old imprinting control region (ICR) mice were injected with GnRH-a (Leuprolide acetate) or saline prior to and concomitantly with cyclophosphamide, doxorubicin or saline and sacrificed at various time-points on a longitudinal follow-up; 24 h (n = 36), 1 week (n = 40), 1 month (n = 36) and 9 months (n = 66) post chemotherapy treatment. Blood samples were drawn on Day 0 and on a monthly basis after chemotherapy treatment. On the day of sacrifice, blood samples were drawn and ovaries excised and processed for either immunohistochemistry (IHC), protein or RNA extraction. In vitro model: 21-23 days old Wistar-derived rats were sacrificed, their ovaries excised and primary granulosa cells (PGC) were either isolated for in vitro culture, or processed for immunofluorescence (IF) as well as for protein or RNA extraction. MATERIALS, SETTING, METHODS: Ovarian reserve was estimated by serial measurements of serum anti-mullerian hormone (AMH), quantified by the AMH Gen II ELISA assay. Ovarian AMH and phosphorylated Akt (pAkt) were detected by immunoblotting. Vascular endothelial growth factor (VEGF) was measured by quantitative PCR. Ovarian GnRH receptor (GnRHR), AMH and CD34 were visualized by IHC, and apoptosis was evaluated using TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL). MAIN RESULTS AND THE ROLE OF CHANCE: Cyclophosphamide-induced ovarian injury caused a prompt decrease in AMH level (P < 0.01) and a further long-term decline in serum AMH (P = 0.017), indicating damage to the ovarian reserve. Pretreatment with GnRH a diminished AMH-decrease (P < 0.05) and maintained serum AMH level in the long run (P < 0.05). Doxorubicin-exerted ovarian-vascular-injury is also displayed by an acute increase in ovarian VEGF level (P < 0.05) and a sustained decrease in serum AMH level (P < 0.001). This was followed by ovarian recovery manifested by increased neovascularization. GnRH-a delayed the recovery in AMH level and decreased the level of VEGF (P < 0.001), thus interfering with the vascular recovery subsequent to doxorubicin-induced vascular damage. LIMITATIONS, REASONS FOR CAUTION: To portray the differential mechanism of each chemotherapy, cyclophosphamide and doxorubicin were given separately, whereas most of the clinical protocols include several types of chemotherapies. Thus, future study should explore a prospective evaluation of various chemotherapies, as well as combined chemotherapeutic protocols. WIDER IMPLICATIONS OF THE FINDINGS: Our study demonstrates that different chemotherapy agents affect the ovary via diverse mechanisms and thus the administration of GnRH-a concomitantly, could be beneficial to a subpopulation of patients treated with cyclophosphamide-based protocols. STUDY FUNDING/COMPETING INTERESTS: This work was partially supported by a grant from the Israel Science Foundation (ISF) to I.B.-A. The authors have no conflict of interest to disclose. PMID- 25796552 TI - CRISPR-Cas9: how research on a bacterial RNA-guided mechanism opened new perspectives in biotechnology and biomedicine. PMID- 25796553 TI - Determining Predictors for Intra-abdominal Septic Complications Following Ileocolonic Resection for Crohn's Disease-Considerations in Pre-operative and Peri-operative Optimisation Techniques to Improve Outcome. AB - BACKGROUND AND AIMS: Intra-abdominal septic complications [IASC] following ileocolonic resection for Crohn's disease are common. Determining risk factors for these complications can aid pre-operative and peri-operative strategies to reduced morbidity. This study aims to determine the incidence and predictors of intra-abdominal septic complications following ileocolonic resection for Crohn's disease. METHODS: A single-centre, retrospective study was conducted. The clinical case notes of patients with histopathologically proven Crohn's disease, who underwent an ileocolonic resection as a one-stage or two-stage procedure, were reviewed. The primary endpoint was the formation of intra-abdominal septic complications within a 30-day post-operative time frame. RESULTS: Overall 163 patients underwent 175 ileocolonic procedures. Post-operative intra-abdominal septic complications were demonstrated in 9% [13/142] of one-stage procedures and 12% [4/33] of two-stage procedures [p = 0.2]. Post-operative IASCs following a one-stage procedure demonstrated associations with smokers [p = 0.004], intraoperative abdominal sepsis [p = 0.005], concomitant upper gastrointestinal Crohn's [p = 0.015], the presence of peri-operative anaemia [p = 0.037], hypoalbuminaemia [< 25g/l] [p = 0.04], and histologically involved margins [p = 0.001]. Multivariate analysis demonstrated the presence of intra-abdominal sepsis (hazard ratio [HR] 8.6, 95% confidence interval [CI]: 1.2 60.1] and the use of peri-operative biologicals [HR 24.6, 95% CI: 2.0-298] as independent predictors of post-operative intra-abdominal septic complications. CONCLUSIONS: This study highlights specific variables that may be contributory to poor outcome. These findings may be important when optimising patients for surgery, as well as planning an appropriate operative strategy. Further prospective studies and a larger sample size are required to validate these findings. PMID- 25796554 TI - Retained Capsule in Crohn's Disease: What Happens if I Get Pregnant? PMID- 25796555 TI - How probable is common ancestry according to different evolutionary processes? AB - Darwin and contemporary biologists argue that all present-day life traces back to one or a few common ancestors. Here we investigate the relationship of different evolutionary processes to this hypothesis of common ancestry. We identify the property of an evolutionary process that determines what its probabilistic impact on the common ancestry thesis will be. The point of this exercise is to understand how the parts of Darwin's powerful theory fit together, not to call into question common ancestry or natural selection, since these two pillars of Darwin's theory enjoy strong support. PMID- 25796556 TI - Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein. AB - Our previous studies have demonstrated that expression of epidermal fatty acid binding protein (E-FABP) in tumor associated macrophages (TAMs) promotes macrophage anti-tumor activity by enhancing IFNbeta responses in tumor models. Thus, E-FABP represents a new protective factor in enhancing tumor immune surveillance against tumor development. Herein, we report the compound 5 (benzylamino)-2-(3-methylphenyl)-1,3-oxazole-4-carbonitrile (designated EI-05) as a novel E-FABP activator for inhibition of mammary tumor growth. EI-05 was selected from the ZINC compound library using molecular docking analysis based on the crystal structure of E-FABP. Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation. Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNbeta production, which further promotes the anti-tumor activity of macrophages. Importantly, administering EI-05 in vivo significantly inhibits mammary tumor growth in a syngeneic mouse model. Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti tumor treatment through enhancing E-FABP activity and IFNbeta responses in macrophages. PMID- 25796557 TI - Impact of antimicrobial strategies on clinical outcomes of adults with septic shock and community-onset Enterobacteriaceae bacteremia: de-escalation is beneficial. AB - To investigate the clinical outcomes of patients with septic shock related to community-onset monomicrobial Enterobacteriaceae (CoME) bacteremia as categorized by the strategy of antimicrobial therapy, a retrospective and observational study was conducted. Clinical information on the patients was obtained from medical records. Antibiotic regimens were ranked according to their activity spectrum against Enterobacteriaceae (category IV, highest; I, lowest). De-escalation was defined as a switch to a category with a narrower spectrum of coverage within 5days after the bacteremic onset. Of the 189 eligible patients, 86 (45.5%) patients received de-escalation antibiotic therapy, and most (48, 55.8%) of the patients were empirically treated first with a category IV antibiotic. In a multivariate analysis for 28-day mortality, of several independent predictors, the de-escalation strategy was protective (odds ratio, 0.37; P=0.04). In conclusion, for patients with CoME bacteremia and available susceptibility data, de-escalation of antimicrobial therapy was beneficial for improving clinical outcome. PMID- 25796558 TI - Multiplex gastrointestinal pathogen panels: implications for infection control. AB - In the acute care hospital inpatient setting, there is a wide variety of causes for both infectious and noninfectious diarrhea. However, without molecular assays for the wide range of agents causing gastroenteritis, there is no reliable way to determine which individuals should be placed in contact precautions, as recommended by CDC. We tested 158 inpatient diarrheal stool specimens with the FilmArray GI Panel (BioFire Diagnostics, Salt Lake City, UT, USA) that had been stored at -70 degrees C after testing negative by conventional methods for Clostridium difficile and/or rotavirus. We found that 22.2% had at least 1 other infectious agent detected, and 60% of these patients were never placed in appropriate isolation for a total of 109 patient-days. In addition, 20.3% of patients with negative GI panel results could have been removed from isolation. Use of multiplex gastrointestinal panels may improve decisions regarding patient isolation and reduce nosocomial transmission. PMID- 25796559 TI - Comment on: The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study: reply. PMID- 25796560 TI - Does disease activity at the start of biologic therapy influence health care costs in patients with RA? AB - OBJECTIVE: To investigate whether disease activity at baseline influences health care costs in patients with RA initiating biologic treatment. METHODS: In the Swedish Biologics Register, we identified patients with RA with baseline 28-joint DAS (DAS28) recorded and starting their first biologic in 2007-11 [n = 1638 with moderate disease activity (DAS28 3.2-5.1) and n = 1870 with high disease activity (DAS28 > 5.1)]. Data on inpatient and outpatient care and prescription drugs were retrieved from nationwide registers. Mean cost differences were estimated adjusted for age, sex and costs the year before treatment start. RESULTS: Patients with high (vs moderate) disease activity were older (60 vs 56 years; P < 0.001), but did not differ in sex distribution (75 vs 74% women; P = 0.99) or disease duration (10 vs 10 years; P = 0.13). The year after initiation of biologics, patients with high (vs moderate) baseline disease activity accumulated 9% higher health care costs, but the difference was not statistically significant after adjustment [?19,333 vs ?17,810; adjusted difference ?870 (95% CI -2, 1742)]. In the subgroup of patients with up to 4 years of follow-up data, decreasing costs were observed over the follow-up time, but no difference was found between patients with high compared with moderate baseline disease activity [?13,704 vs ?12,349; adjusted difference 878 (95% CI -364, 2120)]. Irrespective of baseline disease activity, health care costs were approximately three times higher the year after initiation of biologics than the year before due to increased drug costs. CONCLUSION: Over up to 4 years of follow-up, no difference in health care costs was found after adjustment in patients starting their first biologic treatment with high vs moderate baseline disease activity. PMID- 25796561 TI - Purification of dendritic cell and macrophage subsets from the normal mouse small intestine. AB - Mononuclear phagocytes are essential for protecting against pathogens breaching the intestinal mucosa and maintaining the integrity of the gastrointestinal tract. The mononuclear phagocyte family of the healthy intestine is represented by a small population of hematopoietic cells including dendritic cells and macrophages. Distinct mononuclear phagocyte subsets strategically accumulate within and below the mucosal epithelium and are distributed in the submucosa and muscularis externa. Shaped by its unique microenvironment, each mononuclear phagocyte subset is developmentally and functionally unique and phenotypically distinct. Here we summarize our recent advances on identifying and purifying various intestinal mononuclear phagocyte subsets by flow cytometry in the context of their developmental properties and location within the intestinal tissue. PMID- 25796562 TI - Efficient duplex solid-phase fluorescent assay (dFISA) for the simultaneous detection of specific anti-T. gondii IgG and IgM due to refined conjugates. AB - Toxoplasma gondii infections are very common, causing occasional central nervous system and eye diseases, and must be screened in prenatal care for efficient therapy. Here, we developed a duplex solid-phase fluorescent assay (dFISA) for the simultaneous detection of anti-T. gondii IgG and IgM antibodies in prenatal care screening for toxoplasmosis. Assays using commercially available ion exchange purified conjugates yielded poor results and high background fluorescence. Same-well IgG/IgM dFISA with refined conjugates was used to test 140 samples from university students, 120 samples from pregnant women and 24 samples from adult volunteers at a large public hospital. We found that dFISA offers high concordance, specificity and reproducibility for IgG (Kappa=0.883) and IgM (Kappa=0.918), which is useful in high-throughput applications for antenatal care. PMID- 25796563 TI - Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse. AB - Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippocampus, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins. PMID- 25796564 TI - Evaluation of TrkB and BDNF transcripts in prefrontal cortex, hippocampus, and striatum from subjects with schizophrenia, bipolar disorder, and major depressive disorder. AB - Brain-derived neurotrophic factor (BDNF) signaling is integral to a range of neural functions, including synaptic plasticity and exhibits activity-dependent regulation of expression. As altered BDNF signaling has been implicated in multiple psychiatric diseases, here we report a quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis of mRNAs encoding TrkB, total BDNF, and the four most abundant BDNF transcripts (I, IIc, IV, and VI) in postmortem tissue from matched tetrads of subjects with schizophrenia, bipolar disorder, or major depressive disorder (MDD) and healthy comparison subjects. In all three regions examined, dorsolateral prefrontal cortex (DLPFC), associative striatum and hippocampus, total BDNF mRNA levels did not differ in any disease state. In DLPFC, BDNF IIc was significantly lower in schizophrenia relative to healthy comparison subjects. In hippocampus, BDNF I, IIc, and VI were lower in subjects with both schizophrenia and bipolar disorder relative to comparison subjects. In striatum, TrkB mRNA was lower in bipolar disorder and MDD, while BDNF IIc was elevated in MDD, relative to comparison subjects. These data highlight potential alterations in BDNF signaling in the corticohippocampal circuit in schizophrenia, and within the striatum in mood disorders. Novel therapies aimed at improving BDNF-TrkB signaling may therefore have potential to impact on a range of psychiatric disorders. PMID- 25796566 TI - mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy. AB - Compelling evidence indicates that the mammalian target of rapamycin (mTOR) signaling pathway is involved in cellular senescence, organismal aging and age dependent diseases. mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signalling. In multicellular organisms, mTOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy conditions. Growing studies highlight that disturbance in mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function, cell growth and autophagy. All these events are key players in age-related cognitive decline such as development of Alzheimer disease (AD). The current review discusses the main regulatory roles of mTOR signalling in the brain, in particular focusing on autophagy, glucose metabolism and mitochondrial functions. Targeting mTOR in the CNS can offer new prospective for drug discovery; however further studies are needed for a comprehensive understanding of mTOR, which lies at the crossroads of multiple signals involved in AD etiology and pathogenesis. PMID- 25796567 TI - Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice. AB - Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of neurotransmitters. The event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy. The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy. Therefore, we selectively blocked MAGL by JZL184 (8mg/kg, i.p.) in mice to analyze the effects of increased 2-AG levels on kindling acquisition and to exclude an anticonvulsive potential. Our results showed that JZL184 treatment significantly delayed the development of generalized seizures (p=0.0066) and decreased seizure (p<0.0001) and afterdischarge duration (p<0.001) in the kindling model of temporal lobe epilepsy, but caused only modest effects in fully kindled mice. Moreover, we proved that JZL184 treatment had no effects in conditional CB1R knockout mice lacking expression of the receptor in principle neurons of the forebrain. In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures but has no relevant acute anticonvulsive effects. Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated. Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach. PMID- 25796565 TI - Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. AB - Nitric oxide (NO) is a gasotransmitter that impacts fundamental aspects of neuronal function in large measure through S-nitrosylation, a redox reaction that occurs on regulatory cysteine thiol groups. For instance, S-nitrosylation regulates enzymatic activity of target proteins via inhibition of active site cysteine residues or via allosteric regulation of protein structure. During normal brain function, protein S-nitrosylation serves as an important cellular mechanism that modulates a diverse array of physiological processes, including transcriptional activity, synaptic plasticity, and neuronal survival. In contrast, emerging evidence suggests that aging and disease-linked environmental risk factors exacerbate nitrosative stress via excessive production of NO. Consequently, aberrant S-nitrosylation occurs and represents a common pathological feature that contributes to the onset and progression of multiple neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. In the current review, we highlight recent key findings on aberrant protein S-nitrosylation showing that this reaction triggers protein misfolding, mitochondrial dysfunction, transcriptional dysregulation, synaptic damage, and neuronal injury. Specifically, we discuss the pathological consequences of S nitrosylated parkin, myocyte enhancer factor 2 (MEF2), dynamin-related protein 1 (Drp1), protein disulfide isomerase (PDI), X-linked inhibitor of apoptosis protein (XIAP), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) under neurodegenerative conditions. We also speculate that intervention to prevent these aberrant S-nitrosylation events may produce novel therapeutic agents to combat neurodegenerative diseases. PMID- 25796568 TI - Tonic zinc inhibits spontaneous firing in dorsal cochlear nucleus principal neurons by enhancing glycinergic neurotransmission. AB - In many synapses of the CNS, mobile zinc is packaged into glutamatergic vesicles and co-released with glutamate during neurotransmission. Following synaptic release, the mobilized zinc modulates ligand- and voltage-gated channels and receptors, functioning as an inhibitory neuromodulator. However, the origin and role of tonic, as opposed to phasically released, zinc are less well understood. We investigated tonic zinc in the dorsal cochlear nucleus (DCN), a zinc-rich, auditory brainstem nucleus. Our results show that application of a high-affinity, extracellular zinc chelator (ZX1) enhances spontaneous firing in DCN principal neurons (fusiform cells), consistent with inhibition of this neuronal property by tonic zinc. The enhancing effect was prevented by prior application of strychnine, a glycine receptor antagonist, suggesting that ZX1 interferes with zinc-mediated modulation of spontaneous glycinergic inhibition. In particular, ZX1 decreased the amplitude and the frequency of glycinergic miniature inhibitory postsynaptic currents in fusiform cells, from which we conclude that tonic zinc enhances glycinergic inhibitory neurotransmission. The observed zinc-mediated inhibition in spontaneous firing is present in mice lacking the vesicular zinc transporter (ZnT3), indicating that non-vesicular zinc inhibits spontaneous firing. Noise-induced increase in the spontaneous firing of fusiform cells is crucial for the induction of tinnitus. In this context, tonic zinc provides a powerful break of spontaneous firing that may protect against pathological run-up of spontaneous activity in the DCN. PMID- 25796569 TI - Caspase-2 modulates osteoclastogenesis through down-regulating oxidative stress. AB - The loss of caspase-2 (Casp-2) in mice results in an osteopenic phenotype associated with increased numbers of osteoclasts in vivo. In this study, we show that Casp-2 is involved in osteoclastogenesis. Protein levels of Casp-2 decrease during the differentiation of macrophages to osteoclasts. Furthermore, siRNA mediated Casp-2 knockdown in osteoclast precursors or differentiation of bone marrow macrophage (BMM) precursors from Casp2(-/-) mice results in increased osteoclast numbers and tartrate-resistant acid phosphatase (TRAP) activity. Casp2(-/-) osteoclasts are larger in size compared to wild-type osteoclasts and exhibited increased numbers of nuclei, perhaps due to increased precursor fusion. The loss of Casp-2 did not alter earlier stages of differentiation, but had a greater consequence on later stages involving NFATc1 auto-amplification and pre osteoclast fusion. We have previously shown that the loss of Casp-2 results in increased oxidative stress in the bone. Reactive oxygen species (ROS) is known to play a critical role in late osteoclast differentiation and we show that total ROS and specifically, mitochondrial ROS, significantly increased in Casp2(-/-) BMM precursors after RANKL administration, with a concomitant reduction in FoxO3a and its target antioxidant enzymes, catalase and superoxide 2 (SOD2). Because mitochondrial ROS has been identified as a putative regulator of the later stages of differentiation, the heightened ROS levels in Casp2(-/-) cells likely promote precursor fusion and increased osteoclast numbers. In conclusion, our results indicate a novel role of Casp-2 in the osteoclast as a modulator of total and mitochondrial ROS and osteoclast differentiation. PMID- 25796570 TI - Iodine supplementation and drinking-water perchlorate mitigation. AB - Ensuring adequate iodine intake is important, particularly among women of reproductive age, because iodine is necessary for early life development. Biologically based dose-response modeling of the relationships among iodide status, perchlorate dose, and thyroid hormone production in pregnant women has indicated that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia. We evaluated the possibility of increasing iodine intake to offset potential risks from perchlorate exposure. We also explored the effect of dietary exposures to nitrate and thiocyanate on iodine uptake and thyroid hormone production. Our modeling indicates that the level of thyroid hormone perturbation associated with perchlorate exposures in the range of current regulatory limits is extremely small and would be overwhelmed by other goitrogen exposures. Our analysis also shows that microgram levels of iodine supplementation would be sufficient to prevent the goitrogenic effects of perchlorate exposure at current regulatory limits among at risk individuals. The human health risks from supplementing drinking water with iodine are negligible; therefore, this approach is worthy of regulatory consideration. PMID- 25796571 TI - An electrocardiographic, molecular and biochemical approach to explore the cardioprotective effect of vasopressin and milrinone against phosphide toxicity in rats. AB - The present study was conducted to identify the protective effect of vasopressin (AVP) and milrinone on cardiovascular function, mitochondrial complex activities, cellular ATP reserve, oxidative stress, and apoptosis in rats poisoned by aluminum phosphide (AlP). Rats were divided into five groups (n = 12) including control, AlP (12.5 mg/kg), AlP + AVP (2.0 Units/kg), AlP + milrinone (0.25 mg/kg) and AlP + AVP + milrinone. After treatment, the animals were connected to an electronic cardiovascular monitoring device to monitor electrocardiographic (ECG) parameter. Finally, oxidative stress biomarkers, mitochondrial complex activities, ADP/ATP ratio and apoptosis were evaluated on the heart tissues. Results indicated that AlP administration induced ECG abnormalities along with a decline in blood pressure and heart rate. AVP and milrinone significantly ameliorated these changes in all treated groups. Considerable protective effects on oxidative stress biomarkers, complex IV activity, ADP/ATP ratio and caspase-3 and -9 activities in treated groups were also found. These findings were supported by flow cytometry assay of cardiomyocytes. In conclusion, administration of AVP and milrinone, not only improve cardiovascular functions in AlP poisoned rats in the short time, but after a long time can also restore mitochondrial function and ATP level and reduce the oxidative damage, which prevent cardiomyocytes from entering the apoptotic phase. PMID- 25796573 TI - Klhl31 attenuates beta-catenin dependent Wnt signaling and regulates embryo myogenesis. AB - Klhl31 is a member of the Kelch-like family in vertebrates, which are characterized by an amino-terminal broad complex tram-track, bric-a-brac/poxvirus and zinc finger (BTB/POZ) domain, carboxy-terminal Kelch repeats and a central linker region (Back domain). In developing somites Klhl31 is highly expressed in the myotome downstream of myogenic regulators (MRF), and it remains expressed in differentiated skeletal muscle. In vivo gain- and loss-of-function approaches in chick embryos reveal a role of Klhl31 in skeletal myogenesis. Targeted mis expression of Klhl31 led to a reduced size of dermomyotome and myotome as indicated by detection of relevant myogenic markers, Pax3, Myf5, myogenin and myosin heavy chain (MF20). The knock-down of Klhl31 in developing somites, using antisense morpholinos (MO), led to an expansion of Pax3, Myf5, MyoD and myogenin expression domains and an increase in the number of mitotic cells in the dermomyotome and myotome. The mechanism underlying this phenotype was examined using complementary approaches, which show that Klhl31 interferes with beta catenin dependent Wnt signaling. Klhl31 reduced the Wnt-mediated activation of a luciferase reporter in cultured cells. Furthermore, Klhl31 attenuated secondary axis formation in Xenopus embryos in response to Wnt1 or beta-catenin. Klhl31 mis expression in the developing neural tube affected its dorso-ventral patterning and led to reduced dermomyotome and myotome size. Co-transfection of a Wnt3a expression vector with Klhl31 in somites or in the neural tube rescued the phenotype and restored the size of dermomyotome and myotome. Thus, Klhl31 is a novel modulator of canonical Wnt signaling, important for vertebrate myogenesis. We propose that Klhl31 acts in the myotome to support cell cycle withdrawal and differentiation. PMID- 25796572 TI - Glutamate and GABA imbalance following traumatic brain injury. AB - Traumatic brain injury (TBI) leads to multiple short- and long-term changes in neuronal circuits that ultimately conclude with an imbalance of cortical excitation and inhibition. Changes in neurotransmitter concentrations, receptor populations, and specific cell survival are important contributing factors. Many of these changes occur gradually, which may explain the vulnerability of the brain to multiple mild impacts, alterations in neuroplasticity, and delays in the presentation of posttraumatic epilepsy. In this review, we provide an overview of normal glutamate and GABA homeostasis and describe acute, subacute, and chronic changes that follow injury. We conclude by highlighting opportunities for therapeutic interventions in this paradigm. PMID- 25796574 TI - [Colonic ulcers associated with taking Kayexalate((r)) (sodium polystyrene sulfonate): about two cases]. AB - We report two cases of patients with chronic renal failure showing rectal bleeding due to digestive ulcers, associated with Kayexalate((r)) alone. Kayexalate((r)) crystals correspond to a typical histological picture and it is important to know how to identify them in order to discuss a possible pathogenicity. PMID- 25796575 TI - Exploring the Strange New World of Non-Celiac Gluten Sensitivity. PMID- 25796576 TI - Minor Disorders of Esophageal Peristalsis: Highly Prevalent, Minimally Relevant? PMID- 25796577 TI - The functions of the avian receptor activator of NF-kappaB ligand (RANKL) and its receptors, RANK and osteoprotegerin, are evolutionarily conserved. AB - A new member of the chicken TNF superfamily has recently been identified, namely receptor activator of NF-kappaB ligand (RANKL), as have its signalling receptor, RANK, and its decoy receptor, osteoprotegerin (OPG). In mammals, RANKL and RANK are transmembrane proteins expressed on the surface of Th1 cells and dendritic cells (DC) respectively, whereas OPG is expressed as a soluble protein from osteoblasts and DC. Recombinant soluble chicken RANKL (chRANKL) forms homotrimers whereas chicken OPG (chOPG) forms homodimers, characteristic of these molecules in mammals. ChRANKL, chRANK and chOPG are expressed at the mRNA level in most tissues and organs. ChRANKL is transcriptionally regulated by Ca(2+) mobilisation and enhances the mRNA expression levels of pro-inflammatory cytokines in bone marrow-derived DC (BMDC); this is inhibited by both chOPG-Fc and soluble chRANK Fc. However, chRANKL does not enhance the expression of cell surface markers in either BMDC or BM-derived macrophages (BMM). Furthermore, chRANKL enhances the survival of APC similar to its mammalian orthologue. PMID- 25796578 TI - Economic evaluation of a telephone- and face-to-face-delivered counseling intervention for smoking cessation in patients with coronary heart disease. AB - OBJECTIVE: This study examined the cost-effectiveness and cost-utility of two smoking cessation counseling interventions differing in their modality for patients diagnosed with coronary heart disease from a societal perspective. METHODS: In a randomized controlled trial conducted in Dutch hospital wards, cardiac patients who smoked prior to admission were allocated to usual care (n = 245), telephone counseling (n = 223) or face-to-face counseling (n = 157). The counseling interventions lasted for 3 months and were complemented by nicotine patches. Baseline histories were obtained, and interviews took place 6 months after hospitalization to assess self-reported smoking status and quality adjusted life years (QALYs). Incremental cost-effectiveness ratios per quitter and cost utility ratios per QALY were calculated and presented in acceptability curves. Uncertainty was accounted for by sensitivity analysis. RESULTS: Using continued abstinence as the outcome measure showed that telephone counseling had the highest probability of being cost-effective. Face-to-to-face counseling was also more cost-effective than usual care. No significant improvements and differences in QALYs between the three conditions were found. Varying costs and effect estimations revealed that the results of the primary analyses were robust. CONCLUSIONS: Assuming a willingness-to-pay of ?20,000 per abstinent patient, telephone counseling would be a highly cost-effective smoking cessation intervention assisting cardiac patients to quit. However, the lack of consensus concerning the willingness-to-pay per quitter impedes drawing firm conclusions. Moreover, studies with extended follow-up periods are needed to capture late relapses and possible differences in QALYs. PMID- 25796579 TI - Effect of Immunosuppressive Therapies for the Treatment of Inflammatory Bowel Disease on Response to Routine Vaccinations: A Meta-Analysis. AB - BACKGROUND: Several studies have evaluated the effect of immunosuppressive therapy for the treatment of inflammatory bowel disease (IBD) on response to routine vaccinations. The overall effect of specific classes of medications (i.e., immunomodulator vs. biologics) on vaccine response remains undefined. The aim of this study was to determine the effect of each class of immunosuppressive therapy in IBD patients on response to routine vaccinations. METHODS: A comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and Cochrane databases was performed (December 2014). All studies on adults comparing vaccine response among IBD patients on immunosuppression with non-immunosuppressed patients were included. Meta-analysis was performed using the Mantel-Haenszel (fixed effects) model with odds ratio (OR) to assess for adequate vaccine response. RESULTS: In the pooled analysis of nine studies (N = 1474), we found that there was nearly a 60 % lower chance of achieving adequate seroprotection in the group that received immunosuppressive therapy compared to the group that was not on any immunosuppressive therapies (OR 0.41 95 % CI 0.30, 0.55, p < 0.001). Specifically, we also demonstrated that patients on immunomodulator monotherapy had a twofold higher probability of achieving adequate immune response to vaccination, compared to patients on anti-tumor necrosis factor (anti-TNF) monotherapy (OR 1.92 95 % CI 1.30, 2.84). CONCLUSION: In conclusion, IBD patients on immunosuppressive therapy have a significantly lower response to routine vaccinations. The greatest effect is seen among patients on anti-TNF and combination immunosuppressive therapy. Routine monitoring of vaccine titers post vaccination is important to ensure that adequate immunologic response has been achieved among IBD patients. PMID- 25796580 TI - Erratum to: Safety of Non-anesthesia Provider-Administered Propofol (NAAP) Sedation in Advanced Gastrointestinal Endoscopic Procedures: Comparative Meta Analysis of Pooled Results. PMID- 25796581 TI - Arterial and portal venous liver perfusion using selective spin labelling MRI. AB - PURPOSE: To investigate the feasibility of selective arterial and portal venous liver perfusion imaging with spin labelling (SL) MRI, allowing separate labelling of each blood supply. METHODS: The portal venous perfusion was assessed with a pulsed EPISTAR technique and the arterial perfusion with a pseudo-continuous sequence. To explore precision and reproducibility, portal venous and arterial perfusion were separately quantified in 12 healthy volunteers pre- and postprandially (before and after meal intake). In a subgroup of 6 volunteers, the accuracy of the absolute portal perfusion and its relative postprandial change were compared with MRI flow measurements of the portal vein. RESULTS: The portal venous perfusion significantly increased from 63 +/- 22 ml/100g/min preprandially to 132 +/- 42 ml/100g/min postprandially. The arterial perfusion was lower with 35 +/- 22 preprandially and 22 +/- 30 ml/100g/min postprandially. The pre- and postprandial portal perfusion using SL correlated well with flow-based perfusion (r(2) = 0.71). Moreover, postprandial perfusion change correlated well between SL and flow-based quantification (r(2) = 0.77). The SL results are in range with literature values. CONCLUSION: Selective spin labelling MRI of the portal venous and arterial blood supply successfully quantified liver perfusion. This non invasive technique provides specific arterial and portal venous perfusion imaging and could benefit clinical settings where contrast agents are contraindicated. KEY POINTS: * Perfusion imaging of the liver by Spin Labelling MRI is feasible * Selective Spin Labelling MRI assessed portal venous and arterial liver perfusion separately * Spin Labelling based portal venous liver perfusion showed significant postprandial increase * Spin Labelling based portal perfusion correlated well with phase-contrast based portal perfusion * This non-invasive technique could benefit settings where contrast agents are contraindicated. PMID- 25796582 TI - Treatment of male varicoceles by transcatheter polidocanol foam sclerotherapy: evaluation of clinical success, complications, and patients' satisfaction with regard to alternative techniques. AB - OBJECTIVES: We report our experience with polidocanol foam sclerotherapy with no additional coils, evaluating clinical success, patients' satisfaction, and complications. METHODS: We conducted a retrospective study of 141 patients with 146 varicoceles (mean age: 29.3 years; range: 13 - 60 years) who underwent foam sclerotherapy with polidocanol 2% (range: 2 - 12 ml) in an outpatient setting between January 2007 and December 2013. For the follow-up, telephone interviews with the patients were conducted (mean follow-up time: 46.4 months, standard deviation: 20.17 months). RESULTS: The technical success rate was 91.8%. There was a 55.8% response rate to the telephone interviews. Follow-up revealed a clinical success rate of 83.9% and a persistence or relapse rate of 16.1%. Of the patients, 81.9% were absolutely satisfied with the outcome. In 94.9% of cases, pain or discomfort resolution was reported, and in 97% of cases, aesthetic issues were no longer a problem. Of partners, 63.2% achieved pregnancy, and in 50% of patients with preprocedural testicular atrophy, catch-up growth was observed. One patient with pampiniform plexus phlebitis received inpatient treatment with no long-term damage recorded. CONCLUSIONS: Polidocanol foam varicocele sclerotherapy is a safe and effective procedure, with a high rate of patients' satisfaction, clinical and technical success, and considerable catch-up growth and pregnancy achievement. KEY POINTS: * Varicocele treatment using polidocanol foam sclerotherapy is a safe and effective procedure. * It is easily feasible in an outpatient setting. * The clinical and technical success rates are high. * It shows a high rate of patients' satisfaction and symptom resolution. * Postinterventional catch-up growth and pregnancy achievement are considerable. PMID- 25796583 TI - Differences in genetic variation in antigen-processing machinery components and association with cervical carcinoma risk in two Indonesian populations. AB - Genetic variation of antigen-processing machinery (APM) components has been shown to be associated with cervical carcinoma risk and outcome in a genetically homogeneous Dutch population. However, the role of APM component single nucleotide polymorphisms (SNPs) in genetically heterogeneous populations with different distributions of human papillomavirus (HPV) subtypes remains unclear. Eleven non-synonymous, coding SNPs in the TAP1, TAP2, LMP2, LMP7 and ERAP1 genes were genotyped in cervical carcinoma patients and healthy controls from two distinct Indonesian populations (Balinese and Javanese). Individual genotype and allele distributions were investigated using single-marker analysis, and combined SNP effects were assessed by haplotype construction and haplotype interaction analysis. Allele distribution patterns in Bali and Java differed in relation to cervical carcinoma risk, with four ERAP1 SNPs and one TAP2 SNP in the Javanese population showing significant association with cervical carcinoma risk, while in the Balinese population, only one TAP2 SNP showed this association. Multimarker analysis demonstrated that in the Javanese patients, one specific haplotype, consisting of the ERAP1-575 locus on chromosome 5 and the TAP2-379 and TAP2-651 loci on chromosome 6, was significantly associated with cervical carcinoma risk (global P = 0.008); no significant haplotype associations were found in the Balinese population. These data indicate not only that genetic variation in APM component genes is associated with cervical carcinoma risk in Indonesia but also that the patterns of association differ depending on background genetic composition and possibly on differences in HPV type distribution. PMID- 25796584 TI - A study to evaluate the safety of platelet-derived growth factor for treatment of osteochondral defects of the talus. AB - PURPOSE: An arthroscopic procedure for the treatment of osteochondral defects using platelet-derived growth factor (PDGF) carried out in a matrix of tricalcium phosphate was developed. This prospective, case-series-based study was designed to evaluate the safety and clinical utility of this procedure. METHODS: Patients with an isolated osteochondral defect larger than 5 mm long, 3 mm wide, and 5 mm deep and smaller than 30 mm long, 25 mm wide, or 20 mm deep were considered for enrolment. Only patients with chronic lesions were enroled. Arthroscopic debridement was followed by the placement of recombinant human PDGF in a matrix of tricalcium phosphate. The Ankle Osteoarthritis Scale (AOS), visual analogue scale (VAS) for pain, and SF-36 questionnaires were administered at 0, 2, 6, 12, and 24 weeks. Magnetic resonance imaging (MRI) and computed tomography (CT) scans were taken before and after surgery. RESULTS: Five patients were ultimately enroled in this proof-of-concept trial. All outcome measures demonstrated marked improvement from baseline to final follow-up: The mean weight bearing VAS pain score improved by 49%, and the mean AOS functional score improved by 28%. Bone healing was seen on CT, and reduction in oedema signal was seen on MRI. CONCLUSION: This new procedure may offer a promising alternative for the treatment of osteochondral defects. Further high-quality studies are needed to confirm these results and to analyse the long-term effects of the procedure. The clinical relevance of this study is that the procedure may provide a less invasive option with improved bone healing compared to standard techniques . LEVEL OF EVIDENCE: IV. PMID- 25796585 TI - Can platelet-rich plasma have a role in Achilles tendon surgical repair? AB - PURPOSE: Our hypothesis was that the Achilles tendon healing process after surgical treatment would be promoted by PRP with a faster return to sports activities. METHODS: Thirty patients with Achilles tendon rupture and surgically treated with a combined mini-open and percutaneous technique were prospectively enroled in the study. Patients were alternately case-by-case assigned to Group A (control group; 15 patients) or Group B (study group; 15 patients). In Group B, PRP was locally infiltrated both during surgery and 14 days after surgery. Patients in both groups were followed up at 1, 3, 6 and 24 months post operatively via physical examination, VAS, FAOS and VISA-A scales; ultrasonography (US) and MRI were also conducted at one and 6 months; at the 6 month follow-up, isokinetic and jumping capacity tests were also performed. RESULTS: The VAS, FAOS and VISA-A scale showed no difference between the two groups at 1, 3, 6 and 24 months post-operatively. Isokinetic evaluation showed no differences at both angular speeds. Jumping evaluation showed no difference at 6 months. Also US evaluation showed no differences. MRI data analysis before administration of gadolinium did not reveal significant differences between the two groups. Moreover, after intravenous injection of gadolinium, patients in Group B showed signal enhancement in 30 % of patients compared to 80 % in Group A at 6 months, as indirect evidence of better tendon remodelling (P < 0.05). CONCLUSIONS: A substantial equivalence in structural and functional results in Achilles tendon ruptures surgically treated with and without addition of PRP is shown by present study. Clinical results, morphological features and jumping capability were similar in both groups. The addition of PRP to the surgical treatment of Achilles tendon rupture does not appear to offer superior clinical and functional results. LEVEL OF EVIDENCE: IV. PMID- 25796586 TI - Large strengthening effect of a hip-flexor training programme: a randomized controlled trial. AB - PURPOSE: To investigate the effect on hip-flexion strength of a 6-week hip-flexor training programme using elastic bands as resistance. We hypothesized that the training group, compared to a control group, would increase their hip-flexion strength more. METHODS: Thirty-three healthy subjects (45 % females), 24(5) years of age, were included in a randomized controlled trial and allocated to heavy strength training of the hip-flexor muscles or to control (no strength training). Strength training of the hip-flexors (dominant leg) was performed three times 10 min per week for 6 weeks. The strength training group progressed from 15 repetition maximum (RM) (week 1) to 8 RM (week 6). Isometric hip-flexion strength (primary outcome) was measured by a blinded assessor using a reliable test procedure. RESULTS: In the strength training group, the isometric hip-flexion strength of the trained leg increased by 17 %, (p < 0.001). The between-group difference in hip-flexion strength change in the trained leg (dominant leg, training group) versus the non-trained leg (dominant leg, control group) was significantly different from baseline to follow-up, corresponding to a mean change of 0.34 (95 % CI 0.17-0.52) Nm/kg, in favour of the strength training group (p < 0.001). CONCLUSION: Simple hip-flexor strength training using elastic bands as external loading, for only 6 weeks, substantially improves hip-flexor muscle strength. This simple exercise programme seems promising for future prevention and treatment of acute and longstanding hip-flexor injuries, such as acute rectus femoris injuries and longstanding iliopsoas-related pain and impingement. LEVEL OF EVIDENCE: I. PMID- 25796587 TI - The application of data mining techniques to oral cancer prognosis. AB - This study adopted an integrated procedure that combines the clustering and classification features of data mining technology to determine the differences between the symptoms shown in past cases where patients died from or survived oral cancer. Two data mining tools, namely decision tree and artificial neural network, were used to analyze the historical cases of oral cancer, and their performance was compared with that of logistic regression, the popular statistical analysis tool. Both decision tree and artificial neural network models showed superiority to the traditional statistical model. However, as to clinician, the trees created by the decision tree models are relatively easier to interpret compared to that of the artificial neural network models. Cluster analysis also discovers that those stage 4 patients whose also possess the following four characteristics are having an extremely low survival rate: pN is N2b, level of RLNM is level I-III, AJCC-T is T4, and cells mutate situation (G) is moderate. PMID- 25796588 TI - Chaperones-assisted soluble expression and maturation of recombinant Co-type nitrile hydratase in Escherichia coli to avoid the need for a low induction temperature. AB - Nitrile hydratase (NHase) is an important industrial enzyme that biosynthesizes high-value amides. However, most of NHases expressed in Escherichia coli easily aggregate to inactive inclusion bodies unless the induction temperature is reduced to approximately 20 degrees C. The NHase from Aurantimonas manganoxydans has been functionally expressed in E. coli, and exhibits considerable potential for the production of nicotinamide in industrial application. In this study, the effects of chaperones including GroEL/ES, Dnak/J-GrpE and trigger factor on the expression of the recombinant Co-type NHase were investigated. The results indicate that three chaperones can significantly promote the active expression of the recombinant NHase at 30 degrees C. The total NHase activities reached to 263 and 155U/ml in shake flasks when the NHase was co-expressed with GroEL/ES and DnaK/J-GrpE, which were 52- and 31-fold higher than the observed activities without chaperones, respectively. This increase is possibly due to the soluble expression of the recombinant NHase assisted by molecular chaperones. Furthermore, GroEL/ES and DnaK/J-GrpE were determined to promote the maturation of the Co-type NHase in E. coli under the absence of the parental activator gene. These knowledge regarding the chaperones effect on the NHase expression are useful for understanding the biosynthesis of Co-type NHase. PMID- 25796589 TI - A case of C3 glomerulonephritis successfully treated with eculizumab. AB - BACKGROUND: C3 glomerulonephritis (C3GN) is a rare form of glomerulopathy that is characterized by predominant C3 deposits. Eculizumab, a humanized monoclonal C5 antibody, has recently emerged as a treatment option for C3GN. We report a C3GN patient successfully treated with eculizumab. CASE DIAGNOSIS/TREATMENT: A 5-year old boy who presented with proteinuria, hematuria, high ASO titers, and low C3 levels was initially diagnosed with post-streptococcal GN. His first kidney biopsy confirmed this diagnosis, but complement investigations identified three alternative pathway dysregulation factors: C3 nephritic factor, complement factor I heterozygous mutation (I398L), and anti-factor H autoantibodies (4,500 AU/ml). A second biopsy performed 11 months after initial presentation (nephrotic range proteinuria) showed a C3GN suggestive of isolated C3 deposits. Despite the use of intensive immunosuppressive therapy (rituximab, corticosteroids, mycophenolate), nephrotic-range proteinuria persisted and a third kidney biopsy showed the same C3GN pattern with more endocapillary proliferation. The serum C5b-9 level was elevated. Eculizumab was initiated and resulted in a significant decline of proteinuria (5.3 to 1.3 g/day) and an improvement in pathologic features. A transient interruption of eculizumab resulted in a rapid rise in proteinuria to 9.3 g/day, which decreased to 0.8 g/day after resumption of treatment. CONCLUSIONS: The administration of anti-C5 antibodies may represent a valuable therapeutic option in patients with C3GN. PMID- 25796591 TI - Soft Bodies, Hard Jaws: An Introduction to the Symposium, with Rotifers as Models of Jaw Diversity. AB - Jaws have evolved numerous times in the animal kingdom and they display a wide variety of structural, compositional, and functional characteristics that reflect their polyphyletic origins. Among soft-bodied invertebrates, jaws are known from annelids, chaetognaths, flatworms, gnathostomulids, micrognathozoans, mollusks, rotifers, and several ecdysozoans. Depending on the taxon, jaws may function in the capture of prey (e.g., chaetognaths and flatworms), processing of prey (e.g., gnathostomulids and onychophorans), or both (e.g., rotifers). Although structural diversity among invertebrates' jaws is becoming better characterized with the use of electron microscopy, many details remain poorly described, including neuromuscular control, elemental composition, and physical characteristics, such as hardness and resistance to wear. Unfortunately, absence of relevant data has impeded understanding of their functional diversity and evolutionary origins. With this symposium, we bring together researchers of disparately jawed taxa to draw structural and mechanistic comparisons among species to determine their commonalities. Additionally, we show that rotifers' jaws, which are perhaps the best-characterized jaws among invertebrates, are still enigmatic with regard to their origins and mechanics. Nevertheless, technologies such as energy dispersive X-ray spectroscopy (EDX) and 3D modeling are being used to characterize their chemical composition and to develop physical models that allow exploration of their mechanical properties, respectively. We predict that these methods can also be used to develop biomimetic and bioinspired constructs based on the full range of the complexity of jaws, and that such constructs also can be developed from other invertebrate taxa. These approaches may also shed light on common developmental and physiological processes that facilitate the evolution of invertebrates' jaws. PMID- 25796590 TI - Standardization of the experimental autoimmune myasthenia gravis (EAMG) model by immunization of rats with Torpedo californica acetylcholine receptors- Recommendations for methods and experimental designs. AB - Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR) is characterized by a chronic, fatigable weakness of voluntary muscles. The production of autoantibodies involves the dysregulation of T cells which provide the environment for the development of autoreactive B cells. The symptoms are caused by destruction of the postsynaptic membrane and degradation of the AChR by IgG autoantibodies, predominantly of the G1 and G3 subclasses. Active immunization of animals with AChR from mammalian muscles, AChR from Torpedo or Electrophorus electric organs, and recombinant or synthetic AChR fragments generates a chronic model of MG, termed experimental autoimmune myasthenia gravis (EAMG). This model covers cellular mechanisms involved in the immune response against the AChR, e.g. antigen presentation, T cell-help and regulation, B cell selection and differentiation into plasma cells. Our aim is to define standard operation procedures and recommendations for the rat EAMG model using purified AChR from the Torpedo californica electric organ, in order to facilitate more rapid translation of preclinical proof of concept or efficacy studies into clinical trials and, ultimately, clinical practice. PMID- 25796592 TI - Cannabinoids for the Treatment of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trials. AB - An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain. PMID- 25796593 TI - Factor VII deficiency presenting as a possible child abuse. PMID- 25796594 TI - Linking acknowledgement to action: closing the loop on non-urgent, clinically significant test results in the electronic health record. AB - Failure to follow-up nonurgent, clinically significant test results (CSTRs) is an ambulatory patient safety concern. Tools within electronic health records (EHRs) may facilitate test result acknowledgment, but their utility with regard to nonurgent CSTRs is unclear. We measured use of an acknowledgment tool by 146 primary care physicians (PCPs) at 13 network-affiliated practices that use the same EHR. We then surveyed PCPs to assess use of, satisfaction with, and desired enhancements to the acknowledgment tool. The rate of acknowledgment of non-urgent CSTRs by PCPs was 78%. Of 73 survey respondents, 72 reported taking one or more actions after reviewing a CSTR; fewer (40-75%) reported that using the acknowledgment tool was helpful for a specific purpose. Forty-six (64%) were satisfied with the tool. Both satisfied and nonsatisfied PCPs reported that enhancements linking acknowledgment to routine actions would be useful. EHR vendors should consider enhancements to acknowledgment functionality to ensure follow-up of nonurgent CSTRs. PMID- 25796595 TI - Clinical information modeling processes for semantic interoperability of electronic health records: systematic review and inductive analysis. AB - OBJECTIVE: This systematic review aims to identify and compare the existing processes and methodologies that have been published in the literature for defining clinical information models (CIMs) that support the semantic interoperability of electronic health record (EHR) systems. MATERIAL AND METHODS: Following the preferred reporting items for systematic reviews and meta-analyses systematic review methodology, the authors reviewed published papers between 2000 and 2013 that covered that semantic interoperability of EHRs, found by searching the PubMed, IEEE Xplore, and ScienceDirect databases. Additionally, after selection of a final group of articles, an inductive content analysis was done to summarize the steps and methodologies followed in order to build CIMs described in those articles. RESULTS: Three hundred and seventy-eight articles were screened and thirty six were selected for full review. The articles selected for full review were analyzed to extract relevant information for the analysis and characterized according to the steps the authors had followed for clinical information modeling. DISCUSSION: Most of the reviewed papers lack a detailed description of the modeling methodologies used to create CIMs. A representative example is the lack of description related to the definition of terminology bindings and the publication of the generated models. However, this systematic review confirms that most clinical information modeling activities follow very similar steps for the definition of CIMs. Having a robust and shared methodology could improve their correctness, reliability, and quality. CONCLUSION: Independently of implementation technologies and standards, it is possible to find common patterns in methods for developing CIMs, suggesting the viability of defining a unified good practice methodology to be used by any clinical information modeler. PMID- 25796596 TI - Virtualization of open-source secure web services to support data exchange in a pediatric critical care research network. AB - OBJECTIVES: To examine the feasibility of deploying a virtual web service for sharing data within a research network, and to evaluate the impact on data consistency and quality. MATERIAL AND METHODS: Virtual machines (VMs) encapsulated an open-source, semantically and syntactically interoperable secure web service infrastructure along with a shadow database. The VMs were deployed to 8 Collaborative Pediatric Critical Care Research Network Clinical Centers. RESULTS: Virtual web services could be deployed in hours. The interoperability of the web services reduced format misalignment from 56% to 1% and demonstrated that 99% of the data consistently transferred using the data dictionary and 1% needed human curation. CONCLUSIONS: Use of virtualized open-source secure web service technology could enable direct electronic abstraction of data from hospital databases for research purposes. PMID- 25796597 TI - A needs assessment of health information technology for improving care coordination in three leading patient-centered medical homes. AB - OBJECTIVE: We investigated ways that patient-centered medical homes (PCMHs) are currently using health information technology (IT) for care coordination and what types of health IT are needed to improve care coordination. MATERIALS AND METHODS: A multi-disciplinary team of researchers conducted semi-structured telephone interviews with 28 participants from 3 PCMHs in the United States. Participants included administrators and clinicians from PCMHs, electronic health record (EHR) and health information exchange (HIE) representatives, and policy makers. RESULTS: Participants identified multiple barriers to care coordination using current health IT tools. We identified five areas in which health IT can improve care coordination in PCMHs: 1) monitoring patient populations, 2) notifying clinicians and other staff when specific patients move across care settings, 3) collaborating around patients, 4) reporting activities, and 5) interoperability. To accomplish these tasks, many participants described using homegrown care coordination systems separate from EHRs. DISCUSSION: The participants in this study have resources, experience, and expertise with using health IT for care coordination, yet they still identified multiple areas for improvement. We hypothesize that focusing health IT development in the five areas we identified can enable more effective care coordination. Key findings from this work are that homegrown systems apart from EHRs are currently used to support care coordination and, also, that reporting tools are key components of care coordination. CONCLUSIONS: New health IT that enables monitoring, notifying, collaborating, reporting, and interoperability would enhance care coordination within PCMHs beyond what current health IT enables. PMID- 25796598 TI - Polymorphisms of the CYP1B1 gene and hepatocellular carcinoma risk in a Chinese population. AB - BACKGROUND: CYP1B1 is a P450 enzyme which is involved in the activation of pro carcinogens to carcinogens as well as estrogen metabolism. We hypothesized that genetic variants in CYP1B1 may modify individual susceptibility to hepatocellular carcinoma (HCC). METHODS: To test this hypothesis, we evaluated the associations of three CYP1B1 single nucleotide polymorphisms (SNPs) and HCC risk in a case control study of 468 HCC cases and 515 cancer-free controls in a Chinese population. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry method and direct DNA sequencing were performed to detect these polymorphisms. RESULTS: In overall analysis, we found that only the variant G allele of rs1056836 was associated with a significantly increased risk of HCC among the three SNPs (rs10012, rs1056836 and rs1800440). Moreover, we found that the variant genotypes containing the G allele of rs1056836 were associated with a significantly increased risk of HCC among HbsAg-positive individuals (adjusted OR=2.13, 95% CI=1.18, 3.86), but not among HbsAg-negative individuals. When stratifying by smoking status, we found that the variant GG genotype increased a 13.97-fold (95% CI=1.28, 152.94) risk of HCC among smokers. Furthermore, high risk for liver cirrhosis-positive clinical status was exhibited in HCC patients with rs1056836 CG and GG genotypes as compared with CC homozygotes. For the other two SNPs, we did not find any significant evidence of association with HCC risk in any subgroup. CONCLUSION: This study suggests that CYP1B1 rs1056836 polymorphism may be an important factor contributing to increased susceptibility and pathological development of HCC in Chinese population. PMID- 25796599 TI - Cloning of neuromedin B and its receptor in the rabbit and generating a polyclonal antibody to the neuromedin B protein. AB - Neuromedin B (NMB) is a highly conserved bombesin-related neuropeptide found in mammals. Neuromedin B (NMB) executes its effect by binding to the cell surface receptor, neuromedin B receptor (NMBR). In this study, we cloned the rabbit NMB and NMBR genes. The similarity and phylogenetic analyses of NMB and NMBR gene sequences were performed. The expression of NMB and NMBR mRNA in the rabbit was investigated using real-time RT-PCR. Our bioinformatic analysis demonstrated that the cloned rabbit NMB precursor cDNA encoded Gly-His-Phe-Met-NH2 amino acids at the C-terminus, and that its receptor possessed typical transmembrane features. The NMB mRNA was highly expressed in the CNS, while the NMBR mRNA was widely expressed in many tissues, with the highest expression in the gastrointestinal tract. The studies on the NMB distribution and function are limited by the lack of a specific antibody to this neuropeptide. In this paper, polyclonal NMB antibody was generated in mice. Western blotting analysis revealed that the prepared antibody could specifically recognize the recombinant and the endogenous NMB proteins. Immunohistochemistry analysis indicated that the NMB protein was localized in the cytoplasm of the pituitary cells. The existence of NMB protein in the hypothalamic-pituitary-gonadal axis suggests that NMB might function in rabbit reproduction. PMID- 25796600 TI - Association of SPP1 promoter variants with hip osteoarthritis susceptibility in Chinese population. AB - Three genetic variants in the promoter of SPP1 (secreted phosphoprotein 1) gene have been reported to affect transcriptional activity of SPP1, thus conferring an increased risk for some diseases. To testify if these variants are associated with risk of hip osteoarthritis (OA) as well, we performed a case-control study including 389 hip OA patients and 315 healthy controls. Genotypes of SPP1 were determined by DNA sequencing, and differential expressions of SPP1 in relation with genotypes were evaluated by RT-PCR and ELISA. The results showed that rs17524488 (delG>insG) increased the risk of hip OA, with the adjusted OR 1.48 (95% CI 1.18-1.85, P<0.01) for risk allele insG, 1.90 (95% CI 1.35-2.66, P<0.01) for delG/insG and 2.04 (95% CI 1.20-3.49, P<0.01) for insG/insG respectively. However, as for rs11730582 (T>C), the adjusted ORs were 1.18 (95% CI 0.94-1.49, P=0.148) for allele C, 1.26 (95% CI 0.90-1.75, P=0.158) for TC, and 1.31 (95% CI 0.77-2.24, P=0.293) for CC, indicating no association of rs11730582 with hip OA risk. The variant rs28357094 was not observed in the tested subjects. Furthermore, the delG/insG and insG/insG genotypes of rs17524488 both correlated with higher levels of SPP1 expression in articular cartilage (P<0.01 for all comparisons) as well as in in synovial fluid (P<0.01 for all comparisons) compared with delG/delG, while rs11730582 had no effect on the SPP1 expression (P>0.05 for all comparisons). These results collectively indicate that the genetic variant rs17524488 in SPP1 promoter confers high risk for hip OA in a Chinese population, possibly through enhancing SPP1 expression. PMID- 25796601 TI - Integrated analysis of gene expression and microRNA regulation in three leukemia related lymphoblastic cell lines. AB - RNA-sequencing technology is progressively being applied in various fields since high-throughput data analysis provides deeper mining on both the genomic and transcriptomic level. Lymphoblastic leukemogenesis is a complex process caused by abnormalities occurring during lymphocyte differentiation, and can be initiated by various triggers. Each leukemia subtype has distinct characteristics that can be identified in the corresponding cell lines; the detection of the exclusive genetic signatures of these varying cell lines is critical. Our analysis revealed that approximately 8000 human genes were differentially expressed between samples. Signaling pathways such as the NOD-like signaling pathway, cell surface receptor signaling pathways, and leukemia-related pathways were significantly regulated, as determined by KEGG annotation. Furthermore, several oncogenes and differentiation-related genes were differentially expressed between leukemia cell lines and lymphocyte types, respectively. Our miRNA analysis demonstrated that the expression of approximately one-third of all expressed miRNAs appeared to be significantly different between the leukemia cell lines studied. We also analyzed the mRNA-miRNA regulatory networks of both lymphocyte differentiation and leukemogenesis to determine key regulators of interest. We combined the results of the mRNA and miRNA analyses in order to investigate the regulatory relationship between them. This study not only identifies differences in the pathways and networks of acute lymphocytic leukemia (ALL) relative to normal lymphocytes, but also identifies unique functional characteristics of lymphoid cells and distinct gene expression patterns during lymphoid development. The discovery of leukemia-related miRNAs may provide meaningful insights into the biology of the disease. PMID- 25796603 TI - Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma. AB - Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM. PMID- 25796602 TI - Molecular cloning and characterization of CD3epsilon in Chinese domestic goose (Anser cygnoides). AB - CD3 is one of the most important cell surface markers of T lymphocytes which play an important role in signal transmission of antigen recognition. In this study, goose CD3epsilon gene was cloned by touchdown PCR with the template of goose thymus cDNA. The complete open reading frame of goose CD3epsilon encoded 178 amino acid residues with a 21 signal peptide. Sequence alignments showed that goose CD3epsilon had an amino acid sequence similarity to duck (80.3%) and chicken (66.3%). The extracellular domain of goose CD3epsilon was efficiently expressed as fusion protein in Escherichia coli, purified by a Ni-NTA agarose column, and the purified recombinant protein was used to produce anti GoCD3epsilonex polyclonal antibodies. The characteristics of PAb were identified by Western blot, cellular ELISA, IFA, FCM, and LSCM analysis. These results may be useful for a better understanding of goose CD3epsilon and have a foundation for the study of T cell mediated immune mechanism in waterfowl. PMID- 25796604 TI - The impact of quality filter for RNA-Seq. AB - BACKGROUND: With the emergence of large-scale sequencing platforms since 2005, there has been a great revolution regarding methods for decoding DNA sequences, which have also affected quantitative and qualitative gene expression analyses through the RNA-Sequencing technique. However, issues related to the amount of data required for the analyses have been considered because they affect the reliability of the experiments. Thus, RNA depletion during sample preparation may influence the results. Moreover, because data produced by these platforms show variations in quality, quality filters are often used to remove sequences likely to contain errors to increase the accuracy of the results. However, when reads of quality filters are removed, the expression profile in RNA-Seq experiments may be influenced. RESULT: The present study aimed to analyze the impact of different quality filter values for Corynebacterium pseudotuberculosis (sequenced by SOLiD platform), Microcystis aeruginosa and Kineococcus radiotolerans (sequenced by Illumina platform) RNA-Seq data. Although up to 47.9% of the reads produced by the SOLiD technology were removed after the QV20 quality filter is applied, and 15.85% were removed from K. radiotolerans data set using the QV30 filter, Illumina data showed the largest number of unique differentially expressed genes after applying the most stringent filter (QV30), with 69 genes. In contrast, for SOLiD, the acid stress condition with the QV20 filter yielded only 41 unique differentially expressed genes. Even for the highest quality M. aeruginosa data, the quality filter affected the expression profile. The most stringent quality filter generated a greater number of unique differentially expressed genes: 9 for high molecular weight dissolved organic matter condition and 12 for low P conditions. CONCLUSION: Even high-accuracy sequencing technologies are subject to the influence of quality filters when evaluating RNA-Seq data using the reference approach. PMID- 25796605 TI - Efficacy of intervertebral disc regeneration with stem cells - a systematic review and meta-analysis of animal controlled trials. AB - Management of intervertebral disc (IVD) degenerative disease is challenging, as it is accompanied by irreversible loss of IVD cells. Stem cell transplantation to the disc has shown promise in decelerating or arresting the degenerative process. Multiple pre-clinical animal trials have been conducted, but with conflicting outcomes. To assess the effect of stem cell transplantation, a systematic review and meta-analysis was performed. A comprehensive literature search was conducted through Week 3, 2015. Inclusion criteria consisted of controlled animal trials. Two reviewers screened abstracts and full texts. Disagreements were resolved by a third reviewer. Random effects models were constructed to pool standardized mean difference (SMD). Twenty two studies were included; nine of which were randomized. Statistically significant differences were found with the stem cell group exhibiting increased disc height index (SMD=3.64, 95% confidence interval (CI): 2.49, 4.78; p<0.001), increased MRI T2 signal intensity (SMD=2.28, 95% CI: 1.48, 3.08; p<0.001), increased Type II collagen mRNA expression (SMD=3.68, 95% CI: 1.66, 5.70; p<0.001), and decreased histologic disc degeneration grade (SMD= 2.97, 95% CI: -3.97, -1.97; p<0.001). There was statistical heterogeneity between studies that could not be explained with pre-planned subgroup analyses based on animal species, study designs, and transplanted cell types. Stem cells transplanted to the IVD in quadruped animals decelerate or arrest the IVD degenerative process. Further studies in human clinical trials will be needed to understand if such benefit can be translated to bipedal humans. PMID- 25796606 TI - What's behind these scales? Comments to "The complete mitochondrial genome of Temminck's ground pangolin (Smutsia temminckii; Smuts, 1832) and phylogenetic position of the Pholidota (Weber, 1904)". PMID- 25796607 TI - An evidence-based approach towards the cranio-cervical junction injury classifications. AB - PURPOSE: The cranio-cervical junction (CCJ) is an anatomically, functionally and biomechanically complex region. It is commonly involved in trauma of varying severity that can be managed with a multitude of treatment options and carry diverse prognosis. Our objective is to evaluate the quality of currently used CCJ injury classifications in an evidence-based approach. METHODS: We performed two consecutive literature reviews. In the first, we tried to find which classifications are currently used in CCJ injuries. In the second, we scrutinized the gathered classifications in terms of validity, reliability, severity grading, treatment guidance and prognosis assessment. RESULTS: Twenty classifications are currently used to describe the CCJ injuries and 72 individual injury patterns have been recognized. Almost a third of them can grade severity, guide treatment and assess prognosis. Only two classifications have been tested for validity and reliability. CONCLUSIONS: CCJ injuries are poorly described by the current classifications according to evidence-based criteria. There is an obvious need for a simple and reliable classification tool to guide patient management in the evidence-based medicine era. PMID- 25796608 TI - Medical Rapid Response in Psychiatry: Reasons for Activation and Immediate Outcome. AB - Rapid response teams are used to improve the recognition of acute deteriorations in medical and surgical settings. They are activated by abnormal physiological parameters, symptoms or clinical concern, and are believed to decrease hospital mortality rates. We evaluated the reasons for activation and the outcome of rapid response interventions in a 222-bed psychiatric hospital in New York City using data obtained at the time of all activations from January through November, 2012. The primary outcome was the admission rate to a medical or surgical unit for each of the main reasons for activation. The 169 activations were initiated by nursing staff (78.7 %) and psychiatrists (13 %) for acute changes in condition (64.5 %), abnormal physiological parameters (27.2 %) and non-specified concern (8.3 %). The most common reasons for activation were chest pain (14.2 %), fluctuating level of consciousness (9.5 %), hypertension (9.5 %), syncope or fall (8.9 %), hypotension (8.3 %), dyspnea (7.7 %) and seizures (5.9 %). The rapid response team transferred 127 (75.2 %) patients to the Emergency Department and 46 (27.2 %) were admitted to a medical or surgical unit. The admission rates were statistically similar for acute changes in condition, abnormal physiological parameters, and clinicians' concern. In conclusion, a majority of rapid response activations in a self-standing psychiatric hospital were initiated by nursing staff for changes in condition, rather than for policy-specified abnormal physiological parameters. The findings suggest that a rapid response system may empower psychiatric nurses to use their clinical skills to identify patients requiring urgent transfer to a general hospital. PMID- 25796609 TI - The future of qualitative research in psychology--a students' perspective. AB - The aim of this article is to explore the future of qualitative research as seen from a students' perspective. This exploration will initially be incited through a discussion of the use of the term 'qualitative research', and the risks associated with the use of such an umbrella term. It is discussed that the use of an overarching umbrella term can lead to an overhomogenized understanding of qualitative research, that fails to represent the diversity and variety of methodological and epistemological approaches that exist within this research paradigm. It is also discussed that this overhomogenization reinforces the idea of qualitative research as an anti-doctrine to quantitative research, which is argued to discourage interparadigmatic integration. Lastly, it is considered how these (mis)conceptions of qualitative research influence how psychology students are taught about research methodology and how this education could affect these (mis)conceptions. We advocate that the future for qualitative research in psychology should be ensured through a restructure and a refocus on an educational level. This change should overall be centered around teaching students how to be reflective research practitioners based on an in-depth understanding of the variety of epistemologies within both meta-research paradigms. PMID- 25796610 TI - One cannot rule them all: Are bacterial toxins-antitoxins druggable? AB - Type II (proteic) toxin-antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin generally acts as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a cessation of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the potentials and the challenges that their use may find in the 'real' world. We present strategies to develop TAs as antibacterials in view of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein-protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of Tas are also discussed. PMID- 25796612 TI - Short-term weight gain and breast cancer risk by hormone receptor classification among pre- and postmenopausal women. AB - Obesity is well established as a cause of postmenopausal breast cancer incidence and mortality. In contrast, adiposity in early life reduces breast cancer incidence. However, whether short-term weight change influences breast cancer risk is not well known. We followed a cohort of 77,232 women from 1980 to 2006 (1,445,578 person-years), with routinely updated risk factor information, documenting 4196 incident cases of invasive breast cancer. ER and PR status were obtained from pathology reports and medical records yielding a total of 2033 ER+/PR+ tumors, 595 ER-/PR- tumors, 512 ER+/PR- tumors. The log incidence breast cancer model was used to assess the association of short-term weight gain (over past 4 years) while controlling for average BMI before and after menopause. Short term weight change was significantly associated with breast cancer risk (RR 1.20; 95 % CI 1.09-1.33) for a 4-year weight gain of >=15 lbs versus no change (<=5 lbs) (P_trend < 0.001). The association was stronger for premenopausal women (RR 1.38; 95 % CI 1.13-1.69) (P_trend = 0.004) than for postmenopausal women (RR 1.10; 95 % CI 0.97-1.25) (P_trend = 0.063). Short-term weight gain during premenopause had a stronger association for ER+/PR- (RR per 25 lb weight gain = 2.19; 95 % CI 1.33-3.61, P = 0.002) and ER-/PR- breast cancer (RR per 25 lb weight gain = 1.61; 95 % CI 1.09-2.38, P = 0.016) than for ER+/PR+ breast cancer (RR per 25 lb weight gain = 1.13; 95 % CI 0.89-1.43, P = 0.32). There are deleterious effects of short-term weight gain, particularly during pre-menopause, even after controlling for average BMI before and after menopause. The association was stronger for ER+/PR- and ER-/PR- than for ER+/PR+ breast cancer. PMID- 25796613 TI - Sediment bioaccumulation test with Lumbriculus variegatus: effects of feeding. AB - Standard sediment-bioaccumulation test methods specify that Lumbriculus variegatus should not be fed during the 28-day exposure. This lack of feeding can lead to decreases in L. variegatus weight and lipid content during the 28-day exposure period. Differences in intrinsic nutritional content of sediments could lead to additional variability in organism performance and/or contaminant uptake. To evaluate the potential benefits of feeding, sediment-bioaccumulation tests were performed comparing treatments with and without supplemental feeding with tropical fish food and also comparing performance food introduced as blended slurry versus fine flakes. The ration of food provided had to be limited to 6 mg/300-mL beaker with 250 mg of L. variegatus (ww) receiving three feedings per week to maintain acceptable dissolved oxygen (DO) in the test chambers. Relative weight change during exposure varied across sediments in the absence of food from very little change to as much as a 40 % decrease from starting weight. Feeding slurry and flake foods increased the total weight of recovered organisms by 32 and 48 %, respectively, but they did not decrease variability in weight changes across sediments. Lipid contents of the organisms decreased similarly across all feeding treatments during the test. At test termination, lipid contents of L. variegatus across unfed, slurry-fed, and flake-fed treatments were not significantly different per Tukey's honest significant difference test with 95 % family-wise confidence. Feeding resulted in polychlorinated biphenyl residues in L. variegatus being generally slightly less (median 78 %) and slightly greater (median 135 %) than the unfed treatments with slurry and flake formulated foods, respectively. PMID- 25796614 TI - Specific airway resistance in healthy young Vietnamese and Caucasian adults. AB - In healthy Vietnamese children the respiratory resistance has been suggested to be similar at 110 cm height but larger at 130 cm when compared with data in Caucasians from the literature, suggesting smaller airways in older Vietnamese children (Vu et al., 2008). The hypothesis tested here is whether the difference in airway resistance remains consistent throughout growth, and if it is larger in adult Vietnamese than in Caucasians. Airway resistance and Functional Residual Capacity were measured in healthy young Caucasian and Vietnamese adults in their respective native country using identical equipment and protocols. Ninety five subjects in Vietnam (60 males) and 101 in France (41 males) were recruited. Airway resistance was significantly larger in Vietnamese than in Caucasians and in females than in males, consistent with difference in body dimensions. Specific airway resistance however was not different by ethnicity or gender. The findings do not support the hypothesis that airway size at adult age - once normalized for lung volume - differs between Vietnamese and Caucasians. PMID- 25796615 TI - Mechanism of Rac1-induced amplification in gastric mucosal phospholipase Cgamma2 activation in response to Helicobacter pylori: modulatory effect of ghrelin. AB - Membrane recruitment followed by targeted phosphorylation of specific Tyr and Ser residues and the interaction with Rac GTPases are the crucial parts of an elaborate mechanism of PLCgamma2 activation essential for its role in linking the specific receptor responses to a variety of hormones and bacterial endotoxins with the intended intracellular targets. Here, we explored the involvement of Rac in mediation of PLCgamma2 activation associated with gastric mucosal inflammatory responses to H. pylori LPS and the hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to the membrane translocation of Rac1 as well as PLCgamma2, while the effect of ghrelin is manifested by elevation in the membrane PLCgamma2 activation and suppression in Rac1 translocation. However, blocking the LPS-induced Rac1 translocation, while detrimental to the PLCgamma2 activation, has no effect on its membrane translocation. We reveal further that PLCgamma2, localized in the membrane in association with Rac1 following the LPS stimulation, exhibits a marked increase in phosphorylation on Ser, while the modulatory effect of ghrelin, manifested by a drop in Rac1 translocation, is associated with a distinct decrease in PLCgamma2 phosphorylation on Ser. Thus, the results suggest that H. pylori-elicited increase in gastric mucosal PLCgamma2 phosphorylation on Ser serves as an essential platform for Rac1 colocalization and amplification in PLCgamma2 activation. PMID- 25796611 TI - Bacterial transfer RNAs. AB - Transfer RNA is an essential adapter molecule that is found across all three domains of life. The primary role of transfer RNA resides in its critical involvement in the accurate translation of messenger RNA codons during protein synthesis and, therefore, ultimately in the determination of cellular gene expression. This review aims to bring together the results of intensive investigations into the synthesis, maturation, modification, aminoacylation, editing and recycling of bacterial transfer RNAs. Codon recognition at the ribosome as well as the ever-increasing number of alternative roles for transfer RNA outside of translation will be discussed in the specific context of bacterial cells. PMID- 25796616 TI - Chimeras of channelrhodopsin-1 and -2 from Chlamydomonas reinhardtii exhibit distinctive light-induced structural changes from channelrhodopsin-2. AB - Channelrhodopsin-2 (ChR2) from the green alga Chlamydomonas reinhardtii functions as a light-gated cation channel that has been developed as an optogenetic tool to stimulate specific nerve cells in animals and control their behavior by illumination. The molecular mechanism of ChR2 has been extensively studied by a variety of spectroscopic methods, including light-induced difference Fourier transform infrared (FTIR) spectroscopy, which is sensitive to structural changes in the protein upon light activation. An atomic structure of channelrhodopsin was recently determined by x-ray crystallography using a chimera of channelrhodopsin 1 (ChR1) and ChR2. Electrophysiological studies have shown that ChR1/ChR2 chimeras are less desensitized upon continuous illumination than native ChR2, implying that there are some structural differences between ChR2 and chimeras. In this study, we applied light-induced difference FTIR spectroscopy to ChR2 and ChR1/ChR2 chimeras to determine the molecular basis underlying these functional differences. Upon continuous illumination, ChR1/ChR2 chimeras exhibited structural changes distinct from those in ChR2. In particular, the protonation state of a glutamate residue, Glu-129 (Glu-90 in ChR2 numbering), in the ChR chimeras is not changed as dramatically as in ChR2. Moreover, using mutants stabilizing particular photointermediates as well as time-resolved measurements, we identified some differences between the major photointermediates of ChR2 and ChR1/ChR2 chimeras. Taken together, our data indicate that the gating and desensitizing processes in ChR1/ChR2 chimeras are different from those in ChR2 and that these differences should be considered in the rational design of new optogenetic tools based on channelrhodopsins. PMID- 25796617 TI - Molecular structure of glycogen in diabetic liver. AB - Liver glycogen (involved in maintaining blood-sugar levels) is a hyperbranched glucose polymer containing beta particles (diameter ~20 nm), which can form composite alpha particles (diameter ~50-300 nm), and includes a small but significant amount of bound protein. Size distributions of glycogen from livers of healthy and diabetic mice were examined using size-exclusion chromatography with two separate eluents: aqueous eluent and dimethylsulfoxide (DMSO) eluent. Morphologies were examined with transmission electron microscopy. Diabetic glycogen (DG) exhibited many alpha particles in the mild water-based solvent, but in DMSO, which breaks H bonds, these degraded to beta particles; alpha particles however were always present in healthy glycogen (HG). This DG fragility shows the binding of beta into alpha particles is different in HG and DG. The diabetic alpha particle fragility may be involved with the uncontrolled blood-sugar release symptomatic of diabetes: small beta particles degrade more easily to glucose than alpha particles. This has implications for diabetes management. PMID- 25796618 TI - Multiscreening determination of organic pollutants in molluscs using matrix solid phase dispersion. AB - This work describes the optimisation, validation and application of matrix solid phase dispersion (MSPD) coupled to gas chromatography mass spectrometry, both single quadrupole (GC-MS) and tandem (GC-MS/MS), for the quantification in molluscs of up to 40 different analytes belonging to several families of priority and emerging organic contaminants, including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs), organophosphorus pesticides (OPPs) and musk fragrances. The MSPD procedure was fully optimised with a special focus on the clean-up strategy. The best recoveries were obtained using glass syringes, 0.30 g of freeze-dried sample, 0.30 g of Florisil as solid support, 4.00 g of activated silica and 25 mL of dichloromethane as elution solvent. Using GC-MS/MS the method afforded good linearities (r(2), between 0.980 and 0.9996), adequate repeatability and reproducibility (RSD<17% and 33%, respectively) and low instrumental limits of detection (between 0.010 and 2.74 ng mL(-1)). The accuracy of the method was evaluated using different approaches, i.e. assessment of spiked fish hatchery samples, laboratory reference material and standard reference material (SRM 2977). Satisfactory apparent recoveries were obtained for all the target analytes after correction with the corresponding labelled surrogate, except for PAHs in the case of SRM 2977, which required the use of the standard addition method. Finally, MSPD was applied to mollusc species collected in Colombia and Nicaragua, where PAHs, PCBs, musks and pesticides were detected at low ng g(-1) levels. PMID- 25796619 TI - In silico methods for predicting drug-drug interactions with cytochrome P-450s, transporters and beyond. AB - Drug-drug interactions (DDIs) are associated with severe adverse effects that may lead to the patient requiring alternative therapeutics and could ultimately lead to drug withdrawal from the market if they are severe. To prevent the occurrence of DDI in the clinic, experimental systems to evaluate drug interaction have been integrated into the various stages of the drug discovery and development process. A large body of knowledge about DDI has also accumulated through these studies and pharmacovigillence systems. Much of this work to date has focused on the drug metabolizing enzymes such as cytochrome P-450s as well as drug transporters, ion channels and occasionally other proteins. This combined knowledge provides a foundation for a hypothesis-driven in silico approach, using either cheminformatics or physiologically based pharmacokinetics (PK) modeling methods to assess DDI potential. Here we review recent advances in these approaches with emphasis on hypothesis-driven mechanistic models for important protein targets involved in PK-based DDI. Recent efforts with other informatics approaches to detect DDI are highlighted. Besides DDI, we also briefly introduce drug interactions with other substances, such as Traditional Chinese Medicines to illustrate how in silico modeling can be useful in this domain. We also summarize valuable data sources and web-based tools that are available for DDI prediction. We finally explore the challenges we see faced by in silico approaches for predicting DDI and propose future directions to make these computational models more reliable, accurate, and publically accessible. PMID- 25796620 TI - MIPs as Tools in Environmental Biotechnology. AB - Molecular imprints are potentially fantastic constructions. They are selective, robust, and nonbiodegradable if produced from stable polymers. A range of different applications has been presented, everything from separation of enantiomers, via adsorbents for sample preparation before analysis to applications in wastewater treatment. This chapter deals with molecularly imprinted polymers (MIPs) as tools in environmental biotechnology, a field that has the potential to become very important in the future. PMID- 25796621 TI - Post-imprinting and In-Cavity Functionalization. AB - Molecularly imprinted polymers (MIPs) are artificial materials capable of molecular recognition for target molecules. Currently MIPs have been prepared without further modification after polymerization, and used for predetermined single purposes. Post-imprinting modifications (PIMs) presented here can provide site-specific modifications within the molecularly imprinted binding cavities after polymerization, enabling MIPs to become more complex functional materials as were the cases of naturally occurring conjugated proteins. We present an overview of the research on MIPs involving PIMs, including transformation of binding sites, on/off switching of binding activity, introduction of desirable functions such as fluorescent signalling functions, catalytic activity, and so on. The combination of PIMs with molecular imprinting appears to be a powerful tool for preparing a diverse range of biomimetic functional materials. PMID- 25796622 TI - Characterization of the Binding Properties of Molecularly Imprinted Polymers. AB - The defining characteristic of the binding sites of any particular molecularly imprinted material is heterogeneity: that is, they are not all identical. Nonetheless, it is useful to study their fundamental binding properties, and to obtain average properties. In particular, it has been instructive to compare the binding properties of imprinted and non-imprinted materials. This chapter begins by considering the origins of this site heterogeneity. Next, the properties of interest of imprinted binding sites are described in brief: affinity, selectivity, and kinetics. The binding/adsorption isotherm, the graph of concentration of analyte bound to a MIP versus concentration of free analyte at equilibrium, over a range of total concentrations, is described in some detail. Following this, the techniques for studying the imprinted sites are described (batch-binding assays, radioligand binding assays, zonal chromatography, frontal chromatography, calorimetry, and others). Thereafter, the parameters that influence affinity, selectivity and kinetics are discussed (solvent, modifiers of organic solvents, pH of aqueous solvents, temperature). Finally, mathematical attempts to fit the adsorption isotherms for imprinted materials, so as to obtain information about the range of binding affinities characterizing the imprinted sites, are summarized. PMID- 25796623 TI - MIPs in Aqueous Environments. AB - When organic solvent-compatible molecularly imprinted polymers (MIPs) are used in aqueous environment, how to reduce nonspecific binding is a major challenge. By modifying the binding solvents and introducing appropriate washing and elution steps, even relatively hydrophobic MIPs can gain optimal rebinding selectivity in aqueous conditions. Furthermore, water-compatible MIPs that can be used to treat aqueous samples directly have been prepared. The use of hydrophilic co-monomers, the controlled surface modification through controlled radical polymerization, and the new interfacial molecular imprinting methods are different strategies to prepare water-compatible MIPs. By combining MIPs with other techniques, both organic solvent-compatible and water-compatible MIPs can display better functional performances in aqueous conditions. Intensive studies on MIPs in aqueous conditions can provide new MIPs with much-improved compatibilities that will lead to more interesting applications in biomedicine and biotechnology. PMID- 25796624 TI - The Taming of the Shrew--Controlling the Morphology of Filamentous Eukaryotic and Prokaryotic Microorganisms. AB - One of the most sensitive process characteristics in the cultivation of filamentous biological systems is their complex morphology. In submerged cultures, the observed macroscopic morphology of filamentous microorganisms varies from freely dispersed mycelium to dense spherical pellets consisting of a more or less dense, branched and partially intertwined network of hyphae. Recently, the freely dispersed mycelium form has been in high demand for submerged cultivation because this morphology enhances the growth and production of several valuable products. A distinct filamentous morphology and productivity are influenced by the environment and can be controlled by inoculum concentration, spore viability, pH value, cultivation temperature, dissolved oxygen concentration, medium composition, mechanical stress or process mode as well as through the addition of inorganic salts or microparticles, which provides the opportunity to tailor a filamentous morphology. The suitable morphology for a given bioprocess varies depending on the desired product. Therefore, the advantages and disadvantages of each morphological type should be carefully evaluated for every biological system. Because of the high industrial relevance of filamentous microorganisms, research in previous years has aimed at the development of tools and techniques to characterise their growth and obtain quantitative estimates of their morphological properties. The focus of this review is on current advances in the characterisation and control of filamentous morphology with a separation of eukaryotic and prokaryotic systems. Furthermore, recent strategies to tailor the morphology through classical biochemical process parameters, morphology and genetic engineering to optimise the productivity of these filamentous systems are discussed. PMID- 25796625 TI - Risk factors for overweight and obesity in Swiss primary school children: results from a representative national survey. AB - PURPOSE: Obesity is a global epidemic affecting around 10 % of 5- to 17-year olds. With the causes for obesity being multifactorial, a better understanding of the influencing factors is essential for effective treatment and prevention programs. The aim of this study was therefore to identify specific risk factors for overweight and obesity in children in Switzerland. METHODS: A nationally representative sample of children aged 6-12 years was recruited (n = 2724). Height and weight were measured to calculate BMI (kg/m(2)). In addition, a questionnaire was distributed to all children asking about their physical activity, media consumption, and dietary habits as well as some parental factors. RESULTS: The prevalence of overweight and obesity in boys was 11.8 and 7.5 %, respectively, and in girls, it was 11.9 and 5.7 %. In univariate analyses, a number of parental, dietary, and activity factors were shown to be associated with BMI category. Based on a multinomial logistic regression, parent nationality and media consumption were the most important factors predicting obesity in boys, while in girls it was parental education, nationality, and physical activity. CONCLUSION: We have demonstrated that parental nationality and education play an important role in the development of childhood obesity, together with media consumption and physical activity. However, risk factors are also different according to child gender. Thus, an important target group for the treatment and prevention of childhood obesity in Switzerland are immigrant families, and the problem needs to be tackled differently in boys and girls as their risk factors are not the same. PMID- 25796626 TI - Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety. AB - Bronchopulmonary dysplasia (BPD) is associated with a high incidence of pulmonary artery hypertension (PAH) and is frequently treated with sildenafil. The objective was to investigate the echocardiographic and clinical efficacy and safety of sildenafil in this setting. The hypothesis was that treatment would result in significant echocardiographic and clinical improvements. This was a retrospective study of the cohort of infants who were born between 2004 and 2012 and administered sildenafil as in-patients for BPD-associated PAH. Medical records and archived echocardiographic data were reviewed. Twenty-two infants fulfilled the inclusion criteria and had a mean (+/-SD) gestation age and birth weight of 25.6 (+/-1.3) weeks and 631 (+/-181) g, respectively. Six (27 %) infants died before discharge (predominantly due to respiratory failure; in three of them, a concomitant viral respiratory infection was thought to be an aggravating factor). Amongst survivors, no mortality was noted up to 1 year follow-up. Significant improvement in echocardiographic markers of pulmonary hypertension was noted in the echocardiogram performed 27.5 days (interquartile range 24, 31) post-initiation of therapy, two thirds showing >=20 % decline in the right ventricular systolic pressure. Left ventricular fractional shortening did not alter significantly. At initiation, all infants had 'severe' BPD. The fraction of inspired oxygen (FiO2) decreased significantly from 0.57 (SE +/- 0.05) to 0.42 (SE +/- 0.03) (p = 0.02), and no significant alteration was noted over the timeframe in mean pCO2 (64.4 +/- 3.3 to 63.2 +/- 3.3 mmHg). The number of infants needing endotracheal intubation and mechanical ventilation decreased (from 3 to 1) over the same time. No serious adverse effects were noted. CONCLUSION: Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated. PMID- 25796627 TI - Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment. AB - Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs. PMID- 25796628 TI - Bone-adiposity cross-talk: implications for pediatric obesity. A narrative review of literature. AB - The rising prevalence of overweight and obesity among pediatric populations has become a major global concern. The objective of this review is to demonstrate potential interactions between the products released by fat tissue and the hormonal production of bone tissue in obese children and adolescents. Advancing the understanding of the complex interactions between adipocyte and osteocyte activities may contribute to the mechanistic understanding of the body's responses to weight loss during adolescence. This knowledge could also reveal any side effects encountered with these interventions. Currently, the concept of bone adiposity crosstalk has not been fully elucidated, and the mechanisms remain controversial. Understanding the local interactions between the released products by fat tissue and hormones produced in bone tissue requires further investigations. PMID- 25796631 TI - [Past, present and future of otorhinolaryngology]. PMID- 25796629 TI - Osteoclasts are not activated in middle ear cholesteatoma. AB - It is unclear whether osteoclasts are present and activated in cholesteatomas. We explored the expression of messenger RNA (mRNA) for osteoclast biomarkers and regulating factors in middle ear cholesteatomas to elucidate the level of osteoclast activity in this disease. Bone powder was collected from 14 patients with cholesteatomatous and noncholesteatomatous chronic otitis media during tympanomastoidectomy, separately from cortical bone of the mastoid (clean bone powder), from bone neighboring cholesteatoma (cholesteatomatous bone powder), and from bone of the air cells and antrum of noncholesteatomatous chronic otitis media patients (noncholesteatomatous bone powder). The samples collected were soaked in TRIzol reagent, and total RNA was extracted and purified by the acid guanidinium thiocyanate-phenol-chloroform method, followed by the use of magnetic bead technology. The sample was then subjected to quantitative reverse transcription polymerase chain reaction for receptor activator of nuclear factor kappaB (RANK), tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), osteoclast-associated receptor (OSCAR), calcitonin receptor (CALCR), matrix metalloproteinase 9 (MMP9), receptor activator of nuclear factor kappaB ligand (RANKL), and osteoprotegerin (OPG). There was no significant difference in the expression of TRAP, CTSK, OSCAR, CALCR, MMP9, or OPG among the clean, cholesteatomatous, and noncholesteatomatous bone powder. On the other hand, the expression of RANK and RANKL was significantly lower in the cholesteatomatous bone powder than in the noncholesteatomatous bone powder (P = 0.003 and P = 0.028, respectively). The RANKL mRNA/OPG mRNA ratio did not differ among the three samples. These results indicate that osteoclasts are unlikely to be activated in cholesteatomas. Bone resorption mechanisms not mediated by osteoclasts may need to be reappraised in cholesteatoma research in future studies. PMID- 25796630 TI - Corneal cut closure using temperature-controlled CO2 laser soldering system. AB - We aimed to evaluate the effectiveness of temperature-controlled laser soldering for repair of large perforated corneas in a porcine model. Eight Yorkshire pigs aged 6 months underwent 6-mm-deep 180 degrees crescent-shaped trephination of the central corneas. Right corneal injuries were repaired by placement of 47 % bovine albumin along the cut followed by CO2 laser soldering (power density 16 W/cm(2)) to a target temperature of 65( degrees ). Left corneal injuries were repaired with 10/0 nylon sutures. The groups were compared for operative time, leakage, and histopathological findings. Mean tissue temperature was 63 +/- 4 degrees C. Mean operative time was 31.57 +/- 2.8 min in laser-soldered eyes and 41.38 +/- 2.3 min in controls (p < 0.0001, unpaired Student's t test). Compared to controls, the soldered corneas had less neovascularization, complete re epithelization, and mild stromal inflammation. There was no leakage in either group. Combined CO2 laser and radiometer is effective for the in vivo repair of corneal cuts. These results have important implications for modern corneal surgery. Further studies are needed in the clinical setting. PMID- 25796632 TI - [Hearing disorders of infants and young children]. PMID- 25796633 TI - [Evidence for the treatment of facial paralysis with antiviral drugs]. PMID- 25796634 TI - Emergency medicine. Lee v. Hennepin County, Civil No. 13-1328 PJS/AJB (D. Minn. November 20, 2013). PMID- 25796635 TI - Confidentiality of medical information. C.E. v. Prairie Fields Family Medicine, 287 Neb. 667 (Neb. 2014). PMID- 25796636 TI - Guardianship. In re Guardianship of S.H., No. 13CA0057-M (Ct. App. Ohio October 1, 2013), appeal denied. In re S.H., 138 Ohio St.3d 1417 (Ohio 2014). PMID- 25796637 TI - Nursing licensure. Zablotny v. State Board of Nursing, No. Was-13-42, 2014 Me. 46 (Me. March 20, 2014). PMID- 25796638 TI - Telemedicine. In the Matter of Ann De Jong, MD, Case No. 2012-BOM-582 (Idaho Bd. of Med. January 6, 2014). PMID- 25796639 TI - [Planning of endoscopic surgery of paranasal sinusitis based on preoperative CT interpretation]. PMID- 25796640 TI - Dear Sirs and Madams. PMID- 25796641 TI - Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness. PMID- 25796642 TI - AVMA president denounces 'attack' articles on veterinarians. PMID- 25796643 TI - Congressional session in review. Mobility Act, research funding among AVMA's legislative successes. PMID- 25796644 TI - As time goes by. Many advances seen in equine medicine since AAEP's founding 60 years ago. PMID- 25796645 TI - Hard work pays off for AAEP president. PMID- 25796646 TI - Horse racing model rules see gradual adoption. PMID- 25796647 TI - Senators doubt FDA can control antimicrobial use. PMID- 25796648 TI - Mexican horse meat banned by EU. PMID- 25796649 TI - In-home euthanasia versus hospice. PMID- 25796650 TI - Feral cat policy is about more than cats. PMID- 25796651 TI - Expanding the idea of one health. PMID- 25796652 TI - J. Daniel Subtelny, 1922-2014. PMID- 25796653 TI - [The changes of nuclear imaging technology iin Japanese Journal of Radiological Technology]. PMID- 25796654 TI - [Objective evaluation of tinnitus]. PMID- 25796655 TI - [Functional voice disorders]. PMID- 25796656 TI - [Diagnosis and pathology of nasal cavity and paranasal sinuses]. PMID- 25796657 TI - [Response to deglutition disorders according to a guideline]. PMID- 25796658 TI - [Trends and responses to recent medico-legal problems]. PMID- 25796659 TI - Are we appropriately preparing physicians to care for patients throughout their life journeys? PMID- 25796660 TI - The electronic health record. Are we the tools of our tools? PMID- 25796661 TI - The diverse and promising world of animal derived medications. PMID- 25796662 TI - Training surgery residents to write for publication. PMID- 25796663 TI - The missionary and the peasant. Two women who helped bring modern medicine to Korea. PMID- 25796664 TI - Christmas with Stashu. PMID- 25796665 TI - "The care of the patient". PMID- 25796666 TI - "David Seegal". PMID- 25796667 TI - [Complementary medicine in Israel]. AB - Over the past two decades there has been an increase in the use and popularity of complementary medicine in Israel. Currently, there are over 100 complementary medicine clinics in the public health sector supported by the four health funds and most hospitals in Israel. The number of visits to those clinics reaches close to 3 million visits annually. This reflects an extensive system of care that Israelis utilize in addition to the conventional heaLthcare system. However, the communication between the two systems is still Limited and the education of complementary medicine providers is not regulated by the Ministry of Health. Concurrently, there are a growing number of physicians who expand the knowledge on these therapies and actually integrate them in patients' care. This issue describes experiences and knowledge related to the integration of complementary medicine in the Israeli healthcare system and provides additional research data in support of further integration of complementary medicine within conventional healthcare. PMID- 25796668 TI - [Advances in research of complementary and integrative medicine: a review of recent publications in some of the leading medical journals]. AB - This article assesses the evidence for effectiveness, adverse effects and cost effectiveness of complementary therapies, as reflected in publications in high impact factor medical journals during the years 2012-2014. The search detected 13 randomized controlled studies (RCTs) and 14 meta-analyses, which collectively assessed results of 191 RCTs involving the participation of several thousand patients. Pain was the major focus of acupuncture research in both clinical and fMRI studies, which demonstrated that the effect of acupuncture is beyond the placebo effect. In addition, RCTs supported the use of acupuncture as an adjunctive therapy in chronic obstructive pulmonary disease and in moderate to severe depression. A promising trend was reported for the ameliorating effect of acupuncture in gout. Spinal manipulations may be helpful in cervical pain and yoga may be a useful treatment option for chronic neck pain, chronic low back pain and for pain-related disability. Beneficial effects of adding hypnosis and massage therapy to the treatment of fibromyalgia patients were also documented. Tai-chi may reduce balance impairment in mild-to-moderate Parkinson's disease and improve symptoms in patients with osteoarthritis. Products containing cranberry are associated with protective effects in some subgroups of patients with recurrent urinary tract infections. Chinese herbs may assist in glycemic control of diabetes patients and improve survival rate of patients with non-small cell lung cancer. Some of the complementary therapies were found to be cost-effective. Physicians should be aware of the possible adverse effects of these treatments and of possible drug-herb interactions. Further larger scale trials are justified. PMID- 25796669 TI - [The effects of "The Work" meditation technique on psychological scales among a non-clinical sample]. AB - BACKGROUND: "The Work" is a meditative technique developed by Byron Katie in 1986 and is practiced by hundreds of thousands of people in more than 30 countries. The technique trains individuals to identify the thoughts that cause stress and suffering in a systematic and comprehensive way and to meditatively "investigate" these thoughts, thus enabling them to experience a different interpretation of reality. GOALS: The current study aimed to assess the effect of "The Work" meditation on psychological scales among a non-clinical sample. METHODS: This was a prospective research study conducted without a control group. The intervention consisted of a 9-day workshop of "The Work" meditation technique. Fifty-eight participants completed the following questionnaires before and after the intervention: satisfaction with life (SWLS), sense of coherence (SOC), general well-being (MHI), self-esteem (SES) and demographics. RESULTS: A significant improvement was obtained in all measures after "The Work" intervention: SWLS (21.6 to 25.07, p<0.001); SOC-comprehensibility subscale (4.05 to 4.55, p<0.001), SOC-manageability subscale (4.39 to 4.9, p<0.001) and meaningfulness subscale (4.58 to 5.07, p<0.001); SES (17.61 to 21.56, p<0.001); General wellbeing-well being subscale (4.34 to 4.87, p<0.001) and distress subscale (3.42 to 2.79, p<0.001). DISCUSSION: A sense of coherence is an important resource for coping with challenging life events and promoting well-being and health. This resource can be influenced by mind-body interventions. Satisfaction with life is a subjective judgment of satisfaction with one's life in relation to one's own unique criteria. It is a central resource in mental and physical health promotion. "The Work" meditation technique includes cognitive conceptualization and processes, which may have contributed to the increase demonstrated in this scale. Psychological well-being scales also improved--a finding which has health, social and economic implications in the general population. The findings of the current study should be evaluated in light of its limitations, mainly the lack of a control group. CONCLUSIONS: The current pilot study shows the potentially beneficial effects of "The Work" technique as a method of intervention for improving results on psychological scales and promoting mental health among the general population. Future randomized controlled studies should examine the effectiveness of "The Work" intervention in this population. PMID- 25796670 TI - [Use of a structured integrative oncology evaluation as a tool to improve patient adherence to a complementary medicine treatment program]. AB - BACKGROUND: The introduction of a quality of life (QOL)-centered complementary medicine (CM) consultation over the past decade has been integrated within various oncology departments in Israel and around the globe. The consultation is provided by an integrative physician (IP) trained in CM who recommends treatment options attuned with patients' expectations, concerns and QOL, while taking safety and efficacy into consideration. OBJECTIVE: To identify, based on the initial IP consultation, factors predicting patients' compliance to a QOL oriented integrative treatment. METHODS: Analysis of demographic data was conducted, together with an assessment of patients' concerns and well-being as documented in a registry protocol. Dependent and non-dependent factors were compared in two groups of patients: those with a low and a high degree of adherence to the integrative consultation. RESULTS: Patients in the low- and high adherence groups (83 and 160, respectively) shared similar demographic, disease- and treatment-related, as well as QOL-dependent data. Adherence to the CM treatments was higher in patients reporting prior CM use, and in patients with less severe gastro-intestinal complaints. IP assessment regarding patients' difficulties in undergoing the CM treatment process predicted low patient adherence. CONCLUSIONS: We recommend including an initial IP assessment of patients undergoing chemotherapy, using a structured assessment in order to identify the following factors predicting low adherence to a CM treatment program: absence of prior CM use, severe gastro-intestinal symptoms, and IP assessment of expected difficulties in implementing the treatment plan. PMID- 25796671 TI - [Modeling integrative oncology care program for Arab patients in north Israel: towards quality of life improvement during chemotherapy]. AB - BACKGROUND: In the last decade, a number of integrative oncology programs have been established within leading oncology departments in Israel aiming to provide consultations that address patients' concerns and improve their quality of life (QOL). OBJECTIVE: To identify Arab cancer patients' attitudes, needs and expectations concerning integration of complementary and traditional medicine (CTM) in their supportive oncology care. METHODS: This article presents studies based on both qualitative (including interviews with patients, oncologists and CTM practitioners) and quantitative studies which were designed to evaluate patients' attitudes, needs and expectations regarding CTM integration in supportive oncology care. RESULTS: Of the 313 Arab respondents, 109 reported on the use of herbal medicine for cancer-associated outcomes. Over 78% of respondents considered QOL improvement as their main expectation of integrated CM consultation. Similar expectations were expressed in studies exploring 155 cancer care practitioners in Israel and Arab countries, 27 CTM-trained Arab practitioners, and a sample of 15 Arab patients referred to integrative medicine consultation. CONCLUSIONS: Arab cancer patients support QOL-oriented integrated medicine programs provided in oncology settings. Integrative medicine consultation should provide patients with an evidence-based recommendation on efficacy and safety of herbs commonly used concomitant with chemotherapy. We recommend designing integrative oncology training courses for physicians who will provide evidence-based consultation attuned with Arab patients' needs, concerns and cultural-sensitive orientation. PMID- 25796672 TI - ["Do two walk together unless they have agreed to do so?"--Combining conventional and complementary medicine in the treatment of gastroparesis]. AB - Gastroparesis is a chronic disorder of abnormal gastric motility causing considerable suffering. We describe two cases of gastroparesis which were treated by methods which were not part of routine conventional therapy, but which, nevertheless, led to significant clinical improvement. In the first case, the patient suffered from gastroparesis following a vagal injury while undergoing a lung transplant. During his illness a mega-bezoar formed, a well-described complication of gastroparesis. After conservative measures failed, and in order to avoid a surgical intervention that carried considerable risk under the circumstances, a successful trial consisting of imbibing large amounts of "Coca Cola" and acupuncture was initiated. The bezoar dissolved completely and considerable improvement of the patient's gastric motility was achieved. In the second case, the patient was a young woman suffering from idiopathic gastroparesis, which responded well to treatment with tricyclic antidepressants. Due to her intention to become pregnant, this treatment was discontinued and she was admitted to receive homeopathic treatment. After two failed attempts in finding the right homeopathic remedy to replace the conventional treatment, the third remedy (Sepia) used brought dramatic improvement in her general condition and her dyspepsia. Today, over two years after her successful homeopathic treatment, she is in the middle of her second pregnancy, without any treatment and free of complaints. These two cases are examples of simple solutions for seemingly complicated and complex conditions alleviated by an integration of conventional and complementary/alternative medicine. PMID- 25796673 TI - [Integration of complementary medicine in hospital departments: implementation model and research outline in the Cardiology Department]. AB - BACKGROUND: Systematic integration of complementary medicine in hospital departments for inpatients is rarely discussed in the medical literature. Positive outcomes from trials in this setting should encourage evaluation of complementary medicine services in hospitals. OBJECTIVE: To identify the potential role of complementary medicine in the Cardiology Department, characterize its implementation process, and conduct a feasibility study in this context. METHODS: A narrative overview of the implementation process of complementary medicine in the Cardiology Department was used alongside a statistical analysis of a feasibility trial This was in order to determine the sample size for a larger pragmatic trial that will assess the effectiveness of complementary medicine, as compared to standard of care, in relieving common symptoms of patients hospitalized in the Cardiology Department. RESULTS: Focus groups consisting of representatives from the Cardiology Department, and the Complementary Medicine Service identified areas for possible integration of complementary medicine in the Cardiology Department. A literature review was conducted in order to assess complementary medicine effectiveness and safety in this setting. Consequently, appropriate treatment protocols were developed. The Complementary Medicine team participated in cardiology patient rounds, and presentations on complementary medicine were provided to the cardiology staff. Treatment indications, and contraindications were mutually developed, and questionnaires to assess treatment effectiveness were developed. A feasibility trial was completed for 237 patients who were treated with complementary medicine. CONCLUSIONS: Integration of complementary medicine in an inpatient setting is possible following a carefully structured implementation process that is shared by champions from the medical department and the Complementary Medicine Service. Results from the feasibility trial indicate the potential positive role that complementary medicine treatments have on common symptoms of inpatients at the Cardiology Department. There is a need for high quality trials that will assess the effectiveness of complementary medicine treatments in this setting. PMID- 25796674 TI - [Dietary supplements use during hospitalization]. AB - INTRODUCTION: Consumption of dietary supplements (DS) by patients in the community is rising. DS affect human health, and safety issues regarding concomitant DS-medication use are underemphasized. Consequently, the Ministry of Health issued a directive regarding the need for assessing DS use in every patient and documenting such use in the medical record. AIMS: To evaluate the rate of DS consumption in hospitalized patients, and to assess documentation of such consumption. METHODS: This was a prospective cross-sectional study. Patients hospitalized in the medical wards of a public-academic hospital in Israel, between the years 2009-2010, were interviewed regarding their use of DS. The medical records were searched for documentation of DS use. RESULTS: A total of 895 hospitalized patients were interviewed; 691 agreed to answer the questionnaire (compliance rate 77%). The analysis referred to 648 fully-completed questionnaires. Of the participants, 359 (55.4%) were DS consumers. On multivariable analysis, DS consumption was associated with older age, female gender, higher education status, and the presence of psychiatric disease. Only 11.4% of DS users had documentation of such use in their medical record. CONCLUSIONS: DS consumption is common amongst hospitalized patients, and is overlooked by the medical team. Patients and doctors should be more aware of the possible adverse effects of DS use and their potential herb-drug interactions. Education regarding appropriate communication on DS use should be established. PMID- 25796675 TI - [Use of herbal medicine for cancer treatment-related toxicities]. AB - Cancer treatment-related toxicities often require dose reductions and delays. Herbal medicine use is prevalent among cancer patients. Though evidence is lacking regarding benefits in treatment outcomes and immunity, a large body of evidence supports the use of herbals for reducing treatment-induced toxicities. We present three cases where herbal medicine provided relief from side effects of anti-cancer treatment, enabling the completion of treatment protocols. In the first case, a 79 year-old female patient with metastatic breast cancer developed flushing and excessive sweating from Tamoxifen treatment. Herbal medicine reduced symptoms significantly, enabling the continuation of treatment with partial disease resolution. In the second case, a 69 year-old male with esophageal cancer terminated treatment on the adjuvant treatment protocol because of severe nausea and vomiting, diarrhea, peripheral neuropathy and fatigue. Herbal medicine reduced symptom severity and chemotherapy was reinstituted. In the third case, a 58 year-old female patient with advanced metastatic colon cancer was referred by her oncologist for treatment with herbal medicine for alleviation of fatigue and weakness, flushing and palpitations, mouth ulcers and dyspnea. Despite significant symptom reduction, with completion of treatment regimens, her disease progressed and she subsequently succumbed to the disease. In summary, the above cases illustrate potential benefits of herbal medicine in the reduction of cancer treatment-related symptoms, enabling patients to complete their anti-cancer treatment regimen. Further research examining the efficacy and safety of herbal compounds is needed, in light of potential toxicity and negative interactions with conventional treatment. PMID- 25796676 TI - [Efficacy comparison between Chinese medicine's labor inducement methods and conventional methods customary in hospitals]. AB - INTRODUCTION: According to Chinese medicine, a correct balance of Qi (energy) and quantity of blood are vital in order to commence labor and continue the childbirth process. Correspondingly, there are two main reasons for a delayed or difficult childbirth: lack of Qi and blood or stagnation of Qi and blood. AIM: Efficacy comparison of Chinese medicine's inducement methods to conventional methods and to the combination of both. METHODS: Retrospective study with 80 women participating aged 22-40, who required labor inducement. The study group consisted of 50 women who received Chinese medicine's inducement treatment (Shiatsu and/or Acupuncture) prior to and/or during hospitalization. The control group consisted of 30 women who received customary hospital labor inducement methods. All the women received the questionnaires between one month to 10 years after childbirth. RESULTS: Significant correlation was found between Chinese medicine inducement methods (Shiatsu/Acupuncture) and reduction of additional interventions throughout the birth process, when these were given during hospitalization (x2=47.29, d.f.=21, p=0.001). Correlation close to significant was found when inducement was given prior to hospitalization, especially when labor was induced by Shiatsu (x2=16.8, d.f.=9, p=0.052). An outstanding difference was found in shortening the birth process time (MS=0.45, F(6,72)=2.505, p=0.029) when combining Chinese medicine and conventional inducement methods (medicinal/mechanical). CONCLUSIONS: Study results show that Chinese medicine inducement methods, whether or not combined with conventional methods, are an important and effective tool in their ability to reduce the extent of intervention throughout the birth process and also in reducing delivery completion interventions. SUMMARY: Significant difference was found in shortening labor process when inducement treatment combined both Chinese medicine and conventional methods, in comparison to conventional inducement alone {medicinal/mechanical). This is an important result considering the high availability and low cost of Chinese treatment, and especially because it is a non-harmful method of inducement. PMID- 25796677 TI - [Irritable Bowel Syndrome treatment: a multidisciplinary approach]. AB - Irritable Bowel Syndrome affects 9-23% of the general population. This diagnosis contributes to more frequent doctor visits and multiple consultations by patients. The current approach to treating IBS is symptomatic and consists of a regimen of first line pharmacological treatment options; the use of anti depressant drugs is also common. The efficiency of complementary medicine in the treatment of IBS has been studied in the last few years. Qualitative multidisciplinary approach studies, using personalized medicines with complementary therapies are needed. We present the case of a 39-year-old woman with a diagnosis of IBS since 2009, who complained about gastrointestinal symptoms since the age of 13 and severe episodes of spasmodic stomach aches in the last year self-ranked as 10, on a 0-10 scale; 3-4 episodes a month, which last for 5 days, accompanied by severe flatulence and bloating. In addition, she has constipation (one bowel movement every 10 days), alternating with multiple diarrheic bowel movements (6 times a day). Using a multidisciplinary approach, including medicinal care, Chinese medicine, reflexology and naturopathy resulted in significant improvement in symptoms and quality of life, as well as gradual reduction of drugs, approved by her physician. Stomach ache self-ranked now as 1, on a 0-10 scale; and flatulence and bloating self-ranked as mild. Bowel movement frequency increased and is now every other day. She no longer has diarrheic and/or multiple bowel movements. This case report emphasizes the importance of integrative treatment in IBS and its benefit in improving patients' quality of life. PMID- 25796678 TI - [Curcumin add-on therapy for ulcerative colitis]. AB - Ulcerative Colitis (UC) is a chronic inflammatory disease of colon mucosa, which results from inappropriate inflammatory response. Pharmacological treatments that are used to manage UC are usually targeted to moderate the inflammatory response, however, they are associated with significant adverse effects, which call for finding additional treatment options. Curcumin is a polyphenol that is extracted from turmeric (Curcuma longa). This medicinal plant has been traditionally used in India and in China since ancient times. Recently curcumin has been demonstrated to possess anti-inflammatory, anti-proliferative and antibacterial properties. Based on these reports, our article describes a case report of a patient treated with curcumin in addition to 5-Aminosalicylic acid (5ASA) and presents an integrative approach for the treatment of ulcerative colitis. PMID- 25796679 TI - [Mentoring newly appointed department heads--a new project review and initial findings]. AB - BACKGROUND: In Israel, the training of a department head is based mostly on clinical and professional aspects and often does not include any training in other facets of management he or she will encounter. The newly appointed department head is expected from the start to deal with many diverse tasks, and is exposed to great physical and emotional stress. The Israeli Medical Association, taking note of this situation, initiated a mentoring program for newly appointed heads of medical departments, clinics and units. This article seeks to present a preliminary description of our experience with this mentoring project, in which senior managers mentor novices in the position. METHOD: An announcement of the new project was sent to both senior and beginning managers, detailing the project's goal. The project's content and structure were determined together with the participants, mentors and mentees. The values attending the project were delineated as full and genuine partnership, attention to needs, and personal choice of the mentee. Basic guidelines, adaptive to modification according to personal preferences, were developed based on these values. Though not readily assumed, our decision to allow mentees to choose their mentors was found to be suitable for this project. All participants, mentors and mentees, were asked to complete feedback forms in preparation for the final gathering of the group. RESULTS: The first session of the project included 8 mentor and mentee couples. Feedback indicated a high suitability rate between mentor and mentee, which resulted in high levels of satisfaction among the mentees. Responses to feedback questionnaires depicted that the relationships between the mentors and mentees included trust, openness and a non-judgmental approach, which allowed mentees to share personal difficulties and develop plans to overcome them. Most mentees described the mentorship as providing leverage to personal growth. Mentors expressed satisfaction for the opportunity to contribute of their experience. CONCLUSIONS: The success of the first session and the satisfaction expressed by its participants serve as an indication that the project met an existing need of beginning managers. The successful cooperation between mentors and mentees, closely accompanied by the professional staff, proved that beginning managers are more than willing to work alongside senior managers and learn from their vast experience. The writers believe there is a true need for mentorship for managers in our health system. The method depicted in this project was found to be efficient at this point. The next sessions of the project will allow us to identify more ways to match and oversee the mentor-mentee couples. PMID- 25796680 TI - [Molecular biological studies of erectile dysfunction: an update]. AB - Erectile dysfunction (ED), as a common male disease, seriously affects the patients' sexual life quality. Most ED patients benefit from phosphodiesterase type 5 (PDE5) inhibitors, but some refractory ED sufferers fail to respond to them. With the rapid development of molecular biology, the relevant molecular signaling pathways of penile erection and molecular pathogenesis of ED have been gradually clarified, and attempts have been made at a better management or a complete cure of ED with advanced molecular biological methods such as the gene therapy. This article presents an overview on the research progress in the molecular signaling pathways, molecular pathogenesis, and gene therapy of ED. PMID- 25796681 TI - [Roles of substance P and transient receptor potential vanilloid 1 in neuralgia in rats with chronic nonbacterial prostatitis]. AB - OBJECTIVE: To study the possible mechanisms of chronic nonbacterial prostatitis (CNP) pain. METHODS: CNP models were established in male Wistar rats by the autoimmune method. Then the paw withdrawal threshold (PWT) was detected using the Von Frey filament, prostate pathological examination was conducted, the expressions of substance P (SP) and transient receptor potential vanilloid 1 (TRPV1) in the prostate tissue and L5-S2 spinal segments were determined by immunohistochemistry and their correlations were analyzed. RESULTS: Compared with the control group, the CNP model rats showed markedly decreased PWT (P < 0.05) and obvious inflammation in the prostate tissue, with significant differences in the scope of lesion and interstitial lymphocyte infiltration (P < 0.05). The expressions of SP and TRPV1 in the prostate and spinal cord dorsal horn L5-S2 were remarkably upregulated in the models as compared with the control rats (P < 0.05). However, the expression of SP in the prostate was not correlated with that in the spinal cord (r = 0.099, P = 0.338), nor was that of TRPV1 (r = 0.000, P = 0.5). CONCLUSION: SP and TRPV1 were involved in the formation and persistence of pain in CNP rats through their upregulated expressions in the L5-S2 spinal segments. PMID- 25796682 TI - [Effects of simvastatin on the proliferation and apoptosis of prostatic epithelial RWPE-1 cells]. AB - OBJECTIVE: To investigate the effects of simvastatin on the proliferation and apoptosis of prostatic epithelial RWPE-1 cells. METHODS: RWPE-1 cells cultured in vitro were treated with simvastatin at 0, 10, 20, and 40 MUmol/L for 24, 48, and 72 hours followed by determination of their proliferation by MTT assay, and their apoptosis by flow cytometry. The mRNA and protein expressions of Bcl-2, Bax, and Cx43 were detected by fluorescence quantitative RT-PCR and Western blot, respectively. RESULTS: After 72 hours of treatment with simvastatin at 10, 20, and 40 MUmol/L, the inhibition rates of the RWPE-1 cells were (21.07 +/- 6.41)%, (34.87 +/- 9.65)%, and (47.18 +/- 10.88)%, respectively, significantly higher than (1.21 +/- 0.54)% in the control group (P < 0.05) and in a dose-dependent manner (P < 0.05); the cell apoptosis rates were (0.066 +/- 0.016)%, (0.126 +/- 0.023)%, and (0.192 +/- 0.025)%, respectively, remarkably higher than (0.015 +/- 0.005)% in the control (P < 0.05) and also in a dose-dependent manner (P < 0.05); the mRNA and protein expressions of Bcl-2 were decreasing while those of Bax and Cx43 increasing with the increased concentration of simvastatin (P < 0.05). The expression of Cx43 was correlated negatively with that of Bcl-2 but positively with that of Bax. CONCLUSION: Simvastatin inhibits the proliferation of prostate epithelial cells and induce their apoptosis by acting on the gap junctional intercellular communication. PMID- 25796683 TI - [Bisphenol A alters glucose metabolism in rat Sertoli cells in vitro]. AB - OBJECTIVE: To observe the influence of different concentrations of bisphenol A (BPA) on glucose metabolism and lactate dehydrogenase (LDH) expression in rat Sertoli cells in vitro and investigate the mechanisms of BPA inducing male infertility. METHODS: Using two-step enzyme digestion, we isolated Sertoli cells from male Wistar rats and constructed a primary Sertoli cell system, followed by immunohistochemical FasL staining. We randomly divided the Sertoli cells into a control group to be cultured in the serum-free minimal essential medium (MEM) plus dimethyl sulfoxide (DMSO) and three experimental groups to be treated with 100 nmol/L, 10 MUmol/L, and 1 mmol/L BPA, respectively, in the MEM plus DMSO. After 48 hours of treatment, we measured the proliferation of the cells by CCK-8 assay, determined the concentrations of metabolites by NMR spectroscopy, and detected the expression of LDH in the Sertoli cells by RT-PCR and Western blot. RESULTS: The purity of the isolated Sertoli cells was (96.05 +/- 1.28)% (n = 10). Compared with the control group, the 100 nmol/L, 10 MUmol/L, and 1 mmol/L BPA groups showed no remarkable changes in the proliferation of Sertoli cells ([98 +/ 8]%, [96 +/- 3]%, and [95 +/- 3]%, P >0.05), but the 10 MUmol/L and 1 mmol/L of BPA groups exhibited significantly decreased concentrations of intracellular glucose ([3.89 +/- 0.07] vs [3.36 +/- 0.24] and [3.04 +/- 0.21] pmol/cell, P <0.05) and lactate ([0.43 +/- 0.06] vs [0.29 +/- 0.05] and [0.20 +/- 0.03] pmol/cell, P <0.05). The expression of LDH mRNA was decreased with the increased concentration of BPA, while that of LDH protein reduced only in the 1 mmol/L BPA group (P <0.05). CONCLUSION: High-concentration BPA decreases the expression of LDH and alters glucose metabolism in Sertoli cells, and therefore may reduce the provision of lactate for germ cells and impair spermatogenesis. PMID- 25796684 TI - [Optimization of sperm alkaline single-cell gel electrophoresis]. AB - OBJECTIVE: To investigate the main factors that influence the results of sperm alkaline single-cell gel electrophoresis (SCGE), optimize the conditions, and standardize its procedures. METHODS: Using alkaline SCGE, we detected the DNA fragments of sperm treated with different concentrations of H2O2 and determined the influences of the number of agarose gel layers, pH during DNA unwinding and electrophoresis, the time of DNA unwinding and electrophoresis, and cumulative sperm number on the results of sperm alkaline SCGE. Then we optimized the procedures, analyzed the repeatability of the optimized method, and examined 40 semen samples using the method. RESULTS: Three agarose gel layers could reduce the background. The optimal pH during DNA unwinding and electrophoresis was 10, and the best times for DNA unwinding and electrophoresis were 40 min and 30 min, respectively. Fifty sperm were adequate to ensure the reliability of the results. Based on the percentage of tail DNA, the intra- and inter-assay repeatabilities of the optimized sperm alkaline SCGE were 3.12% and 7.13%, and by the DNA damage score, they were 2.38% and 6.09%, respectively. Sperm DNA fragments were significantly increased in the infertile patients with oligoasthenoteratozoospermia as compared with healthy fertile males (P <0.05). CONCLUSION: The optimized sperm alkaline SCGE, highly repeatable and easy to be standardized, can be applied to the clinical detection of sperm DNA fragmentation in infertile men. PMID- 25796685 TI - [Six-o'clock tunnel holmium laser enucleation of the prostate: a modified procedure for benign prostate hyperplasia]. AB - OBJECTIVE: To evaluate the safety and effectiveness of a modified method of holmium laser enucleation of the prostate (HoLEP)--6-o'clock tunnel HoLEP for the treatment of benign prostate hyperplasia (BPH). METHODS: We included 112 cases of BPH in this study, 57 treated by 6-o'clock tunnel HoLEP (experimental group) and the other 55 by conventional HoLEP (control group). We compared the operation time, volume of the resected prostatic tissue, intraoperative blood transfusion, volume of bladder irrigation solution, postoperative hemoglobin change, and incidence of urinary incontinence between the two groups. RESULTS: Statistically significant differences were observed between the experimental and control groups in the operation time ([56.01 +/- 8.62] min vs [68.65 +/- 9.08] min), cases of intraoperative blood transfusion (0 vs 2), volume of bladder irrigation solution ([27.51 +/- 3.67] L vs [36.89 +/- 6.47] L), postoperative hemoglobin decrease ([10.70 +/- 2.50] g/L vs [12.60 +/- 3.30] g/L), and cases of postoperative stress induced urinary incontinence (2 vs 7) (all P <0.05). One-month follow-up revealed smooth urination in both groups of patients but no true urinary incontinence or secondary bleeding in either. CONCLUSION: Modified 6-o'clock tunnel HoLEP can significantly reduce the operation time, bladder irrigation, and intraoperative bleeding, and therefore can be used as a safe and effective option for the treatment of BPH. PMID- 25796686 TI - [Transurethral resection of the prostate combined with 2-micron continuous-wave laser vaporesection for benign prostatic hyperplasia with the prostate volume > 80 ml]. AB - OBJECTIVE: To sum up the clinical experience in the management of benign prostatic hyperplasia (BPH) with the prostate weighing over 80 ml by transurethral resection of the prostate (TURP) combined with 2 MUm continuous wave laser vaporesection (LVR). METHODS: We retrospectively analyzed the clinical effects of TURP combined with 2 MUm LVR in the treatment of 46 cases of BPH with the prostate volume > 80 ml. RESULTS: All the operations were successfully accomplished. The operation time and intraoperative blood loss were (112.0 +/- 20.0) min (range 86-176 min) and (77.9 +/- 25.9) ml (range 50-200 ml), respectively. The catheters were withdrawn at 7 days after surgery. Transient urinary incontinence occurred in 6 cases and secondary hemorrhage was found in 2 postoperatively. Six-month follow-up revealed no urethral stricture or other complications. Compared with the baseline, the international prostate symptom score (IPSS) was significantly decreased at 6 months after operation (26.3 +/- 1.8 vs 11.6 +/- 1.7, P <0.05), and so were the quality of life (QOL) score (5.3 +/- 0.7 vs 1.3 +/- 1.1, P <0.05) and post-void residual urine (PVR) ([115.5 +/- 55.6] ml vs [19.9 +/- 11.6] ml, P <0.05). However, the maximum urinary flow rate (Qmax) was remarkably increased from (4.1 +/- 2.6) ml/s to (16.2 +/- 1.7) ml/s (P <0.05). CONCLUSION: TURP combined with 2 MUm LVR is safe and effective for the treatment of BPH with the prostate volume >80 ml. PMID- 25796687 TI - [Age correlates with Gleason score in patients with prostate adenocarcinoma]. AB - OBJECTIVE: To investigate the correlation between age and Gleason score (GS) in patients with prostate adenocarcinoma. METHODS: This study included 674 patients with pathologically confirmed prostate adenocarcinoma. We determined the GS, primary grade, and secondary grade of the cases, and compared them among different age groups. RESULTS: The mean age of the patients was (70.22 +/- 8.26) yr, ranging from 25 to 96 years, (69.06 +/- 8.35) yr in those with GS 6, (70.55 +/- 8.16) yr in GS 7, (70.99 +/- 6.54) yr in GS 8, (71.56 +/- 9.18) yr in GS 9, and (72.79 +/- 11.36) in GS 10. The mean GS, primary grade, and secondary grade were 7.08 +/- 1.09, 3.54 +/- 0.72, and 3.53 +/- 0.66, respectively, and the mean GSs in the < 60 yr, 60-69 yr, 70-79 yr, and >= 80 yr groups were 6.86 +/- 1.10, 6.99 +/- 1.10, 7.08 +/- 1.04, and 7.38 +/- 1.23, respectively. Those with GS 6, 7, and >= 8 accounted for 37.7%, 34.3%, and 28.0%, respectively. The patients aged < 60, 60-69, 70-79, and >= 80 years constituted 10.5% (71/674), 30.6% (206/674), 47.6% (321/674), and 11.3% (76/674), respectively. The age of the patients was significantly correlated with GS (r2 = 0.013, P = 0.003) and the primary grade (r2 = 0.014, P = 0.002), but not the secondary grade (r2 = 0.005, P = 0.055). CONCLUSION: Of the prostate adenocarcinoma patients, those aged >= 70 years form a larger proportion, and those with GS >= 7 comprise a higher percentage. The age of the patient is correlated with Gleason score but has a limited value in its prediction. PMID- 25796688 TI - [Semen quality and its influencing factors in preconception males in Nanjing area]. AB - OBJECTIVE: To investigate the semen quality and its influencing factors in preconception males in Nanjing area so as to provide some evidence for working out effective intervention measures. METHODS: Totally 687 men receiving preconceptional physical examination were enrolled in this study. A questionnaire survey was conducted among the subjects along with an analysis of their semen quality. RESULTS: The median of sperm concentration was 63.3 x 10(6)/ml (95% CI [19.88-119] x 10(6)/ml). The median of grade a sperm was 33.03% (95% CI [19.38 55.05]%), that of grade a + b sperm was 52.08% (95% CI [39.53-69.37]%), and that of teratosperm was 91.75% (95% CI [69-100]%). The median concentration of seminal plasma PMN-elastase was 195.55 ng/ml (95% CI [76.16-3330.38] ng/ml) and that of seminal plasma zinc was 7.62 MUmol/L (95% CI [1.5-23, 45] MUmol/L). The positive rates of Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), and Gardnerella vaginalis (GV) were 42.4%, 0.3%, and 2.4%, respectively. The median of sperm DNA fragmentation index (DFI) of those whose wives had a history of adverse pregnancy was 20.25% (95% CI [2.15-68.25]%). Multivariate logistic regression analysis suggested that mental stress (OR 1.567, 95% CI [1.081-2.27]) and sedentariness (OR 1.772, 95% CI [1.211-2.592]) were independent risk factors for asthenospermia. CONCLUSION: The sperm quality of preconception males in Nanjing area is not encouraging, and it can be improved by changing undesirable lifestyle and reducing mental stress. PMID- 25796689 TI - [Penile frenulum lengthening for premature ejaculation]. AB - OBJECTIVE: To evaluate the effect of penile frenulum lengthening in the treatment of premature ejaculation (PE). METHODS: Thirty-four males with PE were enrolled in this study, of whom 8 had received circumcision six months before and 4 had redundant prepuce, all with short frenulum. Those with a history of circumcision underwent reconstruction and lengthening of the frenulum, and those without received frenulum lengthening only. RESULTS: Compared with the baseline, the intravaginal ejaculation latency time (IELT) was significantly increased at 1 month after operation ([1.35 +/- 0.49] vs [5.71 +/- 2.69] min, t = -9.42, P <0.01), (1.42 +/- 0.5) vs (5.31 +/- 2.74) min in the patients without circumcision (t = -7.41, P <0.01), (1.12 +/- 0.35) vs (7.00 +/- 2.20) min in those with circumcision (t = -7.24, P <0.01), and (1.50 +/- 0.58) vs (4.75 +/- 1.71) min in those with redundant prepuce (t = -3.81, P <0.05). Totally, 94% of the patients were satisfied with their sexual intercourse postoperatively. CONCLUSION: Penile frenulum plays an important role in penile erection. Reconstruction and/or lengthening of the frenulum can prolong penile erection and IELT in PE patients. PMID- 25796690 TI - [Three different strategies of urine drainage following hypospadias surgery: clinical nursing and observation]. AB - OBJECTIVE: To study 3 different strategies of urine drainage following hypospadias urethroplasty, the clinical nursing in their application, and their effects. METHODS: We retrospectively analyzed the clinical data of 595 cases of hypospadias treated by urethroplasty. After surgery, 133 of the patients underwent urine drainage by suprapubic cystostomy (group A), 202 by urethral stent- tube indwelling (group B), and 260 by early initiative micturition with the urethral stent-tube (group C). All the patients received routine postoperative nursing care required for hypospadias repair. RESULTS: Operations were successfully completed in all the cases. Group C showed a remarkably shorter hospital stay and lower incidence rates of urinary fistula and urethral stricture than groups A and B (P<0.05), but there were no significant differences in the three indexes between A and B (P<0.05). CONCLUSION: For urine drainage following hypospadias repair, early initiative micturition with the urethral stent-tube can significantly reduce postoperative complications, decrease difficulties and workload of nursing care, and shorten the hospital stay of the patient. PMID- 25796691 TI - [Papillary cystadenoma of the epididymis: a report of 2 cases and review of the literature]. AB - OBJECTIVE: To study the clinicopathological characteristics of papillary cystadenoma of the epididymis. METHODS: Using routine pathology and immunohistochemistry, we observed the surgically obtained samples from 2 cases of papillary cystadenoma of the epididymis, analyzed their pathological features and clinical presentations, and reviewed the related literature. RESULTS: The 2 patients were both adult males. The tumors typically manifested as painless swelling in the epididymis, with occasionally dull pain and tenesmus in 1 of the cases. Pathologically, the lesions exhibited three morphological features, i. e., dilated ducts and small cysts surrounded by fibrous connective tissue, adenoid papillary hyperplasia into the cysts embraced by fibrovascular stroma, and acidophil substance present in the cysts. Immunohistochemistry showed that the tumors were strongly positive for CK8/18, CK7, and EMA, but negative for CK20, CEA, MC, Calretenin, P53, P63, SMA, VHL, and CD10, with the positive rate of Ki 67 <1%. Follow-up visits revealed good prognosis in both cases. CONCLUSION: Papillary cystadenoma of the epididymis is a rare benign tumor in the male urogenital system, which may be accompanied by the VHL syndrome. Surgery is the first choice for its treatment. PMID- 25796692 TI - [Congenital bilateral ejaculatory duct absence complicated with seminal vesicle cyst: a case report and review of the literature]. AB - OBJECTIVE: To report a case of simple congenital bilateral ejaculatory duct absence (EDA) complicated with seminal vesicle cyst and review the relevant literature in order to improve the diagnosis and treatment of the disease. METHODS: We retrospectively reviewed the clinical data of a case of bilateral congenital EDA complicated with seminal vesicle cyst, reviewed the relevant literature at home and abroad, and comprehensively analyzed the embryonic development, diagnosis, and treatment of congenital EDA. RESULTS: The patient was a 23-year-old man, present at the clinic for infertility after married for a year. Vasography and other imaging examinations confirmed simple congenital bilateral EDA complicated with seminal vesicle cyst. Pathologic biopsy showed normal spermatogenic function of the testes. CONCLUSION: Congenital EDA originates from embryonic developmental defect of the mesonephric duct, and it can be confirmed by vasography. Transurethral incision of the ejaculatory duct and intracytoplasmic sperm injection can be employed for the treatment of bilateral EDA. PMID- 25796694 TI - [Prostate cancer stem cells: advances in current research]. AB - Prostate cancer is one of the most common malignancies threatening men's health, and the mechanisms underlying its initiation and progression are poorly understood. Last decade has witnessed encouraging progress in the studies of prostate cancer stem cells (PCSCs), which are considered to play important roles in tumor initiation, recurrence and metastasis, castration resistance, and drug resistance. Therefore, a deeper insight into PCSCs is of great significance for the successful management of prostate cancer. This article presents an overview on the location, origin, and markers of PCSCs as well as their potential correlation with tumor metastasis and castration resistance. PMID- 25796693 TI - [Longbishu Capsule combined with mesylate doxazosin: an efficacious therapy for benign prostatic hyperplasia]. AB - OBJECTIVE: To assess the clinical effect and safety of the Chinese medicine Longbishu Capsule combined with mesylate doxazosin in the treatment of benign prostatic hyperplasia (BPH) of the kidney deficiency and blood stagnation type. METHODS: This was a randomized, double-blind, double-simulation control study. We equally assigned 60 men diagnosed with BPH of the kidney deficiency and blood stagnation type to an experimental and a control group, the former treated with mesylate doxazosin plus Longbishu Capsule and the latter with mesylate doxazosin plus placebo. We compared the International Prostate Symptom Score (IPSS), quality of life (QOL), Chinese symptom score (CSS), maximal urinary flow rate (Qmax), and prostate volume between the two groups of patients before and after 6 months of medication. RESULTS: After treatment, there were 5 cured cases, 13 markedly effective cases, 9 effective cases, 1 ineffective case, and 2 eliminated cases in the experimental group, as compared with 2 cured cases, 8 markedly effective cases, 10 effective cases, 7 ineffective cases, and 3 eliminated cases in the control group. The total effectiveness rate was obviously higher in the former (96.4%) than in the latter (74.1%). IPSS, Qmax, and CSS were improved in both of the groups after medication, even more significantly in the experimental than in the control group (IPSS: 15.22 +/- 2.98 vs 18.15 +/- 5.88, P <0.05; Qmax: [13.56 +/- 2.26] ml/s vs [11.78 +/- 2.97] ml/s, P <0.05; CSS: 6.18 +/- 2.13 vs 9.52 +/- 3.15, P <0.05). Because of the difference in the QOL score between the two groups at the baseline (P = 0.038 <0.05), no more comparison was made in this aspect after treatment. CONCLUSION: The combination of Longbishu Capsule with mesylate doxazosin is safe and effective for the treatment of BPH. PMID- 25796696 TI - Foodborne illness and seasonality related to mobile food sources at festivals and group gatherings in the state of Georgia. AB - Little is known about the relationship of location and season to the pathogen and impact of foodborne illness. A sample of 244 foodborne illness outbreaks from the Foodborne Outbreak Online Database System stemming from festivals (mobile food sources) and group gatherings in Georgia between 1998 and 2010 was examined to determine if season and location were related to pathogen and the number of ill or hospitalized individuals. Results of Chi-square tests of independence, one-way analysis of variance, and the Kruskal-Wallis test showed that norovirus and Salmonella were more strongly associated with group gatherings; Staphylococcus outbreaks were more associated with festivals; norovirus was more frequent during winter; and Salmonella was more associated with summer and autumn events. Location and impact were significant for outbreaks associated with group gatherings, resulting in more hospitalizations than outbreaks associated with festivals. No statistically significant difference occurred between the numbers of reported illnesses stemming from festivals versus group gatherings nor did a seasonal difference occur in the total number of individuals who fell ill or were hospitalized. PMID- 25796695 TI - [Sulfogalactosylglycerolipid in spermatogenesis and fertilization]. AB - Sulfogalactosylglycerolipid (SGG) is the main glycolipid in male mammalian germ cells, which is selectively and highly expressed in mammalian testes and helps form the lipid bilayer of cell membrane. In the process of spermatogenesis, SGG is involved in the meiosis of spermiocytes. Either deficiency or accumulation of SGG will lead to male infertility. SGG homeostasis in the testis is the premise of normal spermatogenesis. In the process of sperm-zona binding, SGG becomes a component of lipid raft and provides a platform for signal transduction. The SGG binding protein plays a role in sperm-egg recognition and membrane fusion. SGG has a great research value and application prospect in male reproduction. PMID- 25796697 TI - An exploratory analysis to determine priority areas for lead poisoning prevention education programs in Missouri. AB - Lead is a strong poison and toxic to many vital organs and body systems especially in the central nervous system of children, who are more vulnerable to lead poisoning than adults. The purpose of the study described in this article was to examine the relationship between elevated blood lead level (BLL) cases of children in the state of Missouri and pre-1980 home construction, lead mine proximity, and median household income and to determine counties and areas for statewide prevention education. Results of the regression analysis indicated that these combined variables were significant predictors (F[3,111] = 19.106, p < .05, R2 = .341), accounting for 34.1% of the explained variance in the number elevated BLL cases. Number of houses built prior to 1980 (beta = .606, p < .05) and median household income (beta = -0.186, p < .05) were specifically revealed to be significant predictors of elevated blood lead cases. In addition to screening in identified counties, Missouri's statewide plan should expand to include prevention education in all low-income counties. PMID- 25796698 TI - Analyses of the contributing factors associated with foodborne outbreaks in school settings (2000-2010). AB - State-reported school foodborne outbreaks account for about 3.8% (n = 464) of all outbreaks and 8.2% (n = 20,667) of all illnesses reported to the Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System. Of 464 school foodborne outbreaks, 122 (26%) outbreaks, 7,603 illnesses, and 301 reported food safety errors met the criteria for inclusion in the analyses. The purpose of the authors' study was to examine the role of contributing factors in school foodborne outbreaks. Contamination factors accounted for the greatest proportion (49.2%) of outbreaks involving some level of food handling interaction by a school food service worker, followed by proliferation (34.9%) and survival factors (15.9%). Over 56% of all illnesses were associated with norovirus and food service worker practices. The results of these analyses highlight the importance of effective food safety education programs that focus on the role of contributing factors and prevention of foodborne disease from food safety errors. PMID- 25796700 TI - 2013 NEHA/UL sabbatical exchange award to Canada: comparing undergraduate environmental health education in Canada and the United States. PMID- 25796699 TI - Evaluation of the Children's Environmental Health Network's environmental stewardship checklist responses. AB - Children are subject to multiple hazards on a daily basis, including in child care facilities. Research has shown that children in the child care setting may be exposed to lead, radon, pesticides, and multiple chemicals that are associated with known or suspected adverse health effects. The authors' study used an existing environmental health endorsement program to describe current practices of child care facilities as related to environmental health and safety. The facilities varied greatly in size and were located mainly in the U.S. with a few from Canada and Australia. A few checklist items had nearly a 100% positive response rate; however, some of the items had more than 10% of the facilities answer "false" or "don't know." Although many areas exist in which these sampled child care facilities are being environmentally responsible, further education is needed, particularly as related to the use of wall-to-wall carpeting, radon testing, aerosols, and air fresheners. PMID- 25796701 TI - Professional training agreement development for undergraduate environmental health internships required by EHAC-accredited program. PMID- 25796702 TI - Modeling health impacts of the transportation built environment: challenges and opportunities. PMID- 25796703 TI - Environmental information for everyone. PMID- 25796704 TI - 2014 environmental health legislation. PMID- 25796705 TI - You will be a different person by the time you reach the end of this article. PMID- 25796706 TI - NEHA staff member Larry Marcum retires. PMID- 25796707 TI - Policy and practice. PMID- 25796708 TI - Lessons in optimism. PMID- 25796709 TI - CDC declares flu epidemic. Are your patients getting antivirals for the flu? PMID- 25796710 TI - Nurse practitioners: a vital role in Michigan's health care. PMID- 25796711 TI - [Comparison between levels of prolactin of mother in relactation and exclusive breast feeding mothers]. AB - Not experimental, prospective, comparative, and longitudinal study conducted in order to compare the levels of prolactin in 15 mothers (study group) with more than two weeks of having suspended the breastfeeding, and trained to relactate according to the method recommended by World Health Organization: nipple and breast stimulation, technique of dripping and drip and mechanical and manual removal, and 25mothers (control group) that breastfeeding exclusively, whose children less than six months, were hospitalized with various diseases, in the Division of Pediatric of University Hospital in Maracaibo, from November 2010 to October 2011. The mothers had between 15 and 25 years of age in both groups (p =0.58), the main cause of the abandonment of breastfeeding was insufficient milk production (46.67%). The time of occurrence of milk secretion was 6+1.60 days. Prolactin levels in the study group mothers in the first 24 hours of admission was 35.58 +18.04 ng/ml, and in the control group 129.83 + 35.01 ng/ml, statistically significant (p=0.01). Initiated the milk secretion was 121.20+16.90 ng/ml, statistically significant (p =0.01 compared to base line study group, but when was compared to the control group was not statistically significant (p =0.13). It concludes that in this group of mothers who left nursing, once started relactation had significantly higher prolactin levels, similar to the levels in mothers exclusively breastfeeding. PMID- 25796712 TI - [Prevalence of deficiency and dietary intake of iron, zinc and copper in Chilean childbearing age women]. AB - The aim of the present study was to evaluate anemia, the biochemical status and dietary adequacy of iron (Fe), zinc (Zn) and copper (Cu), in Chilean childbearing age women. We studied a convenience sample of 86 women aged 18 to 48 years from Santiago, Chile. We determined anemia and the micronutrient status through hemoglobin (Hb) mean corpuscular volume, transferrin saturation, zinc protoporphyrin, serum ferritin (SF), serum Zn and Cu. Dietary adequacy was estimated using a food frequency questionnaire. Of all women, 4.7% had Fe deficiency (ID) anemia, 21 % ID without anemia, 26 % depleted Fe stores and 48.3% normal Fe status. Obese women had higher SF (p<0.01) compared with those classified as having normal BMI. Also, showed higher Hb (p<0.05) concentrations compared with overweight and normal weight women. Partidipants showed 3.5 % and 2.3 % of Zn and Cu deficiency, respectively. Also, 95 %, 94 % and 99 % had adequate intake of Fe, Zn and Cu respectively, according to EAR cut points. There were no significant differences in micronutrients intake across different nutritional status. There was a low prevalence of anemia, Fe, Zn and Cu deficiency. A high percentage of women reached micronutrient adequacy. However, 47% of women had ID without anemia and Fe depleted stores. PMID- 25796713 TI - [In vitro and in vivo effects of mango pulp (Mangifera indica cv. Azucar) in colon carcinogenesis]. AB - Mango pulp contains ascorbic acid, carotenoids, polyphenols, terpenoids and fiber which are healthy and could protect against colon cancer. The aim of this study was to evaluate the antiproliferative and preventive capacity of an aqueous extract of Mangifera indica cv. Azucar on a human colon adenocarcinoma cell line (SW480) and in a rodent model of colorectal cancer, respectively. The content of total phenolics, flavonoids and carotenoids were also analyzed in the extract. SW480 cell growth was inhibited in a dose and time dependent manner by 22.3% after a 72h exposure to the extract (200 ug/ mL). Colon carcinogenesis was initiated in Balb/c mice by two intra-peritoneal injections of azoxymethane (AOM) at the third and fourth week of giving mango in drinking water (0.3%, 0.6%, 1.25%). After 10 weeks of treatment, in the colon of mice receiving 0.3% mango, aberrant crypt foci formation was inhibited more than 60% (p=0,05) and the inhibition was dose-dependent when compared with controls receiving water. These results show that mango pulp, a natural food, non toxic, part of human being diet, contains bioactive compounds able to reduce growth of tumor cells and to prevent the appearance of precancerous lesions in colon during carcinogenesis initiation. PMID- 25796714 TI - [Bone biomarkers and its relation with bone mineral density in adults and adolescents during the first year postpartum]. AB - The objective of this study was to describe the trend of bone biomarkers in adults and adolescents women at 15, 90, 180 and 365 postpartum days (ppd) and its relation with bone mineral density (BMD). It was a prospective cohort of 32 teenager's <=17 and 41 women from 18 to 29 years old. We evaluated diet, anthropometry, BMD, bone biomarkers and hormonal profile. In all, the concentration of N-telopeptide was higher at 15 days postpartum decreasing during first year postpartum, but adolescents had the highest concentration. The lowest N-telopeptide concentration was associated with highest increasing of the BMD. Osteocalcin concentration was lower in adolescents than in adults women (5 +/- 3 vs 13 +/- 4 ng/mL, p<0.001) during first year postpartum. Exclusive breastfeeding did not affect the BMD (p>0.050) or bone biomarkers. Osteocalcin concentration was positively associated with bone BMD (p<0.040), breastfeeding did not affect osteocalcin concentrations. Prolactin was higher among women who breastfed exclusively (p<0.001). Age and breastfeeding inversely correlated with bone biomarkers (p<0.001) N-telopeptide and PTHi respectively. We concluded that a lower N-telopeptide concentration and a higher osteocalcin concentration were associated with a higher increasing of BMD, so then, adolescents showed the lowest recovery of the BMD. Breastfeeding does not affect the BMD. PMID- 25796715 TI - Healthy eating index of elderly: description and association with energy, macronutrients and micronutrients intake. AB - The purpose of this study was to define the Healthy Eating Index (HEI) of the elderly of Southern Brazil and its association with energy, macronutrients and micronutrients intake. A cross-sectional study was conducted with 186 elderly aged 60 and older of the Geriatric Service of Sao Lucas Hospital, Porto Alegre, Brazil. Dietary data were collected by two 24-hour recalls, and diet quality was assessed by HEI adapted to the Brazilian population. The HEI total score was divided into three categories: inadequate diet (below 51 points), diet needs improvement (between 51 and 80 points), and healthy diet (over 80 points). The results showed that the mean HEI score was 58.8+/-10.5 points (ranging from 31.4 to 79.8). Most elderly (74.2%) showed a diet that needed modification and no elderly individual had a healthy diet. The quality of the diet was associated with greater intake of carbohydrates, and lower intake of total lipids, saturated fatty acids, cholesterol, and sodium. Consumption of vitamins C and D and calcium was shown to be positively correlated with the quality of the diet. Less than 1.1% of the elderly consumed a varied diet. The findings suggest that the diet of the majority of the elderly needs improvement, reinforcing the importance of care in relation to adequate nutrition in this population, and can help in guiding the activities and programs of nutritional education and public policies that stimulate increasingly healthy eating. PMID- 25796716 TI - [Levels of Ochratoxin A and total Aflatoxins in Panamanian exportation coffee by an ELISA Method]. AB - A study about processing conditions of exportation coffee in 15 benefits located in Chiriqui, western region of Panama, was conducted. In addition, 21 samples of processed coffee (green beans), from the benefits, were analyzed. The samples were microbiologically tested in order to quantify total aflatoxins (B1, B2, G1 and G2) and Ochratoxin A (OTA), using the immunoaffinity ELISA method. A detection limit of 0.017 ng/mL, was determined for Ochratoxin A, which is equivalent to a concentration of 0.829 ug/kg, and a detection limit of 0.027 ng/mL, for total aflatoxins, which is equivalent to a concentration of 1.350 ug/kg. It was found that four (19%) out of the 21 samples were positive to the presence of Ochratoxin A and three (14%) to the presence of total aflatoxins. Samples showed levels of Ochratoxin A in the range 4.90 - 37.73 ug/kg; only three of them exceeded the maximum limit allowed by the European Union, for the concentration of Ochratoxin, which is of 5.0 ug/kg. Total aflatoxins were found in the range 1.51 - 1.93 ug/kg, below 10 ug/kg which is the maximum limit allowed for coffee by the European Union. The results indicate that the processing of coffee produced in Panama successfully meets international standards for postharvest handling, which leads to a low incidence ofmycotoxins and very low levels ofmycotoxin-producing fungi. PMID- 25796717 TI - [Antioxidant capacity of byproducts from amaranth (Amaranthus hypochondriacus) seeds]. AB - The antioxidant capacity (CA) of byproducts from amaranth (Amaranthus hypochondriacus) seeds from two harvest parcels as a function of three extraction methods and two solvents was evaluated. On a first stage the effect of extraction method (homogenization, low frequency ultrasound, or the combination homogenization-ultrasound) and extraction solvent (methanol or ethanol, 100%) were evaluated; on a second stage, the effect of extraction solvent concentration (100%, 70%, or 50%) was evaluated. CA was determined by DPPH* inhibition, which was expressed as mg Equivalents of Trolox (ET)/g dry matter (DM). Total Phenolic compounds (FT) were determined by means of the FolinCiocalteu assay and expressed as Equivalents of Gallic Acid (EGA)/g DM. Antioxidant compounds were identified by gas chromatography coupled to mass spectrometry. For CA, there was not significant difference (p>0,05) among extraction methods, but there was significant difference (p<0,05) between solvents (3,39 and 1,28 mg ET/g DM, with methanol and ethanol, respectively). For FT, there was not significant difference (p>0,05) between solvents when they were diluted, but a significant difference (p<0,05) was observed when they were used at 100%. For CA, there was a significant (p<0,05) effect of solvent concentration, both studied solvents at 50% provided the best results (21,34 and 21,82 mg ET/g DM with methanol and ethanol, respectively). The qualitative analysis of the extracts exhibited the presence of squalene and 2,5-bis (1,1-dimethylethyl) phenol as the major compounds with antioxidant capacity. PMID- 25796718 TI - [Cybersurgery: human-machine integration for surgery of the future]. AB - The concept whereby human-machine collaboration can enhance surgical performance is briefly reviewed in this editorial. Implementation of computer and robotic technologies in the operating room may enhance the safety, efficacy and precision of the surgical procedure and facilitate minimally invasive approaches. The coming cybernetic revolution in surgery is no longer science fiction: a surgical robot equipped with image recognition, specific algorithms and artificial intelligence has the potential replace surgeons and to perform complex procedures autonomously. PMID- 25796719 TI - [The BAB project (Big Artificial Brain)]. AB - Recent advances in neuroscience allow us to envisage the creation of an artificial brain (BAB, for Big Artificial Brain) in order to reproduce cerebral functions without having to copy individual neurons, the complex properties of which are largely beyond our present technological capabilities. As in the human brain, we intend to combine inputs, a black box ("mentipulator") and expressive outputs. The ZISC and NeuroMem neuronal chips designed by Guy Paillet, Anne Menendez and IBM have been used to built a BAB of 1 million transversally and vertically interconnected neurons with a parallel architecture, as in the human cerebral cortex. Potential applications are multiple and highly promising. PMID- 25796720 TI - [Session dedicated to the commemoration of the bicentenary of the birth of Claude Bernard: "The current medical benefits of Claude Bernard Research"]. PMID- 25796721 TI - [Chemokines: new insights in the treatment of glaucoma and inflammatory diseases of the ocular surface]. AB - The celebrations of the 200th anniversary of Claude Bernard's birth (1813) give us the opportunity to recall all the pioneer work carried out by the great physiologist, which still remains relevant in both scientific and medical fields. The description that tissues are "floating in a liquid milieu" bringing survival molecules and allowing homeostasis, is particularly illustrated in the physiopathology of glaucoma. Second leading cause of blindness worldwide, glaucoma is an optic neuropathy mainly related to an increase of intraocular pressure. Degeneration of the trabecular meshwork, the filter that allows aqueous humor outflow from the eye, includes loss of trabecular cells, extracellular matrix remodeling, oxidative stress, and release of inflammatory cytokines, which are together the hallmarks of glaucoma. Although globally efficient, the topical treatments of glaucoma with eye drops containing active compounds produce, in the long-term, side effects mainly due to benzalkonium chloride, a preservative added to prevent bottle contamination. Such compound induces inflammatory processes. Thus, new data involving chemokines such as CXCL12, known to play a key role in inflammation and cellular crosstalk in the trabecular meshwork, offer new targets for the development of innovative treatments in glaucoma. PMID- 25796722 TI - [Session dedicated to macular degeneration related to age]. PMID- 25796723 TI - [Genetics of AMD]. PMID- 25796724 TI - [Management of wet AMD in 2013]. PMID- 25796725 TI - ["French Tropical Medicine and International Cooperation: Challenges and Opportunities"]. PMID- 25796726 TI - [Guest-discussants]. PMID- 25796727 TI - [Tropical medicine: past and present]. PMID- 25796728 TI - [Training in tropical medicine in France]. AB - Tropical medicine was a key element of the medical structures provided by France to our former colonies and, later; to countries within the scope of our international cooperation. hI recent decades, France has drastically reduced its bilateral commitments to countries in the tropics, and especially in sub-Saharan Africa. At the same time, the teaching of tropical medicine, which was highly regarded even beyond our borders, has lost a good deal of its expertise. Initially available in a few large French centers, and ensured by teachers with extensive field experience, training in tropical medicine is now offered in many universities. However; their programs and educational objectives, focusing mainly on infectious and parasitic diseases, no longer meet the healthcare priorities of southern countries, which are facing an epidemiological transition and the rise of non communicable diseases. Few teachers now have recognized expertise in tropical medicine. These changes have had negative consequences for research programs in tropical medicine and for the image of French assistance to developing countries. In this context, the followving perspectives should be considered: 1) training in tropical medicine should be enhanced by the creation of a national diploma recognized by international bodies. 2) The creation of a doctoral course in tropical medicine is a prerequisite for achieving this goal, and the future diploma must include a significant research component. 3) Teaching in tropical medicine must become more practical and be ensured by teachers with extensive field experience. 4) Training in tropical medicine should be part of a bilateral relationship with countries in the tropics, each party contributing its expertise while respecting that of its partners. 5) Training in tropical medicine should be backed uip by high-level scientific research based on enhanced synergy of our current networks (Institute for Research and Development, Network of overseas Pasteur Institutes, universities, etc.). 6) Teaching of tropical medicine should be coordinated by a supra-university structure whose mission is to ensure coherence. 7) Success in all these objectives will require strong political commitment. This is the only way to restore the enviable position which France occupied in the recent past. PMID- 25796729 TI - [Research in tropical medicine]. AB - In France, research in tropical medicine is carried out by the Institute for Research and Development (IRD), university-affiliated institutes, and other research organizations such as INSERM, CNRS and the Pasteur Institute. Currently, this research is highly fragmented and therefore inefficient. As a result, despite significant financial means, French research in this field is not sufficiently competitive. This research activity should be coordinated by creating a "federation ", that would 1) facilitate the sharing of material and human resources, thereby improving efficiency and resulting in cost savings; 2) valorize French research in tropical medicine and its expert know-how, thus favoring the nomination of French experts in large international research programs (French experts in tropical medicine are currently under-recognized); 3) attract young researchers from France and elsewhere; and 4) adapt to the ongoing demographic and economic evolution of tropical countries. The creation of a Federation of French researchers would also make research in tropical medicine more visible. The objectives to which it leads already must include 1) a better understanding of the priorities of countries in the southern hemisphere, taking into account the social, cultural and economic contexts and ensuring the consistency of current and future projects ; 2) strengthening of research networks in close and equal partnership with researchers in the southern hemisphere, with pooling of resources (scientific, human and material) to reach the critical mass required for major projects ; 3) promoting the emergence of centers of excellence for health research in tropical countries ; and 4) contributing more effectively to training, because there can be no training without research, and no research without training This consolidation will help to empower research in tropical medicine, as in other Western countries, and will allow France to recover the place it deserves. The specific conditions of this Federation of all French stakeholders (universities, research institutes, the military, and NGOs) must be defined by a committee of elected or nominated officials. PMID- 25796730 TI - [The decentralization of state responsibilities in the field of public health]. PMID- 25796731 TI - [National health security agencies: facts and perspectives]. AB - Despite major changes in its composition over the past two decades, the French health security infrastructure, currently consisting of eight agencies, has endured. This infrastructure has reinforced the French state's capacity to protect the health of its population, but it did not yet provide total protection. The future of national health agencies will depend on their ability to maintain the priority given to public health security ; to preserve credible, high-level scientific expertise ; to meet the challenges of healthcare safety ; and to organize health security at the European level. PMID- 25796732 TI - [French National Authority for Health]. AB - The French National Authority for Health (Haute Autorite de Sante, HAS) was created in 2004. The aim of this study was to examine three of its principal responsibilities, namely certification of healthcare facilities, definition of chronic illnesses (ALD, affections de longue duree), and production of clinical practice guidelines. The authors did not assess other HAS responsibilities, such as the role of the drug evaluation and reimbursement committee (Commission de Transparence). Healthcare facility certification cost at least 22.4 million ? in 2012 and involved 89 HAS personnel and 681 external auditors; medical issues were considered from only a very general and theoretical standpoint, leading the national ombudsman (Cour des Comptes) to qualify them as "blind spots". HAS is required to provide only an overall assessment of each healthcare institution, even though different departments may be of highly variable quality. Chronic illnesses are somewhat vaguely defined, permitting flexible interpretation by health insurers' medical experts. This leads to considerable disparities from one region to another in the number of patients qualifyingfor this status. Finally, practice guidelines must be more firmlly based on the results of the most rigorous and properly referenced scientific studies, and the resultinzg documents must be written more strictly, clearly and briefly, hi conclusion, HAS performance in the three roles we examined is disappointing Certification of healthcare institutions could be replaced by unannounced inspections by the General Welfare Inspectorate, health insurers, or regional health agencies. The definition of chronic illnesses and the production of practice guidelines could be handed over to scientific societies or academies, as illustrated by the case of hypertension. PMID- 25796733 TI - [Albert Calmette: celebrating the 150th anniversary of his birth]. AB - Albert Calmette (1863-1933) left a major legacy, ranging from basic research to practical medical applications. His initial work focused on antivenimous serum therapy, as well as the creation of Pasteur Institutes outside France. But his greatest achievement is the discovery of the BCG vaccine, in conjunction with Camille Guerin. This was a major advance at a time when tuberculosis was a veritable scourge, responsible for the deaths of thousands of children each year. He also pioneered early TB control in the field. The validity of BCG vaccination was not called into question despite the Lubeck drama, that he bravely affronted in 1931. PMID- 25796734 TI - Prediction of regulatory gene pairs using dynamic time warping and gene ontology. AB - Selecting informative genes is the most important task for data analysis on microarray gene expression data. In this work, we aim at identifying regulatory gene pairs from microarray gene expression data. However, microarray data often contain multiple missing expression values. Missing value imputation is thus needed before further processing for regulatory gene pairs becomes possible. We develop a novel approach to first impute missing values in microarray time series data by combining k-Nearest Neighbour (KNN), Dynamic Time Warping (DTW) and Gene Ontology (GO). After missing values are imputed, we then perform gene regulation prediction based on our proposed DTW-GO distance measurement of gene pairs. Experimental results show that our approach is more accurate when compared with existing missing value imputation methods on real microarray data sets. Furthermore, our approach can also discover more regulatory gene pairs that are known in the literature than other methods. PMID- 25796735 TI - A group-specific tuning parameter for hybrid of SVM and SCAD in identification of informative genes and pathways. AB - The pathway-based microarray classification approach leads to a new era of genomic research. However, this approach is limited by the issues in quality of pathway data. Usually the pathway data are curated from biological literatures and in specific biological experiment (e.g., lung cancer experiment), context free pathway information collection process takes place leading to the presence of uninformative genes in the pathways. Many methods in this approach neglect these limitations by treating all genes in a pathway as significant. In this paper, we proposed a hybrid of support vector machine and smoothly clipped absolute deviation with group-specific tuning parameters (gSVM-SCAD) to select informative genes within pathways before the pathway evaluation process. Our experiment on canine, gender and lung cancer datasets shows that gSVM-SCAD obtains significant results in identifying significant genes and pathways and in classification accuracy. PMID- 25796736 TI - Combining multiple clusterings for protein structure prediction. AB - Computational annotation and prediction of protein structure is very important in the post-genome era due to existence of many different proteins, most of which are yet to be verified. Mutual information based feature selection methods can be used in selecting such minimal yet predictive subsets of features. However, as protein features are organised into natural partitions, individual feature selection that ignores the presence of these views, dismantles them, and treats their variables intermixed along with those of others at best results in a complex un-interpretable predictive system for such multi-view datasets. In this paper, instead of selecting a subset of individual features, each feature subset is passed through a clustering step so that it is represented in discrete form using the cluster indices; this makes mutual information based methods applicable to view-selection. We present our experimental results on a multi-view protein dataset that are used to predict protein structure. PMID- 25796737 TI - Identifying disease candidate genes via large-scale gene network analysis. AB - Gene Regulatory Networks (GRN) provide systematic views of complex living systems, offering reliable and large-scale GRNs to identify disease candidate genes. A reverse engineering technique, Bayesian Model Averaging-based Networks (BMAnet), which ensembles all appropriate linear models to tackle uncertainty in model selection that integrates heterogeneous biological data sets is introduced. Using network evaluation metrics, we compare the networks that are thus identified. The metric 'Random walk with restart (Rwr)' is utilised to search for disease genes. In a simulation our method shows better performance than elastic net and Gaussian graphical models, but topological quantities vary among the three methods. Using real-data, brain tumour gene expression samples consisting of non-tumour, grade III and grade IV are analysed to estimate networks with a total of 4422 genes. Based on these networks, 169 brain tumour-related candidate genes were identified and some were found to relate to 'wound', 'apoptosis', and 'cell death' processes. PMID- 25796738 TI - Prediction of HLA-DRB1*0401 binding peptides using support vector machine. AB - In recent years, many machine learning methods have been developed to predict HLA binding peptides. However, because only limited types of descriptors characterising the protein features are included in these approaches, these methods have poor prediction accuracy. In this study, we applied support vector machine methods to predict the peptides that bind to the major histocompatibility complexes Class II molecule HLA-DRBl*0401 using six sets of molecular descriptors characterising the primary structures of the peptides. We found that some feature groups provided good prediction accuracies and the overall accuracies were greater than 95% and some feature groups had poor accuracies of only 50%. The performance was improved significantly by additional feature selection and the overall accuracies from each group or combination of descriptors were greater than 90%. Of note, the inclusion of necessary informative and discriminative descriptors improved the prediction accuracies. PMID- 25796739 TI - High throughput computing to improve efficiency of predicting protein stability change upon mutation. AB - Predicting protein stability change upon mutation is important for protein design. Although several methods have been proposed to improve prediction accuracy it will be difficult to employ those methods when the required input information is incomplete. In this work, we integrated a fuzzy query model based on the knowledge-based approach to overcome this problem, and then we proposed a high throughput computing method based on parallel technologies in emerging cluster or grid systems to discriminate stability change. To improve the load balance of heterogeneous computing power in cluster and grid nodes, a variety of self-scheduling schemes have been implemented. Further, we have tested the method by performing different analyses and the results showed that the present method can process hundreds of predication queries in more reasonable response time and perform a super linear speedup to a maximum of 86.2 times. We have also established a website tool to implement the proposed method and it is available at http://bioinformatics.myweb.hinet.net/para.htm. PMID- 25796740 TI - A hybrid of bees algorithm and flux balance analysis (BAFBA) for the optimisation of microbial strains. AB - The development of microbial production system has become popular in recent years as microbial hosts offer a number of unique advantages for both native and heterologous small-molecules. However, the main drawback is low yield or productivity of the desired products. Optimisation algorithms are implemented in previous works to identify the effects of gene knockout. Nevertheless, the previous works faced performance issue. Thus, a hybrid of Bees Algorithm and Flux Balance Analysis (BAFBA) is proposed in this paper to improve the performance in predicting optimal sets of gene deletion for maximising the growth rate and production yield of certain metabolite. This paper involves two datasets which are E. coli and S. cerevisiae. The list of knockout genes, growth rate and production yield after the deletion are the results from the experiments. BAFBA presents better results compared to the other methods and the identified list may be useful in solving genetic engineering problems. PMID- 25796742 TI - [Trend of detection of cefotaxime-resistant Escherichia coli and clinical features of bloodstream infection due to extended-spectrum beta-lactamase producing Escherichia coli in a general hospital]. AB - Recently, the community pandemic infections of cefotaxime (CTX)-M type extended spectrum beta-lactamase (ESBL) producing bacteria, which is mostly resistant to CTX, has been well-known as major problems. When the ESBL-confirmation test cannot be done, CTX-resistant Escherichia coli might be used as the alternation method of infectious control. We investigated tendency of third-generation cephalosporin resistant E. coli and the clinical features of bloodstream infections (BSI) due to ESBL producing E. coli in our hospital, which has no department of microbial examination. We examined the trend of detection of CTX resistant E. coli isolates from clinical samples from January 2009 to November 2013, and antimicrobial use density (AUD) of third-generation cephalosporins in the same period, and the clinical features of BSI of ESBL-producing E. coli. As a result, the percentages of CTX-resistant E. coli in all E. coli were 5.4% in inpatient and 3.9% in outpatient in 2009, but 32.8% and 17.8% in 2013, respectively. Additionally, AUD had increased from 20.6 in 2009 to 28.9 in 2013. In BSI due to E. coli, the clinical features which were male, bedridden patient and using urethral catheter, central venous catheter, chronic renal failure were significantly in the cases of ESBL-producing E. coli (n=8), compared to non-ESBL producing E. coli (n=32). PMID- 25796741 TI - [Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents - Special references to bacteria isolated between April 2011 and March 2012]. AB - Bacteria isolated from surgical infections during the period from April 2011 to March 2012 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 785 strains including 31 strains of Candida spp. were isolated from 204 (78.8%) of 259 patients with surgical infections. Five hundred and twenty three strains were isolated from primary infections, and 231 strains were isolated from surgical site infection. From primary infections, anaerobic Gram-negative bacteria were predominant, followed by aerobic Gram-negative bacteria, while from surgical site infection aerobic Gram-positive bacteria were predominant, followed by anaerobic Gram-negative bacteria. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus spp. was highest, followed by Streptococcus spp. and Staphylococcus spp., in this order, from primary infections, while Enterococcus spp. was highest, followed by Staphylococcus spp. from surgical site infection. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterobacter cloacae, in this order, and from surgical site infection, E. coli was most predominantly isolated, followed by P. aeruginosa, K. pneumoniae, and E. cloacae. Among anaerobic Gram-positive bacteria, the isolation rate of Eggerthella lenta was the highest from primary infections, followed by Parvimonas micra, Collinsella aerofaciens, Lactobacillus acidophilus and Finegoldia magna, and from surgical site infection, E. lenta was most predominantly isolated, followed by P micra and L. acidophilus, in this order. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroidesfragilis was the highest from primary infections, followed by Bilophila wadsworthia, Bacteroides thetaiotaomicron, Bacteroides uniformis and Bacteroides vulgatus, and from surgical site infection, B. fragilis was most predominantly isolated, followed by Bacteroides caccae, B. thetaiotaomicron, Bacteroides ovatus and B. wadsworthia, in this order. In this series, vancomycin-resistant MRSA (methicillin-resistant Staphylococcus aureus), vancomycin-resistant Enterococcus spp. and multidrug-resistant P. aeruginosa were not observed. We should carefully follow up B. wadsworthia which was resistant to various antimicrobial agents, and also Bacteroides spp. which was resistant to many beta-lactams. PMID- 25796743 TI - [Measurement of sitafloxacin MIC for Mycobacterium avium complex and application for treatment of pulmonary nontuberculous mycobacteriosis]. AB - Treatment for pulmonary nontuberculous mycobacteriosis is difficult. Since current treatment has limitation, new application is needed. Fluoroquinolone is one of candidates. We have investigated the feasibility of sitafloxacin (STFX). At first, the drug of MIC (minimum inhibitory concentration) was determined by the methods based on BrothMIC NTM. The MICs of STFX, moxifloxacin (MFLX), gatifloxacin (GFLX) were low. On contrast, the MICs of garenoxacin (GRNX) and tosufloxacin (TFLX) were high. Two cases of pulmonary Mycobacterium avium intracellulare complex (MAC) disease were treated by STFX-contained regimen. In all cases of pulmonary MAC disease, improve of symptoms and chest CT images were attained. Adverse events were slight. These MIC studies and case reports suggest that STFX might have excellent in vitro and in vivo antimicrobial activities against MAC and is considered to be a candidate for the medication against pulmonary MAC disease. PMID- 25796744 TI - [Image of the month. Three-dimensional echocardiography: an almost surgical view]. PMID- 25796745 TI - [How I treat...Recommendations when starting a pharmacological therapy]. AB - Initiating a new pharmacological therapy is an important step in the global medical approach. Such a decision is the final step of a careful reasoning and should respect some rules in order to guarantee the best efficacy, but also safety for the patient. Clinical inertia should be avoided, but the essential principles of the evidence based medicine should also be taken into account. This concise article summarizes the main fundamental rules and cautions that should be respected by any clinician when initiating a new pharmacological therapy. PMID- 25796746 TI - [A wing clipping beverage]. AB - Chronic consumption of soda energizing caffeine has known a growing success. Its deleterious effects, however, are often ignored. We report a case of tetraparesis associated with chronic excessive consumption of cola. The development of muscle weakness is variable, resulting from a hyperpolarization of excitable membranes. The outcome is most often favorable after potassium supplementation and interruption of the offending beverage consumption. The mechanisms involved are multiple and involve both a leakage of fecal and urinary potassium and a potassium entry into the intracellular compartment. Other mechanisms related to caffeine are also involved. It therefore appears mandatory to assess the consumption of such beverages in the presence of hypokalemia and muscle weakness. PMID- 25796747 TI - [Medical regulation and rescue chains; the issue of primary-secondary transfers. The Belgian model and its application in the province of Liege]. AB - Medical regulation represents an essential tool for emergency medical assistance. Even if it is essentially based on a 1964 law, our medical regulation is constantly evolving to meet the present needs and to follow the medical and technological advances. In this article, we shall outline its major components and evoke some long-awaited developments in the field of public health. PMID- 25796748 TI - [Diagnosis and treatment of hereditary angioedema: clinical illustration and brief literature review]. AB - Hereditary angio-oedema is an autosomal dominant transmitted disease that is characterized by swellings of the subcutaneous or mucosal tissues. The edematous manifestations develop over a few hours and disappear spontaneously in a few days. This disease, which is due to an excess of bradykinine, a peptide that induces vasodilatation and increases vascular permeability, is different from angioedema mediated by histamine (frequently accompanied by urticaria). This difference explains the inefficiency of antiallergic therapies to treat the crises. This condition, although rare, is important to know because it is potentially lethal if the edema leads to laryngeal obstruction. After the report of a clinical example, this paper will consider the pathophysiology and the classification of angio-oedema without urticaria. New therapeutic recommendations for the treatment of hereditary angio-oedema will also be considered. PMID- 25796750 TI - [Psoriasis syndrome with its comorbidities]. AB - The recognition of a complex disorder associating skin psoriasis and its comorbidities has considerably progressed over recent years. Beyond the skin lesions, psoriatic arthritis, the metabolic syndrome, type II diabetes, cardiovascular disease, inflammatory bowel diseases, and some cancers represent a group of chronic systemic disorders. The process is initiated and sustained by an immunological pathway involving Th1, Th17 and Th22 lymphocytes. The recognition of this complex disorder indicates that the clinical impact of psoriasis is not exclusively limited to the skin only. PMID- 25796749 TI - [Amiodarone and the thyroid]. AB - Amiodarone is an antiarrhythmic agent among the I most powerful and the most frequently used for the control of recurrent ventricular tachycardia and the secondary prevention of recurrent atrial fibrillation. Its use is not without risk. Although highly effective, it may induce various, sometimes severe, side effects, particularly at the thyroid level.In patients receiving amiodarone, one can encounter biological changes without clinical repercussion. Some may present a true thyroid disease, either hyper- or hypothyroidism. In this literature review, we will see how to prevent, diagnose, and treat these complications,if required. PMID- 25796751 TI - [How I explore and treat...A pancreatic trauma in a child]. AB - We report the case of a pancreatic fracture following a bicycle fall and handlebar injury in a ten years old boy. Pancreatic rupture was detected by abdominal ultrasonography and computed tomography. The child was closely monitored, without undertaking any initial invasive treatment, but the clinical course was complicated by the emergence of a pancreatic pseudocyst. After weeks of monitoring, a transgastric endoscopic echo-guided drainage was performed with success. We present in this paper the guidelines concerning the management of a pancreatic trauma and discuss the indications and drainage methods for pseudocysts. PMID- 25796752 TI - [Fixed dose combination perindopril-indapamide-amlodipine (Triplixam) for the treatment of arterial hypertension]. AB - Triplixam is a fixed dose combination of three well known antihypertensive agents, with complementary activities, to control blood pressure in patients with arterial hypertension: perindopril, an angiotensin converting enzyme inhibitor, indapamide, a diuretic whith thiazide-like effects but also specific properties, and amlodipine, a long-acting calcium antagonist of the dihydropyridine family. The potential synergic action allows better control of blood pressure with once daily administration, while limiting the incidence of adverse events. Various presentations with different dosages are available to facilitate individualized therapy. Warnings and precautions for use of every molecule should of course be respected. Such a fixed dose combination should contribute to limit clinical inertia and to improve therapeutic compliance. PMID- 25796753 TI - [Recurring vertigo]. AB - We report the case of a young patient who was seen at the outpatient clinic for recurring vertigo. The diagnosis was vestibular migraine. Considering the long delay between the onset of symptoms and the definite diagnosis, we found it appropriate to review the diagnostic workup in such cases which is multidisciplinary, implying otologists, ophtalmologists and neurologists.We take also the opportunity to review the diagnosis and treatment of less known, more recently described disorders such as vestibular migraine, perilymph fistula, vestibular paroxysmia and bilateral vestibulopathy. PMID- 25796754 TI - [Ectopic parathyroid gland]. PMID- 25796755 TI - [How I treat...The choice between a sulphonylulrea and a gliptin to manage hyperglycaemia in type 2 diabetes]. AB - The pharmacological therapy of hyperglycaemia in type 2 diabetes becomes increasingly complex. After failure of metformin monotherapy, several choices are possible. In clinical practice, the most common dilemma is to choose between adding a sulphonylurea or adding a dipeptidyl peptidase-4 inhibitor (gliptin). This review analyses the arguments in favour of one or the other pharmacological option, based upon criteria of efficacy, tolerance, safety, easiness of use, use in at risk populations and, last but not least, cost of therapy. In general, a patient-centered approach is recommended with an individualization of the therapy in function of the characteristics of each patient with the aim to obtain the best benefits/ risks ratio, at an affordable cost. PMID- 25796756 TI - [Hymenoptera envenomation. A case report]. AB - Starting with a clinical case study, we present the potential risks of Hymenoptera envenomation and discuss the treatment of victims of multiple stings. PMID- 25796757 TI - [Updates in corneal transplantation]. AB - Corneal transplantation or keratoplasty has rapidly developed over the last 10 years. Penetrating keratoplasty, a well-known operation consisting of full thickness replacement of the cornea, has remained the dominant procedure for a long time. It allows appropriate therapy of most causes of corneal blindness. However, this technique is currently evolving toward slamellar keratoplasties which selectively treat the specific affected layers: deep anterior lamellar keratoplasty replaces the diseased corneal stromal layers; endothelial keratoplasty replace the affected endothelium. This article will present these techniques, and briefly discuss their advantages. PMID- 25796758 TI - [Concerns about glycated haemoglobin and the limitations of its interpretations]. AB - Determining the level of glycated haemoglobin, in particular its major fraction called HbA(1c), is an attractive tool in the management of diabetic patients. In fact, it provides a global evaluation of the glycemic control's level through the past 8-12 weeks. However, this tool must be used with caution. First of all, it does not allow to examine the glycemic kinetics since it represents a glycemic average. Secondly, it does not allow to appreciate the glycemic evolution through the full day. This dosage needs then sometimes to be complemented by fingersticks blood glucose testing. Last but not least, caution is advised in interpreting the results because a number of physiological, pathological and technical factors might interfere with HbA(1c) measurement. It is therefore important that physicians keep a critical view of the values obtained. The paper reviews the different methods used to determine the level of glycated haemoglobin and their limitations. It also emphasizes the medical situations in which over- and under estimation of the real HbA(1c) value could occur. It does not address the specific issue of the new expression values of HbA(1c) in mmol/mol instead of %. Moreover, the medical situations in which over- and underestimation of the real HbA(1c) value could occur will be described. PMID- 25796759 TI - [How I explore a case of suspected arrhythmogenic right ventricular dysplasia]. AB - Arrhythmogenic right ventricular dysplasia is a rare, but not exceptional pathology combining the occurrence of potentially fatal arrhythmias with a gradual deterioration of the structure and function of the right ventricle. In this article, we discuss the etiopathology of the disease and emphasize the diagnostic approach. PMID- 25796761 TI - [Diagnosis and evolution of a keloid]. AB - Keloid is a protruding hypertrophic fibrous formation of the dermis. It corresponds to a tough lesion at palpation. Two clinical types are distinguished. They correspond either to a peculiar evolution of a scar, or to a seemingly spontaneous event. Such lesion is characterized by massive deposits of collagen bundles. This aspect is distinct from hypertrophic scars primarily representing an accumulation of fibroblasts and small vessels. PMID- 25796760 TI - [The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer]. AB - Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer. PMID- 25796762 TI - Making assumptions. PMID- 25796763 TI - Quality? PMID- 25796764 TI - Pilot error. PMID- 25796765 TI - For patients with terminal chronic illness, does more face-to-face time with a healthcare provider decrease aggressive end-of-life (EOL)care such as ICU admission, feeding tube placement, CPR, or intubation? PMID- 25796767 TI - Let's begin with one simple question. PMID- 25796766 TI - Traumatic liver injuries in the elderly as compared to younger adults. AB - BACKGROUND: Comparing elderly (> 55 years) and younger (< 55 and > 15 years) traumatic liver injury patients, we evaluated differences in the need for operative intervention as well as transfusion requirements in those treated non operatively. METHODS: This was a retrospective cohort study of adult patients with liver trauma. The analyses evaluated overall adjusted differences in treatment option and packed red blood utilization in those treated non operatively by age group. RESULTS: 841 patients were included. 83 were elderly. Operative management occurred in 13% and 12% of the younger adults and elderly patients, respectively. After adjustment, age group was not significantly associated with treatment option. In the non-operative setting, elderly patients had twice the red blood cell transfusion requirement as compared to younger adults. CONCLUSIONS: Age does not play a role in considering the need for surgical intervention in patients with liver trauma. However, the geriatric population has twice the transfusion requirement in the non-operative setting. PMID- 25796768 TI - [How I treat...Recommendations for controlling and optimizing a pharmacological therapy]. AB - Any pharmacological treatment should ideally be effective and safe. The supervision of an ongoing therapy should control that individualized goals are reached while tolerance and safety are present. In case of not reaching the predefined objectives, the causes of failure should first be screened (for instance, exclusion of poor patient compliance), and the treatment should be then optimized: dose adjustment, add-on of another drug (if possible synergistic combination) and/or shift to a more effective pharmacological therapy. In some cases, therapeutic monitoring may be useful or even mandatory in order to better adjust drug dosing and thus guarantee both efficacy and safety. PMID- 25796769 TI - [Diagnosis of chronic retinal detachment following the discovery of a crystalline retinopathy]. AB - Crystalline retinopathy is a rare complication of chronic retinal detachment. The observation of crystalline retinal deposits should prompt the search for a chronic retinal detachment. The composition of these crystals is unknown. Some other crystals can be found in other diseases or with drug toxicity. It is essential to make the differential diagnosis and to determine the actual etiology PMID- 25796770 TI - [Defecation after colic transmural migration of a gauze pad left behind during abdomino-pelvic surgery]. AB - We report a case of complete transmural migration through the colic wall, followed by spontaneous defecation, of a surgical sponge left behind in the abdominal cavity (gossypiboma) during a vaginal hysterectomy with oophorectomy. The process results from encapsulation of the surgical sponge with fistulization through the colic wall. No functional damage followed this defecation because either the fistula closed early, or the sponge remained temporarily entrapped in a colic fold. The diagnosis was based on echography and computed tomography. PMID- 25796771 TI - [European Society of Cardiology guidelines on the management of pulmonary embolism]. AB - In recent years, several studies and new molecules have emerged in the field of pulmonary embolism. Initial patient management requires rapid assessment of clinical condition. In case of shock, a primary reperfusion approach is requi- red (i.e., pharmacological, surgical or percutaneous). In the other cases, the assessment of the risk of early mortality is needed and treatment with anticoagulant should be started. Very low risk patients can be discharged early. High-intermediate risk patients can sometimes benefit from a reperfusion approach. Individual risk stratification can be refined by the assessment of right ventricular function and biomarkers (troponin, B-type natriuretic peptide). The new anticoagulants can be used in this indication. For most patients, the duration of treatment is 3 months. In this article, we summarize the 2014 recommendations of the European Society of Cardiology for the management of pulmonary embolism. PMID- 25796772 TI - [The ideal valvular prosthesis is still to come. Which factors can help decide between mechanical and bioprosthetic heart valve replacement?]. AB - The prevalence of valvular heart diseases reaches 2.5% in the overall population. Aortic valve replacement is one of the most common surgical procedures. We report the story of a female patient whose aortic mechanical valve, implanted at the age of 54 years at the time of a mitral valve repair surgery, had to be replaced 14 years later, due to the development of a subvalvular pannus narrowing the valvular orifice. We use this clinical story to compare the advantages and disadvantages of repair surgery and valve replacement with a biological or mechanical prosthesis, and summarize the latest evidence for the choice of the most adequate prosthesis for a particular patient's profile. PMID- 25796773 TI - [Idiopathic pulmonary fibrosis]. AB - Idiopathic pulmonary fibrosis (IPF) is one of the multiple pathologies included in the large family of diffuse interstitial parenchymal lung diseases (IPD). The latter represent a large group of about 200 different diseases, most of which are orphan diseases. Recently, some new therapeutic options have appeared that require an early and accurate diagnosis of pulmonary fibrosis. PMID- 25796774 TI - [Depression and type 2 diabetes: etiopathogenic analysis of a frequent comorbidity]. AB - Recent advances in the neurobiology of depression have underlined the importance of markers of inflammation, neurotrophins, and hypothalamo-pituitary adrenal (HPA) axis dysfunction in the development of this pathology. These disorders could have some impact on other systems such as the glucose metabolism regulation with an increased risk of insulin resistance and type 2 diabetes. Type 2 diabetes is also frequently associated with a pro-inflammatory state that could favour the development of a depressive episode. Inflammatory phenomena and HPA axis dysfunction could be biological links between depression and type 2 diabetes and account not only for the frequent association between those two disorders, but also for the treatment-resistance to classical antidepressants. PMID- 25796775 TI - [Climatic changes and the antinomy of dehydrating water]. AB - The stratum corneum materializes the interface between the body and its environment. Such a structure is influenced by the climate and seasons. A series of physicochemical parameters are involved in this relationship. Among them, the relative humidity, the dew point, the insensible loss of water and the concepts of water-as-ice and the higgledy-piggledy-water. PMID- 25796776 TI - [Quality of life in children with cancer history and parental adaptation]. AB - This study assesses quality of life (Qol) in children with cancer history as well as Qol of their parents and examines the relationship between parental adjustment and children Qol. Two groups were formed: an experimental group composed by children with cancer antecedents and their parents and a control group with healthy children and their parents. Children have filled a questionnaire about their Qol. Parents have completed questionnaires about their coping, their illness perceptions, their parenting stress and their Qol. The results show that Qol was satisfactory and similar in both groups. Significant correlations were found between parental illness representations (threat and personal control) and children Qol as well as between coping strategies based on maintaining family cohesion and children Qol. This study highlights the need to assess the adjustment of parents after child cancer and to develop interventions targeting parental representations and coping strategies. PMID- 25796777 TI - [Early detection to prevent mental illness during adolescence: ethical and theoretical considerations]. AB - In the face of changes that characterise adolescence, a number of youth experience ill-being, as part of a normal developmental process. For some of them, however, this ill-being may represent early signs of a psychopathological process. Regarding depression and psychosis, such early signs are non-specific, which complicates and delays treatment. In addition, issues such as stigmatization and unfamiliarity with these psychopathologies represent major obstacles to treatment access. Attempts to early detection, which involves identifying risk factors in order to provide support and follow-up, making an effort to take these clinical signs seriously, while at the same time avoiding to mistake a normal developmental process for a pathological condition. PMID- 25796778 TI - [Soft tissue calcifications of the legs]. PMID- 25796779 TI - [How I treat....Recommendations for stopping a pharmacological therapy]. AB - To interrupt a pharmacological treatment is sometimes warranted in clinical practice. It may appear as an easy task, simpler to undertake than the initiation of a new therapy, and, yet, it requires that some conditions be fulfilled and some precautions be taken: (1) the reasons why the medication is interrupted should be clearly explained; (2) the physician should make sure that the interruption, even if transient, is without danger; (3) the modalities of interruption should be clearly determined (immediate cessation vs progressive dose reduction), and, finally, (4) an appropriate follow-up of the duly informed patient should be scheduled. PMID- 25796780 TI - [Acute voluntary poisoning by carbamate]. AB - Acute poisoning by organophosphate or carbamate is important to recognize since it can cause severe complications such as cardiorespiratory failure, coma, and even death in the absence of early management. Pharmacologically, the mode of action of these substances is based on an inhibition of cholinesterases; the clinical presentation therefore consists of a cholinergic syndrome. The typical clinical picture can be confirmed by the dosage of plasma cholinesterases. On a therapeutic viewpoint, atropine remains the antidote of choice. In high doses, it is the only molecule with a demonstrated effect for the specific treatment of such poisonings. Pralidoxime is clearly recommended in case of poisoning by an organophosphate, but is more discussed when carbamates are involved. The observation of a case of voluntary poisoning by a powerful carbamate, aldicarbe, offers s the opportunity to review the key elements of this type of poisoning. The rather loose inaugural presentation and the initial absence of diagnosis, underline the value of an adequate premature symptomatic care. PMID- 25796781 TI - [When genetics spices up a severe flare of chronic inflammatory bowel disease]. AB - The simultaneous occurrence of pneumomediastinum, peridural emphysema, subcutaneous emphysema and pneumothorax is extremely rare. We report the case of a young man with severe chronic inflammatory bowel disease presenting with voluminous spontaneous pneumomediastinum complicated by subcutaneous emphysema as well as peridural emphysema and pneumothorax. A genetic disorder is suspected. PMID- 25796782 TI - [Threatened preterm delivery managed in a university medical center devoted to high risk pregnancies: assessment of daily practice in relation to international guidelines]. AB - Premature birth poses a real problem of public health. As the principal cause of foetal ill-health and perinatal mortality, it generates high healthcare costs. By seeking to prevent early labour and to deal with its causes, a good obstetrical practice can reduce its negative impact, both medical and financial, on society. This article describes the results of a study of threatened preterm delivery admissions at the Citadelle hospital in Liege during the year 2012. The findings are compared to international guidelines with a view to identify aspects that could be improved. PMID- 25796783 TI - [Upper airway's 3D analysis of patients with obstructive sleep apnea using tomographic cone beam]. AB - The progress of medical imaging over the last decades has led to a better understanding of the upper airway structure in sleep-disordered patients. The Obstructive Sleep Apnea Syndrome (OSA) is attributed to a functional narrowing of the upper airway, particularly of the oropharynx, during sleep. This narrowing is multifactorial. We have shown that in 60% cases, the maxilla (nasal pyramid) seems too narrow. A mandible retroposition may also play a dominant role in 30% of the cases. Both scenarios can be combined. Cone Beam Computed Tomography (CBCT) is a new medical imaging technique that permits to visualize the upper airway with less ionizing radiation than the conventional scanner. To date, only five authors have performed an upper airway's 3D analysis of sleep apnea patients with cone beam. A better understanding of the affected segment of the upper airway should help refine treatment options. PMID- 25796784 TI - [Sudden cardiac death prevention in athletes. Electrocardiogram interpretation: the Seattle criteria]. AB - Sudden cardiac death is the leading cause of death in athletes. Pre-competition screening including 12-lead electrocardiogram is recommended by the European Society of Cardiology. This attitude contributes to significantly decrease the risk of sudden cardiac death. We review the electrocardiographic criteria of Seattle that increase the specificity of screening in athletes. PMID- 25796785 TI - [Perioperative management of direct oral anticoagulants: not much evidence but several different approaches]. AB - New oral anticoagulants (NOACs) are a major step forward in the field of anticoagulation. As a consequence, the number of patients treated with NOACs that have to undergo surgery constantly increases. The optimal management of such patients is not clearly determined so far as scientifically established data are lacking. A first proposal is to mimic the perioperative management of patients on vitamin-K antagonists. When the risk of perioperative bleeding is low, NOAC intake is stopped 24 hours before surgery. If the risk of postoperative hemorrhage is moderate or high, NOAC treatment is interrupted 5 days before surgery with a low molecular weight heparin bridging whenever necessary. A second option is based on pharmacokinetic data. When the risk of perioperative bleeding is low, NOAC intake is stopped the day before surgery. If the risk of perioperative bleeding is higher, NOAC intake is suspended for 5 half lives before surgery, 48-72 hours or more. This interruption should be for a longer period in the presence of renal failure. When an unforeseen surgery is needed, the procedure must be delayed as late as possible. In case of emergency, non specific pro-hemostatic agents such as prothrombin complexes or recombinant factor VIIa have not strongly proven useful and must only be used in last ditch effort. PMID- 25796786 TI - [Vulnerable children detected by the school health service: the forgotten?]. AB - The current health needs of children largely exceeds the biomedical model. The school doctor occupies a special position where he can take into account the social determinants of health and identify vulneirable children. After the detection by the school health service, the harmonious development of, the child requires that health professionals cooperate in a "preventive network". PMID- 25796787 TI - [Your patient complains about hair loss. Contribution of a skin biopsy in noncicatricial alopecias]. AB - The diagnosis of most alopecia problems is based on the clinical history and a well conducted clinical examination. The additional contributions of dermoscopy, trichoscopy and trichogram are helpful. However, a scalp biopsy is occasionally necessary to establish the correct diagnosis. The main noncicatricial alopecias are represented by androgenetic alopecia, alopecia areata, trichotillomania, traction and pressure alopecia, temporal triangular alopecia, ageing alopecia, loose anagen syndrome, telogen effluvium and anagen effluvium. PMID- 25796788 TI - [Canagliflozin (Invokana): kidney SGLT2 cotransporter inhibitor for treating type 2 diabetes]. AB - Canagliflozin is an inhibitor of sodium-glucose cotransporters type 2 (SGLT2) that are present in renal tubules. This specific insulin-independent mechanism promotes glucosuria, which results in a reduction in fasting and postprandial glycaemia and a decrease of glycated haemoglobin (HbA(1c)). Furthermore, canagliflozin promotes weight loss and lowers arterial (mainly systolic) blood pressure. Its efficacy is decreased in patients with renal insufficiency and the treatment should be stopped if estimated glomerular filtration rate is below 45 ml/min/1.73 m2. Both the efficacy and safety of canagliflozin have been investigated in 24 to 104-week controlled trials versus placebo or versus an active comparator (glimepiride or sitagliptin). The mean reduction in HbA(1c) averages 0.75% when added to other treatments, as compared to placebo. The 100 mg dose is as active as sitagliptin 100 mg while the 300 mg canagliflozin dose is even more efficacious. Adverse events are mostly mycotic genital infections and more rarely mild urinary tract infections. Caution is required in elderly patients and the risk of volume depletion should be checked (hypotension). Hypoglycaemia may occur only in patients already treated with an insulin secreting agent or insulin. Canagliflozin is commercialized under the trade name Invokana, at the doses of 100 mg and 300 mg once daily, for the treatment of type 2 diabetes. PMID- 25796789 TI - ["Synthesis 2014" Scientific research: in addition to the rest!]. PMID- 25796790 TI - [Myocardial remodeling in pediatric congenital cardiac diseases]. AB - Myocardial remodeling in pediatric congenital cardiac diseases is related to myocardial dysfunction and increases morbidity and mortality. The complex mechanisms that characterize this state involve inflammatory-, growth- and death signaling. The studies we have conducted in infants with hemodynamic overload of the right ventricle, associated or not with hypoxemia, show that mechanical stress related to pressure overload of the right ventricle leads to myocardial expression of pro-inflammatory cytokines such as TNF-alpha, IL-1beta et IL-6, mainly via the activation of p38MAPK signaling. Furthermore, hypoxemia induces activation of the transcription factor HIF-1 that, in turn, induces its target genes VEGF and eNOS. This might be interpreted as an adaptive response. Hypoxemia also contributes to stimulation of growth signaling as it induces CT-1 via the JAK/STAT pathway. The observation that hypoxemia is also associated with a higher degree of troponin T degradation might indicate a loss of the protective function of CT-1 to the myocardium in infants with cyanotic congenital cardiac diseases. PMID- 25796791 TI - [Left ventricular contractile reserve in asymptomatic patients with primary mitral regurgitation]. AB - This study aimed to quantify left ventricular contractile reserve (LVCR) and to evaluate its usefulness for risk stratification in asymptomatic patients with primary mitral regurgitation (MR). Resting and exercise echocardiography including two-dimensional speckle tracking was performed in 115 consecutive asymptomatic patients with moderate to severe primary MR. LCVR was defined as an exercise-induced increase in LV ejection fraction >= 4% or in LV global longitudinal strain >= 2%. LVCR was absent in approximately one half of the population. This absence was a strong independent predictor of cardiac events when assessed by exercise-induced changes in LV longitudinal function, but not when measured by exercise-induced changes in LV ejection fraction. PMID- 25796792 TI - [Benefits of positron emission tomography in the management and prognosis of abdominal aortic aneurysms]. AB - Rupture of abdominal aortic aneurysm (AAA) remains a major cause of death in the elderly. Its prediction is a serious challenge for public health. Despite its regular use to identify patients requiring surgical treatment, the diameter of AAA is not a sufficiently precise and reliable parameter for discriminating aneurysms at high risk of rupture. A better targeting of high risk patients needs understanding in deep the processes and mechanisms directing wall rupture. Inflammation is a significant element in the progression ofAAA and can be visualized using medical imaging techniques such as positron emission tomography (PET) using a glucose derivative (FDG) as radiotracer. Studies conducted in our department have established a relationship between PET positivity and the presence of symptoms such as accelerated growth of the aneurysm or pain, signs generally considered as predictive of rupture. Moreover, activation of leukocytes coupled to cellular and molecular alterations of the aneurysmal wall in the sites of FDG uptake may lead to its instability and incompetence to resist blood pressure and rupture. PET therefore represents a new original exploration method to characterize the severity of AAA progression allowing to assess the need for a surgical treatment much better than does the AAA diameter. PMID- 25796793 TI - [The alert algorithm: why, for whom, how, and when?]. AB - Phone cardiopulmonary resuscitation (CPR) assists any cardiac arrest witness, previously trained or not, through standardized instructions given by phone. These instructions are intended to guide the bystander in checking for responsiveness, opening the airway and checking for adequate breathing, and to initiate chest compressions in case of apparent death. The "Algorithme Liegeois d'Encadrement a la Reanimation par Te1ephone" (ALERT) is an original phone CPR protocol helping the dispatchers to guide callers during the dispatcher's time window, between the beginning of the call and the Emergency Medical Services (EMS) arrival on scene. Its use has been demonstrated to increase the frequency and performance of bystanders' initial CPR efforts. Such improvement might increase the survival chances of out-of-hospital cardiac arrest victims (OOHCA). PMID- 25796794 TI - [Endocrine disruption: a challenge in research, public health and clinical practice]. AB - Epidemiological and experimental data highlight the fetal and early postnatal life as critical periods for the effects of endocrine disrupting chemicals (EDCs), since exposure to EDCs during these periods can predispose to disease later in life. EDCs' effects include disorders of the reproductive system throughout life (abnormalities of sexual differentiation, infertility or subfertility and some neoplasia) and disorders of energy balance (obesity and metabolic syndrome). They could also influence the development of the cerebral cortex. However, the demonstration of the involvement of a single EDC remains difficult in human since we are virtually exposed to a mixture of several ubiquitous EDCs which are variably persistent in the environment and the body and have lifelong consequences. Moreover, since their dose-response relationship can be non-monotonic, setting a threshold dose for EDCs effects has become meaningless. Pregnant women, newborns and young children appear to be mostly at risk. However, the role of the physician remains difficult and raises several questions: how can we formulate justified, applicable and updated recommendations that are not counterproductive or alarmist...in a society that has to take the necessary steps to regulate production and protect the population? PMID- 25796795 TI - [The value of electroencephalography monitoring and analysis during anesthesia]. AB - Electroencephalography (EEG) records brain electrical activity at the scalp level. As a functional and non invasive witness of brain activity, EEG has long raised the interest of researchers and practitioners, notably in the domain of anesthesia. Thanks to technical advances, this complex signal can now be dissected, and a huge amount of information can be extracted from it. This information gives the opportunity to quantify theeffects of general anesthesia on the brain, and provides a better understanding of the underlying mechanisms. PMID- 25796796 TI - [18F-FPRGD2 PET/CT imaging of integrin alphaVbeta3]. AB - PET/CT imaging of 15F-FPRGD2 allows the visualization and quantification of integrin alphaVbeta3 in tissues. This imaging technique was developed with the purpose of quantifying tumor angiogenesis and of assessing the efficacy of antiangiogenic treatments. However, the PET signal of 18F-FPRGD2 appears more complex as various tumor cell types, inflammatory cells and osteoclasts express the integrin alphaVbeta3 regulating cell interactions with the extracellular matrix. This article provides data of clinical studies evaluating 18F-FPRGD2 PET/CT imaging in patients with a renal mass or a locally advanced rectal carcinoma and finally reports on the incidental discovery of 18F-FPRGD2 uptake in osteoarticular processes such as osteoarthritis. PMID- 25796797 TI - [Monoclonal gammopathies of undetermined significance - update for referring physicians]. AB - Monoclonal gammopathies of undetermined significance (MGUS) are frequently diagnosed in the global population. Because of its possible transformation into a hematological malignancy, the identification of a MGUS requires a regular and generally long follow-up. However, this risk of transformation differs between the individuals and different laboratory criteria have been identified as predictive factors for progression and were combined in scoring systems that allow correct classification of individuals. The management of these patients needs to be adapted according to the calculated risk profile. PMID- 25796798 TI - [Evaluation of glomerular filtration rate in 2014]. AB - Chronic kidney disease (CKD) is a frequent affection, most often detected by evaluation of the glomerular filtration rate (GFR). Measuring GFR by a reference method is not possible for every single patient, even if these methods are probably underused. However, serum creatinine has several limitations of which clinicians should be aware. Knowing these limitations, creatinine and creatinine based equations (including other parameters like age, gender and ethnicity) still represent the most used and easiest way to detect and assess CKD. PMID- 25796799 TI - [Mesenchymal stromal cells and organ transplantation]. AB - Mesenchymal stromal cells (MSC) are multipotent and self-renewing cells. MSC are studied for their in vivo and in vitro immunomodulatory effects, in the prevention or the treatment of isehemic injury, and for their potential properties of tissue or organ reconstruction. Over the last few years, the potential role of MSC in organ transplantation has been studied both in vitro and in vivo, and their properties make them an ideal potential cell therapy after solid organ transplantation. A prospective, controlled, phase 1-2 study has been initiated at the CHU of Liege, Belgium. This study assesses the potential risks and benefits of MSC infusion after liver or kidney transplantation. Even if the preliminary results of this study look promising, solely a prospective, randomized, large scale, phase 3 study will allow the clinical confirmation of the theoretical benefits of MSC in solid organ transplantation. PMID- 25796800 TI - [NLRP3 inflammasome and visceral adipose tissue]. AB - It is recognized that abdominal obesity is accompanied by a chronic low-grade inflammation that is involved in the pathogenesis of insulin resistance and type 2 diabetes. Metabolic syndrome and type 2 diabetes are associated with an abnormal production of pro-inflammatory cytokines, an increased level of acute phase proteins and an activation of inflammatory signalling pathways. These pro inflammatory cytokines, mainly produced by adipose tissue macrophages, are involved in development of obesity-associated insulin resistance and in the progression from obesity to type 2 diabetes. Particularly, the interleukin-1 beta may play a key role through the activation of the NLRP3 inflammasome. Adipose tissue topography, more than the total amount of fat, may play an important pathogenic role. Indeed, the presence of metabolic abnormalities in obesity is associated with a deleterious immunological and inflammatory profile of visceral adipose tissue and with an increased activation of the NLRP3 inflammasome in macrophages infiltrating visceral adipose tissue. Targeting inflammation, especially NLRP3 inflammasome, may offer potential novel therapeutic perspectives in the prevention and treatment of type 2 diabetes. PMID- 25796801 TI - [Uncontrolled asthma: importance of phenotypes and local and systemic eosinophilia]. AB - Asthma is a complex chronic inflammatory disease of the airways. Eosinophilia is a recognized feature of asthma. Asthma is no more considered as a single disease, but there are several subtypes of bronchial asthma, also called phenotypes, that have therapeutic and prognostic implications. Asthmatics are now classified according to inflammatory phenotypes that allow a personalized therapy. Phenotype identification requires induced sputum analysis that is not widely available. In this context, we have identified surrogate markers for inflammatory phenotypes. An eosinophilic phenotype can lbe suspected in case of concomitant increase of exhaled nitric oxide, blood eosinophils, IgE levels and airway obstruction. We have also identified a subgroup of asthmatics exhibiting diffuse local and systemic eosinophilia. This subgroup has a more severe asthma,a lower asthma control and a higher number of exacerbations. PMID- 25796802 TI - [Failure of zirconia-based prostheses on natural teeth and implants: focus on risk factors]. AB - Cohesive fracture of the veneering ceramic (chipping) is the first cause of failure of zirconia-based prostheses on natural teeth and implants. Besides risk factors related to the material (thermal stresses generated during the manufacturing process, framework inappropriate design), there are some clinical risk factors, which can influence the restoration prognosis. Indeed, unfavorable occlusal relationships and/or the presence of parafunctions such as bruxism and clenching, which are frequent pathologies, engender significant overloading. A retrospective study was performed at the University Hospital Center (CHU) of Liege on 147 dental and implants prostheses, placed between May 2003 and January 2012. This study highlighted a significant correlation between chipping and the absence of an occlusal nightguard (p = 0.0048), the presence of a ceramic restoration as an antagonist (p = 0.013), the presence of occlusal parafunctions (p = 0.018), and the presence of implants as support of the restorations (p = 0.026). These results underline the importance of external stress and occlusal risk factors diagnosis, as the need to perform an occlusal nightguard to patients with parafunctions. PMID- 25796803 TI - [Chronic tendinopathies and platelet-rich plasma]. AB - Platelets contain growth factors released during their degranulation following activation. These growth factors promote tissue remodeling, wound healing and angiogenesis. Currently, the clinical effect of Platelet-Rich Plasma (PRP) is still discussed, or even controversial. Our researches have assessed the effectiveness of PRP on the healing of animal tendons and human beings suffering from chronic jumper's knee. PMID- 25796804 TI - The fit of crowns produced using digital impression systems. AB - Compare the marginal and internal fit of crowns manufactured using four different digital impression systems with crowns manufactured using conventional impression technique, that served as a control group. Fifty all-ceramic crowns were fabricated using 50 standardized dies divided into five groups, each group representing one impression system. Each crown was cemented onto its respective model and sectioned into four segments.The marginal and internal fit were measured at 8 predefined points. A total of 1567 measurements were made, statistically analyzed and compared with crowns fabricated using the five systems. The following was found: (1) No significant difference was found with regard to mar ginal gap when comparing the control group to any of the digital systems. (2) LavaTM had smaller marginal gaps than CEREC(r) and iTero(r), (3) CEREC and Lava had smaller gaps in the chamfer compared to iTero and the control, (4) E4D(r) showed smaller gaps than CEREC at measuring points 4-8 and CEREC a smaller gap at point 2, (5) Lava showed smaller gaps than CEREC at measuring points 1,3 and 5-8. (6) Lava had smaller gaps than iTero at measuring points 1 4,7 and 8. All differences presented were significant. In conclusions, crowns manufactured using digital impressions present a marginal and internal fit equal to, or better than, crowns made using a conventional impression method.The marginal and internal fit of reconstructions made using digital impression techniques could improve with a lower initial setting of the spacer. PMID- 25796805 TI - Implementation of laser technology and treatment at county level in the Swedish Public Dental Service. AB - The aim of this study was to obtain an understanding of the factors that affected the way new technology and methods were used in dentistry after a training program. A qualitative research method was used to collect data. Nine dentists working in the Public Dental Service (PDS) in Uppsala County in Sweden agreed to be interviewed in the study. They worked in five different clinics, all with laser equipment, and had received training in the use of lasers. The interviews were tape recorded and transcribed, and were analysed using manifest and latent qualitative content analysis. The categories in this study were identified as "Prerequisites and obstacles to imple- mentation", "Attitudes to laser technology and treatments" and "Laser technology in the future'". The dentists described working with lasers as complicated and problematic. They had concerns about the method relating to the working environment, evidence of efficacy of treatment, costs, and benefits for patients and dentists. The main finding was that the decision to adopt the technology seemed to be based on individual perceptions of the value of lasers compared to other ways of achieving the same goal. They provided uniform proposals regarding how an organization should implement new methods, including an emphasis on the importance of preparation and having opportunities to be able to test and evaluate the technology. Another important factor was support from surrounding staff, colleagues and management. Despite all the barriers, the respondents were positive about working with lasers in the future, mainly due to their belief that patients would demand laser treatment. In conclusion both individual and organizational factors affected the extent to which the respondents used the laser. The main finding was the individual perception of the value of lasers compared to other methods which could achieve the same goal. PMID- 25796806 TI - Orthodontic treatment by general practitioners in consultation with orthodontists -a survey of appliances recommended by Swedish orthodontists. AB - The aim of the present study was to disclose the treatment procedures most frequently recommended by Swedish orthodontists for use by general practitioners and to determine whether these recommendations are reflected in the undergraduate dental program in orthodontics at Malmo University. Potential differences between the ortho- dontists' recommendations were also investigated. A questionnaire was sent to 169 consulting orthodontists, seeking their recommenda- tions for appliance therapy to be undertaken by general practitioners: 129 (63 males and 66 females) responded. The Quad Helix was the appliance most commonly recommended for correction of posterior crossbite, a plate with Z-springs for correction of anterior crossbite and the headgear activator for correction of Class II malocclusions. A significant gender difference was disclosed with respect to orthodontists' recommendations for treatment of Class II malocclusions by general practitioners, namely that female orthodontists recommended the headgear activator more frequently than males. However, this difference is most likely attributable to the gender distribution among orthodontists qualifying as specialists during the last five decades: more recently qualified orthodontists are predominantly female. The choice of appliances corresponded well with undergraduate training in orthodontics at the Faculty of Odontology in Malmo. PMID- 25796807 TI - Outcome of orthodontic care and residual treatment need in Swedish 19-year-olds. AB - The purpose of the study was to assess the outcome of orthodontic care in Linkoping, Sweden. The dental records of 207 (107 M, 100 F) 19-year-olds registered at one public dental health clinic were studied. A clinical examination was performed where malocclu- sions were registered, where after residual orthodontictreatment need was measured using the Index of Complexity, Outcome and Need (ICON). The 19-year-olds also filled in a questionnaire regarding residual subjective orthodontic treatment demand. Differences between genders were analysed. One hundred and ten (47 M, 63 F) individuals (53.1%) had partaken in orthodontic consultations. Orthodontic appliance treatment had been received by 86 (38 M, 48 F) individuals (41.6%). A residual orthodontic treatment need was registered in 28 (22 M, 6 F) individuals (13.5%). Residual subjective orthodontic treatment demand was expressed by 9 (3 M, 6 F) indi- viduals (4.3%). Eight (2 M, 6 F) of those had no residual treatment need. A higher (p = 0.006) rate of females (63.0%) than males (44.0%) had participated in ort- hodontic consultations. The proportion of males (35.5%) who had experienced orthodontic treatment was not significantly lower (p = 0.069) than among the females (48.0%). However, a lower (p = 0.009) proportion of treated males (55.3%; n = 21 out of 38) than of treated females (81.3%; n = 39 out of 48) had received their treatment by orthodontic specialists. At 19 years of age, the proportion of males with residual treatment need (20.6%) was higher (p = 0.002) than among the females (6.0%). Every patient with orthodontic treatment need and -demand at 19 years of age had previously been offered orthodontic treatment. The conclusion was drawn that the orthodontic care scheme had successfully diagnosed and treated orthodontic problems in the population. However, notable differences between genders regarding treatment modalities and the amount of residual treatment need at age 19 were found. PMID- 25796808 TI - Anamnestic findings from patients with recurrent aphthous stomatitis. AB - Recurrent aphthous stomatitis (RAS) is a common oral disorder with a prevalence varying between 5% and 66%. RAS appears in three forms; minor, major and herpetiform. The aetiology is unknown.The aim of this study was to evaluate associations between specific anamnestic information and different types of recurrent aphthous stomatitis (RAS). A group of 177 patients (mean age = 42.8 years; SD = 14.3; range 17-79 years) participated. Data were collected from a structured interview, consisting of 22 questions. Information about i) health status and medication, ii) predisposing factors, iii) RAS experience, iv) previous treatment methods and v) brand of toothpaste was collected. Sixty-eight per cent of the patients were healthy and 44% of the patients were not taking any medication. Forty-one per cent of the patients did not have any apprehension of the reason for their RAS, while stress (15.8%) was the most common apprehended aetiological factor. Sixty-two per cent had one to three minor ulcers at one time. Forty-eight per cent reported having had a major aphthous ulcer at least once.The most frequent symptom reported was pain (53.7%), followed by a smarting sensation (18.6%) and tenderness (4%). The most common treatment for RAS was ZendiumTM toothpaste/mouthrinse (28%), followed by corticosteroids (25%). Fifty four per cent of the patients experienced no relief from the treatment. When toothpaste habits were investigated, ZendiumTM was used by 32% of the patients and toothpaste containing sodium-lauryl-sulfatase was used by 32%.There was no positive correlation between the use of ZendiumTM toothpaste and the relief of symptoms or the size, number or frequency of the aphthous ulcers. Sixty-four per cent of the patients had never smoked, while 7% were smokers. No positive correlation was found when age, gender, allergy, medication and smoking were correlated to the frequency, number and size of the aphthous ulcers. In conclusion, we found that the aetiology behind RAS is still unclear and probably multifactorial. Standard treatment methods like ZendiumTM should perhaps be questioned and this study did not find any support for smoking as a "protective" factor, i.e. having less likelihood of experiencing major problems from RAS. PMID- 25796809 TI - Adverse events in Public Dental Service in a Swedish county--a survey of reported cases over two years. AB - Adverse events cause suffering and increased costs in health care. The main way of registering adverse event is through dental personnel's reports, but reports from patients can also contribute to the knowledge of such occurrences. This study aimed to analyse the adverse events reported by dental personnel and patients in public dental service (PDS) in a Swedish county. The PDS has an electronic system for reporting and processing adverse events and, in addition, patients can report shortcomings, as regards to reception and treatment, to a patient committee or to an insurance company. The study material consisted of all adverse events reported in 2010 and 2011, including 273 events reported by dental personnel, 53 events reported by patients to the insurance company and 53 events reported by patients to the patient committee. Data concerning patients' age and gender, the nature, severity and cause of the event and the dental personnel's age gender and profession were collected and analysed. Furthermore the records describing the dental personnel's reports from 2011 were studied to investigate if the event had been documented and the patient informed. Age groups 0 to 9 and 20 to 39 years were underrepresented while those between the ages 10 to 19 and 60 to 69 years were overrepresented in dental personnel's reports. Among young patients delayed diagnosis and therapy dominated and among patients over 20 years the most frequent reports dealt with inadequate treatments, especially endodontic treatments. In 29% of the events there was no documentation of the adverse event in the records and 49% of cases had no report about patient information. The majority of the reports from dental personnel were made by dentists (69%). Reporting adverse events can be seen as a reactive way of working with patient safety, but knowledge about frequencies and causes of incidents is the basis of proactive patient safety work. PMID- 25796810 TI - Testing awareness of heart disease among West Australian women. AB - Cardiovascular disease [CVD] is the top cause of death in Australian women. Large studies in the US and Europe have shown that the majority of women do not consider CVD as their greatest health threat. Australian women's awareness has not previously been investigated. The aim of this cross-sectional survey [TAWDAH] was to assess Australian women's awareness of CVD their leading causes of death [LCD]. PMID- 25796811 TI - Immune parameters in patients with asthma. AB - The article is dedicated to researching of conditions of factors of nonspecific resistance of organism in patients with bronchial asthma. Damage of intensity of absorbtive function of neutrophils, activation of metabolism of neutrophils and monocytes of peripheral blood, coupled with a decrease in bactericidal functional reserve of monocytes prevailed in clinical manifestations of immune deficiency at bronchopulmonary diseases. Suppression of interferon genesis was combined with deviations of indicators of cellular and humoral immunity, and leukocyte production of tumor necrosis factor. PMID- 25796812 TI - [Experience and problems of implementation of family medicine in post-socialist countries]. AB - The experience of medical-insurance organisations that provide medical services basing on family medicine principles (HMO-type organizations) shows huge potential opportunities for optimization of health care systems through family physicians operating as fundholders. The experience of training of health care specialists, in particular, family physicians at the Department of Post-Graduate Training calls for further improvement of the training in applied issues of legal, financial and economic nature that provide work of family medicine specialists under the conditions of market economy development and health insurance, in particular. In this article shows huge opportunities for optimization of financial and economic provisions of the system, as well as medical and report facility structure and network that are included in the plans of establishment of medical-insurance organizations working on the principles of family medicine and organized by family physicians. ln this regard, it is very important to provide personnel of such medical-insurance organizations with appropriate training in legal, financial and economic issues. Special attention should be paid to the training of facility administrators and managers of family medicine subunits in legal and economic issues. As this is one of the milestones of their work. PMID- 25796813 TI - Intrapericardial injections using a novel technique. AB - Intrapericardial injections have been proposed as a means to specifically treat diseases of the myocardium, pericardium, and coronary vasculature. The pericardial space is potential drug reservoir, allowing sustained delivery of drug to the target tissue. In this study we have demonstrated a novel method for pericardial delivery in the mouse. PMID- 25796814 TI - Combined effect of appointment telmisartan and atorvastatin on hemodynamic indicators and the indicators of lipid profile in patients with arterial hypertension combined with obesity and steatohepatitis. AB - The results of investigations had showed the high efficiency of the combination of atorvastatin with telmisartan in patients with arterial hypertension combined with obesity and NAFLD. Such combined treatment had led to a significant decrease of cholesterol levels (p < 0.01), LDL cholesterol (p < 0.05) and TG (p < 0.01), helped to decrease in SBP of 159.75 +/- 3,00 to 137.50 +/- 1,38 mm Hg (< 0.01), DBP from 93.75 +/- 1,57 to 79.25 +/- 0,90 mm Hg ( < 0.001), and thus made it possible to significantly improve the health of patients and reduce the risk of cardiovascular complications. According 13C-methacetin breath test, this combination positively influences the lipid metabolism and improves the metabolic function of the liver. One of the mechanisms of action of telmisartan may be its indirect impact on adipokines system, which was demonstrated by an increase in the rate of metabolism and growth of indices of cumulative doses on 40 and 120 minutes. PMID- 25796815 TI - [ApoE gene polymorphism as a predictor of therapeutic response to treatment acetylcholinesterase inhibitor for elderly patients with Alzheimer's and vascular dementia types]. AB - Effectiveness of donepezil hydrochloride treatment for elderly patients with Alzheimer's and vascular dementia types depending on the ApoE genotype. THE AIM: To study the effectiveness of donepezil hydrochloride (Almer "Actavis") for elderly patients with Alzheimer's and vascular dementia types depending on the ApoE genotype. METHODS AND SUBJECTS: The 3-month clinical study included 38 elderly patients (mean age- (71.03 +/- 1.20) years) with dementia. All patients have undergone clinical, neurological, laboratory, instrumental (electrocardiography, CT/MRI brain), neuropsychological examination, ApoE genotype determination RESULTS: Identified certain characteristics of response to treatment of donepezil hydrochloride (acetylcholinesterase inhibitor) with dementia according to ApoE genotype. The effectiveness of donepezil hydrochloride was more pronounced in patients epsilon4 allele carriers compared with epsilon3/epsilon3 group the results of the scale parameter ADAScog, describing episodic memory and complex types of praxis. CONCLUSIONS: The effectiveness of the treatment of donepezil hydrochloride for elderly patients with dementia largely be associated with ApoE genotype available that makes it worthwhile carrying determine ApoE 2, 3, 4 allele in patients with cognitive deficits before starting pharmacotherapy. PMID- 25796816 TI - [Analysis of grant of special nephrological help to childrensi in Chernivtsi region]. AB - Nephrological morbidity is important indicator of the state of the health of children's population. The aim of this study is analysis of the activity of nephrological service care for children's population of the Chernivtsi region. The material for this study is reporting documentation about the condition of the nephrological service care for children's population of the Chernivtsi region in 2008-2012 and the data of The Center of medical statistics of Ministry of Health of Ukraine. The incidence of prevalence of diseases of the urinary system between teenagers of Chernivtsi region during the 2008-2012 period had a wave-like nature and have lower rates comparing general Ukraine rates, with the exception of 2011, when the incidence of child population in the region amounted to 32.60 in 1000 to 29.65 against children 1000 children in Ukraine. The age structure of patients is determined by many factors, including the demographic situation in the region, "continuity" and these primary healthcare units. Value of microbial and inflammatory diseases to nephropathy--2.9:1 (2009), but over the last three years there is a tendency to change its value--3.5-4:1 (2012). Is marked resistance to antibiotic therapy--3/4 of surveyed high school age children and teenagers found mycoplasma pathogens (M. hominis, M. genitalium) and ureaplasma (U. urealyticum) origin, especially against the background of comorbidity of "modern child". Analyzes the main indicators of child nephrology service in Chernivtsi region. The research, carried out by authors, will allow to hold the reasoned medical and rehabilitation events in all stages of rendering of specialized medical care for teenagers with nephrological pathology and to develop the programs, directed on improvement of indicators of health and prevention of disability in children. PMID- 25796817 TI - [The structure of extragenital pathology in pregnant women with diabetes in endemic by iodine region]. AB - We have conducted a complex clinical and paraclinical study of 108 women, 78 of which had diabetes and 30 healthy women that made a control group. In 60.3% of the pregnant patients type 1 diabetes was diagnosed, in 11.5%--type 2. Gestational diabetes was found in 28.2% of pregnant women. The vast number of the surveyed pregnant women (52.6%) was diagnosed with moderate and severe (38.5%) degree of the disease. In 12.5% of them the disease was compensated, in 82.1% subcompensated, while in 5.1%--decompensated. In pregnant women with diabetes a high incidence of extragenital diseases was revealed, the most common of which was iron deficiency anemia, which complicated the pregnancy of more than half of the pregnant of the basic group (57.7%), while in the control--in 13.3% of women (p < 0.05). Thyroid diseases in the study group were more than three times more common compared to the control group (47.4% and 13.3%, p < 0.05), while in pregnant women with type 1 diabetes in 55.3% of the patients. Herewith in 29.4% of cases were diagnosed with hypothyroidism, in 52.9--subclinical hypothyroidism, in 25.5% of pregnant women were found autoimmune thyroiditis. These data indicate the need of screening of the pregnant women with diabetes to identify the pathology of the thyroid gland even if the clinical symptom are absent, particularly in the areas of iodine deficiency. PMID- 25796818 TI - [Rehabilitation features in the prevention of asthma exacerbations in patients with different body weight]. AB - Bronchial asthma patients with excessive body weight compared to persons with normal weight had more severe course of the disease, associating with more pronounced inflammation (increased level of the proinflammatory interleukin-6, interferon-gamma, tumor necrosis factor alpha). After the rehabilitation treatment including speleotherapy we observed the improvement of clinical manifestation and reduction of the studied immune parameters. PMID- 25796819 TI - [The possibilities of congenital pathology primary prophylaxis as responsibility of general practitioner in Ukraine]. AB - The aim was to study some tendencies of congenital pathology primary prophylaxis in context of Governmental measures and general practitioner's activity. MATERIALS AND METHODS: The information basis of investigation was made up from foreign and home publications, lawmaking documents and data of questioners. Questioners were filled in by doctors who obtained general practitioner qualification (152 persons). The questioner contained information about sex, age, marital status of future general practitioners. It also contained questions about progress in studies at Medical University, healthy way of life maintenance during pregnancy, understanding of possibility to prevent child birth with congenital malformation, ways of congenital malformations prophylaxis in general practitioner's activity. RESULTS: System approaches to congenital pathology burden reduce started forming. State possibilities are not applied effectively in congenital pathology primary prophylaxis. Doctors who obtain general practitioner qualification understand the importance of healthy way of life and medical and genetic consultation for birth child with congenital malformations preventing. Future general practitioners consider that it is possible to carry out complex of steps for decreasing congenital pathology burden. SUMMARY: It is impossible to carry out special congenital malformations prophylaxis programs because of economic situation in Ukraine. At the same time some results could be achieved due to professional activity of general practitioners and carrying out specific preventive measures on the way to decrease of congenital malformations burden. PMID- 25796820 TI - [Bilateral breast cancer: risk factors, prognostic factors and patient monitoring]. AB - AIM OF THE STUDY: To identify and explore the most important clinical and morphological and molecular factors that affect the likelihood and prediction bilateral breast cancer (BBC). Develop an algorithm of diagnostic tests and monitoring of patients with high risk of BBC. PATIENTS AND METHODS: 272 cases of BBC during the period from 1995 to 2011 in different oncological institutions of Ukraine have been analyzed, 195 of them were with metachronous and 77 with synchronous BBC. RESULTS: We found that the most important morphological factors that affect the likelihood of bilateral breast cancer development are menstrual status of the patients (p = 0.00007703), the first stage of breast cancer (p = 0.000015), the degree of affection of the regional lymph nodes (p = 0.00006915) and tumor size (p = 0.000112) at the time of first detection of breast cancer. Significant effect on the occurrence BBC makes of the fact that history high doze irradiation in the treatment of the first tumor (p = 0.00779). CONCLUSION: At high risk group of development of metachronous BBC are patients with the following parameters of the first tumor: size > 5 cm, N category > pN2, stage > 2, a history of high doze exposure of contrlateral breast cancer, lack of radiotherapy in standard fractionation, chemotherapy and hormone therapy in complex treatment of the first tumor. Optimal algorithm for monitoring patient group increased risk of BBC for the first 5 years of follow include: monthly self testing, quarterly reviews of mammologist, breast ultrasound every half-year, annual mammography control. PMID- 25796821 TI - [Risk factors for renal dysfunction in patients with hypothyroidism]. AB - SUMMARY In order to study the features of kidney function in patients with hypothyroidism, examined 84 patients with primary hypothyroidism. Of the patients 46 patients had postoperative hypothyroidism in 38--hypothyroidism is autoimmune thyroiditis in the background (AIT). According to our results, in patients with manifest hypothyroidism is present renal dysfunction, which is manifested by increased serum creatinine and a decrease in glomerular filtration rate (GFR),the development and progression of which contributes to the presence of risk factors in patients--hyperlipidemia, excessive body weight and abdominal obesity, which is a pronounced in patients with Hashimoto's thyroiditis. Stated that more meaningful indicators of dyslipidemia associated with major manifestations of abdominal obesity as defined by waist circumference (OT) ((96.58 +/- 1.70) and (98.73 +/- 3.35) cm) and higher body mass index (BMI). PMID- 25796822 TI - [Controversial matters of arrangement of dental assistance within the framework of healthcare system reform and ways to increase of efficiency of diagnosing destructive processes in apical periodont]. AB - In conditions of reform of primary level of medical sanitary assistance a tendency for decrease of availability of dental care for population has been revealed. Increase in number of complicated cases of typical dental diseases, inter alia, destructive affection of apical periodont. An examination of 347 patients with apical periodontitis has been held. For the purpose of improvement of differential diagnostics of radicular cysts and periapical granulomas as well as choice of adequate method of treatment postprocessing of digital dental roentgenograms has been used. 241 granulomas, 106 cysts (simplex and complex) and cystogranulomas--have been diagnosed. For improvement of visualization of destruction zone of alveolar bone possibilities of digital processing of image have been utilized. Postprocessing of digital roentgenograms significantly supplemented results of visual examination and excluded impact of subjective factor in composition of diagnostic conclusion. Upon results of examination of histograms of optical density of radiographic image of pathological zone signs of specific for granulomas, cysts and have been detected. Diagnostic conclusion coincides with results of pathomorphological study. PMID- 25796823 TI - [Cytological screening for cervical cancer in the Transcarpathian region]. AB - The article estimates the effectiveness of screening for cervical cancer pathology among the female population of theTranscarpathian region. The carrying out of screening programs forthe last 5 years has been analyzed. The proof of their effectiveness is the identification of abnormal cervical cancer, including different severity of dysplasia and cancer. The effectiveness of early detection and prevention of cervical cancer increases with the active implementation of screening programs in the work of the family doctor. The effectiveness of screening depends on the skills of family doctors, cytologists, obstetricians and gynecologists, as well as their active cooperation. PMID- 25796824 TI - [Comparative evaluation of L-arginine and nitric oxide levels in hypertensive]. AB - Structural and functional damage of endothelium seems to be one of the most important factors of arterial hypertension evolution. Via release of vasoactive substances, particularly vasoconstrictors and vasodilators. The aim of the study was to assess the role of such vasodilators as L-arginine and nitric oxide (NO) in the pathogenesis of arterial hypertension in patients with obesity. Assessment of 103 hypertensive patients revealed two different patterns of changes in L arginine--NO interrelation in those with obesity and normal BMI. In hypertensive patients with obesity mean NO concentration was approximately in normal range while in those with normal BMI NO levels increased up to 1.5 fold. Obesity depletes compensatory NO-synthetic mechanisms peculiarto endothelium of patients with stage I-II arterial hypertension.Two patterns of co-morbidity development depending on different levels of L-arginine and nitric oxide according to BMI were revealed. PMID- 25796825 TI - [State of dental health of the population according to social status and satisfaction with medical care]. AB - In the article is conducted assessment of the dental health of adults of Zaporozhye on the basis of epidemiological investigation. It is established that despite of the diversity of all diseases that were revealed during examination, adult population seeks dental help in the event of acute pain. It is shown, that there is dependence of level negotiability for dental help from social status, education and income. PMID- 25796826 TI - [Cognitive impairment in patients of different age with metabolic syndrome]. AB - OBJECTIVE: To analyze the characteristics of cognitive impairment (CI) in patients of different age with dyscirculatory encephalopathy (DE) and metabolic syndrome (MS). There were 503 patients aged 45-89 years with DE enrolled into the study, who were divided into two groups: patients without MS (n = 198) and with MS (n = 305). All patients were divided into three subgroups depending on age. In patients with MS more severe CI was diagnosed, compared with patients without MS. The negative impact of MS on the state of cognitive function was found mainly in patients of middle and old age, while in elderly patients we did not find significant influence of MS on cognitive decline. In patients with DE MS influenced more significantly on executive cognitive functions. PMID- 25796827 TI - [Mortality from hypertension: reliability of medical coding of death certificates in primary healthcare]. AB - OBJECTIVE: To examine the reliability of accounting causes of death of the population of hypertension in the centers of primary health care at the regional level and to detect defects that affect the quality of coding of causes of death. MATERIALS AND METHODS: Statistics, death certificate deaths from diseases of the circulatory system, outpatients, medical history dead. The study used methods: statistical, analytical, expert assessments. RESULTS: Comparing the mortality rates of hypertension in Ukraine, it should be noted that statistics on deaths from this nosology is significantly different from that of other European countries. Thus, in 2012 the mortality from hypertension in the Zaporozhye area was 1.7, in Ukraine 1.6 per 100 thousand population, in Russia was 20.1, in Germany 39.5, in Poland 16.4. Analysis of the reliability of the coding of death certificates found a number of errors that significantly affect mortality from hypertension. CONCLUSIONS: A "controlled factors" that affect mortality from cardio-vascular disease, including of hypertension is a significant coding of death certificates. PMID- 25796828 TI - [A new mode of primary health care--pilot regions experience]. AB - It has been analyzed the new model of primary health care (PHC), implemented in the pilot regions, which is based on international approaches with proven efficacy. It has been evaluated the organization of primary health care in the pilot regions from the point of performance by the health care system of its main goals and objectives--improvement of health of the population, optimization of financial resources allocation (distribution), ensuring sensitivity, accessibility and structural efficiency of health care. It is proved that the modernization model of health care in Ukraine is fully consistent with the principles, requirements and criteria produced for the effective operation of the primary health care assistance in the world. Using actual data and taking into account the context, a complex of measures to implement the PHC model of modernization in Ukraine has been determined. PMID- 25796829 TI - [The biochemical markers of hepatobiliary function in children under environmental pollution]. AB - It has been carred out an analysis of biochemical parameters of the hepatobiliary system in 119 children who have been living in ecologically unfavourable districts in order to improve early diagnosis of environmentally triggered hepatobiliary disease. Our results found that 57.2% of patients from polluted region had early signs of liver dysfunction the most frequently of which was elevation of biochemical markers of cholestasis. Among the investigated enzymes the high frequency of abnormal levels of gamma-glutamyltransferase (54.6%) alkaline phosphatase (36.1%), sorbitol dehydrogenase (28.6%) were detected in children from ecologically unfavorable districts which may indicate that these markers were helpful for the early diagnosis of environmentally triggered hepatobiliary disease. It was revealed that almost every third child (41.1% examined children) from the ecologically unfavourable districts had decrease of liver detoxification enzyme activity (arginase). PMID- 25796830 TI - [Ultrastructure of gastric antrum mucosa in patients receiving long-term treatment with nonsteroidal antiinflammatory drugs]. AB - We studied the ultrastructure of gastric antrum mucosa on the background long term use of nonsteroidal antiinflammatory drugs. We demonstrated that long-term use of nonsteroidal antiinflammatory drugs leads to decrease of mucous granule secretion by epitheliocytes of gastric antrum mucous membrane. PMID- 25796831 TI - [Model of organization of HIV counseling and testing services by family physicians, provided to the inhabitants of transcarpathia region, related to labor migration]. AB - SUMMARY Model of organization of HIV counseling and testing services by family physicians, provided to the inhabitants of transcarpathia region, related to labor migration. The purpose of the research is the development, implementation and determination of the viability of the model of organization of HIV counseling and testing services by family physicians, provided to the representatives of a certain section of society, namely to labor migrants and their immediate environment in the Transcarpathia region of Ukraine. MATERIALS AND METHODS: While developing this model the methods of structural and logical analysis, a systematic approach, bibliosemantic and conceptual simulation were used. Estimation of the model functionality was carried out on the basis of the family physicians' monthly reports analysis, which provided HIV counseling and testing services in pilot mode, using rapid tests for the detection of antibodies to HIV, according to the proposed model. RESULTS OF THE RESEARCH AND ITS DISCUSSION: The purpose of the model is to draw the HIV counseling and testing to target group of population as close as possible, so the method of retroaction to HIV and AIDS in the region would me more complex and effective. The model contains the necessary building blocks that perform certain functions. The necessary direction of a patient and information flow between its building blocks is determined in order to ensure the performance of specified functions by them. Within the period of pilot testing of the model (October 2013 to February 2014) on the basis of outpatient clinics of general practice in the Transcarpathia region HIV counseling and testing were provided to 303 representatives of the target population. The most services were provided during religious holydays (it is the period when labor migrants return to the places of their permanent residence). CONCLUSIONS: Analysis of the results of the pilot testing of the developed model has shown its viability and assurance of its drawing to the target group within the period of labor migrants return to their permanent places of residence. PMID- 25796832 TI - [Influence of Helicobacter pylori eradication on the metabolic syndrome components]. AB - The article presents the results of a study that describes the impact of successful Helicobacter pylori infection eradication on the main biochemical markers of metabolic syndrome. It was found that successful anti-helicobacter therapy in patients with MS was accompanied by statistically significant improvement in carbohydrates and lipid metabolism, the liver functional state, lowering hsCRP levels. PMID- 25796833 TI - [Role of virus infection as etiological factors of miscarriage]. AB - Epstein-Barr virus (human herpes virus fourth type HSV-4 NNV-4) is by far one of the most common human viruses, including during pregnancy. Aim of this work was to study the impact of Epstein-Barr virus infection in pregnancy as the fetus fading in the later stages. A significant degree of persistence of infection we set to 64% of women. PMID- 25796834 TI - [Evaluation of the quality of primary health care at the regional level]. AB - Author evaluated the quality and accessibility of primary health care using quality indicators. Discordant established trend indicators. PMID- 25796835 TI - [Prevention of cognitive impairments in patients after stroke]. AB - Previous studies demonstrated that 78.3%-81.6% of patients after stroke have cognitive impairments. In order to prevent vascular cognitive impairments in patients with stroke after discharge from hospital, we have proposed a comprehensive program of activities. PMID- 25796836 TI - [24-hour dynamics of electric ventricular systole in patients with arterial hypertension and obesity: gender peculiarities]. AB - The features of 24-hour dynamics of the corrected electric ventricular systole and QT-interval dispersion were investigated in patients with stage II arterial hypertension and overweight or obesity, according to a gender. Gender distinctions of investigated criteria's were established, which depend on the body mass index. PMID- 25796837 TI - [Cardiovascular continuum: the role of the family doctor in prevention of cardiovascular diseases]. AB - Cardiovascular diseases are the cause of premature death, but the lifestyle modifications, struggle with the major cardiovascular risk factors can significantly reduce the incidence of coronary events, cerebral vascular lesions and the latter of peripheral arteries. In everyday practice, the elimination of risk factors by the family doctor should be a mandatory part of prevention and treatment programs. PMID- 25796838 TI - [Study of efficiency of ceraxon in the treatment of lag psychomotor development of children with hypoxic-ischemic lesions of central nervous system]. AB - The study involved 76 children aged 0-2, who suffered perinatal hypoxic-ischemic central nervous system lesion. Psychomotor development of children has been studied, and the results that demonstrate the effectiveness of incorporating ceraxon in the complex therapy of hypoxic-ischemic encephalopathy, have been obtained. PMID- 25796839 TI - [Prevalence of gastroesophageal reflux disease with cardiologic symptoms in patients with diabetes mellitus 2nd type]. AB - The article represents the research results of the prevalence of typical, secondary and cardiac symptoms of gastroesophageal reflux disease (GERD) in patients with diabetes mellitus (DM) 2nd type. It is established, that the typical symptoms of GERD (heartburn, acid eructation and regurgitation) were significantly more frequent in patients without DM, while the secondary symptoms of GERD (feeling of "lump' behind sternum and dysphagia) and cardiac symptoms (cardialgia, palpitation, disruption of the heart and shortness of breath) were significantly more frequent in patients with DM 2nd type. PMID- 25796840 TI - [Changes of twenty-four-hour profile blood pressure and its correction of patients with arterial hypertension on the background of combined antihypertensive therapy application]. AB - The aim of this research was the study of efficiency and endurance antihypertensive therapy on the basis of fixed combination of enalapril and hydrochlorothiazide (HCTZ) and enalapril and HCTZ in combination with amlodipine according to the twenty-four-hour (? day-and-night) monitoring of blood pressure (? 24H BPM) of patients with arterial hypertension (AH) 2-3 severity. The study included 33 patients with 2-3 grade of hypertension (average age--54,40 +/- 3.45 years). All patients performed ? 24H BPM before treatment and after 12 weeks of therapy. The combination of enalapril and HCTZ allowed to achieve target levels of blood pressure in 79% of patients, amlodipine additional purpose--in 86% of patients. We found that this therapy has a corrective effect on daily blood pressure profile, significantly reducing the load pressure and blood pressure variability. During treatment with the combination of enalapril and HCTZ combination of enalapril, HCTZ with amlodipine optimal daily profile of blood pressure after 12 weeks of reaching respectively 63.1% and 71.4% of patients. The treatment with combination of enalapril and HCTZ and adding of amlodipine is characterized by good endurance and high adherence to treatment. PMID- 25796841 TI - [Risk factors of cardiovascular disease in patients with ulcerative colitis]. AB - This article presents an analysis of the traditional risk factors for adverse cardiovascular events in patients with ulcerative colitis. In addition, special attention is given to additional ("new") cardiovascular risk factors. PMID- 25796842 TI - [Treatment optimization of subclinical atherosclerosis in patients with ulcerative colitis]. AB - In this article we assessed the positive impact of statins and omega-3 polyunsaturated fatty acids on achieving target lipid levels, acute phase proteins in patients with ulcerative colitis and subclinical atherosclerosis. PMID- 25796843 TI - [Pulmonary rehabilitation methods in the prevention of acute respiratory infections in patients with chronic obstructive pulmonary disease, the association with psycho-emotional state]. AB - In patients with chronic obstructive pulmonary disease stage I GOLD we revealed a significant reduction of acute respiratory infections frequency after pulmonary rehabilitation using salt aerosol therapy; however, in patients with chronic obstructive pulmonary disease stage II GOLD such a reduction we have not seen. We didn't find marked reduction of acute respiratory infections frequency also in patients with chronic obstructive pulmonary disease stage I GOLD with higher depression level. PMID- 25796844 TI - [Modern aspects of screening and diagnosing of arterial hypertension in individuals with excessive admission of sodium chloride into the body in the practice of family doctor]. AB - The epidemiology of cardiovascular diseases among workers of saltmines has been analysed in the given article. The pathophysiological mechanisms of hypertension development and clinical features of its flow in the region with a high content of sodium chloride in environmental objects have also been examined in the conducted investigation. PMID- 25796845 TI - [The use of complex tools ezetimibe, hepadyfu fosinopril and correction of blood pressure and endothelial dysfunction in patients with nonalcoholic steatohepatitis and essential hypertension stage II]. AB - The article investigates the impact of complex tools fosinopril, hepadyf and ezetimibe for correction of functional state of the endothelium and changes in blood pressure in patients with nonalcoholic steatohepatitis, obesity and essential hypertension stage II. PMID- 25796846 TI - [Influence of smoking on the effectiveness of peptic ulcer healing]. AB - The article presents the results of the research which was focused on the influence of smoking on the healing of peptic ulcer of different locations. It has been proved that the smoker's factor of erosive and ulcerous disorders healing is 10% lower. The level of marker of mucoid secretion in non-dissolvable mucus in gastric content in H. pylori-positive peptic ulcer smokers is lower comparing to H. pylori-negative patients. It has been concluded that smoking is an additional factor which can affect the course of peptic ulcer disease. PMID- 25796847 TI - [Differential diagnosis between alcoholic cardiomyopathy and coronary heart disease]. AB - The article considers the issue of differential diagnosis between alcoholic cardiomyopathy and coronary heart disease using electrocardiography, echocardiography and multidetector computed tomography. We describe one of the 27 clinical cases of alcoholic cardiomyopathy. PMID- 25796848 TI - [Prevention strategy of chronic non-communicable diseases]. AB - PURPOSE: Based on global experience and modern recommendations to highlight priority directions of struggle against chronic non-communicable diseases. METHODS: Information and analytical, comparative and systematic analysis. RESULTS: The decision of problem of chronic non-communicable diseases requires change of paradigms in health care. Effective step fortransition from centric disease paradigms in health care toward preventive medicine is increase health literacy of the population, formation of principle of prenosological approach to early revealing of non-communicable diseases, development and implementation for target groups of the population screening programs for the most common chronic non-communicable diseases. CONCLUSIONS: Preventive direction of struggle against non-communicable diseases should be based on increase of motivation to health, as own and associates, organization mass screening programs in target groups of the population and reorientation of health care to work with healthy people. PMID- 25796849 TI - [Comparative analysis of programs of complete correction osteogenic in patients with chronic pancreatitis]. AB - SUMMARY The expediency of Risendros using in the complex treatment of the patients with a chronic pancreatitis and osteodeficiency syndrome has been proved. As a result the status of the bone mineralization is improved, the mineral density of the bone tissue is increased. PMID- 25796850 TI - [Condition of service rendering of sexually transmitted infections treatment among representatives of the HIV infection risk group in the Transcarpathian region of Ukraine]. AB - The article reports the results of a study of the treatment dynamics of sexually transmitted infections among representatives of the HIV infection risk group in the Transcarpatian region during the period of 2008-2013. Treatment of cases of sexually transmitted infections are presented for the given period by 823 representatives of task forces associated with the program. During the program period there was a significant fluctuation in the number of rendered services. In 2011 the number of services rendered was 54.6% lower than in 2008. In contrast, in 2013 the quantity of services rendered was almost doubled compared to 2011. It has been proven that the quantity of cases of treatment which are provided by preventive medical establishments depends on the level of screening diagnostics services provided by non-governmental organizations. PMID- 25796851 TI - [The value of transendoscopy thermometry of gastric mucosa in the evaluation of blood flow in patients with osteoarthrosis and atherosclerosis by duplex ultrasound of extracranial brachiocephalic arteries]. AB - The pathogenesis of gastric mucosa lesions in elderly and senile people has many factors. It's based on contradiction between protective factors (mucus secretion, prostaglandins, bicarbonate, microcirculation, regeneration, etc.) and aggression factors (hydrochloric acid, pepsin, bile acids, pancreatic enzymes, bacteria). In addition, such important factors as neurohumoral disorders, nutrition and vascularization of the gastric mucosa have attached. The aim of the study was to evaluate the possible relations between microcirculation and data of gastric mucosa transendoscopy thermometry in elderly and senile patients with atherosclerosis confirmed by duplex ultrasound of extracranial brachiocephalic arteries. PMID- 25796852 TI - [Role of family medicine in the formation of breastfeeding]. AB - The establishment of breastfeeding is a laborious process, which is based not only on legal, medical and social factors, but also on information and psychological ones. As a result it makes women feel confident in their own abilities. The contribution of information and psychological reasons for the lactation emergence was studied on the basis of a multivariate model. In the study of information reason, which had the greatest impact, it was found that the information obtained at the antenatal clinic and maternity hospital is necessary, because it is the largest element of all sufficient information reasons. In the study of the psychological factor--support for the establishment of breastfeeding, it was found that such reason as woman's own desire, is necessary, as it is the largest element of all sufficient reasons. PMID- 25796853 TI - [Experience and problems of the primary health care centers' specialists in the implementation of the integrated health system based on family medicine in Ukraine]. AB - The experience of the primary health care' centers in Lviv, Mykolaiv, Kherson regions on the basis of family medicine, integrated medical space, modern governance mechanisms, market technology, promotion trasmural' approach, intersectoral coordination and collaboration and preventative health care population allows to get the maximum effectiveness of the provision of public health in relation to a particular administrative area with limited resources. PMID- 25796854 TI - [Experience of counseling and testing on human immunodeficiency virus implementation in the practice of general practitioners]. AB - We described experience on implementation of HIV counseling and testing in routine practice of 36 family clinics in 4 regions. Overall from July 2012--till February 2014 (included), the services of counseling and testing were provided to 2 535 clients; 15 of them were found to be HIV-positive. According to data obtained, 40% who tested positive were provided with further services (registered at the AIDS centers, received CD4, prescribed ART). While implementing counseling and testing in GPs practice we found that there are some problems with most at risk groups identification; reporting documents are complicated and need much time to be filled, so there are many mistakes were found; also, there is no clear and effective mechanism of getting accurate and validate information by GPs about patients who were found to be HIV-positive from AIDs Centers, as for now family doctors get this information mainly from their patients. PMID- 25796855 TI - [Types of dislipidemia in children with metabolic syndrome]. AB - AIMS: To study dyslipidemia types in children with metabolic syndrome. MATERIALS AND METHODS: From 1520 children of total population 155 children aged from 9 to 18 years were selected, who formed 2 groups: 1 group--85 children with metabolic syndrome, 2 group--54 children with normal body mass. Anthropometry, blood pressure measurement, estimation of total cholesterol, low density cholesterol, very low density cholesterol, high density cholesterol, tryglicerides in blood were done. RESULTS: The total cholesterol level was 1,1 times higher (p = 0.001), low density cholesterol 1,4 times higher (p = 0.001), very low density cholesterol 1,1 times higher (p= 0.015), tryglicerides 1,1 times higher (p = 0.020) in children with metabolic syndrome than in children of control group. In children with metabolic syndrome sensitively more often IIa, IV dislipidemia types and isolated hypercholesterolemia and less often IIb, III dislipidemia types and high density cholesterol isolated decrease were diagnosed. So children with metabolic syndrome were characterized by atherogenic types of dislipidemias which determine early atherosclerosis development. Children with metabolic syndrome must be examined on the lipid metabolism violation with the aim of its prevention and correction. PMID- 25796856 TI - [Overcoming non-communicabe diseases in Ukraine from the prospective of an integrated cross-sectoral approach]. AB - The paper analyzes the characteristics and trends of chronic non-communicable diseases and their risk factors in the WHO European Region, including in Ukraine. Substantiated strategic directions and measures to reduce chronic diseases and their risk factors. PMID- 25796857 TI - [Gender-sensitive renal hemodynamics in patients with essential arterial hypertension]. AB - The features of renal hemodynamic changes in structural and functional parameters of left ventricular men and women with essential arterial hypertension. Women have found lower rates of renal blood flow compared with men. The factors of progression of kidney damage--IMMLSH higher in men and greater BMI in women. PMID- 25796859 TI - [Assessment of age-old cataract phacoemulsification influence on the morphometric parameters of eye and intraocular pressure level]. AB - Morphometric parameters, hemodynamic and hydrodynamic of the eye before and after cataract phacoemulsification with IOL implantation were studied. 74 patients (97 eyes) with a cataract at the age of 53-79 years including, 49 women and 25 men were examined. Established: it is advisable to make cataract phacoemulsification with IOL implantation in patients accompanied by increased blood flow in the early stages of cataract development. PMID- 25796858 TI - [Condition of neurohumoral regulation of bronchial tone and gallbladder in patients with chronic cholecystitis and chronic obstructive pulmonary disease]. AB - SUMMARY The paper presents data from a study of the neuroendocrine regulation of nonstriated muscles, bronchial tree and the gallbladder tones by means of an assessment of the adrenergic and cholinergic systems state in patients, suffering from chronic obstructive pulmonary disease and chronic acalculous cholecystitis. Adrenergic and cholinergic activities as well as cortisol secretion have significantly changed. OBJECTIVE: To study the features of adrenergic and cholinergic regulations of bronchial tone and that of the gallbladder in patients with combined course of chronic acalculous cholecystitis and chronic obstructive pulmonary disease. MATERIALS AND METHODS: 92 patients were involved in the study: 30 patients with COPD (1st group), 30 patients with COPD of comorbid CAC in the acute phase (2nd group), 32 patients with CAC in the acute phase (3rd group) and a control group--30 practically healthy individuals (PHI) of the respective age. RESULTS AND DISCUSSION: All the patients with COPD and COPD combined with CAC had a marked predominance of the parasympathetic nervous system, as evidenced by the established significant decrease of CDE (Table) in patients with isolated COPD is 1.4 times (p < 0.05), in patients with COPD combined with CAC--there was more intense inhibition of enzyme activity--in 1.8 times (p < 0.05) and in patients with CAC of the 3rd group there were identical changes--a decreased activity of CDE in 1.6 times (p < 0.05) with significant intergroup differences between the groups (p < 0.05). An analysis of the studies showed significant changes in the CDE of the surveyed individuals. For instance, the CDA in the individuals of groups 1 and 2 was lower by 1.6 and 2.4 times respectively (p < 0.001) than in the group of PHI; in the patients of the 3rd group--the changes were minor--a decline of 14.6% (p < 0.05) compared with practically healthy individuals (Table). Participation of sympathoadrenal system in the pathogenesis of COPD occurrence has been proved, however, in patients with COPD and CAC, the ability to deposit CA, when combined with CAC has significantly dropped. The study of cortisol density in the blood serum of the patients under examination showed its significant drop in all groups observed. For instance, the first group patients' blood contained 2.7 times (p < 0.05) less cortisol than that of PHI; in the patients of the second group the inhibition of the functional state of the adrenal cortex was even more intense--cortisol was lower than its index in the control group by 3.7 times (p < 0.05); the 3d group patients had the maximum drop in cortisol secretion by 1.7 times (p < 0.05) with reliable intergroup difference. CONCLUSIONS: The base of regulatory neuroendocrine and paracrine mecganisms imbalance, contributing to a development of COPD, is the cholinergic imbalance (reduction in blood acetylcholinesterase activity, hypertensive sphincter of Oddi dysfunction), adrenergic imbalance, reduction in catecholamine depositing erythrocytes function, hypokinetic gallbladder dysfunction, adrenal dysfunction (decreased cortisol levels) that contribute to the development and progression of chronic cholecystitis against a background of hypokinetic gallbladder dysfunction. PMID- 25796861 TI - [Dynamics of the hemostasis parameters in patients with arterial hypertension in treatment with combined antihypertensive agents]. AB - The paper represents the dynamics of hemostasis values in 42 patients with arterial hypertension of the second stage in complex treatment with combined drug tonorma (atenolon - 100 mg, nifedipine - 10 mg, chlorthalidone - 25 mg). It was established thatthe administration of a dose of 0.5-1 of tonorma tablet once a day for 30 days improves subjective state of patients: helps to normalize blood pressure, reduce headaches, dizziness, frequency of angina pectoris, diminishes malaise. The study of hemostasis parameters in patients with the second stage of AH had revealed imbalance of the following: increased coagulation activity, decreased anticoagulant and fibrinolytic systems activity. The application of the combined drug tonorma promotes normalization of blood coagulation. PMID- 25796860 TI - [Amlodipine and bisoprolol application in patients with arterial hypertension]. AB - SUMMARY The paper represents the changes in the daily monitoring of blood pressure with combined drug alotendyn (bisoprolol and amlodipine). We had examined 28 patients with arterial hypertension stage II, II degree with poorly controlled blood pressure. Alotendynadministered at the dose of 5/5 (1 tablet twice daily) for 10-14 days. The study demonstrated the effectiveness of a fixed dose combination of bisoprolol and amlodipine in patients with hypertension represented by the decrease of average SBP, DBP, heart rate, increase in the number of patients with a normal daily profile ("dipper"), decrease in the time index. The lack of adverse effects, high efficiency, good tolerance increases patients compliance to the treatment. PMID- 25796862 TI - [The assessment of cardiovascular risk factors in patients with nonalcoholic fatty liver disease]. AB - Article presents the result of assessmaent of cardiovascular risk factors in patients with nonalcoholic fatty liver disease (NAFLD). The results show the presence of cardiovascular risk factors in patients with NAFLD, namely the increase of waist and hip circumferences compared with patients of the control group, hyperglycemia and dyslipidemia, decrease in apolipoprotein A1 (AroA1) compared to practically healthy people. PMID- 25796863 TI - [Estimation of efficiency of anti-helicobacter therapy in patients with a chronic pancreatitis combined with an erosive gastropathy]. AB - SUMMARY Eradikacion therapy at patients with chronic pancreatitis and combined with Helicobacter associated erosive gastropathy in a month after treatment appeared successful at 75% patients which accepted therapy of the first line- pantoprazol, amoksicillin, klaritromicin. Inclusion in antihelicobakter therapy of seknidazol in place of klaritromicin rendered a positive antihelicobakter effect at 85% patients with a chronic pancreatitis. Therapy with the use of seknidazole was better tolerated. Application of synbiotik laktiale on a background antihelicobakter therapy helped normalizations of chair and was comfortable in application, which is important in the treatment of patients. Application of synbiotika laktiale on a background antigelikobakter therapy is helped in the improvement of clinical effect. PMID- 25796864 TI - [Improving the quality of life in patients with chronic pancreatitis by using the alternative methods of correction]. AB - SUMMARY The article concerns the study of the quality of life of 64 patients on chronic pancreatitis under the influence of correction programs with the inclusion dyadinamic electroneurostimulation on the proposed schemes. It was found that the level of quality of life in chronic pancreatitis under the influence of conventional regimens have increased by an average of 29.1%, with inclusion of zonal schemes dyadinamic electroneurostimulation 48.9%, and after the application of wire method dyadinamic electroneurostimulation--by 54.6 %. This confirms reliable the inclusion of different types dyadinamic electroneurostimulation in complex rehabilitation of patients with chronic pancreatitis. PMID- 25796865 TI - [Relationship between leptin level, index of insulin resistance and the main indicators of carbohydrate and lipid metabolism in patients with varying degrees of obesity]. AB - In this article highlights the importance of the problem of obesity in modern medicine, analyzes the relationship between leptin level, indexof insulin resistance and main indicators of carbohydrate and lipid metabolism in patients with different degrees of obesity, demonstrated feasibility of measuring the bulk of the body together with body mass index, the definition of leptin levels and HOMA index in patients with excessive body weight for early diagnosis of metabolic disorders. PMID- 25796866 TI - [Variants of the course of non-alcoholic fatty liver disease in patients with ischemic heart disease and possibility of hypolipidemic therapy]. AB - In developed countries cardiovascular pathology is the leading cause of death among the population in more than 50% cases. In 30% of patients the ischemic heart disease is related to obesity, which accompanies steatosis and steatohepatitis. Disturbance of lipid metabolism plays one of the key roles in combination of ischemic heart disease and non-alcoholic fatty liver disease. Possibilities of safe administration of hypolipidemic therapy in patients with disturbance of lipid metabolism have not been studied completely. The aim of the research was to evaluate variants of the course of non-alcoholic fatty liver disease in patients with ischemic heart disease and possibilities of safe hypolipidemic therapy. 60 patients with chronic heart disease in combination with non-alcoholic fatty liver disease have been examined. On investigation three variants of non-alcoholic fatty liver disease course in patients with ischemic heart disease have been differentiated on the basis of portal vein size, levels of liver transaminase and index of 13C-methaticine respiratory test. Important differences of steatohepatitis from steatosis are increased level of aspartate aminotransferase, lowered liver metabolism by 30% and decreased cumulative dose by 42%. Patients with ischemic heart disease and steatosis are recommended hypolipidemic therapy according to standards of treatment. At the same time hypolipidemic agents should be administered with caution to the patients with ischemic heart disease and steatohepatitis. PMID- 25796867 TI - [Peculiarities of constellation of parental pairs as risk factors and resistance factors in the formation of gastroduodenal pathology in children]. AB - INTRODUCTION: Current study is dedicated to determination of psychosocial factors of predisposition and resistance to the formation of upper gastrointestinal pathology in children. MATERIALS AND METHODS: For the examination of parental pairs Minnesota Multiphasic Personality Inventory (MMPI) questionnaire and genealogical method Family Study were used. RESULTS: There were revealed following risk-factors of the formation of gastroduodenal pathology in children: the dominant mother's position; passive and shun father's behavior; protracted conflicts; hidden hostility between the parents; poor support, emotional warmth, and unity in the family; available external control of the family. CONCLUSIONS: Described family constellation can promote basic conflict in patients with gastroduodenal pathology by F. Alexander. This could be an indication for the family psychological counselling, which can be regarded as a "reserve" for increasing of the effectiveness of treatment and prevention of gastroduodenal pathology in children. PMID- 25796868 TI - [Abdominal ischemia and lesions of the pancreas]. AB - The analysis of the results of 50 patients with diseases of coronary heart disease (25 pers.) And chronic pancreatitis (25 people) are submitted. Along with the standard test from these patients underwent Doppler-ultrasonography of abdominal aorta and its visceral branches. Conclusions: A characteristic feature of Doppler indices in AIC is to reduce Vps and Ved, and PI BbA, increase Vps, Ved, IR and PI after exercise in chBA, chC and BbA. At patients with CP with IHD feature is the increase in Ved and IR in the chC, and Ved and PI in BbA under act of loading Bleed a feature at CP with IHD must be taken into account for optimization of treatment of IHD at CP. PMID- 25796869 TI - [Level of pepsinogen in patients with gastroesophageal reflux disease]. AB - We studied level of pepsinogen I and II in blood serum in 50 patients with erosive form of gastroesophageal reflux disease. Increasing concentrations of pepsinogen in 2.1 times and increasing the ratio of pepsinogen I to pepsinogen II in 32% of patients was detected. Which was associated with a higher degree gradation of erosive lesions of the esophagus and acid reflux prevalence with 2.0 2.99 pH range. Higher concentrations of pepsinogen II in serum was diagnosed in 20% of patients, and the results of daily pH monitoring in lower part of esophagus have been registered in them as acidic and alkaline refluxes. PMID- 25796870 TI - [Reasoning of the usage of multimicroelement drugs and monophytodrugs in complex treatment of patients with chronic atrophic gastritis]. AB - It was investigeted 126 patients with chronic atrophic gastritis, aged 19-73 years. Chronic inflammatory and degenerative processes of the gastric mucosa contributed to the destabilization of cell membranes. We found that patients with chronicatrophic gastritis have disturbances of lipid peroxidation and antioxidant defense, which is manifested by the accumulation of products of peroxidation and decreased activity of enzymes of antioxidant defense. Activation of lipid peroxidation, accompanied by increased levels of proinflammatory cytokines and deficiency of essential trace elements imbalance contributes antioxidant defense. After using basic therapy, it was no certain normalization of lipid peroxidation, antioxidant defense and restoration of microelement homeostasis in patients with chronic atrophic gastritis, which served as the justification for the development and testing of methods of treatment with the purpose of regulation of these processes. PMID- 25796871 TI - [Of blood pressure screening in school children with chronic gastro]. AB - The results of screening blood pressure of 80 students who were treated at the department of gastroenterology Municipal health care facility "City Children Clinical Hospital" Chernivtsi. The 16 children were found increased blood pressure: one--in 12 children peredhipertenziyu observed in 4 children- hypertension. The study analyzes the difficulties encountered by researchers during the screening. PMID- 25796872 TI - [The chronic gastritis, the dysbacteriosis and the use of Hylak forte at the treatment]. AB - High effectiveness of a preparation Hylak forte is shown in the treatment of intestinal dysbacteriosis of patients with the chronic gastritis. The received data gives the basis to recommend the prolonged use of Hylak forte after eliminating an exacerbation in order to prevent the relapse of the chronic gastritis. PMID- 25796873 TI - [Non-psychotc mental disorders in patients with primary hypothyroidism and new abilities in their psycho-correction in practice of general practitioners]. AB - The results syndromes' of non-psychotic disorders investigation and peculiarities of mechanisms of psychological defense in patients suffering from hypothyroisis are analyzed in the article. Established a close relationship between the level of intrapsychological adaptation and structuring the clinical picture in these patients. PMID- 25796874 TI - [The results of determination of the ejaculate contagiousness among HIV positive men, depending on clinically-virological specifics of HIV infection course]. AB - Here are presented the results of study of how the HIV viral load level in blood affects ejaculate contagiousness, study of clinical stage of HIV infection and co infection HIV/HCV. It is shown that the risk of infecting with HIV via ejaculate is higher when level of HIV viral load, that men have, exceeds 10000 copies per ml. (p < 0.05), clinical stage of the main decease is 2-3 (p < 0.05 and p < 0.01) and co-infection HIV/HCV is present. All of this should be considered when consulting discordant in relation to HIV infection couples concerning pregnancy planning, establishing indications and contraindications as for applying assistant reproductive technology for discordant couples where HIV positive is man. PMID- 25796875 TI - [Perspectives of selective laboratory screening in children with joint pathology]. AB - The article highlights the problematic issues of the laboratory diagnostic possibilities in children with joint pathology with moden tests (anti-cyclic citrullinated peptide antibodies and antibodies to mutated citrullinated vimentin). The expediency and effectiveness of the proposed laboratory tests is justified for improvement of the early differential diagnosis, joint pathology treatment optimization, and discuss the prospect of selective laboratory screening in families burdened by rheumatic diseases genealogy. PMID- 25796876 TI - [Microbial community in wound defects of patients with diabetic foot syndrome in practice of family doctor]. AB - Microbial content of the wound were analyzed in 49 patients with diabetic foot syndrome before and after ozone treatment. The wound defects was characterized by high level of colonization by microorganisms in associations, prevalence of the staphylococci, was estimated local wound treatment by ozone at 4000 mMU/l has positive effect onto wound healing process. This was manifested by significant decrease in density of the microbial colonization of the wounds and was accompanied by change of degenerative processes onto regeneration. PMID- 25796877 TI - [Internal audit--the foundation of healthcare quality management in health care]. AB - The paper proved the need for internal audit as the basis for quality control of medical care in a health facility, developed the project milestones and explains what needs to be taken into account at every stage during its implementation. PMID- 25796878 TI - [Possible functional treatment of myopia in children]. AB - A retrospective analysis of 70 patients with mild myopia to assess the impact of functional methods of treatment on the progression of myopia in children. Revealed that the maximum effect in the form of increase in non-corrected visual acuity by 1.5 times, reduce clinical refraction by 1.6 times, increase reserves of accommodation by 2.7 times and stock of relative accommodation by 2.1 times observed after the first course of functional treatment in patients with myopia, accompanied by spasm of accommodation. Repeated courses of functional treatment do not affect the clinical refraction and axial length of the eyeball and can be recommended mostly to improve the performance of the ciliary muscle. PMID- 25796879 TI - [Comparative analysis of the effectiveness of different methods of allergen specific immunotherapy of bronchial asthma]. AB - The article presents a comparative analysis of the effectiveness of different methods of allergen- specific immunotherapy of light and medium- severe persistent asthma using a special questionnaire of quality of life of patients. It is noted that traditional survey methods involving physical, laboratory and instrumental studies do not give an opportunity to get a complete assessment of the patient, because it does not provide information about its psychological and social adjustment to illness. It is proved that a comprehensive description of the physical, psychological and social components of the patient's condition allows the assessment of its quality of life. Established that chronic asthma affects the quality of life of patients, making certain psychological, emotional and social problems. The disease limits the vitality of patients, their performance, leading to social exclusion and psychological discomfort. Studies have shown that holding the base of treatment with different ways ASIT it positively affects the quality of life for patients. However, treatment of sublingual allergen patients perceive better adherence to such treatment was higher. PMID- 25796880 TI - [Spatiotemporal variation characteristics and related affecting factors of actual evapotranspiration in the Hun-Taizi River Basin, Northeast China]. AB - Based on the meteorological and hydrological data from 1970 to 2006, the advection-aridity (AA) model with calibrated parameters was used to calculate evapotranspiration in the Hun-Taizi River Basin in Northeast China. The original parameter of the AA model was tuned according to the water balance method and then four subbasins were selected to validate. Spatiotemporal variation characteristics of evapotranspiration and related affecting factors were analyzed using the methods of linear trend analysis, moving average, kriging interpolation and sensitivity analysis. The results showed that the empirical parameter value of 0.75 of AA model was suitable for the Hun-Taizi River Basin with an error of 11.4%. In the Hun-Taizi River Basin, the average annual actual evapotranspiration was 347.4 mm, which had a slightly upward trend with a rate of 1.58 mm . (10 a( 1)), but did not change significantly. It also indicated that the annual actual evapotranspiration presented a single-peaked pattern and its peak value occurred in July; the evapotranspiration in summer was higher than in spring and autumn, and it was the smallest in winter. The annual average evapotranspiration showed a decreasing trend from the northwest to the southeast in the Hun-Taizi River Basin from 1970 to 2006 with minor differences. Net radiation was largely responsible for the change of actual evapotranspiration in the Hun-Taizi River Basin. PMID- 25796882 TI - [Prediction of spatial distribution of forest carbon storage in Heilongjiang Province using spatial error model]. AB - Abstract: Based on the data from Chinese National Forest Inventory (CNFI) and Key Ecological Benefit Forest Monitoring plots (5075 in total) in Heilongjiang Province in 2010 and concurrent meteorological data coming from 59 meteorological stations located in Heilongjiang, Jilin and Inner Mongolia, this paper established a spatial error model (SEM) by GeoDA using carbon storage as dependent variable and several independent variables, including diameter of living trees (DBH), number of trees per hectare (TPH), elevation (Elev), slope (Slope), and product of precipitation and temperature (Rain_Temp). Global Moran's I was computed for describing overall spatial autocorrelations of model results at different spatial scales. Local Moran's I was calculated at the optimal bandwidth (25 km) to present spatial distribution residuals. Intra-block spatial variances were computed to explain spatial heterogeneity of residuals. Finally, a spatial distribution map of carbon storage in Heilongjiang was visualized based on predictions. The results showed that the distribution of forest carbon storage in Heilongjiang had spatial effect and was significantly influenced by stand, topographic and meteorological factors, especially average DBH. SEM could solve the spatial autocorrelation and heterogeneity well. There were significant spatial differences in distribution of forest carbon storage. The carbon storage was mainly distributed in Zhangguangcai Mountain, Xiao Xing'an Mountain and Da Xing'an Mountain where dense, forests existed, rarely distributed in Songnen Plains, while Wanda Mountain had moderate-level carbon storage. PMID- 25796881 TI - [Aboveground biomass and nutrient distribution patterns of larch plantation in a montane region of eastern Liaoning Province, China]. AB - Larch is the main timber species of forest plantations in North China. Imbalance in nutrient cycling in soil emerged due to single species composition and mono system structure of plantation. Thus it is necessary to grasp its biomass and nutrients allocation for scientific management and nutrient cycling studies of larch plantation. We measured aboveground biomass (stem, branch, bark and leaf) and nutrient concentrations (C, N, P, K, Ca, Mg, Fe, Mn, Cu and Zn), and analyzed the patterns of accumulation and distribution of 19-year-old larch plantation with diameter at breast height of 12. 8 cm, tree height of 15. 3 m, and density of 2308 trees . hm(-2), in a montane region of eastern Liaoning Province, China. The results showed that aboveground biomass values were 70.26 kg and 162.16 t . hm(-2) for the individual tree of larch and the stand, respectively. There was a significant difference between biomass of the organs, and decreased in the order of stem > branch > bark > leaf. Nutrient accumulation was 749.94 g and 1730.86 kg . hm(-2) for the individual tree of larch and the stand, respectively. Nutrient accumulation of stem was significantly higher than that of branch, bark and leaf, whether it was macro-nutrient or micro-nutrient. Averagely, 749.94 g nutrient elements would be removed from the system when a 19-year-old larch tree was harvested. If only the stem part was removed from the system, the removal of nutrient elements could be reduced by 40.7%. PMID- 25796883 TI - [Remote sensing estimation of urban forest carbon stocks based on QuickBird images]. AB - Urban forest is one of the positive factors that increase urban carbon sequestration, which makes great contribution to the global carbon cycle. Based on the high spatial resolution imagery of QuickBird in the study area within the ring road in Yiwu, Zhejiang, the forests in the area were divided into four types, i. e., park-forest, shelter-forest, company-forest and others. With the carbon stock from sample plot as dependent variable, at the significance level of 0.01, the stepwise linear regression method was used to select independent variables from 50 factors such as band grayscale values, vegetation index, texture information and so on. Finally, the remote sensing based forest carbon stock estimation models for the four types of forest were established. The estimation accuracies for all the models were around 70%, with the total carbon reserve of each forest type in the area being estimated as 3623. 80, 5245.78, 5284.84, 5343.65 t, respectively. From the carbon density map, it was found that the carbon reserves were mainly in the range of 25-35 t . hm(-2). In the future, urban forest planners could further improve the ability of forest carbon sequestration through afforestation and interplanting of trees and low shrubs. PMID- 25796884 TI - [Carbon density and production in valley spruce-fir forest in Xiaoxing'an Mountains, China]. AB - The carbon density and production were measured using both forest inventory and allometry approaches in the declining valley spruce-fir forest in Xiaoxing' an Mountains. Results showed that the total carbon density of the forest was 268. 14 t C . hm(-2) in 2011, and carbon densities of the vegetation, detritus and soil were 74.25, 16.86 and 177.03 t C . hm(-2), respectively. From 2006 to 2011, tree layer carbon density decreased from 80.86 t C . hm(-2) to 71.73 t C . hm(-2). The average decrease proportions per year of carbon density were 0.5%, 1.2%, 2.7% and 3.7% for Abies nephrolepis, Betula platyphylla, Picea spp., and Larix gmelinii, respectively. However, carbon densities were increased by 2.9%, 3.9% and 7.2% per year for Alnus sibirica, Pinus koraiensis and Acer ukurunduense, respectively. Net primary production (NPP) of the forest was 4.69 t C . hm(-2) . a(-1). The ratio of belowground NPP to aboveground NPP was 0.56. Litterfall accounted for the largest proportion of the NPP of forest with a value of 34.5%. As the two most important carbon output approaches of forest ecosystems, the fluxes of heterotrophic respiration and coarse woody debris decomposition were 293.67 and 119.29 g C . m(-2) . a(-1), respectively. Net ecosystem production (NEP) of the forest was 55.90 g C . m(-2) a(-1). The results indicated that the valley spruce fir forest in the declining state still had a certain carbon sink capacity. PMID- 25796885 TI - [Effects of topography on the diversity and distribution pattern of ground plants in karst montane forests in Southwest Guangxi, China]. AB - Covariance analysis, curve-fitting, and canonical correspondence analysis (CCA) were used to explore the effects of topographic factors on the plant diversity and distribution patterns of ground flora with different growth forms in the karst mountains of Southwest Guangxi, China. A total of 152 ground plants were recorded. Among them, 37 species were ferns, 44 species herbs, 9 species lianas, and 62 species shrubs. Covariance analysis revealed that altitude significantly correlated with the individual number and richness of ground plants, and slope aspect had a significant effect on richness. Statistical analyses showed a highly significant nonlinear correlation between the individual number or richness of ground plants and altitude. Results of CCA revealed that slope aspect had a significant effect on the distribution pattern of ferns, and slope had a significant effect on the distribution patterns of herbs, lianas and shrubs. Ferns were more sensitive than herbs, lianas and shrubs to changes in heat and soil water caused by aspect. The effect of slope was stronger than that of elevation on soil water and nutrients, and it was the most important topographic factor that affected the distribution patterns of herbs, lianas and shrubs in this region. PMID- 25796886 TI - [Change of vegetation net primary productivity in Yellow River watersheds from 2001 to 2010 and its climatic driving factors analysis]. AB - Based on the MODIS-NDVI remotely sensed imagery, this paper analyzed the spatial distribution of vegetation net primary production (NPP) calculated by CASA model in Yellow River watersheds from 2001 to 2010. Associated with the temperature and precipitation data in the same period, this article respectively analyzed the change trends of vegetation NPP in six ecosystems with different spatial and temporal scales, and the relationship between NPP and climate factors. The results indicated that in terms of spatial scale, the vegetation NPP gradually reduced from northwest to southeast, the average of annual NPP was 108.53 Tg C, and the spatial distribution of vegetation NPP was highly related with the land cover types. In terms of temporal scale, the vegetation NPP gradually increased from 2001 to 2010, but this change trend had large differences in these regions. On annual level, the vegetation NPP had no significant correlation with climate factors, but precipitation and temperature had considerable impacts on the vegetation NPP on monthly level. The correlations between NPP and climate factors were different in different ecosystems, so did the time lag effect of the climate factors. The air temperature response of the NPP variation was relatively sensitive in forest ecosystem and the precipitation response was significant in grassland and wetland ecosystems. Additionally, the precipitation response of the NPP variation in grassland ecosystem had time lag effect and so did the air temperature response in desert ecosystem. PMID- 25796887 TI - [Soil humus differentiation and correlation with other soil biochemical properties in pure forests in semi-arid low-hilly area of Inner Mongolia, China]. AB - Whether the content and composition of soil humus in pure forest change due to its simple component of litter and specificity of single-species dominant community is a key problem for forest sustainable management. In this study, soils from 6 kind of pure forests in semi-arid low-hilly area of Inner Mongolia were collected and their humus and other biochemical properties were measured to investigate the differentiation of soil humus and the impact factors. The results showed that the soil of Picea asperata and Betula platyphylla pure forests had the highest contents of humus and better condensation degrees and stabilities, followed by that of Populus simonii, Larix principis-rupprechtii and Ulmus pumila pure forests, while the soil of Pinus tabuliformis pure forest had the lowest content of humus, condensation degree and stability. There were significant positive correlations between soil microorganism biomass, activity of phosphatase and the content and stability of soil humus. In contrast, the soil peroxidate, dehydrogenase activity and soil humus content showed significant negative correlations with each other. Furthermore, the enhancement of dehydrogenase activity might decrease the stability of humus. There were significant positive correlations between available N and the content and stability of soil humus, but total Cu, Zn and Fe had negative correlations with them, and total Cu and Fe might reduce the stability of humus as well. The particularity of pure forest environment and litter properties might be the key inducement to soil humus differentiation, thus reforming the pure forest through mixing with other tree species or planting understory vegetation would be the fundamental way to improve the soil humus composition and stability. PMID- 25796888 TI - [Effects of light intensity contrast on clonal integration of Spartina anglica]. AB - We conducted a greenhouse experiment to test how clonal integration affected the growth responses of Spartina anglica to light intensity heterogeneity in light availability and whether such effects depended on contrast light intensity. The experiment had three homogeneous treatments and two heterogeneous treatments. In the homogeneous treatments, both ramets of a connected ramet pair were unshaded (high light intensity), moderately shaded (medium light intensity, 70% of the high light intensity) and deeply shaded (low light intensity, 30% of the high light intensity). In the heterogeneous treatments, one ramet of a pair was unshaded, but its connected ramet was either moderately shaded (low light intensity contrast) or deeply shaded (high light intensity contrast). In the homogeneous treatments, biomass of S. anglica was significantly higher in the high light intensity treatment than in the medium and low light intensity treatments. Number of leaves, root length, and total biomass were significantly higher in the shaded ramet in the heterogeneous treatment with low light intensity contrast than in the ramet in the homogeneous treatment with medium light intensity. Final size and mass were not significantly different between the unshaded ramet in the heterogeneous treatment with low light intensity contrast and the ramets in the homogeneous high light intensity treatment. These results suggested that clonal integration benefitted a shaded ramet with little cost to an unshaded ramet when contrast in light intensity was low. However, effects of clonal integration were not significant when contrast was high. It therefore appeared that effects of clonal integration on the growth of S. anglica did not increase with increasing light intensity contrast. In natural habitats, clonal integration might improve growth of S. anglica when its ramets are moderately shaded by other plants but not when they are deeply shaded. PMID- 25796889 TI - [Root growth characteristics and competitive effects of Ageratina adenophora and four functional type herbaceous plants]. AB - A field experiment was conducted to explore the root competitive effects of Ageratina adenophora and Setaria sphacelata, S. yunnanensis, Eupatorium fortunei, Chenopodium serotinum in monoculture and mixture, and the relative competitive abilities were evaluated. The results showed that the root length, superficial area and volume of A. adenophora in mixture were lower than in monoculture, but those of S. sphacelata were higher in mixture than in monoculture. The biomass of A. adenophora in mixture decreased by 77.1% and that of S. sphacelata increased by 80.4% compared with those in monoculture. The relative yield and competitive balance index of S. sphacelata were significantly higher than those of A. adenophora, and the relative yield was about 1.0, suggesting that the underground competitive ability of S. sphacelata was higher than A. adenophora. The root morphology of S. yunnanensis in monoculture and mixture was higher than those of A. adenophora, but the root morphology of two species in mixture was lower than in monoculture. The biomass of A. adenophora and S. yunnanensis in mixture decreased by 45.3% and 22.8% compared with those in monoculture, respectively. Competition effect parameters showed that A. adenophora was a mutual antagonism with S. yunnanensis. The root morphology of E. fortunei and A. adenophora in mixture showed no significant difference compared with that in monoculture. The biomass of A. adenophora and E. fortunei was lower than that in monoculture, respectively. Competition effect parameters showed that A. adenophora was a superior competitor. In the mixture of A. adenophora and C. serotinum, the root morphology parameters and competitive ability of A. adenophora were superior to those of C. serotinum. Above all, S. sphacelata is a preference plant material to control the A. adenophorum invasion and recover biodiversity in A. adenophorum invasion fields. PMID- 25796890 TI - [Variation of soil respiration and its underlying mechanism in grasslands of northern China]. AB - Soil respiration is one of the most important variables in terrestrial ecosystem progresses and global carbon cycle, and determines the CO2 flux from soil to atmosphere. Soil respiration also has great implications for predicting regional and even global carbon cycle changes under the background of global climate change. We measured respiration rates of soil samples collected from northern China grassland transect by short term incubation experiment in laboratory. Results showed that soil respiration rates increased with mean annual precipitation (MAP) from west sites to east sites, ranging from 0.35 to 2.09 MUg CO2-C . g(-1) . h(-1). The variation range of soil respiration rates were 0.35 0.73 MUg CO2-C . g(-1) . h(-1) with MAP < 100 mm, 0.57-0.98 MUg CO2-C . g(-1) . h(-1) with MAP between 100 mm and 200 mm and 0.83-2.10 MUg CO2-C . g(-1) . h(-1) with MAP > 300 mm, respectively. Soil respiration had a significant positive relationship with MAP, aboveground biomass, soil organic carbon and nitrogen content, while had a negative relationship with mean annual temperature and soil pH. Analysis of boosted regression tree showed that the predictors accounted for the explained variation included MAP (25.5%), aboveground biomass (23.6%), soil organic carbon content (18.3%) and soil organic nitrogen content (12.5%), and soil pH and mean annual tem- perature only explained 10.8% and 9.2% of the total variation, respectively. PMID- 25796891 TI - [Carbon and nitrogen distributions and microbial characteristics in the soils of four types of wetlands in Sanjiang Plain, Northeast China]. AB - Four typical wetlands in the Honghe Wetland Reserve of Sanjiang Plain (i. e. wetlands with the following dominant plant species: Calamagrostis angustifolia + Salix brachypoda, Calamagrostis angustifolia, Carex lasiocarpa, and Phragmites australis) were selected to analyze the changes of soil organic carbon (SOC) and total nitrogen (TN) contents and various indices of microbial characteristics including soil sucrose, catalase, cellulase, microbial biomass carbon/nitrogen (MBC/MBN), microbial respiration (MBR), microbial quotient (qMB), and metabolic quotient (qCO2), as well as the correlations among them. The results showed that SOC and TN contents de- creased with increasing the soil depth, and varied significantly (P < 0.01) in the different wetland types. Soil enzyme activities (except catalase), MBC, MBN and MBR also decreased significantly with increasing the soil depth in the wetlands with the greatest activities being detected in surface soil (0-10 cm). In soil layer of 0-30 cm, several parameters (including SOC, TN, soil enzyme activities, MBC, MBN, MBR, qMB and qCO2) were higher in the wetlands dominated by C. angustifolia + S. brachypoda and C. angustifolia, compared with those with C. lasiocarpa and P. australis as dominant plant species. Statistical analyses revealed significant correlations (P < 0.01) between major microbial indicators (except qCO2) with SOC and TN contents in the soils. It demonstrated that the microbial characteristics were the major indicators, and played an important role in the changes of SOC and TN in wetland soils. PMID- 25796892 TI - [Comparison of light response models of photosynthesis in Nelumbo nucifera leaves under different light conditions]. AB - The light responses of Nelumbo nucifera 'Boli Furen', a local N. nucifera species was investigated under full light and 50% shading conditions in Shanghai. The net photosynthetic rate-light response curves of N. nucifera leaves were fitted and analyzed through four light response models to identify the best-fit models of different light conditions and explore the adaptability of N. nucifera to shading environment. The results showed that the sequence of fitting effect of the four light response models was in descending order of modified rectangular hyperbola model > exponential model > non-rectangular hyperbola model > rectangular hyperbola model. The latter three models had no extreme values, and could not directly and accurately provide values of light saturation point (LSP) and maximum net photosynthetic rate (Pn max). In contrast, the modified rectangular hyperbola model showed the best fit for LSP, Pn max, dark respiration rate (Rd) and LCP resulting in the minimum relative errors between the measured and fitted values. Light response parameters of N. nucifera declined with the decreasing light. There were no significant differences between full light and shade treatments except for Rd. It was indicated that N. nucifera had good photosynthetic adaptive response and adjustment to weak light to maintain normal growth. PMID- 25796893 TI - [Effects of wheat root exudates on cucumber growth and soil fungal community structure]. AB - With wheat as the donor plant and cucumber as the receptor plant, this study investigated the effects of root exudates from wheat cultivars with different allelopathic potentials (positive or negative) and companion cropping with wheat on soil fungal community structure by PCR-DGGE method and cucumber growth. Results showed that the wheat root exudates with positive allelopathic potential increased height and stem diameter of cucumber seedlings significantly, compared to the control seedlings (W) after 6 days and 12 days treatment, respectively. Also, wheat root exudates with both positive and negative allelopathic potential increased the seedling height of cucumber significantly after 18 days treatment. The wheat root exudates with different allelopathic potentials decreased the band number, Shannon and evenness indices of soil fungal community significantly in cucumber seedling rhizosphere, and those in the soil with the control seedlings (W) were also significantly higher than that in the control soil without seedlings (Wn) after 6 days treatment. The band number, Shannon and evenness indices in all the treatments were significantly higher than those in the control soil without seedlings (Wn) after 18 days treatment. Companion cropping with negative allelopathic potential wheat decreased the Shannon and evenness indices of soil fungi community significantly in the cucumber seedling rhizosphere, suggesting the wheat root exudates and companion cropping with wheat changed soil fungal community structure in the cucumber seedling rhizosphere. The results of DGGE map and the principal component analysis showed that companion cropping with wheat cultivars with different allelopathic potentials changed soil fungal community structure in cucumber seedling rhizosphere. PMID- 25796894 TI - [Effects of nitrogen management on maize nitrogen utilization and residual nitrate nitrogen in soil under maize/soybean and maize/sweet potato relay strip intercropping systems]. AB - A large amount of nitrogen (N) fertilizers poured into the fields severely pollute the environment. Reasonable application of N fertilizer has always been the research hotpot. The effects of N management on maize N utilization and residual nitrate N in soil under maize/soybean and maize/ sweet potato relay strip intercropping systems were reported in a field experiment in southwest China. It was found that maize N accumulation, N harvest index, N absorption efficiency, N contribution proportion after the anthesis stage in maize/soybean relay strip intercropping were increased by 6.1%, 5.4%, 4.3%, and 15.1% than under maize/sweet potato with an increase of 22.6% for maize yield after sustainable growing of maize/soybean intercropping system. Nitrate N accumulation in the 0-60 cm soil layer was 12.9% higher under maize/soybean intercropping than under maize/sweet potato intercropping. However, nitrate N concentration in the 60-120 cm soil layer when intercropped with soybean decreased by 10.3% than when intercropped with sweet potato, indicating a decrease of N leaching loss. Increasing of N application rate enhanced N accumulation of maize and decreased N use efficiency and significantly increased nitrate concentration in the soil profile except in the 60-100 cm soil layer, where no significant difference was observed with nitrogen application rate at 0 to 270 kg . hm(-2). Further application of N fertilizer significantly enhanced nitrate leaching loss. Postponing N application increased nitrate accumulation in the 60-100 cm soil layer. The results suggested that N application rates and ratio of base to top dressing had different influences on maize N concentration and nitrate N between maize/soybean and maize/sweet potato intercropping. Maize N concentration in the late growing stage, N harvest index and N use efficiency under maize/soybean intercropping increased (with N application rate at 180-270 kg . hm(-2) and ratio of base to top dressing = 3:2:5) and decreased nitrate leaching loss with yield reaching 7757 kg . hm(-2) on average. However, for maize/sweet potato, N concentration and use efficiency and maize yield increased significantly with N application rate at 180 kg . hm(-2) and ratio of base to top dressing = 5:5 than that under other treatments with yield reaching 6572 kg . hm(-2). Under these circumstances, it would be possible to realize maize high yield, high efficiency and safety of N man- agement under maize/soybean and maize/sweet potato relay strip intercropping systems. PMID- 25796895 TI - [Effect of short-time drought process on denitrifying bacteria abundance and N2O emission in paddy soil]. AB - In order to investigate the impact of drying process on greenhouse gas emissions and denitrifying microorganisms in paddy soil, wetting-drying process was simulated in laboratory conditions. N2O flux, redox potential (Eh) were monitored and narG- and nosZ-containing denitrifiers abundances were determined by real time PCR. N2O emission was significantly increased only 4 h after drying process began, and it was more than 6 times of continuous flooding (CF) at 24 h. In addition, narG and nosZ gene abundances were increased rapidly with the drying process, and N2O emission flux was significantly correlated with narG gene abundance (P < 0.01). Our results indicated that the narG-containing deniteifiers were the main driving microorganisms which caused the N2O emission in the short time drought process in paddy soil. PMID- 25796896 TI - [Effects of straw incorporation on rice carbon sequestration characteristics and grain yield formation]. AB - A field experiment was conducted to study the effects of straw incorporation on rice dry matter accumulation and transportation, rice carbon sequestration and grain yield formation. The experiment included four levels of straw incorporation: 0 (control), 4000, 6000 and 8000 kg . hm(-2). Hybrid rice cultivar Zhongzheyou 1 was used in this experiment. The results showed that the average rice dry matter accumulation amount of the three straw incorporation treatments was increased by 63.03 g . m(-2) compared with the control, and that of straw incorporation of 6000 kg . hm(-2) showed the most favorable result, which was 154.40 g . m(-2) higher than the control. Effects of straw incorporation on rice dry matter accumulation showed the best performance from the maximum tillering stage to the full heading stage, and the dry matter accumulation at this stage was 71.25 g . m(-2) higher than the control. Compared with the control, the average dry matter exportation rate and apparent transformation rate from rice stem and leaf in the straw incorporation treatments were increased by 4.2% and 3.7%, respectively. The highest dry matter exportation rate and apparent transformation rate from rice stem and leaf were observed in the straw incorporation treatment of 6000 kg . hm(-2), which were increased by 12.8% and 11.1% compared to the control, respectively. The average rice carbon sequestration from the straw incorporation treatments was increased by 55.38 g . m(-2) compared with the control, and straw incorporation of 6000 kg . hm(-2) performed best with an increase of 17.8% compared with the control. Straw incorporation played a positive role in regulating the carbon sequestration of stem and leaf at the early growth stage and carbon sequestration of spike at the late growth stage. The average grain yield from the straw incorporation treatments was increased by 794.59 kg . hm(-2) (9.5% higher) compared with the control. Rice grain yields from the straw incorporation treatments of 6000 and 4000 kg . hm(-2) were significantly higher than the control, while rice grain yield from the straw incorporation treatment of 8000 kg . hm(-2) did not show a significant increase compared to the control. The rice grain yield was closely related to the yield components, and the increase of effective panicles may be the main reason for the higher grain yields in the straw incorporation treatments. Effective panicles in the straw incorporation treatments was averagely 8.41 spikes . m(-2) more than the control. PMID- 25796897 TI - [Effects of climate change on flax development and yield in Guyuan of Ningxia, Northwest China]. AB - Based on variations of the annual mean temperature and precipitation analyzed using ob- servation data in Guyuan of Ningxia, the effects of climate change on the local flax developmental process and yield were investigated. The results showed that the annual mean temperature had an increasing trend (0.3 degrees C . (10 a)-1) and the annual precipitation had a decreasing trend (-20 mm . (10 a) 1) from 1957 to 2012. While the increasing trend of mean temperature during growing season of flax was more obviously than that of the annual temperature, the decreasing trend of precipitation during growing season was similar to that of annual precipitation. With temperature increasing and precipitation decreasing, the flax development rate was accelerated, resulting in the reduced growing period. Seedling stage was advanced 0.7 d with 1 degrees C increase in temperature during the period from sowing to seedling emergence. The duration from seedling emergence to two pairs of needles was shortened by 0.8 d with 1 degrees C increase in temperature and 0.1 d with 1 mm decrease in precipitation. Maturity stage was advanced 1.8 d with 1 degrees C increase in temperature and 0.1 d with 1 mm decrease in precipitation during the period from technical maturity to maturity. The flax development was accelerated because of temperature increasing and precipitation decreasing in the vegetative growth phase, which was one of the main causes of flax yield reduction year by year. Meanwhile, flower bud differentiation and pollination of flax were influenced by temperature increasing in the reproductive growth phase, which would affect the number of capsules and the seed setting rate per plant and lead to the decrease of flax yield. Therefore, adjusting plant structure and enlarging the planting area of late or middle-late variety were the important measures to reduce the effects of climate change on local flax production. PMID- 25796898 TI - [Effects of different nitrogen regulators on nitrogen transformation in different soil types]. AB - Laboratory incubation experiments were conducted to compare the inhibitory effects of dicyandiamide (DCD) and 3,5-dimethylpyrazole (DMP) on nitrification in meadow-cinnamon soil and fluvo-aquic soil, the main soil types of North China Plain. The synergistic effect of DMP combined with urease inhibitor hydroquinone (HQ) on nitrogen transformation in fluvo-aquic soil was further studied. The results indicated that, in contrast to DCD, DMP had a stronger inhibitory effect on the nitrification in the two tested soils. In comparison with the treatment without any inhibitor, the soil NH(4+)-N content in the treatment with DMP increased significantly by 149.5%-387.2% at the peak of nitrogen transformation stage, and the soil NO(3-)-N content reduced by 22.3%-55.3%. The inhibitory effects of DCD and DMP in fluvo-aquic soil were both stronger than in meadow cinnamon soil. In addition, the application of DMP combined with HQ had a significantly synergistic effect on soil nitrogen transformation. PMID- 25796899 TI - [Effects of nitrogen application and winter green manure on soil active organic carbon and the soil carbon pool management index]. AB - Based on a cropping system of "winter green manure-double rice", the 4 x 4 two factor test was used to study the effects of different nitrogen (N) application levels and winter green manure application on soil active organic carbon (AOC) and the C pool management index. The aim was to explore the ecological effects of winter green manure on soil improvement and determine the appropriate application levels of N fertilizer and winter green manure for improved rice yield. Results were as follows: 1) Compared with the control, the SOC and AOC contents increased by 22.2% and 26.7%, respectively, under the green manure only treatment, but the SOC contents decreased by 0.6%-3.4% under the single N fertilizer treatment. Compared with the control, the soil C pool management index increased by 24.55 and 15.17 under the green manure only and green manure plus N fertilizer treatments, respectively, and reduced by 2.59 under the single N fertilizer treatment. Compared with no fertilization, the average microbial biomass carbon (MBC) increased by 54.0%, 95.2% and 14.3% under the green manure, green manure plus N fertilizer and single N fertilizer treatments, respectively. 2) The soil AOC content was significantly positively correlated with the C pool management index (P < 0.01), and had a significant correlation with dis- solved organic C and MBC (P < 0.05). Rice yield was significantly positively correlated with AOC contents and the C pool management index, and the correlation coefficient was significantly greater than that with the total organic C. These results suggested that application of winter green manure at proper rates with inorganic fertilizer could increase SOC contents and the soil C pool management index, improve soil quality and fertility. PMID- 25796900 TI - [Soil pH buffer capacity of tea garden with different planting years]. AB - In order to investigate the effects of long-term tea planting on soil pH buffer capacity (pHBC), the variation of pHBC and its influence factors were investigated in tea gardens of 10, 15, 20, 25 and 30 years in Langxi and Qimen of Anhui Province. The results showed that the acid-base titration method was suitable for the determination of soil pHBC of tea gardens. The amount of acid base added had approximate linear relationship with soil pH value in specific section (pH 4.0-6.0) of acid-base titration curves, so the soil pHBC could be calculated by linear regression equation. Soil pHBC in the tea gardens from the two regions showed a downward trend with increasing the planting years, which decreased at rates of 0.10 and 0.06 mmol . kg(-1) . a(-1) in Langxi and Qimen tea gardens, respectively. Soil pHBC had significant positive correlation with CEC, soil organic matter, base saturation and physical clay content, and significant negative correlation with exchangeable acid and exchange H+. PMID- 25796901 TI - [Effect of 5-aminolevulinic acid on photosynthetic characteristics of tomato seedlings under NaCl stress]. AB - In this research, the possibility of exogenous application of 5-aminolevulinic acid (ALA) on photosynthetic characteristics of tomato seedlings under NaCl stress was investigated. Five leaves seedlings of tomato (Solanum lycopersicum cv. Jinpeng No. 1) were used as starting materials, applied with 50 mg . L(-1) ALA by foliage spray or 10 mg . L(-1) ALA by root soaking to study the changes in their photosynthesis and fluorescence parameters under 100 mmol . L(-1) NaCl. The result showed that, photosynthetic gas exchange parameters (net photosynthetic rate P,, stomata conductance g(s), intercellular CO2 concentration Ci, transpiration Tr) and chlorophyll fluorescence parameters (Fv'/Fm', Fm', PhiPS II, ETR, qP, Pc) were severely reduced under NaCl treatment and ALA application by foliage spray or root soaking with proper concentrations exerted positive influences on tomato seedlings under salt stress, while there were some differences between foliage spray and root soaking in the influence on chlorophyll content, photosynthesis and chlorophyll fluorescence. Both foliage spray with 50 mg . L(-1) ALA and root soaking with 10 mg L(-1) ALA significantly increased Pn, Ci, g(s) and Tr of tomato seedlings under NaCl stress, alleviated photosynthetic inhibition. Root application of ALA had a better effect on the chlorophyll content than foliage application. However, the photosynthetic parameters showed that foliage application of ALA had a better effect than root application, and both treatments had no difference in the influence on chlorophyll fluorescence parameters of tomato seedlings. It could be deduced that the regulating effect of ALA on enhancing salt tolerance of tomato seedlings is attributed to its effect on improving chlorophyll biosynthesis and metabolism, increasing stomatal conductance and reducing stomatal limitation, thus, enhancing the photosynthetic capacity and PS II photochemical efficiency of tomato leaves under NaCl stress. PMID- 25796902 TI - [Effects of cold-shock on tomato seedlings under high temperature stress]. AB - High temperature stress (HTS) is one of the major limiting factors that affect the quality of intensively cultured seedlings in protected facilitates during hot season. Increasing the cross adaptive response of plant induced by temperature stress is an effective way to improve plant stress resistance. In order to explore the alleviating effect of cold-shock intensity on tomato seedlings under HTS, tomato seedlings were subjected to cold-shock treatments every day with 5 degrees C, 10 degrees C, and 15 degrees C for 10 min, 20 min, and 30 min, respectively, in an artificial climate chamber. The effect of single appropriate cold-shock on the gene expression of small heat shock proteins LeHSP 23.8 and CaHSP18 was investigated. The results showed that hypocotyl elongation and plant height of tomato seedlings were restrained by cold-shock treatment before HTS was met. The alleviating effect of tomato seedlings under HTS by cold-shock varied greatly with levels and durations of temperature. The membrane lipids in the leaf of tomato seedlings were subjected to peroxidation injury in the cold-shock treatment at 5 degrees C, in which the penetration of cell membrane was increased and the activities of antioxidant enzyme was inhibited. The alleviating effect to HTS by cold-shock was decreased with the increasing cold-shock duration at 10 degrees C, however, a reverse change was found at 15 degrees C. The results indicated that cross adaptive response of tomato seedling could be induced with a moderate cold-shock temperature for a proper duration before HTS was met. The optimum cold-shock treatment was at 10 degrees C for 10 min per day, under which, the dry mass, healthy index, activities of protective enzymes (including SOD, POD and CAT) in leaves of tomato seedlings were significantly increased, the contents of proline and soluble protein were enhanced, relative conductivity and malondialdehyde concentration were significantly decreased, and the expression levels of Le-HSP23.8 and CaHSP18 were increased compared with that under normal temperature condition. PMID- 25796903 TI - [Effects of irrigation threshold on soil temperature in blossom and fruit-set periods of muskmelon under mulching-drip irrigation in greenhouse]. AB - It is very significant for muskmelon growth and production to maintain optimal conditions of soil moisture and temperature, especially during blossom and fruit bearing periods. The object of this study was to analyze the effects of different soil water thresholds (T1: 55% of the field capacity, T2: 65% of the field capacity, T3: 75% of the field capacity, CK: 85% of the field capacity) on soil temperature under mulching-drip irrigation in greenhouse. Moreover, effects of the ratio of soil moisture to heat in the plough layer (0-20 cm) on muskmelon growth and fruit setting were investigated. Results indicated that during the flowering and fruit bearing periods, the order of mean soil temperature in the plough layer for the different treatments was T1 > T2 > T3 > CK. There was an inverse correlation between soil temperature in the plough layer and moisture. The maximum one-day variations for soil temperature on sunny day, rainy day and after irrigation were observed in the soil surface under the plastic film mulch, while the minimum happened in the soil layer of 20 cm outside the mulch. The soil temperature extreme was closely related with soil depth, and the difference in the extreme soil temperature between the soil surface and the soil layers of 10 and 20 cm was significant. The treatment T3, with the fastest plant growth rate, the minimum duration of fruit bearing and the maximum fruit setting rate, could be selected as the optimal treatment, and the ratio of soil moisture to heat in T3 was 1.62 mm . degrees C(-1). Therefore, taking into consideration the relationship between soil moisture and temperature during flowering and fruit bearing periods of muskmelon under mulching-drip irrigation, the ratio of soil water to heat in the plough layer should be kept at 1.62 mm . C(-1). The result would be very meaningful for drip-irrigated muskmelon production and management in greenhouse in North China. PMID- 25796904 TI - [Responses of stomata and Kranz anatomy of maize leaves to soil water shortages]. AB - Seedlings of the popular maize cultivar "Zhengdan-958" growing in pots individually were exposed to suitable soil water conditions as control, light water shortage, moderate water shortage, and severe water shortage, corresponding to soil water contents between 75%-85%, 65%-75%, 55%-65%, and 45%-55% of field water capacity, respectively. Responses of stomatal aperture, Kranz anatomy, and vascular bundle structure to different water contents of maize leaves were investigated. Results showed that under increased water shortages, the levels of H2O2 in both guard cells and subsidiary cells were enhanced, also the fluorescence intensity of H2O2 labeled with fluorescent dye increased, while stomatal aperture and conductance decreased gradually. Moreover, Kranz cells were messily arranged and the cell size became smaller and smaller, and the structure of bundle sheath cells went irregular; and the sectional area of the big bundle and xylem, the cell number of phloem, and the thickness of whole leaf and of upper and lower epidermis reduced. In addition, the number of chloroplasts in mesophyll cells and vascular bundle sheath cells decreased, particularly under the moderate water deficit, chloroplasts in Kranz cells which located in the inside of cytoplasmic membrane and cling on the cell wall spread to the direction of cell center. It demonstrated that stomatal closing of maize could be regulated by H2O2 in guard cells and subsidiary cells together, and H2O2 in subsidiary cells maybe played a cooperative role. In conclusion, under increased soil water shortages, drought-induced H2O2 accumulations in both guard cells and subsidiary cells of maize leaves participated in the regulation of stomatal closing. And, the size of Kranz cells and bundle sheath cells, the cell number of phloem, and the area of the xylem and phloem re- duced, thereby, reducing water shortage induced damage. PMID- 25796905 TI - [Analysis on accessibility of urban park green space: the case study of Shenyang Tiexi District]. AB - The accessibility of urban park green space is an important indicator to reflect how much the natural service supplied by parks could be enjoyed by citizens conveniently and fairly. This paper took Shenyang Tiexi District as an example to evaluate the accessibility of urban park green space based on QuickBird imagery and GIS software, with four modes of transportation, walking, non-motor vehicle, motor vehicle and public transport being considered. The research compared and analyzed the distribution of the accessible area and the accessible people of park green space. The result demonstrated that park green space in Shenyang Tiexi District was not enough and the distribution was not even. To be precise, the accessibility in southwest part and central part was relatively good, that in marginal sites was worse, and that in east part and north part was the worst. Furthermore, the accessibility based on different modes of transportation varied a lot. The accessibility of motor vehicle was the best, followed by non-motor vehicle and public transport, and walking was the worst. Most of the regions could be reached within 30 minutes by walking, 15 minutes by non-motor vehicle and public transport, and 10 minutes by motor vehicle. This paper had a realistic significance in terms of further, systematic research on the green space spatial pattern optimization. PMID- 25796906 TI - [Land use change dynamics and driving forces of the vulnerable ecological region in northwestern Shanxi Province, China]. AB - By using remote sensing and GIS technology, this paper collected land use information of 1980, 1990, 2000 and 2010 and the relevant statistical data, and analyzed the characteristics of land use change and its driving forces in northwestern Shanxi Province, the typical ecological fragile area. The results showed that there were significant changes in land use patterns in the past 30 years. During 1980-1990, 1990-2000 and 2000-2010 periods, the area of farmland decreased continuously, while the areas of grassland and woodland experienced increase-decrease-increase and decrease-increase-decrease patterns of change, respectively. The areas of industrial and resident lands increased continuously, but the water body and unused land decreased. The farmland was mainly transformed to grassland and woodland, and the areas of industrial and resident lands increased from the farmland. The lost area of water body was transformed to grassland and farmland. The decrease of unused land was due to the implementation of ecological engineering and urban ex-panding. In general, the changes of land use types were significantly higher before 2000 than after 2000. The industrial and resident lands, unused land and grassland changed drastically. The relationships between land use types and driving forces indicated that population pressure and economic development led to the changes of industrial land and farmland; policy of forestry ecological engi- neering drove the changes of woodland and grassland; the drought-characterized climate was the major cause inducing the decrease of water area and hindering the restoration of forest. PMID- 25796907 TI - [Adaptability assessment of economic and environmental development of Tangshan, Hebei, China]. AB - It is vital to explore whether the economic system adapts to the environmental system as the relationship between economy and environment becomes a gradually concerned problem. Tangshan, a typical resource-based city, was chosen to study the adaptabilities and performances of economic developments in response to environmental changes from 1992 to 2011. It was found that the economic environmental adaptation curve of Tangshan City had an overall fluctuating and increasing tendency. The systematic adaptability kept advancing, reflecting Tangshan paid much attention to environmental development in addition to economic performances, and the two aspects became more and more coordinated. Filtering analysis of the adaptive curve with Eviews software revealed that the potential systematic coordinating index was rising continuously, however, the sum of resilience gap for 20 years was still negative, which implied that fundamental contradictions between high economic development and high energy consumption and high pollutant emission still existed. Carrying out adaptive researches not only helps people to adapt to climate changes better, but also has significances for economic and environmental coordination and sustainability research. PMID- 25796908 TI - [Evaluation of comprehensive capacity of resources and environments in Poyang Lake Eco-economic Zone]. AB - With the development of the society and economy, the contradictions among population, resources and environment are increasingly worse. As a result, the capacity of resources and environment becomes one of the focal issues for many countries and regions. Through investigating and analyzing the present situation and the existing problems of resources and environment in Poyang Lake Eco economic Zone, seven factors were chosen as the evaluation criterion layer, namely, land resources, water resources, biological resources, mineral resources, ecological-geological environment, water environment and atmospheric environment. Based on the single factor evaluation results and with the county as the evaluation unit, the comprehensive capacity of resources and environment was evaluated by using the state space method in Poyang Lake Eco-economic Zone. The results showed that it boasted abundant biological resources, quality atmosphere and water environment, and relatively stable geological environment, while restricted by land resource, water resource and mineral resource. Currently, although the comprehensive capacity of the resources and environments in Poyang Lake Eco-economic Zone was not overloaded as a whole, it has been the case in some counties/districts. State space model, with clear indication and high accuracy, could serve as another approach to evaluating comprehensive capacity of regional resources and environment. PMID- 25796909 TI - [Phylogenetic relationships of seabuckthorn based on ITS sequences]. AB - Sequences of the internal transcribed spacer (ITS) was compared in three seabuckthrons (Hippophae rhamnoides subsp. sinensis, H. tibetana and H. neurocarpa) distributed in Qinghai Province, then the systematic positions of 15 seabuckthron samples were analyzed with Elaeagnaceae angustifolia being outgroup. The results showed that ITS sequences in three seabuckthron species varied in length from 600 to 605 bp. ITS-1, 5.8S and ITS-2 varied from 201 to 203 bp, 166 to 167 bp and 232 to 236 bp, respectively. The sequence divergence among three seabuckthorn species was also remarkably high; Cluster analysis based on ITS indicated that H. gonicocarpa subsp. litangensis and H. gonicocarpa subsp. goniocarpa were distinct and could be classified as H. gonicocarpa and H. litangensis. H. gyantsensis had the closest genetic relationship with H. salicifolia and the distant relationship with H. rhamnoides subsp. sinensis. The positions of nine subspecies of H. rhamnoides based on morphological classification were different from the results of ITS. PMID- 25796910 TI - [Effect of silicon on translocation and morphology distribution of lead in soil tobacco system]. AB - Taking tobacco as test material, a pot experiment was conducted to study the effect of silicon on translocation of lead (Pb) form soil to tobacco in order to explore effective measures for reducing Pb concentration in tobacco leaf. The results showed that silicon application promoted the transformation of exchangeable Pb into Fe-Mn oxide-bound Pb in non-rhizospheric soil, and into Fe Mn oxide-bound Pb and residual Pb in rhizospheric soil, which decreased the availability and mobility of Pb in the soil. Silicon application significantly reduced the Pb uptake of tobacco, with the content of Pb being decreased by 6.5% to 44.0% in tobacco, and 3.1% to 60.4% in leaf. Silicon application promoted the transformation of ethanol-extractable, H2O-extractable Pb and NaCl-extractable Pb into HCl-extractable Pb and residual Pb in root, stem and leaf of tobacco, which reduced the toxicity and mobility of Pb in tobacco. Silicon restricted the transportation of Pb from soil to tobacco leaf by reducing the mobility index of Pb from soil to root and the mobility index of Pb from root to stem in soil tobacco system. Meanwhile, the mobility index of Pb from stem to leaf in soil tobacco system showed a rising-and-falling trend with the increase of Pb application. Silicon inhibited the Pb migration from soil to tobacco leaf by reducing availability of Pb, mitigating toxicity of Pb to tobacco, and changing the distribution of Pb forms in tobacco, consequently reducing Pb concentration of tobacco leaf. These results demonstrated silicon application could be effective in reducing translocation of Pb from soil to tobacco. PMID- 25796911 TI - [Enhancement of GA3 and EDTA on Lolium perenne to remediate Pb contaminated soil and its detoxification mechanism]. AB - A pot experiment was conducted to study the effects of plant growth regulator GA3 and metal chelate EDTA on enhancing the remediation of Pb contaminated soil, and the detoxification mechanism of Lolium perenne grown on Pb contaminated soil at 250 and 500 mg . kg(-1). The results showed that cell wall deposition and vacuolar compartmentalization played important roles in the detoxification of Pb in L. perenne shoot. The addition of EDTA alone increased Pb concentration in plants and Pb proportions in soluble fraction and organelles fraction, and enhanced the toxicity of Pb to plant, leading to the significant reduction of the plant biomass (P < 0.05). Foliar spray of lower concentration of GA3 (1 MUmol . L(-1) or 10 MUmol . L(-1)) alone significantly increased Pb accumulation by L. perenne (P < 0.05), but Pb proportions in soluble and organelles fraction were decreased, which alleviated the adverse effects of Pb on plant, thus improving the growth of plants (P < 0.05), with 1 MUmol . L(-1) GA3 being the most effective. In contract, the addition of 100 MUmol . L(-1) GA3 decreased Pb concentration in L. perenne, but increased the proportions of Pb in soluble fraction and organelles fraction, resulting in the reduction of plant biomass. Lower concen- tration of GA3 might alleviate the adverse effects of Pb and/or EDTA on plant, since the biomass amounts in the different treatments were in order of GA3 alone of lower concentration > GA3 of lower concentration + EDTA > EDTA alone. The combination application of low concentration of GA3 and EDTA showed a synergistic effect on the Pb accumulation in L. perenne (P < 0.05). Especially, Pb concentration in shoot and Pb extraction efficiency reached 1250.6 mg . kg(-1) and 1.1%, respec- tively, under the treatment of EDTA + 1 MUmol L(-1) GA3 on the Pb 500 mg . kg(-1) soil. Therefore, the application of 1 MUmol . L(-1) GA3 along with EDTA appeared to be a potential approach for phytoremediation of Pb contaminated soil. PMID- 25796912 TI - [Ecological responses of brown planthopper, Nilaparvata lugens, to triazophos and deltamethrin on transgenic Bt rice lines and their non-Bt parental rice]. AB - In this study, the brown planthopper (BPH), Nilaparvata lugens (Hemiptera: Delphacidae), cultured on Bt rice lines (T1C-19 with cry1C gene and T2A-1 with cry2A gene) and their parental rice MH63, were treated with a series of concentrations of triazophos and deltamethrin when they developed up to the third instar for the evaluation of the effects of Bt rice on BPH resurgence induced by pesticides. The results indicated that BPH nymphal duration decreased with the increasing concentration of deltamethrin, while no significant differences of BPH nymphal duration were observed on the same rice variety treated with the different concentrations of triazophos. Furthermore, the survival rate of BPH significantly declined and their fecundity significantly increased with the increasing concentration of insecticides. However, ecological fitness parameters of BPH including nymphal duration, survival rate, female adult mass, fecundity and egg hatchability were not significantly different among Bt and non-Bt rice varieties when they treated with the same concentration of insecticide. These results implied that no significant difference in the BPH resurgence induced by pesticides was observed among the two tested Bt rice varieties and their non-Bt parental rice variety. PMID- 25796913 TI - [Ecotoxicological effects of chlorotetracycline on earthworm in soil]. AB - Eiseniafoetida was selected to investigate the ecotoxicological effects of chlorotetracycline on the earthworm in soil. The results showed that 1, 10 and 100 mg . kg(-1) chlorotetracycline had no significant effects on earthworm's body mass after a 7-d exposure, but it was significantly inhibited by 10, 100 mg . kg( 1) chlorotetracycline after 21 days. The soluble protein content of earthworm was induced by 1, 10 and 100 mg . kg(-1) chlorotetracycline, and showed a positive response as the con- centration increased. Also, the earthworm treated by 1, 10 and 100 mg . kg(-1) chlorotetracycline induced the increases of SOD, POD and CAT activities to different degrees. The gene expression in earthworm changed significantly after a 28-d exposure. It is suggested that chlorotetracycline had a chronic ecotoxicological effect on earthworm, and the body mass, soluble protein, antioxidant en- zyme and gene expression could be used as the biomarkers to estimate chlorotetracycline toxicity. PMID- 25796915 TI - [Effects of sewage discharge on abundance and biomass of meiofauna]. AB - In order to elucidate the effects of sewage discharge on abundance and biomass of meio- fauna, a seasonal survey was carried out on meiofauna at stations with different distances to a sewage outlet in the middle intertidal zone of No. 1 bathing beach in Huiquan Bay, Qingdao in spring (April), summer (August), autumn (October) and winter (December), 2011. The results showed that the annual average meiofaunal abundance was (1859.9 +/- 705.1) ind . 10 cm(-2), with higher values of (2444.9 +/- 1220.5) ind . 10 cm(-2) at Station S2 (20 m to the sewage outlet) and (2492.2 +/- 1839.9) ind . 10 cm(-2) at Station S3 (40 m to the sewage outlet), while the lowest value of (327.9 +/- 183.2) ind . 10 cm(-2) was observed at Station S1 (0 m to the sewage outlet) in terms of horizontal distribution. The annual average biomass was (1513.4 +/- 372.7) MUg . 10 cm(-2). Meiofaunal abundance and biomass varied seasonally with the highest values in spring and the lowest values in summer. A total of 11 meiofaunal groups were identified, including nematodes, copepods, polychaetes, oligochaetes, tardigrades, halacaroideans, planarians, ostracods, isopods, crustacean nauplii and others. Free-living marine nematodes were the dominant group constituting 83. 1% of the total abundance, followed by benthic copepods, accounting for 12. 8% of the total abundance. In terms of vertical distribution, most of the meiofauna concentrated in the top 0-2 cm, and the meiofauna abundance decreased with increasing the sediment depth. Meiofauna was also noted to migrate deeper into the sediment in the winter. Pearson correlation analysis showed that meiofaunal abundance and biomass had highly significant negative correlations with sediment median particle diameter and organic matter content. In addition, tourism-induced activities affected meiofaunal abundance and distribution. A comparison with historical data from similar studies was carried out, and the applicability of the ratio of abundance of nematodes to copepods in monitoring organic pollution was discussed. PMID- 25796914 TI - [Electrophysiological and behavioral responses of male Apamea apameoides (Draudt) (Lepidoptera: Noctuidae) to sex pheromone components]. AB - The sex pheromone gland extracts collected from calling females of Apamea apameoides (Lepidoptera: Noctuidae) were analyzed with GC-MS, the electrophysiological and behavioral responses of the male adults to serial dilutions of sex pheromone components and their synthetic blends were investigated with Y-tube olfactometer in laboratory and in bamboo forest field. The results indicated that (Z)-11-hexadecenyl acetate and (Z)-11-hexadecen-1-ol were the functional components in the sex pheromone gland extracts. Electroantennogram (EAG) recordings showed that sex pheromone gland extracts, (Z) 11-hexadecenyl acetate, (Z)-11-hexadecen-1-ol and the mixture of (Z)-11 hexadecenyl acetate and (Z)-11-hexadecen-1-ol all could elicit strong EAG responses, and the average EAG values increased with the increasing concentration of the sex pheromone. The blends of (Z)-11-hexadecenyl acetate and (Z)-11 hexadecen-1-ol at the ratio of 57:43 elicited a higher EAG value than each singular component did. The results of behavioral assay by Y-tube olfactometer accorded with those of EAG responses on the whole, and the mixture of (Z)-11 hexadecenyl acetate and (Z)-11-hexadecen-1-ol at the ratio of 57:43 was more attractive than each component alone. In field tests with silicone rubber as pheromone dispensers (concentration = 10(4) ng . uL(-1)), the average number of male adults captured per trap by the mixture was (48.5 +/- 6.7). PMID- 25796916 TI - [Estimation and experiment of carbon sequestration by oysters attached to the enhancement artificial reefs in Laizhou Bay, Shandong, China]. AB - Through sampling investigation of fouling organisms on the enhancement artificial reefs set up in Laizhou Bay, it was proved that oyster (Ostrea plicatula) was the dominant fouling species. Therefore the dry mass of shell (Ms), total fresh mass (Mt) and thickness (T) of oyster attached on the reefs were analyzed. The results showed that the Mt and Ms presented seasonal variation (P < 0.01), that is, the values were the lowest in April and the highest in December. The reef age and the length of the time the enhancement reefs placed in the sea had significant effect on Mt, Ms and T. With the increment of reef ages, all indices increased obviously. The carbon sinks of oysters attaching to the tube enhancement reefs constructed in 2009, 2010 and 2011 in Laizhou Bay were 17.61, 16.33 and 10.45 kg . m(-3), respectively. The oysters on the enhancement reefs of Jincheng marine ranch with an area of 64.25 hm2 had fixed carbon of 297.5 t C (equivalent to 1071 t of CO2) from 2009 to 2013 in Laizhou Bay. To capture and store the same amount of CO2 would cost about 1.6 x 10(5)-6.4 x 10(5) US dollars. Therefore, oysters attaching to the enhancement reefs bring about remarkable ecological benefits. PMID- 25796917 TI - [Research progress on carbon sink function of agroforestry system under climate change]. AB - As a land comprehensive utilization system, agroforestry system can absorb and fix CO2 effectively to increase carbon storage, and also reduces greenhouse effect convincingly while reaching the aim of harvest. The regulatory role in CO2 makes humans realize that agroforestry systems have significant superiority compared with single cropping systems, therefore, understanding the carbon sinks of different components in an agroforestry system and its influencing factors play an important role in studying global carbon cycle and accurate evaluation of carbon budget. This paper reviewed the concept and classification of agroforestry system, and then the carbon sequestration potentials of different components in agroforestry systems and influencing factors. It was concluded that the carbon sequestration rate of plants from different agroforestry systems in different regions are highly variable, ranging from 0.59 to 11.08 t C . hm(-2) . a(-1), and it is mainly influenced by climatic factors and the characteristics of agroforestry systems (species composition, tree density and stand age). The soil C sequestration of any agroforestry system is influenced by the amount and quality of biomass input provided by tree and nontree components of the system and the soil properties such as soil texture and soil structure. Overall the amount of carbon storage in any agroforestry system depends on the structure and function of its each component. The future studies should focus on the carbon sink functions of structurally optimized agroforestry systems, the temporal variation and spatial distribution pattern of carbon storage in agroforestry system and its carbon sequestration mechanism in a long time. PMID- 25796918 TI - [Research advances in ecological stoichiometry of marine plankton]. AB - Ecological stoichiometry can be simply defined as: The biology of elements from molecules to the biosphere, which spans all levels of the environment and of the life. It's a new idea to build a unified theory and becomes an inevitable trend to develop the ecological science. Marine ecosystems, which contribute to 50% of the biosphere biomass, are the important component of the global biogeochemical cycles. Marine zooplankton plays an important role in the material circulation and energy flow of marine ecosystems and serves as a connecting link between the preceding and the following in a more precise understanding of the key elemental cycles. However, research on ecological stoichiometry of marine plankton is fragmentary and rare. This article summarized the ecological phenomena and mechanisms of limiting elements affecting marine plankton, the response of biochemical substances to nutrition limitation, and the food chain transmission and feedback of nutrition limitation. Meanwhile, we also put forward some perspectives for future research of ecological stoichiometry of plankton in China' s seas. PMID- 25796919 TI - [Applications of metaproteomics in the study of wastewater biotreatment process]. AB - With the advent of the post-genomic era, metaproteomics is gradually emerging as a new tool that has been successfully applied in life sciences and pharmacology, and has become one of the most popular methods in many research fields. Although application of metaproteomics in studying wastewater biotreatment is still in its infancy, its strong potential that contributes to basic research has already been well noticed. This paper reviewed the recent research advances in using metaproteomics to biotreatment wastewater. It also reviewed and summarized the research strategies and application of metaproteomics, such as the identification of functional proteins or enzymes, understanding of the mechanisms of pollutant biodegradation, deduction of key metabolic pathways, and investigation of microbial ecosystems within different sludge of microbial habitats. PMID- 25796920 TI - Disseminated mucormycosis infection after the first course of dose-modified R EPOCH for advanced-stage lymphoma. AB - We report the case of a 63-year-old man who presented at our hospital after experiencing fever and dyspnea for more than 1 month. Because his general condition was deteriorating, he was referred to our intensive care unit. He needed critical care and was treated with vasopressors, artificial ventilation, and continuous hemodialysis. Considering his systemic condition, hematological malignancy was suspected. Bone marrow and skin biopsies were performed, and the condition was diagnosed as diffuse large B-cell lymphoma. On the 15th day, suspecting infectious lung disease, we performed bronchoscopy, which showed Rhizopus infection. Thus, the patient was administered high- dose liposomal amphotericin B (10 mg/kg) therapy. On the 54th day, he died of a massive pulmonary hemorrhage. Autopsy revealed mucormycosis infection in multiple organs, including the lungs and liver. Vigilance regarding possible mucormycosis infection is required, even after initial chemotherapy in patients whose bone marrow is significantly affected by lymphoma cells and leukemic changes. PMID- 25796921 TI - Breakthrough disseminated zygomycosis induced massive gastrointestinal bleeding in a patient with acute myeloid leukemia receiving micafungin. AB - A 69-year-old man, who had been receiving prednisolone for 11 months for treatment of interstitial pneumonia, was diagnosed with acute myeloid leukemia. During induction therapy, he developed severe pneumonia. Although meropenem and micafungin were started, he died of circulatory failure owing to massive gastrointestinal bleeding. Autopsy specimens obtained from the stomach revealed fungal hyphae, which had invaded diffusely into submucosal vessels and caused the massive gastric bleeding. The same hyphae were also observed in both lungs. A diagnosis of disseminated zygomycosis was confirmed by its characteristic histopathological findings. Because zygomycetes are spontaneously resistant to the newer antifungal agents, such as voriconazole or micafungin, it seems likely that the prevalence of zygomycosis as a breakthrough infection may increase in the future. Zygomycosis is a rare, but life-threatening, deep fungal infection that appears in immunologically or metabolically compromised hosts. Its manifestations are clinically similar to those of invasive aspergillosis. In addition to the well-established epidemiology of zygomycosis, this case suggests the following new characteristics. (1) Although the gastrointestinal manifestation of zygomycosis is relatively rare, it is observed more frequently than invasive aspergillosis. (2) Gastrointestinal zygomycosis occasionally leads to the development of necrotic ulcers and may induce hemorrhagic shock.(3) We should be cautious of an occurrence of breakthrough zygomycosis when we use echinocandins for patients with known risk factors, especially steroid use and neutropenia. (4) For patients who are receiving broad-spectrum antibiotics and echinocandins, who are negative for culture studies and aspergillus antigen, and who present with unresolved fever, it is important to make a prompt clinical diagnosis of zygomycosis. PMID- 25796922 TI - Predisposing factors, clinical characteristics and outcome of Pneumonocystis jirovecii pneumonia in HIV-negative patients. AB - Pneumocystisjirovecii (former carinii) pneumonia, is a life-threatening opportunistic infection occurring in immunocompromised hosts. The aim of this study was to investigate the predisposing factors, clinical features and outcome of Pneumocystis pneumonia (PCP) in HIV-negative patients. The medical records of 62 adult patients with PCP, hospitalized at the University Hospital of Heraklion, Crete, Greece during a 10-year period (2004-2013) were retrospectively reviewed. All patients were immunosuppressed prior to the development of PCP. Thirty one patients (50%) suffered malignant hematological disease, 16 (26%) solid tumor and 15 (24%) had chronic inflammatory disease. Only 17 (27%) had received long-term systemic corticosteroids. All had symptoms of pneumonia upon admission, while 12 (19%) were suffering respiratory failure. Twenty one (34%) had received trimethoprim/sulfamethoxazole (TMP-SMX) prophylaxis before the PCP onset. Eight patients (13%) were admitted to the ICU. Mortality attributable to PCP reached 29%. Mortality attributable to PCP was higher in patients with solid tumors. TMP SMX prophylaxis failed in a significant portion of the present cohort. Hence, PCP should be included in the differential diagnosis in immunocompromised patients with symptoms from the respiratory tract even if TMP-SMX has been given as prophylaxis. PMID- 25796923 TI - Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies. AB - In human immunodeficiency virus (HIV)-infected patients, Pneumocystis jirovecii pneumonia (PCP) is a well-known opportunistic infection, and its management has been established. However, PCP is an emerging threat to immunocompromised patients without HIV infection, such as those receiving novel immunosuppressive therapeutics for malignancy, organ transplantation, or connective tissue diseases. Clinical manifestations of PCP are quite different between patients with and without HIV-infections. In patients without HIV infection, PCP rapidly progresses, is difficult to diagnose correctly, and causes severe respiratory failure with a poor prognosis. High-resolution computed tomography findings are different between PCP patients with HIV infection and those without. These differences in clinical and radiologic features are the result of severe or dysregulated inflammatory responses that are evoked by a relatively small number of Pneumocystis organisms in patients without HIV infection. In recent years, the usefulness of PCR and serum beta-D-glucan assay for rapid and noninvasive diagnosis of PCP has been revealed. Although corticosteroid adjunctive to anti Pneumocystis agents has been shown to be beneficial in some populations, the optimal dose and duration remain to be determined. Recent investigations revealed that Pneumocystis colonization is prevalent, and that asymptomatic carriers are at riskfor developing PCP and can serve as the reservoir for the spread of Pneumocystis by person-to-person transmission. These findings suggest the need for chemoprophylaxis in immunocompromised patients without HIV infection, although its indication and duration are still controversial. Because a variety of novel immunosuppressive therapeutics have been emerging in medical practice, further innovations in the diagnosis and treatment of PCP are needed. PMID- 25796924 TI - [The forensic medical characteristic of the factors associated with a shot from the 9.0 mm pneumatic rifle and the inflicted injuries]. AB - The objective of the present work was to elucidate the structural characteristics of the 9.0 mm pneumatic rifle and three regular types of the bullets differing in the head shape fired from it. Morphological features of the injuries inflicted by such bullets are described in conjunction with the peculiarities of precipitation of the shot products in their projection as the prerequisites for their objective differentiation. Results: The study allowed to reveal the composition of the gunshot residues and to determine the maximum distance of their distribution. The specific features of experimental damage inflicted by the shots from the 9.0 mm pneumatic rifle to the coarse white calico fabric targets were shown to depend on the shot range. The objective signs of the so-called "short-range" shot from the 9.0 mm pneumatic rifle were described for the first time. PMID- 25796925 TI - [The morphological characteristic of an experimental rupture of the liver for the simulation of the blunt abdominal injury]. AB - The strength and the energy of a striking blow with a clenched fist may be as high as 300 kgf (3,000 H) and 824.4 J respectively. Pressing a human body against a hard surface leads to a deep chest deflection while the rupture of the liver is associated with a lower blow strength and energy (2,000 H and 141.5 J respectively). In such situations, the shockproof mechanisms of the injury prevail giving rise to antishock peripheral and central ruptures of the liver due to the general deformation and displacement of this organ in the direction of the blow. In the absence of barriers preventing the inertial movement of the body, even a strong strike (1950 H) with an energy of 202.5 J does not cause a damage to the liver; it occurs when the strike strength and energy amount to 2650 H and 260.1 J respectively. In such cases, the direct injury mechanism develops manifested in the formation of local liver injures. The results of the study suggest the possibility of the rupture of the liver inflicted by a clenched fist strike delivered to the abdomen. PMID- 25796926 TI - [The application of certain methods of the statistical analysis for the determination of prescription of an injury to the spleen]. AB - The objective of the present study was to elucidate specific morphological features of the injuries inflicted to the spleen that may be of value for determining their prescription by means of the sequential identification procedure with the use of the relevant diagnostic coefficients. The hierarchic cluster analysis has demonstrated that all the cases of interest can be categorized into 6 groups differing in the prescription of delayed injuries to the spleen that are possible to diagnose based on the morphological picture. It is concluded that the proposed sequential identification procedure with the use of the diagnostic coefficients makes it possible to distinguish between specific morphological features characterizing each group of splenic injuries. PMID- 25796927 TI - [Forensic-medical diagnostics of an electrical mark resulting from the injury inflicted by technical electricity in the aqueous environment]. AB - The objective of the present study was to develop the criteria for forensic medical diagnostics of an electrical injury inflicted in the aqueous environment based on the characteristics of the electrical mark. The specific morphological features of the electrical injuries inflicted in the aqueous environment that were discovered in the materials available for the forensic medical expertise were analysed taking into consideration the results of the relevant research reported in the forensic medical literature. It was shown that an electrical injury inflicted in the aqueous environment results in the formation of an unusual mark in the form of blisters containing no watery liquid associated with electrogenic oedema in the surrounding tissues. Macroscopic and microscopic studies of the electrical mark failed to reveal the signs of grade III and IV grade thermal burning or thermally affected hair. It is concluded that the consistent characteristics of the electrical mark resulting from the injury inflicted by technical electricity in the aqueous environment include cell lengthening, blister formation inside the corneal layer, and the separation of epidermis from the skin proper. PMID- 25796928 TI - [Determination of the power jigsaw sawing velocity from the morphological properties of the affected human skin]. AB - The objective of the present work was to elucidate the characteristic morphological features of the injuries inflicted to the human skin by a power jigsaw depending on the sawing velocity. The study has demonstrated the possibility of mathematical analysis of the sawing velocity based on the morphological peculiarities of the injury to the skin. The data obtained indicate that forensic medical expertise of the injuries inflicted by a power jigsaw can be based on the study of the width of the abraded edges of the wound in order to determine the sawing velocity. PMID- 25796929 TI - [The forensic medical identification of the members of the Demidov family]. AB - The objective of the present study was to elucidate the genetic profiles of the biological materials taken from four graves in the Demidov family vault in order to establish kinship between its members. According to the archival documents, two graves contained the remains of Pyotr Grigor'evich Demidov, an adjutant general for the emperor Aleksandr II, and his wife Elizaveta Nikolaevna Demidova (Bezobrazova). Also, it was supposed that two other graves contained the remains of Grigory Petrovich Demidov and Ekaterina Petrovna Demidova (married name princess Kudasheva), the son and the daughter of P.G. Demidov and E.N. Demidova. The bodies remained in the half-ruined crypt during approximately 150 years under conditions of enhanced humidity and seasonal temperature fluctuations which made their bone tissue virtually unsuitable for the genetic analysis. Genotyping was performed with the use of standard AmpF/STR Identifiler-TM and AmpF/STR Yfiler-TM kits ("Applied Biosystems", USA). As a result of the study, the skeletal remains of the boy from grave No2 were identified as actually belonging to the son of P.G. Demidov and E.N. Demidova with a probability of no less than 99.999999998%. whereas the girl buried in grave No4, was not the daughter of these parents. PMID- 25796930 TI - [On the problem of registration of mortality associated with alcohol consumption among the population in the forensic medical practice]. AB - The objective of the present study was the comparative analysis of the data obtained from the available medical documentation with a view to estimating the effectiveness of taking into account the mortality associated with alcohol consumption. The data subjected to the analysis included the age and the gender of the deceased subjects, complete forensic medical diagnoses from 1607 expert reports and acts of forensic medical expertise of the corpses (form 171/y), and information about the cause of death (item 19) from the relevant medical death certificates (form 106y/08). The mortality associated with alcohol consumption estimated based on the expert reports and acts of forensic medical expertise of the corpses (form 171/y) amounted to 6.7% (95% CI: 5.5- 8.1%); the occurrence of pathology attributable to alcohol consumption was estimated at 7.2% (95% CI: 5.9 8.5%) of the total number of deaths. It was shown that forensic medical experts do not employ in the full measure the diagnostic potential of the International Classification of Diseases (ICD-10) when having to deal with the mortality associated with alcohol consumption. The results of the study confirm the qualitative transformation of the alcohol attributable mortality structure associated with the transfer of information from the expert reports and acts of forensic medical expertise of the corpses (form 171/y) to the medical death certificates (form 106/y-08). PMID- 25796931 TI - [Peculiarities of isolation of 4-nitroanilin from the biological material]. AB - The objective of the present work was to elucidate the peculiarities of isolation of 4-nitroanilin from the biological material with the use of TLC and HPLC techniques, low-pressure column chromatography, and spectrophotometry. The results of the study made it possible to substantiate the application of 1,4 dioxane as an agent for the isolation of 4-nitroanilin from the biological material. The optimal conditions of the procedure for isolation of 4-nitroanilin from the hepatic tissue using 1,4-dioxane were determined. It was shown that the 4-nitroanilin thus obtained can be purified from the co-extracted substances on a L 40/100 mcm silicagel column. The quantitative assessment of the isolation of different amounts of 4-nitroanilin from the cadaveric liver is proposed taking into consideration the extraction conditions. PMID- 25796932 TI - [The detection of clozapine in the tissues of an exhumed corpse]. AB - The authors report the case of finding clozapine in the tissues of an exhumed corpse. The circumstances surrounding the death and the results of primary examination of the corpse are described; in addition, the results of repeated expertise are presented. The data obtained in this study are compared with the relevant literature publications. Special attention is given to the peculiarities of interpretation of the results of forensic chemical expertise essential for the formulation of the scientifically-sound conclusion. PMID- 25796933 TI - [Acute butane poisoning]. PMID- 25796935 TI - [Russian-language forensic medical journals: their mission and problems]. AB - The author briefly overviews the history of forensic medical journals published in this country with special reference to their significance for the solution of new problems facing forensic medicine. PMID- 25796937 TI - [Azret Mashtaevich Mechukaev (on the occasion of his 70th birthday anniversary)]. PMID- 25796936 TI - [The topical problems of the car accident injury emerging from the materials of the articles published in the journal "Sudebno-meditsinskaya ekspertiza" during the period from 1958 to 2012]. AB - The authors undertook the scientometric analysis of the articles published in the journal "Sudebno-meditsinskaya ekspertiza" during the last 55 years (from 1958 to 2012) with special reference to the information support of research and practical activities of forensic medical experts in this country concerning the topical problems of the car accident injury. The search for relevant information revealed a total of 111 articles that were categorized into several groups for their further systematization and analysis with the view for improving the effectiveness of research and experimental studies in the framework of the principal activities of the State Sanitary and Epidemiological Department of the Russian Federation. This article is an extension of previous publications of the authors concerning the main aspects of the car accident injury. The forthcoming reports to be published in the journal "Sudebno-meditsinskaya ekspertiza" will present the results of the further in-depth scientometric analysis of the data on road accidents in this country. PMID- 25796938 TI - [The 8th scientific and practical conference of young scientists and specialists of the Moscow society of forensic medical experts with international participation "Forensic medical science and practice"]. PMID- 25796939 TI - [Cardiogenic ischemic stroke]. AB - The place of cardiogenic ischemic stroke in the structure of acute cerebral circulation disorders is discussed with reference to modern methods of prognostication, diagnostics, treatment and clinical features of cardiogenic strokes. PMID- 25796940 TI - [Etiology of internal organ diseases]. AB - The authors discuss I.V. Davydovsky's views expounded in his book "Problems of causality in medicine, Etiology" (1962) where the philosophical method was applied for the first time for the solution of fundamental problems of medicine, such as etiology and pathogenesis. The main provisions of Davydovsky's concept of etiology of internal organ diseases are considered, an attempt is undertaken to develop and apply them in the present-day context. PMID- 25796941 TI - [Gastric sarcoidosis]. AB - Sarcoidosis is a multisystemic disease of unknown etiology characterized by formation of non-caseificating epithelioid cell granulomas in affected organs. The clinically manifest involvement of the gastrointestinal tract (GIT) in the pathological process is documented in less than 1% of the patients, with stomach being involved in 10% ofthe cases. Pancreatic sarcoidosis is a very rare occurrence. Gastric sarcoidosis (GS) is usually an isolated disease but may be just as well a component of a generalized process. Isolated GS is as a rule a latent condition, its clinical symptoms (epigastric pain, nausea, vomiting) develop in association with erosion and ulceration of gastric mucosa. An endoscopic study of upper GIT may reveal narrowing of the distal half of the stomach with pre-pyloric ulcers or erosion and atrophy; thickened gastric folds may show up diffuse manifestations in the form of a "cobblestone pavement". The leading role in GS diagnostics is played by a histological study of gastric biopsies demonstrating classical sarcoid non-caseificating epithelioid cell granulomas. Treatment of GS must include intake of glucocorticoids and proton pump inhibitors. PMID- 25796942 TI - [Relapsing polychondritis]. AB - Relapsing polychondritis (RP) is a systemic inflammatory condition leading to irreversible structural changes in cartilaginous tissue as a result of generalized proteoglycane decomposition. Auricular and nasal cartilage is usually the first to be affected at the onset of the disease which leads to episcleritis. At the later stages, the larynx and trachea become involved, vasculitis develops affecting the organs of hearing, coronary arteries, kidneys, meninges, and other organs. The disease has an intermittent, recurrent character. The clinical course of RP is irregular. The disease is a rare occurrence and difficult to diagnose. The present review is based on the publications by domestic and foreign authors. It is intended to enhance awareness of the clinical picture and peculiarities of RP among clinicians with a view to improving its diagnostics. PMID- 25796943 TI - [Factors associated with thrombosis of the left atrial appendage in patients with chronic atrial fibrillation]. AB - This study was designed to elucidate hemostatic and genetic characteristics associated with thrombosis of the left atrial appendage (LAA) in patients with chronic atrial fibrillation (AF). It included 91 patients (mean age 62 +/- 7.6 years) with coronary heart disease (CHD) and chronic AF. Group I was comprised of 63 patients without LAA thrombosis, group 2 contained 28 patients with LAA thrombosis diagnosed by transesophageal echocardiography. The following parameters were measured: soluble fibrin monomeric complex, fibrinogen, antithrombin, thrombin-activated fibrinolysis inhibitor levels and polymorphism of YP29, VKORC1, PAI-1 genes. Multifactor regression analysis revealed significant association of LAA thrombosis with thrombin-activated fibrinolysis inhibitor level in excess of 245%, the presence of CC genotype of the VKORC1 gene and 4G allele of the PAl-1 gene. PMID- 25796944 TI - [Erythrocyte aggregation in patients with arterial hypertension and dyslipidemia treated with pravastatin]. AB - The aim of the study was to evaluate effect of pravastatin therapy on erythrocyte aggregation in patients with arterial hypertension and dyslipidemia. It included 81 middle-aged patients with grade I-II AH (risk 3) and type IIb dyslipidemia. Control group consisted of 26 age-matched healthy subjects. 47 patients received pravastatin at a dose of 20 mg (in the evening) and 34 one were given placebo plus analapril (10 mg twice daily). Clinical and laboratory parameters were evaluated before, 4, 12, and 52 weeks after therapy. Statistical analysis of the results was performed with the use of Student's t-test. The study demonstrated increased erythrocyte aggregation in patients with arterial hypertension and dyslipidemia, abnormal blood lipid spectrum and lipid composition of erythrocyte membranes, activation of lipid peroxidation. Pravastatin therapy during 52 weeks optimized the lipid composition and their peroxidation in plasma and erythrocytes; erythrocyte aggregation decreased. It is concluded that pravastatin therapy of AH with dyslipidemia during a year significantly decreases erythrocyte aggregation to the near-normal level. PMID- 25796945 TI - [Optimization of the treatment of chronic obstructive pulmonary disease in men with androgen deficiency]. AB - Chronic obstructive pulmonary disease (COPD) is a widespread condition markedly deteriorating quality of life; it is the fourth most frequent cause of death after cardiovascular diseases, diabetes mellitus and injuries. There is significant association between the severity of androgen deficiency occurrence, duration and pharmacotherapy of COPD. Androgen deficiency in men should be regarded as a new systemic pathogenetic mechanism of COPD complicating its clinical course, prognosis of the disease and concomitant pathologies. Therefore, pharmacotherapy of COPD should be prescribed taking into account the androgenic status of the patients. PMID- 25796946 TI - [Relationship between endothelial dysfunction and mechanisms of systemic inflammation in left heart remodeling in patients with bronchial asthma]. AB - The aim of the work was to study clinical and pathophysiological features of endothelial dysfunction, structural and functional state of the left heart in patients with bronchial asthma (BA). The study included 290 patients. 250 of them presented with moderate or severe BA during exacerbation and within 12 months after the onset of observation, 40 healthy volunteers served as controls. The endothelial function was disturbed in 63 and 74% of the patients with moderate and severe BA respectively. They showed reduced endothelium-dependent vasodilation in combination with a significant increase of the plasma sDC31/ sPECAM-1 level. It is concluded that patients with BA develop structural and functional changes in the left ventricular myocardium proportional to the severity of BA which leads to diastolic dysfunction. PMID- 25796947 TI - [The role of cell-mediated immunity in progression of myeloma disease]. AB - The aim of the work was to study the role of cellular and humoral immunity in progression of myeloma disease (MD). The study included 97 patients and 125 age and sex-matched healthy volunteers. The state of cell-mediated and humoral immunity was evaluated at admission, before the pathogenetic treatment, by indirect immunofluorescence technique using anti-CD3, CD4+, CD8+, CD16+, CD19+, HLA-DR+ monoclonal antibodies. Serum IgA, IgM, IgE, IgG were measured by immunoenzymatic assay. The results were analysed using Statistica 7.0 (StatSoft, USA) program. The quantitative values are expressed as the median (Me) and interquartile range (C25-C75). Qualitative variables are presented as absolute values and percentage. The critical statistical significance level was taken as 0.05. The patients with MD developed combined secondary T, B-cell immunodeficiency. The disbalance between CD4+ cells and cytotoxic lymphocytes as well as signs of B-lymphocyte deficit increased with the progress of the disease. The number of NK-cells decreased at all stages of the disease. A rise in the serum level of LgC at all stages compared with control is an identifying sign confirming diagnosis of G-variant of myeloma disease. PMID- 25796948 TI - [Biochemical characteristics associated with diabetes mellitus one year after myocardial infarction]. AB - AIM: To evaluate the most informative parameters of adipokine, anti-inflammatory, and prothrombogenic status associated with diabetes mellitus. MATERIALS AND METHODS: The study included 200 patients with myocardial infarction (MI) in whom markers of adipokine status, grelin, anti-inflammatory factors, CRP and plasminogen activator inhibitor were measured by biochemical methods on days 1 and 12 after admission. RESULTS: In the period of acute MI, the adipokine status was disturbed, FFA and grelin levels decreased, pro-inflammatory and thrombotic potential increased. Patients who developed diabetes within 1 year after MI were characterized by more pronounced changes of the parameters of interest. CONCLUSION: Adiponectin, retinol-binding protein, grelin, TNF-alpha, and plasminogen activator inhibitor are the most informative biochemical parameters associated with diabetes mellitus developing 1 year after MI. PMID- 25796949 TI - [13-year period of application of the 13C-urease breath test for determining Helicobacter pylori in Russian clinical practice]. AB - 13C-urease breath tests have been extensively used in world-wide gastroenterological practice since the 1990s. We have been using them since 2000, but their clinical application in Russia is far from being universal. Moreover, their results are significantly different from those obtained by other methods for determining H. pylori. The authors report original data on the peculiarities of occurrence of this pathogen in its carriers. PMID- 25796950 TI - [Hyperglycemia as a risk factor of complicated acute myocardial infarction in patients of elderly and senile age]. AB - AIM: To study clinical manifestations and functional state of myocardium in diabetic patients and in patients of elderly and senile age with myocardial infarction (MI) free of type 2 diabetes mellitus (DM) with transient hyperglycemia (HG). MATERIALS AND METHODS: The study included 170 patients with acute macrofocal and transmural MI (with Q-wave). They were divided into group 1 comprised of diabetic patients with MI (n = 60; 36 men and 24 women; age median 78.0 (72.5-83.0 years)), group 2 with MI and TH (n = 60, 38 men, 22 women having no diabetes or disturbances of carbohydrate metabolism in the history; age median 77 (67.0-81.0 years)), and group 3 (n = 50, 28 men, 22 women with MI and normal glycemia in the acute period; age median 73.5 (66.0-83.0 years)). RESULTS: Diabetic patients with TH more frequently than normoglycemic ones showed complicated acute Iaccompanied by acute left ventricular insufficiency, arrhythmia, and lethal outcome. Decrease of their left ventricular systolic function was more pronounced than in controls. Patients with MIIand DM and those with MI and TH had a higher frequency of mitral regurgitation. CCONCLUSION:Hvyerglycemia is significant for the evaluation clinical course and outcome of Ml. PMID- 25796951 TI - [The first experience with the use of catheter denervation of renal arteries in patients with refractory hypertension]. AB - The prevalence of refractory arterial hypertension in Russia is estimated at 15%. We report the first experience with surgical treatment of this pathology. The method is based on the reduction of activity of the sympathetic nervous system by selective breaking of connections between of neurons with the help of interventional intravascular radiowave ablation. Renal endovascular sympathetic denervation allows to more effectively control AP and optimize antihypertensive therapy but does not ensure recovery from AH. PMID- 25796952 TI - [Possibilities for the improvement of the quality of knowledge and their evaluation in the course of studying clinical medicine]. AB - The authors consider objective and subjective factors exerting negative influence on the quality of knowledge of physicians. The generally accepted methods for its evaluation (testing and rating-systems) have limitations. Testing reflects the level of knowledge with respect to the mode of thinking of its designer while rating mostly characterizes diligence of the trainee. It is proposed to improve the quality of knowledge by teaching the theory of diagnostics and to evaluate the amount of knowledge from the contents of the descriptive part of the medical history. The quality of knowledge can be assessed based on the contents of professional comments on the clinical picture described in the model case history. PMID- 25796953 TI - Prevalence of Parkinsonism and Parkinson's disease in Qena governorate/Egypt: a cross-sectional community-based survey. AB - BACKGROUND AND PURPOSE: In a previous study we found a high crude prevalence rate (CPR) for Parkinson's disease (PD) in Assiut governorate/Egypt. We therefore surveyed a second Nile valley governorate (Qena) to provide confirmatory evidence for the high prevalence rate of PD in Egypt. SUBJECTS AND METHODS: 10 areas in Qena governorate were selected by random sampling to recruit 8027 inhabitants. Positive cases were identified using a modified screening questionnaire, the unified Parkinson disease rating scale (UPDRS), mini-mental state examination (MMSE) and the non-motor symptoms scale (NMSS) for PD. RESULTS: Forty-four patients were identified with Parkinsonism, giving a CPR of 548/10(5) inhabitants. Among them, 35 patients were diagnosed as PD with CPR of 436/10(5); three cases were diagnosed as drug-induced Parkinsonism with CPR 37/10(5); two cases had atherosclerotic Parkinsonism with CPR 25/10(5).Age-specific CPR of PD among population aged >= 50 years old was 2534/10(5).The highest age-specific CPR was recorded among subjects >= 75 years old. The CPR showed a tendency to be higher in males than females, urban than rural areas and industrial than non industrial areas (503 vs 363/10(5), 474 vs 389/10(5) and 655 vs 312/10(5), respectively). There was a significantly higher CPR among illiterate than literate persons (1982 vs 299/10(5) with P = 0.00001). About one quarter of patients had cognitive impairment. All cases had positive symptoms in at least one or more NMS Domains. CONCLUSION: The overall prevalence of PD disease is high in Nile valley governorates of Upper Egypt compared to other Arabic countries. PMID- 25796954 TI - Increased adrenal responsiveness and delayed hatching date in relation to polychlorinated biphenyl exposure in Arctic-breeding black-legged kittiwakes (Rissa tridactyla). AB - High levels of environmental contaminants such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and mercury (Hg) have been reported in some Arctic top predators such as seabirds. Chronic exposure to these contaminants might alter the response to environmental changes through interference with the regulation of corticosterone (CORT), a glucocorticoid stress hormone released by the hypothalamo-pituitary-adrenal (HPA) axis. Positive and negative relationships between CORT and environmental contaminants have been reported in polar seabirds. However, patterns appear inconclusive and it is difficult to attribute these relationships to a dysfunction of the HPA axis or to other confounding effects. In order to explore the relationships between the HPA axis activity and contaminants, we tested whether different aspects of the HPA axis of an Arctic seabird, the black-legged kittiwakes Rissa tridactyla, would be related to blood Hg, PCB and OCP concentrations. Male kittiwakes were caught during the incubation period in Svalbard and were subjected to different stress series: (1) a capture-restraint stress protocol, (2) an injection of dexamethasone (DEX) that enabled to test the efficacy of the HPA negative feedback and (3) an injection of adrenocorticotropic hormone (ACTH) that informed on the adrenal responsiveness. The HPA axis activity was unrelated to SigmaOCPs and Hg. However, birds with high concentrations of SigmaPCBs released more CORT after the ACTH injection. It is suggested that SigmaPCBs may increase the number of ACTH-receptors on the adrenals. Additionally, hatching date was delayed in males with higher concentrations of SigmaPCBs and SigmaOCPs. This study gives new evidence that PCBs and adrenal activity may be related. Thus high PCB burden may make individuals more prone to other stressors such as ongoing climate change. PMID- 25796955 TI - Third ventricular schwannoma with hydrocephalus. AB - Intraventricular schwannomas are rare, with only 20 cases reported in the literature to our knowledge, including two cases of schwannomas in the third ventricle. We report a 23-year-old man with a mass in the posterior portion of the third ventricle and obstructive hydrocephalus. The intraventricular mass was clearly visualized and removed by neuroendoscopic surgery, and endoscopic third ventriculostomy was simultaneously performed for the hydrocephalus. Histological and immunohistochemical assays of the surgical sample established a diagnosis of intraventricular schwannoma. The patient had a favourable outcome and no neurological deficits 1 year later. The schwannoma was distant from the choroid plexus, which supports the hypothesis that the schwannoma originated from ectopic neural crest cells that were displaced during embryogenesis. PMID- 25796956 TI - Metronidazole toxicity presenting with acute onset of aphasia and right sided weakness. AB - We report a 37-year-old man with a history of cirrhosis and methicillin-sensitive staphylococcus aureus (MSSA) bacteremia who presented from a nursing home with 1 week of progressive confusion followed by acute onset of aphasia, forced left eye deviation and right sided weakness. While clinical presentation was concerning for a left middle cerebral artery stroke, MRI was consistent with leukoencephalopathy. The man had been on metronidazole for 2 months for treatment of Clostridium difficile infection. This case exemplifies a stroke mimic to be considered when a patient presents with an acute focal neurological deficit. PMID- 25796957 TI - Surgical management, outcomes, and recurrence rate of orbital lymphangiomas. AB - Orbital lymphangiomas are rare benign vascular lesions of the orbit. Due to their intimate relationship to the orbital contents, gross total resection can be difficult, resulting in a relatively high recurrence rate. Between May 2002 and June 2013, eight patients (five male, three female) underwent surgical resection for orbital lymphangiomas at our institution. Of the seven patients with follow up, six experienced improvement in presenting symptoms at a mean of 5.3 years (range 1-23 years). Recurrence was seen in five of the seven patients (71.4%). Recurrence developed at a mean of 7.2 years (range 1-23 years) after the initial procedure. New or worsening cranial nerve deficits were seen postoperatively in three of eight patients (37.5%) with follow-up. All postoperative deficits were resolved at last follow-up. Orbital lymphangiomas are challenging surgical lesions in which gross total resection is frequently not possible. Subtotal resection is safe and effective for symptomatic relief. PMID- 25796958 TI - Heterometallic 3d-4f single-molecule magnets: ligand and metal ion influences on the magnetic relaxation. AB - Six tetranuclear 3d-4f single-molecule magnet (SMM) complexes formed using N-n butyldiethanolamine and N-methyldiethanolamine in conjunction with ortho- and para-substituted benzoic acid and hexafluoroacetoacetone ligands yield two families, both having a butterfly metallic core. The first consists of four complexes of type {Co2(III)Dy2(III)} and {Co2(III)Co(II)Dy(III)} using N-n butyldiethanolamine with variation of the carboxylate ligand. The anisotropy barriers are 80 cm-1, (77 and 96 cm-1-two relaxation processes occur), 117 and 88 cm-1, respectively, each following a relaxation mechanism from a single DyIII ion. The second family consists of a {Co2(III)Dy2(III)} and a {Cr2(III)Dy2(III)} complex, from the ligand combination of N-methyldiethanolamine and hexafluoroacetylacetone. Both show SMM behavior, the Co(III) example displaying an anisotropy barrier of 23 cm-1. The Cr(III) complex displays a barrier of 28 cm 1, with longer relaxation times and open hysteresis loops, the latter of which is not seen in the Co(III) case. This is a consequence of strong Dy(III)-Cr(III) magnetic interactions, with the relaxation arising from the electronic structure of the whole complex and not from a single DyIII ion. The results suggest that the presence of strong exchange interactions lead to significantly longer relaxation times than in isostructural complexes where the exchange is weak. The study also suggests that electron-withdrawing groups on both bridging (carboxylate) and terminal (beta-diketonate) ligands enhance the anisotropy barrier. PMID- 25796959 TI - Strategy use, planning, and rule acquisition deficits in spinocerebellar ataxia type 2 patients. AB - Our goal was to improve spinocerebellar ataxia type 2 (SCA2) cognitive profile characterization by testing the hypothesis that strategy, planning and rule acquisition capacities are affected in SCA2. Forty one patients with SCA2 were evaluated with the Spatial Working Memory (SWM), the Stockings of Cambridge (SOC), and the Intra-Extra Dimensional Shift (IED) tests of the Executive module of the Cambridge Neuropsychological Testing Automated Battery (CANTAB). Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) from the CANTAB memory module were also assessed to corroborate previous findings. Motor deterioration was measured using the Scale for the Assessment and Rating of Ataxia (SARA). We found significant SCA2 related deficits in strategy, planning, and rule acquisition. Our results also corroborated significant memory deficits in these patients with SCA2. Further analysis also showed that patients with large motor deterioration had poorer associative learning and spatial planning scores. Patients with SCA2 show strategy, planning, and rule acquisition deficits as revealed with the CANTAB battery. These deficits should be noted when planning an effective therapy for these patients. PMID- 25796960 TI - Does post-artesunate delayed haemolysis change practice? PMID- 25796961 TI - Characterization of graphene-nanoplatelets structure via thermogravimetry. AB - The rapid increase in graphene-based applications has been accompanied by novel top-down manufacturing methods for graphene and its derivatives (e.g., graphene nanoplatelets (GnPs)). The characterization of the bulk properties of these materials by imaging and surface techniques (e.g., electron microscopy and Raman spectroscopy) is only possible through laborious and time-consuming statistical analysis, which precludes simple and efficient quality control during GnP production. We report that thermogravimetry (TG) may be utilized, beyond its conventional applications (e.g., quantification of impurities or surfactants, or labile functional groups) to characterize bulk GnP properties. We characterize the structural parameters of GnP (i.e., defect density, mean lateral dimension, and polydispersity) by imaging and surface techniques, on one hand, and by a systematic TG, on the other. The combined data demonstrate that the combustion temperature of commercially available and laboratory-prepared GnPs is correlated with their mean lateral dimension and defect density, while the combustion temperature range is proportional to their polydispersity index. Mapping all these parameters allows one to evaluate the GnPs' structure following a simple thermogravimetric experiment (without necessitating further statistical analysis). Finally, TG is also used to detect and quantify different GnP constituents in powder and to conduct rapid quality-control tests during GnP production. PMID- 25796962 TI - Improvements in patient-reported outcomes: A prospective, non-interventional study with aclidinium bromide for treatment of COPD. AB - BACKGROUND: The inhaled long-acting muscarinic antagonist aclidinium bromide has been shown to significantly improve lung function parameters and symptom severity in patients with COPD in randomised placebo- and active-controlled clinical studies. To obtain a comprehensive view of the treatment effects, patient reported outcomes were investigated in a real-life COPD population in routine clinical practice in Austria. METHODS: Multicentre, prospective, non interventional study in patients with COPD who were newly initiated on treatment with Eklira(r) Genuair(r) (aclidinium bromide; recommended dose 400 MUg twice daily) as first-line or add-on therapy. Patients were either treatment naive or switched from other COPD medications. Health-related quality of life by means of the COPD Assessment TestTM (CAT) and symptom-related variables were evaluated at the first visit (baseline) and after approximately 12 weeks of treatment. Features of the inhaler were assessed by patients and physicians at the follow-up visit. RESULTS: A total of 795 COPD patients (56% male; median age: 64 years) were enrolled and treated. During the observational period, the proportion of patients with at least moderate nighttime symptoms, early-morning symptoms, and limitations in morning activities decreased from 45.0% to 21.4%, from 57.7% to 26.0%, and from 49.9% to 25.3%, respectively. All improvements from baseline in symptom severity and activity limitation were statistically significant (p < 0.0001, all tests). The mean (+/-SD) frequency of nocturnal awakenings decreased from 1.2 (+/-1.4) to 0.7 (+/-1.2) times per night (p < 0.0001). Quality of life improved significantly in patients treated with aclidinium bromide over 3 months compared to baseline (p < 0.0001; mean CAT total score: 18.5 +/- 7.5 vs. 13.8 +/- 7.3). Up to 90% of the patients and up to 91% of the physicians assessed individual features of the inhaler as 'very good' or 'good'. Aclidinium bromide was well tolerated; 6.9% of the patients reported adverse drug reactions, none of which were serious. CONCLUSIONS: This non-interventional study indicated beneficial effects of Eklira(r) Genuair(r) in the treatment of COPD with regard to nighttime and early-morning symptoms, limitation of morning activities, and quality of life under routine conditions. The acceptance of the inhaler device was high, which is a prerequisite to ensure adherence in long-term therapy. PMID- 25796963 TI - Synthesis of Janus-like gold nanoparticles with hydrophilic/hydrophobic faces by surface ligand exchange and their self-assemblies in water. AB - This study aims at the synthesis of Janus gold nanoparticles (Janus GNPs) with hydrophilic/hydrophobic faces by a simple ligand exchange reaction in an homogeneous system and at the elucidation of the self-assembled structures of the Janus GNPs in water. As hydrophilic surface ligands, we synthesized hexaethylene glycol (E6)-terminated thiolate ligands with C3, C7, or C11 alkyl chains, referred to as E6C3, E6C7, and E6C11, respectively. As a hydrophobic ligand, a butyl-headed thiolate ligand C4-E6C11, in which a C4 alkyl was introduced on the E6C11 terminus, was synthesized. The degree of segregation between the two ligands on the GNPs (5 nm in diameter) was examined by matrix-assisted laser desorption/ionization time-of fright mass spectrometry (MALDI-TOF MS) analysis. We found that the choice of immobilization methods, one-step or two-step addition of the two ligands to the GNP solution, crucially affects the degree of segregation. The two-step addition of a hydrophilic ligand (E6C3) followed by a hydrophobic ligand (C4-E6C11) produced a large degree of segregation on the GNPs, providing Janus-like GNPs. When dispersed in water, these Janus-like GNPs formed assemblies of ~160 nm in diameter, whereas Domain GNPs, in which the two ligands formed partial domains on the surface, were precipitated even when the molar ratio of the hydrophilic ligand and the hydrophobic ligand on the surface of the NPs was almost 1:1. The assembled structure of the Janus-like GNPs in water was directly observed by pulsed coherent X-ray solution scattering using an X-ray free-electron laser, revealing irregular spherical structures with uneven surfaces. PMID- 25796964 TI - Correction to "Carbohydrate receptors combining both a macrocyclic building block and flexible side arms as recognition units: design, syntheses, and binding studies". PMID- 25796965 TI - Abnormalities of acid-base balance and predisposition to metabolic acidosis in Metachromatic Leukodystrophy patients. AB - Metachromatic Leukodystrophy (MLD; MIM# 250100) is a rare inherited lysosomal storage disorder caused by the deficiency of Arylsulfatase A (ARSA). The enzymatic defect results in the accumulation of the ARSA substrate that is particularly relevant in myelin forming cells and leads to progressive dysmyelination and dysfunction of the central and peripheral nervous system. Sulfatide accumulation has also been reported in various visceral organs, although little is known about the potential clinical consequences of such accumulation. Different forms of MLD-associated gallbladder disease have been described, and there is one reported case of an MLD patient presenting with functional consequences of sulfatide accumulation in the kidney. Here we describe a wide cohort of MLD patients in whom a tendency to sub-clinical metabolic acidosis was observed. Furthermore in some of them we report episodes of metabolic acidosis of different grades of severity developed in acute clinical conditions of various origin. Importantly, we finally show how a careful acid base balance monitoring and prompt correction of imbalances might prevent severe consequences of acidosis. PMID- 25796966 TI - Differential effects of online insomnia treatment on executive functions in adolescents. AB - OBJECTIVE: To examine the effects of online Cognitive Behavior Therapy for Insomnia (CBTI) on adolescents' sleep and cognitive functioning. METHODS: 32 adolescents (13-19 years, M = 15.9, SD = 1.6) with DSM-5 insomnia disorder, were randomly assigned to a treatment group (n = 18) or a waiting list (n = 14). Treatment consisted of six guided self-help online CBTI sessions. Both groups were assessed at baseline and post-treatment. Sleep was measured with actigraphy, sleep logs, and questionnaires. Cognitive functioning was assessed with a battery of standard cognitive tests. RESULTS: After CBTI the treatment group showed significant improvements compared to the waiting list group in sleep efficiency from actigraphy and sleep logs. This finding was confirmed by improvements in other sleep variables from sleep logs, and in symptoms of chronic sleep reduction and insomnia. Most participants from the treatment group improved to sub clinical levels of insomnia. Cognitive functioning of the treatment group showed more improvement compared to the waiting list in visuospatial processing, selective attention and phonological working memory, and a trend of improvement in response inhibition and set shifting, letter fluency and sustained attention, but not in declarative memory, visuospatial working memory, category fluency, and general cognitive speed. Changes in sleep appeared to be related to changes in cognitive functioning. CONCLUSIONS: These results indicate that CBTI can have positive effects on cognitive functions in adolescents, with notable improvements in visuospatial processing and phonological working memory but not in visuospatial working memory. PMID- 25796967 TI - Attention deficits detected in cognitive tests differentiate between sleep apnea patients with or without a motor vehicle accident. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is associated with an increased motor vehicle accident (MVA) risk. Conventional measures of OSA severity do not predict individual risk. Cognitive function tests have failed to incorporate outcomes in risk prediction. We aimed to identify markers of cognitive function for MVA risk prediction in OSA. METHODS: OSA patients [n = 114, 75% male, median age 51 (43 61) years, body mass index (BMI) 30 (27-33) kg/m2, apnea-hypopnea index 25 (6-49) n/h, and Epworth Sleepiness (ESS) score 11 (8-16)] were recruited from a sleep laboratory. Two cognitive function tests, the Attention Network Test (ANT) and a modified Oxford Sleep Resistance Test (OSLER) test (GOSLING), were assessed. RESULTS: OSA patients with (n = 11) or without (n = 103) a MVA record in the Swedish traffic accident registry were identified. In patients with a MVA, 64% were commercial drivers. In patients with a MVA history, more lapses [42 (5-121) vs. 5 (1-25), P = 0.02] and fewer responses [238 (158-272) vs. 271 (256-277), P = 0.03] to stimuli in the ANT were found. In the GOSLING, the number of lapses was higher (29 (10-97) vs. 7 (2-19), P = 0.01) and the reaction time was longer [462 (393-551) vs. 407 (361-449) ms, P = 0.05]. OSA severity and ESS score poorly predicted MVAs (P > 0.2). CONCLUSIONS: We have demonstrated that deficit in sustained attention, assessed by daytime neurocognitive function tests, was associated with MVA risk in OSA patients. We were unable to detect an association between MVA history and severity of OSA or the ESS score. The findings provide a rationale for further development of objective MVA risk assessment tools in OSA. PMID- 25796968 TI - Studying translational control in non-model stressed organisms by polysomal profiling. AB - In stressed organisms, strategic proteins are selectively translated even if the global process of protein synthesis is compromised. The determination of protein concentrations in tissues of non-model organisms (thus with limited genomic information) is challenging due to the absence of specific antibodies. Moreover, estimating protein levels quantifying transcriptional responses may be misleading, because translational control mechanisms uncouple protein and mRNAs abundances. Translational control is increasingly recognized as a hub where regulation of gene expression converges to shape proteomes, but it is almost completely overlooked in molecular ecology studies. An interesting approach to study translation and its control mechanisms is the analysis of variations of gene-specific translational efficiencies by quantifying mRNAs associated to ribosomes. In this paper, we propose a robust and streamlined pipeline for purifying ribosome-associated mRNAs and calculating global and gene-specific translation efficiencies from non-model insect's species. This method might found applications in molecular ecology to study responses to environmental stressors in non-model organisms. PMID- 25796969 TI - Bisphenol A and congenital developmental defects in humans. AB - Over 50% of the causes of fetal malformations in humans are still unknown. Recent evidence suggests the relationship between environmental exposure to endocrine disruptors and fetal malformations. Our study aims to establish the role of Bisphenol A (BPA), if any, in altering human reproduction. We enrolled 151 pregnant women who were divided into two groups: case group (CS, n=101), women with established diagnosis of developmental defect, and control group (CL, n=50), pregnant women with normally developed fetus. Total, free and conjugated BPA were measured in their blood using GC-MS with isotopic dilution. The results show a correlation between environmental exposure to BPA and the genesis of fetal malformations. Conjugated BPA, which was higher in the CL, casts light on the hypothesis that a reduced ability to metabolize the chemical in the mother can concur to the occurrence of malformation. In a more detailed manner, in case of chromosomal malformations, the average value of free BPA appears to be nearly three times greater than that of the controls. Similarly, in case of central and peripheral nervous system non-chromosomal malformations, the value of free BPA is nearly two times greater than that of the controls. PMID- 25796970 TI - Targeting dengue virus NS4B protein for drug discovery. AB - The flavivirus nonstructural 4B protein (NS4B) has recently emerged as a valid antiviral target for drug discovery. Here we review (i) the current understanding of the structure and function of DENV NS4B, (ii) the approaches that have been taken to identify NS4B inhibitors, and (iii) the known inhibitors of flavivirus NS4B protein. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery. PMID- 25796971 TI - Carbon nanotube-based nanocarrier loaded with ribavirin against grass carp reovirus. AB - Infectious diseases of viral origin cause major aquatic production losses in different parts of the world. Because of formidable barriers for gastrointestinal tract, skin and cell, large amounts of antiviral drugs have limited therapeutic effect. In the current study, functionalized single-walled carbon nanotubes (SWCNTs) were selected as a drug carrier to carry antiviral drug for the treatment of viral diseases on fish. The results show that increasing antiviral drug (ribavirin) intake was observed by SWCNTs carrier and therapeutic dosage to kill grass carp reovirus is significantly reduced. At 12d post infection, survival rate and infection rate were 29.7% and 50.4% for naked ribavirin treatment group exposed to the highest concentration (20 mg/L); however, survival rate of 96.6% and infection rate of 9.4% were observed in 5 mg/L ribavirin-SWCNTs treatment group. In addition, the drug detention time in different organs and tissues (blood, gill, liver, muscle, kidney and intestine) was also significantly extended (about 72 h) compared with the same dosage in naked ribavirin treatment group. Moreover, the toxicity of functionalized SWCNTs in grass carp can be minimal, and physiological markers (some antioxidant enzymes activities, apoptotic factors activities and their corresponding genes expression) remained within normal ranges following treatment. Our results indicated that drug delivery with functionalized SWCNTs can improve the antiviral effect on grass carp and has a potential application value to control fish viral diseases in aquaculture. PMID- 25796972 TI - Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules. AB - Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 MUM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing. PMID- 25796973 TI - Correlated analysis and pathological study on insulin resistance and cardiovascular endocrine hormone in elderly hypertension patients. AB - AIMS: The correlated analysis and pathological study on insulin resistance and cardiovascular endocrine hormone in elderly hypertension patients was investigated by clinical observation and physical experiments in my hospital. MATERIALS AND METHODS: Randomly enrolled 300 subjects seen at hospital from January 2011 to January 2013, which included 150 hypertension patients and 150 non-hypertension of healthy people, while 150 cases of hypertension patients as the experimental group, 150 cases of healthy people without hypertension acts as the control group. The t-PA of serum (plasma), activity of PAI, ANP, IS, ET were determined in this 300 subjects, and it studied on the correlation and pathological effect between insulin resistance and cardiovascular endocrine hormone in elderly hypertension patients. RESULTS: The levels of PAI, ANP, ET are apparently higher in hypertension patients than in healthy control group (p<0.05), while the t-PA, IS are obviously lower in hypertensive patients than in healthy control group (p>0.05). CONCLUSION: This study has shown that there is a significant correlation and pathological effect between insulin resistance and cardiovascular endocrine hormone in hypertensive patients, and which plays an important role in genesis and development of hypertension in elderly people. PMID- 25796974 TI - A brief review on the periodontal health in metabolic syndrome patients. AB - Metabolic syndrome (METs) and periodontal diseases are emerging worldwide community health problem. These common health problems may result with significant complications and increase community health expenses. METs is defined with the presence of hypertension, increased triglyceride levels, decreased high density lipoprotein cholesterol levels, abdominal obesity and elevated fasting glucose levels. The term "periodontal diseases" defines pathological inflammatory conditions of the gingiva and supporting tooth structures. In this review, basic clinical features and associations between metabolic syndrome and periodontal diseases have been underlined. In addition, basic research topics have been noted. PMID- 25796975 TI - Development of radial optic flow pattern sensitivity at different speeds. AB - The development of sensitivity to radial optic flow discrimination was investigated by measuring motion coherence thresholds (MCTs) in school-aged children at two speeds. A total of 119 child observers aged 6-16years and 24 young adult observers (23.66+/-2.74years) participated. In a 2AFC task observers identified the direction of motion of a 5 degrees radial (expanding vs. contracting) optic flow pattern containing 100 dots with 75% Michelson contrast moving at 1.6 degrees /s and 5.5 degrees /s and. The direction of each dot was drawn from a Gaussian distribution whose standard deviation was either low (similar directions) or high (different directions). Adult observers also identified the direction of motion for translational (rightward vs. leftward) and rotational (clockwise vs. anticlockwise) patterns. Motion coherence thresholds to radial optic flow improved gradually with age (linear regression, p<0.05), with different rates of development at the two speeds. Even at 16years MCTs were higher than that for adults (independent t-tests, p<0.05). Both children and adults had higher sensitivity at 5.5 degrees /s compared to 1.6 degrees /s (paired t-tests, p<0.05). Sensitivity to radial optic flow is still immature at 16years of age, indicating late maturation of higher cortical areas. Differences in sensitivity and rate of development of radial optic flow at the different speeds, suggest that different motion processing mechanisms are involved in processing slow and fast speeds. PMID- 25796976 TI - Intrinsic and extrinsic effects on image memorability. AB - Previous studies have identified that images carry the attribute of memorability, a predictive value of whether a novel image will be later remembered or forgotten. Here we investigate the interplay between intrinsic and extrinsic factors that affect image memorability. First, we find that intrinsic differences in memorability exist at a finer-grained scale than previously documented. Second, we test two extrinsic factors: image context and observer behavior. Building on prior findings that images that are distinct with respect to their context are better remembered, we propose an information-theoretic model of image distinctiveness. Our model can automatically predict how changes in context change the memorability of natural images. In addition to context, we study a second extrinsic factor: where an observer looks while memorizing an image. It turns out that eye movements provide additional information that can predict whether or not an image will be remembered, on a trial-by-trial basis. Together, by considering both intrinsic and extrinsic effects on memorability, we arrive at a more complete and fine-grained model of image memorability than previously available. PMID- 25796977 TI - Security bound of cheat sensitive quantum bit commitment. AB - Cheat sensitive quantum bit commitment (CSQBC) loosens the security requirement of quantum bit commitment (QBC), so that the existing impossibility proofs of unconditionally secure QBC can be evaded. But here we analyze the common features in all existing CSQBC protocols, and show that in any CSQBC having these features, the receiver can always learn a non-trivial amount of information on the sender's committed bit before it is unveiled, while his cheating can pass the security check with a probability not less than 50%. The sender's cheating is also studied. The optimal CSQBC protocols that can minimize the sum of the cheating probabilities of both parties are found to be trivial, as they are practically useless. We also discuss the possibility of building a fair protocol in which both parties can cheat with equal probabilities. PMID- 25796978 TI - Comparative metabolism of Lappaconitine in rat and human liver microsomes and in vivo of rat using ultra high-performance liquid chromatography-quadrupole/time-of flight mass spectrometry. AB - Lappaconitine (LAP), a non-addictive potent analgesic drug, is broadly used to treat cancer and postoperative pain in many countries, and it also has antibiotic activity against Pseudomonas aeruginosa and Salmonella Typhi. Despite its widespread usage and potential for expanded use, its metabolism was poorly investigated. In this work, the metabolic fate of LAP in liver microsomes of the rat and human was compared, and after oral administration, the metabolites in the rat were investigated using ultra high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS). As a result, a total of 51 metabolites were identified, including 48 metabolites that were reported here for the first time. Based on accurate MS/MS spectra and the known structure of LAP, the metabolites structures and their fragment ions were readily characterized. The biotransformations of LAP in vitro and in vivo were shown to involve hydroxylation, N-deacetylation, O-demethylation, N-deethylation, and hydrolysis. Furthermore, the results indicated a quantitative species difference in the metabolites for LAP between the rat and human. However, 16-DMLAP, DAL and 5'-OH-DAL were the main in vitro and in vivo metabolites. This work provides the LAP metabolite profiles in rat and human, which will help better understand the pharmacological and toxicological activities of LAP. PMID- 25796979 TI - Simultaneous determination of selected eicosanoids by reversed-phase HPLC method using fluorescence detection and application to rat and human plasma, and rat heart and kidney samples. AB - Eicosanoids are biologically active lipid-derived oxidative metabolites of arachidonic acid. We, herein, present an improved sensitive, selective and robust high performance liquid chromatography (HPLC)-fluorescence assay for simultaneous quantification of eicosanoids in human plasma and rat tissues. Aliquots of 200 MUL of plasma or 30 mg of heart or kidney tissues were spiked with 16 hydroxydecanoic acid as internal standard, and extracted with anhydrous acetonitrile using solid phase cartridges. The eluted samples were dried, reconstituted in anhydrous acetonitrile and labeled with 2-(2,3 naphthalimino)ethyl-trifluoromethanesulphonate in the presence of saturated potassium fluoride solution in anhydrous acetonitrile and N,N diiospropylethylamine as catalyst. The derivatized eicosanoids were extracted with anhydrous acetonitrile using solid phase cartridges. Chromatographic separation was achieved on a C18 reversed phase column using gradient mobile phase of 0.05% of formic acid:acetonitrile:water at 0.8 mL/min flow rate. The analytes were detected at excitation and emission wavelength of 260 and 396 nm, respectively. The assay was linear (r(2)>= 0.98) in the concentration range of 0.01-2.5 MUg/mL. The intra-day and inter-day coefficients variation was less than 19.8%. Using this assay, we were able to quantify arachidonic acid metabolites simultaneously in human and rat biological samples. PMID- 25796980 TI - Orientation to determine quality attributes of flavoring excipients containing volatile molecules. AB - Pharmaceutical excipients containing volatile odor-active molecules can be used in pharmaceutical development to increase patients' compliance. However, capturing the molecular composition of these odor-active substances is challenging. Therefore, guidance for the analytical investigation of these excipients should be developed. Using a model flavor, lead molecules were chosen and a gas chromatographic method was validated according to pharmaceutical guidelines. Changes during storage as well as batch homogeneity and conformity were investigated. The knowledge gained could be used to understand molecular differences between batches caused by aging. A suitable attempt to capture the volatile molecular composition of flavoring substance was presented and the found results could be used for the determination and interpretation of quality attributes. PMID- 25796981 TI - Application of an LC-MS/MS method for the simultaneous quantification of human intestinal transporter proteins absolute abundance using a QconCAT technique. AB - Transporter proteins expressed in the gastrointestinal tract play a major role in the oral absorption of some drugs, and their involvement may lead to drug-drug interaction (DDI) susceptibility when given in combination with drugs known to inhibit gut wall transporters. Anticipating such liabilities and predicting the magnitude of the impact of transporter proteins on oral drug absorption and DDIs requires quantification of their expression in human intestine, and linking these to data obtained through in vitro experiments. A quantitative targeted absolute proteomic method employing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) together with a quantitative concatenation (QconCAT) strategy to provide proteotypic peptide standards has been applied to quantify ATP1A1 (sodium/potassium-ATPase; Na/K-ATPase), CDH17 (human peptide transporter 1; HPT1), ABCB1 (P-glycoprotein; P-gp), ABCG2 (breast cancer resistance protein; BCRP), ABCC2 (multidrug resistance-associated protein 2; MRP2) and SLC51A (Organic Solute Transporter subunit alpha; OST-alpha), in human distal jejunum (n=3) and distal ileum (n=1) enterocyte membranes. Previously developed selected reaction monitoring (SRM) schedules were optimised to enable quantification of the proteotypic peptides for each transporter. After harvesting enterocytes by calcium chelation elution and generating a total membrane fraction, the proteins were subjected to proteolytic digestion. To account for losses of peptides during the digestion procedure, a gravimetric method is also presented. The linearity of quantifying the QconCAT from an internal standard (correlation coefficient, R(2)=0.998) and quantification of all target peptides in a pooled intestinal quality control sample (R(2)>= 0.980) was established. The assay was also assessed for within and between-day precision, demonstrating a <15% coefficient of variation for all peptides across 3 separate analytical runs, over 2 days. The methods were applied to obtain the absolute abundances for all targeted proteins. In all samples, Na/K-ATPase, HPT1, P-gp and BCRP were detected above the lower limit of quantitation (i.e., >0.2 fmol/MUg membrane protein). MRP2 abundance could be quantified in distal jejunum but not in the distal ileum sample. OST alpha was not detected in 2 out of 3 jejunum samples. This study highlights the utility of a QconCAT strategy to quantify absolute transporter abundances in human intestinal tissues. PMID- 25796983 TI - Regular aspirin use and stomach cancer risk in China. AB - OBJECTIVE: Epidemiological studies on aspirin and stomach cancer have been inconclusive. The purpose of our study was to investigate the association between aspirin and stomach cancer in China. METHOD: A 1:2 matched case-control study was conducted in four large medical centers. A self-designed questionnaire was used to collect information. Unconditional logistic regression was used to compute crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULT: Our study indicated that risk of stomach cancer was greatly reduced for regular aspirin user (OR = 0.62; 95% CI 0.42-0.80). Specifically, dosage and tablet-years of use were associated with lower risk (OR = 0.54; 95% CI 0.29-0.84 for >=7 tabs/week; OR = 0.47; 95% CI 0.32-0.81 for >=10 tablet years, respectively). Furthermore, the finding was strengthened by stratified studies of gender, smoking status, body mass index (BMI) and helicobacter pylori. CONCLUSION: Our study confirmed that regular aspirin use is a protective factor to stomach cancer. PMID- 25796982 TI - Quality by Design approach in the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol and its impurities. AB - This study presents the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol, its endo-isomer and three impurities following Quality by Design (QbD) approach. The main objective of the method was to identify the conditions where adequate separation quality in minimal analysis duration could be achieved within a robust region that guarantees the stability of method performance. The relationship between critical process parameters (acetonitrile content in the mobile phase, pH of the water phase and ammonium acetate concentration in the water phase) and critical quality attributes is created applying design of experiments methodology. The defined mathematical models and Monte Carlo simulation are used to evaluate the risk of uncertainty in models prediction and incertitude in adjusting the process parameters and to identify the design space. The borders of the design space are experimentally verified and confirmed that the quality of the method is preserved in this region. Moreover, Plackett-Burman design is applied for experimental robustness testing and method is fully validated to verify the adequacy of selected optimal conditions: the analytical column ZIC HILIC (100 mm * 4.6 mm, 5 MUm particle size); mobile phase consisted of acetonitrile-water phase (72 mM ammonium acetate, pH adjusted to 6.5 with glacial acetic acid) (86.7:13.3) v/v; column temperature 25 degrees C, mobile phase flow rate 1 mL min(-1), wavelength of detection 254 nm. PMID- 25796984 TI - Robot-assisted surgery for gastric carcinoma: Five years follow-up and beyond: A single western center experience and long-term oncological outcomes. AB - INTRODUCTION: Robot-assisted surgery for the treatment of gastric cancer is considered to be safe and feasible with early post-operative outcomes comparable to open and laparoscopic series. However, data regarding long-term oncological outcomes are lacking. Aim of this study is to evaluate long-term oncological outcomes of a cohort of gastric cancer patients treated surgically with the robot assisted approach. MATERIALS AND METHODS: A prospectively collected database of robot-assisted gastrectomies performed for gastric cancer at the 'Misericordia Hospital' between September 2001 and October 2011 was retrospectively analysed. Data regarding surgical procedures, early postoperative course, and long-term follow-up were analysed. RESULTS: The study included 98 consecutive robot assisted gastrectomies. Fifty-nine distal gastrectomies, 38 total gastrectomies, and 1 proximal gastrectomy. Open conversion occurred in seven patients (7.1%) due to locally advanced disease. Postoperative morbidity and mortality were 12.2% and 4.1% respectively. Post-operative staging showed 46 patients (46.9%) with stage I disease, 25 patients (25.5%) with stage II, 26 (26.5%) with stage III and 1 (1.02%) with stage IV. The mean follow-up was 46.9 months. Cumulative 5-year overall survival (OS) was 73.3% (95% CI: 62.2-84.4). Five-year survival by stage subgroups was 100% for patients with stage IA, 84.6% for stage IB, 76.9% for stage II, and 21.5% for stage III. The only patient in stage IV of this series died eight months after surgery. CONCLUSIONS: Robot-assisted gastrectomy for the treatment of gastric cancer is safe and feasible. It provides long-term outcomes comparable to most open and laparoscopic series. Further studies are necessary to better define its indication. PMID- 25796986 TI - Randomized, double-blind, placebo-controlled study of the efficacy and safety of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen tablets for acute postoperative pain. AB - BACKGROUND: A fixed-dose combination biphasic immediate-release (IR)/extended release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) tablet is being developed for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate. METHODS: This Phase III, randomized, double-blind, placebo-controlled, parallel-group study evaluated the analgesic efficacy and safety of IR/ER HB/APAP (n = 201) versus placebo (n = 202) over a period of 48 hours in patients with acute moderate to severe pain following unilateral bunionectomy. Patients received three tablets of placebo or IR/ER HB/APAP as an initial dose (hour 0) followed by two tablets every 12 hours for a total daily dose of 37.5/1625 mg HB/APAP on day 1 and 30/1300 mg HB/APAP thereafter. The primary efficacy outcome was the summed pain intensity difference (SPID) over the first 48 hours (SPID48) after the first dose. RESULTS: SPID48 was significantly greater with IR/ER HB/APAP versus placebo (p < 0.001). SPID dosing interval analyses demonstrated consistent, superior pain relief with IR/ER HB/APAP for each dosing interval (all p < 0.001). Mean PID was greater with IR/ER HB/APAP versus placebo beginning 30 minutes after the first dose (p < 0.05), and IR/ER HB/APAP demonstrated faster median time to the onset of perceptible, meaningful, and confirmed pain relief (all p < 0.001). Mean total pain relief scores also indicated greater pain relief with IR/ER HB/APAP versus placebo throughout the 48-hour period (p = 0.012) for all comparisons. A greater proportion of IR/ER HB/APAP versus placebo patients was either "very satisfied" or "satisfied" with their pain relief (69.3% vs 49.4%; p < 0.001). Nausea was the most common treatment-emergent adverse event (TEAE; IR/ER HB/APAP, 25%; placebo, 7.9%). All TEAEs in IR/ER HB/APAP-treated patients were mild or moderate in severity. CONCLUSION: IR/ER HB/APAP provided rapid, significant, and consistent analgesic efficacy over a period of 48 hours in an established model of acute pain and was tolerated with a safety profile similar to other low-dose opioids. PMID- 25796985 TI - Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. AB - Cytokines play crucial roles in coordinating the activities of innate and adaptive immune systems. In response to pathogen recognition, innate immune cells secrete cytokines that inform the adaptive immune system about the nature of the pathogen and instruct naive T cells to differentiate into the appropriate T cell subtypes required to clear the infection. These include Interleukins, Interferons and other immune-regulatory cytokines that exhibit remarkable functional redundancy and pleiotropic effects. The focus of this review, however, is on the enigmatic Interleukin 12 (IL-12) family of cytokines. This family of cytokines plays crucial roles in shaping immune responses during antigen presentation and influence cell-fate decisions of differentiating naive T cells. They also play essential roles in regulating functions of a variety of effector cells, making IL 12 family cytokines important therapeutic targets or agents in a number of inflammatory diseases, such as the CNS autoimmune diseases, uveitis and multiple sclerosis. PMID- 25796987 TI - A long-lasting, single-dose nasal vaccine for Ebola: a practical armament for an outbreak with significant global impact. AB - In response to the severity and scale of the 2014 Ebola outbreak, several experimental vaccines were granted fast-track status for clinical testing. Although they may provide long-lasting protection from Ebola, they are, in their current states, far from optimal for populations that need them the most. In this context, nasal immunization addresses the: immune response required at the mucosa where Ebola initiates infection; needs of a population in terms of cost and compliance; and potency of each platform as they contain viruses that naturally infect the respiratory tract. Understanding the attributes of nasal immunization and its application will lead to potent vaccines that can effectively end Ebola and other emerging infectious diseases in developing and industrialized countries. PMID- 25796988 TI - Spatial evolutionary public goods game on complete graph and dense complex networks. AB - We study the spatial evolutionary public goods game (SEPGG) with voluntary or optional participation on a complete graph (CG) and on dense networks. Based on analyses of the SEPGG rate equation on finite CG, we find that SEPGG has two stable states depending on the value of multiplication factor r, illustrating how the "tragedy of the commons" and "an anomalous state without any active participants" occurs in real-life situations. When r is low (<<), the state with only loners is stable, and the state with only defectors is stable when r is high (>>). We also derive the exact scaling relation for r*. All of the results are confirmed by numerical simulation. Furthermore, we find that a cooperator dominant state emerges when the number of participants or the mean degree, , decreases. We also investigate the scaling dependence of the emergence of cooperation on r and . These results show how "tragedy of the commons" disappears when cooperation between egoistic individuals without any additional socioeconomic punishment increases. PMID- 25796989 TI - A novel method for the measurement of hepatitis C virus infectious titres using the IncuCyte ZOOM and its application to antiviral screening. AB - Hepatitis C virus (HCV) is a significant human pathogen infecting 3% of the world population. An infectious molecular clone capable of replicating and releasing infectious virions in cell culture has only been available since 2005, leaving a significant knowledge gap concerning post-RNA replication events such as particle assembly, trafficking and release. Thus, a fast, efficient and accurate method of measuring infectious viral titres is highly desirable. Current methods rely upon manual counting of infected cell foci and so are both labour-intensive and susceptible to human error. Here, we report a novel protocol, which utilises the IncuCyte ZOOM instrument and related software to accurately count infected cells and extrapolation of this data to produce an infectious titre, reported as infectious units per millilitre (IU/mL). This method reduces cost, time and error in experiments. We also demonstrate that this approach is amenable to high throughput compound screening, thereby expediting the identification of novel antivirals. PMID- 25796991 TI - The kinetics and mechanism of nanoconfined molten salt reactions: trimerization of potassium and rubidium dicyanamide. AB - This study highlights the effect of the aggregate state of a reactant on the reaction kinetics under the conditions of nanoconfinement. Our previous work (Phys. Chem. Chem. Phys., 2014, 16, 11409) has demonstrated considerable deceleration of the solid state trimerization of sodium dicyanamide in organically modified silica nanopores. In the present study we use FTIR, NMR, pXRD, TGA and DSC to analyze the kinetics and mechanism of the liquid state trimerization of potassium and rubidium dicyanamide under similar conditions of nanoconfinement. It is found that nanoconfinement accelerates dramatically the kinetics of the liquid state trimerization, whereas it does not appear to affect the reaction mechanism. Kinetic analysis indicates that the acceleration is associated with an increase in the preexponential factor. Although nanoconfinement has the opposite effects on the respective kinetics of solid and liquid state trimerization, both effects are linked to a change in the preexponential factor. The results obtained are consistent with our hypothesis that the effects differ because nanoconfinement may promote disordering of the solid and ordering of the liquid reaction media. PMID- 25796990 TI - Immunogenicity and virulence of attenuated vaccinia virus Tian Tan encoding HIV-1 muti-epitope genes, p24 and cholera toxin B subunit in mice. AB - No effective prophylactic or therapeutic vaccine against HIV-1 in humans is currently available. This study analyzes the immunogenicity and safety of a recombinant attenuated vaccinia virus. A chimeric gene of HIV-1 multi-epitope genes containing CpG ODN and cholera toxin B subunit (CTB) was inserted into Chinese vaccinia virus Tian Tan strain (VTT) mutant strain. The recombinant virus rddVTT(-CCMp24) was assessed for immunogenicity and safety in mice. Results showed that the protein CCMp24 was expressed stably in BHK-21 infected with rddVTT(-CCMp24). And the recombinant virus induced the production of HIV-1 p24 specific immunoglobulin G (IgG), IL-2 and IL-4. The recombinant vaccine induced gamma-interferon secretion against HIV peptides, and elicited a certain levels of immunological memory. Results indicated that the recombinant virus had certain immunogenicity to HIV-1. Additionally, the virulence of the recombinant virus was been attenuated in vivo of mice compared with wild type VTT (wtVTT), and the introduction of CTB and HIV Mp24 did not alter the infectivity and virulence of defective vaccinia virus. PMID- 25796992 TI - Acute kidney injury in survivors of surgery for severe traumatic brain injury: Incidence, risk factors, and outcome from a tertiary neuroscience center in India. AB - BACKGROUND: Non-neurological complications like acute kidney injury (AKI) can affect outcome of traumatic brain injury (TBI). This study aims to analyze the incidence, predictive factors, and impact of AKI in operated patients with severe TBI. METHODS: We retrospectively reviewed the data of 395 patients who underwent surgery for severe TBI and survived to be discharged from the hospital over a 1 year period. Of these, 95 patients were finally included in the analysis. Their demographic data, laboratory parameters, and clinical courses were reviewed. Diagnosis and staging of AKI was made using Acute Kidney Injury Network (AKIN) criteria. RESULTS: The incidence of AKI was 11.6% (11 patients). Out of the 11 patients who had AKI, 7 were in stage I (63.6%), 3 were in stage II (27.3%), and 1 in stage III (9.1%). Nine Patients (81.8%) developed AKI within 5 days of admission. Aminoglycoside therapy had an association with occurrence of AKI. There was no mortality and none of the patients required renal replacement therapy (RRT). Renal function of all these patients returned to baseline before hospital discharge. Hospital stay and intensive care unit (ICU) stay were longer and Glasgow coma scale (GCS) was lower in patients with AKI when compared with patients without AKI group at discharge. CONCLUSION: Reversible AKI without need for RRT occurred in nearly 12% of patients with severe TBI requiring surgical intervention. Aminoglycoside therapy was the only predictive factor for the occurrence of AKI. Patients with AKI have a longer period of mechanical ventilation, longer ICU and hospital stay, and poorer GCS at discharge. PMID- 25796993 TI - Are out-of-hospital cardiac arrest survival rates improving? PMID- 25796994 TI - Videographic assessment of cardiopulmonary resuscitation quality in the pediatric emergency department. AB - OBJECTIVE: To describe the adherence to guidelines for CPR in a tertiary pediatric emergency department (ED) where resuscitations are reviewed by videorecording. METHODS: Resuscitations in a tertiary pediatric ED are videorecorded as part of a quality improvement project. Patients receiving CPR under videorecorded conditions were eligible for inclusion. CPR parameters were quantified by retrospective review. Data were described by 30-s epoch (compression rate, ventilation rate, compression:ventilation ratio), by segment (duration of single providers' compressions) and by overall event (compression fraction). Duration of interruptions in compressions was measured; tasks completed during pauses were tabulated. RESULTS: 33 children received CPR under videorecorded conditions. A total of 650 min of CPR were analyzed. Chest compressions were performed at <100/min in 90/714 (13%) of epochs; 100-120/min in 309/714 (43%); >120/min in 315/714 (44%). Ventilations were 6-12 breaths/min in 201/708 (23%) of epochs and >12/min in 489/708 (70%). During CPR without an artificial airway, compression:ventilation coordination (15:2) was done in 93/234 (40%) of epochs. 178 pauses in CPR occurred; 120 (67%) were <10s in duration. Of 370 segments of compressions by individual providers, 282/370 (76%) were <2 min in duration. Median compression fraction was 91% (range 88-100%). CONCLUSIONS: CPR in a tertiary pediatric ED frequently met recommended parameters for compression rate, pause duration, and compression fraction. Hyperventilation and failure of C:V coordination were very common. Future studies should focus on the impact of training methods on CPR performance as documented by videorecording. PMID- 25796995 TI - Effects of in-hospital low targeted temperature after out of hospital cardiac arrest: A systematic review with meta-analysis of randomized clinical trials. AB - OBJECTIVE: We performed this systematic review to evaluate the effectiveness of in-hospital low targeted temperature in adult patients after out of hospital cardiac arrest on survival and neurologic performance. DATA SOURCE: We systematically searched MEDLINE and PUBMED from inception to April 2014. STUDY SELECTION: Citations were screened for studies evaluating the effect of in hospital low targeted temperature in patients following out of hospital cardiac arrest. DATA EXTRACTION: We analyzed randomized control trials (RCTs) that included adult patients resuscitated from out of hospital cardiac arrest, reporting mortality at hospital discharge and comparing in-hospital low targeted temperature with a control group. DATA SYNTHESIS: This meta-analysis included 6 RCTs and 1418 adult patients. In-hospital low targeted (low T) temperature was associated to a reduction in mortality at hospital discharge and at 6 months when compared with in-hospital targeted and not targeted temperature while there was no reduction in mortality comparing low and high targeted temperature. In patients with initial ventricular fibrillation/ventricular tachycardia rhythm of out of hospital cardiac arrest, low T was associated with a reduction in short and long-term mortality when compared with no targeted temperature while not when compared to high targeted temperature. Low T was associated with good neurologic performance at hospital discharge compared with in-hospital high or not targeted temperature. CONCLUSION: In-hospital low targeted temperature (<4 degrees C) improved short and long-term mortality when compared to no targeted temperature. In contrast, low T did not improve outcome compared with a slightly higher targeted temperature (~ 36 degrees C). PMID- 25796996 TI - Resuscitator's perceptions and time for corrective ventilation steps during neonatal resuscitation. AB - BACKGROUND: The 2010 neonatal resuscitation program (NRP) guidelines incorporate ventilation corrective steps (using the mnemonic--MRSOPA) into the resuscitation algorithm. The perception of neonatal providers, time taken to perform these maneuvers or the effectiveness of these additional steps has not been evaluated. METHODS: Using two simulated clinical scenarios of varying degrees of cardiovascular compromise--perinatal asphyxia with (i) bradycardia (heart rate- 40 min(-1)) and (ii) cardiac arrest, 35 NRP certified providers were evaluated for preference to performing these corrective measures, the time taken for performing these steps and time to onset of chest compressions. RESULTS: The average time taken to perform ventilation corrective steps (MRSOPA) was 48.9 +/- 21.4s. Providers were less likely to perform corrective steps and proceed directly to endotracheal intubation in the scenario of cardiac arrest as compared to a state of bradycardia. Cardiac compressions were initiated significantly sooner in the scenario of cardiac arrest 89 +/- 24 s as compared to severe bradycardia 122 +/- 23 s, p < 0.0001. There were no differences in the time taken to initiation of chest compressions between physicians or mid-level care providers or with the level of experience of the provider. CONCLUSIONS: Effective ventilation of the lungs with corrective steps using a mask is important in most cases of neonatal resuscitation. Neonatal resuscitators prefer early endotracheal intubation and initiation of chest compressions in the presence of asystolic cardiac arrest. Corrective ventilation steps can potentially postpone initiation of chest compressions and may delay return of spontaneous circulation in the presence of severe cardiovascular compromise. PMID- 25796997 TI - Evolution of European Union legislation on emergency research. AB - AIM: Emergency research is necessary to prevent exposure of patients to unvalidated clinical practice (nonmaleficence), and to improve the dismal prognosis of disorders requiring emergent treatment such as cardiac arrest (beneficence). Regulations that govern clinical research should conform to bioethical principles of respect for nonmaleficence, beneficence, autonomy, and justice. Our objectives are to review the evolution of European Union (EU) legislation on emergency research, and to identify potentially remaining problems. DATA SOURCES: EU legislative sources on clinical research and medical literature describing the impact of EU Regulations on emergency research. RESULTS: Article 5 of EU Directive 2001/20/EC required consent before enrolment in a research study to ensure the autonomy of potentially incapacitated research subjects. However, obtaining such consent is often impossible in emergency situations. Directive 2001/20/EC was criticized for potentially preventing emergency research. Several EU Member States addressed this problem by permitting deferred consent. International ethical guidelines supporting deferred consent were also cited by Good Clinical Practice Directive 2005/28/EC. However, Directive 2001/20/EC was not revised to achieve harmonization of EU emergency research, thus resulting in ongoing "ambiguity" as regards to emergency research legitimacy. This will be definitively addressed by applying EU Regulation No. 536/2014 and repealing Directive 2001/20/EC. The new EU Regulation permits using deferred consent under clearly specified conditions, and may foster emergency research that evaluates interventions posing minimal risk relative to standard practice. CONCLUSIONS: Legislation related to emergency research in Europe has evolved to increase concordance with bioethical principles so as to increase evidence-based improvements in emergency care. PMID- 25796998 TI - The Avalanche Victim Resuscitation Checklist, a new concept for the management of avalanche victims. PMID- 25796999 TI - Characterization and quantitative analysis of phenylpropanoid amides in eggplant (Solanum melongena L.) by high performance liquid chromatography coupled with diode array detection and hybrid ion trap time-of-flight mass spectrometry. AB - Eggplant (Solanum melongena L.) is a famous edible and medicinal plant. Despite being widely cultivated and used, data on certain parts other than the fruit are limited. The present study focused on the qualitative and quantitative analysis of the chemical constituents, particularly phenylpropanoid amides (PAs), in eggplant. The mass fragmentation patterns of PAs were proposed using seven authentic compounds with the assistance of a hybrid ion trap time-of-flight mass spectrometer. Thirty-seven compounds (27 PAs and 10 others) were detected and plausibly assigned in the different parts of eggplant. Afterward, a reliable method based on liquid chromatography coupled with diode array detection was developed, validated, and applied for the simultaneous determination of seven PAs and three caffeoylquinic acids in 17 batches of eggplant roots with satisfactory accuracy, precision, and reproducibility, which could not only provide global chemical insight of eggplant but also offer a reliable tool for quality control. PMID- 25797000 TI - A "special perspectives" issue: recent achievements and new directions in biomolecular solid state NMR. PMID- 25797002 TI - Mechanisms of dynamic nuclear polarization in insulating solids. AB - Dynamic nuclear polarization (DNP) is a technique used to enhance signal intensities in NMR experiments by transferring the high polarization of electrons to their surrounding nuclei. The past decade has witnessed a renaissance in the development of DNP, especially at high magnetic fields, and its application in several areas including biophysics, chemistry, structural biology and materials science. Recent technical and theoretical advances have expanded our understanding of established experiments: for example, the cross effect DNP in samples spinning at the magic angle. Furthermore, new experiments suggest that our understanding of the Overhauser effect and its applicability to insulating solids needs to be re-examined. In this article, we summarize important results of the past few years and provide quantum mechanical explanations underlying these results. We also discuss future directions of DNP and current limitations, including the problem of resolution in protein spectra recorded at 80-100 K. PMID- 25797001 TI - MAS NMR of HIV-1 protein assemblies. AB - The negative global impact of the AIDS pandemic is well known. In this perspective article, the utility of magic angle spinning (MAS) NMR spectroscopy to answer pressing questions related to the structure and dynamics of HIV-1 protein assemblies is examined. In recent years, MAS NMR has undergone major technological developments enabling studies of large viral assemblies. We discuss some of these evolving methods and technologies and provide a perspective on the current state of MAS NMR as applied to the investigations into structure and dynamics of HIV-1 assemblies of CA capsid protein and of Gag maturation intermediates. PMID- 25797003 TI - High-resolution proton-detected NMR of proteins at very fast MAS. AB - When combined with high-frequency (currently ~60 kHz) magic-angle spinning (MAS), proton detection boosts sensitivity and increases coherence lifetimes, resulting in narrow ((1))H lines. Herein, we review methods for efficient proton detected techniques and applications in highly deuterated proteins, with an emphasis on 100% selected ((1))H site concentration for the purpose of sensitivity. We discuss the factors affecting resolution and sensitivity that have resulted in higher and higher frequency MAS. Next we describe the various methods that have been used for backbone and side-chain assignment with proton detection, highlighting the efficient use of scalar-based ((13))C-((13))C transfers. Additionally, we show new spectra making use of these schemes for side-chain assignment of methyl ((13))C-((1))H resonances. The rapid acquisition of resolved 2D spectra with proton detection allows efficient measurement of relaxation parameters used as a measure of dynamic processes. Under rapid MAS, relaxation times can be measured in a site-specific manner in medium-sized proteins, enabling the investigation of molecular motions at high resolution. Additionally, we discuss methods for measurement of structural parameters, including measurement of internuclear ((1))H-((1))H contacts and the use of paramagnetic effects in the determination of global structure. PMID- 25797005 TI - NMR of sedimented, fibrillized, silica-entrapped and microcrystalline (metallo)proteins. AB - Resolution and sensitivity in solid state NMR (SSNMR) can rival the results achieved by solution NMR, and even outperform them in the case of large systems. However, several factors affect the spectral quality in SSNMR samples, and not all systems turn out to be equally amenable for this methodology. In this review we attempt at analyzing the causes of this variable behavior and at providing hints to increase the chances of experimental success. PMID- 25797006 TI - Spinning proteins, the faster, the better? AB - Magic-angle spinning (MAS) is a technique that is a prerequisite for high resolution solid-state NMR spectroscopy of proteins and other biomolecules. Recently, the 100 kHz limit for the rotation frequency has been broken, arguably making MAS rotors the man-made objects with the highest rotation frequency. This development is expected to have a significant impact on biomolecular NMR as it facilitates proton detection, which allows to partially compensate the loss in overall sensitivity associated with the small sample amounts that fit into MAS rotors with less than 1 mm outer diameter. Under these conditions, the mass normalized sensitivity of a small rotor becomes much higher than that of larger volume rotor. PMID- 25797004 TI - Structural studies of proteins by paramagnetic solid-state NMR spectroscopy. AB - Paramagnetism-based nuclear pseudocontact shifts and spin relaxation enhancements contain a wealth of information in solid-state NMR spectra about electron-nucleus distances on the ~20 A length scale, far beyond that normally probed through measurements of nuclear dipolar couplings. Such data are especially vital in the context of structural studies of proteins and other biological molecules that suffer from a sparse number of experimentally-accessible atomic distances constraining their three-dimensional fold or intermolecular interactions. This perspective provides a brief overview of the recent developments and applications of paramagnetic magic-angle spinning NMR to biological systems, with primary focus on the investigations of metalloproteins and natively diamagnetic proteins modified with covalent paramagnetic tags. PMID- 25797007 TI - Magic-angle spinning NMR of intact bacteriophages: insights into the capsid, DNA and their interface. AB - Bacteriophages are viruses that infect bacteria. They are complex macromolecular assemblies, which are composed of multiple protein subunits that protect genomic material and deliver it to specific hosts. Various biophysical techniques have been used to characterize their structure in order to unravel phage morphogenesis. Yet, most bacteriophages are non-crystalline and have very high molecular weights, in the order of tens of MegaDaltons. Therefore, complete atomic-resolution characterization on such systems that encompass both capsid and DNA is scarce. In this perspective article we demonstrate how magic-angle spinning solid-state NMR has and is used to characterize in detail bacteriophage viruses, including filamentous and icosahedral phage. We discuss the process of sample preparation, spectral assignment of both capsid and DNA and the use of chemical shifts and dipolar couplings to probe the capsid-DNA interface, describe capsid structure and dynamics and extract structural differences between viruses. PMID- 25797008 TI - Bottom-up and top-down solid-state NMR approaches for bacterial biofilm matrix composition. AB - The genomics and proteomics revolutions have been enormously successful in providing crucial "parts lists" for biological systems. Yet, formidable challenges exist in generating complete descriptions of how the parts function and assemble into macromolecular complexes and whole-cell assemblies. Bacterial biofilms are complex multicellular bacterial communities protected by a slime like extracellular matrix that confers protection to environmental stress and enhances resistance to antibiotics and host defenses. As a non-crystalline, insoluble, heterogeneous assembly, the biofilm extracellular matrix poses a challenge to compositional analysis by conventional methods. In this perspective, bottom-up and top-down solid-state NMR approaches are described for defining chemical composition in complex macrosystems. The "sum-of-the-parts" bottom-up approach was introduced to examine the amyloid-integrated biofilms formed by Escherichia coli and permitted the first determination of the composition of the intact extracellular matrix from a bacterial biofilm. An alternative top-down approach was developed to define composition in Vibrio cholerae biofilms and relied on an extensive panel of NMR measurements to tease out specific carbon pools from a single sample of the intact extracellular matrix. These two approaches are widely applicable to other heterogeneous assemblies. For bacterial biofilms, quantitative parameters of matrix composition are needed to understand how biofilms are assembled, to improve the development of biofilm inhibitors, and to dissect inhibitor modes of action. Solid-state NMR approaches will also be invaluable in obtaining parameters of matrix architecture. PMID- 25797009 TI - The contribution of solid-state NMR spectroscopy to understanding biomineralization: atomic and molecular structure of bone. AB - Solid-state NMR spectroscopy has had a major impact on our understanding of the structure of mineralized tissues, in particular bone. Bone exemplifies the organic-inorganic composite structure inherent in mineralized tissues. The organic component of the extracellular matrix in bone is primarily composed of ordered fibrils of collagen triple-helical molecules, in which the inorganic component, calcium phosphate particles, composed of stacks of mineral platelets, are arranged around the fibrils. This perspective argues that key factors in our current structural model of bone mineral have come about through NMR spectroscopy and have yielded the primary information on how the mineral particles interface and bind with the underlying organic matrix. The structure of collagen within the organic matrix of bone or any other structural tissue has yet to be determined, but here too, this perspective shows there has been real progress made through application of solid-state NMR spectroscopy in conjunction with other techniques. In particular, NMR spectroscopy has highlighted the fact that even within these structural proteins, there is considerable dynamics, which suggests that one should be cautious when using inherently static structural models, such as those arising from X-ray diffraction analyses, to gain insight into molecular roles. It is clear that the NMR approach is still in its infancy in this area, and that we can expect many more developments in the future, particularly in understanding the molecular mechanisms of bone diseases and ageing. PMID- 25797010 TI - Uncovering the triggers for GPCR activation using solid-state NMR spectroscopy. AB - G protein-coupled receptors (GPCRs) span cell membranes with seven transmembrane helices and respond to a diverse array of extracellular signals. Crystal structures of GPCRs have provided key insights into the architecture of these receptors and the role of conserved residues. However, the question of how ligand binding induces the conformational changes that are essential for activation remains largely unanswered. Since the extracellular sequences and structures of GPCRs are not conserved between receptor subfamilies, it is likely that the initial molecular triggers for activation vary depending on the specific type of ligand and receptor. In this article, we describe NMR studies on the rhodopsin subfamily of GPCRs and propose a mechanism for how retinal isomerization switches the receptor to the active conformation. These results suggest a general approach for determining the triggers for activation in other GPCR subfamilies using NMR spectroscopy. PMID- 25797011 TI - Multiple acquisition of magic angle spinning solid-state NMR experiments using one receiver: application to microcrystalline and membrane protein preparations. AB - Solid-state NMR spectroscopy of proteins is a notoriously low-throughput technique. Relatively low-sensitivity and poor resolution of protein samples require long acquisition times for multidimensional NMR experiments. To speed up data acquisition, we developed a family of experiments called Polarization Optimized Experiments (POE), in which we utilized the orphan spin operators that are discarded in classical multidimensional NMR experiments, recovering them to allow simultaneous acquisition of multiple 2D and 3D experiments, all while using conventional probes with spectrometers equipped with one receiver. POE allow the concatenation of multiple 2D or 3D pulse sequences into a single experiment, thus potentially combining all of the aforementioned advances, boosting the capability of ssNMR spectrometers at least two-fold without the addition of any hardware. In this perspective, we describe the first generation of POE, such as dual acquisition MAS (or DUMAS) methods, and then illustrate the evolution of these experiments into MEIOSIS, a method that enables the simultaneous acquisition of multiple 2D and 3D spectra. Using these new pulse schemes for the solid-state NMR investigation of biopolymers makes it possible to obtain sequential resonance assignments, as well as distance restraints, in about half the experimental time. While designed for acquisition of heteronuclei, these new experiments can be easily implemented for proton detection and coupled with other recent advancements, such as dynamic nuclear polarization (DNP), to improve signal to noise. Finally, we illustrate the application of these methods to microcrystalline protein preparations as well as single and multi-span membrane proteins reconstituted in lipid membranes. PMID- 25797012 TI - REDOR solid-state NMR as a probe of the membrane locations of membrane-associated peptides and proteins. AB - Rotational-echo double-resonance (REDOR) solid-state NMR is applied to probe the membrane locations of specific residues of membrane proteins. Couplings are measured between protein (13)CO nuclei and membrane lipid or cholesterol (2)H and (31)P nuclei. Specific (13)CO labeling is used to enable unambiguous assignment and (2)H labeling covers a small region of the lipid or cholesterol molecule. The (13)CO-(31)P and (13)CO-(2)H REDOR respectively probe proximity to the membrane headgroup region and proximity to specific insertion depths within the membrane hydrocarbon core. One strength of the REDOR approach is use of chemically-native proteins and membrane components. The conventional REDOR pulse sequence with 100 kHz (2)H pi pulses is robust with respect to the (2)H quadrupolar anisotropy. The (2)H T1's are comparable to the longer dephasing times (tau's) and this leads to exponential rather than sigmoidal REDOR buildups. The (13)CO-(2)H buildups are well-fitted to A*(1-e(-gammatau)) where A and gamma are fitting parameters that are correlated as the fraction of molecules (A) with effective (13)CO-(2)H coupling d=3gamma/2. The REDOR approach is applied to probe the membrane locations of the "fusion peptide" regions of the HIV gp41 and influenza virus hemagglutinin proteins which both catalyze joining of the viral and host cell membranes during initial infection of the cell. The HIV fusion peptide forms an intermolecular antiparallel beta sheet and the REDOR data support major deeply inserted and minor shallowly-inserted molecular populations. A significant fraction of the influenza fusion peptide molecules form a tight hairpin with antiparallel N- and C-alpha helices and the REDOR data support a single peptide population with a deeply-inserted N-helix. The shared feature of deep insertion of the beta and alpha fusion peptide structures may be relevant for fusion catalysis via the resultant local perturbation of the membrane bilayer. Future applications of the REDOR approach may include samples that contain cell membrane extracts and use of lower temperatures and dynamic nuclear polarization to reduce data acquisition times. PMID- 25797013 TI - On the problem of resonance assignments in solid state NMR of uniformly 15N,13C labeled proteins. AB - Determination of accurate resonance assignments from multidimensional chemical shift correlation spectra is one of the major problems in biomolecular solid state NMR, particularly for relative large proteins with less-than-ideal NMR linewidths. This article investigates the difficulty of resonance assignment, using a computational Monte Carlo/simulated annealing (MCSA) algorithm to search for assignments from artificial three-dimensional spectra that are constructed from the reported isotropic (15)N and (13)C chemical shifts of two proteins whose structures have been determined by solution NMR methods. The results demonstrate how assignment simulations can provide new insights into factors that affect the assignment process, which can then help guide the design of experimental strategies. Specifically, simulations are performed for the catalytic domain of SrtC (147 residues, primarily beta-sheet secondary structure) and the N-terminal domain of MLKL (166 residues, primarily alpha-helical secondary structure). Assuming unambiguous residue-type assignments and four ideal three-dimensional data sets (NCACX, NCOCX, CONCA, and CANCA), uncertainties in chemical shifts must be less than 0.4 ppm for assignments for SrtC to be unique, and less than 0.2 ppm for MLKL. Eliminating CANCA data has no significant effect, but additionally eliminating CONCA data leads to more stringent requirements for chemical shift precision. Introducing moderate ambiguities in residue-type assignments does not have a significant effect. PMID- 25797014 TI - Antisense oligonucleotides in therapy for neurodegenerative disorders. AB - Antisense oligonucleotides are synthetic single stranded strings of nucleic acids that bind to RNA and thereby alter or reduce expression of the target RNA. They can not only reduce expression of mutant proteins by breakdown of the targeted transcript, but also restore protein expression or modify proteins through interference with pre-mRNA splicing. There has been a recent revival of interest in the use of antisense oligonucleotides to treat several neurodegenerative disorders using different approaches to prevent disease onset or halt disease progression and the first clinical trials for spinal muscular atrophy and amyotrophic lateral sclerosis showing promising results. For these trials, intrathecal delivery is being used but direct infusion into the brain ventricles and several methods of passing the blood brain barrier after peripheral administration are also under investigation. PMID- 25797015 TI - Body concentrations of persistent organic pollutants and prostate cancer: a meta analysis. AB - There have been some concerns that persistent organic pollutants (POPs) may be associated with the risk of prostate cancer. Meta-analyses have not yet investigated the association between human-biomonitoring data for POPs and prostate cancer risk. The purpose of this study was to assess the association between body concentration of individual compounds or mixtures of POPs and prostate cancer risk in the general population by performing a meta-analysis. A literature search was performed using PubMed, EMBASE, and KoreaMed from the period 1950 through 2014. The odds ratio (OR) and its 95% confidence interval (CI) of prostate cancer associated with POPs were estimated using fixed-effects model or random-effects model where appropriate. Dose-response relationships were assessed by using the generalized least-squares method for trend estimation. A total of eight (six case-control, one cross-sectional, one nested case-control) studies including 1158 prostate cancer cases among 6932 subjects were selected for the meta-analysis. Total POPs of interest showed positive associations with statistical significance on prostate cancer (OR 1.31, 95% CI 1.13, 1.57). In dose response meta-analysis, 1 MUg/g lipid of PCBs was found to be associated with a 49% increased risk of prostate cancer (OR 1.49, 95% CI 1.07, 2.06). One nanogram per gram (1000 MUg/g) lipid of trans-nonachlor was found to be associated with approximately 2% increased risk of prostate cancer (OR = 1.02/1 ng/g lipid of trans-nonachlor, 95% CI 1.00, 1.03). The available evidence suggests that body concentrations of POPs are positively associated with prostate cancer risk, which implies valuable evidence for prostate cancer prevention. PMID- 25797016 TI - Human exposure and risk assessment associated with mercury contamination in artisanal gold mining areas in the Brazilian Amazon. AB - Mercury (Hg) contamination is an issue of concern in the Amazon region due to potential health effects associated with Hg exposure in artisanal gold mining areas. The study presents a human health risk assessment associated with Hg vapor inhalation and MeHg-contaminated fish ingestion, as well as Hg determination in urine, blood, and hair, of human populations (about 325 miners and 321 non miners) from two gold mining areas in the Brazilian Amazon (Sao Chico and Creporizinho, Para State). In Sao Chico and Creporizinho, 73 fish specimens of 13 freshwater species, and 161 specimens of 11 species, were collected for total Hg determination, respectively. The hazard quotient (HQ) is a risk indicator which defines the ratio of the exposure level and the toxicological reference dose and was applied to determine the threat of MeHg exposure. The mean Hg concentrations in fish from Sao Chico and Creporizinho were 0.83 +/- 0.43 and 0.36 +/- 0.33 MUg/g, respectively. More than 60 and 22 % of fish collected in Sao Chico and Creporizinho, respectively, were above the Hg limit (0.5 MUg/g) recommended by WHO for human consumption. For all sampling sites, HQ resulted from 1.5 to 28.5, except for the reference area. In Creporizinho, the values of HQ are close to 2 for most sites, whereas in Sao Chico, there is a hot spot of MeHg contamination in fish (A2-Sao Chico Reservoir) with the highest risk level (HQ = 28) associated with its human consumption. Mean Hg concentrations in urine, blood, and hair samples indicated that the miners group (in Sao Chico: urine = 17.37 MUg/L; blood = 27.74 MUg/L; hair = 4.50 MUg/g and in Creporizinho: urine = 13.75 MUg/L; blood = 25.23 MUg/L; hair: 4.58 MUg/g) was more exposed to mercury compared to non miners (in Sao Chico: urine = 5.73 MUg/L; blood = 16.50 MUg/L; hair = 3.16 MUg/g and in Creporizinho: urine = 3.91 MUg/L; blood = 21.04 MUg/L, hair = 1.88 MUg/g). These high Hg levels (found not only in miners but also in non-miners who live near the mining areas) are likely to be related to a potential hazard due to exposure to both Hg vapor by inhalation and to MeHg-contaminated fish ingestion. PMID- 25797017 TI - Morpho-anatomical and growth alterations induced by arsenic in Cajanus cajan (L.) DC (Fabaceae). AB - Arsenic (As) is a toxic element to most organisms. Studies investigating anatomic alterations due to As exposure in plants are scarce but of utmost importance to the establishment of environmental biomonitoring techniques. So, this study aimed to investigate the effects of As on the development and initial root growth in Cajanus cajan (Fabaceae), characterize and quantify the possible damages, evaluate genotoxic effects, and identify structural markers to be used in environmental bioindication. Plants were exposed hydroponically to 0.5, 1.0, 1.5, and 2.0 mg As L(-1), as sodium arsenate. Growth parameters were measured, and in the end of the exposure, root samples were analyzed for qualitative and quantitative anatomical alterations. Arsenic genotoxicity was evaluated through analysis of the mitotic index in the root apex. Compared to the control, As treated seedlings showed an altered architecture, with significantly decreased root length (due to the lower mitotic index in the apical meristem and reduced elongation of parenchyma cells) with darkened color, and abnormal development of the root cap. A significant increase in vascular cylinder/root diameter ratio was also detected, due to the reduction of the cellular spaces in the cortex. The secondary xylem vessel elements were reduced in diameter and had sinuous walls. The severest damage was visible in the ramification zone, where uncommon division planes of phellogen and cambium cells and disintegration of the parenchyma cells adjacent to lateral roots were observed. The high sensibility of C. cajan to As was confirmed, since it caused severe damages in root growth and anatomy. The main structural markers for As toxicity were the altered root architecture, with the reduction of the elongation zone and increase of ramification zone length, and the root primordia retained within the cortex. Our results show a new approach about As toxicity and indicate that C. cajan is a promising species to be used for bioindication of environmental contamination by As. PMID- 25797018 TI - Gene regulatory mechanisms orchestrated by p63 in epithelial development and related disorders. AB - The transcription factor p63 belongs to the p53 family and is a key regulator in epithelial commitment and development. Mutations in p63 give rise to several epithelial related disorders with defects in skin, limb and orofacial structures. Since the discovery of p63, efforts have been made to identify its target genes using individual gene approaches and to understand p63 function in normal epithelial development and related diseases. Recent genome-wide approaches have identified tens of thousands of potential p63-regulated target genes and regulatory elements, and reshaped the concept of gene regulation orchestrated by p63. These data also provide insights into p63-related disease mechanisms. In this review, we discuss the regulatory role of p63 in normal and diseased epithelial development in light of these novel findings. We also propose future perspectives for dissecting the molecular mechanism of p63-mediated epithelial development and related disorders as well as for potential therapeutic strategies. PMID- 25797019 TI - Ultrasound-guided percutaneous thrombin injection for post-catheterization pseudoaneurysm. AB - BACKGROUND: The efficacy and safety of ultrasound-guided thrombin injection (UGTI) for the treatment of post-catheterization femoral and brachial artery pseudoaneurysms (PSA) is unclear in Japan. METHODS AND RESULTS: A retrospective study of 32 consecutive patients undergoing percutaneous UGTI of post catheterization PSA between February 2011 and February 2014 was performed. There were 23 femoral PSA and 9 brachial PSA treated with UGTI. The prevalence of CAD and smoking history were higher in the brachial PSA patients, but there were no statistically significant differences in other patient demographic factors or in the preprocedural antiplatelet therapy between the femoral and brachial PSA patients. The median dose of thrombin injected was 200 U (range, 100-600 U). The initial success rate, early recurrence rate and surgical conversion rate were 91%, 0% and 4% in the femoral PSA, and 89%, 11% and 11% in the brachial PSA, respectively. There were 2 cases of medial nerve compression in the brachial PSA group, but there were no complications in the femoral PSA group (P=0.0198). On outpatient clinical follow-up in the successfully treated patients, there were no recurrences after an average follow-up of 16 months. CONCLUSIONS: UGTI is a feasible, safe and effective less-invasive treatment for post-catheterization PSA. Brachial PSA, however, might require additional attention because of their tendency toward higher recurrence and complications. PMID- 25797020 TI - Mitral regurgitation as the cause of atrial tachycardia - 3-dimensional mapping and 3-dimensional transesophageal echocardiography - . PMID- 25797021 TI - Transcatheter aortic valve-in-valve implantation for patients with degenerative surgical bioprosthetic valves. AB - Bioprosthetic tissue valves are increasingly utilized during surgical aortic valve replacement. These valves have limited durability and many fail with time, resulting in stenosis, regurgitation, or both. Repeat cardiac surgery has been the standard of care for patients with failed bioprostheses. Transcatheter valve implantation inside failed surgically implanted bioprostheses (valve-in-valve) is a new less invasive alternative to repeat surgery. We review the potential and challenges of valve-in-valve implantation in patients with failing surgical aortic bioprostheses. PMID- 25797022 TI - Scalable synthesis of freestanding sandwich-structured graphene/polyaniline/graphene nanocomposite paper for flexible all-solid-state supercapacitor. AB - We reported a scalable and modular method to prepare a new type of sandwich structured graphene-based nanohybrid paper and explore its practical application as high-performance electrode in flexible supercapacitor. The freestanding and flexible graphene paper was firstly fabricated by highly reproducible printing technique and bubbling delamination method, by which the area and thickness of the graphene paper can be freely adjusted in a wide range. The as-prepared graphene paper possesses a collection of unique properties of highly electrical conductivity (340 S cm(-1)), light weight (1 mg cm(-2)) and excellent mechanical properties. In order to improve its supercapacitive properties, we have prepared a unique sandwich-structured graphene/polyaniline/graphene paper by in situ electropolymerization of porous polyaniline nanomaterials on graphene paper, followed by wrapping an ultrathin graphene layer on its surface. This unique design strategy not only circumvents the low energy storage capacity resulting from the double-layer capacitor of graphene paper, but also enhances the rate performance and cycling stability of porous polyaniline. The as-obtained all solid-state symmetric supercapacitor exhibits high energy density, high power density, excellent cycling stability and exceptional mechanical flexibility, demonstrative of its extensive potential applications for flexible energy-related devices and wearable electronics. PMID- 25797024 TI - Aqueous benzene-diols react with an organic triplet excited state and hydroxyl radical to form secondary organic aerosol. AB - Chemical processing in atmospheric aqueous phases, such as cloud and fog drops, can play a significant role in the production and evolution of secondary organic aerosol (SOA). In this work we examine aqueous SOA production via the oxidation of benzene-diols (dihydroxy-benzenes) by the triplet excited state of 3,4 dimethoxybenzaldehyde, (3)DMB*, and by hydroxyl radical, OH. Reactions of the three benzene-diols (catechol (CAT), resorcinol (RES) and hydroquinone (HQ)) with (3)DMB* or OH proceed rapidly, with rate constants near diffusion-controlled values. The two oxidants exhibit different behaviors with pH, with rate constants for (3)DMB* increasing as pH decreases from pH 5 to 2, while rate constants with OH decrease in more acidic solutions. Mass yields of SOA were near 100% for all three benzene-diols with both oxidants. We also examined the reactivity of atmospherically relevant mixtures of phenols and benzene-diols in the presence of (3)DMB*. We find that the kinetics of phenol and benzene-diol loss, and the production of SOA mass, in mixtures are generally consistent with rate constants determined in experiments containing a single phenol or benzene-diol. Combining our aqueous kinetic and SOA mass yield data with previously published gas-phase data, we estimate a total SOA production rate from benzene-diol oxidation in a foggy area with significant wood combustion to be nearly 0.6 MUg mair(-3) h(-1), with approximately half from the aqueous oxidation of resorcinol and hydroquinone, and half from the gas-phase oxidation of catechol. PMID- 25797023 TI - A review of improved fixation methods for dental implants. Part II: biomechanical integrity at bone-implant interface. AB - PURPOSE: The purpose of this article is to review the mechanical requirements of the tissue-implant interface and analyze related theories. STUDY SELECTION: The osseointegration capacity of titanium implants has been investigated over the past 50 years. We considered the ultimate goal of osseointegration to which form a desirable interfacial layer and a bone matrix with adequate biomechanical properties. RESULTS: Occasionally, the interface comprises porous titanium and bone ingrowth that enables a functionally graded Young's modulus, thereby allowing reduction of stress shielding. However, the optimal biomechanical connection at the interface has not yet been fully clarified. There have been publications supporting several universal mechanical testing technologies in terms of bone-titanium bonding ability, although the separation of newly formed bone quality is unlikely. CONCLUSIONS: The understanding of complex mechanical bone behavior and size-dependent properties ranging from a nano- to a macroscopic level are essential in the biomechanical optimization of implants. The requirements of regenerated tissue at the interface include high strength, fracture toughness related to ductility, and time-dependent energy dissipation and/or elastic-plastic stress distribution. Moreover, a strong relationship between strain signals and peri-implant tissue turnover could be expected, so that ideal implant biomechanics may enable longevity via adaptive bone remodeling. PMID- 25797025 TI - Iguratimod for the treatment of rheumatoid arthritis in Japan. AB - Iguratimod (IGU), a small-molecule compound, was developed as a disease-modifying antirheumatic drug in Japan. The pharmacological studies showed that inhibition of the production of cytokines and immunoglobulins mainly contributes to its improvement effect on animal arthritis models. The first clinical study of IGU in Japanese patients with rheumatoid arthritis was started in 1992 and Phase III studies were started in 1998. From the results of Phase II studies, a dose escalating regimen was recommended to relieve the side effects. In a double-blind study comparing the efficacy and safety of the drug with those of placebo and salazosulfapyridine, it was confirmed that IGU was superior to placebo and was not inferior to salazosulfapyridine. Furthermore, a double-blind controlled trial of IGU in combination with methotrexate revealed an efficacious and manageable safety profile. IGU would be widely used as a new option for rheumatoid arthritis treatment and combination drug with methotrexate. PMID- 25797026 TI - Systemic Therapy for Psoriasis and the Risk of Herpes Zoster: A 500,000 Person year Study. AB - IMPORTANCE: The risk for herpes zoster (HZ) in patients with psoriasis treated with biologic medications or other systemic treatments has been given little attention to date. OBJECTIVE: To describe the risk for HZ in patients with psoriasis and its relation to treatment. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was performed using the administrative database of Clalit Health Services, the largest public health care provider organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. We extracted information for all patients who received a psoriasis diagnosis from January 2002 to June 2013. Follow-up was conducted until the end of July 2013. The study included 95,941 patients with psoriasis in the analysis, with 522,616 person-years of follow-up. Incidence of HZ events was calculated for each systemic antipsoriatic medication provided, during a follow-up period of 11 years and 7 months. We used a generalized estimating equation Poisson regression model to examine the effect of each systemic treatment for psoriasis on HZ incidence, adjusting for age, sex, psoriasis severity, Charlson comorbidity index, steroid treatment, and socioeconomic status. MAIN OUTCOMES AND MEASURES: Incidence of HZ associated with systemic therapies. RESULTS: In a multivariate analysis, it was observed that treatment with phototherapy (rate ratio [RR], 1.09 [95% CI, 0.62-1.93]; P = .99), methotrexate (RR, 0.98 [95% CI, 0.78-1.23]; P = .83), cyclosporine (RR, 1.16 [95% CI, 0.48-2.80]; P = .49), and biologic medications as a single agent (RR, 2.67 [95% CI, 0.69-10.3]; P = .14) was not associated with HZ. The use of combination treatment with biologic medications and methotrexate was significantly associated with an increased incidence of HZ (RR, 1.66 [95% CI, 1.08-2.57]; P = .02). The use of acitritin was associated with decreased incidence of HZ (RR, 0.69 [95% CI, 0.49-0.97]; P = .004). CONCLUSIONS AND RELEVANCE: Physicians may need to consider offering an HZ preventive vaccine to patients receiving combination treatment with biologic medications and methotrexate, particularly if they have additional risk factors for HZ. PMID- 25797027 TI - Should diffuse bronchiectasis still be considered a CFTR-related disorder? AB - BACKGROUND: Although several comprehensive studies have evaluated the role of the CFTR gene in idiopathic diffuse bronchiectasis (DB), it remains controversial. METHODS: We analyzed the whole coding region of the CFTR gene, its flanking regions and the promoter in 47 DB patients and 47 controls. Available information about demographic, spirometric, radiological and microbiological data for the DB patients was collected. Unclassified CFTR variants were in vitro functionally assessed. RESULTS: CFTR variants were identified in 24 DB patients and in 27 controls. DB variants were reclassified based on the results of in silico predictive analyses, in vitro functional assays and data from epidemiological and literature databases. Except for the sweat test value, no clear genotype phenotype correlation was observed. CONCLUSIONS: DB should not be considered a classical autosomal recessive CFTR-RD. Moreover, although further investigations are necessary, we proposed a new class of "Non-Neutral Variants" whose impact on lung disease requires more studies. PMID- 25797028 TI - The push and pull of grief: Approach and avoidance in bereavement. AB - BACKGROUND AND OBJECTIVES: Prolonged Grief (PG) is recognized as a post bereavement syndrome that is associated with significant impairment. Although approach and avoidance tendencies have both been hypothesized to play key roles in maintaining PG symptoms, understanding of these relationships has been limited by a reliance on self-report methodology. This study applies an experimental paradigm to simultaneously investigate the relationship between PG severity and approach-avoidance behavioral tendencies. METHODS: Fifty-five bereaved individuals with and without PG completed a behavioral measure of approach and avoidance responding in which they pulled or pushed a joystick in response to grief-related, positive, negative and neutral images that appeared on a computer screen. Concurrent visual feedback created the illusion that the images were either approaching or receding from the participant. Half of the participants also received a prime designed to activate their grief prior to the task. RESULTS: Irrespective of prime condition, PG participants pulled grief-related images more quickly than they pushed them. This difference was not observed in response to non-grief related images. Non PG participants showed no difference in their reaction times to grief-stimuli. LIMITATIONS: This study was undertaken in a nonclinical setting and the majority of participants had lost a loved one due to chronic illness. Future research with treatment-seeking populations and sudden loss will be needed to explore the generalizability of the findings. CONCLUSIONS: The findings from this study provide preliminary evidence supporting models of PG that integrate approach and avoidance tendencies. PMID- 25797029 TI - Cytotoxicity of cardiotonic steroids in sensitive and multidrug-resistant leukemia cells and the link with Na(+)/K(+)-ATPase. AB - Cardiotonic steroids have long been in clinical use for treatment of heart failure and are now emerging as promising agents in various diseases, especially cancer. Their main target is Na(+)/K(+)-ATPase, a membrane protein involved in cellular ion homeostasis. Na(+)/K(+)-ATPase has been implicated in cancer biology by affecting several cellular events and signaling pathways in both sensitive and drug-resistant cancer cells. Hence, we investigated the cytotoxic activities of 66 cardiotonic steroids and cardiotonic steroid derivatives in sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Data were then subjected to quantitative structure-activity relationship analysis (QSAR) and molecular docking into Na(+)/K(+)-ATPase, which both indicated a possible differential expression of the pump in the mentioned cell lines. This finding was confirmed by western blotting, intracellular potassium labeling and next generation sequencing which showed that Na(+)/K(+)-ATPase was less expressed in multidrug-resistant than in sensitive cells. PMID- 25797031 TI - New steps forward in the neuroactive steroid field. AB - Evidence accumulated in recent years suggests that the systemic treatment with neuroactive steroids, or the pharmacological modulation of its production by brain cells, represent therapeutic options to promote neuroprotection. However, new findings, which are reviewed in this paper, suggest that the factors to be considered for the design of possible therapies based on neuroactive steroids are more complex than previously thought. Thus, although as recently reported, the nervous system regulates neuroactive steroid synthesis and metabolism in adaptation to modifications in peripheral steroidogenesis, the neuroactive steroid levels in the brain do not fully reflect its levels in plasma. Even, in some cases, neuroactive steroid level modifications occurring in the nervous tissues, under physiological and pathological conditions, are in the opposite direction than in the periphery. This suggests that the systemic treatment with these molecules may have unexpected outcomes on neural steroid levels. In addition, the multiple metabolic pathways and signaling mechanisms of neuroactive steroids, which may change from one brain region to another, together with the existence of regional and sex differences in its neural levels are additional sources of complexity that should be clarified. This complexity in the levels and actions of these molecules may explain why in some cases these molecules have detrimental rather than beneficial actions for the nervous system. This article is part of a Special Issue entitled 'Steroid Perspectives'. PMID- 25797030 TI - A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice. AB - Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with alpha = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with alpha = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are likely to be mechanistic drivers behind the observed tumor growth suppression. PMID- 25797032 TI - Historical overview of nuclear receptors. AB - This review summarizes the birth of the field of nuclear receptors, from Jensen's discovery of estrogen receptor alpha, Gustafsson's discovery of the three-domain structure of the glucocorticoid receptor, the discovery of the glucocorticoid response element and the first partial cloning of the glucocorticoid receptor. Furthermore the discovery of the novel receptors called orphan receptors is described. PMID- 25797033 TI - Methylmercury effects on migratory behaviour in glass eels (Anguilla anguilla): an experimental study using isotopic tracers. AB - The effect of methylmercury (MeHg) on glass eels' propensity to migrate, mitochondrial activity and antioxidative defence systems was investigated. Marine glass eels were first sorted in an experimental flume according to their response to dusk. Fish responding to the decrease in light intensity by ascending in the water column and moving with or against the flow were considered as having a high propensity to migrate (migrant). Glass eels still sheltering at the end of the 24 h catching period were considered as having a low propensity to migrate and were called non-migrant. Migrant and non-migrant glass eels were then individually tagged and exposed to isotopically enriched (201)MeHg (50 ng L(-1)) for 11 days. The effect of contamination was studied on muscle fibre structure, and the expression level of genes involved in mitochondrial activity and antioxidative defence systems. To investigate the effect of MeHg on glass eel behaviour, migrant and non-migrant glass eels were sorted again and the bioaccumulation of (201)MeHg and its demethylation product ((201)Hg(II)) were determined for each individual. MeHg exposure increased activity in non-migrant glass eels but not migratory behaviour. Contamination affected mitochondrial structure and metabolism and suggests a higher oxidative stress and activation of antioxidative defence systems in non-migrant glass eels. Overall, our results suggest that exposure to MeHg might induce an increase in energy expenditure and a higher vulnerability to predation in non-migrant glass eels in the wild. PMID- 25797034 TI - Identification and functional characterization of AclB, a novel cell-separating enzyme from Lactobacillus casei. AB - Autolysis of nonstarter lactic acid bacteria (NSLAB) was favorable for the development of flavor compounds during cheese manufacture. Among these bacteria, Lb. casei was regarded as the most important microbiota involved in cheese processes. In this study, a novel autolysin named AclB was identified in the genome of Lb. casei BL23 and its modular structure was predicted through bioinformatic approaches. Subsequently, its transcription profile in the exponential phase, hydrolytic activities against cell walls, enzymatic properties under different conditions, physiological function via gene inactivation and upregulation assays, as well as potential applications to NSLAB's autolysis were fully investigated. According to the results, AclB was recognized as a species specific cell-separating enzyme, responsible for cell separation after cell division in Lb. casei BL23. The purified AclB showed considerable hydrolyzing activities towards cell walls, indicating its enzymatic nature as peptidoglycan hydrolase, or autolysin. The highest activity of AclB was determined at pH5.0 and 37 degrees C, and the expression vector constructed based on AclB was shown to facilitate the controlled lysis of Lb. casei BL23 hosts. In summary, this study provided insight into the enzymatic properties of a novel autolysin involved in cell separation of Lb. casei BL23, which is promising to accelerate cheese ripening and improve cheese quality. PMID- 25797035 TI - Heart rate variability shows different cardiovascular modulation in Parkinson's disease patients with tremor dominant subtype compared to those with akinetic rigid dominant subtype. AB - Parkinson's disease (PD) can present with different motor subtypes depending on the predominant symptoms (tremor or rigidity/bradykinesia). Slower disease progression and less cognitive decline are observed in tremor-dominant patients compared to those with akinetic-rigid subtype. Autonomic cardiovascular disorders have been described in parkinsonian patients, although the definite correlations with different subtypes of PD are not clear. In this context, heart rate variability (HRV) analysis represents a non-invasive and established tool in assessing cardiovascular autonomic modulation. We investigate cardiovascular autonomic modulation in PD patients with tremor dominant subtype in comparison to akinetic rigid dominant subtype subjects using HRV analysis. Twenty-eight PD patients (17 with tremor dominant subtype and 11 with akinetic rigid dominant subtype) were enrolled and compared to 17 age and sex-matched healthy controls. HRV was analyzed in time- and frequency-domains. Low-frequency (LF) values were significantly lower in the akinetic rigid dominant subtype than in the tremor dominant group [LF 41.4 +/- 13.6 vs 55.5 +/- 11.6 (p < 0.007)] indicating that the disease led to a more evident impairment of the baroreflex modulation of the autonomic outflow mediated by both sympathetic and parasympathetic systems in the first class of patients. These findings support the biological relevance of clinical subtypes supporting the idea of a different pathophysiological process between these subtypes. These differences also suggest that different subtypes may also result in different responses to therapy or in the possible development of cardiovascular side effects of dopaminergic drugs in these different populations. PMID- 25797036 TI - General CuBr2-catalyzed highly enantioselective approach for optically active allenols from terminal alkynols. AB - Here, we show a CuBr2-catalyzed approach for a highly enantioselective synthesis (93-99% ee) of allenols from aldehydes and terminal alkynols with the absolute configuration being controlled by applying readily available (R)- or (S) alpha,alpha-diphenylprolinol. PMID- 25797037 TI - Improving photo-controlled living radical polymerization from trithiocarbonates through the use of continuous-flow techniques. AB - Herein, we report simple flow reactor designs that enable photo-controlled living radical polymerization (photo-CRP) from trithiocarbonates (TTCs) with significant enhancements in scalability and reaction rates compared to the analogous batch reactions. We also demonstrate the "on/off" photo-switchability of this reaction under flow conditions. PMID- 25797038 TI - Unravelling the anomalous dielectric permittivity of nanoconfined electrolyte solutions. AB - The dielectric properties of sodium chloride solutions confined in a hydrophilic nanocavity were investigated by means of molecular dynamics simulations. Unlike what is observed in the bulk phase, three dielectric regimes were evidenced, namely an anomalous increase in the dielectric permittivity at low concentrations (with respect to confined pure water), a dielectric plateau at intermediate concentrations and finally a bulk-like behavior for salt concentrations higher than a critical value. It was shown that this peculiar behavior results from the competition between dielectric saturation due to the electric field generated by ions (which tends to lower the dielectric permittivity) and the ion-induced perturbation of pre-oriented water molecules inside the nanocavity which gain some rotational degrees of freedom (entropic contribution) leading to an increase in dipolar fluctuations responsible for the increase in the dielectric permittivity. PMID- 25797039 TI - Slug transcription factor and nuclear Lamin B1 are upregulated in osteoarthritic chondrocytes. AB - OBJECTIVE: To contribute to clarify molecular mechanisms supporting senescence and de-differentiation of chondrocytes in chondrocyte pathologies such as osteoarthritis (OA). Specifically, we investigated the relationship between the nuclear lamina protein Lamin B1 and the negative regulator of chondrogenesis Slug transcription factor in osteoarthritic chondrocytes. METHODS: Lamin B1 and Slug proteins were analyzed in cartilage explants from normal subjects and OA patients by immunohistochemical technique. Their expression was confirmed on isolated chondrocytes both at passage 0 and passage 2 (de-differentiated chondrocytes) by immunofluorescence and western blot. Subsequently, we explored the "in vivo" binding of Slug on LMNB1 promoter by chromatin immunoprecipitation assay (ChIP). RESULTS: In this study we demonstrated that nuclear lamina protein Lamin B1 and anti-chondrogenic Slug transcription factor are upregulated in cartilage and OA chondrocytes. Furthermore, we found that Slug is "in vivo" recruited by LMNB1 gene promoter mostly when chondrocytes undergo de-differentiation or OA degeneration. CONCLUSIONS: We described for the first time a potential regulatory role of Slug on the LMNB1 gene expression in OA chondrocytes. These findings may have important implications for the study of premature senescence, and degeneration of cartilage, and may contribute to develop effective therapeutic strategies against signals supporting cartilage damage in different subsets of patients. PMID- 25797040 TI - Phylogenetic analysis of avian paramyxovirus serotype-1 in pigeons in Japan. AB - To understand the epidemiology of Avian paramyxovirus serotype-1 (APMV-1) in pigeons in Japan, phylogenetic analysis was comprehensively conducted based on partial fusion protein gene using isolate from the surveillance of this virus with previously known Japanese pigeon strains. This surveillance was conducted using feces obtained from domestic pigeons collected in 40 prefectures throughout Japan from June 2011 to March 2013. From a total of 1,021 samples, a single virus (APMV1/pigeon/Japan/Kanagawa/2013: JP/Kanagawa-pg/2013) was isolated. All Japanese pigeon APMV-1 strains were clustered into a single genetic lineage, which was termed VIb/1 by phylogenetic analysis based on the F gene including the sequence of the cleavage site. These APMV-1 strains were further subdivided into four subgroups identified over 4 separate timeframes: 1984-1995 (group 1), 1995 2000 (group 2), 2001-2007 (group 3) and the novel subgroup isolated in 2013 (group 4). Each subgroup has specific amino acid motifs at a cleavage site of the F protein, namely, (112)GRQKR-F(117)(except for one strain), (112)RRKKR-F(117), (112)RRQKR-F(117) and (112)RRQKR-F(117), respectively. Our data suggest that Japanese APMV-1 strains from pigeons were diverse and reinforced the possibility that there were multiple introduction routes from foreign countries into Japan. PMID- 25797041 TI - Permeability-controlled optical modulator with Tri-gate metamaterial: control of permeability on InP-based photonic integration platform. AB - Metamaterials are artificially structured materials that can produce innovative optical functionalities such as negative refractive index, invisibility cloaking, and super-resolution imaging. Combining metamaterials with semiconductors enables us to develop novel optoelectronic devices based on the new concept of operation. Here we report the first experimental demonstration of a permeability-controlled waveguide optical modulator consisting of an InGaAsP/InP Mach-Zehnder interferometer with 'tri-gate' metamaterial attached on its arms. The tri-gate metamaterial consists of metal resonator arrays and triple-gate field effect elements. It changes its permeability with a change in the controlling gate voltage, thereby changing the refractive index of the interferometer arm to switch the modulator with an extinction ratio of 6.9 dB at a wavelength of 1.55 MUm. The result shows the feasibility of InP-based photonic integrated devices that can produce new functions by controlling their permeability as well as their permittivity. PMID- 25797042 TI - Validation and evaluation of the German version of the Systemic Lupus Activity Questionnaire (SLAQ). AB - OBJECTIVES: Disease activity accounts for damage, overall mortality and co morbidities in SLE and should frequently be assessed to adapt therapeutic patient management. The Systemic Lupus Activity Questionnaire (SLAQ) is a patient reported instrument for the assessment of disease activity derived from the Systemic Lupus Erythematosus Activity Measure (SLAM) and was originally developed in English. Our aim was to validate the SLAQ in German and evaluate its use in a large cohort. METHODS: We translated and adapted the SLAQ questionnaire in German. It was applied to SLE outpatients at a tertiary centre (n=328) and compared to the SLAMnolab and other SLE outcome parameters. Internal consistency, criterion validity, inter-rater and test-retest reliability as well as construct validity were examined. Correlation, Cronbach's alpha, Mann-Whitney U-test or the Kruskal-Wallis one-way analysis of variance test were ascertained where appropriate. Levels of statistical significance were defined at 5% (p<0.05). All reported p-values are two-tailed. RESULTS: The German SLAQ showed a comparable strong correlation with the SLAMnolab (r=0.632, p<0.0001) as the original version of the SLAQ and presented a good to excellent internal consistency reliability (Cronbach's alpha=0.89). Accrued damage as well as low disease activity are factors possibly influencing the score. Amongst others, scores were higher in patients with more reported flares, lower self-reported overall health, lower functional status and higher daily doses of prednisolone. CONCLUSIONS: Our German version of the SLAQ shows a comparable validity as the original SLAQ and is a promising instrument to survey disease activity in clinical routine as well as in clinical and epidemiological studies. Possible interacting factors need to be considered when applying. PMID- 25797043 TI - Failure of many United States Department of Health Web sites to provide accurate information about the female condom. AB - Uptake of the female condom (FC) in the United States has historically been low; inadequate promotion may be one barrier faced by potential users. We performed a content analysis of state and municipal health department Web sites to describe how the FC is being promoted for pregnancy and disease prevention. We found that only a slim majority (60.8%) of health department Web sites mention the FC at all and those that do include numerous inaccuracies in their messaging. These inaccuracies may discourage uptake of the FC or have a detrimental impact on the experience when using the product for the first time. PMID- 25797044 TI - Pharmacological activity of metal binding agents that alter copper bioavailability. AB - Iron, copper and zinc are required nutrients for many organisms but also potent toxins if misappropriated. An overload of any of these metals can be cytotoxic and ultimately lead to organ failure, whereas deficiencies can result in anemia, weakened immune system function, and other medical conditions. Cellular metal imbalances have been implicated in neurodegenerative diseases, cancer and infection. It is therefore critical for living organisms to maintain careful control of both the total levels and subcellular distributions of these metals to maintain healthy function. This perspective explores several strategies envisioned to alter the bioavailability of metal ions by using synthetic metal binding agents targeted for diseases where misappropriated metal ions are suspected of exacerbating cellular damage. Specifically, we discuss chemical properties that influence the pharmacological outcome of a subset of metal binding agents known as ionophores, and review several examples that have shown multiple pharmacological activities in metal-related diseases, with a specific focus on copper. PMID- 25797046 TI - PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling. AB - Proliferating cell nuclear antigen (PCNA), commonly known as a nuclear protein essential for regulation of DNA replication, DNA repair, and epigenetics, has recently been associated with multiple cytosolic functions. Many proteins containing one of the two known PCNA-interacting motifs, the AlkB homologue 2 PCNA interacting motif (APIM) and the PCNA-interacting peptide (PIP)-box, are considered to be mainly cytosolic. APIM is found in more than 20 kinases and/or associated proteins including several direct or indirect members of the mitogen activated protein kinase (MAPK) and PI3K/Akt pathways. Mass spectrometry analysis of PCNA-pull downs verified that many cytosolic proteins involved in the MAPK and PI3K/Akt pathways are in complex with PCNA. Furthermore, treatment of cells with a PCNA-interacting APIM-containing peptide (APIM-peptide) reduced Akt phosphorylation in human peripheral blood monocytes and a human keratinocyte cell line (HaCaT). Additionally, the APIM-peptide strongly reduced the cytokine secretion from monocytes stimulated with toll like receptor (TLR) ligands and potentiated the effects of MAPK and PI3K/Akt inhibitors. Interestingly, the protein level of the APIM-containing PKR/RIG-1 activator protein (PACT) was initially strongly reduced in HaCaT cells stimulated with APIM-peptide in combination with the TLR ligand polyinosinic-polycytidylic acid (polyIC). Our results suggest that PCNA has a platform role in cytosol affecting cellular signaling. PMID- 25797045 TI - High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression. AB - High glucose milieu inhibits PTEN expression to activate Akt kinase and induces glomerular mesangial cell hypertrophy and matrix protein expression in diabetic nephropathy. Specific mechanism by which high glucose inhibits PTEN expression is not clear. We found that high glucose increased the expression of the microRNA 26a (miR-26a) in mesangial cells. Using a sensor plasmid with 3'UTR-driven luciferase, we showed PTEN as a target of miR-26a in response to high glucose. Overexpression of miR-26a reduced the PTEN protein levels resulting in increased Akt kinase activity similar to high glucose treatment. In contrast, anti-miR-26a reversed high glucose-induced suppression of PTEN with concomitant inhibition of Akt kinase activity. Akt-mediated phosphorylation of tuberin and PRAS40 regulates mTORC1, which is necessary for mesangial cell hypertrophy and matrix protein expression. Inhibition of high glucose-induced miR-26a blocked phosphorylation of tuberin and PRAS40, which lead to suppression of phosphorylation of S6 kinase and 4EBP-1, two substrates of mTORC1. Furthermore, we show that expression of miR-26a induced mesangial cell hypertrophy and increased fibronectin and collagen I (alpha2) expression similar to that observed with the cells incubated with high glucose. Anti-miR-26a inhibited these phenomena in response to high glucose. Together our results provide the first evidence for the involvement of miR-26a in high glucose-induced mesangial cell hypertrophy and matrix protein expression. These data indicate the potential therapeutic utility of anti-miR-26a for the complications of diabetic kidney disease. PMID- 25797047 TI - Intersectin adaptor proteins are associated with actin-regulating protein WIP in invadopodia. AB - Invasive cancer cells form actin-rich membrane protrusions called invadopodia that degrade extracellular matrix and facilitate cell invasion and metastasis. WIP (WASP-interacting protein) together with N-WASP (neural Wiskott-Aldrich syndrome protein) are localized in invadopodia and play a crucial role in their formation. Here we show that WIP interacts with endocytic adaptor proteins of the intersectin (ITSN) family, ITSN1 and ITSN2. The interaction is mediated by the SH3 domains of ITSNs and the middle part of the WIP proline-rich motifs. We have also demonstrated that ITSN1, WIP and N-WASP can form a complex in cells. Endogenous ITSN1 and ITSN2 are located in invasive protrusions of MDA-MB-231 breast cancer cell line. Moreover, data from immunofluorescent analysis revealed co-localization of ITSN1 and WIP at sites of invadopodia formation and in clathrin-coated pits. Together, these findings provide insights into the molecular mechanisms of invadopodia formation and identify ITSNs as scaffold proteins involved in this process. PMID- 25797048 TI - Phosphatidylinositol-3,4,5-trisphosphate stimulates Ca(2+) elevation and Akt phosphorylation to constitute a major mechanism of thromboxane A2 formation in human platelets. AB - Phosphatidylinositol trisphosphate (PIP3) has been implicated in many platelet functions however many of the mechanisms need clarification. We have used cell permeable analogues of PIP3,1-O-(1,2-di-palmitoyl-sn-glyero-3-O-phosphoryl)-D-myo inositol-3,4,5-trisphosphate (DiC16-PIP3) or 1-O-(1,2-di-octanoyl-sn-glyero-3-O phosphoryl)-D-myo-inositol-3,4,5-trisphosphate (DiC8-PIP3) to study their effects on activation on washed human platelets. Addition of either DiC8- or DiC16-PIP3 to human platelets induced aggregation in the presence of extracellular Ca(2+). This was reduced by the presence of indomethacin, the phospholipase C inhibitor U73122 and apyrase. DiC8-PIP3 induced the phosphorylation of Akt-Ser(473) which was reduced by the Akt inhibitor IV, wortmannin and EGTA (suggesting a dependence on Ca(2+) entry). In Fura2 loaded platelets DiC8-PIP3 was effective at increasing intracellular Ca(2+) in a distinct and transient manner that was reduced in the presence of indomethacin, U73122 and 2-aminoethyl diphenylborinate (2APB). Ca(2+) elevation was reduced by the non-SOCE inhibitor LOE908 and also by the SOCE inhibitor BTP2. DiC8-PIP3 induced the release of Ca(2+) from stores which was not affected by the proton dissipating agent bafilomycin A1 and was more potent than the two-pore channel agonist DiC8-PI[3,5]P2 suggesting release from an endoplasmic reticulum type store. DiC8-PIP3 weakly induced the tyrosine phosphorylation of Syk but not of PLCgamma2. Finally like thrombin DiC8-PIP3 induced the formation of thromboxane B2 that was inhibited by the Akt inhibitor IV. These studies suggest that PIP3 via Ca(2+) elevation and Akt phosphorylation forms a central role in thromboxane A2 formation and the amplification of platelet activation. PMID- 25797049 TI - Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders. AB - BACKGROUND: Long-term symptomatic status in persons with major depressive and bipolar disorders treated clinically is not well established, although mood disorders are leading causes of disability worldwide. AIMS: To pool data on long term morbidity, by type and as a proportion of time-at-risk, based on published studies and previously unreported data. METHODS: We carried out systematic, computerized literature searches for information on percentage of time in specific morbid states in persons treated clinically and diagnosed with recurrent major depressive or bipolar I or II disorders, and incorporated new data from one of our centers. RESULTS: We analyzed data from 25 samples involving 2479 unipolar depressive and 3936 bipolar disorder subjects (total N=6415) treated clinically for 9.4 years. Proportions of time ill were surprisingly and similarly high across diagnoses: unipolar depressive (46.0%), bipolar I (43.7%), and bipolar II (43.2%) disorders, and morbidity was predominantly depressive: unipolar (100%), bipolar-II (81.2%), bipolar-I (69.6%). Percent-time-ill did not differ between UP and BD subjects, but declined significantly with longer exposure times. CONCLUSIONS: The findings indicate that depressive components of all major affective disorders accounted for 86% of the 43-46% of time in affective morbidity that occurred despite availability of effective treatments. These results encourage redoubled efforts to improve treatments for depression and adherence to their long-term use. PMID- 25797050 TI - Arachidonic acid has a dominant effect to regulate lipogenic genes in 3T3-L1 adipocytes compared to omega-3 fatty acids. AB - BACKGROUND: The effects of long-chain n-3 and n-6 polyunsaturated fatty acids (PUFA) on the regulation of adipocytes metabolism are well known. These fatty acids are generally consumed together in our diets; however, the metabolic regulation of adipocytes in the presence of these fatty acids when given together is not known. OBJECTIVE: To investigate the effects of n-3 PUFA and arachidonic acid (AA), an n-6 PUFA, on the regulation of adipogenic and lipogenic genes in mature 3T3-L1 adipocytes. METHODS: 3T3-L1 adipocytes were incubated in the presence or absence of 100 uM of eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; docosapentaenoic acid, DPA and AA, either alone or AA+n-3 PUFA; control cells received bovine serum albumin alone. The mRNA expression of adipogenic and lipogenic genes was measured. The fatty acid composition of adipocytes was analyzed using gas chromatography. RESULTS: Individual n-3 PUFA or AA had no effect on the mRNA expression of peroxisome-proliferator-activated receptor-gamma; however, AA+EPA and AA+DPA significantly increased (P<0.05) the expression compared to control cells (38 and 42%, respectively). AA and AA+EPA increased the mRNA expression of acetyl-CoA carboxylase 1 (P<0.05). AA treatment decreased the mRNA expression of stearoyl-CoA desaturase (SCD1) (P<0.01), while n 3 PUFA, except EPA, had no effect compared to control cells. AA+DHA and AA+DPA inhibited SCD1 gene expression (P<0.05) suggesting a dominant effect of AA. Fatty acids analysis of adipocytes revealed a higher accretion of AA compared to n-3 PUFA. CONCLUSIONS: Our findings reveal that AA has a dominant effect on the regulation of lipogenic genes in adipocytes. PMID- 25797051 TI - Changes in adolescents' and parents' intakes of sugar-sweetened beverages, fruit and vegetables after 20 months: results from the HEIA study - a comprehensive, multi-component school-based randomized trial. AB - BACKGROUND: Interventions conducted in school-aged children often involve parents, but few studies have reported effects on parents' own behaviour as a result of these interventions. OBJECTIVE: To determine if a multi-component, cluster randomized controlled trial targeting 11-13 year olds influenced their consumption of fruit, vegetables, sugar-sweetened soft drinks and fruit drinks, and to explore whether the results varied by gender, adolescent weight status or parental educational level. A final aim was to assess whether the parents' intakes were affected by the intervention. DESIGN: Participants were 1,418 adolescents, 849 mothers and 680 fathers. Baseline and post-intervention data from the 20 months intervention study HEIA (HEalth In Adolescents) were included. Data were collected assessing frequency (and amounts; beverages only). RESULTS: No significant differences were found at baseline between the intervention and control groups, except for the parental groups (educational level and intakes). At post-intervention, the adolescents in the intervention group consumed fruit more frequently (P<0.001) and had a lower intake of sugar-sweetened fruit drinks compared to the control group (P=0.02). The parental educational level moderated the effect on intake of sugar-sweetened fruit drinks in adolescents. The intake was less frequent in the intervention groups compared to the control groups (P=0.02) for those who had parents with low and medium educational level. Furthermore, the intervention may have affected mothers' fruit intake and the vegetable intake in higher educated fathers. CONCLUSION: Favourable effects in favour of the intervention group were found for intake of fruit and sugar sweetened fruit drinks among the adolescents in the HEIA study. Our results indicate that it is possible to reduce adolescents' intake of sugar-sweetened fruit drinks across parental education, and potentially affect sub-groups of parents. PMID- 25797052 TI - Photoligation of an amphiphilic polymer with mixed coordination provides compact and reactive quantum dots. AB - We introduce a new set of multicoordinating polymers as ligands that combine two distinct metal-chelating groups, lipoic acid and imidazole, for the surface functionalization of QDs. These ligands combine the benefits of thiol and imidazole coordination to reduce issues of thiol oxidation and weak binding affinity of imidazole. The ligand design relies on the introduction of controllable numbers of lipoic acid and histamine anchors, along with hydrophilic moieties and reactive functionalities, onto a poly(isobutylene-alt-maleic anhydride) chain via a one-step nucleophilic addition reaction. We further demonstrate that this design is fully compatible with a novel and mild photoligation strategy to promote the in situ ligand exchange and phase transfer of hydrophobic QDs to aqueous media under borohydride-free conditions. Ligation with these polymers provides highly fluorescent QDs that exhibit great long-term colloidal stability over a wide range of conditions, including a broad pH range (3-13), storage at nanomolar concentration, under ambient conditions, in 100% growth media, and in the presence of competing agents with strong reducing property. We further show that incorporating reactive groups in the ligands permits covalent conjugation of fluorescent dye and redox-active dopamine to the QDs, producing fluorescent platforms where emission is controlled/tuned by Forster Resonance Energy Transfer (FRET) or pH-dependent charge transfer (CT) interactions. Finally, the polymer-coated QDs have been coupled to cell penetrating peptides to facilitate intracellular uptake, while subsequent cytotoxicity tests show no apparent decrease in cell viability. PMID- 25797053 TI - Key-properties outlook of a levofloxacin-loaded acrylic bone cement with improved antibiotic delivery. AB - Antibiotic-loaded acrylic bone cements (ALABCs) are widely used to decrease the occurrence of bone infections in cemented arthroplasties and actually being considered as a more cost-effective procedure when compared to cementless implants. However, ALABCs have a major drawback, which is the incomplete release of the antibiotics and, as a result, pathogens that commonly are responsible for those infections are becoming resistant. Consequently, it is of most relevance to find new antibacterial agents to load into BC with an effective mechanism against those microorganisms. This research work intended to load levofloxacin, a fluoroquinolone with anti-staphylococcal activity and adequate penetration into osteoarticular tissues, on lactose-modified commercial bone cement (BC). This modified BC matrix exhibited increased levofloxacin release and delayed Staphylococcus aureus biofilm formation. Further insights on material-drug interaction during BC setting were investigated by density functional theory calculations. The obtained results suggested that favorable covalent and non covalent interactions could be established between levofloxacin and the BC. Moreover, BC mechanical and biocompatibility properties were maintained. These features justify the potential of levofloxacin-loaded modified-BC as a valuable approach for local antibiotic delivery in bone infections management. PMID- 25797054 TI - Evaluation of pharmacokinetic properties and anaesthetic effects of propofol in a new perfluorohexyloctane (F6H8) emulsion in rats--A comparative study. AB - Propofol (2,6-diisopropylphenol) is a safe and widely used anaesthetic, but due to low water solubility and high lipophilicity a difficult compound to formulate. The solubility of propofol in the semifluorinated alkane perfluorohexyloctane (F6H8) is very high (>300 mg/ml). In the present work we investigate if a F6H8 based emulsion could be used as a new intravenous drug delivery system for propofol from a pharmacokinetic, pharmacodynamic and safety point of view. The pharmacokinetic parameters were evaluated after an intravenous bolus injection of either Disoprivan((r)) or a F6H8-based propofol emulsion in Wistar rats. The onset and end of sedation after multiple dosings (5, 10 and 15 mg/kg bw) were examined. Clinical chemistry and histology were assessed. No significant difference was found for any of the pharmacokinetic parameters. No differences in the onset nor the end of sedation in the tested dosages could be detected. Histology scores revealed no differences. A slightly increased alanine aminotransferase (ALT) was measured after multiple application of the F6H8 propofol emulsion. In conclusion, the F6H8-propofol emulsion showed no significant different pharmacokinetics and sedation properties, compared to a commercial soy-based propofol emulsion. Further, no toxic effects could be detected on the F6H8 emulsion indicating it was a safe excipient in rats. PMID- 25797055 TI - Multivariate modelling to study the effect of the manufacturing process on the complete tablet dissolution profile. AB - Dissolution is invariably identified as a critical quality attribute for oral solid dosage forms, since it is related to when a drug is available for absorption and ultimately exert its effect. In this paper, the influence of granule and compression variability introduced by a design of experiments on the entire dissolution profile was studied with an innovative multivariate tool: bi directional projections to orthogonal structures (O2PLS). This method enabled a more holistic process understanding compared to conventional approaches where only a single response is used to quantify dissolution. The O2PLS analysis of tablet manufacturing data showed that the disintegration phase of dissolution (10 15 min) was controlled by granule attributes and tablet hardness, while the later phase (15-30 min) was solely controlled by granule attributes. The bidirectional nature of the O2PLS model made it more fit for exploratory purposes, but decreased predictive ability. This approach does not require prior knowledge on the dissolution mechanism and is therefore particularly suited for exploratory studies gaining process understanding during early phase development. The outcome can then guide the selection of attributes, parameters and their ranges for the development of predictive models, e.g., models to define a suitable design space for the process. PMID- 25797057 TI - Reforms of the Korean Medical Licensing Examination regarding item development and performance evaluation. AB - PURPOSE: The Korean Medical Licensing Examination (KMLE) has undergone a variety of innovative reforms implemented by the National Health Personnel Licensing Examination Board (NHPLEB) in order to make it a competency-based test. The purpose of this article is to describe the ways in which the KMLE has been reformed and the effect of those innovations on medical education in Korea. METHODS: Changes in the KMLE were traced from 1994 to 2014 by reviewing the adoption of new policies by the NHPLEB and the relevant literature. RESULTS: The most important reforms that turned the examination into a competency-based test were the following: First, the subjects tested on the exam were revised; second, R-type items were introduced; third, the proportion of items involving problem solving skills was increased; and fourth, a clinical skills test was introduced in addition to the written test. The literature shows that the above reforms have resulted in more rigorous licensure standards and have improved the educational environment of medical schools in Korea. CONCLUSION: The reforms of the KMLE have led to improvements in how the competency of examinees is evaluated, as well as improvements in the educational system in medical schools in Korea. PMID- 25797056 TI - Rapid, simple and inexpensive production of custom 3D printed equipment for large volume fluorescence microscopy. AB - The cost of 3D printing has reduced dramatically over the last few years and is now within reach of many scientific laboratories. This work presents an example of how 3D printing can be applied to the development of custom laboratory equipment that is specifically adapted for use with the novel brain tissue clearing technique, CLARITY. A simple, freely available online software tool was used, along with consumer-grade equipment, to produce a brain slicing chamber and a combined antibody staining and imaging chamber. Using standard 3D printers we were able to produce research-grade parts in an iterative manner at a fraction of the cost of commercial equipment. 3D printing provides a reproducible, flexible, simple and cost-effective method for researchers to produce the equipment needed to quickly adopt new methods. PMID- 25797058 TI - How undergraduate medical students reflect on instructional practices and class attendance: a case study from the Shifa College of Medicine, Pakistan. AB - The goal of this study was to assess student perceptions of a variety of instructional practices and attitudes toward class attendance. Data were obtained and analyzed by administering a questionnaire to students of the Shifa College of Medicine, Pakistan in 2011 and 2012. The subjects positively assessed most instructional practices, and in particular felt that teaching sessions conducted in small groups were more valuable than formal lectures in large groups. Students did not like having to give presentations, quizzes, panel discussions, and journal club. A positive correlation was found between the perceived importance of attendance and levels of academic motivation. Of the students surveyed, 11.8% were against mandatory attendance, saying that it reduced motivation and that attendance should be optional. In conclusion, the students had a positive perception of a range of instructional practices, and felt especially positively about practices that involve student activity in small groups. Programmatic improvement in instructional practices might increase class attendance. PMID- 25797060 TI - Successful prevention of varicella outbreak in an overcrowded paediatric oncology ward using oral acyclovir prophylaxis. PMID- 25797059 TI - Laboratory confirmation of clinically diagnosed malaria in a cohort of HIV infected mothers and their children in Malawi. AB - To avoid overdiagnosis, accuracy in the identification of true malaria cases is of critical importance. Samples (either whole blood, dried blood spots or plasma/serum) collected at the time of clinically diagnosed malaria episodes in a cohort of Malawian HIV-infected mothers and their children were retrospectively tested with the enzyme-linked immunosorbent assay (ELISA) for HRP-2 (histidine rich protein 2) detection. There were 55 and 56 clinically diagnosed cases of malaria in mothers and children, respectively, with samples available for testing. Rates of laboratory-confirmed episodes were 20% (11 of 55) in mothers and 16.1% (9 of 56) in children. Hemoglobin was lower in children with confirmed malaria compared to those with clinical malaria diagnosis. The results of our study support the widespread use of rapid diagnostic tests. PMID- 25797061 TI - Scaling drug indication curation through crowdsourcing. AB - Motivated by the high cost of human curation of biological databases, there is an increasing interest in using computational approaches to assist human curators and accelerate the manual curation process. Towards the goal of cataloging drug indications from FDA drug labels, we recently developed LabeledIn, a human curated drug indication resource for 250 clinical drugs. Its development required over 40 h of human effort across 20 weeks, despite using well-defined annotation guidelines. In this study, we aim to investigate the feasibility of scaling drug indication annotation through a crowdsourcing technique where an unknown network of workers can be recruited through the technical environment of Amazon Mechanical Turk (MTurk). To translate the expert-curation task of cataloging indications into human intelligence tasks (HITs) suitable for the average workers on MTurk, we first simplify the complex task such that each HIT only involves a worker making a binary judgment of whether a highlighted disease, in context of a given drug label, is an indication. In addition, this study is novel in the crowdsourcing interface design where the annotation guidelines are encoded into user options. For evaluation, we assess the ability of our proposed method to achieve high-quality annotations in a time-efficient and cost-effective manner. We posted over 3000 HITs drawn from 706 drug labels on MTurk. Within 8 h of posting, we collected 18 775 judgments from 74 workers, and achieved an aggregated accuracy of 96% on 450 control HITs (where gold-standard answers are known), at a cost of $1.75 per drug label. On the basis of these results, we conclude that our crowdsourcing approach not only results in significant cost and time saving, but also leads to accuracy comparable to that of domain experts. PMID- 25797062 TI - PTGBase: an integrated database to study tandem duplicated genes in plants. AB - Tandem duplication is a wide-spread phenomenon in plant genomes and plays significant roles in evolution and adaptation to changing environments. Tandem duplicated genes related to certain functions will lead to the expansion of gene families and bring increase of gene dosage in the form of gene cluster arrays. Many tandem duplication events have been studied in plant genomes; yet, there is a surprising shortage of efforts to systematically present the integration of large amounts of information about publicly deposited tandem duplicated gene data across the plant kingdom. To address this shortcoming, we developed the first plant tandem duplicated genes database, PTGBase. It delivers the most comprehensive resource available to date, spanning 39 plant genomes, including model species and newly sequenced species alike. Across these genomes, 54 130 tandem duplicated gene clusters (129 652 genes) are presented in the database. Each tandem array, as well as its member genes, is characterized in complete detail. Tandem duplicated genes in PTGBase can be explored through browsing or searching by identifiers or keywords of functional annotation and sequence similarity. Users can download tandem duplicated gene arrays easily to any scale, up to the complete annotation data set for an entire plant genome. PTGBase will be updated regularly with newly sequenced plant species as they become available. PMID- 25797063 TI - Phase transformation fabrication of a Cu2S nanoplate as an efficient catalyst for water oxidation with glycine. AB - The synthesis of semiconducting nanoplates (NPs) with defined crystal phase is of particular interest, especially their intriguing properties related to the size, shape, and crystal phase. Herein, a liquid-state transformation process from hexagonal-phase CuS NPs is employed to fabricate the cubic-phase Cu2S NPs. The CuS NPs were converted into Cu2S NPs but maintained the morphology. The Cu2S NPs exhibit better oxygen evolution reaction (OER) activity than CuS NPs. Furthermore, the OER activity of Cu2S NPs can be improved by the addition of a glycine (Gly) solution. The Cu2S NPs with Gly in a phosphate buffer solution exhibit excellent OER activity and durability, which approaches that of the best known commercial Ir/C (20%) nanocatalyst. In this work, a good strategy for fabricating a noble-metal-free OER catalyst has been proposed, which could provide insight into developing new water oxidation catalysts with high activity. PMID- 25797065 TI - Surfactants at the Design Limit. AB - This article analyzes how the individual structural elements of surfactant molecules affect surface properties, in particular, the point of reference defined by the limiting surface tension at the aqueous cmc, gammacmc. Particular emphasis is given to how the chemical nature and structure of the hydrophobic tails influence gammacmc. By comparing the three different classes of surfactants, fluorocarbon, silicone, and hydrocarbon, a generalized surface packing index is introduced which is independent of the chemical nature of the surfactants. This parameter phicmc represents the volume fraction of surfactant chain fragments in a surface film at the aqueous cmc. It is shown that phicmc is a useful index for understanding the limiting surface tension of surfactants and can be useful for designing new superefficient surfactants. PMID- 25797064 TI - Pharmacokinetics of antiretrovirals in mucosal tissue. AB - INTRODUCTION: In the absence of an HIV vaccine or cure, antiretroviral (ARV) based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site of HIV exposure, which is most commonly the mucosal tissue of the lower gastrointestinal tract and the female genital tract. AREAS COVERED: This article collates all known data regarding drug exposure in these vulnerable mucosal tissues and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing ARV pharmacokinetics (PK) in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE(r) or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport and endogenous hormones are also reviewed. EXPERT OPINION: ARVs exhibit highly variable PK in mucosal tissues. In general, ARV exposure is higher in the lower gastrointestinal tract compared with the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing ARV-based prevention strategies. PMID- 25797066 TI - [Effects of a long-term intervention in a work cafeteria on employee vegetable intake]. AB - OBJECTIVES: We examined the effects on employee vegetable intake of a long-term intervention in an employee work cafeteria. METHODS: The subjects were approximately 1,200 employees (aged 19-61 years) of an industrial company in Fukui prefecture. We promoted the intake of typical Japanese style meals that combined three elements (staple foods, main dishes and vegetable dishes) to increase vegetables intake. We displayed all items on the menus of the employee cafeteria using three colors (yellow, red and green to denote three elements) to indicate healthy food choices for the maintenance of a healthy food environment. We advised employees to choose meals containing the three elements at the time of payment, for nutritional education (appropriate portion choice: APC). We evaluated the ratio of APC at the same time. To calculate the mean daily intake per person, we carried out a questionnaire survey similar to the "semi quantitative food frequency questionnaire" and asked about the frequency and approximate intake of vegetables. RESULTS: The APC was 63.5% after one year of intervention, significantly increased to 82.1% after two years (p < 0.001), and was 80.0% after three years of intervention (p < 0.001). Vegetable intake at breakfast (p < 0.001), lunch (p < 0.001) and dinner (p = 0.011), and from vegetable juice (p = 0.030) significantly increased after three years of intervention. The consumption of pickles significantly decreased after three years of intervention (p = 0.009). It was estimated that the vegetable intake of men increased from 167.3 to 184.6 g, and that of women from 157.9 to 187.7 g. CONCLUSIONS: Employee estimated vegetable intake was significantly increased and that of pickles was significantly decreased by a long-term intervention (three years) in the employee work cafeteria. PMID- 25797067 TI - Early versus delayed rehabilitation following arthroscopic rotator cuff repair: A systematic review. AB - BACKGROUND: Early passive range of motion (ROM) following arthroscopic cuff repair is thought to decrease postoperative stiffness and improve functionality. However, early aggressive rehabilitation may compromise repair integrity. Our purpose was to perform a systematic review to determine if there are differences between early and delayed rehabilitation after arthroscopic rotator cuff repair in terms of clinical outcomes and healing. METHODS: We performed a literature search with the terms 'arthroscopic rotator cuff', 'immobilization', 'early', 'delayed', 'late', and 'rehabilitation' using PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Selection criteria included: level I/II evidence <= 6 months in duration, comparing early versus delayed rehabilitation following arthroscopic repair. Data regarding demographics, sample sizes, duration, cuff pathology, surgery, rehabilitation, functional outcomes, pain, ROM and anatomic assessment of healing were analyzed. PRIMSA criteria were followed. RESULTS: We identified six articles matching our criteria. Three reported significantly increased functional scores within the first 3-6 months with early rehabilitation compared to the delayed group, only one of which continued to observe a difference at a final follow-up of 15 months. Four articles showed improved ROM in the first 3-6 months post-operatively with early rehabilitation. One noted transient differences in pain scores. Only one study noted significant differences in ROM at final follow-up. No study reported any significant difference in rates of rotator cuff re-tear. However, two studies noted a trend towards increased re-tear with early rehabilitation that did not reach significance. This was more pronounced in studies including medium-large tears. CONCLUSIONS: Early rehabilitation after arthroscopic cuff repair is associated with some initial improvements in ROM and function. Ultimately, similar clinical and anatomical outcomes between groups existed at 1 year. While there was no significant difference between groups in anatomic failure of the repaired cuff, there may be a trend towards increased re-tear with larger tears. PMID- 25797068 TI - Increased plasma monocyte chemoattractant protein-1 levels in patients with isolated low high-density lipoprotein cholesterol. AB - BACKGROUND: High-density lipoprotein cholesterol (HDL-C) inhibits inflammation associated with the development of atherosclerotic plaques. Monocyte chemoattractant protein-1 (MCP-1) contributes to the pathogenesis of atherosclerosis. The aim of this study was to evaluate the relationship between plasma MCP-1 levels and low HDL-C levels in patients without cardiovascular disease (CVD). METHODS: This study included 55 patients with low HDL-C (<= 35 mg/dL) and 33 age- and sex-matched control subjects with normal HDL-C (? 35 mg/dL). In addition to MCP-1 levels, laboratory parameters associated with inflammation such as neutrophil-lymphocyte ratio (NLR), uric acid and high sensitivity C-reactive protein (hs-CRP) were also evaluated. RESULTS: HDL-C levels was significantly lower in study group compared to that of the control group (p < 0.001). MCP-1 were prominently higher in the low HDL-C group compared with those of the control group (p < 0.01). NLR, uric acid and hs-CRP levels were also higher in patients with low HDL-C than controls. CONCLUSION: These findings suggest that elevated plasma MCP-1 levels and inflammation status might be associated with the increased cardiovascular risk in patients with low HDL-C. PMID- 25797069 TI - New quinolinone alkaloids from chestnut (Castanea crenata Sieb) honey. AB - Two new quinolinone alkaloids and 13 known compounds were isolated from chestnut (Castanea crenata Sieb) honey. Two new compounds were determined to be 3-dihydro spiro[2(1H),3'(1'H)-diquinoline]-3',4,4'-trione (spirodiquinolinone) and 3-(2' piperidine)-kynurenic acid. In addition, 2,3-dihydropyrrolo[1,2-a]quinazolin 5(1H)-one was identified for the first time from nature. In addition, 2,3 dihydropyrrolo[1,2-a]quinazolin-5(1H)-one was newly identified from chestnut honey, although this compound has been synthesized before. The structures were determined by the NMR and electrospray ionization-mass spectroscopy (ESI-MS). Three compounds were qualified and quantitated in chestnut honey by selective multiple reaction monitoring (MRM) detection of LC-ESI-MS using the isolated compounds as external standards. PMID- 25797070 TI - Women's empowerment in agriculture and child nutritional status in rural Nepal. AB - OBJECTIVE: To examine the association between women's empowerment in agriculture and nutritional status among children under 2 years of age in rural Nepal. DESIGN: Cross-sectional survey of 4080 households conducted in 2012. Data collected included: child and maternal anthropometric measurements; child age and sex; maternal age, education, occupation and empowerment in agriculture; and household size, number of children, religion, caste and agro-ecological zone. Associations between the Women's Empowerment in Agriculture Index (WEAI)'s Five Domains of Empowerment (5DE) sub-index and its ten component indicators and child length-for-age Z-scores (LAZ) and weight-for-length Z-scores (WLZ) were estimated, using ordinary least-squares regression models, with and without adjustments for key child, maternal and household level covariates. SETTING: Two hundred and forty rural communities across sixteen districts of Nepal. SUBJECTS: Children under 24 months of age and their mothers (n 1787). RESULTS: The overall WEAI 5DE was positively associated with LAZ (beta=0.20, P=0.04). Three component indicators were also positively associated with LAZ: satisfaction with leisure time (beta=0.27, P<0.01), access to and decisions regarding credit (beta=0.20, P=0.02) and autonomy in production (beta=0.10, P=0.04). No indicator of women's empowerment in agriculture was associated with WLZ. CONCLUSIONS: Women's empowerment in agriculture, as measured by the WEAI 5DE and three of its ten component indicators, was significantly associated with LAZ, highlighting the potential role of women's empowerment in improving child nutrition in Nepal. Additional studies are needed to determine whether interventions to improve women's empowerment will improve child nutrition. PMID- 25797071 TI - Acute effects of Rho-kinase inhibitor fasudil on pulmonary arterial hypertension in patients with congenital heart defects. AB - BACKGROUND: We investigated the acute vasodilator effects of i.v. fasudil, a specific Rho-kinase inhibitor, on pulmonary circulation in patients with congenital heart defects (CHD) and severe pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Thirty-five patients (34.23+/-12.10 years old) with CHD and severe PAH were consecutively enrolled. All patients underwent heart catheterization. At baseline and 30 min after initiation of i.v. fasudil, the following hemodynamic parameters were measured and calculated: right atrial pressure, pulmonary and systemic artery pressure (PAP and SAP), pulmonary and systemic vascular resistance, pulmonary-to-systemic blood pressure ratio (Pp/Ps), pulmonary-to-systemic blood flow ratio (Qp/Qs), cardiac index (CI) and artery oxygen saturation (SaO2). After fasudil treatment, marked decrease in mean PAP (mPAP), pulmonary vascular resistance (PVR), total pulmonary resistance, pulmonary-to-systemic vascular resistance ratio (Rp/Rs) and mean Pp/Ps (mPp/Ps) was found, while Qp/Qs increased significantly without affecting CI and SAP. mPAP, PVR, Rp/Rs and Qp/Qs tended to be improved more significantly in the post tricuspid shunt group compared with the pre-tricuspid shunt group. CONCLUSIONS: Fasudil was well tolerated in patients with CHD and severe PAH, and significantly reduced PAP and PVR without affecting CI, SAP or SaO2. PMID- 25797073 TI - Contribution of mitochondria and endoplasmic reticulum dysfunction in insulin resistance: Distinct or interrelated roles? AB - Mitochondria and the endoplasmic reticulum (ER) regulate numerous cellular processes, and are critical contributors to cellular and whole-body homoeostasis. More important, mitochondrial dysfunction and ER stress are both closely associated with hepatic and skeletal muscle insulin resistance, thereby playing crucial roles in altered glucose homoeostasis in type 2 diabetes mellitus (T2DM). The accumulated evidence also suggests a potential interrelationship between alterations in both types of organelles, as mitochondrial dysfunction could participate in activation of the unfolded protein response, whereas ER stress could influence mitochondrial function. The fact that mitochondria and the ER are physically and functionally interconnected via mitochondria-associated membranes (MAMs) supports their interrelated roles in the pathophysiology of T2DM. However, the mechanisms that coordinate the interplay between mitochondrial dysfunction and ER stress, and its relevance to the control of glucose homoeostasis, are still unknown. This review evaluates the involvement of mitochondria and ER independently in the development of peripheral insulin resistance, as well as their potential roles in the disruption of organelle crosstalk at MAM interfaces in the alteration of insulin signalling. PMID- 25797074 TI - Electronic waste recovery in Finland: Consumers' perceptions towards recycling and re-use of mobile phones. AB - This paper examines consumers' awareness and perceptions towards mobile phone recycling and re-use. The results are based on a survey conducted in the city of Oulu, Finland, and analysed in the theoretical framework based on the theories of planned behaviour (TPB) and value-belief-norm (VBN). The findings indicate that consumers' awareness of the importance and existence of waste recovery system is high; however, awareness has not translated to recycling behaviour. The survey reveals that 55% of respondents have two or more unused mobile phones at homes. The more phones stored at homes, the more often reasons 'I don't know where to return' and/or 'have not got to do it yet' were mentioned. This indicates that proximity and the convenience of current waste management system are inadequate in promoting the return of small waste electrical and electronic equipment (WEEE). To facilitate re-use, and the highest level of recovery, consumers will need to be committed to return end-of-use electronics to WEEE collection centres without delays. Further, the supply and demand of refurbished mobile phones do not meet at this moment in Finland due to consumer's storing habits versus expectations of recent features under guarantee and unrealistic low prizes. The study also points out that, in order to change current storing habits of consumers, there is an explicit need for more information and awareness on mobile phone collection in Finland, especially on regarding retailers' take-back. PMID- 25797075 TI - Efficacy of Surgery and Further Treatment of Progressive Glioblastoma. AB - BACKGROUND: Treatment options for patients with glioblastoma at progression have remained controversial, and selection criteria for the appropriate type of intervention remain poorly defined. The objectives were to determine which factors favor the decision for second surgery and which factors are associated with overall survival (OS) and to evaluate the National Institutes of Health (NIH) recurrent glioblastoma scale. The scale includes tumor involvement of eloquent brain regions, functional status, and tumor volume. METHODS: A retrospective single-center analysis of patients with newly diagnosed glioblastoma undergoing initial surgery between January 2007 and December 2011 was performed. Patients were separated into two groups: those with versus those without second resection surgery at disease progression. OS was compared using the multiple logistic regression model, Cox proportional hazard regression, and Kaplan-Meier survival analysis. RESULTS: The data of 98 patients were statistically analyzed. Among the patients, 58 had initial surgery only (age 61.27 years; median OS [mOS] 14.81 months) and 40 underwent second surgery at disease progression (age 55 years; mOS 18.86 months). Age was the only predictor for repeated surgery (P = 0.012; odds ratio 0.94). At the time of tumor progression, administration of alkylating chemotherapy (P = 0.004; hazard ratio [HR] 0.24) or bevacizumab (P = 0.001; HR 0.23) was associated with longer OS. Reoperation was associated with a lower HR (P = 0.134; HR 0.66). The NIH recurrent glioblastoma scale showed statistically significant improvement of prognosis prediction with the addition of age. CONCLUSIONS: Surgery of progressive glioblastoma and postoperative treatment at the time of progression is associated with improved OS in some patients. The addition of age may improve survival prediction of the NIH recurrent glioblastoma scale. PMID- 25797072 TI - Emerging technologies for studying DNA methylation for the molecular diagnosis of cancer. AB - DNA methylation is an epigenetic mechanism that plays a key role in regulating gene expression and other functions. Although this modification is seen in different sequence contexts, the most frequently detected DNA methylation in mammals involves cytosine-guanine dinucleotides. Pathological alterations in DNA methylation patterns are described in a variety of human diseases, including cancer. Unlike genetic changes, DNA methylation is heavily influenced by subtle modifications in the cellular microenvironment. In all cancers, aberrant DNA methylation is involved in the alteration of a large number of oncological pathways with relevant theranostic utility. Several technologies for DNA methylation mapping have been developed recently and successfully applied in cancer studies. The scope of these technologies varies from assessing a single cytosine-guanine locus to genome-wide distribution of DNA methylation. Here, we review the strengths and weaknesses of these approaches in the context of clinical utility for the molecular diagnosis of human cancers. PMID- 25797076 TI - Fisher Grading Scale Associated with Language Disorders in Patients with Anterior Circulation Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: To associate the presence of language deficits with varying scores of the Fisher grading scale in patients with subarachnoid hemorrhage in the period preceding the treatment of aneurysm in the anterior circulation, as well as to compare the scores of this scale, identifying the grades more associated with the decline of language. METHODS: Database analysis of 185 preoperative evaluations of language, through the Montreal Toulouse Protocol Alpha version and verbal fluency through CERAD battery, of patients from "Hospital da Restauracao" with aneurysmal subarachnoid hemorrhage, divided according to the Fisher grading scale (Fisher I, II, III, or IV) and compared with a control group of individuals considered normal. RESULTS: The various scores of the Fisher grading scale have different levels of language deficits, more pronounced as the amount of blood increases. Fisher III and IV scores are most associated with the decline of language. CONCLUSIONS: Our study made it possible to obtain information not yet available in the literature, by correlating the various scores of the Fisher grading scale with language yet in the period preceding treatment. PMID- 25797078 TI - Primary Malignant Lymphoma of the Trigeminal Nerve: Case Report and Literature Review. AB - BACKGROUND: Primary lymphomas of the cranial nerves are extremely rare except for optic nerve lymphoma, and it is difficult to make a correct diagnosis in the initial stage. Here, we report a case of primary malignant lymphoma of the left trigeminal nerve that presented as trigeminal nerve disorder. CASE DESCRIPTION: A 47-year-old man presented with aggravating left facial pain and hypesthesia within all three divisions of the trigeminal nerve. Magnetic resonance imaging (MRI) revealed a swollen left trigeminal nerve with gadolinium homogenous enhancement. An open biopsy had to be taken from two different locations of the tumor via the lateral suboccipital approach followed by subtemporal approach because adequate specimen volume was not obtained for definitive diagnosis at the first surgery. Histopathological examinations with flow cytometric analysis revealed diffuse large B cell lymphoma. Chemotherapy followed by whole-brain radiation therapy was effective. No recurrence was observed during a 15-month follow-up period. CONCLUSIONS: This is a rare clinical presentation of malignant lymphoma of the trigeminal nerve. It is difficult to establish a correct diagnosis of trigeminal nerve lesions during the initial stages without biopsy. Therefore it is important that a sufficient specimen should be taken for biopsy without hesitation in order to diagnose and treat rapidly. The most suitable operative approach must be selected in trigeminal nerve lesions considering functional preservation, operative difficulty, preference of each surgeon, and quantity of specimen to be removed. PMID- 25797080 TI - Epithelial ovarian cancer and recreational physical activity: A review of the epidemiological literature and implications for exercise prescription. AB - Despite the publication of two dozen observational epidemiological studies investigating the association between recreational physical activity (RPA) and epithelial ovarian cancer (EOC) risk and survival over the past two decades, taken collectively, data from retrospective and prospective studies are mixed and remain inconclusive. OBJECTIVE: Our primary purpose was to conduct a careful review and summary of the epidemiological literature depicting the association between EOC and RPA in the framework of identifying factors which may be impeding our ability to observe consistent associations in the literature. Secondly, in the backdrop of the more broad scientific evidence regarding the benefits of RPA, we provide a summary of guidelines for practitioners to utilize in the context of exercise prescription for cancer patients, including a discussion of special considerations and contraindications to exercise which are unique to EOC patients and survivors. METHODS: We performed a comprehensive literature search via PubMed to identify epidemiologic investigations focused on the association between RPA and EOC. To be included in the review, studies had to assess RPA independently of occupational or household activities. RESULTS: In total, 26 studies were identified for inclusion. Evidence of a protective effect of RPA relative to EOC risk is more consistent among-case control studies, with the majority of studies demonstrating significant risk reductions between 30 and 60% among the most active women. Among cohort studies, half yielded no significant associations, while the remaining studies provided mixed evidence of an association. CONCLUSIONS: Given the limitations identified in the current body of literature, practitioners should not rely on inconclusive evidence to dissuade women from participating in moderate or vigorous RPA. Rather, emphasis should be placed on the greater body of scientific evidence which has demonstrated that RPA results in a plethora of health benefits that can be achieved in all populations, including those with cancer. PMID- 25797081 TI - Controlled removal of a large uterus within a bowel bag and morcellation in the bowel bag from the vagina. PMID- 25797079 TI - Exercise but not (-)-epigallocatechin-3-gallate or beta-alanine enhances physical fitness, brain plasticity, and behavioral performance in mice. AB - Nutrition and physical exercise can enhance cognitive function but the specific combinations of dietary bioactives that maximize pro-cognitive effects are not known nor are the contributing neurobiological mechanisms. Epigallocatechin-3 gallate (EGCG) is a flavonoid constituent of many plants with high levels found in green tea. EGCG has anti-inflammatory and anti-oxidant properties and is known to cross the blood brain barrier where it can affect brain chemistry and physiology. beta-Alanine (B-ALA) is a naturally occurring beta-amino acid that could increase cognitive functioning by increasing levels of exercise via increased capacity of skeletal muscle, by crossing the blood brain barrier and acting as a neurotransmitter, or by free radical scavenging in muscle and brain after conversion into carnosine. The objective of this study was to determine the effects of EGCG (~250mg/kg/day), B-ALA (~550mg/kg/day), and their combination with voluntary wheel running exercise on the following outcome measures: body composition, time to fatigue, production of new cells in the granule layer of the dentate gyrus of the hippocampus as a marker for neuronal plasticity, and behavioral performance on the contextual and cued fear conditioning tasks, as measures of associative learning and memory. Young adult male BALB/cJ mice approximately 2months old were randomized into 8 groups varying the nutritional supplement in their diet and access to running wheels over a 39day study period. Running increased food intake, decreased fat mass, increased time to exhaustive fatigue, increased numbers of new cells in the granule layer of the hippocampus, and enhanced retrieval of both contextual and cued fear memories. The diets had no effect on their own or in combination with exercise on any of the fitness, plasticity, and behavioral outcome measures other than B-ALA decreased percent body fat whereas EGCG increased lean body mass slightly. Results suggest that, in young adult BALB/cJ mice, a 39day treatment of exercise but not dietary supplementation with B-ALA or EGCG enhances measures of fitness, neuroplasticity and cognition. PMID- 25797082 TI - Primary surgery versus primary radiation therapy for FIGO stages I-II small cell carcinoma of the uterine cervix: A retrospective Taiwanese Gynecologic Oncology Group study. AB - OBJECTIVE: To evaluate the role of surgery, radiation therapy and chemotherapy in the management of small cell carcinoma of the uterine cervix (SCCC) through a retrospective study of Taiwanese Gynecologic Oncology Group. METHODS: We reviewed the medical records and histological files of 144 patients with FIGO stages IA IIB SCCC treated in 11 main hospitals in Taiwan from 1987 to 2009. RESULTS: There were 110 patients receiving primary surgery and 34 primary radiation therapy. Most patients in each group also received chemotherapy as part of primary treatment. A lower loco-regional failure rate was observed in patients who received primary radiation therapy than in those who had primary surgery (6% vs. 27%; P=0.009). The 5-year overall survival (OS) was 89% for 13 surgically treated patients with cervical tumor <=2cm and no lymphovascular space involvement (LVSI) in whom recurrence was noted in 2 of 4 patients without receiving adjuvant chemotherapy and none in the 9 patients who had chemotherapy. Excluding these 13 patients, primary radiation therapy with at least 5cycles of platinum-based chemotherapy (n=14, including 12 stages IB2-IIB) resulted in a 5-year OS of 78%, better than that of 46% by primary surgery (n=97, including 40 stages IB2-IIB) (P=0.046). CONCLUSIONS: None of the 9 patients with cervical tumor <=2cm and no LVSI showed disease recurrence after primary surgery and adjuvant chemotherapy. For most patients with stages I-II, primary radiation therapy with aggressive chemotherapy was associated with better survival than surgery. PMID- 25797083 TI - Assessing Diagnostic Tests I: You Can't Be Too Sensitive. AB - Clinicians and patients are always interested in less invasive, cheaper, and faster diagnostic tests. When introducing such a test, physicians must ensure that it is reliable in its diagnoses and does not commit errors. In this article, I discuss several ways that new tests are compared against gold standard diagnostics. PMID- 25797084 TI - American College of Foot and Ankle Surgeons' clinical consensus statement: risk, prevention, and diagnosis of venous thromboembolism disease in foot and ankle surgery and injuries requiring immobilization. AB - The purpose of this document is to provide guidance for physicians regarding the risk, prevention, and diagnosis of venous thromboembolism disease after foot and ankle surgery and while caring for lower extremity injuries that require ankle immobilization. A panel composed of all authors of this document reviewed the published evidence and, through a series of meetings, reached consensus regarding the viewpoints contained herein. We conclude that routine chemical prophylaxis is not warranted; rather, patients should be stratified and have a prevention plan tailored to their individual risk level. An effective venous thromboembolism prevention program is typically multimodal and focuses on addressing any modifiable risk factors, use of mechanical prophylaxis, early mobilization, and careful consideration of the use of chemical prophylaxis. The final decision regarding use and method(s) of prophylaxis adopted should be agreed upon by both the clinician and patient after a discussion of the potential benefits and harms as they relate to the individual. This should take place preferably during the preoperative visit or in the immediate post-injury setting, and it may need to be revisited during the course of care if the patient's risk level changes. Prompt recognition of the signs and symptoms of deep venous thrombosis following surgery or injury is important. Patients suspected of deep venous thrombosis should receive further work-up with either a D-dimer test or duplex venous ultrasound of the symptomatic leg, depending on their pretest probability for the disease. The latter can be determined using a validated clinical decision-making tool (e.g., Well's criteria). PMID- 25797085 TI - Implications of the Sunshine Act--revelations, loopholes, and impact. PMID- 25797086 TI - Re: Halford et al.: Detailed phenotypic and genotypic characterization of Bietti crystalline dystrophy (Ophthalmology 2014;121:1174-84). PMID- 25797087 TI - Re: Bajric et al.: Patient and physician perceptions of Medicare reimbursement policy for blepharoplasty and blepharoptosis surgery (Ophthalmology 2014;121:1474 9). PMID- 25797088 TI - Author reply: To PMID 24480711. PMID- 25797089 TI - Author reply: To PMID 24534753. PMID- 25797090 TI - Re: Gentile et al.: Microbiological spectrum and antibiotic sensitivity in endophthalmitis: a 25-year review (Ophthalmology 2014;121:1634-42). PMID- 25797091 TI - Author reply: To PMID 24702755. PMID- 25797092 TI - Re: Charlson et al.: Nocturnal systemic hypotension increases the risk of glaucoma progression (Ophthalmology 2014;121:2004-12). PMID- 25797094 TI - Cervical dural arteriovenous malformation and large epidural venous varices in a rare adult presentation of congenital vascular bone syndrome. AB - 61-year-old male presented with shortness of breath and chest pain. Workup for acute myocardial infarction was negative; however, computed tomography angiography visualized what a vascular malformation within the cervical spinal canal. Given the patient's history of Servelle-Martorell syndrome, neurovascular imaging was performed. We present the unique vascular findings of a right thyrocervical trunk-based dural arteriovenous malformation (dAVM) and a large epidural venous varix. The cervical dAVM induced intervertebral foraminal widening and polyradiculopathy, representing a rare adult case of congenital vascular bone syndrome. PMID- 25797093 TI - Author reply: To PMID 24869467. PMID- 25797095 TI - The "11K" gene family members sf68, sf95 and sf138 modulate transmissibility and insecticidal properties of Spodoptera frugiperda multiple nucleopolyhedrovirus. AB - The "11K" gene family is notable for having homologs in both baculoviruses and entomopoxviruses and is classified as either type 145 or type 150, according to their similarity with the ac145 or ac150 genes of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). One homolog of ac145 (sf138) and two homologs of ac150 (sf68 and sf95) are present in Spodoptera frugiperda multiple nucleopolyhedrovirus (SfMNPV). Recombinant bacmids lacking sf68, sf95 or sf138 (Sf68null, Sf95null and Sf138null, respectively) and the respective repair bacmids were generated from a bacmid comprising the complete virus genome. Occlusion bodies (OBs) of the Sf138null virus were ~15-fold less orally infective to insects, which was attributed to a 100-fold reduction in ODV infectious titer. Inoculation of insects with Sf138null OBs in mixtures with an optical brightener failed to restore the pathogenicity of Sf138null OBs to that of the parental virus, indicating that the effects of sf138 deletion on OB pathogenicity were unlikely to involve an interaction with the gut peritrophic matrix. In contrast, deletion of sf68 and sf95 resulted in a slower speed-of-kill by 9h, and a concurrent increase in the yield of OBs. Phylogenetic analysis indicated that sf68 and sf95 were not generated after a duplication event of an ancestral gene homologous to the ac150 gene. We conclude that type 145 genes modulate the primary infection process of the virus, whereas type 150 genes appear to have a role in spreading systemic infection within the insect. PMID- 25797096 TI - The RNA structurome: transcriptome-wide structure probing with next-generation sequencing. AB - RNA folds into intricate structures that enable its pivotal roles in biology, ranging from regulation of gene expression to ligand sensing and enzymatic functions. Therefore, elucidating RNA structure can provide profound insights into living systems. A recent marriage between in vivo RNA structure probing and next-generation sequencing (NGS) has revolutionized the RNA field by enabling transcriptome-wide structure determination in vivo, which has been applied to date to human cells, yeast cells, and Arabidopsis seedlings. Analysis of resultant in vivo 'RNA structuromes' provides new and important information regarding myriad cellular processes, including control of translation, alternative splicing, alternative polyadenylation, energy-dependent unfolding of mRNA, and effects of proteins on RNA structure. An emerging view suggests potential links between RNA structure and stress and disease physiology across the tree of life. As we discuss here, these exciting findings open new frontiers into RNA biology, genome biology, and beyond. PMID- 25797097 TI - The neural correlates of semantic richness: evidence from an fMRI study of word learning. AB - We investigated the neural correlates of concrete nouns with either many or few semantic features. A group of 21 participants underwent two days of training and were then asked to categorize 40 newly learned words and a set of matched familiar words as living or nonliving in an MRI scanner. Our results showed that the most reliable effects of semantic richness were located in the left angular gyrus (AG) and middle temporal gyrus (MTG), where activation was higher for semantically rich than poor words. Other areas showing the same pattern included bilateral precuneus and posterior cingulate gyrus. Our findings support the view that AG and anterior MTG, as part of the multimodal network, play a significant role in representing and integrating semantic features from different input modalities. We propose that activation in bilateral precuneus and posterior cingulate gyrus reflects interplay between AG and episodic memory systems during semantic retrieval. PMID- 25797098 TI - Decomposition, lookup, and recombination: MEG evidence for the full decomposition model of complex visual word recognition. AB - There is much evidence that visual recognition of morphologically complex words (e.g., teacher) proceeds via a decompositional route, first involving recognition of their component morphemes (teach + -er). According to the Full Decomposition model, after the visual decomposition stage, followed by morpheme lookup, there is a final "recombination" stage, in which the decomposed morphemes are combined and the well-formedness of the complex form is evaluated. Here, we use MEG to provide evidence for the temporally-differentiated stages of this model. First, we demonstrate an early effect of derivational family entropy, corresponding to the stem lookup stage; this is followed by a surface frequency effect, corresponding to the later recombination stage. We also demonstrate a late effect of a novel statistical measure, semantic coherence, which quantifies the gradient semantic well-formedness of complex words. Our findings illustrate the usefulness of corpus measures in investigating the component processes within visual word recognition. PMID- 25797099 TI - Phonology and arithmetic in the language-calculation network. AB - Arithmetic and language processing involve similar neural networks, but the relative engagement remains unclear. In the present study we used fMRI to compare activation for phonological, multiplication and subtraction tasks, keeping the stimulus material constant, within a predefined language-calculation network including left inferior frontal gyrus and angular gyrus (AG) as well as superior parietal lobule and the intraparietal sulcus bilaterally. Results revealed a generally left lateralized activation pattern within the language-calculation network for phonology and a bilateral activation pattern for arithmetic, and suggested regional differences between tasks. In particular, we found a more prominent role for phonology than arithmetic in pars opercularis of the left inferior frontal gyrus but domain generality in pars triangularis. Parietal activation patterns demonstrated greater engagement of the visual and quantity systems for calculation than language. This set of findings supports the notion of a common, but regionally differentiated, language-calculation network. PMID- 25797101 TI - Does neighborhood deprivation modify the effect of preterm birth on children's first grade academic performance? AB - Children's cognitive development and academic performance are linked to both fetal and early childhood factors, including preterm birth and family socioeconomic status. We evaluated whether the relationship between preterm birth (PTB) and first grade standardized test performance among Georgia public school students was modified by neighborhood deprivation in early childhood. The Georgia Birth to School cohort followed 327,698 children born in Georgia from 1998 to 2002 through to end-of-year first grade standardized tests. Binomial and log binomial generalized estimating equations were used to estimate risk differences and risk ratios for the associations of both PTB and the Neighborhood Deprivation Index for the census tract in which each child's mother resided at the time of birth with test failure (versus passing). The presence of additive and multiplicative interaction was assessed. PTB was strongly associated with test failure, with increasing risk for earlier gestational ages. There was positive additive interaction between PTB and neighborhood deprivation. The main effect of PTB versus term birth increased risk of mathematics failure: 15.9% (95%CI: 13.3 18.5%) for early, 5.0% (95% CI: 4.1-5.9%) for moderate, and 1.3% (95%CI: 0.9 1.7%) for late preterm. Each 1 standard deviation increase in neighborhood deprivation was associated with 0.6% increased risk of mathematics failure. For children exposed to both PTB and higher neighborhood deprivation, test failure was 4.8%, 1.5%, and 0.8% greater than the sum of two main effects for early, moderate, and late PTB, respectively. Results were similar, but slightly attenuated, for reading and English/language arts. Our results suggest that PTB and neighborhood deprivation additively interact to produce greater risk among doubly exposed children than would be predicted from the sum of the effects of the two exposures. Understanding socioeconomic disparities in the effect of PTB on academic outcomes at school entry is important for targeting of early childhood interventions. PMID- 25797100 TI - Puberty and perimenopause: reproductive transitions and their implications for women's health. AB - This scoping review synthesizes existing research on two major transitions in females' lives: puberty and perimenopause. These two periods of vast physiological change demarcate the beginning and the end of the reproductive life cycle and are associated with major neuroendocrine reorganization across two key systems, the hypothalamic-pituitary-gonadal (HPG) axis the hypothalamus-pituitary adrenal (HPA) axis. Despite growing evidence suggesting that the timing and experience of puberty and perimenopause are related to various physical and mental health outcomes (e.g., mood disorders, metabolism, cardiovascular health, autoimmune conditions, and cancer), these two processes are rarely examined together. In this paper, we bridge these disparate literatures to highlight similarities, isolate inconsistencies, and identify important areas for future research in women's health. PMID- 25797102 TI - The associations of anthropometric measurements with subsequent gestational diabetes in Aboriginal women. AB - PROBLEM: To evaluate the associations of different anthropometric measurements on earlier exam with subsequent gestational diabetes mellitus (GDM) in Aboriginal women. METHODS: This is a nested case-control study. Anthropometric measurements were conducted at baseline from 1992 to 1995 in a remote Aboriginal community. All subsequent pregnancies among the original participants were identified through review of hospital records of 20 years. Thirty-two women developed GDM and 99 women were hospitalised for pregnancy-related conditions other than GDM. The association between body mass index (BMI), weight, height, waist circumference, hip circumference, waist-to-hip ratio and waist-to-height ratio with subsequent GDM was examined. RESULTS: Our results showed an increased risk of GDM with increase in one standard deviation of BMI (OR=2.0; 95% CI: 1.3, 3.1), weight (OR=1.7; 95% CI: 1.1, 2.7), waist circumference (OR=1.8; 95% CI: 1.1, 3.0) and waist-to-height ratio (OR=2.3; 95% CI: 1.4, 3.9). High BMI (BMI>=25kg/m(2)) was associated with subsequent GDM (OR=2.8; 95% CI: 1.0, 7.8). CONCLUSIONS: BMI and waist-to-height ratio are better predictors than other anthropometric indices of GDM in Aboriginal women. Given that these measures are associated with future GDM, interventions to reduce BMI, weight and waist circumference in young women need to be assessed for their potential to prevent GDM. PMID- 25797103 TI - Effect of pH buffering capacity and sources of dietary sulfur on rumen fermentation, sulfide production, methane production, sulfate reducing bacteria, and total Archaea in in vitro rumen cultures. AB - The effects of three types of dietary sulfur on in vitro fermentation characteristics, sulfide production, methane production, and microbial populations at two different buffer capacities were examined using in vitro rumen cultures. Addition of dry distilled grain with soluble (DDGS) generally decreased total gas production, degradation of dry matter and neutral detergent fiber, and concentration of total volatile fatty acids, while increasing ammonia concentration. High buffering capacity alleviated these adverse effects on fermentation. Increased sulfur content resulted in decreased methane emission, but total Archaea population was not changed significantly. The population of sulfate reducing bacteria was increased in a sulfur type-dependent manner. These results suggest that types of dietary sulfur and buffering capacity can affect rumen fermentation and sulfide production. Diet buffering capacity, and probably alkalinity, may be increased to alleviate some of the adverse effects associated with feeding DDGS at high levels. PMID- 25797104 TI - Testing the S-R link hypothesis of P3b: The oddball effect on S1-evoked P3 gets reduced by increased task relevance of S2. AB - We had previously reported that the oddball effect on the P3b EEG potential evoked by infrequent vs. frequent S1 presented in a sequence of two stimuli, S1 and S2, gets reduced in a "combination task". In this task, responses were determined by the combinations of S1 and S2 rather than by S1 only. We had attributed this reduction of the oddball effect to increased task difficulty. The present study investigated possible reasons for this reduction of S1-evoked P3b in more detail, by making the combination task easier in several respects: allowing for forming associations from S1 to responses (Experiment 1), reducing the complexity of stimulus-response (S-R) mappings (Experiment 2), and decreasing S2 relevance in defining responses (Experiment 3). The results showed that only S2 relevance affected the oddball effect on S1-evoked P3b. Namely, when S2 attained some relevance by inducing a go/no-go decision for S1-defined responses, the oddball effect on S1-evoked P3b was intermediate between the large effect in the simple oddball task and the small effect in the combination task. The results may be explained in terms of the S-R link hypothesis of P3b which interprets P3b as reflecting reactivation of well-established S-R links. PMID- 25797105 TI - [Treatment of syphilis in Morocco in the early 20th century]. PMID- 25797106 TI - [Rare cause of symptomatic lumbosciatica: Pelvic bone hydatidosis]. PMID- 25797107 TI - Relationship between methanogenic archaea and subgingival microbial complexes in human periodontitis. AB - We compared the amounts of methanogenic archaea with ten of the most important periodontal pathogens in 125 clinical samples. Correlation analysis suggests that the support of the periodontitis-associated bacterial consortium by methanogenic archaea may be driven through direct or indirect interactions with Prevotella intermedia. PMID- 25797108 TI - Ultrasonography of ovarian masses using a pattern recognition approach. AB - As a primary imaging modality, ultrasonography (US) can provide diagnostic information for evaluating ovarian masses. Using a pattern recognition approach through gray-scale transvaginal US, ovarian masses can be diagnosed with high specificity and sensitivity. Doppler US may allow ovarian masses to be diagnosed as benign or malignant with even greater confidence. In order to differentiate benign and malignant ovarian masses, it is necessary to categorize ovarian masses into unilocular cyst, unilocular solid cyst, multilocular cyst, multilocular solid cyst, and solid tumor, and then to detect typical US features that demonstrate malignancy based on pattern recognition approach. PMID- 25797109 TI - GRPR-selective PET imaging of prostate cancer using [(18)F]-lanthionine-bombesin analogs. AB - The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of human malignancies, including prostate cancer. Bombesin (BBN) is a 14 amino acids peptide that selectively binds to GRPR. In this study, we developed two novel Al(18)F-labeled lanthionine-stabilized BBN analogs, designated Al(18)F-NOTA-4,7 lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN, for positron emission tomography (PET) imaging of GRPR expression using xenograft prostate cancer models. (Methyl)lanthionine-stabilized 4,7-lanthionine-BBN and 2,6-lanthionine BBN analogs were conjugated with a NOTA chelator and radiolabeled with Al(18)F using the aluminum fluoride strategy. Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN was labeled with Al(18)F with good radiochemical yield and specific activity>30 GBq/MUmol for both radiotracers. The logD values measured for Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine BBN were -2.14 +/- 0.14 and -2.34 +/- 0.15, respectively. In athymic nude PC-3 xenografts, at 120 min post injection (p.i.), the uptake of Al(18)F-NOTA-4,7 lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN in prostate cancer (PC-3) mouse models was 0.82 +/- 0.23% ID/g and 1.40 +/- 0.81% ID/g, respectively. An excess of unlabeled E-aminocaproic acid-BBN(7-14) (300-fold) was co-injected to assess GRPR binding specificity. Tumor uptake of Al(18)F-NOTA-4,7-lanthionine-BBN and Al(18)F-NOTA-2,6-lanthionine-BBN in PC-3 tumors was evaluated by microPET (MUPET) imaging at 30, 60 and 120 min p.i. Blocking studies showed decreased uptake in PC-3 bearing mice. Stabilized 4,7-lanthionine-BBN and 2,6-lanthionine BBN peptides were rapidly and successfully labeled with (18)F. Both tracers may have potential for GRPR-positive tumor imaging. PMID- 25797110 TI - Relationship of Neutrophil-to-Lymphocyte Ratio with Aortic Stiffness in Type 1 Diabetes Mellitus. AB - OBJECTIVES: Emerging evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) may be a useful marker of inflammation and aortic stiffness. Markers of inflammation and aortic stiffness are both indicators of cardiovascular events. We, therefore, investigated whether the NLR is associated with aortic stiffness in patients with type 1 diabetes mellitus. METHODS: We examined the relationship of the NLR to aortic stiffness in 76 people with type 1 diabetes and 36 healthy controls. RESULTS: The NLRs in the group with type 1 diabetes were higher than in the controls (2.33+/-0.95 vs. 1.80+/-0.68, respectively; p=0.003). Aortic strain and aortic distensibility, the parameters of aortic stiffness, measured noninvasively by the help of echocardiography, were significantly decreased in the patient group compared to controls (8.0%+/-1.5% vs. 13.1%+/-3.3 %; p<0.001 and 3.6+/-1.1 cm(2).dyn(-1).10(-3) vs. 6.0+/-2.1 cm(2).dyn(-1).10(-3); p<0.001, respectively). There were negative correlations between NLR and distensibility (r: -0.40; p<0.001) and strain (r: -0.57; p<0.001) in patients with type 1 diabetes. CONCLUSIONS: We have demonstrated that there is a significant negative correlation between the NLR and markers of aortic stiffness in patients with type 1 diabetes, indicating a potential association between inflammation and arterial stiffness. Accordingly, a higher NLR may be a useful additional measure in determining the cardiovascular risks of patients with type 1 diabetes in our clinical practice. PMID- 25797111 TI - Patients' Perspectives on Wait Times and the Referral-Consultation Process While Attending a Tertiary Diabetes and Endocrinology Centre: Is Econsultation an Acceptable Option? AB - The goal of this study was to establish patients' perspectives on the acceptability of wait times, the impact of wait times on their health and the possibility of using electronic consultations (eConsultations) to avoid visits to specialists. A 2-stage patient survey (self-administered and with a follow-up telephone call) and a chart audit was conducted on a sequential sample of patients attending their initial consultations in a tertiary diabetes and endocrinology centre. Patients' perspectives on actual and ideal wait times, the impact of waiting for access, the effectiveness of the referral-consultation process and attitudes toward eConsultations as an alternative to traditional referral-consultations were collected. The study involved 101 patients (22% for diabetes, 78% for endocrinologic conditions), whose comments were collated and categorized. Of the 101 patients who completed the survey, 61 also completed telephone interviews. The average wait time was 19 weeks; the median 10 weeks. More than 30% of patients waited longer than 6 months and 6% waited longer than 1 year. Overall, 90% of patients thought that the maximum wait time should be less than 3 months. While waiting, 58% of patients worried about a serious undiagnosed disease, 30% found their symptoms had affected their daily activities and 24% had to miss work or school due to symptoms. Of the patients, 46% considered eConsultation a viable alternative to face-to-face visits. Excessive wait times for specialist care remain barriers and have negative impacts on patients. Wait times significantly exceeded times patients considered acceptable. eConsultations provide acceptable alternatives for many patients, and they reduced the number of patients requiring traditional consultations. PMID- 25797112 TI - Effective Management of Diabetic Neuropathic Ulcers by Surgical Restoration of Foot Architecture: A Retrospective Study of 134 Cases. PMID- 25797113 TI - Diabetes Case Management in Primary Care: The New Brunswick Experience and Expanding the Practice of the Certified Diabetes Educator Nurse into Primary Care. AB - The role of the outreach diabetes case manager in New Brunswick, Canada, was first developed in the Moncton Area of Horizon Health Network in response to a physician-identified gap between patients' diagnoses of diabetes and their attendance at the local diabetes education centre. This model of collaborative interprofessional practice increases support for primary care providers and people living with diabetes in that they are being provided the services of certified diabetes educators who can address knowledge gaps with respect to evidence-based guidelines and best practice, promote advancement of diabetes and chronic-disease management therapies and support adherence to treatment plans and self-management practices. This report chronicles a review of the implementation, expansion and evaluation of the outreach diabetes case manager model in the province of New Brunswick, Canada, along with the rationale for development of the role for registered nurses in other jurisdictions. PMID- 25797114 TI - Glycemic Control, Self-Efficacy and Fear of Hypoglycemia Among Iranian Children with Type 1 Diabetes. AB - OBJECTIVE: This study was designed to test the reliability of a Persian version of 2 questionnaires to assess the level of fear of hypoglycemia (FoH) and self efficacy in diabetes management and their association with glycated hemoglobin (A1C) and parents' demographic characteristics in a sample of children with type 1 diabetes. DESIGN: We assessed 61 children with type 1 diabetes (35 boys and girls, 6.0 to 12.7 years of age) using the Hypoglycemia Fear Survey-Child version (HFS-C) and Self-Efficacy for Diabetes Scale-Child version (SED-C). Their glycemic control was evaluated by A1C levels. RESULTS: The internal consistency of the Persian version of HFS-C and SED-C were very good. Our results showed that children older than 10 years of age report lower levels of FoH, which are related to higher levels of self-efficacy (r=-.30, p=0.025 and r=-.30, p=0.02, respectively). Of the children, 42.3% of girls and 31.4% of boys reported that low blood sugar is a big problem for them. These findings suggest that FoH is a significant concern for this target group. Only 19.7% of children had controlled diabetes based on A1C levels. There was no significant association between higher A1C levels and other variables, including HFS-C, SED-C and parents' demographic characteristics. CONCLUSIONS: The Persian version of HFS-C and SED-C are reliable and valid measures of the fear of hypoglycemia and of self-efficacy in children with type 1 diabetes, and these questionnaires could be used in our country for identifying those children who may need diabetes education and other supports. The association between greater self-efficacy and lower fear of hypoglycemia suggests that addressing self-efficacy in diabetes education courses may be effective in helping to overcome FoH. PMID- 25797115 TI - Induction of cell cycle arrest and apoptosis by betulinic acid-rich fraction from Dillenia suffruticosa root in MCF-7 cells involved p53/p21 and mitochondrial signalling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dillenia suffruticosa (Family: Dilleniaceae) or commonly known as "Simpoh air" in Malaysia, is traditionally used for treatment of cancerous growth including breast cancer. AIM OF THE STUDY: D. suffruticosa root dichloromethane extract (DCM-DS) has been reported to induce G0/G1 phase cell cycle arrest and apoptosis in caspase-3 deficient MCF-7 breast cancer cells. The present study was designed to investigate the involvement of p53/p21 and mitochondrial pathway in DCM-DS-treated MCF-7 cells as well as to identify the bioactive compounds responsible for the cytotoxicity of DCM-DS. MATERIALS AND METHODS: Extraction of D. suffruticosa root was performed by the use of sequential solvent procedure. GeXP-based multiplex system was employed to investigate the expression of p53, p21, Bax and Bcl-2 genes in MCF-7 cells treated with DCM-DS. The protein expression was then determined using Western blot analysis. The bioactive compounds present in DCM-DS were isolated by using column chromatography. The structure of the compounds was elucidated by using nuclear magnetic resonance spectroscopy. The cytotoxicity of the isolated compounds towards MCF-7 cells was evaluated by using MTT assay. The percentage of betulinic acid (BA) in DCM-DS was determined by HPLC analysis. RESULTS: The expression of p53 was significantly up-regulated at protein level. The expression of p21 at both gene and protein levels was significantly up-regulated upon treatment with DCM-DS, suggesting that the induction of G0/G1 phase cell cycle arrest in MCF-7 cells was via p53/p21 pathway. Bcl-2 protein was down-regulated with no change at the mRNA level, postulating that post-translational modification has occurred resulting in the degradation of Bcl-2 protein. Overall, treatment with DCM-DS increased the ratio of Bax/Bcl-2 that drove the cells to undergo apoptosis. A total of 3 triterpene compounds were isolated from DCM-DS. Betulinic acid appears to be the most major and most cytotoxic compound in DCM DS. CONCLUSION: DCM-DS induced cell cycle arrest and apoptosis in MCF-7 cells via p53/p21 pathway. In addition, DCM-DS induced apoptosis by increasing the ratio of Bax/Bcl-2. Betulinic acid, which is one of the major compounds, is responsible for the cytotoxicity of the DCM-DS. Therefore, BA can be used as a marker for standardisation of herbal product from D. suffruticosa. DCM-DS can also be employed as BA-rich extract from roots of D. suffruticosa for the management of breast cancer. PMID- 25797116 TI - Metabolomics study of hematopoietic function of Angelica sinensis on blood deficiency mice model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelica sinensis (AS) has been used in traditional Chinese medicine for thousands of years to enrich and invigorate blood. In this study, the aim is to investigate the influence of AS on metabolism of blood deficiency mice model and to explore its anti-blood deficiency mechanism. MATERIALS AND METHODS: The blood deficiency mice model was induced by being hypodermically injected with N-acetyl phenylhydrazine (APH) and being intraperitoneally injected with cyclophosphamide (CTX). Gas chromatography-mass spectrometry (GC-MS), principle component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used to identify potential biomarkers in plasma and splenic tissue. RESULTS: The levels of white blood cell (WBC), red blood cell (RBC), hemoglobin (HGB) and platelet (PLT) showed a trend to return to control group after administrating with AS, while the dose of 10g/kg showed the best effect. Potential metabolite biomarkers (nine in the plasma and nine in the spleen homogenates) were identified in this study. These biomarkers were mainly related to five metabolic pathways, such as arachidonic acid metabolism, valine, leucine and isoleucine biosynthesis, glycine, serine and threonine metabolism, arginine and proline metabolism and TCA cycle. CONCLUSION: Metabolomics was used to reflect an organism's physiological and metabolic state comprehensively, indicating that metabolomics was a potentially powerful tool to reveal the anti blood deficiency mechanism of AS. PMID- 25797117 TI - Substitution between Aristolochia and Bryonia genus in North-Eastern Morocco: toxicological implications. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Although acknowledged as toxic herbs, Aristolochia species are still widely used worldwide. The aristolochic acids (AA) they contain can induce the so-called "aristolochic acid nephropathy", leading to renal fibrosis and upper urinary tract cancer. Traditional Moroccan medicine still often uses Aristolochia species under the vernacular name of Bereztem for the treatment of numerous ailments, notably cancer, diabetes or digestive tract disorders. As the botanical identity and renal toxicity of used species remain unexplored, the safety of patients may be threatened. MATERIAL AND METHODS: Ethnopharmacological data were collected from herbalists from the provinces of Oujda and Berkane, located in North-Eastern Morocco. Samples of Bereztem were collected at herbalist shops and checked for their content in AA using TLC and LC MS methods. The toxicity of crude methanolic extracts of each herb was assessed on a HK-2 cell-based in vitro model by measurement of the cell survival to evaluate cytotoxicity and by assessment of renal-specific toxicity via (i) the evaluation of genes (E-cadherin and alpha-smooth muscle actin) expression by RT qPCR; (ii) the quantities of beta-catenin and vimentin by immunofluorescence microscopy; (iii) the secretion of fibronectin; and (iv) the excretion of interleukin-6. RESULTS: The survey indicated that, among 42 herbalists visited, 33 were retailers of Bereztem, which was generally sold as a cancer treatment. Botanical investigations revealed that Aristolochia longa was frequently substituted by Bryonia dioica, which was associated with a higher cytotoxicity. Parameters specific to renal toxicity were also found to be enhanced, as compared to Aristolochia baetica and A. longa: down-regulation of beta-catenin and E cadherin and up-regulation of vimentin and alpha-smooth muscle actin, and secretion of fibronectin and interleukin-6. CONCLUSION: In accordance with the Moroccan regulations, the use of so-called Aristolochia species should be discontinued. On one hand, the correctly identified aristolochia contain nephrotoxic aristolochic acids; on the other hand, aristolochia are massively substituted in North-Eastern Morocco and adulterated by a well-known toxic herb, B. dioica. Our data indicate that the bryony renal toxicity may be deleterious in shorter time periods than aristolochia. Reinforced on-site controls are needed to remind herbalists and harvesters that these herbs should be prohibited. PMID- 25797118 TI - Fibronectin localization and fibrillization are affected by the presence of serum in culture media. AB - In vitro models of fibrotic phenomena are often based on the fibroblast myofibroblast transition as the contraction-triggering cellular event. There are, however, multiple sources of concern regarding the appropriateness of such models; a first and widely investigated issue is the often inappropriate nature of the interactions between mesenchymal cells and surrounding/underlying matrix/substrate. A second set of problems concerns the composition of the fluid phase, which includes both dispersed/dissolved paracrine messengers and matrix elements. In this study, we have focused on the effects that serum may generate. We have observed that A) serum causes high variability in the expression of typical markers of myofibroblast differentiation (ED-A fibronectin and alpha Smooth Muscle Actin) upon treatment with TGF-beta1; this is probably due to intrinsic variability of cytokine concentrations in different batches of serum. B) the fibrillization of endogenous fibronectin is partially hampered and its localization changed from ventral (on the substrate) to dorsal (upper surface); the latter morphology appears to be largely overlooked in literature, even though it may have a significant role in terms of mechanotransductive signaling. This quite dramatic change possibly occurs as a result of competition with serum proteins, although our data seem to rule out a direct role of serum fibronectin. PMID- 25797119 TI - Prognostic value of echocardiographic calcium score in patients with a clinical indication for stress echocardiography. AB - OBJECTIVES: The value of the echocardiographic calcium score (eCS) was evaluated to predict cardiac events in a multicenter cohort of subjects without known coronary disease, who underwent stress echocardiography (SE) for suspected coronary artery disease (CAD). BACKGROUND: Several studies have established that aortic valve sclerosis and/or calcification and mitral calcification, as detected by echocardiography, predict cardiovascular morbidity and mortality. The use of a semiquantitative total cardiac calcium score (eCS) to assess aortic and mitral valves, papillary muscles, and the ascending aorta has never been tested in multicenter studies; the inherent subjectivity and clinical applicability of such a parameter remains a concern. METHODS: We identified 1,303 patients from 5 Italian institutions and 1 U.S. institution, who had no known CAD and who underwent clinically-indicated pharmacological or exercise SE. They were followed up for myocardial infarction (MI) and all-cause death. eCS was assessed from archived images, and its discrimination and reclassification prognostic potential was determined. RESULTS: Fifty-eight patients met the combined endpoint of all cause death (n = 37; 2.8%) or MI (n = 21; 1.6%) during a median follow-up of 808 days. Age, diabetes mellitus, eCS >0, and ischemic SE were multivariate predictors of hard events. Kaplan-Meier curves demonstrated that patients with ischemic SE or eCS >0 had worse outcomes. When both variables were abnormal, the prognosis was worse (p < 0.001). The multivariate model demonstrated that both eCS and ischemic SE independently contributed to risk prediction more than clinical variables. Both wall motion during SE and eCS were able to significantly reclassify the risk of events, but only stress wall motion demonstrated an incremental discrimination value. CONCLUSIONS: eCS demonstrated significant prognostic value in predicting hard cardiac events in a multicenter population of patients who required noninvasive evaluation. Its value was independent from clinical assessment and wall motion during SE, although it did not show incremental value over these factors for discrimination of patients with and without events. PMID- 25797120 TI - A clinical model to identify patients with high-risk coronary artery disease. AB - OBJECTIVES: This study sought to develop a clinical model that identifies patients with and without high-risk coronary artery disease (CAD). BACKGROUND: Although current clinical models help to estimate a patient's pre-test probability of obstructive CAD, they do not accurately identify those patients with and without high-risk coronary anatomy. METHODS: Retrospective analysis of a prospectively collected multinational coronary computed tomographic angiography (CTA) cohort was conducted. High-risk anatomy was defined as left main diameter stenosis >=50%, 3-vessel disease with diameter stenosis >=70%, or 2-vessel disease involving the proximal left anterior descending artery. Using a cohort of 27,125, patients with a history of CAD, cardiac transplantation, and congenital heart disease were excluded. The model was derived from 24,251 consecutive patients in the derivation cohort and an additional 7,333 nonoverlapping patients in the validation cohort. RESULTS: The risk score consisted of 9 variables: age, sex, diabetes, hypertension, current smoking, hyperlipidemia, family history of CAD, history of peripheral vascular disease, and chest pain symptoms. Patients were divided into 3 risk categories: low (<=7 points), intermediate (8 to 17 points) and high (>=18 points). The model was statistically robust with area under the curve of 0.76 (95% confidence interval [CI]: 0.75 to 0.78) in the derivation cohort and 0.71 (95% CI: 0.69 to 0.74) in the validation cohort. Patients who scored <=7 points had a low negative likelihood ratio (<0.1), whereas patients who scored >=18 points had a high specificity of 99.3% and a positive likelihood ratio (8.48). In the validation group, the prevalence of high risk CAD was 1% in patients with <=7 points and 16.7% in those with >=18 points. CONCLUSIONS: We propose a scoring system, based on clinical variables, that can be used to identify patients at high and low pre-test probability of having high risk CAD. Identification of these populations may detect those who may benefit from a trial of medical therapy and those who may benefit most from an invasive strategy. PMID- 25797121 TI - Accuracy of OCT, grayscale IVUS, and their combination for the diagnosis of coronary TCFA: an ex vivo validation study. AB - OBJECTIVES: This study sought to assess the accuracy of optical coherence tomography (OCT), gray-scale intravascular ultrasound (IVUS), and their combination for detecting thin-cap fibroatheromas (TCFA). BACKGROUND: The extent to which the imaging characteristics of OCT and IVUS correlate with histologically defined TCFA is unknown. METHODS: IVUS and OCT examinations identified focal plaques in 165 coronary arteries from 60 autopsy hearts. A total of 685 pairs of images of OCT and IVUS were compared with histology. By OCT, a TCFA was defined as a signal-poor region with diffuse borders and cap thickness <65 MUm. By IVUS, a TCFA was defined by the presence of echolucent zones and/or ultrasound attenuation in areas of positive remodeling. By histology, 12 of 685 focal plaques were classified as TCFAs. RESULTS: With histology as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for OCT-derived TCFA were 100%, 97%, 41%, 100%, and 98%, respectively. The corresponding numbers for IVUS-derived TCFA were 92%, 93%, 19%, 99%, and 93%, respectively. The histological findings underlying the false positive diagnoses of OCT for TCFA included large amounts of foam cell accumulation on the luminal surface, large amounts of microcalcifications at the surface, large amounts of hemosiderin accumulation, or organized thrombus. In contrast, histological causes of mischaracterization of TCFA by IVUS were mostly TCFA. When both OCT and IVUS criteria for TCFA were required to be met, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy were 92%, 99%, 69%, 99%, and 99%, respectively. CONCLUSIONS: In the present study, neither OCT nor IVUS were optimal to detect TCFA. The combined use of OCT and IVUS may improve TCFA detection accuracy. PMID- 25797122 TI - Regadenoson versus dipyridamole hyperemia for cardiac PET imaging. AB - OBJECTIVES: The goal of this study was to compare regadenoson and dipyridamole hyperemia for quantitative myocardial perfusion imaging. BACKGROUND: Regadenoson is commonly used for stress perfusion imaging. However, no study in nuclear cardiology has employed a paired design to compare quantitative hyperemic flow from regadenoson to more traditional agents such as dipyridamole. Additionally, the timing of regadenoson bolus relative to tracer administration can be expected to affect quantitative flow. METHODS: Subjects underwent 2 rest/stress cardiac positron emission tomography scans using an Rb-82 generator. Each scan employed dipyridamole and a second drug in random sequence, either regadenoson according to 5 timing sequences or repeated dipyridamole. A validated retention model quantified absolute flow and coronary flow reserve. RESULTS: A total of 176 pairs compared regadenoson (126 pairs, split unevenly among 5 timing sequences) or repeated dipyridamole (50 pairs). The cohort largely had few symptoms, only risk factors, and nearly normal relative uptake images, with 8% typical angina or dyspnea, 20% manifest coronary artery disease, and a minimum quadrant average of 80% (interquartile range: 76% to 83%) on dipyridamole scans. Hyperemic flow varied among regadenoson timing sequences but showed consistently lower stress flow and coronary flow reserve compared with dipyridamole. A timing sequence most similar to the regadenoson package insert achieved about 80% of dipyridamole hyperemia, whereas further delaying radiotracer injection reached approximately 90% of dipyridamole hyperemia. Because of the small numbers of pairs for each regadenoson timing protocol and a paucity of moderate or large perfusion defects, we did not observe a difference in relative uptake. CONCLUSIONS: With the standard timing protocol from the package insert, regadenoson achieved only 80% of dipyridamole hyperemia quantitatively imaged by cardiac positron emission tomography using Rb-82. A nonstandard protocol using a more delayed radionuclide injection after the regadenoson bolus improved its effect to 90% of dipyridamole hyperemia. PMID- 25797124 TI - Evidence of a Direct Effect of Myocardial Steatosis on LV Hypertrophy and Diastolic Dysfunction in Adult and Adolescent Obesity. PMID- 25797123 TI - Late gadolinium enhancement among survivors of sudden cardiac arrest. AB - OBJECTIVES: The aim of this study was to describe the role of contrast-enhanced cardiac magnetic resonance (CMR) in the workup of patients with aborted sudden cardiac arrest (SCA) and in the prediction of long-term outcomes. BACKGROUND: Myocardial fibrosis is a key substrate for SCA, and late gadolinium enhancement (LGE) on a CMR study is a robust technique for imaging of myocardial fibrosis. METHODS: We performed a retrospective review of all survivors of SCA who were referred for CMR studies and performed follow-up for the subsequent occurrence of an adverse event (death and appropriate defibrillator therapy). RESULTS: After a workup that included a clinical history, electrocardiogram, echocardiography, and coronary angiogram, 137 patients underwent CMR for workup of aborted SCA (66% male; mean age 56 +/- 11 years; left ventricular ejection fraction 43 +/- 12%). The presenting arrhythmias were ventricular fibrillation (n = 105 [77%]) and ventricular tachycardia (n = 32 [23%]). Overall, LGE was found in 98 patients (71%), with an average extent of 9.9 +/- 5% of the left ventricular myocardium. CMR imaging provided a diagnosis or an arrhythmic substrate in 104 patients (76%), including the presence of an infarct-pattern LGE in 60 patients (44%), noninfarct LGE in 21 (15%), active myocarditis in 14 (10%), hypertrophic cardiomyopathy in 3 (2%), sarcoidosis in 3, and arrhythmogenic cardiomyopathy in 3. In a median follow-up of 29 months (range 18 to 43 months), there were 63 events. In a multivariable analysis, the strongest predictors of recurrent events were the presence of LGE (adjusted hazard ratio: 6.7; 95% CI: 2.38 to 18.85; p < 0.001) and the extent of LGE (hazard ratio: 1.15; 95% CI: 1.11 to 1.19; p < 0.001). CONCLUSIONS: Among patients with SCA, CMR with contrast identified LGE in 71% and provided a potential arrhythmic substrate in 76%. In follow-up, both the presence and extent of LGE identified a group at markedly increased risk of future adverse events. PMID- 25797125 TI - Novel Use of Cardiac Magnetic Resonance Imaging for the Diagnosis of Cobalt Cardiomyopathy. PMID- 25797127 TI - Usefulness of 3D OCT to Diagnose a Noncircumferential Open-Cell Stent Fracture. PMID- 25797126 TI - 3D Transthoracic Echocardiography Provides Accurate Cross-Sectional Area of the RV Outflow Tract. PMID- 25797128 TI - Intravascular Assessment of Arterial Disease Using Compensated OCT in Comparison With Histology. PMID- 25797129 TI - Diagnostic Accuracy of Rapid Kilovolt Peak-Switching Dual-Energy CT Coronary Angiography in Patients With a High Calcium Score. PMID- 25797130 TI - Superficial Calcium Fracture After PCI as Assessed by OCT. PMID- 25797131 TI - Serial Multimodality Evaluation of Aortocoronary Bypass Grafts During the First Year After CABG Surgery. PMID- 25797132 TI - Myocardial Kinetics of a Novel [(18)F]-Labeled Sympathetic Nerve PET Tracer LMI1195 in the Isolated Perfused Rabbit Heart. PMID- 25797133 TI - Anxiety and depression predict quality of life in Turkish patients with systemic lupus erythematosus. AB - OBJECTIVES: The aim of our study was to evaluate quality of life (QoL) in patients with systemic lupus erythematosus (SLE) and assess the impact of disease activity and psychological distress on health-related quality of life (HRQoL) in Turkey. METHODS: The Medical Outcomes Study Short Form (SF) -36 was used in a cohort of 113 consecutive patients with SLE and 123 age- and gender-matched healthy subjects to measure HRQoL. Patients' disease activity was assessed with SLE disease activity index (SLEDAI) and psychological distress was evaluated by the Hospital Anxiety and Depression Scale (HADS) for all participants. Patients' demographic and clinical data were recorded at the time of HRQoL and HADS testing. Multiple logistic regression analysis was performed to explore the relationships between demographics, disease duration, disease activity as well as psychological (anxiety and depression) variables and the HRQoL. RESULTS: SLE patients have lower quality of life than healthy controls. No relationship between HRQoL and SLE activity or disease duration were observed. Patients with anxiety and/or depression reported worse SF-36 scores than those without psychological distress. The results of multivariate analysis suggested that HADS A, HADS-D scores and working status were associated with the impairment of HRQoL. CONCLUSIONS: HRQoL is impaired in patients with SLE and is associated with mood disorders. Physicians should pay close attention to detect anxiety and depression and manage them in order to improve the quality of life in patients with SLE. PMID- 25797134 TI - Bacillus cereus from the environment is genetically related to the highly pathogenic B. cereus in Zambia. AB - To follow-up anthrax in Zambia since the outbreak in 2011, we have collected samples from the environment and the carcasses of anthrax-suspected animals, and have tried to isolate Bacillus anthracis. In the process of identification of B. anthracis, we collected two isolates, of which colonies were similar to B. anthracis; however, from the results of identification using the molecular-based methods, two isolates were genetically related to the highly pathogenic B. cereus, of which clinical manifestation is severe and fatal (e.g., pneumonia). In this study, we showed the existence of bacteria suspected to be highly pathogenic B. cereus in Zambia, indicating the possibility of an outbreak caused by highly pathogenic B. cereus. PMID- 25797135 TI - Enhanced magnetic anisotropies of single transition-metal adatoms on a defective MoS2 monolayer. AB - Single magnetic atoms absorbed on an atomically thin layer represent the ultimate limit of bit miniaturization for data storage. To approach the limit, a critical step is to find an appropriate material system with high chemical stability and large magnetic anisotropic energy. Here, on the basis of first-principles calculations and the spin-orbit coupling theory, it is elucidated that the transition-metal Mn and Fe atoms absorbed on disulfur vacancies of MoS2 monolayers are very promising candidates. It is analysed that these absorption systems are of not only high chemical stabilities but also much enhanced magnetic anisotropies and particularly the easy magnetization axis is changed from the in plane one for Mn to the out-of-plane one for Fe by a symmetry-lowering Jahn Teller distortion. The results point out a promising direction to achieve the ultimate goal of single adatomic magnets with utilizing the defective atomically thin layers. PMID- 25797136 TI - Altered neutrophil functions in elderly patients during a 6-month follow-up period after a hip fracture. AB - BACKGROUND: Fracture of the hip (HF) is a significant cause of morbidity and mortality in elderly individuals. HF is an acute stress that triggers a state of inflammation which may affect immune responses and physical recovery. METHODS: Longitudinal study of the impact of HF on the functions of polymorphonuclear neutrophils (PMNs) in elderly subjects. Data were recorded prior to surgery, 6weeks and 6months later. RESULTS: PMN functions were severely impaired shortly after HF (chemotaxis, phagocytosis, superoxide production) but there was a time related recovery of some PMN functions (chemotaxis, phagocytosis) over time, except in the case of superoxide production. Whereas FcgammaRII (CD32) expression remained unchanged, FcgammaRIII (CD16) increased from low values before surgery to levels of controls 6months post-surgery. This was also the case for the C5a complement receptor and CD11b. TLR2 and TLR4 expressions were unchanged. Cytokine and chemokine secretions by stimulated PMN were altered. TNFalpha and IL-10 secretions were increased following HF but IL-8 secretion was decreased. Impaired PMN functions prior to surgery were related to alterations in PI3K and NF-kappaB signaling pathways. Recovery of these functions paralleled increased PI3K activity, although superoxide production remained low. Sustained activation of the NF-kappaB pathway by TNFalpha has been reported to involve upregulation of IKKbeta kinase activity. Activated IKKbeta kinase inhibits ERK1/2 and results in concomitant downstream inhibition of NADPH oxidase complex which can account for sustained impaired production of ROS in HF patients. CONCLUSION: Our data showed that the stress caused by HF negatively affects initial PMN responses shortly after the event and that may negatively influence clinical outcomes such as resolving long-term inflammation and recovery, as well as explaining susceptibility to opportunistic infections. PMID- 25797138 TI - Anisotropic superconducting gap and elongated vortices with Caroli-De Gennes Matricon states in the new superconductor Ta4Pd3Te16. AB - The superconducting state is formed by the condensation of a large number of Cooper pairs. The normal state electronic properties can give significant influence on the superconducting state. For usual type-II superconductors, the vortices are cylinder like with a round cross-section. For many two dimensional superconductors, such as Cuprates, albeit the in-plane anisotropy, the vortices generally have a round shape. In this paper we report results based on the scanning tunnelling microscopy/spectroscopy measurements on a newly discovered superconductor Ta4Pd3Te16. The chain-like conducting channels of PdTe2 in Ta4Pd3Te16 make a significant anisotropy of the in-plane Fermi velocity. We suggest at least one anisotropic superconducting gap with gap minima or possible node exists in this multiband system. In addition, elongated vortices are observed with an anisotropy of xi||b/xi&bottom?b ~ 2.5. Clear Caroli-de Gennes Matricon states are also observed within the vortex cores. Our results will initiate the study on the elongated vortices and superconducting mechanism in the new superconductor Ta4Pd3Te16. PMID- 25797139 TI - Plantar loading and foot-strike pattern changes with speed during barefoot running in those with a natural rearfoot strike pattern while shod. AB - BACKGROUND: Claims of injury reduction related to barefoot running has resulted in interest from the running public; however, its risks are not well understood for those who typically wear cushioned footwear. OBJECTIVES: Examine how plantar loading changes during barefoot running in a group of runners that ordinarily wear cushioned footwear and demonstrate a rearfoot strike pattern (RFSP) without cueing or feedback alter their foot strike pattern and plantar loading when asked to run barefoot at different speeds down a runway. METHOD: Forty-one subjects ran barefoot at three different speeds across a pedography platform which collected plantar loading variables for 10 regions of the foot; data were analyzed using two-way mixed multivariate analysis of variance (MANOVA). RESULTS: A significant foot strike position (FSP)*speed interaction in each of the foot regions indicated that plantar loading differed based on FSP across the different speeds. The RFSP provided the highest total forces across the foot while the pressures displayed in subjects with a non-rearfoot strike pattern (NRFSP) was more similar between each of the metatarsals. CONCLUSIONS: The majority of subjects ran barefoot with a NRFSP and demonstrated lower total forces and more uniform force distribution across the metatarsal regions. This may have an influence in injuries sustained in barefoot running. PMID- 25797140 TI - Selection and implementation of expanded CODIS core loci in the United States. PMID- 25797137 TI - Design of a PDZbody, a bivalent binder of the E6 protein from human papillomavirus. AB - Chronic infection by high risk human papillomavirus (HPV) strains may lead to cancer. Expression of the two viral oncoproteins E6 and E7 is largely responsible for immortalization of infected cells. The HPV E6 is a small (approximately 150 residues) two domain protein that interacts with a number of cellular proteins including the ubiquitin ligase E6-associated protein (E6AP) and several PDZ domain containing proteins. Our aim was to design a high-affinity binder for HPV E6 by linking two of its cellular targets. First, we improved the affinity of the second PDZ domain from SAP97 for the C-terminus of HPV E6 from the high-risk strain HPV18 using phage display. Second, we added a helix from E6AP to the N terminus of the optimized PDZ variant, creating a chimeric bivalent binder, denoted PDZbody. Full-length HPV E6 proteins are difficult to express and purify. Nevertheless, we could measure the affinity of the PDZbody for E6 from another high-risk strain, HPV16 (Kd = 65 nM). Finally, the PDZbody was used to co immunoprecipitate E6 protein from HPV18-immortalized HeLa cells, confirming the interaction between PDZbody and HPV18 E6 in a cellular context. PMID- 25797141 TI - Transcriptomic analysis of degraded forensic body fluids. AB - Massively parallel sequencing (MPS) has facilitated a significant increase in transcriptomic studies in all biological disciplines. However, the analysis of degraded RNA remains a genuine challenge in practice. In forensic science the biological samples encountered are often extensively degraded and of low abundance. RNA from these compromised samples is used for body fluid identification through the detection of body fluid-specific transcripts. Here we demonstrate the sequencing of four forensically relevant body fluids: oral mucosa/saliva (buccal), circulatory blood, menstrual blood and vaginal fluid. RNA was extracted from fresh, two and six week aged samples. Despite the extensive degradation of most body fluids, significant high quality sequencing output (>80% sequence above Q30) was generated. An average of over 80% of reads from all but one sample aligned successfully to the reference human genome. Furthermore, FPKMs (fragments per kilobase of exon per million fragments mapped) generated indicate the accurate detection of known body fluid markers in respective body fluids. Assessment of global gene expression levels over degradation time enabled the characterisation of differential RNA degradation in different body fluids. This study demonstrates the practical application of MPS technology for the accurate analysis of degraded RNA from minimal samples. PMID- 25797142 TI - In response: Genomic profile of breast cancer. PMID- 25797144 TI - Analysis of Gill Structure from a Fresh Water Fish (Heteropneustes fossilis) Exposed to Bleached Sulfite Pulp Mill Effluents. AB - The present communication reports toxic effects of bleached sulfite pulp mill effluents in fish (Heteropneustes fossilis) gills, with optical, scanning electron, and transmission electron microscopy. The general adverse effects include dilation of the primary lamellar wall, curling of secondary lamellar terminals, displacement of epithelial cell layers, degeneration of secondary lamella, deposition of mucous, and severe congestion in the gill arch. The significant shortening of secondary lamellae, widening of lamellar tips, and significant decrease in the number of mitochondria in chloride cells as compared to controls are some specific effects of bleached sulfite pulp mill effluents. Scanning electron microscopy demonstrated tearing of tissues in gill lamellae and arches. Transmission electron microscopy revealed membrane distortion of mitochondria in chloride cells, loss of uniformity of microvilli in pavement cells, and abnormalities in nuclear shape in different cells of effluent-exposed fish gills. Toxicity of the bleached sulfite pulp mill effluents and its impact on fish are discussed in the light of existing literature. Further, the importance of microscopy in toxicological evaluation of environmental pollutants is emphasized in view of its specific application potential. PMID- 25797143 TI - Towards a PBMC "virogram assay" for precision medicine: Concordance between ex vivo and in vivo viral infection transcriptomes. AB - BACKGROUND: Understanding individual patient host-response to viruses is key to designing optimal personalized therapy. Unsurprisingly, in vivo human experimentation to understand individualized dynamic response of the transcriptome to viruses are rarely studied because of the obvious limitations stemming from ethical considerations of the clinical risk. OBJECTIVE: In this rhinovirus study, we first hypothesized that ex vivo human cells response to virus can serve as a proxy for otherwise controversial in vivo human experimentation. We further hypothesized that the N-of-1-pathways framework, previously validated in cancer, can be effective in understanding the more subtle individual transcriptomic response to viral infection. METHOD: N-of-1-pathways computes a significance score for a given list of gene sets at the patient level, using merely the 'omics profiles of two paired samples as input. We extracted the peripheral blood mononuclear cells (PBMC) of four human subjects, aliquoted in two paired samples, one subjected to ex vivo rhinovirus infection. Their dysregulated genes and pathways were then compared to those of 9 human subjects prior and after intranasal inoculation in vivo with rhinovirus. Additionally, we developed the Similarity Venn Diagram, a novel visualization method that goes beyond conventional overlap to show the similarity between two sets of qualitative measures. RESULTS: We evaluated the individual N-of-1-pathways results using two established cohort-based methods: GSEA and enrichment of differentially expressed genes. Similarity Venn Diagrams and individual patient ROC curves illustrate and quantify that the in vivo dysregulation is recapitulated ex vivo both at the gene and pathway level (p-values?0.004). CONCLUSION: We established the first evidence that an interpretable dynamic transcriptome metric, conducted as an ex vivo assays for a single subject, has the potential to predict individualized response to infectious disease without the clinical risks otherwise associated to in vivo challenges. These results serve as a foundational work for personalized "virograms". PMID- 25797145 TI - Tuning the reactivity of nanostructured indium tin oxide electrodes toward chemisorption. AB - This contribution highlights correlation between the surface concentration of a chemisorbed organophosphorous probe (flavin mononucleotide) and the relative hydroxyl surface coverage of nanostructured ITO electrodes, which can be tuned during post-deposition reductive annealing. The resulting modified electrodes are very stable in aqueous solution, highly hydrophilic and fully-accessible to the bulk solution. PMID- 25797146 TI - B(C6F5)3 mediated arene hydrogenation/transannulation of para-methoxyanilines. AB - The stoichiometric reaction of para-methoxyanilines and B(C6F5)3 under H2 results in reduction of the N-bound phenyl ring(s), and subsequent transannular ring closure with elimination of methanol, affording the respective 7 azabicyclo[2.2.1]heptane derivatives. PMID- 25797147 TI - Gastrointestinal motility and neurogastroenterology. AB - Nordic research on gastrointestinal motility has since 1965 made substantial contributions to our current understanding of gastrointestinal function. During the last decade, the term neurogastroenterology has widened the concept of motility research into the study of gastrointestinal sensory-motor function, including the complex central nervous system interaction. The discovery of a non adrenergic non-cholinergic (NANC) innervation of the gut in the sixties was made by considerable contributions from the Nordic countries with the Martinson group in Sweden as central innovators. Important discoveries regarding the intramural nerve ganglia as mediators of the autonomic nervous input has also been produced from this research. In clinical motility research, the study of the migrating motor complex in the small bowel has revealed its ability to act as a retroperistaltic pump in the proximal duodenum (Sweden) and its important role for gut microbial homeostasis (Norway). Also in the development of methodology to study gut sensory-motor function, the Nordic countries has contributed. Examples are the physical characteristics of the esophageal manometry catheter (Denmark), the use of ultrasound for assessment of gastric function (Norway), a temporary electrical stimulation method in patients with severe nausea and vomiting (Sweden), a rectal barostat method for clinical evaluation of recto-anal function and a colonic transit time method utilizing radio-opaque markers (Sweden). In later years, the research collaborations have increasingly become worldwide in a manner making it less easy to define pure Nordic contributions. PMID- 25797148 TI - The dominant antigenic group of influenza C infections changed from c/Sao Paulo/378/82-lineage to c/Kanagawa/1/76-lineage in Yamagata, Japan, in 2014. PMID- 25797149 TI - Se...N chalcogen bond and Se...X halogen bond involving F2C?Se: influence of hybridization, substitution, and cooperativity. AB - Quantum-chemical calculations have been performed for the chalcogen- and halogen bonded complexes of F2CSe with a series of nitrogen bases (N2, NCH, NH3, NHCH2, NCLi, and NMe3) and dihalogen molecules (BrCl, ClF, and BrF), respectively. Both types of interactions are mainly driven by the electrostatic and orbital interactions. The chalcogen bond becomes stronger in the order of NCH (sp) < NH3 (sp(3)) < NHCH2 (sp(2)), showing some inconsistence with the electronegativity of the hybridized N atom. The Li and methyl groups have an enhancing effect on the strength of chalcogen bond; however, the former is jointly achieved through the electrostatic and orbital interactions, whereas the orbital interaction has dominant contribution to the latter enhancement. The halogen bond with F2CX (X = O, S, Se) as the electron donor is stronger for the heavier chalcogen atom, exhibiting a reverse dependence on the chalcogen atom with that in hydrogen bonds. The halogen bond is further strengthened by the presence of chalcogen bond in the ternary complexes. In addition, CSD research confirms the abundance of Se...N interaction in crystal materials. PMID- 25797150 TI - Treadmill exercise is associated with reduction of reactive microgliosis and pro inflammatory cytokine levels in the hippocampus of type 2 diabetic rats. AB - OBJECTIVES: In the present study, we investigated the effects of treadmill exercise on microglial activation and the subsequent release of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1-beta in the hippocampus in a rat model of type 2 diabetes. METHODS: At 30 weeks of age, diabetic (Zucker diabetic fatty, ZDF) rats and their littermate control (Zucker lean control, ZLC) rats were either placed on a stationary treadmill or made to run for 1 hour/day at 12-16 m/minute on five consecutive days, for 10 weeks. Once the rats reached 40 weeks, they were perfused and their hippocampus collected for immunohistochemistry or hippocampus collected fresh for the Western blotting or enzyme-linked immunosorbent assay (ELISA). RESULTS: The whole blood glucose levels in exercised ZDF rats were significantly higher than in the sedentary or exercised ZLC rats, but were significantly lower than in the sedentary ZDF rats. In the sedentary ZLC and exercised ZLC rats, ionised calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia showed normal morphology which had small cytoplasm with ramified processes. In the sedentary ZDF rats, some Iba-1 immunoreactive microglia showed abnormal morphology which had hypertrophied cytoplasm with retracted processes. However, exercised ZDF rats had small cytoplasm with highly ramified processes. Levels of TNF-alpha, IL-6 and IL-1beta in the hippocampal homogenates were significantly increased in sedentary ZDF rats compared to sedentary ZLC rats, respectively. However, TNF-alpha, IL-6 and IL 1beta levels in the exercised ZDF rats were significantly decreased compared with those of sedentary ZDF rats, respectively. DISCUSSION: These results suggest that exercise in type 2 diabetic rats reduces microglial activation and the subsequent increase of pro-inflammatory cytokine levels in the hippocampus. PMID- 25797151 TI - Strong coupling electrostatics for randomly charged surfaces: antifragility and effective interactions. AB - We study the effective interaction mediated by strongly coupled Coulomb fluids between dielectric surfaces carrying quenched, random monopolar charges with equal mean and variance, both when the Coulomb fluid consists only of mobile multivalent counterions and when it consists of an asymmetric ionic mixture containing multivalent and monovalent (salt) ions in equilibrium with an aqueous bulk reservoir. We analyze the consequences that follow from the interplay between surface charge disorder, dielectric and salt image effects, and the strong electrostatic coupling that results from multivalent counterions on the distribution of these ions and the effective interaction pressure they mediate between the surfaces. In a dielectrically homogeneous system, we show that the multivalent counterions are attracted towards the surfaces with a singular, disorder-induced potential that diverges logarithmically on approach to the surfaces, creating a singular but integrable counterion density profile that exhibits an algebraic divergence at the surfaces with an exponent that depends on the surface charge (disorder) variance. This effect drives the system towards a state of lower thermal 'disorder', one that can be described by a renormalized temperature, exhibiting thus a remarkable antifragility. In the presence of an interfacial dielectric discontinuity, the singular behavior of counterion density at the surfaces is removed but multivalent counterions are still accumulated much more strongly close to randomly charged surfaces as compared with uniformly charged ones. The interaction pressure acting on the surfaces displays in general a highly non-monotonic behavior as a function of the inter-surface separation with a prominent regime of attraction at small to intermediate separations. This attraction is caused directly by the combined effects from charge disorder and strong coupling electrostatics of multivalent counterions, which dominate the surface-surface repulsion due to the (equal) mean charges on the two surfaces and the osmotic pressure of monovalent ions residing between them. These effects can be quite significant even with a small degree of surface charge disorder relative to the mean surface charge. The strong coupling, disorder-induced attraction is typically much stronger than the van der Waals interaction between the surfaces, especially within a range of several nanometers for the inter-surface separation, where such effects are predicted to be most pronounced. PMID- 25797152 TI - Regeneration of Xenopus laevis spinal cord requires Sox2/3 expressing cells. AB - Spinal cord regeneration is very inefficient in humans, causing paraplegia and quadriplegia. Studying model organisms that can regenerate the spinal cord in response to injury could be useful for understanding the cellular and molecular mechanisms that explain why this process fails in humans. Here, we use Xenopus laevis as a model organism to study spinal cord repair. Histological and functional analyses showed that larvae at pre-metamorphic stages restore anatomical continuity of the spinal cord and recover swimming after complete spinal cord transection. These regenerative capabilities decrease with onset of metamorphosis. The ability to study regenerative and non-regenerative stages in Xenopus laevis makes it a unique model system to study regeneration. We studied the response of Sox2(/)3 expressing cells to spinal cord injury and their function in the regenerative process. We found that cells expressing Sox2 and/or Sox3 are present in the ventricular zone of regenerative animals and decrease in non-regenerative froglets. Bromodeoxyuridine (BrdU) experiments and in vivo time lapse imaging studies using green fluorescent protein (GFP) expression driven by the Sox3 promoter showed a rapid, transient and massive proliferation of Sox2(/)3(+) cells in response to injury in the regenerative stages. The in vivo imaging also demonstrated that Sox2(/)3(+) neural progenitor cells generate neurons in response to injury. In contrast, these cells showed a delayed and very limited response in non-regenerative froglets. Sox2 knockdown and overexpression of a dominant negative form of Sox2 disrupts locomotor and anatomical histological recovery. We also found that neurogenesis markers increase in response to injury in regenerative but not in non-regenerative animals. We conclude that Sox2 is necessary for spinal cord regeneration and suggest a model whereby spinal cord injury activates proliferation of Sox2/3 expressing cells and their differentiation into neurons, a mechanism that is lost in non-regenerative froglets. PMID- 25797153 TI - Differential levels of Neurod establish zebrafish endocrine pancreas cell fates. AB - During development a network of transcription factors functions to differentiate foregut cells into pancreatic endocrine cells. Differentiation of appropriate numbers of each hormone-expressing endocrine cell type is essential for the normal development of the pancreas and ultimately for effective maintenance of blood glucose levels. A fuller understanding of the details of endocrine cell differentiation may contribute to development of cell replacement therapies to treat diabetes. In this study, by using morpholino and gRNA/Cas9 mediated knockdown we establish that differential levels of the basic-helix loop helix (bHLH) transcription factor Neurod are required for the differentiation of distinct endocrine cell types in developing zebrafish. While Neurod plays a role in the differentiation of all endocrine cells, we find that differentiation of glucagon-expressing alpha cells is disrupted by a minor reduction in Neurod levels, whereas differentiation of insulin-expressing beta cells is less sensitive to Neurod depletion. The endocrine cells that arise during embryonic stages to produce the primary islet, and those that arise subsequently during larval stages from the intra-pancreatic duct (IPD) to ultimately contribute to the secondary islets, show similar dependence on differential Neurod levels. Intriguingly, Neurod-deficiency triggers premature formation of endocrine precursors from the IPD during early larval stages. However, the Neurod-deficient endocrine precursors fail to differentiate appropriately, and the larvae are unable to maintain normal glucose levels. In summary, differential levels of Neurod are required to generate endocrine pancreas subtypes from precursors during both embryonic and larval stages, and Neurod function is in turn critical to endocrine function. PMID- 25797154 TI - Identification of singles bar as a direct transcriptional target of Drosophila Myocyte enhancer factor-2 and a regulator of adult myoblast fusion. AB - In Drosophila, myoblast fusion is a conserved process in which founder cells (FCs) and fusion competent myoblasts (FCMs) fuse to form a syncytial muscle fiber. Mutants for the myogenic regulator Myocyte enhancer factor-2 (MEF2) show a failure of myoblast fusion, indicating that MEF2 regulates the fusion process. Indeed, chromatin immunoprecipitation studies show that several genes involved in myoblast fusion are bound by MEF2 during embryogenesis. Of these, the MARVEL domain gene singles bar (sing), is down-regulated in MEF2 knockdown pupae, and has five consensus MEF2 binding sites within a 9000-bp region. To determine if MEF2 is an essential and direct regulator of sing during pupal muscle development, we identified a 315-bp myoblast enhancer of sing. This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity. We show that lack of sing expression resulted in adult lethality and muscle loss, due to a failure of fusion during the pupal stage. Additionally, we sought to determine if sing was required in either FCs or FCMs to support fusion. Interestingly, knockdown of sing in either population did not significantly affect fusion, however, knockdown in both FCs and FCMs resulted in muscles with significantly reduced nuclei numbers, provisionally indicating that sing function is required in either cell type, but not both. Finally, we found that MEF2 regulated sing expression at the embryonic stage through the same 315-bp enhancer, indicating that sing is a MEF2 target at both critical stages of myoblast fusion. Our studies define for the first time how MEF2 directly controls fusion at multiple stages of the life cycle, and provide further evidence that the mechanisms of fusion characterized in Drosophila embryos is also used in the formation of the more complex adult muscles. PMID- 25797155 TI - Accumulation of intra-cellular polyphosphate in Chlorella vulgaris cells is related to indole-3-acetic acid produced by Azospirillum brasilense. AB - Accumulation of intra-cellular phosphate, as polyphosphate, was measured when the microalga Chlorella vulgaris was immobilized in alginate with either of two wild type strains of the microalgae growth-promoting bacterium Azospirillum brasilense or their corresponding IAA-attenuated mutants. Wild type strains of A. brasilense induced higher amounts of intra-cellular phosphate in Chlorella than their respective mutants. Calculations comparing intra-cellular phosphate accumulation by culture or net accumulation by the cell and the amount of IAA that was produced by each of these strains revealed that higher IAA was linked to higher accumulations of intra-cellular phosphate. Application of four levels of exogenous IAA reported for A. brasilense and their IAA-attenuated mutants to cultures of C. vulgaris enhanced accumulation of intra-cellular phosphate; the higher the content of IAA per culture or per single cell, the higher was the amount of accumulated phosphate. When an IAA-attenuated mutant was complemented with exogenous IAA, accumulation of intra-cellular phosphate at the culture level was even higher than phosphate accumulation with the respective wild type strains. When calculating the net accumulation of intra-cellular phosphate in the complementation experiment, net intra-cellular phosphate induced by the IAA attenuated mutant was completely restored and was similar to the wild strains. We propose that IAA produced by A. brasilense is linked to polyphosphate accumulation in C. vulgaris. PMID- 25797156 TI - Regarding sudden cardiac death in soccer players. PMID- 25797157 TI - Ultrasound-assisted selective hydrogenation of C-5 acetylene alcohols with Lindlar catalysts. AB - The selective hydrogenation of 2-methyl-3-butyn-2-ol (MBY) was performed in the presence of Lindlar catalyst, comparing conventional stirring with sonication at different frequencies of 40, 380 and 850 kHz. Under conventional stirring, the reaction rates were limited by intrinsic kinetics, while in the case of sonication, the reaction rates were 50-90% slower. However, the apparent reaction rates were found to be significantly frequency dependent with the highest rate observed at 40 kHz. The original and the recovered catalysts after the hydrogenation reaction were compared using bulk elemental analysis, powder X-ray diffraction and scanning and transmission electron microscopy coupled with energy dispersive X-ray analysis. The studies showed that sonication led to the frequency-dependent fracturing of polycrystalline support particles with the highest impact caused by 40 kHz sonication, while monocrystals were undamaged. In contrast, the leaching of Pd/Pb particles did not depend on the frequency, which suggests that sonication removed only loosely-bound catalyst particles. PMID- 25797158 TI - Letter to the Editor regarding Bajaj D, et al., The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate, Bone 2014;64:57-64. PMID- 25797159 TI - Synthetic approaches to the 2013 new drugs. AB - New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review. PMID- 25797160 TI - A combination of in silico and SAR studies to identify binding hot spots of Bcl xL inhibitors. AB - Inhibition of Bcl-2 family protein-protein interactions (PPI) is a very promising direction in cancer chemotherapy. Hence over the last decade, many medicinal chemistry studies endeavoured to discover drug candidates, and a wealth of chemical scaffolds with striking chemical diversity was reported as Bcl-xL inhibitors. This raises the question of whether all these molecules could occupy a unique binding site, or rather discrete pockets of the protein surface. To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors. PMID- 25797161 TI - Novel 2-(2-phenalkyl)-1H-benzo[d]imidazoles as antitubercular agents. Synthesis, biological evaluation and structure-activity relationship. AB - A series of novel 2-(2-phenalkyl)-1H-benzo[d]imidazole derivatives and analogues (2a-3l) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with phenethyl, styryl and 3,5 dichlorophenethyl moiety were obtained. Compounds 2g, 2h and 2i bearing methyl groups at the benzimidazole system and phenalkyl substituent at the C-2 position showed high tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 0.8 to 6.2 MUg/mL (2.5-25 MUM). More importantly, derivatives 2g (5,6-dimethyl-2-phenethyl-1H-benzo[d]imidazole) and 2i (2-(3,5 dichlorophenethyl)-5,6-dimethyl-1H-benzo[d]imidazole) appeared selective for M. tuberculosis as compared with eukaryotic cells: non-malignant (neonatal human dermal fibroblasts) and malignant (mouse melanoma B16-F10 cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents. SAR studies resulted in interesting conclusions on structural factors affecting tuberculostatic activity. PMID- 25797162 TI - Synthesis, optical properties and preliminary in vitro photodynamic effect of pyridyl and quinoxalyl substituted chlorins. AB - A series of chlorophyll a-based chlorins conjugated with pyridyl or quinoxalyl group at different positions were synthesized, characterized and evaluated for their photodynamic effect in vitro. It was found that all the pyridyl and quinoxalyl chlorins showed promising photocytotoxicities but nontoxic without irradiation in HeLa cells, and the substituted types and positions had a significant influence on the photocytotoxicities of the chlorophyll a-based chlorins. All the chlorins with a pyridyl group at the C-D ring end exhibited relatively high photocytotoxicity as compared to those with 3(2)-pyridyl. Among them, compound 12 conjugated with a pyridyl group at its C12 position showed the best photodynamic effect in HeLa cells with an IC50 value of 0.033MUM. These facts, associated with the relative high long wavelength absorptions of those chlorins may provide valuable ways to design and prepare promising photosensitizers for application in photodynamic therapy. PMID- 25797163 TI - Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators. AB - A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC50 value of 79 nM which is ~2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators. PMID- 25797164 TI - Discovery and structure-activity relationships of pyrazolodiazepine derivatives as the first small molecule agonists of the Drosophila sex peptide receptor. AB - In behavioral research, the sex peptide receptor in Drosophila melanogaster (DrmSPR) is the most interesting G protein-coupled receptor (GPCR) and is involved in post-mating responses such as increased egg-laying and decreased receptivity of the female; during these responses, the receptors are activated by a specific natural peptide agonist (sex peptide, SP). To discover small molecule agonists for DrmSPR, a compound library based on a pyrazolodiazepine scaffold, which was previously reported as a potential privileged structure, was screened. Structure-activity relationship (SAR) studies of the hit compounds, which exhibited weak agonistic effects (69-72% activation at 100MUM), were explored through the synthesis of various analogs with substituents at the R1, R2, R3 and R4 positions of the pyrazolodiazepine skeleton. As a result, compounds 21 and 31 of the 6-benzyl pyrazolodiazepine derivative series were found to be small molecule agonists for DrmSPR with EC50 values of 3-4MUM. PMID- 25797166 TI - Improvement of efficiency in the enzymatic synthesis of lactulose palmitate. AB - Sugar esters are considered as surfactants due to its amphiphilic balance that can lower the surface tension in oil/water mixtures. Enzymatic syntheses of these compounds are interesting both from economic and environmental considerations. A study was carried out to evaluate the effect of four solvents, temperature, substrate molar ratio, biocatalyst source, and immobilization methodology on the yield and specific productivity of lactulose palmitate monoester synthesis. Lipases from Pseudomonas stutzeri (PsL) and Alcaligenes sp. (AsL), immobilized in porous silica functionalized with octyl groups (adsorption immobilization, OS) and with glyoxyl-octyl groups (both adsorption and covalent immobilization, OGS), were used. The highest lactulose palmitate yields were obtained at 47 degrees C in acetone, for all biocatalysts, while the best lactulose:palmitic acid molar ratio differed according to the immobilization methodology, being 1:1 for AsL-OGS biocatalyst (20.7 +/- 3%) and 1:3 for the others (30-50%). PMID- 25797165 TI - Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents. AB - Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease beta-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 MUM and 0.099 MUM, respectively, and the former features equivalent potency on the chloroquine resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study. PMID- 25797167 TI - Pharmacodynamic profile and drug interactions with non-vitamin K antagonist oral anticoagulants: implications for patients with atrial fibrillation. AB - INTRODUCTION: Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to prevent ischemic stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation. Owing to their predictable pharmacological profiles, they can be given in fixed doses without the need for routine coagulation monitoring. However, their distinctive pharmacological properties also raise issues about potential drug interactions. AREAS COVERED: A literature search was conducted to extract published studies on the pharmacodynamics and drug interactions involving NOACs. Available data from US FDA and European Medicine Agency were also included. As these agents are substrates of permeability glycoprotein (P-gp) efflux transporter and/or CYP3A4 enzymes, articles focusing on the co-administration of NOACs and drugs affecting these pathways are discussed. Concomitant use of NOACs with antiplatelet agents may potentially increase bleeding risk. EXPERT OPINION: Measurement of anticoagulant effects is desired to evaluate the risk of thromboembolism or bleeding for patients with NOACs. Prescribers should be vigilant against combination prescription of NOACs with strong inhibitors (such as ketoconazole) or inducers of P-gp and/or CYP3A4 (such as rifampicin). Potential benefit of concurrent use of these agents with antiplatelet drugs should be cautiously balanced against latent risk in specific clinical situations. PMID- 25797168 TI - On the origin and variation of colors in lobster carapace. AB - The chemical basis of the blue-black to pink-orange color change on cooking of lobster, due to thermal denaturation of an astaxanthin-protein complex, alpha crustacyanin, in the lobster carapace, has so far been elusive. Here, we investigate the relaxation of the astaxanthin pigment from its bound enolate form to its neutral hydroxyketone form, as origin of the spectral shift, by analyzing the response of UV-vis spectra of a water-soluble 3-hydroxy-4-oxo-beta-ionone model of astaxanthin to increases in pH, and by performing extensive quantum chemical calculations over a wide range of chemical conditions. The enolization of astaxanthin is consistent with the X-ray diffraction data of beta-crustacyanin (PDB code: ) whose crystals possess the distinct blue color. We find that enolate formation is possible within the protein environment and associated with a large bathochromic shift, thus offering a cogent explanation for the blue-black color and the response to thermal denaturation and revealing the chemistry of astaxanthin upon complex formation. PMID- 25797170 TI - Measurements of the effect of membrane asymmetry on the mechanical properties of lipid bilayers. AB - We detail an approach for constructing asymmetric membranes and characterising their mechanical properties, leading to the first measurement of the effect of asymmetry on lipid bilayer mechanics. Our results demonstrate that asymmetry induces a significant increase in rigidity compared to symmetric membranes. Given that all biological membranes are asymmetric our findings have profound implications for the role of this phenomenon in biology. PMID- 25797171 TI - Conservative Management of Invasive Placenta Using Combined Prophylactic Internal Iliac Artery Balloon Occlusion and Immediate Postoperative Uterine Artery Embolization. AB - PURPOSE: The objective of the study was to evaluate the efficacy and safety of combined prophylactic intraoperative internal iliac artery balloon occlusion and postoperative uterine artery embolization in the conservative management (uterine preservation) of women with invasive placenta undergoing scheduled caesarean delivery. METHODS: Ten women (mean age 35 years) with invasive placenta choosing caesarean delivery without hysterectomy had preoperative insertion of internal iliac artery occlusion balloons, intraoperative inflation of the balloons, and immediate postoperative uterine artery embolization with absorbable gelatin sponge. A retrospective review was performed with institutional review board approval. Outcome measures were intraoperative blood loss, transfusion requirement, hysterectomy rate, endovascular complications, surgical complications, and postoperative morbidity. RESULTS: All women had placenta increta or percreta, and concomitant complete placenta previa. Mean gestational age at delivery was 36 weeks. In 6 women the placenta was left undisturbed in the uterus, 2 had partial removal of the placenta, and 2 had piecemeal removal of the whole placenta. Mean estimated blood loss during caesarean delivery was 1.2 L. Only 2 patients (20%) required blood transfusion. There were no intraoperative surgical complications, endovascular complications, maternal deaths, or perinatal deaths. Three women developed postpartum complications necessitating postpartum hysterectomy; the hysterectomy rate was therefore 30% and uterine preservation was successful in 70%. CONCLUSION: Combined bilateral internal iliac artery balloon occlusion and uterine artery embolization may be an effective strategy to control intraoperative blood loss and preserve the uterus in patients with invasive placenta undergoing caesarean delivery. PMID- 25797169 TI - Deciphering the Roles of Multicomponent Recognition Signals by the AAA+ Unfoldase ClpX. AB - ATP-dependent protein remodeling and unfolding enzymes are key participants in protein metabolism in all cells. How these often-destructive enzymes specifically recognize target protein complexes is poorly understood. Here, we use the well studied AAA+ unfoldase-substrate pair, Escherichia coli ClpX and MuA transposase, to address how these powerful enzymes recognize target protein complexes. We demonstrate that the final transposition product, which is a DNA-bound tetramer of MuA, is preferentially recognized over the monomeric apo-protein through its multivalent display of ClpX recognition tags. The important peptide tags include one at the C-terminus ("C-tag") that binds the ClpX pore and a second one (enhancement or "E-tag") that binds the ClpX N-terminal domain. We construct a chimeric protein to interrogate subunit-specific contributions of these tags. Efficient remodeling of MuA tetramers requires ClpX to contact a minimum of three tags (one C-tag and two or more E-tags), and that these tags are contributed by different subunits within the tetramer. The individual recognition peptides bind ClpX weakly (KD>70 MUM) but impart a high-affinity interaction (KD~1.0 MUM) when combined in the MuA tetramer. When the weak C-tag signal is replaced with a stronger recognition tag, the E-tags become unnecessary and ClpX's preference for the complex over MuA monomers is eliminated. Additionally, because the spatial orientation of the tags is predicted to change during the final step of transposition, this recognition strategy suggests how AAA+ unfoldases specifically distinguish the completed "end-stage" form of a particular complex for the ideal biological outcome. PMID- 25797172 TI - IgE autoantibodies in bullous pemphigoid: supporting role, or leading player? AB - Bullous pemphigoid (BP) is a common autoimmune blistering skin disease in which two hemidesmosomal components--the transmembrane collagen XVII (BP180 or BPAG2) and the plakin family protein BP230 (BPAG1)--are targeted by autoimmunity. Of these, collagen XVII (COL17) is thought to be a major autoantigen, and vital roles of IgG autoantibodies in blister formation have been elucidated. However, BP shows distinct features, including pruritic urticarial erythema and eosinophilic infiltration, which may be independent of IgG-mediated autoimmunity. Recently, it has been revealed that sera from certain patients with BP contain IgE autoantibodies to COL17 and that IgE autoantibodies bind to peri-lesional dermal-epidermal junctions. Mouse models have demonstrated that IgE antibodies to COL17 induce erythema and eosinophilic infiltration in skin. In addition, the successful treatment of severe BP with omalizumab, a humanized monoclonal antibody targeting IgE, has been reported. These findings suggest that both IgG and IgE autoantibodies to COL17 may be involved in the BP pathogenesis. This article summarizes IgE-mediated autoimmunity to COL17 in BP. PMID- 25797173 TI - Circulating IgE anti-BP180 autoantibody and its correlation to clinical and laboratorial aspects in bullous pemphigoid patients. PMID- 25797174 TI - Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors. AB - We enrolled 30 patients on a prospective phase II trial utilizing a total body irradiation (TBI)-based myeloablative preparative regimen (fludarabine 30 mg/m2/day * 3 days and TBI 150 cGy twice per day on day -4 to -1 [total dose 1200 cGy]) followed by infusion of unmanipulated peripheral blood stem cells from a haploidentical family donor (haplo). Postgrafting immunosuppression consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil through day 35, and tacrolimus through day 180. Median patient age was 46.5 years (range, 24 to 60). Transplantation diagnosis included acute myelogenous leukemia (n = 16), acute lymphoblastic leukemia (n = 6), chronic myelogenous leukemia (n = 5), myelodysplastic syndrome (n = 1), and non-Hodgkin's lymphoma (n = 2). Using the Dana Farber/Center for International Blood and Marrow Transplant Research/Disease Risk Index (DRI), patients were classified as low (n = 4), intermediate (n = 12), high (n = 11), and very high (n = 3) risk. All patients engrafted with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Acute graft-versus-host disease (GVHD) grades II to IV and III and IV was seen in 43% and 23%, respectively. The cumulative incidence of chronic GVHD was 56% (severe in 10%). After a median follow-up of 24 months, the estimated 2 year overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and relapse rate were 78%, 73%, 3%, and 24%, respectively. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0%, respectively, compared with 39% and 53% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative HLA-matched unrelated donor (MUD) transplantation (acute myelogenous leukemia [n = 17], acute lymphoblastic leukemia [n = 15], chronic myelogenous leukemia [n = 7], myelodysplastic syndrome [n = 7], non-Hodgkin lymphoma [n = 1], chronic lymphoblastic leukemia [n = 1]), outcomes were statistically similar, with 2-yr OS and DFS being 78% and 73%, respectively after haplo transplantation versus 71% and 64%, respectively, after MUD transplantation. In patients with DRI low/intermediate risk disease, 2-yr DFS was superior after haplo compared with MUD transplantations (100% versus 74%, P = .032), whereas there was no difference in DFS in patients with high/very high risk disease (39% versus 37% for haplo and MUD respectively, P = .821). Grade II to IV acute GVHD was seen less often after haplo compared with MUD transplantation (43% versus 63%, P = .049), as was moderate-to-severe chronic GVHD (22% versus 58%, P = .003). Myeloablative haplo transplantation using this regimen is a valid option for patients with advanced hematologic malignancies who lack timely access to a conventional donor. Outcomes appear at least equivalent to those seen in contemporaneous patients who underwent transplantation from MUD. PMID- 25797175 TI - Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease? AB - Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD-free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3(+) cells >= 50 * 10(6)/kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD. PMID- 25797176 TI - Reply to: transient grades three to four acute hepatitis is a common complication of rabbit antithymocyte globulin (thymoglobulin) administered before allogeneic stem cell transplantation. PMID- 25797177 TI - Dihydromyricetin improves skeletal muscle insulin resistance by inducing autophagy via the AMPK signaling pathway. AB - Skeletal muscle insulin resistance (SMIR) plays an important role in the pathogenesis of type 2 diabetes. Dihydromyricetin (DHM), a natural flavonoid, exerts various bioactivities including anti-oxidative and hepatoprotective effects. Herein, we intended to determine the effect of DHM on SMIR and the underlying mechanisms. We found that DHM increased the expression of phosphorylated insulin receptor substrate-1, phosphorylated Akt and glucose uptake capacity in palmitate-treated L6 myotubes under insulin-stimulated conditions. The expression of light chain 3, Beclin 1, autophagy-related gene 5 (Atg5), the degradation of sequestosome 1 and the formation of autophagosomes were also upregulated by DHM. Suppression of autophagy by 3-methyladenine and bafilomycin A1 or Atg5 and Beclin1 siRNA abolished the favorable effects of DHM on SMIR. Furthermore, DHM increased the levels of phosphorylated AMP-activated protein kinase (AMPK) and Ulk1, and decreased phosphorylated mTOR levels. AMPK inhibitor compound C (CC) and AMPK siRNA abrogated DHM-induced autophagy, subsequently suppressed DHM-induced SMIR improvement. Additionally, DHM inhibited the activity of F1F0-ATPase thereby activating AMPK. Finally, the results of in vivo study conducted in high fat diet-fed rats were consistent with the findings of in vitro study. In conclusion, DHM improved SMIR by inducing autophagy via the activation of AMPK signaling pathway. PMID- 25797178 TI - Insulin receptor isoform A confers a higher proliferative capability to pancreatic beta cells enabling glucose availability and IGF-I signaling. AB - The main compensatory response to insulin resistance is the pancreatic beta cell hyperplasia to account for increased insulin secretion. In fact, in a previous work we proposed a liver-pancreas endocrine axis with IGF-I (insulin-like growth factor type I) secreted by the liver acting on IRA insulin receptor in beta cells from iLIRKO mice (inducible Liver Insulin Receptor KnockOut) that showed a high IRA/IRB ratio. However, the role of insulin receptor isoforms in the IGF-I induced beta cell proliferation as well as the underlying molecular mechanisms remain poorly understood. For this purpose, we have used four immortalized mouse beta cell lines: bearing IR (IRLoxP), lacking IR (IRKO), expressing exclusively IRA (IRA), or alternatively expressing IRB (IRB). Pancreatic beta cell proliferation studies showed that IRA cells are more sensitive than those expressing IRB to the mitogenic response induced by IGF-I, acting through the pathway IRA/IRS-1/2/alphap85/Akt/mTORC1/p70S6K. More importantly, IRA beta cells, but not IRB, showed an increased glucose uptake as compared with IRLoxP cells, this effect being likely owing to an enhanced association between Glut-1 and Glut 2 with IRA. Overall, our results strongly suggest a prevalent role of IRA in glucose availability and IGF-I-induced beta cell proliferation mainly through mTORC1. These results could explain, at least partially, the role played by the liver-secreted IGF-I in the compensatory beta cell hyperplasia observed in response to severe hepatic insulin resistance in iLIRKO mice. PMID- 25797179 TI - Adenosine/guanosine-3',5'-bis-phosphates as biocompatible and selective Zn2+-ion chelators. Characterization and comparison with adenosine/guanosine-5'-di phosphate. AB - Although involved in various physiological functions, nucleoside bis-phosphate analogues and their metal-ion complexes have been scarcely studied. Hence, here, we explored the solution conformation of 2'-deoxyadenosine- and 2'-deoxyguanosine 3',5'-bisphosphates, 3 and 4, d(pNp), as well as their Zn(2+)/Mg(2+) binding sites and binding-modes (i.e. inner- vs. outer-sphere coordination), acidity constants, stability constants of their Zn(2+)/Mg(2+) complexes, and their species distribution. Analogues 3 and 4, in solution, adopted a predominant Southern ribose conformer (ca. 84%), gg conformation around C4'-C5' and C5'-O5' bonds, and glycosidic angle in the anti-region (213-270 degrees ). (1)H- and (31)P-NMR experiments indicated that Zn(2+)/Mg(2+) ions coordinated to P5' and P3' groups of 3 and 4 but not to N7 nitrogen atom. Analogues 3 and 4 formed ca. 100-fold more stable complexes with Zn(2+)vs. Mg(2+)-ions. Complexes of 3 and 4 with Mg(2+) at physiological pH were formed in minute amounts (11% and 8%, respectively) vs. Zn(2+) complexes (46% and 44%). Stability constants of Zn(2+)/Mg(2+) complexes of analogues 3 and 4 (log KML(M) = 4.65-4.75/2.63-2.79, respectively) were similar to those of the corresponding complexes of ADP and GDP (log KML(M) = 4.72-5.10/2.95-3.16, respectively). Based on the above findings, we hypothesized that the unexpectedly low log K values of Zn(2+)-d(pNp) as compared to Zn(2+)-NDP complexes, are possibly due to formation of outer-sphere coordination in the Zn(2+)-d(pNp) complex vs. inner-sphere in the NDP-Zn(2+) complex, in addition to loss of chelation to N7 nitrogen atom in Zn(2+)-d(pNp). Indeed, explicit solvent molecular dynamics simulations of 1 and 3 for 100 ns supported this hypothesis. PMID- 25797180 TI - Understanding charge transfer in carbon nanotube-fullerene bulk heterojunctions. AB - Semiconducting single-walled carbon nanotube/fullerene bulk heterojunctions exhibit unique optoelectronic properties highly suitable for flexible, efficient, and robust photovoltaics and photodetectors. We investigate charge-transfer dynamics in inverted devices featuring a polyethylenimine-coated ZnO nanowire array infiltrated with these blends and find that trap-assisted recombination dominates transport within the blend and at the active layer/nanowire interface. We find that electrode modifiers suppress this recombination, leading to high performance. PMID- 25797181 TI - Improved heart rate recovery despite reduced exercise performance following heavy training: A within-subject analysis. AB - OBJECTIVES: The recovery of heart rate (HRR) after exercise is a potential indicator of fitness which has been shown to respond to changes in training. This study investigated the within-individual association between HRR and exercise performance following three different training loads. DESIGN: 11 male cyclists/triathletes were tested after two weeks of light training, two weeks of heavy training and two days of rest. METHODS: Exercise performance was measured using a 5-min maximal cycling time-trial. HRR was measured over 60s during supine recovery. RESULTS: Exercise performance decreased 2.2+/-2.5% following heavy training compared with post-light training (p=0.01), and then increased 4.0+/ 4.2% following rest (p=0.004). Most HRR indices indicated a more rapid recovery of heart rate (HR) following heavy training, and reverted to post light training levels following two days of rest. HRR indices did not differ between post-light training and after the rest period (p>0.6). There were inverse within-subject relationships between indices of HRR and performance (r=-0.6, p<=0.004). Peak HR decreased 3.2+/-5.1bpm following heavy training (p=0.06) and significantly increased 4.9+/-4.3bpm following recovery (p=0.004). There was a moderate within subject relationship between peak HR and exercise performance (r=0.7, p<=0.001). Controlling for peak HR reduced the relationships between HRR and performance (r= 0.4-0.5, p<0.05). CONCLUSIONS: This study demonstrated that HRR tracks short-term changes in exercise performance within-individuals, such that increases in HRR are associated with poorer exercise performance following heavy training. Peak HR can be compromised under conditions of fatigue, and needs to be taken into account in HRR analyses. PMID- 25797182 TI - Ambiguous effect of signals transmitted by the vagus nerve on fibrosarcoma incidence and survival of tumor-bearing rats. AB - While the parasympathetic nervous system appears to be involved in the regulation of tumor progression, its exact role is still unclear. Therefore, using a rat BP6 TU2 fibrosarcoma tumor model, we investigated the effect of (1) reduction of vagal activity produced by subdiaphragmatic vagotomy; and (2) enhancement of vagal activity produced by continuous delivery of electric impulses to the cervical part of the vagus nerve on tumor development and survival of tumor bearing rats. We also evaluated the expression of cholinergic receptors within in vitro cultivated BP6-TU2 cells. Interestingly, we found that both, vagal stimulation and subdiaphragmatic vagotomy slightly reduced tumor incidence. However, survival of tumor-bearing rats was not affected by any of the experimental approaches. Additionally, we detected mRNA expression of the alpha1, alpha2, alpha5, alpha7, and alpha10 subunits of nicotinic receptors and the M1, M3, M4, and M5 subtypes of muscarinic receptors within in vitro cultivated BP6 TU2 cells. Our data indicate that the role of the vagus nerve in modulation of fibrosarcoma development is ambiguous and uncertain and requires further investigation. PMID- 25797183 TI - Serotonin levels in the dorsal raphe nuclei of both chipmunks and mice are enhanced by long photoperiod, but brain dopamine level response to photoperiod is species-specific. AB - Seasonal affective disorder (SAD) is a subtype of major depressive or bipolar disorders associated with the shortened photoperiod in winter. This depressive disorder is integrally tied to the seasonal regulation of the brain's serotonergic system. Recently, we found that C57BL/6J mice subjected to a forced swim test exhibited immobility, a photoperiod-dependent depression-associated behavior, and suppression of brain serotonin levels. However, mice are nocturnal animals, and it is unclear whether the brain serotonergic system responds similarly to photoperiod in nocturnal and diurnal species. This study compared the responses of brain serotonergic and dopaminergic systems to photoperiod in diurnal chipmunks and nocturnal C57BL/6J mice. In both species, serotonin levels in the dorsal raphe nuclei were higher under long-day conditions than short-day conditions, suggesting a similarity in the photoperiod responses of the serotonergic systems. However, photoperiod affected dopamine levels in various brain regions differently in the two species. Some chipmunk brain regions exhibited stronger photoperiod-induced changes in dopamine levels than those of C57BL/6J mice, and the direction of the changes in the hypothalamus was opposite. In conclusion, photoperiod may regulate the brain serotonergic system through similar mechanisms, regardless of whether the animals are diurnal or nocturnal, but photoperiod-dependent regulation of brain dopamine is species-specific. PMID- 25797184 TI - Immunolocalization of histamine in the optic neuropils of Scutigera coleoptrata (Myriapoda: Chilopoda) reveals the basal organization of visual systems in Mandibulata. AB - Myriapods play a crucial role in considerations of evolutionary transformations of arthropod nervous systems. The existing descriptions of the identity and connectivity of myriapod optic neuropils are contradictory. This study asks if the first and second optic neuropil of the scutigeromorph centipede Scutigera coleoptrata correspond to the optic neuropils of Hexapoda and malacostracan Crustacea, the lamina and medulla which are linked by neurites that are arranged in a characteristic optic chiasm. To identify photoreceptor axons, we used immunohistochemistry against histamine which is the universal transmitter of arthropod photoreceptors. Our results provide evidence that the two optic neuropils of S. coleoptrata correspond to the lamina and medulla of Hexapoda and Malacostraca and strongly argue against a correspondence of the optic neuropils in branchiopod crustaceans and scutigeromorphs, as was previously suggested. We conclude that these two retinotopic optic neuropils and an outer optic chiasm are part of the ground pattern of Mandibulata and that the visual systems of branchiopod crustaceans were simplified from this ground pattern. PMID- 25797185 TI - Muscarinic acetylcholine receptor in cerebellar cortex participates in acetylcholine-mediated blood depressor response in rats. AB - Our previous investigations have revealed that cerebellar cholinergic innervation is involved in cardiovascular regulation. This study was performed to examine the effects of the muscarinic cholinergic receptor (mAChR) in the cerebellar cortex on blood pressure (BP) modulation in rats. Acetylcholine (ACh, 100mM), nonselective mAChR agonist (oxotremorine M; Oxo-M, 10, 30 and 100mM) and 100mM ACh mixed with nonselective mAChR antagonist atropine (1, 3 and 10mM) were microinjected into the cerebellar cortex of anesthetized rats. Mean arterial pressure (MAP), maximal decreased MAP (MDMAP), and reaction time (duration required for BP to return to basal values) were measured and analyzed. The results showed that Oxo-M dose-dependently decreased MAP, increased MDMAP, and prolonged reaction time, which displayed a homodromous effect of ACh-mediated blood depressor response; meanwhile, atropine concentration-dependently blocked the effect of ACh on the BP regulation. In conclusion, the present study showed for the first time that mAChRs in cerebellar cortex could modulate somatic BP by participation in ACh-mediated depressor response. PMID- 25797186 TI - Low-level laser therapy for prevention of noise-induced hearing loss in rats. AB - Noninvasive low-level laser therapy (LLLT) is neuroprotective, but the mechanism of this effect is not fully understood. In this study, the use of LLLT as a novel treatment for noise-induced hearing loss (NIHL) is investigated. Sprague-Dawley rats were exposed to intense noise and their right ears were irradiated with an 808nm diode laser at an output power density of 110 or 165mW/cm(2) for a 30min period for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with LLLT compared with the non-treatment group at days 2, 4, 7 and 14 after noise exposure. Morphological observations also revealed a significantly higher outer hair cell survival rate in the LLLT groups. Immunohistochemical analyses for inducible nitric oxide synthase (iNOS) and cleaved caspase-3 were used to examine oxidative stress and apoptosis. Strong immunoreactivities were observed in the inner ear tissues of the non-treatment group, whereas these signals were decreased in the LLLT group at 165mW/cm(2) power density. Our findings suggest that LLLT has cytoprotective effects against NIHL via the inhibition of iNOS expression and apoptosis. PMID- 25797187 TI - Postural control during transient floor translation while standing with the leg and trunk fixed. AB - Postural movement was restricted above the ankle, and contingent negative variation (CNV) and postural muscle activity were investigated during a transient floor translation (S2) 2s after an auditory warning signal (S1). For 13 healthy young adults, the joints of the knee, hip, and trunk were fixed using a cast brace. Under no-fixation and fixation, a set of 10 translations was repeated at least 4 times, and center of pressure in the anteroposterior direction (CoPap), posterior postural muscle activity of the body (elector spinae (ES), biceps femoris (BF), gastrocnemius (GcM) and soleus (Sol)), and late CNV at Cz were analyzed in the initial two sets (initial set) and last two sets (late set). In the no-fixation, CoPap forward displacement after S2 gradually decreased. In the first trial of the fixation, it had significantly increased, and then rapidly decreased across subsequent trials. CNV peak amplitude was largest in the late set of the fixation. The activity of postural muscles increased just before S2 and in the late set the start time showed high correlations with CNV peak time in all muscles (ES (r=0.88), BF (0.92), GcM (0.80), and Sol (0.89)) under the no fixation, but exclusively in the GcM (0.84) and Sol (0.88) under the fixation. When postural control was restricted mainly to the ankle, attention would have been focused mainly on processing sensory information from the triceps surae just before the floor translation. PMID- 25797188 TI - Behavioral and cognitive effects of tyrosine intake in healthy human adults. AB - The amino acid tyrosine is the precursor to the catecholamine neurotransmitters dopamine and norepinephrine. Increasing tyrosine uptake may positively influence catecholamine-related psychological functioning. We conducted a systematic review to examine the effects of tyrosine on behavior and cognition. Fifteen studies were reviewed. All studies except one involved tyrosine loading during a single test session. In most behavioral studies, there were no significant effects of tyrosine on exercise performance. In contrast, cognitive studies employing neuropsychological measures found that tyrosine loading acutely counteracts decrements in working memory and information processing that are induced by demanding situational conditions such as extreme weather or cognitive load. The buffering effects of tyrosine on cognition may be explained by tyrosine's ability to neutralize depleted brain catecholamine levels. There is evidence that tyrosine may benefit healthy individuals exposed to demanding situational conditions. For future research we recommend moving from studying the acute effects of a single tyrosine load in small samples to studying the behavioral and cognitive effects of tyrosine in larger groups over multiple weeks. PMID- 25797189 TI - [Update of recommendations for evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions. Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology]. AB - OBJECTIVE: To update previous recommendations developed by the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition for the evaluation and treatment of osteoporosis associated to different endocrine and nutritional diseases. PARTICIPANTS: Members of the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition. METHODS: Recommendations were formulated according to the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each condition: AND "osteoporosis", "fractures", "bone mineral density", and "treatment". Papers in English with publication date between 18 October 2011 and 30 October 2014 were included. The recommendations were discussed and approved by all members of the Working Group. CONCLUSIONS: This update summarizes the new data regarding evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions. PMID- 25797190 TI - Low serum interleukin-6 levels as a predictive marker of recurrence in patients with hepatitis B virus related hepatocellular carcinoma who underwent curative treatment. AB - BACKGROUND: We aimed to investigate the use of novel serum biomarkers for predicting the recurrence and survival of patients with hepatitis B virus (HBV) related early hepatocellular carcinoma (HCC) after hepatic resection or radiofrequency ablation (RFA). METHODS: One hundred and five patients with HBV related HCC, who fulfilled the Milan criteria without vascular invasion and underwent hepatic resection or RFA, were followed-up for a median duration of 52months. Pretreatment serum concentrations of 16 cytokines including interleukin 6 (IL-6) were measured by using a Luminex 200 system. The measured serum cytokines and several clinical factors were analyzed retrospectively. RESULTS: Univariate analysis showed that patients with lower pretreatment serum levels of IL-10, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha had significantly shorter disease-free survival (DFS) than those with higher levels. Multivariate analysis revealed that a low serum IL-6 level (?33.00pg/mL; hazard ratio [HR]=5.39; 95% confidence interval [CI]=1.27-22.93; P=0.022), low platelet count (<100*10(9)/L; HR=2.23; 95% CI=1.28-3.89; P=0.005), and low serum albumin level (?3.5g/L; HR=2.26; 95% CI=1.28-3.97; P=0.005) had a negative prognostic impact on DFS. In the analysis for overall survival, a low serum platelet level (<100*10(9)/L; HR=2.80; 95% CI=1.31-5.99; P=0.008) and multiple tumor (?2; HR=4.05; 95% CI=1.56-10.48; P=0.004) showed a negative prognostic impact on the overall survival. CONCLUSION: A low serum IL-6 level is, in addition to low platelet count and low serum albumin level, an independent prognostic factor for DFS in patients with HBV-related early HCC who underwent hepatic resection or RFA with curative intention. PMID- 25797191 TI - Polymorphisms of IL-10 gene in patients infected with HCV under antiviral treatment in southern Brazil. AB - Interleukin-10 (IL-10) is a cytokine that plays an important role in the regulation of the immune system. Gene polymorphisms of IL-10 have been associated with the different expression levels of this cytokine. In hepatitis C virus infection, IL-10 appears to interfere with the progression of disease, viral persistence and the response to therapy. This study investigated genetic variability in the IL-10 gene promoter between patients infected with hepatitis C virus (HCV) and healthy individuals, associating the frequency of polymorphisms with different aspects of viral infection. This is a case-control study with 260 patients who were infected with HCV and 260 healthy individuals. Genotyping of the polymorphisms was performed using the technique of amplification refractory mutation system PCR (ARMS-PCR) for regions of the IL-10 gene promoter (-1082 G/A, -819 C/T, -592 C/A). The frequencies of alleles and genotypes related to polymorphisms in the IL-10 gene promoter showed a higher frequency of the G allele and genotype GG in the -1082 region between the infected group and the control group (p=0.005 and p=0.001, respectively), whereas the AA genotype was significantly more frequent in the control group. The frequencies of the haplotypes GTA and GCC were higher in the group of infected individuals, whereas the haplotype ATA was more frequent in the healthy group (p<0.006). It was also observed that the genotypes GG and AG in the region -1082 were significantly more frequent among patients infected with HCV who were in advanced stages of fibrosis and cirrhosis (p=0.042). No association was observed between polymorphisms of IL 10 and sustained virologic response (SVR). PMID- 25797192 TI - Reduction of ethanol intake by corticotropin-releasing factor receptor-1 antagonist in "heavy-drinking" mice in a free-choice paradigm. AB - RATIONALE: We hypothesized that the corticotropin-releasing factor (CRF) system is hyperresponsive in animals with high ethanol intake, which exhibits a reduction of ethanol intake when administered with a CRF1 receptor antagonist. METHODS: Outbred Swiss mice were subjected to a long-term, three-bottle, free choice paradigm (5 and 10 % [v/v] ethanol and water) that consisted of four phases: acquisition (AC; 10 weeks), withdrawal (W; 2 weeks), reexposure (RE; 2 weeks), and quinine-adulteration (AD; 2 weeks). Based on individual ethanol intake, the mice were classified into three groups: A group, preference for ethanol and persistently high consumption during AD phase; B group, preference for ethanol and a reduction of ethanol intake in the AD phase; and C group; preference for water during all phases. A control group only had access to water. CRF1 receptor messenger RNA (mRNA) levels in the amygdala and the effect of the CRF1 receptor antagonist CP-154,526 on ethanol and water intake in the subgroups were studied. RESULTS: CRF1 transcript levels were higher in the B group than in the control group. The highest dose of CP-154,526 reduced ethanol intake and preference, with no changes in water consumption, in the A group compared with vehicle. The B group exhibited a reduction of both ethanol and water intake, with no changes in preference. The C group exhibited no changes in response to the CRF1 antagonist. CONCLUSIONS: CRF1 receptors appear to be involved in ethanol consumption in mice with high ethanol consumption, and CRF system-mediated neuroadaptations depend on drinking profiles. PMID- 25797193 TI - Preventive use of intra-aortic balloon pump in patients undergoing high-risk coronary artery bypass grafting: a retrospective study. AB - BACKGROUND: Coronary artery bypass grafting (CABG) is an important therapeutic measure for CHD patients. The patients who score more than 12 EuroSCORE points cannot achieve good results because of their low cardiac output and delicate left ventricular function. Therefore, use of an intra-aortic balloon pump (IABP) is essential for coronary surgical patients in the peri-operative period. At present, there is no unified standard about when to insert an IABP. This study aimed to compare the short-term clinical outcomes of the IABP inserted in the preoperative condition with its use in the emergency condition for extremely high risk patients. MATERIAL AND METHODS: IABP support time, respirator support time, and ICU stay time were significantly shorter (all p<0.05) in the preoperative IABP group compared to the emergency IABP group, and the rates of low cardiac output syndrome (LCOS), acute myocardial infarction, and acute kidney injury in the preoperative group were also significantly lower in the preoperative IABP group (all p<0.05). There were no significant differences in IABP-related complications and the mortality (p=0.106) between two groups. RESULTS: Compared to the emergency IABP group, the IABP support time, respirator support time and ICU stay time were significantly lower in the preoperative IABP group (all p<0.05), and the rates of LCOS, acute myocardial infarction, and acute kidney injury in the preoperative group were also significantly lower (all p<0.05). There were no significant differences in IABP-related complications and the mortality (p=0.106) between the 2 groups. CONCLUSIONS: For high-risk patients with CABG, preoperative IABP insertion is a safe and effective measure. PMID- 25797194 TI - Carbon budgets of multispecies seagrass beds at Dongsha Island in the South China Sea. AB - Biomass, production, consumption, and detrital export and decomposition of four dominant seagrass species were determined in tropical multispecies beds as a means of constructing carbon budgets. These processes varied among seagrass species. The living biomass held a high carbon stock. The leaf production of multispecies beds was also higher than that of monospecific beds. However, the sediment organic carbon stock was much lower than the global median stock, which was likely due to decomposition of most of the detritus and export to nearshore waters. Reliable measurements of decomposition and export are particularly needed to estimate the organic carbon storage rate. PMID- 25797195 TI - Analysis of cytokine production in a newly developed canine tracheal epithelial cell line infected with H3N2 canine influenza virus. AB - The Madin-Darby canine kidney (MDCK) cell line is typically used to analyze pathological features after canine influenza virus (CIV) infection. However, MDCK cells are not the ideal cell type, because they are kidney epithelial cells. Therefore, we generated an immortalized canine tracheal epithelial cell line, KU CBE, to more reliably study immune responses to CIV infection in the respiratory tract. KU-CBE cells expressed the influenza virus receptor, alpha-2,3-sialic acid (SA), but not alpha-2,6-SA. KU-CBE and MDCK cells infected with H3N2 CIV demonstrated comparable virus growth kinetics. Gene expression levels of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-beta were estimated in both KU-CBE and MDCK cells infected with CIV by real-time reverse transcription polymerase chain reaction (qRT-PCR). Of these cytokines, IL-4, IL-10, TNF-alpha, and IFN-beta mRNAs were detected in both cell lines. Gene expression of IL-4, IL-10, and TNF alpha was not significantly different in the two cell lines. However, MDCK cells exhibited a significantly higher level of IFN-beta mRNA than KU-CBE cells at 18 h post infection. Additionally, the protein concentrations of these four cytokines were determined by enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants obtained from the two CIV-infected cell lines. MDCK cells produced significantly higher amounts of IL-4 and IFN-beta than KU-CBE cells. However, KU CBE cells produced a significantly higher amount of TNF-alpha than MDCK cells. These data indicated that the newly developed canine tracheal epithelial cells exhibited different cytokine production patterns compared to MDCK cells when infected with CIV. Inflammation of the respiratory tract of dogs induced by CIV infection may be attributed to the elevated expression level of TNF-alpha in canine tracheal epithelial cells. PMID- 25797196 TI - Molecular detection and phylogenetic analysis of bovine astrovirus in Brazil. AB - Bovine astrovirus (BoAstV) is associated with gastroenterical disorders such as diarrhea, particularly in neonates and immunocompromised animals. Its prevalence is >60 % in the first five weeks of the animal's life. The aim of this study was to detect and perform a phylogenetic analysis of BoAstV in Brazilian cattle. A prevalence of 14.3 % of BoAstV in fecal samples from 272 head of cattle from different Brazilian states was detected, and 11 samples were analyzed by nucleotide sequencing. The majority of positive samples were obtained from diarrheic animals (p < 0.01). Phylogenetic analysis revealed that Brazilian samples were grouped in clades along with other BoAstV isolates. There was 74.3 % 96.5 % amino acid sequence similarity between the samples in this study and >74.8 % when compared with reference samples for enteric BoAstV. Our results indicate, for the first time, the occurrence of BoAstV circulation in cattle from different regions of Brazil, prevalently in diarrheic calves. PMID- 25797197 TI - A study of lymphoid organs and serum proinflammatory cytokines in pigs infected with African swine fever virus genotype II. AB - African swine fever virus (ASFV), the causative agent of one of the most important viral diseases of domestic pigs for which no vaccine is available, causes immune system disorders in infected animals. In this study, the serum levels of proinflammatory cytokines, as well as the histological and cellular constitution of lymphoid organs of pigs infected with ASFV genotype II were investigated. The results showed a high degree of lymphocyte depletion in the lymphoid organs, particularly in the spleen and lymph nodes, where ASFV infection led to a twofold decrease in the number of lymphocytes on the final day of infection. Additionally, ASFV-infected pigs had atypical forms of lymphocytes found in all lymphoid organs. In contrast to lymphocytes, the number of immature immune cells, particularly myelocytes, increased dramatically and reached a maximum on day 7 postinfection. The serum levels of TNF-alpha, IL-1beta, IL-6, and IL-8 were evaluated. Proinflammatory cytokines showed increased levels after ASFV infection, with peak values at 7 days postinfection, and this highlights their role in the pathogenesis of ASFV. In conclusion, this study showed that ASFV genotype II, like other highly virulent strains, causes severe pathological changes in the immune system of pigs. PMID- 25797199 TI - Management of cancer in pregnancy. AB - A multidisciplinary discussion is necessary to tackle a complex and infrequent medical problem such as cancer occurring during pregnancy. Pregnancy does not predispose to cancer, but cancers occurring in women of reproductive age are encountered during pregnancy. Ultrasonography and magnetic resonance imaging are the preferred staging examinations, but also a sentinel node staging procedure is possible during pregnancy. Standard cancer treatment is aimed for. Operations can safely be performed during pregnancy, but surgery of genital cancers can be challenging. The observation that chemotherapy administered during the second or third trimester of pregnancy, that is, after the period of organogenesis, has little effect on the long-term outcome of children adds to the therapeutic armamentarium during pregnancy. Cancer treatment during pregnancy adds in the continuation of the pregnancy and the prevention of prematurity. PMID- 25797200 TI - NFAT-1, Sp-1, Sp-3, and miR-21: New regulators of chemokine C receptor 7 expression in mature human dendritic cells. AB - The chemokine C receptor 7 (CCR7) is a G-protein-coupled heptahelical receptor (GPCR) that is expressed on a wide variety of cells including memory T cells, B cells, mature dendritic cells, and cancer cells. Activated by its ligands CCL19 or CCL21, CCR7 plays a major role in metastasis of cancer cells. Recent studies demonstrated the role of NF-kappaB and AP-1 transcription factors in addition to let-7 microRNA in CCR7 expression. Our ChIP assays further show the binding of Sp 1, Sp-3 and NFAT-1 transcription factors to their potential binding sites in the 1Kb promoter region with the later found to inhibit whilst Sp-1, and Sp-3 were found to stimulate CCR7 expression as demonstrated by transfection assays. On the other hand, in addition to the known let-7 regulation of CCR7, we found miR-21 to have a highly conserved target region in CCR7 3'UTR and to be significantly down regulated during the course of dendritic cell maturation, allowing for high expression of CCR7. PMID- 25797198 TI - Sphingolipid transfer proteins defined by the GLTP-fold. AB - Glycolipid transfer proteins (GLTPs) originally were identified as small (~24 kDa), soluble, amphitropic proteins that specifically accelerate the intermembrane transfer of glycolipids. GLTPs and related homologs now are known to adopt a unique, helically dominated, two-layer 'sandwich' architecture defined as the GLTP-fold that provides the structural underpinning for the eukaryotic GLTP superfamily. Recent advances now provide exquisite insights into structural features responsible for lipid headgroup selectivity as well as the adaptability of the hydrophobic compartment for accommodating hydrocarbon chains of differing length and unsaturation. A new understanding of the structural versatility and evolutionary premium placed on the GLTP motif has emerged. Human GLTP-motifs have evolved to function not only as glucosylceramide binding/transferring domains for phosphoinositol 4-phosphate adaptor protein-2 during glycosphingolipid biosynthesis but also as selective binding/transfer proteins for ceramide-1 phosphate. The latter, known as ceramide-1-phosphate transfer protein, recently has been shown to form GLTP-fold while critically regulating Group-IV cytoplasmic phospholipase A2 activity and pro-inflammatory eicosanoid production. PMID- 25797201 TI - Killer cell immunoglobulin-like receptor (KIR) locus profiles in the Tunisian population. AB - Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activatory receptors that are expressed by most natural killer (NK) cells. The KIR gene family is polymorphic: genomic diversity is achieved through differences in gene content and allelic polymorphism. The number of KIR loci has been reported to vary among individuals, resulting in different KIR haplotypes. In this study we report the genotypic structure of KIRs in 267 unrelated and healthy Tunisian subjects by polymerase chain reaction-sequence-specific primer (PCR-SSP) method. All 16 KIR genes were observed in the population with different frequencies; framework genes KIR3DP1 and KIR3DL2 and the nonframework genes KIR2DL1 and KIR2DP1 were present in all individuals. A total of 26 different KIR gene profiles and 54 subgenotypes were observed in the tested population samples. Genotype 1, with a frequency of 36.6%, is the most commonly observed in the Tunisian population. Our results showed that the Tunisian population possesses the previously reported general features of the Caucasian as well as African populations, with some additional interesting differences. Such knowledge of the KIR gene distribution in populations is very useful in the study of associations with diseases and in selection of donors for haploidentical bone marrow transplantation. PMID- 25797202 TI - HLA-A, -B, -C, and -DRB1 genotyping of 1000 Northern Irish individuals from Belfast, Northern Ireland in the United Kingdom. AB - One thousand individuals from Belfast, Northern Ireland were genotyped at the HLA A, -B, -C and -DRB1 loci using sequence-specific oligonucleotide probe methods. HLA-A locus genotypes display a minor Hardy-Weinberg (HW) deviation (p=0.0375); HLA-B, -C and -DRB1 genotypes are consistent with expected HW proportions. These genotype data are available in the Allele Frequencies Net Database under identifier AFND 1243. PMID- 25797203 TI - MICA*078: A novel allele identified in a Moroccan individual affected by celiac disease. AB - A novel MICA allele, MICA(*)078, has been identified during HLA/MICA high resolution typing of Moroccan patients with celiac disease. MICA(*)078 shows an uncommon variation at a highly conserved nucleotide position (nt 493, G -> A), resulting in one amino acid change at codon 142 (V -> I) of MICA gene (compared to MICA(*)002:01), located in the alpha2-domain, in which V142 is the common residue. PMID- 25797204 TI - Alpha tryptase allele of Tryptase 1 (TPSAB1) gene associated with Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) in Vietnam and Philippines. AB - We previously reported, significantly higher levels of Chymase and Tryptase in early stage plasma of DSS patients prior to the occurrence of shock suggesting a possible role of mast cells in dengue pathogenesis. To further investigate, we analyzed CMA1 promoter SNP (rs1800875) and TPSAB1 gene alleles, which encode the Human Chymase and alpha- and beta- tryptase 1 enzymes respectively, for susceptibility to Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) in patients from hospitals in Vietnam (Ho Chi Minh City and Vinh Long) and the Philippines. While the CMA1 promoter SNP (rs1800875) was not associated with DHF/DSS, the homozygous form of alpha-tryptase allele was associated with DSS patients in Vinh Long and the Philippines (OR=3.52, p<0.0001; OR=3.37, p<0.0001, respectively) and with DHF in Ho Chi Minh City (OR=2.54, p=0.0084). Also, a statistically significant association was observed when DHF and DSS were combined in Vinh Long (OR=1.5, p=0.034) and the Philippines (OR=2.36, p=0.0004); in Ho Chi Minh City when DHF and DSS were combine an association was observed, but it was not statistically significant (OR=1.5, p=0.0505). Therefore, the alpha-tryptase might have a possible effect on the susceptibility to severe form of Dengue infection. PMID- 25797205 TI - Role of scavenger receptors in dendritic cell function. AB - Dendritic cells (DCs), the most potent of the antigen-presenting cells, are crucial in initiating and shaping innate and adaptive immune responses. DCs discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include Toll-like receptors and scavenger receptors (SRs). Recent findings underscore the critical role of SRs on DCs in pathogen clearance, atherosclerosis, apoptotic cell recognition, diesel exhaust particle recognition, etc. These new findings present SRs as an unexplored therapeutic target that warrants further basic and applied research, and have implications for vaccine development. This review highlights recent insights into the emerging role of these receptors in DC-mediated immune responses. PMID- 25797207 TI - CCR2-64I polymorphism is associated with Non-Small Cell Lung Cancer in Tunisian patients. AB - Single nucleotide polymorphism (SNPs) in genes coding for chemokines may be associated with some cancer. The purpose of this study was to investigate the impact of CCR2-64I and CXCL12-3'A SNPs on the susceptibility and the clinicopathological characteristics of NSCLC (Non-Small Cell Lung Cancer) in the Tunisian population. 170 NSCLC patients and 225 healthy controls screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis were enrolled. A significant association for the homozygous genotype CCR2 64I/64I with lung cancer risk was observed (P=0.004). An increased significant frequency of the -64I allele (P=0.0006) was noted in the patient's group. Clinical analysis indicated a positive association of the -64I allele among squamous cell lung carcinoma patients (P=0.003). The CCR2 mRNA extracted from peripheral blood mononuclear cells (PBMC) was found highly expressed in NSCLC patients compared to controls. The same higher levels were found in patients carrying the CCR2 64I/64I genotype. No significant association was retrieved with CXCL12-3'A polymorphism. In conclusion, our results revealed that the subjects with -64I allele of CCR2-64I gene polymorphism, expressed a significantly higher risk for NSCLC risk without influence on its pathological progression. PMID- 25797206 TI - Preterm cord blood CD4+ T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4+ T cells in bronchopulmonary dysplasia. AB - BACKGROUND: Chorioamnionitis (CA) is associated with premature delivery and bronchopulmonary dysplasia (BPD). We hypothesize that preterm infants exposed to CA have reduced suppressive regulatory T cells (Treg) and increased non regulatory T cell pro-inflammatory cytokines, increasing risk for BPD. OBJECTIVE: To evaluate cord blood CD4(+) T cell regulatory phenotype and pro-inflammatory cytokine production in CA and BPD groups. STUDY DESIGN: Cord blood mononuclear cells from infants (GA ?32 weeks), with or without placental histological evidence of CA (hChorio), were analyzed by flow cytometry. Clinical information was collected by retrospective chart review. Numbers of putative Treg (CD4(+)FoxP3(+)CD25(+)CD127Dim), CD4(+) non-Tregs, and CD4(+) T cell intracellular cytokine content following in vitro stimulation were compared with CA status and oxygen requirement at 36weeks postmenstrual age. RESULT: Absolute Treg numbers were not different in CA and non-CA exposed samples. However, the infants who developed BPD had a significant decrease in Treg and non-regulatory T cell numbers. Greater IL-6 production was observed in hCA group. CONCLUSION: A pro-inflammatory CD4(+) T cell status is noted in CA and BPD but the later disease is also associated with decrease in Tregs, suggesting that the development of BPD is marked by distinct inflammatory changes from those of CA exposed infants. PMID- 25797208 TI - Heterologous expression and purification of a multiheme cytochrome from a Gram positive bacterium capable of performing extracellular respiration. AB - Microbial electrochemical technologies are emerging as environmentally friendly biotechnological processes. Recently, a thermophilic Gram-positive bacterium capable of electricity production in a microbial fuel cell was isolated. Thermincola potens JR contains several multiheme c-type cytochromes that were implicated in the process of electricity production. In order to understand the molecular basis by which Gram-positive bacteria perform extracellular electron transfer, the relevant proteins need to be characterized in detail. Towards this end, a chimeric gene containing the signal peptide from Shewanella oneidensis MR 1 small tetraheme cytochrome c (STC) and the gene sequence of the target protein TherJR_0333 was constructed. This manuscript reports the successful expression of this chimeric gene in the Gram-negative bacterium Escherichia coli and its subsequent purification and characterization. This methodology opens the possibility to study other multiheme cytochromes from Gram-positive bacteria, allowing the extracellular electron transfer mechanisms of this class of organisms to be unraveled. PMID- 25797209 TI - Recombinant expression and purification of a MAP30-cell penetrating peptide fusion protein with higher anti-tumor bioactivity. AB - MAP30 (Momordica Antiviral Protein 30 Kd), a single-stranded type-I ribosome inactivating protein, possesses versatile biological activities including anti tumor abilities. However, the low efficiency penetrating into tumor cells hampers the tumoricidal effect of MAP30. This paper describes MAP30 fused with a human derived cell penetrating peptide HBD which overcome the low uptake efficiency by tumor cells and exhibits higher anti-tumor bioactivity. MAP30 gene was cloned from the genomic DNA of Momordica charantia and the recombinant plasmid pET28b MAP30-HBD was established and transferred into Escherichia coli BL21 (DE3). The recombinant MAP30-HBD protein (rMAP30-HBD) was expressed in a soluble form after being induced by 0.5mM IPTG for 14h at 15 degrees C. The recombinant protein was purified to greater than 95% purity with Ni-NTA affinity chromatography. The rMAP30-HBD protein not only has topological inactivation and protein translation inhibition activity but also showed significant improvements in cytotoxic activity compared to that of the rMAP30 protein without HBD in the tested tumor cell lines, and induced higher apoptosis rates in HeLa cells analyzed by Annexin V-FITC with FACS. This paper demonstrated a new method for improving MAP30 protein anti-tumor activity and might have potential applications in cancer therapy area. PMID- 25797210 TI - Polarization conversion from a thin cavity array in the microwave regime. AB - Linearly polarized microwave radiation is shown to have its plane of polarization converted to the orthogonal state upon reflection from an ultrathin (lambda/25) cavity array. The structure benefits from an uncomplicated design consisting of a metallic grating closely separated from a ground plane by a dielectric spacer. A single set of periodically spaced slits (monograting) exhibits polarization conversion when the normally incident electric field is aligned at 45 degrees to the slits. Two orthogonal sets of slits (bigrating) allows this narrow-band effect to be broadened when the two orthogonal resonances are separated in frequency. We optimise the design and experimentally demonstrate near loss-less polarization conversion (95% of the incident intensity) across a 3.1 GHz frequency band. Finally, we study the dependence of the structure's performance on incident angle and slit width. PMID- 25797211 TI - Dose reduction with iterative reconstruction: Optimization of CT protocols in clinical practice. AB - OBJECTIVES: To create an adaptable and global approach for optimizing MDCT protocols by evaluating the influence of acquisition parameters and Iterative Reconstruction (IR) on dose reduction and image quality. MATERIALS AND METHODS: MDCT acquisitions were performed on quality image phantom by varying kVp, mAs, and pitch for the same collimation. The raw data were reconstructed by FBP and Sinogram Affirmed Iterative Reconstruction (SAFIRE) with different reconstruction kernel and thickness. A total of 4032 combinations of parameters were obtained. Indices of quality image (image noise, NCT, CNR, SNR, NPS and MTF) were analyzed. We developed a software in order to facilitate the optimization between dose reduction and image quality. Its outcomes were verified on an adult anthropomorphic phantom. RESULTS: Dose reduction resulted in the increase of image noise and the decrease of SNR and CNR. The use of IR improved these indices for the same dose without affecting NCT and MTF. The image validation was performed by the anthropomorphic phantom. The software proposed combinations of parameters to reduce doses while keeping indices of the image quality adequate. We observed a CTDIvol reduction between -44% and -83% as compared to the French diagnostic reference levels (DRL) for different anatomical localization. CONCLUSION: The software developed in this study may help radiologists in selecting adequate combinations of parameters that allows to obtain an appropriate image with dose reduction. PMID- 25797212 TI - Imaging features of extraskeletal mesenchymal chondrosarcoma of the hand. PMID- 25797213 TI - Melatonin prevents oxidative damage induced by maternal ethanol administration and reduces homocysteine in the cerebellum of rat pups. AB - Chronic alcoholism leads to elevated plasma and brain homocysteine (Hcy) levels, as demonstrated by animal experiments. This study was designed to evaluate the alterations in offspring rat cerebellum following increase of plasma Hcy level induced by maternal exposure to ethanol and to investigate the possible protective role of melatonin administration upon cerebellar ethanol-induced neurotoxicity. The adult female rats were divided randomly into 4 groups, including one control and three experimental groups, after vaginal plagues. Group I received normal saline, group II received ethanol (4 g/kg), group III received ethanol+melatonin (10mg/kg) and group IV received melatonin on day 6 of gestation until weaning. 21 days after birth, plasma Hcy level, level of lipid peroxidation, the activities of several antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and levels of bcl 2 and bax mRNA expression in cerebellum were determined. Our results demonstrated that ethanol could induce lipid peroxidation, and decrease antioxidants activities and increase plasma total Hcy level. We also observed that ethanol impaired performance on the rotarod and locomotor activities of rats. However, treatment with melatonin significantly attenuated motoric impairment, the lipid peroxidation process and restored the levels of antioxidant activities and significantly reduced plasma total Hcy levels. Moreover, melatonin reduced bax/bcl-2 ratio in the presence of ethanol. We conclude that these results provide evidence that ethanol neurotoxicity in part is related to increase of plasma Hcy levels and melatonin with reducing of plasma Hcy level has neuroprotective effects against ethanol toxicity in cerebellum. PMID- 25797214 TI - The CAA repeat polymorphism in the ZFHX3 gene is associated with risk of coronary heart disease in a Chinese population. AB - Coronary heart disease (CHD) is a disease resulting from the interaction between genetic variations and environmental factors. Zinc finger homeobox 3 (ZFHX3) is a transcription factor and contains a poly-glutamine tract in a compositionally biased region that is encoded by exon 9, containing a cluster of CAG and CAA triplets followed by the polymorphic CAA repeats: (CAG)2(CAA)2(CAG)3CAACAG(CAA)nGCA. Thus, nine successive glutamine residues precede the poly-glutamine tract, encoded by the polymorphic CAA repeats. The aim of this study was to investigate the association of the CAA repeat polymorphism in exon 9 of the ZFHX3 gene with the risk of CHD in a Chinese population. The CAA repeat polymorphism was determined by polymerase chain reaction followed by DNA sequencing in 321 CHD patients. Genotype frequencies were compared using the non parametric mood median test. Four alleles of CAG(CAA)10GCA, CAG(CAA)8GCA, CAG(CAA)9GCA, and CAG(CAA)11GCA were found in Chinese CHD patients in exon 9 of the ZFHX3 gene. The CAG(CAA)10GCA was a major allele (95.95%), and the CAG(CAA)8GCA was a minor allele (3.58%). The CAG(CAA)9GCA and CAG(CAA)11GCA were rare alleles (0.31% and 0.16%). The CAG(CAA)10GCA allele encodes a poly-glutamine tract of 19 residues. Importantly, the CHD patients homozygous for the CAG(CAA)10GCA allele had a higher risk of CHD, compared to the heterozygous patients carrying a CAG(CAA)8GCA allele. Moreover, the CAG(CAA)10GCA allele was significantly associated with hypertension, diabetes mellitus, or dyslipidemia (P < 0.05). Thus, the CAA repeat polymorphism in exon 9 of the ZFHX3 gene contributes to the CHD susceptibility in the Chinese population. PMID- 25797215 TI - Deletion of exon 4 in the N-acetylgalactosamine-4-sulfatase gene in a Taiwanese patient with mucopolysaccharidosis type VI. AB - Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB), one of the enzymes required for the degradation of dermatan sulfate (DS). Accumulation of DS in connective tissue causes growth failure, resulting in short stature. Here, we observed a 5-year-old girl who was the only one affected member of her family and who presented with an exaggerated, convex curvature of the back at the age of one year. Abnormal excretion of DS in the urine and extremely low leukocyte ARSB activity were noted. The patient was suspected to have MPS VI. Direct DNA sequencing indicated that there was no mutation in the coding region of ARSB. However, RT-PCR analysis of RNA prepared from blood samples indicated the deletion of the entire exon 4. Further analysis of the genomic DNA by quantitative PCR confirmed a homozygous deletion of exon 4, an unusual intragenic deletion in ARSB. The deletion led to a truncated protein that lacks most of the catalytic domain. The patient received recombinant human ARSB as enzyme replacement therapy (ERT) at an early stage (2 years), and responded positively in terms of skeletal development and other developmental milestones. The early identification of type VI MPS patients and subsequent treatment with ERT may be beneficial for the clinical outcome of MPS VI patients. In addition, detailed gene analysis may enhance the ability to provide genetic counseling to families of patients affected by MPS VI. PMID- 25797216 TI - Clinical features of hepatitis E virus infection in Ibaraki, Japan: autochthonous hepatitis E and acute-on-chronic liver failure. AB - Hepatitis E caused by hepatitis E virus (HEV) is a serious public health concern in developing countries where HEV is mainly transmitted through contaminated water. Recently, in industrialized countries, autochthonous hepatitis E, a porcine zoonosis, has been increasingly recognized. In Japan, the number of national notifications of acute hepatitis E has increased since the introduction of anti-HEV IgA antibody measurement, covered by the national health insurance program, in 2011. In the past three years, we examined five patients of acute hepatitis or acute-on-chronic liver failure caused by HEV infection who presented various clinical courses in the southern area of Ibaraki prefecture in Japan. Of these patients, 78-year-old and 63-year-old male patients presented acute hepatitis E and recovered by only bed rest. The latter patient had a history of consuming grilled or undercooked pork and shellfish prior to the onset of hepatitis E. Among the five patients examined, the infection route was detected only in this patient. Of note, a 65-year-old female patient presented severe hepatitis associated with painless thyroiditis. The patient was diagnosed with probable autoimmune hepatitis and was successfully treated with prednisolone (40 mg/day). Lastly, 58-year-old and 62-year-old male patients, both of whom had a history of diabetes mellitus and alcoholic liver disease, developed acute-on chronic liver failure, and the latter patient with pre-existing liver cirrhosis died due to liver failure. Thus, patients with clinical HEV infection who display multiple underlying diseases can develop acute-on-chronic liver failure. In conclusion, HEV infection manifests the diverse clinical courses. PMID- 25797217 TI - Thickness dispersion of surface plasmon of Ag nano-thin films: determination by ellipsometry iterated with transmittance method. AB - Effective optical constants of Ag thin films are precisely determined with effective thickness simultaneously by using an ellipsometry iterated with transmittance method. Unlike the bulk optical constants in Palik's database the effective optical constants of ultrathin Ag films are found to strongly depend on the thickness. According to the optical data two branches of thickness dispersion of surface plasmon energy are derived and agreed with theoretical predication. The thickness dispersion of bulk plasmon is also observed. The influence of substrate on surface plasmon is verified for the first time by using ellipsometry. The thickness dependent effective energy loss function is thus obtained based on this optical method for Ag ultrathin films. This method is also applicable to other ultrathin films and can be used to establish an effective optical database for ultrathin films. PMID- 25797218 TI - Hypercholesterolemia and neurodegeneration. Comparison of hippocampal phenotypes in LDLr knockout and APPswe/PS1dE9 mice. AB - Previous studies suggest that Alzheimer's disease (AD) neurobiology could not be explained solely by an increase in beta-amyloid levels. Recently, it has been proposed that alterations in brain cholesterol metabolism may contribute to the pathogenesis of AD. In the present work, we focus on early changes in the hippocampal phenotypes of two mouse models in which cognitive impairments were previously described: a) the hypercholesterolemic LDL receptor knockout (LDLr -/ ) and b) the APPswe/PS1dE9 (APP/PS1) transgenic model of familial AD. Our initial analysis, subsequent validation and additional experiments at the mRNA and protein levels demonstrate some parallels between the hippocampal phenotypes of these 2 mouse models, however our data suggest that the molecular mechanisms leading to cognitive decline are distinct in LDLr -/- and APP/PS1 animals. Genes related to cytokine signaling were significantly down-regulated in LDLr -/- mice when compared to both the wild-type and APP/PS1 mice, and these include prostaglandin-endoperoxide synthases 1 and 2 (ptgs1 and 2) and nerve grow factor (ngf). We have also detected reduced expression of genes related to lipid metabolism in LDLr -/- mice: peroxisome proliferator activated receptor gamma (pparg), pro-opiomelanocortin-alpha (pomc) and of protein kinase, AMP-activated, alpha 1 catalytic subunit of AMPK (prkaa1). Our array data also indicate that transcriptional activity of early genes involved in memory process, such as FBJ osteosarcoma oncogene (Fos) and the activity regulated cytoskeletal-associated protein (Arc) gene, are increased in the hippocampus of LDLr -/- mice. Several proteins like insulin degrading enzyme (IDE), PGC-1alpha, OXPHOS 1, NMDAR1 and cyclic AMP response element binding protein (CREB) are up-regulated in the LDLr /- mice, while in the APP/PS1 mouse model only OXPHOS complexes 2, 3 and 5 are slightly downregulated. Further studies are necessary to understand the molecular pathways involved in memory loss in hypercholesterolemic LDLr -/- mice. PMID- 25797219 TI - Women's Awareness of, Interest in, and Experiences with Long-acting Reversible and Permanent Contraception. AB - BACKGROUND: Long-acting reversible contraception (LARC) and sterilization are popular contraceptive methods. However, they have been associated with safety concerns and coercive practices. We aimed to understand women's opinions and experiences related to these methods, including whether the methods' fraught histories influence use or interest. METHODS: Between May and July 2013, we conducted an online survey with a convenience sample of 520 women aged 14 to 45. We used quota sampling to ensure women of color were at least 60% of our sample. Descriptive statistics, chi(2) tests, and multivariable logistic regression were used to estimate participants' awareness of, interest in, and experiences with LARCs and sterilization. FINDINGS: Overall, 30% of women reported current LARC use and 67% interest in future LARC use. Four percent reported sterilization use and 48% interest in future sterilization. In multivariate analyses, current LARC use was lower among Asian women versus White women (odds ratio [OR], 0.24), and interest in future use was higher among women aged 14 to 24 versus 35 to 45 (OR, 5.49). Interest in sterilization was higher among women aged 14 to 24 and 25 to 34 versus 35 to 45 (ORs, 3.29-3.66) and women with disabilities (OR, 1.64), and lower among Black compared with White women (OR, 0.41). Method misperceptions were evident, and concerns about contraceptive coercion were reported. CONCLUSIONS: Concerns about contraceptive coercion were not predominant reasons for noninterest in LARCs and sterilization, but were reported by some participants. Lower sterilization interest among Black women and higher sterilization interest among women with disabilities warrant further research. Efforts to address misperceptions about LARCs and sterilization, including their safety and efficacy, are needed. PMID- 25797221 TI - Corrigendum. PMID- 25797220 TI - Availability and distribution of safe abortion services in rural areas: a facility assessment study in Madhya Pradesh, India. AB - BACKGROUND: Unsafe abortion contributes to a significant portion of maternal mortality in India. Access to safe abortion care is known to reduce maternal mortality. Availability and distribution of abortion care facilities can influence women's access to these services, especially in rural areas. OBJECTIVES: To assess the availability and distribution of abortion care at facilities providing childbirth care in three districts of Madhya Pradesh (MP) province of India. DESIGN: Three socio demographically heterogeneous districts of MP were selected for this study. Facilities conducting at least 10 deliveries a month were surveyed to assess availability and provision of abortion services using UN signal functions for emergency obstetric care. Geographical Information System was used for visualisation of the distribution of facilities. RESULTS: The three districts had 99 facilities that conducted >10 deliveries a month: 74 in public and 25 in private sector. Overall, 48% of facilities reported an ability to provide safe surgical abortion service. Of public centres, 32% reported the ability compared to 100% among private centres while 18% of public centres and 77% of private centres had performed an abortion in the last 3 months. The availability of abortion services was higher at higher facility levels with better equipped and skilled personnel availability, in urban areas and in private sector facilities. CONCLUSIONS: Findings showed that availability of safe abortion care is limited especially in rural areas. More emphasis on providing safe abortion services, particularly at primary care level, is important to more significantly dent maternal mortality in India. PMID- 25797222 TI - Photoluminescence of Eu3+-doped glasses with Cu2+ impurities. AB - Glasses activated with Eu(3+) ions are attractive as luminescent materials for various photonic applications. Co-doping with copper has been proposed for enhancing material optical properties, but the quenching effect of Cu(2+) impurities on Eu(3+) emission in glass remains largely unexplored. In this work, Eu2O3/CuO-containing barium-phosphate glasses have been prepared by the melt quench method, and the Eu(3+) photoluminescence (PL) quenching resulting from Eu(3+)->Cu(2+) energy transfer was evaluated. Optical absorption spectroscopy showed that with the increase in CuO concentration the Cu(2+) absorption band resonant with Eu(3+) emission (e.g. (5)D0->(7)F2 transition around 615 nm) developed steadily. As a result, Eu(3+) PL was progressively quenched. Evaluation of the quenching constants as a function of temperature in the 298-673K range showed differences basically within experimental error, consistent with a resonant transfer and lack of phonon-assisted processes. Moreover, analysis of the Eu(3+) emission decay dynamics revealed a strong correlation between the decay rates and Cu(2+) impurity levels. Results imply that for practical applications the levels of Cu(2+) in Eu(3+)/Cu(+)-activated glasses should be reduced if not removed as these will significantly limit device efficiency. PMID- 25797223 TI - Photocatalytic activity of nanostructured ZnO-ZrO2 binary oxide using fluorometric method. AB - Evaluation of the photocatalytic activity of ZnO-ZrO2 nanomaterials using fluorescence based technique has rarely been reported. In the present work, ZnO ZrO2 mixed oxides coupled with various ZnO dosages (0, 10, 30, 50, 70wt%) were prepared by impregnation method. These nanomaterials were characterized by studying their structural, surface and optical properties. The photocatalytic activity in term of quantitative determination of the active oxidative species (OH) produced on the surface of binary oxide was evaluated using fluorescent probe method. The interaction between ZnO and ZrO2 was affected on the photocatalytic efficiency of mixture. The results show that, the addition of ZnO to ZrO2 decreased the electron-hole recombination and increased the rate of OH radicals formation. 50 wt% ZnO-ZrO2 photocatalyst exhibited much higher photocatalytic activity. The profound effect of binary oxide catalyst was generally considered due to the high surface area, small particle size, high monoclinic phase of ZrO2 content, low band gap and the presence of surface OH groups. PMID- 25797224 TI - Elaboration, Rietveld refinements and vibrational spectroscopic study of Na1 xKxCaPb3(PO4)3 lacunar apatites (0 ? x ? 1). AB - Synthesis of apatites, Na1-xKxCaPb3(PO4)3 0 ? x ? 1, with anion vacancy were carried out using solid state reactions. The solid solution of apatite-type structure crystallize in the hexagonal system, space group P63/m (No. 176). Rietveld refinements showed that around 90% of Pb(2+) cations are located in the (6h) sites, the left amount of Pb(2+) cations are located in the (4f) sites; 27 31% of Ca(2+) cations are located in the (6h) sites, the left amount of Ca(2+) cations are located in the (4f) sites. The ninefold coordination sites (4f) are also occupied by the K(+) and Na(+) monovalent ions. The structure can be described as built up from [PO4](3-) tetrahedra and Pb(2+)/Ca(2+) of sixfold coordination cavities (6h positions), which delimit void hexagonal tunnels running along [001]. These tunnels are connected by cations of mixed sites (4f) which are half occupied by Pb(2+)/Ca(2+) and half by Na(+)/K(+) mixed cations. The assignment of the observed frequencies in the Raman and infrared spectra is discussed on the basis of a unit cell group analysis and by comparison with other apatites. Vibrational spectra of all the compositions are similar and show some linear shifts of the frequencies as a function of the composition toward lower values due the substitutions of Na(+) by K(+) with a larger radius. PMID- 25797225 TI - Raman spectroscopic analysis of iron chromium oxide microspheres generated by nanosecond pulsed laser irradiation on stainless steel. AB - Iron chromium oxide microspheres were generated by pulsed laser irradiation on the surface of two commercial samples of stainless steel at room temperature. An Ytterbium pulsed fiber laser was used for this purpose. Raman spectroscopy was used for the characterization of the microspheres, whose size was found to be about 0.2-1.7 MUm, as revealed by SEM analysis. The laser irradiation on the surface of the stainless steel modified the composition of the microspheres generated, affecting the concentration of the main elemental components when laser power was increased. Furthermore, the peak ratio of the main bands in the Raman spectra has been associated to the concentration percentage of the main components of the samples, as revealed by Energy-Dispersive X-ray Spectroscopy (EDS) analysis. These experiments showed that it is possible to generate iron chromium oxide microspheres on stainless steel by laser irradiation and that the concentration percentage of their main components is associated with the laser power applied. PMID- 25797226 TI - Multidisciplinary approach for the study of an Egyptian coffin (late 22nd/early 25th dynasty): combining imaging and spectroscopic techniques. AB - This paper demonstrates that an educated methodology based on both non-invasive and micro invasive techniques in a two-step approach is a powerful tool to characterize the materials and stratigraphies of an Egyptian coffin, which was restored several times. This coffin, belonging to a certain Mesiset, is now located at the Museo Civico Archeologico of Bologna (inventory number MCABo EG 1963). Scholars attributed it to the late 22nd/early 25th dynasty by stylistic comparison. The first step of the diagnostic approach applied imaging techniques on the whole surface in order to select measurements spots and to unveil both original and restored areas. Images and close microscopic examination of the polychrome surface allowed selecting representative areas to be investigated in situ by portable spectroscopic techniques: X-ray Fluorescence (XRF), Fiber Optic Reflectance Spectroscopy (FORS) and Fourier Transform Infrared spectroscopy (FTIR). After the analysis of the results coming from the first step, very few selected samples were taken to clarify the stratigraphy of the polychrome layers. The first step, based on the combination of imaging and spectroscopic techniques in a totally non-invasive modality, is quite unique in the literature on Egyptian coffins and enabled us to reveal many differences in the ground layer's composition and to identify a remarkable number of pigments in the original and restored areas. This work offered also a chance to check the limitations of the non-invasive approach applied on a complex case, namely the right localization of different materials in the stratigraphy and the identification of binding media. Indeed, to dissolve any remaining doubts on superimposed layers belonging to different interventions, it was necessary to sample few micro-fragments in some selected areas and analyze them prepared as cross-sections. The original ground layer is made of calcite, while the restored areas show the presence of either a mixture of calcite and silicates or a gypsum ground, overlapped by lead white. The original pigments were identified as orpiment, cinnabar and red clay, Egyptian blue and green copper based pigments. Some other pigments, such as white lead, Naples yellow, cerulean blue and azurite were only found in the restored areas. PMID- 25797227 TI - FT-IR and Raman spectroscopic and DFT studies of anti-cancer active molecule N {(meta-ferrocenyl) Benzoyl} - l-alanine - glycine ethyl ester. AB - FT-Raman and FT-IR spectra of N-{(meta-ferrocenyl) Benzoyl} - l-alanine - glycine ethyl ester were recorded in solid phase. The optimized molecular geometry, the vibrational wavenumbers, the infrared intensities and the Raman scattering intensities were calculated by using density functional method(B3LYP) with 6 31G(d, p) basis set. Vibrational assignment of the molecule was done by using potential energy distribution analysis. Natural bond orbital analysis, Mulliken charge analysis and HOMO-LUMO energy were used to elucidate the reasons for intra molecular charge transfer. Docking studies were conducted to predict its anticancer activity. PMID- 25797228 TI - Patient-tailored dose reduction of TNF-alpha blocking agents in ankylosing spondylitis patients with stable low disease activity in daily clinical practice. AB - OBJECTIVES: Tumour necrosis factor-alpha (TNF-alpha) blocking agents are very effective in controlling systemic inflammation and improving clinical assessments in ankylosing spondylitis (AS). In view of potential side effects and high costs of long-term treatment, our aim was to investigate whether dose reduction of TNF alpha blocking agents is possible without loss of effectiveness in AS patients in daily clinical practice. METHODS: Patients from the prospective observational GLAS cohort, fulfilling the modified New York criteria for AS, with active disease before start of TNF-alpha blocking therapy and stable (>=6 months) low disease activity on the conventional dose regimen, who started with dose reduction of TNF-alpha blocking therapy before June 2011 were studied. Dose reduction was patient-tailored (step-by-step approach) and consisted of lowering the dose and/or extending the interval between doses. RESULTS: Between June 2005 and March 2011, 58 AS patients started dose reduction of etanercept (n=39), infliximab (n=10), or adalimumab (n=9). Of all patients, 74%, 62%, and 53% maintained their reduced dose or dosing frequency after 6, 12, and 24 months, respectively. The mean dose of TNF-alpha blocking therapy over time corresponded to 62% of the standard dose regimen. Disease activity remained low in the majority of patients who maintained dose reduction after 24 months (94% had BASDAI<4). If there was recurrence of disease symptoms, patients achieved good clinical response after returning to the conventional regimen (88% reached BASDAI<4). CONCLUSIONS: In this observational cohort, patient-tailored dose reduction of TNF-alpha blocking agents was successful preserving stable low disease activity over 24 months in approximately half of the AS patients. PMID- 25797229 TI - Angiogenic markers in pregnancies conceived through in vitro fertilization. AB - OBJECTIVE: Pregnancies that have been conceived through in vitro fertilization (IVF) have been associated with higher rates of preeclampsia and other complications that are associated with placental dysfunction. We evaluated whether IVF pregnancies, when compared with those conceived spontaneously, would be associated with alterations in serum angiogenic markers. STUDY DESIGN: This was a retrospective cohort study from 3 US academic institutions (2006-2008). Women with singleton pregnancies who conceived via IVF or spontaneously were included. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 4 time points throughout gestation. Pregnancy outcomes that included diagnosis of preeclampsia or other obstetric complications were ascertained from the medical record. The relationship among IVF status, PlGF, and sFlt-1 were modeled over gestation and stratified by clinical pregnancy outcome. RESULTS: Of the included 2392 singleton pregnancies, 4.5% (108 pregnancies) were conceived though IVF. IVF pregnancies were significantly more likely to be complicated by preeclampsia (15.7% vs 7.7%). IVF pregnancies had significantly higher levels of sFlt-1 at 18, 26, and 35 weeks of gestation (P = .04, P = .004, P < .0001, respectively) and lower levels of PlGF at 18 and 35 weeks of gestation (P = .007 and .0006, respectively). These differences persisted even after being controlled for maternal comorbidities or obstetric outcomes such as preeclampsia. CONCLUSION: Pregnancies conceived via IVF were found to have an increased antiangiogenic profile (elevated sFlt-1 and decreased PlGF) at multiple time points throughout gestation when compared with spontaneously conceived pregnancies. Alterations in the angiogenic profile persisted even after we controlled for maternal comorbidities of clinically evident disorders of abnormal placentation such as preeclampsia. The increased antiangiogenic profile suggests fundamentally aberrant placentation related to in vitro fertilization, which may warrant closer fetal surveillance in these pregnancies. PMID- 25797230 TI - Prevalence of anal human papillomavirus infection and anal HPV-related disorders in women: a systematic review. AB - The aim of this study was to systematically review the findings of publications addressing the epidemiology of anal human papillomavirus (HPV) infection, anal intraepithelial neoplasia, and anal cancer in women. We conducted a systematic review among publications published from Jan. 1, 1997, to Sept. 30, 2013, to limit to publications from the combined antiretroviral therapy era. Three searches were performed of the National Library of Medicine PubMed database using the following search terms: women and anal HPV, women anal intraepithelial neoplasia, and women and anal cancer. Publications were included in the review if they addressed any of the following outcomes: (1) prevalence, incidence, or clearance of anal HPV infection, (2) prevalence of anal cytological or histological neoplastic abnormalities, or (3) incidence or risk of anal cancer. Thirty-seven publications addressing anal HPV infection and anal cytology remained after applying selection criteria, and 23 anal cancer publications met the selection criteria. Among HIV-positive women, the prevalence of high-risk (HR)-HPV in the anus was 16-85%. Among HIV-negative women, the prevalence of anal HR-HPV infection ranged from 4% to 86%. The prevalence of anal HR-HPV in HIV negative women with HPV-related pathology of the vulva, vagina, and cervix compared with women with no known HPV-related pathology, varied from 23% to 86% and from 5% to 22%, respectively. Histological anal high-grade squamous intraepithelial lesions (anal intraepithelial neoplasia 2 or greater) was found in 3-26% of the women living with HIV, 0-9% among women with lower genital tract pathology, and 0-3% for women who are HIV negative without known lower genital tract pathology. The incidence of anal cancer among HIV-infected women ranged from 3.9 to 30 per 100,000. Among women with a history of cervical cancer or cervical intraepithelial neoplasia 3, the incidence rates of anal cancer ranged from 0.8 to 63.8 per 100,000 person-years, and in the general population, the incidence rates ranged from 0.55 to 2.4 per 100,000 person-years. This review provides evidence that anal HPV infection and dysplasia are common in women, especially in those who are HIV positive or have a history of HPV-related lower genital tract pathology. The incidence of anal cancer continues to grow in all women, especially those living with HIV, despite the widespread use of combined antiretroviral therapy. PMID- 25797231 TI - Fetal ultrasound markers of severity predict resolution of pulmonary hypertension in congenital diaphragmatic hernia. AB - OBJECTIVE: Congenital diaphragmatic hernia (CDH) results in morbidity and death from lung hypoplasia and persistent pulmonary hypertension (PH). We sought to define the relationship between fetal ultrasound markers of severity in CDH and the time to resolution of neonatal PH. STUDY DESIGN: We conducted a retrospective study of fetuses with an antenatal ultrasound scan and left-sided CDH cared for at the University of California San Francisco (2002-2012). Fetal liver position was classified on ultrasound scan as abdominal (entire liver within the abdomen) or thoracic (any portion of the liver within the thorax). Fetal stomach position was classified from least to most aberrant: abdominal, anterior left chest, mid posterior left chest, or retrocardiac (right chest). Lung-to-head ratio (LHR) was determined from available scans at 20-29 weeks of gestational age (GA). Routine neonatal echocardiograms were performed weekly for up to 6 weeks or until PH resolved or until discharge. PH was assessed by echocardiogram with the use of a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. Days to PH-free survival was defined as the age at which pulmonary artery pressure was estimated to be <2/3 systemic blood pressure. Cox proportional hazards models adjusted for GA at birth, era of birth, fetal surgery, and GA at ultrasound scan (LHR model only), with censoring at 100 days. RESULTS: Of 118 patients, the following fetal markers were available: LHR (n = 53), liver position (n = 112), and stomach position (n = 80). Fewer infants experienced resolved PH if they had LHR <1 (P = .006), thoracic liver position (P = .001), or more aberrant stomach position (P < .001). There was also a decreased rate of resolution of PH in infants with LHR <1 (hazard ratio, 0.30; P = .007), thoracic liver position (hazard ratio, 0.38; P < .001), and more aberrant stomach position (hazard ratios, 0.28 [P = .002]; 0.1 [P < .001]; and 0.07 [P < .001]). CONCLUSION: Fetal ultrasound markers of CDH severity are predictive not only of death but also of significant morbidity. LHR <1, thoracic liver, and aberrant stomach position are associated with delayed time to resolution of PH in infants with CDH and may be used to identify fetuses at high risk of persistent PH. PMID- 25797232 TI - Mode of delivery of twin gestation with very low birthweight: is vaginal delivery safe? AB - OBJECTIVE: The purpose of this study was to determine whether planned vaginal delivery is associated with increased risk of perinatal death and morbidity in twin pregnancies that are complicated by a very low birthweight of the second twin. STUDY DESIGN: We conducted a retrospective cohort study of twin pregnancies in which the second twin's birthweight was <=1500 g. One hundred ninety-three twin gestations met the study criteria; patients were classified into 2 groups according to the planned mode of delivery: (1) cesarean delivery (n = 142) and (2) vaginal delivery (n = 51). In the vaginal delivery group, 21 pairs were in cephalic-cephalic presentation at the time of delivery; 28 pairs were cephalic noncephalic, and 2 pairs were noncephalic-noncephalic. Composite adverse neonatal outcome was defined as the presence of neonatal death, respiratory distress syndrome, sepsis, necrotizing enterocolitis, or intraventricular hemorrhage grade 3-4. RESULTS: Trial of vaginal delivery was successful for both twins in 90.5% of cephalic-cephalic twins and 96.4% in cephalic-noncephalic twins. The rate of intraventricular hemorrhage was significantly higher in the vaginal delivery group (29.4% vs 8.5%, respectively; P = .013; adjusted odds ratio [OR], 3.65; 95% confidence interval [CI], 1.32-10.1). The increased risk of intraventricular hemorrhage in the vaginal delivery groups was evident in both twin A (17.6% vs 7.0%; P = .029) and twin B (15.7% vs 4.9%; P = .014); however, these differences were not significant after adjustment for possible confounders (twin A: adjusted OR, 1.79; 95% CI, 0.58-5.55; twin B: adjusted OR, 2.13; 95% CI, 0.63-7.25). In addition, subgroup analysis revealed that both cephalic-cephalic and cephalic noncephalic twins who were delivered vaginally had increased risk for intraventricular hemorrhage. There were no significant differences between the cesarean and vaginal delivery groups in the rates of Apgar score <7 at 5 minutes, arterial cord pH <7.1, composite adverse neonatal outcome, and neonatal mortality rate. However, the rate of respiratory distress syndrome was significantly lower in the vaginal delivery group (66.7% vs 69%; P = .042; OR, 0.34; 95% CI, 0.12 0.96). CONCLUSION: Vaginal delivery of very low birthweight twins is associated with an increased risk of intraventricular hemorrhage, regardless of presentation. Because of the small sample size and the retrospective cohort design, large prospective randomized studies are needed. PMID- 25797233 TI - Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. AB - OBJECTIVE: We sought to evaluate the efficacy of maintenance tocolysis with vaginal progesterone compared to control (placebo or no treatment) in singleton gestations with arrested preterm labor (PTL) in a metaanalysis of randomized controlled trials. STUDY DESIGN: Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials with the use of a combination of key words and text words related to "progesterone," "tocolysis," and "preterm labor" from 1966 through November 2014. We included all randomized trials of singleton gestations that had arrested PTL and then were randomized to maintenance tocolysis treatment with either vaginal progesterone or control (either placebo or no treatment). All published randomized studies on progesterone tocolysis were carefully reviewed. Exclusion criteria included maintenance tocolysis in women with preterm premature rupture of membrane, maintenance tocolysis with 17-alpha-hydroxyprogesterone caproate, and maintenance tocolysis with oral progesterone. The summary measures were reported as relative risks (RRs) with 95% confidence interval (CI). The primary outcome was preterm birth (PTB) <37 weeks. RESULTS: Five randomized trials, including 441 singleton gestations, were analyzed. Women who received vaginal progesterone maintenance tocolysis for arrested PTL had a significantly lower rate of PTB <37 weeks (42% vs 58%; RR, 0.71; 95% CI, 0.57-0.90; 3 trials, 298 women). Women who received vaginal progesterone had significantly longer latency (mean difference 13.80 days; 95% CI, 3.97-23.63; 4 trials, 368 women), later gestational age at delivery (mean difference 1.29 weeks; 95% CI, 0.43-2.15; 4 trials, 368 women), lower rate of recurrent PTL (24% vs 46%; RR, 0.51; 95% CI, 0.31-0.84; 2 trials, 122 women), and lower rate of neonatal sepsis (2% vs 7%; RR, 0.34; 95% CI, 0.12-0.98; 4 trials, 368 women). CONCLUSION: Maintenance tocolysis with vaginal progesterone is associated with prevention of PTB, significant prolongation of pregnancy, and lower neonatal sepsis. However, given the frequent lack of blinding and the generally poor quality of the trials, we do not currently suggest a change in clinical care of women with arrested PTL. We suggest instead well-designed placebo-controlled randomized trials to confirm the findings of our metaanalysis. PMID- 25797234 TI - Vasculoplacental complications in pregnant women with HIV infection: a case control study. AB - OBJECTIVE: Data from the international literature suggest that there may be an association between maternal human immunodeficiency virus (HIV) infection and vasculoplacental complications during pregnancy. Studies on this subject have reached discordant conclusions. The aim of this study was to assess the incidence of vasculoplacental complications during pregnancy in women with and without HIV infection. STUDY DESIGN: This single-center case-control study compared the incidence of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular intrauterine growth restriction in 280 women with HIV and 560 women not infected with HIV, matched for age, parity, and geographic origin. RESULTS: The incidence rates of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular growth restriction did not differ between the women with and without HIV infection. The overall incidence of vasculoplacental complications did not differ between the 2 groups (7.5% vs 9.8%, respectively; P = .27). The risk of these was not associated with exposure to antiretroviral treatments, viral load, or CD4 T cell counts at the beginning of pregnancy. CONCLUSION: This study shows no difference in the incidence of vasculoplacental complications between women with and without HIV infection. PMID- 25797235 TI - The risk of stillbirth and infant death by each additional week of expectant management in twin pregnancies. AB - OBJECTIVE: The objective of the study was to compare the fetal/infant mortality risk associated with each additional week of expectant management with the mortality risk of immediate delivery in women with twin gestations. STUDY DESIGN: A retrospective cohort study was performed utilizing 2006-2008 National linked birth certificate and death certificate data. The incidence of stillbirth and infant death were determined for each week of pregnancy from 32 0/7 weeks' through 40 6/7 weeks' gestation. Pregnancies complicated by fetal anomalies were excluded. These measures were combined to estimate the theoretic risk of remaining pregnant an additional week by adding the risk of stillbirth during the extra week of pregnancy with the risk of infant death encountered with delivery during the following week. This composite fetal/infant mortality risk was compared with the risk of infant death associated with delivery at the corresponding gestational age. RESULTS: The risk of stillbirth increased with increasing gestational age, for example, between 37 and 38 weeks' gestation (12.5 per 10,000 vs 22.5 per 10,000; P<.05). As expected, the risk of infant death following delivery gradually decreased as pregnancies approached term gestation. Week-by-week differences were statistically significant (P<.05) between 32 and 36 weeks with decreasing risk of infant death at advancing gestational ages. The composite risk of stillbirth and infant death associated with an additional week of pregnancy had a significant increase from 37 to 38 weeks' gestation (43.9 per 10,000 vs 59.2 per 10,000; P<.05). At 37 weeks' gestation, the relative risk of mortality was statistically significantly lower with immediate delivery as compared with expectant management (relative risk, 0.87; 95% confidence interval, 0.77-0.99). CONCLUSION: Our results suggest that fetal/infant death risk is minimized at 37 weeks' gestation; however, individual maternal and fetal characteristics must also be taken into account when determining the optimal timing of delivery for twin pregnancies. PMID- 25797236 TI - Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. AB - We sought to evaluate the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH). Searches were conducted on PubMed, SCOPUS, and CENTRAL databases to August 2014, and reference lists of relevant articles were screened. The search was limited to articles conducted on human beings and females. The PRISMA Statement was followed. Seven randomized controlled trials (n = 766 women) were included. Main outcome measures were the therapeutic effect rate (histological response) after 3, 6, 12, and 24 months of treatment; rate of irregular vaginal bleeding; and the hysterectomy rate per woman randomized. The Cochrane Collaboration risk of bias tool was used for quality assessment. Metaanalysis was performed with fixed effects model. LNG-IUS achieved a highly significant therapeutic response rate compared with oral progestins after 3 months of treatment (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.39 3.82; P = .001, 5 trials, I(2) = 0%, n = 376), after 6 months of treatment (OR, 3.16; 95% CI, 1.84-5.45; P < .00001, 4 trials, I(2) = 0%, n = 397), after 12 months of treatment (OR, 5.73; 95% CI, 2.67-12.33; P < .00001, 2 trials, I(2) = 0%, n = 224), and after 24 months of treatment (OR, 7.46; 95% CI, 2.55-21.78; P = .0002, 1 trial, n = 104). Subgroup analysis showed evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins for non atypical simple as well as complex EH (OR, 2.51; 95% CI, 1.14-5.53; P = .02, 6 trials, I(2) = 0%, n = 290; and OR, 3.31; 95% CI, 1.62-6.74; P = .001, 4 trials, I(2) = 0%, n = 216, respectively). Compared with oral progestins, LNG-IUS achieved significantly fewer hysterectomies (OR, 0.26; 95% CI, 0.15-0.45; P < .00001, 3 trials, n = 362, I2 = 42%). No difference was observed in the rate of irregular vaginal bleeding between both groups (OR, 1.12; 95% CI, 0.54-2.32; P = .76, 2 trials, n = 207, I2 = 77%). Funnel plot analysis was not performed because of the relatively small number of included studies. For treatment of non-atypical EH, LNG-IUS achieves higher therapeutic effect rates and lower hysterectomy rates than oral progestins and should be offered as an alternative to oral progestins in these cases. PMID- 25797237 TI - Module organization and variance in protein-protein interaction networks. AB - A module is a group of closely related proteins that act in concert to perform specific biological functions through protein-protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions. PMID- 25797239 TI - Psychogenic paresis following neuraxial anaesthesia in a complex obstetric case. PMID- 25797238 TI - Asymmetric development of dorsal and ventral attention networks in the human brain. AB - Two neural systems for goal-directed and stimulus-driven attention have been described in the adult human brain; the dorsal attention network (DAN) centered in the frontal eye fields (FEF) and intraparietal sulcus (IPS), and the ventral attention network (VAN) anchored in the temporoparietal junction (TPJ) and ventral frontal cortex (VFC). Little is known regarding the processes governing typical development of these attention networks in the brain. Here we use resting state functional MRI data collected from thirty 7 to 12 year-old children and thirty 18 to 31 year-old adults to examine two key regions of interest from the dorsal and ventral attention networks. We found that for the DAN nodes (IPS and FEF), children showed greater functional connectivity with regions within the network compared with adults, whereas adults showed greater functional connectivity between the FEF and extra-network regions including the posterior cingulate cortex. For the VAN nodes (TPJ and VFC), adults showed greater functional connectivity with regions within the network compared with children. Children showed greater functional connectivity between VFC and nodes of the salience network. This asymmetric pattern of development of attention networks may be a neural signature of the shift from over-representation of bottom-up attention mechanisms to greater top-down attentional capacities with development. PMID- 25797240 TI - Reversible peripartum hepato-renal failure in late pregnancy. PMID- 25797241 TI - Management of a parturient with a retrosternal goitre and tracheal compression. PMID- 25797242 TI - The promotion of angiogenesis induced by three-dimensional porous beta-tricalcium phosphate scaffold with different interconnection sizes via activation of PI3K/Akt pathways. AB - The porous architectural characteristics of biomaterials play an important role in scaffold revascularization. However, no consensus exists regarding optimal interconnection sizes for vascularization and its scaffold bioperformance with different interconnection sizes. Therefore, a series of disk-type beta-tricalcium phosphates with the same pore sizes and variable interconnections were produced to evaluate how the interconnection size influenced biomaterial vascularization in vitro and in vivo. We incubated human umbilical vein endothelial cells on scaffolds with interconnections of various sizes. Results showed that scaffolds with a 150 MUm interconnection size ameliorated endothelial cell function evidenced by promoting cell adhesion and migration, increasing cell proliferation and enhancing expression of platelet-endothelial cell adhesion molecules and vascular endothelial growth factor. In vivo study was performed on rabbit implanted with scaffolds into the bone defect on femoral condyles. Implantation with scaffolds with 150 MUm interconnection size significantly improved neovascularization as shown by micro-CT as compared to scaffolds with 100 and 120 MUm interconnection sizes. Moreover, the aforementioned positive effects were abolished by blocking PI3K/Akt/eNOS pathway with LY-294002. Our study explicitly demonstrates that the scaffold with 150 MUm interconnection size improves neovascularization via the PI3K/Akt pathway and provides a target for biomaterial inner structure modification to attain improved clinical performance in implant vascularization. PMID- 25797243 TI - Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. AB - Recently, bacterial infection causing periodontal disease has attracted considerable attention as a risk factor for pancreatic cancer. Fusobacterium species is an oral bacterial group of the human microbiome. Some evidence suggests that Fusobacterium species promote colorectal cancer development; however, no previous studies have reported the association between Fusobacterium species and pancreatic cancer. Therefore, we examined whether Fusobacterium species exist in pancreatic cancer tissue. Using a database of 283 patients with pancreatic ductal adenocarcinoma (PDAC), we tested cancer tissue specimens for Fusobacterium species. We also tested the specimens for KRAS, NRAS, BRAF and PIK3CA mutations and measured microRNA-21 and microRNA-31. In addition, we assessed epigenetic alterations, including CpG island methylator phenotype (CIMP). Our data showed an 8.8% detection rate of Fusobacterium species in pancreatic cancers; however, tumor Fusobacterium status was not associated with any clinical and molecular features. In contrast, in multivariate Cox regression analysis, compared with the Fusobacterium species-negative group, we observed significantly higher cancer-specific mortality rates in the positive group (p = 0.023). In conclusion, Fusobacterium species were detected in pancreatic cancer tissue. Tumor Fusobacterium species status is independently associated with a worse prognosis of pancreatic cancer, suggesting that Fusobacterium species may be a prognostic biomarker of pancreatic cancer. PMID- 25797244 TI - BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner. AB - BRCA1 plays a key role in the regulation of p53-dependent target gene transcription activation. Meanwhile, the p53 inducible gene 3 (PIG3) is a downstream target of p53 and is involved in p53-initiated apoptosis. However, little is known about whether BRCA1 can regulate PIG3-mediated apoptosis. Using a tissue microarray containing 149 breast cancer patient samples, we found that BRCA1 and PIG3 expression status were significantly positively correlated (r = 0.678, P < 0.001) and identified a significant positive correlation between high expression of BRCA1 and/or PIG3 and overall survival (OS). Moreover, we reveal that overexpression of BRCA1 significantly increased expression of PIG3 in cells with intact p53, whereas no increase in PIG3 was observed in p53-null MDA-MB-157 cells and p53-depleted HCT116p53-/- cells. Meanwhile, ectopic expression of BRCA1 could not lead to an increase expression level of prohibitin (PHB), which we have previously identified to induce PIG3-mediated apoptosis. Finally, ChIP analysis revealed that PHB can bind to the PIG3 promoter and activate PIG3 transcription independent of p53, although p53 presence did enhance this process. Taken together, our findings suggest that BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner, and that PIG3 expression is associated with a better OS in breast cancer patients. PMID- 25797245 TI - Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. AB - The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors. PMID- 25797246 TI - Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer. AB - Liver cancer is the second-most frequent cause of cancer death in the world and is highly treatment resistant. We reported previously that inhibition of neddylation pathway with specific NAE inhibitor MLN4924, suppressed the malignant phenotypes of liver cancer. However, during the process, MLN4924 induces pro survival autophagy as a mechanism of drug resistance. Here, we report that blockage of autophagy with clinically-available autophagy inhibitors (e.g. chloroquine) significantly enhanced the efficacy of MLN4924 on liver cancer cells by triggering apoptosis. Mechanistically, chloroquine enhanced MLN4924-induced up regulation of pro-apoptotic proteins (e.g. NOXA) and down-regulation of anti apoptotic proteins. Importantly, the down-regulation of NOXA expression via siRNA silencing substantially attenuated apoptosis of liver cancer cells. Further mechanistic studies revealed that blockage of autophagy augmented MLN4924-induced DNA damage and reactive oxygen species (ROS) generation. The elimination of DNA damage or blockage of ROS production significantly reduced the expression of NOXA, and thereby attenuated apoptosis and reduced growth inhibition of liver cancer cells. Moreover, blockage of autophagy enhanced the efficacy of MLN4924 in an orthotopic model of human liver cancer, with induction of NOXA and apoptosis in tumor tissues. These findings provide important preclinical evidence for clinical investigation of synergistic inhibition of neddylation and autophagy in liver cancer. PMID- 25797247 TI - GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth. AB - The single-agent activity of rapalogs (rapamycin and its analogues) in most tumor types has been modest at best. The underlying mechanisms are largely unclear. In this report, we have uncovered a critical role of GSK3 in regulating degradation of some oncogenic proteins induced by rapalogs and cell sensitivity to rapalogs. The basal level of GSK3 activity was positively correlated with cell sensitivity of lung cancer cell lines to rapalogs. GSK3 inhibition antagonized rapamycin's growth inhibitory effects both in vitro and in vivo, while enforced activation of GSK3beta sensitized cells to rapamycin. GSK3 inhibition rescued rapamcyin-induced reduction of several oncogenic proteins such as cyclin D1, Mcl-1 and c-Myc, without interfering with the ability of rapamycin to suppress mTORC1 signaling and cap binding. Interestingly, rapamycin induces proteasomal degradation of these oncogenic proteins, as evidenced by their decreased stabilities induced by rapamcyin and rescue of their reduction by proteasomal inhibition. Moreover, acute or short-time rapamycin treatment dissociated not only raptor, but also rictor from mTOR in several tested cell lines, suggesting inhibition of both mTORC1 and mTORC2. Thus, induction of GSK3-dependent degradation of these oncogenic proteins is likely secondary to mTORC2 inhibition; this effect should be critical for rapamycin to exert its anticancer activity. PMID- 25797248 TI - New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor. AB - BACKGROUND: We previously showed that growth hormone-releasing hormone (GHRH) agonists are cardioprotective following myocardial infarction (MI). Here, our aim was to evaluate the in vitro and in vivo activities of highly potent new GHRH agonists, and elucidate their mechanisms of action in promoting cardiac repair. METHODS AND RESULTS: H9c2 cells were cultured in serum-free medium, mimicking nutritional deprivation. GHRH agonists decreased calcium influx and significantly improved cell survival. Rats with cardiac infarction were treated with GHRH agonists or placebo for four weeks. MI size was reduced by selected GHRH agonists (JI-38, MR-356, MR-409); this accompanied an increased number of cardiac c-kit+ cells, cellular mitotic divisions, and vascular density. One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-alpha compared to placebo. Gene expression studies revealed favorable outcomes of MR-409 treatment partially result from inhibitory activity on pro-apoptotic molecules and pro-fibrotic systems, and by elevation of bone morphogenetic proteins. CONCLUSIONS: Treatment with GHRH agonists appears to reduce the inflammatory responses post-MI and may consequently improve mechanisms of healing and cardiac remodeling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists. PMID- 25797249 TI - TRPM7 maintains progenitor-like features of neuroblastoma cells: implications for metastasis formation. AB - Neuroblastoma is an embryonal tumor derived from poorly differentiated neural crest cells. Current research is aimed at identifying the molecular mechanisms that maintain the progenitor state of neuroblastoma cells and to develop novel therapeutic strategies that induce neuroblastoma cell differentiation. Mechanisms controlling neural crest development are typically dysregulated during neuroblastoma progression, and provide an appealing starting point for drug target discovery. Transcriptional programs involved in neural crest development act as a context dependent gene regulatory network. In addition to BMP, Wnt and Notch signaling, activation of developmental gene expression programs depends on the physical characteristics of the tissue microenvironment. TRPM7, a mechanically regulated TRP channel with kinase activity, was previously found essential for embryogenesis and the maintenance of undifferentiated neural crest progenitors. Hence, we hypothesized that TRPM7 may preserve progenitor-like, metastatic features of neuroblastoma cells. Using multiple neuroblastoma cell models, we demonstrate that TRPM7 expression closely associates with the migratory and metastatic properties of neuroblastoma cells in vitro and in vivo. Moreover, microarray-based expression profiling on control and TRPM7 shRNA transduced neuroblastoma cells indicates that TRPM7 controls a developmental transcriptional program involving the transcription factor SNAI2. Overall, our data indicate that TRPM7 contributes to neuroblastoma progression by maintaining progenitor-like features. PMID- 25797250 TI - WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C. AB - The wild-type p53 induced phosphatase 1 (WIP1) is an oncogene overexpressed in a variety of human cancers. Here, we demonstrated that WIP1 silencing reduced MMP-9 and VEGF-C expression as well as migration and invasion of salivary adenoid cystic carcinoma (ACC) cells. Overexpression of MMP-9 or VEGF-C restored migration and invasion in WIP1 knockdown cells, indicating that MMP-9 and VEGF-C are downstream targets of WIP1 signaling. Levels of cyclin D1 and c-Myc, targets of Wnt/beta-catenin pathway, were significantly decreased by WIP1 silencing. In addition, WIP1 expression was positively associated with metastasis and prognosis of ACC patients as well as with MMP-9 or VEGF-C in ACC tissues. PMID- 25797251 TI - TERT promoter mutations and telomere length in adult malignant gliomas and recurrences. AB - In this report on 303 gliomas we show the highest frequency of TERT promoter mutations in gliobastomas (80%) followed by oligodendrogliomas (70%) and astrocytomas (39%). We observed positive association between TERT promoter and IDH mutations in oligodendroglial tumors (OR = 26.3; 95% CI 2.5-250.2) and inverse association in primary glioblastomas (OR = 0.13; 95% CI 0.03-0.58). Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations. Tumors with TERT promoter mutations had shorter telomeres than those without. The patients with only TERT promoter mutations showed worst survival (median survival 14.6 months) and patients with both IDH and TERT promoter mutations showed best survival (246.5 months). In patients with astrocytoma, the TERT promoter mutations only associated with poor survival (P < 0.0001); IDH mutations and 1p/19q deletions associated with increased survival (P = 0.0004). TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9). While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome. PMID- 25797252 TI - CRABP-II- and FABP5-independent responsiveness of human glioblastoma cells to all trans retinoic acid. AB - Glioblastomas respond differently to all-trans retinoic acid (RA) for unknown reasons. Because CRABP-II and FABP5 mediate RA intracellular signaling respectively and lead to distinct biological consequences, their expression patterns in different grades of astrocytomas and the glioblastoma cells lines LN18, LN428 and U251 were examined to identify potential correlations with RA sensitivities. The response of glioblastoma cells to RA, decitabine or the FABP5 competitive inhibitor, BMS309403, was analyzed. CRABP-II and FABP5 were expressed to varying degrees by the 84-astrocytoma cases examined. Treatment of LN428, U251 and LN18 cells with RA failed to suppress their growth; however, U251 proliferation was inhibited by decitabine. The combination of decitabine and RA suppressed the growth of all three cell lines and induced significant apoptosis of LN428 and U251 cells. Both CRABP-II and FABP5 were transcribed in the three cell lines but FABP5 proteins were undetectable in U251 cells. The ratio of CRABP II to FABP5 was not altered after RA, decitabine or RA and decitabine treatment and the resistance of cells to RA was not reversed by BMS309403 treatment. In conclusion, CRABP-II and FABP5 expression patterns are neither related to the tumor grades nor correlated with RA sensitivity. Additional molecular factors may be present that determines the sensitivity of glioblastoma cells to RA. Dicitabine may improve the sensitivity of glioblastoma cells to RA, however, its underlying mechanism and its in vivo feasibility need to be investigated. PMID- 25797253 TI - The mitochondrial carrier SLC25A10 regulates cancer cell growth. AB - Dysregulation of cell metabolism is critical for the growth properties of cancer cells. The purpose of this study was to understand the role of substrate transport across the mitochondrial membrane to sustain the metabolic shift and redox defense in cancer cells. Mitochondrial carrier SLC25A10 is up-regulated in a variety of tumors and is involved in regulating intracellular levels of reactive oxygen species. We show that knockdown of SLC25A10 in A549 cells changed the growth properties to a less malignant phenotype and casued increased glutamine dependency and sensitivity to oxidative stress. The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1alpha. We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine. The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies. PMID- 25797254 TI - Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways. AB - We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP 2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21(WAF1/CIP1) and p27(KIP1) expression, and cellular apoptosis in RCC cells. BMP 2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2' deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC. PMID- 25797255 TI - YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence. AB - Attempts to identify biomarkers to detect prostate tumorigenesis, and thus minimize prostate cancer progression and inform treatment decisions have primarily focused on alterations at the DNA and mRNA levels, ignoring alterations at the level of protein synthesis control. We have previously shown that the PI3K AKT-mTOR pathway, frequently deregulated in prostate cancer, specifically induces the synthesis of proteins that contribute to metastasis, most notably YB-1 and MTA1, without altering mRNA levels thereby demonstrating the importance of translation control in driving the expression of these genes in cancer.Here, we analyze genomic sequencing and mRNA expression databases, as well as protein expression employing an annotated tissue microarray generated from 332 prostate cancer patients with 15 years of clinical follow-up to determine the combined prognostic capability of YB-1 and MTA1 alterations in forecasting prostate cancer outcomes. Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse. Moreover, high protein levels of YB-1 and MTA1 are associated with a 3-fold increased risk for requiring future hormone therapy or radiation therapy. Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence. These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression. PMID- 25797256 TI - A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells. AB - Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5'-3' exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer. PMID- 25797257 TI - Adipose-derived stem cells promote tumor initiation and accelerate tumor growth by interleukin-6 production. AB - Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention. Here, we show that ADSCs enhance sphere formation and in vivo tumor initiation of breast and colon cancer cells. In co-culture, ADSCs induced several stem cell markers in cancer cells. ADSCs also accelerated tumor growth. Interaction of ADSCs and cancer cells stimulated secretion of interlukin-6 in ADSCs, which in turn acted in a paracrine manner on cancer cells to enhance their malignant properties. Interleukin-6 regulated stem cell-related genes and activated JAK2/STAT3 in cancer cells. We suggest that ADSCs may enhance tumor initiation and promotion. PMID- 25797258 TI - PTX3 gene activation in EGF-induced head and neck cancer cell metastasis. AB - Overexpression of the epidermal growth factor (EGF) receptor (EGFR) is associated with enhanced invasion and metastasis in head and neck squamous cell carcinoma (HNSCC). Long Pentraxin PTX3 is involved in immune escape in cancer cells. Here, we identified PTX3 as a promoting factor that mediates EGF-induced HNSCC metastasis. EGF-induced PTX3 transcriptional activation is via the binding of c Jun to the activator protein (AP)-1 binding site of the PTX3 promoter. PI3K/Akt and NF-kappaB were essential for the PTX3 activation. EGF-induced PTX3 expression was blocked in c-Jun- and NF-kappaB-knockdown cells. EGF-mediated PTX3 secretion resulted in the enhancement of cell migration and invasion, and interactions between cancer and endothelial cells. The tail-vein injection animal model revealed that depletion of PTX3 decreased EGF-primed tumor cell metastatic seeding of the lungs. In addition, fibronectin, matrix metalloproteinase-9 (MMP9) and E-cadherin were essential components in EGFR/PTX3-mediated cancer metastasis. In conclusion, PI3K/Akt and NF-kappaB-dependent regulation of AP-1 mediates PTX3 transcriptional responses to EGF. Autocrine production of EGF-induced PTX3 in turn induces metastatic molecules, activating inflammatory cascades and metastasis. PMID- 25797259 TI - Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium. AB - Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, remained unclear. In this report, we demonstrated that tumor induced myostatin in turn induced TNF-alpha, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL 6, TNF-alpha and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy. PMID- 25797261 TI - Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial-mesenchymal transition. AB - Mounting evidence has shown that induction of epithelial-mesenchymal transition (EMT) contributes to the the expression of CSC (cancer stem cell) markers. However, whether and how CSC markers could be involved in regulating EMT has rarely been reported. CD44, being one of the most commonly used CSC markers in hepatocellular carcinoma (HCC), has been demonstrated to act as a multidomain, transmembrane platform that serves to integrate a wide variety of extracellular signals. Therefore, we determined to seek whether CD44 is necessary for the EMT process in HCC. First, we noticed that CD44 expression was associated with the mesenchymal phenotype in HCC cell lines, and knocking down CD44 with lentivirus mediated shRNA in HCC cell lines resulted in the mesenchymal-epithelial transition (MET) and the subsequent impaired migration and invasion in vitro. Moreover, in a metastatic mice model established by tail vein injection of luciferase labelled MHCC97-H cells, we confirmed that CD44 knockdown resulted in the decreased metastasis of HCC cells. Furthermore, we found that the induction of MET by CD44 inhibition might be achieved, at least in part, by repressing the ERK/Snail pathway. PMID- 25797260 TI - MicroRNA-200a suppresses metastatic potential of side population cells in human hepatocellular carcinoma by decreasing ZEB2. AB - Although microRNA-200a (miR-200a) is frequently downregulated in cancer, its role in side population (SP) has not been investigated. In this study, 101 pairs of primary hepatocellular carcinoma (HCC) tissues and matched normal control tissues were analyzed for miR-200a expression and its clinicopathological value was determined. We found that miR-200a was downregulated in HCC/SP and this was associated metastasis. MiR-200a suppressed metastasis of SP cells. Overexpression of miR-200a in SP cells decreased metastasis-related markers and expression of ZEB2. The associations between miR-200a, SP cells and ZEB2 were validated in HCC. These findings reveal that miR-200a suppresses metastasis of SP cells by downregulating ZEB2. PMID- 25797262 TI - Pleiotropic modes of action in tumor cells of RNASET2, an evolutionary highly conserved extracellular RNase. AB - As widely recognized, tumor growth entails a close and complex cross-talk among cancer cells and the surrounding tumor microenvironment. We recently described the human RNASET2 gene as one key player of such microenvironmental cross-talk. Indeed, the protein encoded by this gene is an extracellular RNase which is able to control cancer growth in a non-cell autonomous mode by inducing a sustained recruitment of immune-competent cells belonging to the monocyte/macrophage lineage within a growing tumor mass. Here, we asked whether this oncosuppressor gene is sensitive to stress challenges and whether it can trigger cell-intrinsic processes as well. Indeed, RNASET2 expression levels were consistently found to increase following stress induction. Moreover, changes in RNASET2 expression levels turned out to affect several cancer-related parameters in vitro in an ovarian cancer cell line model. Of note, a remarkable rearrangement of the actin cytoskeleton organization, together with changes in cell adhesion and motility, emerged as putative mechanisms by which such cell-autonomous role could occur. Altogether, these biological features allow to put forward the hypothesis that the RNASET2 protein can act as a molecular barrier for limiting the damages and tissue remodeling events occurring during the earlier step of cell transformation. PMID- 25797263 TI - Downregulation of miR-432 activates Wnt/beta-catenin signaling and promotes human hepatocellular carcinoma proliferation. AB - Sustained cell growth and proliferation, one of the hallmarks of cancer, is considered to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation. Aberrant activation of the Wnt/beta catenin signaling pathway leads to cell proliferation, growth and survival, and promotes the development of various human tumors, including hepatocellular carcinoma. Elucidating the molecular mechanism of this abnormality in hepatocellular carcinoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy. Herein, we report that the expression of miR-432 was markedly downregulated in hepatocellular carcinoma cell lines and tissues, and upregulation of miR-432 inhibited, whereas downregulation of miR-432 enhanced the proliferation and tumorigenicity of hepatocellular carcinoma cells both in vitro and in vivo. Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/beta-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/beta-catenin signaling pathway. Finally, miR-432 expression was inversely correlated with three targets in clinical hepatocellular carcinoma samples. These results demonstrated that miR 432 functions as a tumor-suppressive miRNA by suppressing Wnt/beta-catenin signaling activation and may represent a therapeutic target for hepatocellular carcinoma. PMID- 25797264 TI - Vasohibin-1 suppresses colon cancer. AB - Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo. PMID- 25797265 TI - Extracellular vesicles derived from renal cancer stem cells induce a pro tumorigenic phenotype in mesenchymal stromal cells. AB - Renal carcinomas have been shown to contain a population of cancer stem cells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs were shown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules (proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal Stromal Cells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role of MSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have been reported. In this study we analysed the participation of renal CSC-derived EVs in the interaction between tumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase). EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditioned medium. Moreover, EV stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, when co-injected with renal tumor cells. In conclusion, CSC derived EVs induced phenotypical changes in MSCs that are associated with tumor growth. PMID- 25797266 TI - Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells. AB - All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARalpha-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells. PMID- 25797268 TI - Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma. AB - It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC. PMID- 25797267 TI - Ku80 cooperates with CBP to promote COX-2 expression and tumor growth. AB - Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX 2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID- 25797270 TI - Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. AB - The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naive Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy. PMID- 25797269 TI - MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer. AB - MicroRNA-31 (miR-31) is among the most frequently altered microRNAs in human cancers and altered expression of miR-31 has been detected in a large variety of tumor types, but the functional role of miR-31 still hold both tumor suppressive and oncogenic roles in different tumor types. MiR-31 expression was down regulated in a large cohort of hepatocellular carcinoma (HCC) patients, and low expression of miR-31 was significantly associated with poor prognosis of HCC patients. Ectopic expression of miR-31 mimics suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. Additional study evidenced miR-31 directly to suppress HDAC2 and CDK2 expression by inhibiting mRNA translation in HCC cells. We also found that ectopic expression of miR-31 mimics reduced metastatic potential of HCC cells by selectively regulating epithelial mesenchymal transition (EMT) regulatory proteins such as N-cadherin, E-cadherin, vimentin and fibronectin. HCC tissues derived from chemical-induced rat liver cancer models validated that miR-31 expression is significantly down-regulated, and that those cell cycle- and EMT-regulatory proteins are deregulated in rat liver cancer. Overall, we suggest that miR-31 functions as a tumor suppressor by selectively regulating cell cycle and EMT regulatory proteins in human hepatocarcinogenesis providing a novel target for the molecular treatment of liver malignancies. PMID- 25797271 TI - Secreted uPAR isoform 2 (uPAR7b) is a novel direct target of miR-221. AB - miR-221/-222 and components of the urokinase-type plasminogen activator system (uPAS) are associated with metastasis and poor prognosis in breast cancer, including the triple-negative subtype (TNBC). Modification of components of uPAS and involved miRNAs may contribute to targeted therapy for breast cancer patients. miR-221-/-222-overexpressing or miR-221-depleted cells were employed for qRT-PCR and Western blots to show associations of uPAR with miR-221/-222. To substantiate direct targeting of miR-221/-222 within 3' UTR of the uPAR isoform 2, in silico analysesand in vitro assays were conducted. Significant associations between miR-221 and uPAR isoform 2 expressions were observed at the mRNA and protein levels in breast cancer cells representing TNBC. For the first time, the uPAR isoform 2 was demonstrated as direct target for miR-221/-222. Inhibition of miR-221 reduced uPAR protein expression and expression of the tumor cell invasion markers vimentin and RHOC. These results demonstrate a direct and positive regulation of the secreted uPAR isoform 2 by miR-221, increasing its protein expression, a prerequisite for malignancy, while the other uPAR isoforms (1, 3 and 4) are indirectly regulated through miR-10b and miR-221/-222. By targeting uPAR isoforms and/or miRNA-221/-222, the diagnosis and therapy of breast cancer, in particular in TNBC, could be significantly improved. PMID- 25797273 TI - Fine control on the photochemical and photobiological properties of Ru(II) arene complexes. AB - A series of six Ru(arene) complexes, [(eta(6)-p-cymene)Ru(dpb)(py-R)](2+) (1-6, dpb = 2,3-bis(2-pyridyl)benzoquinoxaline, py-R = 4-substituted pyridine, R = N(CH3)2, NH2, OCH3, H, COOCH3 and NO2), were synthesized and their photochemical and photobiological properties were compared in detail. The electron push/pull character of the R groups has a significant impact on both ligand photodissociation and (1)O2 generation of the complexes. The photoinduced DNA covalent binding capabilities increase from 1 to 6 under both aerobic and anaerobic conditions, and DNA photocleavage occurs simultaneously in aerobic environments. 4 has the most potent phototoxicity against human lung carcinoma A549 cells among the examined complexes. The substituent effect may be ascribed to the influences of the R groups on the energy levels of (3)MC and (3)MLCT states as well as the energy gaps between (3)MC, (3)MLCT and dpb-based (3)IL states. Similar chemical modification on bidentate and arene ligands or other sites of the pyridine ligand may lead to more efficient agents with PDT and/or PACT activities. PMID- 25797272 TI - FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors. AB - Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs. PMID- 25797274 TI - Genomic profile of breast cancer. PMID- 25797275 TI - Correction: Tackling poison and leach: catalysis by dangling thiol-palladium functions within a porous metal-organic solid. PMID- 25797276 TI - Association of Helicobacter pylori infection with chronic obstructive pulmonary disease and chronic bronchitis: a meta-analysis of 16 studies. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB) are common respiratory diseases globally. The aim of this meta-analysis was to quantify the risk of these two diseases being associated with Helicobacter pylori infection. METHODS: A literature search was performed to identify studies published before 5 June 2014 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for COPD and CB. RESULTS: Sixteen observational studies involving 1390 patients with COPD, 734 with CB and more than 13 000 controls were included. Helicobacter pylori infection was associated with an increased risk of COPD and CB [odds ratio (OR) 2.07, 95% confidence interval (CI) 1.81-2.36, p for heterogeneity = 0.05; and OR 1.57, 95% CI 1.33 1.86, p for heterogeneity = 0.08]. We discovered a significant association between CagA-positive strains and risk for COPD (OR 3.46, 95% CI 2.29-5.25, p for heterogeneity = 0.20). CONCLUSIONS: Our meta-analysis suggested a potential relationship between H. pylori infection and the development of COPD and CB. PMID- 25797277 TI - Comparison of coronary heart disease genetic assessment with conventional cardiovascular risk assessment in primary care: reflections on a feasibility study. AB - AIM: This study assesses the feasibility of collecting genetic samples and self reported outcome measures after cardiovascular risk assessment, and presenting the genetic test results to participants. BACKGROUND: Coronary heart disease (CHD) genetic tests are increasingly available through direct-to-consumer marketing, but their potential clinical impact on cardiovascular risk assessment is unclear. METHODS: Observational study in 10 British general practices in Central England. A total of 320 individuals, who had completed conventional cardiovascular risk assessment, were offered CHD genetic test, with follow-up outcome questionnaire at eight months for lifestyle change and State-Trait Anxiety. FINDINGS: A total of 119 (37%) participants returned genetic test specimens, with over a third reporting family history of CHD in a specified relative; 79 (66.4%) were categorized above-average risk on conventional cardiovascular risk assessment, 65 of whom (82.3%) were only average risk on genetic assessment. The dietary fat questionnaire was poorly completed while study participation was not associated with increased anxiety (mean increase in anxiety score=2.1; 95% CI -0.1-4.3; P=0.06). CONCLUSION: As a feasibility study, over a third of individuals offered genetic testing in primary care, as part of CVD risk assessment, took up the offer. Although intervention did not appear to increase anxiety, this needs further evaluation. To improve generalizability and effect size, future studies should actively engage individuals from wider socio economic backgrounds who may not have already contemplated lifestyle change. The current research suggests general practitioners will face the clinical challenge of patients presenting with direct-to-consumer genetic results that are inconsistent with conventional cardiovascular risk assessment. PMID- 25797278 TI - Follicular thyroid carcinoma with skull metastases. AB - Thyroid carcinoma with distant metastases at initial presentation, is uncommon. Skull metastases occur very rarely, with a reported incidence of 2.5-5.8%. Here we report two cases of follicular thyroid cancer with skull involvement, and describe the diagnostic and therapeutic approach to metastatic thyroid cancer. We present the cases of a 70-year-old female and a 74-year-old female who presented with painless, large slow-growing masses of the skull. The patients underwent surgical excision of the skull masses, which were histologically diagnosed as metastatic follicular thyroid cancer, and total thyroidectomy, which confirmed the diagnosis of follicular thyroid carcinoma. They were treated with radioiodine and suppressive levothyroxine, which achieved local control of the disease. Management of metastatic thyroid cancer, requires a multidisciplinary approach and multimodality treatment. Distant metastases should be surgically removed whenever possible. Initial aggressive treatment is crucial in the management of metastatic thyroid carcinoma, providing the best chance to prolong patient survival. PMID- 25797279 TI - The expression of neurogenic markers after neuronal induction of chorion-derived mesenchymal stromal cells. AB - OBJECTIVES: Chorion is a tissue of early embryologic period that is discarded after delivery. It might be the potential source of mesenchymal stromal cells (MSCs) that can be used for research and eventually for therapeutic studies. At present, the biological properties and the differentiation capacity of chorion derived MSCs are still poorly characterised. The objective of this study is to characterise and explore the differentiating potential of chorion-derived MSCs towards the neuronal lineages. METHODS: Chorionic membrane was digested with enzyme and cultured in Dulbecco's Modified Eagle's medium supplemented with 10% fetal bovine serum. The expression of MSC markers was examined using flow cytometry. The adipogenic, osteogenic and neurogenic differentiation were examined by culturing in appropriate induction media. The expression of neuronal markers was determined by immunofluorescence and quantitative real time-PCR. RESULTS: Chorion-derived MSCs were easily expanded up to 20 passages. They were positive for MSC markers (CD73, CD90 and CD105), and negative for haematopoietic markers (CD34 and CD45). Chorion-derived MSCs could differentiate into several mesodermal-lineages including adipocytes and osteoblasts. Moreover, chorion derived MSCs could differentiate into neuronal-like cells as characterised by cell morphology and the presence of neural markers including MAP-2, glial fibrillary acidic protein (GFAP) and beta-tubulin III. DISCUSSION: Chorion derived MSCs can be readily obtained and expanded in culture. These cells also have transdifferentiation capacity as evidenced by their neuronal differentiation potential. Therefore, chorion can be used as an alternative source of MSCs for stem cell therapy in nervous system disorders. PMID- 25797280 TI - Transport of spherical colloids in layered phases of binary mixtures with rod like particles. AB - The transport properties of colloids in anisotropic media constitute a general problem of fundamental interest in experimental sciences, with a broad range of technological applications. This work investigates the transport of soft spherical colloids in binary mixtures with rod-like particles by means of Monte Carlo and Brownian Dynamics simulations. Layered phases are considered, that range from smectic phases to lamellar phases, depending on the molar fraction of the spherical particles. The investigation serves to characterize the distinct features of transport within layers versus those of transport across neighboring layers, both of which are neatly differentiated. The insertion of particles into layers and the diffusion across them occur at a smaller rate than the intralayer diffusion modulated by the formation of transitory cages in its initial stages. Collective events, in which two or more colloids diffuse across layers in a concerted way, are described as a non-negligible process in these fluids. PMID- 25797281 TI - In vitro comparison of duration of action of melatonin agonists on melatonin MT1 receptor: possible link between duration of action and dissociation rate from receptor. AB - Melatonin MT1 and MT2 receptors are Gi protein-coupled receptors and promising therapeutic targets for a number of diseases. A proportion of G protein-coupled receptor agonists and antagonists have been classified according to their duration of action, which influences their pharmacological efficacy. However, the duration of action of melatonin agonists remains unclear. In this study, we investigated the duration of action of melatonin agonists (melatonin, 2 iodomelatonin, ramelteon, and the ramelteon metabolite M-II) at the melatonin MT1 receptor, which is more resistant to agonist-induced desensitization than the melatonin MT2 receptor. In Chinese hamster ovary cells stably expressing the human melatonin MT1 receptor, significant differences in the duration of action were observed after 2-h pretreatment with agonists followed by washout. In contrast to melatonin and M-II, the agonist activities of ramelteon and 2 iodomelatonin were persistent (i.e. inhibition of forskolin-stimulated cAMP formation and increase in ERK 1/2 phosphorylation) even after repeated washouts. Similar activities were observed for INS-1 cells endogenously expressing the rat MT1 receptor. Further, we examined potential factors linked to the duration of action. Residual activities of melatonin agonists after washout strongly correlated with their dissociation rates from the human melatonin MT1 receptor, but not their lipophilicity or extent of desensitization. These data suggest that the in vitro duration of action significantly differs between melatonin agonists and might dictate dissociation kinetics. Characterization of these in vitro properties may facilitate further in vivo study of the duration of action. PMID- 25797282 TI - Functional proteomics of synaptic plasma membrane ATP-ases of rat hippocampus: effect of l-acetylcarnitine and relationships with Dementia and Depression pathophysiology. AB - Synaptic energy state and mitochondrial dysfunction are crucial factors in many brain pathologies. l-acetylcarnitine, a natural derivative of carnitine, improves brain energy metabolism, and has been proposed for the Therapy of many neurological and psychiatric diseases. The effects of the drug on the maximum rate (Vmax) of enzymatic activities related to hippocampal synaptic energy utilization were evaluated, in the perspective of its employment for Dementias and Depression Therapy. Two types of synaptic plasma membranes (SPM1 and SPM2) were isolated from the hippocampus of rats treated with l-acetylcarnitine (30 and 60mg/kg i.p., 28 days, 5 days/week). Acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain-insensitive Mg(2+)-ATP-ase; Na(+), K(+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase activities were evaluated. In control animals, enzymatic activities were differently expressed in SPM1 , being the evaluated enzymatic activities higher in SPM2. Subchronic treatment with l-acetylcarnitine (i) did not modify AChE on both SPMs; (ii) increased Na(+), K(+), Mg(2+)-ATP-ase, ouabain insensitive Mg(2+)-ATP-ase and Na(+), K(+)-ATP-ase at the dose of 30 and 60mg/kg on SPM1 and SPM2; (iii) increased Ca(2+), Mg(2+)-ATP-ase activity on both SPMs at the dose of 60mg/kg. These results have been discussed considering the pathophysiology and treatment of Dementias and Depression because, although referred to normal healthy animals, they support the notion that l acetylcarnitine may have positive effects in these pathologies. PMID- 25797283 TI - Quinaldic acid inhibits proliferation of colon cancer ht-29 cells in vitro: effects on signaling pathways. AB - Quinaldic acid is presumed to be a derivative of kynurenic acid, a tryptophan metabolite with proven antiproliferative activity towards cancer cells in vitro. The aim of present study was to evaluate the activity of quinaldic acid in colon cancer cells. The antiproliferative potential of quinaldic acid was assessed in HT-29, LS180 and Caco-2 cells. Suppression of metabolic activity (IC50 of 0.5mM for HT-29 and LS180 cells, 0.9mM for Caco-2 cells) and DNA synthesis (IC50 of 2.7, 4.3, 2mM for HT-29, LS180 and Caco-2 cells, respectively) were observed in all tested cell lines. It is noteworthy that quinaldic acid in antiproliferative concentrations was non-toxic to normal colon epithelium CCD 841 CoTr cells. Concomitantly, alterations in several signaling pathways in HT-29 cells were observed. Quinaldic acid led to changes in the phosphorylation level of extracellular-signal-regulated kinase (ERK) 1/2, p38, cAMP response element binding protein (CREB) and Akt (protein kinase B) kinases. Moreover, changes in the CREB transcription factor were also found at the gene expression level. Antiproliferative activity and signaling pathways modulatory potential of quinaldic acid in colon cancer cells in vitro has been stated. PMID- 25797284 TI - Effect of propane-2-sulfonic acid octadec-9-enyl-amide on the expression of adhesion molecules in human umbilical vein endothelial cells. AB - Oleoylethanolamide (OEA), an endogenous agonist of PPARalpha, has been reported to have anti-atherosclerotic properties. However, OEA can be enzymatically hydrolyzed to oleic acid and ethanolamine and, thus, is not expected to be orally active. In the present study, we designed and synthesized an OEA analog, propane 2-sulfonic acid octadec-9-enyl-amide (N15), which is resistant to enzymatic hydrolysis. The purpose of this study was to investigate the effects of N15 on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). The results showed that N15 inhibited TNFalpha-induced production of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and the adhesion of monocytes to TNFalpha-induced HUVECs. Furthermore, the protective effect of N15 on inflammation is dependent upon a PPAR-alpha/gamma-mediated mechanism. In conclusion, N15 protects against TNFalpha-induced vascular endothelial inflammation. This anti-inflammatory effect of N15 is dependent on PPAR-alpha/gamma dual targets. PMID- 25797285 TI - Production of interleukin (IL)-33 in the lungs during multiple antigen challenge induced airway inflammation in mice, and its modulation by a glucocorticoid. AB - Although interleukin (IL)-33 is a candidate aggravator of asthma, the cellular sources of IL-33 in the lungs during the progression of antigen-induced airway inflammation remain unclear. Furthermore, it has not been determined whether the antigen-induced production of IL-33 can be pharmacologically modulated in vivo. In this study, we examined the production of IL-33 in the lungs of sensitized mice during multiple intratracheal challenges with the antigen, ovalbumin. The 1st challenge clearly induced the IL-33 production in the lungs, and it was enhanced by the 2nd-4th challenges. IL-33 mRNA transcription was also induced after these challenges. An immunohistochemical analysis revealed that the cellular sources of IL-33 after the 1st challenge were mainly bronchial epithelial cells, while those after the 3rd challenge were not only the epithelial cells, but also inflammatory cells that infiltrated the lungs. Flow cytometric analyses indicated that approximately 20% and 10% of the IL-33 producing cells in the lungs were M2 macrophages and conventional dendritic cells, respectively. A systemic treatment with dexamethasone before the 1st challenge potently suppressed the IL-33 production. When dexamethasone was administered before the respective challenges, production of the IL-33 protein and the infiltration of IL-33-producing M2 macrophages and dendritic cells into the lungs in the 3rd challenge were also suppressed. In conclusion, the cellular sources of IL-33 in the lungs were dynamically altered during multiple challenges: not only bronchial epithelial cells, but also the M2 macrophages and dendritic cells that infiltrated the lungs produced IL-33. The production of IL 33 was susceptible to the glucocorticoid treatment. PMID- 25797286 TI - Taraxasterol inhibits IL-1beta-induced inflammatory response in human osteoarthritic chondrocytes. AB - Osteoarthritis (OA), a chronic degenerative joint disease, is a leading cause of disability among elderly patients. Taraxasterol, a pentacyclic-triterpene isolated from Taraxacum officinale, has been shown to have anti-inflammatory effects. However, the protective effect of taraxasterol on OA remains unclear. In order to provide a scientific basis for the applicability of taraxasterol in OA, the anti-inflammatory effects of taraxasterol on IL-1beta-stimulated osteoarthritic chondrocytes were investigated. Chondrocytes were pretreated with taraxasterol 1h before IL-1beta treatment. The productions of MMP-1, MMP3, MMP13, PGE2 and NO were measured by ELISA and Griess reaction. The expression of COX-2, iNOS, and NF-kappaB was detected by western blot analysis. Our results demonstrated that taraxasterol dose-dependently suppressed MMP-1, MMP3, MMP13, PGE2 and NO production induced by IL-1beta. The expression of COX-2 and iNOS was also inhibited by taraxasterol. Western blot analysis showed that taraxasterol suppressed IL-1beta-induced NF-kappaB activation in a dose-dependent manner. Taken together, we found that taraxasterol protected human chondrocytes by inhibiting MMPs, NO and PGE2 production. Taraxasterol may be a useful agent for prevention and treatment of OA. PMID- 25797287 TI - Versatile synthesis of phospholides from open-chain precursors. Application to annelated pyrrole- and silole-phosphole rings. AB - Phospholides are easily obtained by treatment of the open-chain acetylenic phosphines shown by an excess of lithium at room temperature in THF (12 examples). PMID- 25797288 TI - A review and clinical summary of vitamin D in regard to bone health and athletic performance. AB - The large amount of scientific literature regarding vitamin D can be overwhelming and confusing. Some organizations have made specific guidelines and recommendations regarding optimal blood levels of vitamin D. In the sports medicine literature, new information about the effects of vitamin D on performance and bone health abound. Most of these articles seem to raise more questions than they answer. Are athletes at increased risk of vitamin D deficiency? Does vitamin D deficiency affect athletic performance? Should athletes be tested for deficiency? What is the optimal goal for vitamin D levels in athletes and is this different from the general population? The goal of this article is to provide clinical insight and clarity, both for those practicing in the primary care setting as well as for those taking care of athletes. PMID- 25797289 TI - In vitro and in vivo ocular biocompatibility of electrospun poly(E-caprolactone) nanofibers. AB - Biocompatibility is a requirement for the development of nanofibers for ophthalmic applications. In this study, nanofibers were elaborated using poly(epsilon-caprolactone) via electrospinning. The ocular biocompatibility of this material was investigated. MIO-M1 and ARPE-19 cell cultures were incubated with nanofibers and cellular responses were monitored by viability and morphology. The in vitro biocompatibility revealed that the nanofibers were not cytotoxic to the ocular cells. These cells exposed to the nanofibers proliferated and formed an organized monolayer. ARPE-19 and MIO-M1 cells were capable of expressing GFAP, respectively, demonstrating their functionality. Nanofibers were inserted into the vitreous cavity of the rat's eye for 10days and the in vivo biocompatibility was investigated using Optical Coherence Tomography (OCT), histology and measuring the expression of pro-inflammatory genes (IL-1beta, TNF alpha, VEGF and iNOS) (real-time PCR). The OCT and the histological analyzes exhibited the preserved architecture of the tissues of the eye. The biomaterial did not elicit an inflammatory reaction and pro-inflammatory cytokines were not expressed by the retinal cells, and the other posterior tissues of the eye. Results from the biocompatibility studies indicated that the nanofibers exhibited a high degree of cellular biocompatibility and short-term intraocular tolerance, indicating that they might be applied as drug carrier for ophthalmic use. PMID- 25797290 TI - Rapid quantification of 2-hydroxypropyl-beta-cyclodextrin in liquid pharmaceutical formulations by (1)H nuclear magnetic resonance spectroscopy. AB - Quantification of 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) is not yet described in United States Pharmacopeia (USP) and European Pharmacopeia (EP). A useful quality control tool is therefore needed for the specific quantification in finished liquid pharmaceutical products, especially for formulations containing 2-HP-beta-CD as an active ingredient. A new technique is also mandatory for the development of future formulations in which 2-HP-beta-CD concentration could influence the properties of these formulations. Here, we described the use of (1)H NMR for the rapid quantification of 2-HP-beta-CD directly into pharmaceutical solutions without any extraction or separation steps. This technique was successfully applied to different pharmaceutical solutions comprising an i.v. solution (budesonide/2-HP-beta-CD complex), an eye drop solution (Indocollyre(r)) and an oral solution (Sporanox(r)). Specificity, linearity, precision (repeatability and intermediate precision), trueness, limits of quantification (LOQs) and accuracy were used as validation criteria. PMID- 25797291 TI - Decreased expression of Toll-like receptor 4 and 5 during progression of prostate transformation in transgenic adenocarcinoma of mouse prostate mice. AB - Chronic inflammation has been considered an important risk factor for development of prostate cancer. Toll-like receptors (TLRs) recognize microbial moieties or endogenous molecules and play an important role in the triggering and promotion of inflammation. In this study, we examined whether expression of TLR4 and TLR5 was associated with progression of prostate transformation in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The expression of TLR4 and TLR5 was evaluated by immunohistochemisty in formalin-fixed paraffin-embedded prostate tissue from wild-type (WT) and TRAMP mice. Normal prostate tissue from WT mice showed strong expression of TLR4 and TLR5. However, TLR4 expression in the prostate tissue from TRAMP mice gradually decreased as pathologic grade became more aggressive. TLR5 expression in the prostate tissue from TRAMP mice also decreased in low-grade prostate intraepithelial neoplasia (PIN), high-grade PIN and poorly differentiated adenocarcinoma. Overall, our results suggest that decreased expression of TLR4 and TLR5 may contribute to prostate tumorigenesis. PMID- 25797292 TI - Influence of category--heifers, primiparous and multiparous lactating cows--in a large-scale resynchronization fixed-time artificial insemination program. AB - This study was conducted to evaluate the influence of category (heifers, primiparous or multiparous cows) on pregnancy rates in a large scale resynchronization ovulation program. Nelore heifers (n = 903), primiparous lactating cows (n = 338) and multiparous lactating cows (n = 1,223) were synchronized using a conventional protocol of estradiol/P4-based fixed-time artificial insemination (FTAI). Thirty days after ultrasonography, females who failed the first FTAI were resynchronized with the same hormonal protocol prior to a second FTAI. The pregnancy status of each cohort was evaluated by ultrasonography 30 days after each FTAI. The average conception rate after the first FTAI and resynchronization was 80.5%. Heifers had a higher conception rate (85%) than primiparous (76%) or multiparous cows (78%; p = 0.0001). The conception rate after the first FTAI was similar among heifers (57%), primiparous cows (51%) and multiparous cows (56%; p = 0.193). After the second FTAI, heifers exhibited a higher conception rate (66%) than primiparous or multiparous cows (51%; p = 0.0001). These results demonstrate the feasibility of resynchronization in large beef herds for providing consistent pregnancy rates in a short period of time. We also demonstrated that ovulation resynchronization 30 days after FTAI is particularly effective for heifers, providing a conception rate of up to 66%. PMID- 25797293 TI - Rapamycin treatment during in vitro maturation of oocytes improves embryonic development after parthenogenesis and somatic cell nuclear transfer in pigs. AB - This study was conducted to investigate the effects of rapamycin treatment during in vitro maturation (IVM) on oocyte maturation and embryonic development after parthenogenetic activation (PA) and somatic cell nuclear transfer (SCNT) in pigs. Morphologically good (MGCOCs) and poor oocytes (MPCOCs) were untreated or treated with 1 nM rapamycin during 0-22 h, 22-42 h, or 0-42 h of IVM. Rapamycin had no significant effects on nuclear maturation and blastocyst formation after PA of MGCOCs. Blastocyst formation after PA was significantly increased by rapamycin treatment during 22-42 h and 0-42 h (46.6% and 46.5%, respectively) relative to the control (33.3%) and 0-22 h groups (38.6%) in MPCOCs. In SCNT, blastocyst formation tended to increase in MPCOCs treated with rapamycin during 0-42 h of IVM relative to untreated oocytes (20.3% vs. 14.3%, 0.05 < p < 0.1), while no improvement was observed in MGCOCs. Gene expression analysis revealed that transcript abundance of Beclin 1 and microtubule-associated protein 1 light chain 3 mRNAs was significantly increased in MPCOCs by rapamycin relative to the control. Our results demonstrated that autophagy induction by rapamycin during IVM improved developmental competence of oocytes derived from MPCOCs. PMID- 25797294 TI - SNP genetic polymorphisms of MDR-1, CYP1A2 and CYPB11 genes in four canine breeds upon toxicological evaluation. AB - The fields of pharmacogenetics and pharmacogenomics have become increasingly promising regarding the clinical application of genetic data to aid in prevention of adverse reactions. Specific screening tests can predict which animals express modified proteins or genetic sequences responsible for adverse effects associated with a drug. Among the genetic variations that have been investigated in dogs, the multidrug resistance gene (MDR) is the best studied. However, other genes such as CYP1A2 and CYP2B11 control the protein syntheses involved in the metabolism of many drugs. In the present study, the MDR-1, CYP1A2 and CYP2B11 genes were examined to identify SNP polymorphisms associated with these genes in the following four canine breeds: Uruguayan Cimarron, Border Collie, Labrador Retriever and German Shepherd. The results revealed that several SNPs of the CYP1A2 and CYP2B11 genes are potential targets for drug sensitivity investigations. PMID- 25797295 TI - Efficacy of silver ions against Sacbrood virus infection in the Eastern honey bee Apis cerana. AB - Although silver is known to be a broad-spectrum biocidal agent, the effects of this metal against Sacbrood virus have not yet been investigated. In this study, we evaluated the efficacy of silver ions against natural Korean sacbrood virus (KSBV) infection of Apis (A.) cerana. Ten KSBV-infected colonies containing A. cerana with similar strength and activity were selected from an apiary located in Bosung-gun (Korea). Among these, five colonies were randomly assigned to the treatment group that was fed sugar syrup containing 0.2 mg/L silver ions. The other colonies were assigned to the untreated control group in which bees were given syrup without the silver ions. To assess the efficacy of the silver ions, colony strength, colony activity, and the number of dead larvae per hive were measured. During the experimental period, the test group maintained its strength and activity until day 32 while those of bees in the control group decreased sharply after day 8 to 16. Survival duration of the test group was significantly longer (40 days) than that of the control group (21 days). These results strongly indicated that silver ions are effective against KSBV infection in A. cerana. PMID- 25797296 TI - Air assisted lamellar keratectomy for the corneal haze model. AB - To standardize the corneal haze model in the resection depth and size for efficient corneal haze development, air assisted lamellar keratectomy was performed. The ex vivo porcine corneas were categorized into four groups depending on the trephined depth: 250 um (G1), 375 um (G2), 500 um(G3) and 750 um (G4). The stroma was equally ablated at the five measurement sites in all groups. Significant differences were observed between the trephined corneal depths for resection and ablated corneal thickness in G1 (p < 0.001). No significant differences were observed between the trephined corneal depth for resection and the ablated corneal thickness in G2, G3, and G4. The resection percentage was similar in all groups after microscopic imaging of corneal sections. Air assisted lamellar keratectomy (AK) and conventional keratectomy (CK) method were applied to six beagles, after which development of corneal haze was evaluated weekly until postoperative day 28. The occurrence of corneal haze in the AK group was significantly higher than that in the CK group beginning 14 days after surgery. Alpha-smooth muscle actin expression was significantly higher in the AK group (p < 0.001) than the CK group. Air assisted lamellar keratectomy was used to achieve the desired corneal thickness after resection and produce sufficient corneal haze. PMID- 25797297 TI - Helicobacter apodemus sp. nov., a new Helicobacter species identified from the gastrointestinal tract of striped field mice in Korea. AB - A novel Helicobacter species was identified from the gastrointestinal tract of the Korean striped field mouse (Apodemus agrarius). Biochemical testing, ultrastructure characterization, and 16S rRNA gene sequence analysis suggested that this bacterium represents a distinct taxon. The bacterium was positive for urease activity, susceptible to cephalothin and nalidixic acid, and weakly positive for oxidase and catalase activity. Electron microscopy revealed that the bacterium has spirally curved rod morphology with singular bipolar nonsheathed flagella. Genotypically, the isolated bacterial strains (YMRC 000215, YMRC 000216, and YMRC 000419) were most closely related to a reference strain of Helicobacter mesocricetorum (97.25%, 97.32%, and 97.03% 16S rRNA sequence similarities, respectively). The 16S rRNA sequences of these strains were deposited into GenBank under accession numbers AF284754, AY009129, and AY009130, respectively. We propose the name Helicobacter apodemus for this novel species. PMID- 25797298 TI - Quantitative determination of 12-hydroxyeicosatetraenoic acids by chiral liquid chromatography tandem mass spectrometry in a murine atopic dermatitis model. AB - Atopic dermatitis, one of the most important skin diseases, is characterized by both skin barrier impairment and immunological abnormalities. Although several studies have demonstrated the significant relationship between atopic dermatitis and immunological abnormalities, the role of hydroxyeicosatetraenoic acids (HETE) in atopic dermatitis remains unknown. To develop chiral methods for characterization of 12-HETE enantiomers in a 1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model and evaluate the effects of 12-HETE on atopic dermatitis, BALB/c mice were treated with either DNCB or acetone/olive oil (AOO) to induce atopic dermatitis, after which 12(R)- and 12(S)-HETEs in the plasma, skin, spleen, and lymph nodes were quantified by chiral liquid chromatography-tandem mass spectrometry. 12(R)- and 12(S)-HETEs in biological samples of DNCB-induced atopic dermatitis mice increased significantly compared with the AOO group, reflecting the involvement of 12(R)- and 12(S)-HETEs in atopic dermatitis. These findings indicate that 12(R)- and 12(S)-HETEs could be a useful guide for understanding the pathogenesis of atopic dermatitis. PMID- 25797299 TI - Predominant pathologic laughing and crying in a SCA17 patient. PMID- 25797300 TI - Overdiagnosis of breast cancer at screening is clinically insignificant. AB - Long-term follow-up of randomized trials provide the most accurate estimates of overdiagnosis. Estimates from follow-up of service screening studies are almost as accurate if there is sufficient adjustment for lead time and risk status. When properly analyzed data from both of these types of trials indicate that the rate of overdiagnosis at screening mammography is clinically negligible: 0-5%. Population trend studies are a potentially highly inaccurate means to estimate overdiagnosis. Most cases of DCIS detected at screening are medium and high grade with substantial potential to become an invasive disease. To avoid overtreatment, clinicians need to tailor their treatment of DCIS to the histologic and molecular characteristics of each case. PMID- 25797301 TI - Magnetic resonance sentinel lymph node detection in prostate cancer: a new solution to a longstanding problem? PMID- 25797302 TI - Adherence to thresholds: overdiagnosis of left ventricular noncompaction cardiomyopathy. AB - Thresholds derived from quantification in imaging are increasingly used to define disease. This derivation is not an exact science. When one uses a threshold to define a disease, one does not clearly demarcate disease from normality because the threshold includes overlapping spectra of mild disease and normality. Thus, use of the threshold will mislabel normal individuals with disease. In this perspective, we will describe how the threshold has been derived for left ventricular noncompaction cardiomyopathy, the statistical biases in the design of studies used to derive the threshold, and the dangers of overdiagnosis when the threshold is used to rule out left ventricular noncompaction cardiomyopathy. PMID- 25797303 TI - Emerging formats for next-generation antibody drug conjugates. AB - INTRODUCTION: Antibody drug conjugates now make up a significant fraction of biopharma's oncology pipeline due to great advances in the understanding of the three key components and how they should be optimised together. With this clinical success comes innovation to produce new enabling technologies that can deliver more effective antibody-drug conjugates (ADCs) with a larger therapeutic index. AREAS COVERED: There are many reviews that discuss the various strategies for ADCs design but the last 5 years or so have witnessed the emergence of a number of different antibody formats compete with the standard whole immunoglobulin. Using published research, patent applications and conference disclosures, the authors review the many antibody and antibody-like formats, discussing innovations in protein engineering and how these new formats impact on the conjugation strategy and ultimately the performance. The alternative chemistries that are now available offer new linkages, stability profiles, drug:antibody ratio, pharmacokinetics and efficacy. The different sizes being considered promise to address issues, such as tumour penetration, circulatory half-life and side-effects. EXPERT OPINION: ADCs are at the beginning of the next stage in their evolution and as these newer formats are developed and examined in the clinic, we will discover if the predicted features have a clinical benefit. From the commercial activity, it is envisaged that smaller or fragment-based ADCs will expand oncological applications. PMID- 25797304 TI - Measurement invariance of the Driver Behavior Questionnaire across samples of young drivers from Finland and Ireland. AB - This article investigates the factor structure of the 27-item Driver Behavior Questionnaire (DBQ) in two samples of young drivers (18-25 years of age); one from Finland and the other from Ireland. We compare the two-, three-, and four factor solutions using Confirmatory Factor Analysis (CFA) and show that the four factor model (with the latent variables rule violations, aggressive violations, slips and lapses) fits the data from the two countries best. Next, we compare the fit of this model across samples by the means of a measurement invariance analysis in the CFA framework. The analysis shows that the four-factor model fails to fit both samples equally well. This is mainly because the socially oriented latent variables (rule violations and aggressive violations) are different in nature in the two samples. The cognitively-oriented latent variables (slips and lapses) are, however, similar across countries and the mean values of slips can be compared using latent variable models. However, the common practice of calculating sum scores to represent the four latent DBQ variables and comparing them across subgroups of respondents is unfounded, at least when comparing young respondents from Finland and Ireland. PMID- 25797305 TI - Optimisation of DNA extraction and validation of PCR assays to detect Mycobacterium avium subsp. paratuberculosis. AB - The aim of this study was to investigate DNA extraction methods and PCR assays suitable for the detection of Mycobacterium paratuberculosis in bovine tissue. The majority of methods currently used to detect M. paratuberculosis have been developed using bovine samples, such as faeces, blood or tissue and, in many cases, have been based on detection from pooled samples from a herd. However most studies have not compared PCR results to culture results. In order to address this problem, four DNA extraction protocols and three PCR assays were employed to detect M. paratuberculosis in bovine tissue. Given that culture is reliable from cows, the results were then compared with the known M. paratuberculosis culture status. The following DNA extractions were included, two commercial kits, a boiling method, an in house extraction based on a published method and enrichment by sonication. The three PCR assays used included single round IS900 and f57 assays and a nested IS900 assay. In addition, another PCR assay was validated for the detection of any Mycobacterial species and a universal bacterial 16S rRNA gene assay was used to detect sample inhibition. The in-house DNA extraction was the most consistent in extracting good quality DNA compared to all other methods. The use of two PCR markers, IS900 and f57, and a universal PCR enabled the correct samples to be identified as M. paratuberculosis positive. In addition, when compared to the culture result, false-positives did not occur and PCR inhibition was readily identified. Using an in house DNA extraction coupled with the IS900 and f57 PCR markers, this study provides a reliable and simple method to detect M. paratuberculosis in both veterinary and spill over infections. PMID- 25797306 TI - Dodecenylsuccinic anhydride derivatives of gum karaya (Sterculia urens): preparation, characterization, and their antibacterial properties. AB - Esterifications of the tree-based gum, gum karaya (GK), using dodecenylsuccinic anhydride (DDSA) were carried out in aqueous solutions. GK was deacetylated using alkali treatment to obtain deacetylated gum karaya (DGK). The DGK and its DDSA derivative were characterized using gel permeation chromatography/multiangle laser light scattering (GPC/MALLS), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), proton nuclear magnetic resonance spectroscopy ((1)H NMR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) analysis, and rheological studies. The degree of substitution was found to be 10.25% for DGK using (1)H NMR spectroscopy. The critical aggregation concentration of DDSA-DGK was determined using dye solubilization and surface tension methods. The antibacterial activity of the DDSA-DGK derivative was then investigated against Gram-negative Escherichia coli and Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus. The DDSA-DGK derivative has the potential for use as a stabilizing agent in food and nonfood applications. It can also be developed as an antibacterial agent. PMID- 25797307 TI - Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases. AB - INTRODUCTION: The uridine diphosphate (UDP)-glucuronosyltransferase (UGT) superfamily of enzymes (EC 2.4.1.17) conjugates glucuronic acid to an aglycone substrate to make them more polar and readily excreted. In general, this reaction terminates the activities of chemicals, drugs and toxins, although occasionally a more active or toxic species is produced. AREAS COVERED: In addition to their well-known transcriptional responsiveness, UGTs are also regulated by posttranscriptional mechanisms. Here, the authors review these mechanisms, including latency, modulation of co-substrate accessibility and binding, dimerization and oligomerization, protein-protein interactions, allosteric inhibition and activation, posttranslational structural and functional modifications and developmental switching for UGTs. EXPERT OPINION: Posttranscriptional regulation of UGTs has traditionally received less attention than nuclear regulation, in part because mechanisms involving ribosomes and endoplasmic reticula are challenging to investigate. Most promising of the posttranscriptional mechanisms reviewed are likely to be effects on co-substrate (UDP-glucuronic acid) transport and availability and structure-function changes to UGT proteins through, for example, glycosylation and phosphorylation. Although classical biochemistry continues to illuminate many aspects of UGT function, advances in proteomics and structural biology are beginning to assist in the determination of posttranscriptional regulation mechanisms for UGTs. PMID- 25797308 TI - High hydrostatic pressure processing reduces the glycemic index of fresh mango puree in healthy subjects. AB - Dietary guidelines recommend the daily consumption of fruits; however, healthy and type 2 diabetes mellitus (T2DM) subjects receive conflicting messages regarding ingestion of fruits, such as mango, because of its sugar content. We investigated the effects of high hydrostatic pressure (HHP) processing of fresh mango puree (MP) on the glycemic indexes (GIs) and postprandial glycemic responses of 38 healthy Mexican subjects in a randomized cross-over clinical trial. Physicochemical characterization of MP included sugar profiles by HPLC ELSD, starch, fibers, moisture, viscosity, swelling capacity and solubility properties of alcohol insoluble residue (AIR). The mean GI for HHP-MP was significantly lower (32.7 +/- 13.4) than that of unprocessed-MP (42.7 +/- 19.5). A significantly higher proportion of subjects showed a low GI following the consumption of HHP-MP compared to unprocessed-MP and none of them showed a high GI for the HHP-MP, compared to a significantly higher proportion for the unprocessed-MP. The viscosity and AIR solubility values of HHP-MP samples were significantly higher, which influenced glucose peaking later (Tmax) at 45 minutes and induced 20% lower AUC values than unprocessed-MP, corresponding to greater retardation indexes. The study findings support data stating that low GI fruits are appropriate for glycemic control and that mango may be included as part of healthy subjects' diets and potentially T2DM subjects' diets. Furthermore, HHP processing of mango may offer additional benefits for glycemic control, as its performance regarding GI, AUC and Tmax was significantly better than that of the unprocessed-MP. To our knowledge, this is the first report on the impact of this commercial non-thermal pasteurization technology on glucose metabolism. PMID- 25797309 TI - Retinogenesis: stochasticity and the competency model. AB - The vertebrate retina is made up of seven principal cell types. These seven retinal cell types arise from multipotent retinal progenitor cells (RPCs). The competency model was proposed suggesting that RPCs undergo a series of irreversible transitions between competency states, in each of which the RPCs are competent to generate a different subset of cell types, but not retinal cells generated at previous moments. In this work, we generalize the stochastic model of neurogenesis of Barton et al. (2014), assuming that the same factor that regulates the differentiation, regulates the competency. The model reproduces the timing of production of different retinal cell types in rats such as it was experimentally measured. The results show that the evolution of the competency during retinogenesis could be explained by a single factor. Its evolution during the cell cycle and the stochastic inheritance in cell divisions determine the sequence and the overlap of production of different retinal cell types during development. PMID- 25797310 TI - A mathematical model of the carp heart ventricle during the cardiac cycle. AB - The poikilothermic heart has been suggested as a model for studying some of the mechanisms of early postnatal mammalian heart adaptations. We assessed morphological parameters of the carp heart (Cyprinus carpio L.) with diastolic dimensions: heart radius (5.73mm), thickness of the compact (0.50mm) and spongy myocardium (4.34mm), in two conditions (systole, diastole): volume fraction of the compact myocardium (20.7% systole, 19.6% diastole), spongy myocardium (58.9% systole, 62.8% diastole), trabeculae (37.8% systole, 28.6% diastole), and cavities (41.5% systole, 51.9% diastole) within the ventricle; volume fraction of the trabeculae (64.1% systole, 45.5% diastole) and sinuses (35.9% systole, 54.5% diastole) within the spongy myocardium; ratio between the volume of compact and spongy myocardium (0.35 systole, 0.31 diastole); ratio between compact myocardium and trabeculae (0.55 systole, 0.69 diastole); and surface density of the trabeculae (0.095MUm(-1) systole, 0.147MUm(-1) diastole). We created a mathematical model of the carp heart based on actual morphometric data to simulate how the compact/spongy myocardium ratio, the permeability of the spongy myocardium, and sinus-trabeculae volume fractions within the spongy myocardium influence stroke volume, stroke work, ejection fraction and p-V diagram. Increasing permeability led to increasing and then decreasing stroke volume and work, and increasing ejection fraction. An increased amount of spongy myocardium led to an increased stroke volume, work, and ejection fraction. Varying sinus trabeculae volume fractions within the spongy myocardium showed that an increased sinus volume fraction led to an increased stroke volume and work, and a decreased ejection fraction. PMID- 25797311 TI - Synthesis of bradyrhizose, a unique inositol-fused monosaccharide relevant to a Nod-factor independent nitrogen fixation. AB - The symbiosis of Bradyrhizobium sp. BTAi1 with its host plant Aeschynomene indica relies on a Nod-factor independent mechanism, wherein the Bradyrhizobium O antigen is regarded as a key factor. This O-antigen polysaccharide is composed of a unique C10 monosaccharide, namely bradyrhizose, which has a galactose-inositol trans-fused scaffold, via a homogeneous alpha-(1 -> 7)-linkage. Herein, we report the first synthesis of bradyrhizose. The scalable synthesis requires 26 steps in a high overall yield of 9%, with the inositol scaffold being constructed effectively via a Ferrier II rearrangement from a fully functionalized C2 and C4 branched pyranose derivative. PMID- 25797312 TI - Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales. AB - BACKGROUND/OBJECTIVE: Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. METHODS: 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. RESULTS: The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. CONCLUSION: These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH. PMID- 25797313 TI - High prevalence at computed coronary tomography of non-calcified plaques in asymptomatic HIV patients treated with HAART: a meta-analysis. AB - INTRODUCTION: Asymptomatic patients with human immunodeficiency virus (HIV) infection are at increased risk of vascular disease. Whether asymptomatic HIV patients have increased prevalence or structural differences in coronary artery plaques is not clear. METHODS: Pubmed, Cochrane and Google Scholar were searched for articles evaluating asymptomatic HIV patients evaluated with coronary computed tomography. The prevalence of coronary stenosis (defined as >30% and >50%), of calcified coronary plaques (CCP) viewed as more 'stable' plaques, and of non-calcified coronary plaques (NCP) viewed as more 'vulnerable' plaques were the end points of interest. RESULTS: 9 studies with 1229 HIV patients and 1029 controls were included. No significant differences were detected about baseline cardiovascular risk profile. The prevalence of significant coronary stenosis>30% or >50% did not differ between HIV+ and HIV- patients (42% [37-44] and 46% [35 52] with an Odds Ratio [OR] of 1.38 [0.86-2.20] for >30% stenosis) and (15% [9 21] and 14% [7-22] with an OR of 1.11 [0.81-1.52]), respectively. The prevalence of calcified coronary plaques (CCP) (31% [24-32] and 21% [14-30] with an OR of 1.17 [0.63-2.16]) also did not differ among HIV+ and HIV- patients. On the contrary rates of NCP were >3-fold higher in HIV-positive patients [58% (48-60) and 17% (14-27) with an OR of 3.26 (1-30-8.18)], with an inverse relationship with CD4 cell count at meta-regression (Beta -0.20 [-0.35-0.18], p 0.04). CONCLUSION: Asymptomatic HIV patients present a similar burden of coronary stenosis and calcified coronary artery plaques but significantly higher rates of non-calcific coronary plaques at computed tomography. The association between HIV infection, reduced CD4 cell counts and higher prevalence on non-calcific coronary artery plaques may shed light into the pathogenesis in HIV-associated coronary artery disease, stressing the importance of primary prevention in this population. PMID- 25797314 TI - Anxiety, Decision Conflict, and Health in Caregivers of Children with ADHD: A Survey. AB - The purpose of this study was to test a theoretical model to determine the effect of caregiver anxiety and decision conflict on the health of caregivers of children with ADHD. Cross-sectional analyses were conducted on data derived from caregivers (aged 24-70). Participants completed the Decision Conflict Scale, the Zung Anxiety Scale, the Duke Health Profile, and a demographic form. A path model that fit well indicated that anxiety and decision conflict had direct and indirect effects on the caregivers' health. Future study is needed to clarify factors contributing to uncertainty and to decrease emotional symptoms for caregivers, thus promoting their mental health. PMID- 25797315 TI - Aspergillus oryzae pathways that convert phenylalanine into the flavor volatile 2 phenylethanol. AB - The filamentous fungus Aspergillus oryzae RIB40 produced 2-phenylethanol (PE) when cultured in minimum medium containing l-phenylalanine as a sole source of nitrogen. The fungus accumulated less PE in the absence of l-phenylalanine, indicating that it converted l-phenylalanine to PE. The PE production associated with fungal glucose consumption was repressed by exogenous ammonium, indicating that nitrogen-metabolite repression controls the pathway that produces PE. We identified the A. oryzae ppdA gene that is expressed at high levels in the presence of exogenous l-phenylalanine and its encoded protein was an active phenylpyruvate decarboxylase. The fungal genome encodes predicted aminotransferases of phenylalanine and PE dehydrogenases, which, together with PpdA, are likely to constitute an Erlich pathway similar to that in Saccharomyces cerevisiae that produces PE. We also identified an A. oryzae aromatic amino acid decarboxylase (AadA) that converted l-phenylalanine to phenylethylamine (PEA), and phenylalanine-inducible PEA oxidase activity in fungal cell extracts, and found that both constitute an alternative pathway through which PEA generates PE. Incubating fungal cultures with l-[(2)H8] phenylalanine to distinguish PE produced by these pathways, indicated that the fungus produced PE by both pathways, but to a greater extent by the Erlich pathway. Gene disruption of ppdA and aadA showed that both pathways participate in the fungal conversion of l phenylalanine to PE. PMID- 25797316 TI - Gene expression profiles of circulating tumor cells versus primary tumors in metastatic breast cancer. AB - Before using circulating tumor cells (CTCs) as liquid biopsy, insight into molecular discrepancies between CTCs and primary tumors is essential. We characterized CellSearch-enriched CTCs from 62 metastatic breast cancer (MBC) patients with >=5 CTCs starting first-line systemic treatment. Expression levels of 35 tumor-associated, CTC-specific genes, including ESR1, coding for the estrogen receptor (ER), were measured by reverse transcription quantitative polymerase chain reaction and correlated to corresponding primary tumors. In 30 patients (48%), gene expression profiles of 35 genes were discrepant between CTCs and the primary tumor, but this had no prognostic consequences. In 15 patients (24%), the expression of ER was discrepant. Patients with ER-negative primary tumors and ER-positive CTCs had a longer median TTS compared to those with concordantly ER-negative CTCs (8.5 versus 2.1 months, P = 0.05). From seven patients, an axillary lymph node metastasis was available. In two patients, the CTC profiles better resembled the lymph node metastasis than the primary tumor. Our findings suggest that molecular discordances between CTCs and primary tumors frequently occur, but that this bears no prognostic consequences. Alterations in ER-status between primary tumors and CTCs might have prognostic implications. PMID- 25797317 TI - The effects of swainsonine on the activity and expression of alpha-mannosidase in BRL-3A cells. AB - Swainsonine (SW) is the principal toxic ingredient of locoweeds, which can cause intensive vacuolar degeneration because of alpha-mannosidase inhibition after animal ingestion. While SW can lead to obvious liver damage in vivo, the mechanism of hepatotoxic damage caused by SW is not clear. Therefore, BRL-3A cells were treated for 24, 48, and 72 h with SW at various concentrations (0, 700, 900, 1100 MUg/mL). The alpha-mannosidase (AMAN) activity was determined in BRL-3A cells using an enzyme substrate technique. The expression of mRNA and proteins of GM II (MAN2A1) and LAM (MAN2B1) in BRL-3A cells was detected by qPCR and Western-blot. The results showed that SW could significantly reduce the activity of AMAN in a time-dose effect relationship. Compared with the control group, the activity of AMAN significantly decreased only in the group treated with 1100 MUg/mL SW for 24 h (P < 0.01), but the activity decreased significantly (P < 0.05 or P < 0.01) in all experimental groups treated for 48 or 72 h. SW also significantly reduced the expression of MAN2A1 and MAN2B1 mRNA and proteins in a time-dose effect relationship (P < 0.05 or P < 0.01), while the inhibition of SW was stronger for MAN2B1 than for MAN2A1. These results suggest that SW can significantly reduce the activity and expression of alpha-mannosidase thus causing SW-induced hepatotoxic damage. PMID- 25797318 TI - Neutralizing effect of hemolymph from the shore crab, Thalamita crenata, on paralytic shellfish toxins. AB - Several species of crabs are resistant to paralytic shellfish toxins (PSTs) and/or pufferfish toxin, tetrodotoxin, regardless of toxification by the toxins. The shore crab Thalamita crenata, which inhabits Leizhou Peninsula, China, is tolerant to PST toxicity, and the hemolymph has neutralizing effects against the lethal activity of PST. In the present study, we investigated the PST neutralizing factors in the hemolymph from T. crenata and successfully separated PST-binding proteins by PST-ligand affinity chromatography. The neutralization factors, obtained in the fraction with a molecular weight over 10 kDa by ultrafiltration, were susceptible to proteases such as alcalase, animal complex proteases, pancreatin, and papain. The PST-binding protein had high dose dependent neutralization effects on PST toxicity. The PST-binding activity of the protein was stable at 25 degrees C and then decreased with an increase in temperature; heating at 65 degrees C for 60 min eliminated the initial activity by two-thirds. The PST-binding activity was strongly inhibited in the presence of Mg(2+) and Ca(2+), but not Na(+) and K(+). The PST-binding capability of the protein differed among PST components in descending order of neosaxitoxin, gonyautoxins 1 and 4, saxitoxin, and gonyautoxins 2 and 3, suggesting a structure activity relationship in PST binding. PMID- 25797320 TI - Dimetallaborane analogues of pentaborane. AB - The structures of five-vertex dimetallaboranes Cp2M2B3H7 (Cp = eta(5)-C5H5) of the second and third row transition metals, including the experimentally known Cp*2Rh2B3H7 (Cp* = eta(5)-Me5C5), have been investigated by density functional theory. The predicted low-energy structures for Cp2M2B3H7 (M = Rh, Ir) are tetragonal pyramids similar to Cp*2Rh2B3H7 and pentaborane-9 B5H9 and consistent with their 14 Wadean skeletal electrons. Two Cp*2Rh2B3H7 structures with the same central Rh2B3 tetragonal prism are found with energies within ~1 kcal mol(-1) of each other, consistent with the experimental observation of two isomers in solution. The electron-richer Cp2M2B3H7 (M = Pd, Pt) systems having 16 Wadean skeletal electrons are predicted to exhibit more open structures analogous to the known structure for the valence isoelectronic pentaborane-11 B5H11. Trigonal bipyramids with the metal atoms at equatorial vertices are typically found to be low-energy structures for the hypoelectronic Cp2M2B3H7 systems (M = Ru, Os, Re, Mo, W, Ta). In addition, the low-energy Cp2Re2B3H7 structures of the rhenium derivatives Cp2Re2B3H7 provide examples of structures based on a central Re2B2 tetrahedron with the Re-Re edge bridged by the third boron atom. Such structures can be derived from a trigonal bipyramid by the rupture of one of the axial equatorial edges. PMID- 25797321 TI - Photocurrent generation in organic photodetectors with tailor-made active layers fabricated by layer-by-layer deposition. AB - Photodetectors supply an electric response when illuminated. The detectors in this study consist of an active layer and a polyvinylidene fluoride (PVDF) blocking layer, which are sandwiched by an aluminum and an indium tin oxide (ITO) electrode. The active layer was prepared of Zn porphyrins and assembled by covalent layer-by-layer (LbL) deposition. Layer growth was monitored by UV-vis absorbance, ellipsometry, and X-ray photoelectron spectroscopy. Upon exposure to chopped light, the detectors show an alternating transient photocurrent, which is limited by the accumulation of space charges at the blocking layer/active layer interface. We could show that the number of photoactive layers has a significant impact on device performance. The fastest response was achieved with fewer layers. The highest photocurrents were measured for detectors with an intermediate number of layers, beyond which, more layers did not lead to an increase in the photocurrent despite containing more active material. PMID- 25797319 TI - Global cellular responses to beta-methyl-amino-L-alanine (BMAA) by olfactory ensheathing glial cells (OEC). AB - This study utilised a proteomics approach to identify any differential protein expression in a glial cell line, rat olfactory ensheathing cells (OECs), treated with the cyanotoxin beta-methylamino-l-alanine (BMAA). Five proteins of interest were identified, namely Rho GDP-dissociation inhibitor 1 (RhoGDP1), Nck associated protein 1 (NCKAP1), voltage-dependent anion-selective channel protein 1 (VDAC1), 3-hydroxyacyl-CoA dehydrogenase type-2 (3hCoAdh2), and ubiquilin-4 (UBQLN4). Four of these candidates, nuclear receptor subfamily 4 group A member 1 (Nur77), cyclophilin A (CyPA), RhoGDP1 and VDAC1, have been reported to be involved in cell growth. A microarray identified UBQLN4, palladin and CyPA, which have been implicated to have roles in excitotoxicity. Moreover, the NCKAP1, UBQLN4, CyPA and 3hCoAdh2 genes have been associated with abnormal protein aggregation. Differential expression of genes involved in mitochondrial activity, Nur77, 3hCoAdh2, VDAC1 and UBQLN4, were also identified. Confirmatory reverse transcription quantitative PCR (RT-qPCR) analysis of transcripts generated from the genes of interest corroborated the differential expression trends identified in the global protein analysis. BMAA induced cell cycle arrest in the G2/M phase of OEC and apoptosis after 48 h at concentrations of 250 MUM and 500 MUM. Collectively, this work advances our understanding of the mechanism of BMAA mediated glial-toxicity in vitro. PMID- 25797322 TI - Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells. AB - The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self organized into 200 +/- 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX.HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 degrees C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 MUg mL(-1) in PBS. MTT assays on fibroblast cells revealed that DOX.HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells. PMID- 25797323 TI - Evaluation of Markers of Inflammation and Oxidative Stress in COPD Patients with or without Cardiovascular Comorbidities. AB - BACKGROUND: Although both chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) are characterised by chronic, systemic inflammation, their reciprocal interactions are poorly understood. The purpose of this study was to determine the concentrations of both inflammatory and oxidative stress biomarkers in the serum and exhaled breath condensate (EBC) of COPD patients, either with coexisting CVD or without cardio-vascular comorbidities. METHODS: Twenty-four COPD patients with CVD were allocated to group A, 20 COPD patients without CVD were assigned to group B and 16 healthy patients were included as a control. A medical history and physical examination were performed, and the following were measured: serum CRP concentration, glucose level, uraemic acid level and lipid profile. In addition 8-isoprostane, LTB4 and IL-8 concentrations were measured both in serum and EBC. Spirometry, six-minute walk test and echocardiography were performed in all subjects. RESULTS: EBC concentrations of 8-isoprostane and LTB4, and serum levels of CRP, 8-soprostane, LTB4, IL-8 were significantly higher in COPD patients than in healthy controls. COPD patients with CVD were not found to have higher concentrations of the assessed markers than those without CVD, neither in the serum nor EBC. CRP, 8 isoprostane and LTB4 levels in serum, and IL-8 concentration in EBC correlated negatively with the value of forced expiratory volume in one second. CONCLUSIONS: Although systemic inflammation coexists with COPD, it is not elevated in COPD patients with CVD. Since this phenomenon may result from treatment with statins, future studies should state whether COPD patients could benefit from the additional statin therapy. PMID- 25797324 TI - Thread-like Bone Cement in the Right-side Heart and Pulmonary Arteries Causing Diffuse Pulmonary Embolism as a Late Complication. AB - Pulmonary embolism (PE) is usually associated with deep vein thrombosis (DVT) in the lower extremities. However, foreign bodies in the pulmonary arteries can rarely cause PE without evidence of DVT. In this report, we present a case of diffuse PE associated with a migrated thread-like structure of the right-side heart and pulmonary arteries in a 70 year-old woman. The patient underwent several episodes of percutaneous vertebroplasty (PV) to treat compression fractures. The thread-like foreign bodies were identified as the bone cement injected during the previous PV procedures. We present this case study to emphasise that clinicians should consider the possibility of PE as a late complication, especially those with a history of PV. PMID- 25797325 TI - Mechanical circulatory support for the failing heart - progress, pitfalls and promises. PMID- 25797326 TI - Community-Based Cardiac Rehabilitation Maintenance Programs: Use and Effects. AB - BACKGROUND: Cardiac rehabilitation (CR) graduates are encouraged to attend maintenance programs to promote long-term physical activity and preserve gains in function. This study describes the characteristics, attendance and physical function of community-based maintenance CR participants, compared to primary prevention participants. METHODS: In this cross-sectional study, participants from two programs in New Zealand completed an interview, anthropometry, functional assessments (walking tests, chair stand test, handgrip strength), a 12 month physical activity recall, and a cardiopulmonary exercise test (subsample only). Attendance was ascertained from club records. RESULTS: Participants (n=101, 55.4% Secondary Prevention) attended 37.4+/-27.9% of sessions annually. Participants were predominately New Zealand-European (93.5%), retired (80.2%), married (68.3%) elderly individuals, with musculoskeletal problems (60.0%), who lived proximate to the clubs. In Secondary but not Primary Prevention participants, first-year attendance was strongly correlated with attendance in subsequent years (p<0.001). In all participants, greater attendance in the previous 12 months was significantly associated with lower waist circumference, and greater shuttle walk test duration, chair stands and balance (p<.05). Session attendance was positively correlated to peak oxygen consumption (p=0.041) in Secondary Prevention participants only. CONCLUSION: Participation in community based CR maintenance programs is associated with health benefits but these programs are not accessed by a diversity of patients. PMID- 25797327 TI - Characteristics and Outcomes of MI Patients with and without Chest Pain: A Cohort Study. AB - INTRODUCTION: There are conflicting data on patient characteristics and outcomes of myocardial infarction (MI) patients presenting with and without the symptom of chest pain. OBJECTIVES: Compare the characteristics and survival of patients stratified by the symptom chest pain. METHODS: This retrospective cohort study identified patients with an emergency department discharge diagnosis of MI, who arrived by ambulance at a teaching hospital in Perth, Western Australia, between January 2008 to October 2009. The cohort was linked to hospital data and the state-based death register; clinical data were extracted by medical record review. Patient characteristics were compared using logistic regression models and survival analysis using Kaplan-Meier curves and Cox regression models. RESULTS: Of 382 patients, 26% presented without chest pain. The odds of presenting without chest pain were increased if aged 80+ (OR 7.54; 95%CI 2.81 20.3) and aged 70-79 years (OR 4.33; 95% CI 1.50-12.5), and female (OR 1.67; 95%CI 0.99-2.82). The adjusted hazard (median follow-up time 2.2 years) of presenting without chest pain was not significantly associated with survival (HR 1.03; 95%CI 0.71-1.48). CONCLUSION: Characteristics differed between patients with and without chest pain. However, the symptom of chest pain was not associated with survival. PMID- 25797328 TI - Education of Physicians and Implementation of a Formal Referral System Can Improve Cardiac Rehabilitation Referral and Participation Rates after Percutaneous Coronary Intervention. AB - BACKGROUND: Cardiac rehabilitation (CR) is an effective preventive measure that remains underutilised in the United States. The study aimed to determine the CR referral rate (RR) after percutaneous coronary intervention (PCI) at an academic tertiary care centre, identify barriers to referral, and evaluate awareness of CR benefits and indications (CRBI) among cardiologists. Subsequently, it aimed to evaluate if an intervention consisting of physicians' education about CRBI and implementation of a formal CR referral system could improve RR and consequently participation rate (PR). METHODS: Data were retrospectively collected for all consecutive patients who underwent PCI over 12 months. Referral rate was determined and variables were compared for differences between referred and non referred patients. A questionnaire was distributed among the physicians in the Division of Cardiology to assess awareness of CRBI and referral practice patterns. After implementation of the intervention, data were collected retrospectively for consecutive patients who underwent PCI in the following six months. Referral rate and changes in PRs were determined. RESULTS: Prior to the intervention, RR was 17.6%. Different barriers were identified, but the questionnaire revealed lack of physicians' awareness of CRBI and inconsistent referral patterns. After the intervention, RR increased to 88.96% (Odds Ratio 37.73, 95% CI 21.34-66.70, p<0.0001) and PR increased by 32.8% to reach 26%. Personal endorsement of CRBI by cardiologists known to patients increased CR program graduation rate by 35%. CONCLUSIONS: Cardiologists' awareness of CRBI increases CR RR and their personal endorsement improves PR and compliance. Education of providers and implementation of a formal referral system can improve RR and PR. PMID- 25797329 TI - Parenting style and obesity risk in children. AB - BACKGROUND: Parents play a critical role in their children's lifestyle habits. The objective was to assess the effect of parenting style on the risk of childhood obesity, and to determine whether poverty was a moderator of the association. METHODS: Participants were from the 1994-2008 cross-sectional samples of the National Longitudinal Survey of Children and Youth (NLSCY), a nationally representative survey of Canadian youth. Factor and cluster analyses identified four parenting styles consistent with Baumrind's parenting style prototypes. Multivariable logistic regression assessed the risk of obesity based on parenting style after adjusting for covariates. Analyses were stratified by age (preschool: 2-5years of age, n=19,026; school-age: 6-11years of age, n=18,551) and the moderating effect of poverty (household income 1.4 * 10(-6), strategy D was more effective than strategy A; strategy B became cost-effective (i.e. ICER vs strategy A < 3 * French Gross Domestic Product per capita) when PA was > 1 .4 * 10(-4). CONCLUSIONS: In the metropolitan France's very low rabies prevalence context, PEP with rabies vaccine, administered alone or with RIG, is associated with significant and unnecessary costs and unfavourable benefit-risk ratios regardless to exposure category. PMID- 25797367 TI - Web-based intensive monitoring of adverse events following influenza vaccination in general practice. PMID- 25797368 TI - Clinical utility of the worker role interview: a survey study among Swedish users. AB - BACKGROUND: Work ability assessments are used to guide interventions designed to reduce or eliminate work disability and facilitate work participation. The clinical utility of assessments concerns the extent to which the assessment results support clinical decision-making. AIM: The aim was to investigate how users perceive the clinical utility of the Swedish version of the Worker Role Interview (WRI-S). An additional aim was to investigate differences in clinical utility related to the users' level of WRI-S experience, attendance at courses on WRI-S application, and knowledge of the Model of Human Occupation. MATERIAL AND METHODS: Data are based on 187 respondents' answers to a web-based questionnaire and analysed through descriptive and inferential statistics. RESULTS: In total, the respondents performed 12,000 WRI-S assessments. The respondents were mainly satisfied with the clinical utility of the WRI-S and experienced the assessment as supporting clinical practice. The main hindrance affecting clinical utility was the amount of time needed for conducting a WRI-S assessment. Experienced users and users with very good knowledge of MOHO conduct WRI-S assessments in a more time-effective manner. CONCLUSION: This study contributes to further development of the clinical utility of the Swedish version of the WRI-S, mainly focusing on time consumption. PMID- 25797369 TI - Interplay of particle shape and suspension properties: a study of cube-like particles. AB - With advances in anisotropic particle synthesis, particle shape is now a feasible parameter for tuning suspension properties. However, there is a need to determine how these newly synthesized particles affect suspension properties and a need to solve the inverse problem of inferring the particle shape from property measurements. Either way, accurate suspension property predictions are required. Towards this end, we calculated a set of dilute suspension properties for a family of cube-like particles that smoothly interpolate between spheres and cubes. Using three conceptually different methods, we numerically computed the electrical properties of particle suspensions, including the intrinsic conductivity of perfect conductors and insulators. We also considered hydrodynamic properties relevant to particle solutions including the hydrodynamic radius, the intrinsic viscosity and the intrinsic solvent diffusivity. Additionally, we determined the second osmotic virial coefficient using analytic expressions along with numerical integration. As the particles became more cube like, we found that all of the properties investigated become more sensitive to particle shape. PMID- 25797370 TI - Expression of autocrine prolactin and the short isoform of prolactin receptor are associated with inflammatory response and apoptosis in monocytes stimulated with Mycobacterium bovis proteins. AB - Increased levels of prolactin (PRL) have recently been associated with carcinogenesis and the exacerbation of autoimmune diseases, and might be involved in the progression of tuberculosis (TB). To investigate the relationship between PRL and prolactin receptor (PRLr) expression with inflammatory response and apoptosis in monocytes, we used THP-1 cells stimulated with antigens of the Mycobacterium bovis AN5 strain culture filtrate protein (CFP-M. bovis). Western blot (WB), real-time Polymerase chain reaction (PCR), and immunocytochemistry were performed to identify both PRL and PRLr molecules. PRL bioactivity and proinflammatory cytokine detection were assessed. The results showed that PRL and PRLr messenger RNA (mRNA) were synthesized in THP-1 monocytes induced with CFP-M. bovis at peaks of 176- and 404-fold, respectively. PRL forms of 60 and 80kDa and PRLr isoforms of 40, 50, and 65kDa were also identified as time-dependent, while 60-kDa PRL, as well as 40-, and 50-kDa PRLr, were found as soluble forms in culture media and later in the nucleus of THP-1 monocytes. PRL of 60kDa released by monocytes exhibited bioactivity in Nb2 cells, and both synthesized PRL and synthesized PRLr were related with nitrite and proinflammatory cytokine levels proapoptotic activity in CFP-M. bovis-induced monocytes. Our results suggest the overexpression of a full-autocrine loop of PRL and PRLr in monocytes that enhances the inflammatory response and apoptosis after priming with M. bovis antigens. PMID- 25797371 TI - T11TS inhibits Angiopoietin-1/Tie-2 signaling, EGFR activation and Raf/MEK/ERK pathway in brain endothelial cells restraining angiogenesis in glioma model. AB - Malignant gliomas represent one of the most aggressive and hypervascular primary brain tumors. Angiopoietin-1, the peptide growth factor activates endothelial Tie 2 receptor promoting vessel maturation and vascular stabilization steps of angiogenesis in glioma. Epidermal growth factor receptor (EGFR) and Tie-2 receptor on endothelial cells once activated transmits signals through downstream Raf/MEK/ERK pathway promoting endothelial cell proliferation and migration which are essential for angiogenesis induction. The in vivo effect of sheep erythrocyte membrane glycopeptide T11-target structure (T11TS) on angiopoietin-1/Tie-2 axis, EGFR signaling and Raf/MEK/ERK pathway in glioma associated endothelial cells has not been investigated previously. The present study performed with rodent glioma model aims to investigate the effect of T11TS treatment on angiopoietin-1/Tie-2 signaling, EGFR activity and Raf/MEK/ERK pathway in glioma associated endothelial cells within glioma milieu. T11TS administration in rodent glioma model inhibited angiopoietin-1 expression and attenuated Tie-2 expression and activation in glioma associated brain endothelial cells. T11TS treatment also downregulated total and phosphorylated EGFR expression in glioma associated endothelial cells. Additionally T11TS treatment inhibited Raf-1 expression, MEK-1 and ERK-1/2 expression and phosphorylation in glioma associated brain endothelial cells. Thus T11TS therapy remarkably inhibits endothelial angiopoietin-1/Tie-2 signaling associated with vessel maturation and simultaneously antagonizes endothelial cell proliferation signaling by blocking EGFR activation and components of Raf/MEK/ERK pathway. Collectively, the findings demonstrate a multi-targeted anti-angiogenic activity of T11TS which augments the potential for clinical translation of T11TS as an effective angiogenesis inhibitor for glioma treatment. PMID- 25797372 TI - Catalytic domino reaction of ketones/aldehydes with Me3SiCF2Br for the synthesis of alpha-fluoroenones/alpha-fluoroenals. AB - A unique domino reaction of enolizable carbonyl compounds with Me3SiCF2Br to construct alpha-fluoroenones and alpha-fluoroenals is described to undergo the in situ formation of difluorocarbene and silyl enol ether, difluorocyclopropanation, desilylation, ring-opening, and defluorination sequence. In this tandem reaction, Me3SiCF2Br acts as not only the difluorocarbene source but also the TMS transfer agent as well as internal bromide and fluoride anion catalyst. It allows the transformations to occur smoothly under only a catalytic amount of n-Bu4NBr as initiator. PMID- 25797373 TI - Response to: Regarding sudden cardiac death in soccer players. PMID- 25797374 TI - Are the current Australian sun exposure guidelines effective in maintaining adequate levels of 25-hydroxyvitamin D? AB - An adequate vitamin D status, as measured by serum 25-hydroxyvitamin D (25(OH)D) concentration, is important in humans for maintenance of healthy bones and muscle function. Serum 25(OH)D concentration was assessed in participants from Melbourne, Australia (37.81S, 144.96E), who were provided with the current Australian guidelines on sun exposure for 25(OH)D adequacy (25(OH)D >=50 nmol/L). Participants were interviewed in February (summer, n=104) and August (winter, n=99) of 2013. Serum 25(OH)D concentration was examined as a function of measures of sun exposure and sun protection habits with control of key characteristics such as dietary intake of vitamin D, body mass index (BMI) and skin colour, that may modify this relationship. The mean 25(OH)D concentration in participants who complied with the current sun exposure guidelines was 67.3 nmol/L in summer and 41.9 nmol/L in winter. At the end of the study, 69.3% of participants who complied with the summer sun exposure guidelines were 25(OH)D adequate, while only 27.6% of participants who complied with the winter sun exposure guidelines were 25(OH)D adequate at the end of the study. The results suggest that the current Australian guidelines for sun exposure for 25(OH)D adequacy are effective for most in summer and ineffective for most in winter. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25797376 TI - [Quality of care in inflammatory bowel disease]. AB - Since inflammatory bowel disease (IBD) is a chronic and relapsing disorder, maintaining high quality of care plays an important role in the management of patients with IBD. To develop process-based quality indicator set to improve quality of care, the indicator should be based directly on evidence and consensus. Initially, ImproveCareNow group demonstrated quality improvement by learning how to apply quality improvement methods to improve the care of pediatric patients with IBD. The American Gastroenterological Association has developed adult IBD physician performance measures set and Crohn's and Colitis Foundation of America (CCFA) has developed a set of ten most highly rated process and outcome measures. Recently, The Emerging Practice in IBD Collaborative (EPIC) group generated defining quality indicators for best-practice management of IBD in Canada. Quality of Care through the Patient's Eyes (QUOTE-IBD) was developed as a questionnaire to measure quality of care through the eyes of patients with IBD, and it is widely used in European countries. The current concept of quality of care as well as quality indicator will be discussed in this article. PMID- 25797375 TI - Combined effects of androgen anabolic steroids and physical activity on the hypothalamic-pituitary-gonadal axis. AB - Analysing effects of pharmaceutical substances and training on feedback mechanisms of the hypothalamic-pituitary-gonadal axis may be helpful to quantify the benefit of strategies preventing loss of muscle mass, and in the fight against doping. In this study we analysed combined effects of anabolic steroids and training on the hypothalamic-pituitary-gonadal axis. Therefore intact male Wistar rats were dose-dependently treated with metandienone, estradienedione and the selective androgen receptor modulator (SARM) S-1. In serum cortisol, testosterone, 17beta-estradiol (E2), prolactin, inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), Insulin-like growth factor 1 (IGF-1), and thyroxine (T4) concentrations were determined. Six human volunteers were single treated with 1-androstenedione. In addition abusing and clean body builders were analysed. Serum concentrations of inhibin B, IGF-1, cortisol, prolactin, T4, thyroid-stimulating hormone (TSH), testosterone and LH were determined. In rats, administration of metandienone, estradienedione and S-1 resulted in an increase of muscle fiber diameter. Metandienone and estradienedione but not S-1 administration significantly decreases LH and inhibin B serum concentration. Administration of estradienedione resulted in an increase of E2 and S-1 in an increase of cortisol. Single administration of 1 androstenedione in humans decreased cortisol and inhibin B serum concentrations. LH was not affected. In abusing body builders a significantly decrease of LH, TSH and inhibin B and an increase of prolactin, IGF-1 and T4 was detected. In clean body builders only T4 and TSH were affected. PMID- 25797377 TI - [Management of anemia in patients with inflammatory bowel disease]. AB - Anemia is one of the commonest extraintestinal manifestations of inflammatory bowel disease (IBD). The pathogenesis of anemia in IBD is complex but iron deficiency combined with inflammation is the most common factor related to the development of anemia. However, other causes such as vitamin B12 and folate deficiency, hemolysis, myelosuppression and drug also should not be overlooked. In addition to ferritin, inflammatory markers and new biochemical parameters such as hepcidin and ferritin index are being tested as diagnostic a tool. First step for treatment is disease activity control and iron supplementation. Although oral iron is widely used, intravenous iron therapy should be considered in patients who are intolerant to oral iron therapy, have severe and refractory anemia or are in active disease state. Recently, new intravenous iron formulations have been introduced and due to their safety and easy usage, they have become the standard treatment modality for managing anemia in IBD. Erythropoietin and transfusion can be considered in specific situations. Vitamin B12 and folate supplementation is also important in patients who are deficient of these micronutrients. Since anemia in IBD patients could significantly influence the disease outcome, further studies and standard guideline for IBD are needed. PMID- 25797378 TI - [Prevention and treatment of thromboembolism in patients with inflammatory bowel disease]. AB - Although inflammatory bowel disease (IBD) is a chronic disorder that mainly affects the gastrointestinal tract, extraintestinal complications can occur in IBD patients. Among many extraintestinal complications, venous thromboembolism (VTE) is particularly a feared complication due to its significant morbidity and mortality. IBD patients have about 2 to 3 fold higher risk of developing VTE compared with the general population, and the current management guidelines for IBD patients propose recommendations for the prevention of VTE. This review aims to summarize clinical characteristics of VTE in IBD patients and to outline strategies for preventing and treating VTE in these patients. PMID- 25797379 TI - [Ideal vaccination strategy in inflammatory bowel disease]. AB - Inflammatory bowel disease (IBD) is a long-standing disease that often requires long-term use of immunosuppressive agents including immunomodulators (such as azathioprine, 6-mercaptopurine and methotrexate) and tumor necrosis factor-alpha inhibitors (such as infliximab and adalimumab). Introduction of immunosuppressive therapies, however, involves the risk of host susceptibility to opportunistic infections in this patient population. Therefore, adequate immunization for vaccine-preventable infectious diseases is currently recommended for all patients with IBD and is emerging as an important target for quality improvements in IBD care. However, ongoing issues regarding underuse of immunization, safety and efficacy of vaccines in patients with IBD remain. For quality improvements in IBD care, all physicians should follow the recent immunization guidelines proposed by professional IBD societies. Additionally, there are ongoing needs for intensive educational programs regarding a role of immunization in long-term care of IBD and up-to-date immunization guidelines. Immunization status should be checked at the time of diagnosis of IBD and timely vaccination before initiation of immunosuppressive therapies can be a practical solution for maximizing the efficacy of vaccination at this point. Inactivated vaccines can be used safely irrespective of immunization status of patients, while attenuated vaccines are contraindicated in patients on immunosuppressive therapies. This article reviews an ideal strategy for vaccinating patients with IBD based on the currently recommended immunization guidelines. PMID- 25797380 TI - [Medical professionalism-on social responsibilities viewed from historical perspective]. AB - What is medical professionalism and does it matter to the patients? Medical professionals take responsibility for their judgements and the consequences that ensue. Traditionally medical professionalism is defined as a set of values, behaviors, and relationships which support the trust the public has in doctors. The public is well aware that absence of professionalism is harmful to their interests. However, the exercise of medical professionalism is endangered by the political and cultural environment. The values of professionalism have been changed throughout the medical history and the meaning of it was also changed according to social theories. Traditional medical professionalism was based on the virtue of autonomy, self-regulation and competency etc. However, in the new millenium era, the meaning of professionalism has changed under the concept of responsibility which includes the classical virtues. The meaning of professionalism nowadays is only based on the structure and conflicting theories which cannot solve all the issues surrounding professionalism in medical practice. The conditions of medical practice are critical determinants for the future of professionalism. The interaction between doctor and patient is central to the medical care, and medical professionalism has roots in almost every aspect of medical care. I argue that doctors have responsibility to act according to the values which have been determined by the medical profession, history and surrounding society. The new millennium medical professionalism which based on the responsibility could initiate a public dialogue about the role of the doctor in creating a fairer society. PMID- 25797381 TI - Endoscopic submucosal dissection for early gastric cancer in a patient with myelodysplastic syndrome. AB - Endoscopic submucosal dissection (ESD) has been successfully performed in thrombocytopenic conditions such as in patients with liver cirrhosis but successful ESD for early gastric cancer (EGC) in hematologic diseases has rarely been reported. A 52-year-old male patient, who had previously been diagnosed with myelodysplastic syndrome 2 years ago, was admitted to our hospital for ESD of EGC. ESD was performed successfully in this patient after platelet concentrates transfusion on the day of ESD. ESD might be an option for the treatment of EGC in thrombocytopenia due to hematologic diseases when optimal supportive managements are applied. PMID- 25797382 TI - [A case of necrotizing colitis presenting with hepatic portal venous gas and pneumatosis intestinalis]. AB - Hepatic portal venous gas is a very rare radiologic sign which is characterized by gas accumulation in the portal venous circulation. Pneumatosis intestinalis is also very rare and is characterized by multiple air cysts in the serosal or submucosal layers of the gastrointestinal tract walls. These two findings are caused by various pathological conditions and can develop individually or simultaneously. The latter is clinically more significant because it is frequently related to bowel ischemia or necrosis, and represents a poor prognosis. However, prognosis is more influenced by the severity of underlying disease rather than hepatic portal venous gas or pneumatosis intestinalis itself. If bowel ischemia or necrosis is the primary cause, emergency operation is very important to improve patient's prognosis. Herein, we report a case of necrotizing colitis presenting as hepatic portal venous gas and pneumatosis intestinalis which was successfully managed by early surgery. PMID- 25797383 TI - [A case of pleomorphic liposarcoma originating from mesentery]. AB - Liposarcoma is one of the most common soft tissue sarcomas that occurs in adults and is currently divided into five main subgroups: well-differentiated, myxoid, round cell, pleomorphic, and dedifferentiated. Primary mesenteric liposarcoma is extremely rare, and the treatment strategy is surgical resection with a wide free margin, often followed by radiation and adjuvant chemotherapy if distant metastasis is not detected. A 73-year-old male patient presented with lower abdominal distension. Abdominal CT scan revealed a large homogeneously enhancing mass lesion abutting the sigmoid colon and urinary bladder. At laparotomy, the solid mass measured 28*26*12 cm in size, was well-demarcated, and originated from the mesentery of the middle ileum. It was removed along with some small intestine (ileocecal valve upper 50-150 cm) and ileal mesentery because of adhesion. Histologically, the tumor proved to be pleomorphic liposarcoma. The patient did not undergo any adjuvant treatment following surgery, but he remains disease free until 33 months after surgery. Herein, we report a case of pleomorphic liposarcoma arising from small bowel mesentery. PMID- 25797384 TI - [A case of spontaneous bleeding of multiple lumbar arteries in a patient with liver cirrhosis]. AB - Esophageal and gastric varix, portal hypertensive gastropathy, Mallory-Weiss tear and gastric ulcer are common causes of bleeding in patients with liver cirrhosis. However, spontaneous arterial bleeding without a history of trauma is a rare cause of bleeding which can be fatal. We report a case of a 55-year-old woman with alcoholic liver cirrhosis who developed spontaneous bleeding of multiple right lumbar arteries and died in spite of repetitive transfusion and embolization. PMID- 25797385 TI - Enzalutamide: Development from bench to bedside. AB - Prostate tissue, whether benign or malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation. Androgen deprivation therapy has been standard of care for management of metastatic prostate cancer for the past 70 years. AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the receptor. First generation compounds such as bicalutamide had modest efficacy, and in the setting of AR overexpression or specific mutations in the AR ligand-binding domain, these early compounds had partial agonist properties that could stimulate tumor growth. Enzalutamide was developed to overcome these deficiencies, and here, we present the story of its preclinical discovery, clinical development, and ultimate approval as a standard-of-care therapy for castration-resistant prostate cancer. Also discussed are ongoing efforts to elucidate mechanisms of resistance to this agent as well as studies that are investigating its role in other prostate cancer disease states and other cancer types. PMID- 25797386 TI - Fitness-to-drive after mild traumatic brain injury: mapping the time trajectory of recovery in the acute stages post injury. AB - INTRODUCTION: Little is known about the trajectory of recovery in fitness-to drive after mild traumatic brain injury (mTBI). This means that health-care professionals have limited evidence on which to base recommendations to this cohort about driving. OBJECTIVE: To determine fitness-to-drive status of patients with a mTBI at 24h and two weeks post injury, and to summarise issues reported by this cohort about return to driving. METHOD: Quasi-experimental case-control design. Two groups of participants were recruited: patients with a mTBI (n=60) and a control group with orthopaedic injuries (n=60). Both groups were assessed at 24h post injury on assessments of fitness-to-drive. Follow-up occurred at two weeks post injury to establish driver status. MAIN MEASURES: Mini mental state examination, occupational therapy-drive home maze test (OT-DHMT), Road Law Road Craft Test, University of Queensland-Hazard Perception Test, and demographic/interview form collected at 24h and at two weeks. RESULTS: At the 24h assessment, only the OT-DHMT showed a difference in scores between the two groups, with mTBI participants being significantly slower to complete the test (p=0.01). At the two week follow-up, only 26 of the 60 mTBI participants had returned to driving. Injury severity combined with scores from the 24h assessment predicted 31% of the variance in time taken to return to driving. Delayed return to driving was reported due to: "not feeling 100% right" (n=14, 23%), headaches and pain (n=12, 20%), and dizziness (n=5, 8%). CONCLUSION: This research supports existing guidelines which suggest that patients with a mTBI should not to drive for 24h; however, further research is required to map factors which facilitate timely return to driving. PMID- 25797387 TI - Relationship between intra-articular adhesions and disc position in temporomandibular joints: Magnetic resonance and arthroscopic findings and clinical results. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between intra-articular adhesions (IA) and disc position on magnetic resonance imaging (MRI) and direct arthroscopic vision, and to compare the presence of IA and clinical symptoms in patients diagnosed with internal derangements (ID) of temporomandibular joint (TMJ), along with their clinical outcomes. METHODS: A total of 67 patients (134 TMJs) were included in the study. All patients were refractory to previous conservative treatment, and MRI was performed before surgery in all cases. The incidence of IA was evaluated in relation to disc displacement, type of displacement (with or without reduction), and stage of ID according to the Wilkes-Bronstein classification. Patients were divided into an adhesion and non-adhesion group. The association between the two groups with respect to preoperative clinical parameters (maximal interincisal opening, locking duration, joint pain, patient age) and postoperative parameters at 6 and 12 months was evaluated. RESULTS: The incidence of IA was 44% and the most common location was the anterior recess of the joint. IA were found in 58.3% of the joints with disc displacement without reduction, and in 28.9% of those with disc displacement with reduction (p < 0.05). In joints with well-positioned discs, adhesions were found in 15% of the cases. Patient age and locking duration were significantly higher in the adhesions group (p < 0.05). In relation to clinical outcome, there was no clinically relevant difference between groups at 6 and 12 months. CONCLUSIONS: In TMJ with disc displacement without reduction, the presence of IA was significantly higher than in joints with well-positioned discs or displacement with reduction, which leads to the hypothesis that disc hypomobility is an important factor in the genesis of adhesions. PMID- 25797388 TI - Postoperative adjuvant radiotherapy improves loco-regional recurrence of head and neck mucosal melanoma. AB - Primary head and neck mucosal melanoma (HNMM) is a rare tumor with a poor prognosis. Controversy remains as to whether postoperative adjuvant radiotherapy (PORT) achieves a significant benefit in HNMM treatment. Because of the lack of available conclusive prospective data, we performed a systematic review and meta analysis of all relevant available studies to clarify the benefits of PORT. A comprehensive literature search of PubMed and Google Scholar electronic databases was conducted to collect relevant studies until April 30, 2014. Studies published in the English language comparing surgery alone and surgery plus PORT for HNMM were included, with more than 15 study populations. All statistical analyses were performed using STATA version 12.0. A total of 423 patients were available from eight studies and the median sample size was 53 cases. The median follow-up time was 38.2 months (range 18.3-65.2 months). There was a positive association between PORT and loco-regional recurrence of HNMM (odds ratio [OR] = 0.36, 95% confidence interval [CI] = 0.22-0.60, P = 0.000). No associations were found between the PORT and 3-year and 5-year overall survival (OS) (OR = 1.41, 95% CI = 0.94-2.09, P = 0.093 and OR = 1.06, 95% CI = 0.70-1.61, P = 0.161, respectively). PORT had no impact on 3-year and 5-year OS (hazard ratio [HR] = 1.14, 95% CI = 0.80-1.61, P = 0.472 and HR = 1.34, 95% CI = 0.97-1.85, P = 0.227, respectively). PORT improved loco-regional recurrence of HNMM independent of OS. PMID- 25797389 TI - Pharmacotherapy for treatment of lung cancer in the elderly. AB - INTRODUCTION: The chance for elderly patients with NSCLC to receive chemotherapy decreases significantly with age. In addition, older patients are often underrepresented in clinical trials. Consequently, due to the paucity of data, evidence-based decisions with regard to chemotherapy treatment strategies in the elderly are lacking. AREAS COVERED: We performed a literature search to identify mainly randomized trials focusing on treatment of NSCLC in older patients with chemotherapy and targeted therapy, toxicity and quality of life. In conclusion, the efficacy of regular chemotherapy and targeted therapy seems quite similar in older patients compared to their younger counterparts, with increased toxicity, but acceptable. However, these data are mostly derived from subgroup analyses and highly selected fit patients, which may not represent the general older population. EXPERT OPINION: Further research is necessary to investigate the role of a comprehensive geriatric assessment in older patients, before the start of a chemotherapeutic treatment. Proteomic tests can have potential in the future, if these tests turn out to be able to separate patients with advanced NSCLC into groups with better or worse outcomes. It can be of special interest for the elderly population, to prevent unnecessary side effects of a possible inferior treatment. PMID- 25797390 TI - Microtubule appendages mediating T-cell motility and polarity. AB - Polarization of the centrosome and the Golgi apparatus in the T cell (TC) toward the antigen-presenting cell (APC) is essential for the specificity of the immune response on the cellular level. Previously we reported the existence of thin, long processes on the TC surface, which emanated predominantly from the area next to the Golgi apparatus. They appeared to be involved in the orientation of the TC during the initial phases of its attachment, which preceded the formation of the immunological synapse mediated by lamellipodia. Here we improve the visualization of the long, thin protrusions in the cultured TC and demonstrate using cytoskeleton inhibitors and immunofluorescence that microtubules form their cytoskeletal basis. The protrusions are seen prior to the attachment and the development of the broad lamellipodia (within a few minutes). We propose the term "tubulopodia" for this distinct type of cell appendage. Using an established experimental model that replaces the APC surface with a biomimetic substrate coated with antibodies against the TC receptor (TCR), we demonstrate that abrogation of the lamellipodium-mediated synapse formation does not impede the orientation of the TC Golgi apparatus and the centrosome to the contact area. Video microscopy reveals the spreading of the tubulopodia on the TCR-binding substrate, which results in the area of their emanation, and consequently the Golgi apparatus and the centrosome, being closely apposed (polarized) to the TCR binding surface. Treatment with paclitaxel made the tubulopodia rigid, preventing their attachment to the TCR-binding surface and the reorientation of the cell body with the intracellular structures. We speculate that the motility and polarity of the TC in vivo may be mediated on a large scale by differential adhesion through the long, flexible tubulopodia. PMID- 25797391 TI - Novel alpha-L-arabinofuranosidase from Cellulomonas fimi ATCC 484 and its substrate-specificity analysis with the aid of computer. AB - In the process of gene mining for novel alpha-L-arabinofuranosidases (AFs), the gene Celf_3321 from Cellulomonas fimi ATCC 484 encodes an AF, termed as AbfCelf, with potent activity, 19.4 U/mg under the optimum condition, pH 6.0 and 40 degrees C. AbfCelf can hydrolyze alpha-1,5-linked oligosaccharides, sugar beet arabinan, linear 1,5-alpha-arabinan, and wheat flour arabinoxylan, which is partly different from some previously well-characterized GH 51 AFs. The traditional substrate-specificity analysis for AFs is labor-consuming and money costing, because the substrates include over 30 kinds of various 4-nitrophenol (PNP)-glycosides, oligosaccharides, and polysaccharides. Hence, a preliminary structure and mechanism based method was applied for substrate-specificity analysis. The binding energy (DeltaG, kcal/mol) obtained by docking suggested the reaction possibility and coincided with the experimental results. AbfA crystal 1QW9 was used to test the rationality of docking method in simulating the interaction between enzyme and substrate, as well the credibility of the substrate-specificity analysis method in silico. PMID- 25797394 TI - Synthesis, characterization and application of titanium oxide nanocomposites for removal of radioactive cesium, cobalt and europium ions. AB - New nanocomposite material containing TiO2/Poly (acrylamide-styrene sodium sulfonate) [TiO2/(P (AAm-SSS)] was prepared by in-situ intercalative polymerization of poly acrylamide (PAAm) and styrene sodium sulfonate (SSS) in the presence of TiO2 nanoparticles as inorganic filler. N, N-methylene bis acrylamide (MBA) was used as a cross linker. The polymerization process was performed using gamma-radiation as reaction initiator. Moreover, new nanocomposite material containing poly styrene-TiO2 (PS-TiO2) was also prepared by ionic polymerization method. Styrene was catalytically polymerized by Ti(4+) via an ionic polymerization route to produce polystyrene (PS). The structure characteristics of the nanocomposites were investigated by XRD, TGA, SEM, surface area, and FTIR. The nanoparticles and nanocomposites were investigated for removal of some metal ions from aqueous solutions. The effective key parameters on the sorption behavior of radioactive cesium (Cs(+)), cobalt (Co(2+)) and europium (Eu(3+)) were investigated using batch equilibrium technique with respect to solution pH and contact time. The obtained results revealed that the equilibrium for Cs(+), Co(2+) and Eu(3)(+) is reached at 2-3 h for all nanocomposites. The data indicated that there is no significant change in the uptake between TiO2 nanoparticles and TiO2-PS. On the contrary, the uptake process is significantly improved using TiO2/(P (AAm-SSS) nanocomposite and the maximum experimental retention capacities for Cs(+), Co(2+) and Eu(3+) were found to be 120, 100.9 and 85.7 mg/g, respectively. PMID- 25797393 TI - Chimeric nucleolin aptamer with survivin DNAzyme for cancer cell targeted delivery. AB - A chimeric aptamer-DNAzyme conjugate was generated for the first time using a nucleolin aptamer (NCL-APT) and survivin Dz (Sur_Dz) and exhibited the targeted killing of cancer cells. This proof of concept of using an aptamer for the delivery of DNAzyme can be applied to other cancer types to target survivin in cancer cells in a specific manner. PMID- 25797392 TI - Cardiopulmonary Bypass has No Significant Impact on Survival in Patients Undergoing Nephrectomy and Level III-IV Inferior Vena Cava Thrombectomy: Multi Institutional Analysis. AB - PURPOSE: The impact of cardiopulmonary bypass in level III-IV tumor thrombectomy on surgical and oncologic outcomes is unknown. We determine the impact of cardiopulmonary bypass on overall and cancer specific survival, as well as surgical complication rates and immediate outcomes in patients undergoing nephrectomy and level III-IV tumor thrombectomy with or without cardiopulmonary bypass. MATERIALS AND METHODS: We retrospectively analyzed 362 patients with renal cell cancer and with level III or IV tumor thrombus from 1992 to 2012 at 22 U.S. and European centers. Cox proportional hazards models were used to compare overall and cancer specific survival between patients with and without cardiopulmonary bypass. Perioperative mortality and complication rates were assessed using logistic regression analyses. RESULTS: Median overall survival was 24.6 months in noncardiopulmonary bypass cases and 26.6 months in cardiopulmonary bypass cases. Overall survival and cancer specific survival did not differ significantly in both groups on univariate analysis or when adjusting for known risk factors. On multivariate analysis no significant differences were seen in hospital length of stay, Clavien 1-4 complication rate, intraoperative or 30-day mortality and cancer specific survival. Limitations include the retrospective nature of the study. CONCLUSIONS: In our multi-institutional analysis the use of cardiopulmonary bypass did not significantly impact cancer specific survival or overall survival in patients undergoing nephrectomy and level III or IV tumor thrombectomy. Neither approach was independently associated with increased mortality on multivariate analysis. Greater surgical complications were not independently associated with the use of cardiopulmonary bypass. PMID- 25797395 TI - Biodegradable colloidal microgels with tunable thermosensitive volume phase transitions for controllable drug delivery. AB - In this study, we present gelatin-based thermoresponsive colloidal microgels that enable the controlled release of drugs by volume phase transition. The microgel was fabricated by physically entrapping poly(N-isopropylacrylamide-co-acrylamide) chains as a minor component within three-dimensional gelatin networks crosslinked by genipin. We demonstrate that our gelatin-based thermoresponsive microgel exhibits a tunable deswelling to temperature increase, which positively correlated to the release of bovine serum albumin (BSA) as a function of poly(N isopropylacrylamide-co-acrylamide) concentration. The microgel was enzymatically degradable by collagenase treatment. The extent of BSA release and biodegradability were tuned by controlling the crosslinking degree of the gelatin matrix. Meeting a great need for design and synthesis of auto-degenerating smart microgels that enable the controlled release of therapeutic proteins in responsive to external stimuli, our gelatin-based microgels that satisfy both thermoresponsivity and biodegradability have a great potential in tissue engineering applications as a soft microdevice element for drug delivery. PMID- 25797397 TI - Guest editorial for special oral microbes edition. PMID- 25797396 TI - Low compliance with the 2 minutes of uninterrupted chest compressions recommended in the 2010 International Resuscitation Guidelines. AB - BACKGROUND: We aimed to analyze compliance with 2010 European guidelines' quality criteria for external chest compressions (ECC) during 2 minutes of uninterrupted cardiopulmonary resuscitation. METHODS: Seventy-two healthy nurses and physicians trained in advanced cardiopulmonary resuscitation performed 2 uninterrupted minutes of ECC on a training manikin (Resusci Anne Advanced SkillTrainer; Laerdal Medical AS, Stavanger, Norway) that enabled us to measure the depth and rate of ECC. When professionals agreed to participate in the study, we recorded their age, body mass index (BMI), smoking habit, and their own subjective estimation of their physical fitness. To measure fatigue, we analyzed participants' heart rates, percentage of maximum tolerated heart rate (MHR), and subjective perception of their fatigue on a visual analog scale. RESULTS: Nearly half (48.6%) the rescuers failed to achieve a minimum average ECC depth of 50 mm. Only 48.1% of ECCs fulfilled the 2010 guidelines' quality criteria; quality deteriorated mainly after the first minute. Poor ECC quality and deteriorating quality after the first minute were associated with BMI < 23 kg/m(2). Rescuers with BMI >= 23 kg/m(2) fulfilled the quality criteria throughout the 2 minutes, whereas those with BMI < 23 kg/m(2) fulfilled them for 80% of ECCs during the first minute, but for only 30% at the end of the 2 minutes. CONCLUSIONS: Compliance with the 2010 guidelines' quality criteria is often poor, mainly due to lack of proper depth. The greater depth recommended in the 2010 guidelines with respect to previous guidelines requires greater force, so BMI < 23 kg/m(2) could hinder compliance. Limiting each rescuer's uninterrupted time doing ECC to 1 minute could help ensure compliance. PMID- 25797398 TI - Micro RNA expression profiles in peripheral blood cells of rats that were experimentally infected with Trypanosoma congolense and different Trypanosoma brucei subspecies. AB - To identify miRNAs whose expression are differentially regulated during trypanosome infections a microarray targeting more than 600 rat miRNA was used to analyze the miRNA expression profiles between uninfected rats and animals infected by Trypanosoma congolense and Trypanosoma brucei s.l. The potential targets of dysregulated miRNAs as well as their biological pathways and functions were predicted using several bioinformatics software tools. Irrespective of the infecting trypanosome species, eight miRNAs (seven up- and one down-regulated) were dysregulated during infections. Moreover, other miRNAs were differentially regulated in rats infected by specific trypanosome species. Functional analyses of differentially regulated miRNAs indicated their involvement in diverse biological processes. Among these, transcription repressor activity, gene expression control as well as protein transporter activity were predominant. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of dysregulated miRNAs revealed their involvement in several biological pathways and disease conditions. This suggests possible modulation of such pathways following trypanosome infection; for example, the MAPK signaling pathway which is known to play vital roles in apoptosis, innate immune response and response to viral infections was highly affected. Axon guidance was equally highly impacted and may indicate a cross reactivity between pathogen proteins and guidance molecules representing one pathological mechanism as it has been observed with influenza HA. Furthermore, Ingenuity pathway analyses of dysregulated miRNAs and potential targets indicated strong association with inflammatory responses, cell death and survival as well as infectious diseases. The data generated here provide valuable information to understand the regulatory function of miRNAs during trypanosome infections. They improved our knowledge on host-parasite cross-talks and provide a framework for investigations to understand the development of trypanosomes in their hosts as well as the differences in the clinical and pathological evolutions of the disease. PMID- 25797399 TI - Macrophages expressing arginase 1 and nitric oxide synthase 2 accumulate in the small intestine during Giardia lamblia infection. AB - Nitric oxide (NO) has been shown to inhibit Giardia lamblia in vitro and in vivo. This study sought to determine if Giardia infection induces arginase 1 (ARG1) expression in host macrophages to reduce NO production. Stimulations of RAW 264.7 macrophage-like cells with Giardia extract induced arginase activity. Real-time PCR and immunohistochemistry showed increased ARG1 and nitric oxide synthase 2 (NOS2) expression in mouse intestine following infection. Flow cytometry demonstrated increased numbers of macrophages positive for both ARG1 and NOS2 in lamina propria following infection, but there was no evidence of increased expression of ARG1 in these cells. PMID- 25797400 TI - Map kinase and PKC signaling pathways modulate NGF-mediated apoE transcription. AB - The present study assessed the mechanisms by which nerve growth factor (NGF) increased the level of apolipoprotein E (apoE) in PC12 cells. NGF (50ng/mL) significantly increased apoE protein levels following 72h of treatment. Similarly NGF increased luciferase activity in cells transfected with a luciferase reporter construct containing a 500bp fragment of the apoE promoter, indicating NGF induced apoE expression is regulated, at least in part, at the level of transcription. The non-selective nitric oxide synthase (NOS) inhibitor N(omega) nitro-L-arginine methylester (L-NAME; 20mM) did not attenuate the NGF-mediated increase in luciferase activity, while the inducible NOS inhibitor s methylisothiourea (S-MIU; 2mM) partially attenuated this action of NGF. Inhibition of MAP kinase activation with 50MUM U0126 or pre-treatment with the PKC inhibitor bisindolylmaleimide 1 (BIS-1; 10MUM) prevented the NGF-mediated activation of the apoE promoter. Pre-treatment with the phospholipase C (PLC) inhibitor U73122 (5MUM) partially inhibited the NGF-induced increase in luciferase activity while the Akt inhibitor LY294002 (10MUM) had no effect. These data suggest NGF-induced apoE transcription requires MAP kinase and PKC activation and that these TrkA signaling pathways may be modulated by NO. PMID- 25797402 TI - Green bionanocomposite based on kefiran and cellulose nanocrystals produced from beer industrial residues. AB - Environmental concern about synthetic polymers and nanoparticles bring about development of the green bionanocomposite. Nanocellulose (NC) as safe nanofiller was prepared from beer industrial residues by acid hydrolysis in this study. ATR FTIR spectrum showed no change in chemical structure of kefiran and NC after mixing. However, mechanical, visual, and WVP properties of kefiran/NC films improved with NC, but thermal properties and water sensitivity of them declined, simultaneously. PMID- 25797401 TI - Cortical thickness and brain volumetric analysis in body dysmorphic disorder. AB - Individuals with body dysmorphic disorder (BDD) suffer from preoccupations with perceived defects in physical appearance, causing severe distress and disability. Although BDD affects 1-2% of the population, the neurobiology is not understood. Discrepant results in previous volumetric studies may be due to small sample sizes, and no study has investigated cortical thickness in BDD. The current study is the largest neuroimaging analysis of BDD. Participants included 49 medication free, right-handed individuals with DSM-IV BDD and 44 healthy controls matched by age, sex, and education. Using high-resolution T1-weighted magnetic resonance imaging, we computed vertex-wise gray matter (GM) thickness on the cortical surface and GM volume using voxel-based morphometry. We also computed volumes in cortical and subcortical regions of interest. In addition to group comparisons, we investigated associations with symptom severity, insight, and anxiety within the BDD group. In BDD, greater anxiety was significantly associated with thinner GM in the left superior temporal cortex and greater GM volume in the right caudate nucleus. There were no significant differences in cortical thickness, GM volume, or volumes in regions of interest between BDD and control subjects. Subtle associations with clinical symptoms may characterize brain morphometric patterns in BDD, rather than large group differences in brain structure. PMID- 25797403 TI - Effect of chemicals on production, composition and antioxidant activity of polysaccharides of Inonotus obliquus. AB - Polysaccharides are important secondary metabolites from the medicinal mushroom Inonotus obliquus. Various fatty acids, surfactants and organic solvents as cell membrane-reorganizing chemicals were investigated for their stimulatory effects on the growth of fungal mycelium and production of exopolysaccharides (EPS) and endopolysaccharides (IPS) by submerged fermentation of I. obliquus. After evaluation of 14 chemicals, oleic acid, Tween 80, and TritonX-100 were chosen for optimization of addition concentration and addition time. Among the three chemicals, 0.1% (v/v) Tween 80 gave maximum production of mycelial biomass, EPS, IPS1, and IPS2 with a increase of 16.6, 81.6, 37.7 and 18.1%, respectively, when supplemented at the early growth phase (24h after inoculation). These EPS, IPS1, and IPS2 had significantly (p<0.05) stronger scavenging activity against 2,2 diphenyl-1-picrylhydrazyl (DPPH) radicals than those from the control medium. IPS1 from Tween 80-containing medium was the most effective antioxidant, with an estimated IC50 value of 0.74mg/mL. This might be attributed to that the EPS and IPS from the Tween 80-containing medium had significantly (p<0.05) higher content of sugar and glucose among the six monosaccharide compositions than those from the control. The simultaneously enhanced accumulation of bioactive EPS and IPS of cultured I. obliquus supplemented with Tween 80 was evident. PMID- 25797404 TI - Physicochemical properties of native and gamma-irradiated wild arrowhead (Sagittaria sagittifolia L.) tuber starch. AB - Starch isolated from wild arrowhead tuber was treated by gamma-irradiation at 0, 5, 10 and 15kGy doses. Arrowhead tubers yielded 40.33% starch and its chemical composition revealed moisture, protein, ash and fat were 8.34+/-0.09%, 0.26+/ 0.04%, 0.58+/-0.02% and 0%, respectively. Physicochemical, morphological and pasting properties of native and irradiated tuber starches were investigated. The results showed that peak, trough, final, and setback viscosities were significantly (p<=0.05) reduced, whereas the breakdown viscosity increased following irradiation. Physicochemical properties differed significantly and showed strong dose dependent relationship. Solubility, water absorption capacity and transmittance increased, whereas swelling power, bulk density and syneresis decreased upon increase in irradiation of starch. Correlation studies showed that irradiation dose was positively correlated with water absorption capacity and solubility index while it correlated negatively with pasting properties, swelling index, syneresis, and freeze thaw stability. PMID- 25797405 TI - Enzymatic degradation behavior of nanoclay reinforced biodegradable PLA/PBSA blend composites. AB - Films of a biodegradable PLA/PBSA blend and blend-composites containing 2wt% of C20A, C30B and MEE were prepared by solvent casting and spin coating. The films were incubated in vials containing Tris-HCl buffer with Proteinase K, and their weight losses were measured after enzymatic degradation. The surface morphology before and after degradation tests was studied by SEM and in situ AFM. The results showed that neat PLA had a lower percentage weight loss than neat PBSA, whereas blending them resulted in an increased weight loss. The incorporation of C20A into the as-prepared blend accelerated the degradation rate, whereas C30B and MEE decelerated the degradation rate. Annealing at 70 degrees C reduced the degradation rate of the blend, and the presence of nanoclays further reduced the degradation rates. Annealing at 120 degrees C dramatically decelerated the degradation of the blend, whereas the incorporation of nanoclays accelerated the degradations rates. The enhancement of the degradation rates in the presence of nanoclays indicated that the degradation rates were mainly controlled by the PLA matrix. Thin films were also cast onto a silicon substrate using a spin coater, and enzymatic degradation on the completely crystalline surfaces revealed that enzymatic attack occurred by pitting and surface erosion of the thin films. PMID- 25797406 TI - Fabrication of novel magnetic nanocomposite with a number of adsorption sites for the removal of dye. AB - In this current work, a novel functional ionic liquid-coated Fe3O4@chitosan@graphene oxide was synthesized and tested as adsorbents for methylene blue through batch adsorption tests. The physicochemical properties of the adsorbent were investigated using scanning electron microscopy, x-ray diffraction, and fourier transform infrared spectroscopy. The adsorption capacity of the adsorbent was evaluated as a function of initial dye concentration, pH, contact time and temperature. The adsorption results indicated that the adsorption followed a pseudo-second-order kinetics. The equilibrium adsorption was well-described by the Langmuir isotherm model and the maximum adsorption capacity was to be 262 mg/g. The negative value of DeltaH degrees shows exothermic nature of adsorption process and the negative value of DeltaG degrees indicated that the adsorption reaction is spontaneous. Moreover, the ionic liquid coated Fe3O4@chitosan@graphene oxide could be repeatedly used by simple treatment without obvious structure and performance degradation. The obtained results suggested that the potential applications of ionic liquid-coated Fe3O4@chitosan@graphene oxide in deep-purification of polluted water. PMID- 25797407 TI - Cellulase assisted synthesis of nano-silver and gold: Application as immobilization matrix for biocatalysis. AB - In the present study, we report in vitro synthesis of silver and gold nanoparticles (NPs) using cellulase enzyme in a single step reaction. Synthesized nanoparticles were characterized by UV-VIS spectroscopy, Dynamic Light Spectroscopy (DLS), Transmission Electron Microscopy (TEM), Energy-dispersive X ray Spectroscopy (EDX), X-ray Diffraction (XRD), Circular Dichroism (CD) and Fourier Transform Infrared Spectroscopy (FTIR). UV-visible studies shows absorption band at 415nm and 520nm for silver and gold NPs respectively due to surface plasmon resonance. Sizes of NPs as shown by TEM are 5-25nm for silver and 5-20nm for gold. XRD peaks confirmed about phase purity and crystallinity of silver and gold NPs. FTIR data shows presence of amide I peak on both the NPs. The cellulase assisted synthesized NPs were further exploited as immobilization matrix for cellulase enzyme. Thermal stability analysis reveals that the immobilized cellulase on synthesized NPs retained 77-80% activity as compared to free enzyme. While reusability data suggests immobilized cellulase can be efficiently used up to sixth cycles with minimum loss of enzyme activity. The secondary structural analysis of cellulase enzyme during the synthesis of NPs and also after immobilization of cellulase on these NPs was carried out by CD spectroscopy. PMID- 25797408 TI - Understanding thio-effects in simple phosphoryl systems: role of solvent effects and nucleophile charge. AB - Recent experimental work (J. Org. Chem., 2012, 77, 5829) demonstrated pronounced differences in measured thio-effects for the hydrolysis of (thio)phosphodichloridates by water and hydroxide nucleophiles. In the present work, we have performed detailed quantum chemical calculations of these reactions, with the aim of rationalizing the molecular bases for this discrimination. The calculations highlight the interplay between nucleophile charge and transition state solvation in SN2(P) mechanisms as the basis of these differences, rather than a change in mechanism. PMID- 25797410 TI - Clinical tests to diagnose lumbar spondylolysis and spondylolisthesis: A systematic review. AB - The aim of this paper was to systematically review the diagnostic ability of clinical tests to detect lumbar spondylolysis and spondylolisthesis. A systematic literature search of six databases, with no language restrictions, from 1950 to 2014 was concluded on February 1, 2014. Clinical tests were required to be compared against imaging reference standards and report, or allow computation, of common diagnostic values. The systematic search yielded a total of 5164 articles with 57 retained for full-text examination, from which 4 met the full inclusion criteria for the review. Study heterogeneity precluded a meta-analysis of included studies. Fifteen different clinical tests were evaluated for their ability to diagnose lumbar spondylolisthesis and one test for its ability to diagnose lumbar spondylolysis. The one-legged hyperextension test demonstrated low to moderate sensitivity (50%-73%) and low specificity (17%-32%) to diagnose lumbar spondylolysis, while the lumbar spinous process palpation test was the optimal diagnostic test for lumbar spondylolisthesis; returning high specificity (87%-100%) and moderate to high sensitivity (60-88) values. Lumbar spondylolysis and spondylolisthesis are identifiable causes of LBP in athletes. There appears to be utility to lumbar spinous process palpation for the diagnosis of lumbar spondylolisthesis, however the one-legged hyperextension test has virtually no value in diagnosing patients with spondylolysis. PMID- 25797409 TI - Striatal dopamine release regulation by the cholinergic properties of the smokeless tobacco, gutkha. AB - Tobacco products influence striatal dopamine (DA) release primarily through the actions of nicotine, an agonist of nicotinic acetylcholine receptors (nAChR). Gutkha is a smokeless tobacco product that contains not only nicotine, but also includes the habit-forming areca nut and other plant-based constituents that contribute muscarinic acetylcholine receptor (mAChR) agonists and other cholinergic agents. Thus, the net influence of the cholinergic agents in gutkha on striatal DA release is difficult to predict. This study investigated the influence of gutkha extract on evoked DA release in mouse striatal slices using fast-scan cyclic voltammetry. The potency of a given concentration of nicotine in the gutkha extract was found to be significantly lower than that of a comparable concentration of nicotine alone. Atropine, a mAChR antagonist, increased the potency of gutkha-associated nicotine; however, other experiments suggested that this was mediated in part by direct effects of atropine at nAChRs. Overall, these results suggest that the unique constituents of gutkha work together to oppose the influence of gutkha-associated nicotine on evoked striatal DA release. PMID- 25797411 TI - Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents. AB - Five Ru(II)-N-heterocyclic carbenes (NHC) (1-5) were synthesized by reacting the appropriately substituted imidazolium chlorides with Ag2O, forming the NHC-silver chloride in situ followed by transmetalation with dimeric p-cymene ruthenium(II) dichloride. All the complexes were characterized by NMR and ESI-MS, and complex 1 was also characterized by single-crystal X-ray diffraction. The IC50 values of these five complexes were determined by the MTT-based assay on four human cancer cell lines, SKOV-3 (ovarian), PC-3 (prostate), MDA-MB-231 (breast) and EC109 (esophagus). The cytotoxicities of these complexes changed from a moderate effect to a fine one, corresponding to the increasing lipophilicity order of the complex of 2 < 1 < 3 < 4 < 5 (0.91, 0.88, 1.36, 1.85 and 2.62 for 1-5 respectively). Complex 5 showed the most cytotoxicity with the IC50 values 10.3 +/- 0.3 MUM for SKOV-3, 2.9 +/- 0.1 MUM for PC-3, 8.2 +/- 0.6 MUM for MDA-MB-231, 6.4 +/- 0.2 MUM for EC109 cell lines. Due to the superior cytotoxicity of complex 5 against the PC-3 cell lines, further biological evaluations were carried out to elucidate its action mechanism. The morphologic changes and cell cycle analysis showed that complex 5 can inhibit PC-3 cell lines by inducing cell cycle arrest at the G2/M phase. The DNA binding experiments further demonstrate that complex 5 has a better binding ability for DNA (Kb = 2.2 * 10(6) M(-1)) than complexes 1-4 (3.8 * 10(5), 7.0 * 10(5), 5.7 * 10(5), and 1.9 * 10(5) respectively). PMID- 25797412 TI - Multipathways human health risk assessment of trihalomethane exposure through drinking water. AB - Life-time human health risk of cancer attributed to trihalomethanes in drinking water in an urban-industrialized area of Karachi (Pakistan) was conducted through multiple pathways of exposure. The extent of cancer risk was compared with USEPA guidelines. Human health cancer risk for total trihalomethanes (TTHMs) through ingestion and dermal routes were estimated in "acceptable-low risk" (>=1.0E-06; <=5.10E-05), whereas through inhalation route it was estimated under "acceptable high risk" (>=5.10E-05; <=1.0E-04) category. However, at some industrial-urban areas cancer risk for CHCl3 were estimated under "unacceptable risk" (>=1.0E-04) through inhalation route. PMID- 25797413 TI - Effects of post-training modafinil administration in a discriminative avoidance task in mice. AB - OBJECTIVE: Although the cognitive-enhancing abilities after modafinil have been demonstrated, its effects on memory consolidation remain overlooked. We investigated the effects of repeated modafinil administration on consolidation of a discriminative avoidance task. METHODS: Mice were trained in the plus-maze discriminative avoidance task. After training, mice received intraperitonial modafinil (doses of 32, 64 or 128 mg/kg). Animals were treated for more 9 consecutive days; 30 min after the last injection, testing was performed. In addition, the effects of 32 mg/kg modafinil on consolidation at different time points were examined. RESULTS: The smaller dose of modafinil (32 mg/kg) impaired memory consolidation, without modifying anxiety or locomotion. Still, modafinil post-training administration at 1 or 2 h impaired memory persistence. CONCLUSIONS: Modafinil impaired memory consolidation in a dose- and time dependent fashion. PMID- 25797414 TI - Interdevice agreement of eight equivalent dental color measurement devices. AB - OBJECTIVES: The reproducibility of electronic color-measuring devices used in dentistry refers to the consistency of measurements of a single device and also that between identical devices. This in vitro study evaluated the short-term interdevice agreement of eight equivalent dental measurement devices. METHODS: The short-term repeatability of eight identical VITA Easyshade Advance color measurement devices was evaluated. Each device was used to quantify the Commission Internationale de l'Eclairage (CIE) L*a*b* color coordinates of ceramic disks, designed in accordance with guidelines set by the VITA Toothguide 3D-Master shade tab organization. Statistical analysis involved calculating the intraclass correlation coefficients (ICCs) and color differences (DeltaE*) for corresponding measurements taken by the devices. In addition, the mean color difference from the mean (MCDM) was calculated for each color. RESULTS: All devices showed high ICCs for the color coordinates (L = 0.996, a = 0.993, b = 0.999). The DeltaE* by shade ranged from 0.62 to 1.67. The MCDM by color measuring device ranged from 0.11 to 0.23. CONCLUSION: This in vitro study showed that the color-measuring devices used were suitable for determining shade with high repeatability. CLINICAL RELEVANCE: The high interdevice agreement of the VITA Easyshade Advance means that dental professionals can use this device independently, without compromising the consistency and quality of color measurements. PMID- 25797415 TI - Effects of SPAK knockout on sensorimotor gating, novelty exploration, and brain area-dependent expressions of NKCC1 and KCC2 in a mouse model of schizophrenia. AB - SPAK (Sterile 20/SPS1-related proline/alanine-rich kinase) is a protein kinase belonging to the mitogen-activated protein kinase (MAPK) superfamily that has been found to be extensively distributed across the body. The SPAK downstream substrates NKCC1 and KCC2 in the central nervous system are important in the interpretation of developmental mental disorders. The present study aimed to clarify the role of SPAK-NKCC1/KCC2 using a rodent schizophrenia-like model. The mouse paradigm of isolation rearing (IR) was employed, as it simulates the sensorimotor gating abnormalities of schizophrenia. SPAK transgenic mice were used and were divided into four groups: social-wild type, social-SPAK(-/-), isolation-wild type, and isolation-SPAK(-/-). The prepulse inhibition (PPI) test and the novel object recognition test (NORT) were used to measure schizophrenia associated dysfunctions in gating ability and the novelty recognition, respectively. Finally, the protein expressions of NKCC1/KCC2 in the prefrontal cortex and hippocampus were detected to determine correlations with the behavioral data. Our results demonstrated that SPAK-null mice had superior PPI and novelty recognition relative to wild type controls, with a concomitant increase in KCC2 in the prefrontal cortex. IR disrupted PPI and NORT performances with an associated increase in KCC2. Furthermore, rearing environment and gene manipulation had mutually interactive effects, as the IR-induced effects on PPI and NORT were reversed by SPAK knockout, and the increase in KCC2 and the decreased in the NKCC1/KCC2 ratio in the prefrontal cortex induced by SPAK knockout were reversed by IR. Our data supported the gene-environment hypothesis and demonstrated the potential value of SPAK manipulation in future schizophrenia studies. PMID- 25797416 TI - Regional anaesthesia for hip fracture surgery is associated with significantly more peri-operative complications compared with general anaesthesia. AB - INTRODUCTION: Although several studies have advocated the use of regional versus general anaesthesia as a means of reducing peri-operative complications from hip fracture surgery, the ideal method of anaesthesia remains controversial. Our purpose was to investigate the association between anaesthesia type and peri operative complications in hip fracture surgery. METHODS: From the 2005-2011 ACS NSQIP database, all patients with operatively treated hip fractures were identified using CPT codes, and fifteen peri-operative complications were recorded and categorized as either minor or major. Rates of minor, major, and total complications by anaesthesia type were compared using chi-square and Fischer's exact tests. A multivariate model was used to determine odds of minor, major, and total complications between anaesthesia types. Multivariate analysis was then repeated after combining patients who received regional nerve blocks or spinal anaesthesia. RESULTS: A total of 7,764 hip fracture patients were included in our analysis. Spinal anaesthesia had the highest total complication rate (19.6%), followed by general (17.9%) and regional nerve blocks (12.6%). Multivariate analysis demonstrated that spinal anaesthesia was associated with significantly greater odds of minor complications and total complications compared with general anaesthesia. After combining the regional nerve block and spinal anaesthesia groups, multivariate analysis again showed significantly greater odds of minor and total complications with regional versus general anaesthesia. CONCLUSIONS: Using a large multi-centre database, we demonstrate that regional anaesthesia was associated with significantly greater odds of minor and total peri-operative complications compared with general anaesthesia. Our results challenge the notion that regional anaesthesia is the preferred method of anaesthesia for hip fractures in the elderly. PMID- 25797417 TI - Reconsideration of Beta-blocker Therapy in Patients with Peripheral Artery Disease. PMID- 25797418 TI - Sustained attention in context conditioning: Evidence from steady-state VEPs. AB - In classical fear conditioning an aversive event is paired repeatedly with a predictive stimulus, which later elicits fear. Repeated presentation of an aversive event in the absence of a predictive cue however may induce anxiety, and the context may gain a threatening value. As such conditioned anxiety can be considered a sustained reaction compared to phasic fear, it would be interesting to track continuous cortical responses during context conditioning. The present study realized a differential context conditioning paradigm and assessed sustained cortical activations to the threatening and the safe context and how neutral cues are processed within both contexts. Two pictures of different office rooms presented for 20s served as contexts. One room became associated with an unpleasant noise that was presented unpredictably (CTX+) while the other office (CTX-) was never associated with this unpleasant noise. After acquisition, a social agent or an object was presented as a distractor in both contexts. Cortical activations in response to contexts and distractors were assessed separately by steady-state visually evoked potentials (ssVEPs) using frequency tagging. Results revealed enhanced ssVEP-amplitudes for CTX+ compared to CTX- in a lateral occipital cluster during acquisition. Similarly, CTX+ elicited higher ssVEP-amplitudes during the test phase, and these context conditioning effects were not reduced by the simultaneous presentation of novel distractors. These results indicate that context conditioning was successfully implemented and that the anxiety context received facilitated cortical processing across the whole viewing time. We conclude that threatening contexts capture attention over a longer period of time, and are immune to distraction by new objects. PMID- 25797419 TI - Vibrational coherence transfer in an electronically decoupled molecular dyad. AB - The ring opening of a dithienylethene photoswitch incorporated in a bridged boron dipyrromethene - dithienylethene molecular dyad was investigated with ultrafast spectroscopy. Coherent vibrations in the electronic ground state of the boron dipyrromethene are triggered after selective photoexcitation of the closed dithienylethene indicating vibrational coupling although the two moieties are electronically isolated. A distribution of short-lived modes and a long-lived mode at 143 cm(-1) are observed. Analysis of the theoretical frequency spectrum indicates two modes at 97 cm(-1) and 147 cm(-1) which strongly modulate the electronic transition energy. Both modes exhibit a characteristic displacement of the bridge suggesting that the mechanical momentum of the initial geometry change after photoexcitation of the dithienylethene is transduced to the boron dipyrromethene. The relaxation to the dithienylethene electronic ground state is accompanied by significant heat dissipation into the surrounding medium. In the investigated dyad, the boron-dipyrromethene acts as probe for the ultrafast photophysical processes in the dithienylethene. PMID- 25797420 TI - Assembly of forest communities across East Asia--insights from phylogenetic community structure and species pool scaling. AB - Local communities are assembled from larger-scale species pools via dispersal, environmental filtering, biotic interactions, and local stochastic demographic processes. The relative importance, scaling and interplay of these assembly processes can be elucidated by comparing local communities to variously circumscribed species pools. Here we present the first study applying this approach to forest tree communities across East Asia, focusing on community phylogenetic structure and using data from a global network of tropical, subtropical and temperate forest plots. We found that Net Relatedness Index (NRI) and Nearest Taxon Index (NTI) values were generally lower with geographically broad species pools (global and Asian species pools) than with an East Asian species pool, except that global species pool produced higher NTI than the East Asian species pool. The lower NRI for the global relative to the East Asian species pool may indicate an important role of intercontinental migration during the Neogene and Quaternary and climatic conservatism in shaping the deeper phylogenetic structure of tree communities in East Asia. In contrast, higher NTI for the global relative to the East Asian species pool is consistent with recent localized diversification determining the shallow phylogenetic structure. PMID- 25797421 TI - The physiological role of drug transporters. AB - Transporters comprise the largest family of membrane proteins in human organism, including members of solute carrier transporter and ATP-binding cassette transporter families. They play pivotal roles in the absorption, distribution and excretion of xenobiotic and endogenous molecules. Transporters are widely expressed in various human tissues and are routinely evaluated during the process of drug development and approval. Over the past decade, increasing evidence shows that drug transporters are important in both normal physiology and disease. Currently, transporters are utilized as therapeutic targets to treat numerous diseases such as diabetes, major depression, hypertension and constipation. Despite the steady growth of the field of transporter biology, more than half of the members in transporter superfamily have little information available about their endogenous substrate(s) or physiological functions. This review outlines current research methods in transporter studies, and summarizes the drug transporter interactions including drug-drug and drug-endogenous substrate interactions. In the end, we also discuss the therapeutic perspective of transporters based on their physiological and pathophysiological roles. PMID- 25797422 TI - Smoking-related interstitial lung disease. AB - BACKGROUND: Smoking-related interstitial lung diseases (SR-ILDs) are a heterogeneous group of diseases with major clinical significance. Reliable epidemiological data are not yet available. METHOD: Review of pertinent literature retrieved by a selective search in PubMed. RESULTS: The available data on many aspects of SR-ILDs are sparse, but recent studies on the pathophysiology and targeted treatment of these conditions have revealed ways in which clinical outcomes can be improved. Highresolution computerized tomography should be used for differential diagnosis; lung biopsy is often unnecessary. Oncogenic mutations play a role in the pathogenesis of pulmonary Langerhans-cell histiocytosis (PLCH). In the future, cladribine and vemurafenib may be treatment options for PLCH. Desquamative interstitial pneumonia (DIP) may be difficult to distinguish from respiratorybronchiolitis-associated interstitial lung disease (RB-ILD); DIP is treated with steroids and sometimes with immune suppressants. In idiopathic pulmonary fibrosis (IPF), the antifibrotic drugs pirfenidone and nintedanib can delay disease progression. Smoking is also a risk factor for combined pulmonary fibrosis and emphysema (CPFE), rheumatoid-arthritis-associated interstitial lung disease (RA-ILD), pulmonary alveolar proteinosis (PAP), acute eosinophilic pneumonia (AEP), and diffuse alveolar hemorrhage (DAH) in Goodpasture syndrome. CONCLUSION: In smokers with exertional dyspnea and/or a nonproductive cough, SR ILDs must be considered in the differential diagnosis. If an SR-ILD is suspected, the patient should be referred to a pulmonary specialist. Early treatment and smoking cessation can improve clinical outcomes, particularly in the acute and chronically progressive types of SR-ILD. PMID- 25797424 TI - Adrenaline as the medication of choice. PMID- 25797423 TI - Long-term follow-up after allogeneic stem cell transplantation. AB - BACKGROUND: Over 3000 persons undergo allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in Germany every year. Advances in allo-HSCT have prolonged the survival of treated patients but have concomitantly increased the risk of long-term complications that impair their quality of life. METHODS: This literature review of the long-term sequelae of allo-HSCT is based on pertinent articles that were retrieved by a selective search of PubMed, and on current international guidelines. Case reports were excluded from consideration. RESULTS: Hardly any randomized clinical trials have been performed to investigate the long term outcome of allo-HSCT, but international consensus-based guidelines have been published. 50% to 70% of patients treated with allo-HSCT develop chronic graft versus-host disease (cGVHD) within ten years of treatment. Transplant recipients are at higher risk of infection, including the reactivation of dormant herpes viruses; therefore, vaccination is recommended, as described in the current guidelines. Gonadal dysfunction arises in up to 92% of men and up to 99% of women; its frequency depends on the timing of transplantation, on radiotherapy, and on other factors. The medications that transplant recipients need to take can impair liver function, and transfusionassociated hemosiderosis can do so as well. 40% to 50% of patients suffer from lipid metabolic disturbances that increase the risk of myocardial infarction, peripheral arterial occlusive disease, and stroke. Their life expectancy is shorter than that of the overall population. CONCLUSION: Measures should be taken to prevent the potential long-term complications of allo HSCT. All patients who have been treated with allo-HSCT should receive individualized, risk-adapted, and multidisciplinary follow-up care, so that any complications that arise can be correctly diagnosed and appropriately treated. Long-term follow-up care could be improved by prospective clinical trials investigating the long-term sequelae of allo-HSCT, as well as by consistent, uniform documentation of these sequelae in supraregional data registries. PMID- 25797425 TI - Not all legumes are triggers. PMID- 25797426 TI - In reply. PMID- 25797427 TI - Ultrasound-based therapies not mentioned. PMID- 25797428 TI - In reply. PMID- 25797430 TI - Transient Visual Hallucinations due to Posterior Callosal Stroke. AB - BACKGROUND: Stroke of the corpus callosum is uncommon, known to be associated with disturbance of higher brain function including hemifacial metamorphosia, but has never been reported to cause visual hallucinations. METHODS: We report on a case of a 71-year-old woman who presented to the emergency department with a 3 day history of intermittent, formed visual hallucinations in the left visual field, often triggered by eye closure or darkness. RESULTS: Neurologic examination was normal including cognition and affect, visual acuity, and visual fields. Electroencephalogram was normal. Magnetic resonance imaging scan of her brain showed a small stroke in the right inferior forceps major. Hallucinations resolved on day 2 of her admission, and she remains well more than a year later. CONCLUSIONS: This is the first report of transient visual hallucinations after a callosal stroke, which is an uncommon territory of stroke and a rare presentation of stroke. PMID- 25797429 TI - Branch-duct intraductal papillary mucinous neoplasm and embolic stroke of unknown cause. AB - BACKGROUND: In many embolic strokes, the specific embolic source might be uncertain. When we found asymptomatic branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) in patients with ischemic stroke of unknown cause, most of gastroenterologists might undervalue it as a potential thromboembolic sources. METHODS: We report 4 patients with embolic stroke of unknown cause and incidental BD-IPMNs. RESULTS: Magnetic resonance imaging revealed multiple embolic infarctions. Recommended cardiac examinations, such as 24-hour Holter monitoring and transthoracic and transesophageal echocardiography, were normal. Other cancer markers and molecular markers of hypercoagulopathy were normal. On abdominal computed tomography scan, performed to detect hidden malignancy, a low attenuated lesion with a diameter of less than 3 cm was observed in the pancreas. CONCLUSION: Although BD-IPMNs are associated with a lower rate of malignancy than main-duct IPMNs, the BD-IPMNs had some malignant potential and frequently coexist with extrapancreatic or intrapancreatic cancers. Therefore, we suggest that, in some cases, the BD-IPMNs might be considered as a thromboembolic source. PMID- 25797431 TI - The application of ultrasonic velocity vector imaging technique of carotid plaque in predicting large-artery atherosclerotic stroke. AB - BACKGROUND: Large-artery atherosclerotic stroke (LAAs) is related to carotid plaque, but the mechanical mechanism is unclear. We aimed to use ultrasonic velocity vector imaging (VVI) technique to study the mechanical difference of carotid plaque in patients with LAAs and controls. METHODS: We enrolled 43 LAAs patients and 38 controls but all showing plaque on carotid ultrasonography. Ultrasonic VVI technique was used to analyze radial systolic and diastolic peak velocity (R-vs, R-vd), radial and circumferential peak strain (R-s, C-s) and radial displacement (R-dis) of carotid plaque. RESULTS: Compared with controls, LAAs patients showed higher pulse pressure (P = .001), pulse pressure index (PPI, P = .006), and greater stress at carotid plaque as manifested by higher absolute value of radial diastolic peak velocity (R-vd, P = .021), radial systolic peak velocity (R-vs, P = .007), radial peak strain (R-s, P = .015), and radial displacement (R-dis, P = .022). PPI was significantly correlated with R-vs (r = .274, P = .013), R-vd (r = .304, P = .006), and R-dis (r = -.28, P = .011). But there was no correlation between R-s and blood pressure. R-s was screened to be the most predictable parameters for LAAs (odds ratio, 1.118; 95% confidence interval, 1.012~1.236; P = .029). The area under the curve of R-s was .627. CONCLUSIONS: Radial peak strain (R-s) is a predictable parameter for the occurrence of LAAs. We predict using ultrasonic VVI technique to analyze whether the mechanics of carotid plaque is helpful to screen patients with high risks of LAAs. PMID- 25797432 TI - Ethics and equity in research priority-setting: stakeholder engagement and the needs of disadvantaged groups. AB - A transparent and evidence-based priority-setting process promotes the optimal use of resources to improve health outcomes. Decision-makers and funders have begun to increasingly engage representatives of patients and healthcare consumers to ensure that research becomes more relevant. However, disadvantaged groups and their needs may not be integrated into the priority-setting process since they do not have a "political voice" or are unable to organise into interest groups. Equitable priority-setting methods need to balance patient needs, values, experiences with population-level issues and issues related to the health system. PMID- 25797433 TI - Suicidal ideation among patients with Behcet's syndrome. AB - OBJECTIVES: To evaluate the frequency of suicidal ideation among Behcet's syndrome (BS) patients compared to healthy and diseased controls and to delineate possible factors predicting an increase in suicidal ideation. METHODS: We included consecutive BS patients attending our outpatient clinic, patients with ankylosing spondylitis (AS) and healthy hospital staff as controls. Suicidal ideation was assessed by a standard questionnaire. Linear regression was used to identify the factors associated with suicidal ideation, such as demographic and clinical features, drugs, disease activity assessed using the Behcet's disease current activity form (BDCAF) for BS patients and BASDAI for AS patients, Behcet's disease quality of life (BDQoL) and Beck depression inventory (BDI) score. RESULTS: We surveyed 303 BS patients, 52 AS patients and 106 healthy controls. Suicidal thoughts, as reflected by a positive response to the first three items of the questionnaire, were higher among BS patients with major organ involvement (42%) than those with mucocutaneous involvement (35%) and the control groups. There were significantly more BS patients with active major organ involvement who had thought to terminate their lives without plans within the last year (25.5%) compared to those with active mucocutaneous involvement (8.7%) and active AS patients (10%) (p=0.012). Patient-reported joint pain (beta=-0.155, p=0.046), BDQoL (beta=0.176, p=0.032), and BDI (beta=0.017, p<0.0001) scores, suicidal thoughts before the onset of BS (beta=-0.124, p=0.043), neurologic involvement (beta=0.119, p=0.047) and past prednisone use (beta=0.212, p=0.005) were independent predictors of suicidal thoughts. CONCLUSIONS: BS patients with major organ involvement have increased thoughts of suicide during the active stages of their disease. A number of risk factors could help physicians to identify patients with increased suicidal thoughts. PMID- 25797434 TI - Reductive behaviour of acid azo dye based wastewater: Biocatalyst activity in conjunction with enzymatic and bio-electro catalytic evaluation. AB - Present study illustrates the significance of biocatalyst's reductive behaviour in the degradation of dye molecules using glucose as co-substrate. An anaerobic system was operated at a dye concentration of 50mg/l with an organic loading rate (OLR) of 1.36 kg COD/m(3)-day. Decolourization and COD removal efficiencies were observed to be 42% and 48% respectively. Azo reductase (18.9 U) and dehydrogenase enzyme (1.4 MUg/ml) activities showed increment with operation time. Anaerobic microenvironment showed dye reduction converting them into aromatic amines. The presence of mediators viz., cytochromes, quinines and Fe-S proteins depicted in the cyclic voltammetry profiles played a crucial role in transfer of electrons for the reduction of dye molecules. Bio-electro kinetic profiles obtained through Tafel analysis showed persistent reduction behaviour, which is in good correlation with dye degradation in the anaerobic microenvironment. PMID- 25797435 TI - Removal of N-nitrosamines in a membrane bioreactor and nanofiltration hybrid system for municipal wastewater reclamation: Process efficiency and mechanisms. AB - This study investigated the removal efficiency and mechanisms of water contaminants (mainly N-nitrosamines) during municipal wastewater reclamation by a membrane bioreactor (MBR) and nanofiltration (NF) hybrid system. The removal of bulk water contaminants was governed by the microbial activities in the MBR and molecular weight cut-off (MWCO) of the NF membranes. The removal of N nitrosamines by the MBR was primarily attributed to biodegradation by aerobic bacteria, which can be determined by the reactivity of the amine functional groups with the catabolic enzymes (removal efficiency=45-84%). Adsorption and formation of membrane fouling can enhance the removal of N-nitrosamines by the NF membranes. However, size-exclusion is found to play a major role in the removal of N-nitrosamines by the NF membranes since the removal efficiencies of N nitrosamines varied significantly depending on molecular weight of the N nitrosamines and MWCO of the NF membranes (removal efficiency: NE90>NE70). PMID- 25797436 TI - Structural predictions of neurobiologically relevant G-protein coupled receptors and intrinsically disordered proteins. AB - G protein coupled receptors (GPCRs) and intrinsic disordered proteins (IDPs) are key players for neuronal function and dysfunction. Unfortunately, their structural characterization is lacking in most cases. From one hand, no experimental structure has been determined for the two largest GPCRs subfamilies, both key proteins in neuronal pathways. These are the odorant (450 members out of 900 human GPCRs) and the bitter taste receptors (25 members) subfamilies. On the other hand, also IDPs structural characterization is highly non-trivial. They exist as dynamic, highly flexible structural ensembles that undergo conformational conversions on a wide range of timescales, spanning from picoseconds to milliseconds. Computational methods may be of great help to characterize these neuronal proteins. Here we review recent progress from our lab and other groups to develop and apply in silico methods for structural predictions of these highly relevant, fascinating and challenging systems. PMID- 25797437 TI - IKKbeta/NF-kappaB mediated the low doses of bisphenol A induced migration of cervical cancer cells. AB - Cervical cancer is considered as the second most common female malignant disease. There is an urgent need to illustrate risk factors which can trigger the motility of cervical cancer cells. Our present study revealed that nanomolar concentration of bisphenol A (BPA) significantly promoted the in vitro migration and invasion of cervical cancer HeLa, SiHa, and C-33A cells. Further, BPA treatment increased the expression of metalloproteinase-9 (MMP-9) and fibronectin (FN) in both HeLa and SiHa cells, while did not obviously change the expression of MMP-2, vimentin (Vim) or N-Cadherin (N-Cad). BAY 11-7082, the inhibitor of NF-kappaB, significantly abolished BPA induced up regulation of FN and MMP-9 in cervical cancer cells. While the inhibitors of PKA (H89), ERK1/2 (PD 98059), EGFR (AG1478), or PI3K/Akt (LY294002) had no effect on the expression of either FN or MMP-9. BPA treatment rapidly increased the phosphorylation of both IkappaBalpha and p65, stimulated nuclear translocation, and up regulated the promoter activities of NF-kappaB. The BPA induced up regulation of MMP-9 and FN and activation of NF-kappaB were mediated by phosphorylation of IKKbeta via PKC signals. Collectively, our study found for the first time that BPA stimulated the cervical cancer migration via IKK-beta/NF-kappaB signals. PMID- 25797439 TI - An integrated view of redox and catalytic properties of B-type PpDyP from Pseudomonas putida MET94 and its distal variants. AB - PpDyP from Pseudomonas putida MET94 is an extremely versatile B-type dye decolourising peroxidase (DyP) capable of efficient oxidation of a wide range of anthraquinonic and azo dyes, phenolic substrates, the non-phenolic veratryl alcohol and even manganese and ferrous ions. In reaction with H2O2 it forms a stable Compound I at a rate of (1.4+/-0.3)*10(6)M(-1)s(-1), comparable to those of classical peroxidases and other DyPs. We provide the first report of standard redox potential (E(0')) of the Compound I/Native redox couple in a DyP-type peroxidase. The value of E(0')Cpd I/N=1.10+/-0.04 (V) is similar to those found in peroxidases from the mammalian superfamily but higher than in peroxidases from the plant superfamily. Site-directed mutagenesis has been used to investigate the role of conserved distal residues, i.e. to replace aspartate 132 by asparagine, and arginine 214 and asparagine 136 by leucine. The structural, redox and catalytic properties of variants are addressed by spectroscopic, electrochemical and kinetic measurements. Our data point to the importance of the distal arginine in the catalytic mechanism of PpDyP, as also observed in DyPB from Rhodococcus jostii RHA1 but not in DyPs from the A and D subfamilies. This work reinforces the idea of existence of mechanistic variations among members of the different sub-families of DyPs with direct implications for their enzymatic properties and potential for biotechnological applications. PMID- 25797438 TI - Computational strategies for the design of new enzymatic functions. AB - In this contribution, recent developments in the design of biocatalysts are reviewed with particular emphasis in the de novo strategy. Studies based on three different reactions, Kemp elimination, Diels-Alder and Retro-Aldolase, are used to illustrate different success achieved during the last years. Finally, a section is devoted to the particular case of designed metalloenzymes. As a general conclusion, the interplay between new and more sophisticated engineering protocols and computational methods, based on molecular dynamics simulations with Quantum Mechanics/Molecular Mechanics potentials and fully flexible models, seems to constitute the bed rock for present and future successful design strategies. PMID- 25797441 TI - Altering the substrate specificity of methyl parathion hydrolase with directed evolution. AB - Many organophosphates (OPs) are used as pesticides in agriculture. They pose a severe health hazard due to their inhibitory effect on acetylcholinesterase. Therefore, detoxification of water and soil contaminated by OPs is important. Metalloenzymes such as methyl parathion hydrolase (MPH) from Pseudomonas sp. WBC 3 hold great promise as bioremediators as they are able to hydrolyze a wide range of OPs. MPH is highly efficient towards methyl parathion (1 * 10(6) s(-1) M(-1)), but its activity towards other OPs is more modest. Thus, site saturation mutagenesis (SSM) and DNA shuffling were performed to find mutants with improved activities on ethyl paraxon (6.1 * 10(3) s(-1) M(-1)). SSM was performed on nine residues lining the active site. Several mutants with modest activity enhancement towards ethyl paraoxon were isolated and used as templates for DNA shuffling. Ultimately, 14 multiple-site mutants with enhanced activity were isolated. One mutant, R2F3, exhibited a nearly 100-fold increase in the kcat/Km value for ethyl paraoxon (5.9 * 10(5) s(-1) M(-1)). These studies highlight the 'plasticity' of the MPH active site that facilitates the fine-tuning of its active site towards specific substrates with only minor changes required. MPH is thus an ideal candidate for the development of an enzyme-based bioremediation system. PMID- 25797440 TI - Oxidative stress and redox regulation on hippocampal-dependent cognitive functions. AB - Hippocampal-dependent cognitive functions rely on production of new neurons and maintenance of dendritic structures to provide the synaptic plasticity needed for learning and formation of new memories. Hippocampal formation is exquisitely sensitive to patho-physiological changes, and reduced antioxidant capacity and exposure to low dose irradiation can significantly impede hippocampal-dependent functions of learning and memory by reducing the production of new neurons and alter dendritic structures in the hippocampus. Although the mechanism leading to impaired cognitive functions is complex, persistent oxidative stress likely plays an important role in the SOD-deficient and radiation-exposed hippocampal environment. Aging is associated with increased production of pro-oxidants and accumulation of oxidative end products. Similar to the hippocampal defects observed in SOD-deficient mice and mice exposed to low dose irradiation, reduced capacity in learning and memory, diminishing hippocampal neurogenesis, and altered dendritic network are universal in the aging brains. Given the similarities in cellular and structural changes in the aged, SOD-deficient, and radiation-exposed hippocampal environment and the corresponding changes in cognitive decline, understanding the shared underlying mechanism will provide more flexible and efficient use of SOD deficiency or irradiation to model age related changes in cognitive functions and identify potential therapeutic or intervention methods. PMID- 25797442 TI - Quantum dot single-photon switches of resonant tunneling current for discriminating-photon-number detection. AB - Low-noise single-photon detectors that can resolve photon numbers are used to monitor the operation of quantum gates in linear-optical quantum computation. Exactly 0, 1 or 2 photons registered in a detector should be distinguished especially in long-distance quantum communication and quantum computation. Here we demonstrate a photon-number-resolving detector based on quantum dot coupled resonant tunneling diodes (QD-cRTD). Individual quantum-dots (QDs) coupled closely with adjacent quantum well (QW) of resonant tunneling diode operate as photon-gated switches- which turn on (off) the RTD tunneling current when they trap photon-generated holes (recombine with injected electrons). Proposed electron-injecting operation fills electrons into coupled QDs which turn "photon switches" to "OFF" state and make the detector ready for multiple-photons detection. With proper decision regions defined, 1-photon and 2-photon states are resolved in 4.2 K with excellent propabilities of accuracy of 90% and 98% respectively. Further, by identifying step-like photon responses, the photon number-resolving capability is sustained to 77 K, making the detector a promising candidate for advanced quantum information applications where photon-number states should be accurately distinguished. PMID- 25797443 TI - Electromechanical cell lysis using a portable audio device: enabling challenging sample preparation at the point-of-care. AB - Audio sources are ubiquitously available on portable electronic devices, including cell phones. Here we demonstrate lysis of Mycobacterium marinum and Staphylococcus epidermidis bacteria utilizing a portable audio device coupled with a simple and inexpensive electromagnetic coil. The resulting alternating magnetic field rotates a magnet in a tube with the sample and glass beads, lysing the cells and enabling sample preparation for these bacteria anywhere there is a cell phone, mp3 player, laptop, or other device with a headphone jack. PMID- 25797445 TI - Focus on tracheostomy. PMID- 25797444 TI - Preclinical study of SZ2080 material 3D microstructured scaffolds for cartilage tissue engineering made by femtosecond direct laser writing lithography. AB - Over the last decade DLW employing ultrafast pulsed lasers has become a well established technique for the creation of custom-made free-form three-dimensional (3D) microscaffolds out of a variety of materials ranging from proteins to biocompatible glasses. Its potential applications for manufacturing a patient's specific scaffold seem unlimited in terms of spatial resolution and geometry complexity. However, despite few exceptions in which live cells or primitive organisms were encapsulated into a polymer matrix, no demonstration of an in vivo study case of scaffolds generated with the use of such a method was performed. Here, we report a preclinical study of 3D artificial microstructured scaffolds out of hybrid organic-inorganic (HOI) material SZ2080 fabricated using the DLW technique. The created 2.1 * 2.1 * 0.21 mm(3) membrane constructs are tested both in vitro by growing isolated allogeneic rabbit chondrocytes (Cho) and in vivo by implanting them into rabbit organisms for one, three and six months. An ex vivo histological examination shows that certain pore geometry and the pre-growing of Cho prior to implantation significantly improves the performance of the created 3D scaffolds. The achieved biocompatibility is comparable to the commercially available collagen membranes. The successful outcome of this study supports the idea that hexagonal-pore-shaped HOI microstructured scaffolds in combination with Cho seeding may be successfully implemented for cartilage tissue engineering. PMID- 25797446 TI - Facial transplantation: historical developments and future directions. AB - OBJECTIVE: To present the clinical outcomes obtained by the first facial transplant teams worldwide, reviewing current practice and addressing controversies. METHODS: A bibliographic search of Medline and Embase databases was performed, and a comparative analysis of all articles published from 1980 to the present was conducted. Two independent investigators screened the manuscripts in accordance with pre-defined criteria. RESULTS: A total of 12 partial and 5 full facial transplants were recorded in the literature. Procedures included partial and near-total facial myocutaneous flaps, and complex osteomyocutaneous grafts. Fifteen patients had fully vascularised grafts, and two patients died of transplant-related and infectious complications. CONCLUSION: Facial transplantation can restore quality of life and enable the social re-integration of recipients. Results published by the first facial transplant teams are promising. However, long-term reports of aesthetic and functional outcomes are needed to more precisely define outcomes. In addition, significant technical, medical and ethical issues remain to be solved. PMID- 25797447 TI - Immunoglobulin G4 related chronic sclerosing sialadenitis. AB - BACKGROUND: ENT surgeons may be the first specialists to encounter and diagnose patients with salivary gland disease. A new entity involving the salivary glands has recently been described of which ENT surgeons need to be aware: immunoglobulin G4 related chronic sclerosing sialadenitis. METHOD: A literature search of Medline, Embase and Cochrane Library databases was performed, using the search terms 'IgG4', 'hyperIgG4 syndrome' and 'IgG4 related chronic sclerosing sialadenitis'. RESULTS: Knowledge concerning immunoglobulin G4 related chronic sclerosing sialadenitis is rapidly increasing. This new entity is part of a fibro inflammatory corticosteroid-responsive systemic disease (immunoglobulin G4 related disease) and has been described in almost every organ. Biopsy of the submandibular gland can be diagnostic. However, the diagnosis can easily be overlooked if: clinical suspicion is not high, one is unaware of the classical morphology and/or immunoglobulin G4 staining is not performed. This paper presents a summary of the current understanding of the disease and its management. CONCLUSION: ENT surgeons should be aware of this new disease entity. Patients with systemic disease should be managed under a multidisciplinary team, with input from clinicians who have an interest in such diseases (such as gastroenterologists and rheumatologists), and input from histopathologists and radiologists. PMID- 25797448 TI - Litigation in English rhinology. AB - OBJECTIVE: Litigation is a rising financial burden on the National Health Service. This study aims to show if litigation is increasing in rhinology and which procedures lead to the most claims. METHODS: Ten years of data were obtained from the National Health Service Litigation Authority. Rhinology claims were examined for cost, injury, diagnosis and operation type. RESULTS: Of the 123 rhinology claims identified, 52 per cent were successful. There was a 56 per cent increase in the average annual number of claims between the first half of the study period and the second (p = 0.0451). The commonest reasons for a claim were poor cosmesis (15.6 per cent) and lack of informed consent (14 per cent). CONCLUSION: The number of claims in rhinology increased over the study period. Most claims resulted from poor cosmetic outcome, lack of consent or recognised complications. It is suggested that enhanced communication and management of patient expectations could reduce litigation and improve patient satisfaction. PMID- 25797449 TI - Customising the length of the Montgomery T-tube whilst retaining a bevelled edge. AB - BACKGROUND: The Montgomery T-tube is used in a number of conditions that require safe tracheal stenting. Specific lengths of T-tube limbs are occasionally needed in patients with complex airway anatomy or differing neck proportions; this requires customisation of the T-tube limbs. This is done either by pre-ordering customised T-tubes from the manufacturer (which needs to be planned ahead of time) or using a tube cutter in the operating theatre. However, the latter does not provide a 'factory like' bevelled edge when shortened, which increases the risk of mucosal trauma and granulation formation. OBJECTIVE: This paper reports a novel technique for customising the length of existing Montgomery T-tubes, with preservation of the bevelled edges. This technique can be easily performed with basic equipment available in operating theatres. PMID- 25797450 TI - Rare giant frontal sinus osteoma mimicking fibrous dysplasia. AB - OBJECTIVE: To present the first report of a giant frontal sinus osteoma treated by excision and single-stage reconstruction with custom-made titanium cranioplasty and left orbital roof prostheses. CASE REPORT: A 31-year-old man with a history of chronic frontal sinusitis presented with a deforming, painless, midline forehead swelling of 11 years' duration, which had been treated unsuccessfully in Nigeria. Differential diagnosis included both benign and malignant bony tumours. Computerised tomography revealed a giant bony frontal sinus tumour extending beyond the sinus roof and breaching the left orbit, consistent with fibrous dysplasia. Given the extent of the tumour, open craniectomy was performed for surgical extirpation. Histological analysis identified multiple osteomas. This surgical approach achieved excellent cosmesis, with no evidence of recurrence at 12-month follow up. CONCLUSION: Forehead swelling may pose diagnostic and management dilemmas for the ENT surgeon; however, effective management is facilitated by a multidisciplinary approach. PMID- 25797451 TI - Recurrent epistaxis in a nine-year-old boy: benign or malignant? AB - OBJECTIVE: We present the case of a rare cause of epistaxis in a paediatric patient, together with the diagnostic and management challenges associated with this condition. CASE REPORT: A previously well nine-year-old boy presented with a six-month history of intermittent unilateral epistaxis. Radiological investigation and endoscopic biopsy confirmed a highly malignant nasopharyngeal mass consistent with carcinoma. The tumour continued to grow rapidly. Whilst awaiting intervention, the patient experienced a further significant haemorrhage requiring surgical intervention. CONCLUSION: Nasopharyngeal carcinoma is a rare cause of epistaxis amongst children in the UK. Early flexible nasendoscopy can help delineate both benign and sinister causes of symptoms in this region. PMID- 25797452 TI - Correction: ATP dephosphorylation can be either enhanced or inhibited by pH controlled interaction with a dendrimer molecule. PMID- 25797453 TI - Kinetics of colloidal deposition, assembly, and crystallization in steady electric fields. AB - We quantify and model the deposition and crystallization kinetics of initially dilute colloidal spheres due to application of a steady, direct current electric field in the thin gap between parallel electrodes. The system studied is poly(12 hydroxystearic acid) (PHSA)-stabilized poly(methyl methacrylate) (PMMA) spheres dispersed in a mixture of cyclohexylbromide (CHB), decalin, and a low concentration of the partially disassociating salt tetrabutylammonium chloride (TBAC). The temporal and spatial evolution of the colloidal volume fraction in the ~1 mm gap between the electrodes is quantified under conditions of both deposition and relaxation by confocal laser scanning microscopy (CLSM). During deposition assembly, the spatial dependence of the colloid volume fraction approaches steady state at times between hundreds of minutes at the lowest electric field strength (as characterized by a Peclet number, Pe) and at tens of minutes at higher field strengths. During disassembly, the volume fraction relaxes nearly exponentially. The kinetics are modeled by adapting a treatment for sedimentation (Davis and Russel, Phys. Fluids A, 1989, 1, 82) to the case of steady electric fields. The model's predictions show good agreement with the measured kinetics at low Pe; however, agreement progressively deteriorates with increasing Pe. At low Pe the deposits are initially disordered. After an initial delay, 1D crystal growth propagates from the electrode surface at rates of several hundred nm min(-1). The sharp crystal boundary propagates as a characteristic of constant colloidal volume fraction, consistent with an equilibrium crystalline phase transition. The results inform operational ranges for devices that produce active colloidal matter by reversible assembly. PMID- 25797454 TI - Losses as ecological guides: minor losses lead to maximization and not to avoidance. AB - Losses are commonly thought to result in a neuropsychological avoidance response. We suggest that losses also provide ecological guidance by increasing focus on the task at hand, and that this effect may override the avoidance response. This prediction was tested in a series of studies. In Study 1a we found that minor losses did not lead to an avoidance response. Instead, they guided participants to make advantageous choices (in terms of expected value) and to avoid disadvantageous choices. Moreover, losses were associated with less switching between options after the first block of exploration. In Study 1b we found that this effect was not simply a by-product of the increase in visual contrast with losses. In Study 1c we found that the effect of losses did not emerge when alternatives did not differ in their expected value but only in their risk level. In Study 2 we investigated the autonomic arousal dynamics associated with this behavioral pattern via pupillometric responses. The results showed increased pupil diameter following losses compared to gains. However, this increase was not associated with a tendency to avoid losses, but rather with a tendency to select more advantageously. These findings suggest that attention and reasoning processes induced by losses can out-weigh the influence of affective processes leading to avoidance. PMID- 25797455 TI - Deciding on race: a diffusion model analysis of race-categorisation. AB - It has long been known that a person's race can affect their decisions about people of another race; an observation that clearly taps into some deep societal issues. However, in order to behave differently in response to someone else's race, you must first categorise that person as other-race. The current study investigates the process of race-categorisation. Two groups of participants, Asian and Caucasian, rapidly classified facial images that varied from strongly Asian, through racially intermediate, to strongly Caucasian. In agreement with previous findings, there was a difference in category boundary between the two groups. Asian participants more frequently judged intermediate images as Caucasian and vice versa. We fitted a decision model, the Ratcliff diffusion model, to our two choice reaction time data. This model provides an account of the processes thought to underlie binary choice decisions. Within its architecture it has two components that could reasonably lead to a difference in race category boundary, these being evidence accumulation rate and a priori bias. The latter is the expectation or prior belief that a participant brings to the task, whilst the former indexes sensitivity to race-dependent perceptual cues. Whilst we find no good evidence for a difference in a priori bias between our two groups, we do find evidence for a difference in evidence accumulation rate. Our Asian participants were more sensitive to Caucasian cues within the images than were our Caucasian participants (and vice versa). These results support the idea that differences in perceptual sensitivity to race-defining visual characteristics drive differences in race categorisation. We propose that our findings fit with a wider view in which perceptual adaptation plays a central role in the visual processing of own and other race. PMID- 25797456 TI - Context-driven expectations about focus alternatives. AB - What is conveyed by a sentence frequently depends not only on the descriptive content carried by its words, but also on implicit alternatives determined by the context of use. Four visual world eye-tracking experiments examined how alternatives are generated based on aspects of the discourse context and used in interpreting sentences containing the focus operators only and also. Experiment 1 builds on previous reading time studies showing that the interpretations of only sentences are constrained by alternatives explicitly mentioned in the preceding discourse, providing fine-grained time course information about the expectations triggered by only. Experiments 2 and 3 show that, in the absence of explicitly mentioned alternatives, lexical and situation-based categories evoked by the context are possible sources of alternatives. While Experiments 1-3 all demonstrate the discourse dependence of alternatives, only explicit mention triggered expectations about alternatives that were specific to sentences with only. By comparing only with also, Experiment 4 begins to disentangle expectations linked to the meanings of specific operators from those generalizable to the class of focus-sensitive operators. Together, these findings show that the interpretation of sentences with focus operators draws on both dedicated mechanisms for introducing alternatives into the discourse context and general mechanisms associated with discourse processing. PMID- 25797457 TI - Effects of waterlogging on carbon assimilate partitioning in the Zoige alpine wetlands revealed by 13CO2 pulse labeling. AB - Waterlogging has been suggested to affect carbon (C) turnover in wetlands, but how it affects C allocation and stocks remains unclear in alpine wetlands. Using in situ (13)CO2 pulse labelling, we investigated C allocation in both waterlogged and non-waterlogged sites in the Zoige wetlands on the Tibetan Plateau in August 2011. More than 50% of total (13)C fixed by photosynthesis was lost via shoot respiration. Shoots recovered about 19% of total (13)C fixed by photosynthesis at both sites. Only about 26% of total fixed (13)C was translocated into the belowground pools. Soil organic C pool accounted for 19% and roots recovered about 5-7% of total fixed (13)C at both sites. Waterlogging significantly reduced soil respiration and very little (13)C was lost via soil respiration in the alpine wetlands compared to that in grasslands. We conclude that waterlogging did not significantly alter C allocations among the C pools except the (13)CO2 efflux derived from soil respiration and that shoots made similar contributions to C sequestration as the belowground parts in the Zoige alpine wetlands. Therefore, changes in waterlogging due to climate change will not affect C assimilate partitioning but soil C efflux. PMID- 25797458 TI - Relationship between findings of mandibular cortical bone in inferior border and bone mineral densities of lumbar vertebrae in postmenopausal women. AB - It is important to assess the general bone condition in dental implant treatment. The relationships between the bone mineral densities (BMDs) of lumbar vertebrae and mandibular cortical bone condition in the inferior border using multi-slice computed tomography (CT) were assessed in postmenopausal women. If a strong correlation between them is obtained, the mandibular cortical bone condition may be useful to evaluate the general bone condition. Twenty-two postmenopausal women were enrolled in this investigation. The maximum CT value and width of the mandibular cortical bone (MCW-MSCT) were measured, and the mandibular cortical bone index (MCI-MSCT) was classified using multi-slice CT. BMDs of lumbar vertebrae were measured using dual energy X-ray absorptiometry (DXA), and then the percentage of the young adult mean (YAM) was analyzed. The correlations were investigated between the mandibular cortical bone condition and values of lumbar vertebrae. Weak correlations were observed between MCW-MSCT and the percentage of YAM. Also, significant differences in the percentage of YAM were noted between types of MCI-MSCT. The mandibular cortical bone index (MCI-MSCT) in the inferior border using multi-slice CT may be applicable to evaluate the influence of the general bone condition. PMID- 25797459 TI - A histological study of mineralised tissue formation around implants with 3D culture of HMS0014 cells in Cellmatrix Type I-A collagen gel scaffold in vitro. AB - We cultured HMS0014 Yub621b cells within a 3D collagen gel scaffold (Cellmatrix Type I-A) and aimed to study the fate and contribution of human bone-derived mesenchymal stem cells (MSCs) in the guided bone regeneration(GBR)-engineered tissue which has developed around the titanium (Ti) test dental implant (IP) in vitro. The light microscopy (LM) and transmission electron microscopy (TEM) results of the peri-IP tissue indicated that collagen fibrils of the Cellmatrix Type I-A gel were accumulated and fabricated to provide a 3D meshwork for proliferation and differentiation of the HMS0014 cells in the top (cell) layer; mineralisation of the GBR tissue had commenced since day 1 and became markedly deposited between days 7 and 14 of the experiment. TEM observation revealed sedimentation of cement line at the periphery of the interwoven Cellmatrix fibres and fibrils in the ECM scaffold of the GBR tissue; matrix vesicle-mediated and appositional collagen-mediated mineralisation were identified in the peri-IP ECM scaffold. The fine structure study of the plurimorphic osteoblast(Ob)-like osteogeneic cells demonstrated numerous membranous organelles related with vesicular trafficking, secretion and endocytosis in the cytoplasm; well-developed cytoskeleton networks and intercellular junctional complexes were also observed. The specimens on fluorescence immunohistochemistry (IHC) by confocal laser scanning microscopy (LSM) showed the expression of LC3 and Cx43 associated with autophagic-lysosomal degeneration pathway and signal conduction mediated with gap junctions (GJS) in maintaining tissue homeostasis of the Ob-like cells which grew and degenerated in the 3D scaffold. Results from this in vitro study suggest that Ob-like HMS0014 cells actively regulate turnover of the peri-IP ECM to recapitulate the development and formation of osteoid tissue-engineered material which might contribute to augment osseointegration around the dental implant. PMID- 25797460 TI - Anatomical study of the coexistence of the postaortic left brachiocephalic vein with the postaortic left renal vein with a review of the literature. AB - In a student course of gross anatomy dissection at Kanagawa Dental University in 2009, we found an extremely rare case of the coexistence of the postaortic left brachiocephalic vein with the postaortic left renal vein of a 73-year-old Japanese male cadaver. The left brachiocephalic vein passes behind the ascending aorta and connects with the right brachiocephalic vein, and the left renal vein passes behind the abdominal aorta. These two anomalous cases mentioned above have been reported respectively. There have been few reports discussing coexistence of the postaortic left brachiocephalic vein with the postaortic left renal vein. We discuss the anatomical and embryological aspect of this anomaly with reference in the literature. PMID- 25797461 TI - Predictive factors of survival and treatment tolerance in older patients treated with chemotherapy and radiotherapy for locally advanced head and neck cancer. AB - PURPOSE: To report outcomes and predictive factors of overall survival, hospitalization and treatment completion rates in elderly patients with locally advanced head and neck cancer treated with concurrent chemoradiotherapy (CRT). MATERIAL AND METHODS: A retrospective analysis of patients aged 70years or older treated with concurrent CRT for locally advanced head and neck cancer was conducted. Univariate and multivariate analysis as well as competing risk survival analysis were used to determine predictors of mortality. Logistic regression was used to predict for hospitalization and treatment completion rates. RESULTS: In total, 129 patients were included. Median follow-up was 27months (range: 1.7-125months). Completion rate of combined CRT was 84%. Actuarial OS and DSS at 4years were 56% and 75%. Hospitalization rate was 36%. On multivariate analysis, a Karnofsky performance status (KPS) ?80 was predictive of mortality. Using competing risks, KPS ?80 and weight loss >5% were predictive of cancer mortality whereas Charlson score ?3 was predictive of mortality due to other causes. On logistic regression, patients with abnormal renal function and lower body mass index were more likely to be hospitalized during their treatment course. Charlson score and chemotherapy regimen were predictive of treatment completion. CONCLUSION: Concurrent CRT may be a feasible treatment option for healthier older patients at the cost of high hospitalization rates. Pre-treatment factors linked to physiological age such as KPS ?80, Charlson score ?3, abnormal renal function should be considered at the time of treatment decision. PMID- 25797462 TI - Necitumumab for the treatment of stage IV metastatic squamous non-small-cell lung cancer. AB - Over the past two decades, progress in the treatment of patients with metastatic squamous non-small-cell lung cancer has been limited. The EGFR is involved in tumor progression and invasion and therefore it has become the target of several studies in lung cancer. Strategies to block this pathway are focused on the development of small molecule (tyrosine kinase inhibitor) and monoclonal antibodies (mAbs). Some mAbs have been studied in patients with advanced non small-cell lung cancer. For the first time, a fully human immunoglobulin G (IMC 11F8), subclass 1 (IgG1) mAb targeting the EGFR, in combination with standard chemotherapy (cisplatin + gemcitabine), has been shown to increase overall survival in chemo-naive patients with metastatic confirmed squamous cell histology. PMID- 25797464 TI - Laterality effects in motor learning by mental practice in right-handers. AB - Converging evidences suggest that mental movement simulation and actual movement production share similar neurocognitive and learning processes. Although a large body of data is available in the literature regarding mental states involving the dominant arm, examinations for the nondominant arm are sparse. Does mental training, through motor-imagery practice, with the dominant arm or the nondominant arm is equally efficient for motor learning? In the current study, we investigated laterality effects in motor learning by motor-imagery practice. Four groups of right-hander adults mentally and physically performed as fast and accurately as possible (speed/accuracy trade-off paradigm) successive reaching movements with their dominant or nondominant arm (physical-training-dominant-arm, mental-training-dominant-arm, physical-training-nondominant-arm, and mental training-nondominant-arm groups). Movement time was recorded and analyzed before, during, and after the training sessions. We found that physical and mental practice had a positive effect on the motor performance (i.e., decrease in movement time) of both arms through similar learning process (i.e., similar exponential learning curves). However, movement time reduction in the posttest session was significantly higher after physical practice than motor-imagery practice for both arms. More importantly, motor-imagery practice with the dominant arm resulted in larger and more robust improvements in movement speed compared to motor-imagery practice with the nondominant arm. No such improvements were observed in the control group. Our results suggest a superiority of the dominant arm in motor learning by mental practice. We discussed these findings from the perspective of the internal models theory. PMID- 25797463 TI - Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice. AB - We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoE(-/-)Fbn1(C1039G+/-)) develop accelerated atherosclerosis with enhanced inflammation, atherosclerotic plaque rupture, myocardial infarction and sudden death. In the brain, fibrillin-1 functions as an attachment protein in the basement membrane, providing structural support to the blood-brain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the blood-cerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoE(-/-) (n=61) and ApoE(-/-)Fbn1(C1039G+/-) (n=73) mice were fed a Western-type diet (WD). After 14 weeks WD, a significantly higher permeability of the BBB was observed in ApoE(-/-)Fbn1(C1039G+/-) mice compared to age-matched ApoE(-/-) mice. This was accompanied by leukocyte infiltration, enhanced expression of pro-inflammatory cytokines, matrix metalloproteinases and transforming growth factor-beta, and by decreased expression of tight junction proteins claudin-5 and occludin. After 20 weeks WD, 83% of ApoE(-/-)Fbn1(C1039G+/ ) mice showed xanthomas in the brain, compared to 23% of their ApoE(-/-) littermates. Xanthomas were mainly located in fibrillin-1-rich regions, such as the choroid plexus and the neocortex. Our findings demonstrate that dysfunctional fibrillin-1 impairs BBB/BCSFB integrity, facilitating peripheral leukocyte infiltration, which further degrades the BBB/BCSFB. As a consequence, lipoproteins can enter the brain, resulting in accelerated formation of xanthomas. PMID- 25797465 TI - Impaired synaptic plasticity in the visual cortex of mice lacking alpha7 nicotinic receptor subunit. AB - The primary visual cortex (V1) is the first step in visual information processing and its function may be modulated by acetylcholine through nicotinic receptors (nAChRs). Since our previous work demonstrated that visual acuity and cortical spatial resolution limit were significantly reduced in alpha7 knock-out (KO) mice in the absence of retinal alterations, we decided to characterize the contribution of homomeric alpha7 nicotinic receptors (alpha7nAChRs) to visual information processing at the cortical level. We evaluated long-term forms of synaptic plasticity in occipital slices containing V1 from alpha7 KO mice and in wild-type (WT) slices perfused with nAChRs selective blocking agents. In alpha7 KO mice slices, electrophysiological recordings demonstrated the absence of long term potentiation (LTP) and long-term depression (LTD) in layer II/III after the stimulation of different intracortical pathways (layer IV or II/III). Furthermore, the acute and selective blockade of alpha7nAChRs in slices from WT mice with either alpha-bungarotoxin or methyllycaconitine did not alter the expression of LTP and LTD. Conversely, the perfusion with the unspecific nAChRs antagonist mecamylamine impaired LTP and LTD. Our results suggest the presence of impaired synaptic plasticity in the V1 of alpha7 KO mice and indicate a different contribution of nAChRs to visual cortex function. PMID- 25797466 TI - Tandem gold-catalyzed dehydrative cyclization/diels-alder reactions: facile access to indolocarbazole alkaloids. AB - A gold-catalyzed synthesis of cyclic 2-oxodienes from readily prepared propargyl alcohols and the subsequent Diels-Alder reaction are reported. The dehydrative cyclization reactions proceeded smoothly, and the dienes formed in situ were demonstrated to undergo cycloaddition with a variety of dienophiles. This method offers a new strategy for the synthesis of indolocarbazole alkaloids, whereby the convergent synthetic design allows for differentiation between the indole nitrogens. PMID- 25797467 TI - Evaluation of GC-ICP-MS/MS as a New Strategy for Specific Heteroatom Detection of Phosphorus, Sulfur, and Chlorine Determination in Foods. AB - For the first time in the literature, application of a GC-ICP-MS/MS method for the selective and sensitive detection of specific heteroatoms of phosphorus, sulfur, and chlorine has been accomplished. As a proof of concept, organophosphorus, organosulfur, and organochlorine pesticides in various food matrices have been studied. For the detection of organophosphorus and organosulfur pesticides, oxygen was used in the collision reaction cell (CRC) to convert P (m/z 31) to PO(+) (m/z 47) and S (m/z 32) to SO(+) (m/z 48). Similarly, ClH2(+) (m/z 37) was monitored after the reaction of Cl (m/z 35) with hydrogen in the CRC for the determination of organochlorine pesticides. Real food samples (baby food purees, fresh vegetables, loose tea) were screened for their pesticide content, following preparation of triplicate extracts using QuEChERS (quick, easy, cheap, effective, rugged, and safe). Excellent linearity with correlation coefficients R >= 0.997 was achieved, and the lowest detection limits obtained for the organophosphorus, organosulfur, and organochlorine pesticides were 0.0005, 0.675, and 0.144 MUg/kg, respectively. PMID- 25797468 TI - Neuropeptide Y system in the retina: From localization to function. AB - The retina is a highly complex structure where several types of cells communicate through countless different molecules to codify visual information. Each type of cells plays unique roles in the retina, presenting a singular expression of neurotransmitters. Some neurotransmitter systems in the retina are well understood, while others need to be better explored to unravel the intricate signaling system involved. Neuropeptide Y (NPY), a 36 amino acid peptide, is one of the most common peptide neurotransmitter in the CNS and a highly conserved peptide among species. We review the localization of NPY and NPY receptors (mainly NPY Y1, Y2, Y4 and Y5) in retinal cells. Common features of the expression of NPY and NPY receptors in mammalian and non-mammalian species indicate universal roles of this system in the retina. In the present review, we highlight the putative roles of NPY receptor activation in the retina, discussing, in particular, their involvement in retinal development, neurotransmitter release modulation, neuroprotection, microglia and Muller cells function, retinal pigmented epithelium changes, retinal endothelial physiology and proliferation of retinal progenitor cells. Further studies are needed to confirm that targeting the NPY system might be a potential therapeutic strategy for retinal degenerative diseases. PMID- 25797469 TI - The free health care initiative: how has it affected health workers in Sierra Leone? AB - There is an acknowledged gap in the literature on the impact of fee exemption policies on health staff, and, conversely, the implications of staffing for fee exemption. This article draws from five research tools used to analyse changing health worker policies and incentives in post-war Sierra Leone to document the effects of the Free Health Care Initiative (FHCI) of 2010 on health workers.Data were collected through document review (57 documents fully reviewed, published and grey); key informant interviews (23 with government, donors, NGO staff and consultants); analysis of human resource data held by the MoHS; in-depth interviews with health workers (23 doctors, nurses, mid-wives and community health officers); and a health worker survey (312 participants, including all main cadres). The article traces the HR reforms which were triggered by the FHCI and evidence of their effects, which include substantial increases in number and pay (particularly for higher cadres), as well as a reported reduction in absenteeism and attrition, and an increase (at least for some areas, where data is available) in outputs per health worker. The findings highlight how a flagship policy, combined with high profile support and financial and technical resources, can galvanize systemic changes. In this regard, the story of Sierra Leone differs from many countries introducing fee exemptions, where fee exemption has been a stand-alone programme, unconnected to wider health system reforms. The challenge will be sustaining the momentum and the attention to delivering results as the FHCI ceases to be an initiative and becomes just 'business as normal'. The health system in Sierra Leone was fragile and conflict-affected prior to the FHCI and still faces significant challenges, both in human resources for health and more widely, as vividly evidenced by the current Ebola crisis. PMID- 25797470 TI - Programmes for advance distribution of misoprostol to prevent post-partum haemorrhage: a rapid literature review of factors affecting implementation. AB - Recent efforts to prevent post-partum haemorrhage (PPH) in low-income countries have focused on providing women with access to oral misoprostol during home birth. The WHO recommends using lay health workers (LHWs) to administer misoprostol in settings where skilled birth attendants are not available. This review synthesizes current knowledge about the barriers and facilitators affecting implementation of advance community distribution of misoprostol to prevent PPH, where misoprostol may be self-administered or administered by an LHW.We searched for and summarized available empirical evidence, and collected primary data from programme stakeholders about their experiences of programme implementation.We present key outcomes and features of advanced distribution programmes that are in operation or have been piloted globally. We categorized factors influencing implementation into those that operate at the health system level, factors related to the community and policy context and those factors more closely connected to the end user.Debates around advance distribution have centred on the potential risks and benefits of making misoprostol available to pregnant women and community members during pregnancy for administration in the home. However, the risks of advance distribution appear manageable and the benefits of self-administration, especially for women who have little chance of expert care for PPH, are considerable. PMID- 25797471 TI - Does harmonization of payment mechanisms enhance equitable health outcomes in delivery of emergency medical services in Thailand? AB - There are different reimbursement rates by the various insurance schemes in Thailand, which include the Universal Coverage scheme (UCS), civil servant medical benefit scheme (CSMBS) and social security scheme (SSS). Hence, there are concerns about inequitable care standards. Harmonization of the rates of emergency medical services has been started since April 2012. This study analyzed the impact of harmonization on clinical outcomes in private hospitals. Analysis of 22 900 records of the dataset accrued from April 2012 to June 2013 using multiple logistic modelling revealed that beneficiaries under UCS were the worst off [Odds ratio 2.56 95% of confidence interval: 2.35 to 2.80 for non-trauma and 2.19 (1.59-3.0) for trauma, corresponding to 21.26 and 25.09% of bad outcomes, respectively] in terms of not improved or dead outcomes at discharge compared with those under the CSMBS (8.45 and 12.78%, respectively) controlling for age, sex, hospital location, triage priority code, length of stays and adjusted Relative weight (RW) score. Using propensity score, matching analysis found the outcome rates of not improved including dead were highest in UCS 26.27% for trauma and 21.26% for non-trauma patients. Payment mechanism alone is inadequate to ensure equitable distribution of health outcomes in provision of emergency medical care by private providers in urban settings across the country. A secondary finding was that patients accessing hospital services directly showed better improvement or lower in-hospital mortality compared with access through formal pre-hospital means (P < 0.001). Plausible explanations have been discussed with policy implications and recommendations for further studies. PMID- 25797472 TI - Modulation of the coffee-ring effect in particle/surfactant mixtures: the importance of particle-interface interactions. AB - We study the effect of surfactants on the deposits formed after the evaporation of colloidal suspension drops, at initial concentrations lower than the critical micellar concentrations, for various particle/surfactant mixtures. We show that the surfactant-mediated interactions between particles and the liquid-gas (LG) and liquid-solid (LS) interfaces, rather than the flow patterns, primarily define the morphology of the dry deposit in a robust and reproducible manner. For like charged particle/surfactant mixtures, most of the particles form a ring-shaped deposit (according to the so-called "Coffee-Ring Effect"), but some particles can also be deposited inside the ring in a way that is modulated by electrostatic interactions between the particles and the LS interface. For oppositely charged systems, surfactant adsorption to the particle surface strongly affects particle LG interface interactions, which in turn control the deposition pattern. For low surfactant concentrations, coffee-rings are systematically observed. For intermediate concentrations, the charge of surfactant-decorated particles becomes nearly neutral, and their hydrophobicity is enhanced, which promotes particle trapping at the LG interface. A particle skin is formed and its deposition upon drying leads to homogeneous disk-like patterns. For high surfactant concentrations, particle charge is reversed, and coffee-rings are observed again. Notably, this ring-disk-ring evolution of the deposition behavior as a function of surfactant concentration is observed in a variety of mixtures, regardless of particle absolute charge and surface chemistry as well as of surfactant charge and hydrophobicity. Its apparent universal character makes it a promising strategy for a robust control of particle deposition from evaporating drops. PMID- 25797473 TI - Commentary on 'ten year experience with endovascular repair of thoracoabdominal aortic aneurysms: results from 166 consecutive patients'. PMID- 25797474 TI - Myofilament proteins in the synchronous flight muscles of Manduca sexta show both similarities and differences to Drosophila melanogaster. AB - Insect flight muscles have been classified as either synchronous or asynchronous based on the coupling between excitation and contraction. In the moth Manduca sexta, the flight muscles are synchronous and do not display stretch activation, which is a property of asynchronous muscles. We annotated the M. sexta genes encoding the major myofibrillar proteins and analyzed their isoform pattern and expression. Comparison with the homologous genes in Drosophila melanogaster indicates both difference and similarities. For proteins such as myosin heavy chain, tropomyosin, and troponin I the availability and number of potential variants generated by alternative spicing is mostly conserved between the two insects. The exon usage associated with flight muscles indicates that some exon sets are similarly used in the two insects, whereas others diverge. For actin the number of individual genes is different and there is no evidence for a flight muscle specific isoform. In contrast for troponin C, the number of genes is similar, as well as the isoform composition in flight muscles despite the different calcium regulation. Both troponin I and tropomyosin can include COOH terminal hydrophobic extensions similar to tropomyosinH and troponinH found in D. melanogaster and the honeybee respectively. PMID- 25797476 TI - PerFlexMEA: a thin microporous microelectrode array for in vitro cardiac electrophysiological studies on hetero-cellular bilayers with controlled gap junction communication. AB - The new microelectrode array device presented is called PerFlexMEA and it enables controlled coupling between myocytes and nonmyocytes used in cardiovascular conduction studies. The device consists of an 8 MUm thin parylene microporous membrane with a 4 * 5 microelectrode array patterned on one side. Myocytes and nonmyocytes can be plated on either side of the parylene membrane to create a tissue bilayer. The 3-3.5 MUm diameter pores allow inter-layer dye and electrical coupling without transmembrane cell migration. Cell migration was found to vary with cell-type and micropore diameter. Pore density can be varied based on desired coupling ratio. The flexible parylene membrane is packaged between two rigid thermoplastic layers, such that the microelectrode array region is exposed, while the rest of the device remains insulated. The packaged PerFlexMEA fits in a 60 mm culture dish. Recording experiments are performed by simply plugging it into a commercially available multielectrode amplifier system. Recorded signals were processed and analysed using scripts generated in MATLAB. Our experimental results provide evidence of the reliability of this device, as conduction velocity was observed to decrease after inducing lateral hetero-cellular controlled coupling between myocytes and HeLa cells expressing connexin 43. PMID- 25797475 TI - The brominated flame retardant BDE-47 causes oxidative stress and apoptotic cell death in vitro and in vivo in mice. AB - Polybrominated diphenyl ethers (PBDEs), used for decades as flame retardants, have become widespread environmental contaminants. Exposure is believed to occur primarily through diet and dust, and infants and toddlers have the highest body burden, raising concern for potential developmental neurotoxicity. The exact mechanisms of PBDE neurotoxicity have not been elucidated, but two relevant modes of action relate to impairment of thyroid hormone homeostasis and to direct effects on brain cells causing alterations in signal transduction, oxidative stress and apoptotic cell death. The present study shows that BDE-47 (2,2',4,4' tetrabromodiphenyl ether) induces oxidative stress and ensuing apoptotic cell death in mouse cerebellar granule neurons in vitro. Similarly, in vivo administration of BDE-47, according to an exposure protocol shown to induce behavioral and biochemical alterations (10mg/kg, per os on post-natal day 10), induces oxidative stress and apoptosis, without altering serum levels of thyroid hormones. The effects of BDE-47 both in vitro and in vivo were more pronounced in a mouse model lacking the modifier subunit of glutamate cysteine ligase (GCLM) which results in reduced anti-oxidant capability due to low levels of GSH. Concentrations of BDE-47 in brain were in the mid-nanomolar range. These findings indicate that effects observed with BDE-47 in vitro are also present after in vivo administration, suggesting that in addition to potential endocrine effects, which were not seen here, direct interactions with brain cells should be considered as a potential mechanism of BDE-47 neurotoxicity. PMID- 25797477 TI - Retino-retinal projection in juvenile and young adult rats and mice. AB - Identification of retino-retinal projecting RGCs (ret-ret RGCs) has been accomplished by tracing RGCs in one retina after intravitreal injection of different tracers in the other eye. In mammals, rabbit and rat, ret-ret RGCs are scarce and more abundant in newborn than in adult animals. To our knowledge, ret ret RGCs have not been studied in mice. Here we purpose to revisit the presence of ret-ret RGCs in juvenile and young adult rats and mice by using retrograde tracers applied to the contralateral optic nerve instead of intravitreally. In P20 (juvenile) and P60 (young adult) animals, the left optic nerve was intraorbitally transected and Fluorogold (rats) or its analogue OHSt (mice) were applied onto its distal stump. P20 animals were sacrificed 3 (mice) or 5 (rats) days later and adult animals at 5 (mice) or 7 (rats) days. Right retinas were dissected as flat-mounts and double immunodetected for Brn3a and melanopsin. Ret ret RGCs were those with tracer accumulation in their somas. Out of them some expressed Brn3a and/or melanopsin, while other were negative for both markers. In young adult rats, we found 2 ret-ret RGCs displaced to the inner nuclear layer. In both species, ret-ret RGCs are quite scarce and found predominantly in the nasal retina. In juvenile animals there are significantly more ret-ret RGCs (9 +/ 3, rats, 13 +/- 3 mice) than in young adult ones (5 +/- 6 rats, 7 +/- 3 mice). Finally, juvenile and young adult mice have more ret-ret RGCs than rats. PMID- 25797479 TI - Palladium-catalyzed intermolecular oxidative cyclization of N-aryl enamines with isocyanides through double sp(2) C-H bonds cleavage: facile synthesis of 4 aminoquinoline derivatives. AB - An efficient method for the synthesis of 4-aminoquinolines via palladium catalyzed intermolecular oxidative cyclization of N-aryl enamines and isocyanides through double sp(2) C-H bonds cleavage has been developed. PMID- 25797478 TI - Epithelial basement membrane proteins perlecan and nidogen-2 are up-regulated in stromal cells after epithelial injury in human corneas. AB - The epithelial basement membrane (BM) is a specialized extracellular matrix that has been shown to have a critical role in corneal development, wound healing, and disease. Although the epithelial BM contributes to corneal homeostasis, relatively little is know about non-epithelial production of its components that may be important in defective regeneration of the epithelial basement membrane associated with opacity after photorefractive keratectomy. The purpose of the current study was to investigate stromal production of corneal epithelial BM proteins in wounded human corneas using immunohistochemistry. A total of five unwounded control eyes and five 30-min epithelial-wounded corneas were obtained from fresh corneoscleral buttons removed from human eyes enucleated due to choroidal melanoma with normal anterior segments. In the wounded corneas, an eight mm patch of central corneal epithelium and epithelial BM was removed with a Beaver blade when the patient was under general anesthesia. Immunohistochemical analyses were performed to detect perlecan and nidogen-2 proteins-important components of the epithelial BM lamina lucida and lamina densa zones. Perlecan and nidogen-2 proteins were detected in the BM itself and at low levels in keratocytes in all unwounded corneas. After epithelial injury, both perlecan and nidogen-2 were expressed at high levels in stromal keratocytes, including superficial keratocytes in the early phases of apoptosis. Thus, after epithelial and epithelial BM injury, stromal keratocytes contribute important perlecan and nidogen-2 components to the regenerating epithelial BM. PMID- 25797480 TI - Cytotoxicity of corrosion products of degradable Fe-based stents: relevance of pH and insoluble products. AB - Fe-based biodegradable metallic materials (Fe-BMMs) have been proposed for cardiovascular applications and are expected to disappear via corrosion after an appropriate period. However, in vivo studies showed that Fe ions release leads to accumulation of orange and brownish insoluble products at the biomaterial/cell interface. As an additional consequence, sharp changes in pH may affect the biocompatibility of these materials. In the present work, the experimental protocols were designed with the aim of evaluating the relative importance that these factors have on biocompatibility evaluation of BMMs. Mitochondrial activity (MTT assay) and thiobarbituric acid reactive substances (TBARS) assay on mammalian cells, exposed to 1-5 mM of added Fe3+ salt, were assessed and compared with results linked exclusively to pH effects. Soluble Fe concentration in culture medium and intracellular Fe content were also determined. The results showed that: (i) mitochondrial activity was affected by pH changes over the entire range of concentrations of added Fe3+ assayed, (ii) at the highest added Fe3+ concentrations (>=3 mM), precipitation was detected and the cells were able to incorporate the precipitate, that seems to be linked to cell damage, (iii) the extent of precipitation depends on the Fe/protein concentration ratio; and (iv) lipid peroxidation products were detected over the entire range of concentrations of added Fe3+. Hence, a new approach opens in the biocompatibility evaluation of Fe-based BMMs, since the cytotoxicity would not be solely a function of released (and soluble) ions but of the insoluble degradation product amount and the pH falling at the biomaterial/cell interface. The concentration of Fe-containing products at the interface depends on diffusional conditions in a very complex way that should be carefully analyzed in the future. PMID- 25797482 TI - Formulation optimization and in vitro skin penetration of spironolactone loaded solid lipid nanoparticles. AB - The aim of the current investigation was to prepare and evaluate the potential use of solid lipid nanoparticles for the dermal delivery of spironolactone (SP). The spironolactone loaded SLN (SP-SLN) was prepared by emulsion-solvent evaporation method followed by ultrasonication. The properties of obtained SLNs were characterized by photon correlation spectroscopy (PCS), scanning tunneling microscopy (STM) and differential scanning calorimetry. FT-IR was also used to investigate any interaction between SP and excipients in the molecular level during the preparation of SLNs. The performance of the formulations was investigated in terms of drug release, skin permeation and also the retention of drug by the skin. The SP-SLNs presented spherical shape with the mean diameter, zeta potential and entrapment efficiency of 88.9 nm, -23.9 mV and 59.86%, respectively. DSC study showed that SP alone encapsulated in SLNs was in the amorphous form. FT-IR analysis revealed that there were hydrogen bond interactions between the SP alone and SLN components. The dissolution results revealed that the drug release from SP-SLNs was at least 4.9 times faster than original SP within the first 30 min. The cumulative amount of SP penetrated through rat skin from SP-SLNs was almost twofold that of the SP alone in 24h after the administration. In vitro permeation studies indicated that SP-SLN may be a promising vector for use in the topical treatment. It can be concluded that SLNs provide good skin permeation for SP and may be a promising carrier for topical delivery of spironolactone offering the biphasic release pattern that might be interesting for topical application resulting in an effective treatment for skin disorders such as acne. PMID- 25797481 TI - Liposomal co-delivery of curcumin and albumin/paclitaxel nanoparticle for enhanced synergistic antitumor efficacy. AB - Paclitaxel (PTX) and curcumin (CUR) are potent chemotherapeutic agents used in the treatment of cancer. In the present study, hybrid polymer-lipid nanoparticles co-loaded with PTX and CUR were developed to investigate the therapeutic potential of a combination drug regimen. For this purpose, PTX-loaded albumin nanoparticles (APN) were prepared and encapsulated in PEGylated hybrid liposomes containing CUR (CL-APN) via a thin-film hydration technique. CL-APN was nanosized with a uniform spherical morphology. PTX and CUR release was sustained and occurred in a sequential manner, wherein CUR was expected to downregulate the nuclear factor NF-kappaB and Akt pathways and increase the therapeutic efficacy of PTX. The ratiometric combination of PTX and CUR was significantly more cytotoxic than the individual drugs. Importantly, dual-drug-loaded nanocarriers exhibited a superior cytotoxic effect than a cocktail combination at a lower dose. CL-APN induced significantly higher early and late apoptosis, induced a stronger G2/M arrest, and significantly increased the subG1 cell population. By combining CUR, an effective NF-kappaB inhibitor, with PTX, a powerful anticancer drug, in a polymer-lipid hybrid nanoparticle system, we could improve the therapeutic efficacy in cancer treatments. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against various malignancies. PMID- 25797483 TI - Systemic modulation of the stability of pluronic hydrogel by a small amount of graphene oxide. AB - Thermo-sensitive and injectable hydrogels have been widely investigated for drug delivery, tissue engineering, and other biomedical applications. Pluronic copolymers can form thermo-sensitive physical gel state, thus applicable for injectable hydrogels. However, they are not stable in vivo, showing a very fast dissolution, which limits their applications. We propose a novel Pluronic-based physical hydrogel with enhanced stability by simply adding a small quantity of graphene oxide (GO) which has a large surface area and can make strong interactions with Pluronic. Further carboxylated GO could act as a more efficient additive. The addition of GO increased the moduli of hydrogels, but more importantly, it enhanced the stability of Pluronic gel dramatically. The in vitro dissolution rate of Pluronic hydrogel could be systematically modulated by increasing GO content. Upon subcutaneous injection at a sol state, GO-containing hydrogel induced a stable gel state, and was maintained over several weeks whereas very fast degradation was observed without the addition of GO. Furthermore, histological analyses demonstrated that the GO-containing Pluronic hydrogel was biocompatible and showed no severe inflammatory response. Similarly, GO-containing hydrogel resulting from the packing of Pluronic-based nanogel also showed the more enhanced stability by the addition of GO both in vitro and in vivo. In both systems, hydrogels with remarkably enhanced stability by the addition of GO were also effective for the sustained release of loaded protein, and the release rates were mainly determined by the degradation rates of hydrogels. Thus, these GO-containing Pluronic systems can be used as a thermo sensitive injectable system with a sufficient stability in vivo. PMID- 25797484 TI - Composition of betel specific chemicals in saliva during betel chewing for the identification of biomarkers. AB - Betel nut chewing causes cancer in humans, including strong associations with head and neck cancer in Guam. In the search for biomarkers of betel chewing we sought to identify chemicals specific for the 3 most commonly consumed betel preparations in Guam: nut ('BN'), nut + Piper betle leaf ('BL'), and betel quid ('BQ') consisting of nut + lime + tobacco + Piper betle leaf. Chemicals were extracted from the chewing material and saliva of subjects chewing these betel preparations. Saliva analysis involved protein precipitation with acetonitrile, dilution with formic acid followed by LCMS analysis. Baseline and chewing saliva levels were compared using t-tests and differences between groups were compared by ANOVA; p < 0.05 indicated significance. Predominant compounds in chewing material were guvacine, arecoline, guvacoline, arecaidine, chavibetol, and nicotine. In chewing saliva we found significant increases from baseline for guvacine (BN, BQ), arecoline (all groups), guvacoline (BN), arecaidine (all groups), nicotine (BQ), and chavibetol (BL, BQ), and significant differences between all groups for total areca-specific alkaloids, total tobacco-specific alkaloids and chavibetol. From this pilot study, we propose the following chemical patterns as biomarkers: areca alkaloids for BN use, areca alkaloids and chavibetol for BL use, and areca alkaloids plus chavibetol and tobacco-specific alkaloids for BQ use. PMID- 25797485 TI - MRPL44 mutations cause a slowly progressive multisystem disease with childhood onset hypertrophic cardiomyopathy. AB - Defects in mitochondrial translation may lead to combined respiratory chain deficiency and typically cause childhood-onset multisystem disease. Only recently, a homozygous missense mutation (c.467T > G, p.Leu156Arg) in MRPL44, encoding a protein of the large subunit of the mitochondrial ribosome, has been identified in two siblings with hypertrophic cardiomyopathy. Using exome sequencing, we identified two further unrelated patients harboring the previously reported mutation c.467T > G, p.Leu156Arg in MRPL44 in the homozygous state and compound heterozygous with a novel missense mutation c.233G > A, p.Arg78Gln, respectively. Both patients presented with childhood-onset hypertrophic cardiomyopathy, which seems to be the core clinical feature associated with MRPL44 deficiency. However, we observed several additional clinical signs and symptoms including pigmentary retinopathy, hemiplegic migraine, Leigh-like lesions on brain MRI, renal insufficiency, and hepatopathy. Our findings expand the clinical spectrum associated with MRPL44 mutations and indicate that MRPL44 associated mitochondrial dysfunction can also manifest as a progressive multisystem disease with central nervous system involvement. Of note, neurological and neuro-ophthalmological impairment seems to be a disease feature of the second and third decades of life, which should be taken into account in patient management and counseling. PMID- 25797486 TI - Locked-flavylium fluorescent dyes with tunable emission wavelengths based on intramolecular charge transfer for multi-color ratiometric fluorescence imaging. AB - A new class of locked-flavylium fluorophores with tunable emission wavelengths based on intramolecular charge transfer were designed, synthesized, and evaluated. The optical studies indicate that sensor LF3 can display an intriguing character, fluorescence ratiometric response in three channels by tuning the ICT efficiencies. PMID- 25797487 TI - Timing in neural maturation: arrest, delay, precociousness, and temporal determination of malformations. AB - Timing is primordial in initiating and synchronizing each developmental process in tissue morphogenesis. Maturational arrest, delay, and precociousness all are conducive to neurological dysfunction and may determine different malformations depending on when in development the faulty timing occurred, regardless of the identification of a specific genetic mutation or an epigenetic teratogenic event. Delay and arrest are distinguished by whether further progressive development over time can be expected or the condition is static. In general, retardation of early developmental processes, such as neurulation, cellular proliferation, and migration, leads to maturational arrest. Retardation of late processes, such as synaptogenesis and myelination, are more likely to result in maturational delay. Faulty timing of neuronal maturation in relation to other developmental processes causes neurological dysfunction and abnormal electroencephalograph maturation in preterm neonates. Precocious synaptogenesis, including pruning to provide plasticity, may facilitate prenatal formation of epileptic circuitry leading to severe postnatal infantile epilepsies. The anterior commissure forms 3 weeks earlier than the corpus callosum; its presence or absence in callosal agenesis is a marker for the onset of the initial insult. An excessively thick corpus callosum may be due to delayed retraction of transitory collateral axons. Malformations that arise at different times can share a common pathogenesis with variations on the extent: timing of mitotic cycles in mosaic somatic mutations may distinguish hemimegalencephaly from focal cortical dysplasia type 2. Timing should always be considered in interpreting cerebral dysgeneses in both imaging and neuropathological diagnoses. PMID- 25797488 TI - Vulnerability and resilience after early institutional care: The Greek Metera study. AB - The aim of the study was to examine possible influences on individual differences in adolescence in response to early institutional care in infancy not involving either generalized privation or subnutrition. Fifty-two adopted adolescents aged 13 years who received institutional care in infancy at the Metera Babies Centre and 36 adolescents of the same age who were raised in their biological families participated in the study. Adolescents' attachment relationships, cognition, behavioral adjustment and use of psychological services were assessed. Marked heterogeneity in outcomes was found. No predictive effects were found for preinstitutional features or for adoptive circumstances. By contrast a large effect was found for institutional care extending beyond the age of 2 years and for quality of institutional care as experienced at an individual level. There was a close association between prolonged institutional care and disorganized attachment while in the institution, but the main institutional effect derived from the length of time in the institution. PMID- 25797489 TI - Colonic mucosal expression of heat-shock proteins may have a potential prognostic value in ulcerative colitis. AB - BACKGROUND AND STUDY AIMS: Ulcerative colitis (UC) is a lifelong, chronic, progressive, and relapsing inflammatory disease. Endoscopy with biopsies is the mainstay in diagnosis and assessment. The development of biomarkers is important for the diagnosis and follow-up of UC. We investigated the expression of molecular chaperones/heat-shock proteins (HSP70 and HSP90) in relation to the grades of inflammation and dysplasia in patients with UC before and after treatment. PATIENTS AND METHODS: A total of 104 naive patients with UC of varying severity were admitted to the Department of Tropical Medicine and Infectious Diseases, Tanta University Hospital. Ten biopsies from the healthy mucosa of patients with irritable bowel syndrome (IBS) served as a control. Disease activity was assessed clinically using the Mayo score system. Endoscopic mucosal biopsies were taken at diagnosis and 6 months after treatment. Histopathological activity was graded for inflammation and dysplasia. Immunohistochemistry was used to determine the percentage of cells positive for HSPs. The results were expressed in a semiquantitative scale. RESULTS: The expression of both HSP70 and HSP90 increased in patients with UC at the time of disease activity, and it decreased after treatment and remission. There was a significant correlation between the expression of both proteins and the grades of dysplasia as well as inflammation (P < 0.05). Strong expression of HSPs that persisted after treatment has been associated with cases of true dysplasia. CONCLUSIONS: The results indicated that HSP70 and HSP90 had the potential for assessment of the activity and prognosis of UC. They can also predict the presence of dysplasia and differentiate it from reactive atypia. Larger studies are needed to confirm this diagnostic and prognostic value of HSPs. PMID- 25797490 TI - Quantifying nucleoporin stoichiometry inside single nuclear pore complexes in vivo. AB - The nuclear pore complex (NPC) is one of the largest supramolecular structures in eukaryotic cells. Its octagonal ring-scaffold perforates the nuclear envelope and features a unique molecular machinery that regulates nucleocytoplasmic transport. NPCs are composed of ~30 different nucleoporins (Nups), averaged at 8, 16 or 32 copies per NPC. This estimate has not been confirmed for individual NPCs in living cells due to the inherent difficulty of counting proteins inside single supramolecular complexes. Here we used single-molecule SPEED microscopy to directly count the copy-number of twenty-four different Nups within individual NPCs of live yeast, and found agreement as well as significant deviation from previous estimates. As expected, we counted 8 copies of four peripheral Nups and 16 copies of fourteen scaffold Nups. Unexpectedly, we counted a maximum of 16 copies of Nsp1 and Nic96, rather than 32 as previously estimated; and found only 10-15 copies of six other Nups, rather than 8 or 16 copies as expected. This in situ molecular-counting technology can test structure-function models of NPCs and other supramolecular structures in cells. PMID- 25797491 TI - Activation of 5-HT1A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease. AB - Although the medial subdivision of the central nucleus of the amygdala (CeM) and serotonin-1A (5-HT1A) receptors are involved in the regulation of anxiety, their roles in Parkinson's disease (PD)-associated anxiety are still unknown. Here we assessed the importance of CeM 5-HT1A receptors for anxiety in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). The lesion induced anxiety-like behaviors, increased the firing rate and burst-firing pattern of CeM gamma-aminobutyric acid (GABA) neurons, as well as decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), amygdala and ventral part of hippocampus (vHip). Intra-CeM injection of the selective 5-HT1A receptor agonist 8-OH-DPAT produced anxiolytic effects in the lesioned rats, and decreased the firing rate of CeM GABAergic neurons in two groups of rats. Compared to sham-operated rats, the duration of the inhibitory effect on the firing rate of GABAergic neurons was shortened in the lesioned rats. The injection increased DA levels in the mPFC and amygdala in two groups of rats and the vHip in the lesioned rats, and increased 5-HT level in the lesioned rats, whereas it decreased NA levels in the mPFC in two groups of rats and the vHip in the lesioned rats. Moreover, the mean density of 5-HT1A receptor and GABA double-labeled neurons in the CeM was reduced after the lesioning. These results suggest that activation of CeM 5-HT1A receptor produces anxiolytic effects in the 6-OHDA-lesioned rats, which involves decreased firing rate of the GABAergic neurons, and changed monoamine levels in the limbic and limbic-related brain regions. PMID- 25797492 TI - Neuro-anatomic mapping of dopamine D1 receptor involvement in nicotine self administration in rats. AB - Dopaminergic signaling has long been known to be a critical factor in nicotine addiction, as well as other drugs of abuse. Dopaminergic projections from the VTA to the nucleus accumbens and prefrontal cortex have been well established to be critical to the reinforcing effects of these drugs. However, other projections of dopamine neurons are likely to have significant roles in this process. Also, the relative contributions of D1 and D2 dopamine receptors in drug addiction and its treatment remain to be fully understood. In this study, we examined the effects of blocking D1 and D2 receptors in the nucleus accumbens shell (AcS), anterior cingulate cortex (ACC), and parietal association cortex (PtA) on nicotine self administration in rats. Female Sprague-Dawley rats were fitted with jugular catheters and allowed to self-administer nicotine (0.03 mg/kg/infusion) on an FR1 schedule. Rats were fitted with bilateral infusion cannulae to allow infusion of D1 or D2 antagonists (SCH-23390 or haloperidol) into each targeted brain area. Acute local infusions of SCH-23390 (1-4 MUg/side) into the AcS and PtA significantly reduced nicotine self-administration by up to 75%. SCH-23390 infusion into the ACC was less effective with only suggestive non-significant reductions of nicotine self-administration. Acute, local infusions of haloperidol (0.5-2 MUg/side) in any of the brain regions targeted did not have significant effects on nicotine self-administration. These results demonstrate a more significant role for D1 receptor mechanisms in the process of nicotine reinforcement and help provide a more detailed neuroanatomic map of nicotine dependence in the brain. PMID- 25797493 TI - Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons. AB - Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states. PMID- 25797494 TI - Neuronal regulation of expression of hydrogen sulfide-producing enzyme cystathionine beta-synthase in rat spinal cord astrocytes. AB - Cystathionine beta-synthase (CBS), expressed in astrocytes, generates a gaseous neuromodulator, hydrogen sulfide (H2S) in the central nervous system (CNS). However, little is known about the regulatory mechanisms of astrocytic CBS expression and activity. This study evaluated the influence of neurons on astrocytic CBS expression by employing multiple culture systems. Substantial CBS expression was observed in the intact neonatal rat spinal cord, while CBS content was markedly reduced in an astrocyte-enriched culture prepared from the neonatal spinal cord. Immunofluorescence analysis confirmed the localization of spinal cord CBS in astrocytes, but not in neurons. Although CBS expression was weak in the embryonic rat spinal cord, enzyme levels were time-dependently increased in a neuron/astrocyte mixed culture originating from embryonic spinal cord. The reduced CBS expression in isolated neonatal astrocytes was restored by co-culture with embryonic neurons. Together with the observed CBS expression levels, H2S production was relatively low in astrocytes cultured alone, but was considerably higher in astrocytes cultured with neurons. These results indicate that neurons are essential for maintaining the expression and H2S-producing activity of astrocytic CBS in the rat spinal cord. PMID- 25797497 TI - [UO2(NH3)5]Br2.NH3: synthesis, crystal structure, and speciation in liquid ammonia solution by first-principles molecular dynamics simulations. AB - Pentaammine dioxido uranium(VI) dibromide ammonia (1/1), [UO2(NH3)5]Br2.NH3, was synthesized in the form of yellow crystals by the reaction of uranyl bromide, UO2Br2, with dry liquid ammonia. The compound crystallizes orthorhombic in space group Cmcm and is isotypic to [UO2(NH3)5]Cl2.NH3 with a = 13.2499(2), b = 10.5536(1), c = 8.9126(1) A, V = 1246.29(3) A(3) and Z = 4 at 123 K. The UO2(2+) cation is coordinated by five ammine ligands and the coordination polyhedron can be best described as pentagonal bipyramid. Car-Parrinello molecular dynamics simulations are reported for [UO2(NH3)5](2+) in the gas phase and in liquid NH3 solution (using the BLYP density functional). According to free-energy simulations, solvation by ammonia has only a small effect on the uranyl-NH3 bond strength. PMID- 25797495 TI - Dispositional mindfulness and semantic integration of emotional words: Evidence from event-related brain potentials. AB - Initial research shows that mindfulness training can enhance attention and modulate the affective response. However, links between mindfulness and language processing remain virtually unexplored despite the prominent role of overt and silent negative ruminative speech in depressive and anxiety-related symptomatology. Here, we measured dispositional mindfulness and recorded participants' event-related brain potential responses to positive and negative target words preceded by words congruent or incongruent with the targets in terms of semantic relatedness and emotional valence. While the low mindfulness group showed similar N400 effect pattern for positive and negative targets, high dispositional mindfulness was associated with larger N400 effect to negative targets. This result suggests that negative meanings are less readily accessible in people with high dispositional mindfulness. Furthermore, high dispositional mindfulness was associated with reduced P600 amplitudes to emotional words, suggesting less post-analysis and attentional effort which possibly relates to a lower inclination to ruminate. Overall, these findings provide initial evidence on associations between modifications in language systems and mindfulness. PMID- 25797496 TI - Characterization of key odorants in Chinese chixiang aroma-type liquor by gas chromatography-olfactometry, quantitative measurements, aroma recombination, and omission studies. AB - Chixiang aroma-type liquor is extensively welcomed by consumers owing to its typical fatty aroma, particularly in southern China. To our knowledge, no comprehensive characterization of aroma and flavor from chixiang aroma-type liquor has been published. It is still a confused question which components are the most important in characterizing its unique aroma. A total of 56 odorants were identified in chixiang aroma-type liquor by aroma extract dilution analysis (AEDA), and in different quantitative measurements, 34 aroma compounds were further demonstrated as important odorants according to odor activity values (OAVs). Furthermore, this research suggested that the aroma of chixiang aroma type finished liquor could be successfully reconstituted by mixing 34 aroma compounds in the concentrations measured. Omission experiments further confirmed (E)-2-nonenal as the key odorant and revealed the significance of (E)-2-octenal and 2-phenylethanol for the overall aroma of chixiang aroma-type liquor. 3 (Methylthio)-1-propanol (methionol), diethyl 1,7-heptanedioate (diethyl pimelate), diethyl 1,8-octanedioate (diethyl suberate), and diethyl 1,9 nonanedioate (diethyl azelate), identified as the characteristic aromas of chixiang aroma-type liquor in 1995, had no effects on aroma based on omission/addition experiments. PMID- 25797498 TI - White spots in pharmaceutical pipelines-EMA identifies potential areas of unmet medical needs. AB - Unmet medical needs are a priority for organizations such as the WHO and major public-private initiatives, such as Innovative Medicines Initiative, were established to speed up the development of better and safer medicines for patients. To assist such projects, the EMA in its 'Road Map to 2015' considered the mapping of unmet medical needs as a priority. This study has identified medical conditions for which the EMA could not identify developments in the pharmaceutical pipelines, that is, 'white spots'. Our analysis was made using external data sources as well as mining data of the EMA. The main areas for white spots were oncology, infectious diseases and certain psychiatric conditions. According to our data and a review of literature, in a number of these white spots, diagnostic tools may even be missing. The identification of those conditions will benefit stakeholders, including regulators, research funding bodies and patients' organizations. PMID- 25797501 TI - Saturated fat intake and cardiovascular disease in Japanese population. AB - The evidence for the impact of saturated fat intake on cardiovascular disease remains inconsistent. One reason for this inconsistency may be the large difference in the distribution of saturated fat intake between the East and West. In this review, we focus on the published literature on this topic among Japanese population. Three studies have examined the link between saturated fat intake and intraparenchymal hemorrhage, consistently showing an inverse association. However, the association for ischemic stroke is less clear, although it is generally inverse. As for myocardial infarction, the findings in Japanese studies are inconsistent, as are those of Western studies. The JPHC study, however, found a positive association, the first report in Asia. Taken together with the results of the JPHC and Western studies, a saturated fat intake of around 20 g/day (approximately 10% of total energy) may be optimal, which corresponds to 200 g of milk a day and 150 g of meat every other day. PMID- 25797500 TI - Manifestation of pi-pi stacking interactions in luminescence properties and energy transfer in aromatically-derived Tb, Eu and Gd tris(pyrazolyl)borate complexes. AB - The three new complexes Tp(Py)Ln(CH3CO2)2(H2O) (Ln = Eu (1), Gd(2), or Tb (3)) were prepared and characterized crystallographically. In the crystal lattices of these complexes, separate molecules are connected in infinite chains by pi stacking interactions. Complexes 1 and 3 display intense photoluminescence and triboluminescence (red and green respectively), while compound 3 exhibits electroluminescence commencing at 9 V in an ITO/PVK/3/Al device (ITO = indium-tin oxide, PVK = poly(N-vinylcarbazole)). A series of Eu/Tb-doped Gd compounds was prepared by cocrystallization from mixtures of 1 and 2 or 2 and 3, respectively. It was shown that pi-stacking interactions are involved in increasing the efficiency of energy transfer from the gadolinium complex to emitting [Tp(Py)Eu](2+) or [Tp(Py)Tb](2+) centers, and this energy transfer occurs through hundreds of molecules, resembling the process of energy harvesting in chloroplast stacks. PMID- 25797502 TI - Microwave-assisted synthesis, characterization and cytotoxic studies of novel estrogen receptor alpha ligands towards human breast cancer cells. AB - A new, simple, and microwave-assisted, solution-phase T3P(r)-DMSO mediated method for the preparation of a novel class of estrogen receptor alpha (ERalpha) ligands based on the 2-phenylquinoline scaffold was developed. Furthermore, the novel ERalpha ligands were tested for their bioactivity against ERalpha-positive and ERalpha-negative cell lines. The ligand (entry 4), with amine and nitro group substitution at C4 position, displayed significant cytotoxicity against MCF-7 and HepG2 cells with an IC50 value of 6 and 11MUM, respectively. On the other hand, ERalpha-negative cells displayed resistance to quinolines induced cytotoxicity with an IC50 value >100Mm and they does not induce cytotoxicity in normal breast epithelial cells. Molecular docking analyses suggest a consistent binding mode for these ERalpha ligands in the ligand binding domain of the human ERalpha and predict the ligands to occupy the hydrophobic cavity in a similar fashion as estradiol or GW2368. PMID- 25797503 TI - Isolation and sequence analysis of napin seed specific promoter from Iranian Rapeseed (Brassica napus L.). AB - Rapeseed (Brassica napus L.) has become an important crop during the last 30years. In addition to a high lipid level, the seeds also have a significant protein content, which constitutes 20-25% of the dry seed weight. The synthesis of storage proteins is primarily controlled at transcriptional level and seed specific expression has been shown to be conferred upon the promoter regions of many storage protein genes. Napin is one of the main storage proteins in rapeseed(')s embryo that is produced in seed developing stage. Its promoter region located at 5' upstream of the napin gene has already been isolated (GenBank number, EU416279.1). In current research, seed-specific promoter (napin) of Iranian B. napus L. was isolated from the genomic DNA and cloned into pBI121 plant binary vector to use in future researches. For this purpose, the napin promoter was amplified by PCR method using specific primers, cloned in pSK(+) vector and sequenced. Sequencing analysis showed that the cloned promoter contained all of conserved motifs such as TATA box (TATAAA), RY repeats (CATGCA), dist-B (TCAAACACC) and prox-B elements (GCCACTTGTC), G-box (CACGTG) and CAAT Motifs, which constituted the seed-specific promoter activity and according to this analysis, the seed-specific promoter activity of cloned sequence was predicted. Based on sequence distances of nucleotide sequences, our sequence had the highest similarity (99.8%) whit B. napus sequence (with EU416279.1 accession number). Finally the promoter obtained might be interesting not only as a useful tool for biotechnological application but also for fundamental research. PMID- 25797504 TI - Stochastic sampled-data control for synchronization of complex dynamical networks with control packet loss and additive time-varying delays. AB - This study examines the exponential synchronization of complex dynamical networks with control packet loss and additive time-varying delays. Additionally, sampled data controller with time-varying sampling period is considered and is assumed to switch between m different values in a random way with given probability. Then, a novel Lyapunov-Krasovskii functional (LKF) with triple integral terms is constructed and by using Jensen's inequality and reciprocally convex approach, sufficient conditions under which the dynamical network is exponentially mean square stable are derived. When applying Jensen's inequality to partition double integral terms in the derivation of linear matrix inequality (LMI) conditions, a new kind of linear combination of positive functions weighted by the inverses of squared convex parameters appears. In order to handle such a combination, an effective method is introduced by extending the lower bound lemma. To design the sampled-data controller, the synchronization error system is represented as a switched system. Based on the derived LMI conditions and average dwell-time method, sufficient conditions for the synchronization of switched error system are derived in terms of LMIs. Finally, numerical example is employed to show the effectiveness of the proposed methods. PMID- 25797499 TI - Neurobiological background of negative symptoms. AB - Studies investigating neurobiological bases of negative symptoms of schizophrenia failed to provide consistent findings, possibly due to the heterogeneity of this psychopathological construct. We tried to review the findings published to date investigating neurobiological abnormalities after reducing the heterogeneity of the negative symptoms construct. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, genetics and neurobiology of schizophrenia. We searched PubMed with the keywords "negative symptoms," "deficit schizophrenia," "persistent negative symptoms," "neurotransmissions," "neuroimaging" and "genetic." Additional articles were identified by manually checking the reference lists of the relevant publications. Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included. Structural and functional imaging studies addressed the issue of neurobiological background of negative symptoms from several perspectives (considering them as a unitary construct, focusing on primary and/or persistent negative symptoms and, more recently, clustering them into factors), but produced discrepant findings. The examined studies provided evidence suggesting that even primary and persistent negative symptoms include different psychopathological constructs, probably reflecting the dysfunction of different neurobiological substrates. Furthermore, they suggest that complex alterations in multiple neurotransmitter systems and genetic variants might influence the expression of negative symptoms in schizophrenia. On the whole, the reviewed findings, representing the distillation of a large body of disparate data, suggest that further deconstruction of negative symptomatology into more elementary components is needed to gain insight into underlying neurobiological mechanisms. PMID- 25797505 TI - Tranexamic acid: a clinical review. AB - Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases. The evidence of their efficacy has been mounting for years. Tranexamic acid (TXA), a synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to help acute care physicians navigate through the clinical evidence available for TXA therapy, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which necessitate further clinical trials on its usage and safety in various clinical settings. PMID- 25797507 TI - Difficult-to-understand point. PMID- 25797506 TI - Big data in medical science--a biostatistical view. AB - BACKGROUND: Inexpensive techniques for measurement and data storage now enable medical researchers to acquire far more data than can conveniently be analyzed by traditional methods. The expression "big data" refers to quantities on the order of magnitude of a terabyte (1012 bytes); special techniques must be used to evaluate such huge quantities of data in a scientifically meaningful way. Whether data sets of this size are useful and important is an open question that currently confronts medical science. METHODS: In this article, we give illustrative examples of the use of analytical techniques for big data and discuss them in the light of a selective literature review. We point out some critical aspects that should be considered to avoid errors when large amounts of data are analyzed. RESULTS: Machine learning techniques enable the recognition of potentially relevant patterns. When such techniques are used, certain additional steps should be taken that are unnecessary in more traditional analyses; for example, patient characteristics should be differentially weighted. If this is not done as a preliminary step before similarity detection, which is a component of many data analysis operations, characteristics such as age or sex will be weighted no higher than any one out of 10 000 gene expression values. Experience from the analysis of conventional observational data sets can be called upon to draw conclusions about potential causal effects from big data sets. CONCLUSION: Big data techniques can be used, for example, to evaluate observational data derived from the routine care of entire populations, with clustering methods used to analyze therapeutically relevant patient subgroups. Such analyses can provide complementary information to clinical trials of the classic type. As big data analyses become more popular, various statistical techniques for causality analysis in observational data are becoming more widely available. This is likely to be of benefit to medical science, but specific adaptations will have to be made according to the requirements of the applications. PMID- 25797508 TI - Mediterranean diet. PMID- 25797509 TI - Benefit: "therapeutic indication". PMID- 25797510 TI - In reply. PMID- 25797511 TI - No statistics without clinical evaluation. PMID- 25797512 TI - Addition. PMID- 25797513 TI - In reply. PMID- 25797515 TI - Characterization of proteins in S. cerevisiae with subcellular localizations. AB - Acquiring comprehensive knowledge of protein in various subcellular localizations is one of the fundamental goals in cell biology and proteomics. Although recent large-scale experimental and proteomics studies of S. cerevisiae protein subcellular localizations are archived in various databases, only a few studies use a systems biology approach to characterize S. cerevisiae proteins at a subcellular localization level. Based on the topological properties and biological properties of S. cerevisiae proteins, we have compared, contrasted and analyzed the statistical properties across eight different subcellular localizations. Significant differences are found in all topological properties and biological properties among eight protein categories. Network topology analysis indicates that the nuclear proteins differ from the other seven protein categories, and tend to have the most important topological properties and play an important role in the network, including the highest degree, core number, and betweenness centrality. In the light of the above, we hope these findings presented in this study may provide important help for protein subcellular localization prediction in S. cerevisiae and provide many new insights for understanding the proteins directly from subcellular localizations. PMID- 25797514 TI - Diving medicine in clinical practice. AB - BACKGROUND: Diving is a popular sport, and some recreational divers have medical risk factors. Their health can be endangered by high extracorporeal (ambient) pressure and its many systemic effects. METHODS: We review relevant publications on free (breath-hold) diving, scuba diving, medical evaluation for diving, barotrauma, decompression sickness, and diving with medical risk factors, which were retrieved by a selective search of PubMed. RESULTS: Free diving or scuba diving, even at seemingly innocuous depths, puts considerable stress on the cardio - vascular system, ears, and lungs. Unexpected events while diving, diminished functional reserve, and pre-existing medical illnesses increase the risk of a diving accident. An international survey revealed that minor incidents occur in 1.3% of all dives, and decompression accidents in 2 of every 10 000 dives. A properly conducted medical examination to determine diving fitness, followed by appropriate counseling, can make a life-threatening diving accident less likely. CONCLUSION: To be able to certify diving fitness and give competent medical advice about diving, physicians must be well informed about the physical and physiological changes of diving and the associated risks to health, and they need to know how to perform a medical evaluation of prospective divers. In Germany, any licensed physician may judge a person fit to dive. It is recommended that this be done in adherence to the relevant evaluation standards and recommendations of the medical specialty associations. Randomized controlled trials on the effect of preventive behavior would be desirable, as would a central registry of diving accidents. PMID- 25797517 TI - A common ground. PMID- 25797518 TI - Role of lipid microdomains in TLR-mediated signalling. AB - Over the last twenty years, evidence has been provided that the plasma membrane is partitioned with microdomains, laterally mobile in the bilayer, providing the necessary microenvironment to specific membrane proteins for signalling pathways to be initiated. We discuss here the importance of such microdomains for Toll like receptors (TLR) localization and function. First, lipid microdomains favour recruitment and clustering of the TLR machinery partners, i.e. receptors and co receptors previously identified to be required for ligand recognition and signal transmission. Further, the presence of the so-called Cholesterol Recognition Amino-Acid Consensus (CRAC) sequences in the intracellular juxtamembrane domain of several Toll-like receptors suggests a direct role of cholesterol in the activation process. This article is part of a Special Issue entitled: Lipid protein interactions. PMID- 25797516 TI - Overcoming T cell exhaustion in infection and cancer. AB - Inhibitors of the Programmed Cell Death 1: Programmed Cell Death 1 ligand 1 (PD 1:PD-L1) pathway, a central regulator of T cell exhaustion, have been recently shown to be effective for treatment of different cancers. However, clinical responses are mixed, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Here, we review the molecular regulation of T cell exhaustion, placing recent findings on PD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell exhaustion during chronic infection. We discuss the current understanding of the mechanisms involved in reversing T cell exhaustion, and outline critical areas of focus for future research, both basic and clinical. PMID- 25797519 TI - Intra-helical salt-bridge and helix destabilizing residues within the same helical turn: Role of functionally important loop E half-helix in channel regulation of major intrinsic proteins. AB - The superfamily of major intrinsic proteins (MIPs) includes aquaporin (AQP) and aquaglyceroporin (AQGP) and it is involved in the transport of water and neutral solutes across the membrane. Diverse MIP sequences adopt a unique hour-glass fold with six transmembrane helices (TM1 to TM6) and two half-helices (LB and LE). Loop E contains one of the two conserved NPA motifs and contributes two residues to the aromatic/arginine selectivity filter. Function and regulation of majority of MIP channels are not yet characterized. We have analyzed the loop E region of 1468 MIP sequences and their structural models from six different organism groups. They can be phylogenetically clustered into AQGPs, AQPs, plant MIPs and other MIPs. The LE half-helix in all AQGPs contains an intra-helical salt-bridge and helix-breaking residues Gly/Pro within the same helical turn. All non-AQGPs lack this salt-bridge but have the helix destabilizing Gly and/or Pro in the same positions. However, the segment connecting LE half-helix and TM6 is longer by 10 15 residues in AQGPs compared to all non-AQGPs. We speculate that this longer loop in AQGPs and the LE half-helix of non-AQGPs will be relatively more flexible and this could be functionally important. Molecular dynamics simulations on glycerol-specific GlpF, water-transporting AQP1, its mutant and a fungal AQP channel confirm these predictions. Thus two distinct regions of loop E, one in AQGPs and the other in non-AQGPs, seem to be capable of modulating the transport. These regions can also act in conjunction with other extracellular residues/segments to regulate MIP channel transport. PMID- 25797520 TI - A random Q-switched fiber laser. AB - Extensive studies have been performed on random lasers in which multiple scattering feedback is used to generate coherent emission. Q-switching and mode locking are well-known routes for achieving high peak power output in conventional lasers. However, in random lasers, the ubiquitous random cavities that are formed by multiple scattering inhibit energy storage, making Q-switching impossible. In this paper, widespread Rayleigh scattering arising from the intrinsic micro-scale refractive-index irregularities of fiber cores is used to form random cavities along the fiber. The Q-factor of the cavity is rapidly increased by stimulated Brillouin scattering just after the spontaneous emission is enhanced by random cavity resonances, resulting in random Q-switched pulses with high brightness and high peak power. This report is the first observation of high-brightness random Q-switched laser emission and is expected to stimulate new areas of scientific research and applications, including encryption, remote three dimensional random imaging and the simulation of stellar lasing. PMID- 25797521 TI - The relationship between coagulation abnormality and mortality in ICU patients: a prospective, observational study. AB - We conducted a prospective, observational study to assess the prognostic value of hemostasis-related parameters in unselected ICU patients. We collected baseline characteristics from 497 consecutive unselected medical and trauma patients during their ICU stay. Each hemostasis-related parameter was analyzed alone or combined with APACHE II scores for any association with ICU mortality by calculating the under the curve (AUC) of the ROC curve, the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. Of all hemostasis-related indicators examined, the AUC for fibrin degradation products (FDPs) was less than that for APACHE II scores, but larger than that for disseminated intravascular coagulation (DIC) scores. The prediction power of FDPs is relatively low. Multiple regression analysis revealed that FDPs and APACHE II scores significantly predicted primary outcome. The combined use of FDPs level and APACHE II scores generated an NRI of 9.94% and an IDI of 3.54%. In conclusion, FDP is the best independent indicator of ICU mortality among all hemostasis-related indicators examined. The use of FDP level and APACHE II scores in parallel significantly improves the ability to predict ICU mortality, suggesting the application of these parameters could be used to improve patient care and management in the ICU. PMID- 25797523 TI - In situ fabrication and optoelectronic analysis of axial CdS/p-Si nanowire heterojunctions in a high-resolution transmission electron microscope. AB - A high-precision technique was utilized to construct and characterize axial nanowire heterojunctions inside a high-resolution transmission electron microscope (HRTEM). By an in-tandem technique using an ultra-sharp tungsten probe as the nanomanipulator and an optical fiber as the optical waveguide the nanoscale CdS/p-Si axial nanowire junctions were fabricated, and in situ photocurrents from them were successfully measured. Compared to a single constituting nanowire, the CdS/p-Si axial nanowire junctions possess a photocurrent saturation effect, which protects them from damage under high voltages. Furthermore, a set of experiments reveals the clear relationship between the saturation photocurrent values and the incident light intensities. The applied technique is expected to be valuable for bottom-up nanodevice fabrications, and the regarded photocurrent saturation feature may solve the Joule heating-induced failure problem in nanowire optoelectronic devices caused by a fluctuating bias. PMID- 25797522 TI - Intramyocardial bone marrow mononuclear cell transplantation in ischemic heart failure: Long-term follow-up. AB - BACKGROUND: Long-term results regarding treatment of chronic ischemic heart failure with bone marrow mononuclear cells (BMMCs) have been few. We received encouraging results at the 1-year follow-up of patients treated with combined coronary artery bypass grafting (CABG) and BMMCs, so we decided to extend the follow-up. METHODS: The study patients had received injections of BMMCs or vehicle into the myocardial infarction border area during CABG in a randomized and double-blind manner. We could contact 36 of the 39 patients recruited for the original study. Pre-operatively and after an extended follow-up period, we performed magnetic resonance imaging, measured pro-B-type amino-terminal natriuretic peptide, reviewed patient records from the follow-up period, and determined current quality of life with the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey. RESULTS: The median follow-up time was 60.7 months (interquartile range [IQR], 45.1-72.6 months). No statistically significant difference was detected in change of pro-B-type amino-terminal natriuretic peptide values or in quality of life between groups. The median change in left ventricular ejection fraction was 4.9% (IQR, -2.1% to 12.3%) for controls and 3.9% (IQR, -5.2% to 10.2%) for the BMMC group (p = 0.647). Wall thickening in injected segments increased by a median of 17% (IQR, -5% to 30%) for controls and 15% (IQR, -12% to 19%) for BMMC patients (p = 0.434). Scar size in injected segments increased by a median of 2% (IQR, -7% to 19%) for controls but diminished for BMMC patients, with a median change of -17% (IQR, -30% to -6%; p = 0.011). CONCLUSIONS: In the treatment of chronic ischemic heart failure, combining intramyocardial BMMC therapy with CABG fails to affect cardiac function but can sustainably reduce scar size, even in the long-term. PMID- 25797524 TI - Prospective evaluation of frequency of signs of systemic sclerosis in 76 patients with morphea. AB - OBJECTIVES: Some authors consider that morphoea and systemic sclerosis (SSc) could be part of the same disease spectrum. The aim of this study was to analyse the prevalence of signs indicative of SSc in a cohort of patients with morphoea. METHODS: This is a prospective multi-centre study performed in four French academic dermatology departments: 76 patients with morphoea and 101 age- and sex matched controls, who underwent complete clinical examination, were enrolled. A systemic search for signs indicative of SSc (e.g. Raynaud's phenomenon, reflux) was performed with the help of a standardised questionnaire. RESULTS: There were 58 women and 18 men (ration=3/1) with a median age of 59 years. Mean age at diagnosis was 54 years (extremes, 13-87). 49 subjects had plaque morphoea, 9 had generalised morphoea and 18 had linear morphoea. Mean duration of morphoea was 7.9 years. Signs possibly indicative of SSc were noted in four patients of the control group and in 8 patients with morphoea. This difference was not statistically significant (p=0.129). Further investigations ruled out SSc in all patients. CONCLUSIONS: Signs indicative of SSc are statistically not more frequently present in patients with morphoea than in controls and this study does not support the view that those 2 entities are part of a common disease spectrum. PMID- 25797525 TI - B800-B850 coherence correlates with energy transfer rates in the LH2 complex of photosynthetic purple bacteria. AB - Until recently, no analytical measure of many-body delocalization in open systems had been developed, yet such a measure enables characterization of how molecular excitons delocalize in photosynthetic light-harvesting complexes, and in turn helps us understand quantum coherent aspects of electronic energy transfer. In this paper we apply these measures to a model peripheral light-harvesting complex, LH2 from Rhodopseudomonas acidophila. We find how many chromophores collectively contribute to the "delocalization length" of an excitation within LH2 and how the coherent delocalization is distributed spatially. We also investigate to what extent this delocalization length is effective, by examining the impact of bipartite and multipartite entanglement in inter-ring energy transfer in LH2. PMID- 25797526 TI - Access to controlled medicines for palliative care in India: gains and challenges. AB - It was in the early 1990s that an appeal was made, both in India and globally, for access to palliative care to be treated as a human rights issue. Over the past few years, India has witnessed robust advocacy efforts which push for the consideration of palliative care and pain management as a human right. Central to this paper is India's Narcotic Drugs and Psychotropic Substances (NDPS) Act, 1985: its genesis, its critique, and the amendments aimed at enhancing access to the NDPS for medical care and research. I refer to the advocacy efforts in India, particularly the most recent ones, which led to the amendments to the NDPS Act, 1985 in February 2014; and the contribution of the global and local human rights discourse on palliative care to these efforts. This I situate in the overall status of palliative care in India. Towards the end, I briefly set out the agenda that should be pursued in the coming years to enhance access to controlled medicines for pain management and palliative care. PMID- 25797527 TI - Biocatalytic and antibacterial visualization of green synthesized silver nanoparticles using Hemidesmus indicus. AB - In the present investigation, we described the green synthesis of silver nanoparticles using plant leaf extract of Hemidesmus indicus. The synthesized silver nanoparticles were characterized by UV-visible spectroscopy, fourier transform infra-red spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX). TEM images proved that the synthesized silver nanoparticles were spherical in shape with an average particle size of 25.24 nm. To evaluate antibacterial efficacy, bacteria was isolated from poultry gut and subjected to 16S rRNA characterization and confirmed as Shigella sonnei. The in vitro antibacterial efficacy of synthesized silver nanoparticles was studied by agar bioassay, well diffusion and confocal laser scanning microscopy (CLSM) assay. The H. indicus mediated synthesis of silver nanoparticles shows rapid synthesis and higher inhibitory activity (34 +/- 0.2 mm) against isolated bacteria S. sonnei at 40 MUg/ml. PMID- 25797528 TI - Recovery of absorbance spectra of micrometer-sized biological and inanimate particles. AB - In this paper, we first provide an overview of the Mie type scattering at absorbing materials and existing correction methods, followed by a new method to obtain the pure absorbance spectra of biological systems with spherical symmetry. This method is a further development of the recently described iterative algorithm of van Dijk et al. The method is tested on FTIR synchrotron spectra of polymethyl methacrylate (PMMA) microspheres and pollen grains with approximately spherical shape. The imaginary part of the refractive index was successfully recovered for both systems. Good agreement was obtained between the pure absorbance spectra obtained by this method and the measured spectra. PMID- 25797529 TI - Fractions as percepts? Exploring cross-format distance effects for fractional magnitudes. AB - This study presents evidence that humans have intuitive, perceptually based access to the abstract fraction magnitudes instantiated by nonsymbolic ratio stimuli. Moreover, it shows these perceptually accessed magnitudes can be easily compared with symbolically represented fractions. In cross-format comparisons, participants picked the larger of two ratios. Ratios were presented either symbolically as fractions or nonsymbolically as paired dot arrays or as paired circles. Response patterns were consistent with participants comparing specific analog fractional magnitudes independently of the particular formats in which they were presented. These results pose a challenge to accounts that argue human cognitive architecture is ill-suited for processing fractions. Instead, it seems that humans can process nonsymbolic ratio magnitudes via perceptual routes and without recourse to conscious symbolic algorithms, analogous to the processing of whole number magnitudes. These findings have important implications for theories regarding the nature of human number sense - they imply that fractions may in some sense be natural numbers, too. PMID- 25797530 TI - The synergistic potential of the azole fungicides prochloraz and propiconazole toward a short alpha-cypermethrin pulse increases over time in Daphnia magna. AB - Pyrethroid insecticides are highly toxic to non-target aquatic invertebrates. Their high toxicity is synergized when co-occurring with azole fungicides in the aquatic environment. Little is known about the importance of synergy, when pyrethroids only occur during a short pulse of a few hours, as it is likely to happen in the environment, nor about the persistence of synergy over time. This study analyzed the synergistic potential of the fungicides propiconazole and prochloraz toward Daphnia magna, when exposed to a pulse (7.2 h) of alpha cypermethrin at different concentrations (average pulse concentrations 0.07-11 nM). Immobilization was monitored during exposure and a subsequent recovery period (87.5h) with and without continuous co-exposure to the azoles (1.4 and 1.7 MUM, respectively). EC50 values for immobilization decreased exponentially over time with a higher rate in the presence of the azoles. EC50 values for alpha cypermethrin determined at the end of the experiment were 3.3+/-0.5 nM in the absence of azoles and 0.26+/-0.04, and 0.08+/-0.01 nM in the presence of propiconazole and prochloraz, respectively. The synergistic potential of the azoles was strongly dependent on time: no synergism could be detected during the pulse, but with azole co-exposure EC50 values decreased during the recovery period by a factor of up to 13 (propiconazole) and 61 (prochloraz) compared to values without azole exposure. Such high synergistic ratios have not been reported for pesticide mixtures in literature before. Our findings highlight that a pulse of the pyrethroid alpha-cypermethrin is synergized far beyond the actual pulse and beyond standardized test durations. Long post-exposure times are therefore mandatory in order to capture full synergism. PMID- 25797531 TI - Metal accumulation and toxicity: the critical accumulated concentration of metabolically available zinc in an oyster model. AB - Invertebrates typically carry out detoxification of accumulated metals. There is, therefore, no threshold total body concentration of accumulated metal initiating toxicity, the onset of toxic effects rather being related to a critical concentration of metabolically available (MA) accumulated metal. The challenge remains as to whether any particular combination of subcellular fractions of accumulated metal can be identified to represent this theoretical MA component. One candidate combined fraction is the so-termed metal sensitive fraction (MSF), consisting of metal bound to organelles and non-detoxificatory soluble proteins. In this study, we used laboratory zinc accumulation and toxicity data for four populations of the oyster Crassostrea hongkongensis with different histories of zinc exposure in the field to address the challenge. We conclude that in a 'control' population of the oyster, the MSF does approximate to the theoretical metabolically available zinc concentration. In populations with a history of field exposure to raised zinc bioavailabilities, however, the MSF would include more zinc detoxified in the lysosome component of organelle-bound metal, and the MSF in such populations would deviate more from the theoretical MA metal concentration. PMID- 25797532 TI - Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity. AB - The pathogenesis of many autoimmune diseases is initially based on a redundant or prolonged activation of the innate immune system. It was suggested that an excessive activation of the innate immunity is often the result of a chronic inflammatory process in the organism. This inflammation can be induced by exogenous and endogenous alarm factors, or alarmins. We believe that the recently discovered neutrophil extracellular traps, or NETs, completely meet the criteria of alarmins. This review summarizes current knowledge concerning the general characteristics of NETs, their antimicrobial properties, and their role in the development of chronic inflammatory processes that underlie the pathogenesis of psoriasis and atherosclerosis. Studies on the NETosis can provide the foundation for developing new diagnostic methods and effective treatment of chronic inflammatory and autoimmune diseases. PMID- 25797533 TI - Effects of thyroid hormones on the antioxidative status in the uterus of young adult rats. AB - Thyroid hormones and oxidative stress play significant roles in the normal functioning of the female reproductive system. Nitric oxide (NO), a free radical synthesized by nitric oxide synthases (NOS), participates in the regulation of thyroid function and is also a good biomarker for assessment of the oxidative stress status. Therefore, the purpose of this study was to investigate effects of thyroid hormones on uterine antioxidative status in young adult rats. Thirty immature female Sprague-Dawley rats were randomly divided into three groups: control, hypothyroid (hypo-T) and hyperthyroid (hyper-T). The results showed the body weights decreased significantly in both the hypo-T and hyper-T groups and that uterine weights were decreased significantly in the hypo-T group. The serum concentrations of total triiodothyronine (T3) and thyroxine (T4), as well as estradiol (E2), were significantly decreased in the hypo-T group, but increased in the hyper-T group. The progesterone (P4) concentrations in the hypo- and hyperthyroid rats markedly decreased. Immunohistochemistry results provided evidence that thyroid hormone nuclear receptor alpha/beta (TRalpha/beta) and three NOS isoforms were located in different cell types of rat uteri. The NO content and total NOS and inducible NOS (iNOS) activities were markedly diminished in the hypo-T group but increased in the hyper-T group. Moreover, the activities of both glutathione peroxidase (GSH-Px) and catalase (CAT) exhibited significant decreases and increases in the hypo-T and hyper-T groups, respectively. The malondialdehyde (MDA) contents in both the hypo-T and hyper-T groups showed a significant increase. Total superoxide dismutase (T-SOD) activity in the hypo- and hyper-T rats markedly decreased. In conclusion, these results indicated that thyroid hormones have an important influence on the modulation of uterine antioxidative status. PMID- 25797534 TI - Congruent tactile stimulation reduces the strength of visual suppression during binocular rivalry. AB - Presenting different images to each eye triggers 'binocular rivalry' in which one image is visible and the other suppressed, with the visible image alternating every second or so. We previously showed that binocular rivalry between cross oriented gratings is altered when the fingertip explores a grooved stimulus aligned with one of the rivaling gratings: the matching visual grating's dominance duration was lengthened and its suppression duration shortened. In a more robust test, we here measure visual contrast sensitivity during rivalry dominance and suppression, with and without exploration of the grooved surface, to determine if rivalry suppression strength is modulated by touch. We find that a visual grating undergoes 45% less suppression when observers touch an aligned grating, compared to a cross-oriented one. Touching an aligned grating also improved visual detection thresholds for the 'invisible' suppressed grating by 2.4 dB, relative to a vision-only condition. These results show that congruent haptic stimulation prevents a visual stimulus from becoming deeply suppressed in binocular rivalry. Moreover, because congruent touch acted on the phenomenally invisible grating, this visuo-haptic interaction must precede awareness and likely occurs early in visual processing. PMID- 25797535 TI - Clauemarazoles A-G, seven carbazole alkaloids from the stems of Clausena emarginata. AB - Seven new carbazole alkaloids, clauemarazoles A-G, together with 19 known analogues were isolated from the stems of Clausena emarginata. Their structures were established on the basis of spectroscopic analyses, and the absolute configurations of compounds 1a, 1b, 5a, and 5b were confirmed by their ECD spectroscopy. Compounds 4, 13, 15, and 17 exhibited inhibitory abilities on LPS induced NO production. Compounds 10-12, 20, 22, and 24 displayed hepatoprotective effects against DL-galactosamine-induced damage in WB-F344 cells. PMID- 25797536 TI - HIF-prolyl hydroxylase is a potential molecular target for esculetin-mediated anti-colitic effects. AB - We investigated a potential molecular target for anti-colitic effects of esculetin, 6,7-dihydroxycoumarin. Esculetin administered rectally effectively ameliorated TNBS-induced rat colitis and attenuated the expression of pro inflammatory mediators in the inflamed colon. In human colon carcinoma HCT116 cells, esculetin induced hypoxia-inducible factor-1alpha (HIF-1alpha), leading to secretion of vascular endothelial growth factor, a HIF-1 target gene product involved in ulcer healing of the gastrointestinal mucosa. Esculetin directly inhibited HIF prolyl hydroxylase-2 (HPH-2), an enzyme playing a major role in negatively regulating HIF-1alpha protein stability. Esculetin inhibition of HPH and consequent induction of HIF-1alpha were attenuated by escalating dose of either ascorbate or 2-ketoglutarate, the required factors of the enzyme. Structurally, the catechol moiety in esculetin was required for HPH inhibition. Collectively, HPH may be a molecular target for esculetin-mediated anti-colitic effects and the catechol moiety in esculetin is the pharmacophore for HPH inhibition. PMID- 25797537 TI - Minor dehydrogenated and cleavaged dammarane-type saponins from the steamed roots of Panax notoginseng. AB - Nine new minor dehydrogenated and cleavaged dammarane-type triterpenoid saponins, namely notoginsenosides ST6-ST14 (1-9) were isolated from the steamed roots of Panax notoginseng, together with 14 known ones. Among them, 5-7 and 21-22 were protopanaxadiol type and the left 18 compounds, including 1-4, 8-20, and 23 were protopanaxatriol type saponins. Their structures were identified by extensive analysis of MS, 1D and 2D NMR spectra, and acidic hydrolysis. Resulted from the side chain cleavage, the new saponins 1 and 2 featured in a ketone group at C-25, and 3-5 had an aldehyde unit at C-23. The known saponins 12, 16 and 18 displayed the enhancing potential of neurite outgrowth of NGF-mediated PC12 cells at a concentration of 10 MUM, while 20 exhibited acetyl cholinesterase inhibitory activity, with IC50 value of 13.97 MUM. PMID- 25797538 TI - Personalizing surgical margins in retroperitoneal sarcomas. AB - Retroperitoneal sarcomas are a group of diseases that behave differently from one another. Well-differentiated liposarcomas have an indolent biology but show a tendency to recur locally even years after primary resection. Dedifferentiated liposarcomas are characterized by a very high local recurrence risk, while the metastatic risk mainly depends on the histological characteristics of the dedifferentiated component. In leiomyosarcomas, hematogenous spread informs prognosis while local recurrences are far less common. Surgery is the cornerstone of treatment of all retroperitoneal sarcoma subtypes and its quality is the only treatment-related factor able to improve the oncological outcome. A frontline extended surgical approach is all the more critical in subtypes in which local control directly impacts prognosis. PMID- 25797539 TI - Validity of ankylosing spondylitis and undifferentiated spondyloarthritis diagnoses in the Swedish National Patient Register. AB - OBJECTIVES: Epidemiological studies of spondyloarthritis (SpA), using ICD codes from the Swedish National Patient Register (NPR), offer unique possibilities but hinge upon an understanding of the validity of the codes. The aim of this study was to validate the ICD codes for ankylosing spondylitis (AS) and undifferentiated SpA (uSpA) in the NPR against the established classification criteria [modified New York (mNY), Assessment of SpondyloArthritis international Society (ASAS), Amor, and European Spondyloarthropathy Study Group (ESSG) criteria]. METHOD: All patients with an ICD-8/9/10 code of AS or uSpA in the NPR 1966-2009 at a visit to a specialist in rheumatology or internal medicine or corresponding hospitalization, alive and living in Sweden 2009, were identified (n=20,089). Following a structured procedure to achieve geographical representativeness, 500 random patients with a diagnosis of AS or uSpA in 2007 2009 were selected. Based on a structured review of clinical records, positive predictive values (PPVs) for fulfilling the criteria sets were calculated. RESULTS: For those having received an ICD code for AS, the PPVs for fulfilling the mNY criteria or any set of SpA criteria were 70% and 89%, respectively. For those with an uSpA diagnosis (and never an AS diagnosis), the corresponding PPVs were 20% and 79%. The subset with both AS and uSpA diagnoses (overlap=12%) were as likely to fulfil the mNY criteria as the group that had been coded as AS only. CONCLUSIONS: The diagnosis codes for AS or uSpA had high PPVs, suggesting that our case identification in the Swedish NPR can be used for nationwide, population based, epidemiological studies of these diseases. PMID- 25797540 TI - Editorial comment. PMID- 25797541 TI - Editorial comment. PMID- 25797543 TI - Hepatitis C: only a step away from elimination? PMID- 25797544 TI - Water: sustaining the reservoir. PMID- 25797545 TI - Family planning in Iran. PMID- 25797546 TI - Cancer: the elephant in the room. PMID- 25797547 TI - Ending childhood obesity: a multidimensional challenge. PMID- 25797549 TI - The NHS: what are the UK's political parties promising? PMID- 25797550 TI - Beryl Benacerraf: new AIUM President gets the picture. PMID- 25797551 TI - We need a sustainable development goal 18 on global health security. PMID- 25797552 TI - WHO and the health of LGBT individuals. PMID- 25797553 TI - The future of WHO: outsourcing? PMID- 25797554 TI - Population control policies in Iran. PMID- 25797555 TI - Population control policies in Iran - Author's reply. PMID- 25797556 TI - Meningococcal vaccination and Hajj pilgrimage. PMID- 25797557 TI - Putting patients at the heart of health-care research. PMID- 25797558 TI - Directed altruistic kidney donors from overseas mask transplant tourism. PMID- 25797559 TI - Acute eosinophilic pneumonia after recent start of smoking. PMID- 25797561 TI - Silk fibroin nanoparticle as a novel drug delivery system. AB - Design and synthesis of efficient drug delivery systems are of vital importance for medicine and healthcare. Nanocarrier-based drug delivery systems, in particular nanoparticles, have generated great excitement in the field of drug delivery since they provide new opportunities to overcome the limitations of conventional delivery methods with regards to the drugs. Silk fibroin (SF) is a naturally occurring protein polymer with several unique properties that make it a suitable material for incorporation into a variety of drug delivery vehicles capable of delivering a range of therapeutic agents. SF matrices have been shown to successfully deliver anticancer drugs, small molecules, and biomolecules. This review will provide an in-depth discussion of the development of SF nanoparticle based drug delivery systems. PMID- 25797560 TI - A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. AB - We evaluated the safety and biologic activity of the BH3 mimetic protein, navitoclax, combined with rituximab, in comparison to rituximab alone. One hundred and eighteen patients with chronic lymphocytic leukemia (CLL) were randomized to receive eight weekly doses of rituximab (arm A), eight weekly doses of rituximab plus daily navitoclax for 12 weeks (arm B) or eight weekly doses of rituximab plus daily navitoclax until disease progression or unacceptable toxicity (arm C). Investigator-assessed overall response rates (complete [CR] and partial [PR]) were 35% (arm A), 55% (arm B, p = 0.19 vs. A) and 70% (arm C, p = 0.0034 vs. A). Patients with del(17p) or high levels of BCL2 had significantly better clinical responses when treated with navitoclax. Navitoclax in combination with rituximab was well tolerated as initial therapy for patients with CLL, yielded higher response rates than rituximab alone and resulted in prolonged progression-free survival with treatment beyond 12 weeks. PMID- 25797562 TI - Robot-assisted laparoscopic hepaticojejunostomy for advanced malignant biliary obstruction. AB - INTRODUCTION: To report our experience in palliative hepaticojejunostomy for advanced malignant biliary obstruction by means of robotic approach METHODS: Robot-assisted laparoscopic hepaticojejunostomy for advanced malignant biliary obstruction was performed in nine patients from May 2009 to April 2014. RESULTS: During the study period, robotic hepaticojejunostomy for advanced malignant biliary obstruction was completed successfully in nine patients. Roux-en-Y hepaticojejunostomy and double (hepaticojejunostomy, and gastrojejunostomy) bypass were performed in five and four patients, respectively. The mean operating time was 212.8 minutes. The mean blood loss was 38.7 mL. The overall complication rate was 22.2%. Bile leak complication occurred in one patient only. There was no procedure-related mortality. The mean postoperative hospital stay was 13.3 days. Five patients received palliative systemic chemotherapy after bypass surgery. The mean survival time was 11.1 months. During follow up, only three patients with cholangiocarcinoma had recurrent biliary obstruction after end-to-side hepaticojejunostomy due to tumor progression, and needed percutaneous transhepatic biliary drainage. Among these nine patients, there were a total of eight episodes of readmission in four patients due to tumor-related symptoms or complications. CONCLUSIONS: Robot-assisted laparoscopic hepaticojejunostomy for advanced malignant biliary obstruction had a low complication rate and was associated with an improved quality of life. PMID- 25797563 TI - Gastrointestinal bleeding of obscured origin due to cystic artery pseudoaneurysm. AB - Cystic artery pseudoaneurysm is a rare condition, which usually arises from the complication of gallstone disease. Patients may present with Quinke's triad (epigastric pain, obstructive jaundice, and gastrointestinal bleeding). The results can be fatal if present with a ruptured pseudoaneurysm. We report a patient who presented with upper gastrointestinal bleeding, and later diagnosis was confirmed with a computer tomography scan of the abdomen and a three-vessel angiogram. Endovascular intervention was attempted. Although it failed, the patient was eventually cured with an open cholecystectomy. PMID- 25797564 TI - Mitochondrial diseases: From the lab bench to therapies. PMID- 25797565 TI - Core-shell magnetic molecularly imprinted polymers as sorbent for sulfonylurea herbicide residues. AB - Sulfonylurea herbicides are widely used at lower dosage for controlling broad leaf weeds and some grasses in cereals and economic crops. It is important to develop a highly efficient and selective pretreatment method for analyzing sulfonylurea herbicide residues in environments and samples from agricultural products based on magnetic molecularly imprinted polymers (MIPs). The MIPs were prepared by a surface molecular imprinting technique especially using the vinyl modified Fe3O4@SiO2 nanoparticle as the supporting matrix, bensulfuron-methyl (BSM) as the template molecule, methacrylic acid (MAA) as a functional monomer, trimethylolpropane trimethacrylate (TRIM) as a cross-linker, and azodiisobutyronitrile (AIBN) as an initiator. The MIPs show high affinity, recognition specificity, fast mass transfer rate, and efficient adsorption performance toward BSM with the adsorption capacity reaching up to 37.32 mg g( 1). Furthermore, the MIPs also showed cross-selectivity for herbicides triasulfuron (TS), prosulfuron (PS), and pyrazosulfuron-ethyl (PSE). The MIP solid phase extraction (SPE) column was easier to operate, regenerate, and retrieve compared to those of C18 SPE column. The developed method showed highly selective separation and enrichment of sulfonylurea herbicide residues, which enable its application in the pretreatment of multisulfonylurea herbicide residues. PMID- 25797566 TI - Liquid Polyamorphous Transition and Self-Organization in Aqueous Solutions of Ionic Surfactants. AB - Polyamorphous transitions in supercooled water, porous substances, solutions of polyols, and proteins are studied intensively. They accompany the self organization of hydrocarbons and surfactants. In this study, the methods of polyamorphous transition identification are proposed, and their dependence on hydrocarbons and surfactant concentration and sizes is investigated. The place of polyamorphous transitions in the general theory of phase separation is determined, and their bistability, self-oscillations, hysteresis, fluctuations, cooperative effect, enthalpy, and entropy are described. Surface, volume, and diffusion instabilities of polyamorphous transitions are analyzed. Technologies based on the properties of polyamorphous transitions are proposed. PMID- 25797567 TI - Cerebral hemodynamics at altitude: effects of hyperventilation and acclimatization on cerebral blood flow and oxygenation. AB - OBJECTIVE: Alterations in cerebral blood flow (CBF) and cerebral oxygenation are implicated in altitude-associated diseases. We assessed the dynamic changes in CBF and peripheral and cerebral oxygenation engendered by ascent to altitude with partial acclimatization and hyperventilation using a combination of near-infrared spectroscopy, transcranial Doppler ultrasound, and diffuse correlation spectroscopy. METHODS: Peripheral (Spo2) and cerebral (Scto2) oxygenation, end tidal carbon dioxide (ETCO2), and cerebral hemodynamics were studied in 12 subjects using transcranial Doppler and diffuse correlation spectroscopy (DCS) at 75 m and then 2 days and 7 days after ascending to 4559 m above sea level. After obtaining baseline measurements, subjects hyperventilated to reduce baseline ETCO2 by 50%, and a further set of measurements were obtained. RESULTS: Cerebral oxygenation and peripheral oxygenation showed a divergent response, with cerebral oxygenation decreasing at day 2 and decreasing further at day 7 at altitude, whereas peripheral oxygenation decreased on day 2 before partially rebounding on day 7. Cerebral oxygenation decreased after hyperventilation at sea level (Scto2 from 68.8% to 63.5%; P<.001), increased after hyperventilation after 2 days at altitude (Scto2 from 65.6% to 69.9%; P=.001), and did not change after hyperventilation after 7 days at altitude (Scto2 from 62.2% to 63.3%; P=.35). CONCLUSIONS: An intensification of the normal cerebral hypocapnic vasoconstrictive response occurred after partial acclimatization in the setting of divergent peripheral and cerebral oxygenation. This may help explain why hyperventilation fails to improve cerebral oxygenation after partial acclimatization as it does after initial ascent. The use of DCS is feasible at altitude and provides a direct measure of CBF indices with high temporal resolution. PMID- 25797568 TI - Recent trends and predictors of multimodality treatment for oesophageal, oesophagogastric junction, and gastric cancer: A Dutch cohort-study. AB - BACKGROUND: In recent years, evidence supporting multimodality treatment for oesophageal, oesophagogastric junction (OGJ), and gastric cancer has accumulated. This population-based cohort-study investigates trends and predictors of utilisation of multimodality treatment for oesophagogastric cancer in the Netherlands. PATIENTS AND METHODS: Data were obtained from the Netherlands Cancer Registry regarding patients with oesophageal (n = 5450), OGJ (n = 2168) and gastric cancer (n = 6683) without distant metastases who had undergone R0 or R1 surgery diagnosed between 2000 and 2012. Follow-up was completed until February 2014. Preoperative/postoperative chemotherapy and/or radiotherapy combined with surgery were considered multimodality treatment. Logistic regression analysis was performed to analyse the association of age, gender, socioeconomic status, clinical T and N classification, hospital type, comprehensive cancer centre network region, and year of diagnosis, with multimodality treatment receipt. Additional analyses were performed to explore differences in trends of utilisation of multimodality treatment between academic and non-academic hospitals. RESULTS: Multimodality treatment utilisation for oesophageal, OGJ and gastric cancer increased significantly to 90%, 85% and 56% in 2012, respectively. In oesophageal and OGJ cancer patients, preoperative chemoradiotherapy was most frequently administered (85% and 47% in 2012, respectively), and in gastric cancer patients preoperative chemotherapy (47% in 2012). Lower age, higher clinical T and N classification, and diagnosis in more recent years were significantly associated with more frequent multimodality treatment receipt. The adoption of most types of multimodality treatment in academic hospitals preceded non-academic hospitals by a year. CONCLUSION: In the Netherlands, the utilisation of multimodality treatment for oesophagogastric cancer has significantly increased during the past decade, especially in oesophageal and OGJ cancer. Multimodality treatment utilisation was especially dependent on patient and tumour characteristics and year of diagnosis, but multimodality treatment trends seem to be related to the publication of landmark studies, participation in nationally running clinical trials, and hospital type, preceding national guidelines. PMID- 25797569 TI - Ultrasound for the diagnosis of infectious diseases: Approach to the patient at point of care and at secondary level. AB - Bedside ultrasound evaluation for infection can be performed promptly at the bedside, using simple equipment and without irradiation. Visualization of the foci often enables prompt antimicrobial therapy and even early ultrasound-guided procedure, facilitating earlier confirmation. These procedures are made safer using the real-time visual control that ultrasound provides. Future challenges for an infectious diseases specialist include gaining experience about the appropriate use of point-of-care ultrasound (POCUS). Ultrasonography training is required to ensure competent use of this technology. PMID- 25797570 TI - Optimal consistency in microRNA expression analysis using reference-gene-based normalization. AB - Normalization of high-throughput molecular expression profiles secures differential expression analysis between samples of different phenotypes or biological conditions, and facilitates comparison between experimental batches. While the same general principles apply to microRNA (miRNA) normalization, there is mounting evidence that global shifts in their expression patterns occur in specific circumstances, which pose a challenge for normalizing miRNA expression data. As an alternative to global normalization, which has the propensity to flatten large trends, normalization against constitutively expressed reference genes presents an advantage through their relative independence. Here we investigated the performance of reference-gene-based (RGB) normalization for differential miRNA expression analysis of microarray expression data, and compared the results with other normalization methods, including: quantile, variance stabilization, robust spline, simple scaling, rank invariant, and Loess regression. The comparative analyses were executed using miRNA expression in tissue samples derived from subjects with schizophrenia and non-psychiatric controls. We proposed a consistency criterion for evaluating methods by examining the overlapping of differentially expressed miRNAs detected using different partitions of the whole data. Based on this criterion, we found that RGB normalization generally outperformed global normalization methods. Thus we recommend the application of RGB normalization for miRNA expression data sets, and believe that this will yield a more consistent and useful readout of differentially expressed miRNAs, particularly in biological conditions characterized by large shifts in miRNA expression. PMID- 25797571 TI - An Alternative Triage Strategy Based on Preoperative MRI for Avoiding Trimodality Therapy in Stage IB Cervical Cancer. AB - PURPOSE: Adjuvant chemoradiation following primary surgery is frequently indicated in patients with stage IB cervical cancer. The aim of this study is to evaluate the role of a magnetic resonance imaging (MRI)-based strategy in avoiding trimodality therapy. MATERIALS AND METHODS: We retrospectively reviewed all patients with stage IB cervical cancer treated initially with primary surgery at Seoul National University Hospital. We suggest an alternative triage strategy in which the primary treatment modality is determined based on preoperative MRI findings. Using this strategy, primary surgery is only indicated when there is no evidence of parametrial involvement (PMI) and lymph node metastasis (LNM) in the MRI results; when there is evidence of either or both of these factors, primary chemoradiation is selected. Assuming that this strategy is applied to our cohort, we evaluate how the rate of trimodality therapy is affected. RESULTS: Of the 254 patients in our sample, 77 (30.3%) had at least one category 1 risk factor (PMI, LNM, positive resection margin) upon pathologic examination. If the MRI-based strategy had been applied to our cohort, 168 patients would have undergone primary surgery and 86 would have undergone primary chemoradiation. Only 25 patients (9.8%) would have required trimodality therapy based on an indication of at least one category 1 pathologic risk factor following radical hysterectomy. CONCLUSION: The inclusion of MRI in the decision-making process for primary treatment modality could have reduced the number of patients requiring trimodality therapy based on the indication of a category 1 risk factor from 30.3% to 9.8% in our cohort. PMID- 25797572 TI - The Prognostic Role of Mitotic Index in Hepatocellular Carcinoma Patients after Curative Hepatectomy. AB - PURPOSE: High proliferation rate is a hallmark of cancer. The mitotic index is a useful and simple method for analysis of cell proliferation. However, the practical utility of mitotic index as a predictor of prognosis in patients with hepatocellular carcinoma (HCC) has not been determined. Therefore, we examined mitotic index as a prognostic marker in HCC patients. MATERIALS AND METHODS: We counted the number of mitotic cells in 10 high-power fields of the tumor area on hematoxylin and eosin-stained slides representing 282 surgically resected HCCs. The highest number of mitotic cells was defined as the mitotic index. RESULTS: High mitotic index was observed in 127 of 282 HCCs. High mitotic index showed significant association with younger age, larger tumor size, higher Edmondson grade, microvascular invasion, major portal vein invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T-stage, higher Barcelona Clinic Liver Cancer (BCLC) stage, higher alpha-fetoprotein level, hepatitis B virus etiology, and liver cirrhosis. Patients with high mitotic index had shorter disease-specific survival (DSS) (p < 0.001) and tended to have shorter recurrence-free survival (p=0.112). In subgroup analysis among patients with a larger tumor size, microvascular invasion, intrahepatic metastasis, higher AJCC T-stage, and higher BLCL stage, high mitotic index showed unfavorable influences on DSS (p=0.001, p=0.008, p=0.003, p=0.012, and p < 0.001, respectively). In addition, high mitotic index was an independent predictor of shorter DSS (p=0.004). CONCLUSION: High mitotic index may be a novel predictor of DSS in patients with HCC and may have utility as an auxiliary prognostic factor in HCC. PMID- 25797573 TI - PTEN Methylation Dependent Sinonasal Mucosal Melanoma. AB - Sinonasal mucosal melanoma (SMM) is an aggressive and rare type of melanoma. Although the classic RAS-RAF-MEK pathway is thought to be the main pathway involved in melanoma pathogenesis, genetic alterations in the phosphatidylinositol 3-kinase-AKT pathway, including PTEN-regulated signaling, are also thought to contribute. So far, data regarding altered PTEN expression and epigenetic mechanism of PTEN silencing in development of SMM is extremely limited. Herein we report on a case of SMM with liver and bone metastases with an epigenetic alteration of PTEN. Results of mutation analysis for BRAF, NRAS, HRAS, KRAS, PIK3CA, c-Kit, and PTEN were negative; however, methylation of PTEN CpG islands was observed. Our case not only supports PTEN as a major tumor suppressor involved in melanoma tumorigenesis, but also a potential epigenetic mechanism of PTEN silencing in development of SMM. PMID- 25797574 TI - Dermatomyositis in a Patient with Cholangiocarcinoma Detected by an [(18)F] Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Scan. AB - Cholangiocarcinoma with paraneoplastic dermatomyositis (DM) is extremely rare, and the whole body positron emission tomography-computed tomography (PET-CT) finding of paraneoplastic DM is rarely reported. We report a 66-year-old woman with metastatic cholangiocarcinoma, initially presented with bilateral proximal muscle uptake on PET-CT without clinical muscle symptoms. The initial interpretation of the high muscle uptake was metastasis to the muscles. However, while awaiting for chemotherapy, muscle weakness evolved and rapidly progressed. The level of creatine phosphokinase was significantly elevated. Electromyography revealed moderate myopathy, and a muscle biopsy showed degenerating myofibers with variable sizes. The diagnosis of paraneoplastic dermatomyositis was made. This case highlights that, although rare, paraneoplastic dermatomyositis can be present with cholangiocarcinoma. Also, muscle inflammation can precede the clinical muscle symptoms, and paraneoplastic DM should be considered as a possible differential diagnosis in the assessment of cancer patients who present with abnormal muscle tracer uptake in PET-CT scans. PMID- 25797575 TI - Sphingosine kinase 1 mediates neuroinflammation following cerebral ischemia. AB - Sphingosine kinases (Sphks) are the rate-limiting kinases in the generation of sphingosine-1-phosphate, which is a well-established intracellular pro-survival lipid mediator. Sphk2 has been reported to be protective following experimental stroke. We investigated the role of Sphk1 in cerebral ischemia using a mouse middle cerebral artery occlusion (MCAO) model and an in vitro glucose-oxygen deprivation (OGD) model. Sphk expression and activity were assessed in the ischemic brain with quantitative PCR (qPCR), Western blot, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Pharmacological and gene knockdown approaches were utilized to investigate the effects of Sphk1 on stroke outcomes. The expression of Sphk1 but not that of Sphk2 was rapidly induced in the cortical penumbra over 96h after MCAO, and the microglia were one of the major cellular sources of Sphk1 induction. Consistently, Sphk activity was enhanced in the cortical penumbra. In contrast to the protective role of Sphk2, pharmacological inhibition and cortical knockdown of Sphk1 reduced infarction at 24 and 96h after reperfusion. Additionally, the Sphk1 inhibitor improved the neurological deficits at 96h after reperfusion. Mechanistically, Sphk1 inhibition and knockdown significantly attenuated MCAO-induced expression of inflammatory mediators in the cortical penumbra. Moreover, using a conditioned medium transfer approach, we demonstrated that OGD-treated neurons induced the expression of Sphk1 and pro inflammatory mediators in primary microglia, and the microglial induction of pro inflammatory mediators by ischemic neurons was blunted by Sphk1 inhibition. Taken together, our results indicate that Sphk1 plays an essential role in mediating post-stroke neuroinflammation. PMID- 25797576 TI - The secretome of apoptotic human peripheral blood mononuclear cells attenuates secondary damage following spinal cord injury in rats. AB - After spinal cord injury (SCI), secondary damage caused by oxidative stress, inflammation, and ischemia leads to neurological deterioration. In recent years, therapeutic approaches to trauma have focused on modulating this secondary cascade. There is increasing evidence that the success of cell-based SCI therapy is due mainly to secreted factors rather than to cell implantation per se. This study investigated peripheral blood mononuclear cells as a source of factors for secretome- (MNC-secretome-) based therapy. Specifically, we investigated whether MNC-secretome had therapeutic effects in a rat SCI contusion model and its possible underlying mechanisms. Rats treated with MNC-secretome showed substantially improved functional recovery, attenuated cavity formation, and reduced acute axonal injury compared to control animals. Histological evaluation revealed higher vascular density in the spinal cords of treated animals. Immunohistochemistry showed that MNC-secretome treatment increased the recruitment of CD68(+) cells with concomitant reduction of oxidative stress as reflected by lower expression of inducible nitric oxide synthase. Notably, MNC secretome showed angiogenic properties ex vivo in aortic rings and spinal cord tissue, and experiments showed that the angiogenic potential of MNC-secretome may be regulated by CXCL-1 upregulation in vivo. Moreover, systemic application of MNC-secretome activated the ERK1/2 pathway in the spinal cord. Taken together, these results indicate that factors in MNC-secretome can mitigate the pathophysiological processes of secondary damage after SCI and improve functional outcomes in rats. PMID- 25797577 TI - Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice. AB - Intracerebral hemorrhagic stroke (ICH) causes high mortality and morbidity with very limited treatment options. Cell-based therapy has emerged as a novel approach to replace damaged brain tissues and promote regenerative processes. In this study we tested the hypothesis that intranasally delivered hypoxia preconditioned BMSCs could reach the brain, promote tissue repair and improve functional recovery after ICH. Hemorrhagic stroke was induced in adult C57/B6 mice by injection of collagenase IV into the striatum. Animals were randomly divided into three groups: sham group, intranasal BMSC treatment group, and vehicle treatment group. BMSCs were pre-treated with hypoxic preconditioning (HP) and pre-labeled with Hoechst before transplantation. Behavior tests, including the mNSS score, rotarod test, adhesive removal test, and locomotor function evaluation were performed at varying days, up to 21days, after ICH to evaluate the therapeutic effects of BMSC transplantation. Western blots and immunohistochemistry were performed to analyze the neurotrophic effects. Intranasally delivered HP-BMSCs were identified in peri-injury regions. NeuN+/BrdU+ co-labeled cells were markedly increased around the hematoma region, and growth factors, including BDNF, GDNF, and VEGF were significantly upregulated in the ICH brain after BMSC treatment. The BMSC treatment group showed significant improvement in behavioral performance compared with the vehicle group. Our data also showed that intranasally delivered HP-BMSCs migrated to peri injury regions and provided growth factors to increase neurogenesis after ICH. We conclude that intranasal administration of BMSC is an effective treatment for ICH, and that it enhanced neuroregenerative effects and promoted neurological functional recovery after ICH. Overall, the investigation supports the potential therapeutic strategy for BMSC transplantation therapy against hemorrhagic stroke. PMID- 25797578 TI - Mechanism of anomalously increased oil displacement with aqueous viscoelastic polymer solutions. AB - Single-phase flows of viscoelastic polymer solutions in both microfluidic devices and rock cores exhibit apparent flow thickening. We demonstrate that this thickening occurs above a critical Deborah number corresponding to the onset of spatio-temporal fluctuations. These fluctuations are observed to occur over a broad range of spatial and temporal scales consistent with elastic turbulence. The fluctuations provide a previously unreported mechanism for enhancing the displacement of a second, capillary trapped, immiscible phase. PMID- 25797579 TI - The radiobiology of hypofractionation. AB - If the alpha/beta ratio is high (e.g. 10 Gy) for tumour clonogen killing, but low (e.g. 3 Gy) for late normal tissue complications, then delivering external beam radiotherapy in a large number (20-30) of small (~2 Gy) dose fractions should yield the highest 'therapeutic ratio'; this is demonstrated via the linear quadratic model of cell killing. However, this 'conventional wisdom' is increasingly being challenged, partly by the success of stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) extreme hypofractionation regimens of three to five large fractions for early stage non small cell lung cancer and partly by indications that for certain tumours (prostate, breast) the alpha/beta ratio may be of the same order or even lower than that characterising late complications. It is shown how highly conformal dose delivery combined with quasi-parallel normal tissue behaviour (n close to 1) enables 'safe' hypofractionation; this can be predicted by the (alpha/beta)eff concept for normal tissues. Recent analyses of the clinical outcomes of non-small cell lung cancer radiotherapy covering 'conventional' hyper- to extreme hypofractionation (stereotactic ablative radiotherapy) regimens are consistent with linear-quadratic radiobiology, even at the largest fraction sizes, despite there being theoretical reasons to expect 'LQ violation' above a certain dose. Impairment of re-oxygenation between fractions and the very high (alpha/beta) for hypoxic cells can complicate the picture regarding the analysis of clinical outcomes; it has also been suggested that vascular damage may play a role for very large dose fractions. Finally, the link between high values of (alpha/beta)eff and normal-tissue sparing for quasi-parallel normal tissues, thereby favouring hypofractionation, may be particularly important for proton therapy, but more generally, improved conformality, achieved by whatever technique, can be translated into individualisation of both prescription dose and fraction number via the 'isotoxic' (iso-normal tissue complication probability) concept. PMID- 25797580 TI - School performance and alcohol-related disorders in early adulthood: a Swedish national cohort study. AB - BACKGROUND: Alcohol misuse is an important global health determinant and a major contributor to health inequalities. We aimed to investigate the association between school performance and alcohol-related disorders in early adulthood in a longitudinal register-based national cohort study. METHODS: We followed a register-based national cohort of Swedish citizens born 1973-1984 (N = 948,440) from compulsory school graduation at age 15-16 to 2009. We divided the population into five groups: high school marks (> mean + 1 SD); high average (between mean and mean + 1 SD); low average (between mean and mean - 1 SD); low (< mean - 1SD); and missing. Cox proportional hazard models were used to investigate the relation between school marks at time of graduation and hospital care for alcohol-related disorders in early adulthood. RESULTS: There was a steep gradient in the risk of alcohol-related disorders related to school performance. In comparison with peers in the top category of school marks, students with low marks had adjusted hazard ratios of 8.02 [95% confidence interval (CI) 7.20 to 8.91], low average 3.02 (2.72 to 3.35) and high average 1.55 (1.39 to 1.73). The risk associated with low school marks was stronger in the male population and in the group from high socioeconomic background. CONCLUSIONS: The study demonstrated a strong graded relation between low school performance and alcohol-related disorders in young adulthood. School performance should be taken into account when developing prevention programmes/policies targeting alcohol misuse among teenagers and young adults, especially if the aim is to reach high-risk groups. PMID- 25797582 TI - Methyl isobutyl ketone exposure-related increases in specific measures of alpha2u globulin (alpha2u) nephropathy in male rats along with in vitro evidence of reversible protein binding. AB - Chronic exposure to methyl isobutyl ketone (MIBK) resulted in an increase in the incidence of renal tubule adenomas and occurrence of renal tubule carcinomas in male, but not female Fischer 344 rats. Since a number of chemicals have been shown to cause male rat renal tumors through the alpha2u nephropathy-mediated mode of action, the objective of this study is to evaluate the ability of MIBK to induce measures of alpha2u nephropathy including renal cell proliferation in male and female F344 rats following exposure to the same inhalation concentrations used in the National Toxicology Program (NTP) cancer bioassay (0, 450, 900, or 1800ppm). Rats were exposed 6h/day for 1 or 4 weeks and kidneys excised approximately 18h post exposure to evaluate hyaline droplet accumulation (HDA), alpha2u staining of hyaline droplets, renal cell proliferation, and to quantitate renal alpha2u concentration. There was an exposure-related increase in all measures of alpha2u nephropathy in male, but not female rat kidneys. The hyaline droplets present in male rat kidney stained positively for alpha2u. The changes in HDA and alpha2u concentration were comparable to d-limonene, an acknowledged inducer of alpha2u nephropathy. In a separate in vitro study using a two compartment vial equilibration model to assess the interaction between MIBK and alpha2u, the dissociation constant (Kd) was estimated to be 1.27*10(-5)M. This Kd is within the range of other chemicals known to bind to alpha2u and cause nephropathy. Together, the exposure-related increase in measures of alpha2u nephropathy, sustained increase in renal cell proliferation along with an indication of reversible binding of MIBK to alpha2u, support the inclusion of MIBK in the category of chemicals exerting renal effects through a protein droplet alpha2u nephropathy-mediated mode of action (MoA). PMID- 25797583 TI - Panels of cytokines and other secretory proteins as potential biomarkers of ovarian endometriosis. AB - Endometriosis is a gynecologic disease that is characterized by nonspecific symptoms and invasive diagnostics. To date, there is no adequate noninvasive method for the diagnosis of endometriosis. Although more than 100 potential biomarkers have been investigated in blood and/or peritoneal fluid, none of these has proven useful in clinical practice. The aim to find a suitable panel of biomarkers that would allow noninvasive diagnosis thus remains of interest. We evaluated the concentrations of 16 cytokines and other secretory proteins in serum and peritoneal fluid of 58 women with ovarian endometriosis (cases) and 40 healthy women undergoing sterilization or patients with benign ovarian cysts (controls) using multiplexed double fluorescence-based immunometric assay platform and enzyme-linked immunosorbent assay. Significantly higher concentrations of glycodelin-A were shown in serum, and significantly higher levels of glycodelin-A, IL-6, and IL-8, and lower levels of leptin were measured in the peritoneal fluid of cases versus controls. In serum, the best performance was shown by models that included the ratio of leptin/glycodelin-A and the ratio of ficolin 2/glycodelin-A, whereas in the peritoneal fluid the best models included the ratio of biglycan/leptin, regulated on activation normal T-cell expressed and secreted/IL-6 and ficolin-2/glycodelin-A, and IL-8 per milligram of total protein, all in combination with age. The models using serum and peritoneal fluid distinguished between ovarian endometriosis patients and controls regardless of the menstrual cycle phase with relatively high sensitivity (72.5% to 84.2%), specificity (78.4% to 91.2%), and area under the curve (0.85 to 0.90). PMID- 25797584 TI - Levels of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and biphenyls (PCBs) in blood of informal e-waste recycling workers from Agbogbloshie, Ghana, and controls. AB - The formation and environmental release of highly toxic organohalogen compounds associated with informal recycling of waste electric and electronic equipment (e waste) is a growing problem at e-waste dumps/recycling sites (EWRSs) in many developing countries worldwide. We chose a cross-sectional study design to measure the internal exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) as well as polychlorinated biphenyls (PCBs) of individuals working on one of the largest EWRSs of Africa, located at Agbogbloshie, Accra, Ghana, and in controls from a suburb of Accra without direct exposure to EWRS activities. In whole blood samples of 21 age matched male exposed individuals (mean age: 24.7 years, SD 6.0) and 21 male controls (mean age: 24.4 years, SD 5.7) 17 PCDD/F congeners were determined. Moreover three indicator PCB congeners (#138, #153 and #180) were measured in blood of 39 exposed (mean age: 27.5 years, SD 11.7) and 19 non-exposed (mean age: 26.8 years, SD 9.7) patients. Besides a health examination, biometric and demographic data, residential and occupational history, occupational exposures and working conditions were recorded using a standardized questionnaire. In the exposed group, median PCDD/F-concentrations were 6.18 pg/g lipid base WHO2005-TEq (range: 2.1-42.7) and significantly higher compared to the control group with 4.60 pg/g lipid base WHO2005-TEq (range: 1.6-11.6). Concentrations were different for 2,3,7,8-TetraCDD, three HexaCDD and all 10 PCDF congeners, indicating a combustion pattern. Using a multivariate regression analysis exposure to EWRS activities was the most important determinant for PCDD/F exposure. Median PCB levels for the indicator congeners #138, #153 and #180 were 0.011, 0.019 and 0.008 MUg/l whole blood (ranges: 0.002-0.18, 0.003-0.16, 0.002-0.078) in the exposed group and, surprisingly, significantly higher in the controls (0.037, 0.062 and 0.022; ranges: 0.005-0.46, 0.010-0.46, 0.004-0.21). In a multivariate regression approach e-waste related activities had no positive influence on internal PCB exposure, but rather the time living in Accra. The internal PCB exposure is in particular notable for a country where PCBs have historically never been produced or used. The impact of EWRS activities on organohalogen compound exposure of individuals working at and living in the surroundings of the Agbogbloshie EWRS, and the surprisingly high PCB exposure of people living in Accra not involved in e-waste activities require further investigation. PMID- 25797581 TI - Effects of nitrogen-doped multi-walled carbon nanotubes compared to pristine multi-walled carbon nanotubes on human small airway epithelial cells. AB - Nitrogen-doped multi-walled carbon nanotubes (ND-MWCNTs) are modified multi walled carbon nanotubes (MWCNTs) with enhanced electrical properties that are used in a variety of applications, including fuel cells and sensors; however, the mode of toxic action of ND-MWCNT has yet to be fully elucidated. In the present study, we compared the interaction of ND-MWCNT or pristine MWCNT-7 with human small airway epithelial cells (SAEC) and evaluated their subsequent bioactive effects. Transmission electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and X-ray diffraction suggested the presence of N-containing defects in the lattice of the nanotube. The ND-MWCNTs were determined to be 93.3% carbon, 3.8% oxygen, and 2.9% nitrogen. A dose-response cell proliferation assay showed that low doses of ND-MWCNT (1.2MUg/ml) or MWCNT-7 (0.12MUg/ml) increased cellular proliferation, while the highest dose of 120MUg/ml of either material decreased proliferation. ND-MWCNT and MWCNT-7 appeared to interact with SAEC at 6h and were internalized by 24h. ROS were elevated at 6 and 24h in ND-MWCNT exposed cells, but only at 6h in MWCNT-7 exposed cells. Significant alterations to the cell cycle were observed in SAEC exposed to either 1.2MUg/ml of ND-MWCNT or MWCNT-7 in a time and material-dependent manner, possibly suggesting potential damage or alterations to cell cycle machinery. Our results indicate that ND-MWCNT induce effects in SAEC over a time and dose-related manner which differ from MWCNT-7. Therefore, the physicochemical characteristics of the materials appear to alter their biological effects. PMID- 25797585 TI - Assessment of indoor environmental quality in existing multi-family buildings in North-East Europe. AB - Sixteen existing multi-family buildings (94 apartments) in Finland and 20 (96 apartments) in Lithuania were investigated prior to their renovation in order to develop and test out a common protocol for the indoor environmental quality (IEQ) assessment, and to assess the potential for improving IEQ along with energy efficiency. Baseline data on buildings, as well as data on temperature (T), relative humidity (RH), carbon dioxide (CO2), carbon monoxide (CO), particulate matter (PM), nitrogen dioxide (NO2), formaldehyde, volatile organic compounds (VOCs), radon, and microbial content in settled dust were collected from each apartment. In addition, questionnaire data regarding housing quality and health were collected from the occupants. The results indicated that most measured IEQ parameters were within recommended limits. However, different baselines in each country were observed especially for parameters related to thermal conditions and ventilation. Different baselines were also observed for the respondents' satisfaction with their residence and indoor air quality, as well as their behavior related to indoor environment. In this paper, we present some evidence for the potential in improving IEQ along with energy efficiency in the current building stock, followed by discussion of possible IEQ indicators and development of the assessment protocol. PMID- 25797586 TI - Chemiluminescence detection of DNA/microRNA based on cation-exchange of CuS nanoparticles and rolling circle amplification. AB - Cation-exchange-based chemiluminescence amplification (CXCLAmp) was developed in this study. After amplification by rolling circle amplification (RCA), the proposed RCA-CXCLAmp strategy was used to detect miRNA sensitively. PMID- 25797588 TI - [Body plethysmography (I): Standardisation and quality criteria]. AB - Whole body plethysmography is used to measure lung volumes, capacities and resistances. It is a well standardised technique, and although it is widely used in paediatric chest diseases units, it requires specific equipment, specialist staff, and some cooperation by the patient. Plethysmography uses Boyle's law in order to measure the intrathoracic gas volume or functional residual capacity, and once this is determined, the residual volume and total lung capacity is extrapolated. The measurement of total lung capacity is necessary for the diagnosis of restrictive diseases. Airway resistance is a measurement of obstruction, with the total resistance being able to be measured, which includes chest wall, lung tissue and airway resistance, as well as the specific airway resistance, which is a more stable parameter that is determined by multiplying the measured values of airway resistance and functional residual capacity. The complexity of this technique, the reference equations, the differences in the equipment and their variability, and the conditions in which it is performed, has led to the need for its standardisation. Throughout this article, the practical aspects of plethysmography are analysed, specifying recommendations for performing it, its systematic calibration and the calculations that must be made, as well as the interpretation of the results obtained. The aim of this article is to provide a better understanding of the principles of whole body plethysmography with the aim of optimising the interpretation of the results, leading to improved management of the patient, as well as a consensus among the speciality. PMID- 25797587 TI - Susceptibility effects of GABA receptor subunit alpha-2 (GABRA2) variants and parental monitoring on externalizing behavior trajectories: Risk and protection conveyed by the minor allele. AB - Understanding factors increasing susceptibility to social contexts and predicting psychopathology can help identify targets for prevention. Persistently high externalizing behavior in adolescence is predictive of psychopathology in adulthood. Parental monitoring predicts low externalizing behavior, yet youth likely vary in the degree to which they are affected by parents. Genetic variants of GABA receptor subunit alpha-2 (GABRA2) may increase susceptibility to parental monitoring, thus impacting externalizing trajectories. We had several objectives: (a) to determine whether GABRA2 (rs279827, rs279826, rs279858) moderates the relationship between a component of parental monitoring, parental knowledge, and externalizing trajectories; (b) to test the form of this interaction to assess whether GABRA2 variants reflect risk (diathesis-stress) or susceptibility (differential susceptibility) factors; and (c) to clarify GABRA2 associations on the development of problem behavior. This prospective study (N = 504) identified three externalizing trajectory classes (i.e., low, decreasing, and high) across adolescence. A GABRA2 * Parental Monitoring effect on class membership was observed, such that A-carriers were largely unaffected by parental monitoring, whereas class membership for those with the GG genotype was affected by parental monitoring. Findings support differential susceptibility in GABRA2. PMID- 25797589 TI - Do I know you? Examining face and object memory in frontotemporal dementia. AB - The ability to perceive, learn and recognise faces is a complex ability, which is key to successful social interactions. This ability is proposed to be coordinated by neural regions in the occipital and temporal lobes, specialised for face perception and memory. While previous studies have suggested that memory for faces is compromised in some dementia syndromes, it remains unclear whether this simply reflects more generalised memory deficits. Here, we examined basic face perception (Identity-Matching), face recognition (Cambridge Face Memory Task) and object recognition (Cambridge Car Memory Task) in 11 semantic dementia (SD) patients (8 left-lateralised, 3 right-lateralised) and 13 behavioural-variant frontotemporal dementia (bvFTD) patients, compared with 11 controls. On the Identity-Matching task, bvFTD were impaired compared to controls, with a similar trend observed in the SD group. Importantly, both bvFTD and SD also demonstrated impaired face recognition. In contrast, only bvFTD showed impaired object recognition, with SD performing within normal limits on this task. Voxel-based morphometry analyses revealed that Identity-Matching and face recognition were associated with partly dissociable regions including the fusiform cortex and anterior temporal lobe. Object-memory was associated with thalamic integrity in the bvFTD group only. These results reveal that face perception and face memory deficits are common in bvFTD and SD, and have been previously underestimated. These deficits are due to neurodegeneration of key regions within the 'core' and 'extended' face processing system, providing convergent evidence of the neural regions supporting face perception. From a clinical perspective, impaired ability to recognise faces is common in bvFTD and SD and therefore strategies to improve face perception and memory may be beneficial for these patients. PMID- 25797590 TI - Pitch expertise is not created equal: Cross-domain effects of musicianship and tone language experience on neural and behavioural discrimination of speech and music. AB - Psychophysiological evidence supports a music-language association, such that experience in one domain can impact processing required in the other domain. We investigated the bidirectionality of this association by measuring event-related potentials (ERPs) in native English-speaking musicians, native tone language (Cantonese) nonmusicians, and native English-speaking nonmusician controls. We tested the degree to which pitch expertise stemming from musicianship or tone language experience similarly enhances the neural encoding of auditory information necessary for speech and music processing. Early cortical discriminatory processing for music and speech sounds was characterized using the mismatch negativity (MMN). Stimuli included 'large deviant' and 'small deviant' pairs of sounds that differed minimally in pitch (fundamental frequency, F0; contrastive musical tones) or timbre (first formant, F1; contrastive speech vowels). Behavioural F0 and F1 difference limen tasks probed listeners' perceptual acuity for these same acoustic features. Musicians and Cantonese speakers performed comparably in pitch discrimination; only musicians showed an additional advantage on timbre discrimination performance and an enhanced MMN responses to both music and speech. Cantonese language experience was not associated with enhancements on neural measures, despite enhanced behavioural pitch acuity. These data suggest that while both musicianship and tone language experience enhance some aspects of auditory acuity (behavioural pitch discrimination), musicianship confers farther-reaching enhancements to auditory function, tuning both pitch and timbre-related brain processes. PMID- 25797591 TI - Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids. AB - Flavonoids were found previously to modulate efficiency of synthesis of glycosaminoglycans (GAGs), compounds which are accumulated in cells of patients suffering from mucopolysaccharidoses (MPSs). The aim of this work was to determine effects of different flavonoids (genistein, kaempferol, daidzein) used alone or in combinations, on expression of genes coding for proteins involved in GAG metabolism. Analyses with DNA microarray, followed by real-time qRT-PCR revealed that genistein, kaempferol and combination of these two compounds induced dose- and time-dependent remarkable alterations in transcript profiles of GAG metabolism genes in cultures of wild-type human dermal fibroblasts (HDFa). Interestingly, effects of the mixture of genistein and kaempferol were stronger than those revealed by any of these compounds used alone. Similarly, the most effective reduction in levels of GAG production, in both HDFa and MPS II cells, was observed in the presence of genistein, keampferol and combination of these compounds. Forty five genes were chosen for further verification not only in HDFa, but also in MPS II fibroblasts by using real-time qRT-PCR. Despite effects on GAG metabolism-related genes, we found that genistein, kaempferol and mixture of these compounds significantly stimulated expression of TFEB. Additionally, a decrease in MTOR transcript level was observed at these conditions. PMID- 25797592 TI - Metabolic markers associated with high mannose glycan levels of therapeutic recombinant monoclonal antibodies. AB - High mannose (HM) glycan levels on secreted monoclonal antibodies can be influenced by external factors, including osmolality and copper deficiency, and by intrinsic factors determined by different cell lines. In order to identify the metabolic markers associated with HM glycan levels, metabolomics analysis was performed to assess the changes in the extracellular metabolites of recombinant cell lines at different time points during fed-batch production process. Ornithine was identified as the common metabolic marker influenced by both external and intrinsic factors when eight different medium conditions and eight different cell lines exhibiting different levels of HM were compared. A strong correlation was also observed between HM and mRNA expression levels of arginase 1, an enzyme that catalyzes the conversion of arginine to ornithine. The results from functional validation study showed that the supplementation of ornithine to the culture medium leads to an increased level of HM, while reduced concentration of spermine, a downstream product of ornithine metabolism, leads to a decreased level of HM. Additional metabolic markers correlating with HM glycan levels were identified from eight-cell line comparison analysis. A common feature shared by these identified markers is their previously described roles as contributors of cellular redox regulation. PMID- 25797593 TI - Synthesis of atomically thin transition metal disulfides for charge transport layers in optoelectronic devices. AB - Metal sulfides (MeS2) such as MoS2 and WS2 were used as charge transport layers in organic light-emitting diodes (OLEDs) and organic photovoltaic (OPV) cells in order to enhance the stability in air comparing to poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS). MeS2 layers with a polycrystalline structure were synthesized by a chemical deposition method using uniformly spin-coated (NH4)MoS4 and (NH4)WS4 precursor solutions. The ultraviolet ozone (UV-O3) treatment on MeS2 leads to the removal of the surface contaminants produced by the transfer process, resulting in a uniform surface and an increase of the work function. The maximum luminance efficiencies of the OLEDs with UV-O3 treated MoS2 and WS2 were 9.44 and 10.82 cd/A, respectively. The power conversion efficiencies of OPV cells based on UV-O3-treated MoS2 and WS2 were 2.96 and 3.08%, respectively. These values correspond to over 95% of those obtained with ( PEDOT: PSS) based devices. Furthermore, OLEDs and OPV cells based on MeS2 showed two to six times longer stability in air compared with PEDOT: PSS based devices. These results suggest that UV-O3-surface-treated MeS2 could be a promising candidate for a charge transport layer in optoelectronic devices. PMID- 25797594 TI - Gold nanoparticle and carbon dot coated SnO2 nanocomposite with high photo electronic catalytic activity for oxygen evolution reaction. AB - Here, we have reported the design, synthesis and catalytic properties of a gold nanoparticle/carbon dot/SnO2 nanocomposite photo-electronic catalyst for oxygen evolution reaction. PMID- 25797595 TI - New oral anticoagulants versus vitamin K antagonists before cardioversion of atrial fibrillation: a meta-analysis of data from 4 randomized trials. AB - BACKGROUND: Scarce data are available about efficacy and safety of new oral anticoagulants (NOACs) for cardioversion (CV) of atrial fibrillation (AF). We performed a meta-analysis of data from randomized studies reporting outcomes of patients receiving NOACs, as compared to vitamin K antagonists (VKAs), and undergoing CV of AF. METHODS: Data from four studies were selected, including 4268 CVs. The primary endpoints were the incidence of stroke or systemic embolism and the incidence of major bleeding within 30 days. RESULTS: There was not any significant difference in the incidence of stroke or systemic embolism between NOACs and VKAs (RR 0.73, p = 0.47) nor in the incidence of major bleeding (RR 1.39, p = 0.13). CONCLUSIONS: We found no evidence of differential outcomes after CV of AF according to treatment with NOACs or VKAs. This finding warrants confirmation in larger clinical series and in the setting of properly powered randomized trials of newly diagnosed AF. PMID- 25797596 TI - Leishmania infantum in wild rodents: reservoirs or just irrelevant incidental hosts? AB - Wild rodents constitute a very large biomass of potential reservoirs for Leishmania spp. Therefore, an epidemiological study was carried out in a well known focus of canine leishmaniasis from southern Spain, with the objective of detecting and characterizing Leishmania infantum infection in wild rodents. Blood, liver, spleen, bone marrow, and skin from 37 rodents (24 Apodemus sylvaticus, 9 Rattus rattus, and 4 Mus musculus) were analyzed by optical microscopy, culture, and two different polymerase chain reactions. L. infantum DNA was found in 27% (10 out of 37) of the trapped rodents, in a variety of tissues: bone marrow, spleen, or healthy skin (ear lobe). High prevalences of L. infantum infection were found in the three investigated rodent species. The presence of other trypanosomatids was also evidenced. These rodent species are abundant, widely distributed in Europe, and have a long enough lifespan to overcome the low sandfly activity season. They live in a suitable habitat for sandflies and serve as blood sources for these insects, which can become infected when induced to feed on Leishmania-infected animals. Whether they are reservoirs or just irrelevant incidental hosts, it is clear that the epidemiology of L. infantum is more complex than previously thought, and so is its control. The classic epidemiological cycle dog-sandfly-human is turning into a network of animal species that collaborate with the dog in the maintenance of the parasite under natural conditions and probably showing local differences. PMID- 25797597 TI - Synthesis and reactivity of 4,4-Dialkoxy-BODIPYs: an experimental and computational study. AB - A series of boron-disubstituted O-BODIPYs were synthesized, and their structures and spectroscopic properties were investigated using both computational and experimental methods. Three methods were investigated for the preparation of 4,4 dimethoxy-BODIPYs bearing electron-donating or electron-withdrawing 8-aryl groups: method A employs refluxing in the presence of NaOMe/MeOH, method B uses AlCl3 in refluxing dichloromethane followed by addition of methanol as nucleophile, and method C involves activation of the BODIPYs using TMSOTf in refluxing toluene followed by addition of methanol. The yields obtained depend on the method used and the structure of the starting BODIPYs; for example, 1a and 3a were most efficiently prepared using method C (98 and 70%, respectively), while 2a was best prepared by method A (50%). Methods B and C were employed for the synthesis of seven new 4,4-dialkoxy-BODIPYs. 4,4-Dipropargyloxy-BODIPY 1e reacted under Cu(I)-catalyzed alkyne-azide Huisgen cycloaddition conditions to produce 4,4-bis(1,2,3-triazole)-BODIPY 4 in 78% yield. The substitution of the fluorides for alkoxy groups on the BODIPYs had no significant effect on the absorption and emission wavelengths but altered their fluorescence quantum yields. Among this series of dialkoxy-BODIPYs, the 4,4-dipropargyloxy 1e and its corresponding bis(1,2,3-triazole) 4 show the largest quantum yields in toluene and THF, respectively. PMID- 25797598 TI - Extracorporeal membrane oxygenation use, expenditure, and outcomes in taiwan from 2000 to 2010. AB - BACKGROUND: No study to date has systematically examined use, expenditure, and outcomes associated with extracorporeal membrane oxygenation (ECMO) use in Taiwan. The aim of this study was to examine ECMO use, expenditure, and outcomes during an 11-year period in Taiwan. METHODS: Claims data were collected from the Taiwan National Health Insurance Research Database for patients who received >=1 ECMO treatment between January 2000 and December 2010. Measurements included demographics, indications for ECMO use, length of hospital stay, outcome, and expenditure. RESULTS: A total of 3969 patients received ECMO during the study period (median age: 54.6 years). The number of patients receiving ECMO increased from 52 in 2000 to 1045 in 2010. The major indication for ECMO was cardiovascular disease (68.7%), followed by respiratory disease (17.9%). Median length of hospital stay was 13 days in 2000 and 17 days in 2010. Median expenditure (New Taiwan dollars) was $604 317 in 2000 and $673 888 in 2010. Some variables significantly differed by age, sex, hospital setting, calendar year, and indication for ECMO, and were associated with in-hospital and after-discharge mortality. CONCLUSIONS: ECMO use has increased dramatically in Taiwan over the last decade. The high mortality rate of ECMO users suggested that ECMO may be being used in Taiwan for situations in which it provides no added benefit. This situation may be a reflection of the current reimbursement criteria for National Health Insurance in Taiwan. Refinement of the indications for use of ECMO is suggested. PMID- 25797599 TI - Demographic and socioeconomic disparity in knowledge about tuberculosis in Inner Mongolia, China. AB - BACKGROUND: The aim of this study is to evaluate the awareness status, attitudes, and care-seeking behaviors concerning tuberculosis (TB) and associated factors among the public in Inner Mongolia, China. METHODS: A five-stage sampling was conducted, in which counties as the primary survey units and towns, villages, and households as sub-survey units were selected progressively. A standardized questionnaire was used to collect TB information. Complex survey analysis methods, including the procedures of survey frequency and survey logistic regression, were applied for analysis of TB knowledge and associated factors. The sample was weighted by survey design, non-respondent, and post-stratification adjustment. RESULTS: Among 10 581 respondents, awareness that TB is an infectious disease was 86.7%. Knowing that a cough lasting >=3 weeks is suggestive of TB was 26.9%. Knowledge about TB dispensaries in county administrative areas was reported by 68.3% of respondents, and knowledge about the free TB detection/treatment policy was reported by 57.5% of respondents. About 52.5% of participants would stigmatize TB patients. Compared with the majority Han ethnic group, Mongolians and other minorities were 1.52-2.18 times more likely to know about TB curability, TB symptoms, the free detection/treatment policy, and TB dispensaries' locations, but were less likely to know about the TB transmission mode (odds ratio, 0.74; 95% confidence interval, 0.65-0.84). The main sources of TB information were TV (65.6%) and other persons (47.2%). In the past year, 19.7% of TB knowledge was from acquaintances, and 16.1% was from TB institutes. CONCLUSIONS: Improvement in knowledge about TB risk (symptoms and transmission), the free treatment policy, and facilities is necessary and should be provided through effective multimedia for different target populations. PMID- 25797600 TI - The relationship between Asian dust events and out-of-hospital cardiac arrests in Japan. AB - BACKGROUND: Asian dust events are caused by dust storms that originate in the deserts of China and Mongolia and drift across East Asia. We hypothesized that the dust events would increase incidence of out-of-hospital cardiac arrests by triggering acute events or exacerbating chronic diseases. METHODS: We analyzed the Utstein-Style data collected in 2005 to 2008 from seven prefectures covering almost the entire length of Japan to investigate the effect of Asian dust events on out-of-hospital cardiac arrests. Asian dust events were defined by the measurement of light detection and ranging. A time-stratified case-crossover analysis was performed. The strength of the association between Asian dust events and out-of-hospital cardiac arrests was shown by odds ratios and 95% confidence intervals in two conditional logistic models. A pooled estimate was obtained from area-specific results by random-effect meta-analysis. RESULTS: The total number of cases of out-of-hospital cardiac arrest was 59 273, of which 35 460 were in men and 23 813 were in women. The total number of event days during the study period was smallest in Miyagi and Niigata and largest in Shimane and Nagasaki. There was no significant relationship between Asian dust events and out-of hospital cardiac arrests by area in either of the models. In the pooled analysis, the highest odds ratios were observed at lag day 1 in both model 1 (OR 1.07; 95% CI, 0.97-1.19) and model 2 (OR 1.08; 95% CI, 0.97-1.20). However, these results were not statistically significant. CONCLUSIONS: We found no evidence of an association between Asian dust events and out-of-hospital cardiac arrests. PMID- 25797603 TI - (99m)Tc radiolabelling of Fe3O4-Au core-shell and Au-Fe3O4 dumbbell-like nanoparticles. AB - The development of nanoparticle-based dual-modality probes for magnetic resonance imaging (MRI) and positron emission tomography (PET) or single photon emission computed tomography (SPECT) is increasingly growing in importance. One of the most commonly used radionuclides for clinical SPECT imaging is (99m)Tc and the labelling of Fe3O4 nanoparticles with (99m)Tc was shown to be a successful strategy to obtain dual-modality imaging agents. In this work, we focus on gold containing magnetic nanomaterials. The radiolabelling of magnetic Fe3O4-Au core shell and Fe3O4-Au dumbbell-like nanoparticles with the [(99m)Tc(CO)3](+) fragment is described. The key elements for this (99m)Tc labelling approach are novel coating ligands, consisting of an anchor for the Au surface, a polyethylene glycol linker and a strong chelator for the [(99m)Tc(CO)3](+) moiety. PMID- 25797602 TI - TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway. AB - The role of the aryl hydrocarbon receptor (AhR) in hemostasis has recently gained increased attention. Here, we demonstrate, by qRT-PCR and western blot, that human platelets express both AhR mRNA and AhR protein. AhR protein levels increase in a dose dependent manner when incubated with either 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) or omeprazole. Treatment of platelets with puromycin blocks increased AhR protein synthesis in the presence of AhR activators. Additionally, treatment of platelets with either activator results in phosphorylation of p38MAPK and cPLA2, two key signaling molecules in platelet activation pathways. Using the AhR competitive inhibitors alpha naphthoflavone and CH-223191, we show that phosphorylation of p38MAPK is AhR dependent. Further, inhibition of p38MAPK blocks downstream cPLA2 phosphorylation induced by TCDD or omeprazole. Treatment with AhR activators results in platelet priming, as demonstrated by increased platelet aggregation, which is inhibited by AhR antagonists. Our data support a model of the platelet AhR non-genomic pathway in which treatment with AhR activators results in increased expression of the AhR, phosphorylation of p38MAPK and cPLA2, leading to platelet priming in response to agonist. PMID- 25797601 TI - Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins. AB - AlkB proteins are evolutionary conserved Fe(II)/2-oxoglutarate-dependent dioxygenases, which remove alkyl and highly promutagenic etheno(E)-DNA adducts, but their substrate specificity has not been fully determined. We developed a novel assay for the repair of E-adducts by AlkB enzymes using oligodeoxynucleotides with a single lesion and specific DNA glycosylases and AP endonuclease for identification of the repair products. We compared the repair of three E-adducts, 1,N(6)-ethenoadenine (EA), 3,N(4)-ethenocytosine (EC) and 1,N(2) ethenoguanine (1,N(2)-EG) by nine bacterial and two human AlkBs, representing four different structural groups defined on the basis of conserved amino acids in the nucleotide recognition lid, engaged in the enzyme binding to the substrate. Two bacterial AlkB proteins, MT-2B (from Mycobacterium tuberculosis) and SC-2B (Streptomyces coelicolor) did not repair these lesions in either double-stranded (ds) or single-stranded (ss) DNA. Three proteins, RE-2A (Rhizobium etli), SA-2B (Streptomyces avermitilis), and XC-2B (Xanthomonas campestris) efficiently removed all three lesions from the DNA substrates. Interestingly, XC-2B and RE-2A are the first AlkB proteins shown to be specialized for E-adducts, since they do not repair methylated bases. Three other proteins, EcAlkB (Escherichia coli), SA 1A, and XC-1B removed EA and EC from ds and ssDNA but were inactive toward 1,N(2) EG. SC-1A repaired only EA with the preference for dsDNA. The human enzyme ALKBH2 repaired all three E-adducts in dsDNA, while only EA and EC in ssDNA and repair was less efficient in ssDNA. ALKBH3 repaired only EC in ssDNA. Altogether, we have shown for the first time that some AlkB proteins, namely ALKBH2, RE-2A, SA 2B and XC-2B can repair 1,N(2)-EG and that ALKBH3 removes only EC from ssDNA. Our results also suggest that the nucleotide recognition lid is not the sole determinant of the substrate specificity of AlkB proteins. PMID- 25797604 TI - Texture analysis and classification in coherent anti-Stokes Raman scattering (CARS) microscopy images for automated detection of skin cancer. AB - Coherent anti-Stokes Raman scattering (CARS) microscopy is a powerful tool for fast label-free tissue imaging, which is promising for early medical diagnostics. To facilitate the diagnostic process, automatic image analysis algorithms, which are capable of extracting relevant features from the image content, are needed. In this contribution we perform an automated classification of healthy and tumor areas in CARS images of basal cell carcinoma (BCC) skin samples. The classification is based on extraction of texture features from image regions and subsequent classification of these regions into healthy and cancerous with a perceptron algorithm. The developed approach is capable of an accurate classification of texture types with high sensitivity and specificity, which is an important step towards an automated tumor detection procedure. PMID- 25797605 TI - Automatic differentiation of melanoma from dysplastic nevi. AB - Malignant melanoma causes the majority of deaths related to skin cancer. Nevertheless, it is the most treatable one, depending on its early diagnosis. The early prognosis is a challenging task for both clinicians and dermatologist, due to the characteristic similarities of melanoma with other skin lesions such as dysplastic nevi. In the past decades, several computerized lesion analysis algorithms have been proposed by the research community for detection of melanoma. These algorithms mostly focus on differentiating melanoma from benign lesions and few have considered the case of melanoma against dysplastic nevi. In this paper, we consider the most challenging task and propose an automatic framework for differentiation of melanoma from dysplastic nevi. The proposed framework also considers combination and comparison of several texture features beside the well used colour and shape features based on "ABCD" clinical rule in the literature. Focusing on dermoscopy images, we evaluate the performance of the framework using two feature extraction approaches, global and local (bag of words) and three classifiers such as support vector machine, gradient boosting and random forest. Our evaluation revealed the potential of texture features and random forest as an almost independent classifier. Using texture features and random forest for differentiation of melanoma and dysplastic nevi, the framework achieved the highest sensitivity of 98% and specificity of 70%. PMID- 25797606 TI - Using epidemics to map H3 equine influenza virus determinants of antigenicity. AB - Equine influenza is a major cause of respiratory infections in horses and causes widespread epidemics, despite the availability of commercial vaccines. Antigenic drift within the haemagglutinin (HA) glycoprotein is thought to play a part in vaccination breakdown. Here, we carried out a detailed investigation of the 1989 UK outbreak, using reverse genetics and site-directed mutagenesis, to determine the individual contribution of amino acid substitutions within HA. Mutations at positions 159, 189 and 227 all altered antigenicity, as measured by haemagglutination-inhibition assays. We also compared HA sequences for epidemic and vaccine strains from four epidemics and found that at least 8 amino acid differences were present, affecting multiple antigenic sites. Substitutions within antigenic site B and at least one other were associated with each outbreak, we also identified changes in loop regions close to antigenic sites that have not previously been highlighted for human H3 influenza viruses. PMID- 25797608 TI - Night-eating symptoms and 2-year weight change in parents enrolled in the QUALITY cohort. AB - BACKGROUND/OBJECTIVE: The timing of food intake may be implicated in weight gain. This study tested the hypothesis that symptoms commonly associated with night eating syndrome are related to measures of weight gain in adults. SUBJECTS/METHODS: Parents participating in QUALITY (Quebec Adipose and Lifestyle InvesTigation in Youth) completed the night eating questionnaire (NEQ) at baseline (2005-2008) and at follow-up (2008-2010). Height and weight were measured and self-report questionnaire data were available for 388 parents (59% female, mean (s.d.) age: 41.8+/-5.7, mean (s.d.) body mass index (BMI): 29.6+/ 5.7). Linear regression models were used to test the associations between baseline night-eating symptoms (NEQ scores, night-eating behaviours) and percent change in each of BMI and waist circumference (WC). RESULTS: A high NEQ score predicted a small increase in percent change in BMI in nonobese parents but a decrease among those who were severely obese. Nocturnal ingestions of food predicted an increase in percent change in BMI; however, the effect size was small. Morning anorexia predicted an increase in percent change in WC. CONCLUSION: Certain night-eating symptoms may predict measures of weight gain in adults but the effects seem small and the findings need to be confirmed in more symptomatic samples. PMID- 25797607 TI - Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5. AB - Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the beta3 strand of the HIV gp120 bridging sheet that increase M tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120 CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues. PMID- 25797609 TI - Are you also what your mother eats? Distinct proteomic portrait as a result of maternal high-fat diet in the cerebral cortex of the adult mouse. AB - Epidemiological studies suggest an association between maternal obesity and adverse neurodevelopmental outcomes in offspring. Our aim was to compare the global proteomic portrait in the cerebral cortex between mice born to mothers on a high-fat or control diet who themselves were fed a high-fat or control diet. Male mice born to dams fed a control (C) or high-fat (H) diet 4 weeks before conception and during gestation, and lactation were assigned to either C or H diet at weaning. Mice were killed at 19 weeks and their cerebral cortices were analysed using a two-dimensional liquid chromatography-mass spectrometry methodology. In total, 6 695 proteins were identified (q<0.01), 10% of which were modulated in at least one of the groups relative to controls. In silico analysis revealed that mice clustered based on the diet of the mother and not their own diet and that maternal high-fat diet was significantly associated with response to hypoxia/oxidative stress and apoptosis in the cerebral cortex of the adult offspring. Maternal high-fat diet resulted in distinct endophenotypic changes of the adult offspring cerebral cortex independent of its current diet. The identified proteins could represent novel therapeutic targets for the prevention of neuropathological features resulting from maternal obesity. PMID- 25797610 TI - Fluoroquinolones for the treatment of tuberculosis in children. AB - The fluoroquinolones are key components of current multidrug-resistant tuberculosis (MDR-TB) treatment regimens and are being evaluated in shortened treatment regimens as well as in the prevention of drug-resistant TB. The objective of this review was to identify existing evidence for the use of the fluoroquinolones ofloxacin, levofloxacin and moxifloxacin in the treatment of TB in children. Existing data from in vitro, animal and human studies consistently demonstrate the efficacy of the fluoroquinolones against Mycobacterium tuberculosis, with superiority of levofloxacin and moxifloxacin compared to ofloxacin. In vitro and murine studies demonstrated the potential of moxifloxacin to shorten drug-susceptible TB treatment, but in multiple randomized controlled trials shortened fluoroquinolone-containing regimens have not been non-inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration, with newer more potent fluoroquinolones less likely to develop resistance. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-TB in children. There is a paucity of pharmacokinetic data especially in children <5 years of age and HIV-infected children; existing studies show substantially lower serum concentrations in children compared to adults at currently recommended doses, probably due to faster elimination. This has implications for optimizing paediatric treatment and for the development of resistance. Fluoroquinolone use has been restricted in children due to concerns about drug-induced arthropathy. The available data does not demonstrate any serious arthropathy or other severe toxicity in children. Although there is limited paediatric safety data for the prolonged treatment of MDR-TB, extended administration of fluoroquinolones in adults with MDR-TB does not show serious adverse effects and there is no evidence suggesting less tolerability of fluoroquinolones in children. Additional study of moxifloxacin and levofloxacin for TB treatment and prevention in children is an urgent priority. PMID- 25797611 TI - Lipid biomarkers provide evolutionary signposts for the oldest known cases of tuberculosis. AB - Studies on the evolution of tuberculosis, and the influence of this disease on human and animal development and interaction, require the accumulation of indisputable biomarker evidence. Ideally, the determination of full genomes would provide all the necessary information, but for very old specimens DNA preservation may be compromised and only limited DNA amplification may be a possibility. Mycobacterium tuberculosis is characterised by the presence of unusual cell envelope lipids, with specific biomarker potential. Lipid biomarker recognition has been decisive in pinpointing the oldest known cases of human and animal tuberculosis; the former are a woman and child from a pre-pottery settlement at Atlit-Yam, Israel (~9,000 ka) and the latter is an extinct Bison antiquus from Natural Trap Cave, Wyoming (~17,000 ka). Including some new data, it is demonstrated how analysis of a combination of mycolic, mycocerosic and mycolipenic acid and phthiocerol biomarkers provide incontrovertible evidence for tuberculosis in these landmark specimens. PMID- 25797612 TI - Cytokines for monitoring anti-tuberculous therapy: A systematic review. AB - The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-alpha, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment. PMID- 25797613 TI - Tuberculosis - A global emergency: Tools and methods to monitor, understand, and control the epidemic with specific example of the Beijing lineage. AB - We argue in favor of a concerted and coordinated response to stop tuberculosis (TB) by monitoring global TB spread, drug-resistance surveillance and populations at risk using available molecular and web tools to identify circulating clones of Mycobacterium tuberculosis complex (MTBC). We took specific example of the Beijing lineage associated with worldwide emergence of both multiple, and extensively drug resistant (MDR/XDR)-TB. The study dataset (n=10,850 isolates, 92 countries of patient origin) was extracted from our multimarker SITVIT2 database on MTBC genotyping (n=111,635 isolates, 169 countries of patient origin). Epidemiological and demographic information in conjunction with spoligotyping (n=10,850), MIRU-VNTR minisatellites (n=2896), and drug resistance (n=2846) data was mapped at macro-geographical (United Nations subregions) and country level, followed by statistical, bioinformatical, and phylogenetical analysis. The global male/female sex ratio was 1.96, the highest being 4.93 in Russia vs. range of 0.8 1.13 observed in Central America, Caribbean, Eastern Africa and Northern Europe (p < 0.0001). The major patient age-group was 21-40 yrs worldwide except Japan (with majority of patients >60 yrs). Younger patients were more common in South America, South Asia, and Western Africa since 25-33% of TB cases due to Beijing genotype occurred in the age group 0-20 yrs. A continuous progression in the proportion of MDR and XDR strains is visible worldwide since 2003 and 2009 respectively. Pansusceptible TB mainly concerned older patients >60 yrs (44%) whereas Drug resistant, MDR and XDR-TB concerned patients preferentially aged 21 40 yrs (between 52 and 58%). Although the proportion of SIT1 pattern vs. other patterns was very high (93%); the proportion of MDR was highest for an emerging genotype SIT190 (p < 0.0001). Lastly, proportion of pansusceptible strains was highest in Japan, while MDR/XDR strains were most common in Russia and Northern Europe. We underline remarkable macro/micro-geographical cleavages in phylogenetic and epidemiologic diversity of Beijing genotype, with phylogeographical specificity of certain genotypes. PMID- 25797615 TI - Determining the need for pain medications for a patient with a disorder of consciousness. PMID- 25797614 TI - Ice hockey summit II: zero tolerance for head hits and fighting. AB - OBJECTIVE: To present currently known basic science and on-ice influences of sport related concussion (SRC) in hockey, building upon the Ice Hockey Summit I action plan (2011) to reduce SRC. METHODS: The prior summit proceedings included an action plan intended to reduce SRC. As such, the proceedings from Summit I served as a point of departure, for the science and discussion held during Summit II (Mayo Clinic, Rochester MN, October, 2013). Summit II focused on Basic Science of Concussions in Ice Hockey: Taking Science Forward; (2) Acute and Chronic Concussion Care: Making a Difference; (3) Preventing Concussions via Behavior, Rules, Education and Measuring Effectiveness; (4) Updates in Equipment: their Relationship to Industry Standards and (5) Policies and Plans at State, National and Federal Levels to reduce SRC. Action strategies derived from the presentations and discussion described in these sectors were subsequently voted on for purposes of prioritization. The following proceedings include the knowledge and research shared by invited faculty, many of whom are health care providers and clinical investigators. RESULTS: The Summit II evidence based action plan emphasizes the rapidly evolving scientific content of hockey SRC. It includes the most highly prioritized strategies voted on for implementation to decrease concussion. CONCLUSIONS: The highest priority action items identified from the Summit include: 1) eliminate head hits from all levels of ice hockey, 2) change body checking policies, and 3) eliminate fighting in all amateur and professional hockey. PMID- 25797616 TI - Toward coordinated colloids: site-selective growth of titania on patchy silica particles. AB - Rational synthesis of coordinated spherical colloids is reported by site selective growth of secondary hemispherical patches on primary spherical particles with quasi-defined coordination numbers and positions. We clarify the importance of mass transport phenomena on the site-specific secondary nucleation/growth in nanoparticulate colloidal systems. By comparing ultrasonic and conventional agitation during patch growth, we found that enhanced mass transfer is the key to controlled, homogeneous transport of the molecular precursors in a solvent onto the nanoparticles. With chemically defined nucleation sites, the surfaces of spherical silica particles were modified for use as a new kind of colloid with patches at desired coordination positions. Our observations represent a significant breakthrough in colloidal chemistry and self assembly. PMID- 25797617 TI - The association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population: evidence from an updated meta-analysis. AB - Previous studies have reported the association of glutathione S-transferase M1 (GSTM1) deletion polymorphism with genetic susceptibility of lung cancer in Chinese population. However, the results remained controversial. The aim of this study was to clarify the association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population. Systematic searches were performed through the search engines of Medline/Pubmed, Web of Science, EMBASE, CNKI and Wanfang Medical Online. The pooled effects were calculated by STATA 10.0 software package and Review Manager 5.0.24. Overall, we observed an association of GSTM1 deletion polymorphism with increased lung cancer risk in Chinese population (odds ratio (OR) = 1.46, 95% confidence interval (95%CI): 1.32-1.66 for null genotype vs. present genotype) based on 53 studies including 7,833 cases and 10,353 controls. We also observed an increased risk of GSTM1 null genotype for lung cancer in stratified analyses by source of control, smoking status and histological type. The findings suggest that GSTM1 deletion polymorphism may contribute to lung cancer risk in Chinese population. Further, well-designed studies with larger sample sizes are required to verify the results. PMID- 25797618 TI - Complement inhibitor CD55 governs the integrity of membrane rafts in pancreatic beta cells, but plays no role in insulin secretion. AB - CD55 is a glycosylphosphatidylinositol-anchored protein, which inhibits complement activation by acting on the complement C3 convertases. CD55 is widely localized in the cholesterol rich regions of the cell plasma membrane termed membrane rafts. CD55 is attached to these specialized regions via a GPI link on the outer leaflet of the plasma membrane. Membrane rafts anchor many important signaling proteins, which control several cellular functions within the cell. For example, we recently demonstrated that the membrane raft protein and complement inhibitor CD59 also controls insulin secretion by an intracellular mechanism. Therefore, we have in this study aimed at addressing the expression and function of CD55 in pancreatic beta cells. To this end, we observe that CD55 is highly expressed in INS1 832/13 beta cells as well as human pancreatic islets. Diabetic human islets show a tendency for increased expression of CD55 when compared to the healthy controls. Importantly, silencing of CD55 in INS1 832/13 cells does not affect their insulin secretory capacity. On the other hand, silencing of CD55 diminished the intensity of membrane rafts as determined by Atto-SM staining. We hence conclude that CD55 expression is affected by glycemic status in human islets and plays a critical role in maintaining the conserved structure of rafts in pancreatic islets, which is similar to that of the related complement inhibitor CD59. However CD55 does not interfere with insulin secretion in beta cells, which is in sharp contrast to the action of the complement inhibitor CD59. PMID- 25797619 TI - MicroRNA-194 promotes osteoblast differentiation via downregulating STAT1. AB - Osteoblast differentiation is a vital process in maintaining bone homeostasis in which various transcriptional factors, signaling molecules, and microRNAs (miRNAs) are involved. Recently, signal transducer and activator of transcription 1 (STAT1) has been found to play an important role in regulating osteoblast differentiation. Here, we identified that STAT1 expression was regulated by miR 194. Using mouse bone mesenchymal stem cells (BMSCs), we found that miR-194 expression was significantly increased following osteoblast differentiation induction. Overexpression of miR-194 by lentivirus-mediated gene transfer markedly increased osteoblast differentiation, whereas inhibition of miR-194 significantly suppressed osteoblast differentiation of BMSCs. Using a dual luciferase reporter assay, a direct interaction between miR-194 and the 3' untranslated region (UTR) of STAT1 was confirmed. Additionally, miR-194 regulated mRNA and protein expression of STAT1 in BMSCs. Further analysis showed that miR 194 overexpression promoted the nuclear translocation of runt-related transcription factor 2 (Runx2), which is critical for osteoblast differentiation. In contrast, inhibition of miR-194 blocked the nuclear translocation of Runx2. Moreover, overexpression of STAT1 significantly blocked Runx2 nuclear translocation and osteoblast differentiation mediated by miR-194 overexpression. Taken together, our data suggest that miR-194 regulates osteoblast differentiation through modulating STAT1-mediated Runx2 nuclear translocation. PMID- 25797620 TI - (2S)-7,4'-dihydroxy-8-prenylflavan stimulates adipogenesis and glucose uptake through p38MAPK pathway in 3T3-L1 cells. AB - Adipose tissue plays a key role in the development of obesity and diabetes. Natural products are one of the main sources for discovering new lead compounds. In the present study, (2S)-7,4'-dihydroxy-8-prenylflavan (DHPF), a natural prenylated flavan isolated from Morus yunnanensis, was found to significantly promote adipogenesis and increase glucose uptake in 3T3-L1 cells. Real-time PCR results showed that DHPF increased the expression of glucose and lipid metabolism related genes (C/EBPalpha, PPARgamma, aP2, GLUT4 and adiponectin) and decreased the expression of inflammatory cytokine TNF-alpha. Western blotting further revealed that DHPF activated p38 MAPK at the initial stage of 3T3-L1 preadipocyte differentiation. DHPF-induced activation of p38, adipogenesis and glucose uptake were effectively blocked by SB203580, a specific p38 inhibitor. These results indicate that DHPF could stimulate adipogenesis and increase glucose uptake through the p38 MAPK pathway, and DHPF may be useful for the prevention and treatment of obesity-associated disorders such as type 2 diabetes (T2D). PMID- 25797621 TI - The Tomato yellow leaf curl virus (TYLCV) V2 protein inhibits enzymatic activity of the host papain-like cysteine protease CYP1. AB - The viral V2 protein is one of the key factors that Tomato yellow leaf curl geminivirus (TYLCV), a major tomato pathogen worldwide, utilizes to combat the host defense. Besides suppressing the plant RNA silencing defense by targeting the host SGS3 component of the silencing machinery, V2 also interacts with the host CYP1 protein, a papain-like cysteine protease likely involved in hypersensitive response reactions. The biological effects of the V2-CYP1 interaction, however, remain unknown. We addressed this question by demonstrating that V2 inhibits the enzymatic activity of CYP1, but does not interfere with post translational maturation of this protein. PMID- 25797622 TI - Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease. AB - Ob/ob mice provide an animal model for non-alcoholic fatty liver disease/non alcoholic steatohepatitis (NAFLD/NASH) in patients with obesity and type-2 diabetes. Low liver copper has been linked to hepatic lipid build-up (steatosis) in animals with systemic copper deficiency caused by low-copper diets. However, hepatic copper status in patients with NAFLD or NASH is uncertain, and a validated animal model useful for the study of hepatic copper regulation in common forms of metabolic liver disease is lacking. Here, we report parallel measurements of essential metal levels in whole-liver tissue and defatted-dried liver tissue from ob/ob and non-obese control mice. Measurements in whole-liver tissue from ob/ob mice at an age when they have developed NAFLD/NASH, provide compelling evidence for factitious lowering of copper and all other essential metals by steatosis, and so cannot be used to study hepatic metal regulation in this model. By marked contrast, metal measurements in defatted-dried liver samples reveal that most essential metals were actually normal and indicate specific lowering of copper in ob/ob mice, consistent with hepatic copper deficiency. Thus ob/ob mice can provide a model useful for the study of copper regulation in NAFLD and NASH, provided levels are measured in defatted-dried liver tissue. PMID- 25797623 TI - Metallothionein gene activation in the earthworm (Lumbricus rubellus). AB - In order to cope with changing environmental conditions, organisms require highly responsive stress mechanisms. Heavy metal stress is handled by metallothioneins (MTs), the regulation of which is evolutionary conserved in insects and vertebrates and involves the binding of metal transcription factor 1 (MTF-1) to metal responsive elements (MREs) positioned in the promoter of MT genes. However, in most invertebrate phyla, the transcriptional activation of MTs is different and the exact mechanism is still unknown. Interestingly, although MREs are typically present also in invertebrate MT gene promoters, MTF-1 is notably absent. Here we use Lumbricus rubellus, the red earthworm, to study the elusive mechanism of wMT-2 activation in control and Cd-exposed conditions. EMSA and DNase I footprinting approaches were used to pinpoint functional binding sites within the wMT-2 promoter region, which revealed that the cAMP responsive element (CRE) is a promising candidate which may act as a transcriptional activator of invertebrate MTs. PMID- 25797624 TI - Identification of tetranectin as adipogenic serum protein. AB - Fetal bovine serum (FBS) is an essential culture supplement for adipocyte differentiation of various adipogenic precursor cells. Adipocyte differentiation greatly varies depending on the type of serum in the differentiation medium. In this study, we found that FBS supported adipocyte differentiation of 3T3-L1 cells to a significantly higher extent than other types of bovine serum such as adult bovine serum (ABS). This differential adipogenic effect of bovine serum was shown to be due to the protein contents of bovine sera, indicating the presence of an adipogenic protein(s) in FBS. Serum proteome analysis identified tetranectin as an adipogenic protein. The adipogenic effect of tetranectin was confirmed by supplementation of FBS-containing differentiation medium with anti-tetranectin antibody, which suppressed adipocyte differentiation of 3T3-L1 cells. These results demonstrate that tetranectin is an adipogenic serum protein mediating the adipogenic effect of FBS. PMID- 25797625 TI - Prostate cancer cells stimulated by calcium-mediated activation of protein kinase C undergo a refractory period before re-releasing calcium-bearing microvesicles. AB - MVs are released in response to several stress agents, in an attempt to prevent continued cellular damage. After an initial stimulus of prostate cancer cells with sublytic C5b-9 and activation of MV release through PKC, cells take at least 20 min to fully recover their ability to microvesiculate. This release of MVs through activation of sublytic C5b-9 was inhibited by the PKC inhibitor bisindoylmaleimide I but not the Rho kinase inhibitor, Y27632. After stimulus there is a rise of 79 nMs(-1) over 11 s, reaching a peak [Ca(2+)]i of 920 nM. The concentration of cytosolic calcium then falls steadily at 2.4 nMs(-1) over 109 s reaching baseline levels (50-100 nM) within 10-15 min. In PC3 cells the rate of release of MVs from stimulated cells also reaches a minimum within 10-15 min. Using fura-2 AM-loaded cells, upon stimulation, cells were found to release MVs with a concentration of intravesicular calcium estimated at ~ 430 nM. PMID- 25797626 TI - IRE1alpha-TRAF2-ASK1 complex-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to CXC195-induced apoptosis in human bladder carcinoma T24 cells. AB - Bladder urothelial carcinoma (UC) accounts for approximately 5% of all cancer deaths in humans. Current treatments extend the recurrence interval but do not significantly alter patient survival. The objective of the present study was to investigate the anti-cancer effect and the underlying mechanisms of CXC195 against human UC cell line T24 cells. CXC195 inhibited the cells growth and induced caspase- and mitochondrial-dependent apoptosis in T24 cells. In addition, CXC195 triggered activation of proteins involved in ER stress signaling including GRP78, CHOP, IRE1alpha, TRAF2, p-ASK1 and p-JNK in T24 cells. Co immunoprecipitation experiments showed that activation of JNK was induced by the activation of IRE1alpha through formation of an IRE1alpha-TRAF2-ASK1 complex. Knockdown of IRE1alpha by siRNA dramatically abrogated CXC195-induced activation of TRAF2, ASK and JNK, formation of an IRE1alpha-TRAF2-ASK1 complex and caspase- and mitochondrial-dependent apoptosis in T24 cells. These findings provided new insights to understand the mode of action of CXC195 in treatment of human UC. PMID- 25797627 TI - Pyruvate metabolism: A therapeutic opportunity in radiation-induced skin injury. AB - Ionizing radiation is used to treat a range of cancers. Despite recent technological progress, radiation therapy can damage the skin at the administration site. The specific molecular mechanisms involved in this effect have not been fully characterized. In this study, the effects of pyruvate, on radiation-induced skin injury were investigated, including the role of the pyruvate dehydrogenase kinase 2 (PDK2) signaling pathway. Next generation sequencing (NGS) identified a wide range of gene expression differences between the control and irradiated mice, including reduced expression of PDK2. This was confirmed using Q-PCR. Cell culture studies demonstrated that PDK2 overexpression and a high cellular pyruvate concentration inhibited radiation-induced cytokine expression. Immunohistochemical studies demonstrated radiation-induced skin thickening and gene expression changes. Oral pyruvate treatment markedly downregulated radiation-induced changes in skin thickness and inflammatory cytokine expression. These findings indicated that regulation of the pyruvate metabolic pathway could provide an effective approach to the control of radiation induced skin damage. PMID- 25797628 TI - Serum uric acid and cardiovascular risk: an early wake-up call. PMID- 25797629 TI - Data dilemmas and difficult decisions: on dealing with inconsistencies in self reports. PMID- 25797630 TI - Improving research methodology in adolescent sexual health research. PMID- 25797631 TI - Lifetime prevalence of sexual intercourse and contraception use at last sex among adolescents and young adults with congenital heart disease. AB - PURPOSE: Because of the increased risks associated with unplanned pregnancy for males and females with congenital heart disease (CHD), we investigated sexual intercourse and contraception use in these adolescents and young adults (AYA) and compared the same with national and state population data. METHODS: We recruited 337 AYA with structural CHD aged 15-25 years (Mage = 19 years, standard deviation = 3.1; 53% male, 84% white) from an outpatient cardiology clinic to participate in a larger study assessing genetic knowledge and health behaviors. Cumulative lifetime prevalence of adolescent (aged 15-18 years) sexual intercourse was compared with the 2011 Youth Risk Behavior Surveillance System and the 2007 Ohio Youth Risk Behavior Survey. Cumulative lifetime prevalence of young adult (aged 19-25 years) sexual intercourse and contraception use at last sex were compared with the 2006-2008 National Survey of Family Growth. RESULTS: Reported rates of ever having sexual intercourse, 26% of adolescents and 74% of young adults with CHD, were significantly lower than general population rates (47% and 86% respectively; p < .001). Similar to the general population, 77% of previously sexually active young adults with CHD reported using at least one effective method of contraception at last intercourse, whereas 25% used dual effective methods and 23% used no effective method. CONCLUSIONS: Lower rates of ever having sexual intercourse in this population suggest that the psychosexual development of AYA with CHD may lag behind their peers. As nearly one in four participants reported using no effective method of contraception, health care providers should increase discussions of contraception with males and females with CHD. PMID- 25797632 TI - Human papillomavirus vaccination of females in a large health claims database in the United States, 2006-2012. AB - PURPOSE: Information on vaccine utilization from a variety of sources is useful to give a status of the vaccine program and define opportunities to improve uptake. We evaluated MarketScan Commercial Claims and Encounters database on human papillomavirus (HPV) vaccine initiation and completion of all three doses among girls/women from 2006 to 2012. METHODS: Data were obtained from the 2006 2012 MarketScan Commercial Claims and Encounters database. The study population included female enrollees aged 11-26 years who were continuously enrolled in the same private insurance plan from 2006 to 2012 (n = 407,371). We evaluated overall and yearly vaccine initiation and completion, demographic characteristics associated with vaccine initiation, clinical visits in which vaccine was given, and missed opportunities for vaccination. RESULTS: By the end of 2012, 36.9% of females aged 11-26 years had received at least one HPV vaccine dose. Vaccination coverage was highest among females aged 17-18 years (49.3%) and aged 15-16 years (43.1%) and lowest among females aged 11-12 years (16.8%). Between 2007 and 2012, 96.1% of the 246,192 unvaccinated females had at least one missed opportunity (a heath care visit without HPV vaccine administered). CONCLUSIONS: Over a 6 year period, HPV vaccine initiation was lowest in the girls aged 11-12 years. Importantly, most (96.1%) unvaccinated females had at least one missed vaccination opportunity, and providers and health systems should focus efforts on using existing visits for vaccination. PMID- 25797633 TI - Racial and ethnic differences in young men's sex and contraceptive education. AB - PURPOSE: Racial/ethnic disparities exist in young men's contraceptive knowledge. This study examines whether the likelihood of receiving sexual health education varies by race/ethnicity. METHODS: We examined racial/ethnic differences in sex and contraceptive education both in school and from parents with multivariable logistic regression models among 4,104 men aged 15-24 years using data from the 2006-2010 National Survey of Family Growth. RESULTS: Nearly all respondents (96.6%) reported formal sex education. Fewer reported formal birth control education (66.6%), parental sex discussions (66.8%), and parental discussions specifically about birth control (49.2%). In multivariable analysis, black men were less likely than white men to report receiving formal contraceptive education (adjusted odds ratio [aOR], .70; 95% CI, .51-.96). Both black and U.S. born Hispanic men reported more parental sex discussions than white men (aOR, 1.44; 95% CI, 1.07-1.94, aOR, 1.47; 95% CI, 1.09-1.99, respectively). CONCLUSIONS: Nearly all respondents reported having received formal sexual health education. Fewer reported receiving education about birth control either at school or at home. Black men were less likely to report receiving formal contraceptive education. PMID- 25797634 TI - Factors influencing the occupational trajectory of patients with systemic sclerosis: a qualitative study. AB - OBJECTIVES: To describe, from the patient's point of view, the factors influencing the occupational trajectory of patients with systemic sclerosis (SSc). METHODS: This was a qualitative study designed using grounded theory with constant comparison. Data were collected through semi-structured interviews with 14 patients who fulfilled the American College of Rheumatology or Leroy-Medsger criteria for SSc. RESULTS: Based on our interviews, we found that the occupational trajectory of patients with SSc is influenced by the continuous interplay between four groups of factors. The first group concerns the values patients attribute to work, including identity, normality, financial value, social contact, and structure. The meaning of these values and how they relate to each other underlies the desire to work. A second group of factors is those influencing the balance between daily life, work participation, and medical condition (e.g. job content, flexibility in organising work, and the willingness to ask for accommodations at work). The occupational trajectory is also influenced by external factors, including availability of support, know-ledge of the disease, pressure to work, contact with medical professionals, and existing regulations and the patient's knowledge about them. Finally, the occupational trajectory is influenced by personal factors, including socio-demographics, psychological assets, and disease- and work-related personal factors. CONCLUSIONS: The decisions patients with SSc take concerning work depend on an interplay between many factors and, especially, on the patients' personal interpretation of these factors. These need to be taken into account when helping patients with SSc determine their occupational trajectory. PMID- 25797635 TI - The methodology flaws in Hinman's acupuncture clinical trial, part I: design and results interpretation. PMID- 25797636 TI - Functional constipation in children: non-pharmacological approach. PMID- 25797637 TI - Nevada: the first state that fully legalized acupuncture and Chinese medicine in the Unites States - in memory of Arthur Steinberg, Yee Kung Lok and Jim Joyce who made it happen. PMID- 25797638 TI - A review of traditional use, phytoconstituents and biological activities of Himalayan yew, Taxus wallichiana. AB - Plants synthesize certain phytoconstituents for their protection, which, because they are not of primary need, are known as secondary metabolites. These secondary metabolites of plants, have often been found to have medicinal uses for human beings. One such gymnosperm having secondary metabolites of medicinal potential for humans is Taxus wallichiana (Himalayan yew). Besides being the source of taxol, this plant has been investigated for its essential oil, diterpenoids, lignans, steroids, sterols and biflavonoids. Traditionally, it is used to treat disorders of the digestive, respiratory, nervous and skeletal systems. Although pharmacologically underexplored, it has been used for antiepileptic, anti inflammatory, anticancer, antipyretic, analgesic, immunomodulatory and antimicrobial activities. The present review compiles traditional uses, phytochemical constituents (specifically the secondary metabolites) pharmacological activities and the toxicity of T. wallichiana. PMID- 25797639 TI - A critical overview on Thymus daenensis Celak.: phytochemical and pharmacological investigations. AB - Thymus daenensis Celak. is an herb endemic to Iran belonging to the Lamiaceae family. Growing in many parts of Iran, the plant is extensively used in folk medicine. This review was performed to compile phytochemical and pharmacological data of T. daenensis. Databases such as PubMed, Scopus, Web of Science, ScienceDirect, Scientific Information Database, Embase, IranMedex and Google Scholar were searched for the terms "Thymus daenensis" and "Avishan-e-denaii" up to 1st January 2014. Following reported ethnopharmacological uses, various T. daenensis preparations have been investigated for antimicrobial, antioxidant, insecticidal and immunomodulatory effects in recent studies. Moreover, numerous studies have been published on the composition of the herb's essential oil, focusing either on environmental parameters or preparation methods. Due to its high concentration of thymol, the plant's essential oil possesses high antimicrobial activities on human pathogenic strains. However, comprehensive studies on the toxicity and teratogenicity as well as clinical efficacy of Thymus daenensis are missing. PMID- 25797640 TI - Acupuncture accelerates recovery after general anesthesia: a prospective randomized controlled trial. AB - BACKGROUND: Acupuncture anesthesia was created in the 1950's in China and continues to be used there today during most major surgeries. It is widely used in China for such complex operations as brain, heart, and abdominal surgery. It is popular in China because it is economical, practical, and beneficial to the patients. With acupuncture anesthesia there is less bleeding during surgery and there is also quicker post-operative recovery. OBJECTIVE: This randomized prospective study aims at comparing the effect of two acupoints (Yongquan, KI1 and Renzhong, DU26) with sham acupuncture and no acupuncture on the time to recovery of consciousness after general anesthesia by means of the Bispectral Index monitor (BIS). DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a prospective randomized controlled study. We randomly assigned 50 patients to 5 groups during recovery from surgical anesthesia. Four groups had acupuncture on KI1 (group A), DU26 (groups B), both KI1 and DU26 (group C), and sham points (group D), and one had no acupuncture (group E). MAIN OUTCOME MEASURES: Bispectral Index (BIS), time to spontaneous eye opening, time to tracheal extubation, and time to following commands were measured as the main outcome measures. RESULTS: Time to spontaneous eye opening differed among groups (P=0.002), as well as time to tracheal extubation (P<0.000 1) and time to following commands (P=0.000 6). BIS values differed significantly among groups both 5 and 10 min after the end of anesthesia (P<0.000 1 and P=0.000 4, respectively). BIS values of groups D and E were lower than those of the other groups and those of group C were higher. The same pattern was observed also 15 and 30 min after the end of anesthesia, although the difference among groups was not significant at these time points (P=0.164 and P=0.104, respectively). CONCLUSION: Acupuncture on DU26 and KI1 accelerates recovery of consciousness after general anesthesia. Moreover, a possible synergistic effect of DU26 and KI1 is suggested. This issue may play a role in the optimization of operating room management and raise interest about the usefulness of acupuncture on unconsciousness states of different nature. PMID- 25797641 TI - Anti-ulcerogenic activity of aqueous extract of Carica papaya seed on indomethacin-induced peptic ulcer in male albino rats. AB - OBJECTIVE: Carica papaya is an important fruit with its seeds used in the treatment of ulcer in Nigeria. This study investigated the anti-ulcerogenic and antioxidant activities of aqueous extract of Carica papaya seed against indomethacin-induced peptic ulcer in male rats. METHODS: Thirty male rats were separated into 6 groups (A-F) of five rats each. For 14 d before ulcer induction with indomethacin, groups received once daily oral doses of vehicle (distilled water), cimetidine 200 mg/kg body weight (BW), or aqueous extract of C. papaya seed at doses of 100, 150 or 200 mg/kg BW (groups A, B, C, D, E and F, respectively). Twenty-four hours after the last treatment, groups B, C, D, E and F were treated with 100 mg/kg BW of indomethacin to induce ulcer formation. RESULTS: Carica papaya seed extract significantly (P< 0.05) increased gastric pH and percentage of ulcer inhibition relative to indomethacin-induced ulcer rats. The extract significantly (P< 0.05) decreased gastric acidity, gastric acid output, gastric pepsin secretion, ulcer index and gastric secretion volume relative to group B. These results were similar to that achieved by pretreatment with cimetidine. Specific activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase in the extract-treated groups (D, E and F) were increased significantly over the group B (P< 0.05). Pretreatment with the seed extract protected rats from the indomethacin-mediated decrease in enzyme function experienced by the group B. Similarly, indomethacin-mediated decrease in reduced glutathione level and indomethacin-mediated increase in malondialdehyde were reversed by Carica papaya extract. CONCLUSION: In this study, pretreatment with aqueous extract of Carica papaya seed exhibited anti-ulcerogenic and antioxidant effects, which may be due to the enhanced antioxidant enzymes. PMID- 25797642 TI - Protective role of Triphala, an Indian traditional herbal formulation, against the nephrotoxic effects of bromobenzene in Wistar albino rats. AB - OBJECTIVE: The purpose of the present study was to evaluate the nephroprotective and antioxidant properties of Triphala against bromobenzene-induced nephrotoxicity in female Wistar albino rats. METHODS: Animals were divided into five groups of six rats and treated as follows: Group I was a normal control and received no treatment, Group II received only bromobenzene (10 mmol/kg), Groups III and IV received bromobenzene and Triphala (250 and 500 mg/kg, respectively), Group V received Triphala alone (500 mg/kg), and Group VI received bromobenzene and silymarin (100 mg/kg). Antioxidant status and serum kidney functional markers were analyzed. RESULTS: Bromobenzene treatment resulted in significant (P< 0.05) decreases in the activities of antioxidant enzymes such as catalase, superoxide dismutase, glutathione-S-transferase and glutathione peroxidase as well as total reduced glutathione. There was a significant (P< 0.05) increase in lipid peroxidation in kidney tissue homogenates. There were significant (P< 0.05) reductions in the levels of serum total protein and albumin as well as significant (P< 0.05) increases in serum creatinine, urea and uric acid. The oral administration of two different doses (250 and 500 mg/kg) of Triphala in bromobenzene-treated rats normalized the tested parameters. The histopathological examinations of kidney sections of the experimental rats support the biochemical observations. CONCLUSION: Triphala treatment alleviated the nephrotoxic effects of bromobenzene by increasing the activities of antioxidant enzymes and reducing the levels of lipid peroxidation and kidney functional markers. PMID- 25797643 TI - The add-on effect of a Chinese herbal formula for patients with resistant hypertension: study protocol for a pilot cohort study. AB - BACKGROUND: Despite a recent American Heart Association (AHA) consensus statement emphasizing the importance of resistant hypertension (RH), its control is still a challenge for conventional medicine. The Chinese herbal formula, Qutan Huayu Fang, has been used effectively to assist antihypertensive agents in blood pressure control, but its effect for RH patients is still unclear. This pilot study aims to explore the effects of taking the formula in addition to antihypertensive medication in the management of RH. METHODS/DESIGN: A prospective cohort study will be conducted in two first-class hospitals of traditional Chinese medicine (TCM). Eligible RH patients will be classified as the experimental group (n = 100) and the control group (n = 100) based on the interventions they receive. Participants taking antihypertensive agents and the Chinese herbal formula will be in the experimental group and those taking antihypertensive agents alone will be in the control group. The whole study will last 24 weeks, including an 8-week observation and follow-up at 24 weeks. The primary outcomes, assessed against patient baseline conditions, will be the reduction of systolic blood pressure and diastolic blood pressure as well as changes in TCM symptoms and signs. These outcomes will be assessed at weeks 2, 4, 6, and 8. The reductions of blood pressure will also be assessed at week 24. Cardiac events and mortality rate will be secondary outcomes and will be assessed at weeks 8 and 24. Any adverse reactions will be recorded during the study. The causal inference method will be used to assess the effectiveness of the inclusion of TCM herbal medicine in the management of patients with RH. DISCUSSION: This study will determine whether the Chinese herbal formula is helpful for RH patients treated with antihypertensive agents and the findings will provide a basis for further confirmatory studies. PMID- 25797644 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: diseases of paediatrics (Part 2). PMID- 25797645 TI - Silicene as a new potential DNA sequencing device. AB - Silicene, a hexagonal buckled 2D allotrope of silicon, shows potential as a platform for numerous new applications, and may allow for easier integration with existing silicon-based microelectronics than graphene. Here, we show that silicene could function as an electrical DNA sequencing device. We investigated the stability of this novel nano-bio system, its electronic properties and the pronounced effects on the transverse electronic transport, i.e., changes in the transmission and the conductance caused by adsorption of each nucleobase, explored by us through the non-equilibrium Green's function method. Intriguingly, despite the relatively weak interaction between nucleobases and silicene, significant changes in the transmittance at zero bias are predicted by us, in particular for the two nucleobases cytosine and guanine. Our findings suggest that silicene could be utilized as an integrated-circuit biosensor as part of a lab-on-a-chip device for DNA sequencing. PMID- 25797647 TI - Cytomegalovirus initiates infection selectively from high-level beta1 integrin expressing cells in the brain. AB - Cytomegalovirus (CMV) is a prevalent pathogen in intrauterine infections that causes congenital anomalies such as CMV encephalitis, which is characterized by the focal areas of reactive gliosis, reactive mononuclear cells, microglial nodules, and ventriculoencephalitis. To elucidate the mechanisms of CMV susceptibility in the developing brain, cell tropism and the infectious dynamics of CMV infection were investigated. We evaluated intraventricular and intravascular infections from the perspective of the distribution of CMV and its receptor (beta1 integrin) in the earliest phase of infection. Murine CMV (MCMV) immediate early 1-positive cells were colocalized mainly with meninges and choroid plexus (after intraventricular infection) or with endothelial cells and pericytes (after intravascular infection). Using green fluorescent protein expressing recombinant MCMV particles and fluorescent microbeads (100 to 300 nm), we revealed that CMV particle size is the primary factor determining the initial CMV distribution. beta1 Integrin inhibition using a shRNA and functional blocking antibody significantly reduced MCMV infection. IHC analysis, flow cytometric, and brain slice analyses strongly support that high-level beta1 integrin-expressing cells (eg, endothelial cells, pericytes, meninges, choroid plexus, and neural stem progenitor cells) are the first targets of MCMV. Therefore, our data demonstrate that the initial distributions of MCMV particles and beta1 integrin determine the distinct pattern of infection in the brain in the acute phase. PMID- 25797646 TI - Targeted deletion of collagen V in tendons and ligaments results in a classic Ehlers-Danlos syndrome joint phenotype. AB - Collagen V mutations underlie classic Ehlers-Danlos syndrome, and joint hypermobility is an important clinical manifestation. We define the function of collagen V in tendons and ligaments, as well as the role of alterations in collagen V expression in the pathobiology in classic Ehlers-Danlos syndrome. A conditional Col5a1(flox/flox) mouse model was bred with Scleraxis-Cre mice to create a targeted tendon and ligament Col5a1-null mouse model, Col5a1(Deltaten/Deltaten). Targeting was specific, resulting in collagen V-null tendons and ligaments. Col5a1(Deltaten/Deltaten) mice demonstrated decreased body size, grip weakness, abnormal gait, joint laxity, and early-onset osteoarthritis. These gross changes were associated with abnormal fiber organization, as well as altered collagen fibril structure with increased fibril diameters and decreased fibril number that was more severe in a major joint stabilizing ligament, the anterior cruciate ligament (ACL), than in the flexor digitorum longus tendon. The ACL also had a higher collagen V content than did the flexor digitorum longus tendon. The collagen V-null ACL and flexor digitorum longus tendon both had significant alterations in mechanical properties, with ACL exhibiting more severe changes. The data demonstrate critical differential regulatory roles for collagen V in tendon and ligament structure and function and suggest that collagen V regulatory dysfunction is associated with an abnormal joint phenotype, similar to the hypermobility phenotype in classic Ehlers-Danlos syndrome. PMID- 25797649 TI - Ultrasonographic wrist and hand abnormalities in early psoriatic arthritis patients: correlation with clinical, dermatological, serological and genetic indices. AB - OBJECTIVES: The aims of our study are to describe the wrist and hand ultrasound (US) abnormalities compared to clinical examination in early psoriatic arthritis (ePsA) and to analyse their correlation with clinical, dermatological, serological and genetic indices. METHODS: We analysed 1120 fingers and 224 wrists of 112 early PsA, with MyLab70 Xview (Esaote, linear probe) ultrasound (US). Power Doppler active synovitis (AS), erosions, finger tendons tenosynovitis or peritendinitis (TP) and pseudotenosynovitis (PT), were compared to clinical (BASDAI, SHAQ), dermatological (PASI and psoriasis aspects), serological (ESR, CRP, ACPA) and genetic (HLA haplotypes) indices. RESULTS: All US abnormalities were present: AS was more frequent at wrists (50/224 [22.3%]), followed by hand PT (68/1120 [6,1%]) and TS (29/1120 [2.6%]), while erosions were rare (10/1120 [0.8%]). US abnormalities were independent of ePsA clinical indices (except erosions - even if represented only in a low percentage - that correlated to BASDAI [p<0.05]), while they were associated to several dermatological (except PASI), serological and genetic parameters: psoriasis (all p<0.0001), palmoplantar psoriasis (wrist and hand AS p<0.0005 and p<0.005, respectively), hand psoriasis (all p<0.0001), nail dystrophy (hand AS p<0.05, PT p<0.0001, erosions p<0.0001); positive CRP (all p<0.0001), ESR (wrist and hand AS p<0.005 and <0.0005, respectively, TS, PT and erosions p<0.0001) and ACPA - even if represented only in 1.78% of patients - (wrist and hand AS and TS p<0.0001, PT p<0.5); HLA-B27 (wrist and hand AS p<0.0001, TS p<0.01, PT p<0.05), -B35 (wrist and hand AS p<0.01 and p<0.05, respectively), -B38 (wrist and hand AS p<0.0001, TS p<0.0001, PT p<0.005), -CW6 (wrist AS p<0.05), -DR4 (wrist and hand AS p<0.0001, TS p<0.0001, PT p<0.005). CONCLUSIONS: US abnormalities of hand and wrist were independent of clinical ePsA indices (except erosions), while they correlated to dermatological (except PASI), serological and genetic parameters of disease. PMID- 25797648 TI - miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1 lipin-1 signaling. AB - Ethanol-mediated injury, combined with gut-derived lipopolysaccharide (LPS), provokes generation of proinflammatory cytokines in Kupffer cells, causing hepatic inflammation. Among the mediators of these effects, miR-217 aggravates ethanol-induced steatosis in hepatocytes. However, the role of miR-217 in ethanol induced liver inflammation process is unknown. Here, we examined the role of miR 217 in the responses to ethanol, LPS, or a combination of ethanol and LPS in RAW 264.7 macrophages and in primary Kupffer cells. In macrophages, ethanol substantially exacerbated LPS-mediated induction of miR-217 and production of proinflammatory cytokines compared with LPS or ethanol alone. Consistently, ethanol administration to mice led to increases in miR-217 abundance and increased production of inflammatory cytokines in isolated primary Kupffer cells exposed to the combination of ethanol and LPS. miR-217 promoted combined ethanol and LPS-mediated inhibition of sirtuin 1 expression and activity in macrophages. Moreover, miR-217-mediated sirtuin 1 inhibition was accompanied by increased activities of two vital inflammatory regulators, NF-kappaB and the nuclear factor of activated T cells c4. Finally, adenovirus-mediated overexpression of miR-217 led to steatosis and inflammation in mice. These findings suggest that miR-217 is a pivotal regulator involved in ethanol-induced hepatic inflammation. Strategies to inhibit hepatic miR-217 could be a viable approach in attenuating alcoholic hepatitis. PMID- 25797650 TI - Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. AB - These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments. PMID- 25797651 TI - An old workhorse for new applications: Fe(dpm)3 as a precursor for low temperature PECVD of iron(III) oxide. AB - An iron(III) beta-diketonate complex, Fe(dpm)3 (Hdpm = 2,2,6,6-tetramethyl-3,5 heptanedione), has been investigated as a potential precursor for plasma enhanced chemical vapor deposition (PECVD) of iron(III) oxide nanomaterials. Thanks to the combined experimental-theoretical approach, spectroscopic properties, spin state, thermal behavior and fragmentation pathways of Fe(dpm)3 have been carefully analysed, obtaining an excellent agreement between simulation and experiment. Preliminary PECVD tests evidenced the possibility of obtaining pure and homogeneous Fe2O3 deposits with controlled nano-organization at temperatures as low as 100 degrees C, even on flexible plastic substrates. The present results open up intriguing perspectives for the exploitation of Fe(dpm)3 as an efficient molecular source for the preparation of nanostructured iron(III) oxides to be used in energetics and gas sensing applications. PMID- 25797652 TI - Nationwide Twin Birth Weight Percentiles by Gestational Age in Taiwan. AB - BACKGROUND: Nationwide birth weight norms for twins have been reported in several countries across different ethnicities, but such data have not been established in Taiwan. The purpose of this study was to develop reference growth charts that are population-based and contain the information of birth weight percentiles by gestational age for twin neonates in Taiwan. METHODS: In this study, we collected nationwide birth weight data for twins by sex and gestational age through the Taiwan Birth Registry. Percentiles, means, and standard deviations of birth weight for each 1-week increment of gestational age from 21 weeks of gestation were estimated and smoothed using weighted polynomial models. RESULTS: The 10(th), 50(th), and 90(th) percentiles of birth weight born at the 37(th) gestational week were 2174 g, 2580 g, and 3125 g for male twins, respectively, and they were 2100 g, 2500 g, and 3000 g for female twins, respectively. The 10(th), 50(th), and 90(th) percentiles of birth weight born at the 40(th) gestational week were 2326, 3285, and 3790 g for male twins, respectively, and they were 2200 g, 2770 g, and 3690 g for female twins, respectively. CONCLUSION: This is the first nationwide birth weight norm for twins in Taiwan, which is particularly useful for investigation into the predictors and outcomes of altered fetal growth through twin studies in the Taiwanese population. PMID- 25797654 TI - First trimester exposure to topiramate and the risk of oral clefts in the offspring: A systematic review and meta-analysis. AB - Topiramate (TPM) is an increasingly used drug during childbearing ages for treatment of epilepsy, migraine, and appetite suppression as well as for off label indications such as sleep and psychiatric disorders. Presently, while some reports suggested an increased risk of oral cleft (OC), these reports are balanced by studies that could not confirm such association. We conducted a meta analysis of all studies reporting on women exposed to TPM during pregnancy. Of the 2327 publications reviewed, 6 articles met the inclusion criteria including 3420 patients and 1,204,981 controls. The odd ratio (OR) of OC after the first trimester exposure to TPM exposure was 6.26 (95% confidence interval: 3.13-12.51; P = 0.00001). This study provides strong evidence that TPM is associated with an increased risk of OC in infants exposed to TPM during embryogenesis and should lead to a careful review of TPM use in women of reproductive ages. PMID- 25797653 TI - QSAR screening of 70,983 REACH substances for genotoxic carcinogenicity, mutagenicity and developmental toxicity in the ChemScreen project. AB - The ChemScreen project aimed to develop a screening system for reproductive toxicity based on alternative methods. QSARs can, if adequate, contribute to the evaluation of chemical substances under REACH and may in some cases be applied instead of experimental testing to fill data gaps for information requirements. As no testing for reproductive effects should be performed in REACH on known genotoxic carcinogens or germ cell mutagens with appropriate risk management measures implemented, a QSAR pre-screen for 70,983 REACH substances was performed. Sixteen models and three decision algorithms were used to reach overall predictions of substances with potential effects with the following result: 6.5% genotoxic carcinogens, 16.3% mutagens, 11.5% developmental toxicants. These results are similar to findings in earlier QSAR and experimental studies of chemical inventories, and illustrate how QSAR predictions may be used to identify potential genotoxic carcinogens, mutagens and developmental toxicants by high-throughput virtual screening. PMID- 25797655 TI - Prevention of valproic acid-induced neural tube defects by sildenafil citrate. AB - This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10mg/kg. One hour later, animals received a teratogenic dose of VPA (600mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis. PMID- 25797656 TI - A simple PCR-based fluorometric system for detection of mutant fusion DNAs using a quencher-free fluorescent DNA probe and graphene oxide. AB - We propose a facile fluorometric system for detection of gene mutations using graphene oxide (GO). A fluorescent probe DNA anneals to a specific mutant gene and is degraded by the 5'-> 3' exonuclease activity of Taq polymerase during PCR, and the released fluorophore retains fluorescence after addition of GO without quenching. PMID- 25797657 TI - Structural and functional dysconnectivity of the fronto-thalamic system in schizophrenia: a DCM-DTI study. AB - Evidence suggests that cognitive deficits are a core feature of schizophrenia. The concept of "cognitive dysmetria" has been introduced to characterize disintegration of fronto-thalamic-cerebellar circuitry which constitutes a key network for a variety of neuropsychological symptoms in schizophrenia. The present multimodal study aimed at investigating effective and structural connectivity of the fronto-thalamic circuitry in schizophrenia. fMRI effective connectivity analysis using dynamic causal modeling (DCM) and diffusion tensor imaging (DTI) were combined to examine cognitive control processes in 38 patients with schizophrenia and 40 matched healthy controls. Significantly lower fractional anisotropy (FA) was detected in patients in the right anterior limb of the internal capsule (ALIC), the right thalamus and the right corpus callosum. During Stroop task performance patients demonstrated significantly lower activation relative to healthy controls in a predominantly right lateralized fronto-thalamo-cerebellar network. An abnormal effective connectivity was observed in the right connections between thalamus, anterior cingulate and dorsolateral prefrontal cortex. FA in the ALIC was significantly correlated with the thalamic BOLD signal, cognitive performance and fronto-thalamic effective connectivity in patients. Present data provide evidence for the notion of a structural and functional defect in the fronto-thalamo-cerebellar circuitry, which may be the basis of specific cognitive impairments in schizophrenia. PMID- 25797659 TI - [Effect of source positional discrepancy on dose and dose distributions in cobalt 60 stereotactic radiosurgery units]. AB - We assessed the impact of source positional discrepancy on dose and dose distributions in Gamma Knife (GK) Perfexion (PFX) stereotactic radiosurgery. A spherical phantom dedicated in GK machine was used and irradiated by 2 Gy in each position moved at an interval of 0.1 mm from its original position using three types of collimators (4, 8, 16 mm) to evaluate the changes of dose. In addition, to obtain the dose distributions, radiochromic film was inserted in the phantom and irradiated by 6 Gy in each position moved at an interval of 1 mm from its original position using three types of collimators. A distance-to-agreement analysis (DTA) was performed to compare isodose lines from 10% to 90% of dose distributions between the original and deviated position. As a result, when the source moved toward the discrepancy from the center of the collimator, the dose and dose distributions discrepancies increased according to the degree of discrepancy. Especially in 4-mm collimator, 0.5 mm discrepancy caused dose reduction of 5%. On the other hand, 0.5 mm discrepancy showed merely dose differences less than 0.5% in 8 mm and 16 mm collimators. Regarding dose distributions, 1 mm discrepancy in all collimators showed little changes in DTA within 1 mm on average. PMID- 25797660 TI - [An analysis of existing terminology towards constructing ontology in the field of the radiological technology]. AB - PURPOSE: In 1994, Japanese Society of Radiological Technology (JSRT) constructed the lexicon in the field of radiologic technology. However, recently, latest lexicon is not updated yet. The purpose of this article is to compare the terminologies in clinical medicine with the others and to consider reconstructing the lexicon in the radiological technology. MATERIALS AND METHODS: Our study selected three categories from the database of the academic society. These three groups were Clinical medicine (hereafter CM, 167 societies, includes JSRT), Psychology / Education (hereafter P/E, 104 societies), and Comprehensive synthetic engineering (hereafter CSE, 40 societies). First, all societies were surveyed to know whether there were any lexicon in their official website. Second, these terminologies were surveyed on the following criteria: (a) Media of lexicon, (b) Number of terms, (c) File type of lexicon, (d) Terms translated into English, (e) Way of searching terms, and (f) Number of committees of the terminology. RESULTS: Lexicon in CM, P/E, and CSE had 20, 4, and 7. Compared with P/E and CSE, CM showed the following trends: (a) used electronic media frequently, (b) stored large number of terms (about 5,000 to 11,000), (c) enabled to download frequently, and (d) used the alphabet and Japanese syllabary order frequently. CONCLUSIONS: Compared with the lexicon of P/E and CSE, terminology in CM tended to adopt the electronic media of lexicon and to have large number of terms. Additionally, many lexicons were expressed in English terms along with Japanese terms. Following massive lexicon of SNOMED-CT and RadLex, it is necessary to consider applying the web-based term searching and an ontological technique to the lexicon of radiological technology. PMID- 25797661 TI - [Development of computer code PIETAII, for analysis of exposure dose from portable X-ray in neonatal intensive care unit]. AB - The patients in NICU (Neonatal Intensive Care Unit) are more likely to get portable X-ray often while they are in the hospital. These patients potentially may get relatively more exposure dose in total in a short period of time. We developed a software to analyze the exposure dose for the patients in the incubator, which is called PIETAII (Patient Information of Exposure dose Total Analysis in NICU). Then, we compared the accuracy of PIETAII and SDEC (surface dose evaluation code) based on customary method. Using the 5 cm body thickness with exposure setting of 50 kV, 1 mAs, relative error between the customary method and the calculated dose by PIETAII and SDEC were 1.96% and 32.35%, respectively. PIETAII is a useful software to estimate the entrance surface dose using the exposure setting. PMID- 25797662 TI - [Development of simple processing for deleting undershooting artifact using the FBP method ?evaluation of simulation data?]. AB - The undershooting artifact occurs using the filtered back projection (FBP) method. This artifact is influenced by a ramp filter. Thereby, the fall of the target accumulation and a deficit arise and it becomes a clinical problem. We developed a new image reconstruction method based on the FBP method to delete the undershooting artifact of FBP. The image quality of the FBP method is equivalent to that obtained by an evaluation using a digital phantom. The two segmentation and ordinary FBP methods were evaluated in terms of hot contrast, cold contrast, coefficient of variation (%CV), and root mean square uncertainty (%RSMU). The two segmentation FBP method showed equivalent values of hot contrast, % CV, and% RSMU compared with those of the ordinary FBP method. With a threshold level value, cold contrast sharply changed. However, when the threshold level of the two segmentation FBP method was set as the proper value, 90% contrast was obtained. It is necessary to set a threshold level as a proper value using the two segmentation FBP methods. I thought that it can delete an artifact in a simple way, without impairing the image quality. However, it is an examination of only a digital phantom this time. Before using it clinically, one has to use and verify a real phantom. PMID- 25797658 TI - Multimodal neuroimaging based classification of autism spectrum disorder using anatomical, neurochemical, and white matter correlates. AB - Neuroimaging techniques, such as fMRI, structural MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H-MRS) have uncovered evidence for widespread functional and anatomical brain abnormalities in autism spectrum disorder (ASD) suggesting it to be a system-wide neural systems disorder. Nevertheless, most previous studies have focused on examining one index of neuropathology through a single neuroimaging modality, and seldom using multiple modalities to examine the same cohort of individuals. The current study aims to bring together multiple brain imaging modalities (structural MRI, DTI, and 1H-MRS) to investigate the neural architecture in the same set of individuals (19 high-functioning adults with ASD and 18 typically developing (TD) peers). Morphometry analysis revealed increased cortical thickness in ASD participants, relative to typical controls, across the left cingulate, left pars opercularis of the inferior frontal gyrus, left inferior temporal cortex, and right precuneus, and reduced cortical thickness in right cuneus and right precentral gyrus. ASD adults also had reduced fractional anisotropy (FA) and increased radial diffusivity (RD) for two clusters on the forceps minor of the corpus callosum, revealed by DTI analyses. 1H-MRS results showed a reduction in the N acetylaspartate/Creatine ratio in dorsal anterior cingulate cortex (dACC) in ASD participants. A decision tree classification analysis across the three modalities resulted in classification accuracy of 91.9% with FA, RD, and cortical thickness as key predictors. Examining the same cohort of adults with ASD and their TD peers, this study found alterations in cortical thickness, white matter (WM) connectivity, and neurochemical concentration in ASD. These findings underscore the potential for multimodal imaging to better inform on the neural characteristics most relevant to the disorder. PMID- 25797663 TI - [Prediction of hyperperfusion after carotid artery stenting based on preoperative estimation of the cerebral blood flow (according to the Kuroda grading system) by single photon emission computed tomography]. AB - This study was conducted to investigate whether preoperative estimation of the cerebral blood flow (CBF) by single photon emission computed tomography (SPECT) can allow identification of patients at risk for hyperperfusion (HP) after carotid artery stenting (CAS). In 40 patients scheduled to undergo CAS, the CBF and cerebral vascular reserve (CVR) were measured prior to the intervention by resting and acetazolamide loading SPECT. The SPECT findings were classified into 4 types: Type 1, normal CBF in the resting state (CBFrest) and normal CVR; Type 2, normal CBFrest and reduced CVR; Type 3, reduced CBFrest and reduced CVR; and Type 4, reduced CBFrest and normal CVR. Four patients presented with HP after CAS. Patients with high proportions of Type 2 and Type 3 had high risk of HP after CAS. (ROC analysis: AUC=0.94, cutoff value of 75.8% had PPV of 75.0%, NPV of 97.2% and odds ratio of 105.0). The proportions of Type 2 and Type 3 in preoperative SPECT may identify patients at risk for the development of HP. PMID- 25797664 TI - [An introduction and implementation of problem-based learning for radiography positioning training]. AB - The knowledge of radiological technologists is expected to increase with medical development. However, it is impossible to impart all knowledge in a limited time frame. Problem-based learning (PBL) is a learning methodology to solve it. In the PBL, students can gain problem-solving abilities by acquiring necessary knowledge from clinical cases and applying them during practice. We here report to implement the PBL in radiography practice. This practice opened a course at 2nd semester of third-grade students in our school. The practice flow includes presentation of clinical case and a survey of necessary knowledge, group work, radiography, reflection through practice, and deliberation of different cases. The clinical case was the radiography of an emergency patient. The evaluation items were about knowledge, skill, and attitude. By the PBL practice, students could realize a clinical scene, and discover considerable points unwritten in textbooks. PMID- 25797665 TI - [Effect of prostate matching on dose distribution by on board imager kV-CBCT image]. AB - PURPOSE: The purpose of this study was to evaluate the effect of prostate matching on dose distribution using kilovolt cone beam computed tomography (kV CBCT) with image guided radiation therapy for prostate cancer. MATERIALS AND METHOD: Sixteen prostate cancer patients were treated with intensity modulated radiation therapy to 76 Gy at 2 Gy per fraction in 38 fractions. Daily target localization was performed using "bone matching" and "prostate matching" based on planning CT and kV-CBCT. Prostate dose coverage was assessed by the proportion of the CTV fully encompassed by 95%, 98% isodose lines, and mean dose lines. As for rectal and bladder, dose coverage was assessed by volumes which received 40 Gy, 60 Gy, 70 Gy, 75 Gy and mean dose at treatment. And we calculated the tumor control probability (TCP) and normal tissue complication probability (NTCP), accordingly. They were compared to the bone and prostate matching image. RESULT: Our study found an improvement in dose usage in CTV and bladder which enabled us to compare the bone matching image and the prostate matching image. However, it did not improve dose usage in the rectal. Then we chose patients who were a large shift from bone matching image to prostate matching image. As a result, rectal dose and NTCP were reduced. DISCUSSION: Prostate matching is useful and safe when compared to bone matching because of improving CTV dose usage and reducing dose rectal and bladder. PMID- 25797666 TI - [A pilot study of contrast medium dose reduction using low tube voltage and iterative reconstruction: computed tomography angiography of the head]. AB - This study aimed to reduce contrast medium dose without reducing the diagnostic capability of computed tomography (CT) angiography of the head. We evaluated the advanced statistical iterative reconstruction (ASiR) settings to adjust to low tube voltage CT. A syringe phantom was constructed using dilute contrast medium and was imaged at tube voltages of 80-120 kV. The iodine volumes, CT values, and image noise were measured in these images. The noise-power spectrum and modulation transfer function were measured from quality assurance phantom images that had been obtained using the tube voltage selected after considering the image noise results as described above and reconstructed using different ASiR rate settings and convolution kernels. Our results suggested that imaging at 100 kV could reduce the contrast medium dose by 14%, compared with imaging at 120 kV, and that the resulting image quality could equal that of conventional imaging by performing reconstruction at a 40% ASiR rate and detail kernel. PMID- 25797667 TI - [Clinical usefulness of low tube current scanning with full reconstruction and automatic patient motion correction (APMC) reconstruction in a prospective ECG gated coronary CT angiography using 320-row area detector CT]. AB - PURPOSE: The purpose of this study is to validate the clinical usefulness of Advanced Patient Motion Correction (APMC) reconstruction when motion artifacts were observed in a prospective ECG-gated coronary CT angiography (CCTA), which was acquired by low tube current scanning with full reconstruction using 320-row area detector CT (0.275 s/rot.). METHODS: Of 530 consecutive CCTA, we selected 119 patients (M/F: 71/48, Age: 69 +/- 11 y, BMI: 23.5 +/- 2.5) with (RR-PQ) >= 968 ms before scanning, and performed a CCTA with low tube current scanning [30% of usual tube current (30%mA)], adaptive iterative dose reduction 3D, and full reconstruction. Image quality for motion artifacts was subjectively evaluated using a 3-point scale (excellent, acceptable, and unacceptable). RESULTS: Of 119, 102 CCTA had "excellent" images (group A) and 17 had "acceptable" images (group B). The APMC and half reconstruction were retried in the 17 CCTA with "acceptable" images. Finally, all CCTA became "excellent" images. The RR-PQ of group B during scanning (966 +/- 80 ms) was significantly (P = 0.0001) shorter than group A (1,088 +/- 123 ms). Each image noise (standard deviation of CT value) of aorta, left atrium, and left ventricle was 21.7 +/- 2.3, 24.7 +/- 2.3, 24.5 +/- 2.4 in full, 25.7 +/- 2.2, 29.0 +/- 3.4, 28.2 +/- 2.7 in APMC, and 30.4 +/- 2.8, 34.3 +/- 4.2, 33.3 +/- 2.9 HU in half reconstruction. Mean dose-length product of all patients was 66.2 +/- 34.4 mGy . cm. CONCLUSION: "Excellent" CCTA images can be obtained in 85.7% of patients with (RR-PQ)>= 968 ms by full reconstruction. APMC is useful for motion artifacts and image noise reduction when patient' s HR increases during scanning rather than half reconstruction. PMID- 25797668 TI - [Harmony of medical care and radiological technology for ischemic heart disease ?sharing knowledge and technique for safe examination and treatment?]. PMID- 25797669 TI - [7. Application of the Monte Carlo simulation 4: Area of general radiography]. PMID- 25797670 TI - [Dispatch reports to international conferences (held abroad) in 2014]. PMID- 25797671 TI - [Report of short term study abroad in 2014]. PMID- 25797672 TI - [Introduction of JIRA activities on safety measures for MRI]. PMID- 25797674 TI - Spontaneous, non-enzymatic breakdown of peptides during enzymatic protein hydrolysis. AB - It is expected that during the hydrolysis of proteins with specific enzymes only peptides are formed that result from hydrolysis of the specific cleavage sites (i.e. specific peptides). It is, however, quite common to find a-specific peptides (i.e. resulting from a-specific cleavage), which are often ignored, or explained by impurities in the enzyme preparation. In recent work in a whey protein isolate (WPI) hydrolysate obtained with the specific Bacillus licheniformis protease (BLP), 13 peptides of 77 identified were found to be the result of a-specific cleavage. These were formed after degradation of 6 specific peptides, after 5 different types of amino acids. The fact that other peptides were not hydrolyzed after these 5 amino acids suggests that the cleavages were not the result of a contamination with a different enzyme. In other systems, certain peptide sequences have been described to degrade chemically, under relatively mild conditions. This process is referred to as spontaneous cleavage. To test if the a-specific peptides observed in the WPI hydrolysis are the results of spontaneous cleavages, the parental peptides were synthesized. Surprisingly, 4 of the 5 synthesized peptides were indeed spontaneously cleaved under the mild conditions used in this study (i.e. 40 degrees C and pH 8) showing that peptides are less stable than typically considered. The rate of cleavage on the a-specific bonds was found to be enhanced in the presence of BLP. This suggests that the formation of a-specific peptides is not due to side activity but rather an enhancement of intrinsic instability of the peptides. PMID- 25797675 TI - Lifetime measures of ideal cardiovascular health and their association with subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: The American Heart Association recently defined 7 ideal health behaviors and factors that can be used to monitor ideal cardiovascular health (ICH) over time. These relate to smoking, physical activity, diet, body mass index (BMI), blood pressure, blood glucose and total cholesterol. Associations between repeated measures of ICH across the life-course with outcomes of subclinical atherosclerosis in adult life have not been reported. METHODS AND RESULTS: The sample comprised 1465 children and young adults aged 12 to 24 years (mean age 17.5 years) from the Cardiovascular Risk in Young Finns Study cohort. Participants were followed-up for 21 years since baseline (1986) and had complete ICH data available at baseline and follow-up. Average lifetime ICH index was associated with reduced risk of coronary artery calcification (CAC) (P=0.0004), high-risk carotid intima-media thickness (IMT) (P=0.0005) and high-risk carotid distensibility (<0.0001) in middle age. Participants with persistently low ICH status (lower than the median), as compared with persons with persistently high ICH status (higher than the median), had an increased risk of CAC (P=0.02), high risk IMT (P=0.02), and high-risk distensibility (P<0.0001). Participants who improved their ICH status from low to high did not have a different risk of CAC (P=0.90), high-risk IMT (P=0.25), or high-risk distensibility (P=0.80) than participants who always had high ICH status. CONCLUSIONS: The results show that ICH can be lost and regained, and importantly that regaining of ICH has a beneficial effect on cardiometabolic health. Health care providers should work to improve health behaviors especially in those who have lost ICH. PMID- 25797676 TI - Evaluation of the preoperative vasoactive-inotropic score as a predictor of postoperative outcomes in patients undergoing heart transplantation. PMID- 25797677 TI - Comparison of the incidence of postoperative neurologic complications after on pump versus off-pump coronary artery bypass grafting in high-risk patients: A meta-analysis of 11 studies. PMID- 25797679 TI - Rivaroxaban versus warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation: A meta-analysis. PMID- 25797680 TI - Transvenous recovery of an intracardiac fractured port-A catheter fragment. PMID- 25797678 TI - Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution. AB - RATIONALE: Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. OBJECTIVE: The goal was to determine MMP-12 post-MI mechanisms. METHODS AND RESULTS: Male C57BL/6J mice (3-6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5mg/kg/day) was delivered by osmotic mini-pump beginning 3h post-MI, and mice were sacrificed at day (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n=6-12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33 +/- 1% at d1 post MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP 12 directly stimulated CD44, caspase 3, and caspase 8 expression. CONCLUSION: Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function. PMID- 25797681 TI - Atrial fibrillation and incident end-stage renal disease: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study. AB - INTRODUCTION: Atrial fibrillation (AF) is an independent risk factor for end stage renal disease (ESRD) among persons with chronic kidney disease (CKD), however, the association between AF and incident ESRD has not been examined in the general United States population. METHODS: A total of 24,953 participants (mean age 65 +/- 9.0 years; 54% women; 40% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. AF was identified at baseline (2003-2007) from electrocardiogram data and self-reported history. Incident cases of ESRD were identified through linkage with the United States Renal Data System. Cox proportional-hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between AF and incident ESRD. RESULTS: A total of 2,155 (8.6%) participants had AF at baseline. Over a median follow-up of 7.4 years, 295 (1.2%) persons developed ESRD. In a model adjusted for demographics and potential confounders, AF was associated with an increased risk of incident ESRD (HR=1.51, 95% CI=1.08, 2.11). The association between AF and ESRD became non-significant after further adjustment for CKD markers (eGFR <60 mL/min/1.73 m(2) and urine albumin-to-creatinine ratio >= 30 mg/dL) (HR=1.24, 95% CI=0.89, 1.73). CONCLUSION: AF is associated with an increased risk of ESRD in the general United States population and this association potentially is explained by underlying CKD. PMID- 25797682 TI - Lower mortality with pre-hospital electrocardiogram triage by telemedicine support in high risk acute myocardial infarction treated with primary angioplasty: Preliminary data from the Bari-BAT public Emergency Medical Service 118 registry. PMID- 25797683 TI - Quantifying the effect of vegetation on near-road air quality using brief campaigns. AB - Many reports of trees' impacts on urban air quality neglect pattern and process at the landscape scale. Here, we describe brief campaigns to quantify the effect of trees on the dispersion of airborne particulates using high time resolution measurements along short transects away from roads. Campaigns near major highways in Queens, NY showed frequent, stochastic spikes in PM2.5. The polydisperse PM2.5 class poorly represented the behavior of discrete classes. A transect across a lawn with trees had fewer spikes in PM2.5 concentration but decreased more gradually than a transect crossing a treeless lawn. This coincided with decreased Turbulence Kinetic Energy downwind of trees, indicating recirculation, longer residence times and decreased dispersion. Simply planting trees can increase local pollution concentrations, which is a special concern if the intent is to protect vulnerable populations. Emphasizing deposition to leaf surfaces obscures the dominant impact of aerodynamics on local concentration. PMID- 25797684 TI - Efficacy of crizotinib inhibiting specific molecular pathways in non-small-cell lung carcinoma. AB - The US FDA granted approval for crizotinib as the first-line treatment for patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearranged metastatic non-small-cell lung cancer, on November 20, 2013. Crizotinib is a customized and improved therapeutic option for patients with non-small-cell lung cancer that enhances overall survival without increasing toxicity. In the future, new targeted therapies may achieve additional indications for treating patients with lung cancer. This article summarizes data from crizotinib studies. PMID- 25797685 TI - Bevacizumab in high-grade gliomas: past, present, and future. AB - The survival of patients with high-grade gliomas (anaplastic gliomas and glioblastoma) remains poor despite current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. Glioblastoma (GBM) is characterized by extensive microvascular proliferation and the production of large amounts of VEGF. Bevacizumab is a humanized IgG1 monoclonal antibody that selectively binds with high affinity to human VEGF and neutralizes VEGF's biologic activity. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of GBM cells. A number of studies have evaluated the outcomes of both newly diagnosed and recurrent GBM patients with bevacizumab in a prospective manner. Here, we discuss the role of bevacizumab in the treatment of anaplastic gliomas and GBM in the recurrent and upfront setting. PMID- 25797686 TI - The effects of healing touch on pain, nausea, and anxiety following bariatric surgery: a pilot study. AB - CONTEXT: Given the growth in the number of bariatric surgeries, it is important for healthcare practitioners to maximize symptom management for these patients, including the option of complementary therapies such as Healing Touch. OBJECTIVE: A quasi-experimental study was conducted to determine the feasibility of a Healing Touch intervention for reducing pain, nausea, and anxiety in patients undergoing laparoscopic bariatric surgery. DESIGN: Following surgery, a nurse administered the Healing Touch intervention once daily. Study participants reported levels of pain, nausea, and anxiety immediately before and after the Healing Touch intervention using separate numeric rating scales. RESULTS: Significant decreases in pain, nausea, and anxiety were observed immediately following the intervention on post-operative days one and two, and in pain and anxiety on post-operative day three compared with pre-intervention levels. These findings indicate that the Healing Touch intervention is feasible and acceptable to patients undergoing bariatric surgery, and significantly improved pain, nausea, and anxiety in these patients. PMID- 25797687 TI - Continence outcomes after bladder neck preservation during robot-assisted laparoscopic prostatectomy (RALP). AB - PURPOSE: Urinary incontinence is one of the major prostate cancer treatment related morbidities. We review our initial robot-assisted laparoscopic prostatectomy (RALP) experience, focusing on post-surgery continence rates. MATERIAL AND METHODS: Two-hundred and thirty-three consecutive patients were identified from a prospectively maintained RALP database. A bladder neck sparing dissection was preferentially performed during transperitoneal RALP. On postoperative day 5 or 6 (clinic logistics), the urethral catheter was removed following a normal cystogram. RESULTS: Median operative time was 190 minutes and estimated blood loss was 75 mL. Three (1.3%) patients required bladder neck reconstruction, while 198 (85.0%) had bilateral, 20 (8.6%) had unilateral and 15 (6.4%) did not undergo nerve sparing prostatectomy. One-hundred and ninety-nine (85.4%) patients had negative surgical margins. Median hospitalization and urethral catheter duration were 1.0 and 5.0 days, respectively. At six weeks, a median 1.0 pad per day usage was reported and mean AUASS and QoL were significantly improved from baseline (p < 0.05). Of the 220 patients having a minimum three-month follow-up, 152 (69.1%) achieved urinary continence without pads. Age, AUASS, QoL, prostate volume and prior TUR surgery independently had significant impact on early continence rate (p < 0.05). CONCLUSION: A bladder neck sparing dissection allows for early return of urinary continence following RALP without compromising cancer control. PMID- 25797688 TI - Increased Cardiovascular Risk Using Atherogenic Index Measurement Among Healthcare Workers. AB - BACKGROUND AND AIMS: Cardiovascular diseases are one of the leading causes of death worldwide. This burden of disease is particularly high among healthcare workers. The aim of the study was to identify determinants that increase atherogenic index among healthcare workers. METHODS: In 1,678 healthcare workers, cardiovascular risk factors were analyzed: body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Atherogenic index was calculated and determinants were identified. RESULTS: Mean (SD) age was 41.2 (8.4) years; body mass index 28.4 (4.8); waist-hip-ratio 0.88 (0.07); glucose 96.6 (22.2) MUg/dL; TC 195.3 (50.3) mg/dL; HDL 49.0 (16.3) mg/dL; LDL 112.7 (35.0) mg/dL; triglycerides 171.7 (121.2) mg/dL; and atherogenic index 3.3 (1.5). Overweight and obesity prevalence was 77.2%. In the multiple linear regression model, the coefficients for AI were being a physician beta = 0.381, male gender = 0.443, BMI beta = 0.35, waist-to-hip ratio beta = 2.15, age = 0.014, and triglycerides beta = 0.915. CONCLUSIONS: The main contributors to atherogenic index increase were male sex, increased age, waist-to-hip ratio increase, overweight and obesity, high triglyceride levels and working as a physician. Although waist-to-hip ratio was the most powerful determinant, the physician occupational category added risk factors such as stress and adverse psychosocial working conditions, which may potentiate cardiovascular diseases. PMID- 25797689 TI - Clinical handover of the critically ill postoperative patient: an integrative review. AB - OBJECTIVES: The clinical handover of critically ill postoperative patients from the operating theatre to the intensive care unit is a dynamic and complex process that can lead to communication and technical errors. The objectives of this integrative review were to illustrate how the use of structured handover processes between the operating theatre and intensive care unit impacts information transfer, handover duration, post-handover technical error and high risk events. REVIEW METHOD USED: Integrative review methodology was used to allow for the inclusion of broad research designs, summarising current knowledge from existing research and identify gaps in the literature. DATA SOURCES: A systematic search of electronic databases including the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane library, Embase, ProQuest central and PubMed were performed. Original research articles, in either adults or paediatrics, specific to handover between an operating theatre and intensive care unit were included. REVIEW METHODS: Data extracted from studies included country of origin, sample size, number of hospital sites, study design, study aim, measures, key findings and limitations. The quality of the integrative review articles was assessed against the 'Standard Quality Assessment Criteria for Evaluating Primary Research Papers'. RESULTS: Ten articles meeting the inclusion criteria were included in the final analysis. Information transfer, post-handover technical errors and high risk events were positively influenced by the use of structured clinical handover tools. Handover duration did not change when using structured handover protocols. CONCLUSIONS: The body of literature on clinical handover between operating theatre and the intensive care unit is in its early stages of development. Future research using rigorous study designs, broader populations and varied surgical procedures are needed to further evaluate the effect of clinical handover protocols. PMID- 25797690 TI - Maternal weight in pregnancy and offspring body composition in late adulthood: findings from the Helsinki Birth Cohort Study (HBCS). AB - INTRODUCTION: Maternal obesity has long-term consequences for the offspring's later health, including an increased risk of type 2 diabetes and cardiovascular disease. The underlying mechanisms explaining these associations are, however, not fully understood. METHODS: A total of 2003 individuals from the Helsinki Birth Cohort Study born 1934-44, underwent measurements of body size, body composition, and clinical characteristics at a mean age of 62 years. Data on maternal anthropometry were available from hospital records. RESULTS: Maternal BMI was positively associated with BMI in the offspring. Higher maternal BMI was associated with less favorable body composition in the offspring. There was a significant interaction between birth weight and maternal BMI on offspring body fat percentage (P for interaction 0.003). In mothers with low BMI, a higher offspring birth weight was associated with lower fat percentage, while among those with maternal BMI in the highest fourth, higher offspring birth weight predicted higher body fat percentage. DISCUSSION: Our findings suggest that a disadvantageous body composition is programmed in early life. This may in part underlie the association between maternal obesity and later cardio-metabolic health of the offspring. These findings support the importance of prevention of overweight in women of child-bearing age. PMID- 25797691 TI - Functional genomics of tomato for the study of plant immunity. AB - Tomato (Solanum lycopersicum), along with many other economically valuable species, belongs to the Solanaceae family. Understanding how plants in this family defend themselves against pathogens offers the opportunity of improving yield and quality of their edible products. The use of functional genomics has contributed to this purpose through both traditional and recently developed techniques that allow determination of changes in transcript abundance during pathogen attack. Such changes can implicate the affected gene as participating in plant defense. Testing the involvement of these candidate genes in defense has relied largely on posttranscriptional gene silencing, particularly virus-induced gene silencing. We discuss how functional genomics has played a key role in our current understanding of the defense response in tomato and related species and what are the challenges and opportunities for the future. PMID- 25797693 TI - Hepatitis C viral infection is associated with activated cytolytic natural killer cells expressing high levels of T cell immunoglobulin- and mucin-domain containing molecule-3. AB - T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an inhibitory receptor implicated in T cell exhaustion characteristic of chronic viral infection. Limited data exist on NK cell Tim-3 expression and functional consequences. In chronic hepatitis C virus (HCV)-infected subjects, we found increased Tim-3 on NKs, which was associated with an activated phenotype. The high level of Tim-3 was not reversed by successful IFN-alpha-based antiviral therapy. Tim-3(high) NK cells up-regulated TRAIL in response to IFN-alpha to a greater extent and demonstrated greater lymphokine-activated killing activity, viral control, and degranulation but similar cytokine production than their Tim 3(low) counterparts. Our results suggest that Tim-3 on NKs is associated with activation of this innate lymphocyte population that is polarized towards cytotoxicity in chronic HCV. These findings reveal roles for Tim-3 in the regulation of NKs that might represent targets for treatment of chronic viral infections. PMID- 25797692 TI - Double nexus--Doublesex is the connecting element in sex determination. AB - In recent years, our knowledge of the conserved master-switch gene doublesex (dsx) and its function in regulating the development of dimorphic traits in insects has deepened considerably. Here, a comprehensive overview is given on the properties of the male- and female-specific dsx transcripts yielding DSX(F) and DSX(M) proteins in Drosophila melanogaster, and the many downstream targets that they regulate. As insects have cell-autonomous sex determination, it was assumed that dsx would be expressed in every somatic cell, but recent research showed that dsx is expressed only when a cell is required to show its sexual identity through function or morphology. This spatiotemporal regulation of dsx expression has not only been established in D. melanogaster but in all insect species studied. Gradually, it has been appreciated that dsx could no longer be viewed as the master-switch gene orchestrating sexual development and behaviour in each cell, but instead should be viewed as the interpreter for the sexual identity of the cell, expressing this identity only on request, making dsx the central nexus of insect sex determination. PMID- 25797694 TI - New method for the immobilization of pullulanase onto hybrid magnetic (Fe3O4 kappa-carrageenan) nanoparticles by electrostatic coupling with pullulanase/chitosan complex. AB - We present a simple method to immobilize pullulanase onto hybrid magnetic (Fe3O4 kappa-carrageenan) nanoparticles, involving the in situ synthesis of magnetic carrageenan nanoparticles and the formation of pullulanase/chitosan complex. The complex behavior of pullulanase with chitosan as a function of pH and protein polysaccharide ratio was studied by turbidimetric titration. Then, the as prepared immobilized enzymes were characterized by vibrating-sample magnetometer, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffractometer, and thermogravimetric analysis. It was found that the activity retention of immobilized pullulanase and amount of enzyme loaded reached 95.5% and 96.3 mg/g, respectively, under optimal conditions. The immobilized enzyme exhibited great operational stability (retaining approximately 61% residual activity after ten consecutive reuses), demonstrating that enzyme leakage during the catalysis reaction was efficiently reduced. Furthermore, the activity of immobilized pullulanase was significantly (p < 0.01) higher than that of free pullulanase in a low pH range (pH < 3.0) and temperature over 60 degrees C, and the immobilized enzymes retained 45% of their initial activity after 5 h at 60 degrees C, compared to 21% for the free enzyme. These results indicated that immobilized pullulanase was efficient in terms of catalytic activity and can be applied to continuous starch processing applications in the food industry. PMID- 25797695 TI - Nonspherical nanoparticles with controlled morphologies via seeded surface initiated single electron transfer radical polymerization in soap-free emulsion. AB - This work reports a facile novel approach to prepare asymmetric poly(vinylidene fluoride)/polystyrene (PVDF/PS) composite latex particles with controllable morphologies using one-step soap-free seeded emulsion polymerization, i.e., surface-initiated single electron transfer radical polymerization (SET-RP) of styrene (St) at the surface of PVDF seed particles. It was observed that the morphology was influenced mainly by the St/PVDF feed ratio, the polymerization temperature, and the length of the catalyst Cu(0) wire (Phi 1.00 mm). When the feed ratio was St/PVDF = 5.0 g/1.0 g, snowman-like Janus particles were exclusively obtained. Raspberry-like and popcorn-like composite particles were observed at a higher reaction temperature or a shorter length of the catalyst wire. The reaction kinetics plots demonstrated some unique features. The formation of nonspherical composite nanoparticles can be ascribed to the surface nucleation of PS bulges following the SET-RP. PMID- 25797696 TI - The immune system and its modulation mechanism in scallop. AB - Scallops are a cosmopolitan family of bivalves, and some of them are highly prized as dominant aquaculture species. In the past decades, there have been increasing studies on the basic biology and immunology of scallops, and this review summarizes the research progresses of immune system and its modulation mechanism in scallop. As invertebrate, scallops lack adaptive immunity and they have evolved an array of sophisticated strategies to recognize and eliminate various invaders by employing a set of molecules and cells. It is evident that basic immune reactions such as immune recognition, signal transduction, and effector synthesis involved in immune response are accomplished in a variety of ways. They rely upon an extensive repertoire of phagocytosis, apoptosis and encapsulation of the circulating hemocytes for eliminating invasive pathogens, as well as the production of immune effectors that are active against a large range of pathogens or sensitive for the environmental stress. Furthermore, the molecular constitutions, metabolic pathways and immunomodulation mechanisms of the primitive catecholaminergic, cholinergic, enkephalinergic system and NO system in scallop are also discussed, which can be taken as an entrance to better understand the origin and evolution of the neuroendocrine-immune regulatory network in lower invertebrates. PMID- 25797697 TI - Comparative study of the ophthalmological examinations in neurofibromatosis type 1. Proposal for a new screening algorithm. AB - PURPOSE: Efforts are made to unify the protocol concerning the ophthalmological screening, monitoring and treatment of Optic Pathway Gliomas (OPGs) in children with neurofibromatosis type 1 (NF1). The aim of this study is to compare the most recent recommendations published in 2007 with the screening strategies in NF1 centres. The integration of these data resulted into a recommendation for an improved screening strategy. METHODS: A literature search on PubMed between 1984 and 2013 was performed. A questionnaire on the ophthalmological screening in NF1 was sent to centres of expertise in the field of NF1. Literature and questionnaire data were analysed. Also, findings of a round table discussion on the ophthalmological screening of NF1 patients at the European Paediatric Ophthalmological Society (EPOS) meeting in 2013 were summarized. RESULTS: In most centres ophthalmological screening in NF1 patients is well organized, but is performed longer and at more regular intervals than is mentioned in the recommendations. Visual acuity testing, fundoscopy and pupillary reflexes are carried out unanimously. CONCLUSIONS: There is no uniformity of the ophthalmological screening in NF1 patients. The present recommendation advises to screen annually until the age of 8. Because OPGs are likely to develop before the age of 6 and children do not usually complain of visual problems, OPGs can be missed or detection can be delayed if screening is only yearly performed at this young age. Based on these arguments, about half of our responders screen more frequently and until a later age. Therefore, we suggest performing a six monthly screening until the age of 6 and a yearly examination from 6 years until adulthood. This examination should include visual acuity assessment, pupillary reflexes and a fundoscopy. PMID- 25797698 TI - Epigenomes as therapeutic targets. AB - Epigenetics is a molecular phenomenon that pertains to heritable changes in gene expression that do not involve changes in the DNA sequence. Epigenetic modifications in a whole genome, known as the epigenome, play an essential role in the regulation of gene expression in both normal development and disease. Traditional epigenetic changes include DNA methylation and histone modifications. Recent evidence reveals that other players, such as non-coding RNAs, may have an epigenetic regulatory role. Aberrant epigenetic signaling is becoming to be known as a central component of human disease, and the reversible nature of the epigenetic modifications provides an exciting opportunity for the development of clinically relevant therapeutics. Current epigenetic therapies provide a clinical benefit through disrupting DNA methyltransferases or histone deacetylases. However, the emergence of next-generation epigenetic therapies provides an opportunity to more effectively disrupt epigenetic disease states. Novel epigenetic therapies may improve drug targeting and drug delivery, optimize dosing schedules, and improve the efficacy of preexisting treatment modalities (chemotherapy, radiation, and immunotherapy). This review discusses the epigenetic mechanisms that contribute to the disease, available epigenetic therapies, epigenetic therapies currently in development, and the potential future use of epigenetic therapeutics in a clinical setting. PMID- 25797699 TI - Phosphorelay of non-orthodox two component systems functions through a bi molecular mechanism in vivo: the case of ArcB. AB - Two-component systems play a central part in bacterial signal transduction. Phosphorelay mechanisms have been linked to more robust and ultra-sensitive signalling dynamics. The molecular machinery that facilitates such a signalling is, however, only understood in outline. In particular the functional relevance of the dimerization of a non-orthodox or hybrid histidine kinase along which the phosphorelay takes place has been a subject of debate. We use a combination of molecular and genetic approaches, coupled to mathematical and statistical modelling, to demonstrate that the different possible intra- and inter-molecular mechanisms of phosphotransfer are formally non-identifiable in Escherichia coli expressing the ArcB non-orthodox histidine kinase used in anoxic redox control. In order to resolve this issue we further analyse the mathematical model in order to identify discriminatory experiments, which are then performed to address cis- and trans-phosphorelay mechanisms. The results suggest that exclusive cis- and trans-mechanisms will not be operating, instead the functional phosphorelay is likely to build around a sequence of allosteric interactions among the domain pairs in the histidine kinase. This is the first detailed mechanistic analysis of the molecular processes involved in non-orthodox two-component signalling and our results suggest strongly that dimerization facilitates more discriminatory proof reading of external signals, via these allosteric reactions, prior to them being further processed. PMID- 25797700 TI - VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis. AB - BACKGROUND & AIMS: Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC). METHODS: CAC was induced in VEGFR2(DeltaIEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate. Tumor development and inflammation were determined by endoscopy. Colorectal tissues were collected for immunoblot, immunohistochemical, and quantitative polymerase chain reaction analyses. Findings from mouse tissues were confirmed in human HCT116 colorectal cancer cells. We analyzed colorectal tumor samples from patients before and after treatment with bevacizumab. RESULTS: After colitis induction, VEGFR2(DeltaIEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(DeltaIEC) mice were in senescence than tumor cells from control mice. We found VEGFR2 to activate phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, resulting in inactivation of p21 in HCT116 cells. Inhibitors of VEGFR2 and AKT induced senescence in HCT116 cells. Tumor cell senescence promoted an anti-tumor immune response by CD8(+) T cells in mice. Patients whose tumor samples showed an increase in the proportion of senescent cells after treatment with bevacizumab had longer progression-free survival than patients in which the proportion of senescent tumor cells did not change before and after treatment. CONCLUSIONS: Inhibition of VEGFR2 signaling leads to senescence of human and mouse colorectal cancer cells. VEGFR2 interacts with phosphatidylinositol-4,5-bisphosphate-3 kinase and AKT to inactivate p21. Colorectal tumor senescence and p21 level correlate with patient survival during treatment with bevacizumab. PMID- 25797701 TI - Surface indentation and fluid intake generated by the polymer matrix of Bacillus subtilis biofilms. AB - Bacterial biofilms are highly structured, surface associated bacteria colonies held together by a cell-generated polymer network known as EPS (extracellular polymeric substance). This polymer network assists in adhesion to surfaces and generates spreading forces as colonies grow over time. In the laboratory and in nature, biofilms often grow at the interface between air and an elastic, semi permeable nutrient source. As this type of biofilm increases in volume, an accommodating compression of its substrate may arise, potentially driven by the osmotic pressure exerted by the EPS against the substrate surface. Here we study Bacillus subtilis biofilm force generation by measuring the magnitude and rate of deformation imposed by colonies against the agar-nutrient slabs on which they grow. We find that the elastic stress stored in deformed agar is orders of magnitude larger than the drag stress associated with pulling fluid through the agar matrix. The stress exerted by the biofilm is nearly the same as the osmotic pressure generated by the EPS, and mutant colonies incapable of producing EPS exert much lower levels of stress. The fluid flow rate into B. subtilis biofilms suggest that EPS generated pressure provides some metabolic benefit as colonies expand in volume. These results reveal that long-term biofouling and colony expansion may be tied to the hydraulic permeability and elasticity of the surfaces that biofilms colonize. PMID- 25797702 TI - Bonding of universal adhesives to dentine--Old wine in new bottles? AB - OBJECTIVE: Multi-mode universal adhesives offer clinicians the choice of using the etch-and-rinse technique, selective enamel etch technique or self-etch technique to bond to tooth substrates. The present study examined the short-term in vitro performance of five universal adhesives bonded to human coronal dentine. METHODS: Two hundred non-carious human third molars were assigned to five groups based on the type of the universal adhesives (Prime&Bond Elect, Scotchbond Universal, All-Bond Universal, Clearfil Universal Bond and Futurabond U). Two bonding modes (etch-and-rinse and self-etch) were employed for each adhesive group. Bonded specimens were stored in deionized water for 24h or underwent a 10,000-cycle thermocycling ageing process prior to testing (N=10). Microtensile bond testing (MUTBS), transmission electron microscopy (TEM) of resin-dentine interfaces in non-thermocycled specimens and scanning electron microscopy (SEM) of tracer-infused water-rich zones within hybrid layers of thermocycled specimens were performed. RESULTS: Both adhesive type and testing condition (with/without thermocycling) have significant influences on MUTBS. The use of each adhesive in either the etch-and-rinse or self-etch application mode did not result in significantly different MUTBS to dentine. Hybrid layers created by these adhesives in the etch-and-rinse bonding mode and self-etch bonding mode were ~5MUm and <=0.5MUm thick respectively. Tracer-infused regions could be identified within the resin-dentine interface from all the specimens prepared. CONCLUSION: The increase in versatility of universal adhesives is not accompanied by technological advances for overcoming the challenges associated with previous generations of adhesives. Therapeutic adhesives with bio-protective and bio promoting effects are still lacking in commercialized adhesives. CLINICAL SIGNIFICANCE: Universal adhesives represent manufacturers' attempt to introduce versatility in product design via adaptation of a single-bottle self-etch adhesive for other application modes without compromising its bonding effectiveness. PMID- 25797704 TI - A DNA logic gate based on strand displacement reaction and rolling circle amplification, responding to multiple low-abundance DNA fragment input signals, and its application in detecting miRNAs. AB - A conveniently amplified DNA AND logic gate platform was designed for the highly sensitive detection of low-abundance DNA fragment inputs based on strand displacement reaction and rolling circle amplification strategy. Compared with others, this system can detect miRNAs in biological samples. The success of this strategy demonstrates the potential of DNA logic gates in disease diagnosis. PMID- 25797703 TI - Interparental conflict, children's security with parents, and long-term risk of internalizing problems: A longitudinal study from ages 2 to 10. AB - Although the negative impact of marital conflict on children has been amply documented, few studies have examined the process of risk in a long-term, longitudinal design. We examined parent-child attachment security as a mechanism that may account for the impact of interparental conflict on children's long-term risk of internalizing problems. Sixty-two community mothers, fathers, and children were followed from ages 2 to 10. Parents reported on their conflicts when their children were 2. Trained observers produced parent-child attachment security scores (Attachment Q-Set, Waters, 1987), based on lengthy naturalistic observations of the child with each parent. Parents rated children's internalizing problems at age 10. A conditional process model and bootstrap approach were implemented to examine conditional indirect effects of conflict on child internalizing problems through attachment security for girls versus boys. Maladaptive marital conflict (destructive strategies, severity of arguments) increased internalizing problems 8 years later due to the undermined security for girls, whereas negative emotional aftermath of conflict (unresolved, lingering tension) increased internalizing problems for both boys and girls. The emotional aftermath of conflict is often overlooked, yet it appears to be a key dimension influencing emotional security in the family system, with significant consequences for children's development. PMID- 25797705 TI - A soft, stretchable and conductive biointerface for cell mechanobiology. AB - In mechanobiology the study of cell response to mechanical stimuli is fundamental, and the involved processes (i.e., mechanotransduction) need to be investigated by interfacing (mechanically and electrically) with the cells in dynamic and non-invasive natural-like conditions. In this work, we present a novel soft, stretchable and conductive biointerface that allows both cell mechanical stimulation and dynamic impedance recording. The biointerface stretchability and conductivity, jointly to the biocompatibility and transparency needed to perform cell culture studies, were obtained by exploiting the formation of wrinkles on the surface of a 90 nm thick conductive layer of poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) on a pre-stretched 130 MUm thick poly(dimethylsiloxane) (PDMS) substrate. Cell adhesion and proliferation of SH-SY5Y human neuroblastoma cells were evaluated, and cell differentiation on the corrugated surface was assessed. We demonstrate how the biointerface remains conductive when applying uniaxial strain up to 10%, and when cell culturing is performed. Finally, a reduction of about 30% of the relative impedance variation signal was measured, with respect to the control, as a result of the mechanical stimulation of cells. PMID- 25797706 TI - Three-dimensional propagation imaging of left ventricular activation by speckle tracking echocardiography to predict responses to cardiac resynchronization therapy. AB - BACKGROUND: On the basis of the electromechanical coupling theory, an activation imaging system has been developed with three-dimensional speckle-tracking echocardiography. The aim of this study was to determine the association between left ventricular (LV) propagation patterns by activation imaging and response to cardiac resynchronization therapy (CRT). METHODS: This was a retrospective, single-center study. Eighty-one patients undergoing CRT, of whom 50 (61.7%) had left bundle branch block (LBBB), were enrolled. Activation imaging studies were performed with a three-dimensional speckle-tracking echocardiographic system, which allowed visualization of LV activation propagation and measurement of the time from the QRS complex to activation onset. A CRT volume responder was defined as a patient with >=15% reduction of LV end-systolic volume at 6 months after CRT. Clinical outcomes were assessed with the composite end point of death due to cardiac causes or unplanned hospitalization for cardiac diseases. RESULTS: In patients with LBBB, the main activation pattern (74%) was a U-shaped propagation pattern, which was characterized as propagation from the midseptum to the lateral or posterior wall through the apex. In patients without LBBB, various non-U shaped propagation patterns were observed in the majority of patients (97%). Among the 41 CRT responders, almost all (87.8%) had the U-shaped propagation pattern. During follow-up (median, 20 months), 29 patients (35.8%) reached the clinical end points. In a multivariate Cox proportional hazards model, a U-shaped propagation pattern was associated with the end points independently of LBBB or LV end-diastolic volume. CONCLUSIONS: The U-shaped propagation pattern on three dimensional speckle-tracking echocardiography was significantly associated with a favorable CRT response. Activation pattern analysis may provide additional information to predict response to CRT. PMID- 25797707 TI - IgG4-related disease, retrospective histopathological diagnosis. Prevalence in a University Hospital. AB - INTRODUCTION: IgG4 related diseases (IgG4-RD) are characterized mainly by organic dysfunction and inflammation with lymphoplasmacytic cells infiltration. METHODS: We conducted a retrospective study. We analyzed patients with a diagnosis of IgG4 RD through histopathologic registries. We divided the study into three phases: (i)extraction of data from the registries of the Pathology Department, including specimens reported with: non-specific inflammation with plasmatic cell infiltration, inflammatory pseudo-tumors and storiform fibrosis, and excluding any report of cancer or infection; (ii)from the selected specimens, three pathologists microscopically re-analyzed these biopsies and included only those who had at least two of the inclusion criteria cited above; (iii)finally, immunostaining was performed in the specimens selected in the second phase. The selected biopsies were catalogued as compatible for IgG4-RD if they had at least 3 inclusion criteria and as probable if they had 2 inclusion criteria. RESULTS: On the first phase of the study we analyzed 23,720 biopsies, from which we included 71 and excluded 29 specimens; the rest of the specimens (n=41) underwent immunostaining. From the biopsies included, 41.4% (n=17/71) were positive to IgG4, with the most common histological diagnosis for the positive specimens being granulomatous mastitis, which represented 12.1% of the specimens catalogued initially as probable. The rest of the positive biopsies were from aortitis, dacrioadenitis and/or sialoadenitis, lung pseudo-inflammatory tumor, pericarditis and chronic pancreatitis. CONCLUSIONS: The suspicion of IgG4 related disease should not be based solely on clinical manifestations or serology. In the present study we confirm the characteristic changes of IgG4-RD in patients without initial clinical suspicion. PMID- 25797708 TI - Response to Masi and Bouret - commentary on Klailova and Lee's (2014) "Wild western lowland gorillas signal selectively using odor". AB - In a previous paper, we suggested that gorilla silverback males used odour as a chemosignal about levels of risk during interactions with extra-group males. We suggested that, rather than being monotonically associated with arousal as Masi and Bouret have now proposed in their commentary, the strength of an odour was a variable response to within as well as between group risks. We all agree that the phenomenon needs further investigation. PMID- 25797709 TI - Odor signals in wild western lowland gorillas: an involuntary and extra-group communication hypothesis. AB - Odors constitute one of the most ancient ways of communication among animals. Whereas the key role of olfactory communication is well established in insects or rodents, its contribution to primate behavior remains very speculative. In a recent report, Klailova and Lee [1] studied the variations of intensity of the typical steroid musk odor produced by wild adult male gorilla silverbacks during encounters with opponents from other social units (lone males or other groups). The odor intensity increased in situations of potential conflicts, when the silverback encountered another male gorilla, which constitutes a potential threat for his infants and mate competitor for his females. Importantly, the odor intensity was greater when the silverback reacted with a demonstrative threat display, and milder when he decided to react quietly and avoid the conflict by sneaking away. According to the authors, this indicates that silverback gorillas can flexibly adjust the odor signal to the social context, and the mild signal associated with the quiet response is used within the silverback's group to promote cohesion. Rather, based on both physiological and behavioral data, we propose that (1) the odor intensity varies monotonically with arousal, across all situations, and (2) that the function of the odor signal is most relevant for the interactions between males of different groups. In such framework, the odor stimulus might also constitute a non-visual signal indicator of the emitter's identity, and therefore play a role in the regulation of the interactions with other gorillas. Establishing the balance among those potential functions is critical to understand the role of odors in the regulation of social and ecological interactions in primates. PMID- 25797710 TI - Field emission luminescence of nanodiamonds deposited on the aligned carbon nanotube array. AB - Detonation nanodiamonds (NDs) were deposited on the surface of aligned carbon nanotubes (CNTs) by immersing a CNT array in an aqueous suspension of NDs in dimethylsulfoxide (DMSO). The structure and electronic state of the obtained CNT ND hybrid material were studied using optical and electron microscopy and Infrared, Raman, X-ray photoelectron and near-edge X-ray absorption fine structure spectroscopy. A non-covalent interaction between NDs and CNT and preservation of vertical orientation of CNTs in the hybrid were revealed. We showed that current-voltage characteristics of the CNT-ND cathode are changed depending on the applied field; below ~3 V/um they are similar to those of the initial CNT array and at the higher field they are close to the ND behavior. Involvement of the NDs in field emission process resulted in blue luminescence of the hybrid surface at an electric field higher than 3.5 V/um. Photoluminescence measurements showed that the NDs emit blue-green light, while blue luminescence prevails in the CNT-ND hybrid. The quenching of green luminescence was attributed to a partial removal of oxygen-containing groups from the ND surface as the result of the hybrid synthesis. PMID- 25797711 TI - Correction to Sensitive and comprehensive detection of chemical warfare agents in air by atmospheric pressure chemical ionization ion trap tandem mass spectrometry with counterflow introduction. PMID- 25797712 TI - Molecular and electronic structures of donor-functionalized dysprosium pentadienyl complexes. AB - Two dysprosium complexes, [(C5H4Me)2Dy(L(1))] (3) and [(L(1))Dy(MU Cl)3{Li(tmeda)}]2 (4), with amino-functionalized pentadienyl ligands L(1) are described. Crystallographic studies of 3 and 4 show that the pendant amino group influences the pentadienyl conformation and the ligand hapticity. Electronic structure calculations reveal that L(1) has a strong influence on the orientation of the main magnetic axis of the ground Kramers doublets in 3 and 4. PMID- 25797713 TI - Polarization modulated upconversion luminescence: single particle vs. few particle aggregates. AB - Luminescence from crystals is often anisotropic and it leads to the polarization behavior of luminescence from single crystalline particles, as exemplified here with the upconversion luminescence from a single NaYF4 nanodisk. Nanodisk aggregates exhibit polarization dependent luminescence with different polarization degrees, which depends on the orientation and distribution of nanoparticles. PMID- 25797715 TI - Novel acidophilic beta-galactosidase with high activity at extremely acidic pH region from Teratosphaeria acidotherma AIU BGA-1. AB - A beta-galactosidase exhibiting maximal activity at pH 1.0 was purified from Teratosphaeria acidotherma AIU BGA-1. The enzyme had a molecular mass of 180 kDa and consisted of two heterosubunits of 120 kDa and 66 kDa. The N-terminal amino acid sequence of the large subunit was found to be SPNLQDIVTVDGESY. These physicochemical properties differed from those of other microbial beta galactosidases. At pH values of 1.5 and pH 4.5, the enzyme exhibited its highest activity at temperatures of 70 degrees C and 80 degrees C, respectively. Thus, the enzyme exhibited the lowest optimal pH and highest optimal temperature among the microbial beta-galactosidases thus reported. The enzyme retained more than 80% of its original activity in the pH range from 2.0 to 8.0 by incubation at 50 degrees C for 30 min. The enzyme hydrolyzed 4-nitrophenyl-beta-D-fucopyranoside, 2-nitrophenyl-beta-D-galactopyranoside, and 4-nitrophenyl-beta-D-galacto pyranoside at relative reaction rates of 100, 59, and 24, respectively, at pH 1.5, and its affinity for beta-D-galactopyranosides was higher than that for beta D-fucopyranosides. The enzyme also efficiently hydrolyzed lactose in milk and whey from yoghurt at pH 1.5. PMID- 25797716 TI - Potential dental pulp revascularization and odonto-/osteogenic capacity of a novel transplant combined with dental pulp stem cells and platelet-rich fibrin. AB - Our aim is to investigate the cytobiological effects of autologous platelet-rich fibrin (PRF) on dental pulp stem cells (DPSCs) and to explore the ectopic and orthotopic possibilities of dental pulp revascularization and pulp-dentin complex regeneration along the root canal cavities of the tooth by using a novel tissue engineered transplant composed of cell-sheet fragments of DPSCs and PRF granules. Canine DPSCs were isolated and characterized by assaying their colony-forming ability and by determining their cell surface markers and osteogenic/adipogenic differentiation potential. The biological effects of autologous PRF on DPSCs, including cell proliferation, alkaline phosphatase (ALP) activity and odonto /osteogenic gene expression, were then investigated and quantified. A novel transplant consisting of cell-sheet fragments of DPSCs and PRF granules was adopted to regenerate pulp-dentin-like tissues in the root canal, both subcutaneously in nude mice and in the roots of canines. PRF promoted the proliferation of DPSCs in a dose- and time-dependent manner and induced the differentiation of DPSCs to odonto-/osteoblastic fates by increasing the expression of the Alp, Dspp, Dmp1 and Bsp genes. Transplantation of the DPSC/PRF construct led both to a favorable regeneration of homogeneous and compact pulp like tissues with abundantly distributed blood capillaries and to the deposition of regenerated dentin along the intracanal walls at 8 weeks post-operation. Thus, the application of DPSC/PRF tissue constructs might serve as a potential therapy in regenerative endodontics for pulp revitalization or revascularization. PMID- 25797714 TI - Primary immunoglobulin repertoire development: time and space matter. AB - The primary immunoglobulin repertoire develops via opposing forces of expanding diversification balanced by contracting selection mechanisms. The resulting shape is essential for host health and immune fitness. While the molecular mechanisms of Ig diversification have largely been defined, selection forces shaping emerging Ig repertoires are poorly understood. During lifetime, human and mouse early B cell development occurs at distinct locations-beginning in fetal liver before transferring to bone marrow and spleen by the end of gestation. During an early life window of time, the murine gut lamina propria harbors developing immature B cells in proximity to intestinal contents such as commensal microbes and dietary antigens. Location and timing of early B cell development may thus endow neighboring antigens with primary repertoire-shaping capabilities. PMID- 25797717 TI - Micropreparative isolation and NMR structure elucidation of metabolites of the drug candidate 1-isopropyl-4-(4-isopropylphenyl)-6-(prop-2-yn-1-yloxy) quinazolin 2(1H)-one from rat bile and urine. AB - LC-MS based drug metabolism studies are effective in the optimization stage of drug discovery for rapid partial structure identification of metabolites. However, these studies usually do not provide unambiguous structural characterization of all metabolites, due to the limitations of MS-based structure identification. LC-MS-SPE-NMR is a technique that allows complete structure identification, but is difficult to apply to complex in vivo samples (such as bile collected during in vivo drug metabolism studies) due to the presence, at high concentrations, of interfering endogenous components, and potentially also dosage excipient components (e.g. polyethylene glycols). Here, we describe the isolation and structure characterization of seven metabolites of the drug development candidate 1-isopropyl-4-(4-isopropylphenyl)-6-(prop-2-yn-1-yloxy) quinazolin-2(1H)-one from a routine metabolism study in a bile-duct cannulated rat by LC-MS-SPE. The metabolites were isolated from bile and urine by repeated automatic trapping of the chromatographic peak of each metabolite on separate Oasis HLB SPE columns. The micropreparative HPLC/MS was performed on an XBridge BEH130 C18 HPLC column using aqueous formic acid/acetonitrile/methanol as mobile phase for the gradient elution. Mass spectrometric detection was performed on a LTQ XL linear ion trap mass spectrometer using electrospray ionization. Desorption of each metabolite was performed after the separation sequence. NMR spectra ((1)H, (13)C, 2D ROESY, HSQC and HMBC were measured on a Bruker AVANCE III spectrometer (600 MHz proton frequency) equipped with a 1.7 mm (1)H{(13)C,(15)N} Bruker Biospin's TCI MicroCryoProbeTM. PMID- 25797718 TI - Simultaneous determination of sixteen amide fungicides in vegetables and fruits by dispersive solid phase extraction and liquid chromatography-tandem mass spectrometry. AB - A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) method using multi-walled carbon nanotubes (MWCNTs) as a reversed-dispersive solid phase extraction (r-dSPE) material combined with ultra-high liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was developed for the simultaneous determination of 16 novel amide fungicides in vegetables and fruits. After extraction with acetonitrile, a dSPE cleanup procedure, which was developed after the optimization of the type and amount of MWCNTs, the pH value of the extract, the extraction time for MWCNTs, and the type of eluent with MWCNTs material, was conducted. The determination of the target compounds was conducted in less than 7.0 min while the specificity is ensured through the MRM acquisition mode. The linearity of the analytical response across the studied range of concentrations (0.25-500 MUg/L) was excellent, obtaining correlation coefficients higher than 0.997. The samples were quantified with the matrix matched standard solutions. The average recoveries in cabbage, celery, strawberry, and grape at three spiked levels (0.01, 0.5, and 5.0mg/kg) were ranged from 72.4 to 98.5% with all RSDs lower than 10%. The limits of detection were below 0.003 mg/kg and the limits of quantification did not exceed 0.01 mg/kg in all matrices. The method demonstrated to be suitable for the simultaneous determination of 16 novel amide fungicides in vegetables and fruits. PMID- 25797719 TI - Simultaneous determination of 18 preservative residues in vegetables by ultra high performance liquid chromatography coupled with triple quadrupole/linear ion trap mass spectrometry using a dispersive-SPE procedure. AB - A new method combining dispersive-solid phase purification procedure with ultra high performance liquid chromatography-triple quadrupole/linear ion trap mass spectrometry was developed for simultaneous determination of 18 preservative residues in vegetables. The new method not only had the advantages of dispersive solid phase purification procedure such as high recoveries, easy operation, rapid analysis, little solvent usage and wide analysis range of preservatives, but also had the advantages of ultra high performance liquid chromatography-triple quadrupole/linear ion trap mass spectrometry to be operated in positive mode and negative mode simultaneously. The method was validated for the following representative matrices: radish (tuber), tomato (eggplant fruit), cabbage (leafy), cowpea (bean), cucumber (melon) and so on. Samples were extracted with hexane-ethyl acetate (1:2, v/v), and then detected by ultra high performance liquid chromatography-triple quadrupole/linear ion trap mass spectrometry after being cleaned up with dispersive-solid phase purification procedure. Significant matrix effects were compensated by using the matrix-matched calibration curves. 18 preservatives showed good linearity over the range of 5.0-100.0 MUg/L with correlation coefficients of 0.9904-1.000. The limits of detections were in the range of 0.04-4.16 MUg/kg and the limits of quantity were in the range of 0.13 13.85 MUg/kg. The recoveries of 18 preservatives ranged from 76.0% to 120.0% with the spiked levels of 2, 4 and 10 MUg/kg into homogenized vegetables, and the relative standard deviations (RSDs) ranged from 0.3% to 14.8%. Compared with the reported literatures, the method is more rapid, simple, highly sensitive, reliable and can meet testing requirements of 18 preservative residues in vegetables. PMID- 25797720 TI - Breaking the sensitivity limitations of cytochrome P450 oxidation product: dansyl chloride derivatisation of 4-OH mephenytoin, a CYP2C19 metabolite and its application to in vitro CYP inhibition assay. AB - A rapid selective and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed for the quantitative determination of derivatised cytochrome P450-2C19 oxidation product (dansyl-4-OH mephenytoin) and its underivatised form (4-OH mephenytoin). Samples were anaysed on C18 column (Waters Xbridge, 50 mm*4.6 mm, 3.5 MUm particle size) with the mobile phase consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A gradient method with a short run time of 2.5 min and 3.5 min was developed for the analysis of dansyl-4-OH mephenytoin and 4-OH mephenytoin, respectively. The standard curve was linear (r(2)=0.9972 for 4-OH mephenytoin; r(2)=0.9946 for dansyl-4-OH mephenytoin) over the concentration range of 0.16 to 40 ng/mL for both derivatised and underivatised forms. The CV (%) and relative error (RE) for inter and intraassay at three QC levels for dansyl-4-OH mephenytoin was 0.97-5.85% and 9.80 to 2.51%, respectively. Whereas, for 4-OH mephenytoin the CV (%) and RE (%) at three QC levels was 0.82-3.47% and -6.69 to -0.01%, respectively. The developed method was validated for various parameters such as linearity, precision & accuracy, extraction recovery, matrix effect, autosampler stability and was proved to be consistent across three QC levels with overall CV (%) less than 15. Dansylation helped in increasing the sensitivity of hydroxy mephenytoin by 100-200 fold. Given the simplicity involved in derivatisation process, we believe that this novel methodology will change the current approaches used for the enhancing the detection sensitivity of 4-OH mephenytoin. PMID- 25797721 TI - Development and validation of LC-MSMS assay for the determination of the prodrug dabigatran etexilate and its active metabolites in human plasma. AB - Dabigatran etexilate (DABE) is a low-molecular-weight prodrug that is converted after oral administration to dabigatran (DAB)-a directly acting oral anticoagulant. In this study, an LC-MSMS assay was developed and validated for the determination of DABE, free DAB and its equipotent O-glucuronide conjugates in plasma. Owing to the susceptibility of DABE and DAB to chemical hydrolysis, cleavage of the O-glucuronide moiety was carried out using beta-glucuronidase enzyme. Free and total plasma concentrations of DAB were determined in incurred plasma samples before and after enzymatic cleavage (50 degrees C and 3 h), respectively. RP-HPLC separation was carried out using acetonitrile: water (30:70, v/v), adjusted to pH 3.0 using formic acid. Tandem mass spectrometric detection at positive electrospray ionization in the MRM mode was then employed for the determination of DABE and DAB. The analysis was carried out within 5.0 min over a linear concentration range of 1.00-600.00 ng/mL for the prodrug and its active metabolite. Validation was carried out according to FDA guidelines for bioanalytical method. The recoveries were higher than 89.48%, the accuracy was within 98.33-110.12% and the RSD was below 10% for the studied compounds in both incurred plasma and quality control samples. Results of incurred sample re analysis and incurred sample stability revealed less than 10% variability. This indicated good assay precision and sufficient stability of target analytes in their real matrix at the employed experimental conditions. The applicability of the assay for therapeutic drug monitoring and the determination of the pharmacokinetic parameters were demonstrated. PMID- 25797722 TI - Discussion. PMID- 25797723 TI - Discussion. PMID- 25797724 TI - Discussion. PMID- 25797725 TI - Standardization of care: impact of an enhanced recovery protocol on length of stay, complications, and direct costs after colorectal surgery. AB - BACKGROUND: Colorectal surgery is associated with considerable morbidity and prolonged length of stay (LOS). Recognizing the need for improvement, we implemented an enhanced recovery (ER) protocol for all patients undergoing elective colorectal surgery at an academic institution. STUDY DESIGN: A multidisciplinary team implemented an ER protocol based on: preoperative counseling with active patient participation, carbohydrate loading, multimodal analgesia with avoidance of intravenous opioids, intraoperative goal-directed fluid resuscitation, immediate postoperative feeding, and ambulation. Discharge requirements remained identical throughout. A before and after study design was undertaken comparing patients before (August 2012 to February 2013) and after implementation of an ER protocol (August 2013 to February 2014). Risk stratification was performed using the NSQIP risk calculator to calculate the predicted LOS for each patient based on 23 variables. RESULTS: One hundred and nine consecutive patients underwent surgery within the ER protocol compared with 98 consecutive historical controls (conventional). The risk-adjusted predicted LOS was similar for each group at 5.1 and 5.2 days. Substantial reductions were seen in LOS, morphine equivalents, intravenous fluids, return of bowel function, and overall complications with the ER group. There was a $7,129/patient reduction in direct cost, corresponding to a cost savings of $777,061 in the ER group. Patient satisfaction as measured by Press Ganey improved considerably during the study period. CONCLUSIONS: Implementation of an ER protocol led to improved patient satisfaction and substantial reduction in LOS, complication rates, and costs for patients undergoing both open and laparoscopic colorectal surgery. These data demonstrate that small investments in the perioperative environment can lead to large returns. PMID- 25797726 TI - Discussion. PMID- 25797728 TI - Discussion. PMID- 25797727 TI - Determining the hospital trauma financial impact in a statewide trauma system. AB - BACKGROUND: There have been no comprehensive studies across an organized statewide trauma system using a standardized method to determine cost. STUDY DESIGN: Trauma financial impact includes the following costs: verification, response, and patient care cost (PCC). We conducted a survey of participating trauma centers (TCs) for federal fiscal year 2012, including separate accounting for verification and response costs. Patient care cost was merged with their trauma registry data. Seventy-five percent of the 2012 state trauma registry had data submitted. Each TC's reasonable cost from the Medicare Cost Report was adjusted to remove embedded costs for response and verification. Cost-to-charge ratios were used to give uniform PCC across the state. RESULTS: Median (mean +/- SD) costs per patient for TC response and verification for Level I and II centers were $1,689 ($1,492 +/- $647) and $450 ($636 +/- $431) for Level III and IV centers. Patient care cost-median (mean +/- SD) costs for patients with a length of stay >2 days rose with increasing Injury Severity Score (ISS): ISS <9: $6,787 ($8,827 +/- $8,165), ISS 9 to 15: $10,390 ($14,340 +/- $18,395); ISS 16 to 25: $15,698 ($23,615 +/- $21,883); and ISS 25+: $29,792 ($41,407 +/- $41,621), and with higher level of TC: Level I: $13,712 ($23,241 +/- $29,164); Level II: $8,555 ($13,515 +/- $15,296); and Levels III and IV: $8,115 ($10,719 +/- $11,827). CONCLUSIONS: Patient care cost rose with increasing ISS, length of stay, ICU days, and ventilator days for patients with length of stay >2 days and ISS 9+. Level I centers had the highest mean ISS, length of stay, ICU days, and ventilator days, along with the highest PCC. Lesser trauma accounted for lower charges, payments, and PCC for Level II, III, and IV TCs, and the margin was variable. Verification and response costs per patient were highest for Level I and II TCs. PMID- 25797729 TI - Discussion. PMID- 25797730 TI - Discussion. PMID- 25797731 TI - Discussion. PMID- 25797732 TI - Discussion. PMID- 25797733 TI - Discussion. PMID- 25797734 TI - Discussion. PMID- 25797735 TI - Discussion. PMID- 25797736 TI - Discussion. PMID- 25797737 TI - Addition of direct peritoneal lavage to human cadaver organ donor resuscitation improves organ procurement. AB - BACKGROUND: Brain dead organ donors have altered central hemodynamic performance, impaired hormone physiology, exaggerated systemic inflammatory response, end organ microcirculatory dysfunction, and tissue hypoxia. A new treatment, direct peritoneal resuscitation (DPR), stabilizes vital organ blood flow after conventionally resuscitated shock to improve these derangements. STUDY DESIGN: A prospective case-control study of adjunctive DPR compared 26 experimental patients (brain dead organ donors) to 52 controls (protocolized conventionally resuscitated donors). Actual organ procurement rates were compared with the Scientific Registry of Transplant Recipient predicted organ yield per patient. Achievement of donor management goals and effective hepatic blood flow were recorded. RESULTS: Fourteen of 26 (53.8%) patients treated with DPR achieved all donor management goals compared with 17 of 52 (32.7%) patients treated with conventionally resuscitated (odds ratio = 2.4; 95% CI, 0.92-6.3; p = 0.06). Patients treated with DPR were more than 2 times as likely to achieve final pO2 >100 on 40% FiO2 compared with controls (odds ratio = 2.8; 95% CI, 1-7.69; p = 0.03). Also, DPR-treated patients required less IV crystalloid during the first 12 hours of management (DPR: 3,167 +/- 1,893 mL vs 4,154 +/- 2,100 mL; p = 0.046) and required less vasopressor agents at 12 hours post resuscitation (odds ratio = 7.7; 95% CI, 0.82-42; p = 0.02). Direct peritoneal resuscitation patients had enhanced effective hepatic blood flow and significantly higher organs transplanted per donor rates compared with controls (3.7 +/- 1.7 vs 3.1 +/- 1.3; p = 0.024). CONCLUSIONS: Direct peritoneal resuscitation reduced IV fluid requirement and IV pressor use as well as increased hepatic blood flow and organs transplanted per donor. Direct peritoneal resuscitation studies show it to be a safe, effective method to augment organ donor resuscitation and additional large scale trials should be conducted to validate these findings. PMID- 25797738 TI - Discussion. PMID- 25797739 TI - Discussion. PMID- 25797741 TI - Discussion. PMID- 25797740 TI - The SAVE review: sonographic analysis versus excision for axillary staging in breast cancer. AB - BACKGROUND: Health care reform goals involve more cost-effective methods of delivering health care. The cost-effectiveness of axillary ultrasound-guided core needle biopsy (AUS-CNB) was compared with sentinel lymph node biopsy (SLNB) when evaluating the status of the axilla in operable invasive breast cancer. STUDY DESIGN: We performed an IRB-approved retrospective review of patients undergoing ultrasound of the axilla plus core needle biopsy at our institution from 2007 to 2012. An accuracy of technique and cost analysis (TreeAge Pro 2009) of AUS-CNB vs SLNB was conducted. RESULTS: The cohort of 95 patients was divided into 2 groups: clinically positive (CP) (32%) and negative (CN) (68%) axilla. In the CP group, 83% had a suspicious AUS, of which 90% were positive. In the CN group, AUS was suspicious in 70%, with a positive biopsy in 59%. The sensitivity and specificity of AUS-CNB were 90% (95% CI 84.8% to 98.8%) and 100% (95% CI 27% to 59.1%), respectively. Cost estimates comparing AUS-CNB with SLNB demonstrated a cost saving of $236,517 in the CP axilla and $248,490 in the CN axilla, for a total cost savings of $485,007. CONCLUSIONS: Axillary ultrasound-guided core needle biopsy is a sensitive, diagnostic, surgeon-performed procedure. It is time saving, cost-efficient, and less invasive, making it a viable option when evaluating the status of the axilla in invasive breast cancer or staging before neoadjuvant chemotherapy. PMID- 25797742 TI - Discussion. PMID- 25797743 TI - Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma. AB - BACKGROUND: We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance. STUDY DESIGN: Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains. RESULTS: Therapy was tolerated well, with toxicity >= grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen activated protein kinase pathway inhibition. CONCLUSIONS: Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies. PMID- 25797744 TI - Discussion. PMID- 25797745 TI - Discussion. PMID- 25797746 TI - Open retromuscular mesh repair of complex incisional hernia: predictors of wound events and recurrence. AB - BACKGROUND: Mesh repair of incisional hernias has been consistently shown to diminish recurrence rates after repair, with an increased risk of infectious complications. We present a consecutive series of elective, retrorectus mesh repairs of the abdominal wall and attempt to determine predictors of wound events and recurrence. STUDY DESIGN: A retrospective review was performed to include elective, retromuscular mesh repairs of complex incisional hernias from August 2006 to August 2013. Demographics, operative details, and postoperative events including wound events, surgical site infections (SSI), and recurrences were recorded. RESULTS: Over the 7-year period, 255 retromuscular mesh repairs of midline incisional defects were performed. Median age of the patients was 58 years, with an average BMI of 32.2 kg/m(2). Average size of the fascial defect was 181.4 cm(2), with recurrent defects making up 48% of repairs. Wound events occurred in 37.7% of cases; SSIs occurred in 19.6% of cases. Recurrence rate was 16.9%, with mean time to recurrence of 19.2 months. With respect to mesh type, recurrences were 16.2% with synthetic, 17.1% for bioabsorbable, and 25% for biologic mesh. When evaluating polypropylene meshes, recurrence was more likely with lightweight mesh (22.9%) vs midweight mesh (10.6%) (p = 0.045). Predictors of SSI included history of mesh infection (odds ratio [OR] 4.8, 95% CI 1.9 to 12.1; p < 0.001) and recurrent repairs (OR 2.5, 95% CI 1.1 to 5.8; p < 0.05). The only predictor of recurrence was the presence of an SSI (OR 3.1, 95% CI 1.5 to 6.3; p < 0.01). CONCLUSIONS: Wound events are common after open mesh repairs of complex incisional hernias. Previous mesh infections and recurrent repairs increase the likelihood of an SSI, which significantly increases the risk of recurrence. Recurrences after retrorectus mesh repairs are significantly higher with lightweight compared with mid-weight meshes. PMID- 25797747 TI - Discussion. PMID- 25797748 TI - Discussion. PMID- 25797749 TI - Discussion. PMID- 25797750 TI - Discussion. PMID- 25797751 TI - Discussion. PMID- 25797752 TI - Postmastectomy radiation for N2/N3 breast cancer: factors associated with low compliance rate. AB - BACKGROUND: The National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines recommend postmastectomy radiation therapy (PMRT) for women with N2/N3 breast cancer. We examined the compliance rate of PMRT using the National Cancer Data Base and determined what factors are associated with low compliance rate with PMRT. STUDY DESIGN: The National Cancer Data Base, comprising 2,720,368 breast cancer cases diagnosed between 1998 and 2011, was evaluated. From this database, 56,990 women with N2/N3 diseases were evaluated. Statistics used include chi-square test, 2-sample t-test or Wilcoxon rank-sum test, and multivariate analysis. RESULTS: Mean age of the patients was 58 years and median follow-up was 61 months. The majority of patients were from a comprehensive community cancer programs (59%), were Caucasian (81%), had health insurance (96%), resided in urban communities (98%), and had no comorbidities (83%). Approximately 82% received chemotherapy, but only 65% had PMRT. Factors associated with PMRT are tumor grade (p = 0.03), regional lymph node surgery (p = 0.03), readmission within 30 days of surgical discharge (p = 0.03), receipt of chemotherapy (p < 0.01) and hormonal therapy (p < 0.01), and 30-day mortality (p < 0.01). Socioeconomic variables, such as facility type (p = 0.85), facility geographic location (p = 0.27), race/ethnicity (p = 0.12), insurance status (p = 0.10), income level (p = 0.43), education level (p = 0.86), residential location (p = 0.83), and comorbidities (p = 0.83) were not contributory factors. Independent variables predicting compliance with PMRT include receipt of chemotherapy (odds ratio = 4.55; p < 0.01), readmission within 30 days after surgery (odds ratio = 1.14; p = 0.01), and alive within 30 days after surgery (odds ratio = 1.55; p = 0.04). CONCLUSIONS: One third of patients with N2/N3 disease did not receive PMRT. Socioeconomic variables were not contributory factors. Noncompliance with PMRT is related to lack of receipt of chemotherapy, nonreadmission, or death within 30 days after surgery. PMID- 25797753 TI - Discussion. PMID- 25797754 TI - Discussion. PMID- 25797755 TI - Discussion. PMID- 25797756 TI - Discussion. PMID- 25797758 TI - Discussion. PMID- 25797757 TI - A novel risk scoring system reliably predicts readmission after pancreatectomy. AB - BACKGROUND: Postoperative readmissions have been proposed by Medicare as a quality metric and can impact provider reimbursement. Because readmission after pancreatectomy is common, we sought to identify factors associated with readmission to establish a predictive risk scoring system. STUDY DESIGN: A retrospective analysis of 2,360 pancreatectomies performed at 9 high-volume pancreatic centers between 2005 and 2011 was performed. Forty-five factors strongly associated with readmission were identified. To derive and validate a risk scoring system, the population was randomly divided into 2 cohorts in a 4:1 fashion. A multivariable logistic regression model was constructed and scores were assigned based on the relative odds ratio (OR) of each independent predictor. A composite Readmission after Pancreatectomy (RAP) score was generated and then stratified to create risk groups. RESULTS: Overall, 464 (19.7%) patients were readmitted within 90 days. Eight pre- and postoperative factors, including earlier MI (OR = 2.03), American Society of Anesthesiologists class >= 3 (OR = 1.34), dementia (OR = 6.22), hemorrhage (OR = 1.81), delayed gastric emptying (OR = 1.78), surgical site infection (OR = 3.31), sepsis (OR = 3.10), and short length of stay (OR = 1.51) were independently predictive of readmission. The 32 point RAP score generated from the derivation cohort was highly predictive of readmission in the validation cohort (area under the receiver operating curve = 0.72). The low-risk (0 to 3), intermediate-risk (4 to 7), and high-risk (>7) groups correlated with 11.7%, 17.5%, and 45.4% observed readmission rates, respectively (p < 0.001). CONCLUSIONS: The RAP score is a novel and clinically useful risk scoring system for readmission after pancreatectomy. Identification of patients with increased risk of readmission using the RAP score will allow efficient resource allocation aimed to attenuate readmission rates. It also has potential to serve as a new metric for comparative research and quality assessment. PMID- 25797759 TI - Discussion. PMID- 25797760 TI - Discussion. PMID- 25797761 TI - Discussion. PMID- 25797762 TI - Retained foreign bodies: risk and outcomes at the national level. AB - BACKGROUND: Retained foreign bodies (RFB) after operative interventions are linked to an increased risk of morbidity and mortality, and represent a medico legal liability. We aimed to identify associated risk factors and outcomes related to iatrogenic RFB in the United States. STUDY DESIGN: A cross-sectional analysis was performed on all interventions that resulted in a secondary diagnosis of RFB in the Nationwide Inpatient Sample (NIS) from 2003 to 2009. Comparative controls were randomly selected from patients who underwent similar procedures. RESULTS: We identified 3,045 cases of RFB, and 12,592 controls were included. The majority of incidents, 968 (31.8%), were reported after gastrointestinal interventions. Risk of RFB was higher in teaching hospitals (odds ratio [OR] 1.31, 95% CI [1.19, 1.45], p < 0.001). For abdominopelvic procedures, patients admitted with traumatic injuries did not demonstrate a higher risk of RFB compared with electively admitted patients (OR 1.70, 95% CI [0.94, 3.07], p = 0.08). However, for procedures unrelated to abdominopelvic surgery, patients admitted for trauma had a lower risk (OR 0.62, 95% CI [0.50, 0.78], p < 0.001). Obesity (BMI >= 30 kg/m(2)) and older age (>= 65 years) were significantly associated with a higher risk only for abdominopelvic procedures (p < 0.01 for both). Retained foreign bodies were associated with a higher average cost of health services ($26,678.00 +/- $769.69 vs $12,648.00 +/- $192.80, p < 0.001). CONCLUSIONS: Retained foreign bodies have unfavorable and nationally tangible clinical and economic outcomes. The risk profile for RFB at the national level seems to demonstrate an association with demographic and clinical factors including nature of the procedure, type of admission, and trauma status. Teaching hospitals are associated with a higher risk. Targeted efforts toward identified high-risk populations are needed to avoid these morbid and costly complications. PMID- 25797763 TI - Discussion. PMID- 25797764 TI - Acute care surgery: defining mortality in emergency general surgery in the state of Maryland. AB - BACKGROUND: Emergency general surgery (EGS) is a major component of acute care surgery, however, limited data exist on mortality with respect to trauma center (TC) designation. We hypothesized that mortality would be lower for EGS patients treated at a TC vs non-TC (NTC). STUDY DESIGN: A retrospective review of the Maryland Health Services Cost Review Commission database from 2009 to 2013 was performed. The American Association for the Surgery of Trauma EGS ICD-9 codes were used to identify EGS patients. Data collected included demographics, TC designation, emergency department admissions, and All Patients Refined Severity of Illness (APR_SOI). Trauma center designation was used as a marker of a formal acute care surgery program. Primary outcomes included in-hospital mortality. Multivariable logistic regression analysis was performed controlling for age. RESULTS: There were 817,942 EGS encounters. Mean +/- SD age of patients was 60.1 +/- 18.7 years, 46.5% were males; 71.1% of encounters were at NTCs; and 75.8% were emergency department admissions. Overall mortality was 4.05%. Mortality was calculated based on TC designation controlling for age across APR_SOI strata. Multivariable logistic regression analysis did not show statistically significant differences in mortality between hospital levels for minor APR_SOI. For moderate APR_SOI, mortality was significantly lower for TCs compared with NTCs (p < 0.001). Among TCs, the effect was strongest for Level I TC (odds ratio = 0.34). For extreme APR_SOI, mortality was higher at TCs vs NTCs (p < 0.001). CONCLUSIONS: Emergency general surgery patients treated at TCs had lower mortality for moderate APR_SOI, but increased mortality for extreme APR_SOI when compared with NTCs. Additional investigation is required to better evaluate this unexpected finding. PMID- 25797765 TI - Discussion. PMID- 25797766 TI - You have heard of the award, but what do you know about Arthur M Shipley? PMID- 25797768 TI - Tackling obesity--is coercion an option? PMID- 25797769 TI - Diagnostic criteria for osteoporosis should be expanded. PMID- 25797770 TI - Diagnostic criteria for osteoporosis should not be expanded. PMID- 25797771 TI - Ethel Siris: the bare bones of osteoporosis. PMID- 25797772 TI - Cardiovascular calcification: current controversies and novel concepts. AB - Cardiovascular calcification is a commonly observed but incompletely understood mechanism of increased atherosclerotic plaque instability and accelerated aortic valve stenosis. Traditional histological staining and imaging techniques are nonspecific for the type of mineral present in calcified tissues, information that is critical for proper validation of in vitro and in vivo models. This review highlights current gaps in our understanding of the biophysical implications and the cellular mechanisms of valvular and vascular calcification and how they may differ between the two tissue types. We also address the hindrances of current cell culture systems, discussing novel platforms and important considerations for future studies of cardiovascular calcification. PMID- 25797773 TI - Asymmetric Posterior Thoracolumbar Fixation following a Posterolateral Transpedicular Approach for Unilateral Vertebral Disease. AB - The present study aimed to evaluate the clinical outcomes of patients who underwent asymmetrical posterior screw fixation for the treatment of unilateral posterior vertebral pathological entities. The study included 21 patients with a spinal tumor who underwent asymmetrical posterior spinal fusion surgery between April 2009 and March 2012. The American Spinal Injury Association (ASIA) motor score visual analog scale (VAS) score were used as the outcome measure at admission and follow-up. Among the 21 patients, 12 were male and 9 were female, and mean age was 50.71 (range, 24-78) years. Mean follow-up was 16.04 (range, 4 47) months. Postoperatively, neurological findings did not deteriorate in any of the patients. Among the ASIA grade C and D patients, eight (38%) of them exhibited clinical stability or recovery to ASIA E, whereas none of the ASIA B patients scores changed postoperatively. Perioperative complications were noted in six patients (28%). Spinal stability and fusion were achieved in 18 (85%) patients. The surgical asymmetrical fixation technique described reduced the duration of surgery, and the patients required less dissection of paraspinal muscles than bilateral symmetrical fixation. Asymmetrical fixation provides good stabilization for unilateral thoracolumbar vertebral pathological entities, and facilitates rapid rehabilitation of such patients, who are often elderly with comorbidities. PMID- 25797774 TI - An armrest is effective for reducing hand tremble in neurosurgeons. AB - Experienced neurosurgeons reduce hand tremble by placing their hand beside the operative field when performing microneurosurgery conventionally. Another solution to reduce hand tremble is an armrest. However, the reduction of hand tremble by using an armrest or finger-placing technique has not been rigorously measured in microneurosurgery. This study was performed to provide a quantitative assessment of the efficacy of an armrest to reduce hand tremble in comparison with the finger-placing technique. Hand tremble was evaluated in 11 board certified neurosurgeons in a simulated microneurosurgery. The loci of surgical forceps handled by neurosurgeons were measured by a three-dimensional optical coordinate measuring machine. A static task was performed under four conditions: with/without the finger-placing technique and/or an armrest. The radius of an imaginative sphere including 95% of each locus was calculated and reviewed according to the four conditions. Hand tremble was significantly larger when the finger-placing technique was not implemented compared to when the technique was used (P<0.05). The armrest also reduced hand tremble (P<0.05) similar to the finger-placing technique. Non-inferiority was retained between the finger-placing technique and the armrest. Concomitant use of the armrest and the finger-placing technique did not interfere with the efficacy of the technique to reduce neurosurgeon's hand tremble. The finger-placing technique was confirmed to reduce hand tremble. Resting the neurosurgeon's forearm on an armrest also reduced the hand tremble. An armrest is a device that reduces hand tremble in neurosurgeons like the finger-placing technique. PMID- 25797775 TI - Surgical treatment of intraspinal angiomatous meningiomas from a single center. AB - Intraspinal angiomatous meningiomas (AMs) are rare lesions, and no case series have been reported. We retrospectively reviewed the data of 12 patients with intraspinal AMs. All patients underwent magnetic resonance imaging (MRI) of the spine. Computed tomography angiography was performed for three cases with cervical lesion. The series included six females and six males with a mean age of 49.6 years. Five tumors were located in the cervical, one in the cervicothoracic, five in the thoracic, and one in the thoracolumbar spine. The most common symptom was motor deficits and the mean duration of symptoms was 18 months. All patients were treated surgically with gross total resection (GTR) (Simpson grade I and II resection). No patients underwent embolization. After surgery immediately, the neurological function was improved in five patients, remained stable in six patients, and was deteriorated in one patient. During an average follow up of 78.6 months, 11 patients experienced an improvement in the neurological function and one patient maintained preoperative status. No tumor recurrence was observed on MRI. Compared to conventional meningiomas, AMs have no special clinical and radiological features. The accurate diagnosis depends on pathology. Timely GTR (en bloc resection) is the best treatment and embolization is not necessary for most patients. Radiotherapy is not recommended after GTR (Simpson grade I and II resection), and the risk of tumor recurrence is low. PMID- 25797776 TI - Efficacy of monitoring patient's position during neurosurgical procedures: introduction of real-time display and record. AB - There are many reports on position-related complications in neurosurgical literature but so far, continuous quantification of the patient's position during the surgery has not been reported. This study aims to explore the utility of a new surgical table system and its software in displaying the patient's body positions during surgery on real-time basis. More than 200 neurosurgical cases were monitored for their positions intra-operatively. The position was digitally recorded and could be seen by all the members in the operating team. It also displayed the three-dimensional relationship between the head and the heart positions. No position-related complications were observed during the study. The system was able to serve as an excellent indicator for monitoring the patient's position. The recordings were analyzed and even used to reproduce or improve the position in the subsequent operations. The novel technique of monitoring the position of the head and the heart of the patients and the operating table planes are considered to be useful during delicate neurosurgical procedures thereby, preventing inadvertent procedural errors. This can be used to quantify various surgical positions in the future and define safety measures accordingly. PMID- 25797777 TI - Endoscopic transnasal interseptal approach for invasive clival tumors: development of an approach method regarding maximal preservation of the nasal anatomy. AB - Asian people frequently show small noses, narrow nasal apertures, and congestive mucosa on the turbinates and septum. To reduce the risk of nasal morbidity with increased radicality for skull base tumors in these patients, we developed endoscopic transnasal interseptal approach (ETISA) in transsphenoidal surgery for invasive clival tumors (ICTs). Indication for ETISA is radical resection for tumors occupying deep ventral skull base regions, confined posterior to the level of the middle turbinates. After removing ethmoidal air cells, the middle turbinates are laterally deflected. A linear incision is made vertically on each side of the septal mucosa, which is separated from the bony septum as far as the sphenoid rostrum. The blades of an adjustable speculum are inserted submucosally, and the bony septum is temporarily displaced. The surgical pathway is widely maintained from the entrance to the deep surgical field without sacrificing the nasal mucosa and turbinates. Thirty-two consecutive patients with clival tumors (18 chordomas, 11 chondrosarcomas, 3 others) were treated. Bilateral middle turbinectomy was routinely performed in the initial 3 patients, but in only 4 of the remaining 29 (3 unilaterally, 1 bilaterally). Tumor was sufficiently resected in 29 patients (90.6%; gross total removal n=25, subtotal resection n=4). As complications, 6 patients showed mild and transient worsening of cranial nerve symptoms. Nasal complications arose in 3 patients, persisting >3 months in 2 (5.7%). This approach allows fine bimanual handling and swift delivery of surgical equipment while reasonably preserving the nasal anatomy, which is useful in endoscopic transsphenoidal surgery for ICT. PMID- 25797778 TI - Current trends in health insurance systems: OECD countries vs. Japan. AB - Over the past few decades, the longest extension in life expectancy in the world has been observed in Japan. However, the sophistication of medical care and the expansion of the aging society, leads to continuous increase in health-care costs. Medical expenses as a part of gross domestic product (GDP) in Japan are exceeding the current Organization for Economic Co-operation and Development (OECD) average, challenging the universally, equally provided low cost health care existing in the past. A universal health insurance system is becoming a common system currently in developed countries, currently a similar system is being introduced in the United States. Medical care in Japan is under a social insurance system, but the injection of public funds for medical costs becomes very expensive for the Japanese society. In spite of some urgently decided measures to cover the high cost of advanced medical treatment, declining birthrate and aging population and the tendency to reduce hospital and outpatients' visits numbers and shorten hospital stays, medical expenses of Japan continue to be increasing. PMID- 25797779 TI - Surgical management of spinal intramedullary tumors: radical and safe strategy for benign tumors. AB - Surgery for spinal intramedullary tumors remains one of the major challenges for neurosurgeons, due to their relative infrequency, unknown natural history, and surgical difficulty. We are sure that safe and precise resection of spinal intramedullary tumors, particularly encapsulated benign tumors, can result in acceptable or satisfactory postoperative outcomes. General surgical concepts and strategies, technical consideration, and functional outcomes after surgery are discussed with illustrative cases of spinal intramedullary benign tumors such as ependymoma, cavernous malformation, and hemangioblastoma. Selection of a posterior median sulcus, posterolateral sulcus, or direct transpial approach was determined based on the preoperative imaging diagnosis and careful inspection of the spinal cord surface. Tumor-cord interface was meticulously delineated in cases of benign encapsulated tumors. Our retrospective functional analysis of 24 consecutive cases of spinal intramedullary ependymoma followed for at least 6 months postoperatively demonstrated a mean grade on the modified McCormick functional schema of 1.8 before surgery, deteriorating significantly to 2.6 early after surgery (< 1 month after surgery), and finally returning to 1.7 in the late postoperative period (> 6 months after surgery). The risk of functional deterioration after surgery should be taken into serious consideration. Functional deterioration after surgery, including neuropathic pain even long after surgery, significantly affects patient quality of life. Better balance between tumor control and functional preservation can be achieved not only by the surgical technique or expertise, but also by intraoperative neurophysiological monitoring, vascular image guidance, and postoperative supportive care. Quality of life after surgery should inarguably be given top priority. PMID- 25797780 TI - Trends and outcomes in the treatment of gliomas based on data during 2001-2004 from the Brain Tumor Registry of Japan. AB - The committee of Brain Tumor Registry of Japan (BTRJ) was founded in 1973 and conducts surveys and analyses of incidence, therapeutic methods, and treatment outcomes of primary and metastatic brain tumors with the cooperation of the Japan Neurosurgical Society members. Newly diagnosed 3,000-4,000 primary brain tumors and 600-1,000 brain metastases patients were enrolled in each year. This report describes the trends and treatment outcomes of gliomas from BTRJ volume 13, including 13,431 patients with primary brain tumors who newly started treatment from 2001 to 2004. Data from 382 diffuse astrocytomas (DAs), 121 oligodendrogliomas (OLs), 90 oligoastrocytomas (OAs), 513 anaplastic astrocytomas (AAs), 126 anaplastic oligodendrogliomas (AOs), 106 anaplastic oligoastrocytomas (AOAs), and 1,489 glioblastomas (GBMs) were analyzed for overall survival (OS) and progression free survival (PFS) depending on age, symptoms, Karnofsky performance status, location of the tumor, extent of resection (EOR), initial radiotherapy and chemotherapy. The 5-year PFS rates of the patients with DA, OL+OA, AA, AO+AOA, and GBM were 57.0%, 74.6%, 28.7%, 54.0%, and 9.2%, and the 5 year OS rates were 75.0%, 90.0%, 41.1%, 68.2%, and 10.1%, respectively. Higher EOR>=75% in DA and OL+OA and that >=50% in AA, AO+AOA, and GBM significantly prolonged OS. Complications and cause of death were also reported. BTRJ had been edited for all the patients, researchers, and especially for clinicians at bedside to give useful information about brain tumors and to contribute to the advances in brain tumor treatment. This report revealed various clinical problematic issues pertaining to the diagnosis and treatment of gliomas. PMID- 25797781 TI - Recent progress and future issues in the management of abusive head trauma. AB - Head trauma is the leading cause of death in child abuse cases and one of the important issues in the care of abused children. Since the Child Abuse Prevention Law was enforced in 2000 in Japan, various measures have been taken to prevent child abuse over the following decade. Accordingly, medical research on abusive head trauma (AHT) has advanced, leading to significant progress in the medical diagnosis of AHT. This progress has been brought about by (1) the widespread establishment of child protection teams (CPTs) at core hospitals, (2) the progress in neuroradiological imaging and ophthalmoscopic technologies, and (3) the introduction of postmortem imaging. However, the pathological condition of patients with AHT, particularly that of the diffuse brain swelling type, still remains poorly understood. As a result, no clear treatment strategies for AHT have been developed and no treatment outcomes have been improved to date. The development of new treatment strategies for AHT and the construction of a comprehensive database that supports clinical studies are required in the future. PMID- 25797782 TI - Japanese neurosurgeons and microsurgical anatomy: a historical review. AB - Research in microneurosurgical anatomy has contributed to great advances in neurosurgery in the last 40 years. Many Japanese neurosurgeons have traveled abroad to study microsurgical anatomy and played major roles in advancing and spreading the knowledge of anatomy, overcoming their disadvantage that the cadaver study has been strictly limited inside Japan. In Japan, they initiated an educational system for surgical anatomy that has contributed to the development and standardization of Japanese neurosurgery. For example, the Japanese Society for Microsurgical Anatomy started an annual educational meeting in the middle of 1980s and published its proceedings in Japanese every year for approximately 20 years. These are some of the achievements that bring worldwide credit to Japanese neurosurgeons. Not only should Japanese neurosurgeons improve their educational system but they should also contribute to the international education in this field, particularly in Asia. PMID- 25797783 TI - Superior turbinectomy: role for a two-surgeon technique in endoscopic endonasal transsphenoidal surgery--technical note. AB - We describe a practical technique of superior turbinectomy followed by posterior ethmoidectomy as a less invasive procedure for two-surgeon technique on endoscopic endonasal transsphenoidal surgery. After identification of the superior turbinate and the sphenoid ostium, the inferior third portion of the superior turbinate was coagulated and resected. This partial superior turbinectomy procedure exposed the posterior ethmoidal sinus. Resection of the bony walls between the sphenoid and posterior ethmoid sinuses provided more lateral and superior exposure of the sphenoid sinus. This technique was performed in 56 patients with midline skull base lesions, including 49 pituitary adenomas and 7 other lesions. Meticulous manipulation of instruments was performed in all cases without surgical complications such as permanent hyposmia/anosmia or nasal bleeding. Our findings suggested that the partial superior turbinectomy followed by retrograde posterior ethmoidectomy is a simple and safe technique providing a sufficient surgical corridor for two-surgeon technique to approaching midline skull base regions, mainly involving pituitary adenomas. PMID- 25797784 TI - Petrous apex cholesterol granuloma: importance of pedicled nasoseptal flap in addition to silicone T-tube for prevention of occlusion of drainage route in transsphenoidal approach--a technical note. AB - Recently, petrous apex cholesterol granulomas (CGs) have been treated via the endoscopic endonasal transsphenoidal approach (EEA) using a silicone tube, to prevent drainage route occlusion. Occlusion of the drainage route has led to problems with recurrence. The aim of this report is to describe the use of a surgical technique to prevent drainage route occlusion. In surgical technique, the posterolateral wall of the sphenoid sinus was opened by EEA. After cyst debridement, a vascularized nasoseptal flap with a width of approximately 4 cm was inserted into the lumen with a silicone T-tube with a diameter of 7 mm. This technique was used in two patients: the first patient during the second operation after recurrence following occlusion of the drainage route, and the second patient during the first operation. Opening of the cyst wall was confirmed endoscopically in both patients 12-24 months after surgery, even after removal of the T-tube. In conclusion, the use of a pedicled nasoseptal flap with a silicone tube is useful to prevent CG recurrence, by paranasal cavitization of the cystic cavity. PMID- 25797786 TI - Nanoparticle-based lateral flow biosensor for visual detection of fish nervous necrosis virus amplification products. AB - Lateral flow paper biosensors are an attractive analytical platform for detection of human and veterinary disease pathogens because they are optimal for accurate, rapid and sensitive analysis in research laboratory setups, as well as field analysis. Since diseases of viral etiology have been wreaking havoc in aquaculture industry, as well as the environment, the present study aims at the development of a gold nanoparticle-based biosensor for fish nervous necrosis virus (Nodavirus) nucleic acids detection. Total viral RNA, isolated from fish samples was subjected to reverse transcription PCR amplification. The PCR products were mixed with a specific oligonucleotide probe and applied next to oligonucleotide conjugated Au NPs. A red test line was formed when nodavirus product was present. The visual detection of the RT-PCR product was completed within 20 min. Following optimization, the biosensor was able to visually detect 270 pg of nodavirus initial total RNA. The present study describes a simple, accurate, robust and low cost method for nodavirus detection in biological samples. Apart contribution on basic research, the proposed biosensor offers great potential for commercial kit development for use on the site of fish culture by fish farmers. This fact will have great impact on environmental safety and disease monitoring without time consuming and costly procedures. PMID- 25797785 TI - Identification of domestication-related loci associated with flowering time and seed size in soybean with the RAD-seq genotyping method. AB - Flowering time and seed size are traits related to domestication. However, identification of domestication-related loci/genes of controlling the traits in soybean is rarely reported. In this study, we identified a total of 48 domestication-related loci based on RAD-seq genotyping of a natural population comprising 286 accessions. Among these, four on chromosome 12 and additional two on chromosomes 11 and 15 were associated with flowering time, and four on chromosomes 11 and 16 were associated with seed size. Of the five genes associated with flowering time and the three genes associated with seed size, three genes Glyma11g18720, Glyma11g15480 and Glyma15g35080 were homologous to Arabidopsis genes, additional five genes were found for the first time to be associated with these two traits. Glyma11g18720 and Glyma05g28130 were co expressed with five genes homologous to flowering time genes in Arabidopsis, and Glyma11g15480 was co-expressed with 24 genes homologous to seed development genes in Arabidopsis. This study indicates that integration of population divergence analysis, genome-wide association study and expression analysis is an efficient approach to identify candidate domestication-related genes. PMID- 25797787 TI - Cell membrane integrity and distinguishing between metabolically active and inactive cells as a means of improving viability PCR. AB - Viability PCR uses cell membrane integrity to differentiate live cells from dead. Our new approach improves viability PCR by enabling it to also discriminate between cells with an intact cell membrane and the ability to actively maintain bacterial homeostasis and cells that have an intact membrane but are metabolically inactive. PMID- 25797788 TI - An 18-electron system containing a superheavy element: theoretical studies of sg@au12. AB - M@Au12 cage molecules (M = transition element from group 6) are interesting clusters with high-symmetric structure and significant stability. As the heavier homologue of W is (106)Sg, it is interesting to pinpoint whether the Sg@Au12 cluster is also stable. Geometric and electronic structures and bonding of various Sg@Au12 isomers were investigated with density functional theory (PW91, PBE, B3LYP) and wave function theory (MP2, CCSD(T)) approaches. The lowest-energy isomer of Sg@Au12 has icosahedral symmetry with significant Sg(6d)-Au(6s) covalent-metallic interaction and is comparable to the lighter homologues (M = Mo, W), with similar binding energy, although Sg follows (as a rare case) the textbook rule "ns below (n - 1)d". The 12 6s valence electrons from Au12 and the six 7s6d ones from Sg can be viewed as an 18e system below and above the interacting Au 5d band, forming nine delocalized multicenter bond pairs with a high stability of ~0.8 eV of bond energy per each of the 12 Sg-Au contacts. Different prescriptions (orbital, multipole-deformation, charge-partition, and X ray-spectroscopy based ones) assign ambiguous atomic charges to the centric and peripheral atoms; atomic core-level energy shifts correspond to some negative charge shift to the gold periphery, more so for Cr@Au12 than for Sg@Au12 or Au@Au12. PMID- 25797789 TI - Mediolateral angular momentum changes in persons with amputation during perturbed walking. AB - Over 50% of individuals with lower limb amputation fall at least once each year. These individuals also exhibit reduced ability to effectively respond to challenges to frontal plane stability. The range of whole body angular momentum has been correlated with stability and fall risk. This study determined how lateral walking surface perturbations affected the regulation of whole body and individual leg angular momentum in able-bodied controls and individuals with unilateral transtibial amputation. Participants walked at fixed speed in a Computer Assisted Rehabilitation Environment with no perturbations and continuous, pseudo-random, mediolateral platform oscillations. Both the ranges and variability of angular momentum for both the whole body and both legs were significantly greater (p<0.001) during platform oscillations. There were no significant differences between groups in whole body angular momentum range or variability during unperturbed walking. The range of frontal plane angular momentum was significantly greater for those with amputation than for controls for all segments (p<0.05). For the whole body and intact leg, angular momentum ranges were greater for patients with amputation. However, for the prosthetic leg, angular momentum ranges were less for patients than controls. Patients with amputation were significantly more affected by the perturbations. Though patients with amputation were able to maintain similar patterns of whole body angular momentum during unperturbed walking, they were more highly destabilized by the walking surface perturbations. Individuals with transtibial amputation appear to predominantly use altered motion of the intact limb to maintain mediolateral stability. PMID- 25797790 TI - Domains and correlates of clinical balance impairment associated with Huntington's disease. AB - This study sought to (a) determine the domains of clinical balance impairments associated with Huntington's disease (HD), and (b) evaluate associations between balance test scores and other disease-related impairments. Eighteen subjects with genetically definite HD and 17 age-matched control subjects were evaluated on the Mini-BESTest for their clinical balance impairments as well as the Unified HD Rating Scale (UHDRS) motor and total functional capacity scales, Activity Specific Balance Confidence (ABC) Scale-short form, Montreal Cognitive Assessment (MoCA), and Symbol Digit Modalities Test (SDMT). Results showed that subjects with HD exhibited significantly lower total Mini-BESTest scores than subjects without HD (mean (95% CI)=76 (64-87)% with HD, 98 (96-99)% without HD; p=0.0011). Mini-BESTest item scores were significantly lower for subjects with HD on one-leg stance, postural responses, standing with eyes closed on foam, and dual-task timed up-and-go. Mini-BESTest scores significantly correlated with UHDRS motor (r(2)=0.68; p=0.00003) and total functional capacity (r(2)=0.75; p=0.000006) scores as well as with scores on the ABC short form (r(2)=0.45; p=0.0024), SDMT (r(2)=0.42; p=0.0036), and MoCA (r(2)=0.23; p=0.046) assessments. This study, therefore, demonstrates that balance impairments associated with HD span domains of anticipatory postural adjustments, postural responses, stance in challenging sensory conditions, and gait. Although preliminary, clinical balance impairment appears to be an efficient proxy evaluation of multiple HD-related factors due to associations with functional capacity, other motor impairments, balance confidence, and cognitive abilities. PMID- 25797791 TI - Statistical prediction of nanoparticle delivery: from culture media to cell. AB - The application of nanoparticles (NPs) within medicine is of great interest; their innate physicochemical characteristics provide the potential to enhance current technology, diagnostics and therapeutics. Recently a number of NP-based diagnostic and therapeutic agents have been developed for treatment of various diseases, where judicious surface functionalization is exploited to increase efficacy of administered therapeutic dose. However, quantification of heterogeneity associated with absolute dose of a nanotherapeutic (NP number), how this is trafficked across biological barriers has proven difficult to achieve. The main issue being the quantitative assessment of NP number at the spatial scale of the individual NP, data which is essential for the continued growth and development of the next generation of nanotherapeutics. Recent advances in sample preparation and the imaging fidelity of transmission electron microscopy (TEM) platforms provide information at the required spatial scale, where individual NPs can be individually identified. High spatial resolution however reduces the sample frequency and as a result dynamic biological features or processes become opaque. However, the combination of TEM data with appropriate probabilistic models provide a means to extract biophysical information that imaging alone cannot. Previously, we demonstrated that limited cell sampling via TEM can be statistically coupled to large population flow cytometry measurements to quantify exact NP dose. Here we extended this concept to link TEM measurements of NP agglomerates in cell culture media to that encapsulated within vesicles in human osteosarcoma cells. By construction and validation of a data-driven transfer function, we are able to investigate the dynamic properties of NP agglomeration through endocytosis. In particular, we statistically predict how NP agglomerates may traverse a biological barrier, detailing inter-agglomerate merging events providing the basis for predictive modelling of nanopharmacology. PMID- 25797793 TI - Comparative analysis of gill transcriptomes of two freshwater crayfish, Cherax cainii and C. destructor. AB - We undertook deep sequencing of gill transcriptomes from two freshwater crayfish, Cherax cainii and Cherax destructor, in order to generate genomic resources for future genomics research. Over 83 and 100 million high quality (quality score (Q)>=30) paired-end Illumina reads (150 bp) were assembled into 147,101 and 136,622 contigs in C. cainii and C. destructor, respectively. A total of 24,630 and 23,623 contigs received significant BLASTx hits and allowed the identification of multiple gill expressed candidate genes associated with pH and salinity balance. These functionally annotated transcripts will provide a resource to facilitate comparative genomic research in the genus Cherax, and in particular allow insights into respiratory and osmoregulatory physiology of this group of animals. PMID- 25797792 TI - New donors, loyal donors, and regular donors: Which motivations sustain blood donation? AB - BACKGROUND: The present contribution aims to investigate the motivations underlying blood donation and to probe how these differ on the basis of number of donations and donors' gender. MATERIALS AND METHODS: A total of 237 Italian donors (64.6% male) were administered a self-report questionnaire containing socio-demographic variables and Omoto and Snyder's Motivations for Volunteerism Scale adapted to blood donation. RESULTS AND DISCUSSION: The results reveal: (a) significant differences between new donors (1-4 donations) and loyal donors (5-15 donations) as well as between new donors and regular donors (more than 16 donations) emerge with respect to social motivations and ego-protection, which increase proportionately to number of donations; (b) gender differences characterize all the motivations except those related to values; (c) value motivations do not vary either with respect to number of donations or to gender. PMID- 25797794 TI - Predicting protein interface residues using easily accessible on-line resources. AB - It has been more than a decade since the completion of the Human Genome Project that provided us with a complete list of human proteins. The next obvious task is to figure out how various parts interact with each other. On that account, we review 10 methods for protein interface prediction, which are freely available as web servers. In addition, we comparatively evaluate their performance on a common data set comprising different quality target structures. We find that using experimental structures and high-quality homology models, structure-based methods outperform those using only protein sequences, with global template-based approaches providing the best performance. For moderate-quality models, sequence based methods often perform better than those structure-based techniques that rely on fine atomic details. We note that post-processing protocols implemented in several methods quantitatively improve the results only for experimental structures, suggesting that these procedures should be tuned up for computer generated models. Finally, we anticipate that advanced meta-prediction protocols are likely to enhance interface residue prediction. Notwithstanding further improvements, easily accessible web servers already provide the scientific community with convenient resources for the identification of protein-protein interaction sites. PMID- 25797795 TI - Phylogenetics based on partial ORF2 of triatoma virus in triatomines collected over a decade from domiciliary habitats. AB - The only virus sequenced and studied in triatomines is the Triatoma virus, from the Dicistroviridae family, which causes delayed development, reduced oviposition, and premature death of infected insects. With the goal of expanding the sequences already obtained in previous years and verifying if any changes occurred in their genomic sequences, 68 samples of triatomines from several provinces of Argentina were analyzed. Sixteen positive samples were obtained by Reverse Transcription (RT)-polymerase chain reaction using the VP3-VP1 subregion of open reading frame-2 as a diagnostic method; after sequencing, 11 samples were obtained from Triatoma infestans. These new sequences showed no significant differences in the analyzed regions, which were not grouped by species or habitat or geographical distribution. There were no differences when compared with the sequences found during 2002-2012, all obtained from the wild. We conclude that despite being an RNA virus, the different sequences show high homology. PMID- 25797796 TI - Histopathological changes in third-instar and adult Anastrepha ludens (Diptera: Tephritidae) after in vitro heat treatment. AB - The Mexican fruit fly, Anastrepha ludens Loew (Diptera: Tephritidae), is one of the most harmful pests of mango causing direct damage by oviposition on the fruit pulp. Mango for export is subjected to hydrothermal treatment as a quarantine method for the control of this pest, but exposure to heat for long periods of time reduces considerably the quality and shelf-life of treated fruit. The aim of this work was to study morphological changes of third-instar larvae and adults of A. ludens after in vitro exposure to high temperature at sublethal times. A heating block system was used to expose larvae at 46.1 degrees C for 19.6 and 12.9 min, producing 94.6 and 70% mortality, respectively. Treated larvae were processed for optical microscopy. A fraction of surviving treated larvae was separated into containers with artificial diet to allow development into adults. Adult sexual organs were dissected and processed for transmission electron microscopy analysis. Results showed that 94.6% of the treated larvae died at 46.1 degrees C for 19.6 min and none of the surviving larvae eclosed to adulthood, as they developed as malformed puparia. For the in vitro treatment at 46.1 degrees C during 12.9 min, 70% of the treated larvae died and only 3.75% reached the adult stage, but ultrastructural damage in the male testes and in the female ovaries was observed. Additionally, 11.1% of the adult flies from the in vitro treatment also showed wing malformation and were incapable of flying. The analysis showed that surviving flies were unable to reproduce. PMID- 25797797 TI - Peptidoglycan recognition protein S2 from silkworm integument: characterization, microbe-induced expression, and involvement in the immune-deficiency pathway. AB - Peptidoglycan recognition protein (PGRP) binds specifically to peptidoglycan and plays an important role as a pattern recognition receptor in the innate immunity of insects. The cDNA of a short-type PGRP, an open reading frame of 588 bp encoding a polypeptide of 196 amino acids, was cloned from Bombyx mori. A phylogenetic tree was constructed, and the results showed that BmPGRP-S2 was most similar to Drosophila melanogaster PGRP (DmPGRP-SA). The induced expression profile of BmPGRP-S2 in healthy Escherichia coli- and Bacillus subtilis challenged B. mori was measured using semiquantitative reverse transcriptase polymerase chain reaction analysis. The expression of BmPGRP-S2 was upregulated at 24 h by E. coli and Ba. subtilis challenge. In addition, in the integument of B. mori, RNAi knockdown of BmPGRP-S2 caused an obvious reduction in the transcription expression of the transcription factor Relish and in antibacterial effector genes Attacin, Gloverin, and Moricin. The results indicated that BmPGRP S2 participates in the signal transduction pathway of B. mori. PMID- 25797798 TI - Cytogenetics analysis and testis morphology of aquatic species of the families Belostomatidae, Gelastocoridae, Gerridae, Notonectidae, and Veliidae (Heteroptera). AB - The Heteroptera have holocentric chromosomes with kinetic activity restricted to the end of chromosomes. The first meiotic division is reductional for the autosomes and equational for the sexual. Only a few species of this suborder have been analyzed. In this study, we observed the morphologies of the testes of the Heteroptera species Belostoma anurum (Herrich-Schaffer, 1948), Belostoma micantulum (Stal, 1858), Gelastocoris angulatus (Melin, 1929), Gelastocoris flavus flavus (Guerin-Meneville, 1844), Rheumatobates crassifemur crassifemur (Esaki, 1926), Buenoa amnigenus (White, 1879), Buenoa unguis (Truxal, 1953), Martarega brasiliensis (Truxal, 1949), Martarega membranacea (White, 1879), Martarega uruguayensis (Berg, 1883), Rhagovelia tenuipes (Champion, 1898) and Rhagovelia zela (Drake, 1959). We found that the testes of these species can be round, round/spiral, or elongated/spiral. The size of the prophase I cells was found to vary, with the smallest ones being detected in B. micantulum and Rha. zela, the largest in G. f. flavus, and ones of intermediate size in R. c. crassifemur and M. brasiliensis. With respect to the chromosome complement, we verified the presence of 2n = 16: (14A+XY, B. micantulum and G. angulatus), 21: (20A+X0, R. c. crassifemur), 23: (22A+X0, Rha. zela and Rha. tenuipes), 25: (24A+X0, Bu. amnigenus and Bu. unguis; 22A+2m+X0, M. membranacea), 27: (24A+2m+X0, M. brasiliensis and M. uruguayensis), 29: (26A+X1X2Y, B. anurum), and 35: (30A+X1X2X3X4Y, G. f. flavus). We found that the features of spermatogenesis in these species are similar to those of other previously described Heteroptera species, differing only in testicular morphology, chromosome number, and sex chromosome system. PMID- 25797799 TI - Molecular cloning, characterization, and expression analysis of an ecdysone receptor homolog in Teleogryllus emma (Orthoptera: Gryllidae). AB - Ecdysteroids are steroid hormones that play important roles in the regulation of Arthropoda animal growth development, larvae ecdysis, and reproduction. The effect of ecdysteroids is mediated by ecdysteroid receptor (EcR). The ecdysone receptor (EcR) belongs to the superfamily of nuclear receptors (NRs) that are ligand-dependent transcription factors. Ecdysone receptor is present only in invertebrates and plays a critical role in regulating the expression of a series of genes during development and reproduction. Here, we isolated and characterized cDNA of the cricket Teleopgryllus emma (Ohmachi & Matsuura) (Orthoptera: Gryllidae) and studied mRNA expression pattern using real time-polymerase chain reaction. The full-length cDNA of T. emma EcR, termed TeEcR, is 2,558 bp and contains a 5'-untranslated region of 555 bp and a 3'-untranslated region of 407 bp. The open reading frame of TeEcR encodes deduced 531-amino acid peptides with a predicted molecular mass of 60.7 kDa. The amino acid sequence of T. emma EcR was similar to that of known EcR especially in the ligand-binding domain of insect EcR. Real-time quantitative reverse transcription-polymerase chain reaction was performed to compare TeEcR mRNA expression level at the whole body and gonad during T. emma development. The data revealed that TeEcR mRNA is differentially expressed during T. emma development, with the highest expression level in late-instar larvae of the body and lowest in third instar. The levels of TeEcR transcripts also vary among gonads development, and levels in ovaries were higher than in testes at every developmental stage. These results suggest that TeEcR may have potential significance to regulate the morphological structure and gonad development of T. emma, due to its expression in different developmental periods. PMID- 25797800 TI - Detection of the staphylococcal enterotoxin D-like gene from staphylococcal food poisoning isolates over the last two decades in Tokyo. AB - The plasmid is a very well-known mobile genetic element that participates in the acquisition of virulence genes, such as staphylococcal enterotoxins (SEs), via horizontal transfer. SEs are emetic toxins and causative agents in staphylococcal food poisoning (SFP). We herein identified the types of plasmids harbored by seven SFP isolates and examined their production of plasmid-related SE/SEl to determine whether the new types of plasmid-related SE or SE-like (SEl) toxins (i.e. SElJ and SER) were involved in SFP. These isolates harbored pIB485-like plasmids, and all, except for one isolate, produced SElJ and SER. The amount of SER produced by each isolate accounted for the highest or second highest percentage of the total amount of SE/SEl produced. These new types of plasmid related SE/SEls as well as classical SE may play a role in SFP. The seven isolates were classified into two SED-production types; a high SED-production type (>500 ng/ml) and no SED-production type. A nucleotide sequencing analysis revealed that three plasmids harbored by the SED-non-producing isolates had a single-base deletion in the sed gene with a resulting stop codon (from 233 amino acids of the intact SED to 154 amino acids of the mutant SED (mSED)). A real-time reverse transcription-PCR analysis showed that the mRNA of the msed gene was transcribed in the isolates. If the msed gene was translated as a protein, mSED may act as an emetic toxin instead of intact SED. PMID- 25797801 TI - The safety and effectiveness of riociguat to treat chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is an insidious, progressive disease with a poor prognosis. The treatment of choice is pulmonary thromboendarterectomy, although not all patients benefit from surgery at a specialized center. Riociguat, an oral soluble guanylate cyclase (sGC) stimulator is the first pharmacotherapeutic agent that has been shown to improve exercise capacity and hemodynamics in a large multicenter, double-blind, randomized placebo-controlled trial for the treatment of patients with inoperable or persistent CTEPH. Riociguat stimulates sGC directly in a nitric oxide (NO) independent manner, thereby increasing the sensitivity of sGC to NO, and also in synergy with NO, leading to increased production of cyclic guanosine monophosphate, an intracellular messenger involved in regulating vascular tone, smooth muscle cell proliferation, fibrosis and inflammation. This review will summarize the pharmacodynamics, pharmacokinetics as well as safety and efficacy data of riociguat in inoperable or persistent CTEPH. PMID- 25797802 TI - Balance maintenance as an acquired motor skill: Delayed gains and robust retention after a single session of training in a virtual environment. AB - Does the learning of a balance and stability skill exhibit time-course phases and transfer limitations characteristic of the acquisition and consolidation of voluntary movement sequences? Here we followed the performance of young adults trained in maintaining balance while standing on a moving platform synchronized with a virtual reality road travel scene. The training protocol included eight 3 min long iterations of the road scene. Center of Pressure (CoP) displacements were analyzed for each task iteration within the training session, as well as during tests at 24h, 4 weeks and 12 weeks post-training to test for consolidation phase ("offline") gains and assess retention. In addition, CoP displacements in reaction to external perturbations were assessed before and after the training session and in the 3 subsequent post-training assessments (stability tests). There were significant reductions in CoP displacements as experience accumulated within session, with performance stabilizing by the end of the session. However, CoP displacements were further reduced at 24h post-training (delayed "offline" gains) and these gains were robustly retained. There was no transfer of the practice-related gains to performance in the stability tests. The time-course of learning the balance maintenance task, as well as the limitation on generalizing the gains to untrained conditions, are in line with the results of studies of manual movement skill learning. The current results support the conjecture that a similar repertoire of basic neuronal mechanisms of plasticity may underlay skill (procedural, "how to" knowledge) acquisition and skill memory consolidation in voluntary and balance maintenance tasks. PMID- 25797803 TI - A novel analgesic approach to optogenetically and specifically inhibit pain transmission using TRPV1 promoter. AB - Chronic pain is a pathological condition that results in significant loss of life quality, but so far no specific treatment for chronic pain has been developed. Currently available analgesia drugs are either not specific enough or have severe side effects. Therefore a non-invasive approach with high specificity to inhibit nociception becomes essential. In this study, a recombinant virus (AAV5-TRPV1 ArchT-eGFP) was constructed and injected into the mouse dorsal root ganglion (DRG). The Transient Receptor Potential Vanilloid type 1 (TRPV1) channel promoter was used to selectively express inhibitory light-sensitive pump ArchT (the archaerhodopsin from Halorubrum strain TP009) in nociceptive DRG neurons. The successful transfer of ArchT gene was confirmed by a robust expression of green florescent protein in the DRG neurons. In vivo behavioral tests demonstrated that both the mechanical paw withdrawal threshold and the radiant heat evoked paw withdrawal latency were significantly increased upon illumination by a 532 nm green laser light to the paw of a viral-vector injected mice, while the same laser light did not induce any observable change in naive mice. In conclusion, we have established a novel analgesic approach that can noninvasively and selectively inhibit pain transmission using an acute and controllable optogenetics method. This study may shed light on the application of a novel optogenetic strategy for the treatment of pain. PMID- 25797804 TI - An efficient synthesis of SK-658 and its analogs as potent histone deacetylase inhibitors. AB - SK-658 is a potent histone deacetylase (HDAC) inhibitor that showed higher activity than SAHA due to the presence of extended hydrophobic group. We designed and synthesized thioester and SS-hybrid bearing SK-658 analogs as HDAC inhibitors. All the compounds were active in nano molar range and showed higher inhibitory activity than SAHA and SK-658. Among these, disulfide compounds showed the highest activity. PMID- 25797805 TI - Risk factors for established vertebral fractures in Japanese patients with rheumatoid arthritis: Results from a large prospective observational cohort study. AB - OBJECTIVE: The aim of this study was to evaluate the associations between potential risk factors and the occurrence of established vertebral fractures in Japanese patients with rheumatoid arthritis (RA). METHODS: A total of 10,469 patients with RA were enrolled in a prospective, observational study from 2000 to 2011. Self-reported vertebral fractures were verified using patient's medical records and radiographs. Cox proportional hazards models were used to analyze independent contributions of various risk factors for established vertebral fracture occurrence. RESULTS: During a mean follow-up of 5.8 years, established vertebral fractures in 170 patients were verified with medical records and radiographs. Multivariate Cox regression analyses estimated that the hazards ratios of sustaining vertebral fractures increased by 1.84 for female gender, 1.72 for every 10 years of increased age, 1.26 for Disease Activity Score in 28 joints (DAS28), 1.44 for Japanese Health Assessment Questionnaire-Disability Index (J-HAQ-DI), 2.21 for history of any previous fractures, and 1.09 for daily prednisolone dose (mg/day). CONCLUSION: We confirmed the associations between vertebral fractures and advanced age, J-HAQ-DI, and high daily prednisolone dose; and found significant correlations between vertebral fractures and female gender, DAS28, and history of any previous fracture in Japanese RA patients. PMID- 25797806 TI - Klippel-Feil syndrome associated with congenital atlantooccipital dislocation and absent C1 posterior arch. PMID- 25797807 TI - Complex split cord malformation. PMID- 25797809 TI - The biomechanics of pedicle screw augmentation with cement. AB - BACKGROUND CONTEXT: A persistent challenge in spine surgery is improving screw fixation in patients with poor bone quality. Augmenting pedicle screw fixation with cement appears to be a promising approach. PURPOSE: The purpose of this study was to survey the literature and assess the previous biomechanical studies on pedicle screw augmentation with cement to provide in-depth discussions of the biomechanical benefits of multiple parameters in screw augmentation. STUDY DESIGN/SETTING: This is a systematic literature review. METHODS: A search of Medline was performed, combining search terms of pedicle screw, augmentation, vertebroplasty, kyphoplasty, polymethylmethacrylate, calcium phosphate, or calcium sulfate. The retrieved articles and their references were reviewed, and articles dealing with biomechanical testing were included in this article. RESULTS: Polymethylmethacrylate is an effective material for enhancing pedicle screw fixation in both osteoporosis and revision spine surgery models. Several other calcium ceramics also appear promising, although further work is needed in material development. Although fenestrated screw delivery appears to have some benefits, it results in similar screw fixation to prefilling the cement with a solid screw. Some differences in screw biomechanics were noted with varying cement volume and curing time, and some benefits from a kyphoplasty approach over a vertebroplasty approach have been noted. Additionally, in cadaveric models, cemented-augmented screws were able to be removed, albeit at higher extraction torques, without catastrophic damage to the vertebral body. However, there is a risk of cement extravasation leading to potentially neurological or cardiovascular complications with cement use. A major limitation of these reviewed studies is that biomechanical tests were generally performed at screw implantation or after a limited cyclic loading cycle; thus, the results may not be entirely clinically applicable. This is particularly true in the case of the bioactive calcium ceramics, as these biomechanical studies would not have measured the effects of osseointegration. CONCLUSIONS: Polymethylmethacrylate and various calcium ceramics appear promising for the augmentation of pedicle screw fixation biomechanically in both osteoporosis and revision spine surgery models. Further translational studies should be performed, and the results summarized in this review will need to be correlated with the clinical outcomes. PMID- 25797808 TI - In vivo dynamic changes of dimensions in the lumbar intervertebral foramen. AB - BACKGROUND CONTEXT: Previous studies have reported position-dependent changes of the lumbar intervertebral foramen (LIVF) dimensions at different static flexion extension postures. However, the changes of the LIVF dimensions during dynamic body motion have not been reported. PURPOSE: The objective of this study was to investigate the in vivo dimensions of the LIVF during a dynamic weight-lifting activity. STUDY DESIGN/SETTING: This was a retrospective study. METHODS: Ten asymptomatic subjects were recruited for this study. Three-dimensional (3D) vertebral models of the lumbar segments from L2 to S1 were constructed for each subject using magnetic resonance images. The lumbar spine was then imaged using a dual fluoroscopic imaging system as the subject performed a dynamic weight lifting activity from an upper body position of 45 degrees to a maximal extension position. The in vivo positions of the vertebrae along the motion path were reproduced using the 3D vertebral models and the fluoroscopic images. The minimal area, height, and width of each LIVF during the dynamic body motion were analyzed. RESULTS: The LIVF area and width monotonically decreased with lumbar extension at all levels except L5-S1 (p<.05). On average, the LIVF area decreased by 7.4+/-6.7%, 10.8+/-7.7%, and 10.0+/-8.0% at the L2-L3, L3-L4, and L4-L5 levels, respectively, from the flexion to the upright standing position, and by 6.4+/-5.0%, 7.7+/-7.4%, and 5.1+/-5.1%, respectively, from the upright standing to the extension position. The LIVF height remained relatively constant at all segments during the dynamic activity. The foramen area, height, and width of the L5-S1 remained relatively constant throughout the activity. CONCLUSIONS: Human lumbar foramen dimensions show segment-dependent characteristics during the dynamic weight-lifting activity. PMID- 25797810 TI - Elevated levels of phosphorylated neurofilament heavy subunit in the cerebrospinal fluid of patients with lumbar spinal stenosis: preliminary findings. AB - BACKGROUND CONTEXT: The phosphorylated neurofilament heavy subunit (pNfH) is an axon fiber structural protein that is released into the cerebrospinal fluid (CSF) after nerve damage. Although the previous studies have reported elevated CSF levels of pNfH in various neurological diseases, including amyotrophic lateral sclerosis, these levels have not been examined in patients with spinal stenosis. PURPOSE: The purpose of this study was to investigate the CSF levels of pNfH in patients with lumbar spinal stenosis (LSS) and to examine the relationship between CSF levels of pNfH and the severity of LSS. STUDY DESIGN: This is a prospective observational study. PATIENT SAMPLE: We included consecutive patients with LSS who were undergoing myelography for preoperative evaluation. The CSF samples from patients with idiopathic scoliosis were used as the controls. OUTCOME MEASURES: Physiological measures: CSF levels of pNfH were measured using an enzyme-linked immunosorbent assay. The Zurich Claudication Questionnaire (ZCQ) and the Numerical Rating Scale (NRS) for sciatic pain were used to assess the clinical severity of LSS, and patients were grouped into tertiles according to their symptom severity and pain grading. Axial magnetic resonance imaging was used to evaluate the morphological severity of LSS, and patients were classified into three groups based on their morphological grading (using the CSF/rootlet ratio). METHODS: Analysis of variance was used to examine the relationship between the CSF levels of pNfH and the severity of LSS. RESULTS: Thirty-three patients with LSS were included (13 men and 20 women and mean age 73.2 [range 58 88] years). Most patients (n=32) were positive for pNfH in their CSF (mean 1,344 [149-9,250] pg/mL), whereas all control subjects were negative for pNfH in their CSF. Regarding the association with clinical severity, patients in the third tertiles of ZCQ and NRS tended to have higher levels of pNfH compared with the other groups. There was no association between the CSF level of pNfH and the morphological severity of LSS. CONCLUSIONS: This study detected elevated pNfH levels in the CSF of patients with LSS. Patients with severe clinical symptoms were more likely to exhibit high levels of pNfH. Our results indicate the potential usefulness of pNfH as a biomarker for compressive spinal disorders. PMID- 25797811 TI - Crowned dens syndrome. PMID- 25797812 TI - Effects of proinflammatory cytokines on axonal outgrowth from adult rat lumbar dorsal root ganglia using a novel three-dimensional culture system. AB - BACKGROUND CONTEXT: Degeneration of the intervertebral disc is often associated with low back pain and increased infiltration of nerve fibers originating from dorsal root ganglia (DRG). The degenerated disc is also characterized by the presence of proinflammatory cytokines, which may influence axonal outgrowth. Toward an improved understanding of the growth of DRG neurons into compliant extracellular matrices, we developed a novel experimental system to measure axonal outgrowth of adult rat lumbar DRG neurons within three-dimensional (3D) collagen hydrogels and used this system to examine the effects of interleukin 1beta (IL-1beta) and tumor necrosis factor (TNF)-alpha treatment. PURPOSE: The aim was to investigate the effects of proinflammatory cytokines on 3D neuronal growth into collagen matrices. STUDY DESIGN: This was an in vitro study of neurite outgrowth from adult rat lumbar DRG into collagen gels in response to IL 1beta and TNF-alpha. METHODS: Lumbar DRG were obtained from adult Sprague Dawley rats, bisected to expose cell bodies and placed onto collagen gel constructs prepared in 24-well Transwell inserts. Dorsal root ganglia were then treated with nerve growth factor (NGF)-free Neurobasal media (negative control) or NGF supplemented media containing 0, 1, and 10 ng/mL of IL-1beta and TNF-alpha. After 7 days, collagen gel-DRG constructs were immunostained for phosphorylated neurofilament, an axonal marker. Simple Neurite Tracer (Fiji/ImageJ) was used to quantify 3D axonal outgrowth from confocal image stacks. Data were analyzed using one-way analysis of variance, with Tukey HSD post hoc correction at a level of p<.05. RESULTS: Immunostaining showed robust axonal outgrowth into collagen gels from all NGF-treated DRG. The negative control demonstrated very few and short neurites. Tumor necrosis factor-alpha (1 and 10 ng/mL) significantly inhibited axonal outgrowth compared with NGF-only media (p<.026 and p<.02, respectively). After IL-1beta treatment, average axon length was 10% lower at 1 ng/mL and 7.5% higher at 10 ng/mL, but these differences were not statistically significant. Among cytokine treatments, however, average axon length in the IL-1beta (10 ng/mL) group was significantly higher than that in the other groups (p<.05). CONCLUSIONS: A novel 3D collagen gel culture system was used to investigate factors modulating neuronal ingrowth. Our results showed that NGF was necessary to promote neurite growth into collagen gels. In the presence of proinflammatory cytokines, high concentrations of IL-1beta induced significantly higher axonal outgrowth than TNF-alpha and low levels of IL-1beta. PMID- 25797813 TI - Spinal Type II arteriovenous malformation and endovascular treatment. PMID- 25797814 TI - Glycopeptide and daptomycin susceptibility trends among clinical isolates of methicillin-resistant Staphylococcus aureus in a tertiary care center in North India. AB - Increased vancomycin minimum inhibitory concentration (MIC) levels in Staphylococcus aureus and their association with vancomycin treatment failure are well-known problems. Few studies have recognized progressive increases in glycopeptide MIC levels for S. aureus strains in recent years. This study determined glycopeptide and daptomycin susceptibility among methicillin resistant S. aureus (MRSA) strains. A total of 776 clinical isolates of MRSA recovered from 2009 to 2012 were studied for glycopeptide and daptomycin susceptibility using the E-test method. The vancomycin MIC geometric mean (GM) of the MRSA isolates was 0.923, 0.944, 1.134 and 1.294 mg/L in the years 2009, 2010, 2011 and 2012, respectively, and the trend significantly increased over the years (P < 0.0001). Similarly, the teicoplanin MIC GM was 1.47, 1.49, 1.8 and 2.04 mg/L in the years from 2009 to 2012, respectively (P < 0.0001). MIC shifts were not found for daptomycin (P > 0.232). A significant increase in the MIC for glycopeptides was observed among the clinical MRSA isolates at our center over a 4-year period. However, the daptomycin MIC did not increase in the observed MRSA isolates. PMID- 25797815 TI - Prenatal diagnosis of chromosomal abnormalities--shifting paradigm. PMID- 25797816 TI - Are pregnant women adequately equipped for autonomy in pregnancy screening? AB - INTRODUCTION: Aneuploidy screening is widely practised in the field of obstetrics in current times. This study thus aims to gain an insight on pregnant women's knowledge and risk perception of Down syndrome and first trimester screening (FTS), as well as their views on various potential pregnancy outcomes and how these may affect their decision-making processes. MATERIALS AND METHODS: A cross sectional questionnaire-based qualitative study of consecutive 50 women choosing to undergo FTS at KK Women's and Children's Hospital (KKH), Singapore was conducted. The women completed a questionnaire after their FTS pretest counselling session. Basic knowledge of Down syndrome and FTS as well as participants' risk perception with regards to various cut-off values used in FTS were examined. Patients' views of various potential pregnancy outcomes were also studied. RESULTS: Most patients had good retention and comprehension of what FTS entailed after a FTS counselling session at the KKH Antenatal Monitoring Clinic. However, knowledge of the risks of invasive diagnostic testing was poor. Patients also did not possess an adequate understanding of FTS risk values. With regards to risk perception, patients had very different views on acceptable pregnancy outcomes and what constituted a high-risk FTS value to them personally. A significant number of women were concerned even at medically low-risk values of 1:500 and 1:1000 in FTS. The majority of patients viewed highest detection rate followed by a lowest false positive rate as the more important factors impacting their choice of a Down syndrome screening test. CONCLUSION: This study demonstrates the diversity of pregnant women's risk perception, risk aversion and participation in decision processes when there are 2 different values in competition. The study also highlights our patients' gaps in knowledge and lack of understanding of risk values used in FTS. PMID- 25797817 TI - Risk Factors for Severe Adenovirus Infection in Children during an Outbreak in Singapore. AB - BACKGROUND: Human adenoviruses (HAdVs) can cause a variety of human illnesses, with associated temporal and geographic changes in disease incidence. We report the emergence of an outbreak of HAdV infections in Singapore, presumably caused by a change of the predominating type to HAdV-7. We examined the clinical features of children admitted with HAdV infection to 1 institution and the risk factors for severe infection. MATERIALS AND METHODS: This is a retrospective case control study of all HAdV-infected children admitted during weeks 1 to 19 in 2013, as identified from laboratory records. A descriptive retrospective analysis of epidemiology, clinical data and the outcome of these children was also performed. Patients with severe infections were defined as cases, those with non severe infections as controls, and the 2 groups were compared to find possible independent risk factors. RESULTS: Eighty-five patients with HAdV infection were studied, including 11 (12.9%) cases and 74 (87.1%) controls. Binary logistic regression showed that cases were more likely to be <2 years old (adjusted OR 10.6, 95% CI, 1.8 to 63.2) and to have significant comorbidities (adjusted OR 19.9, 95% CI, 3.4 to 116.1) compared to controls. The predominant type in 2013 was HAdV-7, which differed from 2011 and 2012, when HAdV-3 was more common. There was a trend towards pneumonia being more common in patients infected with HAdV-7 than in patients infected with other types, although this did not reach statistical significance (OR 2.8, 95% CI, 0.9 to 8.7). CONCLUSION: The emergence of HAdV-7 in a population where other HAdV types had circulated previously may have caused the outbreak in Singapore, and this was associated with more serious infections in children. Young age (<2 years) and significant comorbidities were associated with more severe HAdV infection. PMID- 25797818 TI - Relationships between Prostatic Volume and Intravesical Prostatic Protrusion on Transabdominal Ultrasound and Benign Prostatic Obstruction in Patients with Lower Urinary Tract Symptoms. AB - INTRODUCTION: The objective of this study is to determine the relationships between prostatic volume (PV) and intravesical prostatic protrusion (IPP) with benign prostatic obstruction (BPO). MATERIALS AND METHODS: A total of 408 males (aged 50 years and above) who presented with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) were recruited. All had International Prostate Symptoms Score (IPSS), quality of life (QOL) index, uroflowmetry (Qmax) and postvoid residual urine (PVR) measured by transabdominal ultrasonography (TAUS). The PV and the degree of IPP were also measured by TAUS in the transverse and sagittal planes respectively. The PV is classified as Grade a, (20 ml or less), Grade b, (more than 20 ml to 40 ml) and Grade c, (more than 40 ml), while the IPP is graded as Grade 1 (5 mm or less), Grade 2 (more than 5 mm to 10 mm) and Grade 3 (more than 10 mm). RESULTS: There was a fair positive correlation between the PV and IPP (Spearman, r(s) = 0.62, P <0.001) with important clinical exceptions. There was negative correlation between the PV and Qmax (rs = -0.20, P = 0.022), IPP and Qmax (r(s) = -0.30, P <0.001). PV and IPP were good predictors of BPO. However, IPP was slightly better (r(s) of -0.30 vs 0.20) than PV. CONCLUSION: PV is related to IPP with important clinical exceptions. IPP is a better predictor of BPO than PV. PMID- 25797819 TI - Pharmacomechanical Thrombolysis versus Surgical Thrombectomy for the Treatment of Thrombosed Haemodialysis Grafts. AB - INTRODUCTION: The key to treatment of a thrombosed dialysis graft is restoration and maintenance of function as long as possible. The objective of this study was to compare the outcomes of pharmacomechanical thrombolysis and surgical thrombectomy in the treatment of thrombosed haemodialysis grafts. MATERIALS AND METHODS: During a 3-year period, 108 patients with 114 thrombosed dialysis grafts were referred to our institute for treatment. Fifty thrombosed dialysis grafts underwent pulse-spray catheter thrombolysis using recombinant tissue plasminogen activator (rt-PA) with angioplasty, and 64 thrombosed dialysis grafts underwent surgical thrombectomy. The procedural success rates, complications and average patency times and patency rates were compared between the 2 procedures. P values less than 0.05 were considered to be statistically significant. RESULTS: There were no statistically significant differences between the pharmacomechanical thrombolysis group and the thrombectomy group in the procedural success rates (94% and 93.8%, P = 0.15) or average patency times (6.24 months and 6.30 months, P = 0.17). The primary and secondary patency rates at 12 months were 28.0% +/- 8.4% and 54.3% +/- 7.8% for the thrombolysis with angioplasty group, and 30.0% +/ 6.3% and 57.0% +/- 4.8% for the thrombectomy group, respectively (P = 0.65 and P = 0.49, respectively). There were no procedural-related major complications. CONCLUSION: Our study found no differences in outcomes between patients treated with pharmacomechanical thrombolysis and surgical thrombectomy for thrombosed haemodialysis grafts. Pharmacomechanical thrombolysis can be considered as an alternative treatment for dialysis graft thrombosis. PMID- 25797820 TI - Localised dermatitic nodules but no itch. PMID- 25797821 TI - Ultrasound-guided thyroid fine needle aspiration biopsy--the way forward. PMID- 25797822 TI - Avulsed tip of a systemic iceberg. PMID- 25797824 TI - Bedaquiline for the treatment of drug-resistant tuberculosis. AB - Bedaquiline is a much-needed novel drug which is highly effective against drug resistant tuberculosis. While its clinical development has been laudably fast tracked and the drug is now available for inclusion into treatment regimens when no suitable alternatives exist, clinical experience with bedaquiline is still limited. Phase III trial data and Phase IV studies are needed particularly to study different patient populations and to optimize treatment regimens. Drug resistance to bedaquiline needs to be monitored carefully, and full access to bedaquiline treatment where it is appropriate and needed must be promoted. PMID- 25797823 TI - Responses of primary production, leaf litter decomposition and associated communities to stream eutrophication. AB - We assessed the eutrophication effects on leaf litter decomposition and primary production, and on periphytic algae, fungi and invertebrates. According to the subsidy-stress model, we expected that when algae and decomposers were nutrient limited, their activity and diversity would increase at moderate levels of nutrient enrichment, but decrease at high levels of nutrients, because eutrophication would lead to the presence of other stressors and overwhelm the subsidy effect. Chestnut leaves (Castanea sativa Mill) were enclosed in mesh bags and immersed in five streams of the Ave River basin (northwest Portugal) to assess leaf decomposition and colonization by invertebrates and fungi. In parallel, polyethylene slides were attached to the mesh bags to allow colonization by algae and to assess primary production. Communities of periphytic algae and decomposers discriminated the streams according to the trophic state. Primary production decomposition and biodiversity were lower in streams at both ends of the trophic gradient. PMID- 25797825 TI - Importance of polarization transfer in reaction products for interpreting and analyzing CIDNP at low magnetic fields. AB - The magnetic field dependence of Chemically Induced Dynamic Nuclear Polarization (CIDNP) was studied for the amino acids N-acetyl histidine, N-acetyl tryptophan and N-acetyl tyrosine. It is demonstrated that at low field CIDNP is strongly affected by polarization redistribution in the diamagnetic molecules. Such a polarization transfer is of coherent nature and is due to spin coherences formed together with non-equilibrium population of the spin states. These coherences clearly manifest themselves in an oscillatory time dependence of polarization. Polarization transfer effects are most pronounced at nuclear spin Level Anti Crossings (LACs), which also result in sharp features in the CIDNP field dependence. Thus, polarization transfer is an important factor, which has to be taken into account in order to interpret low-field CIDNP data on both qualitative and quantitative level. Possible applications of polarization transfer phenomena are also discussed in the paper. In particular, the role of LACs in spin order transfer is highlighted: LACs provide a new tool for precise manipulation of spin hyperpolarization and NMR enhancement of selected target spins. PMID- 25797826 TI - Rituximab, fludarabine, and cyclophosphamide versus fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia: A systematic review with meta-analysis. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is a disease of the lymphoid system, in which the most common therapy is fludarabine plus cyclophosphamide (FC). The addition of rituximab to FC has been used, a combination known as FCR. OBJECTIVES: To perform a systematic review with meta-analysis of clinical trials between 2000 and 2012 comparing FC and FCR in patients with CLL. MATERIAL AND METHODS: Electronic databases were searched using keywords related to the objectives of this review. The outcomes examined were progression-free survival and complete remission. RESULTS: The progression-free survival and the overall survival showed significant difference between the two regimens, with complete remission being more frequent in FCR-treated patients (odds ratio=2.58; 95% CI: 2.13-3.13). Patients treated with FCR showed significantly higher neutropenia and serious adverse reactions. CONCLUSION: Despite the favorable results of the FCR regimen on outcomes including complete remission, progression-free survival, and overall survival, there is a lack of methodological rigor and appropriate analyses in many of these studies, and thus, there is a need for further studies examining the effect of rituximab in CLL patients. PMID- 25797827 TI - Cascade upgrading of gamma-valerolactone to biofuels. AB - Cascade upgrading of gamma-valerolactone (GVL), produced from renewable cellulosic biomass, with selective conversion to biofuels pentyl valerate (PV) and pentane in one pot using a bifunctional Pd/HY catalyst is described. Excellent catalytic performance (over 99% conversion of GVL, 60.6% yield of PV and 22.9% yield of pentane) was achieved in one step. These biofuels can be targeted for gasoline and jet fuel applications. PMID- 25797828 TI - Influence of cultivar and harvest year on the volatile profiles of leaves and roots of carrots (Daucus carota spp. sativus Hoffm.). AB - The focus of the present work centers on the diversity of volatile patterns of carrots. In total 15 main volatiles were semiquantified in leaves and roots using isolation by headspace solid phase microextraction followed by gas chromatography with FID and MS detection. Significant differences in the main number of compounds were detected between the cultivars as well as the years. Genotype environment interactions (G * E) are discussed. The most abundant metabolites, beta-myrcene (leaves) and terpinolene (roots), differ in the sum of all interactions (cultivar * harvest year) by a factor of 22 and 62, respectively. A statistical test indicates significant metabolic differences between cultivars for nine volatiles in leaves and 10 in roots. In contrast to others the volatiles alpha-pinene, gamma-terpinene, limonene, and myristicine in leaves as well as beta-pinene, humulene, and bornyl acetate in roots are relatively stable over years. A correlation analysis shows no strict clustering regarding root color. While the biosynthesis in leaves and roots is independent between these two organs for nine of the 15 volatiles, a significant correlation of the myristicine content between leaves and roots was determined, which suggests the use of this compound as a bitter marker in carrot breeding. PMID- 25797829 TI - The development of the Athens Emotional States Inventory (AESI): collection, validation and automatic processing of emotionally loaded sentences. AB - OBJECTIVES: The development of ecologically valid procedures for collecting reliable and unbiased emotional data towards computer interfaces with social and affective intelligence targeting patients with mental disorders. METHODS: Following its development, presented with, the Athens Emotional States Inventory (AESI) proposes the design, recording and validation of an audiovisual database for five emotional states: anger, fear, joy, sadness and neutral. The items of the AESI consist of sentences each having content indicative of the corresponding emotion. Emotional content was assessed through a survey of 40 young participants with a questionnaire following the Latin square design. The emotional sentences that were correctly identified by 85% of the participants were recorded in a soundproof room with microphones and cameras. A preliminary validation of AESI is performed through automatic emotion recognition experiments from speech. RESULTS: The resulting database contains 696 recorded utterances in Greek language by 20 native speakers and has a total duration of approximately 28 min. Speech classification results yield accuracy up to 75.15% for automatically recognizing the emotions in AESI. CONCLUSIONS: These results indicate the usefulness of our approach for collecting emotional data with reliable content, balanced across classes and with reduced environmental variability. PMID- 25797831 TI - Partial volume correction for in vivo (23)Na-MRI data of the human brain. AB - The concentration of sodium is a functional cell parameter and absolute quantification can be interesting for diagnostical purposes. The accuracy of sodium magnetic resonance imaging ((23)Na-MRI) is strongly biased by partial volume effects (PVEs). Hence our purpose was to establish a partial volume correction (PVC) method for (23)Na-MRI. The existing geometric transfer matrix (GTM) correction method was transferred from positron emission tomography (PET) to (23)Na-MRI and tested in a phantom study. Different parameters, as well as accuracy of registration and segmentation were evaluated prior to first in vivo measurements. In vivo sodium data-sets of the human brain were obtained at B0=7T with a nominal spatial resolution of (3mm)(3) using a density adapted radial pulse sequence. A volunteer study with four healthy subjects was performed to measure partial volume (PV) corrected tissue sodium concentration (TSC) which was verified by means of an intrinsic correction control. In the phantom study the PVC algorithm yielded a good correction performance and reduced the discrepancy between the measured sodium concentration value and the expected value in the smallest compartments of the phantom by 11% to a mean PVE induced discrepancy of 5.7% after correction. The corrected in vivo data showed a reduction of PVE bias for the investigated compartments for all volunteers, resulting in a mean reduction of discrepancy between two separate CSF compartments from 36% to 7.6%. The absolute TSC for two separate CSF compartments (sulci, lateral ventricles), gray and white brain matter after correction were 129+/-8mmol/L, 138+/-4mmol/L, 48+/-1mmol/L and 43+/-3mmol/L, respectively. The applied PVC algorithm reduces the PV-bias in quantitative (23)Na-MRI. Accurate, high-resolution anatomical data is required to enable appropriate PVC. The algorithm and segmentation approach is robust and leads to reproducible results. PMID- 25797830 TI - Accelerated vs. unaccelerated serial MRI based TBM-SyN measurements for clinical trials in Alzheimer's disease. AB - OBJECTIVE: Our primary objective was to compare the performance of unaccelerated vs. accelerated structural MRI for measuring disease progression using serial scans in Alzheimer's disease (AD). METHODS: We identified cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD subjects from all available Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with usable pairs of accelerated and unaccelerated scans. There were a total of 696 subjects with baseline and 3 month scans, 628 subjects with baseline and 6 month scans and 464 subjects with baseline and 12 month scans available. We employed the Symmetric Diffeomorphic Image Normalization method (SyN) for normalization of the serial scans to obtain tensor based morphometry (TBM) maps which indicate the structural changes between pairs of scans. We computed a TBM-SyN summary score of annualized structural changes over 31 regions of interest (ROIs) that are characteristically affected in AD. TBM-SyN scores were computed using accelerated and unaccelerated scan pairs and compared in terms of agreement, group-wise discrimination, and sample size estimates for a hypothetical therapeutic trial. RESULTS: We observed a number of systematic differences between TBM-SyN scores computed from accelerated and unaccelerated pairs of scans. TBM-SyN scores computed from accelerated scans tended to have overall higher estimated values than those from unaccelerated scans. However, the performance of accelerated scans was comparable to unaccelerated scans in terms of discrimination between clinical groups and sample sizes required in each clinical group for a therapeutic trial. We also found that the quality of both accelerated vs. unaccelerated scans were similar. CONCLUSIONS: Accelerated scanning protocols reduce scan time considerably. Their group-wise discrimination and sample size estimates were comparable to those obtained with unaccelerated scans. The two protocols did not produce interchangeable TBM-SyN estimates, so it is arguably important to use either accelerated pairs of scans or unaccelerated pairs of scans throughout the study duration. PMID- 25797832 TI - The smelling of Hedione results in sex-differentiated human brain activity. AB - A large family of vomeronasal receptors recognizes pheromone cues in many animals including most amphibia, reptiles, rhodents, and other mammals. Humans possess five vomeronasal-type 1 receptor genes (VN1R1-VN1R5), which code for proteins that are functional in recombinant expression systems. We used two different recombinant expression systems and identified Hedione as a ligand for the putative human pheromone receptor VN1R1 expressed in the human olfactory mucosa. Following the ligand identification, we employed functional magnetic resonance imaging (fMRI) in healthy volunteers to characterize the in vivo action of the VN1R1 ligand Hedione. In comparison to a common floral odor (phenylethyl alcohol), Hedione exhibited significantly enhanced activation in limbic areas (amygdala, hippocampus) and elicited a sex-differentiated response in a hypothalamic region that is associated with hormonal release. Utilizing a novel combination of methods, our results indicate that the putative human pheromone receptor VN1R1 is involved in extra-olfactory neuronal activations induced by the odorous substance Hedione. The activation of VN1R1 might play a role in gender specific modulation of hormonal secretion in humans. PMID- 25797834 TI - The neural basis of novelty and appropriateness in processing of creative chunk decomposition. AB - Novelty and appropriateness have been recognized as the fundamental features of creative thinking. However, the brain mechanisms underlying these features remain largely unknown. In this study, we used event-related functional magnetic resonance imaging (fMRI) to dissociate these mechanisms in a revised creative chunk decomposition task in which participants were required to perform different types of chunk decomposition that systematically varied in novelty and appropriateness. We found that novelty processing involved functional areas for procedural memory (caudate), mental rewarding (substantia nigra, SN), and visual spatial processing, whereas appropriateness processing was mediated by areas for declarative memory (hippocampus), emotional arousal (amygdala), and orthography recognition. These results indicate that non-declarative and declarative memory systems may jointly contribute to the two fundamental features of creative thinking. PMID- 25797833 TI - Prestimulus EEG alpha oscillations modulate task-related fMRI BOLD responses to auditory stimuli. AB - EEG alpha-band activity is generally thought to represent an inhibitory state related to decreased attention and play a role in suppression of task-irrelevant stimulus processing, but a competing hypothesis suggests an active role in processing task-relevant information - one in which phase dynamics are involved. Here we used simultaneous EEG-fMRI and a whole-brain analysis to investigate the effects of prestimulus alpha activity on the event-related BOLD response during an auditory oddball task. We separately investigated the effects of the posterior alpha rhythm's power and phase on activity related to task-relevant stimulus processing and also investigated higher-level decision-related processing. We found stronger decision-related BOLD activity in areas late in the processing stream when subjects were in the high alpha power state prior to stimulus onset, but did not detect any effect in primary sensory regions. Our phase analysis revealed correlates in the bilateral thalamus, providing support for a thalamo cortical loop in attentional modulations and suggesting that the cortical alpha rhythm acts as a cyclic modulator of task-related responses very early in the processing stream. Our results help to reconcile the competing inhibition and active-processing hypotheses for ongoing alpha oscillations and begin to tease apart the distinct roles and mechanisms underlying their power and phase. PMID- 25797835 TI - Multimodal effective connectivity analysis reveals seizure focus and propagation in musicogenic epilepsy. AB - Dynamic causal modeling (DCM) is a method to non-invasively assess effective connectivity between brain regions. 'Musicogenic epilepsy' is a rare reflex epilepsy syndrome in which seizures can be elicited by musical stimuli and thus represents a unique possibility to investigate complex human brain networks and test connectivity analysis tools. We investigated effective connectivity in a case of musicogenic epilepsy using DCM for fMRI, high-density (hd-) EEG and MEG and validated results with intracranial EEG recordings. A patient with musicogenic seizures was examined using hd-EEG/fMRI and simultaneous '256-channel hd-EEG'/'whole head MEG' to characterize the epileptogenic focus and propagation effects using source analysis techniques and DCM. Results were validated with invasive EEG recordings. We recorded one seizure with hd-EEG/fMRI and four auras with hd-EEG/MEG. During the seizures, increases of activity could be observed in the right mesial temporal region as well as bilateral mesial frontal regions. Effective connectivity analysis of fMRI and hd-EEG/MEG indicated that right mesial temporal neuronal activity drives changes in the frontal areas consistently in all three modalities, which was confirmed by the results of invasive EEG recordings. Seizures thus seem to originate in the right mesial temporal lobe and propagate to mesial frontal regions. Using DCM for fMRI, hd-EEG and MEG we were able to correctly localize focus and propagation of epileptic activity and thereby characterize the underlying epileptic network in a patient with musicogenic epilepsy. The concordance between all three functional modalities validated by invasive monitoring is noteworthy, both for epileptic activity spread as well as for effective connectivity analysis in general. PMID- 25797836 TI - The relationship between nailfold capillaroscopic assessment and telangiectasia score with severity of peripheral vascular involvement in systemic sclerosis. AB - OBJECTIVES: To determine the association of nailfold video-capillaroscopy (NVC) findings and telangiectasia score with digital ulcer (DU) history and severity of peripheral vascular involvement (PVI) in systemic sclerosis (SSc). METHODS: Fifty nine SSc patients fulfilling Leroy & Medsger criteria were evaluated including telangiectasia score, disease activity and severity scores. NVC was performed according to qualitative (early, active and late patterns) and semi-quantitative assessments. RESULTS: When DU+ and DU- groups were compared; the mean score of capillary number (CN) was 2.0+/-0.5 vs. 1.4+/-0.7 (p<0.001), irregularly enlarged capillaries (IEC) was 1.8+/-0.6 vs. 1.4+/-0.7 (p<0.05), microangiopathy evolution score (MES) was 2.5+/-1.5 vs. 1.8+/-1.0 (p<0.05) and 'early' pattern was significantly less frequent in DU+ patients (1 vs. 9, p=0.016). The frequency of severe-PVI (Medsger severity score of 2-4) was 22% in females (12/54) and 80% in males (4/5). When severe and non-severe groups were compared; the mean score of CN was 2.1+/-0.4 vs. 1.5+/-0.7 (p<0.001), MES was 2.8+/-1.6 vs. 1.8+/-1.1 (p<0.05) and 'early' pattern was significantly less frequent in patients with severe PVI (0 vs. 9, p=0.049). The mean values of telangiectasia score were similar between groups. CONCLUSIONS: DU history and severe PVI in SSc were associated with capillary loss and microangiopathy. 'Early' NVC pattern was very rare in patients with DU history and was not found in severe PVI. Severe PVI in males was more frequent than females. Telangiectasia scores were not found to be related to PVI. NVC may be a helpful method in the assessment of SSc patients for PVI prognosis, warranting prospective studies. PMID- 25797837 TI - Authors report lack of time as main reason for unpublished research presented at biomedical conferences: a systematic review. AB - OBJECTIVES: To systematically review reports that queried abstract authors about reasons for not subsequently publishing abstract results as full-length articles. STUDY DESIGN AND SETTING: Systematic review of MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, and study bibliographies for empirical studies in which investigators examined subsequent full publication of results presented at a biomedical conference and reasons for nonpublication. RESULTS: The mean full publication rate was 55.9% [95% confidence interval (CI): 54.8%, 56.9%] for 24 of 27 eligible reports providing this information and 73.0% (95% CI: 71.2%, 74.7%) for seven reports of abstracts describing clinical trials. Twenty-four studies itemized 1,831 reasons for nonpublication, and six itemized 428 reasons considered the most important reason. "Lack of time" was the most frequently reported reason [weighted average = 30.2% (95% CI: 27.9%, 32.4%)] and the most important reason [weighted average = 38.4% (95% CI: 33.7%, 43.2%)]. Other commonly stated reasons were "lack of time and/or resources," "publication not an aim," "low priority," "incomplete study," and "trouble with co-authors." CONCLUSIONS: Across medical specialties, the main reasons for not subsequently publishing an abstract in full lie with factors related to the abstract author rather than with journals. PMID- 25797838 TI - There are challenges in conducting systematic reviews in developing countries: the Jamaican experience. AB - OBJECTIVES: To describe some contextual and methodological challenges to conduct systematic reviews (SR) in developing countries using experiences from Jamaica. STUDY DESIGN AND SETTING: We identified four overarching challenges to conducting SRs in our setting, and present approaches used to overcome them. Challenges were evaluated using experiences in primary research and examples from SRs being conducted by the team. The applicability of global networking to increase capacity for SRs in Jamaica was described. RESULTS: Challenges were: 1) accessibility to the literature, 2) human resources in research, 3) local funding and 4) knowledge translation (KT). We found access to published literature was incomplete. There were limited human resources to conduct SRs, especially information scientists, knowledge brokers and expert SR methodologists as well as limited research funding. The approaches to overcome these challenges were; establishing membership within research networks, implementing training fellowship for SR authors, conducting sensitization and training workshops with specialized groups, and collaborating with developed country researchers for wider access to both funding and human resources. CONCLUSION: Challenges in conducting SR in developing countries can be overcome. Approaches to strengthen KT should be prioritized in order to generate and promote a robust, generalizable evidence base for healthcare and policy. PMID- 25797839 TI - Proteomic analysis of human glioblastoma cell lines differently resistant to a nitric oxide releasing agent. AB - Glioblastoma multiforme is the most aggressive astrocytoma characterized by the development of resistant cells to various cytotoxic stimuli. Nitric oxide (NO) is able to overcome tumor resistance in PTEN mutated rat C6 glioma cells due to its ability to inhibit cell growth by influencing the intracellular distribution of ceramide. The aim of this study is to monitor the effects of NO donor PAPANONOate on ceramide trafficking in human glioma cell lines, CCF-STTG1 (PTEN-mutated, p53 wt) and T98G (PTEN-harboring, p53-mutated), together with the assessment of their differential molecular signature by 2D-DIGE and MALDI mass spectrometry. In the CCF-STTG1 cell line, the results indicate that treatment with PAPANONOate decreased cell proliferation (<50%) and intracellular trafficking of ceramide, assessed by BODIPY-C5Cer, while these events were not observed in the T98G cell line. Proteomic results suggest that CCF-STTG1 cells are characterized by an increased expression of proteins involved in NO-associated ER stress (i.e. protein disulfide-isomerase A3, calreticulin, 78 kDa glucose-regulated protein), which could compromise ceramide delivery from ER to Golgi, leading to ceramide accumulation in ER and partial growth arrest. Conversely, T98G cell lines, resistant to NO exposure, are characterized by increased levels of cytosolic antioxidant proteins (i.e. glutathione-S-transferase P, peroxiredoxin 1), which might buffer intracellular NO. By providing differential ceramide distribution after NO exposure and differential protein expression of two high grade glioma cell lines, this study highlights specific proteins as possible markers for tumor aggressiveness. This study demonstrates that, in two different high grade glioma cell lines, NO exposure results in a different ceramide distribution and protein expression. Furthermore, this study highlights specific proteins as possible markers for tumor aggressiveness. PMID- 25797840 TI - Time to face the challenge of multimorbidity. A European perspective from the joint action on chronic diseases and promoting healthy ageing across the life cycle (JA-CHRODIS). AB - Research on multimorbidity has rapidly increased in the last decade, but evidence on the effectiveness of interventions to improve outcomes in patients with multimorbidity is limited. The European Commission is co-funding a large collaborative project named Joint Action on Chronic Diseases and Promoting Healthy Ageing across the Life Cycle (JA-CHRODIS) in the context of the 2nd EU Health Programme 2008-2013. The present manuscript summarizes first results of the JA-CHRODIS, focuses on the identification of a population with multimorbidity who has a high or very high care demand. Identification of characteristics of multimorbid patients associated with a high rate of resource consumption and negative health outcomes is necessary to define a target population who can benefit from interventions. Indeed, multimorbidity alone cannot explain the complexity of care needs and further, stratification of the general population based on care needs is necessary for allocating resources and developing personalized, cost-efficient, and patient-centered care plans. Based on analyses of large databases from European countries a profile of the most care-demanding patients with multimorbidity is defined. Several factors associated with adverse health outcomes and resource consumption among patients with multimorbidity were identified in these analyses, including disease patterns, physical function, mental health, and socioeconomic status. These results underline that a global assessment is needed to identify patients with multimorbidity who are at risk of negative health outcomes and that a comprehensive approach, targeting not only diseases, but also social, cognitive, and functional problems should be adopted for these patients. PMID- 25797841 TI - In vivo electrochemical corrosion study of a CoCrMo biomedical alloy in human synovial fluids. AB - The present study was initiated with the aim to assess the in vivo electrochemical corrosion behaviour of CoCrMo biomedical alloys in human synovial fluids in an attempt to identify possible patient or pathology specific effects. For this, electrochemical measurements (open circuit potential OCP, polarization resistance Rp, potentiodynamic polarization curves, electrochemical impedance spectroscopy EIS) were carried out on fluids extracted from patients with different articular pathologies and prosthesis revisions. Those electrochemical measurements could be carried out with outstanding precision and signal stability. The results show that the corrosion behaviour of CoCrMo alloy in synovial fluids not only depends on material reactivity but also on the specific reactions of synovial fluid components, most likely involving reactive oxygen species. In some patients the latter were found to determine the whole cathodic and anodic electrochemical response. Depending on patients, corrosion rates varied significantly between 50 and 750 mg dm(-2)year(-1). PMID- 25797842 TI - Investigating the psychosocial determinants of child health in Africa: The Drakenstein Child Health Study. AB - BACKGROUND: Early life psychobiological and psychosocial factors play a key role in influencing child health outcomes. Longitudinal studies may help elucidate the relevant risk and resilience profiles, and the underlying mechanisms that impact on child health, but there is a paucity of birth cohort data from low and middle income countries (LMIC). We describe the rationale for and present baseline findings from the psychosocial component of the Drakenstein Child Health Study (DCHS). METHODS: We review the psychosocial measures used in the DCHS, a multidisciplinary birth cohort study in a peri-urban area in South Africa, and provide initial data on psychological distress, depression, substance use, and exposure to traumatic stressors and intimate partner violence (IPV). These and other measures will be assessed longitudinally in mothers in order to investigate associations with child neurodevelopmental and health outcomes. RESULTS: Baseline psychosocial data is presented for mothers (n=634) and fathers (n=75) who have completed antenatal assessments to date. The sample of pregnant mothers is characterized by multiple psychosocial risk factors, including a high prevalence of psychological distress and depression, high levels of substance use, and high exposure to traumatic stressors and IPV. DISCUSSION: These data are consistent with prior South African studies which have documented a high prevalence of a multitude of risk factors during pregnancy. Further longitudinal assessment of mothers and children may clarify the underlying psychobiological and psychosocial mechanisms which impact on child health, and so inform clinical and public health interventions appropriate to the South African and other LMIC contexts. PMID- 25797843 TI - Capturing subject variability in fMRI data: A graph-theoretical analysis of GICA vs. IVA. AB - BACKGROUND: Recent studies using simulated functional magnetic resonance imaging (fMRI) data show that independent vector analysis (IVA) is a superior solution for capturing spatial subject variability when compared with the widely used group independent component analysis (GICA). Retaining such variability is of fundamental importance for identifying spatially localized group differences in intrinsic brain networks. NEW METHODS: Few studies on capturing subject variability and order selection have evaluated real fMRI data. Comparison of multivariate components generated by multiple algorithms is not straightforward. The main difficulties are finding concise methods to extract meaningful features and comparing multiple components despite lack of a ground truth. In this paper, we present a graph-theoretical (GT) approach to effectively compare the ability of multiple multivariate algorithms to capture subject variability for real fMRI data for effective group comparisons. The GT approach is applied to components generated from fMRI data, collected from individuals with stroke, before and after a rehabilitation intervention. COMPARISON WITH EXISTING METHOD: IVA is compared with widely used GICA for the purpose of group discrimination in terms of GT features. In addition, masks are applied for motor related components generated by both algorithms. CONCLUSIONS: Results show that IVA better captures subject variability producing more activated voxels and generating components with less mutual information in the spatial domain than Group ICA. IVA-generated components result in smaller p-values and clearer trends in GT features. PMID- 25797844 TI - Affective patterns in triadic family interactions: Associations with adolescent depression. AB - Affective family processes are associated with the development of depression during adolescence. However, empirical description of these processes is generally based on examining affect at the individual or dyadic level. The purpose of this study was to examine triadic patterns of affect during parent adolescent interactions in families with or without a depressed adolescent. We used state space grid analysis to characterize the state of all three actors simultaneously. Compared to healthy controls, triads with depressed adolescents displayed a wider range of affect, demonstrated less predictability of triadic affective sequences, spent more time in and returned more quickly to discrepant affective states, and spent less time in and returned more slowly to matched affective states, particularly while engaged in a problem-solving interaction. Furthermore, we identified seven unique triadic states in which triads with depressed adolescents spent significantly more time than triads with healthy controls. The present study enhances understanding of family affective processes related to depression by taking a more systemic approach and revealing triadic patterns that go beyond individual and dyadic analyses. PMID- 25797845 TI - Existence of ultrafine crevices and functional groups along the edge surfaces of graphitized thermal carbon black. AB - Adsorption of different gases on graphitized thermal carbon black (GTCB) has been studied with a new molecular model to examine the consequences of micropore crevices and functional groups at the junctions between adjacent basal planes. Adsorption was simulated in the Grand Canonical Monte Carlo ensemble and the theoretical Henry constants were calculated by Monte Carlo volume integration over the Boltzmann factor of the solid-fluid potential. The simulation results are in good agreement with high-resolution experimental isotherms for argon on mineralogical graphite measured by Lopez-Gonzalez et al.1 From detailed inspection of the argon isotherms at extremely low coverages, we find two distinct Henry law regions, separated by a plateau (suggesting saturation of the stronger sites) that spans over a few decades of pressure. The first Henry law region is attributed to adsorption in the ultrafine crevices at the junctions between two adjacent basal planes, and the second region corresponds to adsorption on the basal plane, as confirmed by the theoretical Henry constant. The simulated isosteric heat and snapshots of molecular configurations show that argon adsorbs preferentially in the ultrafine crevices where there is a deep potential well due to overlap from the opposite pore walls. Similar behavior was found for other nonassociating fluids (Ar, N2, and CO2); however, for associating fluids (NH3 and H2O), the strong sites for adsorption and nucleation come from the combined effects of functional groups and ultrafine crevices, since the latter cannot alone account for the observed adsorption. PMID- 25797846 TI - Delayed periocular hemorrhage after upper blepharoplasty. AB - Periocular and orbital hemorrhage are rare complications of blepharoplasty, with a reported incidence of 0.055%. These complications are even less common more than 48 h after surgery. The authors report 2 cases of postoperative hemorrhage 5 and 8 days following uncomplicated upper blepharoplasty in which the initiating factor seems to have been uncontrolled hypertension. Details of the presentation, management and follow-up of each patient are described. These cases serve as an important reminder that patients must be appropriately counseled regarding the postoperative implications of their systemic conditions. PMID- 25797848 TI - Synthesis of cadmium, lead and copper alginate nanobeads as immunosensing probes for the detection of AFP, CEA and PSA. AB - A double-water-in-oil-emulsion procedure was designed to synthesize cadmium, lead and copper alginate nanobeads less than 200n m diameter under mild conditions. The cadmium, lead and copper alginate nanobeads can be activated to immobilize biomacromolecules and can directly produce distinctive electrochemical signals. Using the novel alginate nanobeads labeled with antibodies as electrochemical probes, a sandwich-type immunosensor was constructed using AFP, CEA and PSA as model analytes. This proposed immunosensor shows wide linear range with detection limits of 0.01, 0.0086 and 0.0075 ng mL(-1) for AFP, CEA and PSA, respectively. Analysis of clinical serum samples using this immunosensor was well consistent with the data determined by the enzyme-linked immunosorbent assay (ELISA). It suggested that the alginate nanobeads electrochemical probes could be generally extended to other multiple analytes detection. PMID- 25797847 TI - Analysis of optic disk color changes in Alzheimer's disease: a potential new biomarker. AB - PURPOSE: In the present study, we evaluated changes in the retinal nerve fiber layer (RNFL) and optic disk color (i.e., the level of paleness as an indirect sign of axonal loss) in patients with Alzheimer's disease (AD) compared with healthy controls. The usefulness of this method as a new biomarker for AD was also evaluated. METHODS: Fifty-six patients with mild or moderate AD and 56 sex and age-matched healthy subjects were included in this cross-sectional study. All subjects underwent a complete neuro-ophthalmologic examination, including analysis of the RNFL thickness with Cirrus optical coherence tomography (OCT). One photograph of the optic disk was obtained using a Canon CF 60 DSi retinograph, and new colorimetric analysis software (Laguna ONhE) was used to detect color changes in the photographs based on hemoglobin (Hb) values as reference pigment. RESULTS: Mean Hb percentage and Hb content in the outer ring, which corresponds with the neuroretinal rim, calculated by the Laguna ONhE program were significantly lower in AD patients than in healthy controls (P<0.005). OCT measurements revealed that the mean RNFL thickness was significantly decreased in AD patients compared with healthy controls (P<0.003). CONCLUSION: Analysis of the optic disk color assessed by Laguna ONhE software revealed papillary paleness due to axonal loss and perfusion alterations, even in the early stages of AD. Application of this simple method in routine clinical practice may provide a good biomarker of AD. PMID- 25797849 TI - Investigating the effect of design parameters on the response time of a highly sensitive microbial hydrogen sulfide biosensor based on oxygen consumption. AB - A novel hydrogen sulfide microbial biosensor was developed based on investigating the influence of four design parameters: cell concentration, immobilization bed type, hydrogen sulfide concentration, and geometrical shape of the biosensor. Thiobacillus thioparus was used as the recognition element and it was immobilized on sodium alginate as well as agarose bed. The results were optimized by the application of statistical optimization software based on response time of the system. Oxygen reduction was considered as the detection sign. Sodium alginate solution with a concentration of 2.3% (w/v) and optical density of 10 at 605 nm was found as the optimum conditions for immobilization with response time of 72s . Optimum response time of immobilized T. thioparus on agarose was also found equal to 120 s at agarose concentration of 1.2% (w/v) and optical density of 10.83. Performance of the biosensor in different temperatures, pH and agitation speeds was also analyzed. The designed biosensor could detect concentrations of hydrogen sulfide as low as 0.5 ppm. T. thioparus could retain 99% of the original activity in both systems, after ten days passing the fabrication. A fractal analysis was also done theoretically to investigate the diffusion of oxygen in immobilized cells which showed a satisfactory value of oxygen take up by the immobilized cells. PMID- 25797850 TI - An electrochemical-sensor system for real-time flow measurements in porous materials. AB - Flow monitoring in porous materials is critical for the engineering of paper based microfluidic bioassays. Here, we present an electrochemical-sensor system that monitors the liquid flow in porous materials without affecting the real flow in paper-strip samples. The developed microfluidic sensor records an amperometric signal created by the solution movement mediated by paper wicking. This approach allows the in situ monitoring of the different hydrodynamic conditions of a specific paper geometry or composition. In addition, the method proposed in this work was employed to characterise the fluid flow of different nitrocellulose paper strips after oxygen-plasma treatment or dextran coating. The dextran fluid flow modifiers were further used on the paper strip-based assays as means of signal enhancement. The proposed electrochemical-sensing method offers a valuable alternative to existing optical-based monitoring techniques for flow measurement in paper-based microfluidic systems. PMID- 25797852 TI - Modulation of the electron transfer processes in Au-ZnO nanostructures. AB - Plasmonic nanostructures comprising Au and ZnO nanoparticles synthesized by the spontaneous reduction of HAuCl4 in ethylene glycol were used to assess the possibility of modulating the direction of the electron transfer processes at the interface. One electron UV reduction and visible oxidation of the reversible couple TEMPOL/TEMPOL-H was confirmed by EPR spectroscopy. The apparent quantum yield for TEMPOL-H conversion under continuous wave visible excitation depends on the irradiation wavelength, being 0.57% and 0.27% at 450 +/- 12 and 530 +/- 12 nm, respectively. These results indicate that both the surface plasmon resonance and the interband transition from the 5d to the 6s level of Au nanoparticles contribute to the visible activity of the nanostructure. In addition, by detecting free electron conduction band electrons in ZnO, after the visible excitation of Au/ZnO nanostructures, we provide direct evidence of the photoexcited electron transfer from gold nanoparticles to ZnO. PMID- 25797851 TI - Label-free impedimetric aptasensor for detection of femtomole level acetamiprid using gold nanoparticles decorated multiwalled carbon nanotube-reduced graphene oxide nanoribbon composites. AB - Gold nanoparticles (Au NPs) decorated multiwalled carbon nanotube-reduced graphene oxide nanoribbon (Au/MWCNT-rGONR) composites were synthesized by a one pot reaction. By employing the resulting Au/MWCNT-rGONR composites as the support for aptamer immobilization, we developed an ultrasensitive label-free electrochemical impedimetric aptasensor for acetamiprid detection, which was based on that the variation of electron transfer resistance was relevant to the formation of acetamiprid-aptamer complex at the modified electrode surface. Compared with pure Au NPs and MWCNT-rGONR, the Au/MWCNT-rGONR composites modified electrode was the most sensitive aptasensing platform for the determination of acetamiprid. The proposed aptasensor displayed a linear response for acetamiprid in the range from 5*10(-14) M to 1*10(-5) M with an extremely low detection limit of 1.7*10(-14) M (S/N=3). In addition, this impedimetric aptasensor possessed great advantages including the simple operation process, low-cost, selectivity and sensitivity, which provided a promising model for the aptamer-based detection with a direct impedimetric method. PMID- 25797853 TI - Electronic Structure of Ni2E2 Complexes (E = S, Se, Te) and a Global Analysis of M2E2 Compounds: A Case for Quantized E2(n-) Oxidation Levels with n = 2, 3, or 4. AB - The diamagnetic compounds Cp'2Ni2E2 (1: E = S, 2: E = Se, 3: E = Te; Cp' = 1,2,3,4,-tetraisopropylcyclopentadienyl), first reported by Sitzmann and co workers in 2001 [Sitzmann, H.; Saurenz, D.; Wolmershauser, G.; Klein, A.; Boese, R. Organometallics 2001, 20, 700], have unusual E...E distances, leading to ambiguities in how to best describe their electronic structure. Three limiting possibilities are considered: case A, in which the compounds contain singly bonded E2(2-) units; case B, in which a three-electron E?E half-bond exists in a formal E2(3-) unit; case C, in which two E(2-) ions exist with no formal E-E bond. One-electron reduction of 1 and 2 yields the new compounds [Cp*2Co][Cp'2Ni2E2] (1red: E = S, 2red: E = Se; Cp* = 1,2,3,4,5 pentamethylcyclopentadieyl). Evidence from X-ray crystallography, X-ray absorption spectroscopy, and X-ray photoelectron spectroscopy suggest that reduction of 1 and 2 is Ni-centered. Density functional theory (DFT) and ab initio multireference methods (CASSCF) have been used to investigate the electronic structures of 1-3 and indicate covalent bonding of an E2(3-) ligand with a mixed-valent Ni2(II,III) species. Thus, reduction of 1 and 2 yields Ni2(II,II) species 1red and 2red that bear unchanged E2(3-) ligands. We provide strong computational and experimental evidence, including results from a large survey of data from the Cambridge Structural Database, indicating that M2E2 compounds occur in quantized E2 oxidation states of (2 * E(2-)), E2(3-), and E2(2 ), rather than displaying a continuum of variable E-E bonding interactions. PMID- 25797854 TI - Therapeutic approach to Candida bezoar in children. AB - INTRODUCTION: Candida bezoar (CB) is a rare finding in neonates and infants with candiduria, presenting as necrotic debris with proliferating mycelia in the collecting system of the kidney. If initial antifungal medical treatment does not result in clearance of candiduria and disappearance of CB on ultrasound in dilated kidneys, invasive interventions like insertion of nephrostomy tubes (NT) or surgical interventions to drain the kidney are sometimes advocated(.). However, NT placement can be a technical challenge, especially in pre- and dysmature neonates, and NT displacement or obstruction by the CB can lead to suboptimal treatment. Identification of those children who will benefit from invasive renal drainage is important. OBJECTIVE: This study evaluates the management of patients with CB in three tertiary referral hospitals to determine criteria for intervention. MATERIALS AND METHODS: A retrospective multicenter chart analysis was conducted of children with candiduria and ultrasonographic demonstration of CB (diagnosed between March 1995 and August 2012). The indication for invasive renal drainage (if performed) and subsequent clinical outcome, serum creatinine levels and ultrasound findings were assessed. RESULTS: A total of 12 children were included, two of which were premature neonates. Eight children had congenital urogenital anomalies. One older child with acute myeloid leukemia had CB during chemotherapy and one ex-premature developed CB following cerebral candidiasis. All children received systemic antifungal medication; in seven children invasive treatment was added. Indications for invasive treatment were clinical deterioration, progressive renal dilation, pyonephrosis, rising creatinine levels and persistence of CB. Two underwent a Y-cutaneous ureterostomy and nephrostomy tubes were inserted in five children. Percutaneous renal drainage by nephrostomy led to complications in 3 of 6 procedures. In all patients, irrespective of therapeutic modality, follow-up ultrasound demonstrated no de novo changes. No additional parenchymal defects or deterioration of split renal function were seen on DMSA or MAG-3 scan. DISCUSSION: In the literature renal drainage is suggested in case of complete obstruction. However dilatation is a frequent finding in children as part of the congenital renal anomaly and does not necessarily mean that there is obstruction of the urinary tract. Even in children without candida infections the diagnosis of obstruction is not straightforward, while the results of a MAG 3 scan can be obscured by compromised kidney function, parenchymal bacterial infiltration and neonatal immaturity of the kidney. If candiduria and CB persist despite intensive medical treatment, intensive consultation is required before renal drainage, because NT insertion might be a surgical challenge. Complications such as displacement of the NT, urinoma development, or NT obstruction can occur and was seen in three of six procedures. Premature neonates seem to be more prone to complications due to their small anatomical proportions, requiring medical equipment with small diameters prone to displacement and obstruction. Some studies describe successful pharmaceutical management in the majority of patients with CB. Other studies describe unilateral surgical intervention in children with bilateral CB where unilateral drainage did not influence overall renal outcome. This is in line with our results. A limitation of the present study is its retrospective design. In this population, the motivation for invasive renal drainage or conservative management was not well documented in all cases, and was mainly based on clinical and diagnostic parameters like creatinine levels and radiographic findings. CONCLUSION: Renal drainage should be considered in selected cases after failure of systemic antifungal treatment. Inserting and maintaining a nephrostomy tube in young children is associated with a high rate of complications; conservative treatment is likely to be sufficient in the majority of patients with candiduria and CB. PMID- 25797855 TI - Further analysis of the Glans-Urethral Meatus-Shaft (GMS) hypospadias score: correlation with postoperative complications. AB - INTRODUCTION AND OBJECTIVE: The Glans-Urethral Meatus-Shaft (GMS) score is a concise and reproducible way to describe hypospadias severity. We classified boys undergoing primary hypospadias repair to determine the correlation between GMS score and postoperative complications. STUDY DESIGN: Between February 2011 and August 2013, patients undergoing primary hypospadias repair were prospectively scored using the GMS classification. GMS scoring included a 1-4 scale for each component: G - glans size/urethral plate quality, M - meatal location, and S - degree of shaft curvature, with more unfavorable characteristics assigned higher scores [Figure]. Demographics, repair type, and complications (urethrocutaneous fistula, meatal stenosis, glans dehiscence, phimosis, recurrent chordee and stricture) were assessed. Total and individual component scores were tested in uni- and multivariate analysis. RESULTS: Two-hundred and sixty-two boys (mean age 12.3 +/- 13.7 months) undergoing primary hypospadias repair had a GMS score assigned. Mean GMS score was 7 +/- 2.5 (G 2.1 +/- 0.9, M 2.4 +/- 1, S 2.4 +/- 1). Mean clinical follow-up was 17.7 +/- 9.3 months. Thirty-seven children (14.1%) had 45 complications. A significant relationship between the total GMS score and presence of any complication (p < 0.001) was observed; for every unit increase in GMS score the odds of any postoperative complication increased 1.44 times (95% CI, 1.24-1.68). Urethrocutaneuous fistula was the most common complication, occurring in 21 of 239 (8.8%) of single-stage repairs. Patients with mild hypospadias (GMS 3-6) had a 2.4% fistula rate vs. 11.1% for moderate (GMS 7-9) and 22.6% for severe (GMS 10-12) hypospadias (p < 0.001). Degree of chordee was an independent predictor of fistula on multivariate analysis; S4 (>60 degrees ventral curvature) patients were 27 times more likely to develop a fistula than S1 (no curvature) boys (95% CI, 3.2-229). DISCUSSION: The GMS score is based on anatomic features (i.e. glans size/urethral plate quality, location of meatus, and degree of chordee) felt to most likely impact functional and cosmetic outcomes following hypospadias repair. We demonstrated a statistically significant increase in the likelihood of any postoperative complication with every unit increase in total GMS score. The concept that factors aside from meatal location affect hypospadias repair and outcomes is not novel, and degree of ventral curvature and urethral plate quality are often cited as important factors. In our series, boys with greater than 60 degrees of ventral curvature undergoing a single-stage repair were 27 times more likely to develop a fistula than those without chordee on multivariate analysis, making severe curvature an independent predictor of urethrocutaneous fistula formation. That meatal location did not retain significance on multivariate analysis highlights the importance of considering the entire hypospadias complex when determining severity, rather than just evaluating the position of the meatus. Our study has several limitations that warrant consideration. While GMS scores were assigned prospectively, the data was collected retrospectively, subjecting it to flaws inherent with such study design. Furthermore, type of repair is influenced by surgeon preference and subjective assessment of hypospadias characteristics not incorporated in our scoring system (i.e. tissue quality, urethral hypoplasia, penoscrotal transposition). Despite these limitations, our study demonstrates a strong correlation between the GMS classification and surgical complications, furthering supporting its potential as a tool to standardize hypospadias severity and gauge postoperative complications. CONCLUSION: The Glans-Urethral Meatus-Shaft (GMS) classification provides a means by which hypospadias severity and reporting can be standardized, which may improve inter-study comparison of reconstructive outcomes. There is a strong correlation between complication risk and total GMS score. Degree of chordee (S score) is independently predictive of fistula rate. PMID- 25797856 TI - Laparoscopic extravesical detrusorraphy, a minimally invasive treatment option for vesicoureteral reflux: a single centre experience. AB - INTRODUCTION: Laparoscopy in pediatric patients offers more benefits than was earlier presumed and these widely reported benefits significantly outweigh any concerns regarding the technical difficulties. Laparoscopic correction of vesicoureteral reflux aims to duplicate the excellent results of open surgery while at the same time reducing perioperative morbidity and analgesic requirements, improving cosmesis and shortening hospital stay. OBJECTIVE: To share our experience of laparoscopic extravesical detrusorraphy, highlight our technical modification of intraoperative minimal "atraumatic" ureteric handling of the ureter, which we hypothesize may decrease ureteral complications, and report our results. STUDY DESIGN: This was a retrospective chart review of 76 toilet-trained children (98 refluxing units), in the age group of 3-16 years, with Grade I-IV reflux, who underwent laparoscopic detrusorraphy from June 2006 to January 2014. A ureteric catheter is inserted into the refluxing ureter and is tied to the Foleys to drain into a common bag. A three port technique is used. During ureteral dissection, a vascular sling in the form of a Rumel loop is used for atraumatic handling of the ureter. A detrusor tunnel is created with hook electrocautery. A stay suture is later passed through the abdominal wall and slings around the dissected ureter, which helps in holding the ureter approximated against the mucosal trough during detrusorraphy. Detrusor fibers are approximated with 5-0 Vicryl. No drain is placed and the Foley and ureteric catheter(s) are removed after 24 h. Intravenous ketorolac is given every 6 h for the first 24 h. Oral paracetamol is used for analgesia after the first 24 h. Adequate bladder emptying is ensured by assessment of post void residual urine before discharge. Renal USG alone is performed 2 weeks post operatively and repeated after 3 months along with a VCUG (voiding cystourethrography). Success was defined as absence of reflux in the follow-up VCUG done at 3 months. RESULTS: Mean operative time was 102 +/- 26.5 min for unilateral detrusorraphy and 165 +/- 18 min for bilateral extravesical detrusorraphy. The mean duration of hospital stay was 1.5 +/- 1.7 days. There was one case of urinary retention that was managed with temporary recatheterization. There were no cases of ureteral ischemia, obstruction, hematuria or bladder spasms. Surgery was successful in 97.9% of the refluxing units (96/98). In two patients with grade IV reflux, there was downgrading to grade II on VCUG done at 3 months' follow-up. The reflux resolved at 8 and 14 months' follow-up, respectively. DISCUSSION: Our technique of atraumatic handling of the ureter, initially with the help of a vascular sling and later with the help of a stay suture passed percutaneously through the abdominal wall, resulted in no ureteric injuries. The postoperative morbidity of this procedure is low because the bladder is not opened, the ureter is not transected, no new UVJ is created and there is no need for placement of a drain. The risk of postoperative bowel adhesions is low as the ureter is dissected out through a narrow peritoneal window, which is again extraperitonealized at the end of the procedure (see figure). The postoperative complications of gross hematuria and bladder spasms, which may be especially encountered in patients undergoing laparoscopic Cohen's, were not seen in our case series. CONCLUSION: Laparoscopic extravesical detrusorraphy provides a minimally invasive treatment option for treatment of unilateral/bilateral grade I-IV vesicoureteral reflux. The postoperative morbidity is low and the success rate is favorable. Our technical modification of a "vascular sling" around the ureter facilitates atraumatic ureteric handling, which may reduce distal ureteral complications like ureteral ischemia and obstruction. PMID- 25797857 TI - Obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome should be redefined as ipsilateral renal anomalies: cases of symptomatic atrophic and dysplastic kidney with ectopic ureter to obstructed hemivagina. AB - OBJECTIVE: Obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome is a rare syndrome characterized by mullerian and renal anomalies. Renal agenesis is classically considered to be part of the definition of OHVIRA syndrome. There are increasing reports that the lack of an ipsilateral kidney on imaging studies is not from true renal agenesis but renal dysplasia and atrophy. We have observed cases where this ipsilateral dysplastic and atrophic kidney leads to clinical symptoms. The objective of this study is to report cases of OHVIRA syndrome where an ipsilateral dysplastic and atrophic kidney led to clinical symptoms, and to raise awareness in the pediatric urology community of this variant of OHVIRA syndrome. MATERIAL AND METHODS: All cases of OHVIRA syndrome with an ipsilateral dysplastic and atrophic kidney were identified from January 2010 to June 2013. The patient's presentation, clinical course, surgical management, radiologic findings, and pathologic finding were reviewed. RESULTS: There were three cases of OHVIRA syndrome with a symptomatic ipsilateral dysplastic and atrophic kidney identified. All three of these dysplastic and atrophic kidneys had an ectopic ureter to the obstructed hemivagina and led to persistent vaginal drainage after resection of the vaginal septum. These dysplastic and atrophic kidneys were not visualized on any imaging studies. Laparoscopic removal of the dysplastic and atrophic kidney led to cessation of vaginal drainage in all cases. CONCLUSION: This study reports additional cases to the literature that do not fit the classic definition of OHVIRA syndrome. In the cases in this study, there was no ipsilateral renal agenesis, but an ipsilateral dysplastic and atrophic kidney with an ectopic ureter to the obstructed hemivagina. In addition, these cases demonstrate that the dysplastic and atrophic kidney may cause symptoms such as persistent vaginal drainage after resection of vaginal septum. The dysplastic and atrophic kidneys may not be detected by any imaging modality including MRI and DMSA scan and may be ectopic in location. All three of our cases had persistent vaginal drainage after resection of the vaginal septum which was cured by removal of the dysplastic and atrophic kidney ipsilateral to the obstructed hemivagina. The limitations of this study include the small number of patients and retrospective nature. While the classic definition of OHVIRA syndrome includes ipsilateral renal agenesis, there is increasing evidence that the absence of a kidney on imaging is due to renal dysplasia and atrophy and not true renal agenesis. In addition, we have observed that this dysplastic and atrophic kidney may cause clinically significant issues such as persistent vaginal drainage through an ectopic ureter to the ipsilateral hemivagina after resection of vaginal septum. This small dysplastic and atrophic kidney may not be visualized on imaging studies and laparoscopy can be diagnostic and therapeutic if indicated. Ipsilateral renal anomalies, not ipsilateral renal agenesis, should be considered part of the definition of OHVIRA syndrome. Pediatric urologists need to be aware of the spectrum of renal anomalies in OHVIRA syndrome. PMID- 25797858 TI - Combined robotic and open approach to excision of accessory bladder and urethral triplication. AB - BACKGROUND: Management of urethral and bladder duplication anomalies centers on prevention of recurrent infections and preservation of renal function. We present a surgical approach to urethral triplication and bladder duplication utilizing a combined robotic and open approach. METHODS: A 17-year-old male presenting with fevers and abdominal pain was found to have two accessory urethras dorsal to a normal orthotopic ventral meatus. A large cavity anterior to the bladder was identified on a computed tomography scan and drained of purulent fluid. After improvement with antibiotics, endoscopic evaluation revealed no distinct connection between the cavities. The patient subsequently underwent open excision of the urethral triplication followed by robotic excision of the accessory bladder. RESULTS: Total console time for the robotic portion was 2 hours 18 minutes and estimated blood loss was 30mL. The dissection was difficult due to reaction from prior infections, but the accessory bladder was able to be dissected off without opening the native bladder. The accessory bladder specimen was consistent with a urothelial lining exhibiting reactive changes. CONCLUSION: To our knowledge, robotic excision of a urethral/bladder duplication anomaly has not yet been described in the literature. The robotic approach allowed for excellent visualization and is technically feasible. PMID- 25797859 TI - Assessment of the introduction of an adolescent transition urology clinic using a validated questionnaire. AB - BACKGROUND: Adolescents with complex urological conditions are at risk of bladder dysfunction, metabolic disturbances, neoplastic changes and deterioration in renal function. Hence they require appropriate transition to the adult service to ensure lifelong urological care is adequately provided. OBJECTIVE: Barriers and difficulties to the transition process have been identified in the literature. To overcome these difficulties an Adolescent Transition Urology Clinic (ATUC) was established in 2009 where the patients are seen by a paediatric and an adult urologist, a urology nurse and if needed an adolescent gynaecologist. Our aim was to assess the ATUC and present the patient's perspective to this new service using a validated questionnaire. MATERIALS AND METHODS: Data of all patients seen at the ATUC over the study period were prospectively recorded. Patients who completed the transition were contacted and asked to complete two online urological transition questionnaires: 1) The Care Transition Measure 15 (CTM-15) which is a validated questionnaire to assess the quality of care during transition from the patients' perspective. 2) The Transition Care Experience (TCE) which was created for the purpose of this study. RESULTS: Thirty patients attended the ATUC over 4.5 years, with 26 (87%) completing the transition to the adult urological care. Of the 26 patients there were 14 (54%) males with a mean age of 18 years. The most common underlying urological condition was neurogenic bladder (85%). Nineteen (73%) patients completed the questionnaires. Only 1 (5%) patient thought that attending the ATUC was not beneficial, 17 (89%) would recommend the ATUC to other adolescents and 9 (47%) patients considered 18 as the appropriate transition age. Overall, 74% thought that written information would have been useful and 21% considered the adult hospital as an inappropriate environment for young adults. After attending the ATUC, 2 (11%) patients thought their preferences were not met and 3 (16%) patients were not confident that they can take care of their health. DISCUSSION: Transition of patients with complex urological conditions should aim to facilitate transferring the care from the parent to the patient and preparing the adolescent to adult life by addressing their sexual and reproductive functions. Inadequate transition can have serious health consequences. On-going communication between the paediatric and the adult urologist facilitates the transition process even after the transfer of care has occurred. The CTM-15 has been considered as "the only available measure of quality of care during transition from the patients' perspective". Our study suggests that the large majority of adolescent attending the clinic are confident in looking after their complex urological condition. In addition one patient in 5 found the adult hospital environment an inappropriate place for adolescents and they would have preferred longer follow up in a children's hospital. The value of written information after clinic consultation seems to be a useful adjunct that might facilitate the complex transition process. CONCLUSION: This is the first report evaluating the transition of adolescents with complex urological conditions using a validated transition questionnaire. The combined paediatric/adult urology clinic is beneficial in addressing the patients' needs and allowing smooth transition of these complex patients to the adult service. PMID- 25797861 TI - Disease-specific direct-to-consumer advertising of pharmaceuticals: An examination of endorser type and gender effects on consumers' attitudes and behaviors. AB - BACKGROUND: Direct-to-consumer (DTC) advertising is still a controversial topic for pharmaceutical manufacturers' and researchers, and while numerous studies have examined the DTC phenomenon, little research has examined the effect of gender, particularly gender of the endorser and consumer. OBJECTIVE: The objective of this research was to assess the impact of the endorser (celebrity vs. expert vs. non-celebrity) and gender - both gender of the endorser and gender of the consumer - on consumers' attitudes and behaviors in response to a print disease-specific direct-to-consumer advertisement. METHODS: Using Qualtrics consumer panel, data were obtained for 514 US adults (age 18 years and above) who demonstrated at least minimal symptoms of depression and need for monitoring based on the Patient Health Questionnaire (PHQ) score. Data were analyzed using a 3 (Endorser Type: Celebrity/Expert/Non-Celebrity) * 2 (Endorser Gender: Male/Female) * 2 (Consumer Gender: Male/Female) full factorial between subjects multivariate analysis of variance (MANOVA) and necessary univariate analysis. RESULTS: Only the type of the endorser (celebrity vs. expert vs. non-celebrity) used in the ad had a significant main effect on the dependent variables. Further univariate analyses revealed that, of the several dependent variables, endorser type had a significant influence only on attitude towards the ad, attention paid to the ad, and endorser credibility, with gender being non-significant in all cases. CONCLUSIONS: Expert endorser generated significantly more favorable levels of attitude towards the ad, and endorser credibility compared to the non celebrity endorser. Celebrity endorser attracted more consumer attention towards the ad and generated favorable endorser credibility perceptions compared to the non-celebrity endorser. However, celebrity and expert endorsers did not significantly differ from each other on the abovementioned ad effectiveness variables. Lastly, endorser gender and consumer gender did not have a significant influence on ad effectiveness. PMID- 25797860 TI - Grade of hypospadias is the only factor predicting for re-intervention after primary hypospadias repair: a multivariate analysis from a cohort of 474 patients. AB - BACKGROUND: There is an ongoing quest on how to minimize complications in hypospadias surgery. There is however a lack of high-quality data on the following parameters that might influence the outcome of primary hypospadias repair: age at initial surgery, the type of suture material, the initial technique, and the type of hypospadias. OBJECTIVES: The objective of this study was to identify independent predictors for re-intervention in primary hypospadias repair. STUDY DESIGN: We retrospectively analyzed our database of 474 children undergoing primary hypospadias surgery. Univariate and multivariate logistic regression was performed to identify variables associated with re-intervention. A p-value <0.05 was considered statistically significant and therefore considered as a prognostic factor for re-intervention. RESULTS: Distal penile hypospadias was reported in 77.2% (n = 366), midpenile in 11.4% (n = 54) and proximal in 11.4% (n = 54) of children. Initial repair was based on an incised plate technique in 39.9% (n = 189), meatal advancement in 36.0% (n = 171), an onlay flap in 17.3% (n = 82) and other or combined techniques in 5.3% (n = 25). In 114 patients (24.1%) re-intervention was required (n = 114) of which 54 re interventions (47.4%) were performed within the first year post-surgery, 17 (14.9%) in the second year and 43 (37.7%) later than 2 years after initial surgery. The reason for the first re-intervention was fistula in 52 patients (46.4%), meatal stenosis in 32 (28.6%), cosmesis in 35 (31.3%) and other in 14 (12.5%). The median time for re-intervention was 14 months after surgery [range 0 114]. Significant predictors for re-intervention on univariate logistic regression (polyglactin suture material versus poliglecaprone, proximal hypospadias, lower age at operation and other than meatal advancement repair) were put in a multivariate logistic regression model. Of all significant variables, only proximal hypospadias remained an independent predictor for re intervention (OR 3.27; p = 0.012). DISCUSSION: The grade of hypospadias remains according to our retrospective analysis the only objective independent predicting factor for re-intervention in hypospadias surgery. This finding is rather obvious for everyone operating hypospadias. Curiously midpenile hypospadias cases were doing slightly better than distal hypospadias in terms of re-intervention rates. Our study however has also some shortcomings. First of all, data was gathered retrospectively and follow-up time was ill-balanced for several variables. We tried to correct this by applying sensitivity analysis, but possible associations between some variables and re-intervention might still be obscured by this. Standard questionnaires to analyze surgical outcome were not available. Therefore, we focused our analysis on re-intervention rate as this is a hard and clinically relevant end point. CONCLUSIONS: This retrospective analysis of a large hypospadias database with long-term follow-up indicates that the long lasting debate about factors influencing the reoperation rate in hypospadias surgery might be futile: in experienced hands, the only variable that independently predicts for re-intervention is the severity of hypospadias, the only factor we cannot modify. This retrospective multivariate analysis of a large hypospadias database with long-term follow-up suggests that the only significant independent predictive factor for re-intervention is proximal hypospadias. In our series, technique did not influence the re-intervention rate. PMID- 25797862 TI - Excellent spin transport in spin valves based on the conjugated polymer with high carrier mobility. AB - Organic semiconductors (OSCs) are characteristic of long spin-relaxation lifetime due to weak spin-orbit interaction and hyperfine interaction. However, short spin diffusion length and weak magnetoresistance (MR) effect at room temperature (RT) was commonly found on spin valves (SVs) using an organic spacer, which should be correlated with low carrier mobility of the OSCs. Here, N-type semiconducting polymer P(NDI2OD-T2) with high carrier mobility is employed as the spacer in the SV devices. Exceedingly high MR ratio of 90.0% at 4.2 K and of 6.8% at RT are achieved, respectively, via improving the interface structure between the polymer interlayer and top cobalt electrode as well as optimal annealing of manganite bottom electrode. Furthermore, we observe spin dependent transport through the polymeric interlayer and a large spin diffusion length with a weak temperature dependence. The results indicate that this polymer material can be used as a good medium for spintronic devices. PMID- 25797863 TI - The specificity and accuracy of (111)In-hexavalent lactoside in estimating liver reserve and its threshold value for mortality in mice. AB - BACKGROUND & AIMS: The asialoglycoprotein receptor on hepatocyte membranes recognizes the galactose residues of glycoproteins. We investigated the specificity, accuracy and threshold value of asialoglycoprotein receptor imaging for estimating liver reserve via scintigraphy using (111)In-hexavalent lactoside in mouse models. METHODS: (111)In-hexavalent lactoside scintigraphy for asialoglycoprotein receptor imaging was performed on groups of normal mice, orthotopic SK-HEP-1-bearing mice, subcutaneous HepG2-bearing mice, mice with 20 80% partial hepatectomy and mice with acute hepatitis induced by acetaminophen. Liver reserve was measured by relative liver uptake and compared with normal mice. Asialoglycoprotein receptor blockade was performed via an in vivo asialofetuin competitive binding assay. RESULTS: A total of 73.64+/-7.11% of the injection dose accumulated in the normal liver tissue region, and radioactivity was barely detected in the hepatoma region. When asialoglycoprotein receptor was blocked using asialofetuin, less than 0.41+/-0.04% of the injection dose was detected as background in the liver. Asialoglycoprotein receptor imaging data revealed a linear correlation between (111)In-hexavalent lactoside binding and residual liver mass (R(2)=0.8548) in 20-80% of partially hepatectomized mice, demonstrating the accuracy of (111)In-hexavalent lactoside imaging for measuring the functional liver mass. Asialoglycoprotein receptor imaging data in mice with liver failure induced using 600mg/kg acetaminophen revealed 19-45% liver reserve relative to normal mice and a fatal threshold value of 25% liver reserve. CONCLUSION: The (111)In-hexavalent lactoside imaging method appears to be a good, specific, visual and quantitative predictor of functional liver reserve. The diagnostic threshold for survival was at 25% liver reserve in mice. PMID- 25797864 TI - Successful use of intra-arrest thrombolysis for electrical storm due to acute myocardial infarction. AB - Acute vascular thrombotic disease, including acute myocardial infarction and pulmonary embolism, accounts for 70% of sudden outpatient cardiac arrest. The role of intra-arrest thrombolytic administration aimed at reversing the underlying cause of cardiac arrest remains an area of debate with recent guidelines advising against routine use. We present a case of prolonged refractory ventricular fibrillation electrical storm in a patient who demonstrated intra-arrest electrocardiographic and sonographic markers confirming acute myocardial infarction. Return of spontaneous circulation was rapidly achieved after rescue intra-arrest bolus thrombolysis.Highlights of this case are discussed in the context of the current evidence for thrombolytic therapy in cardiac arrest with specific attention to the issue of patient selection. PMID- 25797865 TI - Do emergency pediatric psychiatric visits for danger to self or others correspond to times of school attendance? AB - BACKGROUND: Pediatric and adolescent mental health complaints are growing problems for emergency departments and inpatient facilities. We sought to investigate the relationship between weeks when school is in session (vs vacation) and presentation with concern for danger to self or others. METHODS: We retrospectively studied the risk of presenting with these complaints while school is in attendance compared to the risk while on vacation over a 4-year period (2009-2012) at an academic pediatric emergency department. The week of presentation was recorded for all children making psychiatric visits related to suicidality or homicidality, and these were correlated with the public school calendar for the local school district. The incidence rate ratio (IRR) was calculated for psychiatric visits while in school status vs vacation. Similar data were collected for a diagnosis of urinary tract infection to serve as a control. RESULTS: Of 3223 eligible patients (mean age, 13.8 years), 82.7% presented while in school, although the students only spent 68.6% of their time in school, yielding an IRR of 2.18. By comparison, the IRR for the diagnosis of urinary tract infection was 1.25. CONCLUSIONS: Children and adolescents are more likely to present with concerns for danger to self or others while attending school compared with while on vacations. Causation and opportunities for intervention require further study. PMID- 25797866 TI - The new technique for reduction of bilateral mandibular dislocation. PMID- 25797868 TI - Intrathyroidal epithelial thymoma: carcinoma showing thymus-like differentiation mimicking squamous cell carcinoma of the thyroid. PMID- 25797869 TI - Brain plasticity and rehabilitation in stroke patients. AB - In recent years, our understanding of motor learning, neuroplasticity and functional recovery after the occurrence of brain lesion has grown significantly. Novel findings in basic neuroscience have provided an impetus for research in motor rehabilitation. The brain reveals a spectrum of intrinsic capacities to react as a highly dynamic system which can change the properties of its neural circuits. This brain plasticity can lead to an extreme degree of spontaneous recovery and rehabilitative training may modify and boost the neuronal plasticity processes. Animal studies have extended these findings, providing insight into a broad range of underlying molecular and physiological events. Neuroimaging studies in human patients have provided observations at the systems level that often parallel findings in animals. In general, the best recoveries are associated with the greatest return toward the normal state of brain functional organization. Reorganization of surviving central nervous system elements supports behavioral recovery, for example, through changes in interhemispheric lateralization, activity of association cortices linked to injured zones, and organization of cortical representational maps. Evidence from animal models suggests that both motor learning and cortical stimulation alter intracortical inhibitory circuits and can facilitate long-term potentiation and cortical remodeling. Current researches on the physiology and use of cortical stimulation animal models and in humans with stroke related hemiplegia are reviewed in this article. In particular, electromyography (EMG) -controlled electrical muscle stimulation improves the motor function of the hemiparetic arm and hand. A multi channel near-infrared spectroscopy (NIRS) studies in which the hemoglobin levels in the brain were non-invasively and dynamically measured during functional activity found that the cerebral blood flow in the injured sensory-motor cortex area is greatest during an EMG-controlled FES session. Only a few idea is, however, known for the optimal timing of the different processes and therapeutic interventions and for their interactions in detail. Finding optimal rehabilitation paradigms requires an optimal organization of the internal processes of neural plasticity and the therapeutic interventions in accordance with defined plastic time windows. In this review the mechanisms of spontaneous plasticity after stroke and experimental interventions to enhance plasticity are summarized, with an emphasis on functional electrical stimulation therapy. PMID- 25797867 TI - Bridging the osteoporosis treatment gap: performance and cost-effectiveness of a fracture liaison service. AB - Individuals who sustain fragility fractures are at high risk of refracture. However, osteoporosis treatment rates remain low for these patients. Therefore, we aimed to assess the performance and cost-effectiveness of introducing a fracture liaison service (FLS) into a tertiary hospital. In "nonhospitalized" ambulatory patients who had sustained fragility fractures, we assessed baseline osteoporosis investigation and treatment rates, and subsequently, the impact of introducing an orthopedic osteoporosis policy and an FLS. Outcomes measured were uptake of osteoporosis intervention, patient satisfaction, and quality-adjusted life years (QALYs) gained. QALYs were calculated over 5 years using predicted fracture risks without intervention and estimated fracture risk reduction with intervention. At baseline (n = 49), 2% of ambulatory patients who had sustained fragility fractures underwent dual-energy X-ray absorptiometry (DXA) and 6% received osteoporosis-specific medication. After introduction of an osteoporosis policy (n = 58), 28% were investigated with DXA (p < 0.0001). However, treatment rates were unchanged. An FLS was introduced, reviewing 203 new patients over the inaugural 2 years (mean age [standard deviation], 67 (11) years; 77% female). All underwent DXA, and criteria for osteoporosis and osteopenia were identified in 44% and 40%, respectively. Osteoporosis medications were prescribed to 61% patients (risedronate: 22%, alendronate: 16%, strontium ranelate: 13%, zoledronic acid: 8%, other: 2%). Eighty-five of 90 questionnaire respondents were very satisfied or satisfied with the FLS. With the treatment prescribed over 5 years, we conservatively estimated that this FLS would reduce nonvertebral refractures from 59 to 50, improving QALYs by 0.054 and costing $1716 per patient (incremental cost-effectiveness ratio: $31749). This FLS model improves uptake of osteoporosis intervention guidelines, is popular among patients, and improves cost-effectiveness. Thus, it has the capacity to substantially improve health in a cost-effective way. PMID- 25797870 TI - A comparison of microsurgical venous anastomosis techniques. AB - BACKGROUND: Successful vascular anastomosis is essential for the survival of transferred free tissue. Arterial anastomosis is typically uncomplicated because the lumen is easily maintained and the vessel walls have elasticity. Venous anastomosis, however, is more time consuming because the vessel walls are thin and extensible. This article describes, reviews, and compares 3 currently used venous anastomosis techniques. METHODS: From April 2012 through January 2014, free tissue transfer and supercharging pedicled tissue transfer were performed in 107 and 10 patients, respectively, at our hospital. According to the anastomotic technique used, patients (83 men and 34 women; mean age, 60.6 years) were divided into interrupted suture, continuous suture, and microvascular anastomotic coupling device (MACD) groups. Medical records were reviewed, and postoperative results were analyzed. RESULTS: The diameter of anastomosed veins did not differ significantly among the groups. However, among the interrupted suture, continuous suture, and MACD groups, there were significant differences in vascular anastomosis time (51, 43.9, and 29.5 minutes, respectively) and transferred tissue ischemic time (151.9, 139.1, and 117.5 minutes, respectively). Surgical site infection occurred in 9 patients, and flap necrosis occurred in 2 patients. However, complication rates did not differ significantly among the 3 groups. CONCLUSIONS: The venous anastomosis technique does not affect the complication rate but does affect anastomosis time and flap ischemia time. On the basis of these results, we believe that the continuous suture and MACD techniques are easier and safer for venous anastomosis than is the traditional interrupted suture technique. PMID- 25797871 TI - Comparison of pain and efficacy of darbepoetin alfa and epoetin Beta pegol treatment in patients receiving peritoneal dialysis. AB - BACKGROUND: Sustained erythropoiesis-stimulating agents (ESAs) have recently been identified as the standard therapeutic agent for anemia in patients undergoing peritoneal dialysis (PD). However, few reports have compared pain between various types of sustained ESAs or between administration routes. Furthermore, the change ratio of the dose of sustained ESAs reportedly ranges from 0.8 to 1.3. In the present study, to compare darbepoetin alfa and epoetin beta pegol (a continuous erythropoietin receptor activator [CERA]), we examined the dolorific differences between administration routes and the effect on anemia by using a chjange ratio of 0.8 with darbepoetin alfa in patients with renal anemia undergoing PD. SUBJECTS AND METHOD: We randomly assigned 20 patients with stable hemoglobin levels undergoing PD to either a darbepoetin alfa therapy group or a CERA therapy group. Based on a previous report, the change ratio of the CERA group from CERA to darbepoetin alfa therapy was assumed to be 0.8, and therapy was crossed-over to darbepoetin alfa again 2 months later. The dolorific evaluation (pain measurement) used both a face scale and a visual analogue scale. We compared the agents as well as administration routes with respect to pain. We also measured variables related to anemia and iron metabolism. RESULTS: The change ratio of the CERA group at the start of the study was 0.821. On resumption of darbepoetin alfa therapy 2 months later, the doses of darbepoetin alfa increased. The darbepoetin alfa group showed a stronger tendency for pain, although the difference was not significant. In contrast, subcutaneous administration in the CERA group showed significant pain just after injection. The CERA group, however, showed a significant decrease in hemoglobin levels after 2 months of treatment (p=0.0489). No significant change was found in the hematocrit or the reticulocyte count. There were no significant differences in iron metabolism, as shown by serum iron levels and total iron-binding capacity, in either group. However, serum ferritin levels showed a tendency to decrease in the darbepoetin alfa group. CONCLUSION: No significant difference in pain was found between darbepoetin alfa and CERA therapies, but a significant difference in pain was noted between administration routes, just after injection, in the CERA group. The results also suggest that a change ratio of 0.8 from darbepoetin alfa to CERA is low for managing anemia. PMID- 25797872 TI - Glomerular capillary and endothelial cell injury is associated with the formation of necrotizing and crescentic lesions in crescentic glomerulonephritis. AB - BACKGROUND: The associations of glomerular capillary and endothelial injury with the formation of necrotizing and crescentic lesions in cases of crescentic glomerulonephritis (GN) have not been evaluated in detail. METHODS: Glomerular capillary and endothelial cell injury were assessed in renal biopsy specimens of crescentic GN, including those from patients with anti-neutrophil cytoplasmic autoantibodies (ANCA) -associated GN (n=45), anti-glomerular basement membrane (GBM) GN (n=7), lupus GN (n=21), and purpura GN (n=45) with light and electron microscopy and immunostaining for CD34. RESULTS: In ANCA-associated GN, anti-GBM GN, lupus GN, and purpura GN, almost all active necrotizing glomerular lesions began as a loss of individual CD34-positive endothelial cells in glomerular capillaries, with or without leukocyte infiltration. Subsequently, necrotizing lesions developed and were characterized by an expansive loss of CD34-positive cells with fibrin exudation, GBM rupture, and cellular crescent formation. With electron microscopy, capillary destruction with fibrin exudation were evident in necrotizing and cellular crescentic lesions. During the progression to the chronic stage of crescentic GN, glomerular sclerosis developed with the disappearance of both CD34-positive glomerular capillaries and fibrocellular-to fibrous crescents. In addition, the remaining glomerular lobes without crescents had marked collapsing tufts, a loss of endothelial cells, and the development of glomerular sclerosis. CONCLUSIONS: The loss of glomerular capillaries with endothelial cell injury is commonly associated with the formation of necrotizing and cellular crescentic lesions, regardless of the pathogeneses associated with different types of crescentic GN, such as pauci-immune type ANCA-associated GN, anti-GBM GN, and immune-complex type GN. In addition, impaired capillary regeneration and a loss of endothelial cells contribute to the development of glomerular sclerosis with fibrous crescents and glomerular collapse. PMID- 25797873 TI - Clinical characteristics of pregnancies with a history of recurrent miscarriage at a Japanese perinatal center. AB - OBJECTIVE: We examined obstetric and fetal/neonatal outcomes in women with a history of recurrent miscarriage. METHODS: We reviewed the obstetric records of all 5,829 nulliparous pregnant women who delivered at #8805;14 weeks' gestation from 2008 through 2013 at our perinatal center. Of these women, 74 had a history of recurrent miscarriage (1.3%). The control population consisted of 4,176 nulliparous women without a history of miscarriage. Demographic information and characteristics of labor were extracted from patient charts. RESULTS: The rate of maternal age #8805;40 years (p<0.01) and the rate of in vitro fertilization use (p<0.01) were higher in women with recurrent miscarriage than in women without miscarriage. Eleven women with recurrent miscarriage (14.9%) were treated with low-dose aspirin with and without subcutaneous heparin. In addition, the rate of cesarean delivery was higher in women with recurrent miscarriage than in women without miscarriage (p=0.02). However, fetal/neonatal outcomes did not differ significantly between the populations. CONCLUSION: The pregnancy of women with a history of recurrent miscarriage is not associated with adverse outcomes at our perinatal center. PMID- 25797874 TI - A case of obesity hypoventilation syndrome with respiratory failure that improved with abdominoplasty. AB - We report on a 70-year-old man with severe respiratory failure caused by obesity hypoventilation syndrome due to abdominal adiposis. Obesity hypoventilation syndrome is a severe condition that is diagnosed when all of the following criteria are satisfied: body-mass index >30 kg/m(2); apnea hypopnea index >30; PaCO2 >45 mm Hg (in the daytime); and marked daytime somnolence. Abdominoplasty, which is generally used for abdominal laxness, striae, and rectus muscle diastases and for women in the postpartum period, was performed for this patient to facilitate ventilator weaning and produced a satisfactory result. PMID- 25797875 TI - Single-incision laparoscopic cholecystectomy with an additional needle grasper: a novel technique. AB - BACKGROUND: Single-incision laparoscopic surgery has gained increasing attention due to its potential to improve the benefits of laparoscopic surgery. However, the technique remains technically challenging for most surgeons. We developed a new technique utilizing a needle grasper held in the surgeon's left hand as an alternative to conventional single-incision laparoscopic cholecystectomy (SILC). PATIENTS AND METHODS: From August 2011 through May 2013, 29 patients at Nippon Medical School Musashi Kosugi Hospital, with gallbladder stones or polyps underwent single-incision laparoscopic cholecystectomy (SILC) with an additional needle grasper that was held in the surgeon's left hand (SILCAN) and introduced in the right subcostal region without a trocar. We analyzed intraoperative and postoperative outcomes of 29 patients for whom SILCAN was performed and retrospectively compared these outcomes to those of 32 patients who underwent conventional 4-port laparoscopic cholecystectomy (CLC) from January 2011 through May 2013. RESULTS: No differences in patient characteristics or intraoperative/postoperative outcomes were observed between the groups. None of the patients in either group required conversion to an open procedure or additional ports. In the SILCAN group, no patients had complications within the first 4 weeks after surgery, with the exception of 1 patient with severe chronic cholecystitis in whom bile duct stenosis developed due to inadvertent clipping of the common hepatic duct. The frequency of postoperative analgesic use was similar in both groups, although none of the patients in the SILCAN group received analgesics for pain from the small, inconspicuous wound in the right subcostal region. CONCLUSIONS: SILCAN is a safe and feasible alternative to SILC which does not compromise the qualities of CLC. It is less technically challenging, and postoperative pain and cosmesis are comparable to those of conventional SILC. PMID- 25797876 TI - Technical arrangement of the Williams-Isu method for anterior cervical discectomy and fusion. AB - Anterior cervical fixation with autologous bone transplantation-without the need for harvesting bone from other sites, such as the ilium-was developed by Williams and modified by Isu et al. In recent intervertebral fusion procedures, after harvesting the cuboid bone from vertebral bodies, a hydroxyapatite block is placed between two harvested vertebral bones in the same way as in the sandwich method for intervertebral fixation. According to previous studies, this procedure has the following disadvantages: (i) as the corrective force for cervical kyphosis is insufficient, it could not be adapted for patients with preoperative kyphosis; (ii) special devices, including a microsurgical saw, are required for harvesting vertebral bones. In our modified method, we used a conventional high speed drill instead of a microsurgical saw. Nevertheless, the results show that the operated spine can be stabilized to a greater extent by decreasing the height of the grafted bone, and this might help in reducing postoperative kyphosis. PMID- 25797877 TI - A case of maternal vitamin K deficiency associated with hyperemesis gravidarum: its potential impact on fetal blood coagulability. AB - Vitamin K deficiency is associated with malnutrition in some complications, such as hyperemesis gravidarum, active gastrointestinal diseases, and psychological disorders. Maternal vitamin K deficiency can cause fetal bleeding, in particular, fetal intracranial hemorrhage. Although fetal hemorrhage is uncommon, severe damage to the fetus may be inevitable. We describe a pregnant woman with vitamin K deficiency possibly due to hyperemesis gravidarum. The patient was treated for the deficiency, and no fetal or neonatal hemorrhagic diseases were manifested. PMID- 25797878 TI - Poststreptococcal glomerulonephritis in a patient with essential thrombocytosis. AB - In addition to being the main cause of glomerulonephritis in children, poststreptococcal glomerulonephritis (PSGN) has recently been shown in older patients, especially those with malignancy or diabetes mellitus. The pathogenesis of PSGN has been ascribed to activation of complement 3 (C3) of the alternative complement cascade which, along with immunoglobulin (Ig) G and IgM deposits, is observed in renal tissue. Our aim here is to discuss the probable causes of PSGN developing with isolated IgM deposition in a 52-year-old patient with essential thrombocytosis followed-up over the previous 3.5 years. These characteristics make our case the first to be reported in the literature. PMID- 25797879 TI - Refractory leg ulcers associated with Klinefelter syndrome. AB - We present a man with refractory leg ulcers, bilateral varicosis of the lower extremities, and Buerger disease. Autoimmune work-up was negative. However, chromosome analysis showed Klinefelter syndrome (48 XXY). Ulcerative lesions of the lower extremities are a complication of Klinefelter syndrome. To date, the pathogenesis of ulcers in Klinefelter syndrome has not been clarified, but several factors, such as abnormalities of fibrinolysis and prothrombotic states, might be involved. Our present case emphasizes the importance of considering Klinefelter syndrome in the differential diagnosis of a male patient with nonhealing ulcers of the lower extremities. PMID- 25797881 TI - Aqueous phase selective detection of 2,4,6-trinitrophenol using a fluorescent metal-organic framework with a pendant recognition site. AB - Prompt and selective detection of nitro explosives in the aqueous phase is in high demand to meet homeland security and environmental concerns. Herein we report the chemically stable porous metal organic framework UiO-68@NH2 with a pendant recognition site for selective detection of the nitro-aromatic explosive TNP in the aqueous phase. The pendant Lewis basic amine moieties are expected to selectively interact with TNP via electrostatic interactions and act as recognition sites for TNP. The MOF can detect the presence of TNP in water at a concentration as low as 0.4 ppm with a response time of a few seconds. In addition, both excitation and emission wavelengths of the MOF are in the visible region. The high selectivity was observed even in the presence of competing nitro analytes in the aqueous phase. The quenching constant for TNP was found to be 5.8 * 10(4) M(-1) which is 23 times higher than that for TNT and for RDX, demonstrating superior and selective quenching ability. This unprecedented selectivity is ascribed to electron-transfer and energy-transfer mechanisms as well as electrostatic interactions between TNP and the MOF. An MOF-coated paper strip that we prepared demonstrated fast and selective response to TNP in water, which represents a first step towards a practical application. PMID- 25797880 TI - Long-term observation of lateral medullary infarction due to vertebral artery dissection assessed with multimodal neuroimaging. AB - A 33-year-old man presented with a lateral medullary infarction, vertigo, and nausea. At the time of hospital admission, he had Wallenberg syndrome. Although initial magnetic resonance imaging showed no abnormalities, subsequent diffusion weighted magnetic resonance imaging showed a high-intensity area in the right lateral medulla oblongata. The right vertebral artery was shown to be dilated on basi-parallel anatomical scanning but to be stenosed on magnetic resonance angiography (MRA). Cerebral angiography 7 days after onset showed the "pearl and string sign" in the right vertebral artery. Follow-up MRA showed gradual improvement of the stenosis in the right vertebral artery. Multiple neuroimaging studies, such as MRA, basi-parallel anatomical scanning, 3-dimensional computed tomographic angiography, and cerebral angiography, should be performed soon after onset in suspected cases of cerebral artery dissection. In addition, serial imaging examinations increase diagnostic accuracy, and the medical history and neurological examination are important. PMID- 25797882 TI - Physiotherapy in the prevention of falls in older people. AB - [Sherrington C, Tiedemann A (2015) Physiotherapy in the prevention of falls in older people.Journal of Physiotherapy61: 54-60]. PMID- 25797883 TI - The NADPH oxidase NOX5 protects against apoptosis in ALK-positive anaplastic large-cell lymphoma cell lines. AB - Reactive oxygen species (ROS) are key modulators of apoptosis and carcinogenesis. One of the important sources of ROS is NADPH oxidases (NOXs). The isoform NOX5 is highly expressed in lymphoid tissues, but it has not been detected in any common Hodgkin or non-Hodgkin lymphoma cell lines. In diverse, nonlymphoid malignant cells NOX5 exerts an antiapoptotic effect. Apoptosis suppression is the hallmark feature of a rare type of lymphoma, termed anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and a major factor in the therapy resistance and relapse of ALK(+) ALCL tumors. We applied RT-PCR and Western blot analysis to detect NOX5 expression in three ALK(+) ALCL cell lines (Karpas-299, SR-786, SUP-M2). We investigated the role of NOX5 in apoptosis by small interfering RNA (siRNA)-mediated gene silencing and chemical inhibition of NOX5 using FACS analysis and examining caspase 3 cleavage in Karpas-299 cells. We used immunohistochemistry to detect NOX5 in ALK(+) ALCL pediatric tumors. NOX5 mRNA was uniquely detected in ALK(+) ALCL cells, whereas cell lines of other lymphoma classes were devoid of NOX5. Transfection of NOX5-specific siRNA and chemical inhibition of NOX5 abrogated calcium-induced superoxide production and increased caspase 3-mediated apoptosis in Karpas-299 cells. Immunohistochemistry revealed focal NOX5 reactivity in pediatric ALK(+) ALCL tumor cells. These results indicate that NOX5-derived ROS contribute to apoptosis blockage in ALK(+) ALCL cell lines and suggest NOX5 as a potential pharmaceutical target to enhance apoptosis and thus to suppress tumor progression and prevent relapse in pediatric ALK(+) ALCL patients that resist classical therapeutic approaches. PMID- 25797884 TI - Presence and abundance of non-native plant species associated with recent energy development in the Williston Basin. AB - The Williston Basin, located in the Northern Great Plains, is experiencing rapid energy development with North Dakota and Montana being the epicenter of current and projected development in the USA. The average single-bore well pad is 5 acres with an estimated 58,485 wells in North Dakota alone. This landscape-level disturbance may provide a pathway for the establishment of non-native plants. To evaluate potential influences of energy development on the presence and abundance of non-native species, vegetation surveys were conducted at 30 oil well sites (14 ten-year-old and 16 five-year-old wells) and 14 control sites in native prairie environments across the Williston Basin. Non-native species richness and cover were recorded in four quadrats, located at equal distances, along four transects for a total of 16 quadrats per site. Non-natives were recorded at all 44 sites and ranged from 5 to 13 species, 7 to 15 species, and 2 to 8 species at the 10 year, 5-year, and control sites, respectively. Respective non-native cover ranged from 1 to 69, 16 to 76, and 2 to 82%. Total, forb, and graminoid non-native species richness and non-native forb cover were significantly greater at oil well sites compared to control sites. At oil well sites, non-native species richness and forb cover were significantly greater adjacent to the well pads and decreased with distance to values similar to control sites. Finally, non-native species whose presence and/or abundance were significantly greater at oil well sites relative to control sites were identified to aid management efforts. PMID- 25797885 TI - Reduction of nutrients, microbes, and personal care products in domestic wastewater by a benchtop electrocoagulation unit. AB - To preserve environmental and human health, improved treatment processes are needed to reduce nutrients, microbes, and emerging chemical contaminants from domestic wastewater prior to discharge into the environment. Electrocoagulation (EC) treatment is increasingly used to treat industrial wastewater; however, this technology has not yet been thoroughly assessed for its potential to reduce concentrations of nutrients, a variety of microbial surrogates, and personal care products found in domestic wastewater. This investigation's objective was to determine the efficiency of a benchtop EC unit with aluminum sacrificial electrodes to reduce concentrations of the aforementioned biological and chemical pollutants from raw and tertiary-treated domestic wastewater. EC treatment resulted in significant reductions (p < 0.05, alpha = 0.05) in phosphate, all microbial surrogates, and several personal care products from raw and tertiary treated domestic wastewater. When wastewater was augmented with microbial surrogates representing bacterial, viral, and protozoan pathogens to measure the extent of reduction, EC treatment resulted in up to 7-log10 reduction of microbial surrogates. Future pilot and full-scale investigations are needed to optimize EC treatment for the following: reducing nitrogen species, personal care products, and energy consumption; elucidating the mechanisms behind microbial reductions; and performing life cycle analyses to determine the appropriateness of implementation. PMID- 25797886 TI - Ba termination of Ge(001) studied with STM. AB - We use controlled annealing to tune the interfacial properties of a sub-monolayer and monolayer coverages of Ba atoms deposited on Ge(001), enabling the generation of either of two fundamentally distinct interfacial phases, as revealed by scanning tunneling microscopy. Firstly we identify the two key structural phases associated with this adsorption system, namely on-top adsorption and surface alloy formation, by performing a deposition and annealing experiment at a coverage low enough (~0.15 ML) that isolated Ba-related features can be individually resolved. Subsequently we investigate the monolayer coverage case, of interest for passivation schemes of future Ge based devices, for which we find that the thermal evaporation of Ba onto a Ge(001) surface at room temperature results in on-top adsorption. This separation (lack of intermixing) between Ba and Ge layers is retained through successive annealing steps to temperatures of 470, 570, 670 and 770 K although a gradual ordering of the Ba layer is observed at 570 K and above, accompanied by a decrease in Ba layer density. Annealing above 770 K produces the 2D surface alloy phase accompanied by strain relief through monolayer height trench formation. An annealing temperature of 1070 K sees a further change in surface morphology but retention of the 2D surface alloy characteristic. These results are discussed in view of their possible implications for future semiconductor integrated circuit technology. PMID- 25797887 TI - The interdialytic weight gain: a simple marker of left ventricular hypertrophy in children on chronic haemodialysis. AB - Despite multiple advances in haemodialysis (HD) technology over the years, the morbidity and mortality of HD patients remain unacceptably high. Cardiovascular disease is the most common cause of death, and left ventricular hypertrophy (LVH), seen in two-thirds of children on dialysis, is a significant contributor. The importance of volume control is increasingly recognized by nephrologists and now considered to be as important as urea kinetics, both in the day-to-day management and the long-term outcome of dialysis patients. The results published by Paglialonga et al. ( 10.1007/s00467-014-3005-2 ) in this issue of Pediatric Nephrology clearly demonstrate that there is a significant correlation between interdialytic weight gain (IDWG) and LVH in oligoanuric children on chronic HD and that children with an IDWG of >4 % are at high risk of LVH. One common practice to achieve euvolaemia is to prescribe very high ultrafiltration rates. However, both volume overload and aggressive fluid removal can induce circulatory stress and multi-organ injury. In adults, ultrafiltration rates of >1.24 % body weight per hour, even if well tolerated, are associated with a significant increase in mortality. Nephrologists should be aware of the risk of a high ultrafiltration rate, especially if tolerance is obtained by a positive dialysate to-plasma sodium gradient. Haemodiafiltration, which allows for higher ultrafiltration rates with greater intradialytic haemodynamic stability, or more frequent and longer dialysis sessions allow for safe and effective fluid removal. PMID- 25797888 TI - Interactions between antiepileptic drugs and hormones. AB - Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation. PMID- 25797889 TI - Intrauterine growth retardation in foetuses of women with epilepsy. AB - PURPOSE: Various factors may affect intrauterine foetal growth, amongst which conditions such as epilepsy and the use of anti-epileptic drugs (AED) may play a role. This study investigated intrauterine growth of foetuses in women with epilepsy, as compared with controls, and explored whether intrauterine growth was affected by prenatal exposure to AED. METHOD: Data were obtained from prospectively registered data regarding pregnancy and prenatal and perinatal factors in women in Oppland County in Norway. The final analysis included information from 166 mothers with epilepsy and 287 children. The control group consisted of 40,553 pregnancies in women without epilepsy registered in the same database. RESULTS: There was a significantly higher risk of the ponderal index being below the 10th percentile and infants being small for gestational age (SGA) in the epilepsy group; exposure to AED increased the risk. The frequency of SGA and low ponderal index was highest in Lamotrigine exposed infants. In the AED group, head circumference was significantly smaller among Carbamazepine exposed. CONCLUSION: Impaired intrauterine growth of foetuses in women with epilepsy was identified. The frequency of SGA and low ponderal index was highest in Lamotrigine exposed infants. The epilepsy group had a higher risk profile for having smaller babies, in being younger at age, lower in body weight and more frequent smokers. However despite these differences, the effects of epilepsy and AED exposure were significant. The ponderal index may be a useful supplement to more established measures assessing intrauterine growth in epilepsy. PMID- 25797890 TI - Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome. AB - Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ T-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5 year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach. PMID- 25797891 TI - Immunoglobulin A nephropathy: current progress and future directions. AB - Immunoglobulin A (IgA) nephropathy is the most prevalent form of primary glomerulonephritis that often leads to end-stage kidney failure, thereby representing a major health challenge worldwide. Tremendous effort has been dedicated to the diagnosis, monitoring, and treatment of the disease, and the past several years have witnessed exciting advances that have enriched our understanding of the biology, etiology, and pathology of IgA nephropathy. The disease is characterized by predominant deposition of IgA immune complexes that progressively causes activation of mesangial cells, glomerular inflammation, and ultimately renal injury. Multiple recent independent high-throughput studies in cohorts have identified key susceptibility alleles, such as the major histocompatibility complex loci that are significantly associated with the risk of disease occurrence. Notably, a fraction of these risk loci encode proteins that participate in immune defense against mucosal pathogens, particularly intestinal nematodes, indicating a linkage between IgA-mediated antihelminth immunity and the pathogenesis of IgA nephropathy. The emerging "omics" technology also allows for systemic analysis of urinary and serum samples as a noninvasive procedure for diagnosis and prognosis, as demonstrated by several studies implicating the proteomic signature and microRNA profile as promising diagnostic and prognostic parameters. In the clinic, the current treatment protocol relies on suppression of the renin-angiotensin system to control blood pressure and proteinuria. This review scrutinizes and summarizes recent relevant findings that aim to translate researchers' benchside knowledge of disease initiation and development into patients' bedside diagnosis and therapy. PMID- 25797892 TI - Does imitation act as an oxytocin nebulizer in autism spectrum disorder? PMID- 25797893 TI - Scanning electrochemical cell microscopy platform for ultrasensitive photoelectrochemical imaging. AB - The development of techniques for nanoscale structure-activity correlations is of major importance for the fundamental understanding and rational design of (photo)electrocatalysts. However, the low conversion efficiency of characteristic materials generates tiny photoelectrochemical currents at the submicrometer to nanoscale, in the fA range, which are challenging to detect and measure accurately. Here, we report the coupling of scanning electrochemical cell microscopy (SECCM) with photoillumination, to create a submicrometer spatial resolution cell that opens up high resolution structure-(photo)activity measurements. We demonstrate the capabilities of the technique as a tool for: (i) high spatial resolution (photo)activity mapping using an ionic liquid electrolyte at a thin film of TiO2 aggregates, commonly used as a photoanode in dye sensitized solar cells (DSSCs) and (ii) in situ (photo)activity measurements of an electropolymerized conjugated polymer on a transparent Au substrate in a controlled atmospheric environment. Quantitative data, including localized (photo)electrochemical transients and external quantum efficiency (EQE), are extracted, and prospects for further technique development and enhancement are outlined. PMID- 25797894 TI - Anti-cytomegalovirus antibody levels are associated with carotid atherosclerosis and inflammatory cytokine production in elderly Koreans. AB - BACKGROUND: Recent studies have implicated human cytomegalovirus (HCMV) infection as a possible etiological factor in cardiovascular disease. We assessed whether anti-HCMV antibody levels are associated with carotid atherosclerosis and inflammatory cytokine production in elderly Koreans. METHODS: Participants (age, >=65 years) were prospectively enrolled from September 2012 to July 2013 at a 2000-bed university hospital. During the study period, 71 participants (29 males) were prospectively enrolled, and thirty-five (49.3%) of these individuals were in the group designated as high intima-media thickness (IMT). RESULTS: Multivariate logistic regression analysis revealed three independent risk factors of high IMT: higher levels of anti-HCMV antibody (odds ratio [OR] 1.04, p=0.003), Framingham score (OR 1.14, p=0.018), and levels of IL-1beta (OR 2.96, p=0.013). Anti-HCMV antibody levels had a significantly positive correlation with max-IMT (r=0.523, p<0.001), free T4 levels (r=0.315, p=0.021), and Log(TNF-alpha) (r=0.562, p<0.001) in multivariate correlation analysis. CONCLUSIONS: These findings may provide insight into the role of HCMV in the pathogenesis of atherosclerosis and chronic inflammation in elderly individuals. PMID- 25797895 TI - L-FABP: A novel biomarker of kidney disease. AB - Human liver-type fatty acid-binding protein (hL-FABP), which is found in both the normal and the diseased human kidney, has been observed to bind free fatty acids. Recently, the predictive and prognostic value of L-FABP in kidney diseases has attracted considerable attention. Numerous studies have demonstrated that L-FABP is a promising biomarker of several kidney diseases, and it has also been shown to attenuate renal injury. We performed a literature review regarding the ability of L-FABP to identify patients at risk of developing kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD) and to protect the kidneys in the course of kidney disease. PMID- 25797896 TI - Role of glycated hemoglobin in the screening and diagnosis of posttransplantation diabetes mellitus after renal transplantation: A diagnostic accuracy study. AB - BACKGROUND: The role of glycated hemoglobin (A1C) in the screening and diagnosis of posttransplantation diabetes mellitus (PTDM) is still not entirely understood. We evaluated the use of A1C test in renal transplant recipients at four months after transplantation. METHODS: A total of 122 out of 274 patients without previous diabetes that underwent kidney transplantation were enrolled. ROC curve was used to analyze the performance of A1C to diagnose PTDM considering OGTT as the reference standard. RESULTS: OGTT identified 32 (26.2%) patients with PTDM, whereas A1C>=6.5% (48 mmol/mol) identified only 16 patients. A1C showed moderate accuracy to detect PTDM in the ROC curve [AUC 0.832 (95% CI 0.740-0.924, p<0.001)]. A1C of 5.8% (40 mmol/mol) was the equilibrium point (sensitivity 75% and specificity 72.2%) and A1C>=6.2% (44 mmol/mol) showed high specificity of 93.3%. CONCLUSIONS: A1C>=6.5% (48 mmol/mol) is not enough to be used alone in the diagnosis of PTDM. The combined use of A1C cut-off points of <=5.8% (40 mmol/mol) and >=6.2% (44 mmol/mol) would reduce the number of OGTT by 85%. The use of an algorithm with A1C test in combination with FPG and/or 2h-PG proved to be the most efficient strategy to diagnose or rule out PTDM. PMID- 25797897 TI - An efficient screening method for simultaneous detection of recurrent copy number variants associated with psychiatric disorders. AB - Several recurrent copy number variants (CNVs) increasing risk to neuropsychiatric diseases have been identified in recent years. They show variable clinical expressivity, being associated with different disorders, and incomplete penetrance. However, due to its very low frequency, the full variety of clinical outcomes associated with each one of these CNVs is unknown. Current methods for detection of CNVs are labor intensive, expensive or not suitable for high throughput analysis. Quantitative interspecies competitive PCR linked to variant minisequencing and detection by mass-spectrometry may overcome these limitations. Here, we present two multiplex assays based on this method to screen for eleven psychiatric risk CNVs, such as 1q21, 16p11.2, 3q29, or 16p13.11 regions, among others. The assays were tested in our collection of 514 schizophrenia patients. Results were compared with MLPA at two CNVs. Additional positive results were confirmed by exome sequencing. A total of fourteen patients were CNV carriers. The method presents high sensitivity and specificity, showing its utility as a cheap, accurate, high throughput screening tool for recurrent CNVs. The method may be very useful for management of psychiatric patients as well as screening of different collections of samples to better identify the full spectrum of clinical variability. PMID- 25797898 TI - Rapid single nucleotide polymorphism based method for hematopoietic chimerism analysis and monitoring using high-speed droplet allele-specific PCR and allele specific quantitative PCR. AB - BACKGROUND: Chimerism analysis is important for the evaluation of engraftment and predicting relapse following hematopoietic stem cell transplantation (HSCT). We developed a chimerism analysis for single nucleotide polymorphisms (SNPs), including rapid screening of the discriminable donor/recipient alleles using droplet allele-specific PCR (droplet-AS-PCR) pre-HSCT and quantitation of recipient DNA using AS-quantitative PCR (AS-qPCR) following HSCT. METHODS: SNP genotyping of 20 donor/recipient pairs via droplet-AS-PCR and the evaluation of the informativity of 5 SNP markers for chimerism analysis were performed. Samples from six follow-up patients were analyzed to assess the chimerism via AS-qPCR. These results were compared with that determined by short tandem repeat PCR (STR PCR). RESULTS: Droplet-AS-PCR could determine genotypes within 8min. The total informativity using all 5 loci was 95% (19/20). AS-qPCR provided the percentage of recipient DNA in all 6 follow-up patients without influence of the stutter peak or the amplification efficacy, which affected the STR-PCR results. CONCLUSION: The droplet-AS-PCR had an advantage over STR-PCR in terms of rapidity and simplicity for screening before HSCT. Furthermore, AS-qPCR had better accuracy than STR-PCR for quantification of recipient DNA following HSCT. The present chimerism assay compensates for the disadvantages of STR-PCR and is readily performable in clinical laboratories. PMID- 25797899 TI - Polymer-immobilized ready-to-use recombinant yeast assays for the detection of endocrine disruptive compounds. AB - Recombinant yeast assays (RYAs) constitute a suitable tool for the environmental monitoring of compounds with endocrine disrupting activities, notably estrogenicity and androgenicity. Conventional procedures require yeast reconstitution from frozen stock, which usually takes several days and demands additional equipment. With the aim of applying such assays to field studies and making them more accessible to less well-equipped laboratories, we have optimized RYA by the immobilization of Saccharomyces cerevisiae cells in three different polymer matrices - gelatin, Bacto agar, and Yeast Extract Peptone Dextrose agar - to obtain a ready-to-use version for the fast assessment of estrogenic and androgenic potencies of compounds and environmental samples. Among the three matrices, gelatin showed the best results for both testosterone (androgen receptor yeast strain; AR-RYA) and 17beta-estradiol (estrogen receptor yeast strain; ER-RYA). AR-RYA was characterized by a lowest observed effect concentration (LOEC), EC50 and induction factor (IF) of 1nM, 2.2nM and 51, respectively. The values characterizing ER-RYA were 0.4nM, 1.8nM, and 63, respectively. Gelatin immobilization retained yeast viability and sensitivity for more than 90d of storage at 4 degrees C. The use of the immobilized yeast reduced the assay duration to only 3h without necessity of sterile conditions. Because immobilized RYA can be performed either in multiwell microplates or glass tubes, it allows multiple samples to be tested at once, and easy adaptation to existing portable devices for direct in-field applications. PMID- 25797900 TI - Efficacy and safety of rivaroxaban in real-life patients with atrial fibrillation. AB - Rivaroxaban is a once-daily oral anticoagulant currently marketed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This indication is largely based on the results of the ROCKET-AF trial. Although these results are robust, studies performed in clinical practice are necessary to confirm these data in real-life patients. These studies have shown rates of stroke and bleeding similar to that found in ROCKET-AF. As an anticoagulant, attention should be paid to making a correct prescription of rivaroxaban, particularly in fragile patients, to reduce the risk of bleeding. In addition, a number of studies have shown that rivaroxaban is cost-effective in clinical practice. Moreover, rivaroxaban is a good alternative to warfarin in patients undergoing elective cardioversion or atrial fibrillation ablation. PMID- 25797901 TI - SALTIRE-RAAVE: targeting calcific aortic valve disease LDL-density-radius theory. AB - SALTIRE and RAAVE were the first two studies to evaluate the use of statin therapy for impeding calcific aortic valve disease (CAVD). This review presents the findings of low-density lipoprotein (LDL)-density-radius theory as tested using the combined results from the SALTIRE and RAAVE studies. Patients who received statin therapy had a greater degree of LDL cholesterol lowering, seen as the % change in LDL (47 vs 2%, p = 0.012), which in itself was significantly associated with a lesser change in aortic valve area (AVA; p < 0.001 and R(2) = 0.27). The percent change in the AVA for the treated patients was 5% and 15% for the nontreated patients (p = 0.579 and R(2) = 0.03). In summary, these published findings suggest that when applying the LDL-density-radius theory, which combines the cellular biology and the hemodynamics as defined by the continuity equation for AVA, there may be a role for lipid-lowering therapy in contemporary patients with calcific aortic valve disease (CAVD). PMID- 25797902 TI - Current diagnosis and management of cardiac myxomas. AB - Cardiac myxoma is the most common cardiac neoplasm. In the majority of cases, it is isolated (non-syndromic) and located in the left atrium. In up to 10% cases, it is seen in syndromic association with the Carney complex where it is encountered in younger patients, with atypical and multiple locations, such as the right atrium or ventricles, and carries a high risk of recurrence. Imaging is pivotal in the diagnosis, management guidance and surveillance. Surgical excision is the established definitive treatment. Further research should address management strategies in incidentally discovered small myxomas in asymptomatic patients and the role of genetic testing and screening in syndromic myxomas. PMID- 25797903 TI - 2015 update on the diagnosis and management of neoplastic pericardial disease. AB - The best approach in diagnosis and treatment of neoplastic pericardial disease has not been defined yet. The authors report the most recent literature about the new diagnostic techniques that are useful to improve the diagnosis. The literature about the therapeutic options is critically reviewed, in order to give suggestions of use to the clinical practice. Pericardial effusion may require urgent drainage; the solid component, however, becomes predominant in some cases. Neoplastic pericardial disease should be assessed following oncologic criteria evaluation of the neoplastic burden; outcome classified as complete or partial response, stable or progressive disease and - in cases with progression - event free survival. Systemic chemotherapy may be effective in lymphomas and possibly in breast carcinomas. Intrapericardial chemotherapy with systemic chemotherapy is the treatment of choice in lung cancer. Pericardial window with systemic chemotherapy is also effective in preventing the accumulation of large amount of fluid. PMID- 25797904 TI - Laparoscopic spleen-preserving distal pancreatectomy for IPMN (with video). PMID- 25797905 TI - New methodologies for patients rehabilitation. AB - OBJECTIVE: The present editorial is part of the focus theme of Methods of Information in Medicine titled "New Methodologies for Patients Rehabilitation", with a specific focus on technologies and human factors related to the use of Information and Communication Technologies (ICT) for improving patient rehabilitation. METHODS: The focus theme explores different dimensions of empowerment methodologies for disabled people in terms of rehabilitation and health care, and to explores the extent to which ICT is a useful tool in this process. RESULTS: The focus theme lists a set of research papers that present different ways of using ICT to develop advanced systems that help disabled people in their rehabilitation process. PMID- 25797906 TI - Healthcare interventions for depression in low socioeconomic status populations: A systematic review and meta-analysis. AB - The prevalence and impact of depressive disorders in developed countries are associated with certain population characteristics, including socioeconomic status. The aim of this systematic review and meta-analysis was to identify, characterize and analyze the short- and long-term effectiveness of healthcare interventions for depressive disorders in low socioeconomic status populations. The main biomedical databases were searched and fifteen articles assessing seventeen interventions were included in the review. Most interventions were implemented in the US (n=11) and culturally adapted (n=11). We conducted two meta analyses for assessing both the short- (n=11) and long-term effectiveness (n=12) of interventions. There was a statistically significant reduction in overall depressive symptoms (-0.58, 95% CI [-0.74, -0.41]) at short-term (up to three months after the intervention), especially for combined and psychotherapeutic interventions. The overall effect slightly decreased at long-term (-0.42, 95% CI [-0.63, -0.21]). Those interventions including culturally specific training for providers and booster sessions seemed to be more effective in reducing depressive disorders at short and long term, respectively. In conclusion, healthcare interventions are effective in decreasing clinically significant depressive disorders in low socioeconomic status populations. Future interventions should take into account the key characteristics identified in this review. PMID- 25797908 TI - Maxillary sinus bone augmentation techniques. AB - Maxillary sinus expansion and atrophy can be difficult to overcome for patients who require functional dental prostheses. One solution for this problem is sinus augmentation and implant placement. Patients are evaluated and diagnosis is ascertained, leading to development of a treatment plan and surgical strategy. The surgeon decides on a surgical technique and grafting material, based on ultimate success, stability, and function as they relate to the goals. Complications can occur during an operation or during the postoperative healing phase. Dealing with these complications can be challenging; however, solving these problems positively affects the overall outcome and success. PMID- 25797909 TI - Lipopeptides: from self-assembly to bioactivity. AB - This Feature Article discusses several classes of lipopeptide with important biomedical applications as antimicrobial and antifungal agents, in immune therapies and in personal care applications among others. Two main classes of lipopeptide are considered: (i) bacterially-expressed lipopeptides with a cyclic peptide headgroup and (ii) linear lipopeptides (with one or more lipid chains) based on bio-derived and bio-inspired amino acid sequences with current clinical applications. The applications are briefly summarized, and the biophysical characterization of the molecules is reviewed, with a particular focus on self assembly. For several of these types of biomolecule, the formation of micelles above a critical micelle concentration has been observed while others form bilayer structures, depending on conditions of pH and temperature. As yet, there are few studies on the possible relationship between self-assembly into structures such as micelles and bioactivity of this class of molecule although this is likely to attract further attention. PMID- 25797910 TI - New synthesis and biological evaluation of benzothiazole derivates as antifungal agents. AB - In search of new antifungal agrochemicals that could replace commercially available, aryl-2-mercaptobenzothiazoles were synthesized. They were prepared by two methodologies, using both photostimulated reaction and microwave assisted reaction. These reactions took place without the use of metallic catalyst by a one-pot procedure with excellent yields (70-98%). Synthesized compounds were evaluated for fungal growth inhibition against Botrytis cinerea. Most of the compounds have an excellent antifungal activity, and three of these showed a superior inhibitory effect to commercial fungicide Triadimefon. IC50 values observed for 2-(phenylthio)benzothiazole, 2-(2-chlorophenylthio)benzothiazole, and 2-(3-chlorophenyl thio)benzothiazole were 0.75, 0.69, and 0.65 MUg mL(-1), respectively. PMID- 25797911 TI - Syntheses of sugar poly(orthoesters) through reverse anomeric effect. AB - High molecular weight sugar poly(orthoesters) were synthesized through reverse anomeric effect (RAE). We demonstrated that when RAE-enabled promoters, such as 4 (dimethylamino)pyridine (DMAP), triphenylphosphine (TPP) or imidazole, were employed, efficient polymerizations were achieved, giving sugar poly(orthoesters) with molecular weights up to 18 kDa. PMID- 25797907 TI - Human mesenchymal stem cells - current trends and future prospective. AB - Stem cells are cells specialized cell, capable of renewing themselves through cell division and can differentiate into multi-lineage cells. These cells are categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes). MSCs express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 and lack the expression of CD14, CD34, CD45 and HLA (human leucocyte antigen)-DR. hMSCs for the first time were reported in the bone marrow and till now they have been isolated from various tissues, including adipose tissue, amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly which harbours potential MSCs. hMSCs have been cultured long-term in specific media without any severe abnormalities. Furthermore, MSCs have immunomodulatory features, secrete cytokines and immune-receptors which regulate the microenvironment in the host tissue. Multilineage potential, immunomodulation and secretion of anti inflammatory molecules makes MSCs an effective tool in the treatment of chronic diseases. In the present review, we have highlighted recent research findings in the area of hMSCs sources, expression of cell surface markers, long-term in vitro culturing, in vitro differentiation potential, immunomodulatory features, its homing capacity, banking and cryopreservation, its application in the treatment of chronic diseases and its use in clinical trials. PMID- 25797912 TI - Scleroderma renal crisis as an initial presentation of systemic sclerosis: a case report and review of the literature. AB - Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) that is characterised by new-onset malignant hypertension and progressive acute renal failure, often with associated microangiopathic haemolytic anaemia and thrombocytopenia. SRC was at one time almost uniformly fatal, with death often occurring within a few weeks. With the development of angiotensin-converting-enzyme inhibitors (ACE-I), survival has improved dramatically, but death rates still remain unacceptably high. About 20% of SRC cases occur prior to making a diagnosis of SSc and, in some cases, there is no evidence of skin sclerosis at the time that SRC develops. In this report, we present a case in which a patient developed SRC prior to being diagnosed with scleroderma. Additionally, we review the pathogenesis, presenting signs and symptoms, management and prognosis of SRC. PMID- 25797913 TI - Children's safety in community context. PMID- 25797914 TI - Modeling the structure and thermodynamics of ferrocenium-based ionic liquids. AB - A new force-field for the description of ferrocenium-based ionic liquids is reported. The proposed model was validated by confronting Molecular Dynamics simulations results with available experimental data-enthalpy of fusion, crystalline structure and liquid density-for a series of 1-alkyl-2,3,4,5,6,7,8,9 octamethylferrocenium bis(trifluoromethylsulfonyl)imide ionic liquids, [CnFc][NTf2] (3 <= n <= 10). The model is able to reproduce the densities and enthalpies of fusion with deviations smaller than 2.6% and 4.8 kJ mol(-1), respectively. The MD simulation trajectories were also used to compute relevant structural information for the different [CnFc][NTf2] ionic liquids. The results show that, unlike other ILs, the alkyl side chains present in the cations are able to interact directly with the ferrocenium core of other ions. Even the ferrocenium charged cores (with relatively mild charge densities) are able to form small contact aggregates. This causes the partial rupture of the polar network and precludes the formation of extended nano-segregated polar-nonpolar domains normally observed in other ionic liquids. PMID- 25797915 TI - Relationship between endothelial dysfunction and osteoprotegerin, vitamin D, and bone mineral density in patients with rheumatoid arthritis. AB - OBJECTIVES: We aimed to investigate whether the abnormalities in bone mineral density (BMD) that occur in patients with rheumatoid arthritis (RA) are associated with the presence of endothelial dysfunction. METHODS: Cross-sectional study encompassing 216 subjects (111 patients with RA and 105 age- and sex matched controls) without history of cardiovascular disease. Endothelial function was determined by brachial artery flow-mediated dilatation (FMD) and BMD by dual x-ray absorptiometry (DXA) measurements. Plasma vitamin D and osteoprotegerin serum (OPG) levels were assessed in patients and controls. Multiple regression analysis was performed to study the relationship between BMD with endothelial function, taking into account vitamin D and OPG levels. RESULTS: After adjusting for traditional cardiovascular risk factors, vitamin D and OPG levels, BMD emerged as an independent factor associated with lower FMD values in controls, but not in patients with RA. Although OPG levels were inversely associated with FMD values in both RA patients and controls after adjusting for BMD, vitamin D showed this relationship only in the controls. CONCLUSIONS: Whilst OPG is associated with endothelial function in RA patients and controls, vitamin D levels and BMD are related to endothelial function in controls but not in patients with RA. PMID- 25797916 TI - The 55S mammalian mitochondrial ribosome and its tRNA-exit region. AB - Mitochondria carry their own genetic material and gene-expression machinery, including ribosomes, which are responsible for synthesizing polypeptides that form essential components of the complexes involved in oxidative phosphorylation (or ATP generation) for the eukaryotic cell. Mitochondrial ribosomes (mitoribosomes) are quite divergent from cytoplasmic ribosomes in both composition and structure even as their main functional cores, such as the mRNA decoding and peptidyl transferase sites, are highly conserved. Remarkable progress has been made recently towards understanding the structure of mitoribosomes, by obtaining high-resolution cryo-electron microscopic (cryo-EM) maps. These studies confirm previous structural findings that had revealed that a significant reduction in size of ribosomal RNAs has caused topological changes in some of the functionally relevant regions, including the transfer RNA (tRNA) binding sites and the nascent polypeptide-exit tunnel, within the structure of the mammalian mitoribosome. In addition, these studies provide unprecedented detailed views of the molecular architecture of those regions. In this review, we summarize the current state of knowledge of the structure of the mammalian mitoribosome and describe the molecular environment of its tRNA-exit region. PMID- 25797917 TI - Alcohol-induced histone H3K9 hyperacetylation and cardiac hypertrophy are reversed by a histone acetylases inhibitor anacardic acid in developing murine hearts. AB - BACKGROUND: The expression of cardiac genes is precisely regulated, and any perturbation may cause developmental defects. In a previous study, we demonstrated that alcohol consumption during pregnancy could lead to uncontrolled expressions of cardiac genes and eventually result in cardiac dysplasia. However, the underlying mechanisms remain unclear. In the present study, we have investigated the alcohol-induced cardiac hypertrophy and its potential mechanisms. Furthermore, the protective effect of anacardic acid against the alcohol-induced cardiac hypertrophy has been explored in experimental mice. METHODS AND RESULTS: C57BL/6 pregnant mice were gavaged with 56% ethanol or saline and the hearts of their fetus were collected for analysis. Binding of p300, CBP, PCAF, SRC1, except GCN5, were increased to the NKX2.5 promoter in fetal mouse hearts exposed to alcohol. Increased acetylation of H3K9 and increased mRNA expression of NKX2.5, beta-MHC and Cx43 were observed in the same samples. Treatment with a pan-acetylase inhibitor, anacardic acid, reduced the binding affinity of p300 and PCAF to the NKX2.5, beta-MHC, Cx43 promoters and attenuated H3K9 hyperacetylation. Interestingly, anacardic acid down-regulated over-expression of these cardiac genes induced by alcohol and ultimately attenuated ethanol-induced cardiac hypertrophy in fetal mice. CONCLUSIONS: Our results indicate that alcohol exposure during pregnancy could lead to fetal cardiac hypertrophy. The over-expression of NKX2.5, beta-MHC, Cx43 mediated by p300 and PCAF may be critical mechanisms of alcohol-induced cardiac hypertrophy. Anacardic acid can down-regulate the over-expression of cardiac genes and reverse cardiac hypertrophy caused by alcohol treatment in pregnant mice, suggesting it could be a potential therapeutic agent for the treatment of cardiac hypertrophy. PMID- 25797919 TI - Bimanual coupling effects during arm immobilization and passive movements. AB - When humans simultaneously perform different movements with both hands, each limb movement interferes with the contralateral limb movement (bimanual coupling). Previous studies on both healthy volunteers and patients with central or peripheral nervous lesions suggested that such motor constraints are tightly linked to intentional motor programs, rather than to movement execution. Here, we aim to investigate this phenomenon, by using a circles-lines task in which, when subjects simultaneously draw lines with the right hand and circles with the left hand, both the trajectories tend to become ovals (bimanual coupling effect). In a first group, we immobilized the subjects' left arm with a cast and asked them to try to perform the bimanual task. In a second group, we passively moved the subjects' left arm and asked them to perform voluntary movements with their right arm only. If the bimanual coupling arises from motor intention and planning rather than spatial movements, we would expect different results in the two groups. In the Blocked group, where motor intentionality was required but movements in space were prevented by immobilization of the arm, a significant coupling effect (i.e., a significant increase of the ovalization index for the right hand lines) was found. On the contrary, in the Passive group, where movements in space were present but motor intentionality was not required, no significant coupling effect was observed. Our results confirmed, in healthy subjects, the central role of the intentional and predictive operations, already evidenced in pathological conditions, for the occurrence of bimanual coupling. PMID- 25797918 TI - Integrating clinical indexes into four-diagnostic information contributes to the Traditional Chinese Medicine (TCM) syndrome diagnosis of chronic hepatitis B. AB - Traditional Chinese Medicine (TCM) treatment has been commonly used to treat Chronic Hepatitis B (CHB) in Asian countries based on TCM syndrome diagnosis, also called "ZHENG". The syndrome is identified through the four-diagnostic methods, with certain degree of subjectivity and ambiguity from individual doctors. Normally those CHB patients also receive series of parameters from modern clinical examination, while they are routinely believed to be unrelated with the TCM syndrome diagnosis. In this study, we investigated whether these biomedical indexes in modern medicine could be beneficial to TCM syndrome diagnostics in an integrative way. Based on 634 patient samples from health controls and three subtypes of CHB syndromes, a two-view based hierarchical classification model was tested for TCM syndromes prediction based on totally 222 parameters integrated from both TCM practice and modern clinical tests. The results indicated that the performance of syndrome classification based on a proper integration of TCM and modern clinical indexes was significantly higher than those based on one view of parameters only. Furthermore, those indexes correlated with CHB syndrome diagnosis were successfully identified for CM indexes and biochemical indexes respectively, where potential associations between them were hinted to the MAPK signaling pathway. PMID- 25797920 TI - Multi-stimuli responsive Cu2S nanocrystals as trimodal imaging and synergistic chemo-photothermal therapy agents. AB - A size and shape tuned, multifunctional metal chalcogenide, Cu2S-based nanotheranostic agent is developed for trimodal imaging and multimodal therapeutics against brain cancer cells. This theranostic agent was highly efficient in optical, photoacoustic and X-ray contrast imaging systems. The folate targeted NIR-responsive photothermal ablation in synergism with the chemotherapeutic action of doxorubicin proved to be a rapid precision guided cancer-killing module. The multi-stimuli, i.e., pH-, thermo- and photo-responsive drug release behavior of the nanoconjugates opens up a wider corridor for on demand triggered drug administration. The simple synthesis protocol, combined with the multitudes of interesting features packed into a single nanoformulation, clearly demonstrates the competing role of this Cu2S nanosystem in future cancer treatment strategies. PMID- 25797921 TI - Identification of adenine modulating AMPK activation in NIH/3T3 cells by proteomic approach. AB - AMP-activated protein kinase (AMPK) is a metabolic master switch maintaining the energy homeostasis in cells and thought to modulate cellular response to stresses. Adenine as well as a pharmacological AMPK activator, 5-aminoimidazole-4 carboxamide ribonucleoside (AICAR), induced the phosphorylation of AMPK and acetyl-CoA carboxylase in NIH/3T3 cells. Administration of adenine or AICAR increased the expression and translocation of glucose transporter 4, enhanced the cellular glucose uptake, and elevated the intracellular ATP level. To better understand the proteomic changes in response to exogenous adenine treatment, we performed two-dimensional difference gel electrophoresis (2DE-DIGE) and grouped protein spots with similar intensities prior to MS analysis. These process allowed us to exclude these constant expressed proteins, reduce the coverage from abundant signals and increase the identification of middle/lower expressed proteins. Bioinformatics analysis on the proteomic alterations suggested that both of adenine and AICAR could induce up-regulation of a panel of proteins associated with glucose metabolism. We also found that adenine upregulated expression of the glycolytic enzyme, hexokinase 2, indicating a link between adenine and AMPK-mediated glycolysis. Taken together, by demonstrating the adenine-mediated proteome changes in NIH/3T3 cells, our study provides useful information for the characteristics of adenine-induced AMPK activation and development of efficient AMPK activator. BIOLOGICAL SIGNIFICANCE: AMPK is a fuel sensing enzyme that responds to a central role of energy homeostasis and contributes to the acceleration of insulin signaling. Recently, we have shown that exogenous adenine exerted anti-inflammatory effects through activation of AMPK, suggesting the treatment is a potent therapeutic strategy against hyperglycemia. Adenine had similar effects with 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) in modulating glucose uptake via AMPK mediated signaling. In this study, we performed a 2DE-DIGE/MS-based approach to investigate the mechanism of exogenous adenine in NIH/3T3 cells. Our results provide evidence of a novel role for adenine in AMPK-mediated signaling and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions. PMID- 25797922 TI - A survey of transposable element classification systems--a call for a fundamental update to meet the challenge of their diversity and complexity. AB - The increase of publicly available sequencing data has allowed for rapid progress in our understanding of genome composition. As new information becomes available we should constantly be updating and reanalyzing existing and newly acquired data. In this report we focus on transposable elements (TEs) which make up a significant portion of nearly all sequenced genomes. Our ability to accurately identify and classify these sequences is critical to understanding their impact on host genomes. At the same time, as we demonstrate in this report, problems with existing classification schemes have led to significant misunderstandings of the evolution of both TE sequences and their host genomes. In a pioneering publication Finnegan (1989) proposed classifying all TE sequences into two classes based on transposition mechanisms and structural features: the retrotransposons (class I) and the DNA transposons (class II). We have retraced how ideas regarding TE classification and annotation in both prokaryotic and eukaryotic scientific communities have changed over time. This has led us to observe that: (1) a number of TEs have convergent structural features and/or transposition mechanisms that have led to misleading conclusions regarding their classification, (2) the evolution of TEs is similar to that of viruses by having several unrelated origins, (3) there might be at least 8 classes and 12 orders of TEs including 10 novel orders. In an effort to address these classification issues we propose: (1) the outline of a universal TE classification, (2) a set of methods and classification rules that could be used by all scientific communities involved in the study of TEs, and (3) a 5-year schedule for the establishment of an International Committee for Taxonomy of Transposable Elements (ICTTE). PMID- 25797923 TI - Species tree phylogeny and biogeography of the Neotropical genus Pradosia (Sapotaceae, Chrysophylloideae). AB - Recent phylogenetic studies in Sapotaceae have demonstrated that many genera need to be redefined to better correspond to natural groups. The Neotropical genus Pradosia is believed to be monophyletic and includes 26 recognized species. Here we reconstruct the generic phylogeny by a species-tree approach using (*)BEAST, 21 recognized species (36 accessions), sequence data from three nuclear markers (ITS, ETS, and RPB2), a relaxed lognormal clock model, and a fossil calibration. We explore the evolution of five selected morphological characters, reconstruct the evolution of habitat (white-sand vs. clayish soils) preference, as well as space and time by using a recently developed continuous diffusion model in biogeography. We find Pradosia to be monophyletic in its current circumscription and to have originated in the Amazon basin at ~47.5Ma. Selected morphological characters are useful to readily distinguish three clades. Preferences to white sand and/or clay are somewhat important for the majority of species, but speciation has not been powered by habitat shifts. Pradosia brevipes is a relative young species (~1.3Ma) that has evolved a unique geoxylic life strategy within Pradosia and is restricted to savannahs. Molecular dating and phylogenetic pattern indicate that Pradosia reached the Brazilian Atlantic coast at least three times: at 34.4Ma (P. longipedicellata), at 11.7Ma (P. kuhlmannii), and at 3.9Ma (weakly supported node within the red-flowered clade). PMID- 25797924 TI - Evolutionary origin of Ceratonova shasta and phylogeny of the marine myxosporean lineage. AB - In order to clarify the phylogenetic relationships among the main marine myxosporean clades including newly established Ceratonova clade and scrutinizing their evolutionary origins, we performed large-scale phylogenetic analysis of all myxosporean species from the marine myxosporean lineage based on three gene analyses and statistical topology tests. Furthermore, we obtained new molecular data for Ceratonova shasta, C. gasterostea, eight Ceratomyxa species and one Myxodavisia species. We described five new species: Ceratomyxa ayami n. sp., C. leatherjacketi n. sp., C. synaphobranchi n. sp., C. verudaensis n. sp. and Myxodavisia bulani n. sp.; two of these formed a new, basal Ceratomyxa subclade. We identified that the Ceratomyxa clade is basal to all other marine myxosporean lineages, and Kudoa with Enteromyxum are the most recently branching clades. Topologies were least stable at the nodes connecting the marine urinary clade, the marine gall bladder clade and the Ceratonova clade. Bayesian inference analysis of SSU rDNA and the statistical tree topology tests suggested that Ceratonova is closely related to the Enteromyxum and Kudoa clades, which represent a large group of histozoic species. A close relationship between Ceratomyxa and Ceratonova was not supported, despite their similar myxospore morphologies. Overall, the site of sporulation in the vertebrate host is a more accurate predictor of phylogenetic relationships than the morphology of the myxospore. PMID- 25797925 TI - Sex in troubled waters: Widespread agricultural contaminant disrupts reproductive behaviour in fish. AB - Chemical pollution is a pervasive and insidious agent of environmental change. One class of chemical pollutant threatening ecosystems globally is the endocrine disrupting chemicals (EDCs). The capacity of EDCs to disrupt development and reproduction is well established, but their effects on behaviour have received far less attention. Here, we investigate the impact of a widespread androgenic EDC on reproductive behaviour in the guppy, Poecilia reticulata. We found that short-term exposure of male guppies to an environmentally relevant concentration of 17beta-trenbolone-a common environmental pollutant associated with livestock production-influenced the amount of male courtship and forced copulatory behaviour (sneaking) performed toward females, as well as the receptivity of females toward exposed males. Exposure to 17beta-trenbolone was also associated with greater male mass. However, no effect of female exposure to 17beta trenbolone was detected on female reproductive behaviour, indicating sex-specific vulnerability at this dosage. Our study is the first to show altered male reproductive behaviour following exposure to an environmentally realistic concentration of 17beta-trenbolone, demonstrating the possibility of widespread disruption of mating systems of aquatic organisms by common agricultural contaminants. PMID- 25797926 TI - Seed-induced growing various TiO2 nanostructures on g-C3N4 nanosheets with much enhanced photocatalytic activity under visible light. AB - In this study, we provide a seed-induced solvothermal method to grow various TiO2 nanostructures on the surfaces of g-C3N4, such as 0D nanoparticles, 1D nanowires 2D nanosheets and 3D mesoporous nanocrystals. We show that the "seeding" endows g C3N4 with anchoring sites toward the heterogeneous nucleation growth of TiO2, and the distribution of the loaded TiO2 can be controlled by tuning the amount of nucleation in the dispersion. Among synthesized nanostructures, seed-grown Meso TiO2/g-C3N4 hybrids exhibit the highest photocatalytic activity upon visible light irradiation using methyl orange and phenol as probe organics, which are about 2-4 times and 29-37 times as high as those of direct-grown Meso-TiO2/g-C3N4 without seeding and bare g-C3N4 for degradation of MO and phenol, respectively. The enhancement of photocatalysis can be ascribed to the adequate separation of photogenerated electrons at the heterojunction interfaces and dominant contribution of photoinduced holes mainly caused by the well-constructed nano- architectures. PMID- 25797927 TI - Investigation on efficient adsorption of cationic dyes on porous magnetic polyacrylamide microspheres. AB - We report here the preparation of porous magnetic polyacrylamide microspheres for efficient removal of cationic dyes by a simple polymerization-induced phase separation method. Characterizations by various techniques indicate that the microspheres show porous structures and magnetic properties. They can adsorb methylene blue with high efficiency, with adsorption capacity increasing from 263 to 1977 mg/g as the initial concentration increases from 5 to 300 mg/L. Complete removal of methylene blue can be obtained even at very low concentrations. The equilibrium data is well described by the Langmuir isotherm models, exhibiting a maximum adsorption capacity of 1990 mg/g. The adsorption capacity increases with increasing initial pH and reaches a maximum at pH 8, revealing an electrostatic interaction between the microspheres and the methylene blue molecules. The microspheres also show high adsorption capacities for neutral red and gentian violet of 1937 and 1850 mg/g, respectively, as well as high efficiency in adsorption of mixed-dye solutions. The dye-adsorbed magnetic polyacrylamide microspheres can be easily desorbed, and can be repeatedly used for at least 6 cycles without losing the adsorption capacity. The adsorption capacity and efficiency of the microspheres are much higher than those of reported adsorbents, which exhibits potential practical application in removing cationic dyes. PMID- 25797928 TI - Exploring the diameter and surface dependent conformational changes in carbon nanotube-protein corona and the related cytotoxicity. AB - In this work, we investigated and compared carbon nanotubes (CNTs) of different diameters regarding their interaction with bovine serum albumin (BSA) and their ability to alter protein structure. BSA was exposed to CNT solutions, and the effects were assessed by utilizing fluorescence spectroscopy, UV-vis absorption spectroscopy, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), bichinchoninic acid (BCA) and zeta-potential measurement assays. We demonstrate that CNT diameter and surface area play key roles in influencing the stability of adsorbed proteins. Results showed that the secondary and tertiary structural stability of BSA decreased upon adsorption onto CNTs, with greater decrease on smaller-diametered nanotubes. Besides, more protein was loaded onto CNTs with small diameter, reducing the cytotoxicity. This study, therefore, provides fundamental information for the influence of CNT diameter and surface on protein behavior, which may be helpful to understand toxic effects of CNTs and prove beneficial for developing novel biomedical devices and safe use of nanomaterials. PMID- 25797929 TI - Investigation of sodium silicate-derived gels as encapsulants for hazardous materials--the case of scorodite. AB - High content arsenic waste generated in the metallurgical industry can be converted into a synthetic mineral, scorodite, FeAsO4.2H2O, and deposited into a landfill site. Scorodite is most stable in weakly acidic to neutral pH range under oxic conditions. A novel way to enhance the range of stability for scorodite is to encapsulate it with an inert material. In this work, silicate gel is developed and investigated as a possible encapsulating material for scorodite. The initial method of gel formation in this study produced a silicate gel with high alkalinity (pH 10) that was incompatible with scorodite. A reverse titration method was developed producing a gel with optimum pH profile (5-6.5). This technique proved to have only marginal effect on scorodite stabilization prompting an investigation of different ageing techniques (drying; 22, 44 degrees C and hydrothermal treatment; 110, 160 degrees C) as a means of producing silica like coatings with better stabilization potential. Interestingly most of these measures proved counterproductive as aged scorogels showed a higher release of As than scorodite alone. Through surface-sensitive depth profile analysis (XPS), and molecular-sensitive analysis (Raman and FTIR mapping), it was discovered that the silicate engaged into an "ion-exchange" type reaction on the surface of scorodite by bonding to iron, hence the observed release of arsenic. Development of a hydrothermally-induced iron silicate layer may lead to an effective encapsulant. PMID- 25797930 TI - Reducing the cytotoxicity of inhalable engineered nanoparticles via in situ passivation with biocompatible materials. AB - The cytotoxicity of model welding nanoparticles was modulated through in situ passivation with soluble biocompatible materials. A passivation process consisting of a spark discharge particle generator coupled to a collison atomizer as a co-flow or counter-flow configuration was used to incorporate the model nanoparticles with chitosan. The tested model welding nanoparticles are inhaled and that A549 cells are a human lung epithelial cell line. Measurements of in vitro cytotoxicity in A549 cells revealed that the passivated nanoparticles had a lower cytotoxicity (>65% in average cell viability, counter-flow) than the untreated model nanoparticles. Moreover, the co-flow incorporation between the nanoparticles and chitosan induced passivation of the nanoparticles, and the average cell viability increased by >80% compared to the model welding nanoparticles. As a more convenient way (additional chitosan generation and incorporation devices may not be required), other passivation strategies through a modification of the welding rod with chitosan adhesive and graphite paste did also enhance average cell viability (>58%). The approach outlined in this work is potentially generalizable as a new platform, using only biocompatible materials in situ, to treat nanoparticles before they are inhaled. PMID- 25797931 TI - Prevalence and outcomes of non-ST-segment elevation myocardial infarction resulting from stent thrombosis. AB - BACKGROUND/PURPOSE: Stent thrombosis is an infrequent yet one of the most feared complications after stent implantation. Stent thrombosis most commonly manifests as ST-segment elevation myocardial infarction, thus the data regarding non-ST segment elevation myocardial infarction (NSTEMI) resulting from stent thrombosis are still sparse. The aim of the study is to evaluate the prevalence and outcomes of NSTEMI resulting from stent thrombosis. METHODS/MATERIALS: We performed a retrospective analysis of 378 consecutive NSTEMI patients who underwent coronary angiography. Patients were divided into those with and without stent thrombosis. The primary outcome was in-hospital mortality. Secondary outcome was the incidence of large myocardial infarction defined as a peak troponin I value greater than 90th percentile of the entire study population (26.5 MUg/L). RESULTS: Among 378 patients with NSTEMI, 12 (3.2%) patients had angiographically confirmed definite stent thrombosis. With respect to the timing of stent thrombosis, 2 patients had early, 3 had late and 7 had very-late stent thrombosis. Patients with stent thrombosis had a higher incidence of large myocardial infarction (33% vs. 9%, p = 0.02) and a higher albeit statistically insignificant peak troponin value (interquartile, 4.62 [0.19-64.0] MUg/L vs. 1.21 [0.14-7.12] MUg/L, p = 0.25) compared to those without stent thrombosis. There was no significant difference in in-hospital mortality between the two groups (8% vs. 2%, p = 0.2). CONCLUSIONS: Stent thrombosis accounted for 3.2% cases of NSTEMI in our cohort of patients and patients with NSTEMI resulting from stent thrombosis had a higher incidence of large myocardial infarction. PMID- 25797932 TI - Group C Streptococcus Causing Rheumatic Heart Disease in a Child. AB - BACKGROUND: Human infection with group C Streptococcus is extremely rare and a select number of cases have been reported to cause acute pharyngitis, acute glomerulonephritis, skin and soft tissue infections, septic arthritis, osteomyelitis, pneumonitis, and bacteremia. In pediatrics, this bacteria is known to cause epidemic food-borne pharyngitis, pneumonia, endocarditis, and meningitis, and has reportedly been isolated in the blood, meninges, sinuses, fingernail, peritonsillar abscess, and thyroglossal duct cyst, among others. CASE REPORT: Our patient was a 7-year-old previously healthy female who presented with abnormal movements of her upper body and grimaces of her face that progressively worsened over time. Initial laboratory resulted revealed 3+ protein on urinalysis and elevated antistreptolysin-O and anti-DNAse antibody levels, and echocardiogram showed mild-to-moderate mitral regurgitation. We describe a rare case of group C Streptococcus resulting in rheumatic heart disease in a child, with a detailed review of the literature pertaining to the diagnosis and management of this infection. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Early recognition of rheumatic heart disease is crucial in the overall outcome of the condition and therefore knowledge of the symptoms associated with condition is also imperative. Group C Streptococcus is rarely associated with rheumatic heart disease and most children exhibiting acute onset of common symptoms, such as chorea, fever, carditis, and rash (erythema marginatum) will present to the emergency department first. Increased awareness and prompt recognition, as done with this child, will result in proper follow-up and adequate management of this condition in all patients. PMID- 25797933 TI - Trauma-Induced Bilateral Ectopia Lentis Diagnosed with Point-of-Care Ultrasound. AB - BACKGROUND: Ocular trauma and acute loss of vision are high-yield patient presentations that may benefit from the use of bedside ultrasound to aid in the diagnosis of a variety of vision-threatening problems. CASE REPORT: We present a case of bilateral lens dislocation in which the diagnosis of lens dislocation was missed on initial computed tomography of the orbits but detected on bedside ultrasound. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Point-of-care ultrasound can rapidly identify ocular pathology and expedite specialist consultation, and if necessary, transfer to a specialty center for further management. PMID- 25797934 TI - Confirmation of hCG Point-of-Care Qualitative Device Limitations in the Emergency Department. PMID- 25797935 TI - Ingestion of Portland Cement. AB - BACKGROUND: The common toxicities of cement are allergic dermatitis, abrasions, and chemical burns, but reports of cement ingestion are rare. In this study, we report a case of successful treatment of cement ingestion using emergency gastrointestinal endoscopy. CASE REPORT: An 83-year-old female was admitted to the emergency department with altered mental state and abdominal pain. We assumed that she ingested cement based on her medical history and radiologic examination. A previous report recommended surgical removal with gastric lavage. However, we thought that wet cement is highly alkaline, and gastric lavage is contraindicated. We performed emergency gastrointestinal endoscopy, instead of gastric lavage. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: If a patient ingests cement, the recommendation is to check the status of the upper gastrointestinal tract and remove the cement by emergency gastrointestinal endoscopy as soon as possible. PMID- 25797937 TI - Wilcox Reply to Sever and Vanholder. PMID- 25797936 TI - Myasthenia Gravis Presenting as Persistent Unilateral Ptosis with Facial Droop. AB - BACKGROUND: Myasthenia gravis (MG) is an autoimmune neuromuscular disorder that is classically characterized by fluctuating weakness and fatigability of the ocular, bulbar, limb, or respiratory muscles. Over half of patients with MG will initially experience isolated ocular symptoms in one or both eyes. Most patients report that ocular symptoms are mild or undetectable upon awakening, and worsen throughout the day or with tasks such as driving. We describe an unusual case of MG presenting with an acute onset of persistent unilateral ptosis and ipsilateral facial droop without diurnal variation or other fluctuation in severity. CASE REPORT: A 58-year-old man presented to the Emergency Department with a 3-day history of persistent, unilateral ptosis with facial droop, concerning for stroke. However, magnetic resonance imaging of the head found no evidence of stroke or any other central etiology. Routine laboratory testing was unremarkable. Neurology was consulted and they recommended sending acetylcholine receptor antibody tests. At the patient's subsequent neurology clinic visit, these tests were found to be abnormal. Electromyography was also done at this visit, confirming the diagnosis of MG. The patient subsequently underwent thymectomy and immunosuppressive therapy, with great improvement in his symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: MG may present as unilateral ptosis or facial drooping without the hallmark characteristic of fluctuating muscle weakness. Early diagnosis and subsequent treatment of MG improves long term prognosis and remission rates. Emergency physicians should consider myasthenia gravis in cases of unilateral ocular symptoms after ruling out emergent central etiologies. PMID- 25797938 TI - Impact of Rocuronium and Succinylcholine on Sedation Initiation After Rapid Sequence Intubation. AB - BACKGROUND: Rapid sequence intubation (RSI) involves a rapidly acting sedative plus a neuromuscular blocking agent (NMBA) to facilitate endotracheal intubation. Rocuronium and succinylcholine are NMBAs commonly used in RSI with drastically different durations of action. OBJECTIVES: Evaluate whether patients receiving RSI with a longer-acting NMBA had a greater delay in sedation or analgesia than patients that received a short-acting NMBA. METHODS: This was a retrospective review of patients presenting to the emergency department requiring endotracheal intubation. Exclusions included age < 18 years, pregnancy, prior intubation, and contraindication to sedation and analgesia. Primary endpoint was time to continuous sedation or analgesia after RSI in patients receiving rocuronium or succinylcholine. Secondary endpoints included hospital length of stay (HLOS), intensive care unit length of stay (ICU LOS), and impact of an emergency medicine pharmacist (EPh). RESULTS: A total 106 patients met inclusion criteria, 76 patients receiving rocuronium and 30 receiving succinylcholine. Mean time to sedation or analgesia was longer in the rocuronium group when compared to the succinylcholine group at 34 +/- 36 min vs. 16 +/- 21 min (p = 0.002). In the presence of an EPh, the mean time to sedation or analgesia was 20 +/- 21 min, vs. 49 +/- 45 min (p < 0.001). Time spent on ventilator, HLOS, and ICU LOS were not significantly different between groups. CONCLUSIONS: Patients receiving rocuronium in RSI had a significantly longer time to sedation or analgesia when compared to patients receiving succinylcholine. The presence of an EPh significantly decreased the time to administration of sedation or analgesia after RSI. PMID- 25797939 TI - Early Detection of Traumatic Retrobulbar Hemorrhage Using Bedside Ocular Ultrasound. PMID- 25797940 TI - Aortoenteric fistula identified by clinical ultrasound. AB - BACKGROUND: Aortoenteric fistula is a rare but serious cause of gastrointestinal bleeding. Early diagnosis and definitive treatment with fistula repair may improve patient outcomes. We report the use of point-of-care ultrasound to identify an aortoenteric fistula in a patient presenting with abdominal pain and shock. CASE REPORT: A 78-year old man presented to the Emergency Department with abdominal pain and 5 days of minimal hematochezia. He was hypotensive and had diffuse abdominal tenderness. Point-of-care ultrasound was performed, demonstrating an abdominal aortic aneurysm with a hypoechoic projection into a segment of bowel abutting the aorta. Color flow was present through the structure, consistent with an aortoenteric fistula. After resuscitation with red blood cells, computed tomography was performed to confirm the diagnosis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Clinical ultrasound has a well established role in the detection of aortic aneurysm. This case illustrates that point-of-care ultrasound can also be used to rapidly identify an aortoenteric fistula and expedite timely care and surgical evaluation. PMID- 25797941 TI - Oligoanalgesia in blunt geriatric trauma. AB - BACKGROUND: Research suggests that older age can influence perception, assessment, and treatment of acute pain, resulting in inadequate pain control for geriatric patients. OBJECTIVE: The purpose of this study was to determine if geriatric trauma patients are less likely to receive analgesia in our emergency department (ED). METHODS: This retrospective chart review includes blunt trauma adult patients who presented to a Level I trauma center ED between June 1 and December 31, 2012. Age was categorized as >=65 years old and 18-64 years old. chi(2) was used to analyze differences in patients receiving pain medication by age groups. Analysis excluded those with no or low pain. A logistic regression model estimated the odds ratio of analgesic use controlling for age, pain level, sex, race, alcohol, drugs, Glasgow Coma Scale, ED length of stay, and Injury Severity Score. T-test compared differences in analgesia administration time. RESULTS: Four hundred and sixty-three blunt trauma patients were included in the analysis. Seventy percent of those >=65 years received analgesia, compared with 84% of those 18-64 years old (p < 0.01). The mean time to analgesia administration was 92 min (>=65 years) compared to 61 min (18-64 years) (p = 0.03). Those >=65 years were 69% less likely (odds ratio = 0.31; 95% confidence interval 0.16-0.59) to receive analgesia compared to patients aged 18-64 years, after controlling for confounders. CONCLUSIONS: Trauma patients >= 65 years of age are less likely to receive analgesia than the younger cohort in our ED and waited longer to get it. PMID- 25797942 TI - Accuracy of Electronic Medical Record Medication Reconciliation in Emergency Department Patients. AB - BACKGROUND: Medication history discrepancies have the potential to cause significant adverse clinical effects for patients. More than 40% of medication errors can be traced to inadequate reconciliation. OBJECTIVE: The objective of this study was to determine the accuracy of electronic medical record (EMR) reconciled medication lists obtained in an academic emergency department (ED). METHODS: Comprehensive research medication ingestion histories for the 48 h preceding ED visit were performed and compared to reconciled EMR medication lists in a convenience sample of ED patients. The reconciled EMR list of prescription, nonprescription, vitamins, herbals, and supplement medications were compared against a structured research medication history tool. We measured the accuracy of the reconciled EMR list vs. the research history for all classes of medications as the primary outcome. RESULTS: Five hundred and two subjects were enrolled. The overall accuracy of EMR-recorded ingestion histories in the preceding 48 h was poor. The EMR was accurate in only 21.9% of cases. Neither age >= 65 years (odds ratio [OR] = 1.3; 95% confidence interval [CI] 0.6-2.6) nor sex (female vs. male: OR = 1.5; 95% CI 0.9-2.5) were predictors of accurate EMR history. In the inaccurate EMRs, prescription lists were more likely to include medications that the subject did not report using (78.9%), while the EMR was more likely not to capture nonprescriptions (76.1%), vitamins (73.0%), supplements (67.3%), and herbals (89.1%) that the subject reported using. CONCLUSIONS: Medication ingestion histories procured through triage EMR reconciliation are often inaccurate, and additional strategies are needed to obtain an accurate list. PMID- 25797943 TI - Topical Review: Families Coping With Child Trauma: A Naturalistic Observation Methodology. AB - OBJECTIVE: To introduce a novel, naturalistic observational methodology (the Electronically Activated Recorder; EAR) as an opportunity to better understand the central role of the family environment in children's recovery from trauma. METHODS: Discussion of current research methods and a systematic literature review of EAR studies on health and well-being. RESULTS: Surveys, experience sampling, and the EAR method each provide different opportunities and challenges for studying family interactions. We identified 17 articles describing relevant EAR studies. These investigated questions of emotional well-being, communicative behaviors, and interpersonal relationships, predominantly in adults. 5 articles reported innovative research in children, triangulating EAR-observed behavioral data (e.g., on child conflict at home) with neuroendocrine assay, sociodemographic information, and parent report. Finally, we discussed psychometric, practical, and ethical considerations for conducting EAR research with children and families. CONCLUSIONS: Naturalistic observation methods such as the EAR have potential for pediatric psychology studies regarding trauma and the family environment. PMID- 25797944 TI - Contamination in the Prospective Study of Child Maltreatment and Female Adolescent Health. AB - OBJECTIVE: To evaluate the impact of contamination, or the presence of child maltreatment in a comparison condition, when estimating the broad, longitudinal effects of child maltreatment on female health at the transition to adulthood. METHODS: The Female Adolescent Development Study (N = 514; age range: 14-19 years) used a prospective cohort design to examine the effects of substantiated child maltreatment on teenage births, obesity, major depression, and past-month cigarette use. Contamination was controlled via a multimethod strategy that used both adolescent self-report and Child Protective Services records to remove cases of child maltreatment from the comparison condition. RESULTS: Substantiated child maltreatment significantly predicted each outcome, relative risks = 1.47-2.95, 95% confidence intervals: 1.03-7.06, with increases in corresponding effect size magnitudes, only when contamination was controlled using the multimethod strategy. CONCLUSIONS: Contamination truncates risk estimates of child maltreatment and controlling it can strengthen overall conclusions about the effects of child maltreatment on female health. PMID- 25797947 TI - Photoluminescent calcium azolium carboxylates with diversified calcium coordination geometry and thermal stability. AB - Despite the popularity and versatility of transition-metal-azolium carboxylate coordination polymers, there are very few examples of group 2 complexes supported by azolium carboxylate ligands in the literature, and there are none featuring luminescent calcium azolium carboxylates. New ionic calcium coordination networks, {[Ca2(L(1))2(H2O)4](Br)4.6H2O}infinity (1), {[(L(3))2Ca(H2O)2]2(Br)2}infinity (3), {[(L(4))2Ca(H2O)2]2(Br)2}infinity (4), and {[(L(5))2Ca3(Na)(H2O)9(Cl)](Br)6.2H2O}infinity (5) along with binuclear {[Ca2(L(2))2(H2O)9](Br)4.4H2O} (2), and trinuclear {[(L(6))2Ca3(H2O)9](Br)6} (6) were isolated from the reaction between the corresponding azolium carboxylates and calcium carbonate in aqueous solution. 1-6 were characterized by FT-IR, NMR, TGA, UV-vis, fluorescence and single crystal X-ray diffraction techniques. Interestingly, the first tetra-cationic binuclear calcium 2 was isolated using L(2)H2Br2 and hexa-cationic trinuclear calcium 6 was isolated using L(6)H3Br3. The 3D coordination polymers 1 and 4 were derived with the help of L(1)H2Br2 and L(4)H2Br2, respectively, through Br...H hydrogen bonding. The 3D MOF 3 with rhomboidal channels was constructed using L(3)H2Br2, where the channel size is about 4.8 * 2.9 nm. 5 was isolated as a rare 1D coordination polymer. The choice of azolium carboxylates in these solids not only changes the topology of the network but also affects the chemistry exhibited by the network. Calcium azolium carboxylate assemblies 1-4 and 6 exhibit interesting solid-state photoluminescence properties, driven by azolium carboxylate ligands. Variation of the bridging chromophore produced significant effects on the fluorescence properties. 1-4 and 6 represent the first examples of luminescent calcium azolium carboxylate complexes. As can be seen in the six metal-organic assemblies presented in this report, a combination of carboxylate groups and steric hindrance affects the topology and physical properties of the resultant solids. PMID- 25797946 TI - Racial Differences in Obesity-Related Risk Factors Between 2-Year-Old Children Born of Overweight Mothers. AB - OBJECTIVE: Investigate racial differences in a range of obesity-related socio behavioral risk factors in children born of obese mothers. METHODS: 142 Black and 151 White 2-year-old children and their parents were surveyed on their physical activity environment, food environment, parental role modeling, eating behaviors, feeding practices, child physical activity, dietary intake, and eating behaviors; body mass index (BMI) for parents and children (BMI z-score) were calculated. RESULTS: In bivariate analyses, Black families reported significantly more risk factors for early-childhood obesity than White families, including greater availability of soda, more television viewing, and poorer dietary intake. In multivariate analyses adjusting for maternal and socioeconomic factors, the differences between Black and White families on factors including television watching and dietary intake remained significant. CONCLUSION: These data show a greater number of risk factors for obesity among Black children and their families compared with White children even after adjustment for maternal BMI and socioeconomic status. PMID- 25797945 TI - Children's Food Allergies: Development of the Food Allergy Management and Adaptation Scale. AB - OBJECTIVE: Develop a measure that evaluates effective pediatric food allergy (FA) management, child and parent FA anxiety, and integration of FA into family life. METHODS: A semistructured family interview was developed to evaluate FA management using a pilot sample (n = 27). Rating scales evaluated eight dimensions of FA management (FAMComposite), child anxiety, parent anxiety, and overall balanced integration (BI). Families of children with IgE-mediated food allergies (n = 60, child age: 6-12) were recruited for interview and rating scale validation. RESULTS: FAMComposite was correlated with physician ratings for families' food avoidance and reaction response readiness. FA anxiety was correlated with general anxiety measures for children, but not parents. Parents' FA anxiety was correlated with expectations of negative outcomes from FA. Low BI was associated with poor quality of life and negative impact on family functioning. CONCLUSIONS: Preliminary analyses support Food Allergy Management and Adaptation Scale validity as a measure of family adaptation to pediatric FA. PMID- 25797948 TI - National Clinical Database feedback implementation for quality improvement of cancer treatment in Japan: from good to great through transparency. AB - The National Clinical Database (NCD) of Japan was established in April, 2010 with ten surgical subspecialty societies on the platform of the Japan Surgical Society. Registrations began in 2011 and over 4,000,000 cases from more than 4100 facilities were registered over a 3-year period. The gastroenterological section of the NCD collaborates with the American College of Surgeons' National Surgical Quality Improvement Program, which shares a similar goal of developing a standardized surgical database for surgical quality improvement, with similar variables for risk adjustment. Risk models of mortality for eight procedures; namely, esophagectomy, partial/total gastrectomy, right hemicolectomy, low anterior resection, hepatectomy, pancreaticoduodenectomy, and surgery for acute diffuse peritonitis, have been established, and feedback reports to participants will be implemented. The outcome measures of this study were 30-day mortality and operative mortality. In this review, we examine the eight risk models, compare the procedural outcomes, outline the feedback reporting, and discuss the future evolution of the NCD. PMID- 25797949 TI - Dating Violence and Substance Use as Longitudinal Predictors of Adolescents' Risky Sexual Behavior. AB - The objectives of this study is to examine dating violence perpetration and victimization (physical, psychological, and sexual) and lifetime substance use (alcohol, marijuana, and hard drugs) as longitudinal predictors of adolescents' risky sexual behavior across 1 year and to determine whether predictors varied across adolescents' gender and ethnicity. A sample of Caucasian, African American, and Hispanic male and female adolescents from seven public high schools in Texas (N = 882) participated. Adolescents completed self-report measures of dating violence, lifetime substance use, and risky sexual behavior at baseline and, 1-year later, completed a second assessment of their risky sexual behavior. Path analysis demonstrated that greater physical dating violence victimization, lifetime alcohol use, lifetime marijuana use, and age (being older) were all significant predictors of risky sexual behavior at the 1-year follow-up. These results did not vary across gender or the three ethnic groups (Caucasian, African American, and Hispanic). Overall, substance use was a longitudinal predictor of risky sexual behavior across the three ethnic groups, with physical dating violence victimization being the only type of dating violence longitudinally predicting risky sexual behavior. Prevention efforts should consider the roles of physical dating violence and substance use in preventing risky sexual behavior. PMID- 25797950 TI - Bending spring rate investigation of nanopipette for cell injection. AB - Bending of nanopipette tips during cell penetration is a major cause of cell injection failure. However, the flexural rigidity of nanopipettes is little known due to their irregular structure. In this paper, we report a quantitative method to estimate the flexural rigidity of a nanopipette by investigating its bending spring rate. First nanopipettes with a tip size of 300 nm are fabricated from various glass tubes by laser pulling followed by focused ion beam (FIB) milling. Then the bending spring rate of the nanopipettes is investigated inside a scanning electron microscope (SEM). Finally, a yeast cell penetration test is performed on these nanopipettes, which have different bending spring rates. The results show that nanopipettes with a higher bending spring rate have better cell penetration capability, which confirms that the bending spring rate may well reflect the flexural rigidity of a nanopipette. This method provides a quantitative parameter for characterizing the mechanical property of a nanopipette that can be potentially taken as a standard specification in the future. This general method can also be used to estimate other one-dimensional structures for cell injection, which will greatly benefit basic cell biology research and clinical applications. PMID- 25797951 TI - Complementary hydrogen bonding interaction triggered co-assembly of an amphiphilic peptide and an anti-tumor drug. AB - We report a new tumor-targeting amphiphilic peptide that can form complementary hydrogen bonds with anti-tumor drug methotrexate (MTX), leading to reversible self-assembled morphology transition from loose micelles to densely packed nanorods or nanofibers. The MTX loaded nanorods can target tumor cells and show more than 2-fold higher cytotoxicity (IC50 = 0.38 mg L(-1)) than that towards normal cells (IC50 = 0.89 mg L(-1)). PMID- 25797952 TI - 4-Hydroxy-1-naphthaldehydes: proton transfer or deprotonation. AB - A series of naphthaldehydes, including a Mannich base, have been investigated by UV-Vis spectroscopy, NMR and theoretical methods to explore their potential tautomerism. In the case of 4-hydroxy-1-naphthaldehyde concentration dependent deprotonation has been detected in methanol and acetonitrile. For 4-hydroxy-3 (piperidin-1-ylmethyl)-1-naphthaldehyde (a Mannich base) an intramolecular proton transfer involving the OH group and the piperidine nitrogen occurs. In acetonitrile the equilibrium is predominantly at the OH-form, whereas in methanol the proton transferred tautomer is the preferred form. In chloroform and toluene, the OH form is completely dominant. Both 4-hydroxy-1-naphthaldehyde and 4-methoxy 1-naphthaldehyde (fixed enol form) show dimerization in the investigated solvents and the crystallographic data, obtained for the latter, confirm the existence of a cyclic dimer. PMID- 25797954 TI - Aristotle's Theory of Deviance and Contemporary Symbolic Interactionist Scholarship: Learning from the Past, Extending the Present, and Engaging the Future. AB - Although his work has been largely overlooked by symbolic interactionists and other students of deviance, Aristotle (c384-322BCE) addresses community life, activity, agency, and persuasive interchange in ways that not only are remarkably consistent with contemporary symbolic interactionist approaches to deviance, but that also conceptually inform present day theories of deviance and provide valuable transhistorical comparison points for subsequent analysis. Following (1) a brief overview of an interactionist approach to the study of deviance, attention is given to (2) classical Greek conceptions of good and evil (especially as these are articulated by Plato) before turning more directly to (3) Aristotle's notions of wrongdoing as this is reflected in his considerations of community, morality, agency, and culpability. While informed by Aristotle's considerations of causality (as addressed in Physics and Metaphysics), this statement builds most centrally on Aristotle's Nicomachean Ethics and Rhetoric. Striving for a broader understanding of deviance as a humanly engaged feature of community life, the paper briefly compares Aristotle's "theory of deviance" with Prus and Grills (2003) interactionist analysis of deviance. The paper (4) concludes with an assessment of the relative contributions of contemporary interactionist scholarship and Aristotle's materials for the study of deviance as a community-engaged process. PMID- 25797953 TI - Leptin ameliorates ischemic necrosis of the femoral head in rats with obesity induced by a high-fat diet. AB - Obesity is a risk factor for ischemic necrosis of the femoral head (INFH). The purpose of this study was to determine if leptin treatment of INFH stimulates new bone formation to preserve femoral head shape in rats with diet-induced obesity. Rats were fed a high-fat diet (HFD) or normal chow diet (NCD) for 16 weeks to induce progressive development of obesity. Avascular necrosis of the femoral head (AVN) was surgically induced. Adenovirus-mediated introduction of the leptin gene was by intravenous injection 2 days before surgery-induced AVN. At 6 weeks post surgery, radiologic and histomorphometric assessments were performed. Leptin signaling in tissues was examined by Western blot. Osteogenic markers were analyzed by real-time RT-PCR. Radiographs showed better preservation of femoral head architecture in the HFD-AVN-Leptin group than the HFD-AVN and HFD-AVN-LacZ groups. Histology and immunohistochemistry revealed the HFD-AVN-Leptin group had significantly increased osteoblastic proliferation and vascularity in infarcted femoral heads compared with the HFD-AVN and HFD-AVN-LacZ groups. Intravenous injection of leptin enhanced serum VEGF levels and activated HIF-1alpha pathways. Runx 2 and its target genes were significantly upregulated in the HFD-AVN-Leptin group. These results indicate that leptin resistance is important in INFH pathogenesis. Leptin therapy could be a new strategy for INFH. PMID- 25797955 TI - Estimation of mean response via effective balancing score. AB - We introduce effective balancing scores for estimation of the mean response under a missing at random mechanism. Unlike conventional balancing scores, the effective balancing scores are constructed via dimension reduction free of model specification. Three types of effective balancing scores are introduced: those that carry the covariate information about the missingness, the response, or both. They lead to consistent estimation with little or no loss in efficiency. Compared to existing estimators, the effective balancing score based estimator relieves the burden of model specification and is the most robust. It is a near automatic procedure which is most appealing when high dimensional covariates are involved. We investigate both the asymptotic and the numerical properties, and demonstrate the proposed method in a study on Human Immunodeficiency Virus disease. PMID- 25797956 TI - New WHO Classification of Endometrial Hyperplasias. PMID- 25797957 TI - Is the Outcome Indicator "3rd/4th Degree Perineal Tear in Spontaneous Singleton Births" a Reliable Quality Parameter in Obstetrics? AB - Obstetric sphincter damage is the most common cause of fecal incontinence in women. Between one-third and two-thirds of women who sustain a recognized third degree tear during delivery subsequently suffer from fecal incontinence. We should therefore try to reduce the rate of high-grade tears as much as possible. But this rate can only be used as an outcome indicator for the quality of obstetric departments if the recognition and classification of sphincter injury is similar across departments in different hospitals. PMID- 25797958 TI - Surgical Methods for the Treatment of Uterine Fibroids - Risk of Uterine Sarcoma and Problems of Morcellation: Position Paper of the DGGG. AB - The appropriate surgical technique to treat patients with uterine fibroids is still a matter of debate as is the potential risk of incorrect treatment if histological examination detects a uterine sarcoma instead of uterine fibroids. The published epidemiology for uterine sarcoma is set against the incidence of accidental findings during surgery for uterine fibroids. International comments on this topic are discussed and are incorporated into the assessment by the German Society for Gynecology and Obstetrics (DGGG). The ICD-O-3 version of 2003 was used for the anatomical and topographical coding of uterine sarcomas, and the "Operations- und Prozedurenschlussel" (OPS) 2014, the German standard for process codes and interventions, was used to determine surgical extirpation methods. Categorical qualifiers were defined to analyze the data provided by the Robert Koch Institute (RKI), the German Federal Bureau of Statistics (DESTATIS; Hospital and Causes of Death Statistics), the population-based Cancer Register of Bavaria. A systematic search was done of the MEDLINE database and the Cochrane collaboration, covering the period from 1966 until November 2014. The incidence of uterine sarcoma and uterine fibroids in uterine surgery was compared to the literature and with the different registries. The incidence of uterine sarcoma in 2010, standardized for age, was 1.53 for Bavaria, or 1.30 for every 100 000 women, respectively, averaged for the years 2002-2011, and 1.30 for every 100 000 women in Germany. The mean incidence collated from various surveys was 2.02 for every 100 000 women (0.35-7.02; standard deviation 2.01). The numbers of inpatient surgical procedures such as myoma enucleation, morcellation, hysterectomy or cervical stump removal to treat the indication "uterine myoma" have steadily declined in Germany across all age groups (an absolute decrease of 17 % in 2012 compared to 2007). There has been a shift in the preferred method of surgical access from an abdominal/vaginal approach to endoscopic or endoscopically assisted procedures to treat uterine fibroids, with the use of morcellation increasing by almost 11 000 coded procedures in 2012. Based on international statements (AAGL, ACOG, ESGE, FDA, SGO) on the risk of uterine sarcoma as an coincidental finding during uterine fibroid surgery and the associated risk of a deterioration of prognosis (in the case of morcellation procedures), this overview presents the opinion of the DGGG in the form of four Statements, five Recommendation and four Demands. PMID- 25797959 TI - Psychosomatic Aspects of Urinary Incontinence in Women. AB - Urinary incontinence in women is a common problem. With increasing age its prevalence and severity of its manifestations increase. Among nursing home residents the frequency is between 43 and 77 %, 6 to 10 % of all admissions to nursing homes are due to urinary incontinence. The risk for urinary incontinence among women with cognitive deficits is 1.5- to 3.4-fold higher than for women without mental disorders. The most common form is stress incontinence (50 %), followed by mixed stress-urge incontinence (40 %) and purely urge incontinence (OAB = overactive bladder, 20 %). With regard to its cause, the latter remains unclarified in about 80 % of the cases. It is often difficult to treat. There are also cases in which urge incontinence is related to traumatic events. In such cases behavioural and psychotherapeutic options may be helpful. Almost inevitably every form of incontinence has psychological consequences: shame and insecurity are often results of uncontrolled loss of urine. Among others, in the long term, they lead to the avoidance of social contacts and possibly to depression and isolation. Consideration of the psychosomatics is important in the therapy for female urinary incontinence from three points of view: 1) the efficacy of treatment is better suited to the patient, 2) the treatment costs are lower, 3) the professional satisfaction of the responsible physician increases. PMID- 25797961 TI - Multifocal Tumorous Pseudoangiomatous Stromal Hyperplasia Presenting as Asymmetric Bilateral Breast Enlargement. AB - PASH is a benign proliferation of stromal myofibroblasts that affects mostly premenopausal women and typically shows estrogen and progesterone receptor expression, allowing speculation regarding a hormonal cause. It usually presents as an incidental finding on a mammogram or as a palpable mass. We present a case of diffuse asymmetrical massive breast enlargement in a premenopausal woman with history of previous multiple PASH excisions for recurrent lesions, caused by multifocal tumorous PASH virtually replacing the breast parenchyma. Immunohistochemistry examination showed no hormone receptor expression. Despite its benign nature, such presentation of PASH is managed with bilateral mastectomy and immediate reconstruction with expanders for cosmetic and comfort reasons, while tumor excision or expectant management is deemed to lead to recurrence and progression. Although a hormonal origin is speculated based on hormone expression studies and typical patient profile, this case showed 0 % estrogen/progesterone expression in the final histology specimen. PMID- 25797960 TI - Breast Cancer Update 2014 - Focus on the Patient and the Tumour. AB - The therapy for patients with breast cancer has developed markedly in the past ten years. Our understanding of the molecular biology of tumours and the characteristics of the patients has shaped the recent advances. In this review we present the latest knowledge about the therapy for breast cancer. There are new tests and options not only in the field of anti-HER2 therapy but also in the management of triple negative and hormone receptor-positive patients. Comprehension of prognosis and therapeutic response to chemotherapies is little by little helping to define patient groups who will not respond to chemotherapy or who do not need treatment because their prognosis is extremely good. In the field of anti-HER2 therapy, work is continuing on the development of drugs suitable for and able to overcome trastuzumab resistance. For hormone receptor positive cancers, we now have a better understanding of which therapy groups will benefit from which anti-endocrine drugs, and which will be able to overcome a possible resistance (treatment of the PI3K pathways, inhibition of the cell cycle). Molecular tests are still being evaluated with regard to the clinical situations in which they may have the greatest relevance for therapeutic decision making; however, evidence is also increasing as to the fields in which good predictions for the prognosis can be obtained. On the whole, more work is needed to promote our understanding of the new developments in diagnostics and therapy and to involve both physicians and patients equally in the procedures. PMID- 25797962 TI - Changing Diagnostic and Treatment Criteria for Chronic Illness: A Critical Consideration of their Impact on Low-Income Hispanic Patients. AB - Low-income Hispanics are often identified as especially at risk for common chronic conditions like diabetes, and targeted for aggressive screening and treatment. Anthropologists and other social scientists have extensively explored barriers and facilitators to chronic illnesses management in minority populations, but have not yet considered the impact of recently lowered diagnostic and treatment thresholds on such groups. In this paper, we critically review recent changes in diabetes, hypertension and high cholesterol diagnostic and treatment standards which have dramatically increased the number of people being treated for these conditions. Drawing on an ethnographic study of chronic illness management in two Hispanic-serving clinics in the Midwest, we examine how these new standards are being applied, and consider the resulting health care challenges these Hispanic patients face. Our analysis leads us to question the value of promoting narrowly defined treatment goals, particularly when patients lack reliable access to the health care resources these goals require. While improving the health of low-income Hispanics is a worthwhile goal, it is important to consider whether these efforts may be promoting over-diagnosis and over-treatment, drawing them into an expensive chronic patient role with uncertain benefit. PMID- 25797963 TI - Attitudes Toward and Sexual Partnerships With Drug Dealers Among Young Adult African American Females in Socially Disorganized Communities. AB - Drug markets in disadvantaged African American neighborhoods have altered social and sexual norms as well as sexual networks, which impact an individual's risk of contracting a sexually transmitted infection. Presently, we describe the prevalence of sexual partnerships with males involved with illegal drugs among a sample of non-drug-dependent females. In 2010, 120 Black females aged 18 to 30 years completed a semistructured HIV-risk interview. Descriptive statistics revealed approximately 80% of females perceived neighborhood drug activity as a major problem, 58% had sex with a male drug dealer, 48% reported sex with a male incarcerated for selling drugs, and 56% believed drug dealers have the most sexual partners. Our results suggest sexual partnerships with males involved in the distribution of drugs are prevalent. These partnerships may play a substantial role in the spread of sexually transmitted infections among low-risk females, as drug dealers likely serve as a bridge between higher HIV-risk drug and prison populations and lower HIV-risk females. However, the significance of partnerships with males involved in drug dealing has received little attention in HIV and drug abuse literature. Presently, there is a need for more research focused on understanding the extent to which the drug epidemic affects the HIV risk of non-drug-dependent Black female residents of neighborhoods inundated with drugs. Special consideration should be given to the role of the neighborhood drug dealer in the spread of sexually transmitted infections. PMID- 25797964 TI - Quantifying variation in delta13C and delta15N isotopes within and between feathers and individuals: Is one sample enough? AB - Studies of avian migration increasingly use stable isotope analysis to provide vital trophic and spatial markers. However, when interpreting differences in stable isotope values of feathers, many studies are forced to make assumptions about the timing of moult. A fundamental question remains about the consistency of these values within and between feathers from the same individual. In this study, we examine variation in carbon and nitrogen isotopes by sub-sampling feathers collected from the wings of adults of two small congeneric petrel species, the broad-billed Pachyptila vittata and Antarctic prion P. desolata. Broad-billed prion feather vane material was enriched in 15N compared to feather rachis material, but there was no detectable difference in delta13C. Comparison of multiple samples taken from Antarctic prion feathers indicated subtle difference in isotopes; rachis material was enriched in 13C compared to vane material, and there were differences along the length of the feather, with samples from the middle and tip of the feather depleted in 15N compared to those from the base. While the greatest proportion of model variance was explained by differences between feathers and individuals, the magnitude of these within feather differences was up to 0.5 0/00 in delta15N and 0.8 0/00 in delta13C. We discuss the potential drivers of these differences, linking isotopic variation to individual-level dietary differences, movement patterns and temporal dietary shifts. A novel result is that within-feather differences in delta13C may be attributed to differences in keratin structure within feathers, suggesting further work is required to understand the role of different amino acids. Our results highlight the importance of multiple sampling regimes that consider both within- and between-feather variation in studies using stable isotopes. PMID- 25797965 TI - IRON METABOLISM AND AUTOPHAGY: A POORLY EXPLORED RELATIONSHIP THAT HAS IMPORTANT CONSEQUENCES FOR HEALTH AND DISEASE. AB - Autophagy is an important cell survival pathway which is up-regulated under stress conditions.1) It is a well regulated catabolic process and enables the cell to recycle its constituents and organelles for re-use.1) Autophagy has been implicated to play an important role in a variety of disorders such as cancer and protein aggregatory neurodegenerative diseases e.g., Alzheimer's disease, Parkinson's disease and Huntington's disease.2) Iron is a critical metal required for normal cellular functioning.3) A very tightly regulated balance of iron levels is required for the normal physiological functioning of the cell.3) Both an excess and deficiency of iron can lead to cellular stress, and thereby, alters the autophagic status within the cell. Thus, it is important to completely understand how iron can affect the autophagic pathway and its potential implications under physiological as well as pathological conditions. PMID- 25797966 TI - FLT3 INHIBITORS: RECENT ADVANCES AND PROBLEMS FOR CLINICAL APPLICATION. AB - FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells as well as normal hematopoietic stem/progenitor cells. Mutation in the FLT3 gene is the most frequent genetic alteration in acute myeloid leukemia (AML) and is well known as an important driver mutation for the development of myeloid malignancies. FLT3 mutation is a strong poor prognostic factor for the long-term survival in AML patients, while neither high-dose chemotherapy nor allogeneic hematopoietic stem cell transplantation can overcome a poor prognosis. Development of an FLT3 inhibitor is, therefore, much awaited. To date, several potent FLT3 inhibitors have been developed and some of them were evaluated for efficacy in clinical trials, although no FLT3 inhibitor has been yet approved. Moreover, several problems for clinical use, such as adverse effects, blood concentration and resistance have been apparent. Recently developed AC220 is a highly selective and sensitive FLT3 inhibitor. In Phase I and II trials, AC220 so far showed the best efficacy of AML cells harboring FLT3 mutation among clinically evaluated FLT3 inhibitors, while severe bone marrow suppression and QTc prolongation should be resolved for the clinical use. In this review, I summarize the characteristics of FLT3 inhibitors in clinical development and discuss important issues to be resolved for clinical use. PMID- 25797967 TI - ROLES OF PUBLIC HEALTH CENTERS (HOKENJO) IN TUBERCULOSIS CONTROL IN JAPAN. AB - Public health centers (PHCs, hokenjo in Japanese) are local government authorities responsible for public health in Japan. PHCs have an important role in tuberculosis (TB) control. Typically, their responsibilities include 1) the recommendation to admit infectious TB patients to an isolation ward, 2) health checkups with chest X-ray of those in a close contact with infectious TB patients, and 3) public subsidy of medical expenses for TB treatments. Facing the emergence of multi-drug resistant tuberculosis (MDR-TB), the national TB control program was drastically changed; the Japanese version of the Directly Observed Treatment in Short-course (DOTS) strategy was started in 2005. New roles were added to PHCs' responsibilities; 1) active screening of latent TB infection by interferon gamma release assays for those in a close contact with infectious TB patients, 2) community DOTS to promote treatment adherence to outpatients, 3) cohort analysis of outcomes of TB treatment, and 4) national MDR-TB surveillance. These roles are important in preventing MDR-TB and eliminating TB in Japan. PMID- 25797968 TI - Factors associated with access to antiretroviral therapy among people living with hiv in vientiane capital, lao pdr. AB - Since 2001, antiretroviral therapy (ART) has been available for people living with HIV (PLHIV) in Lao People's Democratic Republic (PDR). Over 10 years of the ART program many HIV patients were found with advanced-stage AIDS in health care service facilities. This study aimed to examine factors associated with delayed access to ART among PLHIV in the capital of Vientiane. A cross-sectional study was conducted with 283 respondents (131 males and 152 females) aged 15 years or over. In this study, delayed access to ART was defined by a CD4 cell count of less than 350 cells/mm(3) at the first screening, or those who presented with advanced AIDS-related symptoms. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by a logistic model. After adjustment, young people (OR=2.17; 95% CI: 1.00-4.68; p=0.049), low education (OR=0.23; 95% CI: 0.10-0.55; p=0.001) and duration between risk behavior and HIV test (OR=3.83; 95% CI: 1.22-12.00; p=0.021) were significantly associated with delayed access to ART. Low perception of high risk behaviors was one of the obstacles leading to delayed testing and inability to access ART. Almost all reported feeling self stigma, and only 30.5% of men and 23.7% of women disclosed the HIV status to his/her partner/spouse. In conclusion, delayed access to ART was associated with individual factors and exposure to health care facility. In order to improve early detection HIV infection following access to ART, an improvement in perceptional knowledge of HIV, as well as reduction of HIV/AIDS-related stigma, might be needed. PMID- 25797969 TI - Tuberculosis and rifampicin resistance among migrants in kyrgyzstan: detection by a new diagnostic test. AB - This cross-sectional study aimed to describe suspected tuberculosis (TB) cases among migrants in Kyrgyzstan and to estimate the accuracy of Xpert MTB/RIF, which has been operated in Kyrgyzstan since 2012. Characteristics of 3,714 suspected cases among migrants were analysed. In addition, by using data of 300 cases with culture results, sensitivity and specificity of Xpert MTB/RIF, both for detection of TB and rifampicin susceptibility, were assessed. Among 3,714 suspected cases, 56.1% were male, and the median age was 35 years old. Of the suspected cases, 17.2% were previously-treated. In total, 809 (21.8%) were smear-positive; 36.8% among previously-treated cases and 18.7% among new cases. Among 300 selected participants, 235 (78.3%) were culture-positive. Of those who were confirmed as TB positive, recurrent cases showed a higher proportion of rifampicin resistance than new cases (59.3% vs 42.6%). For detection of TB, the sensitivity and specificity of XpertMTB/RIF (81.3% and 98.2%) were higher than those of microscopy (70.2% and 71.4%). Sensitivity and specificity for detection of rifampicin resistance were 96.8% and 91.8%, respectively. The rifampicin resistance rate in the study population was higher than the national average. Xpert MTB/RIF showed higher accuracy in detecting TB cases than microscopic diagnosis. Higher accuracy and earlier detection of drug susceptibility is especially important for those who have difficulty in accessing healthcare and those who are easily lost from tracking, including migrants. PMID- 25797970 TI - Surgical skills training for primary total hip arthroplasty. AB - A total of 483 hips treated by primary total hip arthroplasty (THA) were investigated to evaluate the surgical skill of the performing surgeon. Surgical trainees operated on 259 hips and instructors on 224 hips. The average age of the patients at the time of THA in the trainee and instructor group was 61.9 and 60.8 years old, respectively. The average follow-up duration was 5.1 years. The operative time in the trainee group and instructor group was 87.0 and 73.1 min, respectively (p=0.031). Complications were noted in 11 hips (3.5%) in the trainee group; acetabular fracture, 3 hips; dislocation, 3 hips; femoral artery lacerations that needed repair surgery, 2 hips; sciatic nerve palsy, 2 hips; and skin necrosis, 1 hip. Complication were noted in three hips (1.3%) in the instructor group; femoral fracture, 1 hip; acetabular fracture, 1 hip; dislocation, 1 hip. Complication rate in the trainee group was higher than in the instructor group. The monitored quality of the surgeries performed by trainees and instructors was not significantly different. Poor quality was identified in 14 hips in the trainee group and 6 hips in instructor group. No significant difference was found in the hip score between the trainees and instructors before and after surgery. Revision arthroplasty was defined as the end-point for primary THA. Kaplan-Meier survivorship at 5 years after primary THA was 97.2% in trainee group and 97.3% in the instructor group. Short-term clinical and radiographic results of primary THA in the trainee and instructor groups were considered safe and satisfactory. PMID- 25797971 TI - Burden of bacterial meningitis: a retrospective review on laboratory parameters and factors associated with death in meningitis, kelantan malaysia. AB - To describe the clinical characteristics and the risk factors associated with mortality in patients with meningitis. This is a retrospective review of patients diagnosed to have meningitis with positive culture of the cerebrospinal fluid (CSF) specimen. All cases aged 19 > years who were admitted to Hospital USM between January 2004 and December 2011 were included in the study. The CSF results database were obtained from the Department of Medical Microbiology and Parasitology, Hospital USM, Kelantan. A checklist was used to record the clinical characteristics. A total of 125 cases met the inclusion criteria. The age of patients ranged between newborn and 19 years old (Mean+/-SD, 74.5+/-80.6 months). The majority of them were males (65.6%). Fever was the most common presentation (73.6%) followed by poor oral intake (48.0%), seizure (36.0%) and headache (24.8%). The mortality rate was 31.2%. Coagulase negative staphylococcus was the most frequent pathogens isolated (21.6%), followed by Acinetobacter spp. (17.6%), Staphylococcus aureus (13.6%), Streptococcus spp. (11.2%) and Klebsiella pneumoniae (6.4%). There were significant association of in-hospital death with age (p=0.020) and conscious level (p=0.001). Infectious meningitis is a big health concern, especially among children. We found that coagulase negative staphylococcus, Acinetobacter species, S. aureus, Streptococcus spp and K. pneumoniae were prevalent in our hospital. These microorganisms were hospital associated pathogens. The 31% mortality linked to hospital acquired meningitis specifies the need for focused physician attention especially among younger aged patients. PMID- 25797972 TI - Delivery care satisfaction at government hospitals in xiengkhuang province under the maternal and child health strategy in lao pdr. AB - Satisfaction with delivery care for mothers giving birth at medical facilities, particularly hospitals, affects birth place selection. Lao PDR faces high maternal and infant mortality, and the government had introduced the Maternal and Child Health Strategy to Xiengkhuang Province in 2009 to combat high maternal and infant mortality there. This study aimed to determine the levels of delivery care satisfaction among mothers who gave birth in hospitals and examine the associations between satisfaction and background factors. This was a cross sectional study, conducted from July to August of 2013, for 246 mothers who gave birth at three hospitals. A logistic regression model was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of the factors. The majority of respondents were <= 25 years of age (57.3%), educated in <=12 years (64.2%), unemployed (77.6%), and with more than one child (60.2%). Most mothers (93.5%) received antenatal care at least one time. Among the 16 components of satisfaction, less than half of the respondents were satisfied with sanitary facilities (22.0%), cleanliness (39.4%), their infant's health condition (42.7%), opportunity to clarify doubts about baby care (48.8%), their own health condition (43.5%), and privacy maintained during care (45.5%). The components with more than 80% satisfaction among the respondents were the politeness and respect shown by midwives (88.6%), nurses (85.4%), and doctors (80.1%) as well as medical service facilities (81.7%). Overall satisfaction was significantly associated with higher husband's education (OR=2.36, 95% CI=1.07-5.19) and longer hospital stay (OR=2.30, 95% CI=1.28-4.14) when 15 background factors were adjusted. In conclusion, mothers who gave birth at hospitals in Lao PDR were generally satisfied, except for sanitary facilities, and cleanliness of facilities. PMID- 25797973 TI - Efficacy and safety of celecoxib compared with placebo and etodolac for acute postoperative pain: a multicenter, double-blind, randomized, parallel-group, controlled trial. AB - Celecoxib is a nonsteroidal anti-inflammatory drug (selective cyclooxygenase-2 inhibitor) that is widely used. The efficacy and safety of celecoxib for treatment of acute postoperative pain were evaluated in Japanese patients. The objective was to assess whether celecoxib showed superiority over placebo treatment and non-inferiority versus etodolac (another selective cyclooxygenase-2 inhibitor) that has been widely used for the management of acute pain. A multicenter, double-blind, randomized, parallel-group, controlled study was performed, in which 616 patients with postoperative pain received celecoxib, etodolac, or placebo. Their impressions of study drug efficacy (overall assessment) and pain intensity were evaluated. Based on each patient's overall assessment of pain, the efficacy rate was 63.7% in the placebo group, 76.2% in the celecoxib group, and 68.0% in the etodolac group, with these results demonstrating superiority of celecoxib to placebo and noninferiority versus etodolac. The efficacy rate was significantly higher in the celecoxib group than in the etodolac group. There were no adverse events specific to celecoxib, and the safety of celecoxib was similar to that of placebo. Celecoxib was superior to etodolac for controlling acute postoperative pain. PMID- 25797974 TI - Effects of a custom-made hinged knee brace with knee flexion support for patients with knee osteoarthritis:a preliminary study. AB - A knee brace for medial knee osteoarthritis (OA) is required to restrict knee adduction moment (KAM), but must not restrict knee flexion during swing phase. There is no report of a knee brace with both functions. The purpose of this study is to investigate the effect of the custom-made hinged knee brace for patients with knee OA compared to the hinged knee brace generally used, and to assess the KAM and knee flexion angle during swing phase. Fifteen patients (average age: 71.6 +/- 7.8 years old) with medial knee OA participated. Gait analysis was performed using a 3-D motion analysis system to measure two conditions: hinged knee brace (KB), and a custom-made hinged knee brace with knee-flexion support- equipped rubber tubes at the posterior of the lateral and medial side poles (KBF). The peak KAM with KBF was significantly smaller than those with the KB (P=0.004, the difference between these conditions of KAM: 0.06 Nm/kg). The peak knee flexion angles during swing phase with KBF were also significantly larger than those with the KB (P=0.004, the difference between these conditions of knee flexion angle: 1.5 degrees). The custom-made brace with one type of tube actuator in the present study could decrease KAM and make for a small increase of knee flexion angle as opposed to the hinged knee brace. PMID- 25797975 TI - Clinical features, current treatments and outcome of pregnant women with preeclampsaia/eclampsia in northern afghanistan. AB - In Afghanistan, preeclampsia/eclampsia is the second leading cause of maternal deaths following maternal hemorrhage. This study aimed to describe clinical features, current treatments, and outcome among preeclampsia and eclampsia patients in the north region of Afghanistan. This was a retrospective study based on medical records of four center hospitals (one regional hospital and three provincial hospitals) in the north region of Afghanistan. Subjects were 322 patients with preeclampsia/eclampsia, admitted from March 2012 to March 2013. Out of 322 cases, 72.7% were diagnosed as preeclampsia and the rest as eclampsia. Those aged 30-39 years were 41.0% among preeclampsia patients and 29 years and younger were 35.2% among eclampsia patients (p= 0.002). The first delivery was significantly higher (p=0.045) among eclampsia patients (51.1%) than among preeclampsia patients (36.8%). While none died among the preeclampsia patients, 12 out of 88 eclampsia patients died in the hospitals. The causes of the 12 deaths were pulmonary edema (6 patients), renal failure (3 patients), cerebrovascular attack (2 patients), and hemorrhage (1 patient). There were no clinical findings at admission significantly associated with the deaths within the eclampsia patient group. Although the sample size was not large enough, patients admitted to the regional/provincial hospitals at the stage of preeclampsia had a low risk of death. Access at the stage of preeclampsia and improvement in treatments for eclampsia would reduce maternal mortality in Afghanistan. PMID- 25797976 TI - Evaluation of emphysema using three-dimensional computed tomography: association with postoperative complications in lung cancer patients. AB - Three-dimensional computed tomography (3D-CT) enables in vivo volumetry of total lung volume (TLV) and emphysematous low-attenuation volume (LAV) in patients with chronic obstructive pulmonary disease (COPD). We retrospectively investigated the correlation between preoperative 3D-CT volumetry and postoperative complications in lung cancer patients. We searched our institution's surgical records from December 2006 to December 2009 and selected patients who had undergone pulmonary lobectomy for primary lung cancer. From 3D-CT data, TLV and LAV <-950 HU of thresholds were retrospectively measured. The LAV% was calculated as follows: LAV% = LAV/TLV*100. The associations between the seven independent variables (LAV%, age, gender, body mass index, smoking history, forced expiratory volume in 1 second as percent forced vital capacity [FEV1%], and resected lobe) and the two outcomes (postoperative complications and prolonged postoperative stay [PPS]) were compared using logistic regression analysis. A total of 309 patients (222 males, 87 females; mean age, 67 years; range, 40-87 years) were evaluated. On multivariate analysis, age and LAV% were significantly correlated with postoperative complications (p = 0.006 and p = 0.006, respectively), and LAV% was significantly correlated with PPS (p = 0.031). LAV% measured using 3D-CT is more sensitive for predicting complications after lobectomy for lung cancer than FEV1%. PMID- 25797977 TI - Patients' level of medical term recognition as estimated by healthcare workers. AB - To render risk communication between patients and healthcare workers more effective, gaps in the patients' level of medical term recognition as estimated by healthcare workers was examined. This was a cross-sectional study conducted via an Internet survey. A total of 244 nurses and 211 medical doctors were surveyed. We examined 90 medical terms, including 57 medical terms examined by the National Institute for Japanese Language and 33 newly added medical terms. Differences between medical doctors and nurses with respect to the estimation of patients' level of medical term recognition were assessed. The level of medical term recognition by patients was higher when estimated by nurses than when estimated by medical doctors. As members of team care, nurses must consider that patients find technical medical terms to be more difficult than anticipated and that patients are aware of these terms only to a certain extent while receiving healthcare information, such as drug information. Currently, nurses are expected to perform activities as clinical research coordinators and also are requested to work as home-visiting nurses. Therefore they also need ensure that patients understand the medical information provided to them. PMID- 25797978 TI - Factors influencing non-institutional deliveries in afghanistan: secondary analysis of the afghanistan mortality survey 2010. AB - Home delivery in unhygienic environments is common among Afghan women; only one third of births are delivered at health facilities. Institutional delivery is central to reducing maternal mortality. The factors associated with place of delivery among women in Afghanistan were examined using the Afghanistan Mortality Survey 2010 (AMS 2010), which was open to researchers. The AMS 2010 data were collected through an interviewer-led questionnaire from 18,250 women. Odds ratio (OR) and 95% confidence interval (CI) of non-institutional delivery were estimated by logistic regression analysis. When age at survey, education, parity, residency, antenatal care frequency, remoteness, wealth and regions were adjusted, the OR of non-institutional delivery was 8.37 (95% CI, 7.47-9.39) for no antenatal care relative to four or more antenatal care visits, 4.07 (95% CI, 3.45-4.80) for poorest household relative to women from richest household, 2.02 (95% CI, 1.43-2.84) for no education relative to higher education, 1.78 (95% CI, 1.52-2.09) for six or more deliveries relative to one delivery, and 1.50 (95% CI, 1.36-1.67) for rural relative to urban residency. Since antenatal care was strongly associated with non-institutional delivery after adjustment of the other factors, antenatal care service may promote institutional deliveries, which can reduce maternal mortality ratio in Afghanistan. PMID- 25797980 TI - Left ventricular dyssynchrony in patients with moderate coronary stenosis and border line fractional flow reserve. AB - The cutoff values of fractional flow reserve (FFR) to detect physiological myocardial ischemia are still controversial. Some studies have reported that left ventricular (LV) dyssynchrony occurs in patients with coronary artery disease (CAD). The purpose of this study was to investigate LV dyssynchrony in patients with moderate coronary stenosis and borderline FFR, using stress electrocardiographically-gated myocardial perfusion single-photon emission computed tomography (SPECT). The study population comprised 10 patients with moderate (50-75% diameter) stenosis and an FFR in the range 0.75-0.90, who were compared to 10 control subjects. All underwent stress myocardial (99m)Tc sestamibi (MIBI) or tetrofosmin SPECT imaging. The regional time to end systole (TES), time to peak ejection (TPE), and time to peak filling (TPF) were obtained as indexes of perfusion and function, using gated SPECT (pFAST) in combination with Cardio Gated SPECT Regional Assessment for LV Function (cardioGRAF). The dyssynchrony index (DI) was also calculated. The DI of post-stress TES was significantly greater than that of rest in patients with moderate CAD (4.8 +/- 2.8 vs. 2.7 +/- 1.5, P = 0.01), but there were no significant differences in the control subjects (3.0 +/- 1.7 vs. 2.9 +/- 1.9, P = 0.99). There were no significant differences in TPE and TPF between the groups. In conclusion, LV dyssynchrony may occur after stress in patients with coronary stenosis and borderline FFR, even without a significant reduction in perfusion. PMID- 25797979 TI - Protective effects of phyllanthus emblica leaf extract on sodium arsenite mediated adverse effects in mice. AB - Groundwater contamination of arsenic is the major cause of a serious health hazard in Bangladesh. No specific treatment is yet available to manage the large number of individuals exposed to arsenic. In this study, we evaluated the protective effects of Phyllanthus emblica (Indian gooseberry or Amla) leaf extract (PLE) on arsenic-mediated toxicity in experimental mice. Male Swiss albino mice were divided into three different groups (n=6/group). 'Control' mice received arsenic free water together with normal feed. Mice in the remaining two groups designated 'SA' and 'SA+PLE' were exposed to sodium arsenite (SA, 10 ug/g body weight/day) through drinking water in addition to receiving normal feed and PLE-supplemented feed, respectively. The weight gain of SA-exposed mice was decreased compared with the controls; however, this decrease in body weight gain was prevented when the feed was supplemented with PLE. A secondary effect of arsenic was enlargement of the liver, kidney and spleen of SA-group mice. Deposition of arsenic in those organs was demonstrated by ICP-MS. When PLE was supplemented in the feed the enlargement of the organs was minimized; however, the deposition of arsenic was not significantly reduced. These results indicated that PLE may not block arsenic deposition in tissue directly but rather may play a protective role to reduce arsenic-induced toxicity. Therefore, co administration of PLE in arsenic-exposed animals might have a future therapeutic application for protecting against arsenic-mediated toxicity. PMID- 25797981 TI - Solitary fibrous tumors in the extremities: imaging findings for six patients. AB - The purpose of this study was to describe the magnetic resonance imaging (MRI) and computed tomography (CT) findings for solitary fibrous tumors (SFTs) in the extremities in correlation with histopathological findings. Between 2006 and 2013, 6 consecutive patients with SFT in an extremity were studied with MRI (6 patients) and CT (4 patients). Diffusion-weighted images were also performed in 3 patients and dynamic contrast-enhanced CT in 2 patients. All 6 tumors were diagnosed after surgical excision, and the pre-surgical imaging findings were correlated with the histopathological findings. As a result, all 6 patients were female, and each had a clearly palpable, well-circumscribed, round or oval mass adjacent to fascia in an extremity, of less than 10 cm maximum diameter in 5 patients. On MRI, the tumors were iso-intense with muscle on T1-weighted image, and appeared heterogeneous and high-intensity on T2-weighted image. After injection of a contrast agent, the tumors demonstrated strong enhancement. A vascular pedicle was detected in 4 patients with tumors having a maximum diameter more than 5 cm. Diffusion-weighted images demonstrated high signal intensities, and apparent diffusion coefficient values were iso to high compared to muscle (from 1.41-2.10*10(-3) mm(2)/s). All the tumors were benign histopathologically and clinically. In 1 patient, the imaging appearance revealed underlying histopathological components, including fibrous-rich, cellular-rich, and myxoid change areas. In conclusion, a SFT in an extremity comprises a well-circumscribed mass adjacent to fascia having a fibrous-dominant area, strong contrast enhancement, and a vascular pedicle. PMID- 25797982 TI - Progress toward measles elimination in kyrgyzstan. AB - Measles is one of the most severe infectious diseases of childhood, and one of the major causes of mortali-ty, especially in developing countries. Despite rare measles outbreaks in recent years, Kyrgyzstan seeks to show its commitment towards the global anti-measles campaign. The aim of this article is to summarize the scattered information on the recent status of measles, valid surveillance system, and measles elimination strategies in Kyrgyzstan, based on sources that include non-confidential but usually inaccessible governmental data. Infor-mation was extracted from the reports to the Ministry of Health and documents on the national surveillance system, in addition to outbreak cases extracted from the Republican Infectious Diseases Hospital's archive. To tackle the worsening measles situation in Kyrgyzstan, the Ministry of Health established the Republican Center for Immunoprophylaxis in 1994. Measles related death, which was rampant up until 1992, has not been registered since 2000 due to improved routine vaccination coverage, increasing from 88% in 1994 to 97% and over in 1997. The national surveillance system was modernized thanks to the World Health Organization, helping to detect measles cases and prevent major outbreaks. The system identified 222 cases in the outbreak of 2011, and the case cards in the hospital provided the findings of 69 admitted cases (42 infants, 22 children aged 1 to 14 years, and 5 aged 15 years or over), including 32 severe cases. This article provides a whole view on measles in Kyrgyzstan, which would be useful to control measles worldwide. PMID- 25797983 TI - Minimally invasive extraction of a foreign body from the small intestine using double-balloon endoscopy. AB - Double-balloon endoscopy (DBE) can be used to treat disorders of the small intestine and can also be used to retrieve foreign bodies from the small intestine without surgery. We describe the findings of 22 cases in which DBE was used to try and retrieve foreign bodies from the small intestine. The foreign bodies included 12 capsule endoscopes, 3 artificial teeth, 3 medical tubes, 2 worms, 1 press-through packet of medicine, and 1 intestinal stone. The retrieval success rate was 86.3% (19/22), and there were no complications related to the retrieval procedures. Snare forceps were the most useful device for grasping the foreign bodies, and DBE was usually performed via an oral route. If an anal route is selected in cases involving stenosis of the small intestine, endoscopic balloon dilation will be necessary to reach the target. In conclusion, DBE is very useful for extracting foreign bodies from the small intestine, and the careful selection of the DBE route and the removal device are important for successfully retrieving foreign bodies. PMID- 25797984 TI - Minimal inflammogenicity of pristine single-wall carbon nanotubes. AB - Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi-wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 MUg/cm(2) SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low-risk material with respect to mesothelial carcinogenesis. PMID- 25797985 TI - Health care expenditure of households in magway, myanmar. AB - Myanmar has a high proportion of out-of-pocket (OOP) health care expenditures with limited cost-sharing mechanisms. In Myanmar, there were limited data on the frequency of catastrophic health expenditure (CHE) due to OOP payments, as well as on the factors associated with CHE. This study aimed to investigate health care expenditure, the frequency of CHE, and the factors influencing CHE among households in Magway, Myanmar. A cross-sectional household survey was conducted in 2012 for 700 households (350 in urban areas and 350 in rural areas) in Magway. CHE was defined as a condition wherein the total amount of household health care expenditure was 40% or more of non-food expenditure in the past year. Multiple logistic regression analysis was applied to estimate odds ratios (ORs) and 95% confident intervals (CIs) of CHE. In the previous year, 28.3% of 350 urban households and 51.4% of 350 rural households utilized outpatient services. Households with at least one member admitted to a medical facility were 10.0% and 12.9%, respectively. Those with CHE were 25.2% in the urban areas and 22.7% in the rural areas. The adjusted OR of CHE was 7.79 (95% CI 3.73-16.26) for hospitalization and 1.08 (95% CI 0.36-3.23) for outpatient care, relative to no services used. These findings indicated that nearly one fourth of households in Magway faced CHE due to inpatient care. A safety-net mechanism to protect households from CHE in Myanmar seems essential. PMID- 25797986 TI - Treatment outcomes of intradiscal steroid injection/selective nerve root block for 161 patients with cervical radiculopathy. AB - Patients with cervical radiculopathy (CR) were treated with intradiscal injection of steroids (IDIS) and/or selective nerve root block (SNRB) at our hospital. We retrospectively report the outcomes of these nonsurgical treatments for CR. 161 patients who were followed up for >2months were enrolled in this study. Patients' clinical manifestations were classified as arm pain, arm numbness, neck and/or scapular pain, and arm paralysis. Improvement in each manifestation was classified as "disappeared," "improved," "poor," or "worsened." Responses of "disappeared" or "improved" manifestations suggested treatment effectiveness. Final clinical outcomes were evaluated using the Odom criteria. Changes in herniated disc size were evaluated by comparing the initial and final MRI scans. On the basis of these changes, the patients were divided into regression, no change, or progression groups. We investigated the relationship between the Odom criteria and changes observed on MRI. Effectiveness rates were 89% for arm pain, 77% for arm numbness, 82% for neck and/or scapular pain, and 76% for arm paralysis. In total, 91 patients underwent repeated MRI. In 56 patients (62%), the size of the herniated disc decreased, but 31 patients (34%) exhibited no change in disc size. The regression group showed significantly better Odom criteria results than the no-change group. In conclusion, IDIS and SNRB for CR are not widely performed. However, other extremely effective therapies that can rapidly improve neuralgia should be considered before surgery. PMID- 25797987 TI - Range of motion determined by multidetector-row computed tomography in patients with cervical ossification of the posterior longitudinal ligament. AB - The purpose of this study was to measure range of motion (ROM) in patients with cervical ossification of posterior longitudinal ligament (C-OPLL) by multidetector-row computed tomography (MDCT), and to investigate the influence of dynamic factors. The study included 101 patients with C-OPLL and 99 normal control patients. Preoperative MDCT were taken in all subjects in maximum neck flexion and extension. ROM at each disc level between C2/3 and C7/T1 in sagittal view was measured. Ossification morphology at each disc segment was divided into 6 groups: covered disc, covered vertebra, unconnected vertebra, connected vertebra (continuous), connected vertebra (localized), and others. The relationship between ROM and the group of ossification morphology was also investigated. ROM of adjacent intervertebral disc in connected vertebrae (continuous and localized) and those of others were investigated for each group. The average ROM of covered disc group was significantly higher than that of connected vertebra (continuous, localized). The average ROM of connected vertebra (continuous) group was significantly lower than that of covered disc group, others group, and normal control. There was no significant difference between ROM of adjacent intervertebral disc in connected vertebrae and others, but the average ROM of the connected vertebra group was significantly lower than that of the covered disc group and normal control group. Dynamic factor was reduced at continuous segment, but it was not increased in adjacent intervertebral disc. PMID- 25797988 TI - The renal tumor morphological characteristics that affect surgical planning for laparoscopic or open partial nephrectomy. AB - The purpose of this study is to investigate the morphological characteristics of renal tumors which affect the surgeons' decision-making for the selection of open or laparoscopic partial nephrectomy. We included 147 patients who underwent partial nephrectomy for renal masses with elective indications in this study. Laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN) were performed in 72 and 75 patients, respectively. Preoperative trans-sectional images were used to assess tumor characteristics such as tumor size, endophyticity, distance from the sinus, distance from the kidney equator, hilar designation, inside designation, and R.E.N.A.L. nephrometry score. Univariate logistic regression analyses demonstrated that tumor size, endophyticity, distance from the sinus, hilar designation, inside designation, and R.E.N.A.L. nephrometry score were associated with decision of laparoscopic partial nephrectomy. Among these factors, multiple regression analyses showed that endophyticity (odds ratio = 0.92, p = 0.007) and distance from the sinus (odds ratio = 1.201, p < 0.001) had statistically significant associations with the type of operation performed. ROC analyses demonstrated cut-off values of 16 mm for endophyticity (sensitivity 69%, specificity 77%) and of 4 mm for distance from the sinus (sensitivity 79%, specificity 65%) for predicting the selection of laparoscopic surgery. In conclusion, this study revealed that endophyticity and distance from the sinus were important for the surgical planning of partial nephrectomy. PMID- 25797989 TI - Suitability of surveillance colonoscopy for patients with ulcerative colitis to detect colorectal cancer: current guidelines miss some early-stage cases. AB - Surveillance colonoscopy (SC) is considered important for the early detection and treatment of colorectal cancer (CRC) in patients with ulcerative colitis (UC). Here, we investigated whether current guidelines are appropriate in preventing UC patients from being diagnosed with CRC at an incurable stage. Among 1583 patients under treatment for UC, 27 patients were diagnosed with CRC. Of these, we excluded two patients who had not undergone colonoscopy before CRC diagnosis. We then divided the remaining patients into three groups based on colonoscopy interval (A, 1 year or less; B, between 1 and 2 years; and C, 2 years or longer). Fifteen patients had tubular adenocarcinomas, and 10 had other types (8 poorly differentiated adenocarcinomas, 1 mucinous adenocarcinoma, 1 endocrine cell carcinoma). Five (20%) of 25 patients developed CRC within 8 years after the onset of UC, of which one case was detected at stage IV. Six patients were classified into group A, 8 into group B, and 11 into group C. On distribution by histologic type, tubular adenocarcinomas were detected in stages 0 - II in 100% in group A, 100% in group B, and 57.1% in group C. In contrast, other types of carcinomas were detected in stage 0 - II in 100% in group A, 40% in group B, and 0% in group C. Current guideline recommendations for SC are not sufficient for the detection of early stage CRC in patients with UC. SC should be commenced earlier than recommended in the current guidelines and repeated annually. PMID- 25797990 TI - High osmolarity effect of intravitreal plasmin enzyme on rabbit retina. AB - We conducted a study of the effect of intravitreal plasmin on retinal thickness in rabbits. Forty rabbit eyes were injected with 0.4, 1, 2, and 5 IU of plasmin (8 eyes/group). The same volume of BSS-plus((r)) was injected in control eyes. Four eyes in each group underwent vitrectomy 60 minutes after the injections. The retinal thickness was measured in optical coherence tomographic (OCT) images before, 30 minutes, and 1 week after the injection. To study the effect of hyperosmolarity, 4 eyes received an injection of mannitol solution whose osmolarity was the same as the plasmin solutions. Thirty minutes after the plasmin injection, 4 eyes developed a serous retinal detachment (SRD). The mean retinal thickness including SRD was increased at 30 minutes in a dose-dependent way. The increase in eyes with 5 IU of plasmin was significantly greater than that in eyes with BSS-Plus((r)) or 0.4 IU of plasmin (P = 0.0266, P = 0.0371, respectively). One week after the injection, SRD disappeared, and the mean retinal thickness decreased. The eyes injected with mannitol, the same osmolarity of 1, 2, 5 IU of plasmin, developed SRD at 30 minutes, and it disappeared after 1 week in all eyes. The results of this study demonstrated that an intravitreal injection of plasmin increases the retinal thickness in a dose-dependent way in rabbit eyes. The results with mannitol suggest that the increase in retinal thickness following plasmin is most likely caused by the hyperosmolarity of plasmin solution. PMID- 25797991 TI - Successful transplantation of motoneurons into the peripheral nerve depends on the number of transplanted cells. AB - Transplantation of motoneurons (MN) into the peripheral nerve to provide a source of neurons for muscle reinnervation, termed motoneuron integrated striated muscle (MISM), may provide the potential to restore functional muscle activity, when combined with computer-programmed functional electrical stimulation (FES). The number of MNs required to restore innervation to denervated muscles in adult Fischer 344 rats was investigated by comparing two groups, one transplanted with 2 * 10(5) cells (group A) and the other with 1 * 10(6) cells (group B). Twelve weeks after transplantation, electrophysiological analysis, muscle function analysis, and tissue analysis were performed. The mean motor nerve conduction velocity was faster (12.4 +/- 1.0 m/s vs. 8.5 +/- 0.7 m/s, P = 0.011) and the mean amplitude of compound muscle action potential was larger (1.6 +/- 0.4 mV vs. 0.7 +/- 0.2 mV, P = 0.034) in group B. The dorsiflexed ankle angle was larger in group B (27 +/- 5 degrees vs. 75 +/- 8 degrees , P = 0.02). The mean myelinated axon number in the peroneal nerve and the proportion of reinnervated motor end plates were also greater in group B (317 +/- 33 vs. 104 +/- 17, 87.5 +/- 3.4% vs. 40.6 +/- 7.7%; P < 0.01, respectively). When sufficient MNs are transplanted into the peripheral nerve, MISM forms functional motor units. MISM, in conjunction with FES, provides a new treatment strategy for paralyzed muscles. PMID- 25797992 TI - Impact of the intraoperative use of fibrinogen concentrate for hypofibrinogenemia during thoracic aortic surgery. AB - Thoracic aortic surgery often causes massive bleeding due to coagulopathy. Hypofibrinogenemia is one of the major causative factors, but the utility of the intraoperative administration of fibrinogen concentrate has not yet been proven. The aim of this study was to estimate incidence of hypofibrinogenemia and to evaluate efficacy of using fibrinogen concentrate intraoperatively. The perioperative serum fibrinogen levels (SFL) had routinely been measured in consecutive 216 thoracic aortic surgeries performed from 2010 to 2012. Fibrinogen concentrate was principally used for hypofibrinogenemia (< 150 mg/dl of SFL) at cardiopulmonary bypass (CPB) termination. The patients who received fibrinogen concentrate (FIB group) were compared with the patients who did not received (non Fib group). There were 147 patients (68%) in FIB group at a dose of 5.5+/-3.5 g. The SFL were dramatically decreased with values of 164+/-71 mg/dl at CPB termination, compared to the preoperative SFL of 352+/-131 mg/dl. In the FIB group, the intraoperative and postoperative SFLs were 139+/-53 and 262+/-75 (mg/dl), respectively. Thus the SFL was recovered quickly by the administration. 110 cases (51%) showed hypofibrinogenemia at the termination of CPB. The predictors of hypofibrinogenemia were preoperative SFL < 250 mg/dl, emergency surgery and thracoabdominal aortic surgery. Hypofibrinogenemia frequently was observed at the termination of CPB during thoracic aortic surgery. Administering intraoperative fibrinogen concentrate appears to be a useful option to treat coagulopathy. PMID- 25797993 TI - Roles of oxidative stress and the mineralocorticoid receptor in cardiac pathology in a rat model of metabolic syndrome. AB - Oxidative stress and the mineralocorticoid receptor (MR) are implicated in the pathogenesis of salt-induced left ventricular (LV) diastolic dysfunction associated with metabolic syndrome (MetS). We recently characterized DahlS.Z Lepr(fa) /Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt sensitive and Zucker rats, as a new animal model of MetS. We investigated the pathophysiological roles of increased oxidative stress and MR activation in cardiac injury with this model. DS/obese rats were treated with the antioxidant tempol (1 mmol/L in drinking water) or the selective MR antagonist eplerenone (15 mg/kg per day, per os) for 5 weeks beginning at 10 weeks of age. The increased systolic blood pressure and LV hypertrophy that develop in untreated DS/obese rats were substantially ameliorated by eplerenone but not by tempol. Eplerenone also attenuated LV fibrosis and diastolic dysfunction more effectively than did tempol in DS/obese rats, whereas cardiac oxidative stress and inflammation were reduced similarly by both drugs. Both the ratio of plasma aldosterone concentration to plasma renin activity and cardiac expression of the MR and serum/glucocorticoid-regulated kinase 1 genes were decreased to a greater extent by eplerenone than by tempol. Our results indicate that both increased oxidative stress and MR activation in the heart may contribute to the development of LV remodeling and diastolic dysfunction in DS/obese rats. The superior cardioprotective action of eplerenone is likely attributable to its greater antihypertensive effect, which is likely related to its greater inhibition of aldosterone-MR activity in the cardiovascular system. PMID- 25797994 TI - Laparoscopic partial gastrectomy of a huge gastric duplication cyst in an infant. AB - Gastric duplication cyst is a rare anomaly, and most cases are recognized during childhood. Recently, several pediatric cases with small gastric duplication cysts treated by laparoscopic resection have been reported. Here, we describe an infant in whom we successfully performed laparoscopic partial gastrectomy for the treatment of a huge gastric duplication cyst. To the best of our knowledge, this is the largest gastric duplication cyst treated by laparoscopic surgery among infants. We introduce our procedure and some tips. PMID- 25797995 TI - Recurrent ectopic craniopharyngioma in the sylvian fissure thirty years after resection through a pterional approach: a case report and review of the literature. AB - Local recurrence of craniopharyngiomas after apparently complete resection occurs frequently. Ectopic recurrence remote from the original site has been reported in 18 adult patients. The interval between the original diagnosis and the time of recurrence varies widely in these reports (1-26 years). We report a case of an ectopic recurrence in the sylvian fissure of an adamantinomatous type craniopharyngioma 34 years after the initial presentation and 30 years after the last surgical resection. In addition to this being the latest reported ectopic recurrence, the location of this new lesion in the sylvian fissure is fairly rare, having been reported in only three other cases. We also reviewed the English literature for reports of ectopic recurrent craniopharyngiomas in order to conduct an analysis of surveillance and treatment strategies. PMID- 25797996 TI - A case of ruptured intrameatal aneurysm successfully treated with coil embolization. AB - Aneurysms within the internal acoustic canal are rare. We report the case of a 71 year-old female with subarachnoid hemorrhage resulting from a ruptured distal anterior inferior cerebellar artery which was not detected on initial radiological examination. A second rupture was detected by contrast-enhanced computed tomography and successfully treated by endovascular coil embolization. The patient recovered without neurological deficits. To the best of our knowledge, this is the first report of an intrameatal aneurysm treated by endovascular coil embolization. We suggest endovascular coil embolization as an alternative to open surgery, even in cases of deep intrameatal aneurysm. PMID- 25797997 TI - Grafted vertebral fracture after implant removal in a patient with spine shortening vertebral osteotomy. AB - We experienced the rare complication of a vertebral fracture that was caused by implant removal after bony fusion had been achieved in a patient who underwent spine-shortening osteotomy (SSO) for tethered cord syndrome (TCS). We propose that the removal of the implant used for SSO should be contraindicated. The patient (a 27-year-old female) presented to our institution with a history of progressive severe lower back pain, gait disturbance, and urinary incontinence. As an infant, she had undergone surgery for spina bifida with lipoma. Magnetic resonance imaging of the spine revealed tethering of the spinal cord to a lipoma. We performed SSO at the level of the L1 vertebra level. After spine shortening and fixation using a posterior approach, the L1 vertebral body was completely removed anteriorly and replaced with a left iliac bone graft. The patient's symptoms improved after surgery. After bony fusion was achieved after surgery, we decided to remove the spinal implant after we explained the advantages and disadvantages of the procedure to the patient. We performed implant removal surgery safely 2 years later; however, the patient complained of severe lower back pain 10 days after the surgery without any history of trauma. Reconstruction computed tomography showed fracture of the grafted vertebra. We performed a repeat posterior fixation, which relieved the lower back pain; she has experienced no complications in the subsequent 5 years. In summary, we report a case of a rare complication of the fracture of a grafted vertebra after removal of an implant used in SSO for TCS. Spinal stability could not be maintained without the spinal posterior implant after SSO. Postoperative fracture after spinal implant removal is rare but possible, and patients must be informed of this potential risk. PMID- 25797998 TI - Rhabdoid glioblastoma: an aggressive variaty of astrocytic tumor. AB - Rhabdoid glioblastoma (RGBM) is rare, but the most malignant among astrocytic tumors. Accumulating evidence indicates its highly aggressive nature and distinct histopathological features. Here, we report a new case of RGBM and review previously reported cases of astrocytic tumors with rhabdoid components. We describe a 58-year-old man who presented with aphasia and right-sided weakness. Magnetic resonance imaging revealed a well-delineated intramedullary tumor in the left cerebral hemisphere. Partial resection of the tumor was performed. The tumor was histologically found to contain two distinct areas: a typical glioblastoma, and a rhabdoid component. Immunohistochemical analyses revealed expression of glial fibrillary acidic protein (GFAP) and focal loss of the INI1 protein in rhabdoid cells, although fluorescence in situ hybridization analysis showed no loss of the INI1 gene. Despite subsequent radiochemotherapy for the glioblastoma, the patient died 4.3 months after surgery. Our literature review illustrates the aggressive clinical course and histopathological features of these tumors with GFAP and INI1 expression. INI1 protein dysfunction may be a possible cause of the rhabdoid phenotype. Gross total resection of the tumor and intensive radiochemotherapy may lead to better survival outcomes. PMID- 25797999 TI - Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development. AB - The cytochrome P450 (CYP) enzymes are a versatile superfamily of heme-containing monooxygenases, perhaps best known for their role in the oxidation of xenobiotic compounds. However, due to their unique oxidative chemistry, CYPs are also important in natural product drug discovery and in the generation of active metabolites with unique therapeutic properties. New tools for the analysis and production of CYP metabolites, including microscale analytical technologies and combinatorial biosynthesis, are providing medicinal chemists with the opportunity to use CYPs as a novel platform for lead discovery and development. In this review, we will highlight some of the recent examples of drug leads identified from CYP metabolites and the exciting possibilities of using CYPs as catalysts for future drug discovery. PMID- 25798000 TI - Computed tomography findings of paracoccidiodomycosis in musculoskeletal system. AB - OBJECTIVE: To evaluate musculoskeletal involvement in paracoccidioidomycosis at computed tomography. MATERIALS AND METHODS: Development of a retrospective study based on a review of radiologic and pathologic reports in the institution database. Patients with histopathologically confirmed musculoskeletal paracoccidioidomycosis and submitted to computed tomography were included in the present study. The imaging findings were consensually described by two radiologists. In order to avoid bias in the analysis, one patient with uncountable bone lesions was excluded from the study. RESULTS: A total of seven patients were included in the present study. A total of 18 bone lesions were counted. The study group consisted of 7 patients. A total number of 18 bone lesions were counted. Osteoarticular lesions were the first manifestation of the disease in four patients (57.14%). Bone lesions were multiple in 42.85% of patients. Appendicular and axial skeleton were affected in 85.71% and 42.85% of cases, respectively. Bone involvement was characterized by well-demarcated osteolytic lesions. Marginal osteosclerosis was identified in 72.22% of the lesions, while lamellar periosteal reaction and soft tissue component were present in 5.55% of them. One patient showed multiple small lesions with bone sequestra. CONCLUSION: Paracoccidioidomycosis can be included in the differential diagnosis of either single or multiple osteolytic lesions in young patients even in the absence of a previous diagnosis of pulmonary or visceral paracoccidioidomycosis. PMID- 25798001 TI - The role of transrectal ultrasound in the diagnosis of prostate cancer: new contributions. AB - OBJECTIVE: The present study was aimed at evaluating the contribution of transrectal prostate ultrasound in the screening for prostate neoplasias and in the guidance of prostate biopsies. MATERIALS AND METHODS: Prospective study developed over a one-year period. All the patients with indication for prostate biopsy were evaluated. Regardless of PSA values, the patients underwent ultrasound in order to identify suspicious nodules (confirmed by two observers). Sextant biopsy was subsequently performed. In cases of finding suspicious nodules, an additional puncture directed to such nodules was done. RESULTS: In a total of 155 cases the prevalence of malignancy was of 53%. Suspicious nodules were detected in 34 patients, and 25 where malignant (positive predictive value of 74%). The specificity and sensitivity for suspicious nodules were 88% and 31% respectively. Comparatively with the randomly obtained sextant specimens, the rate of findings of neoplasia was higher in the specimens obtained with puncture directed to the nodule (p = 0.032). No statistically significant difference was observed in the Gleason score for both types of specimens (p = 0.172). CONCLUSION: The high positive predictive value and the high rate of findings of neoplasia in specimens of suspicious nodules should be taken into consideration in the future. The authors suggest a biopsy technique similar to the one described in the present study (sextant biopsy plus puncture directed to the suspicious nodule). PMID- 25798002 TI - Value of renal cortical thickness as a predictor of renal function impairment in chronic renal disease patients. AB - OBJECTIVE: To determine the presence of linear relationship between renal cortical thickness, bipolar length, and parenchymal thickness in chronic kidney disease patients presenting with different estimated glomerular filtration rates (GFRs) and to assess the reproducibility of these measurements using ultrasonography. MATERIALS AND METHODS: Ultrasonography was performed in 54 chronic renal failure patients. The scans were performed by two independent and blinded radiologists. The estimated GFR was calculated using the Cockcroft-Gault equation. Interobserver agreement was calculated and a linear correlation coefficient (r) was determined in order to establish the relationship between the different renal measurements and estimated GFR. RESULTS: The correlation between GFR and measurements of renal cortical thickness, bipolar length, and parenchymal thickness was, respectively, moderate (r = 0.478; p < 0.001), poor (r = 0.380; p = 0.004), and poor (r = 0.277; p = 0.116). The interobserver agreement was considered excellent (0.754) for measurements of cortical thickness and bipolar length (0.833), and satisfactory for parenchymal thickness (0.523). CONCLUSION: The interobserver reproducibility for renal measurements obtained was good. A moderate correlation was observed between estimated GFR and cortical thickness, but bipolar length and parenchymal thickness were poorly correlated. PMID- 25798003 TI - Comparison of standardized uptake values measured on F-NaF PET/CT scans using three different tube current intensities. AB - OBJECTIVE: To analyze standardized uptake values (SUVs) using three different tube current intensities for attenuation correction on (18)FNaF PET/CT scans. MATERIALS AND METHODS: A total of 254 (18)F-NaF PET/CT studies were analyzed using 10, 20 and 30 mAs. The SUVs were calculated in volumes of interest (VOIs) drawn on three skeletal regions, namely, right proximal humeral diaphysis (RH), right proximal femoral diaphysis (RF), and first lumbar vertebra (LV1) in a total of 712 VOIs. The analyses covered 675 regions classified as normal (236 RH, 232 RF, and 207 LV1). RESULTS: Mean SUV for each skeletal region was 3.8, 5.4 and 14.4 for RH, RF, and LV1, respectively. As the studies were grouped according to mAs value, the mean SUV values were 3.8, 3.9 and 3.7 for 10, 20 and 30 mAs, respectively, in the RH region; 5.4, 5.5 and 5.4 for 10, 20 and 30 mAs, respectively, in the RF region; 13.8, 14.9 and 14.5 for 10, 20 and 30 mAs, respectively, in the LV1 region. CONCLUSION: The three tube current values yielded similar results for SUV calculation. PMID- 25798004 TI - Ambient radiation levels in positron emission tomography/computed tomography (PET/CT) imaging center. AB - OBJECTIVE: To evaluate the level of ambient radiation in a PET/CT center. MATERIALS AND METHODS: Previously selected and calibrated TLD-100H thermoluminescent dosimeters were utilized to measure room radiation levels. During 32 days, the detectors were placed in several strategically selected points inside the PET/CT center and in adjacent buildings. After the exposure period the dosimeters were collected and processed to determine the radiation level. RESULTS: In none of the points selected for measurements the values exceeded the radiation dose threshold for controlled area (5 mSv/year) or free area (0.5 mSv/year) as recommended by the Brazilian regulations. CONCLUSION: In the present study the authors demonstrated that the whole shielding system is appropriate and, consequently, the workers are exposed to doses below the threshold established by Brazilian standards, provided the radiation protection standards are followed. PMID- 25798005 TI - Dose calibrator linearity test: (99m)Tc versus (18)F radioisotopes. AB - OBJECTIVE: The present study was aimed at evaluating the viability of replacing (18)F with (99m)Tc in dose calibrator linearity testing. MATERIALS AND METHODS: The test was performed with sources of (99m)Tc (62 GBq) and (18)F (12 GBq) whose activities were measured up to values lower than 1 MBq. Ratios and deviations between experimental and theoretical (99m)Tc and (18)F sources activities were calculated and subsequently compared. RESULTS: Mean deviations between experimental and theoretical (99m)Tc and (18)F sources activities were 0.56 (+/- 1.79)% and 0.92 (+/- 1.19)%, respectively. The mean ratio between activities indicated by the device for the (99m)Tc source as measured with the equipment pre calibrated to measure (99m)Tc and (18)F was 3.42 (+/- 0.06), and for the (18)F source this ratio was 3.39 (+/- 0.05), values considered constant over the measurement time. CONCLUSION: The results of the linearity test using (99m)Tc were compatible with those obtained with the (18)F source, indicating the viability of utilizing both radioisotopes in dose calibrator linearity testing. Such information in association with the high potential of radiation exposure and costs involved in (18)F acquisition suggest (99m)Tc as the element of choice to perform dose calibrator linearity tests in centers that use (18)F, without any detriment to the procedure as well as to the quality of the nuclear medicine service. PMID- 25798006 TI - Magnetic resonance imaging of the chest in the evaluation of cancer patients: state of the art. AB - Magnetic resonance imaging (MRI) has several advantages in the evaluation of cancer patients with thoracic lesions, including involvement of the chest wall, pleura, lungs, mediastinum, esophagus and heart. It is a quite useful tool in the diagnosis, staging, surgical planning, treatment response evaluation and follow up of these patients. In the present review, the authors contextualize the relevance of MRI in the evaluation of thoracic lesions in cancer patients. Considering that MRI is a widely available method with high contrast and spatial resolution and without the risks associated with the use of ionizing radiation, its use combined with new techniques such as cine-MRI and functional methods such as perfusion- and diffusion-weighted imaging may be useful as an alternative tool with performance comparable or complementary to conventional radiological methods such as radiography, computed tomography and PET/CT imaging in the evaluation of patients with thoracic neoplasias. PMID- 25798008 TI - Assessment of embryo/fetus during pregnancy by threedimensional ultrasonography using the HD live software: iconographic essay. AB - Fetal development is studied since the advent of two-dimensional ultrasonography. However, a detailed assessment of structures and surfaces improved with three dimensional ultrasonography. Currently, it is possible to identify embryonic components and fetal parts with greater detail, at all pregnancy trimesters, using the HD live software, where the images gain realistic features by means of appropriate control of lighting and shadowing effects. In the present study, the authors utilized this resource to follow-up, by means of images, the development of a normal pregnancy along all trimesters. PMID- 25798009 TI - Sclerosing encapsulating peritonitis: a case report. AB - Sclerosing encapsulating peritonitis, a rare cause of bowel obstruction, was described as a complication associated with peritoneal dialysis which is much feared because of its severity. The authors report a case where radiological findings in association with clinical symptoms have allowed for a noninvasive diagnosis of sclerosing encapsulating peritonitis, emphasizing the high sensitivity and specificity of computed tomography to demonstrate the characteristic findings of such a condition. PMID- 25798007 TI - The role of gadoxetic acid as a paramagnetic contrast medium in the characterization and detection of focal liver lesions: a review. AB - Recent studies have demonstrated that the use of paramagnetic hepatobiliary contrast agents in the acquisition of magnetic resonance images remarkably improves the detection and differentiation of focal liver lesions, as compared with extracellular contrast agents. Paramagnetic hepatobiliary contrast agents initially show the perfusion of the lesions, as do extracellular agents, but delayed contrast-enhanced images can demonstrate contrast uptake by functional hepatocytes, providing further information for a better characterization of the lesions. Additionally, this intrinsic characteristic increases the accuracy in the detection of hepatocellular carcinomas and metastases, particularly the small sized ones. Recently, a hepatobiliary contrast agent called gadolinium ethoxybenzyl dimeglumine, that is simply known as gadoxetic acid, was approved by the National Health Surveillance Agency for use in humans. The authors present a literature review and a practical approach of magnetic resonance imaging utilizing gadoxetic acid as contrast agent, based on patients' images acquired during their initial experiment. PMID- 25798010 TI - Peripheral primitive neuroectodermal tumor of chest wall in young adult. PMID- 25798012 TI - Pre- and postnatal findings of a dicephalus tetrabrachius-dipus conjoined twins with a diaphragmatic hernia. PMID- 25798011 TI - Melorheostosis. PMID- 25798013 TI - Epidural cavernous hemangioma of the spine: magnetic resonance imaging findings. PMID- 25798014 TI - Giant pilomatrixoma: conventional and diffusion-weighted magnetic resonance imaging findings. PMID- 25798015 TI - Which is your diagnosis? PMID- 25798016 TI - Changes in radiologia brasileira for 2015. PMID- 25798017 TI - Contribution of transrectal ultrasonography-guided biopsy in the diagnosis of prostate cancer: looking back and ahead. PMID- 25798018 TI - Differential Reporting of Adolescent Stress as a Function of Maternal Depression History. AB - The depression-distortion hypothesis posits that depressed mothers report child characteristics in a negatively-biased manner, motivating research on discrepant reporting between depressed mothers and their children. However, the literature has predominately focused on report discrepancies of youth psychopathological and behavioral outcomes, with limited focus on youth stress despite the marked increase of stressful events during adolescence. The current study investigated whether the presence versus absence of a maternal history of major depressive disorder differentially influenced reporting of adolescent stress when compared to her child's report, utilizing a community sample of diverse adolescents. As hypothesized, mothers with a history of depression were more likely to report more youth stress than their children reported. Specifically, mothers with a history of depression were more likely than nondepressed mothers to report more familial, social, and youth-dependent stressors relative to their children; nondepressed mothers were more likely to report less independent stressors than their children. PMID- 25798019 TI - Implementing outside the box: Community-based social service provider experiences with using an alcohol screening and intervention. AB - OBJECTIVE: The aim of this study is better understand perceptions of front-line social service workers who are not addiction specialists, but have to address addiction-related issues during their standard services. METHOD: Six social service organizations implemented a validated alcohol assessment and brief education intervention. After a 3-month trial implementation period, a convenience sample of 64 front-line providers participated in six focus groups to examine barriers and facilitators to the implementation of an alcohol screening and brief intervention. RESULTS: Three themes emerged: (1) usefulness of the intervention, (2) intervention being an appropriate fit with the agency and client population, and (3) worker commitment and proper utilization during the implementation process. CONCLUSIONS: A cross-cutting theme that emerged was the context in which the intervention was implemented, as this was central to each of the three primary themes identified from the focus groups (i.e., the usefulness and appropriateness of the intervention and the implementation process overall). Practitioner buy-in concerns also indicate the need for better addiction service training opportunities for those without addiction-specific educational backgrounds. Future research should assess whether targeted trainings increase addiction screening and education in social services settings. PMID- 25798020 TI - Central limit theorems under special relativity. AB - Several relativistic extensions of the Maxwell-Boltzmann distribution have been proposed, but they do not explain observed lognormal tail-behavior in the flux distribution of various astrophysical sources. Motivated by this question, extensions of classical central limit theorems are developed under the conditions of special relativity. The results are related to CLTs on locally compact Lie groups developed by Wehn, Stroock and Varadhan, but in this special case the asymptotic distribution has an explicit form that is readily seen to exhibit lognormal tail behavior. PMID- 25798022 TI - Thermodynamically Controlled, Dynamic Binding of Diols to a 1,2-BN Cyclohexane Derivative. AB - The reversible covalent binding of diols to an N-Bn 1,2-BN cyclohexane has been studied by 11B and 1H NMR spectroscopy and single-crystal X-ray diffraction analysis. The activation barrier for the reversible B-N Lewis acid-base interaction has been measured by variable-temperature NMR with bound (2R,3R)-(-) 2,3-butanediol (Tc = -40 degrees C, DeltaG? = 11.2 +/- 0.2 kcal mol-1). Deuterium labeling experiments demonstrate that ligand exchange is reversible and rapid at room temperature, and competitive binding studies establish diol association as a thermodynamically controlled process. PMID- 25798021 TI - Fish do not feel pain and its implications for understanding phenomenal consciousness. AB - Phenomenal consciousness or the subjective experience of feeling sensory stimuli is fundamental to human existence. Because of the ubiquity of their subjective experiences, humans seem to readily accept the anthropomorphic extension of these mental states to other animals. Humans will typically extrapolate feelings of pain to animals if they respond physiologically and behaviourally to noxious stimuli. The alternative view that fish instead respond to noxious stimuli reflexly and with a limited behavioural repertoire is defended within the context of our current understanding of the neuroanatomy and neurophysiology of mental states. Consequently, a set of fundamental properties of neural tissue necessary for feeling pain or experiencing affective states in vertebrates is proposed. While mammals and birds possess the prerequisite neural architecture for phenomenal consciousness, it is concluded that fish lack these essential characteristics and hence do not feel pain. PMID- 25798023 TI - Territorial competition and the evolutionary loss of sexual size dimorphism. AB - Non-sexual social selection can underlie the evolution of sexually monomorphic phenotypes. A causal relationship between territorial competition and sexual monomorphism predicts that male and female competitors should employ similar contest behavior and that contest outcome should depend on the same traits in males and females. We test this prediction in a sexually monomorphic cichlid fish of the genus Tropheus, in which males and females defend individual feeding territories. Lineages basal to Tropheus are sexually dimorphic and have non territorial females, suggesting that a switch to female territoriality and loss of sexual dimorphism occurred in the Tropheus lineage. We compare rates of agonistic behavior and the effects of body size asymmetries on competitive success between male-male and female-female contests in an experimental setup. Body size asymmetry had the same effect in male and female contests, being negatively correlated with contest duration and positively correlated with the probability of winning. Male and female winners employed the same rates of frontal and lateral displays as well as charges against their opponents. Contest duration was longer in females. In tied contests, females displayed more than males. Our data suggest that intraspecific contest competition for territories selects for large body size in both sexes and support a link between the evolution of female territoriality and the loss of sexual size dimorphism in Tropheus. PMID- 25798024 TI - Dislikable Clients or Countertransference: A Clinician's Perspective. AB - Dislike of one's clients is a problem many clinicians encounter and it can have a drastic negative impact on client-clinician rapport, as well as the intervention outcome. Reasons for dislike can be varied and are not clearly known, as little research has been done on the topic. The purpose of this pilot study was to begin to understand how clinicians experience and navigate dislike for clients in practice. The study yielded critical information regarding the factors that influence dislike and the coping skills utilized by practitioners to counter or ameliorate such feelings. Recommendations for practitioners are provided, including a better understanding of feelings of dislike for one's client outside of the countertransference framework of understanding. PMID- 25798025 TI - THE ROLE OF LOCATION IN EVALUATING RACIAL WAGE DISPARITY. AB - A standard object of empirical analysis in labor economics is a modified Mincer wage function in which an individual's log wage is specified to be a function of education, experience, and an indicator variable identifying race. We analyze this approach in a context in which individuals live and work in different locations (and thus face different housing prices and wages). Our model provides a justification for the traditional approach, but with the important caveat that the regression should include location-specific fixed effects. Empirical analyses of men in U.S. labor markets demonstrate that failure to condition on location causes us to (i) overstate the decline in black-white wage disparity over the past 60 years, and (ii) understate racial and ethnic wage gaps that remain after taking into account measured cognitive skill differences that emerge when workers are young. PMID- 25798026 TI - PERSONALITY PREDISPOSITIONS IN CHINESE ADOLESCENTS: THE RELATION BETWEEN SELF CRITICISM, DEPENDENCY, AND PROSPECTIVE INTERNALIZING SYMPTOMS. AB - The present study examined the prospective relation between two personality predispositions, self-criticism and dependency, and internalizing symptoms. Specifically, it was examined whether self-criticism and dependency predicted symptoms of depression and social anxiety, and if a moderation (e.g. diathesis stress) or mediation model best explained the relation between the personality predispositions and emotional distress in Chinese adolescents. Participants included 1,150 adolescents (597 females and 553 males) from mainland China. Participants completed self-report measures of self-criticism, dependency, and neuroticism at baseline, and self-report measures of negative events, depressive symptoms, and social anxiety symptoms once a month for six months. Findings showed that self-criticism predicted depressive symptoms, while dependency predicted social anxiety symptoms. In addition, support was found for a mediation model, as opposed to a moderation model, with achievement stressors mediating the relation between self-criticism and depressive symptoms. Overall, these findings highlight new developmental pathways for the development of depression and social anxiety symptoms in mainland Chinese adolescents. Implications for cross-cultural developmental psychopathology research are discussed. PMID- 25798027 TI - Investigating the Effects of Surface-Initiated Polymerization of epsilon Caprolactone to Bioactive Glass Particles on the Mechanical Properties of Settable Polymer/Ceramic Composites. AB - Injectable bone grafts with strength exceeding that of trabecular bone could improve the management of a number of orthopaedic conditions. Ceramic/polymer composites have been investigated as weight-bearing bone grafts, but they are typically weaker than trabecular bone due to poor interfacial bonding. We hypothesized that entrapment of surface-initiated poly(epsilon-caprolactone) (PCL) chains on 45S5 bioactive glass (BG) particles within an in situ-formed polymer network would enhance the mechanical properties of reactive BG/polymer composites. When the surface-initiated PCL molecular weight exceeded the molecular weight between crosslinks of the network, the compressive strength of the composites increased 6- to 10-fold. The torsional strength of the composites exceeded that of human trabecular bone by a factor of two. When injected into femoral condyle defects in rats, the composites supported new bone formation at 8 weeks. The initial bone-like strength of BG/polymer composites and their ability to remodel in vivo highlight their potential for development as injectable grafts for repair of weight-bearing bone defects. PMID- 25798028 TI - An Examination of a New Psychometric Method for Optimizing Multi-Faceted Assessment Instruments in the Context of Trait Emotional Intelligence. AB - Driven by the challenge of representing and measuring psychological attributes, this article outlines a psychometric method aimed at identifying problem facets. The method, which integrates theoretical and empirical steps, is applied in the context of the construct of trait emotional intelligence (trait EI), using data from six different samples (N = 1284) collected across Europe. Alternative representations of the trait EI variance, derived from the outcome variables used in previous validation studies of the Trait Emotional Intelligence Questionnaire, were regressed on the 15 trait EI facets using the stepwise method. The analyses revealed five facets, which did not occupy unique construct variance in any of the six samples. As expected, a composite of the remaining 10 facets consistently showed greater construct validity than the original 15-facet composite. Implications for construct and scale development are discussed, and directions for further validation of the method and for its application to other constructs are provided. (c) 2014 The Authors. European Journal of Personality published by John Wiley & Sons Ltd on behalf of European Association of Personality Psychology. PMID- 25798029 TI - Where is the Child in Family Therapy Service After Family Violence? A Study from the Norwegian Family Protection Service. AB - Extensive documentation on consequences of family violence laid the ground for a politically decided mandate for the Norwegian Family Protection Service (FPS) to prioritize families with children and violence. This study explores the practice of one of the country's larger FPS offices following this mandate and its kick off start. Data from all cases in 1 year with families with children and violence were gathered (106) as to what were cases referred, services provided, main cross points, dilemmas, and challenges. Descriptive statistical analyses were utilized and qualitative analysis conducted. The study shows success in supplying a direct, much used route both for private persons and main collaborative agencies, although all abusers need others as promoters for change. The service succeeds to pioneer brief treatment combined with taking a stand against violence. However, while services are provided fairly quickly when violence is reported, several changes are called for: A more violence-sensitive intake procedure, stronger cooperation with specialty mental health service and primary health service, extended use of assessment tools and outcome measures. Given the nature of violence, particularly follow up measures are required. However, first and foremost, the study calls for a better inclusion of the child. Despite mandated priority, a major neglect of children takes place. In line with the UN Convention on the Rights of the Child, the Norwegian Family Protection Services in a country complying with this Convention is obliged to take the child more successfully into account in its own right. Future efforts are required to safeguard child focused services. PMID- 25798030 TI - Exploiting the Symmetry of the Resonator Mode to Enhance PELDOR Sensitivity. AB - Pulsed electron paramagnetic resonance (EPR) spectroscopy using microwaves at two frequencies can be employed to measure distances between pairs of paramagnets separated by up to 10 nm. The method, combined with site-directed mutagenesis, has become increasingly popular in structural biology for both its selectivity and capability of providing information not accessible through more standard methods such as nuclear magnetic resonance and X-ray crystallography. Despite these advantages, EPR distance measurements suffer from poor sensitivity. One contributing factor is technical: since 65 MHz typically separates the pump and detection frequencies, they cannot both be located at the center of the pseudo Lorentzian microwave resonance of a single-mode resonator. To maximize the inversion efficiency, the pump pulse is usually placed at the center of the resonance, while the observer frequency is placed in the wing, with consequent reduction in sensitivity. Here, we consider an alternative configuration: by spacing pump and observer frequencies symmetrically with respect to the microwave resonance and by increasing the quality factor, valuable improvement in the signal-to-noise ratio can be obtained. PMID- 25798031 TI - Black box modeling of PIDs implemented in PLCs without structural information: a support vector regression approach. AB - In this report, the parameters identification of a proportional-integral derivative (PID) algorithm implemented in a programmable logic controller (PLC) using support vector regression (SVR) is presented. This report focuses on a black box model of the PID with additional functions and modifications provided by the manufacturers and without information on the exact structure. The process of feature selection and its impact on the training and testing abilities are emphasized. The method was tested on a real PLC (Siemens and General Electric) with the implemented PID. The results show that the SVR maps the function of the PID algorithms and the modifications introduced by the manufacturer of the PLC with high accuracy. With this approach, the simulation results can be directly used to tune the PID algorithms in the PLC. The method is sufficiently universal in that it can be applied to any PI or PID algorithm implemented in the PLC with additional functions and modifications that were previously considered to be trade secrets. This method can also be an alternative for engineers who need to tune the PID and do not have any such information on the structure and cannot use the default settings for the known structures. PMID- 25798033 TI - Erratum: environmental heavy metal exposure and chronic kidney disease in the general population. AB - [This corrects the article on p. 272 in vol. 30, PMID: 25729249.]. PMID- 25798032 TI - Familiar and novel reproductive endocrine disruptors: xenoestrogens, dioxins and nanoparticles. AB - Environmental contaminants are known to exert endocrine-disrupting effects on the reproductive axis of animals. Many of these molecules can affect steroid biosynthesis or estrogen-receptor signaling by behaving as estrogen-like molecules ("xenoestrogens"), or by exerting estrogenmodulatory effects. Exposure to some compounds has been correlated with the skewing of sex ratios in aquatic species, feminization and demasculinization of male animals, declines in human sperm counts, and overall diminution in fertility of birds, fish, and mammals. We herein devote space to several classes of endocrine-disrupting compounds (EDCs), including estrogenic substances such as bisphenol A (BPA), molecules that can behave at times anti-estrogenically while activating the aromatic hydrocarbon receptor (AHR), such as dioxins (a known human carcinogen), and novel, ubiquitous molecules such as nanoparticles, particularly gold nanoparticles (GNPs), that appear to alter the sexsteroid biosynthetic pathway. PMID- 25798035 TI - Sidetracks on the safety express: interruptions lead to errors and ... wait, what was I doing? AB - Interruptions and distractions can sidetrack patient safety. PMID- 25798034 TI - Multianalyte Microphysiometry of Macrophage Responses to Phorbol Myristate Acetate, Lipopolysaccharide, and Lipoarabinomannan. AB - This study examined the hypothesis that mycobacterial antigens generate different metabolic responses in macrophages as compared to gram-negative effectors and macrophage activators. The metabolic activation of macrophages by PMA is a useful tool for studying virulent agents and can be compared to other effectors. While phorbol myristate acetate (PMA) is commonly used to study macrophage activation, the concentration used to create this physiological response varies. The response of RAW-264.7 macrophages is concentration-dependent, where the metabolic response to high concentrations of PMA decreases suggesting deactivation. The gram negative effector, lipopolysaccharide (LPS), was seen to promote glucose and oxygen production which were used to produce a delayed onset of oxidative burst. Pre-incubation with interferon-gamma (IFN-gamma) increased the effect on cell metabolism, where the synergistic effects of IFN-gamma and LPS immediately initiated oxidative burst. These studies exhibited a stark contrast with lipoarabinomannan (LAM), an antigenic glycolipid component associated with the bacterial genus Mycobacterium. The presence of LAM effectively inhibits any metabolic response preventing consumption of glucose and oxygen for the promotion of oxidative burst and to ensure pathogenic proliferation. This study demonstrates for the first time the immediate inhibitory metabolic effects LAM has on macrophages, suggesting implications for future intervention studies with Mycobacterium tuberculosis. PMID- 25798036 TI - FDA Advisory Committee Approval of First Biosimilar Leaves Questions Unanswered: Sandoz's Filgrastim Faces Naming and Court Hurdles. AB - As first biosimilar approval nears, key questions remain. PMID- 25798038 TI - Conjugated Estrogens/Bazedoxifene (Duavee): A Novel Agent for the Treatment of Moderate-to-Severe Vasomotor Symptoms Associated With Menopause And the Prevention of Postmenopausal Osteoporosis. AB - Conjugated estrogens/bazedoxifene (Duavee): a novel agent for the treatment of moderate-to-severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis. PMID- 25798039 TI - Medication-induced hypokalemia. AB - A potassium deficiency can impair metabolic functions, and medications cause hypokalemia through a variety of mechanisms. The authors report on a 58-year-old female suffering from fatigue and weakness after a recent diagnosis of adrenal insufficiency. PMID- 25798040 TI - A review of 2014 cancer drug approvals, with a look at 2015 and beyond. AB - The number of cancer medications approved by the Food and Drug Administration has risen steadily in recent years. This article provides a concise overview of drugs and indications added to the cancer armamentarium in 2014 and to date in 2015. PMID- 25798041 TI - Employers and Drugstores Press for PBM Transparency: A Labor Department Advisory Committee Has Recommended Changes. AB - Efforts are under way to convince the U.S. Department of Labor to require more transparency from pharmacy benefit managers, which divulge few details of their financial arrangements to their customers. PMID- 25798042 TI - Bivalirudin Versus Heparin: A Fight Far From Finished?: Efficacy, Safety, and Cost Remain Battlegrounds for the Treatment Of ST-Segment Elevation Myocardial Infarction. AB - A strident debate has been surging in the interventional cardiology community over the triumvirate of efficacy, safety, and cost of bivalirudin compared with heparin for anticoagulation of patients with ST-segment elevation myocardial infarction. PMID- 25798043 TI - In the Veteran's Voice: Psychosocial Needs After Cancer Treatment. AB - To better understand psychosocial distress in veterans treated for cancer, these researchers conducted a series of 3 focus groups. Emerging themes suggest that cancer survivorship is a process, and interventions need to be tailored to each patient. PMID- 25798044 TI - Protective effect of butylated hydroxylanisole against hydrogen peroxide-induced apoptosis in primary cultured mouse hepatocytes. AB - Butylated hydroxyanisole (BHA) is a synthetic phenolic compound consisting of a mixture of two isomeric organic compounds: 2-tert-butyl-4-hydroxyanisole and 3 tert-butyl-4-hydroxyanisole. We examined the effect of BHA against hydrogen peroxide (H2O2)-induced apoptosis in primary cultured mouse hepatocytes. Cell viability was significantly decreased by H2O2 in a dose-dependent manner. Additionally, H2O2 treatment increased Bax, decreased Bcl-2, and promoted PARP-1 cleavage in a dose-dependent manner. Pretreatment with BHA before exposure to H2O2 significantly attenuated the H2O2-induced decrease of cell viability. H2O2 exposure resulted in an increase of intracellular reactive oxygen species (ROS) generation that was significantly inhibited by pretreatment with BHA or N-acetyl cysteine (NAC, an ROS scavenger). H2O2-induced decrease of cell viability was also attenuated by pretreatment with BHA and NAC. Furthermore, H2O2-induced increase of Bax, decrease of Bcl-2, and PARP-1 cleavage was also inhibited by BHA. Taken together, results of this investigation demonstrated that BHA protects primary cultured mouse hepatocytes against H2O2-induced apoptosis by inhibiting ROS generation. PMID- 25798045 TI - Intercostal thoracotomy in 20 dogs: muscle-sparing versus traditional techniques. AB - The levels of pain, duration of approaching and closure, and surgical exposure associated with intercostal thoracotomy were compared between muscle-sparing and traditional techniques in 20 dogs. Postoperative pain was assessed based on numerical pain scores using behavioral observation, heart rate, respiratory rate, and wound palpation. Time for approaching and closure were measured, and the extent of intrathoracic organ exposure for the surgical procedures was described for each technique. There were significant differences in numerical pain scores at 2 h as well as 1, 2, 3, 4, 5, 6, and 7 days after surgery between the two groups (p < 0.0001). There was no significant (p = 0.725) difference in times for approaching and closure between the two groups. Compared to the traditional method, the muscle-sparing technique also achieved the desired exposure without compromising exposure of the target organs. Our results suggest that the muscle sparing technique is more effective than the traditional method for providing a less painful recovery during the first 7 days after intercostal thoracotomy. Additionally, the muscle-sparing technique is as effective as the traditional modality for providing an appropriate time for approaching and closure during intercostal thoracotomy as well as adequate organ exposure for the surgical procedures. PMID- 25798046 TI - Lenticulostriate vasculopathy in extremely low gestational age newborns: Inter rater variability of cranial ultrasound readings, antecedents and postnatal characteristics. AB - Although lenticulostriate vasculopathy (LSV) was first detected on a cranial ultrasound nearly 30 years ago, its clinical implications and significance remain unknown. The objective of this study was to evaluate the inter-rater reliability of cranial ultrasound readings of LSV, and to explore relationships with potential antecedents and developmental correlates in extremely low gestational age newborns. Of the 1506 infants enrolled during the years 2002-2004, 1450 had at least one set of ultrasound scans evaluated for LSV and 939 had all three sets. To evaluate the inter-rater agreement for identifying LSV, we compared readings from two independent radiologists on days 1-4, 5-14, and on or after day 15. We then evaluated the relationships between LSV and maternal, antenatal, and postnatal characteristics. Our results showed that kappa values were 0.18, 0.33, and 0.36 on days 1-4, days 5-14, and day 15 or greater. Infants who were identified as LSV positive by two readers had higher Score for Neonatal Acute Physiology-II (an illness severity indicator), higher rates of tracheal infection and bacteremia, lower partial pressure of arterial oxygen and pH levels on 2 of the first 3 postnatal days, and they were more likely to have a lower psycho motor development index at age 2 years. Positive agreement on the presence of LSV was low, as was the kappa value, an index of inter-rater reliability. Infants with high illness severity scores and their correlates were at increased risk of developing LSV, while those who develop LSV appear to be at increased risk of motor dysfunction. PMID- 25798047 TI - Toward refined estimates of ambient PM2.5 exposure: Evaluation of a physical outdoor-to-indoor transport model. AB - Because people spend the majority of their time indoors, the variable efficiency with which ambient PM2.5 penetrates and persists indoors is a source of error in epidemiologic studies that use PM2.5 concentrations measured at central-site monitors as surrogates for ambient PM2.5 exposure. To reduce this error, practical methods to model indoor concentrations of ambient PM2.5 are needed. Toward this goal, we evaluated and refined an outdoor-to-indoor transport model using measured indoor and outdoor PM2.5 species concentrations and air exchange rates from the Relationships of Indoor, Outdoor, and Personal Air Study. Herein, we present model evaluation results, discuss what data are most critical to prediction of residential exposures at the individual-subject and populations levels, and make recommendations for the application of the model in epidemiologic studies. This paper demonstrates that not accounting for certain human activities (air conditioning and heating use, opening windows) leads to bias in predicted residential PM2.5 exposures at the individual-subject level, but not the population level. The analyses presented also provide quantitative evidence that shifts in the gas-particle partitioning of ambient organics with outdoor-to-indoor transport contribute significantly to variability in indoor ambient organic carbon concentrations and suggest that methods to account for these shifts will further improve the accuracy of outdoor-to-indoor transport models. PMID- 25798048 TI - An instrumental variable random-coefficients model for binary outcomes. AB - In this paper, we study a random-coefficients model for a binary outcome. We allow for the possibility that some or even all of the explanatory variables are arbitrarily correlated with the random coefficients, thus permitting endogeneity. We assume the existence of observed instrumental variables Z that are jointly independent with the random coefficients, although we place no structure on the joint determination of the endogenous variable X and instruments Z, as would be required for a control function approach. The model fits within the spectrum of generalized instrumental variable models, and we thus apply identification results from our previous studies of such models to the present context, demonstrating their use. Specifically, we characterize the identified set for the distribution of random coefficients in the binary response model with endogeneity via a collection of conditional moment inequalities, and we investigate the structure of these sets by way of numerical illustration. PMID- 25798049 TI - Phosphomannose isomerase affects the key enzymes of glycolysis and sucrose metabolism in transgenic sugarcane overexpressing the manA gene. AB - Sugarcane is one of the most important crops cultivated for the production of sugar and ethanol. In our previous studies, an innovative positive selection system for obtaining transgenic sugarcane, which utilized the E. coli-derived manA gene as the selectable marker and mannose as the selective agent, was developed and patented in China. In this paper, the influence of phosphomannose isomerase (PMI) overexpression on the key enzymes of both glycolysis and sucrose metabolism was investigated in transgenic sugarcane through the manA gene. Overexpressed PMI increased hexokinase activity by approximately 24 % compared with non-transgenic control plants, but pyruvate kinase (PK) activity was reduced by approximately 14 %. In comparison with the non-transgenic control plants, the activities of sucrose synthase, sucrose-phosphate synthase, and acid invertase were also modestly affected in the PMI-overexpressing transgenic plants, but no significant differences were observed at the stalk elongation and maturity stages. However, agronomic and technical traits were not affected by manA gene overexpression in the transgenic sugarcane. In conclusion, PMI overexpression significantly affected the hexokinase and PK activities by catalyzing the reversible interconversion between mannose-6-phosphate and fructose-6-phosphate, which is an intermediate of glycolysis. However, it had no significant effects on sucrose accumulation in sugarcane. PMID- 25798050 TI - Development of molecular markers tightly linked to Pvr4 gene in pepper using next generation sequencing. AB - It is imperative to identify highly polymorphic and tightly linked markers of a known trait for molecular marker-assisted selection. Potyvirus resistance 4 (Pvr4) locus in pepper confers resistance to three pathotypes of potato virus Y and to pepper mottle virus. We describe the use of next-generation sequencing technology to generate molecular markers tightly linked to Pvr4. Initially, comparative genomics was carried out, and a syntenic region of tomato on chromosome ten was used to generate PCR-based markers and map Pvr4. Subsequently, the genomic sequence of pepper was used, and more than 5000 single-nucleotide variants (SNVs) were identified within the interval. In addition, we identified nucleotide binding site-leucine-rich repeat-type disease resistance genes within the interval. Several of these SNVs were converted to molecular markers desirable for large-scale molecular breeding programmes. PMID- 25798051 TI - Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. AB - BACKGROUND: Heat shock proteins (HSPs) are overexpressed in human hepatocellular carcinoma (HCC) tissue and correlate with aggressiveness and prognosis of HCC. METHODS: Using the GSE14520 microarray expression profile from Gene Expression Omnibus, we compared HSP gene expression between tumour and non-tumour tissues and correlated this with outcomes in HCC patients. RESULTS: We analysed 220 hepatitis B virus (HBV)-related HCC patients and 25 HSPs in this study. With the exception of HSPA4L, HSPA12A and HSPB8, members of the HSP family, including HSPH1, HSPBP1, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4, HSPA5, HSPA8, HSPA9, HSPAA1, HSPAB1, HSPA14, HSPB11, HSPA13, HSP90B1 and HSPBAP1, were all overexpressed in tumour tissues (all P < 0.001). In contrast, HSPB6, HSPB7, HSPA6, HSPB2 and HSPB3 were upregulated in non-tumour tissues (all P < 0.001). Multivariate analysis showed that cirrhosis (HR = 5.282, 95% CI = 1.294-21.555, P = 0.02), Barcelona Clinic liver cancer (BCLC) staging (HR = 2.151, 95% CI = 1.682-2.750, P < 0.001), HSPA12A (HR = 1.042, 95% CI = 1.003-1.082, P = 0.033) and HSP90B1 (HR = 1.001, 95% CI = 1.000-1.001, P = 0.011) were negatively associated with survival of HBV related HCC patients. Furthermore, advanced BCLC staging (HR = 1.797, 95% CI = 1.439-2.244, P < 0.001) was also associated with earlier recurrence of HCC. The high expression of HSPA4 (HR = 1.002, 95% CI = 1.000-1.004, P = 0.019), HSPA5 (HR = 1.0, 95% CI = 1.0-1.0, P = 0.046) and HSPA6 (HR = 1.008, 95% CI = 1.001-1.015, P = 0.021) was similarly associated with HCC recurrence. CONCLUSIONS: The expression of most HSPs was higher in tumour tissues than in non-tumour tissues. High BCLC staging scores, advanced cirrhosis and the overexpression of HSPA12A and HSP90B1 might be associated with poor survival from HCC, whereas high levels of HSPA4, HSPA5 and HSPA6 might be associated with earlier recurrence of HCC. PMID- 25798052 TI - Industrial noise and tooth wear - experimental study. AB - Tooth wear is a complex multifactorial process that involves the loss of hard dental tissue. Parafunctional habits have been mentioned as a self-destructive process caused by stress, which results in hyperactivity of masticatory muscles. Stress manifests itself through teeth grinding, leading to progressive teeth wear. The effects of continuous exposure to industrial noise, a "stressor" agent, cannot be ignored and its effects on the teeth must be evaluated. AIMS: The aim of this study was to ascertain the effects of industrial noise on dental wear over time, by identifying and quantifying crown area loss. MATERIAL AND METHODS: 39 Wistar rats were used. Thirty rats were divided in 3 experimental groups of 10 animals each. Animals were exposed to industrial noise, rich in LFN components, for 1, 4 and 7 months, with an average weekly exposure of 40 hours (8h/day, 5 days/week with the weekends in silence). The remaining 9 animals were kept in silence. The areas of the three main cusps of the molars were measured under light microscopy. STATISTICAL ANALYSIS USED: A two-way ANOVA model was applied at significance level of 5%. RESULTS: The average area of the molar cusps was significantly different between exposed and non-exposed animals. The most remarkable differences occurred between month 1 and 4. The total crown loss from month 1 to month 7 was 17.3% in the control group, and 46.5% in the exposed group, and the differences between these variations were significant (p<0.001). CONCLUSIONS: Our data suggest that industrial noise is an important factor in the pathogenesis of tooth wear. PMID- 25798053 TI - Paradoxical response to mechanical unloading in bone loss, microarchitecture, and bone turnover markers. AB - BACKGROUND: Sclerostin, encoded by the SOST gene, has been implicated in the response to mechanical loading in bone. Some studies demonstrated that unloading leads to up-regulated SOST expression, which may induce bone loss. PURPOSE: Most reported studies regarding the changes caused by mechanical unloading were only based on a single site. Considering that the longitudinal bone growth leads to cells of different age with different sensitivity to unloading, we hypothesized that bone turnover in response to unloading is site specific. METHODS: We established a disuse rat model by sciatic neurectomy in tibia. In various regions at two time-points, we evaluated the bone mass and microarchitecture in surgically-operated rats and control rats by micro-Computed Tomography (micro-CT) and histology, sclerostin/SOST by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (qPCR), tartrate resistant acid phosphatase 5b (TRAP 5b) by ELISA and TRAP staining, and other bone markers by ELISA. RESULTS: Micro-CT and histological analysis confirmed bone volume in the disuse rats was significantly decreased compared with those in the time-matched control rats, and microarchitecture also changed 2 and 8 weeks after surgery. Compared with the control groups, SOST mRNA expression in the diaphysis was down-regulated at both week 2 and 8. On the contrary, the percentage of sclerostin-positive osteocytes showed an up-regulated response in the 5 - 6 mm region away from the growth plate, while in the 2.5 - 3.5 mm region, the percentage was no significant difference. Nevertheless, in 0.5 - 1.5 mm region, the percentage of sclerostin positive osteocytes decreased after 8 weeks, consistent with serum SOST level. Besides, the results of TRAP also suggested that the expression in response to unloading may be opposite in different sites or system. CONCLUSION: Our data indicated that unloading-induced changes in bone turnover are probably site specific. This implies a more complex response pattern to unloading and unpredictable therapeutics which target SOST or TRAP 5b. PMID- 25798054 TI - No significant detectable anti-infection effects of aspirin and statins in chronic obstructive pulmonary disease. AB - BACKGROUND: Past studies have shown that aspirin and statins decrease the rate and severity of exacerbation, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). Although these studies are relatively new, there is evidence that new therapeutic strategies could prevent exacerbation of COPD. TRIAL DESIGN: This article examines retrospectively the possibility of using aspirin and statins to prevent exacerbation and infection in patients with COPD. METHODS: All patients with COPD were identified from hospital charts in the Department of Internal Medicine, Saarland University Medical Center, Germany, between 2004 and 2014. RESULTS: The study examined 514 medical reports and secured a study population of 300 with COPD. The mean age was 69 +/- 10 years (206 men, 68.7%, 95% CI, 63.4-73.9; 94 women, 31.3%, 95% CI, 26.1-36.6). The study results did not show a causal relationship between aspirin and statins and prevention of exacerbation and infection in patients with COPD. CONCLUSION: In contrast, in this study, the exacerbation and infection rates increased under medication with aspirin and statins (p = 0.008). PMID- 25798055 TI - FDG-PET and NeuN-GFAP immunohistochemistry of hippocampus at different phases of the pilocarpine model of temporal lobe epilepsy. AB - PURPOSE: Hippocampal glucose hypometabolism has been implicated in the pathogenesis of temporal lobe epilepsy (TLE). However, the underlying pathophysiological basis for this hypometabolism remains elusive. The aim of this study was to investigate the relationship between hippocampal hypometabolism and the histological changes seen in rats after systemic pilocarpine treatment. METHODS: (18)F-fluorodeoxyglucose (FDG) small-animal positron emission tomography (microPET) was performed on day zero (untreated), day seven (latent) and day sixty (chronic phase) after the initial status epilepticus. The microPET imaging data were correlated with the immunoreactivity of neuron-specific nuclear protein (NeuN) and glial fibrillary acidic protein (GFAP) in the hippocampus at each time point. RESULTS: (18)F-FDG-microPET images showed the hippocampus presented with persistent hypometabolism during epileptogenesis and partly recovered in the chronic phase. Hippocampal glucose uptake defects correlate with NeuN immunoreactivity in the latent phase and GFAP immunoreactivity in the chronic phase. CONCLUSIONS: Severe glucose hypometabolism in the hippocampus during the latent phase correlates with neuronal cell loss. The partial recovery of hippocampal glucose uptake in the chronic phase may be due to astrogliosis. PMID- 25798056 TI - PKD1 mono-allelic knockout is sufficient to trigger renal cystogenesis in a mini pig model. AB - PKD1 and PKD2 mutations could lead to autosomal dominant polycystic kidney disease (ADPKD), which afflicts millions of people worldwide. Due to the marked differences in the lifespan, size, anatomy, and physiology from humans, rodent ADPKD models cannot fully mimic the disease. To obtain a large animal model that recapitulates the disease, we constructed a mini-pig model by mono-allelic knockout (KO) of PKD1 using zinc finger nuclease. The mono-allelic KO pigs had lower PKD1 expression than their wild-type littermates at both the transcriptional and translational levels. After approximately six months, renal cysts appeared and grew progressively in the KO pigs. Histological analysis showed that renal cysts were scatteredly distributed in the mutant pig kidneys and were lined by either cuboidal or flattened epithelial cells. Contrast enhanced computed tomography confirmed that all of the mutant pigs had renal and hepatic cysts, when they were 11-month-old. Immunohistochemical analysis revealed that most of the cysts were derived from the proximal tubules and collecting ducts. Therefore, the PKD1 mono-allelic knockout is sufficient to trigger renal cystogenesis, and this pig model may provide a platform for future study of renal cyst formation. PMID- 25798057 TI - Caveolin-1 is a modulator of fibroblast activation and a potential biomarker for gastric cancer. AB - Stromal fibroblasts play an important role in chronic cancer-related inflammation and the development as well as progression of malignant diseases. However, the difference and relationship between inflammation-associated fibroblasts (IAFs) and cancer-associated fibroblasts (CAFs) are poorly understood. In this study, gastric cancer-associated fibroblasts (GCAFs) and their corresponding inflammation-associated fibroblasts (GIAFs) were isolated from gastric cancer (GC) with chronic gastritis and cultured in vitro. These activated fibroblasts exhibited distinct secretion and tumor-promoting behaviors in vitro. Using proteomics and bioinformatics techniques, caveolin-1 (Cav-1) was identified as a major network-centric protein of a sub-network consisting of 121 differentially expressed proteins between GIAFs and GCAFs. Furthermore, immunohistochemistry in a GC cohort showed significant difference in Cav-1 expression score between GIAFs and GCAFs and among patients with different grades of chronic gastritis. Moreover, silencing of Cav-1 in GIAFs and GCAFs using small interfering RNA increased the production of pro-inflammatory and tumor-enhancing cytokines and chemokines in conditioned mediums that elevated cell proliferation and migration when added to GC cell lines AGS and MKN45 in vitro. In addition, Cav-1 status in GIAFs and GCAFs independently predicted the prognosis of GC. Our findings indicate that Cav-1 loss contributes to the distinct activation statuses of fibroblasts in GC microenvironment and gastritis mucosa, and Cav-1 expression in both GCAFs and GIAFs may serve as a potential biomarker for GC progression. PMID- 25798058 TI - Lethal (2) giant larvae: an indispensable regulator of cell polarity and cancer development. AB - Cell polarity is one of the most basic properties of all normal cells and is essential for regulating numerous biological processes. Loss of polarity is considered a hallmark for cancer. Multiple polarity proteins are implicated in maintenance of cell polarity. Lethal (2) giant larvae (Lgl) is one of polarity proteins that plays an important role in regulating cell polarity, asymmetric division as well as tumorigenesis. Lgl proteins in different species have similar structures and conserved functions. Lgl acts as an indispensable regulator of cell biological function, including cell polarity and asymmetric division, through interplaying with other polarity proteins, regulating exocytosis, mediating cytoskeleton and being involved in signaling pathways. Furthermore, Lgl plays a role of a tumor suppressor, and the aberrant expression of Hugl, a human homologue of Lgl, contributes to multiple cancers. However, the exact functions of Lgl and the underlying mechanisms remain enigmatic. In this review, we will give an overview of the Lgl functions in cell polarity and cancer development, discuss the potential mechanisms underlying these functions, and raise our conclusion of previous studies and points of view about the future studies. PMID- 25798060 TI - Identification of novel focal adhesion kinase substrates: role for FAK in NFkappaB signaling. AB - Focal adhesion kinase (FAK) is a major signaling molecule which functions downstream of integrins or in conjunction with mitogenic signaling pathways. FAK is overexpressed and/or activated in many types of human tumors, in which it promotes cell adhesion, survival, migration and invasion. In addition to FAK's ability to regulate signaling through its scaffolding activities, FAK encodes an intrinsic kinase activity. Although some FAK substrates have been identified, a more comprehensive analysis of substrates is lacking. In this study, we use a protein microarray to screen the human proteome for FAK substrates. We confirm that several of the proteins identified are bona fide in vitro FAK substrates, including several factors which are known to regulate the NFkappaB pathway. Finally, we identify a role for FAK's kinase activity in both canonical and non canonical NFkappaB signaling. Our screen therefore represents the first high throughput screen for FAK substrates and provides the basis for future in-depth analysis of the role of FAK's kinase activity in the processes of tumorigenesis. PMID- 25798059 TI - MicroRNA-23a participates in estrogen deficiency induced gap junction remodeling of rats by targeting GJA1. AB - Increased incidence of arrhythmias in women after menopause has been widely documented, which is considered to be related to estrogen (E2) deficiency induced cardiac electrophysiological abnormalities. However, its molecular mechanism remains incompletely clear. In the present study, we found cardiac conduction blockage in post-menopausal rats. Thereafter, the results showed that cardiac gap junctions were impaired and Connexin43 (Cx43) expression was reduced in the myocardium of post-menopausal rats. The phenomenon was also observed in ovariectomized (OVX) rats, which was attenuated by E2 supplement. Further study displayed that microRNA-23a (miR-23a) level was significantly increased in both post-menopausal and OVX rats, which was reversed by daily E2 treatment after OVX. Importantly, forced overexpression of miR-23a led to gap junction impairment and Cx43 downregulation in cultured cardiomyocytes, which was rescued by suppressing miR-23a by transfection of miR-23a specific inhibitory oligonucleotide (AMO-23a). GJA1 was identified as the target gene of miR-23a by luciferase assay and miRNA masking antisense ODN (miR-Mask) assay. We also found that E2 supplement could reverse cardiac conduction blockage, Cx43 downregulation, gap junction remodeling and miR-23a upregulation in post-menopausal rats. These findings provide the evidence that miR-23a mediated repression of Cx43 participates in estrogen deficiency induced damages of cardiac gap junction, and highlights a new insight into molecular mechanism of post-menopause related arrhythmia at the microRNA level. PMID- 25798061 TI - MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer. AB - The serine-threonine kinase CK2 exhibits genomic alterations and aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we investigated the effects of CK2 inhibitor CX-4945 in human HNSCC cell lines and xenograft models. The IC50's of CX-4945 for 9 UM-SCC cell lines measured by MTT assay ranged from 3.4-11.9 MUM. CX-4945 induced cell cycle arrest and cell death measured by DNA flow cytometry, and inhibited prosurvival mediators phospho-AKT and p-S6 in UM-SCC1 and UM-SCC46 cells. CX-4945 decreased NF-kappaB and Bcl-XL reporter gene activities in both cell lines, but upregulated proapoptotic TP53 and p21 reporter activities, and induced phospho-ERK, AP-1, and IL-8 activity in UM-SCC1 cells. CX-4945 exhibited modest anti-tumor activity in UM-SCC1 xenografts. Tumor immunostaining revealed significant inhibition of PI3K-Akt-mTOR pathway and increased apoptosis marker TUNEL, but also induced p-ERK, c-JUN, JUNB, FOSL1 and proliferation (Ki67) markers, as a possible resistance mechanism. To overcome the drug resistance, we tested MEK inhibitor PD-0325901 (PD-901), which inhibited ERK-AP-1 activation alone and in combination with CX-4945. PD-901 alone displayed significant anti-tumor effects in vivo, and the combination of PD 901 and CX-4945 slightly enhanced anti-tumor activity when compared with PD-901 alone. Immunostaining of tumor specimens after treatment revealed inhibition of p AKT S129 and p-AKT T308 by CX-4945, and inhibition of p-ERK T202/204 and AP-1 family member FOSL-1 by PD-901. Our study reveals a drug resistance mechanism mediated by the MEK-ERK-AP-1 pathway in HNSCC. MEK inhibitor PD-0325901 is active in HNSCC resistant to CX-4945, meriting further clinical investigation. PMID- 25798062 TI - Biased signaling in naturally occurring mutations in human melanocortin-3 receptor gene. AB - The melanocortin-3 receptor (MC3R) is primarily expressed in the hypothalamus and plays an important role in the regulation of energy homeostasis. Recently, some studies demonstrated that MC3R also signals through mitogen-activated protein kinases (MAPKs), especially extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 signaling is known to alter gene expression, potentially contributing to the prolonged action of melanocortins on energy homeostasis regulation. In the present study, we performed detailed functional studies on 8 novel naturally occurring MC3R mutations recently reported, and the effects of endogenous MC3R agonist, alpha-melanocyte stimulating hormone (MSH), on ERK1/2 signaling on all 22 naturally occurring MC3R mutations reported to date. We found that mutants D158Y and L299V were potential pathogenic causes to obesity. Four residues, F82, D158, L249 and L299, played critical roles in different aspects of MC3R function. alpha-MSH exhibited balanced activity in Gs-cAMP and ERK1/2 signaling pathways in 15 of the 22 mutant MC3Rs. The other 7 mutant MC3Rs were biased to either one of the signaling pathways. In summary, we provided novel data about the structure-function relationship of MC3R, identifying residues important for receptor function. We also demonstrated that some mutations exhibited biased signaling, preferentially activating one intracellular signaling pathway, adding a new layer of complexity to MC3R pharmacology. PMID- 25798063 TI - Tetratricopeptide repeat domain 9A negatively regulates estrogen receptor alpha activity. AB - Tetratricopeptide repeat domain 9A (TTC9A) is a target gene of estrogen and progesterone. It is over-expressed in breast cancer. However, little is known about the physiological function of TTC9A. The objectives of this study were to establish a Ttc9a knockout mouse model and to study the consequence of Ttc9a gene inactivation. The Ttc9a targeting vector was generated by replacing the Ttc9a exon 1 with a neomycin cassette. The mice homozygous for Ttc9a exon 1 deletion appear to grow normally and are fertile. However, further characterization of the female mice revealed that Ttc9a deficiency is associated with greater body weight, bigger thymus and better mammary development in post-pubertal mice. Furthermore, Ttc9a deficient mammary gland was more responsive to estrogen treatment with greater mammary ductal lengthening, ductal branching and estrogen target gene induction. Since Ttc9a is induced by estrogen in estrogen target tissues, these results suggest that Ttc9a is a negative regulator of estrogen function through a negative feedback mechanism. This is supported by in vitro evidence that TTC9A over-expression attenuated ERalpha activity in MCF-7 cells. Although TTC9A does not bind to ERalpha or its chaperone protein Hsp90 directly, TTC9A strongly interacts with FKBP38 and FKBP51, both of which interact with ERalpha and Hsp90 and modulate ERalpha activity. It is plausible therefore that TTC9A negatively regulates ERalpha activity through interacting with co-chaperone proteins such as FKBP38 and FKBP51. PMID- 25798064 TI - Signal transducer and activator of transcription 4 in liver diseases. AB - STAT4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus. STAT4 activation is detected virtually in the liver of several mouse models of liver injury, as well as the human liver of chronic liver diseases. STAT4 gene polymorphism has been shown to be associated with the antiviral response in chronic hepatitis C and drug-induced liver injury (DILI), primary biliary cirrhosis (PBC), HCV-associated liver fibrosis and in hepatocellular carcinoma (HCC). However, the roles of STAT4 in the pathogeneses of liver diseases are still not understood entirely. This review summarizes the recent advances on the functional roles of STAT4 and its related cytokines in liver diseases, especially in regulating hepatic anti-viral responses, inflammation, proliferation, apoptosis and tumorigenesis. Targeting STAT4 signaling pathway might be a promising strategy in developing therapeutic approaches for treating hepatitis in order to prevent further injury like cirrhosis and liver cancer. PMID- 25798065 TI - Hints for metal-preference protein sequence determinants: different metal binding features of the five tetrahymena thermophila metallothioneins. AB - The metal binding preference of metallothioneins (MTs) groups them in two extreme subsets, the Zn/Cd- and the Cu-thioneins. Ciliates harbor the largest MT gene/protein family reported so far, including 5 paralogs that exhibit relatively low sequence similarity, excepting MTT2 and MTT4. In Tetrahymena thermophila, three MTs (MTT1, MTT3 and MTT5) were considered Cd-thioneins and two (MTT2 and MTT4) Cu-thioneins, according to gene expression inducibility and phylogenetic analysis. In this study, the metal-binding abilities of the five MTT proteins were characterized, to obtain information about the folding and stability of their cognate- and non-cognate metal complexes, and to characterize the T. thermophila MT system at protein level. Hence, the five MTTs were recombinantly synthesized as Zn(2+)-, Cd(2+)- or Cu(+)-complexes, which were analyzed by electrospray mass spectrometry (ESI-MS), circular dichroism (CD), and UV-vis spectrophotometry. Among the Cd-thioneins, MTT1 and MTT5 were optimal for Cd(2+) coordination, yielding unique Cd17- and Cd8- complexes, respectively. When binding Zn(2+), they rendered a mixture of Zn-species. Only MTT5 was capable to coordinate Cu(+), although yielding heteronuclear Zn-, Cu-species or highly unstable Cu-homometallic species. MTT3 exhibited poor binding abilities both for Cd(2+) and for Cu(+), and although not optimally, it yielded the best result when coordinating Zn(2+). The two Cu-thioneins, MTT2 and MTT4 isoforms formed homometallic Cu-complexes (major Cu20-MTT) upon synthesis in Cu-supplemented hosts. Contrarily, they were unable to fold into stable Cd-complexes, while Zn MTT species were only recovered for MTT4 (major Zn10-MTT4). Thus, the metal binding preferences of the five T. thermophila MTs correlate well with their previous classification as Cd- and Cu-thioneins, and globally, they can be classified from Zn/Cd- to Cu-thioneins according to the gradation: MTT1>MTT5>MTT3>MTT4>MTT2. The main mechanisms underlying the evolution and specialization of the MTT metal binding preferences may have been internal tandem duplications, presence of doublet and triplet Cys patterns in Zn/Cd-thioneins, and optimization of site specific amino acid determinants (Lys for Zn/Cd- and Asn for Cu-coordination). PMID- 25798066 TI - Stem cell transplantation upregulates Sirt1 and antioxidant expression, ameliorating fatty liver in type 2 diabetic mice. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance, oxidative stress, and obesity. The db/db mouse model displays increased levels of insulin resistance, obesity, and an over-accumulation of hepatic triglycerides, making it an excellent model for studying NAFLD. In db/db mice, intra-bone marrow bone marrow transplantation plus thymus transplantation (IBM-BMT+TT) improves type 2 diabetes mellitus (T2 DM) by normalizing the T-cell imbalance. We hypothesized that this approach would improve Sirt1 expression in the liver and benefit liver development. The db/db mice were treated with IBM-BMT+TT, and plasma MCP-1, IL-6, adiponection, LDL, Sirt1, and HO-1 levels were then assessed. Stem cell transplantation decreased the levels of plasma inflammatory cytokines and LDL while it increased the expression of Sirt1 and HO-1, resulting in decreased progression of fatty liver. Moreover, Sirt1 and HO-1 expression were both detected in the thymus and many HO-1-positive cells were observed in the bone marrow. This is the first report of stem cell transplantation improving the antioxidant function in the liver, thymus, and bone marrow of db/db mice by increasing the levels of Sirt1 and HO-1. This approach may prove useful in the treatment of nonalcoholic steatohepatitis and its clinical manifestations. PMID- 25798068 TI - Drinking Water Quality Governance: A Comparative Case Study of Brazil, Ecuador, and Malawi. AB - Human health is greatly affected by inadequate access to sufficient and safe drinking water, especially in low and middle-income countries. Drinking water governance improvements may be one way to better drinking water quality. Over the past decade, many projects and international organizations have been dedicated to water governance; however, water governance in the drinking water sector is understudied and how to improve water governance remains unclear. We analyze drinking water governance challenges in three countries-Brazil, Ecuador, and Malawi-as perceived by government, service providers, and civil society organizations. A mixed methods approach was used: a clustering model was used for country selection and qualitative semi-structured interviews were used with direct observation in data collection. The clustering model integrated political, economic, social and environmental variables that impact water sector performance, to group countries. Brazil, Ecuador and Malawi were selected with the model so as to enhance the generalizability of the results. This comparative case study is important because similar challenges are identified in the drinking water sectors of each country; while, the countries represent diverse socio economic and political contexts, and the selection process provides generalizability to our results. We find that access to safe water could be improved if certain water governance challenges were addressed: coordination and data sharing between ministries that deal with drinking water services; monitoring and enforcement of water quality laws; and sufficient technical capacity to improve administrative and technical management of water services at the local level. From an analysis of our field research, we also developed a conceptual framework that identifies policy levers that could be used to influence governance of drinking water quality on national and sub-national levels, and the relationships between these levers. PMID- 25798067 TI - Activation of TLR3 induces osteogenic responses in human aortic valve interstitial cells through the NF-kappaB and ERK1/2 pathways. AB - Calcific aortic valve disease (CAVD) is characterized by chronic inflammation and progressive calcification in valve leaflets. Aortic valve interstitial cells (AVICs) play a critical role in the pathogenesis of CAVD. Previous studies show that stimulation of Toll-like receptor (TLR) 2 or TLR4 in AVICs in vitro up regulates the expression of osteogenic mediators. Double-stranded RNA (dsRNA) can activate pro-inflammatory signaling through TLR3, the NLRP3 inflammasome and RIG I-like receptors. The objective of this study is to determine the effect of dsRNA on AVIC osteogenic activities and the mechanism of its action. METHODS AND RESULTS: AVICs isolated from normal human valves were exposed to polyinosinic polycytidylic acid [poly(I:C)], a mimic of dsRNA. Treatment with poly(I:C) increased the production of bone morphogenetic protein-2 (BMP-2), transforming growth factor beta-1 (TGF-beta1) and alkaline phosphatase (ALP), and resulted in calcium deposit formation. Poly(I:C) induced the phosphorylation of NF-kappaB and ERK1/2. Knockdown of TLR3 essentially abrogated NF-kappaB and ERK1/2 phosphorylation, and markedly reduced the effect of poly(I:C) on the production of BMP-2, TGF-beta1 and ALP. Further, inhibition of either NF-kappaB or ERK1/2 markedly reduced the levels of BMP-2, TGF-beta1 and ALP in cells exposed to poly(I:C). CONCLUSION: Poly(I:C) up-regulates the production of BMP-2, TGF-beta1 and ALP, and promotes calcium deposit formation in human AVICs. The pro osteogenic effect of poly(I:C) is mediated primarily by TLR3 and the NF-kappaB and ERK1/2 pathways. These findings suggest that dsRNA, when present in aortic valve tissue, may promote CAVD progression through up-regulation of AVIC osteogenic activities. PMID- 25798069 TI - Which types of peripheral nerve blocks should be included in residency training programs? AB - BACKGROUND: Despite the increasing use of regional anesthesia, specific recommendations regarding the type of procedures to be included in residency training programs are not currently available. We aimed to determine the nerve block techniques that practicing Chilean anesthesiologists perceived as essential to master during residency training. METHODS: After institutional ethics committee approval, an online survey was sent to 154 anesthesiologists that graduated between 2005-2012, from the two largest university residency programs in Chile. Multiple-choice questions elicited responses concerning the use of regional anesthesia. RESULTS: A total of 109 questionnaires were completed, which corresponded to a response rate of 70.8%. Almost all (98.2%) of the respondents used regional anesthesia in their clinical practice, 86.7% regularly performed peripheral nerve blocks (PNBs) and 51% used continuous PNB techniques. Residency programs represented their primary source of training. The most common PNB techniques performed were interscalene (100%), femoral (98%), popliteal sciatic (93%), and Bier block (90%). Respondents indicated that they were most confident performing femoral (98%), Bier block (90%), interscalene (90%), and popliteal sciatic (85%) blocks. The PNBs perceived as essential for their actual clinical practice were femoral (81%), interscalene (80%), popliteal sciatic (76%), and Bier blocks (62%). CONCLUSIONS: Requesting information from former anesthesiology residents may be a source of information, guiding the specific types of PNBs that should be included in residency training. Other groups can easily replicate this methodology to create their own evidence and clinical practice based guidelines for residency training programs. PMID- 25798070 TI - Drug concentrations in the serum and cerebrospinal fluid of patients treated with cefoperazone/sulbactam after craniotomy. AB - BACKGROUND: To identify changes in cefoperazone/sulbactam penetration into cerebrospinal fluid (CSF) after craniotomy and to investigate preliminarily whether cefoperazone/sulbactam CSF concentration can reach therapeutic level when administered intravenously after neurosurgical operation. METHODS: Neurosurgical patients with an indwelling ventricular drainage pipe who received prophylactic cefoperazone/sulbactam for the treatment of intracranial infection were received a cefoperazone/sulbactam 2:1, 3.0-g infusion for 3 hours every 6 hours for 24 h. Venous blood and CSF specimens were collected to determine cefoperazone/sulbactam concentrations. RESULTS: The cefoperazone and sulbactam concentrations in serum were highest at the second hour (237.54 +/- 336.72 mg/L and 66.52 +/- 80.38 mg/L, respectively) and then decreased. The cefoperazone and sulbactam concentrations in CSF were highest at the 4th hour (39.22 +/- 75.55 mg/L and 6.24 +/- 8.35 mg/L, respectively) and then decreased. CSF penetration measured by the ratio of peak concentrations (CSF/serum) was 8.6% +/- 7.2% for cefoperazone and 13.5% +/- 11.9% for sulbactam, CSF penetration measured by the ratio of trough concentrations (CSF/serum) was 13.4% +/- 5.3% for cefoperazone and 106.5% +/- 87.5% for sulbactam. CSF penetration represented by the ratio of area under the curve (AUC) of CSF and serum was 14.5% for cefoperazone and 22.6% for sulbactam. Neurosurgical impairment of the blood-brain barrier may improve the CSF penetration of these drugs, but it is difficult to reach the MIC90 of resistant bacteria. If single intravenous administration time was extended to 3 hours, the serum concentrations of drugs were able to meet the PK/PD standard (T> MIC%> 50%) for treating common, highly resistant bacteria. CONCLUSIONS: The CSF penetration of cefoperazone/sulbactam may be enhanced after neurosurgical impairment of the blood-brain barrier. This study is a pilot research of cefoperazone/sulbactam using in neurosurgical individuals, However, it needs to be confirmed by further large-scale studies. PMID- 25798071 TI - The effect of caregiving on bereavement outcome: study protocol for a longitudinal, prospective study. AB - BACKGROUND: The aim of the current study is to determine the effects of caregiving on bereavement outcome. The study will address two important gaps in the research literature: (1) the relationship between pre-death distress and post death outcomes and (2) family caregivers' anticipation and preparation of the death of the person for whom they care. METHODS/DESIGN: We will conduct a longitudinal, prospective study of adult family caregivers of adult patients receiving palliative care. All participants will complete a questionnaire administered at four points - approximately 4-8 weeks prior to bereavement, and 3 4, 6-7, and 9-10 months post-bereavement. The questionnaire includes measures of multidimensional caregiving experiences (strain, distress, positive appraisals, and family wellbeing), caregiver prolonged grief, multidimensional grief responses (despair, panic behaviour, blame and anger, detachment, disorganisation, and personal growth), prolonged grief, quality of life, general health (psychological and physical) and demographics. These caregivers' data will be compared to a comparison group matched for age, sex, and postcode, allowing the caregivers' general health and quality of life to be compared to a normative group. The caregivers will also be invited to participate in a semi-structured interview about preparing for impending bereavement. DISCUSSION: This is the first study to address the methodological limitations in the current literature and will likely make a significant contribution to both our understanding of caregiving on bereavement outcome and to bereavement care offered in palliative and hospice settings. PMID- 25798072 TI - Increasingly mobile: How new technologies can enhance qualitative research. AB - Advances in technology, such as the growth of smart phones, tablet computing, and improved access to the internet have resulted in many new tools and applications designed to increase efficiency and improve workflow. Some of these tools will assist scholars using qualitative methods with their research processes. We describe emerging technologies for use in data collection, analysis, and dissemination that each offer enhancements to existing research processes. Suggestions for keeping pace with the ever-evolving technological landscape are also offered. PMID- 25798073 TI - Combination of cyclophosphamide and double-stranded DNA demonstrates synergistic toxicity against established xenografts. AB - BACKGROUND: Extracellular double-stranded DNA participates in various processes in an organism. Here we report the suppressive effects of fragmented human double stranded DNA along or in combination with cyclophosphamide on solid and ascites grafts of mouse Krebs-2 tumor cells and DNA preparation on human breast adenocarcinoma cell line MCF-7. METHODS: Apoptosis and necrosis were assayed by electrophoretic analysis (DNA nucleosomal fragmentation) and by measurements of LDH levels in ascitic fluid, respectively. DNA internalization into MCF-7 was analyzed by flow cytometry and fluorescence microscopy. RESULTS: Direct cytotoxic activity of double-stranded DNA (along or in combination with cyclophosphamide) on a solid transplant was demonstrated. This resulted in delayed solid tumor proliferation and partial tumor lysis due to necrosis of the tumor and adjacent tissues. In the case of ascites form of tumor, extensive apoptosis and secondary necrosis were observed. Similarly, MCF-7 cells showed induction of massive apoptosis (up to 45%) as a result of treatments with double-stranded DNA preparation. CONCLUSIONS: Double-stranded DNA (along or in combination with cyclophosphamide) induces massive apoptosis of Krebs-2 ascite cells and MCF-7 cell line (DNA only). In treated mice it reduces the integrity of gut wall cells and contributes to the development of systemic inflammatory reaction. PMID- 25798075 TI - Erosion of the healthy soldier effect in veterans of US military service in Iraq and Afghanistan. AB - BACKGROUND: This research explores the healthy soldier effect (HSE) - a lower mortality risk among veterans relative to the general population-in United States (US) veterans deployed in support of operations in Iraq and Afghanistan (OEF/OIF/OND). While a HSE has been affirmed in other OEF/OIF/OND populations, US veterans of OEF/OIF/OND have not been systematically studied. METHODS: Using US Department of Veterans Affairs (VA) administrative data, we identified veterans who (1) had been deployed in support of OEF/OIF/OND between 2002 and 2011 and (2) were enrolled in the VA health care system. We divided the VA population into VA health care utilizers and non-utilizers. We obtained Department of Defense (DOD) administrative data on the OEF/OIF/OND population and obtained VA and DOD mortality data excluding combat deaths from the analyses. Indirect standardization was used to compare VA and DOD cohorts to the US population using total population at risk to compute the Standardized Mortality Ratio (SMR). A directly standardized relative risk (DSRR) was calculated to enable comparisons between cohorts. To compare VA enrollee mortality on military specific characteristics, we used a DOD population standard. RESULTS: The overall VA SMR of 2.8 (95% Confidence Interval [CI] 2.8-2.9), VA utilizer SMR of 3.2 (95% CI 3.1 3.3), VA non-utilizer SMR of 0.9 (95% CI 0.8-1.1), and DOD SMR of 1.5 (95% CI 1.4 1.5) provide no evidence of a HSE in any cohort relative to the US standard population. Relative to DOD, both the total VA population SMR of 2.1 (95% CI 2.0 2.2) and the SMR for VA utilizers of 2.3 (95% CI 2.3-2.4) indicate mortality twice what would be expected given DOD mortality rates. In contrast, the VA enrollees who had not used clinical services had 40% lower than expected mortality relative to DOD. CONCLUSIONS: No support was found for the HSE among US veterans of OEF/OIF/OND. These findings may be attributable to a number of factors including post-deployment risk-taking behavior, an abbreviated follow up period, and the nature of the OEF/OIF/OND conflict. PMID- 25798074 TI - New interaction partners for Nek4.1 and Nek4.2 isoforms: from the DNA damage response to RNA splicing. AB - BACKGROUND: Neks are serine-threonine kinases that are similar to NIMA, a protein found in Aspergillus nidulans which is essential for cell division. In humans there are eleven Neks which are involved in different biological functions besides the cell cycle control. Nek4 is one of the largest members of the Nek family and has been related to the primary cilia formation and in DNA damage response. However, its substrates and interaction partners are still unknown. In an attempt to better understand the role of Nek4, we performed an interactomics study to find new biological processes in which Nek4 is involved. We also described a novel Nek4 isoform which lacks a region of 46 amino acids derived from an insertion of an Alu sequence and showed the interactomics profile of these two Nek4 proteins. RESULTS AND DISCUSSION: Isoform 1 and isoform 2 of Nek4 were expressed in human cells and after an immunoprecipitation followed by mass spectrometry, 474 interacting proteins were identified for isoform 1 and 149 for isoform 2 of Nek4. About 68% of isoform 2 potential interactors (102 proteins) are common between the two Nek4 isoforms. Our results reinforce Nek4 involvement in the DNA damage response, cilia maintenance and microtubule stabilization, and raise the possibility of new functional contexts, including apoptosis signaling, stress response, translation, protein quality control and, most intriguingly, RNA splicing. We show for the first time an unexpected difference between both Nek4 isoforms in RNA splicing control. Among the interacting partners, we found important proteins such as ANT3, Whirlin, PCNA, 14-3-3epsilon, SRSF1, SRSF2, SRPK1 and hNRNPs proteins. CONCLUSIONS: This study provides new insights into Nek4 functions, identifying new interaction partners and further suggests an interesting difference between isoform 1 and isoform 2 of this kinase. Nek4 isoform 1 may have similar roles compared to other Neks and these roles are not all preserved in isoform 2. Besides, in some processes, both isoforms showed opposite effects, indicating a possible fine controlled regulation. PMID- 25798076 TI - A comparison of skin tone discrimination among African American men: 1995 and 2003. AB - This study investigated perceptions of skin tone discrimination among adult African American men. Research suggests that through negative African American stereotypes, out-group members (Whites) perceive light-skinned African Americans favorably and dark-skinned African Americans unfavorably. However, it is unclear how treatment by in-group members (other African Americans) uniquely affects men. Using data from the 1995 Detroit Area Study and the 2003 National Survey of American Life, we investigated these relationships among African American men representing a wide range of socioeconomic groups. We found that African American men's perceptions of out-group and in-group treatment, respectively, were similar across time. Light-skinned men perceived the least out-group discrimination while dark-skinned men perceived the most out-group discrimination. In appraisals of skin tone discrimination from in-group members, medium-skinned men perceived the least discrimination while both light- and dark-skinned men perceived more in group discrimination. Additionally, men of lower social economic groups were more affected by skin tone bias than others. Future research should explore the influence of these out- and in-group experiences of skin tone discrimination on social and psychological functioning of African American men. PMID- 25798077 TI - Healthy Libraries Develop Healthy Communities: Public Libraries and their Tremendous Efforts to Support the Affordable Care Act. AB - This article is about the dedication of public library staff and my role as the Consumer Health Coordinator for the National Network of Libraries of Medicine, Middle Atlantic Region (NN/LM MAR) to support outreach efforts for health insurance enrollment under the Patient Protection and Affordable Care Act (ACA). ACA was created in order to ensure that all Americans have access to affordable health care. What we didn't know is that public libraries across the nation would play such an integral role in the health insurance enrollment process. The National Network of Libraries of Medicine (NN/LM) worked closely with public libraries in order to assist with this new role. As we approach the second enrollment and re-enrollment periods, public libraries are gearing up once again to assist with ACA. PMID- 25798079 TI - 'Julian Huxley and the Continuity of Eugenics in Twentieth-century Britain'. PMID- 25798078 TI - The Comet Cometh: Evolving Developmental Systems. AB - In a recent opinion piece, Denis Duboule has claimed that the increasing shift towards systems biology is driving evolutionary and developmental biology apart, and that a true reunification of these two disciplines within the framework of evolutionary developmental biology (EvoDevo) may easily take another 100 years. He identifies methodological, epistemological, and social differences as causes for this supposed separation. Our article provides a contrasting view. We argue that Duboule's prediction is based on a one-sided understanding of systems biology as a science that is only interested in functional, not evolutionary, aspects of biological processes. Instead, we propose a research program for an evolutionary systems biology, which is based on local exploration of the configuration space in evolving developmental systems. We call this approach which is based on reverse engineering, simulation, and mathematical analysis-the natural history of configuration space. We discuss a number of illustrative examples that demonstrate the past success of local exploration, as opposed to global mapping, in different biological contexts. We argue that this pragmatic mode of inquiry can be extended and applied to the mathematical analysis of the developmental repertoire and evolutionary potential of evolving developmental mechanisms and that evolutionary systems biology so conceived provides a pragmatic epistemological framework for the EvoDevo synthesis. PMID- 25798080 TI - 3-Dimensional Tracking of Non-blinking 'Giant' Quantum Dots in Live Cells. AB - While semiconductor quantum dots (QDs) have been used successfully in numerous single particle tracking (SPT) studies due to their high photoluminescence efficiency, photostability, and broad palette of emission colors, conventional QDs exhibit fluorescence intermittency or 'blinking,' which causes ambiguity in particle trajectory analysis and limits tracking duration. Here, non-blinking 'giant' quantum dots (gQDs) are exploited to study IgE-FcepsilonRI receptor dynamics in live cells using a confocal-based 3D SPT microscope. There is a 7 fold increase in the probability of observing IgE-FcepsilonRI for longer than 1 min using the gQDs compared to commercially available QDs. A time-gated photon pair correlation analysis is implemented to verify that selected SPT trajectories are definitively from individual gQDs and not aggregates. The increase in tracking duration for the gQDs allows the observation of multiple changes in diffusion rates of individual IgE-FcepsilonRI receptors occurring on long (>1 min) time scales, which are quantified using a time-dependent diffusion coefficient and hidden Markov modeling. Non-blinking gQDs should become an important tool in future live cell 2D and 3D SPT studies, especially in cases where changes in cellular dynamics are occurring on the time scale of several minutes. PMID- 25798081 TI - Intrapersonal and interpersonal processes of social exclusion. AB - People have a fundamental need to belong with others. Social exclusion impairs this need and has various effects on cognition, affect, and the behavior of excluded individuals. We have previously reported that activity in the dorsal anterior cingulate cortex (dACC) and right ventrolateral prefrontal cortex (rVLPFC) could be a neurocognitive index of social exclusion (Kawamoto et al., 2012). In this article, we provide an integrative framework for understanding occurrences during and after social exclusion, by reviewing neuroimaging, electrophysiological, and behavioral studies of dACC and rVLPFC, within the framework of intrapersonal and interpersonal processes of social exclusion. As a result, we have indicated directions for future studies to further clarify the phenomenon of social exclusion from the following perspectives: (1) constructional elements of social exclusion, (2) detection sensitivity and interpretation bias in social exclusion, (3) development of new methods to assess the reactivity to social exclusion, and (4) sources of social exclusion. PMID- 25798082 TI - Multiple brain networks contribute to the acquisition of bias in perceptual decision-making. AB - Bias occurs in perceptual decisions when the reward associated with a particular response dominates the sensory evidence in support of a choice. However, it remains unclear how this bias is acquired and once acquired, how it influences perceptual decision processes in the brain. We addressed these questions using model-based neuroimaging in a motion discrimination paradigm where contextual cues suggested which one of two options would receive higher rewards on each trial. We found that participants gradually learned to choose the higher-rewarded option in each context when making a perceptual decision. The amount of bias on each trial was fit well by a reinforcement-learning model that estimated the subjective value of each option within the current context. The brain mechanisms underlying this bias acquisition process were similar to those observed in reward based decision tasks: prediction errors correlated with the fMRI signals in ventral striatum, dlPFC, and parietal cortex, whereas the amount of acquired bias correlated with activity in ventromedial prefrontal (vmPFC), dorsolateral frontal (dlPFC), and parietal cortices. Moreover, psychophysiological interaction analysis revealed that as bias increased, functional connectivity increased within multiple brain networks (dlPFC-vmPFC-visual, vmPFC-motor, and parietal anterior-cingulate), suggesting that multiple mechanisms contribute to bias in perceptual decisions through integration of value processing with action, sensory, and control systems. These provide a novel link between the neural mechanisms underlying perceptual and economic decision-making. PMID- 25798083 TI - Auditory distraction transmitted by a cochlear implant alters allocation of attentional resources. AB - Cochlear implants (CIs) are auditory prostheses which restore hearing via electrical stimulation of the auditory nerve. The successful adaptation of auditory cognition to the CI input depends to a substantial degree on individual factors. We pursued an electrophysiological approach toward an analysis of cortical responses that reflect perceptual processing stages and higher-level responses to CI input. Performance and event-related potentials on two cross modal discrimination-following-distraction (DFD) tasks from CI users and normal hearing (NH) individuals were compared. The visual-auditory distraction task combined visual distraction with following auditory discrimination performance. Here, we observed similar cortical responses to visual distractors (Novelty-N2) and slowed, less accurate auditory discrimination performance in CI users when compared to NH individuals. Conversely, the auditory-visual distraction task was used to combine auditory distraction with visual discrimination performance. In this task we found attenuated cortical responses to auditory distractors (Novelty P3), slowed visual discrimination performance, and attenuated cortical P3 responses to visual targets in CI users compared to NH individuals. These results suggest that CI users process auditory distractors differently than NH individuals and that the presence of auditory CI input has an adverse effect on the processing of visual targets and the visual discrimination ability in implanted individuals. We propose that this attenuation of the visual modality occurs through the allocation of neural resources to the CI input. PMID- 25798084 TI - Adult neurogenesis 20 years later: physiological function vs. brain repair. PMID- 25798085 TI - Ca(2+) and Ca(2+)-interlocked membrane guanylate cyclase signal modulation of neuronal and cardiovascular signal transduction. PMID- 25798086 TI - Compensatory mechanisms in genetic models of neurodegeneration: are the mice better than humans? AB - Neurodegenerative diseases are one of the main causes of mental and physical disabilities. Neurodegeneration has been estimated to begin many years before the first clinical symptoms manifest, and even a prompt diagnosis at this stage provides very little advantage for a more effective treatment as the currently available pharmacotherapies are based on disease symptomatology. The etiology of the majority of neurodegenerative diseases remains unknown, and even for those diseases caused by identified genetic mutations, the direct pathways from gene alteration to final cell death have not yet been fully elucidated. Advancements in genetic engineering have provided many transgenic mice that are used as an alternative to pharmacological models of neurodegenerative diseases. Surprisingly, even the models reiterating the same causative mutations do not fully recapitulate the inevitable neuronal loss, and some fail to even show phenotypic alterations, which suggests the possible existence of compensatory mechanisms. A better evaluation of these mechanisms may not only help us to explain why neurodegenerative diseases are mostly late-onset disorders in humans but may also provide new markers and targets for novel strategies designed to extend neuronal function and survival. The aim of this mini-review is to draw attention to this under-explored field in which investigations may reasonably contribute to unveiling hidden reserves in the organism. PMID- 25798087 TI - Transcriptome analyses of adult mouse brain reveal enrichment of lncRNAs in specific brain regions and neuronal populations. AB - Despite the importance of the long non-coding RNAs (lncRNAs) in regulating biological functions, the expression profiles of lncRNAs in the sub-regions of the mammalian brain and neuronal populations remain largely uncharacterized. By analyzing RNASeq datasets, we demonstrate region specific enrichment of populations of lncRNAs and mRNAs in the mouse hippocampus and pre-frontal cortex (PFC), the two major regions of the brain involved in memory storage and neuropsychiatric disorders. We identified 2759 lncRNAs and 17,859 mRNAs in the hippocampus and 2561 lncRNAs and 17,464 mRNAs expressed in the PFC. The lncRNAs identified correspond to ~14% of the transcriptome of the hippocampus and PFC and ~70% of the lncRNAs annotated in the mouse genome (NCBIM37) and are localized along the chromosomes as varying numbers of clusters. Importantly, we also found that a few of the tested lncRNA-mRNA pairs that share a genomic locus display specific co-expression in a region-specific manner. Furthermore, we find that sub regions of the brain and specific neuronal populations have characteristic lncRNA expression signatures. These results reveal an unexpected complexity of the lncRNA expression in the mouse brain. PMID- 25798088 TI - GluA2 is rapidly edited at the Q/R site during neural differentiation in vitro. AB - The majority of AMPA receptors in the adult brain contain GluA2 subunits, which can be edited at the Q/R site, changing a glutamine to an arginine within the ion pore. Q/R editing renders AMPARs virtually Ca(2+)-impermeable, which is important for normal AMPA receptor function. Thus, all GluA2 subunits are Q/R-edited in the adult brain. However, it has remained controversial precisely when editing sets in during development. In the present study, we show that GluA2 mRNA is very rapidly Q/R-edited immediately after its appearance, which is after 4.5 days of differentiation from 46C embryonic stem cells (ESCs) to neuroepithelial precursor cells (NEPs). At this time point, most of the GluA2 transcripts were already edited, with only a small fraction remaining unedited, and half a day later all GluA2 transcripts were edited. This can be explained by the observation that the enzyme that Q/R-edits GluA2 transcripts, ADAR2, is already expressed in the cell well before GluA2 transcription starts, and later is not significantly upregulated any more. Editing at another site works differently: The R/G site within the ligand-binding domain was never completely edited at any of the developmental stages tested, and the enzyme that performs this editing, ADAR1, was significantly upregulated during neural differentiation. This confirms previous data suggesting that R/G editing, in contrast to Q/R editing, progresses gradually during development. PMID- 25798089 TI - Positive taxis and sustained responsiveness to water motions in larval zebrafish. AB - Larval zebrafish (Danio rerio) have become favored subjects for studying the neural bases of behavior. Here, we report a highly stereotyped response of zebrafish larvae to hydrodynamic stimuli. It involves positive taxis, motion damping and sustained responsiveness to flows derived from local, non-stressful water motions. The response depends on the lateral line and has a high sensitivity to stimulus frequency and strength, sensory background and rearing conditions--also encompassing increased threshold levels of response to parallel input. The results show that zebrafish larvae can use near-field detection to locate sources of minute water motions, and offer a unique handle for analyses of hydrodynamic sensing, sensory responsiveness and arousal with accurate control of stimulus properties. PMID- 25798090 TI - The dendritic spine story: an intriguing process of discovery. AB - Dendritic spines are key components of a variety of microcircuits and they represent the majority of postsynaptic targets of glutamatergic axon terminals in the brain. The present article will focus on the discovery of dendritic spines, which was possible thanks to the application of the Golgi technique to the study of the nervous system, and will also explore the early interpretation of these elements. This discovery represents an interesting chapter in the history of neuroscience as it shows us that progress in the study of the structure of the nervous system is based not only on the emergence of new techniques but also on our ability to exploit the methods already available and correctly interpret their microscopic images. PMID- 25798091 TI - Distribution of vesicular glutamate transporters in the human brain. AB - Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains. PMID- 25798092 TI - Correlation of in vivo and ex vivo (1)H-MRI with histology in two severities of mouse spinal cord injury. AB - Spinal cord injury (SCI) is a debilitating neuropathology with no effective treatment. Magnetic resonance imaging (MRI) technology is the only method used to assess the impact of an injury on the structure and function of the human spinal cord. Moreover, in pre-clinical SCI research, MRI is a non-invasive method with great translational potential since it provides relevant longitudinal assessment of anatomical and structural alterations induced by an injury. It is only recently that MRI techniques have been effectively used for the follow-up of SCI in rodents. However, the vast majority of these studies have been carried out on rats and when conducted in mice, the contusion injury model was predominantly chosen. Due to the remarkable potential of transgenic mice for studying the pathophysiology of SCI, we examined the use of both in and ex vivo (1)H-MRI (9.4 T) in two severities of the mouse SCI (hemisection and over-hemisection) and documented their correlation with histological assessments. We demonstrated that a clear distinction between the two injury severities is possible using in and ex vivo (1)H-MRI and that ex vivo MR images closely correlate with histology. Moreover, tissue modifications at a remote location from the lesion epicenter were identified by conventional ex vivo MRI analysis. Therefore, in vivo MRI has the potential to accurately identify in mice the progression of tissue alterations induced by SCI and is successfully implemented by ex vivo MRI examination. This combination of in and ex vivo MRI follow-up associated with histopathological assessment provides a valuable approach for further studies intended to evaluate therapeutic strategies on SCI. PMID- 25798093 TI - Improved discriminability of spatiotemporal neural patterns in rat motor cortical areas as directional choice learning progresses. AB - Animals learn to choose a proper action among alternatives to improve their odds of success in food foraging and other activities critical for survival. Through trial-and-error, they learn correct associations between their choices and external stimuli. While a neural network that underlies such learning process has been identified at a high level, it is still unclear how individual neurons and a neural ensemble adapt as learning progresses. In this study, we monitored the activity of single units in the rat medial and lateral agranular (AGm and AGl, respectively) areas as rats learned to make a left or right side lever press in response to a left or right side light cue. We noticed that rat movement parameters during the performance of the directional choice task quickly became stereotyped during the first 2-3 days or sessions. But learning the directional choice problem took weeks to occur. Accompanying rats' behavioral performance adaptation, we observed neural modulation by directional choice in recorded single units. Our analysis shows that ensemble mean firing rates in the cue-on period did not change significantly as learning progressed, and the ensemble mean rate difference between left and right side choices did not show a clear trend of change either. However, the spatiotemporal firing patterns of the neural ensemble exhibited improved discriminability between the two directional choices through learning. These results suggest a spatiotemporal neural coding scheme in a motor cortical neural ensemble that may be responsible for and contributing to learning the directional choice task. PMID- 25798094 TI - The effect of immature adult-born dentate granule cells on hyponeophagial behavior is related to their roles in learning and memory. AB - The neurogenesis hypothesis of depression is based on the correlation between the rate of adult hippocampal neurogenesis and the affective status of rodents. However, studies investigating the role of neurogenesis in the causation of mood regulation have reported inconsistent results. Here, we explored whether the affective state can be affected differentially by adult-born neurons with distinctive physiological characteristics at different maturation stages. We revealed that reducing the immature newborn neuron population had no effect on anxiety- or depression-like behaviors in an array of tests; however, it enhanced hyponeophagia in a novelty suppressed feeding test, but only when the novel environment was drastically different from the home cage. We further demonstrated that reducing the immature newborn neuron population led to delayed habituation to a novel environment and impaired contextual learning. Hence, rather than being directly involved in mood regulation, our studies raise the possibility that adult neurogenesis may influence hyponeophagia through its role in mnemonic processing. PMID- 25798095 TI - The effects of hearing loss on neural processing and plasticity. PMID- 25798096 TI - Anterior insular cortex regulation in autism spectrum disorders. AB - Autism spectrum disorders (ASDs) comprise a heterogeneous set of neurodevelopmental disorders characterized by dramatic impairments of interpersonal behavior, communication, and empathy. Recent neuroimaging studies suggested that ASD are disorders characterized by widespread abnormalities involving distributed brain network, though clear evidence of differences in large-scale brain network interactions underlying the cognitive and behavioral symptoms of ASD are still lacking. Consistent findings of anterior insula cortex hypoactivation and dysconnectivity during tasks related to emotional and social processing indicates its dysfunctional role in ASD. In parallel, increasing evidence showed that successful control of anterior insula activity can be attained using real-time fMRI paradigms. More importantly, successful regulation of this region was associated with changes in behavior and brain connectivity in both healthy individuals and psychiatric patients. Building on these results we here propose and discuss the use of real-time fMRI neurofeedback in ASD aiming at improving emotional and social behavior. PMID- 25798097 TI - Exercise-mode-related changes in task-switching performance in the elderly. AB - The objective of the current study was to explore the relationships between exercise modes and executive functions in the elderly. Twenty-one elderly individuals in the open-skill group, 22 in the closed-skill group, and 21 in the sedentary-behavior (control) group were recruited in the current study, and performed a task-switching paradigm during which the switches occurred unpredictably and infrequently, while the behavioral and electrophysiological performances were assessed simultaneously. The results indicated that although there were no group differences in accuracy rates, the two exercise groups exhibited shorter reaction times (RTs), and larger P2 and P3 amplitudes across all conditions compared to the control group. In addition, the exercise-mode differences revealed a relatively smaller specific cost, and faster motor RTs and larger P3 amplitudes, in the switch condition for the open-skill group in comparison with the closed-skill and control groups. These findings suggest that regularly participating in physical exercise can enhance behavioral and electrophysiological performance with regard to executive control in the elderly, and provide further evidence for the beneficial effects of open-skill exercise on the task-switching paradigm. PMID- 25798098 TI - Neural evidence for the use of digit-image mnemonic in a superior memorist: an fMRI study. AB - Some superior memorists demonstrated exceptional memory for reciting a large body of information. The underlying neural correlates, however, are seldom addressed. C.L., the current holder of Guinness World Record for reciting 67,890 digits in pi, participated in this functional magnetic resonance imaging (fMRI) study. Thirteen participants without any mnemonics training were included as controls. Our previous studies suggested that C.L. used a digit-image mnemonic in studying and recalling lists of digits, namely associating 2-digit groups of "00" to "99" with images and generating vivid stories out of them (Hu et al., 2009). Thus, 2 digit condition was included, with 1-digit numbers and letters as control conditions. We hypothesized that 2-digit condition in C.L. should elicit the strongest activity in the brain regions which are associated with his mnemonic. Functional MRI results revealed that bilateral frontal poles (FPs, BA10), left superior parietal lobule (SPL), left premotor cortex (PMC), and left dorsolateral prefrontal cortex (DLPFC), were more engaged in both the study and recall phase of 2-digit condition for C.L. relative to controls. Moreover, the left middle/inferior frontal gyri (M/IFG) and intraparietal sulci (IPS) were less engaged in the study phase of 2-digit condition for C.L. (vs. controls). These results suggested that C.L. relied more on brain regions that are associated with episodic memory other than verbal rehearsal while he used his mnemonic strategies. This study supported theoretical accounts of restructured cognitive mechanisms for the acquisition of superior memory performance. PMID- 25798099 TI - Differential influences of unilateral tDCS over the intraparietal cortex on numerical cognition. AB - Recent neuro-imaging research identified the bilateral intraparietal sulcus (IPS) to be a key area associated with number processing. However, causal structure function relationships are hard to evaluate from neuro-imaging techniques such as fMRI. Nevertheless, brain stimulation methods like transcranial direct current stimulation (tDCS) allow for investigating the functional relevance of the IPS for number processing. Following up on a study using bilateral bi-cephalic tDCS over the IPS, the current study aimed at evaluating the differential lateralized functional contributions of the left and right IPS to number processing using unilateral bi-cephalic tDCS over either the left or right IPS. Results indicated a right lateralization for the processing of the place-value structure of the Arabic number system. Importantly, the processing of number magnitude information was not affected by unilateral IPS corroborating the assumption that number magnitude is processed in the bilateral IPS. Taken together, these data suggest that even though number magnitude is represented bilaterally, the left and right IPS seem to contribute differentially to numerical cognition with respect to the processing of specific other aspects of numerical information. PMID- 25798100 TI - A contemporary research topic: manipulative approaches to human brain dynamics. PMID- 25798101 TI - Cognitive control and the non-conscious regulation of health behavior. PMID- 25798102 TI - Neural correlates of decision making after unfair treatment. AB - Empirical evidence indicates that people are inequity averse. However, it is unclear whether and how suffering unfairness impacts subsequent behavior. We investigated the consequences of unfair treatment in subsequent interactions with new interaction partners and the associated neural mechanisms. Participants were experimentally manipulated to experience fair or unfair treatment in the ultimatum game (UG), and subsequently, they were given the opportunity to retaliate in the dictator game (DG) in their interactions with players who had not played a role in the previous fair or unfair treatment. The results showed that participants dictated less money to unrelated partners after frequently receiving unfair offers in the previous UG (vs. frequently receiving fair offers in the previous UG), but only when they were first exposed to unfair UG/DG. Stronger activation in the right dorsal anterior insula was found during receiving unfair offers and during the subsequent offer-considering phase. The regional homogeneity (ReHo), a measure of the local synchronization of neighboring voxels in resting-state brain activity, in the left ventral anterior insula and left superior temporal pole was positively correlated with the behavior change. These findings suggest that unfair treatment may encourage a spread of unfairness, and that the anterior insula may be not only engaged in signaling social norm violations, but also recruited in guiding subsequent adaptive behaviors. PMID- 25798104 TI - A long journey into reproducible computational neuroscience. PMID- 25798103 TI - Cortical hot spots and labyrinths: why cortical neuromodulation for episodic migraine with aura should be personalized. AB - Stimulation protocols for medical devices should be rationally designed. For episodic migraine with aura we outline model-based design strategies toward preventive and acute therapies using stereotactic cortical neuromodulation. To this end, we regard a localized spreading depression (SD) wave segment as a central element in migraine pathophysiology. To describe nucleation and propagation features of the SD wave segment, we define the new concepts of cortical hot spots and labyrinths, respectively. In particular, we firstly focus exclusively on curvature-induced dynamical properties by studying a generic reaction-diffusion model of SD on the folded cortical surface. This surface is described with increasing level of details, including finally personalized simulations using patient's magnetic resonance imaging (MRI) scanner readings. At this stage, the only relevant factor that can modulate nucleation and propagation paths is the Gaussian curvature, which has the advantage of being rather readily accessible by MRI. We conclude with discussing further anatomical factors, such as areal, laminar, and cellular heterogeneity, that in addition to and in relation to Gaussian curvature determine the generalized concept of cortical hot spots and labyrinths as target structures for neuromodulation. Our numerical simulations suggest that these target structures are like fingerprints, they are individual features of each migraine sufferer. The goal in the future will be to provide individualized neural tissue simulations. These simulations should predict the clinical data and therefore can also serve as a test bed for exploring stereotactic cortical neuromodulation. PMID- 25798105 TI - High frequency switched-mode stimulation can evoke post synaptic responses in cerebellar principal neurons. AB - This paper investigates the efficacy of high frequency switched-mode neural stimulation. Instead of using a constant stimulation amplitude, the stimulus is switched on and off repeatedly with a high frequency (up to 100 kHz) duty cycled signal. By means of tissue modeling that includes the dynamic properties of both the tissue material as well as the axon membrane, it is first shown that switched mode stimulation depolarizes the cell membrane in a similar way as classical constant amplitude stimulation. These findings are subsequently verified using in vitro experiments in which the response of a Purkinje cell is measured due to a stimulation signal in the molecular layer of the cerebellum of a mouse. For this purpose a stimulator circuit is developed that is able to produce a monophasic high frequency switched-mode stimulation signal. The results confirm the modeling by showing that switched-mode stimulation is able to induce similar responses in the Purkinje cell as classical stimulation using a constant current source. This conclusion opens up possibilities for novel stimulation designs that can improve the performance of the stimulator circuitry. Care has to be taken to avoid losses in the system due to the higher operating frequency. PMID- 25798106 TI - Hippocampal "cholinergic interneurons" visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation. AB - Release of acetylcholine (ACh) in the hippocampus (HC) occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB) is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa) mice were examined in HC. The HC of ChAT tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlap with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM) exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP) of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT tauGFP and ChAT-Rosa mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations. PMID- 25798108 TI - Retinoic acid-loaded polymeric nanoparticles induce neuroprotection in a mouse model for Parkinson's disease. AB - Retinoic acid (RA) plays an important role in the commitment, maturation and survival of neural cells. Recently, RA was pointed as a therapeutic option for some neurodegenerative diseases, including Parkinson's disease (PD). The administration of RA has been defying, and in this sense we have previously developed novel RA-loaded polymeric nanoparticles (RA-NPs) that ensure the efficient intracellular transport and controlled release of RA. Herein, we show that nanoformulation as an efficient neuroprotective effect on dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mouse model for PD. The results showed that the RA-NPs administration induced a significant reduction of DA neuron loss in the substantia nigra (SN) as well as their neuronal fiber/axonal innervations in the striatum. Furthermore, we observed an increase in the expression levels of the transcription factors Pitx3 and Nurr1 induced by RA-NPs, showing its supportive effect on the development and functional maintenance of DA neurons in PD. This is the first study showing that RA-NPs can be an innovative strategy to halt the progression of PD pathogenesis, suggesting that this nanoformulation could be of particular interest for the development of new approaches for PD therapeutics. PMID- 25798107 TI - DNA methylation dynamics in muscle development and disease. AB - DNA methylation is an essential epigenetic modification for mammalian development and is crucial for the establishment and maintenance of cellular identity. Traditionally, DNA methylation has been considered as a permanent repressive epigenetic mark. However, the application of genome-wide approaches has allowed the analysis of DNA methylation in different genomic contexts revealing a more dynamic regulation than originally thought, since active DNA methylation and demethylation occur during cellular differentiation and tissue specification. Satellite cells are the primary stem cells in adult skeletal muscle and are responsible for postnatal muscle growth, hypertrophy, and muscle regeneration. This review outlines the published data regarding DNA methylation changes along the skeletal muscle program, in both physiological and pathological conditions, to better understand the epigenetic mechanisms that control myogenesis. PMID- 25798109 TI - Computer processable classification of craniofacial clefts. PMID- 25798110 TI - Light induces changes in activities of Na(+)/K(+)-ATPase, H(+)/K(+)-ATPase and glutamine synthetase in tissues involved directly or indirectly in light-enhanced calcification in the giant clam, Tridacna squamosa. AB - The objective of this study was to determine the effects of 12 h of exposure to light, as compared with 12 h of exposure to darkness (control), on enzymatic activities of transporters involved in the transport of NH(+) 4 or H(+), and activities of enzymes involved in converting NH(+) 4 to glutamate/glutamine in inner mantle, outer mantle, and ctenidia of the giant clam, Tridacna squamosa. Exposure to light resulted in a significant increase in the effectiveness of NH(+) 4 in substitution for K(+) to activate Na(+)/K(+)-ATPase (NKA), manifested as a significant increase in the Na(+)/NH(+) 4-activated-NKA activity in the inner mantle. However, similar phenomena were not observed in the extensible outer mantle, which contained abundant symbiotic zooxanthellae. Hence, during light-enhanced calcification, H(+) released from CaCO3 deposition could react with NH3 to form NH(+) 4 in the extrapallial fluid, and NH(+) 4 could probably be transported into the shell-facing inner mantle epithelium through NKA. Light also induced an increase in the activity of glutamine synthetase, which converts NH(+) 4 and glutamate to glutamine, in the inner mantle. Taken together, these results explained observations reported elsewhere that light induced a significant increase in pH and a significant decrease in ammonia concentration in the extrapallial fluid, as well as a significant increase in the glutamine concentration in the inner mantle, of T. squamosa. Exposure of T. squamosa to light also led to a significant decrease in the N-ethylmaleimide (NEM)-sensitive V-H(+)-ATPase (VATPase) in the inner mantle, and significant increases in the Na(+)/K(+)-activated-NKA, H(+)/NH(+) 4-activated-H(+)/K(+)-ATPase, and NEM sensitive-VATPase activities in ctenidia, indicating that light-enhanced calcification might perturb Na(+) homeostasis and acid/base balance in the hemolymph, and might involve the active uptake of NH(+) 4 from the environment. This is the first report on light having direct enhancing effects on activities of certain transporters/enzymes related to light-enhanced calcification in the inner mantle and ctenidia of T. squamosa. PMID- 25798111 TI - Gray matter axonal connectivity maps. AB - Structural brain connectivity is generally assessed through methods that rely on pre-defined regions of interest (e.g., Brodmann's areas), thus preventing analyses that are largely free from a priori anatomical assumptions. Here, we introduce a novel and practical technique to evaluate a voxel-based measure of axonal projections connecting gray matter tissue [gray matter axonal connectivity map (GMAC)]. GMACs are compatible with voxel-based statistical approaches, and can be used to assess whole brain, scale-free, gray matter connectivity. In this study, we demonstrate how whole-brain GMACs can be generated from conventional structural connectome methodology, describing each step in detail, as well as providing tools to allow for the calculation of GMAC. To illustrate the utility of GMAC, we demonstrate the relationship between age and gray matter connectivity, using voxel-based analyses of GMAC. We discuss the potential role of GMAC in further analyses of cortical connectivity in healthy and clinical populations. PMID- 25798112 TI - Needed Relapse-Prevention Research on Novel Framework (ASPIRE Model) for Substance Use Disorders Treatment. PMID- 25798113 TI - Age differences in high frequency phasic heart rate variability and performance response to increased executive function load in three executive function tasks. AB - The current study examines similarity or disparity of a frontally mediated physiological response of mental effort among multiple executive functioning tasks between children and adults. Task performance and phasic heart rate variability (HRV) were recorded in children (6 to 10 years old) and adults in an examination of age differences in executive functioning skills during periods of increased demand. Executive load levels were varied by increasing the difficulty levels of three executive functioning tasks: inhibition (IN), working memory (WM), and planning/problem solving (PL). Behavioral performance decreased in all tasks with increased executive demand in both children and adults. Adults' phasic high frequency HRV was suppressed during the management of increased IN and WM load. Children's phasic HRV was suppressed during the management of moderate WM load. HRV was not suppressed during either children's or adults' increasing load during the PL task. High frequency phasic HRV may be most sensitive to executive function tasks that have a time-response pressure, and simply requiring performance on a self-paced task requiring frontal lobe activation may not be enough to generate HRV responsitivity to increasing demand. PMID- 25798114 TI - How do subvocal rehearsal and general attentional resources contribute to verbal short-term memory span? AB - Whether rehearsal has a causal role in verbal STM has been controversial in the literature. Recent theories of working memory emphasize a role of attentional resources, but leave unclear how they contribute to verbal STM. Two experiments (with 49 and 102 adult participants, respectively) followed up previous studies with children, aiming to clarify the contributions of attentional capacity and rehearsal to verbal STM. Word length and presentation modality were manipulated. Experiment 1 focused on order errors, Experiment 2 on predicting individual differences in span from attentional capacity and articulation rate. Structural equation modeling showed clearly a major role of attentional capacity as a predictor of verbal STM span; but was inconclusive on whether rehearsal efficiency is an additional cause or a consequence of verbal STM. The effects of word length and modality on STM were replicated; a significant interaction was also found, showing a larger modality effect for long than short words, which replicates a previous finding on children. Item errors occurred more often with long words and correlated negatively with articulation rate. This set of findings seems to point to a role of rehearsal in maintaining item information. The probability of order errors per position increased linearly with list length. A revised version of a neo-Piagetian model was fit to the data of Experiment 2. That model was based on two parameters: attentional capacity (independently measured) and a free parameter representing loss of partly-activated information. The model could partly account for the results, but underestimated STM performance of the participants with smaller attentional capacity. It is concluded that modeling of verbal STM should consider individual and developmental differences in attentional capacity, rehearsal rate, and (perhaps) order representation. PMID- 25798115 TI - Larger hippocampal dimensions in meditation practitioners: differential effects in women and men. AB - On average, the human hippocampus shows structural differences between meditators and non-meditators as well as between men and women. However, there is a lack of research exploring possible sex effects on hippocampal anatomy in the framework of meditation. Thus, we obtained high-resolution magnetic resonance imaging data from 30 long-term meditation practitioners (15 men/15 women) and 30 well-matched control subjects (15 men/15 women) to assess if hippocampus-specific effects manifest differently in male and female brains. Hippocampal dimensions were enlarged both in male and in female meditators when compared to sex- and age matched controls. However, meditation effects differed between men and women in magnitude, laterality, and location on the hippocampal surface. Such sex divergent findings may be due to genetic (innate) or acquired differences between male and female brains in the areas involved in meditation and/or suggest that male and female hippocampi are differently receptive to mindfulness practices. PMID- 25798116 TI - How space-number associations may be created in preliterate children: six distinct mechanisms. AB - The directionality of space-number association (SNA) is shaped by cultural experiences. It usually follows the culturally dominant reading direction. Smaller numbers are generally associated with the starting side for reading (left side in Western cultures), while larger numbers are associated with the right endpoint side. However, SNAs consistent with cultural reading directions are present before children can actually read and write. Therefore, these SNAs cannot only be shaped by the direction of children's own reading/writing behavior. We propose six distinct processes - one biological and five cultural/educational - underlying directional SNAs before formal reading acquisition: (i) Brain lateralization, (ii) Monitoring adult reading behavior, (iii) Pretend reading and writing, and rudimentary reading and writing skills, (iv) Dominant attentional directional preferences in a society, not directly related to reading direction, (v) Direct spatial-numerical learning, (vi) Other spatial-directional processes independent of reading direction. In this mini-review, we will differentiate between these processes, elaborate when in development they might emerge, discuss how they may create the SNAs observed in preliterate children and propose how they can be studied in the future. PMID- 25798117 TI - Explanations of a magic trick across the life span. AB - Studying how children and adults explain magic tricks can reveal developmental differences in cognition. We showed 167 children (aged 4-13 years) a video of a magician making a pen vanish and asked them to explain the trick. Although most tried to explain the secret, none of them correctly identified it. The younger children provided more supernatural interpretations and more often took the magician's actions at face value. Combined with a similar study of adults (N = 1008), we found that both young children and older adults were particularly overconfident in their explanations of the trick. Our methodology demonstrates the feasibility of using magic to study cognitive development across the life span. PMID- 25798118 TI - Mathematics and reading difficulty subtypes: minor phonological influences on mathematics for 5-7-years-old. AB - Linguistic influences in mathematics have previously been explored through subtyping methodology and by taking advantage of the componential nature of mathematics and variations in language requirements that exist across tasks. The present longitudinal investigation aimed to examine the language requirements of mathematical tasks in young children aged 5-7 years. Initially, 256 children were screened for mathematics and reading difficulties (RDs) using standardized measures. Those scoring at or below the 35th percentile on either dimension were classified as having difficulty. From this screening, 115 children were allocated to each of the mathematical difficulty (MD; n = 26), MDRD (n = 32), RD (n = 22) and typically achieving (n = 35) subtypes. These children were tested at four time points, separated by 6 monthly intervals, on a battery of seven mathematical tasks. Growth curve analysis indicated that, in contrast to previous research on older children, young children with MD and MDRD had very similar patterns of development on all mathematical tasks. Overall, the subtype comparisons suggested that language played only a minor mediating role in most tasks, and this was secondary in importance to non-verbal skills. Correlational evidence suggested that children from the different subtypes could have been using different mixes of verbal and non-verbal strategies to solve the mathematical problems. PMID- 25798119 TI - Neurocognitive development of memory for landmarks. AB - The capacity to detect landmarks in the environment and to associate each landmark with its spatial context is a fundamental operation for navigation, especially when the context is relevant for successful navigation. Recent evidence suggests robust age-related improvements in contextual memory. The current study investigated the effect of spatial context on landmark recognition memory in children and adolescents. Participants, ages 8-18, watched a video depicting a route through a virtual environment. The location at which landmarks occurred was manipulated to test the hypothesis that memory processes vary as a function of context. Functional magnetic resonance imaging data was acquired while participants performed an old-new recognition memory test of the landmarks. Old compared to new landmarks recruited a network of regions including the hippocampus and the inferior/middle frontal gyrus in all participants. Developmental differences were observed in the functional organization of the parahippocampal gyrus and the anterior cingulate cortex, such that memory representations strengthened linearly with age only when the associated spatial context was relevant for navigation. These results support the view that medial temporal lobe regions become increasingly specialized with development; these changes may be responsible for the development of successful navigation strategies. PMID- 25798120 TI - Learning of a simple grapho-motor task by young children and adults: similar acquisition but age-dependent retention. AB - Many new skills are acquired during early childhood. Typical laboratory skill learning tasks are not applicable for developmental studies that involve children younger than 8 years of age. It is not clear whether young children and adults share a basic underlying skill learning mechanism. In the present study, the learning and retention of a simple grapho-motor pattern were studied in three age groups: 5-6, 7-8, and 19-29 years. Each block of the task consists of identical patterns arranged in a spaced writing array. Progression across the block involves on-page movements while producing the pattern, and off-page movements between patterns. The participants practiced the production of the pattern using a digitizing tablet and were tested at 24 h and 2 weeks post-practice. All age groups produced the task blocks more quickly with practice, and the learning rate was inversely related to the initial production time. All groups exhibited additional gains 24 h post-practice that were well-retained 2 weeks later. The accuracy of the participants was maintained throughout the 2-weeks period. These findings suggest that young children and young adults use a similar mechanism when learning the task. Nevertheless, the 6-years-old spent more time off-page during retention testing than when tested at 24 h post-practice, thus supporting the notion that an age advantage may exists in the long-term retention of skills due to planning-dependent aspects. PMID- 25798122 TI - When "good" is not always right: effect of the consequences of motor action on valence-space associations. AB - Since the work of Casasanto (2009), it is now well established that valence and laterality are associated. Participants tend to prefer objects presented on their dominant side over items presented on their non-dominant side, and to place good items on their dominant side and bad items on the other side. Several studies highlight that those associations of valence and laterality are accounted for by the greater motor fluency of the dominant hand and various studies noted that these associations could be reversed depending on the way people interact with their environment. Consistently with the Theory of Event Coding, the aim of this work is to show that the consequences of motor actions could also reverse the associations between valence and laterality. Thus, if participants had to place two animals (one good, one bad) on two supports, one stable (no risk of falling), one unstable (risk of falling), we hypothesized that the good item would be placed on the stable support, regardless of the side where it would be put (i.e., on the dominant or non-dominant side). We expected the opposite for the bad item. The results of two experiments are consistent with this prediction and support the claim that the consequences of motor action bias the hedonic connotation of our dominant side. PMID- 25798121 TI - Forelimb preferences in human beings and other species: multiple models for testing hypotheses on lateralization. AB - Functional preferences in the use of right/left forelimbs are not exclusively present in humans but have been widely documented in a variety of vertebrate and invertebrate species. A matter of debate is whether non-human species exhibit a degree and consistency of functional forelimb asymmetries comparable to human handedness. The comparison is made difficult by the variability in hand use in humans and the few comparable studies conducted on other species. In spite of this, interesting continuities appear in functions such as feeding, object manipulation and communicative gestures. Studies on invertebrates show how widespread forelimb preferences are among animals, and the importance of experience for the development of forelimb asymmetries. Vertebrate species have been extensively investigated to clarify the origins of forelimb functional asymmetries: comparative evidence shows that selective pressures for different functions have likely driven the evolution of human handedness. Evidence of a complex genetic architecture of human handedness is in line with the idea of multiple evolutionary origins of this trait. PMID- 25798123 TI - Transcranial direct current stimulation as a treatment for auditory hallucinations. AB - Auditory hallucinations (AH) are a symptom of several psychiatric disorders, such as schizophrenia. In a significant minority of patients, AH are resistant to antipsychotic medication. Alternative treatment options for this medication resistant group are scarce and most of them focus on coping with the hallucinations. Finding an alternative treatment that can diminish AH is of great importance. Transcranial direct current stimulation (tDCS) is a safe and non invasive technique that is able to directly influence cortical excitability through the application of very low electric currents. A 1-2 mA direct current is applied between two surface electrodes, one serving as the anode and the other as the cathode. Cortical excitability is increased in the vicinity of the anode and reduced near the cathode. The technique, which has only a few transient side effects and is cheap and portable, is increasingly explored as a treatment for neurological and psychiatric symptoms. It has shown efficacy on symptoms of depression, bipolar disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, epilepsy, and stroke. However, the application of tDCS as a treatment for AH is relatively new. This article provides an overview of the current knowledge in this field and guidelines for future research. PMID- 25798124 TI - Is the call to abandon p-values the red herring of the replicability crisis? PMID- 25798125 TI - Data science of stroke imaging and enlightenment of the penumbra. AB - Imaging protocols of acute ischemic stroke continue to hold significant uncertainties regarding patient selection for reperfusion therapy with thrombolysis and mechanical thrombectomy. Given that patient inclusion criteria can easily introduce biases that may be unaccounted for, the reproducibility and reliability of the patient screening method is of utmost importance in clinical trial design. The optimal imaging screening protocol for selection in targeted populations remains uncertain. Acute neuroimaging provides a snapshot in time of the brain parenchyma and vasculature. By identifying the at-risk but still viable penumbral tissue, imaging can help estimate the potential benefit of a reperfusion therapy in these patients. This paper provides a perspective about the assessment of the penumbral tissue in the context of acute stroke and reviews several neuroimaging models that have recently been developed to assess the penumbra in a more reliable fashion. The complexity and variability of imaging features and techniques used in stroke will ultimately require advanced data driven software tools to provide quantitative measures of risk/benefit of recanalization therapy and help aid in making the most favorable clinical decisions. PMID- 25798126 TI - Short- and long-term neurological and psychiatric sequelae of developmental exposure to antiepileptic and anesthetic drugs. PMID- 25798127 TI - Impact of the circadian clock on the aging process. AB - The increase of life expectancy and the decline of biological functions with advancing age are impending obstacles for our society. In general, age-related changes can be separated into two processes. Primary aging is based on programs governing gradual changes which are generally not harmful. On the other hand, secondary aging or senescence is more aleatory in nature and it is at this stage that the progressive impairment of metabolic, physiological, and neurological functions increases the risk of death. Exploiting genetic animal models, we obtain more and more information on the underlying regulatory networks. The aim of this review is to identify potential links between the output of the circadian oscillator and secondary aging. The reasons to suspect such links rely on the fact that the mouse models without functional circadian clocks sometimes exhibit reduced life expectancy. This may be due to their inability to properly control and synchronize energy expenditure, affecting, for example, the integrity of neurons in the brain. Hence, it is tempting to speculate that re-synchronization of metabolic and physiological functions by the circadian clock may slow down the aging process. PMID- 25798128 TI - Mechanism of Action of 2-Aminobenzamide HDAC Inhibitors in Reversing Gene Silencing in Friedreich's Ataxia. AB - The genetic defect in Friedreich's ataxia (FRDA) is the hyperexpansion of a GAA*TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. However, only compounds targeting the class I HDACs 1 and 3 are active in increasing FXN mRNA in these cells. Structural analogs of the active HDAC inhibitors that selectively target either HDAC1 or HDAC3 do not show similar increases in FXN mRNA levels. To understand the mechanism of action of these compounds, we probed the kinetic properties of the active and inactive inhibitors, and found that only compounds that target HDACs 1 and 3 exhibited a slow-on/slow-off mechanism of action for the HDAC enzymes. HDAC1- and HDAC3 selective compounds did not show this activity. Using siRNA methods in the FRDA neuronal cells, we show increases in FXN mRNA upon silencing of either HDACs 1 or 3, suggesting the possibility that inhibition of each of these class I HDACs is necessary for activation of FXN mRNA synthesis, as there appears to be redundancy in the silencing mechanism caused by the GAA*TTC repeats. Moreover, inhibitors must have a long residence time on their target enzymes for this activity. By interrogating microarray data from neuronal cells treated with inhibitors of different specificity, we selected two genes encoding histone macroH2A (H2AFY2) and Polycomb group ring finger 2 (PCGF2) that were specifically down-regulated by the inhibitors targeting HDACs1 and 3 versus the more selective inhibitors for further investigation. Both genes are involved in transcriptional repression and we speculate their involvement in FXN gene silencing. Our results shed light on the mechanism whereby HDAC inhibitors increase FXN mRNA levels in FRDA neuronal cells. PMID- 25798129 TI - Adrenocortical zonation, renewal, and remodeling. AB - The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homolog 1, fibroblast growth factor, and WNT/beta-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation. PMID- 25798130 TI - Novel Aspects Concerning the Functional Cross-Talk between the Insulin/IGF-I System and Estrogen Signaling in Cancer Cells. AB - The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated levels of circulating insulin have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes. Numerous studies have documented that estrogens cooperate with the insulin/IGF system in multiple pathophysiological conditions. The biological responses to estrogens are mainly mediated by the estrogen receptors (ER)alpha and ERbeta, which act as transcription factors; however, several studies have recently demonstrated that a member of the G protein-coupled receptors, named GPR30/G-protein estrogen receptor (GPER), is also involved in the estrogen signaling in normal and malignant cells as well as in cancer-associated fibroblasts (CAFs). In this regard, novel mechanisms linking the action of estrogens through GPER with the insulin/IGF system have been recently demonstrated. This review recapitulates the relevant aspects of this functional cross-talk between the insulin/IGF and the estrogenic GPER transduction pathways, which occurs in various cell types and may account for cancer progression. PMID- 25798131 TI - An overview of the characteristics of the novel avian influenza A H7N9 virus in humans. AB - The novel avian influenza A H7N9 virus which caused the first human infection in Shanghai, China; was reported on the 31st of March 2013 before spreading rapidly to other Chinese provinces and municipal cities. This is the first time the low pathogenic avian influenza A virus has caused human infections and deaths; with cases of severe respiratory disease with pneumonia being reported. There were 440 confirmed cases with 122 fatalities by 16 May 2014; with a fatality risk of ~28%. The median age of patients was 61 years with a male-to-female ratio of 2.4:1. The main source of infection was identified as exposure to poultry and there is so far no definitive evidence of sustained person-to-person transmission. The neuraminidase inhibitors, namely oseltamivir, zanamivir, and peramivir; have shown good efficacy in the management of the novel H7N9 virus. Treatment is recommended for all hospitalized patients, and for confirmed and probable outpatient cases; and should ideally be initiated within 48 h of the onset of illness for the best outcome. Phylogenetic analysis found that the novel H7N9 virus is avian in origin and evolved from multiple reassortments of at least four origins. Indeed the novel H7N9 virus acquired human adaptation via mutations in its eight RNA gene segments. Enhanced surveillance and effective global control are essential to prevent pandemic outbreaks of the novel H7N9 virus. PMID- 25798133 TI - Recent trends in non-invasive in situ techniques to monitor bacterial colonies in solid (model) food. AB - Planktonic cells typically found in liquid systems, are routinely used for building predictive models or assessing the efficacy of food preserving technologies. However, freely suspended cells often show different susceptibility to environmental hurdles than colony cells in solid matrices. Limited oxygen, water and nutrient availability, metabolite accumulation and physical constraints due to cell immobilization in the matrix, are main factors affecting cell growth. Moreover, intra- and inter-colony interactions, as a consequence of the initial microbial load in solid systems, may affect microbial physiology. Predictive food microbiology approaches are moving toward a more realistic resemblance to food products, performing studies in structured solid systems instead of liquids. Since structured systems promote microbial cells to become immobilized and grow as colonies, it is essential to study the colony behavior, not only for food safety assurance systems, but also for understanding cell physiology and optimizing food production processes in solid matrices. Traditionally, microbial dynamics in solid systems have been assessed with a macroscopic approach by applying invasive analytical techniques; for instance, viable plate counting, which yield information about overall population. In the last years, this approach is being substituted by more mechanistically inspired ones at mesoscopic (colony) and microscopic (cell) levels. Therefore, non-invasive and in situ monitoring is mandatory for a deeper insight into bacterial colony dynamics. Several methodologies that enable high-throughput data collection have been developed, such as microscopy-based techniques coupled with image analysis and OD based measurements in microplate readers. This research paper provides an overview of non-invasive in situ techniques to monitor bacterial colonies in solid (model) food and emphasizes their advantages and inconveniences in terms of accuracy, performance and output information. PMID- 25798132 TI - The pathogenesis, detection, and prevention of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus, a Gram-negative motile bacterium that inhabits marine and estuarine environments throughout the world, is a major food-borne pathogen that causes life-threatening diseases in humans after the consumption of raw or undercooked seafood. The global occurrence of V. parahaemolyticus accentuates the importance of investigating its virulence factors and their effects on the human host. This review describes the virulence factors of V. parahaemolyticus reported to date, including hemolysin, urease, two type III secretion systems and two type VI secretion systems, which both cause both cytotoxicity in cultured cells and enterotoxicity in animal models. We describe various types of detection methods, based on virulence factors, that are used for quantitative detection of V. parahaemolyticus in seafood. We also discuss some useful preventive measures and therapeutic strategies for the diseases mediated by V. parahaemolyticus, which can reduce, to some extent, the damage to humans and aquatic animals attributable to V. parahaemolyticus. This review extends our understanding of the pathogenic mechanisms of V. parahaemolyticus mediated by virulence factors and the diseases it causes in its human host. It should provide new insights for the diagnosis, treatment, and prevention of V. parahaemolyticus infection. PMID- 25798134 TI - Mining proteomic data to expose protein modifications in Methanosarcina mazei strain Go1. AB - Proteomic tools identify constituents of complex mixtures, often delivering long lists of identified proteins. The high-throughput methods excel at matching tandem mass spectrometry data to spectra predicted from sequence databases. Unassigned mass spectra are ignored, but could, in principle, provide valuable information on unanticipated modifications and improve protein annotations while consuming limited quantities of material. Strategies to "mine" information from these discards are presented, along with discussion of features that, when present, provide strong support for modifications. In this study we mined LC MS/MS datasets of proteolytically-digested concanavalin A pull down fractions from Methanosarcina mazei Go1 cell lysates. Analyses identified 154 proteins. Many of the observed proteins displayed post-translationally modified forms, including O-formylated and methyl-esterified segments that appear biologically relevant (i.e., not artifacts of sample handling). Interesting cleavages and modifications (e.g., S-cyanylation and trimethylation) were observed near catalytic sites of methanogenesis enzymes. Of 31 Methanosarcina protein N-termini recovered by concanavalin A binding or from a previous study, only M. mazei S layer protein MM1976 and its M. acetivorans C2A orthologue, MA0829, underwent signal peptide excision. Experimental results contrast with predictions from algorithms SignalP 3.0 and Exprot, which were found to over-predict the presence of signal peptides. Proteins MM0002, MM0716, MM1364, and MM1976 were found to be glycosylated, and employing chromatography tailored specifically for glycopeptides will likely reveal more. This study supplements limited, existing experimental datasets of mature archaeal N-termini, including presence or absence of signal peptides, translation initiation sites, and other processing. Methanosarcina surface and membrane proteins are richly modified. PMID- 25798136 TI - Measurement of pH micro-heterogeneity in natural cheese matrices by fluorescence lifetime imaging. AB - Cheese, a product of microbial fermentation may be defined as a protein matrix entrapping fat, moisture, minerals and solutes as well as dispersed bacterial colonies. The growth and physiology of bacterial cells in these colonies may be influenced by the microenvironment around the colony, or alternatively the cells within the colony may modify the microenvironment (e.g., pH, redox potential) due to their metabolic activity. While cheese pH may be measured at macro level there remains a significant knowledge gap relating to the degree of micro-heterogeneity of pH within the cheese matrix and its relationship with microbial, enzymatic and physiochemical parameters and ultimately with cheese quality, consistency and ripening patterns. The pH of cheese samples was monitored both at macroscopic scale and at microscopic scale, using a non-destructive microscopic technique employing C-SNARF-4 and Oregon Green 488 fluorescent probes. The objectives of this work were to evaluate the suitability of these dyes for microscale pH measurements in natural cheese matrices and to enhance the sensitivity and extend the useful pH range of these probes using fluorescence lifetime imaging (FLIM). In particular, fluorescence lifetime of Oregon Green 488 proved to be sensitive probe to map pH micro heterogeneity within cheese matrices. Good agreement was observed between macroscopic scale pH measurement by FLIM and by traditional pH methods, but in addition considerable localized microheterogeneity in pH was evident within the curd matrix with pH range between 4.0 and 5.5. This technique provides significant potential to further investigate the relationship between cheese matrix physico-chemistry and bacterial metabolism during cheese manufacture and ripening. PMID- 25798135 TI - Diversity of thermophiles in a Malaysian hot spring determined using 16S rRNA and shotgun metagenome sequencing. AB - The Sungai Klah (SK) hot spring is the second hottest geothermal spring in Malaysia. This hot spring is a shallow, 150-m-long, fast-flowing stream, with temperatures varying from 50 to 110 degrees C and a pH range of 7.0-9.0. Hidden within a wooded area, the SK hot spring is continually fed by plant litter, resulting in a relatively high degree of total organic content (TOC). In this study, a sample taken from the middle of the stream was analyzed at the 16S rRNA V3-V4 region by amplicon metagenome sequencing. Over 35 phyla were detected by analyzing the 16S rRNA data. Firmicutes and Proteobacteria represented approximately 57% of the microbiome. Approximately 70% of the detected thermophiles were strict anaerobes; however, Hydrogenobacter spp., obligate chemolithotrophic thermophiles, represented one of the major taxa. Several thermophilic photosynthetic microorganisms and acidothermophiles were also detected. Most of the phyla identified by 16S rRNA were also found using the shotgun metagenome approaches. The carbon, sulfur, and nitrogen metabolism within the SK hot spring community were evaluated by shotgun metagenome sequencing, and the data revealed diversity in terms of metabolic activity and dynamics. This hot spring has a rich diversified phylogenetic community partly due to its natural environment (plant litter, high TOC, and a shallow stream) and geochemical parameters (broad temperature and pH range). It is speculated that symbiotic relationships occur between the members of the community. PMID- 25798137 TI - Exploring the risk factors for sudden infant deaths and their role in inflammatory responses to infection. AB - The risk factors for sudden infant death syndrome (SIDS) parallel those associated with susceptibility to or severity of infectious diseases. There is no evidence that a single infectious agent is associated with SIDS; the common thread appears to be induction of inflammatory responses to infections. In this review, interactions between genetic and environmental risk factors for SIDS are assessed in relation to the hypothesis that many infant deaths result from dysregulation of inflammatory responses to "minor" infections. Risk factors are assessed in relation to three important stages of infection: (1) bacterial colonization (frequency or density); (2) induction of temperature-dependent toxins; (3) induction or control of inflammatory responses. In this article, we review the interactions among risk factors for SIDS for their effects on induction or control of inflammatory responses. The risk factors studied are genetic factors (sex, cytokine gene polymorphisms among ethnic groups at high or low risk of SIDS); developmental stage (changes in cortisol and testosterone levels associated with 2- to 4-month age range); environmental factors (virus infection, exposure to cigarette smoke). These interactions help to explain differences in the incidences of SIDS observed between ethnic groups prior to public health campaigns to reduce these infant deaths. PMID- 25798139 TI - Reproduction and the pheromonal regulation of sex type in fern gametophytes. AB - The fern life cycle includes a haploid gametophyte that is independent of the sporophyte and functions to produce the gametes. In homosporous ferns, the sex of the gametophyte is not fixed but can vary depending on its social environment. In many species, the sexual phenotype of the gametophyte is determined by the pheromone antheridiogen. Antheridiogen induces male development and is secreted by hermaphrodites once they become insensitive to its male-inducing effect. Recent genetic and biochemical studies of the antheridiogen response and sex determination pathway in ferns, which are highlighted here, reveal many similarities and interesting differences to GA signaling and biosynthetic pathways in angiosperms. PMID- 25798140 TI - Genome-wide association study for crown rust (Puccinia coronata f. sp. avenae) and powdery mildew (Blumeria graminis f. sp. avenae) resistance in an oat (Avena sativa) collection of commercial varieties and landraces. AB - Diseases caused by crown rust (Puccinia coronata f. sp. avenae) and powdery mildew (Blumeria graminis f. sp. avenae) are among the most important constraints for the oat crop. Breeding for resistance is one of the most effective, economical, and environmentally friendly means to control these diseases. The purpose of this work was to identify elite alleles for rust and powdery mildew resistance in oat by association mapping to aid selection of resistant plants. To this aim, 177 oat accessions including white and red oat cultivars and landraces were evaluated for disease resistance and further genotyped with 31 simple sequence repeat and 15,000 Diversity Arrays Technology (DArT) markers to reveal association with disease resistance traits. After data curation, 1712 polymorphic markers were considered for association analysis. Principal component analysis and a Bayesian clustering approach were applied to infer population structure. Five different general and mixed linear models accounting for population structure and/or kinship corrections and two different statistical tests were carried out to reduce false positive. Five markers, two of them highly significant in all models tested were associated with rust resistance. No strong association between any marker and powdery mildew resistance at the seedling stage was identified. However, one DArT sequence, oPt-5014, was strongly associated with powdery mildew resistance in adult plants. Overall, the markers showing the strongest association in this study provide ideal candidates for further studies and future inclusion in strategies of marker-assisted selection. PMID- 25798138 TI - Platelets in inflammation and atherogenesis. AB - Platelets contribute to processes beyond thrombus formation and may play a so far underestimated role as an immune cell in various circumstances. This review outlines immune functions of platelets in host defense, but also how they may contribute to mechanisms of infectious diseases. A particular emphasis is placed on the interaction of platelets with other immune cells. Furthermore, this article outlines the features of atherosclerosis as an inflammatory vascular disease highlighting the role of platelet crosstalk with cellular and soluble factors involved in atheroprogression. Understanding, how platelets influence these processes of vascular remodeling will shed light on their role for tissue homeostasis beyond intravascular thrombosis. Finally, translational implications of platelet-mediated inflammation in atherosclerosis are discussed. PMID- 25798141 TI - Modeling of bud break of Scots pine in northern Finland in 1908-2014. AB - Bud break and height-growth of Scots pine (Pinus sylvestris L.) in the northern boreal zone in Lapland, Finland, was followed through the entire growing seasons in the periods 2001-2003 and 2008-2010 in sapling stands in two different locations in northern Finland set some 250 km apart along a latitudinal transect. Field measurements continued at the southern site also in 2011-2013. Air temperature was recorded hourly at the sites. A simple optimization algorithm (GA) was used to adjust parameters of the models predicting the timing of bud break of Scots pine in order to minimize the difference between observed and predicted dates. The models giving the best performance and century-long daily temperatures were used to reconstruct bud-break time series. The temperature observations were recorded for the period 1908-2014 in Sodankyla, which is located in-between the sapling stands in the north-south direction and for the period 1877-2014 in Karasjok, which is in Norway about 145 km north-west from the northernmost stand of this study. On average buds began to extend in the beginning of May in the southernmost stand and in mid-May in the northernmost stands, and the variation between years was in the range of 3 weeks. A simple day length-triggered (fixed date) model predicted most accurately the date of bud break; root mean square error (RMSE) was 2 and 4 days in the northern and southern site, respectively. The reconstructed bud-break series indicated that based on temperature observations from Sodankyla, growth onset of Scots pine has clearly advanced since the 1960s, though it currently matches that of the early 1920s and early 1950s. The temperature record from Karasjok indicated a similar variation, though there was a weak linear trend advancing bud break by about 3-4 days over a 100-year period. PMID- 25798142 TI - The "sensor domains" of plant NLR proteins: more than decoys? PMID- 25798143 TI - Retraction: Mechanosensitive channel candidate MCA2 is involved in touch-induced root responses in Arabidopsis. AB - [This retracts the article on p. 421 in vol. 5, PMID: 25191336.]. PMID- 25798144 TI - A case study on strains of Busa cattle structured into a metapopulation to show the potential for use of single-nucleotide polymorphism genotyping in the management of small, cross-border populations of livestock breeds and varieties. PMID- 25798145 TI - Proteostasis collapse, inter-tissue communication, and the regulation of aging at the organismal level. PMID- 25798146 TI - Corrigendum: Patterns of diversification amongst tropical regions compared: a case study in Sapotaceae. AB - [This corrects the article on p. 362 in vol. 5, PMID: 25520736.]. PMID- 25798147 TI - Computational epigenomics: challenges and opportunities. PMID- 25798148 TI - Mycobacterium tuberculosis: 2014 Clinical trials in review. PMID- 25798149 TI - Hepatitis C virus seroconversion among HIV-positive men who have sex with men with no history of injection drug use: Results from a clinical HIV cohort. AB - BACKGROUND: Internationally, there is a growing recognition that hepatitis C virus (HCV) may be sexually transmitted among HIV-positive men who have sex with men (MSM). OBJECTIVE: To report the first Canadian estimate of HCV seroincidence in 2000 to 2010 and its risk factors among HIV-positive MSM with no known history of injection drug use. METHODS: Data from the Ontario HIV Treatment Network Cohort Study, an ongoing cohort of individuals in HIV care in Ontario, were analyzed. Data were obtained from medical charts, interviews and record linkage with the provincial public health laboratories. The analysis was restricted to 1534 MSM who did not report injection drug use and had undergone >=2 HCV antibody tests, of which the first was negative (median 6.1 person-years [PY] of follow up; sum 9987 PY). RESULTS: In 2000 to 2010, 51 HCV seroconversions were observed, an overall incidence of 5.1 per 1000 PY (95% CI 3.9 to 6.7). Annual incidence varied from 1.6 to 8.9 per 1000 PY, with no statistical evidence of a temporal trend. Risk for seroconversion was elevated among men who had ever had syphilis (adjusted HR 2.5 [95% CI 1.1 to 5.5) and men who had acute syphilis infection in the previous 18 months (adjusted HR 2.8 [95% CI 1.0 to 7.9]). Risk was lower for men who had initiated antiretroviral treatment (adjusted HR 0.49 [95% CI 0.25 to 0.95]). There were no statistically significant effects of age, ethnicity, region, CD4 cell count or HIV viral load. CONCLUSIONS: These findings suggest that periodic HCV rescreening may be appropriate in Ontario among HIV-positive MSM. Future research should seek evidence whether syphilis is simply a marker for high-risk sexual behaviour or networks, or whether it potentiates sexual HCV transmission among individuals with HIV. PMID- 25798150 TI - Cost effectiveness of 'on demand' HIV pre-exposure prophylaxis for non-injection drug-using men who have sex with men in Canada. AB - BACKGROUND: Recent trials report the efficacy of continuous tenofovir-based pre exposure prophylaxis (PrEP) for prevention of HIV infection. The cost effectiveness of 'on demand' PrEP for non-injection drug-using men who have sex with men at high risk of HIV acquisition has not been evaluated. OBJECTIVE: To conduct an economic evaluation of the societal costs of HIV in Canada and evaluate the potential benefits of this PrEP strategy. METHODS: Direct HIV costs comprised outpatient, inpatient and emergency department costs, psychosocial costs and antiretroviral costs. Resource consumption estimates were derived from the Centre Hospitalier de l'Universite de Montreal HIV cohort. Estimates of indirect costs included employment rate and work absenteeism. Costs for 'on demand' PrEP were modelled after an ongoing clinical trial. Cost-effectiveness analysis compared costs of 'on demand' PrEP to prevent one infection with lifetime costs of one HIV infection. Benefits were presented in terms of life years and quality-adjusted life-years. RESULTS: The average annual direct cost of one HIV infection was $16,109 in the least expensive antiretroviral regimen scenario and $24,056 in the most expensive scenario. The total indirect cost was $11,550 per year. Total costs for the first year of HIV infection ranged from $27,410 to $35,358. Undiscounted lifetime costs ranged from $1,439,984 ($662,295 discounted at 3% and $448,901 at 5%) to $1,482,502 ($690,075 at 3% and $485,806 at 5%). The annual cost of PrEP was $12,001 per participant, and $621,390 per infection prevented. The PrEP strategy was cost-saving in all scenarios for undiscounted and 3% discounting rates. At 5% discounting rates, the strategy is largely cost-effective: according to least and most expensive scenarios, incremental cost-effectiveness ratios ranged from $60,311 to $47,407 per quality adjusted life-year. CONCLUSION: This 'on demand' PrEP strategy ranges from cost saving to largely cost-effective. The authors believe it represents an important public health strategy for the prevention of HIV transmission. PMID- 25798151 TI - Low awareness but positive attitudes toward fecal transplantation in Ontario physicians. AB - BACKGROUND: Despite mounting evidence supporting fecal transplantation (FT) as a treatment for recurrent Clostridium difficile infection (CDI), adoption into clinical practice has been slow. OBJECTIVE: To determine the health literacy and attitudes of academic physicians in Toronto and infectious disease physicians in Ontario toward FT as a treatment for recurrent CDI, and to determine whether these are significant barriers to adoption. METHODS: Surveys were distributed to 253 general internists, infectious diseases specialists, gastroenterologists and family physicians. RESULTS: The response rate was 15%. More than 60% of physicians described themselves as being 'not at all' or 'somewhat' familiar with FT. Of the 76% of physicians who had never referred a patient for FT, the most common reason (50%) was lack of awareness of where to access the treatment. The 'ick factor' accounted for only 13% of reasons for not referring. No respondent believed that the procedure was too risky to consider. CONCLUSION: Despite general poor health literacy on FT, most physicians sampled share similar positive attitudes toward the treatment. PMID- 25798152 TI - Value of an aggregate index in describing the impact of trends in antimicrobial resistance for Escherichia coli. AB - BACKGROUND: Drug resistance indexes (DRIs) quantify the cumulative impact of antimicrobial resistance on the likelihood that a given pathogen will be susceptible to antimicrobial therapy. OBJECTIVE: To derive a DRI for community urinary tract infections caused by Escherichia coli in British Columbia for the years 2007 to 2010, and to examine trends over time and across patient characteristics. METHODS: Indication-specific utilization data were obtained from BC PharmaNet for outpatient antimicrobial prescriptions linked to diagnostic information from physician payment files. Resistance data for E coli urinary isolates were obtained from BC Biomedical Laboratories (now part of LifeLabs Medical Laboratory Services). DRIs were derived by multiplying the rate of resistance to a specific antimicrobial by the proportional rate of utilization for that drug class and aggregating across drug classes. Higher index values indicate more resistance. RESULTS: Adaptive-use DRIs remained stable over time at approximately 18% (95% CI 17% to 18%) among adults >=15 years of age and approximately 28% (95% CI 26% to 31%) among children <15 years of age. Similar results were observed when proportional drug use was restricted to the baseline year (ie, a static-use model). Trends according to age group suggest a U-shaped distribution, with the highest DRIs occurring among children <10 years of age and adults >=65 years of age. Males had consistently higher DRIs than females for all age groups. CONCLUSIONS: The stable trend in adaptive-use DRIs over time suggests that clinicians are adapting their prescribing practices for urinary tract infections to local resistance patterns. Results according to age group reveal a higher probability of resistance to initial therapy among young children and elderly individuals. PMID- 25798153 TI - An elderly long-term care resident with crusted scabies. AB - Crusted scabies is a highly contagious form of scabies. Altered immune response, nutritional deficiencies and modified host response are all risk factors for crusted scabies. The authors report a case involving a patient found to have a chronic maculopapular, erythematous rash with large hyperkeratotic, white and grey plaques on the soles of both feet. An ultimate diagnosis of crusted scabies was reached after a delay in diagnosis suspected to be caused by the similarity in appearance to more common skin conditions such as psoriasis. After topical permethrin was unsuccessful, intermittent dosing of oral ivermectin resulted in a rapid reduction in cutaneous plaques. PMID- 25798154 TI - Subacute bacterial endocarditis caused by Cardiobacterium hominis: A case report. AB - Cardiobacterium hominis, a member of the HACEK group of organisms, is an uncommon but important cause of subacute bacterial endocarditis. First-line therapy is a third-generation cephalosporin due to rare beta-lactamase production. The authors report a case involving endovascular infection due to C hominis that initially tested resistant to third-generation cephalosporins using an antibiotic gradient strip susceptibility method (nitrocephin negative), but later proved to be susceptible using broth microdilution reference methods (a 'major' error). There are limited studies to guide susceptibility testing and interpretive breakpoints for C hominis in the medical literature, and the present case illustrates some of the issues that may arise when performing susceptibility testing for fastidious organisms in the clinical microbiology laboratory. PMID- 25798155 TI - Fournier's gangrene caused by Listeria monocytogenes as the primary organism. AB - A 70-year-old man with a history of tongue cancer presented with Fournier's gangrene caused by Listeria monocytogenes serotype 4b. Surgical debridement revealed undiagnosed rectal adenocarcinoma. The patient did not have an apparent dietary or travel history but reported daily consumption of sashimi (raw fish). Old age and immunodeficiency due to rectal adenocarcinoma may have supported the direct invasion of L monocytogenes from the tumour. The present article describes the first reported case of Fournier's gangrene caused by L monocytogenes. The authors suggest that raw ready-to-eat seafood consumption be recognized as a risk factor for listeriosis, especially in cases of skin and soft tissue infection. PMID- 25798156 TI - Trichosporon asahii infection after total knee arthroplasty: A case report and review of the literature. AB - Reports of fungal infection after total knee arthroplasty are extremely rare. In most reports, the infecting organism is a Candida species. The present report describes a case involving a 73-year-old immunocompetent woman who underwent total knee arthroplasty and presented one month later with signs of prosthetic infection. She underwent joint debridement and the fluid was sent for culture and sensitivity testing. The culture showed growth of Trichosporon asahii. The patient was administered intravenous and intra-articular injections of amphotericin B, followed by antifungal treatment with voriconazole for one year. At 26 months of follow-up, there was no evidence of infection and the patient was ambulating with a walker. To the authors' knowledge, the present case is the first report of T asahii infection following knee replacement. Early detection, prompt institution of the appropriate antibiotics and regular follow-up are recommended. PMID- 25798157 TI - Pasteurella species peritoneal dialysis-associated peritonitis: Household pets as a risk factor. AB - BACKGROUND: Pasteurella species are Gram-negative coccobacilli that are a part of the normal oropharyngeal flora of numerous domestic animals. They have been recognized as a rare but significant cause of peritonitis in patients undergoing peritoneal dialysis (PD). A consensus about management strategies for PD associated peritonitis caused by Pasteurella species currently does not exist. METHODS: The microbiological database serving the Manitoba Renal Program was searched from 1997 to 2013 for cases of Pasteurella species PD-associated peritonitis, and charts were reviewed. PubMed was searched for case reports and data were abstracted. RESULTS: Seven new local cases and 30 previously reported cases were analyzed. This infection is clinically similar to other forms of PD peritonitis, with household pet exposure appearing to be the strongest risk factor. Cats are the most commonly implicated pet. Direct contact between the pet and the equipment was commonly reported (25 of 37 patients) but was not necessary for infection to develop. The mean duration of treatment was 15 days. Complication rates were low, with only 11% of patients requiring PD catheter removal. There was no mortality reported. CONCLUSION: Pasteurella species are a rare cause of PD-associated peritonitis that can be successfully treated with a two-week course of intraperitoneal antibiotics with a high likelihood of catheter salvage. PMID- 25798158 TI - Guidance for practitioners on the use of antiviral drugs to control influenza outbreaks in long-term care facilities in Canada, 2014-2015 season. AB - The AMMI Canada Guidelines document 'The use of antiviral drugs for influenza: A foundation document for practitioners', published in the Autumn 2013 issue of the Journal, outlines the recommendations for the use of antiviral drugs to treat influenza. This article, which represents the first of two updates to these guidelines published in the current issue of the Journal, aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in long-term care facilities for this season are provided. PMID- 25798159 TI - Guidance on the use of antiviral drugs for influenza in acute care facilities in Canada, 2014-2015. AB - This article represents the second update to the AMMI Canada Guidelines document on the use of antiviral drugs for influenza. The article aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in the acute care setting for this season are provided. PMID- 25798160 TI - Canadian Public Health Laboratory Network laboratory guidelines for the use of direct tests to detect syphilis in Canada. AB - Treponema pallidum subsp. pallidum and/or its nucleic acid can be detected by various methods such as microscopy, rabbit infectivity test or polymerase chain reaction (PCR) tests. The rabbit infectivity test for T. pallidum, although very sensitive, has been discontinued from most laboratories due to ethical issues related to the need for animal inoculation with live T. pallidum, the technically demanding procedure and long turnaround time for results, thus making it impractical for routine diagnostic use. Dark-field and phase-contrast microscopy are still useful at clinic- or hospital-based laboratories for near-bedside detection of T. pallidum in genital, skin or mucous lesions although their availability is decreasing. The lack of reliable and specific anti-T. pallidum antibodies and its inferior sensitivity to PCR may explain why the direct fluorescent antibody test for T. pallidum is not widely available for clinical use. Immunohistochemical staining for T. pallidum also depends on the availability of specific antibodies, and the method is only applicable for histopathological examination of biopsy and autopsy specimens necessitating an invasive specimen collection approach. With recent advances in molecular diagnostics, PCR is considered to be the most reliable, versatile and practical for laboratories to implement. In addition to being an objective and sensitive test for direct detection of Treponema pallidum subsp. pallidum DNA in skin and mucous membrane lesions, the resulting PCR amplicons from selected gene targets can be further characterized for antimicrobial (macrolide) susceptibility testing, strain typing and identification of T. pallidum subspecies. PMID- 25798161 TI - Canadian Public Health Laboratory Network laboratory guidelines for the diagnosis of neurosyphilis in Canada. AB - Neurosyphilis refers to infection of the central nervous system by Treponema pallidum, which may occur at any stage. Neurosyphilis has been categorized in many ways including early and late, asymptomatic versus symptomatic and infectious versus non-infectious. Late neurosyphilis primarily affects the central nervous system parenchyma, and occurs beyond early latent syphilis, years to decades after the initial infection. Associated clinical syndromes include general paresis, tabes dorsalis, vision loss, hearing loss and psychiatric manifestations. Unique algorithms are recommended for HIV-infected and HIV uninfected patients, as immunocompromised patients may present with serologic and cerebrospinal fluid findings that are different from immunocompetent hosts. Antibody assays include a VDRL assay and the FTA-Abs, while polymerase chain reaction for T. pallidum can be used as direct detection assays for some specimens. This chapter reviews guidelines for specimen types and sample collection, and identifies two possible algorithms for use with immunocompromised and immunocompetent hosts using currently available tests in Canada, along with a review of treatment response and laboratory testing follow-up. PMID- 25798162 TI - Canadian Public Health Laboratory Network laboratory guidelines for congenital syphilis and syphilis screening in pregnant women in Canada. AB - Despite universal access to screening for syphilis in all pregnant women in Canada, cases of congenital syphilis have been reported in recent years in areas experiencing a resurgence of infectious syphilis in heterosexual partnerships. Antenatal screening in the first trimester continues to be important and should be repeated at 28 to 32 weeks and again at delivery in women at high risk of acquiring syphilis. The diagnosis of congenital syphilis is complex and is based on a combination of maternal history and clinical and laboratory criteria in both mother and infant. Serologic tests for syphilis remain important in the diagnosis of congenital syphilis and are complicated by the passive transfer of maternal antibodies which can affect the interpretation of reactive serologic tests in the infant. All infants born to mothers with reactive syphilis tests should have nontreponemal tests (NTT) and treponemal tests (TT) performed in parallel with the mother's tests. A fourfold or higher titre in the NTT in the infant at delivery is strongly suggestive of congenital infection but the absence of a fourfold or greater NTT titre does not exclude congenital infection. IgM tests for syphilis are not currently available in Canada and are not recommended due to poor performance. Other evaluation in the newborn infant may include long bone radiographs and cerebrospinal fluid tests but all suspect cases should be managed in conjunction with sexually transmitted infection and/or pediatric experts. PMID- 25798163 TI - Canadian Public Health Laboratory Network laboratory guidelines for the use of point-of-care tests for the diagnosis of syphilis in Canada. AB - Syphilis point-of-care tests (POCT) are widely available in developing countries enabling early diagnosis, treatment and support. The majority of commercially available tests use treponemal antigens and the presence of antibodies does not distinguish between current and past infection, which may lead to unnecessary antibiotic use and stigmatization of having a current STI. In hard-to-reach populations, the benefits may outweigh the risks. Available studies show reasonable performance of POCT with median sensitivity of 86%, specificity of 99% and positive predictive values >80% when prevalence was >0.3%. Although no syphilis POCT are approved in Canada at this time, a single study in an outreach setting in Alberta showed limited benefit due to a high prevalence of previous infection but more studies are needed. Newer dual tests employing treponemal and nontreponemal antigens look promising. PMID- 25798164 TI - Canadian Public Health Laboratory Network national syphilis laboratory testing recommendations: INTRODUCTION. PMID- 25798165 TI - Canadian Public Health Laboratory Network laboratory guidelines for the use of serological tests (excluding point-of-care tests) for the diagnosis of syphilis in Canada. AB - Syphilis, caused by the bacterium Treponema pallidum subsp. pallidum, is an infection recognized since antiquity. It was first reported at the end of the 15th century in Europe. Infections may be sexually transmitted as well as spread from an infected mother to her fetus or through blood transfusions. The laboratory diagnosis of syphilis infection is complex. Because this organism cannot be cultured, serology is used as the principal diagnostic method. Some of the issues related to serological diagnoses are that antibodies take time to appear after infection, and serology screening tests require several secondary confirmatory tests that can produce complex results needing interpretation by experts in the field. Traditionally, syphilis screening was performed using either rapid plasma reagin or Venereal Disease Research Laboratory tests, and confirmed by treponemal tests such as MHA-TP, TPPA or FTA-Abs. Currently, that trend is reversed, ie, most of the laboratories in Canada now screen for syphilis using treponemal enzyme immunoassays and confirm the status of infection using rapid plasma reagin or Venereal Disease Research Laboratory tests; this approach is often referred to as the reverse algorithm. This chapter reviews guidelines for specimen types and sample collection, treponemal and non-treponemal tests utilized in Canada, the current status of serological tests for syphilis in Canada, the complexity of serological diagnosis of syphilis infection and serological testing algorithms. Both traditional and reverse sequence algorithms are recommended and the algorithm used should be based on a combination of local disease epidemiology, test volumes, performance of the proposed assays and available resources. PMID- 25798166 TI - Comparison of Serum Zinc Levels among Children with Simple Febrile Seizure and Control Group: A Systematic Review. AB - OBJECTIVE: Several factors are involved in the etiology of febrile seizure (FS), among them is zinc (Zn), which has been discussed in various studies. The present systematic review compares Zn levels in children with FS and a control group. MATERIALS & METHODS: We searched keywords of febrile seizure, febrile convulsion, children, childhood, fever, trace elements, risk factor, predisposing, zinc, Zn, and epilepsy in the following databases: SCOPUS, PubMed, and Google Scholar. The quality of research papers was assessed using a checklist. Data was extracted from primary studies based on demographic variables and amounts of Zn in case and control groups. RESULTS: Twenty primary studies were entered in the present study. Of which, eighteen studies, reported that Zn serum levels were significantly lower in the case group (patients with FS) than the control group. CONCLUSION: The present systematic review indicated that Zn is one factor for predicting FS. A low level of this element among children can be regarded as a contributing factor for FS, a conclusion with a high consensus among different studies carried out in different parts of the world. PMID- 25798167 TI - The place of psychotherapy in contemporary psychiatry. AB - Psychotherapy has long been an essential component of clinical psychiatry and many young physicians choose to train in psychiatry residency programs in order to acquire necessary knowledge and skills, and become competent psychotherapists. Recent advances in psychopharmacology and neuroscience, and growing dominance of managed care and evidence-based medicine have had dramatic impacts on health care delivery systems and clinical psychiatry practice. Despite these changes in the field of mental health, psychotherapy still remains a crucial part of clinical psychiatry and comprises a great proportion of psychiatrists' clinical practice. Hence, accreditation agencies and regulatory bodies determine compulsory minimum requirements for psychiatry residency programs to ensure that residents, at the end of their specialty training, can demonstrate competence in managing their patients through applying different approaches of psychotherapy. PMID- 25798168 TI - Comparison of therapeutic effects of omega-3 and methylphenidate (ritalin((r))) in treating children with attention deficit hyperactivity disorder. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a fixed pattern of disregard and hyperactivity that is much more severe than what is normal in children of the same age. Multiple drugs are used for the treatment of children with ADHD; however, their side effects and efficacy are not clearly known. This study was designed to evaluate and compare the therapeutic effects of two drugs, that is, omega-3 and methylphenidate hydrochloride (Ritalin((r))), used to treat patients with ADHD. METHODS: In a randomized, placebo control clinical trial in Yazd, Iran, 85 ADHD children were divided into two experimental and one control groups. Thus, 29 subjects were treated with Ritalin((r)), 28 subjects received omega-3, and the remaining 28 received placebo. The data collection tools used in this study consisted of the Conners' Parent Rating Scale and Teacher Rating Scale. The scores obtained from these questionnaires were analyzed using chi square test and paired t-test in PASW Statistics. RESULTS: The average age of the population was 8.22 (+/- 1.65) years. Significant associations were observed between Ritalin((r)) therapy and the changes before and after the treatment, and the omega-3 treatment and the changes before and after treatment (p < 0.001). There was no significant association between the placebo group and the changes before and after the treatment (p > 0.050). Omega-3 had considerable efficacy as well as Ritalin((r)) (P = 0.001). CONCLUSIONS: More attention should be given to screening, prevention, and treatment with omega-3 and its effective role in the development of the brain and mental health, and increasing children's attention span and thinking ability. PMID- 25798169 TI - Problem-solving deficits in Iranian people with borderline personality disorder. AB - OBJECTIVE: Interventions for people suffering from borderline personality disorder (BPD), such as dialectical behavior therapy, often include a problem solving component. However, there is an absence of published studies examining the problem-solving abilities of this client group in Iran. The study compared inpatients and outpatients with BPD and a control group on problem-solving capabilities in an Iranian sample. It was hypothesized that patients with BPD would have more deficiencies in this area. METHODS: Fifteen patients with BPD were compared to 15 healthy participants. Means-ends problem-solving task (MEPS) was used to measure problem-solving skills in both groups. RESULTS: BPD group reported less effective strategies in solving problems as opposed to the healthy group. Compared to the control group, participants with BPD provided empirical support for the use of problem-solving interventions with people suffering from BPD. CONCLUSIONS: The findings supported the idea that a problem-solving intervention can be efficiently applied either as a stand-alone therapy or in conjunction with other available psychotherapies to treat people with BPD. PMID- 25798170 TI - Promoting individual learning for trainees with perceived high helplessness: experiences of a safety training program. AB - OBJECTIVE: The article arises from a research project investigating the effectiveness of safety training on changing attitudes toward safety issues. Followed by the training intervention was observed that employees' helplessness decreased. The researchers have come to the idea of investigating how safety training can reduce perceived helplessness. Thus, this research examined the effectiveness of safety training on reducing employees' helplessness with attention to the mediating role of attitude toward safety issues. METHODS: The current study was an experimental study with the control group. A total of 204 (101 experimental group and 103 control group) completed safety attitude questionnaire and perceived helplessness before a safety training course including four 90-min sessions over 4 consecutive days in Esfahan Steel Company in 2012 between October and December. Only members of the experimental group participated in this course. These questionnaires, approximately 30 days later, again were run on members of both groups. Data were analyzed using descriptive indexes, t-, and F-test. RESULTS: RESULTS by comparing the two groups showed that safety training was effective only on individuals with perceived low helplessness (p = 0.02). CONCLUSION: In individuals with perceived high helplessness, safety training only with changing safety attitudes can reduce the perceived helplessness. PMID- 25798171 TI - Reliability and validity of the persian version of templer death anxiety scale extended in veterans of iran-iraq warfare. AB - OBJECTIVE: The purpose of this study was to determine the validity and reliability of the Persian version of Templer Death Anxiety Scale-Extended (DAS E) in veterans of Iran-Iraq Warfare. METHODS: In this cross-sectional study, 211 male veterans of Iran-Iraq Warfare completed the 51 item DAS-E. Principal components analysis with varimax rotation was used to assess domain structure of the DAS-E. Internal consistency reliability was assessed with Cronbach's alpha. Test-retest reliability was assessed with intra-class correlation coefficients for absolute agreement for the individual items and domains. RESULTS: The construct validity of the scale was obtained using exploratory factor analysis that showed four factors with Eigen values of greater than 1 (1, 11 items, alpha = 0.83; 2, 7 items; alpha = 0.87; 3, 5 items, alpha = 0.73; and 4, 4 items, alpha = 0.75). Test-retest and internal consistency (total alpha) was 0.91 and 0.89, respectively. CONCLUSION: The DAS-E demonstrated suitable validity and reliability among the veterans under study. The factor analysis demonstrated that the DAS-E has a multi-dimensional structure. With consideration of the proper psychometric characteristics, this scale can be used to further research about death anxiety in this population. PMID- 25798172 TI - Depression and interpersonal problems in adolescents: their relationship with alexithymia and coping styles. AB - OBJECTIVE: The aim of the present research was to determine whether depression and interpersonal problems had relationships with alexithymia and coping styles in adolescents. METHODS: The study population was randomly selected from all of the adolescent students in the schools of Sari in Iran; 441 adolescents (228 boys and 213 girls) were included in the study. The participants completed the Toronto Alexithymia Scale, the Coping Inventory for Stressful Situations, the Inventory of Interpersonal Problems, and the Beck Depression Inventory. The data was analyzed using descriptive and inferential statistics and was expressed in means, standard deviations, and Pearson correlation coefficient. RESULTS: Alexithymia was related to depression and interpersonal problems; the adolescents who defined themselves as more alexithymic obtained higher scores in depression and interpersonal problems than the adolescents who classified themselves as less- and non-alexithymic. Furthermore, coping styles were related to depression and interpersonal problems. Regression analyses showed that both alexithymia and coping styles accounted for a unique and significant proportion of the variance in depression and interpersonal problems in adolescents. CONCLUSION: These findings support the positive correlation of alexithymia and maladaptive coping styles with depression and interpersonal problems. PMID- 25798173 TI - Deliberate self-harm among patients referring to the emergency room in damghan, iran. AB - OBJECTIVE: Deliberate self-harm (DHS) is a deviant behavior that has been not completely emphasized in health-related studies in Iran. The current study was conducted to explore the prevalence and reasons associated with the incidence of DSH in patients referring to the emergency room of Baradaran-e Rezaee Hospital in Damghan, Iran. METHODS: Fifty-four clients with the mean age of 29.4 (+/-10.3) years participated in this cross-sectional study in 2010. Firstly, demographics and details of substance use were collected based on items elicited from the Addiction Severity Index (ASI) and a researcher-made questionnaire. Then details of comorbidity and factors associated with the current DHS were collected by a semi-structured interview. Data were analyzed by performing descriptive methods of statistics. RESULTS: Deliberate self-poisoning with using toxic substances such as lead, and poison (44.8%) followed by drug intoxication such as opiate and methamphetamine (35.2%) and body and vessel cutting (20%) were the most prevalent types of DSH. Furthermore, results revealed that comorbidities such as physical illness (38.9%) and psychiatric disorders including depression (31.5%), psychotic symptoms (15%), bipolar disorder (5.6%), stress (5.6%), and anxiety (1.9%) were commonly prevalent. The most frequently reported factors associated with DSH were desires for self-punishing (42%), self-medication for emotional sufferings (33%), experiencing euphoric feelings (24%), and stress (20%), respectively. CONCLUSION: DSH is one of the critical health and treatment priorities, which are prevalent in emergency rooms of hospitals in Iran. Clients with comorbid diagnosis of DSH, especially drug use warrant specific attention in emergency rooms. PMID- 25798174 TI - Relationship of spiritual intelligence with resilience and perceived stress. AB - OBJECTIVE: The purpose of this study was to investigate on relationship between spiritual intelligence, resilience, and perceived stress. METHODS: The study sample consisted of 307 students of Sistan and Baluchistan University. The Connor Davidson Resilience Scale (CD-RISC), the Spiritual Intelligence Self-Report Inventory (SISRI) and the Perceived Stress Scale (PSS) are used as a research instrument. RESULTS: The results show that there is a positive and significant relationship between the SISRI and the CD-RISC. However, there is a negative and significant relationship between the SISRI and the PSS of students. The Enter regression analysis for prediction of the CD-RISC show that the SISRI predicts 0.10 of the CD-RISC variances and also the SISRI predicts 0.11 of the PSS variances. CONCLUSION: Spirituality helps to resilience in people who experience stress. PMID- 25798176 TI - Sexual desire in Iranian female university students: role of marital satisfaction and sex guilt. AB - OBJECTIVE: To determine association between sexual desire and marital satisfaction and sex guilt among a sample of Iranian female university students. METHODS: The data presented here were obtained from a total of 192 married Iranian female university students who were selected via a multi-cluster sampling method from universities of Social Welfare and Rehabilitation, Tarbiat Modarres, and Islamic Azad. The subjects' sociodemographic data, marital satisfaction (using ENRICH Marital Satisfaction Questionnaire), sex guilt (using Mosher Revised Sex-Guilt Inventory), and sexual desire (using Hurlbert Index of Sexual Desire) were gathered. Pearson correlation coefficient and regression analysis methods were used to analyse the data. RESULTS: Findings showed there are significant relationships between sexual desire and marital satisfaction (r = 0.51, p < 0.01) and also between sexual desire and sex guilt (r = -0.44, p < 0.01). Also marital satisfaction and sex guilt were able to predict 31 percent of the variance of sexual desire. CONCLUSION: Marital satisfaction and sex guilt are two factors that significantly affect fluctuations in sexual desire of Iranian female university students. PMID- 25798175 TI - Prospective memory impairments in schizophrenic patients. AB - OBJECTIVE: Memory impairment is one of the most pervasive cognitive dysfunctions in schizophrenic patients. The aim of the current study was to conduct the most comprehensive assessment of how prospective memory (PM) is affected in schizophrenia in comparison with healthy controls. METHODS: In this study, 30 first-episode schizophrenic patients who fulfilled the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders based on the diagnostic interview were recruited from eight regional psychiatric clinics in Iran. All participants were males (age 27-42). Moreover, 28 healthy controls were recruited from the same social-class as the patients. The Prospective and Retrospective Memory Questionnaire (PRMQ), PM tasks, and the Virtual Week Board Game were administered. Moreover, clinical symptoms were rated using the positive and negative symptoms scale. RESULTS: The results showed that in all of the memory types, the group with dominant positive symptoms was superior to the group with dominant negative symptoms. In addition, the results showed that in all of the memory types, the control group had superiority to the schizophrenic group. The most considerable differences between groups were in time-based PM tasks, irregular event-based virtual week tasks, and retrospective tasks (PRMQ). CONCLUSION: The current study confirmed that schizophrenic patients have severe PM deficits. PMID- 25798177 TI - Gender differences in depression scores of Iranian and german medical students. AB - OBJECTIVE: The aim was to evaluate gender differences in depression scores of Iranian and German medical students. METHODS: Two hundred Iranian medical students (100 men and 100 women) and 200 German medical students (100 men and 100 women) were selected randomly and completed the English form of the self-rating Beck Depression Inventory (BDI). RESULTS: Analysis gave a mean rating of 10.7 +/- 6.6 for Iranian men and 10.9 +/- 7.81 for Iranian women (NS). Also, 5 +/- 4.9 for German men and 5.6 +/- 5.0 for German women (NS). On Item 2, which asked whether the person was pessimistic 33% of Iranian men and 30% of Iranian women indicated that they were pessimistic (NS). Also, 21% of German men and 20% of German women indicated that they were pessimistic (NS). On Item 9, which asked about suicidal tendencies, 9% of Iranian men and 13% of Iranian women reported as having suicidal tendencies (NS). Also, 13% of German men and 21% of German women reported as having self-harming thoughts (NS). CONCLUSION: The present study showed no gender differences in Iranian and German medical students' scores on the BDI. PMID- 25798178 TI - Premenstrual syndrome and comorbid depression among medical students in the internship stage: a descriptive study. AB - OBJECTIVE: Premenstrual syndrome (PMS) is a cluster of physical and emotional changes that typically begins several days before the menstrual period that disappears quickly after menstruation. It seems that co-occurrence of depression increases the risk and severity of this syndrome. In this cross-sectional research, we evaluated an association between PMS and depression in medical students. METHODS: A hundred female medical students of Shahid Beheshti University of Medical Sciences that were available assigned for research. They were divided into two groups after administration of demographic questionnaire and PMS questionnaire made by researchers based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Technical Revision; group with or without PMS diagnosis. Then, they completed Beck's Depression Inventory. RESULTS: From 100 participants, 55% (n = 55) met the PMS criteria and 45% had no PMS. In the PMS group 30% (n = 17) had no depression; 38% (n = 21) had mild depression; 23% (n = 13) had moderate depression; and 7% (n = 4) had severe depression. In the group with no PMS 60% (n = 27) had no depression; 20% (n = 9) had mild depression; 17% (n = 8) had moderate depression; 2% (n = 1) had severe depression. The rate of depression was significantly higher in PMS group (p = 0.04). CONCLUSION: In this research, PMS had an elevated frequency in medical students. In students with PMS, rate of depression was higher than students without PMS. PMID- 25798179 TI - An atypical suicide attempt: self-inflicted intra-cardiac injury with sewing needle. AB - Atypical cases of suicide are less likely to be seen in general hospitals, nonetheless require further investigation into the precipitating factors as well as proper follow-up. This paper illustrates a 61-year-old woman with major depressive disorder who experienced auditory hallucinations during delirious periods of taking low-dose benzodiazepines, who referred to the hospital with a sewing needle stuck in her chest wall. The needle was successfully removed. Psychiatric problems are often underdiagnosed, therefore undertreated in general hospitals. Thus close monitoring of the patients during the hospitalization and after discharge is crucial. PMID- 25798180 TI - Strong correlation between protein reagent strip and protein-to-creatinine ratio for detection of renal dysfunction in HIV-infected patients: a cross-sectional study. AB - BACKGROUND: Tubular dysfunction is common in HIV-infected people and detection of proteinuria is essential to identify this problem. In low-income countries, resources for detection of proteinuria using the Kidney Disease Improve Global Outcomes (KDIGO) gold standard urinary protein/creatinine ratio (uPCR) is rarely possible, and use of the protein reagent strip (PRS) could be an option in these places. The aims of this study were to establish the concordance between PRS and uPCR to detect tubular proteinuria in HIV-infected people, and to assess the sensitivity and specificity of PRS as a diagnostic method in this group. METHODS: A cross-sectional study was conducted to evaluate the correlation between the two techniques to detect protein in urine. Participants were enrolled for a period of 6 months. The measurements were performed in participants who were on highly active antiretroviral therapy (HAART) or prior to the start of treatment. Proteinuria was defined as uPCR >= 150 mg/g, and/or >= trace on PRS. A phi coefficient was calculated to establish the degree of correlation. We assessed the sensitivity and specificity of PRS compared with uPCR using standard methods. RESULTS: A total of 799 subjects were included. Of these, 737 (92%) were men. The mean age was 32.9 years (+/-10.1 years). Most (561, 70%) were on antiretroviral treatment. The mean estimated glomerular filtration rate (eGFR) calculated according to Modification of Diet in Renal Disease (MDRD)-4 was 113.0 mL/min (+/ 22.6). Comorbidities included diabetes mellitus (10, 1.3%) and hypertension (17, 2.1%). The prevalence of proteinuria detected by PRS was 8.3% (n = 66) and by uPCR 10.6% (n = 85). The concordance assessed by phi correlation coefficient was 0.70, p < 0.001, with a sensitivity of 51.7% (95% confidence interval [CI] 41% 62%) and specificity 97% (95% CI 39%-97%). CONCLUSIONS: There is a high concordance between detection of proteinuria by PRS and uPCR. Therefore, in low income countries PRS can be helpful for detecting tubular damage in people infected with HIV. PMID- 25798181 TI - The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer. AB - BACKGROUND: Metabolic therapy using ketogenic diets (KD) is emerging as an alternative or complementary approach to the current standard of care for brain cancer management. This therapeutic strategy targets the aerobic fermentation of glucose (Warburg effect), which is the common metabolic malady of most cancers including brain tumors. The KD targets tumor energy metabolism by lowering blood glucose and elevating blood ketones (beta-hydroxybutyrate). Brain tumor cells, unlike normal brain cells, cannot use ketone bodies effectively for energy when glucose becomes limiting. Although plasma levels of glucose and ketone bodies have been used separately to predict the therapeutic success of metabolic therapy, daily glucose levels can fluctuate widely in brain cancer patients. This can create difficulty in linking changes in blood glucose and ketones to efficacy of metabolic therapy. METHODS: A program was developed (Glucose Ketone Index Calculator, GKIC) that tracks the ratio of blood glucose to ketones as a single value. We have termed this ratio the Glucose Ketone Index (GKI). RESULTS: The GKIC was used to compute the GKI for data published on blood glucose and ketone levels in humans and mice with brain tumors. The results showed a clear relationship between the GKI and therapeutic efficacy using ketogenic diets and calorie restriction. CONCLUSIONS: The GKIC is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation. PMID- 25798182 TI - Identification of residues/sequences in the human riboflavin transporter-2 that is important for function and cell biology. AB - BACKGROUND: Riboflavin (RF) is essential for normal cellular metabolic activities. Human cells obtain RF from their surroundings via a carrier-mediated process that involves RF transporters -1, -2 & -3 (hRFVT -1, -2 & -3; products of SLC52A1, -A2 and -A3 genes, respectively). Little is known about the structural features of these transporters that are important for their function/cell biology. Our aim in this study was to address these issues for the hRFVT-2, a transporter linked to the neurodegenerative disorder Brown-Vialetto-Van Laere Syndrome (BVVLS). METHODS: We used comparative protein-structure modelling to predict residues that interact with two amino acids known to be critical for hRFVT-2 function (the clinical mutants L123 and L339), site-directed mutagenesis, and truncation approach in the human-derived brain U87 cell model. RESULTS: First we showed that the defect in the function of the L123 and L339 hRFVT-2 clinical mutants is related to a reduction in protein stability/translation efficiency and to retention of the protein in the ER. Mutating V120 and L121 (residues predicted to interact with L123) and L342 (a residue predicted to interact with L339) also led to a significant inhibition in hRFVT-2 function (with no change in membrane expression); this inhibition was associated with changes in protein stability/translation efficiency (in the case of V120A and L342A) and an impairment in transport function (in the case of L121). Truncating the N- and C- terminals of hRFVT-2 led to significant inhibition in RF uptake, which was associated with changes in protein stability/translation efficiency (it was also associated with a partial impairment in membrane targeting in the case of the N terminal truncation). CONCLUSION: These investigations report on identification of residues/sequences in the hRFVT-2 protein that is important for its physiological function and cell biology. PMID- 25798183 TI - A portable extensional rheometer for measuring the viscoelasticity of pitcher plant and other sticky liquids in the field. AB - BACKGROUND: Biological fluids often have interesting and unusual physical properties to adapt them for their specific purpose. Laboratory-based rheometers can be used to characterise the viscoelastic properties of such fluids. This, however, can be challenging as samples often do not retain their natural properties in storage while conventional rheometers are fragile and expensive devices ill-suited for field measurements. We present a portable, low-cost extensional rheometer designed specifically to enable in situ studies of biological fluids in the field. The design of the device (named Seymour) is based on a conventional capillary break-up extensional rheometer (the Cambridge Trimaster). It works by rapidly stretching a small fluid sample between two metal pistons. A battery-operated solenoid switch triggers the pistons to move apart rapidly and a compact, robust and inexpensive, USB 3 high speed camera is used to record the thinning and break-up of the fluid filament that forms between the pistons. The complete setup runs independently of mains electricity supply and weighs approximately 1 kg. Post-processing and analysis of the recorded images to extract rheological parameters is performed using open source software. RESULTS: The device was tested both in the laboratory and in the field, in Brunei Darussalam, using calibration fluids (silicone oil and carboxymethyl cellulose solutions) as well as Nepenthes pitcher plant trapping fluids as an example of a viscoelastic biological fluid. The fluid relaxation times ranged from 1 ms to over 1 s. The device gave comparable performance to the Cambridge Trimaster. Differences in fluid viscoelasticity between three species were quantified, as well as the change in viscoelasticity with storage time. This, together with marked differences between N. rafflesiana fluids taken from greenhouse and wild plants, confirms the need for a portable device. CONCLUSIONS: Proof of concept of the portable rheometer was demonstrated. Quantitative measurements of pitcher plant fluid viscoelasticity were made in the natural habitat for the first time. The device opens up opportunities for studying a wide range of plant fluids and secretions, under varying experimental conditions, or with changing temperatures and weather conditions. PMID- 25798184 TI - Automated integrative high-throughput phenotyping of plant shoots: a case study of the cold-tolerance of pea (Pisum sativum L.). AB - BACKGROUND: Recently emerging approaches to high-throughput plant phenotyping have discovered their importance as tools in unravelling the complex questions of plant growth, development and response to the environment, both in basic and applied science. High-throughput methods have been also used to study plant responses to various types of biotic and abiotic stresses (drought, heat, salinity, nutrient-starving, UV light) but only rarely to cold tolerance. RESULTS: We present here an experimental procedure of integrative high-throughput in-house phenotyping of plant shoots employing automated simultaneous analyses of shoot biomass and photosystem II efficiency to study the cold tolerance of pea (Pisum sativum L.). For this purpose, we developed new software for automatic RGB image analysis, evaluated various parameters of chlorophyll fluorescence obtained from kinetic chlorophyll fluorescence imaging, and performed an experiment in which the growth and photosynthetic activity of two different pea cultivars were followed during cold acclimation. The data obtained from the automated RGB imaging were validated through correlation of pixel based shoot area with measurement of the shoot fresh weight. Further, data obtained from automated chlorophyll fluorescence imaging analysis were compared with chlorophyll fluorescence parameters measured by a non-imaging chlorophyll fluorometer. In both cases, high correlation was obtained, confirming the reliability of the procedure described. CONCLUSIONS: This study of the response of two pea cultivars to cold stress confirmed that our procedure may have important application, not only for selection of cold-sensitive/tolerant varieties of pea, but also for studies of plant cold-response strategies in general. The approach, provides a very broad tool for the morphological and physiological selection of parameters which correspond to shoot growth and the efficiency of photosystem II, and is thus applicable in studies of various plant species and crops. PMID- 25798185 TI - Erratum: In planta assays involving epigenetically silenced genes reveal inhibition of cytosine methylation by genistein. AB - [This corrects the article DOI: 10.1186/1746-4811-8-10.]. PMID- 25798186 TI - Poor prognostic factors in patients who underwent surgery for acute non-occlusive ischemic colitis. AB - INTRODUCTION: Ischemic colitis (IC) is a disease with high postoperative morbidity and mortality. Knowledge of the risk factors for postoperative mortality could be helpful in clinical decision making and in optimizing postoperative treatment. METHODS: From a prospective database, we conducted a retrospective medical record review of 50 patients who underwent surgery for IC between 2003 and 2011 at our institution. We analyzed the causes and potential risk factors for early mortality after surgery for IC. RESULTS: The early postoperative mortality and morbidity rates were 30.0% (15/50) and 54% (27/50), respectively. The two most common causes of death were multi-organ failure (66.7%, 10/15) and fulminant septic shock (20.0%, 3/15). Univariate analysis showed that postoperative mortality was significantly associated with preoperative nephropathy, coronary artery disease, a previous history of cardiovascular surgery, an ASA score >= 4, surgical delay >= 3 days, preoperative hemodynamic instability, and use of pre- and intraoperative adrenergic vasopressors. In the multivariate analysis, a previous history of cardiovascular surgery (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.2-56.5) and surgical delay >= 3 days (OR, 5.7; 95% CI, 1.2-27.9) were identified as independent risk factors for postoperative mortality. CONCLUSIONS: Because surgical delay is an avoidable determinant of early mortality, a high index of suspicion and early surgical intervention can increase survival. A routine postoperative evaluation for IC may be helpful in patients with a previous history of cardiovascular surgery. PMID- 25798187 TI - Kaempferol pretreatment modulates systemic inflammation and oxidative stress following hemorrhagic shock in mice. AB - BACKGROUND: Kaempferol has been reported as beneficial for both acute and chronic inflammatory diseases. This study aims to investigate whether kaempferol affects systemic inflammation and oxidative stress in the heart, lung, and liver after hemorrhagic shock in mice. METHODS: Male C57/BL6 mice underwent hemorrhagic shock (mean arterial pressure of 35 mmHg for 90 min) and were arbitrarily divided into Sham, hemorrhagic shock (HS), and Kae groups (n = 10 in each group). Mice in the Kae groups received a kaempferol (10-mg/kg body weight) injection 12 h prior to (Group Kae PT) or 90 min after (Group Kae T) the initiation of hemorrhagic shock. Plasma proinflammatory cytokines (TNF-alpha and IL-6), organ myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, and organ malondialdehyde (MDA) concentrations and heme oxygenase-1 (HO-1) expression levels were assessed by enzyme-linked immunosorbent assay (ELISA) or western blot assay. RESULTS: Compared with the HS group and the Kae T group, pretreatment with kaempferol significantly decreased proinflammatory cytokines TNF-alpha (P = 0.012 and 0.015, respectively) and IL-6 (P = 0.023 and 0.014, respectively) following hemorrhagic shock. Kae pretreatment reverted MPO, SOD, and MDA to basal levels in the heart, lung, and liver (Ps < 0.05), while the Kae T group showed no significant differences in these biomarkers compared with the HS group (Ps > 0.05). HO-1 expression was significantly increased in the Kae PT group compared with the other groups (P = 0.011 vs. HS group and P = 0.02 vs. Kae T group). CONCLUSIONS: Pretreatment of hemorrhagic shock mice with kaempferol significantly decreased plasma levels of TNF-alpha and IL-6; reverted MPO, SOD, and MDA in the heart, lung, and liver; and increased expression of HO-1 in the same organs. PMID- 25798188 TI - Tracking humanitarian funding for reproductive health: a systematic analysis of health and protection proposals from 2002-2013. AB - BACKGROUND: The Inter-agency Working Group on Reproductive Health in Crises conducted a ten-year global evaluation of reproductive health in humanitarian settings. This paper examines proposals for reproductive health activities under humanitarian health and protection funding mechanisms for 2002-2013, and the level at which these reproductive health proposals were funded. METHODS: The study used English and French health and protection proposal data for 2002-2013, extracted from the Financial Tracking Service (FTS) database managed by the United Nations Office for the Coordination of Humanitarian Affairs. Every project was reviewed for relevance against pre-determined reproductive health definitions for 2002-2008. An in-depth analysis was additionally conducted for 2009-2013 through systematically reviewing proposals via a key word search and subsequently classifying them under designated reproductive health categories. Among the relevant reproductive health proposals, counts and proportions were calculated in Excel based on their reproductive health components, primarily by year. Contributions, requests, and unfunded requests were calculated based on the data provided by FTS. RESULTS: Among the 11,347 health and protection proposals issued from 345 emergencies between 2002 and 2013, 3,912 were relevant to reproductive health (34.5%). The number of proposals containing reproductive health activities increased by an average of 21.9% per year, while the proportion of health and protection sector appeals containing reproductive health activities increased by an average of 10.1% per year. The total funding request over the 12 years amounted to $4.720 billion USD, of which $2.031 billion USD was received. Among reproductive health components for 2009-2013 proposals, maternal newborn health comprised the largest proportion (56.4%), followed by reproductive health-related gender-based violence (45.9%), HIV/sexually transmitted infections (37.5%), general reproductive health (26.2%), and lastly, family planning (14.9%). CONCLUSION: Findings show that more agencies are responding to humanitarian appeals by proposing to implement reproductive health programs and receiving increased aid over the twelve year period. While such developments are welcome, project descriptions show comparatively limited attention and programming for family planning and abortion care in particular. PMID- 25798189 TI - Progress and gaps in reproductive health services in three humanitarian settings: mixed-methods case studies. AB - BACKGROUND: Reproductive health (RH) care is an essential component of humanitarian response. Women and girls living in humanitarian settings often face high maternal mortality and are vulnerable to unwanted pregnancy, unsafe abortion, and sexual violence. This study explored the availability and quality of, and access barriers to RH services in three humanitarian settings in Burkina Faso, Democratic Republic of the Congo (DRC), and South Sudan. METHODS: Data collection was conducted between July and October 2013. In total, 63 purposively selected health facilities were assessed: 28 in Burkina Faso, 25 in DRC, and nine in South Sudan, and 42 providers completed a questionnaire to assess RH knowledge and attitudes. Thirty-four focus group discussions were conducted with 29 members of the host communities and 273 displaced married and unmarried women and men to understand access barriers. RESULTS: All facilities reported providing some RH services in the prior three months. Five health facilities in Burkina Faso, six in DRC, and none in South Sudan met the criteria as a family planning service delivery point. Two health facilities in Burkina Faso, one in DRC, and two in South Sudan met the criteria as an emergency obstetric and newborn care service delivery point. Across settings, three facilities in DRC adequately provided selected elements of clinical management of rape. Safe abortion was unavailable. Many providers lacked essential knowledge and skills. Focus groups revealed limited knowledge of available RH services and socio-cultural barriers to accessing them, although participants reported a remarkable increase in use of facility-based delivery services. CONCLUSION: Although RH services are being provided, the availability of good quality RH services was inconsistent across settings. Commodity management and security must be prioritized to ensure consistent availability of essential supplies. It is critical to improve the attitudes, managerial and technical capacity of providers to ensure that RH services are delivered respectfully and efficiently. In addition to ensuring systematic implementation of good quality RH services, humanitarian health actors should meaningfully engage crisis-affected communities in RH programming to increase understanding and use of this life-saving care. PMID- 25798190 TI - Reproductive health services for Syrian refugees in Zaatri Camp and Irbid City, Hashemite Kingdom of Jordan: an evaluation of the Minimum Initial Services Package. AB - BACKGROUND: The Minimum Initial Services Package (MISP) for reproductive health, a standard of care in humanitarian emergencies, is a coordinated set of priority activities developed to prevent excess morbidity and mortality, particularly among women and girls, which should be implemented at the onset of an emergency. The purpose of the evaluation was to determine the status of MISP implementation for Syrian refugees in Jordan as part of a global evaluation of reproductive health in crises. METHODS: In March 2013, applying a formative evaluation approach 11 key informant interviews, 13 health facility assessments, and focus group discussions (14 groups; 159 participants) were conducted in two Syrian refugee sites in Jordan, Zaatri Camp, and Irbid City, respectively. Information was coded, themes were identified, and relationships between data explored. RESULTS: Lead health agencies addressed the MISP by securing funding and supplies and establishing reproductive health focal points, services and coordination mechanisms. However, Irbid City was less likely to be included in coordination activities and health facilities reported challenges in human resource capacity. Access to clinical management of rape survivors was limited, and both women and service provider's knowledge about availability of these services was low. Activities to reduce the transmission of HIV and to prevent excess maternal and newborn morbidity and mortality were available, although some interventions needed strengthening. Some planning for comprehensive reproductive health services, including health indicator collection, was delayed. Contraceptives were available to meet demand. Syndromic treatment of sexually transmitted infections and antiretrovirals for continuing users were not available. In general refugee women and adolescent girls perceived clinical services negatively and complained about the lack of basic necessities. CONCLUSIONS: MISP services and key elements to support implementation were largely in place. Pre-existing Jordanian health infrastructure, prior MISP trainings, dedicated leadership and available funding and supplies facilitated MISP implementation. The lack of a national protocol on clinical management of rape survivors hindered provision of these services, while communities' lack of information about the health benefits of the services as well as perceived cultural repercussions likely contributed to no recent service uptake from survivors. This information can inform MISP programming in this setting. PMID- 25798191 TI - Determination of Abraham model solute descriptors for the monomeric and dimeric forms of trans-cinnamic acid using measured solubilities from the Open Notebook Science Challenge. AB - BACKGROUND: Calculating Abraham descriptors from solubility values requires that the solute have the same form when dissolved in all solvents. However, carboxylic acids can form dimers when dissolved in non-polar solvents. For such compounds Abraham descriptors can be calculated for both the monomeric and dimeric forms by treating the polar and non-polar systems separately. We illustrate the method of how this can be done by calculating the Abraham descriptors for both the monomeric and dimeric forms of trans-cinnamic acid, the first time that descriptors for a carboxylic acid dimer have been obtained. RESULTS: Abraham descriptors were calculated for the monomeric form of trans-cinnamic acid using experimental solubility measurements in polar solvents from the Open Notebook Science Challenge together with a number of water-solvent partition coefficients from the literature. Similarly, experimental solubility measurements in non-polar solvents were used to determine Abraham descriptors for the trans-cinnamic acid dimer. CONCLUSION: Abraham descriptors were calculated for both the monomeric and dimeric forms of trans-cinnamic acid. This allows for the prediction of further solubilities of trans-cinnamic acid in both polar and non-polar solvents with an error of about 0.10 log units. Graphical abstractMolar concentration of trans cinnamic acid in various polar and non-polar solvents. PMID- 25798192 TI - Predicting Abraham model solvent coefficients. AB - BACKGROUND: The Abraham general solvation model can be used in a broad set of scenarios involving partitioning and solubility, yet is limited to a set of solvents with measured Abraham coefficients. Here we extend the range of applicability of Abraham's model by creating open models that can be used to predict the solvent coefficients for all organic solvents. RESULTS: We created open random forest models for the solvent coefficients e, s, a, b, and v that had out-of-bag R(2) values of 0.31, 0.77, 0.92, 0.47, and 0.63 respectively. The models were used to suggest sustainable solvent replacements for commonly used solvents. For example, our models predict that propylene glycol may be used as a general sustainable solvent replacement for methanol. CONCLUSION: The solvent coefficient models extend the range of applicability of the Abraham general solvation equations to all organic solvents. The models were developed under Open Notebook Science conditions which makes them open, reproducible, and as useful as possible. Graphical AbstractChemical space for solvents with known Abraham coefficients. PMID- 25798193 TI - Winter rye as a bioenergy feedstock: impact of crop maturity on composition, biological solubilization and potential revenue. AB - BACKGROUND: Winter annual crops such as winter rye (Secale cereale L) can produce biomass feedstock on seasonally fallow land that continues to provide high-value food and feed from summer annuals such as corn and soybeans. As energy double crops, winter grasses are likely to be harvested while still immature and thus structurally different from the fully senesced plant material typically used for biofuels. This study investigates the dynamic trends in biomass yield, composition, and biological solubilization over the course of a spring harvest season. RESULTS: The water soluble fraction decreased with increasing maturity while total carbohydrate content stayed roughly constant at about 65%. The protein mass fraction decreased with increasing maturity, but was counterbalanced by increasing harvest yield resulting in similar total protein across harvest dates. Winter rye was ground and autoclaved then fermented at 15 g/L total solids by either (1) Clostridium thermocellum or (2) simultaneous saccharification and cofermentation (SSCF) using commercial cellulases (CTec2 and HTec2) and a xylose fermenting Saccharomyces cerevisiae strain. Solubilization of total carbohydrate dropped significantly as winter rye matured for both C. thermocellum (from approximately 80% to approximately 50%) and SSCF (from approximately 60% to approximately 30%). C. thermocellum achieved total solubilization 33% higher than that of SSCF for the earliest harvest date and 50% higher for the latest harvest date. Potential revenue from protein and bioethanol was stable over a range of different harvest dates, with most of the revenue due to ethanol. In a crop rotation with soybean, recovery of the soluble protein from winter rye could increase per hectare protein production by 20 to 35%. CONCLUSIONS: Double cropping winter rye can produce significant biomass for biofuel production and feed protein as coproduct without competing with the main summer crop. During a 24-day harvest window, the total carbohydrate content remained relatively constant while the early-harvest yielded much higher carbohydrate solubilization for both C. thermocellum fermentation and SSCF. C. thermocellum fermentation achieved higher carbohydrate solubilization than SSCF across all growth stages tested. Although winter rye's yield, composition, and biological reactivity change rapidly in the spring, it offers a substantial and stable income across the harvest season and thus flexibility for the farmer. PMID- 25798196 TI - Visualisation of quadratic discriminant analysis and its application in exploration of microbial interactions. AB - BACKGROUND: When comparing diseased and non-diseased patients in order to discriminate between the aspects associated with the specific disease, it is often observed that the diseased patients have more variability than the non diseased patients. In such cases Quadratic discriminant analysis is required which is based on the estimation of different covariance structures for the different groups. Having different covariance matrices means the Canonical variate transformation cannot be used to obtain a visual representation of the discrimination and group separation. RESULTS: In this paper an alternative method is proposed: combining the different transformations for the different groups into a single representation of the sample points with classification regions. In order to associate the differences in variables with group discrimination, a biplot is produced which include information on the variables, samples and their relationship. PMID- 25798194 TI - Lipid recovery from a vegetable oil emulsion using microbial enrichment cultures. AB - BACKGROUND: Many waste streams have a relatively high vegetable oil content, which is a potential resource that should be recovered. Microbial storage compound production for the recovery of lipids from lipid-water emulsions with open (unsterilized) microbial cultures was investigated in a sequencing batch reactor using a diluted vegetable oil emulsion as model substrate. RESULTS: After feeding, triacylglycerides (TAG) were accumulated intracellular by the microbial enrichment culture and subsequently used for growth in the remainder of the sequencing batch cycle. Roughly 50% of the added TAG could be recovered as intracellular lipids in this culture. The maximum lipid storage capacity of the enrichment culture was 54% on volatile suspended solids (VSS) mass basis in a separate fed-batch accumulation experiment. The microbial community was dominated by a lipolytic fungus, Trichosporon gracile, that was responsible for intracellular lipid accumulation but also a significant fraction of lipolytic and long chain fatty-acid-utilizing bacteria was present. CONCLUSION: Herewith, we demonstrate an effective strategy for enrichment of a microbial community that can accumulate significant amounts of lipids from wastewaters without the need for sterilization of substrates or equipment. Further optimization of this process will make recovery of lipids from wastewater possible. PMID- 25798197 TI - Climate services for society: origins, institutional arrangements, and design elements for an evaluation framework. AB - Climate services involve the generation, provision, and contextualization of information and knowledge derived from climate research for decision making at all levels of society. These services are mainly targeted at informing adaptation to climate variability and change, widely recognized as an important challenge for sustainable development. This paper reviews the development of climate services, beginning with a historical overview, a short summary of improvements in climate information, and a description of the recent surge of interest in climate service development including, for example, the Global Framework for Climate Services, implemented by the World Meteorological Organization in October 2012. It also reviews institutional arrangements of selected emerging climate services across local, national, regional, and international scales. By synthesizing existing literature, the paper proposes four design elements of a climate services evaluation framework. These design elements include: problem identification and the decision-making context; the characteristics, tailoring, and dissemination of the climate information; the governance and structure of the service, including the process by which it is developed; and the socioeconomic value of the service. The design elements are intended to serve as a guide to organize future work regarding the evaluation of when and whether climate services are more or less successful. The paper concludes by identifying future research questions regarding the institutional arrangements that support climate services and nascent efforts to evaluate them. PMID- 25798198 TI - Machines first, humans second: on the importance of algorithmic interpretation of open chemistry data. AB - The current rise in the use of open lab notebook techniques means that there are an increasing number of scientists who make chemical information freely and openly available to the entire community as a series of micropublications that are released shortly after the conclusion of each experiment. We propose that this trend be accompanied by a thorough examination of data sharing priorities. We argue that the most significant immediate benefactor of open data is in fact chemical algorithms, which are capable of absorbing vast quantities of data, and using it to present concise insights to working chemists, on a scale that could not be achieved by traditional publication methods. Making this goal practically achievable will require a paradigm shift in the way individual scientists translate their data into digital form, since most contemporary methods of data entry are designed for presentation to humans rather than consumption by machine learning algorithms. We discuss some of the complex issues involved in fixing current methods, as well as some of the immediate benefits that can be gained when open data is published correctly using unambiguous machine readable formats. Graphical AbstractLab notebook entries must target both visualisation by scientists and use by machine learning algorithms. PMID- 25798199 TI - Glucose but not insulin or insulin resistance is associated with memory performance in middle-aged non-diabetic women: a cross sectional study. AB - BACKGROUND: Elevated concentrations of plasma glucose appear to play a role in memory impairment, and it has been suggested that insulin might also have a negative effect on cognitive function. Our aim was to study whether glucose, insulin or insulin resistance are associated with episodic or semantic memory in a non-diabetic and non-demented population. METHODS: We linked and matched two population-based data sets identifying 291 participants (127 men and 164 women, mean age of 50.7 +/- 8.0 years). Episodic and semantic memory functions were tested, and fasting plasma insulin, fasting plasma glucose, and 2-hour glucose were analysed along with other potential influencing factors on memory function. Since men and women display different results on memory functions they were analysed separately. Insulin resistance was calculated using the HOMA-IR method. RESULTS: A higher fasting plasma glucose concentration was associated with lower episodic memory in women (r = -0.08, 95% CI -0.14; -0.01), but not in men. Plasma insulin levels and insulin resistance were not associated with episodic or semantic memory in women or in men after adjustments for age, fasting glucose, 2 hour glucose, BMI, education, smoking, cardiovascular disease, hypertension, cholesterol, and physical activity. CONCLUSIONS: This indicates that fasting glucose but not insulin, might have impact on episodic memory in middle-aged women. PMID- 25798200 TI - Biochemical view on: Precocious markers of cardiovascular risk and vascular damage in apparently healthy women with previous gestational diabetes. AB - Women diagnosed with gestational diabetes mellitus have an increased risk of developing diabetes mellitus, which is a known risk factor for cardiovascular disease and insulin resistance. In the recently published article by Zajdenverg et al., they aimed to identify endothelial dysfunction and cardiovascular risk factors in women with previous gestational diabetes mellitus. However, authors did not evaluate the role of total homocysteine, which has important effects for endothelial dysfunction. Vitamin B12 and folic acid are important vitamins since their deficiency may lead to the probable microvascular abnormalities by increasing the tHcy, which is an independent risk factor for endothelial dysfunction. PMID- 25798201 TI - Effect of attachment type on load distribution to implant abutments and the residual ridge in mandibular implant-supported overdentures. AB - This study aimed to investigate the effect of attachment type on the load transmitted to implants and the residual ridge in a mandibular two-implant supported overdenture in a model study. Ball attachments, locator attachments, and round-bar attachments were selected and examined. Static and dynamic vertical loads of 100 N were applied in the right first molar region. The load on the implants was measured by piezoelectric three-dimensional force transducers, and the load on the residual ridge beneath the denture base was measured using a tactile sheet sensor. The load on the implants with ball attachments was significantly higher than that with the other two attachments. The load on the residual ridge with round-bar attachments was significantly higher than that with the other two attachments. Our findings indicate that the three-dimensional load on implants and the residual ridge beneath the denture base is significantly associated with the type of attachment used in implant-supported overdentures. PMID- 25798202 TI - Lung disease as a determinant of cognitive decline and dementia. AB - Almost 40 million people currently live with dementia but this is estimated to double over the next 20 years; despite this, research identifying modifiable risk factors is scarce. There is increasing evidence that cognitive impairment is more frequent in those with chronic lung disease than those without. Chronic obstructive pulmonary disease affects 210 million people, with cognitive impairment present in 60% of certain populations. Co-morbid cognitive dysfunction also appears to impact on important outcomes such as quality of life, hospitalisation and survival. This review summarises the evidence of an association between cognition, impaired lung function and obstructive lung disease. It goes on to examine the contribution of neuro-imaging to our understanding of the underlying pathophysiology. While the mechanisms of brain pathology and cognitive impairment are likely to be complex and multi-factorial, there is evidence to suggest a key role for occult cerebrovascular damage independent of traditional vascular risk factors, including smoking. PMID- 25798203 TI - How to Measure Molecular Forces in Cells: A Guide to Evaluating Genetically Encoded FRET-Based Tension Sensors. AB - The ability of cells to sense and respond to mechanical forces is central to a wide range of biological processes and plays an important role in numerous pathologies. The molecular mechanisms underlying cellular mechanotransduction, however, have remained largely elusive because suitable methods to investigate subcellular force propagation were missing. Here, we review recent advances in the development of biosensors that allow molecular force measurements. We describe the underlying principle of currently available techniques and propose a strategy to systematically evaluate new Forster resonance energy transfer (FRET) based biosensors. PMID- 25798206 TI - New developments in the pathology of malignant lymphoma: a review of the literature published from October 2014-December 2014. PMID- 25798205 TI - Use of TIRF to Monitor T-Lymphocyte Membrane Dynamics with Submicrometer and Subsecond Resolution. AB - A key step of adaptive immune responses is the T lymphocyte capacity to detect the presence of foreign antigens on specialized cells with high speed and specificity during contacts lasting a few minutes. Much evidence suggests that there is a deep link between the lifetime of molecular interactions between T cell receptors and ligands and T cell activation, but the precise mechanisms of bond formation and dissociation remain incompletely understood. Previous experiments done with interference reflection microscopy/reflection interference contrast microscopy disclosed transverse motions with several nanometer average amplitude of micrometer size membrane zones. More recently, total internal reflection fluorescence microscopy was used to show that the initial interaction between primary T lymphocytes and model surfaces involved the tip of microvilli (typically 0.2 um2 area) generating apparent contacts of a few seconds that allowed cells to detect ligands of their membrane receptors. Here we show that these microvilli displayed minimal lateral displacements but quantitative fluorescence measurement suggested the occurrence of spontaneous transverse fluctuations of order of 67 nm amplitude during 1-s observation periods. This may play a major role in membrane receptor engagement and ensuing signal generation. PMID- 25798204 TI - Nanobiotechnology for the Therapeutic Targeting of Cancer Cells in Blood. AB - During metastasis, circulating tumor cells migrate away from a primary tumor via the blood circulation to form secondary tumors in distant organs. Mounting evidence from clinical observations indicates that the number of circulating tumor cells (CTCs) in the blood correlates with the progression of solid tumors before and during chemotherapy. Beyond the well-established role of CTCs as a fluid biopsy, however, the field of targeting CTCs for the prevention or reduction of metastases has just emerged. Conventional cancer therapeutics have a relatively short circulation time in the blood which may render the killing of CTCs inefficient due to reduced exposure of CTCs to drugs. Nevertheless, over the past few decades, the development of nanoparticles and nanoformulations to improve the half-life and release profile of drugs in circulation has rejuvenated certain traditional medicines in the emerging field of CTC neutralization. This review focuses on how the principles of nanomedicine may be applied to target CTCs. Moreover, inspired by the interactions between CTCs and host cells in the blood circulation, novel biomimetic approaches for targeted drug delivery are presented. PMID- 25798207 TI - Inter-locus as well as intra-locus heterogeneity in LINE-1 promoter methylation in common human cancers suggests selective demethylation pressure at specific CpGs. AB - BACKGROUND: Hypomethylation of long interspersed element (LINE)-1 has been observed in tumorigenesis when using degenerate assays, which provide an average across all repeats. However, it is unknown whether individual LINE-1 loci or different CpGs within one specific LINE-1 promoter are equally affected by methylation changes. Conceivably, studying methylation changes at specific LINE-1 may be more informative than global assays for cancer diagnostics. Therefore, with the aim of mapping methylation at individual LINE-1 loci at single-CpG resolution and exploring the diagnostic potential of individual LINE-1 locus methylation, we analyzed methylation at 11 loci by pyrosequencing, next generation bisulfite sequencing as well as global LINE-1 methylation in bladder, colon, pancreas, prostate, and stomach cancers compared to paired normal tissues and in blood samples from some of the patients compared to healthy donors. RESULTS: Most (72/80) tumor samples harbored significant methylation changes at at least one locus. Notably, our data revealed not only the expected hypomethylation but also hypermethylation at some loci. Specific CpGs within the LINE-1 consensus sequence appeared preferentially hypomethylated suggesting that these could act as seeds for hypomethylation. In silico analysis revealed that these CpG sites more likely faced the histones in the nucleosome. Multivariate logistic regression analysis did not reveal a significant clinical advantage of locus-specific methylation markers over global methylation markers in distinguishing tumors from normal tissues. CONCLUSIONS: Methylation changes at individual LINE-1 loci are heterogeneous, whereas specific CpGs within the consensus sequence appear to be more prone to hypomethylation. With a broader selection of loci, locus-specific LINE-1 methylation could become a tool for tumor detection. PMID- 25798208 TI - Does Personality Moderate the Effects of Mindfulness Training for Medical and Psychology Students? AB - The majority of mindfulness research to date has reported only on the group-level effects of interventions. Therefore, there is a need to better understand who is most likely to benefit from mindfulness interventions. This study reports on moderation analyses from a two-centre randomised controlled trial of mindfulness based stress reduction (MBSR) among 288 medical and psychology students. The study investigated whether baseline personality factors (neuroticism, conscientiousness and extroversion) and baseline mindfulness moderated effects on mental distress, study stress and subjective well-being measured after the intervention. An increased effect of the intervention on mental distress and subjective well-being was found in students with higher scores on neuroticism. Students with higher scores on conscientiousness showed an increased effect of mindfulness training on study stress. The training protected students against an increase in mental distress and study stress and a decrease in subjective well being that was seen in the control group. Baseline mindfulness and extroversion did not moderate the effects of the intervention on the outcomes. The majority of the 288 medical and psychology students in the study sample were female. Female participants scored significantly higher on neuroticism and conscientiousness, and they may therefore be an important target group for mindfulness interventions among students. PMID- 25798209 TI - Mindfulness-Based Cognitive Therapy (MBCT) for Health Anxiety (Hypochondriasis): Rationale, Implementation and Case Illustration. AB - Recent research has shown that mindfulness-based cognitive therapy (MBCT) could be a useful alternative approach to the treatment of health anxiety and deserves further investigation. In this paper, we outline the rationale for using MBCT in the treatment of this condition, namely its hypothesised impact on the underlying mechanisms which maintain health anxiety, such as rumination and avoidance, hypervigilance to body sensations and misinterpretation of such sensations. We also describe some of the adaptations which were made to the MBCT protocol for recurrent depression in this trial and discuss the rationale for these adaptations. We use a case example from the trial to illustrate how MBCT was implemented and outline the experience of one of the participants who took part in an 8-week MBCT course. Finally, we detail some of the more general experiences of participants and discuss the advantages and possible limitations of this approach for this population, as well as considering what might be useful avenues to explore in future research. PMID- 25798210 TI - Thiazolidinedione and Metformin Use and the Risk of Benign Prostate Hyperplasia in Veterans with Diabetes Mellitus. AB - BACKGROUND: Chronic inflammation is important in the development of benign prostatic hyperplasia (BPH) and certain oral antidiabetic medications have anti inflammatory properties. The purpose of this study was to determine if use of thiazolidinediones or metformin was associated with a reduced risk of requiring medical or surgical treatment for BPH compared to sulfonylureas among diabetic men. METHODS: We constructed a retrospective cohort of 192,457 male veterans newly prescribed either rosiglitazone, pioglitazone, metformin, or a sulfonylurea. We used Cox proportional hazard regression to assess the association between thiazolidinedione or metformin use and the risk of requiring medical or surgical treatment for BPH compared to sulfonylurea use. New BPH treatment was defined by either a new prescription for a alpha-1 blocker or 5alpha-reductase inhibitors or a surgical procedure indicated for severe BPH. RESULTS: In 259,995 person-years of follow up we identified 14,690 new treatments for BPH. After adjusting for covariates including age, HbA1c, and body mass index, we found no association between rosiglitazone (adjusted hazard ratio [aHR] 1.02, 95% CI 0.86, 1.20), pioglitazone (aHR 0.79, 95% CI 0.45, 1.38), or metformin use (aHR 0.99, 95% CI 0.94, 1.03) and risk of new medical or surgical treatment for BPH compared to sulfonylureas. Analyses ignoring prescriptions for non-selective alpha-1 blockers (terazosin, doxazosin, prazosin) from our BPH case definition (n = 11,079), yielded similar results. CONCLUSIONS: In this large cohort, we observed no association between the use of thiazolidinediones or metformin and new medical or surgical treatment for BPH compared to sulfonylureas. PMID- 25798212 TI - Discussion of 'Bayesian Nonparametric Inference - Why and How', by Peter Muller and Riten Mitra. PMID- 25798211 TI - The c.470 T > C CHEK2 missense variant increases the risk of differentiated thyroid carcinoma in the Great Poland population. AB - BACKGROUND: Differentiated thyroid carcinoma (DTC) originates from thyroid follicular epithelial cells and belongs to a group of slowly progressing tumors with a relatively good prognosis. However, recurrences and metastases are a serious problem in advanced stages. Furthermore, progression from a well differentiated thyroid carcinoma to an aggressive anaplastic one is possible. The majority of differentiated thyroid carcinomas are sporadic but a few alleles increasing the cancer risk are known. One of them is the c.470 T > C (p.I157T, rs17879961) missense substitution in the CHEK2 gene. AIM OF THE STUDY: The aim of this study was to investigate whether this specific CHEK2 alteration, c.470 T > C, predisposes the Great Poland (Wielkopolska) population to thyroid cancer. METHODS: 602 differentiated thyroid carcinoma patients and 829 controls randomly selected from population were genotyped for the presence of the c.470C allele using pyrosequencing. Hardy-Weinberg Equilibrium (HWE) was tested for both groups by chi-square distribution and Fisher's exact test. The odds ratios (ORs), 95% confidence intervals (CIs), and p-values were calculated using the R software. RESULTS: The results of genotyping showed the presence of the c.470C allele in 51 patients with a frequency of 4.49%, while in a controls in 42 patients with a frequency of 2.53%. We demonstrated that in the Great Poland population the c.470C CHEK2 variant increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004). The risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019). CONCLUSIONS: Identification of c.470C CHEK2 gene variant ought to be taken into account by healthcare policymakers. Future well-designed and larger population studies are of great value in confirming these findings. Moreover, a combination of genetic factors together with environmental exposures should also be considered. PMID- 25798213 TI - Cerebrolysin Accelerates Metamorphosis and Attenuates Aging-Accelerating Effect of High Temperature in Drosophila Melanogaster. AB - Cerebrolysin(r) (CBL) is a neuroprotective drug used for the treatment of neurodegenerative diseases. CBL's mechanisms of action remain unclear. Involvement of tryptophan (TRP)-kynurenine (KYN) pathway in neuroprotective effect of CBL might be suggested considering that modulation of KYN pathway of TRP metabolism by CBL, and protection against eclosion defect and prolongation of life span of Drosophila melanogaster with pharmacologically or genetically induced down-regulation of TRP conversion into KYN. To investigate possible involvement of TRP-KYN pathway in mechanisms of neuroprotective effect of CBL, we evaluated CBL effects on metamorphosis and life span of Drosophila melanogaster maintained at 23 degrees C and 28 degrees C ambient temperature. CBL accelerated metamorphosis, exerted strong tendency (p = 0.04) to prolong life span in female but not in male flies, and attenuated aging-accelerating effect of high (28 degrees C) ambient temperature in both female and male flies. Further research of CBL effects on metamorphosis and resistance to aging-accelerating effect of high temperature might offer new insights in mechanisms of its neuroprotective action and expand its clinical applications. PMID- 25798214 TI - Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice. AB - Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migration, pancreatic cancer growth, invasion and unfavorable outcomes. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell (MDSC) activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators. Serp 1 and M-T7 are two such secreted anti-inflammatory myxomaviral proteins. Serp-1 inhibits uPA, plasmin and coagulation factor X while M-T7 inhibits C, CC, and CXC chemokines. We have explored the potential use of these viral proteins for treatment of a range of human cancer isolates engrafted in severe combined immunodeficient (SCID) mice. Engrafted tumors were treated with either Serp-1, neuroserpin, a related mammalian serpin that inhibits thrombolytic proteases, or M-T7. Serp-1 and neuroserpin inhibited growth of the pancreatic cancer cell line Hs766t (P=0.03 and P=0.01, respectively) at 4 weeks after implantation. Serp-1 also inhibited growth of a second pancreatic cancer cell line MIA PaCa-2 in mice (P=0.02). Growth of the human breast cancer line MDA231 was not inhibited by Serp 1. M-T7, in contrast, did not alter growth of any of the cancer cell lines tested after implant into SCID mice. Serpin inhibition of pancreatic tumor growth was associated with a significant decrease in splenocyte MDSC counts by flow cytometry (P=0.009), without detected change in other splenocyte subpopulations. Serp-1 and NSP treatment also significantly reduced macrophage infiltration in tumors (P=0.001). In summary two anti-inflammatory serpins reduced inflammatory macrophage invasion and pancreatic tumor cell growth, suggesting potential therapeutic efficacy. PMID- 25798215 TI - A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism. AB - BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting more than 1% of children. It is characterized by social communication deficits and repetitive behaviors/restricted interests. In the absence of any medications known to improve core symptom domains, parents often use complementary alternative treatments, including omega-3 fatty acid supplements. METHODS: We conducted a 6-month, randomized, placebo controlled trial of omega-3 fatty acid supplements (1.5 g) vs placebo in children 2 to 5 years of age with ASD. Primary outcome measures included the autism composite score of the Pervasive Developmental Disorders Behavioral Inventory (PDDBI) and the externalizing problems score of the Behavior Assessment System for Children (BASC 2). Secondary outcome measures included clinical global improvement (Clinical Global Impression-Improvement (CGI-I)), adaptive function (Vineland Adaptive Behavior Scale (VABS-II)), and language gains (Preschool Language Scale (PLS-4)), as well as safety. Exploratory analysis investigated potential correlations between changes in cytokine profiles and treatment response. RESULTS: Thirty eight participants were randomized in a 1:1 fashion. There was no significant difference between groups on the 0- to 24-week change in PDDBI autism composite scores (p = 0.5). There was a significant group by week interaction on the BASC-2 externalizing problem score, with participants randomized to the treatment group demonstrating worsening scores (p = 0.02). There was no statistically significant week by group effect on either adaptive function (p = 0.09) or language (p = 0.6). Omega-3s were relatively well tolerated. Changes in cytokines during the study did not significantly correlate with treatment response. CONCLUSIONS: This study does not support high dose supplementation of omega-3 fatty acids in young children with ASD. TRIAL REGISTRATION: Clinicaltrials.gov NCT01248728. Registered 22 November 2010. PMID- 25798216 TI - Maternal ancestry and population history from whole mitochondrial genomes. AB - MtDNA has been a widely used tool in human evolutionary and population genetic studies over the past three decades. Its maternal inheritance and lack of recombination have offered the opportunity to explore genealogical relationships among individuals and to study the frequency differences of matrilineal clades among human populations at continental and regional scales. The whole mtDNA genome sequencing delivers molecular resolution that is sufficient to distinguish patterns that have arisen over thousands of years. However, mutation rate is highly variable among the functional and non-coding domains of mtDNA which makes it challenging to obtain accurate split dates of the mitochondrial clades. Due to the shallow coalescent time of mitochondrial TMRCA at approximately 100 to 200 thousand years (ky), mtDNA data have only limited power to inform us about the more distant past and the early stages of human evolutionary history. The variation shared by mitochondrial genomes of individuals drawn from different continents outside Africa has been used to illuminate the details of the colonization process of the Old World, whereas regional patterns of variation have been at the focus of studies addressing questions of a more recent time scale. In the era of whole nuclear genome sequencing, mitochondrial genomes are continuing to be informative as a unique tool for the assessment of female specific aspects of the demographic history of human populations. PMID- 25798218 TI - Contrasting genetic diversity and population structure among three sympatric Madagascan shorebirds: parallels with rarity, endemism, and dispersal. AB - Understanding the relative contributions of intrinsic and extrinsic factors to population structure and genetic diversity is a central goal of conservation and evolutionary genetics. One way to achieve this is through comparative population genetic analysis of sympatric sister taxa, which allows evaluation of intrinsic factors such as population demography and life history while controlling for phylogenetic relatedness and geography. We used ten conserved microsatellites to explore the population structure and genetic diversity of three sympatric and closely related plover species in southwestern Madagascar: Kittlitz's plover (Charadrius pecuarius), white-fronted plover (C. marginatus), and Madagascar plover (C. thoracicus). Bayesian clustering revealed strong population structure in the rare and endemic Madagascar plover, intermediate population structure in the white-fronted plover, and no detectable population structure in the geographically widespread Kittlitz's plover. In contrast, allelic richness and heterozygosity were highest for the Kittlitz's plover, intermediate for the white fronted plover and lowest for the Madagascar plover. No evidence was found in support of the "watershed mechanism" proposed to facilitate vicariant divergence of Madagascan lemurs and reptiles, which we attribute to the vagility of birds. However, we found a significant pattern of genetic isolation by distance among populations of the Madagascar plover, but not for the other two species. These findings suggest that interspecific variation in rarity, endemism, and dispersal propensity may influence genetic structure and diversity, even in highly vagile species. PMID- 25798217 TI - Elucidating Organ-Specific Metabolic Toxicity Chemistry from Electrochemiluminescent Enzyme/DNA Arrays and Bioreactor Bead-LC-MS/MS. AB - Human toxic responses are very often related to metabolism. Liver metabolism is traditionally studied, but other organs also convert chemicals and drugs to reactive metabolites leading to toxicity. When DNA damage is found, the effects are termed genotoxic. Here we describe a comprehensive new approach to evaluate chemical genotoxicity pathways from metabolites formed in-situ by a broad spectrum of liver, lung, kidney and intestinal enzymes. DNA damage rates are measured with a microfluidic array featuring a 64-nanowell chip to facilitate fabrication of films of DNA, electrochemiluminescent (ECL) detection polymer [Ru(bpy)2(PVP)10]2+ {(PVP = poly(4-vinylpyridine)} and metabolic enzymes. First, multiple enzyme reactions are run on test compounds using the array, then ECL light related to the resulting DNA damage is measured. A companion method next facilitates reaction of target compounds with DNA/enzyme-coated magnetic beads in 96 well plates, after which DNA is hydrolyzed and nucleobase-metabolite adducts are detected by LC-MS/MS. The same organ enzymes are used as in the arrays. Outcomes revealed nucleobase adducts from DNA damage, enzymes responsible for reactive metabolites (e.g. cyt P450s), influence of bioconjugation, relative dynamics of enzymes suites from different organs, and pathways of possible genotoxic chemistry. Correlations between DNA damage rates from the cell-free array and organ-specific cell-based DNA damage were found. Results illustrate the power of the combined DNA/enzyme microarray/LC-MS/MS approach to efficiently explore a broad spectrum of organ-specific metabolic genotoxic pathways for drugs and environmental chemicals. PMID- 25798219 TI - Interactive effect of warming, nitrogen and phosphorus limitation on phytoplankton cell size. AB - Cell size is one of the ecologically most important traits of phytoplankton. The cell size variation is frequently related to temperature and nutrient limitation. In order to disentangle the role of both factors, an experiment was conducted to determine the possible interactions of these factors. Baltic Sea water containing the natural plankton community was used. We performed a factorial combined experiment of temperature, type of nutrient limitation (N vs. P), and strength of nutrient limitation. The type of nutrient limitation was manipulated by altering the N:P ratio of the medium (balanced, N and P limitation) and strength by the dilution rate (0% and 50%) of the semicontinuous cultures. The negative effect of temperature on cell size was strongest under N limitation, intermediate under P limitation, and weakest when N and P were supplied at balanced ratios. However, temperature also influenced the intensity of nutrient imitation, because at higher temperature there was a tendency for dissolved nutrient concentrations to be lower, while the C:N or C:P ratio being higher...higher at identical dilution rates and medium composition. Analyzing the response of cell size to C:N ratios (as index of N limitation) and C:P ratios (as index of P limitation) indicated a clear dominance of the nutrient effect over the direct temperature effect, although the temperature effect was also significant. PMID- 25798220 TI - Physiological ecology meets climate change. AB - In this article, we pointed out that understanding the physiology of differential climate change effects on organisms is one of the many urgent challenges faced in ecology and evolutionary biology. We explore how physiological ecology can contribute to a holistic view of climate change impacts on organisms and ecosystems and their evolutionary responses. We suggest that theoretical and experimental efforts not only need to improve our understanding of thermal limits to organisms, but also to consider multiple stressors both on land and in the oceans. As an example, we discuss recent efforts to understand the effects of various global change drivers on aquatic ectotherms in the field that led to the development of the concept of oxygen and capacity limited thermal tolerance (OCLTT) as a framework integrating various drivers and linking organisational levels from ecosystem to organism, tissue, cell, and molecules. We suggest seven core objectives of a comprehensive research program comprising the interplay among physiological, ecological, and evolutionary approaches for both aquatic and terrestrial organisms. While studies of individual aspects are already underway in many laboratories worldwide, integration of these findings into conceptual frameworks is needed not only within one organism group such as animals but also across organism domains such as Archaea, Bacteria, and Eukarya. Indeed, development of unifying concepts is relevant for interpreting existing and future findings in a coherent way and for projecting the future ecological and evolutionary effects of climate change on functional biodiversity. We also suggest that OCLTT may in the end and from an evolutionary point of view, be able to explain the limited thermal tolerance of metazoans when compared to other organisms. PMID- 25798221 TI - Reconciling nature conservation and traditional farming practices: a spatially explicit framework to assess the extent of High Nature Value farmlands in the European countryside. AB - Agriculture constitutes a dominant land cover worldwide, and rural landscapes under extensive farming practices acknowledged due to high biodiversity levels. The High Nature Value farmland (HNVf) concept has been highlighted in the EU environmental and rural policies due to their inherent potential to help characterize and direct financial support to European landscapes where high nature and/or conservation value is dependent on the continuation of specific low intensity farming systems. Assessing the extent of HNV farmland by necessity relies on the availability of both ecological and farming systems' data, and difficulties associated with making such assessments have been widely described across Europe. A spatially explicit framework of data collection, building out from local administrative units, has recently been suggested as a means of addressing such difficulties. This manuscript tests the relevance of the proposed approach, describes the spatially explicit framework in a case study area in northern Portugal, and discusses the potential of the approach to help better inform the implementation of conservation and rural development policies. Synthesis and applications: The potential of a novel approach (combining land use/cover, farming and environmental data) to provide more accurate and efficient mapping and monitoring of HNV farmlands is tested at the local level in northern Portugal. The approach is considered to constitute a step forward toward a more precise targeting of landscapes for agri-environment schemes, as it allowed a more accurate discrimination of areas within the case study landscape that have a higher value for nature conservation. PMID- 25798223 TI - High temperature intensifies negative density dependence of fitness in red flour beetles. AB - Competition for food, space, or other depletable resources has strong impacts on the fitness of organisms and can lead to a pattern known as negative density dependence, where fitness decreases as population density increases. Yet, many resources that have strong impacts on fitness are nondepletable (e.g., moisture or temperature). How do these nondepletable resources interact with depletable resources to modify negative density dependence? We tested the hypothesis that negative density dependence is modulated by temperature in red flour beetles and tested the prediction that the strength of negative density dependence should decrease as temperature decreases. We measured the number of eggs laid, offspring development time, and the number of offspring that reached maturity at three temperatures and two food treatment combinations as we simultaneously manipulated adult population density. We demonstrated that low temperatures weaken negative density dependence in the number of eggs laid; this pattern was most evident when food was abundant. Density had no effect on development time, but low temperatures increased development time. The percent of eggs that emerged as adults decreased with both density and temperature and increased with food. Temperature, an abiotic driver, can thus modulate density-dependent processes in ectotherms. Therefore, models of population growth for ectotherms should incorporate the effects of temperature. PMID- 25798222 TI - Spatially variable coevolution between a haemosporidian parasite and the MHC of a widely distributed passerine. AB - The environment shapes host-parasite interactions, but how environmental variation affects the diversity and composition of parasite-defense genes of hosts is unresolved. In vertebrates, the highly variable major histocompatibility complex (MHC) gene family plays an essential role in the adaptive immune system by recognizing pathogen infection and initiating the cellular immune response. Investigating MHC-parasite associations across heterogeneous landscapes may elucidate the role of spatially fluctuating selection in the maintenance of high levels of genetic variation at the MHC. We studied patterns of association between an avian haemosporidian blood parasite and the MHC of rufous-collared sparrows (Zonotrichia capensis) that inhabit environments with widely varying haemosporidian infection prevalence in the Peruvian Andes. MHC diversity peaked in populations with high infection prevalence, although intra-individual MHC diversity was not associated with infection status. MHC nucleotide and protein sequences associated with infection absence tended to be rare, consistent with negative frequency-dependent selection. We found an MHC variant associated with a ?26% decrease in infection probability at middle elevations (1501-3100 m) where prevalence was highest. Several other variants were associated with a significant increase in infection probability in low haemosporidian prevalence environments, which can be interpreted as susceptibility or quantitative resistance. Our study highlights important challenges in understanding MHC evolution in natural systems, but may point to a role of negative frequency-dependent selection and fluctuating spatial selection in the evolution of Z. capensisMHC. PMID- 25798224 TI - Effects of sampling method on foliar delta (13)C of Leymus chinensis at different scales. AB - Stable carbon isotope composition (delta (13)C) usually shows a negative relationship with precipitation at a large scale. We hypothesized that sampling method affects foliar delta (13)C and its response pattern to precipitation. We selected 11 sites along a precipitation gradient in Inner Mongolia and collected leaves of Leymus chinensis with five or six replications repeatedly in each site from 2009 to 2011. Additionally, we collected leaves of L. chinensis separately from two types of grassland (grazed and fenced) in 2011. Foliar delta (13)C values of all samples were measured. We compared the patterns that foliar delta (13)C to precipitation among different years or different sample sizes, the differences of foliar delta (13)C between grazed and fenced grassland. Whether actual annual precipitation (AAP) or mean annual precipitation (MAP), it was strongly correlated with foliar delta (13)C every year. Significant difference was found between the slopes of foliar delta (13)C to AAP and MAP every year, among the slopes of foliar delta (13)C to AAP from 2009 to 2011. The more samples used at each site the lower and convergent P-values of the linear regression test between foliar delta (13)C and precipitation. Furthermore, there was significant lower foliar delta (13)C value in presence of grazed type than fenced type grassland. These findings provide evidence that there is significant effect of sampling method to foliar delta (13)C and its response pattern to precipitation of L. chinensis. Our results have valuable implications in methodology for future field sampling studies. PMID- 25798225 TI - Use of PIT tags to assess individual heterogeneity of laboratory-reared juveniles of the endangered Cumberlandian combshell (Epioblasma brevidens) in a mark recapture study. AB - The federally endangered Cumberlandian combshell (Epioblasma brevidens) was propagated and reared to taggable size (5-10 mm), and released to the Powell River, Tennessee, to augment a relict population. Methodology using passive integrated transponder (PIT) tags on these mussels greatly facilitated the detection process. The overall mean detection probability and survival rate of released individuals reached 97.8 to 98.4% and 99.7 to 99.9% (per month), respectively, during nine successive recapture occasions in the 2-year study period, regardless of seasonality. Nonhierarchical models and hierarchical models incorporating individual and seasonal variations through a Bayesian approach were compared and resulted in similar performance of prediction for detection probability and survival rate of mussels. This is the first study to apply the mark-recapture method to laboratory-reared mussels using PIT tags and stochastic models. Quantitative analyses for individual heterogeneity allowed examination of demographic variance and effects of heterogeneity on population dynamics, although the individual and seasonal variations were small in this study. Our results provide useful information in implementing conservation strategies of this faunal group and a framework for other species or similar studies. PMID- 25798226 TI - Can environmental constraints determine random patterns of plant species co occurrence? AB - Plant community ecologists use the null model approach to infer assembly processes from observed patterns of species co-occurrence. In about a third of published studies, the null hypothesis of random assembly cannot be rejected. When this occurs, plant ecologists interpret that the observed random pattern is not environmentally constrained - but probably generated by stochastic processes. The null model approach (using the C-score and the discrepancy index) was used to test for random assembly under two simulation algorithms. Logistic regression, distance-based redundancy analysis, and constrained ordination were used to test for environmental determinism (species segregation along environmental gradients or turnover and species aggregation). This article introduces an environmentally determined community of alpine hydrophytes that presents itself as randomly assembled. The pathway through which the random pattern arises in this community is suggested to be as follows: Two simultaneous environmental processes, one leading to species aggregation and the other leading to species segregation, concurrently generate the observed pattern, which results to be neither aggregated nor segregated - but random. A simulation study supports this suggestion. Although apparently simple, the null model approach seems to assume that a single ecological factor prevails or that if several factors decisively influence the community, then they all exert their influence in the same direction, generating either aggregation or segregation. As these assumptions are unlikely to hold in most cases and assembly processes cannot be inferred from random patterns, we would like to propose plant ecologists to investigate specifically the ecological processes responsible for observed random patterns, instead of trying to infer processes from patterns. PMID- 25798227 TI - Uncertainties in the projection of species distributions related to general circulation models. AB - Ecological Niche Models (ENMs) are increasingly used by ecologists to project species potential future distribution. However, the application of such models may be challenging, and some caveats have already been identified. While studies have generally shown that projections may be sensitive to the ENM applied or the emission scenario, to name just a few, the sensitivity of ENM-based scenarios to General Circulation Models (GCMs) has been often underappreciated. Here, using a multi-GCM and multi-emission scenario approach, we evaluated the variability in projected distributions under future climate conditions. We modeled the ecological realized niche (sensu Hutchinson) and predicted the baseline distribution of species with contrasting spatial patterns and representative of two major functional groups of European trees: the dwarf birch and the sweet chestnut. Their future distributions were then projected onto future climatic conditions derived from seven GCMs and four emissions scenarios using the new Representative Concentration Pathways (RCPs) developed for the Intergovernmental Panel on Climate Change (IPCC) AR5 report. Uncertainties arising from GCMs and those resulting from emissions scenarios were quantified and compared. Our study reveals that scenarios of future species distribution exhibit broad differences, depending not only on emissions scenarios but also on GCMs. We found that the between-GCM variability was greater than the between-RCP variability for the next decades and both types of variability reached a similar level at the end of this century. Our result highlights that a combined multi-GCM and multi-RCP approach is needed to better consider potential trajectories and uncertainties in future species distributions. In all cases, between-GCM variability increases with the level of warming, and if nothing is done to alleviate global warming, future species spatial distribution may become more and more difficult to anticipate. When future species spatial distributions are examined, we propose to use a large number of GCMs and RCPs to better anticipate potential trajectories and quantify uncertainties. PMID- 25798228 TI - Complex offspring size effects: variations across life stages and between species. AB - Classical optimality models of offspring size and number assume a monotonically increasing relationship between offspring size and performance. In aquatic organisms with complex life cycles, the size-performance function is particularly hard to grasp because measures of performance are varied and their relationships with size may not be consistent throughout early ontogeny. Here, we examine size effects in premetamorphic (larval) and postmetamorphic (juvenile) stages of brooding marine animals and show that they vary contextually in strength and direction during ontogeny and among species. Larger offspring of the sea anemone Urticina felina generally outperformed small siblings at the larval stage (i.e., greater settlement and survival rates under suboptimal conditions). However, results differed when analyses were conducted at the intrabrood versus across brood levels, suggesting that the relationship between larval size and performance is mediated by parentage. At the juvenile stage (15 months), small offspring were less susceptible than large ones to predation by subadult nudibranchs and both sizes performed similarly when facing adult nudibranchs. In a sympatric species with a different life history (Aulactinia stella), all juveniles suffered similar predation rates by subadult nudibranchs, but smaller juveniles performed better (lower mortalities) when facing adult nudibranchs. Size differences in premetamorphic performance of U. felina were linked to total lipid contents of larvae, whereas size-specific predation of juvenile stages followed the general predictions of the optimal foraging strategy. These findings emphasize the challenge in gathering empirical support for a positive monotonic size-performance function in taxa that exhibit complex life cycles, which are dominant in the sea. PMID- 25789163 TI - FDA approved drugs as potential Ebola treatments. AB - In the search for treatments for the Ebola Virus, multiple screens of FDA drugs have led to the identification of several with promising in vitro activity. These compounds were not originally developed as antivirals and some have been further tested in mouse in vivo models. We put forward the opinion that some of these drugs could be evaluated further and move into the clinic as they are already FDA approved and in many cases readily available. This may be important if there is a further outbreak in future and no other therapeutic is available. PMID- 25798231 TI - Accelerated generation of free radicals by iron oxide nanoparticles in the presence of an alternating magnetic field. AB - The surfaces of iron oxide nanoparticles are capable of catalytically generating reactive oxygen species (ROS) through the Fenton and Haber-Weiss reactions. Fenton chemistry has been shown to be temperature dependent with an increase in activity up to 40 degrees C and then a decrease above this temperature as the hydrogen peroxide degrades into oxygen and water which limits the reaction. When exposed to an alternating magnetic field (AMF), iron oxide nanoparticles absorb the energy from the magnetic field and convert it into heat. In this study, we observed an increase in the degradation of methylene blue when a suspension of magnetite nanoparticles (Fe3O4) was exposed to an AMF indicating there was an increase in the ROS generation in response to the AMF. The increase in ROS generation compared to the Arrhenius prediction was both time and concentration dependent; in which we observed a decrease in ROS enhancement with increased time of exposure and concentration. We postulate that the decrease is due to agglomeration in the presence of the field. As the nanoparticles agglomerate, there is a decrease in surface area per mass limiting the reaction rate. PMID- 25798232 TI - Effect of community mobilization on appropriate care seeking for pneumonia in Haripur, Pakistan. AB - BACKGROUND: Appropriate and timely care seeking reduces mortality for childhood illnesses including pneumonia. Despite over 90 000 Lady Health Workers (LHWs) deployed in Pakistan, whose tasks included management of pneumonia, only 16% of care takers sought care from them for respiratory infections. As part of a community case management trial for childhood pneumonia, community mobilization interventions were implemented to improve care seeking from LHWs in Haripur district, Pakistan. The objective of the study was to increase the number of children receiving treatment for pneumonia and severe pneumonia by Lady Health Workers (LHWs) through community mobilization approaches for prompt recognition and care seeking in 2 to 59 month-old children. METHODS: To assess pneumonia care seeking practices, pre and post-intervention household surveys were conducted in 28 target Union Councils. Formative research to improve existing LHW training materials, job aids and other materials was carried out. Advocacy events were organized, LHWs and male health promoters were trained in community mobilization, non-functional women and male health committees were revitalized and LHWs and male health promoters conducted community awareness sessions. RESULTS: The community mobilization interventions were implemented from April 2008 - December 2009. Project and LHW program staff organized 113 sensitization meetings for opinion leaders, which were attended by 2262 males and 3288 females. The 511 trained LHWs organized 6132 community awareness sessions attended by 50 056 women and 511 male promoters conducted 523 sessions attended by 7845 males. In one year period, the number of LHWs treating pneumonia increased from 11 in April 2008 to 505 in March 2009. The care seeking from LHWs for suspected pneumonia increased from 0.7% in pre-intervention survey to 49.2% in post-intervention survey. CONCLUSION: The increase in care seeking from LHWs benefited the community through bringing inexpensive appropriate care closer to home and reducing burden on overstretched health facilities. The community mobilization interventions led to improvements in appropriate care seeking that would not have been achievable just by strengthening pneumonia case management skills of LHWs. In addition to strengthening skills, community mobilization and behavior change activities should also be included in community case management programmes. PMID- 25798234 TI - Exercise prevents beta-aminopropionitrile-induced morphological changes to type I collagen in murine bone. AB - This study evaluated the effects of reduced enzymatic crosslinking, exercise and the ability of exercise to prevent the deleterious impact of reduced crosslinking on collagen D-spacing. Eight-week-old female mice were divided into four weight matched groups receiving daily injections of either phosphate-buffered saline (PBS) or 300 mg kg(-1) beta-aminopropionitrile (BAPN) while undergoing normal cage activity (Sed) or 30 min per day of treadmill exercise (Ex) for 21 consecutive days. BAPN caused a downward shift in the D-spacing distribution in Sed BAPN compared with Sed PBS (P<0.001) but not in Ex BAPN (P=0.429), indicating that exercise can prevent changes in collagen morphology caused by BAPN. Exercise had no effect on D-spacing in PBS control mice (P=0.726), which suggests that exercise-induced increases in lysyl oxidase may be a possible mechanism for preventing BAPN-induced changes in D-spacing. The D-spacing changes were accompanied by an increase in mineral crystallinity/maturity due to the main effect of BAPN (P=0.016). However, no changes in nanoindentation, reference point indentation or other Raman spectroscopy parameters were observed. The ability of exercise to rescue BAPN-driven changes in collagen morphology necessitates further research into the use of mechanical stimulation as a preventative therapy for collagen-based diseases. PMID- 25798233 TI - Chondrodysplasias and TGFbeta signaling. AB - Human chondrodysplasias are a group of conditions that affect the cartilage. This review is focused on the involvement of transforming growth factor-beta signaling in a group of chondrodysplasias, entitled acromelic dysplasia, characterized by short stature, short hands and restricted joint mobility. PMID- 25798235 TI - Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links. AB - Diabetes and cancer represent two common, multifactorial, chronic and potentially fatal diseases, not infrequently co-diagnosed in the same patient. Epidemiological data demonstrate significant increases of the cancer incidence in patients with obesity and diabetes, which is more evident for certain site specific cancers. Although there is increasing evidence that strongly indicates an augmented risk of cancer in diabetic patients, several confounding factors complicate the ability to precisely assess the risk. Mainly in insulin-resistant states (such as in type 2 diabetes mellitus and in metabolic syndrome), direct associations between obesity-related hyperinsulinemia and increasing circulating insulin-like growth factor-1 (IGF-1) levels have been implicated as key factors in the mechanisms involved in carcinogenesis. Whilst anti-diabetic drugs can increase the cancer risk, anti-proliferative drugs may cause diabetes or aggravate pre-existing diabetes. Additionally, an increasing number of targeted anti-cancer therapies may interfere with the pathways shared by IGF-1 and insulin receptors, showing a adverse effect on glucose metabolism through various mechanisms. Although there is a requirement for large-scale randomized evidence, the present review summarizes the majority of the epidemiological association studies between diabetes and various types of cancer, discussing the pathophysiological mechanisms that may be involved in promoting carcinogenesis in diabetes and the potential impact of different anti-diabetic therapies on cancer risk. PMID- 25798236 TI - Roles of Rheb(S16H) in substantia nigra pars compacta dopaminergic neurons in vivo. AB - Although there are ongoing intensive research efforts, no effective pharmacological therapies for Parkinson's disease (PD) have been developed thus far. However, with the development of efficient gene delivery systems, gene therapy for PD has become a focus of research and increasing evidence suggests that continuous production of neurotrophic factors play a significant role in the functional restoration of the nigrostriatal dopaminergic (DA) system. Our recent study reported that the transduction of DA neurons with ras homolog enriched in brain, which has an S16H mutation [Rheb(S16H)], protected the nigrostriatal DA projection in a neurotoxin model of PD in vivo. In addition, Rheb(S16H) expression significantly increased the levels of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor, which contributed to the neuroprotective effects of Rheb(S16H) in DA neurons in the adult brain, indicating that the activation of the signaling pathways involved in cell survival by a specific gene delivery, such as Rheb(S16H) to adult neurons, may be a useful strategy to protect neural systems in the adult brain. In the present study, a brief overview of our recent studies is provided, which demonstrates the neuroprotective mechanisms of Rheb(S16H) on the nigrostriatal DA projection in the adult brain. PMID- 25798238 TI - Posttraumatic knee osteoarthritis following anterior cruciate ligament injury: Potential biochemical mediators of degenerative alteration and specific biochemical markers. AB - As a common injury, anterior cruciate ligament (ACL) injury is unable to heal itself naturally, which possibly increases knee instability, accelerates the risk of joint degeneration and leads to knee osteoarthritis (OA) in the ACL-injured knee. Thus, ACL reconstruction using an autograft or allograft tendon is proposed to maintain the biomechanical stability of the knee joint. However, previous studies demonstrate that surgical management of ACL reconstruction failed to abrogate the development of OA completely, indicating that biochemical disturbance is responsible for the osteoarthritic changes observed following ACL injury. Inflammatory mediators are elevated subsequent to ACL injury or rupture, inducing matrix metalloproteinase production, proteoglycan degradation, collagen destruction, chondrocyte necrosis and lubricin loss. These potential biochemical mediators may aid in the development of effective biological management to reduce the onset of future posttraumatic OA. Furthermore, during the degenerative process of cartilage, there are a number of cartilage-specific biomarkers, which play a critical step in the loss of structural and functional integrity of cartilage. The present review illustrates several specific biomarkers in the ACL injured knee joint, which may provide effective diagnostic and prognostic tools for investigating cartilage degenerative progression and future posttraumatic OA of ACL-injured patients. PMID- 25798237 TI - The role of the JAK-STAT pathway in neural stem cells, neural progenitor cells and reactive astrocytes after spinal cord injury. AB - Patients with spinal cord injuries can develop severe neurological damage and dysfunction, which is not only induced by primary but also by secondary injuries. As an evolutionarily conserved pathway of eukaryotes, the JAK-STAT pathway is associated with cell growth, survival, development and differentiation; activation of the JAK-STAT pathway has been previously reported in central nervous system injury. The JAK-STAT pathway is directly associated with neurogenesis and glia scar formation in the injury region. Following injury of the axon, the overexpression and activation of STAT3 is exhibited specifically in protecting neurons. To investigate the role of the JAK-STAT pathway in neuroprotection, we summarized the effect of JAK-STAT pathway in the following three sections: Firstly, the modulation of JAK-STAT pathway in proliferation and differentiation of neural stem cells and neural progenitor cells is discussed; secondly, the time-dependent effect of JAK-STAT pathway in reactive astrocytes to reveal their capability of neuroprotection is revealed and lastly, we focus on how the astrocyte-secretory polypeptides (astrocyte-derived cytokines and trophic factors) accomplish neuroprotection via the JAK-STAT pathway. PMID- 25798240 TI - Atrial natriuretic peptide reduces the alpha-subunit of the epithelial sodium channel mRNA expression in the mouse stria vascularis. AB - Atrial natriuretic peptide (ANP) is extensively expressed in the cochlea, including the strial vascularis (StV). ANP may participate in the regulation of the water-electrolyte balance. However, the functional significance of ANP in the cochlea is less understood and little is known regarding the exact mechanisms. Studies suggest that the epithelial sodium channel (ENaC) is important for regulating sodium transport across epithelia. ENaC may be involved in the clearance of endolymphatic Na+ and maintenance of a K-rich and Na-poor composition in the endolymph. Whether ANP has a regulatory effect on the Na+ channel in the StV remains unknown. The aim of the present study was to evaluate whether ANP affects the expression of the alpha-subunit of the ENaC (alpha-ENaC) mRNA in the mouse StV, using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) technique. The mouse StV tissues were incubated with 10 6 mol/1 ANP for different times (2, 6, 12, 24 and 48 h) and were subsequently harvested. alpha-ENaC mRNA was extracted for RT-qPCR analysis of the expression. The study demonstrated the existence of alpha-ENaC in the mouse StV. Tissues treated with ANP (10-6 mol/1) showed a significant reduction in alpha-ENaC mRNA expression (n=3, P<0.05). A maximum effect was reached at 2 h after treatment. The present results indicate that ANP may regulate cochlear ion transport and endolymph fluid balance in the inner ear via reducing expression of the alpha ENaC mRNA in the mouse StV. PMID- 25798241 TI - Method of isolation and characterization of Girardia tigrina stem cells. AB - Tissue regeneration is widely studied due to its importance for understanding the biology of stem cells, aiming at their application in medicine for therapeutic and various other purposes. The establishment of experimental models is necessary, as certain invertebrates and vertebrates have different regeneration abilities depending on their taxon position on the evolutionary scale. Planarians are an efficacious in vivo model for stem cell biology, but the correlation between planarian cellular and molecular neoblast pluripotency mechanisms and those of mammalian stem cells is unknown. The present study had the following objectives: i) Establish Girardia tigrina cell culture, ii) determine the time required for complete cell disintegration and iii) obtain neoblasts by cell subdivision. Twenty-four specimens were deprived of food for seven days. After this time, disintegration was performed by incubation protected at three temperatures for 48 h in an antibiotic, antimycotic and trypsin solution, after which the suspension was homogenized and centrifuged. Histopaque(r) 1077 was used for cell separation and interphases were collected and monitored by optical and fluorescence microscopy. Optical microscopy analysis informed the nucleus-to cytoplasm ratio, cell morphology and cell size. Under fluorescence microscopy, interphase 1 (I1) was subdivided into two groups and neoblasts were marked for characterization; one group was stained with 4',6-diamidino-2-phenylindole and the other was immunolabeled with octamer-binding transcription factor 4 (OCT4) and isolated and observed after 10 days of cultivation. Neoblasts predominated in I1 with a small amount of other cell types. In conclusion, sample disintegration with a trypsin and antibiotic solution was effective at 18C and Iscove's modified Dulbecco's medium supplemented with fetal bovine serum was adequate for the establishment of primary cell cultures after 48-h incubation and centrifugation. Antibody anti-OCT4 was used for the characterization of stem cells and was successfully labeled with concentrated neoblasts on interphase 1. PMID- 25798239 TI - Mechanism of alternative splicing and its regulation. AB - Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing. All these factors contributing to this one fundamental biological process add up to a mechanism that is critical to the proper functioning of cells. Any corruption of the process may lead to disruption of normal cellular function and the eventuality of disease. Cancer is one of those diseases, where alternative splicing may be the basis for the identification of novel diagnostic and prognostic biomarkers, as well as new strategies for therapy. Thus, an in depth understanding of alternative splicing regulation has the potential not only to elucidate fundamental biological principles, but to provide solutions for various diseases. PMID- 25798242 TI - Analysis of gene expression profiles as a tool to uncover tumor markers of liver cancer progression in a rat model. AB - Establishing a transcriptomic profile of human hepatocellular liver cancer (HCC) progression is a complex undertaking. A rat model of HCC was employed to develop a transcriptomic profile. Using three interventions, preneoplastic lesions appeared after 30 days and they progressed to HCC by 9 months. Preneoplastic and cancer lesions were characterized for transcriptomic analysis, and RNA from total liver homogenates was obtained at 1, 7, 11 and 16 days after the initiation treatment. RNA from dissected persistent preneoplastic lesions, adjacent tissue or cancer tissue was used for 30 days, and 5, 9, 12 and 18 months. The GeneChip(r) Rat Exon 1.0 ST arrays, Partek software and an Affymetrix console were employed for these analyses. LGALS3BP was differentially expressed at each time point, from the initial period, through the preneoplastic evolution period and until the end of cancer progression period. Twelve differentially expressed genes common to the preneoplastic evolution and to the cancer progression period were detected, which included ABCC3. Validation of the microarrays was confirmed by reverse transcription-quantitative polymerase chain reaction of six genes, including LGALS3BP and ABCC3. Of note, the proteins of these two genes are associated with the multidrug response complex, and evasion of immune surveillance and negative regulation of T cell proliferation. This model is useful for identifying candidate genes, and to validate them with regards to determining their relevance in rat HCC progression. PMID- 25798243 TI - Pediatric severe pseudomembranous enteritis treated with fecal microbiota transplantation in a 13-month-old infant. AB - Fecal microbiota transplantation (FMT) is a procedure used to restore the intestinal microbiota of a diseased individual using indigenous intestinal microorganisms from a healthy donor. The current case report presents the first case of a 13-month-old male with severe pseudomembranous enteritis (PME) treated with FMT. The infant was admitted to Shanghai Children's Hospital with a 2-month history of diarrhea, and a 1.5-month history of retractable edema, hypoalbuminemia, electrolyte disturbance and malnutrition. Besides necessary nutritional support, the patient was treated twice with oral metronidazole combined with or without vancomycin. Diarrhea was partially remitted. However, the infant had bloody or dark-green feces, and a distended abdomen. On day 96 from the initiation of the disease, a single FMT via a nasal jejuna feeding tube was performed. From day 2 until 4 months post-FMT, the patient presented with no diarrhea, normal feces and a satisfactory weight. To the best of our knowledge, this is the first pediatric PME treated with FMT. The current data show that FMT is an efficient choice for recurrent clostridium difficile infection and PME in adults and a few pediatric cases. Due to a lack of safety and effectiveness data, treatment should be cautiously applied in the pediatric population. PMID- 25798244 TI - Demethylation of the hTERT promoter in normal human gastric mucosal epithelial cells following N-methyl-N'-nitro-N-nitrosoguanidine exposure. AB - N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is an alkylating agent that can induce gastric carcinoma. As a well-known human carcinogen, MNNG has been universally recognized as a methylating agent and is believed to act through methylation mechanism. In the present study, the epigenetic status of the human telomerase reverse transcriptase (hTERT) promoter was investigated in MNNG treated normal human gastric mucosal epithelial cells. After 4 h exposure to MNNG at different concentrations, 6.8 and 68 uM, bisulfite sequencing polymerase chain reaction showed that five methylated cytosines outside the CpG dinucleotides in the 290-bp fragment from the hTERT promoter were demethylated and all the methylated cytosines in CpG dinucleotides remained intact. Furthermore, the epigenetic status of the target region following MNNG exposure was extremely similar to those of the BGC-823, SGC-7901 and MKN-28 lines; the three cell lines from human gastric adenocarcinoma. The result indicates that MNNG-induced demethylation in cytosines outside the CpG dinucleotides may be an early molecular lesion with the potential for impacting malignant transformation and a possible underlying carcinogenic mechanism of MNNG. Thus, it may provide another insight into the mechanisms of MNNG carcinogenesis. PMID- 25798245 TI - Mechanism underlying renal failure caused by pathogenic Candida albicans infection. AB - Candida albicans (C. albicans) is an opportunistic fungal pathogen that commonly causes nosocomial infections. Systemic candidiasis is encountered with increasing frequency in immunocompromised hosts, leading to renal failure that results in severe morbidity and mortality. The present study investigated the mechanisms underlying kidney susceptibility following infection with several C. albicans strains, such as B311 and SC5314. Fungal growth of the highly virulent SC5314 strain was 103-fold higher compared to the nonpathogenic B311 strain in the kidneys. An intravenous challenge of SC5314 in mice, elevated blood urea nitrogen (BUN) and creatine levels, which resulted in mortality at 8 or 35 days after infection in a dose- and time-dependent manner, whereas all the B311-infected mice had BUN and creatinine levels in the normal range and survived. Whether virulent C. albicans may escape clearance by activating signaling pathways that lead to the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, was investigated. B311 infections significantly elevated TNF-alpha and IL-1beta mRNA expression in the kidneys, whereas the expression in SC5314-infected mice remained unchanged. Furthermore, B311 infection significantly elevated the plasma levels of TNF-alpha and IL 1beta. These results indicated that the less virulent strains of C. albicans induced pro-inflammatory cytokines in mice. These results determined that an impairment of the protective mechanisms occurred in the kidneys with virulent C. albicans infection. PMID- 25798246 TI - Vitamin D-binding protein gene polymorphisms and chronic obstructive pulmonary disease susceptibility: A meta-analysis. AB - The vitamin D-binding protein (VDBP) genetic polymorphisms have been associated with chronic obstructive pulmonary disease (COPD). A number of studies have been conducted to investigate the combined effects of the VDBP gene (GC) rs7041 and rs4588 polymorphisms on the COPD risk. However, the results obtained are inconclusive. The present meta-analysis aimed to investigate whether GC polymorphisms may be a potential risk factor for COPD. The Web of Science, PubMed, Google Scholar, Embase, Cochrane Library, China National Knowledge Infrastructure and Wanfang Database were searched from inception until June 1, 2014. The meta-analysis was performed using the STATA 12.0 software. Twelve case control studies, including 2,937 subjects, met the inclusion criteria. Overall, a significantly increased risk was detected in populations of GC*1F homozygotes, whereas no associations between other GC polymorphisms and COPD risk were detected. According to ethnicity, the results demonstrated that the GC*1F homozygotes may be a risk factor for COPD and the GC*2 homozygotes may be a protective factor against COPD in the Asian population. However, similar associations were not observed among the Caucasian population. In conclusion, the current meta-analysis indicates that the GC*1F homozygotes may be a risk factor for COPD and the GC*2 homozygotes may be a protective factors against COPD in the Asian population. PMID- 25798247 TI - p38 mitogen-activated protein kinase/activator protein-1 involved in serum deprivation-induced human alkaline ceramidase 2 upregulation. AB - Our previous study revealed that serum deprivation upregulated human alkaline ceramidase 2 (haCER2) activity and mRNA in HeLa cells, but the mechanism remains unknown. In the present study, serum deprivation also upregulated haCER2 activity in HepG2 human hepatoma cell line cells due to an increase in haCER2 mRNA, in which mRNA transcription, not mRNA stability, is involved. Furthermore, p38 mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathway is involved in haCER2 mRNA upregulation by serum deprivation, and this mechanism may explain why haCER2 is upregulated in human liver cancer. In conclusion, p38 MAPK, AP-1 or haCER2 may be used as targets in liver cancer therapy. PMID- 25798248 TI - Comparison of the post-mortem interval on the effect of vascular responses to the activation of ionotropic and metabotropic receptors. AB - The contractibility of blood vessels depends on their normal structure and the availability of calcium ions; it changes under the influence of numerous contracting and relaxing factors, which control the activities of various pathways of intracellular and intercellular signaling. The main aim of the study was to investigate, by means of perfusion pressure in rat tail arteries, the role of Ca2+ in vascular response to alpha-1 adrenoceptor activation by phenylephrine (PHE) and Bay K8644 agonist of the L-type calcium channel and caffeine before and after a post-mortem interval (PMI) of 2, 4, 6 and 8 h. A phasic increase of perfusion pressure in rat tail arteries, as induced by PHE or caffeine, in Ca2+ free solutions was used as an indicator of intracellular Ca2+ release through the inositol 1,4,5-triphosphate and ryanodine receptor pathways, respectively. In Ca2+-free-ethylene glycol tetraacetic acid (EGTA)-poly(sodium styrenesulfonate) (PSS) and in Ca2+-EGTA-PSS, the PHE induced elevation of perfusion pressure significantly decreased. Vascular responses to caffeine (20 mmol/1) in Ca2+-free EGTA-PSS, with an increase of PMI from 2-8 h, did not change significantly. A similar effect was observed with vascular responses to KCl 40 mmol/1 in Ca2+-EGTA PSS. To confirm whether the inhibitory effect of 2, 4, 6 and 8 h PMI was mediated through the formation of NO, nitro-L-arginine (L-NNA), a potent NO synthase inhibitor, was used. Exposure to L-NNA (10-5 M) blocked the inhibition induced by an increase of PMI. The blocked effects of L-NNA were reversed by L-arginine (10 4 M). In conclusion, these patterns of change in artery responses provide insight into the post-mortem change in the receptor-mediated signaling components in epithelial and smooth muscle cells, and support the further study of post-mortem vascular responses triggered by G protein-coupled receptors (metabotropic) and channel-linked receptors (ionotropic) as potential markers for estimating short and long-term PMIs, respectively. PMID- 25798249 TI - Interaction between neural stem cells and bone marrow derived-mesenchymal stem cells during differentiation. AB - Due to their capacity to self-replicate or produce specific differentiated cell types, neural stem cells (NSCs) and bone marrow derived-mesenchymal stem cells (BMSCs) are potential sources for cell transplantation therapies, particularly for neural injury. However, the interaction between NSCs and BMSCs during differentiation has not yet been defined. The interaction is believed to improve the effectiveness and efficiency of cell therapy. In the present study, human NSCs and BMSCs were cultured and the Transwell co-culture system was used to observe the interplay between NSCs and BMSCs during differentiation. The results revealed that NSCs promoted BMSCs to differentiate into neurons and NSCs; whereas, BMSCs did not affect the differentiation of NSCs. Simultaneously, co culture increased the concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are secreted by NSCs and BMSCs. The present findings suggest that co-culture of NSCs and BMSCs can promote the differentiation and this process may be modulated by BDNF and NGF. PMID- 25798250 TI - Effects of estrogen on glutathione and catalase levels in human erythrocyte during menstrual cycle. AB - The present study evaluated the effects of physiological serum estrogen during the menstrual cycle on glutathione (GSH) and catalase activities. The sample included 43 healthy females between the ages of 22 and 51 years. The subjects were divided into two groups according to the stage of the menstrual cycle. Group A consisted of 16 samples extracted between days 10 and 20 from the first day of menstruation when estrogen levels were considered to be at their highest. Group B consisted of 27 samples extracted during other times of the estimated 30 days of menstruation. Data showed that the estrogen level in group A (184+/-106 pg/ml) was higher than that in group B (105+/-56 pg/ml) (P<0.01). The GSH and catalase levels in group A (4.4+/-2.3 ug/mg and 210+/-72 IU/mg, respectively) were also significantly higher compared to the levels in group B (3.2+/-1.8 ug/mg and 168+/ 62 IU/mg, respectively) (P <0.05). Spearman's rank correlation showed that the expression of catalase in red blood cells significantly correlated with serum estrogen level but not with GSH. However, the changes in estrogen plasma levels, erythrocyte GSH level and catalase activity suggested that the consumption of GSH and catalase in erythrocyte during the menstrual cycle may be associated with the level of estrogen present in the bloodstream. PMID- 25798251 TI - Association between adefovir dipivoxil treatment and the risk of renal insufficiency in patients with chronic hepatitis B: A meta-analysis. AB - Adefovir dipivoxil (ADV) is an effective antiviral drug against hepatitis B virus. The renal tolerance of ADV at the currently approved dose of 10 mg daily for the treatment of chronic hepatitis B (CHB) remains controversial. The present meta-analysis was therefore performed to evaluate the renal safety of ADV treatment in patients with CHB. Two independent investigators searched MEDLINE, Embase and China National Knowledge Infrastructure databases for eligible studies published in English or Chinese until June 1, 2014. The Peto odds ratios (Peto ORs) or the rates of each study were analyzed. Seven randomized controlled trials (RCTs), four cohort studies and six single-arm studies were identified. ADV treatment was not associated with a higher incidence of nephrotoxicity in RCTs [Peto OR, 1.781; 95% confidence interval (CI), 0.637-4.979; P=0.271] but appeared to increase nephrotoxicity significantly in cohort studies (Peto OR, 2.682; 95% CI, 1.470-4.894; P=0.001); the significant increase was further observed in CHB patients receiving long-term ADV treatment in cohort studies (Peto OR, 2.275; 95% CI, 1.127-4.593; P=0.022). The analysis based on single-arm studies showed that the rate of renal dysfunction in the ADV-treated patients was 10.6% (95% CI, 0.059-0.185); the subgroup analysis with the standard of createnine levels showed a lower rate (6.9%, 95% CI, 0.013-0.298) than those in the overall studies. In conclusion, although current evidence indicated a positive link between treatment with ADV in CHB patients and an increased risk of renal dysfunction, optimally designed studies are required for definitive conclusions. PMID- 25798252 TI - Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer. AB - Risk-reducing surgery (RRS) is defined as a prophylactic approach with removal of organs at high risk of developing cancer, which is performed in cases without lesions or absence of clinically significant lesions. Hereditary gynecological cancers for which RRS is performed include hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. For HBOC, RRS in the United States (US) is recommended for women with mutations in the breast cancer susceptibility (BRCA)1 and BRCA2 genes and bilateral salpingo-oophorectomy (BSO) is generally performed. This procedure may reduce the risk of breast, ovarian, Fallopian tube and primary peritoneal cancer, although ovarian deficiency symptoms occur postoperatively. For Lynch syndrome, RRS in the US is considered for postmenopausal women or for women who do not desire to bear children and BSO and hysterectomy are usually performed. This approach may reduce the risk of endometrial and ovarian cancer, although ovarian deficiency symptoms also occur. For RRS, there are several issues that must be addressed to reduce the risk of cancer development in patients with HBOC or Lynch syndrome. To the best of our knowledge, this is the first review to discuss RRS with a focus on hereditary gynecological cancer. PMID- 25798253 TI - Advances in the application of nanotechnology in the diagnosis and treatment of gastrointestinal tumors. AB - Nanotechnology has broad application prospects in the diagnosis and treatment of cancer. Integrating chemistry, engineering, biology and medicine, nanotechnology is a multidisciplinary research field. Nanoscale imaging technology significantly improves the precision and accuracy of tumor diagnosis. Nanocarriers are able to significantly improve the accuracy of dose and targeted drug delivery and reduce the toxic side effects. This review focuses on the emerging roles of these innovative technologies in gastrointestinal cancer diagnostics and therapeutics. Although several problems and barriers are hampering the development of nanodevices, the potential for nanotechnologies to function as multimodal nanotheranostic agents will likely pave the way for the fight against gastrointestinal cancer. PMID- 25798254 TI - A phase II clinical trial of palonosetron for the management of delayed vomiting in gynecological cancer patients receiving paclitaxel/carboplatin therapy. AB - There are currently no studies demonstrating the effects of palonosetron on delayed chemotherapy-induced nausea and vomiting (CINV) in gynecological cancer patients receiving chemotherapy with moderately emetogenic chemotherapeutic agents. We conducted a phase II clinical trial to assess the efficacy and safety of palonosetron in patients receiving paclitaxel/carboplatin (TC) therapy. The study population consisted of 42 patients who had been diagnosed with gynecological malignancies and treated with TC. On day 1, 0.75 mg/body palonosetron and 19.8 mg/body dexamethasone were administered intravenously immediately prior to TC therapy. Dexamethasone in daily doses of 6.6 mg/body was also administered intravenously on days 2 and 3. The efficacy and safety of palonosetron + dexamethasone were evaluated by the self-completion method using the Multinational Association of Supportive Care in Cancer Antiemesis Tool during an observation period lasting from day 1 through day 8 of the initial cycle of TC therapy. The severity of the nausea was assessed using a visual analog scale. During the acute (0-24 h), delayed (24-96 h) and overall (0-96 h) periods, the complete response rates were 95.2, 90.5 and 85.7%, respectively, whereas the complete control rates were 90.5, 85.7 and 78.6%, respectively. Grade >= 2 constipation and diarrhea developed in 1 patient (2.4%) each. The palonosetron + dexamethasone regimen proved to be effective for delayed CINV in gynecological cancer patients receiving TC therapy. This combined antiemetic regimen was associated with only mild adverse reactions and may serve as supportive therapy, allowing cancer chemotherapy to be continued while maintaining an adequate quality of life. PMID- 25798255 TI - Smoking-induced changes in cancer-related factors in patients with upper tract urothelial cancer. AB - Cigarette smoking is a major risk factor for urothelial cancer (UC) development. However, the associations between smoking and changes in the pathological characteristics and molecular expression of cancer-related molecules in upper tract (UT) UC have not been fully elucidated. We investigated the associations between smoking status and cancer-related factors, including cancer cell proliferation, apoptosis, angiogenesis, lymphangiogenesis and expression of vascular endothelial growth factor-A and -C, matrix metalloproteinase (MMP)-2 and -9, cyclooxygenase (COX)-2 and urokinase-type plasminogen activator, in patients with UTUC. A total of 134 patients who underwent nephroureterectomy were retrospectively investigated. Proliferation index (PI), microvessel density and lymphatic vessel density (LVD) were measured using anti-Ki-67, anti-CD105 and anti-D2-40 antibodies in formalin-fixed specimens. The apoptotic index was evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. Other cancer-related molecules were investigated by immunohistochemistry in similar specimens. The patients were divided into three groups; non-smoker (n=54, 40.3%), former smoker (n=46, 34.3%) and current smoker (n=34, 25.4%). The PI and the apoptotic index were not found to be correlated with smoking status; however, the mean/standard deviation level of LVD in current smokers (40.9/12.9) was significantly higher (P=0.034) compared to that in patients who had never smoked (34.4/10.6). In addition, smoking status was positively correlated with the presence of intratumoral lymphatic vessels (iLV) (P=0.010) and the expression of COX-2 and MMP-9 (P=0.032). The multivariate analysis demonstrated that current smoking was independently associated with all the abovementioned smoking-related factors. However, former smoking was correlated with LVD and the presence of iLV. In the survival analysis, LVD, the presence of iLV and the expression of COX-2 and MMP-9 were identified as predictive factors for metastasis following surgery. In conclusion, lymphangiogenesis and the expression levels of COX-2 and MMP-9 were found to be associated with the smoking status of UTUC patients. Our results may provide important insights into the pathological changes precipitated by smoking in these patients. PMID- 25798256 TI - Outcome of Epstein-Barr virus-associated primary breast cancer. AB - The presence of the Epstein-Barr-virus (EBV) has been reported to be a pathogenic factor in breast cancer (BC). We previously demonstrated the aggressiveness of EBV-positive BC. The purpose of the present study was to evaluate the effect of EBV on the prognosis of BC according to the BC phenotype. A total of 117 patients with primary BC previously tested for the presence of EBV were evaluated. The presence of the virus was evaluated in breast specimens using quantitative PCR (qPCR). Disease-free survival (DFS) and overall survival (OS) were evaluated for 4 molecular subtypes, namely luminal A and B (lumA and lumB, respectively), human epidermal growth factor receptor 2 (HER2) and triple-negative (TN) subtypes and according to the EBV status. EBV positivity was observed in 32.5% of the cases. TN, HER2 and lumB tumours were more frequent among EBV-BC cases (P=0.02). The DFS rates were different between BC subtypes (P=0.002), but the differences were not statistically significant when the cases were stratified according to the EBV status (P=0.08 for EBV-negative and 0.06 for EBV-positive cases). The OS rates were similar for BC subtypes (P= 0.50) and when the cases were stratified according to the EBV status (P=0.16 and P=0.67 for EBV-positive and -negative cases, respectively). EBV was not associated with DFS or OS, in contrast to BC phenotypes, tumour size or nodal status. Therefore, EBV positivity was found to exert no effect on survival, despite its association with aggressive BC phenotypes. PMID- 25798257 TI - Accurate diagnosis of axillary lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid. AB - Axillary lymph node enlargement following sentinel lymph node biopsy (SLNB) is often difficult to accurately diagnose. In keeping with the characteristically tortuous and aberrant pattern of tumor neovasculature, metastatic lymph nodes exhibit peripheral and mixed vascularity, resulting in a microvasculature that is often difficult to visualize. Contrast-enhanced ultrasonography (CEUS) with Sonazoid, a new generation contrast agent for ultrasonography, allows for the visualization of lymph node microvessels and may enable a more accurate evaluation of lymph node metastasis. This is a case report of axillary lymph node enlargement following SLNB, in which CEUS with Sonazoid resulted in an accurate diagnosis. On the basis of our experience with this case, we have initiated a clinical trial to evaluate the detection of lymph node metastasis through the use of CEUS in breast cancer patients. PMID- 25798258 TI - Intermittent docetaxel chemotherapy is feasible for castration-resistant prostate cancer. AB - This study was conducted with the aim to investigate the feasibility of intermittent treatment with docetaxel chemotherapy for castration-resistant prostate cancer (CRPC). A total of 51 men with CRPC received docetaxel at 75 mg/m2 every 3 weeks combined with oral dexamethasone 1.0-2.0 mg/day between 2008 and 2013. The prostate-specific antigen (PSA) level was monitored every 3 weeks. Chemotherapy was suspended when the serum PSA level decreased to < 4 ng/ml, with a reduction rate of >50% from the baseline. Treatment was resumed when serum PSA increased to > 2 ng/ml, with an increase rate of >50% from the nadir. Of the 51 cases, 27 (52.9%) qualified for intermittent treatment; 17 patients received two courses of docetaxel chemotherapy and 10 received three courses. The median off treatment interval was 266 days for the first drug holiday, 129.5 days for the second and 146.5 days for the third. The multivariate analysis indicated low baseline PSA (=1 mm and a trend towards a lesser degree of fibrosis. The median follow-up in this cohort of patients was 48 months. Patients with PPAR- alpha staining had a worse overall survival (median, 36 vs. 79 months, P=0.037) compared to those with no PPAR- alpha staining. There was no correlation between PPAR- alpha or-gammapositivity and disease-free survival. In conclusion, PPAR- alpha staining is associated with lobular inflammation and worse overall survival in patients with colorectal liver metastases. The exact mechanism underlying this finding remains unclear and further research into the diagnostic and therapeutic implications is required. PMID- 25798260 TI - Differentiation between benign and malignant ovarian masses in the preoperative period using neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios. AB - The aim of this study was to evaluate the association between preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the pathological diagnosis of adnexal masses. The predictive effect of inflammatory markers on epithelial ovarian cancer was also investigated. The present study included a total of 306 patients with adnexal masses who underwent surgical resection and the diagnosis was based on pathological investigation. The patients were divided into six groups based on their pathological findings and compared with respect to their NLR and PLR values. We used receiver-operating characteristic curves to calculate optimal cut-off values for NLR and PLR to predict ovarian cancer preoperatively. Patients with ovarian cancer exhibited significantly higher NLR and PLR values (P<0.05 and P<0.001, respectively). The multivariate analysis demonstrated that higher NLR and PLR values predicted ovarian cancer at the cut-off value of 3.35, sensitivity of 55% and specificity of 81% for NLR [95% confidence interval (CI): 0.544-0.752, P<0.05] and at the cut off value of 572.9, sensitivity of 100% and specificity of 0.38% for PLR (95% CI: 0.192-0. 381, P=0.001). Therefore, preoperative NLR and PLR values may help identify ovarian cancer in patients with adnexal masses. PMID- 25798261 TI - Combination therapy with S-1 and interferon-alpha in hepatocellular carcinoma patients with lung metastasis. AB - Managing extrahepatic recurrence in hepatocellular carcinoma (HCC) patients is crucial for improving prognosis. The present study aimed to investigate the effectiveness of using combination therapy with S-1 and interferon (IFN)- alpha in HCC patients with lung metastasis. Of the 646 patients who underwent radical surgery for HCC at our institute, 62 developed their first distant metastasis in the lung. Among these patients, 11 received S-1 combination therapy, while the remaining 51 patients received other conventional therapy, such as 5-fluorouracil and cisplatin or best supportive care. We retrospectively evaluated the toxicity and efficiency of combination therapy with S-1 and IFN- alpha. Hematological toxicity was observed in 5 patients and was grade 1 or 2 in all cases, except 1 patient (9.1%) who developed grade 3 leukopenia. Non-hematological toxicity was observed in 6 patients and was grade 1 in all cases, except 1 patient who exhibited a grade 2 increase of serum bilirubin levels. No patient required discontinuation of the S-1 combination therapy and no treatment-related mortality was reported during this study. Patients who received S-1 treatment exhibited significantly better survival after distant recurrence (SADR) compared to those without S-1 treatment (3-year survival rate, 81.8 vs. 43.1%, respectively; P=0.014). The multivariate analysis revealed that the S-1 treatment was prognostically significant for SADR (P=0.0091; hazard ratio = 0.343). In conclusion, combination therapy with S-1 and IFN- alpha may be efficient for HCC patients with lung metastasis. PMID- 25798262 TI - Clinical usefulness of gefitinib for non-small-cell lung cancer with a double epidermal growth factor receptor mutation. AB - The aim of this study was to investigate whether the pattern of epidermal growth factor receptor (EGFR) gene mutations affects sensitivity to gefitinib treatment. We investigated 44 surgically resected non-small-cell lung cancer (NSCLC) specimens obtained between 2001 and 2012 at the Tokyo Medical University Hospital. The specimens were obtained from patients treated with gefitinib as 1st , 2nd-, or 3rd-line therapy for postoperative recurrent NSCLC. We detected EGFR mutations using the cycleave PCR technique. In addition, the specimens from non responders were stained with antibodies against hepatocyte growth factor receptor (HGFR; MET) and hepatocyte growth factor (HGF). We assessed the progression of non-responders over a period of 2 months. Intermediate responders were considered to be patients who responded (exhibiting at least stable disease) to gefitinib therapy for 3-11 months, while long-term responders were defined as those who responded to gefitinib therapy for >12 months. The NSCLCs were histologically classified as 43 adenocarcinomas and one large-cell neuroendocrine carcinoma. One patient had an exon 18 point mutation, 23 an exon 19 deletion, 2 an exon 20 point mutation, 16 an exon 21 point mutation and 2 patients had both exon 20 and 21 point mutations. There were 4 non-responders, including the 2 patients with exon 20 mutation, 25 intermediate responders (including 10 patients under ongoing treatment) and 15 long-term responders (2 of whom are under ongoing treatment), including the 2 patients with both exon 20 and 21 mutations. Of the specimens obtained from non-responders, 3 stained with the anti- MET antibody and 1 stained with the anti-HGF antibody. Therefore, NSCLC with exon 20 mutation may respond to gefitinib treatment in the presence of an additional EGFR mutation. PMID- 25798263 TI - Effect of liver toxicity on clinical outcome of patients with non-small-cell lung cancer treated with pemetrexed. AB - Liver toxicity (LT) is a common side effect of pemetrexed (PEM); however, the effect of LT on clinical outcome has not been investigated in patients with non small-cell lung cancer (NSCLC) treated with PEM. Between June, 2009 and June, 2012, a total of 95 chemo-naive NSCLC patients received a PEM-containing regimen in our hospital. We reviewed the medical records of those 95 patients and evaluated the incidence of LT. Furthermore, we investigated the association between LT and clinical outcome. In this analysis, LT was defined as any grade of aspartate aminotransferase or alanine aminotransferase elevation. A total of 67 patients (70.5%) developed LT, which occurred mostly during the first treatment cycle. Among these, 10 patients (10.5%) required a delay in treatment or a dose reduction from the subsequent cycle and PEM discontinuation was required in 1 patient. The response rate (RR) was 43.3 and 21.4% in patients with and in those without LT, respectively (P=0.0387). The median progression-free survival (PFS) and overall survival (OS) were 6.3 and 24.2 months in patients with LT and 2.9 and 18.3 months in patients without LT, respectively (P<0.0001 for PFS and P=0.2426 for OS). The multivariate analysis demonstrated that LT exerted a significant positive effect on PFS (hazard ratio = 0.341; P<0.0001). In conclusion, LT was frequently observed in NSCLC patients treated with PEM; however, it was generally easily manageable. The improvement in RR and PFS observed in patients with LT suggested that LT may be a useful predictor of a favorable outcome in this patient population. PMID- 25798264 TI - Association of thyroid carcinoma with pregnancy: A meta-analysis. AB - A number of scholars reported that reproductive factors play a significant role in thyroid cancer and the correlation between the two may affect the diagnosis and treatment of thyroid carcinoma during pregnancy. To determine whether pregnancy reproductive factors affect thyroid carcinoma, we conducted a meta analysis of studies that investigated the association between pregnancy factors and thyroid carcinoma. PubMed, OVID and the Cochrane Library were searched from their inception to April 1st, 2013. The searched publications mainly investigated reproductive factors and the morbidity or prognosis of female thyroid carcinoma. The studies were filtered by predetermined standards and the quality of the included studies was evaluated by the Newcastle-Ottawa scale inventory. Two researchers independently extracted information on first author, year of publication, study design (case-control or prospective cohort), compared populations, inclusion and exclusion criteria and total sample size. Other researchers assessed the studies for publication bias and performed statistical analyses. Discrepancies were resolved by consensus. A total of 21 studies were selected for the meta-analysis, including 406,329 cases in total. Compared to the control group, the risk of thyroid carcinoma in women with a history of pregnancy was not significantly discrepant, [odds ratio (OR)=1.00, 95% confidence interval (CI): 0.91-1.11]. However, the risk of thyroid carcinoma in women with a history of >= 3 pregnancies was significantly increased (OR=1.39, 95% CI: 1.21-1.59). Furthermore, an interval of <= 5 years since the last pregnancy was closely associated with thyroid carcinoma (OR=1.53, 95% CI: 1.29-1.81). The patients developed thyroid carcinoma during pregnancy did not exhibit an increased risk of lymphatic metastasis (OR=0.94, 95% CI: 0.53-1.67); the risk of distant metastasis also did not increase significantly (OR=1.03, 95% CI: 0.86-1.24). Therefore, multiple pregnancies and a <= 5-year interval between pregnancies were identified as high-risk factors for thyroid carcinoma, whereas thyroid carcinoma during pregnancy was not associated with a significant risk of lymphatic and distant metastasis. PMID- 25798265 TI - Vascular endothelial growth factor polymorphisms as effect modifiers of oral squamous cell carcinoma risk: A systematic review and meta-analysis. AB - Smoking is one of the main risk factors for the development of oral squamous cell carcinoma (OSCC). Smoking may affect single-nucleotide polymorphism (SNP) dependent vascular endothelial growth factor (VEGF)-induced angiogenic activity. Therefore, we systematically reviewed the published VEGF-SNP genotype data of OSCC patients and healthy individuals and performed a meta-analysis comparing the VEGF-SNP genotypes of smoking and non-smoking patients in association with OSCC incidence. Prospective and retrospective studies on the clinical comparison of OSCC patients with different VEGF-SNP genotypes were reviewed. The meta-analysis re-pooled studies of smoking and non-smoking OSCC patients with different VEGF SNPs between 2006 and 2014. The identified articles were reviewed and those reporting pertinent information, assignment to smoking and non-smoking patient groups and sufficient data for estimation of an odds ratio (OR) with a 95% confidence interval (CI) were selected for the meta-analysis. Pooled ORs and CIs for the comparison of SNP distribution in the smoking and non-smoking subgroups were calculated and compared using the random-effects model. A total of 7 studies were included in the systematic review, which was followed by a meta-analysis using 3 pertinent studies. The reviewed studies reported discrepant findings, with differences between Asian and European patients. The meta-analysis demonstrated marginal but not statistically significant differences, suggesting that specific VEGF-SNPs may be OSCC risk modifiers for smokers, depending on the ethnic background. The performed meta-analysis suggested an increased OSCC risk for smokers carrying specific VEGF-genotypes, although the calculated data did not reach the level of significance. However, data have to be interpreted with caution due to the limited sample size. Therefore, further studies, including larger patient samples, are mandatory. PMID- 25798266 TI - Effect of eosinophil cationic protein on human oral squamous carcinoma cell viability. AB - The exact function of eosinophils in cancer, particularly in oral squamous cell carcinoma (OSCC), has not yet been elucidated and the possible antitumor effect of these leukocytes is associated with the release of cytotoxic proteins, particularly eosinophil cationic protein (ECP). The aim of this study was to evaluate the effect of ECP on human OSCC lines and to provide novel insights into the role of eosinophils in these tumors. The viability of the SCC-4 and SCC-25 OSCC cell lines was assessed by colorimetric assay using 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT). The cells were plated into 96-well plates in Dulbecco's modified Eagle's medium/Ham's nutrient mixture F12 supplemented with 10% fetal bovine serum. After 24 h, the indicated concentration of ECP (0-10 u M) was added to each sample. The plate was read using a microplate reader at a wavelength of 570 nm. The association between variables was estimated by linear regression analysis. There was a significant inverse association between ECP concentrations with SCC-4 (beta=0.16, P=0.019) and SCC-25 cell viability (beta=0.24, P=0.006). To the best of our knowledge, the present study was the first to investigate the effects of ECP on OSCCs and to demonstrate a significant inverse association between ECP concentrations with SCC-4 and SCC-25 cell viability. PMID- 25798267 TI - Prognostic value of osteopontin expression in breast cancer: A meta-analysis. AB - Osteopontin (OPN) has been implicated in tumor development and progression over the last few years. However, the prognostic value of OPN overexpression in patients with breast cancer remains controversial. We performed a meta-analysis to investigate the association of OPN expression in the tumor with the clinicopathological characteristics and survival of breast cancer patients. A total of 8 studies met the inclusion criteria and were entered in the meta analysis. The data analysis demonstrated that OPN expression was positively associated with lymph node metastasis [pooled odds ratio = 2.026, 95% confidence interval (CI): 1.199-3.425, P=0.008, random-effects model]. We also found that OPN expression was positively associated with overall survival [hazard ratio (HR) = 3. 69, 95% CI: 1. 45-9.42, P=0.000, random-effects model) and disease -free survival (pooled HR=2.40, 95% CI: 1.27-4.55, P=0.007, fix ed -effects model). Based on the results of this study, we concluded that OPN overexpression in the tumor is a candidate positive prognostic biomarker for breast cancer patients. PMID- 25798268 TI - Patient age, tumor appearance and tumor size are risk factors for early recurrence of cervical cancer. AB - The recurrence and metastasis of cervical cancer contribute to a poor prognosis. The aim of this study was to investigate the risk factors for cervical cancer progression. A total of 284 patients with recurrent cervical cancer were retrospectively recruited to evaluate the association of disease recurrence with clinicopathological data. The univariate analysis demonstrated that patient age, tumor appearance and tumor size were significantly associated with early recurrence and metastasis of the disease (P<0.05). However, clinical stage, tumor histology, pathological stage and initial treatment options were not associated with early recurrence and metastasis of cervical cancer (P>0.05). The multivariate analysis also demonstrated that patient age, tumor appearance and tumor size were independent risk factors for the early recurrence of cervical cancer (P<0.05). Therefore, these three factors should be taken into consideration in the management of cervical cancer. PMID- 25798269 TI - Fertility following treatment of high-grade malignant bone and soft tissue tumors in young adults. AB - This study was conducted to investigate marriage and fertility in long-term survivors with high-grade bone and soft tissue tumors following chemotherapy. We reviewed issues related to fertility in 47 patients (24 men and 23 women) who had survived for >5 years. The median age at diagnosis was 18.0+/-8.9 years and the mean duration of follow-up 11.0 years. We investigated the proportions of married subjects (number of married/total number of subjects) and fertile subjects (number who had fathered or conceived offspring/total number of subjects), the interval between first delivery and last chemotherapy, type of delivery, congenital deformities in the offspring and the association between cumulative dose of chemotherapeutic agents and subsequent reproduction. The final proportions of married and fertile subjects following sarcoma treatment were 36.2% (17/47) and 29.8% (14/47), respectively. Two subjects had fathered and 8 had conceived a total of 15 offspring. The proportion of fertile men was significantly lower compared to that of women. The mean interval between the last chemotherapy and the first delivery was 9.5 years. Of the 10 first births, 6 were normal transvaginal deliveries and 4 were caesarean sections (1 was a medical termination due to lung metastases, 1 was due to infected amniotic fluid caused by uterine myomas and 2 were performed due to abnormal rotation of the fetus). No offspring presented with congenital deformities. Fertile men had received smaller cumulative chemotherapeutic agent doses, particularly of ifosfamide, compared to those who had not fathered any offspring. In conclusion, infertility occurs more frequently in men compared to women following intensive chemotherapy. All the patients should be offered counseling regarding the potential risk of infertility prior to cancer treatment. PMID- 25798270 TI - Rapid detection of nasopharyngeal cancer using Raman spectroscopy and multivariate statistical analysis. AB - Optical spectroscopic techniques, including Raman spectroscopy, have shown promise for in vivo cancer diagnostics in a variety of organs. In this study, the potential use of a home-made Raman spectral system with a millimeter order excitation laser spot size combined with a multivariate statistical analysis for the rapid detection and discrimination of nasopharyngeal cancer from normal nasopharyngeal tissue was evaluated. Raman scattering signals were acquired from 16 normal and 32 nasopharyngeal carcinoma tissue samples. Linear discriminant analysis (LDA) based on principal component analysis (PCA) and partial least squares (PLS) were employed to generate diagnostic algorithms for the classification of different nasopharyngeal tissue types. Spectral differences in Raman spectra between the two types of tissues were revealed; the normalized intensities of Raman peaks at 1,001, 1,207 and 1,658 cm-1 were more intense for nasopharyngeal carcinoma tissue compared to normal tissue, while Raman bands at 848, 936 and 1,446 cm-1 were stronger in normal nasopharyngeal samples. The PCA LDA algorithm together with leave-one-out cross validation yields a diagnostic sensitivity of 81% and a specificity of 87%, while the PLS method coupled with subwindow permutation analysis improves the diagnostic sensitivity and specificity to 85 and 88%, respectively. Therefore, Raman spectroscopy combined with PCA-LDA/PLS demonstrated good potential for improving the clinical diagnosis of nasopharyngeal cancers. PMID- 25798271 TI - Polaprezinc reduces the severity of radiation-induced mucositis in head and neck cancer patients. AB - Polaprezinc (PZ), an antiulcer drug, has been reported to have antioxidant properties. The aim of the present study was to assess the feasibility and efficacy of administering PZ for radiation-induced mucositis in head and neck cancer patients. Patients with newly diagnosed head and neck cancer were enrolled in this prospective study. PZ was prepared as an oral rinse. The PZ oral rinse was used four times per day during the course of radiotherapy. Sequential changes in radiation mucositis were assessed during and after radiotherapy according to the Common Terminology Criteria for Adverse Events, version 3.0. Furthermore, a retrospective comparison analysis was performed to assess the efficacy of PZ for radiation-induced mucositis. A total of 32 patients were enrolled in the prospective study of the PZ oral rinse. Radiotherapy was performed up to a total dose of 60-66 Gy using a conventional schedule combined with chemotherapy. Of the 32 patients, 30 (93.8%) reported no complaints due to the PZ oral rinse. In addition, PZ was not associated with severe adverse effects. Among the patients who received PZ, grade 3 mucositis was observed in 29.0% based on the mucosal findings and in 39.3% based on the symptoms. In the patients who did not receive PZ, the incidence of grade 3 mucositis was 40.0% based on the mucosal findings and 60.7% based on the symptoms. Moreover, PZ promoted the recovery from mucositis caused by chemoradiotherapy and was not associated with reduced tumor response to radiotherapy. Therefore, the PZ oral rinse was well tolerated and proved to be efficient for the treatment of radiotherapy-induced oral mucositis. PMID- 25798272 TI - High expression of pituitary tumor-transforming gene-1 predicts poor prognosis in clear cell renal cell carcinoma. AB - Pituitary tumor-transforming gene-1 (PTTG1) is a recently identified oncogene involved in the progression of malignant tumors; however, the expression level of PTTG1 in clear cell renal cell carcinoma (ccRCC) and its potential value as a novel prognostic marker for ccRCC remains unclear. In this study, PTTG1 mRNA and protein levels were assessed in 44 paired ccRCC tissues and adjacent normal tissues by quantitative polymerase chain reaction (qPCR) and immunohistochemistry, respectively. Further immunohistochemical analysis was implemented in 192 samples of ccRCC to evaluate the associations between PTTG1 levels and the clinical characteristics in ccRCC. Reverse transcription qPCR and immunohistochemical analysis demonstrated that the PTTG1 mRNA and protein levels were significantly higher in ccRCC compared to normal tissues. In addition, the PTTG1 protein level in 192 ccRCC samples was found to be significantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, whereas it was not associated with age and gender. Patients with low PTTG1 levels exhibited a better survival outcome compared to those with a higher PTTG1 level. PTTG1 expression and N stage were identified as independent prognostic factors for the overall survival of ccRCC patients. The results suggested that the overexpression of PTTG1 indicates a poor prognosis in ccRCC patients and, therefore, PTTG1 may serve as a novel prognostic marker for ccRCC. PMID- 25798273 TI - Pretreatment tumor standardized uptake value as a prognostic factor in primary head and neck squamous cell carcinoma. AB - Our objective was to conduct a systematic review and meta-analysis of studies assessing the diagnostic performance of primary tumor standardized uptake value (SUV) in head and neck squamous cell carcinoma (HNSCC), as measured by positron emission tomography. A systematic search of the indexed medical literature was conducted using appropriate keywords to identify relevant studies. Six articles were identified by searching electronic databases. A statistical analysis was performed with RevMan 4.2.2 software. SUV measurement and the SUV threshold for defining high SUV were studied dependently. For each publication, we first obtained an estimate of the relative risk (RR) for comparing patients with a low and those with a high SUV. Subsequently, we aggregated the individual RRs into a combined RR using the fixed-effects model to yield weighted mean pooled estimates with 95% confidence intervals (CIs). Publication bias was assessed with a funnel plot. A total of 6 clinical trials involving 453 patients were included in the meta-analysis. The combined RR from the 6 reports for local control was 0.72 (95% CI: 0.63-0.81). The funnel plot revealed symmetrical distribution, indicating no evidence of significant publication bias. The increase in the SUV of the primary tumor was found to be a poor prognostic marker for patients with HNSCC in the meta-analysis, which requires further confirmation in a meta-analysis based on individual patient data. PMID- 25798274 TI - Isolated metastases of hepatocellular carcinoma in the left atrium, unresponsive to treatment with sorafenib. AB - Isolated metastases in the left atrium that are discontinuous with an intrahepatic hepatocellular carcinoma (HCC) are extremely rare. This is the case report of a 46-year-old male patient with pulmonary metastases from HCC, who presented with a tumor in the left lung, extending to the left atrium through the left pulmonary vein. Two weeks after the initiation of treatment with sorafenib, the tumor metastasized to the left parietal cerebral lobe, with an intracranial hemorrhage. Although the patient underwent gamma knife radiosurgery for the metastatic brain tumor, his condition gradually deteriorated and he succumbed to multiple organ failure 4 months later. Given the severe complications that have been reported in patients with this type of metastasis, immediate multidisciplinary treatment, including surgical resection, should be considered. PMID- 25798275 TI - Targeted treatment with pazopanib in metastatic soft tissue sarcoma: Nearly complete response in two cases. AB - Soft tissue sarcomas (STS) are a group of rare mesenchymal cancers that include approximately 50 histological types and account for 1% of all adult cancers. The standard curative treatment option for localized disease is surgical resection and, if a surgically removed tumor exhibits high-risk characteristics, adjuvant chemotherapy and radiotherapy may be administered. Sarcoma presenting at an advanced stage has a dismal prognosis and survival has not markedly improved over the last 20 years. The standard first-line treatment for advanced STS, other than gastrointestinal stromal tumors, is cytotoxic chemotherapy. Therapies targeting pro-angiogenic factors have been a focus of drug development for STS over the last few years. Pazopanib, a multitargeted tyrosine kinase inhibitor, is a novel treatment option for patients with metastatic STS in the second-line setting. This is a presentation of 2 case reports of patients with metastatic STS who responded well to treatment with pazopanib. PMID- 25798276 TI - Epidermal growth factor receptor-tyrosine kinase inhibitors for non-small-cell lung cancer patients aged 80 years or older: A retrospective analysis. AB - The efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) in elderly patients with non-small-cell lung cancer (NSCLC) remains uncertain. This retrospective study aimed to evaluate the efficacy and feasibility of EGFR-TKIs for NSCLC patients aged >= 80 years. We analyzed data from 21 NSCLC patients aged >= 80 years who were administered gefitinib and/or erlotinib between January, 2009 and December, 2014. The clinical characteristics, smoking status, type of EFGR mutation and the efficacy and toxicity of EGFR-TKIs were evaluated in these patients. In total, 14 (66.7%), 5 (23.8%) and 2 patients (9.5%) displayed partial response, stable disease and progressive disease, respectively. The median progression-free survival was 182 days, whereas the median overall survival was 371 days. Adverse events >= grade 2 were as follows: skin toxicities, 12 patients; liver function test abnormalities, 7 patients; anorexia, 3 patients; and diarrhea, 2 patients. Dose reduction of EGFR-TKIs due to adverse events was required in 15 patients (71.4%). Although gefitinib and erlotinib therapy may be beneficial in patients aged >= 80 years, EGFR-TKI dose modification may be necessary according to the overall medical condition of elderly patients. Further studies are required to evaluate our findings. PMID- 25798277 TI - Characterization of regulatory sequences in alternative promoters of hypermethylated genes associated with tumor resistance to cisplatin. AB - The development of cisplatin resistance in human cancers is controlled by multiple genes and leads to therapeutic failure. Hypermethylation of specific gene promoters is a key event in clinical resistance to cisplatin. Although the usage of multiple promoters is frequent in the transcription of human genes, the role of alternative promoters and their regulatory sequences have not yet been investigated in cisplatin resistance genes. In a new approach, we hypothesized that human cancers exploit the specific transcription factor-binding sites (TFBS) and CpG islands (CGIs) located in the alternative promoters of certain genes to acquire platinum drug resistance. To provide a useful resource of regulatory elements associated with cisplatin resistance, we investigated the TFBS and CGIs in 48 alternative promoters of 14 hypermethylated cisplatin resistance genes previously reported. CGIs prone to methylation were identified in 28 alternative promoters of 11 hypermethylated genes. The majority of alternative promoters harboring CGIs (93%) were clustered in one phylogenetic subclass, whereas the ones lacking CGIs were distributed in two unrelated subclasses. Regulatory sequences, initiator and TATA-532 prevailed over TATA-8 and were found in all the promoters. B recognition element (BRE) sequences were present only in alternative promoters harboring CGIs, but CCAAT and TAACC were found in both types of alternative promoters, whereas downstream promoter element sequences were significantly less frequent. Therefore, it was hypothesized that BRE and CGI sequences co-localized in alternative promoters of cisplatin resistance genes may be used to design molecular markers for drug resistance. A more extensive knowledge of alternative promoters and their regulatory elements in clinical resistance to cisplatin is likely to usher novel avenues for sensitizing human cancers to treatment. PMID- 25798278 TI - Response to bevacizumab combination chemotherapy of malignant pleural effusions associated with non-squamous non-small-cell lung cancer. AB - Malignant pleural effusion (MPE) is a common complication of lung cancer with devastating consequences. Since vascular endothelial growth factor (VEGF) has been implicated in MPE, we hypothesized that bevacizumab, an anti-VEGF antibody, may be effective against MPE in patients with non-small-cell lung cancer (NSCLC). We analysed the records of 21 patients treated for NSCLC-associated MPE between February, 2010 and August, 2013 who consequently underwent bevacizumab combination chemotherapy at the Institute of Biomedical Research and Innovation Hospital. The results were retrospectively analysed using case records and radiographic imaging records. Three patients exhibited complete response of the pleural effusion to bevacizumab treatment, 8 patients achieved a partial response (PR) and 6 patients showed no response. When efficacy was assessed by the response of the measurable primary or metastatic lesions to the treatment, 5 patients achieved a PR, 13 patients had stable disease and 3 patients exhibited progressive disease. The response rate (RR) of the pleural effusion to the antibody treatment was 71.4% and the overall RR of measurable lesions was 23.8%. The median time-to-response for pleural effusion was 132 days. In conclusion, this study demonstrated a high R R to bevacizumab combination therapy for the MPE associated with non-squamous NSCLC. Therefore, bevacizumab therapy may be considered a therapeutic option for patients with non-squamous NSCLC who develop MPE. PMID- 25798279 TI - Benefit from ifosfamide treatment in small-cell lung cancer: A meta-analysis. AB - This study was conducted to compare the efficacy and safety of ifosfamide plus etoposide plus platinum (IEP) to that of etoposide plus platinum (EP) in patients with previously untreated small-cell lung cancer (SCLC). The Cochrane Library, Embase, MEDLINE and Chinese Biomedical Literature databases were searched to identify all randomized controlled trials comparing IEP to EP in patients with histologically proven SCLC. Two investigators independently assessed the quality of the relevant trials and extracted data. We analyzed the data using Review Manager software, version 4.2.8. A total of 4 trials with 447 previously untreated SCLC patients were included in this meta-analysis. The results of the meta-analysis indicated that there were no significant differences in the overall response [relative risk (RR) = 1.07, 95% confidence interval (CI): 0.97-1.19], 1 year survival rate (RR=1.22, 95% CI: 0.96-1.55) and 2-year survival rate (RR=1.52, 95% CI: 0.75-3.07) between the IEP and EP regimens. However, there were significant differences between the IEP and EP regimens regarding the incidence of grade 3/4 neutropenia (RR=1.52, 95% CI: 1.07-2.17) and grade 3/4 vomiting (RR=1.78, 95% CI: 1.02-3.11). In conclusion, our results suggested that IEP is not superior to EP regimen for the treatment of previously untreated SCLC, whereas the IEP regimen is associated with more severe hematological and gastrointestinal toxicities compared to EP. Therefore, the use of ifosfamide in multimodality treatment regimens requires further investigation. PMID- 25798280 TI - Human leukocyte antigen-DRB1 polymorphism in childhood acute lymphoblastic leukemia. AB - Similar to autoimmune diseases, there are clear associations between resistance or susceptibility to cancer and the classic human leukocyte antigen (HLA) profile of an individual. HLA-associated susceptibility to childhood acute lymphoblastic leukemia (ALL) may provide clues to leukemogenesis in general and to the role of other risk factors. The present study aimed to determine the association between the HLA-DRB1 genotype and susceptibility to ALL in children and to assess the prognostic value of HLA-DRB1 alleles in these patients. This study included 50 ALL patients who were consecutively admitted to the Pediatric Oncology Unit of Zagazig University Hospital and 50 gender-matched healthy volunteers as a control group. The patients were subjected to full clinical history, thorough clinical examination and routine laboratory investigations. Molecular HLA-DRB1 typing for patients and controls using the reverse sequence-specific oligonucleotide probe technique was performed. HLA-DRB1*04 allele frequency was significantly higher in female patients compared to that in female controls (P=0.03) and in patients aged <10 years compared to those aged >=10 years at the time of diagnosis (P=0.01). HLA-DRB1*11 allele frequency was significantly higher in high-risk compared to standard-risk patients (P=0.01) and in refractory patients compared to those who achieved remission (P=0.02). In conclusion, the HLA-DRB1*04 allele appears to be a female-specific susceptibility factor for the acquisition of childhood ALL and it may affect the age of onset of ALL. In addition, the HLA-DRB1*11 allele may be of prognostic significance in childhood ALL. However, further larger studies are required to support the conclusions drawn from this study. PMID- 25798281 TI - Predictors of long-term survival following postoperative radiochemotherapy for pathologically confirmed suprasellar germ cell tumors. AB - The aim of this study was to evaluate the predictors of long-term survival following postoperative therapy for suprasellar germ cell tumors (GCTs). A total of 23 patients with pathologically confirmed suprasellar GCTs were reviewed between April, 1987 and October, 2008. The predictors were identified with a univariate Cox proportional hazards model and the results were used to group patients according to outcome. The overall survival (OS) and progression-free survival (PFS) rates for the good- and poor-prognosis two groups were estimated with Kaplan-Meier analysis, with log-rank tests used to assess differences between the groups. The OS rate for all patients was 82.6% at 5 and 72.9% at 10 years. Lesion size (2-4 vs. >4 cm) and pathological type (pure germinoma vs. mixed GCT) were the only significant predictors of OS (P<0.05). The OS rate for the good-prognosis group was 92.9% at both 5 and 10 years, whereas the corresponding rates for the poor-prognosis group were 66.7 and 40.0%, respectively (P=0.020). The PFS rate for the good-prognosis group was 92.9% at 5 and 85.7% at 10 years, whereas the corresponding PFS rates for the poor-prognosis group were 44.4 and 33.3%, respectively (P=0.007). Lesion size and histology predicted outcome following postoperative therapy for suprasellar GCT. Therefore, pathological diagnosis is recommended whenever possible, as histology may dictate the choice of treatment. PMID- 25798282 TI - Clinical significance of zinc-finger E-box binding homeobox 1 mRNA levels in peritoneal washing for gastric cancer. AB - Zinc-finger E-box binding homeobox 1 (ZEB1) is an important regulator of epithelial-to-mesenchymal transition and is associated with various types of metastasis. Gastric cancer patients often develop peritoneal carcinomatosis, of which the detection of free cancer cells in the peritoneal washes is an important predictor. We analyzed the correlation of ZEB1 mRNA levels in the peritoneal washing (pZEB1) with clinicopathological variables and survival in 107 gastric cancer patients who underwent surgery and peritoneal washing cytology. Reverse transcription-polymerase chain reaction was performed to quantify pZEB1. The patients were classified into the pZEB1High (n=27) and the pZEB1Low (n=80) groups based on their pZEB1 expression. pZEB1 was statistically correlated with pathological T stage (P=0.03) and vascular involvement (P=0.03). At 5 years, the disease-specific survival was 36.4% for the pZEB1High group and 64.7% for the pZEB1Low group (P=0.02), whereas the disease-free survival rate was 46.9% for the pZEB1High group and 83.0% for the pZEB1Low group (P=0.03). When subclassified into 4 categories based on washing cytology and pZEB1, survival was significantly lower in the pZEB1High compared to the pZEB1Low group (cytology -negative group, P=0.01; cytology -positive group, P=0.13). Therefore, pZEB1 may add valuable information to conventional peritoneal washing cytology as a prognostic determinant in gastric cancer. PMID- 25798283 TI - Advantages of CyberKnife for inoperable stage I peripheral non-small-cell lung cancer compared to three-dimensional conformal radiotherapy. AB - This study was conducted to compare the clinical curative effect and acute radiation lung reactions between CyberKnife (CK) and three-dimensional conformal radiotherapy (3DCRT) treatment for inoperable stage I peripheral non-small-cell lung cancer (NSCLC). We retrospectively analyzed 68 patients with inoperable stage I peripheral NSCLC between 2012 and 2013 in our institution. The CK patients were treated with 42-60 Gy in three fractions, while the 3DCRT patients were treated with a total of 60 Gy, at 2 Gy per fraction. The patients were followed up and the clinical outcome was evaluated according to the Response Evaluation Criteria in Solid Tumours. We assessed the presence of acute radiation pneumonitis and pulmonary function status by thoracic scan and pulmonary function tests following CK and 3DCRT treatment. The binary univariate logistic regression analysis demonstrated that treatment method and forced expiratory volume in 1 sec/forced vital capacity (FEV1/FVC) prior to treatment (pre-FEV1/FVC) were the main factors affecting the risk of radiation pneumonitis. The analysis of these factors through multivariate logistic regression method demonstrated that treatment method for grade 1 and 2 [odds ratio (OR)= 7.866 and 11.334, respectively) and pre-FEV1/FVC for grade 1, 2 and 3 (OR = 5.062, 11.498 and 15.042, respectively) were significant factors affecting the risk of radiation pneumonitis (P<0.05). The 68 patients were divided into two subgroups using the threshold of pre-FEV1/FVC selected by the receiver operating characteristic curve. There were significant differences between the 3DCRT and CK treatment in both the pre-FEV1/FVC <68% and >=68% subgroups for radiation pneumonitis (P=0.023 and 0.002, respectively). There was no statistically significant change in FVC, FEV1 and carbon monoxide diffusion capacity (DCLO) in the CK group, whereas there was a decrease in DCLO in the 3DCRT group. The complete remission rate was 40 vs. 34.2% at 1 year in the CK and 3DCRT groups, respectively. In conclusion, in this cohort of patients with inoperable stage I peripheral NSCLC, CK appears to be a safe and superior alternative to conventionally fractionated radiotherapy. PMID- 25798284 TI - Evaluation of the efficacy of maintenance therapy for low-to-intermediate-risk acute promyelocytic leukemia in molecular remission: A retrospective single institution study. AB - The prognosis of acute promyelocytic leukemia (APL) has become the most favorable among all acute myeloid leukemias, due to the efficacy of treatment with all trans retinoic acid (ATRA). ATRA combined with anthracycline-based chemotherapy has significantly improved the long-term outcome for low-to-intermediate-risk APL patients; thus, the efficacy of maintenance therapy for patients achieving molecular complete remission (MCR) following consolidation therapy has become debatable. To evaluate the efficacy of maintenance therapy, we conducted a retrospective analysis of 11 consecutive patients with low-to-intermediate-risk APL who received induction and consolidation therapy with ATRA and anthracyclines according to the PETHEMA LPA protocols at our hospital between January, 2001 and March, 2013. All the patients achieved MCR following consolidation therapy. Of these patients, 7 were followed without maintenance therapy, including 2 patients who discontinued maintenance therapy within 2 months. With a median follow-up of 85 months, the overall survival for all the patients was 100%, while the disease free survival estimate at 5 years with and without maintenance therapy was 100 and 85.7%, respectively; the difference was not statistically significant (P=0.45). Two patients treated with maintenance therapy later developed secondary primary malignancy. Thus, even without maintenance therapy, ATRA combined with anthracyclines exhibited significant efficacy in low-to-intermediate-risk APL patients, suggesting that maintenance therapy, which is associated with adverse events, may be dispensable for patients achieving MCR following adequate consolidation therapy. PMID- 25798285 TI - Interstitial pneumonitis related to rituximab therapy for Waldenstrom's macroglobulinemia. AB - Rituximab-combined therapeutic regimens have been recommended for treatment of Waldenstrom's Macroglobulinemia (WM). We report one WM patient who developed interstitial pneumonitis after rituximab therapy. PMID- 25798287 TI - Establishing advanced practice for medical imaging in New Zealand. PMID- 25798286 TI - Analysis and prediction of defects in UV photo-initiated polymer microarrays. AB - Polymer microarrays are a key enabling technology for the discovery of novel materials. This technology can be further enhanced by expanding the combinatorial space represented on an array. However, not all materials are compatible with the microarray format and materials must be screened to assess their suitability with the microarray manufacturing methodology prior to their inclusion in a materials discovery investigation. In this study a library of materials expressed on the microarray format are assessed by light microscopy, atomic force microscopy and time-of-flight secondary ion mass spectrometry to identify compositions with defects that cause a polymer spot to exhibit surface properties significantly different from a smooth, round, chemically homogeneous 'normal' spot. It was demonstrated that the presence of these defects could be predicted in 85% of cases using a partial least square regression model based upon molecular descriptors of the monomer components of the polymeric materials. This may allow for potentially defective materials to be identified prior to their formation. Analysis of the PLS regression model highlighted some chemical properties that influenced the formation of defects, and in particular suggested that mixing a methacrylate and an acrylate monomer and/or mixing monomers with long and linear or short and bulky pendant groups will prevent the formation of defects. These results are of interest for the formation of polymer microarrays and may also inform the formulation of printed polymer materials generally. PMID- 25798288 TI - Performance evaluation and modeling of a submerged membrane bioreactor treating combined municipal and industrial wastewater using radial basis function artificial neural networks. AB - Treatment process models are efficient tools to assure proper operation and better control of wastewater treatment systems. The current research was an effort to evaluate performance of a submerged membrane bioreactor (SMBR) treating combined municipal and industrial wastewater and to simulate effluent quality parameters of the SMBR using a radial basis function artificial neural network (RBFANN). The results showed that the treatment efficiencies increase and hydraulic retention time (HRT) decreases for combined wastewater compared with municipal and industrial wastewaters. The BOD, COD, [Formula: see text] and total phosphorous (TP) removal efficiencies for combined wastewater at HRT of 7 hours were 96.9%, 96%, 96.7% and 92%, respectively. As desirable criteria for treating wastewater, the TBOD/TP ratio increased, the BOD and COD concentrations decreased to 700 and 1000 mg/L, respectively and the BOD/COD ratio was about 0.5 for combined wastewater. The training procedures of the RBFANN models were successful for all predicted components. The train and test models showed an almost perfect match between the experimental and predicted values of effluent BOD, COD, [Formula: see text] and TP. The coefficient of determination (R(2)) values were higher than 0.98 and root mean squared error (RMSE) values did not exceed 7% for train and test models. PMID- 25798289 TI - Physician styles of decision-making for a complex condition: Type 2 diabetes with co-morbid mental illness. AB - RATIONALE AIMS AND OBJECTIVES: Variation in physician decisions may reflect personal styles of decision-making, as opposed to singular clinical actions and these styles may be applied differently depending on patient complexity. The objective of this study is to examine clusters of physician decision-making for type 2 diabetes, overall and in the presence of a mental health co-morbidity. METHOD: This randomized balanced factorial experiment presented video vignettes of a "patient" with diagnosed, but uncontrolled type 2 diabetes. "Patients" were systematically varied by age, sex, race and co-morbidity (depression, schizophrenia with normal or bizarre affect, eczema as control). Two hundred and fifty-six primary care physicians, balanced by gender and experience level, completed a structured interview about clinical management. RESULTS: Cluster analysis identified 3 styles of diabetes management. "Minimalists" (n=84) performed fewer exams or tests compared to "middle of the road" physicians (n=84). "Interventionists" (n=88) suggested more medications and referrals. A second cluster analysis, without control for co-morbidities, identified an additional cluster of "information seekers" (n=15) who requested more additional information and referrals. Physicians ranking schizophrenia higher than diabetes on their problem list were more likely "minimalists" and none were "interventionists" or "information seekers". CONCLUSIONS: Variations in clinical management encompass multiple clinical actions and physicians subtly shift these decision-making styles depending on patient co-morbidities. Physicians' practice styles may help explain persistent differences in patient care. Training and continuing education efforts to encourage physicians to implement evidence-based clinical practice should account for general styles of decision-making and for how physicians process complicating comorbidities. PMID- 25798292 TI - Predictor Profile to assess Recurrence Phenomenon of Suicidal Incidents among Region Based Target Population. AB - Suicidal attempts have a very significant effect on the society, and they also reflect on the efforts of the supporting health care and counseling facilities and the therapist involved. The impact of suicide is further magnified by the needs of persons who attempt suicide multiple times, requiring emergency health care and rehabilitation. Preventing such activities becomes a major task for the support providing agencies as soon as clients with such tendencies are identified. There are repetitive traits that can be observed during the therapeutic program among the high-risk group individuals, who are susceptible to this kind of activity and such traits indicate for a specific profile. The aim of the instrument is to prevent the occurrence of the repetitive suicidal attempts of the clients in Washington State, which has one of the highest suicide rates. This profile has been constructed on the various parameters recognized in the statistical analysis of the client pool in Washington State, who have been under treatment for their suicidal behavior. This predictor indicates the probability of clients who attempt suicides repetitively by matching the parameters of the profile with that of the client. Building a profile for the purpose of predicting behavior of this kind can strengthen the intervention strategies more comprehensively and reduce such incidents and health care requirements and expenses. PMID- 25798290 TI - Recent Insights into the Control of Human Papillomavirus (HPV) Genome Stability, Loss, and Degradation. AB - Most human papillomavirus (HPV) antiviral strategies have focused upon inhibiting viral DNA replication, but it is increasingly apparent that viral DNA levels can be chemically controlled by approaches that promote its instability. HPVs and other DNA viruses have a tenuous relationship with their hosts. They must replicate and hide from the DNA damage response (DDR) and innate immune systems, which serve to protect cells from foreign or "non-self" DNA, and yet they draft these same systems to support their life cycles. DNA binding antiviral agents promoting massive viral DNA instability and elimination are reviewed. Mechanistic studies of these agents have identified genetic antiviral enhancers and repressors, antiviral sensitizers, and host cell elements that protect and stabilize HPV genomes. Viral DNA degradation appears to be an important means of controlling HPV DNA levels in some cases, but the underlying mechanisms remain poorly understood. These findings may prove useful not only for understanding viral DNA persistence but also in devising future antiviral strategies. PMID- 25798293 TI - Noncontact optical sensor for bone fracture diagnostics. AB - We present the first steps of a device suitable for detection of broken and cracked bones. The approach is based on temporal tracking of back reflected secondary speckle patterns generated when illuminating the limb with a laser and while applying periodic pressure stimulation via a loud speaker. Preliminary experiments are included showing the validity of the proposed device for detection of damaged bones. PMID- 25798294 TI - Versatile optical microscopy using a reconfigurable hemispherical digital condenser. AB - We present a computer-controlled hemispherical digital condenser and demonstrate that a single device can be used to implement a variety of both well established and novel optical microscopy techniques. We verified the condenser capabilities by imaging fabricated periodic patterned structures and biological samples. PMID- 25798295 TI - Developing cross-correlation as a method for microvessel imaging using clinical intravascular optical coherence tomography systems. AB - Current clinical intravascular optical coherence tomography (IV-OCT) imaging systems have limited in-vivo flow imaging capability because of non-uniform catheter rotation and inadequate A-line scan density. Thus any flow-localisation method that seeks to identify sites of variation within the OCT image data-sets, whether that is in amplitude or phase, produces non-representative correlation (or variance) maps. In this study, both mean and the variation within a set of cross-correlation maps, for static OCT imaging was used to differentiate flow from nonflow regions. Variation was quantified by use of standard deviation. The advantage of this approach is its ability to image flow, even in the presence of motion artifacts. The ability of this technique to suppress noise and capture flow maps was demonstrated by imaging microflow in an ex-vivo porcine coronary artery model, by nailfold capillary imaging and in-vivo microvessel imaging from within the human coronary sinus. PMID- 25798291 TI - Personal genomes, quantitative dynamic omics and personalized medicine. AB - The rapid technological developments following the Human Genome Project have made possible the availability of personalized genomes. As the focus now shifts from characterizing genomes to making personalized disease associations, in combination with the availability of other omics technologies, the next big push will be not only to obtain a personalized genome, but to quantitatively follow other omics. This will include transcriptomes, proteomes, metabolomes, antibodyomes, and new emerging technologies, enabling the profiling of thousands of molecular components in individuals. Furthermore, omics profiling performed longitudinally can probe the temporal patterns associated with both molecular changes and associated physiological health and disease states. Such data necessitates the development of computational methodology to not only handle and descriptively assess such data, but also construct quantitative biological models. Here we describe the availability of personal genomes and developing omics technologies that can be brought together for personalized implementations and how these novel integrated approaches may effectively provide a precise personalized medicine that focuses on not only characterization and treatment but ultimately the prevention of disease. PMID- 25798296 TI - Atypical prefrontal cortical responses to joint/non-joint attention in children with autism spectrum disorder (ASD): A functional near-infrared spectroscopy study. AB - Autism spectrum disorder (ASD) is a neuro-developmental disorder, characterized by impairments in one's capacity for joint attention. In this study, functional near-infrared spectroscopy (fNIRS) was applied to study the differences in activation and functional connectivity in the prefrontal cortex between children with autism spectrum disorder (ASD) and typically developing (TD) children. 21 ASD and 20 TD children were recruited to perform joint and non-joint attention tasks. Compared with TD children, children with ASD showed reduced activation and atypical functional connectivity pattern in the prefrontal cortex during joint attention. The atypical development of left prefrontal cortex might play an important role in social cognition defects of children with ASD. PMID- 25798297 TI - Biometry of eyes in type 1 diabetes. AB - This is a comprehensive study of a large range of biometric and optical parameters in people with type 1 diabetes. The parameters of 74 people with type 1 diabetes and an age matched control group were assessed. Most of the people with diabetes had low levels of neuropathy, retinopathy and nephropathy. Marginal or no significant differences were found between groups for corneal shape, corneal thickness, pupil size, and pupil decentrations. Relative to the control group, the diabetes group demonstrated smaller anterior chamber depths, more curved lenses, greater lens thickness and lower lens equivalent refractive index. While the optics of diabetic eyes make them appear as older eyes than those of people of the same age without diabetes, the differences did not increase significantly with age. Age-related changes in the optics of the eyes of people with diabetes need not be accelerated if the diabetes is well controlled. PMID- 25798298 TI - Line-field parallel swept source MHz OCT for structural and functional retinal imaging. AB - We demonstrate three-dimensional structural and functional retinal imaging with line-field parallel swept source imaging (LPSI) at acquisition speeds of up to 1 MHz equivalent A-scan rate with sensitivity better than 93.5 dB at a central wavelength of 840 nm. The results demonstrate competitive sensitivity, speed, image contrast and penetration depth when compared to conventional point scanning OCT. LPSI allows high-speed retinal imaging of function and morphology with commercially available components. We further demonstrate a method that mitigates the effect of the lateral Gaussian intensity distribution across the line focus and demonstrate and discuss the feasibility of high-speed optical angiography for visualization of the retinal microcirculation. PMID- 25798299 TI - Resolution-enhancement for an orthographic-view image display in an integral imaging microscope system. AB - Due to the limitations of micro lens arrays and camera sensors, images on display devices through the integral imaging microscope systems have been suffering for a low-resolution. In this paper, a resolution-enhanced orthographic-view image display method for integral imaging microscopy is proposed and demonstrated. Iterative intermediate-view reconstructions are performed based on bilinear interpolation using neighborhood elemental image information, and a graphics processing unit parallel processing algorithm is applied for fast image processing. The proposed method is verified experimentally and the effective results are presented in this paper. PMID- 25798300 TI - Efficient construction of robust artificial neural networks for accurate determination of superficial sample optical properties. AB - In general, diffuse reflectance spectroscopy (DRS) systems work with photon diffusion models to determine the absorption coefficient MUa and reduced scattering coefficient MUs' of turbid samples. However, in some DRS measurement scenarios, such as using short source-detector separations to investigate superficial tissues with comparable MUa and MUs', photon diffusion models might be invalid or might not have analytical solutions. In this study, a systematic workflow of constructing a rapid, accurate photon transport model that is valid at short source-detector separations (SDSs) and at a wide range of sample albedo is revealed. To create such a model, we first employed a GPU (Graphic Processing Unit) based Monte Carlo model to calculate the reflectance at various sample optical property combinations and established a database at high speed. The database was then utilized to train an artificial neural network (ANN) for determining the sample absorption and reduced scattering coefficients from the reflectance measured at several SDSs without applying spectral constraints. The robustness of the produced ANN model was rigorously validated. We evaluated the performance of a successfully trained ANN using tissue simulating phantoms. We also determined the 500-1000 nm absorption and reduced scattering spectra of in vivo skin using our ANN model and found that the values agree well with those reported in several independent studies. PMID- 25798301 TI - Use of surface-enhanced Raman scattering as a prognostic indicator of acute kidney transplant rejection. AB - We report an early, noninvasive and rapid prognostic method of predicting potential acute kidney dysfunction using surface-enhanced Raman scattering (SERS). Our analysis was performed on urine samples collected prospectively from 58 kidney transplant patients using a He-Ne laser (632.8 nm) as the excitation source. All abnormal kidney function episodes (three acute rejections and two acute kidney failures that were eventually diagnosed independently by clinical biopsy) consistently exhibited unique SERS spectral features in just one day following the transplant surgery. These results suggested that SERS analysis provides an early and more specific indication to kidney function than the clinically used biomarker, serum creatinine (sCr). PMID- 25798302 TI - Characterizing low fluence thresholds for in vitro photodynamic therapy. AB - The translation of photodynamic therapy (PDT) to the clinic has mostly been limited to superficial diseases where traditional light delivery is noninvasive. To overcome this limitation, a variety of mechanisms have been suggested to noninvasively deliver light to deep tissues. This work explores the minimum amount of light required by these methods to produce a meaningful PDT effect in the in vitro setting under representative low fluence and wavelength conditions. This threshold was found to be around 192 mJ/cm(2) using the clinically approved photosensitizer aminolevulinic acid and 12 mJ/cm(2) for the more efficient, second generation photosensitizer TPPS2a. PMID- 25798304 TI - Next-generation Raman tomography instrument for non-invasive in vivo bone imaging. AB - Combining diffuse optical tomography methods with Raman spectroscopy of tissue provides the ability for in vivo measurements of chemical and molecular characteristics, which have the potential for being useful in diagnostic imaging. In this study a system for Raman tomography was developed and tested. A third generation microCT coupled system was developed to combine 10 detection fibers and 5 excitation fibers with laser line filtering and a Cytop reference signal. Phantom measurements of hydroxyapatite concentrations from 50 to 300 mg/ml had a linear response. Fiber placement and experiment design was optimized using cadaver animals with live animal measurements acquired to validate the systems capabilities. Promising results from the initial animal experiments presented here, pave the way for a study of longitudinal measurements during fracture healing and the scaling of the Raman tomography system towards human measurements. PMID- 25798303 TI - Real-time histology in liver disease using multiphoton microscopy with fluorescence lifetime imaging. AB - Conventional histology with light microscopy is essential in the diagnosis of most liver diseases. Recently, a concept of real-time histology with optical biopsy has been advocated. In this study, live mice livers (normal, with fibrosis, steatosis, hepatocellular carcinoma and ischemia-reperfusion injury) were imaged by MPM-FLIM for stain-free real-time histology. The acquired MPM-FLIM images were compared with conventional histological images. MPM-FLIM imaged subsurface cellular and subcellular histopathological hallmarks of live liver in mice models at high resolution. Additional information such as distribution of stellate cell associated autofluorescence and fluorescence lifetime changes was also gathered by MPM-FLIM simultaneously, which cannot be obtained from conventional histology. MPM-FLIM could simultaneously image and quantify the cellular morphology and microenvironment of live livers without conventional biopsy or fluorescent dyes. We anticipate that in the near future MPM-FLIM will be evaluated from bench to bedside, leading to real-time histology and dynamic monitoring of human liver diseases. PMID- 25798305 TI - Imaging of a linear diode bar for an optical cell stretcher. AB - We present a simplified approach for imaging a linear diode bar laser for application as an optical stretcher within a microfluidic geometry. We have recently shown that these linear sources can be used to measure cell mechanical properties; however, the source geometry creates imaging challenges. To minimize intensity losses and simplify implementation within microfluidic systems without the use of expensive objectives, we combine aspheric and cylindrical lenses to create a 1:1 image of the source at the stretcher focal plane and demonstrate effectiveness by measuring the deformation of human red blood cells and neutrophils. PMID- 25798306 TI - 2-D PSTD Simulation of focusing monochromatic light through a macroscopic scattering medium via optical phase conjugation. AB - By employing the pseudospectral time-domain (PSTD) simulation technique, we analyze the propagation of monochromatic light through a macroscopic scattering medium. Simulation results show that, monochromatic light can be directed through a scattering medium and focus into a narrow peak; a range of wavelengths has been simulated. Furthermore, we compare: i) focusing monochromatic light through a macroscopic scattering medium, and, ii) focusing monochromatic light through vacuum. Based upon numerical solutions of Maxwell's equations, we demonstrate: with a fully-surrounding wavefront of specific amplitude and phase, sub diffraction focusing can be achieved with monochromatic light, with or without the presence of a scattering medium. PMID- 25798307 TI - Analysis of flexible substrates for clinical translation of laser-generated shockwave therapy. AB - Bacteria biofilms in chronically infected wounds significantly increase the burden of healthcare costs and resources for patients and clinics. Because biofilms are such an effective barrier to standard antibiotic treatment, new methods of therapy need to be developed to combat these infections. Our group has demonstrated the potential of using Laser Generated Shockwaves as a potential therapy to mechanically disrupt the bacterial biofilms covering the wound. Previous studies have used rigid silica glass as the shockwave propagation medium, which is not compatible with the intended clinical application. This paper describes the exploration of five candidate flexible plastic films to replace the glass substrate. Each material measured 0.254 mm thick and was used to generate shockwaves of varying intensities. Shockwave characterization was performed using a high-speed Michelson displacement interferometer and peak stress values obtained in the flexible substrates were compared to glass using one-way nested Analysis of Variance and Tukey HSD post-hoc analysis. Results demonstrate statistically significant differences between substrate material and indicate that polycarbonate achieves the highest peak stress for a given laser fluence suggesting that it is optimal for clinical applications. PMID- 25798308 TI - Optically investigating Nd(3+)-Yb(3+) cascade sensitized upconversion nanoparticles for high resolution, rapid scanning, deep and damage-free bio imaging. AB - The rapid development of upconversion nanoparticles (UCNPs) has been facing with a great challenge: intense emission, fast scanning, and deep imaging require high power light irradiation with minimized heating effect (the intrinsic 975-nm excitation of Yb(3+)-sensitized UCNPs have overheating problem). By shifting the excitation peak from 975 nm to 795 nm, Nd(3+)-Yb(3+) cascade sensitized upconversion nanoparticles (Nd-UCNPs) with minimized heating effect were reported as the new generation UCNPs. For the first time, within two optically modeled applications in vitro and in vivo, the damage outcomes under long time high power laser excitation were solidly calculated, complementing the damage-free study of Nd-UCNPs. The higher resolution (20% improvement) and five times faster scanning microscopy were successfully performed using Nd-UCNPs under safety laser power level. The computational results showed the Nd(3+)-Yb(3+) energy transfer efficiency would not compromise the deep imaging ability, and the red (650-nm) emission is worth to be enhanced for deep tissue imaging. PMID- 25798309 TI - Reagent- and separation-free measurements of urine creatinine concentration using stamping surface enhanced Raman scattering (S-SERS). AB - We report a novel reagent- and separation-free method for urine creatinine concentration measurement using stamping surface enhanced Raman scattering (S SERS) technique with nanoporous gold disk (NPGD) plasmonic substrates, a label free, multiplexed molecular sensing and imaging technique recently developed by us. The performance of this new technology is evaluated by the detection and quantification of creatinine spiked in three different liquids: creatinine in water, mixture of creatinine and urea in water, and creatinine in artificial urine within physiologically relevant concentration ranges. Moreover, the potential application of our method is demonstrated by creatinine concentration measurements in urine samples collected from a mouse model of nephritis. The limit of detection of creatinine was 13.2 nM (0.15 ug/dl) and 0.68 mg/dl in water and urine, respectively. Our method would provide an alternative tool for rapid, cost-effective, and reliable urine analysis for non-invasive diagnosis and monitoring of renal function. PMID- 25798310 TI - Significant correlation between refractive index and activity of mitochondria: single mitochondrion study. AB - Measurements of refractive indices (RIs) of intracellular components can provide useful information on the structure and function of cells. The present study reports, for the first time, determination of the RI of an isolated mitochondrion in isotonic solution using retardation-modulated differential interference contrast microscopy. The value was 1.41 +/- 0.01, indicating that mitochondria are densely packed with molecules having high RIs. Further, the RIs of each mitochondrion were significantly correlated with the mitochondrial membrane potential, an index of mitochondrial activity. These results will provide useful information on the structures and functions of cells based on the intracellular distribution of RIs. PMID- 25798311 TI - Optimizing modulation frequency for structured illumination in a fiber-optic microendoscope to image nuclear morphometry in columnar epithelium. AB - Fiber-optic microendoscopes have shown promise to image the changes in nuclear morphometry that accompany the development of precancerous lesions in tissue with squamous epithelium such as in the oral mucosa and cervix. However, fiber-optic microendoscopy image contrast is limited by out-of-focus light generated by scattering within tissue. The scattering coefficient of tissues with columnar epithelium can be greater than that of squamous epithelium resulting in decreased image quality. To address this challenge, we present a small and portable microendoscope system capable of performing optical sectioning using structured illumination (SI) in real-time. Several optical phantoms were developed and used to quantify the sectioning capabilities of the system. Columnar epithelium from cervical tissue specimens was then imaged ex vivo, and we demonstrate that the addition of SI achieves higher image contrast, enabling visualization of nuclear morphology. PMID- 25798312 TI - Optimization of the excitation light sheet in selective plane illumination microscopy. AB - Selective plane illumination microscopy (SPIM) allows rapid 3D live fluorescence imaging on biological specimens with high 3D spatial resolution, good optical sectioning capability and minimal photobleaching and phototoxic effect. SPIM gains its advantage by confining the excitation light near the detection focal plane, and its performance is determined by the ability to create a thin, large and uniform excitation light sheet. Several methods have been developed to create such an excitation light sheet for SPIM. However, each method has its own strengths and weaknesses, and tradeoffs must be made among different aspects in SPIM imaging. In this work, we present a strategy to select the excitation light sheet among the latest SPIM techniques, and to optimize its geometry based on spatial resolution, field of view, optical sectioning capability, and the sample to be imaged. Besides the light sheets discussed in this work, the proposed strategy is also applicable to estimate the SPIM performance using other excitation light sheets. PMID- 25798314 TI - 3D multifocus astigmatism and compressed sensing (3D MACS) based superresolution reconstruction. AB - Single molecule based superresolution techniques (STORM/PALM) achieve nanometer spatial resolution by integrating the temporal information of the switching dynamics of fluorophores (emitters). When emitter density is low for each frame, they are located to the nanometer resolution. However, when the emitter density rises, causing significant overlapping, it becomes increasingly difficult to accurately locate individual emitters. This is particularly apparent in three dimensional (3D) localization because of the large effective volume of the 3D point spread function (PSF). The inability to precisely locate the emitters at a high density causes poor temporal resolution of localization-based superresolution technique and significantly limits its application in 3D live cell imaging. To address this problem, we developed a 3D high-density superresolution imaging platform that allows us to precisely locate the positions of emitters, even when they are significantly overlapped in three dimensional space. Our platform involves a multi-focus system in combination with astigmatic optics and an l 1-Homotopy optimization procedure. To reduce the intrinsic bias introduced by the discrete formulation of compressed sensing, we introduced a debiasing step followed by a 3D weighted centroid procedure, which not only increases the localization accuracy, but also increases the computation speed of image reconstruction. We implemented our algorithms on a graphic processing unit (GPU), which speeds up processing 10 times compared with central processing unit (CPU) implementation. We tested our method with both simulated data and experimental data of fluorescently labeled microtubules and were able to reconstruct a 3D microtubule image with 1000 frames (512*512) acquired within 20 seconds. PMID- 25798313 TI - In vivo two-photon imaging of mouse hippocampal neurons in dentate gyrus using a light source based on a high-peak power gain-switched laser diode. AB - In vivo two-photon microscopy is an advantageous technique for observing the mouse brain at high resolution. In this study, we developed a two-photon microscopy method that uses a 1064-nm gain-switched laser diode-based light source with average power above 4 W, pulse width of 7.5-picosecond, repetition rate of 10-MHz, and a high-sensitivity photomultiplier tube. Using this newly developed two-photon microscope for in vivo imaging, we were able to successfully image hippocampal neurons in the dentate gyrus and obtain panoramic views of CA1 pyramidal neurons and cerebral cortex, regardless of age of the mouse. Fine dendrites in hippocampal CA1 could be imaged with a high peak-signal-to background ratio that could not be achieved by titanium sapphire laser excitation. Finally, our system achieved multicolor imaging with neurons and blood vessels in the hippocampal region in vivo. These results indicate that our two-photon microscopy system is suitable for investigations of various neural functions, including the morphological changes undergone by neurons during physiological phenomena. PMID- 25798316 TI - Optimal wavelength combinations for near-infrared spectroscopic monitoring of changes in brain tissue hemoglobin and cytochrome c oxidase concentrations. AB - We analyze broadband near-infrared spectroscopic measurements obtained from newborn piglets subjected to hypoxia-ischemia and we aim to identify optimal wavelength combinations for monitoring cerebral tissue chromophores. We implement an optimization routine based on the genetic algorithm to perform a heuristic search for discrete wavelength combinations that can provide accurate concentration information when benchmarked against the gold standard of 121 wavelengths. The results indicate that it is possible to significantly reduce the number of measurement wavelengths used in conjunction with spectroscopic algorithms and still achieve a high performance in estimating changes in concentrations of oxyhemoglobin, deoxyhemoglobin, and oxidized cytochrome c oxidase. While the use of a 3-wavelength combination leads to mean recovery errors of up to 10%, these errors drop to less than 4% with 4 or 5 wavelengths and to even less than 2% with 8 wavelengths. PMID- 25798315 TI - Optical-resolution photoacoustic endomicroscopy in vivo. AB - Optical-resolution photoacoustic microscopy (OR-PAM) has become a major experimental tool of photoacoustic tomography, with unique imaging capabilities for various biological applications. However, conventional imaging systems are all table-top embodiments, which preclude their use in internal organs. In this study, by applying the OR-PAM concept to our recently developed endoscopic technique, called photoacoustic endoscopy (PAE), we created an optical-resolution photoacoustic endomicroscopy (OR-PAEM) system, which enables internal organ imaging with a much finer resolution than conventional acoustic-resolution PAE systems. OR-PAEM has potential preclinical and clinical applications using either endogenous or exogenous contrast agents. PMID- 25798317 TI - Longitudinal chromatic aberration of the human eye in the visible and near infrared from wavefront sensing, double-pass and psychophysics. AB - Longitudinal Chromatic Aberration (LCA) influences the optical quality of the eye. However, the reported LCA varies across studies, likely associated to differences in the measurement techniques. We present LCA measured in subjects using wavefront sensing, double-pass retinal images, and psychophysical methods with a custom-developed polychromatic Adaptive Optics system in a wide spectral range (450-950 nm), with control of subjects' natural aberrations. LCA measured psychophysically was significantly higher than that from reflectometric techniques (1.51 D vs 1.00 D in the 488-700 nm range). Ours results indicate that the presence of natural aberrations is not the cause for the discrepancies across techniques. PMID- 25798318 TI - Biodynamic imaging of live porcine oocytes, zygotes and blastocysts for viability assessment in assisted reproductive technologies. AB - The success of assisted reproductive technologies relies on accurate assessment of reproductive viability at successive stages of development for oocytes and embryos. The current scoring system used to select good-quality oocytes relies on morphologically observable traits and hence is indirect and subjective. Biodynamic imaging may provide an objective approach to oocyte and embryo assessment by measuring physiologically-relevant dynamics. Biodynamic imaging is a coherence-gated approach to 3D tissue imaging that uses digital holography to perform low-coherence speckle interferometry to capture dynamic light scattering from intracellular motions. The changes in intracellular activity during cumulus oocyte complex maturation, before and after in vitro fertilization, and the subsequent development of the zygote and blastocyst provide a new approach to the assessment of preimplant candidates. PMID- 25798319 TI - Detection of urinary bladder cancer cells using redox ratio and double excitation wavelengths autofluorescence. AB - The optical redox ratio as a measure of cellular metabolism is determined by an altered ratio between endogenous fluorophores NADH and flavin adenine dinucleotide (FAD). Although reported for other cancer sites, differences in optical redox ratio between cancerous and normal urothelial cells have not previously been reported. Here, we report a method for the detection of cellular metabolic states using flow cytometry based on autofluorescence, and a statistically significant increase in the redox ratio of bladder cancer cells compared to healthy controls. Urinary bladder cancer and normal healthy urothelial cell lines were cultured and redox overview was assessed using flow cytometry. Further localisation of fluorescence in the same cells was carried out using confocal microscopy. Multiple experiments show correlation between cell type and redox ratio, clearly differentiating between healthy cells and cancer cells. Based on our preliminary results, therefore, we believe that this data contributes to current understanding of bladder tissue fluorescence and can inform the design of endoscopic probes. This approach also has significant potential as a diagnostic tool for discrimination of cancer cells among shed urothelial cells in voided urine, and could lay the groundwork for an automated system for population screening for bladder cancer. PMID- 25798320 TI - Technique for real-time tissue characterization based on scanning multispectral fluorescence lifetime spectroscopy (ms-TRFS). AB - We report a novel technique for continuous acquisition, processing and display of fluorescence lifetimes enabling real-time tissue diagnosis through a single hand held or biopsy fiber-optic probe. A scanning multispectral time-resolved fluorescence spectroscopy (ms-TRFS) with self-adjustable photon detection range was developed to account for the dynamic changes of fluorescence intensity typically encountered in clinical application. A fast algorithm was implemented in the ms-TRFS software platform, providing up to 15 Hz continuous display of fluorescence lifetime values. Potential applications of this technique, including biopsy guidance, and surgical margins delineation were demonstrated in proof-of concept experiments. Current results showed accurate display of fluorescence lifetimes values and discrimination of distinct fluorescence markers and tissue types in real-time (< 100 ms per data point). PMID- 25798321 TI - Photoacoustic radar phase-filtered spatial resolution and co-registered ultrasound image enhancement for tumor detection. AB - Co-registered ultrasound (US) and frequency-domain photoacoustic radar (FD-PAR) imaging is reported for the first time in this paper. The merits of ultrasound and cross-correlation (radar) frequency-domain photoacoustic imaging are leveraged for accurate tumor detection. Commercial US imagers possess sophisticated, optimized software for rapid image acquisition that could dramatically speed-up PA imaging. The PAR image generated from the amplitude of the cross-correlation between detected and input signals was filtered by the standard deviation (SD) of the phase of the correlation signal, resulting in strong improvement of image spatial resolution, signal-to-noise ratio (SNR) and contrast. Application of phase-mediated image improvement is illustrated by imaging a cancer cell-injected mouse. A 14-15 dB SNR gain was recorded for the phase-filtered image compared to the amplitude and phase independently, while ~340 MUm spatial resolution was seen for the phase PAR image compared to ~840 MUm for the amplitude image. PMID- 25798322 TI - An aspheric intraocular telescope for age-related macular degeneration patients. AB - We have designed an intraocular telescope for the posterior chamber of the human eye of patients with age related macular degeneration. The basic design is composed of two decentered high optical power lenses ( + 66D and -66D) inducing a 3 degrees prismatic effect to project a magnified central field of view into a healthier location off the central fovea. Aspheric surfaces were used to ensure a compromise between good optical quality and high tolerance to the final axial position of both lenses after surgery. With this particular design, the telescope affords an extended range of depth of focus, high tolerance to different axial lengths of the eye and robustness against typical values of astigmatism and higher order aberrations. The final design has been manufactured in a foldable material and is compact enough to facilitate surgical implantation. This telescope is a simple but promising intraocular visual aid for AMD patients. PMID- 25798323 TI - A computational model for label-free detection of non-fluorescent biochromophores by stimulated emission. AB - We created a computational model to investigate the characteristics of label-free molecular detection by stimulated emission, which is the fundamental process of stimulated emission microscopy proposed and experimentally demonstrated by Min et al. In our model the molecule is considered to be a two-state quantum system with finite number of vibrational states. The laser excitations are modelled as zero order Gaussian beams. The field-molecule interaction is considered to be an electric dipole interaction. Based on these assumptions we constructed a Liouville-von Neumann master equation for the reduced density operator. The numerical solution of the master equation determines the expectation value of additional photons produced by stimulated emission. Based on this model algorithms are proposed to evaluate relative excitations. Linear dependence in concentration and quadratic dependence in space resolution were obtained at weak excitations. Time delay dependent relative excitation can be evaluated by taking into account only a single vibrational mode. However, to calculate the spectrum of relative excitation two entangled vibrational modes are necessary. An algorithm is proposed that overcomes the problem of computational complexity and enables to evaluate the spectrum on a high-end computer. High correlation between calculated and measured data of time delay and frequency dependent relative excitation, confirm the validity of the proposed model. PMID- 25798324 TI - Retinal nerve fiber bundle tracing and analysis in human eye by polarization sensitive OCT. AB - We present a new semi-automatic processing method for retinal nerve fiber bundle tracing based on polarization sensitive optical coherence tomography (PS-OCT) data sets. The method for tracing is based on a nerve fiber orientation map that covers the fovea and optic nerve head (ONH) regions. In order to generate the orientation map, two types of information are used: optic axis orientation based on polarization data, and complementary information obtained from nerve fiber layer (NFL) local thickness variation to reveal fiber bundle structures around the fovea. The corresponding two orientation maps are fused into a combined fiber orientation map. En face maps of NFL retardation, thickness, and unit-depth retardation (UDR, equivalent to birefringence) are transformed into "along-trace" maps by using the obtained traces of the nerve fiber bundles. The method is demonstrated in the eyes of healthy volunteers, and as an example of further analyses utilizing this method, maps illustrating the gradients of NFL retardation, thickness, and UDR are demonstrated. PMID- 25798325 TI - Label-free nonlinear optical imaging of mouse retina. AB - A nonlinear optical (NLO) microscopy system integrating stimulated Raman scattering (SRS), two-photon excited fluorescence (TPEF) and second-harmonic generation (SHG) was developed to image fresh mouse retinas. The morphological and functional details of various retinal layers were revealed by the endogenous NLO signals. Particularly, high resolution label-free imaging of retinal neurons and nerve fibers in the ganglion cell and nerve fiber layers was achieved by capturing endogenous SRS and TPEF signals. In addition, the spectral and temporal analysis of TPEF images allowed visualization of different fluorescent components in the retinal pigment epithelium (RPE). Fluorophores with short TPEF lifetime, such as A2E, can be differentiated from other long-lifetime components in the RPE. The NLO imaging method would provide important information for investigation of retinal ganglion cell degeneration and holds the potential to study the biochemical processes of visual cycle in the RPE. PMID- 25798326 TI - Spectrophotometric analysis of lithium carbonate used for bipolar disorder. AB - Lithium therapy is the gold standard of treatment for patients with Bipolar Disorder. However, despite its effectiveness, it is a potentially hazardous drug requiring regular monitoring of blood levels to ensure toxic levels are not reached. This paper describes the spectrophotometric analysis of Lithium carbonate in solution as a first step in developing a portable home monitoring device for blood lithium analysis.. Using a high-end spectrophotometer, solutions of lithium carbonate (Li2CO3) have been optically fingerprinted. Preliminary measurements indicate that the ultraviolet region shows a strong distinction between different lithium concentrations. Utilizing second derivative absorption curves, the region of 220 nm to 230 nm demonstrated the ability to differentiate between concentrations representing those found in patients. Furthermore, the method could determine to within a 1-6% accuracy whether an unknown solution of Li2CO3 is either inside or outside the high-end of the therapeutic limit. PMID- 25798327 TI - Inferring deep-brain activity from cortical activity using functional near infrared spectroscopy. AB - Functional near-infrared spectroscopy (fNIRS) is an increasingly popular technology for studying brain function because it is non-invasive, non irradiating and relatively inexpensive. Further, fNIRS potentially allows measurement of hemodynamic activity with high temporal resolution (milliseconds) and in naturalistic settings. However, in comparison with other imaging modalities, namely fMRI, fNIRS has a significant drawback: limited sensitivity to hemodynamic changes in deep-brain regions. To overcome this limitation, we developed a computational method to infer deep-brain activity using fNIRS measurements of cortical activity. Using simultaneous fNIRS and fMRI, we measured brain activity in 17 participants as they completed three cognitive tasks. A support vector regression (SVR) learning algorithm was used to predict activity in twelve deep-brain regions using information from surface fNIRS measurements. We compared these predictions against actual fMRI-measured activity using Pearson's correlation to quantify prediction performance. To provide a benchmark for comparison, we also used fMRI measurements of cortical activity to infer deep brain activity. When using fMRI-measured activity from the entire cortex, we were able to predict deep-brain activity in the fusiform cortex with an average correlation coefficient of 0.80 and in all deep-brain regions with an average correlation coefficient of 0.67. The top 15% of predictions using fNIRS signal achieved an accuracy of 0.7. To our knowledge, this study is the first to investigate the feasibility of using cortical activity to infer deep-brain activity. This new method has the potential to extend fNIRS applications in cognitive and clinical neuroscience research. PMID- 25798328 TI - Neural basis of nonanalytical reasoning expertise during clinical evaluation. AB - INTRODUCTION: Understanding clinical reasoning is essential for patient care and medical education. Dual-processing theory suggests that nonanalytic reasoning is an essential aspect of expertise; however, assessing nonanalytic reasoning is challenging because it is believed to occur on the subconscious level. This assumption makes concurrent verbal protocols less reliable assessment tools. METHODS: Functional magnetic resonance imaging was used to explore the neural basis of nonanalytic reasoning in internal medicine interns (novices) and board certified staff internists (experts) while completing United States Medical Licensing Examination and American Board of Internal Medicine multiple-choice questions. RESULTS: The results demonstrated that novices and experts share a common neural network in addition to nonoverlapping neural resources. However, experts manifested greater neural processing efficiency in regions such as the prefrontal cortex during nonanalytical reasoning. CONCLUSIONS: These findings reveal a multinetwork system that supports the dual-process mode of expert clinical reasoning during medical evaluation. PMID- 25798329 TI - Education mitigates age-related decline in N-Acetylaspartate levels. AB - BACKGROUND: Greater educational attainment is associated with better neurocognitive health in older adults and is thought to reflect a measure of cognitive reserve. In vivo neuroimaging tools have begun to identify the brain systems and networks potentially responsible for reserve. METHODS: We examined the relationship between education, a commonly used proxy for cognitive reserve, and N-acetylaspartate (NAA) in neurologically healthy older adults (N=135; mean age=66 years). Using single voxel MR spectroscopy, we predicted that higher levels of education would moderate an age-related decline in NAA in the frontal cortex. RESULTS: After controlling for the variance associated with cardiorespiratory fitness, sex, annual income, and creatine levels, there were no significant main effects of education (B=0.016, P=0.787) or age (B=-0.058, P=0.204) on NAA levels. However, consistent with our predictions, there was a significant education X age interaction such that more years of education offset an age-related decline in NAA (B=0.025, P=0.031). When examining working memory via the backwards digit span task, longer span length was associated with greater education (P<0.01) and showed a trend with greater NAA concentrations (P<0.06); however, there was no age X education interaction on digit span performance nor a significant moderated mediation effect between age, education, and NAA on digit span performance. CONCLUSIONS: Taken together, these results suggest that higher levels of education may attenuate an age-related reduction in neuronal viability in the frontal cortex. PMID- 25798330 TI - Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort. AB - INTRODUCTION: Despite the explosion in genetic association studies over the last decade, clearly identified genetic risk factors for depression remain scarce and replication studies are becoming increasingly important. G-protein-coupled receptor 50 (GPR50) has been implicated in psychiatric disorders in a small number of studies, although not consistently. METHODS: Data were obtained from 1010 elderly men and women from the prospective population-based ESPRIT study. Logistic regression and survival models were used to determine whether three common GPR50 polymorphisms were associated with depression prevalence or the incidence of depression over 12-years. The analyses were adjusted for a range of covariates such as comorbidity and cholesterol levels, to determine independent associations. RESULTS: All three variants showed some evidence of an association with late-life depression in women, although these were not consistent across outcomes, the overall effect sizes were relatively small, and most would not remain significant after correction for multiple testing. Women heterozygous for rs13440581, had a 1.6-fold increased risk of baseline depression, while the odds of depression comorbid with anxiety were increased fourfold for women homozygous for the minor allele of rs2072621. When depressed women at baseline were excluded from the analysis, however, neither variant was associated with the 12-year incidence of depression. In contrast, rs561077 was associated with a 1.8-fold increased risk of incident depression specifically. No significant associations were observed in men. DISCUSSION: Our results thus provide only weak support for the involvement of GPR50 variants in late-life depression, which appear specific to certain subgroups of depressed individuals (i.e., women and those with more severe forms of depression). PMID- 25798331 TI - Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder. AB - BACKGROUND: The immune system has been increasingly implicated in the development of mood and anxiety disorders. Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase epsilon (IKBKE) gene encodes IKKepsilon protein that is involved in innate immunity, predominantly antiviral response generation. It also bears pro-inflammatory properties that could affect psychiatric outcomes. In order to investigate the possible role of IKBKE gene in major depressive disorder (MDD) and panic disorder (PD), we conducted a case-control genetic association study concerning these disorders. METHODS: In all, 14 SNPs of IKBKE gene were genotyped in groups of 391 patients with MDD and 190 patients with PD together with respective 389 and 371 healthy control individuals. The given groups were further divided by gender for additional analyses. RESULTS: Substantial genetic associations were revealed between IKBKE SNPs and MDD (multiple testing adjusted P < 0.05) and suggestive associations in case of PD (P(adj) > 0.05). In addition, two SNPs that were only associated with PD among males, also displayed significantly different allele frequencies compared to PD females. This may indicate a specific role of these SNPs in male PD, but caution should be applied here due to the small size of the studied PD males group. CONCLUSIONS: The results of this study confirm our initial findings and indicate a possible role of IKBKE gene in mood and anxiety disorders. PMID- 25798332 TI - Association of cerebral white matter lesions with cognitive function and mood in Japanese elderly people: a population-based study. AB - BACKGROUND: To determine the relationships between regional white matter lesions (WMLs), lifestyle factors, and cognitive, motor function and mood. METHODS: A comprehensive evaluation, including brain MRI, blood tests, the Unified Parkinson's Disease Rating Scale, the Mini Mental State Examination, and the Geriatric Depression Scale, was performed for people aged 65 years or older living in Ama-cho on October 1, 2009. Participants were classified by severity of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) using the Fazekas score. RESULTS: Of 900 eligible participants, 688 (76.4%) were enrolled, including 303 men. Significant predictors of severe PVH were older age, lower low-density lipoprotein cholesterol (LDL-C) levels, elevated blood pressure (BP), cerebral infarction, and no current alcohol use. Significant predictors of severe DWMH were older age, lower 1,5-anhydroglucitol (1,5-AG) levels, elevated BP, cerebral infarction, and no current alcohol use. Higher cognitive function was associated with younger age, female sex, mild DWMH, more years of education, and higher high-density lipoprotein cholesterol levels. Depressive symptoms were associated with lower 1,5-AG levels, lower LDL-C levels, moderate to severe PVH, and no current alcohol use. CONCLUSIONS: White matter lesions in elderly people were related to hypertension and impaired glucose tolerance. The severity of WMLs was associated with cognitive function and mood. PMID- 25798333 TI - Combination of agomelatine and bupropion for treatment-resistant depression: results from a chart review study including a matched control group. AB - INTRODUCTION: Although a growing selection of antidepressants is available, a significant number of patients do not reach clinical remission, despite multiple trials. Data concerning the efficacy and safety of combination therapies with newer antidepressants are limited. METHODS: Fifteen inpatients with treatment resistant depression (TRD), defined as Beck Depression Inventory-2 (BDI-2) scores >14 despite treatment with adequate doses of >= 1 antidepressant classes for >= 6 weeks, were treated with agomelatine plus bupropion for >=6 weeks, and compared to 15 patients on antidepressant monotherapy with TRD matched on age, sex, and TRD stage based on retrospective chart review. The primary outcome was change in BDI-2 scores. Secondary outcomes included treatment response (BDI-2 score decrease by >= 50%), remission (BDI-2 score <13), routinely measured cardiometabolic parameters and adverse effects. RESULTS: After a mean of 6 +/- 1 weeks, BDI-2 scores decreased by 20.3 +/- 5.6 points in the combination group compared to 12.5 +/- 15.1 points in the monotherapy group (P = 0.073; Cohen's d = 0.7). Altogether, 73.3% in the combination group responded compared to 53.3% on monotherapy (P = 0.27). About 60.0% on combination therapy reached remission compared to 40% on monotherapy (P = 0.28), a difference equivalent to a number needed-to-treat = 4. Treatment response was independent of the degree of TRD (P = 0.27). Bupropion-agomelatine cotreatment was well tolerated and laboratory adverse effect parameters were not altered. CONCLUSION: Despite the small sample and uncontrolled study design, the good remission rate in TRD patients receiving agomelatine plus bupropion, particularly in comparison to the monotherapy group, indicates that this combination treatment should be explored further as a potentially promising strategy for patients with TRD. PMID- 25798334 TI - Regional differences of [(18)F]-FDG uptake within the brain during fatiguing muscle contractions. AB - BACKGROUND AND PURPOSE: Many studies have shown that a position task is more difficult than a force task although both are performed at a similar net muscle force. Thus, the time to task failure is consistently shown to be briefer during the position task. The contributions of the central nervous system to these two types of fatiguing contractions are not completely understood. The purpose of this pilot study was to examine differences in regional brain activity between force and position tasks using positron emission tomography (PET) with [(18)F] Fluorodeoxyglucose (FDG). METHODS: Two participants performed both a force and position task, separated by 7 days, with the elbow flexor muscles at 15% maximal voluntary contraction force. During both tasks, each participant was injected with ~ 256 (SD 11) MBq of FDG. Immediately after both tasks PET imaging was performed and images were analyzed to determine FDG uptake within regions of the brain. RESULTS: FDG uptake was greater in the occipital and temporal cortices of the brain during the position task compared to the force task. CONCLUSIONS: These findings suggest that differences in visual-spatial feedback and processing may play a role in the reduced time to failure of position tasks. Future application of these findings may lead to improved designs of rehabilitative strategies involving different types of visual feedback. PMID- 25798335 TI - PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion. AB - BACKGROUND: Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. METHODS: As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. RESULTS: Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. CONCLUSION: Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP. PMID- 25798337 TI - RORA and posttraumatic stress trajectories: main effects and interactions with childhood physical abuse history. AB - BACKGROUND: Longitudinal studies of posttraumatic stress (PTS) have documented environmental factors as predictors of trajectories of higher, versus lower, symptoms, among them experiences of childhood physical abuse. Although it is now well-accepted that genes and environments jointly shape the risk of PTS, no published studies have investigated genes, or gene-by-environment interactions (GxEs), as predictors of PTS trajectories. The purpose of this study was to fill this gap. METHODS AND MATERIALS: We examined associations between variants of the retinoid-related orphan receptor alpha (RORA) gene and trajectory membership among a sample of predominantly non-Hispanic Black urban adults (N = 473). The RORA gene was selected based on its association with posttraumatic stress disorder (PTSD) in the first PTSD genome wide association study. Additionally, we explored GxEs between RORA variants and childhood physical abuse history. RESULTS: We found that the minor allele of the RORA SNP rs893290 was a significant predictor of membership in a trajectory of consistently high PTS, relatively to a trajectory of consistently low PTS. Additionally, the GxE of rs893290 with childhood physical abuse was significant. Decomposition of the interaction showed that minor allele frequency was more strongly associated with membership in consistently high or decreasing PTS trajectories, relative to a consistently low PTS trajectory, among participants with higher levels of childhood physical abuse. CONCLUSION: The results of the study provide preliminary evidence that variation in the RORA gene is associated with membership in trajectories of higher PTS and that these associations are stronger among persons exposed to childhood physical abuse. Replication and analysis of functional data are needed to further our understanding of how RORA relates to PTS trajectories. PMID- 25798336 TI - Determinants of psychological resistance and recovery among women exposed to assaultive trauma. AB - INTRODUCTION: Women exposed to potentially traumatic events (PTEs) are at high risk for developing psychiatric disorders, including posttraumatic stress disorder (PTSD), general anxiety disorder (GAD), major depressive disorder (MDD), and substance-related disorders. However, this risk is not universal. Most women are resistant (i.e., remain asymptomatic), or recover following a brief symptomatic period. This study examined the psychological factors associated with resistant and recovered outcomes in a sample of high-risk women exposed to assault-related PTEs. METHOD: One hundred and fifty-nine women completed the Life Events Checklist and were administered the Structured Clinical Interview for DSM IV Axis I Disorders. This resulted in three groups: (1) no diagnosis (no past or current psychiatric disorder diagnosis; n = 56), (2) past diagnosis (a past psychiatric disorder diagnosis, but none currently; n = 31), and (3) current diagnosis (a current diagnosis of one or more psychiatric disorders; n = 72). Groups were compared on sociodemographics, PTE exposure, psychopathology, health related quality of life (HRQOL), and psychological resilience-related factors. RESULTS: The majority of respondents (79%) did not develop chronic PTSD following assault exposure, and the most common psychiatric outcome was MDD (30%). High endorsement of mastery and social support were associated with the no diagnosis group; and greater reports of mastery and posttraumatic growth were associated with recovery from a past psychiatric disorder. Furthermore, both resilient groups (i.e., no diagnosis and past diagnosis) scored higher on HRQOL measures compared with the current diagnosis group (P < 0.001). CONCLUSION: Psychological resilience has ramifications to health and well-being, and identifying these factors has potential to inform preventive strategies and treatment interventions for assault exposed women. PMID- 25798340 TI - SNP discovery in complex allotetraploid genomes (Gossypium spp., Malvaceae) using genotyping by sequencing. AB - PREMISE OF THE STUDY: Single-nucleotide polymorphism (SNP) marker discovery in plants with complex allotetraploid genomes is often confounded by the presence of homeologous loci (along with paralogous and orthologous loci). Here we present a strategy to filter for SNPs representing orthologous loci. METHODS AND RESULTS: Using Illumina next-generation sequencing, 54 million reads were collected from restriction enzyme-digested DNA libraries of a diversity of Gossypium taxa. Loci with one to three SNPs were discovered using the Stacks software package, yielding 25,529 new cotton SNP combinations, including those that are polymorphic at both interspecific and intraspecific levels. Frequencies of predicted dual homozygous (aa/bb) marker polymorphisms ranged from 6.7-11.6% of total shared fragments in intraspecific comparisons and from 15.0-16.4% in interspecific comparisons. CONCLUSIONS: This resource provides dual-homozygous (aa/bb) marker polymorphisms. Both in silico and experimental validation efforts demonstrated that these markers are enriched for single orthologous loci that are homozygous for alternative alleles. PMID- 25798338 TI - Integration of an EEG biomarker with a clinician's ADHD evaluation. AB - BACKGROUND: This study is the first to evaluate an assessment aid for attention deficit/hyperactivity disorder (ADHD) according to both Class-I evidence standards of American Academy of Neurology and De Novo requirements of US Food and Drug Administration. The assessment aid involves a method to integrate an electroencephalographic (EEG) biomarker, theta/beta ratio (TBR), with a clinician's ADHD evaluation. The integration method is intended as a step to help improve certainty with criterion E (i.e., whether symptoms are better explained by another condition). METHODS: To evaluate the assessment aid, investigators conducted a prospective, triple-blinded, 13-site, clinical cohort study. Comprehensive clinical evaluation data were obtained from 275 children and adolescents presenting with attentional and behavioral concerns. A qualified clinician at each site performed differential diagnosis. EEG was collected by separate teams. The reference standard was consensus diagnosis by an independent, multidisciplinary team (psychiatrist, psychologist, and neurodevelopmental pediatrician), which is well-suited to evaluate criterion E in a complex clinical population. RESULTS: Of 209 patients meeting ADHD criteria per a site clinician's judgment, 93 were separately found by the multidisciplinary team to be less likely to meet criterion E, implying possible overdiagnosis by clinicians in 34% of the total clinical sample (93/275). Of those 93, 91% were also identified by EEG, showing a relatively lower TBR (85/93). Further, the integration method was in 97% agreement with the multidisciplinary team in the resolution of a clinician's uncertain cases (35/36). TBR showed statistical power specific to supporting certainty of criterion E per the multidisciplinary team (Cohen's d, 1.53). Patients with relatively lower TBR were more likely to have other conditions that could affect criterion E certainty (10 significant results; P <= 0.05). Integration of this information with a clinician's ADHD evaluation could help improve diagnostic accuracy from 61% to 88%. CONCLUSIONS: The EEG-based assessment aid may help improve accuracy of ADHD diagnosis by supporting greater criterion E certainty. PMID- 25798341 TI - A genotyping protocol for multiple tissue types from the polyploid tree species Sequoia sempervirens (Cupressaceae). AB - PREMISE OF THE STUDY: Identifying clonal lineages in asexually reproducing plants using microsatellite markers is complicated by the possibility of nonidentical genotypes from the same clonal lineage due to somatic mutations, null alleles, and scoring errors. We developed and tested a clonal identification protocol that is robust to these issues for the asexually reproducing hexaploid tree species coast redwood (Sequoia sempervirens). METHODS: Microsatellite data from four previously published and two newly developed primers were scored using a modified protocol, and clones were identified using Bruvo genetic distances. The effectiveness of this clonal identification protocol was assessed using simulations and by genotyping a test set of paired samples of different tissue types from the same trees. RESULTS: Data from simulations showed that our protocol allowed us to accurately identify clonal lineages. Multiple test samples from the same trees were identified correctly, although certain tissue type pairs had larger genetic distances on average. DISCUSSION: The methods described in this paper will allow for the accurate identification of coast redwood clones, facilitating future studies of the reproductive ecology of this species. The techniques used in this paper can be applied to studies of other clonal organisms as well. PMID- 25798342 TI - Development of polymorphic microsatellite loci in the perennial herb Hepatica nobilis var. japonica (Ranunculaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed and characterized in the vulnerable plant Hepatica nobilis var. japonica (Ranunculaceae) to investigate its genetic diversity, population structure, and gene flow. METHODS AND RESULTS: Fourteen microsatellite markers were developed. The number of alleles per locus ranged from one to 12, and the expected heterozygosity per locus ranged from 0.043 to 0.855. Eleven markers were successfully amplified in the cultivar 'Mego' from Japan. CONCLUSIONS: These microsatellite markers can be used to investigate the genetic diversity, population structure, and gene flow of H. nobilis var. japonica. PMID- 25798343 TI - New microsatellite markers for Campanula pyramidalis (Campanulaceae) and cross amplification in closely related species. AB - PREMISE OF THE STUDY: Microsatellite markers were identified and characterized to study the genetic diversity and structure, conservation status, taxonomy, and biogeography of subspecific taxa and populations of Campanula pyramidalis (Campanulaceae). METHODS AND RESULTS: Eleven microsatellite markers were developed from genomic libraries enriched for di- and trinucleotide repeats. A total of 80 alleles were observed in the tested natural population. The number of alleles per locus, observed heterozygosity, and expected heterozygosity ranged from four to 13, 0.217 to 0.913, and 0.521 to 0.895, respectively. CONCLUSIONS: The new microsatellite markers will be useful for studying genetic diversity and structure as well as for better assessing the conservation status of subspecific taxa and populations of C. pyramidalis. Furthermore, a set of seven loci was successfully cross-amplified in C. secundiflora and C. versicolor and will be of great value for addressing unsolved taxonomic and biogeographic issues within the C. pyramidalis species complex. PMID- 25798344 TI - New microsatellite markers for Campanula scheuchzeri (Campanulaceae), with cross amplification in C. rotundifolia. AB - PREMISE OF THE STUDY: We developed new microsatellite primers for the alpine bellflower Campanula scheuchzeri. Allelic polymorphisms will be used to study differentiation along elevation gradients of C. scheuchzeri populations and in the co-occurring sister-species C. rotundifolia in the Alps. METHODS AND RESULTS: We analyzed C. scheuchzeri from three high-elevation sites and C. rotundifolia from two low-elevation sites in Switzerland. Campanula scheuchzeri was found to be tetraploid (2n = 68 = 4x), and up to 22 alleles were found per locus and population. Of the 15 polymorphic loci developed for C. scheuchzeri, 10 loci were tested, all of which amplified in C. rotundifolia, with similar amplicon length. Campanula rotundifolia individuals also showed tetraploid signals. CONCLUSIONS: We speculate that C. scheuchzeri and C. rotundifolia share a common gene pool and evolve under vicariance. This presents a testable hypothesis that will be evaluated through future work. Our developed primers might also amplify in other related Campanula taxa. PMID- 25798345 TI - Development of microsatellite markers for Carallia brachiata (Rhizophoraceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for Carallia brachiata to assess the genetic diversity and structure of this terrestrial species of the Rhizophoraceae. METHODS AND RESULTS: Based on transcriptome data for C. brachiata, 40 primer pairs were initially designed and tested, of which 18 were successfully amplified and 11 were polymorphic. For these microsatellites, one to three alleles per locus were identified. The observed and expected heterozygosities ranged from 0 to 0.727 and 0 to 0.520, respectively. In addition, all primers were successfully amplified in two congeners: C. pectinifolia and C. garciniifolia. CONCLUSIONS: The microsatellite markers described here will be useful in population genetic studies of C. brachiata and related species, suggesting that developing microsatellite markers from next generation sequencing data can be efficient for genetic studies across this genus. PMID- 25798346 TI - Eleven microsatellites in an emerging invader, Phytolacca americana (Phytolaccaceae), from its native and introduced ranges. AB - PREMISE OF THE STUDY: To facilitate population genetic analyses, microsatellite markers were developed for pokeweed (Phytolacca americana), a large, weedy, perennial herb native to eastern North America that is emerging as a significant invasive species in China. METHODS AND RESULTS: We mined 1,100,538 Illumina MiSeq reads from genomic DNA for microsatellites and identified 58 primer pairs. We screened these primers for polymorphism in two native and two invasive populations. We identified 11 loci that amplified consistently. The number of alleles per locus ranged from two to six, and observed heterozygosity ranged from 0.00 to 1.00. All loci were largely monomorphic within populations but different among populations. The primers were of very limited use in the congener P. acinosa. CONCLUSIONS: These loci will provide a valuable resource to study the population genetics and invasion history of P. americana. PMID- 25798347 TI - Minimally invasive mitral valve repair in a marfan patient with severe scoliokyphosis. AB - A 26-year-old female Marfan patient with extensive scoliokyphosis presented with severe mitral valve regurgitation. The patient was treated with minimally invasive mitral valve repair via a right lateral minithoracotomy. In this report, we discuss the operative procedure followed in this special case and the current literature. PMID- 25798348 TI - Special report: 26-year durability of a bioprosthesis implanted in a 21-year-old patient. AB - The choice of prosthetic heart valve type is largely dependent upon patient's age at implantation and on what, in his eyes, seems more pertinent: avoidance of complications associated with anticoagulation of mechanical valves or structural valve deterioration of bioprosthetic valves. Long lasting and new promising concepts such as transcatheter aortic valve implantation are promoting the use of bioprosthesis even in younger patients. However, it is up to the individual patient to decide. PMID- 25798349 TI - Visualization of thrombosis on a prosthetic pulmonary valve using electrocardiogram-gated multidetector computed tomography. AB - We report a case of prosthetic valve thrombosis in an 18-year-old man. Total surgical repair of tetralogy of Fallot was performed at 3 years of age. At the age of 18, he underwent pulmonary valve replacement because of exacerbating pulmonary trunk obstruction. After surgery, valve malfunction was suspected. We attempted to employ electrocardiogram (ECG)-gated multidetector computed tomography (MDCT). The stuck valve was clearly visualized together with a thrombus within. Thrombolytic therapy was undertaken on these findings. ECG-gated MDCT allowed us to make a definitive diagnosis of valve thrombosis as the cause of valve malfunction, which led us to avoid surgical reintervention. PMID- 25798350 TI - Left apical aneurysm in a patient with severe aortic valve stenosis. AB - We report on a very rare case of left ventricular aneurysm in a 77-year-old patient with aortic valve stenosis and without coronary artery disease. The patient underwent conventional aortic valve replacement and left ventricular aneurysmectomy with an uneventful postoperative course. The cause of the left ventricular aneurysm was suspected to be a long history of aortic valve stenosis that led to severe intraventricular hypertension, subsequently asymmetric septum hypertrophy, and finally apical aneurysm. PMID- 25798351 TI - Traumatic sinus of valsalva aneurysm repaired by partial david operation. AB - We report a case of chronic type A dissection and aneurysm of the sinus of Valsalva after a motor bike accident which remained undetected for 20 years. It was successfully treated with a modified valve-preserving technique. The noncoronary sinus formed a 4.5 * 5.0 cm large and heavily calcified aneurysm, compressing the right atrium and right coronary artery. The pathology was limited to the noncoronary sinus area and here was the annulus dilatated but the remaining sinuses and annulus and the cusps were intact. We have therefore performed a one-third or partial-David procedure with a satisfactory result. PMID- 25798352 TI - Valve-sparing reimplantation technique for treatment of neoaortic root dilatation late after the arterial switch operation: raising the bar. AB - Neoaortic root dilatation can develop during long-term follow-up after an arterial switch operation (ASO). Although few patients require surgical reintervention, significant valve regurgitation is still an important cause of late morbidity. We report on a 15-year-old boy with significant dilatation of the neoaortic root that was treated with the valve-sparing reimplantation technique. There is only one reported case of valve-preserving surgery late after the ASO. Valve preservation is believed to be superior to valve replacement in patients with aortic regurgitation due to better hemodynamic performance and avoidance of anticoagulation therapy. PMID- 25798353 TI - Diastolic aorto-right-atrial fistulation in aortic and tricuspid valve endocarditis. AB - Background Aorto-right-atrial fistula in native valve endocarditis is very rare. Case Description A 45-year-old woman was referred with an endocarditis with a perforated right cusp of the aortic valve with at least moderate insufficiency and an affected tricuspid annulus with vegetations. In addition to this, an aorto cavitary fistula from the aortic sinus to the right atrium with a holodiastolic left-right shunt had been detected. Streptococci viridans were found as underlying pathogen. Complete replacement of the aortic root and resection of the fistula were performed with good result. Conclusion Endocarditis with fistula formation is rare and has to be treated aggressively. PMID- 25798354 TI - Saphenous vein graft aneurysms: a growing problem? Presentation of two cases and surgical management. AB - Background Saphenous vein graft aneurysm is a rare complication after coronary artery bypass grafting leading to reoperations. Case Description In two patients with giant aneurysms, the subclavian artery and femoral vein were cannulated. The first patients' operation was combined with aortic valve replacement. The pulsating mass could be removed. The second patients' operation was planned as an off-pump coronary artery bypass grafting. Upon surgical entry, the aneurysm ruptured and the operation was continued as on-pump beating-heart procedure. Conclusion Because of better follow-up and increasing use of diagnostics, more patients with graft aneurysms will be identified. The question about a treatment algorithm might be answered by aging population and improved survival. PMID- 25798355 TI - Chronic pericardial hematoma with suppression of the right ventricle: a rare complication of a coronary artery aneurysm. AB - We present a case of a 67-year-old patient referred to our department with a pericardial mass lesion measuring 11 * 4 * 7.5 cm as diagnosed in computed tomography scan. The patient showed a history of progredient dyspnea. Video assisted thoracoscopy as well as an explorative full sternotomy to resect the mass lesion had been performed at the referring hospital subsequently before admission to our department. Intermittent hemodynamic instability caused the procedure to stop and a transfer to the cardiothoracic surgery department, following which a resternotomy was performed. Inspection of the surgical site and subsequent intraoperative rapid section revealed an old organized and dense pericardial hematoma adherent to the right ventricle. The suspicion of covered coronary artery perforation led to an intraoperative coronary angiography, which revealed a large proximal coronary aneurysm of the right coronary artery and a subtotal stenosis of the circumflex branch. The hematoma could be removed with decompression of the right ventricle under cardiopulmonary bypass conditions. The further postoperative course was uncomplicated with retransfer to the referring hospital on the postoperative day 8. PMID- 25798356 TI - Left atrial appendage enlarged by coronary artery fistula after surgical closure of appendage. AB - Two years previously, a 73-year-old man with mitral regurgitation underwent mitral annuloplasty and left atrial appendage (LAA) exclusion by suturing the orifice from the endocardium. However, the mitral regurgitation became exacerbated, and the left atrium enlarged rapidly over a 6-month period. Computed tomography showed a heterogenic mass in the LAA, and coronary angiography revealed a coronary artery-LAA fistula. Reoperation revealed a thrombus filling the appendage and two small orifices of the coronary artery-LAA fistula located in the endocardium of the appendage. We excised the LAA and closed these fistula orifices concomitant with mitral valve replacement. PMID- 25798357 TI - An unusual position for the permanent pacing wire. AB - Complications related to permanent pacing wires insertion include ventricular perforation. It commonly perforates the right ventricle. We present images of an unusual case where the pacing wires perforated the anterior left ventricular wall between the left anterior descending artery and diagonal artery. PMID- 25798358 TI - Biatrial recurrence of two independently growing cardiac myxoma in a patient with multiple tumor disease. AB - We report the case of a 56-year-old female patient with biatrial recurrence of cardiac myxoma and extensive comorbidities. In the literature, only few cases of biatrial myxoma can be found and they generally describe a single tumor reaching both atria. We found two independently growing cardiac myxomas of both atria. PMID- 25798359 TI - Use of latissimus dorsi pedicled myocutaneous flap for reconstruction in the chest area of an 8-month-old female infant with ectopia cordis. AB - Ectopia cordis (EC) is characterized by a complete or partial malposition of the heart outside the thorax. Despite the interdisciplinary treatment, the repair of EC is still very difficult and offers new surgical challenges because of its complexity and various combinations with other anomalies. We report the successful outcome after using a pedicled latissimus dorsi flap in reconstructive surgery in the setting of chronic wound dehiscence in an 8-month-old female infant born with a thoracic EC and omphalocele. PMID- 25798360 TI - Port-access thoracoscopic anatomical segmentectomy for pediatric intralobar pulmonary sequestration. AB - This report describes successful port-access thoracoscopic anatomical left lateral and posterior basal (S9 + 10) lung segmentectomy performed for intralobar pulmonary sequestration (ILPS) in a 5-year-old girl with recurrent pneumonia. Computed tomography revealed a multilocular lung abscess and an anomalous artery arising from the left gastric artery supplying the affected segment. After diagnosing ILPS, we performed thoracoscopic anatomical S9 + 10 segmentectomy. We consider thoracoscopic lung segmentectomy to be an important therapeutic option for pediatric ILPS. PMID- 25798361 TI - Pulmonary Pressure Necrosis due to Chronic Pleural Effusion after Heart Transplantation: A Case Report. AB - A 51-year-old woman had severe restrictive cardiomyopathy with heart failure. The first symptoms had started 12 years ago, and her symptoms gradually worsened. She was treated with diuretics, intermittent but repetitive thoracentesis, and paracentesis due to recurrent pleural effusion and ascites. Consequently, a collapse of the right lower lobe (RLL) was noted. We stopped thoracentesis and paracentesis and added continuous intravenous diuretics for 3 months before heart transplantation (HT). Finally, she underwent HT. However, her RLL remained collapsed and chest tube drainage persisted. We performed a RLL lobectomy with video-assisted thoracic surgery. No specific pathologic findings were noted except pulmonary necrotic lesions. We report a rare case of pulmonary necrosis caused by mechanical compression due to chronic pleural effusion after HT. PMID- 25798362 TI - Intercostal neurinoma: a rare cause of persistent thoracic pain. AB - Persistent thoracic pain with no history of trauma demands diagnostic workup. In this case, the patient complained of right thoracic continuous belt-like pain, sometimes experienced as shooting pain, over several months. The symptoms were first treated conservatively with painkillers, which was rather ineffective. A magnetic resonance imaging scan of the thorax surprisingly showed an unclear piston-like enlargement near the seventh rib closely above the spinal canal. Video thoracoscopy was performed to provide further clarification. This showed two lesions of the intercostal nerves of the seventh and eighth ribs. The intercostal nerves were resected in these areas. Histological examination revealed two neurinomas of the intercostal nerves with focal outgrowth of a neural cyst measuring 1.6 cm on the seventh intercostal nerve. The patient was free of any pain after the operation. PMID- 25798363 TI - Transient palsy of recurrent laryngeal nerve postresection of giant substernal goiter. AB - We report a case of a female patient aged 46 years with a history of nodular goiter for which she had a subtotal thyroidectomy 31 years ago. She was referred to the emergency department of our hospital because of dyspnea and chest pain for 20 days, then developed cyanosis and edema of the head and upper extremities. Chest X-ray revealed tracheal repulsion. Cervical and thoracic computed tomography showed a giant solid and a cystic mass in the anterior mediastinum and bilateral pleural effusion. The neck ultrasound did not show any thyroid masses. An exploratory thoracotomy with extensive resection considering the anatomical relation of the mass and the adjacent structures was planned. Immediately after the operation, the patient developed airway complications that resolved in 7 days. The tumor was confirmed pathologically as nodular goiter. The overall outcome of the patient was positive; she is healthy after more than 12 months of follow-up. This report examines the approach to diagnosis and management of one of the most common surgical complication associated with substernal goiters. PMID- 25798364 TI - Chronic thromboembolic pulmonary hypertension after pulmonary embolism, thrombolysis, catheter fragmentation, and embolectomy. AB - A 21-year-old male patient with massive acute pulmonary embolism was treated by thrombolysis, interventional thrombus fragmentation, and surgical pulmonary embolectomy. Within the following 2 years, the patient developed progressive dyspnea at exertion. Chronic thromboembolic pulmonary hypertension was diagnosed by right-heart catheter, VQ scan, magnetic resonance, and conventional pulmonary angiography. A normalization of the patient's exercise capacity and pulmonary hemodynamics could be achieved by pulmonary endarterectomy and patch reconstruction of the right main pulmonary artery. PMID- 25798365 TI - Spontaneous Pneumothorax due to Ectopic Deciduosis: A Case Report. AB - This report presents a 20-week pregnant 38-year-old woman with right-sided pneumothorax due to pulmonary deciduosis. Initial pleural drainage was ineffective. Video-assisted thoracoscopy revealed areas of consolidation within the lung parenchyma. A wedge resection with partial pleurectomy was performed. Histopathological examination showed subpleural decidual implants. The patient made a full recovery and was discharged on day 5. Videoscopic inspection of the lung parenchyma and pleura with resection of decidual foci is the recommended treatment for pneumothorax in pregnant women with pleuropulmonary deciduosis in whom classical pleural drainage is ineffective. PMID- 25798366 TI - Montgomery T-tube for the Management of Postintubation Tracheoesophageal Fistula with Synchronic Subglottic Laryngotracheal Stenosis. AB - A postintubation tracheoesophageal fistula (TEF) complicated with subglottic laryngotracheal stenosis (SLTS) is a challenge to surgical repair. Laryngotracheal resection and primary reconstruction could result in treatment failure. In this report, we describe the successful management of two cases of postintubation TEF complicated with SLTS using a Montgomery T-tube because of the patients' contraindications for laryngotracheal resection and primary anastomosis. PMID- 25798367 TI - A rare case of chylothorax in a patient with schimmelpenning syndrome. AB - Chylothorax originating in a patient with Schimmelpenning syndrome is rare and poses a problem in diagnosis and treatment. A 22-year-old male was admitted with dyspnea indicative of a large pleural chylous effusion. Besides conservative dietary treatment measures, the chylous effusion was drained (2,000 mL/day). Computed tomography-lymphography after ligation of the thoracic duct and pleurectomy revealed a small collateral flow of chylous fluid toward the chest wall and entering the thorax. Eventually, local radiation therapy with 36 Gy effectively treated the chylothorax. Five months later, an epitheloid angiosarcoma developing from a preexisting cutaneous lesion was detected and treated by surgical resection. PMID- 25798368 TI - Posttraumatic arteriovenous fistula of the distal posterior tibial artery as cause of delayed wound healing in an unrecognized arterial injury. AB - Background Cases of posttraumatic arteriovenous (AV) fistula of the distal lower limb are rarely reported. Time from trauma to diagnosis varies from hours to years. Case Description This case report of a 51-year-old male patient shows very impressively the extensive consequences of an unrecognized traumatic AV fistula. The fistula developed here after a car accident led to a massive healing delay in a pilon fracture of the tibia and a wound, resulting in almost 1 year immobilization, 20 operations, and extensive pain drug therapy. After surgical revision of the fistula, bone and wound healing improved quickly. Conclusions The possibility of an AV fistula should be considered in case of persistent swelling after high-energy trauma of an extremity. The therapy of choice is surgery and the long-term result of successful fistula ligature is excellent. PMID- 25798369 TI - A Rare Case of Dacron Graft Rupture due to Friction against a Rib. AB - A 54-year-old man underwent aortic repair for the infected thoracoabdominal aneurysm with a woven Dacron graft (Vascutek, Renfrewshire, Scotland) treated with gentian violet. Four months later, he complained of sudden back pain, resulting in preshock status. Computed tomographic scans showed massive hematoma around the Dacron graft, suggesting graft rupture. Initially, emergency thoracic endovascular aortic repair was performed, which was subsequently followed by open repair. The Dacron graft had a small hole, which was completely compatible with the site contacting with the rib. The graft rupture was considered due to its friction against the rib. We report on a rare event of mechanical Dacron graft rupture after the thoracoabdominal aortic replacement. PMID- 25798371 TI - Challenges in finding and measuring behavioural determinants of childhood obesity in Europe. AB - AIM: Childhood obesity is an important concern for child health. However, despite widespread concern about the increase in childhood obesity, its causes are not monitored systematically in Europe. In 2007, the Scientific Platform Project on Lifestyle Determinants of Obesity identified routine data sources nationally available in European countries to measure childhood obesity. This work was revisited in 2014 to monitor any progress made. SUBJECT AND METHODS: In 2007, a literature review and project discussion resulted in a list of desirable indicators that could be collected in Europe to describe child populations at risk of overweight and obesity. Participants from EU member states, the EEA, Croatia, Macedonia and Turkey set out to discover which countries collected these indicators. Eight years later, a literature search sought to establish if the surveillance of children's nutrition and physical activity behaviour had changed. RESULTS: In 2007, no countries collected all variables for all ages, leading to major gaps in knowledge. A literature search carried out in 2014 suggests that this is unchanged. There remains inconsistency of data surveillance in Europe, and disagreement on which age groups to collect data from or how to define obesity and overweight. CONCLUSION: There is a lack of consistent data collection on upstream influences on obesity. The true causes of the childhood obesity epidemic remain undiscovered, and the ability of research to identify effective prevention and treatment methods is compromised. PMID- 25798372 TI - Conformational Analysis of Retinoic Acids: Effects of Steric Interactions on Nonplanar Conjugated Polyenes. AB - Retinoic acids and other vitamin A analogs contain a trimethylcyclohexenyl ring in conjugation with a polyene chain joined at carbon-6 (C6) and carbon-7 (C7). A MP2-SCS/cc-pVDZ// B3LYP/6-31G(d) 2-D potential energy surface was computed for all-trans retinoic acid, which had 6 minima (3 enantiomeric pairs). The global minima were distorted s-gauche enantiomers (6-7 = 53 degrees ) with half-chair conformations of the ring. Distorted s-gauche enantiomers (6-7 = 55 degrees ) with inverted half-chair ring conformations were 1.7 kJ/mol above the global minima. The s-trans enantiomers (6-7 = 164 degrees ) were 11.3 kJ/mol above the global minima. Steric energies were computed by the method of Guo and Karplus to identify key structural elements in retinoic acids which determines their conformation. Small molecule crystal structures in the CCDC database with trimethylcyclohexenyl ring and exocyclic double bonds have ring-chain geometries near to one of the 6 energy minima of retinoic acids, except for retinaldehyde iminium cations. PMID- 25798370 TI - Mite-Allergic Rhinitis: How to Evaluate Clinical Efficacy in Allergen-Specific Immunotherapy Trials? AB - House dust mite (HDM) allergen exposure is the most important cause of perennial allergic rhinitis and/or asthma. Although allergen-specific immunotherapy (AIT) with HDM is well established, published studies have been characterized by substantial heterogeneity in clinical endpoints. Standardization in measuring clinical efficacy is required. Moreover, when designing an AIT trial with HDM allergens, several considerations have to be taken into account. The history of HDM allergy is less clear cut than the typical history of pollen allergy. In addition, clinical features of HDM allergy may differ from those of pollen allergy. Moreover, although not easily measurable, fluctuation in allergen exposure may cause variation in symptom severity and determine the timing of assessment of clinical effects of HDM AIT. Key points 1. A combined symptom and medication score (CSMS) is recommended as standard for the primary endpoint in future house dust mite (HDM) allergen-specific immunotherapy trials. 2. The diagnosis of HDM allergy is based on a carefully taken history in combination with sensitization to HDM allergens. 3. Eye symptoms are less prominent in patients with HDM-induced allergic rhinitis. Nasal symptoms, but not eye symptoms, should be included in the CSMS and in symptom scores as well. 4. As methods to determine allergen exposure vary and the efficacy of environmental control is a matter of debate, a practical approach consists of restraining patients from implementing HDM-reducing measures, such as removing carpets and introducing anti-mite covers, after the start of the study. 5. Efficacy evaluation in the period with the highest exposure to mites is recommended. PMID- 25798373 TI - Treatment adherence and transitioning youth in pediatric multiple sclerosis. AB - BACKGROUND: Transitioning youth with multiple sclerosis (MS) represent a vulnerable group to potentially poor outcomes. It is unknown how pediatric MS patients transition into adult care. OBJECTIVES: To describe self-management skills that include adherence to disease-modifying therapies, quality of life measures, illness perception, transition readiness and healthcare skills assessments in patients with pediatric MS and associations with clinical and cognitive outcomes. METHODS: This is a prospective cross-sectional study at the pediatric MS center and transitional MS clinic at the University of California, San Francisco. Patients and one of their parents completed validated surveys for self-management skills. Non-adherence is defined as not taking their medication more than 20% of the time in the past 1 month. Wilcoxin matched-pairs rank test and McNemar's tests were used for comparison of patient and parent responses. Univariate and multivariate regression models were used for analyses adjusting for disease duration and socio-economic status. RESULTS: Thirty patients were enrolled with a mean (+/-SD) age of 15.8 years+/-2.8, 53% was female and 47% Hispanic. The rate of non-adherence was 37%. The most common reason for non adherence was forgetting to take their medication reported in 50% of patients. In adjusted regression models, higher EDSS was associated with a lower score on patient's quality of life (13 points decrease, 95% CI 6-18, p<0.0001), and lower healthcare skills (15 points decrease, 95% CI5-26, p=0.006). Four points increase in Symbol Digit Modalities Test score was associated a 0.1 increase in transition readiness score (95% CI0.07-0.2, p=0.001) and 3.9 points increase in health care skills scores (95% CI 1.7-6, p=0.008). PMID- 25798375 TI - The association of anesthetic method with developing back pain after lower extremity operations. AB - BACKGROUND: Selection of anesthetic approach for lower extremity operations is often a controversial issue for anesthesiologists. OBJECTIVES: The aim of this study was to compare the incidence and severity of back pain between general and spinal anesthesia, and to find effective factors in developing postoperative back pain. PATIENTS AND METHODS: In a randomized clinical trail, 148 patients with elective lower extremity surgeries were randomly allocated into two groups of 74. The first group received general anesthesia and the second group underwent spinal anesthesia. The incidence of back pain was observed and documented. The severity of back pain was assessed at the first, fourth and eighth postoperative weeks by visual analogue scale. RESULTS: The mean of patients' age was 35.50 +/- 13.34 years. The incidence and mean of back pain severity among all participants were respectively 35.80% and 15.95% at the first week, 7.40% and 2.43% at the fourth week, and 1.4% and 0.27% at the eighth postoperative week. The incidence and mean of back pain severity in spinal group were respectively 39.2% and 18.11% at the first, 12.2% and 3.92% at the fourth, and 2.7% and 0.54% eighth postoperative weeks. In general anesthesia group, these figures were respectively 32.4% and 13.78% at the first week and 2.7% and 0.95% at the fourth postoperative week. No back pain was reported at the eighth postoperative week. The incidence and severity of back pain in the first week showed significant difference between the two groups, while the mean severity of back pain showed significant difference at the fourth week after operation. CONCLUSIONS: Spinal anesthesia could be probably considered as the sole effective factor in the development of back pain after operation. PMID- 25798374 TI - A Translational Worksite Diabetes Prevention Trial Improves Psychosocial Status, Dietary Intake, and Step Counts among Employees with Prediabetes: A Randomized Controlled Trial. AB - OBJECTIVE: Few worksite trials have examined the impact of diabetes prevention interventions on psychological and behavioral outcomes. Thus, the impact of a worksite lifestyle intervention on psychosocial outcomes, food group intake, and step counts for physical activity (PA) was evaluated. METHOD: A randomized pretest/posttest control group design with 3-month follow-up was employed from October 2012 to May 2014 at a U.S. university worksite among employees with prediabetes. The experimental group (n=35) received a 16-week group-based intervention while the control group received usual care (n=33). Repeated measures analysis of variance compared the change in outcomes between groups across time. RESULTS: A significant difference occurred between groups post intervention for self-efficacy associated with eating and PA; goal commitment and difficulty; satisfaction with weight loss and physical fitness; peer social support for healthful eating; generation of alternatives for problem solving; and intake of fruits, meat, fish, poultry, nuts, and seeds (all ps < .05). The experimental group significantly increased step counts post-intervention (p = .0279) and were significantly more likely to report completing their work at study end (p = .0231). CONCLUSION: The worksite trial facilitated improvement in modifiable psychosocial outcomes, dietary patterns, and step counts; the long term impact on diabetes prevention warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01682954. PMID- 25798376 TI - Injection of intradiscal o2-o3 to reduce pain and disability of patients with low back pain due to prolapsed lumbar disk. AB - BACKGROUND: Disk herniation (DH) is one of the most common disk lesions, inducing low back pain (LBP). Various therapeutic options have been proposed for treatment of disk herniation (DH). Intradiscal injection of ozone has been suggested for treatment of DH. OBJECTIVES: To determine the effect of intradiscal ozone injection on pain score and disability in patients with LBP from disk prolapsed. PATIENTS AND METHODS: Patients with LBP diagnosed with DH were enrolled in this clinical trial study. After prep and drape the area and under the fluoroscopy guide (c-arm), intradiscal injection of ozone/oxygen mixture (4 mL, 40 ug/mL) was performed. Pain score and functional ability of the patients according to Oswestry Disability Index (ODI) were measured prior to the injection (baseline) and then at 2 and 4 weeks and then at 3 and 6 months after the injection. RESULTS: Thirty patients (17 females, 13 males) with the mean age of 58.6 y (range, 42-73 y) enrolled in the study. The mean +/- standard deviation (SD) of pain score before intervention was 8.1 +/- 0.8. After two weeks, it was reduced to 3.2 +/- 0.6 (P < 0.001) and finally dropped to 2.0 +/- 0.6 sixth months after intervention (P = 0.0001). Functional status of ODI was 28.5 +/- 2.1 before intervention and showed significant reduction after two weeks (with the mean of 12.3), and it was almost sustained till sixth months after intervention, with the mean of 11.4 (P = 0.001). CONCLUSIONS: Altogether, ozone had significant positive effects on patients with disk herniation unresponsive to other conservative and minimally invasive treatments. PMID- 25798377 TI - Comparing the efficacy of intravenous acetaminophen and intravenous meperidine in pain relief after outpatient urological surgery. AB - BACKGROUND: Pain relief after surgery is an essential component of postoperative care. OBJECTIVES: The purpose of this study was to compare the efficacy of intravenous acetaminophen and intravenous meperidine in pain relief after outpatient urological surgery. PATIENTS AND METHODS: In a prospective, randomized, double-blind clinical trial, 100 outpatients of urological surgery were studied in two groups of acetaminophen (A) and meperidine (M). Patients in group A received 1g of acetaminophen in 100 mL saline within 15 minutes and patients in group M received a single intravenous injection of meperidine 0.5 mg/kg, 15 minutes prior to the end of operation. Postoperative pain was recorded using visual analog scale (VAS). Vital signs, nausea, vomiting, dizziness and respiratory depressions were compared between the two groups. RESULTS: Pain severity in patients treated with intravenous acetaminophen six hours after the operation within one-hour interval was significantly lower than meperidine group (P < 0.0001). Ninety patients in the meperidine group and five patients in the acetaminophen group required additional doses of analgesics. Nausea was significantly lower in acetaminophen group than meperidine group. CONCLUSIONS: Intravenous acetaminophen reduced pain following outpatient urological surgery more significantly than meperidine. PMID- 25798378 TI - Effects of opium addiction on level of sensory block in spinal anesthesia with bupivacaine for lower abdomen and limb surgery: a case-control study. AB - BACKGROUND: In clinical practice, the level of sensory block in spinal anesthesia in opium abusers is lower than that in non-abusers because of adaptive changes caused by opium use. OBJECTIVES: The aim of this study was to investigate the level of sensory block resulting from the intrathecal administration of 0.5% bupivacaine in opium abuser patients undergoing lower extremity and lower abdominal surgeries. PATIENTS AND METHODS: A total of 100 patients who were candidates of elective lower extremity orthopedic and lower abdominal surgeries were recruited and assigned to two groups based on their history of opium addiction (Case or control). Both groups underwent the same anesthesia procedure and pinprick test was used to assess the level of anesthesia. RESULTS: No statistically significant difference was observed between groups regarding age, duration of the surgery, and type of surgery. The frequency of addiction was higher in males than in females. The level of sensory block at three minutes was significantly lower in the opium abuser group (P = 0.006). The mean time to achieve T10 sensory block was 10.33 +/- 5.79 minutes in the opium abusers and 6.89 +/- 3.88 minutes in the controls (P = 0.001). The level of the highest sensory block was lower in the opium abuser group (P = 0.002). CONCLUSIONS: The findings of this study suggested that after induction of spinal anesthesia with intrathecal administration of bupivacaine, chronic opium abusers would have a lower level of sensory block in comparison with patients without a history of opium abuse. PMID- 25798380 TI - Keys to the successful indexing of the archives of plastic surgery in science citation index expanded. PMID- 25798379 TI - Evaluation of the anti-inflammatory effects of peri-operative infusion of magnesium sulfate on the microsurgical procedures for intracranial tumors. AB - BACKGROUND: The anti-inflammatory properties of magnesium sulfate have never been discussed in brain tumor surgeries. OBJECTIVES: This study is aimed to find anti inflammatory aspects of high dose magnesium sulfate infusion during perioperative period of neurosurgical patients through checking the serial C-reactive protein (CRP) blood levels as a biomarker of inflammation. PATIENTS AND METHODS: Sixty patients who were candidate for elective craniotomy were enrolled randomly into two equal groups to receive either magnesium sulfate or normal saline during their perioperative period. Infusion of magnesium was performed three times during the study and a summation of 15 grams was administered: 1- two days before surgery, 2- one day before surgery, 3- from the beginning of surgery (five grams was infused within six hours in each session). Serum level of CRP was checked just before commencement of magnesium infusion and on the first and second day after surgery as primary outcome. Hemodynamic parameters, total propofol requirement and total blood loss were recorded as well. RESULTS: No significant difference was found between groups in terms of serum CRP levels. The mean arterial blood pressure, heart rate, blood loss and total anesthetic requirement were significantly lower in magnesium group in comparison to the control group. CONCLUSIONS: We did not find conclusive evidence for anti-inflammatory effects of magnesium in craniotomy for microsurgery of intracranial tumors using CRP level changes. However, high dose magnesium might be suggested as a safe anesthetic adjuvant in neurosurgery. PMID- 25798381 TI - Total facelift: forehead lift, midface lift, and neck lift. AB - Patients with thick skin mainly exhibit the aging processes of sagging, whereas patients with thin skin develop wrinkles or volume loss. Asian skin is usually thicker than that of Westerners; and thus, the sagging of skin due to aging, rather than wrinkling, is the chief problem to be addressed in Asians. Asian skin is also relatively large in area and thick, implying that the weight of tissue to be lifted is considerably heavier. These factors account for the difficulties in performing a facelift in Asians. Facelifts can be divided into forehead lift, midface lift, and lower face lift. These can be performed individually or with 2 3 procedures combined. PMID- 25798382 TI - Breast lipofilling: a review of current practice. AB - Lipofilling is a reconstructive and aesthetic technique that has recently grown in popularity and is increasingly being used in breast surgery. Previous concerns had been raised regarding its safety when used for remodelling and reconstruction of the breast; however, these concerns have since been dismissed. Over the subsequent two decades, little evidence has been found to support these early theoretical concerns, and growing numbers of proponents of the procedure are confident in its safety. Many developments and refinements in the technique have taken place in recent years, and several studies have been published regarding the safety of lipofilling in the breast. We reviewed the current literature regarding the use of different lipofilling techniques as well as the current evidence regarding the oncological safety of the procedure in patients seeking aesthetic breast enhancement and in patients requiring reconstruction after treatment for breast cancer. PMID- 25798384 TI - Comparison of the viability of cryopreserved fat tissue in accordance with the thawing temperature. AB - BACKGROUND: Adipose tissue damage of cryopreserved fat after autologous fat transfer is inevitable in several processes of re-transplantation. This study aims to compare and analyze the survivability of adipocytes after thawing fat cryopreserved at -20C by using thawing methods used in clinics. METHODS: The survival rates of adipocytes in the following thawing groups were measured: natural thawing at 25C for 15 minutes; natural thawing at 25C for 5 minutes, followed by rapid thawing at 37C in a water bath for 5 minutes; and rapid thawing at 37C for 10 minutes in a water bath. The survival rates of adipocytes were assessed by measuring the volume of the fat layer in the top layers separated after centrifugation, counting the number of live adipocytes after staining with trypan blue, and measuring the activity of mitochondria in the adipocytes. RESULTS: In the group with rapid thawing for 10 minutes in a water bath, it was observed that the cell count of live adipocytes and the activity of the adipocyte mitochondria were significantly higher than in the other two groups (P<0.05). The volume of the fat layer separated by centrifugation was also measured to be higher, which was, however, not statistically significant. CONCLUSIONS: It was shown that the survival rate of adipocytes was higher when the frozen fat tissue was thawed rapidly at 37C. It can thus be concluded that if fats thawed with this method are re-transplanted, the survival rate of cryopreserved fats in transplantation will be improved, and thus, the effect of autologous fat transfer will increase. PMID- 25798383 TI - Characteristics of women who have had cosmetic breast implants that could be associated with increased suicide risk: a systematic review, proposing a suicide prevention model. AB - Literature indicates an increased risk of suicide among women who have had cosmetic breast implants. An explanatory model for this association has not been established. Some studies conclude that women with cosmetic breast implants demonstrate some characteristics that are associated with increased suicide risk while others support that the breast augmentation protects from suicide. A systematic review including data collection from January 1961 up to February 2014 was conducted. The results were incorporated to pre-existing suicide risk models of the general population. A modified suicide risk model was created for the female cosmetic augmentation mammaplasty candidate. A 2-3 times increased suicide risk among women that undergo cosmetic breast augmentation has been identified. Breast augmentation patients show some characteristics that are associated with increased suicide risk. The majority of women reported high postoperative satisfaction. Recent research indicates that the Autoimmune syndrome induced by adjuvants and fibromyalgia syndrome are associated with silicone implantation. A thorough surgical, medical and psycho-social (psychiatric, family, reproductive, and occupational) history should be included in the preoperative assessment of women seeking to undergo cosmetic breast augmentation. Breast augmentation surgery can stimulate a systematic stress response and increase the risk of suicide. Each risk factor of suicide has poor predictive value when considered independently and can result in prediction errors. A clinical management model has been proposed considering the overlapping risk factors of women that undergo cosmetic breast augmentation with suicide. PMID- 25798385 TI - A rabbit model of fat graft recipient site preconditioning using external negative pressure. AB - BACKGROUND: Fat is widely used in soft tissue augmentation. Nevertheless, it has an unpredictably high resorption rate. Clinically, external expansion with negative pressure is used to increase fat graft survival. In this study, fat graft recipient sites were preconditioned by external application of negative pressure in order to test for improvements in vascularity and fat graft survival. METHODS: Negative pressure was applied randomly to either the left or right dorsal ear of 20 New Zealand male white rabbits at a pressure of -125 mm Hg. The negative pressure was removed one week after the skin perfusion was measured. The skin flap at each ear was elevated, and 1 g of fat was grafted above the dorsal perichondrium. After one week, the fat weight, microvessel density, mature vessel density of the skin and fat, and amount of glycerol released were measured. Three months after the grafting, the same measurements were performed, with the exception of glycerol release. RESULTS: The fat survival rate of the experimental group (75.4%+/-3.9%) was higher than that of the control group (53.1%+/-4.3%) (P<0.001). Skin perfusion was higher in the experimental group. The glycerol release in the experimental group was significantly higher than in the control. The microvessel density of the skin and fat was significantly higher in the experimental group. Three months after the grafting, the skin and fat mature vessel density was significantly higher in the experimental groups. CONCLUSIONS: Negative pressure prior to fat grafting increased the vascularity of the recipient site, and, accordingly, enhanced fat graft survival. PMID- 25798387 TI - Retrospective Analysis of the One-per-Million Tumescent Technique in Post-Burn Hand Deformity Surgeries. AB - BACKGROUND: The use of a tourniquet in hand surgery is generally accepted as necessary to create a clear visualization of the operative field. This study aims to determine the effectiveness of one-per-million tumescent solution (1:1,000,000 epinephrine concentration) in creating a bloodless operative field in post-burn hand deformity surgeries performed without a tourniquet. METHODS: This retrospective observational study was conducted on a series of 12 patients with post-burn hand deformities who underwent surgery between February 2013 and January 2014. A total of 29 operative fields were recorded. The one-per-million tumescent solution was used for hemostatis instead of a tourniquet. The clarity of the operative field, volume of solution injected, duration of surgery, scar thickness and density, and functional outcomes at least three months after the surgery were observed. The relationship of scar thickness and density with the clarity of the operative field was analyzed with the chi-square test. RESULTS: Of the 29 operative fields in which the one-per-million tumescent technique was used, 48.2% were totally bloodless, 44.8% had minimal bleeding, and 6.9% had an acceptable level of bleeding. Both scar thickness and density were shown to have a significant relationship with operative field clarity (P<0.05). CONCLUSIONS: The one-per-million tumescent technique is effective in facilitating post-burn hand deformity surgeries involving meticulous, multiple, and lengthy procedures by creating a relatively clear operative field without the use of a tourniquet. Although scar thickness and density are associated with the clarity of the operative field, this technique can be considered safe and effective in creating a clear operative field. PMID- 25798386 TI - Resident Participation in International Surgical Missions is Predictive of Future Volunteerism in Practice. AB - BACKGROUND: Interest in global health and international mission trips among medical student and resident trainees is growing rapidly. How these electives and international mission experiences affect future practice is still being elucidated. No study has identified if participation in international surgical missions during residency is a predictor of participation in international surgical missions in practice after training completion. METHODS: All trainees of our plastic surgery residency program from 1990 to 2011, during the implementation of optional annual international surgical missions, were surveyed to determine if the graduate had gone on a mission as a resident and as a plastic surgeon. Data were compared between graduates who participated in missions as residents and graduates who did not, from 1990 to 2011 and 1990 to 2007. RESULTS: Of Plastic Surgery graduates from 1990 to 2011 who participated in international missions as residents, 60% participated in missions when in practice, versus 5.9% of graduates participating in missions in practice but not residency (P<0.0001). When excluding last 5 years, graduates participating in international missions in practice after doing so as residents increases to 85.7%, versus 7.41% who participate in practice but not residency P<0.002. CONCLUSIONS: Results reveal plastic surgeons who participate in international surgical missions as residents participate in international surgical missions in practice at higher rates than graduates who did not participate in missions during residency. International missions have significant intrinsic value both to trainee and international communities served, and this opportunity should be readily and easily accessible to all plastic surgery residents nationwide. PMID- 25798388 TI - Early Intervention for Low-Temperature Burns: Comparison between Early and Late Hospital Visit Patients. AB - BACKGROUND: Various focal heating devices are popular in Korea under the cultural influence of the traditional ondol under-floor method of home heating. These devices can cause severe burn-like injuries resulting from device malfunction or extended with low heat contact. In addition to injuries under these high heat contact, burns can be occurred by low heat exposure with prolonged periods despite the devices are properly functioning. In order to develop strategies to reduce the duration of periods of illness due to low-temperature burns, we analyzed and compared treatment methods and therapeutic periods for this type of injury. METHODS: This retrospective study included 43 patients burned under low heat conditions. Patients were divided into an operative group and a conservative group. The patients in the operative group underwent at least one surgical excision, and were further subdivided into early and late visit groups. The conservative group was treated only with dressings. We compared the treatment periods between the operative group and the conservative group, and also compared the preparation periods and treatment periods between the two operative groups. RESULTS: The average treatment period was significantly shorter in the operative group (P=0.02). In the early visit operative group, both wound preparation and treatment were briefer than in the late visit group. CONCLUSIONS: We recommend that early proper burn care and early surgical intervention, including appropriate excision, are feasible ways to reduce the treatment period of low temperature burn patients. PMID- 25798389 TI - The preventive effect of topical zafirlukast instillation for peri-implant capsule formation in rabbits. AB - BACKGROUND: Capsular contracture is the most troublesome complication in breast implant surgery. Although capsule formation can be seen as a normal reaction to a foreign body, it can induce pain, hardness, deformity, and other pathologic problems. Surgical intervention is required in severe cases, but even surgery cannot guarantee a successful outcome without recurrence. This experimental study confirms that single topical administration of leukotriene antagonist zafirlukast (Accolate, Astrazeneca) reduces peri-implant capsule formation and prevents capsular contracture. METHODS: Twelve smooth-surfaced cohesive gel implants were implanted in New Zealand White rabbits. These miniature implants were designed to be identical to currently used products for breast augmentation. The rabbits were divided into 2 groups. In the experimental group (n=6), the implant and normal saline with zafirlukast were inserted in the submuscular pocket. In the control group (n=6), the implant and normal saline alone were used. Two months later, the implants with peri-implant capsule were excised. We evaluated capsule thickness and collagen pattern and performed immunohistochemical staining of myofibroblasts, transforming growth factor (TGF)-beta1, 2. RESULTS: The thickness of the capsules in the experimental group was reduced in both dorsal and ventral directions. The collagen pattern showed parallel alignment with low density, and the number of myofibroblasts as well as the amounts of TGF-beta1 and TGF-beta2 were reduced in the experimental group. CONCLUSIONS: We suggest that single topical administration of leukotriene antagonist zafirlukast can be helpful in reducing capsule formation and preventing capsular contracture via myofibroblast suppression, modulation of fibroblastic cytokines, and anti-inflammatory effect. PMID- 25798390 TI - Polyurethane-coated breast implants revisited: a 30-year follow-up. AB - BACKGROUND: Polyurethane coating of breast implants has been shown to reduce capsular contracture in short-term follow-up studies. This 30-year study is the longest examination of the use of polyurethane-coated implants and their correlation with capsular contracture. METHODS: This study evaluates the senior surgeon's (F.D.P.) experience with the use of polyurethane-coated implants in aesthetic breast augmentation in 382 patients over 30 years. Follow-up evaluations were conducted for six months after surgery. After the six-month follow-up period, 76 patients returned for reoperation. The gross findings, histology, and associated capsular contracture were noted at the time of explantation. RESULTS: No patient during the six-month follow-up period demonstrated capsular contracture. For those who underwent reoperation for capsular contracture, Baker II/III contractures were noted nine to 10 years after surgery and Baker IV contractures were noted 12 to 21 years after surgery. None of the explanted implants had macroscopic evidence of polyurethane, which was only found during the first five years after surgery. The microscopic presence of polyurethane was noted in all capsules up to 30 years after the original operation. CONCLUSIONS: An inverse correlation was found between the amount of polyurethane coating on the implant and the occurrence of capsular contracture. Increasingly severe capsular contracture was associated with a decreased amount of polyurethane coating on the surface of the implants. No contracture occurred in patients whose implants showed incomplete biodegradation of polyurethane, as indicated by the visible presence of polyurethane coating. We recommend research to find a non-toxic, non-biodegradable synthetic material as an alternative to polyurethane. PMID- 25798391 TI - Early Surgical Site Infection Following Tissue Expander Breast Reconstruction with or without Acellular Dermal Matrix: National Benchmarking Using National Surgical Quality Improvement Program. AB - BACKGROUND: Surgical site infections (SSIs) result in significant patient morbidity following immediate tissue expander breast reconstruction (ITEBR). This study determined a single institution's 30-day SSI rate and benchmarked it against that among national institutions participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). METHODS: Women who underwent ITEBR with/without acellular dermal matrix (ADM) were identified using the ACS-NSQIP database between 2005 and 2011. Patient characteristics associated with the 30-day SSI rate were determined, and differences in rates between our institution and the national database were assessed. RESULTS: 12,163 patients underwent ITEBR, including 263 at our institution. SSIs occurred in 416 (3.4%) patients nationwide excluding our institution, with lower rates observed at our institution (1.9%). Nationwide, SSIs were significantly more common in ITEBR patients with ADM (4.5%) compared to non-ADM patients (3.2%, P=0.005), and this trend was observed at our institution (2.1% vs. 1.6%, P=1.00). A multivariable analysis of all institutions identified age >=50 years (odds ratio [OR], 1.4; confidence interval [CI], 1.1-1.7), body mass index >=30 kg/m(2) vs. <25 kg/m(2) (OR, 3.4; CI, 2.6-4.5), and operative time >4.25 hours (OR, 1.9; CI, 1.5-2.4) as risk factors for SSIs. Our institutional SSI rate was lower than the nationwide rate (OR, 0.4; CI, 0.2-1.1), although this difference was not statistically significant (P=0.07). CONCLUSIONS: The 30-day SSI rate at our institution in patients who underwent ITEBR was lower than the nation. SSIs occurred more frequently in procedures involving ADM both nationally and at our institution. PMID- 25798392 TI - Non-melanocytic benign tumors of the face: a retrospective study. AB - BACKGROUND: Although plastic surgeons daily encounter various facial tumors in the field, reports limited on face are scarce. In our study, we want to provide basic epidemiologic data to help clinicians to decide the proper management for their patients. METHODS: We retrospectively reviewed the medical records of patients including age and gender, location and size of the tumor, histopathologic result, recurrence, type of anesthesia and any associated disorders who had undergone a surgical removal of their facial tumors and received the histopathologic report in the same institution between January 2009 and October 2012. RESULTS: One hundred eighty-nine patients with 203 non melanocytic benign tumors were included. The most frequent site of tumors was the central subunit of the forehead, followed by the lateral subunit of the cheek and the auricular unit. Of 36 different histopathologic results, the epidermal cyst was most frequent, followed by lipoma, pilomatricoma and osteoma. Statistical analysis showed that males were dominant in the epidermal cyst and lipoma groups. While, females were dominant in the osteoma and pilomatricoma groups. No associations were found between lesions and other diseases. CONCLUSIONS: Our study is the at most specific and concentrated study on non-melanocytic benign tumors of the face. We expect the epidemiologic data of our study may help plastic surgeons who are confronted with so many facial lesions in the field to decide on the most proper management for their patients. PMID- 25798393 TI - Anatomical characteristics and surgical treatments of pincer nail deformity. AB - BACKGROUND: Pincer nail deformity is a transverse overcurvature of the nail. This study aimed to define the anatomical characteristics of pincer nail deformity and to evaluate the surgical outcomes. METHODS: A retrospective review was conducted on 20 cases of pincer nail deformity of the great toe. Thirty subjects without pincer nail deformity or history of trauma of the feet were selected as the control group. Width and height indices were calculated, and interphalangeal angles and base widths of the distal phalanx were measured with radiography. We chose the surgical treatment methods considering perfusion-related factors such as age, diabetes mellitus, kidney disease, and peripheral vascular disease. The zigzag nail bed flap method (n=9) and the inverted T incision method (n=11) were used to repair deformities. The outcomes were evaluated 6 months after surgery. RESULTS: The interphalangeal angle was significantly greater in the preoperative patient group (14.0 degrees +/-3.6 degrees ) than in the control group (7.9 degrees +/-3.0 degrees ) (P<0.05). The postoperative width and height indices were very close to the measurements in the control group, and most patients were satisfied with the outcomes. CONCLUSIONS: We believe that the width and height indices are useful for evaluating the deformity and outcomes of surgical treatments. We used two different surgical methods for the two patient groups with respect to the perfusion-related factors and found that the outcomes were all satisfactory. Consequently, we recommend taking into consideration the circulatory condition of the foot when deciding upon the surgical method for pincer nail deformity. PMID- 25798394 TI - Treatment of Eyelid Ptosis due to Kearns-Sayre Syndrome Using Frontalis Suspension. AB - Blepharoptosis is a common indication for surgery in plastic surgery units, yet its possible underlying pathology frequently remains unidentified. A 52-year-old man with a 20-year history of progressive bilateral ptosis (right>left) presented with recurrent ptosis of both eyes; he had undergone an operation on the levator aponeurosis 12 years prior. Due to the suspicion of an underlying disease, he was evaluated further. Chronic progressive external ophthalmoplegia in transition to the more severe syndromic variant Kearns-Sayre syndrome, a mitochondrial disorder causing myopathy, was diagnosed. The patient was treated with coenzyme Q10, and he underwent ptosis surgery on both eyes. This case illustrates a potentially multi-systemic disease that was diagnosed by a further evaluation of a common symptom, in this case worsening blepharoptosis. Awareness of myopathic symptoms is necessary to prevent overlooking serious yet improvable conditions. PMID- 25798395 TI - Management of chronic expanding haematoma using triamcinolone after latissimus dorsi flap harvesting. AB - Chronic expanding haematoma (CEH) is a rare type of haematoma that enlarges slowly and continuously without coagulation. It can occur following surgery because of shear stress-induced bleeding in the scar tissue between the subcutaneous fat and fascia. We present three cases of large chronic CEH that were successfully treated with triamcinolone injections. Three female patients developed large chronic CEH at 9 months, 5 years, and 6 years, respectively, after latissimus dorsi flap harvesting for breast reconstruction. Although the condition did not improve after multiple sessions of haematoma aspiration in the first two patients, it resolved following a single 40-mg triamcinolone injection along with appropriate compression dressing for several weeks. In the third patient, triamcinolone was injected immediately after the initial aspiration of the haematoma, and the condition improved considerably. There were no side effects in any of the patients. To the best of our knowledge, this is the first report of successful treatment of large CEH using triamcinolone. Therefore, we suggest that triamcinolone injections be considered for the treatment of CEH. PMID- 25798396 TI - The three-bite technique: a novel method of dog ear correction. AB - The closure of any circular or asymmetric wound can result in puckering or an excess of tissue known as a 'dog ear'. Understanding the mechanism of dog ear formation is a fundamental requirement necessary to facilitate an appropriate treatment. Many solutions have been reported in the literature, but in all cases, the correction entails the extension of the scar and the sacrifice of the dermal plexus. Here, we propose a novel technique of dog ear correction by using a three bite suture that sequentially pierces the deep fascial plane and each dog ear's margin, thus allowing for flattening the dog ear by anchoring the over-projecting tissue to the deep plane. The three-bite technique proved to be a fast, easy, and versatile method of immediate dog ear correction without extending the scar, while maintaining a full and complete local skin blood supply. PMID- 25798397 TI - A Consideration of Breast Imagery in Art as Depicted through Western Painting. AB - The aim of this study is to consider breast imagery in art as depicted through western painting. Twenty western art paintings were collated. Most of the sample paintings were created from the mid-nineteenth century to the late twentieth century and some are from the Renaissance period. Ten anthropometric items were used to measure 15 distances between two landmarks and 3 angles between three points. The distance from the nipple to the sternal notch and to the midclavicular point was the same and they were 0.46 of the distance from the sternal notch to the umbilicus. The shape of the projection of the breast was almost an isosceles triangle and the altitude of the triangle was at a proportion of 0.45 of the bottom length and 0.16 of the distance from the sternal notch to the umbilicus. The distance between the lateral ends of the breasts was 2.14 times the facial width and the distance between nipples was 1.36 times the facial width. Proportions from works of art are more ideal and attractive than clinically measured proportions. The desirable ratios measured from historical paintings might be useful in planning breast surgeries. PMID- 25798399 TI - Incorporating a racket-handle skin bridge and venous supercharging to improve reliability of the distally based anterolateral thigh flap. PMID- 25798400 TI - Thinning: The Difference between Free and Propeller Perforator Flaps. PMID- 25798401 TI - Bart syndrome. PMID- 25798398 TI - Foreign body granulomas after the use of dermal fillers: pathophysiology, clinical appearance, histologic features, and treatment. AB - A foreign body granuloma is a non-allergic chronic inflammatory reaction that is mainly composed of multinucleated giant cells. Foreign body granulomas may occur after the administration of any dermal filler. Factors such as the volume of the injection, impurities present in the fillers, and the physical properties of fillers affect granuloma formation. The formation of granulomas involves five phases: protein adsorption, macrophage adhesion, macrophage fusion, and crosstalk. The clinical and pathologic features of granulomas vary depending on the type of filler that causes them. Foreign body granulomas can be treated effectively with intralesional corticosteroid injections. Surgical excisions of granulomas tend to be incomplete because granulomas have ill-defined borders and moreover, surgical excisions may leave scars and deformities. PMID- 25798402 TI - A severe acute hypersensitivity reaction after a hyaluronic Acid with lidocaine filler injection to the lip. PMID- 25798403 TI - White-eyed medial orbital wall fracture with oculocardiac symptoms. PMID- 25798404 TI - Traumatic oculomotor nerve palsy. PMID- 25798405 TI - Delayed Methicillin-Resistant Staphylococcus aureus Infection on a Mandibular Angle Fracture with Absorbable Plates. PMID- 25798406 TI - Cutaneous Fusariosis in Unprotected Snake Bite Wound of Farmer's Hand. PMID- 25798407 TI - Merkel cell carcinoma of the upper eyelid: when reconstruction becomes a challenge. PMID- 25798408 TI - Cutaneous T-cell lymphoma with nasal necrosis. PMID- 25798409 TI - Angiosarcoma of the breast masquerading as hemangioma: exploring clinical and pathological diagnostic challenges. PMID- 25798410 TI - Reader's Forum. PMID- 25798411 TI - Correlation between skeletal and dental changes after mandibular setback surgery first orthodontic treatment: Cone-beam computed tomography-generated half cephalograms. AB - OBJECTIVE: To investigate skeletal and dental changes after application of a mandibular setback surgery-first orthodontic treatment approach in cases of skeletal Class III malocclusion. METHODS: A retrospective study of 34 patients (23 men, 11 women; mean age, 26.2 +/- 6.6 years) with skeletal Class III deformities, who underwent surgery-first orthodontic treatment, was conducted. Skeletal landmarks in the maxilla and mandible at three time points, pre treatment (T0), immediate-postoperative (T1), and post-treatment (T2), were analyzed using cone-beam computed tomography (CBCT)-generated half-cephalograms. RESULTS: The significant T0 to T1 mandibular changes occurred -9.24 +/- 3.97 mm horizontally. From T1 to T2, the mandible tended to move forward 1.22 +/- 2.02 mm, while the condylar position (Cd to Po-perpendicular plane) shifted backward, and the coronoid process (Cp to FH plane) moved vertically. Between T1 and T2, the vertical dimension changed significantly (p < 0.05). Changes in the vertical dimension were significantly correlated to T1 to T2 changes in the Cd to Po perpendicular plane (r = -0.671, p = 0.034), and in the Cp to FH plane (r = 0.733, p = 0.016), as well as to T0 to T1 changes in the Cp to Po-perpendicular plane (r = 0.758, p = 0.011). CONCLUSIONS: Greater alterations in the vertical dimension caused larger post-treatment (T2) stage skeletal changes. Studying the mandibular position in relation to the post-surgical vertical dimension emphasized the integral importance of vertical dimension control and proximal segment management to the success of surgery-first orthodontic treatment. PMID- 25798412 TI - Three-dimensional cone-beam computed tomography based comparison of condylar position and morphology according to the vertical skeletal pattern. AB - OBJECTIVE: To compare condylar position and morphology among different vertical skeletal patterns. METHODS: Diagnostic cone-beam computed tomography images of 60 adult patients (120 temporomandibular joints) who visited the orthodontic clinic of Hallym University Sacred Heart Hospital were reviewed. The subjects were divided into three equal groups according to the mandibular plane angle: hypodivergent, normodivergent, and hyperdivergent groups. Morphology of the condyle and mandibular fossa and condylar position were compared among the groups. RESULTS: The hypodivergent and hyperdivergent groups showed significant differences in superior joint spaces, antero-posterior condyle width, medio lateral condyle width, condyle head angle, and condylar shapes. CONCLUSIONS: Condylar position and morphology vary according to vertical facial morphology. This relationship should be considered for predicting and establishing a proper treatment plan for temporomandibular diseases during orthodontic treatment. PMID- 25798413 TI - New classification of lingual arch form in normal occlusion using three dimensional virtual models. AB - OBJECTIVE: The purposes of this study were 1) to classify lingual dental arch form types based on the lingual bracket points and 2) to provide a new lingual arch form template based on this classification for clinical application through the analysis of three-dimensional virtual models of normal occlusion sample. METHODS: Maxillary and mandibular casts of 115 young adults with normal occlusion were scanned in their occluded positions and lingual bracket points were digitized on the virtual models by using Rapidform 2006 software. Sixty-eight cases (dataset 1) were used in K-means cluster analysis to classify arch forms with intercanine, interpremolar and intermolar widths and width/depth ratios as determinants. The best-fit curves of the mean arch forms were generated. The remaining cases (dataset 2) were mapped into the obtained clusters and a multivariate test was performed to assess the differences between the clusters. RESULTS: Four-cluster classification demonstrated maximum intercluster distance. Wide, narrow, tapering, and ovoid types were described according to the intercanine and intermolar widths and their best-fit curves were depicted. No significant differences in arch depths existed among the clusters. Strong to moderate correlations were found between maxillary and mandibular arch widths. CONCLUSIONS: Lingual arch forms have been classified into 4 types based on their anterior and posterior dimensions. A template of the 4 arch forms has been depicted. Three-dimensional analysis of the lingual bracket points provides more accurate identification of arch form and, consequently, archwire selection. PMID- 25798414 TI - A reliable method for evaluating upper molar distalization: Superimposition of three-dimensional digital models. AB - OBJECTIVE: The aim of this study was to evaluate the reliability of measurements obtained after the superimposition of three-dimensional (3D) digital models by comparing them with those obtained from lateral cephalometric radiographs and photocopies of plaster models for the evaluation of upper molar distalization. METHODS: Data were collected from plaster models and lateral cephalometric radiographs of 20 Class II patients whose maxillary first molars were distalized with an intraoral distalizer. The posterior movements of the maxillary first molars were evaluated using lateral cephalometric radiographs (group CP), photocopies of plaster models (group PH), and digitized 3D models (group TD). Additionally, distalization and expansion of the other teeth and the degrees of molar rotation were measured in group PH and group TD and compared between the two groups. RESULTS: No significant difference was observed regarding the amount of molar distalization among the three groups. A comparison of the aforementioned parameters between group PH and group TD did not reveal any significant difference. CONCLUSIONS: 3D digital models are reliable to assess the results of upper molar distalization and can be considered a valid alternative to conventional measurement methods. PMID- 25798415 TI - Mandibular changes during initial alignment with SmartClip self-ligating and conventional brackets: A single-center prospective randomized controlled clinical trial. AB - OBJECTIVE: To test the null hypothesis that SmartClip self-ligating brackets are more effective than conventional brackets for initial mandibular alignment and identify influential factors. METHODS: Fifty patients were randomly allocated to two equal treatment groups by using an online randomization program: self ligating group (SmartClip brackets) and conventional group (Gemini brackets). The archwire sequence was standardized. Changes in anterior irregularity index, intercanine width, and intermolar width were assessed on plaster models at 8th and 16th weeks. Changes in incisor position and inclination were assessed on lateral cephalometric radiographs at 16 weeks. Intragroup and intergroup comparisons were performed with paired t-test and Student's t-test, respectively. Multiple linear regression was performed to identify variables affecting improvement in anterior ambiguity. RESULTS: Data of 46 patients were analyzed; those missing an appointment (n = 2) or showing bracket breakage (n = 2) were excluded. Incisor inclination (p < 0.05), intercanine width (p < 0.05), and intermolar width (p > 0.05) increased at 8 and 16 weeks in both the groups; no significant intergroup differences were noted (p > 0.05). Initial anterior irregularity index and intercanine width change were significantly associated with improvement in anterior irregularity (p < 0.001). CONCLUSIONS: The null hypothesis was rejected. Bracket type has little effect on improvement in anterior ambiguity during initial mandibular alignment. PMID- 25798416 TI - Maxillary protraction using skeletal anchorage and intermaxillary elastics in Skeletal Class III patients. AB - The aim of this case report is to describe the treatment of a patient with skeletal Class III malocclusion with maxillary retrognathia using skeletal anchorage devices and intermaxillary elastics. Miniplates were inserted between the mandibular lateral incisor and canine teeth on both sides in a male patient aged 14 years 5 months. Self-drilling mini-implants (1.6 mm diameter, 10 mm length) were installed between the maxillary second premolar and molar teeth, and Class III elastics were used between the miniplates and miniscrews. On treatment completion, an increase in the projection of the maxilla relative to the cranial base (2.7 mm) and significant improvement of the facial profile were observed. Slight maxillary counterclockwise (1 degrees ) and mandibular clockwise (3.3 degrees ) rotations were also observed. Maxillary protraction with skeletal anchorage and intermaxillary elastics was effective in correcting a case of Skeletal Class III malocclusion without dentoalveolar side effects. PMID- 25798417 TI - Functional outcome of distal radius fractures managed by barzullah working classification. AB - BACKGROUND: Management of distal radius fractures (DRFs) is still controversial and may be influenced by the initial fracture classification. Even though numerous classification systems have been proposed in this regard, the evaluation and management of this fracture has remained problematic. OBJECTIVES: The purpose of this study was to evaluate the functional outcome of DRF managed on the basis of a new classification. This classification named as Barzullah Working Classification represents a modification of Melone classification, which is based on fracture stability. PATIENTS AND METHODS: A total of 310 DRFs of patients skeletally matured referred to a tertiary care hospital at a period of 18 months were classified as per the new classification system into four types; metaphyseal stable, metaphyseal unstable, radiocarpal stable, and radiocarpal unstable fractures. They were managed and followed over a mean period of 15.10 +/- 5.4 months, and the results were recorded at the final follow-up. RESULTS: The mean age of the patients was 51.22 +/- 20.58 years. Most of the patients were females (n=189, 64.19%). The minimal follow up was 6 months with a mean of 15.10 +/- 5.4 months. Mean mayo wrist scores were 95 +/- 4, 80 +/- 7.4, 75 +/- 7.4, and 70 +/- 6.9, for stable metaphyseal fractures, unstable metaphyseal radial, stable radiocarpal fractures and unstable radiocarpal fractures, respectively. The overall mean mayo wrist functional score was 80.58 +/- 12.3 (good results) at final follow up. CONCLUSIONS: Various modalities of treatment used differentially in different types of DRFs based on the Barzullah Working Classification give good results in spite of conflicting literature. PMID- 25798418 TI - Persuasive discourse impairments in traumatic brain injury. AB - BACKGROUND: Considering the cognitive and linguistic complexity of discourse production, it is expected that individuals with traumatic brain injury (TBI) should face difficulties in this task. Therefore, clinical examination of discourse has become a useful tool for studying and assessment of communication skills of people suffering from TBI. Among different genres of discourse, persuasive discourse is considered as a more cognitively demanding task. However, little is known about persuasive discourse in individuals suffering from TBI. OBJECTIVES: The purpose of this study was to evaluate the performance of adults with TBI on a task of spoken persuasive discourse to determine the impaired linguistic measures. PATIENTS AND METHODS: Thirteen TBI nonaphasic Persian speaking individuals, ranged between 19 to 40 years (Mean = 25.64 years; SD = 6.10) and 59 healthy adults matched by age, were asked to perform the persuasive discourse task. The task included asking the participants to express their opinion on a topic, and after the analysis of the produced discourse, the two groups were compared on the basis of their language productivity, sentential complexity, maze ratio and cohesion ratio. RESULTS: The TBI group produced discourses with less productivity, sentential complexity, cohesion ratio and more maze ratio compared the control group. CONCLUSIONS: As it is important to consider acquired communication disorders particularly discourse impairment of brain injured patients along with their other clinical impairments and regarding the fact that persuasive discourse is crucial in academic and social situations, the persuasive discourse task presented in this study could be a useful tool for speech therapists, intending to evaluate communication disorders in patients with TBI. PMID- 25798419 TI - Types and causalities in dead patients due to traumatic injuries. AB - BACKGROUND: Trauma constitutes a major public health problem in our country and contributes significantly to unacceptably high morbidity and mortality. OBJECTIVES: This study aimed to evaluate the epidemiology of trauma in dead patients referred to Shahid Rajaee Trauma Hospital, Shiraz, Iran. PATIENTS AND METHODS: In a cross-sectional study, all patients with trauma admitted to our center were enrolled between March 2011 and February 2012. Age, gender, months of referring, causalities, and injured body parts of the victims were extracted from the data registry and analyzed. RESULTS: A total of 9113 patients, including 7163 (78.6%) males and 1950 (21.4%) females were evaluated. Among them, 479 patients (5.3%) had died. There was a significant difference between the age of alive and dead patients (35.70 +/- 0.18 and 45.44 +/- 1.01 years, respectively (P < 0.001)). In addition, dead men had significantly higher percentage than alive men (83.7% and 78.3%, respectively, P = 0.005). The highest percentages of men and women who referred to our center and died were in September. Crashing by car had the most frequency of dead (247 cases) in referred patients and motorcycle accident, stabbing, and falling related injuries with 67, 36 and 26 dead cases were in the next ranks. Thorax injury had the most frequency between dead patients (53.2% of all dead) and the intracranial injury and trauma to extremities altogether were in the next ranks, which constituted more than 18.8% of all dead. CONCLUSIONS: Our data demonstrated that car and motorcycle accidents are the most important cause of trauma and thorax trauma had the most frequency among dead patients. Epidemiological evaluations and preventive measures such as this study should be conducted to provide valuable data. PMID- 25798420 TI - Knowledge, attitudes, and acceptability about influenza vaccination in Korean women of childbearing age. AB - OBJECTIVE: The aims of the present study were to investigate the women's perspective on influenza infection and vaccination and to evaluate how they influence vaccine acceptability, in Korean women of childbearing age. METHODS: This was a prospective study by random survey of women of childbearing age (20 to 45 years). They were asked to complete a questionnaire assessing their knowledge, attitudes and acceptability of influenza vaccination before and during pregnancy. This study utilized data from the Korea National Health and Nutrition Examination Survey (KNHANES) between 2008 and 2012, to analyze the recent influenza vaccination trends. RESULTS: According to KNHANES (2008-2012), influenza vaccination rates in women of childbearing age have increased up to 26.4%, after 2009. The questionnaire was completed by 308 women. Vaccination rate during pregnancy or planning a pregnancy was 38.6%. The immunization rate increased significantly with the mean number of correct answers (P<0.001). Women who received influenza vaccination were more likely to be previously informed of the recommendations concerning the influenza vaccination before or during pregnancy, received the influenza vaccination in the past, and of the opinion that influenza vaccination is not dangerous during pregnancy, with odds ratios of 14.6 (95% confidence interval [CI], 6.44 to 33.33; P<0.0001), 3.6 (95% CI, 1.84 to 6.97; P=0.0002) and 2.7 (95% CI, 1.34 to 5.47; P=0.0057). CONCLUSION: Influenza vaccination rate in women of childbearing age has increased in this study and national data. More information and recommendation by healthcare workers, especially obstetricians, including safety of vaccination, might be critical for improving vaccination rate in women of childbearing age. PMID- 25798422 TI - Clinicopathological aspects of patients with recurrence of borderline ovarian tumors. AB - OBJECTIVE: Despite the good prognosis of borderline ovarian tumors (BOTs), a few BOT patients experience the relapse of disease, either borderline or malignant. However, the risk of recurrence of BOTs is somewhat controversial. We intended to find out the specific characteristics and prognosis of the recurrence of BOTs. METHODS: Between 1995 and 2012, 130 women were diagnosed with BOTs at a single institution. Eleven patients diagnosed and treated for the recurrence of BOTs including seven cancerous and four borderline relapses were included for the analysis in this retrospective study. Clinicopathological characteristics and surgical procedures as well as follow-up data with overall survival were assessed. Statistical analyses was performed using the chi(2) test, t-test and log-rank test with Cox regression. RESULTS: One hundred and thirty patients with mean follow-up of 65.8 months were evaluated, of whom half were below 40 years old at their first diagnosis of BOTs. Among 11 recurrent cases (8.5%), 7 cancerous transformations (5.4%) and 4 borderline recurrences (3.1%) were detected with median time of 6 and 71 months after the primary surgery, respectively. Nine out of 11 recurrences were happened at their equal or below 40 years-old age at the primary diagnosis (P=0.027). Also, all 7 cancerous relapses arose from premenopausal women of median age of 35 years old. Twenty (15%) patients had laparoscopic surgery and they were all treated conservatively. Among those 20, 5 were suffered from relapse of BOTs and laparoscopic approach was proved to be a significant risk factor for disease relapse in our study (P=0.013). Although laparoscopic surgery was revealed had meaningful influence on disease free survival (P=0.024), it was not significant on overall survival (P=0.226). CONCLUSION: Laparoscopic conservative surgery for BOTs can be accepted under close follow-ups. And younger patients should be followed for long period to evaluate recurrence. PMID- 25798421 TI - Clinical characteristics and perinatal outcome of fetal hydrops. AB - OBJECTIVE: To investigate the clinical characteristics of fetal hydrops and to find the antenatal ultrasound findings predictive of adverse perinatal outcome. METHODS: This is a retrospective study of 42 women with fetal hydrops who delivered in a tertiary-referral center from 2005 to 2013. Fetal hydrops was defined as the presence of fluid collection in >=2 body cavities: ascites, pleural effusion, pericardial effusion, and skin edema. Predictor variables recorded included: maternal characteristics, gestational age at diagnosis, ultrasound findings, and identifiable causes. Primary outcome variables analyzed were fetal death and neonatal death. RESULTS: The mean gestational age at diagnosis was 29.3+/-5.4 weeks (range, 18 to 39 weeks). The most common identifiable causes were cardiac abnormality (10), followed by syndrome (4), aneuploidy (3), congenital infection (3), twin-to-twin transfusion syndrome (3), non-cardiac anormaly (2), chorioangioma (2), inborn errors of metabolism (1), and immune hydrops by anti-E antibody isoimmunization (1). Thirteen cases had no definite identifiable causes. Three women elected termination of pregnancy. Fetal death occurred in 4 cases. Among the 35 live-born babies, only 16 survived (54.0% neonatal mortality rate). Fetal death and neonatal mortality rate was not significantly associated with Doppler velocimetry indices or location of fluid collection, but increasing numbers of fluid collection site was significantly associated with a higher risk of neonatal death. CONCLUSION: The incidence of fetal hydrops in our retrospective study was 24.4 per 10,000 deliveries and the perinatal mortality rate was 61.9% (26/42). The number of fluid collection sites was the significant antenatal risk factor to predict neonatal death. PMID- 25798423 TI - Clinical significance of mismatch repair genes immunohistochemical expression of complex endometrial hyperplasia. AB - OBJECTIVE: Women with Lynch syndrome have an increased risk of developing colorectal and gynecologic malignancies such as endometrial cancer. Complex hyperplasia has about a 30% risk of developing into endometrial cancer. The aim of this study was to determine the genetic risk for developing endometrial cancer by immunohistochemical staining of premalignant lesions for mutL homolog 1, mutS homolog 2, mutS homolog 6, and postmeiotic segregation increased 2. METHODS: Twenty cases (n=20) were selected from among patients with available sample blocks for analysis. Clinical information was obtained from medical chart review. Immunohistochemical staining was performed for all of the tumor blocks. Staining was scored based on the intensity (intensity score 0-3) . RESULTS: Among the 20 cases of complex endometrial hyperplasia, 11 (55%) patients showed loss of expression of at least one of the following proteins: mutL homolog 1, mutS homolog 2, mutS homolog 6, or postmeiotic segregation increased 2. Seven (35%) patients were negative for the expression of two or more proteins, and one patient (5%) was negative for the expression of all four proteins. CONCLUSION: More than half of the patients showed loss of expression of at least one mismatch repair protein in our study population. Genetic risk counseling and further tests are recommended for these patients. PMID- 25798424 TI - Characteristics of hereditary nonpolyposis colorectal cancer patients with double primary cancers in endometrium and colorectum. AB - OBJECTIVE: The hereditary nonpolyposis colorectal cancer is inherited syndrome characterized by the development of cancers in various organ system; these includes colorectum, endometrium, and less frequently, small bowel, stomach, urinary tract, ovaries, and brain. We aimed to investigate the clinicopathologic characteristics of hereditary nonpolyposis colorectal cancer patients who had both endometrial and colorectal cancers. METHODS: Between January 2004 and December 2013, 12 women diagnosed with endometrial and colorectal cancers in a single institution were included in this analysis. For these patients, clinical and molecular findings were analyzed retrospectively. RESULTS: All 12 women undertook microsatellite instability analysis, and 9 (75%) were confirmed of having microsatellite instability-high. Among 9 cases with immunohistochemical staining for MLH1 and MSH2, 6 were positive for the loss of mismatch repair protein. Mutational analyses for MLH1 and MSH2 were performed in 3 out of 12 patients; all of them showed germline mutation. CONCLUSION: This study suggests that there is a genetic background in patients with double primary malignancies in their endometrium and colorectum when analyzed with microsatellite instability studies, immunohistochemistry staining, and mutation studies. This finding supports the necessity of re-defining the high-risk groups in endometrial cancers clinically. This will also help diagnose malignancies in such patients in early stages, as well as counsel other family members. PMID- 25798425 TI - Impact of age on the false negative rate of human papillomavirus DNA test in patients with atypical squamous cells of undetermined significance. AB - OBJECTIVE: Human papillomavirus (HPV) test was incorporated into the triage of lesser abnormal cervical cytologies: atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL). This study aimed to evaluate the impact of age on the efficacy of HPV testing in patients with lesser abnormal cervical cytologies. METHODS: A total of 439 patients with ASCUS or LSIL were included. The association between age groups and the diagnostic performances of HPV test for high-grade cervical intraepithelial neoplasia (CIN2+) was evaluated. RESULTS: Median age was 44 years (range, 17 to 75 years). ASCUS was more frequently observed in older patients while LSIL was more common in younger patients (P=0.002). CIN2+ was found in 11.3% (32/284) of the ASCUS patients and 12.9% (20/155) of patients with LSIL. Older patients with ASCUS showed lower HPV infection rates (P=0.025), but not LSIL (P=0.114). However, the prevalence of CIN2+ was similar between the age groups with ASCUS or LSIL. In patients with ASCUS, the false negative rate of HPV test for CIN2+ was 6.2%. The false negative rate of the HPV test became higher with increasing of the age after the age of 50 (P=0.034). CONCLUSION: Our findings suggest that false negative rate of the HPV test for CIN2+ in ASCUS patients older than 50 years might become higher with increasing of the age. Negative HPV results in patients of the age >50 years with ASCUS should be carefully interpreted. PMID- 25798426 TI - Survival analysis of revised 2013 FIGO staging classification of epithelial ovarian cancer and comparison with previous FIGO staging classification. AB - OBJECTIVE: To analyze the prognostic role of revised version of International Federation of Gynecology and Obstetrics (FIGO) stage (2013) in epithelial ovarian cancer and compare with previous version staging classification. METHODS: We retrospectively enrolled patients with epithelial ovarian cancer treated at Samsung Medical Center from 2002 to 2012. We reclassified the patients based on the revised FIGO staging classification. RESULTS: Eight hundred seventy-eight patients were enrolled (stage I, 22.8%; stage II, 10.4%; stage III, 56.2%; stage IV, 10.7%). Previous stage IC (98, 11.1%) was subdivided into IC1 (9, 1.0%), IC2 (57, 6.4%), and IC3 (32, 4.1%). In addition, previous stage IV (94, 1.7%) was categorized into IVA (37, 4.2%) and IVB (57, 6.5%) in new staging classification. Stage IIC (66, 7.5%) has been eliminated and integrated into IIA (36, 4.1%) and IIB (55, 6.2%) in revised classification. Revised FIGO stage IC3 had significant prognostic impact on PFS (hazard ratio [HR], 3.840; 95% confidence interval [CI], 1.361 to 10.83; P=0.011) and revised FIGO stage IIIC appears to be an independent, significant poor prognostic factor for PFS (HR, 2.541; 95% CI, 1.242 to 5.200; P=0.011) but not in the case of previous version of FIGO stage IIIC (HR, 1.070; 95% CI, 0.502 to 2.281; P=0.860). However, any sub-stages of both previous and revised version in stage II and IV, there was no significant prognostic role. CONCLUSION: Revised FIGO stage has more progressed utility for informing prognosis than previous version, especially in stage I and III. For stage II and IV, further validation should be needed in large population based study in the future. PMID- 25798427 TI - Increased bone mineral density according to increase of skeletal muscle mass in 534 Korean women: A retrospective cohort study conducted over 2.7 years. AB - OBJECTIVE: To determine the impact of the changes in the amount of abdominal fat, directly measured by computed tomography, body composition, and the metabolic syndrome (MetS) risk factors on the bone mineral density (BMD) of Korean women. METHODS: A retrospective cohort study involving 534 Korean women aged 29 to 78 years, who had undergone both dual-energy X-ray absorptiometry and abdominal adipose tissue analysis by computed tomography scan more than twice between January 2004 and December 2010. The changes in the BMD values were examined in association with the changes in fat amount, body composition parameters, and risk factors of MetS. RESULTS: On cross sectional analysis, there was a significant positive correlation between femoral BMD and total abdominal fat amount at the initial visit. However, the correlation disappeared when the impact of change of the fat amount on the change in BMD was analyzed over the study period. When the MetS and body composition parameters were analyzed, a significantly positive correlation was found between skeletal muscle mass and BMD. There was no significant relationship between the MetS risk factors or other body composition parameters and BMD throughout the study period after adjusting for age (time interval). CONCLUSION: Among body composition parameters, only increased skeletal muscle mass had a positive correlation with increased BMD over the study period of 2.7 years. PMID- 25798428 TI - Decreased bone mineral density is associated with coronary atherosclerosis in healthy postmenopausal women. AB - OBJECTIVE: This study aimed to assess the association between bone mineral density (BMD) and coronary atherosclerosis in healthy postmenopausal women. METHODS: We performed a retrospective review of 252 postmenopausal women who had visited a health promotion center for a routine checkup. BMD of the lumbar spine (L1-L4) and femoral neck was evaluated using dual-energy X-ray absorptiometry, and coronary atherosclerosis was assessed using 64-row multidetector computed tomography. Participants were divided into normal BMD and osteopenia-osteoporosis groups, according to the T-scores of their lumbar spine or femoral neck. RESULTS: Participants with osteopenia-osteoporosis had a significantly higher proportion of coronary atherosclerosis than did those with normal BMD at the lumbar spine (P=0.003) and femoral neck (P=0.004). Osteopenia-osteoporosis at the lumbar spine (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.12 to 7.27) or femoral neck (OR, 3.35; 95% CI, 1.07 to 10.57) was associated with coronary atherosclerosis, after controlling for age and cardiovascular risk factors. CONCLUSION: Decreased BMD is associated with coronary atherosclerosis in healthy postmenopausal women, independent of age and cardiovascular risk factors. Postmenopausal women with decreased BMD may have a higher risk of developing coronary atherosclerosis. PMID- 25798429 TI - Innervation in women with uterine myoma and adenomyosis. AB - OBJECTIVE: To determine if neurofilament (NF) is expressed in the endometrium and the lesions of myomas and adenomyosis, and to determine their correlation. METHODS: Histologic sections were prepared from hysterectomies performed on women with adenomyosis (n=21), uterine myoma (n=31), and carcinoma in situ of the uterine cervix. Full-thickness uterine paraffin blocks, which included the endometrium and myometrium histologic sections, were stained immunohistochemically using the antibodies for monoclonal mouse antihuman NF protein. RESULTS: NF-positive cells were found in the endometrium and myometrium in 11 women with myoma and in 7 with adenomyosis, but not in patients with carcinoma in situ of uterine cervix, although the difference was statistically not significant. There was no significant difference between the existence of NF positive cells and menstrual pain or phases. The NF-positive nerve fibers were in direct contact with the lesions in nine cases (29.0%) of myoma and in five cases (23.8%) of adenomyosis. It was analyzed if there was a statistical significance between the existence of NF positive cells in the endometrium and the expression of NF-positive cells in the uterine myoma/adenomyosis lesions. When NF-positive cell were detected in the myoma lesions, the incidence of NF-positive nerve cells in the eutopic endometrium was significantly high. When NF-positive cell were detected in the basal layer, the incidence of NF-positive nerve cells in the myoma lesions and adenomyosis lesions was significantly high. CONCLUSION: We assume that NF-positive cells in the endometrium and the myoma and adenomyosis lesions might play a role in pathogenesis. Therefore, more studies may be needed on the mechanisms of nerve fiber growth in estrogen-dependent diseases. PMID- 25798430 TI - Neutrophil-lymphocyte and platelet-lymphocyte ratios in endometrial hyperplasia. AB - OBJECTIVE: The purpose of present study was to evaluate association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) and endometrial hyperplasia (EH). METHODS: One hundred and ten women with abnormal uterine bleeding were included into the study. Blood samples were drawn from all patients to obtain complete blood cell counts, neutrophil-leukocyte ratio and platelet-leukocyte ratio before endometrial curettage procedure initiated. The patients were divided into three groups due to their pathological results: group 1, patients with EH without atypia (n=40); group 2, patients with EH with atypia (n=15); and group 3, patients with neither hyperplasia nor cancer as control group (n=55). Blood cell counts, NLRs and PLRs were compared among these groups. RESULTS: Based on hemoglobin and platelet counts, there was no significant difference among these groups (P>0.05). Leukocyte and neutrophil counts were higher in group 2 (EH with atypia) than group 1 and group 3 (P<0.01). NLR of group 2 was significantly elevated when compared to group 1 and group 3 (P=0.004). PLR was higher in group 1 and group 2 than control group (P=0.024). CONCLUSION: Non-specific inflammatory markers such as NLR and PLR were elevated in women with atypical EH. These markers may be used as a predictor of atypical EH in patients with abnormal uterine bleeding. PMID- 25798431 TI - Therapy of heavy menstrual bleeding in Korea: Subanalysis and results from a multinational clinical trial in the Asian region investigating the levonorgestrel releasing intrauterine system versus conventional therapy. AB - OBJECTIVE: To compare real-life clinical outcomes with the levonorgestrel releasing intrauterine system (LNG-IUS) and conventional medical therapies (CMTs), including combined oral contraceptives and oral progestins in the treatment of idiopathic heavy menstrual bleeding (HMB) in South Korea. METHODS: This prospective, observational cohort study recruited a total of 647 women aged 18 to 45 years, diagnosed with HMB from 8 countries in Asia, including 209 women from South Korea (LNG-IUS, 169; CMTs, 40), who were followed up to one year. The primary outcome was cumulative continuation rate (still treated with LNG-IUS and CMTs) at 12 months. Secondary outcomes included bleeding pattern, assessment of the treatment efficacy by treating physician and safety profile. RESULTS: The continuation rate at 12 months was significantly higher with the LNG-IUS than CMTs (85.1% vs. 48.5%, respectively; P<0.0001). The 51.5% of CMTs patients discontinued treatment and 18.8% of LNG-IUS patients discontinued treatment. The most common reasons for discontinuation for CMTs were switching to another treatment and personal reasons. When compared to CMTs, the LNG-IUS offered better reduction in subjectively assessed menstrual blood loss and the number of bleeding days, tolerability and with better efficacy in HMB, as assessed by physician's final evaluation. CONCLUSION: This study provides novel information on the real-life treatment patterns of HMB in South Korea. The efficacy of CMTs was inferior compared to the LNG-IUS in the clinical outcomes measured in this study. Due to the better compliance with LNG-IUS, the cumulative continuation rate is higher than CMTs. We conclude that the LNG-IUS should be used as the first-line treatment for HMB in Korean women, in line with international guidelines. PMID- 25798432 TI - YS knot: A new technique for a tension-controlled slip knot using a trocar. AB - The Yoon Soon (YS) knot is a laparoscopic extracorporeal slip knot that is easy to learn and apply. Our new technique, which uses the trocar as a knot pusher, is simpler, faster, and has more tension than conventional knot methods. The YS knot will help surgeons save operative time and perform tension-controlled knot-tying during laparoscopic surgery. PMID- 25798433 TI - Endometrial cancer occurence five years after breast cancer in BRCA2 mutation patient. AB - We recently experienced a case of endometrial cancer 5 years after the diagnosis of breast cancer in a patient with a mutation in the BRCA2 gene. A 55-year-old Korean woman who had a past history of breast cancer in her 50s underwent an operation for endometrial cancer. Final pathology confirmed stage Ia, and no adjuvant treatment was performed. After surgery, considering her history of sequential cancer occurrence, genetic counseling was offered. The result showed the BRCA2 variation of unknown significance mutation. This is the first case report of sequential cancers (endometrial and breast) in a patient with a BRCA2 mutation among a Korean population. PMID- 25798434 TI - Polycystic ovary syndrome woman with heterozygous androgen receptor gene mutation who gave birth to a child with androgen insensitivity syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is a multifactorial polygenic disorder with a broad spectrum of clinical manifestations. Although pathogenesis is still unclear, androgen receptor (AR) gene polymorphism may be one of the etiologic factors of PCOS. AR gene polymorphism has been also associated with other forms of androgen pattern diseases. We report a PCOS woman with heterozygous AR gene mutation who gave birth to a baby with andorgen insensitivity syndrome. PMID- 25798435 TI - The human neonatal gut microbiome: a brief review. AB - The field of genomics has expanded into subspecialties such as metagenomics over the course of the last decade and a half. The development of massively parallel sequencing capabilities has allowed for increasingly detailed study of the genome of the human microbiome, the microbial super organ that resides symbiotically within the mucosal tissues and integumentary system of the human host. The gut microbiome, and particularly the study of its origins in neonates, has become subtopics of great interest within the field of genomics. This brief review seeks to summarize recent literature regarding the origins and establishment of the neonatal gut microbiome, beginning in utero, and how it is affected by neonatal nutritional status (breastfed versus formula fed) and gestational age (term versus preterm). We also explore the role of dysbiosis, a perturbation within the fragile ecosystem of the microbiome, and its role in the origin of select pathologic states, specifically, obesity and necrotizing enterocolitis (NEC) in preterm infants. We discuss the evidence supporting enteral pre- and pro-biotic supplementation of commensal organisms such as Bifidobacterium and Lactobacillus in the neonatal period, and their role in the prevention and amelioration of NEC in premature infants. Finally, we review directions to consider for further research to promote human health within this field. PMID- 25798436 TI - Survey and Rapid Detection of Bordetella pertussis in Clinical Samples Targeting the BP485 in China. AB - Bordetella pertussis is an important human respiratory pathogen. Here, we describe a loop-mediated isothermal amplification (LAMP) method for the rapid detection of B. pertussis in clinical samples based on a visual test. The LAMP assay detected the BP485 target sequence within 60 min with a detection limit of 1.3 pg/MUl, a 10-fold increase in sensitivity compared with conventional PCR. All 31 non-pertussis respiratory pathogens tested were negative for LAMP detection, indicating the high specificity of the primers for B. pertussis. To evaluate the application of the LAMP assay to clinical diagnosis, of 105 sputum and nasopharyngeal samples collected from the patients with suspected respiratory infections in China, a total of 12 B. pertussis isolates were identified from 33 positive samples detected by LAMP-based surveillance targeting BP485. Strikingly, a 4.5 months old baby and her mother were found to be infected with B. pertussis at the same time. All isolates belonged to different B. pertussis multilocus sequence typing groups with different alleles of the virulence-related genes including four alleles of ptxA, six of prn, four of tcfA, two of fim2, and three of fim3. The diversity of B. pertussis carrying toxin genes in clinical strains indicates a rapid and continuing evolution of B. pertussis. This combined with its high prevalence will make it difficult to control. In conclusion, we have developed a visual detection LAMP assay, which could be a useful tool for rapid B. pertussis detection, especially in situations where resources are poor and in point-of-care tests. PMID- 25798437 TI - Mutagenic effects induced by the attack of NO2 radical to the guanine-cytosine base pair. AB - We investigate the attack of the nitrogen dioxide radical (NO(*) 2) to the guanine-cytosine (GC) base pair and the subsequent tautomeric reactions able to induce mutations, by means of density functional theory (DFT) calculations. The conducted simulations allow us to identify the most reactive sites of the GC base pair. Indeed, the computed relative energies demonstrate that the addition of the NO(*) 2 radical to the C8 position of the guanine base forms to the most stable adduct. Although the initial adducts might evolve to non-canonical structures via inter-base hydrogen bonds rearrangements, the probability for the proton exchange to occur lies in the same range as that observed for undamaged DNA. As a result, tautomeric errors in NO2-attacked DNA arises at the same rate as in canonical DNA, with no macroscopic impact on the overall stability of DNA. The potential mutagenic effects of the GC-NO(*) 2 radical adducts likely involve side reactions, e.g., the GC deprotonation to the solvent, rather than proton exchange between guanine and cytosine basis. PMID- 25798439 TI - The microbial community of a passive biochemical reactor treating arsenic, zinc, and sulfate-rich seepage. AB - Sulfidogenic biochemical reactors (BCRs) for metal removal that use complex organic carbon have been shown to be effective in laboratory studies, but their performance in the field is highly variable. Successful operation depends on the types of microorganisms supported by the organic matrix, and factors affecting the community composition are unknown. A molecular survey of a field-based BCR that had been removing zinc and arsenic for over 6 years revealed that the microbial community was dominated by methanogens related to Methanocorpusculum sp. and Methanosarcina sp., which co-occurred with Bacteroidetes environmental groups, such as Vadin HA17, in places where the organic matter was more degraded. The metabolic potential for organic matter decomposition by Ruminococcaceae was prevalent in samples with more pyrolyzable carbon. Rhodobium- and Hyphomicrobium related genera within the Rhizobiales order that have the metabolic potential for dark hydrogen fermentation and methylotrophy, and unclassified Comamonadaceae were the dominant Proteobacteria. The unclassified environmental group Sh765B-TzT 29 was an important Delta-Proteobacteria group in this BCR that co-occurred with the dominant Rhizobiales operational taxonomic units. Organic matter degradation is one driver for shifting the microbial community composition and therefore possibly the performance of these bioreactors over time. PMID- 25798440 TI - Electrical and electrochemical monitoring of nucleic Acid amplification. AB - Nucleic acid amplification is a gold standard technique for analyzing a tiny amount of nucleotides in molecular biology, clinical diagnostics, food safety, and environmental testing. Electrical and electrochemical monitoring of the amplification process draws attention over conventional optical methods because of the amenability toward point-of-care applications as there is a growing demand for nucleic acid sensing in situations outside the laboratory. A number of electrical and electrochemical techniques coupled with various amplification methods including isothermal amplification have been reported in the last 10 years. In this review, we highlight recent developments in the electrical and electrochemical monitoring of nucleic acid amplification. PMID- 25798438 TI - Analytical methods in untargeted metabolomics: state of the art in 2015. AB - Metabolomics comprises the methods and techniques that are used to measure the small molecule composition of biofluids and tissues, and is actually one of the most rapidly evolving research fields. The determination of the metabolomic profile - the metabolome - has multiple applications in many biological sciences, including the developing of new diagnostic tools in medicine. Recent technological advances in nuclear magnetic resonance and mass spectrometry are significantly improving our capacity to obtain more data from each biological sample. Consequently, there is a need for fast and accurate statistical and bioinformatic tools that can deal with the complexity and volume of the data generated in metabolomic studies. In this review, we provide an update of the most commonly used analytical methods in metabolomics, starting from raw data processing and ending with pathway analysis and biomarker identification. Finally, the integration of metabolomic profiles with molecular data from other high-throughput biotechnologies is also reviewed. PMID- 25798442 TI - Knowing What's Out There: Awareness of Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder, which poses a significant health burden in the western countries. As the epidemic of obesity slides health downward, the incidence of NAFLD is evidently increasing. AIM: We aimed to ascertain the awareness of NAFLD and its risk factors in the general population, which may be helpful in designing educational tools to promote prevention, early detection, and treatment of this disorder. METHODS: A survey of 5000 non-institutionalized residents of Brooklyn, NY, USA was conducted. Sixteen items were included in the survey questionnaire including awareness of fatty liver, predisposing factors of NAFLD, awareness of cirrhosis, and conditions that advance to cirrhosis. The questionnaire also addressed awareness of prevention, diagnostic methods and treatment of NAFLD, and education of physicians to their patients about NAFLD. RESULTS: Overwhelming majority of the subjects was not aware of NAFLD and stated that their physicians did not have a discussion about NAFLD. CONCLUSION: Non-alcoholic fatty liver disease is a preventable liver disorder with limited treatment options. Thorough counseling by primary care physicians can be of paramount importance in preventive strategy for NAFLD. We should target our teenage population in an era of obesity epidemics of all times. PMID- 25798441 TI - The chromosomal passenger complex (CPC) as a key orchestrator of orderly mitotic exit and cytokinesis. AB - Understanding the molecular network of orderly mitotic exit to re-establish a functional interphase nucleus is critical because disordered mitotic exit inevitably leads to genomic instability. In contrast to the mechanisms of the entrance to mitosis, however, little is known about what controls the orderly exit from mitosis, particularly in mammalian cells. The chromosomal passenger complex (CPC), which is composed of Aurora B, INCENP, Borealin and Survivin, is one of the most widely studied and highly conserved hetero-tetrameric complexes. The CPC orchestrates proper chromosome segregation with cytokinesis by targeting to specific locations at different stages of mitosis. Recent studies reveal that controlling CPC localization and Aurora B kinase activity also serves as a key surveillance mechanism for the orderly mitotic exit. This ensures the reformation of a functional interphase nucleus from condensed mitotic chromosomes by delaying mitotic exit and cytokinetic processes in response to defects in chromosome segregation. In this review, we will summarize the latest insight into the molecular mechanisms that regulate CPC localization during mitotic exit and discuss how targeting Aurora B activity to different locations at different times impacts executing multiple mitotic exit events in order and recently proposed surveillance mechanisms. Finally, we briefly discuss the potential implication of deregulated Aurora B in inducing genomic damage and tumorigenesis with current efforts in targeting Aurora B activity for anti-cancer therapy. PMID- 25798443 TI - The wish to cure and the curiosity to investigate - or how I used my life to become a physician-scientist. AB - The author describes how he became a physician-scientist: difficulties he had to overcome coming from outside of the US (visa, funding, resident training), and his way back to Germany, while experiencing the thrill of actively participating in moving science. Setbacks, scientific success, adaptation to new developments, and the encounter of kindred spirits characterize this lifelong effort. PMID- 25798444 TI - Diagnostic potential of multimodal imaging of ovarian tissue using optical coherence tomography and second-harmonic generation microscopy. AB - Ovarian cancer is particularly deadly because it is usually diagnosed after it has metastasized. We have previously identified features of ovarian cancer using optical coherence tomography (OCT) and second-harmonic generation (SHG) microscopy (targeting collagen). OCT provides an image of the ovarian microstructure while SHG provides a high-resolution map of collagen fiber bundle arrangement. Here we investigated the diagnostic potential of dual-modality OCT and SHG imaging. We conducted a fully crossed, multi-reader, multi-case study using seven human observers. Each observer classified 44 ex vivo mouse ovaries (16 normal and 28 abnormal) as normal or abnormal from OCT, SHG, and simultaneously viewed, co-registered OCT and SHG images and provided a confidence rating on a six-point scale. We determined the average receiver operating characteristic (ROC) curves, area under the ROC curves (AUC), and other quantitative figures of merit. The results show that OCT has diagnostic potential with an average AUC of 0.91 +/- 0.06. The average AUC for SHG was less promising at 0.71 +/- 0.13. The average AUC for simultaneous OCT and SHG was not significantly different from OCT alone, possibly due to the limited SHG field of view. The high performance of OCT and co-registered OCT and SHG warrants further investigation. PMID- 25798445 TI - Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. AB - OBJECTIVE: To determine whether myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) were predictive of a demyelination phenotype in children presenting with acquired demyelinating syndrome (ADS). METHOD: Sixty-five children with a first episode of ADS (12 acute disseminated encephalomyelitis, 24 optic neuritis, 18 transverse myelitis, 11 other clinically isolated syndrome) were identified from 2 national demyelination programs in the United Kingdom and France. Acute serum samples were tested for MOG-Abs by cell-based assay. Antibodies were used to predict diagnosis of multiple sclerosis (MS) at 1 year. RESULTS: Twenty-three of 65 (35%) children had MOG-Abs. Antibody-positive and antibody-negative patients were not clinically different at presentation, but identification of MOG Abs predicted a non-MS course at 1-year follow-up: only 2/23 (9%) MOG-Ab-positive patients were diagnosed with MS compared to 16/42 (38%) MOG-Ab-negative patients (p = 0.019, Fisher exact test). Antibody positivity at outset was a useful predictor for a non-MS disease course, with a positive predictive value of 91% (95% confidence interval [CI] 72-99), negative predictive value of 38% (95% CI 24 54), positive likelihood ratio of 4.02 (CI 1.0-15.4), and odds ratio of 6.5 (CI 1.3-31.3). CONCLUSIONS: MOG-Abs are found at presentation in 35% of patients with childhood ADS, across a range of demyelinating disorders. Antibody positivity can be useful in predicting a non-MS disease course at onset. PMID- 25798446 TI - Is intrathecal anti-CD20 an option to target compartmentalized CNS inflammation in progressive MS? PMID- 25798447 TI - Encephalomyeloneuropathy with CRMP-5 antibodies in a patient with a primary mediastinal serinoma. PMID- 25798448 TI - Neuromyelitis optica phenotype associated with therapy-responsive acute peripheral neuropathy. PMID- 25798449 TI - Progressive multifocal leukoencephalopathy during fumarate monotherapy of psoriasis. PMID- 25798450 TI - Prednisolone and azathioprine are effective in DPPX antibody-positive autoimmune encephalitis. PMID- 25798451 TI - Myelodysplastic syndrome with progressive multifocal predominantly pontine demyelination. PMID- 25798452 TI - Pontine myelinolysis following excessive consumption of commercial energy drinks. PMID- 25798453 TI - Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. AB - OBJECTIVE: The study was designed to test the efficacy of ATX-MS-1467 in a relevant preclinical model and to assess its safety for the treatment of patients with secondary progressive multiple sclerosis (SPMS). METHODS: ATX-MS-1467 was tested for its ability to suppress experimental autoimmune encephalomyelitis (EAE) in the (Ob x DR2)F1 mouse both before and after disease onset. Safety was assessed by clinical assessment, MRI analysis, and the measurement of immune responses to self- and nonself-antigens in patients with SPMS. RESULTS: ATX-MS 1467 displayed a dose-dependent inhibition of EAE and was more effective than glatiramer acetate in the treatment of ongoing disease in humanized mice. A phase 1 open-label dose-escalating study demonstrated that ATX-MS-1467 was safe and well-tolerated in a group of 6 patients with SPMS, up to a dose of 800 ug. CONCLUSIONS: The results of this study support further development of ATX-MS-1467 in a clinical trial powered to investigate the immunologic and clinical benefits of treatment in relapsing-remitting MS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ATX-MS-1467 is safe and tolerated in a group of 6 patients with SPMS. PMID- 25798456 TI - Aqueous-filled polymer microcavity arrays: versatile & stable lipid bilayer platforms offering high lateral mobility to incorporated membrane proteins. AB - A key prerequisite in an ideal supported lipid bilayer based cell membrane model is that the mobility of both the lipid matrix and its components are unhindered by the underlying support. This is not trivial and with the exception of liposomes, many of even the most advanced approaches, although accomplishing lipid mobility, fail to achieve complete mobility of incorporated membrane proteins. This is addressed in a novel platform comprising lipid bilayers assembled over buffer-filled, arrays of spherical cap microcavities formed from microsphere template polydimethoxysilane. Prior to bilayer assembly the PDMS is rendered hydrophilic by plasma treatment and the lipid bilayer prepared using Langmuir Blodgett assembly followed by liposome/proteoliposome fusion. Fluorescence Lifetime Correlation Spectroscopy confirmed the pore suspended lipid bilayer exhibits diffusion coefficients comparable to free-standing vesicles in solution. The bilayer modified arrays are highly reproducible and stable over days. As the bilayers are suspended over deep aqueous reservoirs, reconstituted membrane proteins experience an aqueous interface at both membrane interfaces and attain full lateral mobility. Their utility as membrane protein platforms was exemplified in two case studies with proteins of different dimensions in their extracellular and cytoplasmic domains reconstituted into DOPC lipid bilayers; Glycophorin A, and Integrin alphaIIbbeta3. In both cases, the proteins exhibited 100% mobility with high lateral diffusion coefficients. PMID- 25798454 TI - The Impact of Developmental Timing for Stress and Recovery. AB - Stress can have lasting effects on the brain and behavior. Delineating the impact of stress on the developing brain is fundamental for understanding mechanisms through which stress induces persistent effects on behavior that can lead to psychopathology. The growing field of translational developmental neuroscience has revealed a significant role of the timing of stress on risk, resilience, and neuroplasticity. Studies of stress across species have provided essential insight into the mechanisms by which the brain changes and the timing of those changes on outcome. In this article, we review the neurobiological effects of stress and propose a model by which sensitive periods of neural development interact with stressful life events to affect plasticity and the effects of stress on functional outcomes. We then highlight how early-life stress can alter the course of brain development. Finally, we examine mechanisms of buffering against early life stress that may promote resilience and positive outcomes. The findings are discussed in the context of implications for early identification of risk and resilience factors and development of novel interventions that target the biological state of the developing brain to ultimately ameliorate the adverse consequences of stress during childhood and adolescence. PMID- 25798455 TI - Assessing the Availability of Users to Engage in Just-in-Time Intervention in the Natural Environment. AB - Wearable wireless sensors for health monitoring are enabling the design and delivery of just-in-time interventions (JITI). Critical to the success of JITI is to time its delivery so that the user is available to be engaged. We take a first step in modeling users' availability by analyzing 2,064 hours of physiological sensor data and 2,717 self-reports collected from 30 participants in a week-long field study. We use delay in responding to a prompt to objectively measure availability. We compute 99 features and identify 30 as most discriminating to train a machine learning model for predicting availability. We find that location, affect, activity type, stress, time, and day of the week, play significant roles in predicting availability. We find that users are least available at work and during driving, and most available when walking outside. Our model finally achieves an accuracy of 74.7% in 10-fold cross-validation and 77.9% with leave-one-subject-out. PMID- 25798457 TI - Non-invasive, real-time reporting drug release in vitro and in vivo. AB - We developed a real-time drug-reporting conjugate (CPT-SS-CyN) composed of a near infrared (NIR) fluorescent cyanine-amine dye (CyN), a disulfide linker, and a model therapeutic drug (camptothecin, CPT). Treatment with dithiothreitol (DTT) induces cleavage of the disulfide bond, followed by two simultaneous intramolecular cyclization reactions with identical kinetics, one to cleave the urethane linkage to release the NIR dye and the other to cleave the carbonate linkage to release CPT. The released CyN has an emission wavelength (760 nm) that is significantly different from CPT-SS-CyN (820 nm), enabling easy detection and monitoring of drug release. A linear relationship between the NIR fluorescence intensity at 760 nm and the amount of CPT released was observed, substantiating the use of this drug-reporting conjugate to enable precise, real-time, and non invasive quantitative monitoring of drug release in live cells and semi quantitative monitoring in live animals. PMID- 25798458 TI - Ionic liquid-induced all-alpha to alpha + beta conformational transition in cytochrome c with improved peroxidase activity in aqueous medium. AB - Choline dioctylsulfosuccinate [Cho][AOT] (a surface active ionic liquid) has been found to induce all-alpha to alpha + beta conformational transition in the secondary structure of enzyme cytochrome c (Cyt c) with an enhanced peroxidase activity in its aqueous vesicular phase at pH 7.0. [Cho][AOT] interacted with Cyt c distinctly at three critical concentrations (aggregation C1, saturation C2 and vesicular C3) as detected from isothermal titration calorimetric analysis. Oxidation of heme iron was observed from the disappearance of the Q band in the UV-vis spectra of Cyt c upon [Cho][AOT] binding above C3. Circular dichroism analysis (CD) has shown the loss in both the secondary (190-240 nm) and tertiary (250-300 nm) structure of Cyt c in the monomeric regime until C1, followed by their stabilization until the pre-vesicular regime (C1 -> C3). Loss in both the secondary and tertiary structure has been observed in the post-vesicular regime with the change in Cyt c conformation from all-alpha to alpha + beta which is similar to the conformational changes of Cyt c upon binding with mitochondrial membrane (Biochemistry 1998, 37, 6402-6409), thus citing the potential utility of [Cho][AOT] membranes as an artificial analog for in vitro bio-mimicking. Fluorescence correlation spectroscopy (FCS) measurements confirm the unfolding of Cyt c in the vesicular phase. Dynamic light scattering experiments have shown the contraction of [Cho][AOT] vesicles upon Cyt c binding driven by electrostatic interactions observed by charge neutralization from zeta potential measurements. [Cho][AOT] has been found to enhance the peroxidase activity of Cyt c with maximum activity at C3, observed using 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) diammonium salt as the substrate in the presence of hydrogen peroxide. This result shows the relevance of tuning ionic liquids to surfactants for bio-mimicking of specific membrane protein-lipid interactions. PMID- 25798459 TI - Enhanced visible-light photocatalytic activity of a g-C3N4/BiVO4 nanocomposite: a first-principles study. AB - The structural, electronic, and optical properties of a g-C3N4(001)/BiVO4(010) nanocomposite have been investigated using first-principles calculations. The results indicate that g-C3N4(001) can stably adsorb onto the BiVO4(010) surface, and it tends to form a regular wavy shape. The calculated band gap of the g C3N4(001)/BiVO4(010) nanocomposite is narrower compared with that of BiVO4 or BiVO4(010), primarily due to the introduction of N 2p states near the Fermi level. The g-C3N4(001)/BiVO4(010) nanocomposite has a favorable type-II band alignment; thus, photoexcited electrons can be injected into the conduction band of g-C3N4(001) from the conduction band of BiVO4(010). The proper interface charge distribution facilitates carrier separation in the g-C3N4(001)/BiVO4(010) interface region. The electron injection and carrier separation can prevent the recombination of electron-hole pairs. The calculated absorption coefficients indicate an obvious redshift of the absorption edge, which is in good agreement with the experimental results. Our calculation results suggest that the g C3N4(001)/BiVO4(010) nanocomposite has significant advantages for visible-light photocatalysis. PMID- 25798460 TI - Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. PMID- 25798461 TI - Preface. Gene essentiality. PMID- 25798462 TI - [In Process Citation]. PMID- 25798463 TI - [In Process Citation]. PMID- 25798464 TI - [In Process Citation]. PMID- 25798465 TI - Training tomorrow's doctors, in exercise medicine, for tomorrow's patients. PMID- 25798466 TI - Lessons learnt from engaging with the political system. PMID- 25798467 TI - Donald Metcalf (1929-2014). PMID- 25798468 TI - All-optical electrophysiology in behaving animals. PMID- 25798469 TI - Cryo-EM strikes gold. PMID- 25798470 TI - CRISPR gain-of-function screens. PMID- 25798471 TI - Microbiology: community organizers. PMID- 25798472 TI - Systems biology: an expanded human interactome. PMID- 25798473 TI - Structural biology: XFELs probe protein dynamics. PMID- 25798474 TI - Folates retention in brassica vegetables consumed in Brazil after different cooking methods. AB - The present study aimed to determine the effects of different traditional cooking methods on folate (tetrahydrofolate - THF, 5-methyltetrahydrofolate - 5- MTHF and 5-formyltetrahydrofolate - 5-FTHF) retention in leafy vegetables. The analysis of folates was carried out by high performance liquid chromatography (HPLC), with detection by fluorescence, using gradient elution, mobile phase of acetonitrile and phosphate buf- fer solution. The retention of isomers in vegetables after cooking ranged from 17.0 % to 87.2 % for THF, 53.4 - 94.1% for 5-MTHF and 39.0 - 107.9% for 5-FTHF. The retention of folates depended on the food matrix, the kind of isomer, and the cooking methods used. It is recommended that one should have more control over the choices for methods and time of cooking and the amount of water used at home and at foodservice as well. PMID- 25798475 TI - A comparison of White and Hispanic women's stories of adjustment to the birth of a child. AB - As part of a larger project designed to inform prevention and treatment of postpartum depression and promote positive mother-child relationships in diverse families, this study describes personal stories of postnatal adjustment from 14 White and 9 Hispanic women recruited from prenatal care clinics. Qualitative interviews conducted in the mothers' primary language (English or Spanish) were analyzed using a modified grounded theory content-analysis approach. The coding scheme developed to capture the women's discourse about their experiences included child temperament and health; intergenerational patterns; work demands and job loss; schedule changes; increased responsibilities; difficulties with parenting tasks; emotional distress; social stressors and resources; coping strategies; and changes in work, personal, social, and marital domains. More White mothers than Hispanic mothers reported changes in time structure, work stressors, use of psychotropic medication, informational support, and social support from other mothers and professionals; however, within-group differences were more evident than were cross-group ethnic differences. Analyses of qualitative interviews led to the integration of Belsky's Determinants of Parenting Model (1984) and the Double ABCX Model of Family Adjustment and Adaptation (McCubbin & Patterson, 1983) into a hybrid third theoretical framework. PMID- 25798476 TI - Insightfulness and later infant attachment in clinically depressed and nonclinical mothers. AB - The aim of this pilot study was to investigate the relationship between maternal insightfulness and sensitivity and subsequent infant attachment security and disorganization in clinically depressed and nonclinical mother-infant groups. Nineteen depressed mothers with infants ages 3 to 11 months participated in this study. Twenty nonclinical mother-infant dyads were matched to the clinical sample according to infant sex and age. Maternal depression was assessed using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994), insightfulness using the Insightfulness Assessment (IA), and sensitivity using the Maternal Sensitivity Scales (M.D.S. Ainsworth, 1969). IA classifications and subscales were considered separately. Later infant attachment was assessed by the Strange Situation Procedure (M.D.S. Ainsworth, M.C. Blehar, E. Waters, & S. Wall, 1978). Depressed mothers tended to have less securely attached children than did nonclinical mothers. Within the clinical sample, the insightfulness categories correlated slightly moderately with attachment security, but were not related to attachment disorganization. Within the nonclinical sample, the IA categories were slightly moderately associated with attachment security and with disorganization. On IA subscales, relationship patterns differed in clinically depressed and nonclinical mother infant dyads. These findings provide the first evidence of the predictive power of the IA categorization and subscales on subsequent infant attachment. They also may allow the development of different foci of intervention for enhancing insightful caregiving. PMID- 25798477 TI - Shall we dance? Music as a port of entrance to maternal-infant intersubjectivity in a context of postnatal depression. AB - The present study introduces the concept of a mother-infant group therapy that makes use of music, singing, and moving to establish maternal-infant intersubjectivity. It was conducted in a residential mother-baby unit for mothers with postnatal depression and their infants over a 5-week period. Maternal-infant intersubjectivity of four dyads in relation to the group dynamics were microanalyzed for Sessions 1 and 5. We made within-session (i.e., beginning middle-end) and between-session (Session 1 vs. Session 5) comparisons for the number of intersubjectivity moments (ISMs), total time of intersubjectivity (IST), and the mean duration of ISMs on a dyadic (i.e., own mother/infant involved) and a nondyadic level (i.e., own mother/infant not involved). In addition, three ISM levels (degree of group contribution) were distinguished. The results indicated a significant increase of ISMs/IST from Session 1 to Session 5. Within-session analyses showed that ISMs/IST significantly decreased through Session 1 and remained stable throughout Session 5. Intersubjectivity occurred mainly on ISM Level 1 during Session 1 and on ISM Level 3 during Session 5, suggesting increased dyadic autonomy and self-efficacy. The results are discussed in relation to the musical characteristics of mother-infant dyads, music improvisation techniques, group processes, and intersubjective development. PMID- 25798478 TI - The eye of the begetter: predicting infant attachment disorganization from women's prenatal interpretations of infant facial expressions. AB - Infant-caregiver attachment disorganization has been linked to many long-term negative psychosocial outcomes. While various prevention programs appear to be effective in preventing disorganized attachment, methods currently used to identify those at risk are unfortunately either overly general or impractical. The current investigation tested whether women's prenatal biases in identifying infant expressions of emotion--tendencies previously shown to relate to some of the maternal variables associated with infant attachment, including maternal traumatization, trauma symptoms, and maternal sensitivity--could predict infant attachment classification at 18 months postpartum. Logistic regression analyses revealed that together with women's adult history of high betrayal traumatization, response concordance with a normative reference sample in labeling infant expressions as negatively valenced, and the number of infant facial expressions that participants classified as "sad" and "angry" predicted subsequent infant attachment security versus disorganization. Implications for screening and prevention are discussed. PMID- 25798479 TI - Effects of kangaroo mother care on maternal mood and interaction patterns between parents and their preterm, low birth weight infants: a systematic review. AB - The birth of a premature infant can have adverse effects on the mood of mothers and on the interaction patterns between parents and their preterm babies. The aim of the present systematic review was to examine whether the Kangaroo Mother Care (KMC) intervention can attenuate these adverse psychological effects of a premature birth by ameliorating negative maternal mood and/or promoting more positive interactions between preterm infants and their parents. The results showed that although findings of studies were inconclusive, there is some evidence to suggest that KMC can make a positive difference on these areas. Specifically, it was found that KMC can improve negative maternal mood (e.g., anxiety or depression) and promote more positive parent-child interactions. Limitations and directions for future research are discussed. PMID- 25798480 TI - Transition to parenthood and mental health in first-time parents. AB - This study aimed to examine the transition to parenthood and mental health in first-time parents in detail and explore any differences in this transition in the context of parental gender and postpartum mental health. Semistructured clinical interviews (Birmingham Interview for Maternal Mental Health) were carried out with 46 women and 40 men, 5 months after birth. Parents were assessed on pre- and postpartum anxiety, depression, and postpartum posttraumatic stress disorder (PTSD), and a range of adjustment and relationship variables. One fourth of the men and women reported anxiety in pregnancy, reducing to 21% of women and 8% of men after birth. Pregnancy and postpartum depression rates were roughly equal, with 11% of women and 8% of men reporting depression. Postpartum PTSD was experienced by 5% of parents. Postpartum mental health problems were significantly associated with postpartum sleep deprivation (odds ratio [OR] = 7.5), complications in labor (OR = 5.1), lack of postpartum partner support (OR = 8.0), feelings of parental unworthiness (OR = 8.3), and anger toward the infant (OR = 4.4). Few gender differences were found for these variables. This study thus highlights the importance of focusing interventions on strengthening the couple's relationship and avoiding postnatal sleep deprivation, and to address parents' feelings of parental unworthiness and feelings of anger toward their baby. PMID- 25798481 TI - Maternal sensitivity and latency to positive emotion following challenge: pathways through effortful control. AB - The ability to self-generate positive emotions is an important component of emotion regulation. In this study, we focus on children's latency to express positive emotions following challenging situations and assess whether this ability operates through early maternal sensitivity and children's effortful control. Longitudinal relations between maternal sensitivity, infant negative affect, effortful control, and latency to positive emotion following challenge were examined in 156 children who were 33 months of age. Structural equation models supported the hypothesis that maternal sensitivity during infancy predicted better effortful control and, in turn, shorter latencies to positive emotions following challenge at 33 months. Directions for future research are discussed. PMID- 25798482 TI - Acoustic analysis of oral productions of infants later diagnosed with autism and their mother. AB - Research on early signs of autism in social interactions often focuses on infants' motor behaviors; few studies have focused on speech characteristics. This study examines infant-directed speech of mothers of infants later diagnosed with autism (LDA; n = 12) or of typically developing infants (TD; n = 11) as well as infants' productions (13 LDA, 13 TD). Since LDA infants appear to behave differently in the first months of life, it can affect the functioning of dyadic interactions, especially the first vocal productions, sensitive to expressiveness and emotions sharing. We assumed that in the first 6 months of life, prosodic characteristics (mean duration, mean pitch, and intonative contour types) will be different in dyads with autism. We extracted infants' and mothers' vocal productions from family home movies and analyzed the mean duration and pitch as well as the pitch contours in interactive episodes. Results show that mothers of LDA infants use relatively shorter productions as compared to mothers talking to TD infants. LDA infants' productions are not different in duration or pitch, but they use less complex modulated productions (i.e., those with more than two melodic modulations) than do TD. Further studies should focus on developmental profiles in the first year, analyzing prosody monthly. PMID- 25798483 TI - Foster parents' state of mind with respect to attachment: concordance with their foster children's attachment patterns at 2 and 3 years of age. AB - The present study investigated the possible differences between foster and comparison parents' state of mind with respect to attachment, and the concordance between caregiver state of mind and child attachment classifications among 60 foster children, all placed before the age of 2 years, as well as 42 comparison children. Caregiver state of mind was measured when the children were 2 years old (Time 1) while child attachment classifications were assessed at age 2 and again at age 3 years (Time 2). The associations between foster children's attachment, age at first and final placements, number of placements, and reasons for placement also were investigated. Descriptive analyses, including cross tabulations, and independent sample t tests were used. The results showed that the majority of the foster parents had an autonomous state of mind, and no significant group difference between foster and comparison parents was identified. At both time points, most foster children who were classified as secure had autonomous foster parents, as also was the case for the comparison children. The present results are encouraging, suggesting that placing foster children with autonomous foster parents early in life may help them to remain secure over time. Furthermore, focusing on the recruitment of autonomous foster parents is important when working with young foster children. PMID- 25798484 TI - Stability of biological father presence as a proxy for family stability: cross racial associations with the longitudinal development of emotion regulation in toddlerhood. AB - The current study, utilizing data from the National Early Head Start Research and Evaluation Project (Love et al., 2005) explored the relationship between biological father presence and emotion regulation over toddlerhood among children from low-income families. Conceptualizing biological father presence as a proxy for family role development, results are interpreted from a role development theoretical perspective. The latent growth curve model was compared based on child ethnoracial status (African American, Caucasian, Hispanic) and child gender. Consistent biological father presence was associated with toddlers' regulatory development across toddlerhood, and this relationship was most robust among Caucasian toddlers as compared to African American toddlers. Findings for Hispanic toddlers were not significantly different from those of Caucasian or African American families. Results bolster the literature on father presence and child outcomes. Analyses address consistency in father presence as a proxy for coherent role development and define a link between consistent father presence and children's regulatory development, demonstrating ethnoracial differences which are likely attributed to the social construction of family roles. PMID- 25798485 TI - Intimate partner violence and infant socioemotional development: the moderating effects of maternal trauma symptoms. AB - The aim of the present study was to investigate the impact of intimate partner violence (IPV) on infant regulatory difficulties at 3 months of age and infant socioemotional problems at 12 months of age. Maternal trauma symptoms were explored as potential moderators of these associations. Participants included 120 primarily low-income, ethnically diverse women and their infants. Results revealed that infants whose mothers experienced IPV during pregnancy did not have significantly more regulatory difficulties at 3 months than did infants whose mothers did not experience prenatal IPV. However, infants whose mothers experienced IPV during the first year after birth displayed significantly more socioemotional problems at 12 months, as evidenced by both maternal report and observational data. Furthermore, maternal posttraumatic stress avoidance symptoms served as a moderator of the association between prenatal IPV and infant regulatory difficulties at 3 months whereas maternal posttraumatic stress hyperarousal and reexperiencing symptoms served as moderators of the association between IPV during the first year after birth and infant socioemotional problems at 12 months. The findings highlight the detrimental impact that IPV can have on very young children and the importance of maternal trauma symptoms as a context for understanding the effect of IPV on young children's functioning. PMID- 25798486 TI - A meta-analytic review of relationship-based interventions for low-income families with infants and toddlers: facilitating supportive parent-child interactions. AB - Relationship-based intervention programs are increasingly being implemented as a way to enhance parent-child interaction quality. In this meta-analytic review, we examined the effectiveness of 19 recent relationship-based interventions serving socioeconomically disadvantaged families with infants and toddlers (N = 6,807). This review specifically focused on intervention effectiveness in terms of improving supportive parenting behaviors, as measured by observational assessments of dyadic parent-child interactions. Meta-analytic results indicated significant, yet modest, effectiveness across all interventions (d = .23). Intervention characteristics such as participant randomization, breadth of intervention services offered, duration, child age at the start of the intervention, professional qualifications of the intervenor, and type of play task used during assessment were tested as possible moderators of effectiveness. Significant differences in effectiveness were found between randomized and nonrandomized interventions. Within the subsample of randomized interventions, programs that were shorter in duration, that provided direct services to the parent-child dyad, used intervenors with professional qualifications, and assessed parent-child interactions with free-play tasks were the most effective, highlighting important considerations for designing effective intervention protocol tailored to the needs of this high-risk population. PMID- 25798487 TI - Impact of maternal depression on pregnancies and on early attachment. AB - The relatively high prevalence and duration of depression in the prenatal and postpartum periods reinforce the need for better understanding of maternal depression. The purpose of this article is to explore the main effects of depression to pregnancies' outcome and to early attachment reviewing research from the last decade and to find the best way to prevent the negative effects of maternal depression to infants. Recent studies have reported significant associations between maternal depression and several adverse obstetric, fetal, and neonatal outcomes. Antenatal depression has been associated with shorter gestation and lower birth weight, with consequences for infant development. A number of studies have demonstrated an association between prenatal depression and attachment difficulties, which seems to play an important mediating role in the development of further adverse outcomes for children. This review reveals some potential risks of untreated depression during the antenatal and postnatal periods, with possibly significant implications for practice and further research. Considering the high prevalence of depression, antenatal detection of depressive symptoms and intervention before childbirth has huge importance in prevention. Early interventions also may need to focus on mother-infant interactions as a key factor of later child development. PMID- 25798488 TI - Flexing the frame: contemplating the use of multiple ports of entry in parent infant psychotherapy. AB - Multirelational interventions are well described in the psychoanalytic parent infant literature. Daniel Stern (1995) originally suggested and described five "ports of entry" that may be employed to access the multiperson parent-infant clinical system. Other authors have elaborated and extended Stern's original list of ports of entry. The impact of using multiple ports of entry on the psychoanalytic frame, however, is largely neglected in the parent-infant psychotherapy literature. Danielle Quinodoz's (1992) four facets of the psychoanalytic setting are used to structure a discussion of how the multiplicities associated with parent-infant psychotherapy may impact the frame. The article argues strongly for a necessary flexing of the psychoanalytic frame to establish therapeutic alliances. A fifth facet, that of psychoanalytic mindfulness, is offered as a counterbalance to the risks associated with excessive flexing of the frame, particularly in relation to Quinodoz's fourth facet of "refraining from 'doing.'" This article relies on case material to illustrate the issues under discussion. Further engagement and debate are invited. PMID- 25798489 TI - Prenatal and postnatal maternal representations in nonrisk and at-risk parenting: exploring the influences on mother-infant feeding interactions. AB - The aim of this study was to investigate the mother-infant relationship in depressive, psychosocial, and cumulative-risk parenting by assessing prenatal and postnatal maternal representations and mother-infant interactions during feeding at 4 months of age. The sample consisted of 167 mother-infant pairs: 41 nonrisk women, 40 depressive-risk women, 40 psychosocial-risk women, and 46 cumulative risk women. During pregnancy, the women were interviewed about psychosocial-risk variables. Maternal representations and depressive symptoms were evaluated during pregnancy and again when the infants were 3 and 4 months old, respectively. All mother-infant pairs were observed in 20-min video recordings during breast feeding. Maternal Integrated/balanced representations were more frequent in the nonrisk group whereas the maternal Nonintegrated/ambivalent category was more represented in the cumulative-risk group during pregnancy and after the infant's birth. At 4 months, the cumulative-risk group of mothers and infants showed a lack of reciprocity, conflictual communicative exchanges, and higher food refusal behavior. Moreover, at 4 months, differences between the quality of mother-infant feeding interactions and the quality of prenatal and postnatal maternal representations emerged, showing less adequate maternal scaffolding in the Nonintegrated/ambivalent and Restricted/disengaged women. This study has rich implications for intervention to support the affective and communicative caregiving system and to prevent infant feeding problems and mother-infant relational disturbances in childhood. PMID- 25798490 TI - Forward progress of scientific inquiry into the early father-child relationship: introduction to the special issue on very young children and their fathers. AB - Research on fathering and the father-child relationship has made substantial progress in the most recent 15 years since the last special issue of the Infant Mental Health Journal on fathers and young children. This special issue on fathers and young children contains a series of papers exemplifying this progress, including advances in methodology-more direct assessment and more observational measures-in addition to the increasing dynamic complexity of the conceptual models used to study fathers, the diversity of fathers studied, and the growth of programs to support early father involvement. In assessing the current state of the field, special attention is given to contributions made by the papers contained in this special issue, and two critical areas for continued progress are addressed: (1) methodological and measurement development that specifically address fathers and fathering relationships and (2) cross-cultural and ecologically valid research examining the diversity of models of fathering. PMID- 25798491 TI - Progress on the paternal brain: theory, animal models, human brain research, and mental health implications. AB - With a secure foundation in basic research across mammalian species in which fathers participate in the raising of young, novel brain-imaging approaches are outlining a set of consistent brain circuits that regulate paternal thoughts and behaviors in humans. The newest experimental paradigms include increasingly realistic baby-stimuli to provoke paternal cognitions and behaviors with coordinated hormone measures to outline brain networks that regulate motivation, reflexive caring, emotion regulation, and social brain networks with differences and similarities to those found in mothers. In this article, on the father brain, we review all brain-imaging studies on PubMed to date on the human father brain and introduce the topic with a selection of theoretical models and foundational neurohormonal research on animal models in support of the human work. We discuss potentially translatable models for the identification and treatment of paternal mood and father-child relational problems, which could improve infant mental health and developmental trajectories with potentially broad public health importance. PMID- 25798492 TI - Expectant fathers' intuitive parenting: associations with parent characteristics and postpartum positive engagement. AB - This study examined expectant fathers' intuitive parenting behavior and its correlates and associations with fathers' postpartum positive engagement. One hundred eighty-two expectant couples completed the Prenatal Lausanne Trilogue Play in the third trimester of pregnancy. Coders rated expectant fathers' and mothers' intuitive parenting behavior during this procedure. Expectant parents also completed surveys regarding their psychological and demographic characteristics. At 3 months postpartum, fathers completed time diaries that assessed the time that they spent in developmentally appropriate, positive engagement activities with their infants. Examination of correlates of expectant fathers' intuitive parenting behavior revealed that expectant fathers showed lower levels of these behaviors than did expectant mothers, that intuitive parenting behavior was moderately positively associated for mothers and fathers, and that individual differences in expectant fathers' intuitive parenting behavior were associated with parent demographic and psychological characteristics. In particular, expectant fathers showed greater intuitive parenting behavior when they had greater human capital and more progressive beliefs about parent roles, and when their partners had lower parenting self efficacy. Findings also indicated that expectant fathers' greater intuitive parenting behavior was predictive of fathers' greater subsequent engagement in developmentally appropriate activities at 3 months postpartum, but only when expectant mothers demonstrated low levels of intuitive parenting behavior. PMID- 25798493 TI - Father participation in a community-doula home-visiting intervention with young, African American mothers. AB - This article examines the extent and nature of father participation in a perinatal, community-based doula home-visiting intervention that served young, African American mothers from low-income backgrounds and their infants. Home visitor service records were used to assess the quantity, setting, and content of father-attended visits. Correlates of fathers' participation and thematic insights from mothers' and home-visitors' perspectives on how fathers perceived and interacted with the home-visiting program were analyzed to further characterize the nature of father participation. Although the community-doula home-visiting model does not include special outreach to increase father participation, almost half of the mothers had a doula visit at which their baby's father was present, many of which took place in medical settings. Mothers and doulas reported that fathers were generally positive about the doula, but expressed that fathers viewed the doula as a substitute provider of support that fathers seemed reticent to provide themselves. These results suggest that community doulas who visit pre- and postpartum in multiple settings have unique opportunities to have contact with fathers that traditional home visitors or early childhood specialists may not have. PMID- 25798494 TI - Observed coparenting and triadic dynamics in African American fragile families at 3 months' postpartum. AB - This report examines coparenting and triadic interactions in 19 unmarried, first time African American families as fathers, mothers, and 3-month-old infants navigated the Lausanne Trilogue Play (LTP; E. Fivaz-Depeursinge & A. Corboz Warnery, ). Parents in 10 of the 19 families reported coresidence at the time of the 3-month assessment, and the other 9 sets of coparents lived apart. All participating families had taken part in a prenatal intervention emphasizing the importance of father engagement in children's lives, and in all families, parents reported episodic to regular father contact with the children at 3 months. Analyses of LTP sessions revealed that 9 of the 19 families exhibited high levels of coparenting solidarity-cooperation and family warmth accompanied by low levels of coparenting competition and disengagement. Among the remaining 10 families, competitiveness (verbal sparring, interference) and/or disengagement (repeated, episodic absenting by one or both parents from the ongoing interaction) signaled strain and challenges to solidarity. Differences between the higher and lower solidarity groups were found in father-reported relationship rapport. However, coresidentiality versus noncoresidentiality of the parents did not distinguish high- from low-solidarity groups. A case analysis of one family's triadic session is presented to elucidate the rich potential for clinical intervention in triadic work with fragile family systems. Implications of the study and its findings for theory, research, and clinical work with unmarried fathers and families, along with limits of the study design and generalizability of findings, are discussed. PMID- 25798495 TI - An initial examination of the association of reflective functioning to parenting of fathers. AB - Parental reflective functioning (RF) is a parent's capacity to understand and take into account the mental states of their children. Research on RF is somewhat scarce and has focused primarily on mothers. Mothers high in RF have improved parent-child relationships in terms of attachment, sensitivity, and more balanced mental representations of their children, in addition to displaying more caregiving behaviors than do those low in this characteristic. Moreover, better maternal RF appears to be a key to the parenting success of substance-abusing mothers and predicts changes in the caregiving behaviors of these mothers following attachment-based interventions. Research on RF in fathers, on the other hand, has been limited to a few studies. This research has suggested that about half of new fathers have deficits in RF, but did not assess predictors of RF or measure RF in relation to parenting. The present study sought to present an initial exploration of the association of RF to the parenting of fathers in a sample of 79 fathers, approximately half with substance-abuse and violence problems and half without. Fathers were administered the Parent Developmental Interview-Revised (A. Slade, J.L. Aber, I. Bresgi, B. Berger, & M. Kaplan, ) and self-report measures of parenting. Results suggested that less education and increased drug use are associated with lower RF. RF was not predictive of self reported parenting behaviors in this sample. Although RF may vary with substance abuse level and socioeconomic status among men and women, these results indicate that RF may be less associated with parenting behaviors of fathers. However, further research in this area is needed. PMID- 25798496 TI - Low-income, minority fathers' control strategies and their children's regulatory skills. AB - The current study explored the bidirectional association of children's individual characteristics, fathers' control strategies at 24 months, and children's regulatory skills at prekindergarten (pre-K). Using a sample of low-income, minority families with 2-year-olds from the Early Head Start Research and Evaluation Project (n = 71), we assessed the association between child gender and vocabulary skills, fathers' control strategies at 24 months (e.g., regulatory behavior and regulatory language), and children's sustained attention and emotion regulation at prekindergarten. There were three main findings. First, fathers overwhelmingly used commands (e.g., "Do that.") to promote compliance in their 24 month-old children. Second, children's vocabulary skills predicted fathers' regulatory behaviors during a father-child interaction whereas children's gender predicted fathers' regulatory language during an interaction. Third, controlling for maternal supportiveness, fathers' regulatory behaviors at 24 months predicted children's sustained attention at pre-K whereas fathers' regulatory language at 24 months predicted children's emotion regulation at pre-K. Our findings highlight the importance of examining paternal contributions to children's regulatory skills. PMID- 25798497 TI - Mother-child and father-child interaction with their 24-month-old children during feeding, considering paternal involvement and the child's temperament in a community sample. AB - The article aims to study mother-child and father-child interactions with 24 month-old children during feeding, considering the possible influence of time spent by the parent with the child, the infantile temperament, and the parental psychological profile. The families were recruited from 12 preschools in Italy (N = 77 families). Through an observation of the feeding [Scala di Valutazione dell'Interazione Alimentare (SVIA - Feeding Scale; I. Chatoor et al., ; L. Lucarelli et al., )], self-reporting [Symptom Checklist-90-Revised (SCL-90-R; L.R. Derogatis, ), and report-form questionnaires [Italian Questionnaires on Temperament (QUIT; G. Axia, )], and information provided by the parents about the amount of time spent with their children, results showed that the overall quality of father-child interactions during feeding is lower than that of mother-child interactions. Fathers showed higher psychological symptoms than did mothers. No associations were found between the fathers' psychopathological risk and the quality of interactions with their children during feeding. Mothers' psychopathological risks predicted less contingent exchanges interactions with their children during feeding. Children's temperaments significantly influence mother-child interactions, but no association exists between maternal involvement and the quality of interactions with their children. Paternal involvement predicts a better quality of father-infant interactions when associated with a child's higher scores on Social Orientation. The quality of parents' interactions with their children during feeding are impacted by different issues originating from the parent's psychological profile, the degree of involvement, and from the child's temperament. PMID- 25798498 TI - Making children laugh: parent-child dyadic synchrony and preschool attachment. AB - The current study examined whether dyadic synchrony of father-child and mother child interactions in a playful context were associated with attachment organization in preschool children. One hundred seven children (48 boys, Mage = 46.67 months, SD = 8.57) and their mothers and fathers (counterbalanced order of lab visits) participated in a playful interaction without toys (Laughing Task procedure). Playful interactions were coded based on the degree to which the dyads demonstrated a variety of behavior representing dyadic synchrony and task management. Children's attachment behavior toward fathers and mothers was observed in a modified separation-reunion procedure adapted for the preschool period. Results demonstrate that mothers and fathers are similar in their effort to arouse and engage their child in a playful context, but mothers achieved a greater synchrony with their child. Disorganized attachment to either mother or father is linked with a lack of synchrony in dyadic interaction. Findings are in contrast with prevailing theory, suggesting that despite gender-related differences in parental playful behaviors, dyadic synchrony is equally important in both mother- and father-child relationships for the development of organized social and affectional bonds. PMID- 25798499 TI - Maternal depression in association with fathers' involvement with their infants: spillover or compensation/buffering? AB - Both concurrent and prospective associations between maternal depression and father involvement were tested to evaluate support for the spillover model (higher depressive symptom levels associated with lower father involvement) and the compensatory/buffering model (higher depressive symptom levels associated with higher father involvement). Participants in this longitudinal study were women at risk for perinatal depression in association with their histories of mood or anxiety disorders, their husbands/partners, and their infants at 3, 6, and 12 months of age. Maternal depressive symptoms were measured with depression rating scales at multiple times over the infants' first year. Paternal involvement was measured with a questionnaire (relative perceived responsibility) and a time diary (accessibility and engagement) inquiring about a recent weekday and a recent weekend, completed in a telephone interview, at infant ages 3, 6, and 12 months. Findings consistently supported the compensatory/buffering model for depression in the first 6 months' postpartum, along with an indication of spillover regarding maternal depressive symptoms that persist into the second half of the infants' first year. Findings are discussed in terms of implications for clinical practice and policy as well as suggestions for future research. PMID- 25798501 TI - Retooling: evolution in research on fathers - a commentary. PMID- 25798500 TI - Strong, safe, and secure: negotiating early fathering and military service across the deployment cycle. AB - Military fathers of young children often endure repeated separations from their children, and these may disrupt the early parent-child relationship. Postdeployment reunification also poses challenges; disruptions that have occurred must often be repaired in the context of heightened emotions on the part of each family member at a time when fathers are themselves readjusting to the routines and responsibilities of family life. The current study employed qualitative research with the central aim of informing a richer understanding of these experiences. Interviews were conducted with 14 military fathers of young children who had experienced separation from their families during deployment. Narratives were coded using principles of grounded theory, and common parenting themes were extracted. Fathers shared their hopes that their young children would develop qualities of strength, confidence, and self-sufficiency. They also discussed difficulty in supporting the development of these qualities in their young children due to problems dealing with the negative emotions and difficult behaviors that their children exhibited. Reliance on their parenting partner was commonly cited as an effective strategy as fathers transitioned back to family life. Implications for intervention programs include the provision of parenting and self-care skills and inclusion of the father's parenting partner in the intervention. PMID- 25798502 TI - Transition: wrapping up and moving on. PMID- 25798503 TI - Detached parenting and toddler problem behavior in Early Head Start families. AB - This study examined detached parenting among Early Head Start mothers, and associated maternal characteristics and child behavior. Participants included 81 mother-child dyads. Data were collected in participants' homes during two visits. Mothers reported on demographic factors, parenting stress, and children's problem behaviors. Children's neurodevelopment was assessed, and videotaped parent-child play interactions were coded. Path analyses indicated that demographic risk factors and parenting stress were associated with higher levels of detached parenting. As a mediator, detached parenting significantly predicted children's later problem behavior. There was a direct effect of parenting stress on children's behavior problems, but no direct effect of children's neurodevelopmental risk. Detached parenting partially mediated the influence of parenting stress on children's problem behavior. The final model moderately accounted for the variance in detached parenting and children's problem behaviors. The results suggest that parents who experience multiple risks and high levels of parenting stress are more likely to demonstrate detached parenting. In addition, detached parenting leads to higher levels of toddler problem behavior, and may increase the problem behavior displayed by toddlers of parents experiencing multiple risks and parenting stress. These findings are discussed in the context of infant mental health practice. PMID- 25798504 TI - Prevalence and relationship between adverse childhood experiences and child behavior among young children. AB - Exposure to adverse childhood experiences (ACEs) such as child abuse and neglect impact a child's socioemotional development. Drawing from the methods employed in the Adverse Childhood Experiences (ACE; Felitti et al.,) Study, the present study utilized data from the National Survey of Child and Adolescent Well-Being to examine the prevalence of ACEs among children birth to 6 years, and the relationship of ACEs to emotional and behavioral outcomes 59 to 97 months after the close of investigation or assessment. Logistic regression also was used to examine the cumulative impact of ACEs on child behavior outcomes. By the age of 6, approximately 70% of children experienced three or more ACEs, and there were strong relationships between ACEs. Numerous ACEs were associated with long-term behavioral problems, and results supported a dose-response effect. Three or greater ACEs more than quadrupled the risk of experiencing internalizing problems, and almost quadrupled the risk of experiencing either externalizing or total problems at 59 to 97 months' postinvestigation. Based on these findings, it is crucial for both early screening/assessment and increased collaboration between child welfare and early intervention programs. PMID- 25798505 TI - Attendance and implementation of strategies in a behavioral parent-training program: comparisons between English and Espanol programs. AB - Low levels of attendance and implementation of strategies in behavioral parent training programs may limit their impact. The purpose of this study was to examine attendance and implementation across a behavioral parent-training program delivered in English and Espanol. Participants included parents (n = 739) of young children who attended a behavioral parent-training program. The mean number of sessions attended for the entire sample was 4.46 (SD = 1.66, range = 1-6) of six sessions, and the mean number of strategies implemented was 17.66 (SD = 11.43, range = 0-35) of a possible 35. There were no significant differences across the number of sessions attended among the participants in the English (M = 4.45) and Espanol versions (M = 4.48) of the course, t(737) = -0.20, p = .85. There also were no significant differences between the English (M = 17.97) and Espanol (M = 16.87) versions for the number of Tip Trackers completed, t(737) = 1.18, p = .24. Only child diagnosis predicted parent attendance in the English group. Implications for research and practice are discussed. PMID- 25798507 TI - A South African study on caregiver perceptions of a parent-infant intervention implemented to foster secure attachment. AB - Community-based interventions that support the parent-infant dyad present an ideal opportunity to help foster secure attachment relationships. This study set out to investigate a parent-infant intervention that was implemented in a peri urban township in South Africa. The aim of the research was to understand caregivers' experience of this intervention and shed light on why some caregivers make optimal use of this intervention whereas others do not. Data for this study were collected by holding a focus group with 11 caregivers, who were selected using purposive sampling. The discussion that took place in the group was video recorded and transcribed verbatim. Thematic content analysis of this data indicates that caregivers are very receptive to the intervention, which they see in the role of "grandmother." Yet, their socially and economically weak position hinders them from making full use of the intervention. Ideally, they want professionals to reach out to them. This research highlights how important it is for early parent-infant interventions to move beyond the consulting room and to meet caregivers on their terms. PMID- 25798506 TI - Home environments of infants from immigrant families in the United States: findings from the new immigrant survey. AB - Data from the New Immigrant Survey were used to describe the home environments of 638 children ages birth to 3 years whose parents legally immigrated to the United States. Thirty-two indicators of home conditions were clustered into four domains: discipline and socioemotional in support, learning materials, enriching experiences, and family activities. Results revealed variation in how frequently infants from every country (Mexico, El Salvador, India, Philippines) and region (East Asia, Europe, Caribbean, Africa) studied experienced each home environmental condition. There were differences between countries and regions on many indicators as well as differences based on parents' level of education. The experiences documented for children of recent legal immigrants were similar to those documented for children of native-born families in other studies. PMID- 25798508 TI - "New beginnings" in South African shelters for the homeless: piloting of a group psychotherapy intervention for high-risk mother-infant dyads. AB - The New Beginnings program was developed at the Anna Freud Centre and originally piloted in Her Majesty Prisons in the United Kingdom. This study aimed to explore the use of this manualized parent-infant psychotherapy group model in an African setting with high-risk mother-infant dyads, and describes the implementation and investigation of this 12-week group psychotherapy intervention in two Johannesburg shelters for homeless women. The measures used to investigate treatment efficacy were the Parent Development Interview (A. Slade, J.L. Aber, I. Bresgi, B. Berger, & M. Kaplan,), the Emotional Availability Scales (Z. Biringen, J.L. Robinson, & R.N. Emde,), the Kessler-10 (R.C. Kessler et al.,), and the Griffiths Scales of Mental Development (D. Luiz et al., . At pretesting, infants exhibited delays in a number of developmental areas, and mothers showed high levels of depression and generally low capacities for reflective function. While significant shifts in the mothers' capacities for reflective function were not found in the treatment condition, significant shifts were found in the infants' speech abilities and in the mothers' abilities to structure their interactions with their infants. This suggests that the program enabled mothers to become more sensitized to their infants' needs in interaction and that communication between mother and infant increased. The number of sessions attended by the dyads correlated with improvements made by the mothers and their infants. PMID- 25798509 TI - Decreasing harsh discipline in mothers at risk for maltreatment: a randomized control trial. AB - This study tested the effectiveness of the attachment-based program Video feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD; F. Juffer, M.J. Bakermans-Kranenburg, & M.H. van IJzendoorn, 2008) in decreasing harsh discipline of 43 mothers and their 1- to 4-year-old-children from severely deprived families. Based on previous studies, parenting stress was tested as a potential moderator of intervention effects on harsh discipline. Using a randomized control design, maternal harsh discipline was observed during home visits at the pretest and posttest, and mothers filled in questionnaires at both assessments. The VIPP-SD proved to be effective in decreasing maternal harsh discipline, but only for mothers who experienced higher levels of parenting stress at intake. These findings provide support for the program's ability to improve parenting in families who are most at risk for harsh parenting and for potentially maltreating child-parent interactions. The results are discussed in terms of the VIPP-SD elements most relevant to decreasing harsh discipline, and the challenges of parenting interventions in severely deprived populations. PMID- 25798510 TI - Optimizing parent-infant sleep from birth to 6 months: a new paradigm. AB - Currently, the dominant paradigm for infant sleep from birth to 6 months is behavioral sleep interventions that aim to entrain the infant's biological patterns of sleep using techniques such as delayed response to cues, feed-play sleep routines, sleep algorithms, and education of parents about "tired cues" and "overstimulation." A recent systematic literature review has identified that while behavioral sleep interventions may modestly increase the length of time an infant sleeps at night without signaling, they are not associated with improved infant or maternal outcomes and may have unintended negative consequences (Douglas & Hill, 2013). This article reviews the empirical literature on behavioral infant sleep interventions, sleep regulation, and sleep disturbance. Based on the available scientific literature, a new paradigm for infant sleep intervention, from birth to 6 months of age, is proposed. This new approach, the Possums Sleep Intervention, integrates interdisciplinary knowledge from developmental psychology, medical science, lactation science, evolutionary science, and neuroscience with third-wave contextual behaviorism, acceptance and commitment therapy, to create a unique, new intervention that supports parental flexibility, cued care, and the establishment of healthy biopsychosocial rhythms. PMID- 25798511 TI - Imbalances in the knowledge about infant mental health in rich and poor countries: too little progress in bridging the gap. AB - The vast majority of infants are born in poor countries, but most of our knowledge about infants and children has emerged from high-income countries. In 2003, M. Tomlinson and L. Swartz conducted a survey of articles on infancy between 1996 and 2001 from major international journals, reporting that a meager 5% of articles emanated from parts of the world other than North America, Europe, or Australasia. In this article, we conducted a similar review of articles on infancy published between 2002 and 2012 to assess whether the status of cross national research has changed in the subsequent decade. Results indicate that despite slight improvements in research output from the rest of world, only 2.3% of articles published in 11 years included data from low- and middle-income countries--where 90% of the world's infants live. These discrepancies are indicative of the progress still needed to bridge the so-called 10/90 gap (S. Saxena, G. Paraje, P. Sharan, G. Karam, & R. Sadana,) in infant mental health research. Cross-national collaboration is urgently required to ensure expansion of research production in low-resource settings. PMID- 25798512 TI - Efficacy of preventative parenting interventions for parents of preterm infants on later child behavior: a systematic review and meta-analysis. AB - The aim of this systematic review was to determine the efficacy of parenting interventions for parents of preterm infants to improve child behavior. Randomized controlled trials (RCTs) of parenting interventions for parents of preterm infants were included. Searchers were conducted of PubMed from 1951 to April 2013, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1982 to April 2013, Scopus from 1966 to April 2013, PsycINFO from 1840 to April 2013, the Web of Science, and the Cochrane Library. Twelve RCTs were identified that assessed child behavior. Of these studies, only data from three were able to be pooled for meta-analysis: the Infant Health and Development Program (IHDP) at 3 years, the Mother-Infant Transaction Program (modified; MITP M) at 5 years, and the Victorian Infant Brain Studies (VIBeS Plus) at 4 years. Outcome from this analysis revealed a small, but significant, effect on child behavior favoring the intervention (95% CI: 0.08-0.32; p = .001). There is evidence that preterm parenting interventions can improve child behavior. Streamlined interventions such as MITP-M and VIBeS Plus that have a strong focus on the mother-infant relationship may have greatest potential. PMID- 25798513 TI - Attachment and caregiver-infant interaction: a review of observational-assessment tools. AB - The relationship between maternal-infant interaction and attachment quality to infant developmental outcomes has long been established. As children mature, problems stemming from troubled caregiver-infant relations may result in referral to mental health or child protection services. The accurate and appropriate assessment of attachment is critical for early recognition of problematic relations and for informing suitable treatment modalities. Evaluating the quality of attachment poses a challenge for researchers and clinicians seeking to explore the association between infant development and the quality of early caregiving experiences. Although providing a definitive answer to the question of which of these assessment procedures is the single universal standard for measuring attachment quantity is beyond the scope of this article, readers will be provided with a description and comparison of strengths and limitations of the most commonly used measures of attachment, including the Strange Situation Procedure (M.D.S. Ainsworth, M.C. Blehar, E. Waters, & S. Wall, 1978), Attachment Q-Sort (E. Waters & K.E. Deane, 1985), Toddler Attachment Sort (TAS-45; J. Kirkland, D. Bimler, A. Drawneek, M. McKim, & A. Scholmerich, 2004), CARE-Index (P. Crittenden, 1985), Atypical Maternal Behavior Instrument for Assessment and Classification (AMBIANCE; E. Bronfman, E. Parsons, & K. Lyons-Ruth, 1999), Massie Campbell Scale of Mother-Infant Attachment Indicators During Stress Scale (Attachment During Stress Scale; H.N. Massie & B.K. Campbell, 1983), and the Risky Situation Procedure (D. Paquette & M. Bigras, 2010). PMID- 25798514 TI - Global research, practice, and policy issues on the care of infants and young children at risk: the articles in context. AB - This Special Issue includes articles that contribute to (a) the global research base pertaining to the development of infants and toddlers at risk, primarily those who are institutionalized in lower resource countries; (b) interventions in institutions and to promote family alternatives to institutionalization; and (c) attempts to create modern child welfare systems emphasizing family care in entire states and countries. This introduction places these articles into the broader contexts of the literature in these three domains of interest. Across the world, urbanization, migration, armed conflict, epidemics, and famine disrupt families. Add poverty, abuse, neglect, and parental incapacity due to substance abuse and mental health problems, and the result is millions of children without parental care who come under governmental responsibility, often to be reared in institutions, and at risk for long-term developmental deficiencies and problems. Over the last 2 decades and especially recently, national and international governments and nongovernment organizations have increased efforts to help such children, especially those in low-resource countries. Two types of efforts have been made: one to improve the quality of care provided by institutions and the other to minimize the use of institutions and promote family residential care alternatives. The latter effort includes preventing family separations in the first place, reunification of children with birth families, and developing systems of kinship care, foster care, and adoption. This Special Issue of IMHJ is devoted to reports pertaining to issues in the research knowledge base, program practices, and countrywide policies for infants and young children at risk. We attempt in this introduction to place these reports in the broader context of this field, identify their unique contributions, and highlight lessons learned that can contribute to improved care practices and better child welfare systems. PMID- 25798515 TI - Growth, nutritional, and developmental status of young children living in orphanages in Kazakhstan. AB - This article describes the nutritional and developmental status of young children living in Baby Houses (orphanages for children ages 0-3 years) in Kazakhstan. In 2009/2010, 308 children under age 3 years living in 10 Baby Houses were measured for height/length and weight. The Bayley Scales of Infant Development (N. Bayley, 2006) were used to assess mental and motor development. Blood was collected on a subsample to assess key nutritional factors. The World Health Organization growth charts were used to calculate Z-scores. Cut points for wasting (moderate to severe low weight for length/height growth), underweight (low weight for age), stunting (low length/height for age), development, and biomarkers used established guidelines. Most (n = 286) children had complete data on z-scores. Of these, 22.1% were experiencing wasting, 31.5% were underweight, and 36.7% had stunting. The nutritional status of the children, based on blood biomarkers, revealed that 37.1% of the children were anemic, 21.4% had low albumin, 38.1% had low vitamin D, 5.5% were iodine-deficient, and 2% had low serum zinc. One half had mild to significant mental and motor delays. Children living at these Baby Houses in Kazakhstan have substantial nutritional deficits and developmental delays. Focused attention is needed to provide a nutritionally enhanced diet and improved developmental opportunities to improve the long-term outcomes for these children. PMID- 25798516 TI - Maltreatment and mental health in institutional care--comparing early and late institutionalized children in Tanzania. AB - Research has shown the harmful potential of institutional care on young children; however, little is known about the consequences of institutional care on infants in Sub-Saharan Africa. We compared 35 Tanzanian children who were institutionalized at birth to 4 years of age with a matched group of 35 children who were institutionalized at 5 to 14 years of age. We examined adverse childhood experiences over the course of their entire lives, in their family of origin and in institutional care, and mental health problems at primary school age, such as depressive symptoms, aggressive behavior, and internalizing and externalizing problems. Results showed that early institutionalized children reported more adverse experiences during their time in institutional care and a greater variety of mental health problems than did late institutionalized children. Moreover, maltreatment in institutional care was positively related to mental health problems only in early institutionalized children. We conclude that adverse experiences in institutional care play an important role for early institutionalized children who need special care from adequately educated caregivers. Therefore, training concepts focusing on the needs of the youngest children have to be developed, tested, and established. Countries such as Tanzania need policies that apply to all orphanages to ensure an adequate standard of quality in childcare. PMID- 25798517 TI - Behavior problems in children transferred from a socioemotionally depriving institution to St. Petersburg (Russian Federation) families. AB - Behavior problems were studied in fifty 5- to 8-year-old children transferred from a socioemotionally depriving Russian institution to domestic families. Results indicated that the postinstitutional (PI) sample as a whole had higher clinical/borderline behavior problem rates on the parent-reported Child Behavior Checklist for Ages 6-18 (T.M. Achenbach & L.A. Rescorla, 2001) aggressive and lower rates on the withdrawn/depressed and internalizing problems scales than did non-institutionalized (non-I) children reared in Russian families. Compared with the U.S. standardization sample, PI children had significantly higher rates for aggressive, externalizing, and social problems; the non-I children had higher rates for withdrawn/depressed and internalizing problems; and both groups had higher rates for rule-breaking behavioral problems. PI children placed in domestic families at 18 months or older had higher rates of problems than did the U.S. non-I standardization sample, but children placed at younger ages did not. PI children transferred to nonbiological families had lower rates of problems compared to U.S. norms than did children transferred to biological families. Thus, prolonged early socioemotional deprivation was associated with a higher percentage of behavior problems in children placed in domestic families, especially if transferred to biological families. PMID- 25798518 TI - Psychopathology in young children in two types of foster care following institutional rearing. AB - Institutional rearing of young children has been demonstrated to increase risk for a broad range of psychiatric disorders and other impairments. This has led many countries to consider or to invest in foster care. However, no study to date has explored potential differences in psychiatric symptoms in children placed in different types of foster care. We assessed internalizing disorders, externalizing disorders, and attention deficit hyperactivity disorder (ADHD) in 54-month-old children living with foster families. We compared one group of children living in high-quality foster families who had benefited from specialized training and support to another group of children placed with government-sponsored foster care in Bucharest, Romania. After controlling for duration of time spent in foster care, there was a main group effect in predicting ADHD (p = .021) and a marginal group * gender interaction effect. No effects were noted for signs of externalizing disorders. There was, however, a significant group * gender interaction effect of signs of internalizing disorders (p = .007), with the girls in high-quality foster care having less severe symptomatology than did their counterparts in the government-sponsored group. Governments must invest in quality interventions for their most vulnerable citizens to prevent serious and potentially lasting problems. PMID- 25798519 TI - From maid to mother: transforming facilities, staff training, and caregiver dignity in an institutional facility for young children in Nepal. AB - This article provides a case study of a project to improve the health, safety, and development of children birth to 6 years old in a large orphanage in Nepal. Two interventions were conducted: improvement of physical infrastructure and training, mentoring, and support for caregiving staff. As a result of these interventions, positive outcomes in terms of children's health and development have been observed, including reduction of communicable diseases and increased social interactions with caregivers. As part of the new training initiative, the caregivers began to meet regularly to share their ideas and experiences, and came to realize their vital role in the holistic development of the children in their care. One important change was a greater sense of dignity for the caregivers. The caregivers were formerly called Maids (Aaya), but asked to be called Mothers (Aama). The project also faced challenges, including communication barriers related to organizational structure. PMID- 25798520 TI - Residential care for abandoned children and their integration into a family-based setting in Uganda: lessons for policy and programming. AB - This article describes a model of care for abandoned and neglected infants in need of urgent physical, social, and medical support as implemented by the Child's i Foundation, an international, nongovernmental organization operating in Uganda. The model discounts the need for long-term care of young children within institutions and challenges the basis for intercountry adoption. Underpinned by the essentials of care continuum provided under the Uganda National Alternative Care Framework (Ministry of Gender, Labour and Social Development, 2012), the model emphasizes the need to effect the reintegration of the separated child within the family of his or her birth, or locally organize foster care or adoption. Highlighting policy and programming lessons, the model showcases a holistic approach to the problem and puts emphasis on interventions that are protective, promotional, and transformational and the use of a community-oriented approach. The model offers guidance to both government and nongovernment actors in addressing the problems of child neglect and abandonment through the implementation of the alternative care framework. PMID- 25798521 TI - Effects of an intervention to promote socioemotional development in terms of attachment security: a study in early institutionalization in Chile. AB - The Chilean government commissioned a quasi-experimental study with a pre /postintervention design that had two general aims: (a) to assess infants' psychoaffective developmental levels (pre-intervention phase) and (b) to evaluate whether an intervention based on the promotion of socioemotional development modifies the infant's psychoaffective development. Sixty-two institutionalized infants and their alternative caregivers were evaluated at a pre-intervention stage. An intervention then took place, with the caregivers trained according to an "attachment sensitivity manual." Results showed normal ranges of psychomotor development (64% normal, 9% delayed) and a very high frequency of attachment insecurity, as compared to the normative population (53%).The intervention significantly improved social orientation and object orientation as well as activity and reactivity levels. We conclude that although institutionalized infants in Chile do not exhibit high levels of atypical attachment, socioemotional deterioration may lead to vulnerability in present and future development. Finally, the scope of this study affected public policies regarding children, initiating a change to a foster family system and a variety of modifications in the strategies for adopting institutionalized infants. PMID- 25798522 TI - Adoption policy and evidence-based domestic adoption practice: a comparison of Romania, Ukraine, India, Guatemala, and Ethiopia. AB - The United Nations Convention on the Rights of the Child (1989), The Hague Convention on the Protection of Children and Co-operation in Respect of Intercountry Adoption (The Hague Permanent Bureau, 1993), and the Guidelines for the Alternative Care of Children (2009) have provided a comprehensive, rights based framework and guidance for developing domestic adoption and alternative, family based care programs. Domestic adoption is a critical component of any child-protection system and a core part of the range of alternative care options that the United Nations and other international organizations recommend be developed, resourced, and made accessible to children without parental care. This article uses data collected from adoptive parents' postadoption and governmental data in Romania, Ukraine, India, Guatemala, and Ethiopia to focus on domestic adoption in each of these countries. The article highlights both promising practices in domestic adoption as well as policies and practices that require additional research. PMID- 25798523 TI - From institutional care to family support: development of an effective early intervention network in the Nizhny Novgorod Region, Russian Federation, to support family care for children at risk for institutionalization. AB - Despite efforts of the government to reform child protection, Russia continues to rely on institutional care due to the lack of support services for families in crisis, children with disabilities, and foster and adoptive parents.The project goal was to establish a replicable professional model that would direct the child welfare system in the Nizhny Novgorod Region away from institutional care and toward services for young children and their families that reduce the risk of institutionalization. The program was carried out over a 3-year period through a public-private partnership, which included the Ministries of Social Policy and Health of the Nizhny Novgorod Region, Firefly, and KPMG with partial funding by the United States Agency for International Development (USAID). Participation of professionals was excellent, attitudinal changes were extensive, and there were significant improvements in the understanding and utilization of early intervention concepts. The number of visits to program sites increased from essentially none to almost 1,000/month during the course of the project. Difficulties employing standardized child-based measures of success and developing ministry data-collection systems were encountered. Changes within the child welfare system in Russia are possible, but require a knowledgeable and adequately funded and supported program within regions receptive to change. PMID- 25798524 TI - How the Republic of Georgia has nearly eliminated the use of institutional care for children. AB - Countries throughout Eastern Europe and Central Asia struggle to change their childcare systems from one that is predominantly based on large-institution care to one that has a continuum of services and is family-focused. Georgia has shown, in large part, that the laudable goal of ending large-scale institutions for children is possible, including for children under the age of 6 years. Between 2005 and 2013, the Government in the Republic of Georgia closed 32 large, state run institutions housing children without adequate family care. Social work was strengthened, a robust program was created to reunite children with their families, a foster care system was put into place and scaled up, and small group homes housing 8 to 10 children were established. What happened in Georgia is unique in the region. The Ukraine, which by many accounts has 100,000 children living in large, Soviet-style orphanages, has struggled to reform its childcare system. It has been estimated by childcare professionals in the Ukraine that institutional care for children accounts for over 1% of the gross domestic product. Romania, which has made considerable progress over the past 10 years, still has over 40,000 children in large-institution care. This article aims to tell how this transformation was accomplished, the conditions in Georgia that made the reform possible, how the institutions were closed, how the alternatives were established, and how sustainable the progress has been. PMID- 25798525 TI - Mononeuritis multiplex associated with primary livedoid vasculopathy: neuropathological evidence of ischemic nerve damage. PMID- 25798526 TI - A qualitative study of smoking within a Western Sydney Arabic-speaking community: a focus on men in the context of their families. AB - ISSUE ADDRESSED: Smoking rates are high among Arabic-speaking populations, particularly men, and there is limited evidence to formulate effective tobacco control strategies in this group. This study explored smoking within an Arabic speaking community in Sydney, focusing on men's smoking in the context of their families. METHODS: We conducted six focus groups with a total of 60 Arabic speaking participants recruited through health workers, counsellors and community leaders in Western Sydney, Australia. The focus groups, conducted in Arabic or English, discussed smoking experiences, family issues and quit attempts. Focus group data were recorded, transcribed and analysed for emerging themes. RESULTS: Male smoking was normalised in home, social and religious settings. There was concern about children's exposure to environmental tobacco smoke (ETS), but less concern for adults, particularly wives. Smoking created conflict within families and quit attempts were often made without assistance. There was a lack of enthusiasm for telephone support services with participants suggesting free Nicotine Replacement Therapy (NRT) and programs in religious settings as potential strategies. CONCLUSIONS: Smoking is normalised in Arabic-speaking society and is socially acceptable. Strategies to de-normalise smoking, particularly among men, are critical. Ongoing ETS exposure of wives is concerning and suggests the need to empower women to control their exposure. There is an opportunity to create locally tailored interventions by engaging leaders in religious settings and to improve perceptions of telephone support services. SO WHAT?: Culturally appropriate strategies to de-normalise smoking for Arabic speaking male smokers are needed together with novel approaches that incorporate families and involve community leaders. PMID- 25798527 TI - Arsenicosis and stigmatisation. AB - Arsenicosis is believed to have debilitating effects on social relations, but with arsenic poisoning previously associated directly with economic and cognitive impacts, the degree to which stigmatisation is influenced by socio-economic or health status has not been established in the literature. Based on face-to-face interviews with 100 arsenic outpatients from specialist arsenic clinics in rural Bangladesh, this study represents an early quantitative analysis of factors predicting social impacts of arsenicosis. Physical health status, average years of schooling, family size and the presence of non-government organisation (NGO) and government-run arsenic-awareness campaigns significantly predicted social impacts. We found that the presence of awareness-raising activities was by far the most significant predictor of social impacts after other key variables, including gender and income, thus underscoring the importance of public health interventions in mitigating the impact of stigmatised diseases. The study confirms previous qualitative findings that ostracism is a pervasive problem for arsenicosis patients, and that public health interventions can be a valuable counter to such social problems. PMID- 25798528 TI - Bioactive Limonoid Constituents of Munronia henryi. AB - Fourteen new limonoids, munronins A-N (1-14), and eight known limonoids (15-22) were isolated from the whole plants of Munronia henryi. The structures of the new compounds were elucidated by 2D NMR spectroscopy and mass spectrometry, and the structure of 8 was confirmed by single-crystal X-ray diffraction analysis. Compound 1 represents the first limonoid found with a novel 7 oxabicyclo[2.2.1]heptane moiety produced by incorporating C-11 and C-14 via an oxygen atom. All compounds were evaluated for their anti-tobacco mosaic virus (TMV) activity and in vitro cytotoxicity against the human cancer HL-60, SMMC 7721, A-549, MCF-7, and SW-480 cell lines. Among them, compounds 2, 8, 9, 10, 11, 12, 18, and 20 showed significant anti-TMV activity, with IC50 values in the range 19.6-44.4 MUg/mL. Compounds 1 and 18 exhibited cytotoxic effects for all five cancer cell lines, with IC50 values between 0.4 and 4.8 MUM. PMID- 25798529 TI - Structural characterization and anticancer activity of cell-bound exopolysaccharide from Lactobacillus helveticus MB2-1. AB - A novel cell-bound exopolysaccharide (c-EPS) was isolated from Lactobacillus helveticus MB2-1 by ultrasonic extraction, anion exchange, and gel filtration chromatography before being structurally characterized. The c-EPS is a heteropolysaccharide with an average molecular weight of 1.83 * 10(5) Da and is composed of glucose, mannose, galactose, rhamnose, and arabinose at a molar ratio of 3.12:1.01:1.00:0.18:0.16. Methylation analysis and nuclear magnetic resonance analysis revealed that the c-EPS is a linear glucomannogalactan containing repeating units of -> 6)-beta-D-Manp-(1 -> 3)-beta-D-Glcp-(1 -> 3)-beta-D-Glcp-(1 -> 3)-beta-D-Glcp-(1 -> 4)-alpha-D-Galp-(1 -> and trace amounts of Rhap-(1 -> and (1 -> 4)-Arap residues. Complex formation with Congo red demonstrated a triple strand helical conformation for the c-EPS. Scanning electron microscopy of the c EPS revealed many regular feather-like structural units. Topographical examination of c-EPS by atomic force microscopy revealed that the c-EPS formed rounded-to-spherical lumps with different sizes and chain formations. Furthermore, preliminary in vitro tests revealed that c-EPS significantly inhibited the proliferation of HepG-2, BGC-823, and especially HT-29 cancer cells. PMID- 25798532 TI - Simple ethanol impregnation treatment can enhance photocatalytic activity of TiO2 nanoparticles under visible-light irradiation. AB - Doping with impurities as well as introducing oxygen vacancies has been recognized as an important means to enhance photocatalytic activity of TiO2 under visible-light irradiation. Here we report that simple ethanol impregnation followed with mild heat treatment (150-400 degrees C) can color TiO2 nanoparticles and enhance visible-light photocatalytic activity of the material. The coloration and photocatalytic activity for beta-naphthol and rhodamine B (RhB) degradation were observed to be dependent on heat-treatment temperature, and the highest activity as well as the most coloration was obtained at temperatures around 200 to 250 degrees C. Comprehensive analyses based on X-ray photoelectron spectroscopy (XPS) and electron paramagnetic resonance (EPR) investigations as well as first-principle density functional calculation suggest that the simple ethanol impregnation treatment leads to the generation of oxygen vacancy on TiO2 surface which should be responsible for the coloration and enhanced photocatalytic activity. PMID- 25798530 TI - The role of PI3K/Akt in human herpesvirus infection: From the bench to the bedside. AB - The phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway regulates several key cellular functions including protein synthesis, cell growth, glucose metabolism, and inflammation. Many viruses have evolved mechanisms to manipulate this signaling pathway to ensure successful virus replication. The human herpesviruses undergo both latent and lytic infection, but differ in cell tropism, growth kinetics, and disease manifestations. Herpesviruses express multiple proteins that target the PI3K/Akt cell signaling pathway during the course of their life cycle to facilitate viral infection, replication, latency, and reactivation. Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus associated malignancies. Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections. PMID- 25798531 TI - Adenovirus membrane penetration: Tickling the tail of a sleeping dragon. AB - As is the case for nearly every viral pathogen, non-enveloped viruses (NEV) must maintain their integrity under potentially harsh environmental conditions while retaining the ability to undergo rapid disassembly at the right time and right place inside host cells. NEVs generally exist in this metastable state until they encounter key cellular stimuli such as membrane receptors, decreased intracellular pH, digestion by cellular proteases, or a combination of these factors. These stimuli trigger conformational changes in the viral capsid that exposes a sequestered membrane-perturbing protein. This protein subsequently modifies the cell membrane in such a way as to allow passage of the virion and accompanying nucleic acid payload into the cell cytoplasm. Different NEVs employ variations of this general pathway for cell entry (Moyer and Nemerow, 2011, Curr. Opin. Virol., 1, 44-49), however this review will focus on significant new knowledge obtained on cell entry by human adenovirus (HAdV). PMID- 25798533 TI - Surveillance against the odds: Addressing the challenges of animal health surveillance. Introduction. PMID- 25798534 TI - A cross-sectional study on the prevalence and risk factors for foot and limb lesions in piglets on commercial farms in Ireland. AB - A cross-sectional survey of 68 integrated Irish pig farms was conducted to determine the prevalence and risk factors for foot and limb lesions in 2948 piglets from 272 litters. One litter was selected per age category; 3-7 days, 8 14 days, 15-21 days and 22-28 days per farm. All piglets were examined for sole bruising, sole erosion, coronary band injuries, limb abrasions, alopecia, swollen limbs and swollen feet and scored from 0 to 3 based on relative size. Environmental parameters were recorded for each litter examined. A questionnaire was completed on management, health and performance factors for each farm. The overall prevalence of each lesion was calculated and multilevel mixed effect logistic regression models were used to elucidate risk factors. The prevalence (farm range) of lesions were: sole bruising=61.5% (7-100%), sole erosion=34.1% (0 100%), coronary band injuries=11.3% (0-46%), limb abrasions=55.7% (11-98%), alopecia=24.8% (0-83%), swollen limbs=2.4% (0-11%) and swollen feet=4.4% (0-14%). Age was negatively associated with sole bruising (OR 0.42; CI 0.37, 0.50) and coronary band injury (OR 0.69; CI 0.60, 0.81) and positively associated with limb abrasions (OR 1.54; CI 1.12, 2.14). There was a reduced risk of sole bruising in piglets in pens with plastic slats with oval voids in the piglet area of the pen with a plastic solid area for piglets and metal slats under the crate (OR 0.32; CI 0.15, 0.70) compared with plastic stats throughout and a plastic solid area for piglets. There was an increased risk of sole erosion (OR 1.81; CI 1.07, 3.09) and foot and limb swellings (OR 1.90; CI 1.01, 3.57) in pigs in pens with metal slats only and a solid plastic area for piglets compared with plastic stats throughout and a solid plastic area for piglets. There was an increased risk of coronary band injury in pens with metal slats throughout and a metal solid area for piglets (OR 4.25; CI 1.96, 3.57) compared with plastic stats throughout and a plastic solid area for piglets. We conclude no single floor type was ideal for piglet foot and limb health with all floors influencing different lesions in different ways, however, the positive association between sole erosions, coronary band injury and foot and limb swellings and metal slats suggest that this floor type was most detrimental and most likely to be associated with joint infections that lead to severe health and welfare concerns. PMID- 25798535 TI - Coadministration of HMG-CoA reductase inhibitors, atorvastatin and rosuvastatin, does not affect contraceptive efficacy of centchroman. AB - OBJECTIVE: The study aimed to investigate the effect of concomitant use of atorvastatin or rosuvastatin on the pharmacokinetic and pharmacodynamic profile of centchroman, a non-steroidal female oral contraceptive. METHODS: A rat model was used to predict pharmacokinetic drug-drug interactions between centchroman and atorvastatin or rosuvastatin. A dried blood spot sampling technique followed by liquid chromatography-tandem mass spectrometry detection was employed for analysis of the pharmacokinetic interaction study samples. Sperm-positive female rats were investigated for postcoital contraceptive activity of centchroman with or without coadministration of atorvastatin or rosuvastatin. RESULTS: Coadministration of atorvastatin or rosuvastatin may increase the systemic availability of centchroman in blood, but it does not affect the pharmacodynamic profile of centchroman. CONCLUSION: Atorvastatin or rosuvastatin may be prescribed with centchroman without compromising the contraceptive efficacy of centchroman. PMID- 25798536 TI - Derived Trail Making Test indices: demographics and cognitive background variables across the adult life span. AB - We examined the contribution of demographics and cognitive background variables (processing speed, visuospatial skill, working memory, and interference control) on derived Trail Making Test (TMT) scores in a large sample of Greek healthy participants. We included 775 participants and administered the TMT (TMT-A and TMT-B) and the Wechsler Intelligence Adult Scale (WAIS). Direct (TMT-A & TMT-B time-to-completion) and derived [difference TMT-(B - A) & ratio TMT-(B/A)] scores were calculated. Demographics (age, age(2), education, and gender) and WAIS Full Intelligence Quotient significantly predicted the direct TMT-A (R(2) = 0.426) and TMT-B (R(2) = 0.593) scores and to a lesser extent, the derived TMT-(B - A) (R(2) = 0.343) and TMT-(B/A) (R(2) = 0.088) scores. In a subsample of 537 healthy participants who also completed the Stroop Neuropsychological Screening Test (SNST), demographics (age and education), WAIS Digit Symbol, Block Design, Arithmetic, and SNST accounted for 44.8% and 59.7% of the variance on TMT-A and TMT-B, and 32.5% and 9.6% of the variance on TMT-(B - A) and TMT-(B/A), respectively. We found minimal influence of Block Design and Arithmetic on TMT-(B - A) and an absence of significant influence of any cognitive variable on TMT (B/A) score. Concluding, derived TMT scores are suggested as indices to detect impairment in cognitive flexibility across the adult life span, since they minimize the effect of demographics and other cognitive background variables. PMID- 25798537 TI - Univariate and bivariate symbolic analyses of cardiovascular variability differentiate general anesthesia procedures. AB - General anesthesia attenuates autonomic function and baroreflex control. This side effect should be prevented as much as possible because it limits the subject's ability in responding to physiological challenges during surgery (e.g. arterial pressure and ventricular contractility drops). This study is designed to rank two of the most commonly exploited general anesthesia treatments, i.e. intravenous anesthesia (IA) based on a propofol-opioid combination and volatile anesthesia (VA) based on a sevoflurane-opioid combination, according to their ability to maintain autonomic nervous system activity and baroreflex control. Univariate and bivariate symbolic techniques were applied to spontaneous heart period (HP) and systolic arterial pressure (SAP) variability series recorded during IA and VA procedures in 19 and 18 patients undergoing elective intracranial neurosurgery. Traditional linear univariate and bivariate frequency domain markers of the autonomic nervous system state and baroreflex control were evaluated as well. We found that: (i) univariate symbolic analysis of HP series suggests a better preservation of vagal modulation in VA than in IA; (ii) bivariate symbolic markers assessing the degree of HP-SAP association differentiate IA from VA, while baroreflex sensitivity and squared coherence function cannot; (iii) bivariate symbolic analysis indicates a better preservation of the HP-SAP association at slow frequencies in IA than in VA, thus suggesting a more active baroreflex control in IA. We conclude that symbolic indexes can be fruitfully exploited to rank general anesthesia treatments, and their performance appears to be superior to that of more traditional linear markers. PMID- 25798538 TI - Utilizing pulsed laser deposition lateral inhomogeneity as a tool in combinatorial material science. AB - Pulsed laser deposition (PLD) is widely used in combinatorial material science, as it enables rapid fabrication of different composite materials. Nevertheless, this method was usually limited to small substrates, since PLD deposition on large substrate areas results in severe lateral inhomogeneity. A few technical solutions for this problem have been suggested, including the use of different designs of masks, which were meant to prevent inhomogeneity in the thickness, density, and oxidation state of a layer, while only the composition is allowed to be changed. In this study, a possible way to take advantage of the large scale deposition inhomogeneity is demonstrated, choosing an iron oxide PLD-deposited library with continuous compositional spread (CCS) as a model system. An Fe2O3 Nb2O5 library was fabricated using PLD, without any mask between the targets and the substrate. The library was measured using high-throughput scanners for electrical, structural, and optical properties. A decrease in electrical resistivity that is several orders of magnitude lower than pure alpha-Fe2O3 was achieved at ~20% Nb-O (measured at 47 and 267 degrees C) but only at points that are distanced from the center of the PLD plasma plume. Using hierarchical clustering analysis, we show that the PLD inhomogeneity can be used as an additional degree of freedom, helping, in this case, to achieve iron oxide with much lower resistivity. PMID- 25798539 TI - RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer. AB - We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2alpha are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expression of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinase(T172) [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKKbeta pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation. PMID- 25798541 TI - DOCK8 primary immunodeficiency syndrome. PMID- 25798540 TI - Differences in planning performance, a neurocognitive endophenotype, are associated with a functional variant in PER3 gene. AB - Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3 VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogota, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p = 0.003). These results appear to be independent from effects of this polymorphism on self reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders. PMID- 25798542 TI - In situ X-ray diffraction monitoring of a mechanochemical reaction reveals a unique topology metal-organic framework. AB - Chemical and physical transformations by milling are attracting enormous interest for their ability to access new materials and clean reactivity, and are central to a number of core industries, from mineral processing to pharmaceutical manufacturing. While continuous mechanical stress during milling is thought to create an environment supporting nonconventional reactivity and exotic intermediates, such speculations have remained without proof. Here we use in situ, real-time powder X-ray diffraction monitoring to discover and capture a metastable, novel-topology intermediate of a mechanochemical transformation. Monitoring the mechanochemical synthesis of an archetypal metal-organic framework ZIF-8 by in situ powder X-ray diffraction reveals unexpected amorphization, and on further milling recrystallization into a non-porous material via a metastable intermediate based on a previously unreported topology, herein named katsenite (kat). The discovery of this phase and topology provides direct evidence that milling transformations can involve short-lived, structurally unusual phases not yet accessed by conventional chemistry. PMID- 25798543 TI - Early socioeconomic adversity, youth positive development, and young adults' cardio-metabolic disease risk. AB - OBJECTIVE: Recent research suggests that psychosocial resources, including self esteem, personality, and educational attainment, may be mechanisms explaining the socioeconomic variation in health risks. However, less research has examined this possibility over the early life course. METHOD: A nationally representative sample of 12,424 respondents with data collected over a 13-year period from National Longitudinal Study of Adolescent to Adult Health (Add Health) was examined. This study utilized a cumulative measure of early socioeconomic adversity capturing multiple dimensions of adversity to test resource focused models in a structural equation framework estimating the influence of early adversity on young adults' (ages 25-34) risk for cardio-metabolic disease, as measured by metabolic and cardiovascular bio-markers, through psychosocial resources (i.e., self-esteem, personality, and educational attainment). Lastly, potential model differences by sex and race/ethnicity were examined. RESULTS: The findings showed that early adversity contributed to young adults' cardio metabolic disease risk directly. Additionally, early adversity increased young adults' cardio-metabolic disease risk indirectly through its' negative influence on the development of youths' psychosocial resources: self-esteem, positive personality, and educational attainment. The association between psychosocial resources and young adults' cardio-metabolic disease risk differed for men and women and across racial/ethnic groups. CONCLUSIONS: These findings contribute valuable knowledge to existing research by elucidating how early adversity exerts an enduring long-term influence on young adults' cardio-metabolic disease risk directly and indirectly through psychosocial resources. Furthermore, this information suggests that effective intervention and prevention programs should focus on early adversity and the development of youths' psychosocial resources. PMID- 25798544 TI - Depression trajectories, inflammation, and lifestyle factors in adolescence: The TRacking Adolescents' Individual Lives Survey. AB - OBJECTIVE: In adults, depression and inflammation are bidirectionally related. This association is less clear in adolescents. Moreover, somatic and cognitive depressive symptoms might be differentially related to inflammation. Lifestyle factors, as in adults, may play an important mediating role in adolescents. For the current study we evaluated trajectories of depressive symptoms in adolescence over a 5-year course and their relation with subsequent high-sensitivity C reactive protein (hsCRP) levels, and examined lifestyle factors as mediators. METHOD: Participants of the TRacking Adolescents' Individual Lives' Survey (TRAILS; N = 1166) were followed from 2001 until 2008. Three biennial youth self report (YSR) assessments of depressive symptoms were taken. Demographics, health, and lifestyle factors and levels of hsCRP were assessed at Wave 3. Latent-class analysis was used to determine trajectories of depression and general linear models to determine the association between depression trajectories and hsCRP. Finally, mediation analysis was performed to test mediation of lifestyle factors. RESULTS: Persistently moderate to high depressive symptoms were associated with higher hsCRP levels. Results were unaltered when we adjusted for demographics and health variables. Smoking mediated the association between depressive symptoms total score and hsCRP, in large part. Persistently higher scores on somatic and cognitive symptom subscales were associated with higher levels of hsCRP than persistently low scores. These results were rendered nonsignificant after covariate adjustment. CONCLUSION: Persistent depressive symptoms were associated with subsequent higher levels of hsCRP, with somatic and cognitive symptoms contributing equally. The association was mediated by smoking behavior. These findings suggest that reducing adolescent depression and smoking are important starting points in the prevention of inflammatory diseases. PMID- 25798546 TI - Pectineal Ligament Hysteropexy for Uterine Prolapse in Premenopausal Women by Open and Laparoscopic Approach in Indian Urban and Rural Centers. AB - OBJECTIVE: The aim of this study was to evaluate (a) the surgical outcomes of pectineal ligament hysteropexy (PLH) for uterine prolapse by laparotomy and (b) the feasibility and safety of the procedure by laparoscopic route. METHODS: This is a retrospective consecutive case series of women who underwent PLH from January 1998 to December 2011. The prolapsed uterus was suspended with polyester tape to pectineal ligament on either side through a Cherney incision or laparoscopically at 3 urban and 3 rural hospitals in India. RESULTS: In 194 women who underwent PLH (176 open and 18 laparoscopic), there were no intraoperative complications. The mean follow-up was 6.5 years (range, 0.5-12 years) for open method and 1 year (range, 0.5-2 years) for laparoscopic approach. There were 46 births in 40 women after the procedure including 32 vaginal and 14 cesarean deliveries. Overall, 10 women (5.1%) had uterine prolapse recurrence; 7 of these occurred after vaginal delivery. One woman had tape erosion into the bladder because of pelvic tuberculosis. At follow-up, 12 women developed cystocele, and 7 women developed portio vaginalis elongation. There were no postoperative enteroceles. Overall reoperation rate was 14.9%. Laparoscopic PLH had minimal morbidity with no recurrence over 2 years. CONCLUSIONS: Open PLH for uterine prolapse may be safely performed and gives durable support to the prolapsed uterus with low recurrence risk. PMID- 25798545 TI - Depressive symptoms, daily stress, and adherence in late adolescents with type 1 diabetes. AB - OBJECTIVE: To examine whether depressive symptoms are associated with greater perceived daily stress and moderate the link between stress severity and poorer daily adherence in late adolescents with Type 1 diabetes (T1D). METHOD: 175 late adolescents with T1D completed measures of depressive symptoms and glycemic control during a baseline laboratory assessment. This assessment was followed by a 14-day daily diary during which adolescents rated the severity of general (GS) and diabetes-specific (DSS) stressful events, as well as adherence to their diabetes regimen. RESULTS: Multilevel modeling revealed that adolescents with more depressive symptoms reported more severe daily stress and poorer daily adherence on average, and had poorer glycemic control. On days with more severe DSS, but not GS, adolescents reported poorer adherence. This association was moderated by an interaction between depressive symptoms and the mean level of DSS severity experienced across the 2-week diary. In adolescents with low levels of depressive symptoms, poorer adherence was reported on days with more severe DSS across all levels of mean DSS severity. In adolescents with average or high levels of depressive symptoms, poorer adherence was reported on days with more severe DSS only when mean DSS severity was average or high. CONCLUSIONS: Depressive symptoms are associated with poorer daily adherence and greater stress severity, and interact with mean DSS severity to moderate the link between daily stress and adherence. The results point to the importance of depressive symptoms for understanding associations between stress and adherence during late adolescence. PMID- 25798547 TI - High levels of polybrominated diphenyl ethers in vacuum cleaner dust from California fire stations. AB - Firefighters are exposed to chemicals during fire events and may also experience chemical exposure in their fire stations. Dust samples from used vacuum cleaner bags were collected from 20 fire stations in California and analyzed for polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs) using gas chromatography-mass spectrometry. Median dust concentrations were higher for PBDEs (e.g., 47 000 ng/g for BDE-209) than for PAHs (e.g., 220 ng/g for benzo[a]pyrene) or PCBs (e.g., 9.3 ng/g for PCB 180). BDE-209 concentrations in dust from California fire stations were among the highest of any previously documented homes or occupational settings in the world. We examined factors such as the frequency of emergency responses, the number of fire vehicles on site, and building age, but we could not account for the high levels of BDE-209 observed in fire station dust. Based on the findings of our pilot study, we hypothesize that possible sources of BDE-209 in fire stations include contaminated ash tracked back from fire events via boots, clothing, and other equipment as well as specialized equipment treated with BDE-209, including turnout gear and fire vehicles. We suggest possible follow-up studies to confirm these hypotheses. PMID- 25798548 TI - Revisiting the Kinetics and Thermodynamics of the Low-Temperature Oxidation Pathways of Alkanes: A Case Study of the Three Pentane Isomers. AB - This paper describes our developing understanding of low-temperature oxidation kinetics. We have investigated the ignition of the three pentane isomers in a rapid compression machine over a wide range of temperatures and pressures, including conditions of negative temperature coefficient behavior. The pentane isomers are small alkanes, yet have structures that are complex enough to allow for the application of their kinetic and thermochemical rules to larger molecules. Updates to the thermochemistry of the species important in the low temperature oxidation of hydrocarbons have been made based on a thorough literature review. An evaluation of recent quantum-chemically derived rate coefficients from the literature pertinent to important low-temperature oxidation reaction classes has been performed, and new rate rules are recommended for these classes. Several reaction classes have also been included to determine their importance with regard to simulation results, and we have found that they should be included when developing future chemical kinetic mechanisms. A comparison of the model simulations with pressure-time histories from experiments in a rapid compression machine shows very good agreement for both ignition delay time and pressure rise for both the first- and second-stage ignition events. We show that revisions to both the thermochemistry and the kinetics are required in order to replicate experiments well. A broader validation of the models with ignition delay times from shock tubes and a rapid compression machine is presented in an accompanying paper. The results of this study enhance our understanding of the combustion of straight- and branched-chained alkanes. PMID- 25798549 TI - Basaloid squamous cell carcinoma of the maxilla: Report of a case and literature review. AB - PURPOSE: Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma characterized by a highly aggressive clinical course. Though typically found in the larynx, oropharynx, and hypopharynx, we report a rare case of BSCC originating in the maxillary sinus in an otherwise healthy 32-year-old male. MATERIALS AND METHODS: Single case report of a patient with BSCC of the maxillary sinus and retrospective chart review of all cases of BSCC of the maxilla at a single academic institution between January 1, 1986 and December 31, 2013. The MEDLINE database was additionally queried for all case series or reports of BSCC arising in the maxilla, and pertinent clinical data were extracted. RESULTS: The clinical presentation, disease course, and management of a patient with BSCC of the maxilla are presented. In this recent case, the patient presented with persistent alveolar pain and a nonhealing tooth infection. Radiographic studies demonstrated a large necrotic mass in the left maxillary sinus that was biopsy-proven as BSCC. The patient underwent surgical resection followed by postoperative radiation without complications. CONCLUSIONS: BSCC of the maxilla is a rare oncologic entity that may progress to late disease stage without obvious clinical signs or symptoms. Optimal treatment involves complete surgical resection followed by postoperative. PMID- 25798550 TI - Electronically coupled hybrid structures by graphene oxide directed self-assembly of Cu(2-x)S nanocrystals. AB - Here, we describe an electronically coupled hybrid material consisting of graphene oxide (GO) flakes and inorganic Cu(2-x)S nanocrystals (NCs) formed via a self-assembly route. As a result of the amphiphilic nature of the water dispersible GO flakes, the hydrophobic Cu(2-x)S NCs self-assemble in between the GO flakes, resulting in a large-interface hybrid structure with ordered close packed NCs. We demonstrate that the optical properties of the hybrid GO/Cu(2-x)S structures are governed by the injection of electrons from the GO flakes to the valence band of the vacancy-doped plasmonic Cu(2-x)S NCs. This leads to a suppression of the plasmon band of the Cu(2-x)S NCs and to a softening of the Raman G-band of the GO flakes. Our results indicate that graphene derivatives can act not only as a self-assembly directing template, but also as a tool to affect the optical properties of self-assembled NCs in a chemical process, enhanced by the high interface area of the composite. PMID- 25798551 TI - Social network approaches to leadership: an integrative conceptual review. AB - Contemporary definitions of leadership advance a view of the phenomenon as relational, situated in specific social contexts, involving patterned emergent processes, and encompassing both formal and informal influence. Paralleling these views is a growing interest in leveraging social network approaches to study leadership. Social network approaches provide a set of theories and methods with which to articulate and investigate, with greater precision and rigor, the wide variety of relational perspectives implied by contemporary leadership theories. Our goal is to advance this domain through an integrative conceptual review. We begin by answering the question of why-Why adopt a network approach to study leadership? Then, we offer a framework for organizing prior research. Our review reveals 3 areas of research, which we term: (a) leadership in networks, (b) leadership as networks, and (c) leadership in and as networks. By clarifying the conceptual underpinnings, key findings, and themes within each area, this review serves as a foundation for future inquiry that capitalizes on, and programmatically builds upon, the insights of prior work. Our final contribution is to advance an agenda for future research that harnesses the confluent ideas at the intersection of leadership in and as networks. Leadership in and as networks represents a paradigm shift in leadership research-from an emphasis on the static traits and behaviors of formal leaders whose actions are contingent upon situational constraints, toward an emphasis on the complex and patterned relational processes that interact with the embedding social context to jointly constitute leadership emergence and effectiveness. PMID- 25798552 TI - The effects of civility on advice, leadership, and performance. AB - Workplace incivility is rampant and on the rise-with costs to individuals and organizations. Despite the increased need for civility, little is known about potential individual benefits of civility, defined as behavior involving politeness and regard for others in the workplace, within workplace norms for respect (Andersson & Pearson, 1999). Recent research has suggested that being civil may be hazardous to influence, power, and income (see Forni, 2002; Judge et al., 2012).Yet, throughout history, civil behavior has been extolled because it paid dividends to the person who behaved well. The focus of this research is whether that holds true in organizations. Using social exchange theory, we developed hypotheses about how civility benefits people, and investigated this in 2 studies. First, in a 2-wave social network study of a research and development department (n = 31) of a biotechnology firm, we found that people who perceived a colleague as civil would be more likely to seek that person out for work advice and to see that person as a leader. The more the individual was perceived as civil by others in his or her network, the better his or her performance. Being sought out for work advice and being viewed as a leader mediated this effect. In the second experiment (n = 162), we extended our understanding of what drove these benefits. We found that people who are civil were perceived as warm and competent, and these positive perceptions, in turn, helped to explain the benefits garnered. We discuss theoretical and practical implications. PMID- 25798553 TI - Destructive de-energizing relationships: How thriving buffers their effect on performance. AB - In this paper, we establish the relationship between de-energizing relationships and individual performance in organizations. To date, the emphasis in social network research has largely been on positive dimensions of relationships despite literature from social psychology revealing the prevalence and detrimental impact of de-energizing relationships. In 2 field studies, we show that de-energizing relationships in organizations are associated with decreased performance. In Study 1, we investigate how de-energizing relationships are related to lower performance using data from 161 people in the information technology (IT) department of an engineering firm. In Study 2, in a sample of 439 management consultants, we consider whether the effects of de-energizing relationships on performance may be moderated by the extent to which an individual has the psychological resource of thriving at work. We find that individuals who are thriving at work are less susceptible to the effects of de-energizing relationships on job performance. We close by discussing implications of this research. PMID- 25798554 TI - It matters how old you feel: Antecedents and performance consequences of average relative subjective age in organizations. AB - This article extends the conceptual knowledge of average relative subjective age in organizations by exploring organizational-level antecedents and consequences of employees, on average, feeling younger than their chronological age. We draw from the theories of selection-optimization-compensation and socioemotional selectivity to build a theoretical framework for relative subjective age in organizations. We hypothesize that companies in which employees, on average, perceive themselves to be younger than they actually are have a higher average individual goal accomplishment and, in turn, experience higher company performance. We further hypothesize that employees' average experience of high work-related meaning relates to a lower subjective age in organizations. In addition, we assess the role of environmental dynamism and age-inclusive human resource management as moderators in this theoretical model. Through empirically testing this model in a multisource dataset, including 107 companies with 15,164 participating employees, we received support for the hypothesized relationships. Our results contribute to current debates in the scientific literature on age and have important practical implications in light of the demographic changes faced by many companies. This research indicates to both researchers and practitioners that it is not employees' chronological age but their subjective age, a factor that can be influenced, which drives organizational performance outcomes. PMID- 25798555 TI - A review of the content, criterion-related, and construct-related validity of assessment center exercises. AB - This study uses meta-analysis and a qualitative review of exercise descriptions to evaluate the content, criterion-related, construct, and incremental validity of 5 commonly used types of assessment center (AC) exercises. First, we present a meta-analysis of the relationship between 5 types of AC exercises with (a) the other exercise types, (b) the 5-factor model of personality, (c) general mental ability (GMA), and (d) relevant criterion variables. All 5 types of exercises were significantly related to criterion variables (rho = .16-.19). The nomological network analyses suggested that the exercises tend to be modestly associated with GMA, Extraversion and, to a lesser extent, Openness to Experience but largely unrelated to Agreeableness, Conscientiousness, and Emotional Stability. Finally, despite sparse reporting in primary studies, a content analysis of exercise descriptions yielded some evidence of complexity, ambiguity, interpersonal interaction, and fidelity but not necessarily interdependence. (PsycINFO Database Record PMID- 25798556 TI - Microbleeds, Mortality, and Stroke in Alzheimer Disease: The MISTRAL Study. AB - IMPORTANCE: Microbleeds are more prevalent in patients with Alzheimer disease (AD) compared with the general elderly population. In addition, microbleeds have been found to predict mortality in AD. OBJECTIVE: To investigate whether microbleeds in AD increase the risk for mortality, stroke (including intracerebral hemorrhage), and cardiovascular events. DESIGN, SETTING AND PARTICIPANTS: The MISTRAL (do MIcrobleeds predict STRoke in ALzheimer's disease) Study is a longitudinal cohort study within the memory clinic-based Amsterdam Dementia Cohort. We selected all patients with AD with a baseline visit between January 2, 2002, and December 16, 2009, and microbleeds (n = 111) and matched those (1:2) for age, sex, and magnetic resonance imaging scanner to 222 patients with AD without microbleeds. After a minimal follow-up of 3 years, information on all-cause mortality, stroke-related mortality, and cardiovascular mortality was obtained between November 1, 2012, and May 1, 2014. In addition, we obtained information on the occurrence of incident stroke or transient ischemic attack, cardiovascular events, and nursing home admittance. MAIN OUTCOMES AND MEASURES: Stroke-related mortality, incident stroke, and intracerebral hemorrhage. RESULTS: Patients had a mean (SD) age of 71.2 (7.8) years and 127 (42%) were female. Compared with having no microbleeds, microbleeds in lobar locations were associated with an increased risk for stroke-related mortality (hazard ratio [HR], 33.9; 95% CI, 2.5-461.7), whereas nonlobar microbleeds were associated with an increased risk for cardiovascular mortality (HR, 12.0; 95% CI, 3.2-44.7). In addition, lobar microbleeds were associated with an increased risk for incident stroke (HR, 3.8; 95% CI, 1.5-10.1) and nonlobar microbleeds with an increased risk for cardiovascular events (HR, 6.2; 95% CI, 1.5-25.0). Even higher risks for incident stroke and cardiovascular events were found in patients using antithrombotic medication. All 5 patients with an intracerebral hemorrhage had lobar microbleeds at baseline; 4 of them used antithrombotics. CONCLUSIONS AND RELEVANCE: In patients with AD, the presence of nonlobar microbleeds was associated with an increased risk for cardiovascular events and cardiovascular mortality. Patients with lobar microbleeds had an increased risk for stroke and stroke-related mortality, indicating that these patients should be treated with the utmost care. PMID- 25798557 TI - Aqueous Cr (VI) removal by Friedel's salt adsorbent prepared from calcium aluminate-rich cementitious materials. AB - This research paper investigated a novel absorbent of calcium aluminate-rich cementitious materials (Friedel's salt adsorbent, FA) for aqueous hexavalent chromium (VI) removal. The adsorption kinetics showed that the maximum adsorption capacities of FA were 3.36, 14.66, and 26.17 mg/g when the initial Cr(VI) concentration was 10, 50, and 100 mg/L, respectively. The adsorption fitted with the pseudo-second-order kinetic model, suggesting the important roles of intercalation in the adsorption process with increasing Cr(VI) concentrations. This Friedel's salt adsorbent is suggested as an adaptive and effective adsorbent for Cr(VI) removal in contaminated groundwater. PMID- 25798564 TI - [Perineal hypospadia in a red Holstein-calf. A case report]. AB - Hypospadia is a congenital deformation of the urethra. Several surgical correction methods have been described, but there are also cases when an operation is not necessarily required. In this report, the case of a bull calf which did not need an invasive therapy will be presented. PMID- 25798565 TI - Assessing percutaneous intervention: re-appraising the significance of residual angina. PMID- 25798566 TI - Stenting the arterial duct. PMID- 25798567 TI - The EAPCI and continuing education for Fellows. PMID- 25798568 TI - The MITRA-FR study: design and rationale of a randomised study of percutaneous mitral valve repair compared with optimal medical management alone for severe secondary mitral regurgitation. AB - AIMS: Percutaneous mitral valve repair (pMVR) is a new therapeutic option for mitral valve regurgitation. Positive preliminary results in non-randomised studies have been published supporting the use of the MitraClip system in patients with secondary mitral regurgitation (MR) and poor left ventricular (LV) function contraindicated to surgery. The aim of the MITRA-FR study is to provide a higher level of evidence for the efficacy of the MitraClip device in this setting. METHODS AND RESULTS: The MITRA-FR study is a national, multicentre, investigator-initiated, open-label, randomised trial to evaluate the benefits and safety of pMVR using the MitraClip system plus optimal medical therapy (OMT) compared with OMT alone (control) in patients with severe symptomatic secondary MR contraindicated to surgical repair. The trial aims to enrol 144 MitraClip treated subjects and 144 control (OMT alone) patients. The primary endpoint is a composite of all-cause mortality and unplanned hospitalisations for heart failure at 12 months after randomisation CONCLUSIONS: MITRA-FR is a randomised controlled national trial designed to evaluate the performance of pMVR in comparison to OMT in patients with severe symptomatic secondary MR contraindicated to cardiac surgery. PMID- 25798569 TI - Tools and techniques - statistical: it's statistically significant, but is it clinically relevant? PMID- 25798571 TI - Semantic structure can be inferred from category fluency tasks via clustering analyses: Reply to Voorspoels et al. (2014). PMID- 25798570 TI - Racial bias in neural response to others' pain is reduced with other-race contact. AB - Observing the pain of others has been shown to elicit greater activation in sensory and emotional areas of the brain suggested to represent a neural marker of empathy. This modulation of brain responses to others' pain is dependent on the race of the observed person, such that observing own-race people in pain is associated with greater activity in the anterior cingulate and bilateral insula cortices compared to other-race people. Importantly, it is not known how this racial bias to pain in other-race individuals might change over time in new immigrants or might depend on the level and quality of contact with people of the other-race. We investigated these issues by recruiting Chinese students who had first arrived in Australia within the past 6 months to 5 years and assessing their level of contact with other races across different social contexts using comprehensive rating scales. During fMRI, participants observed videos of own race/other-race individuals, as well as own-group/other-group individuals, receiving painful or non-painful touch. The typical racial bias in neural responses to observed pain was evident, whereby activation in the anterior cingulate cortex (ACC) was greater for pain in own-race compared to other-race people. Crucially, activation in the anterior cingulate to pain in other races increased significantly with the level of contact participants reported with people of the other race. Importantly, this correlation did not depend on the closeness of contact or personal relationships, but simply on the overall level of experience with people of the other race in their every-day environment. Racial bias in neural responses to others' pain, as a neural marker of empathy, therefore changes with experience in new immigrants at least within 5 years of arrival in the new society and, crucially, depends on the level of contact with people of the other race in every-day life contexts. PMID- 25798573 TI - Nickel-catalyzed regio- and enantioselective aminolysis of 3,4-epoxy alcohols. AB - The first catalytic regio- and enantioselective aminolysis of 3,4-epoxy alcohols has been accomplished. Under the catalysis of Ni(ClO4)2.6H2O, the C4 selective ring opening of various 3,4-epoxy alcohols proceeded in a stereospecific manner with high regioselectivities. Furthermore, with the Ni-BINAM catalytic system the enantioselective ring opening of 3,4-epoxy alcohols furnished various gamma hydroxy-delta-amino alcohols as products with complete regiocontrol and high enantioselectivities (up to 94% ee). PMID- 25798574 TI - Management of Hypothermia for Perinatal Asphyxia in Austria - a Survey of Current Practice Standards. PMID- 25798576 TI - Photoinduced interactions of supramolecular ruthenium(II) complexes with plasmid DNA: synthesis and spectroscopic, electrochemical, and DNA photocleavage studies. AB - Two new bridging ligands have been synthesized by combining substituted benzaldehydes with phenanthrolinopyrrole (php), resulting in new polyazine bridging ligands. The ligands have been characterized by (1)H NMR, mass spectroscopy, and elemental analysis. These new ligands display pi-pi* transitions above 500 nm with modest molar absorptivities. Upon excitation at the ligand-centered charge-transfer transition, weak emission with a maximum wavelength of 612 nm is observed. When coordinated to two ruthenium(II) bis(bipyridyl) groups, the new bimetallic complexes generated give an overall 4+ charge. The electronic transitions of the bimetallic ruthenium(II) complexes display traditional pi-pi* transitions at 287 nm and metal-to-ligand charge transfer transitions at 452 nm with molar absorptivities greater than 30000 M(-1) cm(-1). Oxidation of the ruthenium(II) metal centers to ruthenium(III) occurs at potentials above 1.4 V versus the Ag/AgCl reference electrode. Spectroscopic and electrochemical measurements indicate that the ruthenium(II) moieties behave independently. Both complexes are water-soluble and show the ability to photonick plasmid DNA when irradiated with low-energy light above 550 nm. In addition, one of the complexes, [Ru(bpy)2php]2Van(4+), shows the ability to linearize plasmid DNA and gives evidence, by gel electrophoresis, of photoinduced binding to plasmid DNA. PMID- 25798577 TI - Simulating magnetic nanotubes using a chain of ellipsoid-rings model with a magnetization reversal process by fanning rotation. AB - Recently, magnetic nanotubes have attracted great attention owing to the advantages of tubular geometry. Of all the physical properties of magnetic nanotubes, the magnetic behavior plays a pivotal role in potential applications, particularly in biotechnology. Modeling magnetic nanotubes provides an effective way to determine the geometry dependent magnetic properties. In the present article, we model the nanotube as a chain of ellipsoid-rings; thus the magnetic behavior of nanotubes is simulated by the fanning rotation of magnetic moments. Based on this model, we further discuss the influence of tubular geometric parameters on the magnetic properties. The calculated magnetic properties of Fe, Co, Ni, Fe3O4 and CoFe2O4 nanotubes are all consistent with their experimental data. Consequently, our model provides an easy and general approach to magnetic nanotubes. PMID- 25798575 TI - Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. AB - IMPORTANCE: For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy. OBJECTIVE: To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, to May 2, 2013. All analyses were performed using an intent-to-treat approach. INTERVENTIONS: Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins. MAIN OUTCOMES AND MEASURES: Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings. RESULTS: A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90% CI, -3.5% to 10.5%; P=.36) and did not meet the noninferiority end point. Total QOL was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P=.04). Few participants experienced cardiovascular events (13 in the discontinuation group vs 11 in the continuation group). Mean cost savings were $3.37 per day and $716 per patient. CONCLUSIONS AND RELEVANCE: This pragmatic trial suggests that stopping statin medication therapy is safe and may be associated with benefits including improved QOL, use of fewer nonstatin medications, and a corresponding reduction in medication costs. Thoughtful patient-provider discussions regarding the uncertain benefit and potential decrement in QOL associated with statin continuation in this setting are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01415934. PMID- 25798579 TI - Dependency links can hinder the evolution of cooperation in the prisoner's dilemma game on lattices and networks. AB - Networks with dependency links are more vulnerable when facing the attacks. Recent research also has demonstrated that the interdependent groups support the spreading of cooperation. We study the prisoner's dilemma games on spatial networks with dependency links, in which a fraction of individual pairs is selected to depend on each other. The dependency individuals can gain an extra payoff whose value is between the payoff of mutual cooperation and the value of temptation to defect. Thus, this mechanism reflects that the dependency relation is stronger than the relation of ordinary mutual cooperation, but it is not large enough to cause the defection of the dependency pair. We show that the dependence of individuals hinders, promotes and never affects the cooperation on regular ring networks, square lattice, random and scale-free networks, respectively. The results for the square lattice and regular ring networks are demonstrated by the pair approximation. PMID- 25798578 TI - SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation. AB - Short interspersed nuclear elements (SINEs), such as Alu, spread by retrotransposition, which requires their transcripts to be copied into DNA and then inserted into new chromosomal sites. This can lead to genetic damage through insertional mutagenesis and chromosomal rearrangements between non-allelic SINEs at distinct loci. SINE DNA is heavily methylated and this was thought to suppress its accessibility and transcription, thereby protecting against retrotransposition. Here we provide several lines of evidence that methylated SINE DNA is occupied by RNA polymerase III, including the use of high-throughput bisulphite sequencing of ChIP DNA. We find that loss of DNA methylation has little effect on accessibility of SINEs to transcription machinery or their expression in vivo. In contrast, a histone methyltransferase inhibitor selectively promotes SINE expression and occupancy by RNA polymerase III. The data suggest that methylation of histones rather than DNA plays a dominant role in suppressing SINE transcription. PMID- 25798580 TI - Morphological features and important parameters of large optic discs for diagnosing glaucoma. AB - PURPOSE: To compare the optic disc parameters of glaucomatous eyes to those of non-glaucomatous eyes with large discs. METHODS: We studied 225 consecutive eyes with large optic discs (>2.82 mm2): 91 eyes with glaucoma and 134 eyes without glaucoma. An eye was diagnosed with glaucoma when visual field defects were detected by the Humphrey Field Analyzer. All of the Heidelberg Retina Tomograph II (HRT II) parameters were compared between the non-glaucomatous and glaucomatous eyes. A logistic regression analysis of the HRT II parameters was used to establish a new formula for diagnosing glaucoma, and the sensitivity and specificity of the Moorfields Regression Analysis (MRA) was compared to the findings made by our analyses. RESULTS: The mean disc area was 3.44+/-0.50 mm2 in the non-glaucomatous group and 3.40+/-0.52 mm2 in the glaucoma group. The cup area, cup volume, cup-to-disc area ratio, linear cup/disc ratio, mean cup depth, and the maximum cup depth were significantly larger in glaucomatous eyes than in the non-glaucomatous eyes. The rim area, rim volume, cup shape measurement, mean retinal nerve fiber layer (RNFL) thickness, and RFNL cross-sectional area were significantly smaller in glaucomatous eyes than in non-glaucomatous eyes. The cup to-disc area ratio, the height variation contour (HVC), and the RNFL cross sectional area were important parameters for diagnosing the early stage glaucoma, and the cup-to-disc area ratio and cup volume were useful for diagnosing advanced stage glaucoma in eyes with a large optic disc. The new formula had higher sensitivity and specificity for diagnosing glaucoma than MRA. CONCLUSIONS: The cup-to-disc area ratio, HVC, RNFL cross-sectional area, and cup volume were important parameters for diagnosing glaucoma in eyes with a large optic disc. The important disc parameters to diagnose glaucoma depend on the stage of glaucoma in patients with large discs. PMID- 25798581 TI - Contralateral masking in bilateral cochlear implant patients: a model of medial olivocochlear function loss. AB - Contralateral masking is the phenomenon where a masker presented to one ear affects the ability to detect a signal in the opposite ear. For normal hearing listeners, contralateral masking results in masking patterns that are both sharper and dramatically smaller in magnitude than ipsilateral masking. The goal of this study was to investigate whether medial olivocochlear (MOC) efferents are needed for the sharpness and relatively small magnitude of the contralateral masking function. To do this, bilateral cochlear implant patients were tested because, by directly stimulating the auditory nerve, cochlear implants circumvent the effects of the MOC efferents. The results indicated that, as with normal hearing listeners, the contralateral masking function was sharper than the ipsilateral masking function. However, although there was a reduction in the magnitude of the contralateral masking function compared to the ipsilateral masking function, it was relatively modest. This is in sharp contrast to the results of normal hearing listeners where the magnitude of the contralateral masking function is greatly reduced. These results suggest that MOC function may not play a large role in the sharpness of the contralateral masking function but may play a considerable role in the magnitude of the contralateral masking function. PMID- 25798582 TI - Involvement of cytochrome P450 1A1 and glutathione S-transferase P1 polymorphisms and promoter hypermethylation in the progression of anti-tuberculosis drug induced liver injury: a case-control study. AB - BACKGROUND: Anti-tuberculosis (anti-TB) drug-induced liver injury (ADLI) is one of the most common adverse effects associated with TB treatment. Cytochrome P450 (CYP) 1A1 and glutathione S-transferase (GST) P1 are important phase I/II metabolizing enzymes involved in drug metabolism and detoxification. Genetic polymorphism and CpG island methylation have been reported as factors influencing the expression of CYP1A1 and GSTP1. OBJECTIVE: This study aimed to determine the potential relationships of CYP1A1 and GSTP1 polymorphisms and CpG island methylation with ADLI risk. DESIGN: This was a population-based one-to-one matched case-control study. SETTING: The subjects were patients with TB receiving treatment in China from December 2010 to June 2013. PATIENTS: In total, 127 patients with TB and ADLI (case group) and 127 patients with TB but without liver injury (control group) were included in this study. Subjects were matched in terms of sex, age, and therapeutic regimen. METHODS: The general condition of each patient was assessed using questionnaires. The CYP1A1 MspI and GSTP1 Ile105Val polymorphisms as well as methylation status were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism and the methylation specific PCR method. RESULTS: We found no significant difference in GSTP1 and CYP1A1 genotypes between the two groups, probably because the sample size was not large enough; however, patients with ADLI had significantly higher GSTP1 and CYP1A1 promoter methylation rates than control subjects [odds ratio (OR) = 2.467 and 2.000, respectively]. After adjusting for drinking, which significantly differed between the groups as per univariate analysis, we found that hypermethylation of GSTP1 and CYP1A1 promoters was associated with ADLI (OR = 2.645 and 2.090, respectively). CONCLUSION: Hypermethylation of CpG islands of GSTP1 and CYP1A1 promoters may thus play important roles in the development of ADLI and provide evidence of being used as novel markers for ADLI risk prediction. PMID- 25798583 TI - Enhancing MALDI time-of-flight mass spectrometer performance through spectrum averaging. AB - Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometers are simple and robust mass spectrometers used for analysis of biologically relevant molecules in diverse fields including pathogen identification, imaging mass spectrometry, and natural products chemistry. Despite high nominal resolution and accuracy, we have observed significant variability where 30-50% of individual replicate measurements have errors in excess of 5 parts-per-million, even when using 5-point internal calibration. Increasing the number of laser shots for each spectrum did not resolve this observed variability. What is responsible for our observed variation? Using a modern MALDI-TOF/TOF instrument, we evaluated contributions to variability. Our data suggest a major component of variability is binning of the raw flight time data by the electronics and clock speed of the analog-to-digital (AD) detection system, which requires interpolation by automated peak fitting algorithms and impacts both calibration and the observed mass spectrum. Importantly, the variation observed is predominantly normal in distribution, which implies multiple components contribute to the observed variation and suggests a method to mitigate this variability through spectrum averaging. Restarting the acquisition impacts each spectrum within the electronic error of the AD detector system and defines a new calibration function. Therefore, averaging multiple independent spectra and not a larger number of laser shots leverages this inherent binning error to mitigate variability in accurate MALDI-TOF mass measurements. PMID- 25798584 TI - The role of edaphic environment and climate in structuring phylogenetic pattern in seasonally dry tropical plant communities. AB - Seasonally dry tropical plant formations (SDTF) are likely to exhibit phylogenetic clustering owing to niche conservatism driven by a strong environmental filter (water stress), but heterogeneous edaphic environments and life histories may result in heterogeneity in degree of phylogenetic clustering. We investigated phylogenetic patterns across ecological gradients related to water availability (edaphic environment and climate) in the Caatinga, a SDTF in Brazil. Caatinga is characterized by semiarid climate and three distinct edaphic environments - sedimentary, crystalline, and inselberg -representing a decreasing gradient in soil water availability. We used two measures of phylogenetic diversity: Net Relatedness Index based on the entire phylogeny among species present in a site, reflecting long-term diversification; and Nearest Taxon Index based on the tips of the phylogeny, reflecting more recent diversification. We also evaluated woody species in contrast to herbaceous species. The main climatic variable influencing phylogenetic pattern was precipitation in the driest quarter, particularly for herbaceous species, suggesting that environmental filtering related to minimal periods of precipitation is an important driver of Caatinga biodiversity, as one might expect for a SDTF. Woody species tended to show phylogenetic clustering whereas herbaceous species tended towards phylogenetic overdispersion. We also found phylogenetic clustering in two edaphic environments (sedimentary and crystalline) in contrast to phylogenetic overdispersion in the third (inselberg). We conclude that while niche conservatism is evident in phylogenetic clustering in the Caatinga, this is not a universal pattern likely due to heterogeneity in the degree of realized environmental filtering across edaphic environments. Thus, SDTF, in spite of a strong shared environmental filter, are potentially heterogeneous in phylogenetic structuring. Our results support the need for scientifically informed conservation strategies in the Caatinga and other SDTF regions that have not previously been prioritized for conservation in order to take into account this heterogeneity. PMID- 25798585 TI - Urinary biomarkers TIMP-2 and IGFBP7 early predict acute kidney injury after major surgery. AB - OBJECTIVE: To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients. INTRODUCTION: Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function. METHODS: In this prospective study, urinary [TIMP-2]*[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]*[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]*[IGFBP7] test. RESULTS: 107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l2/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]*[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001). CONCLUSIONS: Urinary [TIMP-2]*[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI. PMID- 25798586 TI - Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing. AB - Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease. PMID- 25798587 TI - Ion channel expression in the developing enteric nervous system. AB - The enteric nervous system arises from neural crest-derived cells (ENCCs) that migrate caudally along the embryonic gut. The expression of ion channels by ENCCs in embryonic mice was investigated using a PCR-based array, RT-PCR and immunohistochemistry. Many ion channels, including chloride, calcium, potassium and sodium channels were already expressed by ENCCs at E11.5. There was an increase in the expression of numerous ion channel genes between E11.5 and E14.5, which coincides with ENCC migration and the first extension of neurites by enteric neurons. Previous studies have shown that a variety of ion channels regulates neurite extension and migration of many cell types. Pharmacological inhibition of a range of chloride or calcium channels had no effect on ENCC migration in cultured explants or neuritogenesis in vitro. The non-selective potassium channel inhibitors, TEA and 4-AP, retarded ENCC migration and neuritogenesis, but only at concentrations that also resulted in cell death. In summary, a large range of ion channels is expressed while ENCCs are colonizing the gut, but we found no evidence that ENCC migration or neuritogenesis requires chloride, calcium or potassium channel activity. Many of the ion channels are likely to be involved in the development of electrical excitability of enteric neurons. PMID- 25798588 TI - Evolution of bow-tie architectures in biology. AB - Bow-tie or hourglass structure is a common architectural feature found in many biological systems. A bow-tie in a multi-layered structure occurs when intermediate layers have much fewer components than the input and output layers. Examples include metabolism where a handful of building blocks mediate between multiple input nutrients and multiple output biomass components, and signaling networks where information from numerous receptor types passes through a small set of signaling pathways to regulate multiple output genes. Little is known, however, about how bow-tie architectures evolve. Here, we address the evolution of bow-tie architectures using simulations of multi-layered systems evolving to fulfill a given input-output goal. We find that bow-ties spontaneously evolve when the information in the evolutionary goal can be compressed. Mathematically speaking, bow-ties evolve when the rank of the input-output matrix describing the evolutionary goal is deficient. The maximal compression possible (the rank of the goal) determines the size of the narrowest part of the network-that is the bow tie. A further requirement is that a process is active to reduce the number of links in the network, such as product-rule mutations, otherwise a non-bow-tie solution is found in the evolutionary simulations. This offers a mechanism to understand a common architectural principle of biological systems, and a way to quantitate the effective rank of the goals under which they evolved. PMID- 25798589 TI - Nutrient pathways regulating the nuclear maturation of mammalian oocytes. AB - Oocyte maturation is defined as that phase of development whereby a fully grown oocyte reinitiates meiotic maturation, completes one meiotic division with extrusion of a polar body, then arrests at MII until fertilisation. Completion of maturation depends on many different factors, not the least of which is the proper provision of energy substrates to fuel the process. Interaction of the oocyte and somatic compartment of the follicle is critical and involves numerous signals exchanged between the two cell types in both directions. One of the prominent functions of the cumulus cells is the channelling of metabolites and nutrients to the oocyte to help stimulate germinal vesicle breakdown and direct development to MII. This entails the careful integration and coordination of numerous metabolic pathways, as well as oocyte paracrine signals that direct certain aspects of cumulus cell metabolism. These forces collaborate to produce a mature oocyte that, along with accompanying physiological changes called cytoplasmic maturation, which impart subsequent developmental competence to the oocyte, can be fertilised and develop to term. This review focuses on nuclear maturation and the metabolic interplay that regulates it, with special emphasis on data generated in the mouse. PMID- 25798590 TI - Rational manipulation of mRNA folding free energy allows rheostat control of pneumolysin production by Streptococcus pneumoniae. AB - The contribution of specific factors to bacterial virulence is generally investigated through creation of genetic "knockouts" that are then compared to wild-type strains or complemented mutants. This paradigm is useful to understand the effect of presence vs. absence of a specific gene product but cannot account for concentration-dependent effects, such as may occur with some bacterial toxins. In order to assess threshold and dose-response effects of virulence factors, robust systems for tunable expression are required. Recent evidence suggests that the folding free energy (DeltaG) of the 5' end of mRNA transcripts can have a significant effect on translation efficiency and overall protein abundance. Here we demonstrate that rational alteration of 5' mRNA folding free energy by introduction of synonymous mutations allows for predictable changes in pneumolysin (PLY) expression by Streptococcus pneumoniae without the need for chemical inducers or heterologous promoters. We created a panel of isogenic S. pneumoniae strains, differing only in synonymous (silent) mutations at the 5' end of the PLY mRNA that are predicted to alter DeltaG. Such manipulation allows rheostat-like control of PLY production and alters the cytotoxicity of whole S. pneumoniae on primary and immortalized human cells. These studies provide proof of-principle for further investigation of mRNA DeltaG manipulation as a tool in studies of bacterial pathogenesis. PMID- 25798591 TI - K+-dependent selectivity and external Ca2+ block of Shab K+ channels. AB - Potassium channels allow the selective flux of K+ excluding the smaller, and more abundant in the extracellular solution, Na+ ions. Here we show that Shab is a typical K+ channel that excludes Na+ under bi-ionic, Na(o)/K(i) or Na(o)/Rb(i), conditions. However, when internal K+ is replaced by Cs+ (Na(o)/Cs(i)), stable inward Na+ and outward Cs+ currents are observed. These currents show that Shab selectivity is not accounted for by protein structural elements alone, as implicit in the snug-fit model of selectivity. Additionally, here we report the block of Shab channels by external Ca2+ ions, and compare the effect that internal K+ replacement exerts on both Ca2+ and TEA block. Our observations indicate that Ca2+ blocks the channels at a site located near the external TEA binding site, and that this pore region changes conformation under conditions that allow Na+ permeation. In contrast, the latter ion conditions do not significantly affect the binding of quinidine to the pore central cavity. Based on our observations and the structural information derived from the NaK bacterial channel, we hypothesize that Ca2+ is probably coordinated by main chain carbonyls of the pore's first K+-binding site. PMID- 25798592 TI - Difference in the breast milk proteome between allergic and non-allergic mothers. AB - BACKGROUND: Breastfeeding has been linked to a reduction in the prevalence of allergy and asthma. However, studies on this relationship vary in outcome, which may partly be related to differences in breast milk composition. In particular breast milk composition may differ between allergic and non-allergic mothers. Important components that may be involved are breast milk proteins, as these are known to regulate immune development in the newborn. The objective of this study was therefore to explore differences in the proteins of breast milk from 20 allergic and non-allergic mothers. The results from this comparison may then be used to generate hypotheses on proteins associated with allergy in their offspring. METHODS: Milk samples from allergic and non-allergic mothers were obtained from the PIAMA project, a prospective birth cohort study on incidence, risk factors, and prevention of asthma and inhalant allergy. Non-targeted proteomics technology, based on liquid chromatography and mass spectrometry, was used to compare breast milk from allergic and non-allergic mothers. RESULTS: Nineteen proteins, out of a total of 364 proteins identified in both groups, differed significantly in concentration between the breast milk of allergic and non-allergic mothers. Protease inhibitors and apolipoproteins were present in much higher concentrations in breast milk of allergic than non-allergic mothers. These proteins have been suggested to be linked to allergy and asthma. CONCLUSIONS: The non-targeted milk proteomic analysis employed has provided new targets for future studies on the relation between breast milk composition and allergy. PMID- 25798593 TI - Molecular mechanisms linking high dose medroxyprogesterone with HIV-1 risk. AB - BACKGROUND: Epidemiological studies suggest that medroxyprogesterone acetate (MPA) may increase the risk of HIV-1. The current studies were designed to identify potential underlying biological mechanisms. METHODS: Human vaginal epithelial (VK2/E6E7), peripheral blood mononuclear (PBMC), and polarized endometrial (HEC-1-A) cells were treated with a range of concentrations of MPA (0.015-150 MUg/ml) and the impact on gene expression, protein secretion, and HIV infection was evaluated. RESULTS: Treatment of VK2/E6E7 cells with high doses (>15 MUg/ml] of MPA significantly upregulated proinflammatory cytokines, which resulted in a significant increase in HIV p24 levels secreted by latently infected U1 cells following exposure to culture supernatants harvested from MPA compared to mock-treated cells. MPA also increased syndecan expression by VK2/E6E7 cells and cells treated with 15 MUg/ml of MPA bound and transferred more HIV-1 to T cells compared to mock-treated cells. Moreover, MPA treatment of epithelial cells and PBMC significantly decreased cell proliferation resulting in disruption of the epithelial barrier and decreased cytokine responses to phytohaemagglutinin, respectively. CONCLUSION: We identified several molecular mechanisms that could contribute to an association between DMPA and HIV including proinflammatory cytokine and chemokine responses that could activate the HIV promoter and recruit immune targets, increased expression of syndecans to facilitate the transfer of virus from epithelial to immune cells and decreased cell proliferation. The latter could impede the ability to maintain an effective epithelial barrier and adversely impact immune cell function. However, these responses were observed primarily following exposure to high (15-150 MUg/ml) MPA concentrations. Clinical correlation is needed to determine whether the prolonged MPA exposure associated with contraception activates these mechanisms in vivo. PMID- 25798595 TI - New insights into the developing rabbit brain using diffusion tensor tractography and generalized q-sampling MRI. AB - The use of modern neuroimaging methods to characterize the complex anatomy of brain development at different stages reveals an enormous wealth of information in understanding this highly ordered process and provides clues to detect neurological and neurobehavioral disorders that have their origin in early structural and functional cerebral maturation. Non-invasive diffusion tensor magnetic resonance imaging (DTI) is able to distinguish cerebral microscopic structures, especially in the white matter regions. However, DTI is unable to resolve the complicated neural structure, i.e., the fiber crossing that is frequently observed during the maturation process. To overcome this limitation, several methods have been proposed. One such method, generalized q-sampling imaging (GQI), can be applied to a variety of datasets, including the single shell, multi-shell or grid sampling schemes that are believed to be able to resolve the complicated crossing fibers. Rabbits have been widely used for neurodevelopment research because they exhibit human-like timing of perinatal brain white matter maturation. Here, we present a longitudinal study using both DTI and GQI to demonstrate the changes in cerebral maturation of in vivo developing rabbit brains over a period of 40 weeks. Fractional anisotropy (FA) of DTI and generalized fractional anisotropy (GFA) of GQI indices demonstrated that the white matter anisotropy increased with age, with GFA exhibiting an increase in the hippocampus as well. Normalized quantitative anisotropy (NQA) of GQI also revealed an increase in the hippocampus, allowing us to observe the changes in gray matter as well. Regional and whole brain DTI tractography also demonstrated refinement in fiber pathway architecture with maturation. We concluded that DTI and GQI results were able to characterize the white matter anisotropy changes, whereas GQI provided further information about the gray matter hippocampus area. This developing rabbit brain DTI and GQI database could also be used for educational purposes and neuroscience investigations. PMID- 25798596 TI - Online health check for reducing alcohol intake among employees: a feasibility study in six workplaces across England. AB - BACKGROUND: Most hazardous and harmful drinkers are of working age and do not seek help with their drinking. Occupational health services are uniquely placed to universally screen employees across the range of socioeconomic and ethnic groups. The aim was to explore the feasibility and acceptability of offering electronic screening and brief intervention for alcohol misuse in the context of a health check in six different workplace settings. METHODS AND FINDINGS: Employees were recruited from six workplaces across England, including three local authorities, one university, one hospital and one petro-chemical company. A total of 1,254 (8%) employees completed the health check and received personalised feedback on their alcohol intake, alongside feedback on smoking, fruit and vegetable consumption and physical activity. Most participants were female (65%) and of 'White British' ethnicity (94%), with a mean age of 43 years (SD 11). Participants were mostly in Intermediate occupations (58%), followed by Higher managerial / professional (39%) and Routine and manual occupations (2%). A quarter of participants (25%) were drinking at hazardous levels (33% male, 21% female), which decreased with age. Sixty-four percent (n=797) of participants completed online follow-up at three months. Most participants were supportive of workplaces offering employees an online health check (95%), their preferred format was online (91%) and many were confident of the confidentiality of their responses (60%). Whilst the feedback reminded most participants of things they already knew (75%), some were reportedly motivated to change their behaviour (13%). CONCLUSIONS: Online health screening and personalised feedback appears feasible and acceptable, but challenges include low participation rates, potentially attracting 'worried well' employees rather than those at greatest health risk, and less acceptance of the approach among older employees and those from ethnic minority backgrounds and routine or manual occupations. PMID- 25798594 TI - Complete genome sequence of Borrelia afzelii K78 and comparative genome analysis. AB - The main Borrelia species causing Lyme borreliosis in Europe and Asia are Borrelia afzelii, B. garinii, B. burgdorferi and B. bavariensis. This is in contrast to the United States, where infections are exclusively caused by B. burgdorferi. Until to date the genome sequences of four B. afzelii strains, of which only two include the numerous plasmids, are available. In order to further assess the genetic diversity of B. afzelii, the most common species in Europe, responsible for the large variety of clinical manifestations of Lyme borreliosis, we have determined the full genome sequence of the B. afzelii strain K78, a clinical isolate from Austria. The K78 genome contains a linear chromosome (905,949 bp) and 13 plasmids (8 linear and 5 circular) together presenting 1,309 open reading frames of which 496 are located on plasmids. With the exception of lp28-8, all linear replicons in their full length including their telomeres have been sequenced. The comparison with the genomes of the four other B. afzelii strains, ACA-1, PKo, HLJ01 and Tom3107, as well as the one of B. burgdorferi strain B31, confirmed a high degree of conservation within the linear chromosome of B. afzelii, whereas plasmid encoded genes showed a much larger diversity. Since some plasmids present in B. burgdorferi are missing in the B. afzelii genomes, the corresponding virulence factors of B. burgdorferi are found in B. afzelii on other unrelated plasmids. In addition, we have identified a species specific region in the circular plasmid, cp26, which could be used for species determination. Different non-coding RNAs have been located on the B. afzelii K78 genome, which have not previously been annotated in any of the published Borrelia genomes. PMID- 25798597 TI - Imbalance in fatty-acid-chain length of gangliosides triggers Alzheimer amyloid deposition in the precuneus. AB - Amyloid deposition, a crucial event of Alzheimer's disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid beta-protein (Abeta) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Abeta assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Abeta assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid free precuneus nor the calcarine cortex, markedly accelerate the Abeta assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Abeta assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition. PMID- 25798598 TI - Functional characterization of the 1,5-benzodiazepine clobazam and its major active metabolite N-desmethylclobazam at human GABA(A) receptors expressed in Xenopus laevis oocytes. AB - The 1,5-benzodiazepine clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older in the United States, and for treatment of anxiety and various forms of epilepsy elsewhere. Clobazam has been reported to exhibit different in vivo adverse effects and addiction liability profile than the classic 1,4 benzodiazepines. In this study, it was investigated whether the in vitro pharmacological properties of clobazam and its major active metabolite N desmethylclobazam could explain some of these clinical differences. The functional properties of the two 1,5-benzodiazepines were characterized at the human gamma-aminobutyric acid type A receptor (GABA(A)R) subtypes alpha1beta2gamma(2S), alpha2beta2gamma(2S), alpha3beta2gamma(2S), alpha5beta2gamma(2S) and alpha6beta2delta expressed in Xenopus laevis oocytes by use of two-electrode voltage-clamp electrophysiology and compared to those exhibited by the 1,4-benzodiazepine clonazepam. All three compounds potentiated GABA EC20-evoked responses through the alpha(1,2,3,5)beta2gamma(2S) GABA(A)Rs in a reversible and concentration-dependent manner, with each displaying similar EC50 values at the four subtypes. Furthermore, the degrees of potentiation of the GABA EC20 currents through the four receptors mediated by saturating modulator concentrations did not differ substantially for any of the three benzodiazepines. The three compounds were substantially less potent (200-3900 fold) as positive allosteric modulators at the alpha6beta2delta GABA(A)R than at the alpha(1,2,3,5)beta2gamma(2S) receptors. Interestingly, however, clobazam and especially N-desmethylclobazam were highly efficacious potentiators of alpha6beta2delta receptor signaling. Although this activity component is unlikely to contribute to the in vivo effects of clobazam/N-desmethylclobazam, the 1,5 benzodiazepine could constitute an interesting lead for novel modulators targeting this low-affinity binding site in GABAARs. In conclusion, the non selective modulation exerted by clobazam, N-desmethylclobazam and clonazepam at the alpha1beta2gamma(2S), alpha2beta2gamma(2S), alpha3beta2gamma(2S) and alpha5beta2gamma(2S) GABA(A)Rs indicate that the observed clinical differences between clobazam and 1,4-benzodiazepines are likely to arise from factors other than their respective pharmacological properties at the GABA(A)Rs as investigated here. PMID- 25798601 TI - Sprint conditioning of junior soccer players: effects of training intensity and technique supervision. AB - The aims of the present study were to compare the effects of 1) training at 90 and 100% sprint velocity and 2) supervised versus unsupervised sprint training on soccer-specific physical performance in junior soccer players. Young, male soccer players (17 +/- 1 yr, 71 +/- 10 kg, 180 +/- 6 cm) were randomly assigned to four different treatment conditions over a 7-week intervention period. A control group (CON, n = 9) completed regular soccer training according to their teams' original training plans. Three training groups performed a weekly repeated-sprint training session in addition to their regular soccer training sessions performed at A) 100% intensity without supervision (100UNSUP, n = 13), B) 90% of maximal sprint velocity with supervision (90SUP, n = 10) or C) 90% of maximal sprint velocity without supervision (90UNSUP, n=13). Repetitions x distance for the sprint training sessions were 15 x 20 m for 100UNSUP and 30 x 20 m for 90SUP and 90UNSUP. Single-sprint performance (best time from 15 x 20 m sprints), repeated sprint performance (mean time over 15 x 20 m sprints), countermovement jump and Yo-Yo Intermittent Recovery Level 1 (Yo-Yo IR1) were assessed during pre-training and post-training tests. No significant differences in performance outcomes were observed across groups. 90SUP improved Yo-Yo IR1 by a moderate margin compared to controls, while all other effect magnitudes were trivial or small. In conclusion, neither weekly sprint training at 90 or 100% velocity, nor supervised sprint training enhanced soccer-specific physical performance in junior soccer players. PMID- 25798600 TI - Inhibition of Zn(II) binding type IA topoisomerases by organomercury compounds and Hg(II). AB - Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisomerase poison inhibitors that form stabilized ternary complexes with the topoisomerase covalent intermediate, so it is desirable to identify such inhibitors for type IA topoisomerases. Here we report that organomercury compounds were identified during a fluorescence based screening of the NIH diversity set of small molecules for topoisomerase inhibitors that can increase the DNA cleavage product of Yersinia pestis topoisomerase I. Inhibition of relaxation activity and accumulation of DNA cleavage product were confirmed for these organomercury compounds in gel based assays of Escherichia coli topoisomerase I. Hg(II), but not As(III), could also target the cysteines that form the multiple Zn(II) binding tetra-cysteine motifs found in the C-terminal domains of these bacterial topoisomerase I for relaxation activity inhibition. Mycobacterium tuberculosis topoisomerase I activity is not sensitive to Hg(II) or the organomercury compounds due to the absence of the Zn(II) binding cysteines. It is significant that the type IA topoisomerases with Zn(II) binding domains can still cleave DNA when interfered by Hg(II) or organomercury compounds. The Zn(II) binding domains found in human Top3alpha and Top3beta may be potential targets of toxic metals and organometallic complexes, with potential consequence on genomic stability and development. PMID- 25798599 TI - Susceptibility to invasive meningococcal disease: polymorphism of complement system genes and Neisseria meningitidis factor H binding protein. AB - BACKGROUND: Neisseria meningitidis can cause severe infection in humans. Polymorphism of Complement Factor H (CFH) is associated with altered risk of invasive meningococcal disease (IMD). We aimed to find whether polymorphism of other complement genes altered risk and whether variation of N. meningitidis factor H binding protein (fHBP) affected the risk association. METHODS: We undertook a case-control study with 309 European cases and 5,200 1958 Birth Cohort and National Blood Service cohort controls. We used additive model logistic regression, accepting P<0.05 as significant after correction for multiple testing. The effects of fHBP subfamily on the age at infection and severity of disease was tested using the independent samples median test and Student's T test. The effect of CFH polymorphism on the N. meningitidis fHBP subfamily was investigated by logistic regression and Chi squared test. RESULTS: Rs12085435 A in C8B was associated with odds ratio (OR) of IMD (0.35 [95% CI 0.19 0.67]; P = 0.03 after correction). A CFH haplotype tagged by rs3753396 G was associated with IMD (OR 0.56 [95% CI 0.42-0.76], P = 1.6x10-4). There was no bacterial load (CtrA cycle threshold) difference associated with carriage of this haplotype. Host CFH haplotype and meningococcal fHBP subfamily were not associated. Individuals infected with meningococci expressing subfamily A fHBP were younger than those with subfamily B fHBP meningococci (median 1 vs 2 years; P = 0.025). DISCUSSION: The protective CFH haplotype alters odds of IMD without affecting bacterial load for affected heterozygotes. CFH haplotype did not affect the likelihood of infecting meningococci having either fHBP subfamily. The association between C8B rs12085435 and IMD requires independent replication. The CFH association is of interest because it is independent of known functional polymorphisms in CFH. As fHBP-containing vaccines are now in use, relationships between CFH polymorphism and vaccine effectiveness and side-effects may become important. PMID- 25798603 TI - Correction: Neonicotinoid-contaminated puddles of water represent a risk of intoxication for honey bees. PMID- 25798602 TI - Antisecretory, gastroprotective, antioxidant and anti-Helicobcter pylori activity of zerumbone from Zingiber zerumbet (L.) Smith. AB - BACKGROUND: Zingiber zerumbet Smith is a perennial herb, broadly distributed in many tropical areas. In Malaysia, it's locally known among the Malay people as "lempoyang" and its rhizomes, particularly, is widely used in traditional medicine for the treatment of peptic ulcer disease beyond other gastric disorders. AIM OF THE STUDY: The aim of the current study is to evaluate the gastroprotective effect of zerumbone, the main bioactive compound of Zingiber zerumbet rhizome, against ethanol-induced gastric ulcer model in rats. MATERIALS AND METHODS: Rats were pre-treated with zerumbone and subsequently exposed to acute gastric ulcer induced by absolute ethanol administration. Following treatment, gastric juice acidity, ulcer index, mucus content, histological analysis (HE and PAS), immunohistochemical localization for HSP-70, prostaglandin E2 synthesis (PGE2), non-protein sulfhydryl gastric content (NP-SH), reduced glutathione level (GSH), and malondialdehyde level (MDA) were evaluated in ethanol-induced ulcer in vivo. Ferric reducing antioxidant power assay (FRAP) and anti-H. pylori activity were investigated in vitro. RESULTS: The results showed that the intragastric administration of zerumbone protected the gastric mucosa from the aggressive effect of ethanol-induced gastric ulcer, coincided with reduced submucosal edema and leukocyte infiltration. This observed gastroprotective effect of zerumbone was accompanied with a significant (p <0.05) effect of the compound to restore the lowered NP-SH and GSH levels, and to reduce the elevated MDA level into the gastric homogenate. Moreover, the compound induced HSP-70 up-regulation into the gastric tissue. Furthermore, zerumbone significantly (p <0.05) enhanced mucus production, showed intense PAS stain and maintained PG content near to the normal level. The compound exhibited antisecretory activity and an interesting minimum inhibitory concentration (MIC) against H. pylori strain. CONCLUSION: The results of the present study revealed that zerumbone promotes ulcer protection, which might be attributed to the maintenance of mucus integrity, antioxidant activity, and HSP-70 induction. Zerumbone also exhibited antibacterial action against H. pylori. PMID- 25798604 TI - New insights into samango monkey speciation in South Africa. AB - The samango monkey is South Africa's only exclusively forest dwelling primate and represents the southernmost extent of the range of arboreal guenons in Africa. The main threats to South Africa's forests and thus to the samango are linked to increasing land-use pressure and increasing demands for forest resources, resulting in deforestation, degradation and further fragmentation of irreplaceable habitats. The species belongs to the highly polytypic Cercopithecus nictitans group which is sometimes divided into two species C. mitis and C. albogularis. The number of subspecies of C. albogularis is also under debate and is based only on differences in pelage colouration and thus far no genetic research has been undertaken on South African samango monkey populations. In this study we aim to further clarify the number of samango monkey subspecies, as well as their respective distributions in South Africa by combining molecular, morphometric and pelage data. Overall, our study provides the most comprehensive view to date into the taxonomic description of samango monkeys in South Africa. Our data supports the identification of three distinct genetic entities namely; C. a. labiatus, C. a. erythrarchus and C. a. schwarzi and argues for separate conservation management of the distinct genetic entities defined by this study. PMID- 25798605 TI - Neuropeptide Y and alpha-MSH circadian levels in two populations with low body weight: anorexia nervosa and constitutional thinness. AB - CONTEXT: Anorexia nervosa (AN) presents an adaptive appetite regulating profile including high levels of ghrelin and 26RFa (orexigenic) and low levels of leptin and PYY (anorexigenic). However, this adaptive mechanism is not effective in promoting food intake. The NPY/proopiomelanocortin (POMC) system plays a crucial role in the regulation of feeding behavior as NPY is the most potent orexigenic neuropeptide identified so far and as the POMC-derived peptide alpha-MSH drastically reduces food intake, and this peptidergic system has not been thoroughly studied in AN. OBJECTIVE: The aim of the present study was thus to investigate whether a dysfunction of the NPY/POMC occurs in two populations with low body weight, AN and constitutional thinness (CT). DESIGN AND SETTINGS: This was a cross-sectional study performed in an endocrinological unit and in an academic laboratory. INVESTIGATED SUBJECTS: Three groups of age-matched young women were studied: 23 with AN (AN), 22 CT and 14 normal weight controls. MAIN OUTCOME MEASURES: Twelve-point circadian profiles of plasma NPY and alpha-MSH levels were measured in the three groups of investigated subjects. RESULTS: No significant circadian variation of NPY was detected between the three groups. Plasma alpha-MSH levels were significantly lower in AN (vs controls) all over the day. The CT group, compared to controls, presented lower levels of alpha-MSH in the morning and the evening, and an important rise during lunchtime. CONCLUSION: In AN patients, the NPY system is not up-regulated under chronic undernutrition suggesting that this may play a role in the inability of anorectic women to adapt food intake to their energy demand. In contrast, low circadian alpha-MSH levels integrate the adaptive profile of appetite regulation of this disease. Finally, in CT women, the important alpha-MSH peak detected during lunchtime could explain why these patients are rapidly food satisfied. PMID- 25798606 TI - Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis. AB - Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogenic aggregation mechanism. This paper reports analysis of compiled patient data and experimental and computed protein properties for variants of human SOD1, a major risk factor of ALS. Both stability and reduced net charge correlate significantly with disease, with larger significance than previously observed. Using two independent methods and two data sets, a probability < 3% (t-statistical test) is found that ALS-causing mutations share average stability with all possible 2907 SOD1 mutations. Most importantly, un-weighted patient survival times correlate strongly with the misfolded/unfolded protein copy number, expressed as an exponential function of the experimental stabilities (R2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R2 = 0.51, p = 1.8 x 10-5). This finding suggests that disease relates to the copy number of misfolded proteins. Exhaustion of motor neurons due to expensive protein turnover of misfolded protein copies is consistent with the data but can further explain e.g. the expression-dependence of SOD1 pathogenicity, the lack of identification of a molecular toxic mode, elevated SOD1 mRNA levels in sporadic ALS, bioenergetic effects and increased resting energy expenditure in ALS patients, genetic risk factors affecting RNA metabolism, and recent findings that a SOD1 mutant becomes toxic when proteasome activity is recovered after washout of a proteasome inhibitor. Proteome exhaustion is also consistent with energy-producing mitochondria accumulating at the neuromuscular junctions where ALS often initiates. If true, this exhaustion mechanism implies a complete change of focus in treatment of ALS towards actively nursing the energy state and protein turnover of the motor neurons. PMID- 25798607 TI - Incidence of HIV and the prevalence of HIV, hepatitis B and syphilis among youths in Maputo, Mozambique: a cohort study. AB - BACKGROUND: Prevalence of HIV in Mozambique among individuals aged 15-49 years is 11.5%. The HIV prevalence is higher in women than in men across the country, peaking at ages 25-29 years and 35-39 years, respectively. In this study, we aimed at determining the prevalence and incidence of HIV, prevalence of Hepatitis B (HBV), and prevalence of syphilis in youths. We also characterized a cohort of youths for future participation in phase I/II HIV vaccine trials. METHODS: The study was conducted at a youth clinic in Maputo Central Hospital from August 2009 to October 2011. Youths of both genders aged 18-24 years (n = 1380) were screened for HIV using a sequential algorithm of two immunochromatographic assays, HBV using an enzyme linked immunosorbant test, and syphilis using a treponemal immunochromatographic strip test. The HIV seronegative participants (n = 1309) were followed-up for 12 months with quarterly study visits. The clinical and behavioral data were collected using structured questionnaires. The HIV seroconversions were confirmed by a molecular assay. RESULTS: The study population was female dominant (76.8%). All participants had a formal education, with 44.6% studying for technical or higher education degrees. The mean age at sexual debut was 16.6 years (SD: +/- 1.74), with 85.6% reporting more than one sexual partner in life. The screening showed the prevalence of HIV, HBV, and syphilis at 5.1% (95% CI: 3.97-6.31), 12.2% (95% CI 10.5%-14.0%), and 0.36% (95% CI 0.15%-0.84%), respectively. The HIV incidence rate was found to be 1.14/100 person years (95% CI: 0.67-1.92). Retention rates were stable throughout the study being 85.1% at the last visit. CONCLUSION: Incidence of HIV in this cohort of youths in Maputo was relatively low. Also, the prevalence of HIV and syphilis was lower than the national values in this age group. However, the HBV prevalence was higher than in previous reports in the country. PMID- 25798608 TI - A multiscale approach indicates a severe reduction in Atlantic Forest wetlands and highlights that Sao Paulo Marsh Antwren is on the brink of extinction. AB - Over the last 200 years the wetlands of the Upper Tiete and Upper Paraiba do Sul basins, in the southeastern Atlantic Forest, Brazil, have been almost-completely transformed by urbanization, agriculture and mining. Endemic to these river basins, the Sao Paulo Marsh Antwren (Formicivora paludicola) survived these impacts, but remained unknown to science until its discovery in 2005. Its population status was cause for immediate concern. In order to understand the factors imperiling the species, and provide guidelines for its conservation, we investigated both the species' distribution and the distribution of areas of suitable habitat using a multiscale approach encompassing species distribution modeling, fieldwork surveys and occupancy models. Of six species distribution models methods used (Generalized Linear Models, Generalized Additive Models, Multivariate Adaptive Regression Splines, Classification Tree Analysis, Artificial Neural Networks and Random Forest), Random Forest showed the best fit and was utilized to guide field validation. After surveying 59 sites, our results indicated that Formicivora paludicola occurred in only 13 sites, having narrow habitat specificity, and restricted habitat availability. Additionally, historic maps, distribution models and satellite imagery showed that human occupation has resulted in a loss of more than 346 km2 of suitable habitat for this species since the early twentieth century, so that it now only occupies a severely fragmented area (area of occupancy) of 1.42 km2, and it should be considered Critically Endangered according to IUCN criteria. Furthermore, averaged occupancy models showed that marshes with lower cattail (Typha dominguensis) densities have higher probabilities of being occupied. Thus, these areas should be prioritized in future conservation efforts to protect the species, and to restore a portion of Atlantic Forest wetlands, in times of unprecedented regional water supply problems. PMID- 25798609 TI - Delta neutrophil index as a promising prognostic marker in out of hospital cardiac arrest. AB - BACKGROUND: The post-resuscitation phase after out-of-hospital cardiac arrest (OHCA) is characterised by a systemic inflammatory response (e.g., severe sepsis), for which the immature granulocyte count is a diagnostic marker. In this study we evaluated the prognostic significance of the delta neutrophil index (DNI), which is the difference in leukocyte subfractions as assessed by an automated blood cell analyser, for early mortality after OHCA. MATERIALS AND METHODS: OHCA records from the emergency department cardiac arrest registry were retrospectively analysed. Patients who survived at least 24 h after return of spontaneous circulation were included in the analysis. We evaluated mortality and cerebral performance category scores at 30 days. RESULTS: A total of 83 patients with OHCA were included in the study. Our results showed that DNI >8.4% on day 1 (hazard ratio [HR], 3.227; 95% CI, 1.485-6.967; p = 0.001) and DNI >10.5% on day 2 (HR, 3.292; 95% CI, 1.662-6.519; p<0.001) were associated with increased 30-day mortality in patients with OHCA. Additionally, DNI >8.4% on day 1 (HR, 2.718; 95% CI, 1.508-4.899; p<0.001) and DNI >10.5% on day 2 (HR, 1.709; 95% CI, 1.051 2.778; p = 0.02) were associated with worse neurologic outcomes 30 days after OHCA. CONCLUSION: A higher DNI is a promising prognostic marker for 30-day mortality and neurologic outcomes after OHCA. Our findings indicate that patients with elevated DNI values after OHCA might be closely monitored so that appropriate treatment strategies can be implemented. PMID- 25798610 TI - Improved assessment of orbital stability of rhythmic motion with noise. AB - Mathematical techniques have provided tools to quantify the stability of rhythmic movements of humans and machines as well as mathematical models. One archetypal example is the use of Floquet multipliers: assuming periodic motion to be a limit cycle of a nonlinear oscillator, local stability has been assessed by evaluating the rate of convergence to the limit-cycle. However, the accuracy of the assessment in experiments is questionable: Floquet multipliers provide a measure of orbital stability for deterministic systems, but various components of biological systems and machines involve inevitable noise. In this study, we show that the conventional estimate of orbital stability, which depends on regression, has bias in the presence of noise. We quantify the bias, and devise a new method to estimate orbital stability more accurately. Compared with previous methods, our method substantially reduces the bias, providing acceptable estimates of orbital stability with an order-of-magnitude fewer cycles. PMID- 25798611 TI - Correction: Geographical variability in the likelihood of bloodstream infections due to gram-negative bacteria: correlation with proximity to the equator and health care expenditure. PMID- 25798612 TI - RNA preservation agents and nucleic acid extraction method bias perceived bacterial community composition. AB - Bias is a pervasive problem when characterizing microbial communities. An important source is the difference in lysis efficiencies of different populations, which vary depending on the extraction protocol used. To avoid such biases impacting comparisons between gene and transcript abundances in the environment, the use of one protocol that simultaneously extracts both types of nucleic acids from microbial community samples has gained popularity. However, knowledge regarding tradeoffs to combined nucleic acid extraction protocols is limited, particularly regarding yield and biases in the observed community composition. Here, we evaluated a commercially available protocol for simultaneous extraction of DNA and RNA, which we adapted for freshwater microbial community samples that were collected on filters. DNA and RNA yields were comparable to other commonly used, but independent DNA and RNA extraction protocols. RNA protection agents benefited RNA quality, but decreased DNA yields significantly. Choice of extraction protocol influenced the perceived bacterial community composition, with strong method-dependent biases observed for specific phyla such as the Verrucomicrobia. The combined DNA/RNA extraction protocol detected significantly higher levels of Verrucomicrobia than the other protocols, and those higher numbers were confirmed by microscopic analysis. Use of RNA protection agents as well as independent sequencing runs caused a significant shift in community composition as well, albeit smaller than the shift caused by using different extraction protocols. Despite methodological biases, sample origin was the strongest determinant of community composition. However, when the abundance of specific phylogenetic groups is of interest, researchers need to be aware of the biases their methods introduce. This is particularly relevant if different methods are used for DNA and RNA extraction, in addition to using RNA protection agents only for RNA samples. PMID- 25798613 TI - Limitations of stroke volume estimation by non-invasive blood pressure monitoring in hypergravity. AB - BACKGROUND: Altitude and gravity changes during aeromedical evacuations induce exacerbated cardiovascular responses in unstable patients. Non-invasive cardiac output monitoring is difficult to perform in this environment with limited access to the patient. We evaluated the feasibility and accuracy of stroke volume estimation by finger photoplethysmography (SVp) in hypergravity. METHODS: Finger arterial blood pressure (ABP) waveforms were recorded continuously in ten healthy subjects before, during and after exposure to +Gz accelerations in a human centrifuge. The protocol consisted of a 2-min and 8-min exposure up to +4 Gz. SVp was computed from ABP using Liljestrand, systolic area, and Windkessel algorithms, and compared with reference values measured by echocardiography (SVe) before and after the centrifuge runs. RESULTS: The ABP signal could be used in 83.3% of cases. After calibration with echocardiography, SVp changes did not differ from SVe and values were linearly correlated (p<0.001). The three algorithms gave comparable SVp. Reproducibility between SVp and SVe was the best with the systolic area algorithm (limits of agreement -20.5 and +38.3 ml). CONCLUSIONS: Non-invasive ABP photoplethysmographic monitoring is an interesting technique to estimate relative stroke volume changes in moderate and sustained hypergravity. This method may aid physicians for aeronautic patient monitoring. PMID- 25798614 TI - Transcriptional regulation of autophagy in RAS-driven cancers. AB - RAS-driven cancers exhibit variable dependency on autophagy for survival; however, it is not fully understood how. In this issue of the JCI, Cheong and colleagues demonstrate that RAS-dependent elevation of casein kinase 1alpha (CK1alpha) negatively regulates autophagy at the level of autophagy gene transcription. Moreover, combined inhibition of both CK1alpha and autophagy reduced proliferation of RAS-driven tumors. The results of this study provide insight into the connection between mutant RAS and autophagy, and suggest targeting CK1alpha as a potential therapeutic strategy to modulate autophagy in RAS-driven cancers. PMID- 25798615 TI - Exploiting metabolic and antioxidant pathways to maintain vision in blinding disease. AB - The use of gene therapy for blinding disease shows growing promise; however, due to an ever-expanding list of disease-causing genes and mutations, the identification of a generic gene-based treatment is urgently needed. In many forms of degenerative retinal disease, there may be a window of opportunity to preserve daylight vision, as the cone photoreceptors degenerate more slowly than do the rods. In this issue of the JCI, Venkatesh et al. and Xiong et al. exploit two different pathways to promote cone cell survival and preserve vision in murine retinal degeneration models. These studies provide hope for developing a universal reagent to treat many different blinding disorders. PMID- 25798616 TI - NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage. AB - Oxidative stress contributes to the loss of neurons in many disease conditions as well as during normal aging; however, small-molecule agents that reduce oxidation have not been successful in preventing neurodegeneration. Moreover, even if an efficacious systemic reduction of reactive oxygen and/or nitrogen species (ROS/NOS) could be achieved, detrimental side effects are likely, as these molecules regulate normal physiological processes. A more effective and targeted approach might be to augment the endogenous antioxidant defense mechanism only in the cells that suffer from oxidation. Here, we created several adeno-associated virus (AAV) vectors to deliver genes that combat oxidation. These vectors encode the transcription factors NRF2 and/or PGC1a, which regulate hundreds of genes that combat oxidation and other forms of stress, or enzymes such as superoxide dismutase 2 (SOD2) and catalase, which directly detoxify ROS. We tested the effectiveness of this approach in 3 models of photoreceptor degeneration and in a nerve crush model. AAV-mediated delivery of NRF2 was more effective than SOD2 and catalase, while expression of PGC1a accelerated photoreceptor death. Since the NRF2-mediated neuroprotective effects extended to photoreceptors and retinal ganglion cells, which are 2 very different types of neurons, these results suggest that this targeted approach may be broadly applicable to many diseases in which cells suffer from oxidative damage. PMID- 25798617 TI - Casein kinase 1alpha-dependent feedback loop controls autophagy in RAS-driven cancers. AB - Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we report that casein kinase 1alpha (CK1alpha), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS induced autophagy. Depletion or pharmacologic inhibition of CK1alpha enhanced autophagic flux in oncogenic RAS-driven human fibroblasts and multiple cancer cell lines. FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, was a critical target of CK1alpha, as depletion of CK1alpha reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1alpha protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1alpha increased phosphorylation of nuclear FOXO3A, thereby inhibiting transactivation of genes critical for RAS-induced autophagy. In both RAS-driven cancer cells and murine xenograft models, pharmacologic CK1alpha inactivation synergized with lysosomotropic agents to inhibit growth and promote tumor cell death. Together, our results identify a kinase feedback loop that influences RAS-dependent autophagy and suggest that targeting CK1alpha-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS-driven cancers. PMID- 25798618 TI - S-nitrosoglutathione reductase-dependent PPARgamma denitrosylation participates in MSC-derived adipogenesis and osteogenesis. AB - Bone marrow-derived mesenchymal stem cells (MSCs) are a common precursor of both adipocytes and osteoblasts. While it is appreciated that PPARgamma regulates the balance between adipogenesis and osteogenesis, the roles of additional regulators of this process remain controversial. Here, we show that MSCs isolated from mice lacking S-nitrosoglutathione reductase, a denitrosylase that regulates protein S nitrosylation, exhibited decreased adipogenesis and increased osteoblastogenesis compared with WT MSCs. Consistent with this cellular phenotype, S nitrosoglutathione reductase-deficient mice were smaller, with reduced fat mass and increased bone formation that was accompanied by elevated bone resorption. WT and S-nitrosoglutathione reductase-deficient MSCs exhibited equivalent PPARgamma expression; however, S-nitrosylation of PPARgamma was elevated in S nitrosoglutathione reductase-deficient MSCs, diminishing binding to its downstream target fatty acid-binding protein 4 (FABP4). We further identified Cys 139 of PPARgamma as an S-nitrosylation site and demonstrated that S-nitrosylation of PPARgamma inhibits its transcriptional activity, suggesting a feedback regulation of PPARgamma transcriptional activity by NO-mediated S-nitrosylation. Together, these results reveal that S-nitrosoglutathione reductase-dependent modification of PPARgamma alters the balance between adipocyte and osteoblast differentiation and provides checkpoint regulation of the lineage bifurcation of these 2 lineages. Moreover, these findings provide pathophysiological and therapeutic insights regarding MSC participation in adipogenesis and osteogenesis. PMID- 25798619 TI - Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice. AB - Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP. PMID- 25798620 TI - Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. AB - The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an alpha-ketoglutarate-dependent (alphaKG dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance. PMID- 25798621 TI - NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. AB - Metabolic reprogramming is implicated in macrophage activation, but the underlying mechanisms are poorly understood. Here, we demonstrate that the NOTCH1 pathway dictates activation of M1 phenotypes in isolated mouse hepatic macrophages (HMacs) and in a murine macrophage cell line by coupling transcriptional upregulation of M1 genes with metabolic upregulation of mitochondrial oxidative phosphorylation and ROS (mtROS) to augment induction of M1 genes. Enhanced mitochondrial glucose oxidation was achieved by increased recruitment of the NOTCH1 intracellular domain (NICD1) to nuclear and mitochondrial genes that encode respiratory chain components and by NOTCH dependent induction of pyruvate dehydrogenase phosphatase 1 (Pdp1) expression, pyruvate dehydrogenase activity, and glucose flux to the TCA cycle. As such, inhibition of the NOTCH pathway or Pdp1 knockdown abrogated glucose oxidation, mtROS, and M1 gene expression. Conditional NOTCH1 deficiency in the myeloid lineage attenuated HMac M1 activation and inflammation in a murine model of alcoholic steatohepatitis and markedly reduced lethality following endotoxin mediated fulminant hepatitis in mice. In vivo monocyte tracking further demonstrated the requirement of NOTCH1 for the migration of blood monocytes into the liver and subsequent M1 differentiation. Together, these results reveal that NOTCH1 promotes reprogramming of mitochondrial metabolism for M1 macrophage activation. PMID- 25798623 TI - Comparative experimental study of wound healing in mice: Pelnac versus Integra. AB - Strategies for skin regeneration have been developed to provide effective treatment for cutaneous wounds and disease. Dermal substitutes have been used to cover the lesion to facilitate cell colonization, thereby promoting dermal regeneration. However, very little is known about Pelnac matrix especially at histological level. Therefore, the present work carried out an experimental in vivo comparative analysis between Pelnac and Integra, the most used dermal templates, in a mouse model of full-thickness skin wounds. Histological sections performed at the 3rd, 6th and 9th days after surgery were analyzed with regard to inflammatory response and vascularization. Both templates were completely incorporated in all animals at the end of the analyzed period. Pelnac-treated animals displayed reduced granulation tissue during the first 6 days of treatment compared to the animals treated with Integra at the same time period. The number of inflammatory cells (neutrophils) was similar in both groups during the period, significantly reducing at the end of inflammatory phase (9th day of treatment) consistent with the progression of healing process. In addition, the density of blood vessels was also statistically similar in both matrices. Therefore, the two dermal templates displayed comparable biological behavior in tissue repair. It is noteworthy that this is the first experimental study comparing Pelnac and Integra dermal templates with focus on full-thickness skin wounds. PMID- 25798622 TI - Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. AB - Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity. PMID- 25798624 TI - Post-flowering nitrate uptake in wheat is controlled by N status at flowering, with a putative major role of root nitrate transporter NRT2.1. AB - In bread wheat (Triticum aestivum L.), the simultaneous improvement of both yield and grain protein is difficult because of the strong negative relationship between these two traits. However, some genotypes deviate positively from this relationship and this has been linked to their ability to take up nitrogen (N) during the post-flowering period, regardless of their N status at flowering. The physiological and genetic determinants of post-flowering N uptake relating to N satiety are poorly understood. This study uses semi-hydroponic culture of cv. Recital under controlled conditions to explore these controls. The first objective was to record the effects of contrasting N status at flowering on post flowering nitrate (NO3-) uptake under non-limiting NO3- conditions, while following the expression of key genes involved in NO3- uptake and assimilation. We found that post-flowering NO3- uptake was strongly influenced by plant N status at flowering during the first 300-400 degree-days after flowering, overlapping with a probable regulation of nitrate uptake exerted by N demand for growth. The uptake of NO3- correlated well with the expression of the gene TaNRT2.1, coding for a root NO3- transporter, which seems to play a major role in post-flowering NO3- uptake. These results provide a useful knowledge base for future investigation of genetic variability in post-flowering N uptake and may lead to concomitant gains in both grain yield and grain protein in wheat. PMID- 25798626 TI - Heart rate dynamics in doxorubicin-induced cardiomyopathy. AB - The clinical use of doxorubicin, an effective chemotherapeutic is hampered by the development of irreversible cardiotoxicity. Here we test time-frequency analysis of heart rate (HR) variability (HRV) for early detection of doxorubicin-induced cardiotoxicity. Experiments were conducted in adult male Wistar rats treated for 15 days with doxorubicin (DOXO, total dose 15 mg kg(-1), i.p.) or saline (CONT). DOXO rats exhibited cardiotoxicity confirmed by histological examination without developing heart failure as estimated by echocardiography. However, HR variability increase reflected subtle microscopic changes of cardiac toxicity in DOXO rats. The results recommend time-frequency analysis of HRV for early detection of doxorubicin-induced cardiomyopathy. PMID- 25798627 TI - History of psychological knowledge in Brazilian culture: Weaving threads on the loom of time. AB - After a brief presentation of the research program on the "history of psychological knowledge in the ambit of cultural history," this article addresses 2 issues that we consider particularly important from the methodological point of view: the notion of multiple temporalities (regimes of historicity) and of complexity as characteristics of the contexture of Brazilian culture. It will be shown how both require specific attention from the researcher, because the process of incorporation of psychology in Brazil over time is complex and articulated according to various regimes of historicity that intersect and interpenetrate each other, without being exclusive. Our approach will be exemplified by the concept of memory, showing how this can be grasped in its constitution in Brazilian culture, which is composed of several sedimented layers according to different temporalities. PMID- 25798625 TI - Can we undo our first impressions? The role of reinterpretation in reversing implicit evaluations. AB - Little work has examined whether implicit evaluations can be effectively "undone" after learning new revelations. Across 7 experiments, participants fully reversed their implicit evaluation of a novel target person after reinterpreting earlier information. Revision occurred across multiple implicit evaluation measures (Experiments 1a and 1b), and only when the new information prompted a reinterpretation of prior learning versus did not (Experiment 2). The updating required active consideration of the information, as it emerged only with at least moderate cognitive resources (Experiment 3). Self-reported reinterpretation predicted (Experiment 4) and mediated (Experiment 5) revised implicit evaluations beyond the separate influence of how thoughtfully participants considered the new information in general. Finally, the revised evaluations were durable 3 days later (Experiment 6). We discuss how these results inform existing theoretical models, and consider implications for future research. PMID- 25798628 TI - Techniques for processing eyes implanted with a retinal prosthesis for localized histopathological analysis: Part 2 Epiretinal implants with retinal tacks. AB - Retinal prostheses for the treatment of certain forms of blindness are gaining traction in clinical trials around the world with commercial devices currently entering the market. In order to evaluate the safety of these devices, in preclinical studies, reliable techniques are needed. However, the hard metal components utilised in some retinal implants are not compatible with traditional histological processes, particularly in consideration for the delicate nature of the surrounding tissue. Here we describe techniques for assessing the health of the eye directly adjacent to a retinal implant secured epiretinally with a metal tack. Retinal prostheses feature electrode arrays in contact with eye tissue. The most commonly used location for implantation is the epiretinal location (posterior chamber of the eye), where the implant is secured to the retina with a metal tack that penetrates all the layers of the eye. Previous methods have not been able to assess the proximal ocular tissue with the tack in situ, due to the inability of traditional histological techniques to cut metal objects. Consequently, it has been difficult to assess localized damage, if present, caused by tack insertion. Therefore, we developed a technique for visualizing the tissue around a retinal tack and implant. We have modified an established technique, used for processing and visualizing hard bony tissue around a cochlear implant, for the soft delicate tissues of the eye. We orientated and embedded the fixed eye tissue, including the implant and retinal tack, in epoxy resin, to stabilise and protect the structure of the sample. Embedded samples were then ground, polished, stained, and imaged under various magnifications at incremental depths through the sample. This technique allowed the reliable assessment of eye tissue integrity and cytoarchitecture adjacent to the metal tack. PMID- 25798629 TI - Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline. AB - In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions. PMID- 25798630 TI - Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation. AB - The ability to attend to appropriate stimuli, to plan actions and then alter those actions when environmental conditions change, is essential for an organism to thrive. There is increasing evidence that these executive control processes are mediated in part by N-methyl-D-aspartate receptors (NMDAR). NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules and are differentially expressed during development. Recent findings have suggested that the GluN2B subunit may play a unique role in both the acquisition of adaptive choice and the behavioral flexibility required to shift between choices. Here we investigated the role of GluN2B containing NMDARs in the ability to learn, reverse and shift between stimulus dimensions. Mutant mice (floxed-GluN2B x CaMKII-Cre) lacking GluN2B in the dorsal CA1 of the hippocampus and throughout the cortex were tested on an attentional set-shifting task. To explore the role that alterations in motor behavior may have on these behaviors, gross and fine motor behaviors were analyzed in mutant and floxed-control mice. Results show that corticohippocampal loss of GluN2B selectively impaired an initial reversal in a stimulus specific manner and impaired the ability of mutant mice to form an attentional set. Further, GluN2B mice showed normal motor behavior in both overall movement and individual limb behaviors. Together, these results further support the role of NMDAR, and GluN2B in particular, in aspects of executive control including behavioral flexibility and attentional processes. PMID- 25798631 TI - NMDA blockade inhibits experience-dependent modification of anterior thalamic head direction cells. AB - Head Direction (HD) cells of the rodent Papez circuit are thought to reflect the spatial orientation of the animal. Because NMDA transmission is important for spatial behavior, we sought to determine the effects of NMDA blockade on the basic directional signal carried by HD cells and on experience-dependent modification of this system. In Experiment 1, HD cells were recorded from the anterior dorsal thalamus in female Long-Evans rats while they foraged in a familiar enclosure following administration of the NMDA antagonist CPP or saline. While the drug produced a significant decrease in peak firing rates, it failed to affect the overall directional specificity and landmark control of HD cells. Experiment 2 took place over 2 days and assessed whether the NMDA antagonist would interfere with the stabilization of the HD network in a novel environment. On Day 1 the animal was administered CPP or saline and placed in a novel enclosure to allow the stabilization of the HD signal relative to the new environmental landmarks. On Day 2 the animal was returned to the formerly novel enclosure to determine if the enclosure specific direction-dependent activity established on Day 1 was maintained. In contrast to HD cells from control animals, cells from animals receiving CPP during the initial exposure to the novel enclosure did not maintain the same direction-dependent activity relative to the enclosure in the subsequent drug-free exposure. These findings demonstrate that plasticity in the HD system is dependent on NMDA transmission similar to many other forms of spatial learning. PMID- 25798633 TI - Postcontest blockade of dopamine receptors inhibits development of the winner effect in the California mouse (Peromyscus californicus). AB - The winner effect is an accumulation of previous wins that increase future winning. A primary unanswered question about the winner effect is how do individuals integrate information about previous wins? Dopamine (DA) has been implicated because phosphorylated tyrosine hydroxylase (pTH), the rate-limiting enzyme for DA biosynthesis, is elevated following multiple winning experiences. Moreover, DA receptor blockers and agonists influence aggression when administered prior to male-male contests. In the current study, we administered D1- and D2-like DA receptor antagonists immediately after a contest and examined the development of the winner effect in the territorial California mouse, Peromyscus californicus. During a 3-contest training phase, resident males experienced winning contests, followed immediately by a peripheral injection of either a DA receptor antagonist or vehicle or a handling experience (without injection). The DA receptor antagonists used in this study did not influence locomotion. To assess the cumulative effects of previous winning, males were subjected to a final test contest with a more competitive intruder. The winner effect was significantly decreased by both D1- and D2-like receptor antagonists administered during training. During the test contest, attack behavior was significantly reduced by previous administration of both types of DA receptor antagonists compared with controls. D1-like receptor blockade also diminished chasing behavior, whereas D2-antagonist treated animals continued to pursue opponents. During training against a less competitive intruder, there was no difference in aggressive behaviors between experimental and controls males. Our data indicate that DA activity between contests is concomitant with the competitive advantage gained from multiple winning experiences. PMID- 25798632 TI - Dopamine D2 receptors act upstream of AVP in the latero-anterior hypothalamus to modulate adolescent anabolic/androgenic steroid-induced aggression in Syrian hamsters. AB - In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), that is, a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the coinfusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response. PMID- 25798635 TI - A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPD. AB - BACKGROUND: COPD guidelines recommend the combined use of inhaled long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) if symptoms are not improved by a single agent. This systematic review tested the hypothesis that the bronchodilator effect of the LABA/LAMA combination, umeclidinium (UMEC)/vilanterol (VIL), would translate into better outcomes without incurring increased adverse events (AEs). METHODS: This was a systematic review of randomized, placebo-controlled or crossover trials (> 4 weeks) involving UMEC/VIL compared with its monocomponents, tiotropium, or fluticasone/salmeterol. Primary outcomes were trough FEV1, serious adverse events (SAEs), and serious cardiovascular events (SCVEs). RESULTS: Eleven trials from 10 studies (9,609 patients) showed that UMEV/VIL provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV1, 60, 110, 90, and 90 mL, respectively; P < .0001). Also, UMEC/VIL had a greater likelihood of demonstrating a minimal clinically important difference on the Transition Dyspnea Index compared with UMEC and VIL (number needed to treat for benefit [NNTB] = 14 and 10, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences between UMEC/VIL and tiotropium with respect to dyspnea, health status, or risk of COPD exacerbation. Regarding safety issues, the incidence of AEs, SAEs, SCVEs, and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination. CONCLUSIONS: Once-daily inhaled UMEC/VIL showed superior efficacy compared with its monocomponents, tiotropium, and fluticasone/combination in patients with moderate to severe COPD. PMID- 25798634 TI - Seeking behavior, place conditioning, and resistance to conditioned suppression of feeding in rats intermittently exposed to palatable food. AB - Binge eating disorder is characterized by excessive consumption of highly palatable food within short periods of time accompanied by loss of control over eating. Extensive evidence provides support for the consideration of binge eating disorder as an addiction-like disorder. In this study, we wanted to determine whether rats undergoing an operant binge-like eating procedure could develop maladaptive forms of conditioned feeding behaviors. For this purpose, we trained male rats to self-administer either a sugary, highly palatable diet ("Palatable" rats) or a chow diet ("Chow" rats) for 1 hour a day. After escalation and stabilization of palatable food intake, we tested Chow and Palatable rats in (a) a conditioned place preference test, (b) a second-order schedule of reinforcement, (c) a cue-induced suppression of feeding test. In the conditioned place preference task, Palatable rats spent significantly more time in the compartment that was previously paired with the palatable food, compared to Chow controls. Furthermore, in the second-order schedule of reinforcement task, Palatable rats exhibited active lever responding 4- to 6-fold higher than Chow control rats. Finally, in the cue-induced suppression of feeding test, although Chow control subjects reduced responding by 32% in the presence of the conditioned punishment, Palatable rats persevered in responding despite the aversive cue. These results further characterize this animal model of binge-like eating and provide additional evidence for the addictive properties of highly palatable food. PMID- 25798636 TI - Serial optical coherence tomography of drug-eluting stent in-stent restenosis treated with the Absorb bioresorbable scaffold: an effective treatment? PMID- 25798637 TI - The "plastic healing concept": implantation of bioabsorbable scaffolds in spontaneous coronary artery dissection. PMID- 25798638 TI - First report on free expansion simulations of a dedicated bifurcation stent mounted on a stepped balloon. PMID- 25798639 TI - How should I treat a complex left subclavian artery stenosis involving the vertebral artery in a patient with subclavian steal syndrome and left internal mammary artery bypass graft? AB - BACKGROUND: A 68-year-old male smoker presented with progressive symptoms of vertebrobasilar insufficiency and angina. His past medical history included arterial hypertension, diabetes mellitus, dyslipidaemia as well as diffuse coronary artery disease including left main disease. Of note, he had undergone coronary bypass surgery 12 years earlier utilising the left internal mammary artery. INVESTIGATION: Physical examination, laboratory tests, duplex ultrasound imaging, contrast-enhanced magnetic resonance imaging and coronary angiography. DIAGNOSIS: Severe bifurcation stenosis of the left subclavian and vertebral artery with consecutive subclavian steal syndrome and myocardial ischaemia. MANAGEMENT: Bifurcation T-stenting using a self-expandable bare metal and a coronary drug-eluting stent. PMID- 25798640 TI - In vitro effects of Panax ginseng in aristolochic acid-mediated renal tubulotoxicity: apoptosis versus regeneration. AB - This in vitro study aimed to determine the effects of a Panax ginseng extract on aristolochic acid-mediated toxicity in HK-2 cells. A methanolic extract of ginseng (50 ug/mL) was able to reduce cell survival after treatment with 50 uM aristolochic acid for 24, 48, and 72 h, as evidenced by a resazurin reduction assay. This result was confirmed by a flow cytometric evaluation of apoptosis using annexin V-PI staining, and indicated higher apoptosis rates in cells treated with aristolochic acid and P. ginseng extract compared with aristolochic acid alone. However, P. ginseng extract by itself (5 and 50 ug/mL) increased the Ki-67 index, indicating an enhancement in cellular proliferation. Cell cycle analysis excluded a P. ginseng extract-mediated induction of G2/M cell cycle arrest such as the one typically observed with aristolochic acid. Finally, beta catenin acquisition was found to be accelerated when cells were treated with both doses of ginseng, suggesting that the epithelial phenotype of renal proximal tubular epithelial cells was maintained. Also, ginseng treatment (5 and 50 ug/mL) reduced the oxidative stress activity induced by aristolochic acid after 24 and 48 h. These results indicate that the ginseng extract has a protective activity towards the generation of cytotoxic reactive oxygen species induced by aristolochic acid. However, the ginseng-mediated alleviation of oxidative stress did not correlate with a decrease but rather with an increase in aristolochic acid-induced apoptosis and death. This deleterious herb-herb interaction could worsen aristolochic acid tubulotoxicity and reinforce the severity and duration of the injury. Nevertheless, increased cellular proliferation and migration, along with the improvement in the epithelial phenotype maintenance, indicate that ginseng could be useful for improving tubular regeneration and the recovery following drug-induced kidney injury. Such dual activities of ginseng certainly warrant further in vivo studies. PMID- 25798641 TI - Antibacterial and antioxidant xanthones and benzophenone from garcinia smeathmannii. AB - A new prenylated xanthone, 1,3,5,8-tetrahydroxy-2-(3-methybut-2-enyl)-4-(3,7 dimethylocta-2,6-dienyl) xanthone (1), and a new benzophenone (2), together with four known xanthone derivatives, cheffouxanthone (3), smeathxanthone A (4), smeathxanthone B (5), ananixanthone (6), and two pentacyclic triterpenes, epi friedelinol (7) and friedelin (8), were isolated from the stem bark of Garcinia smeathmannii. The structures of the compounds were elucidated on the basis of 1D and 2D NMR experiments, and compound 2 was further characterized and confirmed by single X-ray analysis. Compounds 1, 2, and 3 exhibited the most prominent antibacterial activity against gram-positive Enterococcus faecalis with minimal inhibitory concentration values of 8, 8, and 2 ug/mL, respectively, while compounds 1, 3, 4, and 6 showed the capacity to scavenge free radicals. PMID- 25798642 TI - Intensified Separation of Steviol Glycosides from a Crude Aqueous Extract of Stevia rebaudiana Leaves Using Centrifugal Partition Chromatography. AB - Aqueous extracts of Stevia rebaudiana leaves have been approved since 2008 by the Joint Expert Committee for Food Additives as sugar substitutes in many food and beverages in Western and Far East Asian countries. The compounds responsible for the natural sweetness of Stevia leaves include a diversity of diterpenoid glycosides derived from a steviol skeleton. These steviol glycosides also exhibit a low calorific value as well as promising therapeutic applications, particularly for the treatment of sugar metabolism disturbances. In this work, centrifugal partition chromatography is proposed as an efficient technical alternative to purify steviol glycosides from crude aqueous extracts of Stevia leaves on a multigram scale. Two different commercial instruments, including an ASCPC250(r) and a FCPE300(r) made of columns containing 1890 and 231 twin-cells, respectively, were evaluated and compared. All experiments were performed with a polar biphasic solvent system composed of ethyl acetate, n-butanol, and water in a gradient elution mode. When using the 1890 partition cell centrifugal partition chromatography column of 250 mL, 42 mg of stevioside, 68 mg of dulcoside A, and 172 mg of rebaudioside A, three major constituents of the initial extract were obtained from 1 g of the initial mixture at purities of 81%, 83%, and 99%, respectively. The productivity was further improved by intensifying the procedure on the 231 partition cell centrifugal partition chromatography column of 303 mL with the sample mass loading increased up to 5 g, resulting in the recovery of 1.2 g of stevioside, 100 mg of dulcoside A, and 1.1 g of rebaudioside A at purities of 79%, 62%, and 98%, respectively. The structures of the isolated compounds were validated by HPLC-UV, ESI-MS, (1)H, and (13)C NMR analyses. Altogether, the results demonstrate that the column design (i.e., the partition cell number) is an important aspect to be considered for a larger scale centrifugal partition chromatography isolation of Stevia-derived natural sweeteners. PMID- 25798643 TI - Inhalation administration of the sesquiterpenoid aristolen-1(10)-en-9-ol from Nardostachys chinensis has a sedative effect via the GABAergic system. AB - Spikenard, the dried roots of Nardostachys chinensis, contains sesquiterpenoids and is widely used as an herbal tranquilizer. We previously demonstrated that spikenard vapor showed a sedative effect when administered by inhalation, and we identified hydrocarbon sesquiterpenoids as active components. Here we investigated the other components that contribute to the effects of spikenard. Six oxygenated sesquiterpenoids, including aristolane- and guaiane-types, were isolated from an acetone extract of spikenard. We evaluated the sedative activities of these oxygenated compounds using an inhalation administration method in a caffeine-treated excitatory mouse model. We identified aristolen 1(10)-en-9-ol and patchouli alcohol as highly effective sedative components. These compounds inhibited locomotion in mice by approximately 60% at a dose of 300 ug/cage. In addition, aristolen-1(10)-en-9-ol prolonged pentobarbital-induced sleep to the same extent as 1 mg/kg diazepam. This effect completely disappeared with the administration of the GABAA-benzodiazepine receptor antagonist flumazenil (3 mg/kg), suggesting that the sedative effect of aristolen-1(10)-en-9 ol is expressed via the GABAergic system. Furthermore, differently from diazepam, inhalation of aristolen-1(10)-en-9-ol for 1 h did not affect the motor coordination in the rota-rod test. In the present study, we identified active components and provided evidence supporting the traditional sedative use of spikenard. Our research suggests that aristolen-1(10)-en-9-ol may be an effective aromatherapy, providing mild sedation. PMID- 25798644 TI - Control of propulsion and body lift during the first two stances of sprint running: a simulation study. AB - The aim of this study was to relate the contribution of lower limb joint moments and individual muscle forces to the body centre of mass (COM) vertical and horizontal acceleration during the initial two steps of sprint running. Start performance of seven well-trained sprinters was recorded using an optoelectronic motion analysis system and two force plates. Participant-specific torque-driven and muscle-driven simulations were conducted in OpenSim to quantify, respectively, the contributions of the individual joints and muscles to body propulsion and lift. The ankle is the major contributor to both actions during the first two stances, with an even larger contribution in the second compared to the first stance. Biarticular gastrocnemius is the main muscle contributor to propulsion in the second stance. The contribution of the hip and knee depends highly on the position of the athlete: During the first stance, where the athlete runs in a forward bending position, the knee contributes primarily to body lift and the hip contributes to propulsion and body lift. In conclusion, a small increase in ankle power generation seems to affect the body COM acceleration, whereas increases in hip and knee power generation tend to affect acceleration less. PMID- 25798645 TI - Leukoaraiosis with mild cognitive impairment. AB - As the ageing population continues to increase, the prevalence of age-related cognitive impairment has been on the rise. Mild cognitive impairment (MCI) is now widely recognised as the early stage of dementia. Mild cognitive impairment is closely associated with cerebral white matter lesions (WMLs), specifically in the case of leukoaraiosis (LA). A previous diffusion tensor imaging (DTI) has demonstrated that white matter changes might damage cognitive function in LA patients, and the cognitive function might decrease with the deterioration of LA. Through consulting and analysing documents, we found that both of them share similarities in risk factors, pathogenesis, pathological changes, and imaging manifestations. The main characteristics of LA patients with MCI (LACI) are the early and apparent manifestations of delayed memory, attention, impaired executive function, and close association with dementia. This analysis of LACI may contribute to an early diagnosis of LACI and provide possible treatment for LACI. PMID- 25798646 TI - Cytoskeletal alterations associated with donor age and culture interval for equine oocytes and potential zygotes that failed to cleave after intracytoplasmic sperm injection. AB - Intracytoplasmic sperm injection (ICSI) is an established method to fertilise equine oocytes, but not all oocytes cleave after ICSI. The aims of the present study were to examine cytoskeleton patterns in oocytes after aging in vitro for 0, 24 or 48h (Experiment 1) and in potential zygotes that failed to cleave after ICSI of oocytes from donors of different ages (Experiment 2). Cytoplasmic multiasters were observed after oocyte aging for 48h (P<0.01). A similar increase in multiasters was observed with an increased interval after ICSI for young mares (9-13 years) but not old (20-25 years) mares. Actin vesicles were observed more frequently in sperm-injected oocytes from old than young mares. In the present study, multiasters appeared to be associated with cell aging, whereas actin vesicles were associated with aging of the oocyte donor. PMID- 25798647 TI - Prognostic value of electrically evoked auditory brainstem responses in cochlear implantation. AB - OBJECTIVES: The aim of this study was to investigate whether electrical auditory brainstem responses (eABRs) obtained during cochlear implantation (CI) can predict CI outcomes. We also aimed to assess whether eABR can be used to select patients for auditory brainstem implantation (ABI). METHODS: This was a retrospective study. The latencies and quality of the eABR waveforms from adult patients implanted with CI in Uppsala from 2011 to 2013 (n = 74) and four children with severe cochlear abnormalities were analyzed. Speech perception was assessed through postoperative monosyllabic word (MS-word) recognition. A score was constructed for each patient based on wave II, III, and V patency. RESULTS: eABR latencies increased towards base stimulation of the cochlea. Wave V for the mid- and low-frequency regions was the most robust. Significant latency shifts occurred in wave V from the low- to high-frequency regions (**P < 0.01) and from the mid- to high-frequency regions (**P < 0.01). No correlations were found between waveform score, wave V-III interval, wave V latency, and MS-word scores. A negative eABR always predicted a negative outcome. Among the patients with negative outcomes, 75% had eABRs. DISCUSSION: Implant electrical stimulation and brain stem recordings can be used (eABRs wave V) to predict a negative functional outcome. Low-frequency waves V were observed in all patients with successful CI outcomes. Patients for whom eABR waveforms were completely absent had unsuccessful CI outcomes. PMID- 25798648 TI - The protective role of glutamine against acute induced toxicity in rats. AB - CONTEXT: Deltamethrin (DLM) is an insecticide commonly used to protect agricultural crops against pests. QT prolongation with malignant ventricular arrhythmias are amongst the most common cardiovascular complications. DLM intoxication cause decreased level of antioxidant enzymes. Glutamine is the precursor of glutathione which is an antioxidant and has been demonstrated to improve outcome after several critical illnesses. OBJECTIVE: We hypothesized that glutamine, by means of antioxidant characteristics, may antagonize the cardiotoxic effects of DLM. MATERIALS AND METHODS: All experiments were performed on 8-week-old male Wistar albino rats. The rats were divided into following groups (n = 10); Group I: control, Group II: l-glutamine, Group III: DLM, Group IV: DLM and after 4 h l-glutamine. Total antioxidant status (TAS), total oxidant status (TOS) and parameter analyses were performed in cardiac tissue. RESULTS: We found that TAS was higher and TOS lower in DLM group. We also found that interstitial edema and inflammatory cell infiltration was significantly more frequent in DLM group and QT and QTc of DLM group were higher than others. DISCUSSION: Recent studies have shown that several special amino acids, such as glutamine, glycine, arginine and taurine, exhibit cytoprotective effect on the cardiocyte, and have established the cardioprotective properties of glutamine. CONCLUSION: In this study, we showed the protective role of glutamine against cardiotoxic effects of DLM in rats. This protective effect was confirmed by showing both tissue level improvement in oxidative stress markers and improvement in prolonged QT interval. PMID- 25798649 TI - Sodium fluoride generates ROS and alters transcription of genes for xenobiotic metabolizing enzymes in adult zebrafish (Danio rerio) liver: expression pattern of Nrf2/Keap1 (INrf2). AB - Anthropogenic activities have resulted in an increase in the level of fluoride (F), a natural pollutant in water, causing great threat to the aquatic organisms including fishes. Earlier we reported that sodium fluoride (NaF) exposure alters histological ultrastructure in zebrafish (Danio rerio) liver evidenced by hyperplasia, cytoplasmic degeneration, heteropycnosis etc. In this study, zebrafish were exposed to 7.5, 15 and 30 mg NaF l(-1) for 30 days as well as to 15 mg NaF l(-1) for 90 days. In NaF treated fish, generation of reactive oxygen species (ROS), depletion of glutathione (GSH) and increase in malondialdehyde (MDA) content along with enhanced activities of oxyradical-scavenging enzymes like catalase (CAT) and superoxide dismutase (SOD) were recorded. Activity of GSH metabolizing enzyme, glutathione-S-transferase (GST) was also enhanced. The mRNA levels of genes for xenobiotic metabolizing enzymes (XMEs) like cytochrome P450 1A (Cyp1A), NADPH Q Oxidase 1 (Nqo1) and Heme Oxygenase 1 (Ho-1) increased along with nuclear factor (erythroid-derived 2)-like 2 (Nrf2) whereas Kelch-like ECH associated protein 1 (Keap1) decreased in the treated groups in comparison to their controls. The increase in Nrf2 protein levels in NaF treated fish confirmed its key regulatory role in F-induced oxidative stress. Chromatin condensation and nuclear fragmentations were evidenced in NaF-treated groups indicating possible induction of apoptosis. The modulation of these toxicological parameters at genetic and biochemical levels may be used as an early warning for the environmental risk assessment of F(-) toxicity to aquatic organisms including fishes. PMID- 25798650 TI - Effects of silver and gold nanoparticles of different sizes in human pulmonary fibroblasts. AB - Silver and gold nanoparticles (Ag-AuNPs) are currently some of the most manufactured nanomaterials. Accordingly, the hazards associated with human exposure to Ag-AuNPs should be investigated to facilitate the risk assessment process. In particular, because pulmonary exposure to Ag-AuNPs occurs during handling of these nanoparticles, it is necessary to evaluate the toxic response in pulmonary cells. The aim of this study was to evaluate the in vitro mechanisms of toxicity of different sizes of silver (4.7 and 42 nm) and gold nanoparticles (30, 50 and 90 nm) in human pulmonary fibroblasts (HPF). The toxicity was evaluated by observing cell viability and oxidative stress parameters. Data showed that AgNPs-induced cytotoxicity was size-dependent, whereas the AuNPs of the three sizes showed similar cytotoxicity. Silver nanoparticles of 4.7 nm were much more toxic than the large silver nanoparticles and the AuNPs. However, the pre-treatment with the antioxidant, N-acetyl-L-cysteine, protected HPF cells against treatment with Ag-AuNPs. The oxidative stress parameters revealed significant increase in reactive oxygen species levels, depletion of glutathione level and slight, but not statistically significant inactivation of superoxide dismutase, suggesting generation of oxidative stress. Hence, care has to be taken while processing and formulating the Ag-AuNPs till their final finished product. PMID- 25798651 TI - Genotoxic and oxidative stress effects of 2-amino-9H-pyrido[2,3-b]indole in human hepatoma G2 (HepG2) and human lung alveolar epithelial (A549) cells. AB - 2-Amino-9H-pyrido[2,3-b]indole (AalphaC), which is present in high quantities in cigarette smoke and also in fried food, has been reported to be a probable human carcinogen. However, few studies have reported on the genotoxicity and oxidative stress induced by AalphaC. This study investigated the genotoxic effects of AalphaC in human hepatoma G2 (HepG2) and human lung alveolar epithelial (A549) cells using the comet assay. Significant increases in DNA fragment migration indicated that AalphaC causes serious DNA damage in HepG2 and A549 cells. The role of oxidative stress in the mechanism of AalphaC-induced genotoxicity was clarified by measuring the level of intracellular reactive oxygen species (ROS), the GSH/GSSG ratio and the formation of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage. The results showed that the levels of ROS and 8 OHdG increased, whereas the GSH/GSSG ratio decreased. The concentration of 8-OHdG was positively related to DNA damage. Taken together, these results indicate that AalphaC can induce genotoxicity and oxidative stress and that AalphaC likely exerts genotoxicity in HepG2 and A549 cells through ROS-induced oxidative DNA damage. This is the first report to describe AalphaC-induced genotoxic and oxidative stress in HepG2 and A549 cells. PMID- 25798652 TI - Advances in molecular signaling mechanisms of beta-phenethyl isothiocyanate antitumor effects. AB - beta-Phenethyl isothiocyanate (PEITC) is an important phytochemical from cruciferous vegetables and is being evaluated for chemotherapeutic activity in early phase clinical trials. Moreover, studies in cell culture and in animals found that the anticarcinogenic activities of PEITC involved all the major stages of tumor growth: initiation, promotion, and progression. A number of mechanisms have been proposed for the chemopreventive activities of this compound. Here, we focus on the major molecular signaling pathways for the anticancer activities of PEITC. These include (1) activation of apoptosis pathways; (2) induction of cell cycle arrest; and (3) inhibition of the survival pathways. Furthermore, we also discussed the regulation of drug-metabolizing enzymes, including cytochrome P450s, metabolizing enzymes, and multidrug resistance. PMID- 25798653 TI - Layered Bi2Se3 nanoplate/polyvinylidene fluoride composite based n-type thermoelectric fabrics. AB - In this study, we report the fabrication of n-type flexible thermoelectric fabrics using layered Bi2Se3 nanoplate/polyvinylidene fluoride (PVDF) composites as the thermoelectric material. These composites exhibit room temperature Seebeck coefficient and electrical conductivity values of -80 MUV K(-1) and 5100 S m(-1), respectively, resulting in a power factor approaching 30 MUW m(-1)K(-2). The temperature-dependent thermoelectric properties reveal that the composites exhibit metallic-like electrical conductivity, whereas the thermoelectric power is characterized by a heterogeneous model. These composites have the potential to be used in atypical applications for thermoelectrics, where lightweight and flexible materials would be beneficial. Indeed, bending tests revealed excellent durability of the thermoelectric fabrics. We anticipate that this work may guide the way for fabricating high performance thermoelectric fabrics based on layered V-VI nanoplates. PMID- 25798654 TI - Electrostatic occlusion and quaternary structural ion pairing are key determinants of Cu(I)-mediated allostery in the copper-sensing operon repressor (CsoR). AB - The copper-sensing operon repressor (CsoR) is an all-alpha-helical disc-shaped D2 symmetric homotetramer that forms a 2:1 tetramer/DNA operator complex and represses the expression of copper-resistance genes in a number of bacteria. A previous bioinformatics analysis of CsoR-family repressors distributes Cu(I) sensing CsoRs in four of seven distinct clades on the basis of global sequence similarity. In this work, we define energetically important determinants of DNA binding in the apo-state (DeltaDeltaGbind), and for allosteric negative coupling of Cu(I) binding to DNA binding (DeltaDeltaGc) in a model clade IV CsoR from Geobacillus thermodenitrificans (Gt) of known structure, by selectively targeting for mutagenesis those charged residues uniquely conserved in clade IV CsoRs. These include a folded N-terminal "tail" and a number of Cu(I)-sensor and clade specific residues that when mapped onto a model of Cu(I)-bound Gt CsoR define a path across one face of the tetramer. We find that Cu(I)-binding prevents formation of the 2:1 "sandwich" complex rather than DNA binding altogether. Folding of the N-terminal tail (residues R18, E22, R74) upon Cu-binding to the periphery of the tetramer inhibits assembly of the 2:1 apoprotein-DNA complex. In contrast, Ala substitution of residues that surround the central "hole" (R65, K101) in the tetramer, as well R48, impact DNA binding. We also identify a quaternary structural ion-pair, E73-K101", that crosses the tetramer interface, charge-reversal of which restores DNA binding activity, allosteric regulation by Cu(I), and transcriptional derepression by Cu(I) in cells. These findings suggest an "electrostatic occlusion" model, in which basic residues important for DNA binding and/or allostery become sequestered via ion-pairing specifically in the Cu(I)-bound state, and this aids in copper-dependent disassembly of a repression complex. PMID- 25798655 TI - Atomically thin epitaxial template for organic crystal growth using graphene with controlled surface wettability. AB - A two-dimensional epitaxial growth template for organic semiconductors was developed using a new method for transferring clean graphene sheets onto a substrate with controlled surface wettability. The introduction of a sacrificial graphene layer between a patterned polymeric supporting layer and a monolayer graphene sheet enabled the crack-free and residue-free transfer of free-standing monolayer graphene onto arbitrary substrates. The clean graphene template clearly induced the quasi-epitaxial growth of crystalline organic semiconductors with lying-down molecular orientation while maintaining the "wetting transparency", which allowed the transmission of the interaction between organic molecules and the underlying substrate. Consequently, the growth mode and corresponding morphology of the organic semiconductors on graphene templates exhibited distinctive dependence on the substrate hydrophobicity with clear transition from lateral to vertical growth mode on hydrophilic substrates, which originated from the high surface energy of the exposed crystallographic planes of the organic semiconductors on graphene. The optical properties of the pentacene layer, especially the diffusion of the exciton, also showed a strong dependency on the corresponding morphological evolution. Furthermore, the effect of pentacene substrate interaction was systematically investigated by gradually increasing the number of graphene layers. These results suggested that the combination of a clean graphene surface and a suitable underlying substrate could serve as an atomically thin growth template to engineer the interaction between organic molecules and aromatic graphene network, thereby paving the way for effectively and conveniently tuning the semiconductor layer morphologies in devices prepared using graphene. PMID- 25798656 TI - Aminotrifluoromethylation of olefins via cyclic amine formation: mechanistic study and application to synthesis of trifluoromethylated pyrrolidines. AB - We examined the mechanism of our previously reported aminotrifluoromethylation reaction, which proceeds via intramolecular cyclization of alkenylamines in the presence of the combination of copper catalyst and Togni reagent (1). Kinetic studies revealed that the initial rate of the reaction was first order with respect to Togni reagent and CuI, as well as the substrate. Changes of the (19)F NMR chemical shift of Togni reagent during the reaction suggested the existence of a dynamic equilibrium involving coordination of not only Togni reagent, but also the substrate amine and the product aziridine to copper. ESI-MS analysis provided evidence of involvement of reactive Cu(II) intermediates in the catalytic cycle. Overall, our results indicate that the reaction proceeds at the hypervalent iodine moiety of Togni reagent, which is activated by Cu(II) species acting as a Lewis acid catalyst. On the basis of these mechanistic considerations, we developed an efficient synthesis of trifluoromethylated pyrrolidine derivatives. This transformation exhibited a remarkable rate enhancement upon addition of Et3N. PMID- 25798657 TI - Assessment of baroreflex sensitivity from spontaneous oscillations of blood pressure and heart rate: proven clinical value? AB - The baroreceptor-heart rate reflex (baroreflex sensitivity, BRS) is a key mechanism contributing to the neural regulation of the cardiovascular system. Several methods have been proposed so far to assess BRS by analyzing the spontaneous beat-to-beat fluctuations of arterial blood pressure and heart rate. These methods are inherently simple, non-invasive and low-cost. This study is an attempt to address the question of whether spontaneous baroreflex methods have proven to be of value in the clinical setting. In the first part of this article, we critically review most representative clinical studies using spontaneous BRS techniques either for risk stratification or treatment evaluation, these being major issues in the clinical management of the patients. In the second part, we address two important aspects of spontaneous BRS measurements: measurability and reliability. Estimation of BRS in the studies selected for the review was performed according to the sequence, transfer function, alpha-index and phase rectified signal averaging method. Arterial blood pressure was recorded non invasively during supine, short-term (<30 min) laboratory recordings. The conclusion from this review is that spontaneous BRS techniques have been shown to be of great value in clinical practice but further work is needed to confirm the validity of previous findings and to widen the field of clinical applications. Measurability and reliability can be a major issue in the measurement of spontaneous BRS, particularly in some patient populations like post-myocardial infarction and heart failure patents. Main causes of poor measurability are: non sinus rhythm, a high rate of ectopic beats and the need for recorded time series of RR interval and arterial blood pressure to satisfy the constraints of the different BRS estimation algorithms. As for reliability, within-subject variability is rather high in the measurements of spontaneous BRS and, therefore, should be carefully taken into account when BRS measurements are used to detect treatment effects in individual patients. PMID- 25798658 TI - Erratum. AB - [This corrects the article on p. 689 in Vol. 36, Issue 9, PMID: 25147985. The second author's name was misspelled. The correct author's name should be: Jason Reutter or Reutter J]. PMID- 25798659 TI - Analysis and calculation of electronic properties and light absorption of defective sulfur-doped silicon and theoretical photoelectric conversion efficiency. AB - Most material properties can be traced to electronic structures. Black silicon produced from SF6 or sulfur powder via irradiation with femtosecond laser pulses displays decreased infrared absorption after annealing, with almost no corresponding change in visible light absorption. The high-intensity laser pulses destroy the original crystal structure, and the doping element changes the material performance. In this work, the structural and electronic properties of several sulfur-doped silicon systems are investigated using first principle calculations. Depending on the sulfur concentration (level of doping) and the behavior of the sulfur atoms in the silicon lattice, different states or an absence of states are exhibited, compared with the undoped system. Moreover, the visible-infrared light absorption intensities are structure specific. The results of our theoretical calculations show that the conversion efficiency of sulfur doped silicon solar cells depends on the sulfur concentrations. Additionally, two types of defect configurations exhibit light absorption characteristics that differ from the other configurations. These two structures produce a rapid increase in the theoretical photoelectric conversion efficiency in the range of the specific chemical potential studied. By controlling the positions of the atomic sulfur and the sulfur concentration in the preparation process, an efficient photovoltaic (PV) material may be obtainable. PMID- 25798660 TI - Comparative life cycle assessment of battery storage systems for stationary applications. AB - This paper presents a comparative life cycle assessment of cumulative energy demand (CED) and global warming potential (GWP) of four stationary battery technologies: lithium-ion, lead-acid, sodium-sulfur, and vanadium-redox-flow. The analyses were carried out for a complete utilization of their cycle life and for six different stationary applications. Due to its lower CED and GWP impacts, a qualitative analysis of lithium-ion was carried out to assess the impacts of its process chains on 17 midpoint impact categories using ReCiPe-2008 methodology. It was found that in general the use stage of batteries dominates their life cycle impacts significantly. It is therefore misleading to compare the environmental performance of batteries only on a mass or capacity basis at the manufacturing outlet ("cradle-to-gate analyses") while neglecting their use stage impacts, especially when they have different characteristic parameters. Furthermore, the relative ranking of batteries does not show a significant dependency on the investigated stationary application scenarios in most cases. Based on the results obtained, the authors go on to recommend the deployment of batteries with higher round-trip efficiency, such as lithium-ion, for stationary grid operation in the first instance. PMID- 25798661 TI - Interaction of cisplatin with 5'-dGMP: a combined IRMPD and theoretical study. AB - IR multiple photon dissociation (IRMPD) spectroscopy of cis-[Pt(NH3)2(5'-dGMP H)](+) and cis-[PtCl(NH3)2(5'-dGMP)](+) ions (where 5'-dGMP is 2'-deoxyguanosine 5'-monophosphate), generated in the gas phase by electrospray ionization, was performed in two spectral regions, namely, 700-1900 cm(-1) and 2800-3800 cm(-1). For structural assignment, experimental IRMPD spectra were compared to IR spectra computed at the B3LYP/LACV3P/6-311G** level of theory. In agreement with computational results, the vibrational spectroscopic characterization of the cis [Pt(NH3)2(5'-dGMP-H)](+) ion points to macrochelate species resulting from the simultaneous interaction of the metal with both the N7 atom of the guanine residue and an O atom of the phosphate group, structures that bear features in common with those characterized in solution by NMR spectroscopy. Concerning the cis-[PtCl(NH3)2(5'-dGMP)](+) ion, our study points to a monodentate complex involving exclusively the N7 position of guanine, as observed in solution. Also this species exhibits a compact form due to the formation of two hydrogen bonds involving the same ammonia ligand. For both complexes, IRMPD experiments show that a strong intramolecular hydrogen bond is established between one ammonia hydrogen and the carbonyl group of guanine. The strength of this particular interaction can be qualitatively estimated by looking at the redshift of the CO vibration with respect to an unperturbed C?O stretching mode in the fingerprint region. This point is also highlighted in the X-H (X = N, O) stretch region, by the shift of the N-H stretch frequency as a function of the number of hydrogen bonds involving the ammonia ligand. PMID- 25798662 TI - PCRA revisited: Testing the validity of the Federal Post Conviction Risk Assessment (PCRA). AB - The Post Conviction Risk Assessment (PCRA) was developed for use in the U.S. Probation System in 2009. Although previous publications have demonstrated the predictive validity of the PCRA using development and validation samples, this study uses assessments completed by U.S. probation officers on 113,281 offenders during the course of supervision. The current research assesses the PCRA's validity in predicting arrest for any new criminal conduct and arrest for violent offenses at 6, 12, 18, and 24 months. Bivariate and multivariate models were estimated based on race, gender, and ethnicity. The area under the receiver operating characteristic curve (AUC-ROC) values ranged between .70 and .77 depending on the subsample, outcome being predicted, and follow-up time. Overall, this research indicates that the PCRA predicts equally well across race, gender, and ethnicity and for differing follow-up time periods. In addition, the PCRA is a valid predictor of arrest for any criminal behavior and arrest for violent criminal behavior. PMID- 25798663 TI - LGBTQ relationally based positive psychology: An inclusive and systemic framework. AB - Positive psychologists have contributed to our understandings of how positive emotions and flexible cognition enhance resiliency. However, positive psychologists' research has been slow to address the relational resources and interactions that help nonheterosexual families overcome adversity. Addressing overlooked lesbian, gay, bisexual, transgender, or queer (LGBTQ) and systemic factors in positive psychology, this article draws on family resilience literature and LGBTQ literature to theorize a systemic positive psychology framework for working with nonheterosexual families. We developed the LGBTQ relationally based positive psychology framework that integrates positive psychology's strengths-based perspective with the systemic orientation of Walsh's (1996) family resilience framework along with the cultural considerations proposed by LGBTQ family literature. We theorize that the LGBTQ relationally based positive psychology framework takes into consideration the sociopolitical adversities impacting nonheterosexual families and sensitizes positive psychologists, including those working in organized care settings, to the systemic interactions of same-sex loving relationships. PMID- 25798664 TI - Functional cerebral lateralization and interhemispheric interaction in patients with callosal agenesis. AB - OBJECTIVE: The corpus callosum (CC), the largest commissure in the human brain, is thought to play an essential part in the formation and maintenance of lateralized cognitive and motor functions. In particular, it has been suggested that inhibition of the subdominant hemisphere via commissural fiber tracts plays a crucial role for functional lateralization. However, many studies supporting this idea have either been conducted in nonhuman model species or used indirect measures of callosal functioning. METHOD: In order to directly assess the impact of the presence or absence of the CC on both the existence and the extent of functional hemispheric asymmetries, we investigated handedness and language lateralization, as well as interhemispheric information integration, in 6 high functioning individuals with partial or complete agenesis of the CC (AgCC). Performance was compared with that of 30 IQ- and age-matched controls with intact CC. RESULTS: We found a stronger predisposition for ambidexterity in individuals with AgCC. Similarly, the typical right ear advantage in the dichotic listening task was significantly reduced in AgCC. Furthermore, AgCC patients generally reacted slower than controls in a test of interhemispheric information integration, and showed reduced accuracy in trials that required interhemispheric integration. CONCLUSIONS: These findings indicate that reduced hemispheric specialization in the acallosal brain might be due to a higher degree of hemispheric autonomy in AgCC. PMID- 25798665 TI - Study of naive and memory cells in a cohort of Egyptian chronic granulomatous disease patients. AB - CONTEXT: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder caused by inherited defects in the NADPH oxidase complex which may be involved in important pathways that connect innate and adaptive immunity. OBJECTIVES: Characterize the naive and memory compartment of B and T lymphocytes in patients with CGD. METHODS: Twenty CGD patients and twenty healthy controls matched for age and sex were enrolled in this study. Flow cytometric assessment of the naive and memory compartments of peripheral blood lymphocytes was done using cell surface markers CD45RO, CD45RA, CD27, CD3 and CD19. RESULTS: There were 15 (79%) autosomal recessive CGD patients (8 females (53%) and 7 males (47%), 100% positive parental consanguinity) and four (21%) X-linked CGD patients. On comparing the 3 groups; AR CGD, X-linked CGD and controls, there was a positive statistical significant difference for the percentage and absolute count of CD19 + CD27+ memory B cell (p = 0.028 and p = 0.047 respectively), CD45RA cells (with p values of p = 0.000 and 0.033, respectively), the naive compartment CD3 + CD45RA+ cells percentage and absolute counts (p = 0.005, 0.01respectively), CD3 + CD27 + cells percentage and absolute counts (p = 0.001, 0.012 respectively), CD3 + CD45RA + CD27+ cells percentage and absolute counts (p = 0.015, 0.005, respectively). The significance was mainly attributed to the decrease in the X-linked group than control group. CONCLUSION: There was an altered naive and memory B profile in CGD patients, this may increase susceptibility of the patients to opportunistic infections and autoimmune disorders. T-cell alterations have to be interpreted cautiously especially in the presence of infections. PMID- 25798666 TI - In vitro studies on mangiferin protection against cadmium-induced human renal endothelial damage and cell death via the MAP kinase and NF-kappaB pathways. AB - The therapeutic effects of the natural antioxidant mangiferin (a xanthonoid and potent oxygen free radical scavenger), which is widely distributed in mango fruit, against CdCl(2)-induced toxicity in human renal glomerulus endothelial cells (HRGEC) were investigated. The viability of HREGCs that were treated with CdCl(2) (25 u mol) and co-treated with mangiferin (75 u mol) for 24 h was measured by crystal violet dye. The exposure of human glomerulus renal endothelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL 8, two pivotal proinflammatory cytokines known to play a significant role in renal inflammation. Proinflammatory cytokine secretion by human renal glomerulus endothelial cells could be the result of cadmium-induced IL-6 secretion via an NF kappaB-dependent pathway. However, IL-8 secretion involves the phosphor-JNK phospho-p38 signaling pathway. The results of the current study reveal that mangiferin could prevent both cadmium-induced IL-6 and IL-8 secretion by human glomerulus endothelial cells and be used to prevent renal inflammation. PMID- 25798667 TI - [Peer review--a system fall of problems but the least worse we have...]. PMID- 25798668 TI - [Biofeedback and neurofeedback: applications in psychosomatic medicine and psychotherapy]. PMID- 25798669 TI - The impact of circulating suppressor cells in multiple myeloma patients on clinical outcome of DLIs. AB - Allo-SCT followed by DLIs can establish long-term remissions in multiple myeloma (MM) patients. In many patients, however, the immunotherapeutic graft-versus tumor (GVT) effect is moderate and not sustained, implying that immune suppression is mediated, among other factors, by regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). Towards a better understanding and, eventually, manipulation of the immune-regulatory mechanisms in transplanted MM patients, we retrospectively sought a correlation between DLI outcome and circulating CD14(+) MDSCs, CD14(-) MDSCs and Tregs in 53 MM patients before their first DLI. We found significantly elevated frequencies of highly suppressive CD14(+) MDSCs, CD14(-) MDSCs and Tregs in pre-DLI samples from patients. Higher frequencies of Tregs, but not of MDSCs, were significantly associated with non responsiveness to DLI. Furthermore, a lower frequency of Tregs predicted the development of chronic GVHD, which, in turn, displayed a high association with GVT. Elevated Treg frequencies before DLI were also associated with significantly shorter PFS and OS. Hence, our data reinforce the idea of active suppression of antitumor responses by Tregs in MM patients and therefore suggest that targeting patient Tregs before DLI may improve outcome of DLI. PMID- 25798670 TI - Very late-onset reversible cardiomyopathy in patients with chronic GvHD. PMID- 25798671 TI - Racial differences in allogeneic hematopoietic cell transplantation outcomes among African Americans and whites. AB - The impact of race on outcome has been identified in a number of cancers, with African Americans having poorer survival compared with whites. We conducted a study to investigate the association of race with allogeneic hematopoietic cell transplant (HCT) outcomes. We identified 789 patients (58 African Americans and 731 whites) who underwent allogeneic HCT for hematologic disorders. There were no significant differences between African Americans and white patients in gender, performance status or comorbidity score. However, African Americans were younger than whites (median 40 years versus 47 years, P=0.003) and were more likely to be in remission at HCT (74% versus 57%, P=0.011), to have an HLA-mismatched donor (36% versus 14%, P<0.001), to have positive donor or recipient CMV serostatus (90% versus 69%, P<0.001) and to have received a cord blood transplant (21% versus 6%, P<0.001). In univariate analysis, African Americans had worse overall survival (OS) (HR 1.41, P=0.026) compared with whites, with no significant differences in acute or chronic GvHD, non-CMV infection or relapse. However, after adjusting for several transplant and disease-related factors in multivariate analysis, the OS difference between African Americans and whites became nonsignificant (HR 1.27, P=0.18). These results suggest that race in and of itself does not lead to worse survival post HCT. PMID- 25798673 TI - Comparison of upfront tandem autologous-allogeneic transplantation versus reduced intensity allogeneic transplantation for multiple myeloma. AB - We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma. PMID- 25798674 TI - Pretransplant vaccinations in allogeneic stem cell transplantation donors and recipients: an often-missed opportunity for immunoprotection? AB - Immune deficiency following hematopoietic cell transplantation predisposes the patient to potentially deadly infections. Vaccinations can improve immunity and thus reduce the morbidity and mortality associated with these infections. Over the years different sets of guidelines have been published the most recent by the Infectious Diseases Society of American (IDSA). There is limited evidence that vaccination of donors and/or recipients before transplantation may improve immunity. However, despite the possibility of augmented immunity, there remain logistical, ethical and medical concerns about such a vaccination strategy. PMID- 25798675 TI - Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients. AB - Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P<0.0001) and without GVHD (73% vs 48%; P<0.0001) or invasive fungal infection (85% vs 73%; P=0.0003) despite a stable admission rate (21.7%). These changes were associated with significantly better 90-day survival (49% vs 31%). Independent predictors of hospital mortality were GVHD, mechanical ventilation (MV) and renal replacement therapy (RRT). Among patients who required MV or RRT, survival was 29% and 18%, respectively, but dropped to 18% and 6% in those with GVHD. The use of ICU admission has changed and translated into improved survival, but advanced life support in patients with GVHD usually provides no benefits. PMID- 25798672 TI - Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. AB - This is the sixth special report that the European Society for Blood and Marrow Transplantation regularly publishes on the current practice and indications for haematopoietic SCT for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred in the field of haematopoietic SCT over the last years. Cord blood units as well as haploidentical donors have been increasingly used as stem cell sources for allo-SCT, thus, augmenting the possibility of finding a suitable donor for a patient. Continuous refinement of conditioning strategies has also expanded not only the number of potential indications but also has permitted consideration of older patients or those with co-morbidity for a transplant. There is accumulating evidence of the role of haematopoietic SCT in non-haematological disorders such as autoimmune diseases. On the other hand, the advent of new drugs and very effective targeted therapy has challenged the role of SCT in some instances or at least, modified its position in the treatment armamentarium of a given patient. An updated report with revised tables and operating definitions is presented. PMID- 25798676 TI - Adverse health events and late mortality after pediatric allogeneic hematopoietic SCT-two decades of longitudinal follow-up. AB - Treatment-related late toxicities after pediatric allogeneic hematopoietic SCT (allo-HSCT) are increasingly important as long-term survival has become an expected outcome for many transplanted children and adolescents. In a retrospective cohort study, we assessed long-term health outcomes in 204 allo HSCT survivors transplanted in childhood or adolescence (<20 years) between 1978 through 2000 after a median follow-up time of 12 (range 4-28) years. Data on conditioning regimen, adverse health events (AE) and growth and hormonal substitutions (hormone replacement therapies (HRTs)) were obtained from medical records. AEs were graded retrospectively according to Common Terminology Criteria for Adverse Events v3.0. Late deaths (?48 months after allo-HSCT) were evaluated separately. Multivariate analysis demonstrated that chronic GVHD (P<0.000) and longer follow-up time (P<0.05) correlated with AEs, whereas CY-based conditioning was inversely correlated (P<0.002). TBI and longer follow-up duration predicted more severe AEs (P<0.001 and P<0.001, respectively). HRTs were more frequent after TBI. Diabetes type II, dyslipidemia and hypertension were detected in 9, 7 and 7% of the survivors, respectively. Late deaths (n=22) were most frequently due to pulmonary failure (n=7), followed by secondary malignancy (n=5). The occurrence of AEs after pediatric allo-HSCT is high and likely to increase during extended follow-up, particularly in patients who have received TBI. PMID- 25798677 TI - Preferential depletion of host over donor T cells through in vivo decay of active rabbit-anti-thymocyte globulin levels during reduced intensity conditioning. AB - Inadequate T-cell chimerism following reduced-intensity conditioning transplantation may contribute to graft rejection and disease relapse. Anti thymocyte globulin (ATG) enhances early donor T-cell chimerism, but may also deplete donor T cells, increasing risks of infection and relapse. We prospectively tested administration of rabbit ATG (rATG) ?14 days before the infusion of the graft, followed by in vivo decay of active rATG levels, to selectively deplete host T cells. Twenty-three patients received rATG total dose 4.5 mg/kg on days -16 and -15, fludarabine 30 mg/m(2) per day on day -7 through 3, IV busulfan 130 mg/m(2) per day on days -4 and -3 and cyclophosphamide 1500 mg/m(2) on day -2. rATG levels were therapeutic in all patients on day -14, but were sub-therapeutic (<1 MUg/mL) by day 0 in 82% of patients. Median donor T-cell chimerisms on days 30 and 180 were 100% (75-100%) and 100% (90-100%), respectively. Non-relapse mortality and relapse/progression at 48 months were 17 and 30%. Cumulative incidences of acute GvHD grades II-IV and III-IV were 39 and 9%. Median follow-up is 64 months (46-79 months). Survival and disease-free survival at 48 months were 70 and 52%. These data suggest that selective depletion of host T cells using this regimen is a feasible and effective strategy. PMID- 25798678 TI - Pre-transplant sirolimus might improve the outcome of haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide for patients with severe aplastic anemia. PMID- 25798679 TI - Prognostic significance of liver parameters at 1-year follow-up in children and adults undergoing myeloablative allogeneic stem cell transplantation. PMID- 25798680 TI - Evaluation of pretransplant influenza vaccination in hematopoietic SCT: a randomized prospective study. AB - Pretransplant influenza vaccination of the donor or allogeneic hematopoietic SCT (HSCT) candidate was evaluated in a randomized study. One hundred and twenty-two HSCT recipients and their donors were assigned to three randomization groups: no pretransplant vaccination (n=38), donor pretransplant vaccination (n=44) or recipient pretransplant vaccination (n=40). Specific IgG was assessed by both hemagglutinin inhibition (HI) and, in 57 patients, by an indirect influenza specific ELISA at specified times after HSCT. Vaccinated donors had seroprotective HI titers for Ags H1 and H3 (P<0.001) compared with the other groups at the time of donation. The titers against H1 (P=0.028) and H3 (P<0.001) were highest in the pretransplant recipient vaccination group until day 180 after transplantation. A significant difference was found in the specific Ig levels against pandemic H1N1 at 6 months after SCT (P=0.02). The mean IgG levels against pandemic H1N1 and generic H1N1 and H3N2 were highest in the pretransplant recipient vaccination group. We conclude that pretransplant recipient vaccination improved the influenza-specific seroprotection rates. PMID- 25798681 TI - Impact of length of cryopreservation and origin of cord blood units on hematologic recovery following cord blood transplantation. AB - As the history of the cord blood banking system has lengthened, the number of cord blood units (CBUs) cryopreserved for years has increased. The global expansion of cord blood banking resulted in active international exchange of CBUs. To determine whether long-term cryopreservation and international shipment of CBUs affect the quality of the units and outcome after transplantation, we retrospectively analyzed the quality of 95 CBUs and the hematologic recovery of 127 patients with hematological malignancy following single-unit cord blood transplantation. Of the 127 CBUs used to transplant, 42 units were cryopreserved for long periods (5-11.8 years), and 44 units were shipped from distant countries. We found that length of cryopreservation and origin of CBUs did not affect the ratio of viable total-nucleated cells after thawing. Also, neutrophil engraftment was not affected by long-term cryopreservation (> 5 years) or origin (from distant countries), (hazard ratio, 0.91 and 1.2; P=0.65 and 0.41; respectively). The number of CD34(+) cells before freezing (> 1.4 cells/kg recipient) was the only factor that enhanced neutrophil engraftment (hazard ratio, 1.8; P<0.01). This suggests that length of cryopreservation and origin need not be prioritized over the CD34(+) cell dose when selecting CBUs. PMID- 25798683 TI - Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy. AB - OBJECTIVES: Randomised trials have shown the efficacy of antiplatelet therapy with cilostazol to prevent secondary ischaemic stroke. Recently, cilostazol has been reported to prevent the development and/or recurrence of atrial fibrillation (AF), which can potentially prevent cardioembolic stroke in patients undergoing antiplatelet therapy. Herein, we examined the impact of prior antiplatelet therapy with cilostazol on the incidence of cardioembolic stroke, which had not been fully investigated. METHODS: Using the multicenter retrospective study of stroke risk in antithrombotic therapy (RESTATE) database, we analysed consecutive patients with primary or secondary stroke under single antiplatelet therapy. We evaluated the characteristics of ischaemic stroke based on the type of antiplatelet agent used: aspirin, ticlopidine/clopidogrel or cilostazol. RESULTS: Of 1069 consecutive patients with primary or secondary stroke during antithrombotic therapy from January to December 2012, 615 patients received single antiplatelet therapy (293 and 322 cases of primary and secondary strokes, respectively). Interestingly, the percentage of cardioembolic infarction was significantly lower in patients taking cilostazol compared with other agents. Multivariate regression analysis found that age (OR: 1.03, 95% CI: 1.01-1.06, P = 0.0029), serum creatinine (OR: 1.17, 95% CI: 1.03-1.34, P = 0.0198), aspirin (OR: 1.75, 95% CI: 1.00-3.22, P = 0.0486), cilostazol (OR: 0.19, 95% CI: 0.03-0.73, P = 0.0125), and smoking (OR: 1.86, 95% CI: 1.16-2.94, P = 0.0102) were independently associated with cardioembolic stroke. CONCLUSIONS: Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy. This could be a novel strategy for cardioembolic stroke prevention potentially by affecting cardiac remodelling, in contrast to secondary anticoagulant therapy. PMID- 25798684 TI - Role of interferon gamma and tumor necrosis factor-related apoptosis-inducing ligand receptor 1 single nucleotide polymorphism in natural clearance and treatment response of HCV infection. AB - Hepatitis C virus (HCV) pathogenesis and treatment outcomes are multifactorial phenomena involving both viral and host factors. This study was designed to determine the role of tumor necrosis factor-related apoptosis-inducing ligand receptor 1(TRAIL-R1) and interferon gamma (IFN-gamma) genetic mutations in susceptibility and response to interferon-based therapy of hepatitis C virus (HCV) infection. The detection of TRAIL-R1 rs4242392 and IFN-gamma rs2069707 single nucleotide polymorphisms was completed in 118 chronic HCV patients and 96 healthy controls by allele-specific polymerase chain reaction and restriction fragment length polymorphisms polymerase chain reaction. Patients were further categorized into sustained virological responder (SVR) and nonresponder (NR) groups on the basis of their response to interferon-based therapy for HCV infection. Real-time PCR was used for HCV quantification. HCV genotyping was performed by Ohno's method. The results demonstrated that the distribution of the TRAIL-R1 rs4242392TT genotype was significantly higher in the SVR group (78%) compared to the NR group (36%). It showed that chronic HCV patients possessing the TRAIL-R1 rs4242392TT genotype are better responders to interferon-based therapy (p<0.05). The prevalence of the TRAIL-R1 rs4242392TT genotype in healthy controls and chronic HCV patients was 56% and 65% respectively. It indicated that there is the TRAIL-R1 rs4242392 genetic variation plays no role in the spontaneous clearance of HCV infection (p>0.05). The distribution of IFN-gamma rs2069707 was the opposite to TRAIL-R1 rs4242392 prevalence, that is, there was high distribution of the IFN-gamma rs2069707GG genotype in patients and healthy controls (p<0.05), while the prevalence of IFN-gamma rs2069707GG in SVR and NR groups was comparable (p>0.05). In conclusion, genetic variation of TRAIL-R1 rs4242392 is linked with response to interferon-based therapy for HCV infection, and genetic variation IFN-gamma rs2069707 is associated with natural clearance of HCV infection. PMID- 25798685 TI - Simple chalcones and bis-chalcones ethers as possible pleiotropic agents. AB - The synthesis, the antioxidative properties and the lipoxygenase (LOX) and acetylcholinesterase (AChE) inhibition of a number of 4-hydroxy-chalcones diversely substituted as well as of a series of bis-chalcones ether derivatives are reported. The chalcones derivatives were readily produced using a Claisen Schmidt condensation in a ultra sound bath in good yields. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity is experimentally determined by reversed-phase thin-layer chromatography method. Most of them are potent in vitro inhibitors of lipid peroxidation and of LOX. Compounds b2 and b3 were found to be the most potent LOX and AChE inhibitors among the tested derivatives with a significant anti-lipid peroxidation profile. The results led us to propose these enone derivatives as new multifunctional compounds against Alzheimer's disease. The results are discussed in terms of structural and physicochemical characteristics of the compounds. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods. PMID- 25798682 TI - Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). AB - Sinusoidal obstruction syndrome or veno-occlusive disease (SOS/VOD) is a potentially life-threatening complication of hematopoietic SCT (HSCT). This review aims to highlight, on behalf of the European Society for Blood and Marrow Transplantation, the current knowledge on SOS/VOD pathophysiology, risk factors, diagnosis and treatments. Our perspectives on SOS/VOD are (i) to accurately identify its risk factors; (ii) to define new criteria for its diagnosis; (iii) to search for SOS/VOD biomarkers and (iv) to propose prospective studies evaluating SOS/VOD prevention and treatment in adults and children. PMID- 25798686 TI - Relaxant effects of selected sildenafil analogues in the rat aorta. AB - A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their relaxant effects in the rat aorta. Evaluation of prepared derivatives demonstrated that compound (8a) is probably a non-selective phosphodiesterase (PDE) inhibitor, as it induced aortic relaxation through endothelium-independent mechanism. PMID- 25798687 TI - Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. AB - Because of the complexity of Alzheimer's disease (AD), the multi-target-directed ligand (MTDL) strategy is expected to provide superior effects for the treatment of AD, instead of the classic one-drug-one-target strategy. In this context, we focused on the design, synthesis and evaluation of homoisoflavonoid derivatives as dual acetyl cholinesterase (AChE) and monoamine oxidase (MAO-B) inhibitors. Among all the synthesized compounds, compound 10 provided a desired balance of AChE and hMAO-B inhibition activities, with IC50 value of 3.94 and 3.44 MUM, respectively. Further studies revealed that compound 10 was a mixed-type inhibitor of AChE and an irreversible inhibitor of hMAO-B, which was also confirmed by molecular modeling studies. Taken together, the data indicated that 10 was a promising dual functional agent for the treatment of AD. PMID- 25798688 TI - In vitro effects of some flavonoids and phenolic acids on human pyruvate kinase isoenzyme M2. AB - Pyruvate kinase isoenzyme M2 (PKM2) is one of the most important control point enzyme in glycolysis pathway. Hence, its inhibitors and activators are currently considered as the potential anticancer agents. The effect of 28 polyphenolic compounds on the enzyme activity was investigated in vitro. Among these compounds, neoeriocitrin, (-)-catechin gallate, fisetin, (+/-)-taxifolin and (-) epicatechin have the highest inhibition effect with IC50 value within 0.65-1.33 uM range. Myricetin and quercetin 3-beta-D-glucoside exhibited the highest activation effect with 0.51 and 1.34 uM AC50 values, respectively. Twelve of the compounds showed inhibition effect within 7-38 uM range of IC50 value. Sinapinic acid and p-coumaric acid showed an activation effect with 26.2 and 22.2 uM AC50 values, respectively. The results propose that the polyphenolics may be the potential PKM2 inhibitors/activators, and they may be used as lead compounds for the synthesis of new inhibitors or activators of this enzyme. PMID- 25798689 TI - Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3 ethoxycarbonylmethylurea derivatives. AB - Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a-3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H imidazolidine-2-imines (1a-1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R1 are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4 methyl and 4-chloro substitution is tolerated as R1, whereas 4-chloro and 2 methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds. PMID- 25798690 TI - 3-methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents. AB - In a new group of 3-methyl-2-phenyl-1-substituted-indole derivatives (10a-f), the indomethacin analogs were prepared via the Fisher indole synthesis reaction of propiophenone with appropriately substituted phenylhydrazine hydrochloride. This is followed by the insertion of the appropriate benzyl or benzoyl fragment. All the synthesized compounds were evaluated for their anti-inflammatory (in vitro and in vivo) and analgesic activities. The methanesulphonyl derivatives 10d, e and f showed the highest anti-inflammatory (in vitro and in vivo) and analgesic activities. In addition, molecular docking studies were performed on compounds 10a-f and the results were in agreement with that obtained from the in vitro COX inhibition assays. The significant anti-inflammatory and analgesic activities exhibited by 10d and 10e warrant continued preclinical development as potential anti-inflammatory and analgesic agents. PMID- 25798691 TI - Abl1 inhibitory contaminants leach from plastic tubes. AB - Plastic materials are widely used in research laboratories. Disposable plasticware facilitates life science research in the storage, transportation and manipulation of biological samples. However, recent findings have shown that some disposable plasticwares release bioactive contaminants. The bioactive leachates from plastic tubes, used as Abl1 catalytic incubator in this report, were noticed to interfere with the activity of Abl1. Extraction of these bioactive leachates was performed, and their inhibitory activity against Abl1 and cytotoxicity were tested. Results indicated that the tube extracts had no significant cytotoxicity but could inhibit the activity of Abl1. Therefore, these bioactive leachates from plastic tubes might be a specific inhibitor of tyrosine kinase. PMID- 25798692 TI - Partial purification and characterization of lipase from Geobacillus stearothermophilus AH22. AB - The lipase was partially purified by ion exchange chromatography and gel filtration column chromatography, and was characterized from Geobacillus stearothermophilus AH22 strain. The lipase was purified 18.3-folds with 19.7% recovery. The lipase activity was determined by using p-nitrophenyl esters (C2 C12) as substrates. The Km values of the enzyme for these substrates were found as 0.16, 0.02, 0.19 and 0.55 mM, respectively, while Vmax values were 0.52, 1.03, 0.72 and 0.15 U mg(-1). The enzyme showed maximum activity at 50 degrees C and between pH 8.0 and 9.0. The enzyme was found to be quite stable at pH range of 4.0-10.0, and thermal stability between 50 and 60 degrees C. It was found that the best inhibitory effect of the enzyme activity was of Hg(2+). The inhibitory effect as orlistat, catechin, propyl paraben, p-coumaric acid, 3,4-dihydroxy hydro-cinnamic acid was examined. These results suggest that G. stearothermophilus AH22 lipase presents very suitable properties for industrial applications. PMID- 25798693 TI - Genetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis. AB - Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiological studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clinical trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clinical trials with large cohorts could provide answers with respect to the clinical effects of vitamin D in MS. However, genetic studies have suggested that genes associated with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels. PMID- 25798694 TI - Effectiveness of erbium:YAG laser and cryosurgery in seborrheic keratoses: Randomized, prospective intraindividual comparison study. AB - BACKGROUND AND OBJECTIVE: Seborrheic keratoses (SK) are benign cutaneous lesions frequently seen in old age. The aim of the study is to compare the efficiency of Er:YAG lasers with cryotherapy in the treatment of SK. PATIENTS AND METHODS: The study was carried out on 42 patients with SK sized 0.5-3 cm, located on the back, chest, face and neck. Lesions with a similar size and location on the same patient were matched. In the same session, half of the lesions were treated with cryotherapy, while the other half were treated with Er:YAG lasers. All of the patients were clinically evaluated in two recalls with a one-month interval between appointments. The efficiency of the treatments was clinically evaluated. RESULTS: Following the first treatment, complete healing was detected in all of the lesions (100%) treated with Er:YAG lasers, while the healing rate was 68% in the cryotherapy group (p < 0.01). In the Er:YAG laser-treated group, hyperpigmentation was significantly lower and more erythema developed than in the cryotherapy group. CONCLUSION: Er:YAG lasers offer a one-step procedure which is a very simple and economic treatment and provides an alternative treatment method with better cosmetic results compared to cryotherapy. PMID- 25798695 TI - Intravenous human immunoglobulin for treatment of folliculitis decalvans. AB - We report a case of folliculitis decalvans (FD) successfully treated with intravenous human immunoglobulin (HIG). Many conventional treatments with topical agents and oral antibiotics had failed to achieve disease remission, treatment with HIG at a dose of 2 g/kg for the first month, reduced to 1 g/kg for second to fourth months was therefore started, which resulted in rapid improvement and ultimately complete resolution of FD. Clinical improvement was noted after the first infusion of HIG and remission of inflammation was achieved after the fourth infusion. Disease remission was sustained for six months following the last HIG infusion. The exact mechanism of action of HIG is poorly understood. However, it is thought to act as an immunomodulatory agent by altering different components of immune functions. To our knowledge, this is the first case reported in the literature of FD successfully treated with intravenous HIG. PMID- 25798696 TI - Atypical expression of circadian clock genes in denervated mouse skeletal muscle. AB - The central circadian clock in the suprachiasmatic nucleus of the hypothalamus synchronizes peripheral clocks through neural and humoral signals in most mammalian tissues. Here, we analyzed the effects of unilateral sciatic denervation on the expression of circadian clock- and clock-controlled genes in the gastrocnemius muscles of mice twice per day on days 0, 3, 7, 9, 11 and 14 after denervation and six times on each of days 7 and 28 after denervation to assess the regulation mechanism of the circadian clock in skeletal muscle. Sciatic denervation did not affect systemic circadian rhythms since core body temperature (Day 7), corticosterone secretion (Days 7 and 28), and hepatic clock gene expression remained intact (Days 7 and 28). Expression levels of most circadian clock-related genes such as Arntl, Per1, Rora, Nr1d1 and Dbp were reduced in accordance with the extent of muscle atrophy, although circadian Per2 expression was significantly augmented (Day 28). Cosinor analysis revealed that the circadian expression of Arntl (Days 7 and 28) and Dbp (Day 28) was phase advanced in denervated muscle. The mRNA expression of Clock was significantly increased in denervated muscle on Day 3 when the severe atrophy was absent, and it was not affected by atrophic progression for 28 days. Sciatic denervation did not affect the expression of these genes in the contralateral muscle (Days 7 and 28), suggesting that humoral changes were not involved in denervation-induced muscle clock disruption. We then analyzed genome-wide gene expression using microarrays to determine the effects of disrupting the molecular clock in muscle on circadian rhythms at Day 7. Among 478 circadian genes, 313 lost rhythmicity in the denervated muscles. These denervation-sensitive genes included the lipid metabolism-related genes, Nrip1, Bbs1, Ptgis, Acot1, Scd2, Hpgd, Insig1, Dhcr24, Ldlr and Mboat1. Our findings revealed that sciatic denervation disrupts the circadian expression of clock and clock-controlled genes either directly or indirectly via muscle atrophy in the gastrocnemius muscles of mice in a gene specific manner. PMID- 25798697 TI - Other factors to consider in the formation of chloropropandiol fatty esters in oil processes. AB - This paper examines the processing steps of extracting palm oil from fresh fruit bunches in a way that may impact on the formation of chloropropandiol fatty esters (3-MCPD esters), particularly during refining. Diacylglycerols (DAGs) do not appear to be a critical factor when crude palm oils are extracted from various qualities of fruit bunches. Highly hydrolysed oils, in spite of the high free fatty acid (FFA) contents, did not show exceptionally high DAGs, and the oils did not display a higher formation of 3-MCPD esters upon heat treatment. However, acidity measured in terms of pH appears to have a strong impact on 3 MCPD ester formation in the crude oil when heated at high temperatures. The differences in the extraction process of crude palm oil from current commercial processes and that from a modified experimental process showed clearly the effect of acidity of the oil on the formation of 3-MCPD esters. This paper concludes that the washing or dilution step in palm oil mills removes the acidity of the vegetative materials and that a well-optimised dilution/washing step in the extraction process will play an important role in reducing formation of 3-MCPD esters in crude palm oil upon further heat processing. PMID- 25798699 TI - Soya Saponins Induce Enteritis in Atlantic Salmon (Salmo salar L.). AB - Soybean meal-induced enteritis (SBMIE) is a well-described condition in the distal intestine of salmonids, and saponins have been implicated as the causal agent. However, the question remains whether saponins alone cause SBMIE. Moreover, the dose-response relationship has not been described. In a 10 week feeding trial with Atlantic salmon, a highly purified (95%) soya saponin preparation was supplemented (0, 2, 4, 6, or 10 g/kg) to two basal diets, one containing fishmeal as the major protein source (FM) and the other 25% lupin meal (LP). Saponins caused dose-dependent increases in the severity of inflammation independent of the basal diet, with concomitant alterations in digestive functions and immunological marker expression. Thus, saponins induced inflammation whether the diet contained other legume components or not. However, responses were often the same or stronger in fish fed the corresponding saponin supplemented LP diets despite lower saponin exposure, suggesting potentiation by other legume component(s). PMID- 25798700 TI - Voltage induced electrochemical reactions in the single lithium-rich layer-oxide nanoparticles. AB - As a crucial building block of the electrode in the lithium-ion battery (LIB), single nanoparticles that respond to an electric field have rarely been characterized experimentally. It is important to study the intrinsic properties of nanoparticles independently, excluding the effects from binders and additives. In this paper, isolated Li-rich layer-oxide (Li1.2Mn0.54Ni0.13Co0.13O2) nanoparticles are studied in comparison with individual Li2MnO3 and LiNi1/3Co1/3Mn1/3O2 nanoparticles. The bias triggered changes in morphology and material properties are characterized using dual-frequency scanning probe microscopy (SPM) techniques in ambient air, synthetic air, and an argon atmosphere. Inhomogeneous stiffness/composition is observed on single nanoparticles. The change in local Li(+)-ion concentration may contribute to the stiffness variation. Bias induced Li(+)-ion redistributions and electrochemical reactions are observed. Nanoparticles are fragmented at high voltage (>5 V) when an excessive amount of Li-ions are removed. This work further demonstrates the application of multi-frequency SPM techniques for the characterization of nanoparticles for energy storage applications. PMID- 25798701 TI - Large photocurrent response and external quantum efficiency in biophotoelectrochemical cells incorporating reaction center plus light harvesting complexes. AB - Bacterial photosynthetic reaction centers (RCs) are promising materials for solar energy harvesting, due to their high ratio of photogenerated electrons to absorbed photons and long recombination time of generated charges. In this work, photoactive electrodes were prepared from a bacterial RC-light-harvesting 1 (LH1) core complex, where the RC is encircled by the LH1 antenna, to increase light capture. A simple immobilization method was used to prepare RC-LH1 photoactive layer. Herein, we demonstrate that the combination of pretreatment of the RC-LH1 protein complexes with quinone and the immobilization method results in biophotoelectrochemical cells with a large peak transient photocurrent density and photocurrent response of 7.1 and 3.5 MUA cm(-2), respectively. The current study with monochromatic excitation showed maximum external quantum efficiency (EQE) and photocurrent density of 0.21% and 2 MUA cm(-2), respectively, with illumination power of ~6 mW cm(-2) at ~875 nm, under ambient conditions. This work provides new directions to higher performance biophotoelectrochemical cells as well as possibly other applications of this broadly functional photoactive material. PMID- 25798702 TI - Composite microdiscs with a magnetic belt: preparation, chaining properties, and use as switchable catalyst carriers. AB - We describe an emulsion-based preparation of patchy composite particles (diameter of 100-500 MUm) consisting of a disclike epoxy core and a belt of porous polystyrene particles (diameter of 30 MUm) with magnetite within the pores. Compared to the magnetically uniform polystyrene particles, the spontaneous aggregation of composite particles is suppressed when dispersed into liquid, which is attributed to the increased particle size, reduced magnetic susceptibility, and the shape of the magnetic domain distribution within the particles (spherical versus a belt). When the composite particles are coated by platinum-palladium layer we demonstrate they can be employed as switchable catalyst carriers, moving from one liquid phase to another when controlled by an external magnetic field. PMID- 25798703 TI - Management of a case of recognized perforation of the globe during strabismus surgery. PMID- 25798705 TI - ICAM still roll with it. PMID- 25798704 TI - "Mommy, I see only half of you with my left eye". PMID- 25798706 TI - Comparing suture materials used in frontalis suspension procedures. PMID- 25798707 TI - Intravitreal anti-VEGF therapy as a treatment for retinopathy of prematurity: what we know after 7 years. AB - The authors review published clinical case reports, case series, and clinical trials evaluating the use of anti-vascular endothelial growth factor (VEGF) medications for the primary or adjunctive treatment of retinopathy of prematurity (ROP). A literature search of peer reviewed reports on PubMed was performed. More than 50 pertinent peer-reviewed publications between 2006 and 2014 were selected to be included in this review and are summarized in this report. There is a growing body of literature on the use of anti-VEGF therapy as a treatment for ROP, predominately in the form of case reports and small case series. Adverse effects from anti-VEGF treatment for ROP have been reported, but with limited follow-up time. The use of anti-VEGF as a treatment for ROP remains off-label. PMID- 25798708 TI - The Eagles Eye Mobile: assessing its ability to deliver eye care in a high-risk community. AB - PURPOSE: The Philadelphia Eagle Eye Mobile (EEM) provides optometric vision care to children who fail a vision screening performed by nurses at schools in low income areas. METHODS: Data for children seen on the EEM between 2006 and 2008 for whom school nurse feedback was available regarding glasses wear at 1-, 4-, and 12-month intervals served as the study population. Optometric findings and glasses prescriptions at initial examination were recorded in the EEM database. The ophthalmic records for children referred for pediatric ophthalmology consultation at our institution were reviewed and those who did not attend were counted. RESULTS: A random subset of 689 students at 28 different schools at which follow-up forms were distributed to the school nurses regarding glasses wear was studied. This represents 10.8% of 6,365 children screened at 131 public schools visited by the EEM during that period. False-positive rates of school nurse screening averaged 16.11% (0% to 44%) for 689 children from 28 schools. Glasses compliance was 71% at 12 months and correlated to higher prescriptions. Only 53% of children attended their pediatric ophthalmology referral. CONCLUSIONS: Nurse training to reduce false-positive screening and strategies to improve attendance at arranged pediatric ophthalmologist consultations are recommended. The EEM effectively gets glasses to students where needed and use rates are satisfactory. PMID- 25798709 TI - Spondylometaphyseal dysplasia with developmental cataract: first report of the association in two sibling pairs. PMID- 25798710 TI - Congenital teratoma of the orbit: a rare tumor. PMID- 25798711 TI - Isolation, biological activity, biosynthesis and synthetic studies towards the rubromycin family of natural products. AB - The rubromycins are an ever growing family of natural products isolated from various Actinomycetes over the last 60 years. Exhibiting a highly attractive array of antimicrobial and enzyme activity, this unique family of compounds have attracted significant attention from many synthetic chemists. Investigations into the synthesis of the densely functionalised hexacyclic ring system have revealed many hidden synthetic challenges. This review covers the isolation, the reported biological activity and the detailed synthetic studies towards these complex natural products. PMID- 25798712 TI - Directing energy transport in organic photovoltaic cells using interfacial exciton gates. AB - Exciton transport in organic semiconductors is a critical, mediating process in many optoelectronic devices. Often, the diffusive and subdiffusive nature of excitons in these systems can limit device performance, motivating the development of strategies to direct exciton transport. In this work, directed exciton transport is achieved with the incorporation of exciton permeable interfaces. These interfaces introduce a symmetry-breaking imbalance in exciton energy transfer, leading to directed motion. Despite their obvious utility for enhanced exciton harvesting in organic photovoltaic cells (OPVs), the emergent properties of these interfaces are as yet uncharacterized. Here, directed exciton transport is conclusively demonstrated in both dilute donor and energy-cascade OPVs where judicious optimization of the interface allows exciton transport to the donor-acceptor heterojunction to occur considerably faster than when relying on simple diffusion. Generalized systems incorporating multiple exciton permeable interfaces are also explored, demonstrating the ability to further harness this phenomenon and expeditiously direct exciton motion, overcoming the diffusive limit. PMID- 25798713 TI - Medium effects are as important as catalyst design for selectivity in electrocatalytic oxygen reduction by iron-porphyrin complexes. AB - Several substituted iron-porphyrin complexes were evaluated for oxygen reduction reaction (ORR) electrocatalysis in different homogeneous and heterogeneous media. The selectivity for four-electron reduction to H2O versus two-electron reduction to H2O2 varies substantially from one medium to another for a given catalyst. In many cases, the influence of the medium in which the catalyst is evaluated has a larger effect on the observed selectivity than the factors attributable to chemical modification of the catalyst. For instance, introduction of potential proton relays has variable effects depending on the catalyst medium. Thus, comparisons of selectivity results from supported and soluble molecular ORR electrocatalysts must be interpreted with caution, as selectivity is a property not only of the catalyst, but also of the larger mesoscale environment beyond the catalyst. Still, in all the direct pairwise comparisons in the same medium, the catalysts with potential proton relays have similar or better selectivity for the preferred 4e(-) path. PMID- 25798714 TI - Effects of reinforcer distribution during response elimination on resurgence of an instrumental behavior. AB - Resurgence has commonly been viewed as the recovery of an extinguished instrumental behavior that occurs when an alternative behavior that has replaced it is also extinguished. Three experiments with rat subjects examined the effects on resurgence of the temporal distribution of reinforcement for the alternative behavior that is presented while the first response is being eliminated. Experiments 1 and 2 examined resurgence when rich rates of reinforcement at the onset of response elimination became leaner over sessions (i.e., forward thinning) and when lean rates became richer (i.e., reverse thinning). Both procedures weakened resurgence compared with that in a group that received the richest rate during all sessions. However, forward thinning was more effective than reverse thinning at reducing the resurgence effect. Experiment 3 found that final resurgence was eliminated when the alternative behavior was reinforced and extinguished in alternating response elimination sessions. The results are consistent with the hypothesis that reinforcer delivery during response elimination provides a contextual stimulus for the extinction of the original behavior; its removal during resurgence testing causes ABC renewal to occur. The results are less consistent with an alternative account that emphasizes the removal of response disruption caused by alternative reinforcement (Shahan & Sweeney, 2011). Other theoretical and applied implications are discussed. PMID- 25798715 TI - Limits of permutation-based entropies in assessing complexity of short heart period variability. AB - The study compares permutation-based and coarse-grained entropy approaches for the assessment of complexity of short heart period (HP) variability recordings. Shannon permutation entropy (SPE) and conditional permutation entropy (CPE) are computed as examples of permutation-based entropies, while the k-nearest neighbor conditional entropy (KNNCE) is calculated as an example of coarse-grained conditional entropy. SPE, CPE and KNNCE were applied to ad-hoc simulated autoregressive processes corrupted by increasing amounts of broad band noise and to real HP variability series recorded after complete vagal blockade obtained via administration of a high dose of atropine (AT) in nine healthy volunteers and during orthostatic challenge induced by 90 degrees head-up tilt (T90) in 15 healthy individuals. Over the simulated series the performances of SPE and CPE degraded more rapidly with the amplitude of the superimposed broad band noise than those of KNNCE. Over real data KNNCE identified the expected decrease of the HP variability complexity both after AT and during T90. Conversely SPE and CPE detected the decrease of HP variability complexity solely during T90 as a likely result of the more favorable signal-to-noise ratio during T90 than after AT. Results derived from both simulations and real data indicated that permutation based entropies had a larger susceptibility to broad band noise than KNNCE. We recommend caution in applying permutation-based entropies in presence of short HP variability series characterized by a low signal-to-noise ratio. PMID- 25798716 TI - Sequential adsorption of an irreversibly adsorbed nonionic surfactant and an anionic surfactant at an oil/aqueous interface. AB - Aerosol-OT (AOT) and Tween 80 are two of the main surfactants in commercial dispersants used in response to oil spills. Understanding how multicomponent surfactant systems interact at oil/aqueous interfaces is crucial for improving both dispersant design and application efficacy. This is true of many multicomponent formulations; a lack of understanding of competition for the oil/water interface hinders formulation optimization. In this study, we have characterized the sequential adsorption behavior of AOT on squalane/aqueous interfaces that have been precoated with Tween 80. A microtensiometer is used to measure the dynamic interfacial tension of the system. Tween 80 either partially or completely irreversibly adsorbs to squalane/aqueous interfaces when rinsed with deionized water. These Tween 80 coated interfaces are then exposed to AOT. AOT adsorption increases with AOT concentration for all Tween 80 coverages, and the resulting steady-state interfacial tension values are interpreted using a Langmuir isotherm model. In the presence of 0.5 M NaCl, AOT adsorption significantly increases due to counterion charge screening of the negatively charged head groups. The presence of Tween 80 on the interface inhibits AOT adsorption, reducing the maximum surface coverage as compared to a clean interface. Tween 80 persists on the interface even after exposure to high concentrations of AOT. PMID- 25798717 TI - Job crafting in changing organizations: Antecedents and implications for exhaustion and performance. AB - The present study addressed employee job crafting behaviors (i.e., seeking resources, seeking challenges, and reducing demands) in the context of organizational change. We examined predictors of job crafting both at the organizational level (i.e., perceived impact of the implemented changes on the working life of employees) and the individual level (i.e., employee willingness to follow the changes). Job crafting behaviors were expected to predict task performance and exhaustion. Two-wave longitudinal data from 580 police officers undergoing organizational changes were analyzed with structural equation modeling. Findings showed that the degree to which changes influence employees' daily work was linked to reducing demands and exhaustion, whereas employee willingness to change was linked to seeking resources and seeking challenges. Furthermore, while seeking resources and seeking challenges were associated with high task performance and low exhaustion respectively, reducing demands seemed to predict exhaustion positively. Our findings suggest that job crafting can act as a strategy of employees to respond to organizational change. While seeking resources and seeking challenges enhance employee adjustment and should be encouraged by managers, reducing demands seems to have unfavorable implications for employees. PMID- 25798718 TI - Don't let it get to you! A moderated mediated approach to the (in)justice-health relationship. AB - The present study investigates the consequences of overall justice perceptions on employees' mental health and work-family conflict. While many studies have found that perceiving injustice at work is harmful, little is known about the underlying processes. Based on the allostatic load model, it is hypothesized that mental preoccupation with work, defined as a cognitive state, is a mediator linking overall justice perceptions to employee health. Moreover, we argue that locus of control is a moderator for the mediated relationship. We tested our hypotheses with panel data consisting of 412 Swedish office workers. Results support that mental preoccupation with work mediates the relationship between overall justice and mental health, and overall justice and work-family conflict. Results also reveal that mental preoccupation with work plays a greater mediating role for individuals with an external locus of control. Implications and suggestions for future studies on the emerging relationship between organizational justice and health are discussed. PMID- 25798719 TI - Is outcome responsibility at work emotionally exhausting? Investigating employee proactivity as a moderator. AB - This study investigates the relationship between outcome responsibility and employees' well-being in terms of emotional exhaustion. Outcome responsibility is a job demand implying that employees' decisions at work have high material and/or nonmaterial consequences. Previous research indicates that outcome responsibility can have both positive and negative effects on employee well-being. Based on the person-job fit approach we hypothesize that whether or not outcome responsibility is positively or negatively related to emotional exhaustion depends on whether employees' behavioral style fits with this job demand. We investigate the role of proactive behavior as a personal resource that fits with high responsibility. We test our hypothesis in a multisource study among 138 employee-colleague dyads. Results of hierarchical moderated regression analysis reveal that peer-rated proactive behavior moderates the relationship between outcome responsibility and emotional exhaustion, such that the relationship is negative for employees showing high and nonsignificant for employees showing low proactivity. This finding holds also when controlling for trait positive and negative affect. The current study contributes to previous research on job design, proactivity, and occupational well-being and offers practical implications in terms of selection and training of employees for jobs high in outcome responsibility. PMID- 25798720 TI - Political skill: A proactive inhibitor of workplace aggression exposure and an active buffer of the aggression-strain relationship. AB - In the current study we examined the role of 4 dimensions of political skill (social astuteness, interpersonal influence, networking ability, and apparent sincerity) in predicting subsequent workplace aggression exposure based on the proactive coping framework. Further, we investigated their buffering effects on the negative outcomes of experienced workplace aggression based on the transactional stress model. Data were collected from nurses at 3 time points: before graduation (Time 1, n = 346), approximately 6 months after graduation (Time 2, n = 214), and approximately 12 months after graduation (Time 3, n = 161). Results showed that Time 1 interpersonal influence and apparent sincerity predicted subsequent physical aggression exposure. Exposure to physical and/or psychological workplace aggression was related to increased anger and musculoskeletal injury, and decreased job satisfaction and career commitment. Further, all dimensions of political skill but networking ability buffered some negative effects of physical aggression, and all dimensions but social astuteness buffered some negative effects of psychological aggression. PMID- 25798721 TI - Productive and counterproductive job crafting: A daily diary study. AB - The present study aims to uncover the way daily job crafting influences daily job performance (i.e., task performance, altruism, and counterproductive work behavior). Job crafting was conceptualized as "seeking resources," "seeking challenges," and "reducing demands" and viewed as strategies individuals use to optimize their job characteristics. We hypothesized that daily job crafting relates to daily job demands and resources (work pressure and autonomy), which consequently relate to daily work engagement and exhaustion and ultimately to job performance. A sample of 95 employees filled in a quantitative diary for 5 consecutive working days (n occasions = 475). We predicted and found that daily seeking resources was positively associated with daily task performance because daily autonomy and work engagement increased. In contrast, daily reducing demands was detrimental for daily task performance and altruism, because employees lower their daily workload and consequently their engagement and exhaustion, respectively. Only daily seeking challenges was positively (rather than negatively) associated with daily counterproductive behavior. We conclude that employee job crafting can have both beneficial and detrimental effects on job performance. PMID- 25798722 TI - Bridging the gap between the development of advanced biomedical signal processing tools and clinical practice. Preface. PMID- 25798723 TI - [Football as risk factor for a non-injury-related knee osteoarthritis - results from a systematic review and metaanalysis]. AB - Aim and Hyopthesis: This systematic review and the metanalysis were performed to investigate the relation between football activity and the potential risk of knee osteoarthritis (possible occupational disease). It was hypothesised that soccer players suffer more than controls from knee osteoarthritis also in cases with an absence of documented major injuries. METHODS: The review and the metaanalysis were performed accordingly to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. On 2014.02.01 a search was conducted within the medical databases PubMed, Medline, Cochrane, EMBASE und Web of-Science. A total of 4,649 papers underwent a "Title-Abstract-Review". Finally 6 publications were included in the metaanaylsis. RESULTS: There were no longitudinal community-based studies as well as no Cochrane Reviews regarding the risk of knee osteoarthritis in soccer players. After adjustment of major injuries of the knee, soccer players have a slightly increased risk for knee osteoarthritis: relative risk 1.3 (95 % CI 1.0 - 1.7); I(2) = 37.4 %; p = 0.002. In contrast, in studies without differentiation of injured and non-injured knees, the relative risk was significantly increased: 2.9 (95 % CI 2.0 - 4.1); I(2) = 56.3 %; p < 0.001. CONCLUSIONS: Soccer players are a very heterogeneous group. The soccer player's knee undergoes different loadings including minor and major injuries. But the individual load also strongly depends on the player's status, his position within the football field and many other factors. In the absence of a major trauma the soccer player has only a slightly increased risk for the development of osteoarthritis. Thus we conclude that an injury in professional football does not fulfil the characteristics of an occupational disease. PMID- 25798724 TI - [Frequencies of injuries and causes of accidents during ski touring on ski slopes - a pilot study]. AB - INTRODUCTION: Ski touring along ski slopes (slope touring) increased in recent years on Austrian ski slopes. However, ascending on the border of the slope and skiing downhill on the slope might be associated with a certain injury risk. Thus, the aim of this pilot study was to evaluate frequencies of injuries, causes of accidents and potential risk factors during slope touring. METHODS: Slope tourers were interviewed from March to April 2014 at the bottom of 4 Austrian ski areas. Interviews were conducted during the week and at the weekend from 7.30 a. m. to 8.45 p. m. RESULTS: A total of 451 slope-tourers (60.1 % males) with a mean age of 39.3 +/- 14.4 years were interviewed. Interviewed persons reported that they perform about 20.6 +/- 16.0 slope tours per season mainly with a partner (48 %) and during the day (51 %). Ski helmet use was 60 %. A total of 57 persons (12.6 %) reported that they suffered at least once from an injury during slope touring needing medical care. This corresponds to a rate of 6 injuries per 1000 slope tours. Main injury causes were a fall (78 %) and a collision with another person (15 %) and the main injured body part was the knee (36 %). Slope-tourers with an injury were wearing more often back protectors, and were falling more often during downhill skiing, and were abstaining less often from alcohol and were listening more often to music during downhill skiing compared to slope tourers without an injury. CONCLUSION: Based on the findings of this pilot study we recommend abstaining from alcohol and not listening to music during downhill skiing to reduce the injury risk during slope touring. PMID- 25798725 TI - [Popliteal artery aneurysma as an important differential diagnosis]. AB - A common reason for painful lesions of the popliteal fossa are baker's cysts. An important differential diagnosis is the popliteal artery aneurysm, which is rare, but is associated with severe complications. The preferred method of diagnosis is the colour-coded duplex ultrasound. By showing the case of a 58-year-old man, who experienced life-threatening complications caused by an insufficient diagnosis before the operation of a Baker's cyst, we want to underline the importance of preoperative duplex ultrasound diagnosis in this context. PMID- 25798726 TI - Nivolumab: targeting PD-1 to bolster antitumor immunity. AB - Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway mediated T-cell inhibition. Nivolumab is approved in Japan and the USA for the treatment of patients with advanced melanoma. A Phase I trial reported overall objective response rates of 17, 32 and 29% in patients with advanced non-small cell lung cancer, melanoma and renal cell carcinoma, respectively, which included many heavily pretreated patients. 1-/2-year overall survival rates were 42%/24%, 63%/48% and 70%/50% for non-small-cell lung cancer, melanoma and renal cell carcinoma, respectively. Nivolumab significantly improved survival versus dacarbazine in previously untreated patients with metastatic melanoma in a Phase III trial. Nivolumab is associated with a manageable adverse event profile. Numerous clinical trials are investigating nivolumab alone or in combination with other therapies in multiple cancer settings. This article summarizes the development of nivolumab as of November 2014. PMID- 25798727 TI - Fitting in and standing out: increasing the use of alcohol protective behavioral strategies with a deviance regulation intervention. AB - OBJECTIVE: Heavy alcohol use remains a consistent public health concern on college campuses. The current pilot study used deviance regulation theory (DRT) to modify protective behavioral strategies (PBS) among college student drinkers to reduce alcohol use and alcohol-related consequences. METHOD: The sample was comprised of current college student drinkers (n = 76; 53.95% female) ranging in age from 18-24 (M = 19.29, SD = 1.42). Participants were randomly assigned to receive a positively or negatively framed message. They then reported on use of alcohol PBS (via the Protective Behavioral Strategies Scale), alcohol consumption (via the Modified Daily Drinking Questionnaire), and alcohol-related consequences (via the Young Adult Alcohol Consequences Questionnaire) each week for 6 weeks. RESULTS AND CONCLUSIONS: Among drinkers with low PBS use norms, a positively, versus a negatively, framed message resulted in increased PBS use and consequently less alcohol consumption and fewer alcohol-related consequences. Among drinkers with high PBS use norms, a negatively, versus positively, framed message resulted in increased PBS use and consequently lower alcohol consumption and fewer alcohol-related consequences. However, these effects were only relevant among those who strongly believed the DRT frame. Findings suggest assigning drinkers to frames based on perceived PBS use norms and increasing belief in the frame may be 1 approach to increasing responsible drinking patterns among college students. Furthermore, the current data suggests important boundary conditions for norm-based interventions. PMID- 25798728 TI - Preliminary evaluation of a multimodal early intervention program for behaviorally inhibited preschoolers. AB - OBJECTIVE: Approximately 15%-20% of young children can be classified as having a behaviorally inhibited (BI) temperament. Stable BI predicts the development of later anxiety disorders (particularly social anxiety), but not all inhibited children develop anxiety. Parenting characterized by inappropriate warmth/sensitivity and/or intrusive control predicts the stability of BI and moderates risk for anxiety among high-BI children. For these reasons, we developed and examined the preliminary efficacy of the Turtle Program: a multimodal early intervention for inhibited preschool-age children. METHOD: Forty inhibited children between the ages of 42-60 months and their parent(s) were randomized to either the Turtle Program (n = 18) or a waitlist control (WLC; n = 22) condition. Participants randomized to the Turtle Program condition received 8 weeks of concurrent parent and child group treatment. Participants were assessed at baseline and posttreatment with multisource assessments, including parent and teacher report measures of child anxiety, diagnostic interviews, and observations of parenting behavior. RESULTS: The Turtle Program resulted in significant beneficial effects relative to the WLC condition on maternal-reported anxiety symptoms of medium to large magnitude; large effects on parent-reported BI; medium to large effects on teacher-rated school anxiety symptoms; and medium effects on observed maternal positive affect/sensitivity. CONCLUSIONS: This study provides encouraging preliminary support for the Turtle Program for young behaviorally inhibited children. Effects of the Turtle Program generalized to the school setting. Future studies should examine whether this early intervention program improves long-term developmental outcomes for this at-risk group. PMID- 25798729 TI - Initial abstinence status and contingency management treatment outcomes: does race matter? AB - OBJECTIVE: Limited research has evaluated African American substance users' response to evidence-based treatments. This study examined the efficacy of contingency management (CM) in African American and White cocaine users. METHOD: A secondary analysis evaluated effects of race, treatment condition, and baseline cocaine urine sample results on treatment outcomes of African American (n = 444) and White (n = 403) cocaine abusers participating in one of six randomized clinical trials comparing CM to standard care. RESULTS: African American and White patients who initiated treatment with a cocaine-negative urine sample remained in treatment for similar durations and submitted a comparable proportion of negative samples during treatment regardless of treatment type; CM was efficacious in both races in terms of engendering longer durations of abstinence in patients who began treatment abstinent. Whites who began treatment with a cocaine positive sample remained in treatment longer and submitted a higher proportion of negative samples when assigned to CM than standard care. African Americans who initiated treatment with a cocaine positive sample, however, did not remain in treatment longer with CM compared with standard care, and gains in terms of drug use outcomes were muted in nature relative to Whites. This interaction effect persisted through the 9-month follow-up period. CONCLUSIONS: CM is not equally effective in reducing drug use among all subgroups, specifically African American patients who are using cocaine upon treatment entry. Future research on improving treatment outcomes in this population is needed. PMID- 25798731 TI - Reducing inappropriate polypharmacy: the process of deprescribing. AB - Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application. PMID- 25798730 TI - Remote versus in-lab computer-delivered personalized normative feedback interventions for college student drinking. AB - OBJECTIVE: Computer-based interventions aimed at reducing college student drinking have shown positive effects. The authors compare differences in effects of computer-based personalized normative feedback (PNF) interventions based on delivery modality (in-person vs. remotely) across six previously evaluated studies with similar content. METHOD: Three studies included evaluations of a computer-based PNF intervention in which baseline and intervention procedures took place inside a laboratory setting; three separate studies included evaluations of the same intervention in which participants completed the procedures remotely over the Web. Thus, we tested for differences in intervention efficacy by delivery modality. Outcomes included drinks per week, drinking related consequences, and the putative intervention mechanism, perceived drinking norms. RESULTS: Evidence from hierarchical linear models indicated that computer based interventions are less effective at reducing drinking and related consequences when delivered remotely than when delivered in person. CONCLUSION: The advantages of interventions delivered remotely are not without cost. Suggestions for why remote computer-based interventions may be less effective are discussed. PMID- 25798733 TI - The 2015 standards for diabetes care: maintaining a patient-centered approach. PMID- 25798734 TI - Robotic resection of a superior sulcus neurogenic tumor. AB - Neurogenic tumors do not often occur in the superior sulcus or apex of the chest cavity. Historically, surgical approaches have been dictated by the location of the tumor and its relation to the contiguous structures such as the vertebral bodies, subclavian vessels, and chest wall. Resection is hampered by difficulties with visualization and access within a narrow working space. The shortcomings associated with the traditional surgical approaches create a potential of injury to nearby structures. We present a case of a 43-year-old woman with a superior sulcus neurogenic tumor impinging on the left subclavian vein, who underwent a successful resection without injury to nearby structures. We found that a robotic approach improved visualization of the tumor and nearby structures and increased instrument maneuverability relative to a thoracoscopic approach, along with less pain and recovery time compared with a thoracotomy. This experience suggests that robotics provides a promising alternative for excision of superior sulcus neurogenic tumors, which may reduce associated morbidity. PMID- 25798735 TI - Exciton radiative lifetimes in two-dimensional transition metal dichalcogenides. AB - Light emission in two-dimensional (2D) transition metal dichalcogenides (TMDs) changes significantly with the number of layers and stacking sequence. While the electronic structure and optical absorption are well understood in 2D-TMDs, much less is known about exciton dynamics and radiative recombination. Here, we show first-principles calculations of intrinsic exciton radiative lifetimes at low temperature (4 K) and room temperature (300 K) in TMD monolayers with the chemical formula MX2 (X = Mo, W, and X = S, Se), as well as in bilayer and bulk MoS2 and in two MX2 heterobilayers. Our results elucidate the time scale and microscopic origin of light emission in TMDs. We find radiative lifetimes of a few picoseconds at low temperature and a few nanoseconds at room temperature in the monolayers and slower radiative recombination in bulk and bilayer than in monolayer MoS2. The MoS2/WS2 and MoSe2/WSe2 heterobilayers exhibit very long lived (~20-30 ns at room temperature) interlayer excitons constituted by electrons localized on the Mo-based and holes on the W-based monolayer. The wide radiative lifetime tunability, together with the ability shown here to predict radiative lifetimes from computations, hold unique potential to manipulate excitons in TMDs and their heterostructures for application in optoelectronics and solar energy conversion. PMID- 25798736 TI - Erythematotelangiectatic Rosacea and Telangiectatic Photoaging: Same, Separate, and/or Sequential? PMID- 25798737 TI - Phosphinite-Ni(0) mediated formation of a phosphide-Ni(II)-OCOOMe species via uncommon metal-ligand cooperation. AB - Reversible transformations are observed between a phosphide-nickel(II) alkoxide and a phosphinite-nickel(0) species via a P-O bond formation coupled with a 2-e( ) redox change at the nickel center. In the forward reaction, the nickel(0) dinitrogen species (PP(OMe)P)Ni(N2) (2) and {(PP(OMe)P)Ni}2(MU-N2) (3) were formed from the reaction of (PPP)NiCl (1) with a methoxy anion. In the backward reaction, a (PPP)Ni(II) moiety was regenerated from the CO2 reaction of 3 with the concomitant formation of a methyl carbonate ligand in (PPP)Ni(OCOOMe) (7). Thus, unanticipated metal-ligand cooperation involving a phosphide based ligand is reported. PMID- 25798738 TI - Thermoelectric characterization of individual bismuth selenide topological insulator nanoribbons. AB - Bismuth selenide (Bi2Se3) nanoribbons have attracted tremendous research interest recently to study the properties of topologically protected surface states that enable new opportunities to enhance the thermoelectric performance. However, the thermoelectric characterization of individual Bi2Se3 nanoribbons is rare due to the technological challenges in the measurements. One challenge is to ensure good contacts between the nanoribbon and electrodes in order to determine the thermal and electrical properties accurately. In this work, we report the thermoelectric characterization of individual Bi2Se3 nanoribbons via a suspended microdevice method. Through careful measurements, we have demonstrated that contact thermal resistance is negligible after the electron-beam-induced deposition (EBID) of platinum/carbon (Pt/C) composites at the contacts between the nanoribbon and electrodes. It is shown that the thermal conductivity of the Bi2Se3 nanoribbons is less than 50% of the bulk value over the whole measurement temperature range, which can be attributed to enhanced phonon boundary scattering. Our results indicate that intrinsic Bi2Se3 nanoribbons prepared in this work are highly doped n-type semiconductors, and therefore the Fermi level should be in the conduction band and no topological transport behavior can be observed in the intrinsic system. PMID- 25798739 TI - Elevated mobility of persistent organic pollutants in the soil of a tropical rainforest. AB - Semivolatile persistent organic pollutants (POP) are bioaccumulative and toxic contaminants. Their global distribution depends on source distribution, atmospheric transport, degradation, and the exchange with ocean and land surfaces. Forests are crucial terrestrial reservoirs due to the commonly envisaged high capacity of their surface soils to store and immobilize airborne contaminants bound to soil organic matter. Our results show that POPs can be unexpectedly mobile in the soil of a tropical rainforest due to fast litter turnover (leading to rapid POP transfer to the subsoil) and leaching rates exceeding degradation rates especially for more hydrophobic congeners. Co transport in association with leaching fine particulate and dissolved organic matter appears as a relevant driver of this PCB export. A markedly different distribution pattern is displayed in this soil in comparison to soils of colder environments with lower overall storage capacity. These findings show that biogeochemistry of organic matter degradation and weathering can influence POP soil fate. Because tropical forests represent 60% of the global terrestrial productivity, the highlighted dynamics might have an implication for the general distribution of these contaminants. PMID- 25798732 TI - FBN-1, a fibrillin-related protein, is required for resistance of the epidermis to mechanical deformation during C. elegans embryogenesis. AB - During development, biomechanical forces contour the body and provide shape to internal organs. Using genetic and molecular approaches in combination with a FRET-based tension sensor, we characterized a pulling force exerted by the elongating pharynx (foregut) on the anterior epidermis during C. elegans embryogenesis. Resistance of the epidermis to this force and to actomyosin-based circumferential constricting forces is mediated by FBN-1, a ZP domain protein related to vertebrate fibrillins. fbn-1 was required specifically within the epidermis and FBN-1 was expressed in epidermal cells and secreted to the apical surface as a putative component of the embryonic sheath. Tiling array studies indicated that fbn-1 mRNA processing requires the conserved alternative splicing factor MEC-8/RBPMS. The conserved SYM-3/FAM102A and SYM-4/WDR44 proteins, which are linked to protein trafficking, function as additional components of this network. Our studies demonstrate the importance of the apical extracellular matrix in preventing mechanical deformation of the epidermis during development. PMID- 25798740 TI - Metabolic disposition of the anti-cancer agent [(14)C]laromustine in male rats. AB - 1. Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. This article describes the use of quantitative whole-body autoradiography (QWBA) and mass balance to study the tissue distribution, the excretion mass balance and pharmacokinetics after intravenous administration of [(14)C]VNP40101M to rats. A single 10 mg/kg IV bolus dose of [(14)C]VNP40101M was given to rats. 2. The recovery of radioactivity from the Group 1 animals over a 7-day period was an average of 92.1% of the administered dose, which was accounted for in the excreta and carcass. Most of the radioactivity was eliminated within 48 h via urine (48%), with less excreted in feces (5%) and expired air accounted for (11%). The plasma half-life of [(14)C]laromustine was approximately 62 min and the peak plasma concentration (Cmax) averaged 8.3 MUg/mL. 3. The QWBA study indicated that the drug-derived radioactivity was widely distributed to tissues through 7 days post dose after a single 10 mg/kg IV bolus dose of [(14)C]VNP40101M to male pigmented Long-Evans rats. The maximum concentrations were observed at 0.5 or 1 h post-dose for majority tissues (28 of 42). The highest concentrations of radioactivity were found in the small intestine contents at 0.5 h (112.137 ug equiv/g), urinary bladder contents at 3 h (89.636 ug equiv/g) and probably reflect excretion of drug and metabolites. The highest concentrations in specific organs were found in the renal cortex at 1 h (28.582 ug equiv/g), small intestine at 3 h (16.946 ug equiv/g), Harderian gland at 3 h (12.332 ug equiv/g) and pancreas at 3 h (12.635 ug equiv/g). Concentrations in the cerebrum (1.978 ug equiv/g), cerebellum (2.109 ug equiv/g), medulla (1.797 ug equiv/g) and spinal cord (1.510 ug equiv/g) were maximal at 0.5 h post-dose and persisted for 7 days. 4. The predicted total body and target organ exposures for humans given a single 100 uCi IV dose of [(14)C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects. PMID- 25798741 TI - Combined effect of rifampicin-induced P-glycoprotein expression and lipopolysaccharide-induced intestinal sepsis on the effective permeability and pharmacokinetics of an anti-malarial candidate CDRI 97/78 in rats. AB - 1. The study aimed to investigate the influences on the pharmacokinetics (PK) of an anti-malarial drug 97/78 in rats pretreated with orally administered rifampicin and bacterial endotoxin lipopolysaccharide (LPS). 2. In-situ intestinal absorption studies were conducted on rats pretreated with rifampicin and LPS or both to estimate effective permeability (Peff) of 97/78. In-vivo studies were then conducted to explore 97/78 PK profile under these conditions. In-situ studies revealed that Peff value decreased to 64% (2.7 +/- 0.6) * 10(-4 )cm/s in rats pretreated with rifampicin. This decrease was further enhanced very significantly to 4.5% (0.19 +/- 0.03) * 10(-4 )cm/s in rats pretreated both with rifampicin and LPS (p<0.05). For PK studies, it was found that relative bioavailability (RB) was decreased to 22.56% in rifampicin-pretreated rats and to 8.02% in rats pretreated both with rifampicin and LPS. About five-fold decrease was observed in systemic exposure (AUC) of 97/78 in rifampicin-pretreated rats. This decrease was further augmented to 12-fold upon rifampicin and LPS pretreatment. 3. Orally administered rifampicin decreased the concentration of 97/78 in circulation. This decrease was further enhanced significantly to a very low level by LPS-induced intestinal sepsis. PMID- 25798744 TI - Vitamin D: a panacea for autoimmune diseases? PMID- 25798743 TI - Evaluating the Clinical Utility of the Medical Symptom Validity Test (MSVT): A Clinical Series. AB - Performance validity tests (PVTs) are not widely used beyond medico-legal contexts in the UK. A UK survey suggests clinicians have reservations about their accuracy in clinical settings. This study sought to explore the validity of PVTs in an acute adult neuropsychology setting and to establish a potential "false positive" (FP) base rate. Failures on the Medical Symptom Validity Test (MSVT) in a consecutive clinical series of 405 patients were evaluated systematically and allocated to groups depending on clinical context. All failures were checked against the test's "dementia profile". Of the 405 participants, 329 passed the MSVT (81.2%), while 76 participants (18.8%) failed based on standard criteria. A 5.2% rate of potentially 'unexplained' failures was found. Other reasons for failure were classified as: presumed malingered neurocognitive dysfunction (4.6%), dementia/significant cognitive impairment (3.7%), technical/visual problems (1.8%), and "unexplained failure" with contributory factors (2.4%). These results suggest test specificity between 0.95 and 0.90. Most of the clinically significantly impaired patients matched the dementia profile (86.7%). Our results support the sensitivity, but not the specificity, of the dementia profile. However, approximately 1 in 20 patients failed the MSVT despite an otherwise unremarkable neuropsychological presentation; moreover, mood and pain may affect MSVT performance. Clinical implications for interpreting test scores are discussed. PMID- 25798742 TI - Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation. AB - 1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (<0.25 * Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 * Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2 fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials. PMID- 25798745 TI - Computational study on thermochemical properties for perhalogenated methanols (CX3OH) (X = F, Cl, Br). AB - The perhalogenated methanols (CX3OH; X = F, Cl, and Br) are found in the atmosphere as products of the degradation of halocarbons. The thermochemical properties for these molecules have been calculated at the HF, MP2, and B3LYP levels of theories in conjunction with six different basis sets as well as at G3MP2 and CBS-QB3. Calculated properties include the gas-phase enthalpies of formation (DeltafH(0)), gas-phase acidities (DeltaacidG(0)), gas-phase proton affinity, and bond dissociation energies of the C-O and O-H bonds of CX3OH. Excellent agreement is found between the results obtained using G3MP2 and CBS-QB3 methods and the available experimental data. The results obtained using MP2 are more consistent with the experimental, G3MP2, and CBS-QB3 values than those computed at B3LYP. In general, the 6-311+G(d,p) basis set when combined with the HF or MP2 level of theory produced better results than other basis sets considered in this study. PMID- 25798746 TI - Measles: To Vaccinate or Not? PMID- 25798747 TI - Reproductive Health Concerns in Women with Systemic Lupus Erythematosus. AB - Women are far more likely than men to have a diagnosis of systemic lupus erythematosus (SLE), with a peak incidence during the childbearing years. Contraceptive methods and pregnancy can both adversely affect the health of women with SLE, thus careful planning and interventions are necessary to help women manage their reproductive health choices. Women with SLE may experience infertility, difficulties conceiving and maintaining pregnancy, and ultimately have less children than they had planned. Although poor health status may account for some of this disparity, inadequate counseling and management by members of the healthcare team may also be responsible. The purpose of this article is to review the pathophysiology of SLE and its effects on reproductive health, as well as to highlight recent literature supporting evidence-based practices in reproductive health counseling, nursing care during pregnancy, and monitoring for disease complications in women with SLE. Nurses play a central role in care coordination and patient education for women with SLE making decisions about family planning. PMID- 25798748 TI - Bladder Management With Epidural Anesthesia During Labor: A Randomized Controlled Trial. AB - PURPOSE: Many labor nurses routinely include continuous urinary catheterization (CC) as part of their standard care for women who receive intrapartum epidural anesthesia, to prevent urinary retention, thought to delay fetal descent. Recent studies question use of CCs during labor, as they may predispose patients to urinary tract infections (UTIs), even though the catheters are in place for a relatively short period of time. The objective of this study was to determine the influence of CCs versus intermittent catheters (ICs) (only as needed) on the duration of second stage of labor and the incidence of postpartum UTIs. STUDY DESIGN AND METHODS: Randomized controlled trial. English-speaking low-risk nulliparous women >=37 weeks gestation with a single fetus in a vertex presentation who requested an epidural were eligible for participation. Prior to epidural placement, cervical status was documented, women were encouraged to void, and then women were randomized to receive either CC or IC as the method for urinary bladder management for the duration of the first stage of labor. Final sample size included 123 participants; 55 in the CC group and 68 in the IC group. RESULTS: No differences were noted in length of second stage labor, and the overall incidence of UTIs in both groups was low. There was a significantly increased likelihood of cesarean birth in women who had CC (P < .01) when compared to women who had IC. The overall cesarean rate in the CC group was 27.3%, versus 10.3% in the IC group. CLINICAL IMPLICATIONS: Intermittent catheterization only as needed appears to be best practice for bladder management for laboring women with an epidural. There was a significantly higher rate of cesarean birth among women in the CC group. The relationship between route of birth and use of continuous indwelling urinary catheters for women in labor with epidurals for pain relief needs more study. PMID- 25798749 TI - Field-induced density wave in the heavy-fermion compound CeRhIn5. AB - Strong electron correlations lead to a variety of distinct ground states, such as magnetism, charge order or superconductivity. Understanding the competitive or cooperative interplay between neighbouring phases is an outstanding challenge in physics. CeRhIn5 is a prototypical example of a heavy-fermion superconductor: it orders anti-ferromagnetically below 3.8 K, and moderate hydrostatic pressure suppresses the anti-ferromagnetic order inducing unconventional superconductivity. Here we show evidence for a phase transition to a state akin to a density wave (DW) under high magnetic fields (>27 T) in high-quality single crystal microstructures of CeRhIn5. The DW is signalled by a hysteretic anomaly in the in-plane resistivity accompanied by non-linear electrical transport, yet remarkably thermodynamic measurements suggest that the phase transition involves only small portions of the Fermi surface. Such a subtle order might be a common feature among correlated electron systems, reminiscent of the similarly subtle charge DW state in the cuprates. PMID- 25798750 TI - Parasite biology: Dual-core centrosomes power cell division. PMID- 25798751 TI - Fabrication of High-Performance Ultrathin In2O3 Film Field-Effect Transistors and Biosensors Using Chemical Lift-Off Lithography. AB - We demonstrate straightforward fabrication of highly sensitive biosensor arrays based on field-effect transistors, using an efficient high-throughput, large-area patterning process. Chemical lift-off lithography is used to construct field effect transistor arrays with high spatial precision suitable for the fabrication of both micrometer- and nanometer-scale devices. Sol-gel processing is used to deposit ultrathin (~4 nm) In2O3 films as semiconducting channel layers. The aqueous sol-gel process produces uniform In2O3 coatings with thicknesses of a few nanometers over large areas through simple spin-coating, and only low-temperature thermal annealing of the coatings is required. The ultrathin In2O3 enables construction of highly sensitive and selective biosensors through immobilization of specific aptamers to the channel surface; the ability to detect subnanomolar concentrations of dopamine is demonstrated. PMID- 25798753 TI - Iridium-catalyzed single-step N-substituted lactam synthesis from lactones and amines. AB - Catalytic lactam synthesis was achieved directly from lactones and amines using an Ir catalyst. Three sequential transformations-aminolysis of lactone, N alkylation of amine with hydroxyamide, and intramolecular transamidation of aminoamide-afforded the corresponding N-substituted lactams. PMID- 25798752 TI - SIRT1 and circadian gene expression in pancreatic ductal adenocarcinoma: Effect of starvation. AB - Pancreatic cancer (PC), the fourth leading cause of cancer-related deaths, is characterized by high aggressiveness and resistance to chemotherapy. Pancreatic carcinogenesis is kept going by derangement of essential cell processes, such as proliferation, apoptosis, metabolism and autophagy, characterized by rhythmic variations with 24-h periodicity driven by the biological clock. We assessed the expression of the circadian genes ARNLT, ARNLT2, CLOCK, PER1, PER2, PER3, CRY1, CRY2 and the starvation-activated histone/protein deacetylase SIRT1 in 34 matched tumor and non-tumor tissue specimens of PC patients, and evaluated in PC derived cell lines if the modulation of SIRT1 expression through starvation could influence the temporal pattern of expression of the circadian genes. We found a significant down-regulation of ARNLT (p = 0.015), CRY1 (p = 0.013), CRY2 (p = 0.001), PER1 (p < 0.0001), PER2 (p < 0.001), PER3 (p = 0.001) and SIRT1 (p = 0.017) in PC specimens. PER3 and CRY2 expression levels were lower in patients with jaundice at diagnosis ( < 0.05). Having adjusted for age, adjuvant therapy and tumor stage, we evidenced that patients with higher PER2 and lower SIRT1 expression levels showed lower mortality (p = 0.028). Levels and temporal patterns of expression of many circadian genes and SIRT1 significantly changed upon serum starvation in vitro, with differences among four different PC cell lines examined (BXPC3, CFPAC, MIA-PaCa-2 and PANC-1). Serum deprivation induced changes of the overall mean level of the wave and amplitude, lengthened or shortened the cycle time and phase-advanced or phase-delayed the rhythmic oscillation depending on the gene and the PC cell line examined. In conclusion, a severe deregulation of expression of SIRT1 and circadian genes was evidenced in the cancer specimens of PC patients, and starvation influenced gene expression in PC cell lines, suggesting that the altered interplay between SIRT1 and the core circadian proteins could represent a crucial player in the process of pancreatic carcinogenesis. PMID- 25798754 TI - Priority effects during fungal community establishment in beech wood. AB - Assembly history of fungal communities has a crucial role in the decomposition of woody resources, and hence nutrient cycling and ecosystem function. However, it has not been clearly determined whether the fungal species that arrive first may, potentially, dictate the subsequent pathway of community development, that is, whether there is a priority effect at the species level. We used traditional culture-based techniques coupled with sequencing of amplified genetic markers to profile the fungal communities in beech (Fagus sylvatica) disks that had been pre colonised separately with nine species from various stages of fungal succession. Clear differences in community composition were evident following pre colonisation by different species with three distinct successor communities identified, indicating that individual species may have pivotal effects in driving assembly history. Priority effects may be linked to biochemical alteration of the resource and combative ability of the predecessor. PMID- 25798755 TI - Aquatic heterotrophic bacteria have highly flexible phosphorus content and biomass stoichiometry. AB - Bacteria are central to the cycling of carbon (C), nitrogen (N) and phosphorus (P) in every ecosystem, yet our understanding of how tightly these cycles are coupled to bacterial biomass composition is based upon data from only a few species. Bacteria are commonly assumed to have high P content, low biomass C:P and N:P ratios, and inflexible stoichiometry. Here, we show that bacterial assemblages from lakes exhibit unprecedented flexibility in their P content (3% to less than 0.01% of dry mass) and stoichiometry (C:N:P of 28: 7: 1 to more than 8500: 1200: 1). The flexibility in C:P and N:P stoichiometry was greater than any species or assemblage, including terrestrial and aquatic autotrophs, and suggests a highly dynamic role for bacteria in coupling multiple element cycles. PMID- 25798756 TI - What is the role of the oral and maxillofacial department in the preoperative management of patients awaiting cardiac operations? AB - There is limited evidence and guidance on best practice regarding preoperative dental assessments of patients awaiting cardiac operations. To analyse current practice in oral and maxillofacial units across the United Kingdom, we did a telephone survey to find out how these patients are managed. All maxillofacial departments in the United Kingdom were contacted, with a response rate of 77%. Those attached to dental schools were excluded. Most departments did extractions only, and in many, patients were assessed and treated within 7 days of being referred, although this varied. Most units did not offer antibiotic prophylaxis to patients at high risk of infective endocarditis, but some did after advice had been sought from a cardiologist. Respondents in 76% thought that preoperative dental assessments for cardiac patients were an appropriate use of resources. We propose a more integrated pathway for the management of these patients (particularly considering the pressure on time for treatment) that focuses primary and secondary resources accordingly. PMID- 25798757 TI - Panoramic imaging is not suitable for quantitative evaluation, classification, and follow up in unilateral condylar hyperplasia. AB - Patients with suspected unilateral condylar hyperplasia are often screened radiologically with a panoramic radiograph, but this is not sufficient for routine diagnosis and follow up. We have therefore made a quantitative analysis and evaluation of panoramic radiographs in a large group of patients with the condition. During the period 1994-2011, 132 patients with 113 panoramic radiographs were analysed using a validated method. There was good reproducibility between observers, but the condylar neck and head were the regions reported with least reliability. Although in most patients asymmetry of the condylar head, neck, and ramus was confirmed, the kappa coefficient as an indicator of agreement between two observers was poor (-0.040 to 0.504). Hardly any difference between sides was measured at the gonion angle, and the body appeared to be higher on the affected side in 80% of patients. Panoramic radiographs might be suitable for screening, but are not suitable for the quantitative evaluation, classification, and follow up of patients with unilateral condylar hyperplasia. PMID- 25798758 TI - Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharide-stimulated microglia: critical role of 5'-adenosine monophosphate-activated protein kinase signaling pathway. AB - Ginsenoside Rh3 is a bacterial metabolite of Rg5, which is the main constituent of heat-processed ginseng. The present study was undertaken to examine the anti inflammatory effect of ginsenoside Rh3 in lipopolysaccharide (LPS)-stimulated microglia. Rh3 inhibits the expressions of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, at mRNA and protein levels, while Rh3 enhanced anti inflammatory hemeoxygenase-1 expression. Moreover, Rh3 inhibited nuclear factor kappaB (NF-kappaB) by upregulation of sirtuin 1 (SIRT1) and enhanced Nrf2 DNA binding activities. Analysis of signaling pathways revealed that Rh3 enhanced the phosphorylation of 5'-adenosine monophosphate-activated protein kinase (AMPK) and inhibited Akt and janus kinase 1 (JAK1)/signal transducer and activator of transcription 1 (STAT1) induced by LPS. By treatment of BV2 cells with AICAR (a pharmacological activator of AMPK), we found that AMPK is an upstream regulator of phosphatidylinositol 3-kinase (PI3K)/Akt and JAK1/STAT1. Furthermore, AMPK knockdown experiments demonstrated the anti-inflammatory role of AMPK in LPS/Rh3 treated BV2 microglia. Our data collectively suggest that Rh3 exerts an anti inflammatory effect in microglia by modulating AMPK and its downstream signaling pathways. PMID- 25798759 TI - The role of inflammation in the initiation of osteoarthritis after meniscal damage. AB - Meniscal damage and meniscectomy lead to subsequent osteoarthritis (OA) of the knee joint through multiple and diverse mechanisms, yet the interaction of these mechanisms remains unknown. Therefore, the aim of this review is to suggest the multi-scale, multi-faceted components involved between meniscal injury or meniscectomy and the initiation of OA. There is evidence of structural, mechanical, and biological changes after meniscal damage, all of which can be greatly affected by the presence of local or systemic inflammation. Meniscal damage or resection causes changes in knee mechanics during walking, resulting in altered cartilage loading. Because cartilage is mechanically sensitive, these loading changes can initiate a catabolic effect, culminating in tissue degeneration. The evidence suggests that the addition of elevated inflammation at the time of meniscal damage or meniscectomy results in an accelerated progression toward cartilage degradation. Initial cartilage degradation produces inflammation and pain in conjunction with structural changes to the joint, thus perpetuating the cycle of altered cartilage loading and subsequent degradation. Furthermore, the inflammation secondary to obesity and aging introduces an increased risk of developing OA following meniscal injury. Therefore, an overall route between meniscal damage or resection and OA is presented here in a manner that considers two distinct pathways; these pathways reflect the absence or presence of conditions that cause elevated inflammation. PMID- 25798760 TI - Mathematical model of microbicidal flow dynamics and optimization of rheological properties for intra-vaginal drug delivery: Role of tissue mechanics and fluid rheology. AB - Topically applied microbicide gels can provide a self-administered and effective strategy to prevent sexually transmitted infections (STIs). We have investigated the interplay between vaginal tissue elasticity and the yield-stress of non Newtonian fluids during microbicide deployment. We have developed a mathematical model of tissue deformation driven spreading of microbicidal gels based on thin film lubrication approximation and demonstrated the effect of tissue elasticity and fluid yield-stress on the spreading dynamics. Our results show that both elasticity of tissue and yield-stress rheology of gel are strong determinants of the coating behavior. An optimization framework has been demonstrated which leverages the flow dynamics of yield-stress fluid during deployment to maximize retention while reaching target coating length for a given tissue elasticity. PMID- 25798761 TI - Hemodynamic transition driven by stent porosity in sidewall aneurysms. AB - The healing process of intracranial aneurysms (IAs) treated with flow diverter stents (FDSs) depends on the IA flow modifications and on the epithelization process over the neck. In sidewall IA models with straight parent artery, two main hemodynamic regimes with different flow patterns and IA flow magnitude were broadly observed for unstented and high porosity stented IA on one side, and low porosity stented IA on the other side. The hemodynamic transition between these two regimes is potentially involved in thrombosis formation. In the present study, CFD simulations and multi-time lag (MTL) particle imaging velocimetry (PIV) measurements were combined to investigate the physical nature of this transition. Measurable velocity fields and non-measurable shear stress and pressure fields were assessed experimentally and numerically in the aneurysm volume in the presence of stents with various porosities. The two main regimes observed in both PIV and CFD showed typical flow features of shear and pressure driven regimes. In particular, the waveform of the averaged IA velocities was matching both the shear stress waveform at IA neck or the pressure gradient waveform in parent artery. Moreover, the transition between the two regimes was controlled by stent porosity: a decrease of stent porosity leads to an increase (decrease) of pressure differential (shear stress) through IA neck. Finally, a good PIV-CFD agreement was found except in transitional regimes and low motion eddies due to small mismatch of PIV-CFD running conditions. PMID- 25798762 TI - Reliability of the walking speed and gait dynamics variables while walking on a feedback-controlled treadmill. AB - The purpose of this study is to identify the reliability of walking speed and gait dynamics measured with a feedback-controlled treadmill and to assess the applicability of the treadmill to gait dynamics studies. The intraclass correlation coefficient (ICC) and the standard error of measurement (SEM) for the walking speed and the mean, variability (coefficient of variance, CV), and fractal dynamics (the scaling exponent alpha of detrended fluctuation analysis, DFA) of the stride time and stride length were used to evaluate the within-day and between-day reliability. Fifteen subjects walked on a feedback-controlled treadmill for three trials that were each more than 10 min in length (within day); this protocol was repeated on another day to identify the between-day reliability. The results showed that all variables were consistent for within-day and between-day reliability (ICC: 0.633-0.982, p<0.05; SEM: 0.02-0.43). The within- and between-day reliability of the walking speed and the mean, variability, and fractal dynamics for the stride time and stride length were identified. Good ICCs and low SEMs for within-day and between-day reliability were obtained for all variables. Therefore, it is concluded that it is possible to use a feedback-controlled treadmill to the study of gait dynamics. PMID- 25798763 TI - Bootstrap prediction bands for cervical spine intervertebral kinematics during in vivo three-dimensional head movements. AB - There is substantial inter-subject variability in intervertebral range of motion (ROM) in the cervical spine. This makes it difficult to define "normal" ROM, and to assess the effects of age, injury, and surgical procedures on spine kinematics. The objective of this study was to define normal intervertebral kinematics in the cervical spine during dynamic functional loading. Twenty-nine participants performed dynamic flexion?extension, axial rotation, and lateral bending while biplane radiographs were collected at 30 images/s. Vertebral motion was tracked with sub-millimeter accuracy using a validated volumetric model-based tracking process that matched subject-specific CT-based bone models to the radiographs. Gaussian point-by-point and bootstrap techniques were used to determine 90% prediction bands for the intervertebral kinematic curves at 1% intervals of each movement cycle. Cross validation was performed to estimate the true achieved coverage for each method. For a targeted coverage of 90%, the estimated true coverage using bootstrap prediction bands averaged 86+/-5%, while the estimated true coverage using Gaussian point-by-point intervals averaged 56+/ 10% over all movements and all motion segments. Bootstrap prediction bands are recommended as the standard for evaluating full ROM cervical spine kinematic curves. The data presented here can be used to identify abnormal motion in patients presenting with neck pain, to drive computational models, and to assess the biofidelity of in vitro loading paradigms. PMID- 25798764 TI - It takes a village...to transition care. PMID- 25798765 TI - Working together to improve the patient experience. PMID- 25798766 TI - Measures that matter, part 2: performance data. PMID- 25798768 TI - One rung at a time: what affects clinical ladder participation? PMID- 25798769 TI - The effect of nursing presence on patient satisfaction. PMID- 25798770 TI - The voice of the nurse...what's being said about shared governance? PMID- 25798771 TI - Putting the I in integrity. PMID- 25798772 TI - Leadership q&a. PMID- 25798774 TI - Implementing systems thinking for infection prevention: The cessation of repeated scabies outbreaks in a respiratory care ward. AB - BACKGROUND: Root cause analysis (RCA) is often adopted to complement epidemiologic investigation for outbreaks and infection-related adverse events in hospitals; however, RCA has been argued to have limited effectiveness in preventing such events. We describe how an innovative systems analysis approach halted repeated scabies outbreaks, and highlight the importance of systems thinking for outbreaks analysis and sustaining effective infection prevention and control. METHODS: Following RCA for a third successive outbreak of scabies over a 17-month period in a 60-bed respiratory care ward of a Taiwan hospital, a systems oriented event analysis (SOEA) model was used to reanalyze the outbreak. Both approaches and the recommendations were compared. RESULTS: No nosocomial scabies have been reported for more than 1975 days since implementation of the SOEA. Previous intervals between seeming eradication and repeat outbreaks following RCA were 270 days and 180 days. Achieving a sustainable positive resolution relied on applying systems thinking and the holistic analysis of the system, not merely looking for root causes of events. CONCLUSION: To improve the effectiveness of outbreaks analysis and infection control, an emphasis on systems thinking is critical, along with a practical approach to ensure its effective implementation. The SOEA model provides the necessary framework and is a viable complementary approach, or alternative, to RCA. PMID- 25798775 TI - Healthcare worker influenza declination form program. AB - BACKGROUND: Health care worker (HCW) vaccination rates have been low for many years (approximately 50%). Our goal was to implement an influenza declination form program (DFP) to assess feasibility, participation, HCW vaccination, and costs. METHODS: This was a prospective interventional pilot study using mixed methods to evaluate the DFP implementation processes and outcomes. We conducted a formative evaluation and interviews; data were transcribed and coded into themes. Secondary outcomes included self-reported HCW influenza vaccine uptake (pre /postsurvey) and program costs; data were evaluated using descriptive and bivariate analyses. RESULTS: The DFP was compatible with ongoing strategies and unit culture. Barriers included multiple hospital shifts and competing demands. Facilitators included complementary ongoing strategies and leadership engagement. HCW vaccination rates were higher post- versus preimplementation (77.4% vs 53.5%, P =.01). To implement the DFP at site 1, using a mobile flu cart, 100% of declination forms were completed in 42.5 staff hours over <2 months. At site 2, using a vaccination table on all staff meeting days, 49% of forms were completed in 26.5 staff hours over 4.5 months. Average cost of staff time was $2,093 per site. CONCLUSION: DFP implementation required limited resources and resulted in increased HCW influenza vaccine rates; this may have positive clinical implications for influenza infection control/prevention. PMID- 25798776 TI - Influenza vaccination uptake and its socioeconomic determinants in the older adult Iranian population: A national study. AB - BACKGROUND: The relationship between socioeconomic status and influenza vaccine uptake has a different pattern in different societies. The objective of this study was to assess the socioeconomic factors influencing influenza vaccination uptake in the older adult Iranian population. METHODS: In this cross-sectional study, 1,350 Iranian adults aged >=60 years were selected using a multistage sampling method. Self-report questionnaires were administered to collect information on the status of influenza vaccine uptake within the last year. RESULTS: Overall, 10.4% of the older adult Iranian population had received influenza vaccinations within the last year. Several determinants were associated with influenza vaccination uptake, such as current occupation, education level, ethnicity, source of income, financial support from relatives, satisfaction with income, type of health insurance, and having complementary health insurance for outpatient services. Other factors, such as age, sex, marital status, residential area, and having health insurance, had no influence on the probability of vaccine uptake. After adjusting for desired variables, we found that having an occupation (odds ratio [OR] = 2.08; 95% confidence interval [CI], 1.08-4.02) and having complementary health insurance for outpatient services (OR = 1.65; 95% CI, 1.06 2.56) remained associated with higher influenza vaccine uptake. CONCLUSIONS: The influenza vaccination rate in older adult Iranians was found to be low. Occupation and having complementary health insurance were associated with influenza vaccination uptake among Iranian older adults. Considering the mentioned variables in future studies is advised. PMID- 25798777 TI - Slow adoption of automated infection prevention surveillance: are human factors contributing? AB - Although automated surveillance technology has been evolving for decades, adoption of these technologies is in a nascent state. The current trajectory of public reporting, continued emergence of multidrug-resistant organisms, and mandated antimicrobial stewardship initiatives will result in an increased surveillance workload for ICPs. The use of traditional surveillance methods will be inefficient in meeting the demands for more data and are potentially flawed by subjective interpretation. An examination is offered of the slow adoption of automated surveillance technology from a system perspective with the inherent ambiguities that may operate within the ICP work structure. Formal qualitative research is needed to assess the human factors associated with lack of acceptance of automated surveillance systems. Identification of these factors will allow the National Healthcare Safety Network and professional organizations to offer educational programs and mentoring to the ICP community that target knowledge deficits and the embedded culture that embraces the status quo. With the current focus on fully electronic surveillance systems that perform surveillance in its entirety without case review, effective use of the data will be dependent on ICP skills and their understanding of the strengths and limitations of output from algorithmic detection models. PMID- 25798778 TI - Chlorhexidine daily bathing: impact on health care-associated infections caused by gram-negative bacteria. AB - BACKGROUND: Health care-associated infections (HAIs) are a major cause of morbidity and mortality in intensive care unit (ICU) patients. Our objective was to evaluate the impact of daily bathing with chlorhexidine gluconate (CHG) on the incidence rates of HAIs, with a focus on their causative bacteria, in a French ICU. METHODS: From March 2012-May 2013, we enrolled 325 patients with at least 1 episode of suspected sepsis in the ICU, during two 6-month periods. The intervention group was subjected daily to skin cleansing with 2% CHG-impregnated cloths, whereas the control group was bathed daily with soap and water. HAI included bloodstream infections, ventilator-associated pneumonia, and urinary tract infections. Incidence rates corresponded to the number of infections per 1,000 patient days. RESULTS: Incidence of HAI was significantly decreased in the intervention group (29 vs 56; P = .01). After adjustment for baseline patient characteristics, the increased risk of HAI in the water and soap group was significant (odds ratio = 1.993; 95% confidence interval [CI], 1.132-3.508; P = .017). The incidence rate of clinical cultures positive for gram-negative bacteria, including Enterobacteriaceae and nonfermenting bacilli, decreased in the intervention group (risk ratio = 0.588; 95% CI, 0.346-0.978; P = .04). CONCLUSIONS: CHG daily cleansing reduced the incidence rate of HAI caused by gram negative bacteria, highlighting the role of the transient gram-negative bacteria skin colonization in the pathogenesis of HAI. PMID- 25798779 TI - Clinical decision support systems and infection prevention: to know is not enough. AB - Clinical decision support (CDS) systems are an increasingly used form of technology designed to guide health care providers toward established protocols and best practices with the intent of improving patient care. Utilization of CDS for infection prevention is not widespread and is particularly focused on antimicrobial stewardship. This article provides an overview of CDS systems and summarizes key attributes of successfully executed tools. A selection of published reports of CDS for infection prevention and antimicrobial stewardship are described. Finally, an individual organization describes its CDS infrastructure, process of prioritization, design, and development, with selected highlights of CDS tools specifically targeting common infection prevention quality improvement initiatives. PMID- 25798781 TI - Microfluidics for sperm research. AB - One in six couples of reproductive age worldwide are affected at least once by some form of infertility. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are widely-available assisted reproductive technologies (ART). The identification and isolation of the most-motile sperm with DNA integrity are essential to IVF and ICSI, ultimately affecting treatment consequences and the health of offspring. Recently, microfluidic technologies been developed to sort sperm according to sperm morphology, motility, DNA integrity, and functionality for IVF techniques. There have also been emerging applications in wildlife conservation, high-throughput single-sperm genomics, sperm-driven robotics, and in-home fertility testing. We review a broad range of studies applying the principles of microfluidics to sperm research. PMID- 25798780 TI - Targeted diversity generation by intraterrestrial archaea and archaeal viruses. AB - In the evolutionary arms race between microbes, their parasites, and their neighbours, the capacity for rapid protein diversification is a potent weapon. Diversity-generating retroelements (DGRs) use mutagenic reverse transcription and retrohoming to generate myriad variants of a target gene. Originally discovered in pathogens, these retroelements have been identified in bacteria and their viruses, but never in archaea. Here we report the discovery of intact DGRs in two distinct intraterrestrial archaeal systems: a novel virus that appears to infect archaea in the marine subsurface, and, separately, two uncultivated nanoarchaea from the terrestrial subsurface. The viral DGR system targets putative tail fibre ligand-binding domains, potentially generating >10(18) protein variants. The two single-cell nanoarchaeal genomes each possess >=4 distinct DGRs. Against an expected background of low genome-wide mutation rates, these results demonstrate a previously unsuspected potential for rapid, targeted sequence diversification in intraterrestrial archaea and their viruses. PMID- 25798782 TI - Emergent complexity matching in interpersonal coordination: Local dynamics and global variability. AB - Rhythmic coordination with stimuli and other people's movements containing variable or unpredictable fluctuations might involve distinct processes: detecting the fluctuation structure and tuning to or matching the structure's temporal complexity. This framework predicts that global tuning and local parameter adjustments (e.g., position, velocity or phase) can operate independently during coordination (Marmelat & Delignieres, 2012). Alternatively, we propose that complexity matching is a result of local phase adjustments during coordination (Delignieres & Marmelat, 2014; Torre, Varlet, & Marmelat, 2013). The current study examined this relationship in a rhythmic interpersonal coordination task. Dyads coordinated swinging pendulums that differed in their uncoupled frequencies (detuning). We predicted that frequency detuning would require increased local corrections to maintain the intended phase pattern (in phase). This was expected to yield a relative phase shift accompanied by a change in period complexity and matching. Experimental data and numerical modeling of the pendulum dynamics confirmed our predictions. Increased relative phase shifts occurred simultaneously with increased dissociation between individuals' movement period complexity. This provided evidence that global complexity matching is intricately linked to local movement adjustments and is not a distinct coordination mechanism. These findings are considered with respect to dynamical and computational approaches to interpersonal coordination. PMID- 25798783 TI - Unconscious analyses of visual scenes based on feature conjunctions. AB - To efficiently process a cluttered scene, the visual system analyzes statistical properties or regularities of visual elements embedded in the scene. It is controversial, however, whether those scene analyses could also work for stimuli unconsciously perceived. Here we show that our brain performs the unconscious scene analyses not only using a single featural cue (e.g., orientation) but also based on conjunctions of multiple visual features (e.g., combinations of color and orientation information). Subjects foveally viewed a stimulus array (duration: 50 ms) where 4 types of bars (red-horizontal, red-vertical, green horizontal, and green-vertical) were intermixed. Although a conscious perception of those bars was inhibited by a subsequent mask stimulus, the brain correctly analyzed the information about color, orientation, and color-orientation conjunctions of those invisible bars. The information of those features was then used for the unconscious configuration analysis (statistical processing) of the central bars, which induced a perceptual bias and illusory feature binding in visible stimuli at peripheral locations. While statistical analyses and feature binding are normally 2 key functions of the visual system to construct coherent percepts of visual scenes, our results show that a high-level analysis combining those 2 functions is correctly performed by unconscious computations in the brain. PMID- 25798784 TI - Divide and conquer: How perceptual contrast sensitivity and perceptual learning cooperate in reducing input variation in speech perception. AB - Listeners have to overcome variability of the speech signal that can arise, for example, because of differences in room acoustics, differences in speakers' vocal tract properties, or idiosyncrasies in pronunciation. Two mechanisms that are involved in resolving such variation are perceptually contrastive effects that arise from surrounding acoustic context and lexically guided perceptual learning. Although both processes have been studied in great detail, little attention has been paid to how they operate relative to each other in speech perception. The present study set out to address this issue. The carrier parts of exposure stimuli of a classical perceptual learning experiment were spectrally filtered such that the acoustically ambiguous final fricatives sounded relatively more like the lexically intended sound (Experiment 1) or the alternative (Experiment 2). Perceptual learning was found only in the latter case. The findings show that perceptual contrast effects precede lexically guided perceptual learning, at least in terms of temporal order, and potentially in terms of cognitive processing levels as well. PMID- 25798785 TI - Placental pathology measures: Can they be rapidly and reliably integrated into large-scale perinatal studies? AB - INTRODUCTION: Normal placental function is critical to optimize fetal growth and development, but few perinatal studies incorporate placental measures. Our objectives were to link clinical placental pathology records to birth records, and validate an automated abstraction strategy. METHODS: Of the 47,329 deliveries at our hospital from 2008 to 2012, we retrieved electronic copies of pathology reports (n = 21,585, 45.4%). Pathology data were extracted with Extensible Markup Language (XML) script using Java and structured query language (SQL) transformed the text information into variables that were linked to delivery data. A subgroup of records was selected for a validation study that compared automated to manual abstraction (n = 144). RESULTS: Linked birth-placental records included 93% of all preterm (<37 weeks, n = 5108) and 37.1% of term births (n = 14,019). Over 90% of deliveries complicated by preeclampsia, chronic hypertension, or gestational diabetes included pathology data. The validation study indicated excellent agreement, sensitivity and specificity between the two abstraction strategies. DISCUSSION: We demonstrate a reliable approach to electronically integrate placental pathology and delivery data. These linked data provide a platform to identify risk factors and sequelae associated with placental lesions. PMID- 25798787 TI - Vesicle solubilization by bile salts: comparison of macroscopic theory and simulation. AB - Lipid metabolism is accompanied by the solubilization of lipid bilayer membranes by bile salts. We use Brownian dynamics simulations to study the solubilization of model membranes and vesicles by sodium cholate. The solubilization pathways of small and large vesicles are found to be different. Both results for small and large vesicles can be compared with predictions of a macroscopic theoretical description. The line tension of bilayer edges is an important parameter in the solubilization process. We propose a simple method to determine the line tension by analyzing the shape fluctuations of planar membrane patches. Macroscopic mechanical models provide a reasonable explanation for processes observed when a spherical vesicle consisting of lipids and adsorbed bile salt molecules is transformed into mixed lipid-bile salt micelles. PMID- 25798786 TI - Cardiovascular parameters and neural sympathetic discharge variability before orthostatic syncope: role of sympathetic baroreflex control to the vessels. AB - We tested the hypothesis that altered sympathetic baroreceptor control to the vessels (svBRS) and disrupted coupling between blood pressure (BP) fluctuations and muscle sympathetic activity (MSNA) discharge pattern in the low frequency band (LF, around 0.1 Hz) precede vasovagal syncope. Seven healthy males underwent ECG, BP, respiratory, and MSNA recordings at baseline (REST) and during a 15 min 80 degrees head-up tilt, followed by a -10 mmHg step wise increase of lower body negative pressure up to presyncope. Spectral and coherence analyses of systolic arterial pressure (SAP) and MSNA variability provided the indexes of vascular sympathetic modulation, LFSAP, and of the linear coupling between MSNA and SAP in the low frequency band (around 0.1 Hz), K(2)MSNA-SAP(LF). svBRS was assessed as the slope of the regression line between MSNA and diastolic arterial pressure (DAP). Data were analyzed at REST, during asymptomatic and presyncope periods of tilt. svBRS declined during presyncope period compared to REST and asymptomatic tilt. The presyncope period was characterized by a decrease of RR interval, LFMSNA, LFSAP, and K(2)MSNA-SAP(LF) values compared to the asymptomatic one, whereas MSNA burst rate was unchanged. The reduction of svBRS producing an altered coupling between MSNA and SAP variability at 0.1 Hz, may provoke circulatory changes leading to presyncope. PMID- 25798788 TI - Electrospun polystyrene fiber diameter influencing bacterial attachment, proliferation, and growth. AB - Electrospun materials have been widely investigated in the past few decades as candidates for tissue engineering applications. However, there is little available data on the mechanisms of interaction of bacteria with electrospun wound dressings of different morphology and surface chemistry. This knowledge could allow the development of effective devices against bacterial infections in chronic wounds. In this paper, the interactions of three bacterial species (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) with electrospun polystyrene meshes were investigated. Bacterial response to meshes with different fiber diameters was assessed through a combination of scanning electron microscopy (SEM) and confocal microscopy. Experiments included attachment studies in liquid medium but also directly onto agar plates; the latter was aimed at mimicking a chronic wound environment. Fiber diameter was shown to affect the ability of bacteria to proliferate within the fibrous networks, depending on cell size and shape. The highest proliferation rates occurred when fiber diameter was close to the bacterial size. Nanofibers were found to induce conformational changes of rod shaped bacteria, limiting the colonization process and inducing cell death. The data suggest that simply tuning the morphological properties of electrospun fibers may be one strategy used to control biofilm formation within wound dressings. PMID- 25798789 TI - Controlled surface functionality of magnetic nanoparticles by layer-by-layer assembled nano-films. AB - Over the past several years, the preparation of functionalized nanoparticles has been aggressively pursued in order to develop desired structures, compositions, and structural order. Among the various nanoparticles, iron oxide magnetic nanoparticles (MNPs) have shown great promise because the material generated using these MNPs can be used in a variety of biomedical applications and possible bioactive functionalities. In this study, we report the development of various functionalized MNPs (F-MNPs) generated using the layer-by-layer (LbL) self assembly method. To provide broad functional opportunities, we fabricated F-MNP bio-toolbox by using three different materials: synthetic polymers, natural polymers, and carbon materials. Each of these F-MNPs displays distinct properties, such as enhanced thickness or unique morphologies. In an effort to explore their biomedical applications, we generated basic fibroblast growth factor (bFGF)-loaded F-MNPs. The bFGF-loaded F-MNPs exhibited different release mechanisms and loading amounts, depending on the film material and composition order. Moreover, bFGF-loaded F-MNPs displayed higher biocompatibility and possessed superior proliferation properties than the bare MNPs and pure bFGF, respectively. We conclude that by simply optimizing the building materials and the nanoparticle's film composition, MNPs exhibiting various bioactive properties can be generated. PMID- 25798790 TI - Cooperative dry-electrode sensors for multi-lead biopotential and bioimpedance monitoring. AB - Cooperative sensors is a novel measurement architecture that allows the acquiring of biopotential signals on patients in a comfortable and easy-to-integrate manner. The novel sensors are defined as cooperative in the sense that at least two of them work in concert to measure a target physiological signal, such as a multi-lead electrocardiogram or a thoracic bioimpedance.This paper starts by analysing the state-of-the-art methods to simultaneously measure biopotential and bioimpedance signals, and justifies why currently (1) passive electrodes require the use of shielded or double-shielded cables, and (2) active electrodes require the use of multi-wired cabled technologies, when aiming at high quality physiological measurements.In order to overcome the limitations of the state-of the-art, a new method for biopotential and bioimpedance measurement using the cooperative sensor is then presented. The novel architecture allows the acquisition of the aforementioned biosignals without the need of shielded or multi-wire cables by splitting the electronics into separate electronic sensors comprising each of two electrodes, one for voltage measurement and one for current injection. The sensors are directly in contact with the skin and connected together by only one unshielded wire. This new configuration requires one power supply per sensor and all sensors need to be synchronized together to allow them to work in concert.After presenting the working principle of the cooperative sensor architecture, this paper reports first experimental results on the use of the technology when applied to measuring multi-lead ECG signals on patients. Measurements performed on a healthy patient demonstrate the feasibility of using this novel cooperative sensor architecture to measure biopotential signals and compliance with common mode rejection specification accordingly to international standard (IEC 60601-2-47) has also been assessed.By reducing the need of using complex wiring setups, and by eliminating the presence of central recording devices (cooperative sensors directly sense and store the measured biosignals on the site), the depicted novel technology is a candidate to a novel generation of highly-integrated, comfortable and reliable technologies that measure physiological signals in real-life scenarios. PMID- 25798791 TI - Lipoxygenase-inhibiting phenolic glycosides and monoterpene glycosides from Paeonia lactiflora. AB - The EtOH extract of the roots of Paeonia lactiflora afforded a new phenolic glycoside paenoside A (1) and a new monoterpene glycoside paeonin D (2), and five known monoterpene glycosides. Their structures were elucidated on the basis of spectroscopic means and hydrolysis products. All compounds displayed inhibitory potential against enzyme lipoxygenase. PMID- 25798792 TI - Long-term effects of infant attachment organization on adult behavior and health in nursery-reared, captive chimpanzees (Pan troglodytes). AB - This research traces the long-term effects on health, well-being, personality, and behavior of adult chimpanzees as a function of their attachment to a primary human caregiver assessed when they were 1 year of age. Of the 46 chimpanzees assessed at 1 year of age, we assessed health in 43 individuals, adult behavior in 20 individuals, and adult well-being and personality in 21 individuals. Attachment disorganization was found to be a significant predictor of stereotypic rocking in adult chimpanzees, F(1, 18) = 7.50, p = .013. For those subjects (N = 24) with a full 20 years (birth through age 20 years) of health data available, both rearing experience and disorganized attachment were significant predictors of upper respiratory infection frequency, F(2, 21) = 8.86, p = .002. Chimpanzees with disorganized attachment exhibited average subjective well-being as adults, whereas chimpanzees with organized strategies exhibited higher than average subjective well-being as adults. These results support the findings of human attachment research and are in line with attachment-based predictions for chimpanzees, such that the consequences of an early history of disorganized attachment may be adverse and long lasting. PMID- 25798794 TI - Humans (Homo sapiens) judge the emotional content of piglet (Sus scrofa domestica) calls based on simple acoustic parameters, not personality, empathy, nor attitude toward animals. AB - The vocal expression of emotion is likely driven by shared physiological principles among species. However, which acoustic features promote decoding of emotional state and how the decoding is affected by their listener's psychology remain poorly understood. Here we tested how acoustic features of piglet vocalizations interact with psychological profiles of human listeners to affect judgments of emotional content of heterospecific vocalizations. We played back 48 piglet call sequences recorded in four different contexts (castration, isolation, reunion, nursing) to 60 listeners. Listeners judged the emotional intensity and valence of the recordings and were further asked to attribute a context of emission from four proposed contexts. Furthermore, listeners completed a series of questionnaires assessing their personality (NEO-FFI personality inventory), empathy [Interpersonal Reactivity Index (IRI)] and attitudes to animals (Animal Attitudes Scale). None of the listeners' psychological traits affected the judgments. On the contrary, acoustic properties of recordings had a substantial effect on ratings. Recordings were rated as more intense with increasing pitch (mean fundamental frequency) and increasing proportion of vocalized sound within each stimulus recording and more negative with increasing pitch and increasing duration of the calls within the recording. More complex acoustic properties (jitter, harmonic-to-noise ratio, and presence of subharmonics) did not seem to affect the judgments. The probability of correct context recognition correlated positively with the assessed emotion intensity for castration and reunion calls, and negatively for nursing calls. In conclusion, listeners judged emotions from pig calls using simple acoustic properties and the perceived emotional intensity might guide the identification of the context. PMID- 25798795 TI - Nudging students toward healthier food choices--applying insights from behavioral economics. PMID- 25798793 TI - Looking ahead? Computerized maze task performance by chimpanzees (Pan troglodytes), rhesus monkeys (Macaca mulatta), capuchin monkeys (Cebus apella), and human children (Homo sapiens). AB - Human and nonhuman primates are not mentally constrained to the present. They can remember the past and-at least to an extent-anticipate the future. Anticipation of the future ranges from long-term prospection such as planning for retirement to more short-term future-oriented cognition such as planning a route through a maze. Here we tested a great ape species (chimpanzees), an Old World monkey species (rhesus macaques), a New World monkey species (capuchin monkeys), and human children on a computerized maze task. All subjects had to move a cursor through a maze to reach a goal at the bottom of the screen. For best performance on the task, subjects had to "plan ahead" to the end of the maze to move the cursor in the correct direction, avoid traps, and reverse directions if necessary. Mazes varied in difficulty. Chimpanzees were better than both monkey species, and monkeys showed a particular deficit when moving away from the goal or changing directions was required. Children showed a similar pattern to monkeys regarding the effects of reversals and moves away from the goal, but their overall performance in terms of correct maze completion was similar to the chimpanzees. The results highlight similarities as well as differences in planning across species and the role that inhibitory control may play in future oriented cognition in primates. PMID- 25798796 TI - Huckel theory and optical activity. AB - Optical rotations and rotatory strengths are calculated for achiral, conjugated hydrocarbons with the aim of determining to what extent the sum-over-pi -> pi* rotatory strengths are sufficient to account for nonresonant optical activity. The separability of sigma and pi electrons might provide a short cut to the interpretation of chiroptical structure-property relations in some cases. It is shown that by restricting the analyses to planar, C(2v)-symmetric pi-systems and their one electron HOMO-LUMO excitations, an intuitive understanding of the vexing property of optical activity is forthcoming for the following reasons: Huckel wave functions are simply calculated, and in some cases, they can even be approximated by inspection of structure. Wave functions of planar molecules can be multiplied with one another graphically or, in the mind's eye, to yield transition electric and magnetic moments. The gyration tensors have just one independent component. Transition dipole moments are orthogonal to one another. And, the most optically active directions are found at their bisectors. Throughout, emphasis is on the evaluation of long wavelength optical rotation, consistent with quantum chemical computation, using simple models that are part of the fabric of organic chemistry pedagogy. PMID- 25798797 TI - Instant Cage Making with PMMA. PMID- 25798798 TI - Placement of Teflon Sponges in Microvascular Decompression Procedure for Treatment of Hemifacial Spasm. AB - Background Hemifacial spasm (HFS) is generally treated by microvascular decompression (MVD). Inadequate separation of vessel and nerve or adhesive inflammation surrounding the nerve root may cause recurrence. Objective To explore a method to reduce the incidence of adhesions and to ensure sufficient separation of the offending vessel and nerve during MVD. Methods Fifty-one patients diagnosed with HFS were studied. During the MVD procedure, Teflon sponges were placed between the offending vessels and medulla oblongata to push compressing vessels away from the facial nerve without contacting the nerve. Results Our method of placement of the Teflon sponge effectively shifts the compressing artery and ensures that both the Teflon sponge and offending vessels do not contact the root exit zone. This method also ensures that the Teflon sponge is fixed in place. Conclusion The technique described for the treatment of HFS provides an effective, safe, and durable resolution to patient symptoms that minimizes surgical complications and may be useful in treating HFS. PMID- 25798799 TI - Effect of insurance and racial disparities on outcomes in traumatic brain injury. AB - INTRODUCTION: We evaluated outcome and resource utilization disparities between commercially insured, Medicaid, and Medicare patients. We further analyzed racial disparities in a subset cohort. METHODS: We reviewed the MarketScan database (2000-2009) for adult traumatic brain injury (TBI) patients. Analyses were performed to evaluate outcome differences by insurance type and race. Outpatient service utilization disparities by insurance and race were also evaluated. RESULTS: Our study included 92,159 TBI patients, 44,108 (47.9%) of whom utilized commercial insurance, 19,743 (21.4%) utilized Medicaid, and 28,308 (30.7%) utilized Medicare. In-hospital mortality was lowest for commercially insured (5.0%) versus 7.6% and 8.5% for Medicaid and Medicare patients, respectively (p < 0.0001). Medicaid patients had a longer hospitalization than commercially insured (12 days versus 6 days; p < 0.0001). Medicaid patients were 1.29 and 1.78 times more likely to die and experience complications than the commercially insured. Females had a lower mortality risk (odds ratio [OR]: 0.80, p < 0.0001) and less complications (OR: 0.67; p < 0.0001) than males. Higher comorbidities increased mortality risk (OR: 2.71; p < 0.0001) and complications (OR: 2.96, p < 0.0001). Mild injury patients had lower mortality (OR: 0.01; p < 0.0001) and less complications (OR: 0.07; p < 0.0001). Medicare (OR: 1.33; p < 0.0001) and higher comorbidity (OR: 1.26; p < 0.0001) patients utilized outpatient rehabilitation services more frequently. Medicare patients had twice the emergency department visits as the commercially insured (p < 0.0001). Medicare (16.6%) patients utilized more rehabilitation than commercially insured (13.4%) and Medicaid (9.1%) patients. Racial disparities were analyzed in a subset of 12,847 white and 4,780 African American (AA) patients. Multivariate analysis showed that AAs were more likely to experience a complication than white patients (OR: 1.13; p = 0.0024) and less likely to utilize outpatient rehabilitation services (OR: 0.83; p = 0.0025) than whites. CONCLUSIONS: Insurance and racial disparities continue to exist for TBI patients. Insurance status appears to have an impact on short- and long-term outcomes to a greater degree than patient race. PMID- 25798800 TI - Biopsy of Brainstem Gliomas Using Flexible Endoscopes. AB - OBJECTIVES: To describe our experience and the results obtained in performing transventricular brainstem biopsy with the use of flexible neuroendoscops. METHODS: We identified patients who underwent a neuroendoscopic procedure with brainstem lesion biopsy to obtain histopathologic diagnosis and to treat obstructive hydrocephalus. All patients had follow-up examinations at months 1, 3, 6, and 12 postsurgery and then annually. RESULTS: Seven patients had a transventricular biopsy of the brainstem performed. Of those, five were pediatric patients. The median age was 10 years (range: 3-26 years). Five of them were female and two male. Four patients presented with secondary obstructive hydrocephalus. The main clinical presentations were intracranial hypertension syndrome in four patients, motor neuron disease in four patients, two with decreased state of alertness, two with gait ataxia, and one with Parinaud syndrome. The types of tumors found in the histopathology and their location were one ventral (pons) and one aqueductal anaplastic astrocytoma, two ventral, one aqueductal, and one attached to the floor of the fourth ventricle pilocytic astrocytoma and one ventral low-grade astrocytoma. The route taken to approach the ventral tumors was made through premammillary fenestration. The tumors of the aqueduct and floor of the fourth ventricle were approached transaqueductally. CONCLUSION: The use of flexible endoscops for biopsy of ventral, dorsal (tectum lamina quadrigemina), and diffuse brainstem tumors is a useful, effective, and safe procedure that also allows to treat obstructive hydrocephalus secondary to the tumors. PMID- 25798801 TI - Will an Asymptomatic Meningioma Grow or Not Grow? A Meta-analysis. AB - BACKGROUND: The treatment strategy for patients with an asymptomatic meningioma is still controversial. Key to an optimal decision is a careful evaluation of the growth possibilities of the meningioma by taking the patient's clinicoradiologic factors into consideration. However, previous studies have disagreed about the risk factors relating to tumor growth. METHODS: A comprehensive search of PubMed, Embase, and the ISI Web of Knowledge was performed. Using a meta-analysis with nine subsidiary studies including 777 patients, we analyzed the correlation of the growth pattern of meningioma with patient gender, tumor location, tumor calcification, magnetic resonance imaging (MRI) T2 signal intensity, and peritumoral brain edema. RESULTS: The growth rate of meningioma was negatively correlated with tumor calcification (odds ratio [OR]: 0.23; 95% confidence interval (CI), 0.11-0.46; p < 0.001) but positively associated with MRI T2 signal intensity (OR: 2.75; 95% CI, 1.75-4.33; p < 0.001). No correlations were found between tumor growth and other factors such as gender (OR: 1.29; 95% CI, 0.84 1.99; p = 0.24), skull base location (OR: 0.80; 95% CI, 0.25-2.58; p = 0.70), and peritumoral brain edema (OR: 1.24; 95% CI, 0.29-5.27; p = 0.77). CONCLUSIONS: Two factors, tumor calcification and low MRI T2 signal intensity, indicate the possibility of a slow growth meningioma. In such cases of asymptomatic meningioma, a follow-up strategy can be preferentially considered. PMID- 25798802 TI - Therapeutic management of intraventricular cavernoma: case series and review of the literature. AB - Intraventricular cavernoma (IVC) is a rare intracranial vascular malformation and only 100 cases of IVC have been described in the literature. Although IVCs share some common characteristics with intraparenchymal cavernomas, they also have some distinct features involving structure, clinical symptoms, radiologic appearance, and onset of symptoms. This review presents our experience, consisting of five IVC cases over a period of 11 years. We describe the symptoms leading to hospital admission, the main radiologic findings, the management of each ICV case, and the patients' clinical status after surgery. We also reviewed the international literature on IVC, presenting the main demographic characteristics, their most common location in the ventricular system, and the main signs and symptoms. Finally, we present the management options according to the current literature, the advantages and disadvantages of every management option, accompanied by a brief follow-up of most IVC cases, whether the cavernoma was treated surgically or conservatively. PMID- 25798803 TI - Spinal Cord Stereotaxy: An Overview. AB - The origin of spinal cord stereotaxy can be traced back to the 19th-century work of Woroshiloff, the pioneer of brain stereotaxy. The development of clinical brain stereotaxy began in the mid-20th century, but spinal cord stereotaxy lagged behind. The first stereotactic spinal cord surgery was successfully performed by Hitchcock for pain treatment in the 1960s, and surgery for urinary bladder hyperspasticity performed by Nadvornik followed several years later. Other stereotactic surgeries of the spinal cord movement system could not be considered until Slovak anatomist Cierny used animal experiments (with cats) to discover the exact location of motoneurons for the individual muscles in the anterior horns of the spinal cord. Having compared the data with the pattern of Riley's atlas based on microscopic investigation of the human spinal cord (only motoneuron groups without functional properties), the first stereotactic spinal cord atlas was transferred to human structures. With the construction of a universal spinal cord stereotactic device began a new era in spinal cord stereotaxy. The investigation of spinal cord movement functions will probably become the main focus of this discipline that aims to restore physiologic movement after spinal cord injury associated with paraplegia. PMID- 25798804 TI - Predictors of Tumor Response to Cetuximab and Panitumumab in 116 Patients and a Review of Approaches to Managing Skin Toxicity. AB - INTRODUCTION AND OBJECTIVES: Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) in the treatment of metastatic colorectal cancer. Most patients develop a papulopustular rash, which may predict tumor response. We studied whether the other adverse cutaneous effects associated with these monoclonal antibodies are also clinical predictors of response. We also reviewed publications describing approaches to treating the papulopustular rash since no evidence-based guidelines have yet been published. MATERIAL AND METHODS: We performed a retrospective study of 116 patients with metastatic colorectal cancer receiving anti-EGRF therapy with cetuximab or panitumumab at Hospital Universitario Donostia. RESULTS: In total, 81.9% of the patients developed a papulopustular rash. Patients who received the most cycles of treatment with the EGFR inhibitor were at the highest risk of developing the rash, and these patients also had the most severe rash reactions (P=.03). All of the patients who exhibited a complete tumor response had the rash, and the incidence of rash was lower in patients with poor tumor response (P=.03). We also observed an association between tumor response and xerosis (53.4% of the patients who developed xerosis also exhibited tumor response, P=.002). The papulopustular rash was managed according to an algorithm developed by our department. CONCLUSIONS: Severe papulopustular rash and xerosis may be clinical predictors of good response to anti-EGFR therapy. Patients who develop a papulopustular rash should be treated promptly because suboptimal treatment of this and other adverse effects can lead to delays in taking the prescribed anti-EGFR dose or to interruption of therapy. PMID- 25798806 TI - Fat and Adipose-Derived Stem Cell Grafts in Acute Burns. PMID- 25798805 TI - Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for thyroid disease. METHODS: The USPSTF reviewed the evidence on the benefits and harms of screening for subclinical and "overt" thyroid dysfunction without clinically obvious symptoms, as well as the effects of treatment on intermediate and final health outcomes. POPULATION: This recommendation applies to nonpregnant, asymptomatic adults. RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant, asymptomatic adults. (I statement). PMID- 25798807 TI - Methylene Blue for Acute Septic Cardiomyopathy in a Burned Patient. AB - The objective of this case summary was to describe the use of methylene blue (MB) in a burned patient with acute septic cardiomyopathy. A 60-year-old Caucasian man was admitted to the Burn Intensive Care Unit with 45% TBSA burns after a house explosion. During the course of his care, he experienced hypotension that was refractory to fluid therapy and vasoactive medications. Echocardiography and right heart catheterization showed new acute systolic dysfunction with concurrent elevated systemic vascular resistance (SVR). High-dose inotropic agents did not improve cardiac function, and septic shock rendered him a poor candidate for mechanical intra-aortic balloon pump support. MB was administered to sensitize the myocardium to catecholamines and improve contractility with the goal of weaning the other vasoactive medications and diuresing for afterload reduction when hemodynamic stability was achieved. MB has been described in critical care medicine predominately for vasoplegia after cardiopulmonary bypass and vasodilatory septic shock., Our patient had acute septic cardiomyopathy that was refractory to standard pharmacologic approaches to inotropy with concurrent elevated SVR. Hypothesizing the differential temporal effect of inducible nitric oxide synthase on the vasculature and myocardium, we administered MB to improve contractility and support the impending vasodilatory effects of distributive shock. Although MB is not a new drug, the application for septic cardiomyopathy with a supranormal SVR is a unique application. Because of the risk profile associated with MB, we recommend drug monitoring utilizing serial echocardiography and/or right heart catheterization. PMID- 25798808 TI - Improving and Maintaining Conformity of Acticoat(r) Dressings with Shear Reducing Transfixion Suture. PMID- 25798809 TI - Exposure to an Iridium-192 Source in an Industrial Safety Worker: Follow-Up Period Should be Longer. PMID- 25798810 TI - Creating optical near-field orbital angular momentum in a gold metasurface. AB - Nanocavities inscribed in a gold thin film are optimized and designed to form a metasurface. We demonstrate both numerically and experimentally the creation of surface plasmon (SP) vortex carrying orbital angular momentum in the metasurface under linearly polarized optical excitation that carries no optical angular momentum. Moreover, depending on the orientation of the exciting linearly polarized light, we show that the metasurface is capable of providing dynamic switching between SP vortex formation or SP subwavelength focusing. The resulting SP intensities are experimentally measured using a near-field scanning optical microscope and are found in excellent quantitative agreements as compared to the numerical results. PMID- 25798812 TI - An ab initio and DFT study of the autoxidation of THF and THP. AB - Tetrahydropyran (THP) is known to undergo autoxidation much more slowly than tetrahydrofuran (THF). To investigate the difference in reactivity in the autoxidation of these two ethers, ab initio and DFT calculations were carried out. At the BHandHLYP/aug-cc-pVDZ//BHandHLYP/cc-pVDZ level of theory, the energy barrier for hydrogen abstraction from THP is predicted to be 104.1 kJ mol(-1), whereas that for THF is calculated as 94.1 kJ mol(-1). Including solvation effects in the calculations lowers these barriers to 98.0 (THP) and 84.4 kJ mol( 1) (THF); the energy barrier for the process involving THP is smaller by 14 kJ mol(-1) than that for THF. While scanning the potential energy surface for the radical coupling process between the THP (or THF) radical with molecular oxygen, an energy barrier of 11.2 kJ mol(-1) (BHandHLYP/6-311G**) was found for the process involving the THP radical, although no barrier was found for the reaction involving THF. Analysis of the Kohn-Sham singly occupied molecular orbitals (SOMOs) in the hydroperoxy complexes reveals that the SOMO of the THP complex would be blocked by the neighbouring hydrogen atoms in the THP ring. These factors would work together to delay the autoxidation of THP. PMID- 25798811 TI - Clinical, Histologic, and Molecular Analysis of Differences Between Erythematotelangiectatic Rosacea and Telangiectatic Photoaging. AB - IMPORTANCE: Facial erythema and telangiectasia are commonly associated with the erythematotelangiectatic subtype of rosacea (ETR). It is important for clinicians to recognize that these findings can also be associated with a subtype of photoaging, which we term telangiectatic photoaging (TP). OBJECTIVE: To demonstrate that ETR and TP are distinct dermatologic disorders. DESIGN: A case control observational study comparing clinical, histologic, and gene expression features of 26 participants with ETR, 20 with TP, and 11 age- and sex-matched controls in the Program for Clinical Research in Dermatology at University of Michigan. MAIN OUTCOMES AND MEASURES: Findings of clinical history and examination, light and electron microscopy, immunohistochemical analyses, and real-time quantitative reverse-transcriptase polymerase chain reaction gene expression. RESULTS: Transient erythema was greater in the ETR group (38% graded moderate to severe) than in the TP (0%; P < .001) and control groups (0%; P = .002). Nontransient erythema was also greater in the ETR group (50% graded moderate to severe) than in the TP (25%; P = .03) and control groups (0%; P < .001). Participants with ETR tended to have erythema and telangiectasia primarily on the central face (79%), whereas those with TP tended to have more lateral involvement (57%; P < .001). Those with ETR had significantly less clinical evidence of photodamage (0% graded 6-8 on a photonumeric scale) than those with TP (40% graded 6-8; P = .01). Histologically, there was less evidence of photodamage in ETR than in TP, which had wispy collagen and solar elastosis surrounding blood vessels. Immunohistologic analysis demonstrated greater geometric mean immunostained area by mast cell tryptase staining in ETR samples (0.018%) than in TP (0.004%; P = .01) or control samples (0.001%; P < .001) but no increase in mast cell number, indicative of greater mast cell degranulation. Gene expression of matrix metalloproteinase-3 was 4-fold greater in ETR samples than in TP samples (P = .004) and 5-fold higher than in control samples (P = .004). Gene expression of the neuropeptides calcitonin gene-related peptide (CGRP alpha) and substance P was significantly increased in ETR compared with TP (9 fold [P < .001] and 5-fold [P = .002], respectively) and control samples (10-fold [P < .001] and 28-fold [P < .001], respectively). CONCLUSIONS AND RELEVANCE: Telangiectatic photoaging is characterized by less transient and nontransient erythema, a more lateral distribution of erythema and telangiectasia, less neurogenic mast cell activation, and less MMP-mediated matrix remodeling than ETR. These data demonstrate that TP is a distinct clinical entity from ETR that can be distinguished on the basis of clinical, histologic, and gene expression findings. PMID- 25798813 TI - Prenatal restraint stress decreases the expression of alpha-7 nicotinic receptor in the brain of adult rat offspring. AB - Prenatal stress (PS) strongly impacts fetal brain development and function in adulthood. In normal aging and Alzheimer's disease, there is hypothalamic pituitary-adrenal axis dysfunction and loss of cholinergic neurons and neuronal nicotinic acetylcholine receptors (nAChRs). This study investigated whether prenatal restraint stress affects nAChR expression in the brain of adult offspring. For PS, pregnant dams were placed in a plastic restrainer for 45 min, three times daily during the last week of pregnancy; controls were undisturbed. Male offspring were analyzed at postnatal day (PND) 60 (n = 4 rats per group). Western blot (WB) and fluorescence microscopy showed that PS decreased alpha7 AChR subunit expression (~50%) in the frontal cortex in the adult offspring. PS decreased significantly the number of alpha7-AChR-expressing cells in the medial prefrontal cortex (by ~25%) and in the sensory-motor cortex (by ~20%) without affecting the total cell number in those areas. No alterations were found in the hippocampus by quantitative polymerase chain reaction (qPCR), or WB analysis, but a detailed fluorescence microscopy analysis showed that PS affected alpha7-AChR mainly in the CA3 and dentate gyrus subfields: PS decreased alpha7-AChR subunit expression by ~25 and ~30%, respectively. Importantly, PS decreased the number of alpha7-AChR-expressing cells and the total cell number (by ~15 and 20%, respectively) in the dentate gyrus. PS differently affected alpha4-AChR: PS impaired its mRNA expression in the frontal cortex (by ~50%), without affecting protein levels. These results demonstrate that disturbances during gestation produce long-term alterations in the expression pattern of alpha7-AChR in rat brain. PMID- 25798814 TI - Patterns of technology use in patients attending a cardiopulmonary outpatient clinic: a self-report survey. AB - BACKGROUND: Self-management education for cardiopulmonary diseases is primarily provided through time-limited, face-to-face programs, with access limited to a small percentage of patients. Telecommunication tools will increasingly be an important component of future health care delivery. OBJECTIVE: The purpose of this study was to describe the patterns of technology use in patients attending a cardiopulmonary clinic in an academic medical center. METHODS: A prevalence survey was developed to collect data on participant demographics (age in years, sex, and socioeconomic status); access to computers, Internet, and mobile phones; and use of current online health support sites or programs. Surveys were offered by reception staff to all patients attending the outpatient clinic. RESULTS: A total of 123 surveys were collected between March and April 2014. Technological devices were a pervasive part of everyday life with respondents engaged in regular computer (102/123, 82.9%), mobile telephone (115/117, 98.3%), and Internet (104/121, 86.0%) use. Emailing (101/121, 83.4%), researching and reading news articles (93/121, 76.9%), social media (71/121, 58.7%), and day-to-day activities (65/121, 53.7%) were the most common telecommunication activities. The majority of respondents reported that access to health support programs and assistance through the Internet (82/111, 73.9%) would be of use, with benefits reported as better understanding of health information (16/111, 22.5%), avoidance of difficult travel requirements and time-consuming face-to-face appointments (13/111, 18.3%), convenient and easily accessible help and information (12/111, 16.9%), and access to peer support and sharing (9/111, 12.7%). The majority of patients did not have concerns over participating in the online environment (87/111, 78.4%); the few concerns noted related to privacy and security (10/15), information accuracy (2/15), and computer literacy and access (2/15). CONCLUSIONS: Chronic disease burden and long-term self-management tasks provide a compelling argument for accessible and convenient avenues to obtaining ongoing treatment and peer support. Online access to health support programs and assistance was reported as useful and perceived as providing convenient, timely, and easily accessible health support and information. Distance from the health care facility and a lack of information provision through traditional health sources were both barriers and enablers to telehealth. This is particularly important in the context of a cardiopulmonary clinic that attracts patients from a large geographical area, and in patients who are most likely to have high health care utilization needs in the future. Telecommunication interfaces will be an increasingly important adjunct to traditional forms of health care delivery. PMID- 25798816 TI - Hallucinations and inhibitory functioning in healthy young adults with high and low levels of hypomanic personality traits. AB - INTRODUCTION: Hallucinations in schizophrenia and hallucination proneness in healthy young adults are associated with a common cognitive mechanism, namely impaired inhibitory control. Hallucinatory-like experiences also seem related to hypomanic symptoms in non-clinical participants; however, the mechanisms involved are unknown. We sought to examine self-reported hallucinatory/anomalous perceptual experiences in students selected for high versus low levels of hypomanic personality traits, and whether hypomania is characterised by deficient inhibitory control. METHOD: Undergraduate students with either high (n = 26) or low (n = 28) scores on the Hypomanic Personality Scale-Revised (HPS-20) were compared on: (1) the Launay Slade Hallucination Scale-Revised (LSHS-R), a measure of hallucination proneness, (2) the Cardiff Anomalous Perceptions Scale (CAPS) and (3) the Inhibition of Currently Irrelevant Memories (ICIM) task, an index of intentional inhibition. RESULTS: The high HPS group had higher total scores, as well as higher frequency (on CAPS only), intrusiveness and distress (CAPS) scores compared to the low HPS group. They also produced significantly more false alarms on the second run of the ICIM task than the low hypomania traits group. CONCLUSIONS: Frequent, intrusive and distressing perceptual anomalies and proneness to hallucinations tend to occur in healthy individuals with hypomanic personality traits and may be associated with transient difficulties with inhibitory control. Inhibitory control may be a cognitive marker of vulnerability to hallucinations across diagnostic boundaries. PMID- 25798815 TI - Expression of KRASG12V in Zebrafish Gills Induces Hyperplasia and CXCL8 Associated Inflammation. AB - The zebrafish (Danio rerio) represents an important animal model for analyzing genetic contributors to carcinogenesis. To assess the role for mutationally activated Ras in ovarian cancer, we developed a transgenic zebrafish model using the putative promoter for zebrafish insulin-like growth factor 3 (igf3) to drive expression of the human oncogene KRAS(G12V) fused to EGFP. A member of the IGF family, igf3 is unique to teleosts and reportedly exhibits gonad-specific expression in fish species. In contrast to previous studies, we observed igf3 expression in wild-type zebrafish gills in addition to gonads, indicating that igf3 expression is not necessarily gonad specific. In transgenic zebrafish, expression of EGFP-KRAS(G12V) driven by the igf3 promoter occurred only in the gills and resulted in proliferation of a putative progenitor cell population, chondroid hyperplasia, and localized inflammation. KRAS(G12V)-transformed cells in transgenic zebrafish showed activation of the ERK-MAP kinase pathway and expressed the zebrafish homologue for human CXCL8, a cytokine produced by mammalian Ras-transformed cells in tumor-associated inflammatory lesions. These findings indicate that KRAS(G12V)-transformed cells in zebrafish recruit inflammatory cells, but may require additional mutational events for neoplastic transformation. The conserved role for mutationally activated KRAS in leukocyte recruitment indicates that zebrafish can provide a valuable comparative model for Ras-associated inflammation. PMID- 25798817 TI - Isomer profiles of perfluoroalkyl substances in water and soil surrounding a chinese fluorochemical manufacturing park. AB - Despite that China is the largest global manufacturer of perfluoroalkyl substances (PFASs), the manufacturing methods and isomer purity of these chemicals are generally unknown. Here, sampling was conducted around a major fluorochemical manufacturing park in China in 2012, including soil and water collection inside the park, including from a wastewater treatment plant (WWTP), as well as in surrounding rivers and soil (~15 km radius). Perfluoroalkyl sulfonates (PFSAs) were lower than perfluoroalkyl carboxylates (PFCAs) in all samples, and short-chain (C4-C6) PFCAs were predominant. Perfluoroalkyl phosphonates and phosphate diesters were occasionally detected, but at low detection frequency. Branched isomers of perfluorobutanesulfonate (PFBS) are reported for the first time, accounting for 15-27% of total PFBS in water. An enrichment of isopropyl-PFOA (28%) was found in WWTP influent, suggesting its manufacturing primarily by isopropyl telomerization. More numerous branched isomers were observed for the longer C9-C13 PFCAs (e.g., C12 PFCA had 16 branched isomers), including high proportions of one major branched isomer (likely isopropyl), possibly as impurities from isopropyl-PFOA manufacturing. Overall, short-chain perfluorinated acids were the predominant PFASs being released, but PFOA was still a major chemical in use at this site, primarily from isopropyl telomerization. PMID- 25798819 TI - From the field to the lab: best practices for field preservation of bat specimens for molecular analyses. AB - Studies in molecular ecology depend on field-collected samples for genetic information, and the tissue sampled and preservation conditions strongly affect the quality of the DNA obtained. DNA yields from different tissue types have seldom been compared, and the relative performance of storage media has never been directly tested, even though these media may influence DNA degradation under field conditions. We analyzed DNA yield from buccal swabs and wing punches harvested from live bats using nucleic acid quantification as well as quantitative PCR for a single-copy nuclear locus. We also compared DNA yields from wing tissue preserved in three media: ethanol, NaCl-saturated dimethyl sulfoxide (DMSO), and silica desiccant. Wing punches yielded more total DNA than did buccal swabs, and wing tissues preserved in silica beads yielded significantly more total and nuclear DNA than those preserved in DMSO or ethanol. These results show that tissue type and preservation media strongly influence the quantity of DNA obtained from non-lethal genetic samples, and based on these effects we provide recommendations for field collection of tissues for genetic analyses. PMID- 25798820 TI - A spin-frustrated trinuclear copper complex based on triaminoguanidine with an energetically well-separated degenerate ground state. AB - We present the synthesis and crystal structure of the trinuclear copper complex [Cu3(saltag)(bpy)3]ClO4.3DMF [H5saltag = tris(2 hydroxybenzylidene)triaminoguanidine; bpy = 2,2'-bipyridine]. The complex crystallizes in the trigonal space group R3, with all copper ions being crystallographically equivalent. Analysis of the temperature dependence of the magnetic susceptibility shows that the triaminoguanidine ligand mediates very strong antiferromagnetic interactions (JCuCu = -324 cm(-1)). Detailed analysis of the magnetic susceptibility and magnetization data as well as X-band electron spin resonance spectra, all recorded on both powdered samples and single crystals, show indications of neither antisymmetric exchange nor symmetry lowering, thus indicating only a very small splitting of the degenerate S = (1)/2 ground state. These findings are corroborated by density functional theory calculations, which explain both the strong isotropic and negligible antisymmetric exchange interactions. PMID- 25798818 TI - Understanding the long-lasting attraction of malaria mosquitoes to odor baits. AB - The use of odor baits for surveillance and control of malaria mosquitoes requires robust dispensing tools. In this study, the residual activity of a synthetic mosquito attractant blend dispensed from nylon or low density polyethylene (LDPE) sachets was evaluated at weekly intervals for one year without re-impregnation. The potential role of bacteria in modulating the attraction of mosquitoes to odor treated nylon that had been used repeatedly over the one year study period, without re-impregnation, was also investigated. Significantly higher proportions of female Anopheles gambiae sensu stricto mosquitoes were consistently attracted to treated nylon strips than the other treatments, up to one year post-treatment. Additional volatile organic compounds and various bacterial populations were found on the treated nylon strips after one year of repeated use. The most abundant bacteria were Bacillus thuringiensis and Acinetobacter baumannii. Autoclaving of treated nylon strips prior to exposure had no effect on trap collections of laboratory-reared female An. Gambiae (P = 0.17) or wild female An. Gambiae sensu lato (P = 0.26) and Mansonia spp. (P = 0.17) mosquitoes. Trap catches of wild female An. Funestus (P < 0.001) and other anophelines (P < 0.007) were higher when treated strips had been autoclaved prior to deployment as opposed to when the treated nylon strips were not autoclaved. By contrast, wild female Culex mosquitoes were more strongly attracted to non-autoclaved compared to autoclaved treated nylon strips (P < 0.042). This study demonstrates the feasibility of using odor baits for sampling and surveillance of malaria as well as other mosquito vectors over prolonged periods of time. Preliminary evidence points towards the potential role of bacteria in sustaining prolonged use of nylon material for dispensing synthetic attractant odorants for host-seeking malaria and other mosquito vectors but further investigations are required. PMID- 25798821 TI - Effect of spaceflight on the circadian rhythm, lifespan and gene expression of Drosophila melanogaster. AB - Space travelers are reported to experience circadian rhythm disruption during spaceflight. However, how the space environment affects circadian rhythm is yet to be determined. The major focus of this study was to investigate the effect of spaceflight on the Drosophila circadian clock at both the behavioral and molecular level. We used China's Shenzhou-9 spaceship to carry Drosophila. After 13 days of spaceflight, behavior tests showed that the flies maintained normal locomotor activity rhythm and sleep pattern. The expression level and rhythm of major clock genes were also unaffected. However, expression profiling showed differentially regulated output genes of the circadian clock system between space flown and control flies, suggesting that spaceflight affected the circadian output pathway. We also investigated other physiological effects of spaceflight such as lipid metabolism and lifespan, and searched genes significantly affected by spaceflight using microarray analysis. These results provide new information on the effects of spaceflight on circadian rhythm, lipid metabolism and lifespan. Furthermore, we showed that studying the effect of spaceflight on gene expression using samples collected at different Zeitgeber time could obtain different results, suggesting the importance of appropriate sampling procedures in studies on the effects of spaceflight. PMID- 25798823 TI - Electronic circular dichroism of highly conjugated pi-systems: breakdown of the Tamm-Dancoff/configuration interaction singles approximation. AB - We show that the electronic circular dichroism (ECD) of delocalized pi-systems represents a worst-case scenario for Tamm-Dancoff approximated (TDA) linear response methods. We mainly consider density functional theory (TDA-DFT) variants together with range-separated hybrids, but the conclusions also apply for other functionals as well as the configuration interaction singles (CIS) approaches. We study the effect of the TDA for the computation of ECD spectra in some prototypical extended pi-systems. The C76 fullerene, a chiral carbon nanotube fragment, and [11]helicene serve as model systems for inherently chiral, pi chromophores. Solving the full linear response problem is inevitable in order to obtain accurate ECD spectra for these systems. For the C76 fullerene and the nanotube fragment, TDA and CIS approximated methods yield spectra in the origin independent velocity gauge formalism of incorrect sign which would lead to the assignment of the opposite (wrong) absolute configuration. As a counterexample, we study the ECD of an alpha-helix polypeptide chain. Here, the lowest-energy transitions are dominated by localized excitations within the individual peptide units, and TDA methods perform satisfactorily. The results may have far-reaching implications for simple semiempirical methods which often employ TDA and CIS for huge molecules. Our recently presented simplified time-dependent DFT approach proves to be an excellent low-cost linear response method which together with range-separated density functionals like omegaB97X-D3 produces ECD spectra in very good agreement with experiment. PMID- 25798822 TI - The neural correlates of emotion regulation by implementation intentions. AB - Several studies have investigated the neural basis of effortful emotion regulation (ER) but the neural basis of automatic ER has been less comprehensively explored. The present study investigated the neural basis of automatic ER supported by 'implementation intentions'. 40 healthy participants underwent fMRI while viewing emotion-eliciting images and used either a previously-taught effortful ER strategy, in the form of a goal intention (e.g., try to take a detached perspective), or a more automatic ER strategy, in the form of an implementation intention (e.g., "If I see something disgusting, then I will think these are just pixels on the screen!"), to regulate their emotional response. Whereas goal intention ER strategies were associated with activation of brain areas previously reported to be involved in effortful ER (including dorsolateral prefrontal cortex), ER strategies based on an implementation intention strategy were associated with activation of right inferior frontal gyrus and ventro-parietal cortex, which may reflect the attentional control processes automatically captured by the cue for action contained within the implementation intention. Goal intentions were also associated with less effective modulation of left amygdala, supporting the increased efficacy of ER under implementation intention instructions, which showed coupling of orbitofrontal cortex and amygdala. The findings support previous behavioural studies in suggesting that forming an implementation intention enables people to enact goal-directed responses with less effort and more efficiency. PMID- 25798825 TI - Two novel vocalizations are used by veeries (Catharus fuscescens) during agonistic interactions. AB - Avian vocalizations are common examples of the complex signals used by animals to negotiate during agonistic interactions. In this study, we used two playback experiments to identify agonistic signals in a songbird species with several acoustically complex songs and calls, the veery. In the first experiment, we compared veery singing behavior in response to simulated territorial intrusions including playback of three variations of veery song: 1) song alone as a control, 2) songs with added whisper calls, and 3) songs with introductory notes removed. In the second experiment, we used multimodal stimuli including songs, whisper calls and songs with introductory notes removed, along with a robotic veery mount. Focal males readily responded to all of the playback stimuli, approached the speaker and/or robotic mount, and vocalized. Male veeries gave more whisper calls, and sang more songs without the introductory note in response to all types of playback. However, veeries responded similarly to all types of stimuli presented, and they failed to physically attack the robotic mount. These results indicate that rival veeries use two different types of novel vocalizations: whisper calls and songs lacking the introductory note as agonistic signals, but do not allow us to discern the specific functions of these two vocalizations. PMID- 25798824 TI - Suppression of dual specificity phosphatase I expression inhibits hepatitis C virus replication. AB - It was reported that dual specificity phosphatase 1 (DUSP1) is specifically upregulated in the liver of patients with chronic hetpatitis C virus (HCV) infection who do not respond to peginterferon (PegIFN) treatment. Here, we have investigated the role of DUSP1 in HCV replication in hepatoma cells stably expressing the full HCV replicon (FK). DUSP1 was silenced in cells harboring the FK replicon using a lentiviral vector encoding a DUSP1-specific short hairpin RNA (LV-shDUSP1). We demonstrated that knock-down of DUSP1 significantly inhibited HCV RNA and protein expression. Also, DUSP1 silencing enhanced the expression of phosphorylated signal transducer and activator of transcription 1 (phosho-STAT1) and facilitated the translocation of STAT1 into the nucleus. The mRNA expression levels of myxovirus resistance protein A (MxA), 2'-5'-oligoadenylate synthetase 1 (OAS1), ISG15 ubiquitin-like modifier (ISG15), chemokine C-X-C motif ligand 10 (CXCL10), and ubiquitin-specific protease 18 (USP18) were also accelerated by silencing of DUSP1. Furthermore, combined with the IFN treatment, DUSP1 silencing synergistically decreased the levels of HCV RNA. These results suggest that suppression of DUSP1 expression enhances phosphorylation and nuclear translocation of STAT1, resulting in increasing expression of interferon stimulated genes (ISGs), which synergizes with IFN's antiviral effect against HCV. In conclusion, DUSP1 is involved in the antiviral host defense mechanism against a HCV infection and thus DUSP1 might be a target to treat chronic HCV infection. PMID- 25798826 TI - The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPARalpha. AB - Long-term moderate consumption of red wine is associated with a reduced risk of developing lifestyle-related diseases such as cardiovascular disease and cancer. Therefore, resveratrol, a constituent of grapes and various other plants, has attracted substantial interest. This study focused on one molecular target of resveratrol, the peroxisome proliferator activated receptor alpha (PPARalpha). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPARalpha; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPARalpha by performing a docking mode simulation and examining the structure-activity relationships of various polyphenols. The results of experiments using the crystal structure of the PPARalpha ligand-binding domain and an analysis of the activation of PPARalpha by a resveratrol analog 4-phenylazophenol (4-PAP) in vivo indicate that the 4'-hydroxyl group of resveratrol is critical for the direct activation of PPARalpha. Activation of PPARalpha by 5 MUM resveratrol was enhanced by rolipram, an inhibitor of phosphodiesterase (PDE) and forskolin, an activator of adenylate cyclase. We also found that resveratrol has a higher PDE inhibitory activity (IC50 = 19 MUM) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC50 = 27-28 MUM), both of which has only 4'-hydroxyl group, indicating that this 4' hydroxyl group of resveratrol is not sufficient for the inhibition of PDE. This result is consistent with that 10 MUM resveratrol has a higher agonistic activity of PPARalpha than these analogs, suggesting that there is a feedforward activation loop of PPARalpha by resveratrol, which may be involved in the long term effects of resveratrol in vivo. PMID- 25798827 TI - Genetic association of SNPs near ATOH7, CARD10, CDKN2B, CDC7 and SIX1/SIX6 with the endophenotypes of primary open angle glaucoma in Indian population. AB - Primary open angle glaucoma (POAG) belonging to a group of optic neuropathies, result from interaction between genetic and environmental factors. Study of associations with quantitative traits (QTs) is one of the successful strategies to understand the complex genetics of POAG. The current study attempts to explore the association of variations near/in genes like ATOH7, SIX1/SIX6 complex, CDKN2B, CARD10, and CDC7 with POAG and its QTs including vertical cup to disc ratio (VCDR), central corneal thickness (CCT), intra ocular pressure (IOP), and axial length (AL). Case-control study design was carried out in a sample size of 97 POAG cases and 371 controls from South India. Model-based (additive, recessive, dominant) association of the genotypes and their interaction was carried out between cases and controls using chi-square, linear and logistic regression methods. Nominal significance (P<0.05) was observed for QTs like i) VCDR with SNPs rs1900004 (ATOH7); rs1192415 (CDC7); rs10483727 (SIX1/SIX6), rs9607469 (CARD10); ii) CCT with rs1192415; iii) IOP with rs1900004 and iv) AL with rs1900004 and rs1063192 (CDKN2B). We were able to replicate previously known interactions between ATOH7-SIX6 and SIX6-CDKN2B along with few novel interactions between ATOH7-CDC7 and SIX6 with genes including CARD10 and CDC7. In summary, our results suggest that a probable interaction among the candidate genes for QTs, play a major role in determining the individual's susceptibility to POAG. PMID- 25798828 TI - The carbapenem inactivation method (CIM), a simple and low-cost alternative for the Carba NP test to assess phenotypic carbapenemase activity in gram-negative rods. AB - A new phenotypic test, called the Carbapenem Inactivation Method (CIM), was developed to detect carbapenemase activity in Gram-negative rods within eight hours. This method showed high concordance with results obtained by PCR to detect genes coding for the carbapenemases KPC, NDM, OXA-48, VIM, IMP and OXA-23. It allows reliable detection of carbapenemase activity encoded by various genes in species of Enterobacteriaceae (e.g., Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae), but also in non-fermenters Pseudomonas aeruginosa and Acinetobacter baumannii. The CIM was shown to be a cost-effective and highly robust phenotypic screening method that can reliably detect carbapenemase activity. PMID- 25798829 TI - Skeletal lesions in primary hyperparathyroidism. AB - BACKGROUND: Osteitis fibrosa cystica (OFC), a relatively rare skeletal disorder caused by excess parathyroid hormone, is often misdiagnosed as a neoplasm. A summary of the diagnostic procedures and treatment protocols, especially the indications for orthopedic surgery, is helpful to avoid overtreatment. METHODS: Eight patients from the Orthopedic Department of Qilu Hospital of Shandong University diagnosed with OFC caused by primary hyperparathyroidism were treated, and the clinical manifestations, biochemical and radiography examination findings, surgeries and prognoses were recorded. RESULTS: All cases (5 female and 3 male) were admitted to our department with the complaint of bone pain (5/8) or fracture after mild trauma (3/8). Biochemical screening revealed hypercalcemia and high parathyroid hormone of varying levels. Two cases were misdiagnosed as primary bone lesion and metastasis. All cases were treated with parathyroidectomy and experienced spontaneous and progressive regression of the boney disease. Four cases underwent orthopedic surgery. Bone biopsies were necessary to exclude malignant tumors, especially with orthopedic procedures. CONCLUSIONS: OFC can easily be misdiagnosed in orthopedic patients because of a lack of radiological and histologic specificity. Reaching the correct diagnosis requires a combination of clinical manifestations, routine biochemical screenings, radiographic examinations of bone and parathyroid and bone biopsy. It is generally acknowledged that parathyroidectomy is effective, but orthopedic surgery is sometimes necessary after a correct diagnosis and parathyroidectomy. However, the indications for orthopedic surgery must be strictly controlled to avoid overtreatment. PMID- 25798830 TI - Disequilibrium syndrome and prevention in nonhemodialysis patients. AB - Disequilibrium syndrome (DS) is a central nervous system disorder described in hemodialysis (HD) patients. The authors present 4 cases of elevated blood urea nitrogen (BUN); the first patient passed away from suspected DS, whereas the other 3 patients were identified as having a high risk of developing DS on the basis of their BUN. The authors tried to lower their BUN slowly and prevent rapid correction by different methods. This is the first study in which DS has been studied in patients who are not on HD, and methods are described to identify and prevent DS in such patients. They also review the existing literature on the pathogenesis of DS and highlight the importance of recognizing this syndrome in non-HD patients, while suggesting some innovative ways to prevent it. PMID- 25798831 TI - A Patient With BCR-ABL and JAK2 V617F Double-Positive Myeloproliferative Neoplasm With Overlapping Clinical Phenotypes. PMID- 25798832 TI - Morphine-Induced Gastroparesis. PMID- 25798833 TI - The miR-200 family and the miR-183~96~182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers. AB - Metastatic lung cancer is one of the most lethal forms of cancer and molecular pathways driving metastasis are still not clearly elucidated. Metastatic cancer cells undergo an epithelial-mesenchymal transition (EMT) where they lose their epithelial properties and acquire a migratory and invasive phenotype. Here we identify that the expression of microRNAs from the miR-200 family and the miR 183~96~182 cluster are significantly co-repressed in non-small cell lung cancer cell lines and primary tumors from multiple TCGA dataset with high EMT scores. Ectopic expression of the miR-183~96~182 cluster inhibited cancer cell migration and invasion, whereas its expression was tightly modulated by miR-200. We identified Foxf2 as a common, novel and direct target of both these microRNA families. Foxf2 expression tightly correlates with the transcription factor Zeb1 and is elevated in mesenchymal-like metastatic lung cancer cells. Foxf2 expression induced robust EMT, migration, invasion and metastasis in lung cancer cells, whereas Foxf2 inhibition significantly repressed these phenotypes. We also demonstrated that Foxf2 transcriptionally represses E-cadherin and miR-200, independent of Zeb1, to form a double-negative feedback loop. We, therefore, identified a novel mechanism whereby the miR-200 family and the miR-183~96~182 cluster inhibit lung cancer invasion and metastasis by targeting Foxf2. PMID- 25798834 TI - Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors. AB - We have identified a new t(1;21)(p32;q22) chromosomal translocation in a MDS/AML patient that results in expression of an aberrant C-terminally truncated RUNX1 protein lacking several regulatory domains. As similar truncated RUNX1 proteins are generated by genetic aberrations including chromosomal translocations and point mutations, we used the t(1;21)(p32;q22) chromosomal translocation as a model to explore whether C-terminally truncated RUNX1 proteins trigger effects similar to those induced by well-characterized leukemogenic RUNX1 fusion genes. In vitro analysis of transduced human hematopoietic/progenitor stem cells showed that truncated RUNX1 proteins increase proliferation and self-renewal and disrupt the differentiation program by interfering with RUNX1b. These effects are similar to but milder than those induced by the RUNX1/ETO fusion protein. GSEA analysis confirmed similar altered gene expression patterns in the truncated RUNX1 and RUNX1/ETO models, with both models showing alterations in genes involved in self renewal and leukemogenesis, including homeobox genes, primitive erythroid genes and leukemogenic transcription factors. We propose that C-terminally truncated RUNX1 proteins can contribute to leukemogenesis in a similar way to RUNX1 fusion genes but through a milder phenotype. PMID- 25798835 TI - YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression. AB - Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces the expression of epidermal growth factor (EGF) receptors (EGFR, ERBB3) and production of EGF like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, whereas knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF & NRGs/ERBBs/YAP/HBEGF & NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression. PMID- 25798836 TI - Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes. AB - The mammalian homolog of Drosophila diaphanous (mDia), actin nucleator, has been known to participate in the process of invasion and metastasis of cancer cells via regulating a number of actin-related biological processes. We have previously reported that tumor suppressor TIS21(/BTG2/Pc3) (TIS21) inhibits invadopodia formation by downregulating reactive oxygen species (ROS) in MDA-MB-231 cells. We herein report that TIS21(/BTG2/Pc3) downregulates diaphanous-related formin (DRF) expression via reducing NADPH oxidase 4 (Nox4)-derived ROS generation by Akt1 activation and subsequently impairs invasion activity of the highly invasive breast cancer cells. Knockdown of Akt1 by RNA interference recovered the TIS21(/BTG2/Pc3)-inhibited F-actin remodeling and ROS generation by recovering Nox4 expression. Furthermore, Sp1-mediated Nox4 transcription was downregulated by TIS21(/BTG2/Pc3)-Akt1 signals, leading to the inhibition of cancer cell invasion via F-actin remodeling by mDia genes. To our best knowledge, this is the first study to show that TIS21(/BTG2/Pc3)-Akt1 inhibited Sp1-Nox4-ROS cascade, subsequently reducing invasion activity via inhibition of mDia family genes. PMID- 25798837 TI - Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. AB - The cross-talk between ovarian cancer (OvCa) cells and the metastatic microenvironment is an essential determinant of successful colonization. MicroRNAs (miRNAs) have several critical roles during metastasis; however, the role of microenvironmental cues in the regulation of miRNAs in metastasizing cancer cells has not been studied. Using a three-dimensional culture model that mimics the human omentum, one of the principal sites of OvCa metastasis, we identified and characterized the microenvironment-induced downregulation of a tumor suppressor miRNA, miR-193b, in metastasizing OvCa cells. The direct interaction of the OvCa cells with mesothelial cells, which cover the surface of the omentum, caused a DNA methyltransferase 1-mediated decrease in the expression of miR-193b in the cancer cells. The reduction in miR-193b enabled the metastasizing cancer cells to invade and proliferate into human omental pieces ex vivo and into the omentum of a mouse xenograft model of OvCa metastasis. The functional effects of miR-193b were mediated, in large part, by the concomitant increased expression of its target, urokinase-type plasminogen activator, a known tumor-associated protease. These findings link paracrine signals from the microenvironment to the regulation of a key miRNA in cancer cells. Targeting miR 193b, which is essential for metastatic colonization of cancer cells could prove effective in the treatment of OvCa metastasis. PMID- 25798838 TI - An enhanced functional interrogation/manipulation of intracellular signaling pathways with the peptide 'stapling' technology. AB - Specific protein-protein interactions (PPIs) constitute a key underlying mechanism for the presence of a multitude of intracellular signaling pathways, which are essential for the survival of normal and cancer cells. Specific molecular blockers for a crucial PPI would therefore be invaluable tools for an enhanced functional interrogation of the signaling pathway harboring this particular PPI. On the other hand, if a particular PPI is essential for the survival of cancer cells but is absent in or dispensable for the survival of normal cells, its specific molecular blockers could potentially be developed into effective anticancer therapeutics. Due to the flat and extended PPI interface, it would be conceivably difficult for small molecules to achieve an effective blockade, a problem which could be potentially circumvented with peptides or proteins. However, the well-documented proteolytic instability and cellular impermeability of peptides and proteins in general would make their developing into effective intracellular PPI blockers quite a challenge. With the advent of the peptide 'stapling' technology which was demonstrated to be able to stabilize the alpha-helical conformation of a peptide via bridging two neighboring amino acid side chains with a 'molecular staple', a linear parent peptide could be transformed into a stronger PPI blocker with enhanced proteolytic stability and cellular permeability. This review will furnish an account on the peptide 'stapling' technology and its exploitation in efforts to achieve an enhanced functional interrogation or manipulation of intracellular signaling pathways especially those that are cancer relevant. PMID- 25798839 TI - LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines. AB - A hallmark of cancer cells is an activated telomere maintenance mechanism, which allows prolonged survival of the malignant cells. In more than 80% of tumours, telomeres are elongated by the enzyme telomerase, which adds de novo telomere repeats to the ends of chromosomes. Cancer cells are also characterized by expression of active LINE-1 elements (L1s, long interspersed nuclear elements-1). L1 elements are abundant retrotransposons in the eukaryotic genome that are primarily known for facilitating aberrant recombination. Using L1-knockdown (KD), we show for the first time that L1 is critical for telomere maintenance in telomerase-positive tumour cells. The reduced length of telomeres in the L1-KD treated cells correlated with an increased rate of telomere dysfunction foci, a reduced expression of shelterin proteins and an increased rate of anaphase bridges. The decreased telomere length was associated with a decreased telomerase activity and decreased telomerase mRNA level; the latter was increased upon L1 overexpression. L1-KD also led to a decrease in mRNA and protein expression of cMyc and KLF-4, two main transcription factors of telomerase and altered mRNA levels of other stem-cell-associated proteins such as CD44 and hMyb, as well as a corresponding reduced growth of spheroids. The KD of KLF-4 or cMyc decreased the level of L1-ORF1 mRNA, suggesting a specific reciprocal regulation with L1. Thus, our findings contribute to the understanding of L1 as a pathogenicity factor in cancer cells. As L1 is only expressed in pathophysiological conditions, L1 now appears to be target in the rational treatment of telomerase-positive cancer. PMID- 25798840 TI - beta2-AR signaling controls trastuzumab resistance-dependent pathway. AB - Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that beta2-adrenergic receptor (beta2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and beta2-AR affects the bio-behaviors of breast cancer cells, suggesting that the beta2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of beta2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced beta2-AR activation. The data indicate that beta2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that beta-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of beta blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus beta-blocker in Her2-overexpressing breast cancer. PMID- 25798841 TI - Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion. AB - Glioblastomas (GBMs) are aggressive brain tumors that always recur after radiotherapy. Cystine, mainly provided by the system X(c)(-) antiporter, is a requirement for glioma cell synthesis of glutathione (GSH) which has a critical role in scavenging free radicals, for example, after radiotherapy. Thus, we hypothesized that the X(c)(-)-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Here, we show that the catalytic subunit of system X(c)(-), xCT, was uniformly expressed in a panel of 30 human GBM biopsies. SAS treatment significantly reduced cystine uptake and GSH levels, whereas it significantly increased the levels of reactive oxygen species (ROS) in glioma cells in vitro. Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared with controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients. PMID- 25798842 TI - Loss of LKB1 and p53 synergizes to alter fallopian tube epithelial phenotype and high-grade serous tumorigenesis. AB - Liver kinase B1 (LKB1) is a tumor suppressor ubiquitously expressed serine/threonine protein kinase involved in energy metabolism and cellular polarity. In microarray experiments that compared normal tubal epithelium with high-grade serous carcinoma (HGSC), we observed a decrease in LKB1 mRNA expression in HGSC. In this study, we demonstrate that loss of cytoplasmic and nuclear LKB1 protein expression is frequently observed in tubal cancer precursor lesions as well as in both sporadic and hereditary HGSCs compared with other ovarian cancer histotypes. Bi-allelic genomic loss of LKB1 in HGSC did not account for the majority of cases with a decrease in protein expression. In vitro, shLKB1-fallopian tube epithelial (FTE) cells underwent premature cellular arrest and in ex vivo FTE culture, LKB1 loss and p53 mutant synergized to disrupt apical to basal polarity and decrease the number of ciliated cells. Overexpression of cyclin E1 allowed for bypass of LKB1-induced cellular arrest, and increased both proliferation and anchorage-independent growth of transformed FTE cells. These data suggest that LKB1 loss early in ovarian serous tumorigenesis has an integral role in tumor promotion by disrupting apical to basal polarity in the presence of mutated p53 in fallopian tube cells. PMID- 25798843 TI - A novel cysteine cathepsin inhibitor yields macrophage cell death and mammary tumor regression. AB - Although cysteine cathepsins have been identified as key regulators of cancer growth, their specific role in tumor development remains unclear. Recent studies have shown that high activity levels of tumor cathepsins are primarily a result of increased cathepsin activity in cancer-promoting tumor-associated macrophages (TAMs). To further investigate the role of cysteine cathepsin activity in normal and polarized macrophages, we established in vitro and in vivo models of macrophage differentiation and polarization and used a novel cysteine cathepsin inhibitor, GB111-NH2, to block the activity of cathepsins B, L and S. Here we show that in vitro, cysteine cathepsin inhibition yields both apoptosis and proliferation of macrophages, owing to increased oxidative stress. Proteomic analysis of cathepsin- inhibited macrophages demonstrates inhibition of autophagy, suggesting a likely cause of elevated reactive oxygen species (ROS) levels. In vivo models of mammary cancer further show that cathepsin inhibition yields TAM death owing to increased ROS levels. Strikingly, apoptosis in TAMs yields a seemingly cell non-autonomous death of neighboring cancer cells, and regression of the primary growth. These results show that cysteine cathepsin inhibitors can specifically trigger macrophage cell death and may function as an effective anticancer therapy in tumors with high levels of TAMs. PMID- 25798845 TI - Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate. AB - Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10( 13); adjusted p= 2.2 x 10(-3)). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10 6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans. PMID- 25798844 TI - miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes. AB - The miR-200 family promotes the epithelial state by suppressing the Zeb1/Zeb2 epithelial gene transcriptional repressors. To identify other miR-200-regulated genes, we isolated mRNAs bound to transfected biotinylated miR-200c in mouse breast cancer cells. In all, 520 mRNAs were significantly enriched in miR-200c binding at least twofold. Putative miR-200-regulated genes included Zeb2, enriched 3.5-fold in the pull down. However, Zeb2 knockdown does not fully recapitulate miR-200c overexpression, suggesting that regulating other miR-200 targets contributes to miR-200's enhancement of epithelial gene expression. Candidate genes were highly enriched for miR-200c seed pairing in their 3'UTR and coding sequence and for genes that were downregulated by miR-200c overexpression. Epidermal growth factor receptor and downstream MAPK signaling pathways were the most enriched pathways. Genes whose products mediate transforming growth factor (TGF)-beta signaling were also significantly overrepresented, and miR-200 counteracted the suppressive effects of TGF-beta and bone morphogenic protein 2 (BMP-2) on epithelial gene expression. miR-200c regulated the 3'UTRs of 12 of 14 putative miR-200c-binding mRNAs tested. The extent of mRNA binding to miR-200c strongly correlated with gene suppression. Twelve targets of miR-200c (Crtap, Fhod1, Smad2, Map3k1, Tob1, Ywhag/14-3-3gamma, Ywhab/14-3-3beta, Smad5, Zfp36, Xbp1, Mapk12, Snail1) were experimentally validated by identifying their 3'UTR miR-200 recognition elements. Smad2 and Smad5 form a complex with Zeb2 and Ywhab/14-3-3beta and Ywhag/14-3-3gamma form a complex with Snail1. These complexes that repress transcription assemble on epithelial gene promoters. miR 200 overexpression induced RNA polymerase II localization and reduced Zeb2 and Snail1 binding to epithelial gene promoters. Expression of miR-200-resistant Smad5 modestly, but significantly, reduced epithelial gene induction by miR-200. miR-200 expression and Zeb2 knockdown are known to inhibit cell invasion in in vitro assays. Knockdown of each of three novel miR-200 target genes identified here, Smad5, Ywhag and Crtap, also profoundly suppressed cell invasion. Thus, miR 200 suppresses TGF-beta/BMP signaling, promotes epithelial gene expression and suppresses cell invasion by regulating a network of genes. PMID- 25798846 TI - NLRP3 inflammasome activation in dialyzed chronic kidney disease patients. AB - To assess whether NLR pyrin domain-containing protein 3 (NLRP3) inflammasome, a multiprotein complex that mediates the activation of caspase-1 (CASP-1) and pro inflammatory cytokines IL-18 and IL-1beta, could be involved in the chronic inflammatory state observed in chronic kidney disease patients undergoing hemodialysis treatment (CKD-HD), we employed several biomolecular techniques including RT-PCR, western blot, FACS analysis, confocal microscopy and microarray. Interestingly, peripheral blood mononuclear cells from 15 CKD-HD patients showed higher mRNA levels of NLRP3, CASP-1, ASC, IL-1beta, IL-18 and P2X7 receptor compared to 15 healthy subjects. Western blotting analysis confirmed the above results. In particular, active forms of CASP-1, IL1-beta and IL-18 resulted significantly up-regulated in CKD-HD versus controls. Additionally, elevated mitochondrial ROS level, colocalization of NLRP3/ASC/mitochondria in peripheral blood mononuclear cells from CKD-HD patients and down-regulation of CASP-1, IL1-beta and IL-18 protein levels in immune-cells of CKD-HD patients stimulated with LPS/ATP in presence of mitoTEMPO, inhibitor of mitochondrial ROS production, suggested a possible role of this organelle in the aforementioned CKD-associated inflammasome activation. Then, microarray analysis confirmed, in an independent microarray study cohort, that NLRP3 and CASP-1, along with other inflammasome-related genes, were up-regulated in 17 CKD-HD patients and they were able to clearly discriminate these patients from 5 healthy subjects. All together these data showed, for the first time, that NLRP3 inflammasome was activated in uremic patients undergoing dialysis treatment and they suggested that this unphysiological condition could be possibly induced by mitochondrial dysfunction. PMID- 25798847 TI - Access and use of interventions to prevent and treat malaria among pregnant women in Kenya and Mali: a qualitative study. AB - BACKGROUND: Coverage of malaria in pregnancy interventions in sub-Saharan Africa is suboptimal. We undertook a systematic examination of the operational, socio economic and cultural constraints to pregnant women's access to intermittent preventive treatment (IPTp), long-lasting insecticide-treated nets (LLINs) and case management in Kenya and Mali to provide empirical evidence for strategies to improve coverage. METHODS: Focus group discussions (FGDs) were held as part of a programme of research to explore the delivery, access and use of interventions to control malaria in pregnancy. FGDs were held with four sub-groups: non-pregnant women of child bearing age (aged 15-49 years), pregnant women or mothers of children aged <1 year, adolescent women, and men. Content analysis was used to develop themes and sub-themes from the data. RESULTS: Women and men's perceptions of the benefits of antenatal care were generally positive; motivation among women consisted of maintaining a healthy pregnancy, disease prevention in mother and foetus, checking the position of the baby in preparation for delivery, and ensuring admission to a facility in case of complications. Barriers to accessing care related to the quality of the health provider-client interaction, perceived health provider skills and malpractice, drug availability, and cost of services. Pregnant women perceived themselves and their babies at particular risk from malaria, and valued diagnosis and treatment from a health professional, but cost of treatment at health facilities drove women to use herbal remedies or drugs bought from shops. Women lacked information on the safety, efficacy and side effects of antimalarial use in pregnancy. CONCLUSION: Women in these settings appreciated the benefits of antenatal care and yet health services in both countries are losing women to follow-up due to factors that can be improved with greater political will. Antenatal services need to be patient-centred, free-of charge or highly affordable and accountable to the women they serve. PMID- 25798849 TI - Formation of nickel cobalt sulfide ball-in-ball hollow spheres with enhanced electrochemical pseudocapacitive properties. AB - While the synthesis of hollow structures of transition metal oxides is well established, it is extremely challenging to fabricate complex hollow structures for mixed transition metal sulfides. Here we report an anion exchange method to synthesize a complex ternary metal sulfides hollow structure, namely nickel cobalt sulfide ball-in-ball hollow spheres. Uniform nickel cobalt glycerate solid spheres are first synthesized as the precursor and subsequently chemically transformed into nickel cobalt sulfide ball-in-ball hollow spheres. When used as electrode materials for electrochemical capacitors, these nickel cobalt sulfide hollow spheres deliver a specific capacitance of 1,036 F g(-1) at a current density of 1.0 A g(-1). An asymmetric supercapacitor based on these ball-in-ball structures shows long-term cycling performance with a high energy density of 42.3 Wh kg(-1) at a power density of 476 W kg(-1), suggesting their potential application in high-performance electrochemical capacitors. PMID- 25798848 TI - Conjoined use of EM and NMR in RNA structure refinement. AB - More than 40% of the RNA structures have been determined using nuclear magnetic resonance (NMR) technique. NMR mainly provides local structural information of protons and works most effectively on relatively small biomacromolecules. Hence structural characterization of large RNAs can be difficult for NMR alone. Electron microscopy (EM) provides global shape information of macromolecules at nanometer resolution, which should be complementary to NMR for RNA structure determination. Here we developed a new energy term in Xplor-NIH against the density map obtained by EM. We conjointly used NMR and map restraints for the structure refinement of three RNA systems-U2/U6 small-nuclear RNA, genome-packing motif (Psi(CD))2 from Moloney murine leukemia virus, and ribosome-binding element from turnip crinkle virus. In all three systems, we showed that the incorporation of a map restraint, either experimental or generated from known PDB structure, greatly improves structural precision and accuracy. Importantly, our method does not rely on an initial model assembled from RNA duplexes, and allows full torsional freedom for each nucleotide in the torsion angle simulated annealing refinement. As increasing number of macromolecules can be characterized by both NMR and EM, the marriage between the two techniques would enable better characterization of RNA three-dimensional structures. PMID- 25798851 TI - Ecological and geographical analysis of the distribution of the mountain tapir (Tapirus pinchaque) in Ecuador: importance of protected areas in future scenarios of global warming. AB - In Ecuador, Tapirus pinchaque is considered to be critically endangered. Although the species has been registered in several localities, its geographic distribution remains unclear, and the effects of climate change and current land uses on this species are largely unknown. We modeled the ecological niche of T. pinchaque using MaxEnt, in order to assess its potential adaptation to present and future climate change scenarios. We evaluated the effects of habitat loss due by current land use, the ecosystem availability and importance of Ecuadorian System of Protected Areas into the models. The model of environmental suitability estimated an extent of occurrence for species of 21,729 km2 in all of Ecuador, mainly occurring along the corridor of the eastern Ecuadorian Andes. A total of 10 Andean ecosystems encompassed ~98% of the area defined by the model, with herbaceous paramo, northeastern Andean montane evergreen forest and northeastern Andes upper montane evergreen forest being the most representative. When considering the effect of habitat loss, a significant reduction in model area (~17%) occurred, and the effect of climate change represented a net reduction up to 37.86%. However, the synergistic effect of both climate change and habitat loss, given current land use practices, could represent a greater risk in the short-term, leading to a net reduction of 19.90 to 44.65% in T. pinchaque's potential distribution. Even under such a scenarios, several Protected Areas harbor a portion (~36 to 48%) of the potential distribution defined by the models. However, the central and southern populations are highly threatened by habitat loss and climate change. Based on these results and due to the restricted home range of T. pinchaque, its preference for upland forests and paramos, and its small estimated population size in the Andes, we suggest to maintaining its current status as Critically Endangered in Ecuador. PMID- 25798850 TI - Mitotic UV irradiation induces a DNA replication-licensing defect that potentiates G1 arrest response. AB - Cdt1 begins to accumulate in M phase and has a key role in establishing replication licensing at the end of mitosis or in early G1 phase. Treatments that damage the DNA of cells, such as UV irradiation, induce Cdt1 degradation through PCNA-dependent CRL4-Cdt2 ubiquitin ligase. How Cdt1 degradation is linked to cell cycle progression, however, remains unclear. In G1 phase, when licensing is established, UV irradiation leads to Cdt1 degradation, but has little effect on the licensing state. In M phase, however, UV irradiation does not induce Cdt1 degradation. When mitotic UV-irradiated cells were released into G1 phase, Cdt1 was degraded before licensing was established. Thus, these cells exhibited both defective licensing and G1 cell cycle arrest. The frequency of G1 arrest increased in cells expressing extra copies of Cdt2, and thus in cells in which Cdt1 degradation was enhanced, whereas the frequency of G1 arrest was reduced in cell expressing an extra copy of Cdt1. The G1 arrest response of cells irradiated in mitosis was important for cell survival by preventing the induction of apoptosis. Based on these observations, we propose that mammalian cells have a DNA replication-licensing checkpoint response to DNA damage induced during mitosis. PMID- 25798852 TI - Associations between polymorphisms in the NR1D1 gene encoding for nuclear receptor REV-ERBalpha and circadian typologies. AB - Nuclear receptor REV-ERBalpha, a key component of an internal timekeeping system, has been considered to be related to disrupted circadian rhythms and mood disorder. In this study, we aimed to evaluate the relationship between the genotype frequencies of single gene polymorphisms (SNPs) of the NR1D1 gene encoding REV-ERBalpha and circadian typologies. The classification of chronotypes and genotyping of three SNPs (rs2314339, rs2071427, rs12941497) of the NR1D1 gene were conducted in 602 healthy young adults (355 males, 247 females). A significant association was found between the genotypes of rs12941497 and three chronotype categories. These findings support the role of NR1D1 polymorphisms in the regulation of circadian rhythms. PMID- 25798854 TI - Isoquinolone synthesis through S(N)Ar reaction of 2-halobenzonitriles with ketones followed by cyclization. AB - An efficient method for the synthesis of isoquinolones through base KO(t)Bu promoted S(N)Ar reaction of 2-halobenzonitriles with ketones followed by Lewis acid Cu(OAc)2-catalyzed cyclization is described. Isoquinolone derivatives were obtained in satisfactory to good yields. PMID- 25798853 TI - C:N:P stoichiometry and leaf traits of halophytes in an arid saline environment, northwest China. AB - Salinization is an important and increasingly prevalent issue which has broad and profound effects on plant survival and distribution pattern. To understand the patterns and potential drivers of leaf traits in saline environments, we determined the soil properties, leaf morphological traits (specific leaf area, SLA, and leaf dry matter content, LDMC), leaf chemical traits (leaf carbon, C, nitrogen, N, and phosphorus, P, stoichiometry) based on 142 observations collected from 23 sites in an arid saline environment, which is a vulnerable ecosystem in northwest China. We also explored the relationships among leaf traits, the responses of leaf traits, and plant functional groups (herb, woody, and succulent woody) to various saline environments. The arid desert halophytes were characterized by lower leaf C and SLA levels, higher N, but stable P and N:P. The leaf morphological traits were correlated significantly with the C, N, and P contents across all observations, but they differed within each functional group. Succulent woody plants had the lowest leaf C and highest leaf N levels among the three functional groups. The growth of halophytes might be more limited by N rather than P in the study area. GLM analysis demonstrated that the soil available nutrients and plant functional groups, but not salinity, were potential drivers of leaf C:N:P stoichiometry in halophytes, whereas species differences accounted for the largest contributions to leaf morphological variations. Our study provides baseline information to facilitate the management and restoration of arid saline desert ecosystem. PMID- 25798855 TI - Over a decade of neuroimaging studies of placebo analgesia in humans: what is next? PMID- 25798856 TI - No evidence of enemy release in pathogen and microbial communities of common wasps (Vespula vulgaris) in their native and introduced range. AB - When invasive species move to new environments they typically experience population bottlenecks that limit the probability that pathogens and parasites are also moved. The invasive species may thus be released from biotic interactions that can be a major source of density-dependent mortality, referred to as enemy release. We examined for evidence of enemy release in populations of the common wasp (Vespula vulgaris), which attains high densities and represents a major threat to biodiversity in its invaded range. Mass spectrometry proteomic methods were used to compare the microbial communities in wasp populations in the native (Belgium and England) and invaded range (Argentina and New Zealand). We found no evidence of enemy release, as the number of microbial taxa was similar in both the introduced and native range. However, some evidence of distinctiveness in the microbial communities was observed between countries. The pathogens observed were similar to a variety of taxa observed in honey bees. These taxa included Nosema, Paenibacillus, and Yersina spp. Genomic methods confirmed a diversity of Nosema spp., Actinobacteria, and the Deformed wing and Kashmir bee viruses. We also analysed published records of bacteria, viruses, nematodes and fungi from both V. vulgaris and the related invader V. germanica. Thirty-three different microorganism taxa have been associated with wasps including Kashmir bee virus and entomophagous fungi such as Aspergillus flavus. There was no evidence that the presence or absence of these microorganisms was dependent on region of wasp samples (i.e. their native or invaded range). Given the similarity of the wasp pathogen fauna to that from honey bees, the lack of enemy release in wasp populations is probably related to spill-over or spill-back from bees and other social insects. Social insects appear to form a reservoir of generalist parasites and pathogens, which makes the management of wasp and bee disease difficult. PMID- 25798857 TI - Assessment of the effects of body weight unloading on overground gait biomechanical parameters. AB - BACKGROUND: Gait rehabilitation with body weight unloading is a common method of gait rehabilitation for clinical subjects with neurological and musculoskeletal impairments. However, the efficiency of this method was hard to assess given the confounding variables walking modality (treadmill vs. overground) and subjects' inability to maintain a comfortable speed when pulling a body weight unloading system by which they were suspended. By controlling the gait modality (overground) and devising a mechanical device that pulled the system at a constant speed, this study could examine the unique effects of body weight unloading on the biomechanical parameters of healthy subjects walking overground at comfortable speed. METHODS: Ten healthy subjects were instructed to walk overground under a control (no suspension vest) and three (0%, 15%, 30%) body weight unloading experimental conditions. Hip, knee and ankle spatiotemporal, kinematic, and kinetic measures were recorded for all conditions (six trials per condition). FINDINGS: ANOVA showed no changes in cadence, speed and stride length, a reduction in double limb support and increase in single limb support. Pairwise comparisons of gait parameters under 0%,15% and 30% body weight unloading conditions indicated significant reductions in lower joint kinematics and kinetics with increased body weight unloading. Additionally, despite changes in the peak values of kinematic and kinetic measures, the curvature patterns remained unchanged. INTERPRETATION: This study shows that overground gait with up to 30% body weight unloading reduces joint loads without modifying gait curvature patterns or the plantarflexion angle. Several clinical applications for gait reeducation conducted in situ with unloading are enumerated. PMID- 25798859 TI - X-ray crystal structures of Escherichia coli RNA polymerase with switch region binding inhibitors enable rational design of squaramides with an improved fraction unbound to human plasma protein. AB - Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human plasma protein from below minimum detection levels, i.e., <1% to 4-6%, while retaining biochemical potency. Since in vitro antimicrobial activity against an efflux negative strain of Haemophilus influenzae was 4- to 8-fold higher, the combined improvement was at least 20- to 60-fold. Cocrystal structures of Escherichia coli RNA polymerase with two key squaramides showed displacement of the switch 2, predicted to interfere with the conformational change of the clamp domain and/or with binding of template DNA, a mechanism akin to that of natural product myxopyronin. Furthermore, the structures confirmed the chemical features required for biochemical potency. The terminal isoxazole and benzyl rings bind into distinct relatively narrow, hydrophobic pockets, and both are required for biochemical potency. In contrast, the linker composed of squarate and piperidine accesses different conformations in their respective cocrystal structures with RNA polymerase, reflecting its main role of proper orientation of the aforementioned terminal rings. These observations further explain the tolerance of hydrophilic substitutions in the linker region that was exploited to improve the fraction unbound to human plasma protein while retaining biochemical potency. PMID- 25798860 TI - Hepatic expression of detoxification enzymes is decreased in human obstructive cholestasis due to gallstone biliary obstruction. AB - BACKGROUND & AIMS: Levels of bile acid metabolic enzymes and membrane transporters have been reported to change in cholestasis. These alterations (e.g. CYP7A1 repression and MRP4 induction) are thought to be adaptive responses that attenuate cholestatic liver injury. However, the molecular mechanisms of these adaptive responses in human obstructive cholestasis due to gallstone biliary obstruction remain unclear. METHODS: We collected liver samples from cholestatic patients with biliary obstruction due to gallstones and from control patients without liver disease (n = 22 per group). The expression levels of bile acid synthetic and detoxification enzymes, membrane transporters, and the related nuclear receptors and transcriptional factors were measured. RESULTS: The levels of bile acid synthetic enzymes, CYP7B1 and CYP8B1, and the detoxification enzyme CYP2B6 were increased in cholestatic livers by 2.4-fold, 2.8-fold, and 1.9-fold, respectively (p<0.05). Conversely, the expression levels of liver detoxification enzymes, UGT2B4/7, SULT2A1, GSTA1-4, and GSTM1-4, were reduced by approximately 50% (p<0.05) in human obstructive cholestasis. The levels of membrane transporters, OSTbeta and OCT1, were increased 10.4-fold and 1.8-fold, respectively, (p<0.05), whereas those of OSTalpha, ABCG2 and ABCG8 were all decreased by approximately 40%, (p<0.05) in human cholestatic livers. Hepatic nuclear receptors, VDR, HNF4alpha, RXRalpha and RARalpha, were induced (approximately 2.0-fold, (p<0.05) whereas FXR levels were markedly reduced to 44% of control, (p<0.05) in human obstructive cholestasis. There was a significantly positive correlation between the reduction in FXR mRNA and UGT2B4/7, SULT2A1, GSTA1, ABCG2/8 mRNA levels in livers of obstructive cholestatic patients (p<0.05). CONCLUSIONS: The levels of hepatic detoxification enzymes were significantly decreased in human obstructive cholestasis, and these decreases were positively associated with a marked reduction of FXR levels. These findings are consistent with impaired detoxification ability in human obstructive cholestasis. PMID- 25798862 TI - Improved characterization of EV preparations based on protein to lipid ratio and lipid properties. AB - In recent years the study of extracellular vesicles has gathered much scientific and clinical interest. As the field is expanding, it is becoming clear that better methods for characterization and quantification of extracellular vesicles as well as better standards to compare studies are warranted. The goal of the present work was to find improved parameters to characterize extracellular vesicle preparations. Here we introduce a simple 96 well plate-based total lipid assay for determination of lipid content and protein to lipid ratios of extracellular vesicle preparations from various myeloid and lymphoid cell lines as well as blood plasma. These preparations included apoptotic bodies, microvesicles/microparticles, and exosomes isolated by size-based fractionation. We also investigated lipid bilayer order of extracellular vesicle subpopulations using Di-4-ANEPPDHQ lipid probe, and lipid composition using affinity reagents to clustered cholesterol (monoclonal anti-cholesterol antibody) and ganglioside GM1 (cholera toxin subunit B). We have consistently found different protein to lipid ratios characteristic for the investigated extracellular vesicle subpopulations which were substantially altered in the case of vesicular damage or protein contamination. Spectral ratiometric imaging and flow cytometric analysis also revealed marked differences between the various vesicle populations in their lipid order and their clustered membrane cholesterol and GM1 content. Our study introduces for the first time a simple and readily available lipid assay to complement the widely used protein assays in order to better characterize extracellular vesicle preparations. Besides differentiating extracellular vesicle subpopulations, the novel parameters introduced in this work (protein to lipid ratio, lipid bilayer order, and lipid composition), may prove useful for quality control of extracellular vesicle related basic and clinical studies. PMID- 25798863 TI - Terms of endearment? PMID- 25798861 TI - Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity. AB - GABA transporters control extracellular GABA, which regulates the key aspects of neuronal and network behaviour. A prevailing view is that modest neuronal depolarization results in GABA transporter type-1 (GAT-1) reversal causing non vesicular GABA release into the extracellular space during intense network activity. This has important implications for GABA uptake-targeting therapies. Here we combined a realistic kinetic model of GAT-1 with experimental measurements of tonic GABAA receptor currents in ex vivo hippocampal slices to examine GAT-1 operation under varying network conditions. Our simulations predict that synaptic GABA release during network activity robustly prevents GAT-1 reversal. We test this in the 0 Mg(2+) model of epileptiform discharges using slices from healthy and chronically epileptic rats and find that epileptiform activity is associated with increased synaptic GABA release and is not accompanied by GAT-1 reversal. We conclude that sustained efflux of GABA through GAT-1 is unlikely to occur during physiological or pathological network activity. PMID- 25798864 TI - The new decree "troncalidad". PMID- 25798865 TI - Urology at the European university: adaptations to the Bologna Plan. The model of the Autonomous University of Madrid. AB - The fundamental objective of the Convergence Plan of Bologna is to normalize, harmonize and standardize the teaching of medicine in European medical schools by implementing a similar curriculum. This objective assumes the presence of Urology as a university discipline in all European medical schools. At the same time, the teaching techniques and subject distributions have been modified, emphasizing practical teaching and active participation of the student in the acquisition of expertise and skills. This approach enhances the curricular presence of Urology and requires increased dedication from the teaching staff. These staff members, with limited face-to-face and classroom time, must inform and educate medical students on the broad healthcare commitment of urology as a surgical/medical specialty. The adaptation of the numerous European medical schools to the Bologna Plan raises a number of problems that can be easily overcome, as can be seen in the plan designed by the Faculty of Medicine at the Universidad Autonoma de Madrid. PMID- 25798866 TI - Fabrication of enzyme-immobilized halloysite nanotubes for affinity enrichment of lipase inhibitors from complex mixtures. AB - Lipase is the key enzyme for catalyzing triglyceride hydrolysis in vivo, and lipase inhibitors have been used in the management of obesity. We present the first report on the use of lipase-adsorbed halloysite nanotubes as an efficient medium for the selective enrichment of lipase inhibitors from natural products. A simple and rapid approach was proposed to fabricate lipase-adsorbed nanotubes through electrostatic interaction. Results showed that more than 85% lipase was adsorbed into nanotubes in 90 min, and approximately 80% of the catalytic activity was maintained compared with free lipase. The specificity and reproducibility of the proposed approach were validated by screening a known lipase inhibitor (i.e., orlistat) from a mixture that contains active and inactive compounds. Moreover, we applied this approach with high performance liquid chromatography-mass spectrometry technique to screen lipase inhibitors from the Magnoliae cortex extract, a medicinal plant used for treating obesity. Two novel biphenyl-type natural lipase inhibitors magnotriol A and magnaldehyde B were identified, and their IC50 values were determined as 213.03 and 96.96 MUM, respectively. The ligand-enzyme interactions of magnaldehyde B were further investigated by molecular docking. Our findings proved that enzyme-adsorbed nanotube could be used as a feasible and selective affinity medium for the rapid screening of enzyme inhibitors from complex mixtures. PMID- 25798867 TI - Peak distortions arising from large-volume injections in supercritical fluid chromatography. AB - Preparative separations in supercritical fluid chromatography (SFC) involve the injection of large volumes of the solute. In SFC, the mobile phase is typically high pressure CO2+modifier and the solute to be injected is usually dissolved in the modifier. Two-types of injection methods, modifier-stream and mixed-stream, are common in commercial preparative SFC systems. In modifier-stream injection, the injection is made in the modifier stream which is later mixed with the CO2 stream, while in the mixed-stream injection, the injection is made in a mixed CO2+modifier stream. In this work a systematic experimental and modelling study of the two techniques is reported using single-enantiomers of flurbiprofen on Chiralpak AD-H with CO2+methanol as the mobile phase. While modifier-stream injection shows non-distorted peaks, mixed-stream injection results in severe peak-distortion. By comparing the modelling and experimental results, it is shown that the modifier "plug" introduced in the mixed-stream injection is the primary cause of the peak distortions. The experimental results also point to the possible existence of viscous fingering which contributes to further peak distortion. PMID- 25798868 TI - Asymmetric flow field-flow fractionation of manufactured silver nanoparticles spiked into soil solution. AB - Manufactured metallic silver nanoparticles (AgNP) are intensively utilized in consumer products and this will inevitably lead to their release to soils. To assess the environmental risks of AgNP in soils, quantification of both their concentration and size in soil solution is essential. We developed a methodology consisting of asymmetric flow field-flow fractionation (AF4) in combination with on-line detection by UV-vis spectroscopy and off-line HR-ICP-MS measurements to quantify the concentration and size of AgNP, coated with either citrate or polyvinylpyrrolidone (PVP), in water extracts of three different soils. The type of mobile phase was a critical factor in the fractionation of AgNP by AF4. In synthetic systems, fractionation of a series of virgin citrate- and PVP-coated AgNP (10-90 nm) with reasonably high recoveries could only be achieved with ultrahigh purity water as a mobile phase. For the soil water extracts, 0.01% (w:v) sodium dodecyl sulfate (SDS) at pH 8 was the key to a successful fractionation of the AgNP. With SDS, the primary size of AgNP in all soil water extracts could be determined by AF4, except for PVP-coated AgNP when clay colloids were present. The PVP-coated AgNP interacted with colloidal clay minerals, leading to an overestimation of their primary size. Similar interactions between PVP-coated AgNP and clay colloids can take place in the environment and facilitate their transport in soils, aquifers, and surface waters. In conclusion, AF4 in combination with UV-vis spectroscopy and HR-ICP-MS measurements is a powerful tool to characterize AgNP in soil solution if the appropriate mobile phase is used. PMID- 25798869 TI - The quantitative impact of the mesopore size on the mass transfer mechanism of the new 1.9 MUm fully porous Titan-C18 particles II--analysis of biomolecules. AB - The kinetic performances of 3.0 * 100 mm columns packed with 1.9 MUm Titan-C18 particles with average mesopore sizes of 80 A and 120 A were investigated quantitatively for the analysis of biomolecules. Large mesopores are expected to speed up the rate of diffusivity of high-molecular-weight compounds across the stationary phase and to generate higher plate counts at high velocities. The mass transfer mechanism of bradykinin acetate salt (1060 Da) and insulin (5733 Da) was determined over a range of flow rates from 0.025 to 1.0 mL/min. The pore diffusivities of these two biomolecules were accurately measured from the peak parking method. Even though the gain in column efficiency was not found significant for small molecules such as valerophenone (162 Da), enlarging the average pore size from 80 to 120 A induces a measurable diminution of the reduced plate height, h, of bradykinin (from 17 to 11 or -35% at a reduced velocity of 50) and a significant reduction for insulin (from 43 to 12 or -72% at a reduced velocity of 90). Remarkably, while the increase of the column efficiency for bradykinin is consistent with a faster diffusivity of bradykinin across the 120 A Titan-C18 particles, the higher column efficiencies measured for insulin are mostly due to a faster absorption kinetics into the 120 A than that into the 80 A Titan-C18 particles. This result is supported by the fact that the effective pore diffusivity of insulin is even slightly smaller across the 120 A than that across the 80 A 1.9MUm Titan-C18 particles. PMID- 25798870 TI - Small heat-shock proteins, IbpAB, protect non-pathogenic Escherichia coli from killing by macrophage-derived reactive oxygen species. AB - Many intracellular bacterial pathogens possess virulence factors that prevent detection and killing by macrophages. However, similar virulence factors in non pathogenic bacteria are less well-characterized and may contribute to the pathogenesis of chronic inflammatory conditions such as Crohn's disease. We hypothesize that the small heat shock proteins IbpAB, which have previously been shown to reduce oxidative damage to proteins in vitro and be upregulated in luminal non-pathogenic Escherichia strain NC101 during experimental colitis in vivo, protect commensal E. coli from killing by macrophage-derived reactive oxygen species (ROS). Using real-time PCR, we measured ibpAB expression in commensal E. coli NC101 within wild-type (wt) and ROS-deficient (gp91phox(-/-)) macrophages and in NC101 treated with the ROS generator paraquat. We also quantified survival of NC101 and isogenic mutants in wt and gp91phox(-/-) macrophages using gentamicin protection assays. Similar assays were performed using a pathogenic E. coli strain O157:H7. We show that non-pathogenic E. coli NC101inside macrophages upregulate ibpAB within 2 hrs of phagocytosis in a ROS dependent manner and that ibpAB protect E. coli from killing by macrophage derived ROS. Moreover, we demonstrate that ROS-induced ibpAB expression is mediated by the small E. coli regulatory RNA, oxyS. IbpAB are not upregulated in pathogenic E. coli O157:H7 and do not affect its survival within macrophages. Together, these findings indicate that ibpAB may be novel virulence factors for certain non-pathogenic E. coli strains. PMID- 25798872 TI - Measuring thought content valence after a breakup: Development of the Positive and Negative Ex-Relationship Thoughts (PANERT) scale. AB - The end of a romantic relationship is a common and serious presenting concern among clients at university counseling centers. Researchers have highlighted the need to understand the nature of thoughts about an ex-relationship, because they may lead to unique clinical interventions. One aspect of thought that may be clinically relevant is content valence, or the positive or negative emotions associated with the content of the thought. Unfortunately, content valence has not been addressed in the romantic relationship dissolution literature. To address this omission, we developed the 12-item Positive and Negative Ex Relationship Thoughts (PANERT) scale across 4 samples. In Sample 1 (n = 475), exploratory factor analyses demonstrated a multidimensional scale with 2 factors: positive content valence and negative content valence. Sample 2 (n = 509) and Sample 3 (n = 291) confirmed the factor structure in college and community samples. Internal consistencies ranged from .88-.94 for positive content valence and from .87-.94 for negative content valence. In Sample 4 (n = 133), construct validity was supported, with the PANERT factors uniquely predicting breakup distress, relationship preoccupation, depression, loss of self-concept, rediscovery of self-concept, negative emotional adjustment, and positive emotional adjustment. Further, the direction of these relationships suggest that positive thought content valence may be consistently maladaptive to recovery from an ex-relationship, and negative thought content valence may have maladaptive and adaptive features. Implications for future research and practice are discussed. PMID- 25798873 TI - A comprehensive meta-reanalysis of the robustness of the experience-accuracy effect in clinical judgment. AB - Experience is one of the most commonly studied variables in clinical judgment research. In a meta-analysis of research from 1970 to 1996 of judgments made by 4,607 participants from 74 studies, Spengler, White, AEgisdottir, Maugherman, Anderson, et al. (2009) found an experience-accuracy fixed effect of d = .121 (95% CI [.06, .18]), indicating that with more experience, counseling and other psychologists obtain only modest gains in decision-making accuracy. We sought to conduct a more rigorous assessment of the experience-accuracy effect by synthesizing 40 years of research from 1970 to 2010, assessing the same and additional moderators, including subgroup analyses of extremes of experience, and conducting a sensitivity analysis. The judgments formed by 11,584 clinicians from 113 studies resulted in a random effects d of .146 (95% CI [.08, .21]), reflecting the robustness of only a small impact of experience on decision-making accuracy. The sensitivity analysis revealed that the effect is consistent across analysis and methodological considerations. Mixed effects metaregression revealed no statistically significant relation between 40 years of time and the experience accuracy effect. A cumulative meta-analysis indicated that the experience accuracy effect stabilized in the literature in the year 1999, after the accumulation of 82 studies, with no appreciable change since. We assessed a broader range of experience comparing no experience to some experience and comparing nonexperts with experts, and for differences as a function of decision making based on psychological tests; however, these and most other moderators were not significant. Implications are discussed for clinical decision-making research, training, and practice. PMID- 25798871 TI - Genes expressed in grapevine leaves reveal latent wood infection by the fungal pathogen Neofusicoccum parvum. AB - Some pathogenic species of the Botryosphaeriaceae have a latent phase, colonizing woody tissues while perennial hosts show no apparent symptoms until conditions for disease development become favorable. Detection of these pathogens is often limited to the later pathogenic phase. The latent phase is poorly characterized, despite the need for non-destructive detection tools and effective quarantine strategies, which would benefit from identification of host-based markers in leaves. Neofusicoccum parvum infects the wood of grapevines and other horticultural crops, killing the fruit-bearing shoots. We used light microscopy and high-resolution computed tomography (HRCT) to examine the spatio-temporal relationship between pathogen colonization and anatomical changes in stem sections. To identify differentially-expressed grape genes, leaves from inoculated and non-inoculated plants were examined using RNA-Seq. The latent phase occurred between 0 and 1.5 months post-inoculation (MPI), during which time the pathogen did not spread significantly beyond the inoculation site nor were there differences in lesion lengths between inoculated and non-inoculated plants. The pathogenic phase occurred between 1.5 and 2 MPI, when recovery beyond the inoculation site increased and lesion lengths of inoculated plants tripled. By 2 MPI, inoculated plants also had decreased starch content in xylem fibers and rays, and increased levels of gel-occluded xylem vessels, the latter of which HRCT revealed at a higher frequency than microscopy. RNA-Seq and screening of 21 grape expression datasets identified 20 candidate genes that were transcriptionally-activated by infection during the latent phase, and confirmed that the four best candidates (galactinol synthase, abscisic acid-induced wheat plasma membrane polypeptide-19 ortholog, embryonic cell protein 63, BURP domain containing protein) were not affected by a range of common foliar and wood pathogens or abiotic stresses. Assuming such host responses are consistent among cultivars, and do not cross react with other trunk/foliar pathogens, these grape genes may serve as host-based markers of the latent phase of N. parvum infection. PMID- 25798874 TI - Mediators between self-criticism and depression: Fear of compassion, self compassion, and importance to others. AB - This study was an investigation of the relationships between internalized self criticism and depression and between comparative self-criticism and depression as these relationships are mediated by the fear of self-compassion, fear of compassion from others, self-compassion, and the perception that one is important to others. To examine these relationships, data were gathered via online survey methods from 206 university students at a large public Midwestern university in the United States. The Self-Criticism/Compassion Mediation Model, in which internalized and comparative self-criticism were both modeled to predict depression, was built and tested via structural equation modeling (SEM). In the presence of 4 competing models, this model effectively modeled relationships among the study variables. In the Self-Criticism/Compassion Mediation Model, the fear of self-compassion, and the perception that one is important to others serially mediated the relationship between comparative self-criticism and depression. Additionally, self-compassion partially mediated both the relationship between internalized self-criticism and depression, and the relationship between comparative self-criticism and depression. Implications include the use of the model as a guide to developing evidence-based practice for highly self-critical, depressed clients. PMID- 25798875 TI - IL-33 and soluble ST2 levels as novel predictors for remission and progression of carotid plaque in early rheumatoid arthritis: A prospective study. AB - OBJECTIVES: To study the association between the baseline IL-33 and soluble ST2 (sST2) levels with disease remission and progression of carotid atherosclerosis in early rheumatoid arthritis (ERA) patients. METHODS: A total of 98 ERA patients were enrolled. Disease activity and the presence of carotid plaque were evaluated at baseline and 12 months later. Plasma IL-33 and sST2 levels were determined using enzyme-linked immunosorbent assay kits. RESULTS: Baseline IL-33 and sST2 levels were associated with inflammatory markers and cardiovascular (CV) risk factors. Overall, 44(45%), 18(18%), and 21(21%) patients achieved remission based on 28-joint disease activity score (DAS28), Boolean, and simplified disease activity score (SDAI) criteria at 12 months, respectively. Patients with detectable IL-33 at baseline were less likely to achieve DAS28 (P = 0.010) and SDAI remission (P = 0.021), while a lower baseline sST2 level was able to predict DAS28, Boolean, and SDAI remission (P = 0.005, 0.001, and <0.001, respectively). Using multivariate analysis, a lower baseline sST2 level independently predict Boolean (OR = 0.789; P = 0.005) and SDAI remission (0.812; P = 0.008). Regarding carotid atherosclerosis, 9/98(9.2%) patients had plaque progression at 12 months. Baseline IL-33 was detectable in 8/9(89%) and 42/83(51%) of patients with and without plaque progression respectively (P = 0.029). Baseline detectable IL-33 was an independent predictor for plaque progression after adjusting for traditional CV risk factors (P = 0.017). CONCLUSIONS: Lower baseline sST2 levels independently predict disease remission and baseline detectable IL-33 independently predicts carotid plaque progression in ERA patients. This study suggests that inflammation induced by the IL-33/ST2 axis may play a significant role in the development of cardiovascular disease in RA. PMID- 25798876 TI - Analysis of river health variation under the background of urbanization based on entropy weight and matter-element model: A case study in Huzhou City in the Yangtze River Delta, China. AB - Maintaining the health of the river ecosystem is an essential ecological and environmental guarantee for regional sustainable development and one of the basic objectives in water resource management. With the rapid development of urbanization, the river health situation is deteriorating, especially in urban areas. The river health evaluation is a complex process that involves various natural and social components; eight eco-hydrological indicators were selected to establish an evaluation system, and the variation of river health status under the background of urbanization was explored based on entropy weight and matter element model. The comprehensive correlative degrees of urban river health of Huzhou City in 2001, 2006 and 2010 were then calculated. The results indicated that river health status of the study area was in the direction of pathological trend, and the impact of limiting factors (such as Shannon's diversity index and agroforestry output growth rate) played an important role in river health. The variation of maximum correlative degree could be classified into stationary status, deterioration status, deterioration-to-improvement status, and improvement-to-deterioration status. There was a severe deterioration situation of river health under the background of urbanization. PMID- 25798877 TI - Aberrant expression of the CHFR prophase checkpoint gene in human B-cell non Hodgkin lymphoma. AB - Checkpoint with FHA and Ring Finger (CHFR) is a checkpoint protein that reportedly initiates a cell cycle delay in response to microtubule stress during prophase in mitosis, which has become an interesting target for understanding cancer pathogenesis. Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. In the present study, we examined the expression of CHFR in B-cell non-Hodgkin lymphoma (B-NHL) in vitro and in vivo. Our results showed that the expression level of CHFR mRNA and protein was reduced in B-NHL tissue samples and B cell lines. Furthermore, CHFR methylation was detected in 39 of 122 B-NHL patients, which was not found in noncancerous reactive hyperplasia of lymph node (RH) tissues. CHFR methylation correlated with the reduced expression of CHFR, high International Prognostic Index (IPI) scores and later pathologic Ann Arbor stages of B-NHL. Treatment with demethylation reagent, 5-Aza-dC, could eliminate the hypermethylation of CHFR, enhance CHFR expression and cell apoptosis and inhibit the cell proliferation of Raji cells, which could be induced by high expression of CHFR in Raji cells. Our results indicated that aberrant methylation of CHFR may be associated with the pathogenesis, progression for B-NHL, which might be a novel molecular marker as prognosis and treatment for B-NHL. PMID- 25798878 TI - Combining Raman and infrared spectroscopy as a powerful tool for the structural elucidation of cyclodextrin-based polymeric hydrogels. AB - A detailed experimental and theoretical vibrational analysis of hydrogels of beta cyclodextrin nanosponges (beta-CDNS), obtained by polymerization of beta cyclodextrin (beta-CD) with the cross-linking agent ethylenediaminetetraacetic acid (EDTA), is reported here. Thorough structural characterization is achieved by exploiting the complementary selection rules of FTIR-ATR and Raman spectroscopies and by supporting the spectral assignments by DFT calculations of the spectral profiles. The combined analysis of the FTIR-ATR spectra of the polymers hydrated with H2O and D2O allowed us to isolate the HOH bending of water molecules not involved in symmetrical, tetrahedral environments. The analysis of the HOH bending mode was carried out as a function of temperature, showing the existence of a supercooled state of the water molecules. The highest level of cooperativity of the hydrogen bond scheme was reached at a value of the beta CD/EDTA molar ratio n = 6. Finally, the connectivity pattern of "uncoupled" water molecules bound to the nanosponge backbone was found to be weakened by increasing T. The temperature above which the population of non-tetracoordinated water molecules becomes predominant turned out to be independent of the parameter n. PMID- 25798879 TI - Preparation of novel porphyrin nanomaterials based on the pH-responsive shape evolution of porphyrin microspheres. AB - The shapes and properties of self-assembled materials can be adjusted easily using environmental stimuli. Yet, the stimulus-triggered shape evolution of organic microspheres in aqueous solution has rarely been reported so far. Here, a novel type of poly(allylamine hydrochloride)-g-porphyrin microspheres (PAH-g-Por MPs) was prepared by a Schiff base reaction between 2-formyl-5,10,15,20 tetraphenylporphyrin (Por-CHO) and PAH doped in 3.5-MUm CaCO3 microparticles, followed by template removal. The PAH-g-Por MPs had an average diameter of 2.5 MUm and could be transformed into one-dimensional nanorods (NRs) and wormlike nanostructures (WSs) after being incubated for different times in pH 1-4 HCl solutions. The rate and degree of hydrolysis had a significant effect on the formation and morphologies of the nanorods. The NRs@pH1, NRs@pH2, and NRs@pH3 were all composed of the released Por-CHO and the unhydrolyzed PAH-g-Por because of the incomplete hydrolysis of the Schiff base. However, the WSs@pH4 were formed by a pure physical shape transformation, because they had the same composition as the PAH-g-Por MPs and the Schiff base bonds were not hydrolyzed. The self assembled NRs and WSs exhibited good colloidal stability and could emit stable red fluorescence over a relatively long period of time. PMID- 25798880 TI - Leftover prescription opioids after minor procedures: an unwitting source for accidental overdose in children. PMID- 25798881 TI - Characterization of volume and shape modifications of PET-positive nodes during Tomotherapy for head and neck cancer as assessed by MVCTs. AB - PURPOSE: Characterizing the changes of PET-positive lymphnodes (PNs) of head-neck cancer patients during image-guided Tomotherapy in order to verify if our clinical margin for PTV(boost) are adequate. MATERIAL AND METHODS: Weekly MVCTs of 30 patients were matched with the planning kVCT (kVCT_pl) on bony anatomy: 42 visible PNs were contoured on kVCT_pl/MVCTs. Intra/inter-observer and inter modality variability in contouring PNs was evaluated by blind re-delineation. Shrinkage of PNs and center-of-mass (CM) shifts were measured and Van Herk margins for the residual error were estimated. In addition, due to the PNs' shrinkage during therapy, probability coverage maps were considered to estimate the fraction of the high probability contours missed by the clinical PTV (5 mm margin); larger margins were tried for PNs showing some missing. RESULTS: MVCTs were adequate for PNs' delineation (DICE=0.85; range=0.79-0.91). Twenty-seven PNs showed a significant volume shrinkage at the end of therapy (median: 71%, range: 27-94%, rho=-0.93). Time-trend of 3D-CM shift was significant for 38% of PNs (median: 5.1 mm at the end of treatment, range: 1.0-8.9). The clinical PTV included 95% of the 90%/100% probability contours in 40/36 (95%/86%) PNs respectively. Van Herk margins (not considering shrinkage) were approximately 7 mm for all three main axes. The clinical PTV included 95% of the 90%/100% probability contours in 40/36 (95%/86%) PNs respectively. CONCLUSIONS: The residual error relative to PNs after bone match is relatively small; the impact of CM shifts is partially counterbalanced by shrinkage. Our results do not seem to support an extensive use of adaptive re-planning to avoid the missing of PNs in dose-escalated protocols, although more information about the dosimetry impact of the reported changes is warranted. PMID- 25798882 TI - Clinical outcomes of prospectively treated 140 women with early stage breast cancer using accelerated partial breast irradiation with 3 dimensional computerized tomography based brachytherapy. AB - PURPOSE: To study the clinical outcomes of women with early breast cancer (EBC) treated with accelerated partial breast irradiation (APBI) with multicatheter interstitial brachytherapy (MIB) using 3 dimensional computerized tomography (3DCT) based planning. MATERIALS AND METHODS: During August 2005 to January 2013, 140 women with EBC were treated prospectively with APBI using high dose rate (HDR) MIB. After 3DCT based planning patients were treated to a dose of 34 Gy/10 #/1 week with bid regimen. RESULTS: Median age was 57 years and tumor size 2 cm (range: 0.6-3.2 cm). Infiltrating duct carcinoma (IDC) was the most common histology; grade III tumors were seen in 82%. Median dose homogeneity index (DHI) was 0.76 (range: 0.49-0.85). The median coverage index (CI) of the cavity was 90% (61.4-100) and 80.5% (53.6-97.4) for planning target volume (PTV). Median follow up was 60 months (1-102 months). The 5 and 7 year local control rates (LC) were 97% and 92% respectively. Her2 positivity was the only prognostic factor which had an adverse impact on LC (p=0.01). Five and 7 year disease free survival (DFS) and overall survival (OAS) were 93%, 84%, 97.5% and 89% respectively. Good to excellent cosmetic outcomes at last follow up were seen in 87 (77%) women. CONCLUSIONS: 3DCT based MIB results in excellent long term outcomes and good to excellent cosmesis. Her2 positivity has an adverse impact on LC rates. PMID- 25798883 TI - Hierarchical mesoporous In2O3 with enhanced CO sensing and photocatalytic performance: distinct morphologies of In(OH)3 via self assembly coupled in situ solid-solid transformation. AB - The present investigation details our interesting findings and insights into the evolution of exotic hierarchical superstructures of In(OH)3 under solvothermal conditions. Controlled variation of reaction parameters such as, reactant concentration, solvent system, crystal structure modifiers, water content along with temperature and time, yielded remarkable architectures. Diverse morphologies achieved for the first time includes (i) raspberry-like hollow spheres, (ii) nanosheet-assembled spheres, (iii) nanoparticle-assembled spheres, (iv) nanocube assembled hollow spheres, (v) yolk-like spheres, (vi) solid spheres, (vii) nanosheets/flakes, and (viii) ultrafine nanosheets. A plausible mechanism is proposed based on the evidence gathered from a comprehensive analysis aided by electron microscopy and X-ray diffraction studies. Key stages of morphological evolution could be discerned and rationally correlated with nucleation, growth, oriented attachment, and Ostwald ripening mediated by dissolution-redeposition mechanism coupled with solid evacuation. Remarkably phase-pure bcc-In2O3 with retention of precursor morphology could be realized postcalcination at 400 degrees C, which underlines the advantage of this strategy. Two typical hierarchical structures (raspberry-like hollow spheres and nanoparticles assembled spheres) were investigated for their gas sensing and photocatalytic performances to highlight the advantages offered by nanostructuring. An impressive sensor response, Smax ~ 7340 and 4055, respectively for the two structures along with appreciably fast response/recovery times over a wide concentration range and as low as 1 ppm exhibits the superior sensitivity toward carbon monoxide (CO). When compared to commercial In2O3, estimated rate constant indicates ~3-4 times enhancement in photocatalytic activity of the substrates toward Rhodamine-B. PMID- 25798884 TI - Single-plex quantitative assays for the detection and quantification of most pneumococcal serotypes. AB - Streptococcus pneumoniae globally kills more children than any other infectious disease every year. A prerequisite for pneumococcal disease and transmission is colonization of the nasopharynx. While the introduction of pneumococcal conjugate vaccines has reduced the burden of pneumococcal disease, understanding the impact of vaccination on nasopharyngeal colonization has been hampered by the lack of sensitive quantitative methods for the detection of >90 known S. pneumoniae serotypes. In this work, we developed 27 new quantitative (q)PCR reactions and optimized 26 for a total of 53 qPCR reactions targeting pneumococcal serotypes or serogroups, including all vaccine types. Reactions proved to be target-specific with a limit of detection of 2 genome equivalents per reaction. Given the number of probes required for these assays and their unknown shelf-life, the stability of cryopreserved reagents was evaluated. Our studies demonstrate that two-year cryopreserved probes had similar limit of detection as freshly-diluted probes. Moreover, efficiency and limit of detection of 1-month cryopreserved, ready-to use, qPCR reaction mixtures were similar to those of freshly prepared mixtures. Using these reactions, our proof-of-concept studies utilizing nasopharyngeal samples (N=30) collected from young children detected samples containing >=2 serotypes/serogroups. Samples colonized by multiple serotypes/serogroups always had a serotype that contributes at least 50% of the pneumococcal load. In addition, a molecular approach called S6-q(PCR)2 was developed and proven to individually detect and quantify epidemiologically-important serogroup 6 strains including 6A, 6B, 6C and 6D. This technology will be useful for epidemiological studies, diagnostic platforms and to study the pneumobiome. PMID- 25798885 TI - Two new secondary metabolites from the marine-derived fungus Nigrospora sphaerica. AB - Two new secondary metabolites, (2S)-5-acetamidopentyl-2-hydroxypropanoate (1) and 2, 5, 7-trihydroxy-4-(3'-methylbut-2'-en-1'-yl) oxy-2H-naphtho [1, 8-b c] furan-9 one (2) were isolated from the marine-derived fungus Nigrospora sphaerica. The structures were established on the basis of their spectroscopic data, including 1D NMR and 2D NMR, HR-TOF-MS, and the absolute configuration of compound 1 was determined by the Mosher method. PMID- 25798886 TI - Correction: Persistence of health inequalities in childhood injury in the UK; a population-based cohort study of children under 5. PMID- 25798888 TI - Enterococcus species diversity and molecular characterization of biomarker genes in Enterococcus faecalis in Port Blair Bay, Andaman and Nicobar Islands, India. AB - This study was performed to evaluate the abundance and diversity of Enterococcus sp. and the distribution of biomarker genes in Enterococcus faecalis in Port Blair Bay, Andaman and Nicobar Islands. The Enterococcus sp. densities at the seven sampling stations were highly influenced by tidal fluctuations and season. The distributions and diversities of species varied in the inner and outer regions of Port Blair Bay. Among the 1816 total isolates, the occurrence of fecal Enterococcus was high (1.78*10(4) CFU/100 mL) in Phoenix Bay. Moreover, 67.76% of the isolates were identified as Enterococcus, and the most frequently identified species were E. hirae, E. avium and E. faecalis. Assessments of antibiotic resistance and biomarker genes revealed the maximum occurrence in the Aberdeen Bay isolates. The most prevalent biomarker genes observed in the E. faecalis isolates were gelE and asa1, whereas cyl was not found among the isolates. In silico sequence analysis of biomarker genes of E. faecalis also revealed that they are evolutionarily well conserved with those of earlier reports. Further, multivariate analysis distinguished the JB, PB and OS stations from the other stations according to distinctive microbial densities and compositions. In addition, the Shannon-Wiener diversity indices and box-whisker plots further facilitated and supported the multivariate results. PMID- 25798887 TI - Exosomes released from breast cancer carcinomas stimulate cell movement. AB - For metastasis to occur cells must communicate with to their local environment to initiate growth and invasion. Exosomes have emerged as an important mediator of cell-to-cell signalling through the transfer of molecules such as mRNAs, microRNAs, and proteins between cells. Exosomes have been proposed to act as regulators of cancer progression. Here, we study the effect of exosomes on cell migration, an important step in metastasis. We performed cell migration assays, endocytosis assays, and exosome proteomic profiling on exosomes released from three breast cancer cell lines that model progressive stages of metastasis. Results from these experiments suggest: (1) exosomes promote cell migration and (2) the signal is stronger from exosomes isolated from cells with higher metastatic potentials; (3) exosomes are endocytosed at the same rate regardless of the cell type; (4) exosomes released from cells show differential enrichment of proteins with unique protein signatures of both identity and abundance. We conclude that breast cancer cells of increasing metastatic potential secrete exosomes with distinct protein signatures that proportionally increase cell movement and suggest that released exosomes could play an active role in metastasis. PMID- 25798889 TI - Symbolic transformations of heart rate variability preserve information about cardiac autonomic control. AB - Traditional measures of heart rate variability (HRV) in the time or frequency domain (e.g. standard deviation of normal-to-normal intervals, SDNN, or the high frequency component of spectral analysis, HF) may be used to track vagal and sympathetic modulation directed to the sinus node. In this study, we assess the ability of symbolic analysis to monitor cardiac autonomic regulation during two autonomic challenges (phenylephrine and nitroprusside; low and high dose of atropine). To assess the effect of the coarse graining procedure, symbolic series obtained from four different transformations over the original series and the series of successive differences of the original values. The analysis focused on patterns of length 3 and exploited a redundancy reduction strategy to group patterns into a small number of families. It turns out that each symbolic series created by the four transformations still contained sufficient dynamical features to quantify differences of cardiovascular changes during the pharmacological challenges. The symbolic series created by transformations of the beat-to-beat interview, i.e RR interval series, showed that patterns without variations (0V) appear more often during a high dose of atropine compared to rest or to a low dose of atropine. Furthermore, patterns with two unlike variations (2UV) appear more often during a low dose of atropine and less often during a high dose of atropine. Differences of nitroprusside and phenylephrine could also be assessed by patterns with these variations. In conclusion, the changes of cardiovascular regulation during pharmacological challenges can be assessed by the analysis of symbolic dynamics derived from the RR interval series independently of the specific symbolic transformation. PMID- 25798890 TI - Coupling between arterial pressure, cerebral blood velocity, and cerebral tissue oxygenation with spontaneous and forced oscillations. AB - We tested the hypothesis that transmission of arterial pressure to brain tissue oxygenation is low under conditions of arterial pressure instability. Two experimental models of hemodynamic instability were used in healthy human volunteers; (1) oscillatory lower body negative pressure (OLBNP) (N = 8; 5 male, 3 female), and; (2) maximal LBNP to presyncope (N = 21; 13 male, 8 female). Mean arterial pressure (MAP), middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO2) were measured non-invasively. For the OLBNP protocol, between 0 and -60 mmHg negative pressure was applied for 20 cycles at 0.05 Hz, then 20 cycles at 0.1 Hz. For the maximal LBNP protocol, progressive 5 min stages of chamber decompression were applied until the onset of presyncope. Spectral power of MAP, mean MCAv, and ScO2 were calculated within the VLF (0.04 0.07 Hz), and LF (0.07-0.2 Hz) ranges, and cross-spectral coherence was calculated for MAP-mean MCAv, MAP-ScO2, and mean MCAv-ScO2 at baseline, during each OLBNP protocol, and at the level prior to pre-syncope during maximal LBNP (sub-max). The key findings are (1) both 0.1 Hz OLBNP and sub-max LBNP elicited increases in LF power for MAP, mean MCAv, and ScO2 (p <= 0.08); (2) 0.05 Hz OLBNP increased VLF power in MAP and ScO2 only (p <= 0.06); (3) coherence between MAP mean MCAv was consistently higher (>=0.71) compared with MAP-ScO2, and mean MCAv ScO2 (<=0.43) during both OLBNP protocols, and sub-max LBNP (p <= 0.04). These data indicate high linearity between pressure and cerebral blood flow variations, but reduced linearity between cerebral tissue oxygenation and both arterial pressure and cerebral blood flow. Measuring arterial pressure variability may not always provide adequate information about the downstream effects on cerebral tissue oxygenation, the key end-point of interest for neuronal viability. PMID- 25798892 TI - Aligned silicon nanofins via the directed self-assembly of PS-b-P4VP block copolymer and metal oxide enhanced pattern transfer. AB - 'Directing' block copolymer (BCP) patterns is a possible option for future semiconductor device patterning, but pattern transfer of BCP masks is somewhat hindered by the inherently low etch contrast between blocks. Here, we demonstrate a 'fab' friendly methodology for forming well-registered and aligned silicon (Si) nanofins following pattern transfer of robust metal oxide nanowire masks through the directed self-assembly (DSA) of BCPs. A cylindrical forming poly(styrene) block-poly(4-vinyl-pyridine) (PS-b-P4VP) BCP was employed producing 'fingerprint' line patterns over macroscopic areas following solvent vapor annealing treatment. The directed assembly of PS-b-P4VP line patterns was enabled by electron-beam lithographically defined hydrogen silsequioxane (HSQ) gratings. We developed metal oxide nanowire features using PS-b-P4VP structures which facilitated high quality pattern transfer to the underlying Si substrate. This work highlights the precision at which long range ordered ~10 nm Si nanofin features with 32 nm pitch can be defined using a cylindrical BCP system for nanolithography application. The results show promise for future nanocircuitry fabrication to access sub-16 nm critical dimensions using cylindrical systems as surface interfaces are easier to tailor than lamellar systems. Additionally, the work helps to demonstrate the extension of these methods to a 'high chi' BCP beyond the size limitations of the more well-studied PS-b-poly(methyl methylacrylate) (PS-b-PMMA) system. PMID- 25798891 TI - Employment experiences of immigrant workers in aged care in regional South Australia. AB - PURPOSE: The contributions of immigrant workers to the aged care workforce cannot be overemphasised. The report of the National Institute of Labour Studies records a significant number of immigrants in the aged care industry in Australia. The number of overseas-born workers in the residential aged care sector had risen steadily, according to recent workforce statistics. However, the employment positions these immigrant workers fill have perennially been labelled as low paying and low-status, warranting more research into the plight of immigrant workers, especially those in regional areas. This study investigates the current employment experience of immigrant workers working in aged care in regional South Australia. METHODS: This qualitative study is based on a focus group consisting of seven immigrant workers (five personal carers, one home support worker and one allied health assistant), who shared their individual perceptions of their employment experience. The workers were employed by three aged care facilities run by a community-based not-for-profit organisation governed by one incorporated body. Thematic analysis was used to analyse the focus group data. This article reports on part of the findings of a larger research study where the authors have included the perceptions of co-workers and managers about working with immigrant workers. RESULTS: This study reveals mixed experiences of immigrant workers with employment in aged care. Satisfaction came from positive and encouraging client feedback, enriching work experience, flexible hours and simply having a job. Dissatisfaction came from constraints with time, workload, staffing, poor peer relations, discriminatory practices and the nature of the job itself. Immigrant workers do not experience a strong support infrastructure. Limitations of the study include the small sample size used and the focus on one regional city. CONCLUSIONS: This study suggests that aged care facility managers and executive officers can enhance positive work experience of immigrant workers by making some workplace reforms. PMID- 25798893 TI - Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring. AB - Systematic structure-activity studies on a diverse family of nucleoside phosphonic acids has led to the development of potent antiviral drugs such as HPMPC (CidofovirTM), PMEA (AdefovirTM), and PMPA (TenofovirTM), which are used in the treatment of CMV-induced retinitis, hepatitis B, and HIV, respectively. Here, we present the synthesis of a novel class of acyclic phosphonate nucleotides that have a locked conformation via a pyrrolidine ring. NMR analysis of these compounds revealed that the pyrrolidine ring has a constrained conformation when in the cis-form at pD < 10 via hydrogen bonding. Four of these compounds were tested as inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases. The most potent has a Ki of 0.6 MUM for Plasmodium falciparum HGXPRT. PMID- 25798894 TI - Positive aspects of being a heterosexual ally to lesbian, gay, bisexual and transgender (LGBT) people. AB - Research on heterosexual allies has focused on heterosexual identity development models and pathways to ally activism. The positive aspects or positive experiences of identifying as an ally to lesbian, gay, bisexual, and transgender (LGBT) identified individuals and communities have received little attention. Using an online survey of participants recruited from LGBT ally related social media, we collected open-ended responses to a question about the positive aspects of self-identifying as a heterosexual ally. A final analytic sample of 292 self identified male and female heterosexual adults (age 18-71, M = 33.47, SD = 13.32) provided responses that generated 8 themes. Positive aspects of being a heterosexual ally were: (a) increased knowledge and awareness, (b) upholding values of justice, (c) beneficial individual relationships, (d) community belonging, (e) educating others, (f) being a role model, (g) using social privilege, and (h) speaking out and taking a stand. The findings suggest that being a heterosexual ally is rewarding and may enhance individual well-being. These findings provide information that may contribute to effective ally development efforts. PMID- 25798895 TI - A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds. AB - Solanacol, isolated from tobacco (Nicotiana tabacum L.), is a germination stimulant for seeds of root parasitic weeds. A concise synthesis of optically active solanacol has been achieved by employing enzymatic resolution as a key step. PMID- 25798896 TI - Coupling localized plasmonic and photonic modes tailors and boosts ultrafast light modulation by gold nanoparticles. AB - Plasmonic nanoparticles offer a broad range of functionalities, owing to their ability to amplify light in the near-field or convert it into heat. However, their ultrafast nonlinear optical response remains too low to envisage all optical high-rate photonic processing applications. Here, we tackle this challenge by coupling the localized plasmon mode in gold nanoparticles with a localized photonic mode in a 1D resonant cavity. Despite the nonradiative losses, we demonstrate that a strong, reversible, and ultrafast optical modulation can be achieved. By using a light pumping fluence of less than 1 mJ cm(-2), a change of signal transmittance of more than 100% is generated within a few picosecond time scale. The nanoparticle transient optical response is enhanced by a factor of 30 to 40 while its spectral profile is strongly sharpened. The large nonlinear response of such plasmonic cavities could open new opportunities for ultrafast light processing at the nanoscale. PMID- 25798897 TI - Identification of reference genes for real-time quantitative PCR experiments in the liverwort Marchantia polymorpha. AB - Real-time quantitative polymerase chain reaction (qPCR) has become widely used as a method to compare gene transcript levels across different conditions. However, selection of suitable reference genes to normalize qPCR data is required for accurate transcript level analysis. Recently, Marchantia polymorpha has been adopted as a model for the study of liverwort development and land plant evolution. Identification of appropriate reference genes has therefore become a necessity for gene expression studies. In this study, transcript levels of eleven candidate reference genes have been analyzed across a range of biological contexts that encompass abiotic stress, hormone treatment and different developmental stages. The consistency of transcript levels was assessed using both geNorm and NormFinder algorithms, and a consensus ranking of the different candidate genes was then obtained. MpAPT and MpACT showed relatively constant transcript levels across all conditions tested whereas the transcript levels of other candidate genes were clearly influenced by experimental conditions. By analyzing transcript levels of phosphate and nitrate starvation reporter genes, we confirmed that MpAPT and MpACT are suitable reference genes in M. polymorpha and also demonstrated that normalization with an inappropriate gene can lead to erroneous analysis of qPCR data. PMID- 25798899 TI - Familial spontaneous coronary artery dissection: evidence for genetic susceptibility. AB - IMPORTANCE: Spontaneous coronary artery dissection (SCAD) is a major cause of acute coronary syndrome in young women, especially among those without traditional cardiovascular risk factors. Prior efforts to study SCAD have been hampered by underrecognition and lack of registry-based studies. Risk factors and pathogenesis remain largely undefined, and inheritability has not been reported. OBSERVATIONS: Using novel research methods, patient champions, and social media, the Mayo Clinic SCAD Registry has been able to better characterize this condition, which was previously considered rare. Of 412 patient enrollees, we identified 5 familial cases of SCAD comprising affected mother-daughter, identical twin sister, sister, aunt-niece, and first-cousin pairs, implicating both recessive and dominant modes of inheritance. The mother-daughter pair also reported fatal myocardial infarction in 3 maternal relatives. None of the participants had other potential risk factors for SCAD, including connective tissue disorders or peripartum status. CONCLUSIONS AND RELEVANCE: To our knowledge, this series is the first to identify a familial association in SCAD suggesting a genetic predisposition. Recognition of SCAD as a heritable disorder has implications for at-risk family members and furthers our understanding of the pathogenesis of this complex disease. Whole-exome sequencing provides a unique opportunity to identify the molecular underpinnings of SCAD susceptibility. PMID- 25798900 TI - The cobalt hydride that never was: revisiting Schrauzer's "hydridocobaloxime". AB - Molecular cobalt-dmg (dmg = dimethylglyoxime) complexes are an important class of electrocatalysts used heavily in mechanistic model studies of the hydrogen evolution reaction (HER). Schrauzer's early isolation of a phosphine-stabilized "[H-Co(III)(dmgH)2P(nBu)3]" complex has long provided circumstantial support for the plausible intermediacy of Co(III)-H species in HER by cobaloximes in solution. Our investigation of this complex has led to a reassignment of its structure as [Co(II)(dmgH)2P(nBu)3], a complex that contains no hydride ligand and dimerizes to form an unsupported Co-Co bond in the solid state. A paramagnetic S = 3/2 impurity that forms during the synthesis of [Co(II)(dmgH)2P(nBu)3] when exposed to adventitious oxygen has also been characterized. This impurity features a (1)H NMR resonance at -5.06 ppm that was recently but erroneously attributed to the hydride resonance of "[H Co(III)(dmgH)2P(nBu)3]". We draw attention to this reassignment because of its relevance to cobaloxime hydrides and HER catalysis and because Schrauzer's "hydridocobaloxime" is often cited as the primary example of a bona fide hydride that can be isolated and characterized on this widely studied HER platform. PMID- 25798902 TI - Diagnosis and prognosis of ischemic heart disease: the framework of cardiac magnetic resonance. AB - Cardiac magnetic resonance is considered the gold standard in the evaluation of morphology, function, viability and tissue characterization owing to its high spatial resolution and excellent signal-to-noise ratio. Its accuracy and reproducibility, also thanks to steady-state free precession sequences allowing superior blood-myocardium delineation, are ascertained. Its current indications in the field of ischemic heart disease are multiple and continuously evolving. This technology can provide information on myocardium at risk, infarcted myocardium, microvascular obstruction and intramyocardial haemorrhage. The evaluation of each of these indexes has pivotal importance from a prognostic point of view. Rapid technological innovation engenders faster sequences and new contrast agents whereby a more accurate study of the myocardium and coronary artery disease is possible. On the contrary, there is the huge potentiality of noncontrast cardiac magnetic resonance that is especially appealing as a screening tool in asymptomatic younger patients because of radiation-free ionizing. Last but not the least, it is necessary to underline that the employment of cardiac magnetic resonance in clinical practice is restricted to few centres. This is mainly due to the need for a very high competence level and to the complexity of technical challenges required to industrial engineering, whereas the concerns expressed for its relatively high costs seem partly unfounded. PMID- 25798901 TI - Childhood obesity and cardiac remodeling: from cardiac structure to myocardial mechanics. AB - Epidemic of obesity, especially morbid obesity, among children and adolescents, is a key factor associated with the dramatic increase in prevalence of type 2 diabetes mellitus, arterial hypertension, and metabolic syndrome in this population. Furthermore, childhood obesity represents a very important predictor of obesity in adulthood that is related to cardiovascular and cerebrovascular diseases. Overweight and obesity in children and adolescents are associated with impairment of cardiac structure and function. The majority of studies investigated the influence of obesity on left ventricular remodeling. However, the impact of obesity on the right ventricle, both the atria, and myocardial mechanics has been insufficiently studied. The aim of this review article is to summarize all data about heart remodeling in childhood, from cardiac size, throughout systolic and diastolic function, to myocardial mechanics, using a wide range of mainly echocardiographic techniques and parameters. Additionally, we sought to present current knowledge about the influence of weight loss, achieved by various therapeutic approaches, on the improvement of cardiac geometry, structure, and function in obese children and adolescents. PMID- 25798903 TI - Novel oral anticoagulants in atrial fibrillation: which novel oral anticoagulant for which patient? AB - Atrial fibrillation is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Current european society of cardiology guidelines recommend to stratify atrial fibrillation patients according to the CHA2DS2-VASc score and to administer anticoagulation, preferably with novel oral anticoagulants, that is, dabigatran, rivaroxaban, or apixaban, if the CHA2DS2 VASc score is at least 1. All novel anticoagulants have shown the same, if not greater, efficacy and safety as warfarin, with some advantages. The choice among the novel oral anticoagulants depends on their different pharmacokinetic profile, patients' stroke and bleeding risk, comorbidities, drug tolerability and costs and, finally, patients' preferences. PMID- 25798904 TI - Left ventricular noncompaction presenting like a double-chambered left ventricle. PMID- 25798905 TI - Dpp-expressing and non-expressing cells: two different populations of growing cells in Drosophila. AB - There are different models that explain growth during development. One model is based on insect and amphibian regeneration studies. This model proposes that growth is directed by pattern, and growth takes place by intercalation at a growth discontinuity; therefore, proliferation should surround the discontinuity. Currently, this model, apart from regenerative studies on mostly adult patterning, has not found supporting evidence in Drosophila that shows proliferation surrounding a discontinuity. Despite this lack of evidence, the importance of discontinuities has been shown in different experiments, even under wt conditions, more specifically in the formation of the leg joints because of the occurrence of cell death at their boundaries. Here, we show the existence of a sharp discontinuity in Decapentaplegic (Dpp) in the genital discs at the third larvae stage (L3), which determines the upregulation in the Jun-NH2-Terminal Kinase (JNK) pathway, reaper (rpr), head involution defective (hid) and active caspases from its boundaries. The proliferation and cell death surrounding the discontinuity suggest that growth can proceed by intercalation and competitive death takes place in this area. Finally, we show that the Rpr, Grim and Hid (RGH) products are a few of the factors that define the growth discontinuity because they are negative regulators of growth, a new function that is unique from their known functions in apoptosis. PMID- 25798906 TI - Double transgenic zebrafish for somatotrophic axis: a tool for muscle development and growth studies. PMID- 25798907 TI - Predictors of duration and treatment failure of severe pneumonia in hospitalized young Nepalese children. AB - BACKGROUND: Pneumonia in young children is still the most frequent cause of death in developing countries. We aimed to identify predictors for recovery and treatment failure in children hospitalized with severe pneumonia. METHODS: We enrolled 610 Nepalese children, aged 2 - 35 months from February 2006 to June 2008. Study participants were provided with standard treatment for pneumonia and followed up until discharge. Three multiple regression models representing clinical variables, clinical and radiological combined and all variables, including C-reactive protein (CRP) and viral etiology were used to assess the associations. RESULTS: The median age of study participants was 6 months with 493 (82%) infants and 367 (61%) males. The median time (IQR) till recovery was 49 (31, 87) hours and treatment failure was experienced by 209 (35%) of the children. Younger age, hypoxia on admission and radiographic pneumonia were independent predictors for both prolonged recovery and risk of treatment failure. While wasting and presence of any danger sign also predicted slower recovery, Parainfluenza type 1 isolated from the nasopharynx was associated with earlier resolution of illness. Gender, being breastfed, stunting, high fever, elevated CRP, presence of other viruses and supplementation with oral zinc did not show any significant association with these outcomes. CONCLUSION: Age, hypoxia and consolidation on chest radiograph were significant predictors for time till recovery and treatment failure in children with severe pneumonia. While chest radiograph is not always needed, detection and treatment of hypoxia is a crucial step to guide the management of hospitalized children with pneumonia. PMID- 25798909 TI - Wettability alteration: A comprehensive review of materials/methods and testing the selected ones on heavy-oil containing oil-wet systems. AB - Changing the wetting state of materials is a growing field of research in many areas of engineering and science. In the oil industry, the term wettability alteration usually refers to the process of making the reservoir rock more water wet. This is of particular importance in naturally hydrophobic carbonates, fractured formations, and heavy-oil systems. This shift in wettability enhances oil recovery in oil-wet and weakly water-wet reservoirs and eventually increases the ultimate oil recovery. For wettability alteration, two methods have been traditionally used: Thermal and chemical. Although many attempts have been made on reviewing the advancement of research in certain aspects of wettability, a comprehensive review of these techniques, especially in terms of the classification of the chemicals used, has been ignored. In this paper, we begin with this review and provide the past experience of wettability alteration in sandstone and carbonate reservoirs. More than 100 papers were reviewed extensively with an in-depth analysis of different methods suggested in literature. The areas of controversy and contradicted observations are discussed. The limitations and the applicability of each method were analyzed. Concerns on up-scaling laboratory findings to field scale are also addressed. The most promising potential methods are identified and their critical conditions highlighted. At the end, a selection of reviewed methods is validated experimentally for one of the most challenging cases: Extra heavy-oil and bitumen recovery from fractured-strongly-oil-wet carbonates. Berea sandstone (aged to be oil-wet) and Indiana limestone samples were saturated with heavy oil (3600cp). Next, the process was initiated by soaking the cores into solvent (heptane or diluent oil) and the oil recovery was estimated using refractive index measurements. Note that solvent was selected to dilute the oil and recover a considerable amount of oil as any chemical or thermal methods yielded inefficiently low recoveries. After the solvent phase, the samples were exposed to wettability alteration through selected chemicals at different temperature conditions through spontaneous imbibition tests to recover more oil and retrieve the solvent diffuse into the sample back. The most promising wettability alteration agents for each type of rock were marked and optimal application conditions (temperatures, injection sequence) were identified. Selected wettability alteration chemicals were finally tested on the bitumen (5-9 degrees API-1,600,000cp) containing Grosmont carbonate sample from Alberta, Canada. It is hoped that this review fills in the gap in the area of wettability alteration processes by summarizing, critically analyzing, and testing the methods suggested in the literature. PMID- 25798910 TI - Prevalence of incidental pancreatic cysts on 3 tesla magnetic resonance. AB - OBJECTIVES: To ascertain the prevalence of pancreatic cysts detected incidentally on 3-Tesla magnetic resonance imaging (MRI) of the abdomen and correlate this prevalence with patient age and gender; assess the number, location, and size of these lesions, as well as features suspicious for malignancy; and determine the prevalence of incidentally detected dilatation of the main pancreatic duct (MPD). METHODS: Retrospective analysis of 2,678 reports of patients who underwent abdominal MRI between January 2012 and June 2013. Patients with a known history of pancreatic conditions or surgery were excluded, and the remaining 2,583 reports were examined for the presence of pancreatic cysts, which was then correlated with patient age and gender. We also assessed whether cysts were solitary or multiple, as well as their location within the pancreatic parenchyma, size, and features suspicious for malignancy. Finally, we calculated the prevalence of incidental MPD dilatation, defined as MPD diameter >= 2.5 mm. RESULTS: Pancreatic cysts were detected incidentally in 9.3% of patients (239/2,583). The prevalence of pancreatic cysts increased significantly with age (p<0.0001). There were no significant differences in prevalence between men and women (p=0.588). Most cysts were multiple (57.3%), distributed diffusely throughout the pancreas (41.8%), and 5 mm or larger (81.6%). In 12.1% of cases, cysts exhibited features suspicious for malignancy. Overall, 2.7% of subjects exhibited incidental MPD dilatation. CONCLUSIONS: In this sample, the prevalence of pancreatic cysts detected incidentally on 3T MRI of the abdomen was 9.3%. Prevalence increased with age and was not associated with gender. The majority of cysts were multiple, diffusely distributed through the pancreatic parenchyma, and >= 5 mm in size; 12.1% were suspicious for malignancy. An estimated 2.7% of subjects had a dilated MPD. PMID- 25798908 TI - Comprehensive evaluation of microRNA expression profiling reveals the neural signaling specific cytotoxicity of superparamagnetic iron oxide nanoparticles (SPIONs) through N-methyl-D-aspartate receptor. AB - Though nanomaterials are considered as drug carriers or imaging reagents targeting the central nervous system their cytotoxicity effect on neuronal cells has not been well studied. In this study, we treated PC12 cells, a model neuronal cell line, with a nanomaterial that is widely accepted for medical use, superparamagnetic iron oxide nanoparticles (SPIONs). Our results suggest that, after treated with SPIONs, the expression pattern of the cellular miRNAs changed widely in PC12 cells. As potential miRNA targets, NMDAR, one of the candidate mRNAs that were selected using GO and KEGG pathway enrichment, was significantly down regulated by SPIONs treatment. We further illustrated that SPIONs may induce cell death through NMDAR suppression. This study revealed a NMDAR neurotoxic effect of SPIONs and provides a reliable approach for assessing the neurocytotoxic effects of nanomaterials based on the comprehensive annotation of miRNA profiling. PMID- 25798911 TI - Fesoterodine clinical efficacy and safety for the treatment of overactive bladder in relation to patient profiles: a systematic review. AB - OBJECTIVE: To summarize published evidence on the pharmacology, efficacy, and safety of fesoterodine for the treatment of overactive bladder (OAB) symptoms in relation to patient clinical and demographic profiles. METHODS: A systematic review of published articles on fesoterodine was conducted via a PubMed search. Articles were identified using the search term fesoterodine, with limits of human species and abstract available. Review and meta-analysis articles, validation studies, articles focused on treatment compliance/adherence, meeting abstracts, and articles not focused on oral fesoterodine administration in human subjects were excluded. Data from retained articles were summarized descriptively. RESULTS: Of 137 articles identified, 61 (15 articles on the pharmacology and 46 articles on the efficacy and/or safety of fesoterodine) met inclusion criteria. Superiority trials demonstrated the additional efficacy of fesoterodine 8 mg versus fesoterodine 4 mg and tolterodine extended release 4 mg in treating OAB. Prospective trials in specific patient populations indicated beneficial effects of fesoterodine in elderly patients, vulnerable elderly patients, patients dissatisfied with or with a suboptimal response to previous antimuscarinic therapy, patients with urge urinary incontinence (UUI) or nocturnal urgency, and men with persistent LUTS during alpha-blocker treatment. With two effective doses, the fesoterodine dose can be adjusted to achieve optimal efficacy and tolerability in individual patients. The most common adverse events during fesoterodine treatment are dry mouth and constipation. CONCLUSIONS: Extensive evidence demonstrates the efficacy and safety of fesoterodine in relieving OAB symptoms, including urgency, urinary frequency, UUI, and nocturnal urgency, in patients with various clinical and demographic profiles. Trial results provide valuable information on fesoterodine treatment in specific patient populations, including both elderly and vulnerable elderly patients. Potential limitations of this review are that only English language articles in PubMed were searched and included. PMID- 25798912 TI - Patient use of email for health care communication purposes across 14 European countries: an analysis of users according to demographic and health-related factors. AB - BACKGROUND: The use of the Internet for health purposes is growing steadily, yet the use of asynchronous communication tools for health care purposes remains undeveloped. The introduction of email as a method of communication in health care has the potential to impact on both patients and health care professionals. OBJECTIVE: This study aims to describe the characteristics of people who have sent or received an email to or from their doctor, nurse, or health care organization, by country and in relation to demographics, health care resource use, and health status factors. METHODS: We conducted a secondary analysis of data (N=14,000) collected from the online Citizens and Information Communication Technology for Health survey, a project undertaken in 2011 by the Institute for Prospective Technology Studies of the European Commission's Joint Research Centre. The survey was developed to understand and characterize European citizens' use of information communication technologies for health. Descriptive and statistical analyses of association were used to interpret the data. RESULTS: Denmark reported the highest level of emails sent/received (507/1000, 50.70%). The lowest level reported was by participants in France (187/1000, 18.70%). Men used email communication for health care more than women, as did respondents in the 16-24 age group and those educated to tertiary level or still within the education system. As self-reported health state worsens, the proportion of people reporting having sent or received an email within the context of health care increases. Email use, poor health, multimorbidity, and number of visits to a physician are positively correlated. CONCLUSIONS: The use of email communication within the context of European health care is extremely varied. The relationship between high email use, poor health, doctor visits, and multimorbidity is especially pertinent: provision of asynchronous communication for such groups is favored by policymakers. Low reported email use by country may not necessarily reflect low interest in using email for health care: local health policies and technical infrastructures may be significant factors in the delay in implementation of alternative forms of routine health communication. PMID- 25798913 TI - Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets. AB - Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30 mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests. PMID- 25798915 TI - Synthesis, spectral characterization and crystals structure of some arsane derivatives of gold (I) complexes: a comparative density functional theory study. AB - A series of complexes of the type LAuCl where L = tris(p-tolylarsane), tris(m tolylarsane), bis(diphenylarsano)ethane, and tris(naphthyl)arsane have been synthesized. All of the new complexes, 1-4, have been fully characterized by means of 1H NMR and 13C NMR spectroscopy and single crystal X-ray crystallography. The structures of complexes 1-4 have been determined from X-ray diffraction data. The linear molecules have an average bond distance between gold arsenic and gold-chlorine of 2.3390A and 2.2846A, respectively. Aurophilic interaction was prominent in complex 1 and 3, whereas complex 2 and 4 do not show any such interaction. The intermolecular gold interaction bond length was affected by the electronegativity of the molecule. The computed values calculated at DFT level using B3LYP function are in good agreement with the experimental results. PMID- 25798914 TI - Structural and functional studies of phosphoenolpyruvate carboxykinase from Mycobacterium tuberculosis. AB - Tuberculosis, the second leading infectious disease killer after HIV, remains a top public health priority. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), which can cause both acute and clinically latent infections, reprograms metabolism in response to the host niche. Phosphoenolpyruvate carboxykinase (Pck) is the enzyme at the center of the phosphoenolpyruvate pyruvate-oxaloacetate node, which is involved in regulating the carbon flow distribution to catabolism, anabolism, or respiration in different states of Mtb infection. Under standard growth conditions, Mtb Pck is associated with gluconeogenesis and catalyzes the metal-dependent formation of phosphoenolpyruvate. In non-replicating Mtb, Pck can catalyze anaplerotic biosynthesis of oxaloacetate. Here, we present insights into the regulation of Mtb Pck activity by divalent cations. Through analysis of the X-ray structure of Pck-GDP and Pck-GDP-Mn2+ complexes, mutational analysis of the GDP binding site, and quantum mechanical (QM)-based analysis, we explored the structural determinants of efficient Mtb Pck catalysis. We demonstrate that Mtb Pck requires presence of Mn2+ and Mg2+ cations for efficient catalysis of gluconeogenic and anaplerotic reactions. The anaplerotic reaction, which preferably functions in reducing conditions that are characteristic for slowed or stopped Mtb replication, is also effectively activated by Fe2+ in the presence of Mn2+ or Mg2+ cations. In contrast, simultaneous presence of Fe2+ and Mn2+ or Mg2+ inhibits the gluconeogenic reaction. These results suggest that inorganic ions can contribute to regulation of central carbon metabolism by influencing the activity of Pck. Furthermore, the X-ray structure determination, biochemical characterization, and QM analysis of Pck mutants confirmed the important role of the Phe triad for proper binding of the GDP-Mn2+ complex in the nucleotide binding site and efficient catalysis of the anaplerotic reaction. PMID- 25798916 TI - An age-wise comparison of human airway smooth muscle proliferative capacity. AB - We compared the proliferation of neonatal and adult airway smooth muscle cells (ASMC) with no/moderate lung disease, in glucose- (energy production by glycolysis) or glucose-free medium (ATP production from mitochondrial oxidative phosphorylations only), in response to 10% fetal calf serum (FCS) and PDGF-AA. In the presence of glucose, cell counts were significantly greater in neonatal vs. adult ASMC. Similarly, neonatal ASMC DNA synthesis in 10% FCS and PDGF-AA, and [Ca2+]i responses in the presence of histamine were significantly enhanced vs. adults. In glucose-free medium, cell proliferation was preserved in neonatal cells, unlike in adult cells, with concomitant increased porin (an indicator of mitochondrial activity) protein expression. Compared to adults, stimulated neonatal human ASMC are in a rapid and robust proliferative phase and have the capacity to respond disproportionately under abnormal environmental conditions, through increased mitochondrial biogenesis and altered calcium homeostasis. PMID- 25798917 TI - A new look at the structural properties of trisodium uranate Na3UO4. AB - The crystal structure of trisodium uranate, which forms following the interaction between sodium and hyperstoichiometric urania, has been solved for the first time using powder X-ray and neutron diffraction, X-ray absorption near-edge structure spectroscopy, and solid-state (23)Na multiquantum magic angle spinning nuclear magnetic resonance. The compound, isostructural with Na3BiO4, has monoclinic symmetry, in space group P2/c. Moreover, it has been shown that this structure can accommodate some cationic disorder, with up to 16(2)% sodium on the uranium site, corresponding to the composition alpha-Na3(U1-x,Nax)O4 (0 < x < 0.18). The alpha phase adopts a mixed valence state with the presence of U(V) and U(VI). The two polymorphs of this compound described in the literature, m- and beta-Na3(U1 x,Nax)O4, have also been investigated, and their relationship to the alpha phase has been established. The completely disordered low-temperature cubic phase corresponds to a metastable phase. The semiordered high-temperature beta phase is cubic, in space group Fd3m. PMID- 25798918 TI - Frequency-dependent changes of local resting oscillations in sleep-deprived brain. AB - Sleep deprivation (SD) adversely affects brain function and is accompanied by frequency dependent changes in EEG. Recent studies have suggested that BOLD fluctuations pertain to a spatiotemporal organization with different frequencies. The present study aimed to investigate the frequency-dependent SD-related brain oscillatory activity by using the amplitude of low-frequency fluctuation (ALFF) analysis. The ALFF changes were measured across different frequencies (Slow-4: 0.027-0.073 Hz; Slow-5: 0.01-0.027 Hz; and Typical band: 0.01-0.08 Hz) in 24 h SD as compared to rested wakeful during resting-state fMRI. Sixteen volunteers underwent two fMRI sessions, once during rested wakefulness and once after 24 h of SD. SD showed prominently decreased ALFF in the right inferior parietal lobule (IPL), bilateral orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC), while increased ALFF in the visual cortex, left sensorimotor cortex and fusiform gyrus. Across the Slow-4 and Slow-5, results differed significantly in the OFC, DLPFC, thalamus and caudate in comparison to typical frequency band; and Slow-4 showed greater differences. In addition, negative correlations of behavior performance and ALFF patterns were found mainly in the right IPL across the typical frequency band. These observations provided novel insights about the physiological responses of SD, identified how it disturbs the brain rhythms, and linked SD with frequency-dependent alterations in amplitude patterns. PMID- 25798920 TI - iMonDB: Mass Spectrometry Quality Control through Instrument Monitoring. AB - Over the past few years, awareness has risen that for mass-spectrometry-based proteomics methods to mature into everyday analytical and clinical practices, extensive quality assessment is mandatory. A currently overlooked source of qualitative information originates from the mass spectrometer itself. Apart from the actual mass spectral data, raw-data objects also contain parameter settings and sensory information about the mass instrument. This information gives a detailed account of the operation of the instrument, which eventually can be related to observations in mass spectral data. The advantage of instrument information at the lowest level is the high sensitivity to detect emerging defects in a timely fashion. To this end, we introduce the Instrument MONitoring DataBase (iMonDB), which allows us to automatically extract, store, and manage the instrument parameters from raw-data objects into a highly efficient database structure. This enables us to monitor the instrument parameters over a considerable time period. Time course information about the instrument performance is necessary to define the normal range of operation and to detect anomalies that may correlate with instrument failure. The proposed tools foster an additional handle on quality control and are released as open source under the permissive Apache 2.0 license. The tools can be downloaded from https://bitbucket.org/proteinspector/imondb. PMID- 25798919 TI - Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs. AB - Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer. PMID- 25798921 TI - Dioxins and Nonortho PCBs in Breast Milk of Vietnamese Mothers Living in the Largest Hot Spot of Dioxin Contamination. AB - Bien Hoa Air Base is the largest dioxin contamination hot spot in Vietnam. In 2012, we recruited 216 mothers who were living in 10 communities around Bien Hoa Air Base and had delivered newborns at a prefecture hospital, and we investigated recent exposure levels of dioxins and nonortho PCBs in their breast milk. 2,3,7,8 Tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD) was present at 2.6 pg/g lipid in primiparae and 2.2 pg/g lipid in multiparae. Among multiparae and total subjects, significant high prevalence of 2,3,7,8-tetraCDD>=5 pg/g lipid and 2,3,7,8 tetraCDD contribution>=40% were observed in mothers living in the five communities closest to Bien Hoa Air Base. The TEQ for nonortho PCBs was 1.6 pg TEQ/g lipid for primiparae, and this was even lower than that in the unsprayed area. The length of residency was a strong factor to increase dioxins, including 2,3,7,8-tetraCDD. Residency in the five communities with the highest exposure was a specific risk factor for increased 2,3,7,8-tetraCDD in breast milk. Food intake might contribute partly to the increased levels of dioxin congeners other than 2,3,7,8-tetraCDD in breast milk. These results suggest that Bien Hoa Air Base has led to elevated 2,3,7,8-tetraCDD levels in breast milk of mothers in nearby areas even in the recent years. PMID- 25798922 TI - Overexpression of SIRT1 in rat skeletal muscle does not alter glucose induced insulin resistance. AB - SIRT1 is a NAD+-dependent deacetylase thought to regulate cellular metabolic pathways in response to alterations in nutrient flux. In the current study we investigated whether acute changes in SIRT1 expression affect markers of muscle mitochondrial content and also determined whether SIRT1 influenced muscle insulin resistance induced by acute glucose oversupply. In male Wistar rats either SIRT1 or a deacetylase inactive mutant form (H363Y) was electroprated into the tibialis cranialis (TC) muscle. The other leg was electroporated with an empty control vector. One week later, glucose was infused and hyperglycaemia was maintained at ~11mM. After 5 hours, 11mM glucose induced significant insulin resistance in skeletal muscle. Interestingly, overexpression of either SIRT1 or SIRT1 (H363Y) for 1 week did not change markers of mitochondrial content or function. SIRT1 or SIRT1 (H363Y) overexpression had no effect on the reduction in glucose uptake and glycogen synthesis in muscle in response to hyperglycemia. Therefore we conclude that acute increases in SIRT1 protein have little impact on mitochondrial content and that overexpressing SIRT1 does not prevent the development of insulin resistance during hyperglycaemia. PMID- 25798923 TI - Engineering Bi2O3-Bi2S3 heterostructure for superior lithium storage. AB - Bismuth oxide may be a promising battery material due to the high gravimetric (690 mAh g(-1)) and volumetric capacities (6280 mAh cm(-3)). However, this intrinsic merit has been compromised by insufficient Li-storage performance due to poor conductivity and structural integrity. Herein, we engineer a heterostructure composed of bismuth oxide (Bi2O3) and bismuth sulphide (Bi2S3) through sulfurization of Bi2O3 nanosheets. Such a hierarchical Bi2O3-Bi2S3 nanostructure can be employed as efficient electrode material for Li storage, due to the high surface areas, rich porosity, and unique heterogeneous phase. The electrochemical results show that the heterostructure exhibits a high Coulombic efficiency (83.7%), stable capacity delivery (433 mAh g(-1) after 100 cycles at 600 mA g(-1)) and remarkable rate capability (295 mAh g(-1) at 6 A g(-1)), notably outperforming reported bismuth based materials. Such superb performance indicates that constructing heterostructure could be a promising strategy towards high-performance electrodes for rechargeable batteries. PMID- 25798924 TI - Oligodendrocyte birth and death following traumatic brain injury in adult mice. AB - Oligodendrocytes are responsible for producing and maintaining myelin throughout the CNS. One of the pathological features observed following traumatic brain injury (TBI) is the progressive demyelination and degeneration of axons within white matter tracts. While the effect of TBI on axonal health has been well documented, there is limited information regarding the response of oligodendrocytes within these areas. The aim of this study was to characterize the response of both mature oligodendrocytes and immature proliferative oligodendrocyte lineage cells across a 3 month timecourse following TBI. A computer-controlled cortical impact model was used to produce a focal lesion in the left motor cortex of adult mice. Immunohistochemical analyses were performed at 48 hours, 7 days, 2 weeks, 5 weeks and 3 months following injury to assess the prevalence of mature CC-1+ oligodendrocyte cell death, immature Olig2+ cell proliferation and longer term survival in the corpus callosum and external capsule. Decreased CC-1 immunoreactivity was observed in white matter adjacent to the site of injury from 2 days to 2 weeks post TBI, with ongoing mature oligodendrocyte apoptosis after this time. Conversely, proliferation of Olig2+ cells was observed as early as 48 hours post TBI and significant numbers of these cells and their progeny survived and remained in the external capsule within the injured hemisphere until at least 3 months post injury. These findings demonstrate that immature oligodendrocyte lineage cells respond to TBI by replacing oligodendrocytes lost due to damage and that this process occurs for months after injury. PMID- 25798925 TI - Efficient hole-blocking layer-free planar halide perovskite thin-film solar cells. AB - Efficient lead halide perovskite solar cells use hole-blocking layers to help collection of photogenerated electrons and to achieve high open-circuit voltages. Here, we report the realization of efficient perovskite solar cells grown directly on fluorine-doped tin oxide-coated substrates without using any hole blocking layers. With ultraviolet-ozone treatment of the substrates, a planar Au/hole-transporting material/CH3NH3PbI3-xClx/substrate cell processed by a solution method has achieved a power conversion efficiency of over 14% and an open-circuit voltage of 1.06 V measured under reverse voltage scan. The open circuit voltage is as high as that of our best reference cell with a TiO2 hole blocking layer. Besides ultraviolet-ozone treatment, we find that involving Cl in the synthesis is another key for realizing high open-circuit voltage perovskite solar cells without hole-blocking layers. Our results suggest that TiO2 may not be the ultimate interfacial material for achieving high-performance perovskite solar cells. PMID- 25798926 TI - CCL21/CCR7 enhances the proliferation, migration, and invasion of human bladder cancer T24 cells. AB - OBJECTIVE: To investigate the effects of CCL21/CCR7 on the proliferation, migration, and invasion of T24 cells and the possible associated mechanisms: expression of MMP-2 and MMP-9, and regulation of BCL-2 and BAX proteins. METHODS: T24 cells received corresponding treatments including vehicle control, antibody (20 ng/mL CCR7 antibody and 50 ng/ml CCL21), and 50, 100, and 200 ng/ml CCL21. Proliferation was evaluated by MTT assay; cell migration and invasion were assayed using a transwell chamber. Cell apoptosis was induced by Adriamycin (ADM). The rate of cell apoptosis was examined by flow cytometry using annexin V FITC/PI staining. Western-blot was used to analyze MMP-2 and MMP-9 and BCL-2 and BAX proteins. RESULTS: CCL21 promoted T24 cell proliferation in concentration dependent manner with that 200 ng/mL induced the largest amount of proliferation. Significant differences of cell migration were found between CCL21treatment groups and the control group in both the migration and invasion studies (P < 0.001 for all). The expressions of MMP-2 and MMP-9 proteins were significantly increased after CCL21 treatment (p < 0.05 for all). Protein expression of Bcl-21 follows an ascending trend while the expression of Bax follows a descending trend as the concentration of CCL21 increases. No difference was found between the control group and antibody group for all assessments. CONCLUSION: CCL21/CCR7 promoted T24 cell proliferation and enhanced its migration and invasion via the increased expression of MMP-2 and MMP-9. CCL21/CCR7 had antiapoptotic activities on T24 cells via regulation of Bcl-2 and Bax proteins. CCL21/CCR7 may promote bladder cancer development and metastasis. PMID- 25798927 TI - Maternal gestational smoking, diabetes, alcohol drinking, pre-pregnancy obesity and the risk of cryptorchidism: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Maternal gestational smoking, diabetes, alcohol drinking, and pre pregnancy obesity are thought to increase the risk of cryptorchidism in newborn males, but the evidence is inconsistent. METHOD: We conducted a systematic review and meta-analysis of studies on the association between maternal gestational smoking, diabetes, alcohol drinking, and pre-pregnancy obesity and the risk of cryptorchidism. Articles were retrieved by searching PubMed and ScienceDirect, and the meta-analysis was conducted using Stata/SE 12.0 software. Sensitivity analysis was used to evaluate the influence of confounding variables. RESULTS: We selected 32 articles, including 12 case-control, five nested case-control, and 15 cohort studies. The meta-analysis showed that maternal smoking (OR = 1.17, 95% CI: 1.11-1.23) or diabetes (OR = 1.21, 95%CI: 1.00-1.46) during pregnancy were associated with increased risk of cryptorchidism. Overall, the association between maternal alcohol drinking (OR = 0.97, 95% CI: 0.87-1.07), pre-pregnancy body mass index (OR = 1.02, 95% CI: 0.95-1.09) and risk of cryptorchidism were not statistically significant. Additional analysis showed reduced risk (OR = 0.89, 95% CI: 0.82-0.96) of cryptorchidism with moderate alcohol drinking during pregnancy. No dose-response relationship was observed for increments in body mass index in the risk of cryptorchidism. Sensitivity analysis revealed an unstable result for the association between maternal diabetes, alcohol drinking and cryptorchidism. Moderate heterogeneity was detected in studies of the effect of maternal alcohol drinking and diabetes. No publication bias was detected. CONCLUSION: Maternal gestational smoking, but not maternal pre-pregnancy overweight or obesity, was associated with increased cryptorchidism risk in the offspring. Moderate alcohol drinking may reduce the risk of cryptorchidism while gestational diabetes may be a risk factor, but further studies are needed to verify this. PMID- 25798929 TI - Glial and light-dependent glutamate metabolism in the suprachiasmatic nuclei. AB - The suprachiasmatic nuclei, the main circadian clock in mammals, are entrained by light through glutamate released from retinal cells. Astrocytes are key players in glutamate metabolism but their role in the entrainment process is unknown. We studied the time dependence of glutamate uptake and glutamine synthetase (GS) activity finding diurnal oscillations in glutamate uptake (high levels during the light phase) and daily and circadian fluctuations in GS activity (higher during the light phase and the subjective day). These results show that glutamate related astroglial processes exhibit diurnal and circadian variations, which could affect photic entrainment of the circadian system. PMID- 25798928 TI - Analyses of the pathways involved in early- and late-phase induction of IFN-beta during C. muridarum infection of oviduct epithelial cells. AB - We previously reported that the IFN-beta secreted by Chlamydia muridarum-infected murine oviduct epithelial cells (OE cells) was mostly dependent on the TLR3 signaling pathway. To further characterize the mechanisms of IFN-beta synthesis during Chlamydia infection of OE cells in vitro, we utilized specific inhibitory drugs to clarify the roles of IRF3 and NF-kappaB on both early- and late-phase C. muridarum infections. Our results showed that the pathways involved in the early phase of IFN-beta production were distinct from that in the late-phase of IFN beta production. Disruption of IRF3 activation using an inhibitor of TBK-1 at early-phase Chlamydia infection had a significant impact on the overall synthesis of IFN-beta; however, disruption of IRF3 activation at late times during infection had no effect. Interestingly, inhibition of NF-kappaB early during Chlamydia infection also had a negative effect on IFN-beta production; however, its impact was not significant. Our data show that the transcription factor IRF7 was induced late during Chlamydia infection, which is indicative of a positive feedback mechanism of IFN-beta synthesis late during infection. In contrast, IRF7 appears to play little or no role in the early synthesis of IFN-beta during Chlamydia infection. Finally, we demonstrate that antibiotics that target chlamydial DNA replication are much more effective at reducing IFN-beta synthesis during infection versus antibiotics that target chlamydial transcription. These results provide evidence that early- and late-phase IFN-beta production have distinct signaling pathways in Chlamydia-infected OE cells, and suggest that Chlamydia DNA replication might provide a link to the currently unknown chlamydial PAMP for TLR3. PMID- 25798930 TI - Severe portal hypertension in cirrhosis: evaluation of perfusion parameters with contrast-enhanced ultrasonography. AB - OBJECTIVE: To investigate the role of contrast-enhanced ultrasonography (CEUS) and Doppler ultrasonography (DUS) in the diagnosis of severe portal hypertension (PH) in patients with liver cirrhosis (LC). METHODS: Patients with PH scheduled to receive hepatic venous pressure gradient (HVPG) measurement were recruited for this study. Hepatic DUS and CEUS were performed successively. Several Doppler and CEUS parameters were explored for correlation with HVPG values and their association with severe PH (>= 12 mmHg of HVPG). Comparison of the parameters between the severe and non-severe PH groups and their correlation with HVPG values was evaluated. A receiver operating characteristic (ROC) curve analysis was also performed to investigate the performance in order to diagnose severe PH. RESULTS: Fifty-three consecutive patients were enrolled in this study. Among them, 43 patients did not have significant ascites. Compared with the non-severe PH group, portal venous velocity and intrahepatic transit time (ITT) were significantly reduced in the severe PH group (all p<0.05). Difference between inspiratory and expiratory hepatic venous damping indices (DeltaHVDI), hepatic venous arrival time (HVAT) and ITT moderately correlated with HVPG (r = -0.358, 0.338, and -0.613, respectively). Areas under the curves for severe PH were 0.94 of ITT and 0.72 of HVAT, respectively (all p<0.05). ITT under 6 seconds indicated severe PH with a sensitivity of 92% and a specificity of 89%. CONCLUSIONS: Hepatic CEUS may be more useful in estimating the HVPG value and determining the presence of severe PH compared to DUS, and ITT was the most accurate parameter to diagnose severe PH. PMID- 25798931 TI - Crossmodal discrimination of 2 vs. 4 objects across touch and vision in 5-month old infants. AB - Infants are known to possess two different cognitive systems to encode numerical information. The first system encodes approximate numerosities, has no known upper limit and is functional from birth on. The second system relies on infants' ability to track up to 3 objects in parallel, and enables them to represent exact numerosity for such small sets. It is unclear, however, whether infants may be able to represent numerosities from all ranges in a common format. In various studies, infants failed to discriminate a small vs. a large numerosity (e.g., 2 vs. 4, 3 vs. 6), although more recent studies presented evidence that infants can succeed at these discriminations in some situations. Here, we used a transfer paradigm between the tactile and visual modalities in 5-month-olds, assuming that such cross-modal paradigm may promote access to abstract representations of numerosities, continuous across the small and large ranges. Infants were first familiarized with 2 to 4 objects in the tactile modality, and subsequently tested for their preference between 2 vs. 4, or 3 vs. 6 visual objects. Results were mixed, with only partial evidence that infants may have transferred numerical information across modalities. Implications on 5-month-old infants' ability to represent small and large numerosities in a single or in separate formats are discussed. PMID- 25798932 TI - An enantioselective approach to functionalized amino acids: total synthesis of antiepileptic drug (R)-lacosamide. AB - A short and highly efficient synthetic approach to enantiopure functionalized amino acids (FAAs) 1 skeleton from racemic butadiene monoepoxide as a starting material and its application to the total synthesis of an antiepileptic drug (R) lacosamide 2 are described. The synthesis utilizes the palladium catalyzed Trost's Dynamic Kinetic Asymmetric Transformation (DYKAT) as key step. PMID- 25798933 TI - TBI server: a web server for predicting ion effects in RNA folding. AB - BACKGROUND: Metal ions play a critical role in the stabilization of RNA structures. Therefore, accurate prediction of the ion effects in RNA folding can have a far-reaching impact on our understanding of RNA structure and function. Multivalent ions, especially Mg2+, are essential for RNA tertiary structure formation. These ions can possibly become strongly correlated in the close vicinity of RNA surface. Most of the currently available software packages, which have widespread success in predicting ion effects in biomolecular systems, however, do not explicitly account for the ion correlation effect. Therefore, it is important to develop a software package/web server for the prediction of ion electrostatics in RNA folding by including ion correlation effects. RESULTS: The TBI web server http://rna.physics.missouri.edu/tbi_index.html provides predictions for the total electrostatic free energy, the different free energy components, and the mean number and the most probable distributions of the bound ions. A novel feature of the TBI server is its ability to account for ion correlation and ion distribution fluctuation effects. CONCLUSIONS: By accounting for the ion correlation and fluctuation effects, the TBI server is a unique online tool for computing ion-mediated electrostatic properties for given RNA structures. The results can provide important data for in-depth analysis for ion effects in RNA folding including the ion-dependence of folding stability, ion uptake in the folding process, and the interplay between the different energetic components. PMID- 25798934 TI - Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds. AB - Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM) can persist in the absence of drugs for considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare. Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS). All treatment-naive individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR) determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities) and were included in the survival models as explanatory variables. In 857 sequential samples from 168 treatment-naive patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person years;CI=[51.4, 588.8] (for 184V) to 2.7/100-person-years;[0.7, 10.9] (for 215D). RR increased significantly with fitness cost (increase by 1.6[1.3,2.0] per standard deviation of fitness costs). When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates. Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation. PMID- 25798935 TI - Multiplexed tracking of combinatorial genomic mutations in engineered cell populations. AB - Multiplexed genome engineering approaches can be used to generate targeted genetic diversity in cell populations on laboratory timescales, but methods to track mutations and link them to phenotypes have been lacking. We present an approach for tracking combinatorial engineered libraries (TRACE) through the simultaneous mapping of millions of combinatorially engineered genomes at single cell resolution. Distal genomic sites are assembled into individual DNA constructs that are compatible with next-generation sequencing strategies. We used TRACE to map growth selection dynamics for Escherichia coli combinatorial libraries created by recursive multiplex recombineering at a depth 10(4)-fold greater than before. TRACE was used to identify genotype-to-phenotype correlations and to map the evolutionary trajectory of two individual combinatorial mutants in E. coli. Combinatorial mutations in the human ES2 ovarian carcinoma cell line were also assessed with TRACE. TRACE completes the combinatorial engineering cycle and enables more sophisticated approaches to genome engineering in both bacteria and eukaryotic cells than are currently possible. PMID- 25798936 TI - MutMap accelerates breeding of a salt-tolerant rice cultivar. PMID- 25798937 TI - Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. AB - Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy. PMID- 25798939 TI - Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. AB - Methods to introduce targeted double-strand breaks (DSBs) into DNA enable precise genome editing by increasing the rate at which externally supplied DNA fragments are incorporated into the genome through homologous recombination. The efficiency of these methods is limited by nonhomologous end joining (NHEJ), an alternative DNA repair pathway that competes with homology-directed repair (HDR). To promote HDR at the expense of NHEJ, we targeted DNA ligase IV, a key enzyme in the NHEJ pathway, using the inhibitor Scr7. Scr7 treatment increased the efficiency of HDR mediated genome editing, using Cas9 in mammalian cell lines and in mice for all four genes examined, up to 19-fold. This approach should be applicable to other customizable endonucleases, such as zinc finger nucleases and transcription activator-like effector nucleases, and to nonmammalian cells with sufficiently conserved mechanisms of NHEJ and HDR. PMID- 25798938 TI - Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. AB - Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes. PMID- 25798940 TI - Potent anti-proliferative, pro-apoptotic activity of the Maytenus royleanus extract against prostate cancer cells: evidence in in-vitro and in-vivo models. AB - Prostate cancer is a leading of cause of cancer related death in men. Despite intensive investment in improving early diagnosis, it often escapes timely detection. Mortality remains high in advanced stage prostate cancer where palliative care remains the only option. Effective strategies are therefore needed to prevent the occurrence and progression of the disease. Plant-derived compounds have been an important source of several clinically useful anti-cancer agents and offer an attractive approach against prostate cancer. We previously showed that the methanol extract of Maytenus royleanus (MEM) leaves and its fractions possess significant antioxidant activity with therapeutic potential against free-radical associated damages. The present study evaluated the anti proliferative activity of MEM in the prostate cancer model system. Analysis of MEM and its various fractions revealed the presence of triterpenoids, flavonoids and tannins, conjugated to one or more polar groups and carbohydrate moieties. Further studies against known standards established the existence of caffeic acid and quercetin 3-rhamnoside in varying concentration in different MEM fractions. Time course analysis of MEM treated prostate cancer cells indicated significant decrease in cell viability, assessed by MTT and clonogenic survival assays. This was accompanied by G2 phase arrest of cell cycle, downregulation of cyclin/cdk network and increase in cdk inhibitors. MEM treated cells exhibited cleavage of Caspase-3 and PARP, and modulation of apoptotic proteins, establishing apoptosis as the primary mechanism of cell death. Notably MEM suppressed AR/PSA signaling both in prostate cancer cell cultures and in the in vivo model. Intraperitoneal injection of MEM (1.25 and 2.5 mg/ animal) to athymic nude mice implanted with androgen sensitive CWR22Rnu1 cells showed significant inhibition in tumor growth and decreased serum PSA levels reciprocating in vitro findings. Taken together, our data suggest that MEM may be explored further for its potential therapeutic effects against prostate cancer progression in humans. PMID- 25798941 TI - The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice. AB - The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy. PMID- 25798943 TI - Letter to the Editor. PMID- 25798942 TI - The Fun30 chromatin remodeler Fft3 controls nuclear organization and chromatin structure of insulators and subtelomeres in fission yeast. AB - In eukaryotic cells, local chromatin structure and chromatin organization in the nucleus both influence transcriptional regulation. At the local level, the Fun30 chromatin remodeler Fft3 is essential for maintaining proper chromatin structure at centromeres and subtelomeres in fission yeast. Using genome-wide mapping and live cell imaging, we show that this role is linked to controlling nuclear organization of its targets. In fft3? cells, subtelomeres lose their association with the LEM domain protein Man1 at the nuclear periphery and move to the interior of the nucleus. Furthermore, genes in these domains are upregulated and active chromatin marks increase. Fft3 is also enriched at retrotransposon-derived long terminal repeat (LTR) elements and at tRNA genes. In cells lacking Fft3, these sites lose their peripheral positioning and show reduced nucleosome occupancy. We propose that Fft3 has a global role in mediating association between specific chromatin domains and the nuclear envelope. PMID- 25798944 TI - Temperature and oxygen dependent metabolite utilization by Salmonella enterica serovars Derby and Mbandaka. AB - Salmonella enterica is a zoonotic pathogen of clinical and veterinary significance, with over 2500 serovars. In previous work we compared two serovars displaying host associations inferred from isolation statistics. Here, to validate genome sequence data and to expand on the role of environmental metabolite constitution in host range determination we use a phenotypic microarray approach to assess the ability of these serovars to metabolise ~500 substrates at 25 degrees C with oxygen (aerobic conditions) to represent the ex vivo environment and at 37 degrees C with and without oxygen (aerobic/anaerobic conditions) to represent the in vivo environment. A total of 26 substrates elicited a significant difference in the rate of metabolism of which only one, D galactonic acid-g-lactone, could be explained by the presence (S. Mbandaka) or the absence (S. Derby) of metabolic genes. We find that S. Mbandaka respires more efficiently at ambient temperatures and under aerobic conditions on 18 substrates including: glucosominic acid, saccharic acid, trehalose, fumaric acid, maltotriose, N-acetyl-D-glucosamine, N-acetyl-beta-D-mannosamine, fucose, L serine and dihydroxy-acetone; whereas S. Derby is more metabolically competent anaerobically at 37 degrees C for dipeptides, glutamine-glutamine, alanine lysine, asparagine-glutamine and nitrogen sources glycine and nitrite. We conclude that the specific phenotype cannot be reliably predicted from the presence of metabolic genes directly relating to the metabolic pathways under study. PMID- 25798945 TI - Effect of Roux-en-Y gastric bypass surgery on bile acid metabolism in normal and obese diabetic rats. AB - In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB mediated changes in BA metabolism to further understand the role of BAs in RYGB induced metabolic effects in humans. PMID- 25798946 TI - CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity. AB - Patients with early stage, radial growth phase (RGP) melanoma have a 97% survival rate; however, when the melanoma progresses to the invasive vertical growth phase (VGP), survival rates decrease to 15%. The targets of many clinical trials are the known genetic and molecular mechanisms involved in melanoma progression, with the most common oncogenic mutation being the BRAFV600E. However, less than half of melanomas harbor this mutation, and consequently, do not respond to the current BRAF targeted treatments. It is therefore critical to elucidate alternative mechanisms regulating melanoma progression. Increased expression of the chemokine receptor, CXCR3, on melanoma cells is correlated with increased metastasis and poor patient outcomes, suggesting a role for CXCR3 in the RGP to VGP transition. We found that endogenous CXCR3 can be induced in two RGP cell lines, BOWES (BRAFWT) and WM35 (BRAFV600E), with in vitro environmental stress and nutrient deprivation. Signaling via induced endogenous CXCR3 is linked with IL-8 expression in BOWES cells. Ectopic overexpression of CXCR3 in BOWES cells leads to increased ligand-mediated phERK, cellular migration, and IL-8 expression in vitro, and to increased tumorigenesis and lymph node metastasis in vivo. Our results demonstrate that, in BRAFWT melanomas, CXCR3 signaling mediates significant increases in IL-8 expression, suggesting that CXCR3 expression and signaling may represent a transformative event that drives the progression of BRAFWT melanomas. IMPLICATIONS: Expression of CXCR3 on BRAFWT melanoma cells may be a mediator of melanoma progression. PMID- 25798947 TI - Whole exome sequencing identifies mutations in Usher syndrome genes in profoundly deaf Tunisian patients. AB - Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss. PMID- 25798948 TI - Policies and programs to facilitate access to targeted cancer therapies in Thailand. AB - BACKGROUND: Increasing access to clinically beneficial targeted cancer medicines is a challenge in every country due to their high cost. We describe the interplay of innovative policies and programs involving multiple stakeholders to facilitate access to these medicines in Thailand, as well as the utilization of selected targeted therapies over time. METHODS: We selected two medicines on the 2013 Thai national list of essential medicines (NLEM) [letrozole and imatinib] and three unlisted medicines for the same indications [trastuzumab, nilotinib and dasatinib]. We created timelines of access policies and programs for these products based on scientific and grey literature. Using IMS Health sales data, we described the trajectories of sales volumes of the study medicines between January 2001 and December 2012. We compared estimated average numbers of patients treated before and after the implementation of policies and programs for each product. RESULTS: Different stakeholders implemented multiple interventions to increase access to the study medicines for different patient populations. During 2007-2009, the Thai Government created a special NLEM category with different coverage requirements for payers and issued compulsory licenses; payers negotiated prices with manufacturers and engaged in pooled procurement; pharmaceutical companies expanded patient assistance programs and lowered prices in different ways. Compared to before the interventions, estimated numbers of patients treated with each medicine increased significantly afterwards: for letrozole from 645 (95% CI 366-923) to 3683 (95% CI 2,748-4,618); for imatinib from 103 (95% CI 72-174) to 350 (95% CI 307-398); and for trastuzumab from 68 (95% CI 45-118) to 412 (95% CI 344-563). CONCLUSIONS: Government, payers, and manufacturers implemented multi-pronged approaches to facilitate access to targeted cancer therapies for the Thai population, which differed by medicine. Routine monitoring is needed to assess clinical and economic impacts of these strategies in the health system. PMID- 25798949 TI - The initial inflammatory response to bioactive implants is characterized by NETosis. AB - Implants trigger an inflammatory response, which is important for osseointegration. Here we studied neutrophil extracellular trap (NET) release of human neutrophils in response to sandblasted large-grit acid etched (SLA) implants using fluorescent, confocal laser scanning and scanning electron microscopy. Our studies demonstrate that human neutrophils rapidly adhered to SLA surfaces, which triggered histone citrullination and NET release. Further studies showed that albumin or acetylsalicylic acid had no significant effects on the inflammatory response to SLA surfaces. In contrast to bioinert materials, which do not osseointegrate, the bioactivity of SLA surfaces is coupled with the ability to release NETs. Further investigations are necessary for clarifying the role of NETosis for osseointegration. PMID- 25798952 TI - Well-defined phosphino-phenolate neutral nickel(II) catalysts for efficient (co)polymerization of norbornene and ethylene. AB - Phosphino-phenolate neutral nickel catalysts 1-3/B(C6F5)3, without the help of any organoaluminum compound, were found to be efficient catalytic systems for norbornene polymerization and its copolymerization with norbornene derivatives. The amount of B(C6F5)3 required for achieving a high efficiency (3 equiv.) was markedly lower compared to previous reports, and high molecular weight polymers were obtained (>10(6) g mol(-1)). Efficient incorporation of polar monomers NBC, NBA, and NBM was also achieved in a controllable fashion, yielding high molecular weight copolymers. Catalysts 1-3 were highly active for ethylene polymerization as single component catalysts, with an activity of up to 10(7) g molNi(-1) h(-1), and catalyst 3 was more readily initiated at lower temperature. Catalysts 1-3 were also efficient in incorporating norbornene (up to 30%) into the polyethylene backbone. Bisligated phosphino-phenolate nickel complex 4 and salicylaldimine complex 5 were also studied for comparison, which further verified the unique performance of catalysts 1-3. Preliminary NMR analyses were conducted to explore the norbornene polymerization mechanism. PMID- 25798950 TI - Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase. AB - Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate KM values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface. PMID- 25798951 TI - Linking human health and livestock health: a "one-health" platform for integrated analysis of human health, livestock health, and economic welfare in livestock dependent communities. AB - BACKGROUND: For most rural households in sub-Saharan Africa, healthy livestock play a key role in averting the burden associated with zoonotic diseases, and in meeting household nutritional and socio-economic needs. However, there is limited understanding of the complex nutritional, socio-economic, and zoonotic pathways that link livestock health to human health and welfare. Here we describe a platform for integrated human health, animal health and economic welfare analysis designed to address this challenge. We provide baseline epidemiological data on disease syndromes in humans and the animals they keep, and provide examples of relationships between human health, animal health and household socio-economic status. METHOD: We designed a study to obtain syndromic disease data in animals along with economic and behavioral information for 1500 rural households in Western Kenya already participating in a human syndromic disease surveillance study. Data collection started in February 2013, and each household is visited bi weekly and data on four human syndromes (fever, jaundice, diarrhea and respiratory illness) and nine animal syndromes (death, respiratory, reproductive, musculoskeletal, nervous, urogenital, digestive, udder disorders, and skin disorders in cattle, sheep, goats and chickens) are collected. Additionally, data from a comprehensive socio-economic survey is collected every 3 months in each of the study households. FINDINGS: Data from the first year of study showed 93% of the households owned at least one form of livestock (55%, 19%, 41% and 88% own cattle, sheep, goats and chickens respectively). Digestive disorders, mainly diarrhea episodes, were the most common syndromes observed in cattle, goats and sheep, accounting for 56% of all livestock syndromes, followed by respiratory illnesses (18%). In humans, respiratory illnesses accounted for 54% of all illnesses reported, followed by acute febrile illnesses (40%) and diarrhea illnesses (5%). While controlling for household size, the incidence of human illness increased 1.31-fold for every 10 cases of animal illness or death observed (95% CI 1.16-1.49). Access and utilization of animal source foods such as milk and eggs were positively associated with the number of cattle and chickens owned by the household. Additionally, health care seeking was correlated with household incomes and wealth, which were in turn correlated with livestock herd size. CONCLUSION: This study platform provides a unique longitudinal dataset that allows for the determination and quantification of linkages between human and animal health, including the impact of healthy animals on human disease averted, malnutrition, household educational attainment, and income levels. PMID- 25798953 TI - Unlocking Bloch-type chirality in ultrathin magnets through uniaxial strain. AB - Chiral magnetic domain walls are of great interest because lifting the energetic degeneracy of left- and right-handed spin textures in magnetic domain walls enables fast current-driven domain wall propagation. Although two types of magnetic domain walls are known to exist in magnetic thin films, Bloch- and Neel walls, up to now the stabilization of homochirality was restricted to Neel-type domain walls. Since the driving mechanism of thin-film magnetic chirality, the interfacial Dzyaloshinskii-Moriya interaction, is thought to vanish in Bloch-type walls, homochiral Bloch walls have remained elusive. Here we use real-space imaging of the spin texture in iron/nickel bilayers on tungsten to show that chiral domain walls of mixed Bloch-type and Neel-type can indeed be stabilized by adding uniaxial strain in the presence of interfacial Dzyaloshinskii-Moriya interaction. Our findings introduce Bloch-type chirality as a new spin texture, which may open up new opportunities to design spin-orbitronics devices. PMID- 25798954 TI - Optimization of pre-emptive isolations in a polyvalent ICU through implementation of an intervention strategy. AB - BACKGROUND: Pre-emptive isolation refers to the application of contact precaution measures in patients with strongly suspected colonization by multiresistant bacteria. OBJECTIVE: To assess the impact of an intervention program involving the implementation of a consensus-based protocol of pre-emptive isolation (CPPI) on admission to a polyvalent ICU of a general hospital. METHODS: A comparative analysis of 2 patient cohorts was made: a historical cohort including patients in which pre-emptive isolation was established according to physician criterion prior to starting CPPI (from January 2010 to February 2011), and a prospective cohort including patients in which CPPI was implemented (from March to November 2011). CPPI included the identification and diffusion of pre-emptive isolation criteria, the definition of sampling methodology, the evaluation of results, and the development of criteria for discontinuation of pre-emptive isolation. Pre emptive isolation was indicated by the medical staff, and follow-up was conducted by the nursing staff. Pre-emptive isolation was defined as "adequate" when at least one multiresistant bacteria was identified in any of the samples. Comparison of data between the 2 periods was made with the chi-square test for categorical variables and the Student t-test for quantitative variables. Statistical significance was set at P<.05. RESULTS: Among the 1,740 patients admitted to the ICU (1,055 during the first period and 685 during the second period), pre-emptive isolation was indicated in 199 (11.4%); 111 (10.5%) of these subjects corresponded to the historical cohort (control group) and 88 (12.8%) to the posterior phase after the implementation of CPPI (intervention group). No differences were found in age, APACHE II score or patient characteristics between the 2 periods. The implementation of CPPI was related to decreases in non indicated pre-emptive isolations (29.7 vs. 6.8%, P<.001), time of requesting surveillance cultures (1.56 vs. 0.37 days, P<.001), and days of duration of treatment (4.77 vs. 3.58 days, P<.001). In 44 patients (22.1%) in which pre emptive isolation was indicated, more than one multiresistant bacteria was identified, with an "adequate pre-emptive isolation rate" of 19.8% in the first period and 25.0% in the second period (P<.382). CONCLUSIONS: The implementation of CPPI resulted in a significant decrease in pre-emptive isolations which were not indicated correctly, a decrease in the time elapsed between isolation and collection of samples, and a decrease in the duration of isolation measures in cases in which isolation was unnecessary, without increasing the rate of "adequate pre-emptive isolation". PMID- 25798955 TI - [Patients treated with micafungin during their stay in intensive care unit]. AB - OBJECTIVES: To determine the reasons of prescription, the characteristics of patients and factors that affected the outcome of critically ill patients treated with micafungin (MCF) during their stay in Spanish ICUs. MATERIAL AND METHODS: Observational, retrospective and multicenter study. Patients admitted to the ICU between March 2011 and October 2012 (20-month period) treated with MCF for any reason were included in the study. Severity of patients at the beginning of treatment was measured with the APACHE II, SOFA, Child-Pugh and MELD scores. Reasons for the use of MCF were classified as prophylaxis, preemptive treatment, empirical treatment and directed treatment. Continuous variables are expressed as mean and standard deviation or median, and categorical variables as percentages. A multivariate analysis was performed to identify variables related to intra-ICU mortality. RESULTS: The study population included 139 patients admitted to 19 Spanish ICUs, with a mean age of 57.3 (17.1) years, 89 (64%) men, with surgical (53.2%) and/or medical (44.6%) conditions, APACHE II score of 20.6 (7.7) and SOFA score of 8.4 (4.3), with 84.2% of patients requiring mechanical ventilation, 59% parenteral nutrition, 37.4% extrarenal depuration procedures and 37.4% treatment with steroids. MCF was indicated as empirical treatment of a proven infection in 51 (36.7%) cases, pre-emptive treatment in 50 (36%) especially as a result of the application of the Candida score (32 cases), directed treatment of fungal infection in 23 (16.5%) and as prophylactic treatment in 15 (10.8%) cases. In 108 (77%) cases, a daily dose of 100mg was administered, with a loading dose in only 9 cases (6.5%). The mean duration of treatment was 13.1 (13) days. A total of 59 (42.4%) patients died during their stay in the ICU and 16 after ICU discharge (hospital mortality 53.9%). Independent risk factors for intra-ICU mortality were the Child-Pugh score (OR 1.45, 95% CI 1.162-1.813; P=.001) and the MELD score (OR 1.05, 95% CI 1.011-1.099; P=.014). CONCLUSIONS: MCF is usually administered at a dose of 100mg/day, without loading dose and in 72.7% of cases as pre-emptive or empirical treatment. Factors that better predicted mortality were indicators of liver insufficiency at the time of starting treatment. PMID- 25798957 TI - Left Retrocaval Ureter around the Ipsilateral Limb of a Double Caudal Vena Cava in a Cat. AB - Necropsy examination of an adult neutered male cat, which was humanely destroyed as it had feline immunodeficiency virus (FIV) infection, demonstrated the presence of a left retrocaval ureter that was entrapped around the left limb of a double caudal vena cava. These associated anomalies originate from the complex embryofetal development of the caudal vena cava. Since no clinical signs had been reported and no gross lesions related to this anomaly were observed, this manifestation should be simply considered as an anatomical variation. PMID- 25798956 TI - [Usefulness of copeptin in discarding non-ST elevation acute myocardial infarction in patients with acute chest pain and negative first troponin I]. AB - AIM: To evaluate the usefulness of copeptin as a rapid and reliable marker for discarding non-ST elevation acute myocardial infarction (NSTEMI) in patients attended in an Emergency Care Department due to acute chest pain with a normal or non-diagnostic electrocardiogram and a negative first troponin I result. DESIGN: A prospective observational study was carried out. SETTING: The Emergency Care Department of a university hospital. PATIENTS: The study comprised a total of 97 patients attended in the Emergency Care Department due to chest pain suggestive of acute coronary syndrome with an evolution of under 12h, a non-diagnostic electrocardiogram and a negative first troponin I result. INTERVENTIONS: None. VARIABLES OF INTEREST: Patient demographic data and baseline characteristics, copeptin upon admission, troponin I upon admission and after 6h, and final diagnosis. RESULTS: The final diagnosis was NSTEMI in 14 patients (14.4%) -no significant differences in copeptin concentration being observed between the 2 groups, though a tendency towards higher values was recorded in the NSTEMI group (median: 24.6pmol/l [interquartile range: 42.0] vs. 12.0pmol/l [16.1]; P=.06). The AUC ROC for copeptin upon admission was 0.657 (95%CI: 0.504-0.810), with a negative predictive value of 92% for a cutoff point of 14pmol/l. CONCLUSIONS: Copeptin determination upon admission to the Emergency Care Department in patients with chest pain for <=12h, suggestive of acute coronary syndrome, with a non-diagnostic electrocardiogram and a negative first troponin I determination does not allow rapid and reliable exclusion of the presence of NSTEMI. Serial troponin I measurements are needed in this respect. PMID- 25798958 TI - Diverse CD36 expression among Japanese population: defective CD36 mutations cause platelet and monocyte CD36 reductions in not only deficient but also normal phenotype subjects. AB - INTRODUCTION: CD36 is a multifunctional glycoprotein expressed on various human cells, including platelets and monocytes. Five CD36 gene mutations (C268T, 949insA, 329-339del, 1228-1239del and 629-631del/insAAAAC) are mainly responsible for CD36-deficient phenotypes in Japan. It has also been reported that platelet CD36 expression varies widely among normal phenotype individuals. Here, in order to obtain further insight into CD36 expression, we investigated the association between platelet and monocyte CD36 expression levels and defective mutations in the Japanese population. MATERIALS AND METHODS: Blood samples were collected from 135 healthy Japanese volunteers. CD36 expression levels on platelets and monocytes were quantitatively analyzed by flow cytometry. Real-time PCR, PCR-RFLP and allele-specific PCR were performed to detect mutant genotypes. RESULTS: In this population, we found 2 (1.5%) and 9 (6.7%) CD36-deficient subjects as type I and type II, respectively. Among normal phenotype subjects, CD36 expression levels ranged from 1,259 to 11,002 (4,487+/-2,017) molecules/platelet and from 211 to 5,150 (1,628+/-986) molecules/monocyte. Genotyping assay showed that heterozygotes with the defective mutations were present in normal (12.9%) and type II-deficient (66.7%) subjects, and that these heterozygous mutations led to decreases in CD36 surface expression on platelets and monocytes. CONCLUSIONS: Heterozygous CD36 mutations, previously known to lead to deficiency in this molecule, are one of the factors responsible for the diversity of CD36 surface expression levels on platelets and monocytes in normal phenotype subjects. PMID- 25798959 TI - The developmental dynamics of children's academic performance and mothers' homework-related affect and practices. AB - This study investigated the longitudinal associations between children's academic performance and their mothers' affect, practices, and perceptions of their children in homework situations. The children's (n = 2,261) performance in reading and math was tested in Grade 1 and Grade 4, and the mothers (n = 1,476) filled out questionnaires on their affect, practices, and perceptions while their children were in Grades 2, 3, and 4. The results showed, first, that the more help in homework the mothers reported, the slower was the development of their children's academic performance from Grade 1 to Grade 4. This negative association was true especially if mothers perceived their children not to be able to work autonomously. Second, children's good academic performance in Grade 1 predicted mothers' perception of child's ability to be autonomous and positive affect in homework situations later on, whereas poor performance predicted mothers' negative affect, help, and monitoring. Finally, mothers' negative affect mediated the association between children's poor performance, maternal practices, and perceptions of their children. PMID- 25798960 TI - Diagnosis and surgical treatment of stress urinary incontinence. PMID- 25798961 TI - In reply. PMID- 25798962 TI - Postterm, postdates, and prolonged pregnancy: need for simplification of terminology. PMID- 25798963 TI - In reply. PMID- 25798964 TI - Identification of iPhone and iPad applications for obstetrics and gynecology providers. PMID- 25798965 TI - In reply. PMID- 25798966 TI - Postablation risk factors for pain and subsequent hysterectomy. PMID- 25798967 TI - Postablation risk factors for pain and subsequent hysterectomy. PMID- 25798968 TI - In reply. PMID- 25798969 TI - Advanced reproductive age and maternal mortality. PMID- 25798970 TI - In reply. PMID- 25798971 TI - In reply. PMID- 25798972 TI - Enough already! PMID- 25798973 TI - In reply. PMID- 25798974 TI - Enough already! PMID- 25798975 TI - In reply. PMID- 25798976 TI - Medicaid pregnancy termination funding and racial disparities in congenital anomaly-related infant deaths. PMID- 25798977 TI - In reply. PMID- 25798978 TI - Posttraumatic stress disorder and risk of spontaneous preterm birth. PMID- 25798979 TI - Posttraumatic stress disorder and risk of spontaneous preterm birth. PMID- 25798980 TI - In reply. PMID- 25798985 TI - Practice Bulletin No. 148: Thyroid disease in pregnancy. PMID- 25798986 TI - Practice Bulletin No. 149: Endometrial cancer. PMID- 25798987 TI - Committee Opinion No. 629: Clinical guidelines and standardization of practice to improve outcomes. AB - Protocols and checklists have been shown to reduce patient harm through improved standardization and communication. Implementation of protocols and guidelines often is delayed because of lack of health care provider awareness or difficult clinical algorithms in medical institutions. However, the use of checklists and protocols clearly has been demonstrated to improve outcomes and their use is strongly encouraged. Checklists and protocols should be incorporated into systems as a way to help practitioners provide the best evidence-based care to their patients. PMID- 25798988 TI - Synthesis, crystal structure and anaerobic DNA photocleavage of ruthenium complexes [Ru(tpy)(dpoq)Cl](+) and [Ru(tpy)(dpoq)CH3CN](2.). AB - Two new Ru(II) complexes [Ru(tpy)(dpoq)Cl](+)1 and [Ru(tpy)(dpoq)CH3CN](2+)2 (tpy = 2,2':6',2''-terpyridine; dpoq = dipyrido[1,2,5]oxadiazolo[3,4-b]quinoxaline) have been synthesized and characterized by elemental analysis, (1)H NMR, electrospray ionization mass spectra (ESI-MS) and X-ray crystallographic study. The experimental results of spectra titration, thermal denaturation and viscosity measurements suggest that the two complexes intercalatively bind to DNA. When irradiated under light, the two complexes could efficiently photocleave DNA both under aerobic and anaerobic condition. The mechanism studies reveal that the photocleavage reaction functions through both oxygen-independent (photoinduced electron transfer, type III reaction) and oxygen-dependent (singlet oxygen generation, type II reaction) pathways and the oxygen-independent pathway is the major process. These complexes will be more promising photodynamic therapy (PDT) candidates used for treating hypoxic tumors. PMID- 25798989 TI - Rhenium(I) polypyridine dibenzocyclooctyne complexes as phosphorescent bioorthogonal probes: Synthesis, characterization, emissive behavior, and biolabeling properties. AB - We report the development of rhenium(I) polypyridine complexes appended with a dibenzocyclooctyne (DIBO) moiety as bioorthogonal probes for azide-modified biomolecules. Three phosphorescent rhenium(I) polypyridine DIBO complexes [Re(N^N)(CO)3(py-C6-DIBO)][CF3SO3] (py-C6-DIBO=3-(N-(6-(3,4:7,8 dibenzocyclooctyne-5-oxycarbonylamino)hexyl)aminocarbonyl)pyridine; N^N=1,10 phenanthroline (phen) (1a), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen) (2a), 4,7-diphenyl-1,10-phenanthroline (Ph2-phen) (3a)) and their DIBO-free counterparts [Re(N^N)(CO)3(py-C6-BOC)][CF3SO3] (py-C6-BOC=3-(N-(6-(tert butoxycarbonylamino)hexyl)aminocarbonyl)pyridine; N^N=phen (1b), Me4-phen (2b), Ph2-phen (3b)) were synthesized and characterized. Upon photoexcitation, all the complexes displayed intense and long-lived yellow triplet metal-to-ligand charge transfer ((3)MLCT) (dpi(Re)->pi*(N^N)) emission. The DIBO complexes underwent facile reactions with benzyl azide in methanol at 298 K with second-order rate constants (k2) in the range of 0.077 to 0.091 M(-1) s(-1). As revealed from SDS PAGE analysis, the DIBO complexes can selectively label azide-modified proteins and the resulting bioconjugates displayed strong phosphorescence upon photoexcitation. Results of inductively coupled plasma mass spectrometry (ICP-MS) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays indicated that the DIBO complexes accumulated in Chinese Hamster Ovary (CHO) cells with considerable cytotoxic activity. Upon incubation of CHO cells with these complexes, relatively weak intracellular emission was observed. In contrast, upon pretreatment of the cells with 1,3,4,6-tetra-O-acetyl-N azidoacetyl-D-mannosamine (Ac4ManNAz), intense emission was observed from the cell membrane and some internal compartments. The results suggest that the DIBO complexes are promising candidates for imaging azide-labeled biomolecules. PMID- 25798990 TI - Effects of choice architecture and chef-enhanced meals on the selection and consumption of healthier school foods: a randomized clinical trial. AB - IMPORTANCE: Little is known about the long-term effect of a chef-enhanced menu on healthier food selection and consumption in school lunchrooms. In addition, it remains unclear if extended exposure to other strategies to promote healthier foods (eg, choice architecture) also improves food selection or consumption. OBJECTIVE: To evaluate the short- and long-term effects of chef-enhanced meals and extended exposure to choice architecture on healthier school food selection and consumption. DESIGN, SETTING, AND PARTICIPANTS: A school-based randomized clinical trial was conducted during the 2011-2012 school year among 14 elementary and middle schools in 2 urban, low-income school districts (intent-to-treat analysis). Included in the study were 2638 students in grades 3 through 8 attending participating schools (38.4% of eligible participants). INTERVENTIONS: Schools were first randomized to receive a professional chef to improve school meal palatability (chef schools) or to a delayed intervention (control group). To assess the effect of choice architecture (smart cafe), all schools after 3 months were then randomized to the smart cafe intervention or to the control group. MAIN OUTCOMES AND MEASURES: School food selection was recorded, and consumption was measured using plate waste methods. RESULTS: After 3 months, vegetable selection increased in chef vs control schools (odds ratio [OR], 1.75; 95% CI, 1.36-2.24), but there was no effect on the selection of other components or on meal consumption. After long-term or extended exposure to the chef or smart cafe intervention, fruit selection increased in the chef (OR, 3.08; 95% CI, 2.23 4.25), smart cafe (OR, 1.45; 95% CI, 1.13-1.87), and chef plus smart cafe (OR, 3.10; 95% CI, 2.26-4.25) schools compared with the control schools, and consumption increased in the chef schools (OR, 0.17; 95% CI, 0.03-0.30 cups/d). Vegetable selection increased in the chef (OR, 2.54; 95% CI, 1.83-3.54), smart cafe (OR, 1.91; 95% CI, 1.46-2.50), and chef plus smart cafe schools (OR, 7.38, 95% CI, 5.26-10.35) compared with the control schools, and consumption also increased in the chef (OR, 0.16; 95% CI, 0.09-0.22 cups/d) and chef plus smart cafe (OR, 0.13; 95% CI, 0.05-0.19 cups/d) schools; however, the smart cafe intervention alone had no effect on consumption. CONCLUSIONS AND RELEVANCE: Schools should consider both collaborating with chefs and using choice architecture to increase fruit and vegetable selection. Efforts to improve the taste of school foods through chef-enhanced meals should remain a priority because this was the only method that also increased consumption. This was observed only after students were repeatedly exposed to the new foods for 7 months. Therefore, schools should not abandon healthier options if they are initially met with resistance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02309840. PMID- 25798991 TI - A bio-inspired memory model embedded with a causality reasoning function for structural fault location. AB - Structural health monitoring (SHM) is challenged by massive data storage pressure and structural fault location. In response to these issues, a bio-inspired memory model that is embedded with a causality reasoning function is proposed for fault location. First, the SHM data for processing are divided into three temporal memory areas to control data volume reasonably. Second, the inherent potential of the causal relationships in structural state monitoring is mined. Causality and dependence indices are also proposed to establish the mechanism of quantitative description of the reason and result events. Third, a mechanism of causality reasoning is developed for the reason and result events to locate faults in a SHM system. Finally, a deformation experiment conducted on a steel spring plate demonstrates that the proposed model can be applied to real-time acquisition, compact data storage, and system fault location in a SHM system. Moreover, the model is compared with some typical methods based on an experimental benchmark dataset. PMID- 25798992 TI - Binding of methylene blue onto Langmuir monolayers representing cell membranes may explain its efficiency as photosensitizer in photodynamic therapy. AB - We provide evidence for the electrostatic interactions between the cationic photosensitizer methylene blue (MB) and cell membrane models represented by neat and mixed Langmuir monolayers of dioleylphosphatidylcholine (DOPC) and 1,1',2,2' tetraoleoylcardiolipin (CL). From surface pressure measurements, MB was found to adsorb strongly and expand CL-containing monolayers, while it caused an apparent decreasing in molecular area on neat DOPC monolayer. The binding site of MB could be inferred from data with the surface-specific polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS) technique, where changes induced by MB were observed in the vibrational modes of the phosphate groups of both CL and DOPC. The incorporation of MB also affected the carbonyl groups and the packing of the alkyl chains, thus indicating that MB binding site favors singlet oxygen generation close to the double bonds in the alkyl chains, an important requirement for photodynamic efficiency. Significantly, the data presented here demonstrate that MB may act in membranes composed by PCs, such as mammalian plasma membranes, and in those containing CL, as in bacterial and inner mitochondrial membranes. PMID- 25798993 TI - Hydrocarbon stapled peptides as modulators of biological function. AB - Peptide-based drug discovery has experienced a significant upturn within the past decade since the introduction of chemical modifications and unnatural amino acids has allowed for overcoming some of the drawbacks associated with peptide therapeutics. Strengthened by such features, modified peptides become capable of occupying a niche that emerges between the two major classes of today's therapeutics-small molecules (<500 Da) and biologics (>5000 Da). Stabilized alpha helices have proven particularly successful at impairing disease-relevant PPIs previously considered "undruggable." Among those, hydrocarbon stapled alpha helical peptides have emerged as a novel class of potential peptide therapeutics. This review provides a comprehensive overview of the development and applications of hydrocarbon stapled peptides discussing the benefits and limitations of this technique. PMID- 25798995 TI - The effect of simvastatin treatment on bone repair of femoral fracture in animal model. AB - The aim of this research was to evaluate the fracture healing area in osteoporotic femur of female rats restrained by stainless steel wire by statin administration in two different doses (5 mg and 20 mg). Ninety female rats were divided into six groups (n = 15): SH, SH-5 mg, SH-20 mg, OVX, OVX-5 mg, and OVX 20 mg. The surgery consisted of the fracture of the left femur bone and stabilization by K-wire and the administration was restricted and weekly controlled in the drinking water. The euthanasia was conducted at three different moments, five animals per period: 7 d, 14 d, and 28 d. Densitometry, zymography, and histological analyses showed a significant difference between some groups. According to these findings, simvastatin promoted a positive action for bone repair, especially in the osteometabolic group treated with 20 mg of the drug. PMID- 25798994 TI - The practice of cranial neurosurgery and the malpractice liability environment in the United States. AB - OBJECT: The potential imbalance between malpractice liability cost and quality of care has been an issue of debate. We investigated the association of malpractice liability with unfavorable outcomes and increased hospitalization charges in cranial neurosurgery. METHODS: We performed a retrospective cohort study involving patients who underwent cranial neurosurgical procedures from 2005-2010, and were registered in the National Inpatient Sample (NIS) database. We used data from the National Practitioner Data Bank (NPDB) from 2005 to 2010 to create measures of volume and size of malpractice claim payments. The association of the latter with the state-level mortality, length of stay (LOS), unfavorable discharge, and hospitalization charges for cranial neurosurgery was investigated. RESULTS: During the study period, there were 189,103 patients (mean age 46.4 years, with 48.3% females) who underwent cranial neurosurgical procedures, and were registered in NIS. In a multivariable regression, higher number of claims per physician in a state was associated with increased ln-transformed hospitalization charges (beta 0.18; 95% CI, 0.17 to 0.19). On the contrary, there was no association with mortality (OR 1.00; 95% CI, 0.94 to 1.06). We observed a small association with unfavorable discharge (OR 1.09; 95% CI, 1.06 to 1.13), and LOS (beta 0.01; 95% CI, 0.002 to 0.03). The size of the awarded claims demonstrated similar relationships. The average claims payment size (ln transformed) (Pearson's rho=0.435, P=0.01) demonstrated a positive correlation with the risk-adjusted hospitalization charges but did not demonstrate a correlation with mortality, unfavorable discharge, or LOS. CONCLUSIONS: In the present national study, aggressive malpractice environment was not correlated with mortality but was associated with higher hospitalization charges after cranial neurosurgery. In view of the association of malpractice with the economics of healthcare, further research on its impact is necessary. PMID- 25798996 TI - Synthesis and biological evaluation of novel structure-related hGHRH agonistic analogs. AB - Activity and half-life play key roles in the application of GHRH analogues. The GHRH monomers produced in a solid synthesizer were incubated, respectively, in NH4OH solution and lyophilized to obtain their dimers. The activities, specificities, and receptor affinities of the GHRH dimers were evaluated in rGH release/inhibition, rACTH/LH/PRL release, pituitary homogenate binding, and fluorescent staining. Compared to hGHRH(1-44)NH2 (S), PP-hGHRH(1-44)-GGC-CGG hGHRH(44-1)-PP (2D), P-hGHRH(1-44)-GGC-CGG-hGHRH(44-1)-P (2E), (1)P-hGHRH(2-44) GGC-CGG-hGHRH(44-2)-(1)P (2F), or hGHRH(1-44)-GGC-CGG-hGHRH(44-1) (2Y) had potency of 104 +/- 16.7%, 94 +/- 32.6%, 114 +/- 16.6%, or 122 +/- 14.5% and similar specificities. The inhibition effect of GHIH on rGH stimulated by GHRH dimer was in dose-/time-dependent manner. The staining of FITC-labeled dimer showed cytomembrane distribution and the binding ranking was 2F>2D>2Y>2E>S. 2F presents the strongest activity and the highest affinity to pituitary cells. The dimer with (1)Pro-GHRH stimulates stronger rGH release than that with (1)Tyr-GHRH and the N-terminal single cyclic amino acid is required for the stimulation. PMID- 25798997 TI - Quantification of ventricular repolarization heterogeneity during moxifloxacin or sotalol administration using [Formula: see text]-index. AB - Drug-induced alterations of ventricular heterogeneity must be limited to avoid induction of lethal ventricular arrhythmias. In here, a new parameter called [Formula: see text]-index, able to measure the standard deviation of myocites' repolarization times, was evaluated after moxifloxacin and sotalol administration. The two drugs are known to provide different alteration of the QT interval length ranging from subtle (moxifloxacin) to evident (sotalol). In fact, while the former is employed as active-comparator in thorough QT studies, the latter might induce torsades de pointes. 24 h Holter ECGs of 39 (sotalol) and 68 (moxifloxacin) healthy subjects were retrospectively analyzed. The recordings were performed after infusion of the drugs and after the placebo (moxifloxacin) or at baseline (sotalol). The corrected QT interval (QTc) was included as well in the study, for a direct comparison. In both populations, [Formula: see text] index and QTc increased along with the drugs' serum concentration and were statistically different from values in the placebo arm or at baseline (p < 0.05).With sotalol, the maximum value of [Formula: see text]-index occurred, on average, after 5.64 h from the infusion, whereas for QTc after about 4.27 h. The two metrics displayed evident changes ([Formula: see text]-index: 27.79 ms +/- 4.89 ms versus 60.13 ms +/- 18.52 ms; QT corrected: 387.07 ms +/- 19.84 ms versus 437.76 +/- 32.05 ms; p < 0.05). Regarding moxifloxacin, maximum values were reached, on average, 5.01 h after administration for [Formula: see text]-index (30.70 ms +/- 8.32 ms versus 40.48 ms +/- 7.61 ms; p < 0.05), and 4.37 h for QTc (404.29 ms +/- 29.05 ms versus 426.77 +/- 36.67 ms; p < 0.05). They were statistically different from baseline values. With both drugs, the maximal percent variation after administration was higher for [Formula: see text]-index than QTc (moxifloxacin: 34.56% +/- 24.60% versus 5.56% +/- 2.98% ; sotalol: 114.77% +/- 33.15% versus 12.13% +/- 2.85% ; p < 0.05).The study suggests that the standard deviation of the ventricular repolarization times, as quantified by the [Formula: see text]-index, might be an effective measure of spatial heterogeneity. PMID- 25798998 TI - Cardiovascular neural regulation is impaired in amyotrophic lateral sclerosis patients. A study by spectral and complexity analysis of cardiovascular oscillations. AB - Although the clinical hallmark of amyotrophic lateral sclerosis (ALS) is a progressive motor weakness, different combinations of autonomic nervous system (ANS) dysfunction have been described. No clear correlation between ANS abnormalities and ALS clinical characteristics has been found so far. We investigated the cardiovascular neural regulation in ALS with a non-invasive methodology, using spectral and complexity analysis of heart rate variability (HRV) and systolic arterial pressure (SAP) variability. In all patients, we found low RR variance and an altered response to orthostasis, witnessed by the indices derived from both spectral and complexity analysis of HRV and SAP variability. Besides, we identified two groups with distinct autonomic profiles at rest, those with higher, and those with lower cardiac sympathetic activity. In both groups the cardiovascular response to tilting was impaired. Our study outlined that ANS is invariably impaired in ALS, and patients can present with different baseline patterns. Our findings suggest important pathophysiological, clinical and prognostic insights. The presence of different autonomic profiles at rest supports the new concept of ALS as a multisystem disorder with phenotypic heterogeneity. Our results are also relevant in clinical practice. They can help to improve patients' management, and to identify prognostic factors. PMID- 25799000 TI - A hanging plasmonic droplet: three-dimensional SERS hotspots for a highly sensitive multiplex detection of amino acids. AB - A novel and simple platform for an efficient SERS detection was demonstrated in a hanging plasmonic droplet of Ag sols by virtue of three-dimensional (3D) SERS hotspots. The platform was a single droplet of concentrated Ag sols with analytes hung on a hydrophobically treated transparent cover glass. Liquid adhesive force, solvent evaporation, and hydrophobic interaction induced a concentration of dense nanoparticles into a 3D space. The generated 3D hotspots enable the highly sensitive detection of ultratrace analytes and simultaneous multiplex identification of different amino acids, which are well-known molecules with low Raman cross-sections. This platform demonstrates an excellent mechanical stability and is suitable for the excellent examination of ultratrace analytes, with detection limits as low as 0.01 fmol of dye molecules and 5 pmol of amino acids with extremely low Raman cross-sections. PMID- 25798999 TI - Imaging human brown adipose tissue under room temperature conditions with (11)C MRB, a selective norepinephrine transporter PET ligand. AB - INTRODUCTION: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS: Ten healthy, Caucasian subjects (5 M: age 24.6+/-2.6, BMI 21.6+/-2.7kg/m(2); 5 F: age 25.4+/-2.1, BMI 22.1+/-1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15 degrees C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS: As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0+/-0.3 vs. cold 1.1+/-0.3, p=0.31; BAT/muscle DVR: RT 2.3+/-0.7 vs. cold 2.5+/-0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS: Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions. PMID- 25799001 TI - Usefulness of an app in improving oral hygiene compliance in adolescent orthodontic patients. AB - OBJECTIVE: To evaluate the influence of an app-based approach in a protocol for domestic oral hygiene maintenance in a group of adolescent patients wearing fixed multibracket appliances. MATERIALS AND METHODS: Eighty adolescent patients scheduled to start an orthodontic multibracket treatment were randomly divided into two groups of 40. Plaque index (PI), gingival index (GI), white spots (WS), and caries presence were recorded in all patients, and they were instructed regarding domestic oral hygiene maintenance on the day of braces application (t0) and every 3 months (t1, t2, t3, t4) during the first year of treatment. Study group (SG) patients were enrolled in a WhatsApp chat room-based competition and instructed to share monthly with the other participants two self-photographs (selfies) showing their oral hygiene status. RESULTS: SG patient participation in the chat room was regular and active throughout the observation period. At t2, t3, and t4, SG patients had significantly lower values of both PI and GI and a lower incidence of new WS and caries, compared with the control group. CONCLUSION: Integration of new "social" technologies in a standard oral hygiene motivation protocol is effective in improving compliance of adolescent patients and in improving their oral health status during orthodontic multibracket treatment. PMID- 25799002 TI - Single-molecule super-resolution microscopy reveals how light couples to a plasmonic nanoantenna on the nanometer scale. AB - The greatly enhanced fields near metal nanoparticles have demonstrated remarkable optical properties and are promising for applications from solar energy to biosensing. However, direct experimental study of these light-matter interactions at the nanoscale has remained difficult due to the limitations of optical microscopy. Here, we use single-molecule fluorescence imaging to probe how a plasmonic nanoantenna modifies the fluorescence emission from a dipole emitter. We show that the apparent fluorophore emission position is strongly shifted upon coupling to an antenna and that the emission of dyes located up to 90 nm away is affected by this coupling. To predict this long-ranged effect, we present a framework based on a distance-dependent partial coupling of the dye emission to the antenna. Our direct interpretation of these light-matter interactions will enable more predictably optimized, designed, and controlled plasmonic devices and will permit reliable plasmon-enhanced single-molecule nanoscopy. PMID- 25799003 TI - Secular changes in late-life cognition and well-being: Towards a long bright future with a short brisk ending? AB - How sociocultural contexts shape individual functioning is of prime interest for psychological inquiry. Secular increases favoring later-born cohorts in fluid intelligence measures are widely documented for young adults. In the current study, we quantified such trends in old age using data from highly comparable participants living in a narrowly defined geographical area and examined whether these trends would generalize to quality-of-life indicators. To do so, we compared data obtained 20 years apart in the Berlin Aging Study (in 1990-1993) and the Berlin Aging Study II (in 2013-2014), applied a case-matched control design (per cohort, n = 161, Mage = 75), quantified sample selection using a nationally representative sample as the reference, and controlled for number of physical diseases. The later cohort performed better on the fluid intelligence measure (d = .85) and reported higher morale, less negative affect, and more positive affect (ds > .39) than the earlier cohort. We concluded that secular advances have resulted in better cognitive performance and perceived quality of life among older adults and discuss when and how advantages of later cohorts reach their limits. PMID- 25799004 TI - The natural frequency of human prospective memory increases with age. AB - Autobiographical memory (AM), the recollection of past experiences, and prospective memory (PM), the prospection of future events, are prominent components of subjective life, yet data on the frequencies of their occurrence are limited. Using experience sampling, we quantified the incidence of AM and PM in natural settings among various age groups. Individuals of all ages reported engaging in AM approximately 10% of the time. In contrast, whereas younger subjects recalled PMs as often as they recalled AMs, older subjects experienced PM twice as frequently. AM occurrence was positively correlated with PM occurrence, most strongly among younger individuals. AM and PM durations were also positively correlated and remarkably stable across age groups. Together, these data identify an age-associated shift in the temporal orientation of recollection and quantify the relationship between AM and PM. More broadly, this approach provides a quantitative foundation of AM and PM occurrence, a crucial yet largely unexplored dimension of recollection. PMID- 25799005 TI - N-Heterocyclic carbene-catalyzed annulation of cyclic beta-enamino esters with enals: access to functionalized indolo[2,3-a]quinolizidines. AB - A novel synthetic approach to functionalized indolo[2,3-a]quinolizidines is developed via an N-heterocyclic carbene (NHC)-catalyzed annulation of cyclic beta enamino esters with enals . This methodology offers a pathway for quick and efficient construction of an indolo[2,3-a]quinolizidine skeleton which is a core structure of many natural products with diverse bioactivities. PMID- 25799006 TI - Protein arginine methyltransferase 10 is required for androgen-dependent proliferation of LNCaP prostate cancer cells. AB - Androgen receptor (AR) signaling is the master regulator of prostate cell growth. Here, to better understand AR signaling, we searched for AR-interacting proteins by yeast two-hybrid screening and identified protein arginine methyltransferase 10 (PRMT10) as one of the interacting proteins. PRMT10 was highly expressed in reproductive tissues, such as prostate. Immunostaining showed that PRMT10 was expressed in the nucleus of both epithelia and stroma of rat prostate. In human prostate cancer LNCaP cells, PRMT10 co-immunoprecipitated with AR in both the presence and absence of dihydrotestosterone (DHT). Knockdown of PRMT10 by siRNA decreased DHT-dependent LNCaP cell growth and induction of prostate-specific antigen, an AR-target gene, without apparent loss of AR. DHT decreased PRMT10 at both the mRNA and protein levels. The decrease in PRMT10 was canceled by knockdown of AR or an AR antagonist. These results indicate that PRMT10 plays an important role in androgen-dependent proliferation of prostate cancer cells. PMID- 25799007 TI - Screening and treating subclinical thyroid disease: getting past the impasse. PMID- 25799008 TI - Dead element replicating: degenerate R2 element replication and rDNA genomic turnover in the Bacillus rossius stick insect (Insecta: Phasmida). AB - R2 is an extensively investigated non-LTR retrotransposon that specifically inserts into the 28S rRNA gene sequences of a wide range of metazoans, disrupting its functionality. During R2 integration, first strand synthesis can be incomplete so that 5' end deleted copies are occasionally inserted. While active R2 copies repopulate the locus by retrotransposing, the non-functional truncated elements should frequently be eliminated by molecular drive processes leading to the concerted evolution of the rDNA array(s). Although, multiple R2 lineages have been discovered in the genome of many animals, the rDNA of the stick insect Bacillus rossius exhibits a peculiar situation: it harbors both a canonical, functional R2 element (R2Brfun) as well as a full-length but degenerate element (R2Brdeg). An intensive sequencing survey in the present study reveals that all truncated variants in stick insects are present in multiple copies suggesting they were duplicated by unequal recombination. Sequencing results also demonstrate that all R2Brdeg copies are full-length, i. e. they have no associated 5' end deletions, and functional assays indicate they have lost the active ribozyme necessary for R2 RNA maturation. Although it cannot be completely ruled out, it seems unlikely that the degenerate elements replicate via reverse transcription, exploiting the R2Brfun element enzymatic machinery, but rather via genomic amplification of inserted 28S by unequal recombination. That inactive copies (both R2Brdeg or 5'-truncated elements) are not eliminated in a short term in stick insects contrasts with findings for the Drosophila R2, suggesting a widely different management of rDNA loci and a lower efficiency of the molecular drive while achieving the concerted evolution. PMID- 25799009 TI - Assessing the perception of trunk movements in military personnel with chronic non-specific low back pain using a virtual mirror. AB - Chronic pain, including chronic non-specific low back pain (CNSLBP), is often associated with body perception disturbances, but these have generally been assessed under static conditions. The objective of this study was to use a "virtual mirror" that scaled visual movement feedback to assess body perception during active movement in military personnel with CNSLBP (n = 15) as compared to military healthy control subjects (n = 15). Subjects performed a trunk flexion task while sitting and standing in front of a large screen displaying a full-body virtual mirror-image (avatar) in real-time. Avatar movements were scaled to appear greater, identical, or smaller than the subjects' actual movements. A total of 126 trials with 11 different scaling factors were pseudo-randomized across 6 blocks. After each trial, subjects had to decide whether the avatar's movements were "greater" or "smaller" than their own movements. Based on this two alternative forced choice paradigm, a psychophysical curve was fitted to the data for each subject, and several metrics were derived from this curve. In addition, task adherence (kinematics) and virtual reality immersion were assessed. Groups displayed a similar ability to discriminate between different levels of movement scaling. Still, subjects with CNSLBP showed an abnormal performance and tended to overestimate their own movements (a right-shifted psychophysical curve). Subjects showed adequate task adherence, and on average virtual reality immersion was reported to be very good. In conclusion, these results extend previous work in patients with CNSLBP, and denote an important relationship between body perception, movement and pain. As such, the assessment of body perception during active movement can offer new avenues for understanding and managing body perception disturbances and abnormal movement patterns in patients with pain. PMID- 25799010 TI - Construction of DNA hemicatenanes from two small circular DNA molecules. AB - DNA hemicatenanes, one of the simplest possible junctions between two double stranded DNA molecules, have frequently been mentioned in the literature for their possible function in DNA replication, recombination, repair, and organization in chromosomes. They have been little studied experimentally, however, due to the lack of an appropriate method for their preparation. Here we have designed a method to build hemicatenanes from two small circular DNA molecules. The method involves, first, the assembly of two linear single strands and their circularization to form a catenane of two single stranded circles, and, second, the addition and base-pairing of the two single stranded circles complementary to the first ones, followed by their annealing using DNA topoisomerase I. The product was purified by gel electrophoresis and characterized. The arrangement of strands was as expected for a hemicatenane and clearly distinct from a full catenane. In addition, each circle was unwound by an average of half a double helical turn, also in excellent agreement with the structure of a hemicatenane. It was also observed that hemicatenanes are quickly destabilized by a single cut on either of the two strands passing inside the junction, strongly suggesting that DNA strands are able to slide easily inside the hemicatenane. This method should make it possible to study the biochemical properties of hemicatenanes and to test some of the hypotheses that have been proposed about their function, including a possible role for this structure in the organization of complex genomes in loops and chromosomal domains. PMID- 25799013 TI - Mild coronary artery stenosis has no impact on cardiac and vascular parameters in miniature swine exposed to positive acceleration stress. AB - BACKGROUND: Exposure of pilots' heart to acceleration-associated stress (+Gz stress) is an adverse effect of high-performance aviation. The occurrence of coronary heart diseases is one of the most frequent medical causes leading to cessation of flying. AIM: To assess the effects of +Gz stress on coronary artery stenosis (CAS) in a minimally invasive miniature swine model with a fast recovery. METHODS: The proximal left anterior descending branch was ligated in 20 swine using silk suture. CAS degree (mild, moderate, severe) was analyzed by quantitative computerized angiography. Five swine underwent a sham operation. +Gz stress exposure was performed and venous blood was collected before/after exposure. Plasma C-reactive protein (CRP), endothelin (ET)-1, angiotensin (Ang) II and urotensin 2 (U2) levels were measured. RESULTS: CAS models were successful in 18 animals. Two swine exhibited ventricular fibrillation during the procedure and died. Plasma CRP, ET-1, Ang II and U2 changed significantly after maximal tolerated +Gz stress exposure (all P < 0.05). After maximal tolerated +Gz stress exposure, plasma CRP, ET-1, Ang II and U2 levels increased in the moderate and severe stenosis groups, compared with the sham group (all P < 0.05), but there was no significant difference between the mild stenosis group and the sham group (all P > 0.05). CONCLUSION: The fully endoscopic operation method successfully generated animal models of different degrees of CAS. Plasma CRP, ET-1, Ang II and U2 levels increased after +Gz stress exposure with increasing CAS severity. Animals with mild stenosis showed no ill effect under +Gz stress, suggesting that pilots with mild stenosis might be allowed to continue flying, but it must be confirmed in humans. PMID- 25799012 TI - SNP marker discovery in koala TLR genes. AB - Toll-like receptors (TLRs) play a crucial role in the early defence against invading pathogens, yet our understanding of TLRs in marsupial immunity is limited. Here, we describe the characterisation of nine TLRs from a koala immune tissue transcriptome and one TLR from a draft sequence of the koala genome and the subsequent development of an assay to study genetic diversity in these genes. We surveyed genetic diversity in 20 koalas from New South Wales, Australia and showed that one gene, TLR10 is monomorphic, while the other nine TLR genes have between two and 12 alleles. 40 SNPs (16 non-synonymous) were identified across the ten TLR genes. These markers provide a springboard to future studies on innate immunity in the koala, a species under threat from two major infectious diseases. PMID- 25799014 TI - Vitamin D and falls-fitting new data with current guidelines. PMID- 25799011 TI - Vitamin D metabolic pathway genes and pancreatic cancer risk. AB - Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (<=50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk. PMID- 25799015 TI - Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. AB - The optimal antiaggregant therapy after coronary stenting in patients receiving oral anticoagulants (OACs) is currently debated. MEDLINE and Cochrane Library were searched for studies reporting outcomes of patients who underwent PCI and who were on triple therapy (TT) or dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel or dual therapy (DT) with OAC and clopidogrel. Major bleeding was the primary end point, whereas all-cause death, myocardial infarction (MI), stent thrombosis, and stroke were secondary ones. Results were reported for all studies and separately for those deriving from randomized controlled trials or multivariate analysis. In 9 studies, 1,317 patients were treated with DAPT and 1,547 with TT. DAPT offered a significant reduction of major bleeding at 1 year for overall studies and for the subset of observational works providing adjusted data (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.39 to 0.68, I2 60% and OR 0.36, 95% CI 0.28 to 0.46) compared to TT. No increased risk of major adverse cardiac events (MACE: death, MI, stroke, and stent thrombosis) was reported (OR 0.71, 95% CI 0.46 to 1.08), although not deriving from randomized controlled trials or multivariate analysis. Six studies tested OAC and clopidogrel (1,263 patients) versus OAC, aspirin, and clopidogrel (3,055 patients) with a significant reduction of bleeding (OR 0.79, 95% CI 0.64 to 0.98), without affecting rates of death, MI, stroke, and stent thrombosis (OR 0.90, 95% CI 0.69 to 1.23) also when including clinical data from randomized controlled trials or multivariate analysis. In conclusion, compared to TT, both aspirin and clopidogrel and clopidogrel and OAC reduce bleeding. No difference in major adverse cardiac events is present for clopidogrel and OAC, whereas only low-grade evidence is present for aspirin and clopidogrel. PMID- 25799016 TI - Should the price for cardiac rehabilitation programs be increased? PMID- 25799017 TI - Effects of wind waves versus ship waves on tidal marsh plants: a flume study on different life stages of Scirpus maritimus. AB - Recent research indicates that many ecosystems, including intertidal marshes, follow the alternative stable states theory. This theory implies that thresholds of environmental factors can mark a limit between two opposing stable ecosystem states, e.g. vegetated marshes and bare mudflats. While elevation relative to mean sea level is considered as the overall threshold condition for colonization of mudflats by vegetation, little is known about the individual driving mechanisms, in particular the impact of waves, and more specifically of wave period. We studied the impact of different wave regimes on plants in a full scale flume experiment. Seedlings and adult shoots of the pioneer Scirpus maritimus were subjected to two wave periods at two water levels. Drag forces acting on, and sediment scouring occurring around the plants were quantified, as these are the two main mechanisms determining plant establishment and survival. Depending on life stage, two distinct survival strategies emerge: seedlings present a stress avoidance strategy by being extremely flexible, thus limiting the drag forces and thereby the risk of breaking. Adult shoots present a stress tolerance strategy by having stiffer stems, which gives them a higher resistance to breaking. These strategies work well under natural, short period wind wave conditions. For long period waves, however, caused e.g. by ships, these survival strategies have a high chance to fail as the flexibility of seedlings and stiffness of adults lead to plant tissue failure and extreme drag forces respectively. This results in both cases in strongly bent plant stems, potentially limiting their survival. PMID- 25799018 TI - A new molybdenum nitride catalyst with rhombohedral MoS2 structure for hydrogenation applications. AB - Nitrogen-rich transition-metal nitrides hold great promise to be the next generation catalysts for clean and renewable energy applications. However, incorporation of nitrogen into the crystalline lattices of transition metals is thermodynamically unfavorable at atmospheric pressure; most of the known transition metal nitrides are nitrogen-deficient with molar ratios of N:metal less than a unity. In this work, we have formulated a high-pressure route for the synthesis of a nitrogen-rich molybdenum nitride through a solid-state ion exchange reaction. The newly discovered nitride, 3R-MoN2, adopts a rhombohedral R3m structure, isotypic with MoS2. This new nitride exhibits catalytic activities that are three times more active than the traditional catalyst MoS2 for the hydrodesulfurization of dibenzothiophene and more than twice as high in the selectivity to hydrogenation. The nitride is also catalytically active in sour methanation of syngas with >80% CO and H2 conversion at 723 K. Our formulated route for the synthesis of 3R-MoN2 is at a moderate pressure of 3.5 GPa and, thus, is feasible for industrial-scale catalyst production. PMID- 25799019 TI - Correction: genomic characterisation of three mapputta group viruses, a serogroup of Australian and papua new guinean bunyaviruses associated with human disease. PMID- 25799020 TI - Electrographic waveform structure predicts laminar focus location in a model of temporal lobe seizures in vitro. AB - Temporal lobe epilepsy is the most common form of partial-onset epilepsy and accounts for the majority of adult epilepsy cases in most countries. A critical role for the hippocampus (and to some extent amygdala) in the pathology of these epilepsies is clear, with selective removal of these regions almost as effective as temporal lobectomy in reducing subsequent seizure risk. However, there is debate about whether hippocampus is 'victim' or 'perpetrator': The structure is ideally placed to 'broadcast' epileptiform activity to a great many other brain regions, but removal often leaves epileptiform events still occurring in cortex, particularly in adjacent areas, and recruitment of the hippocampus into seizure like activity has been shown to be difficult in clinically-relevant models. Using a very simple model of acute epileptiform activity with known, single primary pathology (GABAA Receptor partial blockade), we track the onset and propagation of epileptiform events in hippocampus, parahippocampal areas and neocortex. In this model the hippocampus acts as a potential seizure focus for the majority of observed events. Events with hippocampal focus were far more readily propagated throughout parahippocampal areas and into neocortex than vice versa. The electrographic signature of events of hippocampal origin was significantly different to those of primary neocortical origin - a consequence of differential laminar activation. These data confirm the critical role of the hippocampus in epileptiform activity generation in the temporal lobe and suggest the morphology of non-invasive electrical recording of neocortical interictal events may be useful in confirming this role. PMID- 25799021 TI - Comparison of contrast-enhanced isotropic 3D-GRE-T1WI sequence versus conventional non-isotropic sequence on preoperative staging of cervical cancer. AB - PURPOSE: To compare contrast-enhanced isotropic 3D-GRE-T1WI sequence vs. conventional non-isotropic sequence in terms of image quality, estimated signal to-noise ratio (eSNR), relative tumor contrast and performance of cervical cancer staging. METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. Seventy-one patients (47 +/- 9.4 years), with pathologically-confirmed cervical cancer underwent axial contrast enhanced 1 mm3 isotropic 3D-GRE-T1WI sequence (herein referred to Isotropy), and 3-mm-thick non-isotropic sagittal and coronal sequences. Image quality score, eSNR and relative contrast between tumor to myometrium, gluteal muscle, and fat respectively, were compared between 3-mm-thick reconstructed images from Isotropy and directly scanned non-isotropic images by paired t-test. Difference in tumor staging obtained from Isotropy and combined Three-planes including reconstructed axial images, directly scanned sagittal and coronal sequence were compared by McNemar test. RESULTS: Both sequences showed similar image quality. Reconstructed images demonstrated higher eSNR, equal or lower relative tumor contrast compared with non-isotropic images. Compared with performing diagnosis on Three-planes, both reviewers showed higher accuracy when diagnosing vaginal invasion on Isotropy (p = 0.039 and 0.003, respectively). CONCLUSION: Compared with non isotropic sequence, 3.0T MR isotropic 3D-GRE-T1WI sequence exhibited better eSNR, providing more reliable clinical information for preoperative staging of cervical cancer. PMID- 25799022 TI - S100 calcium-binding protein A6 promotes epithelial-mesenchymal transition through beta-catenin in pancreatic cancer cell line. AB - The pathogenesis of pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. S100 calcium-binding protein A6 (S100A6) has been associated with PDAC; however, the effect of S100A6 on PDAC migration and invasion has not yet been explored. In this study, Panc-1 cells were transfected with a plasmid to induce overexpression of S100A6, and beta-catenin was knocked down using a specific short hairpin RNA (shRNA). The wound-healing and Transwell assays demonstrated that S100A6 promoted PDAC cell migration and invasion. Furthermore, beta-catenin shRNA inhibited the migration and invasion of PDAC cells. We confirmed that S100A6 induces PDAC cell migration and invasion via activation of beta-catenin in vitro. Assessment of mRNA and protein levels revealed that S100A6 induces increased expression of beta-catenin, N-cadherin and vimentin, and decreased expression of E-cadherin in PDAC cells. beta-catenin shRNA also altered the expression of epithelial-mesenchymal transition (EMT)-related markers in PDAC cells. Specifically, expression of E-cadherin was increased, whereas expression of N-cadherin and vimentin was decreased. Finally, we demonstrated that S100A6 alters the expression of EMT-related markers via beta-catenin activation. In conclusion, S100A6 induces EMT and promotes cell migration and invasion in a beta catenin-dependent manner. S100A6 may therefore represent a novel potential therapeutic target for the treatment of pancreatic cancer. PMID- 25799025 TI - Urban and rural fitness level: comparison between Italian and Croatian students. AB - The goal of this study was to investigate the differences in physical fitness in relation to urban or rural living environment and between two countries: Italy and Croatia. Over 14,000 students were tested during physical education (PE) lessons. Croatian students were taller and heavier than Italian students, with women achieving better results in flexibility. Urban students were fitter in abdominal strength than rural students. Age seemed to be the major factor influencing the performance. This study's results indicate a trend: urban students performed "indoor" tests better than rural students; the opposite may be true for rural students. Living environment, socio-economic-status, or cultural correlation differences could be decreased during school experiences. Thus, PE programs could train all people toward an adequate, age-based fitness level. PMID- 25799023 TI - Amelioration of Atherosclerosis by the New Medicinal Mushroom Grifola gargal Singer. AB - The beneficial effects of edible mushrooms for improving chronic intractable diseases have been documented. However, the antiatherogenic activity of the new medicinal mushroom Grifola gargal is unknown. Therefore, we evaluated whether Grifola gargal can prevent or delay the progression of atherosclerosis. Atherosclerosis was induced in ApoE lipoprotein-deficient mice by subcutaneous infusion of angiotensin II. Grifola gargal extract (GGE) was prepared and intraperitoneally injected. The weight of heart and vessels, dilatation/atheroma formation of thoracic and abdominal aorta, the percentage of peripheral granulocytes, and the blood concentration of MCP-1/CCL2 were significantly reduced in mice treated with GGE compared to untreated mice. By contrast, the percentage of regulatory T cells and the plasma concentration of SDF-1/CXCL12 were significantly increased in mice treated with the mushroom extract compared to untreated mice. In vitro, GGE significantly increased the secretion of SDF 1/CXCL12, VEGF, and TGF-beta1 from fibroblasts compared to control. This study demonstrated for the first time that Grifola gargal therapy can enhance regulatory T cells and ameliorate atherosclerosis in mice. PMID- 25799026 TI - Effects of practice on variability of muscle force. AB - The motor skill required to decrease the variability in muscle force steadiness can be challenging. The purposes of this study were to determine whether muscle force steadiness improved following repeated trials and whether the number of trials varied for healthy younger adults, healthy older adults, and older adults who have fallen to obtain stable muscle force steadiness measures. Sixty participants performed 30 concentric and eccentric contractions of the knee extensors on an isokinetic dynamometer. Each group had significant improvements in muscle force steadiness and obtained stable measures within six to nine trials. Healthy younger and older adults, and older adults who have fallen, can improve muscle force steadiness. These findings provide a framework for methodological approaches when testing steadiness in varying populations. PMID- 25799024 TI - Web-based psychotherapy for posttraumatic stress disorder in war-traumatized Arab patients: randomized controlled trial. AB - BACKGROUND: In recent years, armed conflicts in the Middle East have resulted in high rates of exposure to traumatic events. Despite the increasing demand of mental health care provision, ongoing violence limits conventional approaches of mental health care provision. Internet-based interventions for posttraumatic stress disorder (PTSD) have proved feasible and effective in Western countries, but their applicability and efficacy in war and conflict regions remains unknown. OBJECTIVE: This study investigated the efficacy of a cognitive behavioral Internet-based intervention for war-traumatized Arab patients, with focus on Iraq. METHODS: A total of 159 individuals with PTSD participated in a parallel group randomized trial. Participants were randomly allocated by a computer generated sequence to a treatment group (n=79) or a waiting list control group (n=80). The treatment group received 2 weekly 45-minute cognitive behavioral interventions via Internet over a 5-week period (10 sessions in total). The primary outcome was recovery from posttraumatic stress symptoms. RESULTS: Posttraumatic stress symptoms were significantly reduced from baseline to posttreatment (intention-to-treat analysis) in the treatment group relative to the control group (F1,157=44.29, P<.001, d=0.92). Treatment effects were sustained at 3-month follow-up. Completer analysis indicated that 29 of 47 patients (62%) in the treatment group had recovered from posttraumatic stress symptoms at posttreatment (reliable change and Posttraumatic Stress Diagnostic Scale score <20) versus 1 patient (2%) in the control group (OR 74.19, 95% CI 9.93-585.8, P<.001) indicating that the chance of recovering was 74.19 times higher in the treatment than in the control group. CONCLUSIONS: The results indicate, even in unstable and insecure settings with ongoing exposure to human rights violations through war and dictatorships, people with posttraumatic stress symptoms benefit from a cognitive behavioral treatment provided entirely through the Internet. This method of delivery could improve patients' access to humanitarian aid in the form of e-mental health services. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12611001019998; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347505 (Archived by WebCite at http://www.webcitation.org/6Wto4HCdH). PMID- 25799027 TI - Influence of spatial accuracy constraints on reaction time and maximum speed of performance of unilateral movements. AB - The goal was to study reaction time and maximal velocity of upper limbs of healthy young adults of both sexes during transition from a simple to a more involved task. Performance of dominant and non-dominant arms was recorded. Participants were 43 healthy, right-handed, untrained men (n=22) and women (n=21), 18-22 years old. The simple task required a single jerk-like movement. The involved task required both speed and accuracy where necessity for high speed of performance was emphasized. The effectiveness of transition between tasks was calculated for both reaction time and maximal velocity. No lateral differences were found. Men usually had a shorter reaction time on both tasks and a higher maximal velocity in the simple task. Women were more effective at modifying velocity. PMID- 25799028 TI - Paths with more turns are perceived as longer: misperceptions with map-based and abstracted path stimuli. AB - When navigating, people tend to overestimate distances when routes contain more turns, termed the route-angularity effect. Three experiments examined the source and generality of this effect. The first two experiments examined whether route angularity effects occur while viewing maps and might be related to sex differences or sense of direction. The third experiment tested whether the route angularity effect would occur with stimuli devoid of spatial context, reducing influences of environmental experience and visual complexity. In the three experiments, participants (N=1,552; M=32.2 yr.; 992 men, 560 women) viewed paths plotted on maps (Exps. 1 and 2) or against a blank background (Exp. 3). The depicted paths were always the same overall length, but varied in the number of turns (from 1 to 7) connecting an origin and destination. Participants were asked to estimate the time to traverse each path (Exp. 1) or the length of each path (Exps. 2 and 3). The Santa Barbara Sense of Direction questionnaire was administered to assess whether overall spatial sense of direction would be negatively related to the magnitude of the route-angularity effect. Repeated measures analyses of variance (ANOVAs) indicated that paths with more turns elicited estimates of greater distance and travel times, whether they were depicted on maps or blank backgrounds. Linear regressions also indicated that these effects were significantly larger in those with a relatively low sense of direction. The results support the route-angularity effect and extend it to paths plotted on map-based stimuli. Furthermore, because the route-angularity effect was shown with paths plotted against blank backgrounds, route-angularity effects are not specific to understanding environments and may arise at the level of visual perception. PMID- 25799029 TI - Errata. PMID- 25799030 TI - The Godin-Shephard leisure-time physical activity questionnaire: validity evidence supporting its use for classifying healthy adults into active and insufficiently active categories. AB - This study provided validity evidence for the Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) to classify respondents into active and insufficiently active categories. Members of a fitness center [45 women and 55 men; mean (SD) age=45.5 (10.6) yr.] completed the questionnaire. Using only moderate and strenuous scores, those with a leisure score index>=24 were classified as active; those with a score<=23 were classified as insufficiently active. VO2max, percentage of body fat, and electronic records of fitness center attendance were the validation variables. In a visit to the fitness center, participants completed the GSLTPAQ and a certified exercise specialist performed a physical fitness evaluation. A multivariate analysis of covariance (MANCOVA) indicated the group of respondents classified as active had higher VO2max and lower percentage of body fat than the group of respondents classified as insufficiently active. An analysis of covariance (ANCOVA) indicated the group of respondents classified as active had higher electronic records of fitness center attendance than the group of respondents classified as insufficiently active. Therefore, these pieces of validity evidence support the use of the questionnaire's classification system among healthy adults. PMID- 25799031 TI - Performance by middle school children with and without asthma on the pacer. AB - Asthma is a chronic lung disease characterized by airway hyper-reactivity, inflammation, and obstruction. Asthma is also a leading cause of school absenteeism, and thus of concern to physical educators and health professionals. The purpose of this study was to assess aerobic performance by children with and without asthma. All participants were tested on the Progressive Aerobic Cardiovascular Endurance Run (PACER). Of particular interest was children's aerobic performance over an extended time, i.e., 15 months. Participants (Grades 4-8, N=809) were tested on the PACER three times during the school year with two follow-up tests during the succeeding school year. Among the 809 participants were 103 children with mild-moderate asthma. Hierarchical Linear Modeling (HLM) was applied to analyze the data. Notwithstanding their lower scores at baseline (intercept), children with asthma increased their PACER scores at a rate more than double that of their peers without asthma. Although more than one PACER trial may be needed to accurately determine children's aerobic performance, repeated trials may be especially necessary for children with asthma. It was further concluded that the PACER is an effective tool with which to assess aerobic performance by middle school children with well-managed asthma. PMID- 25799032 TI - Relationship between Brazilian adolescents' physical activity and social and economic indicators of the cities where they live. AB - This study investigated the relationship between sufficient amounts of physical activity among Brazilian adolescents and the economic and social indicators of the cities where they live. Data from a large national survey including 109,104 boys and girls ages 13 to 15 yr. (47.8% boys, 52.2% girls) were analyzed. The economic and social indicators were the Human Development Index (HDI), which is a comparative measure to rank cities according to their degree of human development, the Gini index (income inequality), population density, and maternal education. Stepwise regression was used to identify associations between physical activity and economic and social indicators of the cities. The physical activity of Brazilian adolescents was associated with the social and economic conditions of the cities where they live. The amount of physical activity of girls was greater in the cities with fewer income inequalities. For boys, physical activity was greater in the cities with a higher HDI and fewer income inequalities. PMID- 25799033 TI - EVALUATION OF PERIPHERAL AND FOCAL VISION in PROPRIOCEPTIVE DIFFERENTIATION OF UNDERFOOT INVERSION ANGLES: COMMENT ON WITCHALLS, ET AL. (2013) (.). AB - A study by Witchalls, et al. (2013) mentioned that the addition of focal vision to proprioception testing with walking produces greater proprioceptive acuity than peripheral vision alone (measured ankle proprioception in athletes with or without chronic ankle instability during a stepping task on the Active Movement Extent Discrimination Apparatus; AMEDA). According to this study, people with impaired proprioception, e.g., athletes with chronic ankle instability, may profit from looking down during walking or running. This commentary notes that the active stepping task may not be truly comparable to rhythmic stepping, which is characteristic for walking. In addition, we suggest several amendments to the methodology for further studies related to ankle proprioception measurement, e.g., monitoring of proband eye attention during a stepping task or clear objective evaluation of the subject sample. PMID- 25799034 TI - Effects of f-f interactions on the single-molecule magnet properties of terbium(III)-phthalocyaninato quintuple-decker complexes. AB - Single-molecule magnet (SMM) properties of terbium(III)-phthalocyaninato quintuple-decker complex TbCdCdTb were studied and were compared with those of other multiple-decker complexes (triple-decker: TbTb, quadruple-decker: TbCdTb) to elucidate the relationship between magnetic dipole interactions and SMM properties. From X-ray crystallography performed with synchrotron radiation, the Tb(III)-Tb(III) distance in TbCdCdTb was determined to be 9.883 A. From alternating current magnetic studies on TbCdCdTb, the activation energy for spin reversal (Delta) increased with an increase in the direct current magnetic field (Hdc). This behavior is similar to that of TbCdTb, although the increase in Delta for TbCdTb is smaller. On the other hand, for TbTb, which has shortest Tb(III) Tb(III) distance, Delta did not depend on Hdc, indicating that there is a correlation between SMM properties and the strength of the Tb(III)-Tb(III) interactions. By comparing the Zeeman diagrams for multiple-decker complexes, we found that the Tb(III)-Tb(III) interactions affected the magnetic field regions where quantum tunnelling of the magnetization was active. The results obtained from Zeeman diagrams are consistent with the results obtained from the magnetic studies. PMID- 25799035 TI - Compressive Mediastinal Mass and Large Pericardial Effusion in a Child. PMID- 25799036 TI - On His Own Two Feet. PMID- 25799037 TI - High areal capacity hybrid magnesium-lithium-ion battery with 99.9% Coulombic efficiency for large-scale energy storage. AB - Hybrid magnesium-lithium-ion batteries (MLIBs) featuring dendrite-free deposition of Mg anode and Li-intercalation cathode are safe alternatives to Li-ion batteries for large-scale energy storage. Here we report for the first time the excellent stability of a high areal capacity MLIB cell and dendrite-free deposition behavior of Mg under high current density (2 mA cm(-2)). The hybrid cell showed no capacity loss for 100 cycles with Coulombic efficiency as high as 99.9%, whereas the control cell with a Li-metal anode only retained 30% of its original capacity with Coulombic efficiency well below 90%. The use of TiS2 as a cathode enabled the highest specific capacity and one of the best rate performances among reported MLIBs. Postmortem analysis of the cycled cells revealed dendrite-free Mg deposition on a Mg anode surface, while mossy Li dendrites were observed covering the Li surface and penetrated into separators in the Li cell. The energy density of a MLIB could be further improved by developing electrolytes with higher salt concentration and wider electrochemical window, leading to new opportunities for its application in large-scale energy storage. PMID- 25799038 TI - Developmental changes in ERP responses to spatial frequencies. AB - Social interaction starts with perception of other persons. One of the first steps in perception is processing of basic information such as spatial frequencies (SF), which represent details and global information. However, although behavioural perception of SF is well investigated, the developmental trajectory of the temporal characteristics of SF processing is not yet well understood. The speed of processing of this basic visual information is crucial, as it determines the speed and possibly accuracy of subsequent visual and social processes. The current study investigated developmental changes in the temporal characteristics of selective processing of high SF (HSF; details) versus low SF (LSF; global). To this end, brain activity was measured using EEG in 108 children aged 3-15 years, while HSF or LSF grating stimuli were presented. Interest was in the temporal characteristics of brain activity related to LSF and HSF processing, specifically at early (N80) or later (P1 or N2) peaks in brain activity. Analyses revealed that from 7-8 years onwards HSF but not LSF stimuli evoked an N80 peak. In younger children, aged 3-8 years, the visual manipulation mainly affected the visual N2 peak. Selective processing of HSF versus LSF thus occurs at a rather late time-point (N2 peak) in young children. Although behavioural research previously showed that 3-6 year-olds can perceive detailed information, the current results point out that selective processing of HSF versus LSF is still delayed in these children. The delayed processing in younger children could impede the use of LSF and HSF for emotional face processing. Thus, the current study is a starting point for understanding changes in basic visual processing which underlie social development. PMID- 25799039 TI - Multiple signal amplified electrochemiluminescent immunoassay for Hg2+ using graphene-coupled quantum dots and gold nanoparticles-labeled horseradish peroxidase. AB - A multiple signal amplification strategy was designed for an ultrasensitive competitive immunoassay for Hg(2+). This strategy was achieved using graphene conjugated with a large number of CdSe quantum dots to enhance the basal signal and enormous horseradish peroxidase (HRP) labeled with gold nanoparticles (AuNPs) to consume the coreactant H2O2 generated in situ. The immunosensor was constructed by immobilization of coating antigen on poly(diallyldimethylammonium chloride)-graphene-CdSe composites (PDDA-GN-CdSe), and a strong electrochemiluminescence (ECL) signal was obtained. When the immunosensor was immersed in antibody-AuNPs-HRP composites, the ECL signal greatly decreased, which was ascribed to the bound enzyme on the electrode surface. The self produced coreactant H2O2 was consumed by o-phenylenediamine in the presence of enzyme, effectively decreasing the ECL intensity from the quantum dots. The Hg(2+) in solution and the corresponding coating antigen competed for the limited antibody, and thus, the ECL intensity was linearly dependent on the logarithm of the mercury(II) concentration from 0.2 to 1000 ng mL(-1) with a detection limit of 0.06 ng mL(-1). The immunoassay exhibited good stability and accuracy and acceptable reproducibility, indicating that it provides a promising approach for the detection of trace mercury and other small molecular compounds in environmental samples. PMID- 25799040 TI - Global network influences on local functional connectivity. AB - A central neuroscientific pursuit is understanding neuronal interactions that support computations underlying cognition and behavior. Although neurons interact across disparate scales, from cortical columns to whole-brain networks, research has been restricted to one scale at a time. We measured local interactions through multi-neuronal recordings while accessing global networks using scalp electroencephalography (EEG) in rhesus macaques. We measured spike count correlation, an index of functional connectivity with computational relevance, and EEG oscillations, which have been linked to various cognitive functions. We found a non-monotonic relationship between EEG oscillation amplitude and spike count correlation, contrary to the intuitive expectation of a direct relationship. With a widely used network model, we replicated these findings by incorporating a private signal targeting inhibitory neurons, a common mechanism proposed for gain modulation. Finally, we found that spike count correlation explained nonlinearities in the relationship between EEG oscillations and response time in a spatial selective attention task. PMID- 25799041 TI - Model-based choices involve prospective neural activity. AB - Decisions may arise via 'model-free' repetition of previously reinforced actions or by 'model-based' evaluation, which is widely thought to follow from prospective anticipation of action consequences using a learned map or model. While choices and neural correlates of decision variables sometimes reflect knowledge of their consequences, it remains unclear whether this actually arises from prospective evaluation. Using functional magnetic resonance imaging and a sequential reward-learning task in which paths contained decodable object categories, we found that humans' model-based choices were associated with neural signatures of future paths observed at decision time, suggesting a prospective mechanism for choice. Prospection also covaried with the degree of model-based influences on neural correlates of decision variables and was inversely related to prediction error signals thought to underlie model-free learning. These results dissociate separate mechanisms underlying model-based and model-free evaluation and support the hypothesis that model-based influences on choices and neural decision variables result from prospection. PMID- 25799042 TI - Highly-efficient GaN-based light-emitting diode wafers on La 0.3 Sr 1.7 AlTaO6 substrates. AB - Highly-efficient GaN-based light-emitting diode (LED) wafers have been grown on La 0.3 Sr 1.7 AlTaO6 (LSAT) substrates by radio-frequency molecular beam epitaxy (RF-MBE) with optimized growth conditions. The structural properties, surface morphologies, and optoelectronic properties of as-prepared GaN-based LED wafers on LSAT substrates have been characterized in detail. The characterizations have revealed that the full-width at half-maximums (FWHMs) for X-ray rocking curves of GaN(0002) and GaN(10-12) are 190.1 and 210.2 arcsec, respectively, indicating that high crystalline quality GaN films have been obtained. The scanning electron microscopy and atomic force microscopy measurements have shown the very smooth p GaN surface with the surface root-mean-square (RMS) roughness of 1.3 nm. The measurements of low-temperature and room-temperature photoluminescence help to calculate the internal quantum efficiency of 79.0%. The as-grown GaN-based LED wafers have been made into LED chips with the size of 300 * 300 MUm(2) by the standard process. The forward voltage, the light output power and the external quantum efficiency for LED chips are 19.6 W, 2.78 V, and 40.2%, respectively, at a current of 20 mA. These results reveal the high optoelectronic properties of GaN-based LEDs on LSAT substrates. This work brings up a broad future application of GaN-based devices. PMID- 25799043 TI - A Statewide Child Telepsychiatry Consult System Yields Desired Health System Changes and Savings. AB - BACKGROUND: Telepsychiatry has clinical efficacy with children, but questions remain about cost-effectiveness. State agencies and health systems need to know if a child telepsychiatry consult system can address system concerns and improve care quality while lowering costs. MATERIALS AND METHODS: To assist care in a rural state with few child and adolescent psychiatrists, an academic center coordinated a consult system of (1) televideo consults for high-needs children with Medicaid and state Multidisciplinary Team (MDT)/foster care involvement, (2) remote medication reviews for beyond guidelines prescribing, and (3) elective community provider telephone-based consults. Consult service data were collected and analyzed with Wyoming's Medicaid and Foster Care Divisions between the program start in January 2011 until March 2013. RESULTS: There were 229 televideo MDT/foster care consults, 125 mandatory medication reviews, and 277 elective phone consultations supporting community providers during this period. Following implementation, the number of Medicaid children <=5 years of age using psychotropic medications decreased by 42% (p<0.001), and the number of children using psychotropic doses >150% of the Food and Drug Administration maximum decreased by 52% (p<0.001). Televideo consults redirected 60% of children slated by caseworkers for a psychiatric residential treatment facility admission into alternative community treatment and placements. A financial return on investment was 1.82 to 1 for combined services. CONCLUSIONS: This coordinated child telepsychiatry consult system for a state Medicaid division reduced outlier pediatric psychiatric medication prescribing, supported local community-delivered treatments, and reduced unnecessary hospitalizations in a financially advantageous manner that was well received by the practice community. PMID- 25799044 TI - Cytokine profiles at admission can be related to outcome in AIDS patients with cryptococcal meningitis. AB - Cryptococcal meningitis (CM) remains as common life-threatening AIDS-defining illness mainly in resource-limited settings. Previous reports suggested that baseline cytokine profiles can be associated to fungal burden and clinical outcome. This study aimed to evaluate the baseline cytokine profiles in AIDS patients with CM and its relation with the outcome at weeks 2 and 10. Thirty AIDS patients with CM diagnosed by cerebrospinal fluid (CSF) Cryptococcus neoformans positive culture, India ink stain and cryptococcal antigen test were prospectively evaluated. As controls, 56 HIV-infected patients without CM and 48 non-HIV individuals were included. Baseline CSF and sera levels of IL-2, IL-4, IL 8, IL-10, IL-12p40, IL-17A, INF-gamma and TNF-alpha were measured by ELISA. Of 30 CM patients, 24 (80%) were male, median age of 38.1. The baseline CSF high fungal burden and positive blood culture were associated with a positive CSF culture at week 2 (p = 0.043 and 0.029). Most CSF and sera cytokines presented higher levels in CM patients than control subjects (p < 0.05). CSF levels of IL-8, IL-12p40, IL 17A, TNF-alpha, INF-gamma and sera TNF-alpha were significantly higher among survivors at weeks 2 and 10 (p < 0.05). Patients with increased intracranial pression exhibited CSF IL-10 high levels and poor outcome at week 10 (p = 0.032). Otherwise, baseline CSF log10 IFN-gamma and IL-17A were negatively correlated with fungal burden (r = -0.47 and -0.50; p = 0.0175 and 0.0094, respectively). The mortality rate was 33% (10/30) at week 2 and 57% (17/30) at week 10. The severity of CM and the advanced immunodeficiency at admission were related to a poor outcome in these patients. Otherwise, the predominant Th1 cytokines profile among survivors confirms its pivotal role to infection control and would be a prognostic marker in cryptococcal meningitis. PMID- 25799045 TI - Migration of myeloid cells during inflammation is differentially regulated by the cell surface receptors Slamf1 and Slamf8. AB - Previous studies have demonstrated that the cell surface receptor Slamf1 (CD150) is requisite for optimal NADPH-oxidase (Nox2) dependent reactive oxygen species (ROS) production by phagocytes in response to Gram- bacteria. By contrast, Slamf8 (CD353) is a negative regulator of ROS in response to Gram+ and Gram- bacteria. Employing in vivo migration after skin sensitization, induction of peritonitis, and repopulation of the small intestine demonstrates that in vivo migration of Slamf1-/- dendritic cells and macrophages is reduced, as compared to wt mice. By contrast, in vivo migration of Slamf8-/- dendritic cells, macrophages and neutrophils is accelerated. These opposing effects of Slamf1 and Slamf8 are cell intrinsic as judged by in vitro migration in transwell chambers in response to CCL19, CCL21 or CSF-1. Importantly, inhibiting ROS production of Slamf8-/- macrophages by diphenyleneiodonium chloride blocks this in vitro migration. We conclude that Slamf1 and Slamf8 govern ROS-dependent innate immune responses of myeloid cells, thus modulating migration of these cells during inflammation in an opposing manner. PMID- 25799046 TI - Genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis: a systematic review. AB - BACKGROUND: Tuberculosis (TB) incidence and mortality are declining worldwide; however, poor detection of drug-resistant disease threatens to reverse current progress toward global TB control. Multiple, rapid molecular diagnostic tests have recently been developed to detect genetic mutations in Mycobacterium tuberculosis (Mtb) genes known to confer first-line drug resistance. Their utility, though, depends on the frequency and distribution of the resistance associated mutations in the pathogen population. Mutations associated with rifampicin resistance, one of the two first-line drugs, are well understood and appear to occur in a single gene region in >95% of phenotypically resistant isolates. Mutations associated with isoniazid, the other first-line drug, are more complex and occur in multiple Mtb genes. OBJECTIVES/METHODOLOGY: A systematic review of all published studies from January 2000 through August 2013 was conducted to quantify the frequency of the most common mutations associated with isoniazid resistance, to describe the frequency at which these mutations co occur, and to identify the regional differences in the distribution of these mutations. Mutation data from 118 publications were extracted and analyzed for 11,411 Mtb isolates from 49 countries. PRINCIPAL FINDINGS/CONCLUSIONS: Globally, 64% of all observed phenotypic isoniazid resistance was associated with the katG315 mutation. The second most frequently observed mutation, inhA-15, was reported among 19% of phenotypically resistant isolates. These two mutations, katG315 and inhA-15, combined with ten of the most commonly occurring mutations in the inhA promoter and the ahpC-oxyR intergenic region explain 84% of global phenotypic isoniazid resistance. Regional variation in the frequency of individual mutations may limit the sensitivity of molecular diagnostic tests. Well-designed systematic surveys and whole genome sequencing are needed to identify mutation frequencies in geographic regions where rapid molecular tests are currently being deployed, providing a context for interpretation of test results and the opportunity for improving the next generation of diagnostics. PMID- 25799047 TI - Homologous expression of the Caldicellulosiruptor bescii CelA reveals that the extracellular protein is glycosylated. AB - Members of the bacterial genus Caldicellulosiruptor are the most thermophilic cellulolytic microbes described with ability to digest lignocellulosic biomass without conventional pretreatment. The cellulolytic ability of different species varies dramatically and correlates with the presence of the multimodular cellulase CelA, which contains both a glycoside hydrolase family 9 endoglucanase and a glycoside hydrolase family 48 exoglucanase known to be synergistic in their activity, connected by three cellulose-binding domains via linker peptides. This architecture exploits the cellulose surface ablation driven by its general cellulase processivity as well as excavates cavities into the surface of the substrate, revealing a novel paradigm for cellulase activity. We recently reported that a deletion of celA in C. bescii had a significant effect on its ability to utilize complex biomass. To analyze the structure and function of CelA and its role in biomass deconstruction, we constructed a new expression vector for C. bescii and were able, for the first time, to express significant quantities of full-length protein in vivo in the native host. The protein, which contains a Histidine tag, was active and excreted from the cell. Expression of CelA protein with and without its signal sequence allowed comparison of protein retained intracellularly to protein transported extracellularly. Analysis of protein in culture supernatants revealed that the extracellular CelA protein is glycosylated whereas the intracellular CelA is not, suggesting that either protein transport is required for this post-translational modification or that glycosylation is required for protein export. The mechanism and role of protein glycosylation in bacteria is poorly understood and the ability to express CelA in vivo in C. bescii will allow the study of the mechanism of protein glycosylation in this thermophile. It will also allow the study of glycosylation of CelA itself and its role in the structure and function of this important enzyme in biomass deconstruction. PMID- 25799048 TI - The molecular mechanism of bisphenol A (BPA) as an endocrine disruptor by interacting with nuclear receptors: insights from molecular dynamics (MD) simulations. AB - Bisphenol A (BPA) can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERalpha, hERRgamma and hPPARgamma. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA. PMID- 25799049 TI - Civil time ? biological time: Recent options for empirically testing possible effects of chronodisruption. PMID- 25799051 TI - Correction: Role of actin filaments in correlating nuclear shape and cell spreading. PMID- 25799050 TI - Role of microRNA-30c targeting ADAM19 in colorectal cancer. AB - MicroRNAs (miRNAs) are deregulated in a number of cancers including colorectal cancer. MiR-30c belongs to miR-30 family, and is involved in a variety of malignant diseases. In this study, we detected the expression of miR-30c in colon cancer cell lines and clinical colon cancer specimens. MiR-30c was shown to be dramatically down-regulated both in cell lines and cancer tissues. Additionally, miR-30c could inhibit cancer cell growth, migration and invasion in vitro. Consistently, stable over-expression of miR-30c inhibited the growth and lung metastasis of colon cancer cell xenografts in vivo. Furthermore, bioinformatics algorithm and luciferase reporter assay indicated ADAM19 as a direct target of miR-30c. Of interest, further experiments demonstrated that inhibition of ADAM19 by miR-30c partially mediated the anti-tumor effect of miR-30c. Overall, our study provides the new insight that miR-30c inhibited colon cancer cells via targeting ADAM19. Thus, miR-30c might serve as a promising therapeutic strategy for colon cancer treatment. PMID- 25799052 TI - Skin innervation: important roles during normal and pathological cutaneous repair. AB - The skin is a highly sensitive organ. It is densely innervated with different types of sensory nerve endings, which discriminate between pain, temperature and touch. Autonomic nerve fibres which completely derive from sympathetic (cholinergic) neurons are also present. During all the phases of skin wound healing (inflammatory, proliferative and remodelling phases), neuromediators are involved. Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area. Patients with cutaneous sensory defects due to lepromatous leprosy, spinal cord injury and diabetic neuropathy develop ulcers that fail to heal. In addition, numerous experimental observations suggest that neurogenic stimuli profoundly affect wound repair after injury and that delayed wound healing is observed in animal models after surgical resection of cutaneous nerves. All these observations clearly suggest that innervation and neuromediators play a major role in wound healing. Interactions between neuromediators and different skin cells are certainly crucial in the healing process and ultimately the restoration of pain, temperature, and touch perceptions is a major challenge to solve in order to improve patients' quality of life. PMID- 25799053 TI - A method for identification and analysis of non-overlapping myeloid immunophenotypes in humans. AB - The development of flow cytometric biomarkers in human studies and clinical trials has been slowed by inconsistent sample processing, use of cell surface markers, and reporting of immunophenotypes. Additionally, the function(s) of distinct cell types as biomarkers cannot be accurately defined without the proper identification of homogeneous populations. As such, we developed a method for the identification and analysis of human leukocyte populations by the use of eight 10 color flow cytometric protocols in combination with novel software analyses. This method utilizes un-manipulated biological sample preparation that allows for the direct quantitation of leukocytes and non-overlapping immunophenotypes. We specifically designed myeloid protocols that enable us to define distinct phenotypes that include mature monocytes, granulocytes, circulating dendritic cells, immature myeloid cells, and myeloid derived suppressor cells (MDSCs). We also identified CD123 as an additional distinguishing marker for the phenotypic characterization of immature LIN-CD33+HLA-DR- MDSCs. Our approach permits the comprehensive analysis of all peripheral blood leukocytes and yields data that is highly amenable for standardization across inter-laboratory comparisons for human studies. PMID- 25799055 TI - Fish oil improves gene targets of Down syndrome in C57BL and BALB/c mice. AB - We have considered a novel gene targeting approach for treating pathologies and conditions whose genetic bases are defined using diet and nutrition. One such condition is Down syndrome, which is linked to overexpression of RCAN1 on human chromosome 21 for some phenotypes. We hypothesize that a decrease in RCAN1 expression with dietary supplements in individuals with Down syndrome represents a potential treatment. Toward this, we used in vivo studies and bioinformatic analysis to identify potential healthy dietary RCAN1 expression modulators. We observed Rcan1 isoform 1 (Rcan1-1) protein reduction in mice pup hippocampus after a 4-week curcumin and fish oil supplementation, with only fish oil reduction being statistically significant. Focusing on fish oil, we observed a 17% Rcan1-1 messenger RNA (mRNA) and 19% Rcan1-1 protein reduction in BALB/c mice after 5 weeks of fish oil supplementation. Fish oil supplementation starting at conception and in a different mouse strain (C57BL) led to a 27% reduction in hippocampal Rcan1-1 mRNA and a 34% reduction in spleen Rcan1-1 mRNA at 6 weeks of age. Hippocampal protein results revealed a modest 11% reduction in RCAN1-1, suggesting translational compensation. Bioinformatic mining of human fish oil studies also revealed reduced RCAN1 mRNA expression, consistent with the above studies. These results suggest the potential use of fish oil in treating Down syndrome and support our strategy of using select healthy dietary agents to treat genetically defined pathologies, an approach that we believe is simple, healthy, and cost-effective. PMID- 25799056 TI - Not seeing the forest for the trees: size of the minimum spanning trees (MSTs) forest and branch significance in MST-based phylogenetic analysis. AB - Trees, including minimum spanning trees (MSTs), are commonly used in phylogenetic studies. But, for the research community, it may be unclear that the presented tree is just a hypothesis, chosen from among many possible alternatives. In this scenario, it is important to quantify our confidence in both the trees and the branches/edges included in such trees. In this paper, we address this problem for MSTs by introducing a new edge betweenness metric for undirected and weighted graphs. This spanning edge betweenness metric is defined as the fraction of equivalent MSTs where a given edge is present. The metric provides a per edge statistic that is similar to that of the bootstrap approach frequently used in phylogenetics to support the grouping of taxa. We provide methods for the exact computation of this metric based on the well known Kirchhoff's matrix tree theorem. Moreover, we implement and make available a module for the PHYLOViZ software and evaluate the proposed metric concerning both effectiveness and computational performance. Analysis of trees generated using multilocus sequence typing data (MLST) and the goeBURST algorithm revealed that the space of possible MSTs in real data sets is extremely large. Selection of the edge to be represented using bootstrap could lead to unreliable results since alternative edges are present in the same fraction of equivalent MSTs. The choice of the MST to be presented, results from criteria implemented in the algorithm that must be based in biologically plausible models. PMID- 25799054 TI - Dietary amelioration of Helicobacter infection. AB - We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability, and cultural acceptability. This review, therefore, highlights specific foods, food components, and food products, grouped as follows: bee products (eg, honey and propolis); probiotics; dairy products; vegetables; fruits; oils; essential oils; and herbs, spices, and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and preclinical evidence must now be followed up with rationally designed, unambiguous human trials. PMID- 25799057 TI - Metagenomic profile of the viral communities in Rhipicephalus spp. ticks from Yunnan, China. AB - Besides mosquitoes, ticks are regarded as the primary source of vector-borne infectious diseases. Indeed, a wide variety of severe infectious human diseases, including those involving viruses, are transmitted by ticks in many parts of the world. To date, there are no published reports on the use of next-generation sequencing for studying viral diversity in ticks or discovering new viruses in these arthropods from China. Here, Ion-torrent sequencing was used to investigate the presence of viruses in three Rhipicephalus spp. tick pools (NY-11, NY-13, and MM-13) collected from the Menglian district of Yunnan, China. The sequencing run resulted in 3,641,088, 3,106,733, and 3,871,851 reads in each tick pool after trimming. Reads and assembled contiguous sequences (contigs) were subject to basic local alignment search tool analysis against the GenBank database. Large numbers of reads and contigs related to known viral sequences corresponding to a broad range of viral families were identified. Some of the sequences originated from viruses that have not been described previously in ticks. Our findings will facilitate better understanding of the tick virome, and add to our current knowledge of disease-causing viruses in ticks living under natural conditions. PMID- 25799058 TI - Structural basis for ubiquitin recognition by ubiquitin-binding zinc finger of FAAP20. AB - Several ubiquitin-binding zinc fingers (UBZs) have been reported to preferentially bind K63-linked ubiquitin chains. In particular, the UBZ domain of FAAP20 (FAAP20-UBZ), a member of the Fanconi anemia core complex, seems to recognize K63-linked ubiquitin chains, in order to recruit the complex to DNA interstrand crosslinks and mediate DNA repair. By contrast, it is reported that the attachment of a single ubiquitin to Rev1, a translesion DNA polymerase, increases binding of Rev1 to FAAP20. To clarify the specificity of FAAP20-UBZ, we determined the crystal structure of FAAP20-UBZ in complex with K63-linked diubiquitin at 1.9 A resolution. In this structure, FAAP20-UBZ interacts only with one of the two ubiquitin moieties. Consistently, binding assays using surface plasmon resonance spectrometry showed that FAAP20-UBZ binds ubiquitin and M1-, K48- and K63-linked diubiquitin chains with similar affinities. Residues in the vicinity of Ala168 within the alpha-helix and the C-terminal Trp180 interact with the canonical Ile44-centered hydrophobic patch of ubiquitin. Asp164 within the alpha-helix and the C-terminal loop mediate a hydrogen bond network, which reinforces ubiquitin-binding of FAAP20-UBZ. Mutations of the ubiquitin interacting residues disrupted binding to ubiquitin in vitro and abolished the accumulation of FAAP20 to DNA damage sites in vivo. Finally, structural comparison among FAAP20-UBZ, WRNIP1-UBZ and RAD18-UBZ revealed distinct modes of ubiquitin binding. UBZ family proteins could be divided into at least three classes, according to their ubiquitin-binding modes. PMID- 25799059 TI - The suture provides a niche for mesenchymal stem cells of craniofacial bones. AB - Bone tissue undergoes constant turnover supported by stem cells. Recent studies showed that perivascular mesenchymal stem cells (MSCs) contribute to the turnover of long bones. Craniofacial bones are flat bones derived from a different embryonic origin than the long bones. The identity and regulating niche for craniofacial-bone MSCs remain unknown. Here, we identify Gli1+ cells within the suture mesenchyme as the main MSC population for craniofacial bones. They are not associated with vasculature, give rise to all craniofacial bones in the adult and are activated during injury repair. Gli1+ cells are typical MSCs in vitro. Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population. Twist1(+/ ) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells. Our study indicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis and repair. PMID- 25799060 TI - Cell-sized spherical confinement induces the spontaneous formation of contractile actomyosin rings in vitro. AB - During cell division, many animal cells transform into a spherical shape and assemble a contractile ring composed of actin filaments and myosin motors at the equator to separate the cell body into two. Although actomyosin regulatory proteins are spatio-temporally controlled during cytokinesis, the direct contribution of cell shape and actomyosin activity to the contractile ring assembly remains unclear. Here, we demonstrated in vitro that actin polymerization inside cell-sized spherical droplets induced the spontaneous formation of single ring-shaped actin bundles in the presence of bundling factors. Despite a lack of spatial regulatory signals, the rings always assembled at the equator to minimize the elastic energy of the bundles. Myosin promoted ring formation by the dynamic remodelling of actin networks, and an increase in the effective concentration of myosin triggered ring contraction. These results will help us understand how animal cells coordinate cell shape and actomyosin activities to direct cytokinesis. PMID- 25799061 TI - EARP is a multisubunit tethering complex involved in endocytic recycling. AB - Recycling of endocytic receptors to the cell surface involves passage through a series of membrane-bound compartments by mechanisms that are poorly understood. In particular, it is unknown if endocytic recycling requires the function of multisubunit tethering complexes, as is the case for other intracellular trafficking pathways. Herein we describe a tethering complex named endosome associated recycling protein (EARP) that is structurally related to the previously described Golgi-associated retrograde protein (GARP) complex. The two complexes share the Ang2, Vps52 and Vps53 subunits, but EARP contains an uncharacterized protein, syndetin, in place of the Vps54 subunit of GARP. This change determines differential localization of EARP to recycling endosomes and GARP to the Golgi complex. EARP interacts with the target SNARE syntaxin 6 and various cognate SNAREs. Depletion of syndetin or syntaxin 6 delays recycling of internalized transferrin to the cell surface. These findings implicate EARP in canonical membrane-fusion events in the process of endocytic recycling. PMID- 25799062 TI - Cellular chirality arising from the self-organization of the actin cytoskeleton. AB - Cellular mechanisms underlying the development of left-right asymmetry in tissues and embryos remain obscure. Here, the development of a chiral pattern of actomyosin was revealed by studying actin cytoskeleton self-organization in cells with isotropic circular shape. A radially symmetrical system of actin bundles consisting of alpha-actinin-enriched radial fibres (RFs) and myosin-IIA-enriched transverse fibres (TFs) evolved spontaneously into the chiral system as a result of the unidirectional tilting of all RFs, which was accompanied by a tangential shift in the retrograde movement of TFs. We showed that myosin-IIA-dependent contractile stresses within TFs drive their movement along RFs, which grow centripetally in a formin-dependent fashion. The handedness of the chiral pattern was shown to be regulated by alpha-actinin-1. Computational modelling demonstrated that the dynamics of the RF-TF system can explain the pattern transition from radial to chiral. Thus, actin cytoskeleton self-organization provides built-in machinery that potentially allows cells to develop left-right asymmetry. PMID- 25799063 TI - Disruption of the pdhB pyruvate dehydrogenase [corrected] gene affects colony morphology, in vitro growth and cell invasiveness of Mycoplasma agalactiae. AB - The utilization of available substrates, the metabolic potential and the growth rates of bacteria can play significant roles in their pathogenicity. This study concentrates on Mycoplasma agalactiae, which causes significant economic losses through its contribution to contagious agalactia in small ruminants by as yet unknown mechanisms. This lack of knowledge is primarily due to its fastidious growth requirements and the scarcity of genetic tools available for its manipulation and analysis. Transposon mutagenesis of M. agalactiae type strain PG2 resulted in several disruptions throughout the genome. A mutant defective in growth in vitro was found to have a transposon insertion in the pdhB gene, which encodes a component of the pyruvate dehydrogenase complex. This growth difference was quite significant during the actively dividing logarithmic phase but a gradual recovery was observed as the cells approached stationary phase. The mutant also exhibited a different and smaller colony morphology compared to the wild type strain PG2. For complementation, pdhAB was cloned downstream of a strong vpma promoter and upstream of a lacZ reporter gene in a newly constructed complementation vector. When transformed with this vector the pdhB mutant recovered its normal growth and colony morphology. Interestingly, the pdhB mutant also had significantly reduced invasiveness in HeLa cells, as revealed by double immunofluorescence staining. This deficiency was recovered in the complemented strain, which had invasiveness comparable to that of PG2. Taken together, these data indicate that pyruvate dehydrogenase might be an important player in infection with and colonization by M. agalactiae. PMID- 25799064 TI - The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family. AB - The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy. Nucleoside-based inhibitors have broad-spectrum activity but often exhibit off-target effects. Most non-nucleoside inhibitors (NNIs) target surface cavities, which are structurally more flexible than the nucleotide-binding pocket, and hence have a more narrow spectrum of activity and are more prone to resistance development. Here, we report a novel NNI, GPC-N114 (2,2'-[(4-chloro-1,2-phenylene)bis(oxy)]bis(5-nitro-benzonitrile)) with broad-spectrum activity against enteroviruses and cardioviruses (another genus in the picornavirus family). Surprisingly, coxsackievirus B3 (CVB3) and poliovirus displayed a high genetic barrier to resistance against GPC-N114. By contrast, EMCV, a cardiovirus, rapidly acquired resistance due to mutations in 3Dpol. In vitro polymerase activity assays showed that GPC-N114 i) inhibited the elongation activity of recombinant CVB3 and EMCV 3Dpol, (ii) had reduced activity against EMCV 3Dpol with the resistance mutations, and (iii) was most efficient in inhibiting 3Dpol when added before the RNA template-primer duplex. Elucidation of a crystal structure of the inhibitor bound to CVB3 3Dpol confirmed the RNA binding channel as the target for GPC-N114. Docking studies of the compound into the crystal structures of the compound-resistant EMCV 3Dpol mutants suggested that the resistant phenotype is due to subtle changes that interfere with the binding of GPC-N114 but not of the RNA template-primer. In conclusion, this study presents the first NNI that targets the RNA template channel of the picornavirus polymerase and identifies a new pocket that can be used for the design of broad spectrum inhibitors. Moreover, this study provides important new insight into the plasticity of picornavirus polymerases at the template binding site. PMID- 25799066 TI - The effect of sign language structure on complex word reading in Chinese deaf adolescents. AB - The present study was carried out to investigate whether sign language structure plays a role in the processing of complex words (i.e., derivational and compound words), in particular, the delay of complex word reading in deaf adolescents. Chinese deaf adolescents were found to respond faster to derivational words than to compound words for one-sign-structure words, but showed comparable performance for two-sign-structure words. For both derivational and compound words, response latencies to one-sign-structure words were shorter than to two-sign-structure words. These results provide strong evidence that the structure of sign language affects written word processing in Chinese. Additionally, differences between derivational and compound words in the one-sign-structure condition indicate that Chinese deaf adolescents acquire print morphological awareness. The results also showed that delayed word reading was found in derivational words with two signs (DW-2), compound words with one sign (CW-1), and compound words with two signs (CW-2), but not in derivational words with one sign (DW-1), with the delay being maximum in DW-2, medium in CW-2, and minimum in CW-1, suggesting that the structure of sign language has an impact on the delayed processing of Chinese written words in deaf adolescents. These results provide insight into the mechanisms about how sign language structure affects written word processing and its delayed processing relative to their hearing peers of the same age. PMID- 25799065 TI - Heading toward the right direction--solution package for endoscopic submucosal tunneling resection in the stomach. AB - BACKGROUND: The emerging submucosal tunneling and endoscopic resection (STER) technique provides definitive histological diagnosis as well as a therapeutic method for the gastric submucosal tumors (SMTs). We aim to present our experience and discuss key technical issues of STER. METHODS: 45 patients with gastric SMTs arising from MP received STER. First, a mucosal incision was made 3 cm proximal to the tumour, a submucosal tunnel was subsequently built from the incision to the tumor. The tumor was gradually exposed and dissected from surrounding tissue and retrieved from the tunnel. The initial mucosal incision was closed by metal clips. For SMTs in the gastric fundus near cardia, the submucosal tunnel was built from lower esophagus, through the angle of His, to the tumor for resection. RESULTS: STER was successfully performed in 43 patients; the other two were converted to surgery. Mean operating time was 79.3 min (range 45-150 min). Mean tumor size was 1.4 cm (range 0.5-5 cm). Of the total 47 resected SMTs, 36 were GISTs, 10 were leiomyomas and 1 was schwannoma. Complete resection was achieved in all patients. Intra-procedural peumoperitoneum occurred in 3 cases because of iatrogenic perforation, no special treatment was given. 7 patients presented with mild abdominal pain/distention and fever were given antibotics. No severe post operative complication happened. No tumor recurrence occurred in the median 11 month follow-up period. CONCLUSION: Based on short-term follow-up observation, STER is a feasible, safe and minimally invasive method for the diagnosis and treatment of small (<3 cm) SMTs in gastric body, antrum and proximal cardia. PMID- 25799067 TI - Correction: Spatiotemporal transmission dynamics of hemorrhagic fever with renal syndrome in China, 2005-2012. PMID- 25799068 TI - Correction: Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PMID- 25799069 TI - High salt intake damages the heart through activation of cardiac (pro) renin receptors even at an early stage of hypertension. AB - OBJECTIVE: It has not yet been fully elucidated whether cardiac tissue levels of prorenin, renin and (P)RR are activated in hypertension with a high salt intake. We hypothesized that a high salt intake activates the cardiac tissue renin angiotensin system and prorenin-(pro)renin receptor system, and damages the heart at an early stage of hypertension. METHODS: Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) received regular (normal-salt diet, 0.9%) and high-salt (8.9%) chow for 6 weeks from 6 to 12 weeks of age. The systolic blood pressure, plasma renin activity (PRA) and plasma angiotensin II concentration were measured, and the protein expressions of prorenin, (pro)renin receptor, angiotensinogen, angiotensin II AT1 receptor, ERK1/2, TGF-beta, p38MAPK and HSP27 in the myocardium were investigated. The cardiac function was assessed by echocardiography, and histological analysis of the myocardium was performed. RESULTS: The high-salt diet significantly increased the systolic blood pressure, and significantly reduced the PRA and plasma angiotensin II concentration both in the WKYs and SHRs. Cardiac expressions of prorenin, renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p p38MAPK, TGF-beta and p-HSP27 were significantly increased by the high salt diet both in the WKYs and SHRs. The high-salt diet significantly increased the interventricular septum thickness and cardiomyocyte size, and accelerated cardiac interstitial and perivascular fibrosis both in the WKYs and SHRs. On the other hand, dilatation of left ventricular end-diastolic dimension and impairment of left ventricular fractional shortening was shown only in salt loaded SHRs. CONCLUSION: The high-salt diet markedly accelerated cardiac damage through the stimulation of cardiac (P)RR and angiotensin II AT1 receptor by increasing tissue prorenin, renin and angiotensinogen and the activation of ERK1/2, TGF-beta, p38MAPK and HSP27 under higher blood pressure. PMID- 25799070 TI - Genetic heterogeneity of induced pluripotent stem cells: results from 24 clones derived from a single C57BL/6 mouse. AB - Induced pluripotent stem cells (iPSCs) have tremendous potential as a tool for disease modeling, drug testing, and other applications. Since the generation of iPSCs "captures" the genetic history of the individual cell that was reprogrammed, iPSC clones (even those derived from the same individual) would be expected to demonstrate genetic heterogeneity. To assess the degree of genetic heterogeneity, and to determine whether some cells are more genetically "fit" for reprogramming, we performed exome sequencing on 24 mouse iPSC clones derived from skin fibroblasts obtained from two different sites of the same 8-week-old C57BL/6J male mouse. While no differences in the coding regions were detected in the two parental fibroblast pools, each clone had a unique genetic signature with a wide range of heterogeneity observed among the individual clones: a total of 383 iPSC variants were validated for the 24 clones (mean 16.0/clone, range 0-45). Since these variants were all present in the vast majority of the cells in each clone (variant allele frequencies of 40-60% for heterozygous variants), they most likely preexisted in the individual cells that were reprogrammed, rather than being acquired during reprogramming or cell passaging. We then tested whether this genetic heterogeneity had functional consequences for hematopoietic development by generating hematopoietic progenitors in vitro and enumerating colony forming units (CFUs). While there was a range of hematopoietic potentials among the 24 clones, only one clone failed to differentiate into hematopoietic cells; however, it was able to form a teratoma, proving its pluripotent nature. Further, no specific association was found between the mutational spectrum and the hematopoietic potential of each iPSC clone. These data clearly highlight the genetic heterogeneity present within individual fibroblasts that is captured by iPSC generation, and suggest that most of the changes are random, and functionally benign. PMID- 25799072 TI - Electrochemical synthesis of mesoporous gold films toward mesospace-stimulated optical properties. AB - Mesoporous gold (Au) films with tunable pores are expected to provide fascinating optical properties stimulated by the mesospaces, but they have not been realized yet because of the difficulty of controlling the Au crystal growth. Here, we report a reliable soft-templating method to fabricate mesoporous Au films using stable micelles of diblock copolymers, with electrochemical deposition advantageous for precise control of Au crystal growth. Strong field enhancement takes place around the center of the uniform mesopores as well as on the walls between the pores, leading to the enhanced light scattering as well as surface enhanced Raman scattering (SERS), which is understandable, for example, from Babinet principles applied for the reverse system of nanoparticle ensembles. PMID- 25799071 TI - Comparative and evolutionary analyses of Meloidogyne spp. Based on mitochondrial genome sequences. AB - Molecular taxonomy and evolution of nematodes have been recently the focus of several studies. Mitochondrial sequences were proposed as an alternative for precise identification of Meloidogyne species, to study intraspecific variability and to follow maternal lineages. We characterized the mitochondrial genomes (mtDNAs) of the root knot nematodes M. floridensis, M. hapla and M. incognita. These were AT rich (81-83%) and highly compact, encoding 12 proteins, 2 rRNAs, and 22 tRNAs. Comparisons with published mtDNAs of M. chitwoodi, M. incognita (another strain) and M. graminicola revealed that they share protein and rRNA gene order but differ in the order of tRNAs. The mtDNAs of M. floridensis and M. incognita were strikingly similar (97-100% identity for all coding regions). In contrast, M. floridensis, M. chitwoodi, M. hapla and M. graminicola showed 65-84% nucleotide identity for coding regions. Variable mitochondrial sequences are potentially useful for evolutionary and taxonomic studies. We developed a molecular taxonomic marker by sequencing a highly-variable ~2 kb mitochondrial region, nad5-cox1, from 36 populations of root-knot nematodes to elucidate relationships within the genus Meloidogyne. Isolates of five species formed monophyletic groups and showed little intraspecific variability. We also present a thorough analysis of the mitochondrial region cox2-rrnS. Phylogenies based on either mitochondrial region had good discrimination power but could not discriminate between M. arenaria, M. incognita and M. floridensis. PMID- 25799073 TI - [Autoimmune pancreatitis]. AB - Autoimmune pancreatitis is a benign fibroinflammatory disease of the pancreas of probable autoimmune origin, which includes 2 different phenotypes: type 1 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic duct-centric pancreatitis). Its clinical presentation as obstructive jaundice in patients with a pancreatic mass is common and therefore it must be included in the differential diagnosis of pancreatic neoplasia. Many diagnostic criteria have been described throughout history. The most famous are the HISORT criteria of the Mayo Clinic and the international consensus criteria of 2011. One of the main features of autoimmune pancreatitis is its dramatic response to steroid therapy, without the need for surgical treatment. Knowledge of this disease can dramatically change the management of patients with obstructive jaundice, who would otherwise be subjected to a pancreaticoduodenectomy. PMID- 25799075 TI - Ocular ischemic syndrome presenting as retinal vasculitis in a patient with moyamoya syndrome. AB - PURPOSE: To report a case of ocular ischemic syndrome presenting as retinal vasculitis in a patient with Moyamoya syndrome. METHODS: A retrospective chart review was conducted to record clinical data including fluorescein angiography, optical coherence tomography, and serologic testing. A review of the literature from 1969 to 2014 of ocular involvement in Moyamoya syndrome was performed. RESULTS: A 51-year-old woman with long history of bilateral retinal vasculitis and refractory cystoid macular edema was eventually diagnosed with Moyamoya syndrome after sustaining a perioperative cerebrovascular accident. Moyamoya syndrome has been associated in the literature with ocular ischemic syndrome, presenting with narrowed retinal arteries, dilated veins, and midperipheral retinal hemorrhages, but retinal vasculitis with cystoid macular edema has not been reported. CONCLUSION: Moyamoya-related ocular ischemic syndrome can present as retinal vascular leakage and macular edema. Ophthalmologists should be cognizant that signs of the disease may be first observed in the eye before manifestations in the cerebrovascular system. PMID- 25799074 TI - Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. AB - Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology. PMID- 25799076 TI - Bilateral acute endophthalmitis associated with munchausen syndrome. AB - PURPOSE: Endophthalmitis is a potentially blinding intraocular infection that requires urgent intervention. Self-inflicted endophthalmitis is rare, difficult to diagnose, and requires a multidisciplinary approach for management. The purpose is to present a rare case of sequential self-inflicted acute endophthalmitis as a feature of Munchausen syndrome. METHODS: This is a case report reviewing imaging and laboratory studies. RESULTS: A 42-year-old female patient developed culture-proven acute endophthalmitis sequentially in both eyes with different bacterial strains. There was clear evidence of self-inflicted corneal puncture tracks in the right eye, and during the course of inpatient psychiatric evaluation, the patient admitted to self-inflicted ocular perforations. CONCLUSION: Patients with Munchausen syndrome often injure themselves as a method of drawing attention, sympathy, or reassurance. Although ocular injuries due to psychiatric disease are known to occur, intraocular injection as a mode of self-injury is extremely rare. A high index of suspicion must be maintained when the reported history and clinical course are inconsistent. PMID- 25799077 TI - Antitumor properties of platinum(iv) prodrug-loaded silk fibroin nanoparticles. AB - Platinum(iv) complexes take advantage of the exclusive conditions that occur within the tumor to carry out their cytotoxic activity. On the other hand, silk fibroin has natural properties which make it very interesting as a biomaterial: high biocompatibility, biodegradability, low immunogenicity, high cellular penetration capacity and high reactive surface. Herein we report the preparation of silk fibroin nanoparticles (SFNs) loaded with the hydrophobic Pt(iv) complex cis,cis,trans-[Pt(NH(3))(2)Cl(2)(O(2)CC(6)H(5))(2)] (PtBz). Only a small fraction of the loaded PtBz is released (less than 10% after 48 h). PtBz-SFNs trigger strong cytotoxic effects against human ovarian carcinoma A2780 cells and their cisplatin-resistant variant A2780cisR cells. Interestingly, PtBz-SFNs are very cytotoxic (nanomolar IC(50) values) toward the triple negative breast tumor cell line MDA-MB-231, and also toward SK-BR-3 and MCF-7, while maintaining an excellent selectivity index. PMID- 25799078 TI - The battle against antimicrobial resistance: time for the emergency department to join the fight. PMID- 25799079 TI - Serum thiols as a biomarker of disease activity in lupus nephritis. AB - Lupus Nephritis (LN) develops in more than half of the Systemic Lupus Erythematous (SLE) patients. However, lack of reliable, specific biomarkers for LN hampers clinical management of patients and impedes development of new therapeutics. The goal of this study was to investigate whether oxidative stress biomarkers in patients with SLE is predictive of renal pathology. Serum biochemical and oxidative stress markers were measured in patients with inactive lupus, active lupus with and without nephritis and compared to healthy control group. To assess the predictive performance of biomarkers, Receiver Operating Characteristic (ROC) curves were constructed and cut-offs were used to identify SLE patients with nephritis. We observed an increased oxidative stress response in all SLE patients compared to healthy controls. Among the several biomarkers tested, serum thiols had a significant inverse association with SLE Disease Activity Index (SLEDAI). Interestingly, thiols were able too aptly differentiate between SLE patients with and without renal pathology, and serum thiol levels were not affected by immunosuppressive drug therapy. The decreased thiols in SLE correlated significantly with serum creatinine and serum C3 levels. Further retrospective evaluation using serum creatinine or C3 levels in combination with thiol's cutoff values from ROC analysis, we could positively predict chronicity of renal pathology in SLE patients. In summary, serum thiols emerge as an inexpensive and reliable indicator of LN, which may not only help in early identification of renal pathology but also aid in the therapeutic management of the disease, in developing countries with resource poor settings. PMID- 25799080 TI - Cognition in the Finnish diabetes prevention study. AB - We studied cognition in the Finnish Diabetes Prevention Study (DPS), a trial of lifestyle intervention that prevented diabetes in persons with impaired glucose tolerance. Cognition was similar in the randomization arms 9 years after the intervention in 364 participants, suggesting that the intervention did not benefit cognition. PMID- 25799081 TI - Building an aptamer/graphene oxide FRET biosensor for one-step detection of bisphenol A. AB - Bisphenol A (BPA) is an important industrial chemical for polycarbonate (PC) and epoxy resins in paper and plastic industries. In our work, a kind of new method for detection of BPA was designed based on graphene oxide and anti-BPA aptamer. The graphene oxide can specifically adsorb and quench the fluorescence of fluorescently modified ssDNA probes. Meanwhile, the BPA can combine with anti-BPA optamer and switch its configuration to prevent the aptamer from adsorbing on the surface of graphene oxide (GO). Under different concentrations of BPA, based on the target-induced conformational change of anti-BPA aptamer and the interactions between the fluorescently modified anti-BPA aptamer (FAM-ssDNA) and GO, the experimental results show that the intensity of the fluorescence signal was changed. A low limit of detection of 0.05 ng/mL was obtained in the range 0.1-10 ng/mL. In addition, the specificity was outstanding among analogues of BPA. The recovery rate in actual water samples spiked with BPA can be 96.0% to 104.5%. The developed method was successfully used to determine BPA in actual water samples. PMID- 25799082 TI - Measuring electric fields and noncovalent interactions using the vibrational stark effect. AB - Over the past decade, we have developed a spectroscopic approach to measure electric fields inside matter with high spatial (<1 A) and field (<1 MV/cm) resolution. The approach hinges on exploiting a physical phenomenon known as the vibrational Stark effect (VSE), which ultimately provides a direct mapping between observed vibrational frequencies and electric fields. Therefore, the frequency of a vibrational probe encodes information about the local electric field in the vicinity around the probe. The VSE method has enabled us to understand in great detail the underlying physical nature of several important biomolecular phenomena, such as drug-receptor selectivity in tyrosine kinases, catalysis by the enzyme ketosteroid isomerase, and unidirectional electron transfer in the photosynthetic reaction center. Beyond these specific examples, the VSE has provided a conceptual foundation for how to model intermolecular (noncovalent) interactions in a quantitative, consistent, and general manner. The starting point for research in this area is to choose (or design) a vibrational probe to interrogate the particular system of interest. Vibrational probes are sometimes intrinsic to the system in question, but we have also devised ways to build them into the system (extrinsic probes), often with minimal perturbation. With modern instruments, vibrational frequencies can increasingly be recorded with very high spatial, temporal, and frequency resolution, affording electric field maps correspondingly resolved in space, time, and field magnitude. In this Account, we set out to explain the VSE in broad strokes to make its relevance accessible to chemists of all specialties. Our intention is not to provide an encyclopedic review of published work but rather to motivate the underlying framework of the methodology and to describe how we make and interpret the measurements. Using certain vibrational probes, benchmarked against computer models, it is possible to use the VSE to measure absolute electric fields in arbitrary environments. The VSE approach provides an organizing framework for thinking generally about intermolecular interactions in a quantitative way and may serve as a useful conceptual tool for molecular design. PMID- 25799083 TI - Quantifying the causal strength of multivariate cardiovascular couplings with momentary information transfer. AB - This article studies a recently introduced information-theoretic approach to detect and quantify the causal couplings in a complex cardiovascular system. In the first step a causal algorithm detects the coupling delays and in the second step the causal strength of each coupling mechanism is quantified using the recently introduced momentary information transfer. As an example, the method is applied to time series of respiration, systolic and diastolic blood pressure, and heart rate of pregnant healthy women and women suffering from pre-eclampsia. A possible explanation for the influence of heart rate on systolic blood pressure is found and some differences between healthy women and patients are discussed. PMID- 25799084 TI - Can ultrasonography reduce the need for CT scan in diagnosing acute appendicitis? PMID- 25799085 TI - Safety and efficacy of perflubron-induced lung growth in neonates with congenital diaphragmatic hernia: Results of a prospective randomized trial. AB - BACKGROUND: Mechanical transduction has been shown to promote fetal lung growth. We examined the safety and efficacy of perflubron-induced lung growth (PILG) in neonates with congenital diaphragmatic hernia (CDH) requiring extracorporeal membrane oxygenation (ECMO). METHODS: Infants with left-sided CDH requiring ECMO were eligible. Exclusion criteria included active air leak, intracranial hemorrhage, major congenital anomalies, and oxygenation index >25 for 24hours. Perflubron was instilled endotracheally and continuous positive airway pressure was applied without ventilation. Survival to discharge was the primary outcome. Daily chest radiographs were used to quantify lung size (the secondary outcome). Midway through the study our institutional practice shifted toward earlier repair of CDH. RESULTS: Eight infants were randomized to each arm. In the conventional ventilation arm, six survived to discharge (75%). In the perflubron arm, four survived (50%); the others succumbed to suprasystemic pulmonary hypertension. No adverse events related to perflubron occurred. Within the perflubron group, 4/8 patients had "late repair" (15-19days of life [DOL]) and 4 had "early repair" (2 3 DOL). "Early repair" patients had similar total lung growth, but accelerated growth and shorter ECMO runs. CONCLUSION: PILG is safe in CDH and doubles the total lung size on average (accelerated with early repair). Despite amelioration of pulmonary hypoplasia with PILG, pulmonary hypertension persists. PMID- 25799086 TI - The making of a surgeon: 10,000 hours? AB - There have been many changes in the "making of a surgeon". Some of the key aspects that have altered residency/fellow training include work hour restrictions; a decrease in autonomy; and the explosion in knowledge, the change in technology, and the movement of complex cases away from General Surgery. There are a number of opportunities for enhancing current surgical training which include the following: 1) returning to reasonable work hour limits; 2) improving the efficiency of resident/fellow training by promoting early development of operative skills and starting down the path toward competency-based education; 3) increasing autonomy in the General and Pediatric Surgery residencies by developing and implementing structured processes for graded autonomy, further promoting the teaching assistant role, and even incorporating time as an attending into the period of training; and 4) developing a paradigm of uniform core surgery training followed by additional qualifications and training in both General Surgery and the surgical specialties. PMID- 25799087 TI - Serum brain-derived neurotrophic factor differences between the luteal and follicular phases in premenstrual dysphoric disorder. AB - OBJECTIVE: We hypothesized that comparison of the serum brain-derived neurotrophic factor (BDNF) levels between women with premenstrual dysphoric disorder (PMDD) and women without PMDD in the luteal and follicular phases of their menstrual cycles would reflect the altered neuromodulator responses that compensate the underlying pathogenesis in PMDD. METHOD: Twenty-nine participants without PMDD and 20 with PMDD were enrolled in the study. The serum BDNF, estrogen and progesterone levels were assessed at the follicular and luteal phases in their two consecutive menstrual cycles. RESULTS: Participants with PMDD had significantly higher luteal serum BDNF levels than the control subjects. The serum BDNF levels were significantly higher in the luteal phase than in the follicular phase in women with PMDD. The difference in the serum BDNF levels between the luteal and follicular phases were significantly higher in the PMDD patients than in the control. CONCLUSIONS: The higher serum BDNF levels in the luteal phase in the PMDD patients may reflect compensatory process that results in subsequent improvement of the PMDD-associated depressive symptoms in the follicular phase. The higher difference in the serum BDNF levels between the phases in PMDD patients may reflect an altered neuromodulator response. PMID- 25799089 TI - A novel transition metal free [bis-(trifluoroacetoxy)iodo]benzene (PIFA) mediated oxidative ipso nitration of organoboronic acids. AB - A mild, convenient and transition metal free methodology for oxidative ipso nitration of diversely functionalized organoboronic acids, including heteroaryl- and alkylboronic acids, has been developed at ambient temperature using a combination of [bis-(trifluoroacetoxy)]iodobenzene (PIFA) - N-bromosuccinimide (NBS) and sodium nitrite as the nitro source. It is anticipated that the reaction proceeds through in situ generation of NO2 and O-centred organoboronic acid radicals followed by the formation of an O-N bond via combination of the said radicals. Finally transfer of the NO2 group to the aryl moiety occurs through 1,3 aryl migration to provide the nitroarenes. PMID- 25799088 TI - Mitochondrial myopathy and comorbid major depressive disorder: effectiveness of dTMS on gait and mood symptoms. AB - BACKGROUND: Mitochondrial myopathies (MMs) often present with leukoencephalopathy and psychiatric symptoms, which do not respond to or worsen with psychiatric drugs. CASE REPORT: A 67-year-old woman with a 10-year history of probable chronic progressive external ophthalmoplegia, an MM, had drug-resistant, anxious depressive symptoms. Since she had never had seizures, we proposed 20 sessions of deep transcranial magnetic stimulation (dTMS) for her depression. Surprisingly, besides the expected improvement of depression, we observed marked improvement of movement disorder that lasted as long as the patient was undergoing dTMS. She also improved her performance on neuropsychological tests of executive function and cognitive speed. Depressive symptom improvement was persistent, while anxiety symptoms recurred after the end of the sessions. CONCLUSIONS: dTMS may be an alternative antidepressant strategy in patients with MMs, provided that they are free from seizures. The mechanism of improvement of motor disturbance may relate to dorsolateral prefrontal cortex stimulation and improved executive function and needs further investigation. PMID- 25799091 TI - Polymorphic variants of GSTM1, GSTT1, and GSTP1 genes in childhood acute leukemias: A preliminary study in Argentina. AB - BACKGROUND AND AIM: Despite recent major advances in leukemia research, the etiopathogenesis of childhood leukemias remains far elusive. Individual predisposing factors, including polymorphisms in detoxification enzymes, have been implicated in the molecular pathogenesis and heterogeneity of the disease. Genetic polymorphisms of glutathione S-transferases (GSTs) that alter enzyme activity could be an additional factor that increases the risk of acute leukemia, but data are lacking in Argentina. We assessed the association of GST polymorphisms and the susceptibility to childhood leukemia in Argentina by conducting an exploratory case-control study and correlated patients' genotype to clinical and biological features. METHODS: Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.313A>G (rs1695; p.105Ile>Val) were genotyped by PCR-RFLP in 36 patients and 133 healthy individuals. RESULTS: GSTM1-null genotype was associated with a lower risk of developing acute leukemia (P = 0.013; OR: 0.31; CI: 0.12-0.80), while GSTP1-GG variants displayed an increased risk (P = 0.01; OR: 3.9; CI: 1.85-8.2). However, no differences were found for GSTT1 gene. Conclusion These preliminary results, to be validated in a larger population from Argentina, suggest that the development of pediatric leukemia may be differentially influenced by polymorphic variants in GST genes. PMID- 25799092 TI - Measurement of DSM-5 section II personality disorder constructs using the MMPI-2 RF in clinical and forensic samples. AB - In the current study, we evaluated the associations between the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008) scale scores and the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) Section II personality disorder (PD) criterion counts in inpatient and forensic psychiatric samples from The Netherlands using structured clinical interviews to operationalize PDs. The inpatient psychiatric sample included 190 male and female patients and the forensic sample included 162 male psychiatric patients. We conducted correlation and count regression analyses to evaluate the utility of relevant MMPI-2-RF scales in predicting PD criterion count scores. Generally, results from these analyses emerged as conceptually expected and provided evidence that MMPI-2-RF scales can be useful in assessing PDs. At the zero-order level, most hypothesized associations between Section II disorders and MMPI-2-RF scales were supported. Similarly, in the regression analyses, a unique set of predictors emerged for each PD that was generally in line with conceptual expectations. Additionally, the results provided general evidence that PDs can be captured by dimensional psychopathology constructs, which has implications for both DSM-5 Section III specifically and the personality psychopathology literature more broadly. PMID- 25799093 TI - Influence of bench angle on upper extremity muscular activation during bench press exercise. AB - This study compared the muscular activation of the pectoralis major, anterior deltoid and triceps brachii during a free-weight barbell bench press performed at 0 degrees , 30 degrees , 45 degrees and -15 degrees bench angles. Fourteen healthy resistance trained males (age 21.4 +/- 0.4 years) participated in this study. One set of six repetitions for each bench press conditions at 65% one repetition maximum were performed. Surface electromyography (sEMG) was utilised to examine the muscular activation of the selected muscles during the eccentric and concentric phases. In addition, each phase was subdivided into 25% contraction durations, resulting in four separate time points for comparison between bench conditions. The sEMG of upper pectoralis displayed no difference during any of the bench conditions when examining the complete concentric contraction, however differences during 26-50% contraction duration were found for both the 30 degrees [122.5 +/- 10.1% maximal voluntary isometric contraction (MVIC)] and 45 degrees (124 +/- 9.1% MVIC) bench condition, resulting in greater sEMG compared to horizontal (98.2 +/- 5.4% MVIC) and -15 (96.1 +/- 5.5% MVIC). The sEMG of lower pectoralis was greater during -15 degrees (100.4 +/- 5.7% MVIC), 30 degrees (86.6 +/- 4.8% MVIC) and horizontal (100.1 +/- 5.2% MVIC) bench conditions compared to the 45 degrees (71.9 +/- 4.5% MVIC) for the whole concentric contraction. The results of this study support the use of a horizontal bench to achieve muscular activation of both the upper and lower heads of the pectoralis. However, a bench incline angle of 30 degrees or 45 degrees resulted in greater muscular activation during certain time points, suggesting that it is important to consider how muscular activation is affected at various time points when selecting bench press exercises. PMID- 25799094 TI - Heart rate variability and stroke volume variability to detect central hypovolemia during spontaneous breathing and supported ventilation in young, healthy volunteers. AB - Cardiovascular oscillations exist in many different variables and may give important diagnostic and prognostic information in patients. Variability in cardiac stroke volume (SVV) is used in clinical practice for diagnosis of hypovolemia, but currently is limited to patients on mechanical ventilation. We investigated if SVV and heart rate variability (HRV) could detect central hypovolemia in spontaneously breathing humans: We also compared cardiovascular variability during spontaneous breathing with supported mechanical ventilation.Ten subjects underwent simulated central hypovolemia by lower body negative pressure (LBNP) with >10% reduction of cardiac stroke volume. The subjects breathed spontaneously and with supported mechanical ventilation. Heart rate, respiratory frequency and mean arterial blood pressure were measured. Stroke volume (SV) was estimated by ModelFlow (Finometer). Respiratory SVV was calculated by: 1) SVV% = (SVmax - SVmin)/SVmean during one respiratory cycle, 2) SVIntegral from the power spectra (Fourier transform) at 0.15-0.4 Hz and 3) SVV_norm = (?SVIntegral)/SVmean. HRV was calculated by the same methods.During spontaneous breathing two measures of SVV and all three measures of HRV were reduced during hypovolemia compared to baseline. During spontaneous breathing SVIntegral and HRV% were best to detect hypovolemia (area under receiver operating curve 0.81). HRV% <= 11% and SVIntegral <= 12 ml(2) differentiated between hypovolemia and baseline during spontaneous breathing.During supported mechanical ventilation, none of the three measures of SVV changed and two of the HRV measures were reduced during hypovolemia. Neither measures of SVV nor HRV were classified as a good detector of hypovolemia.We conclude that HRV% and SVIntegral detect hypovolemia during spontaneous breathing and both are candidates for further clinical testing. PMID- 25799096 TI - ASM-024, a piperazinium compound, promotes the in vitro relaxation of beta2 adrenoreceptor desensitized tracheas. AB - Inhaled beta2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. beta2 Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the beta2-adrenoreceptors (beta2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite beta2-AR tachyphylaxis. beta2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or beta2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of beta2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than beta2 adrenergic receptor agonists. These findings suggest ASM-024 could potentially provide clinical benefit when used adjunctively with inhaled beta2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use. PMID- 25799095 TI - Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation. AB - Carbon tetrachloride (CCl4) is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS) in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in a mouse model of CCl4 induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL)-1alpha, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor-alpha (TNF-alpha)], as well as decreased expression of granulocyte colony stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1alpha, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-alpha were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response. PMID- 25799097 TI - p38 MAP kinase inhibitor suppresses transforming growth factor-beta2-induced type 1 collagen production in trabecular meshwork cells. AB - Glaucoma is an age-related neurodegenerative disease of retinal ganglion cells, and appropriate turnover of the extracellular matrix in the trabecular meshwork is important in its pathology. Here, we report the effects of Rho-associated kinase (ROCK) and p38 MAP kinase on transforming growth factor (TGF)-beta2 induced type I collagen production in human trabecular meshwork cells. TGF-beta2 increased RhoA activity, actin polymerization, and myosin light chain 2 phosphorylation. These effects were significantly inhibited by Y-27632, but not SB203580. TGF-beta2 also increased promoter activity, mRNA synthesis, and protein expression of COL1A2. These effects were significantly inhibited by SB203580, but not Y-27632. Additionally, Y-27632 did not significantly inhibit TGF-beta2 induced promoter activation, or phosphorylation or nuclear translocation of Smad2/3, whereas SB203580 partially suppressed these processes. Collectively, TGF beta2-induced production of type 1 collagen is suppressed by p38 inhibition and accompanied by partial inactivation of Smad2/3, in human trabecular meshwork cells. PMID- 25799098 TI - Characterisation of the subaquatic groundwater discharge that maintains the permanent stratification within Lake Kivu; East Africa. AB - Warm and cold subaquatic groundwater discharge into Lake Kivu forms the large scale density gradients presently observed in the lake. This structure is pertinent to maintaining the stratification that locks the high volume of gases in the deepwater. Our research presents the first characterisation of these inflows. Temperature and conductivity profiling was conducted from January 2010 to March 2013 to map the locations of groundwater discharge. Water samples were obtained within the lake at the locations of the greatest temperature anomalies observed from the background lake-profile. The isotopic and chemical signatures of the groundwater were applied to assess how these inflows contribute to the overall stratification. It is inferred that Lake Kivu's deepwater has not been completely recharged by the groundwater inflows since its turnover that is speculated to have occurred within the last ~1000 yrs. Given a recent salinity increase in the lake constrained to within months of seismic activity measured beneath the basin, it is plausible that increased hydrothermal-groundwater inflows into the deep basin are correlated with episodic geologic events. These results invalidate the simple two-component end-member mixing regime that has been postulated up to now, and indicate the importance of monitoring this potentially explosive lake. PMID- 25799099 TI - Design and characterization of a membrane protein unfolding platform in lipid bilayers. AB - Accurate measurement of membrane protein stability--and particularly how it may vary as a result of disease-phenotypic mutations--ideally requires a denaturant that can unfold a membrane-embedded structure while leaving the solubilizing environment unaffected. The steric trap method fulfills this requirement by using monovalent streptavidin (mSA) molecules to unfold membrane proteins engineered with two spatially close biotin tags. Here we adapted this method to an 87 residue helix-loop-helix (hairpin) construct derived from helices 3 and 4 in the transmembrane domain of the human cystic fibrosis transmembrane conductance regulator (CFTR), wherein helix-helix tertiary interactions are anticipated to confer a portion of construct stability. The wild type CFTR TM3/4 hairpin construct was modified with two accessible biotin tags for mSA-induced unfolding, along with two helix-terminal pyrene labels to monitor loss of inter-helical contacts by pyrene excimer fluorescence. A series of eight constructs with biotin tags at varying distances from the helix-terminal pyrene labels were expressed, purified and labeled appropriately; all constructs exhibited largely helical circular dichroism spectra. We found that addition of mSA to an optimized construct in lipid vesicles led to a complete and reversible loss in pyrene excimer fluorescence and mSA binding, and hence hairpin unfolding--results further supported by SDS-PAGE visualization of mSA bound and unbound species. While some dimeric/oligomeric populations persist that may affect quantitation of the unfolding step, our characterization of the design yields a promising prototype of a future platform for the systematic study of membrane protein folding in a lipid bilayer environment. PMID- 25799100 TI - Spatial variation in the storages and age-related dynamics of forest carbon sequestration in different climate zones-evidence from black locust plantations on the Loess Plateau of China. AB - Knowledge about the long-term influences of climate change on the amount of potential carbon (C) sequestration in forest ecosystems, including age-related dynamics, remains unclear. This study used two similar age-sequences of black locust forests (Robinia pseudoacacia L.) in the semi-arid and semi-humid zones of China's Loess Plateau to assess the variation in C stocks and age-related dynamics. Our results demonstrated that black locust forests of the semi-humid zone stored significantly more C than did forests in the semi-arid zone, across the chronosequence (p < 0.001). The C carrying capacity of the plantations was measured at 166.4 Mg C ha-1 (1 Mg = 106 g) in the semi-humid zone, while the semi arid zone had a capacity of only 79.4 Mg C ha-1. Soil organic C (SOC) increased continuously with stand age in the semi-arid zone (R2 = 0.84, p = 0.010). However, in the semi-humid zone, SOC declined sharply by 47.8% after the initial stage (5 to 10 y). The C stock in trees increased continuously with stand age in the semi-humid zone (R2 = 0.83, p = 0.011), yet in the semi-arid zone, it decreased dramatically from 43.0 Mg C ha-1 to 28.4 Mg C ha-1 during the old forest stage (38 to 56 y). The shift from being a net C sink to a net C source occurred at the initial stage in the semi-humid zone versus at the old forest stage in the semi-arid zone after reforestation. Surprisingly, with the exception of the initial and later stages (55 y), the patterns of C allocation among trees, soils, understory and litter were not statistically different between the two climate zones. Our results suggest that climate factors can alter the potential amount and age-related dynamics of forest C sequestration. PMID- 25799102 TI - Introgression threatens the survival of the critically endangered freshwater crayfish Cherax tenuimanus (Decapoda: Parastacidae) in the wild. AB - Hybridization and genetic introgression following the introduction of exotic species can pose a significant threat to the survival of geographically restricted species. A remnant population of the critically endangered freshwater crayfish Cherax tenuimanus in the upper reaches of the Margaret River in southwestern Australia is under threat following the introduction and spread of its congener Cherax cainii. Here, we examine the extent of hybridization and introgression between the two species using twelve polymorphic microsatellite loci. Our study reveals there are three times more C. cainii than C. tenuimanus at our study site in the upper reaches of the Margaret River. There is also evidence of hybridization and introgression between C. tenuimanus and C. cainii at this site, with F1, F2 and backcrossed individuals identified. While interbreeding was confirmed in this study, our simulations suggest that the levels of introgression are much lower than would be expected under random mating, indicating partial reproductive barriers exist. Nevertheless, it is apparent that hybridization and introgression with C. cainii pose a serious threat to C. tenuimanus and their survival in the wild will require active adaptive management and continued genetic monitoring to evaluate management effectiveness. PMID- 25799101 TI - Autophagic signaling and proteolytic enzyme activity in cardiac and skeletal muscle of spontaneously hypertensive rats following chronic aerobic exercise. AB - Hypertension is a cardiovascular disease associated with deleterious effects in skeletal and cardiac muscle. Autophagy is a degradative process essential to muscle health. Acute exercise can alter autophagic signaling. Therefore, we aimed to characterize the effects of chronic endurance exercise on autophagy in skeletal and cardiac muscle of normotensive and hypertensive rats. Male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were assigned to a sedentary condition or 6 weeks of treadmill running. White gastrocnemius (WG) of hypertensive rats had higher (p<0.05) caspase-3 and proteasome activity, as well as elevated calpain activity. In addition, skeletal muscle of hypertensive animals had elevated (p<0.05) ATG7 and LC3I protein, LAMP2 mRNA, and cathepsin activity, indicative of enhanced autophagic signaling. Interestingly, chronic exercise training increased (p<0.05) Beclin-1, LC3, and p62 mRNA as well as proteasome activity, but reduced (p<0.05) Beclin-1 and ATG7 protein, as well as decreased (p<0.05) caspase-3, calpain, and cathepsin activity. Left ventricle (LV) of hypertensive rats had reduced (p<0.05) AMPKalpha and LC3II protein, as well as elevated (p<0.05) p-AKT, p-p70S6K, LC3I and p62 protein, which collectively suggest reduced autophagic signaling. Exercise training had little effect on autophagy-related signaling factors in LV; however, exercise training increased (p<0.05) proteasome activity but reduced (p<0.05) caspase-3 and calpain activity. Our results suggest that autophagic signaling is altered in skeletal and cardiac muscle of hypertensive animals. Regular aerobic exercise can effectively alter the proteolytic environment in both cardiac and skeletal muscle, as well as influence several autophagy-related factors in skeletal muscle of normotensive and hypertensive rats. PMID- 25799104 TI - Reassuring patients about low back pain. PMID- 25799103 TI - VDJSeq-Solver: in silico V(D)J recombination detection tool. AB - In this paper we present VDJSeq-Solver, a methodology and tool to identify clonal lymphocyte populations from paired-end RNA Sequencing reads derived from the sequencing of mRNA neoplastic cells. The tool detects the main clone that characterises the tissue of interest by recognizing the most abundant V(D)J rearrangement among the existing ones in the sample under study. The exact sequence of the clone identified is capable of accounting for the modifications introduced by the enzymatic processes. The proposed tool overcomes limitations of currently available lymphocyte rearrangements recognition methods, working on a single sequence at a time, that are not applicable to high-throughput sequencing data. In this work, VDJSeq-Solver has been applied to correctly detect the main clone and identify its sequence on five Mantle Cell Lymphoma samples; then the tool has been tested on twelve Diffuse Large B-Cell Lymphoma samples. In order to comply with the privacy, ethics and intellectual property policies of the University Hospital and the University of Verona, data is available upon request to supporto.utenti@ateneo.univr.it after signing a mandatory Materials Transfer Agreement. VDJSeq-Solver JAVA/Perl/Bash software implementation is free and available at http://eda.polito.it/VDJSeq-Solver/. PMID- 25799106 TI - A statistical approach for rare-variant association testing in affected sibships. AB - Sequencing and exome-chip technologies have motivated development of novel statistical tests to identify rare genetic variation that influences complex diseases. Although many rare-variant association tests exist for case-control or cross-sectional studies, far fewer methods exist for testing association in families. This is unfortunate, because cosegregation of rare variation and disease status in families can amplify association signals for rare variants. Many researchers have begun sequencing (or genotyping via exome chips) familial samples that were either recently collected or previously collected for linkage studies. Because many linkage studies of complex diseases sampled affected sibships, we propose a strategy for association testing of rare variants for use in this study design. The logic behind our approach is that rare susceptibility variants should be found more often on regions shared identical by descent by affected sibling pairs than on regions not shared identical by descent. We propose both burden and variance-component tests of rare variation that are applicable to affected sibships of arbitrary size and that do not require genotype information from unaffected siblings or independent controls. Our approaches are robust to population stratification and produce analytic p values, thereby enabling our approach to scale easily to genome-wide studies of rare variation. We illustrate our methods by using simulated data and exome chip data from sibships ascertained for hypertension collected as part of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. PMID- 25799107 TI - Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. AB - Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across three to five chromosomes. Two mothers did not show any phenotypic abnormalities, although 3-13 protein-coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy-number changes in two children. This resulted in gene-dosage changes, which are probably responsible for the severe congenital phenotypes of these two children. In contrast, the third child, who has a severe congenital disease, harbored all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy-number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein-coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals affects reproduction and is expected to substantially increase the risk of miscarriages, abortions, and severe congenital disease. PMID- 25799105 TI - Absence of heterozygosity due to template switching during replicative rearrangements. AB - We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders. PMID- 25799108 TI - Mutations in HPCA cause autosomal-recessive primary isolated dystonia. AB - Reports of primary isolated dystonia inherited in an autosomal-recessive (AR) manner, often lumped together as "DYT2 dystonia," have appeared in the scientific literature for several decades, but no genetic cause has been identified to date. Using a combination of homozygosity mapping and whole-exome sequencing in a consanguineous kindred affected by AR isolated dystonia, we identified homozygous mutations in HPCA, a gene encoding a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum, as the cause of disease in this family. Subsequently, compound-heterozygous mutations in HPCA were also identified in a second independent kindred affected by AR isolated dystonia. Functional studies suggest that hippocalcin might play a role in regulating voltage-dependent calcium channels. The identification of mutations in HPCA as a cause of AR primary isolated dystonia paves the way for further studies to assess whether "DYT2 dystonia" is a genetically homogeneous condition or not. PMID- 25799110 TI - Occurrence and control of sporadic proliferation in growth arrested Swiss 3T3 feeder cells. AB - Growth arrested Swiss mouse embryonic 3T3 cells are used as feeders to support the growth of epidermal keratinocytes and several other target cells. The 3T3 cells have been extensively subcultured owing to their popularity and wide distribution in the world and, as a consequence selective inclusion of variants is a strong possibility in them. Inadvertently selected variants expressing innate resistance to mitomycin C may continue to proliferate even after treatment with such growth arresting agents. The failure of growth arrest can lead to a serious risk of proliferative feeder contamination in target cell cultures. In this study, we passaged Swiss 3T3 cells (CCL-92, ATCC) by different seeding densities and incubation periods. We tested the resultant cultures for differences in anchorage-independent growth, resumption of proliferation after mitomycin C treatment and occurrence of proliferative feeder contaminants in an epidermal keratinocyte co-culture system. The study revealed subculture dependent differential responses. The cultures of a particular subculture procedure displayed unique cell size distribution and disintegrated completely in 6 weeks following mitomycin C treatment, but their repeated subculture resulted in feeder regrowth as late as 11 weeks after the growth arrest. In contrast, mitomycin C failed to inhibit cell proliferation in cultures of the other subculture schemes and also in a clone that was established from a transformation focus of super confluent culture. The resultant proliferative feeder cells contaminated the keratinocyte cultures. The anchorage-independent growth appeared in late passages as compared with the expression of mitomycin C resistance in earlier passages. The feeder regrowth was prevented by identifying a safe subculture protocol that discouraged the inclusion of resistant variants. We advocate routine anchorage independent growth assay and absolute confirmation of feeder disintegration to qualify feeder batches and caution on the use of fetal bovine serum. PMID- 25799109 TI - Diversity, metabolic properties and arsenic mobilization potential of indigenous bacteria in arsenic contaminated groundwater of West Bengal, India. AB - Arsenic (As) mobilization in alluvial aquifers is caused by a complex interplay of hydro-geo-microbiological activities. Nevertheless, diversity and biogeochemical significance of indigenous bacteria in Bengal Delta Plain are not well documented. We have deciphered bacterial community compositions and metabolic properties in As contaminated groundwater of West Bengal to define their role in As mobilization. Groundwater samples showed characteristic high As, low organic carbon and reducing property. Culture-independent and -dependent analyses revealed presence of diverse, yet near consistent community composition mostly represented by genera Pseudomonas, Flavobacterium, Brevundimonas, Polaromonas, Rhodococcus, Methyloversatilis and Methylotenera. Along with As resistance and -reductase activities, abilities to metabolize a wide range carbon substrates including long chain and polyaromatic hydrocarbons and HCO3, As3+ as electron donor and As5+/Fe3+ as terminal electron acceptor during anaerobic growth were frequently observed within the cultivable bacteria. Genes encoding cytosolic As5+ reductase (arsC) and As3+ efflux/transporter [arsB and acr3(2)] were found to be more abundant than the dissimilatory As5+ reductase gene arrA. The observed metabolic characteristics showed a good agreement with the same derived from phylogenetic lineages of constituent populations. Selected bacterial strains incubated anaerobically over 300 days using natural orange sand of Pleistocene aquifer showed release of soluble As mostly as As3+ along with several other elements (Al, Fe, Mn, K, etc.). Together with the production of oxalic acid within the biotic microcosms, change in sediment composition and mineralogy indicated dissolution of orange sand coupled with As/Fe reduction. Presence of arsC gene, As5+ reductase activity and oxalic acid production by the bacteria were found to be closely related to their ability to mobilize sediment bound As. Overall observations suggest that indigenous bacteria in oligotrophic groundwater possess adequate catabolic ability to mobilize As by a cascade of reactions, mostly linked to bacterial necessity for essential nutrients and detoxification. PMID- 25799111 TI - Correction: Genetic features of metachronous esophageal cancer developed in hodgkin's lymphoma or breast cancer long-term survivors: an exploratory study. PMID- 25799113 TI - Cost-effectiveness analysis of endoscopic ultrasound versus magnetic resonance cholangiopancreatography in patients with suspected common bile duct stones. AB - BACKGROUND: Patients with suspected common bile duct (CBD) stones are often diagnosed using endoscopic retrograde cholangiopancreatography (ERCP), an invasive procedure with risk of significant complications. Using endoscopic ultrasound (EUS) or Magnetic Resonance CholangioPancreatography (MRCP) first to detect CBD stones can reduce the risk of unnecessary procedures, cut complications and may save costs. AIM: This study sought to compare the cost effectiveness of initial EUS or MRCP in patients with suspected CBD stones. METHODS: This study is a model based cost-utility analysis estimating mean costs and quality-adjusted life years (QALYs) per patient from the perspective of the UK National Health Service (NHS) over a 1 year time horizon. A decision tree model was constructed and populated with probabilities, outcomes and cost data from published sources, including one-way and probabilistic sensitivity analyses. RESULTS: Using MRCP to select patients for ERCP was less costly than using EUS to select patients or proceeding directly to ERCP ($1299 versus $1753 and $1781, respectively), with similar QALYs accruing to each option (0.998, 0.998 and 0.997 for EUS, MRCP and direct ERCP, respectively). Initial MRCP was the most cost effective option with the highest monetary net benefit, and this result was not sensitive to model parameters. MRCP had a 61% probability of being cost-effective at $29,000, the maximum willingness to pay for a QALY commonly used in the UK. CONCLUSION: From the perspective of the UK NHS, MRCP was the most cost-effective test in the diagnosis of CBD stones. PMID- 25799112 TI - Ionotropic glutamate receptors mediate inducible defense in the water flea Daphnia pulex. AB - Phenotypic plasticity is the ability held in many organisms to produce different phenotypes with a given genome in response to environmental stimuli, such as temperature, nutrition and various biological interactions. It seems likely that environmental signals induce a variety of mechanistic responses that influence ontogenetic processes. Inducible defenses, in which prey animals alter their morphology, behavior and/or other traits to help protect against direct or latent predation threats, are among the most striking examples of phenotypic plasticity. The freshwater microcrustacean Daphnia pulex forms tooth-like defensive structures, "neckteeth," in response to chemical cues or signals, referred to as "kairomones," in this case released from phantom midge larvae, a predator of D. pulex. To identify factors involved in the reception and/or transmission of a kairomone, we used microarray analysis to identify genes up-regulated following a short period of exposure to the midge kairomone. In addition to identifying differentially expressed genes of unknown function, we also found significant up regulation of genes encoding ionotropic glutamate receptors, which are known to be involved in neurotransmission in many animal species. Specific antagonists of these receptors strongly inhibit the formation of neckteeth in D. pulex, although agonists did not induce neckteeth by themselves, indicating that ionotropic glutamate receptors are necessary but not sufficient for early steps of neckteeth formation in D. pulex. Moreover, using co-exposure of D. pulex to antagonists and juvenile hormone (JH), which physiologically mediates neckteeth formation, we found evidence suggesting that the inhibitory effect of antagonists is not due to direct inhibition of JH synthesis/secretion. Our findings not only provide a candidate molecule required for the inducible defense response in D. pulex, but also will contribute to the understanding of complex mechanisms underlying the recognition of environmental changes, which form the basis of phenotypic plasticity. PMID- 25799114 TI - Visible light-driven water oxidation promoted by host-guest interaction between photosensitizer and catalyst with a high quantum efficiency. AB - A highly active supramolecular system for visible light-driven water oxidation was developed with cyclodextrin-modified ruthenium complex as the photosensitizer, phenyl-modified ruthenium complexes as the catalysts, and sodium persulfate as the sacrificial electron acceptor. The catalysts were found to form 1:1 host-guest adducts with the photosensitizer. Stopped-flow measurement revealed the host-guest interaction is essential to facilitate the electron transfer from catalyst to sensitizer. As a result, a remarkable quantum efficiency of 84% was determined under visible light irradiation in neutral aqueous phosphate buffer. This value is nearly 1 order of magnitude higher than that of noninteraction system, indicating that the noncovalent incorporation of sensitizer and catalyst is an appealing approach for efficient conversion of solar energy into fuels. PMID- 25799115 TI - Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles. AB - Interpretation of mass spectra is challenging because they report a ratio of two physical quantities, mass and charge, which may each have multiple components that overlap in m/z. Previous approaches to disentangling the two have focused on peak assignment or fitting. However, the former struggle with complex spectra, and the latter are generally computationally intensive and may require substantial manual intervention. We propose a new data analysis approach that employs a Bayesian framework to separate the mass and charge dimensions. On the basis of this approach, we developed UniDec (Universal Deconvolution), software that provides a rapid, robust, and flexible deconvolution of mass spectra and ion mobility-mass spectra with minimal user intervention. Incorporation of the charge state distribution in the Bayesian prior probabilities provides separation of the m/z spectrum into its physical mass and charge components. We have evaluated our approach using systems of increasing complexity, enabling us to deduce lipid binding to membrane proteins, to probe the dynamics of subunit exchange reactions, and to characterize polydispersity in both protein assemblies and lipoprotein Nanodiscs. The general utility of our approach will greatly facilitate analysis of ion mobility and mass spectra. PMID- 25799116 TI - Single-molecule magnet of a tetranuclear dysprosium complex disturbed by a salen type ligand and chloride counterions. AB - A series of three salen-type lanthanide complexes, e.g., [Dy4(L)2(HL)2Cl2(MU3 OH)2]2Cl2(OH)2.3CH3CH2OH.H2O (1) and [Ln4(L)2(HL)2Cl2(MU3-OH)2]Cl2.5CH3OH.4CH2Cl2 (Ln = Tb(III), 2; Ho(III), 3) have been isolated by the reactions of H2L (H2L = N,N'-bis(3-methoxysalicylidene)cyclohexane-1,2-diamine) with LnCl3.6H2O. X-ray crystallographic analysis reveals that all complexes 1-3 are isostructural, in which four Ln ions and eight O atoms form the distorted defective dicubane {Dy4O8} cores. Magnetic studies indicate that complex 1 exhibits two slow magnetic relaxation processes with effective energy barrier Ueff = 55.71 K under a zero direct-current field, which is attributed to the two coordination geometries of the Dy(III) ions with a salen-type ligand and coordination of a chloride counterion. It represents the highest energy barrier among the salen type tetranuclear lanthanide single-molecule magnets. PMID- 25799118 TI - Test of Antonovsky's postulate: high sense of coherence helps people avoid negative life events. AB - This study tested Antonovsky's postulate that a high sense of coherence (SOC) helps people avoid negative life events. It was assumed that negative life events that were uncontrollable would not show this effect, while those events that potentially could be controlled would show a significant relationship with SOC. 1,012 female nurses (M age=46.9 yr.; SD=8.9) participated in this longitudinal study and were divided into groups with low, moderate, and high SOC. Sixteen negative life events were categorized into uncontrollable and controllable events, with the controllable events divided into three sub-categories. Five one way analyses of variance (ANOVAs) for independent measures followed up with post hoc tests were performed, with the number of experienced events in a given category by each participant (at Time 2) as the dependent variable and the three SOC groups (formed at Time 1) as the independent variable. The results indicated that the high SOC group reported fewer controllable negative life events, while there was no significant relationship between the SOC level and uncontrollable negative life events. The findings support the postulate in Antonovsky's model, with the distinction between controllable and uncontrollable negative life events. PMID- 25799119 TI - Creating a positive learning environment for students with English classroom anxiety. AB - Students situated in post-structural feminist pedagogical learning (PFPL) in a freshman English course (37 students) were expected to have lower English classroom anxiety, score higher in English, and have greater satisfaction with the class they attended than those in conventional lecture classes (40 students). Seventy-four students participated in the study (M age=18.5 yr., SD=0.5; 34 men, 43 women). The measures included the English Classroom Anxiety Scale (ECAS), English proficiency tests, the Student Satisfaction Questionnaire (SSQ), and student interviews. After the classes were completed, students in PFPL reported a significant decrease in anxiety toward the English classroom, scored significantly higher on English proficiency, and expressed significantly greater satisfaction with the course. PFPL potentially decreases students' English classroom anxiety and increases their English proficiency. PMID- 25799121 TI - Stress, coping, and work engagement within the -specific job context: comment on Kaiseler, et Al. (2014). AB - This work discusses the use of tools that make use of context information. Comments are based on a previous study that looked into the relationship between stressors, coping, and work engagement (Kaiseler, Queiros, Passos & Sousa, 2014). A set of propositions are provided for research that will allow the design of contextualized stress interventions in specific job settings. PMID- 25799120 TI - Cyber dating abuse: prevalence, context, and relationship with offline dating aggression. AB - The use of information and communication technologies (ICT) as tools to intimidate, harass, and control the partner has been, so far, little studied in the literature. The aim of this study was to determine the extension and sex differences of victimization of cyber dating abuse, as well as the context in which it occurs, and its relationship with offline psychological and physical aggressions. The sample consisted of 433 college students ages 18 to 30 years. The results showed that over 50% of the participants had been victims of some type of cyber dating abuse in the last six months. The most common behavior was the use of ICT to control the partner. Also, victims of cyber dating abuse were victimized repeatedly, an average of 23 times in the last six months. The data also showed that cyber dating abuse appear usually in a context of jealousy. Finally, the results revealed a significant relationship between cyber dating abuse and offline psychological dating aggressions. Limitations and future lines of research are discussed. PMID- 25799122 TI - Perspectives of Taiwanese pastoral counselors on the use of scripture and prayer in the counseling process. AB - Interviews were carried out with 10 Christian pastoral counselors to explore their perspectives on the use of Scripture and prayer in the counseling process. Grounded Theory was utilized. Five main categories including a theological framework of pastoral counseling, counselors' considerations of using Scripture and prayer, preparation for Christian spiritual intervention, implications of spiritual resources, and ethical issues in the pastoral counseling process were generated. The results suggest the theological framework of pastoral counseling is crucial to the use of Scripture and prayer, and the issue of a neutral response should first be clarified for clients. Basic guidelines for ethically using Scripture and prayer for working with Christian clients are proposed for further pastoral counselor training, practice, and research. PMID- 25799123 TI - RELATIONSHIP OF COGNITIVE BEHAVIORAL THERAPY EFFECTS AND HOMEWORK IN AN INDICATED PREVENTION OF DEPRESSION INTERVENTION FOR NON-PROFESSIONAL CAREGIVERS (.). AB - Activities designed to be performed outside of the intervention are considered an essential aspect of the effectiveness of cognitive-behavioral therapy. However, these have received little attention in interventions aimed at individuals with subclinical depressive symptoms who do not yet meet diagnostic criteria for depression (indicated prevention). In this study, the completion of tasks given as homework and their relationship with post-treatment depressive symptoms was with relation to an indicated prevention of depression intervention. Eighty-nine female non-professional caregivers recruited from an official registry completed an intervention involving 11 homework tasks. Tasks performed were recorded and depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D). Among caregivers, 80.9% completed 9-11 tasks. The number of tasks performed was associated with post-treatment depressive symptoms, with 9 being optimal for clinically significant improvement. These findings highlight the relationship between homework and post-treatment depressive symptoms. PMID- 25799124 TI - Hydroxypyridinonate complex stability of group (IV) metals and tetravalent f block elements: the key to the next generation of chelating agents for radiopharmaceuticals. AB - The solution thermodynamics of the water-soluble complexes formed between 3,4,3 LI(1,2-HOPO) and Zr(IV) or Pu(IV) were investigated to establish the metal coordination properties of this octadentate chelating agent. Stability constants log beta110 = 43.1 +/- 0.6 and 43.5 +/- 0.7 were determined for [Zr(IV)(3,4,3 LI(1,2-HOPO))] and [Pu(IV)(3,4,3-LI(1,2-HOPO))], respectively, by spectrophotometric competition titrations against Ce(IV). Such high thermodynamic stabilities not only confirm the unparalleled Pu(IV) affinity of 3,4,3-LI(1,2 HOPO) as a decorporation agent but also corroborate the great potential of hydroxypyridinonate ligands as new (89)Zr-chelating platforms for immuno-PET applications. These experimental values are in excellent agreement with previous estimates and are discussed with respect to ionic radius and electronic configuration, in comparison with those of Ce(IV) and Th(IV). Furthermore, a liquid chromatography assay combined with mass spectrometric detection was developed to probe the separation of the neutral [M(IV)(3,4,3-LI(1,2-HOPO))] complex species (M = Zr, Ce, Th, and Pu), providing additional insight into the coordination differences between group IV and tetravalent f-block metals and on the role of d and f orbitals in bonding interactions. PMID- 25799125 TI - Pt-free and efficient counter electrode with nanostructured CoNi2S4 for dye sensitized solar cells. AB - The counter electrode has a great influence on the performance of the dye sensitized solar cells (DSSCs). The research and development of Pt-free counter electrode is becoming one of the hot areas in the field of DSSCs. Herein, we successfully synthesized a ternary metal sulfide (CoNi2S4) nanostructure on FTO substrate by hydrothermal method and investigated its application as counter electrode. The as-synthesized sample could exhibit better electrocatalystic property than that of Pt, and corresponding DSSCs have comparable conversion efficiency with typical Pt catalyzed cells. The easy synthesis, low cost and excellent electrocatalytic property may help the CoNi2S4 nanostructure stand out as an alternative counter electrode in DSSCs. PMID- 25799127 TI - Remote, Synchronous, Hands-On Ultrasound Education. AB - BACKGROUND: Ultrasound has become a major diagnostic tool in many parts of the world, with broad clinical applications. Ultrasound provides a noninvasive, painless mode of diagnostics that produces instant results. Disseminating ultrasound skills to remote and rural communities has become a challenge for many medical schools, particularly those where distances are great and the density of population is low. MATERIALS AND METHODS: The University of California, Irvine School of Medicine and the University of New England School of Rural Medicine in Australia piloted the use of dual video feeds in two scenarios: (1) to display the instructor's ultrasound feed and the instructor's transducer placement to provide guidance for remote students; and (2) to display side-by-side views of the instructor's and the remote student's ultrasound feeds to allow the instructor to guide the remote student in his or her transducer placement. RESULTS AND CONCLUSIONS: Using high-speed broadband connections, the two schools demonstrated the feasibility of remote, synchronous, practical, and hands-on ultrasound training and instruction over international distances. This opens up a broad range of possibilities for future remote ultrasound education. PMID- 25799128 TI - Not all total joint replacement patients are created equal: preoperative factors and length of stay in hospital. AB - BACKGROUND: We conducted a cross-sectional study of primary total joint replacement (TJR) patients to determine predictors for prolonged length of stay (LOS) in hospital to identify patient characteristics that may inform resource allocation, accounting for patient complexity. METHODS: Preoperative demographics, medical comorbidities and acute hospital LOS from a consecutive series of primary TJR patients from an academic arthroplasty centre were abstracted. We categorized patients as LOS of 3 or fewer days, 4 days, or 5 or more days to align results with varying LOS benchmarks. To identify predictors for LOS, we used a generalized logistic regression model fitted on an LOS ternary outcome, using LOS of 3 or fewer days as a reference category. RESULTS: The sample included 1459 patients: 61.7% total knee and 38.3% total hip. Male sex was predictive of an LOS of 3 or fewer days (4 d: odds ratio [OR] 0.48, 95% confidence interval [CI] 0.364-0.631; >= 5 d: OR 0.57, 95% CI 0.435-0.758), as was current smoking status (4 d: OR 0.425, 95% CI 0.274-0.659; >= 5 d: OR 0.489, 95% CI 0.314-0.762). Strong predictors of prolonged LOS included total hip versus total knee arthroplasty, age 75 years or older, American Society of Anesthesiologists classification of 3 and 4 and number of cardiovascular comorbidities. CONCLUSION: Not all patients undergoing TJR are equal. The goal should be individual patient-focused care rather than a predetermined LOS that is not achievable for all patients. Hospital resource planning must account for patient complexity when planning future bed management. PMID- 25799126 TI - The kinase Jnk2 promotes stress-induced mitophagy by targeting the small mitochondrial form of the tumor suppressor ARF for degradation. AB - Mitophagy is essential for cellular homeostasis, but how mitophagy is regulated is largely unknown. Here we found that the kinase Jnk2 was required for stress induced mitophagy. Jnk2 promoted ubiquitination and proteasomal degradation of the small mitochondrial form of the tumor suppressor ARF (smARF). Loss of Jnk2 led to the accumulation of smARF, which induced excessive autophagy that resulted in lysosomal degradation of the mitophagy adaptor p62 at steady state. Depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress. Jnk2 deficient mice displayed defective mitophagy, which resulted in tissue damage under hypoxic stress, as well as hyperactivation of inflammasomes and increased mortality in sepsis. Our findings define a unique mechanism of maintaining immunological homeostasis that protects the host from tissue damage and mortality. PMID- 25799129 TI - Occult pneumothoraces in ventilated pediatric trauma patients: a review. AB - BACKGROUND: Currently there is no clinical consensus on how to treat occult pneumothoraces in adults, and even less research has been done in children. We sought to understand the outcomes of severely injured, ventilated children with occult pneumothoraces. METHODS: Using the Alberta Trauma Registry, we retrospectively reviewed the charts of all ventilated pediatric patients at a children's hospital from 2001 to 2011 who had an injury severity score greater than 12 and a diagnosis of occult pneumothorax (seen on computed tomography scan but not on supine chest radiograph). RESULTS: There were 1689 severely injured children, with 496 admitted to the pediatric intensive care unit (PICU) and ventilated. A total of 130 children were found to have pneumothoraces, and of those, 96 were admitted to the PICU. Of those, 15 children had a total of 19 occult pneumothoraces, and all were successfully treated without chest tubes. The average age was 13.4 (range 2.0-17.0) years, and 54% of these children were male. The average time spent on the ventilator was 2.3 (range 0-13) days, and 7 children had at least 1 operation. CONCLUSION: In our institution, occult pneumothoraces occur in very few severely injured, ventilated pediatric trauma patients. Our study adds to the increasing evidence in the adult and pediatric literature suggesting that occult pneumothoraces may be safely observed even while under positive-pressure ventilation. PMID- 25799130 TI - In search of the best reconstructive technique after pancreaticoduodenectomy: pancreaticojejunostomy versus pancreaticogastrostomy. AB - BACKGROUND: It has been suggested that pancreaticogastrostomy (PG) is a safer reconstruction than pancreaticojejunostomy (PJ), resulting in lower morbidity, including lower pancreatic leak rates and decreased postoperative mortality. We compared PJ and PG after pancreaticoduodenectomy (PD). METHODS: A randomized clinical trial was designed. It was stopped with 50% accrual. Patients underwent either PG or PJ reconstruction. The primary outcome was the pancreatic fistula rate, and the secondary outcomes were overall morbidity and mortality. We used the Student t, Mann-Whitney U and chi(2) tests for intention to treat analysis. The effect of randomization, American Society of Anesthesiologists score, soft pancreatic texture and use of pancreatic stent on overall complications and fistula rates was calculated using logistic regression. RESULTS: Our trial included 98 patients. The rate of pancreatic fistula formation was 18% in the PJ and 25% in the PG groups (p = 0.40). Postoperative complications occurred in 48% of patients in the PJ and 58% in the PG groups (p = 0.31). There were no significant predictors of overall complications in the multivariate analysis. Only soft pancreatic gland predicted the occurrence of pancreatic fistula (odds ratio 5.89, p = 0.003). CONCLUSION: There was no difference in the rates of pancreatic leak/fistula, overall complications or mortality between patients undergoing PG and and those undergoing PJ after PD. PMID- 25799131 TI - Starting a new laparoscopic liver surgery program: initial experience and improved efficiency. AB - BACKGROUND: Owing to the anatomic complexity of the liver and the risk of hemorrhage, most liver resections are still performed using an open procedure. We evaluated the outcomes of introducing a laparoscopic liver program to a community teaching hospital. METHODS: We retrospectively reviewed laparoscopic liver resections performed between August 2010 and July 2013 at St. Joseph's Health Centre in Toronto. The primary outcomes were mortality, major morbidity and negative margins. Secondary outcomes included other perioperative outcomes. We used nonparametric tests to compare the outcomes during the first (group A) and second (group B) halves of the study period. RESULTS: Group A included 19 patients and group B had 25 patients; 9 and 4 patients, respectively, had major resections. Group A had the only death due to liver failure. There was no difference in major complications (10.6% v. 16%) or length of stay (4.5 v. 4.6 d) between the groups. One patient in group B had a positive margin. There was a significant decrease in duration of surgery (from 237 to 170 min, p = 0.007), with a trend toward shorter duration for major resections (from 318 to 238 min, p = 0.07). Furthermore, more procedures were performed for malignancy in group B than group A (36.8% v. 84.0%, p = 0.001). CONCLUSION: Laparoscopic liver resection can be safely introduced into a Canadian community teaching hospital. Average duration of surgery decreased by 67 minutes despite a 2-fold increase in the number of cases performed for malignancy. PMID- 25799132 TI - Colonic perforation with intraluminal stents and bevacizumab in advanced colorectal cancer: retrospective case series and literature review. AB - BACKGROUND: Self-expanding metal stents (SEMS) are increasingly used in the treatment of malignant large bowel obstruction in the setting of inoperable colorectal cancer. Perforation is a well-known complication associated with these devices. The addition of the vascular endothelial growth factor inhibitor bevacizumab is suspected to increase the rate, but the extent of the increase is not known. METHODS: We retrospectively reviewed the records of patients receiving SEMS in tertiary hospitals in Calgary, Alta., between October 2001 and January 2012. RESULTS: We reviewed the records of 87 patients with inoperable colorectal cancer who received SEMS during our study period. Nine perforations occurred in total: 4 of 30 (13%) patients who received no chemotherapy, 3 of 47 (6%) who received chemotherapy but no bevacizumab, and 2 of 10 (20%) who received chemotherapy and bevacizumab. These two patients received bevacizumab with FOLFIRI after SEMS placement, and they had peritoneal disease. CONCLUSION: Our case series and other studies suggest that bevacizumab may increase the risk of colonic perforation in the setting of SEMS. Caution should be used when combining these therapies. PMID- 25799133 TI - Interpretation of surgical neuromonitoring data in Canada: a survey of practising surgeons. AB - Intraoperative neuromonitoring is a specialized skill set performed in the operating room to reduce the risk of neurologic injury. There appears to be a shortage of qualified personnel and a lack of Canadian guidelines on the performance of the task. We distributed a web-based survey on the attitude of the surgeons to the interpretation of intraoperative neuromonitoring data among surgeons who use the technique. At present, most of the interpretation is performed by either technologists or by the surgeons themselves. Most surgeons would prefer professional oversight from a neurologist or neurophysiologist at the doctoral level. There is a lack of personnel in Canada with the appropriate training and expertise to interpret intraoperative neuromonitoring data. PMID- 25799134 TI - Growth-factor-driven rescue to receptor tyrosine kinase (RTK) inhibitors through Akt and Erk phosphorylation in pediatric low grade astrocytoma and ependymoma. AB - Up to now, several clinical studies have been started investigating the relevance of receptor tyrosine kinase (RTK) inhibitors upon progression free survival in various pediatric brain tumors. However, single targeted kinase inhibition failed, possibly due to tumor resistance mechanisms. The present study will extend our previous observations that vascular endothelial growth factor receptor (VEGFR)-2, platelet derived growth factor receptor (PDGFR)beta, Src, the epidermal growth factor receptor (ErbB) family, and hepatocyte growth factor receptor (HGFR/cMet) are potentially drugable targets in pediatric low grade astrocytoma and ependymoma with investigations concerning growth-factor-driven rescue. This was investigated in pediatric low grade astrocytoma and ependymoma cell lines treated with receptor tyrosine kinase (RTK) inhibitors e.g. sorafenib, dasatinib, canertinib and crizotinib. Flow cytometry analyses showed high percentage of cells expressing VEGFR-1, fibroblast growth factor receptor (FGFR) 1, ErbB1/EGFR, HGFR and recepteur d'origine nantais (RON) (respectively 52-77%, 34-51%, 63-90%, 83-98%, 65-95%). Their respective inhibitors induced decrease of cell viability, measured with WST-1 cell viability assays. At least this was partially due to increased apoptotic levels measured by Annexin V/Propidium Iodide apoptosis assays. EGF, HGF and FGF, which are normally expressed in brain (tumor) tissue, showed to be effective rescue inducing growth factors resulting in increased cell survival especially during treatment with dasatinib (complete rescue) or sorafenib (partial rescue). Growth-factor-driven rescue was less prominent when canertinib or crizotinib were used. Rescue was underscored by significantly activating downstream Akt and/or Erk phosphorylation and increased tumor cell migration. Combination treatment showed to be able to overcome the growth-factor-driven rescue. In conclusion, our study highlights the extensive importance of environmentally present growth factors in developing tumor escape towards RTK inhibitors in pediatric low grade astrocytoma and ependymoma. It is of great interest to anticipate upon these results for the design of new therapeutic trials with RTK inhibitors in these pediatric brain tumors. PMID- 25799136 TI - Circadian rhythm of intraocular pressure in the adult rat. AB - Ocular hypertension is a risk factor for developing glaucoma, which consists of a group of optic neuropathies characterized by progressive degeneration of retinal ganglion cells and subsequent irreversible vision loss. Our understanding of how intraocular pressure damages the optic nerve is based on clinical measures of intraocular pressure that only gives a partial view of the dynamic pressure load inside the eye. Intraocular pressure varies over the course of the day and the oscillator regulating these daily changes has not yet been conclusively identified. The purpose of this study was to compare and contrast the circadian rhythms of intraocular pressure and body temperature in Brown Norway rats when these animals are housed in standard light-dark and continuous dim light (40-90 lux) conditions. The results from this study show that the temperature rhythm measured in continuous dim light drifted forward relative to external time, indicating that the rhythm was free running and being regulated by an internal biological clock. Also, the results show that there is a persistent, but dampened, circadian rhythm of intraocular pressure in continuous dim light and that the circadian rhythms of temperature and intraocular pressure are not synchronized by the same central oscillator. We conclude that once- or twice daily clinical measures of intraocular pressure are insufficient to describe intraocular pressure dynamics. Similarly, our results indicate that, in experimental animal models of glaucoma, the common practice of housing animals in constant light does not necessarily eliminate the potential influence of intraocular pressure rhythms on the progression of nerve damage. Future studies should aim to determine whether an oscillator within the eye regulates the rhythm of intraocular pressure and to better characterize the impact of glaucoma on this rhythm. PMID- 25799138 TI - Revealing the intricate effect of collaboration on innovation. AB - We studied the Japan and U.S. patent records of several decades to demonstrate the effect of collaboration on innovation. We found that statistically inventor teams slightly outperform solo inventors while company teams perform equally well as solo companies. By tracking the performance record of individual teams, we found that inventor teams' performance generally degrades with more repeat collaborations. Though company teams' performance displays strongly bursty behavior, long-term collaboration does not significantly help innovation. To systematically study the effect of repeat collaboration, we defined the repeat collaboration number of a team as the average number of collaborations over all the teammate pairs. We found that mild repeat collaboration improves the performance of Japanese inventor teams and U.S. company teams. Yet, excessive repeat collaboration does not significantly help innovation at both the inventor and company levels in both countries. To control for unobserved heterogeneity, we performed a detailed regression analysis and the results were consistent with our simple observations. The presented results revealed the intricate effect of collaboration on innovation, which may also be observed in other creative projects. PMID- 25799137 TI - Predictors of Rapid Progression of Glomerular and Nonglomerular Kidney Disease in Children and Adolescents: The Chronic Kidney Disease in Children (CKiD) Cohort. AB - BACKGROUND: Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression. STUDY DESIGN: Prospective multicenter observational cohort study. SETTING & PARTICIPANTS: 496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study. PREDICTORS: Proteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia. OUTCOMES: Parametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR). RESULTS: 398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally. LIMITATIONS: Small number of events in glomerular patients and use of internal cross-validation. CONCLUSIONS: Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD. PMID- 25799139 TI - Co-conserved MAPK features couple D-domain docking groove to distal allosteric sites via the C-terminal flanking tail. AB - Mitogen activated protein kinases (MAPKs) form a closely related family of kinases that control critical pathways associated with cell growth and survival. Although MAPKs have been extensively characterized at the biochemical, cellular, and structural level, an integrated evolutionary understanding of how MAPKs differ from other closely related protein kinases is currently lacking. Here, we perform statistical sequence comparisons of MAPKs and related protein kinases to identify sequence and structural features associated with MAPK functional divergence. We show, for the first time, that virtually all MAPK-distinguishing sequence features, including an unappreciated short insert segment in the beta4 beta5 loop, physically couple distal functional sites in the kinase domain to the D-domain peptide docking groove via the C-terminal flanking tail (C-tail). The coupling mediated by MAPK-specific residues confers an allosteric regulatory mechanism unique to MAPKs. In particular, the regulatory alphaC-helix conformation is controlled by a MAPK-conserved salt bridge interaction between an arginine in the alphaC-helix and an acidic residue in the C-tail. The salt-bridge interaction is modulated in unique ways in individual sub-families to achieve regulatory specificity. Our study is consistent with a model in which the C-tail co-evolved with the D-domain docking site to allosterically control MAPK activity. Our study provides testable mechanistic hypotheses for biochemical characterization of MAPK-conserved residues and new avenues for the design of allosteric MAPK inhibitors. PMID- 25799140 TI - Arterial levels of oxygen stimulate intimal hyperplasia in human saphenous veins via a ROS-dependent mechanism. AB - Saphenous veins used as arterial grafts are exposed to arterial levels of oxygen partial pressure (pO2), which are much greater than what they experience in their native environment. The object of this study is to determine the impact of exposing human saphenous veins to arterial pO2. Saphenous veins and left internal mammary arteries from consenting patients undergoing coronary artery bypass grafting were cultured ex vivo for 2 weeks in the presence of arterial or venous pO2 using an established organ culture model. Saphenous veins cultured with arterial pO2 developed intimal hyperplasia as evidenced by 2.8-fold greater intimal area and 5.8-fold increase in cell proliferation compared to those freshly isolated. Saphenous veins cultured at venous pO2 or internal mammary arteries cultured at arterial pO2 did not develop intimal hyperplasia. Intimal hyperplasia was accompanied by two markers of elevated reactive oxygen species (ROS): increased dihydroethidium associated fluorescence (4-fold, p<0.05) and increased levels of the lipid peroxidation product, 4-hydroxynonenal (10-fold, p<0.05). A functional role of the increased ROS saphenous veins exposed to arterial pO2 is suggested by the observation that chronic exposure to tiron, a ROS scavenger, during the two-week culture period, blocked intimal hyperplasia. Electron paramagnetic resonance based oximetry revealed that the pO2 in the wall of the vessel tracked that of the atmosphere with a ~30 mmHg offset, thus the cells in the vessel wall were directly exposed to variations in pO2. Monolayer cultures of smooth muscle cells isolated from saphenous veins exhibited increased proliferation when exposed to arterial pO2 relative to those cultured at venous pO2. This increased proliferation was blocked by tiron. Taken together, these data suggest that exposure of human SV to arterial pO2 stimulates IH via a ROS dependent pathway. PMID- 25799141 TI - Particle swarm optimization based feature enhancement and feature selection for improved emotion recognition in speech and glottal signals. AB - In the recent years, many research works have been published using speech related features for speech emotion recognition, however, recent studies show that there is a strong correlation between emotional states and glottal features. In this work, Mel-frequency cepstralcoefficients (MFCCs), linear predictive cepstral coefficients (LPCCs), perceptual linear predictive (PLP) features, gammatone filter outputs, timbral texture features, stationary wavelet transform based timbral texture features and relative wavelet packet energy and entropy features were extracted from the emotional speech (ES) signals and its glottal waveforms(GW). Particle swarm optimization based clustering (PSOC) and wrapper based particle swarm optimization (WPSO) were proposed to enhance the discerning ability of the features and to select the discriminating features respectively. Three different emotional speech databases were utilized to gauge the proposed method. Extreme learning machine (ELM) was employed to classify the different types of emotions. Different experiments were conducted and the results show that the proposed method significantly improves the speech emotion recognition performance compared to previous works published in the literature. PMID- 25799142 TI - Socioeconomic position early in adolescence and mode of delivery later in life: findings from a Portuguese birth cohort. AB - OBJECTIVE: This study assessed the influence of socioeconomic position at 12 years of age (SEP-12) on the variability in cesarean rates later in life. METHODS: As part of the Portuguese Generation XXI birth cohort we evaluated 7358 women with a singleton pregnancy who delivered at five Portuguese public hospitals serving the region of Porto (April/2005-September/2006). Based on the twelve items that described socioeconomic circumstances at age 12, a latent class analysis was used to classify women's SEP-12 as high, intermediate and low. Multiple Poisson regression was used to estimate adjusted risk ratio (RR) and respective 95% confidence interval (95% CI). RESULTS: The cesarean rates in high, intermediate and low SEP-12 were, respectively, 40.9%, 37.5% and 40.5% (p = 0.100) among primiparous women; 14.2%, 11.6% and 15.5% (p = 0.04) among multiparous women with no previous cesarean and 78.6%, 72.2% and 70.0% (p = 0.08) among women with a previous cesarean. A low to moderate association between SEP 12 and cesarean rates was observed among multiparous women with a previous cesarean, illustrating that women from higher SEP-12 were more likely to have a surgical delivery (RR = 1.12;95%CI:1.01-1.24 comparing high with low SEP-12 and RR = 1.03:95%CI:0.94-1.14 comparing intermediate with low SEP-12) not explained by potential mediating factors. No such association was found either in primiparous or in multiparous women without a previous cesarean. CONCLUSIONS: The association between SEP-12 and cesarean rates suggests the effect of past socioeconomic context on the decision concerning the mode of delivery, but only among women who experienced a previous cesarean. Accordingly, it appears that early-life socioeconomic circumstances drive cesarean rates but the effect can be modified by lived experiences concerning childbirth. PMID- 25799143 TI - Epidemics in interconnected small-world networks. AB - Networks can be used to describe the interconnections among individuals, which play an important role in the spread of disease. Although the small-world effect has been found to have a significant impact on epidemics in single networks, the small-world effect on epidemics in interconnected networks has rarely been considered. Here, we study the susceptible-infected-susceptible (SIS) model of epidemic spreading in a system comprising two interconnected small-world networks. We find that the epidemic threshold in such networks decreases when the rewiring probability of the component small-world networks increases. When the infection rate is low, the rewiring probability affects the global steady-state infection density, whereas when the infection rate is high, the infection density is insensitive to the rewiring probability. Moreover, epidemics in interconnected small-world networks are found to spread at different velocities that depend on the rewiring probability. PMID- 25799144 TI - Monitoring methionine sulfoxide with stereospecific mechanism-based fluorescent sensors. AB - Methionine can be reversibly oxidized to methionine sulfoxide (MetO) under physiological and pathophysiological conditions, but its use as a redox marker suffers from the lack of tools to detect and quantify MetO within cells. In this work, we created a pair of complementary stereospecific genetically encoded mechanism-based ratiometric fluorescent sensors of MetO by inserting a circularly permuted yellow fluorescent protein between yeast methionine sulfoxide reductases and thioredoxins. The two sensors, respectively named MetSOx and MetROx for their ability to detect S and R forms of MetO, were used for targeted analysis of protein oxidation, regulation and repair as well as for monitoring MetO in bacterial and mammalian cells, analyzing compartment-specific changes in MetO and examining responses to physiological stimuli. PMID- 25799146 TI - Correction: A sniffer-camera for imaging of ethanol vaporization from wine: the effect of wine glass shape. PMID- 25799145 TI - Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behcet disease. AB - INTRODUCTION: The etiology of Behcet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts. METHODS: We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published. RESULTS: We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3. DISCUSSION: We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases. PMID- 25799147 TI - Synthesis of vinyl boronates from aldehydes by a practical boron-Wittig reaction. AB - A highly stereoselective boron-Wittig reaction between stable and readily accessible 1,1-bis(pinacolboronates) and aldehydes furnishes a variety of synthetically useful di- and trisubstituted vinyl boronate esters. PMID- 25799148 TI - Modulation of NF-kappaB/miR-21/PTEN pathway sensitizes non-small cell lung cancer to cisplatin. AB - BACKGROUND: Platinum-based chemotherapy is a standard strategy for non-small cell lung cancer (NSCLC), while chemoresistance remains a major therapeutic challenge in current clinical practice. Our present study was aimed to determine whether inhibition of the NF-kappaB/miR-21/PTEN pathway could increase the sensitivity of NSCLC to cisplatin. METHODS: The expression of miR-21 in NSCLC tissues was determined using in situ hybridization. Next, the effect of miR-21 on the sensitivity of A549 cells to cisplatin was determined in vitro. Whether miR-21 regulated PTEN expression was assessed by luciferase assay. Furthermore, whether NF-kappaB targeted its binding elements in the miR-21 gene promoter was determined by luciferase and ChIP assay. Finally, we measured the cell viability and apoptosis under cisplatin treatment when NF-kappaB was inhibited. RESULTS: An elevated level of miR-21 was observed in NSCLC lung tissues and was related to a short survival time. Exogenous miR-21 promoted cell survival when exposed to cisplatin, while miR-21 inhibition could reverse this process. The RNA and protein levels of PTEN were significantly decreased by exogenous miR-21, and the 3'-untranslated region of PTEN was shown to be a target of miR-21. The expression of miR-21 was regulated by NF-kappaB binding to its element in the promoter, a finding that was verified by luciferase and ChIP assay. Hence, inhibition of NF kappaB by RNA silencing protects cells against cisplatin via decreasing miR-21 expression. CONCLUSION: Modulation of the NF-kappaB/miR-21/PTEN pathway in NSCLC showed that inhibition of this pathway may increase cisplatin sensitivity. PMID- 25799150 TI - Correction: the IQD gene family in soybean: structure, phylogeny, evolution and expression. PMID- 25799149 TI - Evaluation of clinical risk factors to predict high on-treatment platelet reactivity and outcome in patients with stable coronary artery disease (PREDICT STABLE). AB - OBJECTIVES: This study was designed to identify the multivariate effect of clinical risk factors on high on-treatment platelet reactivity (HPR) and 12 months major adverse events (MACE) under treatment with aspirin and clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI). METHODS: 739 consecutive patients with stable coronary artery disease (CAD) undergoing PCI were recruited. On-treatment platelet aggregation was tested by light transmittance aggregometry. Clinical risk factors and MACE during one-year follow-up were recorded. An independent population of 591 patients served as validation cohort. RESULTS: Degree of on-treatment platelet aggregation was influenced by different clinical risk factors. In multivariate regression analysis older age, diabetes mellitus, elevated BMI, renal function and left ventricular ejection fraction were independent predictors of HPR. After weighing these variables according to their estimates in multivariate regression model, we developed a score to predict HPR in stable CAD patients undergoing elective PCI (PREDICT-STABLE Score, ranging 0-9). Patients with a high score were significantly more likely to develop MACE within one year of follow-up, 3.4% (score 0-3), 6.3% (score 4-6) and 10.3% (score 7-9); odds ratio 3.23, P=0.02 for score 7-9 vs. 0-3. This association was confirmed in the validation cohort. CONCLUSIONS: Variability of on-treatment platelet function and associated outcome is mainly influenced by clinical risk variables. Identification of high risk patients (e.g. with high PREDICT-STABLE score) might help to identify risk groups that benefit from more intensified antiplatelet regimen. Additional clinical risk factor assessment rather than isolated platelet function-guided approaches should be investigated in future to evaluate personalized antiplatelet therapy in stable CAD-patients. PMID- 25799151 TI - The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes. AB - OBJECTIVES: A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants. METHODS: Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naive to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta analyses including up to 6,486 Danes. RESULTS: We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, beta=-0.042, p=0.012) and insulinogenic index (n=5,181, beta= 0.032, p=0.043) in Inter99 and these associations remained significant in meta analyses including four additional Danish studies (disposition index n=6,486, beta=-0.042, p=0.0044; and insulinogenic index n=6,486, beta=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, beta=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, beta=0.062, p=0.0040). CONCLUSION: Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1 rs17106184 on increased 2-hour insulin levels is however unexplained. PMID- 25799152 TI - Detection of G-quadruplex DNA using primer extension as a tool. AB - DNA sequence and structure play a key role in imparting fragility to different regions of the genome. Recent studies have shown that non-B DNA structures play a key role in causing genomic instability, apart from their physiological roles at telomeres and promoters. Structures such as G-quadruplexes, cruciforms, and triplexes have been implicated in making DNA susceptible to breakage, resulting in genomic rearrangements. Hence, techniques that aid in the easy identification of such non-B DNA motifs will prove to be very useful in determining factors responsible for genomic instability. In this study, we provide evidence for the use of primer extension as a sensitive and specific tool to detect such altered DNA structures. We have used the G-quadruplex motif, recently characterized at the BCL2 major breakpoint region as a proof of principle to demonstrate the advantages of the technique. Our results show that pause sites corresponding to the non-B DNA are specific, since they are absent when the G-quadruplex motif is mutated and their positions change in tandem with that of the primers. The efficiency of primer extension pause sites varied according to the concentration of monovalant cations tested, which support G-quadruplex formation. Overall, our results demonstrate that primer extension is a strong in vitro tool to detect non B DNA structures such as G-quadruplex on a plasmid DNA, which can be further adapted to identify non-B DNA structures, even at the genomic level. PMID- 25799155 TI - High-resolution vector microwave magnetometry based on solid-state spins in diamond. AB - The measurement of the microwave field is crucial for many developments in microwave technology and related applications. However, measuring microwave fields with high sensitivity and spatial resolution under ambient conditions remains elusive. In this work, we propose and experimentally demonstrate a scheme to measure both the strength and orientation of the microwave magnetic field by utilizing the quantum coherent dynamics of nitrogen vacancy centres in diamond. An angular resolution of 5.7 mrad and a sensitivity of 1.0 MUT Hz(-1/2) are achieved at a microwave frequency of 2.6000 GHz, and the microwave magnetic field vectors generated by a copper wire are precisely reconstructed. The solid-state microwave magnetometry with high resolution and wide frequency range that can work under ambient conditions proposed here enables unique potential applications over other state-of-art microwave magnetometry. PMID- 25799153 TI - An 18 kDa scaffold protein is critical for Staphylococcus epidermidis biofilm formation. AB - Virulence of the nosocomial pathogen Staphylococcus epidermidis is crucially linked to formation of adherent biofilms on artificial surfaces. Biofilm assembly is significantly fostered by production of a bacteria derived extracellular matrix. However, the matrix composition, spatial organization, and relevance of specific molecular interactions for integration of bacterial cells into the multilayered biofilm community are not fully understood. Here we report on the function of novel 18 kDa Small basic protein (Sbp) that was isolated from S. epidermidis biofilm matrix preparations by an affinity chromatographic approach. Sbp accumulates within the biofilm matrix, being preferentially deposited at the biofilm-substratum interface. Analysis of Sbp-negative S. epidermidis mutants demonstrated the importance of Sbp for sustained colonization of abiotic surfaces, but also epithelial cells. In addition, Sbp promotes assembly of S. epidermidis cell aggregates and establishment of multilayered biofilms by influencing polysaccharide intercellular-adhesin (PIA) and accumulation associated protein (Aap) mediated intercellular aggregation. While inactivation of Sbp indirectly resulted in reduced PIA-synthesis and biofilm formation, Sbp serves as an essential ligand during Aap domain-B mediated biofilm accumulation. Our data support the conclusion that Sbp serves as an S. epidermidis biofilm scaffold protein that significantly contributes to key steps of surface colonization. Sbp-negative S. epidermidis mutants showed no attenuated virulence in a mouse catheter infection model. Nevertheless, the high prevalence of sbp in commensal and invasive S. epidermidis populations suggests that Sbp plays a significant role as a co-factor during both multi-factorial commensal colonization and infection of artificial surfaces. PMID- 25799156 TI - [Specialist geriatric training to face the challenges of the 21st century]. PMID- 25799154 TI - Elevated levels of the complement activation product C4d in bronchial fluids for the diagnosis of lung cancer. AB - Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71-0.94) and 0.67 (95%CI = 0.58 0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56-0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease. PMID- 25799157 TI - Charge-bistable Pd(III)/Pd(II,IV) coordination polymers: phase transitions and their applications to optical properties. AB - Quasi-one-dimensional halogen-bridged Pt, Pd, and Ni complexes (MX chains) are a family of materials with potential charge bistability: M(II)-M(IV) mixed valence charge-density-wave (CDW) and M(III) averaged valence Mott-Hubbard (MH) states can form. However, until recently, no examples of MX chains showing charge bistability have been reported. Charge-bistable Pd MX chains, [Pd(en)2Br](Y1 C(n))2.H2O (en = 1,2-diaminoethane; Y1-C(n) = dialkyl 2-sulfosuccinate; n = the number of carbon atoms in alkyl chains) and [Pd(en)2Br](Y2-C(n))2.H2O (Y2-C(n) = dialkyl alpha-sulfomalonate), both of which showed phase transitions between Pd(III) MH and Pd(II,IV) CDW states, were prepared by utilizing chemical pressure. In addition, [Pd(en)2Br](Y1-C(n))2.H2O underwent pressure- and photo induced MH-CDW phase transitions. [Pd(en)2Br](Y2-C(n))2.H2O has a higher transition temperature, i.e., higher stability of the MH state, than [Pd(en)2Br](Y1-C(n))2.H2O does due to the difference in the crystal packing. The recent progress will lead to new pressure sensing and optical switching devices. PMID- 25799158 TI - Volume of Distribution in Drug Design. AB - Volume of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic molecule will tend to exhibit higher volume of distribution than a neutral molecule. Acids often exhibit low volumes of distribution. Although a design strategy against volume of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effects to other important properties. Strategies to increase volume of distribution include adding lipophilicity and introducing basic functional groups in a way that does not increase metabolic clearance. PMID- 25799159 TI - Recombinant Human Annexin A5 Can Repair the Disrupted Cardiomyocyte Adherens Junctions in Endotoxemia. AB - Recombinant human annexin A5 (Anx5) is known to protect cardiac function during endotoxemia, although the underlying mechanisms have yet to be elucidated. In this study, we demonstrated that Anx5 could repair the disrupted cardiomyocyte adherens junctions and improve the myocardial contractile function in lipopolysaccharide (LPS)-induced endotoxemia. Mechanistic studies revealed that Anx5 could antagonize the disassociation between p120-catenin (p120) and N cadherin as well as the dephosphorylation of p120 in LPS-treated cardiomyocytes. Small interference RNA and specific inhibitors experiment demonstrated that Anx5 regulated p120 functions by inhibition of p21-activated kinase 5 in a protein kinase Calpha-dependent way. Moreover, Anx5 could inhibit nuclear factor kappaB activation and downregulate the level of inflammatory cytokines, such as tumor necrosis factor alpha and interleukin 1beta, which contributed to improving tissue pathological damage in LPS-induced mouse endotoxemia model. Taken together, Anx5 could protect cardiomyocytes adherens junctions and improve myocardial contractile function via regulation of p120 and anti-inflammation in LPS-induced endotoxemia. This study provided novel insights in the prevention and treatment of septic shock. PMID- 25799160 TI - Emotional disclosure and victim blaming. AB - Victim blaming occurs when people are unfairly held responsible for their misfortunes. According to just world theory, witnessing another's victimization threatens just world beliefs, which arouses distress. Victim blaming redeems just world beliefs, thereby reducing distress. However, negative emotions can also be resolved through emotional disclosure, suggesting that disclosure can prevent victim blaming. Two experiments confirmed this prediction. In Study 1 participants viewed a woman being victimized or a woman in a nonvictimizing conflict. Participants then disclosed or suppressed the emotions aroused by these scenes and 1 week later evaluated the woman they had viewed. Disclosure reduced blaming of the victim but did not affect blaming of the nonvictim. Further, the more distress participants disclosed, the less they blamed the victim. Study 2 replicated the primary results of Study 1 and also showed that (a) disclosure exclusively reduces blaming of victims; it does not moderate judgments of victimizers, and (b) the effects of disclosure on blaming applies across genders. These 2 studies confirm that victim blaming is a form of emotion management (per just world theory), and that emotional disclosure prevents blaming by supplying an alternative mode of emotion management. This research also suggests that emotional disclosure moderates social perception, in general. PMID- 25799161 TI - Treatment of melanoidin wastewater by anaerobic digestion and coagulation. AB - Melanoidins are dark-coloured recalcitrant pollutants found in many industrial wastewaters including coffee-manufacturing effluent, molasses distillery wastewater (MDWW) and other wastewater with molasses as the raw material. The wastewaters are mostly treated with anaerobic digestion after some dilution to minimize the inhibition effect. However, the dark colour and recalcitrant dissolved organic carbon (DOC) mainly caused by melanoidin are not effectively removed. The aim of this study was to investigate the removal of colour and remnant DOC by different coagulants from anaerobically digested MDWW. From the six coagulants tested, ferric chloride had the highest melanoidin (48%), colour (92.7%) and DOC (63.3%) removal at pH 5 and a dosage of 1.6 g/l. Both polymer and inorganic salt coagulants tested had optimal colour, melanoidin and DOC removal at acidic pH. The molecular size distribution of synthetic melanoidins by liquid chromatography-organic carbon detection indicated a preferential removal of high molecular-weight melanoidins over low weight melanoidins by the coagulation. Further studies should focus on how to improve biodegradability of the treated effluent for it to be reused as dilution water for anaerobic digestion. PMID- 25799162 TI - The platform trial: an efficient strategy for evaluating multiple treatments. PMID- 25799163 TI - [Febrile neutropenia in onco-hematology patients hospitalized in Intensive Care Unit]. AB - Febrile neutropenia in cancer patients is associated with a high mortality. Patients are frequently admitted to Intensive Care Unit (ICU) for severe sepsis or septic shock. Empirical antibiotic treatment, including monotherapy beta lactam covering Pseudomonas aeruginosa, must be prompt. The ICU management is slightly different, due to a particular microbial ecology. A standardized approach to obtain a microbiological documentation is the cornerstone in these patients, leading to an adapted antimicrobial treatment. Systematic reassessment of initial antibiotic regimen should be realised. Neutropenic patients with severe sepsis or septic shock should receive promptly a beta-lactam aminoglycoside combination, as well as glycopeptides in case of severity or absence of documented infection. Early catheter removal should be considered widely. In the actual context of growing resistance, antibiotics saving became a major concern. According to context and microbial documentation, an escalade or de-escalade approach is recommended, to take into account multi-resistant pathogens. The addition of antifugal treatment is also a major issue in these patients and has well-defined indications. In neutropenic patients admitted in the ICU for severe sepsis or septic shock, controlling local microbial epidemiology and the emergence of multi-resistant bacteria are the key issues. PMID- 25799164 TI - [The role of pre-transplant debulking treatment in patients undergoing allogeneic stem cell transplantation for high-risk myelodysplastic syndrome]. AB - Treatment of myelodysplastic syndromes (MDS) remains unsatisfactory. Variable success in the correction of blood cytopenias, reduction of the proportion of marrow myeloblasts, and normalization of cytogenetics has been achieved with a variety of treatment strategies, including the use of immunosuppressive drugs, differentiating agents, conventional chemotherapy, and hypomethylating agents (HMAs) However, in general, responses have not been complete and have been of limited duration; prolongation of survival, if achieved, on average has been in the range of months. Currently, allogeneic hematopoietic stem-cell transplantation (allo-SCT) remains the only approach with curative potential for patients with higher risk/advanced MDS. Yet, despite the beneficial effects of allo-SCT, post-transplant relapse is a major cause of failure. Debulking prior to transplant treatment in patients with MDS is a matter of debate. The achievement of complete remission (CR) before allo-SCT improves post-transplantation outcome, although it is not clear whether this reflects the selection of patients with more responsive disease or is related to a reduction in disease burden. Higher CR rates in patients with MDS are obtained with induction chemotherapy (ICT) than with hypomethylating agents (HMAs), although HMAs may be active in patients with complex karyotypes in whom ICT almost invariably fails. Furthermore, HMAs have a good toxicity profile compared with ICT and may therefore be considered especially in older patients and in patients with comorbidities. However, all interventions aimed at reducing disease burden before allo-SCT expose patients to the risk of complications, which may prevent them from undergoing transplantation. Therefore, up-front allo-SCT is an option, particularly for patients with life-threatening cytopenias. In the absence of prospective randomized trials, the main therapeutic approaches are discussed in this review. PMID- 25799165 TI - The human cytomegalovirus UL133-138 gene locus attenuates the lytic viral cycle in fibroblasts. AB - The genomes of HCMV clinical strains (e.g. FIX, TR, PH, etc) contain a 15 kb region that encodes 20 putative ORFs. The region, termed ULb', is lost after serial passage of virus in human foreskin fibroblast (HFF) cell culture. Compared to clinical strains, laboratory strains replicate faster and to higher titers of infectious virus. We made recombinant viruses with 22, 14, or 7 ORFs deleted from the ULb' region using FIX and TR as model clinical strains. We also introduced a stop codon into single ORFs between UL133 and UL138 to prevent protein expression. All deletions within ULb' and all stop codon mutants within the UL133 to UL138 region increased to varying degrees, viral major immediate early RNA and protein, DNA, and cell-free infectious virus compared to the wild type viruses. The wild type viral proteins slowed down the viral replication process along with cell-free infectious virus release from human fibroblast cells. PMID- 25799166 TI - Isoflurane anesthesia initiated at the onset of reperfusion attenuates oxidative and hypoxic-ischemic brain injury. AB - This study demonstrates that in mice subjected to hypoxia-ischemia (HI) brain injury isoflurane anesthesia initiated upon reperfusion limits a release of mitochondrial oxidative radicals by inhibiting a recovery of complex-I dependent mitochondrial respiration. This significantly attenuates an oxidative stress and reduces the extent of HI brain injury. Neonatal mice were subjected to HI, and at the initiation of reperfusion were exposed to isoflurane with or without mechanical ventilation. At the end of HI and isoflurane exposure cerebral mitochondrial respiration, H2O2 emission rates were measured followed by an assessment of cerebral oxidative damage and infarct volumes. At 8 weeks after HI navigational memory and brain atrophy were assessed. In vitro, direct effect of isoflurane on mitochondrial H2O2 emission was compared to that of complex-I inhibitor, rotenone. Compared to controls, 15 minutes of isoflurane anesthesia inhibited recovery of the compex I-dependent mitochondrial respiration and decreased H2O2 production in mitochondria supported with succinate. This was associated with reduced oxidative brain injury, superior navigational memory and decreased cerebral atrophy compared to the vehicle-treated HI-mice. Extended isoflurane anesthesia was associated with sluggish recovery of cerebral blood flow (CBF) and the neuroprotection was lost. However, when isoflurane anesthesia was supported with mechanical ventilation the CBF recovery improved, the event associated with further reduction of infarct volume compared to HI-mice exposed to isoflurane without respiratory support. Thus, in neonatal mice brief isoflurane anesthesia initiated at the onset of reperfusion limits mitochondrial release of oxidative radicals and attenuates an oxidative stress. This novel mechanism contributes to neuroprotective action of isoflurane. The use of mechanical ventilation during isoflurane anesthesia counterbalances negative effect of isoflurane anesthesia on recovery of cerebral circulation which potentiates protection against reperfusion injury. PMID- 25799167 TI - Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model. AB - Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure. PMID- 25799168 TI - Mass drug administration for trachoma: how long is not long enough? AB - BACKGROUND: Blinding trachoma is targeted for elimination by 2020 using the SAFE strategy (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements). Annual mass drug administration (MDA) with azithromycin is a cornerstone of this strategy. If baseline prevalence of clinical signs of trachomatous inflammation - follicular among 1-9 year-olds (TF1-9) is >= 10% but <30%, the World Health Organization guidelines are for at least 3 annual MDAs; if >= 30%, 5. We assessed the likelihood of achieving the global elimination target of TF1-9 <5% at 3 and 5 year evaluations using program reports. METHODOLOGY/PRINCIPAL FINDINGS: We used the International Trachoma Initiative's prevalence and treatment database. Of 283 cross-sectional survey pairs with baseline and follow-up data, MDA was conducted in 170 districts. Linear and logistic regression modeling was applied to these to investigate the effect of MDA on baseline prevalence. Reduction to <5% was less likely, though not impossible, at higher baseline TF1-9 prevalences. Increased number of annual MDAs, as well as no skipped MDAs, were significant predictors of reduced TF1-9 at follow-up. The probability of achieving the <5% target was <50% for areas with >= 30% TF1-9 prevalence at baseline, even with 7 or more continuous annual MDAs. CONCLUSIONS: Number of annual MDAs alone appears insufficient to predict program progress; more information on the effects of baseline prevalence, coverage, and underlying environmental and hygienic conditions is needed. Programs should not skip MDAs, and at prevalences >30%, 7 or more annual MDAs may be required to achieve the target. There are five years left before the 2020 deadline to eliminate blinding trachoma. Low endemic settings are poised to succeed in their elimination goals. However, newly-identified high prevalence districts warrant immediate inclusion in the global program. Intensified application of the SAFE strategy is needed in order to guarantee blinding trachoma elimination by 2020. PMID- 25799170 TI - Managed bumblebees outperform honeybees in increasing peach fruit set in China: different limiting processes with different pollinators. AB - Peach Prunus persica (L.) Batsch is self-compatible and largely self-fertile, but under greenhouse conditions pollinators must be introduced to achieve good fruit set and quality. Because little work has been done to assess the effectiveness of different pollinators on peach trees under greenhouse conditions, we studied 'Okubo' peach in greenhouse tunnels near Beijing between 2012 and 2014. We measured pollen deposition, pollen-tube growth rates, ovary development, and initial fruit set after the flowers were visited by either of two managed pollinators: bumblebees, Bombus patagiatus Nylander, and honeybees, Apis mellifera L. The results show that B. patagiatus is more effective than A. mellifera as a pollinator of peach in greenhouses because of differences in two processes. First, B. patagiatus deposits more pollen grains on peach stigmas than A. mellifera, both during a single visit and during a whole day of open pollination. Second, there are differences in the fertilization performance of the pollen deposited. Half of the flowers visited by B. patagiatus are fertilized 9-11 days after bee visits, while for flowers visited by A. mellifera, half are fertilized 13-15 days after bee visits. Consequently, fruit development is also accelerated by bumblebees, showing that the different pollinators have not only different pollination efficiency, but also influence the subsequent time course of fertilization and fruit set. Flowers visited by B. patagiatus show faster ovary growth and ultimately these flowers produce more fruit. Our work shows that pollinators may influence fruit production beyond the amount of pollen delivered. We show that managed indigenous bumblebees significantly outperform introduced honeybees in increasing peach initial fruit set under greenhouse conditions. PMID- 25799169 TI - The effects of secretion factors from umbilical cord derived mesenchymal stem cells on osteogenic differentiation of mesenchymal stem cells. AB - Factors synthesized by mesenchymal stem cells (MSCs) contain various growth factors, cytokines, exosomes and microRNAs, which may affect the differentiation abilities of MSCs. In the present study, we investigated the effects of secretion factors of human umbilical cord derived mesenchymal stem cells (hUCMSCs) on osteogenesis of human bone marrow derived MSCs (hBMSCs). The results showed that 20 MUg/ml hUCMSCs secretion factors could initiate osteogenic differentiation of hBMSCs without osteogenic induction medium (OIM), and the amount of calcium deposit (stained by Alizarin Red) was significantly increased after the hUCMSCs secretion factors treatment. Real time quantitative reverse transcription polymerase chain reaction (real time qRT-PCR) demonstrated that the expression of osteogenesis-related genes including ALP, BMP2, OCN, Osterix, Col1alpha and Runx2 were significantly up-regulated following hUCMSCs secretion factors treatment. In addition, we found that 10 MUg hUCMSCs secretion factors together with 2*10(5) hBMSCs in the HA/TCP scaffolds promoted ectopic bone formation in nude mice. Local application of 10 MUg hUCMSCs secretion factors with 50 MUl 2% hyaluronic acid hydrogel and 1*10(5) rat bone marrow derived MSCs (rBMSCs) also significantly enhanced the bone repair of rat calvarial bone critical defect model at both 4 weeks and 8 weeks. Moreover, the group that received the hUCMSCs secretion factors treatment had more cartilage and bone regeneration in the defect areas than those in the control group. Taken together, these findings suggested that hUCMSCs secretion factors can initiate osteogenesis of bone marrow MSCs and promote bone repair. Our study indicates that hUCMSCs secretion factors may be potential sources for promoting bone regeneration. PMID- 25799171 TI - Comparison of clinical efficacy and safety between indacaterol and tiotropium in COPD: meta-analysis of randomized controlled trials. AB - Two once-daily inhaled bronchodilators, indacaterol and tiotropium, are widely used as first-line therapy in stable COPD patients. This study was performed to compare the clinical efficacy and safety between indacaterol and tiotropium in patients with moderate-to-severe COPD. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched to identify all published randomized controlled trials (RCTs). The primary outcome was trough forced expiratory volume in 1 second (FEV1) at week 12. Four RCTs were eligible for inclusion (three RCTs with moderate-to-severe COPD patients and one RCT with only severe COPD patients). Trough FEV1 at weeks 12 and 26 were not significantly different between indacaterol and tiotropium by the standardized mean difference with 0.014 (95% CI, -0.036, 0.063, I2= 23.5%) and with 0.037 (95% CI, -0.059 to 0.133, I2= 0%) along with differences in means of 0.003L and 0.014L, respectively. Indacaterol and tiotropium also showed similar St. George's Respiratory Questionnaire (SGRQ) total scores and percentages of patients with SGRQ improvement (>= 4 units) at week 26. The incidences of nasopharyngitis, serious cardiovascular events, and serious adverse events were not different between indacaterol and tiotropium, while those of cough (OR = 1.68, P < 0.001, and RR = 1.63) and COPD worsening (OR = 1.18, P = 0.003, and RR = 1.12) were higher for indacaterol than tiotropium. However, when one study with only severe COPD patients was removed from the meta-analysis, the difference in the incidence of COPD worsening between indacaterol and tiotropium became non-significant (OR = 1.13, P = 0.204, and RR = 1.09). The clinical efficacy and serious adverse events between indacaterol and tiotropium were equivocal in patients with moderate-to severe COPD. Cough is a common complaint associated with indacaterol, and COPD worsening needs to be carefully monitored in severe COPD patients when treated with indacaterol. PMID- 25799172 TI - Extended Granger causality: a new tool to identify the structure of physiological networks. AB - Granger causality (GC) is a very popular tool for assessing the presence of directional interactions between two time series of a multivariate data set. In its original formulation, GC does not account for zero-lag correlations possibly existing between the observed time series. In the present study we compare the GC with a novel measure, termed extended GC (eGC), able to capture instantaneous causal relationships. We present a two-step procedure for the practical estimation of eGC based on first detecting the existence of zero-lag correlations, and then assigning them to one of the two possible causal directions using pairwise measures of non-Gaussianity. The proposed method was validated in a simulation study, showing that the estimation procedure based on the extended representation overcomes the limits of the classic computation of GC, correctly detecting the presence and direction of zero-lag interactions and providing a meaningful causal interpretation based on the eGC. Then, GC and eGC were computed on the physiological variability series of heart period (HP), mean arterial pressure (AP) and cerebral blood flow velocity (FV) in ten subjects with postural related syncope (PRS), during different epochs of an head-up tilt test protocol. We found that both measures reflect the baroreflex impairment and the loss of cerebral autoregulation during pre-syncope. Furthermore, eGC analysis suggests that fast, within-beat effects between AP and FV variability contribute substantially to the mutual regulation of these physiological variables, and may play an important role in the impairment of cerebrovascular regulation associated with PRS. PMID- 25799173 TI - The immunomodulating effect of seminal plasma on T cells. AB - Seminal plasma (SP) contains immunomodulatory factors that may contribute to the formation of a tolerogenic environment at the embryo implantation site. The main focus of this study was to investigate the influence of SP on female T cells in the presence and absence of antigen-presenting cells (APCs) in an in vitro model. Female PBMCs and T cells were incubated with SP from seminal fluid samples of known and variable sperm quality. The immediate effect of SP on the mRNA expression of CD25, IL-10, IFN-gamma, and Foxp3 was measured. Furthermore, proliferative responses, cytokine production, and CD25 expression were determined. Exposure to SP leads to increased mRNA expression of CD25, IL-10, and Foxp3 in T cells. Induction of mRNA for IL-10 and CD25 was dependent on the presence of APCs. Both PBMCs and T cells exposed to SP showed a proliferative response and produced several cytokines. The proliferative effects of SP on T cells observed were independent of sperm quality parameters, cytokines or soluble HLA molecules in SP. Furthermore, the presence of SP induced a higher expression of CD25 on the membrane of CD4+ T cells. SP has a direct immunomodulatory effect on T cells, as reflected in a proliferative response and upregulation of Foxp3. The presence of APCs is needed to induce IL-10 and CD25 upregulation in T cells exposed to SP. In conclusion, SP has both a direct and an indirect effect mediated through APCs on T cells. PMID- 25799174 TI - What is the impact of policy differences on nursing home utilization? The cases of Germany and the Netherlands. AB - Though need factors would predict a higher rate of institutional use in Germany, in 2004 the percentage of people over 65 in institutions in the Netherlands was almost double the percentage in Germany. The lower nursing home utilization in Germany coincided with lower out-of-pocket costs, de facto means-testing of social assistance for such care, a lower perceived quality of nursing home, and less acceptance of the nursing home as a main care modality for adults experiencing functional impairments. These factors have developed over time and are consistent with a--relatively--large government responsibility toward care for the elderly and a preference for institutional care over home care in the Netherlands. The policy to encourage older adults to move to elderly homes to decrease the housing shortage after WWII might have had long-lasting effects. This paper points out that a key in the success of a reform is a behavioral change in the system. As there seems to be no single factor to decrease the percentage of older adults in nursing homes, a sequence of policies might be a more promising route. PMID- 25799175 TI - Acute right varicocele: a clue to congenital vascular anomaly. AB - Workup of acute unilateral right varicocele should encompass imaging to look for abdominal and retroperitoneal pathology, as well as congenital vascular anomalies. Management of the acute symptomatic varicocele due to upstream venous thrombosis should be primarily medical, with initiation of anticoagulation and early involvement of our hematology colleagues. PMID- 25799176 TI - The Effect of Androgen Deprivation Therapy Before Salvage Whole-gland Cryoablation After Primary Radiation Failure in Prostate Cancer Treatment. AB - OBJECTIVE: To define the effects of androgen deprivation therapy (ADT) used prior to salvage cryoablation (SC) for the treatment of recurrent localized prostate cancer after radiation. METHODS: Patients from the Cryo On-Line Database registry undergoing SC after radiation failure were divided according to whether they had previously received or not received ADT. Baseline characteristics including demographics and presalvage cancer risk were compared. Biochemical progression free survival (bPFS) as defined by the Phoenix criteria was compared between the 2 groups as a whole and also in D'Amico risk-stratified subgroups. In addition, postsurgical complications such as urinary fistula, retention, incontinence, and erectile dysfunction were compared. RESULTS: Two groups consisting of 254 and 486 patients with and without pre-SC ADT were analyzed. The patients who received ADT were younger (P = .003) and had higher presalvage D'Amico risks (P <.001). The 5 year bPFS was 63.8% and 39.3% for the hormone-naive and the pre-SC ADT patients, respectively (P <.001). On subgroup analysis, the difference in 5-year bPFS was significant only for patients with a high D'Amico cancer risk (54.3% vs 30.5%; P = .013). On multivariate analysis, presalvage prostate-specific antigen (hazard ratio [HR], 1.7), Gleason score >= 8 (HR, 2.5), and use of pre-SC ADT (HR, 1.7) correlated with biochemical recurrence. Additionally, patients receiving pre-SC ADT experienced less urinary retention (P = .001) and incontinence (P = .008) but were more likely to be impotent (P = .010). CONCLUSION: Patients receiving ADT before SC, especially those with high-risk prostate cancer, had worse 5-year bPFS. Added caution is needed when selecting patients having previously received ADT for salvage cryotherapy. PMID- 25799177 TI - Early Detection Tool of Intestinal Dysfunction: Impact on Necrotizing Enterocolitis Severity. AB - OBJECTIVE: The aim of this study is to determine the use of an early clinical signs and symptoms warning tool in early identification of intestinal dysfunction as a clinical strategy to decrease necrotizing enterocolitis (NEC) severity. DESIGN: Using signs and symptoms of 297 infants, of which 33 infants were diagnosed with stage II and III EC intestinal dysfunction, a five clinical category scoring tool (Neonatal Necrotizing Enterocolitis Early Detection Score [NeoNEEDS]) and strategy with abdominal X-ray alert was developed. The categories included behavior, cardiac, respiratory, gastrointestinal, and feeding tolerance. The strategy was tested in a prospective cohort of 72 infants < 1,500 g, utilizing 532 observations between 10/2012 and 9/1/2013. The statistical analysis utilized the Statistical Analysis Software (SAS). RESULTS: The earliest signs and symptoms of intestinal dysfunction (Stage I NEC) were cardiorespiratory baseline changes, p < 0.001. Abdominal distension and/or feeding intolerance were late findings associated with stage II or III NEC. Tool scores >= 5 predicted intestinal dysfunction (p < 0.00). Sensitivity was high (95%) with specificity of 82% and positive and negative predictive values of 76% and 95%, respectively. Use of the tool during the study period was associated with decreased NEC severity rates (Bell NEC stage II and III). CONCLUSION: Cardiorespiratory symptoms precede gastrointestinal symptoms of intestinal dysfunction. Targeting signs and symptoms in an early warning tool to identify intestinal dysfunction can impact NEC severity progression. PMID- 25799178 TI - Source space estimation of oscillatory power and brain connectivity in tinnitus. AB - Tinnitus is the perception of an internally generated sound that is postulated to emerge as a result of structural and functional changes in the brain. However, the precise pathophysiology of tinnitus remains unknown. Llinas' thalamocortical dysrhythmia model suggests that neural deafferentation due to hearing loss causes a dysregulation of coherent activity between thalamus and auditory cortex. This leads to a pathological coupling of theta and gamma oscillatory activity in the resting state, localised to the auditory cortex where normally alpha oscillations should occur. Numerous studies also suggest that tinnitus perception relies on the interplay between auditory and non-auditory brain areas. According to the Global Brain Model, a network of global fronto-parietal-cingulate areas is important in the generation and maintenance of the conscious perception of tinnitus. Thus, the distress experienced by many individuals with tinnitus is related to the top-down influence of this global network on auditory areas. In this magnetoencephalographic study, we compare resting-state oscillatory activity of tinnitus participants and normal-hearing controls to examine effects on spectral power as well as functional and effective connectivity. The analysis is based on beamformer source projection and an atlas-based region-of-interest approach. We find increased functional connectivity within the auditory cortices in the alpha band. A significant increase is also found for the effective connectivity from a global brain network to the auditory cortices in the alpha and beta bands. We do not find evidence of effects on spectral power. Overall, our results provide only limited support for the thalamocortical dysrhythmia and Global Brain models of tinnitus. PMID- 25799179 TI - Enhanced performance of nanocrystalline ZnO DNA biosensor via introducing electrochemical covalent biolinkers. AB - Zinc oxide (ZnO) is considered to be one of the most promising candidates for the third-generation DNA biosensor because of its good chemical stability, wonderful biocompatibility, easy surface modification, and numerous kinds of nanostructures. In this work, we report a new and simple method to modify ZnO surface for the immobilization of oligonucleotides by electrochemical covalent grafting of diazonium salts. The atomic force microscope, X-ray photoelectron spectroscopy, surface contact angle system, and electrochemical workstation were employed to characterize the functionalization process. Fluorescence results show that this kind of DNA biosensor from covalently linking strategy has an enhanced performance compared to that based on an electrostatic adsorption route. The functionalized ZnO biosensor has the capability to distinguish four-base mismatched, one-base mismatched, and complementary DNA sequences. Moreover, a linear relationship has been observed between the fluorescence intensity and the concentration of the complementary DNA in the solution within the range from 10( 6) to 10(-9) M, offering us a possibility in the qualitative determination of the level of target DNA. PMID- 25799181 TI - A copper-catalyzed one-pot, three-component tandem conjugative alkynylation/6 endo cyclization sequence: access to pyrano[2,3-d]-pyrimidines. AB - A copper catalyzed one-pot, three component reaction between barbituric acid, aldehydes and terminal alkynes has been developed for the construction of pyrano[2,3-d]pyrimidines via a tandem conjugative alkynylation/6-endo cyclization pattern. Screening of barbituric acid derived organic acceptors in conjugative alkynylation reaction and the synthetic applicability of conjugative addition products under one-pot conditions were documented for the first time. PMID- 25799180 TI - Long-term hyperphagia and caloric restriction caused by low- or high-density husbandry have differential effects on zebrafish postembryonic development, somatic growth, fat accumulation and reproduction. AB - In recent years, the zebrafish (Danio rerio) has emerged as an alternative vertebrate model for energy homeostasis and metabolic diseases, including obesity and anorexia. It has been shown that diet-induced obesity (DIO) in zebrafish shares multiple pathophysiological features with obesity in mammals. However, a systematic and comprehensive analysis of the different pathways of energy expenditure in obese and starved fish had been missing thus far. Here, we carry out long-term ad libitum feeding (hyperphagia) and caloric restriction studies induced by low- or high-density husbandry, respectively, to investigate the impact of caloric intake on the timing of scale formation, a crucial step of postembryonic development and metamorphosis, and on somatic growth, body weight, fat storage and female reproduction. We show that all of them are positively affected by increased caloric intake, that middle-aged fish develop severe DIO, and that the body mass index (BMI) displays a strict linear correlation with whole-body triglyceride levels in adult zebrafish. Interestingly, juvenile fish are largely resistant to DIO, while BMI and triglyceride values drop in aged fish, pointing to aging-associated anorexic effects. Histological analyses further indicate that increased fat storage in white adipose tissue involves both hyperplasia and hypertrophy of adipocytes. Furthermore, in ovaries, caloric intake primarily affects the rate of oocyte growth, rather than total oocyte numbers. Finally, comparing the different pathways of energy expenditure with each other, we demonstrate that they are differentially affected by caloric restriction / high-density husbandry. In juvenile fish, scale formation is prioritized over somatic growth, while in sexually mature adults, female reproduction is prioritized over somatic growth, and somatic growth over fat storage. Our data will serve as a template for future functional studies to dissect the neuroendocrine regulators of energy homeostasis mediating differential energy allocation. PMID- 25799182 TI - Influence of the Expression Level of O6-Alkylguanine-DNA Alkyltransferase on the Formation of DNA Interstrand Crosslinks Induced by Chloroethylnitrosoureas in Cells: A Quantitation Using High-Performance Liquid Chromatography-Mass Spectrometry. AB - Chloroethylnitrosoureas (CENUs), which are bifunctional alkylating agents widely used in the clinical treatment of cancer, exert anticancer activity by inducing crosslink within a guanine-cytosine DNA base pair. However, the formation of dG dC crosslinks can be prevented by O6-alkylguanine-DNA alkyltransferase (AGT), ultimately leading to drug resistance. Therefore, the level of AGT expression is related to the formation of dG-dC crosslinks and the sensitivity of cells to CENUs. In this work, we determined the CENU-induced dG-dC crosslink in mouse L1210 leukemia cells and in human glioblastoma cells (SF-763, SF-767 and SF-126) containing different levels of AGT using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The results indicate that nimustine (ACNU) induced more dG-dC crosslinks in L1210 leukemia cells than those induced by carmustine (BCNU), lomustine (CCNU) and fotemustine (FTMS). This result was consistent with a previously reported cohort study, which demonstrated that ACNU had a better survival gain than BCNU, CCNU and FTMS for patients with high-grade glioma. Moreover, we compared the crosslinking levels and the cytotoxicity in SF-763, SF-767 and SF-126 cells with different AGT expression levels after exposure to ACNU. The levels of dG-dC crosslink in SF-126 cells (low AGT expression) were significantly higher than those in SF-767 (medium AGT expression) and SF-763 (high AGT expression) cells at each time point. Correspondingly, the cytotoxicity of SF-126 was the highest followed by SF-767 and SF-763. The results obtained in this work provided unequivocal evidence for drug resistance to CENUs induced by AGT-mediated repair of DNA ICLs. We postulate that the level of dG-dC crosslink has the potential to be employed as a biomarker for estimating drug resistance and anticancer efficiencies of novel CENU chemotherapies. PMID- 25799183 TI - Ambient ionization mass spectrometry imaging of rohitukine, a chromone anti cancer alkaloid, during seed development in Dysoxylum binectariferum Hook.f (Meliaceae). AB - Rohitukine, a chromone alkaloid, possesses anti-inflammatory, anti-cancer and immuno-modulatory properties. It has been reported from four species, belonging to the families, Meliaceae and Rubiaceae. Stem bark of Dysoxylum binectariferum (Meliaceae) accumulates the highest amount of rohitukine (3-7% by dry weight). In this study, we examine the spatial and temporal distribution of rohitukine and related compounds during various stages of seed development in D. binectariferum using desorption electrospray ionization mass spectrometry imaging (DESI MSI). Rohitukine (m/z 306.2) accumulation increased from early seed development to seed maturity stage. The spatial distribution of rohitukine was largely restricted to the cotyledonary tissue followed by the embryo and least in the seed coat. Besides rohitukine, rohitukine acetate (m/z 348.2) and glycosylated rohitukine (m/z 468.2) were also detected, both through mass fragmentation and exact mass analysis through Orbitrap mass spectrometry. These results indicate a dynamic pattern of chromane alkaloid accumulation through seed development in D. binectariferum. PMID- 25799184 TI - Calcium acetate or calcium carbonate for hyperphosphatemia of hemodialysis patients: a meta-analysis. AB - BACKGROUND: High levels of serum phosphorus both at baseline and during follow-up are associated with increased mortality in dialysis patients, and administration of phosphate binders was independently associated with improved survival among hemodialysis population. Calcium-based phosphate binders are the most commonly used phosphate binders in developing countries for their relatively low costs. OBJECTIVES: To compare the efficacy and safety between calcium carbonate and calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. METHODS: PubMed, EMBASE, Cochrane Library, Google scholar and Chinese databases (Wanfang, Weipu, National Knowledge Infrastructure of China) were searched for relevant studies published before March 2014. Reference lists of nephrology textbooks and review articles were checked. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of calcium acetate and calcium carbonate in adult patients with MHD was performed using Review Manager 5.0. RESULTS: A total of ten studies (625 participants) were included in this meta-analysis. There was insufficient data in all-cause mortality and cardiovascular events for meta-analysis. Compared with calcium carbonate group, the serum phosphorus was significantly lower in calcium acetate group after4 weeks' administration (MD -0.15 mmol/L, 95% CI -0.28 to 0.01) and after 8 weeks' administration (MD -0.25 mmol/L, 95% CI -0.40 to -0.11). There was no difference in serum calcium levels or the incidence of hypercalcemia between two groups at 4 weeks and 8 weeks. No statistical difference was found in parathyroid hormone (PTH) levels or serum calcium by phosphorus (Ca x P) product. There was significantly higher risk of intolerance with calcium acetate treatment (RR 3.46, 95% CI 1.48 to 8.26). CONCLUSIONS: For hyperphosphatemia treatment, calcium acetate showed better efficacy and with a higher incidence of intolerance compared with calcium carbonate. There are insufficient data to establish the comparative superiority of the two calcium-based phosphate binders on all-cause mortality and cardiovascular end-points in hemodialysis patients. PMID- 25799185 TI - Pregnancy outcome in proteinuria-onset and hypertension-onset preeclampsia. AB - OBJECTIVE: To evaluate pregnancy outcome in preeclampsia (PE), according to the timing of onset of proteinuria and hypertension. METHODS: Preeclamptic women were retrospectively divided into proteinuria-onset and hypertension-onset PE according to the first symptom. Maternal and perinatal outcome were assessed in both the groups. RESULTS: One hundred and ninety five single pregnancies complicated by PE were included. According to the first symptom, they were divided into two groups: proteinuria-onset PE (n = 49, 25.1%) and hypertension onset PE (n = 146, 74.9%). Pregnancy and neonatal outcome was significantly worse in proteinuria-onset PE. CONCLUSION: Proteinuria-onset PE is associated with an increased risk of adverse pregnancy outcome than hypertension-onset PE. PMID- 25799186 TI - Life expectancy with and without cognitive impairment in seven Latin American and Caribbean countries. AB - BACKGROUND: The rising prevalence of cognitive impairment is an increasing challenge with the ageing of our populations but little is known about the burden in low- and middle- income Latin American and Caribbean countries (LAC) that are aging more rapidly than their developed counterparts. We examined life expectancies with cognitive impairment (CILE) and free of cognitive impairment (CIFLE) in seven developing LAC countries. METHODS: Data from The Survey on Health, Well-being and Ageing in LAC (N = 10,597) was utilised and cognitive status was assessed by the Mini-Mental State Examination (MMSE). The Sullivan Method was applied to estimate CILE and CIFLE. Logistic regression was used to determine the effect of age, gender and education on cognitive outcome. Meta regression models were fitted for all 7 countries together to investigate the relationship between CIFLE and education in men and women at age 60. RESULTS: The prevalence of CI increased with age in all countries except Uruguay and with a significant gender effect observed only in Mexico where men had lower odds of CI compared to women [OR = 0.464 95% CInt (0.268 - 0.806)]. Low education was associated with increased prevalence of CI in Brazil [OR = 4.848 (1.173-20.044)], Chile [OR = 3.107 (1.098-8.793), Cuba [OR = 2.295 (1.247-4.225)] and Mexico [OR = 3.838 (1.368-10.765). For males, total life expectancy (TLE) at age 60 was highest in Cuba (19.7 years) and lowest in Brazil and Uruguay (17.6 years). TLE for females at age 60 was highest for Chileans (22.8 years) and lowest for Brazilians (20.2 years). CIFLE for men was greatest in Cuba (19.0 years) and least in Brazil (16.7 years). These differences did not appear to be explained by educational level (Men: p = 0.408, women: p = 0.695). CONCLUSION: Increasing age, female sex and low education were associated with higher CI in LAC reflecting patterns found in other countries. PMID- 25799188 TI - Correction: Nitric oxide modulates the temporal properties of the glutamate response in type 4 OFF bipolar cells. PMID- 25799187 TI - Retroviruses hijack chromatin loops to drive oncogene expression and highlight the chromatin architecture around proto-oncogenic loci. AB - The majority of the genome consists of intergenic and non-coding DNA sequences shown to play a major role in different gene regulatory networks. However, the specific potency of these distal elements as well as how these regions exert function across large genomic distances remains unclear. To address these unresolved issues, we closely examined the chromatin architecture around proto oncogenic loci in the mouse and human genomes to demonstrate a functional role for chromatin looping in distal gene regulation. Using cell culture models, we show that tumorigenic retroviral integration sites within the mouse genome occur near existing large chromatin loops and that this chromatin architecture is maintained within the human genome as well. Significantly, as mutagenesis screens are not feasible in humans, we demonstrate a way to leverage existing screens in mice to identify disease relevant human enhancers and expose novel disease mechanisms. For instance, we characterize the epigenetic landscape upstream of the human Cyclin D1 locus to find multiple distal interactions that contribute to the complex cis-regulation of this cell cycle gene. Furthermore, we characterize a novel distal interaction upstream of the Cyclin D1 gene which provides mechanistic evidence for the abundant overexpression of Cyclin D1 occurring in multiple myeloma cells harboring a pathogenic translocation event. Through use of mapped retroviral integrations and translocation breakpoints, our studies highlight the importance of chromatin looping in oncogene expression, elucidate the epigenetic mechanisms crucial for distal cis-regulation, and in one particular instance, explain how a translocation event drives tumorigenesis through upregulation of a proto-oncogene. PMID- 25799189 TI - Activation of intestinal epithelial Stat3 orchestrates tissue defense during gastrointestinal infection. AB - Gastrointestinal infections with EHEC and EPEC are responsible for outbreaks of diarrheal diseases and represent a global health problem. Innate first-line defense mechanisms such as production of mucus and antimicrobial peptides by intestinal epithelial cells are of utmost importance for host control of gastrointestinal infections. For the first time, we directly demonstrate a critical role for Stat3 activation in intestinal epithelial cells upon infection of mice with Citrobacter rodentium - a murine pathogen that mimics human infections with attaching and effacing Escherichia coli. C. rodentium induced transcription of IL-6 and IL-22 in gut samples of mice and was associated with activation of the transcription factor Stat3 in intestinal epithelial cells. C. rodentium infection induced expression of several antimicrobial peptides such as RegIIIgamma and Pla2g2a in the intestine which was critically dependent on Stat3 activation. Consequently, mice with specific deletion of Stat3 in intestinal epithelial cells showed increased susceptibility to C. rodentium infection as indicated by high bacterial load, severe gut inflammation, pronounced intestinal epithelial cell death and dissemination of bacteria to distant organs. Together, our data implicate an essential role for Stat3 activation in intestinal epithelial cells during C. rodentium infection. Stat3 concerts the host response to bacterial infection by controlling bacterial growth and suppression of apoptosis to maintain intestinal epithelial barrier function. PMID- 25799190 TI - Pathological features of localized prostate cancer in China: a contemporary analysis of radical prostatectomy specimens. AB - There has been a rapid increase in the incidence of prostate cancer in China, especially in areas with boosted economic development. In this study, we analyzed the pathological features of a contemporary series of radical prostatectomy cases. A total of 230 consecutive, whole-mounted radical prostatectomy specimens collected from 2012 to 2014 were reviewed. The median age of the patients was 68 years, and 64.3% of patients presented with prostate specific antigen alone. Pathological examination indicated that a high proportion (77.4%) of patients had intermediate- or high-risk disease according to the Cancer of the Prostate Risk Assessment Post-Surgical score. After surgery, only 28 patients met the criteria for active surveillance (organ-confined Gleason >=6 disease). The Prostate Cancer Research International Active Surveillance criteria achieved a sensitivity of 57.1% and a specificity of 98.0% for identifying candidates. The probability of Gleason score upgrading was 24.8% in the entire group and 59.0% in biopsy confirmed Gleason >=6 disease. The predominant tumor was located in the transition zone in 14.8% of cases, while only three patients (1.3%) had a predominant tumor located in the anterior region. Patients with transition zone predominant tumor were likely to have been referred with urinary symptoms and high prostate specific antigen levels. The results of this study highlight the contemporary pathological features of localized prostate cancer in urban China. There was an increased trend towards asymptomatic cases, though most patients had intermediate- or high-risk disease and were suitable for definitive treatment. The low prevalence of dominant cancer in the anterior region may reflect race based pathological differences. PMID- 25799191 TI - Sternal osteomyelitis associated with bacillus Calmette-Guerin Moscow strain. PMID- 25799192 TI - Lung ultrasound: a useful tool for the follow-up of neonatal localized interstitial emphysema. PMID- 25799193 TI - Comparison of Limestone and Ground Fish for Treatment of Nutritional Rickets in Children in Nigeria. AB - OBJECTIVE: To determine whether children with calcium-deficiency rickets respond better to treatment with calcium as limestone or as ground fish. STUDY DESIGN: Nigerian children with active rickets (n = 96) were randomized to receive calcium as powdered limestone (920 mg of elemental calcium) or ground fish (952 mg of elemental calcium) daily for 24 weeks. Radiographic healing was defined as achieving a score of 1.5 or less on a 10-point scale. RESULTS: The median (range) age of enrolled children was 35 (6-151) months. Of the 88 children who completed the study, 29 (66%) in the ground fish group and 24 (55%) in the limestone group achieved the primary outcome of a radiographic score of 1.5 or less within 6 months (P = .39). The mean radiographic score improved from 6.2 +/- 2.4 to 1.8 +/ 2.2 in the ground fish group and from 6.3 +/- 2.2 to 2.1 +/- 2.4 in the limestone group (P = .68 for group comparison). In an intention to treat analysis adjusted for baseline radiographic score, age, milk calcium intake, and serum 25 hydroxyvitamin D concentration, the response to treatment did not differ between the 2 groups (P = .39). Younger age was associated with more complete radiographic healing in the adjusted model (aOR 0.74 [95% CI 0.57-0.92]). After 24 weeks of treatment, serum alkaline phosphatase had decreased, calcium and 25 hydroxyvitamin D increased, and bone mineral density increased in both groups, without significant differences between treatment groups. CONCLUSION: In children with calcium-deficiency rickets, treatment with calcium as either ground fish or limestone for 6 months healed rickets in the majority of children. PMID- 25799194 TI - Renal microabscesses: a presentation of cat scratch disease. PMID- 25799195 TI - Pediatric palliative care: current evidence and evidence gaps. PMID- 25799196 TI - Effects of disruption of the nucleotide pattern in CRID element and Kozak sequence of interferon beta on mRNA stability and protein production. AB - Interferon beta (IFNbeta) is the most important drug that has been used frequently for multiple sclerosis treatment. This study has tried to improve the IFNbeta production by introducing mutations in the coding region of IFNbeta, while its amino acid sequence is intact. Two recombinant vectors IFNbeta(K) and IFNbeta(K+CRID )were designed by site-directed mutagenesis. The IFNbeta(K) and IFNbeta(K+CRID) have two substitutions in Kozak sequence and four substitutions in CRID sequence, respectively. The Chinese hamster ovary (CHO) cell codon usage optimization was also performed for both of them. They were transiently transfected to CHO-dhfr(-) cell line using Lipofectamine kit (Invitrogen, Grand Island, NY). The amount of mRNA and protein was determined by real time PCR and ELISA. The results of this study indicate that the amount of IFNbeta protein produced by CHO cells containing IFNbeta(K) has been elevated up to 3.5-fold. On the other hand, enormous amounts of IFNbeta mRNA and protein were produced by cells containing IFNbeta(K+CRID) construct; more than 4.6-fold and 6-fold, respectively. It could be concluded that disruption of AT pattern in CRID element increase RNA and protein production, improve IFNbeta mRNA stability and, may also enhance mRNA half-life. In a similar way, more proteins are produced by modification of Kozak sequence. PMID- 25799198 TI - Exploring differences in the content of job interviews between youth with and without a physical disability. AB - OBJECTIVE: Although people with disabilities have great potential to provide advantages to work environments, many encounter barriers in finding employment, especially youth who are looking for their first job. A job interview is an essential component of obtaining employment. The objective of this study is to explore the content of the answers given in job interviews among youth with disabilities compared to typically developing youth. METHODS: A purposive sample of 31 youth (16 with typical development and 15 with disability) completed a mock job interview as part of an employment readiness study. The interview questions focused on skills and experiences, areas for improvement, and actions taken during problem-based scenarios. Transcribed interviews were analyzed using a content analysis of themes that emerged from the interviews. RESULTS: We found several similarities and differences between youth with disabilities and typically developing youth. Similarities included giving examples from school, emphasizing their "soft skills" (i.e., people and communication skills) and giving examples of relevant experience for the position. Both groups of youth gave similar examples for something they were proud of but fewer youth with disabilities provided examples. Differences in the content of job interview answers between the two groups included youth with disabilities: (1) disclosing their condition; (2) giving fewer examples related to customer service and teamwork skills; (3) experiencing greater challenges in providing feedback to team members and responding to scenario-based problem solving questions; and (4) drawing on examples from past work, volunteer and extra curricular activities. CONCLUSIONS: Clinicians and educators should help youth to understand what their marketable skills are and how to highlight them in an interview. Employers need to understand that the experiences of youth with disabilities may be different than typically developing youth. Our findings also help to inform employment readiness programs by highlighting the areas where youth with disabilities may need extra help as compared to typically developing youth. PMID- 25799200 TI - Correction: increase in resistance to extended-spectrum cephalosporins in salmonella isolated from retail chicken products in Japan. PMID- 25799199 TI - Anticipated survival and health behaviours in older English adults: cross sectional and longitudinal analysis of the English Longitudinal Study of Ageing. AB - BACKGROUND: Individuals may make a rational decision not to engage in healthy behaviours based on their assessment of the benefits of such behaviours to them, compared to other uncontrollable threats to their health. Anticipated survival is one marker of perceived uncontrollable threats to health. We hypothesised that greater anticipated survival: a) is cross-sectionally associated with healthier patterns of behaviours; b) increases the probability that behaviours will be healthier at follow up than at baseline; and c) decreases the probability that behaviours will be 'less healthy' at follow than at baseline. METHODS: Data from waves 1 and 5 of the English Longitudinal Survey of Ageing provided 8 years of follow up. Perceptions of uncontrollable threats to health at baseline were measured using anticipated survival. Health behaviours considered were self reported cigarette smoking, physical activity level, and frequency of alcohol consumption. A wide range of socio-economic, demographic, and health variables were adjusted for. RESULTS: Greater anticipated survival was cross-sectionally associated with lower likelihood of smoking, and higher physical activity levels, but was not associated with alcohol consumption. Lower anticipated survival was associated with decreased probability of adopting healthier patterns of physical activity, and increased probability of becoming a smoker at follow up. There were no associations between anticipated survival and change in alcohol consumption. CONCLUSIONS: Our hypotheses were partially confirmed, though associations were inconsistent across behaviours and absent for alcohol consumption. Individual assessments of uncontrollable threats to health may be an important determinant of smoking and physical activity. PMID- 25799201 TI - Assessing maladaptive traits in youth: An English-language version of the Dimensional Personality Symptom Itempool. AB - The present study addresses the psychometric properties of the English version of the Dimensional Personality Symptom Item Pool (DIPSI), a comprehensive taxonomy of trait-related symptoms in childhood. The structural invariance of the English DIPSI and the original Flemish version was investigated in a large sample of Canadian (n = 341) and Flemish (n = 509) adolescents, using both self- and maternal ratings. The original 4-factor structure of the DIPSI, including the dimensions Emotional Instability, Disagreeableness, Introversion, and Compulsivity, was replicated in the Canadian sample across informants. Results provided support for metric invariance across the English and Flemish DIPSI version, indicating that associations between variables across samples can be confidently made, although the meaning of specific items may slightly differ across the different DIPSI versions. Across raters, the Flemish and English DIPSI dimensions showed a similar covariation pattern with internalizing and externalizing psychopathology. High intercorrelations between the DIPSI dimensions in both the Flemish and English version suggest low discriminant validity, potentially resulting from lower variance on personality pathology in general populations, from a general pathology factor, or from developmental issues. To conclude, the English version of the DIPSI can be considered a promising tool for assessing maladaptive traits in younger age groups in internationally oriented research designs. PMID- 25799203 TI - Evidence-based deprescribing of statins in patients with advanced illness. PMID- 25799202 TI - Maternal borderline personality disorder symptoms and convergence between observed and reported infant negative emotional expressions. AB - To date, the influence of maternal borderline personality disorder (BPD) on perceptions of infants' emotional expressions has not been examined. This study investigated the relation of maternal BPD symptoms to discrepancies between mother-reported and observed infant expressions of fear and anger. Emotional expressions in response to fear- and anger-eliciting stimuli were observed among 101 12- to 23-month-old infants of mothers with a range of BPD symptoms. Mothers also reported on their infants' past-month fear and anger expressions. Findings from polynomial regression analyses revealed that maternal BPD symptoms (particularly BPD interpersonal symptoms) are associated with greater convergence of mother-reported and observed infant anger expressions. Furthermore, although maternal BPD symptoms were not related to discrepancies between mother-reported and observed infant fear, findings did reveal a relation between maternal BPD symptoms and observed infant fear expressions, such that maternal BPD symptoms related to both low and high (vs. moderate) levels of fear expressions in the laboratory. Moreover, BPD behavioral symptoms in particular were associated with greater convergence of mother-reported and observed infant fear expressions. Overall, findings contribute to the literature on the impact of maternal BPD on parenting and infant outcomes, and highlight the relevance of maternal BPD symptoms to discrepancies between perceived and observed infant negative emotional expressions. PMID- 25799204 TI - Catalytic silylation of dinitrogen with a dicobalt complex. AB - A dicobalt complex catalyzes N2 silylation with Me3SiCl and KC8 under 1 atm N2 at ambient temperature. Tris(trimethylsilyl)amine is formed with an initial turnover rate of 1 N(TMS)3/min, ultimately reaching a turnover number of ~200. The dicobalt species features a metal-metal interaction, which we postulate is important to its function. Although N2 functionalization occurs at a single cobalt site, the second cobalt center modifies the electronics at the active site. Density functional calculations reveal that the Co-Co interaction evolves during the catalytic cycle: weakening upon N2 binding, breaking with silylation of the metal-bound N2 and reforming with expulsion of [N2(SiMe3)3](-). PMID- 25799205 TI - Linear and non-linear brain-heart and brain-brain interactions during sleep. AB - In this study, the physiological networks underlying the joint modulation of the parasympathetic component of heart rate variability (HRV) and of the different electroencephalographic (EEG) rhythms during sleep were assessed using two popular measures of directed interaction in multivariate time series, namely Granger causality (GC) and transfer entropy (TE). Time series representative of cardiac and brain activities were obtained in 10 young healthy subjects as the normalized high frequency (HF) component of HRV and EEG power in the delta, theta, alpha, sigma, and beta bands, measured during the whole duration of sleep. The magnitude and statistical significance of GC and TE were evaluated between each pair of series, conditional on the remaining series, using respectively a linear model-based approach exploiting regression models, and a nonlinear model free approach combining nearest-neighbor entropy estimation with a procedure for dimensionality reduction. The contribution of nonlinear dynamics to the TE was also assessed using surrogate data. GC and TE consistently detected structured networks of physiological interactions, with links directed predominantly from HRV to the EEG waves in the brain-heart network, and from the sigma and beta EEG waves to the delta, theta, and alpha waves in the brain-brain network. While these common patterns supported the suitability of a linear model-based analysis, we also found a significant contribution of nonlinear dynamics, particularly involving the information transferred out of the delta node in the two networks. This suggested the importance of nonparametric TE estimation for evidencing the fine structure of the physiological networks underlying the autonomic regulation of cardiac and brain functions during sleep. PMID- 25799206 TI - The effect of animal movement on line transect estimates of abundance. AB - Line transect sampling is a distance sampling method for estimating the abundance of wild animal populations. One key assumption of this method is that all animals are detected at their initial location. Animal movement independent of the transect and observer can thus cause substantial bias. We present an analytic expression for this bias when detection within the transect is certain (strip transect sampling) and use simulation to quantify bias when detection falls off with distance from the line (line transect sampling). We also explore the non linear relationship between bias, detection, and animal movement by varying detectability and movement type. We consider animals that move in randomly orientated straight lines, which provides an upper bound on bias, and animals that are constrained to a home range of random radius. We find that bias is reduced when animal movement is constrained, and bias is considerably smaller in line transect sampling than strip transect sampling provided that mean animal speed is less than observer speed. By contrast, when mean animal speed exceeds observer speed the bias in line transect sampling becomes comparable with, and may exceed, that of strip transect sampling. Bias from independent animal movement is reduced by the observer searching further perpendicular to the transect, searching a shorter distance ahead and by ignoring animals that may overtake the observer from behind. However, when animals move in response to the observer, the standard practice of searching further ahead should continue as the bias from responsive movement is often greater than that from independent movement. PMID- 25799207 TI - Anterior and posterior ocular biometry in healthy Chinese subjects: data based on AS-OCT and SS-OCT. AB - BACKGROUND: To measure the anterior and posterior ocular biometric characteristics concurrently and to determine the relationship between the iris and choroid in healthy Chinese subjects. METHODS: A total of 148 subjects (270 eyes) were enrolled in this cross-section study. The anterior and posterior ocular biometric characteristics were measured simultaneously by anterior segment optical coherence tomography (AS-OCT) and swept-source optical coherence tomography (SS-OCT). RESULTS: Compared with male eyes, female eyes had narrower anterior biometric parameters that presented with smaller anterior segment parameters [including anterior chamber depth (ACD), width (ACW), area (ACA), and volume (ACV); (all p<0.001)], narrower anterior chamber angle parameters [including angle opening distance (AOD750), trabecular-iris space area (TISA750), and angle recess area (ARA); (all p<0.001)], higher iris curvature (ICURV) (p = 0.003), and larger lens vaults (LV) (p = 0.019). These anterior ocular biometric parameters were correlated with increasing age (p<0.01). Iris thickness (IT750) and iris area (IAREA) were associated with age, ACW, and pupil diameter (all p<0.05), while choroidal thickness (CT) was associated with age, gender, and axial length (all p<0.05). Univariate regression analysis showed that greater CT was significantly associated with smaller IAREA (p = 0.026). CONCLUSION: Compared with male eyes, female eyes had narrower anterior biometric parameters that correlated with increasing age, which would be helpful in explaining the higher prevalence of angle closure rates in the female gender and in aging people. Increased CT might be associated with smaller iris area; however, this possibility needs to be investigated in future studies before this conclusion is made. PMID- 25799208 TI - Digoxin use and risk of mortality in hypertensive patients with atrial fibrillation. AB - BACKGROUND: Digoxin is widely used for rate control of atrial fibrillation. However, recent studies have reported conflicting results on the association of digoxin with mortality when used in patients with atrial fibrillation. Moreover, the relationship of digoxin use to mortality in hypertensive patients with atrial fibrillation has not been examined. METHODS AND RESULTS: All-cause mortality was examined in relation to in-treatment digoxin use in 937 hypertensive patients with ECG left ventricular hypertrophy in atrial fibrillation at baseline (n = 134) or who developed atrial fibrillation during follow-up (n = 803), randomly assigned to losartan or atenolol-based treatment, in post-hoc analysis of a substudy of the Losartan Intervention For Endpoint Reduction in hypertension (LIFE) trial. During 4.7 +/- 1.1 years of mean follow-up, 167 patients died (17.8%) and 372 (39.7%) were treated with digoxin. In univariate Cox analyses, in treatment digoxin use, entered as a time-varying covariate, was associated with a 61% higher risk of dying (hazard ratio 1.61, 95% confidence interval 1.18-2.19, P = 0.003). After adjusting for other univariate predictors of death in this population, including age, diabetes, history of ischemic heart disease, stroke, or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and high-density lipoprotein cholesterol, and a propensity score for digoxin use entered as standard covariates, and for in-treatment heart rate, pulse pressure, and Sokolow-Lyon voltage treated as time-varying covariates, digoxin use was no longer a significant predictor of mortality (hazard ratio 1.04, 95% confidence interval 0.73-1.48, P = 0.839). CONCLUSION: In hypertensive patients with ECG left ventricular hypertrophy with existing or new atrial fibrillation, digoxin use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use digoxin in this population. These findings suggest that factors other than digoxin use may account for the increased mortality found with digoxin use in some studies. CLINICAL TRIALS REGISTRATION: . PMID- 25799209 TI - Performance of parental history for the targeted screening of hypertension in children. AB - OBJECTIVES: Several guidelines recommend universal screening for hypertension in childhood and adolescence. Targeted screening to children with parental history of hypertension could be a more efficient strategy than universal screening. Therefore, we assessed the association between parental history of hypertension and hypertension in children, and estimated the sensitivity, specificity, negative, and positive predictive values of parental history of hypertension for hypertension in children. METHODS: The present study was a school-based cross sectional study including 5207 children aged 10-14 years from all public 6th grade classes in the Canton of Vaud, Switzerland. Children had hypertension if they had sustained elevated blood pressure over three separate visits. RESULTS: In children, the prevalence of hypertension was 2.2%. Some 8.5% of mothers and 12.9% of fathers reported to be hypertensive. Maternal history of hypertension (odds ratio 2.0, 95% confidence interval 1.2-3.3) and paternal history of hypertension (odds ratio 2.2, 95% confidence interval 1.4-3.6) were independent risk factors for hypertension in children. Nevertheless, the sensitivity of parental history of hypertension for the identification of hypertension in children was low (from 4% for both parents' positive history up to 41% for at least one parent's positive history). Positive predictive values were also low (between 4 and 5%). CONCLUSION: Children with hypertensive parents were at higher risk of hypertension. Nevertheless, parental history of hypertension helped only marginally to identify hypertension in offspring. Targeting screening only toward children with a parental history of hypertension may not be a substantially better strategy to identify hypertension in children compared with universal screening. PMID- 25799210 TI - Impact of birth parameters and early life growth patterns on retinal microvascular structure in children: The Generation R Study. AB - OBJECTIVE: The aim of the study was to examine the associations of birth outcomes and longitudinally measured fetal and infant growth patterns with retinal vessel calibers in childhood. METHODS: In a population-based prospective cohort study among 4122 children, we measured growth characteristics in second and third trimester of pregnancy, at birth, and at 6, 12, 24, 36, 48, and 72 months. At the age of 6 years, we measured retinal arteriolar and venular calibers from digitized retinal photographs. RESULTS: We observed that compared with term-born children, those born preterm had narrower retinal arteriolar caliber [differences -0.46 standard deviation score (95% confidence interval -0.77 to -0.15) and -0.24 standard deviation score (95% confidence interval -0.42 to -0.05) for children born <34 and 34-37 weeks of gestation, respectively]. Children born with a low birth weight (<2500 g) had narrower retinal arteriolar caliber than children with a normal birth weight, but this association was fully explained by gestational age at birth. Accelerated infant growth until 24 months was associated with narrow retinal arteriolar caliber, especially among preterm-born children (P < 0.05). Early growth measures were not associated with retinal venular caliber. CONCLUSION: Preterm birth and accelerated infant growth are associated with narrower retinal arteriolar caliber in childhood. Whether these microvascular adaptations explain the well known associations of fetal and infant characteristics with cardiovascular disease in later life should be further studied. PMID- 25799211 TI - The assessment of changes in macular thickness in diabetic and non-diabetic patients: the effect of topical ketorolac on macular thickness change after ND:YAG laser capsulotomy. AB - PURPOSE: The purpose of our study is to assess the changes in macular thickness (MT) in diabetic and non-diabetic patients and to research effects of topical ketorolac (Acular(r), Allergan, Irvine, CA) on MT change after neodymium:yttrium aluminum garnet (Nd:YAG) laser capsulotomy. MATERIAL AND METHODS: This study involved 88 eyes of 88 patients diagnosed as posterior capsule opacification (PCO). Patients were divided into four groups according to presence of diabetes mellitus (DM) and drugs used after capsulotomy. Group 1: Patients with DM using only 0.1% Fluorometholon (FML(r), Allergan, Irvine, CA) after capsulotomy (22 patients). Group 2: Patients with DM using 0.5% ketorolac (Acular(r)) and 0.1 Fluorometholon (FML(r), Allergan, Irvine, CA) after capsulotomy (20 patients). Group 3: Patients without DM using only 0.1% Fluorometholon (FML(r), Allergan, Irvine, CA) (22 patients). Group 4: Patients without DM using 0.5% ketorolac (Acular(r)) and 0.1% Fluorometholon (FML(r), Allergan, Irvine, CA) (24 patients). A plus-shaped capsulotomy was performed using VISULAS(r) YAGIII (Carl Zeiss) laser microscope. MT measurement with Cirrus SD-OCT (Carl Zeiss Opthalmic System Inc., Model 400, Dublin, CA, Software 5) were done. Measurements were done before laser, and on the first day, first week, first month, third month and sixth month after laser capsulotomy. We compared the four groups for MT change during 6 months. RESULTS: Group 1 involving patients with DM using only 0.1% Fluorometholon (FML(r), Allergan, Irvine, CA) after capsulotomy had increased MT at the first week, and the first, third, and sixth month after laser (p < 0.001). Group 3 involving patients without DM using only 0.1% Fluorometholon (FML(r), Allergan, Irvine, CA) had increased MT at the first week, and at the first and third month, there was no statistically significant difference at the sixth month (p > 0.05). There was no statistically significant increase in MT during the follow-up period in group 2 involving patients with DM using 0.5% ketorolac (Acular(r)) and 0.1 Fluorometholon (FML(r), Allergan, Irvine, CA) after capsulotomy and group 4 involving patients without DM using 0.5% ketorolac (Acular(r)) and 0.1% Fluorometholon (FML(r), Allergan, Irvine, CA) (p > 0.05). CONCLUSION: An increase in MT can be observed after Nd:YAG laser capsulotomy, especially in diabetic patients. Adding topical ketorolac (Acular(r), Allergan, Irvine, CA) to topical Fluorometholon (FML(r), Allergan, Irvine, CA) therapy after YAG laser capsulotomy can prevent this increase. PMID- 25799212 TI - Voriconazole-associated visual disturbances and hallucinations. AB - Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis. We report a case of 16 year-old girl who developed visual disturbance and visual and auditory hallucinations after intravenous voriconazole treatment for invasive pulmonary aspergillosis. Due to the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other cause could be determined, the symptoms were considered to be the side effects of voriconazole. Simultaneous development of visual side effects and hallucinations rarely have been reported before. PMID- 25799213 TI - Short-term isotretinoin-induced elkonyxis and median nail dystrophy. AB - Elkonyxis and median nail distrophy are very rare nail fold disorders due to the damage in nail matrix and proximal nail fold. Herein, we report a patient with both elkonyxis and median nail distrophy occured two months into a treatment course of isotretinoin that is to our knowledge for the first time. PMID- 25799214 TI - Exacerbation of psoriasis induced by interferon-alpha treatment for melanoma. AB - Interferon-alpha is one of the major immune modulating agents used in current oncology practice, including melanoma. We present a case of psoriasis exacerbation induced by INF-alpha in a patient with melanoma. PMID- 25799215 TI - Control of oxo-group functionalization and reduction of the uranyl ion. AB - Uranyl complexes of a large, compartmental N8-macrocycle adopt a rigid, "Pacman" geometry that stabilizes the U(V) oxidation state and promotes chemistry at a single uranyl oxo-group. We present here new and straightforward routes to singly reduced and oxo-silylated uranyl Pacman complexes and propose mechanisms that account for the product formation, and the byproduct distributions that are formed using alternative reagents. Uranyl(VI) Pacman complexes in which one oxo group is functionalized by a single metal cation are activated toward single electron reduction. As such, the addition of a second equivalent of a Lewis acidic metal complex such as MgN"2 (N" = N(SiMe3)2) forms a uranyl(V) complex in which both oxo-groups are Mg functionalized as a result of Mg-N bond homolysis. In contrast, reactions with the less Lewis acidic complex [Zn(N")Cl] favor the formation of weaker U-O-Zn dative interactions, leading to reductive silylation of the uranyl oxo-group in preference to metalation. Spectroscopic, crystallographic, and computational analysis of these reactions and of oxo metalated products isolated by other routes have allowed us to propose mechanisms that account for pathways to metalation or silylation of the exo-oxo-group. PMID- 25799216 TI - Correction: Association of childhood physical and sexual abuse with intimate partner violence, poor general health and depressive symptoms among pregnant women. PMID- 25799217 TI - Dual Ionic and Photo-Crosslinked Alginate Hydrogels for Micropatterned Spatial Control of Material Properties and Cell Behavior. AB - Biomaterial properties such as mechanics, degradation rate, and cell adhesivity affect cell behaviors including spreading, proliferation, and differentiation. To engineer complex tissues, it is often desirable to achieve precise spatial control over these properties. Here, methacrylated alginate (MA-ALG) was used to create hydrogels comprising a single base material with regions of different types and levels of crosslinking and subsequently different material properties. Ionic and ultraviolet light crosslinking mechanisms were combined to create dual crosslinked hydrogels with significantly increased stiffness and decreased swelling compared to calcium-crosslinked or UV-crosslinked hydrogels. MC3T3 cells showed significantly enhanced proliferation on the surface of dual-crosslinked hydrogels compared with calcium-crosslinked hydrogels. Photomasks were then used to create patterned hydrogels with precise spatial control over regions that were only calcium-crosslinked versus dual-crosslinked. This spatial variation in crosslinking mechanism permitted local regulation of the hydrogel physical properties and alignment of cells seeded on their surface. Photomasks were also used to create hydrogels with patterned presentation of cell adhesion ligands, leading to spatial control over cell attachment and proliferation. This biomaterial system can be useful for providing patterned, instructive cues to guide cell behavior for engineering complex tissues. PMID- 25799218 TI - Near infra-red photoimmunotherapy with anti-CEA-IR700 results in extensive tumor lysis and a significant decrease in tumor burden in orthotopic mouse models of pancreatic cancer. AB - Photoimmunotherapy (PIT) of cancer utilizes tumor-specific monoclonal antibodies conjugated to a photosensitizer phthalocyanine dye IR700 which becomes cytotoxic upon irradiation with near infrared light. In this study, we aimed to evaluate the efficacy of PIT on human pancreatic cancer cells in vitro and in vivo in an orthotopic nude mouse model. The binding capacity of anti-CEA antibody to BxPC-3 human pancreatic cancer cells was determined by FACS analysis. An in vitro cytotoxicity assay was used to determine cell death following treatment with PIT. For in vivo determination of PIT efficacy, nude mice were orthotopically implanted with BxPC-3 pancreatic tumors expressing green fluorescent protein (GFP). After tumor engraftment, the mice were divided into two groups: (1) treatment with anti-CEA-IR700 + 690 nm laser and (2) treatment with 690 nm laser only. Anti-CEA-IR700 (100 MUg) was administered to group (1) via tail vein injection 24 hours prior to therapy. Tumors were then surgically exposed and treated with phototherapy at an intensity of 150 mW/cm2 for 30 minutes. Whole body imaging was done subsequently for 5 weeks using an OV-100 small animal imaging system. Anti-CEA-IR700 antibody bound to the BxPC3 cells to a high degree as shown by FACS analysis. Anti-CEA-IR700 caused extensive cancer cell killing after light activation compared to control cells in cytotoxicity assays. In the orthotopic models of pancreatic cancer, the anti-CEA-IR700 group had significantly smaller tumors than the control after 5 weeks (p<0.001). There was no significant difference in the body weights of mice in the anti-CEA-IR700 and control groups indicating that PIT was well tolerated by the mice. PMID- 25799219 TI - Micropatterning of TiO2 thin films by MOCVD and study of their growth tendency. AB - In this work, we studied the growth tendency of TiO2 thin films deposited on a narrow-stripe area (<10 MUm). TiO2 thin films were selectively deposited on OTS patterned Si(100) substrates by MOCVD. The experimental data showed that the film growth tendency was divided into two behaviors above and below a line patterning width of 4 MUm. The relationship between the film thickness and the deposited area was obtained as a function of f(x) = a[1 - e((-bx))]c. To find the tendency of the deposition rate of the TiO2 thin films onto the various linewidth areas, the relationship between the thickness of the TiO2 thin film and deposited linewidth was also studied. The thickness of the deposited TiO2 films was measured from the alpha-step profile analyses and cross-sectional SEM images. At the same time, a computer simulation was carried out to reveal the relationship between the TiO2 film thickness and deposited line width. The theoretical results suggest that the mass (velocity) flux in flow direction is directly affected to the film thickness. PMID- 25799220 TI - Evaluation of the therapeutic efficacy of sequential therapy involving percutaneous microwave ablation in combination with 131I-hypericin using the VX2 rabbit breast solid tumor model. AB - PURPOSE: Combination of percutaneous microwave ablation (PMWA) and intravenous injection of 131I-hypericin(IIIH) may bear potential as a mini-invasive treatment for tumor. The objective of this study was to assess the effect of PMWA and IIIH in breast tumor growth. METHODS: Ten New Zealand White rabbits bearing VX2 breast carcinomas were randomly divided into two groups (each 5 examples) and processed using PMWA followed by IIIH and IIIH alone. The IIIH activity was evaluated using planar scintigraphy, autoradiography and biodistribution analysis. The maximum effective safe dose of IIIH was found through 48 rabbits with VX2 breast tumor, which were randomized into six groups (n=8 per group). Subsequently, a further 75 rabbits bearing VX2 breast solid tumors were randomly divided into five groups (each 15 examples) and treated as follows: A, no treatment group; B, PMWA alone; C, IIIH alone; D, PMWA+IIIH*1 (at 8 h post-PMWA); and E, PMWA+IIIH*2 (at 8 h and at 8 days post-PMWA). The therapeutic effect was assessed by measurement of tumor size and performation of positron emission tomography/computed tomograph (PET/CT) scans, liver and renal function tests and Kaplan-Meier survival analysis. RESULTS: The planar scintigraphy findings suggested a significant uptake of 131I in necrotic tumor tissue. The autoradiography gray scales indicated higher selective uptake of IIIH by necrotic tissue, with significant differences between the groups with and those without necrotic tumor tissue (P<0.05). The maximum effective safe dose of IIIH was 1 mCi/kg. The PET/CT scans and tumor size measurement suggested improvements in treatment groups at all time points (P<0.01). Significant differences were detected among Groups A, B, D and E (P<0.05). Lower levels of lung metastasis were detected in Groups D and E (P<0.05). There were no abnormalities in liver and renal functions tests or other reported side effects. CONCLUSION: IIIH exhibited selective uptake by necrotic tumor tissue. Sequential therapy involving PMWA+IIIH was successfully inhibiting tumor growth and prolonging survival. PMID- 25799222 TI - Association between GWAS-identified genetic variations and disease prognosis for patients with colorectal cancer. AB - Genome-wide association studies (GWASs) have already identified at least 22 common susceptibility loci associated with an increased risk of colorectal cancer (CRC). This study examined the relationship between these single nucleotide polymorphisms (SNPs) and the clinical outcomes of patients with colorectal cancer. Seven hundred seventy-six patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Twenty-two of the GWAS identified SNPs were genotyped using a Sequenom MassARRAY. Among the 22 SNPs, two (rs1321311G>T in CDKN1A and rs10411210C>T in RHPN2) were significantly associated with the survival outcomes of CRC in a multivariate survival analysis. In a recessive model, the rs1321311 TT genotype (vs. GG + GT) and rs10411210 TT genotype (vs. CC + CT) were associated with a worse prognosis for disease-free survival (adjusted HR = 1.90; 95% confidence interval = 1.00-3.60; P = 0.050, adjusted HR = 1.94; 95% confidence interval = 1.05-3.57; P = 0.034, respectively) and overall survival (adjusted HR = 2.05; 95% confidence interval = 1.00-4.20; P = 0.049, adjusted HR = 2.06; 95% confidence interval = 1.05-4.05; P = 0.036, respectively). None of the other SNPs was significantly associated with any clinicopathologic features or survival. The present results suggest that the genetic variants of the CDKN1A (rs1321311) and RHPN2 (rs10411210) genes can be used as prognostic biomarkers for patients with surgically resected colorectal cancer. PMID- 25799221 TI - Protection against multiple influenza A virus strains induced by candidate recombinant vaccine based on heterologous M2e peptides linked to flagellin. AB - Matrix 2 protein ectodomain (M2e) is considered a promising candidate for a broadly protective influenza vaccine. M2e-based vaccines against human influenza A provide only partial protection against avian influenza viruses because of differences in the M2e sequences. In this work, we evaluated the possibility of obtaining equal protection and immune response by using recombinant protein on the basis of flagellin as a carrier of the M2e peptides of human and avian influenza A viruses. Recombinant protein was generated by the fusion of two tandem copies of consensus M2e sequence from human influenza A and two copies of M2e from avian A/H5N1 viruses to flagellin (Flg-2M2eh2M2ek). Intranasal immunisation of Balb/c mice with recombinant protein significantly elicited anti M2e IgG in serum, IgG and sIgA in BAL. Antibodies induced by the fusion protein Flg-2M2eh2M2ek bound efficiently to synthetic peptides corresponding to the human consensus M2e sequence as well as to the M2e sequence of A/Chicken/Kurgan/05/05 RG (H5N1) and recognised native M2e epitopes exposed on the surface of the MDCK cells infected with A/PR/8/34 (H1N1) and A/Chicken/Kurgan/05/05 RG (H5N1) to an equal degree. Immunisation led to both anti-M2e IgG1 and IgG2a response with IgG1 prevalence. We observed a significant intracellular production of IL-4, but not IFN-gamma, by CD4+ T-cells in spleen of mice following immunisation with Flg 2M2eh2M2ek. Immunisation with the Flg-2M2eh2M2ek fusion protein provided similar protection from lethal challenge with human influenza A viruses (H1N1, H3N2) and avian influenza virus (H5N1). Immunised mice experienced significantly less weight loss and decreased lung viral titres compared to control mice. The data obtained show the potential for the development of an M2e-flagellin candidate influenza vaccine with broad spectrum protection against influenza A viruses of various origins. PMID- 25799223 TI - Circadian typology is related to resilience and optimism in healthy adults. AB - The relationships between circadian typology and several aspects related to mental health, such as satisfaction with life, emotional intelligence, perceived well-being and psychopathological symptomatology have been documented. However, their relationships with two psychological strengths such as resilience and optimism have not been examined yet. Therefore, the purpose of the present study was to explore whether circadian typology is related to both measures, taking into consideration the possible influence of sex. A sample of 1922 participants (978 men), aged between 18 and 60 yrs (30.08 +/- 10.53) completed the reduced Morningness-Eveningness Questionnaire (rMEQ), the 10-item Connor-Davidson Resilience Scale (10-item CD-RISC) and the Life Orientation Test-Revised (LOT-R). Circadian typology was associated with different values in resilience (F(2,1915) = 45.89; p < 0.001; [Formula: see text]( )= 0.046) and optimism (F(2,1915) = 37.74; p < 0.001; [Formula: see text]( )= 0.038), independently of the sex. Morning-type subjects showed the highest resilience and optimism scores while the lowest scores were shown by evening-type, exhibiting the neither-type subjects intermediate scores (p < 0.007, in all cases). These results suggest that evening type subjects could display less capacity to face adversity and adapt positively, as well as less expectance of the occurrence of positive events compared to neither and morning-type individuals. In addition, these results provide new evidence that might improve our understanding about the relationships between circadian typology and psychological traits and disorders. Although future studies with longitudinal designs are needed, the obtained results emphasize that the evening-type could be a risk factor for the development of psychological problems and mental disorders, whereas the morning-type could be considered as a protective factor. PMID- 25799224 TI - Temporally adaptive sampling: a case study in rare species survey design with marbled salamanders (Ambystoma opacum). AB - Improving detection rates for elusive species with clumped distributions is often accomplished through adaptive sampling designs. This approach can be extended to include species with temporally variable detection probabilities. By concentrating survey effort in years when the focal species are most abundant or visible, overall detection rates can be improved. This requires either long-term monitoring at a few locations where the species are known to occur or models capable of predicting population trends using climatic and demographic data. For marbled salamanders (Ambystoma opacum) in Massachusetts, we demonstrate that annual variation in detection probability of larvae is regionally correlated. In our data, the difference in survey success between years was far more important than the difference among the three survey methods we employed: diurnal surveys, nocturnal surveys, and dipnet surveys. Based on these data, we simulate future surveys to locate unknown populations under a temporally adaptive sampling framework. In the simulations, when pond dynamics are correlated over the focal region, the temporally adaptive design improved mean survey success by as much as 26% over a non-adaptive sampling design. Employing a temporally adaptive strategy costs very little, is simple, and has the potential to substantially improve the efficient use of scarce conservation funds. PMID- 25799225 TI - Brain derived neurotrophic factor contributes to the cardiogenic potential of adult resident progenitor cells in failing murine heart. AB - AIMS: Resident cardiac progenitor cells show homing properties when injected into the injured but not to the healthy myocardium. The molecular background behind this difference in behavior needs to be studied to elucidate how adult progenitor cells can restore cardiac function of the damaged myocardium. Since the brain derived neurotrophic factor (BDNF) moderates cardioprotection in injured hearts, we focused on delineating its regulatory role in the damaged myocardium. METHODS AND RESULTS: Comparative gene expression profiling of freshly isolated undifferentiated Sca-1 progenitor cells derived either from heart failure transgenic alphaMHC-CyclinT1/Galphaq overexpressing mice or wildtype littermates revealed transcriptional variations. Bdnf expression was up regulated 5-fold during heart failure which was verified by qRT-PCR and confirmed at protein level. The migratory capacity of Sca-1 cells from transgenic hearts was improved by 15% in the presence of 25 ng/ml BDNF. Furthermore, BDNF-mediated effects on Sca-1 cells were studied via pulsed Stable Isotope Labeling of Amino acids in Cell Culture (pSILAC) proteomics approach. After BDNF treatment significant differences between newly synthesized proteins in Sca-1 cells from control and transgenic hearts were observed for CDK1, SRRT, HDGF, and MAP2K3 which are known to regulate cell cycle, survival and differentiation. Moreover BDNF repressed the proliferation of Sca-1 cells from transgenic hearts. CONCLUSION: Comparative profiling of resident Sca-1 cells revealed elevated BDNF levels in the failing heart. Exogenous BDNF (i) stimulated migration, which might improve the homing ability of Sca-1 cells derived from the failing heart and (ii) repressed the cell cycle progression suggesting its potency to ameliorate heart failure. PMID- 25799226 TI - Activation of AMPKalpha2 in adipocytes is essential for nicotine-induced insulin resistance in vivo. AB - Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase alpha2 (AMPKalpha2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results establish AMPKalpha2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity. PMID- 25799227 TI - Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. AB - Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668*) validated by site-specific amplicon sequencing (100 347,499*) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD. PMID- 25799229 TI - Maternal mortality in rural south Ethiopia: outcomes of community-based birth registration by health extension workers. AB - INTRODUCTION: Rural communities in low-income countries lack vital registrations to track birth outcomes. We aimed to examine the feasibility of community-based birth registration and measure maternal mortality ratio (MMR) in rural south Ethiopia. METHODS: In 2010, health extension workers (HEWs) registered births and maternal deaths among 421,639 people in three districts (Derashe, Bonke, and Arba Minch Zuria). One nurse-supervisor per district provided administrative and technical support to HEWs. The primary outcomes were the feasibility of registration of a high proportion of births and measuring MMR. The secondary outcome was the proportion of skilled birth attendance. We validated the completeness of the registry and the MMR by conducting a house-to-house survey in 15 randomly selected villages in Bonke. RESULTS: We registered 10,987 births (81.4% of expected 13,492 births) with annual crude birth rate of 32 per 1,000 population. The validation study showed that, of 2,401 births occurred in the surveyed households within eight months of the initiation of the registry, 71.6% (1,718) were registered with similar MMRs (474 vs. 439) between the registered and unregistered births. Overall, we recorded 53 maternal deaths; MMR was 489 per 100,000 live births and 83% (44 of 53 maternal deaths) occurred at home. Ninety percent (9,863 births) were at home, 4% (430) at health posts, 2.5% (282) at health centres, and 3.5% (412) in hospitals. MMR increased if: the male partners were illiterate (609 vs. 346; p= 0.051) and the villages had no road access (946 vs. 410; p= 0.039). The validation helped to increase the registration coverage by 10% through feedback discussions. CONCLUSION: It is possible to obtain a high coverage birth registration and measure MMR in rural communities where a functional system of community health workers exists. The MMR was high in rural south Ethiopia and most births and maternal deaths occurred at home. PMID- 25799228 TI - Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. AB - More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE2) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus specific CTLs. Thus, PGE2 inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections. PMID- 25799231 TI - Selective lability of ruthenium(II) arene amino acid complexes. AB - A series of organometallic complexes of the form [(PhH)Ru(amino acid)](+) have been synthesized using amino acids able to act as tridentate ligands. The straightforward syntheses gave enantiomerically pure complexes with two stereogenic centers due to the enantiopurity of the chelating ligands. Complexes were characterized in the solid-state and/or solution-state where the stability of the complex allowed. The propensity toward labilization of the coordinatively saturated complexes was investigated. The links between complex stability and structural features are very subtle. Nonetheless, H/D exchange rates of coordinated amino groups reveal more significant differences in reactivity linked to metallocycle ring size resulting in decreasing stability of the metallocycle as the amino acid side-chain length increases. The behavior of these systems in acid is unusual, apparently labilizing the carboxylate residue of the amino acid. This acid-catalyzed hemilability in an organometallic is relevant to the use of Ru(II) arenes in medicinal contexts due to the relatively low pH of cancerous cells. PMID- 25799230 TI - Nitric oxide enhances keratinocyte cell migration by regulating Rho GTPase via cGMP-PKG signalling. AB - OBJECTIVE: Nitric oxide (NO) has been shown to improve wound healing, but the mechanism underlying this function is not well defined. Here, we explored the effect of NO on the migration of a human keratinocyte cell line (HaCaT) and its possible mechanism. METHODS: The effects of NO on HaCaT cells in the presence of different concentrations of the NO donor sodium nitroprusside (SNP) were evaluated in a cell migration assay. Subsequently, the cytoskeleton reorganization of cultured HaCaT cells stained with rhodamine-phalloidin was observed with a confocal laser scanning microscope. The mRNA expression and active proteins of CDC42, Rac1 and RhoA in the cultured cells were determined via RT-PCR and pull-down assays, respectively. Furthermore, the roles of various inhibitors or agonists specific to cGMP, PKG and CDC42, Rac1, RhoA in the effects of NO on HaCaT cell migration, F-actin stress fibre formation, and Rho GTPase expression were observed. RESULTS: It was also found HaCaT cell migration was increased by SNP in a dose-dependent manner, and the other two NO donors either spermine NONOate or SNAP had almost the same effects on HaCat cell migrations. The formation of F-actin stress fibres in SNP-treated HaCaT cells was increased. The mRNA expression and the active proteins of CDC42, Rac1 and RhoA were found to be upregulated after SNP treatment. Similar effects were observed after the cells were treated with a cGMP or PKG agonist. Additionally, the SNP-mediated upregulation of the mRNA expression and the active proteins of CDC42, Rac1 and RhoA were inhibited by the addition of an inhibitor of cGMP or PKG. Moreover, the SNP-mediated promoting effects of migration and cytoskeleton reorganization were inhibited by treatment with inhibitors of cGMP, PKG, CDC42, Rac1 and RhoA respectively. CONCLUSION: Our data indicated that the stimulatory effects of NO on cell migration of HaCaT cells are mediated by the cGMP signalling pathway via the upregulation of Rho-GTPase expression, which might promote cytoskeleton reorganization. PMID- 25799232 TI - Development of tea tree oil-loaded liposomal formulation using response surface methodology. AB - The aim of this study is to prepare tea tree oil liposome (TTOL) and optimize the preparation condition by single factor experiment and statistical design. TTOL was prepared using a thin-film hydration with the combination of sonication method and the preparation conditions of TTOL were optimized with response surface methodology (RSM). The optimal preparation conditions for TTOL by response surface methodology were as follows: the mass ratio of PC and Cho 5.51, TTO concentration 1.21% (v/v) and Tween 80 concentration 0.79% (v/v). The response surface analysis showed that the significant (p < 0.05) second-order polynomial regression equations successfully fitted for all dependent variables with no significant (p > 0.05) lack of fit for the reduced models. Furthermore, the interaction of the mass ratio of PC/Cho and TTO concentration had a significant effect. The amounts of Tween 80 required were also reduced with RSM. Under these conditions, the experimental encapsulation efficiency of TTOL was 97.81 +/- 0.33%, which was close with the predicted value. Therefore, the optimized preparation condition was very reliable. The increased entrapment efficiency would significantly improve the TTO stability and bioavailability. PMID- 25799233 TI - A Comparison of Mental Health Diagnoses Treated via Interactive Video and Face to Face in the Veterans Healthcare Administration. AB - OBJECTIVE: This study compares the mental health diagnoses of encounters delivered face to face and via interactive video in the Veterans Healthcare Administration (VHA). MATERIALS AND METHODS: We compiled 1 year of national-level VHA administrative data for Fiscal Year 2012 (FY12). Mental health encounters were those with both a VHA Mental Health Stop Code and a Mental Health Diagnosis (n=11,906,114). Interactive video encounters were identified as those with a Mental Health Stop Code, paired with a VHA Telehealth Secondary Stop Code. Primary diagnoses were grouped into posttraumatic stress disorder (PTSD), depression, anxiety, bipolar disorder, psychosis, drug use, alcohol use, and other. RESULTS: In FY12, 1.5% of all mental health encounters were delivered via interactive video. Compared with face-to-face encounters, a larger percentage of interactive video encounters was for PTSD, depression, and anxiety, whereas a smaller percentage was for alcohol use, drug use, or psychosis. CONCLUSIONS: Providers and patients may feel more comfortable treating depression and anxiety disorders than substance use or psychosis via interactive video. PMID- 25799235 TI - Guiding healthcare technology implementation: a new integrated technology implementation model. AB - Healthcare technology is used to improve delivery of safe patient care by providing tools for early diagnosis, ongoing monitoring, and treatment of patients. This technology includes bedside physiologic monitors, pulse oximetry devices, electrocardiogram machines, bedside telemetry, infusion pumps, ventilators, and electronic health records. Healthcare costs are a challenge for society, and hospitals are pushed to lower costs by discharging patients sooner. Healthcare technology is being used to facilitate these early discharges. There is little understanding of how healthcare facilities purchase, implement, and adopt technology. There are two areas of theories and models currently used when investigating technology: technology adoption and implementation science. Technology adoption focuses mainly on how the end users adopt technology, whereas implementation science describes methods, interventions, and variables that promote the use of evidence-based practice. These two approaches are not well informed by each other. In addition, amplifying the knowledge gap is the limited conceptualization of healthcare technology implementation frameworks. To bridge this gap, an all-encompassing model is needed. To understand the key technology implementation factors utilized by leading healthcare facilities, the prevailing technology adoption and implementation science theories and models were reviewed. From this review, an integrated technology implementation model will be set forth. PMID- 25799234 TI - Double-exposure optical sectioning structured illumination microscopy based on Hilbert transform reconstruction. AB - Structured illumination microscopy (SIM) with axially optical sectioning capability has found widespread applications in three-dimensional live cell imaging in recent years, since it combines high sensitivity, short image acquisition time, and high spatial resolution. To obtain one sectioned slice, three raw images with a fixed phase-shift, normally 2pi/3, are generally required. In this paper, we report a data processing algorithm based on the one dimensional Hilbert transform, which needs only two raw images with arbitrary phase-shift for each single slice. The proposed algorithm is different from the previous two-dimensional Hilbert spiral transform algorithm in theory. The presented algorithm has the advantages of simpler data processing procedure, faster computation speed and better reconstructed image quality. The validity of the scheme is verified by imaging biological samples in our developed DMD-based LED-illumination SIM system. PMID- 25799236 TI - Diagnostic classification of schizophrenia patients on the basis of regional reward-related FMRI signal patterns. AB - Functional neuroimaging has provided evidence for altered function of mesolimbic circuits implicated in reward processing, first and foremost the ventral striatum, in patients with schizophrenia. While such findings based on significant group differences in brain activations can provide important insights into the pathomechanisms of mental disorders, the use of neuroimaging results from standard univariate statistical analysis for individual diagnosis has proven difficult. In this proof of concept study, we tested whether the predictive accuracy for the diagnostic classification of schizophrenia patients vs. healthy controls could be improved using multivariate pattern analysis (MVPA) of regional functional magnetic resonance imaging (fMRI) activation patterns for the anticipation of monetary reward. With a searchlight MVPA approach using support vector machine classification, we found that the diagnostic category could be predicted from local activation patterns in frontal, temporal, occipital and midbrain regions, with a maximal cluster peak classification accuracy of 93% for the right pallidum. Region-of-interest based MVPA for the ventral striatum achieved a maximal cluster peak accuracy of 88%, whereas the classification accuracy on the basis of standard univariate analysis reached only 75%. Moreover, using support vector regression we could additionally predict the severity of negative symptoms from ventral striatal activation patterns. These results show that MVPA can be used to substantially increase the accuracy of diagnostic classification on the basis of task-related fMRI signal patterns in a regionally specific way. PMID- 25799237 TI - Codon optimization of the human papillomavirus E7 oncogene induces a CD8+ T cell response to a cryptic epitope not harbored by wild-type E7. AB - Codon optimization of nucleotide sequences is a widely used method to achieve high levels of transgene expression for basic and clinical research. Until now, immunological side effects have not been described. To trigger T cell responses against human papillomavirus, we incubated T cells with dendritic cells that were pulsed with RNA encoding the codon-optimized E7 oncogene. All T cell receptors isolated from responding T cell clones recognized target cells expressing the codon-optimized E7 gene but not the wild type E7 sequence. Epitope mapping revealed recognition of a cryptic epitope from the +3 alternative reading frame of codon-optimized E7, which is not encoded by the wild type E7 sequence. The introduction of a stop codon into the +3 alternative reading frame protected the transgene product from recognition by T cell receptor gene-modified T cells. This is the first experimental study demonstrating that codon optimization can render a transgene artificially immunogenic through generation of a dominant cryptic epitope. This finding may be of great importance for the clinical field of gene therapy to avoid rejection of gene-corrected cells and for the design of DNA- and RNA-based vaccines, where codon optimization may artificially add a strong immunogenic component to the vaccine. PMID- 25799238 TI - Birds flush early and avoid the rush: an interspecific study. AB - Since 1986, studies about the escape decisions made by prey are grounded in optimal escape theory (OET) which states that prey will initiate escape when the risk of remaining and the costs of leaving are equal. However, a recent hypothesis, Flush Early and Avoid the Rush (FEAR), acknowledged that the cost of monitoring approaching predators might be a ubiquitous cost. The FEAR hypothesis predicts that prey will generally flee soon after they detect a predator so as to minimize the costs incurred by monitoring the predator. Knowing whether animals flee to reduce monitoring costs is of applied interest because wildlife managers use escape behavior to create set-back zones to reduce human-wildlife conflict. Here we provide the most comprehensive assessment of the FEAR hypothesis using data collected from 178 bird species representing 67 families from two continents. The FEAR hypothesis explains escape behavior in 79% of studied species. Because the FEAR hypothesis is a widespread phenomenon that drives escape behavior in birds, alert distance must be systematically incorporated into the design of set-back zones to protect vulnerable species. PMID- 25799239 TI - Analysing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors. AB - Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we have prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and midneurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage-specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modelling development in health and disease. PMID- 25799241 TI - Medical memorialization. PMID- 25799240 TI - Transcriptomic analysis of human polarized macrophages: more than one role of alternative activation? AB - BACKGROUND: Macrophages are a heterogeneous cell population which in response to the cytokine milieu polarize in either classically activated macrophages (M1) or alternatively activated macrophages (M2). This plasticity makes macrophages essential in regulating inflammation, immune response and tissue remodeling and a novel therapeutic target in inflammatory diseases such as atherosclerosis. The aim of the study was to describe the transcriptomic profiles of differently polarized human macrophages to generate new hypotheses on the biological function of the different macrophage subtypes. METHODS AND RESULTS: Polarization of circulating monocytes/macrophages of blood donors was induced in vitro by IFN gamma and LPS (M1), by IL-4 (M2a), and by IL-10 (M2c). Unstimulated cells (RM) served as time controls. Gene expression profile of M1, M2a, M2c and RM was assessed at 6, 12 and 24h after polarization with Whole Human Genome Agilent Microarray technique. When compared to RM, M1 significantly upregulated pathways involved in immunity and inflammation, whereas M2a did the opposite. Conversely, decreased and increased expression of mitochondrial metabolism, consistent with insulin resistant and insulin sensitive patterns, was seen in M1 and M2a, respectively. The time sequence in the expression of some pathways appeared to have some specific bearing on M1 function. Finally, canonical and non-canonical Wnt genes and gene groups, promoting inflammation and tissue remodeling, were upregulated in M2a compared to RM. CONCLUSION: Our data in in vitro polarized human macrophages: 1. confirm and extend known inflammatory and anti-inflammatory gene expression patterns; 2. demonstrate changes in mitochondrial metabolism associated to insulin resistance and insulin sensitivity in M1 and M2a, respectively; 3. highlight the potential relevance of gene expression timing in M1 function; 4. unveil enhanced expression of Wnt pathways in M2a suggesting a potential dual (pro-inflammatory and anti-inflammatory) role of M2a in inflammatory diseases. PMID- 25799243 TI - Dr. Bernard Langer - inductee into the Canadian Medical Hall of Fame. AB - Dr. Bernard Langer's induction into the Canadian Medical Hall of Fame acknowledges his profound effect on medicine and surgery in Canada and an impact that has been truly international. In this brief biography, we highlight the major accomplishments that have made Dr. Langer a pre-eminent leader, innovator, teacher and exemplary surgeon. PMID- 25799244 TI - Endovenous radiofrequency ablation for the treatment of varicose veins. AB - Varicose veins are a common condition that can be treated surgically. Available operative modalities include saphenous venous ligation and stripping, phlebectomy, endovenous laser therapy and radiofrequency ablation. Radiofrequency ablation is the newest of these technologies, and to our knowledge our group was the first to use it in Canada. Our experience suggests that it is a safe and effective treatment for varicose veins, with high levels of patient satisfaction reported at short-term follow-up. More studies are needed to assess long-term effectiveness and compare the various available treatment options for varicose veins. PMID- 25799245 TI - A novel method for assessing visual perception of surgical planes. AB - BACKGROUND: Recognition of tissue planes during surgery appears to be a skill acquired with experience. We conducted a pilot study to test this hypothesis using a novel method for evaluating this skill in a simulated environment. METHODS: Twelve surgeons of varying levels of experience were shown 16 captured images from a mesorectal excision. For each image, they were asked to draw the ideal dissection plane with a stylus on a tablet computer. We used a novel metric for comparing agreement between lines to determine the level of precision observed between junior and senior trainees and consultant surgeons and measure the accuracy of junior and senior trainees compared with consultant surgeons. RESULTS: We observed significant differences in precision for 9 of 16 images; 7 of these followed the predicted stepwise pattern associated with level of experience. Using consultant surgeons as the reference standard, we observed significant differences in accuracy between senior and junior trainees for 11 images, with senior trainees being more accurate in 10 of them. Only 2 images failed to contribute significant findings to our analysis. CONCLUSION: The findings of this pilot evaluation of a novel method for measuring a surgeon's ability to recognize tissue planes in a simulated model show that skill improves with experience. Further evaluation of this method will reveal its utility as an assessment tool and possibly as a training instrument. PMID- 25799246 TI - Outcomes of infection following pediatric spinal fusion. AB - BACKGROUND: Removal of instrumentation is often recommended as part of treatment for spinal infections, but studies have reported eradication of infection even with instrumentation retention by using serial debridements and adjuvant antibiotic pharmacotherapy. We sought to determine the effect of instrumentation retention or removal on outcomes in children with spinal infections. METHODS: We retrospectively reviewed the cases of patients who experienced early (< 3 mo) or late (>= 3 mo) infected spinal fusions. Patients were evaluated at least 2 years after eradication of the infection using the following protocol outcomes: follow up Cobb angle, curve progression and nonunion rates. RESULTS: Our sample included 35 patients. The mean age at surgery was 15.1 +/- 6.0 years, 65.7% were girls, and mean follow-up was 41.7 +/- 26.9 months. The mean Cobb angle was 63.6 degrees +/- 14.5 degrees preoperatively, 29.4 degrees +/- 16.5 degrees immediately after surgery and 37.2 degrees +/- 19.6 degrees at follow-up. Patients in the implant removal group (n = 21) were more likely than those in the implant retention group (n = 14) to have a lower ASA score (71.4% v. 28.6%, p = 0.03), fewer comorbidities (66.7% v. 21.4%, p = 0.03), late infections (81.0% v. 14.3%, p = 0.01) and deep infections (95.2% v. 64.3%, p = 0.03). Implants were retained in 12 of 16 (75.0%) patients with early infections and 2 of 19 (10.5%) with late infections. Patients with implant removal had a higher pseudarthrosis rate (38.1% v. 0%, p = 0.02) and a faster curve progression rate (5.8 +/- 9.8 degrees per year v. 0.2 +/- 4.7 degrees per year, p = 0.04). CONCLUSION: Implant retention should be considered, irrespective of the timing or depth of the infection. PMID- 25799247 TI - Persistent neuropathic pain after inguinal herniorrhaphy depending on the procedure (open mesh v. laparoscopy): a propensity-matched analysis. AB - BACKGROUND: A greater incidence of persistent pain after inguinal herniorrhaphy is suspected with the open mesh procedure than with laparoscopy (transabdominal preperitoneal), but the involvement of neuropathy needs to be clarified. METHODS: We examined the cumulative incidence of neuropathic persistent pain, defined as self-report of pain at the surgical site with neuropathic aspects, within 6 months after surgery in 2 prospective subcohorts of a multicentre study. We compared open mesh with laparoscopy using different analysis, including a propensity-matched analysis with the propensity score built from a multivariable analysis using a generalized linear model. RESULTS: Considering the full patient sample (242 open mesh v. 126 laparoscopy), the raw odds ratio for neuropathic persistent pain after inguinal herniorrhaphy was 4.3. It reached 6.8 with the propensity-matched analysis conducted on pooled subgroups of 194 patients undergoing open mesh and 125 undergoing laparoscopy (95% confidence interval 1.5 30.4, p = 0.012). A risk factor analysis of these pooled subgroups revealed that history of peripheral neuropathy was an independent risk factor for persistent neuropathic pain, while older age was protective. CONCLUSION: We found a greater risk of persistent pain with open mesh than with laparoscopy that may be explained by direct or indirect lesion of nerve terminations. Strategies to identify and preserve nerve terminations with the open mesh procedure are needed. PMID- 25799248 TI - Canadian practice patterns for pancreaticoduodenectomy. AB - BACKGROUND: Discordant practice patterns may be a consequence of evidence practice gaps or deficiencies in knowledge translation. We examined the current strategies used by hepato-pancreatico-biliary (HPB) surgeons in Canada for the perioperative management of pancreaticoduodenectomy (PD). METHODS: We generated a web-based survey that focused on the perioperative measures surrounding PD. The survey was distributed to all members of the Canadian Hepato-Pancreatico-Biliary Association. RESULTS: The survey was distributed to 74 surgeons and received a response rate of 50%. Many similarities in surgical techniques were reported; for example, most surgeons (86.5%) reconstruct the pancreas with pancreaticojejunostomy rather than pancreaticogastrostomy. In contrast, variable techniques regarding the use of peritoneal drainage tubes, anastomotic stents, octreotide and other intraoperative modalities were reported. Most surgeons (75.7%) reported that their patients frequently required preoperative biliary drainage, yet there was minimal agreement with the designated criteria. There was variability in postoperative care, including the use of epidural analgesia and timing of postoperative oral nutrition. CONCLUSION: We identified heterogeneity among Canadian HPB surgeons, suggesting a number of evidence-practice gaps within specific domains of pancreatic resections. Focused research in these areas may facilitate technical agreement and improve patient outcomes following PD. PMID- 25799250 TI - Metal-free [3+2] cycloaddition of azides with Tf2C=CH2 for the regioselective preparation of elusive 4-(trifluoromethylsulfonyl)-1,2,3-triazoles. AB - 1,2-Dipole Tf2C=CH2 is generated in situ and immediately reacts at room temperature with an azide to afford previously unknown 4-trifluoromethanesulfonyl 1,2,3-triazoles through a stepwise [3+2] cycloaddition reaction. Noteworthily, this mild and powerful uncatalyzed protocol is highly regio- and chemoselective. PMID- 25799249 TI - Surgical approach in primary total hip arthroplasty: anatomy, technique and clinical outcomes. AB - Total hip arthroplasty (THA) has revolutionized the treatment of hip arthritis. A number of surgical approaches to the hip joint exist, each with unique advantages and disadvantages. The most commonly used approaches include the direct anterior, direct lateral and posterior approaches. A number of technical intricacies allow safe and efficient femoral and acetabular reconstruction when using each approach. Hip dislocation, abductor insufficiency, fracture and nerve injury are complications of THA, although their relative risk varies by approach. Numerous clinical trials have sought to elicit differences in patient-reported outcomes, complication rates and return to function among the surgical approaches. This review outlines some of the technical pearls of performing a THA through either a direct anterior, direct lateral or posterior approach. A literature review outlines the impact of surgical approach on clinical outcomes and clinically relevant complication rates. PMID- 25799251 TI - Deep brain stimulation of the subthalamic nucleus: taking the ouch out of Parkinson disease. PMID- 25799252 TI - Dehydrogenation of ammonia-borane by cationic Pd(II) and Ni(II) complexes in a nitromethane medium: hydrogen release and spent fuel characterization. AB - A highly electrophilic cationic Pd(II) complex, [Pd(MeCN)4][BF4]2 (1), brings about the preferential activation of the B-H bond in ammonia-borane (NH3.BH3, AB). At room temperature, the reaction between 1 in CH3NO2 and AB in tetraglyme leads to Pd nanoparticles and formation of spent fuels of the general formula MeNHxBOy as reaction byproducts, while 2 equiv. of H2 is efficiently released per AB equiv. at room temperature within 60 seconds. For a mechanistic understanding of dehydrogenation by 1, the chemical structures of spent fuels were intensely characterized by a series of analyses such as elemental analysis (EA), X-ray photoelectron spectroscopy (XPS), solid state magic-angle-spinning (MAS) NMR spectra ((2)H, (13)C, (15)N, and (11)B), and cross polarization (CP) MAS methods. During AB dehydrogenation, the involvement of MeNO2 in the spent fuels showed that the mechanism of dehydrogenation catalyzed by 1 is different from that found in the previously reported results. This AB dehydrogenation derived from MeNO2 is supported by a subsequent digestion experiment of the AB spent fuel: B(OMe)3 and N-methylhydroxylamine ([Me(OH)N]2CH2), which are formed by the methanolysis of the AB spent fuel (MeNHxBOy), were identified by means of (11)B NMR and single crystal structural analysis, respectively. A similar catalytic behavior was also observed in the AB dehydrogenation catalyzed by a nickel catalyst, [Ni(MeCN)6][BF4]2 (2). PMID- 25799253 TI - Biohydrogen production from lactose: influence of substrate and nitrogen concentration. AB - Hydrogen produced from renewable sources may be considered the energy vector of the future. However, reducing process costs is imperative in order to achieve this goal. In the present research, the effect of nitrogen (N), initial pH and substrate content for starting up the dark fermentative process was studied using the response surface methodology. Anaerobic digested dried sludge (biosolid pellets) was used as the inoculum. Synthetic wastewater was used as the substrate in batch reactors. A decrease in H2 production was observed with the increase in N and lactose concentrations. This drop was considerably greater when the concentration of lactose was at its lower level. Although the increase in lactose concentration results in a lower H2 production, the effect of N on the response is attenuated at higher levels of lactose. On the other hand, the effect of initial pH on the fermentation system was not significant. The evaluation on the process under semi-continuous conditions was performed using anaerobic sequencing batch reactors (ASBRs). The process was evaluated at different C/N ratios using synthetic wastewater. Results showed higher hydrogen yields with the gradual decrease in nitrogen content. The addition of cheese whey to the ASBR resulted in a H2 production rate of 0.18 L H2 L(-1) d(-1). PMID- 25799254 TI - The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers. AB - Flexibility is an intrinsic property of proteins and essential for their biological functions. However, because of structural flexibility, obtaining high quality crystals of proteins with heterogeneous conformations remain challenging. Here, we show a novel approach to immobilize traditional precipitants onto molecularly imprinted polymers (MIPs) to facilitate protein crystallization, especially for flexible proteins. By applying this method, high-quality crystals of the flexible N-terminus of human fragile X mental retardation protein are obtained, whose absence causes the most common inherited mental retardation. A novel KH domain and an intermolecular disulfide bond are discovered, and several types of dimers are found in solution, thus providing insights into the function of this protein. Furthermore, the precipitant-immobilized MIPs (piMIPs) successfully facilitate flexible protein crystal formation for five model proteins with increased diffraction resolution. This highlights the potential of piMIPs for the crystallization of flexible proteins. PMID- 25799255 TI - Influence of a quality improvement learning collaborative program on team functioning in primary healthcare. AB - Quality improvement (QI) programs are frequently implemented to support primary healthcare (PHC) team development and to improve care outcomes. In Ontario, Canada, the Quality Improvement and Innovation Partnership (QIIP) offered a learning collaborative (LC) program to support the development of interdisciplinary team function and improve chronic disease management, disease prevention, and access to care. A qualitative study using a phenomenological approach was conducted as part of a mixed-method evaluation to explore the influence of the program on team functioning in participating PHC teams. A purposive sampling strategy was used to identify PHC teams (n = 10), from which participants of different professional roles were selected through a purposeful recruitment process to reflect maximum variation of team roles. Additionally, QI coaches working with the interview participants and the LC administrators were also interviewed. Data were collected through semistructured telephone interviews that were audiotaped and transcribed verbatim. Thematic analysis was conducted through an iterative and interpretive approach. The shared experience of participating in the program appeared to improve team functioning. Participants described increased trust and respect for each other's clinical and administrative roles and were inspired by learning about different approaches to interdisciplinary care. This appeared to enhance collegial relationships, collapse professional silos, improve communication, and increase interdisciplinary collaboration. Teamwork involves more than just physically grouping healthcare providers from multiple disciplines and mandating them to work together. The LC program provided opportunities for participants to learn how to work collaboratively, and participation in the LC program appeared to enhance team functioning. PMID- 25799256 TI - Endoscopic vacuum-assisted closure with sponge for esophagotracheal fistula after esophagectomy. AB - We experienced a case of endoscopic vacuum-assisted closure with sponge for esophagotracheal fistula diagnosed after esophagectomy due to squamous cell esophageal cancer. The patient, who had undergone a robotic-assisted thoracoscopic esophagectomy and esophageal reconstruction of the stomach, was referred for the management of esophagotracheal fistula. Diagnostic esophagogastroduodenoscopy and imaging studies were performed, and they indicated anastomotic leakage with esophagotracheal fistula. The patient was treated by the endoscopic placement of full-covered self-expanding metal stents, but the fistula persisted. Then, we applied a size-adjusted sponge endoscopically with continuous suction by a vacuum system in the fistula lesion. Complete closure was achieved without any procedure-related complications. After 40 days, symptomatic esophageal stricture was detected and treated successfully with endoscopic balloon dilation. Endoscopic vacuum-assisted closure with a sponge might be an adequate alternative treatment option for esophageal stenting for esophagotracheal fistula after esophagectomy. PMID- 25799257 TI - Endoscopy Lithotomy for Intrahepatic Gallstones: A Meta-Analysis. AB - BACKGROUND: Endoscopy lithotomy (percutaneous transhepatic cholangioscopic lithotomy or through a T-tube track) has become a well-established treatment for intrahepatic gallstones. However, the relationship between strictures and the results of this treatment is still controversial. MATERIALS AND METHODS: We searched PubMed, EMBASE, Cochrane Library databases, clinicaltrails, CBM, and Google scholar systematically for all articles. The rate of complete clearance, the recurrence rate, and major complications were analyzed. A meta-analysis was performed by RevMan 5.2. RESULTS: Thirteen studies were included. In patients with intrahepatic duct stricture, the rate of complete clearance was significantly lower, but the rate of recurrence was significantly higher. The morbidity rate of major complications was significantly lower in complete stone removal patients. CONCLUSIONS: Intrahepatic biliary stricture is a major cause of treatment failure for intrahepatic stones and stone recurrence. To prevent recurrent cholangitis or cholangiocarcinoma, complete removal of intrahepatic gallstones is very important. PMID- 25799258 TI - Laparoscopic common bile duct exploration: choledochotomy versus transcystic approach? AB - PURPOSE: To compare the difference of primary suture following 3-port laparoscopic common bile duct exploration (LCBDE) between modified transcystic and transcholedochal approach in the treatment of choledocholithiasis. MATERIALS AND METHODS: Patients who underwent 3-port LCBDE by modified transcystic approach (n = 80) and those who underwent 3-port LCBDE by transcholedochal approach (n = 209) were included in this study. The operative time, duration of hospital stay, diameter of the cystic duct, diameter of the common bile duct (CBD), complications, and demographics were retrospectively analyzed in all patients. RESULTS: All operations were successfully performed. No patient was converted to laparotomy. No mortality was associated with the 2 groups. There was no significant difference between the 2 groups for the operative time (91.94 +/- 34.21 min vs. 96.13 +/- 32.15 min), duration of hospital stay (9.82 +/- 3.48 d vs. 10.74 +/- 5.34 d), diameter of cystic duct (0.47 +/- 0.09 cm vs. 0.47 +/- 0.08 cm), and complications (2.5% vs. 2.87%) (all P > 0.05). A significant difference was observed in terms of the diameter of CBD (1.18 +/- 0.29 cm vs. 1.04 +/- 0.24 cm P < 0.05). CONCLUSIONS: The modified transcystic LCBDE was safe and feasible for treating choledocholithiasis but it might be more suitable for the CBD with a smaller diameter. PMID- 25799259 TI - A New Device to Prevent Irregular Adsorption of Fatty Tissue While Using an Irrigation-suction Instrument for Laparoscopic Surgery: Divided Silicone Drain Tip. AB - BACKGROUND: While using an irrigation-suction instrument for laparoscopic surgery, irregular adsorption of fatty tissue may damage the tissue or obstruct continuous sucking. A new device made up of a divided silicone drain tip to prevent irregular adsorption was reported. MATERIALS AND METHODS: A cigarette type silicone drain was cut 4 cm in length. It was slipped over the instrument to cover the side holes, leaving 1.0 to 1.5 cm free from the end of the instrument. It was fixed by means of 1-0 silk above the side holes. Finally, the free tip was divided vertically into 4 even pieces like octopus arms. RESULTS: This device could prevent the irregular adsorption of fatty tissue (greater and lesser omentum, or epiploic appendices) and could suck saline, fresh, and coagulated blood almost continuously. CONCLUSIONS: This simple and easy device facilitated the prevention of irregular adsorption of fatty tissue while using an irrigation suction instrument for laparoscopic surgery. PMID- 25799260 TI - Laparoscopic Surgery for Perforated Duodenal Ulcer Disease: Analysis of 70 Consecutive Cases From a Single Surgeon. AB - BACKGROUND: In the surgical treatment of perforated duodenal ulcer disease, laparoscopic surgery has become a key technique. However, difficult cases are not eligible for laparoscopic surgery. The purpose of this study was to evaluate the risk factors for postoperative complications and to examine the safety and effectiveness of laparoscopic surgery. MATERIALS AND METHODS: Seventy duodenal ulcer perforation patients who underwent laparoscopic surgery between July 2010 and March 2014 were reviewed. The type of surgery was chosen on the basis of the size of the perforation. All patients were classified into 2 groups according to the surgical treatment method: primary repair with omentopexy (PR group, n=56) and distal gastrectomy with truncal vagotomy (DG group, n=14). RESULTS: No conversions to open surgery occurred. Three deaths (mortality rate, 4.1%) occurred within 90 postoperative days. Postoperative complications, including 5 severe complications, occurred in 9 patients. There were no differences between the PR and DG groups, except in the mean operation time. In univariate analysis, history of nonsteroidal anti-inflammatory drug use, American Society of Anesthesiologist score (over 3), presence of shock, and time to surgery from symptom onset until surgery (over 48 h) were prognostic factors for postoperative complications. Of particular note, the different perforation sizes were not significantly different. Multivariate analysis showed that history of nonsteroidal anti-inflammatory drug use and treatment delay (48 h) were independent risk factors for overall postoperative complications. The presence of shock on admission was a risk factor for severe postoperative complications. CONCLUSIONS: Our results suggest that laparoscopic surgery may be applied to all duodenal ulcer perforations. However, because of the learning period, we believe that laparoscopic surgery may not be suited to every surgeon. However, when performed by laparoscopic experts, laparoscopic surgery can be a valuable approach for treating difficult duodenal ulcer perforations. PMID- 25799261 TI - Meta-Analysis of Early Endoscopic Retrograde Cholangiopancreatography (ERCP) +/- Endoscopic Sphincterotomy (ES) Versus Conservative Management for Gallstone Pancreatitis (GSP). AB - CONTEXT: The utility of early endoscopic retrograde cholangiopancreatography (ERCP) +/- endoscopic sphincterotomy (ES) in the treatment of gallstone pancreatitis (GSP) is still contentious. OBJECTIVES: The aim was to conduct a meta-analysis of randomized controlled trials (RCTs) investigating the treatment of GSP by early ERCP +/- ES versus conservative management and analyzing the patient outcomes. DATA SOURCES: A search of Medline, Embase, Science Citation Index, Current Contents, PubMed, and the Cochrane Database of Systematic Reviews identified all RCTs comparing early ERCP to conservative management in GSP published between January 1970 and January 2014. Search terms included "Endoscopic retrograde cholangiopancreatography (ERCP)"; "Endoscopic sphincterotomy"; "Gallstones"; "Bile duct stones"; "Gallstone pancreatitis"; "Biliary pancreatitis"; "Randomize/Randomised controlled trials"; "Conservative management/treatment"; "Human"; "English." STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Only prospective RCTs comparing early intervention (ie, between 24 and 72 h) with ERCP +/- ES versus conservative management in GSP were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Data extraction and critical appraisal was carried out independently by 2 authors (M.J.B. and M.A.M.) using predefined data fields. Variables analyzed included severity of pancreatitis (mild or severe), overall mortality, overall complications which included pseudocyst formation, organ failure (renal, respiratory, and cardiac), abnormal coagulation, biliary sepsis, and development of pancreatic abscess/phlegmon. The quality of RCTs was assessed using Jadad's scoring system. Random-effects model was used to calculate the outcomes of both binary and continuous data. Heterogeneity among the outcome variables of these trials was determined by the Cochran Q statistic and I2 index. The meta-analysis was prepared in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. RESULTS: Eleven RCTs consisting of 1314 patients (conservative management=662, ERCP=652) were analyzed. There was a near significant decrease in mortality for ERCP group compared with conservatively managed patients with severe pancreatitis [odds ratio (OR) 0.45; 95% confidence interval (CI), 0.19, 1.09; P=0.08]. In patients with mild pancreatitis, mortality results were comparable for both groups (OR 0.66; 95% CI, 0.02, 28.75; P=0.83). Overall complications were significantly reduced in the ERCP group in severe pancreatic patients (OR 0.32; 95% CI, 0.17, 0.61; P=0.00). In those with mild disease, a strong trend to decreased complications in the ERCP group was seen, however, this was not significant (OR 0.67; 95% CI, 0.43, 1.03; P=0.06). CONCLUSIONS: This meta-analysis demonstrates a significant decrease in complications in patients with severe GSP managed with early ERCP/ES compared with conservative management. As far as the mortality is concerned, no significant decrease was observed in mortality even in severe GSP patients treated with early ERCP/ES. PMID- 25799262 TI - Protein stabilization by an amphiphilic short monodisperse oligo(ethylene glycol). AB - A short, monodisperse additive (octa(ethylene glycol) monophenyl ether) functions to suppress aggregation of thermally and chemically denatured lysozyme. Control studies with shorter and non-amphiphilic derivatives revealed that the amphiphilic structure is essential, and octa(ethylene glycol) is nearly the minimum chain length for amphiphilic poly(ethylene glycol)s to stabilize proteins. PMID- 25799263 TI - Evaluation of the Versant CT/GC DNA 1.0 assay (kPCR) for the detection of extra genital Chlamydia trachomatis and Neisseria gonorrhoeae infections. AB - Screening for extra-genital Chlamydia trachomatis and Neisseria gonorrhoeae infections is a crucial component for sexually transmitted diseases management, even if at present days no commercial methods have been approved for use on pharyngeal and rectal specimens by the US FDA or have received the conformity CE marking. Here we report the analytical sensitivities of the Versant CT/GC 1.0 assay (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) on rectal and pharyngeal swabs, and an evaluation about the suitability for this assay with two widely used swab collection devices (E-Swab and eNAT, Copan, Brescia, Italy). The limits of detection for rectal and pharyngeal specimens with the Versant assay were 10 copies/ml and 1.0 copies/ml, for C. trachomatis and N. gonorrhoeae, respectively. False positive results due to the presence of non-gonococcal Neisseria species were excluded when clinical rectal and pharyngeal samples containing organisms identified as N. meningitidis, N. sicca, N. flavescens and N. subflava were tested. Due to its sensitivity and specificity, the Versant assay represents a good choice for the diagnosis of chlamydial and/or gonococcal infections not only in genito-urinary samples, but also on rectal and pharyngeal swabs. PMID- 25799264 TI - Design and Synthesis of New alpha-Naphthoflavones as Cytochrome P450 (CYP) 1B1 Inhibitors To Overcome Docetaxel-Resistance Associated with CYP1B1 Overexpression. AB - CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking alpha-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-alpha naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3') on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble alpha-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new alpha-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics. PMID- 25799265 TI - Generation, utilization, and transformation of cathode electrons for bioreduction of Fe(III)EDTA in a biofilm electrode reactor related to NOx removal from flue gas. AB - A chemical absorption-biological reduction (CABR) integrated system, which employs iron chelate as a solvent, is under development for NOx removal from flue gas. Biofilm electrode reactor (BER) is deemed as a promising bioreactor to regenerate the iron chelate. Although it has been proved that BER can significantly enhance the bioreduction of Fe(III)EDTA, the bioelectrochemistry mechanism involved in the bioreduction of Fe(III)EDTA remains unknown. This work aims to explore this mechanism via the analysis of the generation, utilization, and transformation of cathode electrons in the BER. The results indicate that the generation of cathode electrons follows Faraday's law. The generated cathode electrons were used to produce H2 and directly reduce Fe(III)EDTA in the BER. Meanwhile, the produced H2 served as an electron donor for bioreduction of Fe(III)EDTA. The excess H2 product was transformed to simple organics, e.g., methanol by the hydrogen autotrophy of Pseudomonas under the inorganic and anaerobic conditions. Overall, this work revealed that the reduction of Fe(III)EDTA in the BER was enhanced by both direct electrochemical reduction and indirect bioreduction using H2 as an intermediate. It is also interesting that the excess H2 product was transformed to methanol for microbial metabolism and energy storage in the BER. PMID- 25799266 TI - Interictal cardiorespiratory variability in temporal lobe and absence epilepsy in childhood. AB - It is well known that epilepsy has a profound effect on the autonomic nervous system, especially on the autonomic control of heart rate and respiration. This effect has been widely studied during seizure activity, but less attention has been given to interictal (i.e. seizure-free) activity. The studies that have been done on this topic, showed that heart rate and respiration can be affected individually, even without the occurrence of seizures. In this work, the interactions between these two individual physiological variables are analysed during interictal activity in temporal lobe and absence epilepsy in childhood. These interactions are assessed by decomposing the predictive information about heart rate variability, into different components like the transfer entropy, cross-entropy, self- entropy and the conditional self entropy. Each one of these components quantifies different types of shared information. However, when using the cross-entropy and the conditional self entropy, it is possible to split the information carried by the heart rate, into two main components, one related to respiration and one related to different mechanisms, like sympathetic activation. This can be done after assuming a directional link going from respiration to heart rate. After analysing all the entropy components, it is shown that in subjects with absence epilepsy the information shared by respiration and heart rate is significantly lower than for normal subjects. And a more remarkable finding indicates that this type of epilepsy seems to have a long term effect on the cardiac and respiratory control mechanisms of the autonomic nervous system. PMID- 25799267 TI - Practical, asymmetric route to sitagliptin and derivatives: development and origin of diastereoselectivity. AB - The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S?O, consistent with MsOH being crucial for high selectivity. The second is a novel C-H...F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand. PMID- 25799268 TI - [Profiles of resilience and quality of life in people with acquired disability due to traffic accidents]. AB - OBJECTIVES: To identify distinct profiles of resilience in people with spinal cord injuries due to traffic accidents and to determine whether the profiles identified are related to differences in subjective well-being. METHODS: The Resilience Scale (Wagnild and Young, 1993) and an adapted quality of life scale (GENCAT) were administered to 98 people with physical disabilities due to traffic accidents. RESULTS: Cluster analyses identified three different resilience profiles: a high-resilience group, a low-resilience group, and a group showing a predominance of high scores in self and life acceptance and social competence. The results also revealed statistically significant differences among profiles in most domains of subjective well-being. CONCLUSION: The results suggest the need to study resilience in greater depth and to design programs to enhance quality of life among people with disabilities due to traffic accidents. PMID- 25799269 TI - Relationship of the perceived social and physical environment with mental health related quality of life in middle-aged and older adults: mediating effects of physical activity. AB - BACKGROUND: Mental health conditions are among the leading non-fatal diseases in middle-aged and older adults in Australia. Proximal and distal social environmental factors and physical environmental factors have been associated with mental health, but the underlying mechanisms explaining these associations remain unclear. The study objective was to examine the contribution of different types of physical activity in mediating the relationship of social and physical environmental factors with mental health-related quality of life in middle-aged and older adults. METHODS: Baseline data from the Wellbeing, Eating and Exercise for a Long Life (WELL) study were used. WELL is a prospective cohort study, conducted in Victoria, Australia. Baseline data collection took place in 2010. In total, 3,965 middle-aged and older adults (55-65 years, 47.4% males) completed the SF-36 Health Survey, the International Physical Activity Questionnaire, and a questionnaire on socio-demographic, social and physical environmental attributes. Mediation analyses were conducted using the MacKinnon product-of-coefficients test. RESULTS: Personal safety, the neighbourhood physical activity environment, social support for physical activity from family or friends, and neighbourhood social cohesion were positively associated with mental health-related quality of life. Active transportation and leisure-time physical activity mediated 32.9% of the association between social support for physical activity from family or friends and mental health-related quality of life. These physical activity behaviours also mediated 11.0%, 3.4% and 2.3% respectively, of the relationship between the neighbourhood physical activity environment, personal safety and neighbourhood social cohesion and mental health-related quality of life. CONCLUSIONS: If these results are replicated in future longitudinal studies, tailored interventions to improve mental health-related quality of life in middle aged and older adults should use a combined strategy, focusing on increasing physical activity as well as social and physical environmental attributes. PMID- 25799270 TI - Group 2 innate lymphoid cell proportions are diminished in young helminth infected children and restored by curative anti-helminthic treatment. AB - BACKGROUND: Group 2 Innate lymphoid cells (ILC2s) are innate cells that produce the TH2 cytokines IL-5 and IL-13. The importance of these cells has recently been demonstrated in experimental models of parasitic diseases but there is a paucity of data on ILC2s in the context of human parasitic infections and in particular of the blood dwelling parasite Schistosoma haematobium. METHODOLOGY/PRINCIPAL FINDINGS: In this case-control study human peripheral blood ILC2s were analysed in relation to infection with the helminth parasite Schistosoma haematobium. Peripheral blood mononuclear cells of 36 S. haematobium infected and 36 age and sex matched uninfected children were analysed for frequencies of ILC2s identified as Lin-CD45+CD127+CD294+CD161+. ILC2s were significantly lower particularly in infected children aged 6-9 years compared to healthy participants. Curative anti helminthic treatment resulted in an increase in levels of the activating factor TSLP and restoration of ILC2 levels. CONCLUSION: This study demonstrates that ILC2s are diminished in young helminth infected children and restored by removal of the parasites by treatment, indicating a previously undescribed association between a human parasitic infection and ILC2s and suggesting a role of ILC2s before the establishment of protective acquired immunity in human schistosomiasis. PMID- 25799272 TI - Overnight suppression of HPA axis after mineraolocorticoid receptor stimulation: A sleep endocrine study. AB - Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback inhibition with stress-related conditions such as major depression and sleep disorders. To characterize the role of mineralocorticoid (MR) in regulation of HPA axis activity during nocturnal sleep and involvement in sleep architecture, we investigated sleep endocrine effects of the MR agonist fludrocortisone in healthy men after pretreatment with metyrapone to minimize the impact of endogenous cortisol. Subjects (n=8) were treated on three occasions in a single-blinded design in random order with a) metyrapone, b) fludrocortisone after metyrapone, and c) placebo. Polysomnography was recorded and blood samples were drawn for determination of adrenocorticotropic hormone (ACTH) and cortisol during the entire night. After metyrapone administration ACTH was significantly enhanced, while overall nocturnal cortisol secretion remained largely unchanged. Whereas administration of fludrocortisone induced a significant inhibitory effect on basal ACTH and cortisol secretion, no considerable effects on sleep pattern were detectable. While the involvement of MR in sleep regulation needs further study, endocrine findings underline the role of MR in tonic regulation of HPA axis during nocturnal sleep and demonstrate the ability of fludrocortisone to further suppress HPA axis activity overnight. Additional studies would be required to evaluate endocrine and clinical fludrocortisone effects in depressive patients showing HPA hyperactivity. PMID- 25799274 TI - Correction: Fin whale sound reception mechanisms: skull vibration enables low frequency hearing. PMID- 25799271 TI - De novo transcriptome assembly of pummelo and molecular marker development. AB - Pummelo (Citrus grandis) is an important fruit crop worldwide because of its nutritional value. To accelerate the pummelo breeding program, it is essential to obtain extensive genetic information and develop relative molecular markers. Here, we obtained a 12-Gb transcriptome dataset of pummelo through a mixture of RNA from seven tissues using Illumina pair-end sequencing, assembled into 57,212 unigenes with an average length of 1010 bp. The annotation and classification results showed that a total of 39,584 unigenes had similar hits to the known proteins of four public databases, and 31,501 were classified into 55 Gene Ontology (GO) functional sub-categories. The search for putative molecular markers among 57,212 unigenes identified 10,276 simple sequence repeats (SSRs) and 64,720 single nucleotide polymorphisms (SNPs). High-quality primers of 1174 SSR loci were designed, of which 88.16% were localized to nine chromosomes of sweet orange. Of 100 SSR primers that were randomly selected for testing, 87 successfully amplified clear banding patterns. Of these primers, 29 with a mean PIC (polymorphic information content) value of 0.52 were effectively applied for phylogenetic analysis. Of the 20 SNP primers, 14 primers, including 54 potential SNPs, yielded target amplifications, and 46 loci were verified via Sanger sequencing. This new dataset will be a valuable resource for molecular biology studies of pummelo and provides reliable information regarding SNP and SSR marker development, thus expediting the breeding program of pummelo. PMID- 25799273 TI - Highly heterogeneous soil bacterial communities around Terra Nova Bay of Northern Victoria Land, Antarctica. AB - Given the diminished role of biotic interactions in soils of continental Antarctica, abiotic factors are believed to play a dominant role in structuring of microbial communities. However, many ice-free regions remain unexplored, and it is unclear which environmental gradients are primarily responsible for the variations among bacterial communities. In this study, we investigated the soil bacterial community around Terra Nova Bay of Victoria Land by pyrosequencing and determined which environmental variables govern the bacterial community structure at the local scale. Six bacterial phyla, Actinobacteria, Proteobacteria, Acidobacteria, Chloroflexi, Cyanobacteria, and Bacteroidetes, were dominant, but their relative abundance varied greatly across locations. Bacterial community structures were affected little by spatial distance, but structured more strongly by site, which was in accordance with the soil physicochemical compositions. At both the phylum and species levels, bacterial community structure was explained primarily by pH and water content, while certain earth elements and trace metals also played important roles in shaping community variation. The higher heterogeneity of the bacterial community structure found at this site indicates how soil bacterial communities have adapted to different compositions of edaphic variables under extreme environmental conditions. Taken together, these findings greatly advance our understanding of the adaption of soil bacterial populations to this harsh environment. PMID- 25799275 TI - Factors influencing quality of life of obese students in Hangzhou, China. AB - OBJECTIVE: To evaluate the quality of life (QOL) of overweight and obese middle or high school students and identify relevant factors influencing their QOL scores. METHODS: 716 students were recruited from 6 middle or high schools in Hangzhou, China. The Chinese version of the Youth Quality of Life Instrument Weight Module (YQOL-W) was self administered. The YQOL-W scores were compared among different BMI groups, gender, educational status, annual household income, parental education and recruitment community using t test or one-way analysis of variance. The independent association of these variables with QOL among overweight and obese students was examined using multivariable linear regression modeling. RESULTS: Overweight and obese students reported lower total scores, self, social and environment scores than their normal weight peers (all P<0.001). The QOL of overweight and obese middle and high school students was associated with BMI value, gender, educational status, parental education, and recruitment community. Girls had lower total scores, self, social and environment domain scores than boys (all P<0.001); high school students had lower total and three domain scores than middle school students (all P<0.05). Students whose fathers had higher education reported higher total scores, self and social scores than students with less educated fathers (all P<0.05). Students whose mothers had higher education reported higher environment scores than students with less educated mothers (P = 0.01). Students from migrant communities reported significantly lower total scores, self and social scores than those from rural communities (all P<0.05), but comparable scores with those from urban communities (P>0.05). Students from migrant communities reported comparable environment scores with those from rural and urban communities (P>0.05). CONCLUSIONS: Overweight and obesity have negative effects on students' quality of life. Therefore weight specific QOL could be included in weight reduction interventions as a relevant outcome. PMID- 25799276 TI - [Vaccination in pulmonology]. PMID- 25799277 TI - Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. AB - PURPOSE: The immune checkpoint ligand programmed cell death 1 ligand 1 (PD-L1) is expressed in various tumors and is associated with the response to anti programmed cell death 1 (PD-1)/PD-L1 drugs. We evaluated PD-L1 expression in thymomas and thymic carcinomas to determine whether PD-L1 represents a therapeutic target in unresectable thymomas or thymic carcinomas that could be amenable to antibody-based immunotherapy. METHOD: A tissue microarray (TMA) comprised of 101 thymomas and 38 thymic carcinomas samples was evaluated. After validation of the rabbit monoclonal PD-L1 antibody (clone E1L3N), the TMA was stained and the tumor PD-L1 expression score was calculated using a semiquantitive method (by multiplying the intensity [0-3] by the staining area [0 100%]). RESULTS: Seventy percent of thymic carcinoma (type C) and 23% of thymoma (types A, AB, and B) samples stained positive for PD-L1 (P<.001). A WHO classification (type C vs types A, AB, and B) was significantly associated with positive PD-L1 expression (P=0.006), though multivariate analysis did not show PD L1 positive was a significant negative factor of overall survival (hazard ratio=0.99, 95% confidence interval=0.35-2.73; P=0.987). CONCLUSIONS: To the best of our knowledge, this is the largest-scale study to evaluate PD-L1 expression in thymomas and thymic carcinomas. The data suggest that the anti PD-1/PD-L1 drug could be of potential use in immunotherapy for unresectable or relapsed thymomas and thymic carcinomas. PMID- 25799278 TI - Lewisy promotes migration of oral cancer cells by glycosylation of epidermal growth factor receptor. AB - Aberrant glycosylation changes normal cellular functions and represents a specific hallmark of cancer. Lewisy (Ley) carbohydrate upregulation has been reported in a variety of cancers, including oral squamous cell carcinoma (OSCC). A high level of Ley expression is related to poor prognosis of patients with oral cancer. However, it is unclear how Ley mediates oral cancer progression. In this study, the role of Ley in OSCC was explored. Our data showed that Ley was upregulated in HSC-3 and OC-2 OSCC cell lines. Particularly, glycosylation of epidermal growth factor receptor (EGFR) with Ley was found in OC-2 cells, and this modification was absent upon inhibition of Ley synthesis. The absence of Ley glycosylation of EGFR weakened phosphorylation of AKT and ERK in response to epidermal growth factor (EGF). Additionally, EGF-triggered cell migration was reduced, but cell proliferation was not affected. Ley modification stabilized EGFR upon ligand activation. Conversely, absence of Ley glycosylation accelerated EGFR degradation. In summary, these results indicate that increased expression of Ley in OSCC cells is able to promote cell migration by modifying EGFR which in turn stabilizes EGFR expression and downstream signaling. Targeting Ley on EGFR could have a potential therapeutic effect on oral cancer. PMID- 25799279 TI - pHe-induced charge-reversible NIR fluorescence nanoprobe for tumor-specific imaging. AB - Inspired by the specificity of acid tumor microenvironment, we constructed a flexible charge-reversible near-infrared (NIR) fluorescence nanoprobe in response to tumor extracellular pH (pHe) for effective tumor-specific imaging. The nanoprobe consists of an NIR-emitted CuInS2/ZnS quantum dot (CIS/ZS QDs) core and a tailored lauric acid and 2,3-dimethylmaleic anhydride modified epsilon polylysine (epsilon-PL-g-LA/DMA) shell, which provides not only a dense protective layer for the QDs but also the ability of pHe-induced positive charge mediated endocytosis into tumor cells. The results showed that the QDs@epsilon-PL g-LA/DMA nanoprobe with a uniform size of 40 nm had high chemical stability at pH 7.4 and excellent optical properties. Especially, it swiftly reversed its surface charge to positive in 20 min when exposed to pHe due to the cleavage of the beta carboxyl amide bond of epsilon-PL-g-LA/DMA. Moreover, the cell uptake of the pHe sensitive QDs nanoprobe exposed at pH 6.8 into HeLa cells is much more significant than that at pH 7.4, which further verified the availability of the electrostatic adsorptive endocytosis facilitated targeting ability. The pHe induced targeting imparted the QDs nanoprobe a broad targeting ability in a variety of solid tumors. Furthermore, as an effective alternative mechanism for tumor targeting, responsive charge reversion is also universally applicable to other cancer theranostics agent. PMID- 25799280 TI - Effects of ex-vivo and in-vivo treatment with probiotics on the inflammasome in dogs with chronic enteropathy. AB - Inflammasomes coordinate the maturation of IL-1beta and IL-18 in response to danger signals. They are vital for maintenance of intestinal homeostasis and have been linked to chronic intestinal inflammation in humans. Probiotics have been advocated as treatment in intestinal inflammation. So far, no study has investigated the role of the inflammasome in canine chronic enteropathy (CE). In this study the intestinal expression of inflammasome components was assessed in CE dogs compared to controls, when treated with probiotic Enterococcus faecium (EF) ex-vivo and in-vivo. RNA extraction from endoscopic biopsies and reverse transcriptase quantitative PCR was performed for NLRP3, casp-1, IL-1beta and IL 18. Immunohistochemistry was performed to investigate protein expression in tissues. Gene expression of casp-1 and NLRP3 was lower in CE samples than controls. Ex-vivo treatment with EF reduced NLRP3 expression in control samples. Treatment of CE dogs with EF alongside dietary intervention had no effect on gene expression. In contrast, IL-1beta protein expression in CE decreased with dietary treatment (but not with probiotics). The results of this study suggest that the inflammasome or its components may be partially involved in the inflammatory process seen in CE, but distinct from intestinal inflammation in humans. PMID- 25799281 TI - Flavone derivatives as inhibitors of insulin amyloid-like fibril formation. AB - Several natural and synthetic flavone derivatives have been reported to inhibit formation of amyloid fibrils or to remodel existing fibrils. These studies suggest that the numbers and positions of hydroxyl groups on the flavone rings determine their effectiveness as amyloid inhibitors. In many studies the primary method for determining the effectiveness of inhibition is measuring Thioflavin T (ThT) fluorescence. This method demonstrably results in a number of false positives for inhibition. We studied the effects of 265 commercially available flavone derivatives on insulin fibril formation. We enhanced the effectiveness of ThT fluorescence measurements by fitting kinetic curves to obtain halftime of aggregation (t50). Maximal values of ThT fluorescence varied two fold or more in one third of all cases, but this did not correlate with changes in t50. Changes in t50 values were more accurate measures of inhibition of amyloid formation. We showed that without a change in an assay, but just by observing complete kinetic curves it is possible to eliminate numbers of false positive and sometimes even false negative results. Examining the data from all 265 flavones we confirmed previous observations that identified the importance of hydroxyl groups for inhibition. Our evidence suggests the importance of hydroxyl groups at locations 5, 6, 7, and 4', and the absence of a hydroxyl group at location 3, for inhibiting amyloid formation. However, the main conclusion is that the positions are not additive. The structures and their effects must be thought of in the context of the whole molecule. PMID- 25799282 TI - Globular protein-coated Paclitaxel nanosuspensions: interaction mechanism, direct cytosolic delivery, and significant improvement in pharmacokinetics. AB - About 40% of the marketed drugs and 70-90% of new drug candidates are insoluble in water and therefore poorly bioavailable, which significantly compromises their therapeutic effects. A formulation of nanosuspensions achieved by reducing the pure drug particle size down to seb-micron range is one of the most promising approaches to overcome the insolubility. However, the nanosuspension formulations are subject to instability because of nucleation and particle growth. Therefore, a stabilizer is needed to be incorporated into the nanosuspension formulation during the preparation process to suppress the aggregation of drug particles. beta-LG, a globular protein, is broken by heat-induced denaturation, and its hydrophobic area is exposed, which allows it to associate with organic particles. PTX, an insoluble drug, is widely used for the clinical treatment of human cancer. However, this drug's clinical application is greatly limited by intrinsic defects including poor solubility, adverse side effects, and poor tumor penetration. In this study, we prepared beta-LG-stabilized PTX nanosuspensions (PTX-NS) by coating the protein onto nanoscaled drug particles, investigating the stabilization effect of beta-LG on PTX-NS, and evaluating its in vitro and in vivo performance. PTX-NS with a diameter of approximately 200 nm was easily prepared. beta-LG produced significantly stabilized effect on PTX-NS via the interaction between the hydrophobic area of the protein and the hydrophobic surface of the drug particles, which resulted in a conformational change of the protein, the loss of both secondary and tertiary structures, and the transition of Trp residues to a less hydrophobic condition. Importantly, unlike other conventional nanoparticles, PTX-NS could directly translocated across the membrane into the cytosol in an energy-independent manner, without entrapment within the endosomal-lysosomal system. Moreover, compared with Taxol, PTX-NS increased AUC and Cmax by 26- and 16-fold, respectively, and prolonged T1/2 by 314-fold. As expected, PTX-NS had better in vitro and in vivo antitumor activity compared to PTX alone. Additionally, beta-LG is cyto- and bio-compatible, and PTX NS is not toxic to healthy tissues. In conclusion, the present study has suggested the high potency of globular proteins, such as beta-LG, as novel biomaterials for nanosuspension platform to improve the drug delivery for disease treatment. PMID- 25799283 TI - Effect of hydrofluoric acid concentration and etching duration on select surface roughness parameters for zirconia. AB - STATEMENT OF PROBLEM: The surface of zirconia is resistant to chemical treatment. Roughening the surface of densely sintered zirconia still poses a challenge in dentistry. PURPOSE: The purpose of the study was to examine the effects of hydrofluoric acid on the quality of surface roughening of zirconia. MATERIAL AND METHODS: One hundred cylindrical disks made from zirconia (Ceramill Zi; Amann Girrbach AG) were divided into 4 groups. Three groups (n=30) were distinguished on the basis of hydrofluoric acid (HF) concentration: 40% HF, 9.5% HF, and 5% HF. The groups were then further divided into 3 groups of 10 specimens, each based on etch time (1, 5, or 15 minutes). The control group (n=10) consisted of specimens polished with SiC abrasive paper. The surface was examined with scanning electron microscopy, and the roughness was measured with a profilometer and confocal laser scanning microscope. The mean arithmetic profile deviation (Ra(mean)) and mean maximum height of profile (Rz(mean)) results for the etched surfaces in relationship to the baseline surfaces were compared with the Student t test for averaged data (alpha=.05). RESULTS: When etched with 40% HF concentration, the Ra(mean) and Rz(mean) results were statistically higher (P<.01) for the etched surfaces than for the baseline surfaces. When etched with 9.5% HF concentration, the higher Ra(mean) and Rz(mean) results were only statistically significant (P<.01) after 15 minutes. Etching with 5% HF concentration showed no significant differences (P>.05). CONCLUSIONS: Etching with a 5% HF solution should not be recommended as a method for roughening zirconia surfaces. PMID- 25799284 TI - A method of temporarily preserving the emergence profile in implant dentistry. PMID- 25799285 TI - A technique to transfer the contours of an interim implant restoration to the definitive cast. AB - Achieving proper soft tissue contours with implant restorations is important for successful esthetic outcomes, particularly in the anterior region. In some situations, clinicians may not be able to deliver interim restorations for proper gingival contouring immediately after implant placement or at the uncovering session, but only at the definitive impression session. The described technique allows clinicians to transfer the soft tissue contours of an interim implant restoration to the definitive cast at the definitive impression session for the fabrication of definitive restorations. This technique may prevent irregular soft tissue contours around definitive restorations at the placement session, thereby reducing the number of appointments. PMID- 25799286 TI - Isorhamnetin attenuates atherosclerosis by inhibiting macrophage apoptosis via PI3K/AKT activation and HO-1 induction. AB - BACKGROUND AND PURPOSE: Isorhamnetin (Iso) is a flavonoid compound extracted from the Chinese herb Hippophae rhamnoides L. Previous studies have revealed its anti cancer, anti-inflammatory, and anti-oxidant activities. This study investigated the ability of Iso to inhibit oxidized low-density lipoprotein (ox-LDL)-induced cell apoptosis in THP-1-derived macrophages. The effects of Iso on atherosclerosis in vivo were also evaluated in apolipoprotein E knockout (ApoE-/ ) mice fed a high fat diet. METHODS AND RESULTS: Iso showed significant inhibitory effects on ox-LDL-induced THP-1-derived macrophage injuries via decreasing reactive oxygen species levels, lipid deposition, and caspase-3 activation, restoring mitochondrial membrane potential, reducing the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) positive cells, and regulating apoptosis-related proteins. We also determined the protective effects of Iso by PI3K/AKT activation and HO-1 induction. Iso reduced the atherosclerotic plaque size in vivo in ApoE-/- mice as assessed by oil red O, Sudan IV staining, and CD68-positive cells, and reduced macrophage apoptosis as assessed by caspase-3 and TUNEL assays in lesions. CONCLUSION: In conclusion, our results show that Iso inhibited atherosclerotic plaque development in ApoE-/- mice by PI3K/AKT activation and HO-1 induction. PMID- 25799288 TI - [Assessment of patient-education on obstetric epidural analgesia received in the third quarter of pregnancy]. PMID- 25799289 TI - Analysis of the temporal regression of the QRS widening induced by bupivacaine after Intralipid administration. Study in an experimental porcine model. AB - OBJECTIVE: The principal mechanism of cardiac toxicity of bupivacaine relates to the blockade of myocardial sodium channels, which leads to an increase in the QRS duration. Recently, experimental studies suggest that lipid emulsion is effective in reversing bupivacaine cardiac toxicity. We aimed to evaluate the temporal evolution of the QRS widening induced by bupivacaine with the administration of Intralipid. MATERIAL AND METHODS: Twelve pigs were anesthetized with intravenous sodium thiopental 5mg kg(-1) and sevoflurane 1 MAC (2.6%). Femoral artery and vein were canalized for invasive monitoring, analysis of blood gases and determination of bupivacaine levels. After instrumentation and monitoring, a bupivacaine bolus of 4-6 mg kg(-1) was administered in order to induce a 150% increase in QRS duration (defined as the toxic point). The pigs were randomized into two groups of six individuals. Intralipid group (IL) received 1.5 mL kg( 1)of IL over one minute, followed by an infusion of 0.25 mL kg min(-1). Control group (C) received the same volume of a saline solution. The electrocardiographic parameters were recorded, and blood samples were taken after bupivacaine and 1, 5, 10 and 30 minutes after Intralipid/saline administration. RESULTS: Bupivacaine (4.33+/-0.81 mg/kg in IL group and 4.66+/-1.15 mg/kg in C group) induced similar electrocardiographic changes in both groups; mean maximal percent increase in QRS interval was 184+/-62% in IL group, and 230+/-56% in control group (NS). Lipid administration reversed the QRS widening previously impaired by bupivacaine. After ten minutes of the administration of IL, the mean QRS interval decreased to 132+/-56% vs. 15+/-76% relative to the maximum widening induced by bupivacaine, in IL and C group, respectively. CONCLUSION: Intralipid reversed the lengthening of QRS interval induced by the injection of bupivacaine. Time to normalization of electrocardiographic parameters can last more than 10 minutes. While the phenomena of cardiac toxicity persist, resuscitation measures and adequate monitoring should be continued until adequate heart conduction parameters are restored. PMID- 25799287 TI - Catheter-based ultrasound technology for image-guided thermal therapy: current technology and applications. AB - Catheter-based ultrasound (CBUS) is applied to deliver minimally invasive thermal therapy to solid cancer tumours, benign tissue growth, vascular disease, and tissue remodelling. Compared to other energy modalities used in catheter-based surgical interventions, unique features of ultrasound result in conformable and precise energy delivery with high selectivity, fast treatment times, and larger treatment volumes. We present a concise review of CBUS technology being currently utilized in animal and clinical studies or being developed for future applications. CBUS devices have been categorised into interstitial, endoluminal and endovascular/cardiac applications. Basic applicator designs, site-specific evaluations and possible treatment applications have been discussed in brief. Particular emphasis has been given to ablation studies that incorporate image guidance for applicator placement, therapy monitoring, feedback control, and post procedure assessment. Examples of devices included here span the entire spectrum of the development cycle from preliminary simulation-based design studies to implementation in clinical investigations. The use of CBUS under image guidance has the potential for significantly improving precision and applicability of thermal therapy delivery. PMID- 25799290 TI - Subpleural artifact in lung pulse evidenced by M-mode ultrasound in a patient with atelectasis. PMID- 25799291 TI - Maize varieties released in different eras have similar root length density distributions in the soil, which are negatively correlated with local concentrations of soil mineral nitrogen. AB - Larger, and deeper, root systems of new maize varieties, compared to older varieties, are thought to have enabled improved acquisition of soil resources and, consequently, greater grain yields. To compare the spatial distributions of the root systems of new and old maize varieties and their relationships with spatial variations in soil concentrations of available nitrogen (N), phosphorus (P) and potassium (K), two years of field experiments were performed using six Chinese maize varieties released in different eras. Vertical distributions of roots, and available N, P and K in the 0-60 cm soil profile were determined in excavated soil monoliths at silking and maturity. The results demonstrated that new maize varieties had larger root dry weight, higher grain yield and greater nutrient accumulation than older varieties. All varieties had similar total root length and vertical root distribution at silking, but newer varieties maintained greater total root length and had more roots in the 30-60 cm soil layers at maturity. The spatial variation of soil mineral N (Nmin) in each soil horizon was larger than that of Olsen-P and ammonium-acetate-extractable K, and was inversely correlated with root length density (RLD), especially in the 0-20 cm soil layer. It was concluded that greater acquisition of mineral nutrients and higher yields of newer varieties were associated with greater total root length at maturity. The negative relationship between RLD and soil Nmin at harvest for all varieties suggests the importance of the spatial distribution of the root system for N uptake by maize. PMID- 25799292 TI - Serotonin Modulation of Prefronto-Hippocampal Rhythms in Health and Disease. AB - There is mounting evidence that most cognitive functions depend upon the coordinated activity of neuronal networks often located far from each other in the brain. Ensembles of neurons synchronize their activity, generating oscillations at different frequencies that may encode behavior by allowing an efficient communication between brain areas. The serotonin system, by virtue of the widespread arborisation of serotonergic neurons, is in an excellent position to exert strong modulatory actions on brain rhythms. These include specific oscillatory activities in the prefrontal cortex and the hippocampus, two brain areas essential for many higher-order cognitive functions. Psychiatric patients show abnormal oscillatory activities in these areas, notably patients with schizophrenia who display psychotic symptoms as well as affective and cognitive impairments. Synchronization of neural activity between the prefrontal cortex and the hippocampus seems to be important for cognition and, in fact, reduced prefronto-hippocampal synchrony has been observed in a genetic mouse model of schizophrenia. Here, we review recent advances in the field of neuromodulation of brain rhythms by serotonin, focusing on the actions of serotonin in the prefrontal cortex and the hippocampus. Considering that the serotonergic system plays a crucial role in cognition and mood and is a target of many psychiatric treatments, it is surprising that this field of research is still in its infancy. In that regard, we point to future investigations that are much needed in this field. PMID- 25799293 TI - When data sharing gets close to 100%: what human paleogenetics can teach the open science movement. AB - This study analyzes data sharing regarding mitochondrial, Y chromosomal and autosomal polymorphisms in a total of 162 papers on ancient human DNA published between 1988 and 2013. The estimated sharing rate was not far from totality (97.6% +/- 2.1%) and substantially higher than observed in other fields of genetic research (evolutionary, medical and forensic genetics). Both a questionnaire-based survey and the examination of Journals' editorial policies suggest that this high sharing rate cannot be simply explained by the need to comply with stakeholders requests. Most data were made available through body text, but the use of primary databases increased in coincidence with the introduction of complete mitochondrial and next-generation sequencing methods. Our study highlights three important aspects. First, our results imply that researchers' awareness of the importance of openness and transparency for scientific progress may complement stakeholders' policies in achieving very high sharing rates. Second, widespread data sharing does not necessarily coincide with a prevalent use of practices which maximize data findability, accessibility, useability and preservation. A detailed look at the different ways in which data are released can be very useful to detect failures to adopt the best sharing modalities and understand how to correct them. Third and finally, the case of human paleogenetics tells us that a widespread awareness of the importance of Open Science may be important to build reliable scientific practices even in the presence of complex experimental challenges. PMID- 25799295 TI - The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on peroral endoscopic myotomy. PMID- 25799296 TI - The role of different stigma perceptions in treatment seeking and dropout among active duty military personnel. AB - OBJECTIVE: Many military personnel with mental health problems do not seek treatment from mental health professionals, and if they do seek treatment, they drop out of treatment before receiving the recommended number of sessions. The present study examined the role of 4 different stigma perceptions on these outcomes: perceived stigma to career, perceived stigma of differential treatment, self-stigma from seeking treatment, and stigmatizing perceptions of soldiers who seek treatment. METHOD: One thousand three hundred twenty-four active duty soldiers completed a self-report survey assessment that included measures of the 4 different stigma perceptions, indices of mental health symptoms, receipt of mental health treatment, and whether they had dropped out of treatment before it was completed. RESULTS: Participants screening positive for a mental health problem reported higher scores on all 4 stigma perceptions. All 4 stigma perceptions were each associated with a reduced likelihood of treatment seeking when considered individually, but only stigmatizing beliefs about those who seek treatment were uniquely associated with treatment seeking. Perceived stigma for one's career and differential treatment from others, along with self-stigma from treatment seeking, were associated with an increased probability of dropping out of mental health treatment. Self-stigma from treatment seeking was the only unique predictor of dropout. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Different stigma perceptions were associated with treatment seeking and dropout. Further longitudinal research is needed to examine how stigma perceptions influence these important outcomes. Practitioners need to be aware of how different stigma perceptions can influence treatment seeking and potentially target stigma perceptions during treatment to prevent dropout. PMID- 25799297 TI - Retrospective accounts of self-stigma experienced by young people with attention deficit/hyperactivity disorder (ADHD) or depression. AB - OBJECTIVE: Little is known about self-stigma experienced by young people with mental health problems, despite the fact that research has demonstrated its existence. In the present study, we sought to investigate the experiences of self stigma in childhood and adolescence, and particularly the nature of change in self-stigma across this developmental period. Young adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) or depression before their 18th birthdays were interviewed about their experiences within their peer groups during childhood and adolescence. METHODS: This qualitative study involved open ended interviews with 16 young adults aged 18-30 years. Interviews focused on the experience of stigmatization, responses to stigma, and how these changed over time. RESULTS: Three main themes pertaining to self-stigma emerged: (a) being different, (b) peer stigmatization and associated experiences of self-stigma, and (c) selective disclosure and a move toward greater openness. The findings also suggested that the passing of time and changes in young people's social networks and/or degrees of recovery were associated with changes in their experiences of self-stigma. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: During childhood and adolescence, self-stigma is characterized by a sense of being different from peers and negative self-evaluation as a consequence of that difference. However, our findings also demonstrated that some young people were prepared to challenge the stigma they experienced. Further research is needed to understand the factors that contribute to these differing responses and to develop antistigma interventions that facilitate the inclusion of young people with mental health problems in their peer groups. PMID- 25799298 TI - The relationship between stigma sentiments and self-identity of individuals with schizophrenia. AB - OBJECTIVE: Stigma sentiments are the attitudes held toward a culturally devalued label or group. The present study measures schizophrenia stigma sentiments and self-identity to assess self-stigma experienced by people with schizophrenia. METHOD: Ninety individuals with schizophrenia and 23 controls with no history of psychosis rated the evaluation, potency, and activity of "A person with schizophrenia or schizoaffective disorder," (stigma sentiments) and of "Myself as I really am" (self-identity). t tests, correlations, and regression analysis were used to (a) test relationships among stigma sentiments and self-identity in the groups separately; (b) test a model for predicting self-identity in the schizophrenia group, using stigma sentiments, current symptoms, and current functioning; and (c) compare the participant groups' stigma sentiments and self identities. RESULTS: The evaluation category of self-identity and of stigma sentiment were correlated in the schizophrenia group, r(88) = .44, p < .001, but not in the control group. Current symptoms and the evaluation category of stigma sentiments were significant predictors of the evaluation category of self identity in the schizophrenia group. The evaluation and potency stigma sentiments reported by the 2 groups did not differ; the control group rated itself more favorably on evaluation and potency than did the schizophrenia group. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Self-evaluation of individuals with schizophrenia was less favorable than self-evaluation of individuals with no psychosis history, and evaluation attitudes held by individuals with schizophrenia regarding the schizophrenia label were associated with their self-identity. Results suggest preliminary utility of this simple measure in identifying self-stigma experienced by individuals with schizophrenia. PMID- 25799299 TI - The companion project: Recovery among volunteer peer support providers in South Korea. AB - OBJECTIVE: This article explores the benefits of recovery among volunteer peer providers who participated in The Companion Project-the first peer-delivered mental health services project in South Korea. METHOD: The effect of the program on the recovery and symptoms of peer providers (N = 31) was quantitatively analyzed using a nonequivalent control group design. A subset of 12 participants was interviewed on the perceived recovery benefits. RESULTS: Results of the statistical analysis indicated that peer support activities affected the recovery and symptoms of peer providers. Through in-depth interviews, the following themes were identified: self-awareness and redefinition, growth through participation and role-taking, and new potential and hope. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Peer providers experienced the benefits of recovery through relationships with peers and meaningful roles. These results contribute to an expansion of peer support in Korea and the development of new jobs for people with psychiatric disabilities. PMID- 25799300 TI - Prediction of changes in self-stigma among veterans participating in partial psychiatric hospitalization: The role of disability status and military cohort. AB - OBJECTIVE: Interventions addressing internalized stigma are a new area of research, and it is important to identify the types of clientele who derive benefit from existing interventions. METHOD: Information was provided by 235 veterans attending a partial psychiatric hospitalization program, regarding their levels of internalized stigma on admission and discharge from a 3-week program that included interventions targeting internalized stigma. RESULTS: Upon discharge, veterans receiving disability benefits demonstrated less reduction in internalized stigma than those not receiving disability benefits. Time of service moderated the relationship between disability status and change in internalized stigma, such that veterans serving in the more recent Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) cohort who received disability benefits had a more difficult time resolving internalized stigma. Further analyses suggested that OEF/OIF/OND cohort veterans receiving disability benefits have more difficulty developing effective stigma resistance, and more difficulty resolving stigma-related alienation, than other veterans. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Based on this research, particular attention should be devoted to internalized stigma among OEF/OIF/OND veterans. PMID- 25799301 TI - Co-occurring substance use and mental disorders in the criminal justice system: a new frontier of clinical practice and research. AB - This editorial introduces this special section of the Psychiatric Rehabilitation Journal, which focuses on justice-involved persons with co-occurring mental and substance use disorders (CODs). It contains seven original articles examining CODs among justice-involved populations that vary by gender, age, setting (e.g., community/ court, jail, prison), environment (urban, rural), geographic region, and nationality. (PsycINFO Database Record PMID- 25799302 TI - Behavioral health treatment history among persons in the justice system: Findings from the Arrestee Drug Abuse Monitoring II Program. AB - OBJECTIVE: Despite the high prevalence of substance use disorders, mental disorders, and co-occurring disorders among persons in the justice system, there is a fairly low rate of treatment utilization among this population. This study explored rates of lifetime behavioral health treatment utilization and factors associated with involvement in treatment. METHODS: The study examined data from the Arrestee Drug Abuse Monitoring II program from 2007 to 2010, including over 18,000 arrestees in 10 U.S. metropolitan jails. Logistic regression and chi2 analyses were used to explore the relationship between self-reported lifetime treatment history and sociodemographic characteristics, self-reported substance use, and severity of substance use. RESULTS: Over half of arrestees reported no history of behavioral health treatment (62%), and Caucasians were significantly more likely to have received treatment than African Americans and Hispanics. Rates of treatment for substance use disorders or for both substance use and mental disorders were lowest among arrestees reporting marijuana and alcohol use and highest for heroin users. Methamphetamine users were the most likely to have received prior mental health treatment. Severity of alcohol and drug use was the highest among arrestees who had received both substance abuse and mental health treatment. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Considering the high rates of mental and substance use disorders in this population, the overall lack of behavioral health service utilization among offenders is concerning and points to the need to engage offenders in mental health and substance abuse treatment and to expand these services in jails, prisons, diversionary programs, and community corrections settings. (PsycINFO Database Record PMID- 25799303 TI - Co-occurring mental illness, substance use disorders, and antisocial personality disorder among clients of forensic mental health services. AB - OBJECTIVE: Despite the number of studies investigating co-occurring disorders, and more recently, co-occurring disorders and criminal offending, few studies have considered samples from forensic mental health services. The present study was conducted to investigate the relationship between mental illness, substance use disorders, antisocial personality disorder, and offending. METHOD: The prevalence of co-occurring disorders was investigated in 130 male offenders who had contact with the statewide forensic mental health service in Victoria, Australia. Offense histories and severity of offending were compared among participants diagnosed with a single mental illness (or no mental illness), co occurring mental illness and substance use, and co-occurring disorders plus antisocial personality disorder. RESULTS: The majority of participants had co occurring mental and substance use disorders; a significant minority met the criteria for antisocial personality disorder. Participants with co-occurring mental illness and substance use disorders, and those who had an additional diagnosis of antisocial personality disorder, were responsible for more serious and frequent offending than those with mental illness alone. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Forensic mental health services must take into account the effect that co-occurring disorders have on clients' functioning and offending. Those who work with people with psychiatric disabilities and co occurring substance use disorders must ensure that the substance disorders are addressed to help ensure recovery from the mental illness and to reduce the likelihood of offending. (PsycINFO Database Record PMID- 25799304 TI - Comorbidity among female detainees in drug treatment: an exploration of internalizing and externalizing disorders. AB - OBJECTIVE: The current study explored the prevalence and comorbidity of major internalizing and externalizing psychiatric disorders in a sample of female detainees participating in drug treatment programs in the nation's largest single site jail, the Cook County (Chicago) Department of Corrections. METHODS: A total of 253 women participated in a Needs Inventory. The study incorporated an extensive combination of measures, which captured the women's demographic characteristics and psychological problems as well as their substance use and drug treatment histories and their criminal thinking tendencies. For the purpose of analyses, women were combined into 3 groups: women with substance use problems but no comorbid psychiatric disorders, women with 1 comorbid psychiatric disorder (either internalizing or externalizing), and women with both internalizing and externalizing disorders. RESULTS: More than 3/4 of the women were comorbid for another psychiatric (an internalizing or externalizing) disorder. Comorbid disorders were related to lower self-esteem, greater drug use severity, and higher levels of criminal thinking. For example, measures of reported histories of criminal activities and trauma exposure increased with comorbidity. The most critical variables in differentiating between female detainees with no and both internalizing and externalizing disorders were criminal thinking and exposure to trauma. CONCLUSIONS: The women in the present investigation and other female detainees in drug treatment programs require interventions that focus on both criminal and psychiatric recidivism. These interventions are most effectively delivered in a person-focused recovery framework that provides integrated modules of services. (PsycINFO Database Record PMID- 25799305 TI - An exploratory study of mental health and HIV risk behavior among drug-using rural women in jail. AB - OBJECTIVE: Rural women, particularly those in the criminal justice system, are at risk for HIV related to the increasing prevalence of injection drug use as well as limited services. Research on HIV risk correlates, including drug use and mental health, has primarily focused on urban women incarcerated in prisons. The purpose of this exploratory study is to examine dual HIV risk by 3 different mental health problems (depression, anxiety, and posttraumatic stress disorder [PTSD]) among drug-using women in rural jails. METHOD: This study involved random selection, screening, and face-to-face interviews with 136 women in 1 Appalachian state. Analyses focused on the relationship between mental health and HIV risk. RESULTS: Nearly 80% of women self-reported symptoms of depression, and more than 60% endorsed symptoms consistent with anxiety and PTSD symptoms. Mental health significantly correlated with severity of certain types of drug use, as well as risky sexual activity. In addition, for women experiencing anxiety and PTSD, injection drug use moderated the relationship between mental health and risky sexual activity. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Based on these rates of drug use, mental health problems, and the emergence of injection drug use in rural Appalachia, the need to explore the relationships between these issues among vulnerable and understudied populations, such as rural women, is critical. Because of service limitations in rural communities, criminal justice venues such as jails provide opportune settings for screening, assessment, and intervention for drug use, mental health, and HIV education and prevention. (PsycINFO Database Record PMID- 25799307 TI - Education and training column: the learning collaborative. AB - TOPIC: This column describes the key components of a learning collaborative, with examples from the experience of 1 organization. PURPOSE: A learning collaborative is a method for management, learning, and improvement of products or processes, and is a useful approach to implementation of a new service design or approach. SOURCES USED: This description draws from published material on learning collaboratives and the authors' experiences. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The learning collaborative approach offers an effective method to improve service provider skills, provide support, and structure environments to result in lasting change for people using behavioral health services. This approach is consistent with psychiatric rehabilitation principles and practices, and serves to increase the overall capacity of the mental health system by structuring a process for discovering and sharing knowledge and expertise across provider agencies. (PsycINFO Database Record PMID- 25799306 TI - The efficacy of two adolescent substance abuse treatments and the impact of comorbid depression: results of a small randomized controlled trial. AB - OBJECTIVE: The purpose of this randomized trial was to investigate the efficacy of 2 behavioral treatments focusing on different change mechanisms in ameliorating a borderline personality disorder constellation of behaviors and substance use in adolescents referred by juvenile diversion programs. METHODS: Forty adolescents 14-17 years of age and meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria for borderline personality disorder and substance use disorders were randomized to integrative borderline personality disorder-oriented adolescent family therapy (I-BAFT) or individual drug counseling. This design allowed a comparison of 2 manualized interventions, 1 family based and 1 individually oriented. Profiles of clinical change were used to detect impact and estimate treatment effect sizes. RESULTS: Primary analyses showed that both interventions had a clinically significant impact on borderline personality disorder behaviors 12 months after baseline but with no differential treatment effects. The impact on substance use was more complex. Subgroup analyses revealed that adolescents with depression had significantly more severe profiles of borderline personality disorder and substance use. These youths were the only group to show reductions in substance use, but they only did so if they received the I-BAFT intervention. Study data also documented the high dosage of intensive residential treatment needed by this population. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Results highlight the intensive treatment needs of juvenile justice-involved youths with co-occurring substance use and borderline personality disorder including depression, the hybrid outpatient and residential treatment often required by this population, and the promise of a family-oriented approach, particularly for youths with severe symptoms and co-occurring depression. (PsycINFO Database Record PMID- 25799308 TI - Effect of Primary Care-Based Education on Reassurance in Patients With Acute Low Back Pain: Systematic Review and Meta-analysis. AB - IMPORTANCE: Reassurance is a core aspect of daily medical practice, yet little is known on how it can be achieved. OBJECTIVE: To determine whether patient education in primary care increases reassurance in patients with acute or subacute low back pain (LBP). DATA SOURCES: Medline, EMBASE, Cochrane Central Register for Controlled Trials, and PsychINFO databases were searched to June 2014. DESIGN: Systematic review and meta-analysis of randomized and nonrandomized clinical trials. STUDY SELECTION: To be eligible, studies needed to be controlled trials of patient education for LBP that were delivered in primary care and measured reassurance after the intervention. Eligibility criteria were applied, and studies were selected by 2 independent authors. MAIN OUTCOMES AND MEASURES: The primary outcomes were reassurance in the short and long term and health care utilization at 12 months. DATA EXTRACTION AND SYNTHESIS: Data were extracted by 2 independent authors and entered into a standardized form. A random-effects meta analysis tested the effects of patient education compared with usual care on measures of reassurance. To investigate the effect of study characteristics, we performed a preplanned subgroup analysis. Studies were stratified according to duration, content, and provider of patient education. RESULTS: We included 14 trials (n=4872) of patient education interventions. Trials assessed reassurance with questionnaires of fear, worry, anxiety, catastrophization, and health care utilization. There is moderate- to high-quality evidence that patient education increases reassurance more than usual care/control education in the short term (standardized mean difference [SMD], -0.21; 95% CI, -0.35 to -0.06) and long term (SMD, -0.15; 95% CI, -0.27 to -0.03). Interventions delivered by physicians were significantly more reassuring than those delivered by other primary care practitioners (eg, physiotherapist or nurse). There is moderate-quality evidence that patient education reduces LBP-related primary care visits more than usual care/control education (SMD, -0.14; 95% CI, -0.28 to -0.00 at a 12-month follow up). The number needed to treat to prevent 1 LBP-related visit to primary care was 17. CONCLUSIONS AND RELEVANCE: There is moderate- to high-quality evidence that patient education in primary care can provide long-term reassurance for patients with acute or subacute LBP. PMID- 25799309 TI - Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism. AB - Hepatic expression profiling has revealed miRNA changes in liver diseases, while hepatic miR-155 expression was increased in murine non-alcoholic fatty liver disease, suggesting that miR-155 might regulate the biological process of lipid metabolism. To illustrate the effects of miR-155 gain of function in transgenic mouse liver on lipid metabolism, transgenic mice (i.e., Rm155LG mice) for the conditional overexpression of mouse miR-155 transgene mediated by Cre/lox P system were firstly generated around the world in this study. Rm155LG mice were further crossed to Alb-Cre mice to realize the liver-specific overexpression of miR-155 transgene in Rm155LG/Alb-Cre double transgenic mice which showed the unaltered body weight, liver weight, epididymal fat pad weight and gross morphology and appearance of liver. Furthermore, liver-specific overexpression of miR-155 transgene resulted in significantly reduced levels of serum total cholesterol, triglycerides (TG) and high-density lipoprotein (HDL), as well as remarkably decreased contents of hepatic lipid, TG, HDL and free fatty acid in Rm155LG/Alb-Cre transgenic mice. More importantly, microarray data revealed a general downward trend in the expression profile of hepatic genes with functions typically associated with fatty acid, cholesterol and triglyceride metabolism, which is likely at least partially responsible for serum cholesterol and triglyceride lowering observed in Rm155LG/Alb-Cre mice. In this study, we demonstrated that hepatic overexpression of miR-155 alleviated nonalcoholic fatty liver induced by a high-fat diet. Additionally, carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) was identified as a direct miR-155 target gene that is potentially responsible for the partial liver phenotypes observed in Rm155LG/Alb-Cre mice. Taken together, these data from miR-155 gain of function study suggest, for what we believe is the first time, the altered lipid metabolism and provide new insights into the metabolic state of the liver in Rm155LG/Alb-Cre mice. PMID- 25799310 TI - Abnormality of the corpus callosum in coalmine gas explosion-related posttraumatic stress disorder. AB - Abnormal corpus callosum (CC) has been reported in childhood trauma-related posttraumatic stress disorder (PTSD); however, the nature of white matter (WM) integrity alterations in the CC of young adult-onset PTSD patients is unknown. In this study, 14 victims of a coal mine gas explosion with PTSD and 23 matched coal miners without experiencing the coal mine explosion were enrolled. The differences in fractional anisotropy (FA) within 7 sub-regions of the CC were compared between the two groups. Compared to the controls, PTSD coal miners exhibited significantly reduced FA values in the anterior sub-regions of the CC (P < 0.05, Bonferroni-corrected), which mainly interconnect the bilateral frontal cortices. Our findings indicated that the anterior part of the CC was more severely impaired than the posterior part in young adult-onset PTSD, which suggested the patterns of CC impairment may depend on the developmental stage of the structure when the PTSD occurs. PMID- 25799312 TI - Phosphine-catalyzed highly enantioselective [3 + 3] cycloaddition of Morita Baylis-Hillman carbonates with C,N-cyclic azomethine imines. AB - The first phosphine-catalyzed highly enantioselective [3 + 3] cycloaddition of Morita-Baylis-Hillman carbonates with C,N-cyclic azomethine imines is described. Using a spirocyclic chiral phosphine as the catalyst, a novel class of pharmaceutically interesting 4,6,7,11b-tetrahydro-1H-pyridazino[6,1-a]iso quinoline derivatives were obtained in high yields with good to excellent diastereoselectivities and extremely excellent enantioselectivities (98->99% ee). PMID- 25799311 TI - Shared dosimetry error in epidemiological dose-response analyses. AB - Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope beta is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of beta) is biased for beta?0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed. PMID- 25799313 TI - QT variability improves risk stratification in patients with dilated cardiomyopathy. AB - Recently it could be demonstrated that systolic and diastolic blood pressure variability (BPV) as well as segmented Poincare plot analysis (SPPA) contribute to risk stratification in patients suffering from dilated cardiomyopathy (DCM). The aim of this study was to improve the risk stratification applying a multivariate technique including QT variability (QTV). We enrolled and significantly separated 56 low risk and 13 high risk DCM patients by nearly all applied BPV and QTV methods, but not with traditional heart rate variability analysis. The optimum set of two indices calculating the multivariate discriminate analysis (DA) included one BPV index calculated by symbolic dynamics method (DBP(Shannon)) and one index calculated from QTV (QTV(log)) achieving an area under the receiver operating characteristics curve (AUC) of 92%, sensitivity of 92.3% and specificity of 89.3%. Performing only electrocardiogram analysis, the optimum multivariate approach including indices from segmented Poincare plot analysis and QTV still achieved a remarkable AUC of 88.3%. Increasing the number of indices for multivariate DA up to three, we achieved an AUC of 95.7%, sensitivity of 100% and specificity of 85.7% including one clinical, one BPV and one QTV index. Summarizing, we identified DCM patients with an increased risk of sudden cardiac death applying QTV analysis in a multivariate approach. PMID- 25799314 TI - The phi6 cystovirus protein P7 becomes accessible to antibodies in the transcribing nucleocapsid: a probe for viral structural elements. AB - Protein P7 is a component of the cystovirus viral polymerase complex. In the unpackaged procapsid, the protein is situated in close proximity to the viral directed RNA polymerase, P2. Cryo-electron microscopy difference maps from the species phi6 procapsid have demonstrated that P7 and P2 likely interact prior to viral RNA packaging. The location of P7 in the post-packaged nucleocapsid (NC) remains unknown. P7 may translocate closer to the five-fold axis of a filled procapsid but this has not been directly visualized. We propose that monoclonal antibodies (Mabs) can be selected that serve as probe- reagents for viral assembly and structure. A set of Mabs have been isolated that recognize and bind to the phi6 P7. The antibody set contains five unique Mabs, four of which recognize a linear epitope and one which recognizes a conformational epitope. The four unique Mabs that recognize a linear epitope display restricted utilization of Vkappa and VH genes. The restricted genetic range among 4 of the 5 antibodies implies that the antibody repertoire is limited. The limitation could be the consequence of a paucity of exposed antigenic sites on the phi6 P7 surface. It is further demonstrated that within phi6 nucleocapsids that are primed for early phase transcription, P7 is partially accessible to the Mabs, indicating that the nucleocapsid shell (protein P8) has undergone partial disassembly exposing the protein's antigenic sites. PMID- 25799315 TI - Development of microbeads of chicken yolk antibodies against Clostridium difficile toxin A for colonic-specific delivery. AB - The incidence of Clostridium difficile infection has increased in Western world in the past 10 years, similar infection rates are also reported in developing countries such as China. Current antibiotics treatments have recurrence rates between 15% and 30%. IgY antibodies against toxin A of C. difficile could protect animal models from the challenge of lethal dose of C. difficile spores. However, IgY is sensitive to the low pH environment of the stomach and proteinases in the intestine. The objective of this study was to prepare colonic-specific delivery system of toxin A antigen-specific IgY to block the recognition of toxin A to the colon mucosa cells. Egg-laying hens were immunized with purified C. difficile toxin A C-terminal domain for 3 times, then egg IgY against the recombinant ToxA C protein was purified from immunized egg yolk and frozen dried. IgY-loaded microbeads were prepared using mini fluid bed system; the loading efficiency was 21%. The pH and temperature stabilities of the microbeads were assayed. The IgY loaded microbeads coated with 35% Eudragit S100 had colonic-specific IgY release specificity both in vitro and in vivo, the colonic-specific release of biological active IgY was 87.5% in the rat. Our study provides a new option for the biological treatment C. difficile infection. PMID- 25799316 TI - Chalcogen extrusion from heteroallenes and carbon monoxide by a three-coordinate rh(i) disilylamide. AB - We report the reactions of several heteroallenes (carbon disulfide, carbonyl sulfide, and phenyl isocyanate) and carbon monoxide with a three-coordinate, bis(phosphine)-supported Rh(I) disilylamide (1). Carbon disulfide reacts with 1 to afford a silyltrithiocarbonate complex similar to an intermediate previously invoked in the deoxygenation of CO2 by 1, and prolonged heating affords a structurally unusual MU-kappa(2)(S,S'):kappa(2)(S,S')-trithiocarbonate dimer. Carbonyl sulfide reacts with 1 to afford a structurally unique Rh(SCNCS) metallacycle derived from two insertions of OCS and N-to-O silyl-group migrations. Phenyl isocyanate reacts with 1 to afford a dimeric bis(phenylcyanamido)-bridged complex resulting from multiple silyl-group migrations and nitrogen-for-oxygen metathesis, akin to reactivity previously observed with carbon dioxide. The ability of 1 to activate carbon-chalcogen multiple bonds via silyl-group migration is further supported by its reactivity with carbon monoxide, where a nitrogen-for-oxygen metathesis is also observed with expulsion of hexamethyldisiloxane. For all reported reactions, intermediates are observable under appropriate conditions, allowing the formulation of mechanisms where insertion of the unsaturated substrate is followed by one or more silyl-group migrations to afford the observed products. This rich variety of reactivity confirms the ability of metal silylamides to activate exceptionally strong carbon-element multiple bonds and suggests that silylamides may be useful intermediates in nitrogen-atom and nitrene-group-transfer schemes. PMID- 25799317 TI - LTA4H genotype is associated with susceptibility to bacterial meningitis but is not a critical determinant of outcome. AB - Adjunctive dexamethasone saves lives in the treatment of tuberculous meningitis but this response is influenced by the patient's LTA4H genotype. Despite less certain benefit, adjunctive dexamethasone is also frequently used in the treatment of pyogenic bacterial meningitis, but the influence of LTA4H genotype on outcomes has not been previously investigated. We genotyped the LTA4H promoter region SNP (rs17525495) in 390 bacterial meningitis patients and 751 population controls. rs17525495 was associated with susceptibility to bacteriologically confirmed bacterial meningitis (P = 0.01, OR 1.27 95% confidence interval [CI] 1.05-1.54) but did not influence clinical presentation, disease severity or survival following dexamethasone treatment. PMID- 25799318 TI - Long-term sequelae of severe acute kidney injury in the critically ill patient without comorbidity: a retrospective cohort study. AB - BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) necessitating renal replacement therapy (RRT) is associated with high mortality and increased risk for end stage renal disease. However, it is unknown if this applies to patients with a preliminary unremarkable medical history. The purpose of this study was to describe overall and renal survival in critically ill patients with AKI necessitating RRT stratified by the presence of comorbidity. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A retrospective cohort study was performed, between 1994 and 2010, including all adult critically ill patients with AKI necessitating RRT, stratified by the presence of comorbidity. Logistic regression, survival curve and cox proportional hazards analyses were used to evaluate overall and renal survival. Standardized mortality rate (SMR) analysis was performed to compare long-term survival to the predicted survival in the Dutch population. RESULTS: Of the 1067 patients included only 96(9.0%) had no comorbidity. Hospital mortality was 56.6% versus 43.8% in patients with and without comorbidity, respectively. In those who survived hospitalization 10-year survival was 45.0% and 86.0%, respectively. Adjusted for age, sex and year of treatment, absence of comorbidity was not associated with hospital mortality (OR=0.74, 95%-CI=0.47-1.15), while absence of comorbidity was associated with better long-term survival (adjusted HR=0.28, 95%-CI = 0.14-0.58). Compared to the Dutch population, patients without comorbidity had a similar mortality risk (SMR=1.6, 95%-CI=0.7-3.2), while this was increased in patients with comorbidity (SMR=4.8, 95%-CI=4.1-5.5). Regarding chronic dialysis dependency, 10-year renal survival rates were 76.0% and 92.9% in patients with and without comorbidity, respectively. Absence of comorbidity was associated with better renal survival (adjusted HR=0.24, 95%-CI=0.07-0.76). CONCLUSIONS: While hospital mortality remains excessively high, the absence of comorbidity in critically ill patients with RRT-requiring AKI is associated with a relative good long-term prognosis in those who survive hospitalization. PMID- 25799320 TI - Preparation and characterization of Fe3O4 particles with novel nanosheets morphology and magnetochromatic property by a modified solvothermal method. AB - Novel-morphological Fe3O4 nanosheets with magnetochromatic property have been prepared by a modified solvothermal method. Such nanosheets could form one dimension photonic crystal under an external magnetic field. The Fe3O4 nanosheets suspension could strongly diffract visible light and display varied colors with changing the intensity of the magnetic field. The photonic response is rapid, fully reversible and widely tunable in the entire visible spectrum. Excellent magnetic properties of these Fe3O4 nanosheets are exhibited with a high saturation magnetization (82.1 emu/g), low remanence (13.85 emu/g) and low coercive force (75.95 Oe). The amount of the solvent diethylene glycol (DEG) plays a key role in the formation of the sheet-shaped morphology. When the ratio of the DEG reaches 100%, the growing of the crystal plane (111) of Fe3O4 is inhibited and the sheet-like Fe3O4 crystals are formed. PMID- 25799319 TI - Inverse thio effects in the hepatitis delta virus ribozyme reveal that the reaction pathway is controlled by metal ion charge density. AB - The hepatitis delta virus (HDV) ribozyme self-cleaves in the presence of a wide range of monovalent and divalent ions. Prior theoretical studies provided evidence that self-cleavage proceeds via a concerted or stepwise pathway, with the outcome dictated by the valency of the metal ion. In the present study, we measure stereospecific thio effects at the nonbridging oxygens of the scissile phosphate under a wide range of experimental conditions, including varying concentrations of diverse monovalent and divalent ions, and combine these with quantum mechanical/molecular mechanical (QM/MM) free energy simulations on the stereospecific thio substrates. The RP substrate gives large normal thio effects in the presence of all monovalent ions. The SP substrate also gives normal or no thio effects, but only for smaller monovalent and divalent cations, such as Li(+), Mg(2+), Ca(2+), and Sr(2+); in contrast, sizable inverse thio effects are found for larger monovalent and divalent cations, including Na(+), K(+), NH4(+), and Ba(2+). Proton inventories are found to be unity in the presence of the larger monovalent and divalent ions, but two in the presence of Mg(2+). Additionally, rate-pH profiles are inverted for the low charge density ions, and only imidazole plus ammonium ions rescue an inactive C75Delta variant in the absence of Mg(2+). Results from the thio effect experiments, rate-pH profiles, proton inventories, and ammonium/imidazole rescue experiments, combined with QM/MM free energy simulations, support a change in the mechanism of HDV ribozyme self-cleavage from concerted and metal ion-stabilized to stepwise and proton transfer-stabilized as the charge density of the metal ion decreases. PMID- 25799321 TI - Acid hydrolysis and molecular density of phytoglycogen and liver glycogen helps understand the bonding in glycogen alpha (composite) particles. AB - Phytoglycogen (from certain mutant plants) and animal glycogen are highly branched glucose polymers with similarities in structural features and molecular size range. Both appear to form composite alpha particles from smaller beta particles. The molecular size distribution of liver glycogen is bimodal, with distinct alpha and beta components, while that of phytoglycogen is monomodal. This study aims to enhance our understanding of the nature of the link between liver-glycogen beta particles resulting in the formation of large alpha particles. It examines the time evolution of the size distribution of these molecules during acid hydrolysis, and the size dependence of the molecular density of both glucans. The monomodal distribution of phytoglycogen decreases uniformly in time with hydrolysis, while with glycogen, the large particles degrade significantly more quickly. The size dependence of the molecular density shows qualitatively different shapes for these two types of molecules. The data, combined with a quantitative model for the evolution of the distribution during degradation, suggest that the bonding between beta into alpha particles is different between phytoglycogen and liver glycogen, with the formation of a glycosidic linkage for phytoglycogen and a covalent or strong non-covalent linkage, most probably involving a protein, for glycogen as most likely. This finding is of importance for diabetes, where alpha-particle structure is impaired. PMID- 25799322 TI - Complex environmental forcing across the biogeographical range of coral populations. AB - Although there is a substantial body of work on how temperature shapes coastal marine ecosystems, the spatiotemporal variability of seawater pH and corresponding in situ biological responses remain largely unknown across biogeographic ranges of tropical coral species. Environmental variability is important to characterize because it can amplify or dampen the biological consequences of global change, depending on the functional relationship between mean temperature or pH and organismal traits. Here, we characterize the spatiotemporal variability of pH, temperature, and salinity at fringing reefs in Moorea, French Polynesia and Nanwan Bay, Taiwan using advanced time series analysis, including wavelet analysis, and infer their potential impact on the persistence and stability of coral populations. Our results demonstrate that both the mean and variance of pH and temperature differed significantly between sites in Moorea and Taiwan. Seawater temperature at the Moorea site passed the local bleaching threshold several times within the ~45 day deployment while aragonite saturation state at the Taiwan site was often below commonly observed levels for coral reefs. Our results showcase how a better understanding of the differences in environmental conditions between sites can (1) provide an important frame of reference for designing laboratory experiments to study the effects of environmental variability, (2) identify the proximity of current environmental conditions to predicted biological thresholds for the coral reef, and (3) help predict when the temporal variability and mean of environmental conditions will interact synergistically or antagonistically to alter the abundance and stability of marine populations experiencing climate change. PMID- 25799324 TI - Depression-associated ARNTL and PER2 genetic variants in psychotic disorders. AB - Circadian rhythm disturbances overlap between psychotic disorders, e.g. schizophrenia, and major depression. We hypothesized that circadian gene variants previously associated with unipolar depression would be overrepresented also in patients with psychotic disorder. Six genetic polymorphisms in ARNTL, PER2 and CRY2 were genotyped in 566 schizophrenia spectrum disorder patients and 926 controls. The rs2290036-C variant of ARNTL was over-represented in psychosis patients, and the variants rs934945-G and rs10462023-G of PER2 were associated with a more severe psychotic disorder. The directions of these genetic associations were in line with those previously identified for depression. PMID- 25799323 TI - Oxidative stress induces caveolin 1 degradation and impairs caveolae functions in skeletal muscle cells. AB - Increased level of oxidative stress, a major actor of cellular aging, impairs the regenerative capacity of skeletal muscle and leads to the reduction in the number and size of muscle fibers causing sarcopenia. Caveolin 1 is the major component of caveolae, small membrane invaginations involved in signaling and endocytic trafficking. Their role has recently expanded to mechanosensing and to the regulation of oxidative stress-induced pathways. Here, we increased the amount of reactive oxidative species in myoblasts by addition of hydrogen peroxide (H2O2) at non-toxic concentrations. The expression level of caveolin 1 was significantly decreased as early as 10 min after 500 MUM H2O2 treatment. This reduction was not observed in the presence of a proteasome inhibitor, suggesting that caveolin 1 was rapidly degraded by the proteasome. In spite of caveolin 1 decrease, caveolae were still able to assemble at the plasma membrane. Their functions however were significantly perturbed by oxidative stress. Endocytosis of a ceramide analog monitored by flow cytometry was significantly diminished after H2O2 treatment, indicating that oxidative stress impaired its selective internalization via caveolae. The contribution of caveolae to the plasma membrane reservoir has been monitored after osmotic cell swelling. H2O2 treatment increased membrane fragility revealing that treated cells were more sensitive to an acute mechanical stress. Altogether, our results indicate that H2O2 decreased caveolin 1 expression and impaired caveolae functions. These data give new insights on age related deficiencies in skeletal muscle. PMID- 25799325 TI - Phonon-induced diamagnetic force and its effect on the lattice thermal conductivity. AB - Phonons are displacements of atoms around their rest positions in a crystalline solid. They carry sound and heat, but are not classically associated with magnetism. Here, we show that phonons are, in fact, sensitive to magnetic fields, even in diamagnetic materials. We do so by demonstrating experimentally that acoustic phonons in a diamagnetic semiconductor (InSb) scatter more strongly from one another when a magnetic field is applied. We attribute this observation to the magnetic-field sensitivity of the anharmonicity of the interatomic bonds that govern the probability of phonon-phonon interactions. The displacements of atoms locally affect the orbital motion of valence band electrons, which, in the presence of an external magnetic field, spatially modulates the orbital diamagnetism around the displaced atoms. The spatial gradient in magnetic moment results in an anharmonic magnetic force exerted on the displaced atom. The process is modelled by ab initio calculations that, without the use of a single adjustable parameter, reproduce the observed 12% decrease in the lattice thermal conductivity under a 7 T magnetic field at a temperature of 5.2 K. PMID- 25799326 TI - Hybrid optical-electrical detection of donor electron spins with bound excitons in silicon. AB - Electrical detection of spins is an essential tool for understanding the dynamics of spins, with applications ranging from optoelectronics and spintronics, to quantum information processing. For electron spins bound to donors in silicon, bulk electrically detected magnetic resonance has relied on coupling to spin readout partners such as paramagnetic defects or conduction electrons, which fundamentally limits spin coherence times. Here we demonstrate electrical detection of donor electron spin resonance in an ensemble by transport through a silicon device, using optically driven donor-bound exciton transitions. We measure electron spin Rabi oscillations, and obtain long electron spin coherence times, limited only by the donor concentration. We also experimentally address critical issues such as non-resonant excitation, strain, and electric fields, laying the foundations for realizing a single-spin readout method with relaxed magnetic field and temperature requirements compared with spin-dependent tunnelling, enabling donor-based technologies such as quantum sensing. PMID- 25799327 TI - Detection of clenbuterol hydrochloride residuals in pork liver using a customized surface plasmon resonance bioanalyzer. AB - A surface plasmon resonance (SPR) immunoassay with an immobilization of self assembled molecular identification membrane for the detection of residual Clenbuterol Hydrochloride (CLB) in pork liver was systematically investigated and experimentally validated for its high performance. SPR immunoassay with a regular competitive inhibition assay cannot be directly verified to detect CLB residuals. In this study, the binding of Au film with mercaptopropionic acid was investigated using the known form of the strong S-Au covalent bonds formed by the chemical radical of the mercaptopropionic acid and the Au film. After that, the immunoglobulin IgG of swine (SwIgG-CLB) was bonded with the mercaptopropionic acid by covalent -CO-NH- amide bonding. The modified comprehensive analysis of how the membrane structure works was introduced together with the customized SPR bioanalyzer. In order to evaluate the performance of this biomembrane structure, the concentrations of CLB-contained solutions of 0 ng . mL(-1), 10 ng . mL(-1), 20 ng . mL(-1), 33.3 ng . mL(-1), and 40 ng . mL(-1) were prepared by adding CLB reagents into the solutions of CLB antibody (Clenbuterol Hydrochloride Antibody, CLB-Ab), successively and then the response unit (RU) was measured individually. Using the data collected from the linear CCD array, the fitting curve was established with the R-Square value of 0.9929. Correspondingly, the recovery rate ranged from 88.48% to 103.21% was experimented and the limit of detection of CLB in 1.26 ng . mL(-1) was obtained efficiently. It was concluded that the detection method associated with biomembrane properties is expected to contribute much to the determination of residual CLB in pork liver quantitatively by using the customized SPR bioanalyzer. PMID- 25799328 TI - Jumping acoustic bubbles on lipid bilayers. AB - In the context of sonoporation, we use supported lipid bilayers as a model for biological membranes and investigate the interactions between the bilayer and microbubbles induced by ultrasound. Among the various types of damage caused by bubbles on the surface, our experiments exhibit a singular dynamic interaction process where bubbles are jumping on the bilayer, forming a necklace pattern of alteration on the membrane. This phenomenon was explored with different time and space resolutions and, based on our observations, we propose a model for a microbubble subjected to the combined action of van der Waals, acoustic and hydrodynamic forces. Describing the repeated jumps of the bubble, this model explains the lipid exchanges between the bubble and bilayer. PMID- 25799329 TI - Science to practice: can photoacoustic imaging be used to monitor tumor oxygenation and the effects of antivascular chemotherapies? AB - Rich and Seshadri showed improved quantitative imaging in terms of detection sensitivity with photoacoustic imaging relative to blood oxygenation level dependent magnetic resonance (MR) imaging, which can be exploited to monitor smaller changes in tissue oxygenation when assessing other chemotherapies or radiation-based treatments. PMID- 25799330 TI - DOIs for DICOM raw images: enabling science reproducibility. PMID- 25799331 TI - Nikola Tesla: an extraordinary life. PMID- 25799332 TI - New screening technologies and practices: a different approach to estimation of performance improvement by using data from the transition period. PMID- 25799333 TI - Pancreas transplant imaging: how I do it. AB - Pancreas transplantation aims to restore physiologic normoglycemia in diabetic patients with glomerulopathy and avoid or delay the onset of diabetic retinopathy and arteriopathy. Simultaneous pancreas-kidney transplant is the most common approach, using a cadaveric pancreas donation in conjunction with either cadaveric or live donor renal transplant. Alternative techniques include pancreas after kidney transplant, in which the pancreas transplant is performed some years after renal transplant. Pancreas transplant alone is utilized rarely in diabetic patients with compensated renal function. Pancreas grafts have vascular and enteric connections that vary in their anatomic approach, and understanding of this is critical for imaging with ultrasonography, computed tomography, or magnetic resonance imaging. Imaging techniques are directed to display the pancreatic transplant arterial and venous vasculature, parenchyma, and intestinal drainage pathway. Critical vascular information includes venous thrombosis (partial or complete), arterial occlusion, or aneurysm. Parenchymal abnormalities are nonspecific and occur in pancreatitis, graft rejection, and subsequent graft ischemia. Peripancreatic fluid collections include hematoma/seroma, pseudocyst, and abscess. The latter two are related to pancreatitis, duct disruption, or leak from the duodenojejunostomy. An understanding of transplant anatomy and complications will lead to appropriate use of imaging techniques to diagnose or exclude important complications. PMID- 25799334 TI - Incompletely characterized incidental renal masses: emerging data support conservative management. AB - With imaging, most incidental renal masses can be diagnosed promptly and with confidence as being either benign or malignant. For those that cannot, management recommendations can be devised on the basis of a thorough evaluation of imaging features. However, most renal masses are either too small to characterize completely or are detected initially in imaging examinations that are not designed for full evaluation of them. These masses constitute a group of masses that are considered incompletely characterized. On the basis of current published guidelines, many masses warrant additional imaging. However, while the diagnosis of renal cancer at a curable stage remains the first priority, there is the additional need to reduce unnecessary healthcare costs and radiation exposure. As such, emerging data now support foregoing additional imaging for many incompletely characterized renal masses. These data include the low risk of progression to metastases or death for small renal masses that have undergone active surveillance (including biopsy-proven cancers) and a better understanding of how specific imaging features can be used to diagnose their origins. These developments support (a) avoidance of imaging entirely for those incompletely characterized renal masses that are highly likely to be benign cysts and (b) delay of further imaging of small solid masses in selected patients. Although more evidence-based data are needed and comprehensive management algorithms have yet to be defined, these recommendations are medically appropriate and practical, while limiting the imaging of many incompletely characterized incidental renal masses. PMID- 25799338 TI - Case 216: hypertrophic spinal pachymeningitis. PMID- 25799339 TI - A new biomarker coincident with elastography: viscosity. PMID- 25799340 TI - The propaedeutics of structured reporting. PMID- 25799341 TI - High-spatial-resolution bone densitometry with dual-energy X-ray absorptiometric region-free analysis. PMID- 25799345 TI - Correction to "Coexistence of high-Tc ferromagnetism and n-type electrical conductivity in FeBi2Se4". PMID- 25799346 TI - How watching Pinocchio movies changes our subjective experience of extrapersonal space. AB - The way we experience the space around us is highly subjective. It has been shown that motion potentialities that are intrinsic to our body influence our space categorization. Furthermore, we have recently demonstrated that in the extrapersonal space, our categorization also depends on the movement potential of other agents. When we have to categorize the space as "Near" or "Far" between a reference and a target, the space categorized as "Near" is wider if the reference corresponds to a biological agent that has the potential to walk, instead of a biological and non-biological agent that cannot walk. But what exactly drives this "Near space extension"? In the present paper, we tested whether abstract beliefs about the biological nature of an agent determine how we categorize the space between the agent and an object. Participants were asked to first read a Pinocchio story and watch a correspondent video in which Pinocchio acts like a real human, in order to become more transported into the initial story. Then they had to categorize the location ("Near" or "Far") of a target object located at progressively increasing or decreasing distances from a non-biological agent (i.e., a wooden dummy) and from a biological agent (i.e., a human-like avatar). The results indicate that being transported into the Pinocchio story, induces an equal "Near" space threshold with both the avatar and the wooden dummy as reference frames. PMID- 25799348 TI - The F-type complete mitochondrial genome of Chinese freshwater mussels Cuneopsis pisciculus. AB - The complete F-type mitochondrial genome of Cuneopsis pisciculus was first determined in this research. This circular genome (15,907 bp in size) contained 13 protein-coding genes, 22 tRNA genes and 2rRNA genes. The protein-coding genes initiated with orthodox ATG or ATA start codon. Twenty-five non-coding regions were found throughout the mitochondrial genome of C. pisciculus, ranging in size from 1 to 326 bp. The maximum was between tRNA(Gln) and gene ND5 (326 bp). PMID- 25799349 TI - The mitochondrial genome of the Arizona Snowfly Mesocapnia arizonensis (Plecoptera, Capniidae). AB - We assembled the mitochondrial genome of the capniid stonefly Mesocapnia arizonensis (Baumann & Gaufin, 1969) using Illumina HiSeq sequence data. The recovered mitogenome is 14,921 bp in length and includes 13 protein-coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes. The control region could only be assembled partially. Gene order resembles that of basal arthropods. This is the first partial mitogenome sequence for the stonefly superfamily group Euholognatha and will be useful in future phylogenetic analyses. PMID- 25799347 TI - De novo origin of VCY2 from autosome to Y-transposed amplicon. AB - The formation of new genes is a primary driving force of evolution in all organisms. The de novo evolution of new genes from non-protein-coding genomic regions is emerging as an important additional mechanism for novel gene creation. Y chromosomes underlie sex determination in mammals and contain genes that are required for male-specific functions. In this study, a search was undertaken for Y chromosome de novo genes derived from non-protein-coding sequences. The Y chromosome orphan gene variable charge, Y-linked (VCY)2, is an autosome-derived gene that has sequence similarity to large autosomal fragments but lacks an autosomal protein-coding homolog. VCY2 locates in the amplicon containing long DNA fragments that were transposed from autosomes to the Y chromosome before the ape-monkey split. We confirmed that VCY2 cannot be encoded by autosomes due to the presence of multiple disablers that disrupt the open reading frame, such as the absence of start or stop codons and the presence of premature stop codons. Similar observations have been made for homologs in the autosomes of the chimpanzee, gorilla, rhesus macaque, baboon and out-group marmoset, which suggests that there was a non-protein-coding ancestral VCY2 that was common to apes and monkeys that predated the transposition event. Furthermore, while protein-coding orthologs are absent, a putative non-protein-coding VCY2 with conserved disablers was identified in the rhesus macaque Y chromosome male specific region. This finding implies that VCY2 might have not acquired its protein-coding ability before the ape-monkey split. VCY2 encodes a testis specific expressed protein and is involved in the pathologic process of male infertility, and the acquisition of this gene might improve male fertility. This is the first evidence that de novo genes can be generated from transposed autosomal non-protein-coding segments, and this evidence provides novel insights into the evolutionary history of the Y chromosome. PMID- 25799350 TI - The complete mitochondrial genome of Rhynchocypris oxycephalus (Cypriniformes: Cyprinidae). AB - The Rhynchocypris oxycephalus (Cypriniformes: Cyprinidae) is an ecological important fish in East Asia. In this study, we firstly sequenced the complete mitochondrial genome of R. oxycephalus. The mitogenome is 16,606 bp in length, including 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and two non-coding regions (origin of light-strand replication and control region). The gene content and order is in accord with the common vertebrate form. The nucleotide base composition of H-strand is 28.4% A, 27.2% T, 26.4% C and 18.0% G. The complete mitochondrial genome data would be useful for further studies of genetics, conservation biology and adaptive evolution of R. oxycephalus. PMID- 25799351 TI - The complete mitochondrial genome of jade perch, Scortum barcoo (Perciformes: Terapontidae: Scortum). AB - This is the first documentation of the complete mitochondrial genome sequence of the jade perch, Scortum barcoo. The 16,843 bp mitogenome containes 37 genes (13 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes) and two main non-coding regions (the control region and the origin of the light strand replication) as do other vertebrate mitogenomes. The overall base composition of S. barcoo is 27.39% for A, 24.74% for T, 31.14% for C and 16.73% for G, with a slight A + T bias of 52.13%. All protein-coding genes are initiated with ATG except for COX1, which begin with GTG instead. Meanwhile, the termination codons of 13 protein-coding genes are varied with TAA, TAG, TA, T or AGG. The measure of complete mitogenome sequence of S. barcoo will provide fundamental data for the phylogenetic and biogeographic studies of the Terapontidae. PMID- 25799352 TI - Whole mitochondrial genome sequence for an osteoarthritis model of spontaneous mice DBA/1 strain. AB - Animal models play an important role in osteoarthritis studies. Here, the complete mitochondrial genome sequence of the spontaneous mice DBA/1 strain was reported for the first time. The total length of the mitogenome was 16,769 bp. It contained the typical structure, including two ribosomal RNA genes, 13 protein coding genes, 22 transfer RNA genes, and one non-coding control region (D-loop region). The overall GC content of the mitogenome was estimated to be 39.2%. This mitochondrial genome sequence will provide new genetic resource into osteoarthritis disease. PMID- 25799353 TI - Single particle fluorescence burst analysis of epsin induced membrane fission. AB - Vital cellular processes, from cell growth to synaptic transmission, rely on membrane-bounded carriers and vesicles to transport molecular cargo to and from specific intracellular compartments throughout the cell. Compartment-specific proteins are required for the final step, membrane fission, which releases the transport carrier from the intracellular compartment. The role of fission proteins, especially at intracellular locations and in non-neuronal cells, while informed by the dynamin-1 paradigm, remains to be resolved. In this study, we introduce a highly sensitive approach for the identification and analysis of membrane fission machinery, called burst analysis spectroscopy (BAS). BAS is a single particle, free-solution approach, well suited for quantitative measurements of membrane dynamics. Here, we use BAS to analyze membrane fission induced by the potent, fission-active ENTH domain of epsin. Using this method, we obtained temperature-dependent, time-resolved measurements of liposome size and concentration changes, even at sub-micromolar concentration of the epsin ENTH domain. We also uncovered, at 37 degrees C, fission activity for the full-length epsin protein, supporting the argument that the membrane-fission activity observed with the ENTH domain represents a native function of the full-length epsin protein. PMID- 25799355 TI - Dilemma of dilemmas: how collective and individual perspectives can clarify the size dilemma in voluntary linear public goods dilemmas. AB - Empirical findings on public goods dilemmas indicate an unresolved dilemma: that increasing size-the number of people in the dilemma-sometimes increases, decreases, or does not influence cooperation. We clarify this dilemma by first classifying public goods dilemma properties that specify individual outcomes as individual properties (e.g., Marginal Per Capita Return) and group outcomes as group properties (e.g., public good multiplier), mathematically showing how only one set of properties can remain constant as the dilemma size increases. Underpinning decision-making regarding individual and group properties, we propose that individuals are motivated by both individual and group preferences based on a theory of collective rationality. We use Van Lange's integrated model of social value orientations to operationalize these preferences as an amalgamation of outcomes for self, outcomes for others, and equality of outcomes. Based on this model, we then predict how the public good's benefit and size, combined with controlling individual versus group properties, produce different levels of cooperation in public goods dilemmas. A two (low vs. high benefit) by three (2-person baseline vs. 5-person holding constant individual properties vs. 5-person holding constant group properties) factorial experiment (group n = 99; participant n = 390) confirms our hypotheses. The results indicate that when holding constant group properties, size decreases cooperation. Yet when holding constant individual properties, size increases cooperation when benefit is low and does not affect cooperation when benefit is high. Using agent-based simulations of individual and group preferences vis-a-vis the integrative model, we fit a weighted simulation model to the empirical data. This fitted model is sufficient to reproduce the empirical results, but only when both individual (self-interest) and group (other-interest and equality) preference are included. Our research contributes to understanding how people's motivations and behaviors within public goods dilemmas interact with the properties of the dilemma to lead to collective outcomes. PMID- 25799354 TI - Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia. AB - Sepsis-induced acute kidney injury (AKI) contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1) and vitronectin (Vn) are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1-/-) or expressing a PAI-1-mutant (PAI-1R101A/Q123K) in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT) mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC) in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity. PMID- 25799356 TI - A nasal high-flow system prevents hypoxia in dental patients under intravenous sedation. AB - PURPOSE: Hypoxia is a major complication in dental patients under intravenous sedation (IVS). A nasal high-flow (NHF) system has been reported to achieve effective oxygenation in patients with sleep apnea syndrome. This study investigated the ability of the NHF system to prevent hypoxia in dental patients under IVS. MATERIALS AND METHODS: Thirty patients scheduled for dental treatment under IVS were enrolled. Patients were randomly divided into 3 groups: patients spontaneously breathing oxygen at 5 L/minute through a nasal cannula (NC5 group), patients administered oxygen at 30 L/minute through the NHF system, and patients administered oxygen at 50 L/minute through the NHF system. Hypnosis was induced by bolus administration of midazolam (0.05 mg/kg) followed by continuous administration of propofol (target blood concentration, 1.2 to 2 MUg/mL). Noninvasive blood pressure, peripheral capillary oxygen saturation (SpO2), heart rate, and bispectral index values were recorded every 2.5 minutes before the induction of anesthesia. Interventions, such as jaw lifting, were recorded during IVS and arterial blood gas analysis was performed at the end of sedation. Patient and surgeon satisfaction with IVS was evaluated by interview. RESULTS: Minimum SpO2 was lowest in and surgeons were least satisfied with the NC5 group. In addition, interventions were required most frequently in the NC5 group (P < .05). Compared with the NC5 group, use of the NHF system improved partial pressures of oxygen and carbon dioxide in dental patients under IVS (P < .05). CONCLUSIONS: These results suggest that use of the NHF system can prevent hypoxia in dental patients under IVS. Further studies are necessary to determine the appropriate flow rate and indications for NHF in obese patients. PMID- 25799357 TI - Is anterior disc displacement without reduction associated with temporomandibular joint condylar height in juvenile patients younger than 20 years? AB - PURPOSE: Because disc displacement might be accompanied by degenerative changes in the condyle, this study explored the association between condylar height and anterior disc displacement without reduction in juvenile patients. MATERIALS AND METHODS: This was a retrospective cohort study that enrolled a sample of patients younger than 20 years with unilateral disc displacement without reduction. All patients had 2 magnetic resonance imaging records taken from January 2010 to June 2013 (interval, >6 months). Condylar height, disc length, and displacement distance were measured. The predictor variable was joint status (healthy vs affected side), and the outcome variables were changes in condylar height, displacement distance, and disc length over time. SAS 9.13 was used for analysis and the P value was set at .05. RESULTS: One hundred twenty-four patients (101 female and 23 male; mean age, 16.4 yr; mean interval, 13.6 months) were included. During the interval, the condylar height of the healthy side increased 0.75 mm, whereas the condylar height of the affected side decreased 0.41 mm. The disc of the affected side was shortened and more anteriorly displaced. CONCLUSION: Anterior disc displacement without reduction could be accompanied by a decrease in condylar height in juvenile patients, and the disc might be shortened and more anteriorly displaced. PMID- 25799358 TI - Correction: Worldwide niche and future potential distribution of Culicoides imicola, a major vector of bluetongue and African horse sickness viruses. PMID- 25799360 TI - Corrigendum: alphaB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes. PMID- 25799359 TI - Cell membrane integrity in myotonic dystrophy type 1: implications for therapy. AB - Myotonic Dystrophy type 1 (DM1) is a multisystemic disease caused by toxic RNA from a DMPK gene carrying an expanded (CTG*CAG)n repeat. Promising strategies for treatment of DM1 patients are currently being tested. These include antisense oligonucleotides and drugs for elimination of expanded RNA or prevention of aberrant binding to RNP proteins. A significant hurdle for preclinical development along these lines is efficient systemic delivery of compounds across endothelial and target cell membranes. It has been reported that DM1 patients show elevated levels of markers of muscle damage or loss of sarcolemmal integrity in their serum and that splicing of dystrophin, an essential protein for muscle membrane structure, is abnormal. Therefore, we studied cell membrane integrity in DM1 mouse models commonly used for preclinical testing. We found that membranes in skeletal muscle, heart and brain were impermeable to Evans Blue Dye. Creatine kinase levels in serum were similar to those in wild type mice and expression of dystrophin protein was unaffected. Also in patient muscle biopsies cell surface expression of dystrophin was normal and calcium-positive fibers, indicating elevated intracellular calcium levels, were only rarely seen. Combined, our findings indicate that cells in DM1 tissues do not display compromised membrane integrity. Hence, the cell membrane is a barrier that must be overcome in future work towards effective drug delivery in DM1 therapy. PMID- 25799361 TI - Identifying trends and descriptors for selective CO2 conversion to CO over transition metal carbides. AB - Catalytic reduction of CO2 requires active, selective and low-cost catalysts. Results of this study show that transition metal carbides are a class of promising catalysts and their activity is correlated with oxygen binding energy and reducibility as shown by DFT calculations and in situ measurements. PMID- 25799363 TI - Diagnosis of cervical artery dissection using 3-T magnetic resonance imaging. PMID- 25799362 TI - Application of the phylogenetic species concept to Wallemia sebi from house dust and indoor air revealed by multi-locus genealogical concordance. AB - A worldwide survey of Wallemia occurring in house dust and indoor air was conducted. The isolated strains were identified as W. sebi and W. muriae. Previous studies suggested that the W. sebi phylogenetic clade contained cryptic species but conclusive evidence was lacking because only the internal transcribed spacer (ITS) marker was analyzed. The ITS and four protein-coding genes (MCM7, RPB1, RPB2, and TSR1) were sequenced for 85 isolates. Based on an initial neighbor joining analysis of the concatenated genes, W. muriae remained monophyletic but four clades were found in W. sebi, which we designated as W. sebi clades 1, 2, 3, and 4. We hypothesized that these clades represent distinct phylogenetic species within the Wallemia sebi species complex (WSSC). We then conducted multiple phylogenetic analyses and demonstrated genealogical concordance, which supports the existence of four phylogenetic species within the WSSC. Geographically, W. muriae was only found in Europe, W. sebi clade 3 was only found in Canada, W. sebi clade 4 was found in subtropical regions, while W. sebi clade 1 and 2 were found worldwide. Haplotype analysis showed that W. sebi clades 1 and 2 had multiple haplotypes while W. sebi clades 3 and 4 had one haplotype and may have been under sampled. We describe W. sebi clades 2, 3, and 4 as new species in a companion study. PMID- 25799365 TI - Varied forms of lamellar [Sn3Se7]n(2n-) anion: the competitive and synergistic structure-directing effects of metal-amine complex and imidazolium cations. AB - Presented are the syntheses, characterizations and properties of a series of selenidostannate compounds directed by metal-amine complex (MAC) cations and/or [Bmmim](+) (Bmmim = 1-butyl-2,3-dimethylimidazolium). Mixtures of the ionic liquid (IL) (Bmmim)Cl and amines, such as ethylenediamine (en) and diethylenetriamine (dien), in various ratios were used to ionothermally/solvothermally prepare four selenidostannates, namely, [Mn(en)3]Sn3Se7 (1), [Mn(dien)2]Sn3Se7.H2O (2), (Bmmim)3[Mn(en)3]2[Sn9Se21]Cl (3) and (Bmmim)6[Mn(dien)2]2Sn15Se35 (4). Single-crystal X-ray diffraction analyses revealed that these compounds exhibit lamellar anionic [Sn3Se7]n(2n-) structures. [Sn3Se7]n(2n-) layers in all 1-4 possess a {6(3)} net, considering [Sn3Se10] semi cube unit as a 3-connected node; however, diverse multi-membered rings exist there. In compounds 1 and 2, all the [Sn3Se10] units are 3-connected nodes interlinking with each other via edge-sharing two Se atoms to produce six membered rings. However, in compound 3, the insertion of two [Sn3Se9] units into a six-membered ring results in a novel eight-membered heart-shaped ring, which has never been observed before in the family of chalcogenidostannates. More interestingly, the [Sn3Se7]n(2n-) layer in compound 4 consists of mixed six- and eight-membered rings. The phase composition is strongly dependent on the ratio of IL to MAC in the syntheses, e.g., 1 and 2 were obtained with IL:MAC ratios less than 3:1 and 4:1, while 3 and 4 were obtained when the ratios were increased to 4:1 and 5:1, respectively. The structural variation from 1 to 4 clearly indicates the competitive and synergistic effects between MAC and IL cation on the formation of lamellar selenidostannates. A synthetic approach via varying the ratio of IL to MAC cation as solvent and structure-directing agent will be attractive in the synthesis of novel chalcogenidometallates. PMID- 25799364 TI - Assessing myeloma bone disease with whole-body diffusion-weighted imaging: comparison with x-ray skeletal survey by region and relationship with laboratory estimates of disease burden. AB - AIM: To estimate and compare the extent of myeloma bone disease by skeletal region using whole-body diffusion-weighted imaging (WB-DWI) and skeletal survey (SS) and record interobserver agreement, and to investigate differences in imaging assessments of disease extent and apparent diffusion coefficient (ADC) between patients with pathological high versus low disease burden. MATERIALS AND METHODS: Twenty patients with relapsed myeloma underwent WB-DWI and SS. Lesions were scored by number and size for each skeletal region by two independent observers using WB-DWI and SS. Observer scores, ADC, and ADC-defined volume of tumour-infiltrated marrow were compared between patients with high and low disease burden (assessed by serum paraproteins and marrow biopsy). RESULTS: Observer scores were higher on WB-DWI than SS in every region (p<0.05) except the skull, with greater interobserver reliability in rating the whole skeleton (WB DWI: ICC = 0.74, 95% CI: 0.443-0.886; SS: ICC = 0.44, 95% CI: 0.002-0.730) and individual body regions. WB-DWI scores were not significantly higher in patients with high versus low disease burden (observer 1: mean +/- SD: 48.8 +/- 7, 38.6 +/ 14.5, observer 2: mean +/- SD: 37.3 +/- 13.5, 30.4 +/- 15.5; p = 0.06, p = 0.35). CONCLUSION: WB-DWI demonstrated more lesions than SS in all regions except the skull with greater interobserver agreement. Sensitivity is not a limiting factor when considering WB-DWI in the management pathway of patients with myeloma. PMID- 25799366 TI - Low temperature SCR of NO with catalysts prepared by modified ACF loading Mn and Ce: effects of modification method. AB - Achievement of a higher NOx conversion ratio in selective catalytic reduction (SCR) at low temperature is challenging. In this work, pure activated carbon fibres (ACFs) were modified with different ratios of H2O (g), NaOH, CO2 and HNO3, respectively (named as modified ACF). The chemical and physical properties of modified ACFs were identified by Brunauer-Emmett-Teller, X-ray diffraction, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy methods. The NOx conversion ratio of ACF was improved from 56.1% to 82.4% at 80 degrees C after modification with 30% (mass ratio) NaOH. These modified ACFs were further loaded with the mixture of MnO2 and CeO2 in the form of metal salt solutions (named as Mn0.5Ce0.5O2/modified ACF). The NOx conversion ratio of 30% SHACF remained similar at 80 degrees C but was increased from 60.0% to 98.5% at 360 degrees C after loading with Mn and Ce, which showed the best performance in SCR of NOx at low temperature. It could be seen that ACF delivered higher performance in low temperature SCR after being modified with the aforementioned reactants and further loading with metals. Based on chemical and physical characterization and the performance of the catalysts, the reasons for different performances of these catalysts in low temperature SCR are discussed. PMID- 25799368 TI - Correction: Low cognitive load and reduced arousal impede practice effects on executive functioning, metacognitive confidence and decision making. PMID- 25799369 TI - Amphibian diversity and threatened species in a severely transformed neotropical region in Mexico. AB - Many regions around the world concentrate a large number of highly endangered species that have very restricted distributions. The mountainous region of central Veracruz, Mexico, is considered a priority area for amphibian conservation because of its high level of endemism and the number of threatened species. The original tropical montane cloud forest in the region has been dramatically reduced and fragmented and is now mainly confined to ravines and hillsides. We evaluated the current situation of amphibian diversity in the cloud forest fragments of this region by analyzing species richness and abundance, comparing assemblage structure and species composition, examining the distribution and abundance of threatened species, and identifying the local and landscape variables associated with the observed amphibian diversity. From June to October 2012 we sampled ten forest fragments, investing 944 person-hours of sampling effort. A total of 895 amphibians belonging to 16 species were recorded. Notable differences in species richness, abundance, and assemblage structure between forest fragments were observed. Species composition between pairs of fragments differed by an average of 53%, with the majority (58%) resulting from species replacement and the rest (42%) explained by differences in species richness. Half of the species detected are under threat of extinction according to the International Union for Conservation of Nature, and although their distribution and abundance varied markedly, there were also ubiquitous and abundant species, along with rare species of restricted distribution. The evident heterogeneity of the ten study sites indicates that to conserve amphibians in a mountainous region such as this one it is necessary to protect groups of fragments which represent the variability of the system. Both individually and together cloud forest fragments are very important to conservation because each remnant is inhabited by several threatened species, some of them at imminent risk of extinction. PMID- 25799367 TI - Silencing TRPM7 in mouse cortical astrocytes impairs cell proliferation and migration via ERK and JNK signaling pathways. AB - Transient receptor potential melastatin 7 (TRPM7), a non-selective cation channel, is highly expressed expressed in the brain and plays a critical role in ischemic neuronal death. Astrocyte, the most abundant cell type in central nervous system (CNS), exerts many essential functions in the physiological and pathological conditions. Here we investigated the expression and functions of the TRPM7 channel in mouse cortical astrocytes. Using reverse transcription (RT)-PCR, immunostaining, western blot and patch clamp recording, we showed that functional TRPM7 channel is expressed in cultured mouse cortical astrocytes. Knocking down TRPM7 with specific siRNA impairs the proliferation and migration of astrocytes by 40.2% +/- 3.9% and 40.1% +/- 11.5%, respectively. Consistently, inhibition of TRPM7 with 2-aminoethoxydiphenyl borate (2-APB) also decreases astrocyte proliferation and migration by 46.1% +/- 2.5% and 64.2% +/- 2.4%. MAPKs and Akt signaling pathways have been shown to be implicated in TRPM7-mediated responses including cell proliferation and migration. Our data show that suppression of TRPM7 in astrocytes reduces the phosphorylation of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK), but not p38 mitogen-activated protein kinase and Akt. In addition, TRPM7, as a cation channel, has been involved in the Ca2+ and Mg2+ homeostasis in several types of cells. In our study, we found that silencing TRPM7 decreases the intracellular basal Mg2+ concentration without affecting Ca2+ concentration in astrocytes. However, an addition of Mg2+ to the growth medium could not rescue the impaired proliferation of astrocytes. Together, our data suggest that TRPM7 channel may play a critical role in the proliferation and migration of astrocytes via the ERK and JNK pathways. PMID- 25799370 TI - Protease-degradable electrospun fibrous hydrogels. AB - Electrospun nanofibres are promising in biomedical applications to replicate features of the natural extracellular matrix (ECM). However, nearly all electrospun scaffolds are either non-degradable or degrade hydrolytically, whereas natural ECM degrades proteolytically, often through matrix metalloproteinases. Here we synthesize reactive macromers that contain protease cleavable and fluorescent peptides and are able to form both isotropic hydrogels and electrospun fibrous hydrogels through a photoinitiated polymerization. These biomimetic scaffolds are susceptible to protease-mediated cleavage in vitro in a protease dose-dependent manner and in vivo in a subcutaneous mouse model using transdermal fluorescent imaging to monitor degradation. Importantly, materials containing an alternate and non-protease-cleavable peptide sequence are stable in both in vitro and in vivo settings. To illustrate the specificity in degradation, scaffolds with mixed fibre populations support selective fibre degradation based on individual fibre degradability. Overall, this represents a novel biomimetic approach to generate protease-sensitive fibrous scaffolds for biomedical applications. PMID- 25799371 TI - ABCB1 gene C3435T polymorphism and drug resistance in epilepsy: evidence based on 8,604 subjects. AB - BACKGROUND: The present study aimed to assess the role of C3435T polymorphism in drug-resistance in epilepsy by a meta-analysis. MATERIAL AND METHODS: Databases were obtained from the Cochrane Library, MEDLINE, EMBASE, PubMed, Science Direct database, CNKI, and Wanfang up to October 2014. All the case-control association studies evaluating the role of ABCB1 C3435T in pharmacoresistance to anti epileptic drug (AED) were identified. RevMan 5.0 software was utilized to perform quantitative analyses in an allele model (C vs. T) and a genotype model (CC vs. CT+TT). RESULTS: From the 189 potential studies, we included 28 articles for the meta-analysis, including 30 independent case-control studies involving 4124 drug resistant epileptic patients and 4480 epileptic patients for whom drug treatment was effective. We excluded 164 studies because of duplication, lack of genotype data, and non-clinical research. We found that C3435T polymorphism was not significantly associated with drug resistance in epilepsy, either in allele model (C vs. T: OR=1.07; 95%CI: 0.95-1.19) or in genotype model (CC vs. CT+TT: OR=1.05; 95%CI: 0.89-1.24, P=0.55). Subgroup analyses suggested that in Caucasian populations there are significant differences between resistance group (NR) and control group (R) in both allele model (C vs. T: OR=1.09; 95%CI: 1.00-1.18, P=0.05) and genotype model (CC vs. CT+TT: OR=1.20; 95%CI: 1.04-1.40, P=0.01). However, we did not find this association in Asian populations. CONCLUSIONS: We conclude that the ABCB1 C3435T polymorphism may be a genetic marker for drug resistance in epilepsy in Caucasian populations. PMID- 25799372 TI - Fibrillar amyloid plaque formation precedes microglial activation. AB - In Alzheimer's disease (AD), hallmark beta-amyloid deposits are characterized by the presence of activated microglia around them. Despite an extensive characterization of the relation of amyloid plaques with microglia, little is known about the initiation of this interaction. In this study, the detailed investigation of very small plaques in brain slices in AD transgenic mice of the line APP-PS1(dE9) revealed different levels of microglia recruitment. Analysing plaques with a diameter of up to 10 MUm we find that only the half are associated with clear morphologically activated microglia. Utilizing in vivo imaging of new appearing amyloid plaques in double-transgenic APP-PS1(dE9)xCX3CR1+/- mice further characterized the dynamic of morphological microglia activation. We observed no correlation of morphological microglia activation and plaque volume or plaque lifetime. Taken together, our results demonstrate a very prominent variation in size as well as in lifetime of new plaques relative to the state of microglia reaction. These observations might question the existing view that amyloid deposits by themselves are sufficient to attract and activate microglia in vivo. PMID- 25799373 TI - Neuroactive Steroids. 1. Positive Allosteric Modulators of the (gamma Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21. AB - Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators. PMID- 25799374 TI - Synergetic sustainability enhancement via utilization of carbon dioxide as carbon neutral chemical feedstock in the thermo-chemical processing of biomass. AB - This study investigated the utilization of CO2 as carbon neutral chemical feedstock in the thermo-chemical processing (i.e., pyrolysis and gasification) of biomass to enhance sustainability via modification of the composition of end products. To justify the universal function of CO2 in the thermo-chemical process, the biomass experimented on in this work was not limited to ligno cellulosic biomass; seaweed (i.e., red macroalgae) was used to expand biofuel feedstock beyond terrestrial biomass. Our experimental results validated the achieved enhanced generation of ~200% for H2 and ~1000% for CO by means of adopting CO2 in the thermo-chemical process, as compared to the case in N2. This can be explained by the enhanced thermal cracking of volatile organic carbons (VOCs) evolved from the thermal degradation of biomass and the reaction between CO2 and VOCs. Considering mass balance under our experimental conditions, we confirmed reaction between CO2 and VOCs, which was universally observed in pyrolysis of all biomass samples used in this work. Thus, the identified influence of CO2 in the thermo-chemical process can be directly applied in a variety of research and industrial fields, which would be environmentally desirable. PMID- 25799375 TI - Rh(III)-catalyzed decarboxylative ortho-heteroarylation of aromatic carboxylic acids by using the carboxylic acid as a traceless directing group. AB - Highly selective decarboxylative ortho-heteroarylation of aromatic carboxylic acids with various heteroarenes has been developed through Rh(III)-catalyzed two fold C-H activation, which exhibits a wide substrate scope of both aromatic carboxylic acids and heteroarenes. The use of naturally occurring carboxylic acid as the directing group avoids troublesome extra steps for installation and removal of an external directing group. PMID- 25799376 TI - Structure-based hybridization, synthesis and biological evaluation of novel tetracyclic heterocyclic azathioxanthone analogues as potential antitumor agents. AB - A series of tetracyclic heterocyclic azathioxanthones were synthesized and evaluated for cell proliferations, topoisomerase inhibitions, and NCI-60 cell panel assay, respectively. Compounds 5, 7, 8, 16, and 19 were selected for topoisomerase assay after MTT assay. 7 not only showed cytotoxic effect (IC50 = 2.84 +/- 0.64 MUM) in PC-3 cells but also revealed topoisomerases inhibition with IC50 (10-25 MUM) and increased apoptotic cleavage of PARP and caspase 3 activity. The overall of novel azathioxanthones with different cytostatic and cytotoxic activities should be further developed as new potential candidates for anticancer drugs. PMID- 25799378 TI - [Health services research is a service to the population health]. PMID- 25799379 TI - [Social medicine and (normative) health services research]. PMID- 25799377 TI - Plasma cytokine levels fall in preterm newborn infants on nasal CPAP with early respiratory distress. AB - INTRODUCTION: Early nCPAP seems to prevent ventilator-induced lung injury in humans, although the pathophysiological mechanisms underlying this beneficial effect have not been clarified yet. OBJECTIVE: To evaluate plasma levels IL 1beta, IL-6, IL-8, IL-10, and TNF-alpha immediately before the start of nCPAP and 2 hours later in preterm infants. METHODS: Prospective cohort including preterm infants with 28 to 35 weeks gestational age with moderate respiratory distress requiring nCPAP. Extreme preemies, newborns with malformations, congenital infections, sepsis, surfactant treatment, and receiving ventilatory support in the delivery room were excluded. Blood samples were collected right before and 2 hours after the start of nCPAP. RESULTS: 23 preterm infants (birth weight 1851+/ 403 grams; GA 32.3+/-1.7 weeks) were treated with nCPAP. IL-1beta, IL-10, TNF alpha levels were similar, IL-8 levels were reduced in 18/23 preterm infants and a significant decrease in IL-6 levels was observed after 2 hours of nCPAP. All newborns whose mothers received antenatal steroids had lower cytokine levels at the onset of nCPAP than those whose mothers didn't receive it; this effect was not sustained after 2 hours of nCPAP. CONCLUSION: Early use nCPAP is not associated with rising of plasma pro-inflammatory cytokines and it seems to be a less harmful respiratory strategy for preterm with moderate respiratory distress. PMID- 25799380 TI - [Psychotrauma after occupational accidents in public transportation. A pilot study to support concepts, influencing factors and occupational health-care]. AB - BACKGROUND AND AIM OF THE STUDY: Accidents, assaults and suicides occur quite frequently in public transportation. As a result of such extreme events at work, drivers are particularly prone to psychotrauma (PT). Therefore accident insurers stipulate support from the accident site to workplace reintegration with the inclusion of occupational medicine. The present study investigates the incidence, factors influencing psychological trauma as well as the occupational health-care after critical incidents. METHODS: In a Bavarian public transportation corporation 59 employees were evaluated according to ICD-10 for trauma-related disorders, using full collection after application of a specific mental first aid programme and a subsequent occupational health examination. RESULTS: The incidence of PT was 44.1%, with 8.5% showing a post-traumatic stress disorder (PTSD) as consequence of the accident. As significant influencing factors the nature of the accident, the severity of third party injury, and own physical injuries were identified. The occupational medical care depended on the severity of the disease. PT led to the need for rehabilitation. Sick leave was most pronounced in drivers with PTSD. CONCLUSION: The study group showed high levels of emotional strain within the first month. With respect to occupational health care, particular attention should be paid to drivers after serious accidents or those who sustained own injuries. As foundation for evidence based health-care measures after PT in transport must be scientifically evaluated and the identified risk factors must be well-founded as well. PMID- 25799381 TI - Letter to the editor regarding "The 70-degree telescope as a teaching tool for cleft palate repair and pharyngoplasty surgery". PMID- 25799382 TI - Is very early hearing assessment always reliable in selecting patients for cochlear implants? A case series study. AB - INTRODUCTION: This study concerns a case series of 23 infants with a diagnosis of severe-to-profound hearing loss at 3 months old, who significantly improved (even reaching a normal auditory threshold) within their first year of life. METHODS: All infants were routinely followed up with audiological tests every 2 months after being fitted with hearing aids as necessary. A reliable consistency between the various test findings (DPOAE, ABR, behavioral responses, CAEP and ECoG) clearly emerged in most cases during the follow-up, albeit at different times after birth. RESULTS: The series of infants included 7 cases of severe prematurity, 6 of cerebral or complex syndromic malformations, 5 healthy infants, 2 with asymptomatic congenital CMV infection, and 1 case each of hyperbilirubinemia, hypoxia, and sepsis. All term-born infants showed a significant improvement over their initial hearing threshold by 6 months of age, while in most of those born prematurely the first signs of threshold amelioration occurred beyond 70 weeks of gestational age, and even beyond 85 weeks in one case. CONCLUSIONS: Cochlear implantation (CI) should only be considered after a period of auditory stimulation and follow-up with electrophysiological and behavioral tests, and an accurate analysis of their correlation. In our opinion, CI can be performed after a period of 8 months in all term-born infants with persistent severe-to-profound hearing loss without risk of diagnostic error, whereas the follow-up for severely preterm infants should extend to at least 80 weeks of gestational age. PMID- 25799383 TI - Pediatric atrophic rhinosinusitis: what can we do? AB - A 5-year-old female had history of chronic foul smelling nasal discharge. Rhinoscopy showed greenish crusts lining the nasal cavities and inferior turbinates were shriveled significantly. Nasal cavity cultures of crusts by swab revealed Klebsiella ozaenae making the diagnosis of primary atrophic rhinosinusitis. After several unsuccessful treatment, we have decided to try sulfamethoxazole-trimethoprim prophylaxis and 1 year later there was a complete clinical improvement. There are many medical therapies and surgical options described, but none of them showed effective at long term. We present antibiotic prophylaxis as a viable alternative for long term control of the disease. PMID- 25799384 TI - Actin flows mediate a universal coupling between cell speed and cell persistence. AB - Cell movement has essential functions in development, immunity, and cancer. Various cell migration patterns have been reported, but no general rule has emerged so far. Here, we show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale. Our analysis relies on a theoretical model that we validate by measuring the persistence of cells upon modulation of actin flow speeds and upon optogenetic manipulation of the binding of an actin regulator to actin filaments. Beyond the quantitative prediction of the coupling, the model yields a generic phase diagram of cellular trajectories, which recapitulates the full range of observed migration patterns. PMID- 25799387 TI - Post-traumatic cilia in the anterior chamber. PMID- 25799386 TI - Enhanced NMDA receptor-mediated modulation of excitatory neurotransmission in the dorsal vagal complex of streptozotocin-treated, chronically hyperglycemic mice. AB - A variety of metabolic disorders, including complications experienced by diabetic patients, have been linked to altered neural activity in the dorsal vagal complex. This study tested the hypothesis that augmentation of N-Methyl-D Aspartate (NMDA) receptor-mediated responses in the vagal complex contributes to increased glutamate release in the dorsal motor nucleus of the vagus nerve (DMV) in mice with streptozotocin-induced chronic hyperglycemia (i.e., hyperglycemic mice), a model of type 1 diabetes. Antagonism of NMDA receptors with AP-5 (100 MUM) suppressed sEPSC frequency in vagal motor neurons recorded in vitro, confirming that constitutively active NMDA receptors regulate glutamate release in the DMV. There was a greater relative effect of NMDA receptor antagonism in hyperglycemic mice, suggesting that augmented NMDA effects occur in neurons presynaptic to the DMV. Effects of NMDA receptor blockade on mEPSC frequency were equivalent in control and diabetic mice, suggesting that differential effects on glutamate release were due to altered NMDA function in the soma-dendritic membrane of intact afferent neurons. Application of NMDA (300 MUM) resulted in greater inward current and current density in NTS neurons recorded from hyperglycemic than control mice, particularly in glutamatergic NTS neurons identified by single-cell RT-PCR for VGLUT2. Overall expression of NR1 protein and message in the dorsal vagal complex were not different between the two groups. Enhanced postsynaptic NMDA responsiveness of glutamatergic NTS neurons is consistent with tonically-increased glutamate release in the DMV in mice with chronic hyperglycemia. Functional augmentation of NMDA-mediated responses may serve as a physiological counter-regulatory mechanism to control pathological disturbances of homeostatic autonomic function in type 1 diabetes. PMID- 25799388 TI - [Cat eye syndrome]. PMID- 25799385 TI - Inter-cellular forces orchestrate contact inhibition of locomotion. AB - Contact inhibition of locomotion (CIL) is a multifaceted process that causes many cell types to repel each other upon collision. During development, this seemingly uncoordinated reaction is a critical driver of cellular dispersion within embryonic tissues. Here, we show that Drosophila hemocytes require a precisely orchestrated CIL response for their developmental dispersal. Hemocyte collision and subsequent repulsion involves a stereotyped sequence of kinematic stages that are modulated by global changes in cytoskeletal dynamics. Tracking actin retrograde flow within hemocytes in vivo reveals synchronous reorganization of colliding actin networks through engagement of an inter-cellular adhesion. This inter-cellular actin-clutch leads to a subsequent build-up in lamellar tension, triggering the development of a transient stress fiber, which orchestrates cellular repulsion. Our findings reveal that the physical coupling of the flowing actin networks during CIL acts as a mechanotransducer, allowing cells to haptically sense each other and coordinate their behaviors. PMID- 25799389 TI - Surface modification of bacterial cellulose aerogels' web-like skeleton for oil/water separation. AB - The cellulose nanofibers of bacterial cellulose aerogel (BCA) are modified only on their surfaces using a trimethylsilylation reaction with trimethyichlorosilane in liquid phase followed by freeze-drying. The obtained hydrophobic bacterial cellulose aerogels (HBCAs) exhibit low density (<=6.77 mg/cm(3)), high surface area (>=169.1 m(2)/g), and high porosity (~ 99.6%), which are nearly the same as those of BCA owing to the low degrees of substitution (<=0.132). Because the surface energy of cellulose nanofibers decreased and the three-dimensional web like microstructure, which was comprised of ultrathin (20-80 nm) cellulose nanofibers, is maintained during the trimethylsilylation process, the HBCAs have hydrophobic and oleophilic properties (water/air contact angle as high as 146.5 degrees ) that endow them with excellent selectivity for oil adsorption from water. The HBCAs are able to collect a wide range of organic solvents and oils with absorption capacities up to 185 g/g, which depends on the density of the liquids. Hence, the HBCAs are wonderful candidates for oil absorbents to clean oil spills in the marine environment. This work provides a different way to multifunctionalize cellulose aerogel blocks in addition to chemical vapor deposition method. PMID- 25799390 TI - Health-related quality of life in patients with primary cutaneous amyloidosis. AB - BACKGROUND: Primary cutaneous amyloidosis (PCA) is a relatively rare and itchy skin disorder characterized by amyloid deposits in the superficial dermis. The cosmetic disfigurement and severe pruritus dramatically affects the patient's quality of life. In spite of the prevalence of the disease in China, the quality of life (QoL) impact of the PCA has not been well defined and is the focus of this study. OBJECTIVE: To examine the HRQoL of patients with PCA and to evaluate the association between HRQoL scores, disease, and socio-demographic determinants. METHODS: A total of 104 PCA patients and 101 healthy participants completed the questionnaires. HRQoL was measured using dermatology life quality index (DLQI) and SF-36. The socio demographic and clinical data such as age, sex, duration of disease and distribution of lesion pattern were analyzed mainly by hierarchical multiple regression analyses. RESULTS: Patients with PCA experienced significantly impaired health-related quality of life. The mean DLQI score was 9.05. Younger age, female gender, more pruritus and distribution pattern were independent predictor correlates of the high DLQI scores. The PCA group showed significantly decreasing average scores in several aspects of psychological symptoms, including SF, RE and MH. CONCLUSIONS: PCA disease has a negative impact on the HRQoL of patients, and the HRQoL is associated with various disease characteristics. In conjunction with medical interventions, psychological and sociocultural assessment and intervention should be an essential part of the management of these cases. PMID- 25799391 TI - Viral RNA intermediates as targets for detection and discovery of novel and emerging mosquito-borne viruses. AB - Mosquito-borne viruses encompass a range of virus families, comprising a number of significant human pathogens (e.g., dengue viruses, West Nile virus, Chikungunya virus). Virulent strains of these viruses are continually evolving and expanding their geographic range, thus rapid and sensitive screening assays are required to detect emerging viruses and monitor their prevalence and spread in mosquito populations. Double-stranded RNA (dsRNA) is produced during the replication of many of these viruses as either an intermediate in RNA replication (e.g., flaviviruses, togaviruses) or the double-stranded RNA genome (e.g., reoviruses). Detection and discovery of novel viruses from field and clinical samples usually relies on recognition of antigens or nucleotide sequences conserved within a virus genus or family. However, due to the wide antigenic and genetic variation within and between viral families, many novel or divergent species can be overlooked by these approaches. We have developed two monoclonal antibodies (mAbs) which show co-localised staining with proteins involved in viral RNA replication in immunofluorescence assay (IFA), suggesting specific reactivity to viral dsRNA. By assessing binding against a panel of synthetic dsRNA molecules, we have shown that these mAbs recognise dsRNA greater than 30 base pairs in length in a sequence-independent manner. IFA and enzyme-linked immunosorbent assay (ELISA) were employed to demonstrate detection of a panel of RNA viruses from several families, in a range of cell types. These mAbs, termed monoclonal antibodies to viral RNA intermediates in cells (MAVRIC), have now been incorporated into a high-throughput, economical ELISA-based screening system for the detection and discovery of viruses from mosquito populations. Our results have demonstrated that this simple system enables the efficient detection and isolation of a range of known and novel viruses in cells inoculated with field caught mosquito samples, and represents a rapid, sequence-independent, and cost effective approach to virus discovery. PMID- 25799393 TI - Correction: Quantitative evaluation of the reticuloendothelial system function with dynamic MRI. PMID- 25799392 TI - Dysregulated serum IL-23 and SIRT1 activity in peripheral blood mononuclear cells of patients with rheumatoid arthritis. AB - Sirtuin 1 (Sirt1) is a class III histone deacetylase (HDAC) that modulates gene expression and is involved in the regulation of proinflammatory cytokines. Interleukin-23 (IL-23) is produced by activated macrophages and dendritic cells and could fuel the progression of rheumatoid arthritis (RA). The goal of our study was to evaluate serum IL-23 levels and both Sirt1 activity and expression in peripheral blood mononuclear cells (PBMCs) in patients with RA compared to healthy controls (HC) and to determine the relationship between Sirt1 activity/expression and IL-23 levels. We assessed apoptosis in PBMCs of RA patients and its association with Sirt1 expression and serum IL-23. Serum IL-23 levels were increased in RA patients in comparison with controls. We found a positive correlation between the levels of serum IL-23 and serum IL-6 in RA patients. Decreased cytoplasmic Sirt1 activity was observed in RA patients with severe disease compared to HC. The expression of Sirt1 protein was significantly decreased in PBMCs of RA patients compared to HC using western blotting. Serum IL 23 levels correlated positively with the cytoplasmic Sirt1 activity in RA patients. Apoptosis rate of PBMCs isolated from RA patients was increased compared to HC and correlated negatively with the expression of Sirt1 protein and serum IL-23 levels. Levels of serum IL-23 and Sirt1 activity and expression were disturbed in RA parallel to increased PBMC apoptosis. Our findings might provide the rationale for the development of new therapeutic approaches in RA. PMID- 25799394 TI - Functional analysis of the engineered cardiac tissue grown on recombinant spidroin fiber meshes. AB - In the present study, we examined the ability of the recombinant spidroin to serve as a substrate for the cardiac tissue engineering. For this purpose, isolated neonatal rat cardiomyocytes were seeded on the electrospun spidroin fiber matrices and cultured to form the confluent cardiac monolayers. Besides the adhesion assay and immunostaining analysis, we tested the ability of the cultured cardiomyocytes to form a functional cardiac syncytium by studying excitation propagation in the cultured tissue with the aid of optical mapping. It was demonstrated that recombinant spidroin fiber meshes are directly suitable for the adherence and growth of the cardiomyocytes without additional coating with the attachment factors, such as fibronectin. PMID- 25799395 TI - Big five personality factors and cigarette smoking: a 10-year study among US adults. AB - The present study examined the relation between the big five personality traits and any lifetime cigarette use, progression to daily smoking, and smoking persistence among adults in the United States (US) over a ten-year period. Data were drawn from the Midlife Development in the US (MIDUS) I and II (N = 2101). Logistic regression was used to examine the relationship between continuously measured personality factors and any lifetime cigarette use, smoking progression, and smoking persistence at baseline (1995-1996) and at follow-up (2004-2006). The results revealed that higher levels of openness to experience and neuroticism were each significantly associated with increased risk of any lifetime cigarette use. Neuroticism also was associated with increased risk of progression from ever smoking to daily smoking and persistent daily smoking over a ten-year period. In contrast, conscientiousness was associated with decreased risk of lifetime cigarette use, progression to daily smoking, and smoking persistence. Most, but not all, associations between smoking and personality persisted after adjusting for demographic characteristics, depression, anxiety disorders, and substance use problems. The findings suggest that openness to experience and neuroticism may be involved in any lifetime cigarette use and smoking progression, and that conscientiousness appears to protect against smoking progression and persistence. These data add to a growing literature suggesting that certain personality factors--most consistently neuroticism--are important to assess and perhaps target during intervention programs for smoking behavior. PMID- 25799396 TI - Dyslipidemia and chronic inflammation markers are correlated with telomere length shortening in Cushing's syndrome. AB - INTRODUCTION: Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging. AIM: To evaluate relationships between TL, CVR and inflammation markers in CS. METHODS: In a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking matched controls were included. Total white blood cell TL was measured by TRF Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL. RESULTS: Dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328+/-1274 vs 7957+/-1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187+/-1309 vs 7868+/-1104; active: 7203+/-1262 vs 8615+/-1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r 0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and 0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956+/-1280 vs 7860+/-1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL. CONCLUSION: TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a "low" grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS. PMID- 25799397 TI - Evaluation of MDCK cell-derived influenza H7N9 vaccine candidates in ferrets. AB - Avian-origin influenza A (H7N9) viruses emerged as human pathogens in China in early 2013 and have killed >100 persons. Influenza vaccines are mainly manufactured using egg-based technology which could not meet the surging demand during influenza pandemics. In this study, we evaluated cell-based influenza H7N9 vaccines in ferrets. An egg-derived influenza H7N9 reassortant vaccine virus was adapted in MDCK cells. Influenza H7N9 whole virus vaccine antigen was manufactured using a microcarrier-based culture system. Immunogenicity and protection of the vaccine candidates with three different formulations (300 MUg aluminum hydroxide, 1.5 MUg HA, and 1.5 MUg HA plus 300 MUg aluminum hydroxide) were evaluated in ferrets. In ferrets receiving two doses of vaccination, geometric mean titers of hemagglutination (HA) inhibition and neutralizing antibodies were <10 and <40 for the control group (adjuvant only), 17 and 80 for the unadjuvanted (HA only) group, and 190 and 640 for the adjuvanted group (HA plus adjuvant), respectively. After challenge with wild-type influenza H7N9 viruses, virus titers in respiratory tracts of the adjuvanted group were significantly lower than that in the control, and unadjuvanted groups. MDCK cell derived influenza H7N9 whole virus vaccine candidate is immunogenic and protective in ferrets and clinical development is highly warranted. PMID- 25799398 TI - Leptin promotes wound healing in the skin. AB - INTRODUCTION: Leptin, a 16 kDa anti-obesity hormone, exhibits various physiological properties. Interestingly, skin wound healing was proven to delay in leptin-deficient ob/ob mice. However, little is known on the mechanisms of this phenomenon. In this study, we attempted to elucidate a role of leptin in wound healing of skin. METHODS: Immunohistochemical analysis was performed to confirm the expression of the leptin receptor (Ob-R) in human and mouse skin. Leptin was topically administered to chemical wounds created in mouse back skin along with sustained-release absorbable hydrogel. The process of wound repair was histologically observed and the area of ulceration was measured over time. The effect of leptin on the proliferation, differentiation and migration of human epidermal keratinocytes was investigated. RESULTS: Ob-R was expressed in epidermal cells of human and mouse skin. Topical administration of leptin significantly promoted wound healing. Histological analysis showed more blood vessels in the dermal connective tissues in the leptin-treated group. The proliferation, differentiation/function and migration of human epidermal keratinocytes were enhanced by exogenous leptin. CONCLUSION: Topically administered leptin was proven to promote wound healing in the skin by accelerating proliferation, differentiation/function and migration of epidermal keratinocytes and enhancing angiogenesis around the wounded area. These results strongly suggest that topical administration of leptin may be useful as a treatment to promote wound healing in the skin. PMID- 25799399 TI - Role for the propofol hydroxyl in anesthetic protein target molecular recognition. AB - Propofol is a widely used intravenous general anesthetic. We synthesized 2-fluoro 1,3-diisopropylbenzene, a compound that we call "fropofol", to directly assess the significance of the propofol 1-hydroxyl for pharmacologically relevant molecular recognition in vitro and for anesthetic efficacy in vivo. Compared to propofol, fropofol had a similar molecular volume and only a small increase in hydrophobicity. Isothermal titration calorimetry and competition assays revealed that fropofol had higher affinity for a protein site governed largely by van der Waals interactions. Within another protein model containing hydrogen bond interactions, propofol demonstrated higher affinity. In vivo, fropofol demonstrated no anesthetic efficacy, but at high concentrations produced excitatory activity in tadpoles and mice; fropofol also antagonized propofol induced hypnosis. In a propofol protein target that contributes to hypnosis, alpha1beta2gamma2L GABAA receptors, fropofol demonstrated no significant effect alone or on propofol positive allosteric modulation of the ion channel, suggesting an additional requirement for the 1-hydroxyl within synaptic GABAA receptor site(s). However, fropofol caused similar adverse cardiovascular effects as propofol by a dose-dependent depression of myocardial contractility. Our results directly implicate the propofol 1-hydroxyl as contributing to molecular recognition within protein targets leading to hypnosis, but not necessarily within protein targets leading to side effects of the drug. PMID- 25799400 TI - Enteric bacterial pathogens in children with diarrhea in Niger: diversity and antimicrobial resistance. AB - BACKGROUND: Although rotavirus is the leading cause of severe diarrhea among children in sub-Saharan Africa, better knowledge of circulating enteric pathogenic bacteria and their antimicrobial resistance is crucial for prevention and treatment strategies. METHODOLOGY/PRINCIPAL FINDINGS: As a part of rotavirus gastroenteritis surveillance in Maradi, Niger, we performed stool culture on a sub-population of children under 5 with moderate-to-severe diarrhea between April 2010 and March 2012. Campylobacter, Shigella and Salmonella were sought with conventional culture and biochemical methods. Shigella and Salmonella were serotyped by slide agglutination. Enteropathogenic Escherichia coli (EPEC) were screened by slide agglutination with EPEC O-typing antisera and confirmed by detection of virulence genes. Antimicrobial susceptibility was determined by disk diffusion. We enrolled 4020 children, including 230 with bloody diarrhea. At least one pathogenic bacterium was found in 28.0% of children with watery diarrhea and 42.2% with bloody diarrhea. Mixed infections were found in 10.3% of children. EPEC, Salmonella and Campylobacter spp. were similarly frequent in children with watery diarrhea (11.1%, 9.2% and 11.4% respectively) and Shigella spp. were the most frequent among children with bloody diarrhea (22.1%). The most frequent Shigella serogroup was S. flexneri (69/122, 56.5%). The most frequent Salmonella serotypes were Typhimurimum (71/355, 20.0%), Enteritidis (56/355, 15.8%) and Corvallis (46/355, 13.0%). The majority of putative EPEC isolates was confirmed to be EPEC (90/111, 81.1%). More than half of all Enterobacteriaceae were resistant to amoxicillin and co-trimoxazole. Around 13% (46/360) Salmonella exhibited an extended-spectrum beta-lactamase phenotype. CONCLUSIONS: This study provides updated information on enteric bacteria diversity and antibiotic resistance in the Sahel region, where such data are scarce. Whether they are or not the causative agent of diarrhea, bacterial infections and their antibiotic resistance profiles should be closely monitored in countries like Niger where childhood malnutrition pre-disposes to severe and invasive infections. PMID- 25799401 TI - Prevalence of serum celiac antibodies in a multiracial Asian population--a first study in the young Asian adult population of Malaysia. AB - BACKGROUND: Celiac disease (CD) is an immune-mediated disorder induced by the ingestion of gluten in genetically susceptible persons. The prevalence of CD in Malaysia is unknown. We aim to determine the seroprevalence of CD antibodies and also investigate the correlation between H. pylori infection and CD in the young and healthy multiracial Malaysian population. METHODS: Healthy young adult volunteers between the ages of 18-30 years were consecutively recruited from June 2012 to May 2014 at the University of Malaya Medical Centre (UMMC), Kuala Lumpur. Serum samples from all the participants were tested for anti-gliadin antibody immunoglobulin A/immunoglobulin G (IgA/IgG) and anti-tissue transglutaminase antibody (tTG) IgA/IgG. Samples positive for both anti-gliadin and anti-tTG were further validated for anti-human endomysial IgA antibodies (EmA). Serological diagnosis of CD was made when anti-gliadin, anti-tTG and anti-EmA were positive. RESULTS: 562 qualified participants with mean age 24 +/- 2.4 years old were recruited into our study. CD was found in 7 participants where most of them were asymptomatic and unaware of their CD status. The median of anti-gliadin and anti tTG IgA/IgG value was 38.2 U/ml (interquartile range, 28.3-60.4 U/ml) and 49.2 U/ml (interquartile range, 41.1-65.9 U/ml), respectively. Seroprevalence of CD antibodies was 1.9% (6 out of 324) in female while only 0.4% (1 out of 238) in male. Seroprevalence among Malay was 0.8% (2 of 236), Chinese was 1.7% (3 of 177) and Indian was 1.3% (2 of 149). Overall, seroprevalence of CD antibodies in healthy asymptomatic adults in the Malaysian population was 1.25% (95% CI, 0.78% 1.72%). No significant relationship was discovered between CD and H. pylori infection. CONCLUSIONS: The seroprevalence of CD antibodies in healthy young adults in the Malaysian population was 1.25% (1 in 100). CD is underdiagnosed and it could be a much greater problem in Malaysia than previously thought. PMID- 25799402 TI - Exercise and vitamin D in fall prevention among older women: a randomized clinical trial. AB - IMPORTANCE: While vitamin D supplementation and exercise are recommended for prevention of falls for older people, results regarding these 2 factors are contradictory. OBJECTIVE: To determine the effectiveness of targeted exercise training and vitamin D supplementation in reducing falls and injurious falls among older women. DESIGN, SETTING, AND PARTICIPANTS: A 2-year randomized, double blind, placebo-controlled vitamin D and open exercise trial conducted between April 2010 and March 2013 in Tampere, Finland. Participants were 409 home dwelling women 70 to 80 years old. The main inclusion criteria were at least 1 fall during the previous year, no use of vitamin D supplements, and no contraindication to exercise. INTERVENTIONS: Four study groups, including placebo without exercise, vitamin D (800 IU/d) without exercise, placebo and exercise, and vitamin D (800 IU/d) and exercise. MAIN OUTCOMES AND MEASURES: The primary outcome was monthly reported falls. Injurious falls and the number of fallers and injured fallers were reported as secondary outcomes. In addition, bone density, physical functioning (muscle strength, balance, and mobility), and vitamin D metabolism were assessed. RESULTS: Intent-to-treat analyses showed that neither vitamin D nor exercise reduced falls. Fall rates per 100 person-years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively. Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17-0.83) and without vitamin D (0.47; 95% CI, 0.23-0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning. CONCLUSIONS AND RELEVANCE: The rate of injurious falls and injured fallers more than halved with strength and balance training in home dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00986466. PMID- 25799404 TI - Binder-free layered Ti3C2/CNTs nanocomposite anodes with enhanced capacity and long-cycle life for lithium-ion batteries. AB - A two-dimensional layered Ti3C2/carbon nanotubes (CNTs) hybrid thin film was prepared. Owing to the excellent conductivity of the CNTs, this unique layered structure provides a rapid charge transfer path during the electrochemical reaction, as a lithium ion battery anode, which exhibits higher capacitance and better cycling stability (a reversible capacity of 428.1 mA h g(-1) at 0.5 C after 300 cycles) compared with 96.2 mA h g(-1) of pure Ti3C2 nanosheets, as well as superior rate capability. PMID- 25799403 TI - Longitudinal study of performance on the Ruff Figural Fluency Test in persons aged 35 years or older. AB - The Ruff Figural Fluency Test (RFFT) is a cognitive test to measure executive function. Longitudinal studies have shown that repeated testing improves performance on the RFFT. Such a practice effect may hinder the interpretation of test results in a clinical setting. Therefore, we investigated the longitudinal performance on the RFFT in persons aged 35-82 years. Performance on the RFFT was measured three times over an average follow-up period of six years in 2,515 participants of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study in Groningen, the Netherlands: 53% men; mean age (SD), 53 (10) years. The effect of consecutive measurements on performance on the RFFT was investigated with linear multilevel regression models that also included age, gender, educational level and the interaction term consecutive measurement number x age as independent variables. It was found that the mean (SD) number of unique designs on the RFFT increased from 73 (26) at the first measurement to 79 (27) at the second measurement and to 83 (26) at the third measurement (p<0.001). However, the increase per consecutive measurement number was negatively associated with age and decreased with 0.23 per one-year increment of age (p<0.001). The increase per consecutive measurement number was not dependent on educational level. Similar results were found for the median (IQR) number of perseverative errors which showed a small but statistically significant increase with repeating testing: 7 (3-13) at the first measurement, 7 (4-14) at the second measurement and 8 (4-15) at the third measurement (p trend = 0.002). In conclusion, the performance on the RFFT improved by repeating the test over an average follow-up period of three to six years. This practice effect was the largest in young adults and not dependent on educational level. PMID- 25799406 TI - Catalytic asymmetric direct-type 1,4-addition reactions of simple amides. AB - The development of catalytic asymmetric direct-type reactions of less acidic carbonyl compounds such as amides and esters has been a challenging theme in organic chemistry for decades. Here we describe the asymmetric direct 1,4 addition reactions of simple amides with alpha,beta-unsaturated carbonyl compounds using a catalytic amount of a novel chiral catalyst consisting of a potassium base and a macrocyclic chiral crown ether. The desired 1,5-dicarbonyl compounds were obtained in high yields with excellent diastereo- and enantioselectivities. This is the first example of a highly enantioselective catalytic direct-type reaction of simple amides. In addition, the structure of the chiral potassium catalyst has been investigated by X-ray crystallographic, dynamic (1)H NMR, and MALDI-TOF MS analyses. PMID- 25799405 TI - Polymorphisms in endothelin system genes, arsenic levels and obesity risk. AB - BACKGROUND/OBJECTIVES: Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity. SUBJECTS/METHODS: We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex. RESULTS: We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53). CONCLUSIONS: Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels. PMID- 25799407 TI - Development of a molecularly evolved, highly sensitive CaMKII FRET sensor with improved expression pattern. AB - Genetically encoded fluorescence resonance energy transfer (FRET) biosensors have been successfully used to visualize protein activity in living cells. The sensitivity and accuracy of FRET measurements directly depend on biosensor folding efficiency, expression pattern, sensitivity, and dynamic range. Here, to improve the folding efficiency of the Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) FRET biosensor, we amplified the association domain of the CaMKIIalpha gene using error-prone polymerase chain reaction (PCR) and fused it to the N-terminus of mCherry in a bacterial expression vector. We also created an Escherichia coli expression library based on a previously reported fluorescent protein folding reporter method, and found a bright red fluorescent colony that contained the association domain with four mutations (F394L, I419V, A430T, and I434T). In vitro assays using the purified mutant protein confirmed improved folding kinetics of the downstream fluorescent protein, but not of the association domain itself. Furthermore, we introduced these mutations into the previously reported CaMKIIalpha FRET sensor and monitored its Ca2+/calmodulin dependent activation in HeLa cells using 2-photon fluorescence lifetime imaging microscopy (2pFLIM), and found that the expression pattern and signal reproducibility of the mutant sensor were greatly improved without affecting the autophosphorylation function and incorporation into oligomeric CaMKIIalpha. We believe that our improved CaMKIIalpha FRET sensor would be useful in various types of cells and tissues, providing data with high accuracy and reproducibility. In addition, the method described here may also be applicable for improving the performance of all currently available FRET sensors. PMID- 25799408 TI - Three new quaternary actinide chalcogenides Ba2TiUTe7, Ba2CrUTe7, and Ba2CrThTe7: syntheses, crystal structures, transport properties, and theoretical studies. AB - The three new quaternary actinide chalcogenides Ba2TiUTe7, Ba2CrUTe7, and Ba2CrThTe7 have been synthesized. From single-crystal X-ray diffraction studies these isostructural compounds are found to crystallize in a new structure type in space group D2h16-Pnma of the orthorhombic system. The structure features infinity1[MAnTe74-] strips (M = Cr or Ti; An = Th or U) that propagate in the b direction and are separated by Ba cations. An atoms are coordinated to eight Te atoms in a bicapped trigonal-prismatic geometry while M atoms are octahedrally coordinated to six Te atoms. Sharing of the AnTe8 and MTe6 polyhedra forms infinity1[MAnTe74-] strips. The presence of the infinite linear Te-Te-Te chains in these compounds makes assignment of oxidation states arbitrary. Resistivity measurements and DFT calculations provide further insight into the properties of these compounds. PMID- 25799410 TI - Correction: Exploring the distribution of genetic markers of pharmacogenomics relevance in Brazilian and Mexican populations. PMID- 25799409 TI - Hook proteins: association with Alzheimer pathology and regulatory role of hook3 in amyloid beta generation. AB - Defects in intracellular transport are implicated in the pathogenesis of Alzheimer's disease (AD). Hook proteins are a family of cytoplasmic linker proteins that participate in endosomal transport. In this study we show that Hook1 and Hook3 are expressed in neurons while Hook2 is predominantly expressed in astrocytes. Furthermore, Hook proteins are associated with pathological hallmarks in AD; Hook1 and Hook3 are localized to tau aggregates and Hook2 to glial components within amyloid plaques. Additionally, the expression of Hook3 is reduced in AD. Modelling of Hook3 deficiency in cultured cells leads to slowing of endosomal transport and increases beta-amyloid production. We propose that Hook3 plays a role in pathogenic events exacerbating AD. PMID- 25799412 TI - SCF, regulated by HIF-1alpha, promotes pancreatic ductal adenocarcinoma cell progression. AB - Stem cell factor (SCF) and hypoxia-inducible factor-1alpha (HIF-1alpha) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF 1alpha in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1alpha expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1alpha in PDAC cells at the protein and RNA levels. When HIF-1alpha was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1alpha can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1alpha knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1alpha expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1alpha and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1alpha, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC. PMID- 25799411 TI - Characterization of a novel N-acetylneuraminic acid lyase favoring industrial N acetylneuraminic acid synthesis. AB - N-Acetylneuraminic acid lyase (NAL, E.C. number 4.1.3.3) is a Class I aldolase that catalyzes the reversible aldol cleavage of N-acetylneuraminic acid (Neu5Ac) from pyruvate and N-acetyl-D-mannosamine (ManNAc). Due to the high Neu5Ac cleavage activity in most isozyme forms, the enzyme catalyzes the rate-limiting step of two biocatalytic reactions producing Neu5Ac in industry. We report the biochemical characterization of a novel NAL from a "GRAS" (General recognized as safe) strain C. glutamicum ATCC 13032 (CgNal). Compared to all previously reported NALs, CgNal exhibited the lowest kcat/Km value for Neu5Ac and highest kcat/Km values for ManNAc and pyruvate, which makes CgNal favor industrial Neu5Ac synthesis process in a non-equilibrium condition. The recombinant CgNal reached the highest expression level (480 mg/L culture), and the highest reported yield of Neu5Ac was achieved (194 g/L, 0.63 M). All these unique properties make CgNal a promising biocatalyst for industrial Neu5Ac biosynthesis. Additionally, although showing the best Neu5Ac synthesis activity among the NAL family, CgNal is more related to dihydrodipicolinate synthase (DHDPS) by phylogenetic analysis. The activities of CgNal towards both NAL's and DHDPS' substrates are fairly high, which indicates CgNal a bi-functional enzyme. The sequence analysis suggests that CgNal might have adopted a unique set of residues for substrates recognition. PMID- 25799413 TI - Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile. AB - Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as alpha-methoxy-omega-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); alpha-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol. PMID- 25799414 TI - Mycobacterial dihydrofolate reductase inhibitors identified using chemogenomic methods and in vitro validation. AB - The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s) and mechanism of action of the hits. This target identification, or deorphanization step, is often essential in further optimization and validation studies. Direct experimental identification of the molecular target of a screening hit is often complex, precisely because the properties and specificity of the hit are not yet optimized against that target, and so many false positives are often obtained. An alternative is to use computational, predictive, approaches to hypothesize a mechanism of action, which can then be validated in a more directed and efficient manner. Specifically here we present experimental validation of an in silico prediction from a large-scale screen performed against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. The two potent anti-tubercular compounds studied in this case, belonging to the tetrahydro-1,3,5-triazin-2-amine (THT) family, were predicted and confirmed to be an inhibitor of dihydrofolate reductase (DHFR), a known essential Mtb gene, and already clinically validated as a drug target. Given the large number of similar screening data sets shared amongst the community, this in vitro validation of these target predictions gives weight to computational approaches to establish the mechanism of action (MoA) of novel screening hit. PMID- 25799415 TI - Association between thiopurine S-methyltransferase polymorphisms and thiopurine induced adverse drug reactions in patients with inflammatory bowel disease: a meta-analysis. AB - PURPOSE: Thiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Although several studies have investigated the association between TPMT polymorphisms and thiopurine-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs using meta-analysis. METHODS: We explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and thiopurine-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in IBD patients were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratio (OR) with corresponding 95% confidence intervals were calculated using Revman 5.3 software. RESULTS: Fourteen published studies, with a total of 2,206 IBD patients, which investigated associations between TPMT polymorphisms and thiopurine-induced ADRs were included this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with thiopurine-induced overall ADRs and bone marrow toxicity; pooled ORs were 3.36 (95%CI: 1.82-6.19) and 6.67 (95%CI: 3.88-11.47), respectively. TPMT polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60-2.71), 0.97 (95%CI: 0.38-2.48), 1.82 (95%CI: 0.93-3.53), 1.28 (95%CI: 0.47-3.46) and 2.32 (95%CI: 0.86-6.25), respectively. CONCLUSIONS: Our meta-analysis demonstrated an association of TPMT polymorphisms with overall thiopurine-induced ADRs and bone marrow toxicity, but not with hepatotoxicity, pancreatitis, flu-like symptoms, gastric intolerance and skin reactions. These findings suggest that pretesting the TPMT genotype could be helpful in clinical practice before initiating thiopurine therapy. However, white blood cell count analysis should be the mainstay for follow-up. PMID- 25799416 TI - Vitamin D receptor Cdx-2 polymorphism and premenopausal breast cancer risk in southern Pakistani patients. AB - BACKGROUND: Vitamin D3 is a secoster oid that exerts its effect by binding to its nuclear receptor called vitamin D receptor (VDR), inducing apoptosis and thereby inhibiting cell proliferation in cancer cells. The VDR receptor, located in the nucleus, is known to regulate the functions of over 200 genes. Various allelic forms of hVDR have been discovered that increase susceptibility to various cancers. The VDR-Cdx2 polymorphism, located in the promoter region of exon 1e in the VDR gene, influences the functional activity of the receptor, since the hVDR lacks consensus TATA and CAAT boxes. The current investigation examines the association between VDR-Cdx2 polymorphism and breast cancer in premenopausal females from Southern Pakistan. METHODS: We conducted a case control study on 264 subjects (103 cases and 161 controls) who were recruited from a tertiary hospital located in Karachi, Pakistan. Genomic DNA was extracted from peripheral blood using a commercial kit method, and the VDR-Cdx2 polymorphism was genotyped using tetraprimer amplification refractory mutation system polymerase chain reaction (T ARMS-PCR) method. Pearson chi square test was used to assess the association between VDR-Cdx2 genotype and breast cancer while genotype distribution in controls was evaluated by Hardy-Weinberg equilibrium (HWE). Breast cancer risk was calculated using odds ratios and 95% confidence intervals. RESULTS: The genotype distribution in the control group was in HWE (p > 0.05) for the VDR-Cdx2 polymorphism. A non-significant association was observed between VDR cdx2 polymorphism and breast cancer, however the GG genotype was at risk (OR = 1.832, 95% CI = 0.695-4.828) of developing breast cancer. CONCLUSION: The GG genotype of Cdx2-VDR gene polymorphism may increase the risk of developing breast cancer in young female patients in South Pakistan. Further investigations examining additional single nucleotide polymorphisms (SNPs) in VDR are required to assess their relationships with breast cancer. PMID- 25799417 TI - Development of a targeted flip-in system in avian DT40 cells. AB - Gene-targeting to create null mutants or designed-point mutants is a powerful tool for the molecular dissection of complex phenotypes involving DNA repair, signal transduction, and metabolism. Because gene-targeting is critically impaired in mutants exhibiting attenuated homologous recombination (HR), it is believed that gene-targeting is mediated via homologous recombination, though the precise mechanism remains unknown. We explored gene-targeting in yeast and avian DT40 cells. In animal cells, gene-targeting is activated by DNA double strand breaks introduced into the genomic region where gene-targeting occurs. This is evidenced by the fact that introducing double strand breaks at targeted genome sequences via artificial endonucleases such as TALEN and CRISPR facilitates gene targeting. We found that in fission yeast, Schizosaccharomyces pombe, gene targeting was initiated from double strand breaks on both edges of the homologous arms in the targeting construct. Strikingly, we also found efficient gene targeting initiated on the edges of homologous arms in avian DT40 cells, a unique animal cell line in which efficient gene-targeting has been demonstrated. It may be that yeast and DT40 cells share some mechanism in which unknown factors detect and recombine broken DNA ends at homologous arms accompanied by crossover. We found efficient targeted integration of gapped plasmids accompanied by crossover in the DT40 cells. To take advantage of this finding, we developed a targeted flip-in system for avian DT40 cells. This flip-in system enables the rapid generation of cells expressing tag-fused proteins and the stable expression of transgenes from OVA loci. PMID- 25799418 TI - Assessment of rosacea severity: A review of evaluation methods used in clinical trials. AB - BACKGROUND: Novel rosacea treatments are needed. Assessment methodologies for clinical trials of rosacea treatments are not standardized and are relatively inadequate. To determine the efficacy of new treatments, a valid and reliable assessment methodology is needed. OBJECTIVE: We sought to determine the assessment methodologies used in clinical trials for rosacea treatments, to demonstrate the need for a valid and reliable assessment tool, and to describe the relevant properties of such a tool. METHODS: PubMed and MEDLINE were searched for clinical trials of rosacea treatments since January 1, 1985. RESULTS: In all, 32 clinical trials met inclusion criteria. Assessment methodologies were highly variable, and standardized assessment methodologies were used in only 3 studies. The various manifestations of rosacea were assessed inconsistently. LIMITATIONS: Eighteen articles could not be included as a result of lack of access to the full text. CONCLUSIONS: The diverse methodologies make the assessment of novel treatments and comparison of treatments difficult. A valid and reliable assessment tool is needed to properly assess novel treatments to improve the management of rosacea. PMID- 25799419 TI - Field evaluation of personal sampling methods for multiple bioaerosols. AB - Ambient bioaerosols are ubiquitous in the daily environment and can affect health in various ways. However, few studies have been conducted to comprehensively evaluate personal bioaerosol exposure in occupational and indoor environments because of the complex composition of bioaerosols and the lack of standardized sampling/analysis methods. We conducted a study to determine the most efficient collection/analysis method for the personal exposure assessment of multiple bioaerosols. The sampling efficiencies of three filters and four samplers were compared. According to our results, polycarbonate (PC) filters had the highest relative efficiency, particularly for bacteria. Side-by-side sampling was conducted to evaluate the three filter samplers (with PC filters) and the NIOSH Personal Bioaerosol Cyclone Sampler. According to the results, the Button Aerosol Sampler and the IOM Inhalable Dust Sampler had the highest relative efficiencies for fungi and bacteria, followed by the NIOSH sampler. Personal sampling was performed in a pig farm to assess occupational bioaerosol exposure and to evaluate the sampling/analysis methods. The Button and IOM samplers yielded a similar performance for personal bioaerosol sampling at the pig farm. However, the Button sampler is more likely to be clogged at high airborne dust concentrations because of its higher flow rate (4 L/min). Therefore, the IOM sampler is a more appropriate choice for performing personal sampling in environments with high dust levels. In summary, the Button and IOM samplers with PC filters are efficient sampling/analysis methods for the personal exposure assessment of multiple bioaerosols. PMID- 25799420 TI - miRNA expression profile and involvement of Let-7d-APP in aged rats with isoflurane-induced learning and memory impairment. AB - MicroRNAs (miRNAs) play a key role in different nervous system diseases. We sought to determine the role of miRNAs in isoflurane-induced learning and memory impairment in aged rats. Male Sprague-Dawley (SD) rats of 18 month were randomly assigned to control group (exposed to mock anesthesia), 2-hour group and 6-hour group (exposed to 2% isoflurane for 2 and 6 hours respectively). By Morris Water Maze, 6-hour group showed impaired learning and memory ability while 2-hour group not. As shown by miRNA array, control group and 2-hour group showed a similar miRNA expression profile. And 38 miRNAs are differently expressed in 6-hour group compared to the other 2 groups, including 21 up-regulated miRNAs and 17 down regulated miRNAs. And 4 of the differentially expressed miRNAs were validated independently by qRT-PCR. Let-7d was downregulated in 6-hour group. Additionally, we demonstrated that amyloid precursor protein (APP) was a direct target of let 7d by Fluorescent report assay. Increased expression of APP and amyloid-beta (Abeta) were found in the hippocampi of 6-hour group. Downregulation of let-7d might contribute to isoflurane-induced learning and memory impairment through upregulating its target APP, and increasing the production of Abeta subsequently. PMID- 25799421 TI - Outbreak of multidrug resistant NDM-1-producing Klebsiella pneumoniae from a neonatal unit in Shandong Province, China. AB - Despite worldwide dissemination of New Delhi metallo-beta-lactamase1 (blaNDM-1), outbreaks remain uncommon in China. In this study, we describe the characteristics of the outbreak-related blaNDM-1-producing K. pneumonia isolates in a neonatal unit in Shandong province, China. We recovered 21 non-repetitive carbapenem-resistant K. pneumoniae isolates with a positively modified Hodge test (MHT) or EDTA synergistic test from patients and environmental samples in Shandong provincial hospital. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) data show K. pneumoniae isolates from 19 patients were clonally related and belong to the clonal groups ST20 and ST17. We note two outbreaks, the first caused by ST20 during August 2012 involving four patients, and the second caused by ST20 and ST17 during January 2012 and September 2013 involving fourteen patients. We found the bed railing of one patient was the source of the outbreak. We verified the presence of the blaNDM-1 gene in 21 K. pneumoniae isolates. The genes blaCTX-M-15, blaCTX-M-14, blaDHA-1, blaTEM-1 and Class I integron were also present in 18 (85.7%), 3 (14.3%), 18 (85.7%), 19 (90.5%) and 19 (90.5%) isolates, respectively. We also found an isolate with both blaNDM-1 and blaIMP-4. All of the isolates exhibited a multidrug-resistance phenotype. The beta-lactam resistance of 20 isolates was transferable via conjugation. In addition, we show the resistance of 21 K. pneumoniae isolates to carbapenem is not related to lack of outer-membrane proteins OmpK35 and OmpK36 nor overpression of efflux pumps. This study provides the first report confirming blaNDM-1-producing K. pneumoniae ST20 and ST17 were associated with outbreak. Early detection of resistance genes is an effective strategy in preventing and controlling infection by limiting the dissemination of these organisms. PMID- 25799422 TI - Rapid-rate paired associative stimulation over the primary somatosensory cortex. AB - Rapid-rate paired associative stimulation (rPAS) involves repeat pairing of peripheral nerve stimulation and Transcranial magnetic stimulation (TMS) pulses at a 5 Hz frequency. RPAS over primary motor cortex (M1) operates with spike timing dependent plasticity such that increases in corticospinal excitability occur when the nerve and TMS pulse temporally coincide in cortex. The present study investigates the effects of rPAS over primary somatosensory cortex (SI) which has not been performed to date. In a series of experiments, rPAS was delivered over SI and M1 at varying timing intervals between the nerve and TMS pulse based on the latency of the N20 somatosensory evoked potential (SEP) component within each participant (intervals for SI-rPAS: N20, N20-2.5 ms, N20 + 2.5 ms, intervals for M1-rPAS: N20, N20+5 ms). Changes in SI physiology were measured via SEPs (N20, P25, N20-P25) and SEP paired-pulse inhibition, and changes in M1 physiology were measured with motor evoked potentials and short latency afferent inhibition. Measures were obtained before rPAS and at 5, 25 and 45 minutes following stimulation. Results indicate that paired-pulse inhibition and short-latency afferent inhibition were reduced only when the SI-rPAS nerve TMS timing interval was set to N20-2.5 ms. SI-rPAS over SI also led to remote effects on motor physiology over a wider range of nerve-TMS intervals (N20-2.5 ms - N20+2.5 ms) during which motor evoked potentials were increased. M1-rPAS increased motor evoked potentials and reduced short-latency afferent inhibition as previously reported. These data provide evidence that, similar to M1, rPAS over SI is spike-timing dependent and is capable of exerting changes in SI and M1 physiology. PMID- 25799424 TI - Irreversible collective migration of cyanobacteria in eutrophic conditions. AB - In response to natural or anthropocentric pollutions coupled to global climate changes, microorganisms from aquatic environments can suddenly accumulate on water surface. These dense suspensions, known as blooms, are harmful to ecosystems and significantly degrade the quality of water resources. In order to determine the physico-chemical parameters involved in their formation and quantitatively predict their appearance, we successfully reproduced irreversible cyanobacterial blooms in vitro. By combining chemical, biochemical and hydrodynamic evidences, we identify a mechanism, unrelated to the presence of internal gas vesicles, allowing the sudden collective upward migration in test tubes of several cyanobacterial strains (Microcystis aeruginosa PCC 7005, Microcystis aeruginosa PCC 7806 and Synechocystis sp. PCC 6803). The final state consists in a foamy layer of biomass at the air-liquid interface, in which micro organisms remain alive for weeks, the medium lying below being almost completely depleted of cyanobacteria. These "laboratory blooms" start with the aggregation of cells at high ionic force in cyanobacterial strains that produce anionic extracellular polymeric substances (EPS). Under appropriate conditions of nutrients and light intensity, the high photosynthetic activity within cell clusters leads the dissolved oxygen (DO) to supersaturate and to nucleate into bubbles. Trapped within the EPS, these bubbles grow until their buoyancy pulls the biomass towards the free surface. By investigating a wide range of spatially homogeneous environmental conditions (illumination, salinity, cell and nutrient concentration) we identify species-dependent thresholds and timescales for bloom formation. We conclude on the relevance of such results for cyanobacterial bloom formation in the environment and we propose an efficient method for biomass harvesting in bioreactors. PMID- 25799423 TI - Low-dose irradiation affects expression of inflammatory markers in the heart of ApoE -/- mice. AB - Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNFalpha, INFgamma, IL-1beta, TGFbeta, INFgamma, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNFalpha and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long term side effects but also give important implications for low dose anti inflammatory radiotherapy. PMID- 25799426 TI - Teaching qualitative research as a means of socialization to nursing. AB - The aim of the present article is to present a model for teaching qualitative research as part of nursing education. The uniqueness of the course model is that it seeks to combine two objectives: (1) initial familiarization of the students with the clinical-nursing environment and the role of the nurse; and (2) understanding the qualitative research approach and inculcation of basic qualitative research skills. The article describes how teaching two central genres in qualitative research - ethnographic and narrative research - constitutes a way of teaching the important skills, concepts, and values of the nursing profession. The article presents the model's structure, details its principal stages, and explains the rationale of each stage. It also presents the central findings of an evaluation of the model's implementation in eight groups over a two-year period. In this way the article seeks to contribute to nursing education literature in general, and to those engaged in clinical training and teaching qualitative research in nursing education in particular. PMID- 25799425 TI - gamma-H2AX as a marker for dose deposition in the brain of wistar rats after synchrotron microbeam radiation. AB - OBJECTIVE: Synchrotron radiation has shown high therapeutic potential in small animal models of malignant brain tumours. However, more studies are needed to understand the radiobiological effects caused by the delivery of high doses of spatially fractionated x-rays in tissue. The purpose of this study was to explore the use of the gamma-H2AX antibody as a marker for dose deposition in the brain of rats after synchrotron microbeam radiation therapy (MRT). METHODS: Normal and tumour-bearing Wistar rats were exposed to 35, 70 or 350 Gy of MRT to their right cerebral hemisphere. The brains were extracted either at 4 or 8 hours after irradiation and immediately placed in formalin. Sections of paraffin-embedded tissue were incubated with anti gamma-H2AX primary antibody. RESULTS: While the presence of the C6 glioma does not seem to modulate the formation of gamma-H2AX in normal tissue, the irradiation dose and the recovery versus time are the most important factors affecting the development of gamma-H2AX foci. Our results also suggest that doses of 350 Gy can trigger the release of bystander signals that significantly amplify the DNA damage caused by radiation and that the gamma-H2AX biomarker does not only represent DNA damage produced by radiation, but also damage caused by bystander effects. CONCLUSION: In conclusion, we suggest that the gamma-H2AX foci should be used as biomarker for targeted and non-targeted DNA damage after synchrotron radiation rather than a tool to measure the actual physical doses. PMID- 25799427 TI - Curcuminoids extract, hydrolyzed collagen and green tea extract synergically inhibit inflammatory and catabolic mediator's synthesis by normal bovine and osteoarthritic human chondrocytes in monolayer. AB - The main objective of this study was to assess the in vitro effects of curcuminoids extract, hydrolyzed collagen and green tea extract in normal bovine chondrocytes and osteoarthritic human chondrocytes cultured in monolayer. This study also investigated the synergic or additive effects of these compounds. Enzymatically isolated primary bovine or human chondrocytes were cultured in monolayer until confluence and then incubated for 24 hours or 48 hours in the absence or in the presence of interleukin-1beta and with or without curcuminoids extract, hydrolyzed collagen or green tea extract, added alone or in combination, at different concentrations. Cell viability was neither affected by these compounds, nor by interleukin 1beta. In the absence of interleukin-1beta, compounds did not significantly affect bovine chondrocytes metabolism. In human chondrocytes and in the absence of interleukin 1beta, curcuminoids extract alone or in combination with hydrolyzed collagen and green tea extract significantly inhibited matrix metalloproteinase-3 production. In interleukin-1beta-stimulated bovine chondrocytes, interleukin-6, inducible nitric oxide synthase, cyclooxygenase2, matrix metalloproteinase 3, a disintegrin and metalloproteinase with thrombospondin type I motifs 4 and a disintegrin and metalloproteinase with thrombospondin type I motifs 5 expressions were decreased by curcuminoids extract alone or in combination with hydrolyzed collagen and green tea extract. The combination of the three compounds was significantly more efficient to inhibit interleukin-1beta stimulated matrix metalloproteinase-3 expression than curcuminoids extract alone. In interleukin-1beta-stimulated human chondrocytes, nitric oxide, interleukin-6 and matrix metalloproteinase 3 productions were significantly reduced by curcuminoids extract alone or in combination with hydrolyzed collagen and green tea extract. These findings indicate that a mixture of curcuminoids extract, hydrolyzed collagen and green tea extract has beneficial effects on chondrocytes culture in inflammatory conditions and provide a preclinical basis for the in vivo testing of this mixture. PMID- 25799428 TI - [Massive panniculectomy and bilateral subtotal mastectomy in a case of calciphylaxis: A case report and up date]. AB - Calciphylaxis or calcific arteriolopathy is a rare, life-threatening obstructive pathology of the small cutaneous and subcutaneous vessels. It mainly affects patients with chronic renal failure but it also has been described in patients with normal renal function. The principal risks factors apart from renal failure and phosphocalcic metabolism imbalance are: the female sex, obesity, peripheral vascular disease, diabetes and oral anti-coagulation. We present a very rare case of abdominal, mammarian and upper thighs calciphylaxis in a patient with normal renal function. She presented a severe obesity with a recent important loss of weight and had been treated by oral anticoagulants for a long time. She benefited of a multidisciplinary approach with dermatologists, plastic surgeons and anesthesists permitting a recovery in fourteen weeks. Multidisciplinary approach is necessary but the place of the surgery is not well defined. We report a case in which early and wide surgical approach permitted to obtain a favourable evolution of the pathology. Then, we propose a therapeutic strategy after review of the literature. PMID- 25799429 TI - Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice. AB - Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor gamma (PPARgamma) rather than PPARalpha. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID- 25799430 TI - Incomplete but infectious vaccinia virions are produced in the absence of oncolysis in feline SCCF1 cells. AB - Vaccinia virus is a large, enveloped virus of the poxvirus family. It has broad tropism and typically virus replication culminates in accumulation and lytic release of intracellular mature virus (IMV), the most abundant form of infectious virus, as well as release by budding of extracellular enveloped virus (EEV). Vaccinia viruses have been modified to replicate selectively in cancer cells and clinically tested as oncolytic agents. During preclinical screening of relevant cancer targets for a recombinant Western Reserve strain deleted for both copies of the thymidine kinase and vaccinia growth factor genes, we noticed that confluent monolayers of SCCF1 cat squamous carcinoma cells were not destroyed even after prolonged infection. Interestingly, although SCCF1 cells were not killed, they continuously secreted virus into the cell culture supernatant. To investigate this finding further, we performed detailed studies by electron microscopy. Both intracellular and secreted virions showed morphological abnormalities on ultrastructural inspection, suggesting compromised maturation and morphogenesis of vaccinia virus in SCCF1 cells. Our data suggest that SCCF1 cells produce a morphologically abnormal virus which is nevertheless infective, providing new information on the virus-host cell interactions and intracellular biology of vaccinia virus. PMID- 25799431 TI - Enhancing sensorimotor activity by controlling virtual objects with gaze. AB - This fMRI work studies brain activity of healthy volunteers who manipulated a virtual object in the context of a digital game by applying two different control methods: using their right hand or using their gaze. The results show extended activations in sensorimotor areas, not only when participants played in the traditional way (using their hand) but also when they used their gaze to control the virtual object. Furthermore, with the exception of the primary motor cortex, regional motor activity was similar regardless of what the effector was: the arm or the eye. These results have a potential application in the field of the neurorehabilitation as a new approach to generate activation of the sensorimotor system to support the recovery of the motor functions. PMID- 25799432 TI - Soil-applied imidacloprid translocates to ornamental flowers and reduces survival of adult Coleomegilla maculata, Harmonia axyridis, and Hippodamia convergens lady beetles, and larval Danaus plexippus and Vanessa cardui butterflies. AB - Integrated Pest Management (IPM) is a decision making process used to manage pests that relies on many tactics, including cultural and biological control, which are practices that conserve beneficial insects and mites, and when needed, the use of conventional insecticides. However, systemic, soil-applied neonicotinoid insecticides are translocated to pollen and nectar of flowers, often for months, and may reduce survival of flower-feeding beneficial insects. Imidacloprid seed-treated crops (0.05 mg AI (active ingredient) /canola seed and 1.2 mg AI/corn seed) translocate less than 10 ppb to pollen and nectar. However, higher rates of soil-applied imidacloprid are used in nurseries and urban landscapes, such as 300 mg AI/10 L (3 gallon) pot and 69 g AI applied to the soil under a 61 (24 in) cm diam. tree. Translocation of imidacloprid from soil (300 mg AI) to flowers of Asclepias curassavica resulted in 6,030 ppb in 1X and 10,400 ppb in 2X treatments, which are similar to imidacloprid residues found in another plant species we studied. A second imidacloprid soil application 7 months later resulted in 21,000 ppb in 1X and 45,000 ppb in 2X treatments. Consequently, greenhouse/nursery use of imidacloprid applied to flowering plants can result in 793 to 1,368 times higher concentration compared to an imidacloprid seed treatment (7.6 ppb pollen in seed- treated canola), where most research has focused. These higher imidacloprid levels caused significant mortality in both 1X and 2X treatments in 3 lady beetle species, Coleomegilla maculata, Harmonia axyridis, and Hippodamia convergens, but not a fourth species, Coccinella septempunctata. Adult survival were not reduced for monarch, Danaus plexippus and painted lady, Vanessa cardui, butterflies, but larval survival was significantly reduced. The use of the neonicotinoid imidacloprid at greenhouse/nursery rates reduced survival of beneficial insects feeding on pollen and nectar and is incompatible with the principles of IPM. PMID- 25799433 TI - Prevalence of gestational diabetes mellitus and its risk factors in Chinese pregnant women: a prospective population-based study in Tianjin, China. AB - OBJECTIVE: We compared the increases in the prevalence of gestational diabetes mellitus (GDM) based on the 1999 World Health Organization (WHO) criteria and its risk factors in Tianjin, China, over a 12-year period. We also examined the changes in the prevalence using the criteria of International Association of Diabetes and Pregnancy Study Group (IADPSG). METHODS: In 2010-2012, 18589 women who registered within 12 weeks of gestation underwent a glucose challenge test (GCT) at 24-28 gestational weeks. Amongst them, 2953 women with 1-hour plasma glucose >= 7.8 mmol/L underwent a 75-gram 2-hour oral glucose tolerance test (OGTT) and 781 women had a positive GCT but absented from the standard OGTT. An adjusted prevalence of GDM was calculated for the whole cohort of women by including an estimate of the proportion of women with positive GCTs who did not have OGTTs but would have been expected to have GDM. Logistic regression was used to obtain odds ratios and 95% confidence intervals using the IADPSG criteria. The prevalence of GDM risk factors was compared to the 1999 survey. RESULTS: The adjusted prevalence of GDM by the 1999 WHO criteria was 8.1%, a 3.5-fold increase as in 1999. Using the IADPSG criteria increased the adjusted prevalence further to 9.3%. Advanced age, higher pre-pregnancy body mass index, Han-nationality, higher systolic blood pressure (BP), a family history of diabetes, weight gain during pregnancy and habitual smoking were risk factors for GDM. Compared to the 1999 survey, the prevalence of overweight plus obesity had increased by 1.8 folds, age >= 30 years by 2.3 folds, systolic BP by 2.3 mmHg over the 12-year period. CONCLUSIONS: Increasing prevalence of overweight/obesity and older age at pregnancy were accompanied by increasing prevalence of GDM, further increased by change in diagnostic criteria. PMID- 25799435 TI - Paroxysmal atrial fibrillation and clinically reversible cor pulmonale in a horse with complicated recurrent airway obstruction. AB - Cor pulmonale is considered an uncommon complication in horses with recurrent airway obstruction (RAO). This case report describes the history, clinical and further examination findings, treatment, progression and outcome of a horse diagnosed with cor pulmonale and paroxysmal atrial fibrillation of 2 days duration due to a severe exacerbation of RAO. To our best knowledge, this is the first report of RAO induced pulmonary hypertension in a horse causing atrial fibrillation. However, even severe cardiac changes due to respiratory dysfunction seem to be largely reversible in horses. PMID- 25799434 TI - Improved detection of extended spectrum beta-lactamase (ESBL)-producing Escherichia coli in input and output samples of German biogas plants by a selective pre-enrichment procedure. AB - The presence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli was investigated in input (manure from livestock husbandry) and output samples of six German biogas plants in 2012 (one sampling per biogas plant) and two German biogas plants investigated in an annual cycle four times in 2013/2014. ESBL-producing Escherichia coli were cultured by direct plating on CHROMagar ESBL from input samples in the range of 100 to 104 colony forming units (CFU) per g dry weight but not from output sample. This initially indicated a complete elimination of ESBL-producing E. coli by the biogas plant process. Detected non target bacteria were assigned to the genera Acinetobacter, Pseudomonas, Bordetella, Achromobacter, Castellaniella, and Ochrobactrum. A selective pre enrichment procedure increased the detection efficiency of ESBL-producing E. coli in input samples and enabled the detection in five of eight analyzed output samples. In total 119 ESBL-producing E. coli were isolated from input and 46 from output samples. Most of the E. coli isolates carried CTX-M-type and/or TEM-type beta lactamases (94%), few SHV-type beta lactamase (6%). Sixty-four blaCTX-M genes were characterized more detailed and assigned mainly to CTX-M-groups 1 (85%) and 9 (13%), and one to group 2. Phylogenetic grouping of 80 E. coli isolates showed that most were assigned to group A (71%) and B1 (27%), only one to group D (2%). Genomic fingerprinting and multilocus sequence typing (MLST) showed a high clonal diversity with 41 BOX-types and 19 ST-types. The two most common ST-types were ST410 and ST1210. Antimicrobial susceptibility testing of 46 selected ESBL-producing E. coli revealed that several isolates were additionally resistant to other veterinary relevant antibiotics and some grew on CHROMagar STEC but shiga-like toxine (SLT) genes were not detected. Resistance to carbapenems was not detected. In summary the study showed for the first time the presence of ESBL-producing E. coli in output samples of German biogas plants. PMID- 25799436 TI - Variation in prolactin is related to variation in sexual behavior and contact affiliation. AB - Prolactin is associated with both maternal and paternal care and appears important in developing a bond between parent and infant. In contrast with oxytocin, another hormone important in infant care, there is scant information on the role of prolactin in maintaining adult heterosexual relationships. We present here the first results demonstrating a relationship between prolactin levels and sexual and contact affiliation behavior in a pair-bonded species. We studied cotton-top tamarins, a socially-monogamous, cooperatively-breeding primate. We measured chronic urinary prolactin levels over a four week period to include the entire female ovulatory cycle and correlated prolactin levels in males and females with simultaneous measures of contact affiliation and sexual behavior. Current mothers who were no longer nursing displayed lower amounts of sexual behavior and proximity than non-breeding females and also had marginally lower levels of prolactin. The prolactin levels of males and females were similar within pairs, and variation in prolactin levels for both sexes was explained both by the amount of sexual behavior and contact affiliation. The results parallel a previous study that compared oxytocin levels with sociosexual behavior in the same species, and supports the hypothesis that both prolactin and oxytocin are involved in pair-bonding as well as in infant care. PMID- 25799437 TI - Correction: Diagnostic criteria for depression in type 2 diabetes: a data-driven approach. PMID- 25799438 TI - Internalizing and externalizing psychopathology as predictors of cannabis use disorder onset during adolescence and early adulthood. AB - Risk-related liabilities associated with the development of cannabis use disorders (CUDs) during adolescence and early adulthood are thought to be established well before the emergence of the index episode. In this study, internalizing and externalizing psychopathology from earlier developmental periods were evaluated as risk factors for CUDs during adolescence and early adulthood. Participants (N = 816) completed 4 diagnostic assessments between the ages 16 and 30, during which current and past CUDs were assessed as well as a full range of psychiatric disorders associated with internalizing and externalizing psychopathology domains. In unadjusted and adjusted time-to-event analyses, externalizing but not internalizing psychopathology from proximal developmental periods predicted subsequent CUD onset. A large proportion of adolescent and early adult cases, however, did not manifest any externalizing or internalizing psychopathology during developmental periods before CUD onset. Findings are consistent with the emerging view that externalizing disorders from proximal developmental periods are robust risk factors for CUDs. Although the identification of externalizing liabilities may aid in the identification of individuals at risk for embarking on developmental pathways that culminate in CUDs, such liabilities are an incomplete indication of overall risk. PMID- 25799439 TI - Insecure attachment styles, relationship-drinking contexts, and marital alcohol problems: Testing the mediating role of relationship-specific drinking-to-cope motives. AB - Research and theory suggest that romantic couple members are motivated to drink to cope with interpersonal distress. Additionally, this behavior and its consequences appear to be differentially associated with insecure attachment styles. However, no research has directly examined drinking to cope that is specific to relationship problems, or with relationship-specific drinking outcomes. Based on alcohol motivation and attachment theories, the current study examines relationship-specific drinking-to-cope processes over the early years of marriage. Specifically, it was hypothesized that drinking to cope with a relationship problem would mediate the associations between insecure attachment styles (i.e., anxious and avoidant) and frequencies of drinking with and apart from one's partner and marital alcohol problems in married couples. Multilevel models were tested via the actor-partner interdependence model using reports of both members of 470 couples over the first nine years of marriage. As expected, relationship-specific drinking-to-cope motives mediated the effects of actor anxious attachment on drinking apart from one's partner and on marital alcohol problems, but, unexpectedly, not on drinking with the partner. No mediated effects were found for attachment avoidance. Results suggest that anxious (but not avoidant) individuals are motivated to use alcohol to cope specifically with relationship problems in certain contexts, which may exacerbate relationship difficulties associated with attachment anxiety. Implications for theory and future research on relationship-motivated drinking are discussed. PMID- 25799440 TI - Improved specificity of TALE-based genome editing using an expanded RVD repertoire. AB - Transcription activator-like effector (TALE) proteins have gained broad appeal as a platform for targeted DNA recognition, largely owing to their simple rules for design. These rules relate the base specified by a single TALE repeat to the identity of two key residues (the repeat variable diresidue, or RVD) and enable design for new sequence targets via modular shuffling of these units. A key limitation of these rules is that their simplicity precludes options for improving designs that are insufficiently active or specific. Here we address this limitation by developing an expanded set of RVDs and applying them to improve the performance of previously described TALEs. As an extreme example, total conversion of a TALE nuclease to new RVDs substantially reduced off-target cleavage in cellular studies. By providing new RVDs and design strategies, these studies establish options for developing improved TALEs for broader application across medicine and biotechnology. PMID- 25799441 TI - Identification of active transcriptional regulatory elements from GRO-seq data. AB - Modifications to the global run-on and sequencing (GRO-seq) protocol that enrich for 5'-capped RNAs can be used to reveal active transcriptional regulatory elements (TREs) with high accuracy. Here, we introduce discriminative regulatory element detection from GRO-seq (dREG), a sensitive machine learning method that uses support vector regression to identify active TREs from GRO-seq data without requiring cap-based enrichment (https://github.com/Danko-Lab/dREG/). This approach allows TREs to be assayed together with gene expression levels and other transcriptional features in a single experiment. Predicted TREs are more enriched for several marks of transcriptional activation-including expression quantitative trait loci, disease-associated polymorphisms, acetylated histone 3 lysine 27 (H3K27ac) and transcription factor binding-than those identified by alternative functional assays. Using dREG, we surveyed TREs in eight human cell types and provide new insights into global patterns of TRE function. PMID- 25799442 TI - Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms. AB - Most disease associations detected by genome-wide association studies (GWAS) lie outside coding genes, but very few have been mapped to causal regulatory variants. Here, we present a method for detecting regulatory quantitative trait loci (QTLs) that does not require genotyping or whole-genome sequencing. The method combines deep, long-read chromatin immunoprecipitation-sequencing (ChIP seq) with a statistical test that simultaneously scores peak height correlation and allelic imbalance: the genotype-independent signal correlation and imbalance (G-SCI) test. We performed histone acetylation ChIP-seq on 57 human lymphoblastoid cell lines and used the resulting reads to call 500,066 single nucleotide polymorphisms de novo within regulatory elements. The G-SCI test annotated 8,764 of these as histone acetylation QTLs (haQTLs)-an order of magnitude larger than the set of candidates detected by expression QTL analysis. Lymphoblastoid haQTLs were highly predictive of autoimmune disease mechanisms. Thus, our method facilitates large-scale regulatory variant detection in any moderately sized cohort for which functional profiling data can be generated, thereby simplifying identification of causal variants within GWAS loci. PMID- 25799443 TI - Learning to control actions: transfer effects following a procedural cognitive control computerized training. AB - Few studies have addressed action control training. In the current study, participants were trained over 19 days in an adaptive training task that demanded constant switching, maintenance and updating of novel action rules. Participants completed an executive functions battery before and after training that estimated processing speed, working memory updating, set-shifting, response inhibition and fluid intelligence. Participants in the training group showed greater improvement than a no-contact control group in processing speed, indicated by reduced reaction times in speeded classification tasks. No other systematic group differences were found across the different pre-post measurements. Ex-Gaussian fitting of the reaction-time distribution revealed that the reaction time reduction observed among trained participants was restricted to the right tail of the distribution, previously shown to be related to working memory. Furthermore, training effects were only found in classification tasks that required participants to maintain novel stimulus-response rules in mind, supporting the notion that the training improved working memory abilities. Training benefits were maintained in a 10-month follow-up, indicating relatively long-lasting effects. The authors conclude that training improved action-related working memory abilities. PMID- 25799445 TI - Denture-frame modifications in class III patients treated with rapid palatal expansion and facemask: a prospective controlled study. AB - AIM: The aim of this prospective controlled investigation was to analyze the short-term cephalometric treatment outcomes, according to the denture frame analysis proposed by Sato, of rapid palatal expansion (RPE) and facial mask (FM) therapy. METHODS: A group of 21 patients with Class III malocclusion treated with the RPE and FM (TG) was compared with untreated Class III controls (CG). The mean age of treatment group was 8.8 years; treatment consisted of 4 weeks of RPE activation (0.20 mm/die) followed by 14 hours wear of the FM for a mean of 333.1 days. As CG were used the data published by Tanaka and Sato. Pre- and post treatment cephalometric values were compared and statistical analyzed with one sample t-test. A P-value <0.05 was considered statistically significant. RESULTS: For almost all parameters the differences pre and post treatment values resulted significantly different compared to those observed in CG. Regarding conventional occlusal plane (POC) values some differences compared to control group were found but they were not statistically significant (P=0.067) while for aterior occlusal plane (POA) no differences where noticed. CONCLUSION: This study revealed an increase in inter-jaw angle during treatment with FM and RPE, an increase in the inclination of the posterior occlusal plane with respect to the Frankfurt plane and a posterior and lower adaptation of the mandible. PMID- 25799444 TI - Chemoradiation for advanced oral and (pharyngo) laryngeal carcinoma: single institution outcome analysis. AB - AIM: Chemoradiation ( CRT) is a valuable treatment option for(pharyngo)laryngeal squamous cell cancer and a palliative cure in advanced oral cancers. However, toxicity is scarcely reported. Therefore, efficacy, acute and toxic effects of chemoradiation for advanced head and neck squamous cell carcinomas were evaluated, using retrospective study. METHODS: Previously untreated patients with stage III-IV head and neck squamous cell carcinomas were included. Radiotherapy consisted of 70 Gy/7 weeks/35 fractions. All patients received concurrent Cisplatin 40 mg/m2 weekly. RESULTS: The most common acute toxic effects were dysphagia and mucositis. Dysphagia and xerostomia remained problematic during follow-up. Loco regional disease control was respectively 91% and 98% after 6 months. The median overall survival (calculating starting form the end of the treatment) was 33 months (range 0-111months). The 5-year disease specific survival was 41%. CONCLUSION: The results indicated that concurrent chemoradiotherapy for advanced head and neck squamous cell carcinoma is associated with high locoregional control and disease-specific survival. However, significant acute and long-term toxic effects occur, and organ preservation appears not necessarily equivalent to preservation of function in pharyngolaryngeal cancers. PMID- 25799446 TI - Apical microleakage of AH Plus and MTA Fillapex(r) sealers in association with immediate and delayed post space preparation: a bacterial leakage study. AB - AIM: The aim of the present study was to compare the apical microleakage of root canals obturated with AH Plus and MTA Fillapex(r) sealers. METHODS: A total of 76 anterior teeth were randomly divided into 4 groups (N.=15) and in each group 2 positive and 2 negative control teeth. All the teeth were cleaned, shaped and obturated using lateral compaction technique with gutta-percha and AH Plus(r) sealer in groups 1 and 2 and MTA Fillapex(r) sealer in groups 3 and 4. In groups 1 and 3 post spaces were prepared immediately and groups 2 and 4 were stored for 1 week at 100% relative humidity and then post spaces were prepared. The teeth were connected to a bacterial microleakage evaluation system. Each 72 hours, E. faecalis bacteria were inoculated into the coronal thirds of the root canals. The study period was 90 days and the samples were evaluated on a daily basis, Meier Kaplan technique was used for estimation of the mean time of microleakage to occur. Log-rank test was used for comparison of microleakage. RESULTS: Contamination occurred in positive control groups on the first day of bacterial inoculation; however, the negative control groups did not exhibit any contamination up to the end of 90-day study period. the difference was not statistically significant between two materials (P>0.05). CONCLUSION: There were no significant differences between AH Plus(r) and MTA Fillapex(r) sealers with the two immediate and delayed postspace preparation techniques. PMID- 25799447 TI - Bonding durability of silorane and methacrylate-based resins to enamel. AB - AIM: Few studies compared the silorane and mechacrylate based resins bonded to enamel. The aim of this study was to evaluate the bonding durability of silorane and methacrylate-based resins to enamel. METHODS: Twenty seven molars were divided into G1 Clearfil SE Bond/Filtek Z350; G2 Adper Easy One/Filtek Z350; and G3 P90 Adhesive System/Filtek P90 groups. Following application of adhesive systems, blocks of composites were built, samples were stored in water (24 hours/37 oC), sectioned (0.8 mm2) and tested in tensile (24 hours and 6 months). Fractures were observed (40*). Bond strength (in MPa) was analysed by MANOVA General Linear Model and Tukey's post-hoc test at 5%. The power test was calculated. The etching pattern was observed. RESULTS: There were differences for material (P=0.029), storage time (P=0.012) and their interaction (P=0.000). Similar bond strengths were found at 24 h for all. The bond strength of G1 decreased after 6 months. At 6 months, G2 showed higher bond strength than G1 and G3, that were similar. The power-test value was 0.87. Mixed fractures and enamel rods were observed. CONCLUSION: Bond strength varied over time depending on the restorative system. PMID- 25799448 TI - Further considerations in terms of the permanent impairment of the of chewing organ. AB - Nowadays, the drawbacks to utilizing criminal law with regards to a traumatic event, whether accidental or iatrogenic, involving the dental apparatus are still prevailing. A lesion affecting the stomatognathic apparatus can in fact integrate the offense of grievous bodily harm under Art.583 of the Italian Criminal Code (cc) as "permanent weakening of the organ" or the functions to which is appointed, i.e. the masticatory function, but also to the indwelling voice, appearance and taste. Repeatedly, jurisprudence, in the past and more recently, has set an opinion on the issue and, currently, it is possible to indicate some recognized cornerstones as deep-seated on the matter. It is a well-known fact that the organ of mastication does not represent a defined anatomical organ but, instead, it is an anatomical and functional entity consisting of a complex of different structures and not just from the dental apparatus. Moreover, any functional anatomic alteration of any single entity can have a certain weight on the other components and, therefore, on the whole organ in its entirety. Medical legal doctrine, already in the past, supported the need for a tangible assessment of the impairment, determining whether and how much the loss of even one anatomical element could have a negative impact on the operational equilibrium of the entire stomatognathic system, whilst verifying the actual subsistence of a weakening. The loss of a dental element can take on a different meaning when such event occurs on a system already functionally deficient. In such instances, one should consider whether any pre-existing condition compromise the system, and to what extent, so that the trauma has considerable bearing on the remaining masticatory function. If the apparatus is in a position to perform even in part its function, the blunt force trauma is likely to set the aggravating circumstance. PMID- 25799449 TI - Efficient transmission of subthreshold signals in complex networks of spiking neurons. AB - We investigate the efficient transmission and processing of weak, subthreshold signals in a realistic neural medium in the presence of different levels of the underlying noise. Assuming Hebbian weights for maximal synaptic conductances- that naturally balances the network with excitatory and inhibitory synapses--and considering short-term synaptic plasticity affecting such conductances, we found different dynamic phases in the system. This includes a memory phase where population of neurons remain synchronized, an oscillatory phase where transitions between different synchronized populations of neurons appears and an asynchronous or noisy phase. When a weak stimulus input is applied to each neuron, increasing the level of noise in the medium we found an efficient transmission of such stimuli around the transition and critical points separating different phases for well-defined different levels of stochasticity in the system. We proved that this intriguing phenomenon is quite robust, as it occurs in different situations including several types of synaptic plasticity, different type and number of stored patterns and diverse network topologies, namely, diluted networks and complex topologies such as scale-free and small-world networks. We conclude that the robustness of the phenomenon in different realistic scenarios, including spiking neurons, short-term synaptic plasticity and complex networks topologies, make very likely that it could also occur in actual neural systems as recent psycho-physical experiments suggest. PMID- 25799450 TI - Paraquat induces epithelial-mesenchymal transition-like cellular response resulting in fibrogenesis and the prevention of apoptosis in human pulmonary epithelial cells. AB - The aim of this study is to investigate the molecular mechanisms underlying delayed progressive pulmonary fibrosis, a characteristic of subacute paraquat (PQ) poisoning. Epithelial-mesenchymal transition (EMT) has been proposed as a cause of organ fibrosis, and transforming growth factor-beta (TGF-beta) is suggested to be a powerful mediator of EMT. We thus examined the possibility that EMT is involved in pulmonary fibrosis during PQ poisoning using A549 human alveolar epithelial cells in vitro. The cells were treated with various concentrations of PQ (0-500 MUM) for 2-12 days. Short-term (2 days) high-dose (>100 MUM) treatments with PQ induced cell death accompanied by the activation of caspase9 as well as a decrease in E-cadherin (an epithelial cell marker), suggesting apoptotic cell death with the features of anoikis (cell death due to the loss of cell-cell adhesion). In contrast, long-term (6-12 days) low-dose (30 MUM) treatments with PQ resulted in a transformation into spindle-shaped mesenchymal-like cells with a decrease of E-cadherin as well as an increase of alpha-smooth muscle actin (alpha-SMA). The mesenchymal-like cells also secreted the extracellular matrix (ECM) protein fibronectin into the culture medium. The administration of a TGF-beta1 receptor antagonist, SB431542, almost completely attenuated the mesenchymal transformation as well as fibronectin secretion, suggesting a crucial role of TGF-beta1 in EMT-like cellular response and subsequent fibrogenesis. It is noteworthy that despite the suppression of EMT fibrogenesis, apoptotic death was observed in cells treated with PQ+SB431542. EMT like cellular response and subsequent fibrogenesis were also observed in normal human bronchial epithelial (NHBE) cells exposed to PQ in a TGF-beta1-dependent manner. Taken together, our experimental model reflects well the etiology of PQ poisoning in human and shows the involvement of EMT-like cellular response in both fibrogenesis and resistance to cell death during subacute PQ poisoning of pulmonary epithelial cells. PMID- 25799451 TI - An 8-Year Follow-up on the Effect of Subthalamic Nucleus Deep Brain Stimulation on Pain in Parkinson Disease. AB - IMPORTANCE: Pain is a common and distressing feature in Parkinson disease (PD). The major indication of subthalamic nucleus deep brain stimulation (STN DBS) is motor complications in advanced PD; however, pain reduction after STN DBS has been noted. OBJECTIVE: To evaluate the long-term effect of STN DBS on pain in PD. DESIGN, SETTING, AND PARTICIPANTS: Twenty-four patients who underwent STN DBS at the Movement Disorder Center at Seoul National University Hospital from June 1, 2005, through March 31, 2006, were studied. The assessments of pain were performed preoperatively and 8 years after surgery. Because 13 of the total 24 patients had additional 2-year postoperative data, the serial change between the preoperative and the 2- and 8-year follow-ups after surgery was also evaluated. MAIN OUTCOMES AND MEASURES: Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr staging scale. The severity of pain was scored according to an ordinal scale ranging from 0 (absent) to 10 (maximal pain) in 7 parts of the body (head, neck, trunk, and the upper and lower extremities on each side of the body). For each body part, the quality of pain was grouped into 1 of 4 categories: dystonic, musculoskeletal, radiculoneuritic, and central. RESULTS: Sixteen of the 24 patients (67%) experienced pain at baseline when not taking medication (off-state). All off state pain at baseline improved or disappeared at 8 years after surgery. The number of body parts with pain was 21 at baseline and decreased to 11 at 8 years after the surgery. The mean (SD) and median scores of the off-state pain were 6.2 (2.5) and 7.0 at baseline and improved to 3.5 (2.2) and 2.5 at 8 years after the surgery, respectively. However, new pain developed in 18 of 24 patients (75%) during the 8-year follow-up period. The number of body parts with newly developed pain was 47, and the mean (SD) and median scores for new pain were 4.4 (3.0) and 3.0, respectively. The types of new pain at 8 years were musculoskeletal in 11 patients, central in 4 patients, radiculoneuritic in 3 patients, and dystonic in 1 patient. CONCLUSIONS AND RELEVANCE: Pain associated with PD is improved by STN DBS, and the beneficial effect persists after a long-term follow-up of 8 years. In addition, new pain, especially the musculoskeletal type, developed in most patients, becoming a long-term distressing problem. PMID- 25799452 TI - Clostridium perfringens type E virulence traits involved in gut colonization. AB - Clostridium perfringens type E disease in ruminants has been characterized by hemorrhagic enteritis or sudden death. Although type E isolates are defined by the production of alpha and iota toxin, little is known about the pathogenesis of C. perfringens type E infections. Thus far, the role of iota toxin as a virulence factor is unknown. In this report, iota toxin showed positive effects on adherence and colonization of C. perfringens type E while having negative effect on the adherence of type A cells. In-vitro and in-vivo models suggest that toxinotype E would be particularly adapted to exploit the changes induced by iota toxin in the surface of epithelial cells. In addition, type E strains produce metabolites that affected the growth of potential intra-specific competitors. These results suggest that the alteration of the enterocyte morphology induced by iota toxin concomitantly with the specific increase of type E cell adhesion and the strong intra-specific growth inhibition of other strains could be competitive traits inherent to type E isolates that improve its fitness within the bovine gut environment. PMID- 25799454 TI - Fear of disease progression questionnaire for parents: Psychometric properties based on a sample of caregivers of children and adolescents with cystic fibrosis. AB - BACKGROUND: Parents caring for a child with a chronic somatic condition are at risk of increased distress and impaired quality of life. Fear of disease progression (FoP) is known to be an important source of distress in patients and their partners, and may be of relevance for parents as well. Existing measures are not applicable to parents. This study describes the adaptation of the FoP questionnaire for parental caregivers and investigated its psychometric properties. METHODS: Sixteen items appropriate for parents were derived from existing measures and from interviews with clinical experts in family-oriented psychosocial care. Factor structure, internal consistency, validity and sensitivity to change were analyzed in a clinical sample of 162 caregivers (M(age)=42.07 years, SD=6.0 years, 87.8% female) of a child with cystic fibrosis. RESULTS: The exploratory factor analysis reveal ed a two-factor structure, which was not supported by confirmatory analysis. Cronbach's alpha was examined for total score (.91) and significant positive correlations of the total score with anxiety (HADS: r=.70) and depression (CES-D: r=.60, BDI-II: r=.59), and a significant negative correlations with quality of life (r=-.66) could be demonstrated. A significant decrease in FoP was found (d=1.11) in a group of highly distressed caregivers undergoing web-based cognitive behavioral intervention. CONCLUSIONS: The FoP questionnaire is a reliable and valid instrument for parents of children with CF. Further studies in larger samples are needed to clarify dimensionality and validity among parents of children with other chronic conditions. PMID- 25799453 TI - Advanced enzymology, expression profile and immune response of Clonorchis sinensis hexokinase show its application potential for prevention and control of clonorchiasis. AB - BACKGROUND: Approximately 35 million people are infected with Clonorchis sinensis (C. sinensis) globally, of whom 15 million are in China. Glycolytic enzymes are recognized as crucial molecules for trematode survival and have been targeted for vaccine and drug development. Hexokinase of C. sinensis (CsHK), as the first key regulatory enzyme of the glycolytic pathway, was investigated in the current study. PRINCIPAL FINDINGS: There were differences in spatial structure and affinities for hexoses and phosphate donors between CsHK and HKs from humans or rats, the definitive hosts of C. sinensis. Effectors (AMP, PEP, and citrate) and a small molecular inhibitor regulated the enzymatic activity of rCsHK, and various allosteric systems were detected. CsHK was distributed in the worm extensively as well as in liver tissue and serum from C. sinensis infected rats. Furthermore, high-level specific IgG1 and IgG2a were induced in rats by immunization with rCsHK. The enzymatic activity of CsHK was suppressed by the antibody in vitro. Additionally, the survival of C. sinensis was inhibited by the antibody in vivo and in vitro. CONCLUSIONS/SIGNIFICANCE: Due to differences in putative spatial structure and enzymology between CsHK and HK from the host, its extensive distribution in adult worms, and its expression profile as a component of excretory/secretory products, together with its good immunogenicity and immunoreactivity, as a key glycolytic enzyme, CsHK shows potential as a vaccine and as a promising drug target for Clonorchiasis. PMID- 25799455 TI - Non-aqueous glycerol monolaurate gel exhibits antibacterial and anti-biofilm activity against Gram-positive and Gram-negative pathogens. AB - BACKGROUND: Skin and surgical infections due to Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii are causes of patient morbidity and increased healthcare costs. These organisms grow planktonically and as biofilms, and many strains exhibit antibiotic resistance. This study examines the antibacterial and anti-biofilm activity of glycerol monolaurate (GML), as solubilized in a non-aqueous vehicle (5% GML Gel), as a novel, broadly-active topical antimicrobial. The FDA has designated GML as generally recognized as safe for human use, and the compound is commonly used in the cosmetic and food industries. METHODS: In vitro, bacterial strains in broths and biofilms were exposed to GML Gel, and effects on bacterial colony-forming units (CFUs) were assessed. In vivo,subcutaneous incisions were made in New Zealand white rabbits; the incisions were closed with four sutures. Bacterial strains were painted onto the incision sites, and then GML Gel or placebo was liberally applied to cover the sites completely. Rabbits were allowed to awaken and were examined for CFUs as a function of exposure time. RESULTS: In vitro, GML Gel was bactericidal for all broth culture and biofilm organisms in <1 hour and <4 hour, respectively; no CFUs were detected after the entire 24 h test period. In vivo, GML Gel inhibited bacterial growth in the surgical incision sites, compared to no growth inhibition in controls. GML Gel significantly reduced inflammation, as viewed by lack of redness in and below the incision sites. CONCLUSIONS: Our findings suggest that 5% GML Gel is useful as a potent topical antibacterial and anti-inflammatory agent for prevention of infections. PMID- 25799456 TI - Quantifying the impact of transporters on cellular drug permeability. AB - The conventional model of drug permeability has recently been challenged. An alternative model proposes that transporter-mediated flux is the sole mechanism of cellular drug permeation, instead of existing in parallel with passive transmembrane diffusion. We examined a central assumption of this alternative hypothesis; namely, that transporters can give rise to experimental observations that would typically be explained with passive transmembrane diffusion. Using systems-biology simulations based on available transporter kinetics and proteomic expression data, we found that such observations are possible in the absence of transmembrane diffusion, but only under very specific conditions that rarely or never occur for known human drug transporters. PMID- 25799457 TI - Nanomedicine to overcome radioresistance in glioblastoma stem-like cells and surviving clones. AB - Radiotherapy is one of the standard treatments for glioblastoma, but its effectiveness often encounters the phenomenon of radioresistance. This resistance was recently attributed to distinct cell contingents known as glioblastoma stem like cells (GSCs) and dominant clones. It is characterized in particular by the activation of signaling pathways and DNA repair mechanisms. Recent advances in the field of nanomedicine offer new possibilities for radiosensitizing these cell populations. Several strategies have been developed in this direction, the first consisting of encapsulating a contrast agent or synthesizing metal-based nanocarriers to concentrate the dose gradient at the level of the target tissue. In the second strategy the physicochemical properties of the vectors are used to encapsulate a wide range of pharmacological agents which act in synergy with the ionizing radiation to destroy the cancerous cells. This review reports on the various molecular anomalies present in GSCs and the predominant role of nanomedicines in the development of radiosensitization strategies. PMID- 25799458 TI - Scanning Electron Microscopy Findings With Energy-Dispersive X-ray Investigations of Cosmetically Tinted Contact Lenses. AB - OBJECTIVE: To investigate the surfaces and principal elements of the colorants of cosmetically tinted contact lenses (Cos-CLs). METHODS: We analyzed the surfaces and principal elements of the colorants of five commercially available Cos-CLs using scanning electron microscopy with energy-dispersive x-ray analysis. RESULTS: In two Cos-CLs, the anterior and posterior surfaces were smooth, and colorants were found inside the lens. One lens showed colorants located to a depth of 8 to 14 MUm from the anterior side of the lens. In the other lens, colorants were found in the most superficial layer on the posterior surface, although a coated layer was observed. The colorants in the other three lenses were deposited on either lens surface. Although a print pattern was uniform in embedded type lenses, uneven patterns were apparent in dot-matrix design lenses. Colorants used in all lenses contained chlorine, iron, and titanium. In the magnified scanning electron microscopy images of a certain lens, chlorine is exuded and spread. CONCLUSIONS: Cosmetically tinted contact lenses have a wide variety of lens surfaces and colorants. Colorants may be deposited on the lens surface and consist of an element that has tissue toxicity. PMID- 25799459 TI - Supramolecular gels with high strength by tuning of calix[4]arene-derived networks. AB - Supramolecular gels comprised of low-molecular-weight gelators are generally regarded as mechanically weak and unable to support formation of free-standing structures, hence, their practical use with applied loads has been limited. Here, we reveal a technique for in situ generation of high tensile strength supramolecular hydrogels derived from low-molecular-weight gelators. By controlling the concentration of hydrochloric acid during hydrazone formation between calix-[4]arene-based gelator precursors, we tune the mechanical and ductile properties of the resulting gel. Organogels formed without hydrochloric acid exhibit impressive tensile strengths, higher than 40 MPa, which is the strongest among self-assembled gels. Hydrogels, prepared by solvent exchange of organogels in water, show 7,000- to 10,000-fold enhanced mechanical properties because of further hydrazone formation. This method of molding also allows the gels to retain shape after processing, and furthermore, we find organogels when prepared as gel electrolytes for lithium battery applications to have good ionic conductivity. PMID- 25799460 TI - Bayesian modeling and chronological precision for Polynesian settlement of Tonga. AB - First settlement of Polynesia, and population expansion throughout the ancestral Polynesian homeland are foundation events for global history. A precise chronology is paramount to informed archaeological interpretation of these events and their consequences. Recently applied chronometric hygiene protocols excluding radiocarbon dates on wood charcoal without species identification all but eliminates this chronology as it has been built for the Kingdom of Tonga, the initial islands to be settled in Polynesia. In this paper we re-examine and redevelop this chronology through application of Bayesian models to the questioned suite of radiocarbon dates, but also incorporating short-lived wood charcoal dates from archived samples and high precision U/Th dates on coral artifacts. These models provide generation level precision allowing us to track population migration from first Lapita occupation on the island of Tongatapu through Tonga's central and northern island groups. They further illustrate an exceptionally short duration for the initial colonizing Lapita phase and a somewhat abrupt transition to ancestral Polynesian society as it is currently defined. PMID- 25799461 TI - Correction: Results of a "GWAS Plus:" general cognitive ability is substantially heritable and massively polygenic. PMID- 25799462 TI - Sulfate-based anionic diblock copolymer nanoparticles for efficient occlusion within zinc oxide. AB - Occlusion of copolymer particles within inorganic crystalline hosts not only provides a model for understanding the crystallisation process, but also may offer a direct route for the preparation of novel nanocomposite materials with emergent properties. In the present paper, a series of new well-defined anionic diblock copolymer nanoparticles are synthesised by polymerisation-induced self assembly (PISA) via reversible addition-fragmentation chain transfer (RAFT) aqueous emulsion polymerisation and then evaluated as crystal habit modifiers for the in situ formation of ZnO in aqueous solution. Systematic studies indicate that both the chemical nature (i.e. whether sulfate-based or carboxylate-based) and the mean degree of polymerisation (DP) of the anionic stabiliser block play vital roles in determining the crystal morphology. In particular, sulfate functionalised nanoparticles are efficiently incorporated within the ZnO crystals whereas carboxylate-functionalised nanoparticles are excluded, thus anionic character is a necessary but not sufficient condition for successful occlusion. Moreover, the extent of nanoparticle occlusion within the ZnO phase can be as high as 23% by mass depending on the sulfate-based nanoparticle concentration. The optical properties, chemical composition and crystal structure of the resulting nanocomposite crystals are evaluated and an occlusion mechanism is proposed based on the observed evolution of the ZnO morphology in the presence of sulfate-based anionic nanoparticles. Finally, controlled deposition of a 5 nm gold sol onto porous ZnO particles (produced after calcination of the organic nanoparticles) significantly enhances the rate of photocatalytic decomposition of a model rhodamine B dye on exposure to a relatively weak UV source. PMID- 25799463 TI - Prevalence of suicidal ideation and other suicide warning signs in veterans attending an urgent care psychiatric clinic. AB - BACKGROUND: Suicide prevention in the clinical setting is focused on evaluating risk in the coming hours to days, yet little is known about which factors increase acute risk. PURPOSE: To determine the prevalence of factors that may serve as warnings of heightened acute risk. METHODS: Veterans attending an urgent care psychiatric clinic (n=473) completed a survey on suicidal ideation and other acute risk warning signs. RESULTS: More than half the sample (52%) reported suicidal ideation during the prior week. Of these, more than one-third (37%) had active ideation which included participants with a current suicide plan (27%) and those who had made preparations to carry out their plan (12%). Other warning signs were also highly prevalent, with the most common being: sleep disturbances (89%), intense anxiety (76%), intense agitation (75%), hopelessness (70%), and desperation (70%). Almost all participants (97%) endorsed at least one warning sign. Participants with depressive syndrome and/or who screened positive for post traumatic stress disorder endorsed the largest number of warning signs. Those with both depressive syndrome and post-traumatic stress disorder were more likely to endorse intense affective states than those with either disorder alone. All p values for group comparisons are <.008. CONCLUSION: Our major findings are the strikingly high prevalence of past suicidal ideation, suicide attempts, current suicidal ideation and intense affective states in veterans attending an urgent care psychiatric clinic; and the strong associations between co-occurring post traumatic stress disorder and depressive syndrome with intense affective states. PMID- 25799464 TI - Psychometric evidence of the Brazilian version of Driving Cognitions Questionnaire (DCQ). AB - This paper examined the psychometric data obtained by the Brazilian version DCQ (Driving Cognitions Questionnaire) and its convergence with DBS (Driving Behavior Survey). The research included 187 participants of both genders, aged between 19 and 79years (mean 34years), with driving license in category 'B' (cars). The internal consistency obtained by research (Cronbach's alpha) was alpha=0.96 for full DCQ; alpha=0.89 for the subscale panic in the direction, alpha=0.91 for the subscale of concern in causing accidents and alpha=0.92 for the subscale of social concern. Psychometrically the results are positive and confirm the relevance of using the instrument. The survey also found positive convergence (although less pronounced) with the DBS, which is another instrument that comes to difficulties when driving or dealing with traffic or driving a car. Thus, this article demonstrates psychometric results that point to the profitable use of the Brazilian version of DCQ as an adjunct in the diagnosis of difficulty in driving. PMID- 25799466 TI - Laparoscopic right hepatectomy combined with partial diaphragmatic resection for colorectal liver metastases: Is it feasible and reasonable? AB - BACKGROUND: The impact of diaphragmatic invasion in patients with colorectal liver metastases (CRLMs) remains poorly evaluated. We aimed to evaluate feasibility and safety of laparoscopic right hepatectomy (LRH) with or without diaphragmatic resection for CRLM. METHODS: From 2002 to 2012, 52 patients underwent LRH for CRLM. Of them, 7 patients had combined laparoscopic partial diaphragmatic resection ("diaphragm" group). Data were retrospectively collected and short and long-term outcomes analyzed. RESULTS: Operative time was lower in the control group (272 vs 345 min, P = .06). Six patients required conversion to open surgery. Blood loss and transfusion rate were similar. Portal triad clamping was used more frequently in the "diaphragm" group (42.8% vs 6.6%, P = .02). Maximum tumor size was greater in the "diaphragm" group (74.5 vs 37.1 mm, P = .002). Resection margin was negative in all cases. Mortality was nil and general morbidity similar in the 2 groups. Specific liver-related complications occurred in 2 patients in the "diaphragm" group and 17 in the control group (P = .69). Mean hospital stay was similar (P = 56). Twenty-two (42.3%) patients experienced recurrence. One-, 3-, and 5-year overall survival after surgery in "diaphragm" and control groups were 69%, 34%, 34%, and 97%, 83%, 59%, respectively (P = .103). One- and 3-year disease-free survival after surgery in "diaphragm" and control groups were 57%, 47% and 75%, 54%, respectively (P = .310). CONCLUSION: LRH with en-bloc diaphragmatic resection could be reasonably performed for selected patients in expert centers. Technical difficulties related to diaphragmatic invasion must be circumvented. Further experience must be gained to confirm our results. PMID- 25799467 TI - Outcomes of laparoscopic right posterior sectionectomy in patients with hepatocellular carcinoma in the era of laparoscopic surgery. AB - BACKGROUND: Although there are very few reports of laparoscopic right posterior sectionectomy (RPS), we believe this is a promising operative method for lesions confined to the right posterior section of the liver. METHOD: Between September 2003 and June 2012, laparoscopic liver resection was performed in 408 patients at Seoul National University Bundang Hospital. We analyzed the clinical data of 24 patients who underwent laparoscopic RPS for hepatocellular carcinoma (HCC) and compared outcomes with patients who underwent open RPS (n = 19). RESULTS: The mean operation time was 567 minutes, and the mean postoperative hospital stay was 10.6 +/- 4.8 days. The mean tumor-free margin was 3.0 +/- 5.8 cm. There were no deaths or major complications. Two complications occurred, which were managed by percutaneous drainage. There were three conversions to laparotomy because of an insufficient tumor margin. These patients were treated when we had limited experience of laparoscopic resection. Extended RPS (n = 6), which involved RPS and resection of the right hepatic vein, was performed to achieve an adequate margin if the tumor was located very close to the right hepatic vein. The mean operation time was longer in laparoscopy group than that in open group (P < .001), but there was no difference in the mean resection margin (P = .450) and the rate of postoperative complications (P = .380) between 2 groups. There was no statistical difference in 5-year overall patient survival rate (79.1% vs 77.7%; P = .754) and the 5-year disease-free survival rate (42.2% vs 51.5%; P = .752) between the 2 groups. CONCLUSION: Laparoscopic RPS is feasible when performed by experienced surgeons, but further refinements of the surgical technique are needed to reduce operation time. PMID- 25799465 TI - Renal intercalated cells sense and mediate inflammation via the P2Y14 receptor. AB - Uncontrolled inflammation is one of the leading causes of kidney failure. Pro inflammatory responses can occur in the absence of infection, a process called sterile inflammation. Here we show that the purinergic receptor P2Y14 (GPR105) is specifically and highly expressed in collecting duct intercalated cells (ICs) and mediates sterile inflammation in the kidney. P2Y14 is activated by UDP-glucose, a damage-associated molecular pattern molecule (DAMP) released by injured cells. We found that UDP-glucose increases pro-inflammatory chemokine expression in ICs as well as MDCK-C11 cells, and UDP-glucose activates the MEK1/2-ERK1/2 pathway in MDCK-C11 cells. These effects were prevented following inhibition of P2Y14 with the small molecule PPTN. Tail vein injection of mice with UDP-glucose induced the recruitment of neutrophils to the renal medulla. This study identifies ICs as novel sensors, mediators and effectors of inflammation in the kidney via P2Y14. PMID- 25799468 TI - Impact of preoperative quality as well as quantity of skeletal muscle on survival after resection of pancreatic cancer. AB - BACKGROUND: Skeletal muscle depletion, referred to as sarcopenia, is predictive of mortality in patients undergoing digestive operations. The impact of muscle quality on outcomes, however, is unclear. This retrospective study investigated the impact of preoperative skeletal muscle quantity and quality on survival in patients undergoing resection of pancreatic cancer. METHODS: We investigated 230 patients who underwent resection of pancreatic cancer between 2004 and 2013. The quantity and quality of skeletal muscle, indicated by psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), were measured in preoperative computed tomography images. Overall survival (OS) and recurrence free survival (RFS) rates were compared according to PMI and IMAC, and prognostic factors after pancreatic resection were assessed. RESULTS: The OS and RFS rates in patients with low PMI were lesser than in those with normal/high PMI (P < .001, P < .001), with a mean survival time of 17.7 and 33.2 months, respectively. The OS and RFS rates in patients with high IMAC also were less than in those with normal/low IMAC (P < .001, P = .003) (mean survival time = 21.5 and 56.5 months, respectively). Low PMI (low muscle mass) and high IMAC (low muscle quality) were independent prognostic factors of poor OS (hazard ratio [HR] = 1.999, P < .001; HR = 2.527, P < .001) and RFS (HR = 1.607, P = .007; HR = 1.640, P = .004), respectively. CONCLUSION: Preoperative sarcopenia, indicating low quality and quantity of skeletal muscle, is closely related to mortality after resection of pancreatic cancer. PMID- 25799470 TI - Oviduct binding ability of porcine spermatozoa develops in the epididymis and can be advanced by incubation with caudal fluid. AB - The sperm reservoir is formed when spermatozoa bind to the epithelium of the uterotubal junction and caudal isthmus of the oviduct. It is an important mechanism that helps synchronize the meeting of gametes by regulating untimely capacitation and polyspermic fertilization. This study investigated the influence of epididymal maturation and caudal fluid on the ability of spermatozoa to bind to oviduct epithelium using a model porcine oviduct explant assay. Spermatozoa from the rete testis, middle caput (E2-E3), middle corpus (E6), and cauda (E8) of Large White or Large White * Landrace boars aged 10 to 14 months were diluted in modified Androhep solution and incubated with porcine oviduct explants. Results reported in this study support our hypothesis that testicular spermatozoa need to pass through the regions of the epididymis to acquire the ability to bind to the oviduct. There was a sequential increase in the number of spermatozoa that bound to oviduct explants from the rete testis to caudal epididymis. Binding of caudal spermatozoa to isthmic explants was the highest (15.0 +/- 1.2 spermatozoa per 1.25 mm(2), mean +/- standard error of the mean; P <= 0.05) and lowest by spermatozoa from the rete testis (2.0 +/- 0.3 per 1.25 mm(2)), and higher to isthmus from sows compared to gilts (35.8 +/- 6.7 per 1.25 mm(2) vs. 14.8 +/- 3.0 per 1.25 mm(2); P <= 0.05). Binding of ejaculated spermatozoa to porcine isthmus was higher than that for caudal spermatozoa (26.3 +/- 1.4 per 1.25 mm(2) vs. 15.0 +/- 0.8 per 1.25 mm(2); P <= 0.05) and higher to porcine than to bovine isthmus (26.3 +/- 2.3 per 1.25 mm(2) vs. 18.8 +/- 1.9 per 1.25 mm(2); P <= 0.05). Incubation of spermatozoa from the caput and corpus in caudal fluid increased the ability of spermatozoa to bind to the oviduct epithelium (P <= 0.05). In conclusion, the capacity of testicular spermatozoa to bind to the oviduct epithelium increases during their maturation in the epididymis and can be advanced by components of the caudal fluid. PMID- 25799469 TI - Single-nucleotide polymorphisms g.151435C>T and g.173057T>C in PRLR gene regulated by bta-miR-302a are associated with litter size in goats. AB - Single-nucleotide polymorphisms (SNPs) located at microRNA-binding sites (miR SNPs) can affect the expression of genes. This study aimed to identify the miR SNPs associated with litter size. Guanzhong (n = 321) and Boer (n = 191) goat breeds were used to detect SNPs in the caprine prolactin receptor (PRLR) gene by DNA sequencing, primer-introduced restriction analysis-polymerase chain reaction, and polymerase chain reaction-restriction fragment length polymorphism. Three novel SNPs (g.151435C>T, g.151454A>G, and g.173057T>C) were identified in the caprine PRLR gene. Statistical results indicated that the g.151435C>T and g.173057T>C SNPs were significantly associated with litter size in Guanzhong and Boer goat breeds. Further analysis revealed that combinative genotype C6 (TTAACC) was better than the others for litter size in both goat breeds. Furthermore, the PRLR g.173057T>C polymorphism was predicted to regulate the binding activity of bta-miR-302a. Luciferase reporter gene assay confirmed that 173057C to T substitution disrupted the binding site for bta-miR-302a, resulting in the reduced levels of luciferase. Taken together, these findings suggested that bta miR-302a can influence the expression of PRLR protein by binding with 3'untranslated region, resulting in that the g.173057T>C SNP had significant effects on litter size. PMID- 25799471 TI - Effect of donor cell type on developmental competence, quality, gene expression, and epigenetic status of interspecies cloned embryos produced using cells from wild buffalo and oocytes from domestic buffalo. AB - This study compared the cloning efficiency of donor cells of fibroblast and epithelial origin isolated from ear skin of a wild buffalo (Bubalus arnee) and used with cytoplasts from domestic buffalo (Bubalus bubalis) in interspecies SCNT by hand-made cloning. The cleavage (93.0 +/- 2.8% vs. 85.6 +/- 2.4%) and blastocyst rates (50.6 +/- 4.0% vs. 20.5 +/- 2.6%) were higher (P < 0.05) for fibroblasts than those for epithelial cells, whereas the total cell number (490 +/- 42 and 492 +/- 95, respectively) and apoptotic index (2.3 +/- 0.3 and 2.5 +/- 0.6, respectively) of blastocysts were similar. The global level of H3K18ac and H3K27me3 was lower (P < 0.05) in fibroblasts than that in epithelial cells. The global level of H3K18ac was higher (P < 0.05) in fibroblast than that in epithelial cell-derived blastocysts, whereas that of H3K27me3 was similar between the two groups. The expression level of HDAC1, DNMT1, DNMT3a, and P53 was higher (P < 0.05) in fibroblasts than that in epithelial cells; that of CASPASE3 showed an opposite pattern (P < 0.001), whereas CASPASE7 expression level was similar in the two groups. In the embryos, the expression level of HDAC1, DNMT3a, and CDX2 was lower (P < 0.05) in fibroblast than that in epithelial cell-derived blastocysts; that of NANOG showed an opposite pattern (P < 0.05), whereas that of OCT4 was similar between the two groups. In conclusion, donor cells of fibroblast origin are easier to reprogram than those of epithelial origin in interspecies SCNT, and cloning efficiency, epigenetic status, and gene expression pattern vary among cells having different origin although they may be from the same tissue. PMID- 25799472 TI - Teletriage for patients with traumatic finger injury directing emergency medical transportation services to appropriate hospitals: a pilot project in Nagoya City, Japan. AB - INTRODUCTION: Emergency medical technicians in Japan have experienced difficulties in identifying hospitals that will accept patients with severe finger injuries. We developed and managed a system named Interactive Teletriage using mobile phone photos to aid efficient patient transportation. The aim of this study was to investigate features related to the transportation of patients with severe finger injuries and to evaluate the feasibility of this system. MATERIALS AND METHODS: We prospectively analysed data from the medical association of Aichi Prefecture and the Nagoya City Fire Department in Japan. We investigated features related to the transportation of 474 patients with severe finger injuries in Nagoya from 2010 to 2013: 100 in 2010, 134 in 2011, 125 in 2012, and 115 in 2013. We began using Teletriage in August 2011 and compared the periods before and after its implementation. RESULTS: The time of injury showed two different peaks from 09:00 to 11:00h and at 13:00h. The number of patients injured during each weekday was generally the same, while cases on Saturdays and Sundays reflected 70% and 47% of the weekday average, respectively. Of the 474 patients, 395 (83%) were accepted to hospitals after 3 or fewer requests for admission: 160 of 202 (79.2%) before and 235 of 272 (86.4%) after Teletriage, constituting a significant increase (p=0.039). Furthermore, the number of patients who required 4 or more requests significantly decreased after implementation of Teletriage (p=0.039): 42 patients (20.8%) before and 37 (13.6%) after Teletriage. Our data showed that as the number of requests until final determination increased, the transportation period increased. Furthermore, the mean transportation period significantly decreased from 22.3min before to 18.1min after Teletriage (p=0.021). As the number of requests until final determination increased, the proportion of patients transported to Level I and II hospitals decreased; conversely, the proportion of patients transported to Level III, IV, and V hospitals increased. CONCLUSIONS: Our results indicated that the implementation of Teletriage has the potential to ease the problem of emergency medical transportation for those with severe finger injuries. PMID- 25799473 TI - Aggressive operative treatment of isolated blunt traumatic brain injury in the elderly is associated with favourable outcome. AB - Outcome after traumatic brain injury (TBI) in the elderly has not been fully elucidated. The present retrospective observational study investigates the age dependent outcome of patients suffering from severe isolated TBI with regard to operative and non-operative treatment. Data were prospectively collected in the TraumaRegister DGU. Anonymous datasets of 8629 patients with isolated severe blunt TBI (AISHead>=3, AISBody<=1) documented from 2002 to 2011 were analysed. Patients were grouped according to age: 1-17, 18-59, 60-69, 70-79 and >=80 years. Cranial fractures (44.8%) and subdural haematomas (42.6%) were the most common TBIs. Independent from the type of TBI the group of patients with operative treatment declined with rising age. Subgroup analysis of patients with critical TBI (AISHead=5) revealed standardised mortality ratios (SMRs) of 0.81 (95% CI 0.75-0.87) in case of operative treatment (n=1201) and 1.13 (95% CI 1.09-1.18) in case of non-operative treatment (n=1096). All age groups >=60 years showed significantly reduced SMRs in case of operative treatment. Across all age groups the group of patients with low/moderate disability according to the GOS (4 or 5 points) was higher in case of operative treatment. Results of this retrospective observational study have to be interpreted cautiously. However, good outcome after TBI with severe space-occupying haemorrhage is more frequent in patients with operative treatment across all age groups. Age alone should not be the reason for limited care or denial of operative intervention. PMID- 25799474 TI - Femoral vein injury from a trochanteric hip fracture. AB - A case of a comminuted trochanteric fracture where the lesser trochanteric fragment had displaced significantly injuring and becoming lodged within the common femoral vein. PMID- 25799475 TI - Transosseous braided-tape and double-row fixations are better than tension band for avulsion-type greater tuberosity fractures. AB - INTRODUCTION: The optimal treatment for avulsion-type greater tuberosity fractures is yet to be determined. Three fixation methods are tested: tension band with #2 wire suture (TB), double-row suture bridge with anchors (DR), and simple transosseous fixation with braided tape (BT). MATERIALS AND METHODS: Twenty-four porcine proximal humeri were randomised into three groups: TB, DR and BT. A standardised greater tuberosity (GT) osteotomy was performed at 90 degrees to the humeral diaphysis axis. A mechanical testing machine was used to simulate supraspinatus contraction. The force required to produce 3mm and 5mm displacement, as well as complete failure was measured with an axial load cell. Also, three cycles of shoulder flexion/extension with 25 N of supraspinatus contraction were performed. Maximum GT fragment translation and rotation amplitude during one cycle were measured. RESULTS: During supraspinatus contraction, DR and BT groups (p < 0.05) were superior to TB group for both displacements. The BT technique had the strongest maximal load to failure (BT = 466 N; DR = 386 N; TB = 320 N). For the flexion/extension, DR and BT groups had less displacement and rotation than TB group (anterio-posterior displacement: BT = 2.0mm, DR = 1.9 mm, TB = 5.8 mm; anterio-posterior angular displacement: BT = 1.4 degrees , DR = 1.0 degrees , TB = 4.8 degrees ). No significant difference was observed between DR and BT groups, except for the medio-lateral rotation favouring the DR group. CONCLUSION: In conclusion, BT and DR are good fixation methods to treat displaced avulsion-type greater tuberosity fractures. They have similar mechanical properties, and are stronger and more stable that the TB construct. Potential advantages of the BT over the DR may be a lower cost and easier surgery. LEVEL OF EVIDENCE: Basic science study (LEVEL II). PMID- 25799476 TI - [Association of hand grip strength with subjective health and work ability. results of the baseline survey of the lidA study]. AB - AIM: In the BMBF-funded lidA study - leben in der Arbeit - hand grip strength is taken as an objective measure for describing the health of the study population. The aim is to analyse the association of grip strength with characteristics of subjective health and work ability. METHODS: During the 1(st) investigation in 2011 there were 6 585 interviews with employed persons born in 1959 and 1965 and subject to social insurance contributions. The survey included aspects of employment and health. The maximum isometric hand grip strength was determined with a dynamometer from a series of 4 measurements. The examination refers to 6 195 employed persons who approved the realisation of the grip strength test. The determinants of grip strength are analysed bivariately based on non-parametric methods and examined concerning their relative importance using a multiple linear regression. RESULTS: In the descriptive analyses statistically significant median differences (p<0.05) appear between men and women as well as persons of the younger and older cohort. After excluding implausible values some statistically significant differences in grip strength can be observed between the categories of current health condition, physical and mental work ability and the number of pain localisations. The trend for the larger grip strength occurrences can be noted in the categories of better health and work ability plus a smaller number of pain localisations. From the combined analysis of the explanatory variables of age, BMI, health and work ability within the estimated regression model results a corrected R2 of 0.036 for men or, respectively, 0.05 for women. CONCLUSION: Between the categories of selected health and work ability related variables some statistically significant differences of grip strength (+/- 0.0-4.0 kg) were observed. However, the variability of grip strength cannot be explained sufficiently by the data used. Although the results obtained support the preliminary assumptions, the relevance of this matter could not be resolved adequately with the data under consideration. Given that analysing grip strength is important in the individual temporal process, the results will be extended by longitudinal analyses to facilitate the analysis of hand grip strength as predictor of the development of individual health. PMID- 25799477 TI - [Oversupplied? Undersupplied? - The Perspective of Local Governments of the Federal State of Baden-Wurttemberg: A Contribution to the Discussion of Close-to Home Health Care]. AB - BACKGROUND: The ageing of physicians working in ambulatory care make regional health planning a challenging task. This study examines the current supply of general practitioners (GP) within the communities from the perspective of mayors. The information gained on a community level can be used when discussing over- and undersupply as well as future health care planning. METHODS: A questionnaire was sent to all 1101 mayors of the Federal state of Baden-Wurttemberg (BW) in May 2011. For the evaluation of the location of the communities, subjective ratings by the mayors were compared with official criteria, provided by the Federal Institute for Research on Building, Urban Affairs and Spatial Development (BBSR). RESULTS: The participation rate was 63% (n=698). According to the mayors about 70% (n=468) were located in a rural area, according to BBSR criteria were about 26% (n=177) of answers given by rural communities. Of the participating mayors about 54% (n=355) stated that their community is cared for merely by GPs. From this information there was a locally experienced undersupply of GPs calculated for 13.5% (n=86) of the communities. This affected rural as well as non-rural communities. In communities up to 20 000 inhabitants, the ratio between GPs and other specialists seems to be 60:40 whereas in bigger cities the proportion of other specialists appears to be much higher. CONCLUSION: Half of the participating communities seem to not have a practicing specialised physician. An accumulation of specialised physicians in larger cities was reported. The GP shortage appears to mainly be experienced subjectively. Regarding the location (urban vs. rural) of the community, subjective views differ distinctly from the BBSR criteria. This discrepancy could influence a community's marketing strategy when competing for new physicians. PMID- 25799478 TI - [Position Paper of the German Respiratory Society (DGP) on Electronic Cigarettes (E-Cigarettes) in Cooperation with the following Scientific Societies and Organisations: BVKJ, BdP, DGAUM, DGG, DGIM, DGK, DKG, DGSMP, GPP]. PMID- 25799479 TI - Correction: Strategies to create hierarchical self-assembled structures via cooperative non-covalent interactions. AB - Correction for 'Strategies to create hierarchical self-assembled structures via cooperative non-covalent interactions' by Christina Rest et al., Chem. Soc. Rev., 2015, DOI: 10.1039/c4cs00497c. PMID- 25799480 TI - DFT studies on the mechanism of alcohol oxidation by the (bpy)Cu(I)-TEMPO/NMI catalytic system. AB - Density functional theory (DFT) calculations have been performed to investigate the oxidation of alcohol to acetaldehyde, catalyzed by the (bpy)Cu(I)-TEMPO/NMI catalytic system. Three pathways (path A, path B and path C) are presented. Our calculations indicate that path B is the favourable pathway. In path B, the alcohol coordinating to the Cu(I) center provides a H atom to TEMPO to form TEMPOH. Another TEMPO then replaces TEMPOH to abstract the H atom from the Calpha H of the alcoholate (RCH2O(-)) to generate the aldehyde product. On the basis of the studied pathway, a possible mechanism is presented to explain the experimental observations. PMID- 25799481 TI - Effect of contact precautions for MRSA on patient satisfaction scores. AB - Contact precautions may have an adverse effect on a patient's hospital experience and the delivery of care. This case-control study compared patient satisfaction scores between 70 patients isolated for MRSA and 139 non-isolated patients. Based on an adjusted analysis, there was no difference in patient satisfaction between the two groups. Age and educational status were found to affect patient satisfaction. PMID- 25799482 TI - Detection of Escherichia coli sequence type 131 by matrix-assisted laser desorption ionization time-of-flight mass spectrometry: implications for infection control policies? AB - BACKGROUND: Sequence type 131 (ST131) is a predominant lineage among extraintestinal pathogenic Escherichia coli. It plays a major role in the worldwide dissemination of extended-spectrum beta-lactamase (ESBL)-producing E. coli. The ST131 pandemic is mainly the result of clonal expansion of the single well-adapted subclone H30-Rx, which is acquired in hospitals more frequently than other ESBL-producing E. coli clones. AIM: To develop a rapid method using matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to identify ST131 for infection control purposes. METHODS: Peak biomarkers of ST131 were identified from the mass spectrum profiles of 109 E. coli isolates (including 50 ST131 isolates). FINDINGS: The models accurately identified ST131 isolates from mass spectrum profiles obtained with and without protein extraction. CONCLUSIONS: The rapid identification of ST131 isolates with MALDI TOF MS can be easily implemented in the laboratory, and could help to target infection control measures in patients carrying multi-drug-resistant E. coli that are more likely to spread. PMID- 25799483 TI - Controlling urinary tract infections associated with intermittent bladder catheterization in geriatric hospitals. AB - BACKGROUND: Controlling urinary tract infections (UTIs) associated with intermittent catheterization in geriatric patients. AIM: After a local epidemiological study identified high rates of UTI, a multi-disciplinary working group implemented and evaluated corrective measures. METHODS: In 2009, a one month prospective study measured the incidence of UTI, controlled for risk factors and exposure, in six geriatric hospitals. In 2010, a self-administered questionnaire on practices was administered to physicians and nurses working in these geriatric units. In 2011, the working group developed a multi-modal programme to: improve understanding of micturition, measurement of bladder volume and indications for catheter drainage; limit available medical devices; and improve prescription and traceability procedures. Detailed training was provided to all personnel on all sites. The epidemiological study was repeated in 2012 to assess the impact of the programme. FINDINGS: Over 1500 patients were included in the 2009 study. The incidence of acquired infection was 4.8%. The infection rate was higher in patients with intermittent catheters than in patients with indwelling catheters (29.7 vs 9.9 UTI per 100 patients, P = 0.1013) which contradicts the literature. In 2010, the 269 responses to the questionnaire showed that staff did not consider catheterization to place patients at risk of infection, staff had poor knowledge of the recommended indications and techniques, and the equipment varied widely between units. Following implementation of the programme, the study was repeated in 2012 with over 1500 patients. The frequency of UTI in patients with intermittent catheters fell to rates in the published literature. CONCLUSION: Multi-modal programmes are an effective means to control UTI. PMID- 25799484 TI - Detection and characterization of extended-spectrum beta-lactamase-producing Enterobacteriaceae in high-risk patients in an Irish tertiary care hospital. AB - BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL E) are Gram-negative, multi-drug-resistant organisms that are of major clinical significance among immunocompromised patients in high-risk areas in hospital settings. In Ireland, the number of ESBL-E bloodstream infections is increasing. AIMS: To conduct a prevalence study of ESBL-E among immunocompromised patients in high-risk areas [intensive care unit (ICU), liver transplantation and haematology/oncology wards], characterize any ESBL genes detected by polymerase chain reaction (PCR), and perform epidemiological typing using pulsed-field gel electrophoresis (PFGE). METHODS: In total, 317 non-duplicate rectal swabs from patients in high-risk wards were screened anonymously for ESBL-E carriage. Positive isolates were characterized using PCR to detect blaCTX-M, blaTEM, blaOXA 1 and blaSHV ESBL-E genes. Clonal relationships of these isolates were investigated using PFGE. FINDINGS: Fifty (15.8%) high-risk patients were found to harbour ESBL-E. Prevalence rates of 21.9% (N = 28), 14.3% (N = 15) and 8.3% (N = 7) of ESBL-E were isolated from patients on the liver transplantation, ICU and haematology/oncology wards, respectively. Seventy percent of ESBL-E isolates carried more than one resistance gene. Of the 25 ESBL-producing Escherichia coli isolates typed by PFGE, two pairs of two isolates demonstrated >80% homology, and four of the five ESBL-producing Enterobacter cloacae isolates typed by PFGE demonstrated >80% homology, suggesting clonal relatedness and potential cross transmission from individual patients. CONCLUSION: A significant proportion of the patients screened were found to be colonized with ESBL-E. Typing revealed three incidents of potential cross-infection. Therefore, timely detection of ESBL E among patients in high-risk wards is critical for treatment and infection control. PMID- 25799485 TI - Relatedness, conflict, and the evolution of eusociality. AB - The evolution of sterile worker castes in eusocial insects was a major problem in evolutionary theory until Hamilton developed a method called inclusive fitness. He used it to show that sterile castes could evolve via kin selection, in which a gene for altruistic sterility is favored when the altruism sufficiently benefits relatives carrying the gene. Inclusive fitness theory is well supported empirically and has been applied to many other areas, but a recent paper argued that the general method of inclusive fitness was wrong and advocated an alternative population genetic method. The claim of these authors was bolstered by a new model of the evolution of eusociality with novel conclusions that appeared to overturn some major results from inclusive fitness. Here we report an expanded examination of this kind of model for the evolution of eusociality and show that all three of its apparently novel conclusions are essentially false. Contrary to their claims, genetic relatedness is important and causal, workers are agents that can evolve to be in conflict with the queen, and eusociality is not so difficult to evolve. The misleading conclusions all resulted not from incorrect math but from overgeneralizing from narrow assumptions or parameter values. For example, all of their models implicitly assumed high relatedness, but modifying the model to allow lower relatedness shows that relatedness is essential and causal in the evolution of eusociality. Their modeling strategy, properly applied, actually confirms major insights of inclusive fitness studies of kin selection. This broad agreement of different models shows that social evolution theory, rather than being in turmoil, is supported by multiple theoretical approaches. It also suggests that extensive prior work using inclusive fitness, from microbial interactions to human evolution, should be considered robust unless shown otherwise. PMID- 25799486 TI - Diagnostic criteria for malnutrition - An ESPEN Consensus Statement. AB - OBJECTIVE: To provide a consensus-based minimum set of criteria for the diagnosis of malnutrition to be applied independent of clinical setting and aetiology, and to unify international terminology. METHOD: The European Society of Clinical Nutrition and Metabolism (ESPEN) appointed a group of clinical scientists to perform a modified Delphi process, encompassing e-mail communications, face-to face meetings, in group questionnaires and ballots, as well as a ballot for the ESPEN membership. RESULT: First, ESPEN recommends that subjects at risk of malnutrition are identified by validated screening tools, and should be assessed and treated accordingly. Risk of malnutrition should have its own ICD Code. Second, a unanimous consensus was reached to advocate two options for the diagnosis of malnutrition. Option one requires body mass index (BMI, kg/m(2)) <18.5 to define malnutrition. Option two requires the combined finding of unintentional weight loss (mandatory) and at least one of either reduced BMI or a low fat free mass index (FFMI). Weight loss could be either >10% of habitual weight indefinite of time, or >5% over 3 months. Reduced BMI is <20 or <22 kg/m(2) in subjects younger and older than 70 years, respectively. Low FFMI is <15 and <17 kg/m(2) in females and males, respectively. About 12% of ESPEN members participated in a ballot; >75% agreed; i.e. indicated >=7 on a 10-graded scale of acceptance, to this definition. CONCLUSION: In individuals identified by screening as at risk of malnutrition, the diagnosis of malnutrition should be based on either a low BMI (<18.5 kg/m(2)), or on the combined finding of weight loss together with either reduced BMI (age-specific) or a low FFMI using sex specific cut-offs. PMID- 25799487 TI - Prediction of asthma exacerbations in children by innovative exhaled inflammatory markers: results of a longitudinal study. AB - BACKGROUND: In asthma management guidelines the primary goal of treatment is asthma control. To date, asthma control, guided by symptoms and lung function, is not optimal in many children and adults. Direct monitoring of airway inflammation in exhaled breath may improve asthma control and reduce the number of exacerbations. AIM: 1) To study the use of fractional exhaled nitric oxide (FeNO) and inflammatory markers in exhaled breath condensate (EBC), in the prediction of asthma exacerbations in a pediatric population. 2) To study the predictive power of these exhaled inflammatory markers combined with clinical parameters. METHODS: 96 asthmatic children were included in this one-year prospective observational study, with clinical visits every 2 months. Between visits, daily symptom scores and lung function were recorded using a home monitor. During clinical visits, asthma control and FeNO were assessed. Furthermore, lung function measurements were performed and EBC was collected. Statistical analysis was performed using a test dataset and validation dataset for 1) conditionally specified models, receiver operating characteristic-curves (ROC-curves); 2) k-nearest neighbors algorithm. RESULTS: Three conditionally specified predictive models were constructed. Model 1 included inflammatory markers in EBC alone, model 2 included FeNO plus clinical characteristics and the ACQ score, and model 3 included all the predictors used in model 1 and 2. The area under the ROC-curves was estimated as 47%, 54% and 59% for models 1, 2 and 3 respectively. The k-nearest neighbors predictive algorithm, using the information of all the variables in model 3, produced correct predictions for 52% of the exacerbations in the validation dataset. CONCLUSION: The predictive power of FeNO and inflammatory markers in EBC for prediction of an asthma exacerbation was low, even when combined with clinical characteristics and symptoms. Qualitative improvement of the chemical analysis of EBC may lead to a better non-invasive prediction of asthma exacerbations. PMID- 25799488 TI - Validation of LRG1 as a potential biomarker for detection of epithelial ovarian cancer by a blinded study. AB - BACKGROUND: Leucine-rich alpha-2-glycoprotein (LRG1) was found to be differentially expressed in sera from patients with Epithelial Ovarian Cancer (EOC). The aim of this study is to investigate the performance of LRG1 for detection of EOC, including early stage EOC, and to evaluate if LRG1 can complement CA125 in order to improve EOC detection using two independent blinded sample sets. METHODS AND RESULTS: Serum LRG1 and CA125 were measured by immunoassays. All assays were performed blinded to clinical data. Using the two independent sample sets (156 participants for sample set 1, and 233 for sample set 2), LRG1 was differentially expressed in EOC cases as compared to healthy, surgical, and benign controls, and its performance was not affected by the conditions of blood collection. The areas under the ROC curve (AUC) for LRG1 in differentiating EOC cases from non-cases were 0.797 and 0.786 for sample set 1 and 2. For differentiating EOC cases from healthy controls, the AUC values for LRG1 were 0.792 and 0.794. At a fixed specificity of 95%, LRG1 detects 52%, and 53.5% of EOC cases from healthy controls for sample set 1 and 2. When combining LRG1 and CA125, the AUC value increased to 0.927, which was improved compared to CA125 (AUC=0.916) (p=0.008) alone in distinguishing EOC cases from non-cases. More importantly, LRG1 also showed potential performance in differentiating early stage EOC from non-cases with an AUC of 0.715 for sample set 1, and 0.690 for sample set 2. The combination of LRG1 and CA125 resulted in an AUC of 0.838, which outperforms CA125 (AUC=0.785) (p=0.018) in detecting early stage EOC cases from non-cases using the larger sample set. CONCLUSIONS: LRG1 could be a useful biomarker alone or in combination with CA125 for the diagnosis of ovarian cancer. PMID- 25799490 TI - StakeMeter: value-based stakeholder identification and quantification framework for value-based software systems. AB - Value-based requirements engineering plays a vital role in the development of value-based software (VBS). Stakeholders are the key players in the requirements engineering process, and the selection of critical stakeholders for the VBS systems is highly desirable. Based on the stakeholder requirements, the innovative or value-based idea is realized. The quality of the VBS system is associated with the concrete set of valuable requirements, and the valuable requirements can only be obtained if all the relevant valuable stakeholders participate in the requirements elicitation phase. The existing value-based approaches focus on the design of the VBS systems. However, the focus on the valuable stakeholders and requirements is inadequate. The current stakeholder identification and quantification (SIQ) approaches are neither state-of-the-art nor systematic for the VBS systems. The existing approaches are time-consuming, complex and inconsistent which makes the initiation process difficult. Moreover, the main motivation of this research is that the existing SIQ approaches do not provide the low level implementation details for SIQ initiation and stakeholder metrics for quantification. Hence, keeping in view the existing SIQ problems, this research contributes in the form of a new SIQ framework called 'StakeMeter'. The StakeMeter framework is verified and validated through case studies. The proposed framework provides low-level implementation guidelines, attributes, metrics, quantification criteria and application procedure as compared to the other methods. The proposed framework solves the issues of stakeholder quantification or prioritization, higher time consumption, complexity, and process initiation. The framework helps in the selection of highly critical stakeholders for the VBS systems with less judgmental error. PMID- 25799489 TI - Non-viral nanoparticle delivers small interfering RNA to macrophages in vitro and in vivo. AB - Macrophages are increasingly being viewed as therapeutic target for various cancers and many inflammatory diseases. Sequence specific gene reduction by siRNA represents an attractive approach to modulate macrophage function. However, delivery of the therapeutic siRNA into macrophages by non-viral nanoparticles has been a major technical challenge. In this study, we developed a glucan-based siRNA carrier system (BG34-10-Re-I) and demonstrated that the BG34-10-Re-I can effectively assemble siRNA into uniformly distributed nanoparticles of the novel core-shell structure. The BG34-10-Re-I/siRNA nanoparticles effectively reduced gene expression of macrophage migration inhibitory factor (MIF) in primary macrophages at both protein and mRNA level. The nanoparticles also mediated a sustained reduction of MIF within primary macrophages. Moreover, systemic injection of the nanoparticles into the Balb/c mice bearing 4T1 mammary tumors resulted in the MIF reduction in tumor-associated macrophages. Mechanistic studies demonstrated that the glucan-shell and the siRNA-core structure contribute to the effective delivery of MIF siRNA to macrophages both in vitro and in vivo. This study represents the first development of the primary macrophage MIF gene targeted non-viral nanoparticle system for both in vitro and in vivo applications. PMID- 25799491 TI - De novo characterization of fall dormant and nondormant alfalfa (Medicago sativa L.) leaf transcriptome and identification of candidate genes related to fall dormancy. AB - Alfalfa (Medicago sativa L.) is one of the most widely cultivated perennial forage legumes worldwide. Fall dormancy is an adaptive character related to the biomass production and winter survival in alfalfa. The physiological, biochemical and molecular mechanisms causing fall dormancy and the related genes have not been well studied. In this study, we sequenced two standard varieties of alfalfa (dormant and non-dormant) at two time points and generated approximately 160 million high quality paired-end sequence reads using sequencing by synthesis (SBS) technology. The de novo transcriptome assembly generated a set of 192,875 transcripts with an average length of 856 bp representing about 165.1 Mb of the alfalfa leaf transcriptome. After assembly, 111,062 (57.6%) transcripts were annotated against the NCBI non-redundant database. A total of 30,165 (15.6%) transcripts were mapped to 323 Kyoto Encyclopedia of Genes and Genomes pathways. We also identified 41,973 simple sequence repeats, which can be used to generate markers for alfalfa, and 1,541 transcription factors were identified across 1,350 transcripts. Gene expression between dormant and non-dormant alfalfa at different time points were performed, and we identified several differentially expressed genes potentially related to fall dormancy. The Gene Ontology and pathways information were also identified. We sequenced and assembled the leaf transcriptome of alfalfa related to fall dormancy, and also identified some genes of interest involved in the fall dormancy mechanism. Thus, our research focused on studying fall dormancy in alfalfa through transcriptome sequencing. The sequencing and gene expression data generated in this study may be used further to elucidate the complete mechanisms governing fall dormancy in alfalfa. PMID- 25799492 TI - ARF6 promotes the formation of Rac1 and WAVE-dependent ventral F-actin rosettes in breast cancer cells in response to epidermal growth factor. AB - Coordination between actin cytoskeleton assembly and localized polarization of intracellular trafficking routes is crucial for cancer cell migration. ARF6 has been implicated in the endocytic recycling of surface receptors and membrane components and in actin cytoskeleton remodeling. Here we show that overexpression of an ARF6 fast-cycling mutant in MDA-MB-231 breast cancer-derived cells to mimick ARF6 hyperactivation observed in invasive breast tumors induced a striking rearrangement of the actin cytoskeleton at the ventral cell surface. This phenotype consisted in the formation of dynamic actin-based podosome rosette-like structures expanding outward as wave positive for F-actin and actin cytoskeleton regulatory components including cortactin, Arp2/3 and SCAR/WAVE complexes and upstream Rac1 regulator. Ventral rosette-like structures were similarly induced in MDA-MB-231 cells in response to epidermal growth factor (EGF) stimulation and to Rac1 hyperactivation. In addition, interference with ARF6 expression attenuated activation and plasma membrane targeting of Rac1 in response to EGF treatment. Our data suggest a role for ARF6 in linking EGF-receptor signaling to Rac1 recruitment and activation at the plasma membrane to promote breast cancer cell directed migration. PMID- 25799493 TI - Hydroxyethyl starch (HES 130/0.4) impairs intestinal barrier integrity and metabolic function: findings from a mouse model of the isolated perfused small intestine. AB - BACKGROUND: The application of hydroxyethyl starch (HES) for volume resuscitation is controversially discussed and clinical studies have suggested adverse effects of HES substitution, leading to increased patient mortality. Although, the intestine is of high clinical relevance and plays a crucial role in sepsis and inflammation, information about the effects of HES on intestinal function and barrier integrity is very scarce. We therefore evaluated the effects of clinically relevant concentrations of HES on intestinal function and barrier integrity employing an isolated perfused model of the mouse small intestine. METHODS: An isolated perfused model of the mouse small intestine was established and intestines were vascularly perfused with a modified Krebs-Henseleit buffer containing 3% Albumin (N=7) or 3% HES (130/0.4; N=7). Intestinal metabolic function (galactose uptake, lactate-to-pyruvate ratio), edema formation (wet-to dry weight ratio), morphology (histological and electron microscopical analysis), fluid shifts within the vascular, lymphatic and luminal compartments, as well as endothelial and epithelial barrier permeability (FITC-dextran translocation) were evaluated in both groups. RESULTS: Compared to the Albumin group, HES perfusion did not significantly change the wet-to-dry weight ratio and lactate-to-pyruvate ratio. However, perfusing the small intestine with 3% HES resulted in a significant loss of vascular fluid (p<0.01), an increased fluid accumulation in the intestinal lumen (p<0.001), an enhanced translocation of FITC-dextran from the vascular to the luminal compartment (p<0.001) and a significantly impaired intestinal galactose uptake (p<0.001). Morphologically, these findings were associated with an aggregation of intracellular vacuoles within the intestinal epithelial cells and enlarged intercellular spaces. CONCLUSION: A vascular perfusion with 3% HES impairs the endothelial and epithelial barrier integrity as well as metabolic function of the small intestine. PMID- 25799494 TI - The effect of locomotion on the mobilization of minerals from the maternal skeleton. AB - Bone is a dynamic tissue from which minerals are deposited or withdrawn according to the body's demand. During late pregnancy and lactation, female mammals mobilize mineral from bone to support the ossification of offspring skeleton(s). Conversely, in response to mechanical loading, minerals are deposited in bone enabling it to develop a stronger architecture. Despite their central importance to reproductive performance and skeletal integrity, the interactions between these potentially opposing forces remains poorly understood. It is possible that inter-individual differences in the loading imposed by different forms of locomotion may alter the amount of mineral mobilized during reproduction. Here, the impact of vertical versus horizontal locomotion on bone mobilization was examined during reproduction in the laboratory mouse. The vertical, or climbing, group had access to a 60-cm tower, increasing strain on their appendicular skeleton. The horizontal, or tunnel, group had access to a 100-cm tunnel, which encouraged movements within the horizontal plane. Form of locomotion did not impact the amount of bone females mobilized during reproduction or the amount of mineral females deposited in the litter, but maternal bone architecture differed between groups. The climbing group displayed more trabeculae than the tunnel group, whereas the tunnel group displayed greater cortical bone mineral density mid-shaft. Interestingly, pups born to mothers in the climbing group had a higher concentration of total body calcium at 16 days than pups of mothers in the tunnel group. As maternal total body calcium composition and the amount of calcium invested in the full litter were not different between groups, the difference in the relative calcium content of pups between groups is not suspected to reflect difference in mineral allocation. Future research should consider the impact of maternal activity on the efficiency of offspring skeletal ossification via hormones and other bioactive factors transferred in utero and in milk. PMID- 25799495 TI - Inter-simple sequence repeat data reveals high genetic diversity in wild populations of the narrowly distributed endemic Lilium regale in the Minjiang River Valley of China. AB - Lilium regale E.H. Wilson is endemic to a narrow geographic area in the Minjiang River valley in southwestern China, and is considered an important germplasm for breeding commercially valuable lily varieties, due to its vigorous growth, resistance to diseases and tolerance for low moisture. We analyzed the genetic diversity of eight populations of L. regale sampled across the entire natural distribution range of the species using Inter-Simple Sequence Repeat markers. The genetic diversity (expected heterozygosity= 0.3356) was higher than those reported for other narrowly distributed endemic plants. The levels of inbreeding (Fst = 0.1897) were low, and most of the genetic variability was found to be within (80.91%) than amongpopulations (19.09%). An indirect estimate of historical levels of gene flow (Nm =1.0678) indicated high levels of gene flow among populations. The eight analyzed populations clustered into three genetically distinct groups. Based on these results, we recommend conservation of large populations representing these three genetically distinct groups. PMID- 25799496 TI - Potentiation of insulin-mediated glucose lowering without elevated hypoglycemia risk by a small molecule insulin receptor modulator. AB - Insulin resistance is the key feature of type 2 diabetes and is manifested as attenuated insulin receptor (IR) signaling in response to same levels of insulin binding. Several small molecule IR activators have been identified and reported to exhibit insulin sensitization properties. One of these molecules, TLK19781 (Cmpd1), was investigated to examine its IR sensitizing action in vivo. Our data demonstrate that Cmpd1, at doses that produced minimal efficacy in the absence of insulin, potentiated insulin action during an OGTT in non-diabetic mice and enhanced insulin-mediated glucose lowering in diabetic mice. Interestingly, different from insulin alone, Cmpd1 combined with insulin showed enhanced efficacy and duration of action without increased hypoglycemia. To explore the mechanism underlying the apparent glucose dependent efficacy, tissue insulin signaling was compared in healthy and diabetic mice. Cmpd1 enhanced insulin's effects on IR phosphorylation in both healthy and diabetic mice. In contrast, the compound potentiated insulin's effects on Akt phosphorylation in diabetic but not in non-diabetic mice. These differential effects on signaling corresponding to glucose levels could be part of the mechanism for reduced hypoglycemia risk. The in vivo efficacy of Cmpd1 is specific and dependent on IR expression. Results from these studies support the idea of targeting IR for insulin sensitization, which carries low hypoglycemia risk by standalone treatment and could improve the effectiveness of insulin therapies. PMID- 25799497 TI - Correction: learning probabilistic features for robotic navigation using laser sensors. AB - [This corrects the article DOI: 10.1371/journal.pone.0112507.]. PMID- 25799499 TI - Are the Diagnostic Criteria for Asthma-COPD Overlap Syndrome Appropriate in Biomass Smoke-Induced chronic obstructive pulmonary disease? PMID- 25799498 TI - pH dependence of the stress regulator DksA. AB - DksA controls transcription of genes associated with diverse stress responses, such as amino acid and carbon starvation, oxidative stress, and iron starvation. DksA binds within the secondary channel of RNA polymerase, extending its long coiled-coil domain towards the active site. The cellular expression of DksA remains constant due to a negative feedback autoregulation, raising the question of whether DksA activity is directly modulated during stress. Here, we show that Escherichia coli DksA is essential for survival in acidic conditions and that, while its cellular levels do not change significantly, DksA activity and binding to RNA polymerase are increased at lower pH, with a concomitant decrease in its stability. NMR data reveal pH-dependent structural changes centered at the interface of the N and C-terminal regions of DksA. Consistently, we show that a partial deletion of the N-terminal region and substitutions of a histidine 39 residue at the domain interface abolish pH sensitivity in vitro. Together, these data suggest that DksA responds to changes in pH by shifting between alternate conformations, in which competing interactions between the N- and C-terminal regions modify the protein activity. PMID- 25799500 TI - Trends and inequities in use of maternal health care services in Bangladesh, 1991 2011. AB - BACKGROUND AND METHODS: Monitoring use-inequity is important to measure progress in efforts to address health-inequities. Using data from six Bangladesh Demographic and Health Surveys (BDHS), we examine trends, inequities and socio demographic determinants of use of maternal health care services in Bangladesh between 1991 and 2011. FINDINGS: Access to maternal health care services has improved in the last two decades. The adjusted yearly trend was 9.0% (8.6%-9.5%) for any antenatal care (ANC), 11.9% (11.1%-12.7%) for institutional delivery, and 18.9% (17.3%-20.5%) for C-section delivery which is above the WHO recommended rate of 5-15%. Use-inequity was significant for all three indicators but is reducing over time. Between 1991-1994 and 2007-2011 the rich:poor ratio reduced from 3.65 to 1.65 for ANC and from 15.80 to 6.77 for institutional delivery. Between 1995-1998 and 2007-2011, the concentration index reduced from 0.27 (0.25 0.29) to 0.15 (0.14-0.16) for ANC, and from 0.65 (0.60-0.71) to 0.39 (0.37-0.41) for institutional delivery during that period. For use of c-section, the rich:poor ratio reduced from 18.17 to 13.39 and the concentration index from 0.66 (0.57-0.75) to 0.47 (0.45-0.49). In terms of rich:poor differences, there was equity-gain for ANC but not for facility delivery or C-section delivery. All socio-demographic variables were significant predictors of use; of them, maternal education was the most powerful. In addition, the contribution of for-profit private sector is increasingly growing in maternal health. CONCLUSION: Both access and equity are improving in maternal health. We recommend strengthening ongoing health and non-health interventions for the poor. Use-inequity should be monitored using multiple indicators which are incorporated into routine health information systems. Rising C-section rate is alarming and indication of C sections should be monitored both in private and public sector facilities. PMID- 25799501 TI - Olfactory dysfunction and neurotransmitter disturbance in olfactory bulb of transgenic mice expressing human A53T mutant alpha-synuclein. AB - Parkinson disease is a multi-system neurodegenerative disease characterized by both motor and non-motor symptoms. Hyposmia is one of the early non-motor symptoms occurring in more than 90% of Parkinson disease cases, which can precede motor symptoms even several years. Up to now, the relationship between hyposmia and Parkinson disease remains elusive. Lack of proper animal models of hyposmia restricts the investigation. In this study we assessed olfactory function in Prp A53T-alpha-synuclein transgenic (alphaSynA53T) mice which had been reported to show age-dependent motor impairments and intracytoplasmic inclusions. We also examined cholinergic and dopaminergic systems in olfactory bulb of alphaSynA53T mice by immunofluorescent staining, enzyme linked immunosorbent assay and western blot. We found that compared to wild type littermates, alphaSynA53T mice at 6 months or older displayed a deficit of odor discrimination and odor detection. No significant changes were found in olfactory memory and odor habituation. Furthermore compared to wildtype littermates, in olfactory bulb of alphaSynA53T mice at 10 months old we detected a marked decrease of cholinergic neurons in mitral cell layer and a decrease of acetylcholinesterase activity, while dopaminergic neurons were found increased in glomerular layer, accompanied with an increase of tyrosine hydroxylase protein. Our studies indicate that alphaSynA53T mice have olfactory dysfunction before motor deficits occur, and the cholinergic and dopaminergic disturbance might be responsible for the Parkinson disease-related olfactory dysfunction. PMID- 25799502 TI - Prevalence, pharmacological treatment, and control of cardiometabolic risk factors among older people in central Stockholm: a population-based study. AB - BACKGROUND: Cardiometabolic risk factors and related cardiovascular diseases represent major threats to healthy aging. OBJECTIVE: We aimed to estimate distribution, pharmacological treatment, and control of main cardiometabolic risk factors among older people. METHODS: This population-based study included 3363 participants (age>=60 years, 64.9% women) in the Swedish National study on Aging and Care in Kungsholmen, in central Stockholm, Sweden (2001-2004). Data on demographics, cardiometabolic risk factors (hypertension, obesity, diabetes, and high cholesterol), and medication use were collected through face-to-face interviews, clinical examinations, laboratory tests, and the inpatient register. Cardiometabolic risk factors were defined following the most commonly used criteria. Prevalence was standardized using local census data. RESULTS: The age- and sex-standardized prevalence of diabetes, obesity, high cholesterol, and hypertension was 9.5%, 12.8%, 49.7%, and 74.9%, respectively. The prevalence of hypertension and diabetes increased with age, whereas the prevalence of obesity and high cholesterol decreased with age. Forty-nine percent of older adults had two or more cardiometabolic risk factors; 9.8% had three or more. Overall, 55.5% of people with hypertension, 50.3% with diabetes, and 25.0% with high cholesterol received pharmacological treatment. Of those treated pharmacologically, 49.4%, 38.1%, and 85.5% reached therapeutic goals for hypertension (blood pressure<150/90 mmHg), diabetes (glycated haemoglobin<7%), and high cholesterol (total cholesterol<6.22 mmol/l), respectively. CONCLUSIONS: Hypertension, high cholesterol, and clustering of cardiometabolic risk factors were common among older people in Stockholm, but pharmacological treatment and control of these major factors can be improved. Appropriate management of cardiometabolic profiles among older people may help improve cardiovascular health and achieve healthy aging. PMID- 25799503 TI - Comparative 3D genome structure analysis of the fission and the budding yeast. AB - We studied the 3D structural organization of the fission yeast genome, which emerges from the tethering of heterochromatic regions in otherwise randomly configured chromosomes represented as flexible polymer chains in an nuclear environment. This model is sufficient to explain in a statistical manner many experimentally determined distinctive features of the fission yeast genome, including chromatin interaction patterns from Hi-C experiments and the co locations of functionally related and co-expressed genes, such as genes expressed by Pol-III. Our findings demonstrate that some previously described structure function correlations can be explained as a consequence of random chromatin collisions driven by a few geometric constraints (mainly due to centromere-SPB and telomere-NE tethering) combined with the specific gene locations in the chromosome sequence. We also performed a comparative analysis between the fission and budding yeast genome structures, for which we previously detected a similar organizing principle. However, due to the different chromosome sizes and numbers, substantial differences are observed in the 3D structural genome organization between the two species, most notably in the nuclear locations of orthologous genes, and the extent of nuclear territories for genes and chromosomes. However, despite those differences, remarkably, functional similarities are maintained, which is evident when comparing spatial clustering of functionally related genes in both yeasts. Functionally related genes show a similar spatial clustering behavior in both yeasts, even though their nuclear locations are largely different between the yeast species. PMID- 25799504 TI - Functional characterization of a strong bi-directional constitutive plant promoter isolated from cotton leaf curl Burewala virus. AB - Cotton leaf curl Burewala virus (CLCuBuV), belonging to the genus Begomovirus, possesses single-stranded monopartite DNA genome. The bidirectional promoters representing Rep and coat protein (CP) genes of CLCuBuV were characterized and their efficacy was assayed. Rep and CP promoters of CLCuBuV and 35S promoter of Cauliflower mosaic virus (CaMV) were fused with beta-glucuronidase (GUS) and green fluorescent protein (GFP) reporter genes. GUS activity in individual plant cells driven by Rep, CP and 35S promoters was estimated using real-time PCR and fluorometric GUS assay. Histochemical staining of GUS in transformed tobacco (Nicotiana tabacum cv. Xanthi) leaves showed highest expression driven by Rep promoter followed by 35S promoter and CP promoter. The expression level of GUS driven by Rep promoter in transformed tobacco plants was shown to be two to four fold higher than that of 35S promoter, while the expression by CP promoter was slightly lower. Further, the expression of GFP was monitored in agroinfiltrated leaves of N. benthamiana, N. tabacum and cotton (Gossypium hirsutum) plants using confocal laser scanning microscopy. Rep promoter showed strong consistent transient expression in tobacco and cotton leaves as compared to 35S promoter. The strong constitutive CLCuBuV Rep promoter developed in this study could be very useful for high level expression of transgenes in a wide variety of plant cells. PMID- 25799505 TI - Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice. AB - DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (DeltaGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(DeltaE)). Dyt1 DeltaGAG heterozygous knock-in (KI) mice, which mimic DeltaGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(DeltaE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia. PMID- 25799507 TI - A comprehensive study on micellization of dissymmetric pyrrolidinium headgroup based gemini surfactants. AB - Three groups of pyrrolidinium headgroup-based gemini surfactants of 1,1'-(propane 1,3-diyl)bis(1-alkyl pyrrolidinium) bromide, in categories of symmetric CmC3CmPB (m = 10, 12, 14), dissymmetric CmC3C14PB (m = 10, 12, 14) and CmC3CnPB (m = 8, 10, 12, m + n = 24) surfactants, are studied using equilibrium surface tension, conductivity, fluorescence, and NMR techniques. The importance of the dissymmetry on the micellization has been revealed in detail. The increase in the hydrophobic chain length m for CmC3CmPB and CmC3C14PB or in the dissymmetry (n/m) for CmC3CnPB can strengthen the aggregation ability and surface activity of the surfactants significantly, i.e., a lower critical micelle concentration (cmc) and a lower surface tension at cmc (gammacmc). However, the aggregation number at cmc (N*) obeys the opposite variation tendency and it becomes smaller upon increasing m or n/m, due to the formation of premicelles. Thermodynamic results reveal that the contribution of enthalpy (DeltaH) to the Gibbs free energy (DeltaG) is strengthened by increasing m or n/m during the spontaneous micellization process. Moreover, (1)H NMR results confirm the microenvironment change of the surfactants from polar water to micelles during the micellization, and 2D Noesy NMR spectra suggest that the methylene groups in the ring should adopt a conformation toward the nonpolar micellar core rather than in the polar water. PMID- 25799506 TI - Ecuadorian banana farms should consider organic banana with low price risks in their land-use portfolios. AB - Organic farming is a more environmentally friendly form of land use than conventional agriculture. However, recent studies point out production tradeoffs that often prevent the adoption of such practices by farmers. Our study shows with the example of organic banana production in Ecuador that economic tradeoffs depend much on the approach of the analysis. We test, if organic banana should be included in economic land-use portfolios, which indicate how much of the land is provided for which type of land-use. We use time series data for productivity and prices over 30 years to compute the economic return (as annualized net present value) and its volatility (with standard deviation as risk measure) for eight crops to derive land-use portfolios for different levels of risk, which maximize economic return. We find that organic banana is included in land-use portfolios for almost every level of accepted risk with proportions from 1% to maximally 32%, even if the same high uncertainty as for conventional banana is simulated for organic banana. A more realistic, lower simulated price risk increased the proportion of organic banana substantially to up to 57% and increased annual economic returns by up to US$ 187 per ha. Under an assumed integration of both markets, for organic and conventional banana, simulated by an increased coefficient of correlation of economic return from organic and conventional banana (rho up to +0.7), organic banana holds significant portions in the land use portfolios tested only, if a low price risk of organic banana is considered. We conclude that uncertainty is a key issue for the adoption of organic banana. As historic data support a low price risk for organic banana compared to conventional banana, Ecuadorian farmers should consider organic banana as an advantageous land-use option in their land-use portfolios. PMID- 25799508 TI - Selective dicer suppression in the kidney alters GSK3beta/beta-catenin pathways promoting a glomerulocystic disease. AB - Dicer is a crucial enzyme for the maturation of miRNAs. Mutations in the Dicer gene are highly associated with Pleuro Pulmonary Blastoma-Family Dysplasia Syndrome (PPB-FDS, OMIM 601200), recently proposed to be renamed Dicer syndrome. Aside from the pulmonary phenotype (blastoma), renal nephroma and thyroid goiter are frequently part of Dicer syndrome. To investigate the renal phenotype, conditional knockout (cKO) mice for Dicer in Pax8 expressing cells were generated. Dicer cKO mice progressively develop a glomerulocystic phenotype coupled with urinary concentration impairment, proteinuria and severe renal failure. Higher cellular turnover of the parietal cells of Bowman's capsule precedes the development of the cysts and the primary cilium progressively disappears with cyst-enlargement. Upregulation of GSK3beta precedes the development of the glomerulocystic phenotype. Downregulation of beta-catenin in the renal cortex and its cytosolic removal in the cells lining the cysts may be associated with observed accumulation of GSK3beta. Alterations of beta-catenin regulating pathways could promote cystic degeneration as in other models. Thus, miRNAs are fundamental in preserving renal morphology and function. Alteration of the GSK3beta/beta-catenin pathway could be a crucial mechanism linking miRNA dysregulation and the development of a glomerulocystic disease. PMID- 25799510 TI - Eye-head coordination for visual cognitive processing. AB - We investigated coordinated movements between the eyes and head ("eye-head coordination") in relation to vision for action. Several studies have measured eye and head movements during a single gaze shift, focusing on the mechanisms of motor control during eye-head coordination. However, in everyday life, gaze shifts occur sequentially and are accompanied by movements of the head and body. Under such conditions, visual cognitive processing influences eye movements and might also influence eye-head coordination because sequential gaze shifts include cycles of visual processing (fixation) and data acquisition (gaze shifts). In the present study, we examined how the eyes and head move in coordination during visual search in a large visual field. Subjects moved their eyes, head, and body without restriction inside a 360 degrees visual display system. We found patterns of eye-head coordination that differed those observed in single gaze shift studies. First, we frequently observed multiple saccades during one continuous head movement, and the contribution of head movement to gaze shifts increased as the number of saccades increased. This relationship between head movements and sequential gaze shifts suggests eye-head coordination over several saccade-fixation sequences; this could be related to cognitive processing because saccade-fixation cycles are the result of visual cognitive processing. Second, distribution bias of eye position during gaze fixation was highly correlated with head orientation. The distribution peak of eye position was biased in the same direction as head orientation. This influence of head orientation suggests that eye-head coordination is involved in gaze fixation, when the visual system processes retinal information. This further supports the role of eye-head coordination in visual cognitive processing. PMID- 25799511 TI - Rescue of NBD2 mutants N1303K and S1235R of CFTR by small-molecule correctors and transcomplementation. AB - Although, the most common Cystic Fibrosis mutation, DeltaF508, in the cystic fibrosis transmembrane regulator. (CFTR), is located in nucleotide binding domain (NBD1), disease-causing mutations also occur in NBD2. To provide information on potential therapeutic strategies for mutations in NBD2, we studied, using a combination of biochemical approaches and newly created cell lines, two disease causing NBD2 mutants, N1303K and S1235R. Surprisingly, neither was rescued by low temperature. Inhibition of proteasomes with MG132 or aggresomes with tubacin rescued the immature B and mature C bands of N1303K and S1235R, indicating that degradation occurs via proteasomes and aggresomes. We found no effect of the lysosome inhibitor E64. Thus, our results show that these NBD2 mutants are processing mutants with unique characteristics. Several known correctors developed to rescue DeltaF508-CFTR, when applied either alone or in combination, significantly increased the maturation of bands B and C of both NBD 2 mutants. The best correction occurred with the combinations of C4 plus C18 or C3 plus C4. Co-transfection of truncated CFTR (?27-264) into stably transfected cells was also able to rescue them. This demonstrates for the first time that transcomplementation with a truncated version of CFTR can rescue NBD2 mutants. Our results show that the N1303K mutation has a more profound effect on NBD2 processing than S1235R and that small-molecule correctors increase the maturation of bands B and C in NBD2 mutants. In addition, ?27-264 was able to transcomplement both NDB2 mutants. We conclude that differences and similarities occur in the impact of mutations on NBD2 when compared to DeltaF508-CFTR suggesting that individualized strategies may be needed to restore their function. Finally our results are important because they suggest that gene or corrector molecule therapies either alone or in combination individualized for NBD2 mutants may be beneficial for patients bearing N1303K or S1235R mutations. PMID- 25799512 TI - Effects of Spartina alterniflora invasion on soil respiration in the Yangtze River estuary, China. AB - Many studies have found that plant invasion can enhance soil organic carbon (SOC) pools, by increasing net primary production (NPP) and/or decreased soil respiration. While most studies have focused on C input, little attention has been paid to plant invasion effects on soil respiration, especially in wetland ecosystems. Our study examined the effects of Spartina alterniflora invasion on soil respiration and C dynamics in the Yangtze River estuary. The estuary was originally occupied by two native plant species: Phragmites australis in the high tide zone and Scirpus mariqueter in the low tide zone. Mean soil respiration rates were 185.8 and 142.3 mg CO2 m(-2) h(-1) in S. alterniflora and P. australis stands in the high tide zone, and 159.7 and 112.0 mg CO2 m(-2) h(-1) in S. alterniflora and S. mariqueter stands in the low tide zone, respectively. Aboveground NPP (ANPP), SOC, and microbial biomass were also significantly higher in the S. alterniflora stands than in the two native plant stands. S. alterniflora invasion did not significantly change soil inorganic carbon or pH. Our results indicated that enhanced ANPP by S. alterniflora exceeded invasion induced C loss through soil respiration. This suggests that S. alterniflora invasion into the Yangtze River estuary could strengthen the net C sink of wetlands in the context of global climate change. PMID- 25799509 TI - DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status. AB - Cholangiocarcinoma (CCA) is a cancer arising from the neoplastic transformation of cholangiocytes. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(beta-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on CCA cells. We demonstrate that zebularine exerts an antitumor effect on CCA cells. Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1. DNA methylation analysis demonstrated that zebularine induced DNA demethylation, and the GO Biological Process terms "hemophilic cell adhesion", "regulation of transcription, DNA-dependent" and "Wnt signaling pathway" were found to be significantly enriched in association with demethylated genes. Furthermore, we observed that zebularine treatment decreased beta-catenin protein levels in TFK-1 and HuCCT1 cells. These results suggest that zebularine alters DNA methylation status, and that some aspect of DNA demethylation by zebularine induces suppression of the Wnt signaling pathway, which leads to apoptotic cell death in CCA. We previously reported a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma via a DNA methylation independent pathway. Together, our present and previous studies indicate that zebularine could function as both a DNMT inhibitor and a non-DNMT inhibitor reagent, and that, while the optimal usage of zebularine may depend on cancer type, zebularine may be useful for chemotherapy against cancer. PMID- 25799513 TI - High-resolution harmonics ultrasound imaging for non-invasive characterization of wound healing in a pre-clinical swine model. AB - This work represents the first study employing non-invasive high-resolution harmonic ultrasound imaging to longitudinally characterize skin wound healing. Burn wounds (day 0-42), on the dorsum of a domestic Yorkshire white pig were studied non-invasively using tandem digital planimetry, laser speckle imaging and dual mode (B and Doppler) ultrasound imaging. Wound depth, as measured by B-mode imaging, progressively increased until day 21 and decreased thereafter. Initially, blood flow at the wound edge increased up to day 14 and subsequently regressed to baseline levels by day 21, when the wound was more than 90% closed. Coinciding with regression of blood flow at the wound edge, there was an increase in blood flow in the wound bed. This was observed to regress by day 42. Such changes in wound angiogenesis were corroborated histologically. Gated Doppler imaging quantitated the pulse pressure of the primary feeder artery supplying the wound site. This pulse pressure markedly increased with a bimodal pattern following wounding connecting it to the induction of wound angiogenesis. Finally, ultrasound elastography measured tissue stiffness and visualized growth of new tissue over time. These studies have elegantly captured the physiological sequence of events during the process of wound healing, much of which is anticipated based on certain dynamics in play, to provide the framework for future studies on molecular mechanisms driving these processes. We conclude that the tandem use of non-invasive imaging technologies has the power to provide unprecedented insight into the dynamics of the healing skin tissue. PMID- 25799514 TI - Increased expressions of ADAMTS-13, neuronal nitric oxide synthase, and neurofilament correlate with severity of neuropathology in Border disease virus infected small ruminants. AB - Border Disease (BD), caused by Pestivirus from the family Flaviviridae, leads to serious reproductive losses and brain anomalies such as hydranencephaly and cerebellar hypoplasia in aborted fetuses and neonatal lambs. In this report it is aimed to investigate the expression of neuronal nitric oxide synthase (nNOS), A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13 (ADAMTS 13), and neurofilament (NF) in the brain tissue in small ruminants infected with Border Disease Virus (BDV) and to identify any correlation between hypomyelinogenesis and BD neuropathology. Results of the study revealed that the levels of ADAMTS-13 (p<0.05), nNOS (p<0.05), and NF (p<0.05) were remarkably higher in BDV-infected brain tissue than in the uninfected control. It was suggested that L-arginine-NO synthase pathway is activated after infection by BDV and that the expression of NF and nNOS is associated with the severity of BD. A few studies have focused on ADAMTS-13 expression in the central nervous system, and its function continues to remain unclear. The most prominent finding from our study was that ADAMTS-13, which contain two CUB domains, has two CUB domains and its high expression levels are probably associated with the development of the central nervous system (CNS). The results also clearly indicate that the interaction of ADAMTS-13 and NO may play an important role in the regulation and protection of the CNS microenvironment in neurodegenerative diseases. In addition, NF expression might indicate the progress of the disease. To the best of the authors'knowledge, this is the first report on ADAMTS-13 expression in the CNS of BDV-infected small ruminants. PMID- 25799515 TI - Comparative genomics of a Helicobacter pylori isolate from a Chinese Yunnan Naxi ethnic aborigine suggests high genetic divergence and phage insertion. AB - Helicobacter pylori is a common pathogen correlated with several severe digestive diseases. It has been reported that isolates associated with different geographic areas, different diseases and different individuals might have variable genomic features. Here, we describe draft genomic sequences of H. pylori strains YN4-84 and YN1-91 isolated from patients with gastritis from the Naxi and Han populations of Yunnan, China, respectively. The draft sequences were compared to 45 other publically available genomes, and a total of 1059 core genes were identified. Genes involved in restriction modification systems, type four secretion system three (TFS3) and type four secretion system four (TFS4), were identified as highly divergent. Both YN4-84 and YN1-91 harbor intact cag pathogenicity island (cagPAI) and have EPIYA-A/B/D type at the carboxyl terminal of cagA. The vacA gene type is s1m2i1. Another major finding was a 32.5-kb prophage integrated in the YN4-84 genome. The prophage shares most of its genes (30/33) with Helicobacter pylori prophage KHP30. Moreover, a 1,886 bp transposable sequence (IS605) was found in the prophage. Our results imply that the Naxi ethnic minority isolate YN4-84 and Han isolate YN1-91 belong to the hspEAsia subgroup and have diverse genome structure. The genome has been extensively modified in several regions involved in horizontal DNA transfer. The important roles played by phages in the ecology and microevolution of H. pylori were further emphasized. The current data will provide valuable information regarding the H. pylori genome based on historic human migrations and population structure. PMID- 25799517 TI - Metal exchange method using Au25 nanoclusters as templates for alloy nanoclusters with atomic precision. AB - A metal exchange method based upon atomically precise gold nanoclusters (NCs) as templates is devised to obtain alloy NCs including CuxAu25-x(SR)18, AgxAu25 x(SR)18, Cd1Au24(SR)18, and Hg1Au24(SR)18 via reaction of the template with metal thiolate complexes of Cu(II), Ag(I), Cd(II), and Hg(II) (as opposed to common salt precursors such as CuCl2, AgNO3, etc.). Experimental results imply that the exchange between gold atoms in NCs and those of the second metal in the thiolated complex does not necessarily follow the order of metal activity (i.e., galvanic sequence). In addition, the crystal structure of the exchange product (Cd1Au24(SR)18) is successfully determined, indicating that the Cd is in the center of the 13-atom icosahedral core. This metal exchange method is expected to become a versatile new approach for synthesizing alloy NCs that contain both high and low-activity metal atoms. PMID- 25799516 TI - Comparative transcriptome analysis of genes involved in anthocyanin biosynthesis in the red and yellow fruits of sweet cherry (Prunus avium L.). AB - BACKGROUND: Fruit color is one of the most important economic traits of the sweet cherry (Prunus avium L.). The red coloration of sweet cherry fruit is mainly attributed to anthocyanins. However, limited information is available regarding the molecular mechanisms underlying anthocyanin biosynthesis and its regulation in sweet cherry. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a reference transcriptome of P. avium L. was sequenced and annotated to identify the transcriptional determinants of fruit color. Normalized cDNA libraries from red and yellow fruits were sequenced using the next-generation Illumina/Solexa sequencing platform and de novo assembly. Over 66 million high-quality reads were assembled into 43,128 unigenes using a combined assembly strategy. Then a total of 22,452 unigenes were compared to public databases using homology searches, and 20,095 of these unigenes were annotated in the Nr protein database. Furthermore, transcriptome differences between the four stages of fruit ripening were analyzed using Illumina digital gene expression (DGE) profiling. Biological pathway analysis revealed that 72 unigenes were involved in anthocyanin biosynthesis. The expression patterns of unigenes encoding phenylalanine ammonia-lyase (PAL), 4 coumarate-CoA ligase (4CL), chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3-hydroxylase (F3H), flavanone 3'-hydroxylase (F3'H), dihydroflavonol 4 reductase (DFR), anthocyanidin synthase (ANS) and UDP glucose: flavonol 3-O glucosyltransferase (UFGT) during fruit ripening differed between red and yellow fruit. In addition, we identified some transcription factor families (such as MYB, bHLH and WD40) that may control anthocyanin biosynthesis. We confirmed the altered expression levels of eighteen unigenes that encode anthocyanin biosynthetic enzymes and transcription factors using quantitative real-time PCR (qRT-PCR). CONCLUSIONS/SIGNIFICANCE: The obtained sweet cherry transcriptome and DGE profiling data provide comprehensive gene expression information that lends insights into the molecular mechanisms underlying anthocyanin biosynthesis. These results will provide a platform for further functional genomic research on this fruit crop. PMID- 25799518 TI - Metallic 1T phase MoS2 nanosheets as supercapacitor electrode materials. AB - Efficient intercalation of ions in layered materials forms the basis of electrochemical energy storage devices such as batteries and capacitors. Recent research has focused on the exfoliation of layered materials and then restacking the two-dimensional exfoliated nanosheets to form electrodes with enhanced electrochemical response. Here, we show that chemically exfoliated nanosheets of MoS2 containing a high concentration of the metallic 1T phase can electrochemically intercalate ions such as H(+), Li(+), Na(+) and K(+) with extraordinary efficiency and achieve capacitance values ranging from ~400 to ~700 F cm(-3) in a variety of aqueous electrolytes. We also demonstrate that this material is suitable for high-voltage (3.5 V) operation in non-aqueous organic electrolytes, showing prime volumetric energy and power density values, coulombic efficiencies in excess of 95%, and stability over 5,000 cycles. As we show by X ray diffraction analysis, these favourable electrochemical properties of 1T MoS2 layers are mainly a result of their hydrophilicity and high electrical conductivity, as well as the ability of the exfoliated layers to dynamically expand and intercalate the various ions. PMID- 25799519 TI - Graphene-templated directional growth of an inorganic nanowire. AB - Assembling inorganic nanomaterials on graphene is of interest in the development of nanodevices and nanocomposite materials, and the ability to align such inorganic nanomaterials on the graphene surface is expected to lead to improved functionalities, as has previously been demonstrated with organic nanomaterials epitaxially aligned on graphitic surfaces. However, because graphene is chemically inert, it is difficult to precisely assemble inorganic nanomaterials on pristine graphene. Previous techniques based on dangling bonds of damaged graphene, intermediate seed materials and vapour-phase deposition at high temperature(,) have only formed randomly oriented or poorly aligned inorganic nanostructures. Here, we show that inorganic nanowires of gold(I) cyanide can grow directly on pristine graphene, aligning themselves with the zigzag lattice directions of the graphene. The nanowires are synthesized through a self organized growth process in aqueous solution at room temperature, which indicates that the inorganic material spontaneously binds to the pristine graphene surface. First-principles calculations suggest that this assembly originates from lattice matching and pi interaction to gold atoms. Using the synthesized nanowires as templates, we also fabricate nanostructures with controlled crystal orientations such as graphene nanoribbons with zigzag-edged directions. PMID- 25799520 TI - Coaxial lithography. AB - The optical and electrical properties of heterogeneous nanowires are profoundly related to their composition and nanoscale architecture. However, the intrinsic constraints of conventional synthetic and lithographic techniques have limited the types of multi-compositional nanowire that can be created and studied in the laboratory. Here, we report a high-throughput technique that can be used to prepare coaxial nanowires with sub-10 nm control over the architectural parameters in both axial and radial dimensions. The method, termed coaxial lithography (COAL), relies on templated electrochemical synthesis and can create coaxial nanowires composed of combinations of metals, metal oxides, metal chalcogenides and conjugated polymers. To illustrate the possibilities of the technique, a core/shell semiconductor nanowire with an embedded plasmonic nanoring was synthesized--a structure that cannot be prepared by any previously known method--and its plasmon-excitation-dependent optoelectronic properties were characterized. PMID- 25799521 TI - Water desalination using nanoporous single-layer graphene. AB - By creating nanoscale pores in a layer of graphene, it could be used as an effective separation membrane due to its chemical and mechanical stability, its flexibility and, most importantly, its one-atom thickness. Theoretical studies have indicated that the performance of such membranes should be superior to state of-the-art polymer-based filtration membranes, and experimental studies have recently begun to explore their potential. Here, we show that single-layer porous graphene can be used as a desalination membrane. Nanometre-sized pores are created in a graphene monolayer using an oxygen plasma etching process, which allows the size of the pores to be tuned. The resulting membranes exhibit a salt rejection rate of nearly 100% and rapid water transport. In particular, water fluxes of up to 10(6) g m(-2) s(-1) at 40 degrees C were measured using pressure difference as a driving force, while water fluxes measured using osmotic pressure as a driving force did not exceed 70 g m(-2) s(-1) atm(-1). PMID- 25799522 TI - Prevalence and incidence estimation of HSV-2 by two IgG ELISA methods among South African women at high risk of HIV. AB - INTRODUCTION: Previous comparison studies of the Kalon and HerpeSelect 2 ELISA IgG assays on sub-Saharan samples have found differences in the sensitivity and specificity of these assays. Using longitudinal samples from an HIV prevention study, we compared both assays and determined the HSV-2 prevalence and incidence in a South African young female population at elevated risk of acquiring HIV. METHODS: Samples at baseline were tested in both assays using the manufacturers' guidelines (cut-off > 1.10). When non-reactive in one assay, the final visit samples were tested to determine the incidence rate. Using correlation and regression analyses, the intra- and inter-assay variabilities were assessed. RESULTS: The prevalence rate was 41.1% and 44.9% for Kalon and HerpeSelect using the manufacturer guidelines, respectively. Agreement between the two tests were high (kappa = 0.92). The original optical density values of both assays were highly correlated (R = 0.94), but the calibrator and correspondingly cut-off index values differed between the assays. Lowering the index value cut-off for the Kalon assay by 40% (to 0.66) resulted in a HSV-2 prevalence of 43.2%, and increased agreement between the assays (to kappa = 0.96). The incidence rate was 16.3/100 Person Years using the lower cut-off for the Kalon assay. DISCUSSION: In this longitudinal study, we showed that the performance of the two assays was very similar. After lowering the cut-off for the Kalon assay to 0.66 early infections were detected without impairing its specificity. The prevalence and incidence rates are in line with previously described rates for sub-Saharan African cohorts. PMID- 25799523 TI - Impact of biodiversity loss on production in complex marine food webs mitigated by prey-release. AB - Public concern over biodiversity loss is often rationalized as a threat to ecosystem functioning, but biodiversity-ecosystem functioning (BEF) relations are hard to empirically quantify at large scales. We use a realistic marine food-web model, resolving species over five trophic levels, to study how total fish production changes with species richness. This complex model predicts that BEF relations, on average, follow simple Michaelis-Menten curves when species are randomly deleted. These are shaped mainly by release of fish from predation, rather than the release from competition expected from simpler communities. Ordering species deletions by decreasing body mass or trophic level, representing 'fishing down the food web', accentuates prey-release effects and results in unimodal relationships. In contrast, simultaneous unselective harvesting diminishes these effects and produces an almost linear BEF relation, with maximum multispecies fisheries yield at ~40% of initial species richness. These findings have important implications for the valuation of marine biodiversity. PMID- 25799524 TI - Prediction of perioperative cardiac events through preoperative NT-pro-BNP and cTnI after emergent non-cardiac surgery in elderly patients. AB - OBJECTIVES: Clinical risk stratification has an important function in preoperative evaluation of patients at risk for cardiac events prior to non cardiac surgery. The aim of this study was to determine whether the combined measurement of pre-operative N-terminal pro-brain natriuretic peptide (NT-pro BNP) and cardiac troponin I (cTnI) could provide useful prognostic information about postoperative major adverse cardiac events (MACE) within 30 days in patients aged over 60 years undergoing emergent non-cardiac surgery. METHODS: The study group comprised 2519 patients aged over 60 years that were undergoing emergent non-cardiac surgery between December 2007 and December 2013. NT-pro-BNP and cTnI were measured during hospital admission. The patients were monitored for MACE (cardiac death, non-fatal myocardial infarction, or cardiac arrest) during the 30-day postoperative follow-up period. RESULTS: MACE occurred in 251 patients (10.0%). Preoperative NT-pro-BNP and cTNI level were significantly higher in the individuals that experienced MACE than in those who did not (P < 0.001). The confounding factors of age, sex, co-morbidities and preoperative medications were adjusted in a multivariate logistic regression analysis. This analysis showed that preoperative NT-proBNP level > 917 pg/mL (OR 4.81, 95% CI 3.446-6.722, P < 0.001) and cTnI >= 0.07 ng/mL (OR 8.74, 95% CI 5.881-12.987, P < 0.001) remained significantly and independently associated with MACE after the adjustment of the confounding factors. Kaplan-Meier event-free survival curves demonstrated that patients with preoperative simultaneous NT-proBNP level > 917 pg/mL and cTnT >= 0.07 ng/mL had worse event-free survival than individual assessments of either biomarker. CONCLUSION: Preoperative plasma NT-proBNP and cTnI are both independently associated with an increased risk of MACE in elderly patients after emergent non-cardiac surgery. The combination of these biomarkers provides better prognostic information than using either biomarker separately. PMID- 25799525 TI - Beyond emergency surgery: redefining acute care surgery. AB - BACKGROUND: Considerable debate exists regarding the definition, skill set, and training requirements for the new specialty of acute care surgery (ACS). We hypothesized that a patient subset could be identified that requires a level of care beyond general surgical training and justifies creation of this new specialty. MATERIALS AND METHODS: Reviewed patient admissions over 1-y to the only general surgical service at a level I trauma center-staffed by trauma and/or critical care trained physicians. Patients classified as follows: trauma, ACS, emergency general (EGS), or elective surgery. ACS patients are nonelective, nontrauma patients with significantly altered physiology requiring intensive care unit admission and/or specific complex operative interventions. Differences in demographics, hospital course, and outcomes were analyzed. RESULTS: In-patient service evaluated approximately 5500 patients, including 3300 trauma patients. A total of 2152 admissions include 37% trauma, 30% elective, 28% EGS, and 4% ACS. ACS and trauma patients were more likely to require multiple operations (ACS relative risk [RR] = 11.5; trauma RR = 5.7, P < 0.0001), have longer hospital and intensive care unit length of stay, and higher mortality (P < 0.0001). They were less likely to be discharged home (ACS RR = 0.75; trauma RR = 0.67, P < 0.0001) compared with that of the EGS group. EGS and elective patients were most similar to each other in multiple areas. CONCLUSIONS: ACS and EGS patients represent distinct patient cohorts, as reflected by significant differences in critical care needs, likelihood of multiple operations, and need for postdischarge rehabilitation. The skills required to care for ACS patients, including ability to rescue from complications and provide critical care, differ from those required for EGS patients and supports development of ACS training and regionalization of care. PMID- 25799526 TI - Apigenin inhibits pancreatic stellate cell activity in pancreatitis. AB - BACKGROUND: Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. MATERIALS AND METHODS: Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 MUg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro. Finally, we assessed apigenin's effect on the gene expression in PSCs stimulated with parathyroid hormone-related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. RESULTS: After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone-related protein-stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. CONCLUSIONS: These in vivo and in vitro studies provide novel insights regarding apigenin's mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP. PMID- 25799527 TI - Photoimmunotherapy lowers recurrence after pancreatic cancer surgery in orthotopic nude mouse models. AB - BACKGROUND: Photoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted human pancreatic cancer in a nude mouse model to eliminate microscopic disease in the post-surgical tumor bed and prevent local as well as metastatic recurrence. MATERIALS AND METHODS: Athymic nude mice were orthotopically implanted with the human pancreatic cancer cell line BxPC3 expressing green fluorescent protein. After tumor engraftment, the mice were divided into two groups as follows: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT); and BLS only. Anti-CEA-IR700 (100 MUg) was administered to the treatment group via tail-vein injection 24 h before therapy. Tumors were resected, and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm(2) for 30 min. Mice were imaged noninvasively for 8 wk using an OV-100 small animal fluorescence imager. RESULTS: BLS + PIT reduced local recurrence to 1/7 mice from 7/7 mice with BLS-only (P = 0.001) and metastatic recurrence to 2/7 mice compared with 6/7 mice with BLS-only (P = 0.03). Local tumor growth continued at a rapid rate after BLS-only compared with BLS + PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS + PIT (2.14 mm(2), 95% confidence interval [CI] [-2.06 to 6.34] and BLS-only groups (115.2 mm(2), 95% CI [88.8-141.6]) at 6 wk after surgery (P < 0.001). There was also a significant difference in tumor weight between the BLS + PIT group (6.65 mg, 95% CI [-6.35 to 19.65] and BLS-only group (1100 mg, 95% CI [794-1406] at 8 wk after surgery (P < 0.001). CONCLUSIONS: PIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that can lead to both local and metastatic recurrence. Further studies are warranted to investigate the potential toxicities of PIT, especially with regard to anastomoses, such as those involved in pancreaticoduodenectomy. PMID- 25799528 TI - Racial variation in the number of spontaneous abortions before a first successful pregnancy, and effects on subsequent pregnancies. AB - OBJECTIVE: To assess the relationship between race and spontaneous abortion, whether the relationship varies by risk factors, and the effect of spontaneous abortions on subsequent pregnancies. METHODS: A retrospective study was undertaken using data collected in London, UK, between 1988 and 2000. Logistic regression evaluated histories of spontaneous abortion and associations with small-for-gestational-age and preterm births in black African, black Caribbean, and South Asian women relative to white European women. Interactions with risk factors were assessed. RESULTS: Overall, 196 040 women were included. Compared with white Europeans, the odds of a previous spontaneous abortion were increased in black African (adjusted odds ratio [aOR] 1.20; 95% confidence interval [CI] 1.12-1.29) and black Caribbean women (aOR 1.31; 95% CI 1.21-1.41). The strength of the association with black African race increased with age (P=0.002), and the association with South Asian race increased with age and body mass index (P<0.001 for both). Spontaneous abortion was associated with preterm birth in all races, but was strongest in black African women (aOR 1.47; 95% CI 1.29-1.67). CONCLUSION: The greater incidence of spontaneous abortion in black African and black Caribbean women should prompt further study of risk factors in relation to race. The interaction with age in black African and South Asian women could be important for counseling in relation to timing of pregnancy. PMID- 25799529 TI - Voluntary exercise decreases atherosclerosis in nephrectomised ApoE knockout mice. AB - Cardiovascular disease is the main cause of morbidity and mortality in patients with kidney disease. The effectiveness of exercise for cardiovascular disease that is accelerated by the presence of chronic kidney disease remains unknown. The present study utilized apolipoprotein E knockout mice with 5/6 nephrectomy as a model of combined kidney disease and cardiovascular disease to investigate the effect of exercise on aortic plaque formation, vascular function and systemic inflammation. Animals were randomly assigned to nephrectomy or control and then to either voluntary wheel running exercise or sedentary. Following 12-weeks, aortic plaque area was significantly (p<0.05, d=1.2) lower in exercising nephrectomised mice compared to sedentary nephrectomised mice. There was a strong, negative correlation between average distance run each week and plaque area in nephrectomised and control mice (r=-0.76, p=0.048 and r=-0.73, p=0.062; respectively). In vitro aortic contraction and endothelial-independent and endothelial-dependent relaxation were not influenced by exercise (p>0.05). Nephrectomy increased IL-6 and TNF-alpha concentrations compared with control mice (p<0.001 and p<0.05, respectively), while levels of IL-10, MCP-1 and MIP 1alpha were not significantly influenced by nephrectomy or voluntary exercise (p>0.05). Exercise was an effective non-pharmacologic approach to slow cardiovascular disease in the presence of kidney disease in the apolipoprotein E knockout mouse. PMID- 25799530 TI - Effects of metalinguistic awareness on reading comprehension and the mediator role of reading fluency from grades 2 to 4. AB - PURPOSE: This study examined the contribution of metalinguistic awareness including morphological awareness, phonological awareness and orthographical awareness to reading comprehension, and the role of reading fluency as a mediator of the effects of metalinguistic awareness on reading comprehension from grades 2 to 4. METHODS: Four hundred and fifteen elementary students in China mainland were administered a test battery that included measures of morphological awareness, phonological awareness, orthographical awareness, reading fluency, reading comprehension and IQ. Hierarchical regression and structural equation models (SEM) were used to analyze the data. RESULTS: Morphological awareness uniquely explained 9%, 10% and 13% variance of reading comprehension respectively from grade 2 to grade 4, however, phonological awareness and orthographical awareness did not contribute to reading comprehension; Reading fluency partially mediated the effect of morphological awareness on reading comprehension in grades 2-4. CONCLUSIONS: These findings indicated that reading fluency and morphological awareness should be facilitated in the Chinese instruction. Morphological awareness played an important role in Chinese reading and affected reading comprehension in grades 2 to 4; Reading fluency was a significant link between morphological awareness and reading comprehension in grades 2-4. PMID- 25799531 TI - De novo RNA sequencing and transcriptome analysis of Colletotrichum gloeosporioides ES026 reveal genes related to biosynthesis of huperzine A. AB - Huperzine A is important in the treatment of Alzheimer's disease. There are major challenges for the mass production of huperzine A from plants due to the limited number of huperzine-A-producing plants, as well as the low content of huperzine A in these plants. Various endophytic fungi produce huperzine A. Colletotrichum gloeosporioides ES026 was previously isolated from a huperzine-A-producing plant Huperzia serrata, and this fungus also produces huperzine A. In this study, de novo RNA sequencing of C. gloeosporioides ES026 was carried out with an Illumina HiSeq2000. A total of 4,324,299,051 bp from 50,442,617 high-quality sequence reads of ES026 were obtained. These raw data were assembled into 24,998 unigenes, 40,536,684 residues and 19,790 genes. The majority of the unique sequences were assigned to corresponding putative functions based on BLAST searches of public databases. The molecular functions, biological processes and biochemical pathways of these unique sequences were determined using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) assignments. A gene encoding copper amine oxidase (CAO) (unigene 9322) was annotated for the conversion of cadaverine to 5-aminopentanal in the biosynthesis of huperzine A. This gene was also detected in the root, stem and leaf of H. serrata. Furthermore, a close relationship was observed between expression of the CAO gene (unigene 9322) and quantity of crude huperzine A extracted from ES026. Therefore, CAO might be involved in the biosynthesis of huperzine A and it most likely plays a key role in regulating the content of huperzine A in ES026. PMID- 25799533 TI - Influence of coronal restoration and root canal filling quality on periapical status: clinical and radiographic evaluation. AB - INTRODUCTION: The purpose of this study was to evaluate the relationship between periapical status and the quality of coronal restoration and of root canal filling, assessed both clinically and radiographically, in a cohort of Brazilian patients. METHODS: A total of 523 teeth from 337 patients submitted to endodontic treatment were clinically and radiographically reexamined 2-10 years postoperatively. Restoration and root canal filling quality were classified according to modified criteria from Tronstad et al. Periapical status was evaluated according to periapical index scores. Mann-Whitney and Friedman tests were used to conduct the descriptive analysis. Correlations were analyzed by using simple and multivariate logistic regression analysis. RESULTS: No significant difference was observed between the rates of apical periodontitis for adequate or inadequate coronal restorations assessed clinically (12.8% versus 19.4%), whereas these rates were significantly different when the restoration quality was assessed radiographically (11.6% versus 28.7%, P < .001). The rates of apical periodontitis in teeth with inadequate root canal filling, with or without adequate restoration, were significantly higher than in teeth with adequate canal filling, with or without adequate restoration (38.6% and 48.4% versus 6.5% and 14.6%, respectively; P < .0001). CONCLUSIONS: Using either a radiographic or clinical assessment alone was not a reliable method to ascertain whether restoration quality could be correlated with postoperative periapical status. Poor root canal filling quality was a prognostic determinant of endodontic treatment failure, whereas coronal restoration quality had a lesser impact on the outcome of the endodontic treatment. PMID- 25799532 TI - Color stability, radiopacity, and chemical characteristics of white mineral trioxide aggregate associated with 2 different vehicles in contact with blood. AB - INTRODUCTION: Discoloration of mineral trioxide aggregate (MTA) can be exacerbated by the interaction of the cement with body fluids such as blood. This study aimed to analyze the color alteration, chemical characteristics, and radiopacity of MTA manipulated with 2 different vehicles after immersion in blood or distilled water (DW). METHODS: MTA mixed with 100% DW or 80% DW/20% propylene glycol (PG) as vehicles were placed into rubber rings and incubated at 37 degrees C and 100% relative humidity until set. Color assessment and scanning electron microscopy/energy-dispersive spectroscopy analysis were performed after setting and repeated after 7, 15, and 30 days after immersion in blood and DW. Statistical analysis for color alteration and radiopacity was performed using nonparametric Kruskal-Wallis and Dunn tests (P < .05). RESULTS: When 80% DW/20% PG was used as the vehicle, significantly lower color alterations were observed for all time periods compared with 100% DW when immersed in blood (P < .05). All surfaces displayed morphologic changes after immersion in both media because of loss of bismuth. A decrease in radiopacity was observed over time in all groups, with a statistically significant difference after 30 days for groups DW immersed in blood and 80% DW/20% immersed in both media (P < .05). CONCLUSIONS: The ratio of 80% DW/20% PG as a vehicle for MTA results in a lower color alteration when in contact with blood. PMID- 25799534 TI - Endodontic infection and endothelial dysfunction are associated with different mechanisms in men and women. AB - INTRODUCTION: To investigate the potential link between apical periodontitis (AP) and cardiovascular (CV) function, inflammation markers, endothelial flow reserve (EFR), and levels of asymmetrical dimethylarginine (ADMA), the endogenous inhibitor of nitric oxide synthase (NOS), were measured in young adults with AP aged 20-40 years of both sexes. METHODS: Forty men and 41 women (31 +/- 5.71 years) free from periodontal disease, CV disease, and traditional CV risk factors were enrolled in the study. Twenty men and 21 women had AP; 40 healthy individuals matched for age, sex, and physical characteristics were also recruited as controls. All subjects underwent dental and complete physical examination, electrocardiography, conventional and tissue Doppler imaging echocardiography, and measurement of EFR. Interleukin (IL)-2, tumor necrosis factor alpha, reactive oxygen species (ROS), and ADMA were also assessed. Data were analyzed using the 2-tailed Student t test, the Pearson t test (or the Spearman t test for nonparametric variables), and multivariate linear regression analysis. RESULTS: Echocardiography excluded any morphologic and functional cardiac alteration in all the subjects studied. Patients with AP of both sexes showed a significant reduction in EFR (P < .05) and a significant increase in IL 2 (men: P < .01, women: P < .05), whereas ROS were increased significantly only in women (P < .05). ADMA levels were unchanged in women with AP, but they were significantly increased in men (P < .05). A significant direct correlation between ADMA and IL-2 (r = 0.67, P < .001) and an inverse correlation between ADMA and EFR (r = -0.42, P < .05) in men and a significant inverse correlation between ROS and EFR (r = -0.71, P < .01) in female patients were observed. CONCLUSIONS: The presence of chronic inflammation in young adults with AP may cause early endothelial dysfunction documented by the reduced EFR. AP in men may influence the metabolism of NOS, whereas in women it appears to implicate a more direct detrimental mechanism. This difference is sex dependent and may be attributable to the protective action of estrogen in women. PMID- 25799535 TI - Endodontic Management of a Maxillary Lateral Incisor with 4 Root Canals and a Dens Invaginatus Tract. AB - Dens invaginatus (DI) is associated with complex internal anatomy. This article represents a maxillary lateral incisor with 5 root canals including DI. The treatment was planned and performed using cone-beam computed tomographic (CBCT) imaging. After clinical and radiographic evaluations, tooth #7 was diagnosed with DI and pulp necrosis with symptomatic apical periodontitis. Periapical radiographs of the tooth showed 2 roots and complex internal anatomy. CBCT evaluation revealed tooth #7 had 5 separate canals (4 root canals and 1 DI canal extending through the root to the periodontal ligament), communication between DI and the root canal system, and severe and multiple curvatures of the palatal canals. Root canal treatment was completed in 2 visits. Modified access openings were required to safely treat the dilacerated palatal canals. At the 6-month re evaluation, the patient reported he had remained asymptomatic and his tooth had remained functional since the treatment was completed. Clinical examination showed tooth #7 had no sensitivity to percussion or palpation, probe depths within normal limits (<=3 mm), and no mobility. Radiographic assessment of the tooth showed significant osseous healing of the preoperative lesion. Three dimensional imaging is a valuable tool for endodontic management of teeth with complex internal anatomy. Three-dimensional imaging is recommended for evaluating and treatment planning cases with DI. PMID- 25799536 TI - Do cell phones affect establishing electronic working length? AB - INTRODUCTION: Patients often keep their cell phones on and nearby during root canal therapy. Cell phones release electromagnetic interference, which might disturb electronic working length measurements. The purpose of this ex vivo study was to determine the effect of a cell phone (Apple iPhone 5 [Apple, Cupertino, CA] or KP100 [LG, Seoul, Korea]) placed into direct contact with an electronic apex locator (EAL) (Dentaport Root ZX module [J Morita Corp, Tokyo, Japan] or Propex II [Dentsply Maillefer, Ballaigues, Switzerland]) on working length determination. METHODS: Twenty-six human premolars without fractures or carious lesions were used; previously cleaned; and observed under magnification (*15) in order to check for the presence of only 1 apical foramen, the absence of apical resorption, an "open" apex, and accessory canals. The working length measurement was performed with a #15 K-file in the presence of 2.6% sodium hypochlorite under 4 conditions: (1) visually, under the microscope until the file tip reached the canal terminus; (2) electronically, without the cell phone in proximity; (3) electronically, with the cell phone in standby mode placed in physical contact with the EAL; and (4) electronically, with the cell phone activated by a call in the same position. The experimental model for electronic working length determination was a screw top plastic container filled with a saline solution. The measurements were repeated 3 times per canal under each condition. Scores of 1 to 3 categorized the stability of the readings as follows: (1) good stability; (2) unstable reading with minor difficulties determining the working length; and (3) major difficulties or impossible to determine the working length. A 2-way repeated measures analysis of variance (way 1: cell phone type and way 2: EAL model) was performed, and a second repeated measures analysis of variance was performed to seek a difference among the 4 working length determination conditions. RESULTS: Neither the cell phone type nor the EAL affected the measurements (not significant). The electronic working length measurements gave the same results as the visual examination, and this length was not influenced by direct contact with a cell phone (not significant). It was also possible to determine the electronic working length under all the experimental conditions. CONCLUSIONS: Within the limitations of the present study, it can be concluded that patients can keep their cell phones on during root canal therapy without any adverse effect on electronic working length determination. PMID- 25799537 TI - Evaluation of apically extruded bacteria associated with different nickel titanium systems. AB - INTRODUCTION: The aim of this in vitro study was to evaluate the amount of apically extruded bacteria associated with several root canal preparation systems. METHODS: Forty-four extracted human mandibular premolar root canals were contaminated with an Enterococcus faecalis suspension. After incubation at 37 degrees C for 24 hours, the root canals were instrumented using the Twisted File (SybronEndo, Orange, CA), OneShape (Micro Mega, Besancon, France), and ProTaper Next (Dentsply Maillefer, Ballaigues, Switzerland). During instrumentation, apically extruded bacteria were collected into vials containing 0.9% NaCl. The microbiological samples were taken from the vials and incubated in brain-heart agar medium for 24 hours. The numbers of colony-forming units were determined. The data obtained were analyzed using Welch analysis of variance followed by post hoc Games-Howell tests. RESULTS: ProTaper Next extruded the highest amount of bacteria, whereas OneShape extruded the least compared with all the other instruments (P = .004). There was a significant difference between OneShape and ProTaper Next in the number of colony-forming units (P = .007) but not between OneShape and Twisted File (P > .05). CONCLUSIONS: All instrumentation systems extruded bacteria beyond the foramen. The OneShape system extruded less bacteria compared with the Twisted File and ProTaper Next systems. PMID- 25799538 TI - Short-chain Fatty Acids in Infected Root Canals of Teeth with Apical Periodontitis before and after Treatment. AB - INTRODUCTION: Short-chain fatty acids (SCFAs) are bacterial metabolic end products that may function as virulence factors. This study evaluated the occurrence of SCFAs in infected root canals before and after treatment. METHODS: Samples were taken from root canals of teeth with apical periodontitis before (S1) and after (S2) chemomechanical preparation with either NaOCl or chlorhexidine as the irrigant and then after interappointment medication with calcium hydroxide (S3). High-performance liquid chromatography was used for detection of SCFAs. Selected bacterial taxa that are recognized producers of the target SCFAs were identified by real-time polymerase chain reaction. RESULTS: Butyric acid was the most common fatty acid in S1, followed by propionic acid. Both molecules were also found in S2 and S3 from both NaOCl and chlorhexidine groups. Lactic acid was not present in detectable levels in S1, but it occurred in 1 postinstrumentation sample and in 9 samples taken after calcium hydroxide medication. Of the target taxa, Fusobacterium nucleatum was the most prevalent in S1 (76%), followed by members of the Actinobacteria phylum (71%), Streptococcus species (59%), and Parvimonas micra (53%). Gram-positive taxa, especially streptococci, were the most prevalent bacteria in S2 and S3. SCFA detection was matched with the respective potential producer species in most cases. CONCLUSIONS: This first report of SCFAs in infected root canals suggests that these molecules may play a role in the pathogenesis of apical periodontitis. Significance of persistence of SCFAs after treatment and its effects on the long term outcome await elucidation. PMID- 25799539 TI - SELEX aptamer used as a probe to detect circulating tumor cells in peripheral blood of pancreatic cancer patients. AB - Many studies have shown that the quantity and dynamics of circulating tumor cells (CTCs) in peripheral blood of patients afflicted with solid tumours have great relevance in therapeutic efficacy and prognosis. Different methods based on various strategies have been developed to isolate and identify CTCs, but their efficacy needs to be improved because of the rarity and complexity of CTCs. This study was designed to examine the possibility of using a SELEX aptamer (BC-15) as a probe to identify rare CTCs out of background nucleated cells. Aptamer BC-15 was selected from a random oligonucleotide library screened against human breast cancer tissue. Fluorescence staining showed that BC-15 had a high affinity for nuclei of human cancer cell lines of various origins as well as CTCs isolated from pancreatic cancer patients, whereas its binding capacity for non-tumor breast epithelial cells and leukocytes was almost undetectable. BC-15+/CD45- cells in cancer patient blood were also found to be cytokeratins 18-positive and aneuploid by immunofluorescence staining and fluorescent in situ hybridization, respectively. Finally, the aptamer method was compared with the well-established anti-cytokeratin method using 15 pancreatic cancer patient blood samples, and enumeration indicated no difference between these two methods. Our study establishes a novel way to identify CTCs by using a synthetic aptamer probe. This new approach is comparable with the anti-cytokeratin-based CTC identification method. PMID- 25799541 TI - Epidemic 2014 enterovirus D68 cross-reacts with human rhinovirus on a respiratory molecular diagnostic platform. AB - Enterovirus D68 (EV-D68) is an emerging virus known to cause sporadic disease and occasional epidemics of severe lower respiratory tract infection. However, the true prevalence of infection with EV-D68 is unknown, due in part to the lack of a rapid and specific nucleic acid amplification test as well as the infrequency with which respiratory samples are analyzed by enterovirus surveillance programs. During the 2014 EV-D68 epidemic in the United States, we noted an increased frequency of "low-positive" results for human rhinovirus (HRV) detected in respiratory tract samples using the GenMark Diagnostics eSensor respiratory viral panel, a multiplex PCR assay able to detect 14 known respiratory viruses but not enteroviruses. We simultaneously noted markedly increased admissions to our Pediatric Intensive Care Unit for severe lower respiratory tract infections in patients both with and without a history of reactive airway disease. Accordingly, we hypothesized that these "low-positive" RVP results were due to EV-D68 rather than rhinovirus infection. Sequencing of the picornavirus 5' untranslated region (5'-UTR) of 49 samples positive for HRV by the GenMark RVP revealed that 33 (67.3%) were in fact EV-D68. Notably, the mean intensity of the HRV RVP result was significantly lower in the sequence-identified EV-D68 samples (20.3 nA) compared to HRV (129.7 nA). Using a cut-off of 40 nA for the differentiation of EV-D68 from HRV resulted in 94% sensitivity and 88% specificity. The robust diagnostic characteristics of our data suggest that the cross-reactivity of EV D68 and HRV on the GenMark Diagnostics eSensor RVP platform may be an important factor to consider in making accurate molecular diagnosis of EV-D68 at institutions utilizing this system or other molecular respiratory platforms that may also cross-react. PMID- 25799540 TI - The Leber congenital amaurosis protein AIPL1 and EB proteins co-localize at the photoreceptor cilium. AB - PURPOSE: The aim of this study was to investigate the interaction and co localization of novel interacting proteins with the Leber congenital amaurosis (LCA) associated protein aryl hydrocarbon receptor interacting protein-like 1 (AIPL1). METHODS: The CytoTrapXR yeast two-hybrid system was used to screen a bovine retinal cDNA library. A novel interaction between AIPL1 and members of the family of EB proteins was confirmed by directed yeast two-hybrid analysis and co immunoprecipitation assays. The localization of AIPL1 and the EB proteins in cultured cells and in retinal cryosections was examined by immunofluorescence microscopy and cryo-immunogold electron microscopy. RESULTS: Yeast two-hybrid (Y2H) analysis identified the interaction between AIPL1 and the EB proteins, EB1 and EB3. EB1 and EB3 were specifically co-immunoprecipitated with AIPL1 from SK-N SH neuroblastoma cells. In directed 1:1 Y2H analysis, the interaction of EB1 with AIPL1 harbouring the LCA-causing mutations A197P, C239R and W278X was severely compromised. Immunofluorescent confocal microscopy revealed that AIPL1 did not co localize with endogenous EB1 at the tips of microtubules, endogenous EB1 at the microtubule organising centre following disruption of the microtubule network, or with endogenous beta-tubulin. Moreover, AIPL1 did not localize to primary cilia in ARPE-19 cells, whereas EB1 co-localized with the centrosomal marker pericentrin at the base of primary cilia. However, both AIPL1 and the EB proteins, EB1 and EB3, co-localized with centrin-3 in the connecting cilium of photoreceptor cells. Cryo-immunogold electron microscopy confirmed the co localization of AIPL1 and EB1 in the connecting cilia in human retinal photoreceptors. CONCLUSIONS: AIPL1 and the EB proteins, EB1 and EB3, localize at the connecting cilia of retinal photoreceptor cells, but do not co-localize in the cellular microtubule network or in primary cilia in non-retinal cells. These findings suggest that AIPL1 function in these cells is not related to the role of EB proteins in microtubule dynamics or primary ciliogenesis, but that their association may be related to a specific role in the specialized cilia apparatus of retinal photoreceptors. PMID- 25799542 TI - Profiling of volatile compounds and associated gene expression and enzyme activity during fruit development in two cucumber cultivars. AB - Changes in volatile content, as well as associated gene expression and enzyme activity in developing cucumber fruits were investigated in two Cucumis sativus L. lines (No. 26 and No. 14) that differ significantly in fruit flavor. Total volatile, six-carbon (C6) aldehyde, linolenic and linoleic acid content were higher during the early stages, whereas the nine-carbon (C9) aldehyde content was higher during the latter stages in both lines. Expression of C. sativus hydroperoxide lyase (CsHPL) mirrored 13-hydroperoxide lyase (13-HPL) enzyme activity in variety No. 26, whereas CsHPL expression was correlated with 9 hydroperoxide lyase (9-HPL) enzyme activity in cultivar No. 14. 13-HPL activity decreased significantly, while LOX (lipoxygenase) and 9-HPL activity increased along with fruit ripening in both lines, which accounted for the higher C6 and C9 aldehyde content at 0-6 day post anthesis (dpa) and 9-12 dpa, respectively. Volatile compounds from fruits at five developmental stages were analyzed by principal component analysis (PCA), and heatmaps of volatile content, gene expression and enzyme activity were constructed. PMID- 25799543 TI - The tyrosine phosphatase SHP-1 regulates hypoxia inducible factor-1alpha (HIF 1alpha) protein levels in endothelial cells under hypoxia. AB - INTRODUCTION: The tyrosine phosphatase SHP-1 negatively influences endothelial function, such as VEGF signaling and reactive oxygen species (ROS) formation, and has been shown to influence angiogenesis during tissue ischemia. In ischemic tissues, hypoxia induced angiogenesis is crucial for restoring oxygen supply. However, the exact mechanism how SHP-1 affects endothelial function during ischemia or hypoxia remains unclear. We performed in vitro endothelial cell culture experiments to characterize the role of SHP-1 during hypoxia. RESULTS: SHP-1 knock-down by specific antisense oligodesoxynucleotides (AS-Odn) increased cell growth as well as VEGF synthesis and secretion during 24 hours of hypoxia compared to control AS-Odn. This was prevented by HIF-1alpha inhibition (echinomycin and apigenin). SHP-1 knock-down as well as overexpression of a catalytically inactive SHP-1 (SHP-1 CS) further enhanced HIF-1alpha protein levels, whereas overexpression of a constitutively active SHP-1 (SHP-1 E74A) resulted in decreased HIF-1alpha levels during hypoxia, compared to wildtype SHP 1. Proteasome inhibition (MG132) returned HIF-1alpha levels to control or wildtype levels respectively in these cells. SHP-1 silencing did not alter HIF 1alpha mRNA levels. Finally, under hypoxic conditions SHP-1 knock-down enhanced intracellular endothelial reactive oxygen species (ROS) formation, as measured by oxidation of H2-DCF and DHE fluorescence. CONCLUSIONS: SHP-1 decreases half-life of HIF-1alpha under hypoxic conditions resulting in decreased cell growth due to diminished VEGF synthesis and secretion. The regulatory effect of SHP-1 on HIF 1alpha stability may be mediated by inhibition of endothelial ROS formation stabilizing HIF-1alpha protein. These findings highlight the importance of SHP-1 in hypoxic signaling and its potential as therapeutic target in ischemic diseases. PMID- 25799545 TI - Correction: Ontology-based data integration between clinical and research systems. PMID- 25799544 TI - Genome-wide identification, characterization and evolutionary analysis of long intergenic noncoding RNAs in cucumber. AB - Long intergenic noncoding RNAs (lincRNAs) are intergenic transcripts with a length of at least 200 nt that lack coding potential. Emerging evidence suggests that lincRNAs from animals participate in many fundamental biological processes. However, the systemic identification of lincRNAs has been undertaken in only a few plants. We chose to use cucumber (Cucumis sativus) as a model to analyze lincRNAs due to its importance as a model plant for studying sex differentiation and fruit development and the rich genomic and transcriptome data available. The application of a bioinformatics pipeline to multiple types of gene expression data resulted in the identification and characterization of 3,274 lincRNAs. Next, 10 lincRNAs targeted by 17 miRNAs were also explored. Based on co-expression analysis between lincRNAs and mRNAs, 94 lincRNAs were annotated, which may be involved in response to stimuli, multi-organism processes, reproduction, reproductive processes, and growth. Finally, examination of the evolution of lincRNAs showed that most lincRNAs are under purifying selection, while 16 lincRNAs are under natural selection. Our results provide a rich resource for further validation of cucumber lincRNAs and their function. The identification of lincRNAs targeted by miRNAs offers new clues for investigations into the role of lincRNAs in regulating gene expression. Finally, evaluation of the lincRNAs suggested that some lincRNAs are under positive and balancing selection. PMID- 25799547 TI - Emerging ecosystems change the spatial distribution of top carnivores even in poorly populated areas. AB - Humans affect biological diversity and species distribution patterns by modifying resource availability and generating novel environments where generalist species benefit and specialist species are rare. In particular, cities create local homogenization while roads fragment habitat, although both processes can increase food availability for some species that may be able to take advantage of this new source. We studied space use by birds of prey in relation to human construction, hypothesizing that these birds would be affected even in poorly populated areas. We worked in Northwestern Patagonia, Argentina, which is experiencing a high population growth, but still having very large unpopulated areas. We related the presence of raptors with different sources of human disturbance and found that both the abundance and richness of these birds were positively associated with anthropogenic environments. These results are driven mostly by a strong association between the medium-sized generalist species and these novel environments (mainly roads and cities). This may create an imbalance in intra guild competitive abilities, modifying the normal structures of top carnivore hierarchies. Indeed, the structure of raptor communities seems to be changing, even in poorly populated areas, with anthropogenic constructions seemingly producing changes in wild areas more promptly than thought, a cause for concern in ecosystems conservation issues. PMID- 25799546 TI - Placental expression of miR-517a/b and miR-517c contributes to trophoblast dysfunction and preeclampsia. AB - Preeclampsia is a pregnancy specific hypertensive disease that confers significant maternal and fetal risks. While the exact pathophysiology of preeclampsia is unknown, it is widely accepted that placental dysfunction is mechanistically involved. Recent studies reported aberrant expression of placenta specific microRNAs (miRNAs) in preeclampsia including miR-517a/b and miR-517c. Using placental biopsies from a preeclampsia case-control study, we found increased expression of miR-517a/b in term and preterm preeclampsia vs controls, while, miR-517c was increased only in preterm preeclampsia vs controls. To determine if miR-517a/b and miR-517c are regulated by hypoxia, we treated first trimester primary extravillous trophoblast cells (EVTs) with a hypoxia mimetic and found both were induced. To test for a mechanistic role in placental function, we overexpressed miR-517a/b or miR-517c in EVTs which resulted in decreased trophoblast invasion. Additionally, we found that miR-517a/b and miR 517c overexpression increased expression of the anti-angiogenic protein, sFLT1. The regulation of sFLT1 is mostly unknown, however, TNFSF15, a cytokine involved in FLT1 splicing, was also increased by miR-517a/b and miR-517c in EVTs. In summary, we demonstrate that miR-517a/b and miR-517c contribute to the development of preeclampsia and suggest that these miRNAs play a critical role in regulating trophoblast and placental function. PMID- 25799548 TI - Correction: Acute cutaneous wounds treated with human decellularised dermis show enhanced angiogenesis during healing. PMID- 25799549 TI - Diagnostic value of run chart analysis: using likelihood ratios to compare run chart rules on simulated data series. AB - Run charts are widely used in healthcare improvement, but there is little consensus on how to interpret them. The primary aim of this study was to evaluate and compare the diagnostic properties of different sets of run chart rules. A run chart is a line graph of a quality measure over time. The main purpose of the run chart is to detect process improvement or process degradation, which will turn up as non-random patterns in the distribution of data points around the median. Non random variation may be identified by simple statistical tests including the presence of unusually long runs of data points on one side of the median or if the graph crosses the median unusually few times. However, there is no general agreement on what defines "unusually long" or "unusually few". Other tests of questionable value are frequently used as well. Three sets of run chart rules (Anhoej, Perla, and Carey rules) have been published in peer reviewed healthcare journals, but these sets differ significantly in their sensitivity and specificity to non-random variation. In this study I investigate the diagnostic values expressed by likelihood ratios of three sets of run chart rules for detection of shifts in process performance using random data series. The study concludes that the Anhoej rules have good diagnostic properties and are superior to the Perla and the Carey rules. PMID- 25799550 TI - Correction: the reading of components of diabetic retinopathy: an evolutionary approach for filtering normal digital fundus imaging in screening and population based studies. AB - [This corrects the article DOI: 10.1371/journal.pone.0066730.]. PMID- 25799551 TI - DNA template dependent accuracy variation of nucleotide selection in transcription. AB - It has been commonly assumed that the effect of erroneous transcription of DNA genes into messenger RNAs on peptide sequence errors are masked by much more frequent errors of mRNA translation to protein. We present a theoretical model of transcriptional accuracy. It uses experimentally estimated standard free energies of double-stranded DNA and RNA/DNA hybrids and predicts a DNA template dependent transcriptional accuracy variation spanning several orders of magnitude. The model also identifies high-error as well a high-accuracy transcription motifs. The source of the large accuracy span is the context dependent variation of the stacking free energy of pairs of correct and incorrect base pairs in the ever moving transcription bubble. Our model predictions have direct experimental support from recent single molecule based identifications of transcriptional errors in the C. elegans transcriptome. Our conclusions challenge the general view that amino acid substitution errors in proteins are mainly caused by translational errors. It suggests instead that transcriptional error hotspots are the dominating source of peptide sequence errors in some DNA template contexts, while mRNA translation is the major cause of protein errors in other contexts. PMID- 25799552 TI - The response of farmland bird communities to agricultural intensity as influenced by its spatial aggregation. AB - The shape of the relationship between biodiversity and agricultural intensity determines the range of intensities that should be targeted by conservation policies to obtain the greatest environmental benefits. Although preliminary evidence of this relationship exists, the influence of the spatial arrangement of intensity on biodiversity remains untested. We conducted a nationwide study linking agricultural intensity and its spatial arrangement to a farmland bird community of 22 species. Intensity was described with a continuous indicator based on Input Cost per hectare, which was relevant for both livestock and crop production. We used the French Breeding Bird Survey to compute several descriptors of the farmland bird community along the intensity gradient and tested for the significance of an interaction effect between intensity and its spatial aggregation on these descriptors. We found that the bird community was comprised of both winner and loser species with regard to intensity. The community composition descriptors (trophic level, specialisation, and specialisation for grassland indices) displayed non-linear relationships to intensity, with steeper slopes in the lower intensity range. We found a significant interaction effect between intensity and its spatial aggregation on the grassland specialisation index of the bird community; the effect of agricultural intensity was strengthened by its spatial aggregation. We suggest that an opportunity to improve the effectiveness of conservation policies exists by targeting measures in areas where intensity is moderate to low and aggregated. The effect of the aggregation of agricultural intensity on biodiversity should be considered in other scales and taxa when developing optimal policy targeting and intensity allocation strategies. PMID- 25799553 TI - A comparison of radiologic tumor volume and pathologic tumor volume in renal cell carcinoma (RCC). AB - OBJECTIVE: To investigate the difference between preoperative radiologic tumor volume (RTV) and postoperative pathologic tumor volume (PTV) in patients who received nephrectomy for renal cell carcinoma (RCC). MATERIALS AND METHODS: We reviewed 482 patients who underwent preoperative computed tomography (CT) within 4 weeks before radical or partial nephrectomy for renal cell carcinoma. RTV measured by a three dimensional rendering program was compared with PTV (pi/6 x height x length x width) measured in surgical specimen according to pathologic tumor size and histologic subtype. Correlation of the inter-quartile range (IQR) of the RTV and Fuhrman nuclear grade was also investigated. RESULTS: There was a significant positive linear correlation between RTV and PTV (p < 0.001, r = 0.911), and the mean RTV and mean PTV were not significantly different (79.0 vs 76.9 cm3, p = 0.393). For pathologic tumor size (PTS) < 4 cm, the mean RTV was larger than the mean PTV (10.9 vs 7.1 cm3, p < 0.001). For a PTS of 4-7 cm, the mean RTV was larger than the mean PTV (56.0 vs 44.7 cm3, p < 0.001). However, for a PTS >= 7 cm, there was no statistical difference between RTV and PTV (p > 0.05). Among patients with clear cell RCC, the mean RTV was significantly larger than the mean PTV (p = 0.042), not for non-clear cell group (p = 0.055). As the quartile of the RTV increased, the Fuhrman grade also increased (p < 0.001). CONCLUSIONS: RTV was correlated with PTV and pathologic grade. RTV was larger than the PTV for a tumor size 7 cm or less or in clear cell RCC. RTV may be useful to measure tumor burden preoperatively. PMID- 25799554 TI - Epidermal growth factor-mediated mitogen-activated protein kinase3/1 pathway is conducive to in vitro maturation of sheep oocytes. AB - Epidermal growth factor (EGF) has been shown to facilitate the in vitro maturation of sheep oocytes, and enhance embryo's capability for further development. However, such kind of molecular mechanism has not yet been elucidated. In the present study, we investigated the effect of EGF-mediated mitogen-activated protein kinases 3 and 1 (MAPK3/1) pathway on in vitro maturation of sheep oocytes. U0126, a specific inhibitor of MEK (MAPK kinase), was added into the maturation culture medium to block the EGF-mediated MAPK3/1 pathway with different doses. Then, the nuclear maturation of sheep oocytes was examined. Additionally, the effect of EGF-mediated MAPK3/1 on cytoplasmic maturation was examined though in vitro fertilization and embryonic development. The rate of germinal vesicle breakdown (GVBD) after 6 h of culture with 10-4 mol/l of U0126 (50.4%) was significantly decreased compared with control (67.2%, p < 0.05), and the first polation body (PB1) extrusion rate after 22 h of culture in drug treatment was also significantly inhibited compared with control (28.6% vs. 48.4%, p < 0.05). However, 10-6 mol/l U0126 had slight effect on oocyte nuclear maturation. The normal distribution rate of alpha-tubulin in the oocytes after 22 h of in vitro maturation was significantly decreased in the 10-4 mol/l U0126 group (54%) compared with control (68%, p < 0.05). After in vitro fertilization, the cleavage rate in drug treatments (56.8% in 10-6 mol/l U0126 group and 42.6% in 10-4 mol/l U0126 group) was significantly decreased compared with control (72.3%, p < 0.01). The blastocyst rate in 10-4 mol/l U0126 group (17.6%) was also significantly decreased compared with control (29.9%, p < 0.05). Collectively, these results suggest that EGF-mediated MAPK3/1 pathway is conducive to in vitro maturation of sheep oocytes. PMID- 25799555 TI - Particle backtracking improves breeding subpopulation discrimination and natal source identification in mixed populations. AB - We provide a novel method to improve the use of natural tagging approaches for subpopulation discrimination and source-origin identification in aquatic and terrestrial animals with a passive dispersive phase. Our method integrates observed site-referenced biological information on individuals in mixed populations with a particle-tracking model to retrace likely dispersal histories prior to capture (i.e., particle backtracking). To illustrate and test our approach, we focus on western Lake Erie's yellow perch (Perca flavescens) population during 2006-2007, using microsatellite DNA and otolith microchemistry from larvae and juveniles as natural tags. Particle backtracking showed that not all larvae collected near a presumed hatching location may have originated there, owing to passive drift during the larval stage that was influenced by strong river- and wind-driven water circulation. Re-assigning larvae to their most probable hatching site (based on probabilistic dispersal trajectories from the particle backtracking model) improved the use of genetics and otolith microchemistry to discriminate among local breeding subpopulations. This enhancement, in turn, altered (and likely improved) the estimated contributions of each breeding subpopulation to the mixed population of juvenile recruits. Our findings indicate that particle backtracking can complement existing tools used to identify the origin of individuals in mixed populations, especially in flow dominated systems. PMID- 25799556 TI - A modeling approach on why simple central pattern generators are built of irregular neurons. AB - The crustacean pyloric Central Pattern Generator (CPG) is a nervous circuit that endogenously provides periodic motor patterns. Even after about 40 years of intensive studies, the rhythm genesis is still not rigorously understood in this CPG, mainly because it is made of neurons with irregular intrinsic activity. Using mathematical models we addressed the question of using a network of irregularly behaving elements to generate periodic oscillations, and we show some advantages of using non-periodic neurons with intrinsic behavior in the transition from bursting to tonic spiking (as found in biological pyloric CPGs) as building components. We studied two- and three-neuron model CPGs built either with Hindmarsh-Rose or with conductance-based Hodgkin-Huxley-like model neurons. By changing a model's parameter we could span the neuron's intrinsic dynamical behavior from slow periodic bursting to fast tonic spiking, passing through a transition where irregular bursting was observed. Two-neuron CPG, half center oscillator (HCO), was obtained for each intrinsic behavior of the neurons by coupling them with mutual symmetric synaptic inhibition. Most of these HCOs presented regular antiphasic bursting activity and the changes of the bursting frequencies was studied as a function of the inhibitory synaptic strength. Among all HCOs, those made of intrinsic irregular neurons presented a wider burst frequency range while keeping a reliable regular oscillatory (bursting) behavior. HCOs of periodic neurons tended to be either hard to change their behavior with synaptic strength variations (slow periodic burster neurons) or unable to perform a physiologically meaningful rhythm (fast tonic spiking neurons). Moreover, 3 neuron CPGs with connectivity and output similar to those of the pyloric CPG presented the same results. PMID- 25799557 TI - Application of time dependent probabilistic collision state checkers in highly dynamic environments. AB - When computing the trajectory of an autonomous vehicle, inevitable collision states must be avoided at all costs, so no harm comes to the device or pedestrians around it. In dynamic environments, considering collisions as binary events is risky and inefficient, as the future position of moving obstacles is unknown. We introduce a time-dependent probabilistic collision state checker system, which traces a safe route with a minimum collision probability for a robot. We apply a sequential Bayesian model to calculate approximate predictions of the movement patterns of the obstacles, and define a time-dependent variation of the Dijkstra algorithm to compute statistically safe trajectories through a crowded area. We prove the efficiency of our methods through experimentation, using a self-guided robotic device. PMID- 25799559 TI - Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells. AB - The transcriptional repressors Hey1 and Hey2 are primary target genes of Notch signaling in the cardiovascular system and induction of Hey gene expression is often interpreted as activation of Notch signaling. Here we report that treatment of primary human endothelial cells with serum or fresh growth medium led to a strong wave of Hey1 and Hey2 transcription lasting for approximately three hours. Transcription of other Notch target genes (Hes1, Hes5, ephrinB2, Dll4) was however not induced by serum in endothelial cells. Gamma secretase inhibition or expression of dominant-negative MAML1 did not prevent the induction of Hey genes indicating that canonical Notch signaling is dispensable. Pretreatment with soluble BMP receptor Alk1, but not Alk3, abolished Hey gene induction by serum. Consequently, the Alk1 ligand BMP9 stimulated Hey gene induction in endothelial cells. Several other cell types however did not show such a strong BMP signaling and consequently only a very mild induction of Hey genes. Taken together, the experiments revealed that bone morphogenic proteins within the serum of cell culture medium are potent inducers of endothelial Hey1 and Hey2 gene expression within the first few hours after medium change. PMID- 25799558 TI - Scalable production in human cells and biochemical characterization of full length normal and mutant huntingtin. AB - Huntingtin (Htt) is a 350 kD intracellular protein, ubiquitously expressed and mainly localized in the cytoplasm. Huntington's disease (HD) is caused by a CAG triplet amplification in exon 1 of the corresponding gene resulting in a polyglutamine (polyQ) expansion at the N-terminus of Htt. Production of full length Htt has been difficult in the past and so far a scalable system or process has not been established for recombinant production of Htt in human cells. The ability to produce Htt in milligram quantities would be a prerequisite for many biochemical and biophysical studies aiming in a better understanding of Htt function under physiological conditions and in case of mutation and disease. For scalable production of full-length normal (17Q) and mutant (46Q and 128Q) Htt we have established two different systems, the first based on doxycycline-inducible Htt expression in stable cell lines, the second on "gutless" adenovirus mediated gene transfer. Purified material has then been used for biochemical characterization of full-length Htt. Posttranslational modifications (PTMs) were determined and several new phosphorylation sites were identified. Nearly all PTMs in full-length Htt localized to areas outside of predicted alpha-solenoid protein regions. In all detected N-terminal peptides methionine as the first amino acid was missing and the second, alanine, was found to be acetylated. Differences in secondary structure between normal and mutant Htt, a helix-rich protein, were not observed in our study. Purified Htt tends to form dimers and higher order oligomers, thus resembling the situation observed with N-terminal fragments, although the mechanism of oligomer formation may be different. PMID- 25799560 TI - Adaptation of sensorimotor coupling in postural control is impaired by sleep deprivation. AB - The purpose of the study was to investigate the effects of sleep deprivation (SD) in adaptation of the coupling between visual information and body sway in young adults' postural control due to changes in optic flow characteristics. Fifteen young adults were kept awake for approximately 25 hours and formed the SD group, while fifteen adults who slept normally the night before the experiment participated as part of the control group. All participants stood as still as possible in a moving room before and after being exposed to one trial with higher amplitude and velocity of room movement. Postural performance and the coupling between visual information, provided by a moving room, and body sway were examined. Results showed that after an abrupt change in visual cues, larger amplitude, and higher velocity of the room, the influence of room motion on body sway was decreased in both groups. However, such a decrease was less pronounced in sleep deprived as compared to control subjects. Sleep deprived adults were able to adapt motor responses to the environmental change provided by the increase in room motion amplitude. Nevertheless, they were not as efficient as control subjects in doing so, which demonstrates that SD impairs the ability to adapt sensorimotor coupling while controlling posture when a perturbation occurs. PMID- 25799561 TI - Is autonomic modulation different between European and Chinese astronauts? AB - PURPOSE: The objective was to investigate autonomic control in groups of European and Chinese astronauts and to identify similarities and differences. METHODS: Beat-to-beat heart rate and finger blood pressure, brachial blood pressure, and respiratory frequency were measured from 10 astronauts (five European taking part in three different space missions and five Chinese astronauts taking part in two different space missions). Data recording was performed in the supine and standing positions at least 10 days before launch, and 1, 3, and 10 days after return. Cross-correlation analysis of heart rate and systolic pressure was used to assess cardiac baroreflex modulation. A fixed breathing protocol was performed to measure respiratory sinus arrhythmia and low-frequency power of systolic blood pressure variability. RESULTS: Although baseline cardiovascular parameters before spaceflight were similar in all astronauts in the supine position, a significant increase in sympathetic activity and a decrease in vagal modulation occurred in the European astronauts when standing; spaceflight resulted in a remarkable vagal decrease in European astronauts only. Similar baseline supine and standing values for heart rate, mean arterial pressure, and respiratory frequency were shown in both groups. Standing autonomic control was based on a balance of higher vagal and sympathetic modulation in European astronauts. CONCLUSION: Post-spaceflight orthostatic tachycardia was observed in all European astronauts, whereas post spaceflight orthostatic tachycardia was significantly reduced in Chinese astronauts. The basis for orthostatic intolerance is not apparent; however, many possibilities can be considered and need to be further investigated, such as genetic diversities between races, astronaut selection, training, and nutrition, etc. PMID- 25799562 TI - Pituitary androgen receptor signalling regulates prolactin but not gonadotrophins in the male mouse. AB - Production of the androgen testosterone is controlled by a negative feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. Stimulation of testicular Leydig cells by pituitary luteinising hormone (LH) is under the control of hypothalamic gonadotrophin releasing hormone (GnRH), while suppression of LH secretion by the pituitary is controlled by circulating testosterone. Exactly how androgens exert their feedback control of gonadotrophin secretion (and whether this is at the level of the pituitary), as well as the role of AR in other pituitary cell types remains unclear. To investigate these questions, we exploited a transgenic mouse line (Foxg1 Cre/+; AR fl/y) which lacks androgen receptor in the pituitary gland. Both circulating testosterone and gonadotrophins are unchanged in adulthood, demonstrating that AR signalling is dispensable in the male mouse pituitary for testosterone-dependent regulation of LH secretion. In contrast, Foxg1 Cre/+; AR fl/y males have a significant increase in circulating prolactin, suggesting that, rather than controlling gonadotrophins, AR-signalling in the pituitary acts to suppress aberrant prolactin production in males. PMID- 25799563 TI - Phytoplankton assemblage characteristics in recurrently fluctuating environments. AB - Annual variations in biogeochemical and physical processes can lead to nutrient variability and seasonal patterns in phytoplankton productivity and assemblage structure. In many coastal systems river inflow and water exchange with the ocean varies seasonally, and alternating periods can arise where the nutrient most limiting to phytoplankton growth switches. Transitions between these alternating periods can be sudden or gradual and this depends on human activities, such as reservoir construction and interbasin water transfers. How such activities might influence phytoplankton assemblages is largely unknown. Here, we employed a multispecies, multi-nutrient model to explore how nutrient loading switching mode might affect characteristics of phytoplankton assemblages. The model is based on the Monod-relationship, predicting an instantaneous growth rate from ambient inorganic nutrient concentrations whereas the limiting nutrient at any given time was determined by Liebig's Law of the Minimum. Our simulated phytoplankton assemblages self-organized from species rich pools over a 15-year period, and only the surviving species were considered as assemblage members. Using the model, we explored the interactive effects of complementarity level in trait trade-offs within phytoplankton assemblages and the amount of noise in the resource supply concentrations. We found that the effect of shift from a sudden resource supply transition to a gradual one, as observed in systems impacted by watershed development, was dependent on the level of complementarity. In the extremes, phytoplankton species richness and relative overyielding increased when complementarity was lowest, and phytoplankton biomass increased greatly when complementarity was highest. For low-complementarity simulations, the persistence of poorer-performing phytoplankton species of intermediate R*s led to higher richness and relative overyielding. For high-complementarity simulations, the formation of phytoplankton species clusters and niche compression enabled higher biomass accumulation. Our findings suggest that an understanding of factors influencing the emergence of life history traits important to complementarity is necessary to predict the impact of watershed development on phytoplankton productivity and assemblage structure. PMID- 25799564 TI - alpha1B-adrenergic receptors differentially associate with Rab proteins during homologous and heterologous desensitization. AB - Internalization of G protein-coupled receptors can be triggered by agonists or by other stimuli. The process begins within seconds of cell activation and contributes to receptor desensitization. The Rab GTPase family controls endocytosis, vesicular trafficking, and endosomal fusion. Among their remarkable properties is the differential distribution of its members on the surface of various organelles. In the endocytic pathway, Rab 5 controls traffic from the plasma membrane to early endosomes, whereas Rab 4 and Rab 11 regulate rapid and slow recycling from early endosomes to the plasma membrane, respectively. Moreover, Rab 7 and Rab 9 regulate the traffic from late endosomes to lysosomes and recycling to the trans-Golgi. We explore the possibility that alpha1B adrenergic receptor internalization induced by agonists (homologous) and by unrelated stimuli (heterologous) could involve different Rab proteins. This possibility was explored by Fluorescence Resonance Energy Transfer (FRET) using cells coexpressing alpha1B-adrenergic receptors tagged with the red fluorescent protein, DsRed, and different Rab proteins tagged with the green fluorescent protein. It was observed that when alpha1B-adrenergic receptors were stimulated with noradrenaline, the receptors interacted with proteins present in early endosomes, such as the early endosomes antigen 1, Rab 5, Rab 4, and Rab 11 but not with late endosome markers, such as Rab 9 and Rab 7. In contrast, sphingosine 1-phosphate stimulation induced rapid and transient alpha1B-adrenergic receptor interaction of relatively small magnitude with Rab 5 and a more pronounced and sustained one with Rab 9; interaction was also observed with Rab 7. Moreover, the GTPase activity of the Rab proteins appears to be required because no FRET was observed when dominant-negative Rab mutants were employed. These data indicate that alpha1B-adrenergic receptors are directed to different endocytic vesicles depending on the desensitization type (homologous vs. heterologous). PMID- 25799565 TI - Alterations of monetary reward and punishment processing in chronic cannabis users: an FMRI study. AB - Alterations in reward and punishment processing have been reported in adults suffering from long-term cannabis use. However, previous findings regarding the chronic effects of cannabis on reward and punishment processing have been inconsistent. In the present study, we used functional magnetic resonance imaging (fMRI) to reveal the neural correlates of reward and punishment processing in long-term cannabis users (n = 15) and in healthy control subjects (n = 15) with no history of drug abuse. For this purpose, we used the well-established Monetary Incentive Delay (MID) task, a reliable experimental paradigm that allows the differentiation between anticipatory and consummatory aspects of reward and punishment processing. Regarding the gain anticipation period, no significant group differences were observed. In the left caudate and the left inferior frontal gyrus, cannabis users were - in contrast to healthy controls - not able to differentiate between the conditions feedback of reward and control. In addition, cannabis users showed stronger activations in the left caudate and the bilateral inferior frontal gyrus following feedback of no punishment as compared to healthy controls. We interpreted these deficits in dorsal striatal functioning as altered stimulus-reward or action-contingent learning in cannabis users. In addition, the enhanced lateral prefrontal activation in cannabis users that is related to non-punishing feedback may reflect a deficit in emotion regulation or cognitive reappraisal in these subjects. PMID- 25799566 TI - The effect of adjuvant chemotherapy on survival in patients with residual nasopharyngeal carcinoma after undergoing concurrent chemoradiotherapy. AB - BACKGROUND: Guidelines from the U.S. National Comprehensive Cancer Network have recommended use of concurrent chemoradiotherapy (CCRT), followed by a 3-cycles combination of platinum and 5-fluorouracil chemotherapy as standard treatment for nasopharyngeal carcinoma (NPC). The benefits of CCRT for treatment of locally advanced NPC have been established. Whether platinum and 5-fluorouracil chemotherapy should be routinely added to locally advanced NPC after CCRT is still open to debate. Whether adjuvant chemotherapy provides an additional survival benefit for the subgroup of patients with residual nasopharyngeal carcinoma who have undergone CCRT is also unclear. This retrospective study was initiated to determine the survival benefit of adjuvant chemotherapy (AC) in residual NPC patients who have undergone concurrent chemoradiotherapy. METHODS: The retrospective study included 155 nasopharyngeal carcinoma patients who had local residual lesions after the platinum-based CCRT without or with AC. Kaplan Meier analysis and the log-rank test were used to estimate overall survival (OS), failure-free survival (FFS), local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS). RESULTS: Median follow-up was 47 months. Adjuvant cisplatin or nedaplatin plus 5-fluorouracil chemotherapy did not significantly improve 3-year OS, LRFS, FFS, and DMFS for patients with residual nasopharyngeal carcinoma after undergoing CCRT. The 3-year OS rates for the no-AC group and AC group were 71.6% and 73.7%, respectively (P= 0.44). The 3-year FFS rates for no-AC group and AC group were 57.5% and 66.9%, respectively ((P= 0.19). The 3-year LRFS rates for no-AC group and AC group were 84.7% and 87.9%, respectively ((P= 0.51). The 3-year DMFS rates for no-AC group and AC group were 71.4% and 77.4%, respectively ((P= 0.23). CONCLUSIONS: Since we did not find sufficient data to support significant survival in 3-year OS, LRFS, FFS, and DMFS, whether Adjuvant cisplatin or nedaplatin and 5-fluorouracil chemotherapy should be routinely added to residual nasopharyngeal carcinoma patients after undergoing CCRT remain uncertain. PMID- 25799567 TI - The effect of a bidirectional exchange on faculty and institutional development in a global health collaboration. AB - PURPOSE: The MUYU Collaboration is a partnership between Mulago Hospital-Makerere University College of Health Sciences (M-MakCHS), in Kampala, Uganda, and the Yale University School of Medicine. The program allows Ugandan junior faculty to receive up to 1 year of subspecialty training within the Yale hospital system. The authors performed a qualitative study to assess the effects of this program on participants, as well as on M-MakCHS as an institution. METHODS: Data was collected via semi-structured interviews with exchange participants. Eight participants (67% of those eligible as of 4/2012) completed interviews. Study authors performed data analysis using standard qualitative data analysis techniques. RESULTS: Analysis revealed themes addressing the benefits, difficulties, and opportunities for improvement of the program. Interviewees described the main benefit of the program as its effect on their fund of knowledge. Participants also described positive effects on their clinical practice and on medical education at M-MakCHS. Most respondents cited financial issues as the primary difficulty of participation. Post-participation difficulties included resource limitations and confronting longstanding institutional and cultural habits. Suggestions for programmatic improvement included expansion of the program, ensuring appropriate management of pre departure expectations, and refinement of program mentoring structures. Participants also voiced interest in expanding post-exchange programming to ensure both the use of and the maintenance of new capacity. CONCLUSIONS: The MUYU Collaboration has benefitted both program participants and M-MakCHS, though these benefits remain difficult to quantify. This study supports the assertion that resource-poor to resource-rich exchanges have the potential to provide significant benefits to the resource-poor partner. PMID- 25799568 TI - Gender differences in health expectancies across the disablement process among older Thais. AB - OBJECTIVES: To estimate health expectancies based on measures that more fully cover the stages in the disablement process for the older Thais and examine gender differences in these health expectancies. METHODS: Health expectancies by genders using Sullivan's method were computed from the fourth Thai National Health Examination Survey conducted in 2009. A total of 9,210 participants aged 60 years and older were included in the analysis. Health measures included chronic diseases; cognitive impairment; depression; disability in instrumental activities of daily living (IADL); and disability in activities of daily living (ADL). RESULTS: The average number of years lived with and without morbidity and disability as measured by multiple dimensions of health varied and gender differences were not consistent across measures. At age 60, males could expect to live the most years on average free of depression (18.6 years) and ADL disability (18.6 years) and the least years free of chronic diseases (9.1 years). Females, on the contrary, could expect to live the most years free of ADL disability (21.7 years) and the least years free of IADL disability (8.1 years), and they consistently spent more years with all forms of morbidity and disability. Finally, and for both genders, years lived with cognitive impairment, depression and ADL disability were almost constant with increasing age. CONCLUSION: This study adds knowledge of gender differences in healthy life expectancy in the older Thai population using a wider spectrum of health which provides useful information to diverse policy audiences. PMID- 25799569 TI - Preliminary biomechanical study of different acetabular reinforcement devices for acetabular reconstruction. AB - BACKGROUND: Acetabular reinforcement devices (ARDs) are frequently used as load sharing devices to allow allograft incorporation in revision hip arthroplasty with massive acetabular bone loss. The key to a successful reconstruction is robust fixation of the device to the host acetabulum. Interlocking fixation is expected to improve the initial stability of the postoperative construct. However, all commercially available ARDs are designed with non-locking fixation. This study investigates the efficacy of standard ARDs modified with locking screw mechanisms for improving stability in acetabular reconstruction. METHODS: Three types of ARDs were examined to evaluate the postoperative compression and angular stability: i) standard commercial ARDs, ii) standard ARDs modified with monoaxial and iii) standard ARDs modified with polyaxial locking screw mechanisms. All ARDs were implanted into osteomized synthetic pelvis with pelvic discontinuity. Axial compression and torsion tests were then performed using a servohydraulic material testing machine that measured load (angle) versus displacement (torque). Initial stability was compared among the groups. RESULTS: Equipping ARDs with interlocking mechanisms effectively improved the initial stability at the device/bone interface compared to standard non-locked ARDs. In both compression and torsion experiments, the monoaxial interlocking construct demonstrated the highest construct stiffness (672.6 +/- 84.1 N/mm in compression and 13.3 +/- 1.0 N . m/degree in torsion), whereas the non-locked construct had the lowest construct stiffness (381.4 +/- 117.2 N/mm in compression and 6.9 +/- 2.1 N . m/degree in torsion) (P < 0.05). CONCLUSIONS: Our study demonstrates the potential benefit of adding a locking mechanism to an ARD. Polyaxial ARDs provide the surgeon with more flexibility in placing the screws at the cost of reduced mechanical performance. This in vitro study provides a preliminary evaluation of biomechanical performance for ARDs with or without interlocking mechanisms, actual clinical trial deserves to be further investigated in future studies. PMID- 25799570 TI - Psychometric properties of the Chinese version of the fear of negative evaluation scale-brief (BFNE) and the BFNE-straightforward for middle school students. AB - BACKGROUND: The 12-item brief version of the Fear of Negative Evaluation Scale (BFNE) is one of the most widely used instruments to assess fear of negative evaluation. Recent evidence strongly supports the version composed of 8 straightforward items (BFNE-S), which possessesstronger psychometric properties. The purpose of the current study is to examine the psychometric prop-erties of the Chinese versions of the BFNE and BFNE-S for middle school students. METHODOLOGY: A total of 1009 middle school students were recruited in this study. The BFNE, the BFNE-S, the Friedman-Bendas Text Anxiety Scale (FBTAS), and the Social Anxiety Scale (SAS) were administered to 497 participants, and 52 participants were re-tested after four weeks. The BFNE, the BFNE-S, the Rosenberg Self-Esteem Scale (RSES), and the Balanced Inventory of Desirable Responding (BIDR) wereadministered to 492 participants. The BFNE and BFNE-S significantly cor-related with all the scales, supporting their convergent, divergent and concurrent validity. PRINCIPAL FINDINGS: The Cronbach's alpha of the BFNE (BFNE S) was 0.864 (0.867) with 497 par-ticipants and 0.886 (0.844) with 492 participants, and the test-retest reliability coefficient was 0.791 (0.855) (ICC). Although the EFA identified a two-factor solution in which the 8 straightfor-ward items loaded on one factor and the 4 reversed items loaded on the other, the CFA, using a random intercept model to control the wording effect, supported a unidimensional factor struc-ture of the BFNE. Both EFA and CFA supported the unidimensional assumption of the BFNE-S. The correlations of the BFNE and BFNE-S were 0.929 and 0.952 in two samples. CONCLUSIONS: The Chinese versions of the BFNE and BFNE-S demonstrate adequate psychometric properties for assessing fear of negative evaluation. The results support their use among the Chinese middle school students. Considering its greater parsimony and excellent reliability and validity, the BFNE-S is a better tool. PMID- 25799571 TI - Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes. AB - BACKGROUND: The pervasive nature of plastics has raised concerns about the impact of continuous exposure to plastic additives on human health. Of particular concern is the use of phthalates in the production of flexible polyvinyl chloride (PVC) products. Di-2-ethylhexyl-phthalate (DEHP) is a commonly used phthalate ester plasticizer that imparts flexibility and elasticity to PVC products. Recent epidemiological studies have reported correlations between urinary phthalate concentrations and cardiovascular disease, including an increased risk of high blood pressure and coronary risk. Yet, there is little direct evidence linking phthalate exposure to adverse effects in human cells, including cardiomyocytes. METHODS AND RESULTS: The effect of DEHP on calcium handling was examined using monolayers of gCAMP3 human embryonic stem cell-derived cardiomyocytes, which contain an endogenous calcium sensor. Cardiomyocytes were exposed to DEHP (5 - 50 MUg/mL), and calcium transients were recorded using a Zeiss confocal imaging system. DEHP exposure (24 - 72 hr) had a negative chronotropic and inotropic effect on cardiomyocytes, increased the minimum threshold voltage required for external pacing, and modified connexin-43 expression. Application of Wy-14,643 (100 MUM), an agonist for the peroxisome proliferator-activated receptor alpha, did not replicate DEHP's effects on calcium transient morphology or spontaneous beating rate. CONCLUSIONS: Phthalates can affect the normal physiology of human cardiomyocytes, including DEHP elicited perturbations in cardiac calcium handling and intercellular connectivity. Our findings call for additional studies to clarify the extent by which phthalate exposure can alter cardiac function, particularly in vulnerable patient populations who are at risk for high phthalate exposure. PMID- 25799572 TI - Temporal expectation and attention jointly modulate auditory oscillatory activity in the beta band. AB - The neural response to a stimulus is influenced by endogenous factors such as expectation and attention. Current research suggests that expectation and attention exert their effects in opposite directions, where expectation decreases neural activity in sensory areas, while attention increases it. However, expectation and attention are usually studied either in isolation or confounded with each other. A recent study suggests that expectation and attention may act jointly on sensory processing, by increasing the neural response to expected events when they are attended, but decreasing it when they are unattended. Here we test this hypothesis in an auditory temporal cueing paradigm using magnetoencephalography in humans. In our study participants attended to, or away from, tones that could arrive at expected or unexpected moments. We found a decrease in auditory beta band synchrony to expected (versus unexpected) tones if they were unattended, but no difference if they were attended. Modulations in beta power were already evident prior to the expected onset times of the tones. These findings suggest that expectation and attention jointly modulate sensory processing. PMID- 25799573 TI - Cranial nerve development requires co-ordinated Shh and canonical Wnt signaling. AB - Cranial nerves govern sensory and motor information exchange between the brain and tissues of the head and neck. The cranial nerves are derived from two specialized populations of cells, cranial neural crest cells and ectodermal placode cells. Defects in either cell type can result in cranial nerve developmental defects. Although several signaling pathways are known to regulate cranial nerve formation our understanding of how intercellular signaling between neural crest cells and placode cells is coordinated during cranial ganglia morphogenesis is poorly understood. Sonic Hedgehog (Shh) signaling is one key pathway that regulates multiple aspects of craniofacial development, but whether it co-ordinates cranial neural crest cell and placodal cell interactions during cranial ganglia formation remains unclear. In this study we examined a new Patched1 (Ptch1) loss-of-function mouse mutant and characterized the role of Ptch1 in regulating Shh signaling during cranial ganglia development. Ptch1(Wig/ Wig) mutants exhibit elevated Shh signaling in concert with disorganization of the trigeminal and facial nerves. Importantly, we discovered that enhanced Shh signaling suppressed canonical Wnt signaling in the cranial nerve region. This critically affected the survival and migration of cranial neural crest cells and the development of placodal cells as well as the integration between neural crest and placodes. Collectively, our findings highlight a novel and critical role for Shh signaling in cranial nerve development via the cross regulation of canonical Wnt signaling. PMID- 25799574 TI - Characterization of trh2 harbouring Vibrio parahaemolyticus strains isolated in Germany. AB - BACKGROUND: Vibrio parahaemolyticus is a recognized human enteropathogen. Thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH) as well as the type III secretion system 2 (T3SS2) are considered as major virulence factors. As tdh positive strains are not detected in coastal waters of Germany, we focused on the characterization of trh positive strains, which were isolated from mussels, seawater and patients in Germany. RESULTS: Ten trh harbouring V. parahaemolyticus strains from Germany were compared to twenty-one trh positive strains from other countries. The complete trh sequences revealed clustering into three different types: trh1 and trh2 genes and a pseudogene Psitrh. All German isolates possessed alleles of the trh2 gene. MLST analysis indicated a close relationship to Norwegian isolates suggesting that these strains belong to the autochthonous microflora of Northern Europe seawaters. Strains carrying the pseudogene Psitrh were negative for T3SS2beta effector vopC. Transcription of trh and vopC genes was analyzed under different growth conditions. Trh2 gene expression was not altered by bile while trh1 genes were inducible. VopC could be induced by urea in trh2 bearing strains. Most trh1 carrying strains were hemolytic against sheep erythrocytes while all trh2 positive strains did not show any hemolytic activity. TRH variants were synthesized in a prokaryotic cell-free system and their hemolytic activity was analyzed. TRH1 was active against sheep erythrocytes while TRH2 variants were not active at all. CONCLUSION: Our study reveals a high diversity among trh positive V. parahaemolyticus strains. The function of TRH2 hemolysins and the role of the pseudogene Psitrh as pathogenicity factors are questionable. To assess the pathogenic potential of V. parahaemolyticus strains a differentiation of trh variants and the detection of T3SS2beta components like vopC would improve the V. parahaemolyticus diagnostics and could lead to a refinement of the risk assessment in food analyses and clinical diagnostics. PMID- 25799575 TI - Pigmented villonodular synovitis: a retrospective multicenter study of 237 cases. AB - PURPOSE: To review clinical characteristics of pigmented villonodular synovitis (PVNS) in China. METHODS: Electronic medical records (EMR) of four Chinese institutes were queried for patients with histologically proven PVNS between January 2005 and February 2014. Their data were collected including gender, age at diagnosis, clinical presentation, affected site, symptom duration, comorbidities, treatment strategy, recurrence and routine laboratories. RESULTS: A total of 237 patients with biopsy-proven PVNS were investigated. The gender ratio was 1.35 for a female predominance (101 males and 136 females). The average age was 36 years (range, 2 to 83 years). The median delay from initial clinical symptom to diagnosis was 18 months. Main affected areas were the knee (73.84%) and the hip (18.14%). Forty patients had a clear history of joint trauma. Six patients were concurrently diagnosed with PVNS and avascular necrosis (AVN). Five patients suffered from PVNS following implantation of orthopaedic devices including artificial prosthesis, plate and wire. One hundred and twenty-nine patients underwent arthroscopic synovectomy and 108 open synovectomy. Altogether 48 patients (26 males and 22 females) had recurrence of disease. The relapse rate was 24% (knee) and 6.98% (hip), 20.93% (open surgery) and 19.44% (arthroscopy), respectively. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) rate were elevated in 45.83% and 38.41% of the patients respectively. CONCLUSIONS: To our knowledge, this study is the largest sample size of PVNS patients reported as well as the largest sample of PVNS with concurrent AVN reported to date. Our outcomes suggest that PVNS shows a female predominance, occurs mostly between 20-40 years and favors the knee and hip. Recurrence is frequent, particularly in the knee. Serum ESR and CRP may be elevated in some patients. Additionally, the present study supports the theory of an association between PVNS and orthopedic surgery, which is not limited to joint replacement. PMID- 25799576 TI - Enteric neurospheres are not specific to neural crest cultures: implications for neural stem cell therapies. AB - OBJECTIVES: Enteric neural stem cells provide hope of curative treatment for enteric neuropathies. Current protocols for their harvesting from humans focus on the generation of 'neurospheres' from cultures of dissociated gut tissue. The study aims to better understand the derivation, generation and composition of enteric neurospheres. DESIGN: Gut tissue was obtained from Wnt1-Cre;Rosa26Yfp/Yfp transgenic mice (constitutively labeled neural crest cells) and paediatric patients. Gut cells were cultured either unsorted (mixed neural crest/non-neural crest), or following FACS selection into neural crest (murine-YFP+ve/human p75+ve) or non-neural crest (YFP-ve/p75-ve) populations. Cultures and resultant neurospheres were characterized using immunolabelling in vitro and following transplantation in vivo. RESULTS: Cultures of (i) unsorted, (ii) neural crest, and (iii) non-neural crest cell populations generated neurospheres similar in numbers, size and morphology. Unsorted neurospheres were highly heterogeneous for neural crest content. Neural crest-derived (YFP+ve/p75+ve) neurospheres contained only neural derivatives (neurons and glia) and were devoid of non-neural cells (i.e. negative for SMA, c-Kit), with the converse true for non-neural crest derived (YFP-ve/p75-ve) 'neurospheres'. Under differentiation conditions only YFP+ve cells gave rise to neural derivatives. Both YFP+ve and YFP-ve cells displayed proliferation and spread upon transplantation in vivo, but YFP-ve cells did not locate or integrate within the host ENS. CONCLUSIONS: Spherical accumulations of cells, so-called 'neurospheres' forming in cultures of dissociated gut contain variable proportions of neural crest-derived cells. If they are to be used for ENS cell replacement therapy then improved protocols for their generation, including cell selection, should be sought in order to avoid inadvertent transplantation of non-therapeutic, non-ENS cells. PMID- 25799578 TI - Correction: Circadian mechanisms of food anticipatory rhythms in rats fed once or twice daily: clock gene and endocrine correlates. PMID- 25799577 TI - The sexual and mating system of the shrimp Odontonia katoi (Palaemonidae, Pontoniinae), a symbiotic guest of the ascidian Polycarpa aurata in the Coral Triangle. AB - Theory predicts that monogamy is adaptive in symbiotic crustaceans inhabiting relatively small and morphologically simple hosts in tropical environments where predation risk away from hosts is high. We tested this prediction in the shrimp Odontonia katoi, which inhabits the atrial chamber of the ascidian Polycarpa aurata in the Coral Triangle. Preliminary observations in O. katoi indicated that males were smaller than females, which is suggestive of sex change (protandry) in some symbiotic organisms. Thus, we first investigated the sexual system of O. katoi to determine if this shrimp was sequentially hermaphroditic. Morphological identification and size frequency distributions indicated that the population comprised males that, on average, were smaller than females. Gonad dissections demonstrated the absence of transitional individuals. Thus, O. katoi is a gonochoric species with reverse sexual dimorphism. The population distribution of O. katoi in its ascidian host did not differ significantly from a random distribution and shrimps inhabiting the same host individual as pairs were found with a frequency similar to that expected by chance alone. This is in contrast to that reported for other socially monogamous crustaceans in which pairs of heterosexual conspecifics are found in host individuals more frequently than expected by chance alone. Thus, the available information argues against monogamy in O. katoi. Furthermore, that a high frequency of solitary females were found brooding embryos and that the sex ratio was skewed toward females suggests that males might be roaming among hosts in search of receptive females in O. katoi. Symbiotic crustaceans can be used as a model system to understand the adaptive value of sexual and mating systems in marine invertebrates. PMID- 25799579 TI - Correction: Increased N-glycosylation efficiency by generation of an aromatic sequon on N135 of antithrombin. PMID- 25799580 TI - Activation of CNTF/CNTFRalpha signaling pathway by hRheb(S16H) transduction of dopaminergic neurons in vivo. AB - Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor alpha (CNTFRalpha). It is still unclear whether the levels of CNTFRalpha change in the substantia nigra of Parkinson's disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFRalpha signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb), with an S16H mutation [hRheb(S16H)], significantly upregulated the levels of both CNTF and CNTFRalpha in dopaminergic neurons. Moreover, the hRheb(S16H)-activated CNTF/CNTFRalpha signaling pathway was protective against 1-methyl-4 phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRalpha signaling pathway by specific gene delivery such as hRheb(S16H) may have therapeutic potential in the treatment of PD. PMID- 25799581 TI - Interaction between fiscal and monetary policy in a dynamic nonlinear model. AB - The objective of this study is to verify the dynamics between fiscal policy, measured by public debt, and monetary policy, measured by a reaction function of a central bank. Changes in monetary policies due to deviations from their targets always generate fiscal impacts. We examine two policy reaction functions: the first related to inflation targets and the second related to economic growth targets. We find that the condition for stable equilibrium is more restrictive in the first case than in the second. We then apply our simulation model to Brazil and United Kingdom and find that the equilibrium is unstable in the Brazilian case but stable in the UK case. PMID- 25799582 TI - Use of droplet digital PCR for estimation of fish abundance and biomass in environmental DNA surveys. AB - An environmental DNA (eDNA) analysis method has been recently developed to estimate the distribution of aquatic animals by quantifying the number of target DNA copies with quantitative real-time PCR (qPCR). A new quantitative PCR technology, droplet digital PCR (ddPCR), partitions PCR reactions into thousands of droplets and detects the amplification in each droplet, thereby allowing direct quantification of target DNA. We evaluated the quantification accuracy of qPCR and ddPCR to estimate species abundance and biomass by using eDNA in mesocosm experiments involving different numbers of common carp. We found that ddPCR quantified the concentration of carp eDNA along with carp abundance and biomass more accurately than qPCR, especially at low eDNA concentrations. In addition, errors in the analysis were smaller in ddPCR than in qPCR. Thus, ddPCR is better suited to measure eDNA concentration in water, and it provides more accurate results for the abundance and biomass of the target species than qPCR. We also found that the relationship between carp abundance and eDNA concentration was stronger than that between biomass and eDNA by using both ddPCR and qPCR; this suggests that abundance can be better estimated by the analysis of eDNA for species with fewer variations in body mass. PMID- 25799583 TI - Alternative polyadenylation allows differential negative feedback of human miRNA miR-579 on its host gene ZFR. AB - About half of the known miRNA genes are located within protein-coding host genes, and are thus subject to co-transcription. Accumulating data indicate that this coupling may be an intrinsic mechanism to directly regulate the host gene's expression, constituting a negative feedback loop. Inevitably, the cell requires a yet largely unknown repertoire of methods to regulate this control mechanism. We propose APA as one possible mechanism by which negative feedback of intronic miRNA on their host genes might be regulated. Using in-silico analyses, we found that host genes that contain seed matching sites for their intronic miRNAs yield longer 32UTRs with more polyadenylation sites. Additionally, the distribution of polyadenylation signals differed significantly between these host genes and host genes of miRNAs that do not contain potential miRNA binding sites. We then transferred these in-silico results to a biological example and investigated the relationship between ZFR and its intronic miRNA miR-579 in a U87 cell line model. We found that ZFR is targeted by its intronic miRNA miR-579 and that alternative polyadenylation allows differential targeting. We additionally used bioinformatics analyses and RNA-Seq to evaluate a potential cross-talk between intronic miRNAs and alternative polyadenylation. CPSF2, a gene previously associated with alternative polyadenylation signal recognition, might be linked to intronic miRNA negative feedback by altering polyadenylation signal utilization. PMID- 25799584 TI - Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC. AB - Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis. A previously reported missense mutation in the CTSC gene (NM_001814.4:c.899G>A:p.(G300D)) was identified in a homozygous state in two siblings diagnosed with PLS in a consanguineous family of Arabic ancestry. The variant was initially identified in a heterozygous state in a PLS unaffected sibling whose whole exome had been sequenced as part of a previous Primary ciliary dyskinesia study. Using this information, a proxy molecular diagnosis was made on the PLS affected siblings after consent was given to study this second disorder found to be segregating within the family. The prevalence of the mutation was then assayed in the local population using a representative sample of 256 unrelated individuals. The variant was absent in all subjects indicating that the variant is rare in Saudi Arabia. This family study illustrates how whole-exome sequencing can generate findings and inferences beyond its primary goal. PMID- 25799585 TI - Rich-cores in networks. AB - A core comprises of a group of central and densely connected nodes which governs the overall behaviour of a network. It is recognised as one of the key meso-scale structures in complex networks. Profiling this meso-scale structure currently relies on a limited number of methods which are often complex and parameter dependent or require a null model. As a result, scalability issues are likely to arise when dealing with very large networks together with the need for subjective adjustment of parameters. The notion of a rich-club describes nodes which are essentially the hub of a network, as they play a dominating role in structural and functional properties. The definition of a rich-club naturally emphasises high degree nodes and divides a network into two subgroups. Here, we develop a method to characterise a rich-core in networks by theoretically coupling the underlying principle of a rich-club with the escape time of a random walker. The method is fast, scalable to large networks and completely parameter free. In particular, we show that the evolution of the core in World Trade and C. elegans networks correspond to responses to historical events and key stages in their physical development, respectively. PMID- 25799586 TI - Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells. AB - Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2 Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells. PMID- 25799587 TI - Light-dependent phosphorylation of the Drosophila inactivation no afterpotential D (INAD) scaffolding protein at Thr170 and Ser174 by eye-specific protein kinase C. AB - Drosophila inactivation no afterpotential D (INAD) is a PDZ domain-containing scaffolding protein that tethers components of the phototransduction cascade to form a supramolecular signaling complex. Here, we report the identification of eight INAD phosphorylation sites using a mass spectrometry approach. PDZ1, PDZ2, and PDZ4 each harbor one phosphorylation site, three phosphorylation sites are located in the linker region between PDZ1 and 2, one site is located between PDZ2 and PDZ3, and one site is located in the N-terminal region. Using a phosphospecific antibody, we found that INAD phosphorylated at Thr170/Ser174 was located within the rhabdomeres of the photoreceptor cells, suggesting that INAD becomes phosphorylated in this cellular compartment. INAD phosphorylation at Thr170/Ser174 depends on light, the phototransduction cascade, and on eye-Protein kinase C that is attached to INAD via one of its PDZ domains. PMID- 25799588 TI - Differential effects of dietary oils on emotional and cognitive behaviors. AB - Several dietary oils have been used preventatively and therapeutically in the setting of neurological disease. However, the mechanisms underlying their influence on brain function and metabolism remain unknown. It was investigated whether 3 types of dietary oils affected emotional behaviors in mice. Wild-type (WT) mice and sialyltransferase ST3Gal IV-knockout (KO) mice, which exhibit increased emotional and cognitive behaviors, were fed diets containing 20% dietary oils from post-weaning to adulthood. Mice were fed pellets made from control feed AIN93G powder containing 18% fish oil, soybean oil, or a mixture of 1-palmitoyl-2-oleoyl-3-palmitoyl glycerol (POP) and 1-stearoyl-2-oleoyl-3 stearoyl glycerol (SOS), plus 2% soybean oil. Once mice reached adulthood, they were subjected to fear conditioning test to measure cognitive anxiety and forced swim test to measure depression. WT mice fed the POP-SOS diet showed a 0.6-fold decrease in percent freezing with contextual fear compared with WT mice fed the control diet. KO mice fed the fish oil diet showed a 1.4-fold increase in percent freezing with contextual fear compared with KO mice fed the control diet. These findings indicate that response to contextual fear was improved in WT mice that consumed POP-SOS but aggravated in KO mice that consumed fish oils. Furthermore, KO mice showed a 0.4-fold decrease in percent freezing in response to tone fear when they were fed POP-SOS diet compared to a control diet. Thus, POP-SOS diet reduced tone fear level of KO mice until the same level of WT mice. Finally, KO mice fed the soybean oil diet showed a 1.7-fold increase in immobility in the forced swim test compared to KO mice fed the control diet. Taken together, oil rich diets differentially modulate anxiety and depression in normal and anxious mice. Oils rich in saturated fatty acids may alleviate anxiety more strongly than other oils. PMID- 25799589 TI - The HIP2~ubiquitin conjugate forms a non-compact monomeric thioester during di ubiquitin synthesis. AB - Polyubiquitination is a post-translational event used to control the degradation of damaged or unwanted proteins by modifying the target protein with a chain of ubiquitin molecules. One potential mechanism for the assembly of polyubiquitin chains involves the dimerization of an E2 conjugating enzyme allowing conjugated ubiquitin molecules to be put into close proximity to assist reactivity. HIP2 (UBE2K) and Ubc1 (yeast homolog of UBE2K) are unique E2 conjugating enzymes that each contain a C-terminal UBA domain attached to their catalytic domains, and they have basal E3-independent polyubiquitination activity. Although the isolated enzymes are monomeric, polyubiquitin formation activity assays show that both can act as ubiquitin donors or ubiquitin acceptors when in the activated thioester conjugate suggesting dimerization of the E2-ubiquitin conjugates. Stable disulfide complexes, analytical ultracentrifugation and small angle x-ray scattering were used to show that the HIP2-Ub and Ubc1-Ub thioester complexes remain predominantly monomeric in solution. Models of the HIP2-Ub complex derived from SAXS data show the complex is not compact but instead forms an open or backbent conformation similar to UbcH5b~Ub or Ubc13~Ub where the UBA domain and covalently attached ubiquitin reside on opposite ends of the catalytic domain. Activity assays showed that full length HIP2 exhibited a five-fold increase in the formation rate of di-ubiquitin compared to a HIP2 lacking the UBA domain. This difference was not observed for Ubc1 and may be attributed to the closer proximity of the UBA domain in HIP2 to the catalytic core than for Ubc1. PMID- 25799591 TI - Parents' beliefs and intentions toward supporting physical activity participation for their children with disabilities. AB - The purpose of this study was to examine validity and reliability evidence of a questionnaire regarding parents' beliefs and intentions toward supporting physical activity (PA) participation of their children with disabilities (CWD). A total of 220 parents of CWD in South Korea completed a questionnaire that was developed using the theory of planned behavior (TPB). Exploratory factor analysis revealed that behavioral, control, and normative beliefs accounted for 31.13%, 20.45%, and 19.63% of the total variance of the intention, respectively. Reliability of entire scale was .85 using Cronbach's alpha. Reliabilities of the 3 beliefs were .86, .82, and .87, respectively. Standard multiple-regression analysis indicated that behavioral and normative beliefs significantly predicted parents' intention, p < .01. Intention was a significant predictor of parents' behavior, p < .01. The results of this study indicated that the TPB can be useful to examine parental support for PA participation of their CWD. PMID- 25799590 TI - AUDIT, AUDIT-C, and AUDIT-3: drinking patterns and screening for harmful, hazardous and dependent drinking in Katutura, Namibia. AB - OBJECTIVES: To describe alcohol drinking patterns among participants in Katutura, Namibia, and to evaluate brief versions of the AUDIT against the full AUDIT to determine their effectiveness in detecting harmful drinking. METHODS: A cross sectional survey was conducted in four constituencies and 639 participants, 18 years or older, completed a sociodemographic survey and the AUDIT. The effectiveness of the AUDIT-C (first three questions) and the AUDIT-3 (third question) was compared to the full AUDIT. RESULTS: Approximately 40% were identified as harmful, hazardous or likely dependent drinkers, with men having a higher likelihood than women (57.2% vs. 31.0%, p<.0001). Approximately 32% reported making and/or selling alcohol from home. The AUDIT-C performed best at a cutoff >= 3, better in men (sensitivity: 99.3%, specificity: 77.8%) than women (sensitivity: 91.7%, specificity: 77.4%). The AUDIT-3 performed poorly (maximum sensitivity: < 90%, maximum specificity: <51%). According to AUROC, the AUDIT-C performed better than the AUDIT-3. CONCLUSIONS: A large proportion of participants met criteria for alcohol misuse, indicating a need for screening and referral for further evaluation and intervention. The AUDIT-C was almost as effective as the full AUDIT and may be easier to implement in clinical settings as a routine screening tool in resource-limited settings because of its brevity. PMID- 25799592 TI - Understanding dignity: experiences of impairment in an exercise facility. AB - Dignity, as an essential quality of being human, has been overlooked in exercise contexts. The aim of this interpretative phenomenological study was to understand the meaning of dignity and its importance to exercise participation. The experiences of 21 adults (11 women and 10 men) from 19 to 65 yr of age who experience disability, who attended a specialized community exercise facility, were gathered using the methods of focus-group and one-on-one interviews, visual images, and field notes. The thematic analysis revealed 4 themes: the comfort of feeling welcome, perceptions of otherness, negotiating public spaces, and lost autonomy. Dignity was subjectively understood and nurtured through the respect of others. Indignities occurred when enacted social and cultural norms brought dignity to consciousness through humiliation or removal of autonomy. The specialized exercise environment promoted self-worth and positive self-beliefs through shared life experiences and a norm of respect. PMID- 25799593 TI - Influences of physical fitness on bone mass in women with fibromyalgia. AB - The aim of this study was to provide information about the relationship of bone mineral content (BMC) and density (BMD) with some physical-fitness-related variables in a sample of women with fibromyalgia (FM) and age-matched women without FM. Twenty-eight women clinically diagnosed with FM (age 51.1 +/- 8.4 yr, M +/- SD) and 22 age-matched controls participated in the study. Whole-body BMC and BMD, lean mass, handgrip strength, quadriceps strength, and cardiovascular fitness were measured in all participants. The association between physical fitness variables and bone-related variables was tested by linear regression controlling for body weight as a possible confounder. There were no differences in BMC or BMD between groups. Women with FM had lower values of handgrip strength, quadriceps strength, and VO2peak than the control group. Handgrip strength and aerobic capacity were associated with BMC and BMD and quadriceps strength was associated with BMD in women with FM; however, only VO2peak was associated with BMC in the group of women without FM. Bone mass of women with FM may be more susceptible to changes in physical fitness than that of the women without fibromyalgia. PMID- 25799594 TI - Beliefs of chinese physical educators on teaching students with disabilities in general physical education classes. AB - This study examined the behavioral beliefs of physical education (PE) teachers about teaching students with disabilities in their general PE (GPE) classes and to identify the factors that contribute to their beliefs. A total of 195 PE teachers from a region in eastern China were surveyed. Results of the Physical Educators' Attitudes Toward Teaching Individuals With Disabilities-III survey indicate that although some teachers felt that including students with disabilities in GPE classes provides benefit for them, they were concerned about the practical difficulties of teaching students with disabilities in GPE classes, the lack of support, and the possible rejection of students with disabilities by their peers. Moreover, the behavioral beliefs of teachers vary according to the disability conditions of the students. Results show that there is no significant effect of demographic factors on the beliefs of PE teachers. Quality of experience predicts positive beliefs. The study has important implication for teacher training, provision of equipment, and support from teacher assistants. PMID- 25799595 TI - Physical activity interventions for children and youth with visual impairments. AB - The authors conducted a systematic literature review on physical activity interventions for children and youth with visual impairment (VI). Five databases were searched to identify studies involving the population of interest and physical activity practices. After evaluating 2,495 records, the authors found 18 original full-text studies published in English they considered eligible. They identified 8 structured exercise-training studies that yielded overall positive effect on physical-fitness and motor-skill outcomes. Five leisure-time-physical activity and 5 instructional-strategy interventions were also found with promising proposals to engage and instruct children and youth with VI to lead an active lifestyle. However, the current research on physical activity interventions for children and youth with VI is still limited by an absence of high-quality research designs, low sample sizes, use of nonvalidated outcome measures, and lack of generalizability, which need to be addressed in future studies. PMID- 25799598 TI - Consensus statements: applying structure. AB - The Instructions for Authors in this issue of THE JOURNAL describe a new format to be used for consensus statements.The format is epitomized in a structured abstract but affects the text itself. This Editorial explains why we are making this change, tells why each item is important, gives specific instructions for implementation, and provides examples. PMID- 25799600 TI - [In commemoration of Wang Baoen]. PMID- 25799599 TI - Vince Radke, MPH, RS, CP-FS, DAAS, CPH Sanitarian. PMID- 25799601 TI - [Long-term treatment of chronic hepatitis B]. AB - Nucleoside and nucleotide analogs (NAs) have been successfully used for treatment of chronic hepatitis B. Hepatitis B virus (HBV) replication is now recognized as the key driver of liver injury and disease progression, so the primary aim of treatment for chronic HBV infection is to maximize sustained suppression of HBV replication to undetectable levels. The long-term treatment has also been shown to achieve substantial histological improvement and regression of liver fibrosis or cirrhosis, and reduction of hepatocellular carcinoma. This paper has reviewed the necessity, clinical benefits, and the management of long-term treatment for chronic hepatitis B. PMID- 25799602 TI - [Unconditional logistic regression analysis of risk factors for nonalcoholic fatty liver disease in the Urumqi population]. PMID- 25799603 TI - [Interferon treatment of chronic hepatitis C-induced ischemic bowel disease: two case reports and a literature review]. PMID- 25799604 TI - [Diagnosis and treatment of hyperosmolar non-ketotic hyperglycemic coma induced by glucocorticoid pulse therapy for acute rejection after liver transplantation]. PMID- 25799606 TI - Vaccinations: why they still matter. PMID- 25799605 TI - [Biological function of IL-33 and hepatic fibrosis]. PMID- 25799607 TI - Contemporary diagnosis and management of Warthin's tumor. AB - OBJECTIVE: Determine if the pathophysiology of Warthin's tumor, clinical presentation, cytology, and frozen section analysis signal an opportunity for less invasive parotid surgery and reduced morbidity. STUDY DESIGN: Retrospective review of 120 human parotidectomies identified 50 consecutive Warthin's tumors. SETTING: Single surgeon, single institutional study. SUBJECTS AND METHODS: Surgeon performed ultrasound guided Fine Needle Aspiration (FNA) and intra operative frozen section with nerve integrity monitoring were used in all cases. Partial superficial parotidectomy was performed in the initial 25 patients and extracapsular dissection in the subsequent 25 patients. RESULTs: Smoking history was acknowledged in 45/50 (90 percent) of patients. The mean age was 63. Lower parotid pain and cellulitis occurred 23/50 (46 percent) and 11/50 (22 percent), respectively. Tumor in the lower parotid pole occurred in 48/50 (96 percent). Frozen section diagnosis for Warthin's tumor was confirmed by final pathology in all 50/50 (100 percent) patients. Two of 50 patients (8 percent) in the partial superficial parotidectomy group and no patient in the extracapsular dissection group had transient facial nerve dysfunction (p > 0.05). CONCLUSIONS: Warthin's tumor presents with a high rate of symptomatic inflammation, overwhelmingly in the lower parotid pole. Cytology largely excludes malignancy. Frozen section analysis diagnosing Warthin's tumor is highly specific in predicting final diagnosis. Minimally invasive approaches can be performed with confidence with extracapsular dissection or partial superficial parotidectomy resulting in potentially reduced morbidity. PMID- 25799608 TI - Patent ductus arteriosus incidentally suspected on a routine intracranial ultrasound for prematurity; confirmed on echocardiogram. AB - A patent ductus arteriosus is a very common problem in the neonatal intensive care unit. This condition is far more common among premature infants and is most likely related to physiological factors related to prematurity rather than an inherent abnormality in the ductus. At our institution, infants which are 32 weeks gestation or before undergo routine screening examinations with transcranial ultrasound to evaluate for intraventricular hemorrhage and other conditions which are related to prematurity. In this case report, during one of these routine screenings, the ultrasound demonstrated prominent pulsatility of the cerebral vascularity with a high pulsatility index and high resistive index on spectral Doppler, suggesting the presence of a patent ductus arteriosus. Subsequent echocardiography confirmed the diagnosis. PMID- 25799609 TI - Road map to developing a fellowship program in a tertiary care hospital. AB - BACKGROUND: The American Academy of Pediatrics has identified the need for more subspecialists. Beginning a pediatric pulmonary fellowship program in a tertiary care hospital can be a challenging process. Persistence, perseverance, and working through barriers to education are important strides to take toward achieving this goal. We share our experience with this endeavor. The objective of this study was to describe our experience developing a pediatric pulmonary fellowship program, the challenges we faced, and the methods we used to meet and overcome those challenges. METHODS: Self-reflection by the program director, associate director, and coordinator involved in the development and implementation of a successful fellowship program. This includes the step by step process, effort, and time commitment needed for planning and implementing a fellowship program. Our goals are to share this information with the medical community. RESULTS/OUTCOMES/IMPROVEMENTS: Planning, preparing, and implementing a pediatric pulmonary fellowship program can be challenging in the current economic climate, especially considering budget constraints and increasingly demanding clinical mandates. Department chairs and administrators view work relative value units as a marker for remuneration; educational efforts are more often an unfunded mandate. Major difficulties included imposing new educational expectations on the clinical staff and expanding the budget to include fellows' costs. Developing a program information form (PIF) was a work-in-progress over a two-year period with the dedicated staff meeting regularly during this time. PMID- 25799610 TI - Ebola and moral philosophy: the trolley problem as a guide. PMID- 25799611 TI - HHS announces timeline for accelerated transition to value-based payments in Medicare program. PMID- 25799613 TI - Eclipse and the London Veterinary College. PMID- 25799612 TI - Uncloaking cognitive decline: the emergence of canine cognitive dysfunction in veterinary medicine and its implications for understanding Alzheimer's disease. PMID- 25799614 TI - One health: back to our roots. PMID- 25799615 TI - American veterinary history: before the nineteenth century. 1940. AB - With the development of our present day domesticated animals in America (during the 16th and 17th centuries), it was not long before animal diseases became troublesome and destructive (especially during the latter half of the 18th century). Though veterinary medicine became rather firmly established in many European countries (including England) during the latter half of the 18th century, veterinary medicine was relatively nonexistent in America, with only self-styled animal doctors and farriers (with their empirical and often destructive remedies). PMID- 25799616 TI - A 'starter' bookshelf on veterinary medical history, part I. PMID- 25799617 TI - Liver transplantations in Bulgaria--initial experience. AB - The filed of liver transplantation (LT) continues to evolve and is highly effective therapy for many patients with acute and chronic liver failure resulting from a variety of causes. Improvement of perioperative care, surgical technique and immunosuppression in recent years has led to its transformation into a safe and routine procedure with steadily improving results. The aim of this paper is to present the initial experience of the transplant team at Military Medical Academy - Sofia, Bulgaria. For the period of April 2007 - August 2014 the team performed 38 liver transplants in 37 patients (one retransplantation). Patients were followed up prospectively and retrospectively. In 36 (95%) patients a graft from a cadaveric donor was used and in two cases--a right liver grafts from live donor. The mean MELD score of the transplanted patients was 17 (9-40). The preferred surgical technique was "piggyback" with preservation of inferior vena cava in 33 (86%) of the cases and classical technique in 3 (8%) patients. The overall complication rate was 48%. Early mortality rate was 13% (5 patients). The overall 1- and 5-year survival is 81% and 77% respectivelly. The setting of a new LT program is a complex process which requires the effort and effective colaboration of a wide range of speciacialists (hepatologists, surgeons, anesthesiologists, psychologists, therapists, coordinators, etc.) and institutions. The good results are function of a proper selection of the donors and the recipients. Living donation is an alternative in the shortage of cadaveric donors. PMID- 25799618 TI - Radiotherapy in the multimodality management of esophageal cancer. AB - Squamous cell carcinoma and adenocarcinoma of the esophagus represent more than 90% of all cases of esophageal carcinoma. Although the incidence of squamous cell carcinoma has decreased, a continues increase in the incidence of adenocarcinoma has been observed, due to the increasing rate of obesity and gastroesophageal reflux disease. Treatment of carcinoma of the esophagus is complex and include surgery, chemotherapy and radiotherapy. The authors investigate the role of radiotherapy in the modern multimodality treatment of esophageal carcinomain order to derive recommendations for its implementation. The results of clinical trials and meta-analysis dealing with the radiotherapy application alone or as chemoradiation in preoperative, postoperative or definitive settings are summarized. When summarizing the data from the clinical trials and the meta analyzes in esophageal carcinoma radiotherapy recommendations are drawn up. As a single modality radiotherapy is recommended only in palliative setting. Current data indicates that the neoadjuvant chemoradiation followed by the surgery is accepted as a standard treatment achieving 3-year overall survival rateraging between 30% and 60%. No improvement in local control or survival is observed when total irradiation dose is increased over 50.4Gy. Neoadjuvant or definitive chemoradiation became a standard treatmentin locally advanced tumors of the esophagus. Preoperative chemoradiation has proven contribution to improving treatment results when compared to surgery alone in both squamous cell and adenocarcinoma of esophagus. There is also a trend towards improved survival when neoadjuvant chemoradiation is applied compared to neoadjuvant chemotherapy alone. Data in favor of definitive radiotherapy as radical treatment are limited and its use is recommended only in case of palliation. PMID- 25799619 TI - Postoperative complications after Nissen fundoplication. AB - Anti-reflux laparoscopic operations replaced conventional surgery and are now widely available, because of the advantages of this type of surgery. One of the main reasons for the high complications rate in this type of operations is the lack of experience of the surgeons, although recently in the reports of most leading authors complications and increased mortality rate is due to the older patients undergoing this type of surgery. The main causes of death were gastrointestinal hemorrhage, necrosis with perforation of the esophagus or stomach, cardiac arrest, respiratory and inflammatory complications, and pulmonary thromboembolism. PMID- 25799620 TI - Advantages and disadvantages of Seldniger transthoracic drainage in purulent destructive diseases of the lung and pleura in childhood. AB - BACKGROUND: Suppurative-destructive diseases of the lung and pleura are prevalent kind of diseases occurring in children. They represent 9.1% of thoracic surgical diseases in this age. In such diseases, the pleural drainage is the most commonly used at present time. One of the methods is the transthoracic drainage by Seldinger. MATERIAL AND METHODS: Over the period of 13 years (2000-2012), 101 children with different forms of acute purulent destructive processes of the lung and pleura were treated in the Department of Pediatric Surgery of the University Hospital "St. George "- Plovdiv. We used percutaneous (transthoracic) drainage (Seldinger method) in the case of three children with lung abscess complicated pleuropneumonia with empyema. RESULTS: We achieved positive effect in treatment with all three children, without introducing additional operating procedures. CONCLUSION: There is still no consensus regarding the surgical treatment of various forms of acute suppurative-destructive diseases of the lungs and pleura (ASDDLP). Some authors attach great importance to the puncture method of treating ASDDLP, whilst they recommend the application of another treatment in case of failure. PMID- 25799621 TI - Cortisol and perioperative period. Could be certified any correlation? . AB - AIM: The purpose of this study is to investigate the correlation of general, epidural or spinal anesthesia on fluctuations of the perioperative cortisol concentrations. MATERIAL AND METHODS: Seventy five (75)--ASA physical status I, II--patients who were scheduled to undergo a medium severity surgery with general, spinal and epidural anesthesia, were enrolled in this study. These patients were divided in three groups. Twenty five (25) of these patients where received general anesthesia (group G) , twenty five (25) of these patients where received spinal anesthesia (group R) and twenty five (25) of these patients where received epidural anaesthesia (group Ep). Five blood samples were collected from each patient at intervals: A) 1h preoperative, B) immediately after the introduction in anesthesia and the intubation for group G, after the process of spinal anesthesia completion for group S and after the process of epidural anesthesia completion for group E, C) at the end of the surgery, D) 8h, and E) 24h after the operation. The quantitative determination of cortisol that was possible with the electro- chemiluminescence immunoassay method, detected the fluctuation of perioperative cortisol concentrations. RESULTS: The cortisol levels (MUg/dl) of group G were: A) 18.7056, B)18.8272, C)22.1384, D)25.232, E)19.4344. The cortisol levels (MUg/dl) of group Ep were: A)28.8132, B)22.6876, C)23.002, D)21.92, E)16.36. The cortisol levels (MUg/dl) of group R were: A)19.1688, B)16.0988, C)15.5656, D)18.5992, E)20.35. CONCLUSIONS: In conclusion we found that there is correlation between the type of anaesthesia and the fluctuation of perioperative cortisol levels. We would like to point out the fact that there is statistically significant correlation between the age and the preoperative value of cortizol concentration (Stage A) in the blood serum of the patients who participated in this study. PMID- 25799622 TI - Diagnostic imaging of intestinal malrotation in association with other inborn malformations in children and adults--case presentations and a review of the literature on the subject. AB - Intestinal malrotation is defined as a group of anomalies in the rotation and fixation of the small intestines and the colon during the embryological development. It can affect the duodenojejunal segment, the cecocolic segment or both. Its most common complication is the midgut volvulus. It is considered to be a childhood pathology, as it usually affects newborns and infants, but with the advent of modern imaging modalities in everyday practice, it is discovered in adults more often. This places it in the group of rare, but important causes for acute and chronic abdominal complaints in children and adults. When it is asymptomatic, it is hard to predict if and in whom complications will occur, which imposes the need to know its variants and diagnostic techniques to prove it. Extremely often the malrotation is associated with other inborn malformations and congenital cardiovascular defects. We report 6 cases of intestinal malrotation, diagnosed in the Medical Imaging Department of Tokuda Hospital Sofia between 2011 and 2014, in order to revise the condition's potential risks and to mark the role of the different imaging modalities in the diagnostic process. PMID- 25799623 TI - Clinical case of echinococcus of the pancreas. AB - Hydatid disease is a major health problem worldwide. Its frequency is different worldwide depending to the climate and locoregional factors. Primary hydatid disease of the pancreas is very rare. We report the case of a 61-year-old man who presented with a cystic lesion in the body and tail region of the pancreas. A diagnosis of hydatid cyst in tail region of the pancreas, measuring 55/75 mm, was established by abdominal computed tomography before surgery. The treatment consisted of a distal pancreatectomy. The postoperative period was uneventful. PMID- 25799624 TI - Mucinous cystic neoplasm of the liver with low grade dysplasia of the liver. AB - Mucinous cystic neoplasm (MCN) with low grade dysplasia of the liver is rare. It had been previously called hepatobiliary cystadenoma and is seen almost exclusively in women without an associated invasive carcinoma. There are different theories for development of MCN of the liver. One of these is developing from endodermal immature stroma or primary yolk cells implanted during embryogenesis. Another theory refers to the prevalence of hepatic mucinous cystic neoplasm in segment IV, which may support an implant origin because hamartomatous lesions commonly develop in segment IV. The third theory concerns the expression of oestrogen receptor or progesterone receptor in ovarian-like stroma, which also supports a putative role for female hormones in the tumorogenesis. MCN of the liver is a cystic-forming epithelial neoplasm, usually showing no communication with the bile ducts, composed of cuboidal to columnar, variably mucin-producing epithelium, associated with ovarian-type subepithelial stroma. We present a case of MCN with low grade dysplasia of the liver in a young woman whose working surgical diagnosis was Echinococcus cyst. The MCN diagnosis was confirmed with Immunohistochemical study. PMID- 25799625 TI - Novelty, self-determination and communication as essential traits of human action. Reflections on K. Wojtyla's theory of action. PMID- 25799626 TI - On so-called negative emotions. PMID- 25799627 TI - [The notion of extinction: the case of the aurochs]. PMID- 25799628 TI - [History of Polish botany through the correspondence of Joseph Decaisne (1807 1882), preserved at the Institute of France and the National Museum of Natural History in Paris]. PMID- 25799629 TI - Sources for the forgotten 1912 discovery of the probiotic bacterium Bacillus carpathicus in Huslanka and the forgotten discoverer: Dr. W. S. Kindraczuk: pharmacist of Lancut. PMID- 25799630 TI - Huslanka and yogurt and the comparison of the acidifiers in two types of fermented milk [1912]. PMID- 25799631 TI - A healthy South Dakota. PMID- 25799632 TI - Keeping baby safe. PMID- 25799633 TI - Infant mortality in South Dakota. PMID- 25799634 TI - A cause for concern? PMID- 25799635 TI - Regional Infant and Child Mortality Review Committee 2013 final report. AB - The Regional Infant and Child Review Committee serves 10 counties in southeastern South Dakota and its mission is to review of deaths of infants and children under the age of 18 so that information can be transformed into action to protect young lives. In 2013, the committee's interdisciplinary team reviewed 32 deaths that met its criteria. The manner of 13 of these deaths was natural, nine accidental, one homicide, five suicide, and four undetermined. There were five infant deaths during sleep and each of these occurred in an unsafe sleep environment. The number of suicides in 2013 was considerably higher than the typical one death by suicide that previously has been observed per year in the area. The report provides the Committee's recommendations for community action that could prevent future deaths of infants and children. PMID- 25799636 TI - Bowen-Conradi Syndrome: a trisomy 18-like autosomal recessive disorder common in Hutterites. AB - Bowen-Conradi syndrome (BCS) is a common lethal condition amongst infants of Hutterite ancestry. We describe a newborn infant with features of BCS, which may mimic trisomy 18 and other conditions such as cerebro-oculo-facial syndrome (COFS) and CHARGE syndrome. We describe the constellation of clinical findings in BCS. We believe this is the first case of BCS clinically confirmed by molecular testing for mutation in the EMG1 gene. PMID- 25799638 TI - Adult immunizations: an update. PMID- 25799637 TI - Review of acute coronary syndromes: diagnosis and management of unstable angina and non ST-elevation myocardial infarction. AB - Coronary artery disease (CAD) is the leading cause of death in the U.S. Acute coronary syndrome (ACS), in specific, unstable angina (UA) and a non ST-elevation myocardial infarction (NSTEMI) are life threatening conditions that need prompt diagnosis and treatment. This is the second part of a two-part review series that aims to discuss the different types of ACS. The focus of this review is UA/NSTEMI, and it provides answers to some of the fundamental questions through evidence-based guidelines. PMID- 25799639 TI - Transparency: where do you stand? PMID- 25799640 TI - The Interstate Medical Licensure Compact: what physicians should know. PMID- 25799641 TI - Patient education. The country doctor in crisis. PMID- 25799642 TI - Reimbursement for chronic care management. PMID- 25799643 TI - [The humanities at the heart of medical practice]. PMID- 25799644 TI - [Addiction]. AB - This year, the actuality about addiction is on psychopharmacology, in the controversy about the prescription of baclofene to reduce the craving for alcohol. More results from controlled studies are expected. The development of smartphones to access toe-Health skills is questionable, especially in matterofevaluation of these programs. Despite of encouraging results, open questions are remaining for clinicians, to be compared with clinical practice. Finally, it is necessary to keep in touch with translational neurosciences; in fact, research is showing that populations of addicts present a deficit in matter of empathy. This is the cause of a handicap in the social relationships. At a lower level, a difficulty to take the other's place could be the cause of this deficit at a higher level. Rehabilitation perspectives could come out of this discovery. PMID- 25799645 TI - [Allergic rhinitis: still insufficiently responsive to therapies]. AB - Allergic rhinitis is still in need of efficient therapies, in particular for its most severe manifestations, including polyposis, and despite rather satisfying treatments for the benign to moderate presentations. A better understanding of its mechanisms, although still incomplete, of its phenotypes and endotypes, a better evaluation of its severity with adequate scoring systems, and of its risk factors pave the way to innovative but eagerly awaited therapies. PMID- 25799646 TI - [Biologics in asthma: what's new?]. AB - Biologic therapies such as monoclonal antibodies are currently being developed in the field of asthma. The molecules mentioned in this article, for the majority still under development, are expected to treat certain severe asthma subgroups in a more optimal way in the near future. PMID- 25799647 TI - [Novel autoantibodies in inflammatory myopathies and systemic sclerosis]. AB - Acquired inflammatory myopathies and systemic sclerosis are chronic autoimmune conditions. These diseases arise from sustained activation of the innate and adaptive immune system, resulting in damage to blood vessels, muscles, connective tissues and internal organs. Auto-antibodies are found in a majority of cases, which makes the immune serology an important diagnostic tool. The immuno dot assays detect a variety of disease-specific-or-associated antibodies. A positive result should be correlated with the indirect immunofluorescence pattern of the antinuclear antibody screen. Some antibodies are associated with specific organ involvement, other may indicated an underlying neoplastic condition. The scope of this article is to review the diagnostic and prognostic value of antibodies in inflammatory myopathies and systemic sclerosis. PMID- 25799648 TI - [Cardiology update in 2014]. AB - Important clinical trials and therapeutic advances in the field of cardiology have been presented in 2014. New evidences on the management of acute myocardial infarction and the duration of dual antiplatelet therapy after coronary stent implantation have been published. A new class of therapeutic agents seems to offer promising perspectives for patients with heart failure and reduced ejection fraction. The new generation of subcutaneous or MRI-compatible implantable defibrillators is a major technological breakthrough. Finally, the European Society of Cardiology published new recommendations for the management of patients with cardiovascular diseases. This selective review of the literature summarizes the most important studies in the field of interventional cardiology, rhythmology, heart failure and cardiac imaging. PMID- 25799650 TI - [Dermatology: re-defining psoriasis]. AB - Psoriasis has long been regarded to be one entity, comprising both plaque-type and non plaque-type manifestations. Genetic studies now provide evidence that some pustular forms should be classified separately: a mutation in the gene encoding for the interleukin 36 receptor antagonist (IL36Ra) was f6und to be associated with generalized pustular psoriasis (GPP) in several Tunesian families. This finding was subsequently confirmed in different psoriasis cohorts around the world. Additionally, gain-of-function mutations in the gene for CARD 14 were identified. Clinical implications comprise a different approach to treat GPP through blocking interleukin 1beta. PMID- 25799649 TI - [Novelties in surgery in 2014]. AB - In 2014, surgical management of complex digestive pathology requires a multimodal approach. The association of chemotherapy combined with surgery allows obtaining promising 5 years survival, particularly for borderline adenocarcinoma of the head of the pancreas or for liver metastasis. The incremental use of cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy provides a clear benefit in long-term survival for selected patients with primary or secondary peritoneal carcinomatosis. Finally, the use of Enhanced recovery pathways (ERAS) after surgery is now validated in colorectal surgery, and the preliminary results in hepato-biliary and pancreatic surgery are very promising. The implementation of ERAS provides a reduction in hospital stays, postoperative complications and costs, even in elderly patients. PMID- 25799651 TI - [News in diabetology]. AB - News on the front of diabetes have revealed the remarkable results of multifactorial treatment of type 2 diabetes on morbidity and mortality. Micro and macro-angiopathic complications have markedly decreased during the last 20 years. However, intervention trials on glycemic control alone show a slight or no benefit on cardiovascular complications or mortality when intensive treatment aims at HbA1c below 7.0-7.5%. Life adaption remains a critical part of diabetes treatment to decrease cardiovascular risk. Recent knowledge on nutrition and meal frequency has taught us to distrust old dogmas. PMID- 25799652 TI - [News in endocrinology: Management of asymptomatic primary hyperparathyroidism in 2014]. AB - Primary hyperparathyroidism, a disorder in wich there is a hypercalcemia caused by autonomous hypersecretion of parathormone, usually by parathyroid adenoma. It is asymptomatic in most cases. After excluding a cause of secondary elevation of parathyroid hormone, a search for renal stones and osteoporosis has to be done. The treatment of choice is parathyroidectomy and it is recommended in case of complications, hypercalcemia with calcium up to 0.25 mmol/l higher than the upper limit and in patients <50 years. Specific pharmacological approaches (bisphosphonate or cinacalcet) may be of value if the patient meet surgical guidelines but is not a candidate for parathyroid surgery. Patient who do not meet surgical indications should be monitored. PMID- 25799653 TI - [Review in geriatric medicine 2014]. AB - Several studies contributed to improving the diagnostic and prognostic assessment of delirium in hospitalized older patients. Direct patient education proved efficient in benzodiazepines withdrawal. A position statement of the American Geriatrics Society does not recommend tube feeding when eating difficulties arise in older persons suffering from advanced dementia. Several studies emphasized once again the potential importance of preventative interventions (in particular physical activity) to prevent or delay dementia occurrence. Two randomized controlled trials of monoclonal antibodies that bind amyloid did not show benefit in patients with mild-to-moderate Alzheimer's dementia (AD). In contrast, vitamin E reduced functional decline in these patients, and citalopram reduced agitation among AD patients as well as their caregiver's stress. PMID- 25799654 TI - [Pregnancy care in women older than 40 years and after egg donation]. AB - Pregnancies in older women are increasing. These women often have comorbidities. These pregnancies, spontaneous, after IVF or egg donation are at high risk of complications, particularly hypertension, preeclampsia, gestational diabetes, low birth weight, and delivery by cesarean section. Women with Turner syndrome can conceive only by egg donation and are at very high risk of cardiovascular complications. Screening of these comorbidities and pregnancy care by maternal fetal medicine specialists, with pluridisciplinary collaboration, are mandatory. Delivery in a tertiary care center able to offer optimal care to the mothers and their newborns is recommended. PMID- 25799655 TI - [Infections disease update: 2014 is viral]. AB - Chikungunya's phenomenal dissemination imposes now infection suspicion when returning from endemic areas. Colorectal cancer screening may be dependent of the microbiome. Even a small amount of E. coli in catheter sampled urine is predictive for a urinary infection. Prevention of pharyngitis suppurated late complications doesn't justify systematic antimicrobial therapy. A bitherapy is probably better for severe community acquired pneumonias. Due to epidemiology and resistances, management of gonorrhoea has changed. Enterovirus 68 is particular because of its almost exclusive lung tropism in children. The question is no longer how to treat hepatitis C but which patients to treat and when. Pritelivir clearly improves herpes genitalis symptoms. The first confirmed case of Ebola has reach our contry. PMID- 25799656 TI - [A new perspective in adolescent contraception--why prescribe an IUD first?]. AB - Adolescent girls are very fertile and therefore need a reliable contraceptive strategy in order to prevent unwanted pregnancies. Although highly recommended by international gynecological and adolescent societies and in spite of its high efficiency, good tolerance and ease of use, only minority of adolescents use IUD as a contraceptive method. This article will focus on available IUDs suitable for adolescents and will address misconceptions and barriers to use of IUDs in this age group. We believe this information will encourage physicians in recommending IUD use to adolescents during their most vulnerable years. PMID- 25799657 TI - [Emergency medicine: updates 2014]. AB - The year 2014 was marked by new therapeutic acquisitions in emergency medicine. Nephrolithiasis likelihood estimation should avoid imaging in patients at high risk. Therapeutic hypothermia post cardio-respiratory arrest has no benefit compared to a strategy of controlled normothermia. Treatment of acute bronchitis with no signs of severity by coamoxicillin or NSAIDs is useless. Adding colchicine to standard treatment of acute pericarditis reduces the rate of recurrence. The D-dimerthreshold adjustment by age reduces the number of imaging in case of low or intermediate risk of pulmonary embolism. Finally, the speed of the initial management of septic shock is crucial to the outcome of patients, but an early invasive monitoring provides no benefit. PMID- 25799658 TI - [Nephrology: news in renal transplantation]. AB - The selection of potential living donors will have to consider the latest data on risk factors for morbidity and mortality when a first degree relationship exists with a recipient in end-stage renal disease of unknown, and for women of childbearing age. Renal transplant patients with active hepatitis C of unknow origin will benefit from new antivirals without the risk of acute rejection. Preemptive CYP3A5 genotyping and extended-release tacrolimus formulations should allow the prescription of a suitable dose of tacrolimus immediately and avoid overexposure as a source of nephrotoxicity. The place of everolimus and belatacept in the panel of immunosuppressive treatments is being defined, based on infectious and immunologic risk factors. PMID- 25799659 TI - [News in neurology 2014]. AB - In 2014, breastfeeding during maternal antiepileptic therapy seems to be safe for the children and can be recommended. Intravenous thrombolysis by Alteplase improves the outcome after a stroke if administered within 4.5 hours and it is also recommended in elderly population over 80 years. ProSavin genic therapy for Parkinson disease is under investigation. The Transcranial Magnetic Stimulation (TMS) has an analgesic effect in neuropathic pain as well as an antidepressant effect. Antagonists of calcitonin gene-related peptide can have a beneficial role in migraine prevention. Diagnostic biomarker panels for Alzheimer disease are under investigation. Oral teriflunomide and dimethyl fumarate (BG-12) for relapsing multiple sclerosis treatment are now available in Switzerland. PMID- 25799660 TI - [Oxytocin: metabolic effects and potential use for obesity treatment]. AB - Oxytocin is a hormone known for a long time, mainly used in the field of gynecology. Apart from these well-defined effects, the role of oxytocin in controlling the stress response or behavior and the regulation of glucose/lipid metabolism seems to be very interesting, especially in obese patients. Several clinical studies are currently underway to assess the impact of oxytocin in the treatment of obesity. Taking these new data into consideration, the use of this hormone for weight loss in obese patients or as a complementary treatment in diabetic patients seems to be promising. PMID- 25799661 TI - [Diabetic retinopathy: new therapeutic possibilities]. AB - Diabetic retinopathy affects an increasing number of persons, about 4 millions in Europe, a number that will probably double until 2030. If we consider that 25-30% of patients are affected by diabetic retinopathy, an ophthalmologic screening and early therapy will allow a better visual prognosis and avoid severe ocular complications such as diabetic macular edema and proliferative diabetic retinopathy. A summary of current ophthalmologic literature was performed and was focused on the role of anti-VEGF (vascular endothelial growth factor) therapies and intraocular drug delivery of corticosteroids in a pathology that was recently classified in inflammatory pathologies. PMID- 25799662 TI - [Osteoporosis]. AB - Bone events related to bariatric surgery remain controversial. Denosumab, used in osteoporosis treatment, is safe and efficient. Romosozumab, an antibody raised against sclerostin, is a promising bone anabolic agent. Odanacatib, a cathepsin-K inhibitor, decreases bone resorption and reduces osteoporotic fracture risk. Denosumab, as bone resorption inhibitor, and Teriparatide, as anabolic agent, have been tested together in patients with osteoporosis. Calcium supplements and cardiovascular risk are still debated. Drug holiday, after long-term treatment with bisphosphonates, is not associated with an increased fracture rate in patients with moderate risk. PMID- 25799663 TI - [Inguinal hernias in girls: is caryotype necessary?]. AB - The incidence of inguinal hernias in children is 1-4% with predominance in boys (10 to 1). Based on the data, 0.8-2.4% of premenstrual girls presenting with inguinal hernias have a complete androgen insensitivity syndrome (CAIS). On the other hand, 80-90% of girls with CAIS present uni- or bilateral inguinal hernias. Unfortunately, this burdened pathology is very rarely looked for by pediatricians, or paediatric surgeons. PMID- 25799664 TI - [Sport medicine consultation for adolescents]. AB - Sport activity is a determinant of health and well-being for adolescents' psychological and physic development. Early detection of traumatic lesions or pathological condition among sportive adolescent in the light of their developmental stage is of outmost importance and is best done by an interdisciplinary team. This clinical management also aims at preventing consequences of inappropriate training. The CHUV has set-up a specific sports medicine outpatient consultation clinic for adolescents in the order to provide the best integrative management of young athletes. PMID- 25799665 TI - [Adolescents and electronic cigarettes]. AB - The use of electronic cigarettes (vaping) is increasing among young people and health professionals feel ill-prepared. This short article provides some practical information. PMID- 25799666 TI - [Paediatric emergency: creation of an independent nurse practitioner consultation]. AB - Consultations in the Paediatric Emergency Department (PED) continue to climb regularly. Emergency Nurse Practitioner consultations have long been created in the English speaking countries. Since January 2013, an indepen- dent nurse consultation, under delegated medical responsibility, exists in the multidisciplinary PED of the Children's Hospital of Lausanne. The mean consultation time is the same as the medical consultation and the overall waiting time hasn't decreased yet. But a well definite working frame, a systematic approach, as well as the continual medical supervision possibility, make it a safe, efficient and appreciated consultation, by both patients and professionals. PMID- 25799667 TI - [Which maintenance intravenous fluid in paediatrics in 2015?]. AB - For 50 years, hypotonic solutions have been used as liquid of maintenance in paediatrics owing to the article of Holliday and Segar. For two decades, studies have shown that these hypotonic fluids can foster the acquisition of hyponatremias. The most recent literature data (meta-analysis and randomized studies) confirm that hypotonic fluids are not suitable for children hospitalized with surgical or medical problems. Current recommendations must take these results into account and advocate the use of isotonic saline solutions as maintenance intravenous fluid therapy. PMID- 25799668 TI - [Pharmacovigilance update]. AB - The main pharmacovigilance updates in 2014 are reviewed. Ivabradine: increased risk of cardiovascular death and myocardial infarction in patients with symptomatic angina treated with high dosages. Clopidogrel: rare observations of acquired hemophilia. Orlistat: may reduce the absorption of HIV antiretrovirals. Ponatinib: increased risk of arteriopathy and thrombosis. Axitinib: significant risk of heart failure (class effect). Tocilizumab: possible causal relationship with the emergence or aggravation of psoriasis. Lithium: hypercalcemia and hyperparathyroidism commonly observed. Sildenalfil: suspected causal association with melanoma, so far not proven, Methylphenidate: rare observations of priapism. St John's wort (Hypericum): reduced effectiveness of hormonal contraceptives, including implants. PMID- 25799669 TI - [New therapeutic approaches in 2014 in pulmonary medicine: COPD, asthma and lung fibrosis]. AB - In 2014, among new therapeutic approaches in pulmonary medicine, the role of inhaled corticosteroids has to be revaluated after the publication of the WISDOM and other studies. Their prescription should no longer be systematic even for "at risk" groups of patients, as defined by the GOLD consensus, but rather be considered on an individual basis. In the field of asthma, two major studies confirm the efficacy of mepoluzimab for the treatment of severe, eosinophilic asthma. Finally, for idiopathic pulmonary fibrosis, 2014 has taught us that treatment with N-acetylcystein is of no proven benefit, while pirfenidone and nintedanib are two new drugs that may attenuate the downhill course of the disease. PMID- 25799670 TI - [New developments in psychiatry]. AB - In this review of recent therapeutic developments in psychiatry, we will report on three domains where new strategies have been proposed. First we will discuss the concept of neuroprotection in patients at "ultra high risk" to develop psychosis and the encouraging results of a randomised controlled trial comparing the effect of placebo and fish oil. We will then present the impact of metacognition programs which aim at adding some flexibility to thought processes used by patients with psychosis in order to reduce psychotic symptoms. We finally will report on a program of supported employment which was developed in order to help patients find an active place in society. PMID- 25799671 TI - [Update in psoriatic arthritis treatment]. AB - Psoriatic arthritis is a chronic inflammatory disease. It affects up to 40% of patients suffe- ring from skin psoriasis. Joint involvement is relatively heterogeneous. Some clinical manifestations are similar to those of rheumatoid arthritis, others are close to spondylarthritis manifestations and are therefore considered as part of this entity. Treatment depends on initial presentation (peripheral or axial) but often begins with non-steroidal anti-inflammatory drugs and methotrexate, followed by anti-TNFalpha if needed. New therapeutic op- tions are available or under evaluation, parti- cularly targeting cytokines involved in psoriatic arthritis (IL-12/IL-23 and IL-17). PMID- 25799672 TI - [Urology]. AB - This article is addressed to general practitioners and summarizes some of the latest developments in urology. Recent advances in screening, diagnosis and medical as well as surgical treatments of common urological diseases are reviewed. PMID- 25799673 TI - [What's new in HIV in 2014?]. AB - The latest UNAIDS GAP report suggests the end of the HIV/AIDS epidemic by 2030 based on the progress in the fight against the disease during recent years. While the number of new infections and deaths related to HIV has decreased globally, more than half of people living with HIV do not know that they are infected with the virus. HIV testing and early initiation of antiretroviral therapy are both crucial elements in transmission prevention. Many treatment regimens are now available with new fixed dose combinations and new drugs that are better tolerated and with fewer drug interactions. A world without HIV will be possible only with an effective vaccine and cure--these are still hypothetical--and will require removal of societal, economical and political barriers. PMID- 25799674 TI - [Whose dignity? The dignity of a few hundred who committed suicide voluntarily or the dignity of 60,000 people who die each year in Switzerland?]. PMID- 25799675 TI - [Blood pressure: the proven virtues of medicalized self-measurement]. PMID- 25799676 TI - [Ethics as user instructions]. PMID- 25799677 TI - [Cancer: is scientific truth compatible with public health?]. PMID- 25799678 TI - [Can we improve the control of hypertension by involving patients?]. PMID- 25799679 TI - [Ebola will remain current throughout all of 2015]. PMID- 25799680 TI - [Mauro Poggia signs an agreement with private clinics]. PMID- 25799681 TI - [Alain Berset wants to reduce the number of optional deductibles]. PMID- 25799682 TI - [Freedom, whatever its cost]. PMID- 25799683 TI - [Prevalence of no alcohol fatty liver disease (NAFLD) in a population of obese children in Valencia, Venezuela]. AB - No Alcoholic Fatty Liver Disease (NAFLD) is characterized by an abnormal accumulation of fat in hepatocytes, without alcohol, where overweight and obesity are determinants. Ecosonografia evaluated the prevalence of fatty liver in obese pediatric patients and its relation to nutritional assessment. The sample consisted of 85 children (51 females, 34 males), age 3-17. The abdominal ecosonography, BMI, waist circumference were performed; Godard Test for physical activity, history of diabetes, dyslipidemia, obesity and cardiovascular disease were questioned. Lipid profile, glucose and insulin resistance were determined. Data analyzed from descriptive and comparative tables. We obtained: mean age 9.8 +/- 2.7 females and males 9.6 +/- 2.7 years. The ecosonography indicated 50% and 50% fatty liver-pancreas fatty liver in children aged 3-6 years; 7-11 years 39.7% fatty liver-pancreas; 12-17yrs 31.6% fatty liver-pancreas (p > 0.05); BMI > 26 kg/m2 42.9% fatty liver-pancreas; 21 to 25 kg/m2 44.7% fatty liver; 15 to 20 kg/m2 60%fatty liver-pancreas (p> 0.05). 97.6% with high CC; 68.2% with inadequate physical activity; high frequency of history of chronic non communicable diseases. We concluded that this population had predominantly fatty liver fatty replacement of the pancreas (HG-RGP) in the groups with higher BMI, CC and high male unrelated insulin resistance, altered lipid profile and diagnosis HG. We inferred that the anthropometric assessment of waist circumference and abdominal ecosonography indicate the presence of visceral obesity, a condition that predisposes to hepatic steatosis, pancreas and/or liver pancreas. PMID- 25799684 TI - [Analysis of the recommendations for cancer prevention given by the global fund for research on cancer (FMIC) and the situation in Chile]. AB - Cancer is one of the most important causes of death in the world corresponding to 63% annually, is the second in the Americas with 1.2 million deaths in 2008 and Chile in 2007 representing 25.6% of all deaths. Obesity is associated with a third of all cancers and is associated with body fat, abdominal fat, weight gain in adulthood, all modifiable factors through a healthy diet pattern and physical activity. The aim was to analyze the recommendations of Public Health issued by the International Fund for Cancer Research (WCRF) and American Institute for Cancer Research (AICR) in 2007 to prevent cancer. Compare the recommendations of the report Food, Nutrition and physical activity and cancer prevention: a global perspective, "with the national situation regarding these recommendations. Then, we propose national recommendations in accordance with the proposals of WCRF. The analysis reveals that Chile has a population level cancer risks associated with lifestyle, diet, body mass index and physical inactivity. The pattern of food consumption and nutritional profile and behaviors associated with the lifestyles of the population does not reflect the recommendations of international organizations, on the consumption of protective (vegetables, fruits high in antioxidants, fiber) and high risk (sugary drinks and juices, processed, high in sodium, total fat). Is required to educate people about healthy eating and lifestyles to maintain health PMID- 25799685 TI - Dietary quality improvement after a short-term nutritional counseling program in individuals with metabolic syndrome. AB - Metabolic Syndrome is a complex clinical condition that brings together a set of cardiovascular risk factors. Lifestyle changes, such as eating habit improvements, are first-choice therapies for the treatment of this clinical condition. This study aimed to evaluate the effect of short-term nutritional counseling, on the diet quality and total energetic value (TEV) in individuals with Metabolic Syndrome. Eighty subjects (men and women) aged 30 to 60 years with metabolic syndrome were followed over three months. The Healthy Eating Index tool adapted to the Brazilian population was used for the evaluation of diet quality. Mean age was 51 + 6 years, and 68.6% were women. The mean score of the dietary quality of the population studied increased significantly from 53.02 to 61.65 after intervention. The amount of individuals classified as Inappropriate Diet decreased significantly six-fold, the amount of individuals classified as Healthy Diet increased four-fold, and the percent of diets classified as Diet that Needs Change decreased by 25% when compared to the beginning of the study. Adequate intake of vegetables was inversely associated to abdominal circumference, as well as adequate intake of sodium and fasting serum insulin. The amount of TEV presented a significant reduction (p <0.000) after intervention. The short-term nutritional counseling showed to be efficient to improve dietary quality. Associations between dietary quality and variables studied highlight the importance of nutritional intervention in individuals with metabolic syndrome. PMID- 25799686 TI - [Adolescent pregnancy: maternal characteristics and their association with birth weight of the newborn]. AB - In Colombia, adolescent pregnancy is a public health problem, with serious implications for the health and nutrition of the binomial mother-child. OBJECTIVE: assess socio-demographic, economic, food security, health and maternal nutritional status characteristics by anthropometric measures in a group of pregnant adolescents in Medellin-Colombia on their third trimester of pregnancy and associate them with the newborns weight. METHODS AND MATERIALS: A cross sectional analytical study was made with 294 pregnant women (week 27 to 40), who participating in prenatal control program of the public hospital network in Medellin-Colombia. We sought Association of weight at birth with the explanatory variables. RESULTS: underweight in pregnant women was presented in families that had lower income wages than the Standard Minimum Wage Income--SMWI-, adolescents who were younger than 15 years old and those who had a gynecological age less than five years. In newborns, the highest proportion of small children for pregnancy age was found in mothers who presented infections, low pregnancy weight and low family income less than the minimum wage. For those whose earnings was less than the minimum income the newborn weight decreased 118g (CI 95%: -2.5 a - 234.7), in addition, for each kilogram that increased the pre-pregnancy weight, newborn weight increased in 10,26g (CI 95%: 1.98 a-18.5). CONCLUSIONS: low-weight pregnancy and low-weight newborns are associated with low family income. Pre pregnancy weight, body mass index in the third trimester of pregnancy and mother's presence of urinary tract and vaginal infections were associated with the newborn's weight. PMID- 25799687 TI - Molar ratio iron: zinc and folic acid in Brazilian biscuits and snacks and test for classification using principal component analyses. AB - The aim of the present work was to evaluate molar ratio iron: zinc and the levels of folic acid in biscuit and snacks commercialized in Brazil, prepared with folic acid and iron fortified flours. These nutrients are important for human nutrition; however, iron can have a negative effect on zinc absorption. Molar ratio iron:zinc can indicate if there will be any problems for absorption of these nutrients. The folic acid content varied from 58 to 433 MUg/100 g and iron and zinc levels varied from 2.9 to 9.4 mg/100 g and from 0.2 to 1.3 mg/100 g, respectively, for 75 analyzed samples. The average iron contents observed in the products and molar ratio iron:zinc (in average 8:1 for biscuits and 12.8:1 for snacks) could result in problems with the zinc absorption. Moreover, principal compo- nent analyses (PCA) indicated low uniformity in the distribution of minerals and vitamin in the majority of the samples, mainly among brands. The results indicated that for the majority of the samples tested folic acid and iron content was higher than expected for flours and could be useful to governmental authorities in their evaluation program of flour fortification. PMID- 25799688 TI - Comparative study on the nutritional and antioxidant properties of two Mexican corn (Zea mays) based meals versus processed cereals. AB - The present study was conducted to analyze the chemical composition, total phenolics content and antioxidant capacity of two whole corn (Zea mays) based meals traditional from Mexico: "traditional pinole" and "seven grain pinole"; and compare it with information available from ready to eat cereal products based on refined corn and whole grain cereals. Proximate analyses (moisture, ash, fat, protein and fiber) were carried out according to the procedures of AOAC, sugars content was determined by HPLC method; calcium and iron were quantified using atomic absorption spectroscopy. Total phenolic compounds were determined by Folin Ciocalteu spectrophotometric method; the antiradical capacity was determined by DPPH colorimetric method and total antioxidant capacity was determined by FRAP method. Traditional and seven grain pinole presented higher energy content and nutrient density (protein and fat) than processed cereals. Calcium content was higher in processed cereals than pinole; seven grain pinole presented the highest conentration of iron. Polyphenolic concentration was higher in both kinds of pinole compared to processed cereals; traditional pinole presented the highest antioxidant activity measured by DPPH and FRAP methods. The results provide evidence about the important nutrient and antioxidant content of traditional and seven grain pinole compared to processed cereals based on corn and other grains. It is recommended their incorporation in to regular diet as a healthy food, with a good protein level, low sugar content and good antioxidant capacity. PMID- 25799689 TI - [Husk of Venezuelan cocoa as raw material of infusions]. AB - In the cocoa bean industry, some by-products go underutilized. Some of these components could provide other innovative products, and such is the case with the husk of the cocoa bean. Previous studies have attributed the husk with a high antioxidant capacity, which added to its relative low cost, makes it an attractive ingredient for the production of infusions. However, prior to promoting it as such, its quality needs to be guaranteed. This study evaluated the chemical composition of the husk of cocoa, its microbiologic quality and other parameters in order to be considered raw material in the preparation of infusions. The cocoa was cultivated in two different states in Venezuela. Moisture, protein, fat, ash, carbohydrates, microbiologic quality and ochratoxin A as well antioxidant properties, content of foreign matter, insoluble ash in HCL and aqueous extract were evaluated in the husk of cocoa seeds. Applied methods were in compliance with national and international norms. Significant differences were determined between the samples through the ANOVA application. A low level in moisture content, but high in ash, along with a microbiologic quality that met the norm, and an absence of ochratoxin A were observed in the totality of the analyzed samples. Low levels of foreign matter, the high value of its aqueous extract and high phenolic compounds content with antioxidant activity allow for the recommendation of the husk of cocoa as raw material for the preparation of infusions. PMID- 25799690 TI - [Chemical characterization and quantification of fructooligosaccharides, phenolic compounds and antiradical activity of Andean roots and tubers grown in Northwest of Argentina]. AB - There is great interest in consuming foods that can provide the nutrients for a good nutrition and other health beneficial compounds. The aim of this work was to determine the chemical composition of native foods of the Andean region and to quantify some functional com-ponents. Proximal composition, vitamin C, total phenolic compounds, antiradical activity (DPPH) in peel and pulp, dietary fiber soluble and insoluble, fructooligosaccharides (FOS), total and resistant starch (in tubers and raw roots, boiled and boiled and stored) of 6 varieties of Oca (Oxalis tuberosa), 4 clones of manioc (Manihot esculenta Crantz) and yacon (Smallanthus sonchifolius were determined. The results showed greater amount of bioactive compounds and antiradical activity in the skin of these products. The highest content was found in the oca peel. In all cases, the content of insoluble fiber was greater than the soluble. The manioc had higher total starch than Andean roots and tubers. The boiling process decreased the resistant starch content of ocas and maniocs, but when these are stored for 48 h at 5 degrees C, the resistant starch content increased. The FOS content of the ocas was similar for all varieties (7%). The main component of yacon carbohydrates were FOS (8.89%). The maniocs did not contain FOS. It can be concluded that the roots and tubers studied, in addition to provide nutrients, contain functional compounds that confer additional helpful value for preventing no communicable diseases. PMID- 25799691 TI - Timely topics and varied approaches characterize issue. PMID- 25799692 TI - Mentorship, teamwork, and the doctor of nursing practice capstone project: a personal perspective. PMID- 25799693 TI - Korean immigrant women's physical activity experience: a situation-specific theory. AB - To develop successful physical activity promotion programs for midlife immigrant women, especially for Korean immigrant midlife women, concrete theoretical bases are needed. However, virtually no theoretical frameworks and/or theories exist that can explain the influences of immigration transition on the physical activity experience of midlife immigrant women in general or Korean immigrant midlife women in specific. The purpose of this article is to present a situation specific theory on physical activity experience of Korean immigrant midlife women (SPAKIM) with its development process. An integrative approach was used to develop the theory based on the midlife women's attitudes toward physical activity (MAPA) theory, the transitions theory, a review of the relevant literature, and two studies on midlife women's attitudes toward physical activity. The proposed theory includes nature of transitions, nonmodifiable and modifiable transition conditions, contexts of daily life, patterns of response, and nursing therapeutics as major concepts, and each major concept includes several related subconcepts. Because several concepts of the theory were developed mainly based on the literature review, the major concepts and related subconcepts need to be further developed and evaluated in future studies. PMID- 25799694 TI - Liminality in cultural transition: applying ID-EA to advance a concept into theory-based practice. AB - As global migration increases worldwide, nursing interventions are needed to address the effects of migration on health. The concept of liminality emerged as a pivotal concept in the situation-specific theory of well-being in refugee women experiencing cultural transition. As a relatively new concept in the discipline of nursing, liminality is explored using a method, called ID-EA, which we developed to advance a theoretical concept for application to nursing practice. Liminality in the context of cultural transition is further developed using the five steps of inquiry of the ID-EA method. The five steps are as follows: (1) inductive inquiry: qualitative research, (2) deductive inquiry: literature review, (3) synthesis of inductive and deductive inquiry, (4) evaluation inquiry, and (5) application-to-practice inquiry. The overall goal of this particular work was to develop situation-specific, theory-based interventions that facilitate cultural transitions for immigrants and refugees. PMID- 25799695 TI - Exploring mHealth as a new route to bridging the nursing theory-practice gap. AB - The purpose of this article is to evaluate mHealth as a tool for research and development of nursing theories. Mobile health (mHealth) is one of the most promising new advances in health care technology. mHealth is defined as the use of mobile technology in the provision of health care delivery or health promotion (Qiang, Yamamichi, Hausman, & Altman, 2011). The need for innovative and effective interventions for the prevention and management of chronic illness is evident. The use of mHealth interventions in the treatment and monitoring of chronic illness is still young but shows great promise. Currently, the public health and psychological sciences are using their theories to guide interventional studies by operationalizing concepts through mHealth's multifaceted capabilities for patient interaction. Outcomes measures from chronic illness-mHealth studies are thematically evaluated by using theoretical nursing outcome-related concepts of Meleis's transitions theory and Mishel's uncertainty in illness theory. Despite a small sample of articles, there are strong themes of activation and engagement within this literature review. The application of nursing theory in mHealth offers a new method to operationalize theoretical concepts, test theory-based interventions, and gain new contextual insight into the health-illness patient experience. PMID- 25799696 TI - Patient safety culture and nurse-reported adverse events in outpatient hemodialysis units. AB - AIMS: Patient safety culture is an important quality indicator in health care facilities and has been associated with key patient outcomes in hospitals. The purpose of this analysis was to examine relationships between patient safety culture and nurse-reported adverse patient events in outpatient hemodialysis facilities. METHODS: A cross-sectional correlational, mailed survey design was used. The analytic sample consisted of 422 registered nurses who worked in outpatient dialysis facilities in the United States. The Handoff and Transitions and the Overall Patient Safety Grade scales of the Agency for Healthcare Research and Quality's (AHRQ) Hospital Patient on Safety Survey were modified and used to measure patient safety culture in outpatient dialysis facilities. Nurse-reported adverse patient events was measured as a series of questions designed to capture the frequency with which nurses report that 13 adverse events occur in the outpatient dialysis facility setting. RESULTS: Handoff and transitions safety during patient shift change in dialysis centers was perceived negatively by a majority of nurses. On the other hand, a majority of nurses rated the overall patient safety culture in their dialysis facility as good to excellent. All relationships between patient safety culture items and adverse patient events were in the expected direction. Negative ratings of handoffs and transitions safety were independently associated with increased odds of frequent occurrences of vascular access thrombosis and patient complaints. Negative ratings of overall patient safety culture in dialysis units were independently associated with increased odds of frequent occurrences of medication errors by nurses, patient hospitalization, vascular access infection, and patient complaints. CONCLUSION: Findings from this analysis indicate that a positive patient safety culture is an important antecedent for optimal patient outcomes in ambulatory care settings. PMID- 25799697 TI - Frailty in older adults: an evolutionary concept analysis. AB - The term frailty is often used to describe a subset of the older population with complex health issues. It is associated with dependence, disability, increased health care use, and mortality. An emergent problem is the lack of consensus as to the etiology and definition of frailty. The purpose of this concept analysis is to clarify the concept of frailty in the context of older adults and propose a definition of frailty that may be relevant to identification of frail older adults. The results from this analysis conclude frailty in older adults is a tenuous state of health that is the result of the complex interplay of physiological, psychosocial, and environmental stressors that increases an older adult's susceptibility to adverse health outcomes. PMID- 25799698 TI - Emergency department management of seizures in pediatric patients. AB - Seizures account for 1% of all emergency department visits for children, and the etiologies range from benign to life-threatening. The challenge for emergency clinicians is to diagnose and treat the life-threatening causes of seizures while avoiding unnecessary radiation exposure and painful procedures in patients who are unlikely to have an emergent pathology. When treating patients in status epilepticus, emergency clinicians are also faced with the challenge of choosing anticonvulsant medications that will be efficacious while minimizing harmful side effects. Unfortunately, evidence to guide the evaluation and management of children presenting with new and breakthrough seizures and status epilepticus is limited. This review summarizes available evidence and guidelines on the diagnostic evaluation of first-time, breakthrough, and simple and complex febrile seizures. Management of seizures in neonates and seizures due to toxic ingestions is also reviewed. PMID- 25799699 TI - Optimal timing of valve replacement in asymptomatic severe aortic stenosis. AB - Patients with asymptomatic severe aortic stenosis (AS) constitute a heterogeneous group which includes not only certain cases who are at high risk of sudden death and valve-related heart failure, but also those at low risk for these events. Degenerative AS, which includes a majority of patients with AS, is characterized by stricture of the valve, increased arterial stiffness, and diverse left ventricular response to the valvular plus arterial vascular load. In addition to using traditional primary parameters, the severity of AS and the total left ventricular load should be assessed using new measures such as energy loss index and valvulo-arterial impedance. Natriuretic peptide levels and global longitudinal strain imaging may also be used as secondary parameters to obtain information about left ventricular systolic function, although these parameters do not correlate with the severity of AS. Exercise stress testing and exercise echocardiography are also beneficial when assessing the patient if they are symptomatic, and for determining valvular and left ventricular contractile reserves. The aim of this review was to emphasize the importance of risk stratifications in asymptomatic severe AS cases, and to assess the severity of AS using not only conventional methods but also new methods on which much emphasis has been placed during recent years. PMID- 25799700 TI - Transcatheter aortic valve implantation with a giant vegetation successfully treated with antibiotics: insights into a new group of patients with endocarditis. AB - During recent years, transcatheter aortic valve implantation (TAVI) has become an alternative therapeutic option for patients with severe symptomatic aortic stenosis who are at high surgical risk. Although infective endocarditis (IE) is a potential and serious complication in this group of patients, the best therapeutic approach for IE in patients with TAVI has not been well established. Here, the case is reported of a patient with a giant vegetation after TAVI infection that was successfully treated without surgery. The hope is to provide some clinical insight into this new group of patients with IE. PMID- 25799701 TI - B-type natriuretic peptide is a strong independent predictor of long-term outcome after transcatheter aortic valve implantation. AB - BACKGROUND AND AIM OF THE STUDY: The aim of this prospective study was to determine the impact of plasma B-type natriuretic peptide (BNP) on long-term outcome in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: TAVI was performed either transfemorally or transaxillary using either the CoreValve prosthesis or Edwards SAPIEN prosthesis in 226 patients with symptomatic severe aortic valve stenosis and at high surgical risk. The examinations included measurements of plasma BNP and echocardiography before and at 30 days after TAVI. The primary study end-point was death from any cause after TAVI; the secondary end-point was defined as cardiovascular death. RESULTS: During a mean follow up of 728 +/- 549 days, 72 patients died; 52 deaths were cardiovascular-related. Those patients who died had higher preprocedural plasma BNP levels compared to those who survived (1,305 +/- 1,238 pg/ml versus 716 +/- 954 pg/ml; p < 0.001). Plasma BNP was the strongest independent predictor of all cause mortality (BNP > 475 pg/ml, hazard risk [HR] 3.049; 95% confidence interval [CI] 1.804-5.151; p < 0.001) and cardiovascular mortality (BNP > 475 pg/ml, HR 3.479; 95% CI 1.817-6.662; p < 0.001). In surviving patients, plasma BNP levels were decreased by 30 days after TAVI (pre-TAVI 874 +/- 1,122 pg/ml; post TAVI 471 +/- 569 pg/ml; p < 0.001). A plasma BNP level > 328 pg/ml at 30 days postoperatively was also associated with all-cause mortality (HR 8.125; 95% CI 3.097-21.318; p < 0.001). CONCLUSION: In patients undergoing TAVI, plasma BNP is the strongest independent predictor of all-cause mortality and cardiovascular mortality. Plasma BNP levels at 30 days after TAVI may provide prognostic information that should, potentially, lead to a more intensive therapy of these patients. PMID- 25799702 TI - A novel in-vitro model of human aortic valve mineralization. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to develop an in-vitro model of human aortic valve homograft (AVH) mineralization, as a basis for further research on the subject of calcific aortic valve disease (CAVD). METHODS: Human aortic valves were excised during autopsy (12-24 h post-mortem) from donors who had died due to accident or suicide. The mean (+/-SD) donor age was 32.5 +/- 11.4 years. Under sterile conditions each aortic cusp (three cusps per valve) was cut in half to provide a total of 240 tissue samples. AVH mineralization was assessed in solutions with different Ca and P concentrations and CaxPO4 ionic product values. The impact of time on aortic valve mineralization rate was assessed using energy-dispersive X-ray fluorescence (ED-XRF). RESULTS: The model showed that human AVH mineralization can be best observed in a solution with a CaxPO4 ionic product of 2.2 mmol2/l2. The optimum incubation time for observing AVH mineralization was 21 days. CONCLUSION: A novel in-vitro AVH mineralization model was developed for use in future studies. PMID- 25799703 TI - Clinical outcomes and lessons learned with aortic valve repair in 508 patients. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve repair is an attractive alternative to valve replacement. Herein is presented the authors' single-center experience and lessons learned from 508 patients undergoing AVR, in three different groups. METHODS: Between 1993 and 2010, a total of 508 patients (148 females, 360 males; mean age 54 +/- 17 years) underwent aortic valve repair. Operations included valve-sparing surgery (n = 253), isolated leaflet intervention (n = 158), and sinotubular junction (STJ) remodeling (n = 97). Aortic valve repair was defined as any primary or concomitant procedure performed at the level of the aortic valve or root for the restoration of function and/or anatomy of the valve. The mean follow up was 6.9 +/- 3.8 years (range: 0-18 years; median: 6.3 years; total: 3,477 patient-years). The completeness of clinical follow up was 95%. RESULTS: The 30-day mortality with and without dissection was 4.4% (8/180) and 1.8% (6/328), respectively. Late survival without dissection, although statistically inferior, followed closely the expected general population. In total, 53 patients required a cardiac, valve-related reoperation. Among the valve sparing group, no significant difference in freedom from reoperation at 10 years was observed between the David and Yacoub types (n = 147 (89%) versus n = 113 (79%); p = 0.373, respectively). Among patients who underwent isolated leaflet interventions, the number required to restore valve function (repair score) significantly affected the durability and incidence of reoperations (hazard ratio 1.47; 95% CI 1.1-2.0; p = 0.01), with the risk for failure being higher early after the operation. Patients with functional aortic insufficiency (AI) requiring only STJ remodeling resulted in the most durable outcome (freedom from reoperation 97.5% at 10 years). At the latest echocardiographic follow up (448 patients; total: 2,755 pt-yr; mean: 6.4 +/- 3.7 years; completeness 88%), 97% of patients had AI of grade <= 2. CONCLUSION: Aortic valve repair is an attractive alternative to conventional replacement in many patients and pathologies. In particular, pathologies requiring multiple leaflet interventions and repair techniques may lead to suboptimal results. Leaflet quality and leaflet-adjusted root stabilization/reconstruction are key elements for durable results. PMID- 25799704 TI - Nuclear factor-kappaB-hypoxia-inducible factor-2 pathway in aortic valve stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Valvular calcification is a prominent feature of aortic valve stenosis (AS), and calcified aortic valves share several features with bone tissue. Hypoxia-inducible factor-2 (HIF-2) is activated by nuclear factor-kappaB (NF-kappaB) and plays a critical role in an osteoblastic differentiation. The study aim was to determine whether the NF-kappaB-HIF-2 pathway is involved in the pathophysiology of calcified aortic valve disease. METHODS: A total of 50 specimens of aortic valve leaflets obtained from patients who had undergone aortic valve replacement for AS was examined. The aortic valve leaflets from 10 patients with annulo-aortic ectasia (AAE) served as controls. The stenotic valve leaflets were examined using immunohistochemistry to detect NF kappaB, HIF-2alpha, vascular endothelial growth factor (VEGF), vascular endothelial cells, and collagen X. The calcification area was measured and any correlation between the calcification area and NF-kappaB-HIF-2 pathway was assessed. RESULTS: NF-kappaB and HIF-2alpha were expressed in the leaflets from patients with AS, but not in those from AAE controls. Both factors were expressed around massive calcified lesions, and HIF-2alpha was co-localized with NF-kappaB. VEGF, neoangiogenesis and collagen X were located in the area where HIF-2alpha was expressed, and correlated positively with HIF-2alpha expression. The calcification area correlated positively with collagen X expression. CONCLUSION: The NF-kappaB-HIF-2 pathway was expressed in calcified aortic valves and associated with an increased expression of VEGF and collagen X. This signaling pathway may play important roles in the pathophysiology of AS. PMID- 25799705 TI - Prediction of 30-day mortality after transcatheter aortic valve implantation: a comparison of logistic EuroSCORE, STS score, and EuroSCORE II. AB - BACKGROUND AND AIM OF THE STUDY: The logistic EuroSCORE and STS score have been used for the selection of suitable TAVI patients, but their predictive ability is unsatisfactory. The study aim was to evaluate the performance of the EuroSCORE II in predicting 30-day mortality after TAVI in comparison to the logistic EuroSCORE and STS scoring systems. METHODS: Between January 2008 and April 2013, a total of 123 consecutive patients underwent TAVI (transapical, n = 85; transfemoral, n = 38) at the authors' institution. Calibration and discriminatory ability was evaluated for three risk scores models (logistic EuroSCORE, STS score, and EuroSCORE II), and compared for the prediction of 30-day mortality using the Hosmer-Lemeshow test for goodness-of-fit and receiver operating characteristics curve analysis. RESULTS: The overall 30-day mortality was 4.1% (5/123). Predicted mortality was 25.0 +/- 15.7% by logistic EuroSCORE, 7.3 +/- 6.9% by STS score, and 7.8 +/- 8.7% by EuroSCORE II. The observed/expected mortality ratio was 0.16 for logistic EuroSCORE, 0.56 for STS score, and 0.52 for EuroSCORE II. The area under the curve was 0.69 (95% CI 0.54-0.84) for the logistic EuroSCORE, 0.60 (95% CI 0.38-0.82) for the STS score, and 0.66 (95% CI 0.46-0.86) for the EuroSCORE II. CONCLUSION: In the present study, the EuroSCORE II was found to predict 30 day mortality more accurately for the TAVI cohort than did the more established logistic EuroSCORE, and also to compare (at present) on a par with the STS score. However, there were no differences in discriminatory power between the models. It is believed that, in the absence of a more TAVI-oriented risk stratification system, the EuroSCORE II may be a valuable adjunct in the clinical setting. PMID- 25799706 TI - Routine cine-CMR for prosthesis-associated mitral regurgitation: a multicenter comparison to echocardiography. AB - BACKGROUND AND AIM OF THE STUDY: Mitral regurgitation (MR) is an important complication after prosthetic mitral valve (PMV) implantation. Transthoracic echocardiography is widely used to screen for native MR, but can be limited with PMV. Cine-cardiac magnetic resonance (CMR) holds the potential for the non invasive assessment of regurgitant severity based on MR-induced inter-voxel dephasing. The study aim was to evaluate routine cine-CMR for the visual assessment of PMV-associated MR. METHODS: Routine cine-CMR was performed at nine sites. A uniform protocol was used to grade MR based on jet size in relation to the left atrium (mild < 1/3, moderate 1/3-2/3, severe > 2/3). MR was graded in each long-axis orientation, with overall severity based on cumulative grade. Cine CMR was also scored for MR density and pulmonary vein systolic flow reversal (PVSFR). Visual interpretation was compared to quantitative analysis in a single center (derivation) cohort, and to transesophageal echocardiography (TEE) in a multicenter (validation) cohort. RESULTS: The population comprised 85 PMV patients (59% mechanical valves, 41% bioprostheses). Among the derivation cohort (n = 25), quantitative indices paralleled visual scores, with stepwise increases in jet size and density in relation to visually graded MR severity (both p = 0.001). Patients with severe MR had an almost three-fold increase in quantitative jet area (p = 0.002), and a two-fold increase in density (p = 0.04) than did other patients. Among the multicenter cohort, cine-CMR and TEE (Delta =. 2 +/- 3 days) demonstrated moderate agreement (kappa = 0.44); 64% of discordances differed by <= 1 grade (Delta = 1.2 +/- 0.5). Using a TEE reference, cine-CMR yielded excellent diagnostic performance for severe MR (sensitivity, negative predictive value = 100%). Patients with visually graded severe MR also had more frequent PVSFR (p < 0.001), denser jets (p < 0.001), and larger left atria (p = 0.01) on cine-CMR. CONCLUSION: Cine-CMR is useful for the assessment of PMV associated MR, which manifests concordant quantitative and qualitative changes in size and density of inter-voxel dephasing. Visual MR assessment based on jet size provides an accurate non-invasive means of screening for TEE-evidenced severe MR. PMID- 25799707 TI - Real-time three-dimensional transthoracic echocardiography for predicting mitral annuloplasty ring size. AB - BACKGROUND AND AIM OF THE STUDY: Despite advances in mitral valve repair techniques, including robotic surgeries, few studies are available on predicting mitral annuloplasty ring size using echocardiography. Furthermore, these studies either had limited accuracy or else required the use of three-dimensional transesophageal echocardiography (3D-TEE), an expensive and semi-invasive tool. The study aim was to predict the mitral annuloplasty ring size preoperatively using real-time, three-dimensional transthoracic echocardiography (RT3D-TTE), which is a cheaper, non-invasive technique. METHODS: This prospective study included 47 consecutive patients scheduled for elective mitral valve surgery. All participants underwent preoperative RT3D-TTE. The mitral annular transverse diameter during early systole and the maximum height of the A2 scallop were measured in the multiplanar reconstruction mode. The surgeon, who was blinded to the echocardiographic measurements, also measured these two variables intraoperatively. A Pearson correlation coefficient was used to assess the association between the echocardiographic and operative measurements. A linear regression analysis was used to predict the annuloplasty ring size. RESULTS: A total of 34 patients (72.3%) underwent mitral valve repair. The echocardiographic measurements of the mitral annular transverse diameter were well correlated with the operative measurements (r = 0.64, p < 0.001). A moderate correlation was observed between the echocardiographic and operative measurements of A2 height (r = 0.59, p < 0.001). Linear regression analysis yielded an equation that predicted the annuloplasty ring size (R = 0.828, p < 0.001). CONCLUSION: RT3D-TTE was used successfully to predict the mitral annuloplasty ring size. This technique may potentially aid surgical planning, particularly before robotic procedures are performed. PMID- 25799708 TI - Mitral regurgitation in left ventricular noncompaction cardiomyopathy assessed by cardiac MRI. AB - BACKGROUND AND AIM OF THE STUDY: Previous case reports have described patients with left ventricular noncompaction cardiomyopathy (LVNC) with significant mitral regurgitation (MR). The study aim was to determine if LVNC is associated with MR, as assessed by cardiac magnetic resonance imaging (cMRI). METHODS: LVNC, assessed with cMRI, was observed retrospectively among 122 consecutive cases, 31 of whom had an end-systolic noncompacted-to-compacted ratio (ESNCCR) >= 2. In addition, 40 normal subjects undergoing cMRI and 40 with moderate to severe MR were included as controls. Using cine images, the ESNCCR and left ventricular (LV) and right ventricular (RV) stroke volumes were measured. The mitral regurgitant fraction (MRF) was calculated by dividing the difference between the RV and LV stroke volumes by the LV stroke volume. The total papillary muscle (TPM) area was measured from the mid short-axis view. Adjusting for age, race, gender and body surface area, an analysis of covariance was conducted to determine whether MRF and TPM were associated with ESNCCR >= 2. Adjusted means were presented with 95% confidence intervals. RESULTS: After adjustment, the MRF in patients with ESNCCR >= 2 was higher than in controls, but did not differ from that in patients with significant MR (21 +/- 6.5% versus 2.7 +/- 12% versus 29.2 +/- 11%, p = 0.039 and p = 0.3, respectively). Further, patients with ESNCCR >= 2 had a lower TPM than normal controls or those with moderate to severe MR (1.89 +/- 0.28 cm2 versus 3.6 +/- 0.26 cm2 versus 3.7 +/- 0.24 cm2; p < 0.001 and p < 0.001, respectively). CONCLUSION: LVNC is associated with increased MR, as assessed using cMRI. LVNC is also associated with abnormalities in the papillary muscle anatomy, which may predispose to MR. PMID- 25799709 TI - Could anterior papillary muscle partial necrosis explain early mitral valve repair failure? AB - Standardized techniques of mitral valve repair (MVR) have recently witnessed the introduction of a 'respect rather than resect' concept, the strategy of which involves the use of artificial chordae. MVR displays several advantages over mitral valve replacement in degenerative mitral regurgitation (MR), but the risk of reoperation for MVR failure must be taken into account. Different mechanisms could be advocated as the leading cause of MVR failure; procedure-related mechanisms are usually involved in early MVR failure, while valve-related mechanisms are common in late failure. Here, the case is reported of an early failure of MVR using artificial chordae that could be explained by an unusual procedure-related mechanism, namely anterior papillary muscle necrosis. MVR failure is a well-known complication after surgical repair of degenerative MR, but anterior papillary muscle partial necrosis might also be considered a possible mechanism of procedure-related MVR failure, especially when considering the increasing use of artificial chordae. Owing to the encouraging results obtained, mitral valve re-repair might be considered a viable solution, but must be selected after only a meticulous evaluation of the underlying mechanism of MVR failure. PMID- 25799710 TI - Early and mid-term outcomes of aggressive tricuspid annuloplasty with the MC3 ring. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the mid-term outcome of tricuspid annuloplasty (TAP) in the repair of functional tricuspid regurgitation (TR), using the three-dimensional (3D) MC3 ring with 'aggressive' stitches. METHODS: Between May 2007 and December 2012, a total of 165 patients (104 women, 61 men; mean age 68.0 +/- 9.0 years) underwent TAP using the MC3 ring. Horizontal mattress sutures were placed on the annulus beyond the anteroseptal commissure and away from the deemed atrioventricular node artery/vein, which could be detected in the triangle of Koch. Transthoracic echocardiography was performed preoperatively and postoperatively. The severity of TR was graded from 0 to 4. The mean follow up was 30.3 +/- 20.4 months. RESULTS: Both, TR grade and pulmonary artery systolic pressure (PASP) were significantly improved postoperatively. After a median of 24 months, the mean TR grade and PASP remained satisfactory. The overall survival rates were 97.6% and 94.8% at one and four years, respectively. The rates of freedom from recurrent TR (grade > 2) were 97.3% and 90.5% at one and four years, respectively. There were neither impulse conduction disorders requiring new pacemaker implantation, nor reoperations for recurrent TR. Multivariate analysis showed that recurrent TR during the follow up period was significantly related to severe preoperative TR. CONCLUSION: The clinical and echocardiographic results of TAP with the MC3 ring and 'aggressive' stitches were excellent, though further follow up is mandatory to confirm the safety and durability of this technique. Detection of the prominent vessel in the triangle of Koch can be helpful in avoiding impulse conduction disorders after TAP. PMID- 25799711 TI - Stroke is not a treatment dilemma for early valve surgery in active infective endocarditis. AB - BACKGROUND AND AIM OF THE STUDY: While early valve surgery for active infective endocarditis (AIE) is recommended, surgeons have hesitated to operate on patients complicated by cerebral septic embolism resulting in cerebral bleeding when cardiopulmonary bypass is required intraoperatively. The study aim was to review the outcomes of operations for AIE, and to determine the risks of neurologic complications resulting from cerebral septic embolism. METHODS: Between 1994 and June 2011, among 278 patients who underwent heart valve surgery for AIE at the authors' institution, 39 (14%) had cerebral septic embolisms. Cerebral lesions were verified by imaging, and were predominantly multiple embolic infarctions (34 patients; 87.2%). Five patients had brain abscess, and 10 had hemorrhage with or without infarction. The mean interval between the recent onset of a stroke and surgery was 10.1 +/- 10.1 days (range: 0-43 days). RESULTS: One patient died postoperatively of septic shock. New neurologic complications occurred in five patients, including secondary hemorrhagic transformation in the previous lesions (n = 2), newly developed subdural and subarachnoid hemorrhage (n = 2), and an increased degree of subarachnoid hemorrhage (n = 1). One patient needed a craniotomy, and the others were treated medically. There were five late deaths, including one cardiac death, and one redo valve surgery due to repaired valve failure during the follow up period of 46.3 +/- 40.4 months (range: 1.9-127.4 months). The overall and event-free survival rates at five and 10 years were 84.3 +/- 6.5% and 75.9 +/- 9.9%, and 81.7 +/- 6.8% and 73.6 +/- 9.9%, respectively. CONCLUSION: Surgery for AIE with cerebral septic embolisms can be performed safely, with good early and mid-term follow-up results. When urgent or emergent surgery for AIE is needed, neurologic complications should not be a reason for delay. PMID- 25799712 TI - Neutrophil-to-lymphocyte ratio as a prognostic marker in infective endocarditis: in-hospital and long-term clinical results. AB - BACKGROUND AND AIM OF THE STUDY: The neutrophil-to-lymphocyte ratio (NLR) is an independent predictor of poor prognosis in different clinical conditions such as infectious and cardiovascular diseases. It was hypothesized that a patient's admission NLR would be predictive of an adverse clinical outcome in cases of infective endocarditis (IE). METHODS: A total of 171 patients with IE was enrolled retrospectively, and allocated to two tertiles based on admission NLR values. The high-NLR group (n = 76) was defined as having an NLR value in the third tertile (> 5.46), and the low-NLR group (n = 95) as having a value in the lower two tertiles (<= 5.46). RESULTS: Patients in the high-NLR group had a significantly higher incidence of in-hospital mortality than the low-NLR group (39.4% versus 18.9%, p = 0.003). A high NLR was found to be an independent predictor of in-hospital mortality (odds ratio 2.53, 95% confidence interval 1.19 5.3; p = 0.01). The mean follow up was 25.5 months, and long-term follow up mortality was similar in both groups (12.9% versus 19.5%; p = 0.33). CONCLUSION: A high NLR at admission is associated with increased in-hospital mortality in patients with IE. During the long-term follow up, NLR showed no predictive indication of mortality. PMID- 25799713 TI - Clinical, echocardiographic and microbiological study, and analysis of outcomes of infective endocarditis in tropical countries: a prospective analysis from India. AB - BACKGROUND AND AIM OF THE STUDY: The aim of this prospective observational study was to evaluate the clinical, echocardiographic, microbiological profile and outcomes of patients with definitive infective endocarditis (IE) in tropical countries. METHODS: Between September 2010 and March 2013, a total of 109 patients with 111 episodes of definitive IE (as per the modified Duke's criteria) was enrolled in the study. The mean age at presentation was 32.7 +/- 17.2 years (range: 2-70 years), and there was a male preponderance (3:1). RESULTS: Native valve disease was identified in 57 cases of IE, followed by congenital heart disease (n = 35), prosthetic valve disease (n = 11), normal valves (n = 5) and pacemaker lead infection (n = 1). Echocardiography was diagnostic in all patients except one. Positive blood cultures were obtained in 68 episodes, with streptococci (n = 34) and staphylococci (n = 11) the most common organisms. At least one major complication was identified in 60 patients. Ultimately, only 15 patients underwent surgery for IE, but 25 died during their hospital stay. On multivariate analysis, prosthetic valve involvement, combined mitral and aortic valve involvement, male gender, and leukocytosis were independent predictors of mortality. CONCLUSION: IE in India is associated with a higher mortality and lower rates of culture positivity compared to the west; rates of surgery for IE in India are unacceptably low. Changing epidemiological trends may pose newer challenges in the near future. PMID- 25799714 TI - Early hemodynamic evaluation of Trifecta and Freestyle bioprostheses in patients with a small aortic root: preliminary results from a prospective randomized study. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement (AVR) in patients with a small aortic root is often associated with some degree of obstruction and residual gradients. Stentless valves display better hemodynamic performance than stented valves, and might be ideal in patients with a small aortic annulus. A new stented bioprosthesis, the Trifecta valve, has recently become available and has yielded interesting early results. The study aim was to compare the hemodynamic performance of the Trifecta valve with that of the Freestyle valve in patients with an aortic annulus <= 2.3 cm. METHODS: Between September 2011 and September 2013, a total of 40 patients with pure aortic stenosis and native aortic annulus diameter <= 2.3 cm was randomized to receive either a St. Jude Medical Trifecta stented prosthesis (n = 20) or a Medtronic Freestyle stentless prosthesis (n = 20). Hemodynamics results were compared between the two groups on discharge from hospital. RESULTS: The Trifecta valve showed slightly better hemodynamics, with peak gradients of 11 +/- 5 mmHg and 17 +/- 9 mmHg (p = 0.009), and mean gradients of 5.5 +/- 3 mmHg and 7.5 +/- 4 mmHg (p = 0.06) for the Trifecta and Freestyle valves, respectively. The average indexed effective orifice area (EOAi) was 1.14 +/- 0.23 cm2/m2 and 1.09 +/- 0.20 cm2/m2 (p = 0.520) for the Trifecta and Freestyle, respectively. Patient-prosthesis mismatch (PPM) occurred in two patients of the Freestyle group, and in three patients of the Trifecta group. CONCLUSION: In the present study, the stentless and stented prostheses each yielded comparable and excellent early hemodynamics results. The data obtained suggest that Trifecta valve implantation is a valid means of avoiding PPM after AVR in patients with a small native aortic annulus. PMID- 25799715 TI - Numerical analysis of the hemodynamic performance of bileaflet mechanical heart valves at different implantation angles. AB - BACKGROUND AND AIM OF THE STUDY: The effects of the implantation angle of bileaflet mechanical heart valves (BMHVs) on the sinus region and downstream flow profiles were investigated. Three-dimensional numerical simulations of BMHVs were performed under physiologic pulsatile flow conditions. The study aim was to examine how the flow fields of different aortic sinus shapes and the downstream aortic arch geometry would be affected by implantation angle. METHODS: Two geometric models of sinus were investigated: a simplified axisymmetric sinus; and a three-sinus aortic root model, with two different downstream geometries, namely a straight pipe and a simplified curved aortic arch. A 29 mm St. Jude Medical BMHV geometric model was used and positioned at four different angles (0 degrees, 30 degrees, 60 degrees and 90 degrees). RESULTS: The simulation results showed variation in downstream flow profiles at different implantation angles. Generally, at position Z = 1D along the centerline (where Z refers to the axis normal to the x-y plane and D is the inlet diameter), the triple-jet structures were observed with a slight shift of the center jet for three-sinus aortic cases. Apparent differences were observed at position Z = 2D and 4D, such as higher velocity profiles at the inner arch wall. The flow field downstream of the valve implanted at 0 degrees (anatomic position) showed the smallest overall asymmetry at peak systole, while the flow field downstream of the valve implanted at 90 degrees (anti-anatomic position) exhibited high regions of recirculation. CONCLUSION: Valve orientation was found not to affect the shear stress distribution significantly in the downstream aorta, and this was in agreement with the findings of earlier studies. PMID- 25799716 TI - An uncommon case of isolated parachute-like asymmetric mitral valve in an adult. AB - A 31-year-old asymptomatic male was referred to hospital for an examination of right bundle brunch block. Both, transthoracic and transesophageal echocardiography revealed normal left ventricular function, and two different sized papillary muscles; the anterolateral muscle was more pronounced, with almost major chordae tendineae inserted into this dominant muscle, whereas the immature, flat posteromedial papillary muscle had very short chordae tendineae and was located higher in the left ventricle, inserted directly into the mitral annulus. The mitral valve orifice was eccentrically located at the lateral side, but no significant mitral stenosis or regurgitation was observed. No other congenital heart anomalies were identified. Thus, the final diagnosis was isolated parachute-like asymmetric mitral valve (PLAMV), without any other congenital heart anomalies. The patient was followed up closely with periodic echocardiographic examinations. Parachute mitral valve is a rare congenital cardiac defect characterized by focalized attachment of the chordae tendineae of both leaflets to a single papillary muscle. In contrast to true parachute mitral valve, PLAMV has two separate papillary muscles, one of which is more pronounced and into which all chordae are inserted. PLAMV was highly associated with other congenital heart anomalies, and the involved dominant muscle was most frequently a posteromedial papillary muscle. Isolated PLAMV in an adult is even more rare, while the presence of an immature posteromedial papillary muscle--as in the present case--is extremely rare. PMID- 25799717 TI - Feasibility of sutureless valve implantation in reoperation for degenerated 19 mm aortic valvular bioprostheses. AB - BACKGROUND AND AIM OF THE STUDY: Transcatheter aortic valve implantation (TAVI) is a promising option to treat degenerated aortic valve bioprostheses, and may involve Valve-in-Valve (ViV) procedures. Unfortunately, the ViV technique may provide an inadequate relief of stenosis in small-diameter degenerated bioprostheses, especially in the 19 mm valve subgroup. The study aim was to determine the feasibility and reliability of reoperating 19 mm degenerated bioprostheses, using a minimally invasive sutureless valve implantation. METHODS: Between March and December 2012, three reoperative procedures for degenerated 19 mm conventional aortic bioprostheses were performed at the authors' unit. Stenosis was the main modality of structural deterioration. A partial upper ministernotomy approach was used, whereby part of the sewing ring of the previous bioprosthesis was left in place and a 19 mm Medtronic Enable sutureless valve was implanted in all cases. RESULTS: The average valve implantation time was 10.3 min. There were no cases of operative mortality or major morbidity. One permanent pacemaker was required. At discharge, transthoracic echocardiography showed no paravalvular leakages; the average transvalvular gradient was 16 mmHg. The one year follow up showed no paravalvular leakages and unchanged gradients. CONCLUSION: The use of a surgical sutureless valve after explanting a 19 mm degenerated bioprosthesis is feasible and effective for relieving stenosis However, larger series are needed to confirm these preliminary results. PMID- 25799718 TI - Hybrid internal mammary to left anterior descending bypass and transaortic transcatheter aortic valve implantation: a new treatment option for patients with complex disease. AB - The case is described of a hybrid trans-aortic transcatheter aortic valve implantation and off-pump left internal mammary artery to left anterior descending artery bypass surgery in a man with a tight left main lesion and severe symptomatic aortic stenosis. PMID- 25799719 TI - Cavernous hemangioma of the mitral valve in an adult male patient successfully treated with surgical resection: a case report. AB - Cavernous hemangioma is a very rare benign primary cardiac tumor that commonly involves any part of the heart, having been found in the atria, ventricles, interventricular septum, pericardium, and epicardium. A predominant location in the avascular cardiac valves is extremely rare, however. The case is reported of a 48-year-old male with recurrent anginal chest pain who subsequently underwent coronary angiography that revealed a mobile, rounded mass at the mitral valve which was fed by the left circumflex artery. Echocardiography revealed a left atrial echogenic mass attached to the posterior leaflet of the mitral valve. Histopathology of the mass following its surgical resection was consistent with hemangioma of the cavernous type. The patient recovered uneventfully. To the present authors' knowledge, this is the first reported case of cavernous hemangioma of the mitral valve in an adult male to be successfully treated with surgical resection. PMID- 25799720 TI - [Are there alternatives to antimicrobial therapy and prophylaxis of uncomplicated urinary tract infections?]. AB - The acute uncomplicated cystitis in women is one of the most frequently diagnosed bacterial infection. A clinically symptomatic urinary tract infection must be differentiated from the asymptomatic bacteriuria, which is not considered an infectionbut rather a colonization which should not be treated. For the antimicrobial therapy according to the European guidelines the old oral antibiotics (fosfomycin trometamol, nitrofurantoin, pivmecillinam) should be prescribed, against which E. coli is still susceptible in over 90%. With new therapeutic concepts not mainly the elimination of bacteria but rather the treatment of the inflammatory (over)reaction of the host is highlighted. To establish the significance of these therapeutic options as compared to the standard antibiotic therapy, the results of the ongoing and planned phase 3 studies need to be awaited. Thus reliable clinical measuring parameters for diagnostics and outcome are needed. The acute cystitis symptom score (ACSS) was developed and validated in Russian and Uzbec languages. Because of its high reliability, validity and predictive value it can be used not only in daily practice but also for clinical studies for the diagnosis of an acute uncomplicated cystitis in women. PMID- 25799721 TI - [Development and clinical testing of the Russian version of the Acute Cystitis Symptom Score - ACSS]. AB - The Acute Cystitis Symptom Score - ACSS was originally developed in the Uzbek language and has demonstrated high reliability and validity. The study was aimed to develop a Russian version of the ACSS questionnaire and evaluate its psychometric properties. Translation and adaptation of the ACSS questionnaire containing 18 questions, 6 of them - for the typical symptoms of acute cystitis (AC), 4 - for the differential diagnosis; 3 - for the quality of life, and 5 - for the conditions that may affect the choice of treatment, were performed according to the recommendations developed by the Mapi Research Institute. Study involved 83 Russian-speaking women (mean age, 35.6 +/-13.7 years); 38 (45.8%) patients were in the main group (patients with AC), and 45 (54.2%) - in the control group (without AC). Medical examination and appropriate treatment of the respondents were conducted in accordance with approved standards. After completing the course of therapy, 19 (50%) patients of the main group came for the control examination. There was statistically significant difference in the scores obtained in the two groups. Score profiles positively correlated with the results of laboratory tests (rho = 0.26-0.48). Cronbach's alpha for the Russian version of the questionnaire was 0.86 (95% CI, 0.81-0.91), area under the curve in the ROC analysis was 0.96. The results of testing the Russian version correspond to those of the original version. The Russian version of the ACSS questionnaire has high. reliability and validity, and can be recommended for clinical research and diagnosis of primary AC, and dynamic monitoring of the effectiveness of the treatment of the Russian-speaking population of patients. PMID- 25799722 TI - [Influence of combined phytotherapy on sexual function in patients with chronic abacterial prostatitis]. AB - An open, prospective, comparative, randomized, placebo-controlled study on the evaluation of the efficacy and safety of combined drug prolit super in patients with chronic abacterial prostatitis without signs of inflammation (NIH 3B category), complicated by sexual dysfunction, was performed. The study included 57 men aged 28 to 50 years. Patients in group 1 (n=29) have received daily 4 capsules of prolit super for 2 months, patients in group 2 (n=28) - placebo for the same period. Excellent results were noted in 58.6% of patients in Group 1 and in 17.9% - in group 2; good results - in 20.7 and 21.4%, satisfactory results - in 20.7 and 17.9%, respectively. Weak effect and its absence were registered only in patients in group 2 - 28.6 and 14.3% of cases, respectively. Significant adverse events or complications against the background of therapy were not observed. The results of the study allows to recommend the appointment of prolit super.in routine clinical practice for patients with chronic abacterial prostatitis without signs of inflammation, complicated by sexual dysfunction. PMID- 25799723 TI - [Combination therapy of prostatitis-associated copulative dysfunction]. AB - Chronic prostatitis is characterized by clinical polymorphism, that may include pain, dysuria, asthenovegetative syndrome, and others. Symptoms associated with impaired copulatory cycle in chronic prostatitis have a significant impact on the quality of life of patient. Sexual dysfunction and sexuality cessation can exacerbate the inflammation of the prostate gland and worsen the underlying disease. The study included 60 patients diagnosed with chronic bacterial prostatitis, complicated by sexual disorders. Patients were divided into two comparable groups of 30 persons. Control group ofpatients received standard antibacterial therapy; study group ofpatients in addition received phytodrug prostanorm. At the end of treatment, higher IIEF-5 scores, increasing number of lecithin granules in the prostate secretion, as well as reducing the severity of irritative symptoms were registered in the study group. PMID- 25799724 TI - [Potentials for the use of complex drugs in the treatment of patients with chronic abacterial prostatitis]. AB - Efficiency and safety of complex preparation prostadoz was evaluated in 25 patients with chronic abacterial prostatitis. It is proved that the use of prostadoz has a positive effect on the main subjective and objective signs of the disease: improves urination, reduces the severity of pain, moderately reduces the prostate volume, improves sexual-ejaculatory performance and improves quality of life. PMID- 25799725 TI - [Diagnosis of tuberculosis of bladder]. AB - A comparative analysis of cystoscopic and pathologic patterns in 190 patients hospitalized for differential diagnosis or treatment of genitourinary tuberculosis in 2008-2011 was performed. All patients underwent polyfocal biopsy followed by pathologic examination of biopsy specimens. Furthermore, a comparison of results ofpathomorphological studies of tissue obtained by biopsy and after cystectomy was conducted. Cystoscopy in all patients with tuberculosis of the bladder (TB) revealed the reduced bladder capacity in contrast to patients with other urological diseases. Deformation of orifices, trabecularity and contact bleeding were observed in 66.7 to 94.4% of cases in patients with TB, which were significantly more common than in other diseases. Polymorphism of pathological pattern and the lack of specific changes in the majority of patients with TB were noted; multinucleated Pirogov-Langhans cells were found only in 11.8% of cases, and only in biopsies, whereas in the tissues obtained after cystectomy in same patients, lymphocytic infiltration and fibrosis were observed. The algorithm of diagnosis of tuberculosis of the bladder is suggested. PMID- 25799726 TI - [Experimental validation of the developing a matrix based on decellularized vascular wall for subsequent substitution urethroplasty]. AB - Urethral strictures are urgent urological problem. Anastomotic and substitution urethroplasty are the most effective treatments. For substitution urethroplasty, buccal mucosa is most often used. There are the following difficulties associated with the substitution urethroplasty: complications in the donor area, the lack of tissue for substitution, an additional incision, and increased timing of surgery due to the need to obtain a flap or graft. Tissue engineering can be useful in solving the above problems. Tissue engineering involves the use a matrix without cells and matrix with one or more types of cells (tissue-engineering designs). In our study we have evaluated the ability to create a matrix for the substitution urethroplasty in animal experiments. The decellularized cadaveric arterial wall was used as a matrix. Decellularization was performed using enzymatic method. At the first stage, we transplanted matrix fragments in interscapular region in rats. An extremely weak bioactivity dof decellularized matrix of cadaveric arterial wall (DMCAW) due to the low immunogenicity of the material was revealed. Thus resorption of DMCAW was quite slow (60-90 days). At the second stage, in an experiment on rabbits, substitution urethroplasty using tubular DMCAW was successfully performed. Intraoperative urethral defect up to 1.8 cm was created, which was replaced by a tubular DMCAW. The use of this type of matrix has showed good structural and functional results: urethral strictures did not arise, the rejection of the matrix was not observed. A slow degradation of the matrix and progressive epithelialization of onnective tissue capsule were revealed. Decellularized matrix based on cadaveric arterial wall can be considered as a material for substitution urethroplasty. PMID- 25799727 TI - [Long-term outcomes of the use of alpha-blockers tamsulosin in men with lower urinary tract symptoms and benign prostatic hyperplasia]. AB - The retrospective evaluation of efficacy and safety of tamsulosin omnik (0.4 mg once a day) for 8 years in 17 patients with BPH and LUTS was performed. At the time of appointment of tamsulosin, mean age of patients was 61.9 years (range, 51 to 69 years). Efficacy of tamsulosin was evaluated based on the change of obstructive and irritative symptoms according to items of I-PSS scale, maximum urinary flow rate, residual urine volume and prostate volume. The study found that factors for favorable prognosis against the background of use of tamsulosin include moderate LUTS, small- or medium-sized BPH, maximum urinary flow rate of not less than 9 ml/s, and residual urine volume not more than 100 ml. PMID- 25799728 TI - [Benign mimics of prostatic adenocarcinoma]. AB - Prostate cancer occupies 2nd place on the prevalence and 6th place on mortality among all cancers in men. That is not to deny the social importance of prostate cancer, but attention is drawn to significant advantage of newly detected cases above the cancer-specific mortality. "Gold standard" for diagnosis includes morphological study of tissue fragments after transrectal multifocal prostate biopsy. The importance of the differential diagnosis is particularly relevant when analyzing fragments of prostate tissue obtained from biopsies as a false positive result may cause unnecessary and excessive treatment. This article presents the most common benign processes that can simulate various grade adenocarcinoma. Awareness about the presence of such cancer mimics and careful examination of micropreparations in most cases allows to come to the correct conclusion. PMID- 25799729 TI - [Modern aspects of classification of the complications of extracorporeal shock wave lithotripsy]. AB - Postoperative complications of extracorporeal shock wave lithotripsy (ESWL) develops due to inadequate assessment of the clinical course of urolithiasis, incorrectly defined indications for treatment, lack of adequate preoperative preparation and ESWL technology. Based on the analysis of the results of treatment of 4500 patients with urolithiasis in the Clinic of Urology of the First MSMU n.a. I.M. Sechenov, taking into account the Clavien-Dindo classification of postoperative complications, we proposed a classification of complications of extracorporeal shock wave lithotripsy, which allows to estimate the degree of complications and determine the sequence of the provision of special medical care. PMID- 25799730 TI - [Individual learning curve for radical robot-assisted prostatectomy based on the example of three professionals working in one clinic]. AB - The appearance of new surgical technique always requires evaluation of its effectiveness and ease of acquisition. A comparative study of the results of the first three series of successive robot-assisted radical prostatectomy (RARP) performed on at time by three surgeons, was conducted. The series consisted of 40 procedures, and were divided into 4 groups of 10 operations for the analysis. When comparing data, statistically significant improvement of intra- and postoperative performance in each series was revealed, with increase in the number of operations performed, and in each subsequent series compared with the preceding one. We recommend to perform the planned conversion at the first operation. In our study, previous laparoscopic experience did not provide any significant advantages in the acquisition of robot-assisted technology. To characterize the individual learning curve, we recommend the use of the number of operations that the surgeon looked in the life-surgery regimen and/or in which he participated as an assistant before his own surgical activity, as well as the indicator "technical defect". In addition to the term "individual learning curve", we propose to introduce the terms "surgeon's individual training phase", and "clinic's learning curve". PMID- 25799731 TI - [Treatment of prostate cancer using cryoablation: a prospective study]. AB - Currently, the choice of tactics of treatment of the patient with prostate cancer (PCa) requires to take into account the degree of differentiation and stage of tumor, age of the patient and his somatic diseases, the risk of complications, as well as the patient's desire and physician's experience. Due to the progressive development of medical technology, interest in minimally invasive treatments for prostate cancer, such as cryoablation, interstitial brachytherapy and HIFU therapy, has grown. Cryoablation of the prostate gland is a tissue ablation by local effects of very low temperatures and is minimally invasive, highly effective treatment for prostate cancer that can be used as the primary treatment, and in the case of tumor recurrence after radiotherapy. Focal cryoablation of the prostate allows to selectively destroy the known tumor with preservation of organ function and without reducing the quality of life of the patient. Focal therapy for prostate cancer is an alternative to radical treatment and active surveillance, occupying an intermediate position between them. Due to the lack of long-term results, focal cryoablation is an experimental type of treatment. First cryoablation of the prostate using modern equipment was carried out in Russia in March 2010, at the Department of Urology MSMSU. Since that time, we performed this procedure in 122 patients with prostate cancer; cryoablation was primary treatment in 110 patients and was used as salvage treatment in 12 patients. In most cases, the operation was performed under epidural or spinal anesthesia. According to the protocol, all the patients underwent 2 cycles of freezing and thawing under transrectal ultrasound guidance. A significant improvement of equipment for cryosurgery, the use of cryoneedles with smaller diameter, and the use of temperature sensors and catheters to warm the urethral mucosa have allowed to minimize the number of complications in comparison with other methods of treatment of prostate cancer and achieve a high disease-free survival. Our prospective study was aimed to analyze our own results cryoablation of the prostate gland. PMID- 25799732 TI - [Experience in the treatment of autoimmune male infertility in patients with category 4 chronic prostatitis]. AB - Administration of longidaza at a dose of 3000 IU intramuscularly twice a week after 1 month of treatment leads to the statistically significant reduction of antisperm antibodies (ASAB) at the surface of sperm cells to 23% (7-48%) for MARIgG and to 14.5% (3-34%) for MARIgA. Maximum reduction of ASAB, however, was observed after third month of treatment, mean MARIgG was 2% (1-26,5%) and MARIgA 1% (0-11.5%). ASAB level has not reduced less than 50% only in one patient (1.67%). At follow-up three months after the cancellation of Longidaza, only 17 (28.33%) men showed an increase of ASAB IgG and (or) IgA more than 50%. Inthe study group, during the observation, spontaneous pregnancy occurred in 6 (10%) pairs, and IVF was successfully performed in 3 (5%) pairs. Thus, we consider it necessary to appoint Longidaza in patients with category 4 chronic prostatitis and elevated levels of antisperm antibodies on sperm cells, who preparing for assisted reproductive technologies, or preparing for natural pregnancy, as a high effective pathogenetical agent for the treatment of autoimmune infertility. PMID- 25799733 TI - [Optimization of modern conservative therapy of micropenis in hypogonadal men]. AB - The study was aimed to the optimization of conservative therapy of micropenis in hypogonadal men using combination of traction therapy and androgen replacment therapy (ART) with injections of prolonged testosterone undecanoate (Nebido) and to evaluatiom of the safety of ART in terms of the risk of prostate cancer against the background of combined treatment of micropenis by both methods within 12 months. The study included 16 men aged 22-62 years with micropenis and hypogonadism. 10 men were diagnosed with primary hypogonadism, 6 men were diagnosed with secondary hypogonadism without reserve gonadal function; therefore, all 16 patients were treated with testosterone undecanoate 1000 mg intramuscularly according to the scheme: the second injection 6 weeks after the first injection, then each injection once a 12 weeks, the course of 12 months. During the first 3 months of ART, hypogonadism in all men was eliminated, but only at 6 month of ART, the length of the penis in the flaccid state at maximum extension increased from 5.8+/-1.2 to 8.3+/-1.2 cm (p<0.05), and the length of the erect penis - from 6.8+/-1.1 to 11.8+/-0.9 (p<0,05). At the next stage, from the 6th to the 12th month of ART, traction therapy was simultaneously carried out. At the end of the treatment, the length of the penis in the flaccid state at maximum extension increased by 58% of the original length, and in a state of erection - by 114% (p<0.05). During the 12 months of treatment, prostate volume in all men increased from 3.4+/-1.2 to 16.3+/-1.2 (p<0.05), which corresponds to the size of the prostate in healthy men. Total blood PSA level increased from 0.72+/-0.03 to 1.4+/-0.05 ng/ml (p<0.05), but it was in the acceptable range of reference values for healthy men during whole period of ART in all patients. Start therapy with prolonged testosterone undecanoate for 6 months significantly increases the efficiency of traction therapy in men with hypogonadism and micropenis, but for maintenance of the effect, ART should be continued during all period of treatment. PMID- 25799734 TI - [Selection of type of urinary tract drainage in laparoscopic ureterolithotomy]. AB - The article presents the results of 44 laparoscopic ureterolithotomies performed for large stones in upper and middle third of the ureter. Patients' age ranged from 35 to 82 years. The different types of drainage of the urinary tract depending on the characteristics of surgical treatment (retro- or transperitoneal ureterolithotomy) were used. The effectiveness was evaluated according to the results of plain urography, ultrasound, and multi-layer spiral CT. The results showed that the preferred method of urinary tract drainage is a preoperative deployment of ureteral catheter-stent. However, in the case of impossibility of such procedure, preoperative deployment of ureteral catheter with subsequent intraoperative replacing it on catheter-stent is permissible. With retroperitoneal approach, tubeless ureterolithotomy is feasible in the absence of the ipsilateral kidney stones, residual ureteral stones and pronounced changes in the area of finding the stones. PMID- 25799736 TI - [Simultaneous radical retropubic prostatectomy, diverticulectomy]. AB - Presented clinical case demonstrates a combination of rare congenital abnormality - giant true diverticula of the bladder - and high-risk prostate cancer, as well as a successful result of simultaneous operation - a radical prostatectomy with diverticulectomy. PMID- 25799735 TI - [Search for new modes of antibiotic prophylaxis of septic complications after percutaneous nephrolithotripsy]. AB - The risk of infectious and inflammatory complications after PNL is based on presence of microorganisms in the form of biofilms inside the stone. Destruction of stones during surgery or lithotripsy may be a trigger for the growth of microorganisms that are integrated into the biofilms, and the migration of bacteria and their toxins in the blood flow under pressure of irrigation fluid can cause septic complications. The danger of infectious and inflammatory complications after percutaneous interventions for kidney stones requires a search for specific antibiotics for antimicrobial prophylaxis and efficient modes of their administration. The results of a comparative study of pharmacokinetic parameters of ciprofloxacin, and the effectiveness of two modes of administration (bolus dosing and prolonged intravenous administration) at a dose of 1000 mg are presented. PMID- 25799737 TI - [Sildenafil citrate in the treatment of men with erectile dysfunction]. AB - Based on literature data and the results of own authors' research, the review article considers the efficacy and safety of sildenafil, including its long-term use. Application of this drug leads to an improvement of erectile function in patients of all ages, regardless of etiology, severity and duration of erectile dysfunction (ED). Drug has long-term efficacy. Sildenafil affects both arterial and venous blood flow to the penis, which makes it indicated in vasculogenic erectile dysfunction first. Treatment with sildenafil is accompanied by improvement of the cavernous electrical activity, which justifies its use in neurogenic form of the disease. According to results of IIEF questionnaire, sildenafil provides quick and lasting therapeutic effect. Efficacy and safety of sildenafil is rated as good. As for short-term and long-term use, sildenafil does not cause dependence and addiction. PMID- 25799738 TI - [Problems of testosterone deficiency and erectile dysfunction in men (literature review)]. AB - In recent years, treatment of men with testosterone deficiency has become an important part of andrological and urological practice. Clinical manifestations of testosterone deficiency syndrome are usually diverse. Testosterone deficiency and erectile dysfunction often occur against the background of some systemic diseases, and sometimes are markers or predictors of these diseases. It is important that erectile dysfunction and testosterone deficiency syndrome are closely interrelated, and the correction of these conditions requires account of specific treatment of both diseases. PMID- 25799739 TI - [Cryoablation in urology]. AB - Modern science opens up new potentials for the effective treatment of complex diseases using minimally invasive techniques. One of the obvious achievements of recent years is cryoablation - technology of local freezing of tissues, allowing to create a precision zone of tumor cell death in renal cancer and prostate cancer. The literature review presents historical information, highlighting the main stages in the development of cryosurgery since the XIX century. The analysis of domestic and foreign literature has shown that in urological practice cryoablation has been widely used. Based on the literature data, indications, contraindications and complications of cryoablation in renal cancer and prostate cancer, as well as long-term results of treatment are discussed. Cryoablation has been used actively abroad; in the Russia, method is developing, but without a doubt, will be actively introduced in medical practice. PMID- 25799740 TI - [Epidemiologyand risk factors for urinary disorders in diabetic patients]. AB - The article presents the current data on the prevalence of lower urinary tract complications in diabetic patients. The role of such factors as the type of diabetes, its duration, and the degree of compensation, in the development of complications is demonstrated. Special attention is given to the importance of low physical activity and increased body mass index as risk factors for urological complications of diabetes mellitus. PMID- 25799741 TI - [3D-technologies in the kidney surgery]. PMID- 25799742 TI - [The organizational principles and technologies of prevention of the XXI century]. AB - The article considers organizational principles, technologies and criteria of effectiveness of actual preventive activities considering indicators of health condition of children and adolescents. The structures participating in implementation of general and specific prevention among children and adolescents are presented. The structures' functions are enumerated concerning development of succession and unity of preventive environment. The particular attention is paid to development of informational and telecommunication technologies in the fields of health care legal support of health care of children and adolescents, manpower development in area of preventive pediatrics. PMID- 25799743 TI - [The condition and problems of adolescents' health in Russia]. AB - The article presents data concerning health condition of adolescents aged 15-19 years in the Russian Federation during 2002-2012. The official statistical data concerning morbidity, disability and mortality of adolescents were analyzed. In children of this age group increasing of morbidity, disability and decreasing of mortality are established. The special studies demonstrated that true indicators of morbidity of adolescents exceed official indicators up to 1.5-2 times. The morbidity of adolescents is characterized by increasing of socially significant pathology and diseases related to behavioral risk factors. In adolescent age, the unfavorable tendencies in psychic and reproductive health are observed. In the structure of disability mental disorders and behavior disorders, diseases of nervous system and inherited malformations are in the lead. The principal limitation of vital activity is "capacity to learning". It is demonstrated that in the Russian Federation there is underestimation of cases of disability among children and adolescents. PMID- 25799744 TI - [The regional model of three-level system of of medical social monitoring of children and adolescents: the pilot project in the Republic of Tatarstan]. AB - The absence of system of medical social monitoring of children being in difficult life situations is one of main causes of preventable losses of health and life of children and adolescents. The plan of activities of the working group No3 under the Coordination council under the President of the Russian Federation of the national strategy realization of actions in interest of children for 2012-2017 includes a point: "The development and implementation of standard model of medical social monitoring of children and adolescents in the subjects of the Russian Federation". The implementation of this task is assigned to the Department of social pediatrics of The research center of children health of Moscow and the Ministry of Health of the Republic of Tatarstan. The research methods included analysis and generalization of advanced experience of medical social monitoring of children population; expertise technique; modeling. The regional model of three-level system of medical social monitoring of children population is developed and implemented. The model includes level I (consulting rooms of medical social care of children polyclinics, feldsher obstetric stations, first-aid centers), level II--inter-municipal (departments of medical social monitoring in central district hospitals, medical institutions, clinical diagnostic centers) and level III--regional (the Republican center of medical social monitoring of children and adolescents). The immediate tasks necessary for effective functioning of system of medical social monitoring were determined. Within the framework of implementation of the pilot project the legal and normative legislative acts were developed to regulate functioning of regional model of three-level system of medical social care. The other documents necessary for effective functioning of this system were elaborated. The practical significance of this system is in the implementation of effective three-level model of medical social monitoring of children and adolescents supporting decrease of morbidity, mortality and "risk behaviors" suicidal included. The model is to prevent child neglect and homelessness and cruel treatment of children and adolescents. PMID- 25799745 TI - [The basic medical demographic indicators of population health of Russia up to 2013]. AB - The actual medical demographic situation in Russia is characterized by positive trends of natality and mortality. At that, deepening of habitation differences in rate of lethal outcomes at the first year of life and gender differences in level of mortality at able-bodied age is established. PMID- 25799746 TI - [The clinical economic analysis of application of immune correcting preparations to prevent respiratory infections and their complications in frequently ill children of early school age]. AB - The article presents the results of clinical economic analysis of effect of different immune correcting preparations on rate of respiratory infections in 548 frequently ill children of early school age. It is established that preventive immune correction with lysates of bacteria or glucosaminyl muramyl dipeptide in aggregate with vitamin mineral complex results in statistically significant decreasing of rate of respiratory infections and dramatic decreasing of direct and indirect costs of treatment of infectious diseases of respiratory ways. The preventive application of juice of cone-flower herb or interferon in aggregate with vitamnin mineral complex statistically significantly decreases rate of respiratory infections and negligibly decreases direct and indirect costs of their treatment. PMID- 25799747 TI - [About economic aspects of provision of medical services]. AB - The contradiction between economic and social components of medical services is present in any state. Initially, the state undertakes the commitment no provide citizen with equal access to medical services. However, this means to provide social equity between all members of society which not always is effective from economic point of view. The article analyzes the problems originated in public system of provision of medical services. These problems are determined by service specificity itself model of provision of medical services and public priorities in social sector. PMID- 25799748 TI - [The risk factors and dangerous regimens of alcohol consumption in physicians' community]. AB - The study was carried out to determine percentage of hazardous, dangerous and possibly dependent alcohol consumption among physicians of Yakutsk. The relationship between social hygienic aspects accompanying hazardous and dangerous alcohol consumption was analyzed. The risk factors were established. The means of prevention of alcohol dependence among physicians were proposed. PMID- 25799749 TI - [The gender aspects of diet factors effect on development of diseases of circulatory system among rural population]. AB - The unhealthy diet is one of important controllable risk factors of development of noninfectious diseases. The gender differences in attitude to one's own health confirm significance of their effect on health condition. The study was carried out to establish the effect of diet factors on the rate of diseases of circulatory system in rural population with consideration of gender distribution. The analysis of results of sampling examination of rural population established that 51% of disease rate in males and 22% of disease rate in females are related to diseases of circulatory system. In males and females rate of diseases of circulatory system is determined by diet factors. The direction of relationship is direct and inverse, differs in males and females and depends on diet factors. The gender differences were manifested not only in conditionality of rate of diseases of circulatory system by diet factors but also by their mutual interaction. The health management of rural population is based on examination and analysis of relationship between health of rural population and factors of their diet. PMID- 25799750 TI - [The evaluation of costs: standards of medical care and clinical statistic groups]. AB - The article presents the comparative analysis of techniques of evaluation of costs of hospital treatment using medical economic standards of medical care and clinical statistical groups. The technique of evaluation of costs on the basis of clinical statistical groups was developed almost fifty years ago and is largely applied in a number of countries. Nowadays, in Russia the payment for completed case of treatment on the basis of medical economic standards is the main mode of payment for medical care in hospital. It is very conditionally a Russian analogue of world-wide prevalent system of diagnostic related groups. The tariffs for these cases of treatment as opposed to clinical statistical groups are counted on basis of standards of provision of medical care approved by Minzdrav of Russia. The information derived from generalization of cases of treatment of real patients is not applied. PMID- 25799751 TI - [The development of organization of medical social care of adolescents]. AB - The model of the subject of the Russian Federation is used to consider means of development of health protection and health promotion in adolescents including implementation of the National strategy of activities in interest of children for 2012-2017 approved by decree No761 of the President of Russia in June 1 2012. The analysis is carried out concerning organization of medical social care to this group of population in medical institutions and organizations of different type in the Republic of Bashkortostan. Nowadays, in 29 territories medical social departments and rooms, 5 specialized health centers for children, 6 clinics friendly to youth are organized. The analysis of manpower support demonstrates that in spite of increasing of number of rooms and departments of medical social care for children and adolescents decreasing of staff jobs both of medical personnel and psychologists and social workers occurs. The differences in priorities of functioning of departments and rooms of medical social care under children polyclinics, health centers for children and clinics friendly to youth are established. The questionnaire survey of pediatricians and adolescents concerning perspectives of development of adolescent service established significant need in development of specialized complex center. At the basis of such center problems of medical, pedagogical, social, psychological, legal profile related to specific characteristics of development and medical social needs of adolescents can be resolved. The article demonstrates organizational form of unification on the functional basis of the department of medical social care of children polyclinic and clinic friendly to youth. During three years, number of visits of adolescents to specialists of the center increases and this testifies awareness of adolescents and youth about activities of department of medical social care. The most percentage of visits of adolescents to specialists was made with prevention purpose. Among physicians about 93% approved the given model of development of medical social service for adolescents. PMID- 25799752 TI - [The informational analytical support of management of regional health care on the basis of expertise]. AB - The development of the system of informational analytical support based on expertise data is one of most important stage of increasing of effectiveness of management of regional health care. The study was organized to substantiate formation of the system of informational analytical support of management of regional health care on the basis of expertise data. The study was carried out on the basis of expertise data from subjects involved in informational analytical support of management of regional health care (health care management executives, chief specialists and directors of medical organizations in the subjects of the Russian Federation situated in the Siberian federal okrug). The study established that alongside with statistical information the expertise is enough important, objective and informative information to be applied in developing of managerial decisions. The highest integral estimated value of importance, objectiveness and informativeness has the information concerning competence of medical personnel, proportions of medical care of population and conditions of material technical base of health institutions. The most foreground issues concerning expertise are population health condition, pharmaceutical and medical equipment support of medical institutions, level and quality of population medical care. The degree of impact of expertise information on managerial decision making is highest in such directions as support of population with medical care, increasing of availability of medical care and degree of organization of medical care rendering. The probability of increasing of degree of impact of expertise information on managerial decision making is the highest in such directions as population provision with medical care, competence of medical personnel, level and quality of medical care, level of organization of medical care support, that is to be considered during implementation of expertise. The study data was used in developing the major principles of elaboration of system of informational analytical support of management of regional health care. The unified expertise questionnaire was developed to be used as a document basis of expertise system. The study results can be implemented in practical activities of regional health administration and medical organizations. The results of study made it possible to substantiate the development of the system of informational analytical support of regional health care and to determine priority directions of its formation. PMID- 25799753 TI - [The development of laboratory service of the Republic of Bashkortostan in conditions of health care modernization]. AB - The article presents the analysis of organizational aspects of laboratory service of the Republic of Bashkortostan. The investigation of public opinions concerning functioning of private laboratories was organized using technique of anonymous questionnaire survey. The sampling included 200 patients visiting clinical diagnostic laboratory "MediaLab". The survey established several issues to be resolved to assist development of laboratory service. PMID- 25799754 TI - [The ambulatory polyclinic institutions in closed administrative territorial municipality]. AB - The article presents the results characterizing functioning of ambulatory polyclinic institutions included into medical sanitary unit of closed administrative territorial municipality of lesser towns. The study established the resource support of staff and full-time positions of physician and paramedical personnel, dynamics of indicators from 2005 to 2013, coverage of population of able-bodied age with preventive and target medical examinations for syphilis and tuberculosis. The progression of contingents under dispensary registration was determined. PMID- 25799755 TI - [For fortieth anniversary of organization of national narcological service]. AB - The 1975 is a year of organization in the USSR of independent service with the competence to regulate problems of alcoholism, drug addiction and toxicomania. The narcological dispensary, public narcological posts and night-time preventoriums were organized. The persons with chronic alcoholism were directed to forced treatment for preventive purpose. PMID- 25799756 TI - [The role of yearbook "The significant and anniversary dates of history of medicine" in training of historians of medicine]. AB - The N.A. Semashko national research institute of public health during 57 years published collections "The significant and anniversary dates of history of medicine" reflecting main dates of universal and national medicine. The particular attention was paid to jubilees of scientific medical discoveries, publishing of works and organization of medical institutions. PMID- 25799758 TI - [Andrei Mikhailovitch Stochik (75th anniversary)]. PMID- 25799757 TI - [The Moscow Stomatological Institute as a third Moscow medical institute]. AB - The article presents a short history of three third medical institutes existed in Moscow in different time. PMID- 25799759 TI - The shame of Mississippi Medicaid. PMID- 25799760 TI - IgG4-associated cholangitis. AB - We report a young female patient with IgG4-associated cholangitis (IAC) who presented with common bile duct (CBD) stricture and review the features that distinguish IAC from both primary sclerosing cholangitis (PSC) and other types of secondary sclerosing cholangitis (SSC). IAC is a biliary manifestation of IgG4 related sclerosing disease, an autoimmune condition characterized by elevated serum IgG4 and infiltrates containing lymphocytes and IgG4-positive plasma cells, accompanied by sclerosis. On endoscopic retrograde cholangiopancreatography, IAC consists of segmental biliary strictures with a predilection for the distal CBD, whereas in PSC the strictures are more band-like; other types of SSC often demonstrate unifocal ductal obstructions, sometimes associated with choleliths. On histologic examination, the bile duct wall in IAC contains a denser lymphocytic infiltrate and sparser sclerosis than in PSC; other types of SSC can be distinguished histologically by the types of inflammatory cells present. Unlike those of PSC, IAC-related strictures are reversible with corticosteroids. PMID- 25799761 TI - Sent for a loop. PMID- 25799762 TI - Skinny insurance plans can weigh you down. PMID- 25799763 TI - Follow the physician leader. PMID- 25799764 TI - President page. A warm and hearty holiday wish. PMID- 25799765 TI - Remembering JMSMA editor emeritus Myron W. Lockey MD. PMID- 25799766 TI - Looking forward. The ACS and U.S. Department of Defense Military Health System partner to improve educational opportunities, systems-based practices and research capabilities. PMID- 25799767 TI - The disruptive physician: addressing the issues. PMID- 25799768 TI - Patient loss: surgeons describe how they cope. PMID- 25799769 TI - The benefits of attending a 2015 ACS Surgical Coding Workshop. PMID- 25799770 TI - ACS develops ICD-9 to ICD-10 crosswalk to assist in billing. PMID- 25799771 TI - Hospitals continue to improve on surgical care accountability measures. PMID- 25799772 TI - NTDBA data points: 2014 pediatric report: how severe is it? PMID- 25799773 TI - Google Glass liability risks. PMID- 25799775 TI - Electronic health record. PMID- 25799774 TI - Gloving technique. PMID- 25799777 TI - AMA house of delegates takes action on spectrum of issues. PMID- 25799776 TI - In memoriam: Renowned trauma surgeon and former COT chair, Erwin Thal, MD, FACS. PMID- 25799778 TI - Acriva UD Reviol multifocal intraocular lens in patients undergoing cataract surgery--6-month follow-up. AB - PURPOSE: To evaluate visual outcomes and complications in patients after binocular Acriva UD Reviol MFB 625 (VSY Biotechnology) multifocal intraocular lens implantation. METHODS: 40 eyes of 20 patients were reassessed at six months following bilateral IOL implantation. The following were evaluated: binocular UDVA and near, binocular uncorrected intermediate visual acuity, spectacle independence, uncorrected binocular photopic contrast sensitivity for distance and near, uncorrected binocular mesopic contrast sensitivity for distance (CS-CSV 1000, F.A.C.T.); stereoscopic vision (Lang Stereotest II), patient satisfaction, subjective symptoms (modified NE VFQ-25) and postoperative complications. RESULTS: Six months after surgery the mean binocular UDVA was logMAR -0.05 +/- 0.07, UIVA was +0.04 +/- 0.09 and uncorrected near visual acuity was +0.06 +/- 0.08. At six months postoperatively, all patients were totally spectacle independent. Contrast sensitivity under different conditions was within the normal range at all spacial frequencies. Stereoscopic vision was normal in all patients. Low level of glare/halo perception was detected in 55% of patients. General vision quality was high and rated as 1.85 (1--the best, 5--the worst). No severe postoperative complications were observed. CONCLUSION: Cataract surgery with Acriva UD Reviol MFB 625 implantation in a selected group of patients was very effective for all distances and provided excellent patient satisfaction. PMID- 25799779 TI - [The role of orthoptic assessment in outcome prognosis in patients undergoing reconstruction surgery for orbital blow-out fracture]. AB - AIM: The aim of this study is to analyze the results of orthoptic examination in patients with orbital blow-out fractures, who underwent reconstruction surgery and to determine which preoperative factors influence the outcome prognosis. MATERIAL AND METHODS: 113 patients after orbital injury were examined. 78 subjects after reconstruction surgery for orbital floor or floor and medial wall fracture, with or without orbital rim involvement, were included in further analysis. All subjects underwent the orthoptic assessment at baseline and at 3 months after the surgery. RESULTS: Ordinal regression model was utilized in order to determine which orthoptic parameters significantly affect the surgical outcome of a reconstructive procedure. We have found that the following factors were associated with less favourable treatment outcomes: the large field of binocular single vision, the large angle of deviation in upgaze and downgaze, the positive forced duction test and the concomitant inferior rectus paresis. CONCLUSIONS: The thorough orthoptic assessment and identifying the potential oculomotor dysfunction prior to reconstructive surgery enables proper outcome prognosis in patients with orbital blow-out fractures. PMID- 25799780 TI - [Micropulse 577 nm laser trabeculoplasty--a prospective pilot study]. AB - PURPOSE: To evaluate the efficacy of micropulse 577 nm laser trabeculoplasty. MATERIAL AND METHODS: Prospective clinical trial designed for 30 patients diagnosed with open angle glaucoma. The micropulse 577 nm laser trabeculoplasty was performed in one eye of each patient in the lower half of trabecular meshwork. The intraocular pressure was measured using two independent methods- Pascal tonometer and iCare tonometer--at baseline (before surgery), at 3 h, 24 h, 2 weeks and 1 month following the procedure. Pressure measurement results were compared between the treated and untreated eyes. Treatment was considered successful if the intraocular pressure dropped by >= 3 mmHg or >= 20% as compared to the baseline values or >= 20% as compared to the fellow eye. RESULTS: The study was conducted on 11 patients. In the treated group, Pascal tonometry showed the mean decrease of the intraocular pressure by 1.7 mmHg (7.5%). The same value for the untreated eyes was 1.8 mmHg (8.1%). The results obtained using iCare tonometer showed the same proportions. The treatment did not lower intraocular pressure as compared to the untreated fellow eyes. There were no adverse effects. Even though it was impossible to perform the proper statistical analysis due to the small number of treated patients the study was eventually interrupted for ethical reasons, because of the failure to decrease the intraocular pressure in the treated group of 11 patients. CONCLUSIONS: The treatment appeared to be safe but ineffective in the treated group. Further research is needed to modify laser parameters for the improvedefficacy and the maintained good safety profile of the procedure. PMID- 25799781 TI - High-altitude retinopathy--case report. AB - High-altitude retinopathy is one of altitude-related illnesses. Its signs include high-altitude retinal hemorrhages, dilated vessels and peripapillary hyperemia. Increased intracranial pressure seems to be the main cause of all high-altitude diseases including high-altitude retinopathy, cerebral oedema and high-altitude pulmonary oedema. We present the case of high-altitude retinopathy in a 35-year old woman who reported decreased vision in her right eye, scotomas and high altitude retinopathy after ascending to more than 7000 meters above sea level. The associated optical coherence tomography findings, fundus photography and literature review are presented. High-altitude retinopathy is an important multifactorial condition of unknown mechanism and etiology, which significantly impacts human vision. Climbing high mountains can cause retinopathy in otherwise healthy people and may lead to permanent sequelae such as retinal nerve fiber layer and optic nerve defects. These symptoms, however, may resolve without causing any permanent damage to the retina. Conservative treatment may help to relieve them. With increasing popularity of mountaineering, ophthalmologists should be prepared to diagnose and treat high-altitude retinopathy. PMID- 25799782 TI - [Ocular manifestations of acute T-cell lymphoblastic leukemia in hematological remission--a case report]. AB - The paper presents a case of a 60 year-old female referred to the Department of Ophthalmology and Ocular Oncology, Medical College, Jagiellonian University in Krakow with the sudden severe vision deterioration in both eyes. The patient was treated for T-cell acute lymphoblastic leukemia at the local Department of Hematology, at that time she was considered to be in hematological remission. Based on findings of clinical examination and additional tests, the patient was diagnosed with leukemic infiltration of the retina and optic nerve with secondary retinal detachment. Systemic and intrathecal chemotherapy as well as local radiotherapy to both eyes were administered. Ocular manifestations of T-cell acute lymphoblastic leukemia may develop in patients in hematological remission. Standard management of leukemic infiltrates involving the retina, choroid and optic nerve includes the intrathecal chemotherapy and lo- cal radiotherapy. Such therapy caused regression and cicatrization of the ocular infiltrates, but did not improve visual acuity in the described patient. PMID- 25799783 TI - X-linked retinoschisis--clinical manifestation, genetic and electrophysiological analysis of three generations with p.Arg197Cys mutation of RS1 gene. AB - The aim of the study is to present an atypical case of late-onset X-linked retinoschisis. We present a case of a 37 year-old male patient with a few months' history of visual impairment. A clinical exam with optical coherence tomography and flash electroretinography (flash-ERG) was performed and the patient was diagnosed with X-linked retinoschisis. Genetic testing of the patient's family confirmed the disease and p.Arg197Cys mutation of RS1 gene was identified. In conclusion, optical coherence tomography and flash electroretinography enabled a proper diagnosis of X-linked retinoschisis in a patient with symptoms manifesting in the fourth decade of life. Genetic testing revealed male sufferers and female carriers among his family members. PMID- 25799784 TI - [Contemporary views on perioperative prophylaxis of postoperative endophthalmitis]. AB - INTRODUCTION: Post-operative endophthalmitis, although infrequent, leads to severe, often irreversible consequences. For many years in the medical literature there have been reports on the effectiveness of various forms of prevention including antibiotics used. AIM: The aim of this study was to systematize the principles of prevention on the basis of the literature. MATERIAL: Medical reports published in recent years were compared to the conclusions of the European Society of Cataract and Refractive Surgeons (ESCRS) conducted in 16 European countries between 2003 and 2005. RESULTS: The results indicate the lack of a uniform pattern of conduct not only in a global context, but even within European countries. Povidone iodine remains the basis of prophylaxis used before surgery to decontaminate the skin of eyelids and conjunctival sac. Topical antibiotics, mainly the new generation fluoroquinolones, are also commonly used perioperatively. Intracameral injections of cefuroxime at the end of surgery are increasingly used in endophthalmitis prophylaxis. Although their high efficacy and safety have been confirmed a few years ago, the drug formulation intended and registered for use in ophthalmology has been available in most countries since 2013. CONCLUSIONS: Contemporary post-operative endophthalmitis prophylaxis, although varied in different countries, allowed for a significant reduction in the incidence of this complication in recent years. Most ophthalmologists in European countries declare to follow the ESCRS recommendations. PMID- 25799785 TI - [Ocular abnormalities in patients with prediabetes]. AB - Prediabetes is recognized as the major risk factor for type 2 diabetes. Nearly 7% of adults worldwide are estimated to have prediabetes and the prevalence is increasing. There is evidence of microvascular and macrovascular complications in patients with prediabetes. Early detection of prediabetes and lifestyle modification could therefore contribute to the prevention of type 2 diabetes and its complications. Many reports indicate the possibility of ocular abnormalities in prediabetes. A number of studies show associations between prediabetes and early forms of retinopathy. There is also evidence that colour vision and contrast sensitivity are impaired in these patients. Our study analyses data regarding ocular abnormalities in prediabetes. PMID- 25799786 TI - [Enhanced ocular staining score in patients with primary Sjogren's syndrome]. AB - The authors focus on the assessment of ocular manifestation in patients with primary Sjogren's syndrome using the Ocular Staining Score. The method offers the possibility to stain different ocular structures separately: cornea with fluorescein and conjunctiva with lissamine green dye and provides for separate evaluation of abnormalities, unlike the current system assessing ocular damage where ocular tissues are stained either with bengal rose or lissamine green dye. The paper presents new criteria for the diagnosis of dry eye secondary to the autoimmune Sjogren's syndrome and their high specificity (94.7% and 93.3%)o based on the results of clinical trials in 1618 patients, conducted by an international research team. PMID- 25799787 TI - [Molecular aspects of corneal neovascularization]. AB - In this article, we try to describe the fundamentals of the molecular mechanisms implicated in the corneal neovascularization. Corneal avascularity is maintained by a subtle balance between the constant and active production of proangiogenic and angiostatic factors. At present, the prospect of clinical and therapeutic application of this knowledge seems to be distant, but some of the recent studies investigating the already known substances instill optimism. This work is based on data from the recently published reports on the corneal angiogenesis in its complexity. PMID- 25799788 TI - [Visual impairment in posterior cortical atrophy--visual variant of Alzheimer's disease in the ophthalmic practice]. AB - Posterior cortical atrophy, also known as visual variant of Alzheimer's disease, is a rare dementia syndrome characterized by the predominant visuospatial functional deficit. The ophthalmologist is usually the first specialist consultant the patient is referred to with such complaints as: reading difficulty, face recognition problems, feeling of visual field restriction, difficulty perceiving more than one object at a time, difficulty grabbing objects under visual control, recognizing familiar surroundings, watching television or driving a car. Posterior cortical atrophy is one of early-onset (below 65 years of age) dementia syndromes and is most often associated with Alzheimer's pathology. Visual impairment is due to the disturbance of one or two visual pathways in the brain (dorsal--analyzing the stimulus localization, ventral- enabling the stimulus recognition) and subsequent atrophy of parietal and/or occipital lobe. The article presents the clinical characteristics and diagnostic criteria of posterior cortical atrophyas well as abnormal findings of the extended ophtalmic examination and methods utilised in differential diagnosis of cortical vision deficits. Early diagnosis of posterior cortical atrophy can be ensured by the close cooperation between the ophtalomogist and a neurologist specializing in the diagnosis of neurodegenerative diseases. PMID- 25799789 TI - [Michal Borysiekiewicz (1848-1899)--ophthalmology professor, head of departments in Innsbruck and Graz]. AB - Michal Borysiekiewicz (1848-1899) was an ophthalmology professor, head of the Eye Clinics in Innsbruck (1887-1892) and Graz (1892-1899). He studied medicine at the University of Vienna, where he was awarded the M.D. title in 1872. A student of Carl Ferdinand von Arlt and Carl Stellwag von Carion, the author of several clinical and research projects published in German, he focused his work on pharmacology, cataract surgery and retinal examination techniques. He also published some clinical cases. In his research, he particularly emphasized the comparative anatomy and physiology of the retina. PMID- 25799790 TI - [Bone regeneration induced by stem cells--recent research and future outlook]. AB - Alveolar bone resorption is the consequence of periodontal diseases, trauma or malignancies. Regeneration of the lost bone is crucial for the patient rehabilitation of function, phonetics and aesthetics. The surgical techniques for jaw-bone augmentation include: distraction osteogenesis, bone blocks (autologic/allogenic or xenogenic) and guided bone regeneration (GBR). These techniques have low predictability and high morbidity. As an alternative to the classical surgical approaches, in recent years, there have been developments in the field of tissue engineering which integrates the use of different scaffolds, growth factors and stem cells. This method aims to induce bone augmentation of large defects essentially mimicking biological processes that occure during craniofacial development. This article will review recent studies and a future outlook for the use of adult mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC)--in order to induce bone augmentation in cases of severe bone resorption. Regenerative therapy using stem cells may open a new horizon in periodontology, maxillofacial surgery and implantology. PMID- 25799791 TI - [Biocompatibility of composites--literature review]. AB - Composites are a large family of materials composed of polymer matrices imbedded with different types of fillers. The specific properties achievable with diverse chemical combinations provide for a wide range of implications in many industrial fields. Materials designed for medical use must not only efficiently serve the purpose of their use, but also be biocompatible to the tissues they contact and the body as a whole. Dental composites and their components have been studied intensely to assess their potential local and systemic side effects, to establish biocompatibility, in order to receive the proper conformation allowing their safe clinical use. The purpose of the following paper is to summarize several aspects of research focused on determining cytotoxicity, genotoxicity, carcinogenicity, hypersensitivity, and microbial effects of composite components, in order to ascertain in fact how biocompatible dental composite materials are. Research shows that several chemical components may be released from different types of composites, and are able to cause toxic, allergic, mutagenic and other biological effects. However, because of the small amounts applied and the unique conditions in the oral cavity, the clinical relevance of these findings is questionable. Nevertheless, caution should be taken when using these materials, to avoid possible negative outcomes. Future studies should focus on targeting most toxic components and finding biocompatible alternatives and development of materials with high polymerization efficiency in order to reduce the amount of leachable components. PMID- 25799792 TI - [A call for qualitative research in Orthodontics]. AB - Qualitative research is an umbrella term for an array of attitudes and strategies for conducting inquiries that are aimed at discerning how human beings understand, experience, and interpret the social world. It is employed in many different academic disciplines most particularly in the social sciences and humanities, however recently more and more qualitative research is being conducted under the medical sciences including dentistry and orthodontics. This is due to its nature of in-depth investigation, which can provide answers to questions that cannot be satisfactorily answered using quantitative methods alone. The aims of this article are to discuss the characteristics of qualitative research, to review the orthodontic English literature, and to highlight the advantages of qualitative research in orthodontics. The literature review yielded several important conclusions regarding qualitative research in orthodontics: 1. most of the qualitative research done in orthodontics chose to use semi structured in-depth interviews for data collection; 2. qualitative research highlights aspects that are very important, and sometimes crucial to everyday practice and long term treatment; 3. there is a lack of qualitative studies in the field of orthodontics. Taking into account the nature of the orthodontic treatment, which is a prolonged one, demanding of a good orthodontist-patient rapport, and a wide perspective on behalf of the clinician, filling the gap in the discipline through conducting more qualitative studies aimed at understanding the point of view of the patient, as well as that of the clinician, may be beneficial for the improvement of the treatment. PMID- 25799793 TI - [Teeth whitening with 6% hydrogen peroxide vs. 35% hydrogen peroxide, a comparative controlled study]. AB - INTRODUCTION: In light of the lately changes in regulations regarding teeth whitening in Europe, the use of 6% hydrogen peroxide using a dedicated device becomes the first choice treatment option. The purpose of this controlled, randomized, parallel, blinded six months prospective study was to compare this method of teeth whitening treatment with that of in-office method using 35% hydrogen peroxide. MATERIALS AND METHODS: 75 healthy american individuals, ages 18-62, participated in this study. The participants were divided into 3 groups: a 6% hydrogenperoxide group, a 35% hydrogen peroxide group and a placebo control group. Whitening procedures were performed on intact frontal teeth with color shade of A3 or higher. A controlled color measurement was performed before, immediately after, three and six months post treatment. Clinical periodontal indices, oral mucosa changes, side effects and participant satisfaction, were recorded. RESULTS: In the 6% group, the change in color shades immediately after treatment, three and six months after treatment were 2.37, 2.17 and 1.95, respectively. Tooth color changes in 35% group immediately after completion of treatment, three and six months after treatment were 3.68, 2.60 and 1.70, respectively. Statistical significant differences were found in both treatment groups between the baseline color shade and the post treatment color shade. The results were stable three and six months after treatment. Statistically significant difference between the groups immediately after treatment (p < 0.0001). No statistically significant difference was found between the two groups three and six months after treatment (p > 0.5000). Side effects such as oral mucosa irritation, burns or sensitive teeth were mild and resolved without intervention. A high satisfaction level was recorded. CONCLUSIONS: Tooth color shade can be substantially improved using a dedicated device with 6% hydrogen peroxide only. This whitening method can be helpful for the dentist in: home continuing treatment post in- office whitening specially in case with severe staining, maintenance of in-office whitening treatment outcomes or as an OTC home whitening procedure for patients with limmited budget. PMID- 25799794 TI - [Oral cancer--not only a disease of elder patients with risk factors]. AB - Head and neck cancer is currently the 7th most common malignancy worldwide with more than 600,000 new cases diagnosed each year; oral cancer alone comprises about half of these cases. Tobacco and alcohol are the main etiologic factors for oral cancer. The mean age of patients is 60 years. However, in the recent years, an alarming increase in the incidence of oral cancer among patients younger than 60 years of age with seemingly no relation to the classical etiologic factors, has been reported from several regions, mainly from Western countries. In line with this, we report the case of a non-smoker, non-alcohol user, 26-year old patient who was diagnosed with cancer of the tongue (anterior two-thirds). The tumor mimicked a traumatic ulcer, however immediate biopsy procedure enabled an accurate diagnosis and referral of the patient to treatment without delay. PMID- 25799795 TI - Effect of video-assisted teaching programme on management of breastfeeding problems. AB - With a view to assess the effectiveness of video-assisted teaching programme on management of breastfeeding problems, a quasi-experimental study with a quantitative approach was undertaken on 100 post-natal mothers. Purposive sampling technique was used in selecting the post-natal mothers. Prior to implementation of video-assisted teaching programme, the post-natal mothers had poor knowledge, whereas after implementation of video-assisted, teaching program the post-natal mothers knowledge was significantly improved with the difference of mean percentage revealing effectiveness of video-assisted teaching module. It was also found that the post-natal mothers were not aware of the importance of exclusive breastfeeding. PMID- 25799796 TI - Managing restless leg syndrome. PMID- 25799797 TI - Application of ice cube prior to subcutaneous injection of heparin in pain perception and ecchymosis of patients with cardiovascular problems. AB - In this experimental study of patients with cardiovascular problems, conducted at Safdarjung Hospital, New Delhi, purposive sampling technique was done from cardiology ward and CCU to obtain adequate samples. The sample comprised of 30 experimental group patients and 30 control group patients. The conceptual framework was based on the system model proposed by Ludwig Van Bertalanffy in 1957. Quasi experimental research approach was adopted for the study with post test only control group design. The independent variable for the study was the ice cube application for 3 min and the dependent variables were pain perception and ecchymosis. The tools used for data collection were, structured interview schedule for sample characteristics, numerical rating scale for pain for subjective assessment, transparent ruler scale to measure the total surface area of ecchymosis, and for treatment ice-cubes in latex glove for giving cold compress. Subjects were asked to rate pain by showing the flash chart of standard pain rating scale immediately after the needle was withdrawn and ecchymosis was observed 48 hrs after the day of injection. The obtained difference between experimental and control group ecchymosis score, and pain perception score was statistically significant as evident from t-value at 0.05 level of significance. PMID- 25799798 TI - Anxiety and depression levels in clients with epilepsy in selected hospital of Pune City. AB - In clients with epilepsy, the psychosocial impact of epilepsy is overwhelming. Epilepsy is chronic disease and needs long-term management. The study was conducted with the purpose to assess the level of anxiety and depression in the client with epilepsy. Results showed that there was a presence of anxiety in 40 percent cases and depression in 15 percent cases with epilepsy. The findings of this study reveal that there is no significant correlation present between the anxiety and depression level with selected sociodemographic variables. It also shows that type of family, monthly income and effect on work are potential risk factors for developing anxiety and depression in clients with epilepsy. Education and support can help clients to deal with the emotional impact of epilepsy. PMID- 25799799 TI - MCH services in Delhi in terms of beneficiaries' awareness, coverage and satisfaction. AB - Maternal and child health (MCH) services have seen many changes, the recent one being introduction of a trained female community health activist under NRHM - 'ASHA' (i.e. Accredited Social Health Activist) to actas a link worker in MCH programmes. But any programme, no matter how relevant its components are, is likely to fail unless it succeeds in improving the coverage, knowledge and imparting satisfaction to its clients. Literature and anecdotes reported a mismatch between the people's need and the services delivered. People have a right to be involved in the decision making. Clients' (beneficiaries') perception and satisfaction will help to understand the gaps and adopting a bottom-up approach i.e. the understanding of the ground realities from the mothers so as to throw light on quality, need and sustainability of the MCH-related programmes. In this descriptive study conducted in Delhi from September to December 2012 to analyse MCH services in Delhi in terms of beneficiaries' awareness, coverage and satisfaction, a multi stage sampling technique was used and a sample size of 1000 beneficiaries was selected randomly from the list of mothers obtained from the conveniently selected Primary Health Centre. Data were analysed by descriptive and inferential statistics in SPSS. The study findings showed that 92.65 percent mothers received their first ante-natal check-up in the first trimester but 48.3 percent of mothers only received three ante natal check-ups. Home visits were found to be performed by health worker both in ante natal and post natal period during 3rd month of pregnancy and within 6 week after delivery. Among the health workers who visited beneficiaries, ASHA visited mothers the most during ante natal and post-natal period and ANM visited less during ante-natal period and somewhat nil (0.1%) within first 6 weeks after delivery (post-natal). Also, 99.6percent of mothers received IFA tablets and there was 100 percent coverage of TT immunisation. Most deliveries (96%) were indicated to be institutional and 40 mothers (4%) delivered at home. The reason for home delivery was that they did not feel institutional delivery as necessary; 92.2 percent mothers were given breastfeeding within first two hours of delivery; 99.6 percent of mothers were aware about various components of MCH services and the major source of information regarding MCH services was found to be ASHA followed by ANM. Majority of beneficiaries (86%) were found to be fully satisfied with the MCH services and there was no rating below average satisfaction. No significant difference in satisfaction based on their age & educational qualification was observed; however significant difference was observed in the satisfaction based on the number of children as the mothers with more than one child were more satisfied than mothers with one child which may be due to high expectations level of mothers during first child birth than the second. PMID- 25799800 TI - An open label study to compare the efficacy of topical mometasone furoate with topical placental extract versus topical mometasone furoate with topical tacrolimus in patients with vitiligo involving less than 10% body surface area. AB - Vitiligo is a common skin disorder affecting about 1 to 2% of the world population. The prevalence in Nepal is 2-3%. This disease is associated with profound psychological distress. Though many treatment options are available none of these are universally effective. The main objective of the study is to compare the efficacy and rate of repigmentation with use of topical steroid and topical placental extract versus topical steroid and topical tacrolimus 0.1% in treating patients with localized vitiligo. One hundred patients visiting the dermatology outpatient department of Nepal Medical College and Teaching Hospital with the diagnosis of vitiligo involving less than 10% of body surface area were taken. 50 of these patients (Category A) were randomly selected and treated with topical steroid (Mometasone furoate 0.1% cream) and Topical placental extract gel. Other 50 patients (Category B) were given the same topical steroid with Topical Tacrolimus 0.1% cream. The patients were examined every month and final outcome was seen at the end of 3 months. Of the total 100 patients 51% were male and 49% were female. Seventeen percent of patients had lesions over face and neck, 49% had lesions over the extremities and 34% had lesions over trunk. At the end of 3 months the rate of repigmentation was better in patients of Category B than Category A and the result was statistically significant. Topical Tacrolimus 0.1% ointment could be better option for the treatment of localized vitiligo when compared to topical placental extract but in combination with a steroid cream. PMID- 25799801 TI - Effects of intrathecal fentanyl as an adjunct to hyperbaric bupivacaine in spinal anesthesia for elective caesarean section. AB - Hyperbaric bupivacaine is the most common drug used in spinal anesthesia for caesarean section. The aim of this study was to compare the effects of adding fentanyl to intrathecal bupivacaine on the onset and duration of spinal anesthesia and its effect on mother and neonate. Seventy healthy parturients with singleton pregnancy scheduled for elective cesarean section were randomly allocated to receive subarachnoid block with 0.5% bupivacaine heavy 2.4 ml (Group A) or fentanyl 20 microgram (0.4 ml) added to 0.5% bupivacaine heavy 2 ml (Group B). Blood pressure, heart rate, respiratory rate, oxygen saturation, along with characteristics of spinal block were assessed throughout the surgery and in the postoperative ward until the patient requested for analgesia. It was found that duration of sensory block was prolonged in fentanyl group (p < 0.05). Duration of complete analgesia (97 +/- 8.23 minutes vs 153 +/- 7 minutes; p value = 0.00) and effective analgesia (134 +/- 5.6 minutes vs 164 +/- 9; p value = 0.00) were also found to be prolonged in Group B. There was not much difference in the occurrence of side effects in both the groups. Addition of fentanyl to intrathecal bupivacaine for cesarean section increases the duration of postoperative analgesia without increasing maternal or neonatal side effects. PMID- 25799802 TI - Cystoscopic bladder biopsies: a histopathological study. AB - Urothelial carcinoma is the most common tumor of the bladder and is a major cause of morbidity and mortality. Cystitis constitutes an important source of clinical signs and symptoms. In this study 31 cystoscopic biopsies subjected for histopathological examination were taken. The study was conducted in the department of Pathology of Nepal Medial College Teaching Hospital over a period of two years (October 2012 to September 2014). The mean age of the patient undergoing cystoscopic biopsy was 61.3 years, most of the patients being elderly male. 51.6% cases were clinically malignant. The most common histopathological diagnoses were cystitis (29%) and non invasive papillary urothelial carcinoma, low grade (29%). 58% are neoplastic lesions. 51.6% of the case was malignant lesions on histopathology. Among the malignant lesion of urinary bladder 93.7% were urothelial tumor and 6.3% were glandular neoplasm (adenocarcinoma, signet ring cell). There was no detrusor muscle in 33.3% cases of urothelial tumor to assess the muscle invasion. 26.7% cases of urothelial tumor shows muscle invasion. Histopathological study of cystoscopic biopsy helps in early detection of tumor and its management. PMID- 25799803 TI - Diagnostic yield of pleural biopsy in exudative pleural effusion. AB - To know the diagnostic role of pleural biopsy in determining underlying etiological causes of exudative pleural effusion. A total of 47 patients, aged 16 104 years with mean age of 47.36 years, of either sex, with exudative pleural effusion underwent closed pleural biopsy with Abram's needle in standard way. Average 4-6 biopsy specimens were obtained from each patient, which were sent for histopathological examination. In this study, 47 cases of exudative pleural effusion were included, among them 26 (55.31%) cases were male and 21 (44.69%) were female with mean age 47.36 years. Cough was reported by 42 (89.36%) cases, expectoration 28 (59.57%), hemoptysis 3 (6.38%), breathlessness 27 (57.44%), wheezing 3 (6.38%), chest pain 38 (80.85%) and fever by 30 (63.82%) cases. Out of 47 cases, 28 (59.57%) cases had a positive yield, whereas in 19 (40.43%) cases the result was nonspecific inflammation. Out of 28 (59.57%) cases with positive yield 21 (44.68%) were found to have granulomatous inflammation and 10 (21.28%) cases were malignant. Among malignant pleural effusion, 4 cases were squamous cell carcinoma; 3 small cell carcinoma; 1 case adenocarcinoma and 1 case found to have mesothelioma. Tuberculosis and malignancy are the two most common causes of exudative pleural effusion in our set up. Pleural biopsy is a safe, simple and well validated diagnostic tool that helps us to differentiate between malignancy and tuberculosis. PMID- 25799804 TI - A qualitative assessment of methadone maintenance therapy program in Nepal: evidence to scaling up at national level. AB - Methadone maintenance therapy is widely accepted form of substitution therapy in people with Opioid dependent client. It is a kind of harm reduction strategy which prevents the spread of HIV and hepatitis among injecting drug users. It also improves quality of life and help decrease crime and other social issues. The program has been in Nepal for few years. The clients are increasing more each day and the demand for the program is also increasing. There is an urgent need of scaling-up the program in Nepal to address the increasing number of clients and unreached clients. This is an attempt to assess qualitatively the methadone maintenance therapy program in Nepal to generate evidences as a support to existing programs and to scale up the program in unreached population. The qualitative study revealed that the clients had adequate knowledge on the program and the program is quite satisfactory. However, they have to wait for a long to get enrollment in the program, there is no counseling session and they were more concern about the quality of the drug. Despite many lacunae, the participants found the program very useful in terms of developing good relation with family members, decreasing the necessity of money, being able to attend social functions, health and economic benefits, time saving, easily getting job. On the other hand, they were experiencing adverse effect such as decreasing sexual performance, dental caries, nausea, social stigma due to misuse of the program by some clients which are not properly addressed by the program. The program can be improved by making it priority problem at national level by the government, improving it as one stop shopping such as providing counseling, medicine and skill development program at one place. PMID- 25799805 TI - Re-evaluation of the formalin-ether sedimentation method for the improvement of parasite egg recovery efficiency. AB - The formalin-ether sedimentation (FES) method is considered as reliable method of fecal examination for the detection of parasites. In this study, we re-evaluated several aspects of FES such as (i) pretreatment of feces; (ii) filtration of fecal suspensions; (iii) test-tube material and (iv) substitution of ether by other organic solvents as to see an improvement in parasite egg recovery. The egg count was represented by the number of ova detected per 100 MUg of sediment. Pre treatment of feces with formalin (pH 7) increased egg detection rate remarkably compared with original FES method. Use of three layers of gauze dramatically reduced the sediment in the final product, and led to an increase in the number of ova detected. Use of polypropylene test tubes instead of glass test tubes also increased the number of egg detection. None of the organic solvents used to replace the ether produced better results. Based on these findings, we proposed a modified FES procedure. Further, we also compared the parasite positive rate and the number of ova recovered by using original FES and the modified FES procedures by examining 112 fecal samples collected from school children of parasite endemic area in Nepal. Feces collected from Nepal had many parasite ova, and these fecal samples barely displayed false-negative results even by method with low sensitivity. When the mean number of Hemenolepis nana, hookworm, T. trichiura, and A. lumbricoides ova recovered by original FES and the modified FES methods was compared, the values obtained by modified FES were superior (higher). This result suggested that the modified FES is effective and better for the recovery of parasite ova in areas of low-intensity parasitic infection. PMID- 25799806 TI - USG assisted and USG guided percutaneous renal biopsy at Nepal Medical College Teaching Hospital: a three and half years study. AB - A prospective study was carried out from 2009 to 2013 in the Department of Radiology and Imaging of Nepal Medical College and Teaching Hospital, Attarkhel, Jorpati, Kathmandu, Nepal, in which a total of 75 patients underwent percutaneous renal biopsy with a 16 or 18 gauge needles. This was done blindly by marking a site on the skin, or, whenever there was difficulty with the blind procedure, by direct real time USG guidance. In all cases, the marking in the skin was done by the radiologist and the biopsy was performed by the Nephrologist, with the aid of the radiologist in cases of real-time USG guided renal biopsy. This study was carried out to assess the safety and efficacy of the USG aided, and USG guided renal biopsy, to see for the types and severity of complications arising from renal biopsies to determine the optimal period of observation required after the procedure. All renal biopsies were performed after the patients were admitted to the hospital at least 1 day prior to the procedure. Coagulation profile was done in all patients prior to the procedure. All patients were kept under strict complete bed rest for 24 hours post procedure. The ages of the patients ranged between 14 years to 71 years, with 42 female and 33 male patients. A mean of 21.8 glomeruli was obtained in each specimen, with absent glomerular yield seen in only 3 patients. Minimal change disease was seen in 19 patients, being the most common histopathological diagnosis followed by a spectrum of others. The overall complication rate was 4% and all of these were self-limiting needing no other intervention, or management except for observation and bed rest. Late complications were not seen. Percutaneous renal biopsy with the help of USG is a safe and efficacious procedure with less chance of minor complications. PMID- 25799807 TI - Serum uric acid level in normal pregnant and preeclamptic ladies: a comparative study. AB - Preeclampsia is a serious pregnancy complication characterized by hypertension, proteinuria with or without pathological edema. According to some studies, serum uric acid lacks sensitivity and specificity as a diagnostic tool whereas another group of the researchers indicated uricemia as a predictor of preeclampsia in pregnant ladies. The present study was designed to assess whether serum uric acid can be used as a biochemical indicator or not in preeclamptic patients. Pre eclamptic patients admitted in Nepal Medical College Teaching Hospital from June 2012 to June 2013 were included in this study. Age matched normal healthy pregnant ladies served as control. The record of their blood pressure and serum uric acid level was evaluated. Results showed significantly high blood pressure [SBP 149.42+/-12.35 vs 109.00+/-7.93 mm Hg; DBP 96.85+/-8.32 vs 72.5+/-7.10 mm Hg], and serum uric acid level [6.27+/-1.37 vs 4.27+/-0.61 mg/dl] in pre eclamptic patients compared to their healthy counterparts. Uric acid is a terminal metabolite of the degradation of nucleotides, which increases their blood levels in patients with preeclampsia increasing its synthesis by damage and death of trophoblastic cells and proliferation. Uricemia in preeclampsia likely results from reduced uric acid clearance from diminished glomerular filtration, increased tubular reabsorption and decreased secretion. Results of the present study indicated association of elevated serum uric acid level with preeclampsia which could be used as a biochemical indicator of preeclampsia in pregnant women. PMID- 25799808 TI - Acute otitis media: a simple diagnosis, a simple treatment. AB - To assess the symptoms and signs of acute otitis media and efficiency of simple antibiotics like amoxicillin in its treatment in the primary health care setup. This is a prospective longitudinal study including 204 patients from different institutions. Patients were diagnosed as suffering from acute otitis media when presented with earache, fever, fullness and or otorrhea. Patients were divided into two equal groups on basis of the treatment they received, Group A received only symptomatic treatment while Group B were given Amoxicillin (40 mg/kg/day) for 7 days. Acute otitis media was common in children under 15 years (64.7%). Patients presented with earache (100%), aural fullness (90.68%), fever (76.47%) associated with recent onset of upper respiratory tract infections (88.23%). In group A, improvement was noticed in 28.43% in 3 days while 35.29% in 7 days. In group B, improvement was noticed in 48.03% in day 3 while 86.27% in day 7. In countries where medical care is scarce, patients lost to follow up, it is wise to treat with simple antibiotics like amoxicillin in adequate dose than to treat only symptomatically. It prevents chronicity, early hearing impairments and reduces antibiotic resistance. PMID- 25799809 TI - Clinical and contact allergological observations on hand eczema: a descriptive study. AB - Hand eczema (HE) is a common and distressing condition that is perplexing to the patient and the physician alike. To study the frequency and clinical features of hand eczema and to correlate the frequency of atopy and contact sensitization with different clinical features a total of 61 clinically diagnosed patient of Hand eczema were included within a period of one year. Patch test was done in 47 patients and graded accordingly. The frequency of hand eczema was 0.57%. Morphologically pompholyx was the most common type while aetiologically endogenous hand eczema was the commonest. Contact allergy was observed in 55.3% of the cases of which nickel sulphate (18.5%) was found to be the commonest sensitiser followed by Gentamicin and Fragrance mix though contact allergens with positive patch test in different morphological types of hand eczema have no apparent relevance but it still could contribute to the persistence or exacerbation of hand eczema. PMID- 25799810 TI - Reduced susceptibility to vancomycin in methicillin resistant staphylococcus aureus: a time for action. AB - Infections by Methicillin resistant Staphylococcus aureus (MRSA) is an often encountered therapeutic challenge. The problem is accentuated by the emergence of MRSA strains which are resistant to Vancomycin, the recommended agent for the treatment of MRSA infections. We therefore carried out this study to determine the MIC values ofvancomycin for the MRSA isolated from different clinical specimens in Nepal Medical College. MICs were determined by agar dilution method. Out of the 82 MRSA isolates tested, 18 showed MIC of 2 MUg/ml and 29 isolates had MIC of 1 MUg/ml and 35 isolates had MIC of 0.5 MUg/ml. Although none had a MIC in the intermediate or resistant zone, 18 (2.9%) had MIC in the upper limit of the sensitive zone which is a matter of concern and calls for prompt preventive actions. PMID- 25799811 TI - Effectivity of Nd Yag PI in treatment of acute primary angle closure glaucoma. AB - A Prospective hospital based study to note the efficacy of Nd Yag Peripheral Iridotomy (PI) in the treatment of acute primary angle closure glaucoma was carried out in Nepal Eye Hospital from Jan 2007 to Jan 2008. All the Patients (n=50) with acute primary angle closure glaucoma admitted to our hospital were selected for the study. Patients with secondary angle closure glaucoma were excluded. It is more common in age of 56-65 years (20%), in females (70%), and in tibetoburman ethnic group (56%). Mean duration of presentation to hospital was 5 days (22%) (Range 4-7 days). Grade 1 Angle closure was present in 74%. All 50 patients (100%) with AACG had undergone Yag PI. Out of 50 patients, 11 patients (22%) were surgically operated i.e. trabeculectomy. Among 11, 1 patient (9%) who had undergone trabeculectomy had presented with acute on chronic angle closure glaucoma. Majority of cases (66%) presented with visual acuity (VA) 1/60-PL at the time of presentation and the Intraocular pressure (IOP) in affected eye was 31-40 mmHg (42%). After performing Yag PI the mean visual acuity in the affected eye at the time of discharge was 6/60 (20%) and the IOP was 12 mmHg (40%). Prolonged duration of attack, elderly age, acute on chronic angle closure glaucoma, very high IOP at presentation, patients needing repeat Yag PI were found to have failure Yag PI. In this study 78% eyes had controlled IOP following Yag PI. PMID- 25799812 TI - Prevalence of intestinal parasitic infections among public school children in a rural village of Kathmandu Valley. AB - Intestinal parasitic infections (IPI) are one of the most prevalent infections in humans residing in developing countries and its burden is high among school aged children. This cross-sectional study was conducted to determine the prevalence of intestinal parasitic infection and types of intestinal parasites in rural public school children of Nepal. It included students from Nursery to Class X of a rural public school located in the northeast part of the Kathmandu Valley, Nepal. Among the 194 participating children, prevalence of intestinal parasitic infection was found as 23.7%; (28.2% for boys; 20.2% for girls). Amongst the infected children, single and mixed parasitic infection was detected in 43 (93.5%) and 3 (6.5%) children respectively. Among protozoan parasites, Giardia lamblia was the most common (58.6%) whereas Hymenolepis nana was the most common (21.7%) among the helminths. Statistically different prevalence of intestinal parasitic infection was observed among children aged above 10 years and children aged below 6 years as well as 6 to 10 years. Gender-wise, there was no statistical difference in prevalence of intestinal parasitic infection. This study suggests the need of health education program in schools along with regular screening of intestinal parasites and treatment for effective management of the intestinal parasites among school children in Nepal. PMID- 25799813 TI - Status of iron, oxidant and antioxidants in chronic type 2 diabetes mellitus patients. AB - Diabetes mellitus is a common health problem of the world. Iron may be a part of the cause of the disease and its complications. Iron is a trace element which produces reactive oxygen species (ROS) participating through Fenton reaction and that ROS may be a cause to produce oxidative stress and further diabetic complications. The study aims to access the iron and its effect in producing oxidative stress in type 2 diabetic patients. Serum iron, total iron binding capacity (TIBC) and percentage transferrin saturation are calculated as the index of iron. Malondialdehyde (MDA) is estimated as index of oxidant and vitamin C, vitamin E are measured as index of antioxidants. This is a case control study conducted in the department of Biochemistry in collaboration with department of Medicine at B P Koirala Institute of Health Sciences (BPKIHS), Dharan, Nepal. 52 chronic type 2 diabetes mellitus patients and 52 age and sex matched normal healthy controls were included in the study. Plasma iron, TIBC, percentage transferrin saturation were found (89.14+/-30.50 MUg/dL), (266.78+/-48.80 MUg/dL), (36.61+/-14.31%) in diabetic cases as compared to (83.98+/-24.19 MUg/dL), (279.08+/-40.23 MUg/dL), (31.05+/-10.98%) of healthy controls. A significant increase in MDA level (6.35+/-1.52 nmol/ml in cases and 4.18+/-1.12 nmol/ml in controls, p<0.001) and significant decrease in vitamin C (0.85+/-0.19 mg/dL in cases and 1.28+/-0.21 mg/dL in controls, p<0.001) and vitamin E (0.85+/ 0.25 mg/dL in cases and 1.34+/-0.38 mg/dL in controls, p<0.001) were observed. PMID- 25799814 TI - Outcome of treatment of nonunion tibial shaft fracture by intramedullary interlocking nail augmentated with autogenous cancellous bone graft. AB - To assess results of operative treatment of non union fracture shaft of Tibia by intramedullary interlocking nail augmented with autogenous cancellous bone graft in our setup. A total of 25 nonunion tibial shaft fractures were evaluated among which 20 cases were male and 5 female with the mean age 31.84 years. Hypertrophic non-union were 14 and atrophic non union were 11. Upper one third of tibial diaphysis was involved in 4 cases, middle one third in 14 cases and lower one third in 7 cases. In all cases open reduction, interlocking nailing and autogenous cancellous bone graft was applied. The mean follow up was one year. Mean time for healing was 8.08 months. Mean operation time was 110 minutes (range 70 to 160 minutes). Satisfactory results (excellent and good) were achieved in 88% cases and unsatisfactory (fair and poor) results in 12% cases. This operative treatment option appears to have a high success rate and should be considered in nonunion of tibial diaphysis. PMID- 25799815 TI - Value of conventional cervical cytology as a screening test for cervical cancer. AB - This is a prospective study conducted in the department of Obstetrics and Gynecology of Nepal Medical College Teaching Hospital, Kathmandu, Nepal. The main Objective of the study is to see the value of opportunistic screening program for cervical pre-cancerous lesion for prevention of cervical cancer. It also aims to see how many cases can be picked up by such screening test and is it worth doing this test? We analysed 1751 cases of pap smear taken during almost 2 years period and found inflammatory smear being the predominant finding and it was found in reproductive age group. We had 1.14% cases of abnormal smear and 0.74% cases were proved by biopsy. PMID- 25799816 TI - Evaluation of intradermal vaccination at the anti rabies vaccination OPD. AB - Rabies is a virtually 100% fatal acute viral encephalitis caused by an RNA virus belonging to family Rhabdoviridae and genus Lyssavirus. The virus can infect all warm blooded animals. The disease is transmitted to humans by the bite, lick or scratch of an infected animal. More than 99% of all human rabies deaths occur in the developing world. It is preventable with timely and proper usage of modern immunobiologicals (vaccines and immunoglobulins). Once exposure occurs, modern prophylaxis entails immediate wound care, local infiltration of rabies immune globulin and parenteral administration of modern cell culture vaccines in multiple doses. The annual medicinal (vaccines and other drugs) cost for animal bite treatment is Rs. 2 billion approximately (2004). The objective of the present study is to evaluate the performance of the Intradermal (i.d.) route visa vis the Intramuscular (i.m.) route in our clinical setting the Antirabies Vaccination (ARV) OPD, Sir J.J. Hospital, Mumbai. A total of 1460 patients were administered the Antirabies vaccine by the Intradermal route over the 1 year period as compared to 1075 patients who were administered the Antirabies vaccine by the Intramuscular route in the previous year. 1230 (84.2) of the patients who were administered the vaccine by the i.d. route completed the schedule and 230 (15.8%) partially completed the schedule. Four hundred thirty two (40%) of the patients who were administered the vaccine by the Intramuscular route completed the schedule and 643 (59.8%) partially completed the schedule. The vaccine cost for i.d. was Rs. 2,80,600. The vaccine cost for the intramuscular (i.m.) assuming 84% compliance was estimated as Rs. 15, 64, 000. Assuming 40% compliance the cost was estimated as Rs. 7, 82, 230. Thus a saving of Rs. 5, 01, 630 to Rs. 12, 83, 400 was effected. In our setting, the Intradermal regime was cost effective and increased patient adherence and enrolment. It has now been routinely adopted at the clinic. PMID- 25799817 TI - Stapled haemorrhoidectomy in the operative treatment of grade III and IV haemorrhoids. AB - Stapled haemorrhoidectomy (SH) is a minimally invasive intervention that uses a stapling device which avoids the need for wounds in the sensitive anal area and reduces the pain after surgery. This study was undertaken in Nepal Medical College Teaching Hospital from January 2010 to December 2012 to evaluate the efficacy of this modality of treatment among patients (32) who presented in the Surgery OPD with grade III and grade IV haemorrhoids. The results of SH were evaluated by the relief of symptoms, severity of post operative pain, and complications of SH. Twenty five (78.1%) patients had grade III and 7 (21.9%) presented with grade IV hemorrhoids. The most frequent presentation reported in our study was bleeding per rectum with perianal prolapse. Mean operating time was 40-60 minutes whereas mean hospital stay was 1.9 days. Urinary retention was the most common complication found in 12 (37.5%) patients in the immediate post operative period. SH is a safe, rapid, and convenient surgical remedy for grade III and grade IV hemorrhoids with low rate of complications, minimal postoperative pain, and shorter hospital stay. PMID- 25799818 TI - Spectrum of bacterial pathogens and their antibiogram from cases of urinary tract infection among renal disorder patients. AB - Urinary tract infection (UTI) is the commonest bacterial infection occurring in renal disorder patients and is associated with significant morbidity. Resistance to antibiotics is highly prevalent in bacterial isolates and is an emerging problem in UTI. A hospital based cross sectional study was conducted from April 2011 to September 2011 to determine the frequency and bacterial profile of urinary tract infections in the patients with renal disorders visiting KIST Hospital along with their antimicrobial susceptibility pattern. Urine samples were collected from 300 clinically-suspected cases of UTI among renal disorder patients and investigated by conventional semi-quantitative culture technique, microscopy and antibiotic susceptibility test. Significant bacteriuria were detected in 34% of the total subjects, mostly from patients with Chronic Kidney Disease. Incidence of bacteriuria was found higher in females (40.40%) than in males (27.52%) and mostly occurred in elderly patients. Escherichia coli (62.75%) was the predominant isolate followed by Klebsiella pneumoniae (10.78%), Staphylococcus aureus (9.80%), Coagulase negative Staphylococcus aureus (CoNS) (5.88%), Enterococcus spp (3.92%), Klebsiella oxytoca (2.00%), Pseudomonas aeruginosa (2.00%), Proteus mirabilis (2.00%) and Proteus vulgaris (1.00%). Multidrug resistance was observed in 68.82% of the total bacterial isolates. PMID- 25799819 TI - Computed tomogram guided fine-needle aspiration cytology of lung and mediastinal masses with cytological correlation: a study of 257 cases in Western region of Nepal. AB - Computed tomogram guided fine needle aspiration cytology (FNAC) is an important and useful investigation to differentiate between benign and malignant lesions of lungs. To evaluate the lung and mediastinal masses and to analyze and compare the results with cytological findings, 257 patients were retrospectively studied who underwent CT guided FNAC over a period of 2007 to 2013. The study was done in patients who presented with respiratory symptoms with a localized lung lesion which was confirmed radiologically. 252 cases of lung masses and 5 cases of mediastinal cases were included. Patients' age ranged from 24 to 84 year and the male to female ration was 1.2:1. Radiologically, out of 257 cases, 225 cases were given as malignant, 8 cases as benign and 24 cases as inflammatory lesions. Cytologically, 212 cases were malignant, 12 cases were benign and 21 cases were inflammatory. Most common lung malignancy was adenocarcinoma (87 cases) followed by squamous cell carcinoma (56 cases). 8 cases of lung metastasis were seen. Compared to biopsy, CT guided FNAC shortens the diagnostic interval and helps in differentiating lung malignancy into different cytopathological types which aids in proper management of the malignant lesion. PMID- 25799820 TI - Dental caries status and oral health practice among 12-15 year old children in Jorpati, Kathmandu. AB - Oral health is an essential component of health throughout life. There has been a decline in dental caries and periodontal disease in developed countries which can be attributed to the implementation of preventive programmes but in developing countries dental diseases are still on the rise. Therefore this cross sectional study was carried out to assess the prevalence of dental caries and oral hygiene practices among 12 to 15 years old children. Self administered close ended questionnaires were used to assess the oral hygiene practice. The overall dental caries prevalence was 58.3% and the mean DMFT score was 1.2 (+/- 1.79) and the deft score was 0.6 (+/- 1.24). Majority of the children (84.1%) presented with the practice of brushing their teeth once everyday using tooth brush and toothpaste. Regular dental check up was very poor (5.6%) but 77.4% reported that they visited a dentist in case of pain or presence of stains in the teeth. Females (63.4%) and children studying in higher secondary class (74.2%) showed a "good" level of oral hygiene practice than males and children in secondary class respectively. Children having "good" practice presented with "low" dental caries severity. The utilization of dental services was poor in the children, therefore highlighting the necessity to implement preventive programmes is important which would help in reducing the incidence of the dental caries as well as aiding in prompt treatment of dental caries at its initial stages. PMID- 25799821 TI - D test: a simple test with big implication for Staphylococcus aureus macrolide lincosamide-streptograminB resistance pattern. AB - D test is a simple disc diffusion test giving high throughput results. It is used to study the macrolide lincosamide streptogramin resistance (MLSB), both constitutive and inducible as well as macrolide streptogramin resistance (MSB) in Staphylococcus aureus. In this test, erythromycin (macrolide) and clindamycin (lincosamide derivative) discs are placed adjacent to each other over the Mueller Hinton agar medium inoculated with the test organism. The growth of the organism up to the edges of the disc, flattening of the clindamycin zone (D test positive) near the erythromycin disc (resistant) and susceptible to both antibiotics implicate that the organism is having constitutive MLSB (CMLSB), inducible MLSB (IMLSB) and no resistance respectively. Further, the organism susceptible to clindamycin without any flattening of the zone (D test negative) near clindamycin disc (resistant) implicates that the organism is having macrolide streptogramin resistance (MSB). The test is performed in the same MHA plate in which the antibiotic sensitivity test is being done, taking into consideration that the discs are placed adjacent to each other maintaining the distance. Since clindamycin and streptogramin are among the few drugs of choice in the treatment of methicillin resistant S. aureus (MRSA) infections, knowing the resistance to these antibiotics is imperative. PMID- 25799822 TI - Bedside sonographic evaluation of the diaphragm in ventilator dependent patients with amyotrophic lateral sclerosis. A report of two cases. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive and inexorable loss of bulbar and limb functions. Respiratory muscle weakness and failure is a common complication late in the course of disease. Bedside ultrasonography of the diaphragm was done in two ventilator dependent patients with ALS. Thickness of the diaphragm was markedly reduced during both end expiration and end of deep inspiration. The degree of diaphragmatic thickening was also significantly reduced. The diaphragmatic excursion during deep inspiration was sub-optimal. The findings were consistent with diaphragmatic atrophy and paralysis. Sonography of the diaphragm can be a useful non-invasive bedside tool for the diagnosis and follow up of diaphragmatic involvement in patients with amyotrophic lateral sclerosis. PMID- 25799823 TI - Axillary arch and other neurovascular anomalies in a cadaver. AB - The co-existence of multiple variants in the axilla has been rarely documented. Hence, we report the multiple variations of axillary structures and axillary arch. During a dissection of axilla of adult male cadaver, following variations were encountered. a) One superficial and complete type of axillary arch on left axilla only. b) Venous chiasma between the basilic vein and brachial vein of both sides. c) Abnormal course of intercosto-brachial nerve on left side d) Presence of two medial cutaneous nerve of forearm and the absence of medial cutaneous nerve of arm on left side only. The presence of such variations should be kept in mind while performing various invasive and surgical techniques. PMID- 25799824 TI - [The working classification and early diagnostics of ankylosing spondylitis]. AB - A work classification of ankylosing spondylitis is presented including such novel concepts as the stage of the disease (instead of sacroiliitis), extra-axial and extra-skeletal manifestations. Modern approaches to the evaluation of disease activity are described Extensive explanations of these notions are presented together with the recommendations on formulation of diagnosis. The advent of new and more eficacious methods of visualization as well as more sensitive and specific criteria for inflammatory nature of back pain are considered The authors modified the traditional criteria for ankylosing spondylitis and developed their version to be verified in clinical practice in this country. PMID- 25799825 TI - [Ectopic varicosis: a rare case of gastrointestinal hemorrhage]. AB - The author discusses causes, diagnostics and treatment of ectopic varicosis of the gastrointestinal tract. Bleeding from these pathologically dilatedprotosystemic collateral veins at sites beyond the gastroesophagealjunction is rare, but the high lethality rate associated with this condition is a serious challenge. The author emphasizes the necessity of multicentre clinical studies yielding important data on epidemiology ofectopic varicosis for the development ofa diagnostic and therapeutic algorithm for the management of accompanying hemorrhage. PMID- 25799826 TI - [The clinical significance of hepcidin detection in the patients with anemia and rheumatoid arthritis]. AB - The prevalence of anemia in patients with rheumatoid arthritis (RA) varies from 30 to 70%. 25% of the cases are diagnosed within 1 year after onset of the disease. On the whole, anemia in RA is described as anemia of a chronic disease (ACD). Pathogenesis ofACD is a multifactor process underlain by an immune mechanism: cytokines and cells ofthe reticuloendothelial system cause changes in iron homeostasis, proliferation of erythroid precursors, erythropoietin production and lifespan of erythrocytes. The key pathogenetic factor is disordered iron metabolism. IL-6 increasing hepatic production acute-phase protein (hepcidin) is the most important cytokine involved in ACD pathogenesis. Hence the necessity to measure its serum level for differential diagnostics of anemic syndrome in patients with RA and the choice of effective basal therapy. Recent data on the therapeutic potency of tocilizumab (IL-6 receptor inhibitor) demonstrate not its safety and sustainable beneficial clinical effect in combination with the favourable action on hemoglobin profile and reduction offatigue. PMID- 25799827 TI - [Multicenter retrospective analysis of the patients with sarcoidosis with a 10 year interval in observations]. AB - Comparison of the state of 83 patients with histologically confirmed sarcoidosis observed with a 10 year interval revealed remission in 47% of the cases. The main factors having negative effect on prognosis of the disease included extrapulmonary symptoms, the use ofcorticosteroids (at all stages, especially at stage I and in Lofgren syndrome) and antituberculosis drugs, positive TB test. Risk factors of relapses were stage II sarcoidosis, the use of systemic corticosteroids in patients with Lofgren syndrome and antituberculosis drugs, initially low FEV1/FVLC ratio and the number of lymphocytes in peripheral blood. PMID- 25799828 TI - [Community-acquired pneumonia: from national recommendations to regional standards]. AB - Community-acquired pneumonia (CAP) is a major challenge facing health service. The aim of this work was to estimate the effectiveness of introduction of Sverdlovsk region territorial CAP standards into clinical practice in 2002-2011. MATERIALS AND METHODS: Retrospective analysis included 523 case histories of the patients who diedfrom CAP and 127 one who recovered after treatment (groups 1 and 2 respectively). The primary end-point was general and intrahospital mortality rate, secondary end-points the day of admission to the intensive therapy unit (ITI) and the onset of starting antibiotic therapy (ABT), conformity of ABT to the regional standard. Independent and patient/hospital-dependent risk factors of unfavourable outcome of CAP were subjected to statistical analysis. RESULTS: In 2002-2011 mortality rate among the able-bodied population and hospitalized patients with CAP decreased by 46 and 15.4% respectively (overall 30.7%). Chronic alcoholism, poor social status (to 53.9 +/- 2.4%), late application for medical aid (77% of the patients applied later than 3 days after the onset of CAP) were risk factors of unfavourable outcome. The time of CAP onset in groups 1 an d 2 was 5.7 +/- 10.3 and 2.2 +/- 4.5 hr respectively (OR: 5.31 [95% CI 2.32 = 12.16] p < 0.01). ABT conformed with the regional standards in 7.4 and 92.1% of the cases in groups I and 2. CONCLUSION: Strict compliance with national guidelines and regional programs ensures success of diagnostics and treatment of CAR PMID- 25799829 TI - [Peculiarities of thrombin generation and prognosis of unfavourable outcome in patients with severe pneumonia and pneumogenic sepsis]. AB - The study of thrombin production included 68 patients with severe pneumonia (SP) undergoing monitoring plasma thrombin potential in the thrombin generation test. Thrombin production was found to decrease in the patients who died compared with those alive on days 3-5 and 7-10 after onset of the disease. Endogenous thrombin potential decreased progressively during the first 7-10 days among the patients with the fatal outcome of SP. This trend in thrombin generation can be used to predict the unfavourable outcome of SP. PMID- 25799830 TI - [Interstitial lung diseases in the practical work of pulmonological and rheumatological departments of a multifield hospital]. AB - The aim of this work was to study the incidence, diagnostics and clinical features of interstitial lung diseases (ILD) in the practical work of pulmonological and rheumatological departments of a multifield hospital Theanalysis included 565 case histories of the patients admitted to these departments in 2008-2012. The structure of ILD was elucidated along with the frequency of major clinical symptoms ofsarcoidosis and rheumatic diseases, the occurrence of clinico-morphological variants of ILD. Difficulties encountered in diagnostics of ILD and systemic scleroderma as well as their causes are discussed Resultsof the 5 year followup of 40 patients are presented. PMID- 25799831 TI - [The use of stepwise antibacterial therapy of community-acquired pneumonia]. AB - The need of stepwise antibacterial therapy of community-acquired pneumonia is an important indicator of patient's condition and provides clinical and economic advantages for both the patients and the medical facility. High compliance with this approach is promoted by the regular retrospective assessment of its advantages and the availability ofproper dosage forms of the prescribed antibiotics. PMID- 25799832 TI - [Systemic and local stiffness of the arteries in young patients with arterial hypertension]. AB - The aim of the work was to study characteristics of systemic and local arterial stiffness in young patients with arterial hypertension (AH) suffering this condition in the childhood or adulthood and to relate them to risk factors of cardiovascular complications. Materials and methods. 54 patients aged 18-35 (mean 25.3 +/- 3.4) years with AH. 37 of them had AH since 18 year and 27 ones starting from the childhood or adulthood Control group included 26 healthy volunteers aged 25.8 +/- 3.7 year. The carotid-femoral pulse wave propagation rate (PWPR) was measured by applanation tonometry with a SphygmoCor apparatus. Parameters of carotid stiffness of CCA were studied by the echo-tracking method using Aloka ProSound a7 device. Results. Patients with AH and without it in the childhood or adulthood showed higher PWPR values than controls (7.1 +/- 1.2 and 7.5 +/- 1.4 vs. 6.3 +/- 1.0 m/s respectively) Ep and AC values were higher in patients who did not have AH in the childhood or adulthood: right Ep 89 +/- 24.4 and 68.7 +/- 18.4 kPa, AC 0.9 +/- 0.2 and 1.1 +/- 0.1 mm2/kPa respectively; left Ep 86.1 +/- 20.3 and 71/4 +/- 16 kP AC 0.9 +/- 0.2 and 1.1 +/- 0.1 mm2/kPA (p < 0.05). In the patients with AH since the childhood or adulthood with concomitant metabolic syndrome (MS) the PWPR values and carotid artery stiffness were higher than in the absence of MS (p < 0.05). CONCLUSION: Young patients with AH showed carotid femoral PWPR compared with control regardless of AH in the childhood or adulthood Parameters of local carotid stiffness were increased only in patients having no AH in the childhood or adulthood Patients with AH since the childhood or adulthood with concomitant MS had higher carotid stiffness and carotid-femoral PWPR than in the absence of MS PMID- 25799833 TI - [The role of adipose tissue in rheumatoid arthritis]. AB - AIM: To estimate the frequency of obesity in a Russian cohort of patients with early rheumatoid arthritis (RA), determine adipocytokine (adiponectin, leptin) levels and their relation to RA activity. MATERIALS AND METHODS: 47 patients with early RA fulfilling ACR/EULAR(2010) criteria and using no BAID or GC. Mean age 57 [47;62] yr, duration of disease 7 [4;8] yr, median of DAS28 5.9 [5.3; 69]. Control group included 30 age-matched healthy donors. The degree of obesity was assessedfrom metabolic syndrome criteria (NCEP/ATPIII, RSSC, WHO); leptin and adiponectin were measured by ELISA, the L/A ratio was calculated. RESULTS: Patients with RA had the same mean BMI but greater waist circumference (WC) and waist/hip ratio than controls (p=0.003 and p = 0.04). Obesity was diagnosed in 63.8 and 40% of the patients in these groups (p=0.04) based on NCEP/ ATPIII criteria and in 65.9 and 40% respectively by WHO criteria. The occurrence of obesity by RSSC criteria was not significantly different (p = 0.9). In patients with RA adiponectin level was higher (p=0.04) while leptin level and L/A ratio lower (p=0.02 and 0.003) than in controls. BMI correlated with ESR, CRB, DAS28, leptin and L/A (p<0.05) in both groups. ESR positively correlated with leptin level andA/L but negatively with adiponectin level (p<0.05). CONCLUSION: The study showed high prevalence ofobesity in patients with early RA and its relation to inflammation. It was associated with increased serum adiponectin level, decreased leptin level and insulin resistance. PMID- 25799834 TI - [Clinical, endoscopic and morphological manifestations of oesophageal lesion in systemic scleroderma]. AB - Oesophageal lesion is the commonest visceral manifestation of systemic scleroderma (SSD) affecting the quality of life and fraught with serious complications. The aim of this study was to evaluate clinical, endoscopic andmorphological manifestations of oesophageal lesion in systemic scleroderma and its relationships with other clinical symptoms and pharmacotherapy of the disease. MATERIALS AND METHODS: 479 patients with SSD (93.7% women, 6.3% men, mean age 48.7 +/- 19.2 yr). All of them underwent EGDS in 2005-2010. 123 patients were examined for the detection of Barrett's oesophagus (BO), total screening regardless of complaints was conducted in 2010. Control group included 1018 age and sex-matched patients with RA who underwent EGDS in 2008-2009. RESULTS: Oesophageal lesions occurred much more frequently in SSD than in RA. Oesophageal symptoms were documented in 70.0 and 29.9% cases, non-erosive oesopahgitis in 28.8 and 1.5%, erosive esophagitis in 22.5 and 2.2% ulcers in 0.8 and 0% (p < 0.001). BO manifested as intestinal metaplasia (histological study of mucosal biopsy) was found in 30 SSD patients (4.2%). Screening revealed BO in 8.9% of the patients. The development of erosive oesophagitis was unrelated to the age of the patients, duration of the disease and its form (localized or diffusive), lung pathology or Sjogren's syndrome. Cytotoxic medicines significantly increased the frequency of erosive oesophagitis, it tended to increase under effect of NSAID and low doses of aspirin. Long-term intake of PPI did not reduce the risk of oesophagitis and BO. CONCLUSION: Half of the patients with SSD have oesophagitis. Over 20% of them suffer its complications (erosion and ulcers) and 9% have BO. All such patients need endoscopic study ofoesophagus regardless of clinical symptoms. PMID- 25799835 TI - [Results of analysis of clinical effectiveness of cytoprotectors used in therapy of widespread forms of psoriasis]. AB - The authors report comparative analysis of the efficacy of cytoprotectors and basal therapy used to treat widespread forms of psoriasis. Combination of both modalities including remaxol and ademetionine increases the effectiveness of the treatment by 23% as appears from the decrease of PASI of 89.6% patients from 23.6 +/- 2.2 to 5.7 +/- 2.2 scores. PMID- 25799836 TI - [Answer to the paper by Shamov I. A]. PMID- 25799838 TI - [Studies on Yakushi Buddha and its medicinal container]. AB - In Japan, there are about 250 Yakushi Buddha (i.e., Buddha of Healing) statues in Buddhist temples. They are listed as Important Cultural Properties and 14 of them are National Treasures. Belief in Yakushi Buddha was especially prevalent from the 7th to the 13th centuries in Japan. The oldest wooden Yakushi Buddha statue is in Horin-ji Temple in Nara. Among the approximately 250 Yakushi Buddha statues, about 200 have medicinal containers-or rarely, a bowl-in the palm of the left hand. However, these medicinal containers are wooden blocks. Very recently, it was found that the Yakushi Buddha statue in the Suho-Kokubun-ji Temple in Yamaguchi Prefecture, Japan has a medicinal container in the palm of his left hand, in which an offering (i.e., 220 g of materials) was found. The date on the reverse side of the lid places the offering at October 12, 1699. The offering is composed of five cereals (rice, barley, wheat, soybean and azuki bean), five medicinal plants (Acori graminei, Acori calami, Ginseng, Flos caryophylli and Lignum santali albi) and six minerals (rock crystals, purple and blue lead glass, CaCO3 particles, and silver and golden foils). Recently, the pharmacy educational program was extended from four to six years in order to meet clinical pharmacy requirements for patients. From studying the Buddha of Healing and its medicinal container described above, the author suggests that, in addition to pharmaceutical bioscience, philosophical concept be studied as part of the history of pharmacy in the future. PMID- 25799837 TI - [A historical review on International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and internationalization of Japan's new drugs development and regulation]. PMID- 25799839 TI - [Transitions of psychotropic drugs in the Japanese Pharmacopoeia (JP) (Part 14). Transitions in the standards and test methods of Valerian root in the Deutsches Arzneibuch (DAB) and comparison between the USP, BP, EP and JP, and Oleum Valerianae (Japan Kesso oil) listed in DAB6 (1926)]. AB - Valerian has been used as a name for Japanese Valerian and European Valerian root. Valerian in the German market today was originally called Baldrian. Transitions in the standards and the test methods of Valerian root listed in the DAB were studied this time. Moreover, we compared these standards and test methods with those in the USP, BP, EP and JP. We also considered the pharmacology evaluation in Germany. At the time, the standards and test methods had content in accordance with the EP from DAB9 (1986) of the West Germany publication. It also agreed with the EP and BP of the same period. To date in the DAB, botanical features have been mainly derived from the discriminating characteristics of the Valerian root. In DAB9 (1986), standards and test methods were added to the content, enhancing it and making it more stringent. This is thought to have happened as a result of a new, academic finding showing an improvement in the pharmacology level. Valerian root has been listed continuously in the DAB. These listings suggest that Valerian root has continally been evaluated as a sedative. We think that the listing was connected with a relisting in the BP as a result of scientific communications between Britain and Germany, EC member nations, such as through EP publications. On the other hand, the oil made with Japanese Valerian was listed in a radical field in DAB6 (1926) in the past. This is a valuable result, proving that it was used and evaluated as an important herbal medicine from Japan and foreign countries at that time. The Japanese Valerian referred to is not grown in Japan today. Moreover, it is not possible that cultivation will be restarted through good quality revaluation. However, this fact introduces a valuable piece of history supporting the survival of Japanese Valerian and European Valerian root as a sedative in the future. PMID- 25799840 TI - [History of pharmaceutical packaging in modern Japan. II--Package size of pharmaceuticals]. AB - When planning pharmaceutical packaging, the package size for the product is important for determining the basic package concept. Initially, the sales unit for herbal medicines was the weight; however in 1868, around the early part of the Meiji era, Japanese and Western units were being used and the sales unit was confusing. Since the Edo era, the packing size for OTC medicines was adopted using weight, numbers, dosage or treatment period. These were devised in various ways in consideration of convenience for the consumer, but the concept was not simple. In 1887, from the time that the first edition of the Japanese Pharmacopoeia came out, use of the metric system began to spread in Japan. Its use spread gradually for use in the package size of pharmaceutical products. At the time, the number of pharmaceutical units (i.e., tablets), became the sales unit, which is easy to understand by the purchaser. PMID- 25799841 TI - [The history of developing anticancer Drugs and their evaluation guidelines in Japan]. AB - The cancer therapies currently available do not yet offer fully satisfactory treatments, even in 21st century, and efforts and progress are being made daily in the area of drug development. Anticancer drugs, which play the leading role in cancer therapy, are being developed dynamically around the world, and Japan is not an exception. Looking back on the history of developing anticancer drugs, cytotoxic drugs were the mainstream of drug development until the end of the 20th century. In the 21st century, they have been replaced by molecularly targeted drugs, and thus the development of cytotoxic drugs has been declining rapidly. There were various approaches to the development of anticancer drugs and clinical trial endpoints until the 1980s. In 1991, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was issued. From 2000 onwards, there was vigorous discussion on the clinical trial endpoints of anticancer drugs in the United States. In conjunction with this discussion, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was revised in 2005. The revised guidelines required survival data at the time of filing a new drug application (NDA) as a general rule. Around 2005, a bridging strategy was promoted as the "International Conference on Harmonization E5" was promulgated among Japan, the U.S. and EU, resulting in an outflow of clinical trials to overseas, with more non-Japanese survival data generated outside of Japan used for NDAs than Japanese data. Subsequently, the "Guideline for Basic Principles on Global Clinical Trials" was issued in 2007, which promoted the change in the mainstream approach from a bridging strategy to a pivotal, global study involving Japan. Thus, an era of full-fledged globalization in clinical trials began. We believe Japan will need systems to enhance the motivation for anticancer drug development, such as an expedited program or pediatric program, from now on. We hope that the enhancement of these systems will contribute to shortening the period required for approving an anticancer drug and reducing developmental costs. Furthermore, we expect Japan to be creating breakthrough anticancer drugs in the near future. PMID- 25799842 TI - [The history of regulatory system for plasma fractionation products in the United States]. AB - In Japan, biologics have been described as special sorts of medicines in the Pharmaceutical Affairs Law and are regulated by the Ministry of Health, Labour and Welfare (MHLW). In contrast, in the United States, some of the regulatory laws for biologics are different from other medicines and the relevant regulatory agencies have been changed historically. We reviewed the histories of the laws and changes in regulatory agencies for biologics, especially focusing plasma fractionation products in the United States, which may give suggestions and advice for the regulation of biologics in Japan. In the earliest stage, biologics were regulated by the Biologics Control Act (BC Act) of 1902 and as parts of the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938. The effectiveness of these regulations was not equivalent to that of other drugs; therefore, Congress passed some amendments to the FD&C Act, in which biologics were treated in the same way as other drugs. In 1972, the authority for biologics control was transferred from the National Institutes of Health (NIH) to the Food and Drug Administration (FDA). Thereafter, in order to achieve the most efficient regulation under the rapidly evolution of biologics, the biologics regulating sections in the FDA have changed several times. At present, some biologics that are used in ways similar to other drugs (e.g., cytokines, monoclonal antibodies and immunomodulators) are regulated by the Center for Drug Evaluation and Research (CDER), and other biologics (e.g., vaccines, blood products and cellular products) are regulated by the Center for Biologics Evaluation and Research (CBER) of the FDA. PMID- 25799843 TI - [A historical walk in Hachinohe--research on Andou Shoueki]. PMID- 25799844 TI - [Report of the 19th Japanese-German Symposium]. PMID- 25799845 TI - Effect of tobacco smoking on the maternal and fetal adipokine axis in relation to newborn birth weight and length. AB - We examined the effect of tobacco smoking on the concentrations of leptin, soluble leptin receptor (sOB-R), total adiponectin, and free leptin index (FLI) in the serum of maternal-cord pairs. We also investigated the correlations between these biochemical parameters and newborn birth weight and length. The study included eighty-five healthy pregnant women, who were divided into smoking and tobacco- abstinent groups according to serum cotinine concentrations. We found that maternal and fetal leptin, sOB-R concentrations, and free leptin index were similar in smoking and tobacco abstinent groups. We observed significant negative relationship between the reported number of cigarettes smoked daily during pregnancy and cord blood leptin (r=-0.37; p<0.05). In the group of smoking women, total serum adiponectin concentrations were significantly lower than in the tobacco abstinent group in mothers as well as in cord blood (p<0.05). A significant negative association between the number of cigarettes smoked per day and total adiponectin concentration in maternal as well as newborn serum was observed (r=-0.38; p<0.05). Umbilical serum leptin, sOB-R, and FLI levels were significantly lower and adiponectin higher compared with maternal concentrations at birth (p<0.05). Mean birth weight and body length of the smoking mothers' infants were significantly lower (p<0.001; p=0.015, respectively) compared with the abstinent group, and negatively correlated with the daily number of cigarettes consumed (birth weight r=-0.39; p<0.05; birth length r=-0.37; p<0.05). Cord blood values of leptin, FLI and adiponectin were significantly correlated with newborn birth weight. We also observed a positive relationship between cord blood adiponectin levels and the birth body length in the two studied groups (r=0.49; p<0.002). Tobacco smoking during pregnancy decreases maternal and fetal serum adiponectin levels but does not have a significant effect on blood leptin concentrations. The direct association between the cord blood values of these adipokines and birth weight and length suggest that rather fetal (not maternal) adiponectin and leptin concentrations may be involved in fetal development during pregnancy. PMID- 25799846 TI - Influence of inhaled nicotine source on arterial stiffness. AB - INTRODUCTION: Tobacco smoking leads to changes in hemodynamic parameters such as heart rate and systolic or diastolic blood pressure. It has a direct influence on the elasticity of blood vessels and increases arterial stiffness, which can result in development of atherosclerosis. Data show that the nicotine in tobacco smoke probably is responsible for these changes. Electronic cigarettes (e cigarettes) were supposedly a healthier alternative to combustible cigarettes because they imitate a process of cigarettes smoking but generate nicotine aerosol without the toxic substances from tobacco combustion. However, the use of e-cigarettes is still controversial because their toxicity, safety and long term use health impact have not been sufficiently studied. AIM: The aim of this study was to evaluate changes in arterial stiffness parameters after smoking a cigarette or e-cigarette use. METHODS: Fifteen healthy women, aged 19-25 years old, smoking >=5 cigarettes per day for at least two years participated in the study. A non-invasive measurement of arterial stiffness parameters - Stiffness Index (SI) and Reflection Index (RI) - was conducted and systolic and diastolic blood pressure and heart rate were measured before and after smoking a conventional cigarette as well as use of an e-cigarette. RESULTS: Statistically significant changes in the SI and RI were observed before and after smoking of a conventional cigarette [SI: 6.75m/s (6.66 - 6.85, 95% CI) vs 6.56m/s (6.46 - 6.65. 95% CI), p=0.0056; RI: 54.0% (51.5 - 56.7, 95% CI) vs 49.6% (47.5 - 51.8, 95% CI), p=0.010]. The use of e-cigarettes resulted in no statistically significant changes in the SI and RI. After both product use systolic and diastolic blood pressure and heart rate increased but the changes were not statistically significant. CONCLUSIONS: In contrast to conventional cigarette use, the use of electronic cigarettes causes no changes in arterial stiffness. This may indicate lower bioavailability of nicotine from the e-cigarette or an additional effect of other substances present in cigarette smoke but absent in an e-cigarette aerosol. PMID- 25799847 TI - [10 years comparative clinico-epidemiological analysis of smoking and alcohol consumption in TB patients (Myc. Tuberculosis) and with mycobacteriosis (Myc. Kansas]. AB - INTRODUCTION: Smoking and alcohol consumption are a major public health problem. More and more are mentioned, also, these two drugs, tobacco and alcohol as risk factors for tuberculosis and mycobacteriosis. AIM OF STUDY: Comparative analysis of epidemiological and clinical patients with tuberculosis and mycobacteriosis M.kansasii smoking cigarettes and abuse alcohol. MATERIAL AND METHOD: The study included 2025 patients with tuberculosis and 140 patients with diagnosed lung mycobacteriosis hospitalized in Kuyavian-Pomeranian Center of Pulmonology in the years 2003-2013. Data were obtained from the central database of the hospital on admission to the hospital. RESULTS: There were 1403 smokers (69.3%) of tuberculosis patients and 79 (56.4%) with mycobacteriosis, and alcohol dependence were 534 (26.4%) and 16 (11.4%) respectively. Both of smokers and drinkers, men prevailed. Smokers who have developed tuberculosis were significantly younger than patients with mycobacteriosis, often touched their homelessness and unemployment, and often lived in rural areas. Conversely, smokers with mycobacteriosis are people often married, professionally active. In the group of abusers, patients with tuberculosis were younger, living in the country. side, often unemployed, homeless and single compared to patients with my. cobacteriosis. The clinical picture of patients with tuberculosis and mycobacteriosis did not differ significantly between the groups. CONCLUSIONS: A retrospective study of patients with tuberculosis and my. cobacteriosis showed significantly more use of tobacco and alcohol abuse than in the general Polish population. It should be noted that cigarette smoking and alcohol abuse are major risk and mycobacteriosis. Therefore, it is important to conduct anti-tobacco education and prevention of alcohol abuse. PMID- 25799848 TI - [Effect of tobacco smoking on albumin concentration and beta-glucuronidase activity in urine of smelters]. AB - The aim of present study was to estimate the nephrotoxicity of occupational exposure to heavy metals on albumin concentration and beta-glucuronidase activity in the urine of smoking and non-smoking smelters. The study was performed in urine of 101 smoking and non-smoking smelters as well as 65 smoking and non smoking male subjects unexposed to heavy metals. Section into smoking and non smoking groups was made on basis on direct personal interview and by determination of serum cotinine concentration. The concentration of albumin in urine was measured with commercial test (Micro-Albumin ELISA Cat. No 5MA 74212, ORGENTEC Diagnostika Gmbh, Germany). The activity of beta-glucuronidase in urine were determined in urine using 4-nitrophenyl beta D-glucuronide (Cat. No 73677, Sigma Aldrich, Germany) as a substrate. We have observed higher albumin concentration and beta-glucuronidase activity in urine of smoking and non-smoking smelters when compared to control groups. We have also found the influence of tobacco smoke as well as amount of cigarettes smoked on albumin concentration in urine of smoking smelters. A statistically significant difference was detected between activity of beta-glucuronidase in urine of smoking and non-smoking smelters, which suggest as additional negative factor of exposure to tobacco smoke. Analyzing the impact of smoking intensity we have found higher albumin concentration and beta-glucuronidase activity in urine of smelters smoking >=20 cigarettes per day when compared to smelters smoking <20 cigarettes per day. The elevation of albumin concentration and beta-glucuronidase activity in urine of workers occupational exposure to heavy metals and tobacco smoke indicated, that environmental exposure on these factors can disorders kidney functions. PMID- 25799849 TI - [Assessment of lipid profile in non-smoking and smoking young health persons]. AB - The coexistence of hypertension, obesity and dyslipidemia constitutes combination of factors, which in adulthood and old can generate atherosclerotic-dependent disease entities. Cigarette smoking, which is considered a major risk factor for atherosclerosis and coronary heart disease, may lead to changes in normal plasma lipid profile. The aim of the study was to evaluate the effect of cigarette smoking on lipid parameters and the concentration of lipid peroxidation products in young healthy persons. The study population consisted of 57 healthy volunteers aged 19-26 years. They were qualified to planned analyzes based on research conducted by primary care clinicians. The study population was divided into smokers and non-smokers on the basis of determining the concentration of cotinine (ELISA method). It has been shown that concentrations of lipid profile parameters in the study groups remained within the reference ranges, however, in the group of smoking healthy persons were higher as compared with non-smoking healthy persons, except HDL cholesterol. It has been demonstrated 1.5 times higher concentration of LDL cholesterol in the serum of smokers (112.8 +/- 37.9 mg/dl) when compared to non-smoking subjects (77.6 +/- 43.7 mg/dl, p=0.006). There was a significant difference between the mean value in the group of triglycerides of healthy non-smokers (72.9 +/- 24.1 mg/dl) and the average value of those in smokers (93.9 +/- 40.3 mg/dl, p=0.034). There was a significant difference between the mean value of the concentration of lipid peroxidation products reacting with thiobarbituric acid (TBARS) in the non-smoking healthy persons (0.5 +/- 0.3 mmol/l), and the mean value of TBARS in the group of smoking persons (0.8 +/- 0.6 mmol/l, p=0.019). The results show that cigarette smoking may be an important factor in potential changes in lipid profile already in young healthy people, which in the future may result in the onset of atherosclerosis and coronary heart disease. PMID- 25799850 TI - [Frequency of smoking tobacco, drinking alcohol and using drugs by the junior high school youth]. AB - There is systematic decrease in the age of tobacco, alcohol and drug initiation in Poland among children and adolescents. Education concerning damage caused by smoking tobacco drinking alcohol and taking drugs, if started in due course, is of essence when it comes to the inhibition of these unfavourable phenomena. The aim of this work was to recognise the participation of smokers, people who drink alcohol and take drugs among students of junior high school as well as checking the dependency between early tobacco initiation and taking to drugs and alcohol among the youth. In March 2014, 288 students of 1-3 grades were included in the study of some selected junior high schools from the Moniecki region in Podlaskie voivodeship. While collecting empirical material, anonymous survey was carried out including 35 questions. Students were asked to fill it in freely during a lesson. In order to elaborate the collected data, descriptive meth, ods were used as well as methods of statistical interference. 163 women (56.6%) and 125 men (43.4%) were included in the survey. The most numerous group consisted of respondents at the age of 15 (40.1%) In the surveyed group, 100 students (34.7%) admitted to smoking at least one cigarette in their life. 6.3% of the respondents (18 people) smoked daily, whereas 9.0% (26 people) claimed they smoked occasionally. Majority of the surveyed people (51%, 147 people) answered that they had already drunk alcohol. 2.4% of the respondents (7 people) declared drinking daily whereas 18.4% (53 people) claimed to be drinking occasionally. Every tenth junior high school student stated the had used drugs at least once in their life (10.1%, 29 people). Despite the law in Poland prohibiting drug possession and trade as well as alcohol and tobacco purchase and consumption among minors, frequency of drinking alcohol, smoking cigarette, and using drugs was high among the junior high school students. PMID- 25799851 TI - [Drinking motivates, depending on the use of tobacco and cannabis among adolescents]. AB - INTRODUCTION: Alcohol, tobacco and marijuana are the most common drugs used by adolescents. There is evidence of co-occurrence of alcohol use by young people with taking other problem behaviors, little is known about the causes of drinking depending on the type and severity of different substances use. Aim of the study is to find differences in the structure and the rank of drinking motives among people who smoke cigarettes or use marijuana. MATERIAL AND METHODS: The study was carried out on a nationwide sample of 1411 in mean age 17.7 years (53.3% girls) as a part of next series of HBSC study (Health Behaviour in School aged Children) conducted in 2010 .To investigate reasons for alcohol use, research instrument DMQ-R (Drinking Motives Questionnaire-Revised) was used. Questions about currently tobacco smoking and marijuana or, hashish use during last year were also asked. One-way ANOVA with post-hoc test Scheffe were used for analysis. Results: The highest means were noticed in the dimension of social motives and they differed significantly due to smoking (F (2, 1170) = 35.76, p <0.001) and marijuana use (F (2, 1.139) = 30.73, p <0.001). Regular smokers have obtained lower mean (M = 61.2, SD = 25.2) than frequently marijuana users (M = 65.9, SD = 25.1). Conformity motives were the weakest motives of drinking among tobacco or marijuana users. Significant differences due to the type and frequency of substance use occurred only in the groups were taking into account tobacco smoking, (F (2,1176)= 4.25, p <0.05). Differences of the levels of motivation to deal with problems (coping motives) were obtained due to tobacco smoking (F (2,1172) = 44.20, p <0.001) and marijuana use (F (2, 1143) = 9.18, p <0.001). Regular smokers were more pointed on the negative intrinsic motivation (M = 38.1, SD = 29.4) than marijuana users (M = 33.5, SD = 29.6). Means in terms of motivation for enhancement also differed in the groups taking into account tobacco smoking (F (2,1174) = 30.63, p <0.001) and cannabis use (F(2,1143)= 52.69, p <0.001). Marihuana users were more likely to have a greater means in this type of motivation (M = 42.6, SD = 27) than regular smokers (M = 32.9, SD = 25.8). Along with a decrease of smoking frequency, means in the studied dimensions were also decreased. Girls were more likely to drink to cope with problems than boys. In other dimensions of motivation to drink means were higher in boys. Means obtained among adolescents who used tobacco or marijuana were slightly higher than in the overall sample. CONCLUSIONS: The strongest reasons for alcohol drinking among adolescent's tobacco smokers and cannabis users are social motives. Smokers are more likely to drink alcohol in order to cope with the problems, and among adolescents who use marijuana more important reason of drinking is to improve good mood. Ranking of drinking motives varies according to gender. PMID- 25799852 TI - [Patterns of drinking alcohol tobacco smoking among 6th year students of the faculty of medicine in Bialstok]. AB - INTRODUCTION: Alcohol and tobacco are legal, easily available addictive substances. There are no universal criteria of safe alcohol consumption but some scientific studies have allowed for determination of consumption levels helpful in evaluation of the pattern of drinking and evoking readiness to limit the amount of consumed alcohol. THE AIM: The aim of the work was to evaluate and compare the knowledge of 6th year students of the Faculty of Medicine of the Medical University of Biatystok in the academic years 2011/12 and 2012/13 concerning the effects of alcohol abuse, as well as to determine their drinking patterns and tobacco smoking structure. MATERIALS AND METHODS: The study material was collected by means of anonymous voluntary surveys carried out before classes concerning the issues of addictions within the framework of family medicine subject block. RESULTS: 356 students took part in the study: 226 (63.5%) women and 130 (36.5%) men (p<0.000). 4.86% of the respondents displayed a high level of knowledge on the harmfulness of alcohol abuse; 63.43% had an average level of knowledge and 31.71% - a low one. 51,32% women and 62,3% men drank alcohol in a hazardous way. A relation was found between a low level of knowledge and the amount of alcohol consumed on a typical drinking day (rS=-0.15, p=0.03) as well as between a low level of knowledge and hazardous drinking (rS=-0.13, p=0.03). Among the respondents, 18,58% women and 14,63% men smoked cigarettes regularly. Those who are 6th year students in the academic year 2012/13 usually had started smoking within the first three years of study at the Medical University and drank greater amounts of alcohol on a typical drinking day than students surveyed in the 2011/12 year. A correlation was found between tobacco smoking and a greater frequency of getting drunk occasionally (rS=-0.18, p=0.002) among students of both years. CONCLUSION: Insufficient knowledge on the effects of alcohol abuse and smoking coexist with a higher risk of drinking alcohol. PMID- 25799854 TI - [Analisys of changes of risky behaviors among students from south-eastern Poland. Long-term prospective study]. AB - AIM OF STUDY: The aim of this study was a comparative evaluation of the dynamics of change during selected behavior patterns related to students health. MATERIALS AND METHODS: The study covered a total of 1.496 students from University of Rzeszow and Rzeszow University of Technology, studying following disciplines: medical, humanities and exact sciences. The study was performed by using a diagnostic survey questionnaire technique. The study used a statistical test of independence chi-square. It was conducted from October to December 2009. Afterwards the study was repeated in 2012 in the same group of students. The percentage of students who were in class on the day of the study reached 59.1% of the assumed research sample. RESULTS: The research found that in 2009 and 2012, in the scope of selected unhealthy behavior, the respondents did not differ in the level of statistical significance in any of following categories: drinking alcohol (p=0.4951); drug usage (p=0.2968); tobacco smoking (p=0.6053) and usage of psychoactive substances (p=0.6581). Students used the drugs occasionally, mostly at social events in order to achieve pleasure. If it comes to sex of respondents who presented risky behaviors men occurred more often (5.3% [2009] vs. 2.2% [2012]). University students derived from municipal areas had frequent contact with drugs (14.2% vs. 8.0%). Students of non-medical fields consumed alcohol more often than the ones from medical fields of studies (11.7%, 7.9%). Repeated study shows in this category increase towards medical studies (23.2% vs. 8.9%). The same study (2012) indicates statistical differences between field of study and smoking (p = 0.0064) in reference to students of medical sciences (respectively 38.2% and 27.5%). ONCLUSIONS: This work showed that the stabilization prevalence of risky behaviors considerina students. may be the result of positive changes and prevention pro. grams aimed at children and teenagers, constantly put on the national and regional level. PMID- 25799853 TI - [Use of stimulants among dental students]. AB - INTRODUCTION: The use of stimulants including cigarettes, alcohol and psychoactive substances among young people is very common. Students of medical universities are exposed to stress, like those at other universities, however, have a greater knowledge concerning the dangers of certain addiction. AIM: The paper aimed to collect data on the use of stimulants by dental students. MATERIAL AND METHODS: Questionnaire survey was carried out among 60 dental students (41 females and 19 males), aged 23-29 years, in their final year of studies. The questionnaire was completed by respondents who gave their consent. Closed-ended questions were related to the use of stimulants such as cigarettes, alcohol and psychoactive substances. The Poznan University of Medical Sciences ethics committee approved the study. RESULTS: Five students (8.34%) declared the use of cigarettes every day, while 39 people (65.00%) had never smoked. Alcohol was consumed by 57 students (95.00%), mainly on the occasion of get-together (78.33%), passed exams (55.00%) and family events (48.33%). The vast majority of students admitted that they had not used any psychoactive substances (81.66%). On the other hand, people who used this type of stimulants reported consumption of energy drinks and stimulants (16.67%) as well as hallucinogens (1.67%). CONCLUSIONS: In the examined environment, relatively low dependence on cigarette smoking and consumption of psychoactive substances is observed. On the other hand, drinking of alcohol is quite common. PMID- 25799855 TI - [Risk factors for smoking in persons over 45]. AB - Tobacco smoking has long been one of the most important risk factors contributing to the development of many health problems e.g. cardiovascular diseases respiratory diseases and cancers. Smoking is a modifiable factor, which means that every smoker who quit smoking has a great chance to lower the risk of developing these diseases. The aim of the study was to identify the factors influencing smoking among people over 45 and to estimate the extent of the phenomenon of smoking in 2 Polish provinces: Wielkopolskie and Dolnoslaskie. The sample was 867 persons over 45. The number of study subjects was proportional to the sex and age structure of Polish population. The sampling was random and the research tool was a self-made survey questionnaire. In order to identify factors contributing to smoking a logistic regression analysis was applied. Tobacco was smoked by 16.7% of the research subjects (15.1% of women and 19.1% of men). In Wielkopolskie province smokers constituted 19% of the sample (17.7% of women and 22% of men), in Dolnoslaskie province 14.1% of the respondents were smokers (12.5% of women and 16.2% of men). Smoking is more prevalent among men aged 55-65 years (OR=4.34; 95% CI: 2.0-9.41). The lowest prevalence of smoking without statistical significance was in rural areas (OR=0.63; 95% CI: 3.6-1.10) and among persons with low educational levels (OR=0.74; 95% Cl: 0.36-1.56). Significantly higher prevalence of smoking was found among the unemployed (OR=2.90; 95% CI: 1.07-7.84) and people performing partly physical work (OR=2.82; 95% Cl: 1.37 5.79). The prevalence of smoking was higher among people being in a relationship (OR=1.63; 95% Cl: 1.0-2.66) and declaring income below PLN 1,000 per month (OR=2.82; 95% CI: 0.81-3.55). Statistically significantly lower risk of smoking was among obese subjects (OR-0.42; 95% CI: 0.24-0.74). It was found that the number of years of smoking significantly correlated with high systolic blood pressure and the number of smoked cigarettes was associated with hinh level of LDL cholesterol. The smokers aged over 45 can be generally characterized as strongly addicted and have been smoking for many years. Anti-tobacco activities targeted at this group should be intensified in order to reduce the number of cigarettes smoked daily. These interventions should take into account group characteristics and its needs. PMID- 25799856 TI - [Cotinine concentration in the saliva in relation to oral hygiene procedures]. AB - Cotinine is a biomarker of the exposure to the tobacco smoke, nicotine metabolite with half-life in the saliva which is 17 hours. Assessment of cotinine concentration enables among others verification of the questionnaire data as well as evaluation of both smokers and non-smokers exposure to the tobacco smoke. Practicing proper oral hygiene procedures is an essential factor of the prophylaxis of dental caries and periodontal diseases which influence general health state. The removal of dental calculus is achieved by proper teeth brushing and the use of additional oral aids. The aim of the study was evaluation of cotinine concentration in non-stimulated saliva in order to verify questionnaire data (smoker/non-smoker) and analysis of practicing oral hygiene procedures in relation to the status of cigarette smoking. Questionnaire and biochemical studies were conducted in the group of 116 people aged 20-54. In questionnaire survey 53 people (45.69%) confirmed cigarette smoking, 63 (54.31%) declared they had never smoked and never tried to smoke. Non-stimulated saliva was collected between 9(30) and 11(30), 1,5-2 hours after meal. Cotinine concentration was assayed with the use of Cotinine ELISA (Calbiotech, USA). Obtained study results were submitted to statistic analysis with the use of Chi2. Statistically essential test values were those with p<0,05. In the study group the mean value of cotinine concentration was 155.76 ng/ml. Brushing teeth once a day or less frequently was reported by 26.92% smokers and 4.76% non-smokers, brushing teeth at least twice a day was reported subsequently by 73.08% and 95.24% participants. Non-smokers in comparison with smokers considerably more frequently brushed their teeth, at least twice a day (XZ=11.11, p<0.001). Smokers used a toothbrush with medium hardness bristle (X2=6.05, p<0.05) as well as toothpicks to maintain hygiene of interdental spaces and teeth contact surfaces (X2=21.34, p<0.001) whereas they used dental floss less frequently (X2=10.64, p<0.01). Smokers more fre. quently brushed their teeth improperly (X2=1 3.41, p<0.001). Smokers in comparison with non-smokers did not practice proper oral hygiene which is an essential risk factor of the oral health. It is crucial for dental surgeons to conduct oral hygiene instructions in smokers as well as realization of health threats resulting from cigarette smoking. PMID- 25799857 TI - [Alcohol and other psychoactive substances addiction risk assessment among chosen high school students test group]. AB - Use of nicotine, alcohol and other psychoactive substances plays an important role in youth death rate and incidence proportion. The probability of accidents, risky sexual behaviors or interpersonal aggression rises when young people are under the influence of alcohol or other drugs. In all the developed countries alcohol and other psychoactive substances are the main risk factors leading to youth death caused by traffic accidents, murders and suicides. That is the reason why the popularization of a simple and effective screening tool that would allow choosing the high risk youth group and implementing early intervention program is so important to conduct in Poland. AIM: Alcohol and other psychoactive substances addiction risk assessment within the chosen test group of high school youth attending different types of schools in a medium size city. MATERIAL AND METHODOLOGY: Study was conducted in February 2014 in three high schools - public high school, catholic high school and technical high school, located in Stalowa Wola reaching 119 students from 3rd grade (18-19 years old). Study utilized CRAFFT test (Alcohol and Other Drug Screening Test). RESULTS: Within the past 12 months previous to the screening 92.4% of tested students drunk alcohol, 26.1% smoked marihuana and 10.9% used other psychoactive substances. One fourth of students admitted to driving or riding the car with the driver who was under the influence of alcohol or other drug. One half of the students ad. mitted drinking alcohol or using drugs to relax, improve the mood or to fit in. One in five students was confronted by friends or family members and asked to limit use of alcohol or drugs. CONCLUSION: Based on CRAFFT test results over a half of students (53.6%) may be diagnosed with significant psychoactive substances addiction risk and should be promptly subjected to preventive actions. PMID- 25799858 TI - [Television and Internet as sources of women knowledge of tobacco smoking, alcohol consumption and energy drinks impact on health]. AB - INTRODUCTION: Accessibility of the Internet allows obtaining information on different areas of life, including the impact of smoking, alcohol consumption and energy drinks on health. Environmental exposure to tobacco smoke and active smoking are a serious risk for women's health, especially for women in reproductive age and children at any time in their lives. Alcohol is a risk factor for the development of general diseases, and consumed by pregnant women has a toxic effect on the body of women and a child in the prenatal period. Due to the increased consumption of energy drinks containing among others nervous system stimulants and carbohydrates, their consumption should be a conscious choice of the consumers. Knowledge of the health risks resulting from the lifestyle can be a decisive factor for the implementation of health behaviour. The aim of the study was to determine the sources from which men and women acquire information concerning the effects of cigarette smoking, alcohol consumption and energy drinks on health. The respondents interest in the above mentioned subjects was also evaluated. MATERIAL AND METHODS: The survey study was carried out in a group of 160 persons (114 women and 46 men), aged 19-60 years, randomly selected from the patients presenting to the Department of Conservative Dentistry with Endodontics of the Medical University of Lublin. An author's questionnaire was prepared for this research. The data were analyzed statistically with the use of Pearson's X2 test. Statistically significant test values were those with p<0.05. RESULTS: The internet was a source of information about the impact of smoking cigarettes on health for 52.63% women and 56.52% men, about the alcohol effect on health for 57.02% women and 45.65% men, while about energy drinks for 61.40 % of women and 47.83% men. Differences between sex of the respondents and indicated source of information were not statistically significant. Obtaining information from television programmes on the impact of smoking on health reported 70.18% of women and 63.04% of men, about alcohol consumption - 66.67% women and 58.70% men respectively. There was no statistically significant correlation between sex of the respondents and obtaining information concerning cigarette smoking and alcohol consumption. Women showed significantly more frequently TV programmes as a source of information about energy drinks (61.40%) compared to males (43.48%) (X2 = 4.28, p <0.05). Interest in the subject of the impact of smoking, alcohol consumption and energy drinks on health was not dependent on sex of the respondents. CONCLUSIONS: Most women acquire knowledge about the effects of cigarette smoking, alcohol consumption and energy drinks on health from TV programmes, although the internet is an increasingly important source of information in this respect. PMID- 25799859 TI - [Knowledge about breastfeeding profits among primiparas]. AB - Breastfeeding is the only way to nourish newborns and toddlers and it enables them to have an optimal health condition and growth. Both a child and a mother draw a lot of profits from breastfeeding. Woman's milk is perfectly balanced as far as quantity and quality is concerned. It has specific generic nourishment that ensures optimal psychological emotional and physical development of a child. Breastfeeding also protects infants from immunological problems and infections. Having the skills and knowledge about breastfeeding is the main factor that enables a smooth process of lactation. All the medical staff and midwives especially are obliged to promote breastfeeding and they should provide information as well as emotional and technical support for mums through the whole period of lactation. The aim of this thesis was to examine the level of knowledge about breastfeeding among first-time mothers. An anonymous survey was used as an analytic tool. The survey was specifically created for this research and it contained 30 questions. Majority of responders (98%) declared a will for breastfeeding. Also majority of women (94%) knew that their milk contains all the needed ingredients for proper development of their young. According to the pregnant women in labor (98%) breastfeeding is a key element in establishing an emotional connection with the child. Most of the responders knew the influence of breastfeeding on child's health. Minority of the questioned women (14%) attended birthing courses. The responders were equipped in knowledge on various levels. It proves the necessity of systematic and planned education for women. The system of lactation counseling should be an integral part of post-labor care in obstetrician clinics. PMID- 25799860 TI - [Assessment of knowledge on conrraceptives and contraceptive method among high school students]. AB - Undertaking sexual intercourse by maturing youth has become a common phenomenon. The research shows that 27% of 17-18-year-olds and 42% of teenagers at the age of 14 and younger did not use any method of contraception during the sexual initiation. This is a very alarming phenomenon, and therefore, the author of the thesis attempted to assess the level of knowledge of high school students in the municipality of Wolsztyn on the available methods of contraception, contraceptives and their effectiveness. The study used a method of diagnostic survey. The research tool was a questionnaire containing 33 questions. Surveys were filled by 290 students (including 159 women and 131 men) of secondary schools in the municipality of Wolsztyn. The average age of the participants was 16.9 +/- 1.0 years. Participation in the study was voluntary and anonymous. The respondents' knowledge on reproductive physiology was at the average level. 63.8% of the students know what the sexual cycle consists of, 72.8% were familiar with the concept of ovulation, but only 11% have information on how long the egg cell lives. The best known contraceptive is a condom. Young people consider hormonal and mechanical methods as the most effective contraceptives. According to the respondents natural methods are characterized by the minimum efficiency. The respondents mainly derived their knowledge from the Internet and from colleagues, only every third person has talked to their parents or the gynecologist. The knowledge of students about the methods and contraceptives is average; they received an average of 22.6 points out of 52 possible. PMID- 25799861 TI - Tobacco - a producer of recombinant interferons. AB - The approved therapeutic interferons, which are chiefly indicated for a treatment of hepatitis C or hairy cell leukaemia (IFN-alpha), relapsingl remitting sclerosis multiplex (IFN-beta) and chronic granulomatous disease (IFN-gamma), are commercially produced by recombinant DNA technology, mainly in bacteria Escherichia coli (IFN-alpha, IFN-beta1b, IFN-gamma), rarely in a mammalian cell line CHO (IFN-betala). A serum half-life time of some non-glycosylated IFN-alpha products was extended by a chemical attachment of a branched polyethylene glycol (PEG) to give PEGylated IFN-alpha. The therapy with recombinant interferons proves expensive and hence much hope is concerned with their production in other platforms assumed to be cheaper, like transgenic plants. Currently, tobacco, botanically species Nicotiana tabacum, its cultivars and some related species, especially N. benthamiana, is one of the most important plant expression systems tested for the production of therapeutical polypeptides and proteins (so-called biopharmaceuticals or biologics), especially vaccines, by using either greenhouse or field cultivated plants or cell suspension culture. IFN-alpha subtypes were expressed in tobacco nuclear genom e (IFN-alpha2a and 2b), chloroplast genome (IFN-alpha2b) and by transient expression (IFN-alpha2b). The IFalpha-a2b chimera fusions with O-glycosylated protein with O-a-rabinogalactans expressed in tobacco BY-2 cell culture showed increased half-life time similar to that obtained by PEGylation. The production of IFN-alpha2b (non-glycosydated) in tobacco glasshouse or field cultivation has been also elaborated. One report concerned expression of IFN-beta but with low yield. N-glycosylated IFN-gamma could be efficiently expressed in tobacco protoplast infected with recombinant brome mosaic virus (BMV) with the yield of 5-10% of total extracted protein. This type interferon (non-glycosylated), when expressed in chloroplast genome, proved unstable and could be obtained with reasonable yield as a fusion with GUS (beta glucuronidase). PMID- 25799862 TI - [Electronic cigarettes - effects on health. Previous reports]. AB - Currently very popular in the market of tobacco products have gained electronic cigarettes (ang. E-cigarettes). These products are considered to be potentially less harmful in compared to traditional tobacco products. However, current reports indicate that the statements of the producers regarding to the composition of the e- liquids not always are sufficient, and consumers often do not have reliable information on the quality of the product used by them. This paper contain a review of previous reports on the composition of e-cigarettes and their impact on health. Most of the observed health effects was related to symptoms of the respiratory tract, mouth, throat, neurological complications and sensory organs. Particularly hazardous effects of the e-cigarettes were: pneumonia, congestive heart failure, confusion, convulsions, hypotension, aspiration pneumonia, face second-degree burns, blindness, chest pain and rapid heartbeat. In the literature there is no information relating to passive exposure by the aerosols released during e-cigarette smoking. Furthermore, the information regarding to the use of these products in the long term are not also available. PMID- 25799863 TI - [Effects of smoking on periodontal tissues and benefits of tobacco quitting]. AB - Tobacco smoking is one of the most common addictions. Epidemiological studies show a significant effect of smoking on oral health and the development of periodontal diseases. The purpose of this study is to analyze existing research on the impact of cigarette smoking on periodontal condition and present the benefits of tobacco quitting. In the mouth of a smoker comes to faster loss of connective tissue and bone, increased tooth mobility and greater number of missing teeth than non-smokers. The negative effects of smoking on periodontal tissues correlate with the length and frequency of smoking. Also, people exposed to environmental tobacco smoke (ETS) are at a higher risk of developing periodontal disease than those who had no contact with tobacco smoke. Quitting smoking has a positive effect on periodontal health and is an absolute prerequisite for the health of the entire oral cavity. With the prolongation of tobacco abstinence negative consequences for oral health are gradually reduced. Each patient should be aware of his addiction, the risks arising from exposure to tobacco smoke and be motivated to eliminate it. The role of general practitioners, particularly family doctors and dentists is crucial in evaluation of active and passive smoking as well as motivation and support smokers in quitting the habit and maintaining smoking abstinence. PMID- 25799864 TI - [Do we always correctly interpret the results of statistical nonparametric tests]. AB - Mann-Whitney, Wilcoxon, Kruskal-Wallis and Friedman tests create a group of commonly used tests to analyze the results of clinical and laboratory data. These tests are considered to be extremely flexible and their asymptotic relative efficiency exceeds 95 percent. Compared with the corresponding parametric tests they do not require checking the fulfillment of the conditions such as the normality of data distribution, homogeneity of variance, the lack of correlation means and standard deviations, etc. They can be used both in the interval and or dinal scales. The article presents an example Mann-Whitney test, that does not in any case the choice of these four nonparametric tests treated as a kind of gold standard leads to correct inference. PMID- 25799865 TI - [Investigation of team processes that enhance team performance in business organization]. AB - Many researchers have suggested team processes that enhance team performance. However, past team process models were based on crew team, whose all team members perform an indivisible temporary task. These models may be inapplicable business teams, whose individual members perform middle- and long-term tasks assigned to individual members. This study modified the teamwork model of Dickinson and McIntyre (1997) and aimed to demonstrate a whole team process that enhances the performance of business teams. We surveyed five companies (member N = 1,400, team N = 161) and investigated team-level-processes. Results showed that there were two sides of team processes: "communication" and "collaboration to achieve a goal." Team processes in which communication enhanced collaboration improved team performance with regard to all aspects of the quantitative objective index (e.g., current income and number of sales), supervisor rating, and self-rating measurements. On the basis of these results, we discuss the entire process by which teamwork enhances team performance in business organizations. PMID- 25799866 TI - [Relations among higher brain function, trust, and gullibility in middle-aged and elderly people]. AB - In this study, we examined the relationships among higher brain function, trust or distrust, and gullibility in middle-aged and elderly people. It has been pointed out that the trust can be regarded the psychological frame of automatic processing in decision-makinig. The participants were 309 rural community dwellers (127-males and 182 females) whose mean age was 64.9 years old (SD = 9.9). The trust scale of Amagai (1997) and the Nagoya University Cognitive Assessment Battery were used to measure sense of trust and higher brain function, respectively. Gullibility was measured by self-report using two items. Correlation analyses showed that higher brain function positively correlated with degree of trust in others and negatively correlated with distrust. However, regression analysis demonstrated that only the relationship between category fluency and distrust was significant. Furthermore, the degree of distrust positively correlated with gullibility. PMID- 25799867 TI - [Researching identity development and statuses with the Dimensions of Identity Development Scale: the Japanese version]. AB - The Dimensions of Identity Development Scale (DIDS) provides a new method of researching identity development based on the dual-process model pertaining to lifespan development. This study developed and evaluated the Japanese version of this scale (DIDS-J). Two surveys of undergraduate and high school students showed that the DIDS-J had good reliability and validity and that it consisted of 25 items with five factors: commitment making, identity with commitment, exploration in breadth, exploration in depth, and ruminative exploration. Through cluster analysis of the DIDS-J, five identity statuses were found that were not clearly distinguished by previous scales: foreclosure, achievement, searching moratorium, diffused diffusion, and carefree diffusion. Research using the DIDS-J has two advantages: it enables us to examine the process of identity development among adolescents with a wider age range, and to compare results cross-culturally in future research. The trial investigations compared student scores with those from previous research in Western cultures, demonstrating that DIDS-J may lead to further explanations of identity development. PMID- 25799868 TI - [Unfolding item response model using best-worst scaling]. AB - In attitude measurement and sensory tests, the unfolding model is typically used. In this model, response probability is formulated by the distance between the person and the stimulus. In this study, we proposed an unfolding item response model using best-worst scaling (BWU model), in which a person chooses the best and worst stimulus among repeatedly presented subsets of stimuli. We also formulated an unfolding model using best scaling (BU model), and compared the accuracy of estimates between the BU and BWU models. A simulation experiment showed that the BWU modell performed much better than the BU model in terms of bias and root mean square errors of estimates. With reference to Usami (2011), the proposed models were apllied to actual data to measure attitudes toward tardiness. Results indicated high similarity between stimuli estimates generated with the proposed models and those of Usami (2011). PMID- 25799869 TI - [Subjective impressions of bowing actions and their appropriateness in specific social contexts]. AB - The current study used video clips of bowing actions depicted by three dimensional computer graphics. The bend angle (15 degrees and 45 degrees) and duration of the bent posture (0-4.5 seconds) were varied. In the first experiment, the participants rated their subjective impressions of the bowing actions. The bowing actions that were made at a 45 degrees angle and held for more than 1 second were rated as courteous. Bowing motions held for shorter durations were rated as smooth. In the second experiment, the participants evaluated whether a bowing action was appropriate for a specific social context. The participants judged 15 degrees-angle bowing of no/ very short duration appropriate for greeting, 45 degrees-angle bowing of no / short duration appropriate for gratitude, and 45 degrees-angle bowing for about 2 seconds appropriate for an apology. The results of these two experiments are discussed in terms of how angle and duration influence the impressions and evaluations of the appropriateness of a bowing acion. PMID- 25799870 TI - [Development of the Emotion and Arousal Checklist (EACL)]. AB - We developed the 33-item Emotion and Arousal Checklist (EACL), which consisted of five subscales to assess emotions (Fear, Anger, Sadness, Disgust, and Happiness) and four subscales to assess arousal (Energetic arousal + Energetic arousal -, Tense arousal+, and Tense arousal -). This checklist was developed to assess psychological state, both at a given moment and during the past week. In Study 1, confirmatory factor analyses identified nine subscales, whose internal consistency was indicated by their reliability. In Study 2, the EACL's validity was demonstrated by its correlation with the State-Trait Anxiety Inventory, Multiple Mood Scale, General Arousal Checklist, Japanese UWIST Mood Adjective Checklist, and Profile of Mood States. In Study 3, changes caused by tasks that involved either reading emotion-inducing articles or performing a calculation indicated the validity of the EACL for measuring psychological state at a given moment. Further, the test-retest reliability of the EACL for assessing psychological state during the past week was confirmed. These studies confirmed the reliability and the validity of the EACL. PMID- 25799871 TI - [Effects of empathy on fund-raising activities on behalf of victims of the 2011 Great East Japan Earthquake, focusinig on the residents in the South Kanto area]. AB - Fund-raising activities on behalf of victims of the 2011 Great East Japan Earthquake during the year after the earthquake were investigated in residents of the South Kanto area (N = 749), which is adjacent to the disaster area. The percentage of people that raised funds was 67.4%. We investigated the effects of the following on fundraising activities: demographic variables (sex, age, and educational background), trait empathy (empathic concern, perspective taking, and personal distress), former experience with fund-raising activities, effects of similarity to victims (e.g., experienced inconveniences because of the disaster, or had problems returning home), and psychological closeness to victims (e.g, have family members or acquaintances that suffered from the disaster, or that once lived in the disaster area). The results indicated that fund-raising activities were affected by former experience with fund-raising, similarity to victims, psychological closeness to victims, empathic concern, and being female. The relationship between fund-raising activities for victims and empathy are discussed. PMID- 25799872 TI - [Judgments and reactions of women being approached by an unknown man in town]. AB - The purpose of this study was to examine how women reacted to the approach of an unknown-man in town. 105 female Japanese undergraduates participated in the pilot survey. This survey identified six types of judgments made by women when they were approached by an unknown man in town. To investigate the relation between these six types of judgments and the reaction of women to an unknown man, 290 female Japanese undergraduates participated in the main study. The results showed that judgments concerning risks and situation, as well as personality, intentions, and appearance of, an unknown man were related to the reactions of women. The importance of judgments about personality of an unknown man and about risk in initiating relationships with males not belonging to the females' social network are discussed. PMID- 25799873 TI - [The role of sustained attention in shift-contingent change blindness]. AB - Previous studies of change blindness have examined the effect of temporal factors (e.g., blank duration) on attention in change detection. This study examined the effect of spatial factors (i.e., whether the locations of original and changed objects are the same or different) on attention in change detection, using a shift-contingent change blindness task. We used a flicker paradigm in which the location of a to-be-judged target image was manipulated (shift, no-shift). In shift conditions, the image of an array of objects was spatially shifted so that all objects appeared in new locations; in no-shift conditions, all object images of an array appeared at the same location. The presence of visual stimuli (dots) in the blank display between the two images was.manipulated (dot, no-dot) under the assumption that abrupt onsets of these stimuli would capture attention. Results indicated that change detection performance was improved by exogenous attentional capture in the shift condition. Thus, we suggest that attention can play an important role in change detection during shift-contingent change blindness. PMID- 25799874 TI - Psychometric properties of the Thai Spiritual Well-Being Scale. AB - OBJECTIVE: The purpose of this study was to investigate the psychometric properties of the modified Thai Spiritual Well-Being Scale in patients with advanced cancer. METHOD: This cross-sectional study was employed to investigate psychometric properties. Some 196 participants from three tertiary hospitals in Bangkok and suburban Thailand were asked to complete a Personal Information Questionnaire (PIQ), The Memorial Symptom Assessment Scale (MSAS), and the Spiritual Well-Being Scale (SWBS). Validity was determined by known-group, concurrent, and constructs validity. Reliability was estimated using internal consistency by Cronbach's alpha coefficients. RESULTS: Three factors were extracted: so-called existential well-being, religious well-being, and peacefulness accounted for 71.44% of total variance. The Cronbach's alpha coefficients for total SWB, EWB, RWB, and peacefulness were 0.96, 0.94, and 0.93, respectively. SIGNIFICANCE OF RESULTS: These findings indicate that the Thai SWBS is a valid and reliable instrument, and it presented one more factor than the original version. PMID- 25799875 TI - [Health-related quality of life in phase III cancer clinical trials: from questionnaire administration to statistical analysis]. AB - Endpoints refer to clinical and biological measurements that assess efficacy of therapeutic strategies. As the American Society of Clinical Oncology states, active treatment in cancer is generally undertaken with the goal of providing improved quantity and/or quality of patient survival. Health-related quality of life (HRQoL) reflects the patient-perceived evaluation of one's health, including physical, emotional, and social dimensions as well as symptoms due to disease or treatment. HRQoL is recognized as a component endpoint for cancer therapy approvals by the American Society of Clinical Oncology and the FDA. Many self completion HRQoL questionnaires have been developed and validated. Two main statistical methods have been developed to longitudinally analyze HRQoL. The first is the linear mixed model for repeated measure (LMM). The second is a survival approach, which estimates the time to HRQoL deterioration. However, there is no guideline for methods of analyzing and reporting longitudinal changes in HRQoL scores. Moreover, HRQoL could also be combined with other endpoints like progression-free survival as co-primary endpoint, but the use of co-primary endpoints in cancer clinical trials is a new approach and methodological researches must be pursued to promote such designs. PMID- 25799876 TI - [Multicenter validation study of a questionnaire assessing patient satisfaction with and acceptance of totally-implanted central venous access devices]. AB - OBJECTIVE: Most cancer patients require a totally-implanted central venous access device (TIVAD) for their treatment. This was a prospective, multicenter, open study to: (i) develop and validate a French-language questionnaire dubbed QASICC (Questionnaire for Acceptance of and Satisfaction with Implanted Central Venous Catheter) assessing patient's satisfaction with and acceptance of their TIVAD; (ii) develop a mean score of patient's acceptance and satisfaction; (iii) look for correlation between QASICC score and TIVAD patient/tumor pathology/device characteristics. METHODS: From 2011 November to 2012 December, the first version of the QASICC questionnaire that included 27 questions assessing seven dimensions was re-tested among 998 cancer patients in eleven French cancer hospitals (eight cancer research institutes and three university/general hospitals). The goal was: (i) to reduce the questionnaire item and dimension number (pertinency, saturation effect, item correlation); (ii) to assess its psychometric properties, demonstrate its validity and independency compared to (EORTC) QLQC30; (iii) to correlate clinical and pathological patient's/tumor's/TIVAD's parameters with the QASICC questionnaire score (the higher the overall score, the greater the acceptance and satisfaction). The questionnaire was administered to the patient 30 days (+/-15 days) after TIVAD's implantation. RESULTS: Among 998 questionnaires given to cancer patients, 658 were analyzed and 464 were fully assessed as there was no missing data. Time to fill-in the questionnaire was five minutes in 90% patients. Final QASICC tool included twenty-two questions assessing four homogeneous dimensions (65%4%. Our results suggest the need to promote the use of primin-free P. obconica in Italy. PMID- 25799881 TI - Development of Small Molecules Targeting the Wnt Signaling Pathway in Cancer Stem Cells for the Treatment of Colorectal Cancer. AB - Colorectal cancer (CRC) was ranked third in morbidity and mortality in the United States in 2013. Although substantial progress has been made in surgical techniques and postoperative chemotherapy in recent years, the prognosis for colon cancer is still not satisfactory, mainly because of cancer recurrence and metastasis. The latest studies have shown that cancer stem cells (CSCs) play important roles in cancer recurrence and metastasis. Drugs that target CSCs might therefore have great therapeutic potential in prevention of cancer recurrence and metastasis. The wingless-int (Wnt) signaling pathway in CSCs has been suggested to play crucial roles in colorectal carcinogenesis, and has become a popular target for anti-CRC therapy. Dysregulation of the Wnt signaling pathway, mostly by inactivating mutations of the adenomatous polyposis coli tumor suppressor or oncogenic mutations of beta-catenin, has been implicated as a key factor in colorectal tumorigenesis. Abnormal increases of beta-catenin levels represents a common pathway in Wnt signaling activation and is also observed in other human malignancies. These findings highlight the importance of developing small molecule drugs that target the Wnt pathway. Herein we provide an overview on the current development of small molecules that target the Wnt pathway in colorectal CSCs and discuss future research directions. PMID- 25799882 TI - Production of polysaccharide-based bioflocculant for the synthesis of silver nanoparticles by Streptomyces sp. AB - Polysaccharide-based bioflocculants have attracted considerable attention in recent years due to their biodegradable, harmless and negligible secondary pollution. Bioflocculants are organic macromolecular substances secreted by microorganisms. A simple, cost-effective and green method was developed for the biosynthesis of silver nanoparticles using polysaccharides as reducing and stabilizing agents. In this paper, we report on the production and optimization of polysaccharide-based bioflocculant for the green synthesis of silver nanoparticles by Streptomyces sp. MBRC-91. Medium composition and culture conditions for polysaccharide-based bioflocculants were statistically optimized by response surface methodology (RSM). The bioflocculant production was statistically optimized with most significant factors, namely palm jaggery (18.73g/L), yeast extract (2.07g/L), K2HPO4 (3.74g/L) and NaCl (0.38g/L), respectively. The biosynthesized silver nanoparticles were characterized by UV vis spectroscopy, XRD, FTIR, FESEM, EDXA and HRTEM. The biosynthesized silver nanoparticles revealed strong antibacterial activity in sewage water and this result could make a new avenue in the wastewater treatment. Therefore, the biosynthesized silver nanoparticles can be extended as an alternative for the development of new bactericidal bionanomaterials for wastewater treatment and biotechnological applications. PMID- 25799883 TI - In silico and proteomic analysis of protein methyltransferase CheR from Bacillus subtilis. AB - Protein methyltransferase (CheR) catalyzes the methylation of the cytosolic domain of the membrane bound chemotaxis receptors, and plays a pivotal role in the chemotactic signal transduction pathway in bacteria. Crystal structure of CheR is available only from the gram-negative bacterium Salmonella typhimurium (StCheR), which contain a catalytic C-terminal domain, encompassing a beta subdomain, connected via a linker to the N-terminal domain. The structural functional similitude between CheR of the gram-negative and the gram-positive bacteria remains obscure. We investigated CheR, from a gram-positive bacterium, Bacillus subtilis (BsCheR), and have identified the functional roles of its N terminal domain, by using the in silico molecular modeling and docking approach along with mass spectrophotometry and sequence analysis. The structural studies established that the N-terminal domain directly bound to S-Adenosyl-l homocysteine (SAH). Structural and sequence analyses revealed that the alpha2 helix of the N-terminal domain was involved in the recognition of the methylation site of the chemotactic receptor. Additionally, immunoblot analysis showed that the purified BsCheR was phosphorylated. Further, mass spectrometry studies detected the phosphorylation at Thr3 position in the N-terminal domain of BsCheR. Phosphorylation of BsCheR suggested a regulatory role of the N-terminal domain, analogous to its antagonistic enzyme, the chemotaxis-specific methylesterase (CheB). PMID- 25799884 TI - Quercetin as a finer substitute to aminoguanidine in the inhibition of glycation products. AB - Non-enzymatic glycation is the addition of a free carbonyl group of a reducing sugar to the free amino groups of proteins, which results in the formation of early and advanced glycation end-products (AGEs). Glycation reaction is profoundly associated with diabetes and its secondary complications, such as nephropathy and neuropathy. Glyoxal is a carbonyl species that reacts rapidly with the free amino groups of proteins to form AGEs. While the formation of AGEs with various glycating agents has previously been demonstrated, no extensive studies have been conducted to assess the role of quercetin in all three stages of glycation (early, intermediate and late). In this study, we report the glycation of HSA (human serum albumin) and its characterization by several spectroscopic techniques. Furthermore, inhibition of products at all stages of glycation was studied by various assays. Spectroscopic analysis suggests structural perturbations in the HSA macromolecule as a result of modification, which might be due to the generation of free radicals and the formation of AGEs. Inhibition in the formation of glycation has established that quercetin is a better and a more potent antiglycating agent than aminoguanidine at all stages of glycation. PMID- 25799885 TI - Unresolved Pain Interference among Colorectal Cancer Survivors: Implications for Patient Care and Outcomes. AB - OBJECTIVE: Using a large sample of colorectal cancer (CRC) survivors we 1) describe pain interference (PI) prevalence across the cancer continuum; 2) identify demographic and clinical factors associated with PI and changes in PI; and 3) examine PI's relationship with survivors' job changes. METHODS: CRC participants of the Cancer Care Outcomes Research and Surveillance Consortium completed surveys during the initial phase of care (baseline, < 1 year, n = 2,961) and follow-up (about 1-year postdiagnosis, n = 2,303). PI was measured using the SF-12 item. Multiple logistic regression was used to identify predictors of PI. Model 1 evaluated moderate/high PI at baseline, Model 2 evaluated new/continued/increasing PI postdiagnosis follow-up, and Model 3 restricted to participants with baseline PI (N = 603) and evaluated predictors of equivalent/increasing PI. Multivariable logistic regression was also used to examine whether PI predicted job change. RESULTS: At baseline and follow-up, 24.7% and 23.7% of participants reported moderate/high PI, respectively. Among those with baseline PI, 46% had equivalent/increasing PI at follow-up. Near diagnosis and at follow-up, female gender, comorbidities, depression, chemotherapy and radiation were associated with moderate/high PI while older age was protective of PI. Pulmonary disease and heart failure comorbidities were associated with equivalent/increasing PI. PI was significantly associated with no longer having a job at follow-up among employed survivors. CONCLUSION: Almost half of survivors with PI during the initial phase of care had continued PI into post-treatment. Comorbidities, especially cardiovascular and pulmonary conditions, contributed to continued PI. PI may be related to continuing normal activities, that is, work, after completed treatment. PMID- 25799886 TI - Improved molecular imaging in rodent brain with time-of-flight-secondary ion mass spectrometry using gas cluster ion beams and reactive vapor exposure. AB - Imaging mass spectrometry has shown to be a valuable method in medical research and can be performed using different instrumentation and sample preparation methods, each one with specific advantages and drawbacks. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) has the advantage of high spatial resolution imaging but is often restricted to low mass molecular signals and can be very sensitive to sample preparation artifacts. In this report we demonstrate the advantages of using gas cluster ion beams (GCIBs) in combination with trifluoracetic acid (TFA) vapor exposure for the imaging of lipids in mouse brain sections. There is an optimum exposure to TFA that is beneficial for increasing high mass signal as well as producing signal from previously unobserved species in the mass spectrum. Cholesterol enrichment and crystallization on the sample surface is removed by TFA exposure uncovering a wider range of lipid species in the white matter regions of the tissue, greatly expanding the chemical coverage and the potential application of TOF-SIMS imaging in neurological studies. Ar4000(+) (40 keV) in combination with TFA treatment facilitates high resolution, high mass imaging closing the gap between TOF-SIMS and matrix-assisted laser desorption ionization (MALDI). PMID- 25799887 TI - Therapeutic potential of umbilical cord blood cells for type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is a chronic disorder that results from autoimmune-mediated destruction of pancreatic islet beta-cells. However, to date, no conventional intervention has successfully treated the disease. The optimal therapeutic method for T1DM should effectively control the autoimmunity, restore immune homeostasis, preserve residual beta-cells, reverse beta-cell destruction, and protect the regenerated insulin-producing cells against re-attack. Umbilical cord blood is rich in regulatory T (T(reg)) cells and multiple types of stem cells that exhibit immunomodulating potential and hold promise in their ability to restore peripheral tolerance towards pancreatic islet beta-cells through remodeling of immune responses and suppression of autoreactive T cells. Recently, reinfusion of autologous umbilical cord blood or immune cells from cord blood has been proposed as a novel therapy for T1DM, with the advantages of no risk to the donors, minimal ethical concerns, a low incidence of graft-versus-host disease and easy accessibility. In this review, we revisit the role of autologous umbilical cord blood or immune cells from cord blood-based applications for the treatment of T1DM. PMID- 25799888 TI - Editorial Comment to Importance of prostate volume in the stratification of patients with intermediate-risk prostate cancer. PMID- 25799889 TI - Molecular dynamics simulations of 2-(dimethylamino)ethanol (DMEA). AB - We develop a multipurpose force field to investigate the properties of the condensed phases of 2-(dimethylamino)ethanol (DMEA). We use ab initio computations at the HF/6-311++G(2d,2p) level to derive partial charges, obtain force constants, and compute the electrostatic potential of the DMEA. We find that the HF predictions for the dipole moment are in excellent agreement with the experimental result (2.6 D). The computations also show the strong preference of DMEA to form intramolecular hydrogen bonds between the hydrogen in the alcohol group and nitrogen. We have tested the accuracy of our force field by computing coexistence and interfacial properties as well as thermal conductivities in wide range of thermodynamic states. In all these instances we find excellent agreement with the available experimental data. We have further investigated the structure of the liquid by computing pair correlations. Our results indicate a clear preference for DMEA to form low-dimensional structures, such as linear and bifurcated chains, which are driven by the association of the DMEA molecules via the alcohol group. Overall, our force field provides a good basis to compute the bulk and interfacial properties of DMEA. PMID- 25799890 TI - Live donor liver transplantation: a valid alternative for critically ill patients suffering from acute liver failure. AB - We report the outcome of live donor liver transplantation (LDLT) for patients suffering from acute liver failure (ALF). From 2006 to 2013, all patients with ALF who received a LDLT (n = 7) at our institution were compared to all ALF patients receiving a deceased donor liver transplantation (DDLT = 26). Groups were comparable regarding pretransplant ICU stay (DDLT: 1 [0-7] vs. LDLT: 1 days [0-10]; p = 0.38), mechanical ventilation support (DDLT: 69% vs. LDLT: 57%; p = 0.66), inotropic drug requirement (DDLT: 27% vs. LDLT: 43%; p = 0.64) and dialysis (DDLT: 2 vs. LDLT: 0 patients; p = 1). Median evaluation time for live donors was 24 h (18-72 h). LDLT versus DDLT had similar incidence of overall postoperative complications (31% vs. 43%; p = 0.66). No difference was detected between LDLT and DDLT patients regarding 1- (DDLT: 92% vs. LDLT: 86%), 3- (DDLT: 92% vs. LDLT: 86%), and 5- (DDLT: 92% vs. LDLT: 86%) year graft and patient survival (p = 0.63). No severe donor complication (Dindo-Clavien >=3 b) occurred after live liver donation. ALF is a severe disease with high mortality on liver transplant waiting lists worldwide. Therefore, LDLT is an attractive option since live donor work-up can be expedited and liver transplantation can be performed within 24 h with excellent short- and long-term outcomes. PMID- 25799891 TI - Cutaneous sparganosis: a rare parasitic infection. PMID- 25799893 TI - A survey of epilepsy surgery in India. AB - PURPOSE: Epilepsy surgery (ES) not only remains one of the most underutilized of all accepted medical interventions, but there has also been a decrease in referrals for ES in recent years in high-income countries. We undertook this study to determine the temporal trends of ES and its current state in India. METHODS: We asked the directors of epilepsy centers across India to complete an online questionnaire about the number and type of ES procedures carried out from 1995 or commencement of the program till December 2012. RESULTS: During the 18 year period, a total of 4252 ES have been undertaken. On an average, 420 ES were being carried out each year in India. Three-fourths of resective surgeries involved the temporal lobe. Although majority of patients were selected for ES by noninvasive strategies, 13 centers had performed long-term invasive EEG monitoring to select complex cases. In between 1995-2000 and 2007-2012, the number of ES carried out in India registered an increase by three-fold. CONCLUSIONS: A steadily increasing number of eligible patients with drug resistant epilepsy in India are undergoing ES in recent years. This temporal trend of ES in India is in contrast to the recent experience of high-income countries. PMID- 25799894 TI - Vagus nerve stimulation and late-onset bradycardia and asystole: case report. PMID- 25799896 TI - Quality of life is social--towards an improvement of social abilities in patients with epilepsy. AB - Quality of life (QoL) for people with epilepsy is considered worse than the condition's clinical and medical prognosis would predict. Quantity and quality of social interaction considerably determine QoL. Research shows that a significant proportion of patients with epilepsy experience difficulties with social functioning that is thought to be related to impaired QoL. The aim of this review article is to provide an evidence base for conceptualising and developing interventions to improve quality of life through social functioning, for adults with epilepsy. Previous and current research is considered initially with regards to why such difficulties arise and established interventions that address social competence and functioning are reviewed and explored from the field of schizophrenia, a condition also associated with similar difficulties in social cognition, cognition and negative symptoms. The paper considers the advantages and disadvantages of these interventions, the outcomes and emerging research in this area. Positive findings are found from interventional studies in schizophrenia such as the enhancing potential and generalisation of training in social cognition, the benefits of an integrated approach to improving social functioning and proposal of 'online' interaction approaches. These findings provide interesting and exciting directions for the ultimate goal towards interventions for the improvement of social functioning and quality of life in patients with epilepsy. This is of particular significance as at present there is currently no such dedicated program for people with epilepsy. PMID- 25799895 TI - Seizure occurrence, pregnancy outcome among women with active convulsive epilepsy: one year prospective study. AB - PURPOSE: To determine the prevalence of active convulsive epilepsy, seizure frequency and the outcome of pregnancy amongst a cohort of pregnant women attending antenatal clinic (ANC) at two tertiary hospitals. METHODS: An observational cohort study conducted at the University of Maiduguri Teaching Hospital and State Specialist Hospital, Northeast Nigeria. Pregnant women attending antenatal care were screened for previous history of active convulsive epilepsy, and recruited consecutively according to a specified protocol. A standardized questionnaire was administered to record pregnancy history, nature of epilepsy and treatments received. They were followed-up during the course of the pregnancy based on the ANC schedule up to delivery. The outcome of pregnancies was recorded. RESULTS: A total of 7063 pregnant women were screened, of whom 103 (1.46%) subjects had at least a past history of seizure. Seventy eight (1.10%) had a past history of seizure(s) from eclampsia and 23 (0.33%) pregnant subjects recruited were identified to have active convulsive epilepsy. The unadjusted prevalence of active convulsive epilepsy in pregnant women was found to be 3.33 per 1000 (95% CI: 2.1-4.8). Subjects who had a history of head injury and encephalitis were more likely to have seizures during pregnancy. (P=0.013 and P=0.041). Those who had recurrent seizures within the last six months before recruitment were more likely to have a negative pregnancy outcome (P=0.043). CONCLUSION: Our study found a prevalence of active epilepsy of 3.33 per 1000 among pregnant women, with about one percent having a past history of seizure from eclampsia. PMID- 25799897 TI - IL-1beta, IL-6 and IL1Ra levels in temporal lobe epilepsy. AB - PURPOSE: There is now extensive evidence to support the involvement of inflammation in the course of epileptic seizures. Seizure-induced changes in serum IL-1beta, IL-6 and IL-1Ra levels are reported in several studies. Serum cytokine levels may also be disturbed in inter-ictal period due to seizure activity. METHODS: Twenty-one patients (12 women; mean age 35+/-12.3) with temporal lobe epilepsy (TLE), 17 patients (8 women; mean age 31.8+/-10.4) with extra-temporal lobe epilepsy (XLE) and 20 normal controls (10 women; mean age 35.6+/-8.8) were included in the study. Serum levels of IL-1beta, IL-6 and IL-1Ra of the TLE, XLE groups in inter-ictal period and of the normal control group were compared. RESULTS: All three cytokine levels are found to be significantly elevated in epilepsy patients when compared to controls (p<0.05). In TLE group, IL-1beta serum levels were significantly higher than in the XLE group (p<0001). CONCLUSION: The major findings in our study were increased levels of IL-1beta, IL 6 and IL-1Ra in epileptic patients and high levels of IL-1beta in TLE group. Our results support the existence of a chronic inflammatory state in epileptic patients. PMID- 25799899 TI - Epileptic seizures in Neuro-Behcet disease: why some patients develop seizure and others not? AB - PURPOSE: Behcet disease (BD) is a chronic relapsing inflammatory disorder. Neuro BD (NBD) is seen in approximately 5% of all patients. The aim of this study is to investigate the frequency, type and prognosis of epileptic seizures in different forms of NBD. METHODS: All files of 42 patients with NBD were evaluated between 2006 and 2012, retrospectively. The demographic data, the presentation of NBD, clinical findings including seizures, EEG and neuroimaging findings were reviewed. RESULTS: The mean age of patients was 35.02+/-8.43 years. Thirty (71.4%) patients were male; the remaining 12 of them were female. Twenty-four patients had brainstem lesions; 16 patients had cerebral venous thrombosis. Spinal cord involvement was seen in two patients. Seven patients had epileptic seizures (six partial onset seizures with or without secondary generalization). Six of them had cerebral sinus thrombosis (CVT). Four patients had a seizure as the first symptom of the thrombosis. One patient had late onset seizure due to chronic venous infarct. The other patient with seizure had brainstem involvement. The remaining was diagnosed as epilepsy before the determination of NBD. CONCLUSION: CVT seen in BD seems to be the main risk factor for epileptic seizures in patients with NBD. The prognosis is usually good especially in patients with CVT. Epileptic seizures in patients with brainstem involvement may be an indicator for poor prognosis. Superior sagittal thrombosis or cortical infarct would be predictor of seizures occurrence because of the high ratio in patients with seizures. PMID- 25799898 TI - Perceived stigma is a critical factor for interictal aggression in people with epilepsy. AB - PURPOSE: Aggression in people with epilepsy (PWE) is not well understood. We investigated interictal aggression in PWE and clarified predictors and the interrelationships among them. METHOD: This was a case-control study. Eligible subjects who consecutively visited the epilepsy clinic completed several questionnaires including the Aggression Questionnaire (AQ), the Revised Stigma Scale (RSS), the Korean version of the Neurological Disorders Depression Inventory for Epilepsy (K-NDDI-E), and the Generalized Anxiety Disorder-7 (GAD 7). RESULTS: PWEs had higher overall AQ scores and anger and hostility subscale scores than controls. Patients with uncontrolled epilepsy also had higher physical and verbal aggression subscale scores than controls. Univariate analyses revealed associations between the overall AQ score and job, household income, marriage, antiepileptic drug (AED) load, seizure control, co-administration of psychiatric drugs, the RSS score, the K-NDDI-E score, and the GAD-7 score. Multivariate analyses indicated that the strongest predictor for the overall AQ score was the RSS score (beta=0.346, p<0.001), followed by the GAD-7 score (beta=0.244, p=0.003), and the K-NDDI-E score (beta=0.172, p=0.047). The RSS score exerted a direct effect on the overall AQ score under the influences of the GAD-7 score and the K-NDDI-E score. The GAD-7 score also exerted a direct effect on the overall AQ score, but the K-NDDI-E score only had an indirect effect on the overall AQ score through the RSS score. CONCLUSION: The degree of interictal aggression is higher in PWE than controls. Perceived stigma is a critical factor for aggression under the influence of depression and anxiety. PMID- 25799900 TI - Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy. AB - PURPOSE: Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE). METHOD: In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation. RESULTS: While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p=0.09), LICF was reduced compared to controls (controls: 141+/ 17% of baseline; untreated patients: 107+/-12%, p=0.2; treated patients: 79+/ 10%, p=0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56+/-4% of baseline vs. 26+/-6% in controls, p=0.004) and normalised with treatment (37+/-12%, p=0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120+/-10% of baseline, p=0.017), but not in treated patients. CONCLUSION: Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis. PMID- 25799901 TI - Exploring the capability of wireless near infrared spectroscopy as a portable seizure detection device for epilepsy patients. AB - PURPOSE: Near infrared spectroscopy (NIRS) has proved useful in measuring significant hemodynamic changes in the brain during epileptic seizures. The advance of NIRS-technology into wireless and portable devices raises the possibility of using the NIRS-technology for portable seizure detection. METHODS: This study used NIRS to measure changes in oxygenated (HbO), deoxygenated (HbR), and total hemoglobin (HbT) at left and right side of the frontal lobe in 33 patients with epilepsy undergoing long-term video-EEG monitoring. Fifteen patients had 34 focal seizures (20 temporal-, 11 frontal-, 2 parietal-lobe, one unspecific) recorded and analyzed with NIRS. Twelve parameters consisting of maximum increase and decrease changes of HbO, HbR and HbT during seizures (1 min before- to 3 min after seizure-onset) for left and right side, were compared with the patients' own non-seizure periods (a 2-h period and a 30-min exercise period). In both non-seizure periods 4 min moving windows with maximum overlapping were applied to find non-seizure maxima of the 12 parameters. Detection was defined as positive when seizure maximum change exceeded non seizure maximum change. RESULTS: When analyzing the 12 parameters separately the positive seizure detection was in the range of 6-24%. The increase in hemodynamics was in general better at detecting seizures (15-24%) than the decrease in hemodynamics (6-18%) (P=0.02). CONCLUSION: NIRS did not seem to be a suitable technology for generic seizure detection given the device, settings, and methods used in this study. There are still several challenges to overcome before the NIRS-technology can be used as a home-monitoring seizure detection device. PMID- 25799902 TI - Evaluation of costs of epilepsy using an electronic practice management software in Germany. AB - PURPOSE: This study used an electronic practice management software in daily routine to gather long-term disease and cost-of-illness (COI) data in patients with epilepsy in Germany. METHODS: Data on socio-economic status, course of epilepsy as well as direct and indirect costs were recorded using practice software-based questionnaires. RESULTS: In 2011 we enrolled 359 patients (170 male (47.4%); mean age 50.5+/-20.7 years) in six neurological practices. The majority of patients had been in long-term seizure remission for more than one year (n=200, 55.7%) and in more than two-thirds the anti-epileptic drug (AED) monotherapy (n=248, 69.1%) was used. Levetiracetam (31%), lamotrigine (26%) and valproate (24%) were the drugs prescribed most frequently. Total annual direct costs amounted to ?1698 per patient with anticonvulsants (59.9% of total direct costs) and hospitalization (30.0%) as the main cost factors. Of the patients enrolled 252 (70.2%) were of working age and indirect annual costs due to absenteeism amounted to ?745 per patient. Potential cost-driving factors were seizure frequency and a recent diagnosis of epilepsy associated with higher costs. Anticonvulsant treatment in patients aged 65 years and older was associated with lower drug costs due to prescription of older AEDs. CONCLUSION: We were able to demonstrate that electronic practice management software can easily be used to perform long-term health economic evaluations with a bottom-up approach. The combination of both physician- and patient-based electronic databases will facilitate performing less expensive studies, but at the same time simplify large, prospective and multicentre clinical trials. PMID- 25799904 TI - Cognition in the early stages of adult epilepsy. AB - PURPOSE: The impact of duration of epilepsy on cognition has been discussed for a long time. More recently, it has been recognized that cognitive deficits are often already present at the onset of epilepsy or even before. From an etiological point of view it is now understood that it is not really the question what comes first, epilepsy or cognitive comorbidity. Instead the evidence suggests that both problems rather originate from a common underlying pathology. METHODS: We selected studies addressing cognition in adult new-onset or newly diagnosed epilepsies before treatment initiation. Potential factors are outlined that affect cognition prior to, around or after epilepsy onset. RESULTS: Most studies investigated newly diagnosed patients, but many included individuals who already had a long history of seizures at the time of diagnosis. Fewer studies focused on new-onset epilepsies. Overall, cognitive problems in the early stages of adult onset epilepsy were found to be common. The occurrence of seizures may initially cause greater concern and lead to an underreporting of cognitive problems prior to or around the time of diagnosis. CONCLUSION: The high prevalence of objective cognitive impairments present at epilepsy onset calls for early neuropsychological assessments soon after the diagnosis of epilepsy, and at best before medical treatment is initiated. Without such baseline assessments subsequent neuropsychological testing during follow-up is difficult to interpret in regard to the effects of treatment success or the course of underlying disease processes. Beyond that, the baseline assessment may also guide treatment choices and serve as an early indicator of the need for support or rehabilitation. In this way neuropsychological monitoring can improve individual medical care, and increase tolerability, adherence, and treatment retention from the point of diagnosis. PMID- 25799903 TI - Wavelet-based EEG processing for computer-aided seizure detection and epilepsy diagnosis. AB - Electroencephalography (EEG) is an important tool for studying the human brain activity and epileptic processes in particular. EEG signals provide important information about epileptogenic networks that must be analyzed and understood before the initiation of therapeutic procedures. Very small variations in EEG signals depict a definite type of brain abnormality. The challenge is to design and develop signal processing algorithms which extract this subtle information and use it for diagnosis, monitoring and treatment of patients with epilepsy. This paper presents a review of wavelet techniques for computer-aided seizure detection and epilepsy diagnosis with an emphasis on research reported during the past decade. A multiparadigm approach based on the integration of wavelets, nonlinear dynamics and chaos theory, and neural networks advanced by Adeli and associates is the most effective method for automated EEG-based diagnosis of epilepsy. PMID- 25799905 TI - Early-onset movement disorder and epileptic encephalopathy due to de novo dominant SCN8A mutation. PMID- 25799906 TI - Rehabilitation for young adults with epilepsy and mild intellectual disabilities: results of a prospective study with repeated measurements. AB - PURPOSE: A residential rehabilitation program of the Bethel Institute in Germany for approximately three years is offered to young adults with epilepsy and mild intellectual disabilities. Participants aim at epilepsy improvements and want to gain more independence. The purpose of this study was to investigate effects of the program and their stability over the course of time. METHOD: Ninety-seven clients completed the program between 1999 and 2011. Data with repeated measurements (T1=four weeks after admission, T2=discharge, T3=at least two years after discharge) were only available for 51 of them. Outcome variables were seizure frequency, carer-ratings on their clients' success, assistance needs after the program (supported housing vs. long-term residential care) and client ratings on activities of daily living, problems at work, on health-related and on global quality of life (QOL), on life satisfaction and on depression and psychological distress. RESULTS: Seizure frequency was significantly reduced, more than half of the clients moved to supported housing. Clients reported improvements in activities of daily living and some aspects of their QOL. These improvements remained constant over at least two years. Baseline data scarcely correlated with outcome measures. Analyses of subgroups demonstrated that changes of client-ratings correspond to changes of external parameters such as seizure frequency and professional assistance. CONCLUSION: Improvements with regard to more independent living, a better seizure control and more favorable self-ratings remained stable over the following years. From a social-welfare point of view, it is especially important that about half of the clients moved to supported housing after the program. PMID- 25799907 TI - Cardiac-based vagus nerve stimulation reduced seizure duration in a patient with refractory epilepsy. AB - PURPOSE: A novel vagus nerve stimulation (VNS) device was recently approved in Europe which rapidly detects increases in heart rates (HR) and applies an additional stimulus if HR-increases exceed a given threshold. The effects of HR triggered VNS-pulses on seizures were not reported yet under controlled conditions. Here, we quantified the effects of HR-triggered VNS-pulses on the seizure duration in one patient. METHODS: The novel VNS device was implanted in a 29-year old man with refractory epilepsy. After implantation, the patient underwent video-EEG telemetry for 68h with no changes in anticonvulsant drugs. On the first day the patient only received sham-stimulation. During the following 46h HR-related VNS-stimulation was set to 2mA. Seizure duration was determined based on clinical signs. RESULTS: Twelve stereotypical seizures were recorded (six during sham- and six during the active stimulation). The VNS device recognised a total of 139 events as a seizure and correctly identified 11 seizures. The HR-triggered VNS-stimulation significantly reduced the total seizure duration from 33.2+/-4.8s to 26.5+/-5s and the remaining seizure duration after the onset of the extra-stimulation from 27.8+/-4.3s to 16.2+/-3.2s. With the given configuration in this patient, sensitivity and specificity of HR-based seizure-detection amounted to 92% and 13.5%, respectively. CONCLUSIONS: This case illustrates that VNS-stimulation in response to seizure-related HR-increases is able to significantly reduce seizure duration. Despite the limitations of our case, its promising results should prompt larger studies to confirm the clinical benefit of this novel device. PMID- 25799908 TI - Epileptic encephalopathy with electrical status epilepticus: an electroclinical study of 59 patients. AB - PURPOSE: To evaluate the electroclinical features, treatment effectiveness, and outcome of 59 patients with epileptic encephalopathy with electrical status epilepticus during sleep. METHODS: Medical-files of 59 patients with electrical status epilepticus during sleep were retrospectively evaluated for data concerning: history, physical and neurological examinations, sleep and awake EEG's, psychometric tests and brain MRI. RESULTS: A total of 31 boys and 28 girls were identified. Patients were evaluated in two groups: symptomatic/structural and idiopathic group. There was no significant difference between the etiological groups in term of mean age at ESES onset, mean interval between the first seizure and the onset of ESES. The mean age at seizure onset was earlier in the symptomatic/structural group than the idiopathic ones. The mean follow-up time after the ESES onset was 4.5 years for all patients. The most effective antiepileptic drugs in our series were clobazam and levetiracetam. In refractory patients, steroid treatment was found effective during the early course of the disease. In the idiopathic group, cognitive decline has improved. However in the symptomatic group, patients did not respond to the treatment and cognitive deterioration did not improve in one third of the group. CONCLUSION: The long term outcome of ESES is highly variable and usually depends on etiology and the duration of ESES. The most efficious antiepileptic drugs in our study are clobazam and levetiracetam. PMID- 25799909 TI - Characteristics and acute outcomes of ICU patients with initial presentation of seizure. AB - PURPOSE: Seizures are a common cause of presentation to the emergency department (ED) but vary widely in severity and prognostic significance, with some cases requiring ICU management. Most evidence regarding seizure outcomes in the ICU comes from patients exclusively with status epilepticus (SE) or with new seizures detected after ICU admission. To aid in determining early prognosis of ICU patients with and without SE, we performed an analysis of patients initially presenting with any type of seizure and requiring ICU management. METHOD: Analysis of hospital records of 247 consecutive patients presenting to the ED initially with seizure and directly admitted to the ICU between January 2010 and June 2013. The primary outcome was composite in-hospital death or discharge to hospice, and the secondary outcome was recurrent ICU seizures. RESULTS: The primary outcome occurred in 7.7% of patients. Both early mechanical ventilation and an acute intracranial process on neuroimaging were associated with a poor outcome. About half of this cohort presented with SE. Although SE was associated with recurrent seizures in the ICU, the primary outcome was similar between patients presenting with and without SE. Patients with SE had greater rates of early intubation in the ED and were treated more aggressively with medication, whereas patients without SE had greater rates of first ever seizure, acute intracranial disease including intracranial hemorrhage, and neurosurgical intervention. CONCLUSION: Patients presenting to the ED with and without SE requiring ICU admission may have similar acute outcomes, yet differ in risk factors and seizure etiologies. PMID- 25799910 TI - Impact of the branched-chain amino acid to tyrosine ratio and branched-chain amino acid granule therapy in patients with hepatocellular carcinoma: A propensity score analysis. AB - BACKGROUND AND AIM: It has been reported that the branched-chain amino acid (BCAA) to tyrosine ratio (BTR) is a useful indicator of liver function and BCAA therapy is associated with a decreased incidence of hepatocellular carcinoma (HCC). However, there has not been sufficient research on the relationship between BTR and the effects of BCAA therapy after initial treatment of HCC. We investigated the impact of BTR and BCAA therapy on survival in patients with HCC. METHODS: A total of 315 patients with HCC who were treated (n = 66) or not treated (n = 249) with BCAA were enrolled; of these, 66 were selected from each group using propensity score matching. Survival from liver-related mortality was analyzed. RESULTS: In patients who did not receive BCAA therapy (n = 249), multivariate analysis for factors associated with survival indicated that low BTR (<= 4.4) was independently associated with poor prognosis in patients with HCC (hazard ratio, 1.880; 95% confidence interval, 1.125-3.143; P = 0.016). In addition, among patients selected by propensity score matching (n = 132), multivariate analysis indicated that BCAA therapy was independently associated with good prognosis in patients with HCC (hazard ratio, 0.524; 95% confidence interval, 0.282-0.973; P = 0.041). BTR was not significantly associated with survival. CONCLUSIONS: Intervention involving BCAA therapy improved survival in patients with HCC versus untreated controls, regardless of BTR. In addition, low BTR was associated with poor prognosis in patients who did not receive BCAA therapy. PMID- 25799911 TI - Surgical Considerations for Massive Tarsal Coalitions in Multiple Synostosis Syndrome: A Case Report. AB - Tarsal-carpal coalition syndrome is an autosomal dominant inherited condition characterized by fusion of the carpal and tarsal bones and foot deformity. Associated pain and/or gait disturbance are the main complaints. The deformity usually consists of varying degrees of hindfoot varus and forefoot supination. The treatment of these patients is mainly aimed at symptomatic relief. We performed a published data review of this condition and discuss our findings in the context of the case of a 10-year-old female with congenital varus deformity of both feet. The tarsal-carpal coalition syndrome has been included in the spectrum of heritable disorders related to mutations in the NOG gene. Deformity management should be customized to the patient's requirements, and satisfactory results are achievable with adequate rehabilitation. It is important to remember that surgery is only necessary for symptomatic relief and that patients with tarsal-carpal coalition syndrome should be followed up over time because the condition can evolve. PMID- 25799913 TI - Histological concordance in familial central nervous system tumors: Evidence from nationwide Swedish Family-Cancer Database. AB - BACKGROUND: Published studies have shown that familial risks in the primary central nervous system (CNS) tumors are usually histology-specific. If genetic factors indeed determine tumor histology it would be expected that histological types would agree between affected first-degree relatives (FDRs). MATERIAL AND METHODS: This study was conducted using the nationwide Swedish Family-Cancer Database. FDR pairs were defined where both of them had the same histological subtype of CNS tumor. The histological concordance was determined using kappa agreement test. RESULTS: We identified 858 familial patients (333 parent offspring pairs, 97 sibling pairs) with primary CNS tumors. Proportion of spinal hemangioblastoma out of all familial hemangioblastomas (21%) was significantly higher than that in sporadic patients (7%; P=0.001). The highest kappa value was found for hemangioblastoma among parent-child pairs (kappa=86%, 95% CI: 74-98%). There was a moderate agreement for concordant neurinoma among father-daughter pairs (kappa=48% 95% CI: 15-81%). Low grade glioma showed significant agreement among mother-daughter (kappa=33%, 95% CI: 9-57%) and father-daughter pairs (kappa=39%, 95% CI: 11-67%), but not in mother-son (kappa=10%, 95% CI: -13% to 32%) and father-son pairs (kappa=9%, 95% CI: -1% to 40%). There was histological agreements for meningioma in mother-offspring (kappa range=20-27%) but not in father-daughter (kappa=14%, 95% CI: -8% to 35%) and father-son pairs (kappa=9%, 95% CI: -12% to 30%). CONCLUSIONS: Our findings suggest that shared genetic risk factors between family members could lead to specific histological types in the familial CNS tumors, especially in hemangioblastoma and neurinoma. Our data may also suggest interactions between sex hormone and some genes contributing to familial meningioma and low grade glioma. PMID- 25799912 TI - Plasma matrix metalloproteinase 2 levels and breast cancer risk. AB - Matrix metalloproteinase 2 (MMP2) is an enzyme with important functions in breast cancer invasion and metastasis. However, it is unclear whether circulating MMP2 levels may predict breast cancer risk. We conducted a prospective nested case control analysis in the Nurses' Health Study among 1136 cases who were diagnosed with invasive breast cancer between 1992 and 2004 and 1136 matched controls. All participants provided blood samples in 1989-1990, and a subset (170 cases, 170 controls) contributed an additional sample in 2000-2002. Pre-diagnostic plasma MMP2 levels were measured via immunoassay, and conditional logistic regression was performed to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs), adjusted for breast cancer risk factors. No association was observed between plasma MMP2 levels and risk of total invasive breast cancer (top vs. bottom quartile, OR=1.0; 95% CI: 0.7, 1.2; p-trend=0.89). Findings did not vary significantly by time since blood draw, body mass index, postmenopausal hormone use, or menopausal status at either blood draw or breast cancer diagnosis. MMP2 was associated with a greater risk of nodal metastases at diagnosis (top vs. bottom quartile, OR=1.5; 95% CI: 1.0, 2.2; p-heterogeneity, any vs. no lymph nodes=0.002), but no significant associations were observed with other tumor characteristics or with recurrent or fatal cancers. Plasma MMP2 levels do not appear to be predictive of total invasive breast cancer risk, although associations with aggressive disease warrant further study. PMID- 25799915 TI - Temporal pattern in biometrics and nutrient stoichiometry of the intertidal seagrass Zostera japonica and its adaptation to air exposure in a temperate marine lagoon (China): Implications for restoration and management. AB - In coastal areas of China, the seagrass Zostera japonica has drastically decreased in the past decades. Swan Lake is an exception, where we found extensive areas of Z. japonica beds. The growth of Z. japonica in the lagoon exhibited strong seasonal variation. The maximum shoot density of 9880+/-2786 shoots m(-2) occurred in August. The maximum specific growth rate (SGR) of 4.99+/ 1.99%?d(-1) was recorded in June 2012. SGR might be a good parameter for assessing the growth status of Z. japonica population. N and P contents in the rhizome were significantly lower than those in the leaf and leaf sheath. Lower C/P ratios suggested P enrichment of the seagrass. The occurrence of Z. japonica in Swan Lake was featured by adapting to the intertidal harsh environments. The transplantation method using sectioned rhizomes would be a potential way for restoration of degraded Z. japonica beds. The establishment of the Rongcheng Swan National Nature Reserve in China has contributed to the survival and expansion of Z. japonica in Swan Lake. PMID- 25799916 TI - Rotation axes analysis of deformed magnesium based on rotation contour contrast in a scanning electron microscope. AB - A crystallographic orientation contrast in the form of cross-shaped and intersecting contours was observed in a backscattered electron (BSE) micrograph of deformed magnesium (Mg) grains in a cold field emission scanning electron microscope (CFE-SEM). This contrast was identified as rotation contour contrast (RCC). A model is presented to link the RCC in the BSE micrograph to the channeling contrast in the corresponding channeling pattern. Based on this model, the appearance of the cross-shaped RCC in the BSE micrograph was attributed to the rotation of the crystal about two rotation axes and the RCC was related to a two dimensional angular scan of the corresponding channeling pattern. This model was experimentally validated using the selected area channeling pattern (SACP) technique. The crystallographic directions of the rotation axes were identified using the electron backscatter diffraction (EBSD) technique. PMID- 25799914 TI - Activation of NALP1 inflammasomes in rats with adjuvant arthritis; a novel therapeutic target of carboxyamidotriazole in a model of rheumatoid arthritis. AB - BACKGROUND AND PURPOSE: Pro-inflammatory cytokines are important in rheumatoid arthritis (RA) and their production is mainly regulated by NF-kappaB and inflammasomes. Carboxyamidotriazole (CAI) exhibits potent anti-inflammatory activities by decreasing cytokines. Here, we have investigated NACHT, LRR and PYD domains-containing protein (NALP) inflammasomes in a rat model of RA and explored the therapeutic effects of CAI in this model and the involvement of NF-kappaB and inflammasomes in the actions of CAI. EXPERIMENTAL APPROACH: The anti-arthritic effects of CAI were assessed in the adjuvant arthritis (AA) model in rats, using radiological and histological techniques. NALP1 and NALP3 inflammasomes, NF kappaB pathway and pro-inflammatory cytokines levels were measured with Western blots, immunohistochemistry and ELISA. KEY RESULTS: CAI decreased the arthritis index, improved radiological and histological changes, and reduced synovial IL 1beta, IL-6, IL-18 and TNF-alpha levels in rats with AA. Compared with normal rats, the 70 kDa NALP1 isoform was up-regulated, NALP3 was down-regulated, and levels of the 165 kDa NALP1 isoform and the adaptor protein ASC were unchanged in synovial tissue from AA rats. CAI reduced the 70 kDa NALP1 isoform and restored NALP3 levels in AA rats; CAI inhibited caspase-1 activation in AA synovial tissue, but not its enzymic activity in vitro. In addition, CAI reduced expression of p65 NF-kappaB subunit and IkappaBalpha phosphorylation and degradation in AA rats. CONCLUSION AND IMPLICATIONS: NALP1 inflammasomes were activated in synovial tissues from AA rats and appeared to be a novel therapeutic target for RA. CAI could have therapeutic value in RA by inhibiting activation of NF-kappaB and NALP1 inflammasomes and by decreasing pro-inflammatory cytokines. PMID- 25799917 TI - Elastic and inelastic electrons in the double-slit experiment: A variant of Feynman's which-way set-up. AB - Modern nanotechnology tools allowed us to prepare slits of 90 nm width and 450 nm spacing in a screen almost completely opaque to 200 keV electrons. Then by covering both slits with a layer of amorphous material and carrying out the experiment in a conventional transmission electron microscope equipped with an energy filter we can demonstrate that the diffraction pattern, taken by selecting the elastically scattered electrons, shows the presence of interference fringes, but with a bimodal envelope which can be accounted for by taking into account the non-constant thickness of the deposited layer. However, the intensity of the inelastically scattered electrons in the diffraction plane is very broad and at the limit of detectability. Therefore the experiment was repeated using an aluminum film and a microscope also equipped with a Schottky field emission gun. It was thus possible to observe also the image due to the inelastically scattered electron, which does not show interference phenomena both in the Fraunhofer or Fresnel regimes. If we assume that inelastic scattering through the thin layer covering the slits provides the dissipative process of interaction responsible for the localization mechanism, then these experiments can be considered a variant of the Feynman which-way thought experiment. PMID- 25799919 TI - 60 years of advances in neuropsychopharmacology for improving brain health, renewed hope for progress. AB - Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing "R and D". The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of "R and D" for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits. PMID- 25799918 TI - Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model. AB - Prefrontal cortical dopamine plays an important role in cognitive control, specifically in attention and response inhibition; the core deficits in ADHD. We have previously shown that methylphenidate and atomoxetine differentially improve these deficits dependent on baseline performance. The present study extends this work to investigate the effects of putative therapeutic targets in our model. A selective dopamine D4 receptor agonist (A-412997) and the catechol-O-methyl transferase (COMT) inhibitor; tolcapone, were investigated in the combined subtype of adult ADHD (ADHD-C). Adult female rats were trained to criterion in the 5C-CPT (5-Choice Continuous Performance Task) and then separated into subgroups according to baseline levels of sustained attention, vigilance, and response disinhibition. The subgroups included: high-attentive (HA) and low attentive with high response disinhibition (ADHD-C). The ADHD-C subgroup was selected to represent the combined subtype of adult ADHD. Effects of tolcapone (3.0, 10.0, 15.0mg/kg) and A-412997 (0.1, 0.3, 1.0umol/kg) were tested by increasing the variable inter-trial-interval (ITI) duration in the 5C-CPT. Tolcapone (15mg/kg) significantly increased sustained attention, vigilance and response inhibition in ADHD-C animals, and impaired attention in HA animals. A 412997 (1.0umol/kg) significantly increased vigilance and response inhibition in ADHD-C animals only, with no effect in HA animals. This is the first study to use the translational 5C-CPT to model the adult ADHD-C subtype in rats and to study new targets in this model. Both tolcapone and A-412997 increased vigilance and response inhibition in the ADHD-C subgroup. D4 and COMT are emerging as important potential therapeutic targets in adult ADHD that warrant further investigation. PMID- 25799920 TI - Delta9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption. AB - Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients. PMID- 25799921 TI - A vascularized elbow allotransplantation model in the rat. AB - BACKGROUND: The aim of this research was to develop a rat model for vascularized composite allotransplantation (VCA) of the elbow. METHODS: We developed an animal model for VCA of the elbow in rats. Microvascular VCA was performed in 9 rats across a major histocompatibility barrier. Three different immunosuppressive regimens were provided. Joint mobility and weight-bearing capability were assessed throughout 90 days of life. Pedicle patency, bone blood flow, and histologic analyses were performed. RESULTS: In the cyclosporine group, forelimb activity was recovered during the postoperative 90 days. The extremity that was operated on was used in daily activities. There was minimal motion or use of the limb in the cyclosporine taper and control groups. The vascular pedicles were patent at the time of death in the cyclosporine-treated group but not in the remaining groups. Micro-computed tomography scan performed 3 months after transplantation revealed union at the bone junctions, and the elbow joint appeared grossly normal on death in the cyclosporine treatment group only. Incomplete healing was observed in the other 2 groups, and the elbow joints were grossly destroyed. Histologic examination revealed normal cartilage and bone cells in the cyclosporine-treated group, whereas the nontreated groups demonstrated lymphocytic infiltration and loss of normal histologic features. Flow cytometry of blood samples obtained on days 14, 30, 60, and 90 showed no recipient cell chimerism in any of the groups. CONCLUSIONS: We developed an animal model for elbow VCA. Immunosuppressed animals regained nearly normal function of forelimbs and maintained grossly normal elbow cartilage. Without cyclosporine treatment, the elbow transplants were rejected. PMID- 25799923 TI - Reconstruction of massive bone loss in the elbow using vascularized fibular transfer: a case report. PMID- 25799922 TI - Shoulder arthroplasty in the patient with metal hypersensitivity. AB - BACKGROUND: The in vivo effects of metal hypersensitivity remain a topic of much debate. At the core of this debate is the possible, although still hotly contested, link between metal hypersensitivity and poorly functioning or failing implants. There are multiple studies on this topic in the hip and knee arthroplasty literature, but the applicability of this experience to shoulder arthroplasty remains unclear. Although how often metal hypersensitivity affects shoulder arthroplasty patients remains uncertain, a multitude of case reports have implicated metallic implants as a source of local and systemic allergic reactions. We recommend a cautious approach to patients with a history of metal hypersensitivity, including a careful evaluation of suspected metal hypersensitivities in all patients undergoing shoulder arthroplasty. If available, we recommend a metallic implant with low to no nickel content in patients with metal hypersensitivity. Given the large and increasing, number of total shoulder arthroplasty procedures and the high percentage of the population having a known or suspected metal hypersensitivity, this review is intended to guide and educate the shoulder surgeon in the evaluation and treatment of this patient population and to point out the areas where evidence-based recommendations are lacking. PMID- 25799924 TI - Chronic bronchitis leads to accelerated hyperinflation in COPD patients during exercise. AB - BACKGROUND AND OBJECTIVE: It is not known whether patients with chronic obstructive pulmonary disease (COPD) have a different exercise capacity with (CB(+) ) or without accompanying chronic bronchitis (CB(-) ). METHODS: We conducted spirometry, a 6-min walk distance test and cardiopulmonary exercise test in 50 age-matched healthy control subjects, 45 COPD patients without CB (CB( ) ) and 37 COPD patients with CB (CB(+) ). A multiple regression model was established to identify factors independently associated with peak oxygen consumption ( V O 2 ). RESULTS: Patients with and without CB had similar forced expiratory volume in 1 s (FEV1 ). CB(+) patients had a lower V O 2 . CB(+) and CB(-) participants had similar increases in tidal volume at peak exercise; however, CB(+) patients had an increased respiratory rate (RR). These patients reached the peak value for ratio of end-expiratory lung volume to total lung capacity (TLC) at a lower work load. A stepwise multiple linear regression analysis identified chronic bronchitis, FEV1 , diffusing capacity for carbon monoxide, the ratio of residual volume to TLC and serum tumour necrosis factor alpha as independent predictors of peak V O 2 . CONCLUSIONS: CB significantly lowers exercise capacity in COPD patients because of dynamic hyperinflation during exercise. The accelerated dynamic hyperinflation may contribute to increased airway and systemic inflammation in COPD patients. PMID- 25799926 TI - Corrigendum: multiple sclerosis-a quiet revolution. PMID- 25799927 TI - Dementia: Cognitive resilience in APOE*epsilon4 carriers-is race important? PMID- 25799934 TI - Dementia: new study puts its FINGER on prevention of cognitive decline. PMID- 25799928 TI - Statins, cognition, and dementia-systematic review and methodological commentary. AB - Firm conclusions about whether mid-life or long-term statin use has an impact on cognitive decline and dementia remain elusive. Here, our objective was to systematically review, synthesize and critique the epidemiological literature that examines the relationship between statin use and cognition, so as to assess the current state of knowledge, identify gaps in our understanding, and make recommendations for future research. We summarize the findings of randomized controlled trials (RCTs) and observational studies, grouped according to study design. We discuss the methods for each, and consider likely sources of bias, such as reverse causation and confounding. Although observational studies that considered statin use at or near the time of dementia diagnosis suggest a protective effect of statins, these findings could be attributable to reverse causation. RCTs and well-conducted observational studies of baseline statin use and subsequent cognition over several years of follow-up do not support a causal preventative effect of late-life statin use on cognitive decline or dementia. Given that much of the human research on statins and cognition in the future will be observational, careful study design and analysis will be essential. PMID- 25799936 TI - Parkinson disease: Traumatic brain injury increases the risk of Parkinson disease. PMID- 25799937 TI - Fungal isolates from a Pu-erh type tea fermentation and their ability to convert tea polyphenols to theabrownins. AB - The natural microbiota involved in the fermentation influence the quality and taste of fully postfermented teas such as China's Pu-erh tea. Ten microbial isolates representing 6 species were recovered from a solid-state fermentation of a Pu-erh type tea. The isolates were Aspergillus tubingensis, Aspergillus marvanovae, Rhizomucor pusillus, Rhizomucor tauricus, Aspergillus fumigatus, and Candida mogii. With the exception of A. marvanovae and C. mogii, all these microorganisms have been previously reported in solid-state fermentations of native Pu-erh tea. The ability of the isolates for converting the tea polyphenols to bioactive theabrownins in infusions of sun-dried green tea leaves in a submerged fermentation process was subsequently investigated. All isolates except C. mogii TISTR 5938 effectively produced theabrownins in a 4-d fermentation in shake flasks at 40 degrees C, 250 rpm. A. tubingensis TISTR 3646, A. tubingensis TISTR 3647, A. marvanovae TISTR 3648, and A. fumigatus TISTR 3654 produced theabrownins at particularly high levels of 6.5, 12.4, 11.1, and 8.4 g/L, respectively. PMID- 25799938 TI - Obesity in Inflammatory Bowel Disease: A Marker of Less Severe Disease. AB - BACKGROUND: Both obesity and inflammatory bowel disease (IBD) are highly prevalent in Western societies. IBD, including Crohn's disease (CD) and ulcerative colitis (UC), has been historically associated with cachexia and malnutrition. It is uncertain how obesity, a chronic pro-inflammatory state, may impact the course of IBD. AIM: The aim of this study was to report the prevalence of obesity in patients with IBD in a metropolitan US population and to assess the impact of obesity on disease phenotypes, treatment, and surgical outcomes in IBD patients. METHODS: We reviewed the medical records of patients identified from the IBD registries of the Dallas Veterans Affairs Medical Center and Parkland Health and Hospital Systems who were seen from January 1, 2000, to December 31, 2012. RESULTS: Of 581 identified IBD patients, 32.7 % were obese (BMI >= 30) and 67.6 % were non-obese (BMI < 30). There were 297 (51.1 %) patients with CD and 284 (48.9 %) patients with UC. The rate of obesity was 30.3 % among CD patients and 35.2 % among UC patients. Overall, obese patients were significantly less likely to receive anti-TNF treatment, undergo surgery, or experience a hospitalization for their IBD than their non-obese counterparts (55.8 vs. 72.1 %, p = .0001). CONCLUSION: Obesity is highly prevalent in our IBD patients, paralleling the obesity rates in the US population. Clinical outcomes were significantly different in obese versus non-obese patients with IBD. Despite the plausible mechanisms whereby obesity might exacerbate IBD, we have found that obesity (as defined by BMI) is a marker of a less severe disease course in IBD. PMID- 25799939 TI - Aryl Hydrocarbon Receptor Activation Down-Regulates IL-7 and Reduces Inflammation in a Mouse Model of DSS-Induced Colitis. AB - BACKGROUND AND AIMS: The pathogenesis of inflammatory bowel disease (IBD) is associated with dysregulation of intestinal immune system. Aryl hydrocarbon receptor (AHR) is believed to control the chronic inflammation in the gut. Besides, interleukin-7 (IL-7) is proved to be an important cytokine that activates mucosal inflammation in IBD. Moreover, intraepithelial lymphocytes (IELs) are one of the key immunological compartments involved in regulating intestinal inflammation. In this study, we investigated the function of 6 formylindolo (3,2-b) carbazole (Ficz), a ligand of AHR, on IL-7, colitis, and IEL phenotypes. METHODS: Colitis was induced by administration of dextran sulfate sodium (DSS) to wild-type C57BL/6J mice for 7 days. Mice were weighted, colon tissues were collected and measured, and histology analyses were performed. IELs were isolated from colon, and the phenotype and activation of IELs were examined using flow cytometry detection. The expression of AHR and IL-7 was measured by immunofluorescence, Western blot, and RT-PCR. RESULTS: Ficz down-regulated epithelial-derived IL-7 expression in mice with DSS-induced colitis and ameliorated DSS-induced colitis. Ficz also decreased CD8alphabeta(+) and CD8(+) IEL subpopulations, enhanced TCRgammadelta(+) IEL subpopulation, and reduced the percentage of activated CD4(+) and CD8(+) subpopulations. CONCLUSIONS: Ficz could down-regulate epithelial-derived IL-7 expression in mice with DSS-induced colitis and inhibit inflammation in the gastrointestinal tract of mice. AHR-related compounds might be the new and promising therapeutic medicaments for the treatment of patients with IBD. PMID- 25799940 TI - The effects of dexamethasone on sleep in young children with acute lymphoblastic leukemia. AB - PURPOSE: Corticosteroids, which are a mainstay in the treatment of acute lymphoblastic leukemia (ALL), have a well-documented adverse effect on sleep. We sought to characterize the effects of dexamethasone on sleep over an entire 28 day treatment cycle using actigraphy, an objective measure of sleep. METHODS: The sleep of 25 children aged 2-9 years (mean 4.5 years) with ALL treated with dexamethasone were evaluated during maintenance chemotherapy using a within subject experimental design, actigraphy, and standardized questionnaires to assess sleep, sleep problems, and fatigue. RESULTS: During the five days of dexamethasone treatment, sleep time increased during the night (535 vs. 498 min; p = 0.004) and daytime napping increased the following day (14 vs. 0 min; p = 0.002), and the number of wake episodes during the night was lower (14 vs. 20; p = <= 0.001). However, when assessed individually, sleep-onset time, efficiency, and wake after sleep onset during the night were unchanged during dexamethasone treatment; when the cumulative effect of all of these factors was assessed, there was a statistically and clinically significant increase in nighttime sleep duration during dexamethasone treatment. CONCLUSIONS: During the five days of treatment with dexamethasone, an increase in nighttime sleep as well as daytime napping was observed in young children with ALL. The increases in sleep duration return to baseline one day after the discontinuation of dexamethasone. PMID- 25799941 TI - Early-life origin of adult insomnia: does prenatal-early-life stress play a role? AB - Insomnia is very common in the adult population and it includes a wide spectrum of sequelae, that is, neuroendocrine and cardiovascular alterations as well as psychiatric and neurodegenerative disorders. According to the conceptualization of insomnia in the context of the 3-P model, the importance of predisposing, precipitating, and perpetuating factors has been stressed. Predisposing factors are present before insomnia is manifested and they are hypothesized to interact with precipitating factors, such as environmental stressful events, contributing to the onset of insomnia. Understanding the early-life origins of insomnia may be particularly useful in order to prevent and treat this costly phenomenon. Based on recent evidence, prenatal-early-life stress exposure results in a series of responses that involve the stress system in the child and could persist into adulthood. This may encompass an activation of the hypothalamic-pituitary-adrenal axis accompanied by long-lasting modifications in stress reactivity. Furthermore, early-life stress exposure might play an important role in predisposing to a vulnerability to hyperarousal reactions to negative life events in the adult contributing to the development of chronic insomnia. Epigenetic mechanisms may also be involved in the development of maladaptive stress responses in the newborn, ultimately predisposing to develop a variety of (psycho-) pathological states in adult life. PMID- 25799942 TI - Monoclonal antibodies specific for oncofetal antigen--immature laminin receptor protein: Effects on tumor growth and spread in two murine models. AB - The oncofetal antigen - immature laminin receptor protein (OFA/iLRP) has been linked to metastatic tumor spread for several years. The present study, in which 2 highly-specific, high-affinity OFA/iLRP-reactive mouse monoclonal antibodies were examined for ability to suppress tumor cell growth and metastatic spread in the A20 B-cell leukemia model and the B16 melanoma model, provides the first direct evidence that targeting OFA/iLRP with exogenous antibodies can have therapeutic benefit. While the antibodies were modestly effective at preventing tumor growth at the primary injection site, both antibodies strongly suppressed end-organ tumor formation following intravenous tumor cell injection. Capacity of anti-OFA/iLRP antibodies to suppress tumor spread through the blood in the leukemia model suggests their use as a therapy for individuals with leukemic disease (either for patients in remission or even as part of an induction therapy). The results also suggest use against metastatic spread with solid tumors. PMID- 25799944 TI - Structural insight into the oxidation of sinapic acid by CotA laccase. AB - Laccases can oxidize plenty of substrates by use of molecular oxygen as the final electron acceptor. The broad substrate spectrum is further expanded by using redox mediators in so-called laccase-mediator systems, but the structural studies on interactions between laccases and natural mediators are still absent. In this study, the crystal structure of CotA/sinapic acid complex is solved, structural comparison has revealed a novel substrate binding mode. The residue of His419 instead of His497 is bonding to the sinapic acid (SA) as the primary electron acceptor. Moreover, the binding of SA leads to 10 degrees rotation on Arg416, our mutagenesis data exhibits that the residue Arg416 is crucial in the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and syringaldazine (SGZ). Furthermore, oxidation of several phenolic acids and one non-phenolic acid by CotA was investigated. By analyzing interactions between CotA and SA, it is indicated that the presence of methoxy groups in the ortho position of the phenolic structure is crucial for the substrate recognition by CotA laccase. This work establishes structure-function relationships for laccase natural mediator system. PMID- 25799945 TI - Effect of lysozyme or antibiotics on faecal zoonotic pathogens in nursery pigs. AB - AIMS: The objective of this study was to determine the effect of lysozyme and antibiotics on zoonotic pathogen shedding in faeces from nursery pigs housed without and with an indirect disease challenge. METHODS AND RESULTS: Two replicates of approximately 650 pigs each were weaned and randomly assigned to one of 24 pens in either a nursery room that had been fully disinfected or a nursery room left unclean. Pigs were randomly assigned to control diet (Control), control diet + antibiotics (Antibiotic; chlortetracycline and tiamulin), or control diet + lysozyme (Lysozyme; 100 mg kg(-1) diet). Rectal swab samples were collected on day 0 and 28 of treatment, and enriched and cultured for Campylobacter spp. and shiga-toxigenic Escherichia coli (STEC). Enrichments from rectal swab samples also were analysed for presence of enterohaemorrhagic E. coli (EHEC) virulence genes (hlyA, eae, stx1 and stx2). Room hygiene had little effect on day 28 results. Percentage of samples culture positive for Campylobacter spp. was lowest for lysozyme diets (P < 0.01), but similar for control and antibiotic diets (43.2, 83.7, and 84.8 respectively). Diet had little effect on the EHEC virulence genes hlyA or eae (P > 0.1), but there was a tendency for fewer samples positive for stx1/stx2 in antibiotic or lysozyme diet groups (P < 0.07) compared to control diet (1.2, 2.1 and 5.8% respectively). Salmonella spp. and specific STEC types tested were rarely detected in the study. CONCLUSIONS: In nursery swine, room hygiene had little effect on pathogen shedding. Dietary chlortetracycline and tiamulin did not reduce pathogen shedding but dietary lysozyme reduced faecal shedding of Campylobacter. SIGNIFICANCE AND IMPACT OF THE STUDY: Lysozyme can effectively replace antibiotics in the diet of nursery swine and can be effective for pathogen control. PMID- 25799946 TI - Comparison of different methods to estimate the uncertainty in composition measurement by chromatography. AB - Natural gas is a mixture that contains hydrocarbons and other compounds, such as CO2 and N2. Natural gas composition is commonly measured by gas chromatography, and this measurement is important for the calculation of some thermodynamic properties that determine its commercial value. The estimation of uncertainty in chromatographic measurement is essential for an adequate presentation of the results and a necessary tool for supporting decision making. Various approaches have been proposed for the uncertainty estimation in chromatographic measurement. The present work is an evaluation of three approaches of uncertainty estimation, where two of them (guide to the expression of uncertainty in measurement method and prediction method) were compared with the Monte Carlo method, which has a wider scope of application. The aforementioned methods for uncertainty estimation were applied to gas chromatography assays of three different samples of natural gas. The results indicated that the prediction method and the guide to the expression of uncertainty in measurement method (in the simple version used) are not adequate to calculate the uncertainty in chromatography measurement, because uncertainty estimations obtained by those approaches are in general lower than those given by the Monte Carlo method. PMID- 25799947 TI - Thoracic Endovascular Aortic Repair for the Treatment of Aortic Dissection: Post operative Imaging, Complications and Secondary Interventions. AB - Thoracic endovascular aortic repair (TEVAR) has become an accepted alternative to surgery for the treatment of aortic dissection (AD). Lifelong surveillance is obligatory following TEVAR to monitor the aortic morphology and detect associated complications. This is particularly important in AD where coverage of the primary intimal tear is necessary in achieving thrombosis and regression of the false lumen. A variety of imaging techniques may be used in assessing the technical success, outcome and complications, which may necessitate re-intervention. Of these, computed tomography angiography offers a fast, accessible and sensitive imaging modality and is established as the default surveillance tool. The purpose of this article is to review the imaging modalities, post-procedural appearances including complications and re-intervention strategies following TEVAR for AD. PMID- 25799948 TI - Trans-Arterial Chemoembolization with Irinotecan-Loaded Drug-Eluting Beads (DEBIRI) and Capecitabine in Refractory Liver Prevalent Colorectal Metastases: A Phase II Single-Center Study. AB - PURPOSE: The purpose of this study was to evaluate feasibility, safety, tolerance, and efficacy of drug-eluting beads loaded with irinotecan (DEBIRI) in combination with capecitabine in the treatment of mCRC refractory to chemotherapy in patients affected by liver predominant metastatic disease. MATERIALS AND METHODS: Twenty patients affected by CRC hepatic metastasis with liver-dominant disease, who had progression after two or more lines of chemotherapy, were enrolled. TACE with 100 mg of Irinotecan loaded into 2-ml of 70-150 um drug eluting beads was administrated every 4 weeks in patients with unilobar disease (2 treatments) and every 2 weeks in patients with bilobar disease (4 treatments). All patients assumed capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks, until disease progression. Primary endpoints were safety, tolerance and overall disease control (ODC); secondary endpoints were progression free survival (PFS) and overall survival (OS). RESULTS: A total of 54 treatments were performed (54/66, 82%). No intra/peri-procedural death occurred. During the mean follow-up of 11 months, two partial responses (PR) were reported with ODC of 60% (2 PR + 10 stable disease). PFS and OS were 4 and 7.3 months, respectively. Univariate analysis showed that patients presenting with KRAS wild-type, good ECOG performance status and unilobar disease had a better prognosis. Only performance status (ECOG) correlated with OS in multivariate analysis (p = 0.03). CONCLUSION: DEBIRI with capecitabine seem to be a safe, technically feasible and well tolerated treatment in chemotherapy refractory liver prevalent colorectal metastases. PMID- 25799949 TI - Endovascular Repair of Abdominal Aortic Aneurysms with the AnacondaTM Stent Graft: Mid-term Results from a Single Center. AB - INTRODUCTION: We aimed to report our experience with the AnacondaTM stent graft (Vascutek, Terumo, Inchinnan, Scotland, UK) for the endovascular treatment of abdominal aortic aneurysms (AAAs). METHODS: The vascular unit database was interrogated to identify all AAA patients who underwent endovascular repair with the AnacondaTM device between March 2007 and June 2014. The peri-operative, short term, and mid-term outcome was recorded focusing on complications and re interventions. RESULTS: Sixty-eight patients had been treated during the study period. Seven of these were symptomatic, one presented with an inflammatory aneurysm, and five presented with a ruptured AAA. The primary and the assisted primary technical success were 86.7 and 97.1%, respectively. There was no 30-day mortality in the elective or symptomatic group, but two of the ruptured AAA patients died. During a mean follow-up of 29 months (range 1-87), 14 patients died, none from aneurysm-related causes. A total of 11 endoleaks (17.5%) were detected in 10 patients during follow-up (1 type Ia, 4 type Ib, 6 type II), 4 of which required re-intervention (all for type Ib endoleak). Two iliac limbs occluded during the follow-up. The estimated overall survival, endoleak-free survival and re-intervention-free survival probability were 88.2, 78.4, and 83.4% at 1 year; 85.9, 73.8, and 78.9% at 2 years; and 80.6, 71.3, and 70.5% at 3 years, respectively. CONCLUSION: Based on this series, the AnacondaTM stent graft appears to be safe and effective for the endovascular treatment of AAAs. Both the short-term and the mid-term results are satisfactory. PMID- 25799950 TI - Percutaneous Long Bone Cementoplasty for Palliation of Malignant Lesions of the Limbs: A Systematic Review. AB - PURPOSE: Percutaneous cementoplasty (PC) is rarely applied to long bone tumours, since cement is not considered to be sufficiently resistant to torsional forces. We reviewed the literature to understand the effects of percutaneous long bone cementoplasty (PLBC) in terms of analgesia, limb function and complications. MATERIALS AND METHODS: This study followed the Cochrane's guidelines for systematic reviews of interventions. Inclusion criteria were (1) prospective/retrospective studies concerning PC; (2) cohort including at least ten patients; (3) at least one patient in the cohort undergoing PLBC; (5) published in English; (6) results not published by the same author more than once. RESULTS: One thousand five hundred and ninety-eight articles were screened and 13 matched the inclusion criteria covering 196 PLBC patients. Pain improvement was high in 68.2% patients (sigma = 0.2) and mild in 27.4% (sigma = 0.2). Functional improvement was high in 71.9% patients (sigma = 0.1) and mild in 6% (sigma = 0.1). Use of PLBC correlated with pain reduction (P < 0.001). Secondary fractures occurred in 16 cases (8%, sigma = 2.5); other complications in 2% cases. Percutaneous stabilisation (PS) was coupled with PLBC in 17% of cases without any subsequent fracture. PS was not associated with absence of secondary fracture (P = 0.08). CONCLUSION: PLBC is safe, offering good pain relief and recovery of impaired limb function. Secondary fractures are uncommon and PS may reduce their occurrence. However, no evidence is currently available to support PS plus PLBC as compared to PLBC alone. PMID- 25799951 TI - Radiodermitis after prostatic artery embolization: case report and review of the literature. AB - Prostate artery embolization (PAE) is a technically demanding new treatment option for benign prostatic hyperplasia. We present a case of radiation-induced dermitis in a 63-year-old patient after a technically successful PAE, due to high radiation exposure (KAP: 8,023,949 mGy cm(2)) and long fluoroscopy time (72 min). Anatomical and technical aspects are discussed, as well as recommendations to decrease radiation exposure in these procedures. PMID- 25799953 TI - Awakening the immune system with radiation: Optimal dose and fractionation. AB - The importance of ionizing radiation has historically been limited to achieving local control of tumor cells. However, emerging evidence over the last decade suggests an increasingly important role for radiation in amplifying the antitumor immune response elicited by immunomodulatory agents. Combination of radiation with immunotherapy has been shown to elicit powerful systemic responses in several pre-clinical tumor models. Additionally, recent clinical observations support the use of radiation therapy for augmenting antitumor immunity in the metastatic setting. However, radiation dose and fractionation schedules for optimal synergy between radiotherapy and immunotherapy are not well defined. Here we review pre-clinical and clinical data relating to radiation dose and fractionation in the setting of immunotherapy and discuss optimal strategies for combining the two therapies. PMID- 25799952 TI - Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism. AB - Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment. PMID- 25799954 TI - Molecular thermodynamics of metabolism: quantum thermochemical calculations for key metabolites. AB - The present work is the first of a series of papers aiming at a coherent and unified development of the thermodynamics of metabolism and the rationalization of feasibility analysis of metabolic pathways. The focus in this part is on high level quantum chemical calculations of the thermochemical quantities of relatively heavy metabolites such as amino acids/oligopeptides, nucleosides, saccharides and their derivatives in the ideal gas state. The results of this study will be combined with the corresponding hydration/solvation results in subsequent parts of this work in order to derive the desired thermochemical quantities in aqueous solutions. The above metabolites exist in a vast conformational/isomerization space including rotational conformers, tautomers or anomers exhibiting often multiple or cooperative intramolecular hydrogen bonding. We examine the challenges posed by these features for the reliable estimation of thermochemical quantities. We discuss conformer search, conformer distribution and averaging processes. We further consider neutral metabolites as well as protonated and deprotonated metabolites. In addition to the traditional presentation of gas-phase acidities, basicities and proton affinities, we also examine heats and free energies of ionic species. We obtain simple linear relations between the thermochemical quantities of ions and the formation quantities of their neutral counterparts. Furthermore, we compare our calculations with reliable experimental measurements and predictive calculations from the literature, when available. Finally, we discuss the next steps and perspectives for this work. PMID- 25799955 TI - Bioelectricity generation in microbial fuel cell using natural microflora and isolated pure culture bacteria from anaerobic palm oil mill effluent sludge. AB - A double-chambered membrane microbial fuel cell (MFC) was constructed to investigate the potential use of natural microflora anaerobic palm oil mill effluent (POME) sludge and pure culture bacteria isolated from anaerobic POME sludge as inoculum for electricity generation. Sterilized final discharge POME was used as the substrate with no addition of nutrients. MFC operation using natural microflora anaerobic POME sludge showed a maximum power density and current density of 85.11mW/m(2) and 91.12mA/m(2) respectively. Bacterial identification using 16S rRNA analysis of the pure culture isolated from the biofilm on the anode MFC was identified as Pseudomonas aeruginosa strain ZH1. The electricity generated in MFC using P. aeruginosa strain ZH1 showed maximum power density and current density of 451.26mW/m(2) and 654.90mA/m(2) respectively which were five times higher in power density and seven times higher in current density compared to that of MFC using anaerobic POME sludge. PMID- 25799956 TI - Helix pomatia hemocyanin - a novel bio-adjuvant for viral and bacterial antigens. AB - BACKGROUND: New generated subunit vaccines are characterized by increased safety and lack of side effects, however they suffer from weak immunogenicity. The adjuvants are substances that have the ability to enhance the magnitude and duration of the immune response and to increase vaccine efficacy, but the different vaccines may require diverse adjuvants. The urgent need of novel adjuvant formulations occurs, thus ensuring protective cellular and humoral responses against infectious pathogens. The hemocyanins, oxygen binding copper proteins in the hemolymph of molluscs and arthropods, are widely used as peptide carriers and vaccine adjuvants. RESULTS: In the present study we promote the hemocyanin isolated from the terrestrial gastropod Helix pomatia (HPH) as bio adjuvant, combined with standard antigens. The purified HPH combined with influenza virus hemagglutinin intersubunit peptide (IP) or with tetanus toxoid (TT) were used for immunization. Administration of tetanus toxoid combined with HPH in mice resulted in an increased number of anti-TT IgG producing plasmocytes and induced a significant increase of B and T cell proliferation. The level of the anti-TT IgG antibodies in mice sera was comparable to the group administered with TT+Al(OH)3. An immunization of experimental animals with IP combined with H. pomatia hemocyanin led to generation of strong anti-influenza cytotoxic response. CONCLUSION: The vaccination of mice demonstrates that the HPH is acceptable as a potential bio-adjuvant for subunit vaccines and it could be used as a natural adjuvant or protein carrier. PMID- 25799957 TI - Pinning out pathological specimens--are we risking an unnecessary escalation of treatment? AB - The importance of surgical resection margins is paramount, and it is vital that they are accurately delineated so that clinicians' decisions about adjuvant treatment can be validated. Pathological specimens therefore are often pinned to aid orientation and maintain mucosal margins. However, in cadaveric resections of bovine tongues, pinning of the specimens significantly reduced the depth of tissue. In clinical practice, if results are affected by the fixation method and not based on the true margins, it could profoundly influence the use of adjuvant treatment in patients with cancer. Pinning the specimens with the mucosal surface against the board will maintain any theoretical benefit for the mucosa and does not compress the specimens. PMID- 25799958 TI - Orbital soft tissue surgery for patients with Treacher-Collins or Nager syndrome. A new surgical approach with early correction of soft tissue: prospective study. AB - Orbitopalpebral anomalies in mandibulofacial dysostosis (Treacher-Collins syndrome) can be difficult to correct surgically and most authors recommend correction of the malar bone after the age of 8 years. We propose a new, early surgical approach for periorbital defects that involves initial implantation of autologous fat and subperiosteal malar lift with a pedicled upper eyelid flap. We prospectively studied 5 children, 3 of whom had previously had orbital reconstruction. Initial fat graft into the periorbital area was followed by a subperiosteal malar lift with lateral canthopexy, and a pedicled upper eyelid flap if needed. Two surgeons independently assessed the patients' characteristics including scleral show before and after operation, antimongoloid palpebral fissures, canthal dystopia, number 6 cleft (Tessier classification), skin quality, and surgical and ophthalmic complications. Before operation 3 patients had had ophthalmic problems. Postoperative evaluation showed improvements in scleral show, canthal dystopia, and skin quality, and correction of antimongoloid palpebral fissures and subcutaneous number 6 clefts. There were no postoperative complications. The proposed protocol gave satisfactory aesthetic and functional results in children with Treacher-Collins syndrome. We recommend that it is considered for periorbital reconstruction in all patients with a mandibulofacial deformity. PMID- 25799960 TI - Aggressive multimodal therapy may prolong disease-free survival in recurrent primary retroperitoneal embryonal carcinoma. AB - INTRODUCTION: Primary retroperitoneal extragonadal tumours relapsing after initial chemotherapy have a poor prognosis. PRESENTATION OF THE CASE: We report a case of primary retroperitoneal embryonal carcinoma in a patient with negative open testes biopsy. After the first line of chemotherapy (4 cycles BEP) secondary surgery with extirpation of a retroperitoneal residual mass was performed. The residuum proved histologically to be a mature teratoma, and no adjuvant treatment was given according to current recommendations. The patient had regular follow up. 3.5 years later, patient developed recurrence in the ipsilateral adrenal gland, which was treated with surgery and 4 cycles of salvage VeIP chemotherapy. Seven months after the second surgical intervention the patient underwent multivisceral "desperation surgery" for early metastatic disease progression followed by 2 cycles of salvage TIP chemotherapy. The patient is currently disease-free at 34 months. CONCLUSION: Initial postchemotherapy retroperitoneal lymph node dissection is crucial for local retroperitoneal disease control. Aggressively treated metastatic recurrent disease does not preclude prolonged survival. Despite a generally poor prognosis, repeated complex oncosurgical therapy for retroperitoneal extragonadal tumours may be worthwhile. PMID- 25799961 TI - Early isolated bone metastases without local recurrence in non-muscle invasive bladder cancer. AB - INTRODUCTION: Bladder cancer exhibits a broad spectrum of heterogenous clinical behavior. Conventionally used clinicopathological factors are associated with certain limitations regarding the accurate prediction of outcome. Recent studies have focused on the predictive role of cellular regulatory markers. PRESENTATION: The present case aimed to describe an extremely rare case of non-muscle invasive bladder cancer (NMIBC) patient with early isolated bone metastases following curative surgery. An assessment of the alterations of cellular regulatory biomarkers using immunohistochemistry was performed and a review of previous literatures is presented. DISCUSSION: It is very unusual feature that the patients with NMIBC who developed bone metastases without regional lymph node metastasis or local invasion. The patient had a solitary, high-grade T1 tumor which was not associated with carcinoma in situ and microscopic lymphovascular invasion. However, it had rapidly metastasized to distant sites following definitive surgery and exclusively limited to bones. Of special interest appears that altered expressions of combined cellular biomarkers including p53, Ki-67, and epidermal growth factor receptor were not observed focally, but rather diffusely and intensively throughout the tumor tissue. CONCLUSION: As an accurate prediction of outcome in patient with bladder cancer is currently limited, individual targeted approach based on pathological biomarkers may be helpful to determining what treatments are best or when the optimal time is. PMID- 25799959 TI - The use of probiotics in pediatric gastroenterology: a review of the literature and recommendations by Latin-American experts. AB - OBJECTIVE: The stability and composition of intestinal flora plays a vital role in human wellbeing throughout life from as early as birth. Over the past 50 years, several studies have been conducted to evaluate the effect of probiotic administration in pediatric gastroenterology. This document aims to provide a recommendation score on probiotic utilization in pediatric gastroenterology, together with a review of current knowledge concerning its benefits, tolerability, and safety. STUDY DESIGN: Published literature was selected without study design restriction: clinical guidelines, meta-analyses, randomized controlled trials (RCTs), cohort studies, outcomes research and case-controlled studies were selected using the following MESH-validated terms: probiotics, diarrhea, acute diarrhea, antibiotic-associated diarrhea, traveler's diarrhea, bacterial diarrhea, nosocomial diarrhea, prophylactic diarrhea, Helicobacter pylori infection, colic, infantile colic, necrotizing enterocolitis (NEC), inflammatory bowel disease, constipation, and allergy. Once the validity and the quality of results were evaluated, a recommendation score and level of evidence were assigned for pediatric gastrointestinal-related conditions, according to the updated Evidence-Based Medicine guidelines: 1a for systematic review (SR) of RCTs, 1b for individual RCT, 1c for SR and individual RCT, 2a for SR of cohort studies, 2b for individual cohort studies, 2c for outcomes research, and 3a for SR of case-control studies. RESULTS AND CONCLUSIONS: The Latin American Expert group consensus recommends the use of the following probiotics for pediatric gastrointestinal conditions: prevention of acute infectious diarrhea (AID): 1b for Bifidobacterium lactis, Lactobacillus rhamnosus GG (LGG), and L. reuteri; prevention of nosocomial diarrhea: 1 b for B. lactis Bb12, B. bifidum, LGG and Streptococcus thermophiles; treatment of AID: 1a for LGG and S. boulardii, 1b for L. reuteri; prevention of antibiotic-associated diarrhea: 1b for LGG and S. boulardii; prevention of traveler's diarrhea: 1b for S. boulardii; prevention of infantile colic: 1a for L. reuteri DSM 17938; treatment of infantile colic: 1b for L. reuteri DSM 17938; prevention of NEC: 1a for B. breve, mixtures of Bifidobacterium and Streptococcus, LGG, L. acidophilus and L. reuteri DSM 17938; induction and maintenance of remission in ulcerative colitis: 1b for VSL#3; improving symptoms of irritable bowel syndrome: 2c for LGG and VSL#3. PMID- 25799962 TI - Abscess formation within a cerebellar metastasis: Case report and literature review. AB - INTRODUCTION: The managements of brain abscesses and brain tumors including brain metastases differ greatly, especially in terms of surgical procedures. Therefore, differentiating between the two is essential for assuring optimal treatment. However, on rare occasion, these two lesions coexist. Only five cases with both a brain tumor and an abscess have thus, far been reported. We experienced a patient with a brain abscess within a cerebellar metastasis. CASE PRESENTATION: A middle aged man receiving treatment for bile duct cancer presented with headache and nausea. Computed tomography (CT) and magnetic resonance (MR) imaging revealed two lesions, one in each cerebellar hemisphere. Although these lesions appeared to be brain metastases, the right lesion showed high intensity on diffusion-weighted images (DWI), and magnetic resonance spectroscopy (MRS) findings suggested an abscess. Surgical puncture of the lesion identified it as a brain abscess histologically, and we thus, administered antibiotics. However, since the lesion grew, we performed a second surgery for removal, which histopathologically the lesion to be a well-differentiated adenocarcinoma. The final diagnosis was an abscess within a cerebellar metastasis. DISCUSSION/CONCLUSION: Modern diagnostic tools such as DWI and MRS are reportedly reliable for differentiating brain tumors from brain abscesses, though they are not specific in cases with both lesions. The present case highlights the importance of considering coexisting diseases prior to surgery when we encounter a lesion which has the imaging characteristics of both a tumor and an abscess. The patient may have a better outcome if, preoperatively, surgeons take into consideration the possibility of the coexistence of a brain tumor and a brain abscess. PMID- 25799963 TI - High Species C Human Adenovirus Genome Copy Numbers in the Treated Water Supply of a Neotropical Area of the Central-West Region of Brazil. AB - There is little information about the presence of human adenovirus (HAdV) in drinking water in Neotropical regions. Thus, the present study sought to conduct quantification and molecular characterization of HAdVs detected in treated water samples from an area of the Cerrado ecoregion of Brazil. Between August and November 2012, samples were collected from four treated water reservoirs and their respective sites along the water distribution network of the city of Goiania, for a total of 80 samples. All samples were concentrated and analyzed by qPCR, and selected samples were sequenced. Overall, 76.6 (10(0)-10(9) GC mL(-1)) and 37.5% (10(1)-10(8) GC mL(-1)) of samples drawn from reservoirs and their distribution sites, respectively, were positive for virus by qPCR. All samples selected for sequencing were characterized as species C human adenovirus. Such high HAdV counts have in treated water samples. This finding merits special attention, particularly from the sanitation authorities, because the high number of GC mL(-1) may be an indicative of risk to human health. PMID- 25799964 TI - Pyrazolo[3,4-d]pyrimidines as novel inhibitors of O-acetyl-L-serine sulfhydrylase of Entamoeba histolytica: an in silico study. AB - Amoebiasis, a worldwide explosive epidemic, caused by the gastrointestinal anaerobic protozoan parasite Entamoeba histolytica, infects the large intestine and, in advance stages, liver, kidney, brain and lung. Metronidazole (MNZ)-the first line medicament against amoebiasis-is potentially carcinogenic to humans and shows significant side-effects. Pyrazolo[3,4-d]pyrimidine compounds have been reported to demonstrate antiamoebic activity. In silico molecular docking simulations on nine pyrazolo[3,4-d]pyrimidine molecules without linkers (molecules 1-9) and nine pyrazolo[3,4-d]pyrimidine molecules with a trimethylene linker (molecules 10-18) along with the reference drug metronidazole (MNZ) were conducted using the modules of the programs Glide-SP, Glide-XP and Autodock with O-acetyl-L-serine sulfhydrylase (OASS) enzyme-a promising target for inhibiting the growth of Entamoeba histolytica. Docking simulations using Glide-SP demonstrate good agreement with reported biological activities of molecules 1-9 and indicate that molecules 2 and 4 may act as potential high affinity inhibitors. Trimethylene linker molecules show improved binding affinities among which molecules 15 and 16 supersede. MD simulations on the best docked poses of molecules 2, 4, 15, 16 and MNZ were carried out for 20 ns using DESMOND. It was observed that the docking complexes of molecules 4, 15 and MNZ remain stable in aqueous conditions and do not undergo noticeable fluctuations during the course of the dynamics. Relative binding free energy calculations of the ligands with the enzyme were executed on the best docked poses using the molecular mechanics generalized Born surface area (MM-GBSA) approach, which show good agreement with the reported biological activities. PMID- 25799965 TI - Determination of the polarization states of an arbitrary polarized terahertz beam: vectorial vortex analysis. AB - Vectorial vortex analysis is used to determine the polarization states of an arbitrarily polarized terahertz (0.1-1.6 THz) beam using THz achromatic axially symmetric wave (TAS) plates, which have a phase retardance of Delta = 163 degrees and are made of polytetrafluorethylene. Polarized THz beams are converted into THz vectorial vortex beams with no spatial or wavelength dispersion, and the unknown polarization states of the incident THz beams are reconstructed. The polarization determination is also demonstrated at frequencies of 0.16 and 0.36 THz. The results obtained by solving the inverse source problem agree with the values used in the experiments. This vectorial vortex analysis enables a determination of the polarization states of the incident THz beam from the THz image. The polarization states of the beams are estimated after they pass through the TAS plates. The results validate this new approach to polarization detection for intense THz sources. It could find application in such cutting edge areas of physics as nonlinear THz photonics and plasmon excitation, because TAS plates not only instantaneously elucidate the polarization of an enclosed THz beam but can also passively control THz vectorial vortex beams. PMID- 25799966 TI - In this issue and a comment on the contradictions of the preface. PMID- 25799967 TI - Assessing interprofessional teamwork: pilot test of a new assessment module for practicing physicians. AB - INTRODUCTION: Teamwork is a basic component of all health care, and substantial research links the quality of teamwork to safety and quality of care. The TEAM (Teamwork Effectiveness Assessment Module) is a new Web-based teamwork assessment module for practicing hospital physicians. The module combines self-assessment, multisource feedback from members of other professions and specialties with whom the physician exercises teamwork, and a structured review of those data with a peer to develop an improvement plan. METHODS: We conducted a pilot test of this module with hospitalist physicians to evaluate the feasibility and usefulness of the module in practice, focusing on these specific questions: Would physicians in hospitals of different types and sizes be able to use the module; would the providers identified as raters respond to the request for feedback; would the physicians be able to identify one or more "trusted peers" to help analyze the feedback; and how would physicians experience the module process overall? RESULTS: 20 of 25 physicians who initially volunteered for the pilot completed all steps of the TEAM, including identifying interprofessional teammates, soliciting feedback from their team, and identifying a peer to help review data. Module users described the feedback they received as helpful and actionable, and indicated this was information they would not have otherwise received. CONCLUSIONS: The results suggest that a module combining self-assessment, multisource feedback, and a guided process for interpreting these data can provide help practicing hospital physicians to understand and potentially improve their interprofessional teamwork skills and behaviors. PMID- 25799968 TI - Role for assessment in maintenance of certification: physician perceptions of assessment. AB - INTRODUCTION: The Royal College of Physicians and Surgeons of Canada modified its Maintenance of Certification (MOC) framework in 2011 to further incentivize assessment activities compared to group and self-learning. The purpose of this study was to explore physician's perceptions of their access to assessment activities, barriers to participation in assessment, and the need for the Royal College to further support its fellows in gaining access to assessment activities. METHODS: A questionnaire-based survey was sent to all participants of the MOC program as part of a program evaluation examining recent changes to the MOC program. RESULTS: 5259 respondents contributed responses. Most physicians were comfortable with the revised framework for assessment while approximately 40% were neutral regarding whether lack of access to self-assessment activities was a problem. Respondents expressed a need for more self-assessment programs particularly those developed outside of Canada. Neither a lack of feedback about performance or discomfort with recording performance gaps was perceived as a barrier to participation in assessment activities. Physician comments were consistent with the quantitative data and elaborated on the need to develop and recognize more assessment activities. DISCUSSION: Physicians accepted the revised MOC program framework but perceived difficulty in accessing assessment programs, activities, and tools. As the framework changed again January 2014, requiring all fellows and MOC program participants to completion of at least 25 credits in each section of the MOC program (including assessment) during their new 5-year MOC cycle, additional resources will be needed to support opportunities for physicians to engage in assessment. PMID- 25799969 TI - Can rasch analysis enhance the abstract ranking process in scientific conferences? Issues of interrater variability and abstract rating burden. AB - INTRODUCTION: Abstract ranking processes for scientific conferences are essential but controversial. This study examined the validity of a structured abstract rating instrument, evaluated interrater variability, and modeled the impact of interrater variability on abstract ranking decisions. Additionally, we examined whether a more efficient rating process (abstracts rated by two rather than three raters) supported valid abstract rankings. METHODS: Data were 4016 sets of abstract ratings from the 2011 and 2013 national scientific conferences for a health discipline. Many-faceted Rasch analysis procedures were used to examine validity of the abstract rating instrument and to identify and adjust for the presence of interrater variability. The two-rater simulation was created by the deletion of one set of ratings for each abstract in the 2013 data set. RESULTS: The abstract rating instrument demonstrated sound measurement properties. Although each rater applied the rating criteria consistently (intrarater reliability), there was significant variability between raters. Adjusting for interrater variability changed the final presentation format for approximately 10 20% of abstracts. The two-rater simulation demonstrated that abstract rankings derived through this process were valid, although the impact of interrater variability was more substantial. DISCUSSION: Interrater variability exerts a small but important influence on overall abstract acceptance outcome. The use of many-faceted Rasch analysis allows for this variability to be adjusted for. Additionally, Rasch processes allow for more efficient abstract ranking by reducing the need for multiple raters. PMID- 25799970 TI - Do Continuing Medical Education (CME) events cover the content physicians want to know? A content analysis of CME offerings. AB - INTRODUCTION: The purpose of this study is to assess whether annual refresher session offerings match the needs of physicians by coding and comparing session syllabi to physician questions collected electronically at the point of care. METHODS: Thirteen syllabi from annual refresher continuing medical education (CME) events offered to family physicians in Canada were collected and their session titles and descriptions entered into a database. Titles and descriptions were coded using the International Classification for Primary Care version 2 (ICPC-2). Titles and descriptions were further coded depending on whether the sessions involved a drug treatment/medication component. Syllabi content was compared to previously determined questions asked by physicians at the point of care. RESULTS: Of the original 701 session titles, 625 (89.2%) were suitable for analysis. CME sessions focused on musculoskeletal, digestive, skin, urologic, and general categories were underrepresented in comparison to point-of-care questions. The reverse was true for the psychological/mental health category. DISCUSSION: Differences between questions asked by physicians at the point of care and the content of contemporaneous CME refresher courses can be analyzed to identify gaps in CME offerings. This knowledge could be used to develop CME curricula and highlight areas of need for inclusion in refresher courses. PMID- 25799971 TI - Enhancing continuing education activities using audience response systems: a single-blind controlled trial. AB - INTRODUCTION: We investigated whether using an audience response system (ARS) as part of continuing education (CE) activities enhances immediate and long-term knowledge acquisition or learner reactions. METHOD: A multicenter single-blinded controlled trial involving pharmacists at 2 metropolitan teaching hospitals was used for this investigation. Pharmacists were allocated to either (a) an interactive presentation incorporating multiple-choice questions (MCQs) answered using an ARS, or (b) the same, but noninteractive, presentation using summary points instead of MCQs. Baseline knowledge was evaluated using a 10-item questionnaire, which was also used to evaluate immediate and long-term (6 weeks later) knowledge acquisition. Learner reactions were evaluated through feedback questionnaires. RESULTS: The control and ARS intervention presentations were attended by 44 and 35 pharmacists, respectively. The 6-week follow-up questionnaire was completed by 35 control (80%) and 27 (77%) ARS group participants. Baseline knowledge was similar across groups (5.0 +/- 1.6 SD vs 5.2 +/- 1.6; p = .44) with no differences in immediate (8.3 +/- 1.5 vs 7.9 +/- 1.5; p = 0.30) or long-term (7.0 +/- 1.6 vs 7.0 +/- 1.5; p = 0.93) knowledge acquisition. Feedback regarding the use of an ARS was overwhelmingly positive, with participants feeling more strongly that the ARS enabled them to compare knowledge to that of their peers (p < .001). DISCUSSION: There was no observed benefit of an ARS in relation to immediate or long-term knowledge acquisition. The use of an ARS, however, appeared to facilitate enhanced interactivity and participant self-reflection of knowledge, with strong participant desire to continue their use in future CE activities. PMID- 25799972 TI - Outcomes and participant experience of an online train-the-trainer program for Bangladeshi health professionals: a case study evaluation. AB - INTRODUCTION: This study aimed to determine whether an 8-week online training program for developing skills in short-course development and delivery was effective in establishing locally driven, sustainable, evidence-based training for local occupational or physical therapists. METHODOLOGY: Five Bangladeshi therapists from a rehabilitation center participated in the course, which was facilitated online by an Australian university. They completed 8 prerecorded modules over a 3-month period, and were assessed in situ on their ability to deliver a tutorial to their peers. A qualitative explanatory case study design was used to evaluate outcomes, drawing on data gathered from precourse and 1-year follow-up surveys, observations (including interactions during the course and final participant presentations), and a postcourse focus group. RESULTS: The course achieved 6 of its 9 objectives, with all participants satisfactorily planning and delivering an evidence-based interactive tutorial to their peers. Participants noted improved competence and confidence in searching for evidence and developing and executing a teaching plan. This was sustained at 1-year review. The key theme was a shift in participants' capacity for teaching and learning. Enablers were multimodal teaching techniques, the presence of a local leader, and the establishment of informal peer support. Barriers were logistical issues such as access to reliable Internet services and late delivery of course materials. DISCUSSION: Online distance education can be effective in producing sustainable change in practitioner skills in developing countries. Future programs would benefit from a blended learning approach incorporating "face-to face" instructor contact. PMID- 25799973 TI - Using a predictive model of clinician intention to improve continuing health professional education on cancer survivorship. AB - INTRODUCTION: Cancer survivorship is a chronic disease that places patients in limbo between oncologists and primary care clinicians. Strategies have been proposed to ease the shift in coordination of care, including broad-based educational outreach to primary care providers. METHODS: Guided by the theory of planned behavior (TPB), predictors of intention to provide survivorship care, including credentials, experience, perception of barriers, and personal survivorship status, were evaluated using logistic regression with a cohort of physicians, nurse practitioners, and registered nurses participating in an unprecedented online continuing medical education/continuing education survivorship care course. RESULTS: Results showed that physicians were significantly less likely to express intent to provide survivorship care (odds ratio [OR] = .237, p = .0001) compared to the other groups. Overall, clinicians with 6-10 years of experience were 3 times more likely to express intent to provide survivorship care (OR = 2.86, p = .045) than those with less or more experience. When clinicians perceived the presence of a barrier, they were nearly twice as likely to have diminished intent (OR = 1.89, p = .035). Most participants (66%; n = 1185) selected two barriers: lack of survivorship care plans and treatment summaries (45.4%; n = 821) and lack of education (20.1%; n = 364). DISCUSSION: Barriers to the delivery of survivorship care can influence clinicians' intention to provide survivorship care, which varied by years of experience in this study. Interdisciplinary educational strategies featuring midcareer provider champions who have successfully incorporated survivorship care and can offer specific solutions to these barriers are recommended for future interventions. PMID- 25799974 TI - Returning inactive obstetrics and gynecology physicians to clinical practice: the Drexel experience. AB - INTRODUCTION: Physicians returning to clinical practice after inactivity may face many challenges. Few programs provide reeducation, and data are limited about these experiences. We describe the physician refresher/reentry program at Drexel University College of Medicine, Philadelphia, and the lessons learned in our efforts to facilitate obstetrician-gynecologists' clinical reentry. METHODS: In 2006, Drexel relaunched the Medical College of Pennsylvania's physician reentry course. This structured yet individualized program provides reeducation and assessment for physicians who have left clinical medicine for any reason and are hoping to return. We report the results achieved for 9 obstetrician-gynecologists who successfully completed Drexel's course between November 2006 and November 2012. RESULTS: The 6 men and 3 women had left their practices for different reasons. Seven were reentry candidates, and 2 were remediating; none had left practice for medical negligence. Of the reentering physicians, 5 achieved their goal within 1 month. Of the remediating physicians, 1 achieved his/her goal. DISCUSSION: Through continual self-assessment and participant feedback, we have learned to expand our staff and faculty career advisory roles and seek specialty specific assessment. Despite our small sample size, Drexel's experience may provide guidance to the growing field of obstetrician/gynecologist reentry in the United States. PMID- 25799975 TI - Enhancing provider engagement in practice improvement: a conceptual framework. AB - Engaging individual members of clinical teams in practice improvement initiatives is a challenge. In this commentary, we first summarize evidence supporting enhanced practitioner engagement through the creation of a work environment that builds on mutually respectful relationships and valued interdependencies. We then propose a phased, collaborative process that employs practice talk, a term that describes naturally occurring, collegial conversations among members of clinical teams. Planned interactions among team members, facilitated by individuals trained in dialogic techniques, enable health care providers and support staff to share their experiences and expertise, agree on what improvements they would like to make, and test the success of these changes. Participants would be encouraged to express their own suggestions for better practice and disclose strategies that are already working. Dissent would be regarded as an opportunity rather than a barrier. Iterative, sense-making conversations would generate a shared vision, enabling team members to engage in the entire process. Given that practice improvement ultimately depends on frontline providers, we encourage the exploration of innovative engagement strategies that will enable entire clinical teams to develop the collaborative learning skills needed to accomplish their goals. PMID- 25799976 TI - The distribution of Salmonella enterica serovars and subtypes in surface water from five agricultural regions across Canada. AB - Serovar prevalence of the zoonotic pathogen, Salmonella enterica, was compared among 1624 surface water samples collected previously from five different Canadian agricultural watersheds over multiple years. Phagetyping, pulsed field gel electrophoresis (PFGE), and antimicrobial resistance subtyping assays were performed on serovars Enteritidis, Typhimurium, and Heidelberg. Serovars and subtypes from surface water were compared with those from animal feces, human sewage, and serovars reported to cause salmonellosis in Canadians. Sixty-five different serovars were identified in surface water; only 32% of these were isolated from multiple watersheds. Eleven of the 13 serovars most commonly reported to cause salmonellosis in Canadians were identified in surface water; isolates of these serovars constituted >40% of the total isolates. Common phagetypes and PFGE subtypes of serovars associated with illness in humans such as S. Enteritidis and S. Typhimurium were also isolated from surface water and animal feces. Antimicrobial resistance was generally low, but was highest among S. Typhimurium. Monitoring of these rivers helps to identify vulnerable areas of a watershed and, despite a relatively low prevalence of S. enterica overall, serovars observed in surface water are an indication of the levels of specific S. enterica serovars present in humans and animals. PMID- 25799983 TI - Thermodynamics of force-dependent folding and unfolding of small protein and nucleic acid structures. AB - In this paper, we outline the theoretical framework for understanding the equilibrium force-dependent folding and unfolding transitions of protein domains and small nucleic acid structures, both having small rigid folded structures and highly flexible unfolded polymeric chain conformations. A complete statistical description of the state described by the probability function rho(xi)(n,x), is obtained, where n is an index denoting the structural state, and x is the extension of the molecule. xi denotes an external constraint applied to the molecule, which is either a constant force or a harmonic spring attached to one end of the molecule. The extension probability distribution regardless of the structural state: , the free energy landscape: -kBT ln(rho(xi)(x)), and the probability of the states regardless of the extension: , are analyzed using the force-dependent structural transitions of the classic titin I27 domain as an example. The impact of different external constraints is also discussed. PMID- 25799977 TI - Effect of hypoxia on TRPV1 and TRPV4 channels in rat pulmonary arterial smooth muscle cells. AB - Transient receptor potential (TRP) channels of the vanilloid subfamily, mainly TRPV1 and TRPV4, are expressed in pulmonary artery smooth muscle cells (PASMC) and implicated in the remodeling of pulmonary artery, a landmark of pulmonary hypertension (PH). Among a variety of PH subtypes, PH of group 3 are mostly related to a prolonged hypoxia exposure occurring in a variety of chronic lung diseases. In the present study, we thus investigated the role of hypoxia on TRPV1 and TRPV4 channels independently of the increased pulmonary arterial pressure that occurs during PH. We isolated PASMC from normoxic rat and cultured these cells under in vitro hypoxia. Using microspectrofluorimetry and the patch-clamp technique, we showed that hypoxia (1 % O2 for 48 h) significantly increased stretch- and TRPV4-induced calcium responses. qRT-PCR, Western blotting, and immunostaining experiments revealed that the expression of TRPV1 and TRPV4 was not enhanced under hypoxic conditions, but we observed a membrane translocation of TRPV1. Furthermore, hypoxia induced a reorganization of the F-actin cytoskeleton, the tubulin, and intermediate filament networks (immunostaining experiments), associated with an enhanced TRPV1- and TRPV4-induced migratory response (wound-healing assay). Finally, as assessed by immunostaining, exposure to in vitro hypoxia elicited a significant increase in NFATc4 nuclear localization. Cyclosporin A and BAPTA-AM inhibited NFATc4 translocation, indicating the activation of the Ca(2+)/calcineurin/NFAT pathway. In conclusion, these data point out the effect of hypoxia on TRPV1 and TRPV4 channels in rat PASMC, suggesting that these channels can act as direct signal transducers in the pathophysiology of PH. PMID- 25799985 TI - Cardiology: A big-hearted molecule. PMID- 25799986 TI - Nuclear ashes and outflow in the eruptive star Nova Vul 1670. AB - CK Vulpeculae was observed in outburst in 1670-1672 (ref. 1), but no counterpart was seen until 1982, when a bipolar nebula was found at its location. Historically, CK Vul has been considered to be a nova (Nova Vul 1670), but its similarity to 'red transients', which are more luminous than classical novae and thought to be the results of stellar collisions, has re-opened the question of CK Vul's status. Red transients cool to resemble late M-type stars, surrounded by circumstellar material rich in molecules and dust. No stellar source has been seen in CK Vul, though a radio continuum source was identified at the expansion centre of the nebula. Here we report that CK Vul is surrounded by chemically rich molecular gas in the form of an outflow, as well as dust. The gas has peculiar isotopic ratios, revealing that CK Vul's composition was strongly enhanced by the nuclear ashes of hydrogen burning. The chemical composition cannot be reconciled with a nova or indeed any other known explosion. In addition, the mass of the surrounding gas is too large for a nova, though the conversion from observations of CO to a total mass is uncertain. We conclude that CK Vul is best explained as the remnant of a merger of two stars. PMID- 25799984 TI - hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. AB - The structure of messenger RNA is important for post-transcriptional regulation, mainly because it affects binding of trans-acting factors. However, little is known about the in vivo structure of full-length mRNAs. Here we present hiCLIP, a biochemical technique for transcriptome-wide identification of RNA secondary structures interacting with RNA-binding proteins (RBPs). Using this technique to investigate RNA structures bound by Staufen 1 (STAU1) in human cells, we uncover a dominance of intra-molecular RNA duplexes, a depletion of duplexes from coding regions of highly translated mRNAs, an unexpected prevalence of long-range duplexes in 3' untranslated regions (UTRs), and a decreased incidence of single nucleotide polymorphisms in duplex-forming regions. We also discover a duplex spanning 858 nucleotides in the 3' UTR of the X-box binding protein 1 (XBP1) mRNA that regulates its cytoplasmic splicing and stability. Our study reveals the fundamental role of mRNA secondary structures in gene expression and introduces hiCLIP as a widely applicable method for discovering new, especially long-range, RNA duplexes. PMID- 25799987 TI - Ancient proteins resolve the evolutionary history of Darwin's South American ungulates. AB - No large group of recently extinct placental mammals remains as evolutionarily cryptic as the approximately 280 genera grouped as 'South American native ungulates'. To Charles Darwin, who first collected their remains, they included perhaps the 'strangest animal[s] ever discovered'. Today, much like 180 years ago, it is no clearer whether they had one origin or several, arose before or after the Cretaceous/Palaeogene transition 66.2 million years ago, or are more likely to belong with the elephants and sirenians of superorder Afrotheria than with the euungulates (cattle, horses, and allies) of superorder Laurasiatheria. Morphology-based analyses have proved unconvincing because convergences are pervasive among unrelated ungulate-like placentals. Approaches using ancient DNA have also been unsuccessful, probably because of rapid DNA degradation in semitropical and temperate deposits. Here we apply proteomic analysis to screen bone samples of the Late Quaternary South American native ungulate taxa Toxodon (Notoungulata) and Macrauchenia (Litopterna) for phylogenetically informative protein sequences. For each ungulate, we obtain approximately 90% direct sequence coverage of type I collagen alpha1- and alpha2-chains, representing approximately 900 of 1,140 amino-acid residues for each subunit. A phylogeny is estimated from an alignment of these fossil sequences with collagen (I) gene transcripts from available mammalian genomes or mass spectrometrically derived sequence data obtained for this study. The resulting consensus tree agrees well with recent higher-level mammalian phylogenies. Toxodon and Macrauchenia form a monophyletic group whose sister taxon is not Afrotheria or any of its constituent clades as recently claimed, but instead crown Perissodactyla (horses, tapirs, and rhinoceroses). These results are consistent with the origin of at least some South American native ungulates from 'condylarths', a paraphyletic assembly of archaic placentals. With ongoing improvements in instrumentation and analytical procedures, proteomics may produce a revolution in systematics such as that achieved by genomics, but with the possibility of reaching much further back in time. PMID- 25799989 TI - Cancer: A piece of the p53 puzzle. PMID- 25799988 TI - Ferroptosis as a p53-mediated activity during tumour suppression. AB - Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis. PMID- 25799990 TI - MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection. AB - Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3' telomeric overhangs, indicating that MAD2L2 inhibits 5' end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP. Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5' end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis. Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5' end resection downstream of RIF1. PMID- 25799991 TI - Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. AB - Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target. PMID- 25799992 TI - REV7 counteracts DNA double-strand break resection and affects PARP inhibition. AB - Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells. PMID- 25799993 TI - Structural imprints in vivo decode RNA regulatory mechanisms. AB - Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA binding proteins or RNA-modification sites that are consistent with atomic resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N(6)-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression. PMID- 25799994 TI - Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. AB - Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility. Here we show that super-enhancers underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters ('epicentres') of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation. PMID- 25799995 TI - Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. AB - B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ~25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL. PMID- 25799996 TI - MAP4K4 regulates integrin-FERM binding to control endothelial cell motility. AB - Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-beta1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to beta1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, alpha5beta1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target. PMID- 25799997 TI - Two insulin receptors determine alternative wing morphs in planthoppers. AB - Wing polyphenism is an evolutionarily successful feature found in a wide range of insects. Long-winged morphs can fly, which allows them to escape adverse habitats and track changing resources, whereas short-winged morphs are flightless, but usually possess higher fecundity than the winged morphs. Studies on aphids, crickets and planthoppers have revealed that alternative wing morphs develop in response to various environmental cues, and that the response to these cues may be mediated by developmental hormones, although research in this area has yielded equivocal and conflicting results about exactly which hormones are involved. As it stands, the molecular mechanism underlying wing morph determination in insects has remained elusive. Here we show that two insulin receptors in the migratory brown planthopper Nilaparvata lugens, InR1 and InR2, have opposing roles in controlling long wing versus short wing development by regulating the activity of the forkhead transcription factor Foxo. InR1, acting via the phosphatidylinositol 3-OH kinase (PI(3)K)-protein kinase B (Akt) signalling cascade, leads to the long winged morph if active and the short-winged morph if inactive. InR2, by contrast, functions as a negative regulator of the InR1-PI(3)K-Akt pathway: suppression of InR2 results in development of the long-winged morph. The brain-secreted ligand Ilp3 triggers development of long-winged morphs. Our findings provide the first evidence of a molecular basis for the regulation of wing polyphenism in insects, and they are also the first demonstration--to our knowledge--of binary control over alternative developmental outcomes, and thus deepen our understanding of the development and evolution of phenotypic plasticity. PMID- 25799998 TI - N6-methyladenosine marks primary microRNAs for processing. AB - The first step in the biogenesis of microRNAs is the processing of primary microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding protein DGCR8 and the type III RNase DROSHA. This initial event requires recognition of the junction between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which cleaves the RNA duplex to yield the pre-miRNA product. While the mechanisms underlying pri-miRNA processing have been determined, the mechanism by which DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures present in transcripts, is not understood. Here we find in mammalian cells that methyltransferase-like 3 (METTL3) methylates pri-miRNAs, marking them for recognition and processing by DGCR8. Consistent with this, METTL3 depletion reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitro processing reactions confirmed the sufficiency of the N(6)-methyladenosine (m(6)A) mark in promoting pri-miRNA processing. Finally, gain-of-function experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type-specific manner. Our findings reveal that the m(6)A mark acts as a key post-transcriptional modification that promotes the initiation of miRNA biogenesis. PMID- 25799999 TI - Metacognitive training for young subjects (MCT young version) in the early stages of psychosis: Is the duration of untreated psychosis a limiting factor? AB - OBJECTIVES: The treatment program 'Metacognitive training for patients with schizophrenia' (MCT) addresses cognitive biases assumed to play a crucial role in the pathogenesis of delusions (e.g., jumping to conclusions, theory of mind deficits). The aim of our study was to examine the effectiveness and the feasibility of this intervention targeted to early phases of psychosis (MCT young version). DESIGN: An experimental design included two groups of subjects on the basis of their duration of untreated psychosis (DUP) 'short' (less or equal than 12 months) and 'long' DUP (longer than 12 months), assessed at baseline and after the 4-month intervention. METHODS: Fifty-six young subjects affected by early psychosis were assessed on psychopathology, social functioning, neurocognitive, and metacognitive measures. The primary outcome was the reduction of psychopathology. Secondary outcomes included reduction of cognitive and emotional dysfunction and improvement of social functioning. RESULTS: At the end of the 4 month MCT, both groups showed significant improvements in many variables: positive symptoms, cognitive functions, as verbal memory, attention and mental flexibility, and metacognitive functions, as cognitive insight. Significant and positive changes were found in theory of mind abilities and social perception. CONCLUSIONS: The difference in DUP between the two groups of young subjects of our sample did not seem to influence the intervention outcomes, still taking into account that the average difference between the two groups in terms of DUP is 12.6 months. PRACTITIONER POINTS: Metacognition refers to the general ability 'to think about thinking,' that is, the ability to think about one's mental state and the mental states of others. Persons with schizophrenia experience different metacognitive impairments. The metacognitive training for patients with schizophrenia - young version can be applied to young people affected by psychosis and seems to improve symptomatology, social functioning, cognitive, and metacognitive abilities, independently by their Duration of Untreated Psychosis over a 2-year period. PMID- 25800000 TI - Effects of transporting an infant on the posture of women during walking and standing still. AB - We investigated the effects on women of carrying an infant in front, focusing on the pelvic and spinal posture and the displacement of the body's center of gravity. For such, we compared mothers to non-mothers not carrying anything or carrying the same load (a doll) and the mothers carrying their infants. Twenty mothers and 44 women who did not have children were analyzed for their movement and posture during walking and standing still with a motion capture system. Walking while carrying a load was slower and with a shorter stride length than while not carrying a load. The mothers' group walked slower and with a shorter stride length than the non-mothers' group. During walking and standing still, the women decreased their angle of pelvic anteversion, increased lumbar lordosis, increased thoracic kyphosis, and increased trunk backward inclination while carrying a load in comparison with not carrying anything. In addition, we observed some small differences in the spinal angles of mothers when carrying their infants compared to when carrying a doll. When standing still, the women carrying a load displaced backwards their vertical projection of the center of gravity to exactly compensate the destabilizing load at the front that resulted in no net change of the body-plus-load center of gravity. In general, these changes are qualitatively similar to the ones observed during pregnancy. PMID- 25800001 TI - Lower limb control and strength in runners with and without patellofemoral pain syndrome. AB - Recreational runners with patellofemoral pain syndrome (PFPS) have been shown to present altered movement kinematics, muscle activations, and ground reaction forces (GRF) during running as well as decreased lower limb strength. However, these variables have never been concurrently evaluated in a specific cohort. Therefore, the aim of this study was to compare lower limb control variables during running in recreational runners with and without PFPS. Lower limb control during treadmill running under typical training conditions (usual shoes, foot strike pattern, and speed) was compared between runners with (n=21) and without (n=20) PFPS using lower limb kinematics, electromyographic (EMG) recordings from representative muscles (gluteus medius/maximus, quadriceps and soleus), and vertical GRF. Isometric muscle strength was also evaluated. When comparing all runners from both groups, no between-group differences were found in variables commonly associated with PFPS such as peak hip adduction, hip internal rotation, contralateral pelvic drop, EMG of gluteal and quadriceps muscles, vertical loading rate, or lower limb strength. However, runners with PFPS showed significantly higher hip adduction at toe-off, lower excursion in hip adduction during late-stance, and longer duration of soleus activation. Sub-analyses were performed for females and for rearfoot strikers (RFS), and revealed that these subgroups accounted for most of between-group differences in hip adduction kinematics. Specifically for RFS with PFPS, lower activation of gluteus medius as well as lower GRF were observed. Our results suggest that deficits reported in runners with PFPS may vary depending on gender and on foot strike pattern. PMID- 25800002 TI - Attuning one's steps to visual targets reduces comfortable walking speed in both young and older adults. AB - Comfortable walking speed (CWS) is indicative of clinically relevant factors in the elderly, such as fall risk and mortality. Standard CWS tests involve walking on a straight, unobstructed surface, while in reality surfaces are uneven and cluttered and so walkers rely on visually guided adaptations to avoid trips or slips. Hence, the predictive value of CWS may be expected to increase when assessed for walking in more realistic (visually guided) conditions. We examined CWS in young (n=18) and older (n=18) adults for both overground and treadmill walking. Overground CWS was assessed using the 10-meter walk test with and without visual stepping targets. For treadmill walking, four conditions were examined: (i) uncued walking, and (ii-iv) cued walking with visual stepping targets where the inter-stepping target distance varied by 0%, 20%, or 40%. Pre experimental measures were taken so that the average inter-stepping target distance could be adjusted for each belt speed based on each participant's self selected gait characteristics. Results showed that CWS was significantly slower when stepping targets were present in both overground (p<.001) and treadmill walking (p<.001). Thus, attuning steps to visual targets significantly affected CWS, even when the patterning of these targets matched the participant's own gait pattern (viz. 0%-treadmill-walking condition). Results from the treadmill-walking task showed that the amount of variation in inter-stepping target distance did not differentially affect CWS. Our results suggest that it may be worthwhile in clinical assessments to not only determine walking speed using standard conditions but also in situations that require visually guided stepping. PMID- 25800003 TI - Heel strike detection using split force-plate treadmill. AB - A common source of error when detecting heel-strike moments utilizing split force plate treadmills is unwillingly stepping on contra-lateral force-plate. In this study, we quantified this error when heel-strike was detected based on such erroneous data and compared three methods to investigate how well the heel strikes and stride-intervals were detected with erroneous data. Eleven subjects walked on a split force-plate treadmill for more than 20min. We used 20N and 50% body-weight thresholds to detect the heel-strike moments (HS20N and HS50%, respectively). Besides, we used linear approximation to estimate the unaffected force profile from affected force-plate data, and subsequently to detect the heel strike moments (HSest). We used heel-strike moments detected by a foot-switch as a reference to compare accuracy of HS20N, HS50% and HSest. HS20N and HSest detected heel-strike moments accurately for unaffected force-plate data (median(max) errors for all subjects: 9(23) and 9(37) ms) but HS50% showed significantly larger errors (52(74) ms). Unlike HS50% and HSest, HS20N was considerably affected by the affected force-plate data (23(68) ms). The error in stride-interval measurement was relatively small using any methods for unaffected force-plate data (3(7), 6(8), and 6(12) ms), while stride-interval errors were large for some subjects when using HS20N for affected data (6(175) ms). We concluded that unwillingly stepping on contra-lateral force-plate occurred a few percent and up to 37.7% of all strides (median: 12.9%). Our proposed method (HSest) robustly showed small errors for heel-strike detection and stride interval calculation consistently among subjects, while HS50% and HS20N showed large errors depending on subjects. PMID- 25800005 TI - A scalable hybrid separator for a high performance lithium-sulfur battery. AB - A newly designed hybrid separator composed of a glassy fiber paper and a microporous membrane is effectively integrated into a Li-S battery. Superior cell performance up to 500 cycles is achieved even with commercially available pristine sulfur as cathode material. This fascinating study demonstrates a largely restrained polysulfides shuttle process toward practical Li-S battery application. PMID- 25800004 TI - High levels of c-Met is associated with poor prognosis in glioblastoma. AB - The tyrosine kinase receptor c-Met has been suggested to be involved in crucial parts of glioma biology like tumor stemness, growth and invasion. The aim of this study was to investigate the prognostic value of c-Met in a population-based glioma patient cohort. Tissue samples from 238 patients with WHO grade I, II, III and IV tumors were analyzed using immunohistochemical staining and advanced image analysis. Strong c-Met expression was found in tumor cells, blood vessels, and peri-necrotic areas. At the subcellular level, c-Met was identified in the cytoplasm and in the cell membrane. Measurements of high c-Met intensity correlated with high WHO grade (p = 0.006) but no association with survival was observed in patients with WHO grade II (p = 0.09) or III (p = 0.17) tumors. High expression of c-Met was associated with shorter overall survival in patients with glioblastoma multiforme (p = 0.03). However the prognostic effect of c-Met in glioblastomas was time-dependent and only observed in patients who survived more than 8.5 months, and not within the first 8.5 months after diagnosis. This was significant in multivariate analysis (HR 1.99, 95 % CI 1.29-3.08, p = 0.002) adjusted for treatment and the clinical variables age (HR 1.01, 95 % CI 0.99 1.03, p = 0.30), performance status (HR 1.34, 95 % CI 1.17-1.53, p < 0.001), and tumor crossing midline (HR 1.28, 95 % CI 0.79-2.07, p = 0.29). In conclusion, this study showed that high levels of c-Met holds unfavorable prognostic value in glioblastomas. PMID- 25800006 TI - Controlling the origins of inflammation with a photoactive lipopeptide immunopotentiator. AB - Inflammatory immune responses are mediated by signaling molecules that are both produced by and recognized across highly heterogeneous cell populations. As such, the study of inflammation using traditional immunostimulants is complicated by paracrine and autocrine signaling, which obscures the origin of a propagating response. To address this challenge, we developed a small-molecule probe that can photosensitize immune cells, thus allowing light-mediated inflammation. This probe was used to control the origin of inflammation using light. Following this motif, inflammation was initiated from fibroblasts or dendritic cells. The contributions of fibroblasts and dendritic cells in initiating inflammation in heterogeneous co-culture are reported, thus providing insights into the future development of vaccines and treatment of inflammation. PMID- 25800007 TI - Mechanisms Regulating Acquisition of Platelet-Derived Factor V/Va by Megakaryocytes. AB - Factor Va serves as the nonenzymatic protein cofactor for the prothrombinase complex, which converts prothrombin to thrombin in the events leading to formation of a hemostatic plug. Several observations support the concept that platelet-derived factor V/Va is physically and functionally distinct and plays a more important role in thrombin generation at sites of vascular injury as compared to its plasma counterpart. Platelet-derived factor V/Va is generated following endocytosis of the plasma-derived molecule by the platelet precursor cells, megakaryocytes, via a two receptor system consisting of low density lipoprotein (LDL) receptor-related protein-1 (LRP-1) and an unidentified specific "binding site". More recently, it was suggested that a cell surface-expressed beta-galactoside binding protein, galectin-8, was involved in factor V endocytosis. Endocytosed factor V is trafficked through the cell and retailored prior to its storage in alpha-granules. Given the essential role of platelet derived factor Va in clot formation, understanding the cellular and molecular mechanisms that regulate how platelets acquire this molecule will be important for the treatment of excessive bleeding or clotting. PMID- 25800008 TI - Marker assisted separation of resistance genes Rph22 and Rym16 (Hb) from an associated yield penalty in a barley: Hordeum bulbosum introgression line. AB - KEY MESSAGE: The resistance genes Rph22 and Rym16 (Hb) transferred into barley from Hordeum bulbosum have been separated from a large yield penalty locus that was present in the original introgression line '182Q20'. The Hordeum bulbosum introgression line '182Q20' possesses resistance to barley leaf rust (Rph22) and Barley mild mosaic virus (Rym16 (Hb) ) located on chromosome 2HL. Unfortunately, this line also carries a considerable yield penalty compared with its barley genetic background 'Golden Promise'. Quantitative trait locus (QTL) mapping of the components of yield (total yield, thousand grain weight, hectolitre weight, percentage screenings and screened yield) was performed using 75 recombinant lines derived from the original '182Q20' introgression line. A QTL for the yield penalty was located in the proximal region of the introgressed segment. Marker assisted selection targeting intraspecific recombination events between overlapping H. bulbosum introgression segments was used to develop the lines '372E' and '372H' which feature genetically small introgressions around Rph22. Further yield trials validated the separation of both Rph22 and Rym16 (Hb) from the proximal yield penalty. These results, combined with molecular markers closely linked to Rph22 and Rym16 (Hb) , make these resistance genes more attractive for barley breeding. PMID- 25800009 TI - Genome-wide association mapping in plants. AB - KEY MESSAGE: We present new association mapping methods which address the unique challenges of analyzing genome-wide data from multi-environment plant studies. Association studies on a genome-wide scale are being performed in plants. Unlike human studies, plant studies contain replicates whose data may be recorded across different environments. Plant studies also often employ elaborate experimental designs for controlling extraneous phenotypic variation. As a result, the genome wide analysis of data from plant studies can be challenging. In this paper, we present QK-based association mapping for the analysis of data from plant association studies. In doing so, we have developed: (a) a general multivariate QK framework for association mapping in plant studies of arbitrary complexity; (b) a new weighted two-stage analysis approach for QK-based association mapping; (c) a heuristic procedure for determining when two-stage analysis is appropriate; and (d) a Monte Carlo sampling procedure for controlling the genome-wide type I error rate. We conduct a simulation study to evaluate the performance of our genome-wide mapping technique. We also analyze data from a multi-environment association study in wheat. PMID- 25800010 TI - Cutting-edge mass spectrometry characterization of originator, biosimilar and biobetter antibodies. AB - The approval process for antibody biosimilars relies primarily on comprehensive analytical data to establish comparability and high similarity with the originator. Mass spectrometry (MS) in combination with liquid chromatography (LC) and electrophoretic methods are the corner stone for comparability and biosimilarity evaluation. In this special feature we report head-to-head comparison of trastuzumab and cetuximab with corresponding biosimilar and biobetter candidates based on cutting-edge mass spectrometry techniques such as native MS and ion-mobility MS at different levels (top, middle and bottom). In addition, we discuss the advantages and the limitations of sample preparation and enzymatic digestion, middle-up and -down strategies and the use of hydrogen/deuterium exchange followed by MS (HDX-MS). Last but not least, emerging separation methods combined to MS such as capillary zone electrophoresis-tandem MS (CESI-MS/MS), electron transfer dissociation (ETD), top down-sequencing (TDS) and high-resolution MS (HR-MS) that complete the panel of state-of-the-art MS based options for comparability and biosimilarity evaluation are presented. PMID- 25800011 TI - Use of quadrupole time of flight mass spectrometry for the characterization of transformation products of the antibiotic sulfamethazine upon photocatalysis with Pd-doped ceria-ZnO nanocomposite. AB - The photocatalytic degradation of the antibiotic sulfamethazine under excitation at 365 nm of Pd-doped ceria-ZnO nanocomposite, titanium dioxide and iron(III) aqua complex was deeply studied from the analytical point of view. It reveals the formation of nine degradation products that were detected in their protonated forms using LC/electrospray ionization quadrupole time-of-flight MS in the positive mode. Their formation involves the hydroxyl radical, and their concentrations increased with irradiation time. Collision-induced dissociation tandem mass spectrometry associated with the accurate mass measurements was efficiently used for the elucidation of their chemical structures. None of these identified degradation products has been already reported in the literature. Three by-products result from the hydroxylation at the pyrimidine moiety as well as at the aromatic part, two of them arise from the scission of the pyrimidine group, and finally, three of them come from the scission of the sulfamide bridge. This points the evidence of studying the fate of these degradation products if their toxicity is demonstrated because they are clearly the result of the reaction of hydroxyl radical with the antibiotic sulfamethazine. PMID- 25800013 TI - Redox activity and multiple copper(I) coordination of 2His-2Cys oligopeptide. AB - Copper binding motifs with their molecular mechanisms of selective copper(I) recognition are essential molecules for acquiring copper ions, trafficking copper to specific locations and controlling the potentially damaging redox activities of copper in biochemical processes. The redox activity and multiple Cu(I) binding of an analog methanobactin peptide-2 (amb2) with the sequence acetyl-His1-Cys2 Tyr3-Pro4-His5-Cys6 was investigated using ion mobility-mass spectrometry (IM-MS) and UV-Vis spectrophotometry analyses. The Cu(II) titration of amb2 showed oxidation of amb2 via the formation of intra- and intermolecular Cys-Cys disulfide bridges and the multiple Cu(I) coordination by unoxidized amb2 or the partially oxidized dimer and trimer of amb2. The principal product of these reactions was [amb2 + 3Cu(I)](+) which probably coordinates the three Cu(I) ions via two bridging thiolate groups of Cys2 and Cys6 and the deltaN6 of the imidazole groups of His6, as determined by geometry optimized structures at the B3LYP/LanL2DZ level of theory. The products observed by IM-MS showed direct correlation to spectral changes associated with disulfide bond formation in the UV-Vis spectrophotometric study. The results show that IM-MS analysis is a powerful technique for unambiguously determining the major ion species produced during the redox and metal binding chemistry of oligopeptides. PMID- 25800012 TI - Collision induced dissociations of non-derivatized and trimethylsilyl-derivatized estradiols: similarities in fragmentation patterns. AB - Fragmentation mechanisms of estradiol and trimethylsilyl (TMS)-derivatized estradiol were studied by triple quadrupole tandem mass spectrometry (MSMS) and density functional theory (DFT) at B3LYP/6-311G(d,p) level. Collision induced dissociations (CID) of estradiol give product ions that are associated with the cleavage of B, C and D rings. Characteristic fragments from the cleavage of the aromatic ring A were not identified, and this was confirmed with both labeled estradiol and trimethylsilyl (TMS)-derivatized estradiol. The mechanisms are based on charge-site directed, radical-directed and charge remote fragmentations that are consistent with previous studies of steroids. CID spectra show ion pairs at m/z: 145/146, 157/158, 185/186, 211/213 and 225/226 with significant intensities, suggesting that these pairs are not from isotopic contributions. The mechanisms show similarities with some minor differences in the fragmentation patterns between the non-derivatized and the TMS-derivatized estradiol. PMID- 25800014 TI - Targeted quantitative phosphoproteomic analysis of erythrocyte membranes during blood bank storage. AB - One of the hallmarks of blood bank stored red blood cells (RBCs) is the irreversible transition from a discoid to a spherocyte-like morphology with membrane perturbation and cytoskeleton disorders. Therefore, identification of the storage-associated modifications in the protein-protein interactions between the cytoskeleton and the lipid bilayer may contribute to enlighten the molecular mechanisms involved in the alterations of mechanical properties of stored RBCs. Here we report the results obtained analyzing RBCs after 0, 21 and 35 days of storage under standard blood banking conditions by label free mass spectrometry (MS)-based experiments. We could quantitatively measure changes in the phosphorylation level of crucial phosphopeptides belonging to beta-spectrin, ankyrin-1, alpha-adducin, dematin, glycophorin A and glycophorin C proteins. Data have been validated by both western blotting and pseudo-Multiple Reaction Monitoring (MRM). Although each phosphopeptide showed a distinctive trend, a sharp increase in the phosphorylation level during the storage duration was observed. Phosphopeptide mapping and structural modeling analysis indicated that the phosphorylated residues localize in protein functional domains fundamental for the maintenance of membrane structural integrity. Along with previous morphological evidence acquired by electron microscopy, our results seem to indicate that 21-day storage may represent a key point for the molecular processes leading to the erythrocyte deformability reduction observed during blood storage. These findings could therefore be helpful in understanding and preventing the morphology-linked mechanisms responsible for the post-transfusion survival of preserved RBCs. PMID- 25800015 TI - Separation of glycosidic catiomers by TWIM-MS using CO2 as a drift gas. AB - Traveling wave ion mobility mass spectrometry (TWIM-MS) is shown to be able to separate and characterize several isomeric forms of diterpene glycosides stevioside (Stv) and rebaudioside A (RebA) that are cationized by Na(+) and K(+) at different sites. Determination and characterization of these coexisting isomeric species, herein termed catiomers, arising from cationization at different and highly competitive coordinating sites, is particularly challenging for glycosides. To achieve this goal, the advantage of using CO2 as a more massive and polarizable drift gas, over N2, was demonstrated. Post-TWIM-MS/MS experiments were used to confirm the separation. Optimization of the possible geometries and cross-sectional calculations for mobility peak assignments were also performed. PMID- 25800016 TI - Characterization of degradation products of ivabradine by LC-HR-MS/MS: a typical case of exhibition of different degradation behaviour in HCl and H2SO4 acid hydrolysis. AB - A validated stability-indicating HPLC method was established, and comprehensive stress testing of ivabradine, a cardiotonic drug, was carried out as per ICH guidelines. Ivabradine was subjected to acidic, basic and neutral hydrolysis, oxidation, photolysis and thermal stress conditions, and the resulting degradation products were investigated by LC-PDA and LC-HR-MS/MS. The drug was found to degrade in acid and base hydrolysis. An efficient and selective stability assay method was developed on Phenomenex Luna C18 (250 * 4.6 mm, 5.0 um) column using ammonium formate (10 mM, pH 3.0) and acetonitrile as mobile phase at 30 degrees C in gradient elution mode. The flow rate was 0.7 ml/min and detection wavelength was 286 nm. A total of five degradation products (I-1 to I 5) were identified and characterized by LC-HR-MS/MS in combination with accurate mass measurements. The drug exhibited different degradation behaviour in HCl and H2SO4 hydrolysis conditions. It is a unique example where two of the five degradation products in HCl hydrolysis were absent in H2SO4 acid hydrolysis. The present study provides guidance to revise the stress test for the determination of inherent stability of drugs containing lactam moiety under hydrolytic conditions. Most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation pattern of the drug and its degradation products. In silico toxicity revealed that the degradation products (I-2 to I-5) were found to be severe irritants in case of ocular irritancy. The analytical assay method was validated with respect to specificity, linearity, range, precision, accuracy and robustness. PMID- 25800017 TI - Determination of catecholamines and their metabolites in rat urine by ultra performance liquid chromatography-tandem mass spectrometry for the study of identifying potential markers for Alzheimer's disease. AB - In order to investigate the potential links between catecholamines (CAs) and Alzheimer's disease (AD), rapid and sensitive ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) methods in different ionization modes for the quantification of 14 CAs and their metabolites in rat urine without derivatization or complex sample pre-treatments were developed. After addition of the internal standard, isoproterenol, the urine samples were extracted by protein precipitation and separated on an Inertsil ODS-EP column (Shimadzu, Japan) at a flow of 1.0 ml min(-1). Tandem mass spectrometric detection was performed on a 4000Q UPLC-MS/MS in the multiple reaction monitoring mode with turbo ion spray source. Tyrosine, dopamine, noradrenaline, epinephrine, 3-methoxytyramine, normetanephrine and metanephrine were determined in positive mode, while 3,4-dihyroxy-L-phenylalanine (DOPA), 3,4-dihydroxyphenylacetic acid, DL-3,4-dihydroxymandelic acid, DL-3,4-dihydroxyphenyl glycol, homovanillic acid, DL-4-hydroxy-3-methoxymandelic acid and 4-hydroxy-3-methoxy-phenylglycol were determined in negative mode. The methods were examined and were found to be precise and accurate within the linearity range of the assays. The intra-day and inter-day precision and accuracy of the analytes were well within acceptance criteria (+/-15%). The mean extraction recoveries of analytes and internal standard were all more than 60%. The validated methods have been successfully applied to compare CAs profiles in normal and AD rats. The results indicated the urine levels of DL-3,4-dihydroxyphenyl glycol and 4-hydroxy-3-methoxy phenylglycol in AD rats were significantly higher than those in the normal group, and the other CAs have an opposite performance. These may attribute to the difference of some enzyme activity between rats with AD and normal. Furthermore, this may be helpful in clinical diagnostics and monitor the efficacy of AD treatment. PMID- 25800018 TI - Competitive proton and hydride transfer reactions via ion-neutral complexes: fragmentation of deprotonated benzyl N-phenylcarbamates in mass spectrometry. AB - The gas-phase chemistry of deprotonated benzyl N-phenylcarbamates was investigated by electrospray ionization tandem mass spectrometry. Characteristic losses of a substituted phenylcarbinol and a benzaldehyde from the precursor ion were proposed to be derived from an ion-neutral complex (INC)-mediated competitive proton and hydride transfer reactions. The intermediacy of the INC consisting of a substituted benzyloxy anion and a phenyl isocyanate was supported by both ortho-site-blocking experiments and density functional theory calculations. Within the INC, the benzyloxy anion played the role of either a proton abstractor or a hydride donor toward its neutral counterpart. Relative abundances of the product ions were influenced by the nature of the substituents. Electron-withdrawing groups at the N-phenyl ring favored the hydrogen transfer process (including proton and hydride transfer), whereas electron-donating groups favored direct decomposition to generate the benzyloxy anion (or substituted benzyloxy anion). By contrast, electron-withdrawing and electron-donating substitutions at the O-benzyl ring exhibited opposite effects. PMID- 25800019 TI - Comparison of MALDI-TOF mass spectra with microsatellite length polymorphisms in Candida albicans. AB - Candida albicans is the most frequent yeast involved in human infections. Its population structure can be divided into several genetic clades, some of which have been associated with antifungal susceptibility. Therefore, detecting and monitoring fungal clones in a routine laboratory setting would be a major epidemiological advance. Matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectra results are now widely used as bar codes to identify microorganisms in clinical microbiology laboratories. This study aimed at testing MALDI-TOF mass spectra bar codes to identify clades among a set of C. albicans isolates. Accordingly, 102 clinical strains were genotyped using 10 microsatellite markers and analyzed via MALDI-TOF mass spectrometry. The mass spectra were compared with a reference spectral library including 33 well characterized collection strains, using a Microflex(TM) system and Biotyper(TM) software, to test the capacity of the spectrum of a given isolate to match with the reference mass spectrum of an isolate from the same genetic clade. Despite high confidence species identification, the spectra failed to significantly match with the corresponding clade (p = 0.74). This was confirmed with the MALDI-TOF spectra similarity dendrogram, in which the strains were dispersed irrespective of their genetic clade. Various attempts to improve intra-clade spectra recognition were unsuccessful. In conclusion, MALDI-TOF mass spectra bar code analysis failed to reliably recognize genetically related C. albicans isolates. Further studies are warranted to develop alternative MALDI-TOF mass spectra analytical approaches to identify and monitor C. albicans clades in the routine clinical laboratory. PMID- 25800020 TI - Bromine isotopic signature facilitates de novo sequencing of peptides in free radical-initiated peptide sequencing (FRIPS) mass spectrometry. AB - We recently showed that free-radical-initiated peptide sequencing mass spectrometry (FRIPS MS) assisted by the remarkable thermochemical stability of (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) is another attractive radical driven peptide fragmentation MS tool. Facile homolytic cleavage of the bond between the benzylic carbon and the oxygen of the TEMPO moiety in o-TEMPO-Bz-C(O) peptide and the high reactivity of the benzylic radical species generated in *Bz C(O)-peptide are key elements leading to extensive radical-driven peptide backbone fragmentation. In the present study, we demonstrate that the incorporation of bromine into the benzene ring, i.e. o-TEMPO-Bz(Br)-C(O)-peptide, allows unambiguous distinction of the N-terminal peptide fragments from the C terminal fragments through the unique bromine doublet isotopic signature. Furthermore, bromine substitution does not alter the overall radical-driven peptide backbone dissociation pathways of o-TEMPO-Bz-C(O)-peptide. From a practical perspective, the presence of the bromine isotopic signature in the N terminal peptide fragments in TEMPO-assisted FRIPS MS represents a useful and cost-effective opportunity for de novo peptide sequencing. PMID- 25800021 TI - Ambient ionization and direct identification of volatile organic compounds with microwave-induced plasma mass spectrometry. AB - An innovative method of volatile organic compounds analysis by using microwave induced plasma ionization (MIPI) source in combination with an ambient ion trap mass spectrometer is presented here. Using MIPI for direct sample vapor, analysis was achieved without any sample preparation or subsequent heating. The relative abundance of the target compounds can be obtained almost instantly within a few seconds. The ionization processes of different volatile compounds was optimized, and the limits of detection were identified in the range of 0.15-4.5 pptv or 0.73 8.80 pg ml(-1). The relative standard deviation (RSD) is in the range of 4-14%, while correlation coefficients of the working curves (R(2)) are better than 0.98. The new method possesses advantages of ease operation, time-saving, high sensitivity and inexpensive setup. In addition, the ionization processes of short n-alkane chains were investigated with the MIPI technique, and a unique [M + 13](+) was detected, which has not been reported in detail by any other related ionization techniques. An ionization mechanism was proposed on the basis of the experimental results obtained in this work and available information in literatures, in which the n-alkanes in the plasma environment possibly generate protonated cyclopentadiene [M - 5](+) or alkyl-substituted analogues as well as hydrous ions [M + 13](+) and [M + 13 + 18](+), as shown in Scheme 1 in the main text. PMID- 25800022 TI - Dissociation behavior of a bifunctional tempo-active ester reagent for peptide structure analysis by free radical initiated peptide sequencing (FRIPS) mass spectrometry. AB - We have synthesized a homobifunctional active ester cross-linking reagent containing a TEMPO (2,2,6,6-tetramethylpiperidine-1-oxy) moiety connected to a benzyl group (Bz), termed TEMPO-Bz-linker. The aim for designing this novel cross linker was to facilitate MS analysis of cross-linked products by free radical initiated peptide sequencing (FRIPS). The TEMPO-Bz-linker was reacted with all 20 proteinogenic amino acids as well as with model peptides to gain detailed insights into its fragmentation mechanism upon collision activation. The final goal of this proof-of-principle study was to evaluate the potential of the TEMPO Bz-linker for chemical cross-linking studies to derive 3D-structure information of proteins. Our studies were motivated by the well documented instability of the central NO-C bond of TEMPO-Bz reagents upon collision activation. The fragmentation of this specific bond was investigated in respect to charge states and amino acid composition of a large set of precursor ions resulting in the identification of two distinct fragmentation pathways. Molecular ions with highly basic residues are able to keep the charge carriers located, i.e. protons or sodium cations, and consequently decompose via a homolytic cleavage of the NO-C bond of the TEMPO-Bz-linker. This leads to the formation of complementary open shell peptide radical cations, while precursor ions that are protonated at the TEMPO-Bz-linker itself exhibit a charge-driven formation of even-electron product ions upon collision activation. MS(3) product ion experiments provided amino acid sequence information and allowed determining the cross-linking site. Our study fully characterizes the CID behavior of the TEMPO-Bz-linker and demonstrates its potential, but also its limitations for chemical cross-linking applications utilizing the special features of open-shell peptide ions on the basis of selective tandem MS analysis. PMID- 25800023 TI - Studies on the collision-induced dissociation of adipoR agonists after electrospray ionization and their implementation in sports drug testing. AB - AdipoR agonists are small, orally active molecules capable of mimicking the protein adiponectin, which represents an adipokine with antidiabetic and antiatherogenic effects. Two adiponectin receptors were reported in the literature referred to as adipoR1 and adipoR2. Activation of these receptors stimulates mitochondrial biogenesis and results in an improved oxidative metabolism (via adipoR1) and increased insulin sensitivity (via adipoR2). Hence, adipoR agonists are potentially performance enhancing substances and targets of proactive and preventive anti-doping measures. In this study, two adipoR agonists termed AdipoRon and 112254 as well as two isotopically labeled internal standards (ISTDs) were synthesized in three-step reactions. The products were fully characterized by nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS) and density functional theory (DFT) computation. Collision-induced dissociation pathways following electrospray ionization were suggested based on the determined elemental compositions of product ions, comparison to product ions derived from labeled analogs (ISTDs), H/D-exchange experiments and the results of DFT calculations. The most abundant product ions were found at m/z 174, tentatively assigned to protonated 1-benzyl-1,2,3,4-tetrahydropyridine for AdipoRon, and m/z 207, suggested as protonated 1-(4-methoxybenzyl)piperazine, for 112254. Notably, the loss of the heterocyclic ring (i.e. piperazine and piperidine, respectively) in a supposedly intramolecular elimination reaction was observed in both cases. A qualitative determination of both AdipoR agonists in human plasma was established and fully validated for doping control purposes. Validation items such as recovery (86-89%), specificity, linearity, lower limit of detection (1 ng/ml), intraday (3-18%) and interday (5-16%) precision as well as ion suppression or enhancement were determined. Based on these findings adipoR agonists can be implemented in sports drug testing procedures. PMID- 25800024 TI - Strategies for generating peptide radical cations via ion/ion reactions. AB - Several approaches for the generation of peptide radical cations using ion/ion reactions coupled with either collision induced dissociation (CID) or ultraviolet photo dissociation (UVPD) are described here. Ion/ion reactions are used to generate electrostatic or covalent complexes comprised of a peptide and a radical reagent. The radical site of the reagent can be generated multiple ways. Reagents containing a carbon-iodine (C-I) bond are subjected to UVPD with 266-nm photons, which selectively cleaves the C-I bond homolytically. Alternatively, reagents containing azo functionalities are collisionally activated to yield radical sites on either side of the azo group. Both of these methods generate an initial radical site on the reagent, which then abstracts a hydrogen from the peptide while the peptide and reagent are held together by either electrostatic interactions or a covalent linkage. These methods are demonstrated via ion/ion reactions between the model peptide RARARAA (doubly protonated) and various distonic anionic radical reagents. The radical site abstracts a hydrogen atom from the peptide, while the charge site abstracts a proton. The net result is the conversion of a doubly protonated peptide to a peptide radical cation. The peptide radical cations have been fragmented via CID and the resulting product ion mass spectra are compared to the control CID spectrum of the singly protonated, even-electron species. This work is then extended to bradykinin, a more broadly studied peptide, for comparison with other radical peptide generation methods. The work presented here provides novel methods for generating peptide radical cations in the gas phase through ion/ion reaction complexes that do not require modification of the peptide in solution or generation of non covalent complexes in the electrospray process. PMID- 25800025 TI - Selective reagent ionisation-time of flight-mass spectrometry: a rapid technology for the novel analysis of blends of new psychoactive substances. AB - In this study we demonstrate the potential of selective reagent ionisation-time of flight-mass spectrometry for the rapid and selective identification of a popular new psychoactive substance blend called 'synthacaine', a mixture that is supposed to imitate the sensory and intoxicating effects of cocaine. Reactions with H3O(+) result in protonated parent molecules which can be tentatively assigned to benzocaine and methiopropamine. However, by comparing the product ion branching ratios obtained at two reduced electric field values (90 and 170 Td) for two reagent ions (H3O(+) and NO(+)) to those of the pure chemicals, we show that identification is possible with a much higher level of confidence then when relying solely on the m/z of protonated parent molecules. A rapid and highly selective analytical identification of the constituents of a recreational drug is particularly crucial to medical personnel for the prompt medical treatment of overdoses, toxic effects or allergic reactions. PMID- 25800026 TI - The competing radical eliminations in the tandem mass spectrometry of the OH deprotonated benzyl vanillate. PMID- 25800030 TI - Sub-surface laser nanostructuring in stratified metal/dielectric media: a versatile platform towards flexible, durable and large-scale plasmonic writing. AB - Laser nanostructuring of pure ultrathin metal layers or ceramic/metal composite thin films has emerged as a promising route for the fabrication of plasmonic patterns with applications in information storage, cryptography, and security tagging. However, the environmental sensitivity of pure Ag layers and the complexity of ceramic/metal composite film growth hinder the implementation of this technology to large-scale production, as well as its combination with flexible substrates. In the present work we investigate an alternative pathway, namely, starting from non-plasmonic multilayer metal/dielectric layers, whose growth is compatible with large scale production such as in-line sputtering and roll-to-roll deposition, which are then transformed into plasmonic templates by single-shot UV-laser annealing (LA). This entirely cold, large-scale process leads to a subsurface nanoconstruction involving plasmonic Ag nanoparticles (NPs) embedded in a hard and inert dielectric matrix on top of both rigid and flexible substrates. The subsurface encapsulation of Ag NPs provides durability and long term stability, while the cold character of LA suits the use of sensitive flexible substrates. The morphology of the final composite film depends primarily on the nanocrystalline character of the dielectric host and its thermal conductivity. We demonstrate the emergence of a localized surface plasmon resonance, and its tunability depending on the applied fluence and environmental pressure. The results are well explained by theoretical photothermal modeling. Overall, our findings qualify the proposed process as an excellent candidate for versatile, large-scale optical encoding applications. PMID- 25800029 TI - Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. AB - Patients with acute-on-chronic liver failure (ACLF) represent a heterogeneous population. The aim of the study is to identify distinct groups according to the etiologies of precipitating events. A total of 405 ACLF patients were identified from 1,361 patients with cirrhosis with acute decompensation and categorized according to the types of acute insults. Clinical characteristics and prognosis between the hepatic group and extrahepatic group were compared, and the performance of prognostic models was tested in different groups. Two distinct groups (hepatic-ACLF and extrahepatic-ACLF) were identified among the ACLF population. Hepatic-ACLF was precipitated by hepatic insults and had relatively well-compensated cirrhosis with frequent liver and coagulation failure. In contrast, extrahepatic-ACLF was exclusively precipitated by extrahepatic insults, characterized by more severe underlying cirrhosis and high occurrence of extrahepatic organ failures (kidney, cerebral, circulation, and respiratory systems). Both groups had comparably high short-term mortality (28-day transplant free mortality: 48.3% vs. 50.7%; P = 0.22); however, the extra-hepatic-ACLF group had significantly higher 90-day and 1-year mortality (90-day: 58.9% vs. 68.3%, P = 0.035; 1-year: 63.9% vs. 74.6%, P = 0.019). In hepatic-ACLF group, the integrated Model for End-Stage Liver Disease (iMELD) score had the highest area under the receiver operating characteristic curve (auROC = 0.787) among various prognostic models in predicting 28-day mortality, whereas CLIF-Consortium scores for ACLF patients (CLIF-C-ACLF) had the highest predictive value in the other group (auROC = 0.779). CONCLUSIONS: ACLF precipitated by hepatic insults is distinct from ACLF precipitated by extrahepatic insults in clinical presentation and prognosis. The iMELD score may be a better predictor for hepatic-ACLF short term prognosis, whereas CLIF-C-ACLF may be better for extrahepatic-ACLF patients. PMID- 25800031 TI - Assessment of subjective cognitive impairment among older adults. AB - Subjective cognitive impairment (SCI) refers to an individual's everyday concerns related to cognitive functioning, which can exist even in the absence of objectively assessed impairment. SCI is common among older adults, and although symptoms may be mild, SCI is associated with subsequent cognitive decline as well as significant negative effects on everyday functional ability, mood, and social engagement. Despite the potential consequences, SCI is often underreported and undetected. Thus, it is critical to consider assessing for SCI among older adults to determine cognitive impairment risk and support early intervention to promote functional well-being and health management. The current article reviews factors related to SCI, evaluates existing methods for the assessment of SCI, and proposes a person-centered framework for enhancing assessment. Application of the framework is further illustrated through the use of clinical examples. PMID- 25800032 TI - Recent Trends in Diabetes Knowledge, Perceptions, and Behaviors: Implications for National Diabetes Education. AB - OBJECTIVES: Examine trends in diabetes-related knowledge, perceptions, and behavior among U.S. adults with and without a diagnosis of diabetes and among subpopulations at risk. Discuss implications for national diabetes education and for the National Diabetes Education Program (NDEP) in particular. METHODS: Three population-based NDEP National Diabetes Surveys (2006, 2008, and 2011) collected information on diabetes knowledge, education, and self-management; perceived and actual risk of diabetes; and lifestyle changes. RESULTS: Since 2006, U.S. adults significantly advanced their knowledge and awareness of diabetes and prediabetes. Perceived personal risk did not increase among people with prediabetes (PWP) or people at risk. Family history as a risk factor dropped in reported importance, especially among PWP and Hispanics. Diabetes self-management rose modestly, although checking blood sugar significantly declined. Trends in understanding the diabetes and cardiovascular disease link, A1C testing, and adjusted logistic regression results for perceived risk are discussed. DISCUSSION AND IMPLICATIONS: Although diabetes-related knowledge has reached high levels, stagnant perceived risk suggests people at risk are not applying this knowledge to themselves. Future surveys are planned to include additional, specific questions to capture people's movement toward behavior change and to identify where strategic efforts and educational interventions can help promote improved behaviors. PMID- 25800033 TI - Mitochondrial dynamics regulate neointima formation. PMID- 25800034 TI - Structural chromosomal aberrations as potential risk markers in incident cancer patients. AB - Epidemiological prospective studies have shown that increased chromosomal aberrations (CAs) in peripheral blood lymphocytes may predict cancer risk. Here, we report CAs in newly diagnosed 101 colorectal, 87 lung and 158 breast cancer patients and corresponding healthy controls. Strong differences in distributions of aberrant cells (ACs), CAs, chromatid-type aberrations (CTAs) and chromosome type aberrations (CSAs) were observed in lung and breast cancer patients as compared to healthy controls. In colorectal cancer (CRC) patients, only CTAs were significantly elevated. Binary logistic regression, adjusted for main confounders, indicates that all the analysed cytogenetic parameters along with smoking were significantly associated with breast and lung cancer risks. Significant differences in terminal deletions between breast cancer patients and corresponding female controls were recorded (0.39 vs. 0.18; P <= 0.05). We did not find any association of CAs with TNM (tumor nodus metastasis) stages or histopathological grade in either cancer type. CAs were neither associated with additional tumor characteristics-invasivity, ductal and lobular character, estrogene/progesterone receptors in breast tumors nor with non-small/small cell and bronchogenic/pulmonary types of lung tumors. Our study demonstrates that CAs serve as a predictive marker for breast and lung cancer, whereas only CTAs were elevated in incident CRC patients. PMID- 25800035 TI - Suitability of quality-of-life outcome measures in palliative care in the South African setting. AB - OBJECTIVE: Quality of life (QoL) is a multidimensional, subjective, and highly individual phenomenon. The current study speaks to the QoL domains identified by palliative patients living in Africa. The need to identify these domains has been recognized but seemed to still be lacking. This study filled this knowledge gap by providing the domains and by giving directions in terms of the assessment of QoL in palliative patients living in resource-restricted communities in South Africa. METHOD: We followed a multi-method approach and conducted a literature review to identify and describe the multidimensional QoL instruments used in African palliative care. A secondary analysis design and open-coding method was employed to identify the domains influencing the QoL of palliative patients living in a resource-restricted South African community, after which we compared these domains to the domains assessed by the identified QoL instruments. RESULTS: We found that two multidimensional QoL of life instruments-the Missoula-Vitas Quality of Life Index (MVQoLI) and the Functional Assessments of Chronic Illness Therapy-Palliative Care (FACIT-Pal)-have been used in African palliative care and have identified various domains, grouped as four themes: physical concerns, psychosocial issues, financial restraints, and existential issues. The patient identified QoL domains were to a great extent not assessed by the MVQoLI and FACIT-Pal. SIGNIFICANCE OF RESULTS: Our study highlights the complexity of QoL and QoL assessment. A more accurate representation of the QoL of palliative patients living in resource-restricted communities might be obtained by using individualized measures or exploring what QoL means to these patients and selecting QoL instruments accordingly. PMID- 25800036 TI - Stereotactic radiation therapy of renal cancer inferior vena cava tumor thrombus. AB - Renal Cell Carcinoma (RCC) is a common malignancy world-wide that is rising in incidence. Up to 10% of RCC patients present with inferior vena cava (IVC) tumor thrombus (IVC-TT). Although surgery is the only treatment with proven efficacy for IVC-TT, the surgical management of advanced (level III and IV) IVC-TT is difficult with high morbidity and mortality, and offers a poor survival outcome. Currently, there are no treatment options in the setting of recurrent or unresectable RCC IVC-TT. Even though RCC may be resistant to conventionally fractionated radiation therapy, hypofractionated radiation has shown excellent control rates for both primary and metastatic RCC. We report our experience treating 2 RCC patients with Level IV IVC-TT -one recurrent and the other unresectable-with stereotactic ablative radiation therapy (SABR). The first patient is a 75-year-old gentleman with a level IV RCC IVC-TT who presented 9 months after his radical nephrectomy and thrombectomy with a growing level IV IVC TT that became refractory to 4 targeted agents. He received SABR of 50Gy in 5 fractions and at 2-year follow-up is doing well with a significant decrease in the enhancement and size of the IVC-TT. The second patient is an 83-year-old gentleman who presented with metastatic RCC and level IV IVC-TT but was not a surgical candidate. After progression on temsirolimus, he received SABR of 36Gy in 4 fractions to his IVC-TT and survived 18 months post-SABR. Both patients improved symptomatically and did not experience any acute or late treatment related toxicity. Their survival of 24 months and 18 months are comparable to the reported median survival of 20 months in patients with level IV IVC-TT that underwent surgical resection. Therefore, SABR can be a potentially safe treatment option in the unresectable setting for RCC patients with IVC-TT and should be further evaluated in prospective trials. PMID- 25800037 TI - Effect of the TLR2/MyD88/NF-kappaB axis on corneal allograft rejection after penetrating keratoplasty. AB - PURPOSE: To evaluate the effect of the TLR2 (Toll-like receptor 2)/MyD88/NF kappaB axis on the allograft rejection after penetrating keratoplasty (PK). METHODS: The PK rat models were randomly divided into four groups: allograft group, dexamethasone group, PDTC group and isograft group. The mean survival time (MST) and rejection index of corneal grafts were observed. The immunohistochemical staining of TGF-alpha was performed on day 15. The messenger RNA (mRNA) and protein expression of TLR2, MyD88 and NF-kappaB p65 in corneal grafts were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. RESULTS: On days 5, 7, 9, 11, 13 and 15, the rejection index in the allograft group was higher than in the other three groups (p < 0.05). The MST in the PDTC group (MST, 23.30 +/- 0.42 days, n = 10) and in the dexamethasone group (MST, 24.40 +/- 0.50 days, n = 10) were higher than in the allograft group (MST, 14.7 +/- 0.70 days, n = 10) (chi(2) = 18.02, p < 0.01; chi(2) = 21.47, p < 0.01). The expression of TNF-alpha in the PDTC group and in the dexamethasone group decreased compared with the allograft group by immunohistochemistry. On day 15, the mRNA and protein expression of TLR2, MyD88 and NF-kappaB p65 in the PDTC group and the dexamethasone group were less than in the allograft group (p < 0.05). CONCLUSIONS: Expression of TLR2, MyD88 and NF kappaB p65 in rat corneal graft increased significantly and concurred with the allograft rejection, but were effectively inhibited by the treatment with dexamethasone and PDTC after PK. Dexamethasone could improve corneal allograft survival by the TLR2/MyD88/NF-kappaB axis. PDTC could suppress corneal graft rejection by inhibiting the activity of NF-kappaB. The TLR2/MyD88/NF-kappaB axis maybe a potential therapeutic target for corneal allograft rejection. PMID- 25800039 TI - Living donor liver transplantation in emergencies: is it time to say yes? PMID- 25800038 TI - Development and characterization of a novel rat model of estrogen-induced mammary cancer. AB - The ACI rat model of 17beta-estradiol (E2)-induced mammary cancer is highly relevant for use in establishing the endocrine, genetic, and environmental bases of breast cancer etiology and identifying novel agents and strategies for preventing breast cancer. E2 treatment rapidly induces mammary cancer in female ACI rats and simultaneously induces pituitary lactotroph hyperplasia and adenoma. The pituitary tumors can result in undesired morbidity, which compromises long term studies focused on mammary cancer etiology and prevention. We have defined the genetic bases of susceptibility to E2-induced mammary cancers and pituitary tumors and have utilized the knowledge gained in these studies to develop a novel inbred rat strain, designated ACWi, that retains the high degree of susceptibility to E2-induced mammary cancer exhibited by ACI rats, but lacks the treatment-related morbidity associated with pituitary lactotroph hyperplasia/adenoma. When treated with E2, female ACWi rats developed palpable mammary cancer at a median latency of 116 days, an incidence of 100% by 161 days and exhibited an average of 15.6 mammary tumors per rat following 196 days of treatment. These parameters did not differ from those observed for contemporaneously treated ACI rats. None of the E2-treated ACWi rats were killed before the intended experimental end point due to any treatment-related morbidity other than mammary cancer burden, whereas 20% of contemporaneously treated ACI rats exhibited treatment-related morbidity that necessitated premature killing. The ACWi rat strain is well suited for use by those in the research community, focusing on breast cancer etiology and prevention. PMID- 25800040 TI - Botulinum Toxin-A for Painful Diabetic Neuropathy: A Meta-Analysis. AB - OBJECTIVES: Painful diabetic neuropathy (PDN) is a debilitating complication of diabetes that greatly affects the quality of life of those afflicted. There are many treatment options for neuropathic pain. Recent studies show a promising analgesic effect using botulinum toxin-A (BTX-A) for neuropathic pain. METHODS: This article is a meta-analysis of two studies using BTX-A in the treatment of neuropathic pain. Electronic searches of MEDLINE/PubMed, EMBASE, and Cochrane Libraries using the terms "botulinum neurotoxin" and "neuropathic pain" were conducted. Only class I and class II therapeutic trials, as classified by the American Academy of Neurology were included. The primary outcome measured was the difference in visual analogue scale (VAS) from pre-intervention and post intervention after 1 month. Data were analyzed for biases and heterogeneity following Cochrane and PRISMA guidelines. RESULTS: Two studies on PDN were analyzed in the meta-analysis showing improvement of 1.96 VAS points (95% CI, 3.09 to -0.84; Z score = 3.43, P < 0.001) following treatment with BTX-A. This corresponds to clinically significant improvement of "minimum change in pain." The adverse effects of infection at injection site was not statistically significant (P = 0.49). BTX-A may be effective for PDN. CONCLUSION: Tests for significance, low overall risk of bias, and almost no statistical heterogeneity suggests that there is a correlation between BTX-A and improvement of pain scores in PDN. Further large-scale controlled trials are needed. PMID- 25800041 TI - Long-term survival after resection for non-pancreatic periampullary cancer followed by adjuvant intra-arterial chemotherapy and concomitant radiotherapy. AB - BACKGROUND: There is no consensus regarding the optimal adjuvant treatment after resection of non-pancreatic periampullary adenocarcinoma (NPPC; distal common bile duct, ampulla, duodenum). OBJECTIVES: The present study was conducted to evaluate the impacts on longterm survival and recurrence of adjuvant intra arterial chemotherapy (IAC) and concomitant radiotherapy (RT) in patients submitted to resection for NPPC or pancreatic ductal adenocarcinoma (PDAC) in a randomized controlled trial. METHODS: A total of 120 patients with PDAC (n = 62) or NPPC (n = 58) were prestratified at a ratio of 1:1 for tumour origin and randomized. Half of these patients were treated with adjuvant IAC/RT and the other half were treated with surgery alone. Follow-up was completed for all patients up to 5 years after resection or until death. RESULTS: There was no survival benefit in either the whole group (primary endpoint) or the PDAC group after IAC/RT. In the NPPC group, longterm survival was observed in 10 patients in the IAC/RT group and five patients in the control group: median survival was 37 months and 28 months, respectively. The occurrence of liver metastases was reduced by IAC/RT from 57% to 29% (P = 0.038). Cox regression analysis revealed a substantial effect of IAC/RT on survival (hazard ratio: 0.44, 95% confidence interval 0.23-0.83; P = 0.011). CONCLUSIONS: This longterm analysis shows that median and longterm survival were improved after IAC/RT in patients with NPPC, probably because of the effective and sustained reduction of liver metastases. The present results illustrate that NPPC requires an adjuvant approach distinct from that in pancreatic cancer and indicate that further investigation of this issue is warranted. PMID- 25800042 TI - 67-kDa Laminin receptor contributes to hypoxia-induced migration and invasion of trophoblast-like cells by mediating matrix metalloproteinase-9. AB - Insufficient trophoblast invasion often occurs in patients experiencing preeclampsia. The 67-kDa laminin receptor (LR1) is a multifunctional protein that binds to laminin and interacts with the extracellular matrix. We recently demonstrated that LR1 is implicated in trophoblast migration and invasion. However, whether LR1 is involved in hypoxia-mediated trophoblastic invasion remains unclear and requires further investigation. This study demonstrates that two trophoblast-like cell lines (JEG3 and BeWo cells) cultured at 3% oxygen exerted enhanced migratory and invasive capabilities as compared with their counterparts exposed to 20% oxygen. LR1 expression was increased in hypoxic JEG3 cells but decreased after transfection with hypoxia-inducible factor 1 alpha (HIF 1alpha) specific siRNA. Moreover, shRNA targeting LR1 mRNA significantly inhibited hypoxia-induced increase in matrix metalloproteinase (MMP)-9 activity in JEG3 cells. Forced overexpression of LR1 augmented JEG3 cell migration and invasion, and enhanced MMP-9 expression and activity. Additionally, the blockade of the MMP-9 effect with its neutralizing antibody reduced LR1 elevation-promoted trophoblastic invasion. In summary, this study demonstrates that LR1 contributes to hypoxia-induced migration and invasion of trophoblast cells at least partly by mediating MMP-9 in vitro. PMID- 25800043 TI - Heart rate recovery after the 6-min walk test is related to 6-min walk distance and percutaneous oxygen saturation recovery in patients with COPD. AB - Heart rate recovery (HRR) after maximal load exercise affects mortality in chronic obstructive pulmonary disease (COPD). However, the associations of clinical characteristics with HRR after the 6-min walk test (6MWT), which is defined as a submaximal load test, remain unclear. We showed that HRR in patients with COPD after 6MWT was related to 6-min walk distance and percutaneous oxygen saturation recovery. HRR after the 6MWT may be useful to assess exercise capacity in COPD. PMID- 25800046 TI - Distribution of ?(9)-Tetrahydrocannabinol and 11-Nor-9-Carboxy-?(9) Tetrahydrocannabinol Acid in Postmortem Biological Fluids and Tissues From Pilots Fatally Injured in Aviation Accidents. AB - Little is known of the postmortem distribution of ?(9)-tetrahydrocannabinol (THC) and its major metabolite, 11-nor-9-carboxy-?(9)-tetrahydrocannabinol (THCCOOH). Data from 55 pilots involved in fatal aviation accidents are presented in this study. Gas chromatography/mass spectrometry analysis obtained mean THC concentrations in blood from multiple sites, liver, lung, and kidney of 15.6 ng/mL, 92.4 ng/g, 766.0 ng/g, 44.1 ng/g and mean THCCOOH concentrations of 35.9 ng/mL, 322.4 ng/g, 42.6 ng/g, 138.5 ng/g, respectively. Heart THC concentrations (two cases) were 184.4 and 759.3 ng/g, and corresponding THCCOOH measured 11.0 and 95.9 ng/g, respectively. Muscle concentrations for THC (two cases) were 16.6 and 2.5 ng/g; corresponding THCCOOH, "confirmed positive" and 1.4 ng/g. The only brain tested in this study showed no THC detected and 2.9 ng/g THCCOOH, low concentrations that correlated with low values in other specimens from this case. This research emphasizes the need for postmortem cannabinoid testing and demonstrates the usefulness of a number of tissues, most notably lung, for these analyses. PMID- 25800045 TI - Topical Citrullus colocynthis (bitter apple) extract oil in painful diabetic neuropathy: A double-blind randomized placebo-controlled clinical trial. AB - BACKGROUND: The aim of the present study was to examine the safety and efficacy of a topical formulation of Citrullus colocynthis in patients with painful diabetic polyneuropathy (PDPN). METHODS: The study was designed as a two-arm double-blind randomized placebo-controlled clinical trial using a parallel design. Sixty patients with PDPN were randomly allocated to receive either a topical formulation of C. colocynthis or placebo (1:1 allocation ratio) for 3 months. Patients were evaluated before and after the intervention using the neuropathic pain scale, electrodiagnostic findings, World Health Organization Biomedical Research and Education Foundation (BREF) quality of life (WHOQOL-BREF) scores, and reported adverse events. RESULTS: There was a significantly greater decrease in mean pain score after 3 months in the C. colocynthis (-3.89; 95% confidence interval [CI] -3.19, -4.60) than placebo (-2.28; 95% CI -1.66, -2.90) group (P < 0.001). Mean changes in nerve conduction velocity of the tibial nerve, distal latency of the superficial peroneal nerve and sural nerve, and sensory amplitude of the sural nerve were significantly higher in the intervention than placebo group (P < 0.001) in favour of the intervention. In the different domains of WHOQOL-BREF, there was a significant improvement only for the mean score in the physical domain. CONCLUSIONS: Application of a topical formulation of C. colocynthis fruit extract can decrease pain in patients with PDPN. It also may have some uncertain effects on nerve function and the physical domain of quality of life, which require further investigation in studies with larger sample sizes and of longer duration. PMID- 25800047 TI - Bacillus amyloliquefaciens as prophylactic treatment for Clostridium difficile associated disease in a mouse model. AB - BACKGROUND AND AIM: Probiotics might offer an attractive alternative for standard antibiotic therapy to treat Clostridium difficile infections (CDI). We specifically selected a Bacillus amyloliquefaciens strain for its high in vitro antibacterial activity against C. difficile and tested its efficacy to prevent CDI in a mouse model. METHODS: B. amyloliquefaciens supernatant was tested against a large collection of C. difficile strains using an agar well diffusion test. B. amyloliquefaciens was orally administered to C57BL/6 mice in which CDI was induced using C. difficile VPI 10463, and its effect was compared with control mice receiving no treatment and mice receiving Saccharomyces boulardii. Mice were followed up daily for signs of disease including weight loss. At necropsy, the colon was collected and subjected to histopathological analysis. C. difficile toxin A/B levels and colon weight/length and colon/body weight ratios were calculated. RESULTS: B. amyloliquefaciens supernatant was able to inhibit the growth of all C. difficile strains. Results of the in vivo trial indicated a significant weight loss for untreated and S. boulardii-treated mice as compared to B. amyloliquefaciens-treated mice. C. difficile toxin A and B levels were significantly higher for untreated and S. boulardii-treated mice than B. amyloliquefaciens-treated mice. A significantly lower degree of colon damage was detected for B. amyloliquefaciens-treated mice as compared to untreated and S. boulardii-treated mice, based on histopathological analysis, colon weight/length and colon/body weight ratios. CONCLUSION: Administration of B. amyloliquefaciens was successful in preventing CDI in a mouse model. PMID- 25800044 TI - Microglial M1/M2 polarization and metabolic states. AB - Microglia are critical nervous system-specific immune cells serving as tissue resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison with peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by LPS or IFN-gamma to an M1 phenotype for expression of pro inflammatory cytokines or by IL-4/IL-13 to an M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and their relationship to mitochondrial metabolism. Additional supporting experimental data are provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL-13 (M2) polarization. PMID- 25800049 TI - Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. AB - A systematic review and meta-analysis of observational studies were conducted to quantify the association between sickle cell disease in pregnancy and adverse maternal and perinatal outcomes. Data sources (Medline, Embase, Maternity and Infant care, Cochrane, Web of Science, Popline) were searched for publications to June 2014. Eligibility criteria included observational studies reporting maternal and perinatal health outcomes in pregnant women with sickle cell disease against a comparative group of pregnant women without sickle cell disease. Twenty-one studies (including 26,349 women with sickle cell disease; 26,151,746 women without sickle cell disease) were eligible for inclusion. Pregnancies in women with HbSS genotype, compared with women without sickle cell disease, were at increased risk of maternal mortality (relative risk [RR], 5.98; 95% confidence interval [CI], 1.94-18.44), preeclampsia (RR, 2.43; 95% CI, 1.75-3.39), stillbirth (RR, 3.94; 95% CI, 2.60-5.96), preterm delivery (RR, 2.21; 95% CI, 1.47-3.31), and small for gestational age infants (RR, 3.72; 95% CI, 2.32-5.98). Meta-regression demonstrated that genotype (HbSS vs HbSC), low gross national income, and high study quality were associated with increased RRs. Despite advances in the management of sickle cell disease, obstetrics, and neonatal medicine, pregnancies complicated by the disease remain associated with increased risk of adverse maternal and perinatal outcomes. PMID- 25800048 TI - PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. AB - Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint augments antitumor immunity and induces durable responses in patients with solid cancers, but data on clinical efficacy in leukemias are sparse. Chronic lymphocytic leukemia (CLL) is associated with a tumor-supportive microenvironment and a dysfunctional immune system, as shown by "exhausted" T cells, defective immunologic synapse formation, and immunosuppressive myeloid cells. These defects involve aberrant expression of PD-L1 and are closely mirrored in the Eu-TCL1 mouse model for CLL. In this study, we treated mice after adoptive transfer of Eu-TCL1 CLL with PD-L1-blocking antibodies, which prevented CLL development and was accompanied by a reactivation of immune effector functions. This included restoration of mature macrophages and major histocompatibility complex class II-expressing dendritic cells and prevention of aberrant and exhaustion-like T-cell phenotypes. In addition, PD-L1 blockade restored CD8 T-cell cytotoxicity and immune synapse formation and normalized T cell cytokines and proliferation ex vivo and in vivo. Our data demonstrate that early PD-L1 blockade effectively corrects leukemia-induced immune dysfunction and thus prevents CLL development in mice. Targeting PD-L1/PD-1 interactions should therefore be further explored in clinical studies with CLL patients, ideally in combination with novel compounds to help eliminate CLL. PMID- 25800051 TI - Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. AB - Nucleophosmin-1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). Addition of retinoic acid (RA) to chemotherapy was proposed to improve survival of some of these patients. Here, we found that RA or arsenic trioxide synergistically induce proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. NPM1 mutation not only delocalizes NPM1 from the nucleolus, but it also disorganizes promyelocytic leukemia (PML) nuclear bodies. Combined RA/arsenic treatment significantly reduced bone marrow blasts in 3 patients and restored the subnuclear localization of both NPM1 and PML. These findings could explain the proposed benefit of adding RA to chemotherapy in NPM1 mutant AMLs, and warrant a broader clinical evaluation of regimen comprising a RA/arsenic combination. PMID- 25800050 TI - Platelet-delivered ADAMTS13 inhibits arterial thrombosis and prevents thrombotic thrombocytopenic purpura in murine models. AB - ADAMTS13 metalloprotease cleaves von Willebrand factor (VWF), thereby inhibiting platelet aggregation and arterial thrombosis. An inability to cleave ultralarge VWF resulting from hereditary or acquired deficiency of plasma ADAMTS13 activity leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (TTP). Plasma exchange is the most effective initial therapy for TTP to date. Here, we report characterization of transgenic mice expressing recombinant human ADAMTS13 (rADAMTS13) in platelets and its efficacy in inhibiting arterial thrombosis and preventing hereditary and acquired antibody-mediated TTP in murine models. Western blotting and fluorescent resonance energy transfer assay detect full length rADAMTS13 protein and its proteolytic activity, respectively, in transgenic (Adamts13(-/-)Plt(A13)), but not in wild-type and Adamts13(-/-), platelets. The expressed rADAMTS13 is released on stimulation with thrombin and collagen, but less with 2MesADP. Platelet-delivered rADAMTS13 is able to inhibit arterial thrombosis after vascular injury and prevent the onset and progression of Shigatoxin-2 or recombinant murine VWF-induced TTP syndrome in mice despite a lack of plasma ADAMTS13 activity resulting from the ADAMTS13 gene deletion or the antibody-mediated inhibition of plasma ADAMTS13 activity. These findings provide a proof of concept that platelet-delivered ADAMTS13 may be explored as a novel treatment of arterial thrombotic disorders, including hereditary and acquired TTP, in the presence of anti-ADAMTS13 autoantibodies. PMID- 25800052 TI - Microchannel anechoic corner for size-selective separation and medium exchange via traveling surface acoustic waves. AB - We demonstrate a miniaturized acoustofluidic device composed of a pair of slanted interdigitated transducers (SIDTs) and a polydimethylsiloxane microchannel for achieving size-selective separation and exchange of medium around polystyrene particles in a continuous, label-free, and contactless fashion. The SIDTs, deposited parallel to each other, produce tunable traveling surface acoustic waves (TSAWs) at desired locations, which, in turn, yield an anechoic corner inside the microchannel that is used to selectively deflect particles of choice from their streamlines. The TSAWs with frequency fR originating from the right SIDT and propagating left toward the microchannel normal to the fluid flow direction, laterally deflect larger particles with diameter d1 from the hydrodynamically focused sample fluid that carries other particles as well with diameters d2 and d3, such that d1 > d2 > d3. The deflected particles (d1) are pushed into the top-left corner of the microchannel. Downstream, the TSAWs with frequency fL, such that fL > fR, disseminating from the left SIDT, deflect the medium-sized particles (d2) rightward, leaving behind the larger particles (d1) unaffected in the top-left anechoic corner and the smaller particles (d3) in the middle of the microchannel, thereby achieving particle separation. A particle not present in the anechoic corner could be deflected rightward to realize twice the medium exchange. In this work, the three-way separation of polystyrene particles with diameters of 3, 4.2, and 5 MUm and 3, 5, and 7 MUm is achieved using two separate devices. Moreover, these devices are used to demonstrate multimedium exchange around polystyrene particles ~5 MUm and 7 MUm in diameter. PMID- 25800053 TI - Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. AB - Endothelial responses to fluid shear stress are essential for vascular development and physiology, and determine the formation of atherosclerotic plaques at regions of disturbed flow. Previous work identified VE-cadherin as an essential component, along with PECAM-1 and VEGFR2, of a complex that mediates flow signaling. However, VE-cadherin's precise role is poorly understood. We now show that the transmembrane domain of VE-cadherin mediates an essential adapter function by binding directly to the transmembrane domain of VEGFR2, as well as VEGFR3, which we now identify as another component of the junctional mechanosensory complex. VEGFR2 and VEGFR3 signal redundantly downstream of VE cadherin. Furthermore, VEGFR3 expression is observed in the aortic endothelium, where it contributes to flow responses in vivo. In summary, this study identifies a novel adapter function for VE-cadherin mediated by transmembrane domain association with VEGFRs. PMID- 25800054 TI - miR-501-3p mediates the activity-dependent regulation of the expression of AMPA receptor subunit GluA1. AB - The number of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in synapses determines synaptic strength. AMPAR expression can be regulated locally in dendrites by synaptic activity. The mechanisms of activity dependent local regulation of AMPAR expression, however, remain unclear. Here, we tested whether microRNAs (miRNAs) are involved in N-methyl-D-aspartate (NMDA) receptor (NMDAR)-dependent AMPAR expression. We used the 3' untranslated region of Gria1, which encodes the AMPA receptor subunit GluA1, to pull down miRNAs binding to it and analyzed these miRNAs using next-generation deep sequencing. Among the identified miRNAs, miR-501-3p is also a computationally predicted Gria1 targeting miRNA. We confirmed that miR-501-3p targets Gria1 and regulates its expression under physiological conditions. The expression of miR-501-3p and GluA1, moreover, is inversely correlated during postnatal brain development. miR 501-3p expression is up-regulated locally in dendrites through the NMDAR subunit GluN2A, and this regulation is required for NMDA-induced suppression of GluA1 expression and long-lasting remodeling of dendritic spines. These findings elucidate a miRNA-mediated mechanism for activity-dependent, local regulation of AMPAR expression in dendrites. PMID- 25800056 TI - WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility. AB - We previously identified Waf1 Cip1 stabilizing protein 39 (WISp39) as a binding partner for heat shock protein 90 (Hsp90). We now report that WISp39 has an essential function in the control of directed cell migration, which requires WISp39 interaction with Hsp90. WISp39 knockdown (KD) resulted in the loss of directional motility of mammalian cells and profound changes in cell morphology, including the loss of a single leading edge. WISp39 binds Coronin 1B, known to regulate the Arp2/3 complex and Cofilin at the leading edge. WISp39 preferentially interacts with phosphorylated Coronin 1B, allowing it to complex with Slingshot phosphatase (SSH) to dephosphorylate and activate Cofilin. WISp39 also regulates Arp2/3 complex localization at the leading edge. WISp39 KD-induced morphological changes could be rescued by overexpression of Coronin 1B together with a constitutively active Cofilin mutant. We conclude that WISp39 associates with Hsp90, Coronin 1B, and SSH to regulate Cofilin activation and Arp2/3 complex localization at the leading edge. PMID- 25800055 TI - Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia. AB - Mutations in genes essential for protein homeostasis have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Why mature neurons should be particularly sensitive to such perturbations is unclear. We identified mutations in Rab8 in a genetic screen for enhancement of an FTD phenotype associated with ESCRT-III dysfunction. Examination of Rab8 mutants or motor neurons expressing a mutant ESCRT-III subunit, CHMP2B(Intron5), at the Drosophila melanogaster neuromuscular junction synapse revealed synaptic overgrowth and endosomal dysfunction. Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5). In Rab8 mutant synapses, c-Jun N terminal kinase (JNK)/activator protein-1 and TGF-beta signaling were overactivated and acted synergistically to potentiate synaptic growth. We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants. Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes. PMID- 25800058 TI - Insertion mechanism and stability of boron nitride nanotubes in lipid bilayers. AB - We provide insight into the interaction of boron nitride nanotubes (BNNTs) with cell membranes to better understand their improved biocompatibility compared to carbon nanotubes (CNTs). Contrary to CNTs, no computational studies exist investigating the insertion mechanism and stability of BNNTs in membranes. Our molecular dynamics simulations demonstrate that BNNTs are spontaneously attracted to lipid bilayers and are stable once inserted. They insert via a lipid-mediated, passive insertion mechanism. BNNTs demonstrate similar characteristics to more biocompatible functionalized CNTs. PMID- 25800059 TI - Association between respiratory viruses and exacerbation of COPD: a case-control study. AB - BACKGROUND: Respiratory viral infection is the main cause of exacerbations of chronic obstructive pulmonary disease (COPD) in all age groups. The present study aimed to find out the association between viral infection in exacerbated and stable patients with COPD as well as evaluating the frequency of respiratory viruses in the Iranian exacerbated patients. METHODS: The study included 170 patients as the sample group with acute exacerbations and a control group consisting of 96 stable patients over a period of 3 years. Reverse transcription- nested polymerase chain reaction (RT-nested PCR) and nested PCR methods were used to diagnose the presence of 16 respiratory viruses. RESULTS: Viral infection was detected in 81 (47.6%) exacerbations and 24 (25%) stable patients (p < 0.05). Adenovirus was more frequent among the exacerbated patients than the stable patients (p < 0.05). Furthermore, influenza virus, respiratory syncytial virus, and enterovirus turned out to be the most common viruses in both groups. Moreover, respiratory viral co-infection has a possible role in exacerbation, severity, and longer hospitalization. Muscle pain and fever were found as significant symptoms in the infected patients with exacerbations. CONCLUSIONS: The current study investigated the probable roles of the respiratory viruses, and dual infections during acute exacerbations of COPD. Since climate-dependent respiratory viral incidence patterns in Iran are often dissimilar, preparing a comprehensive global model of respiratory infections with seasonal details in different geographical zones might decrease the morbidity and mortality rate in exacerbations of COPD. PMID- 25800060 TI - Composite silicon nanostructure arrays fabricated on optical fibre by chemical etching of multicrystal silicon film. AB - Integrating nanostructures onto optical fibers presents a promising strategy for developing new-fashioned devices and extending the scope of nanodevices' applications. Here we report the first fabrication of a composite silicon nanostructure on an optical fiber. Through direct chemical etching using an H2O2/HF solution, multicrystal silicon films with columnar microstructures are etched into a vertically aligned, inverted-cone-like nanorod array embedded in a nanocone array. A faster dissolution rate of the silicon at the void-rich boundary regions between the columns is found to be responsible for the separation of the columns, and thus the formation of the nanostructure array. The morphology of the nanorods primarily depends on the microstructure of the columns in the film. Through controlling the microstructure of the as-grown film and the etching parameters, the structural control of the nanostructure is promising. This fabrication method can be extended to a larger length scale, and it even allows roll-to-roll processing. PMID- 25800057 TI - YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1. AB - Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5' untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression. PMID- 25800061 TI - Pharmacogenomics of fluorouracil -based chemotherapy toxicity. AB - INTRODUCTION: 5- fluorouracil (5-FU), alone or in combination, is the most prevalent and effective chemotherapeutic agent for the treatment of cancers of the head and neck, breast, pancreas and gastrointestinal tract. AREAS COVERED: Three rare DPYD mutations, a splice mutation in intron 14 (c.1905+1G>A) and two nonsynonymous coding variants (c.1679T>G, c.2846A>T), have consistently been associated with severe 5-FU toxicity. A relatively common haplotype, hapB3, containing three intronic polymorphisms (c.483+18G>A; c.680+139G>A; c.959-51T>C) and a synonymous mutation c.1236G>A linked to c.1129-5923C>G, is a major contributor to early onset severe toxicity. TYMS VNTR 2R and TYMS-3'-UTR 6-bp ins del variants were associated with global toxicity in capecitabine-treated patients. A candidate gene study of capecitabine-related toxicity reported that the s12132152 were strongly associated with hand-foot syndrome (HFS), whereas rs7548189 was associated with diarrhea. The rs2612091 and rs2741171, which are downstream of TYMS and intronic for ENOSF1, were associated with increased global toxicity and HFS. EXPERT OPINION: Sex-dependent differences, ethnicity, cancer types and 5-FU-based chemotherapy regimens might affect the heterogeneity of genetic variants for predictive 5-FU-related toxicity. Future approaches using genome-wide association analyses may help in identifying additional candidate genes causally involved in the path mechanisms of 5-FU-related toxicity. PMID- 25800062 TI - Maintaining everyday life in a family with a dying parent: Teenagers' experiences of adapting to responsibility. AB - OBJECTIVE: Teenagers are living through a turbulent period in their development, when they are breaking away from the family to form their own identities, and so they are particularly vulnerable to the stressful situation of having a parent affected by a progressive and incurable illness. The current study sought to gain more knowledge about the ways that teenagers themselves describe living in a family with a seriously ill and dying parent. More specifically, the aims were to describe how teenagers are emotionally affected by everyday life in a family with a dying parent and to determine how they attempt to adapt to this situation. METHOD: The study employed a descriptive and interpretive design using qualitative content analysis. A total of 10 teenagers (aged 14-19 years, 7 boys and 3 girls) participated through repeated, individual, informal interviews that were carried out as free-ranging conversations. RESULTS: While contending with their own vulnerable developmental period of life, the teenagers were greatly affected by their parent's illness and took on great responsibility for supporting their parents and siblings, and for maintaining family life. Lacking sufficient information and support left them rather unprepared, having to guess and to interpret the vague signs of failing health on their own, with feelings of uncertainty and loneliness as a consequence. SIGNIFICANCE OF RESULTS: Support from healthcare professionals should be designed to help and encourage parents to have open communications about their illness with their teenaged children. Our results add further support to the literature, reinforcing the need for an approach that uses a systemic perspective and considers the family to be the appropriate unit of care and offers a suitable support system. PMID- 25800064 TI - Response to letter to the editor: Reversal by ranolazine of doxorubicin-induced prolongation in the inactivation of late sodium current in rat dorsal root ganglion neurons. PMID- 25800065 TI - A German survey of the abdominal transplantation surgical work force. AB - This manuscript reports the results of a nationwide survey of transplant surgeons in Germany, including the demographics, training, position, individual case loads, center volumes, program structure, professional practice, grade of specialization, workload, work hours, salary, and career expectations. We contacted all 32 German transplant centers that perform liver, kidney, and pancreas transplantation. Surgeons engaged in transplantation were asked to reply to the survey. Eighty-five surgeons responded, with a mean age of 44 +/- 8 years, 13% of whom were female. The median transplant frequency per active transplant surgeon was relatively low, with 16 liver transplants, 15 kidney transplants, and three pancreas transplants. The median reported center volumes were 45 liver transplants, 90 kidney transplants, and five pancreas transplants per year. Most of the surgeons reported a primary focus on hepato-pancreato-biliary surgery, and only 10% of effective work time was actually dedicated to perform transplant surgeries. The majority of respondents estimated their weekly work hours to be between 55 and 66 h. When asked about their career satisfaction and expectations, most respondents characterized their salaries as inappropriately low and their career prospects as inadequate. This survey provides a first impression of the transplant surgery work force in Germany. PMID- 25800063 TI - Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns. AB - Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (beta = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 * 10(-11); N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (beta = -0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (beta = -0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation. PMID- 25800067 TI - Irisin, a newly discovered myokine, is a novel biomarker associated with physical activity in patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise. Physical activity has been emphasized as one of the principal targets of the treatment for chronic obstructive pulmonary disease (COPD). This study was designed to evaluate the possibility of using serum irisin level as a novel biomarker associated with physical activity in patients with COPD. METHODS: We measured the serum irisin level in 72 COPD patients and 27 control subjects, and investigated its correlation to pulmonary function parameters, exercise capacity and physical activity level. In addition, we analysed the effects of acute and chronic exercise on serum irisin level. RESULTS: Fat-free mass index was not significantly different between the two study groups. However, lower serum irisin level was observed in COPD patients than in the control subjects (COPD patients: median (interquartile range) 31.6 (22.7-40.4) ng/mL; control subjects: 50.7 (39.3 65.8) ng/mL; P < 0.001). The serum irisin level did not significantly correlate with any pulmonary function parameters and 6-min walk distance. However, serum irisin level was associated with the physical activity level in all subjects. In COPD patients, acute exercise did not affect serum irisin level, but an 8-week exercise training was linked to the significant increase in its level. CONCLUSIONS: Circulating irisin could be used to evaluate physical activity in COPD patients and increased after an 8-week exercise training. Serum irisin level may prove to be a valuable biomarker in clinical follow up of COPD. PMID- 25800068 TI - The Developing Social Context of Infant Helping in Two U.S. Samples. AB - Theories about the development of helping make different assumptions about infants' everyday experiences. Yet little research has investigated early helping at home. Two studies investigated the presence, encouragement, and social reinforcement of helping in 11- to 25-month-old infants in U.S. middle-class families. In Study 1, 76 mothers provided descriptions of infant helping. Study 2 involved videotaping of naturalistic interactions in 51 families. From around the first birthday, most infants helped at home. Instances of helping were frequently accompanied by encouragement, thanking, or praising. Longitudinal and cross sectional findings were consistent with the view that family members' involvement contributes to infant helping, although the role of family members may depend on infant age. These findings have implications for theories and research about infant helping. PMID- 25800066 TI - A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma. AB - OBJECTIVES: Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU) based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. METHODS: After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). RESULTS: Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. CONCLUSIONS: This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours. PMID- 25800070 TI - One step ahead in the care of Crohn's disease. PMID- 25800071 TI - What happens when we don't operate? PMID- 25800069 TI - Decreased placental and transcellular permeation of cefuroxime in pregnant women with diabetes. AB - BACKGROUND: The present study investigated the transcellular and placental permeation of cefuroxime, an antibiotic used in cesarean sections, in pregnant women with diabetes and hypertension. METHODS: Fifty-three women scheduled for cesarean section were divided into three groups: healthy women (n = 18), women with arterial hypertension (n = 21), and women with gestational diabetes (n = 14). All women received 1.5 g, i.v., cefuroxime. Cefuroxime concentrations were measured in maternal venous plasma before, during, and after delivery, as well as in fetal umbilical cord vein and artery plasma during delivery. The effects of diabetes and hypertension on cefuroxime placental-permeation were assessed by the fetomaternal plasma concentration ratios. Pharmacokinetic non-compartmental model analyses were performed and results were compared using anova. RESULTS: Fetomaternal drug concentration ratios were lower in the diabetic group than in the hypertensive and control groups. There were no significant differences in umbilical arterial : venous plasma drug concentration ratios in the diabetic and hypertensive groups compared with the control group. Apparent volume of distribution and clearance were significantly lower in the diabetic group compared with the control and hypertensive groups. CONCLUSIONS: Diabetes led to decreased placental transfer of cefuroxime, as well as volume of distribution and clearance, but did not affect other pharmacokinetic parameters. Hypertension had no significant effect on the permeation of cefuroxime or on its pharmacokinetics. Prophylactic concentrations of cefuroxime were reached in all groups, but the dosing time of cefuroxime should not be less than 30 min or greater than 2 h prior to delivery. PMID- 25800076 TI - Dissecting Thoracic Aortic Hematoma Masquerading as Blunt Force Injury of the Neck. AB - Discoloration of the skin of the anterior and lateral neck may raise suspicion for blunt force injury, particularly cervical compression, in an unwitnessed death. We present a case of an elderly woman with an unwitnessed death at home which highlights an external examination finding of blue/purple discoloration of the skin of the neck and links this finding with those from internal examination at autopsy. Pertinent negatives include absence of conjunctival and mucosal petechiae, absence of cutaneous abrasions of the neck, and absence of contusions of the anterior neck musculature. This case illustrates a natural disease entity, spontaneous dissection of a thoracic aortic hematoma, masquerading as blunt force injury externally and highlights the importance of having an appropriate index of suspicion when triaging jurisdictional cases for postmortem examination to accurately determine cause and manner of death. PMID- 25800077 TI - Current practices for measuring mental health outcomes in the USA: International overview of routine outcome measures in mental health. AB - The prevalence and impact of mental health conditions calls for measuring the adequacy of care, but progress in measuring mental health outcomes in the USA has been uneven, with some important domains (such as employment and other measures of everyday functioning) rarely captured. Bright spots include progress in adopting uniform measures of the quality of inpatient mental healthcare and early progress in measuring adequacy of medication and psychotherapy treatment. To some extent, progress in measurement has been limited by separate governing structures and payment rules in mental health and overall health settings. This is becoming a critical problem as awareness of the scope and impact of mental health co morbidities emerges at the same time as pressures for healthcare cost controls intensify. A search for better measures may be accelerated as problems linked to co-morbid mental health problems (e.g. readmission to hospitals) come into sharper focus due to changes in healthcare financing related to the US Patient Protection and Affordable Care Act, 2010. PMID- 25800075 TI - Prevalence of CYP2C19 alleles, pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population. AB - The extent to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity between studies. We used the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method for genotyping loss of function (LOF) allele, CYP2C19*2 and gain of function (GOF) allele, CYP2C19*17 in 163 patients undergoing PCI and 165 healthy volunteers from an ethnically distinctive Bangladeshi population. Thirty-eight patients took prasugrel and 125 patients took clopidogrel among whom 30 patients had their clopidogrel active metabolites (CAM) determined by LC-MS/MS 1-1.5 h after clopidogrel intake. All patients who underwent PCI had their P2Y12 per cent inhibition (PRI) measured by VerifyNow System. The impact of different genotypes on CAM and PRI were also determined. We did not find significant variation of CYP2C19*2 (P > 0.05) and CYP2C9*17 (P > 0.05) alleles among healthy volunteers and patients. CAM concentration as well as PRI by clopidogrel varied significantly (P < 0.05) based on genotypic variation of CYP2C19*2 and CYP2C19*17 individually. Such influence was not observed in case of prasugrel. Genotypic variation did not impact PRI but as a whole PRI by prasugrel was better than that of clopidogrel (P < 0.05). Due to presence of both of alleles the effect on PRI by clopidogrel could not be predicted, effectively indicating possible involvement of other factors. Genotype guided clopidogrel dose adjustment would be beneficial and therefore we propose mandatory genotyping before clopidogrel dosing. Prasugrel proved to be less affected by genotypic variability, but due to lack of sufficient long-term toxicity data, caution would be adopted before substituting clopidogrel. PMID- 25800078 TI - Correlates of problematic unrecorded alcohol consumption in Sikkim, Northeast India - Results from a cross-sectional pilot survey. AB - The magnitude and consequences of unrecorded alcohol consumption, defined as home brewed or clandestinely produced illicit liquor or surrogate alcoholic beverage has been little investigated in India. A significant portion of all alcohol consumed globally is unrecorded, therefore these consumers constitute a significant population. Sikkim, a province in Northeast India, lies in the foothills of the Himalayas. Unrecorded alcohol use is traditionally prevalent, with more than ten types available. This study investigated correlates of problematic unrecorded alcohol consumption in rural and urban communities of Sikkim. A cross-sectional, community-based pilot survey was conducted. Intensive case-finding recruited current heavy users (at least 3 days/week) of unrecorded alcohol of either sex above 16 years of age. On enrolment, participants responded to a socio-demographic instrument including 12 questions on their pattern of alcohol consumption and a 4-item CAGE questionnaire. Alcohol problems exist significantly among the young adult population. Although consumption of unrecorded alcohol is traditional in Sikkim, it has emerged as an important public health problem, with alarmingly high rates of problematic consumption. This is also expected to have significant economic costs. Therefore, prevention and treatment measures are an urgent need as well as policy decisions on production and sales of unrecorded alcohol. PMID- 25800080 TI - Routine outcome measures in Germany. AB - The German healthcare system offers comprehensive coverage for people with mental illness including inpatient, day hospital and outpatient services. These services are primarily financed through the statutory health and pension insurances. According to legal regulations, providers are required to base their services on current scientific evidence and to continuously assure the quality of their services. This paper gives an overview of recent initiatives to develop, evaluate and disseminate routine outcome measurement (ROM) in service settings in Germany. A large number of projects have shown outcome monitoring to be feasible, and that feedback of outcome may enhance routine care through an improved allocation of treatment resources. However, none of these initiatives have been integrated into routine care on a nationwide or trans-sectoral level, and their sustainability has been limited. This is due to various barriers in a fragmented mental health service system and to the lack of coordinated national or state-level service planning. The time is ripe for a concerted effort including policy-makers to pick up on these initiatives and move them towards wide-spread implementation in routine care accompanied by practice-oriented research including service user involvement. PMID- 25800079 TI - Online social support networks. AB - Peer support groups have a long history and have been shown to improve health outcomes. With the increasing familiarity with online social networks like Facebook and ubiquitous access to the Internet, online social support networks are becoming popular. While studies have shown the benefit of these networks in providing emotional support or meeting informational needs, robust data on improving outcomes such as a decrease in health services utilization or reduction in adverse outcomes is lacking. These networks also pose unique challenges in the areas of patient privacy, funding models, quality of content, and research agendas. Addressing these concerns while creating patient-centred, patient powered online support networks will help leverage these platforms to complement traditional healthcare delivery models in the current environment of value-based care. PMID- 25800081 TI - In situ electrical characterization of tapered InAs nanowires in a transmission electron microscope with ohmic contacts. AB - The electrical properties of segments of tapered InAs nanowires (NWs) were investigated by in situ transmission electron microscopy with simultaneous I-V measurements using good ohmic contacts, thus excluding experimental artefacts as Joule heating caused by high-resistivity contacts. At low voltage the resistivity of InAs NWs with a diameter larger than 120 nm is constant (~10(-2) Omega . cm). When the current is strongly increased a breakdown of the NW occurs close to the cathode side, whereby the main changes are an electromigration of In and a sublimation of As. The critical current density for breakdown was close to 10(6) A cm(-2) in most cases. A Joule heating and electromigration mechanism for the breakdown process is proposed. PMID- 25800082 TI - Effectiveness and safety of a prehospital program of continuous positive airway pressure (CPAP) in an urban setting. AB - BACKGROUND: Continuous positive airway pressure (CPAP) is commonly used in the treatment of acute cardiogenic pulmonary edema (ACPE) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In-hospital evidence is robust: CPAP has been shown to improve respiratory status and to reduce intubation rates. There is less evidence on prehospital CPAP, although the emergency medical services (EMS) adoption of this modality is increasing. The objectives of this study were to 1) measure the effectiveness of prehospital CPAP on morbidity, mortality, and transport times; and 2) audit the selection of patients by medics for appropriateness and safety. METHODS: We conducted a before-and-after study from August 1 to October 31 in 2010 and 2011, before and after the implementation of prehospital CPAP in a city of one million people with large rural areas. Medics were trained to apply CPAP to patients with respiratory distress and a presumed diagnosis of ACPE or AECOPD. Charts were selected using the search criteria of the chief complaint of shortness of breath, emergent transport to hospital, and any patients receiving CPAP in the field. Data extracted from ambulance call reports and hospital records were analysed with appropriate univariate statistics. RESULTS: A total of 373 patients enrolled (186 pre-non invasive ventilation [NIV] and 187 post-NIV), mean age 71.5 years, female 51.4%, and final diagnoses of ACPE 18.9%, AECOPD 21.9%. In the post group of 84 patients meeting NIV criteria, 41.6% received NIV; and of 102 patients not meeting the criteria, 5.2% received NIV. There were 12 minor adverse events in 36 applications (33.3%) as per protocol. Comparing post versus pre, there were higher rates of emergency department (ED) NIV (20.0% v. 13.4%, p<0.0001) and higher overall mortality (18.8% v. 14.9%, p<0.0001). There were no differences in ED intubation (2.1% v. 2.3%, p<0.001) and length of stay (6.8 v. 8.7 days, p=0.24). CONCLUSION: Despite the robust in-hospital data supporting its use, we could not find benefit from CPAP in our prehospital setting with respect to morbidity, mortality, and length of stay. EMS must exercise caution in making the decision to invest in the equipment and training required to implement prehospital CPAP. PMID- 25800083 TI - Challenges in the development of new therapies for bronchiectasis. AB - INTRODUCTION: Bronchiectasis is a neglected condition for which there are no licensed therapies. Increasing recognition of the disease has led to a surge in interest over recent years, with a number of active drug development programmes. AREAS COVERED: Disappointing results with therapies successful in cystic fibrosis (CF) have forced a re-evaluation of how we develop new treatments for bronchiectasis. Bronchiectasis presents a unique array of challenges. These include a heterogeneous and poorly characterized patient population, a lack of agreed standards of care and a lack of understanding of the natural history. Pre clinical development is limited by the lack of an adequate animal model of disease, and by our limited understanding of pathogenesis. There is no agreement on how to define key clinical trials end points including exacerbations and quality of life. The difficulty in translating positive Phase II data into successful Phase III trials suggests the need for better early phase trial end points. EXPERT OPINION: Extrapolating from CF and chronic obstructive pulmonary disease has been a necessity but now risks holding back development if we do not recognize the unique challenges in bronchiectasis. This article comprehensively reviews the barriers to new drug development for bronchiectasis. PMID- 25800084 TI - Transdermal contraception methods: today's patches and new options on the horizon. AB - INTRODUCTION: The first contraceptive patch with ethinyl estradiol (EE) and norelgestromin in the United States demonstrated that there was a tremendous interest in topical methods, which could provide patient convenience, steady state hormonal levels and reassurance of ongoing coverage, while maintaining efficacy and good bleeding patterns. Unfortunately, concerns about increased risk of venous thromboembolism (VTE) risk diminished its popularity. Another version in Europe and Canada had slightly lower estrogen doses, but questions were raised about its VTE risk too based on its progestin. To fill that gap, two new contraceptive patches with lower estrogen levels have been developed and extensively tested. AREAS COVERED: This article provides a short overview of the first set of patches followed by discussions of the pharmacokinetics of the two experimental patches as well as the results of their clinical trials, including information about efficacy, bleeding patterns and tolerability. EXPERT OPINION: Given the recent increased use of first tier contraceptive methods (Intrauterine devices and implants), there may be interest in new patches. Price will influence their popularity. However, a new nondaily delivery system with lower estrogen levels will provide an important option to women. PMID- 25800085 TI - ABT-450/ ritonavir and ABT-267 in combination with ABT-333 for the treatment of hepatitis C virus. AB - INTRODUCTION: The global prevalence of chronic hepatitis C virus (HCV) is estimated to be 80 - 115 million and currently viremic infections account for 350,000 deaths annually. As the knowledge about HCV evolves, new anti-viral treatments have been developed. The primary goal of antiviral therapies has been to eradicate HCV virus from serum and achieve sustained virologic response (SVR). Historically, interferon has been a staple of nearly all HCV treatment regimens, despite significant toxic effects. AREAS COVERED: In recent years, HCV treatment has changed rapidly and significantly. All-oral treatment regimens show promise for treatment with shorter duration and more manageable side effects. New antivirals aimed at improving SVR may provide a cure to nearly all HCV-infected patients. The unique combination of ABT-450 (paritaprevir) and ABT-267 (ombitasvir) provides highly effective treatment for patients with genotype 1 HCV. This review will examine the antiviral properties, pharmacokinetics, pharmacodynamics, and side effects of these agents. EXPERT OPINION: The combination of ABT-450/r and ABT-267 has improved potency, favorable side effect profile, and low risk of resistance compared to the first-generation protease inhibitors. This combination is likely to be a major part of novel upcoming HCV treatment regimens and is likely to be widely used by clinicians. Additional data is awaited in additional patient populations, and with possible shorter treatment durations. PMID- 25800087 TI - Social radiation oncology. PMID- 25800088 TI - Dynamic Pain Phenotypes are Associated with Spinal Cord Stimulation-Induced Reduction in Pain: A Repeated Measures Observational Pilot Study. AB - OBJECTIVE: Spinal cord stimulation (SCS) has become a widely used treatment option for a variety of pain conditions. Substantial variability exists in the degree of benefit obtained from SCS and patient selection is a topic of expanding interest and importance. However, few studies have examined the potential benefits of dynamic quantitative sensory testing (QST) to develop objective measures of SCS outcomes or as a predictive tool to help patient selection. Psychological characteristics have been shown to play an important role in shaping individual differences in the pain experience and may aid in predicting responses to SCS. Static laboratory pain-induction measures have also been examined in their capacity for predicting SCS outcomes. METHODS: The current study evaluated clinical, psychological and laboratory pain measures at baseline, during trial SCS lead placement, as well as 1 month and 3 months following permanent SCS implantation in chronic pain patients who received SCS treatment. Several QST measures were conducted, with specific focus on examination of dynamic models (central sensitization and conditioned pain modulation [CPM]) and their association with pain outcomes 3 months post SCS implantation. RESULTS: Results suggest few changes in QST over time. However, central sensitization and CPM at baseline were significantly associated with clinical pain at 3 months following SCS implantation, controlling for psycho/behavioral factors and pain at baseline. Specifically, enhanced central sensitization and reduced CPM were associated with less self-reported pain 3 months following SCS implantation. CONCLUSIONS: These findings suggest a potentially important role for dynamic pain assessment in individuals undergoing SCS, and hint at potential mechanisms through which SCS may impart its benefit. PMID- 25800089 TI - Exercise and the microbiota. AB - Sedentary lifestyle is linked with poor health, most commonly obesity and associated disorders, the corollary being that exercise offers a preventive strategy. However, the scope of exercise biology extends well beyond energy expenditure and has emerged as a great 'polypill', which is safe, reliable and cost-effective not only in disease prevention but also treatment. Biological mechanisms by which exercise influences homeostasis are becoming clearer and involve multi-organ systemic adaptations. Most of the elements of a modern lifestyle influence the indigenous microbiota but few studies have explored the effect of increased physical activity. While dietary responses to exercise obscure the influence of exercise alone on gut microbiota, professional athletes operating at the extremes of performance provide informative data. We assessed the relationship between extreme levels of exercise, associated dietary habits and gut microbiota composition, and discuss potential mechanisms by which exercise may exert a direct or indirect influence on gut microbiota. PMID- 25800090 TI - Pax3 and Pax7 play essential safeguard functions against environmental stress induced birth defects. AB - Exposure to environmental teratogenic pollutant leads to severe birth defects. However, the biological events underlying these developmental abnormalities remain undefined. Here, we report a molecular link between an environmental stress response pathway and key developmental genes during craniofacial development. Strikingly, mutant mice with impaired Pax3/7 function display severe craniofacial defects. We show that these are associated with an upregulation of the signaling pathway mediated by the Aryl hydrocarbon receptor (AHR), the receptor to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), revealing a genetic interaction between Pax3 and AHR signaling. Activation of AHR signaling in Pax3 deficient embryos drives facial mesenchymal cells out of the cell cycle through the upregulation of p21 expression. Accordingly, inhibiting AHR activity rescues the cycling status of these cells and the facial closure of Pax3/7 mutants. Together, our findings demonstrate that the regulation of AHR signaling by Pax3/7 is required to protect against TCDD/AHR-mediated teratogenesis during craniofacial development. PMID- 25800092 TI - Severe small bowel pneumatosis in adult heart transplant recipient. PMID- 25800091 TI - Hierarchical microtubule organization controls axon caliber and transport and determines synaptic structure and stability. AB - The dimensions of axons and synaptic terminals determine cell-intrinsic properties of neurons; however, the cellular mechanisms selectively controlling establishment and maintenance of neuronal compartments remain poorly understood. Here, we show that two giant Drosophila Ankyrin2 isoforms, Ank2-L and Ank2-XL, and the MAP1B homolog Futsch form a membrane-associated microtubule-organizing complex that determines axonal diameter, supports axonal transport, and provides independent control of synaptic dimensions and stability. Ank2-L controls microtubule and synaptic stability upstream of Ank2-XL that selectively controls microtubule organization. Synergistically with Futsch, Ank2-XL provides three dimensional microtubule organization and is required to establish appropriate synaptic dimensions and release properties. In axons, the Ank2-XL/Futsch complex establishes evenly spaced, grid-like microtubule organization and determines axonal diameter in the absence of neurofilaments. Reduced microtubule spacing limits anterograde transport velocities of mitochondria and synaptic vesicles. Our data identify control of microtubule architecture as a central mechanism to selectively control neuronal dimensions, functional properties, and connectivity. PMID- 25800093 TI - CD83 is required for the induction of protective immunity by a DNA vaccine in a teleost model. AB - In mammals, CD83 is a surface marker on mature dendritic cells and vital to lymphocyte activation. In teleost, studies on the function of CD83 are very limited. In this study, we examined the potential involvement of turbot (Scophthalmus maximus) CD83, SmCD83, in vaccine-induced immunity. For this purpose, turbot were immunized with pORF75, a DNA vaccine against megalocytivirus, in the presence or absence of pSmCD83, a plasmid that constitutively expresses SmCD83. Immune response and protection analysis showed that the presence of pSmCD83 significantly (i) enhanced the activation of head kidney macrophages (HKM) and immune gene expression, (ii) inhibited viral replication in fish tissues following megalocytivirus challenge and increased the survival of the vaccinated fish, and (iii) stimulated production of specific serum antibody and the cytotoxicity of peripheral blood leukocytes. To further examine the effect of SmCD83, pORF75 was administered into turbot in which SmCD83 was knocked down. Subsequent analysis showed that in fish with SmCD83 knockdown, vaccine-induced HKM activation and antibody production were severely reduced, and, consistently, the protectivity of pORF75 was drastically decreased. Taken together, these results indicate for the first time that teleost CD83 is required for the induction of protective immune response by DNA vaccine. PMID- 25800094 TI - Non-attendance and utilization of a speech and language therapy service: a retrospective pilot study of school-aged referrals. AB - BACKGROUND: Non-attendance and inappropriate referrals affect the effective and efficient running of healthcare services. Non-engagement with speech and language therapy (SLT) services may lead to negative long-term consequences for children in need of SLT intervention. Currently there is a dearth of research on non attendance and non-engagement with SLT services. AIMS: To identify factors associated with (1) non-attendance and (2) parents' non-engagement with SLT services. METHODS & PROCEDURES: Demographic data were collected from 140 case files of children (aged 5;0-17;11 years) discharged from a public community SLT service (November 2011-October 2013) with no intervention provided. Logistic regression analyses explored relationships between demographic data and (1) non attendance and (2) non-engagement with the SLT service. OUTCOMES & RESULTS: There was an increased probability of non-attendance during winter (i.e. September February inclusive; OR = 3.14; p = 0.028) relative to summer, and with each month a child waited for SLT assessment (OR = 1.19; p = 0.066). There was decreased probability of non-attendance with children referred for speech (OR = 0.08; p = 0.011) or language difficulties (OR = 0.15; p = 0.050) relative to dysfluency. The probability of non-engagement with the SLT service increased in each of the following conditions: with each month a child waited for assessment (OR = 1.27; p = 0.004); in urban (OR = 2.40; p = 0.066) relative to rural locations; during winter (OR = 2.65; p = 0.021) relative to summer; and with referrals made by occupational therapists, physiotherapists, psychologists and social workers (OR = 18.65; p = 0.016) relative to doctor referrals. CONCLUSIONS & IMPLICATIONS: Non attendance is influenced by wait times, season and the reason for referral. Location (urban versus rural), referral source, wait times and season are factors related to non-engagement with SLT services. Targeted policies to improve efficiency and effectiveness of SLT services could be designed around these study findings. PMID- 25800095 TI - Child and Adolescent Predictors of Personality in Early Adulthood. AB - This study investigated development of the Big Five personality traits from early childhood into adulthood. An initial group of 137 Swedish children were assessed eight times between ages 2 and 29 years. Initial decreases in extraversion leveled off in early adulthood; agreeableness and conscientiousness increased from ages 2 to 29; neuroticism initially increased, leveled off in later childhood and adolescence, and decreased throughout early adulthood; while openness to experience showed an initial increase, then decreased and leveled off in early adulthood. Individual developmental trajectories varied significantly, particularly in relation to gender. Personality traits became increasingly stable, and the fact that childhood scores predicted scores in adulthood indicated that personalities are fairly stable across this portion of the life span. PMID- 25800096 TI - The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue. AB - OBJECTIVE/BACKGROUND: Matrix metalloproteinases (MMPs) play a pivotal role in the development and progression of abdominal aortic aneurysms (AAAs). The action of MMPs depends on a balance between tissue inhibitors of MMPs (TIMPs) and compounds that may prolong protease activity, such as neutrophil gelatinase-associated lipocalin (NGAL). METHODS: The study was designed to analyse gene expression and protein concentration of MMPs, TIMPs, and NGAL in AAA walls and intraluminal thrombi (ILTs) of patients on simvastatin (n = 10) and not on statins (n = 10). The patients were matched by age, sex, and AAA diameter. Expression of MMP2, MMP9, TIMP1, TIMP2, and NGAL was investigated by real time polymerase chain reaction, and MMP2, MMP9, MMP9/TIMP1, MMP9/TIMP2, and MMP9/NGAL protein levels by enzyme-linked immunosorbent assay. RESULTS: MMP2 and MMP9 protein and mRNA levels were comparable in the simvastatin and non-statin groups (p > .05); however, there was a significant decrease in TIMP1 mRNA in AAA tissue (p = .04). Moreover, a significant increase in MMP9/TIMP2 complex concentration in ILTs of patients on simvastatin was noted (median 94.71 ng/mL in the simvastatin group vs. 36.80 ng/mL in the non-statin group; p = .01). No significant difference was observed for NGAL mRNA or protein content in AAA and ILT. CONCLUSION: Simvastatin treatment in patients with AAAs may influence the concentration of proteases and their inhibitors (TIMPs) in aneurysmal wall tissue and ILTs. Thus, further studies should be undertaken to understand the different influence of statin therapy on the components of the MMP/TIMP system in AAAs and ILTs. PMID- 25800097 TI - Differential promoter activity by nucleotide substitution at a type 2 diabetes genome-wide association study signal upstream of the wolframin gene. AB - BACKGROUND: Functional knowledge of most genetic variants identified from genome wide association studies (GWAS) for type 2 diabetes (T2D) is limited. A recent T2D GWAS revealed an association signal (rs4689388) upstream of the gene encoding Wolfram syndrome 1 (WFS1) whose intrinsic nucleotide variants had been previously associated with T2D in several candidate gene analyses. The aim of the present study was to identify functional variants of the GWAS signal. METHODS: Promoter activity of luciferase reporter constructs was compared with haplotypes including variants composing a linkage disequilibrium block in the vicinity of rs4689388 in HEK293 and HepG2 cells. RESULTS: Promoter activity was highest with the most frequent haplotype (H1; ATCGT) and lowest with second most frequent haplotype (H2; GATCG), whose nucleotide alleles were all complementary to those of H1. Further analysis with artificial haplotypes revealed differential transcriptional activity by nucleotide substitution of rs4320200, rs13107806, or rs13127445 (P < 0.05). This concurred with changes in predicted transcription factor binding site by their allele substitutions. CONCLUSIONS: The previously reported GWAS signal for T2D may be identified by the differential promoter activity of rs4320200, rs13107806, and rs13127445 in the promoter of WFS1 by nucleotide substitution. PMID- 25800098 TI - Environmental and mental conditions predicting the experience of involuntary musical imagery: An experience sampling method study. AB - An experience sampling method (ESM) study on 40 volunteers was conducted to explore the environmental factors and psychological conditions related to involuntary musical imagery (INMI) in everyday life. Participants reported 6 times per day for one week on their INMI experiences, relevant contextual information and associated environmental conditions. The resulting data was modeled with Bayesian networks and led to insights into the interplay of factors related to INMI experiences. The activity that a person is engaged was found to play an important role in the experience of mind wandering, which in turn enables the experience of INMI. INMI occurrence is independent of the time of the day while the INMI trigger affects the subjective evaluation of the INMI experience. The results are compared to findings from earlier studies based on retrospective surveys and questionnaires and highlight the advantage of ESM techniques in research on spontaneous experiences like INMI. PMID- 25800100 TI - Molecular detection and characterization of Hepatozoon spp. in dogs from the central part of Turkey. AB - Canine hepatozoonosis is a tick-borne protozoal disease caused by Hepatozoon spp. Two species of Hepatozoon are currently known to infect dogs as Hepatozoon canis and H. americanum. Although H. canis generally causes a chronic infection with relatively mild clinical alterations compared to H. americanum, infection by H. canis can be life-threatening. The disease is widespread in USA, Africa, Europe, South America, and Asia. To determine the frequency of infection with Hepatozoon spp. in stray dogs from Central Anatolia Region of Turkey, a total of 221 blood samples collected over a three-year period were evaluated by using genus specific Polymerase Chain Reaction (PCR) designed to amplify a fragment of 666bp located in 18 S rRNA gene of Hepatozoon spp. Eight (3.61%) blood samples were positive for Hepatozoon spp. For the classification of species, all positive PCR products were purified with a PCR purification kit and sequenced. Sequencing results of eight representative amplicons indicated that 6 were 98-99% identical to the sequence of H. canis and the other 2 sequences were 95-97% identical to the sequence of Hepatozoon spp. So it was named Hepatozoon sp. MF. A phylogenetic tree was constructed from the sequences of the tick-borne agents identified previously and in this study using the neighbor-joining method. The nucleotide sequences were compared to the H. canis sequences reported in Turkey using the nucleotide Basic Local Alignment Search Tool (BLAST) program. The results of this study are significant in terms of the presence of a novel canine Hepatozoon genotype. PMID- 25800099 TI - Rickettsial agents in avian ixodid ticks in northeast Brazil. AB - Birds are important in the maintenance and spread of ticks and tick-borne diseases. In this context we screened birds in the Atlantic forest north of the Sao Francisco River and Caatinga in northeast Brazil. In the Atlantic forest Amblyomma longirostre, Amblyomma nodosum, Amblyomma varium and Amblyomma auricularium were identified. A. longirostre was infected by "Candidatus Rickettsia amblyommii" and A. nodosum by a Rickettsia parkeri-like agent. In Caatinga, Amblyomma parvum and A. auricularium were identified. A. auricularium was infected by "Ca. R. amblyommii" and Rickettsia bellii. "Canditatus Rickettsia andenae" was also identified in A. parvum collected from birds in Caatinga. In addition, Rickettsia sp. genotype AL was identified in A. varium collected on the clothes of the field team in one area of Atlantic forest. Here we provide a series of new host records for several Neotropical Amblyomma species and document rickettsial infections of "Ca. R. amblyomii" and a R. parkeri-like agent in Paraiba State, and R. bellii and "Ca. R. andenae" in Bahia State. For the first time we provide information regarding the infection of A. varium by "Ca. R. amblyommii". PMID- 25800103 TI - Eruptive disseminated porokeratosis associated with corticosteroid-induced immunosuppression. AB - Eruptive disseminated porokeratosis (EDP) is a disease that presents clinically with sudden onset of erythematous papules and plaques, with a ridge-like border histologically represented by a cornoid lamella. We report a case of EDP occurring in a 39-year-old woman 3 days after completion of a 2-week course of oral corticosteroid therapy for an acute asthma exacerbation. The patient was treated with emollients and sun protection. Unlike the more chronic disseminated superficial (actinic) porokeratosis, EDP secondary to immunosuppression from corticosteroid therapy has very rarely been reported in the dermatological literature. PMID- 25800101 TI - Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients. AB - The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS (KRAS/NRAS) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti-EGFR antibody therapy may be ineffective: First, anti-EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti-EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele-specific PCR-based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin-fixed, paraffin-embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices. PMID- 25800104 TI - Anticoagulant rodenticide toxicity in six dogs presenting for ocular disease. AB - OBJECTIVE: To describe cases of suspected anticoagulant rodenticide toxicity manifesting with predominantly ocular signs. MATERIALS AND METHODS: Six canine cases that presented to veterinary referral hospitals for ocular abnormalities and were diagnosed with suspected or confirmed anticoagulant rodenticide ingestion were reviewed for commonalities in presentation and outcome. RESULTS: Five dogs had unilateral ocular signs and one dog had bilateral manifestations. Signs included subconjunctival hemorrhage, exophthalmos, and commonly orbital pain without other significant physical examination findings. Prothrombin time was measured in 5 of 6 dogs and was prolonged in all. Partial thromboplastin time was measured in 4 of 6 dogs and was prolonged in all. Complete blood cell count and serum chemistry profiles demonstrated mild, if any, abnormalities. Five dogs had known anticoagulant rodenticide exposure, and rodenticide ingestion was suspected in 1 additional case based on clinical signs, clinical pathologic abnormalities, and response to treatment. Five of 6 cases were hospitalized overnight for plasma transfusions along with oral or injectable vitamin K1 , and all dogs were treated with oral vitamin K1 for 30 days. All dogs experienced complete resolution of clinical signs within 6 weeks of initiating treatment. CONCLUSIONS: Anticoagulant rodenticide toxicity can present with predominantly ocular manifestations. Rodenticide ingestion should be considered in dogs with unilateral or bilateral subconjunctival hemorrhage, exophthalmos, and orbital pain. PMID- 25800105 TI - Evaluation of the current opioid misuse measure among substance use disorder treatment patients. AB - The Current Opioid Misuse Measure (COMM) has demonstrated promising psychometric properties among pain clinic and primary care patients. Given the high prevalence of the nonmedical use of prescription opioids among substance use disorder patients, the COMM may also be useful in substance use disorder treatment settings. The purpose of this study was to assess the factor structure and validity of the COMM in a sample of substance use disorder patients. Participants (n = 351) were recruited from a large residential substance use disorder treatment center and completed the COMM and several questionnaires assessing various substance use and health functioning characteristics. Factor analyses yielded a two-factor solution; however, each of the items in the second factor cross-loaded onto the first factor and just one factor was retained. To provide support for this new 11-item COMM, we found that higher scores on this COMM were associated with greater drug use severity, greater endorsement of positive, negative, and pain relief outcome expectancies related to opioid use, increased pain intensity, and decreased physical and mental health functioning. These findings provide initial support for the psychometric properties of this version of the COMM adapted for substance use disorder treatment settings. Given its promising psychometric properties, the 11 items of the COMM to evaluate the nonmedical use of prescription opioids have potential utility among substance use disorder patients. The COMM could be used to examine nonmedical use over the course of treatment and to aid treatment planning. It could also be used in research as an outcome measure. PMID- 25800106 TI - Predictive Utility of Alcohol Use Disorder Symptoms Across Race/Ethnicity. AB - Research has shown differences in alcohol use and problems across race/ethnicity. This study examines whether there are differential effects of alcohol use disorder (AUD) symptoms on drinking outcomes across race/ethnicity. Data from 1483 patients admitted to a hospital for treatment of an injury were utilized (19% Black, 45% non-Latino White, and 36% Latino). AUD symptoms and race/ethnicity reported at baseline and their interaction were the predictor variables. Drinking patterns and associated problems measured at the 6- and 12 month follow-up were the outcome variables of interest. Linear regression was the analytic method employed. Endorsement of "spending a great deal of time to obtain, use, or recover from effects of drinking," "craving," "failure to fulfill major role obligations," and "alcohol use in physically hazardous situations" at baseline was associated with greater levels of subsequent alcohol use and alcohol related problems at both 6- and 12-month follow-ups, regardless of race/ethnicity. Endorsement of "important social, occupational, or recreational activities given up because of drinking" was differentially associated with greater alcohol-related problems at both 6- and 12-month follow-ups dependent on race/ethnicity. Follow-up analyses indicated that this symptom was a significant predictor of alcohol problems among Latino and Black participants, but not non Latino White participants. Brief interventions targeting these AUD symptoms could increase the effectiveness of brief motivational interventions among different racial/ethnic groups. PMID- 25800107 TI - Hyperascyrones A-H, polyprenylated spirocyclic acylphloroglucinol derivatives from Hypericum ascyron Linn. AB - Eight polyprenylated spirocyclic acylphloroglucinol derivatives (PSAPs), hyperascyrones A-H, were isolated from the aerial parts of Hypericum ascyron Linn., together with six known analogs. Their structures were established by spectroscopic analyses including HRESIMS, 1D and 2D NMR, and their absolute configurations were determined by electronic circular dichroism calculations (ECD, Gaussian 09). Structures of previously reported tomoeones C, D, G, and H were revised. Hyperascyrones A-H were evaluated for their cytotoxic and anti-HIV 1 activities, with hyperascyrones C and G exhibiting significant cytotoxicities against HL-60 cell lines with IC50 values of 4.22 and 8.36 MUM, respectively. In addition, the chemotaxonomic significance of these compounds was also discussed. PMID- 25800108 TI - The role of allopregnanolone in the anxiolytic-like effect of free and easy wanderer plus (FEWP), a polyherbal preparation. AB - Anxiety disorders are the serious and burdensome psychiatric illnesses, which are closely correlated with allopregnanolone. The down-regulation of allopregnanolone biosynthesis has been implicated as the possible contributor to the aetiology of anxiety disorders. Free and easy wanderer plus (FEWP) is a well-known traditional Chinese medicine that had been shown to be effective in various mood disorders. The purpose of the present study was to evaluate the anxiolytic-like effect of FEWP and its association with the level of allopregnanolone in the brain. The animal behavioral tests were processed by the acute FEWP (2.5, 5 and 10mg/kg, p.o.) treatment. It had been shown that FEWP produced anxiolytic-like effects in behavioral models, including novelty suppressed feeding (5, 10mg/kg, p.o.), Vogel type conflict test (10mg/kg, p.o.), elevated plus-maze test (5, 10mg/kg, p.o.). The animals were decapitated after the end of the behavioral tests and measured the allopregnanolone level of the prefrontal cortex and hippocampus by enzyme linked immunosorbent assay (ELISA). The allopregnanolone level of the prefrontal cortex and hippocampus was increased by administration of FEWP (5, 10mg/kg, p.o.). Overall, these results indicated that FEWP exerts anxiolytic-like effects that were associated with the stiumlation of the allopregnanolone biosynthesis. PMID- 25800109 TI - Effects of prostaglandin E1 plus methylcobalamin alone and in combination with lipoic acid on nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis. AB - This report was to evaluate the efficacy of lipoic acid, prostaglandin E1 and methylcobalamin (L+P+M) for the treatment of diabetic peripheral neuropathy (DPN) in comparison with that of prostaglandin E1 plus methylcobalamin (P+M), in order to provide the basis and reference for clinical rational drug use. Randomized controlled trials (RCTs) of L+P+M for DPN published up to 3rd August, 2014 were searched. A random or fixed effect model was used to analyze outcomes which were expressed as risk ratios (RRs) or mean difference (MD) with a 95% confidence interval (CI). Eighteen RCTs with 1410 participants were included. Clinical efficacy of L+P+M therapy was significantly better than P+M therapy (fifteen trials; RR 1.32, 95% CI 1.24-1.41, P<0.00001, I(2)=32%). As compared with P+M therapy, the pooled effects of L+P+M therapy on nerve conduction velocities (NCVs) were (fifteen trials; MD 4.70, 95% CI 3.77-5.63, P<0.00001, I(2)=79%) for median MNCV, (thirteen trials; MD 4.73, 95% CI 3.69-5.77, P<0.00001, I(2)=85%) for median SNCV, (sixteen trials; MD 4.22, 95% CI 3.32-5.12, P<0.00001, I(2)=83%) for peroneal MNCV, (fourteen trials; MD 3.09, 95% CI 2.04-4.14, P<0.00001, I(2)=82%) for peroneal SNCV. There was no serious adverse events associated with drugs intervention. L+P+M therapy was superior to P+M therapy for improvement of clinical efficacy and NCVs in DPN patients. These findings should be further verified by high-quality RCTs. PMID- 25800110 TI - The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice. AB - Increasing evidence shows that inflammation may contribute to the pathophysiology of depression. Apigenin, one type of natural flavone, has a number of biological actions including anti-inflammatory effects. Although it has potential antidepressant activity in a chronic mild stress model, the mechanisms of antidepressant effect for apigenin remain unclear. Here, we examined the effects of apigenin on lipopolysaccharide (LPS)-induced depressive-like behavior in male mice. A single administration of LPS (0.5mg/kg, i.p.) increased the immobility time in the tail suspension test (TST) and reduced sucrose preference without changing spontaneous locomotor activity in open field test (OFT). Pre-treatment with apigenin (25, 50mg/kg, i.p.) or fluoxetine (positive control drug, 20mg/kg, i.p.) once daily for 7 consecutive days prevented the abnormal behavior induced by LPS. Apigenin or fluoxetine also effectively attenuated LPS-induced production of pro-inflammatory cytokines IL-1beta (interleukin-1beta) and TNF-alpha (tumor necrosis factor-alpha). Moreover, apigenin or fluoxetine significantly suppressed the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at both the mRNA and protein level via the modulation of nuclear factor-kappaB (NF-kappaB) activation in the prefrontal cortex. Additionally, apigenin (50mg/kg, i.p.) or fluoxetine (20mg/kg, i.p.) effectively reversed the depressive-like behavior induced by TNF-alpha (0.1fg/site, i.c.v.) without altering the locomotor activity. These results demonstrate that apigenin exhibits antidepressant-like effects in LPS treated mice, partially due to its anti inflammatory properties. PMID- 25800111 TI - Post-ischemic administration of pravastatin reduces neuronal injury by inhibiting Bax protein expression after transient forebrain ischemia in rats. AB - This study investigated the neuroprotective effect of pravastatin administration after forebrain ischemia in rats. Forebrain ischemia was induced by bilateral common carotid artery occlusion and systemic hypotension for 8min. Pravastatin at 1mg/kg (pravastatin group, n=10), or an identical volume of normal saline (control group, n=10), was injected 10min, and 1-4 days after reperfusion. Arterial blood gas was analyzed 10min before ischemia onset and 10min after ischemia completion. Viable and apoptotic neuronal cells were evaluated 7 days after ischemia by hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuracil triphosphate biotin in situ nick-end labeling (TUNEL) staining of the hippocampal Cornu Ammonis area (CA1). Expression of Bcl-2 and Bax proteins was quantified by Western blot analysis. The proportion of viable neuronal cells after ischemia was greater in the pravastatin vs. control group (p<0.01), with greater expression of apoptotic cells in the control vs. pravastatin group (p<0.05). Bax protein expression was significantly decreased in the pravastatin group (p<0.05), whereas, Bcl-2 expression was increased, but not significantly (p>0.05). Our findings suggest that pravastatin administration after forebrain ischemia confers neuroprotection in rats by inhibiting Bax protein expression. PMID- 25800112 TI - A single-CRD C-type lectin from oyster Crassostrea gigas mediates immune recognition and pathogen elimination with a potential role in the activation of complement system. AB - C-type lectins (CTLs), serving as pattern recognition receptors (PRRs), are a superfamily of Ca(2+)-dependent carbohydrate-recognition proteins that participate in nonself-recognition and pathogen elimination. In the present study, a single carbohydrate-recognition domain (CRD) CTL was identified from oyster Crassostrea gigas (designated as CgCLec-2). There was only one CRD within the deduced amino acid sequence of CgCLec-2 consisting of 129 amino acid residues. A conserved EPN (Glu246-Pro247-Asn248) motif was found in Ca(2+) binding site 2 of CgCLec-2. The CgCLec-2 mRNA could be detected in all the examined tissues at different expression levels in oysters. The mRNA expression of CgCLec-2 in hemocytes was up-regulated significantly at 6 h post Vibrio splendidus challenge. The recombinant CgCLec-2 (rCgCLec-2) could bind various Pathogen-Associated Molecular Patterns (PAMPs), including lipopolysaccharide, mannan and peptidoglycan, and displayed strong binding abilities to Vibrio anguillarum, V. splendidus and Yarrowiali polytica and week binding ability to Staphylococcus aureus. It could also enhance the phagocytic activity of oyster hemocytes to V. splendidus and exhibited growth suppression activity against gram positive bacteria S. aureus but no effect on gram-negative bacteria V. splendidus. Furthermore, the interaction between rCgCLec-2 and rCgMASPL-1 was confirmed by GST Pull down. The results suggested that CgCLec-2 served as not only a PRR in immune recognition but also a regulatory factor in pathogen elimination, and played a potential role in the activation of complement system. PMID- 25800113 TI - [Functional evaluation of extrinsic compression of the left main coronary artery by a dilated pulmonary artery: Case report]. PMID- 25800114 TI - Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors. AB - We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values). PMID- 25800115 TI - Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. AB - Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported. PMID- 25800116 TI - Synthesis and optimization of picolinamide derivatives as a novel class of 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors. AB - The synthesis and structure-activity relationship of a series of 6-substituted picolinamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 are described. The optimization of the left-hand side of lead compound 1 resulted in the discovery of the highly potent, selective, and orally available inhibitor 24, which demonstrated an excellent activity in a mouse ex vivo pharmacodynamic model. Moreover, compound 24 reduced the blood glucose and improved the lipid profiles in ob/ob mice after oral administration. PMID- 25800117 TI - Radial head implant diameter: A biomechanical assessment of the forgotten dimension. AB - BACKGROUND: The effect of radial head implant length has been a subject of controversy, with the impact on clinical outcomes and forearm biomechanics being extensively studied. However, the impact of radial head diameter on forearm load transfer has not been examined. This study examined the influence of radial head implant diameter on forearm load transfer as measured by interosseous membrane tension and radiocapitellar joint contact characteristics. METHODS: An upper extremity simulator was utilized to study five cadaveric specimens with three different radial head implant diameters (-2mm, anatomically sized, +2mm). A load sensing device was woven into the fibers of the central band of the interosseous membrane to quantify its tension. An inter-positional pressure measurement sensor was used to quantify radiocapitellar joint contact force and area. Axial loads of 160N were applied to the forearm during forearm rotation with the elbow at 90 degrees of flexion. FINDINGS: Changes to the radial head diameter did not change radiocapitellar contact force or area (P=0.4 and P=0.5 respectively). There was a linear relationship between radial head diameter and interosseous membrane tension; increasing radial head diameter increases the interosseous membrane tension (P=0.01). INTERPRETATION: Although radial head diameter was not found to alter radiocapitellar contact area or force, the interosseous membrane tension was impacted. After radial head arthroplasty, an increase in radial head implant diameter increases the interosseous membrane tension, with a potential for increased pain and stiffness. There is also a potential for increased proximal radioulnar joint contact pressures; resulting in stem loosening or radio-ulnar pain. PMID- 25800119 TI - Why phosphoproteomics is still a challenge. AB - Despite continuous improvements phosphoproteomics still faces challenges that are often neglected, e.g. partially poor recovery of phosphopeptide enrichment, assessment of phosphorylation stoichiometry, label-free quantification, poor behavior during chromatography, and general limitations of peptide-centric proteomics. Here we critically discuss current limitations that need consideration in both qualitative and quantitative studies. PMID- 25800118 TI - Cognitive control and schizophrenia: The greatest reliability of the Stroop task. AB - Three components of cognitive inhibition were compared in patients with schizophrenia and healthy controls. Nineteen patients with schizophrenia were compared to 30 healthy controls, matched for age, sex, and educational level. Cognitive inhibition was examined by (i) access to relevant information (Reading with distraction task), (ii) suppression of no longer relevant information (Trail Making Test B), and (iii) restraint of cognitive resources to relevant information (Stroop Test, Hayling Sentence Completion Test, Go/No-Go Test). Beck Depression Inventory, and Positive and Negative Syndrome Scale were also used. Compared to healthy controls, patients with schizophrenia and stabilized for at least 6 months were slower in the inhibition condition at the Stroop task, read more distractors at the RWD, and made more perseverative errors at the TMT, even after controlling for age, Mini-Mental State Examination score, information speed processing, and accuracy. This difference remained significant after taking into account the level of depressive symptoms and the severity of psychotic symptoms. In multivariate analyses, only the Stroop interference index explained cognitive inhibition deficit in patients with schizophrenia. The abnormal cognitive inhibition process observed in patients with schizophrenia could therefore concerns the ability to restraint, rather than the access or the suppression processes. PMID- 25800120 TI - Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles. AB - Exposure to the space radiation environment poses risks for a range of deleterious health effects due to the unique types of radiation encountered. Galactic cosmic rays are comprised of a spectrum of highly energetic nuclei that deposit densely ionizing tracks of damage along the particle trajectory. These tracks are distinct from those generated by the more sparsely ionizing terrestrial radiations, and define the geometric distribution of the complex cellular damage that results when charged particles traverse the tissues of the body. The exquisite radiosensitivity of multipotent neural stem and progenitor cells found within the neurogenic regions of the brain predispose the central nervous system to elevated risks for radiation induced sequelae. Here we show that human neural stem cells (hNSC) exposed to different charged particles at space relevant fluences exhibit significant and persistent oxidative stress. Radiation induced oxidative stress was found to be most dependent on total dose rather than on the linear energy transfer of the incident particle. The use of redox sensitive fluorogenic dyes possessing relative specificity for hydroxyl radicals, peroxynitrite, nitric oxide (NO) and mitochondrial superoxide confirmed that most irradiation paradigms elevated reactive oxygen and nitrogen species (ROS and RNS, respectively) in hNSC over a 1 week interval following exposure. Nitric oxide synthase (NOS) was not the major source of elevated nitric oxides, as the use of NOS inhibitors had little effect on NO dependent fluorescence. Our data provide extensive evidence for the capability of low doses of charged particles to elicit marked changes in the metabolic profile of irradiated hNSC. Radiation induced changes in redox state may render the brain more susceptible to the development of neurocognitive deficits that could affect an astronaut's ability to perform complex tasks during extended missions in deep space. PMID- 25800121 TI - Effect of co-morbidities on disease course in human immunodeficiency virus infected illicit drug users in the era of highly active antiretroviral therapy. PMID- 25800122 TI - HDAC8-deficiency causes an X-linked dominant disorder with a wide range of severity. PMID- 25800124 TI - Recent advances in endocrine metabolic immune disorders drug targeting: an editorial overview. AB - This editorial overview is aimed at reviewing all the work published by the Journal Endocrine Metabolic Immune Disorders-Drug Targets over the period 2012 2014. The main body of publications has been divided either into a section based on special issues and meeting proceedings or various specific sections according to different types of pathologies related to the field of endocrine metabolic immune disorder-drug targeting. PMID- 25800126 TI - Standard medical care for psychogenic nonepileptic seizures in Brazil. AB - Knowledge about health systems can promote implementation of more specific and strategic health practices for patients with psychogenic nonepileptic seizures (PNES). For this purpose, we surveyed the current management of PNES (standard medical care [SMC]) by Brazilian League Against Epilepsy members. Respondents reported diagnosing PNES with a mean frequency of 3patients/month. Video-EEG (vEEG) was considered the best method for the diagnosis. Respondents who have vEEG in their facilities refer to vEEG significantly more often than those who have no vEEG (p<0.001). Therefore, South and Southeast Brazil regions referred patients more frequently to vEEG than other regions (p=0.004). Psychotherapy was considered the most effective (92.2%) treatment option, followed by education (75%) and psychopharmacology (70.3%). There were no regional differences considering treatment. The study identified current national diagnostic and treatment practices across the country and identified relevant Brazilian regional differences. PMID- 25800127 TI - Comparison of coronary artery bypass graft surgery and percutaneous coronary intervention in patients with diabetes. AB - OPINION STATEMENT: The optimal revascularization strategy in patients with diabetes is controversial. The Bypass Angioplasty Revascularization Investigation (BARI) trial, done more than a decade ago, suggested a mortality benefit of coronary artery bypass graft surgery (CABG) when compared with percutaneous coronary intervention (PCI) (with plain old balloon angioplasty) in the subgroup of patients with diabetes. In addition, several observational studies and meta analyses similarly suggest a benefit of CABG over PCI in patients with diabetes. However, most of these studies compared CABG with PCI using balloon angioplasty, bare metal stents, or first-generation drug-eluting stents. In this review, we critically examine the data for optimal revascularization strategy in patients with diabetes and ask the question whether the currently available data from randomized trials that used outdated stents are applicable to current day practice. PMID- 25800128 TI - Study of Toll-like receptor and B-defensins genes expression pattern in porcine reproductive organs. AB - Toll-like receptors (TLRs) and b-defensins (BD) molecules are group of molecules that recognize various microbial components and play a crucial role in the activation of the innate immune system in vertebrate species. Although TLRs gene expression has been studied in various pig tissues, little is known about their expression in porcine reproductive tract. Concerning b-defensins genes, only BD1, 2 and 3 counterparts have been well studied in pigs' reproductive organs. The aim of this study was to investigate the expression pattern of both gene families in pigs' male and female reproductive organs, and embryos, as potential tool for further association studies in respect to immunity and disease resistance. RT-PCR analysis revealed that all of the examined TLR genes were expressed in the reproductive organs of male and female pigs, with TLR3 and TLR5 showing the higher levels and TLR9 the lowest, in all analyzed tissues. BD genes showed a different expression pattern in respect to the examined tissue. In embryos, TLR1 revealed high expression levels, while only BD3, BD108, and BD123 were found to be expressed. PMID- 25800123 TI - A systematic review and meta-analysis of physical activity and endometrial cancer risk. AB - Physical activity is related to decreased endometrial cancer risk. However, a comprehensive investigation of activity domains, intensities, time periods in life, and potential interaction with body mass index is unavailable. We performed a meta-analysis of physical activity and endometrial cancer studies published through October 2014. We identified 33 eligible studies comprising 19,558 endometrial cancer cases. High versus low physical activity was related to reduced endometrial cancer risk [relative risk (RR) = 0.80; 95% confidence interval (CI) 0.75-0.85]. The corresponding RRs for recreational activity, occupational activity, household activity, and walking were 0.84 (95% CI 0.78 0.91), 0.81 (95% CI 0.75-0.87), 0.70 (95% CI 0.47-1.02), and 0.82 (95% CI 0.69 0.97), respectively (Pdifference). Walking/biking for transportation, walking for recreation, and walking without specification revealed summary RRs of 0.70 (95% CI 0.58-0.85), 0.94 (95% CI 0.76-1.17), and 0.88 (95% CI 0.52-1.50), respectively (Pdifference). Inverse associations were noted for light (RR 0.65; 95% CI 0.49 0.86), moderate to vigorous (RR 0.83; 95 % CI 0.71-0.96), and vigorous activity (RR 0.80; 95% CI 0.72-0.90; (Pdifference). A statistically significant inverse relation was found for postmenopausal (RR 0.81; 95% CI 0.67-0.97), but not premenopausal women (RR 0.74; 95% CI 0.49-1.13; (Pdifference). Physical activity performed during childhood/adolescence, young adulthood/midlife, and older age yielded RRs of 0.94 (95% CI 0.82-1.08), 0.77 (95% CI 0.58-1.01), and 0.69 (95% CI 0.37-1.28), respectively (Pdifference). An inverse relation was evident in overweight/obese (RR 0.69; 95% CI 0.52-0.91), but not normal weight women (RR 0.97; 95% CI 0.84-1.13; (Pdifference). In conclusion, recreational physical activity, occupational physical activity, and walking/biking for transportation are related to decreased endometrial cancer risk. Inverse associations are evident for physical activity of light, moderate to vigorous, and vigorous intensities. The inverse relation with physical activity is limited to women who are overweight or obese. PMID- 25800129 TI - Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. AB - Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing-remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe. PMID- 25800130 TI - Guanfacine for the treatment of attention deficit hyperactivity disorder in children and adolescents. AB - Guanfacine is an alpha2A-adrenoreceptor agonist currently indicated for the treatment of attention deficit hyperactivity disorder (ADHD). This article reviews the chemistry, pharmacodynamics and pharmacokinetics of guanfacine, as well as the clinical trial literature on guanfacine for the treatment of ADHD in children and adolescents, mainly focusing on the use of guanfacine extended release (GXR). Six already published prospective randomized controlled trials (RCTs) and one unpublished RCT study were identified for GXR in the treatment of ADHD. All RCTs trials showed superiority over placebo on the primary outcome measure. Guanfacine, especially XR, seems to be an effective and safe treatment option for ADHD in children and adolescents. PMID- 25800132 TI - Flavonoids: true or promiscuous inhibitors of enzyme? The case of deoxyxylulose phosphate reductoisomerase. AB - Flavonoids, due to their physical and chemical properties (among them hydrophobicity and metal chelation abilities), are potential inhibitors of the 1 deoxyxylulose 5-phosphate reductoisomerase and most of the tested flavonoids effectively inhibited its activity with encouraging IC50 values in the micromolar range. The addition of 0.01% Triton X100 in the assays led however, to a dramatic decrease of the inhibition revealing that a non-specific inhibition probably takes place. Our study highlights the possibility of erroneous conclusions regarding the inhibition of enzymes by flavonoids that are able to produce aggregates in micromolar range. Therefore, the addition of a detergent in the assays prevents possible false positive hits in high throughput screenings. PMID- 25800131 TI - Eliminating antibody polyreactivity through addition of N-linked glycosylation. AB - Antibody polyreactivity can be an obstacle to translating a candidate antibody into a clinical product. Standard tests such as antibody binding to cardiolipin, HEp-2 cells, or nuclear antigens provide measures of polyreactivity, but its causes and the means to resolve are often unclear. Here we present a method for eliminating antibody polyreactivity through the computational design and genetic addition of N-linked glycosylation near known sites of polyreactivity. We used the HIV-1-neutralizing antibody, VRC07, as a test case, since efforts to increase VRC07 potency at three spatially distinct sites resulted in enhanced polyreactivity. The addition of N-linked glycans proximal to the polyreactivity enhancing mutations at each of the spatially distinct sites resulted in reduced antibody polyreactivity as measured by (i) anti-cardiolipin ELISA, (ii) Luminex AtheNA Multi-Lyte ANA binding, and (iii) HEp-2 cell staining. The reduced polyreactivity trended with increased antibody concentration over time in mice, but not with improved overall protein stability as measured by differential scanning calorimetry. Moreover, glycan proximity to the site of polyreactivity appeared to be a critical factor. The results provide evidence that antibody polyreactivity can result from local, rather than global, features of an antibody and that addition of N-linked glycosylation can be an effective approach to reducing antibody polyreactivity. PMID- 25800133 TI - Synthesis, evaluation and in silico molecular modeling of pyrroyl-1,3,4 thiadiazole inhibitors of InhA. AB - Enoyl acyl carrier protein reductase (ENR)is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents.Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA).Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4 thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods. PMID- 25800134 TI - Genomics in rugby union: A review and future prospects. AB - This article introduces some aspects of sports genomics in a rugby union context, considers the rugby-specific genetic data in the published literature and outlines the next research steps required if the potential applications of genetic technology in rugby union, also identified here, are to become possible. A substantial proportion of the inter-individual variation for many traits related to rugby performance, including strength, short-term muscle power, VO2 max, injury susceptibility and the likelihood of being an elite athlete is inherited and can be investigated using molecular genetic techniques. In sports genomics, significant efforts have been made in recent years to develop large DNA biobanks of elite athletes for detailed exploration of the heritable bases of those traits. However, little effort has been devoted to the study of rugby athletes, and most of the little research that has focused on rugby was conducted with small cohorts of non-elite players. With steadily growing knowledge of the molecular mechanisms underpinning complex performance traits and the aetiology of injury, investigating sports genomics in the context of rugby is now a viable proposition and a worthwhile endeavour. The RugbyGene project we describe briefly in this article is a multi-institutional research collaboration in rugby union that will perform molecular genetic analyses of varying complexity. Genetic tests could become useful tools for rugby practitioners in the future and provide complementary and additional information to that provided by the non-genetic tests currently used. PMID- 25800135 TI - Abnormalities of the lymphocyte subsets and their immunophenotype, and their prognostic significance in adult patients with hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a final common pathway resulting from diverse immune processes. Most of the current understanding of HLH is based on studies involving pediatric patients (pHLH). Adult HLH (aHLH) is distinct from pHLH, with less frequent genetic basis, higher frequency of chemo-resistance and a higher mortality. Immunological processes underlying aHLH are poorly understood. So far, no immunophenotypic abnormalities associated with aHLH have been described, and their etiopathologic and prognostic significance has not been explored. We reviewed all adult patients with bone marrow hemophagocytosis and identified 21 who fulfilled the criteria for HLH. We then analyzed abnormalities in their lymphocyte subsets and immunophenotype and tested association of these abnormalities with survival. Twenty of 21 patients showed abnormalities in either lymphocyte subsets and/or immunophenotype: 10 showed increased CD8+ cells and decreased CD4:CD8 ratio, 8 had decreased CD3+ cells, 3 each had increased CD56+ cells, increased CD7-/CD4+ cells, and increased CD3+/CD4-/CD8- (DN) cells, and one had increased CD3-/CD4+ cells. Six of 10 patients with increased numbers of CD8+ cells and decreased CD4:CD8 ratio are alive, compared to 2/11 with normal values (p = 0.0385). On the other hand, all 8 patients with decreased CD3+ cells are dead, compared to 8/13 with normal numbers (p = 0.0417). Those who survived were younger than those who did not (median, range: 29 years, 19-88, vs 62 years, 24-81; p = 0.0272). In conclusion, most aHLH patients show diverse abnormalities in either lymphocytes and/or immunophenotype. Young age, increased numbers of CD8+ cells or decreased CD4:CD8 ratio are favorably associated with survival, while a decreased number of CD3+ cells is adversely associated with survival in aHLH patients. PMID- 25800136 TI - Impact of metabolic syndrome on development of contrast-induced nephropathy after elective percutaneous coronary intervention among nondiabetic patients. AB - BACKGROUND: Identifying patients who are vulnerable to development of contrast induced nephropathy (CIN) is essential because of its association with prolonged hospitalization, increased cost, and increased in-hospital and long-term mortality rates. HYPOTHESIS: Individual components of metabolic syndrome (MetS) are well-established risk factors for kidney injury. Nondiabetic patients diagnosed with MetS might be at an increased risk of developing CIN after elective percutaneous coronary intervention (PCI). METHODS: A total of 599 nondiabetic patients were enrolled, of whom 313 met the MetS criteria and 286 were included in the control group. Patients were evaluated for development of CIN after elective PCI. RESULTS: Contrast-induced nephropathy occurred in 9.3% (29 of 313) of the MetS group and 4.9% (14 of 286) of the control group (P = 0.04). The multivariable regression model revealed that baseline glomerular filtration rate < 30 mL/min, multivessel intervention, and MetS increased and use of statin decreased the probability of CIN independent from confounding factors (odds ratio [OR]: 7.84, 95% confidence interval [CI]: 3.46-24.36, P < 0.01 for baseline glomerular filtration rate < 30 mL/min; OR: 0.82, 95% CI: 0.42-0.96, P = 0.02 for statin use; OR: 2.64, 95% CI: 1.46-6.56, P < 0.01 for multivessel intervention; and OR: 1.66, 95% CI: 1.12-2.61, P = 0.03 for MetS). CONCLUSIONS: Metabolic syndrome is a risk factor for CIN in patients with stable coronary artery disease who undergo elective PCI. We suggest that clinicians recognize the patients with MetS before elective coronary interventions. PMID- 25800137 TI - Empirically defining rapid response to intensive treatment to maximize prognostic utility for bulimia nervosa and purging disorder. AB - Rapid response (RR) to eating disorder treatment has been reliably identified as a predictor of post-treatment and sustained remission, but its definition has varied widely. Although signal detection methods have been used to empirically define RR thresholds in outpatient settings, RR to intensive treatment has not been investigated. This study investigated the optimal definition of RR to day hospital treatment for bulimia nervosa and purging disorder. Participants were 158 patients who completed >=6 weeks of day hospital treatment. Receiver operating characteristic (ROC) analysis was used to create four definitions of RR that could differentiate between remission and nonremission at the end of treatment. Definitions were based on binge/vomit episode frequency or percent reduction from pre-treatment, during either the first four or first two weeks of treatment. All definitions were associated with higher remission rates in rapid compared to nonrapid responders. Only one definition (i.e., <=3 episodes in the first four weeks of treatment) predicted sustained remission (versus relapse) at 6- and 12-month follow-up. These findings provide an empirically derived definition of RR to intensive eating disorder treatment, and provide further evidence that early change is an important prognostic indicator. PMID- 25800139 TI - Evaluation of instruments to assess health literacy in Arabic language among Iraqis. AB - BACKGROUND: Low health literacy is associated with lack of medical information, less use of preventive measures, low medication adherence rates, high health care costs and high risk of hospitalization. OBJECTIVE: The aims were to compare the results of the three health literacy tests, to measure for the first time the health literacy level of Iraqis, to describe the use of standardized health literacy tests, to evaluate reliability and validity of the Arabic versions of these tests, and to investigate whether there is relationship between the participant characteristics and the health literacy level. METHODS: A convenience sample of 95 subjects was studied in five community pharmacies in Al-Najaf and Babylon governorates, Iraq. Three health literacy tests, the Single Item Literacy Screener (SILS), the New Vital Sign (NVS) and the Short version of the Test of Functional Health Literacy in Adults (S-TOFHLA), were translated in the Arabic language and administered to the pharmacy customers. RESULTS: There were no statistically significant associations between age, gender, education and current education status and NVS score, but there were significant positive associations between the level of education and each one of SILS, New SILS, and S-TOFHLA scores. CONCLUSIONS: SILS has one subjective, possibly culturally biased question. Since Iraqis are generally not exposed to reading product labels, the NVS test might be not an accurate measure for them. S-TOFHLA was the most comprehensive test and gave equitable results. The Arabic version of S-TOFHLA can be used to measure health literacy in 22 Arabic speaking countries. PMID- 25800140 TI - Creation of vortices by torque in multidimensional media with inhomogeneous defocusing nonlinearity. AB - Recently, a new class of nonlinear systems was introduced, in which the self trapping of fundamental and vortical localized modes in space of dimension D is supported by cubic self-repulsion with a strength growing as a function of the distance from the center, r, at any rate faster that r(D). These systems support robust 2D and 3D modes which either do not exist or are unstable in other nonlinear systems. Here we demonstrate a possibility to create solitary vortices in this setting by applying a phase-imprinting torque to the ground state. Initially, a strong torque completely destroys the ground state. However, contrary to usual systems, where the destruction is irreversible, the present ones demonstrate a rapid restabilization and the creation of one or several shifted vortices orbiting the center. For the sake of comparison, we show analytically that, in the linear system with a 3D trapping potential, the action of a torque on the ground state is inefficient and creates only even-vorticity states with a small probability. PMID- 25800142 TI - Within-class differences of the sulfonylureas should be accounted for. PMID- 25800143 TI - Pituitary tumor apoplexy. AB - We review the etiology, investigations, management and outcomes of pituitary tumor apoplexy. Pituitary tumor apoplexy is a clinical syndrome which typically includes the acute onset of headache and/or visual disturbance, cranial nerve palsy and partial or complete endocrine dysfunction. It is associated with either infarction or hemorrhage of a pre-existing pituitary adenoma and is associated with significant morbidity and potential fatality. Not all patients will present with classic signs and symptoms, therefore it is pertinent to appreciate the clinical spectrum in which this condition can present. PMID- 25800144 TI - Posterior reversible encephalopathy syndrome in Guillain-Barre syndrome. AB - Autonomic dysfunction is a well-known complication of Guillain-Barre syndrome (GBS) and may manifest as hemodynamic fluctuations. Posterior reversible encephalopathy syndrome (PRES) is commonly associated with acute hypertension, but is rarely reported to occur in association with GBS. We describe a patient with GBS who developed PRES in the setting of autonomic dysfunction and review the clinical features of all 12 previously reported patients with co-occurrence of GBS and PRES. Almost all cases have occurred in women over the age of 55, raising the possibility of increased sensitivity to dysautonomia in this patient group. PMID- 25800145 TI - A dorsally located giant posterior fossa neurenteric cyst in a Chinese woman. AB - Neurenteric cysts (NC) are rare, endodermal-derived intracranial lesions, commonly located anteriorly in the posterior cranial fossa. We describe a rare case of a giant posterior fossa NC (6.5 * 5.9 * 4.3cm) located dorsal to the brain stem in a Chinese woman with a 1 week history of cerebellar symptoms. To our knowledge, this is the largest documented cyst of this type and the third dorsally located NC in the posterior fossa. PMID- 25800146 TI - A study of topical methyl-aminolaevulinate red-light photodynamic therapy in the treatment of actinic keratosis in Chinese patients: a Singaporean experience. AB - BACKGROUND: The incidence of skin cancers has been increasing in Singapore, owing to the country's location near the equator and its ageing population. Topical photodynamic therapy (PDT) is a treatment method employing light and a topical photosensitizer to treat actinic keratosis (AK). Most published data to date on PDT have been drawn from studies of patient with Fitzpatrick skin phototypes I and II. AIM: To evaluate the effectiveness of PDT in the treatment of AK in patients with skin phototype IV in Singapore. METHODS: This was a retrospective analysis of 13 East Asian patients with AK treated with PDT at the National Skin Centre, Singapore, from 2006 to 2013. RESULTS: The overall clearance rate of AK at 3 months was 81.8% (9 of 11 patients; the other 2 were lost to follow-up). Mild to moderate pain during therapy was a common adverse event. CONCLUSIONS: PDT is a useful treatment method for AK in East Asian patients with skin phototype IV. Further larger prospective studies will be needed to evaluate its overall efficacy in East Asian patients. PMID- 25800147 TI - Endogenous vasopressin, innate anxiety, and the emission of pro-social 50-kHz ultrasonic vocalizations during social play behavior in juvenile rats. AB - Although the involvement of the neuropeptide arginine vasopressin (AVP) in rodent social interaction is already extensively characterized, little is known about its role in social communication. Rats communicate in the ultrasonic range by means of ultrasonic vocalizations (USV). Depending on developmental stage and affective state, rats emit various distinct types of USV, with appetitive 50-kHz USV being induced by positive social interactions, like juvenile social play, probably serving an affiliative communicative function, namely to (re)establish or induce social proximity. In rats and mice selectively bred for low (LAB) and high (HAB) anxiety-related behavior, the emission of isolation-induced distress USV during maternal deprivation as pups correlates with innate high levels of hypothalamic AVP availability. Moreover, male LAB and HAB rats express deficits in social approach towards conspecifics, together with high and/or abnormal forms of aggression when confronted with harmless opponents, possibly due to a lack of social communication skills. The aim of this study was therefore (1) to investigate and characterize social play behavior and concomitant pro-social 50 kHz USV emission in male and female, juvenile LAB and HAB rats and to compare them to non-selected Wistar (NAB) rats; and (2) to link these findings pharmacologically to the central AVP system via applying an AVP 1a receptor (V1aR) antagonist (0.75 MUg; Manning compound) or synthetic AVP (1 ng) into the lateral ventricle of male juvenile NAB rats. Our results show that reduced social play behavior in highly anxious male and female, juvenile HAB rats is accompanied by low amounts of pro-social 50-kHz USV, as compared to respective LAB and NAB rats, possibly reflecting a lack of positive affective states in expectation of or following social interactions in these individuals. Secondly, although synthetic AVP did not alter social play behavior and pro-social 50-kHz USV, we demonstrated for the first time that a blockade of the central AVP system not only reduces juvenile social play behavior, but at the same time pro-social 50 kHz USV emission rates, indicating an involvement of the social neuropeptide in regulating affiliative communication in rodents. PMID- 25800148 TI - BDNF and cortisol levels in children with or without post-traumatic stress disorder after sustaining sexual abuse. AB - OBJECTIVE: There are studies reporting that cortisol and brain-derived neurotropic factor (BDNF) play a role in the pathophysiology of post-traumatic stress disorder (PTSD). However, up-to-date no study evaluated the relationship between PTSD and the levels of cortisol and BDNF in children and adolescents who have sustained trauma. The aim of this study was to investigate whether BDNF, cortisol and adrenocorticotropine (ACTH) levels differ between individuals who developed PTSD or not following a sexual trauma. METHOD: The study included 55 children aged between 6 and 17 years who sustained sexual assault (M/F: 13/42). The patients were divided into two groups, with or without PTSD based on the results of a structured psychiatric interview (K-SADS-PL and CAPS-CA). Of the participants, 49% (n=27) were diagnosed with PTSD. Cortisol, ACTH, and BDNF levels were evaluated using the ELISA method. RESULTS: There were no significant differences between patients with or without PTSD in terms of cortisol, ACTH, BDNF levels. There were no correlations between CAPS-CA scores and cortisol, ACTH, and BDNF levels in patients with or without PTSD. In patients with PTSD, decreased cortisol levels were found with increasing time after trauma, and no significant correlation was found with the cortisol levels in patients without PTSD. CONCLUSION: Although no significant association was found between biochemical parameters and the presence or severity of PTSD; decreasing cortisol levels with increasing time after trauma in patients with PTSD suggest that cortisol might have played a role in the pathophysiology of this disorder. PMID- 25800149 TI - The late-luteal leptin level, caloric intake and eating behaviors among women with premenstrual dysphoric disorder. AB - OBJECTIVES: A marked increased in food intake in the late-luteal phase is a characteristic symptom of premenstrual dysphoric disorder (PMDD). The aim of the study was to evaluate the leptin level, caloric intake, and eating behaviors of women with PMDD across the menstrual cycle among normal-weight and overweight subjects, respectively. METHODS: A total of 62 women with PMDD and 69 controls were recruited following psychiatric interviewing and underwent prospective investigation. The leptin level, caloric intake, and three factors related to eating behavior were assessed in both the late-luteal and follicular phases. RESULTS: The women with PMDD had greater increases in caloric intake, sweet caloric intake, and uncontrolled eating in the late-luteal phase than the controls. Among the normal-weight women, the leptin level was negatively correlated with caloric intake. The normal-weight women with PMDD had a lower leptin level, a lower leptin/body fat percentage (BFP), a higher caloric intake, and higher uncontrolled eating and emotional eating in the late-luteal phase than the normal-weight controls. Their leptin level was correlated negatively with sweet caloric intake. On the other hand, the overweight women with PMDD had a higher leptin level than the normal-weight women with PMDD and no decline was observed in their leptin level in the late-luteal phase. There were no differences in the leptin level between the overweight women with PMDD and the overweight controls. They also had a higher sweet caloric intake and higher uncontrolled eating and emotional eating than the overweight controls. CONCLUSIONS: A decline in the leptin level is associated with late-luteal overeating among normal-weight women with PMDD. Hyperleptinemia and a high sweet caloric intake of overweight women with PMDD should be monitored and addressed in order to attenuate the risk of leptin resistance. The detailed roles of leptin and other psycho-neuro-endocrinology factors in the mechanism of overeating among women with PMDD should be evaluated in future study. PMID- 25800151 TI - Making sense of it: a brief programme to improve reading comprehension in adolescents with language impairments in main stream school. AB - BACKGROUND: Children with language impairment show academic outcomes that are consistently poorer than those of their typically developing peers. A contributor to this is difficulty with reading comprehension. Although these difficulties are reported to continue well into adolescence, this population is generally underserved with regard to therapy. The efficacy of interventions for reading comprehension is well established in the research literature, but whether the same effects are achievable within a reasonable time reflecting available resources in real-life circumstances is less clear. AIMS: Efficacy trials may significantly overestimate how strong an effect will be when the treatment is used under more natural conditions and within local constraints. The aim was to discover whether a short classroom intervention would be effective in improving reading comprehension in adolescents with the heterogeneous profiles of general or specific learning disabilities, additional diagnoses and behavioural and socio emotional problems found in mainstream schools today. METHOD & PROCEDURES: Twenty eight adolescents with heterogeneous language and reading profiles were recruited from a mainstream school. The intervention programme comprised eight sessions of instruction in multiple reading comprehension strategies, held over 4 weeks. Experiment 1 had 10 participants. Experiment 2 had 18 participants who underwent the same programme, plus the addition of a session dedicated to decoding skills. Efficacy was evaluated within a pre- and post-study design, with baseline and post-therapy measures taken using the York Assessment of Reading for Comprehension (YARC). OUTCOMES & RESULTS: Both experiments showed a significant group difference pre/post-intervention, with similar large effect sizes. Experiment 2 also showed a significant group difference in decoding ability pre and post the single intervention session. CONCLUSIONS & IMPLICATIONS: This short intervention programme proved effective in a population with heterogeneous profiles, and fitted well with delivery in a mainstream school setting. It showed significant gains can be attained for this client group with relatively few resources. PMID- 25800150 TI - Prenatal maternal stress predicts stress reactivity at 21/2 years of age: the Iowa Flood Study. AB - Prenatal maternal stress (PNMS) predicts psychosocial development in offspring. It has been hypothesized that during PNMS, glucocorticoids pass the placenta, reaching the foetus, leading to a long-term reprogramming and dysregulation of the foetal hypothalamic-pituitary-adrenal (HPA) axis. However, results are inconsistent across PNMS studies. One problem may be the confounding of objective degrees of hardship due to the stressor and subjective degrees of distress in the mother. The present study investigated the association between objective and subjective PNMS due to a natural disaster, the June 2008 Iowa floods, and stress reactivity in the offspring at 21/2 years of age. Women who were pregnant during the floods were recruited, on average, within three months of the floods and their stress levels assessed. Mothers and their toddlers (n = 94 dyads) participated in a brief mother-toddler separation to induce physiological stress responses in the offspring. Salivary cortisol samples were collected four times during the procedure. We computed absolute change in cortisol (baseline to 20 minute post-stressor; baseline to 45-minute post-stressor) and Area Under the Curve with respect to increase and ground (AUCi; AUCg). Objective and subjective PNMS were positively correlated with AUCi, as was timing in gestation: the later in pregnancy the exposure occurred, the greater the cortisol increase. Controlling for objective hardship and other covariates, sex-by-subjective PNMS interactions showed a significant and positive association between subjective PNMS and Absolute Increase (45 min) and AUCi in females only, with little effect in males. These results suggest that PNMS leads to long-term alterations in the functioning of the HPA axis, evident as early as 30-months of age. PMID- 25800152 TI - Transabdominal ultrasonography for pregnancy diagnosis and estimation of gestational age in dromedary camels. AB - The objective of this study was to evaluate the use of transabdominal ultrasonography as a method for pregnancy diagnosis and establish some foetal biometrics guidelines of pregnancy staging. Transabdominal ultrasonography was performed weekly on six pregnant camels from the 4th to the 19th week and at 2 week intervals from the 20th to the 52nd week of gestation. Six areas were selected for examination: caudal abdominal (CAA), inside the thigh, above the base of the udder; middle abdominal (MIA), from the base of the udder to the umbilicus; and cranial abdominal (CRA), from the umbilicus to the xiphoid cartilage. Several foetal parameters including orbital diameter (ORD), biparietal diameter (BPD), abdominal diameter (ABD), chest depth (CHD) and ruminal diameter (RUD) were measured using standardized scan plans. The relationships between the gestational age and the foetal parameters were evaluated. From the 6th to the 12th week, the conceptus was always observed through the left CAA approach. Between the 13th and 27th week, the foetus was entirely visualized by the MIA examination. From the 28th to the 52nd week, the conceptus was mainly detected through the left CRA approach. The foetal parameters were measured frequently during mid- and late gestation. All regression and correlation coefficients were highly significant (p < 0.0001). In conclusion, transabdominal ultrasonography was shown to be a reliable technique for pregnancy diagnosis and estimation of gestational age in dromedary camels. PMID- 25800154 TI - Crystalline capsules: metal-organic frameworks locked by size-matching ligand bolts. AB - Metal-organic frameworks (MOFs) are shown to be good examples of a new class of crystalline porous materials for guest encapsulation. Since the encapsulation/release of guest molecules in MOF hosts is a reversible process in nature, how to prevent the leaching of guests from the open pores with minimal and nondestructive modifications of the structure is a critical issue. To address this issue, we herein propose a novel strategy of encapsulating guests by introducing size-matching organic ligands as bolts to lock the pores of the MOFs through deliberately anchoring onto the open metal sites in the pores. Our proposed strategy provides a mechanical way to prevent the leaching of guests and thereby has less dependence on the specific chemical environment of the hosts, thus making it applicable for a wide variety of existing MOFs once the size matching ligands are employed. PMID- 25800155 TI - In memoriam: Harry A. Fozzard, MD, April 22, 1931-December 9, 2014. PMID- 25800153 TI - Muscarinic acetylcholine receptor M3 modulates odorant receptor activity via inhibition of beta-arrestin-2 recruitment. AB - The olfactory system in rodents serves a critical function in social, reproductive and survival behaviours. Processing of chemosensory signals in the brain is dynamically regulated in part by an animal's physiological state. We previously reported that type 3 muscarinic acetylcholine receptors (M3-Rs) physically interact with odorant receptors (ORs) to promote odour-induced responses in a heterologous expression system. However, it is not known how M3-Rs affect the ability of olfactory sensory neurons (OSNs) to respond to odours. Here, we show that an M3-R antagonist attenuates odour-induced responses in OSNs from wild-type, but not M3-R-null, mice. Using a novel molecular assay, we demonstrate that the activation of M3-Rs inhibits the recruitment of beta arrestin-2 to ORs, resulting in a potentiation of odour-induced responses in OSNs. These results suggest a role for acetylcholine in modulating olfactory processing at the initial stages of signal transduction in the olfactory system. PMID- 25800157 TI - Lithium boride sheet and nanotubes: structure and hydrogen storage. AB - A new class of Li-B sheets, along with the related nanotubes, with a Li2B5 primitive cell has been designed using first-principles density functional theory. The dynamical stability of the proposed structures was confirmed by calculation of the soft phonon modes, and the calculated electronic structures show that all are metallic. The application of both the sheets and nanotubes for hydrogen storage has been investigated and it has been found that both of them can adsorb two H2 molecules around each Li atom, with an average binding energy of 0.152-0.194 eV per H2, leading to a gravimetric density of 10.6 wt%. PMID- 25800156 TI - Effect of acute and prolonged alcohol administration on Mg(2+) homeostasis in cardiac cells. AB - Alcoholic cardiomyopathy represents a major clinical complication in chronic alcoholics. Previous studies from our laboratory indicate that acute and chronic exposure of liver cells to ethanol results in a major loss of cellular Mg(2+) as a result of alcohol oxidation. We investigated whether exposure to ethanol induces a similar Mg(2+) loss in cardiac cells. The results indicate that chronic exposure to a 6% ethanol-containing diet depleted cardiac myocytes of >25% of their cellular Mg(2+) content. Acute ethanol exposure, instead, induced a time- and dose-dependent manner of Mg(2+) extrusion from perfused hearts and collagenase-dispersed cardiac ventricular myocytes. Pretreatment with chlormethiazole prevented ethanol-induced Mg(2+) loss to a large extent, suggesting a role of ethanol oxidation via cyP4502E1 in the process. Magnesium extrusion across the sarcolemma occurred via the amiloride-inhibited Na(+)/Mg(2+) exchanger. Taken together, our data indicate that Mg(2+) extrusion also occurs in cardiac cells exposed to ethanol as a result of alcohol metabolism by cyP4502E1. The extrusion, which is mediated by the Na(+)/Mg(2+) exchanger, only occurs at doses of ethanol >=0.1%, and depends on ethanol-induced decline in cellular ATP. The significance of Mg(2+) extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated. PMID- 25800159 TI - Welcome editorial. PMID- 25800158 TI - Association of BAFF -871C/T Promoter Polymorphism with Hepatitis C-Related Mixed Cryoglobulinemia in a Cohort of Egyptian Patients. AB - BACKGROUND: Hepatitis C infection is a major health problem worldwide, especially in Egypt. The high prevalence of mixed cryoglobulinemia (MC) in hepatitis C patients leads to the assumption that there is a direct link between hepatitis C virus (HCV) and cryoglobulinemia. Host genetic factors could be a contributing factor. B cell-activating factor (BAFF) is a tumor necrosis factor (TNF) family member, which has an essential role in B lymphocyte development and survival. The aim of the present work was to study the possible association between the BAFF 871C/T promoter polymorphism and HCV-related MC in a cohort of Egyptian patients. METHODS: The study was conducted in 120 HCV patients classified into two groups: group I (60 HCV patients with MC) and group II (60 HCV patients without MC), with 60 age- and sex-matched healthy control subjects. BAFF -871C/T genotyping was performed in all subjects by polymerase chain reaction (PCR) with restriction fragment length polymorphism analysis. RESULTS: The prevalence of the BAFF -871TT genotype was significantly increased in HCV patients compared with the control group (P=0.036). The BAFF TT genotype was also significantly more prevalent in group I (HCV-MC patients) than in group II (HCV patients without MC) [P<0.001]. CONCLUSION: A significant association was found between the BAFF -871C/T promoter polymorphism and MC, which may indicate that BAFF could be a potential therapeutic target in HCV-MC. PMID- 25800161 TI - Ion-exchange chromatography for the characterization of biopharmaceuticals. AB - Ion-exchange chromatography (IEX) is a historical technique widely used for the detailed characterization of therapeutic proteins and can be considered as a reference and powerful technique for the qualitative and quantitative evaluation of charge heterogeneity. The goal of this review is to provide an overview of theoretical and practical aspects of modern IEX applied for the characterization of therapeutic proteins including monoclonal antibodies (Mabs) and antibody drug conjugates (ADCs). The section on method development describes how to select a suitable stationary phase chemistry and dimensions, the mobile phase conditions (pH, nature and concentration of salt), as well as the temperature and flow rate, considering proteins isoelectric point (pI). In addition, both salt-gradient and pH-gradient approaches were critically reviewed and benefits as well as limitations of these two strategies were provided. Finally, several applications, mostly from pharmaceutical industries, illustrate the potential of IEX for the characterization of charge variants of various types of biopharmaceutical products. PMID- 25800162 TI - PSOVina: The hybrid particle swarm optimization algorithm for protein-ligand docking. AB - Protein-ligand docking is an essential step in modern drug discovery process. The challenge here is to accurately predict and efficiently optimize the position and orientation of ligands in the binding pocket of a target protein. In this paper, we present a new method called PSOVina which combined the particle swarm optimization (PSO) algorithm with the efficient Broyden-Fletcher-Goldfarb-Shannon (BFGS) local search method adopted in AutoDock Vina to tackle the conformational search problem in docking. Using a diverse data set of 201 protein-ligand complexes from the PDBbind database and a full set of ligands and decoys for four representative targets from the directory of useful decoys (DUD) virtual screening data set, we assessed the docking performance of PSOVina in comparison to the original Vina program. Our results showed that PSOVina achieves a remarkable execution time reduction of 51-60% without compromising the prediction accuracies in the docking and virtual screening experiments. This improvement in time efficiency makes PSOVina a better choice of a docking tool in large-scale protein-ligand docking applications. Our work lays the foundation for the future development of swarm-based algorithms in molecular docking programs. PSOVina is freely available to non-commercial users at http://cbbio.cis.umac.mo . PMID- 25800163 TI - Retrograde jejuno-jejunal intussusception 7years after a Roux-en-Y gastric bypass. PMID- 25800164 TI - An unusual complication of urethral catheterization: hydronephrosis with pyelonephritis after ureteral catheterization. PMID- 25800165 TI - Troponin elevation in patients without acute coronary syndrome. AB - INTRODUCTION AND OBJECTIVES: Troponins are specific biomarkers of myocardial injury and are implicated in the diagnosis and prognosis of patients with acute coronary syndrome. Our purpose was to determine the clinical characteristics and prognosis of patients with troponin elevation who are not diagnosed with acute coronary syndrome. METHODS: A total of 1032 patients with an emergency room troponin measurement were studied retrospectively, dividing them into 3 groups: 681 patients with no troponin elevation and without acute coronary syndrome, 139 with acute coronary syndrome, and 212 with troponin elevation and not diagnosed with acute coronary syndrome. The clinical characteristics and in-hospital and 12 month mortality of these 3 groups were compared. RESULTS: Patients with troponin elevation not diagnosed with acute coronary syndrome were older and had greater comorbidity than patients with acute coronary syndrome or no troponin elevation. The 12-month mortality was 30.2%, compared with 15.1% and 4.7% in the other groups (log rank test, P<.001). In the Cox logistic regression model adjusted for confounding variables, patients with troponin elevation and no diagnosis of acute coronary syndrome had higher mortality compared with patients with negative troponin without acute coronary syndrome (hazard ratio=3.99; 95% confidence interval, 2.36-6.75; P<.001) and similar prognosis as patients with acute coronary syndrome. CONCLUSIONS: Troponin elevation is an important predictor of mortality, regardless of the patient's final diagnosis. PMID- 25800166 TI - Impact of Acute Coronary Syndrome Complicated by Ventricular Fibrillation on Long term Incidence of Sudden Cardiac Death. AB - INTRODUCTION AND OBJECTIVES: There is little information on the effect of acute coronary syndrome complicated by ventricular fibrillation on the long-term incidence of sudden cardiac death. We analyzed this effect in a contemporary cohort of patients with acute coronary syndrome. METHODS: We studied 5302 consecutive patients with acute coronary syndrome between December 2003 and December 2012. We compared mortality during and after hospitalization according to the presence or absence of ventricular fibrillation. RESULTS: Ventricular fibrillation was observed in 163 (3.1%) patients, and was early onset in 72.4% of these patients. In-hospital mortality was 36.2% in the group with ventricular fibrillation and 4.7% in the group without (p<.001). After a mean follow-up of 4.7 years (standard deviation, 2.6 years), mortality was 30.7% in the ventricular fibrillation group and 24.7% in the other group (P=.23). After adjusting for confounding variables, the presence of ventricular fibrillation was not associated with an increased risk of death in the follow-up period (hazard ratio=1.29; 95% confidence interval, 0.90-1.87). The cause of death was established in 72% of patients. The incidence of sudden death was 12.9% in the ventricular fibrillation group and 11.9% in the other group (P=.71). Cardiovascular-cause mortality was also similar between the 2 groups (35.5% and 34.4%, respectively. CONCLUSIONS: Patients with acute coronary syndrome complicated by ventricular fibrillation who survive the in-hospital phase do not appear to be at an increased risk of sudden cardiac death or other cardiovascular cause death. PMID- 25800167 TI - Death of Cardiac Origin Following Medical Visit and Discharge: What did my Patient Die of? PMID- 25800168 TI - Pituitary incidentalomas: analysis of a neuroradiological cohort. AB - PURPOSE: Most pituitary lesions are detected during the investigation of symptoms associated with hormonal dysfunction and vision abnormalities. When the lesion is identified in an image performed for reasons not related to the tumor, the term incidentaloma applies. Our aim was to describe the diagnosis behind pituitary incidentalomas, patient characteristics and their follow up. METHODS: We searched for the terms "pituitary", "hypophysis" and "incidentaloma" in the requisitions and reports of all CTs and MRIs performed between 1st September 2008 and 30th October 2013. We retrieved demographic data as well as information regarding presentation and follow-up. RESULTS: We detected 71 pituitary incidentalomas, 3 in children/adolescents. In adult patients, mean age was 51.6 +/- 18.46 years and 42 were female (61.8 %). The most frequent reason for imaging was headache (33.8 %). The image that first detected the incidentaloma was CT scan in 63.2 and 17.6 % patients presented symptoms that could have led to earlier diagnosis. Pituitary adenoma is the most prevalent lesion (n 48; 70.6 %), followed by Rathke's cleft cyst (n 9; 13.2 %). Hormonal evaluation revealed hypopituitarism in 14 patients and hypersecretion in 6: 5 prolactinomas and 1 somatotroph adenoma. Twenty-one (28.8 %) patients underwent surgery and there was no malignancy. CONCLUSIONS: In concordance with available literature, adenomas are the most frequent incidentally found pituitary lesions. Hormonal dysfunction is quite prevalent, including symptomatic presentations, which suggests that there seems to be a low sensitivity for the diagnosis of pituitary disease. PMID- 25800170 TI - Guide dogs as a model for investigating the effect of life experience and training on gazing behaviour. AB - The present study aimed at evaluating possible behavioural differences between guide dogs living in a kennel and interacting with a trainer and those living in a house and interacting with a blind person and their family, when they are faced with an unsolvable task. Fifty-two Labrador retrievers were tested: 13 Trained Guide dogs at the end of their training programme and 11 Working Guide dogs that had been living with their blind owner for at least 1 year. Two control groups of Labrador retrievers were also tested: 14 Young Untrained dogs of the same age as the Trained Guide and 14 Old Untrained dogs of the same age as the Working Guide dogs. Results showed that the Trained Guide dogs gazed towards the owner or the stranger for less time and with a higher latency and spent more time interacting with the experimental apparatus than the other three groups, which all behaved similarly. None of the groups tested showed preferences in gazing towards the stranger or the owner. Together, the results suggest that at the end of their training programme, guide dogs are less prone to engage in human-directed gazing behaviour and more likely to act independently when facing an unsolvable task. Conversely, guide dogs that have been living with a blind person (and their family) for 1 year behave like pet dogs. These findings indicate that guide dogs' gazing towards humans is favoured by living in close proximity with people and by interacting with them. PMID- 25800169 TI - Social learning strategies for nut-cracking by tufted capuchin monkeys (Sapajus spp.). AB - The spontaneous use of stone tools for cracking nuts by tufted capuchin monkeys, now known to be habitual among wild populations in savanna environments, was first described in a semifree group living in the Tiete Ecological Park (SP, Brazil). Nut-cracking at TEP was first observed by our team in 1995 (Ottoni and Mannu in Int J Primatol 22(3):347-358, 2001), and its ontogeny and associated social dynamics, with inexperienced observers highly interested in the activities of proficient individuals, greatly tolerant to scrounging, support hypotheses about social biases on tool-use learning. Here we further analyze the social learning biases, better characterizing: the social context of nut-cracking in which observation by conspecifics occurs, the quality of the nut-cracking behavior itself and whether scrounging may be the motivation behind this behavior. We confirm that the choice of observational targets is an active one; monkeys do not simply observe those who they are socially close to. We investigate social learning strategies, describing how young capuchins choose to observe older, more proficient and dominant individuals during nut-cracking bouts. Monkeys with higher productivity rates were also more frequently targeted by observers, who were tolerated scroungers, further supporting the scrounging hypothesis. Finally, based on changes of the demographic patterns of tool use and observation, we set to retrace data from 14 years of continuous studies. We argue that we have followed the dissemination of the behavior (Transmission Phase) almost from its beginning, when juveniles were the most frequent nutcrackers, to a more common pattern where adults are the most active tool users (Tradition Phase). PMID- 25800171 TI - Influence of volunteer and project characteristics on data quality of biological surveys. AB - Volunteer involvement in biological surveys is becoming common in conservation and ecology, prompting questions on the quality of data collected in such surveys. In a systematic review of the peer-reviewed literature on the quality of data collected by volunteers, we examined the characteristics of volunteers (e.g., age, prior knowledge) and projects (e.g., systematic vs. opportunistic monitoring schemes) that affect data quality with regards to standardization of sampling, accuracy and precision of data collection, spatial and temporal representation of data, and sample size. Most studies (70%, n = 71) focused on the act of data collection. The majority of assessments of volunteer characteristics (58%, n = 93) examined the effect of prior knowledge and experience on quality of the data collected, often by comparing volunteers with experts or professionals, who were usually assumed to collect higher quality data. However, when both groups' data were compared with the same accuracy standard, professional data were more accurate in only 4 of 7 cases. The few studies that measured precision of volunteer and professional data did not conclusively show that professional data were less variable than volunteer data. To improve data quality, studies recommended changes to survey protocols, volunteer training, statistical analyses, and project structure (e.g., volunteer recruitment and retention). PMID- 25800172 TI - Face recognition in schizophrenia disorder: A comprehensive review of behavioral, neuroimaging and neurophysiological studies. AB - Facial emotion processing has been extensively studied in schizophrenia patients while general face processing has received less attention. The already published reviews do not address the current scientific literature in a complete manner. Therefore, here we tried to answer some questions that remain to be clarified, particularly: are the non-emotional aspects of facial processing in fact impaired in schizophrenia patients? At the behavioral level, our key conclusions are that visual perception deficit in schizophrenia patients: are not specific to faces; are most often present when the cognitive (e.g. attention) and perceptual demands of the tasks are important; and seems to worsen with the illness chronification. Although, currently evidence suggests impaired second order configural processing, more studies are necessary to determine whether or not holistic processing is impaired in schizophrenia patients. Neural and neurophysiological evidence suggests impaired earlier levels of visual processing, which might involve the deficits in interaction of the magnocellular and parvocellular pathways impacting on further processing. These deficits seem to be present even before the disorder out-set. Although evidence suggests that this deficit may be not specific to faces, further evidence on this question is necessary, in particularly more ecological studies including context and body processing. PMID- 25800173 TI - Impact of occupational cadmium exposure on spirometry, sputum leukocyte count, and lung cell DNA damage among Indian goldsmiths. AB - BACKGROUND: Cadmium is frequently used in manual jewelry industries. Although its toxicity on lung function is well-known, the mechanism is not well-understood. METHODS: Among 26 goldsmiths exposed to cadmium (mean age 35.9 +/- 5.0 years) and 17 referent workers without direct exposure (36.6 +/- 6.6 years), we measured blood and urinary cadmium concentration and performed spirometry and quantified leukocytes and comet formation in the cells from spontaneously expectorated sputum samples. RESULTS: The goldsmiths had higher cadmium concentration in urine (mean 6.14 +/- 1.63 vs. 0.47 +/- 0.17 MUg/dl) and blood (0.90 +/- 0.23 vs. 0.02 +/- 0.007 MUg/dl) than the referents, which were inversely associated with FEV1 /FVC. Cadmium exposure also resulted in higher neutrophils (%) and lower macrophage (%) prevalence in the sputum and also caused substantial DNA damage in the lung cells among the goldsmiths than the referents (69 vs. 14%). CONCLUSION: Altered lung function among cadmium-exposed goldsmiths was associated with enhanced inflammatory response and increased cellular DNA damage in the lungs. PMID- 25800174 TI - Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats. AB - BACKGROUND: "Burst ketamine" (BK) is the long-term infusion of subanesthetic ketamine in combination with an opioid. It is used clinically with mixed success to provide long-term pain relief and improve opioid response in patients. BK has not been simulated preclinically, therefore, its effectiveness was investigated in an animal model of neuropathic pain--streptozotocin-induced diabetic neuropathy. METHODS: Diabetic neuropathic rats were randomized to receive a subcutaneous infusion of ketamine 20 mg/kg/day plus morphine 20 mg/kg/day (BK), either drug alone at the same dose, or sham treatment. Drugs were administered continuously over 5 days via osmotic minipump. Antihyperalgesic effects and antinociceptive responsiveness to morphine (0.625-10 mg/kg, i.p.) were assessed at 2, 4, 6, and 12 weeks post-treatment using paw withdrawal latency (PWL) from noxious heat (thermal hyperalgesia) and mechanical touch (tactile allodynia). RESULTS: Antihyperalgesic effects with significant increases in PWL from noxious heat occurred following BK and ketamine-only infusion, persisting 12 and 4 weeks, respectively. Opioid-sparing effects from noxious heat with increased sensitivity to morphine analgesia also occurred for 6 weeks after BK and 2 weeks after ketamine treatment; acute treatment with the maximum nonsedating dose of morphine (5 mg/kg) produced an antinociceptive effect in these two groups, but not in sham treated rats. In morphine-only infusion rats, hyperalgesia and opioid insensitivity were both increased. CONCLUSIONS: This is the first preclinical study to use a model of neuropathic pain to demonstrate the utility of the BK procedure for delivering a long-lasting reduction in hyperalgesia and improved antinociceptive responsiveness to opioids. PMID- 25800175 TI - The role of apheresis in hypertriglyceridemia-induced acute pancreatitis: A systematic review. AB - BACKGROUND: Mostly published as case reports or series, the role of apheresis in hypertriglyceridemia (HTG)-related acute pancreatitis (AP) remains unclear. We performed a systematic review of available literature on this topic with specific focus on disease severity. METHODS: A search of electronic databases (PubMed, EMBASE, Cochrane) and gray literature yielded 5020 articles of which 74 met criteria for inclusion (301 unique patients). Relevant data were abstracted from full manuscripts and analyzed. RESULTS: Most patients were young (mean age 37.9 +/- 10.4 years) and male (71.5%). About two-thirds (69.7%) received apheresis within 48 h and most required only 1 or 2 sessions (84.4%). Apheresis resulted in an average reduction of serum TG by 85.4% (p < 0.001). There was high variability in reporting the presence of and criteria to define severe AP (reported 221/301, 73.4%; present 85/221, 38.5%) or organ failure (reported 104/301, 34.6%; present 52/104, 50.0%). Improvement was reported in the majority of patients (reported 144/301, 47.8%, present 136/144, 94.4%) mainly by clinical symptoms or laboratory tests. Overall mortality was 7.1% (21/294) which increased to 11.8% (10/85) with severe AP and 19.2% (10/52) with organ failure. CONCLUSIONS: Apheresis effectively reduces serum TG levels. However, due to uncontrolled data, reporting bias and lack of a comparison group, definitive conclusions on the efficacy of apheresis in reducing AP severity cannot be made. We propose which patients may be best suitable for apheresis, type of studies needed and outcome measures to be studied in order to provide empiric data on the role of apheresis in HTG-related AP. PMID- 25800178 TI - Ionization suppression effects with condensed phase membrane introduction mass spectrometry: methods to increase the linear dynamic range and sensitivity. AB - Condensed phase membrane introduction mass spectrometry (CP-MIMS) is an online analytical method that allows for the direct, trace level measurement of a wide range of analytes in complex samples. The technique employs a semi-permeable membrane that transfers analytes from a sample into a flowing acceptor solvent, which is directly infused to an atmospheric pressure ionization source, such as electrospray or atmospheric pressure chemical ionization. While CP-MIMS and variants of the technique have been in the literature for nearly a decade, much of the work has focused on instrument development. Few studies have thoroughly addressed quantitative methods related to detection limits, ionization suppression, or linear dynamic range. We examine ionization suppression in the direct rapid quantitation of analytes by CP-MIMS and introduce several analytical strategies to mitigate these effects, including the novel implementation of a continuously infused internal standard in the acceptor phase solvent, and modulation of acceptor phase flow rate. Several representative analytes were used to evaluate this approach with spiked, complex sample matrices, including primary wastewater effluent and artificial urine. Also reported are improved measured detection limits in the low part-per-trillion range, using a 'stopped-flow' acceptor mode. PMID- 25800177 TI - Metabolic reprogramming and cell fate regulation in alcoholic liver disease. AB - Alcoholic liver disease (ALD) should be defined as a life-style metabolic disease. Its pathogenesis is driven by altered cell fate of both parenchymal and non-parenchymal liver cell types, contributing to different pathologic spectra. A critical turning point in progression of ALD is chronic alcoholic steatohepatitis (ASH) or alcoholic neutrophilic hepatitis (AH), which markedly predisposes patients to most devastating ALD sequela, cirrhosis and liver cancer. RESULTS: Our research identifies the pivotal roles of unique metabolic reprogramming in M1 activation of hepatic macrophages (HM) and myofibroblastic activation (MF) of hepatic stellate cells (HSC) in the genesis of inflammation and fibrosis, the two key histological features of chronic ASH and neutrophilic AH. For M1 HM activation, heightened proinflammatory iron redox signaling in endosomes or caveosomes results from altered iron metabolism and storage, promoting IKK/NF-kB activation via interactive activation of p21ras, TAK1, and PI3K. For MF cell fate regulation of HSC, activation of the morphogen Wnt pathway caused by the nuclear protein NECDIN or the single-pass trans-membrane protein DLK1, reprograms lipid metabolism via MeCP2-mediated epigenetic repression of the key HSC quiescence gene Ppar-gamma. CONCLUSIONS: The findings from these studies re-enforce the importance of metabolic reprogramming in cell fate regulation required for the pathogenesis of ALD. PMID- 25800176 TI - Fluorescence-guided surgery, but not bright-light surgery, prevents local recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) model resistant to neoadjuvant chemotherapy (NAC). AB - BACKGROUND: The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model. METHODS: A PDOX model was established from a CEA-positive tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS + NAC; FGS only; and FGS + NAC. An anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with a pancreatic cancer PDOX 24 h before surgery. RESULTS: The PDOX was clearly labeled with fluorophore-conjugated anti-CEA antibody. Only one out of 8 mice had local recurrence in the FGS only group and zero out of 8 mice had local recurrence in the FGS + NAC which was significantly lower than BLS only or BLS + NAC mice, where local disease recurred in 6 out of 8 mice in each treatment group (p = 0.041 and p = 0.007, respectively). NAC did not significantly reduce recurrence rates when combined with either FGS or BLS. CONCLUSION: These results indicate that FGS can significantly reduce local recurrence compared to BLS in pancreatic cancer resistant to NAC. PMID- 25800179 TI - Polarization induced electrospray ionization mass spectrometry for the analysis of liquid, viscous and solid samples. AB - In this study, a polarization-induced electrospray ionization mass spectrometry (ESI-MS) was developed. A micro-sized sample droplet was deposited on a naturally available dielectric substrate such as a fruit or a stone, and then placed close to (~2 mm) the orifice of a mass spectrometer applied with a high voltage. Taylor cone was observed from the sample droplet, and a spray emitted from the cone apex was generated. The analyte ion signals derived from the droplet were obtained by the mass spectrometer. The ionization process is similar to that in ESI although no direct electric contact was applied on the sample site. The sample droplet polarized by the high electric field provided by the mass spectrometer initiated the ionization process. The dielectric sample loading substrate facilitated further the polarization process, resulting in the formation of Taylor cone. The mass spectral profiles obtained via this approach resembled those obtained using ESI-MS. Multiply charged ions dominated the mass spectra of peptides and proteins, whereas singly charged ions dominated the mass spectra of small molecules such as amino acids and small organic molecules. In addition to liquid samples, this approach can be used for the analysis of solid and viscous samples. A small droplet containing suitable solvent (5-10 ul) was directly deposited on the surface of the solid (or viscous) sample, placed close the orifice of mass spectrometer applied with a high voltage. Taylor cone derived from the droplet was immediately formed followed by electrospray processes to generate gas-phase ions for MS analysis. Analyte ions derived from the main ingredients of pharmaceutical tablets and viscous ointment can be extracted into the solvent droplet in situ and observed using a mass spectrometer. PMID- 25800180 TI - Quantitative chiral analysis of tryptophan using enantiomer-selective photolysis of cold non-covalent complexes in the gas phase. PMID- 25800181 TI - Analysis of the cyanolichen Lichina pygmaea metabolites using in situ DART-MS: from detection to thermochemistry of mycosporine serinol. AB - Direct Analysis in Real Time DART-HRMS is here first applied to the detection of molecules from a lichen, Lichina pygmaea. The aim was to propose an innovative method of in situ detection of lichen secondary metabolites using the possibilities of elemental composition determination available when a DART source is interfaced with a TOF analyzer. Three kinds of samples have been submitted to DART ionization, i.e. an intact thallus, a powder obtained from the crushed lichen and an aqueous extract. In situ analysis of crushed lichen, yields an extensive chemical profile, comparable to what is obtained from the aqueous extract, comprising both major polar metabolites described in literature along with some other signals that could correspond to potentially unknown metabolites. One of the detected secondary metabolites, mycosporine serinol, underwent a dehydration reaction prior to its transfer in the gas-phase by DART ionization. The consideration of the thermal transfers involved in the DART ionization process and the possibility to record time-dependent mass spectra through the use of the TOF analyzer allowed establishing Arrhenius plots of this water molecule loss to obtain associated thermodynamic quantities. The low values of corresponding activation enthalpy (Deltar?Hm degrees of the order of 25 kJ mol( 1)) enabled formulating some assumption regarding a possible role of such metabolites in the lichen. PMID- 25800182 TI - Commercial formaldehyde standard for mass calibration in mass spectrometry. AB - Common calibration standards for mass spectrometry can be a source of many problems including instrument contamination, ionization suppression and formation of unidentified ions during subsequent analysis. In this article, we present a new approach for the calibration of mass analyzers such as a quadrupole-time-of flight mass spectrometry using a diluted solution of commercial formaldehyde. Formaldehyde is an inexpensive and commonly used solvent, and its intrinsic polymerization leads to the formation of polyoxymethylene (POM) oligomers, which are excellent multiple calibration standards for a low-mass spectral region (up to m/z 400) in the positive and negative mode of electrospray ionization. We explore the nature and origin of these polymeric species and attributed them to chemical reactions of formaldehyde and stabilizing agents in commercial formaldehyde solutions and during electrospray ionization. In contrast to other calibrants, POM oligomers do not contaminate the instrument and can easily be removed from the sample delivery system. Using tandem mass spectrometry, we elucidate the structures of the detected POM oligomers and report their reference masses, which are tightly spaced by 30 mass units. In our calibration method, mass errors of <5 ppm can be obtained from m/z 20-400 using external calibration with a simple one-point zero-order correction of spectral data and without the need for operation of a dual spray or internal calibrants. Our approach will be particularly useful for those interested in the analysis of fragile ions with low m/z values and can function at instrumental conditions required for analysis of the most labile metabolites and environmental contaminants. PMID- 25800183 TI - Combining UV photodissociation with electron transfer for peptide structure analysis. AB - The combination of near-UV photodissociation with electron transfer and collisional activation provides a new tool for structure investigation of isolated peptide ions and reactive intermediates. Two new types of pulse experiments are reported. In the first one called UV/Vis photodissociation electron transfer dissociation (UVPD-ETD), diazirine-labeled peptide ions are shown to undergo photodissociation in the gas phase to form new covalent bonds, guided by the ion conformation, and the products are analyzed by electron transfer dissociation. In the second experiment, called ETD-UVPD wherein synthetic labels are not necessary, electron transfer forms new cation-peptide radical chromophores that absorb at 355 nm and undergo specific backbone photodissociation reactions. The new method is applied to distinguish isomeric ions produced by ETD of arginine containing peptides. PMID- 25800184 TI - Structural characterization of ether lipids from the archaeon Sulfolobus islandicus by high-resolution shotgun lipidomics. AB - The molecular structures, biosynthetic pathways and physiological functions of membrane lipids produced by organisms in the domain Archaea are poorly characterized as compared with that of counterparts in Bacteria and Eukaryota. Here we report on the use of high-resolution shotgun lipidomics to characterize, for the first time, the lipid complement of the archaeon Sulfolobus islandicus. To support the identification of lipids in S. islandicus, we first compiled a database of ether lipid species previously ascribed to Archaea. Next, we analyzed the lipid complement of S. islandicus by high-resolution Fourier transform mass spectrometry using an ion trap-orbitrap mass spectrometer. This analysis identified five clusters of molecular ions that matched ether lipids in the database with sub-ppm mass accuracy. To structurally characterize and validate the identities of the potential lipid species, we performed structural analysis using multistage activation on the ion trap-orbitrap instrument as well as tandem mass analysis using a quadrupole time-of-flight machine. Our analysis identified four ether lipid species previously reported in Archaea, and one ether lipid species that had not been described before. This uncharacterized lipid species features two head group structures composed of a trisaccharide residue carrying an uncommon sulfono group (-SO3) and an inositol phosphate group. Both head groups are linked to a glycerol dialkyl glycerol tetraether core structure having isoprenoid chains with a total of 80 carbon atoms and 4 cyclopentane moieties. The shotgun lipidomics approach deployed here defines a novel workflow for exploratory lipid profiling of Archaea. PMID- 25800185 TI - Characteristic neutral loss of CH3CHO from Thr-containing sodium-associated peptides. AB - A characteristic neutral loss of 44 Da is observed in the MS/MS spectra of Thr containing sodiated peptides. A combination of tandem mass spectrometry and quantum chemical calculations calculated at the B3LYP/6-311G (d, p) level of ab initio theory is used to elucidate this fragmentation pathway. The high resolution mass spectrometry data indicate this neutral loss is acetaldehyde lost from the side chain of Thr rather than CO2. The intensity of this neutral loss can be enhanced when Thr residue is far from the C-terminus and when the C terminus is esterified as well. The mechanism of the acetaldehyde loss is proposed to adopt a McLafferty-type rearrangement reaction, which involves a proton transfer from the hydroxyl of Thr side chain to its C-terminal neighboring carbonyl oxygen inducing the cleavage of the Ca-Cbeta bond. This mechanism is further supported by examining the fragmentation of a [GT(tBu)G + Na](+) peptide derivative and by comparing the product ion spectra of [M + Na-44](+) of [GTGA + Na](+) with [M + Na](+) of [GGGA + Na](+). A similar neutral loss of HCHO can also be detected in Ser-containing peptides. Our computational results reveal that the most stable [GTG + Na](+) ion is present as a tridentate charge-solvated structure and the dissociation leading to the 44 loss is dynamically and energetically favorable. PMID- 25800186 TI - Ion tree-based structure elucidation of acetophenone dimers (AtA) from Acronychia pedunculata and their identification in extracts by liquid chromatography electrospray ionization LTQ-Orbitrap mass spectrometry. AB - Acronychia-type acetophenones (AtA) is a chemical group of compounds of important structural and biological interest, abundant in Acronychia species. However, there are no data available for their characterization using mass spectrometry. In the current work, AtA have been investigated by multistage high resolution mass spectrometry and both electrospray ionization and atmospheric pressure chemical ionization, in positive and negative mode, were utilized for their structure elucidation and identification. The analysis of AtA using a linear ion trap-Orbitrap analyzer enabled the structural determination of key fragment ions and cleavages, which can be used for the structural characterization thereof. A systematic nomenclature based on protonated and deprotonated fragment ions under collision-induced dissociation conditions and decision trees for the structural determination of AtA are proposed. Furthermore, taking advantage of the characteristic fragmentation patterns, a selective Ultra High Performance Liquid Chromatography Electrospray Ionization multistage Mass Spectrometry (UHPLC-ESI(-) MS(n)) method was developed and successfully applied for the dereplication of known AtA and the identification of potentially new ones in Acronychia extracts. Despite the structure similarity and the presence of isomers, accurate characterization of known and unknown AtA derivatives was possible. PMID- 25800187 TI - Combined mass spectrometric and chromatographic methods for in-depth analysis of phenolic secondary metabolites in barley leaves. AB - Structural analysis via HPLC-ESI-MSn, UPLC-HESI-MS/MS and NMR reported 152 phenolic secondary metabolites in spring barley seedlings (Hordeum vulgare L.). Flavonoids with various patterns of glycosylation and acylation, as well as hydroxycinnamic acid glycosides, esters and amides, were identified in methanolic extracts from leaves of nine varieties of barley originating from different regions of the world. Hordatines derivatives, flavones acylated directly on the aglycone, and hydroxyferulic acid derivatives deserve special attention. Preparative chromatography enabled characterization of a number of compounds at trace levels with the 6-C-[6"-O-glycosyl]-glycosides and the 6-C-[2",6"-di-O glycosides]-glucoside structure of flavones. Derivatives of flavonols, quercetin and isorhamnetin were observed only in Syrian varieties. The ultra performance liquid chromatography profiles of UV-absorbing secondary metabolites were used for chemotaxonomic comparison between nine varieties of barley from different climatic conditions. The hierarchical clustering of bred lines from the Fertile Crescent and European and American varieties indicates a great diversity of chemical phenotypes within barley species. PMID- 25800188 TI - Chip-based nanoelectrospray ionization with Fourier transform mass spectrometric detection to screen for local anesthetics intended to mask limb sore in walking horses. AB - We report a high-throughput chip-based nanoelectrospray ionization method coupled with Fourier transform mass spectrometry to screen for local anesthetics in samples collected by swabbing. These drugs have been used to mask pain on the limbs of walking horses after forbidden practices of soring or physical abuse. Optimized for lidocaine, the method afforded sub-ppm mass accuracy for nine local anesthetics included in the study. From doped cotton swabs, two third and all of the analytes were detected after adding 10 ng and 100 ng of each drug, respectively. Benzocaine and/or lidocaine were found on positive swab samples collected during walking horse competitions. PMID- 25800189 TI - SpiderMass: Semantic database creation and tripartite metabolite identification strategy. PMID- 25800190 TI - Separation of catechin epimers by complexation using ion mobility mass spectrometry. AB - Ion mobility coupled with mass spectrometry provides a fast and repeatable method to separate catechin epimers by previous complexation with selected chiral modifiers and transition metals. Several combinations with chiral ligands such as D- and L-amino acids and/or additional metal cations, chiral crown ethers, tartaric acid and heptakis(2,6-di-O-methyl)-beta-cyclodextrin were screened for their ability to affect the separation efficiency. The clusters having the form of [2M + D-amino acid + Cu(2+) - 3H](-) (M stands for (-)-epicatechin or (+) catechin) showed improvement in stereodifferentiation between two epimeric catechins in comparison to the analysis of pure epimers, where no separation was observed or the separation was hampered by the formation of mixed dimer complexes. Among various examined D-amino acids only those possessing hydrophobic side chains induced the improvement of separation efficiency. The best peak-to peak resolution (Rp-p) was determined to be 0.71 for [2M + D-Leucine + Cu(2+) - 3H](-) clusters. PMID- 25800191 TI - Electrospray ionization for determination of non-polar polyaromatic hydrocarbons and polyaromatic heterocycles in heavy crude oil asphaltenes. AB - Electrospray ionization (ESI) is the most common ionization method in atmospheric pressure ionization mass spectrometry because of its easy use and handling and because a diverse range of components can be effectively ionized from high to medium polarity. Usually, ESI is not employed for the analysis of non-polar hydrocarbons, but under some circumstances, they are effectively ionized. Polyaromatic hydrocarbons and aromatic heterocycles can form radical ions and protonated molecules after ESI, which were detected by Fourier transform ion cyclotron resonance mass spectrometry. The highly condensed aromatic structures are obtained from a heavy crude oil, and the results show class distribution from pure hydrocarbons up to more non-basic nitrogen-containing species. By using different solvent compositions [toluene/methanol (50/50 v/v), dichloromethane/methanol (50/50 v/v), dichloromethane/acetonitrile (50/50 v/v) and chloroform], the results show that the lack of proton donor agent helps to preserve the radical formation that was created at the metal/solution interface inside the electrospray capillary. The results demonstrate that with an appropriate selection of solvent and capillary voltage, the ratio between the detected radical ion and protonated molecule form can be manipulated. Therefore, ESI can be expanded for the investigation of asphaltene and other polyaromatic systems beyond the polar constituents as non-polar hydrocarbons can be efficiently analyzed. PMID- 25800192 TI - Direct chemical profiling of olive (Olea europaea) fruit epicuticular waxes by direct electrospray-ultrahigh resolution mass spectrometry. AB - In the present paper, an electrospray ionization (ESI)-Orbitrap method is proposed for the direct chemical profiling of epicuticular wax (EW) from Olea europaea fruit. It constitutes a rapid and efficient tool suitable for a wide ranging screening of a large number of samples. In a few minutes, the method provides a comprehensive characterization of total EW extracts, based on the molecular formula of their components. Accurate mass measurements are obtained by ultrahigh resolution mass spectrometry, and compositional restrictions are set on the basis of the information available from previous studies of olive EW. By alternating positive and negative ESI modes within the same analysis, complementary results are obtained and a wide range of chemical species is covered. This provides a detailed compositional overview that otherwise would only be available by applying multiple analytical techniques. PMID- 25800193 TI - A UPLC-MS/MS method for simultaneous quantitation of three monoterpene glycosides and four alkaloids in rat plasma: application to a comparative pharmacokinetic study of Huo Luo Xiao Ling Dan and single herb extract. AB - The objective of this study was to develop a sensitive and reliable ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantitation of three monoterpene glycosides (paeoniflorin, alibiflorin and oxypaeoniflorin) and four alkaloids (tetrahydropalmatine, corydaline, dehydrocorydaline and berberine), the main active ingredients of Radix Paeoniae Rubra extract (RPE) and Corydalis yanhusuo extract (CYE) in Huo Luo Xiao Ling Dan (HLXLD), and to compare the pharmacokinetics of these active ingredients in normal and arthritic rats orally administrated with HLXLD or RPE/CYE alone. The analytes and internal standard (IS) (geniposide) were separated on a XBridge C18 column (150 * 4.6 mm, 3.5 um) using gradient elution with the mobile phase consisting of methanol and 0.01% formic acid in water at a flow rate of 0.6 ml/min. The detection of the analytes was performed on Acquity UPLC-MS/MS system with an electrospray ionization and multiple reaction monitoring mode via polarity switching between negative (for monoterpene glycosides) and positive (for alkaloids) ionization mode. The lower limits of quantification were 2.5, 1, 0.5, 0.2, 0.2, 0.02 and 0.01 ng/ml for paeoniflorin, alibiflorin, oxypaeoniflorin, tetrahydropalmatine, corydaline, dehydrocorydaline and berberine, respectively. Intra-day and inter-day precision and accuracy of analytes were well within acceptance criteria (15%). The mean extraction recoveries of analytes and IS from rat plasma were all more than 83.1%. The validated method has been successfully applied to determination of the analytes. Results showed that there were remarkable differences in pharmacokinetic properties of the analytes between herbal formula and single herb group, normal and arthritic group. PMID- 25800194 TI - Influence of surface melting effects and availability of reagent ions on LDI-MS efficiency after UV laser irradiation of Pd nanostructures. AB - In this study, the influence of surface morphology, reagent ions and surface restructuring effects on atmospheric pressure laser desorption/ionization (LDI) for small molecules after laser irradiation of palladium self-assembled nanoparticular (Pd-NP) structures has been systematically studied. The dominant role of surface morphology during the LDI process, which was previously shown for silicon-based substrates, has not been investigated for metal-based substrates before. In our experiments, we demonstrated that both the presence of reagent ions and surface reorganization effects--in particular, melting--during laser irradiation was required for LDI activity of the substrate. The synthesized Pd nanostructures with diameters ranging from 60 to 180 nm started to melt at similar temperatures, viz. 890-898 K. These materials exhibited different LDI efficiencies, however, with Pd-NP materials being the most effective surface in our experiments. Pd nanostructures of diameters >400-800 nm started to melt at higher temperatures, >1000 K, making such targets more resistant to laser irradiation, with subsequent loss of LDI activity. Our data demonstrated that both melting of the surface structures and the presence of reagent ions were essential for efficient LDI of the investigated low molecular weight compounds. This dependence of LDI on melting points was exploited further to improve the performance of Pd-NP-based sampling targets. For example, adding sodium hypophosphite as reducing agent to Pd electrolyte solutions during synthesis lowered the melting points of the Pd-NP materials and subsequently gave reduced laser fluence requirements for LDI. PMID- 25800195 TI - Positional isomer differentiation of synthetic cannabinoid JWH-081 by GC-MS/MS. AB - Like many new designer drugs of abuse, synthetic cannabinoids (SC) have structural or positional isomers which may or may not all be regulated under law. Differences in acute toxicity may exist between isomers which impose further burden in the fields of forensic toxicology, medicine and legislation. Isomer differentiation therefore becomes crucial from these standpoints as new designer drugs continuously emerge with just minor positional modifications to their preexisting analogs. The aim of this study was to differentiate the positional isomers of JWH-081. Purchased standard compounds of JWH-081 and its positional isomers were analyzed by gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) first in scan mode to investigate those isomers who could be differentiated by EI scan spectra. Isomers with identical or near-identical EI spectra were further subjected to GC-tandem mass spectrometry (MS/MS) analysis with appropriate precursor ions. EI scan was able to distinguish 3 of the 7 isomers: 2-methoxy, 7-methoxy and 8-methoxy. The remaining isomers exhibited near identical spectra; hence, MS/MS was performed by selecting m/z 185 and 157 as precursor ions. 3-Methoxy and 5-methoxy isomers produced characteristic product ions that enabled the differentiation between them. Product ion spectrum of 6 methoxy isomer resembled that of JWH-081; however, the relative ion intensities were clearly different from one another. The combination of EI scan and MS/MS allowed for the regioisomeric differentiation of the targeted compounds in this study. PMID- 25800196 TI - [M + H]- ion in isodiospyrin detected by ESI-MS. PMID- 25800197 TI - Quick quantification of proteins by MALDI. AB - Previously, we reported that the matrix-assisted laser desorption ionization spectrum of a peptide became reproducible when an effective temperature was held constant. Using a calibration curve drawn by plotting the peptide-to-matrix ion abundance ratio versus the peptide concentration in a solid sample, a peptide could be quantified without the use of any internal standard. In this work, we quantified proteins by quantifying their tryptic peptides with the aforementioned method. We modified the digestion process; e.g. disulfide bonds were not cleaved, so that hardly any reagent other than trypsin remained after the digestion process. This allowed the preparation of a sample by the direct mixing of a digestion mixture with a matrix solution. We also observed that the efficiency of the matrix-to-peptide proton transfer, as measured by its reaction quotient, was similar for peptides with arginine at the C-terminus. With the reaction quotient averaged over many such peptides, we could rapidly quantify proteins. Most importantly, no peptide standard, not to mention its isotopically labeled analog, was needed in this method. PMID- 25800198 TI - Heterogeneity of peptide adducts with carbonylated lipid peroxidation products. AB - Highly reactive lipid peroxidation-derived carbonyls (oxoLPP) modify protein nucleophiles via Michael addition or Schiff base formation. Once formed, Michael adducts can be further stabilized via cyclic hemiacetals with or without loss of water. Depending on the mechanism of their formation, peptide-oxoLPP can carry aldehyde or keto groups and thus be a part of the total protein carbonylation level. If a carbonyl function is lost during consecutive reactions, the oxoLPP peptide adducts will not be detected using the common carbonyl labeling protocols. Because of the differences in adduct stabilities, it is possible to address the heterogeneity of peptide/protein-oxoLPP adducts by careful evaluation of tandem mass spectra of modified peptides. Here, we used hydrophilic interaction liquid chromatography-tandem mass spectrometry analysis of lysine, cysteine and histidine containing model peptides co-incubated with oxidized 1 palmitoyl-2-linoleoyl-sn-glycerophosphatidylcholine to characterize the collision induced dissociation behavior of peptide-carbonyl adducts. Numerous modifications were detected based on the analysis of tandem mass spectra, including Schiff bases on lysine (two), Michael adducts on lysine (six), cysteine (eleven) and histidine (two), as well as 4-hydroxy-2-aldehydes derived dehydrated cyclic hemiacetals on cysteine (five) and histidine (one). Additionally, cysteine and histidine side chains were modified by lipid-bound aldehydes as Michael adducts and dehydrated hemiacetals. The tandem mass spectra revealed collision-induced dissociation characteristics specific for each class of oxoLPP-peptide adducts. PMID- 25800199 TI - Specific tandem mass spectrometric detection of AGE-modified arginine residues in peptides. AB - Glycation is a non-enzymatic reaction of protein amino and guanidino groups with reducing sugars or dicarbonyl products of their oxidative degradation. Modification of arginine residues by dicarbonyls such as glyoxal and methylglyoxal results in formation of advanced glycation end-products (AGEs). In mammals, these modifications impact in diabetes mellitus, uremia, atherosclerosis and ageing. However, due to the low abundance of individual AGE-peptides in enzymatic digests, these species cannot be efficiently detected by LC-ESI-MS based data-dependent acquisition (DDA) experiments. Here we report an analytical workflow that overcomes this limitation. We describe fragmentation patterns of synthetic AGE-peptides and assignment of modification-specific signals required for unambiguous structure retrieval. Most intense signals were those corresponding to unique fragment ions with m/z 152.1 and 166.1, observed in the tandem mass spectra of peptides, containing glyoxal- and methylglyoxal-derived hydroimidazolone AGEs, respectively. To detect such peptides, specific and sensitive precursor ion scanning methods were established for these signals. Further, these precursor ion scans were incorporated in conventional bottom-up proteomic approach based on data-dependent acquisition (DDA) LC-MS/MS experiments. The method was successfully applied for the analysis of human serum albumin (HSA) and human plasma protein tryptic digest with subsequent structure confirmation by targeted LC-MS/MS (DDA). Altogether 44 hydroimidazolone- and dihydroxyimidazolidine-derived peptides representing 42 AGE-modified proteins were identified in plasma digests obtained from type 2 diabetes mellitus (T2DM) patients. PMID- 25800200 TI - Characterization of the dehydration products due to thermal decomposition of peptides by liquid chromatography-tandem mass spectrometry. AB - Thermal decomposition (TD) of proteins is being investigated as a rapid digestion step for bottom-up proteomics. Mass spectrometry (MS) analyses of the TD products of simple peptides and intact proteins have revealed several nonvolatile products at masses lower than the precursor biomolecule (M). In addition to products stemming from site-specific cleavages, many signals are also observed at a corresponding M-18, most likely because of dehydration (M-H2O) during the heating process. Understanding the structural nature of the water loss product is important in establishing the utility of their tandem mass spectra (collision induced dissociation) in determining the precursor ion amino acid sequence in a bottom-up proteomic workflow. Dehydration of a peptide can take place from a variety of sources including side chain groups, C-terminus, and/or intramolecular cyclization (C to N-terminus cyclization). In this work, liquid chromatography tandem MS (LC-MS/MS) and a series of standard peptides (angiotensin II, DRVYIHPF and its cyclic analog) are implemented to decipher the structure of the TD dehydration product. In addition, a derivatization strategy incorporating N terminus acetylation was developed that allowed the direct comparison of tandem mass spectra of standard cyclic peptides with those resulting from the TD process, thus eliminating any ambiguity from the direct comparison of their mass spectra (due to gas-phase cyclization of b-ions, which can result in sequence scrambling of the precursor ion). Results from these investigations indicated that peptide dehydrated TD products were mostly linear in nature, and water loss was favored from the C-terminus carboxyl group or, when present, the aspartic acid side chain. Given the predictable nature of the formation of TD dehydration products, their MS/MS analysis can be of utility in providing complementary and confirmatory sequence information of the precursor peptide. PMID- 25800201 TI - Detection and characterization of prednisolone metabolites in human urine by LC MS/MS. AB - Glucocorticosteroids are prohibited in sports when used by systemic administrations (e.g. oral), whereas they are allowed using other administration ways. Strategies to discriminate between administrations routes have to be developed by doping control laboratories. For this reason, the metabolism of prednisolone (PRED) was studied using liquid chromatography coupled to tandem mass spectrometry. A single oral (10 mg) dose of PRED was administered to two healthy male volunteers. Urine samples were collected up to 6 days after administration. Samples were hydrolyzed with beta-glucuronidase and subjected to liquid-liquid extraction with ethyl acetate in alkaline conditions. The extracts were analyzed by liquid chromatography coupled to tandem mass spectrometry. Precursor ion scan methods (m/z 77, 91, 105, 121, 147 and 171) in positive ionization and neutral loss scan methods (76 and 94 Da) in negative ionization modes were applied for the open detection of PRED metabolites. Using these methods, PRED parent compound plus 20 metabolites were detected. PRED and 11 metabolites were characterized by comparison with standards of the compounds (PRED, prednisone, 20beta-dihydro-PRED and 20alpha-dihydro-PRED, 20beta-dihydro prednisone and 20alpha-dihydro-prednisone, 6beta-hydroxy-PRED and 6alpha-hydroxy PRED, 20beta isomers and 20alpha isomers of 6beta,11beta,17alpha,20,21 pentahydroxypregnan-1,4-diene-3-one, 6alpha,11beta,17alpha,20beta,21 pentahydroxypregnan-1,4-diene-3-one and Delta(6) -PRED). Using mass spectrometric data, feasible structures were proposed for seven of the remaining nine detected metabolites, including several 6-hydroxy-metabolites. Eleven of the characterized metabolites have not been previously described. Maximum excretion rates for PRED metabolites were achieved in first 24 h; however, most of the metabolites were still detectable in the last collected samples (day 6). PMID- 25800202 TI - Proton transfer and isotope-induced reaction in aniline cluster ions. AB - The proton transfer (PT) and other intraclusters reactions occurring after electron ionization of aniline clusters (PhNH2)N are investigated by the time-of flight mass spectrometry. The mass spectra are recorded for different expansion conditions leading to the generation of different cluster sizes. Several fragment ions are shown to originate from intracluster reactions, namely, [Ph](+), [PhNH3](+) and [Ph-N-Ph](+). Reaction schemes are proposed for these ions starting with the PT process. The mass region beyond the monomer mass is dominated by cluster ions (PhNH2)n(+) accompanied by satellites with +/-H and +2H. In experiments with deuterated species, new fragment ions are identified. The aniline isotopomer d5-PhNH2 yields the fragment ions (PhNH2)n?(N-Ph-NH2)(+). Analogical series is observed in experiments with d7-PhND2, and additional fragments occur corresponding to (PhND2)n?(D2N-ND-Ph-ND-ND2)(+) ions. The possible reaction pathways to these ions and the unusual isotope effects are discussed. PMID- 25800205 TI - Catastrophic outcome in a type 1 complex regional pain syndrome. PMID- 25800204 TI - The sedative effects of intramuscular low-dose medetomidine in combination with butorphanol or methadone in dogs. AB - OBJECTIVE: To compare the sedative effects of an intramuscular (IM) low dose of medetomidine in combination with butorphanol or methadone in dogs. STUDY DESIGN: Prospective, blinded, randomized clinical trial. ANIMALS: Forty-eight healthy adult dogs that required sedation for diagnostic or surgical elective procedures. METHODS: Dogs were sedated IM with medetomidine (2.5 MUg kg(-1)) and either butorphanol (0.4 mg kg(-1)) or methadone (0.4 mg kg(-1)). The degree of sedation was assessed every 10 minutes, for 30 minutes, using a numeric descriptive scale. Data on heart rate (HR), respiratory rate, capillary refill time, temperature and response to a toe pinch were recorded. The response to venous catheterization at minute 30 was also evaluated. RESULTS: Both combinations produced moderate to deep sedation with a maximal effect at 20-30 minutes without significant differences in the degree of sedation between the treatments at any studied time point. HR decreased from minute 10 to minute 30 with both opioid combinations (p<0.05); this reduction did not differ between groups (p>0.05). No differences between groups were detected in any of the other variables. CONCLUSIONS AND CLINICAL RELEVANCE: Combinations of a low dose of medetomidine with butorphanol or methadone, respectively, provide similar degrees of sedation. PMID- 25800207 TI - Predicting moment-to-moment attentional state. AB - Although fluctuations in sustained attention are ubiquitous, most psychological experiments treat them as noise, averaging performance over many trials. The current study uses multi-voxel pattern analysis (MVPA) to decode whether, on each trial of a cognitive task, participants are in an optimal or suboptimal attentional state. During fMRI, participants performed n-back tasks, composed of central face images overlaid on distractor scenes, with low, perceptual, and working memory load. Instructions were to respond to novel faces and withhold response to rare repeats. To index attentional state, reaction time variability was calculated at each correct response. Participants' 50% least variable trials were labeled optimal, or "in the zone," and their 50% most erratic trials were labeled suboptimal, or "out of the zone." Support vector machine classifiers trained on activity in the default mode network (DMN), dorsal attention network (DAN), and task-relevant fusiform face area (FFA) distinguished in-the-zone and out-of-the-zone trials in all tasks. Consistent with evidence that distractors are processed when central task load is low, parahippocampal place area (PPA) classifiers were only successful in the low load task. Classification in anatomical regions across the brain revealed widespread coding of attentional state. In contrast to these robust pattern analyses, univariate signal in DMN, DAN, FFA, and PPA did not distinguish states, suggesting a nuanced relationship to sustained attention. In sum, MVPA can be used to decode trial-by-trial attentional state throughout much of cortex, helping to characterize how attention network fluctuations correlate with performance variability. PMID- 25800206 TI - C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema. AB - BACKGROUND: The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. METHODS: C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method. RESULTS: C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo. CONCLUSION: Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system. GENERAL SIGNIFICANCE: The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS. PMID- 25800208 TI - A systematic review and meta-analysis of longitudinal hippocampal atrophy in healthy human ageing. AB - INTRODUCTION: This review aimed to produce hippocampal atrophy rate estimates from healthy ageing studies as well as control samples from observational studies across the adult lifespan which can be used as benchmarks to evaluate abnormal changes in pathological conditions. METHODS: The review followed PRISMA guidelines. PUBMED (to February 2014) was searched for longitudinal MRI studies reporting hippocampal atrophy or volume change in cognitively healthy individuals. Titles were screened and non-English, duplicate or irrelevant entries were excluded. Remaining record abstracts were reviewed to identify studies for full text retrieval. Full text was retrieved and screened against inclusion/exclusion criteria. Bibliographies and previous reviews were examined to identify additional studies. Data were summarised using meta-analysis and age, segmentation technique and study type were tested as potential moderators using meta-regression. It was hypothesised that population studies would produce higher atrophy rates than clinical observational studies. RESULTS: The systematic search identified 4410 entries and 119 studies were retrieved with 58 failing selection or quality criteria, 30 were excluded as multiple reports and 3 studies were unsuitable for meta-analysis. The remaining 28 studies were included in the meta analysis, n=3422, 44.65% male, 11,735 person-years of follow-up, mean age was 24.50 to 83 years. Mean total hippocampal atrophy for the entire sample was 0.85% per year (95% CI 0.63, 1.07). Age based atrophy rates were 0.38% per year (CI 0.14, 0.62) for studies with mean age <55 years (n=413), 0.98% (CI 0.27, 1.70) for 55 to <70 years (n=426), and 1.12% (CI 0.86, 1.38) for >=70 years (n=2583). Meta-regression indicated age was associated with increased atrophy rates of 0.0263% (CI 0.0146, 0.0379) per year and automated segmentation approaches were associated with a reduced atrophy rate of -0.466% (CI -0.841, -0.090). Population studies were not associated with a significant effect on atrophy. Analyses of 11 studies separately measuring left and right hippocampal atrophy (n=1142) provided little evidence of laterality effects. While no study separately reported atrophy by gender, a number tested for gender effects and 2 studies reported higher atrophy in males. CONCLUSIONS: Hippocampal atrophy rates increase with age with the largest increases occurring from midlife onwards. Manual segmentation approaches result in higher measured atrophy rates. PMID- 25800209 TI - MRI-detectable changes in mouse brain structure induced by voluntary exercise. AB - Physical exercise, besides improving cognitive and mental health, is known to cause structural changes in the brain. Understanding the structural changes that occur with exercise as well as the neuroanatomical correlates of a predisposition for exercise is important for understanding human health. This study used high resolution 3D MR imaging, in combination with deformation-based morphometry, to investigate the macroscopic changes in brain structure that occur in healthy adult mice following four weeks of voluntary exercise. We found that exercise induced changes in multiple brain structures that are involved in motor function and learning and memory including the hippocampus, dentate gyrus, stratum granulosum of the dentate gyrus, cingulate cortex, olivary complex, inferior cerebellar peduncle and regions of the cerebellum. In addition, a number of brain structures, including the hippocampus, striatum and pons, when measured on MRI prior to the start of exercise were highly predictive of subsequent exercise activity. Exercise tended to normalize these pre-existing differences between mice. PMID- 25800210 TI - Responsibility modulates pain-matrix activation elicited by the expressions of others in pain. AB - Here we examine whether brain responses to dynamic facial expressions of pain are influenced by our responsibility for the observed pain. Participants played a flanker task with a confederate. Whenever either erred, the confederate was seen to receive a noxious shock. Using functional magnetic resonance imaging, we found that regions of the functionally localized pain-matrix of the participants (the anterior insula in particular) were activated most strongly when seeing the confederate receive a noxious shock when only the participant had erred (and hence had full responsibility). When both or only the confederate had erred (i.e. participant's shared or no responsibility), significantly weaker vicarious pain matrix activations were measured. PMID- 25800212 TI - Which motor cortical region best predicts imagined movement? AB - In brain-computer interfacing (BCI), motor imagery is used to provide a gateway to an effector action or behavior. However, in contrast to the main functional role of the primary motor cortex (M1) in motor execution, the M1's involvement in motor imagery has been debated, while the roles of secondary motor areas such as the premotor cortex (PMC) and supplementary motor area (SMA) in motor imagery have been proposed. We examined which motor cortical region had the greatest predictive ability for imagined movement among the primary and secondary motor areas. For two modes of motor performance, executed movement and imagined movement, in 12 healthy subjects who performed two types of motor task, hand grasping and hand rotation, we used the multivariate Bayes method to compare predictive ability between the primary and secondary motor areas (M1, PMC, and SMA) contralateral to the moved hand. With the distributed representation of activation, executed movement was best predicted from the M1 while imagined movement from the SMA, among the three motor cortical regions, in both types of motor task. In addition, the most predictive information about the distinction between executed movement and imagined movement was contained in the M1. The greater predictive ability of the SMA for imagined movement suggests its functional role that could be applied to motor imagery-based BCI. PMID- 25800213 TI - Experimental arthritis: in vivo noninvasive molecular optical imaging of disease. PMID- 25800211 TI - Dopamine and memory dedifferentiation in aging. AB - The dedifferentiation theory of aging proposes that a reduction in the specificity of neural representations causes declines in complex cognition as people get older, and may reflect a reduction in dopaminergic signaling. The present pharmacological fMRI study investigated episodic memory-related dedifferentiation in young and older adults, and its relation to dopaminergic function, using a randomized placebo-controlled double-blind crossover design with the agonist Bromocriptine (1.25mg) and the antagonist Sulpiride (400mg). We used multi-voxel pattern analysis to measure memory specificity: the degree to which distributed patterns of activity distinguishing two different task contexts during an encoding phase are reinstated during memory retrieval. As predicted, memory specificity was reduced in older adults in prefrontal cortex and in hippocampus, consistent with an impact of neural dedifferentiation on episodic memory representations. There was also a linear age-dependent dopaminergic modulation of memory specificity in hippocampus reflecting a relative boost to memory specificity on Bromocriptine in older adults whose memory was poorer at baseline, and a relative boost on Sulpiride in older better performers, compared to the young. This differed from generalized effects of both agents on task specificity in the encoding phase. The results demonstrate a link between aging, dopaminergic function and dedifferentiation in the hippocampus. PMID- 25800214 TI - Clocking in: chronobiology in rheumatoid arthritis. AB - Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning. Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the 'circadian concept' in rheumatology from bench to bedside. PMID- 25800216 TI - Active-comparator design and new-user design in observational studies. AB - Over the past decade, an increasing number of observational studies have examined the effectiveness or safety of treatments for rheumatoid arthritis. Unlike randomized controlled trials (RCTs), however, observational studies of drug effects have methodological limitations such as confounding by indication. Active comparator designs and new-user designs can help mitigate such biases in observational studies and improve the validity of their findings by making them more closely approximate RCTs. In an active-comparator study, the drug of interest is compared with another agent commonly used for the same indication, rather than with no treatment (a 'non-user' group). This principle helps to ensure that treatment groups have similar treatment indications, attenuating both measured and unmeasured differences in patient characteristics. The new-user study includes a cohort of patients from the time of treatment initiation, enabling assessment of patients' pretreatment characteristics and capture of all events occurring during follow-up. These two principles should be considered when designing or reviewing observational studies of drug effects. PMID- 25800215 TI - Cellular imaging in rheumatic diseases. AB - Developments in cellular imaging now enable the real-time visualization of the choreographed sequence of events that underlie the development of immune responses in vivo. The previously unappreciated dynamics and anatomical context of cellular interactions, revealed in these studies, can have profound consequences for the 'decision' by the immune system to induce immunological priming versus immunological tolerance. Importantly, dysregulation of this balance can result in autoimmune diseases such as rheumatoid arthritis (RA). By further developing our understanding of how, where and when cells interact during immune responses, we can further dissect these events to assess how cell interactions might be aberrant in autoimmunity. A better knowledge of the mechanisms involved in cellular interactions by means of cellular imaging can help the development and targeting of therapies to particular disease stages and tissues in patients with RA in efforts to restore immune homeostasis. PMID- 25800218 TI - Family load impacts orbitofrontal volume in first-episode schizophrenia. AB - In schizophrenia, reduced orbitofrontal cortex (OFC) volume is inconsistently reported. To investigate the impact of genetic load on OFC volume, manual MRI tracing in 23 first-episode schizophrenia patients (FE-SZ) and 23 controls was performed. FE-SZ with genetic load showed a decrease in OFC volume compared to FE SZ without load and controls. PMID- 25800219 TI - RNs' Transitions into Director of Nursing Positions in Nursing Homes: Hiring Practices and Role Development. AB - The current paper discusses RNs' transitions into their first nursing home director of nursing (DON) position, including hiring practice and role development. A convenience sample of 29 current and previous DONs and nursing home administrators completed semistructured interviews for the current qualitative, descriptive study. Using thematic analysis, the finding revealed three primary themes: (a) DON hiring criteria are not necessarily matched to role demands; (b) various pathways to developing DON expertise suggest an undervaluing of the competencies needed to effectively enact this nursing leadership position; and (c) although limited formal training for the DON position was well acknowledged, concerns or reports of the consequences varied, and there is no consensus as to the optimal route to preparation. Overall, the current study findings highlight gaps across practice, policy, and research, emphasizing the consequences of limited attention to gathering evidence of the breadth and depth of DON role demands and related role qualifications. PMID- 25800220 TI - Mitochondrial antiviral signaling adaptor mediated apoptosis in H3N2 swine influenza virus infection is inhibited by viral protein NS1 in vitro. AB - We investigated the in vitro role of mitochondrial antiviral signaling adaptor (MAVS) in apoptosis induced by H3N2 swine influenza virus infection and the influence of viral NS1 (nonstructural protein 1) protein on this process. H3N2 swine influenza virus (SIV, A/Swine/Shandong/3/2005) was co-cultured with human lung epithelial A549 cells. The relationship of MAVS expression to SIV replication and apoptosis, and the influence of viral proteins on MAVS functions were studied. The data indicate that in response to SIV infection, MAVS was significantly upregulated at both the transcriptional and protein levels in the early stages of infection. Its expression and localization to mitochondria are necessary for apoptosis of epithelial cells induced by H3N2 swine influenza virus. Viral protein NS1 can antagonize MAVS-mediated apoptosis. These findings indicate that MAVS have a role in regulating innate mitochondrial responses to viral infection. PMID- 25800217 TI - The clinical spectrum of autoimmune congenital heart block. AB - Autoimmune congenital heart block (CHB) is an immune-mediated acquired disease that is associated with the placental transference of maternal antibodies specific for Ro and La autoantigens. The disease develops in a fetal heart without anatomical abnormalities that could otherwise explain the block, and which is usually diagnosed in utero, but also at birth or within the neonatal period. Autoantibody-mediated damage of fetal conduction tissues causes inflammation and fibrosis and leads to blockage of signal conduction at the atrioventricular (AV) node. Irreversible complete AV block is the principal cardiac manifestation of CHB, although some babies might develop other severe cardiac complications, such as endocardial fibroelastosis or valvular insufficiency, even in the absence of cardiac block. In this Review, we discuss the epidemiology, classification and management of women whose pregnancies are affected by autoimmune CHB, with a particular focus on the autoantibodies associated with autoimmune CHB and how we should test for these antibodies and diagnose this disease. Without confirmed effective preventive or therapeutic strategies and further research on the aetiopathogenic mechanisms, autoimmune CHB will remain a severe life-threatening disorder. PMID- 25800221 TI - Cytokine mRNA profiling and the proliferative response of bovine peripheral blood mononuclear cells to Mycoplasma bovis. AB - Mycoplasma bovis is known as a significant pathogen and cause of large economic losses in beef and dairy calves worldwide. Numerous factors appear to play an important role in the development of disease during infection with M. bovis, e.g., inhibition of immune cell proliferation and induction of lymphocyte apoptosis. However, the mechanisms involved in M. bovis infections have not been explored and remain incompletely understood. We investigated the major cytokine mRNA expression in bovine PBMC stimulated with M. bovis, for comparison, Staphylococcus aureus and Escherichia coli, which are the representative mastitis causing pathogens. Here we demonstrated that live M. bovis significantly induced tumor necrosis factor alpha (TNF-alpha), interleukin 12p40 (IL-12), and interferon gamma (IFN-gamma) mRNA expression in bovine peripheral blood mononuclear cells (PBMC) at a multiplicity of infection (MOI) of 1000 but not at an MOI of 10 and 100. Live M. bovis at MOIs of 1, 10, and 100 induced significant bovine PBMC proliferative responses compared with unstimulated bovine PBMC. Furthermore, we showed that the cultural supernatant of M. bovis induced a significant increase in TNF-alpha, IL-6, and IL-10 mRNA expression in bovine PBMC. Our results suggest that M. bovis weakly affects the cellular integrity of bovine PBMC and induces clear proliferative responses and associated cytokine production in them. However, large numbers of live M. bovis are required to induce an immune response in bovine PBMC. PMID- 25800222 TI - Response to: PLEC1 mutation associated with left ventricular hypertrabeculation/noncompaction. PMID- 25800223 TI - Comparison of light, food, and temperature as environmental synchronizers of the circadian rhythm of activity in mice. AB - Although entrainment (and masking) of circadian rhythms by light has been extensively studied, much less attention has been given to other environmental cycles that can modulate circadian rhythms in mammals. In this study in mice, the entraining strength of different environmental cycles was compared. Running-wheel activity was monitored before, after, and while the animals were under one of four environmental cycles: a full light-dark cycle with 12 h of light and 12 h of darkness each day, a cycle of 1 h of light per day, a cycle of food availability consisting of 80% of the baseline free-feeding amount presented once a day, and an ambient temperature cycle consisting of 23 h at 24 degrees C and 1 h at 12 degrees C each day. Four measures of zeitgeber strength were used: percentage of animals that entrained, rhythm robustness in the entrained state, stability of activity onsets, and stability of acrophases. The results indicate that, at least in mice, a full light-dark cycle is the most powerful modulator of the circadian rhythm of locomotor activity, as a consequence of both entrainment and masking. When entrainment alone is considered, temperature seems to be as strong a modulator as light, while food restriction is a weaker modulator and affects primarily a food-anticipatory component of the activity rhythm. PMID- 25800224 TI - Assessment of the role of silicon in the Cu-tolerance of the C4 grass Spartina densiflora. AB - An experiment was designed to investigate the effect of silicon supply (0 and 500 MUM) on Spartina densiflora plants grown at two copper (Cu) concentrations: 0 and 15 mM. Growth parameters together with total concentrations of calcium, Cu, potassium, magnesium, manganese, sodium and nitrogen were determined in roots and leaves. Photosynthetic traits were followed by measurement of leaf gas exchange, efficiency of PSII biochemistry, total content of photosynthetic pigments and concentration and carbamylation of Rubisco sites concentration ([Rubisco]). Respiration and oxygen isotope fractionation were measured in roots to study the in vivo activities of cytochrome oxidase (COX) and alternative oxidase (AOX) pathways, as well as AOX capacity. The results confirm that Si supply improves growth of S. densiflora under Cu stress. Improved growth was associated with higher net photosynthetic rate. Beneficial effect of Si on S. densiflora photosynthetic apparatus was associated with a reduction of the Cu impact on active Rubisco sites, as well as on the photochemical apparatus and chlorophyll concentration. Moreover, ameliorative effects of Si were associated with the avoidance of Cu translocation from roots to leaves. Finally in vivo activities of COX and AOX pathways were strongly inhibited in Cu-treated plants, and this reduction was not mitigated by Si-treatment. Therefore, Si appears to play an important role in Cu-tolerance of S. densiflora, not by avoiding its uptake by roots, but via some mechanism to avoid Cu translocation from roots to leaves, resulting in a general reduction of Cu-induced deleterious effects on the leaf photosynthetic apparatus. PMID- 25800225 TI - Nitrogen availability regulates proline and ethylene production and alleviates salinity stress in mustard (Brassica juncea). AB - Proline content and ethylene production have been shown to be involved in salt tolerance mechanisms in plants. To assess the role of nitrogen (N) in the protection of photosynthesis under salt stress, the effect of N (0, 5, 10, 20 mM) on proline and ethylene was studied in mustard (Brassica juncea). Sufficient N (10 mM) optimized proline production under non-saline conditions through an increase in proline-metabolizing enzymes, leading to osmotic balance and protection of photosynthesis through optimal ethylene production. Excess N (20 mM), in the absence of salt stress, inhibited photosynthesis and caused higher ethylene evolution but lower proline production compared to sufficient N. In contrast, under salt stress with an increased demand for N, excess N optimized ethylene production, which regulates the proline content resulting in recovered photosynthesis. The effect of excess N on photosynthesis under salt stress was further substantiated by the application of the ethylene biosynthesis inhibitor, 1-aminoethoxy vinylglycine (AVG), which inhibited proline production and photosynthesis. Without salt stress, AVG promoted photosynthesis in plants receiving excess N by inhibiting stress ethylene production. The results suggest that a regulatory interaction exists between ethylene, proline and N for salt tolerance. Nitrogen differentially regulates proline production and ethylene formation to alleviate the adverse effect of salinity on photosynthesis in mustard. PMID- 25800227 TI - Synthetic artificial microRNAs targeting UCA1-MALAT1 or c-Myc inhibit malignant phenotypes of bladder cancer cells T24 and 5637. AB - The biggest concern of using natural microRNAs for treating cancer is that they usually cause few phenotypic changes due to the divergent functions of their target genes. Based on the engineering principles of synthetic biology, we provided a standard platform for constructing artificial microRNAs that can target one or few specific genes and silence both protein-coding genes and long non-coding genes. To prove the utility of this platform, we chose MALAT1, UCA1, and c-Myc as the functional targets and used the bladder cancer cell lines T24 and 5637 as the test models. The relative expression level of the target genes was measured by qRT-PCR. Cell proliferation and migration were determined by MTT assay and wound-healing assay, respectively. Cell apoptosis was revealed by both Hoechst 33258 staining assay and ELISA assay. We found that the artificial microRNAs can effectively silence their target genes and induce anti-cancer effects in T24 and 5637 cells. These devices can inhibit proliferation, induce apoptosis, and suppress migration of the two bladder cancer cell lines. The synthetic artificial microRNAs may represent a kind of novel genetic devices for treating human bladder cancer. PMID- 25800226 TI - Respiratory Care of Infants and Children with Congenital Tracheo-Oesophageal Fistula and Oesophageal Atresia. AB - Despite acute respiratory and chronic respiratory and gastro-intestinal complications, most infants and children with a history of oesophageal atresia / trachea-oesophageal fistula [OA/TOF] can expect to live a fairly normal life. Close multidisciplinary medical and surgical follow-up can identify important co morbidities whose treatment can improve symptoms and optimize pulmonary and nutritional outcomes. This article will discuss the aetiology, classification, diagnosis and treatment of congenital TOF, with an emphasis on post-surgical respiratory management, recognition of early and late onset complications, and long-term clinical outcomes. PMID- 25800228 TI - Rapid separation of cyanidin-3-glucoside and cyanidin-3-rutinoside from crude mulberry extract using high-performance countercurrent chromatography and establishment of a volumetric scale-up process. AB - This study describes the rapid separation of mulberry anthocyanins; namely, cyanidin-3-glucoside and cyanidin-3-rutinoside, using high-performance countercurrent chromatography, and the establishment of a volumetric scale-up process from semi-preparative to preparative-scale. To optimize the separation parameters, biphasic solvent systems composed of tert-butyl methyl ether/n butanol/acetonitrile/0.01% trifluoroacetic acid, flow rate, sample amount and rotational speed were evaluated for the semi-preparative-scale high-performance countercurrent chromatography. The optimized semi-preparative-scale high performance countercurrent chromatography parameters (tert-butyl methyl ether/n butanol/acetonitrile/0.01% trifluoroacetic acid, 1:3:1:5, v/v; flow rate, 4.0 mL/min; sample amount, 200-1000 mg; rotational speed, 1600 rpm) were transferred directly to a preparative-scale (tert-butyl methyl ether/n butanol/acetonitrile/0.01% trifluoroacetic acid, 1:3:1:5, v/v; flow rate, 28 mL/min; sample amount, 5.0-10.0 g; rotational speed, 1400 rpm) to achieve separation results identical to cyanidin-3-glucoside and cyanidin-3-rutinoside. The separation of mulberry anthocyanins using semi-preparative high-performance countercurrent chromatography and its volumetric scale-up to preparative-scale was addressed for the first time in this report. PMID- 25800230 TI - [Review of diverse research contents in this issue]. PMID- 25800229 TI - The Impact of a Multidimensional Exercise Intervention on Physical and Functional Capacity, Anxiety, and Depression in Patients With Advanced-Stage Lung Cancer Undergoing Chemotherapy. AB - INTRODUCTION: Patients with advanced-stage lung cancer face poor survival and experience co-occurring chronic physical and psychosocial symptoms. Despite several years of research in exercise oncology, few exercise studies have targeted advanced lung cancer patients undergoing chemotherapy. The aim of the present study was to investigate the benefits of a 6-week supervised group exercise intervention and to outline the effect on aerobic capacity, strength, health-related quality of life (HRQoL), anxiety, and depression. METHODS: VO2peak was assessed using an incremental exercise test. Muscle strength was measured with one repetition maximum test (1RM). HRQoL, anxiety, and depression were assessed using Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale (HADS). RESULTS: One hundred and forthteen patients with advanced stage lung cancer were recruited. Forty-three patients dropped out. No serious adverse events were reported. Exercise adherence in the group training was 68%. Improvements in VO2peak (P < .001) and 6-minute walk distance (P < .001) and muscle strength measurements (P < .05) were seen. There was a reduction in anxiety level (P = .0007) and improvement in the emotional well-being parameter (FACT-L) but no statistically significant changes in HRQoL were observed. CONCLUSION: The results of the present study show that during a 6-week hospital-based supervised, structured, and group-based exercise program, patients with advanced-stage lung cancer (NSCLC IIIb-IV, ED-SCLC) improve their physical capacity (VO2peak, 1RM), functional capacity, anxiety level, and emotional well-being, but not their overall HRQoL. A randomized controlled trial testing the intervention including 216 patients is currently being carried out. PMID- 25800231 TI - [Crisis in recruit of competent surgeon in Korea]. PMID- 25800232 TI - Perception of interprofessional conflicts and interprofessional education by doctors and nurses. AB - PURPOSE: This study aimed to collect information that is needed to develop interprofessional education curricula by examining the current status of interprofessional conflicts and the demand for interprofessional education. METHODS: A total of 95 doctors and 92 nurses in three university hospitals in Seoul responded to a survey that comprised questions on past experience with interprofessional conflicts, the causes and solutions of such conflicts, past experience with interprofessional education, and the demand for interprofessional education. RESULTS: We found that 86% of doctors and 62.6% of nurses had no interprofessional education experience. Most of them learned about the work of other health professions naturally through work experience, and many had experienced at least one interprofessional conflict. For doctors, the most popular method of resolving interprofessional conflicts was to let the event pass; for nurses, it was to inform the department head. Further, 41.5% of doctors and 56.7% of nurses expressed no knowledge of an official system for resolving interprofessional conflicts within the hospital, and 62.8% of doctors and 78.3% of nurses stated that they would participate in interprofessional education if the opportunity arose. CONCLUSION: In Korean hospital organizations, many doctors and nurses have experienced conflicts with other health professionals. By developing an appropriate curriculum and educational training system, the opportunities for health professionals to receive interprofessional education should expand. PMID- 25800233 TI - [Basic research to guide alterations in an outcome-based curriculum]. AB - PURPOSE: The purpose of this study is to provide basic information that can be used to guide alterations in an outcome-based curriculum by analyzing the current curriculum. METHODS: A survey was administered to 103 juniors, 90 seniors, and 97 professors in Chonbuk National University Medical School on the importance of subgraduate and graduate outcomes, the appropriate curriculum to graduate, operational satisfaction, and self-judged achievement. RESULTS: There were significantly meaningful gaps in the importance of graduate and subgraduate outcomes. However, students considered other competencies, except for medical research, more important. The survey data on the appropriate curriculum for graduation and on the operational satisfaction with the curriculum show that overall reorganization of the curriculum is needed. Students felt that they achieved 50 to 60 of 100 with regard to graduate outcomes. Further, students recognize that there are no differences in achievement level between genders. But, they believe that seniors achieve more than juniors. CONCLUSION: A multilateral basic analysis can be useful to guide the improvement of an outcome based curriculum to help graduates acquire the ability to provide basic medical treatment. PMID- 25800234 TI - [Team dynamics and clinical performance of medical students in web-based and high fidelity simulations]. AB - PURPOSE: The importance of team dynamics with regard to clinical performance is being emphasized to improve patient safety and the quality of health care. The aim of this study was to examine the correlation and differences in team dynamics and team clinical performance in a web-based simulation (WS) and high-fidelity simulation (HS) in the medical students. METHODS: The simulations were held for 15 teams of fourth year medical students (n=52). They were given two clinical cases, dyspnea (case 1) and chest pain (case 2) by WS and then HS. The scores on the team dynamics and the team's clinical performance were analyzed by paired t test and multiple regression using SPSS version 21.0 (IBM Corp.). RESULTS: The teamwork scores on case 2 (22.67 +/- 6.58) were higher than for case 1 in the HS (20.47 +/- 7.22). Team clinical performance scores were the same the WS and HS. Team clinical performances were significantly associated with team dynamics in both cases by HS. Teamwork scores of team dynamics were each explanation on case 1 (74.9%), case 2 (63.4%) in the HS. CONCLUSION: The team dynamics and clinical performance can improve if undergraduate medical students have more opportunities. They should be trained in these endeavors to become future doctors for which scenario-based simulations could be valuable. PMID- 25800235 TI - [Operation of a school adaptation program considering the interpersonal needs of medical freshmen]. AB - PURPOSE: We examined two overarching topics: What are the Fundamental Interpersonal Relations Orientation-Behavior (FIRO-B), Perceived Stress Scale (PSS), and Self-rating Depression Scale (SDS) scores in medical students? Do their interpersonal needs correlate with stress and depression? METHODS: FIRO-B, PSS-10, and SDS were administered to 82 freshmen in College of Medicine, The Catholic University of Korea in 2014. The data were analyzed by descriptive statistics, frequency, two-way analysis of variance, independent t-test, and Pearson correlation analysis using SPSS version 21.0 (IBM Corp.). RESULTS: The level of interpersonal needs was medium range (mean, 24.52). The mean perceived stress score was 18.6. Also, 59.8% and 40.2% of students had normal range (<20) and high stress (>=20). The mean score for depression was 36.3. Further, 97.6% and 2.4% of students had normal range (<=49) and mild depression (<=59). Wanted behavior correlated with stress (r=0.056) and depression (r=0.021). Expressed behavior correlated negatively with stress (r=-0.206) and depression (r=-0.301). CONCLUSION: The interpersonal needs of medical freshmen are related to stress and depression. These results can be used effectively in school adaptation programs for medical students to improve their quality of life. PMID- 25800236 TI - [The relationship between dental graduate students' MBTI types and academic achievement in problem-based learning]. AB - PURPOSE: The study aimed to determine the personality types of the graduate students in Seoul National University School of Dentistry (SNU SD) and analyze the specific personal types that were linked to their performance in problem based learning (PBL). METHODS: A total of 263 graduate students in SNU SD from 2011 to 2013, participated in PBL and completed the Myers-Briggs Type Indicator (MBTI) GS form, which was analyzed statistically to determine whether their MBTI personality types were independent of their PBL performance. In particular, MBTI types were regressed on evaluation subcategories, including tutor evaluation and oral test. RESULTS: ESTJ (20.9%) and ISTJ (18.6%) were the most common MBTI personality types in dental graduate students. Compared with males, female students performed significantly better on the PBL. Judging was the most notable type in PBL performance, with its J-P index being statistically significant. CONCLUSION: PBL is implemented, based on the perspective of student-centered education. Accordingly, the types of personality that usually matriculate in dental school should be monitored, and a student-centered approach to dental education should be adopted. PMID- 25800237 TI - [Academic burnout and selection-optimization-compensation strategy in medical students]. AB - PURPOSE: This study was conducted to examine the relationship between academic demand, academic burnout, and the selection-optimization-compensation (SOC) strategy in medical students. METHODS: A total of 317 students at Yeungnam University, comprising 90 premedical course students, 114 medical course students, and 113 graduate course students, completed a survey that addressed the factors of academic burnout and the selection-optimization-compensation strategy. We analyzed variances of burnout and SOC strategy use by group, and stepwise multiple regression analysis was conducted. RESULTS: There were significant differences in emotional exhaustion and cynicism between groups and year in school. In the SOC strategy, there were no significant differences between groups except for elective selection. The second-year medical and graduate students experienced significantly greater exhaustion (p<0.001), and first-year premedical students experienced significantly higher cynicism (p<0.001). By multiple regression analysis, subfactors of academic burnout and emotional exhaustion were significantly affected by academic demand (p<0.001), and 46% of the variance was explained. Cynicism was significantly affected by elective selection (p<0.05), and inefficacy was significantly influenced by optimization (p<0.001). CONCLUSION: To improve adaptation, prescriptive strategies and preventive support should be implemented with regard to academic burnout in medical school. Longitudinal and qualitative studies on burnout must be conducted. PMID- 25800238 TI - [Medical student perception of physician values in practice by individual characteristics and preferred medical specialty field]. AB - PURPOSE: Medical students' values figure prominently in their choice of medical specialty; yet, little research has been performed on this topic. The purpose of this study was to analyze the differences in values according to medical students' individual characteristics (medical educational system, gender, and grade) and preferred medical specialty. METHODS: A total of 905 medical students participated in the study; 426 were graduate-entry medical students (GEMS), and 479 were undergraduate medical students (UMS). Further, 561 were male and 316 were female; 356 were in year 1, 219 were in year 2, 230 were in year 3, and 100 were in year 4. Students completed the Physician Values in Practice Scale (PVIPS). The PVIPS comprises six dimensions: autonomy, management, prestige, service, lifestyle, and scholarly pursuits. The data were analyzed by t-test and analysis of variance. RESULTS: GEMS had higher scores for service, management, and scholarly pursuits than UMS. Males had higher scores for prestige, lifestyle, and management, whereas female scored higher on service and scholarly pursuits. Higher grade was associated with increased scores for prestige, lifestyle, and management. The differences in lifestyle and scholarly pursuits were significant between preferred specialties. Students in support specialties scored significantly higher on lifestyle. With regard to scholarly pursuits, basic science specialties scored significantly higher than other specialties. CONCLUSION: There were significant differences in PVIPS according to individual characteristics and preferred medical specialty. This result could be useful in developing a medical specialty choice program for medical students. PMID- 25800239 TI - [Development of a code of professional conduct for medical students and residents]. AB - PURPOSE: The purpose of this study was to describe the development of a code of professional conduct that should be practiced by medical students and residents. METHODS: The content of a draft version of a code of professional conduct was generated through extensive literature reviews and the results of surveys that were administered to students and residents. The content validity for the draft version was reviewed by an expert panel: five experts in medical ethics and eight specialists in medical education. The survey was distributed as an email questionnaire and included closed-ended items and open comments. SPSS for Windows version 12.0 (SPSS Inc.) was used for the analysis. RESULTS: After analyzing the experts' reviews and holding a reiterative discussion, we developed the final version of a code of conduct for professional behavior. It consists of nine categories and 44 items for students and 44 items for residents. The nine categories were academic integrity, responsibility during clerkship or hospital work, endeavor to improve clinical competency, respect for patients and keeping confidentiality, honesty in patient care, boundary issues and conflicts of interests, impaired physician behaviors, respect for others, and research ethics. CONCLUSION: Because our code of conduct for professional behaviors cannot extensively include all aspects of medical professionalism, we focused on behaviors that can be used to monitor and prevent misconduct by medical learners. Further studies and discourse among stakeholders should be performed to develop a national consensus statement or code of conduct to reinforce professionalism for learners in medicine. PMID- 25800241 TI - Management of cervical fractures in ankylosing spondylitis: anterior, posterior or combined approach? AB - INTRODUCTION: Ankylosing spondylitis (AS) can lead to an increased risk of cervical fractures. SOURCES OF DATA: A systematic review was undertaken using the keywords 'ankylosing spondylitis', 'spine fractures', 'cervical fractures', 'surgery' and 'postoperative outcomes' on Medline, Pubmed, Google Scholar, Ovid and Embase, and the quality of the studies included was evaluated according to the Coleman Methodology Score. AREAS OF AGREEMENT: Surgery ameliorates neurological function in patients with unstable AS-related cervical fractures. The combined anterior/posterior and the posterior approaches are more effective than the anterior approach. AREAS OF CONTROVERSY: The optimal approach, anterior, posterior or combined anterior/posterior, for the management of AS related cervical fractures has not been defined. GROWING POINTS: Open reduction and internal fixation allows avoiding worsening and enhances neurological function in AS patients with cervical fractures. AREAS TIMELY FOR DEVELOPING RESEARCH: Adequately powered randomized trials with appropriate subjective and objective outcome measures are necessary to reach definitive conclusions. PMID- 25800243 TI - ImmunoPET in Neoplasms of Gastrointestinal Tract, Liver and Pancreas in the XXIst Century: Bridging the Gap Between Diagnosis and Therapy. AB - Monoclonal antibodies (mAbs) are produced by clones of a unique parent cell which has monovalent affinity and can bind to the same epitope. The chronological breakthrough in mAbs clinical utilization was in 1975, when it becomes possible to produce mAbs to known antigens and immortalize the cell lines. However, the clinical usefulness of mAbs was hampered for many years, basically because of their immunogenicity due to the murine origin. This situation lasted until 1988 when a technique to humanize mAbs was defined. Nuclear Medicine researchers were very quick to gathered the opportunity provided by the development of mAbs. The first papers reporting the preclinical use of radiolabelled mAbs date the early 80's soon followed by the first pivotal use in humans. However, mAbs did not gain a wide clinical use for several reasons connected to the chemistry and biochemistry of radiolabelled mAbs the emergence of clinical 18F-FDG PET. However, the "magic bullet" concept has resisted in the cultural background of Nuclear Medicine physicians for almost twenty years, and has regained importance with the development of engineered mAbs. Herein we present a selected review of preclinical and clinical studies of PET/CT with mAbs in gastrointestinal malignancies. PMID- 25800242 TI - Development and validation of a clinical score for predicting risk of adenoma at screening colonoscopy. AB - BACKGROUND: Currently, no clinical tools use demographic and risk factor information to predict the risk of finding an adenoma in individuals undergoing colon cancer screening. Such a tool would be valuable for identifying those who would most benefit from screening colonoscopy. METHODS: We used baseline data from men and women who underwent screening colonoscopy from the randomized, multicenter National Colonoscopy Study (NCS) to develop and validate an adenoma risk model. The study, conducted at three sites in the United States (Minneapolis, MN; Seattle, WA; and Shreveport, LA) asked all participants to complete baseline questionnaires on clinical risk factors and family history. Model parameters estimated from logistic regression yielded an area under the receiver operating characteristic curve (AUROCC) used to assess prediction. RESULTS: Five hundred forty-one subjects were included in the development model, and 1,334 in the validation of the risk score. Variables in the prediction of adenoma risk for colonoscopy screening were age (likelihood ratio test for overall contribution to model, P < 0.001), male sex (P < 0.001), body mass index (P < 0.001), family history of at least one first-degree relative with colorectal cancer (P = 0.036), and smoking history (P < 0.001). The adjusted AUROCC of 0.67 [95% confidence interval (CI), 0.61-0.74] for the derivation cohort was not statistically significantly different from that in the validation cohort. The adjusted AUROCC for the entire cohort was 0.64 (95% CI, 0.60-0.67). CONCLUSION: We developed and validated a simple well-calibrated risk score. IMPACT: This tool may be useful for estimating risk of adenomas in screening eligible men and women. PMID- 25800244 TI - Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association. AB - Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype. PMID- 25800245 TI - Recent Advances in Gas Barrier Thin Films via Layer-by-Layer Assembly of Polymers and Platelets. AB - Layer-by-layer (LbL) assembly has emerged as the leading non-vacuum technology for the fabrication of transparent, super gas barrier films. The super gas barrier performance of LbL deposited films has been demonstrated in numerous studies, with a variety of polyelectrolytes, to rival that of metal and metal oxide-based barrier films. This Feature Article is a mini-review of LbL-based multilayer thin films with a 'nanobrick wall' microstructure comprising polymeric mortar and nano-platelet bricks that impart high gas barrier to otherwise permeable polymer substrates. These transparent, water-based thin films exhibit oxygen transmission rates below 5 * 10(-3) cm(3) m(-2) day(-1) atm(-1) and lower permeability than any other barrier material reported. In an effort to put this technology in the proper context, incumbent technologies such as metallized plastics, metal oxides, and flake-filled polymers are briefly reviewed. PMID- 25800246 TI - Diagnosis of depressed young people--criterion validity of WHO-5 and HSCL-6 in Denmark and Norway. AB - BACKGROUND: According to the World Health Organization, depression ranks as a major contributor to the global burden of disease. A large proportion of adult depressions had their first appearance in adolescence. Brief and reliable rating scales are needed for early detection. OBJECTIVE: The aim of this study is to validate the WHO-5 and the HSCL-6 for detection of depression among adolescents. METHODS: The project is a GP multicentre study conducted in Denmark and Norway. A total of 294 adolescents (14-16 years) responded by answering a paper- or web based questionnaire and later completed a Composite International Diagnostic Interview, which was used as the gold standard. Depression was defined by ICD-10 criteria. Criterion validity was examined, the likelihood ratios measured and cut offs for depression were calculated using the Youden index. RESULTS: The prevalence of depression was 11.8% in our sample. The optimal cut-off point was 11 for the WHO-5 test and 9 for the HSCL-6 test. There were no gender differences. For the WHO-5 and the HSCL-6, respectively, the sensitivity was 0.88 [95% confidence interval (CI): 0.74-0.96] and 0.85 (95% CI: 0.70-0.94), the specificity was 0.80 (95% CI: 0.75-0.85) and 0.79 (95% CI: 0.74-0.84) and the likelihood ratio was 4.5 and 3.8 (P = 0.39). We observed no statistically significant diagnostic differences with respect to nationality or administration procedure. CONCLUSIONS: The WHO-5 and the HSCL-6 may both serve as valid case finding instruments for depression in young people in primary care. PMID- 25800247 TI - Early diagnostic suggestions improve accuracy of family physicians: a randomized controlled trial in Greece. AB - BACKGROUND: In a recent randomized controlled trial, providing UK family physicians with 'early support' (possible diagnoses to consider before any information gathering) was associated with diagnosing hypothetical patients on computer more accurately than control. Another group of physicians, who gathered information, gave a diagnosis, and subsequently received a list of possible diagnoses to consider ('late support'), were no more accurate than control, despite being able to change their initial diagnoses. OBJECTIVE: To replicate the UK study findings in another country with a different primary health care system. METHODS: All study materials were translated into Greek. Greek family physicians were randomly allocated to one of three groups: control, early support and late support. Participants saw nine scenarios in random order. After reading some information about the patient and the reason for encounter, they requested more information to diagnose. The main outcome measure was diagnostic accuracy. RESULTS: One hundred fifty Greek family physicians participated. The early support group was more accurate than control [odds ratio (OR): 1.67 (1.21-2.31)]. Like their UK counterparts, physicians in the late support group rarely changed their initial diagnoses after receiving support. The pooled OR for the early support versus control comparison from the meta-analysis of the UK and Greek data was 1.40 (1.13-1.67). CONCLUSION: Using the same methodology with a different sample of family physicians in a different country, we found that suggesting diagnoses to consider before physicians start gathering information was associated with more accurate diagnoses. This constitutes further supportive evidence of a generalizable effect of early support. PMID- 25800248 TI - Magnetic resonance imaging and the prediction of outcome in first-episode schizophrenia: a review of current evidence and directions for future research. AB - Magnetic Resonance Imaging (MRI) measures are promising outcome markers for schizophrenia, since regional frontal and temporal grey matter volumes reductions, and enlargement of the ventricles, have been associated with outcome in this disorder. However, a number of methodological issues have limited the potential clinical utility of these findings. This article reviewed studies that examined brain structure at illness onset as a predictor of outcome, discusses the limitations of the findings, and highlights the challenges that would need to be addressed if structural data are to inform the management of an individual patient. METHODS: Using a set of a priori criteria, we systematically searched Medline and EMBASE databases for articles evaluating brain structure at the time of the first psychotic episode and assessed response to treatment, symptomatic outcome, or functional outcome at any point in the first 12 months of illness. RESULTS: The 11 studies identified suggest that alterations in medial temporal and prefrontal cortical areas, and in the networks that connect them with subcortical structures, are promising neuroanatomical markers of poor symptomatic and functional outcomes. CONCLUSION: Neuroimaging data, possibly in combination with other biomarkers of disease, could help stratifying patients with psychoses to generate patient clusters clinically meaningful, and useful to detect true therapeutic effects in clinical trials. Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE), a large multicenter study funded by the FP7 European Commission, could generate these much-needed findings. PMID- 25800249 TI - Brain Correlates of Cognitive Remediation in Schizophrenia: Activation Likelihood Analysis Shows Preliminary Evidence of Neural Target Engagement. AB - Cognitive remediation training (CRT) for schizophrenia has been found to improve cognitive functioning and influence neural plasticity. However, with various training approaches and mixed findings, the mechanisms driving generalization of cognitive skills from CRT are unclear. In this meta-analysis of extant imaging studies examining CRT's effects, we sought to clarify whether varying approaches to CRT suggest common neural changes and whether such mechanisms are restorative or compensatory. We conducted a literature search to identify studies appropriate for inclusion in an activation likelihood estimation (ALE) meta-analysis. Our criteria required studies to consist of training-based interventions designed to improve patients' cognitive or social functioning, including generalization to untrained circumstances. Studies were also required to examine changes in pre- vs posttraining functional activation using functional magnetic resonance imaging or positron emission tomography. The literature search identified 162 articles, 9 of which were appropriate for inclusion. ALE analyses comparing pre- and posttraining brain activation showed increased activity in the lateral and medial prefrontal cortex (PFC), parietal cortex, insula, and the caudate and thalamus. Notably, activation associated with CRT in the left PFC and thalamus partially overlapped with previous meta-analytically identified areas associated with deficits in working memory, executive control, and facial emotion processing in schizophrenia. We conclude that CRT interventions from varying theoretic modalities elicit plasticity in areas that support cognitive and socioemotional processes in this early set of studies. While preliminary, these changes appear to be both restorative and compensatory, though thalamocortical areas previously associated with dysfunction may be common sources of plasticity for cognitive remediation in schizophrenia. PMID- 25800250 TI - The Magic of Movement; the Potential of Exercise to Improve Cognition. PMID- 25800251 TI - Cyclopsomyces plurioperculatus: a new genus and species of Lobulomycetales (Chytridiomycota, Chytridiomycetes) from Japan. AB - Lobulomycetales is one of the smallest orders of Chytridiomycota, containing only four genera and five species. In a survey in Japan we isolated a chytrid from a soil sample collected in a broadleaf forest, which grouped in Lobulomycetales by BLAST query. To identify this chytrid and determine its taxonomic position, thallus development and morphology were observed by light microscopy and zoospore ultrastructure was examined using a transmission electron microscopy. We conducted a phylogenetic analysis using nuc 28S rDNA sequences. Thallus morphology was characterized by a spherical zoosporangium with multiple operculate discharge papillae, which is different from that of any other species in Lobulomycetales. This chytrid is similar to Chytriomyces multioperculatus in having multiple operculate discharge papillae, but these are distinguished by characters of the discharge papillae and rhizoidal systems. Zoospores of this chytrid had electron-dense material in the kinetosome, a unique character in the order. Our 28S phylogeny placed it in a distinct clade, sister to all described species in Lobulomycetaceae. Based on these results, we propose a new genus and species of Lobulomycetales, Cyclopsomyces plurioperculatus. PMID- 25800252 TI - Systematics of the Cosmospora viliuscula species complex. AB - The genus Cosmospora includes nectrioid fungi that grow on polypores and xylariaceous fungi. The collections growing on xylariaceous fungi have been identified recently as Cosmospora viliuscula. In this paper the phylogeny and taxonomy of C. viliuscula are investigated. A phylogeny was generated with maximum likelihood and Bayesian inference methods applied to a three-partition dataset (ITS, 28S, MCM7-RPB1-TUB2). Based on these results, we demonstrate that Cosmospora viliuscula represents a diverse species complex comprising more than 10 species. Seven new species are described, including three single-strain lineages, and the sexual states of C. arxii and C. khandalensis are described for the first time. The sexual states of these fungi tend to have a high degree of morphological homoplasy, making it difficult to differentiate among them based on morphological characters alone. However, the apparent host specificity of species in this complex aide in the diagnosis of these fungi. In addition, the RPB1 marker provides sufficient resolution to distinguish these fungi. PMID- 25800253 TI - 1,2-Benzisoxazole compounds: a patent review (2009 - 2014). AB - INTRODUCTION: Benzisoxazoles represent a class of heterocyclic compounds of great importance for the preparation of biologically active compounds. Benzisoxazoles are an important structure and some benzisoxazole-based medicines have been approved for human clinical use, including atypical antipsychotics (risperidone, paliperidone and iloperidone) and an anticonvulsant (zonisamide). AREAS COVERED: This review puts emphasis on the recent progress in therapeutically attractive benzisoxazole derivatives especially 1,2-benzisoxazoles, which were published in the patent literature between 2009 and 2014. As for the class of medicines, the main focus is on atypical antipsychotics and potential therapeutic treatments for other CNS disorders. This review also covers the examples of benzisoxazole-based kinase inhibitors. Moreover, novel benzisoxazoles with significant therapeutic interest are also mentioned. EXPERT OPINION: More recent examples of structural modification of existing drugs led to the discovery of some promising benzisoxazoles for antipsychotic use. The design of multi-target ligands is important for the manipulation of pharmacological properties and safety profiles for the use of antipsychotics. Benzisoxazoles have been widely used as pharmacophores in the search for novel drug candidates in a variety of therapeutic area. It is fair to assume that the wide and frequent use of benzisoxazoles in drug discovery and development will continue into the future. PMID- 25800254 TI - Morphology control of the perovskite films for efficient solar cells. AB - In the past two years, the power conversion efficiency (PCE) of organic-inorganic hybrid perovskite solar cells has significantly increased up to 20.1%. These state-of-the-art new devices surpass other third-generation solar cells to become the most promising rival to the silicon-based solar cells. Since the morphology of the perovskite film is one of the most crucial factors to affect the performance of the device, many approaches have been developed for its improvement. This review provides a systematical summary of the methods for morphology control. Introductions and discussions on the mechanisms and relevant hotspots are also given. Understanding the growth process of perovskite crystallites has great benefits for further efficiency improvement and enlightens us to exploit new technologies for large-scale, low-cost and high-performance perovskite solar cells. PMID- 25800255 TI - [Evaluation in medical education]. PMID- 25800256 TI - [Usefulness of ubiquitous-based testing for evaluations in medical education]. AB - PURPOSE: The purpose of this study was to evaluate the suitability (convenience, objectiveness, and satisfaction) of ubiquitous-based testing (UBT) as a medical education evaluation tool. METHODS: UBT was administered using a smart pad in our medical school in May 2012. A questionnaire was given twice. The pre-UBT questionnaire examined possession of a tablet computer, skillfulness of smart devices, the convenience of UBT, and the usefulness of a medical educational assessment tool. The post-UBT questionnaire evaluated the satisfaction, convenience, and preference of UBT and the usefulness of a medical educational assessment tool, as in the pre-UBT test. The survey was measured on a 4-point scale: 1 is "strongly disagree" and 4 is "strongly agree." RESULTS: One hundred three students (male, 55.3%) participated in the UBT. The mean age was 29.2+/-2.4 years. In the pre-UBT questionnaire analysis, students responded affirmatively to the items about the skillfulness of smart devices, clinical skill assessment, and achievement of educational objectives. The responses to the items on the convenience and satisfaction with the UBT were positive in the post-UBT. The factors that affected the post-UBT questionnaire were as follows: knowledge assessment (p=0.041) and achievement of educational objectives (p=0.015) were significant, based on gender, and satisfaction with the UBT (p=0.002) was significant, based on possession of a tablet computer. The relationship between the ranks of this UBT and the average ranks of the three previous semesters was statistically significant (p<0.001). CONCLUSION: Convenience, objectiveness, knowledge assessment, and composition and completion were useful items in the UBT. PMID- 25800257 TI - [Peer review analysis of lectures using video recordings in an integrated curriculum]. AB - PURPOSE: The purpose of this study is to evaluate the effect of the peer review in an integrated curriculum and to guide further improvements of curriculum. METHODS: In 2012, Seoul National University College of Medicine implemented a peer review system for 11 courses in an integrated curriculum. For each lecture, two reviewers conducted the rating using a 10-item questionnaire on a 4-point scale. We analyzed the correlation between total scores and each item and the inter-rater reliability between the two reviewers by Pearson correlation. Further, the link between peer review scores and the student lecture evaluation was analyzed. RESULTS: The mean total score for the checklist rating was 31.3 (out of 40.0), and the mean score for each item ranged from 2.65 to 3.35 (out of 4.00). The correlation coefficient between the total score and each item was high, ranging from 0.656 to 0.849, except for three items. The mean of difference scores between reviewers was 5.03, and the correlation coefficient was significantly high, which ranged from 0.968 to 0.999. The peer reviews scores and student lecture evaluations generally correlated, but there were some outlying exceptions; the correlation coefficient was 0.105 and 0.093. CONCLUSION: Peer review is a useful method for improving the quality of lectures in an integrated curriculum by monitoring the objectives, contents, and methods of the lectures and providing feedback to the professors. PMID- 25800258 TI - [Factors that influence student ratings of instruction]. AB - PURPOSE: The purpose of this study was to examine the validity of student ratings of instruction by analyzing their relationships with several variables, including gender, academic rank, specialty, teaching time, and teaching method, at a medical school. METHODS: This study analyzed the student ratings of 297 courses at Ajou University School of Medicine in 2013. SPSS version 12.0 was used to analyze the data and statistics by t-test, analysis of variance, and Scheffe test. RESULTS: There were no statistically significant differences in student ratings between gender, rank, and specialty. However, student ratings were significantly influenced by teaching times and methods (p<0.05). Student ratings were high for teaching times of 10 hours or more and small-group learning, compared with lectures. There was relatively mean differences in students ratings by teaching times, specialty and rank, although the difference in ratings was not statistically significant. CONCLUSION: Student ratings can be classified by teaching time and method for summative purposes. To apply student ratings to the evaluation of the performance of faculty, further studies are needed to analyze the variables that influence student ratings. PMID- 25800259 TI - [The relationship between academic self-efficacy and academic burnout in medical students]. AB - PURPOSE: The purpose of this study was to examine the correlation between academic burnout and academic self-efficacy in medical students. METHODS: The study group comprised 446 students in years 1 to 4 of medical school. They were asked to rate their academic burnout and academic self-efficacy on a scale. The data were analyzed by multivariate analysis of variance and regression analysis. RESULTS: Academic self-efficacy was correlated negatively with academic burnout explaining 37% of academic burnout. CONCLUSION: Academic self-efficacy (especially self-confidence) had the greatest effect on academic burnout. The implications of these results are discussed in terms of an evaluation and support system for students. PMID- 25800260 TI - [Returning students' perspectives on adjusting to medical graduate school in Korea: an interview study]. AB - PURPOSE: The recent trend of switching from medical graduate school to medical school in Korea raises questions about the adjustments that students must make in medical education. We examined the perceptions of medical graduate students with regard to their adaptation in medical education. METHODS: Sixteen semistructured, in-depth interviews were administered to medical graduate students who received their first degrees in foreign countries. The interviews addressed their perceptions of their experience in medical graduate school and on how well they adjusted to medical education. RESULTS: Students perceived their adaptation to medical graduate school in two dimensions: academic achievement and cultural adjustment. In academic achievement, a limited student-teacher relationship was recognized by students. Students tended to be passive in the classroom due to an uncomfortable atmosphere. They also reported witnessing culture shock in relation to the paucity of information on entrance into medical graduate school. Freshmen voiced many difficulties in adjusting to the unique culture in medical graduate school, in contrast to upper classmen. However, only 32% of students experienced helpful mentoring for their problems. CONCLUSION: Students' perspectives should guide all decisions made about medical education in an altered educational system.Self-regulated learning and a good mentoring program can help prepare students for medical education and professional life. PMID- 25800261 TI - How to provide tailored career coaching for medical students. AB - PURPOSE: This study was performed to develop a counseling strategy, based on the profiles of medical students' Strong Interest Inventory (STRONG) and Myer-Briggs Type Indicator (MBTI) results, focusing on the three following questions: Into what distinct levels are students categorized by STRONG and MBTI? and What is the dispersion of the integrated profiles? METHODS: Freshmen students from Konyang University College of Medicine who matriculated between March 2011 and 2013 were administered the MBTI personality type test and the STRONG interest inventory assessment. The integrated profiles were categorized per Kim et al. (2006), and frequency analysis was performed with the collected data, using SPSS version 21.0. RESULTS: Regarding MBTI types, 16.9% of students were categorized as ESTJ, and 12.9% was ISTJ. Further, 62.4% of students were Investigative (I) according to STRONG. The integrated profiles were divided into four types, according to their unclear/clear preference in the STRONG and MBTI results. Most students had 'clear preference and clear interest' (n=144, 80.9%), six students (3.4%) had 'clear interest but unclear preference,' and 28 students (15.7%) showed 'unclear interest but clear preference.' CONCLUSION: Using the combined results of the STRONG interest inventory assessment and MBTI tools, we can purvey more tailored information to students. PMID- 25800262 TI - ["The secret weapon of good teachers" series. The first secret weapon: "Good teachers are excellent planners"]. PMID- 25800264 TI - Change of acknowledgments in "The relationship between dental graduate students' MBTI types and academic achievement in problem-based learning". PMID- 25800265 TI - The rate and efficiency of iron generation in an electrocoagulation system. AB - The rate and efficiency of iron generation in a bench-scale electrocoagulation (EC) system was investigated when variations were made to operating voltage, cathode material and electrolyte composition. Two electrolytes were tested, one with organic compounds (naphthalene, acenaphthene and 4-nonylphenol) and one without. While aromatic structures often make good corrosion inhibitors, in this case they had no discernible effect. This is a positive indicator that EC systems will not have adverse effects when treating wastewaters associated with oil and gas production. Using a stainless steel cathode rather than an aluminium one resulted in 35% more production of iron at the anode per volt per minute; it also resulted in greater iron production given equivalent quantities of power. This occurred because the rate-limiting hydrogen evolution reaction at the cathode occurs more quickly on iron than on aluminium. It was also observed that the EC system (using either cathode) produced more iron per unit power when operated at lower voltages. At lower voltages, the corrosion that occurred spontaneously in the absence of an applied current contributed more significantly to the total amount of iron released. This research suggests that it is more efficient to design EC systems using iron-based cathodes rather than aluminium ones. It also indicates that it is more energy efficient to use more electrodes at low power, rather than fewer electrodes at high power. PMID- 25800267 TI - No action is taken against anaesthetist who confessed to falsifying patient's records. PMID- 25800266 TI - Cytotoxicity of chronic exposure to 4 cigarette smoke condensates in 2 cell lines. AB - Tobacco use is the leading preventable cause of death. The cytotoxicity of cigarette smoke condensate (CSC), the particulate fraction of cigarette smoke without the vapor phase, has mostly been tested in short-term in vitro studies lasting from a few hours to a few days. Here, we assessed the toxicity of CSCs from 2 reference cigarettes, 3R4F and CM6, using a primary human small airway epithelial (PSAE) cell line by quantifying adenosine 5'-triphosphate (ATP), 3 (4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium (MTS), total glutathione (reduced glutathione [GSH] + oxidized glutathione [GSSG]), and lactate dehydrogenase (LDH) release over the course of 28 days. The CSCs, 0.3 to 10 MUg/mL, promoted cell proliferation at 120 hours of exposure, but demonstrated cytotoxicity at days 14 and 28. Interestingly, CSCs, 0.3 to 3 MUg/mL, showed a cell death effect at day 14 but induced cell proliferation at day 28. Consistently, transformation associated with morphological changes began by day 14 and the transformed cells grew dramatically at day 28. The LDH assay appeared to be sensitive for assessing early cell damage, whereas the ATP, MTS, and GSH assays were more suitable for determining later stage CSCs-induced cytotoxicity. The ATP assay showed greater sensitivity than the MTS and GSH assays. We also assessed the toxicity of CSCs in an human Telomerase Reverse Transcriptase (hTERT)-immortalized Barrett esophagus cell line (CP-C). The CP-C cells demonstrated dose- and time-dependent cytotoxicity over the course of 28 days but displayed higher resistance to CSCs than PSAE cells. This study demonstrates that CSCs cause cytotoxicity and induce transformation related to cell resistance and cell invasion properties. PMID- 25800268 TI - Late sensorial alterations in different radiotherapy techniques for nasopharyngeal cancer. AB - Intensity-modulated radiation therapy (IMRT) for nasopharyngeal cancer (NPC) allowed a better distribution of the dose to the tumor volume, sparing surrounding structures. Aim of the study is the objective evaluation of olfactory and gustatory impairments in patients who underwent chemo-radiotherapy for NPC. Correlation between smell and taste alterations, xerostomy, and radiation technique was investigated. Thirty healthy subjects and 30 patients treated with chemo-radiation therapy for NPC, with at least a 2-years follow-up period, were evaluated. All subjects underwent symptoms evaluation, endoscopic fiber optic nasal examination, taste strips, Sniffin' sticks tests, Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring system. Patients were divided in 2 groups: 2 dimensional radiotherapy/conformal 3-dimensional radiotherapy and IMRT. A higher percentage of rhinorrhea, nasal obstruction, xerostomy, hyposmia, hypogeusia, mucosal hyperemia, and presence of nasopharyngeal secretions was found in irradiated subjects (P < 0.05). Concerning olfactory and gustatory scores, we demonstrated a statistically significant difference between healthy subjects and irradiated patients (P < 0.05), with lower gustatory total score in IMRT group (P < 0.01). In conclusion, chemo-radiotherapy for NPC induces long-term smell and taste impairments, which can compromise quality of life. Although based on small samples, it is also important to consider that IMRT can induce higher taste dysfunction compared with traditional techniques. PMID- 25800269 TI - Expression of pathogen recognition receptors and pro-inflammatory cytokine transcripts in clinical and sub-clinical endometritis cows. AB - The present study was carried out to examine the expression profile of pathogen recognition receptors (CD14 and toll-like receptor 4) and pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, and TNFalpha) in endometrial tissue of cows with endometritis at different stages of estrous cycle. Genital tracts were collected from 60 cows at slaughter from the killing village. The genitalia were examined for clinical endometritis (CE) and subclinical endometritis (SCE) through physical examination, white side test of cervico-vaginal mucus, endometrial cytology and histopathology. The stage of estrous cycle for each genitalia was determined by visual examination of both the ovaries and classified as either follicular (F) or luteal (L). Depending on the degree of inflammation and stage of estrous cycle, the genitalia were categorized in four groups i.e., FCE, FSCE, LCE, and LSCE with six genitalia in each group. Furthermore, 12 healthy genitalia comprise of six each of follicular (FN) and luteal (LN) were included as control. Endometrial tissue scrapings were collected ex vivo from all the genitalia. Total RNA was extracted and cDNA was transcribed for each sample and relative quantification of mRNA of target genes was done by real-time PCR. The results revealed a significant up-regulation of CD14 (11 fold) and IL-8 (13 fold) in follicular stage and IL-6 (8 fold) and TNFalpha (29 fold) in luteal stages in SCE cows. However, the majority of pro-inflammatory cytokine and pathogen recognition receptors expressed at significant higher level in both follicular and luteal stages in cows with CE. Thus, it is concluded that the endometrial transcripts of pathogen recognition receptors and pro-inflammatory cytokines expressed differentially in cows with endometritis, whereas the fold change is dependent on the severity of inflammation and the stage of cyclicity. Therefore, endometrial transcript profile with a defined threshold level could be used as a possible diagnostic marker in cows with SCE. PMID- 25800270 TI - Akaganeite decorated graphene oxide composite for arsenic adsorption/removal and its proconcentration at ultra-trace level. AB - Carboxylic graphene oxide (GO-COOH) is decorated with akaganeite (beta-FeOOH) to produce a beta-FeOOH@GO-COOH nanocomposite. The nanocomposite acts as an efficient adsorption medium for the uptake of arsenite and arsenate within a wide range of pH 3-10, providing high adsorption capacities of 77.5mgg(-1) for As(III) and 45.7mgg(-1) for As(V), respectively. Adsorption efficiencies of 100% and 97% are achieved for 5 successive operation cycles for the removal of 100MUgL(-1) As(V) and As(III) in 5 fresh portions of aqueous solution (1.0mL for each) with 3mg nanocomposite. After 20 successive adsorption cycles, removal efficiency of >80% is still maintained for both arsenate and arsenite. Further, a removal efficiency of >90% is obtained for 1000MUgL(-1) As(V) with 3mg beta-FeOOH@GO-COOH for 5 successive adsorption cycles, and the presence of 2000-fold SO4(2-), NO3( ), Cl(-) and Mg(2+) pose no interfering effect. beta-FeOOH@GO-COOH also provides a promising medium for the preconcentration of ultra-trace inorganic arsenic. 1mg of nanocomposite is used to adsorb 0.1-3.00MUgL(-1) As(V) in 4.0mL solution, and the retained arsenate is recovered by 400MUL of NaOH (2molL(-1), containing 2.0% NaBH4), followed by detection with atomic fluorescence spectrometry. A detection limit of 29ngL(-1) is obtained for arsenate. This procedure is validated by analyzing arsenic in a certified reference material (GBW 09101b) and further applied for arsenic determination in water samples. PMID- 25800272 TI - Palliative care in critical illness: challenges for research and practice. PMID- 25800271 TI - Balancing cure with comfort: palliative care in critical care. PMID- 25800273 TI - 'Who Will Talk for Me?' Next of Kin is not necessarily the preferred substitute decision maker: findings from an Australian intensive care unit. PMID- 25800275 TI - UVB-emitting Gd(3+)-activated M2O2S (where M = La, Y) for phototherapy lamp phosphors. AB - Gd(3+)-activated oxysulphide (M2O2S) may be used to study Photoluminescence (PL) properties with respect to phototherapy. Gd(3+)-activated phosphor materials are widely used for phototherapy lamps. The Gd(3+) ion gives characteristic Narrow Band (NB) emissions, in particular in the ultraviolet (UV) light region, that are used to treat more than 50 types of skin diseases. In this paper, M2O2S oxysulphide doped with Gd(3+) was synthesized by the solid-state flux fusion method and its down conversion spectral properties were studied as a function of different Gd(3+) concentrations. The sample was characterized by X-ray Diffraction (XRD), Scanning Electron Microscope (SEM), Fourier Transform Infrared Spectroscopy (FT-IR), and PL and the crystal structure was also studied. The lanthanum oxysulphide (La2O2S)-activated Gd(3+) ion showed a sharp emission peak at 314 nm when excited at 275 nm excitation, whereas the yttrium oxysulphide (Y2O2S)-activated Gd(3+) ion showed a sharp emission at 316 nm when excited by 272 nm. The effect of concentration of the Gd(3+) ion on the luminescence properties of M2O2S:Gd(3+) phosphor was also studied. These phosphor materials activated with the Gd(3+) ion may be suitable for phototherapy lamps, which are used to treat many types of skin diseases such as psoriasis, vitiligo, or scleroderma. PMID- 25800274 TI - CD8+ T cells in cutaneous leishmaniasis: the good, the bad, and the ugly. AB - CD8(+) T lymphocytes are components of the adaptive immune response and play an important role in protection against many viral and bacterial infections. However, their role in parasitic infections is less well understood. In leishmaniasis, a disease caused by intracellular protozoan parasites of the genus Leishmania, CD8(+) T cells have been shown to be protective. However, increasing evidence indicates that CD8(+) T cells may also exacerbate disease. In this review, we will describe the situations where CD8(+) T cells are either good or bad for the outcome of the infection and attempt to reconcile the dual role played by CD8(+) T cells in cutaneous leishmaniasis. PMID- 25800276 TI - Pain and psychological well-being among people with dementia in long-term care. AB - OBJECTIVE: To examine the relationship between self-reported pain and psychological well-being of people with dementia (PWD) living in residential long term care as indicated by displays of observed emotional expression over the daytime period. DESIGN: Secondary analysis using repeated measures of self-report and observational data. SETTING AND SUBJECTS: A total of 177 PWD were included from 17 nursing homes and six assisted living facilities in Michigan and Pennsylvania. METHODS: Negative emotional expression was used as an indicator of reduced psychological well-being. Pain was assessed through PWD's response to a question about presence of pain obtained at each observation. Cognitive impairment was assessed using the Mini-Mental Status Examination. Linear mixed models were used that accounted for correlation of negative emotional expression measurements over time for each participant and between participants within the same facility. RESULTS: Among 171 participants who were able to express their pain, 44% of PWD reported pain once or more during the daytime period. Severity of cognitive impairment was related to expression of negative emotion. PWD with pain displayed more negative emotional expression than PWD without pain. CONCLUSIONS: Routine pain assessment is feasible among PWD with moderate to severe dementia and positive report of pain is associated with greater observed negative emotional expression, an indicator of reduced psychological well-being. Improving pain management holds potential for enhancing psychological well-being among PWD living in residential long-term care. PMID- 25800277 TI - Interleukin-34 sustains inflammatory pathways in the gut. AB - IBD (inflammatory bowel disease)-related tissue damage occurs in areas which are massively infiltrated with monocytes/macrophages. These cells respond to inflammatory stimuli with enhanced production of cytokines/chemokines. In the present study, we analysed the expression and role of IL (interleukin)-34, a regulator of monocyte/macrophage differentiation, survival and function, in IBD. A significant increase in IL-34 mRNA and protein expression was seen in inflamed mucosa of patients with CD (Crohn's disease) and patients with UC (ulcerative colitis) compared with the uninvolved areas of the same patients and normal controls. IL-34 was up-regulated in LPMCs (lamina propria mononuclear cells) isolated from normal colon by TNF-alpha (tumour necrosis factor alpha) and TLR (Toll-like receptor) ligands and was down-regulated in intestinal biopsies and LPMCs of IBD patients upon treatment with infliximab. Treatment of normal LPMCs with IL-34 increased TNF-alpha expression in an ERK1/2 (extracellular-signal regulated kinase 1/2)-dependent fashion and neutralization of IL-34 in IBD mucosal explants reduced TNF-alpha and IL-6 synthesis. In conclusion, our results indicate that IL-34 is up-regulated in IBD and suggest a role for this cytokine in sustaining the inflammatory responses in this disease. PMID- 25800278 TI - Perceptions of acceptable conducts by university students. AB - OBJECTIVE: To determine perceptions of acceptable conducts amongst under and postgraduate optometry students and to compare them with students from other disciplines. METHODS: Students (under/postgraduate) of optometry (n=156) and other courses (n=54) from University of Minho participated in a voluntary online questionnaire about perception of conducts, classifying as acceptable or unacceptable 15 academic or professional scenarios. RESULTS: 210 questionnaires were analyzed. Differences in perceptions were found between optometry under and postgraduates in scenario 5, Chi-square(2,156)=4.3, p=0.038, and scenario 7, Chi square(2,156)=7.0, p=0.008 (both with cheating more acceptable for postgrads). Differences between under and postgraduates from other courses were found in scenario 9 (taking supplies from classroom more acceptable for undergrads), Chi square(1,54)=5.0, p=0.025, and scenario 14 (forging a signature more acceptable for postgrads), Chi-square(1,54)=3.9, p=0.046. Differences between optometry and other courses undergraduates were observed in scenario 2 (plagiarism more acceptable for optometry undergrads), Chi-square(1,154)=8.3, p=0.004 and scenario 9 (taking supplies from classroom more acceptable for other undergrads), chi square(1,54)=7.8, p=0.005. Differences between optometry and other courses postgraduates were observed in scenario 7, Chi-square(1,56)=5.8, p=0.016, scenario 10 (both with cheating more acceptable for optometry postgrads), chi square(1,54)=8.1, p=0.004 and scenario 14 (forging a signature more acceptable for other postgrads), Chi-square(1,54)=6.1, p=0.026. CONCLUSION: Academic misconducts were mainly considered more acceptable than professional misconducts. Our results show that perceptions of acceptable conducts amongst optometry students are not very different from other students, and, against our initial prediction, do not show a general change in misconduct perception when students become more mature. Universities should pay more attention to this problem and take action. PMID- 25800280 TI - International pediatric transplant association. PMID- 25800281 TI - Program. PMID- 25800282 TI - IPTA 8th Congress on Pediatric Transplantation. PMID- 25800279 TI - Pattern of astigmatism in a clinical setting in Maldives. AB - BACKGROUND: Patterns of refractive errors have never been reported in Maldives. This study aims to dissect astigmatism and provide a general view in context of this island country. METHODS: A clinic based cross sectional study was designed with 277 patients, aged >=3.5 years and with a primary astigmatism of >=-1.00 diopters (D). They underwent complete eye examination and a vector analysis was done. RESULTS: Mean age was 28.58 (SD 19.15) years. Astigmatic magnitude depended on age (p<0.05) but not on gender (p>0.05). Severity of visual impairment after refractive correction was very less, with only 2.2% having visual acuity <=6/60. Mean spherical, spherical equivalent and astigmatic refraction were -1.35 (SD 2.94 D), -2.40 (SD 3.04) and -2.12 (SD 1.11 D), respectively. Between fellow eyes, refractive and corneal astigmatism highly correlated (0.83 and 0.73). Fifty eyes (18.1%) had an astigmatic error of >=-3.00 D which peaked in the second and third decades of life (p<0.0001) and was corneal in origin (p<0.0001). Internal J45 and J0 tended to be more negative with increasing age, showing a trend toward against the rule astigmatism. Correlation between corneal and refractive J0 and J45 were 0.88 and 0.62 (p<0.0001). With the rule astigmatism was more common followed by against the rule and oblique. CONCLUSION: In conclusion, this study inferred that among patients with relatively higher magnitude of astigmatism attending to the clinics in Maldives, younger patients are affected more, which could possibly link to the environment, genetics and nutrition. The probable association between nutrition and astigmatism needs to be investigated to fill the gap in literature. PMID- 25800283 TI - Molecular phylogenetics and evolutionary history of sect. Quinquefoliae (Pinus): implications for Northern Hemisphere biogeography. AB - Climatic changes and tectonic events in the Cenozoic have greatly influenced the evolution and geographic distribution of the temperate flora. Such consequences should be most evident in plant groups that are ancient, widespread, and diverse. As one of the most widespread genera of trees, Pinus provides a good model for investigating the history of species diversification and biogeographic disjunction in the Northern Hemisphere. In this study, we reconstructed the phylogeny and investigated the evolutionary and biogeographic history of sect. Quinquefoliae (Pinus), a species-rich lineage disjunctly distributed in Asia, Europe and North America, based on complete taxon sampling and by using nine DNA fragments from chloroplast (cp), mitochondrial (mt) and nuclear genomes. The monophyly of the three subsections, Krempfianae, Gerardianae, and Strobus, is well-supported by cpDNA and nuclear gene phylogenies. However, neither subsect. Gerardianae nor subsect. Strobus forms a monophyletic group in the mtDNA phylogeny, in which sect. Quinquefoliae was divided into two major clades, one consisting of the North American and northeastern Asian species as well as the European P. peuce of subsect. Strobus, and the other comprising the remaining Eurasian species belonging to three subsections. The significant topological incongruence among the gene trees, in conjunction with divergence time estimation and ancestral area reconstruction, indicates that both ancient and relatively recent introgressive hybridization events occurred in the evolution of sect. Quinquefoliae, particularly in northeastern Asia and northwestern North America. In addition, the phylogenetic analysis suggests that the species of subsect. Strobus from subtropical eastern Asia and neighboring areas may have a single origin, although species non-monophyly is very widespread in the nuclear gene trees. Moreover, our study seems to support a Tethyan origin of sect. Quinquefoliae given the distributions and phylogenetic positions of subsects. Krempfianae and Gerardianae, and also highlights the importance of active mountain buildings and climatic changes during the Late Neogene in shaping the species diversity and geographic distribution of Pinus. PMID- 25800284 TI - Concordant genetic structure in two species of woodpecker distributed across the primary West African biogeographic barriers. AB - The lowland forests of western and central tropical Africa are separated by several potential biogeographic barriers to dispersal for forest adapted vertebrates. The two primary barriers are (1) the Dahomey Gap, a savanna corridor that reaches the coast of southern Ghana, Togo and Benin, and separates the West African rainforest into the Upper (Ghana west to Guinea) and Lower Guinea (Nigeria to Uganda and Angola) forest blocks, and (2) the Lower Niger River, a large delta that separates Western and Eastern Nigeria. Previous studies on terrestrial vertebrates (lizards, mammals and birds) have highlighted a genetic break in the Dahomey Gap/Lower Niger River area although the relative importance of each barrier has not been assessed due to limitations in geographic sampling. We compared the phylogeographic history of two co-distributed sister-species of woodpeckers (Campethera caroli and C. nivosa) using data from three loci representing all inheritance modes. Our analyses revealed that both the Dahomey Gap and possibly the Lower Niger River acted as strong biogeographic barriers for the two woodpecker species, with the Lower Niger River being the first barrier to have formed, leading to three distinct populations of C. nivosa. Our divergence time analyses revealed that both these biogeographic barriers formed during the Pleistocene, supporting the Pleistocene refuge hypothesis, with the Dahomey Gap likely appearing about 0.5 myr BP. No genetic structure was recovered among sampled populations in either the Upper or the Lower Guinea Forest Block for both species, despite the considerable geographic area covered. PMID- 25800285 TI - Rotational alignment of the tibial component affects the kinematic rotation of a weight-bearing knee after total knee arthroplasty. AB - PURPOSE: The purpose of this study is to elucidate how the rotational malalignment of prosthesis after total knee arthroplasty affects the rotational kinematics in a weight-bearing condition. METHODS: In this study of 18 knees replaced with the posterior stabilizing fixed-bearing system, which has a relatively low-restricting design, rotational angles between the femoral and tibial components and between the femur and tibia during stair climbing were evaluated in vivo in three dimensions using radiologically based image-matching techniques. Rotational alignments of the components were assessed by postoperative CT. The correlations between the rotational alignments and the rotational angles during stair climbing were evaluated. RESULTS: Rotational alignment of the tibial component significantly correlated with rotational angles between the components as well as between bones during stair climbing. Rotational malalignment of the tibial component toward internal rotation caused a rotational mismatch of the tibial component toward internal rotation relative to the femoral component in 0 degrees extension and caused a rotational mismatch of the tibia (bone) toward external rotation relative to the femur (bone). The knee in which the tibial component was placed close to the AP axis of the tibia did not show any rotational mismatch between either components or bones. CONCLUSIONS: Rotational alignment of the tibial component affects the kinematic rotation of the replaced knee during a weight-bearing condition even though using a low restricting designed surface, and the AP axis can be a reliable reference in determining rotational alignment for the tibial component. PMID- 25800286 TI - Photochemical hydrogen production from water catalyzed by CdTe quantum dots/molecular cobalt catalyst hybrid systems. AB - A hybrid system with a coordinative interaction between a cobalt complex of a N2S2-tetradentate ligand and CdTe quantum dots displayed a high activity (initial TOF 850 h(-1)) and improved stability (TON 1.44 * 10(4) based on catalyst over 30 h) for the photochemical H2 generation from water, with a quantum efficiency of 5.32% at 400 nm. PMID- 25800287 TI - Tunable room temperature THz sources based on nonlinear mixing in a hybrid optical and THz micro-ring resonator. AB - We propose and systematically investigate a novel tunable, compact room temperature terahertz (THz) source based on difference frequency generation in a hybrid optical and THz micro-ring resonator. We describe detailed design steps of the source capable of generating THz wave in 0.5-10 THz with a tunability resolution of 0.05 THz by using high second order optical susceptibility (chi((2))) in crystals and polymers. In order to enhance THz generation compared to bulk nonlinear material, we employ a nonlinear optical micro-ring resonator with high-Q resonant modes for infrared input waves. Another ring oscillator with the same outer radius underneath the nonlinear ring with an insulation of SiO2 layer supports the generated THz with resonant modes and out-couples them into a THz waveguide. The phase matching condition is satisfied by engineering both the optical and THz resonators with appropriate effective indices. We analytically estimate THz output power of the device by using practical values of susceptibility in available crystals and polymers. The proposed source can enable tunable, compact THz emitters, on-chip integrated spectrometers, inspire a broader use of THz sources and motivate many important potential THz applications in different fields. PMID- 25800289 TI - Embracing complexity theory can clarify best practice frameworks for simulation education. PMID- 25800290 TI - Embracing complexity: taking the messiness in simulation-based training one step further. PMID- 25800291 TI - More chickens, fewer eggs? On team-based learning, team performance and teamwork skills. PMID- 25800292 TI - Learning and instruction: the world inside the head or the head inside the world? PMID- 25800293 TI - How would an egalitarian health care system operate? Power and conflict in interprofessional education. PMID- 25800294 TI - When I say ... cognitive apprenticeship. PMID- 25800295 TI - When I say ... emotional congruence in medical education. PMID- 25800296 TI - Towards socio-material approaches in simulation-based education: lessons from complexity theory. AB - CONTEXT: Review studies of simulation-based education (SBE) consistently point out that theory-driven research is lacking. The literature to date is dominated by discourses of fidelity and authenticity - creating the 'real' - with a strong focus on the developing of clinical procedural skills. Little of this writing incorporates the theory and research proliferating in professional studies more broadly, which show how professional learning is embodied, relational and situated in social - material relations. A key concern for medical educators concerns how to better prepare students for the unpredictable and dynamic ambiguity of professional practice; this has stimulated the movement towards socio-material theories in education that address precisely this question. OBJECTIVES AND METHODS: Among the various socio-material theories that are informing new developments in professional education, complexity theory has been of particular importance for medical educators interested in updating current practices. This paper outlines key elements of complexity theory, illustrated with examples from empirical study, to argue its particular relevance for improving SBE. RESULTS: Complexity theory can make visible important material dynamics, and their problematic consequences, that are not often noticed in simulated experiences in medical training. It also offers conceptual tools that can be put to practical use. This paper focuses on concepts of emergence, attunement, disturbance and experimentation. These suggest useful new approaches for designing simulated settings and scenarios, and for effective pedagogies before, during and following simulation sessions. CONCLUSIONS: Socio-material approaches such as complexity theory are spreading through research and practice in many aspects of professional education across disciplines. Here, we argue for the transformative potential of complexity theory in medical education using simulation as our focus. Complexity tools open questions about the socio-material contradictions inherent in SBE, draw attention to important material dynamics of emergence, and suggest practical educative ways to expand and deepen student learning. PMID- 25800297 TI - Self-regulated learning in simulation-based training: a systematic review and meta-analysis. AB - CONTEXT: Self-regulated learning (SRL) requires an active learner who has developed a set of processes for managing the achievement of learning goals. Simulation-based training is one context in which trainees can safely practise learning how to learn. OBJECTIVES: The purpose of the present study was to evaluate, in the simulation-based training context, the effectiveness of interventions designed to support trainees in SRL activities. We used the social cognitive model of SRL to guide a systematic review and meta-analysis exploring the links between instructor supervision, supports or scaffolds for SRL, and educational outcomes. METHODS: We searched databases including MEDLINE and Scopus, and previous reviews, for material published until December 2011. Studies comparing simulation-based SRL interventions with another intervention for teaching health professionals were included. Reviewers worked independently and in duplicate to extract information on learners, study quality and educational outcomes. We used random-effects meta-analysis to compare the effects of supervision (instructor present or absent) and SRL educational supports (e.g. goal-setting study guides present or absent). RESULTS: From 11,064 articles, we included 32 studies enrolling 2482 trainees. Only eight of the 32 studies included educational supports for SRL. Compared with instructor-supervised interventions, unsupervised interventions were associated with poorer immediate post-test outcomes (pooled effect size: -0.34, p = 0.09; n = 19 studies) and negligible effects on delayed (i.e. > 1 week) retention tests (pooled effect size: 0.11, p = 0.63; n = 8 studies). Interventions including SRL supports were associated with small benefits compared with interventions without supports on both immediate post-tests (pooled effect size: 0.23, p = 0.22; n = 5 studies) and delayed retention tests (pooled effect size: 0.44, p = 0.067; n = 3 studies). CONCLUSIONS: Few studies in the simulation literature have designed SRL training to explicitly support trainees' capacity to self-regulate their learning. We recommend that educators and researchers shift from thinking about SRL as learning alone to thinking of SRL as comprising a shared responsibility between the trainee and the instructional designer (i.e. learning using designed supports that help prepare individuals for future learning). PMID- 25800298 TI - Team cohesiveness, team size and team performance in team-based learning teams. AB - OBJECTIVES: The purpose of this study was to explore the relationships among variables associated with teams in team-based learning (TBL) settings and team outcomes. METHODS: We administered the National Board of Medical Examiners (NBME) Psychiatry Subject Test first to individuals and then to teams of Year three students at four medical schools that used TBL in their psychiatry core clerkships. Team cohesion was analysed using the Team Performance Scale (TPS). Bivariate correlation and linear regression analysis were used to analyse the relationships among team-level variables (mean individual TPS scores for each team, mean individual NBME scores of teams, team size, rotation and gender make up) and team NBME test scores. A hierarchical linear model was used to test the effects of individual TPS and individual NBME test scores within each team, as well as the effects of the team-level variables of team size, team rotation and gender on team NBME test scores. Individual NBME test and TPS scores were nested within teams and treated as subsampling units. RESULTS: Individual NBME test scores and individual TPS scores were positively and statistically significantly (p < 0.01) associated with team NBME test scores, when team rotation, team size and gender make-up were controlled for. Higher team NBME test scores were associated with teams rotating later in the year and larger teams (p < 0.01). Gender make-up was not significantly associated. CONCLUSIONS: The results of an NBME Psychiatry Subject Test administered to TBL teams at four medical schools suggest that larger teams on later rotations score higher on a team NBME test. Individual NBME test scores and team cohesion were positively and significantly associated with team NBME test scores. These results suggest the need for additional studies focusing on team outcomes, team cohesion, team size, rotation and other factors as they relate to the effective and efficient performance of TBL teams in health science education. PMID- 25800299 TI - A critical appraisal of instruments to measure outcomes of interprofessional education. AB - CONTEXT: Interprofessional education (IPE) is believed to prepare health professional graduates for successful collaborative practice. A range of instruments have been developed to measure the outcomes of IPE. An understanding of the psychometric properties of these instruments is important if they are to be used to measure the effectiveness of IPE. OBJECTIVES: This review set out to identify instruments available to measure outcomes of IPE and collaborative practice in pre-qualification health professional students and to critically appraise the psychometric properties of validity, responsiveness and reliability against contemporary standards for instrument design. METHODS: Instruments were selected from a pool of extant instruments and subjected to critical appraisal to determine whether they satisfied inclusion criteria. The qualitative and psychometric attributes of the included instruments were appraised using a checklist developed for this review. RESULTS: Nine instruments were critically appraised, including the widely adopted Readiness for Interprofessional Learning Scale (RIPLS) and the Interdisciplinary Education Perception Scale (IEPS). Validity evidence for instruments was predominantly based on test content and internal structure. Ceiling effects and lack of scale width contribute to the inability of some instruments to detect change in variables of interest. Limited reliability data were reported for two instruments. Scale development and scoring protocols were generally reported by instrument developers, but the inconsistent application of scoring protocols for some instruments was apparent. CONCLUSIONS: A number of instruments have been developed to measure outcomes of IPE in pre qualification health professional students. Based on reported validity evidence and reliability data, the psychometric integrity of these instruments is limited. The theoretical test construction paradigm on which instruments have been developed may be contributing to the failure of some instruments to detect change in variables of interest following an IPE intervention. These limitations should be considered in any future research on instrument design. PMID- 25800300 TI - Louder than words: power and conflict in interprofessional education articles, 1954-2013. AB - CONTEXT: Interprofessional education (IPE) aspires to enable collaborative practice. Current IPE offerings, although rapidly proliferating, lack evidence of efficacy and theoretical grounding. OBJECTIVES: Our research aimed to explore the historical emergence of the field of IPE and to analyse the positioning of this academic field of inquiry. In particular, we sought to investigate the extent to which power and conflict - elements central to interprofessional care - figure in the IPE literature. METHODS: We used a combination of deductive and inductive automated coding and manual coding to explore the contents of 2191 articles in the IPE literature published between 1954 and 2013. Inductive coding focused on the presence and use of the sociological (rather than statistical) version of power, which refers to hierarchies and asymmetries among the professions. Articles found to be centrally about power were then analysed using content analysis. RESULTS: Publications on IPE have grown exponentially in the past decade. Deductive coding of identified articles showed an emphasis on students, learning, programmes and practice. Automated inductive coding of titles and abstracts identified 129 articles potentially about power, but manual coding found that only six articles put power and conflict at the centre. Content analysis of these six articles revealed that two provided tentative explorations of power dynamics, one skirted around this issue, and three explicitly theorised and integrated power and conflict. CONCLUSIONS: The lack of attention to power and conflict in the IPE literature suggests that many educators do not foreground these issues. Education programmes are expected to transform individuals into effective collaborators, without heed to structural, organisational and institutional factors. In so doing, current constructions of IPE veil the problems that IPE attempts to solve. PMID- 25800301 TI - How do surgeons think they learn about communication? A qualitative study. AB - CONTEXT: Communication education has become integral to pre- and post qualification clinical curricula, but it is not informed by research into how practitioners think that good communication arises. OBJECTIVES: This study was conducted to explore how surgeons conceptualise their communication with patients with breast cancer in order to inform the design and delivery of communication curricula. METHODS: We carried out 19 interviews with eight breast surgeons. Each interview centred on a specific consultation with a different patient. We analysed the transcripts of the surgeons' interviews qualitatively using a constant comparative approach. RESULTS: All of the surgeons described communication as central to their role. Communication could be learned to some extent, not from formal training, but by selectively incorporating practices they observed in other practitioners and by being mindful in consultations. Surgeons explained that their own values and character shaped how they communicated and what they wanted to achieve, and constrained what could be learned. CONCLUSIONS: These surgeons' understanding of communication is consistent with recent suggestions that communication education: (i) should place practitioners' goals at its centre, and (ii) might be enhanced by approaches that support 'mindful' practice. By contrast, surgeons' understanding diverged markedly from the current emphasis on 'communication skills'. Research that explores practitioners' perspectives might help educators to design communication curricula that engage practitioners by seeking to enhance their own ways of learning about communication. PMID- 25800303 TI - 'Sorry, I meant the patient's left side': impact of distraction on left-right discrimination. AB - CONTEXT: Medical students can have difficulty in distinguishing left from right. Many infamous medical errors have occurred when a procedure has been performed on the wrong side, such as in the removal of the wrong kidney. Clinicians encounter many distractions during their work. There is limited information on how these affect performance. OBJECTIVES: Using a neuropsychological paradigm, we aim to elucidate the impacts of different types of distraction on left-right (LR) discrimination ability. METHODS: Medical students were recruited to a study with four arms: (i) control arm (no distraction); (ii) auditory distraction arm (continuous ambient ward noise); (iii) cognitive distraction arm (interruptions with clinical cognitive tasks), and (iv) auditory and cognitive distraction arm. Participants' LR discrimination ability was measured using the validated Bergen Left-Right Discrimination Test (BLRDT). Multivariate analysis of variance was used to analyse the impacts of the different forms of distraction on participants' performance on the BLRDT. Additional analyses looked at effects of demographics on performance and correlated participants' self-perceived LR discrimination ability and their actual performance. RESULTS: A total of 234 students were recruited. Cognitive distraction had a greater negative impact on BLRDT performance than auditory distraction. Combined auditory and cognitive distraction had a negative impact on performance, but only in the most difficult LR task was this negative impact found to be significantly greater than that of cognitive distraction alone. There was a significant medium-sized correlation between perceived LR discrimination ability and actual overall BLRDT performance. CONCLUSIONS: Distraction has a significant impact on performance and multifaceted approaches are required to reduce LR errors. Educationally, greater emphasis on the linking of theory and clinical application is required to support patient safety and human factor training in medical school curricula. Distraction has the potential to impair an individual's ability to make accurate LR decisions and students should be trained from undergraduate level to be mindful of this. PMID- 25800302 TI - The struggling student: a thematic analysis from the self-regulated learning perspective. AB - CONTEXT: Students who engage in self-regulated learning (SRL) are more likely to achieve academic success compared with students who have deficits in SRL and tend to struggle with academic performance. Understanding how poor SRL affects the response to failure at assessment will inform the development of better remediation. METHODS: Semi-structured interviews were conducted with 55 students who had failed the final re-sit assessment at two medical schools in the UK to explore their use of SRL processes. A thematic analysis approach was used to identify the factors, from an SRL perspective, that prevented students from appropriately and adaptively overcoming failure, and confined them to a cycle of recurrent failure. RESULTS: Struggling students did not utilise key SRL processes, which caused them to make inappropriate choices of learning strategies for written and clinical formats of assessment, and to use maladaptive strategies for coping with failure. Their normalisation of the experience and external attribution of failure represented barriers to their taking up of formal support and seeking informal help from peers. CONCLUSIONS: This study identified that struggling students had problems with SRL, which caused them to enter a cycle of failure as a result of their limited attempts to access formal and informal support. Implications for how medical schools can create a culture that supports the seeking of help and the development of SRL, and improves remediation for struggling students, are discussed. PMID- 25800304 TI - Exploring the impact of workplace cyberbullying on trainee doctors. AB - OBJECTIVES: Workplace bullying is an occupational hazard for trainee doctors. However, little is known about their experiences of cyberbullying at work. This study examines the impact of cyberbullying among trainee doctors, and how attributions of blame for cyberbullying influence individual and work-related outcomes. METHODS: Doctors at over 6 months into training were asked to complete an online survey that included measures of cyberbullying, blame attribution, negative emotion, job satisfaction, interactional justice and mental strain. A total of 158 trainee doctors (104 women, 54 men) completed the survey. RESULTS: Overall, 73 (46.2%) respondents had experienced at least one act of cyberbullying. Cyberbullying adversely impacted on job satisfaction (beta = - 0.19; p < 0.05) and mental strain (beta = 0.22; p < 0.001), although attributions of blame for the cyberbullying influenced its impact and the path of mediation. Negative emotion mediated the relationship between self-blame for a cyber bullying act and mental strain, whereas interactional injustice mediated the association between blaming the perpetrator and job dissatisfaction. CONCLUSIONS: Acts of cyberbullying had been experienced by nearly half of the sample during their training and were found to significantly relate to ill health and job dissatisfaction. The deleterious impact of cyberbullying can be addressed through both workplace policies, and training for trainee doctors and experienced medical professionals. PMID- 25800305 TI - Mitigating the impact of oil-palm monoculture on freshwater fishes in Southeast Asia. AB - Anthropogenic land-cover change is driving biodiversity loss worldwide. At the epicenter of this crisis lies Southeast Asia, where biodiversity-rich forests are being converted to oil-palm monocultures. As demand for palm oil increases, there is an urgent need to find strategies that maintain biodiversity in plantations. Previous studies found that retaining forest patches within plantations benefited some terrestrial taxa but not others. However, no study has focused on aquatic taxa such as fishes, despite their importance to human well-being. We assessed the efficacy of forested riparian reserves in conserving freshwater fish biodiversity in oil-palm monoculture by sampling stream fish communities in an oil-palm plantation in Central Kalimantan, Indonesia. Forested riparian reserves maintained preconversion local fish species richness and functional diversity. In contrast, local and total species richness, biomass, and functional diversity declined markedly in streams without riparian reserves. Mechanistically, riparian reserves appeared to increase local species richness by increasing leaf litter cover and maintaining coarse substrate. The loss of fishes specializing in leaf litter and coarse substrate decreased functional diversity and altered community composition in oil-palm plantation streams that lacked riparian reserves. Thus, a land-sharing strategy that incorporates the retention of forested riparian reserves may maintain the ecological integrity of fish communities in oil-palm plantations. We urge policy makers and growers to make retention of riparian reserves in oil-palm plantations standard practice, and we encourage palm-oil purchasers to source only palm oil from plantations that employ this practice. PMID- 25800306 TI - Reversible 1,1-hydroboration: boryl insertion into a C-N bond and competitive elimination of HBR2 or R-H. AB - Boranes with the general formula of HBR2 have been found to undergo a facile 1,1 hydroboration reaction with pyrido[1,2-a]isoindole (A), resulting in insertion of a BR2 unit into a C?N bond and the formation of a variety of BN heterocycles. Investigation on the thermal reactivity of the BN heterocycles revealed that these molecules have two distinct and competitive thermal elimination pathways: HBR2 elimination (or retro-hydroboration) versus R?H elimination, depending on the R group on the B atom and the chelate backbone. Mechanistic aspects of these highly unusual reactions have been established from both experimental and computational evidence. Adduct formation between HBR2 and A was found to be the key intermediate in 1,1-hydroboration of A. PMID- 25800307 TI - The protein l-isoaspartyl (d-aspartyl) methyltransferase protects against dopamine-induced apoptosis in neuroblastoma SH-SY5Y cells. AB - Parkinson's disease (PD) is the most common neurodegenerative motor disorder in the world. The main causes of neurodegeneration in PD are mitochondrial impairment and oxidative stress promoted by dopamine (DA) metabolism in the cytosol. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a protein repair enzyme with anti-apoptotic properties. We previously reported that PIMT was downregulated at both gene and protein levels by DA-induced oxidative stresses in SH-SY5Y neuroblastoma cells. The purpose of the current study was to investigate the anti-apoptotic function of PIMT toward DA-induced cell death to better understand its specific neuroprotective role. Overexpression of wild-type PIMT, in contrast to its inactive mutant, protected SH-SY5Y cells from cell death and caspase 3 activation upon DA treatments. The intrinsic pathway of apoptosis as measured by caspase 9 activity was triggered by reactive oxygen species produced from DA metabolism, and overexpression of wild-type PIMT completely prevented caspase 9 activity stimulated by DA. In addition, cells overexpressing wild-type PIMT produced significantly less reactive oxygen species despite DA treatment compared to cells that do not overexpress PIMT. Together, these data indicate that DA-associated PIMT downregulation is an important event contributing to neuronal cell death. More importantly, the PIMT anti-apoptotic capacity seems to be dependent on its involvement in the cellular antioxidant machinery. PMID- 25800308 TI - V3 interneuron subpopulations in the mouse spinal cord undergo distinctive postnatal maturation processes. AB - Mice develop weight-bearing locomotion within the first 2-3 weeks of birth, a period during which motoneurons (MNs) and interneurons (INs) that control locomotor activities undergo rapid maturation. In this study, we investigate the maturation of two subpopulations of V3 INs in the mouse spinal cord during this period. To do this, we conducted whole-cell patch-clamp recordings of tdTomato fluorescent protein-expressing spinal V3 INs from Sim1(Cre/+);tdTom mice at post natal day (P) 0, P4, P9 and P14 and compared their properties to those at P21. Combining electrophysiology with computational analyses, we show that dorsal and ventral V3 subpopulations are physiologically distinct at birth, but the electrophysiological properties of V3 INs change significantly during the first three post-natal weeks. We further reveal that there are multiple developmental phases of both V3 subpopulations during the maturation process. The different developmental trajectories of physiological properties also coincide with changes in an animal's locomotor behavior. These properties likely reflect the differential functions of V3 subpopulations in maturing spinal locomotor circuits. PMID- 25800310 TI - Epidemiology of diverticular disease -- systematic review of the literature. AB - INTRODUCTION: Associated with the Western diet and life style,diverticular disease is affecting more and more developing countries worldwide. Recent studies show an increase in incidence of the disease at young age, that raises the risk of complications, along with major consequences for the patient but also for the healthcare system. METHOD: Systematic review of the literature with US National Library of Medicine and National Institutes of Health International PubMed Medline, using abstracts and articles available in PubMed Medline, Cochrane databases searching for ("Diverticulosis, Colonic epidemiology" [MeSH] OR"Diverticulosis, Colonic etiology" [MeSH] OR "Diverticulosis,Colonic genetics" [MeSH] OR "Diverticulosis, Colonic history" [MeSH]). RESULTS: Even from the rise of diverticular disease as a public healthcare problem, at the end of the previous century, it was associated with a diet rich in refined sugars, lacking vegetable fibres. The higher incidence in countries like U.S.A., Canada, United Kingdom and the northern states compared with its rare occurrence in the sub Saharan African continent, strengthen the anterior assumptions. In regions like Asia, the disease pattern is characterized by are latively low incidence of colonic diverticular disease, with distribution of diverticula mainly on the right colon. The different incidence by sex and age show the possible existence of hormonal protective factors. Studies from countries with a rich ethnic diversity, bring into question the probable genetic predisposition to diverticular disease, fact backed-up by the few studies on twins and 1st degree relatives available in the literature. DISCUSSION: The rising incidence of colonic diverticular disease in Romania makes our country adhere the epidemiologic model existing in countries with a close socio-economic status.Although with a lower incidence than countries that have adopted a Western diet, Romania is likely to encounter a public health problem, if certain measures to identify and minimise the population exposure to risk factors are not taken. PMID- 25800311 TI - Comparison of effects of devascularization versus shunt on patients with portal hypertension: a meta-analysis. AB - OBJECTIVE: To systematically evaluate the effectiveness of devascularization and shunt on patients with portal hypertension. METHODS: Relevant studies compared devascularization and shunt for the treatment of portal hypertension were identified searching the PubMed, Embase, Elsevier, CNKI (China National Knowledge Infrastructure) database and Cochrane Trial Register searches until December 2013. Data of interest for devascularization and shunt including postoperative recurrent bleeding, postoperative hepatic encephalopathy,ascites, operative mortality rate, and long term survival rate were subjected to meta-analysis. RESULTS: Eleven studies were included in the study, the results of the meta analysis showed that all eleven clinical studies demonstrated a significantly higher postoperative recurrent bleeding rate with devascularization group than with shunt group (Odds Ratio =2.14, 95% CI =(1.42, 3.21), P = 0.0003),the rate of hepatic encephalopathy in the devascularization group was significantly lower compared with the shunt group (Odds Ratio =0.56, 95% CI =(0.38, 0.82), P = 0.003); Our meta-analysis of three clinical studies revealed that the reduction of ascites in the devascularization group was significantly less than the shunt groups (Odds Ratio =0.48, 95% CI =(0.26, 0.89), P = 0.02), the operative mortality rate was not significantly different between the devascularization group than for shunt group (Odds Ratio =1.54, 95% CI = (0.91,2.63), P = 0.11). And the long-term survival rate was not significantly different between the devascularization and shunt groups (Odds=1.13, ratio, 95% CI =(0.64, 1.99), P = 0.68). CONCLUSIONS: Devascularization and shunt have different advantages and disadvantages respectively which reflected in postoperative complications and long term survival rate. PMID- 25800309 TI - Episodic sucrose intake during food restriction increases synaptic abundance of AMPA receptors in nucleus accumbens and augments intake of sucrose following restoration of ad libitum feeding. AB - Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for 10 occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-h chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR. Generally, neither a history of sucrose intake nor a terminal bout of sucrose intake affected AMPA receptor abundance in the NAc PSD of AL subjects. Together, these results are consistent with the hypothesis, but the functional contribution of increased synaptic incorporation of AMPA receptors remains to be established. PMID- 25800312 TI - Clinical significance of the lymphoscintigraphy in the evaluation of non-axillary sentinel lymph node localization in breast cancer. AB - BACKGROUND: Identification and biopsy of the sentinel lymph node (SLN) in early stage breast cancer (T1-T2N0) has become the standard method in the surgical treatment of the axilla, due to its accuracy in the evaluation of axillary lymph node status,thus avoiding extensive axillary lymph node dissection inpatients with negative SLN. The aim of our study is to highlight the role of 99mTc nanocolloid lymphoscintigraphy in the preoperative lymphatic mapping, especially for SLN localizations outside the axilla, as well as the benefits of this technique in the accurate staging of breast cancer. MATERIALS AND METHOD: 430 patients (age 31-81 years) with breast cancer (T1-T2N0 stage) were included in the study group, who underwent lymphoscintigraphy in order to identify the sentinel lymph node in the Nuclear Medicine Department of "??Prof. Dr. Al. Trestioreanu"?? Institute of Oncology, Bucharest,between October 2008 - July 2014. Radiocolloid (99mTc-nanocolloid)was injected using peritumoral or periareolar intradermal technique, doses between 20-37 MBq (0.3-0.5 ml volume), followed by static and dynamic post-injection acquisitions.Intraoperative identification of the SLN was performed using a gamma-probe, guided by the skin marker performed preoperatively after completion of lymphoscintigraphy. RESULTS: 697 sentinel lymph nodes were identified through imaging techniques in 427 patients (99%). Of them, 364 patients had axillary localization of the SLN, while 48 patients(11%) had non-axillary (pectoral, internal mammary, supraclavicular,intra-mammary) localization and 15 patients (3%)had multiple localization (axillary and non-axillary).Intraoperative histopathological exam revealed lymphatic invasion in 74 SLN (12% macrometastases and 88% micrometastases). CONCLUSIONS: The identification and biopsy of the sentinel lymph node in stages I and IIA is a useful routine for accurate breast cancer staging, suited for axillary lymphatic drainage, as well as for unusual non axillary SLN localization, guiding the clinician for further postoperative management of these patients. PMID- 25800313 TI - The incidence and risk factors for occurrence of arm lymphedema after treatment of breast cancer. AB - BACKGROUND: The arm lymphedema is reported as being the most frequent late reaction and complication that influences breast cancer patients'?? quality of life after lymph node dissection and radiotherapy. The aim of the study is to identify the risk factors in arm lymphedema occurrence in breast cancer patients who performed radical conservatory surgery, chemotherapy and radiotherapy. MATERIAL AND METHODS: We analysed 305 breast cancer patients who underwent treatment in the "Sf. Ap. Andrei"?? Emergency Clinical Hospital, Galati, Radiotherapy and Oncology Department, between the 1st of January 2010 and 31st of December 2012. We tried to find the risk factors for arm lymphedema development after treatment of breast cancer: the association of adjuvant radiotherapy with surgery, chemotherapy,hormonal therapy, number of removed lymph nodes,and number of lymph nodes with metastases, the co-morbid illnesses (obesity, diabetes mellitus and high blood pressure). RESULTS: Our study evidences that the association of adjuvant radiotherapy, including the lymph node regions, with radical or conservatory surgery with lymph node dissection represents a statistically significant risk factor, with relative risk, RR =1.87, 95%C.I.=1.39 ?3.51, p<0.001. The number of removed lymph nodes was found to be a risk factor with statistical significance. For more than 25 removed lymph nodes, the relative risk for arm lymphedema development was RR=1.95(95%C.I. =1.79-4.51) and for 16-25 removed lymph nodes the relative risk, RR = 1.78, 95% C.I. = 1.46 - 3.23. Other analysed risk factors, which did not influence lymphedema development, were: associated chemotherapy or hormonal therapy,presence of co-morbid illnesses. CONCLUSIONS: The development of arm lymphedema is an unpredictable occurrence that can happen years after axillary surgery.Breast and arm oedema continue to be late reactions that can be reduced by use of biopsy sentinel technique with avoiding of axillary lymph node dissection, when the sentinel lymph node is negative, knowing that lymphedema risk after sentinel lymph node is 5% comparative with lymphedema risk after axillary lymph node dissection which is 16%, by avoiding obesity, and performing modern therapy techniques. PMID- 25800314 TI - Local and distant recurrences -- a comparative study on conservative and radical surgery for breast cancer. AB - The treatment of breast cancer has evolved over the past 40 years. Followed by radiotherapy, conservative surgical procedures are options increasingly more preferred by surgeons and patients. This paper aims to highlight comparative aspects of local and distant recurrence in patients who had radical or conservative surgery for breast cancer. We performed a retrospective study between January, 2005 - July 2013, that included 477 breast cancer patients from the Regional Institute of Oncology Iasi, who were evaluated by imaging in the Radiology Clinic,Hospital "St. Spiridon", Iasi. We included in the study patients in curable stages 0, I and II; 248 (52 %) patients had radical surgery and 229 (48 %) patients had conservative surgery. We used the ultrasound scan, mammography, CT and MRI, that allowed diagnosis, pretherapeutic staging and diagnosing of the loco-regional and distant recurrences. Local and distant recurrences were higher in patients with conservative surgery(86 recurrences), than in patients who had radical surgery (55 recurrences). Local recurrences are more common in younger individuals and in patients treated with conservative surgery and radiotherapy, than in patients with radical mastectomy.The most common metastases are located in the bone, liver and lung. PMID- 25800315 TI - Bone fracture in breast cancer patients with isolated bone metastasis. AB - AIM: To analyse the incidence of bone fracture of breast cancer patients with isolated bone metastasis and its effect on survival. We tried to find an answer to the question of "Can the development of bone fracture be predicted?" METHODS: Between 1993-2006, 139 breast cancer patients with isolated bone metastasis were examined. Patients were divided into two groups depending on the development of pathologic bone fracture. RESULTS: Fractures were developed in 41 patients (29.5%)within 41 months of follow-up. The locations of pathologic bone fracture were vertebral fracture in 26 patients (63.4%),femur fracture in 11 patients (26.8%), and hip fracture in four patients (9.8%). Fracture rates in hormone sensitive and resistant patients were 31.2% and 14.3%, respectively. The fracture rates in 13 triple negative and non triple negative patients were 7.7% and 31.4%, respectively (p=0.07). High CA 15-3 levels at the time of metastasis in patients with and without fractures were 68.4% and 61.1%, respectively. The risk for fracture was also high in Her2-neu positive patients (38.7% vs. 26.5%). While the incidence of fracture with the presence of one factor mentioned above was 22.2%, it was increased to 36.1% in the presence of two or three factors(p=0.13). Median survivals of the patients with and without fractures were 48 and 39 months, respectively (p= 0.65). CONCLUSION: Hormone sensitivity, high CA 15-3 levels and positive Her2-neu status are slight risk factors for bone fractures. Survival was not different in patients with or without bone fractures. PMID- 25800316 TI - Hepatoprotective effect of pioglitazone in cases of chemotherapy induced steatohepatitis. AB - BACKGROUND/OBJECTIVES: To evaluate the harmful effects of 5-floururacil (5-FU) and Irinotecan on the liver and to determine the role of Pioglitazone in averting liver damage. METHODS: Sixty Sprague-Dawley female rats were divided into 4 groups. The first group (n=20) was administered 40 mg of 5-FU and 40 mg kg of Irinotecan intraperitoneally for 4 cycles, while the second group (n=20) received 4 mg kg of Pioglitazone by gastric gavage at 5 days a week for 20 days in addition to chemotherapy. The third group (n=10) was the sham group; chemotherapy regimen was given as in the first group. In addition, normal saline was given daily for 20 days by gastric gavage. The fourth group (n=10) was only given a standard diet as a control group. Then, blood samples were studied for the evaluation of alanine aminotransferase (AST)and alanine aminotransferase (ALT) levels. And left liver lobes of rats were taken for pathological analysis. RESULTS: Although short-term chemotherapy was administered,aminotransferase (AST) and alanine aminotransferase (ALT)levels were found to be significantly higher in the first and third groups compared to the others (p 0.0001). No significant difference was determined between the second and the control group. Pioglitazone reduced the adverse metabolic effects of chemotherapy on the liver, but had no effect on the histopathological changes. CONCLUSION: short-term CT causes metabolic disruption in hepatocytes, but not relevant with CASH. Preventive treatments like Pioglitazone should be used more carefully. PMID- 25800318 TI - Rectal impalement injury: from cruelty to salvage endeavour. AB - Massive penetrating trauma by rectal impalement is a very rare form of injury, complicated and potentially lethal. It is even rarer for such injury to result in pelvic, abdominal and thoracic internal damages. We report the case of a 62 year old man who was admitted in emergency after an aggression with a sharp wooden stake inserted forcibly into his rectum. Clinical examination revealed the blunt extremity of the stake outside the anus and the prominent sharp end reaching his right supraclavicular fossa. Radiographic examination showed the stake extending from the rectum to the right side of the neck.Surgery disclosed penetration through the rectum, retroperitoneum,large bowel mesentery, liver, diaphragm, right lung and right 2nd rib. The patient survived following management by a multidisciplinary surgical team. As similar reported cases are scarce, knowledge of the management of the few cases that have been successfully treated is likely to prepare the emergency teams to act rationally and efficiently in such exceptionally grave circumstances. PMID- 25800317 TI - Serum C-reactive protein and white blood cell level as markers of successful percutaneous drainage of acute sterile peripancreatic fluid collection. AB - BACKGROUND: Percutaneous drainage is not a widely used therapeutic method recently for evacuating peripancreatic sterile fluid collections in patients with severe acute pancreatitis.However, many clinical studies have proved its positive effects. AIM: We tested the changes in serum laboratory parameters:C-reactive protein (CRP), complement factor 3-4 (C 3-4),tumor necrosis factor a (TNF-a), amylase, lipase and white blood cell (WBC) count in patients treated by percutaneous drainage. PATIENTS AND METHODS: 10 patients with severe acute pancreatitis with peripancreatic fluid collection were monitored.Laboratory parameters and the amount of drained fluid were measured on the 1st, 5th and 10th day. Statistical analysis was performed by using Statistica for Windows (Version 7.0)software. P values less than 0.05 were considered statistically significant. RESULTS: We found significant positive correlation between the CRP and WBC serum level and volumes of the drained fluid. We used these parameters as markers of successful percutaneous drainage in case of patients with severe acute pancreatitis complicated with sterile peripancreatic fluid.There was no significant change in the levels of C 3-4,tumor necrosis factor-I+-, amylase and lipase. CONCLUSIONS: Monitoring of serum CRP and WBC levels maybe recommended for follow up after percutaneous drainage of peripancreatic fluid. ABBREVIATIONS: CRP: C-reactive Protein TNFI+-: Tumour Necrosis Factor a, C3-4: Complement 3-4 WBC: White Blood Cell CT: Computed Tomography. PMID- 25800319 TI - Clinicopathological phenotype of parathyroid carcinoma: therapeutic and prognostic aftermaths. AB - Parathyroid carcinomas (PC) are rare and "devastating"?? causes of hyperparathyroidism (HP), frequently discovered fortuitously,with not always doubtless pathological confirmation, and dissociate post-therapeutic outcomes and prognosis even after well-performed surgery. We herein report four PT neoplasms,three of them proving to be authentic PCs, and one an atypical parathyroid adenoma. There were three females and one male, aged 32-49 (mean 44) years. In three circumstances PC was associated with primary HP and in one case the tumor had developed on a CKD-BMD (renal HP) background. All patients presented marked clinical and biochemical phenomena related to hypercalcemia with greater intensity of renal, bone, neuromuscular and psychological signs and symptoms to which in one observation specific uremic manifestations were added. Preoperative and intraoperative diagnosis was suspected only in two cases (one of them being in fact an atypical PT adenoma), but in the other two it was established by paraffin section on histological evidence of definitive stigma of malignancy. Our little experience underlines the wide and protean range of the origins, clinical aspects, course and prognosis of PC, which adds to the difficulties of pre- and intraoperative diagnosis. Awareness of this lesion must be permanent to detect its presence in any unusual eventuality, imposing a radical en bloc resection at the initial operation, assuring the best chance of cure. PMID- 25800320 TI - Large oesophageal epiphrenic diverticulum resected by transhiatal robotic assisted approach -- case report. AB - INTRODUCTION: Epiphrenic diverticula (ED) represent about 20% of oesophageal diverticula. They are considered to be pulsion diverticula, characterized by out pouchings of the oesophageal mucosa originating in the distal 10 cm of the oesophagus and are frequently associated with spastic oesophageal dysmotility. The most frequent clinical manifestations of ED are dysphagia, regurgitations and chest pain. Only symptomatic diverticula should be treated by surgery. The surgical procedure can be performed minimally invasively by robotic approach and consists of diverticulectomy,hiatus calibration and an antireflux procedure, usually adding an esophagomiotomy as well. CASE-REPORT: We present the case of 43 year-old male patient who was admitted for a four-month history of epigastric pain, pyrosis and regurgitations. Preoperative investigation shave shown an epiphrenic diverticulum 6 cm large in diameter.A robotic-assisted transhiatal diverticulectomy with a linear endostapler, hiatal calibration and a Nissen Rossetti fundoplication were performed using a three-arm da Vinci Robotic System. Operative time was 150 min. Postoperative course was uneventful and the patient was discharged on postoperative day 9, without complications. Ten days later,he came back and was readmitted under emergency status for right chest pain, dyspnoea and fetid breath, being diagnosed with a right empyema secondary to a delayed fistula of the oesophageal suture line. A right minimal pleurotomy and pleural drainage under local anaesthesia were performed and an intravenous antibiotherapy was started with complete remission of symptomatology, the patient remaining asymptomatic after 18 months of follow-up. CONCLUSIONS: Robotic approach is a feasible and safe minimally invasive surgical option in the treatment of selected cases of ED. We consider transhiatal abdominal robotic approach possible in almost all cases of ED, regardless of size,thus avoiding thoracic approach and its possible major complications.The most common serious complication after surgery of ED is post diverticulectomy suture line fistula, but if properly and rapidly diagnosed it could be conservatively treated with very good results. PMID- 25800321 TI - Primary aortoenteric fistula: case report. AB - We report the case of an elderly woman, 81 years old, who was admitted in our department for hematemesis, hematochezia and lower abdominal pain. The abdominal ultrasound and the CT scan diagnosed a primary aortoenteric fistula between an abdominal aortic aneurysm (AAA) and the second part of the duodenum, which is a very rare localization regarding this condition. Surgical pathology,diagnosis and management are discussed. PMID- 25800322 TI - Recurrent perineal hernia -- case report and review of the literature. AB - Perineal hernia is the protrusion of intra-abdominal viscera through the pelvic floor. We present a patient with recurrent perineal hernia - 12x9 cm with a palpable soft, hardly adjustable in the pelvic tunnel formation and attenuated skin over it. The patient was operated by abdominoperineal approach. We performed two layer Titanium mesh plasty of the pelvic floor with the use of the omentum and the pelvic muscles. PMID- 25800323 TI - Left congenital diaphragmatic hernia -- case report. AB - Congenital diaphragmatic hernia (CDH) occurs when the abdominal contents protrude into the thoracic cavity through an anatomical defect in the diaphragm. The incidence of CDH is 1 in 2500 births, with left congenital diaphragmatic hernias(LCDH) being more common than right-side hernias (85% to 12%). While many cases are discovered prenatally or during the immediate postnatal period, 5 to 25% of CDH can be late presenting events which are detected by routine examinations,during medical check-ups, because of respiratory or gastrointestinal problems or complications such as gastric volvulus,occlusion, perforation, peritonitis or necrosis. Trans-abdominal or trans-thoracic approach is mandatory in those cases where complications have been identified. The prognosis for late presenting patients with LCDH is usually favorable. We report he case of a 7-year old girl with recent history of trauma,who was admitted to a local hospital with respiratory distress. In our clinic, LCDH was diagnosed and closure of the defect was performed through an open trans-abdominal approach with favorable outcome. PMID- 25800325 TI - Mediastinal granulomatous lymphadenitis after intravesical bacillus Calmette Guerin treatment mimicking distant metastasis of primary bladder carcinoma. PMID- 25800326 TI - Thoracic cystic lymphangioma in an elderly patient. PMID- 25800324 TI - Emerging from the bottleneck: benefits of the comparative approach to modern neuroscience. AB - Neuroscience has historically exploited a wide diversity of animal taxa. Recently, however, research has focused increasingly on a few model species. This trend has accelerated with the genetic revolution, as genomic sequences and genetic tools became available for a few species, which formed a bottleneck. This coalescence on a small set of model species comes with several costs that are often not considered, especially in the current drive to use mice explicitly as models for human diseases. Comparative studies of strategically chosen non-model species can complement model species research and yield more rigorous studies. As genetic sequences and tools become available for many more species, we are poised to emerge from the bottleneck and once again exploit the rich biological diversity offered by comparative studies. PMID- 25800327 TI - Invasive Bronchial Aspergillosis in a Hematology Patient. PMID- 25800328 TI - Alpha-1 Antitrypsin Deficiency in COPD Patients: A Cross-Sectional Study. AB - INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with early onset chronic obstructive pulmonary disease (COPD) and liver disease. It is also a highly under-diagnosed condition. As early diagnosis could prompt specific interventions such as smoking cessation, testing of family members, genetic counselling and use of replacement therapy, screening programs are needed to identify affected patients. OBJECTIVE: To estimate the prevalence of severe AATD in COPD patients by routine dried blood spot testing and subsequent genotyping in patients with alpha-1 antitrypsin (AAT) levels below an established threshold. MATERIALS AND METHODS: Cross-sectional study of adult COPD patients attending the Hospital Dr. Antonio Cetrangolo (Buenos Aires, Argentina) between 2009 and 2012. The study consisted of capillary blood collection via finger stick to determine AAT levels, clinical evaluation and lung function tests. Genotype was determined in AAT-deficient patients. RESULTS: A total of 1,002 patients were evaluated, of whom 785 (78.34%) had normal AAT levels, while low AAT levels were found in 217 (21.66%). Subsequent genotyping of the latter sub-group found: 15 (1.5%, 95% CI 0.75-2.25) patients with a genotype associated with severe AATD, of whom 12 were ZZ (1.2%, 95% CI 0.52-1.87) and 3 SZ (0.3%, 95% CI 0-0.64). The remaining 202 patients were classified as: 29 Z heterozygotes (2.89%, 95% CI 1.86-3.93), 25 S heterozygotes (2.5%, 95% CI 1.53-3.46) and 4 SS (0.4%, 95% CI 0.01-0.79). A definitive diagnosis could not be reached in 144 patients (14.37%, 95% CI 12.2-16.54). CONCLUSION: The strategy using an initial serum AAT level obtained by dried blood spot testing and subsequent genotyping was a satisfactory initial approach to a screening program for severe AAT, as a definitive diagnosis was achieved in 87% of patients. However, results were not obtained for logistical reasons in the remaining 13%. This major obstacle may be overcome by the use of dried blood spot phenotyping techniques. We believe this approach for detecting AATD in COPD patients, in compliance with national and international guidelines, is supported by our results. PMID- 25800329 TI - Spatial distribution of human asymptomatic Leishmania infantum infection in southeast Spain: a study of environmental, demographic and social risk factors. AB - Recent PCR studies indicate that asymptomatic L. infantum infection is common in people in southern Europe. Understanding its spatial distribution is a requisite to evaluate the public health implications and to design disease control schemes. We investigated infection in blood samples from 657 donors in southeast Spain using PCR and antibody ELISA. They came from 19 blood centers and were interviewed about their residence, occupation, dog ownership and Leishmaniosis awareness. The percentage of PCR and ELISA positives were 8% (49/618) and 2% (13/657). Donor's residences were spatially clustered around blood donning centers and PCR prevalence was 18% in rural municipalities with 20-1330 inhabitants, 12% in those with 1467-5088 inhabitants and 3% in larger communities, and was associated with dog ownership (p<0.05). Further analysis of data from rural donors indicated that PCR status was strongly related to the climate, altitude and soil type in the donor's residence area and not to other demographic or sociologic variables. Mixed logistic regression analysis predicted PCR prevalence to be greatest in the 200-300m altitude range with a mean spring summer (time of highest vector activity) temperature of 18.4-19.0 degrees C. A temperature and altitude risk map was generated that will provide the basis for elaborating evidence-based vector surveillance studies. PMID- 25800330 TI - How much does a diabetes out-patient appointment actually cost? An argument for PLICS. AB - PURPOSE: The national tariff system for clinical processes and procedures aims to put a discrete unit cost on clinical activity. Calculating such costs can be subject to a great deal of local variation and interpretation. Given the rising costs of diabetes the purpose of this paper is to ask the question what does a diabetes outpatient appointment in the UK NHS actually cost? This is important in a time of financial austerity and healthcare rationing because it can be difficult to decipher the attribution of costs within the acute hospital setting. DESIGN/METHODOLOGY/APPROACH: Exploring this question, the author considers the present cost model and analyse in terms of the language of unit model cost; the basic tariff system and how it works in diabetes and looking at internal cost information the author attempts to unbundle the cost to provide a more accurate value for the cost object. FINDINGS: One major finding is that costs and overheads are divided arbitrarily as opposed to being distributed on the basis of measured relative consumption. Alternative costing methods are appraised to demonstrate that a patient level episodic costing approach such as patient level information and costing system (PLICS) which incorporates aspects of activity based costing (ABC) would be far more appropriate. Using time driven ABC (TDABC), a new patient appointment costs L162 for 30 minutes and a follow-up appointment costs L81 for 15 minutes. PRACTICAL IMPLICATIONS: PLICS has the added benefit of greater financial and clinical transparency and this goes some way towards the holy grail of greater engagement with the doctors delivering clinical care. SOCIAL IMPLICATIONS: It would appear that there are different purposes of different costing systems. One can argue that a costing system is there to both contain costs and divide overheads and demonstrate activity. Depending on how data are interpreted costing information can be an agent of enlightenment and behavioural modification for healthcare professionals to show them their direct and indirect costs, their capacity and productivity. ORIGINALITY/VALUE: Clinicians and health service managers can see from this practical example how the distribution of costs and resources are unfair and can impede the delivery of a service. By using alternative costing methodologies such as ABC not only do the author gets a better reflection of the true cost of the finished consultant episode but is also able to engage clinicians in understanding how costs are generated. PMID- 25800331 TI - What is health promotion capacity? A relational perspective. AB - PURPOSE: In organizational health promotion research, health promotion capacity is a central concept that is used to describe the abilities of individuals, organizations, and communities to promote health. The purpose of this paper is to discuss the theoretical underpinnings of the literature on health promotion capacity building and, further, to suggest an alternative theoretical perspective which draws on recent developments in organizational theory. DESIGN/METHODOLOGY/APPROACH: The paper begins by a critical discussion of the capacity building literature, which is juxtaposed with the relational perspective of contemporary organizational theory. The theoretical argument is developed in reference to the case of Danish municipal health promotion agencies, drawing on secondary sources as well as ethnographic fieldwork among public health officers. FINDINGS: The capacity building literature tends to reify the concept of capacity. In contrast, this paper argues that health promotion capacity is constantly defined and redefined through processes of organizing. The case study suggests that, faced with limited resources and limited knowledge, health promotion officials attain a sense of capacity through an ongoing reworking of organizational forms. RESEARCH LIMITATIONS/IMPLICATIONS: Organizational health promotion research should look for the organizational forms that are conducive to health promotion practices under shifting social circumstances. ORIGINALITY/VALUE: This paper makes explicit an inherent theoretical tension in the capacity building literature and suggests a novel theoretical framework for understanding organizational capacity. PMID- 25800332 TI - Vertical and horizontal control dilemmas in public hospitals. AB - PURPOSE: The hospital sector in Norway has been continuously reorganized since 2002 and the reforms have created organizations that are functionally/vertically controlled, whereas the production lines are coordinated on a process or a lateral basis. The purpose of this paper is to focus on both the perceived functional vertical control and horizontal controls within and between the local hospitals and the regional administrative levels. DESIGN/METHODOLOGY/APPROACH: A national survey study, complemented with interviews of some key informants and document studies. FINDINGS: The study shows that the functional and vertical lines of management control are perceived to be operating according to the traditional views of management control. The study indicates that the horizontal tasks are not very well implemented, and we did not find interactive and lateral uses of management control systems for managerial purposes. PRACTICAL IMPLICATIONS: New control problems arise when services are to be coordinated between autonomous units. ORIGINALITY/VALUE: The paper focuses on the control problems found within the horizontal, flat relationship between production units in hospitals; new organizational structures have emerged where lateral relations are important, but traditional control practices follow functional, vertical lines. PMID- 25800333 TI - From translational research to open technology innovation systems. AB - PURPOSE: The purpose of this paper is to question whether the emphasis placed within translational research on a linear model of innovation provides the most effective model for managing health technology innovation. Several alternative perspectives are presented that have potential to enhance the existing model of translational research. A case study is presented of innovation of a clinical decision support system. The paper concludes from the case study that an extending the triple helix model of technology transfer, to one based on a quadruple helix, present a basis for improving the performance translational research. DESIGN/METHODOLOGY/APPROACH: A case study approach is used to help understand development of an innovative technology within a teaching hospital. The case is then used to develop and refine a model of the health technology innovation system. FINDINGS: The paper concludes from the case study that existing models of translational research could be refined further through the development of a quadruple helix model of heath technology innovation that encompasses greater emphasis on user-led and open innovation perspectives. RESEARCH LIMITATIONS/IMPLICATIONS: The paper presents several implications for future research based on the need to enhance the model of health technology innovation used to guide policy and practice. PRACTICAL IMPLICATIONS: The quadruple helix model of innovation that is proposed can potentially guide alterations to the existing model of translational research in the healthcare sector. Several suggestions are made for how innovation activity can be better supported at both a policy and operational level. ORIGINALITY/VALUE: This paper presents a synthesis of the innovation literature applied to a theoretically important case of open innovation in the UK National Health Service. It draws in perspectives from other industrial sectors and applies them specifically to the management and organisation of innovation activities around health technology and the services in which they are embedded. PMID- 25800334 TI - Using sentiment analysis to review patient satisfaction data located on the internet. AB - PURPOSE: The purpose of this paper is to test the usefulness of sentiment analysis and time-to-next-complaint methods in quantifying text-based information located on the internet. As important, the authors demonstrate how managers can use time-to-next-complaint techniques to organize sentiment analysis derived data into useful information, which can be shared with doctors and other staff. DESIGN/METHODOLOGY/APPROACH: The authors used sentiment analysis to review patient feedback for a select group of gynecologists in Virginia. The authors utilized time-to-next-complaint methods along with other techniques to organize this data into meaningful information. FINDINGS: The authors demonstrated that sentiment analysis and time-to-next-complaint techniques might be useful tools for healthcare managers who are interested in transforming web-based text into meaningful, quantifiable information. RESEARCH LIMITATIONS/IMPLICATIONS: This study has several limitations. For one thing, neither the data set nor the techniques the authors used to analyze it will account for biases that resulted from selection issues related to gender, income, and culture, as well as from other socio-demographic concerns. Additionally, the authors lacked key data concerning patient volumes for the targeted physicians. Finally, it may be difficult to convince doctors to consider web-based comments as truthful, thereby preventing healthcare managers from using data located on the internet. PRACTICAL IMPLICATIONS: The report illustrates some of the ways in which healthcare administrators can utilize sentiment analysis, along with time-to-next-complaint techniques, to mine web-based, patient comments for meaningful information. ORIGINALITY/VALUE: The paper is one of the first to illustrate ways in which administrators at clinics and physicians' offices can utilize sentiment analysis and time-to-next-complaint methods to analyze web-based patient comments. PMID- 25800336 TI - A problem-solving routine for improving hospital operations. AB - PURPOSE: The purpose of this paper is to examine empirically why a systematic problem-solving routine can play an important role in the process improvement efforts of hospitals. DESIGN/METHODOLOGY/APPROACH: Data on 18 process improvement cases were collected through semi-structured interviews, reports and other documents, and artifacts associated with the cases. The data were analyzed using a grounded theory approach. FINDINGS: Adherence to all the steps of the problem solving routine correlated to greater degrees of improvement across the sample. Analysis resulted in two models. The first partially explains why hospital workers tended to enact short-term solutions when faced with process-related problems; and tended not seek longer-term solutions that prevent problems from recurring. The second model highlights a set of self-reinforcing behaviors that are more likely to address problem recurrence and result in sustained process improvement. RESEARCH LIMITATIONS/IMPLICATIONS: The study was conducted in one hospital setting. PRACTICAL IMPLICATIONS: Hospital managers can improve patient care and increase operational efficiency by adopting and diffusing problem solving routines that embody three key characteristics. ORIGINALITY/VALUE: This paper offers new insights on why caregivers adopt short-term approaches to problem solving. Three characteristics of an effective problem-solving routine in a healthcare setting are proposed. PMID- 25800335 TI - Impact of the organisational culture on primary care staff members' intention to engage in research and development. AB - PURPOSE: The purpose of this paper is to understand how organisational culture influences the intentions of primary care staff members (PCSM) to engage in research and development (R&D). DESIGN/METHODOLOGY/APPROACH: The participants (n=30) were PCSM employed in a care centre in south-western Sweden. The study had an observational design with an ethnographic approach. The data were collected by means of observations, interviews and analysis of documents. FINDINGS: The results revealed the perceptions of PCSM in two domains, research and clinical practice, both of which existed at three different cultural levels: visible (structures and policy), semi-visible (norms and values) and invisible (taken-for granted attitudes). RESEARCH LIMITATIONS/IMPLICATIONS: It is difficult to conduct a purely objective ethnographic study because the investigation is controlled by its context. However, it is necessary to highlight and discuss the invisible level to improve understanding of negative attitudes and preconceptions related to the implementation of R&D in the clinical setting. PRACTICAL IMPLICATIONS: By highlighting the invisible level of culture, the management of an organisation has the opportunity to initiate discussion of issues related to concealed norms and values as well as attitudes towards new thinking and change in the primary health context. ORIGINALITY/VALUE: This paper is one of the very few studies to investigate the influence of organisational culture on the intentions of PCSM to engage in R&D. PMID- 25800337 TI - Trialability, observability and risk reduction accelerating individual innovation adoption decisions. AB - PURPOSE: The purpose of this paper is to provide a retrospective analysis of computer simulation's role in accelerating individual innovation adoption decisions. The process innovation examined is Lean Systems Thinking, and the organizational context is the imaging department of an Australian public hospital. DESIGN/METHODOLOGY/APPROACH: Intrinsic case study methods including observation, interviews with radiology and emergency personnel about scheduling procedures, mapping patient appointment processes and document analysis were used over three years and then complemented with retrospective interviews with key hospital staff. The multiple data sources and methods were combined in a pragmatic and reflexive manner to explore an extreme case that provides potential to act as an instructive template for effective change. FINDINGS: Computer simulation of process change ideas offered by staff to improve patient-flow accelerated the adoption of the process changes, largely because animated computer simulation permitted experimentation (trialability), provided observable predictions of change results (observability) and minimized perceived risk. RESEARCH LIMITATIONS/IMPLICATIONS: The difficulty of making accurate comparisons between time periods in a health care setting is acknowledged. PRACTICAL IMPLICATIONS: This work has implications for policy, practice and theory, particularly for inducing the rapid diffusion of process innovations to address challenges facing health service organizations and national health systems. Originality/value - The research demonstrates the value of animated computer simulation in presenting the need for change, identifying options, and predicting change outcomes and is the first work to indicate the importance of trialability, observability and risk reduction in individual adoption decisions in health services. PMID- 25800338 TI - Is honey able to potentiate the antioxidant and cytotoxic properties of medicinal plants consumed as infusions for hepatoprotective effects? AB - Due to the enormous variety of phytochemicals present in plants, their extracts have been used for centuries in the treatment of innumerable diseases, being perceived as an invaluable source of medicines for humans. Furthermore, the combination of different plants was reported as inducing an improved effect (synergism) in comparison with the additive activity of the plants present in those mixtures. Nevertheless, information regarding the effects of plant infusions added with honey is still rather scarce. Accordingly, the aim of this study was to evaluate the interaction between chestnut honey, a natural product with well-reported beneficial properties, and three medicinal plants (either as a single plant or as combinations of two and three plants), with regard to their antioxidant activity and hepatotoxicity. Antioxidant activity was evaluated by comparing the results from four different assays; hepatotoxicity was assessed in two different cell lines. Results were compared by analysis of variance and linear discriminant analysis. The addition of honey to the infusions had a beneficial result in both cases, producing a synergistic effect in all samples, except beta-carotene bleaching inhibition for artichoke + milk thistle + honey preparation and also preparations with lower hepatotoxicity, except in the case of artichoke + honey. Moreover, from the discriminant linear analysis output, it became obvious that the effect of honey addition overcame that resulting from using single plant or mixed plant based infusions. Also, the enhanced antioxidant activity of infusions containing honey was confirmed by lower hepatotoxicity. PMID- 25800339 TI - Generation of Foxo3-targeted Mice by Injection of mRNAs Encoding Transcription Activator-like Effector Nucleases (TALENs) into Zygotes. AB - In this study, for exploring the mechanism of forkhead box O3(Foxo3) participating in regulation of the activation of primordial oocytes, Foxo3 targeted mice were generated by injection of mRNAs encoding transcription activator-like effector nucleases (TALENs) into mouse zygotes. The TALEN sites were designed with high conservative homologous region among pig, bovine, buffalo and mouse by commercial bio-companies. The TALENs mutagenic non-homologous end joining (NHEJ) repair activity were determined to be 31.3% in human embryonic kidney 293T (HEK-293T) cells by dual luciferase reporter assay system. Then, we firstly injected TALEN-mRNAs into the cytoplasm of mouse zygotes by micromanipulation, and four of 48 mouse blastocysts were identified as mutation by sequencing. Subsequently, by the method of TALEN-mRNAs injected into the zygotes with pronucleus micromanipulation technique, we obtained seven Foxo3 mutants of 20 FVB/NJ backgrounds mice which were Foxo3-independent alleles with frameshift and deletion mutations. It was very interesting that all seven were heterozygous mutants (Foxo3(-/+) ), and the gene mutagenesis rates of the mice reached 35%. The five Foxo3 mutant females were all infertile in the following 6 months after birth. The histological examination results showed that there were rare primordial follicles and primary follicles in the ovary of Foxo3 mutant compared to that of wide-type female mice. Moreover, one of two mutant males was subfertile and another was fertile normally. Those results suggested that the mutant of Foxo3 severely affected the fertile ability of female and perhaps male in some degree; furthermore, an even more efficient TALENs-based gene mutation method has been established to be poised to revolutionize the study of mouse and other species genetics. PMID- 25800340 TI - Administration of ViperSlideTM for treating severe radial artery spasm: case report and systematic review of the literature. AB - Radial artery spasm is a rare complication of transradial cardiac catheterization. We describe a case of severe radial artery spasm causing catheter entrapment. The spasm was resistant to local and systemic vasodilator administration, moderate sedation, and application of warm blankets over the affected arm. While preparations were being made for inducing general anesthesia, ViperSlideTM (Cardiovascular Systems, Inc. St. Paul, Minnesota) was delivered through the radial sheath resolving the spasm. Coronary angiography could not be performed using standard catheters, but was successfully completed using a 6 French Ikari left guide catheter (Terumo, Somerset, New Jersey). PMID- 25800342 TI - Distribution and accumulation of selenium in wild plants growing naturally in the Gumuskoy (Kutahya) mining area, Turkey. AB - This study investigated selenium uptake and transport from the soil to 12 plant species in the mining area of Gumuskoy (Kutahya), Turkey. Plant samples and their associated soils were collected and analyzed for Se content by ICP-MS. Mean Se values in the soils, roots, and shoots of all plants were 0.9, 0.6, and 0.8 mg kg(-1), respectively. The mean enrichment coefficients for roots (ECR) and shoots (ECS) of these plants were 0.78 and 0.97. The mean translocation factors (TLF) were 1.33. These values indicate that all 12 plant species had the ability to transfer Se from the roots to the shoot, but that transfer was more efficient in plants with higher ECR and ECS. Therefore, these plants may be useful in phytoremediation in rehabilitating areas contaminated by Se because their ECR, ECS and TLFs are >1. PMID- 25800343 TI - Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures. AB - BACKGROUND: Intravenous levetiracetam is an option for treatment of status epilepticus (SE) and acute repetitive seizures (ARS). However, there have been relatively few studies with children and adolescents. Also, an appropriate dosage has yet to be determined. AIM: This study investigated the safety and the efficacy of levetiracetam for intravenous treatment of convulsive status epilepticus and acute repetitive seizures in children and adolescents. METHOD: Retrospectively, the study reviewed the medical records of 19 male and 31 female patients under 18 years of age who had received intravenous levetiracetam treatment either for acute repetitive seizures or for convulsive status epilepticus. The patients were admitted between April 1st, 2010 and December 31st, 2011 to the Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Data were collected on underlying illnesses, etiology of seizures, indication for levetiracetam therapy, initial dosage, rate of infusion, untoward effects during infusion and emerged complications. Efficacy of treatment was defined as the termination of seizure within 30 min of completing levetiracetam infusion and no seizure recurrence within 6 h of initial treatment. RESULTS: The age range of the 50 patients was from one day to 18 years (mean 79.6 months). The analysis included 52 episodes of 34 acute repetitive seizures (63.4%) and 18 convulsive status epilepticus (34.6%). Infusion rates ranged from 2 to 66 mg/kg/min (mean 29.6). Cessation of seizure was obtained in 59.6% of 52 episodes. Patients with underlying drug resistant epilepsy did not respond to levetiracetam therapy as well as patients with other etiology of seizures. There were no adverse drug reactions or untoward effects observed during the therapy. CONCLUSION: Intravenous administration of levetiracetam is safe and effective for treatment of acute repetitive seizures and convulsive status epilepticus in children and adolescents. Failure of treatment may be related to underlying drug resistant epilepsy. Further study of appropriate initial dosage and pharmacokinetic variations in the patients is needed as possible explanation of the unresponsiveness. PMID- 25800344 TI - Oncological safety of breast cancer patients undergoing free-flap reconstruction and lipofilling. AB - BACKGROUND: Autologous fat grafting is a widely accepted approach for breast reconstruction after mastectomy but its oncological safety has not been established. This study aimed to compare recurrence in patients who underwent fat grafting procedures after autologous breast reconstruction and those who did not. PATIENTS AND METHODS: We retrospectively reviewed 207 consecutive patients, who underwent mastectomy and reconstruction using free flap surgery. We divide them in two groups: a study group of patients who underwent fat grafting procedure and a control group of patients who did not. Outcome regarding local and regional recurrence was compared between the two groups. Particularly, we studied recurrences from primary surgery to baseline (first lipofilling) and from baseline to most recent follow-up. RESULTS: Median follow-up was 60 months from surgery to baseline and 29 months from baseline to most recent follow-up. The overall observational period after mastectomy in the control group was 120 months. Local recurrence was observed in 6 patients from the study group, respectively 3 in the first observational period and 3 after the fat grafting procedure. The control group, as the study one, presented a total of 6 recurrences (p = 0.555; Hazard Ratio free flap and lipo vs only free flap: = 0.66; 95% CI 0.16-2.66). CONCLUSIONS: We found no significant differences in recurrence between patients who underwent fat grafting and those who did not. These encouraging findings support previous results but larger series of patients are required to confirm long-term oncological safety in these procedures. PMID- 25800345 TI - Cutaneous manifestations of immunoglobulin G4-related disease: what dermatologists need to know. AB - In this review, we summarize the recent literature and use case examples to reach diagnostic criteria for the diagnosis of immunoglobulin G4 (IgG4)-related diseases that may be of relevance to the practicing dermatologist. PMID- 25800346 TI - Transient bullous dermolysis of the newborn: a novel de novo mutation in the COL7A1 gene. AB - BACKGROUND: Bullous dermolysis of the newborn (BDN), an extremely rare clinical type of dystrophic epidermolysis bullosa (DEB), is characterized by subepidermal blistering at birth or shortly thereafter, followed by rapid improvement with minimal scarring or pigmentation. A total of 38 cases have been reported in the literature since the disease was initially described in 1985, but only 14 mutations in COL7A1, the gene responsible for the disease, have been detected in families with BDN. OBJECTIVES: We report a Chinese male infant with BDN and indirect inguinal hernia, in whom a novel de novo mutation in COL7A1 was demonstrated. METHODS: DNA was obtained from the blood of the patient and his parents. The coding exon and flanking regions of COL7A1 gene were amplified by polymerase chain reaction and subjected to sequence analysis. RESULTS: Sequencing showed a heterozygous substitution of guanine by adenine at nucleotide position 6136 of exon 73 in the triple helical domain of type VII collagen, which predicts a change of glycine by serine at position p.G2046S. The mutation was considered to be a pathogenic and de novo mutation. CONCLUSIONS: The coexistence of BDN and indirect inguinal hernia may simply be coincidental. These data contribute to the expanding database of COL7A1 mutations in DEB and should be useful for genetic counseling and prenatal diagnosis in affected families. PMID- 25800348 TI - Rapid screening of 35 new psychoactive substances by ion mobility spectrometry (IMS) and direct analysis in real time (DART) coupled to quadrupole time-of flight mass spectrometry (QTOF-MS). AB - The recent propagation of new psychoactive substances (NPS) has led to the development of new techniques for the rapid characterization of controlled substances in this category. A commercial bench-top ion mobility spectrometer (IMS) with a (63) Ni ionization source and a direct analysis in real time (DART) coupled to quadrupole time-of-flight (QTOF) were used for the rapid characterization of 35 NPS. The advantages of these techniques are fast response, ease of operation, and minimal sample preparation. The characteristic reduced mobilities of each substance are reported as are the mass spectra of the 35 compounds. The acquired product ion scan mass spectra were also compared to a library database constructed by QTOF with a electrospray ionization (ESI) source and showed a consistent relative abundance for each peak over time. A total of four seized drug samples provided by the local forensic laboratory were analyzed in order to demonstrate the utility of this approach. The results of this study suggest that both IMS and DART-QTOF are promising alternatives for the rapid screening and characterization of these new psychoactive substances. PMID- 25800349 TI - Adding Only One Priority Rule Allows Extending CIP Rules to Supramolecular Systems. AB - There are frequent situations both in supramolecular chemistry and in crystallography that result in stereogenic centers, whose absolute configuration needs to be specified. With this aim we propose the inclusion of one simple additional rule to the Cahn-Ingold-Prelog (CIP) system of priority rules stating that noncovalent interactions have a fictitious number between 0 and 1. PMID- 25800347 TI - Xanthine oxidoreductase regulates macrophage IL1beta secretion upon NLRP3 inflammasome activation. AB - Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1beta upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1beta release and that XO blockade results in impaired IL1beta and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K-AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases. PMID- 25800351 TI - Task constraints distinguish perspective inferences from perspective use during discourse interpretation in a false belief task. AB - Interpreting other peoples' actions relies on an understanding of their current mental states (e.g. beliefs, desires and intentions). In this paper, we distinguish between listeners' ability to infer others' perspectives and their explicit use of this knowledge to predict subsequent actions. In a visual-world study, two groups of participants (passive observers vs. active participants) watched short videos, depicting transfer events, where one character ('Jane') either held a true or false belief about an object's location. We tracked participants' eye-movements around the final visual scene, time-locked to related auditory descriptions (e.g. "Jane will look for the chocolates in the container on the left".). Results showed that active participants had already inferred the character's belief in the 1s preview period prior to auditory onset, before it was possible to use this information to predict an outcome. Moreover, they used this inference to correctly anticipate reference to the object's initial location on false belief trials at the earliest possible point (i.e. from "Jane" onwards). In contrast, passive observers only showed evidence of a belief inference from the onset of "Jane", and did not show reliable use of this inference to predict Jane's behaviour on false belief trials until much later, when the location ("left/right") was auditorily available. These results show that active engagement in a task activates earlier inferences about others' perspectives, and drives immediate use of this information to anticipate others' actions, compared to passive observers, who are susceptible to influences from egocentric or reality biases. Finally, we review evidence that using other peoples' perspectives to predict their behaviour is more cognitively effortful than simply using one's own. PMID- 25800350 TI - Infection homeostasis: implications for therapeutic and immune programming of metabolism in controlling infection. AB - Homeostasis underpins at a systems level the regulatory control of immunity and metabolism. While physiologically these systems are often viewed as independent, there is increasing evidence showing a tight coupling between immune and metabolic functions. Critically upon infection, the homeostatic regulation for both immune and metabolic pathways is altered yet these changes are often investigated in isolation. Here, we summarise our current understanding of these processes in the context of a clinically relevant pathogen, cytomegalovirus. We synthesise from the literature an integrative view of a coupled immune-metabolic infection process, centred on sugar and lipid metabolism. We put forward the notion that understanding immune control of key metabolic enzymatic steps in infection will promote the future development of novel therapeutic modalities based on metabolic modifiers that either enhance protection or inhibit infection. PMID- 25800353 TI - Color generation via subwavelength plasmonic nanostructures. AB - Recent developments in color filtering and display technologies have focused predominantly on high resolution, color vibrancy, high efficiency, and slim dimensions. To achieve these goals, metallic nanostructures have attracted extensive research interest due to their abilities to manipulate the properties of light through surface plasmon resonances. In this paper, we review recent representative developments in plasmonic color engineering at the nanoscale using subwavelength nanostructures, demonstrating their great potential in high resolution and high-fidelity color rendering, spectral filtering applications, holography, three-dimensional stereoscopic imaging, etc. PMID- 25800352 TI - Harmonic biases in child learners: in support of language universals. AB - A fundamental question for cognitive science concerns the ways in which languages are shaped by the biases of language learners. Recent research using laboratory language learning paradigms, primarily with adults, has shown that structures or rules that are common in the languages of the world are learned or processed more easily than patterns that are rare or unattested. Here we target child learners, investigating a set of biases for word order learning in the noun phrase studied by Culbertson, Smolensky, and Legendre (2012) in college-age adults. We provide the first evidence that child learners exhibit a preference for typologically common harmonic word order patterns-those which preserve the order of the head with respect to its complements-validating the psychological reality of a principle formalized in many different linguistic theories. We also discuss important differences between child and adult learners in terms of both the strength and content of the biases at play during language learning. In particular, the bias favoring harmonic patterns is markedly stronger in children than adults, and children (unlike adults) acquire adjective ordering more readily than numeral ordering. The results point to the importance of investigating learning biases across development in order to understand how these biases may shape the history and structure of natural languages. PMID- 25800354 TI - Snorkel/chimney and fenestrated endografts for complex abdominal aortic aneurysms. AB - Complex endovascular aneurysm repair (EVAR) involves extension of the proximal aortic seal zone with preservation of branch vessel patency, thereby expanding the applicability of endografting from the infrarenal to the suprarenal aorta. Snorkel/chimney (Sn-EVAR) and fenestrated EVAR (f-EVAR) serve as the two most commonly utilized advanced endovascular techniques to combat hostile proximal neck anatomy. The purpose of this article is to describe the principles and evolution of these advanced endovascular strategies, technical considerations, and results of sn- and f-EVAR in the management of challenging neck anatomy in abdominal aortic aneurysm disease. PMID- 25800356 TI - Preacclimation alters Salmonella Enteritidis surface properties and its initial attachment to food contact surfaces. AB - Exposure of Salmonella to environmental stress, prior to its adherence to a food contact surface, may change the cell surface properties and consequently affect its initial attachment and biofilm formation. This study investigated the influence of temperature and pH preacclimation on the initial attachment of Salmonella Enteritidis to acrylic and stainless steel. Besides, changes in physicochemical properties of cells were examined; and their surface attachment was modeled by xDLVO theory. Results showed that control cells pre-grown at 37 degrees C had significantly (P<0.05) higher initial attachment, followed by those pre-grown at 25, 42, and 10 degrees C. The initial attachment of cells pre-grown at pH 5.3 or 6.3 was not significantly (P>0.05) different from control cells pre grown at pH 7.3, but they were significantly higher compared to cells pre-grown at pH 8.3 and 9.0. No significant difference was observed between cell attachment to acrylic and stainless steel, although they had different physicochemical properties. The xDLVO theory successfully explained higher attachment for cells pre-grown at optimal condition on both contact surfaces. However, the xDLVO theory could not explain the similar attachment of cells to acrylic and stainless steel. This study elucidates that commonly used intervention technologies including cold storage, thermal treatment, and alkaline antimicrobial agents might alter the physicochemical properties of S. Enteritidis cells and result in varied initial attachment levels. PMID- 25800355 TI - PRRs are watching you: Localization of innate sensing and signaling regulators. AB - To prevent the spread of infection, an invading pathogen must first be recognized by the innate immune system. Host pattern recognition receptors detect distinct pathogen-associated molecules and induce the transcription and release of interferon and inflammatory molecules to resolve infection. Unlike infections with pathogens that replicate autonomously from the host, viral infections blur the boundaries of self and non-self. Differentiation of host from virus is achieved by restricting localization of host nucleic acids and by placing pattern recognition receptors in specific subcellular compartments. Within this review, we discuss how several families of pattern recognition receptors act to provide a comprehensive surveillance network that has the potential to induce interferon expression in response to any viral infection. PMID- 25800357 TI - Biofunctionalization of microgroove titanium surfaces with an antimicrobial peptide to enhance their bactericidal activity and cytocompatibility. AB - A firm peri-implant soft tissue seal is important for the long-term survival of dental implants, which demands the properties of antibacterial and cytocompatibility of the implant surfaces. In this study, GL13K, a cationic antimicrobial peptide, was immobilized onto microgroove surfaces which were 60 MUm in width and 10 MUm in depth, and the modified surfaces improved both the properties of antibacterial and cytocompatibility. The method of silanization was used to immobilize the antimicrobial peptide GL13K, which was confirmed by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), atomic force microscopy (AFM), water contact angle measurement. Then the mechanical stability of the coatings was confirmed by ultrasonication. In vitro antibacterial tests confirmed bactericidal activity against Porphyromonas gingivalis without inhibiting its adhesion. In vitro cytocompatibility tests also confirmed that adhesion at later phase and proliferation of HGFs were greater (P<0.01) on the GL13K-modified microgroove surfaces than on the non-treated microgroove surfaces, and both of them were greater than on the smooth surfaces. The phenomenon of the contact guidance, which is cell growth aligned along the microgrooves, was maintained. Overall, this study developed a promising bi functional surface that combined the physical and chemical properties to promote cytocompatibility and antibacterial activity simultaneously. PMID- 25800358 TI - Quaternary ammonium polyethylenimine nanoparticles for treating bacterial contaminated water. AB - This study highlights the potential application of antimicrobial quaternary ammonium nanomaterials for water disinfection. Quaternary ammonium polyethylenimine (QA-PEI) nanoparticles (NPs) were synthesized by polyethylenimine crosslinking and alkylation with octyl iodide followed by methyl iodide quaternization. Particles modified with octyldodecyl alkyl chains were also prepared and evaluated. The antimicrobial activity of QA-PEI NPs was studied after anchoring in non-leaching polymeric coatings and also in aqueous suspension. Particles at different loadings (w/w) were embedded in polyethylene vinyl acetate and polyethylene methacrylic acid coatings and tested for antimicrobial activity against four representative strains of bacteria in static and dynamic modes. Coatings embedded with fluorescent labelled particles tracked by Axioscope fluorescence microscope during the antimicrobial test indicates no particles leaching out. Coatings loaded with 5% w/w QA-PEI exhibited strong antibacterial activity. Aqueous suspension was tested and found effective for bacterial decontamination at 0.1 ppm and maintains its activity for several weeks. PMID- 25800359 TI - Low molecular weight silicones particularly facilitate human serum albumin denaturation. AB - There is a market trend towards the administration of therapeutic proteins using sterilized, pre-filled glass syringes lubricated with silicone oil. It has been widely reported that initially clear solutions of proteins can become turbid during transport and storage, with unclear outcomes with respect to bioefficacy. While the basic processes of interactions of proteins with hydrophobic entities, leading to denaturation and aggregation, are increasingly well understood, the apparently random occurrence of such processes in syringes is not. To better understand the parameters that may be responsible for this change, we report the systematic examination of a series of factors that can affect the behavior of the protein human serum albumin (HSA) when in contact with silicone oil in water. Fluorescence spectroscopy showed that greater mixing times and greater concentrations of silicones (polydimethylsiloxane (PDMS)), especially lower molecular weight hydrophobic silicones like octamethyltetracyclosiloxane (D4), were associated with increased protein denaturation. The turbidity of HSA solutions, due to the formation both of silicone oil-in-water (O/W) emulsions and protein aggregates, was also facilitated by the presence of D4. A series of mixtures of silicone oils, all of which exhibited a viscosity of 1000 cSt but which were comprised of different silicone constituents, clearly showed a correlation between the presence of lower molecular silicones and enhanced solution turbidity. While the addition of a non-ionic silicone-polyether surfactant led to greater turbidity by increasing the number of stabilized oil droplets, it was not accompanied by protein denaturation. These results are consistent with HSA denaturation and subsequent aggregation as a consequence of contact particularly with low molecular weight, hydrophobic silicones that are more mobile, leading to more efficient protein/silicone contact. PMID- 25800361 TI - Using a single binge drinking question to identify Russian women at risk for an alcohol-exposed pregnancy. AB - INTRODUCTION: Low rates of contraception and at-risk drinking place many Russian women at risk of an alcohol-exposed pregnancy (AEP). The only realistic way to determine when women are at risk of AEP is by self-reports. A U.S. study found that a single binge-drinking question (SBD) effectively identified nearly all women whose drinking placed them at risk of AEP. METHODS: The present study replicated the U.S. STUDY: Participants were 689 non-pregnant Russian women of childbearing age who were at AEP risk. Their answers to SBD, "During the previous three months, how often did you have four or more drinks on one occasion", were compared with their reports of binge drinking on a 90-day Timeline Followback (TLFB) calendar. RESULTS: The SBD identified 99% of at-risk Russian women as binge drinkers, replicating U.S. FINDINGS: Only 8% of the women were identified at-risk using a second AEP criterion of >=8 drinks on average per week. Although Russian women did not report heavy weekly drinking and two-thirds did not meet AUDIT criteria for problem drinking, when they did drink, 40% of the time it was binge drinking. CONCLUSIONS: Almost all Russian women who were at risk of an AEP were identified by a single binge-drinking question. Results from this study suggest that Russian health care practitioners can use SBD to successfully screen women for AEP risk. SBD identified 99% of Russian women who were at AEP risk. Consequently, it is recommended that SBD be incorporated into routine health care screenings at OB/GYN clinic visits. PMID- 25800362 TI - The effect of automatic attentional bias modification on alcohol ambivalence. AB - Conscious strategies such as psychoeducation are commonly used to resolve alcohol ambivalence. However, conscious strategies have had little effect on automatic approach inclination, which is one of the components of alcohol ambivalence. The purpose of this study was to investigate the effect of automatic attentional bias modification that can affect the approach inclination in alcohol ambivalence. The study included 43 problem drinkers with alcohol ambivalence who were recruited from the university and provided informed consent. They were randomly assigned to either a group that underwent attentional bias modification or a group that underwent psychoeducation. The level of alcohol ambivalence and readiness to change was assessed using self-report questionnaires, and the pattern of alcohol ambivalence was assessed using eye movements. The results showed that psychoeducation increased problem drinkers' readiness to change. In addition, attentional bias modification changed their attentional pattern of alcohol ambivalence by decreasing the approach inclination and increasing the avoidance inclination. Based on these results, attentional bias modification was shown to be a useful method for changing the automatic approach inclination as well as the controlled avoidance inclination, and psychoeducation was shown to be a beneficial strategy for increasing problem drinkers' extrinsic readiness to change. PMID- 25800364 TI - Refinement of the myocutaneous anterolateral thigh flap for reconstruction of frontonasal fistula defects. AB - BACKGROUND: Frontonasal fistulas can lead to life-threatening intracranial infections. Our refinement of the myocutaneous anterolateral thigh (ALT) flap for treating these fistulas is described. METHODS: A retrospective review of the microsurgical treatment of frontonasal fistulas is presented. Demographics, etiologies, outcomes, and complications were evaluated. RESULTS: Ten myocutaneous ALT flaps were used to reconstruct frontonasal fistula. The mean follow-up was 35 +/- 2.5 months. Nine fistulas were secondary to oncologic resections, and one was due to a traumatic origin. Complications included a recurrent abscess in 1 case (10%); there were no cases of cerebrospinal fluid (CSF) leak or flap loss. Preoperative intracranial infections were present in 7 cases, with 6 successfully resolving their infection after surgical intervention and flap obliteration of their fistulas. CONCLUSION: Refinements in the myocutaneous ALT flap design have been illustrated to provide robust dead-space obliteration with vascularized muscle and reliable simultaneous scalp coverage in the treatment of frontonasal fistulas. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E552-E558, 2016. PMID- 25800363 TI - Characterization of thyroid cancer cell lines in murine orthotopic and intracardiac metastasis models. AB - Thyroid cancer incidence has been increasing over time, and it is estimated that ~1950 advanced thyroid cancer patients will die of their disease in 2015. To combat this disease, an enhanced understanding of thyroid cancer development and progression as well as the development of efficacious, targeted therapies are needed. In vitro and in vivo studies utilizing thyroid cancer cell lines and animal models are critically important to these research efforts. In this report, we detail our studies with a panel of authenticated human anaplastic and papillary thyroid cancer (ATC and PTC) cell lines engineered to express firefly luciferase in two in vivo murine cancer models-an orthotopic thyroid cancer model as well as an intracardiac injection metastasis model. In these models, primary tumor growth in the orthotopic model and the establishment and growth of metastases in the intracardiac injection model are followed in vivo using an IVIS imaging system. In the orthotopic model, the ATC cell lines 8505C and T238 and the PTC cell lines K1/GLAG-66 and BCPAP had take rates >90 % with final tumor volumes ranging 84-214 mm(3) over 4-5 weeks. In the intracardiac model, metastasis establishment was successful in the ATC cell lines HTh74, HTh7, 8505C, THJ-16T, and Cal62 with take rates >=70 %. Only one of the PTC cell lines tested (BCPAP) was successful in the intracardiac model with a take rate of 30 %. These data will be beneficial to inform the choice of cell line and model system for the design of future thyroid cancer studies. PMID- 25800366 TI - Textural and geochemical characteristics of marine sediments in the SW Gulf of Mexico: implications for source and seasonal change. AB - Two oceanographic cruises were taken during the winter (SAV I, November and December 2007) and summer (SAV II, July and August 2008) across the mouth of the Papaloapan River in the Gulf of Mexico. Surficial sediment samples were collected from shallow (16-30 m), intermediate (30 to 80 m), and deeper areas (>=300 m). Shallow water sediments are coarser, better-sorted, and primarily composed of sands during the winter, while those found in the summer are finer. At depths greater than 30 m, sediments are primarily fine-grained no matter the season. Major element analysis from shallow areas indicates higher SiO2 concentrations during the windy season with negative correlation against Al2O3 during both seasons, following the respective abundances of sand and muds. High organic carbon content was observed in shallow areas during the summer. Trace metals V, Ni, Cu, Zn, Pb, Li, Cr, Co, and Ba were evaluated. The first six metals showed higher average concentration in the deeper areas, although the highest values at some individual sampling sites for Cr, Co, Cu, and Ba were observed in the coastal area. Factor and cluster analysis were used to explain the sediment distribution pattern and the factors that determine the sediment characteristics within the study area. In shallow areas, four clusters were observed during the winter and five during the summer. The geochemical characteristics of the samples in each cluster suggest association with fluvial sediment input, textural characteristics, heavy minerals, and Cu and Ba concentration. To evaluate the variations in heavy metal concentration, metal enrichment factors (EFs) were calculated. Enrichment in V, Cr, Co, Zn, Ba, and Pb was detected at certain sites, whereas Cu behaved differently. The distribution of Cu enrichment suggests that it may be of natural origin, associated with the lithology of the volcanic continental area. The minor enrichment observed for other elements may be associated with river discharge. According to sediment quality guidelines, trace metal concentrations of Cu, Pb, and Zn present occasional risks to aquatic organisms. PMID- 25800365 TI - A cytochrome P450, OsDSS1, is involved in growth and drought stress responses in rice (Oryza sativa L.). AB - Cytochrome P450s are among the largest protein coding gene families in plant genomes. However, majority of the genes remain uncharacterized. Here, we report the characterization of dss1, a rice mutant showing dwarfism and reduced grain size. The dss1 phenotype is caused by a non-synonymous point mutation we identified in DSS1, which is member of a P450 gene cluster located on rice chromosome 3 and corresponds to the previously reported CYP96B4/SD37 gene. Phenotypes of several dwarf mutants characterized in rice are associated with defects in the biosynthesis or perception of the phytohormones gibberellins (GAs) and brassinosteroids (BRs). However, both GA and BR failed to rescue the dss1 phenotype. Hormone profiling revealed the accumulation of abscisic acid (ABA) and ABA metabolites, as well as significant reductions in GA19 and GA53 levels, precursors of the bioactive GA1, in the mutant. The dss1 contents of cytokinin and auxins were not significantly different from wild-type plants. Consistent with the accumulation of ABA and metabolites, germination and early growth was delayed in dss1, which also exhibited an enhanced tolerance to drought. Additionally, expressions of members of the DSS1/CYP96B gene cluster were regulated by drought stress and exogenous ABA. RNA-seq-based transcriptome profiling revealed, among others, that cell wall-related genes and genes involved in lipid metabolism were up- and down-regulated in dss1, respectively. Taken together, these findings suggest that DSS1 mediates growth and stress responses in rice by fine-tuning GA-to-ABA balance, and might as well play a role in lipid metabolism. PMID- 25800367 TI - Ultrasound-assisted ionic liquid-based dispersive liquid-liquid microextraction for preconcentration of patent blue V and its determination in food samples by UV visible spectrophotometry. AB - Ultrasound-assisted ionic liquid-based dispersive liquid-liquid microextraction procedure (UA-IL-DLLME) was developed for determination of trace levels of patent blue V prior to its determination by UV-visible spectrophotometry. Patent blue V was extracted from 25-mL sample into a 100-MUL volume of ionic liquid, 1-butyl-3 methylimidazolium hexafluorophosphate ([bmim][PF6]), with the aid of sonication in an ultrasonic bath. Several variables affecting microextraction efficiency were optimized. Under the optimum experimental conditions, the detection limit (3 s) was 0.68 MUg L(-1), and the preconcentration factor was 100. The relative standard deviation for six replicate determinations of patent blue V was 4.5%. The method was applied to the determination of patent blue V in food samples. The proposed procedure is effective, very simple, and fast. PMID- 25800368 TI - Assessing and monitoring the risk of desertification in Dobrogea, Romania, using Landsat data and decision tree classifier. AB - The risk of the desertification of a part of Romania is increasingly evident, constituting a serious problem for the environment and the society. This article attempts to assess and monitor the risk of desertification in Dobrogea using Landsat Thematic Mapper (TM) satellite images acquired in 1987, 1994, 2000, 2007 and 2011. In order to assess the risk of desertification, we used as indicators the Modified Soil Adjustment Vegetation Index 1 (MSAVI1), the Moving Standard Deviation Index (MSDI) and the albedo, indices relating to the vegetation conditions, the landscape pattern and micrometeorology. The decision tree classifier (DTC) was also used on the basis of pre-established rules, and maps displaying six grades of desertification risk were obtained: non, very low, low, medium, high and severe. Land surface temperature (LST) was also used for the analysis. The results indicate that, according to pre-established rules for the period of 1987-2011, there are two grades of desertification risk that have an ascending trend in Dobrogea, namely very low and medium desertification. An investigation into the causes of the desertification risk revealed that high temperature is the main factor, accompanied by the destruction of forest shelterbelts and of the irrigation system and, to a smaller extent, by the fragmentation of agricultural land and the deforestation in the study area. PMID- 25800369 TI - Environmental impacts of coal mine and thermal power plant to the surroundings of Barapukuria, Dinajpur, Bangladesh. AB - The study was carried out to analyse the environmental impacts of coal mine and coal-based thermal power plant to the surrounding environment of Barapukuria, Dinajpur. The analyses of coal, water, soil and fly ash were carried out using standard sample testing methods. This study found that coal mining industry and coal-based thermal power plant have brought some environmental and socio-economic challenges to the adjacent areas such as soil, water and air pollution, subsidence of agricultural land and livelihood insecurity of inhabitants. The pH values, heavy metal, organic carbon and exchangeable cations of coal water treated in the farmland soil suggest that coal mining deteriorated the surrounding water and soil quality. The SO4(2-) concentration in water samples was beyond the range of World Health Organisation standard. Some physico-chemical properties such as pH, conductivity, moisture content, bulk density, unburned carbon content, specific gravity, water holding capacity, liquid and plastic limit were investigated on coal fly ash of Barapukuria thermal power plant. Air quality data provided by the Barapukuria Coal Mining Company Limited were contradictory with the result of interview with the miners and local inhabitants. However, coal potentially contributes to the development of economy of Bangladesh but coal mining deteriorates the environment by polluting air, water and soil. In general, this study includes comprehensive baseline data for decision makers to evaluate the feasibility of coal power industry at Barapukuria and the coalmine itself. PMID- 25800371 TI - The use of an online community to take the 'Leg Club' model to the next level. PMID- 25800374 TI - Effect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy. AB - OBJECTIVE: To evaluate the prognostic effect of concomitant variant histology (CVH) on survival outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy. MATERIALS AND METHODS: Data on 417 patients with UTUC treated with radical nephroureterectomy without preoperative adjuvant therapy were retrospectively reviewed with a focus on CVH. Clinicopathological features and prognostic factors were compared between patients with pure UTUC and patients with UTUC with CVH. The primary end points were cancer-specific survival (CSS), disease recurrence-free survival (DFS), and overall survival (OS). RESULTS: UTUC with CVH was present in 90 (21.6%) of 417 patients. At a median follow-up of 26 months, 153 (36.7%) had died of UTUC, 161 (38.6%) had experienced a relapse, and 176 (42.2%) had died of other causes. UTUC with CVH was significantly associated with advanced tumor stage, high tumor grade, tumor diameter, lymphovascular invasion, lymph node metastasis, positive surgical margins, and tumor architecture compared with pure UTUC (all P<0.01). The estimated 5-year CSS, DFS, and OS rates were 64.9%, 61.1%, and 62.1%, respectively, in the pure UTUC group, compared with 36.3%, 34.3%, and 26.5%, respectively, in the UTUC with CVH group (P<0.001). Multivariate analysis demonstrated that CVH was an independent predictor of CSS (hazard ratio [HR] = 1.594; 95% CI: 1.125-2.259; P = 0.009), DFS (HR = 1.549; 95% CI: 1.077-2.152; P = 0.017), and OS (HR = 1.685; 95% CI: 1.212-2.343; P = 0.002). CONCLUSIONS: Approximately one-fifth of the specimens of patients with UTUC were observed to exhibit CVH. CVH was an independent prognostic factor for CSS, DFS, and OS in patients with UTUC on both univariate and multivariate analyses. Genitourinary pathologists should look for potential CVH components in UTUC specimens and report this in routine pathological practice. The presence of CVH should identify patients as candidates for consultation regarding early adjuvant therapy and intensive surveillance protocols. PMID- 25800375 TI - What Can We Learn From 20-year Followup Studies of Hip Replacement? AB - BACKGROUND: A patient who dies during the followup period of a study about total hip arthroplasty (THA) cannot subsequently undergo a revision. The presence of competing events (such as deaths, in a study on implant durability) violates an assumption of the commonly used Kaplan-Meier (KM) survivorship approach. In that setting, KM-based estimates of revision frequencies will be high relative to alternative approaches that account for competing events such as cumulative incidence methods. However, the degree to which this difference is clinically relevant, and the degree to which it affects different ages of patient cohorts, has been poorly characterized in orthopaedic clinical research. QUESTIONS/PURPOSES: The purpose of this study was to compare KM with cumulative incidence survivorship estimators to evaluate the degree to which the competing event of death influences the reporting of implant survivorship at long-term followup after THA in patients both younger than and older than 50 years of age. METHODS: We retrospectively reviewed 758 cemented THAs from a prospectively maintained single-surgeon registry, who were followed for a minimum of 20 years or until death. Revision rates were compared between those younger than or older than age 50 years using both KM and cumulative incidence methods. Patient survivorship was calculated using KM methods. A total of 21% (23 of 109) of the cohort who were younger than 50 years at the time of THA died during the 20-year followup period compared with 72% (467 of 649) who were older than 50 years at the time of surgery (p < 0.001). RESULTS: In the cumulative incidence analysis, 19% of the younger than age 50 years cohort underwent a revision for aseptic causes within 20 years as compared with 5% in the older than age 50 years cohort (p < 0.001). The KM method overestimated the risk of revision (23% versus 8.3%, p < 0.001), which represents a 21% and 66% relative increase for the younger than/older than age 50 years groups, respectively. CONCLUSIONS: The KM method overestimated the risk of revision compared with the cumulative incidence method, and the difference was particularly notable in the elderly cohort. Future long term followup studies on elderly cohorts should report results using survivorship curves that take into account the competing risk of patient death. We observed a high attrition rate as a result of patient deaths, and this emphasizes a need for future studies to enroll younger patients to ensure adequate study numbers at final followup. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25800370 TI - Transfer of heavy metals through terrestrial food webs: a review. AB - Heavy metals are released into the environment by both anthropogenic and natural sources. Highly reactive and often toxic at low concentrations, they may enter soils and groundwater, bioaccumulate in food webs, and adversely affect biota. Heavy metals also may remain in the environment for years, posing long-term risks to life well after point sources of heavy metal pollution have been removed. In this review, we compile studies of the community-level effects of heavy metal pollution, including heavy metal transfer from soils to plants, microbes, invertebrates, and to both small and large mammals (including humans). Many factors contribute to heavy metal accumulation in animals including behavior, physiology, and diet. Biotic effects of heavy metals are often quite different for essential and non-essential heavy metals, and vary depending on the specific metal involved. They also differ for adapted organisms, including metallophyte plants and heavy metal-tolerant insects, which occur in naturally high-metal habitats (such as serpentine soils) and have adaptations that allow them to tolerate exposure to relatively high concentrations of some heavy metals. Some metallophyte plants are hyperaccumulators of certain heavy metals and new technologies using them to clean metal-contaminated soil (phytoextraction) may offer economically attractive solutions to some metal pollution challenges. These new technologies provide incentive to catalog and protect the unique biodiversity of habitats that have naturally high levels of heavy metals. PMID- 25800377 TI - Solid-phase extraction of perfluoroalkylated compounds from sea water. AB - This study describes an in-depth investigation of the parameters involved in the solid-phase extraction performance of perfluoroalkylated compounds (seven carboxylates and one sulfonate), particularly with sea water samples. The two most popular sorbents, Oasis WAX and Oasis HLB, were considered and it was observed that the high ionic strength of sea water may impair solid-phase extraction recoveries. In the final protocol, Oasis HLB cartridges were selected, incorporating a 10% methanol clean-up step before elution with methanol, since less matrix effects were obtained. The proposed method allows successful recoveries, higher than 71%, and relative standard deviations lower than 20%. It also provides excellent limits of detection values between 0.01 and 0.21 ng/L. Finally, the method was applied to fresh and sea water samples, where several perfluoroalkylated compounds were found at concentrations ranging between 0.16 and 64 ng/L. In the case of perfluorooctane sulfonate, recently included in the Water Frame Directive, its concentration reached the highest values among the perfluoroalkylated compounds measured (64 ng/L in river samples). PMID- 25800376 TI - Mortality and Revision Surgery Are Increased in Patients With Parkinson's Disease and Fractures of the Femoral Neck. AB - BACKGROUND: Patients with Parkinson's disease are at increased risk for falls and associated hip fractures as a result of tremor, bradykinesia, rigidity, and postural instability. The available literature is limited and conflicting regarding the optimal surgical treatment and risk for postoperative complications and mortality in this unique patient population. QUESTIONS/PURPOSES: We asked: (1) Is there a difference in mortality after surgical treatment of hip fractures in patients with Parkinson's disease compared with similar patients with hip fractures without Parkinson's disease? (2) Does Parkinson's disease lead to a higher rate of reoperation after operative treatment of femoral neck fractures? (3) Does Parkinson's disease lead to a higher rate of dislocation after hemiarthroplasty for displaced femoral neck fractures, and (4) does the operative approach affect dislocation rates? METHODS: In this case-controlled study, we retrospectively reviewed 141 patients with a diagnosis of Parkinson's disease and a fracture of the femoral neck. Each patient with Parkinson's disease was matched with two control patients (n = 282) without Parkinson's disease stratified by age, sex, American Society of Anesthesiologists classification, and fracture type (nondisplaced/displaced). Clinical outcomes included mortality after surgical intervention, rate of reoperation, dislocation events after hemiarthroplasty, and the rate of failure after internal fixation for nondisplaced fractures. RESULTS: The median survival time of the patients with Parkinson's disease after fracture was 31 months (95% CI, 25-37 months) compared with 45 months (95% CI, 39-50 months) in our control group (p = 0.007). The rate of reoperation for displaced and nondisplaced fractures was higher in the Parkinson's disease group compared with the control group (11% versus 4%; p = 0.005). Failure of fixation for patients treated with internal fixation of nondisplaced femoral neck fractures was significantly higher in the Parkinson's disease group compared with our control group (22% versus 5%; p = 0.01). Dislocation rates after hemiarthroplasty were significantly higher in the Parkinson's disease group compared with the control group (8% versus 1%; p = 0.003). Patients treated with a hemiarthroplasty through an anterolateral approach had a significantly lower dislocation rate compared with those treated with a posterior approach (2% versus 15%; p = 0.002). CONCLUSIONS: Parkinson's disease is an independent predictor of mortality after femoral neck fracture and is associated with an increased rate of dislocation, revision surgery, and failure of internal fixation. Although patients with Parkinson's disease with a nondisplaced or valgus impacted femoral neck fracture may be treated with internal fixation, they are at significantly higher risk of failure of fixation compared with patients without Parkinson's disease. Use of a hemiarthroplasty through an anterolateral approach may reduce the likelihood of requiring a revision operation. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25800378 TI - Degradation of 2,4 dichlorobiphenyl via meta-cleavage pathway by Pseudomonas spp. consortium. AB - Two bacterial isolates (Pseudomonas sp. GSa and Pseudomonas sp. GSb) were in close association able to assimilate 2,4 dichlorobiphenyl (2,4 CB), a PCB congener. GC-MS analysis of spent culture medium of the consortium with 2,4 CB as substrate showed 90 % degradation (according to Electron capture detection values) with catechol as one of the important intermediate compounds through meta cleavage pathway. Further, ability of the consortium to utilise PCB congeners, Methoxychlor, Aroclor 1016, Chlorobenzoic acids and Monoaromatic compounds indicated that the consortium of GSa and GSb would be an ideal candidate for in situ bioremediation of PCB. PMID- 25800380 TI - Martial recycling from renewable landfill and associated risks: A review. AB - Landfill is the dominant disposal choice for the non-classified waste, which results in the stockpile of materials after a long term stabilization process. A novel landfill, namely renewable landfill (RL), is developed and applied as a strategy to recycle the residual materials and reuse the land occupation, aim to reduce the inherent problems of large land occupied, materials wasted and long term pollutants released in the conventional landfill. The principle means of RL is to accelerate the waste biodegradation process in the initial period, recover the various material resources disposal and extend the landfill volume for waste re-landfilling after waste stabilized. The residual material available and risk assessment, the methodology of landfill excavation, the potential utilization routes for different materials, and the reclamation options for the unsanitary landfill are proposed, and the integrated beneficial impacts are identified finally from the economic, social and environmental perspectives. RL could be draw as the future reservoirs for resource extraction. PMID- 25800379 TI - The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment. AB - The unique property of trehalose encourages its pharmaceutical application in aggregation-mediated neurodegenerative disorders, including Alzheimer's, Parkinson's, and many polyglutamine (polyQ)-mediated diseases. However, trehalose is digested into glucose by trehalase and which reduced its efficacy in the disease target tissues. Therefore, searching trehalase-indigestible analogs of trehalose is a potential strategy to enhance therapeutic effect. In this study, two trehalase-indigestible trehalose analogs, lactulose and melibiose, were selected through compound topology and functional group analyses. Hydrogen bonding network analyses suggest that the elimination of the hydrogen bond between the linker ether and aspartate 321 (D321) of human trehalase is the key for lactulose and melibiose to avoid the hydrolyzation. Using polyQ-mediated spinocerebellar ataxia type 17 (SCA17) cell and slice cultures, we found the aggregation was significantly prohibited by trehalose, lactulose, and melibiose, which may through up-regulating of autophagy. These findings suggest the therapeutic applications of trehalase-indigestible trehalose analogs in aggregation-associated neurodegenerative diseases. PMID- 25800381 TI - Sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with breast cancer: Are the current false negative rates acceptable? AB - The advent of sentinel lymph node biopsy has revolutionised surgical management of axillary nodal disease in patients with breast cancer. Patients undergoing neo adjuvant chemotherapy for large breast primary tumours may experience complete pathological response on a previously positive sentinel node whilst not eliminating the tumour from the other lymph nodes. Results from 2 large prospective cohort studies investigating sentinel lymph node biopsy after neo adjuvant chemotherapy demonstrate a combined false negative rate of 12.6-14.2% and identification rate of 80-89% with the minimal acceptable false negative rate and identification rate being set at 10% and 90%, respectively. A false negative rate of 14% would have been classified as unacceptable when compared to the figures obtained by the pioneers of sentinel lymph node biopsy which was 5% or less. PMID- 25800382 TI - Broad resistance to acetohydroxyacid-synthase-inhibiting herbicides in feral radish (Raphanus sativus L.) populations from Argentina. AB - BACKGROUND: Soon after the commercial release of sunflower cultivars resistant to imidazolinone herbicides, several uncontrolled feral radish (Raphanus sativus L.) populations were found in south-eastern Buenos Aires, Argentina. These populations were studied in field, glasshouse and laboratory experiments aiming to characterise their resistance profile and to develop management tools. RESULTS: Three feral radish accessions were highly resistant to ten active ingredients of five families of acetohydroxyacid synthase (AHAS)-inhibiting herbicides. Sequence analysis of the AHAS gene detected a Trp574Leu mutation in all resistant accessions. One accession with an intermediate level of resistance was heterozygous for this mutation, probably owing to gene exchange with a susceptible subpopulation located in the field margin. Herbicide-resistant and herbicide-susceptible radish could be controlled in sunflower by alternative herbicides. CONCLUSION: This is the first report of feral radish with resistance to herbicides belonging to all the AHAS-inhibiting herbicide families, conferred by Trp574Leu mutation in the AHAS gene. An appropriate herbicide rotation with alternative herbicides such as fluorochloridone or aclonifen and an increase in the diversity of cropping systems are important for minimising the prevalence of these biotypes. PMID- 25800383 TI - Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug-Coformer Interactions. AB - Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. The present study attempts to improve the physicochemical properties of the drug using a crystal engineering approach with cocrystals. Such multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC cocrystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. When the solubility was high, as in the case of PABA, NCT, and RES cocrystals, the flux/permeability dropped slightly. This is in agreement with the expected interplay between solubility and permeability. Improved solubility/permeability is attributed to new drug-coformer interactions. Cocrystals of SAM, however, showed poor solubility and flux. This cocrystal contains a primary sulfonamide dimer synthon similar to that of HCT polymorphs, which may be a reason for its unusual behavior. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between cocrystal permeability and drug-coformer interactions. PMID- 25800385 TI - Chance or destiny? PMID- 25800386 TI - From heterotopic twins to medical school. PMID- 25800387 TI - Re: economic evaluation of robot-assisted hysterectomy: a cost-minimisation analysis. PMID- 25800388 TI - Authors' reply. PMID- 25800389 TI - Re: removable uterine compression sutures for postpartum haemorrhage. PMID- 25800390 TI - A report from #BlueJC: Is my thyroid problem going to affect my baby? PMID- 25800392 TI - Cardiorespiratory fitness and lung cancer risk: A prospective population-based cohort study. AB - OBJECTIVES: Little is known about the role of cardiorespiratory fitness (CRF) and leisure-time physical activity (LTPA) with the risk of lung cancer. Previous research shows that maintaining a sufficient amount of physical activity may have a protective effect against cancer. The aim of this study is to examine the associations of CRF, LTPA and lung cancer among middle-aged Finnish men. DESIGN: Prospective cohort study. METHODS: In a population-based cohort study of 2305 men from Eastern Finland with no history of cancer at baseline. CRF and LTPA data was collected at baseline, 73 cases of lung cancer occurred during an average follow up of 20-years. RESULTS: In a multivariate adjusted model, every 3.8mL/kg/min (1 SD) increase of CRF was related to a 31% decrease in lung cancer risk across all VO2max quartiles. Furthermore, a 2.8-fold (95% CI 1.14-7.22, p=0.024) increased risk of lung cancer among men in the lowest quartile (<=20.3mL/kg/min) of CRF as compared those in the highest quartile (>35.1mL/kg/min). In a multivariate adjusted model LTPA was not associated to lung cancer. CONCLUSIONS: In middle aged men with no history of lung cancer, increasing levels of CRF serves as a protective factor against lung cancer. Increasing CRF may reduce the risk of lung cancer. Furthermore, CRF is a better predictor of lung cancer than LTPA. PMID- 25800394 TI - Bladder cancer: Blue dye used to selectively label bladder tumours in rats. PMID- 25800393 TI - Expert consensus document: Consensus statement on best practice management regarding the use of intravesical immunotherapy with BCG for bladder cancer. AB - Multiple clinical trials have demonstrated that intravesical Bacillus Calmette Guerin (BCG) treatment reduces recurrences and progression in patients with non muscle-invasive bladder cancer (NMIBC). However, although BCG has been in use for almost 40 years, this agent is often underutilized and practice patterns of administration vary. This neglect is most likely caused by uncertainties about the optimal use of BCG, including unawareness of optimal treatment schedules and about patient populations that most benefit from BCG treatment. To address this deficit, a focus group of specialized urologic oncologists (urologists, medical oncologists and radiation oncologists) reviewed the current guidelines and clinical evidence, discussed their experiences and formed a consensus regarding the optimal use of BCG in the management of patients with NIMBC. The experts concluded that continuing therapy with 3-week BCG maintenance is superior to induction treatment only and is the single most important factor in improving outcomes in patients with NMIBC. They also concluded that a reliable alternative to radical cystectomy in truly BCG-refractory disease remains the subject of clinical trials. In addition, definitions for common terms of BCG failure, such as BCG-refractory and BCG-intolerant, have been formulated. PMID- 25800398 TI - Prostate cancer: ERG fusion and AKR1C3 form AR signalling feed-forward loop. PMID- 25800400 TI - Regenerative medicine: Rapid 3D bladder model engineering. PMID- 25800395 TI - Synergistic action of image-guided radiotherapy and androgen deprivation therapy. AB - The combined use of androgen deprivation therapy (ADT) and image-guided radiotherapy (IGRT) can improve overall survival in aggressive, localized prostate cancer. However, owing to the adverse effects of prolonged ADT, it is imperative to identify the patients who would benefit from this combined-modality therapy relative to the use of IGRT alone. Opportunities exist for more personalized approaches in treating aggressive, locally advanced prostate cancer. Biomarkers--such as disseminated tumour cells, circulating tumour cells, genomic signatures and molecular imaging techniques--could identify the patients who are at greatest risk for systemic metastases and who would benefit from the addition of systemic ADT. By contrast, when biomarkers of systemic disease are not present, treatment could proceed using local IGRT alone. The choice of drug, treatment duration and timing of ADT relative to IGRT could be predicated on these personalized approaches to prostate cancer medicine. These novel treatment intensification and reduction strategies could result in improved prostate-cancer specific survival and overall survival, without incurring the added expense of metabolic syndrome and other adverse effects of ADT in all patients. PMID- 25800403 TI - Comparative study of low-energy ultrasonic and alkaline treatment on biosludge from secondary industrial wastewater treatment. AB - In this study, low-energy ultrasonic (3 and 6 kJ/g volatile solids of feed biomass (FB) which was lower than the heat value of the FB), alkaline, and ultrasonic-alkaline pretreatments were applied on FB, a biosludge from secondary industrial wastewater treatment. Biochemical methane potential (BMP), particle size distribution, Biomass Stress Index (BSITM), soluble chemical oxygen demand (SCOD), protein, carbohydrate, and size-exclusion chromatography (SEC) fingerprints were used to comparatively study the mechanisms of these pretreatment methods. The results indicated that low-energy ultrasonication and alkali exhibited significantly different impacts on the FB. After ultrasonication with energy input of 6 kJ/g-VS, the average particle size of FB was reduced from 102.6 to 19.4 um. However, ultrasonication had no obvious effect on microbial cells rupture, solubilization of protein and carbohydrate, and SEC fingerprint. Consequently, low-energy ultrasonication could not enhance methane generation. However, after alkaline pretreatment with dosage of 0.3 g-NaOH/g-VS, SCOD, soluble protein, and soluble carbohydrate concentration of FB increased from 0.66, 0.00, 0.07 to 2.83, 0.83, 0.47 g/L, respectively. At the same time, BSITM increased from 5.3% to 96.8%, and the SEC fingerprint changed significantly. Consequently, the methane generation in the BMP test increased from 68.9 to 135.0 mL. Ultrasonic-alkaline pretreatment was similar to alkaline pretreatment in terms of methane generation. Based on this study, alkaline pretreatment is recommended over both low-energy ultrasonic and low-energy ultrasonic-alkaline pretreatment to enhance the biodegradability of FB. PMID- 25800404 TI - "Apps" that harm patients will be hunted down, says regulator. PMID- 25800401 TI - Robotic pelvic organ prolapse surgery. AB - Robotic sacrocolpopexy (RSC) has rapidly gained popularity over the past 10 years, owing to claims that it is associated with a reduced learning curve compared with standard laparoscopic sacrocolpopexy (LSC) and that it has equal efficacy to the gold-standard treatment, abdominal sacrocolpopexy (ASC). The specifics of the surgical technique used for RSC vary widely, but the basic steps and principles are largely the same. Although complication rates are low, specific complications can be minimized by meticulous attention to surgical technique at several important points in the procedure. Multiple levels of evidence support the efficacy of RSC, and show that it is associated with a shorter hospital stay and convalescence than ASC. The learning curve for RSC usually comprises 10-20 procedures but for those with extensive experience of laparoscopy it is likely to be even shorter. RSC is more expensive than LSC but cheaper than ASC. As RSC has only been used for about a decade, we await long term outcomes of more than a few years. PMID- 25800405 TI - Involving family members in the implementation and evaluation of technologies for dementia: a dyad case study. AB - An increasing number of individuals worldwide are affected by dementia and it is important to examine nonpharmacological care approaches. A dyadic case study of a 6-month evaluation of a technology designed to engage individuals with dementia in activities in a memory care unit is presented. Findings show one caretaker of an individual with dementia (i.e., her mother) used the computer in a manner consistent with her usual style of interaction and supportive care; she continued to maintain awareness of her mother's activity preferences and cultivated her mother's quality of life by using the provided technology. These findings demonstrate a use for technology to support activities of older adults with dementia while engaging family and provide future directions for technology design and research in this population. PMID- 25800406 TI - Intravenous iron in clinical concentrations does not impair haemoglobin measurement. AB - BACKGROUND: Intravenous iron is commonly administered to anaemic patients to treat iron deficiency, but due to its ferric colouration, it may interfere with the spectrophotometric assessment of haemoglobin concentrations. This paper investigates the potential interference of three clinically used intravenous iron preparations on the measurement of haemoglobin. METHODS: Haemoglobin concentration was measured for neat and Hartmann's solution-diluted iron polymaltose, carboxymaltose and sucrose solutions using bedside (Radiometer HemoCue(r)), point-of-care (Radiometer ABL800 Flex) and laboratory (Abbott CellDyne SapphireTM) devices. Haemoglobin concentration was then assessed with the same devices utilizing anaemic whole blood with the iron solutions added. RESULTS: Neat iron preparations registered clinically significant haemoglobin concentrations on bedside and laboratory measurements. When intravenous iron preparations were diluted to clinical concentrations, their effect on haemoglobin measurements, either in isolation or mixed with anaemic blood, was negligible. CONCLUSION: Although neat preparations of intravenous iron do interfere with spectrophotometric analysis of haemoglobin, concentrations likely to be seen post iron infusion do not significantly interfere with haemoglobin measurement. PMID- 25800407 TI - Average of delta: a new quality control tool for clinical laboratories. AB - BACKGROUND: Average of normals is a tool used to control assay performance using the average of a series of results from patients' samples. Delta checking is a process of identifying errors in individual patient results by reviewing the difference from previous results of the same patient. This paper introduces a novel alternate approach, average of delta, which combines these concepts to use the average of a number of sequential delta values to identify changes in assay performance. METHODS: Models for average of delta and average of normals were developed in a spreadsheet application. The model assessed the expected scatter of average of delta and average of normals functions and the effect of assay bias for different values of analytical imprecision and within- and between-subject biological variation and the number of samples included in the calculations. The final assessment was the number of patients' samples required to identify an added bias with 90% certainty. RESULTS: The model demonstrated that with larger numbers of delta values, the average of delta function was tighter (lower coefficient of variation). The optimal number of samples for bias detection with average of delta was likely to be between 5 and 20 for most settings and that average of delta outperformed average of normals when the within-subject biological variation was small relative to the between-subject variation. CONCLUSIONS: Average of delta provides a possible additional assay quality control tool which theoretical modelling predicts may be more valuable than average of normals for analytes where the group biological variation is wide compared with within-subject variation and where there is a high rate of repeat testing in the laboratory patient population. PMID- 25800408 TI - An Integrative Model of Social Identification: Self-Stereotyping and Self Anchoring as Two Cognitive Pathways. AB - Social identification denotes individuals' psychological bond with their ingroup. It is an indispensable construct in research on intragroup and intergroup dynamics. Today's understanding of social identification is firmly grounded in self-stereotyping principles (i.e., assimilation to the ingroup prototype). However, we argue for a more integrative approach to understand social identification, including a more prominent role for the personal self. We present the Integrative Model of Social Identification (IMSI) and postulate that there are two cognitive pathways to self-group overlap that can simultaneously yet distinctly explain social identification: self-stereotyping and self-anchoring (i.e., projection of personal self onto ingroup). We review different theoretical and methodological approaches to both processes and integrate them into one model. Subsequently, we empirically demonstrate the positive relationship between self-stereotyping, self-anchoring, and identification in various group contexts and individuals. In sum, our model highlights the dynamic interplay of personal and social self as cornerstones of social identification. PMID- 25800409 TI - Interpretation of urine drug testing results in patients using transdermal buprenorphine preparations for the treatment of chronic noncancer pain. AB - OBJECTIVE: To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated. DESIGN: Retrospective chart review. SUBJECTS: Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits. METHODS: Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients. RESULTS: While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients. CONCLUSIONS: These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options. (c) 2014 Wiley Periodicals, Inc. PMID- 25800411 TI - Extraoral autoreduction of temporomandibular joint dislocation: a preliminary clinical study. PMID- 25800410 TI - Fluid management in pediatric patients with DKA and rates of suspected clinical cerebral edema. AB - OBJECTIVE: To compare outcomes of diabetic ketoacidosis (DKA) 6 yrs before and 6 yrs after changing rehydration fluids from 1/2 normal saline to Lactated Ringer's and decreasing the total intended fluid volume administered in the first 24 hrs from 3500 mL/m(2) /d to <= 2500 mL/m(2) /d at Texas Children's Hospital (TCH) in response to recommendations by the ESPE, LWPES, and ISPAD in 2004. SUBJECTS/METHODS: A retrospective cohort study was conducted in which 1868 admissions for DKA were identified and reviewed. The cohort was divided into two groups: Group A, 1998-2004, and Group B, 2004-2010. Subjects with suspected clinical cerebral edema and adverse outcomes were identified. RESULTS: Although not statistically significant, there was an equal number (n = 3) of adverse outcomes (death or neurological damage) in each group despite more than double the admissions in Group B (1264) compared with those in Group A (604). Overall, the incidence of suspected clinical cerebral edema was more than double for those admissions in which fluid resuscitation was initiated at an outside hospital (OSH) vs. at TCH (13.6 vs. 5.3%, p < 0.001). CONCLUSIONS: Decreasing the intended fluid rate during the initial 24 hrs to 2500 mL/m(2) /d and increasing the IV fluid sodium content did not significantly decrease the incidence of adverse outcomes in children with DKA. However, children transferred from an OSH had a higher incidence of suspected clinical cerebral edema. Thus, we need to more readily share our management protocols with the emergency rooms of local referring hospitals to potentially decrease the incidence of suspected clinical cerebral edema and adverse outcomes in children transferred with DKA. PMID- 25800412 TI - Performance of intubation with 4 different airway devices by unskilled rescuers: manikin study. AB - INTRODUCTION: This study was designed to compare the performances of 4 airway devices in achieving successful ventilation. METHODS: A randomized crossover trial was conducted to evaluate 4 airway devices: laryngeal mask airway (LMA), i gel (iGEL), PENTAX Airway Scope (AWS), and Macintosh laryngoscope (MCL). Thirty eight unskilled rescuers performed intubation on a manikin during chest compressions in normal and difficult airway scenarios. The time to ventilation, intubation success rate, and difficulty of intubation were measured. RESULTS: The time to ventilation of the airway devices in the normal scenario had a median value of 8.8 seconds (interquartile range, 7.3-10.5 seconds) for iGEL, 16.1 seconds (13.9-19.3 seconds) for LMA, 30.6 seconds (24.6-37.6 seconds) for AWS, and 35.0 seconds (29.5-45.9 seconds) for MCL. In the difficult airway scenario, the respective time to ventilation was 8.6 seconds (7.8-10.0 seconds), 15.3 seconds (14.3-20.2 seconds), 29.4 seconds (25.7-36.3 seconds) and 59.0 seconds (46.1-103.3 seconds). The success rates were 100% and 100% for LMA, 100% and 100% for iGEL, 97.4% and 94.7% for AWS, and 78.9% and 47.4% for MCL in the normal and difficult airway scenarios. The difficulties of intubation expressed as numerical rating scale were 2.0 and 2.0 (median values) for LMA, 1.0 and 2.0 for iGEL, 3.0 and 3.0 for AWS, and 4.0 and 5.0 for MCL in the normal and difficult airway scenarios, respectively. CONCLUSION: With novice intubators who were unfamiliar with the airway devices, the LMA, iGEL, and AWS were superior to the MCL for establishing an airway without interruption of chest compressions in a manikin study. Intubation with the iGEL was faster and easier than with the other airway devices. PMID- 25800413 TI - Vitiligo in adults and children: surgical interventions. AB - INTRODUCTION: Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, due to the loss of functioning melanocytes. The extent and distribution of vitiligo often changes during the course of a person's lifetime and its progression is unpredictable. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of surgical interventions for vitiligo in adults and in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found four studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: blister grafts, cultured cellular transplantation, non-cultured cellular transplantation, punch/mini grafts, and split thickness skin grafts. PMID- 25800414 TI - Containment of Clostridium difficile infection without reduction in antimicrobial use in Hong Kong. AB - Clostridium difficile ribotype 002 with hypersporulating capacity has been increasingly identified in Hong Kong. Proactive infection control measures are important to prevent the establishment of endemicity of C. difficile ribotype 002. A total of 329 patients with healthcare-associated C. difficile infection (CDI) were recruited in our healthcare network between 1 January 2008 and 30 June 2012 in this study. The incidence rates of healthcare-associated CDI per 10,000 admissions and 10,000 patient-days increased significantly by 15.3 and 17.0%, respectively, per quarter (p < 0.001) from 2008 1Q to 2010 1Q by segmented Poisson regression. With the full implementation of enhanced infection control interventions, there was an immediate significant reduction in both healthcare associated CDI rates per 10,000 admissions and per 10,000 patient-days by 47% (p < 0.001) in 2010 2Q, followed by a further decline of CDI per 10,000 admissions and CDI per 10,000 patient-days by -19.4 and -19.8% from 2010 2Q to 2012 2Q, respectively (p < 0.001), despite a replacement of hand washing with soap and water by alcohol-based hand rub in the healthcare network. The proportion of C. difficile ribotype 002 was not statistically different (34/177, 19.2% vs. 25/152, 16.4%, p = 0.515), and the consumption of broad-spectrum antibiotics presented as divided daily dose per 1,000 acute bed-day occupancy per quarter remained unchanged (140.9 vs. 152.3) before and after infection control interventions. Our results suggested that the reduction of healthcare-associated CDI was attributable to infection control interventions instead of replacement of ribotypes or reduction in antimicrobial selective pressure. PMID- 25800416 TI - Iron oxide-based multifunctional nanoparticulate systems for biomedical applications: a patent review (2008 - present). AB - INTRODUCTION: Iron oxide nanoparticles (IO NPs) exhibit remarkable properties, including inherent magnetism, biocompatibility, high surface to volume ratio, and versatility of engineering, making them ideal candidates for a variety of clinical applications. AREAS COVERED: The review provides an in-depth discussion on recent patents and developments related to IO NPs in Biomedicine from the last 7 years. It covers innovations in the chemical synthesis, surface coating and functionalization, and biomedical applications, including MRI and multimodal imaging, molecular imaging, cell labeling, drug delivery, hyperthermia, hyperphosphatemia, and antibacterial activity. A brief outline of the important properties of IO NPs is also presented. EXPERT OPINION: The main focus of current research is the development of new approaches to generate high-quality IO NPs with optimal properties in terms of particle geometry, crystal structure, surface functionalities, stability, and magnetization. Among chemical synthesis methods, thermal decomposition and hydrothermal synthetics processes allow fine control of the particle properties. Plenty of coating materials have been successfully used as shells for these NPs to provide colloidal stability, even enabling the formulation of nanotheranostics for simultaneous disease diagnosis and therapy. However, long-term toxicity and pharmacokinetic studies are necessary before magnetic nanosystems can be approved for clinical use. PMID- 25800415 TI - Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. AB - OBJECTIVE/METHOD: Aggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA). RESULTS: Structural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover. CONCLUSION: This data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5 selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic. PMID- 25800417 TI - The impact of behavioral couple therapy on attachment in distressed couples. AB - Emotion-focused therapy (EFT; Greenberg & Johnson, Emotionally focused therapy for couples. New York: Guilford Press) is anchored in attachment theory (Johnson, 2003 Attachment processes in couples and families. New York: Guilford) and considers change in attachment schemas essential in the process of improving satisfaction in relationships (Johnson, 1999, Research and couples therapy: Where do we go from here? American Family Therapy Academy Newsletter). However, there are little data on how measures of attachment change over the course of EFT or any other couple therapy. The current study examines whether increases in attachment security predict improvements in marital satisfaction during behavioral couple therapy, which would suggest that change in attachment style is a key process variable even for a non-attachment-focused treatment. Multilevel models of data from 134 couples participating in a randomized clinical trial of integrative behavioral couple therapy and traditional behavioral couple therapy (Christensen et al. Journal of Consulting and Clinical Psychology, 72, 2004, 176) indicate that although there is a trend for early change in attachment-related anxiety and avoidance to predict later change in marital satisfaction, early change in marital satisfaction strongly predicts change in attachment-related anxiety through the end of treatment and 2-year follow-up. These findings suggest that changes in satisfaction may lead to changes in attachment rather than the reverse and that change in attachment may not be the mechanism of change in all efficacious couple therapy. PMID- 25800418 TI - Commentary: of course it is all about attachment! AB - In the reply to the Bensen et al. article, we suggest that representation of the relationship between attachment and relationship satisfaction, the understanding of relationship specific versus general attachment, and the understanding of EFT presented in the paper are incorrect. We also find the analyses and conclusions of the paper highly questionable. It is however, encouraging to find that the field of couple therapy is recognizing the relevance of attachment theory as a core variable in adult bonding relationships and one that must be taken into account in the creation of change in such relationships. PMID- 25800419 TI - Functions and factions: a reflection on possibilities for couple therapy integration. PMID- 25800420 TI - An attachment primer for couple therapists: research and clinical implications. AB - According to attachment theory, humans are relational beings and even a child's earliest experiences with caregivers have a profound effect on emotional development and an overall approach to relationships. With increasing regularity, couple therapy has utilized attachment language as a conceptual tool, but more work is needed to understand the full clinical implications of attachment theory. These include understanding the intergenerational nature of attachment and adapting the delivery, timing, and pace of interventions to client attachment strategies. In this article, we summarize the origins of attachment theory, its measurement, the role of attachment in couple relationships, attachment stability and change, and ways that attachment informs therapy process and intervention. We hope that this article will provide an impetus for couple therapists to expand their conceptualization and use of attachment in their clinical work and for couple researchers to conduct more clinically relevant, attachment-oriented process research. PMID- 25800421 TI - Critical patriotism: incorporating nationality into MFT education and training. AB - Topics such as national identity, patriotism, nationalism, and international issues often lead to polarization within the United States and as a result, critical dialogue about these complex topics often does not occur in a meaningful way. The lack of critical inquiry and interaction about these topics is manifest at the macro and the micro level, including within the context of marriage and family therapy training and practice. While the field of MFT has devoted greater attention to addressing issues of diversity in recent years, limited attention has been focused on examining nationality and nationalism. This article presents a critical patriotism framework that training programs can use to examine nationality and expand awareness of international issues and perspectives. Special attention is focused on examining how nationalism, a problematic extreme version of patriotism, infiltrates MFT training and practice. Recommendations are provided for how training programs can focus on nationality, expand awareness of international issues and perspectives, and guide trainees in exploring how their national identity, beliefs about patriotism, and nationalistic attitudes may influence their clinical work. PMID- 25800423 TI - Responsive persistence part I: therapist influence in postmodern practice. AB - Feminist and social constructionist developments in family therapy highlighted the importance of attending to therapist-client power relations and incorporating clients' understandings and preferences as a part of therapy. Significantly, less attention has been given to how postmodern therapists do use their power and influence. This is an important topic because it is therapists who have the major responsibility for guiding the interaction with clients and persisting in this so that change is facilitated. Therapist persistence in various forms and across dimensions of therapy process is examined to expand understanding of therapist influence in postmodern and collaborative work. An analysis of responsive persistence in a session with Karl Tomm as the therapist is presented to illustrate this conceptual framing. PMID- 25800422 TI - Costs of treating depression with individual versus family therapy. AB - Depression is one of the most common concerns that bring clients to treatment. Although marriage and family therapy has been shown to be an effective treatment, little research exists regarding the cost-effectiveness of related services. In this study, we examined claims data for 164,667 individuals diagnosed with depression to determine (a) differences in the cost of treating depression according to type of therapy and license type, (b) differences in recidivism rates by age, gender, type of therapy, and type of mental health professional, and (c) differences in cost-effectiveness by therapy modality and type of professional. The results showed that services provided by marriage and family therapists resulted in the lowest recidivism rate, and family therapy services were the least expensive. PMID- 25800424 TI - Responsive Persistence Part II. Practices of Postmodern Therapists. AB - This article, a companion to Part I of this series of articles, discusses how therapists informed by social constructionist and postmodern ideas enact persistence in their work with families. Transcripts and video-recordings of therapy interaction facilitated by selected major champions for three postmodern (collaborative) therapies: Michael White (narrative therapy), Harlene Anderson (collaborative language systems approach), and Bill O'Hanlon (solution-oriented therapy) were examined for persistence practices. The article offers a range of possible ways in which postmodern therapists may enact their influence in facilitating generative and helpful conversations with families and remain responsive to clients' preferences and understandings. Implications for family therapy practice, training, and supervision are discussed. PMID- 25800425 TI - Validation of Fear of Partner Scale. AB - Therapists have a responsibility to ascertain if psychological aggression, physical aggression, sexual aggression exist, and if there is fear of the partner. A fear of partner measure was evaluated in 100 couples who sought relationship feedback. Fear of partner's psychological, physical, and sexual aggression was related to actual reports of such behavior. For both men and women, fear of speaking in front of partner and fear of being in therapy with partner were related to reports of psychological aggression perpetrated by the partner, dominance, and isolation by the partner, and one's own marital dissatisfaction. Among respondents who were aggressed against, more men than women reported fear of participating in therapy with their partner. The measure herein can be used to determine the extent of fear of aggression by partners and to assist in the decision-making about the appropriateness of marital therapy and divorce mediation. PMID- 25800426 TI - Liability of newness: assessing couple social support when starting a new business venture. AB - Study purpose was to investigate adapted social support instruments of nurturance and affiliation with male and female entrepreneurs and spouses starting a new business. Family Fundamental Interpersonal Relationship Orientation theory was the theoretical grounding. Business structure differed by entrepreneur gender in both direct and indirect spousal involvement. Both couple types were highly connected with their firms having high nurturance and affiliation scores. When couple discrepancies were compared, more male entrepreneur couples had shared meaning on business-oriented nurturance questions compared with female entrepreneur couples. The opposite was true for shared meaning on relationship oriented nurturance. For all affiliation questions, more male entrepreneur couples had shared meaning than did female entrepreneur couples. Clinical applications of resulting instruments are discussed. PMID- 25800427 TI - Editor's annual report: 2012-2013. PMID- 25800431 TI - Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid. AB - A potent, orally available dual CysLT1 and CysLT2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4 phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC50: CysLT1=13nM, CysLT2=25 nM) showed excellent pharmacokinetic profiles (%Frat=100) compared with our previously reported compound 1 (%Frat=1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat?40) in rats (HBDs: ?2, ClogP: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification. PMID- 25800432 TI - Synthesis and evaluation of 123/131I-Iochlonicotinamide as a novel SPECT probe for malignant melanoma. AB - Malignant melanoma expresses a highly aggressive metastasis. Early diagnosis of malignant melanoma is important for patient survival. Radiolabeled benzamides and nicotinamides have been reported to be attractive candidates for malignant melanoma diagnosis as they bind to melanin, a characteristic substance that displays in malignant melanoma, and show high tumor accumulation and retention. Herein, we designed and synthesized a novel (123/131)I-labeled nicotinamide derivative that specifically binds to melanin. (123/131)I-Iochlonicotinamide was prepared with good radiochemical yield (50-70%, decay corrected) and high specific radioactivity (50-80 GBq/MUmol). (131)I-Iochlonicotinamide exhibited good in vitro stability (radiochemical purity >95% after a 24-h incubation) in human serum. High uptake of (123/131)I-Iochlonicotinamide in B16F0 melanoma cells compared to that in A375 amelanotic cells demonstrated its selective binding to melanin. Intravenous administration of (123/131)I-Iochlonicotinamide in a melanoma-bearing mouse model revealed high uptake in melanotic melanoma and high tumor-to-muscle ratio. MicroSPECT scan of (123/131)I-Iochlonicotinamide injected mice also displayed high contrast tumor imaging as compared with normal organs. The radiation-absorbed dose projection for the administration of (131)I Iochlonicotinamide to human was based on the results of biodistribution study. The effective dose appears to be approximately 0.44 mSv/MBq(-1). The specific binding of (123/131)I-Iochlonicotinamide to melanin along with a prolonged tumor retention and acceptable projected human dosimetry suggest that it may be a promising theranostic agent for treating malignant melanoma. PMID- 25800433 TI - Synthesis of novel 24-amino-25,26,27-trinorlanost-8-enes: cytotoxic and apoptotic potential in U937 cells. AB - In the present study, the synthesis of a range of novel 24-amino-25,26,27 trinorlanost-8-ene derivatives including 24-piperadino-trinorlanost-8-enes, 24 piperazino-trinorlanost-8-enes, 24-morpholino-trinorlanost-8-enes, and 24 diethylamino-trinorlanost-8-enes is reported and their cytotoxic and apoptotic potential evaluated in U937 cell lines. Excellent IC50 results for piperidine and 1-(2-hydroxyethyl)piperazine derivatives have been observed (IC50 values of 1.9 MUM and 2.7 MUM in U937 cells, respectively). PMID- 25800434 TI - Effect of arginine methylation on the RNA recognition and cellular uptake of Tat derived peptides. AB - Arginine (Arg) methylation is a common post-translational modification that regulates gene expression and viral infection. The HIV-1 Tat protein is an essential regulatory protein for HIV proliferation, and is methylated in the cell. The basic region (residues 47-57) of the Tat protein contains six Arg residues, and is responsible for two biological functions: RNA recognition and cellular uptake. In this study, we explore the effect of three different methylation states at each Arg residue in Tat-derived peptides on the two biological functions. The Tat-derived peptides were synthesized by solid phase peptide synthesis. TAR RNA binding of the peptides was assessed by electrophoresis mobility shift assays. The cellular uptake of the peptides into Jurkat cells was determined by flow cytometry. Our results showed that RNA recognition was affected by both methylation state and position. In particular, asymmetric dimethylation at position 53 decreased TAR RNA binding affinity significantly, but unexpectedly less so upon asymmetric dimethylation at position 52. The RNA binding affinity even slightly increased upon methylation at some of the flanking Arg residues. Upon Arg methylation, the cellular uptake of Tat derived peptides mostly decreased. Interestingly, cellular uptake of Tat-derived peptides with a single asymmetrically dimethylated Arg residue was similar to the native all Arg peptide (at 120 MUM). Based on our results, TAR RNA binding apparently required both guanidinium terminal NH groups on Arg53, whereas cellular uptake apparently required guanidinium terminal NH2 groups instead. These results should provide insight into how nature uses arginine methylation to regulate different biological functions, and should be useful for the development of functional molecules with methylated arginines. PMID- 25800435 TI - Ethnic differences in the association of SERPING1 with age-related macular degeneration and polypoidal choroidal vasculopathy. AB - Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are leading causes of irreversible blindness in developed countries. In this study, we investigated the association of single nucleotide polymorphisms (SNPs) in the serpin peptidase inhibitor, clade G, member 1 (SERPING1) gene with neovascular AMD and PCV. Two haplotype-tagging SNPs, rs1005510 and rs11603020, of SERPING1 were genotyped in 708 unrelated Chinese individuals: 200 neovascular AMD, 233 PCV and 275 controls. A meta-analysis was also performed for all reported associations of SERPING1 SNPs with AMD and PCV. None of the tagging SNPs had a significant association with neovascular AMD or PCV (P > 0.05) in our study cohort. The meta-analyses showed that the most studied SNP rs2511989 was not significantly associated with all forms of AMD, neovascular AMD, or PCV in East Asians (P = 0.98, 0.93 and 0.30, respectively) but was associated with AMD in Caucasians (P = 0.04 for all AMD and 0.004 for neovascular AMD). Therefore, the results of our study and meta-analysis suggest that SERPING1 is not a major genetic component of AMD or PCV in East Asians but is a genetic risk factor for AMD in Caucasians, providing evidence for an ethnic diversity in the genetic etiology of AMD. PMID- 25800436 TI - Cerebral and brainstem electrophysiologic activity during euthanasia with pentobarbital sodium in horses. AB - BACKGROUND: An overdose of pentobarbital sodium administered i.v. is the most commonly used method of euthanasia in veterinary medicine. Determining death after the infusion relies on the observation of physical variables. However, it is unknown when cortical electrical activity and brainstem function are lost in a sequence of events before death. HYPOTHESIS/OBJECTIVES: To examine changes in the electrical activity of the cerebral cortex and brainstem during an overdose of pentobarbital sodium solution for euthanasia. Our testing hypothesis is that isoelectric pattern of the brain in support of brain death occurs before absence of electrocardiogram (ECG) activity. ANIMALS: Fifteen horses requiring euthanasia. METHODS: Prospective observational study. Horses with neurologic, orthopedic, and cardiac illnesses were selected and instrumented for recording of electroencephalogram, electrooculogram, brainstem auditory evoked response (BAER), and ECG. Physical and neurologic (brainstem reflexes) variables were monitored. RESULTS: Loss of cortical electrical activity occurred during or within 52 seconds after the infusion of euthanasia solution. Cessation of brainstem function as evidenced by a lack of brainstem reflexes and disappearance of the BAER happened subsequently. Despite undetectable heart sounds, palpable arterial pulse, and mean arterial pressure, recordable ECG was the last variable to be lost after the infusion (5.5-16 minutes after end of the infusion). CONCLUSIONS AND CLINICAL IMPORTANCE: Overdose of pentobarbital sodium solution administered i.v. is an effective, fast, and humane method of euthanasia. Brain death occurs within 73-261 seconds of the infusion. Although absence of ECG activity takes longer to occur, brain death has already occurred. PMID- 25800437 TI - Oxidative stress and hepatocellular injury induced by oral administration of Cr(3+) in chicken. AB - This study aims to investigate the oxidative stress and hepatocellular injury induced by Cr(3+) in chicken. Different doses of CrCl3 solutions (50% LD50 , 25% LD50 , and 12.5% LD50) and equivalent water were orally administered to chicken. Chicken liver samples were measured for the activities of antioxidant enzymes, the contents of glutathione, total antioxidant capacity (T-AOC), malondialdehyde (MDA), and hydrogen peroxide to indirectly evaluate the oxidative stress in chicken liver. Results indicated that the oral administration of Cr(3+) at high dose significantly increased (P < 0.05) the MDA levels after 28 days of exposure, with decreased T-AOC, glutathione, and antioxidant enzymes activities. Low and medium doses groups show that T-AOC, glutathione, and antioxidant enzymes activities increased after 14 days, then decreased gradually, but low and medium groups higher than control group, only high group lower than control group finally. These statistics and histopathological analysis suggest that high dose and long-term exposure of Cr(3+) induce oxidative stress and hepatocellular injury. PMID- 25800438 TI - A constellation of deuterium-labeled silanes as a simple mechanistic probe not requiring absolute configuration determination. AB - A new stereochemical probe for mechanisms at the silicon atom that is based on a deuterium-labeled silolane is synthesized and evaluated. The key synthetic step involves the hydrogenation of a 2,5-dihydrosilole with deuterium gas, giving a complex mixture of isochronic stereoisotopologues. The overall stereochemical imbalance of this mixture is evident in its (2) H NMR spectrum, which provides a good qualitative measure of changes in the configuration at the silicon atom. The technique is rapid, easy to use, and overcomes limitations and biases of traditional methods. The utility of this new procedure is demonstrated by tracking the stereochemical course of several classical reactions as well as contemporary catalytic transformations involving bond formation at the silicon atom. PMID- 25800439 TI - Genetic insight into the role of MRAS in coronary artery disease risk. AB - The muscle Ras (MRAS) gene polymorphisms have been reported to be associated with coronary artery disease (CAD) in white Europeans. The aim of this study was to ascertain the role of MRAS gene polymorphisms in conferring susceptibility to CAD, and to explore the effect on severity of CAD in Chinese population. We genotyped 5009 Chinese individuals (2466 CAD cases and 2543 controls) for eight single nucleotide polymorphisms (SNPs) around MRAS and used logistic regression analysis to determine whether they were associated with CAD. The association of the SNP loci on the severity of CAD was analyzed using a logistic and linear regression analysis, respectively. Our results revealed that an intron SNP, rs1199337, tends to be marginally associated with CAD as previously reported in Caucasians (nominal P=0.01, OR 1.10, 95% CI 1.01-1.20). However, this association did not retain statistically significant levels after applying Bonferroni's correction for multiple testing (corrected P=0.08). There was no significant association between other loci and CAD (nominal P>0.05). We did not observe any significant association between the SNPs and severity of CAD (all P values>0.05). From the above results, the MRAS gene loci might have a minor effect in conferring susceptibility to CAD in Chinese population. PMID- 25800440 TI - Quantitative site-specific ADP-ribosylation profiling of DNA-dependent PARPs. AB - An important feature of poly(ADP-ribose) polymerases (PARPs) is their ability to readily undergo automodification upon activation. Although a growing number of substrates were found to be poly(ADP-ribosyl)ated, including histones and several DNA damage response factors, PARPs themselves are still considered as the main acceptors of poly(ADP-ribose). By monitoring spectral counts of specific hydroxamic acid signatures generated after the conversion of the ADP-ribose modification onto peptides by hydroxylamine hydrolysis, we undertook a thorough mass spectrometry mapping of the glutamate and aspartate ADP-ribosylation sites onto automodified PARP-1, PARP-2 and PARP-3. Thousands of hydroxamic acid conjugated peptides were identified with high confidence and ranked based on their spectral count. This semi-quantitative approach allowed us to locate the preferentially targeted residues in DNA-dependent PARPs. In contrast to what has been reported in the literature, automodification of PARP-1 is not predominantly targeted towards its BRCT domain. Our results show that interdomain linker regions that connect the BRCT to the WGR module and the WGR to the PRD domain undergo prominent ADP-ribosylation during PARP-1 automodification. We also found that PARP-1 efficiently automodifies the D-loop structure within its own catalytic fold. Interestingly, additional major ADP-ribosylation sites were identified in functional domains of PARP-1, including all three zinc fingers. Similar to PARP-1, specific residues located within the catalytic sites of PARP-2 and PARP-3 are major targets of automodification following their DNA-dependent activation. Together our results suggest that poly(ADP-ribosyl)ation hot spots make a dominant contribution to the overall automodification process. PMID- 25800441 TI - Visfatin Protects Rat Pancreatic beta-cells against IFN-gamma-Induced Apoptosis through AMPK and ERK1/2 Signaling Pathways. AB - OBJECTIVE: Interferon-gamma (IFN-gamma) plays an important role in apoptosis and was shown to increase the risk of diabetes. Visfatin, an adipokine, has anti diabetic, anti-tumor, and regulating inflammatory properties. In this study we investigated the effect of visfatin on IFN-gamma-induced apoptosis in rat pancreatic beta-cells. METHODS: The RINm5F (rat insulinoma cell line) cells exposed to IFN-gamma were treated with or without visfatin. The viability and apoptosis of the cells were assessed by using MTT and flow cytometry. The expressions of mRNA and protein were detected by using real-time PCR and western blot analysis. RESULTS: The exposure of RINm5F cells to IFN-gamma for 48 h led to increased apoptosis percentage of the cells. Visfatin pretreatment significantly increased the cell viability and reduced the cell apoptosis induced by IFN-gamma. IFN-gamma-induced increase in expression of p53 mRNA and cytochrome c protein, decrease in mRNA and protein levels of anti-apoptotic protein Bcl-2 were attenuated by visfatin pretreatment. Visfatin also increased AMPK and ERK1/2 phosphorylation and the anti-apoptotic action of visfatin was attenuated by the AMPK and ERK1/2 inhibitor. CONCLUSION: These results suggested that visfatin protected pancreatic islet cells against IFN-gamma-induced apoptosis via mitochondria-dependent apoptotic pathway. The anti-apoptotic action of visfatin is mediated by activation of AMPK and ERK1/2 signaling molecules. PMID- 25800442 TI - Fabrication and Evaluation of Porous Keratin/chitosan (KCS) Scaffolds for Effectively Accelerating Wound Healing. AB - OBJECTIVE: To develop a dressing with desired antibacterial activity, good water maintaining ability and mechanical properties for wound healing and skin regeneration. METHODS: The chitosan with different concentrations were added in keratin solution to form porous keratin/chitosan (KCS) scaffolds. The morphological characteristics, chemical composition, wettability, porosity, swelling ratio and degradation of the scaffolds were evaluated. The antibacterial activity was tested by using S. aureus and E. coli suspension for 2 h. And L929 fibroblast cells culture was used to evaluate the cytotoxicity of the KCS scaffolds. RESULTS: The adding of chitosan could increase the hydrophobicity, decrease porosity, swelling ratio and degradation rate of the KCS porous scaffolds. Mechanical properties of KCS scaffolds could be enhanced and well adjusted by chitosan. KCS scaffolds could obviously decrease bacteria number. The proliferation of fibroblast cells in porous KCS patch increased firstly and then decreased with the increase of chitosan concentration. It was appropriate to add 400 MUg/mL chitosan to form porous KCS scaffold for achieving best cell attachment and proliferation compared with other samples. CONCLUSION: The porous KCS scaffold may be used as implanted scaffold materials for promoting wound healing and skin regeneration. PMID- 25800443 TI - Maternal Disononyl Phthalate Exposure Activates Allergic Airway Inflammation via Stimulating the Phosphoinositide 3-kinase/Akt Pathway in Rat Pups. AB - OBJECTIVE: To evaluate the effect of diisononyl phthalate (DINP) exposure during gestation and lacta- tion on allergic response in pups and to explore the role of phosphoinositide 3-kinase/Akt pathway on it. METHODS: Female Wistar rats were treated with DINP at different dosages (0, 5, 50, and 500 mg/kg of body weight per day). The pups were sensitized and challenged by ovalbumin (OVA). The airway response was assessed; the airway histological studies were performed by hematoxylin and eosin (HE) staining; and the relative cytokines in phosphoinositide 3-kinase (PI3K)/Akt pathway were measured by enzyme-linked immunosorbent assay (ELISA) and western blot analysis. RESULTS: There was no significant difference in DINP's effect on airway hyperresponsiveness (AHR) between male pups and female pups. In the 50 mg/(kg.d) DINP-treated group, airway response to OVA significantly increased and pups showed dramatically enhanced pulmonary resistance (RI) compared with those from controls (P<0.05). Enhanced Akt phosphorylation and NF-kappaB translocation, and Th2 cytokines expression were observed in pups of 50 mg/(kg.d) DINP-treated group. However, in the 5 and 500 mg/(kg.d) DINP-treated pups, no significant effects were observed. CONCLUSION: There was an adjuvant effect of DINP on allergic airway inflammation in pups. Maternal DINP exposure could promote OVA-induced allergic airway response in pups in part by upregulation of PI3K/Akt pathway. PMID- 25800444 TI - Downregulation of Aquaporin 4 Expression through Extracellular Signal-regulated Kinases1/2 Activation in Cultured Astrocytes Following Scratch-injury. AB - OBJECTIVE: To investigate the role of extracellular signal-regulated kinase1/2 (ERK1/2) pathway in the regulation of aquaporin 4 (AQP4) expression in cultured astrocytes after scratch-injury. METHODS: The scratch-injury model was produced in cultured astrocytes of rat by a 10-MUL plastic pipette tip. The morphological changes of astrocytes and lactate dehydrogenase (LDH) leakages were observed to assess the degree of scratch-injury. AQP4 expression was detected by immunofluorescence staining and Western blot, and phosphorylated-ERK1/2 (p ERK1/2) expression was determined by Western blot. To explore the effect of ERK1/2 pathway on AQP4 expression in scratch-injured astrocytes, 10 umol/L U0126 (ERK1/2 inhibitor) was incubated in the medium at 30 min before the scratch injury in some groups. RESULTS: Increases in LDH leakage were observed at 1, 12, and 24 h after scratch-injury, and AQP4 expression was reduced simultaneously. Decrease in AQP4 expression was associated with a significant increase in ERK1/2 activation. Furthermore, pretreatment with U0126 blocked both ERK1/2 activation and decrease in AQP4 expression induced by scratch-injury. CONCLUSION: These results indicate that ERK1/2 pathway down-regulates AQP4 expression in scratch injured astrocytes, and ERK1/2 pathway might be a novel therapeutic target in reversing the effects of astrocytes that contribute to traumatic brain edema. PMID- 25800446 TI - Spatial distribution of liver cancer incidence in shenqiu county, henan province, china: a spatial analysis. AB - Liver cancer is a common and leading cause of cancer death in China. We used the cancer registry data collected from 2009 to 2011 to describe the spatial distribution of liver cancer incidence at village level in Shengqiu county, Henan province, China. Spatial autocorrelation analysis was employed to detect significant differences from a random spatial distribution of liver cancer incidence. Spatial scan statistics were used to detect and evaluate the clusters of liver cancer cases. Spatial clusters were mapped using ArcGIS 10.0 software in order to identify their physical location at village level. High cluster areas of liver cancer incidence were observed in 26 villages of 7 towns and low cluster areas were observed in 16 villages of 4 towns. High cluster areas of liver cancer incidence were distributed along the Sha Ying River which is the largest of tributary of the Huai River. Role of water pollution in Shenqiu County where the high cluster was found deserves further investigation. PMID- 25800445 TI - Relationship Between Serum DNA Replication, Clinicopathological Characteristics and Prognosis of Hepatitis B Virus-associated Glomerulonephritis with Severe Proteinuria by Lamivudine Plus Adefovir Dipivoxil Combination Therapy. AB - OBJECTIVE: To explore the relationship between HBV DNA and the clinical manifestations, pathological types, injury severity, and prognosis with HBV-GN. METHODS: 102 patients with HBV-GN were divided into 3 groups, according to the serum titer of the HBV DNA. 24-h urine protein excretion, and other parameters were measured. Renal biopsy were performed. The association between HBV DNA and the pathological stage of membranous nephropathy was analyzed in 78 patients with HBV-MN. 24-h urine protein excretion was used for the evaluation of the prognosis, and the relationship between HBV DNA and prognosis were analyzed. RESULTS: Several findings were demonstrated with the increase of serum HBV DNA: 24-h urine protein excretion, plasma cholesterol, and triglycerides increased significantly (P%lt;0.05), while the plasma level of albumin decreased significantly (P%lt;0.05); The changes of serum creatinine, C3 and C4 were found but no statistical significance. Glomerular deposition of HBVAg increased, and the pathological injury was more severe. The clinical remission rate was lower in the high replication group after treatment as compared with the low replication group (P%lt;0.01). CONCLUSION: With the increase of serum HBV DNA, the urine protein excretion and the kidney injury were more severe, and the clinical remission rate was decreased. PMID- 25800447 TI - A PCR-based Rapid Neutralization Assay for GII.4 Norovirus Infection in HIEC6 Cell Culture. AB - Because of limited viral replication and lack of cytopathic effect in cell culture, a new PCR-based rapid seroneutralization assay for detection of GII.4 norovirus neutralized antibodies was developed with serum samples from acute phase patients, convalescent-phase patients and healthy controls. According to this study, neutralizing antibodies were detected in 100% of convalescent-phase sera, and in 2.5% of healthy controls sera. However, all of the acute-phase serum samples could not neutralize virus efficiently. Compared to the results from ELISA (96.2% at sensitivity and 80% at specificity), the present in vitro neutralization assay is more specific and more sensitive. PMID- 25800448 TI - Molecular Characteristics and Drug Susceptibility of Mycobacterium tuberculosis Isolates from Patients Co-infected with Human Immunodeficiency Virus in Beijing, China. AB - 70 clinical Mycobacterium tuberculosis strains isolated from AIDS patients in two HIV/AIDS referral hospitals in Beijing were used in this study. M. tuberculosis and non-tuberculosis mycobacterium (NTM) were identified by using multi-locus PCR. M. tuberculosis was genotyped by using 15-locus MIRU-VNTR technique and spoligotyping afterwards. Meanwhile, the drug susceptibilities of the strains to the four first-line anti TB drugs (rifampin, isoniazid, streptomycin, and ethambutol) and the four second-line anti-TB drugs (capreomycin, kanamycin, ofloxacin, and ethionanide) were tested with proportional method. In this study, M. tuberculosis and NTM strains isolated from AIDS patients with TB-like symptoms were identified and genotyping analysis indicated that Beijing genotype was the predominant genotype. In addition, the prevalence of drug-resistant TB, especially the prevalence of XDR-TB, was higher than that in TB patients without HIV infection. PMID- 25800449 TI - Visual detection of murray valley encephalitis virus by reverse transcription loop-mediated isothermal amplification. AB - A sensitive reverse transcription loop-mediated isothermal amplification (RT LAMP) assay was developed for rapid visual detection of Murray valley encephalitis virus (MVEV) infection. The reaction was performed in one step in a single tube at 63 degrees C for 60 min with the addition of the hydroxynaphthol blue (HNB) dye prior to amplification. The detection limit of the RT-LAMP assay was 100 copies per reaction based on 10-fold dilutions of in vitro transcribed RNA derived from a synthetic MVEV DNA template. No cross-reaction was observed with other encephalitis-associated viruses. The assay was further evaluated using spiked cerebrospinal fluid sample with pseudotype virus containing the NS5 gene of MVEV. PMID- 25800450 TI - Protective Effect of 10-Hz, 1-mT Electromagnetic Field Exposure Against Hypoxia/Reoxygenation Injury in HK-2 Cells. AB - We investigated the protective effects of electromagnetic field (EMF) on the survival of the human renal proximal tubular cell line, HK-2, using an in vitro hypoxia/reoxygenation (H/R) injury model. The survival rate of cells cultured under H/R condition declined significantly, while the intracellular reactive oxygen species (ROS) levels markedly increased. The 10 Hz/1 mT EMF exposure reversed the H/R induced reduction in cell survival and induction of intracellular ROS. Our results suggest that 10 Hz/1 mT EMF exposure could inhibit H/R-induced cell death of HK-2 via suppression of intracellular ROS production and that this treatment might be clinically useful for the amelioration of renal ischemia/reperfusion injury. PMID- 25800452 TI - Hydrogen Therapy Reduces Oxidative Stress-associated Risks Following Acute and Chronic Exposure to High-altitude Environment. AB - Low pressure, low oxygen concentration, and intense ultraviolet (UV) radiation in high-altitude environments, can cause oxidative stress which can trigger mountain sickness. A recent study demonstrated that hydrogen gas with a good permeability in biological membranes can treat various disorders by exerting its selective anti-oxidation and anti-inflammatory effects, indicating that hydrogen therapy plays a role in scavenging free radicals and in balancing oxidation and anti oxidation systems of cells. Therefore, we hypothesize that inhaling low-dose hydrogen or drinking hydrogen-saturated water is a novel and simple method to prevent and treat oxidative stress injury caused by low pressure, low oxygen concentration and intense UV radiation in plateaus, thus reducing the risk of mountain sickness. PMID- 25800451 TI - Genetic and environmental effects on the bone development of the hand and wrist in Chinese young twins. AB - We assessed genetic and environmental effects on bone development of the hand and wrist, and on key anthropometric measures in Chinese young twins. In total, 139 monozygotic and 95 dizygotic twin pairs aged from 5 to 18 years were recruited. The twin correlations of total hand and wrist scores for monozygotic (MZ) and dizygotic (DZ) twins were 0.71 and 0.36, respectively. Bivariate model analysis showed moderate genetic correlations only for total skeletal maturity vs. weight and total skeletal maturity vs. waist circumference (r, 0.51 and 0.46, respectively). Our findings demonstrated that genetic factors played important roles in bone development of the hand and wrist in Chinese young twins, and that these genetic effects might be distinct from those influencing anthropometric measures. PMID- 25800453 TI - Collective resistance to HPAI H5N1 surveillance in the Thai cockfighting community: Insights from a social anthropology study. AB - Farmers may organize themselves to collectively manage risks such as animal diseases. Our study shows some evidence of such organization among fighting cock owners in Thailand. Fighting cocks were specifically targeted by HPAI (Highly Pathogenic Avian Influenza) H5N1 surveillance and control measures in Thailand because they were thought to pose a high risk of spreading diseases. In this work, we used a social-anthropological approach to gain an inside view of the issues associated with HPAI H5N1 surveillance in the cockfighting community in Thailand. Based on a qualitative analysis of data collected through in-depth interviews and observation of cockfighters' practices, we found that fighting cock owners share a sense of belonging to the same community based on a common culture, values, interests, practices, and internal rules, including rules to manage poultry diseases. During the HPAI H5N1 outbreaks, these rules may have contributed to mitigating the potential risk associated with the intense movements of fighting cocks inside the country. Nevertheless, this community, despite the high awareness and know-how of its members regarding poultry diseases, has shown a strong reluctance to comply with HPAI surveillance programs. We suggest that this reluctance is due to important gaps between the logic and rationales underlying surveillance and those associated with cockfighting activities. Our study highlights the need for multi and trans disciplinary research involving the social sciences to analyze interactions between stakeholders and the collective actions implemented by communities to face risks. PMID- 25800454 TI - Macular Thickness Profiles of Intraretinal Layers in Myopia Evaluated by Ultrahigh-Resolution Optical Coherence Tomography. AB - PURPOSE: To investigate the thickness and variation profiles of 8 intraretinal layers in myopia. DESIGN: Prospective cross-sectional study. METHODS: Young subjects with spherical equivalents ranging from +0.50 to -10.25 diopters and good corrected vision were divided into emmetropic (n = 20), low myopic (n = 50), and high myopic (n = 30) groups. Retinal images centered on the fovea along the horizontal and vertical meridians were obtained by ultrahigh-resolution optical coherence tomography (OCT). Macular images were segmented into 8 intraretinal layers by an automatic segmentation algorithm to yield thickness profiles within a 6-mm-diameter circle divided into central, pericentral, and peripheral regions. RESULTS: For intraretinal layers in the central region, the outer segment of receptors layer was thicker in the high myopic group and positively correlated with axial length. In the pericentral and peripheral regions, all layers except the ganglion cell and inner plexiform layer had thickness changes in high myopia. The total thickness of the peripheral region was less than in the emmetropic controls owing to thinner inner nuclear layer, combined Henle fiber and outer nuclear layer, and outer segment of receptors layer. Nevertheless, the thicknesses of the combined myoid and ellipsoid zone and the combined interdigitation zone and retinal pigment epithelium/Bruch complex in the peripheral region were greater than for the emmetropic controls. CONCLUSIONS: Intraretinal layer thicknesses in young high myopic eyes varied significantly from emmetropic controls, especially in the peripheral region. Ultrahigh resolution OCT with automated segmentation can detect changes in retinal macular microstructure during the development of myopia. PMID- 25800455 TI - Geometric capture and escape of a microswimmer colliding with an obstacle. AB - Motivated by recent experiments, we consider the hydrodynamic capture of a microswimmer near a stationary spherical obstacle. Simulations of model equations show that a swimmer approaching a small spherical colloid is simply scattered. In contrast, when the colloid is larger than a critical size it acts as a passive trap: the swimmer is hydrodynamically captured along closed trajectories and endlessly orbits around the colloidal sphere. In order to gain physical insight into this hydrodynamic scattering problem, we address it analytically. We provide expressions for the critical trapping radius, the depth of the "basin of attraction," and the scattering angle, which show excellent agreement with our numerical findings. We also demonstrate and rationalize the strong impact of swimming-flow symmetries on the trapping efficiency. Finally, we give the swimmer an opportunity to escape the colloidal traps by considering the effects of Brownian, or active, diffusion. We show that in some cases the trapping time is governed by an Ornstein-Uhlenbeck process, which results in a trapping time distribution that is well-approximated as inverse-Gaussian. The predictions again compare very favorably with the numerical simulations. We envision applications of the theory to bioremediation, microorganism sorting techniques, and the study of bacterial populations in heterogeneous or porous environments. PMID- 25800456 TI - Costing bias in economic evaluations. AB - Determining the cost-effectiveness of healthcare interventions is key to the decision-making process in healthcare. Cost comparisons are used to demonstrate the economic value of treatment options, to evaluate the impact on the insurer budget, and are often used as a key criterion in treatment comparison and comparative effectiveness; however, little guidance is available to researchers for establishing the costing of clinical events and resource utilization. Different costing methods exist, and the choice of underlying assumptions appears to have a significant impact on the results of the costing analysis. This editorial describes the importance of the choice of the costing technique and it's potential impact on the relative cost of treatment options. This editorial also calls for a more efficient approach to healthcare intervention costing in order to ensure the use of consistent costing in the decision-making process. PMID- 25800457 TI - Estimated medical cost reductions for paliperidone palmitate vs placebo in a randomized, double-blind relapse-prevention trial of patients with schizoaffective disorder. AB - OBJECTIVE: The objective of this economic model was to estimate the difference in medical costs among patients treated with paliperidone palmitate once-monthly injectable antipsychotic (PP1M) vs placebo, based on clinical event rates reported in the 15-month randomized, double-blind, placebo-controlled, parallel group study of paliperidone palmitate evaluating time to relapse in subjects with schizoaffective disorder. RESEARCH DESIGN AND METHODS: Rates of psychotic, depressive, and/or manic relapses and serious and non-serious treatment-emergent adverse events (TEAEs) were obtained from the long-term paliperidone palmitate vs placebo relapse prevention study. The total annual medical cost for a relapse from a US payer perspective was obtained from published literature and the costs for serious and non-serious TEAEs were based on Common Procedure Terminology codes. Total annual medical cost differences for patients treated with PP1M vs placebo were then estimated. Additionally, one-way and Monte Carlo sensitivity analyses were conducted. RESULTS: Lower rates of relapse (-18.3%) and serious TEAEs (-3.9%) were associated with use of PP1M vs placebo as reported in the long term paliperidone palmitate vs placebo relapse prevention study. As a result of the reduction in these clinical event rates, the total annual medical cost was reduced by $7140 per patient treated with PP1M vs placebo. One-way sensitivity analysis showed that variations in relapse rates had the greatest impact on the estimated medical cost differences (range: -$9786, -$4670). Of the 10,000 random cycles of Monte Carlo simulations, 100% showed a medical cost difference <$0 (reduction) for patients using PPIM vs placebo. The average total annual medical differences per patient were -$8321 for PP1M monotherapy and -$6031 for PPIM adjunctive therapy. CONCLUSIONS: Use of PP1M for treatment of patients with schizoaffective disorder was associated with a significantly lower rate of relapse and a reduction in medical costs compared to placebo. Further evaluation in the real-world setting is warranted. PMID- 25800458 TI - Interactions Among Different Devices and Electrical Stimulus on the Electroejaculation of Captive Agoutis (Dasyprocta leporina). AB - The interactions among different electroejaculation devices associated with serial or continuous stimuli were investigated to improve the efficiency of the electroejaculation for semen collection in agoutis. Ten sexually matured male Dasyprocta leporina were restrained by the intramuscular administration of xylazine-ketamine association. Each individual was randomly subjected to four electroejaculation protocols, by combining two devices (one presenting longitudinal electrodes emitting square waves and other presenting ring electrodes emitting sine waves) and two electrical stimuli protocols (serial or continuous). A total of 40 attempts for electroejaculation were conducted in agoutis, being 10 per treatment. The most efficient treatment in providing ejaculates containing sperm (p < 0.05) was that using and electroejaculator connected to a probe with ring electrodes and associated with serial stimuli (4/7; 57%). In spite of semen parameters obtained by sine waves were adequate for using the samples for assisted reproduction, higher values for sperm motility and functional membrane integrity were obtained in the use of the square wave, independently of the electric stimulation protocol used (p < 0.05). In conclusion, we verified that the use of a device presenting a probe with ring electrodes and emitting sine waves, associated with a serial stimuli protocol, improves the efficiency for semen obtaining by electroejaculation in adults D. leporina. PMID- 25800459 TI - Feeding ecology of chimpanzees (Pan troglodytes verus) inhabiting a forest mangrove-savanna-agricultural matrix at Caiquene-Cadique, Cantanhez National Park, Guinea-Bissau. AB - With rising conversion of "natural" habitat to other land use such as agriculture, nonhuman primates are increasingly exploiting areas influenced by people and their activities. Despite the conservation importance of understanding the ways in which primates modify their behavior to human pressures, data are lacking, even for well-studied species. Using systematically collected data (fecal samples, feeding traces, and direct observations), we examined the diet and feeding strategies of an unhabituated chimpanzee community (Pan troglodytes verus) at Caiquene-Cadique in Guinea-Bissau that inhabit a forest-savanna mangrove-agricultural mosaic. The chimpanzees experienced marked seasonal variations in the availability of plant foods, but maintained a high proportion of ripe fruit in the diet across months. Certain wild species were identified as important to this community including oil-palm (Elaeis guineensis) fruit and flower. Honey was frequently consumed but no other insects or vertebrates were confirmed to be eaten by this community. However, we provide indirect evidence of possible smashing and consumption of giant African snails (Achatina sp.) by chimpanzees at this site. Caiquene-Cadique chimpanzees were confirmed to feed on nine different agricultural crops, which represented 13.6% of all plant species consumed. Consumption of fruit and nonfruit crops was regular, but did not increase during periods of wild fruit scarcity. Crop consumption is an increasing and potentially problematic behavior, which can impact local people's tolerance toward wildlife. To maximize the potential success of any human-wildlife coexistence strategy (e.g., to reduce primate crop feeding), knowledge of primate behavior, as well as multifaceted social dimensions of interactions, is critical. PMID- 25800460 TI - The Contribution of Community Singing Groups to the Well-Being of Older People: Participant Perspectives From the United Kingdom. AB - Current evidence suggests that participatory arts activities, and particularly group singing, may contribute to the well-being of older people. However, there is currently a paucity of prospective research from the participant perspective. This qualitative study nested within a randomized controlled trial aimed to assess participants' perspectives of the acceptability and effect on health and well-being of a community singing program for older people. Volunteers recruited to the intervention arm (n = 131) were invited to write comments on their experiences over three data collection points of a 14-week singing program. A subsample (n = 19) participated in a retrospective semi-structured interview. Data were subjected to content and thematic analysis. Comments and interviews from 128 individuals suggested that the singing groups led to specific, incremental benefits to physical, psychological, social, and community well being. Benefits tended to tail off after the program ended. Suggestions were made for the future running of such groups. PMID- 25800461 TI - Discharge Criteria and Follow-Up Support for Dementia Care Units. AB - Specialized dementia care units (DCUs) house individuals whose behaviors cannot be managed in other settings. To ensure environmental fit, admission/discharge criteria are recommended for DCUs; however, there is no consensus about what criteria should be used. This study aimed to describe, in a random sample of DCUs, the current admission criteria, current/recommended discharge criteria, and services to support discharge. Usable surveys were returned by 23 of 30 facilities. Residents were most frequently admitted because they had a diagnosis of dementia and exhibited cognitive/behavioral problems. The four most common discharge criteria in place/recommended were resident ability to manage in a non specialized long-term care environment, lack of socially inappropriate behaviors, dependency in activities of daily living, and inability to participate in dementia care activities. These findings suggest that discharge from DCUs is relatively ad hoc. The study lays the groundwork for future research to evaluate the use/appropriateness of these criteria. PMID- 25800462 TI - Relationship Between the Types of Insurance Coverage and Outpatient Mental Health Treatment Use Among Older Adults. AB - Using the public use data files of the 2008 to 2012 National Survey on Drug Use and Health, this study examined (a) the payment sources for mental health treatment among those aged 50 to 64 years and those aged 65+ years and (b) the relationship between outpatient mental health treatment use and different types of insurance coverage among members of these two age groups. The results show that 16% of the 50 to 64 age group and 10% of the 65+ age group used inpatient or outpatient mental health treatment in the preceding year. Logistic regression analyses showed that mental health problem severity and public insurance programs (Medicare, Medicaid, and Department of Veterans Affairs [VA]/military insurance) significantly increased the odds of receiving outpatient treatment. Private insurance was not a significant factor for either age group. Older adults with mental health problems must be encouraged to seek treatment and need to be informed about mental health coverage included in their insurance(s). PMID- 25800463 TI - [Periprosthetic infections of the hip joint : Clinical approach]. AB - BACKGROUND: Increasing rates of periprosthetic joint infections (PJI) will present orthopedic surgeons and the health care system with challenges in the next few years. New concepts in diagnostic and surgical pathways allow specialized centers to offer differentiated therapy of PJI. AIM: This article presents an overview of recent treatment concepts for PJI of the hip emphasizing diagnosis and the clinical approach. METHOD: A selective literature search was performed focusing on evidence-based concepts including diagnostics, surgical treatment, and biofilm active antibiotics. RESULTS: PJI of the hip are classified as mature biofilm or immature biofilm infections. The most important step in the diagnostic procedure is to identify the pathogen and its antimicrobial susceptibility. Preoperative joint aspiration and leukocyte count, differentiation, and microbiological culture should be standard. Arthroscopic biopsy may be necessary to identify the pathogen. Depending on the biofilm maturity and the antimicrobial susceptibility, implant retention or two-stage revisions should be performed. Combination of surgical therapy and biofilm-active antibiotics are of utmost importance for successful treatment. DISCUSSION: PJI represents a significant challenge for the orthopedic surgeon. Evidence-based and standardized clinical pathways are necessary for accurate and rapid diagnosis as well as patient-specific treatment concepts. PMID- 25800464 TI - [Tumor prostheses : Important in modern revision arthroplasty]. AB - BACKGROUND: Due to demographic aging, an increasing number of revision arthroplasty procedures is expected during upcoming years. While the use of a megaprosthesis for bone reconstruction after tumor resection is gold standard, this type of prosthesis still meets with reservation in the field of revision arthroplasty because of numerous risk factors. OBJECTIVES: The purpose of this article is to present the importance of modular megaprostheses in revision arthroplasty, taking into consideration the risks of periprosthetic infection, aseptic loosening, material failure, and hip dislocation. RESULTS: Because of improvements in the field of megaprostheses during the last 30 years, the risks after implantation of this type of prosthesis have significantly decreased. The risk of periprosthetic infection has been reduced about 1/3 by the use of silver surface coating. Improvements in stem design, cement technique, and the additional use of locking screws have minimized the risk of aseptic loosening. Improvements in material composition have reduced the risk of material failure. The risk of hip dislocation could also be minimized by careful tissue preparation and appropriate suture technique. CONCLUSION: There is no need for the conservative use of megaprostheses in revision arthroplasty. There are many benefits in the use of megaprostheses in multimorbid patients (i.e., reduced operating time, the possibility of early full weight bearing, and a reduced risk of periprosthetic infection by the use of silver surface coating) instead of complex bone reconstruction during revision arthroplasty. PMID- 25800465 TI - [Ligament-controlled positioning of the knee prosthesis components]. AB - BACKGROUND: There are at least two predominant goals in total knee replacement: first, the surgeon aims to achieve an optimal postoperative kinematic motion close to the patient's physiological range, and second, he aims for concurrent high ligament stability to establish pain-free movement for the entire range of motion. A number of prosthetic designs and surgical techniques have been developed in recent years to achieve both of these targets. OBJECTIVES: This study presents another modified surgical procedure for total knee implantation. As in common practice the osteotomies are planned preoperatively, referencing well-defined bony landmarks, but their placement and orientation are also controlled intraoperatively in a stepwise sequence via ligamentous linkages. METHOD: This method is open to all surgical approaches and can be applied for PCL conserving or -sacrificing techniques. The anterior femoral osteotomy is carried out first, followed by the distal femoral osteotomy. Then, the extension gap is finalized by tensioning the ligaments and "top-down" referencing at the level of the tibial osteotomy, followed by finishing the flexion gap in the same way, except that the osteotomy of the posterior condyles is referenced in a "bottom up" fashion. DISCUSSION: Hence, this technique relies on both bony and ligament controlled procedures. Thus, it respects the modified ligamentous framework and drives the prosthetic components into the new ligamentous envelope. Further improvement may be achieved by additional control of the kinematics during surgery by applying modern computer navigation technology. PMID- 25800466 TI - [Patella in Place Balancer: Technique for total knee arthroplasty]. AB - BACKGROUND: The gap-balancing technique is well established in primary total knee arthroplasty to determine femoral rotation and flexion gap stability. However, it has been reported that the everted or luxated extensor mechanism during this procedure in addition to soft tissue releases performed may cause inaccurate flexion-gap determination and thus result in malpositioning of the femur or instability. In this article the alternative technique of a Patella in Place Balancer (PIPB) with a no tissue release philosophy is introduced. METHOD: In this procedure, at first, the tibia resection is performed and a tibia baseplate inserted. Then, two pins are drilled into the sagittal profile of the femoral condyles. After anatomical repositioning of the extensor apparatus the pins are screwed in until the flexion gap is spanned. In this position femoral component orientation is determined parallel to the tibia. We describe the current clinical experience based on a retrospective review of 3,000 patients. Moreover, initial results of a prospective study are outlined. RESULTS: The PIPB technique was suitable for the treatment of primary and secondary gonarthrosis if the collateral ligaments were intact. The detected revision rate was about 1.21 %. Only 2 % of the treated patients reported back with an unsatisfactory outcome 1 year after surgery. In the prospective survey of 33 patients a significant improvement in the KOOS Score could be documented (29.3 points preoperatively vs. 63.5 postoperatively (p < 0.05)). DISCUSSION: The PIPB overcomes the major limitation of the gap balancing technique with regard to the inaccuracy caused by the dislocated extensor mechanism. After a learning curve, the technique appears to be safe and reliable. Preliminary data show promising results. PMID- 25800468 TI - Diagnostic accuracy of intraoperative frozen sections during radical cystectomy does not affect disease-free or overall survival: a study of 364 patients with urothelial carcinoma of the urinary bladder. AB - The utility of intraoperative frozen sections for determining ureteral and urethral margin status is controversial. In this study, we evaluated the sensitivity and specificity of frozen section diagnosis with the corresponding final tissue diagnosis in a series of 364 patients undergoing radical cystectomy for urothelial carcinoma of the urinary bladder. Multiple definitions of a positive diagnosis were analyzed. We then used clinical follow-up data to determine the effect of various frozen section diagnoses, frozen/permanent section discordance, and surgical margins on overall survival and disease-free survival. Increasing severity of dysplasia was associated with corresponding increases in positive likelihood ratio, with carcinoma displaying the highest positive likelihood ratio (211.43) for an accurate frozen section diagnosis. A diagnosis of carcinoma on frozen section did not affect overall or disease-free survival nor did a positive surgical margin. Frozen/permanent discordance did not show significant associations with overall survival or disease-free survival. The lone variable approaching statistical significance was an association between frozen/permanent discordance of ureteral samples and disease-free survival (hazard ratio, 3.23; P = .07; multivariate Cox proportional hazards model). The results of this study, the first to evaluate the use of different cutoffs for a positive diagnosis and the effects of frozen/permanent discordance, do not support the routine use of intraoperative frozen section during radical cystectomy for urothelial carcinoma. However, subgroups at high risk for positive ureteral margins may benefit from intraoperative frozen section evaluation. PMID- 25800467 TI - Rotenone Stereospecifically Increases (S)-2-Hydroxyglutarate in SH-SY5Y Neuronal Cells. AB - The alpha-ketoglutarate metabolite, 2-hydroxyglutarate (2-HG), has emerged as an important mediator in a subset of cancers and rare inherited inborn errors of metabolism. Because of potential enantiospecific metabolism, chiral analysis is essential for determining the biochemical impacts of altered 2-HG metabolism. We have developed a novel application of chiral liquid chromatography-electron capture/atmospheric pressure chemical ionization/mass spectrometry, which allows for the quantification of both (R)-2-HG (D-2-HG) and (S)-2-HG (L-2-HG) in human cell lines. This method avoids the need for chiral derivatization, which could potentially distort enantiomer ratios through racemization during the derivatization process. The study revealed that the pesticide rotenone (100 nM), a mitochondrial complex I inhibitor, caused a significant almost 3-fold increase in the levels of (S)-2-HG, (91.7 +/- 7.5 ng/10(6) cells) when compared with the levels of (R)-2-HG (24.1 +/- 1.2 ng/10(6) cells) in the SH-SY5Y neuronal cells, a widely used model of human neurons. Stable isotope tracers and isotopologue analysis revealed that the increased (S)-2-HG was derived primarily from l glutamine. Accumulation of highly toxic (S)-2-HG occurs in the brains of subjects with reduced L-2-HG dehydrogenase activity that results from mutations in the L2HGDH gene. This suggests that the observed stereospecific increase of (S)-2-HG in neuronal cells is due to rotenone-mediated inhibition of L-2-HG dehydrogenase but not D-2-HG dehydrogenase. The high sensitivity chiral analytical methodology that has been developed in the present study can also be employed for analyzing other disruptions to 2-HG formation and metabolism such as those resulting from mutations in the isocitrate dehydrogenase gene. PMID- 25800469 TI - National childhood diabetes program activities in Turkey. AB - Recent census figures in Turkey show that out of a population of 76.6 million, 22.7 million (29.7%) are younger than 18 years old. The great majority (>95%) of pediatric cases of diabetes in Turkey are type 1 diabetes mellitus (T1DM). In recent years, with increase in number of pediatric endocrine centers around the country, the important issue of care for diabetic children and adolescents has been revived and major steps have been taken for improvement in pediatric care and its outreach to all diabetic children. The Childhood Diabetes Group continues its activities in cooperation with the Turkish Ministry of Health. A list of areas of interest of the Group include "School programs", "Incidence/prevalence studies and national registry system", "Educational guidelines for diabetes in children", "Increasing the numbers of camps and summer schools for diabetic children", "Organization of educational programs for the health team", "National guidelines for transition of diabetic children to adult clinics", "Improvement of school canteens", "Educational spots" to improve awareness of diabetes. The activities of the Childhood Diabetes Group will be discussed in detail in this article. PMID- 25800470 TI - beta-3AR W64R Polymorphism and 30-Minute Post-Challenge Plasma Glucose Levels in Obese Children. AB - OBJECTIVE: In this study, we aimed to investigate the association of W64R polymorphism of the beta3-adrenergic receptor gene (beta-3AR) with childhood obesity and related pathologies. METHODS: beta-3AR gene W64R genotyping was carried out in 251 children aged 6-18 years. Of these subjects, 130 were obese (62 boys) and 121 were normal-weight (53 boys). In the obese group, fasting lipids, glucose and insulin levels were measured. Oral glucose tolerance test (OGTT) was performed in 75 of the obese patients. RESULTS: The frequency of W64R genotype was similar in obese and non-obese children. In obese children, relative body mass index, waist-to-hip ratio, serum lipid, glucose and insulin levels, as well as homeostasis model assessment of insulin resistance (HOMA-IR) scores were not different between Arg allele carriers (W64R and R64R) and noncarriers (W64W). In 75 obese children, OGTT results showed that Arg allele carriers had significantly higher 30-minute glucose levels (p=0.027). CONCLUSION: W64R polymorphism of the beta-3AR gene is not associated with obesity and waist-to-hip ratio in Turkish children. Although there were no relationships between the genotypes and lipid, glucose/insulin levels or HOMA-IR, the presence of W64R variant seemed to have an unfavorable influence on early glucose excursion after glucose loading. PMID- 25800471 TI - Ambulatory blood pressure and subclinical cardiovascular disease in patients with congenital adrenal hyperplasia: a preliminary report. AB - OBJECTIVE: There is an increased risk of cardiovascular morbidity in children and adolescents with classical congenital adrenal hyperplasia (CAH), presumably associated with obesity, hypertension, impaired glucose tolerance and dyslipidemia. This study was designed to evaluate the metabolic and cardiovascular profile of a group of children with classical CAH from the perspective of cardiovascular risk. METHODS: Twenty-five CAH patients and 25 healthy controls were included in the study. Metabolic and anthropometric parameters were investigated and compared in these two groups. RESULTS: Subjects in the CAH group were shorter than the controls (p=0.001) and had higher body mass index values (p=0.033). Diastolic blood pressure (DBP) (p=0.027) and carotid intima-media thickness (CIMT) values (p=0.006) were also higher in the patient group. In 24% (n=6) of CAH patients, 24-h ambulatory BP monitoring showed arterial hypertension. CIMT was significantly higher in the hypertensive patients than in those with no hypertension (p=0.013). Twenty percent (n=5) of CAH patients had nocturnal hypertension. CIMT was significantly greater in the nocturnal hypertensive group (p=0.02). Mean systolic BP (SBP) and DBP dipping were significantly different in the CAH patients (p<0.001). CIMT correlated negatively with DBP dipping (r=-0632, p=0.037) in these patients. CONCLUSION: These results provide additional evidence for the presence of subclinical cardiovascular disease in classical CAH patients and its relationship with hypertension. PMID- 25800472 TI - Metabolic and Histopathological Effects of Fructose Intake During Pregestation, Gestation and Lactation in Rats and their Offspring. AB - OBJECTIVE: Studies have demonstrated a significant relationship between maternal fructose intake and metabolic outcome in their offspring. However, there is a paucity of data about the long-term effects of fructose intake on the offspring of fructose-fed dams. Therefore, we planned a study to evaluate the long-term effects of fructose intake on the offspring of dam rats fed a high-fructose diet. METHODS: Sixteen virgin female Sprague-Dawley rats were divided into two groups. Group 1 received a regular diet and Group 2 a high-fructose diet. Both groups received their experimental diets for 8 weeks before conception. They were mated and continued to feed with their experimental diet during mating and during their pregnancy and lactation periods. After weaning, the offspring from each group were divided into two groups. Group 1A received a regular diet, Group 1B - a fructose diet, Group 2A - a regular diet and Group 2B received a fructose diet. After weaning, the offspring were anesthetized and blood samples were collected for biochemical analysis. Liver, kidney and retroperitoneal adipose tissue were harvested for histopathological examination. Primary antibodies against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined as early inflammation markers. RESULTS: After weaning, while daily water consumption was found to be significantly higher in Groups 2B and 1B (p<0.01), daily laboratory chow consumption was significantly lower in Groups 1A and 2A (p<0.01). Body weight was significantly higher in Groups 1B and 2B (p<0.01). Serum glucose, triglyceride, low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol levels were found to be increased and high-density lipoprotein cholesterol levels decreased in Group 2B (p<0.05). The intensities of iNOS staining in the retroperitoneal adipose tissue, COX-2 staining in the liver and both iNOS and COX-2 staining in the kidney were higher in Group 2B (p<0.05). CONCLUSION: Based on our findings, we believe that the offspring of dams which received a high fructose intake during their pregestation, gestation and lactation periods are at risk of developing metabolic syndrome in their later life only if they continue to receive a high intake of fructose. We therefore propose that the risk of developing metabolic syndrome can probably be reduced by modifying the diet of the offspring after weaning. PMID- 25800474 TI - Current practice in diagnosis and treatment of growth hormone deficiency in childhood: a survey from Turkey. AB - OBJECTIVE: Approaches to diagnosis and treatment of growth hormone deficiency (GHD) in children vary among countries and even among centers in the same country. This survey, aiming to facilitate the process of preparing the new consensus on GHD by the Turkish Pediatric Endocrinology and Diabetes Society, was designed to evaluate the current practices in diagnosis and treatment of GHD in different centers in Turkey. METHODS: A questionnaire covering relevant items for diagnosis and treatment of GHD was sent out to all pediatric endocrinology centers. RESULTS: Twenty-four centers returned the questionnaire. The most frequently used GH stimulation test was L-dopa, followed by clonidine. Eighteen centers used a GH cut-off value of 10 ng/mL for the diagnosis of GHD; this value was 7 ng/mL in 4 centers and 5 ng/mL in 2 centers. The most frequently used assay was immunochemiluminescence for determination of GH, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 concentrations. Sex steroid priming in both sexes was used by 19 centers. The most frequently used starting dose of recombinant human GH (rhGH) in prepubertal children was 0.025-0.030 mg/kg/day and 0.030-0.035 mg/kg/day in pubertal children. Growth velocity was used in the evaluation for growth response to rhGH therapy in all centers. Anthropometric measurements of patients every 3-6 months, fasting blood glucose, bone age and thyroid panel evaluation were used by all centers at follow-up. Main indications for cessation of therapy were decreased height velocity and advanced bone age. Fourteen centers used combined treatment (rhGH and gonadotropin releasing analogues) to increase final height. CONCLUSION: Although conformity was found among centers in Turkey in current practice, it is very important to update guideline statements and to modify, if needed, the approach to GHD over time in accordance with new evidence-based clinical studies. PMID- 25800475 TI - Higher body fat and lower fat-free mass in girls with premature adrenarche. AB - OBJECTIVE: Idiopathic premature adrenarche (PA) refers to presence of androgenic signs before the age of eight years in girls in the absence of thelarche. In children with PA, increased adrenal androgens lead to changes in body composition and transient growth acceleration. Although the association between PA and some components of the metabolic syndrome is well known, body composition has not been extensively studied in these patients. METHODS: We examined 47 girls with PA with a median age of 7.39 years and 57 healthy controls with a median age of 7.11 years. For PA group, the inclusion criteria were appearance of pubic/axillary hair before 8 years of age, absence of findings of central puberty and absence of use of any medication. Patients with steroidogenic enzyme defects and virilizing tumors were excluded. Height, body weight, waist and hip circumference were measured. The bioelectrical impedance method was used for body composition analysis. RESULTS: In the PA group, both body weight standard deviation score (SDS) and height SDS were significantly higher than in the controls (p<0.001 for both). While total body fat percentage values were significantly higher in the PA group than in the controls (median 22.8% vs. 19.95%, p=0.049), fat-free mass (FFM) and total muscle mass percentages were significantly lower than in the controls (median 76.8% vs. 79.9%, p=0.024 and 72.6% vs. 75.7%, p=0.018, respectively). CONCLUSION: Our findings revealed that girls with PA have higher body weight and height for age values. They also show significant changes in body composition such as an increase in total body fat percentage with a concomitant decrease in the percentages of FFM, muscle mass and total body water. PMID- 25800473 TI - Turner syndrome and associated problems in Turkish children: a multicenter study. AB - OBJECTIVE: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. METHODS: Our retrospective study included 842 karyotype-proven TS patients aged 0 18 years who were evaluated in 35 different centers in Turkey in the years 2013 2014. RESULTS: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2+/-4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. CONCLUSION: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan. PMID- 25800476 TI - Epidemiologic Features of Type 1 Diabetic Patients between 0 and 18 Years of Age in Istanbul City. AB - OBJECTIVE: To evaluate the epidemiologic, clinical and laboratory characteristics of a group of children with type 1 diabetes mellitus (T1DM) living in a Turkish city. METHODS: The records of 395 (boys/girls: 199/196) children with newly diagnosed T1DM hospitalized in the years 1985-2004 were evaluated retrospectively. The data were assessed by gender and age subgroups (<=5, 6-10 and >=11 years). RESULTS: Mean age of children at diagnosis was 8.1+/-4.1 years. At T1DM onset, the number of children <=5, between 6-10 and >=11 years old was 110 (27.9%), 147 (37.2%) and 138 (34.9%), respectively. The patients were mostly diagnosed at ages 6-8 years (24.1%), followed by cases aged 3-5 years (22.0%). Polyuria and polydipsia were the most common symptoms (94.7%). Mean duration of symptoms was 21.5+/-18.6 days. Although the patients mostly presented in autumn (30.7%), no season-related significant differences were found. The frequency of ketoacidosis was relatively high (48.5%). When compared to boys, the girls experienced higher rates of ketoacidosis (55.1% vs. 41.7%, p=0.042); had a higher frequency of anti-thyroid peroxidase antibodies (11.7% vs. 4.2%, p=0.049) and higher insulin requirement (0.89+/-0.41 vs. 0.77+/-0.36 IU/kg, p=0.005). Cases with a family history of T1DM were more likely to have anti-endomysial antibodies (42.9% vs. 8.1%, p=0.027) and higher initial blood glucose levels (510.5+/-145.0 vs. 436.1+/-156.5 mg/dL, p=0.005). CONCLUSION: The findings possibly indicate a decreasing age of T1DM onset. The high frequency of ketoacidosis at presentation is noteworthy. Girls had higher rates of ketoacidosis, higher frequency of anti thyroid antibodies and higher insulin requirements as compared to boys. Patients with a family history of T1DM had higher initial glucose levels and higher frequency of anti-endomysial antibodies. PMID- 25800477 TI - Recognizing the psychosocial aspects of type 1 diabetes in adolescents. AB - OBJECTIVE: Considering the ever increasing population of diabetic adolescents and the association of the disease with psychosocial problems throughout its course, depression and/or anxiety and social support from parents are issues of special concern in these patients. The study aimed to identify the depression and anxiety state of diabetic adolescents and its impact on the management of diabetes mellitus (DM). METHODS: 295 adolescents with type 1 DM and their parents attended our study. Psychological distress was assessed using the Children's Depression Inventory and the State-Trait Anxiety Inventory (STAI I-II) for Children, Perceived Social Support from Family (PSS-Fa) scale, Beck Depression Inventory for adults, STAI I-II for adults and the Multidimensional Scale of Perceived Social Support (MSPSS). Records of glycemic measurements, insulin dosage and hemoglobin A1c levels were used as glycemic control parameters. RESULTS: Depression rate was 12.9%. State (p<0.001) and trait anxiety (p<0.001) levels were high; PSS-Fa (p<0.001) and MSPSS (p<0.006) scores were low in the depressive patients. Positive correlations were noted between depression, PSS-Fa, STAI-I and STAI-II. CONCLUSION: Therapeutic strategies of DM should include co-existing psychiatric conditions throughout the course of the disease. In diabetic adolescents, PSS-Fa, STAI-I and STAI-II appear to be effective tools in the evaluation of depression. PMID- 25800478 TI - Social anxiety, depression and self-esteem in obese adolescent girls with acanthosis nigricans. AB - OBJECTIVE: To assess the impact of acanthosis nigricans (AN) on depression symptoms, related quality of life and self-esteem scores in obese adolescent girls. METHODS: Fifty-nine obese adolescent girls (mean age: 13.19+/-1.3 years, age range: 12-17 years, mean body mass index: 29.89+/-3.30) were enrolled in this study. The obese adolescent girls were divided into two groups based on presence or absence of AN. Non-obese healthy adolescents constituted the control group (30 girls, mean age: 13.5+/-1.4 years). All subjects were evaluated using the Children's Depression Inventory (CDI), the State-Trait Anxiety Inventory for Children (STAI-C), and the modified Rosenberg Self-Esteem Scale (SES). Higher scores indicated more severe depression and anxiety, as well as low self-esteem status. RESULTS: The AN and non-AN obese groups showed significantly higher CDI, STAI-C and SES scores than the control group, and the two obese groups demonstrated no significant differences for these scores. The AN obese group with higher total testosterone levels (>50 ng/dL) had higher scores for SES (2.55+/ 1.8 vs. 1.42+/-1.2; p=0.03) than the AN obese group with low total testosterone levels. SES scores significantly correlated with total testosterone levels (r=0.362; p=0.03) and fasting insulin (r=0.462; p=0.03) in the AN obese group. CONCLUSION: Higher SES scores (low self-esteem status) were determined in obese adolescents with acanthosis and were related to hyperandrogenism. This study also showed that a high testosterone level may be one of the important indicators of low self-esteem status in obese girls with AN. PMID- 25800479 TI - Rhizomelic Chondrodysplasia Punctata Type 1 Caused by a Novel Mutation in the PEX7 Gene. AB - Peroxisomes are involved in various metabolic reactions. Rhizomelic chondrodysplasia punctata (RCDP) type 1 is one of the peroxisomal biogenesis disorders caused by mutations in the PEX7 gene and is inherited in an autosomal recessive manner. We present a nine-year-old boy with skeletal abnormalities and dysmorphic facial appearance. The patient was born to parents who were first cousins. Very-long-chain fatty acids and pristanic acid levels were in the normal range, but an elevated phytanic acid level was detected by gas chromatography/mass spectrometry. The PEX7 gene was sequenced in the patient and his parents. A novel homozygous mutation, c.192delT (p.F64Lfs*10), was identified in the patient and was present in heterozygosity in both parents. In conclusion, the clinical presentation and peroxisome profile of the patient suggest that this novel mutation leads to RCDP type 1. PMID- 25800480 TI - A case of thanatophoric dysplasia type 2: a novel mutation. AB - Thanatophoric dysplasia (TD) is a lethal form of skeletal dysplasia with short limb dwarfism. Two types distinguished with their radiological characteristics have been defined clinically. The femur is curved in type 1, while it is straight in type 2. TD is known to be due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. We report a male patient who showed clinical findings congruent with TD type 2 and a new mutation in the FGFR3 gene, a finding which has not been reported previously. PMID- 25800481 TI - Recovery of Central Fever after GH Therapy in a Patient with GH Deficiency Secondary to Posttraumatic Brain Injury. AB - Growth hormone (GH) deficiency is the most common pituitary hormone deficiency after traumatic brain injury. Patients with GH deficiency have a reduced sweating capacity which increases the risk of developing hyperthermia. To the best of our knowledge, central fever that developed due to GH deficiency and improved with GH treatment has not yet been reported. In this article, we present a case of dramatic improvement of central fever with recombinant human GH therapy in a patient with posttraumatic GH deficiency. PMID- 25800482 TI - Autoimmune polyglandular syndrome type 2: a rare condition in childhood. AB - Autoimmune polyglandular syndrome type 2 is defined as the occurrence of Addison's disease concomitantly with autoimmune thyroid disease and/or type 1 diabetes mellitus. An 11-year-old boy with Hashimoto's disease, Addison's disease, celiac disease and Langerhans islet cell autoimmunity is described in this case report. Treatment of an endocrine disease may also trigger the onset of another endocrine disease. This case report underlines the importance of early recognition and treatment of critical endocrine diseases as well as the necessity to investigate pediatric patients with autoimmune diseases for coexisting conditions. Furthermore, the role of psychological stress as an inducer of autoimmunity was also discussed. PMID- 25800483 TI - Capillary bedside blood glucose measurement in neonates: missing a diagnosis of galactosemia. AB - A number of factors may lead to inaccuracy in measurement of capillary blood glucose with a glucometer. Measurement of other carbohydrate molecules such as galactose and fructose along with glucose can potentially be a cause of error. We report a newborn patient who was referred to our hospital with conjugated bilirubinemia, hepatomegaly and high capillary blood glucose levels measured with a glucometer. Simultaneous biochemical measurements revealed normal blood glucose levels. Further investigation led to a diagnosis of classical galactosemia. Capillary blood glucose level measured with glucometer also dropped to normal values following cessation of breastfeeding and initiation of feeding with a lactose-free formula. PMID- 25800484 TI - Intracardiac T-Wave Alternans and Ventricular Arrhythmia in Long-QT Syndrome. PMID- 25800485 TI - Causal pathways to hypoxic-ischaemic encephalopathy: detection, prevention and early intervention, 5-6 March 2013, London, UK. Foreword. PMID- 25800486 TI - Does aetiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy influence the outcome of treatment? AB - Neonatal encephalopathy, a clinical syndrome affecting term-born and late preterm newborn infants, increases the risk of perinatal death and long-term neurological morbidity, especially cerebral palsy. With the advent of therapeutic hypothermia, a treatment designed for hypoxic or ischaemic injury, associated mortality and morbidity rates have decreased. Unfortunately, only about one in eight neonates (95% confidence interval) who meet eligibility criteria for therapeutic cooling apparently benefit from the treatment. Studies of infants in representative populations indicate that neonatal encephalopathy is a potential result of a variety of antecedents and that asphyxial complications at birth account for only a small percentage of neonatal encephalopathy. In contrast, clinical case series suggest that a large proportion of neonatal encephalopathy is hypoxic or ischaemic, and trials of therapeutic hypothermia are specifically designed to include only infants exposed to hypoxia or ischaemia. This review addresses the differences, definitional and methodological, between infants studied and investigations undertaken, in population studies compared with cooling trials. It raises the question if there may be subgroups of infants with a clinical diagnosis of hypoxic-ischaemic encephalopathy (HIE) in whom the pathobiology of neonatal neurological depression is not fundamentally hypoxic or ischaemic and, therefore, for whom cooling may not be beneficial. In addition, it suggests approaches to future trials of cooling plus adjuvant therapy that may contribute to further improvement of care for these vulnerable neonates. PMID- 25800487 TI - Early predictors of outcome in infants treated with hypothermia for hypoxic ischaemic encephalopathy. AB - Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of acquired neonatal brain injury. Assessment of the severity of cerebral injury and likely neurological outcome in infants with HIE is important for determining management and prognosis, for counselling parents, and for selection for neuroprotective trials. The condition of the infant at birth, the severity of HIE, neurophysiological tests, including amplitude-integrated electroencephalography (aEEG), biochemical markers, and neuroimaging have been used to assess prognosis and predict long-term outcome. The predictive accuracy of these indicators in the early postnatal period is modest. Neurophysiological assessment seems to be most helpful during the first 24 to 48 hours after birth whilst magnetic resonance imaging (MRI) seems most informative later. Several biochemical markers, including serum S100beta and neuron-specific enolase (NSE), are also associated with HIE but their levels depend on the timing of sampling and their prognostic value is uncertain. Comprehensive neurophysiological assessment and neuroimaging may be limited to specialist centres. Therapeutic hypothermia is now standard care in infants with moderate to severe HIE so it is important to examine the influence of hypothermia on the assessment of prognosis in these infants. PMID- 25800489 TI - Hypoglycaemia and hypoxic-ischaemic encephalopathy. AB - The transition from fetal to neonatal life requires metabolic adaptation to ensure that energy supply to vital organs and systems is maintained after separation from the placental circulation. Under normal conditions, this is achieved through the mobilization and use of alternative cerebral fuels (fatty acids, ketone bodies, and lactate) when blood glucose concentration falls. Severe hypoxia-ischaemia is associated with impaired metabolic adaptation, and animal and human data suggest that levels of hypoglycaemia that are tolerated under normal conditions can be harmful in association with hypoxia-ischaemia. The optimal target blood glucose level for ensuring adequate energy provision in hypoxic-ischaemic encephalopathy (HIE) remains unknown. However, recent data support guidance to maintain a blood glucose concentration of 2.5 mmol/L or more in neonates with signs of acute neurological dysfunction, which includes those with HIE, and this is higher than the accepted threshold of 2 mmol/L in infants without signs of neurological dysfunction or hyperinsulinism. PMID- 25800488 TI - Inflammation-induced sensitization of the brain in term infants. AB - Perinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PMID- 25800490 TI - Erythropoietin: a novel therapy for hypoxic-ischaemic encephalopathy? AB - Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44-53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. In this article, we review the preclinical and clinical evidence for erythropoietin (EPO) as a potential novel neuroprotective agent for the treatment of HIE. EPO is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. There is currently insufficient evidence to support the use of high-dose EPO in newborns with HIE. However, several on-going trials will provide much needed data regarding the safety and efficacy of this potential new therapy when given in conjunction with hypothermia for HIE. Novel neuroprotective therapies are needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. High-dose EPO is a promising therapy that can be administered in conjunction with hypothermia. However, additional data are needed to determine the safety and efficacy of this adjuvant therapy for HIE. PMID- 25800491 TI - Neonatal seizures in hypoxic-ischaemic encephalopathy--risks and benefits of anticonvulsant therapy. AB - The risk of seizures is at its highest during the neonatal period, and the most common cause of neonatal seizures is hypoxic-ischaemic encephalopathy (HIE). This enhanced vulnerability is caused by an imbalance in the expression of receptors for excitatory and inhibitory neurotransmission, which is age dependent. There has been progress in detecting the electrophysiological abnormalities associated with seizures using amplitude-integrated electroencephalography (aEEG). Data from animal studies indicate a variety of risk factors for seizures, but there are limited clinical data looking at the long-term neurodevelopmental consequences of seizures alone. Neonatal seizures are also associated with increased risk of further epileptic seizures; however, it is less clear whether or not this results from an underlying pathology, and whether or not seizures confer additional risk. Phenobarbital and phenytoin are still the first-line antiepileptic drugs (AEDs) used to treat neonatal seizures, although they are effective in only one-third of affected infants. Furthermore, based on findings from animal studies, there are concerns regarding the risks associated with using these AEDs. Clinicians face a difficult challenge because, although seizures can be easily identified using aEEG, treatment options are limited, and there are uncertainties regarding treatment outcomes. There is a need to obtain long-term follow-up data, comparing groups of infants treated with or without current therapies. If these analyses indicate a definite benefit of treating neonatal seizures, then novel therapeutic approaches should be developed. PMID- 25800492 TI - High-density electroencephalography developmental neurophysiological trajectories. AB - Efforts to document early changes in the developing brain have resulted in the construction of increasingly accurate structural images based on magnetic resonance imaging (MRI) in newborn infants. Tractography diagrams obtained through diffusion tensor imaging have focused on white matter microstructure, with particular emphasis on neuronal connectivity at the level of fibre tract systems. Electroencephalography (EEG) provides a complementary approach with more direct access to brain electrical activity. Its temporal resolution is excellent, and its spatial resolution can be enhanced to physiologically relevant levels, through the combination of high-density recordings (e.g. by using 64 channels in newborn infants) and mathematical models (e.g. inverse modelling computation), to identify generators of different oscillation bands and synchrony patterns. The integration of functional and structural topography of the neonatal brain provides insights into typical brain organization, and the deviations seen in particular contexts, for example the effect of hypoxic-ischaemic insult in terms of damage, eventual reorganization, and functional changes. Endophenotypes can then be used for pathophysiological reasoning, management planning, and outcome measurements, and allow a longitudinal approach to individual developmental trajectories. PMID- 25800493 TI - The long-term health, social, and financial burden of hypoxic-ischaemic encephalopathy. AB - Infants who suffer hypoxic-ischaemic encephalopathy (HIE) at term are at risk of dying or developing severe cerebral palsy (CP). Children with severe CP often have other neurodevelopmental disabilities, which may affect their quality of life as much as the CP itself. New treatments for HIE, such as cooling, may improve motor outcomes, but affected infants may still have significant cognitive or communication problems. Infants who have experienced HIE and develop CP will require significant medical input throughout childhood and adult life. The costs of this medical input are high, but the indirect costs to the child, his or her family, and the relevant social services and education systems are many times greater. When demonstrating the cost-effectiveness of interventions aimed at preventing or treating HIE, these additional costs should be taken into account. PMID- 25800494 TI - A graphene field-effect transistor as a molecule-specific probe of DNA nucleobases. AB - Fast and reliable DNA sequencing is a long-standing target in biomedical research. Recent advances in graphene-based electrical sensors have demonstrated their unprecedented sensitivity to adsorbed molecules, which holds great promise for label-free DNA sequencing technology. To date, the proposed sequencing approaches rely on the ability of graphene electric devices to probe molecular specific interactions with a graphene surface. Here we experimentally demonstrate the use of graphene field-effect transistors (GFETs) as probes of the presence of a layer of individual DNA nucleobases adsorbed on the graphene surface. We show that GFETs are able to measure distinct coverage-dependent conductance signatures upon adsorption of the four different DNA nucleobases; a result that can be attributed to the formation of an interface dipole field. Comparison between experimental GFET results and synchrotron-based material analysis allowed prediction of the ultimate device sensitivity, and assessment of the feasibility of single nucleobase sensing with graphene. PMID- 25800495 TI - Spatial distribution of marine airborne bacterial communities. AB - The spatial distribution of bacterial populations in marine bioaerosol samples was investigated during a cruise from the North Sea to the Baltic Sea via Skagerrak and Kattegat. The analysis of the sampled bacterial communities with a pyrosequencing approach revealed that the most abundant phyla were represented by the Proteobacteria (49.3%), Bacteroidetes (22.9%), Actinobacteria (16.3%), and Firmicutes (8.3%). Cyanobacteria were assigned to 1.5% of all bacterial reads. A core of 37 bacterial OTUs made up more than 75% of all bacterial sequences. The most abundant OTU was Sphingomonas sp. which comprised 17% of all bacterial sequences. The most abundant bacterial genera were attributed to distinctly different areas of origin, suggesting highly heterogeneous sources for bioaerosols of marine and coastal environments. Furthermore, the bacterial community was clearly affected by two environmental parameters - temperature as a function of wind direction and the sampling location itself. However, a comparison of the wind directions during the sampling and calculated backward trajectories underlined the need for more detailed information on environmental parameters for bioaerosol investigations. The current findings support the assumption of a bacterial core community in the atmosphere. They may be emitted from strong aerosolizing sources, probably being mixed and dispersed over long distances. PMID- 25800496 TI - Comparison of two types of intervention to enhance placental redistribution in term infants: randomized control trial. AB - The objective of the study was to compare the effect of umbilical cord milking (UCM) and delayed cord clamping (DCC) on hematological parameters (serum ferritin and hemoglobin) at 6 weeks of life in term neonates. It was a randomized controlled trail conducted at a teaching hospital in North India during August 2012 to August 2013. Babies born at >36 weeks of gestation were randomized in two groups, UCM and DCC (100 in each group). Umbilical cord milking was done after cutting and clamping the cord at 25 cm from the umbilicus. In DCC group, clamping was delayed by 60 to 90 s before cutting the cord. The baseline characteristics were comparable in the two groups. Mean serum ferritin (134.0 ng/ml [89.8]) and mean hemoglobin (11.0 gm/dl [2.4]) in umbilical cord milking group was comparable to mean serum ferritin (142.7 ng/ml [87.1]) and hemoglobin (11.3 gm/dl [2.6]) in DCC group at 6 weeks of age. There was no difference in hemodynamic status, cranial Doppler indices, and adverse neonatal outcomes among the two groups. CONCLUSION: In term neonates, the DCC and UCM had comparable effect on hematological parameters at 6 weeks of life. WHAT IS KNOWN: * Delayed cord blood clamping improves certain hematologic parameters for neonates, which is potentially important in populations with high rates of neonatal and childhood anemia, but that delayed cord blood clamping may not be feasible in clinical situations when neonatal resuscitation is urgent. WHAT IS NEW: * There is no significant difference in ferritin and hemoglobin levels at 6 weeks among term, Indian neonates who had UCM and DCC and that this study may give support to the practice of UCM in term deliveries when DCC is not feasible. PMID- 25800498 TI - Kalil AC et al (Clin Infect Dis 2015; 60:216-22). PMID- 25800497 TI - The effects of maternal vitamin D on neonatal growth parameters. AB - Vitamin D facilitates calcium absorption and bone building. Presence of vitamin D is highly important in pregnant women due to its effect on the development of the fetal skeleton. The study population comprised 208 low-risk pregnant women of a heterogeneous population. Maternal and fetal serum concentrations of vitamin D were measured using the Liaison 25(OH)D Assay (DiaSorin, Italy). CONCLUSION: Maternal vitamin D serum concentrations correlate with neonatal vitamin D serum concentrations but do not affect neonatal weight and/or head circumference. WHAT IS KNOWN? * Vitamin D is known to be also involved in immunomodulation and cellular proliferation and differentiation. * Vitamin D is highly important in pregnant women for its effect on fetal musculoskeletal and neurological development. WHAT IS NEW? * No association was detected between maternal or neonatal vitamin D concentration with neonatal growth parameters or obstetrical complications, and no association was found between maternal vitamin D serum concentrations and maternal obstetrical complication rate. * A strong correlation was demonstrated between maternal and neonatal serum vitamin D concentrations. PMID- 25800499 TI - Severity of MIH findings at tooth surface level among German school children. AB - AIM: This study was to investigate the distribution and clinical characteristics of teeth diagnosed with MIH at surface and defect type level in a cohort of German children. METHODS: The study cohort included 242 children diagnosed with MIH which had been recorded during the compulsory dental school examinations of 20 German primary schools. The subjects had been enrolled by cluster sampling. All children attended the second to fourth grade (age 7-10 years, mean 8.1 +/- 0.8). The children were examined by five calibrated examiners (kappa = 0.9) after tooth brushing. The recording comprised teeth, surfaces, type and severity of MIH defects and was conducted using a portable light, mirrors and cotton rolls. MIH was registered according to the EAPD criteria. Defects <1 mm were not recorded. Statistical analysis included descriptive statistics and Spearman's correlation. RESULTS: Most affected teeth were first permanent molars (71.4 %) followed by the maxillary central incisors (15.6 %). The most common defects were demarcated opacities (82.2 %), while the remaining 17.8 % of the affected teeth exhibited severe enamel defects. The most frequently affected surface in molars was the occlusal surface (72.4 %); in incisors, it was the buccal surface (73.5 %). There were no atypical restorations in the affected incisors. Different types of MIH defects at various surfaces of the same tooth were common. The number of affected tooth surfaces was positively correlated with the severity of MIH at child (p < 0.001). CONCLUSIONS: The study demonstrates severe enamel defects involving in almost one-fifth of all MIH teeth. The knowledge of the intra-oral distribution and severity of MIH findings at the enamel surface level is important for assessing the treatment needs. PMID- 25800500 TI - First-time isolation of Candida dubliniensis from plaque and carious dentine of primary teeth. AB - AIM: To determine those organisms of the genus Candida associated with dental caries by investigating samples from active carious lesions. Within the genus Candida, the species Candida albicans and Candida dubliniensis are capable of forming chlamydospores and germ tubes. Until it became possible in 1995 to differentiate between the two species taxonomically, C. dubliniensis was falsely identified as C. albicans. Whilst the importance of C. albicans for rapidly progressing early childhood caries (ECC) has been recognised, so far there have been only reports about C. dubliniensis in connection with children/mothers who have been infected with HIV or already developed AIDS. In the present study, C. dubliniensis was for the first time isolated from plaque and carious dentine of a healthy five-year-old boy. METHODS: As part of the investigation, a number of samples were collected from individual children affected by active dental caries. Amongst the samples, one in particular indicated that Candida species might be involved. The patient was a five-year-old boy with ECC of the primary dentition, scheduled for restorative treatment under general anaesthesia. Before treatment, a salivary, plaque (region of 54/55) and soft carious dentine sample from the tooth 51 was taken before extraction. The counts of yeasts, lactobacilli (LB) and mutans streptococci were determined in the samples. RESULTS: The boy's dmft was 11, which was dominated by the d component. In the saliva of the boy, LB and mutans streptococci (MS) were detected. In plaque and carious dentine, MS and most interestingly C. dubliniensis were present. The yeasts were visualised in carious dentine by means of scanning electron micrographs. CONCLUSIONS: Plaque and carious dentine may be a further habitat of C. dubliniensis. PMID- 25800501 TI - A study of pH-dependence of shrink and stretch of tetrahedral DNA nanostructures. AB - We monitored the shrink and stretch of the tetrahedral DNA nanostructure (TDN) and the i-motif connected TDN structure at pH 8.5 and pH 4.5, and we found that not only the i-motif can change its structure when the pH changes, but also the TDN and the DNA double helix change their structures when the pH changes. PMID- 25800502 TI - Recovery of deambulation after cardiothoracic surgery: a single center experience. AB - BACKGROUND: Surgical procedure and postoperative bed rest lead to musculoskeletal system alterations with a possibility of new walking dependence of patients who undergo cardiothoracic surgery, which is sometimes associated with prolonged hospitalization and increased health expenditure. AIM: The aim of this study was to assess the postoperative motor disability in inpatients admitted to the cardiothoracic surgical ward, and the results of customized rehabilitation in terms of recovery of postural changes and walking capacity with respect to the preoperative condition and destination after discharge. DESIGN: A prospective observational study was conducted. SETTING AND POPULATION: Four hundred seventeen inpatients, who had undergone cardiothoracic surgery, were enrolled between March 2011 and January 2012 in a Hospital Unit of Cardiothoracic Surgery. METHODS: A computerized system was used to collect data about ambulation at home, type and number of rehabilitation sessions proposed, ambulation at discharge, destination after discharge from ward of origin. All patients, who give their consent, undergone rehabilitative treatment on the ward of origin with an expert physiotherapist. RESULTS: Three hundred seventy-five inpatients were examined in Cardiac Surgery. One patient (0.26%) refused rehabilitative treatment. Two patients (0.53%) died. At the time of discharge 236 (74.45%) patients had recovered the ability to walk independently. After discharge 87.64% of patients was transferred to a specialist ward for intensive rehabilitation. Forty-two inpatients were enrolled in thoracic surgery. Two patients died whilst in hospital. At the time of discharge, 36 patients (94.73%) were able to walk independently. After discharge 80% of patients returned home. CONCLUSION: In our study, the application of an early and simple rehabilitation program on the ward of origin after surgery has made possible the recovery of ambulation of most inpatients who referred independence at home in a few days, limiting hospitalization and health expenditure. CLINICAL REHABILITATION IMPACT: Data about recovery of ambulation with respect to the preoperative condition and destination after discharge resume the importance of identifying motor impairment after surgery, in order to apply an adequate, early and feasible rehabilitation protocol to inpatients, limiting hospitalization and health expenditure. PMID- 25800504 TI - Serotype transition in invasive pneumococcal infection in postvaccine era. PMID- 25800503 TI - A limited positioning system for memory. AB - The 2014 Nobel Prize for Physiology or Medicine is an enormous triumph for John O'Keefe and May-Britt and Edvard Moser and an historic event for cognitive and behavioral neuroscience. Neuronal representations decoded from action potentials form a mechanistic bridge between brain and mind and demonstrate the continuity of psychology with biology and physical science. The cognitive map theory powered an ongoing, international research program inspired by Hebb (The Organization of Behavior. New York, NY: Wiley) that showed the way toward linking specific patterns of neuronal activity to high level representation and processing. The prize celebrates a path that led from fundamental, philosophical questions about psychological space to enduring, scientific facts: place, head direction, grid, and boundary fields in the hippocampus, presubiculum, entorhinal cortex, and other brain circuits provide a cellular basis for spatial behavior, learning, and memory. By awarding this prize, the Nobel committee affirmed neuroethology and comparative psychology, marked the end of a chapter in one debate about the existence of animal cognition, and recognized cognitive neurophysiology. The "inner GPS" in the brain" demonstrates "a cellular basis for higher cognitive function." Animals represent, process, and use information defined by abstract relationships among items (O'Keefe and Conway,) to guide flexible, goal-directed actions. Beyond raising the ontological status of "animal mind," the committee agreed that abstract mental representations can be investigated rigorously by recording single unit activity in the brain of behaving animals. PMID- 25800505 TI - Vertical transmission of dengue fever: First case reported in Taiwan. PMID- 25800506 TI - Three distinct fiber pathways of the bed nucleus of the stria terminalis to the amygdala and prefrontal cortex. AB - The bed nucleus of the stria terminalis (BNST) is an important relay for multiple cortical and subcortical regions involved in processing anxiety as well as neuroendocrine and autonomic responses to stress, and it is thought to play a role in the dysregulation of these functions as well as in addictive behavior. While its architecture and connection profile have been thoroughly examined in animals, studies in humans have been limited to post-mortem histological descriptions of the BNST itself, not accounting for the distribution of its various connections. In the current study, we used diffusion-weighted magnetic resonance imaging (DW-MRI) to investigate the courses of fiber tracks connected to the BNST in humans. We restricted our seed region for probabilistic fiber tracking to the dorsal part of the BNST, as the ventral BNST is not distinguishable from the surrounding grey matter structures using magnetic resonance imaging. Our results show two distinct pathways of the BNST to the amygdala via the stria terminalis and the ansa peduncularis, as well as connections to the hypothalamus. Finally, we distinguished a route to the orbitofrontal cortex (OFC) running through the head of the caudate nucleus (CN) and the nucleus accumbens (NAcc). Pathways to brainstem regions were found to show a considerable inter-individual variability and thus no common pathway could be identified across participants. In summary, our findings reveal a complex network of brain structures involved in behavioral and neuroendocrine regulation, with the BNST in a central position. PMID- 25800507 TI - Category search speeds up face-selective fMRI responses in a non-hierarchical cortical face network. AB - The human brain is extremely efficient at detecting faces in complex visual scenes, but the spatio-temporal dynamics of this remarkable ability, and how it is influenced by category-search, remain largely unknown. In the present study, human subjects were shown gradually-emerging images of faces or cars in visual scenes, while neural activity was recorded using functional magnetic resonance imaging (fMRI). Category search was manipulated by the instruction to indicate the presence of either a face or a car, in different blocks, as soon as an exemplar of the target category was detected in the visual scene. The category selectivity of most face-selective areas was enhanced when participants were instructed to report the presence of faces in gradually decreasing noise stimuli. Conversely, the same regions showed much less selectivity when participants were instructed instead to detect cars. When "face" was the target category, the fusiform face area (FFA) showed consistently earlier differentiation of face versus car stimuli than did the "occipital face area" (OFA). When "car" was the target category, only the FFA showed differentiation of face versus car stimuli. These observations provide further challenges for hierarchical models of cortical face processing and show that during gradual revealing of information, selective category-search may decrease the required amount of information, enhancing and speeding up category-selective responses in the human brain. PMID- 25800509 TI - Modulation of immunological responses and amelioration of collagen-induced arthritis by the novel roxithromycin derivative 5-I. AB - OBJECTIVE: Macrolide antibiotics have immunomodulatory properties that are distinct from their antibacterial functions. We synthesized 5-I, which is a new derivative of RXM with less antimicrobial activity, and evaluated its immunomodulatory effects through both in vitro and in vivo studies. METHODS: Proliferative response, cytokine production, and expression of mRNA of T cells stimulated with anti-CD3 and anti-CD28 mAbs in the presence or absence of monocytes, cytokine production of monocytes stimulated with lipopolysaccharide, and transendothelial migration of T cells in various concentrations of 5-I were analyzed. The effect of 5-I treatment was also evaluated in a mouse model of collagen-induced arthritis. RESULTS: 5-I specifically inhibited production of Th1, Th17, and proinflammatory cytokines such as IL-2, IFN-gamma, TNF-alpha, IL 6, and IL-17A. 5-I reduced the expression of RORC on CD4(+) T cells, which codes for RORgammat, the master regulator of Th17, and it also inhibited migration of activated T cells. Importantly, administration of 5-I to mice with collagen induced arthritis reduced the severity of arthritis, and this effect was also observed when treatment was delayed till after the onset of disease. CONCLUSION: Our findings strongly suggest that 5-I may be useful as a potential therapeutic agent for human rheumatoid arthritis. PMID- 25800510 TI - Bisphosphonates in juvenile dermatomyositis with dystrophic calcinosis. AB - OBJECTIVES: Our primary objective was to retrospectively analyze whether bisphosphonates initiated in combination with immunosuppressive drugs and/or intravenous immunoglobulin (IVIG) resulted in a radiological and clinical improvement of dystrophic calcinosis in six female juvenile dermatomyositis (JDM) patients. METHODS: Medical records of the patients were reviewed. All six patients met the Bohan and Peter diagnostic criteria for JDM. RESULTS: A resolution of calcinosis was observed in four of the six patients with JDM following the use of bisphosphonates and intensive immunosuppressive therapy with or without IVIG. Bisphosphonates were unable to either decelerate the progression of calcinosis or improve calcinosis in cases 5 and 6. In case 5, it took a relatively long time to control the disease activity despite the appropriate immunsuppressive treatment and she experienced multiple flares of active JDM. Case 6 had a long duration of severe active disease before treatment initiation. No important adverse event was observed. CONCLUSIONS: Early commencement of aggressive immunosuppressive agents in combination with bisphosphonate is a choice for the treatment of calcinosis in JDM patients. Concomitant use of IVIG may have an additional effect on the resolution of calcinosis. PMID- 25800511 TI - The activation of the Nrf2/ARE pathway in HepG2 hepatoma cells by phytochemicals and subsequent modulation of phase II and antioxidant enzyme expression. AB - Previous studies have shown that naturally occurring phytochemicals, indole-3 carbinol, phenethyl isothiocyanate, protocatechuic acid, and tannic acid increased the activity and protein level of hepatic phase II enzymes in animal models. In order to further explore the mechanism of this activity, we investigated the effect of these compounds on the activation of nuclear factor erythroid-2-related factor 2 (Nrf2)-regulated transcription in human hepatocellular carcinoma HepG2 cells. Treatment with all the tested compounds resulted in the translocation from the cytosol and nuclear accumulation of active phosphorylated Nrf2. Furthermore, phenethyl isothiocyanate and indole-3-carbinol increased the transcript and protein levels of GSTA, GSTP, GSTM, GSTT, and NQO1. On the other hand, protocatechuic and tannic acids enhanced only the expression of GSTA, GSTM, and GSTT. The expression of genes encoding antioxidant enzymes CAT, SOD, GR, and GPx was increased after the treatment with all the tested phytochemicals. These results indicate that isothiocyanates/indoles and protocatechuic and tannic acids induce phase II and antioxidant gene expression in HepG2 cells through the Nrf2-Keap1-ARE signaling pathway. Moreover, the results of this study confirmed that the degradation products of glucosinolates are more effective inducers of phase II and antioxidant enzymes than protocatechuic and tannic acids. PMID- 25800512 TI - Study of the in vitro metabolism of TJ0711 using ultra high performance liquid chromatography with quadrupole time-of-flight and ultra fast liquid chromatography with quadrupole linear ion trap mass spectrometry. AB - TJ0711 (1-[4-(2-methoxyethyl)phenoxy]-3-[2-(2-methoxyphenoxy)ethylamino]-2 propanol) is a novel beta-adrenoreceptor blocker with vasodilating activity. The aim of this study was to investigate the in vitro metabolic properties of TJ0711 from both qualitative and quantitative aspects using mouse, rat, dog, and human liver microsomes as well as rat hepatocytes. Two modern liquid chromatography with tandem mass spectrometry systems, ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and ultra fast liquid chromatography with quadrupole linear ion trap mass spectrometry, were utilized for the analysis. To better characterize the metabolic pathways of TJ0711, two major metabolites were incubated under the same conditions as that for TJ0711. TJ0711 was extensively metabolized in vitro, and a total of 34 metabolites, including 19 phase I and 15 phase II metabolites, were identified. Similar metabolite profiles were observed among species, and demethylation, hydroxylation, carboxylic acid formation, and glucuronidation were proposed as the major metabolic routes. Significant interspecies differences were observed in the metabolic stability studies of TJ0711. Furthermore, gender differences were significant in mice, rats, and dogs, but were negligible in humans. The valuable information provided in this work will be useful in planning and interpreting further pharmacokinetic, in vivo metabolism and toxicological studies of this novel beta-blocker. PMID- 25800513 TI - Assessing the toxicity and biodegradability of deep eutectic solvents. AB - Deep eutectic solvents (DESs) have emerged as a new type of promising ionic solvents with a broad range of potential applications. Although their ecotoxicological profile is still poorly known, DESs are generally regarded as "green" because they are composed of ammonium salts and H-bond donors (HBDs) which are considered to be eco-friendly. In this work, cholinium-based DESs comprised of choline chloride (ChCl) and choline acetate (ChAc) as the salt and urea (U), acetamide (A), glycerol (G) and ethylene glycol (EG) as the HBD were evaluated for their toxic effects on different living organisms such as Escherichia coli (a bacterium), Allium sativum (garlic, a plant) and hydra (an invertebrate), and their biodegradabilities were assessed by means of closed bottle tests. These DESs possessed an anti-bacterial property and exhibited inhibitory effects on the test organisms adopted, depending on the composition and concentration of the DES. The mechanism for the impact of DESs and their components on different living organisms can be associated to their interactions with the cellular membranes. Not all DESs can be considered readily biodegradable. By extending the limited knowledge about the toxicity and biodegradation of this particular solvent family, this investigation on DESs provides insight into our structure-based understanding of their ecotoxicological behavior. PMID- 25800514 TI - Synthesis, biological evaluation and modeling studies of terphenyl topoisomerase IIalpha inhibitors as anticancer agents. AB - We report the synthesis and evaluation of a series of novel terphenyls. Compound 17 had the most potent anticancer activity, indicating that the phenolic hydroxyl was a key group. A DNA relaxation test showed that compound 17 had a strong inhibitory effect on TOP2alpha, but not on TOP1, which was consistent with the docking analysis results. We performed a 3D-QSAR study using CoMFA and CoMSIA to determine, for the first time, the chemical-biological relationship in the inhibition of TOP by terphenyls. The CoMFA and CoMSIA model had good modeling statistics: leave-one-out q(2) of 0.605 and 0.622, r(2) of 0.998 and 0.994, and r(2)pred (test set) of 0.742 and 0.660. These results suggest that the ortho phenolic hydroxyl on ring A is important for producing terphenyls with more efficacious activity. PMID- 25800515 TI - Fluid percussion injury device for the precise control of injury parameters. AB - BACKGROUND: Injury to the brain can occur from a variety of physical insults and the degree of disability can greatly vary from person to person. It is likely that injury outcome is related to the biomechanical parameters of the traumatic event such as magnitude, direction and speed of the forces acting on the head. NEW METHOD: To model variations in the biomechanical injury parameters, a voice coil driven fluid percussion injury (FPI) system was designed and built to generate fluid percussion waveforms with adjustable rise times, peak pressures, and durations. Using this system, pathophysiological outcomes in the rat were investigated and compared to animals injured with the same biomechanical parameters using the pendulum based FPI system. RESULTS IN COMPARISON WITH EXISTING METHODS: Immediate post-injury behavior shows similar rates of seizures and mortality in adolescent rats and similar righting times, toe pinch responses and mortality rates in adult rats. Interestingly, post injury mortality in adult rats was sensitive to changes in injury rate. Fluoro-Jade labeling of degenerating neurons in the hilus and CA2-3 hippocampus were consistent between injuries produced with the voice coil and pendulum operated systems. Granule cell population spike amplitude to afferent activation, a measure of dentate network excitability, also showed consistent enhancement 1 week after injury using either system. CONCLUSIONS: Overall our results suggest that this new FPI device produces injury outcomes consistent with the commonly used pendulum FPI system and has the added capability to investigate pathophysiology associated with varying rates and durations of injury. PMID- 25800516 TI - Characterization of a Synechocystis sp. PCC 6803 double mutant lacking the CyanoP and Ycf48 proteins of Photosystem II. AB - Homologs of the Photosystem II (PS II) subunit PsbP are found in plants, algae, and cyanobacteria. In higher plants, PsbP is associated with mature PS II centers, but in cyanobacteria, the homologous CyanoP protein appears sub stoichiometric to PS II. We have investigated the role of CyanoP by characterizing knockout mutants of the cyanobacterium Synechocystis sp. PCC 6803. Removal of CyanoP resulted in changes to phycobilisome coupling and energy transfer to PS II, but the function of PS II itself remained similar to wild type. We therefore investigated the hypothesis that CyanoP is involved in the biogenesis or repair of PS II by creating a double mutant lacking both CyanoP and the PS II assembly factor Ycf48. This strain exhibited an additive reduction in the amplitude of variable chlorophyll a fluorescence induction relative to either of the single mutants but displayed increased oxygen evolution, slight increases in PS II monomer and dimer levels, and a reduction in accumulation of an early PS II assembly complex containing CP47, compared to the DeltaYcf48 strain. PMID- 25800517 TI - Multiple copies of the PsbQ protein in a cyanobacterial photosystem II assembly intermediate complex. AB - Photosystem II (PSII) undergoes frequent damage owing to the demanding electron transfer chemistry it performs. To sustain photosynthetic activity, damaged PSII undergoes a complex repair cycle consisting of many transient intermediate complexes. By purifying PSII from the cyanobacterium Synechocystis sp. PCC 6803 using a histidine-tag on the PsbQ protein, a lumenal extrinsic subunit, a novel PSII assembly intermediate was isolated in addition to the mature PSII complex. This new complex, which we refer to as PSII-Q4, contained four copies of the PsbQ protein per PSII monomer, instead of the expected one copy. In addition, PSII-Q4 lacked two other lumenal extrinsic proteins, PsbU and PsbV, which are present in the mature PSII complex. We suggest that PSII-Q4 is a late PSII assembly intermediate that is formed just before the binding of PsbU and PsbV, and we incorporate these results into an updated model of PSII assembly. PMID- 25800519 TI - Wrinkling over finger tip. PMID- 25800518 TI - Features of temporal behavior of fluorescence recovery in Synechocystis sp. PCC6803. AB - Under high photon flux density of solar radiation, the photosynthetic apparatus can be damaged. To prevent this photodestruction, cyanobacteria developed special mechanisms of non-photochemical quenching (NPQ) of excitation energy in phycobilisomes. In Synechocystis, NPQ is triggered by the orange carotenoid protein (OCP), which is sensitive to blue-green illumination allowing it to bind to the phycobilisome reducing the flow of energy to the photosystems. Consequent decoupling of OCP and recovery of phycobilisome fluorescence in vivo is controlled by the so called fluorescence recovery protein (FRP). In this work, the role of the phycobilisome core components, apcD and apcF, in non photochemical quenching and subsequent fluorescence recovery in the phycobilisomes of the cyanobacterium Synechocystis sp. PCC6803 has been investigated. Using a single photon counting technique, we have registered fluorescence decay spectra with picosecond time resolution during fluorescence recovery. In order to estimate the activation energy for the photocycle, spectroscopic studies in dependency on the temperature from 5 to 45 degrees C have been performed. It was found that fluorescence quenching and recovery were strongly temperature dependent for all strains exhibiting characteristic non linear time courses. The rise of the fluorescence intensity during fluorescence recovery after NPQ can be completely described by the increase of the phycobilisome core fluorescence lifetime. It was shown that fluorescence recovery of apcD- and apcF-deficient mutants is characterized by a significantly lower activation energy barrier compared to wild type. This phenomenon indicates that apcD and apcF gene products may be required for proper interaction of FRP and OCP coupled to the phycobilisome core. In addition, we found that the rate of fluorescence recovery decreases with an increase of the non-photochemical quenching amplitude, probably due to depletion of substrate for the enzymatic reaction catalyzed by FRP. PMID- 25800520 TI - Feasibility and efficacy of primary tractography during percutaneous catheter drainage. AB - BACKGROUND: The indication of percutaneous catheter drainage (PCD) has expanded with the development of guiding modalities. Since serious complications still occur, efforts and new techniques have been continuously searched for safer PCD. PURPOSE: To evaluate the feasibility and efficacy of primary tractography for establishing a safe needle pathway during PCD. MATERIAL AND METHODS: A total of 42 patients (20 men, 22 women; mean age, 50.7 years) who underwent primary tractography during PCD were prospectively enrolled between April 2009 and August 2013. The locations of fluid collection included sub-phrenic (n = 8), between bowel loops (n = 21), pelvic cavity (n = 8), within solid organ (n = 2), and others (n = 3). The interposed anatomic structures were analyzed on the basis of primary tractography findings. Complications related to PCD or primary tractography were evaluated. RESULTS: Interposition of any significant anatomic structure was confirmed in 10 of 42 patients (23.8%). The entrapped anatomic structures were the omental vessel (n = 4), bowel (n = 2), pleura (n = 2), bile duct (n = 2), and a branch of the left inferior epigastric artery (n = 1). In one patient, both the pleura and bile duct were interposed simultaneously. The technical and clinical success rates of PCD were 97.6% and 97.6%, respectively. No complications related to PCD or primary tractography occurred during the follow-up period. CONCLUSION: Primary tractography is a simple and feasible method to evaluate the entrapment of normal anatomic structure during PCD. This method may aid in preventing possible serious PCD-related complications, such as bleeding and fistula. PMID- 25800521 TI - Small telescopes: detectability and the evaluation of replication results. AB - This article introduces a new approach for evaluating replication results. It combines effect-size estimation with hypothesis testing, assessing the extent to which the replication results are consistent with an effect size big enough to have been detectable in the original study. The approach is demonstrated by examining replications of three well-known findings. Its benefits include the following: (a) differentiating "unsuccessful" replication attempts (i.e., studies yielding p > .05) that are too noisy from those that actively indicate the effect is undetectably different from zero, (b) "protecting" true findings from underpowered replications, and (c) arriving at intuitively compelling inferences in general and for the revisited replications in particular. PMID- 25800522 TI - Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study. AB - OBJECTIVE: To estimate the accuracy of transvaginal ultrasound (TVS) measurement of endometrial thickness (ET) in diagnosing endometrial cancer in postmenopausal women with vaginal bleeding (PMB). DESIGN: Retrospective cohort study. SETTING: One-stop PMB clinic in a Hong Kong teaching hospital. POPULATION: A cohort of 4383 women with PMB. METHODS: Transvaginal ultrasonic measurement of ET and endometrial biopsies were obtained in women presenting with PMB between 2002 and 2013. Endometrial histology was used as the reference standard to calculate accuracy estimates. MAIN OUTCOME MEASURES: Accuracy data for TVS ET presented as sensitivity, specificity, and area under the receiver operator characteristic (ROC) curve. RESULTS: Endometrial cancer was diagnosed in 3.8% of women. The median ET in those with endometrial cancer was significantly higher than those with benign conditions (15.7 versus 3.2 mm, P < 0.001). The area under the ROC curve was 0.92 (95% CI 0.89-0.94). The sensitivity for the detection of endometrial cancer at 3-, 4-, and 5-mm cut-offs were 97.0% (95% CI 94.5-99.6%), 94.1% (95% CI 90.5-97.6%), and 93.5% (95% CI 89.7-97.2%), respectively. The corresponding estimates of specificity at these thresholds were 45.3% (95% CI 43.8-46.8%), 66.8% (65.4-68.2%), and 74.0% (72.7-75.4%). CONCLUSIONS: Transvaginal ultrasound using a 3-mm cut-off has high sensitivity for detecting endometrial cancer and can identify women with PMB who are highly unlikely to have endometrial cancer, thereby avoiding more invasive endometrial biopsy. PMID- 25800524 TI - Emergency Evaluation for Pulmonary Embolism, Part 2: Diagnostic Approach. AB - BACKGROUND: In part 1 of this two-part review, we discussed which risk factors, historical features, and physical findings increase risk for pulmonary embolism (PE) in symptomatic emergency department (ED) patients. OBJECTIVES: Use published evidence to describe criteria that a reasonable and prudent clinician can use to initiate and guide the process of excluding and diagnosing PE. DISCUSSION: The careful and diligent emergency physician can use clinical criteria to safely obviate a formal evaluation of PE, including the use of gestalt reasoning and the pulmonary embolism rule-out criteria (PERC rule, Table 2, part 1). We present published clinical and radiographic features of patients with PE who eluded diagnosis in the ED. D-dimer can be used to exclude PE in many patients, and employing age-based adjustments to the threshold to define an abnormal value can further reduce patient exposure to pulmonary vascular imaging. Moreover, we discuss benefits, limitations, and potential harms of computed tomographic pulmonary vascular imaging relevant to patients and the practice of emergency care. We present algorithms to guide exclusion and diagnosis of PE in patients with suspected PE, including those who are pregnant. CONCLUSIONS: Reasonable and prudent emergency clinicians can exclude PE in symptomatic ED patients on clinical grounds alone in many patients, and many more can have PE ruled out by use of the D-dimer. PMID- 25800523 TI - Validation of an online questionnaire for identifying people at risk of familial and hereditary colorectal cancer. AB - We developed and validated an online questionnaire to document familial cancer history, in order to facilitate the detection of persons with a familial or hereditary colorectal cancer (CRC) risk. The development of the self-administered online questionnaire for the assessment of familial and hereditary CRC risk was based on nationwide criteria for referral to genetic specialists due to a Lynch syndrome suspicion, as well as existing criteria for surveillance colonoscopies because of an increased risk of familial CRC. The questionnaire was validated at a private colonoscopy center. Patients scheduled for colonoscopy were enrolled (n = 150). Performance of the questionnaire was assessed by comparing referrals based on questionnaire data against referral decisions based on full pedigree data. In a second validation phase, referrals based on questionnaire data were compared with referrals based on data collected in a telephone interview. We also calculated inter-observer agreement in referral decisions. In the first validation phase, the questionnaire had a sensitivity of 90% (95% CI 55-98%) at a specificity of 98% (95% CI 87-100%) in identifying persons qualifying for referral. In the second validation phase, sensitivity was 100% (95% CI 63-100) at a specificity of 97% (95% CI 91-99%). In both validation phases an inter-observer agreement of 100% in referral decisions was achieved. The online questionnaire has a high sensitivity and specificity in identifying persons qualifying for referral because of suspected Lynch syndrome or familial CRC. Implementation of this tool in colonoscopy clinics can facilitate the detection of patients with hereditary or familial CRC. PMID- 25800526 TI - Adirondack Park incidents: a retrospective review of search and rescue reports from 2008 and 2009. AB - BACKGROUND: The Adirondack Park is a 6 million acre recreational area in northeastern New York used for activities such as hiking, camping, canoeing, hunting, fishing, snowmobiling, skiing, and rock climbing. Given the large number of people who use the Adirondacks for recreation, there exists the potential for many accidents, injuries, and illnesses to occur in areas ranging from state operated campgrounds to remote backcountry. OBJECTIVE: The aim of this study was to gain insight into the demographics of search and rescue (SAR) operations in the Adirondack Park. METHODS: This study is a retrospective review of the Adirondack Park Forest Ranger SAR reports from January 1, 2008, through December 31, 2009. Epidemiologic data were gathered from the NY State Department of Environmental Conservation for each report, including victim demographics, incident, reason for injury, medical care needed, preparation of victim, and prior medical conditions. RESULTS: In all, 239 SAR missions were carried out involving at least 349 victims. Of all cases, 28% (66) involved an injured victim, and 9% (21) involved illness; 56% (10) of the victims had a known prior illness or medical condition; and 21% (27) of cases were due to victims exceeding their abilities. Of the search missions, 54% of victims (93) had little experience with the activity, and 9% (15) had no experience. Only 43% (62) of victims had any form of orientation equipment. CONCLUSIONS: This study portrays the initial demographics of SAR efforts in Adirondack Park. It will aid in educating people on preparing for wilderness activities, as well as tailoring SAR resources to the demographics of injury and illness within the park. PMID- 25800525 TI - Crush syndrome: a case report and review of the literature. PMID- 25800527 TI - Possible Correlation Between Bile Salt Hydrolysis and AHL Deamidation: Staphylococcus epidermidis RM1, a Potent Quorum Quencher and Bile Salt Hydrolase Producer. AB - The aim of the present work was to isolate a bile salt hydrolase (BSH) producer from fermented soy curd and explore the ability of the BSH produced to cleave bacterial quorum sensing signals. Bacterial isolates with possible ability to deconjugate bile salts were enriched and isolated on De Man, Rogosa and Sharpe (MRS) medium containing 0.2% bile salts. BSH-producing positive isolate with orange-pink-pigmented colonies was isolated and was identified as a strain of Staphylococcus epidermidis using biochemical and phylogenetic tools. S. epidermidis RM1 was shown to possess both potent BSH and N-acyl homoserine lactone (AHL) cleavage activity. Genetic basis of this dual-enzyme activity was explored by means of specific primers designed using S. epidermidis ATCC 12228 genome as template. It was observed that a single enzyme was not responsible for both the activity. Two different genetic elements corresponding to each of the enzymatic activity were successfully amplified from the genomic DNA of the isolate. PMID- 25800528 TI - Production and Characterization of Melanin by Submerged Culture of Culinary and Medicinal Fungi Auricularia auricula. AB - Natural melanin is of great potential value and application in the fields of pharmacology, cosmetics, and functional foods. In the present study, statistically designed experiments were conducted for the optimization of the media to enhance the production of melanin by submerged culture of Auricularia auricula. Glucose, tyrosine, peptone, and CaCO3 were found to have significant effects (P < 0.015) on melanin biosynthesis by a Plackett-Burman experimental design and subsequently optimized using response surface methodology. Optimal media were obtained at the following concentrations: glucose, 0.90 g/L; tyrosine, 6.68 g/L; peptone, 6.99 g/L; and CaCO3, 6.75 g/L. The validity of the optimum media was verified in separate experiments in which the melanin yield of 1008.08 mg/L was obtained under optimum conditions, compared with 306.52 mg/L at other conditions, i.e., a 3.29-fold increase. Furthermore, the important physical and chemical properties of A. auricula melanin were determined. The findings from the present study indicate that large-scale production of natural melanin by submerged culture of A. auricular could be a useful approach. PMID- 25800529 TI - High Performance Protein-Coated Microcrystals of Rhizomucor miehei Lipase: Preparation and Application for Organic Synthesis. AB - The goal of obtaining enzyme forms with higher catalytic activity, greater stability, and improved reusability has been pursued for the last few decades. Various novel biocatalyst designs have been created, and protein-coated microcrystals (PCMCs) are one of them. PCMC is an enzyme immobilization method based on simultaneous precipitation of protein and carrier, forming micron-sized enzyme-coated crystals. Highly active Rhizomucor miehei lipase (RML) PCMCs were prepared by immobilizing the protein onto K2SO4 as a carrier salt in acetone as a precipitating solvent. The formation of RML PCMCs was confirmed by scanning electron microscopy. Preparation of RML PCMCs was optimized by response surface methodology (RSM). Obtained PCMCs were found to be more active and stable during p-nitrophenyl palmitate hydrolysis in n-hexane, compared to liquid RML. The enzymatic activity and temperature optimum increased from 0.011 U/mg(soluble) lipase to 8.70 U/mg(immobilized) lipase and from 30 to 37 degrees C, respectively. Additionally, the ability of RML PCMCs to catalyze flavor ester 2 phenethyl octanoate synthesis was investigated. Some reaction parameters were optimized, resulting in 80 % conversion within 1 h with an enhanced reusability, compared to commercial immobilized RML preparation. Thus, PCMCs offer a cheap and effective technology for obtaining highly active lipase preparations for biocatalysis in organic media. PMID- 25800530 TI - Development of a regulatory testing procedure to study the metabolism of pesticides in farmed fish. AB - BACKGROUND: Diets used in commercial fish farming use significant proportions of crop-derived commodities, and it is important to understand the potential for transfer of any pesticide residues on the crop into edible tissues in fish. It is a current requirement in the EU that fish metabolism studies must be performed when a pesticide is used in crops where commodities or processed fractions are fed to farmed fish. Fish metabolism studies in both rainbow trout and common carp have been carried out, following the new working document on the nature of pesticide residues in fish using (14) C-labelled pesticide. RESULTS: The ingestion of experimental diets by rainbow trout and common carp resulted in the uptake and metabolism of the test item, as shown by liquid scintillation counting combined with radio-thin-layer chromatography. The metabolite profiles for trout and carp were qualitatively similar regarding the main residue. However, species specific differences were found regarding the remaining residue with rainbow trout showing additional metabolites in comparison to carp. CONCLUSIONS: Metabolism studies for regulatory purposes can be carried out with both fish species under laboratory conditions. The experimental design reported is suitable for quantifying the transfer of residues to edible tissues and enables characterisation of the chemical nature of residues. PMID- 25800531 TI - Research on psychotherapy integration: building on the past, looking to the future. AB - Integration has become an important and influential movement within psychotherapy practice, reflected by the fact that many treatment providers now identify as integrative. However, integration has not had as great an influence on psychotherapy research. The goal of this paper is to highlight the growing body of research on psychotherapy integration, and to identify future directions for research that may strengthen the integration movement as well as the field of psychotherapy as a whole. We first summarize the past 25 years of research on integration, with a focus on four approaches to integration: theoretical integration, technical eclectic, common factors, and assimilative integration. Next, we identify directions of research within these four areas that could strengthen and support integrative practice. We then propose ways in which the perspective of integrationists could contribute to psychotherapy research in the critical areas of harmful effects, therapist effects, practice-oriented research, and training. We end this paper by suggesting that a greater collaboration between integrationists and psychotherapy researchers will help to create a unified landscape of knowledge and action that will benefit all participants and advance the field. PMID- 25800532 TI - First World War nursing: new perspectives. PMID- 25800533 TI - Study on the selection of laser wavelengths in the intravascular low-level laser irradiation therapy. AB - According to the absorption spectra of blood and hemoglobin, a photon-bond energy formula is established using physical methods and the effects on hemoglobin of low-level laser at different wavelengths are analyzed. The results show that lasers with the peak wavelengths of 200~240, 275, and 342 nm in the whole blood absorption spectra curve are easy to destroy protein molecules and then lead to hemoglobin lose biological activity. While lasers with wavelengths longer than 800 nm will reduce the oxygen carrying capacity of blood, only lasers with wavelengths between 630 and 670 nm have the best efficacy. PMID- 25800534 TI - The effectiveness of low-level diode laser therapy on orthodontic pain management: a systematic review and meta-analysis. AB - To assess the effectiveness of diode low-level laser therapy (LLLT) for orthodontic pain control, a systematic and extensive electronic search for randomised controlled trials (RCTs) investigating the effects of diode LLLT on orthodontic pain prior to November 2014 was performed using the Cochrane Library (Issue 9, 2014), PubMed (1997), EMBASE (1947) and Web of Science (1956). The Cochrane tool for risk of bias evaluation was used to assess the bias risk in the chosen data. A meta-analysis was conducted using RevMan 5.3. Of the 186 results, 14 RCTs, with a total of 659 participants from 11 countries, were included. Except for three studies assessed as having a 'moderate risk of bias', the RCTs were rated as having a 'high risk of bias'. The methodological weaknesses were mainly due to 'blinding' and 'allocation concealment'. The meta-analysis showed that diode LLLT significantly reduced orthodontic pain by 39 % in comparison with placebo groups (P = 0.02). Diode LLLT was shown to significantly reduce the maximum pain intensity among parallel-design studies (P = 0.003 versus placebo groups; P = 0.000 versus control groups). However, no significant effects were shown for split-mouth-design studies (P = 0.38 versus placebo groups). It was concluded that the use of diode LLLT for orthodontic pain appears promising. However, due to methodological weaknesses, there was insufficient evidence to support or refute LLLT's effectiveness. RCTs with better designs and appropriate sample power are required to provide stronger evidence for diode LLLT's clinical applications. PMID- 25800535 TI - Ultrathin BaTiO3-based ferroelectric tunnel junctions through interface engineering. AB - The ability to change states using voltage in ferroelectric tunnel junctions (FTJs) offers a route for lowering the switching energy of memories. Enhanced tunneling electroresistance in FTJ can be achieved by asymmetric electrodes or introducing metal-insulator transition interlayers. However, a fundamental understanding of the role of each interface in a FTJ is lacking and compatibility with integrated circuits has not been explored adequately. Here, we report an incisive study of FTJ performance with varying asymmetry of the electrode/ferroelectric interfaces. Surprisingly high TER (~400%) can be achieved at BaTiO3 layer thicknesses down to two unit cells (~0.8 nm). Further our results prove that band offsets at each interface in the FTJs control the TER ratio. It is found that the off state resistance (R(Off)) increases much more rapidly with the number of interfaces compared to the on state resistance (ROn). These results are promising for future low energy memories. PMID- 25800536 TI - Erratum to: Extending the type reproduction number to infectious disease control targeting contacts between types. PMID- 25800538 TI - Huge Mediastinal Lipoblastoma in a Nine Year-old Boy Successfully Removed Surgically. AB - A nine year-old boy presented with symptoms of dyspnoea. The chest radiograph and computed tomography scan revealed a large mediastinal tumour. A decision to operate on the patient was made. A huge 2.45 kg mediastinal lipoblastoma was successfully removed from the boy's chest. At three years no evidence of recurrence was found. PMID- 25800539 TI - LV Apical Rupture Complicating Acute Myocardial Infarction: The Role of CMR. AB - PURPOSE: This case illustrates an acute myocardial infarction with occlusion of the left anterior descending coronary artery complicated by apical ventricular rupture and apical thrombus. PROCEDURES: An electrocardiogram, transthoracic echocardiogram (TTE), coronary angiography and cardiac magnetic resonance imaging (CMR) guided optimal management of the patient. FINDINGS: Coronary angiography revealed multivessel disease with an ostial occlusion of the LAD. Echocardiography showed apical dilatation of the left ventricle with a large, echogenic mass at the apex. Contrast echocardiography confirmed the presence of a large apical thrombus, separated from the LV cavity by myocardium. A CMR showed a completed LAD infarct and a filling thrombus was noted in the aneurysmal apical region inferring a contained rupture of the LV apex. PRINCIPLE CONCLUSIONS: Accurate and definitive delineation of unusual cardiac anatomy is best provided by complementary multimodality cardiac imaging, echocardiography and CMR. TTE can miss LV thrombi, particularly when they are large, aneurysmal and apical in nature. CMR provides the cardiac surgeon the ability to visualise in 3D the functional and morphological abnormalities, helping guide necessary intervention. Optimal management of patients with ventricular rupture remains controversial both in terms of timing and choice of intervention. PMID- 25800537 TI - Capturing the dynamics of pathogens with many strains. AB - Pathogens that consist of multiple antigenic variants are a serious public health concern. These infections, which include dengue virus, influenza and malaria, generate substantial morbidity and mortality. However, there are considerable theoretical challenges involved in modelling such infections. As well as describing the interaction between strains that occurs as a result cross-immunity and evolution, models must balance biological realism with mathematical and computational tractability. Here we review different modelling approaches, and suggest a number of biological problems that are potential candidates for study with these methods. We provide a comprehensive outline of the benefits and disadvantages of available frameworks, and describe what biological information is preserved and lost under different modelling assumptions. We also consider the emergence of new disease strains, and discuss how models of pathogens with multiple strains could be developed further in future. This includes extending the flexibility and biological realism of current approaches, as well as interface with data. PMID- 25800540 TI - Adult Scimitar Syndrome: A Surgical Approach. AB - BACKGROUND: Scimitar syndrome is a rare congenital condition characterised by partial or total anomalous pulmonary venous drainage of the right lung. We present an adult case of Scimitar syndrome that was managed with an intra-atrial baffle repair. CASE DESCRIPTION: The patient was a 52 year-old lady who had symptoms of increasing dyspnoea and fatigue with a long-term history of poor exercise tolerance. Several investigations such as a chest X-ray, echocardiogram and coronary angiogram confirmed the diagnosis of Scimitar syndrome with significant left to right shunt. The operation proceeded under cardiopulmonary bypass with a short period of hypothermic circulatory arrest. Postoperative recovery was uneventful and a follow-up echocardiogram confirmed the correction of the condition. DISCUSSION: There are many alternative and novel surgical techniques developed which include the reimplantation of the scimitar vein into the right atrium with the creation of a baffle through an ASD, direct anastomosis of the divided scimitar vein to the left atrium and many others. However, none of them have outcomes which are proven to be better than the technique we chose. CONCLUSION: We utilised a well-recognised technique for a patient that had indications for surgical repair and this resulted in a good prognosis. PMID- 25800541 TI - Carcinoid Heart Disease without Liver Involvement Caused by a Primary Ovarian Carcinoid Tumour. AB - Carcinoid heart disease, caused by primary ovarian carcinoid tumour, is a rare form of valvular heart disease. This form of heart disease usually presents with symptoms of right-sided valvular dysfunction, ultimately leading to right-sided heart failure. This entity is unique as it develops in the absence of liver metastasis. We report a case of 75 year-old woman with primary ovarian carcinoid tumour who presented with symptoms of severe right-sided heart failure and successfully underwent pulmonic and tricuspid valve replacement along with a right ventricular (RV) outflow patch enlargement. This patient later underwent uneventful resection of the primary ovarian carcinoid tumour, with complete resolution of her symptoms. PMID- 25800542 TI - Mother's pre-pregnancy BMI is an important determinant of adverse cardiometabolic risk in childhood. AB - OBJECTIVE: Maternal adiposity is associated with poor offspring cardiometabolic health. We aimed to evaluate the relationship of maternal pre-pregnancy body mass index (BMI) on the BMI, body composition and cardiometabolic characteristics of the offspring. METHODS: Forty offspring of overweight/obese mothers (O-OW) and 28 offspring of normal weight mothers (O-NW) underwent evaluation of body composition, abdominal fat distribution, blood pressure measurement, fasting lipids and an oral glucose tolerance test. The anthropometric and cardiometabolic characteristics of O-OW were compared with those of O-NW, and the relationship to maternal BMI was evaluated. RESULTS: Subjects (mean age: 12.6 +/- 0.4, female: 52.9%) had similar gestational age, birth weight, age, gender, and Tanner stage. However, O-OW had a significantly higher BMI (24.4 +/- 1.2 vs. 19.7 +/- 0.8 kg/m(2) , p = 0.001), % body fat (31.7 +/- 1.6 vs. 24.6 +/- 1.1%, p < 0.001), visceral fat (41.9 +/- 4.7 vs. 26.1 +/- 3.9 cm(2) , p = 0.012) with no difference in lean body mass compared with O-NW. O-OW had lower whole body insulin sensitivity index (WBISI) with an adverse cardiovascular disease risk profile [higher blood pressure (BP), triglycerides to high-density lipoprotein (HDL) ratio, hs-C-reactive protein (CRP) and lower HDL]. In addition to offspring's %body fat (beta = -0.60, p < 0.001), maternal pre-pregnancy BMI (beta = -0.19, p = 0.046) contributed significantly and independently to the offspring's WBISI (R(2) =0.55, p < 0.001). CONCLUSIONS: High pre-pregnancy BMI is an important contributor to excess adiposity, insulin resistance, and cardiometabolic disease risk in the offspring during childhood. PMID- 25800543 TI - Second cancers and Richter transformation are the leading causes of death in patients with trisomy 12 chronic lymphocytic leukemia. AB - BACKGROUND: Trisomy 12 (+12) is detected by fluorescence in-situ hybridization (FISH) analysis in up to 20% of patients with chronic lymphocytic leukemia (CLL). Patients with +12 are known to have unique features and to carry an intermediate prognosis. PATIENTS AND METHODS: In order to better define this large group, we reviewed the characteristics of 250 untreated patients with +12. RESULTS: When compared to 516 untreated patients negative for +12 by FISH, patients with +12 showed a higher incidence of thrombocytopenia, Richter transformation, and second malignant neoplasms (SMN), in addition to the expected increased rate of CD38 positivity and atypical immunophenotype. At a median follow-up of 51 months, 57% of patients needed first-line treatment; median time to first treatment was 38 months, and on multivariate analysis (MVA), it was found to be shorter in patients with advanced Rai stage, palpable splenomegaly, and deletion of 14q by conventional cytogenetic analysis. The overall response rate with first-line treatment was 94%. The median failure-free survival has not been reached, but on MVA, it was found to be shorter in patients whose disease responded in a manner other than complete remission or with FISH negativity for deletion 13q. The median overall survival for the entire group has not been reached, but MVA revealed it to be shorter in patients with an absolute lymphocyte count of > 30 * 10(9)/L or who developed SMN. Eighteen deaths have been observed so far, and Richter transformation and SMN were the leading causes of death (3 and 6, respectively). CONCLUSION: Patients with +12 CLL show characteristic clinical and biologic features, and may benefit from increased surveillance for second cancers. PMID- 25800544 TI - Plasmodium vivax liver stage development and hypnozoite persistence in human liver-chimeric mice. AB - Plasmodium vivax malaria is characterized by periodic relapses of symptomatic blood stage parasite infections likely initiated by activation of dormant liver stage parasites-hypnozoites. The lack of tractable P. vivax animal models constitutes an obstacle in examining P. vivax liver stage infection and drug efficacy. To overcome this obstacle, we have used human liver-chimeric (huHep) FRG KO mice as a model for P. vivax infection. FRG KO huHep mice support P. vivax sporozoite infection, liver stage development, and hypnozoite formation. We show complete P. vivax liver stage development, including maturation into infectious exo-erythrocytic merozoites as well as the formation and persistence of hypnozoites. Prophylaxis or treatment with the antimalarial primaquine can prevent and eliminate liver stage infection, respectively. Thus, P. vivax infected FRG KO huHep mice are a model to investigate liver stage development and dormancy and may facilitate the discovery of drugs targeting relapsing malaria. PMID- 25800546 TI - Evaluation of Two Observational Pain Assessment Tools in Chinese Critically Ill Patients. AB - OBJECTIVES: To examine and compare the reliability and validity of two observational pain assessment tools used in a sample of Chinese critically ill patients. DESIGN: A prospective observational study. SETTING AND SUBJECTS: A convenience sample of 117 adult critically ill patients was recruited from a general Intensive Care Unit in a university-affiliated hospital in China. METHODS: Pain was assessed before and during painful and nonpainful routine care procedures (suctioning and noninvasive blood pressure measurement, respectively) using the Critical-Care Pain Observation Tool (CPOT) and the Behavioral Pain Scale (BPS), including the original BPS and the BPS for Non-Intubated patients (BPS-NI). Internal consistency, test-retest reliability, interrater reliability, and discriminant validity of the CPOT and the BPS were evaluated, and the two scales compared. RESULTS: A total of 608 assessments were obtained using the CPOT and the BPS. Overall Cronbach's alpha coefficient for the CPOT and the BPS was 0.795 and 0.791, respectively. Test-retest reliability of the CPOT and the BPS was 0.950 and 0.941, respectively. Overall weighted kappa between the two raters of the CPOT and the BPS was 0.973 and 0.955, respectively. Scores of the CPOT and the BPS during the painful procedures were both significantly higher than those during the nonpainful procedures, and those at rest before the painful procedures. There was a strong correlation between the two scales with adequate limits of agreement. CONCLUSION: Both the CPOT and the BPS are reliable and valid tools to assess pain in intubated and nonintubated critically ill Chinese patients. PMID- 25800545 TI - Calnexin induces expansion of antigen-specific CD4(+) T cells that confer immunity to fungal ascomycetes via conserved epitopes. AB - Fungal infections remain a threat due to the lack of broad-spectrum fungal vaccines and protective antigens. Recent studies showed that attenuated Blastomyces dermatitidis confers protection via T cell recognition of an unknown but conserved antigen. Using transgenic CD4(+) T cells recognizing this antigen, we identify an amino acid determinant within the chaperone calnexin that is conserved across diverse fungal ascomycetes. Calnexin, typically an ER protein, also localizes to the surface of yeast, hyphae, and spores. T cell epitope mapping unveiled a 13-residue sequence conserved across Ascomycota. Infection with divergent ascomycetes, including dimorphic fungi, opportunistic molds, and the agent causing white nose syndrome in bats, induces expansion of calnexin specific CD4(+) T cells. Vaccine delivery of calnexin in glucan particles induces fungal antigen-specific CD4(+) T cell expansion and resistance to lethal challenge with multiple fungal pathogens. Thus, the immunogenicity and conservation of calnexin make this fungal protein a promising vaccine target. PMID- 25800547 TI - Gradient-modulated SWIFT. AB - PURPOSE: Methods designed to image fast-relaxing spins, such as sweep imaging with Fourier transformation (SWIFT), often utilize high excitation bandwidth and duty cycle, and in some applications the optimal flip angle cannot be used without exceeding safe specific absorption rate (SAR) levels. The aim is to reduce SAR and increase the flexibility of SWIFT by applying time-varying gradient-modulation (GM). The modified sequence is called GM-SWIFT. THEORY AND METHODS: The method known as gradient-modulated offset independent adiabaticity was used to modulate the radiofrequency (RF) pulse and gradients. An expanded correlation algorithm was developed for GM-SWIFT to correct the phase and scale effects. Simulations and phantom and in vivo human experiments were performed to verify the correlation algorithm and to evaluate imaging performance. RESULTS: GM SWIFT reduces SAR, RF amplitude, and acquisition time by up to 90%, 70%, and 45%, respectively, while maintaining image quality. The choice of GM parameter influences the lower limit of short T2 (*) sensitivity, which can be exploited to suppress unwanted image haze from unresolvable ultrashort T2 (*) signals originating from plastic materials in the coil housing and fixatives. CONCLUSIONS: GM-SWIFT reduces peak and total RF power requirements and provides additional flexibility for optimizing SAR, RF amplitude, scan time, and image quality. PMID- 25800548 TI - Changes in Drug Utilization and Outcome With Cardiac Resynchronization Therapy: A MADIT-CRT Substudy. AB - BACKGROUND: This study sought to assess the association between medication utilization, outcome, and the efficacy of resynchronization therapy in the MADIT CRT study. METHODS AND RESULTS: Medication use by patients in the MADIT-CRT study was analyzed. Time-dependent Cox proportional hazard regression analyses were performed to assess differences in hospitalization for heart failure (HF) or death. The greater the efficacy of cardiac resynchronization therapy (CRT) as measured by reduction in left ventricular end-systolic volume (LVESV) and increase in left ventricular ejection fraction (LVEF) between baseline and 1 year of follow-up, the greater the likelihood that patients remained on an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) and avoided use of or reduced treatment with diuretics. Treatment with diuretics was associated with a significantly increased risk of HF hospitalization or death (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.45-2.41; P < .001). In contrast, treatment with an ACE-I/ARB was associated with a significantly decreased risk of HF hospitalization or death (HR 0.58, 95% CI 0.42-0.80; P = .001). CONCLUSIONS: In HF patients in New York Heart Association functional classes I and II and with wide QRS complexes, efficacy of CRT as measured by improvement in LVESV and LVEF was associated with an increased likelihood of remaining on an ACE-I/ARB and discontinuing diuretic therapy. Discontinuation of diuretics was reflective of improved hemodynamic response to CRT. PMID- 25800549 TI - Decompensated Heart Failure Is a Strong Independent Predictor of Functional Outcome After Ischemic Stroke. AB - BACKGROUND: Up to 24% of stroke patients have chronic heart failure. The aim of this study was to determine the frequency and prognostic significance of decompensated heart failure (DHF) in acute stroke patients. METHODS AND RESULTS: Five hundred sixty-six patients (median age 73 y, 48% men) admitted to the stroke unit within 24 hours after stroke were prospectively included. Diagnosis of DHF was made by a cardiologist during hospitalization. Function outcome was assessed 1 month after stroke onset with the use of a modified Rankin Scale. Unfavorable outcome was defined as scores 3-6. DHF was diagnosed in 17% of patients. Fifty seven percent of patients with DHF had preserved ejection fraction. Patients with DHF were older and more often female and more frequently suffered from hypertension, diabetes mellitus, atrial fibrillation, and myocardial infarction. They also had more severe neurologic deficit and more often had hyperglycemia, leukocytosis, fever, pneumonia, and renal failure. After multivariate analysis, adjusting for age, stroke severity, atrial fibrillation, myocardial infarction, hyperglycemia, pneumonia, fever, leukocytosis, proteinuria, and reduced ejection fraction, DHF remained an independent predictor of worse outcome (odds ratio 2.34, 95% CI 1.12-4.89; P = .02). CONCLUSIONS: DHF is a strong independent predictor of poor functional prognosis after ischemic stroke. PMID- 25800550 TI - Patency and Complications of Translumbar Dialysis Catheters. AB - Translumbar tunneled dialysis catheter (TLDC) is a temporary dialysis access for patients exhausted traditional access for dialysis. While few small studies reported successes with TLDC, additional studies are warranted to understand the short- and long-term patency and safety of TLDC. We conducted a retrospective analysis of adult patients who received TLDC for hemodialysis access from June 2006 to June 2013. Patient demographics, comorbid conditions, dialysis details, catheter insertion procedures and associated complications, catheter patency, and patient survival data were collected. Catheter patency was studied using Kaplan Meier curve; catheter functionality was assessed with catheter intervals and catheter-related complications were used to estimate catheter safety. There were 84 TLDCs inserted in 28 patients with 28 primary insertions and 56 exchanges. All TLDC insertions were technically successful with good blood flow during dialysis (>300 ml/minute) and no immediate complications (major bleeding or clotting) were noted. The median number of days in place for initial catheter, secondary catheter, and total catheter were 65, 84, and 244 respectively. The catheter patency rate at 3, 6, and 12 months were 43%, 25%, and 7% respectively. The main complications were poor blood flow (40%) and catheter-related infection (36%), which led to 30.8% and 35.9% catheter removal, respectively. After translumbar catheter, 42.8% of the patients were successfully converted to another vascular access or peritoneal dialysis. This study data suggest that TLDC might serve as a safe, alternate access for dialysis patients in short-term who have exhausted conventional vascular access. PMID- 25800551 TI - Selectivity control in Pt-catalyzed cinnamaldehyde hydrogenation. AB - Chemoselectivity is a cornerstone of catalysis, permitting the targeted modification of specific functional groups within complex starting materials. Here we elucidate key structural and electronic factors controlling the liquid phase hydrogenation of cinnamaldehyde and related benzylic aldehydes over Pt nanoparticles. Mechanistic insight from kinetic mapping reveals cinnamaldehyde hydrogenation is structure-insensitive over metallic platinum, proceeding with a common Turnover Frequency independent of precursor, particle size or support architecture. In contrast, selectivity to the desired cinnamyl alcohol product is highly structure sensitive, with large nanoparticles and high hydrogen pressures favoring C = O over C = C hydrogenation, attributed to molecular surface crowding and suppression of sterically-demanding adsorption modes. In situ vibrational spectroscopies highlight the role of support polarity in enhancing C = O hydrogenation (through cinnamaldehyde reorientation), a general phenomenon extending to alkyl-substituted benzaldehydes. Tuning nanoparticle size and support polarity affords a flexible means to control the chemoselective hydrogenation of aromatic aldehydes. PMID- 25800552 TI - Structural mechanism for the regulation of HCN ion channels by the accessory protein TRIP8b. AB - Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels underlie the cationic Ih current present in many neurons. The direct binding of cyclic AMP to HCN channels increases the rate and extent of channel opening and results in a depolarizing shift in the voltage dependence of activation. TRIP8b is an accessory protein that regulates the cell surface expression and dendritic localization of HCN channels and reduces the cyclic nucleotide dependence of these channels. Here, we use electron paramagnetic resonance (EPR) to show that TRIP8b binds to the apo state of the cyclic nucleotide binding domain (CNBD) of HCN2 channels without changing the overall domain structure. With EPR and nuclear magnetic resonance, we locate TRIP8b relative to the HCN channel and identify the binding interface on the CNBD. These data provide a structural framework for understanding how TRIP8b regulates the cyclic nucleotide dependence of HCN channels. PMID- 25800554 TI - Collision cross sections for structural proteomics. AB - Ion mobility mass spectrometry (IM-MS) allows the structural interrogation of biomolecules by reporting their collision cross sections (CCSs). The major bottleneck for exploiting IM-MS in structural proteomics lies in the lack of speed at which structures and models can be related to experimental data. Here we present IMPACT (Ion Mobility Projection Approximation Calculation Tool), which overcomes these twin challenges, providing accurate CCSs up to 10(6) times faster than alternative methods. This allows us to assess the CCS space presented by the entire structural proteome, interrogate ensembles of protein conformers, and monitor molecular dynamics trajectories. Our data demonstrate that the CCS is a highly informative parameter and that IM-MS is of considerable practical value to structural biologists. PMID- 25800556 TI - Beyond acid strength in zeolites: soft framework counteranions for stabilization of carbocations on zeolites and its implication in organic synthesis. AB - The generation of a carbocation with an acid depends not only on the acid strength but also on the ability of the counteranion to stabilize the positive charge left behind. Here we report that despite their relatively weak acidity, zeolites are able to generate and stabilize medium-size (molecular weight ~300 Da) delocalized carbocations on their surface under mild reaction conditions, as it can be done by strong Bronsted or Lewis acids in solution. The zeolite thus acts as a soft macroanion, prolonging the lifetime of the carbocation sufficiently to perform multifunctionalization reactions with amides, thioamides, and phenols, with high yield and selectivity. Biological studies show that some of the products obtained here present significant inhibition activity against colon cancer cells, illustrating the new possibilities of zeolites to prepare complex organic molecules. PMID- 25800553 TI - Probing the protein interaction network of Pseudomonas aeruginosa cells by chemical cross-linking mass spectrometry. AB - In pathogenic Gram-negative bacteria, interactions among membrane proteins are key mediators of host cell attachment, invasion, pathogenesis, and antibiotic resistance. Membrane protein interactions are highly dependent upon local properties and environment, warranting direct measurements on native protein complex structures as they exist in cells. Here we apply in vivo chemical cross linking mass spectrometry, to reveal the first large-scale protein interaction network in Pseudomonas aeruginosa, an opportunistic human pathogen, by covalently linking interacting protein partners, thereby fixing protein complexes in vivo. A total of 626 cross-linked peptide pairs, including previously unknown interactions of many membrane proteins, are reported. These pairs not only define the existence of these interactions in cells but also provide linkage constraints for complex structure predictions. Structures of three membrane proteins, namely, SecD-SecF, OprF, and OprI are predicted using in vivo cross-linked sites. These findings improve understanding of membrane protein interactions and structures in cells. PMID- 25800557 TI - The Gap Between Couple Therapy Research Efficacy and Practice Effectiveness. AB - Meta-analyses of randomized controlled trials of couple therapy find large improvements in couple adjustment, but published evaluations of the effectiveness of couple therapy in routine practice find only small-to-moderate effects. The current study analyzes possible explanations for the research-efficacy to practice-effectiveness gap and offers suggestions for enhancing couple therapy effectiveness. Major recommendations are that therapists should clarify whether couples' therapy goal is to clarify commitment to the relationship or to improve the relationship; use standardized assessment of the individual partners and the relationship; and use systematic monitoring of therapy progress and the therapeutic alliance. It is also possible that the greater use of evidence-based therapies when treating couple relationship distress could enhance couple therapy outcome. PMID- 25800555 TI - Observing a lipid-dependent alteration in single lactose permeases. AB - Lipids of the Escherichia coli membrane are mainly composed of 70%-80% phosphatidylethanolamine (PE) and 20%-25% phosphatidylglycerol (PG). Biochemical studies indicate that the depletion of PE causes inversion of the N-terminal helix bundle of the lactose permease (LacY), and helix VII becomes extramembranous. Here we study this phenomenon using single-molecule force spectroscopy, which is sensitive to the structure of membrane proteins. In PE and PG at a ratio of 3:1, ~95% of the LacY molecules adopt a native structure. However, when PE is omitted and the membrane contains PG only, LacY almost equally populates a native and a perturbed conformation. The most drastic changes occur at helices VI and VII and the intervening loop. Since helix VII contains Asp237 and Asp240, zwitterionic PE may suppress electrostatic repulsion between LacY and PG in the PE:PG environment. Thus, PE promotes a native fold and prevents LacY from populating a functionally defective, nonnative conformation. PMID- 25800558 TI - Update on autism spectrum disorder: vaccines, genomes, and social skills training. AB - Despite making significant progress in understanding autism spectrum disorder (ASD) and its genetic underpinnings, controversy remains regarding ASD and its historical, erroneous association with vaccines. This controversy includes the latest anti-vaccine movement that caused a recurrence of the almost vanquished measles and mumps diseases. The history of ASD, complexities of research involving ASD genetics, and benefits of social skills training are explored. PMID- 25800559 TI - Fumonisin B1 inhibits apoptosis in HepG2 cells by inducing Birc-8/ILP-2. AB - Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium sp., a common contaminant of maize. FB1 inhibits sphingolipid biosynthesis, alters sphingosine/sphinganine ratios and modifies cell survival and cell death processes at varying propensities at both species- and tissue-specific level. We investigated the effect of FB1 on the apoptotic pathway in human hepatoma (HepG2) cells. We measured: (i) the level of cell proliferation and cell death mechanism of HepG2 cells (MTT assay, annexin V and propidium iodide staining, JC-1 assay, gammaH2AX and cleaved PARP and Hoechst staining); (ii) initiator and executioner caspase activity (luminometric enzyme activity assays); (iii) regulation of mRNA expression of pro- and anti- apoptotic molecules using an apoptosis array (qPCR) and (iv) levels of significantly altered apoptosis-related proteins (Western blotting) following a 24 h incubation. FB1 caused a dose-dependent decrease in cell viability with an inhibitory concentration for 50% of cell growth at 200 MUM. FACS data showed FB1 induced a 2.5-fold increase in annexin V staining, however, caspase activity and mitochondrial depolarization was not significantly influenced. Cleaved PARP and gammaH2AX were significantly lower in treated cells with minimal DNA condensation and fragmentation observed with the Hoechst stain. BIRC-8/ILP-2 was most significantly up-regulated (8-fold; apoptosis array). ILP2 protein levels were elevated (2.3-fold) with a corresponding decrease in Smac/DIABLO protein levels (1.7-fold). Further analysis showed a dose-dependent increase in BIRC-8/ILP-2 mRNA and protein expression in HepG2 cells. We conclude that FB1 modulates apoptosis in a complex dose-dependent regulation of pro- and anti-apoptotic molecules. PMID- 25800560 TI - Mitochondria defects are involved in lead-acetate-induced adult hematopoietic stem cell decline. AB - Occupational high-grade lead exposure has been reduced in recent decades as a result of increased regulation. However, environmental lead exposure remains widespread, and is associated with severe toxicity implicated in human diseases. We performed oral intragastric administration of various dose lead acetate to adult Sprague Dawley rats to define the role of lead exposure in hematopoietic stem cells (HSCs) function, and to clarify its underlying mechanism. Lead acetate exposed rats exhibited developmental abnormalities in myeloid and lymphoid lineages, and a significant decline in immune functions. It also showed HSCs functional decline associated with senescent phenotype with low grade lead acetate exposure or apoptotic phenotype with relative higher grade dose exposure. Mechanistic exploration showed a significant increase in reactive oxygen species (ROS) in the lead acetate-exposed CD90(+)CD45(-) compartment, which correlated with functional defects in cellular mitochondria. Furthermore, in vivo treatment with the antioxidant vitamin C led to reversion of the CD90(+)CD45(-) compartment functional decline. These results indicate that lead acetate perturbs the hematopoietic balance of adult HSCs, associated with cellular mitochondria defects, increased intracellular ROS generation. PMID- 25800561 TI - Role of type I & type II reactions in DNA damage and activation of caspase 3 via mitochondrial pathway induced by photosensitized benzophenone. AB - Sunscreen users have been increased, since excessive sun exposure increased the risk of skin diseases. Benzophenone (BP) and its derivatives are commonly used in sunscreens as UV blocker. Its photosafety is concern for human health. Our study showed the role of type-I and type-II radicals in activation of caspase 3 and phototoxicity of BP under sunlight/UV radiation. BP photodegraded and formed two photoproducts. BP generates reactive oxygen species (ROS) singlet oxygen ((1)O2), superoxide anion (O2(-)) and hydroxyl radical (OH) through type-I and type-II photodynamic mechanisms. Photocytotoxicity significantly reduced cell viability under sunlight, UVB and UVA. DCF fluorescence confirmed intracellular ROS generation. BP showed single strand DNA breakage, further proved by cyclobutane pyrimidine dimmers (CPDs) formation. Lipid peroxidation and LDH leakage were enhanced by BP. P21 dependent cell cycle study showed sub G1 population which advocates apoptotic cell death, confirmed through AO/EB and annexin V/PI staining. BP decreased mitochondrial membrane potential, death protein released and activated caspase. We proposed cytochrome c regulated caspase 3 dependent apoptosis in HaCaT cell line through down regulation of Bcl2/Bax ratio. Phototoxicity potential of its photoproducts is essential to understand its total environmental fate. Hence, we conclude that BP may replace from cosmetics preparation of topical application. PMID- 25800562 TI - Design and performance of a high-flux electrospray ionization source for ion soft landing. AB - We report the design and evaluation of a new high-intensity electrospray ionization source for ion soft-landing experiments. The source incorporates a dual ion funnel, which enables operation with a higher gas load through an expanded diameter heated inlet into the additional first region of differential pumping. This capability allowed us to examine the effect of the inner diameter (ID) of the heated stainless steel inlet on the total ion current transmitted through the dual funnel interface and, more importantly, the mass-selected ion current delivered to the deposition target. The ion transmission of the dual funnel is similar to the transmission of the single funnel used in our previous soft landing studies. However, substantially higher ion currents were obtained using larger ID heated inlets and an orthogonal inlet geometry, in which the heated inlet was positioned perpendicular to the direction of ion propagation through the instrument. The highest ion currents were obtained using the orthogonal geometry and a 1.4 mm ID heated inlet. The corresponding stable deposition rate of ~1 MUg of mass-selected ions per day will facilitate future studies focused on the controlled deposition of complex molecules on substrates for studies in catalysis, energy storage, and self-assembly. PMID- 25800563 TI - Simplified analysis of acetaminophen glucuronide for quantifying gluconeogenesis and glycogenolysis using deuterated water. AB - Measurement of acetaminophen glucuronide (AG) (2)H enrichment from deuterated water ((2)H2O) by (2)H nuclear magnetic resonance (NMR) analysis of its monoacetone glucose (MAG) derivative provides estimation of gluconeogenic and glycogenolytic contributions to endogenous glucose production (EGP). However, AG derivatization to MAG is laborious and unsuitable for high-throughput studies. An alternative derivative, 5-O-acetyl monoacetone glucuronolactone (MAGLA), was tested. Eleven healthy subjects ingested (2)H2O to 0.5% body water enrichment and 500 mg of acetaminophen. Plasma glucose and urinary glucuronide positional (2)H enrichments were measured by (2)H NMR spectroscopy of MAG and MAGLA, respectively. A Bland-Altman analysis indicated agreement at the 95% confidence level between glucose and glucuronide estimates. PMID- 25800564 TI - Using carboxyfluorescein diacetate succinimidyl ester to monitor intracellular protein glycation. AB - Protein glycation is a ubiquitous process involved in vascular complications observed in diabetes. Glyoxal (GO), an intracellular reactive oxoaldehyde that is one of the most potent glycation agents, readily reacts with amines present on proteins to produce the lysine-derived adduct carboxymethyllysine, which is a prevalent advanced glycation end-product (AGE). Our group previously showed that cell exposure to GO leads to an alteration in the cell contractile activity that could occur as a result of the glycation of various proteins regulating the cell contractile machinery. Here, we measured the extent of glycation on three functionally distinct proteins known to participate in cell contraction and cytoskeletal organization-Rho-kinase (ROCK), actin, and gelsolin (GSN)-using an assay based on the reaction of the cell membrane-permeable fluorescent probe carboxyfluorescein diacetate succinimidyl ester (CFDA-SE), which reacts with primary amine groups of proteins. By combining CFDA-SE fluorescence and Western blot detection, we observed (following GO incubation) increased glycation of actin and ROCK as well as an increased interaction between actin and GSN as observed by co-immunoprecipitation. Thus, we conclude that the use of the fluorescent probe CFDA-SE offers an interesting alternative to perform a comparative analysis of the extent of intracellular protein glycation in live cells. PMID- 25800565 TI - Evaluation of an anti-parasitic compound extracted from Streptomyces sp. HL-2-14 against fish parasite Ichthyophthirius multifiliis. AB - The present study was conducted to evaluate the anti-parasitic activity of a pure compound from Streptomyces sp. HL-2-14 against fish parasite Ichthyophthirius multifiliis, and elucidate its chemical structure. By electron ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance spectrum (1H NMR and 13C NMR), the compound was identified as amphotericin B (AmB). The in vitro trials revealed that AmB can effectively kill the theronts and tomonts of I. multifiliis with the median lethal concentration (LC50) of 0.8 mg L-1 at 30 min for the theronts and 4.3 mg L-1 at 2 h for the tomonts, respectively. AmB at 5 mg L-1 significantly reduced I. multifiliis infectivity prevalence and intensity on grass carp (Ctenopharyngodon idella), and consequently decreased fish mortality, from 100% in control group to 30% in treated group. The 72 h acute toxicity (LC50) of AmB on grass carp was 20.6 mg L-1, but fish mortality was occurred when exposure to 13.0 mg L-1. These results indicated that AmB was effective in the therapy of I. multifiliis infection, but the safety concentration margin is relatively narrow. Further efforts aiming to decrease the toxicity and improve the therapeutic profile remain to be needed. PMID- 25800566 TI - Associated anomalies with neural tube defects in fetal autopsies. AB - Neural tube defects (NTD), the consequences of aberrant neural tube closure during embryogenesis, have been mostly investigated in terms of their high prevalence, rate of mortalities and serious morbidities. A proper prenatal outcome counseling of couples coming across a fetal anomaly necessitates the detection and categorization of the primer abnormality, all the co-existing malformations. The aim of this work is to study the incidence and relevance of associated malformations in order to offer a complete pathology report with a true diagnosis. In this study, among 542 fetal autopsy 62 (%11.4) cases with NTD was recorded by the Akdeniz University Pathology Department between January 2006 and June 2012. Twenty (32.4%) NTD cases were associated with anomaly. Twelve cases of associated groups consisted of a congenital syndrome/association, spondylothoracic dysplasia, amniotic band syndrome, Meckel-Gruber syndrome, schisis association. The frequency of associated NTD was 32%, this result was higher than previous reports. NTDs have a significant genetic component to their etiology that interacts with environmental risk factors, which might pose Turkey to be a country with high prevalence of NTD. We want to emphasize that intensive screening, documentation of co-existent abnormalities of NTD, should be conducted in order to exhibit certain diagnosis, to perform proper prenatal genetic counseling of parents for on-going/future pregnancies. PMID- 25800567 TI - [Isolation and identification of CD133 positive and negative cells from human lung cancer and screening of the differential genes between the positive and negative cells]. AB - BACKGROUND AND OBJECTIVE: It has been proven that cancer stem cell existed in variety of cancer, which an significant difference of biological characteristics was observed between the cancer stem cells and non-cancer stem cells. And CD133 is considered to be cancer stem cell marker. So there may be significant differences in CD133- positive cells and CD133-negative cells. The aim of this study is to isolate CD133+ cells and CD133- cells from lung cancer cell line A549, explore their biological characteristics and screen the metastasis-related genes. METHODS: MACS was applied to isolate CD133+ cells and CD133- cells from human lung cancer cell line A549. To observe the formation of sphere, CD133+ cells and CD133- cells were cultured in serum-free DMEM-F12 medium (containing EGF, bFGF) in vitro. The colony formatting efficiency of CD133+ cells, CD133- cells and cells without sorting was tested by colony-forming assay. The differentiation of sphere was induced by culturing in DMEM-F12 medium (containing serum). The metastasis-related genes (84 genes) of CD133+ cells and CD133- cells were detected by using DNA microarray. Immunohistochemistry was used to detect the expression of CD133 protein in Human lung cancer tissue. RESULTS: CD133+ cells formed sphere in serum-free DMEM-F12 medium,while the CD133- cells failed to form sphere. The rates of CD133+ cell colony formation (57.1%) was significantly higher than that of CD133- cells (3.3%). Sphere (CD133+/CK7-) was induced to differentiate, and CK7 expression was found in differentiated cells. The expression levels of 19 metastasis-related genes from CD133+ cells and CD133- cells were significant different. Little CD133 positive cells which distributing around the cancer nests were found in lung cancer tissue. The expression of CD133 was not related to tumor types, cell differentiation or TNM stage. CONCLUSIONS: CD133+ cells exhibit the characteristics of cancer stem cells. The difference of metastasis-related gene expression levels was discovered between CD133+ cells and CD133- cells. CD82 plays an important role in mechanism of tumor metastasis.?. PMID- 25800568 TI - [Association between the epidermal growth receptor status and the efficacy of? first-line chemotherapy in patients with advanced non-small cell lung cancer]. AB - BACKGROUND: Status of epidermal growth factor receptor (EGFR) gene is a predictor of response to EGFR tyrosine kinase inhibitor (TKI). However, little is know about the relationship between EGFR status and response to chemotherapy. We evaluated the prediction value of EGFR mutation status on response to first-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: The data of 181 patients with stage IIIb/IV NSCLC who diagnosed by histopathology from January 10, 2006 to December 20, 2013 in Beijing Chest Hospital, Capital Medical University were collected. The relationships between EGFR gene status, clinical characteristics and response and progression-free survival (PFS) were analyzed. RESULTS: All of the 181 patients' EGFR statuses were determined. 75 (41.4%) patients harbored EGFR-activating mutations and 106 (58.6%) patients were EGFR wild-type. All patients received first-line chemotherapy. The objective response rate (ORR) was 26.0% and disease control rate (DCR) was 70.2%. Patients with EGFR-activating mutations had a higher DCR than patients with EGFR wild-type (84.0% vs 60.4%, P=0.001) did. Subgroup analysis showed that the ORR and DCR in patients with EGFR exon 19 deletions were remarkably higher than those with EGFR wild-type (P = 0.049, 0.002, respectively). The DCR in patients with EGFR exon 21 L858R mutation was significantly higher than that in patients with EGFR wild-type (P=0.010). 168 patients were available for response evaluation in all of 181 patients and median PFS was 4.3 mo. The PFS of patients with adenocarcinoma was significantly higher than that patients with squamous cell carcinoma (4.7 mo vs 3.0 mo, P=0.036). The PFS in patients harbored EGFR-activating mutations was significantly higher than that in the patients with EGFR wild-type (6.3 mo vs 3.0 mo, P=0.002). The PFS of patients with a performance status (PS) of 0-1 was significantly higher than that in patients with a PS of 2 (4.4 months vs. 0.7 months, P= 0.016). Cox multivariate analysis indicates the EGFR-activating mutation is an independent factor affecting PFS (HR=0.654, 95%CI: 0.470-0.909, P=0.012). CONCLUSIONS: EGFR activating mutation is a predictor for PFS of first-line chemotherapy in advanced NSCLC patients.?. PMID- 25800569 TI - [Analysis of differentially expressed proteome in urine ?from non-small cell lung cancer patients]. AB - BACKGROUND: Screen differentially expressed proteins in patients with non-small cell lung cancer (NSCLC), and aim to identify biomarkers for early screening, monitoring prognosis and evaluating therapy of NSCLC. METHODS: Urinary samples were collected from 40 newly diagnosed NSCLC patients, 8 patients with lung benign disorders and 22 healthy people. 0.9% sodium dodecylsulfate- polyacrylamide gel electrophoresis (1D SDS-PAGE) and MS-Thermo-Orbitrap-Velos were applied to separate, extract and identify proteins in urinary samples from non-neoplastic groups and NSCLC patients, in order to find out differentially expressed proteins in patients with NSCLC. Then, sensitivity and specificity of candidate proteins were tested by certain experiments. Finally, biomarkers related to NSCLC could be determined. RESULTS: The differences of urinary proteins between non-neoplastic groups and NSCLC patients mainly focused on 90 kDa, 60 kDa and 20 kDa-30 kDa stripes. Four differently expressed proteins were found in urinary proteins in NSCLC group, including LRG1, CA1 (up-regulating proteins) and VPS4B, YWHAZ (down-regulating proteins). The sensitivity of these four proteins for biomarker of NSCLC was relatively low when they were used to screen or diagnose independently. The sensitivity and specificity of LRG1 was 83.0% (25/30) and 90.0% (18/20), respectively; 60.0% (18/30) and 90.0% (18/20) for CA1; 73.3% (22/30) and 90.0% (18/20) for VPS4B; 60.0% (18/30) and 95.0% (19/20) for YWHAZ. However, the sensitivity and specificity would increase to 96.7% (29/30) and 85% (17/20) after the four biomarkers were combined. CONCLUSIONS: LRG1 and CA1 are abundant in urine in patients with NSCLC, while VPS4B and YWHAZ are low-abundance proteins. They could be regarded as biomarkers for early screening, monitoring prognosis and evaluating therapy of patients with NSCLC because of differential expression. The sensitivity of the four biomarkers of NSCLC is relatively low when they are used to screen or diagnose independently, while significantly improvement if they were in combined pattern, which will be of excellent applications to clinical diagnosis and treatment. PMID- 25800570 TI - [Effectiveness of EGFR-TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a meta-analysis]. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been used for the first-line treatment of non-small cell lung cancer (NSCLC) and has shown good clinical effects. However, some patients fail to benefit from this treatment. The aim of this study is to analyze whether or not clinical-selected patients (Asian, adenocarcinoma histology, non-smoking) and EGFR mutation-selected patients benefit from EGFR-TKIs or chemotherapy. Our results could be used as basis to guide clinical therapy. METHODS: Randomized controlled trials evaluating the efficacy of EGFR-TKIs versus chemotherapy as first-line treatments of NSCLC were obtained from electronic databases, namely, PubMed, Embase, American Society of Clinical Oncology (ASCO), European Society for Medical Oncology, and China Biology Medicine disc. Assessment, data collection, and statistical analysis were performed according to Cochrane Handbook 5.1.0. RESULTS: A total of 14 randomized controlled trials with 5,000 patients were included in this study. Compared with the chemotherapy group, EGFR TKI therapy group in EGFR mutation-selected NSCLC patients showed a higher response rate (RR=2.31; 95%CI: 1.88-2.84) and more significant improvement in progression free survival (PFS; HR=0.39; 95%CI: 0.30-0.49); by contrast, no significant difference was observed in overall survival (OS; HR=0.99; 95%CI: 0.84 1.16). The response rate of clinical-selected patients treated with EGFR-TKI significantly increased (RR=1.30; 95%CI: 1.15-1.47) compared with that of the patients treated with chemotherapy; PFS (HR=0.93; 95%CI: 0.58-1.49) and OS (HR=0.91; 95%CI: 0.81-1.02) of the two groups did not significantly differ. Likewise, the PFS and the OS of the unselected patients in the EGFR-TKI treatment group and the chemotherapy group did not significantly differ, although the OS of the former was shorter than that of the latter. CONCLUSIONS: EGFR mutation selected patients received more benefits from EGFR-TKI first-line treatment than other treatments. First-line EGFR-TKI treatment was recommended for clinically selected patients who were unsuitable for themotherapy. By comparison, first-line EGFR-TKI treatment was not a suitable choice for unselected patients. PMID- 25800572 TI - [Erratum: 99mTc-octreotide Receptor Scintigraphy in NCI-H446 Small Cell Lung Cancer Nude Mice Model]. PMID- 25800571 TI - [Density and SUV ratios from PET/CT in the detection of mediastinal lymph node metastasis in non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Mediastinal involvement in lung cancer is a highly significant prognostic factor for survival, and accurate staging of the mediastinum will correctly identify patients who will benefit the most from surgery. Positron emission tomography/computed tomography (PET/CT) has become the standard imaging modality for the staging of patients with lung cancer. The aim of this study is to investigate 18-fluoro-2-deoxy-glucose (18F-FDG) PET/CT imaging in the detection of mediastinal disease in lung cancer. METHODS: A total of 72 patients newly diagnosed with non-small cell lung cancer (NSCLC) who underwent preoperative whole-body 18F-FDG PET/CT were retrospectively included. All patients underwent radical surgery and mediastinal lymph node dissection. Mediastinal disease was histologically confirmed in 45 of 413 lymph nodes. PET/CT doctors analyzed patients' visual images and evaluated lymph node's short axis, lymph node's maximum standardized uptake value (SUVmax), node/aorta density ratio, node/aorta SUV ratio, and other parameters using the histopathological results as the reference standard. The optimal cutoff value for each ratio was determined by receiver operator characteristic curve analysis. RESULTS: Using a threshold of 0.9 for density ratio and 1.2 for SUV ratio yielded high accuracy for the detection of mediastinal disease. The lymph node's short axis, lymph node's SUVmax, density ratio, and SUV ratio of integrated PET/CT for the accuracy of diagnosing mediastinal lymph node was 95.2%. The diagnostic accuracy of mediastinal lymph node with conventional PET/CT was 89.8%, whereas that of PET/CT comprehensive analysis was 90.8%. CONCLUSIONS: Node/aorta density ratio and SUV ratio may be complimentary to conventional visual interpretation and SUVmax measurement. The use of lymph node's short axis, lymph node's SUVmax, and both ratios in combination is better than either conventional PET/CT analysis or PET/CT comprehensive analysis in the assessment of mediastinal disease in NSCLC patients.?. PMID- 25800573 TI - [Clinical analysis of 80 patients with combined small-cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Studies on combined small cell lung cancer (C-SCLC), which shows continuously increasing incidence, are rare. Accordingly, we explored the relationship between the clinicopathological characteristics and prognostic factors of C-SCLC patients and analyzed the treatment of this disease. METHODS: Between January 2006 and December 2011, 80 patients with pathologically confirmed C-SCLC were retrospectively analyzed. The Kaplan-Meier methods were used to calculate the survival rate, and the Log-rank test was used to examine differences between arms. The Cox regression model was used to analyze the independent factors affecting the overall survival (OS). RESULTS: The OS of the C SCLC patients in all groups had a median of 26.2 mo and a range of 0.3 to 81.4 mo. In univariate analysis, gender, Karnofsky performance score before treatment, tumor diameter, and tumor stage were the considered prognostic factors affecting the OS rate of the C-SCLC patients (P<0.05). Cox multivariate analysis showed that only the TNM stage was the independent prognostic factor influencing the OS of the C-SCLC patients. The majority (75.0%) of the patients received multimodality therapy and platinum-based chemotherapy as the main treatment. However, no significant differences in OS rate were observed between patient groups under conventional SCLC regimens and non-SCLC regimens (P>0.05). CONCLUSIONS: C-SCLC is a specific mixed carcinoma. Combined therapy with platinum based chemotherapy as the main treatment should be adopted in the therapeutic regimen of this disease. TNM stage was the independent prognostic factor influencing the OS of C-SCLC patients.?. PMID- 25800574 TI - [Acute response of right ventricular function to iloprost inhalations in patients with pulmonary arterial hypertension: preliminary evaluation ?with cardiac magnetic resonance imaging]. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally elevated blood pressure of the pulmonary circulation. Without treatment, PAH progresses rapidly to right ventricular (RV) failure and even death. Cardiac magnetic resonance imaging (CMRI) has been an accurate and reproducible tool to assessment of RV morphology and function, which are important factors in the prognosis of patients with PAH. The aim of this study is to investigate acute RV response to inhalation of aerosolized iloprost in patients with PAH using CMRI. METHODS: From March 2012 to March 2014, 48 patients with PAH underwent CMRI before and immediately after inhalation of iloprost with a single dose of 20 MUg over 15 min-20 min. RV function parameters derived from CMRI images were analyzed before and after iloprost inhalation, including end diastolic volume (EDV), end-diastolic area (EDA), end-systolic volume (ESV), end systolic area (ESA), stroke volume (SV), ejection fraction (EF) and cardiac output (CO). Percentage of RV area change was also calculated [%RVAC=(EDA ESA)/EDA*100%]. Wilcoxon's Sign Rank Test or Paired Samples t-Test was used to compare the differences of RV function parameters before and after inhalation. RESULTS: After iloprost inhalation, all patients showed significant decrease in RV EDV and RV ESV (P=0.007, P<0.001 respectively). Whereas, there were significant increase in RV SV (P=0.014), RV EF (P=0.009) and %RVAC (P=0.006). RV CO had no significant difference before and after inhalation (P=0.851). CONCLUSIONS: Inhalation of iloprost can immediately improve RV function in patients with PAH, and noninvasive evaluation of the acute response with CMRI is feasibility. PMID- 25800575 TI - [Genetic characteristics and research progress of targeted therapy in squamous cell carcinoma]. PMID- 25800576 TI - [Mechanism of Warburg effect and its effect on tumor metastasis]. AB - Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis even when the oxygen content is normal, a phenomenon termed "Warburg effect". However the definite molecular mechanisms of Warburg effect remains unclear, recent works indicated that it might be related to the abnormal activity of the oncogene and tumor suppressor genes, also the change of tumor microenvironment, the abnormal expression of glucose metabolic enzyme and so on. Warburg effect has a relationship with tumor progression and provide suitable conditions for tumor metastasis. This review will summarizes the mechanism of Warburg effect and its effect on tumor metastasis. PMID- 25800577 TI - [Advances of human epididymis protein 4 in lung cancer]. AB - Human epididymis 4 (HE4) belongs to whey acidic 4-disulfide center protein family. It has the characteristics of inhibiting trypsin and high expression in the serum or malignant pleural effusion of patients with lung cancer. Clinical data showed that it has certain relevance to the diagnosis and prognosis of lung cancer. HE4 may be a new indicator of clinical diagnosis and prognosis evaluation. PMID- 25800578 TI - Lar gibbon (Hylobates lar) great call reveals individual caller identity. AB - Gibbons (family Hylobatidae) produce loud, elaborate vocalizations (songs), often in well-coordinated male/female duets. The female's great call, the most conspicuous phrase of the gibbon vocal repertoire, functions primarily to mediate territorial defense. Despite the fact that lar gibbons (Hylobates lar) are the most widely distributed and well researched hylobatid species and produce a rich vocal repertoire, the individual-specificity of their great calls has not previously been quantified. In addition, spectral and temporal features of notes occurring at specific locations within the lar great call have not been described. Here we provide such a description, and test the hypothesis that great calls are statistically discriminable between a large sample of individual callers. We compared recordings of great calls from 14 wild lar females in Khao Yai National Park, Thailand. Our analyses of principal components derived from spectral and temporal measures, as well as spectrograms from the entire great call, indicate that acoustic variation is sufficient to allow identification of individual callers (83.5% discriminability based on principal components, and inter-individual call variation exceeding intra-individual variation in overall spectrogram). These vocalizations potentially allow individual recognition of animals. PMID- 25800579 TI - The nuclease activities of both the Smr domain and an additional LDLK motif are required for an efficient anti-recombination function of Helicobacter pylori MutS2. AB - Helicobacter pylori, a human pathogen, is a naturally and constitutively competent bacteria, displaying a high rate of intergenomic recombination. While recombination events are essential for evolution and adaptation of H. pylori to dynamic gastric niches and new hosts, such events should be regulated tightly to maintain genomic integrity. Here, we analyze the role of the nuclease activity of MutS2, a protein that limits recombination during transformation in H. pylori. In previously studied MutS2 proteins, the C-terminal Smr domain was mapped as the region responsible for its nuclease activity. We report here that deletion of Smr domain does not completely abolish the nuclease activity of HpMutS2. Using bioinformatics analysis and mutagenesis, we identified an additional and novel nuclease motif (LDLK) at the N-terminus of HpMutS2 unique to Helicobacter and related epsilon-proteobacterial species. A single point mutation (D30A) in the LDLK motif and the deletion of Smr domain resulted in ~ 5-10-fold loss of DNA cleavage ability of HpMutS2. Interestingly, the mutant forms of HpMutS2 wherein the LDLK motif was mutated or the Smr domain was deleted were unable to complement the hyper-recombination phenotype of a mutS2(-) strain, suggesting that both nuclease sites are indispensable for an efficient anti-recombinase activity of HpMutS2. PMID- 25800580 TI - Diagnostic criteria of well differentiated thyroid tumor of uncertain malignant potential; a histomorphological and immunohistochemical appraisal. AB - BACKGROUND: Well differentiated thyroid tumor of uncertain malignant potential (WDT-UMP) represents a true "gray zone" of "follicular patterned" thyroid lesions, that needs to be characterized in order to outright the diagnosis of carcinoma and avoid unnecessary aggressive treatment. AIM: To emphasize on the histomorphological criteria for more accurate diagnosis of WDT-UMP. Also to compare the immunohistochemical expression of CK19 of WDT-UMP versus adenoma and papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: The study included 60 thyroid specimens; 18 WDT-UMPs, 24 PTC (18 classic variant and 6 follicular variants) and 18 benign thyroid lesions (8 adenoma, 6 Hashimoto's thyroiditis and 4 hyperplastic nodules). H&E stained sections were assessed according to the published major and minor criteria of malignancy in the thyroid. CK 19 immunostaining was examined and evaluated according to the proportion and intensity scores. RESULTS: We could detect the absence of nuclear inclusions, presence of characteristic nuclear groove, nuclear clearing, ovoid nuclei, nuclear crowdness, nuclear enlargement and pleomorphism as important reliable features for diagnosis of WDT-UMP with p value (<0.0001 for each). WDT-UMP showed moderate to strong CK 19 immunostaining with proportion scores 3 and 4; an intermediate expression profile; higher than adenoma and less than papillary carcinoma (p<0.0001). CONCLUSION: The constellations of both major and minor criteria of malignancy are important clues for WDT-UMP diagnosis which could be ascertained by CK 19 immunostaining. PMID- 25800581 TI - Pre-hospital transportation in Western countries for Ebola patients, comparison of guidelines. PMID- 25800582 TI - Survival in patients without acute ST elevation after cardiac arrest and association with early coronary angiography: a post hoc analysis from the TTM trial. AB - PURPOSE: To investigate whether early coronary angiography (CAG) after out-of hospital cardiac arrest of a presumed cardiac cause is associated with improved outcomes in patients without acute ST elevation. METHODS: The target temperature management after out-of-hospital cardiac arrest (TTM) trial showed no difference in all-cause mortality or neurological outcome between an intervention of 33 and 36 degrees C. In this post hoc analysis, 544 patients where the admission electrocardiogram did not show acute ST elevation were included. Early CAG was defined as being performed on admission or within the first 6 h after arrest. Primary outcome was mortality at the end of trial. A Cox proportional hazard model was created to estimate hazard of death, adjusting for covariates. In addition, a propensity score matched analysis was performed. RESULTS: A total of 252 patients (46 %) received early CAG, whereas 292 (54 %) did not. At the end of the trial, 122 of 252 patients who received an early CAG (48 %) and 159 of 292 patients who did not (54 %) had died. The adjusted hazard ratio for death was 1.03 in the group that received an early CAG; 95 % CI 0.80-1.32, p = 0.82. In the propensity score analysis early CAG was not significantly associated with survival. CONCLUSIONS: In this post hoc observational study of a large randomized trial, early coronary angiography for patients without acute ST elevation after out-of-hospital cardiac arrest of a presumed cardiac cause was not associated with improved survival. A randomized trial is warranted to guide clinical practice. PMID- 25800583 TI - Is extracorporeal membrane oxygenation for severe acute respiratory distress syndrome related to intra-abdominal sepsis beneficial? PMID- 25800584 TI - Diastolic dysfunction and mortality in septic patients: a systematic review and meta-analysis. AB - BACKGROUND: Myocardial dysfunction may contribute to the haemodynamic instability which accompanies sepsis, and may result in circulatory failure. There is no association between systolic dysfunction (SD) and mortality in septic patients and there is conflicting evidence regarding the effects of diastolic dysfunction (DD) on mortality in septic patients. METHODS: We conducted a systematic review and meta-analysis to investigate DD and mortality in septic patients. We included studies conducted in this patient population which investigated the association between DD reported according to tissue Doppler imaging (TDI) criteria and mortality, using the longest reported follow-up. As a secondary endpoint, we evaluated the association between SD and mortality according to the results reported by the retrieved studies. RESULTS: We included seven studies in our meta analysis with 636 septic patients, 48% of them were found to have DD. We found a significant association between DD and mortality (RR 1.82, 95% CI 1.12-2.97, p = 0.02). This finding remained valid in a further analysis which including an older study reporting DD without TDI criteria. Five studies reported data on SD for a total of 581 patients, 29.6% of them with SD. No association was found between SD and mortality (RR 0.93, 95% CI 0.62-1.39, p = 0.73). Looking at subgroups, there was a trend towards higher mortality comparing isolated DD or combined SD-DD vs normal heart function (p = 0.10 and p = 0.05, respectively). CONCLUSIONS: Diastolic dysfunction is common in septic patients and it is associated with mortality. Systolic dysfunction is less common and is not associated with mortality in this group of patients. PMID- 25800586 TI - Margaret McCartney: can doctors fix cold homes? PMID- 25800585 TI - Muscle diffusion of liposomal amphotericin B and posaconazole in critically ill burn patients receiving continuous hemodialysis. PMID- 25800587 TI - Influence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology. AB - Cardiac function and dysfunction exhibit striking time-of-day-dependent oscillations. Disturbances in both daily rhythms and sleep are associated with increased risk of heart disease, adverse cardiovascular events, and worsening outcomes. For example, the importance of maintaining normal daily rhythms is highlighted by epidemiologic observations that night shift workers present with increased incidence of cardiovascular disease. Rhythmicity in cardiac processes is mediated by a complex interaction between extracardiac (e.g., behaviors and associated neural and humoral fluctuations) and intracardiac influences. Over the course of the day, the intrinsic properties of the myocardium vary at the levels of gene and protein expression, metabolism, responsiveness to extracellular stimuli/stresses, and ion homeostasis, all of which affect contractility (e.g., heart rate and force generation). Over the past decade, the circadian clock within the cardiomyocyte has emerged as an essential mechanism responsible for modulating the intrinsic properties of the heart. Moreover, the critical role of this mechanism is underscored by reports that disruption, through genetic manipulation, results in development of cardiac disease and premature mortality in mice. These findings, in combination with reports that numerous cardiovascular risk factors (e.g., diet, diabetes, aging) distinctly affect the clock in the heart, have led to the hypothesis that aberrant regulation of this mechanism contributes to the etiology of cardiac dysfunction and disease. Here, we provide a comprehensive review on current knowledge regarding known roles of the heart clock and discuss the potential for using these insights for the future development of innovative strategies for the treatment of cardiovascular disease. PMID- 25800588 TI - Identifying N fertilizer regime and vegetable production system in tropical Brazil using (15) N natural abundance. AB - BACKGROUND: This study was conducted in areas of vegetable production in tropical Brazil, with the objectives of (i) measuring the variation in delta(15) N in soils, organic N fertilizer sources and lettuce (Lactuca sativa L.) from different farming systems, (ii) measuring whether plant delta(15) N can differentiate organic versus conventional lettuce and (iii) identifying the factors affecting lettuce delta(15) N. RESULTS: Samples of soil, lettuce and organic inputs were taken from two organic, one conventional and one hydroponic farm. The two organic farms had different N-sources with delta(15) N values ranging from 0.0 to +14.90/00 (e.g. leguminous green manure and animal manure compost, respectively), and differed significantly (P < 0.05) in lettuce delta(15) N (+9.2 +/- 1.10/00 and +14.3 +/- 1.00/00). Conventional lettuce delta(15) N (+8.5 +/- 2.70/00) differed from hydroponic lettuce delta(15) N (+4.5 +/- 0.20/00) due to manure inputs. The N from leguminous green manure made a small contribution to the N nutrition of lettuce in the multi-N-source organic farm. CONCLUSION: To differentiate organic versus conventional farms using delta(15) N the several subsets of mode of fertilization should be considered. Comparisons of delta(15) N of soil, organic inputs and lettuce allowed a qualitative analysis of the relative importance of different N inputs. PMID- 25800590 TI - Compassion Fatigue in Pediatric Nurses. AB - Compassion fatigue in nursing has been shown to impact the quality of patient care and employee satisfaction and engagement. The aims of this study were to determine the prevalence and severity of compassion fatigue among pediatric nurses and variations in prevalence based on respondent demographics using a cross-sectional survey design. Nurses under 40 years of age, with 6-10 years of experience and/or working in a medical-surgical unit had significantly lower compassion satisfaction and higher levels of burnout. Secondary traumatic stress from caring for children with severe illness or injury or end of life was a key contributor to compassion fatigue. PMID- 25800591 TI - Selective Spleen Scintigraphy in the Evaluation of Accessory Spleen/Splenosis in Splenectomized/Nonsplenectomized Patients and the Contribution of SPECT Imaging. AB - OBJECTIVE: We aimed to evaluate the results of selective spleen scintigraphy (SSS) and contribution of SPECT imaging to planar imaging in splenectomized and nonsplenectomized patients. METHODS: We retrospectively examined 112 SSSs of 96 patients. The patients were divided into two groups as splenectomized group (SP) and non-splenectomized group (NSP). The findings were evaluated by comparing the results of surgery,computerized tomography (CT), ultrasonography (USG) and magnetic resonance imaging (MRI). In addition, whether or not differences existed between the results of SPECT and planar imaging was determined. RESULTS: Of 66 scintigraphies performed in the NSP group, 3 (5%) had positive, 3 (5%) had suspicious and 60 (90%) had negative results. In the NSP group, 28 patients underwent surgery and 12 accessory spleens were removed. Only 3 of these tissues were detected by scintigraphy. Of 46 patients in the SP group, 26 (57%) had positive findings whereas 20 (43%) had negative scintigraphies. Twelve accessory spleens/splenosis were removed surgically in 10 patients with a positive SSS in the SP group. There were no false positive results in both groups of patients who underwent surgery. There was no significant difference between the results of SSS, USG and CT. Of 39 patients to whom SPECT were performed, 10 had positive results both with planar and SPECT imaging. On the other hand, 26 patients, 3 of whom had suspected findings in SPECT images, demonstrated negative results when evaluated with both imaging methods. Remaining 3 were considered suspicious by only SPECT images for the hilar area. CONCLUSION: SSS has high specificity in the detection of accessory spleens/splenosis. The sensitivity of SSS is low in the NSP group,but higher in the SP group. There is no contribution of SPECT imaging to planar imaging. PMID- 25800589 TI - Physical activity and its mechanistic effects on prostate cancer. AB - Beneficial effects of physical activity have been illustrated in numerous aspects of health. With the increasing incidence of prostate cancer and changes in physical activity of men, understanding the link between the two has important implications for changing this cancer burden. Both positive and negative associations between physical activity and prostate cancer have been previously demonstrated in observational epidemiological studies. Elucidating the biological mechanisms would lead to a better understanding of how physical activity influences the progression of prostate cancer. This review was undertaken to: (1) identify evidence in literature that demonstrates the effects of physical activity on skeletal muscle secretomes, (2) indicate the plausible signaling pathways these proteins might activate, and (3) identify evidence in literature that demonstrates the roles of the signaling pathways in prostate cancer progression and regression. We also discuss proposed biological mechanisms and signaling pathways by which physical activity may prevent the development and progression of prostate cancer. We discuss proteins involved in the normal and aberrant growth and development of the prostate gland that may be affected by physical activity. We further identify future directions for research, including a better understanding of the biological mechanisms, the need to standardize physical activity and identify mechanistic end points of physical activity that can then be correlated with outcomes. PMID- 25800592 TI - Sacroiliac indicis increase the specificity of bone scintigraphy in the diagnosis of sacroiliitis. AB - OBJECTIVE: Bone scintigraphy is a highly sensitive method in the evaluation of sacroiliitis. Aim of this study is firstly to evaluate interobserver variation of partial and whole sacroiliac indicis, secondly investigation of clinical importance of these indicis in the diagnosis of sacroiliitis. METHODS: Fourty-six subjects (24 female: 35.4+/-11.9; 22 male: 43.1+/-12.4) without sacroiliitis 45 subjects with low back pain (33 female: 43.3+/-11.5, 11 male: 35.5+/-17.2) were included in the study. For right (R) and left (L) whole indices (WSI) irregular region of interest (ROI), for partial indices superior (S) and inferior (I) rectangular ROI were used. For background activity, rectangular ROI was drawn from the sacral region. Indices were calculated from ratio of average counts of sacroiliac and background regions. Two independent observers calculated sacroiliac indices. Interobserver agreement was evaluated by Pearson analysis. RESULTS: There was no significant interobserver difference (p>0.05). Significant correlation existed between all calculated indices. Among 45 patients with suspicion of sacroiliitis 15 had final diagnosis of sacroiliitis and all of the Tc-99m methilenediphosphonate planar and SPECT bone scintigraphy results of these patients were concordant with sacroiliitis. There were 8 false positive results in other 30 patients. Seven of these eight patients had normal index values. If the scintigraphy would be evaluated in conjuction with indicis the specificity would increase from 73% to 97% but sensitivity decreases from 100% to 80%. There was significant correlation between the observers calculated indicis (p<0.001). CONCLUSION: Superior and inferior sacroiliac index values can be used with confidence. If we use sacroiliac index values to confirm positive results; index values can increase the specificity of bone scintigraphy. PMID- 25800593 TI - The Role of 18F-FDG PET/CT in the Primary Staging of Gastric Cancer. AB - OBJECTIVE: The aim of this study is to explore the role of 18F-FDG PET/CT in the primary staging of gastric cancer in the comparison of ceCT as routine staging method and evaluate influencing parameters of 18F-FDG uptake. METHODS: Thirty-one patients (mean age: 58.9+/-12.6) who underwent 18F-FDG PET/CT for primary staging of gastric cancer between June 2011 and June 2012 were included to the study. 18F FDG PET/CT findings were compared with pathological reports in patients who underwent surgery following PET/CT. 18F-FDG PET/CT findings of primary lesions, lymph nodes and adjacent organs were compared with ceCT findings and pathological reports. Since 6 patients were accepted as inoperable according to 18F-FDG PET/CT and/or ceCT and/or laparotomy and/or laparoscopy findings, pathological confirmation could not be possible. RESULTS: In the postoperative TNM staging of patients, while 1 (4%), 1 (4%), 4 (16%), 2 (8%), 12 (48%) and 5 (20%) patients were staged as T0, Tis, T1, T2, T3 and T4, respectively, 8 (32%), 6 (24%), 6 (24%) and 5 (20%) patients were N0, N1, N2 and N3 respectively. 18F-FDG PET/CT was totally normal in 2 patients. While primary tumors were FDG avid in 27 patients, in 17 and 6 patients FDG uptake was observed in perigastric lymph nodes and distant organs, respectively. Mean SUVmax of FDG avid tumors was calculated as 13.49+/-9.29 (3.00-44.60). However, SUVmax of lymph nodes was computed as 9.28+/-6.92 (2.80-29.10). According to sub-analysis of histopathological subtypes of primary tumors, SUVmax of adenocarsinomas was calculated as 15.16 (3.00 44.60), of signet ring cells as 9.90 (5.50-17.70), of adenocarcinomas with signet ring cell component as 11.27 (6.20-13.90) (p=0.721). In the comparison with histopathological examination while ceCT was TP, TN, FN in 23, 1 and 1 patients, 18F-FDG PET/CT was TP, FP, FN in 20, 1 and 4 patients, respectively. Sensitivity, specificity, accuracy, PPD and NPV of ceCT in the detection of lymph node metastasis was calculated as 83.3%, 75%, 80%, 87.5% and 66.6%, respectively. These parameters for 18F-FDG PET/CT were 64.7%, 100%, 76%, 100% and 57.1%. CONCLUSION: Despite lower sensitivity than ceCT, diagnostic power of 18F-FDG PET/CT in the preoperative staging of gastric cancer is acceptable. Because of its high PPV, it might be beneficial in the evaluation of patients with suspected lymph nodes. The role of 18F-FDG PET/CT seems to be limited in the early stage and signet ring cell carcinomas due to lower 18F-FDG uptake. PMID- 25800594 TI - Insufficiency of bone scintigraphy in vertebral lesions of langerhans cell histiocytosis compared to f-18 fluorodeoxyglucose positron emission tomography/computed tomography and diagnostic computed tomography. AB - Langerhans cell histiocytosis (LCH) is a benign disorder related to the histiocytes which can infiltrate bone tissue. The most effective method for demonstrating severity of this disease is PET/CT and bone scintigraphy might show bone lesions. We present a seventeen year old male patient with disseminated LCH presented with exophtalmos and having multiple vertebral lesions which were identified by F-18 FDG PET/CT scan and diagnostic CT but not in the bone scintigraphy. PMID- 25800595 TI - Diagnosis of Brachiocephalic Thrombophlebitis as the Cause of Fever of Unknown Origin by 18F-FDG-PET/CT. AB - Fever of unknown origin (FUO) represents a challenge in diagnosis and treatment. The role of 18Ffluorodeoxyglucose positron emission tomography (FDG-PET) / computed tomography (CT) in the differential diagnosis of this entity is presently well established. We report the case of a patient with infectious/inflammatory symptoms but no evident localization and subsequent relapse, in which PET/CT showed its ability to not only determine the exact localization of a thrombophlebitic focus as cause of FUO, but also to monitor and determine the success of treatment. After performing a FDG-PET/CT and detecting a thrombophlebitis in the brachiocephalic vein, low molecular heparins were introduced in the course of therapy. Soon (about 24 hours) thereafter, clinical symptoms significantly decreased and could no longer be observed. After continuing the antibiotic and anticoagulant therapy for 4 weeks, a follow-up PET/CT scan was performed. That scan no longer showed abnormal uptake in the previous intravascular localization. Consequently, we suggest that PET/CT is a diagnostic modality feasible to identify and monitor therapy response of intravascular thrombophlebitic foci. PMID- 25800596 TI - Riedel's Thyroiditis with Intense FDG Uptake Demonstrated on FDG PET/CT. AB - A 39 year old female presented with rapidly enlarging goitre, minimal obstructive symptoms and no constitutional symptoms. Clinical examination revealed diffusely enlarged, firm, non-tender thyroid gland. Biochemical investigations showed subclinical hypothyroidism, positive thyroid antibodies and unremarkable inflammatory markers. Ultrasound examination and CT scan of the neck were suspicious of Riedels thyroiditis. The patient was referred for a FDG PET scan to evaluate for systemic fibro-inflammatory process or lymphoma. Subsequent core biopsy of the thyroid gland demonstrated a chronic inflammatory process with fibrosis consistent with Riedels thyroiditis. A FDG PET/CT study showed diffuse FDG uptake in the thyroid gland and no abnormal retroperitoneal FDG uptake elsewhere to suggest active retroperitoneal fibrosis. The goitre reduced in size with thyroid hormone replacement and steroids, however the patient was lost to follow up. PMID- 25800597 TI - 18F-FDG PET-CT for Evaluation of Cardiac Angiosarcoma: A Case Report and Review of Literature. AB - Cardiac angiosarcomas are rare neoplasms. We here present the case of a 24 year old male with a cardiac mass which was characterised as malignant on 18F Fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT). In addition 18F-FDG PET-CT also demonstrated pericardial infiltration and bone metastases. The tumor was confirmed to be angiosarcoma on biopsy and palliative chemotherapy was started. Here we have highlighted the potential role of 18F-FDG PET-CT in patients with cardiac angiosarcoma and presented a brief review. PMID- 25800613 TI - Ultimate thin vertical p-n junction composed of two-dimensional layered molybdenum disulfide. AB - Semiconducting two-dimensional crystals are currently receiving significant attention because of their great potential to be an ultrathin body for efficient electrostatic modulation, which enables to overcome the limitations of silicon technology. Here we report that, as a key building block for two-dimensional semiconductor devices, vertical p-n junctions are fabricated in ultrathin MoS2 by introducing AuCl3 and benzyl viologen dopants. Unlike usual unipolar MoS2, the MoS2 p-n junctions show ambipolar carrier transport, current rectification via modulation of potential barrier in films thicker than 8 nm and reversed current rectification via tunnelling in films thinner than 8 nm. The ultimate thinness of the vertical p-n homogeneous junctions in MoS2 is experimentally found to be 3 nm, and the chemical doping depth is found to be 1.5 nm. The ultrathin MoS2 p-n junctions present a significant potential of the two-dimensional crystals for flexible, transparent, high-efficiency electronic and optoelectronic applications. PMID- 25800614 TI - Leaf respiration (GlobResp)--global trait database supports earth system models. PMID- 25800615 TI - Dimensions of plant flammability. PMID- 25800616 TI - Plants, fungi and oomycetes: a 400-million year affair that shapes the biosphere. PMID- 25800617 TI - Fever during pregnancy and motor development in children: a study within the Danish National Birth Cohort. AB - AIM: The aim of this study was to examine how fever during pregnancy is associated with motor development in the child. METHOD: This cohort study was based on data from females and their children, from the Danish National Birth Cohort, who took part in an 18-month and/or 7-year follow-up study. Information regarding fever (number of episodes, temperature, duration, and pregnancy week) was obtained around gestation week 12 and at the end of pregnancy. Assessments of motor development in early childhood were based on the ages at which the motor milestones 'sitting unsupported' (n=44,256) and 'walking unassisted' (n=53,959) were attained. The Developmental Coordination Disorder Questionnaire 2007 (DCDQ'07) was used to identify children with indication of developmental coordination disorder (DCD) at age 7 years (n=29,401). Any associations between the exposure to fever during pregnancy and motor development were estimated using Cox regression and logistic regression analyses. RESULTS: Fever during pregnancy was reported by 15,234 (28.0%) participants in the 18-month follow-up and by 7965 (26.9%) participants in the 7-year follow-up. Adjusted analyses showed no association between prenatal exposure to fever and either 'sitting unsupported' or 'walking unassisted'. The proportion of children with indication of DCD was 3.1%. The odds ratio of indication of DCD if children were exposed to fever in utero was 1.29 (95% CI 1.12-1.49). However, no dose-response association was found. INTERPRETATION: We found a significant association between maternal fever during pregnancy and DCD in children at age 7 years. The lack of a dose-response association might suggest that this association is explained by the underlying causes of the fever. PMID- 25800618 TI - Effect of Coenzyme Q10 on Th1/Th2 Paradigm in Females with Idiopathic Recurrent Pregnancy Loss. AB - PROBLEM: Recurrent pregnancy loss is characterized by predominant Th1-type immunity and increased reactive oxygen species. Low levels of Coenzyme Q10 are found in the plasma of RPL as compared to healthy pregnant females. Our aim was to investigate whether in vitro supplementation of PBMCs from such females with CoQ10 could change the observed Th1 bias. METHOD OF STUDY: PBMCs were isolated from 20 RPL pregnant and non-pregnant females and 16 healthy pregnant females and incubated with CoQ10 in in vitro conditions. Phenotyping of Th1, Th2, and Th17 cells was performed by flow cytometry. Cytokine levels were determined by ELISA. RESULTS: PBMCs treated with CoQ10 showed significantly decreased percentage of Th1 cells (P < 0.005) in pregnant females with history of RPL than in the untreated ones. Also, levels of IFN-gamma and TNF-alpha were significantly decreased in the culture supernatant of treated PBMCs from RPL. DCFDA staining showed significantly reduced production of ROS in the treated PBMCs in RPL females. CONCLUSION: CoQ10 was effective in maintaining the immune homeostasis by reducing the proportion of IFN-gamma-producing T cells and proinflammatory cytokine levels in the RPL pregnant females. This property could be attributed to the capability of CoQ10 in reducing oxidative stress by decreasing ROS production. PMID- 25800619 TI - Patterns of structural and sequence variation within isotype lineages of the Neisseria meningitidis transferrin receptor system. AB - Neisseria meningitidis inhabits the human upper respiratory tract and is an important cause of sepsis and meningitis. A surface receptor comprised of transferrin-binding proteins A and B (TbpA and TbpB), is responsible for acquiring iron from host transferrin. Sequence and immunological diversity divides TbpBs into two distinct lineages; isotype I and isotype II. Two representative isotype I and II strains, B16B6 and M982, differ in their dependence on TbpB for in vitro growth on exogenous transferrin. The crystal structure of TbpB and a structural model for TbpA from the representative isotype I N. meningitidis strain B16B6 were obtained. The structures were integrated with a comprehensive analysis of the sequence diversity of these proteins to probe for potential functional differences. A distinct isotype I TbpA was identified that co-varied with TbpB and lacked sequence in the region for the loop 3 alpha-helix that is proposed to be involved in iron removal from transferrin. The tightly associated isotype I TbpBs had a distinct anchor peptide region, a distinct, smaller linker region between the lobes and lacked the large loops in the isotype II C-lobe. Sequences of the intact TbpB, the TbpB N-lobe, the TbpB C-lobe, and TbpA were subjected to phylogenetic analyses. The phylogenetic clustering of TbpA and the TbpB C-lobe were similar with two main branches comprising the isotype 1 and isotype 2 TbpBs, possibly suggesting an association between TbpA and the TbpB C-lobe. The intact TbpB and TbpB N-lobe had 4 main branches, one consisting of the isotype 1 TbpBs. One isotype 2 TbpB cluster appeared to consist of isotype 1 N-lobe sequences and isotype 2 C-lobe sequences, indicating the swapping of N lobes and C-lobes. Our findings should inform future studies on the interaction between TbpB and TbpA and the process of iron acquisition. PMID- 25800620 TI - A multi-institutional study of clinicopathological features and molecular epidemiology of epidermal growth factor receptor mutations in lung cancer patients living with human immunodeficiency virus infection. AB - PURPOSE: Lung cancer has become a crucial problem among individuals living with the human immunodeficiency virus (HIV) and causes high mortality in Western countries. Japan has an increasing number of newly infected HIV patients, and lung cancer is becoming a theme in this population. However, clinical factors of this particular population in East Asian are unclear given the identification of ethnic differences in lung cancer in the general population. METHODS: From 1986 to 2013, a retrospective nationwide study involving Japanese patients living with HIV and diagnosed with lung cancer was undertaken. RESULTS: Forty-three lung cancer patients with HIV were identified (median age, 60.0 years; males, 97.7%; early-stage cancer, 37.2%; metastatic cancer, 34.9%), 41 (95.3%) of whom developed lung cancer in the antiretroviral era. The median CD4-positive T-cell count was 326 cells/uL. Adenocarcinoma was the most frequent histology (55.8%), followed by squamous cell carcinoma (27.9%). Epidermal growth factor receptor (EGFR) status was examined in 14 patients; five (35.7%) had EGFR mutations. The median overall survival time was 25.1 months for all stages and 7.9 months for advanced-stage cancer. Using univariate analysis, the only favorable prognostic factor for overall survival was cancer stage (p = 0.02). CONCLUSIONS: The incidence of lung cancer among HIV patients in Japan has been increasing in the past decade. The present Japanese cohort showed similar EGFR mutation status similar to that of general population. The ethnic differences known in the general population were seen even in the population living with HIV, implying distinct clinical characteristics and outcomes from those reported in Western countries. PMID- 25800621 TI - Incidence, treatment, and outcome of parotid carcinoma, 1996-2011: a population based study in Thuringia, Germany. AB - PURPOSE: The objective of this study was to examine patterns of care and survival in a population-based sample of patients with parotid cancer who were treated in Thuringia, a federal state in Germany, between 1996 and 2011. METHODS: Data of 295 patients with primary parotid cancer from the Thuringian cancer registry were evaluated for patient's characteristics, tumor stage, incidence, and trends in treatment, cancer-specific survival (CSS), and overall survival (OS). RESULTS: Stages IV tumors and the amount of tumors in all age cohorts >=45 years of age increased significantly during the observation period (p = 0.002; age all p < 0.05, respectively). The highest increase in crude incidence was observed for salivary duct carcinomas [relative risk per decade (RR) 5.46; 95% confidence interval (CI) 1.14-26.14] and rare carcinoma subtypes (RR 9.99; 95% CI 1.85 53.94). CSS at 5 years and at 10 years for all patients was 82.4 and 82.4%, respectively. OS at 5 years and at 10 years for all patients was 60.1 and 48.2%, respectively. CSS and OS did not improve over the time. Salivary duct carcinoma showed the lowest 5-year OS (35.6%). Acinic cell carcinoma had the highest OS rate (85.3%). Multivariate Cox models revealed that higher grading (G3/G4) was a more powerful independent predictor of decreased OS than TNM stage. CONCLUSIONS: CSS and OS did not improve during the study period. Incidence of parotid cancer increased significantly in elderly patients. It seems that grading is next to patient's age the better predictor of OS than TNM stage. PMID- 25800622 TI - Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia. AB - BACKGROUND: Severe infectious complications reflect a continuing problem in patients with acute myeloid leukemia (AML). Based on data from a randomized clinical trial demonstrating a reduction of proven and probable invasive fungal disease (IFD), posaconazole has been approved for prophylaxis of fungal infections in AML patients during induction chemotherapy. Nevertheless, recently published observational studies show contradictory results concerning the efficacy of posaconazole in this clinical setting. Furthermore, oral suspension posaconazole is associated with an unpredictable bioavailability that especially depends on nutritional factors or gastric pH value. PATIENTS AND METHODS: We retrospectively analyzed the impact of posaconazole prophylaxis in 70 consecutively evaluable AML patients who underwent induction chemotherapy at a tertiary care hospital. The incidence of IFD classified as proven, probable or possible, antifungal therapy including empiric treatment in high-risk patients and tolerability of posaconazole were determined. In addition, important clinical cofactors such as co-treatment with proton pump inhibitors and risk factors for pneumonia were analyzed in this study. RESULTS: We can demonstrate that posaconazole is well tolerated and had to be stopped in only six patients (8.6%). The overall incidence of IFD was 30% including two patients with proven (2.8%), four patients with probable (5.7%) and 15 patients with possible IFD (21.4%). Importantly, 24 out of 49 patients (49.0%) who did not fulfill the criteria of IFD received empiric antifungal therapy. Including patients classified as possible IFD, 39 of 70 patients (55.7%) underwent at least first-line antifungal treatment. CONCLUSION: Our "real-life" data obtained from 70 AML patients after induction chemotherapy demonstrate the frequent necessity of systemic antifungal treatment despite prophylaxis with oral suspension posaconazole. PMID- 25800623 TI - Functional gain following knee replacement in patients aged 75 and older: a prospective follow-up study. AB - BACKGROUND AND AIMS: The aim of this prospective follow-up study was to analyze which patient characteristics predict better functional ability, as well as improvement in the ability, following knee replacement in the aged. The focus was on the impact of specific comorbidities and radiologic data. METHODS: Knee osteoarthritis patients aged >=75 years (n = 167) scheduled for knee replacement answered to a questionnaire asking about performance in the activities of daily living (ADL) before the operation, and 1 year afterwards. Radiologic data were evaluated from the latest radiographs, and comorbidity data from patient records. The primary outcome was a sum score indicating how many ADLs (out of 10) the patient was able to perform without difficulty. The factors associated with ADL performance were analyzed with adjustment for age, gender, Charlson's comorbidity index and Kellgren-Lawrence score. RESULTS: Knee replacement resulted in improved performance in almost all the analyzed ADL activities. Except for cardiac diseases, the effect of the analyzed comorbidities on ADL performance was not significant. Older patients and women attained lower final functional ability than younger patients and men, but improved similarly. In more progressed osteoarthritis, the final ability was lower, but the improvement gained was greater. CONCLUSIONS: Comorbidity, age, or more progressed osteoarthritis should not be considered an impediment to knee replacement. Even though the final functional ability may be lower in some, the improvement gained by surgery is similar regardless of comorbidity, and was more pronounced in more progressed disease. PMID- 25800631 TI - Effects of local administration of ibuprofen on sciatic nerve regeneration and reinnervation after egg shell membrane conduit repair in rat. AB - AIM: The objective was to assess the effect of locally administered ibuprofen (IBU) on transected peripheral nerve regeneration and functional recovery. MATERIALS AND METHODS: Seventy--five male Wistar rats were divided into five experimental groups (n = 15), randomly: In authograft group (AUTO) a segment of sciatic nerve was transected and reimplanted reversely. In transected group (TC), left sciatic nerve was transected and stumps were fixed in the adjacent muscle. In treatment group defect was bridged using an egg shell membrane conduit (ESM/IBU) filled with 10 MUL ibuprofen (100 ng/mL). In ESM conduit group (ESM), the conduit was filled with phosphate--buffered saline alone. In sham--operated group (SHAM), sciatic nerve was exposed and manipulated. Each group was subdivided into three subgroups of five animals each and regenerated nerve fibers were studied 4, 8 and 12 weeks after surgery. RESULTS: Behavioral testing, biomechanical studies, sciatic nerve functional study, electrophysiological, gastrocnemius muscle mass and morphometric indices confirmed faster recovery of regenerated axons in ESM/IBU than ESM group (p < 0.05). In immunohistochemistry, location of reactions to S--100 in ESM/IBU was clearly more positive than that in ESM group. CONCLUSION: Ibuprofen accelerated and improved functional recovery and morphometric indices of sciatic nerve. This study is expected to set a stage for testing the ibuprofen in the human patients. PMID- 25800632 TI - Why vision is important to how we navigate. AB - Place cells are a fundamental component of the rodent navigational system. One intriguing implication of place cells is that humans, by extension, have "map like" (or GPS-like) knowledge that we use to represent space. Here, we review both behavioral and neural studies of human navigation, suggesting that how we process visual information forms a critical component of how we represent space. These include cellular and brain systems devoted to coding visual information during navigation in addition to a location coding system similar to that described in rodents. Together, these findings suggest that while it is highly useful to think of our navigation system involving internal "maps," we should not neglect the importance of high-resolution visual representations to how we navigate space. PMID- 25800633 TI - [Auto-immune hepatitis in chronic granulomatous disease in a 2-year-old girl]. AB - BACKGROUND: Chronic granulomatous disease is a rare inherited primary immune deficiency disease characterized by recurrent infection and an increased susceptibility to autoimmunity disorders. We report on the case of a girl with autoimmune hepatitis in chronic granulomatous disease to describe the clinical and biological features and treatment implications for patients with chronic granulomatous disease associated with autoimmune disorders. CASE REPORT: An 18 month-old girl was referred to our department for investigation of hepatomegaly. She was the third child of non-consanguineous parents. Her two elder sisters had died from infectious diseases at an early age. She had elevated liver transaminase levels with a normal gamma globulin concentration. Negative results were found for all autoimmune markers (antinuclear antibody, anti-smooth muscle, anti-liver-kidney microsomal, anti-liver cytosol and anti-soluble liver antigen). Her liver biopsy showed features of interface hepatitis with portal fibrosis. The diagnosis of seronegative autoimmune hepatitis was established. Treatment with corticosteroids and azathioprine led to clinical improvement with normalization of transaminases. Six months after initial presentation, at the age of 2 years, she was readmitted for fever. Staphylococcus aureus bacteremia was identified with multiple foci of infection (skin infection, arthritis of the right elbow, pneumonia, buttock abscess). The immunological workup revealed chronic granulomatous disease. The course was marked by a fatal outcome despite appropriate antibiotics and intensive care. CONCLUSION: Early diagnosis of the association between chronic granulomatous disease and autoimmune disorders allows for appropriate treatments, improves the quality of life for affected patients, and reduces the risk of mortality. PMID- 25800634 TI - Children's exposure to indoor air in urban nurseries-part I: CO2 and comfort assessment. AB - Indoor air quality (IAQ) in nurseries is an emerging case-study. Thus, this study, as the Part I of the larger study "Children's exposure to indoor air in urban nurseries", aimed to: i) evaluate nurseries' indoor concentrations of carbon dioxide (CO2), a global IAQ indicator, in class and lunch rooms; ii) assess indoor comfort parameters-temperature (T) and relative humidity (RH); and iii) analyse them according to guidelines and references for IAQ, comfort and children's health. Indoor continuous measurements were performed. Non-compliances with guidelines were found in comfort parameters, which could cause discomfort situations and also microbial proliferation. Exceedances in CO2 concentrations were also found and they were caused by poor ventilation and high classroom occupation. More efficient ventilation and control of comfort parameters, as well as to reduce occupation by reviewing Portuguese legislation on that matter, would certainly improve IAQ and comfort in nurseries and consequently safeguard children's health. PMID- 25800636 TI - Surveillance for the use of mycophenolate mofetil for adult patients with lupus nephritis in Japan. AB - OBJECTIVES: Mycophenolate mofetil (MMF) is used as one of the standard induction/maintenance protocols for lupus nephritis (LN). However, MMF has not been approved for treating LN in any country, resulting in worldwide off-label use of this immunosuppressant. In order to clarify the real-world use of MMF as a treatment for LN in Japan, Japan College of Rheumatology surveyed the use of MMF in daily clinical practice. METHODS: Adult patients with LN who visited enrolled hospitals from October 2008 to September 2013 were surveyed for the initial, maximum, and maintenance doses of MMF. The safety and efficacy of MMF were retrospectively evaluated. RESULTS: One hundred and thirty-seven LN patients including 116 females were enrolled. The median of initial, maximum, and maintenance doses of MMF were 1.0 g/day, 1.5 g/day, and 1.0 g/day, respectively. Sixty-one adverse events were reported in 39 patients during the follow-up period. Median urine protein level decreased from 1.89 g/gCr to 0.21 g/gCr, meanC3 level increased from 66.4 mg/dl to 80.3 mg/dl, and median anti-DNA antibody titer decreased from 40.6 IU/ml to 10.6 IU/ml. CONCLUSION: MMF was commonly used for the treatment of adult LN patients with acceptable efficacy and safety in Japan. PMID- 25800637 TI - Outcome of shortened extra-small ulnar component in linked total elbow arthroplasty for patients with rheumatoid arthritis. AB - OBJECTIVE: We compared the clinical and radiological results of the 3-inch shortened ulnar stem of the extra-small component of Coonrad-Morrey prosthesis with those of the other ulnar components for patients with rheumatoid arthritis (RA). METHODS: A total of 33 Coonrad-Morrey total elbow arthroplasty (TEA) procedures were performed. Of these, 27 elbows of 25 patients with RA underwent primary TEA. The results of the clinical and radiological findings were compared between groups of patients receiving the shortened ulnar stem of extra-small components (shortened group) and of those receiving the components of the other sizes (control group). RESULTS: The mean follow-up was 6.2 +/- 2.8 years in the shortened group and 7.2 +/- 2.5 years in the control group. The Mayo elbow performance score and range of motion results were substantially improved after the operation for both groups. We encountered several peri- and postoperative complications, but no significant differences in clinical results were found between the groups. The control group had three cases of osteolysis around the implant, while the shortened group did not. CONCLUSIONS: TEA with a shortened ulnar implant of the extra-small size of the Coonrad-Morrey prosthesis gave satisfactory mid-term results among patients with RA. PMID- 25800638 TI - Early therapeutic intervention with methotrexate prevents the development of rheumatoid arthritis in patients with recent-onset undifferentiated arthritis: A prospective cohort study. AB - OBJECTIVES: To examine whether or not earlier therapeutic intervention with methotrexate (MTX) prevents the development of rheumatoid arthritis (RA) in patients with recent-onset undifferentiated arthritis (UA) showing high anti citrullinated peptide antibody (ACPA) titers. METHODS: The patients were divided into two groups, one was treated with MTX (MTX+ group, n = 29), and the other was treated without MTX (MTX- group, n = 19), and other disease-modifying anti rheumatic drugs were not permitted in the two groups before the primary endpoint was met. The primary endpoint is the occurrence of definite RA, and it was compared in the two groups after 1 year. RESULTS: The percentage of patients who developed definite RA in the MTX+ group (17.2%) was significantly lower than that in the MTX- group (78.9%) (log-rank test, P < 0.001, n = 48); adjusted hazards ratio: 0.028 [95% confidence interval (CI): 0.003-0.250, P = 0.001, n = 39]. Treatment effectiveness was not decreased by major risk factors of RA onset such as smoking habits and human leukocyte antigen-DRB1 shared epitope (SE) (smoking habit, odds ratio [OR]: 0.041 [95% CI: 0.007-0.246] P < 0.001; SE, OR: 0.022 [95% CI: 0.002-0.204] P < 0.001). The safety issues were comparable between the two groups. CONCLUSIONS: This suggests that early therapeutic intervention with MTX could safely prevent the development of RA in patients with recent-onset UA showing high ACPA titers. PMID- 25800639 TI - Protracted arthritis in a Japanese patient with familial Mediterranean fever. AB - The most common arthritic involvement in familial Mediterranean fever (FMF) is acute self- limiting monoarthritis which typically lasts for 72 h. Hip joint involvement is uncommon in FMF and can result either from a process specific to this disease or from a coexisting inflammatory joint disease. We describe a 37 year-old woman with FMF and right osteoarthritis secondary to congenital hip dislocation. Periodic fever with right coxalgia lasting for 6 months was treated using colchicine. Genetic analysis revealed homozygous mutation in the MEFV gene (L110P-E148Q/L110P-E148Q), confirming the FMF diagnosis. Although the clinical presentation and course of FMF arthritis are diverse, delineating these clinical patterns may help with early recognition and treatment to prevent destructive arthritis in FMF. Clinicians should consider the possibility of FMF development in unusual monoarthritis patients with recurrent febrile attacks. PMID- 25800640 TI - Polyarteritis nodosa confined to the breasts associated with polyenthesitis. PMID- 25800641 TI - Clinical utility of antibiotic-loaded hydroxyapatite block for treatment of intractable periprosthetic joint infection and septic arthritis of the hip. AB - OBJECTIVE: Antibiotic-loaded hydroxyapatite block (AHAB) allows gradual release of antibiotics for long duration without thermal damage and, therefore, is potentially a more effective antibacterial spacer than antibiotic-loaded polymethylmethacrylate cement (ALAC). The purposes of this study are to assess the utility of AHAB for the treatment of periprosthetic joint infection (PJI) or septic arthritis (SA) of the hip and to assess the potency of AHAB and ALAC in vitro. METHODS: AHAB was utilized in two-stage reconstruction surgery for 20 PJI and 7 SA patients. Clinical success was confirmed if the patients did not show any sign of recurrence of infection during the follow-up period. Duration and amount of active vancomycin (VCM) released from AHAB and ALAC spacer were investigated in vitro. RESULTS: Two-stage reconstruction using AHAB significantly improved hip function and showed 100% clinical success with mean follow-up of 37 months. The in vitro duration of the active effect of VCM released from AHAB (21 days) was longer than that from ALAC (7 days) and the amount of active VCM released from AHAB was higher than that from ALAC. CONCLUSIONS: AHAB promises to release higher amounts of active VCM for longer durations than ALAC; therefore, it is a promising treatment for intractable PJI or SA. PMID- 25800642 TI - Chitosan Grafted with Phosphorylcholine and Macrocyclic Polyamine as an Effective Gene Delivery Vector: Preparation, Characterization and In Vitro Transfection. AB - Herein, an effective gene delivery vector phosphorylcholine and macrocyclic polyamine grafted chitosan (PC-g(6)-Cs-g(2)-Cyclen) was developed. Chemical characterization of product PC-g(6)-Cs-g(2)-Cyclen was performed by NMR, FT-IR, gel permeation chromatography (GPC), and X-ray photoelectron spectroscopy (XPS) analysis. PC-g(6)-Cs-g(2)-Cyclen could more efficiently bind and protect plasmid DNA than macrocyclic polyamine grafted chitosan (Cs-g-Cyclen) and phosphorylcholine grafted chitosan (Cs-g-PC), as evaluated by agarose gel electrophoresis, circular dichroism spectra, and fluorescence quenching assays. PC-g(6)-Cs-g(2)-Cyclen could wrap DNA into uniform nanoparticles in the size of 112.6 +/- 8.5 nm and possessed net cationic charge. UV spectroscopy and MTT assays showed excellent water-solubility and cell viability for PC-g(6)-Cs-g(2) Cyclen. In addition, three polymer/DNA complexes showed 5.1-15.1-fold greater uptake activity and 10-14-fold higher transfection efficiency in 293 T cells as compared to chitosan/DNA complex, in which PC-g(6)-Cs-g(2)-Cyclen demonstrated the highest transfection activity. These date demonstrated that PC-g(6)-Cs-g(2) Cyclen is a promising vector candidate for gene delivery. PMID- 25800643 TI - Anti-type II collagen antibodies detection and avidity in patients with oligoarticular and polyarticular forms of juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) refers to a heterogeneous group of illnesses that have in common the occurrence of chronic joint inflammation in children younger than 16 years of age. The diagnosis is made only on clinical assessment. The identification of antibody markers could improve the early diagnosis, optimizing the clinical management of patients. Type II collagen is one potential autoantigen that has been implicated in the process of arthritis development. The aims of our study were to investigate the occurrence of anti-type II collagen antibodies and also to determine the avidity of the antibody-antigen binding. Ninety-six patients with oligoarticular or polyarticular JIA, 13 patients with ankylosing spondylitis (AS) and 61 healthy controls (HC) were tested for anti type II collagen antibodies by ELISA and avidity ELISA. Sensitivity and specificity were determined by the receiver operating characteristic (ROC) curve analysis. Forty-two JIA patients (44%) were positive for antibodies against type II collagen. Its detection was significantly higher in JIA patients than in AS patients (p=0.006) and HCs (p<0.0001). Furthermore, anti-type II collagen antibody detection was significantly more frequent in patients with JIA of <=6 months duration (p=0.0007). Antibodies displaying high avidity to type II collagen were associated with disease activity (p=0.004). This study demonstrates that antibodies against type II collagen are present in the serum of patients with oligoarticular and polyarticular JIA, being its presence more prevalent in patients with early disease. It also demonstrates that JIA patients with active disease present antibodies with high avidity against type II collagen. PMID- 25800645 TI - Synthesis, biological evaluation and molecular docking of some substituted pyrazolines and isoxazolines as potential antimicrobial agents. AB - A series of substituted pyrazolines (2a-e, 3a-h and 6a-c) and isoxazolines (4a-e) were synthesized and their structures were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectra. All the synthesized compounds were tested against two bacterial and four fungal strains and found to exhibit moderate to potent antifungal activity. Compounds 2b, 4c, 4d and 6a-c exhibited significant activity against all tested fungal strains. MIC values of all the active compounds were comparable with standard drug fluconazole. The results of the in silico molecular docking study supported the antifungal activity of the synthesized compounds. PMID- 25800644 TI - Relationship Between Metabolites Composition and Biological Activities of Phyllanthus niruri Extracts Prepared by Different Drying Methods and Solvents Extraction. AB - The study investigated the changes in the metabolite, antioxidant and alpha glucosidase inhibitory activities of Phyllanthus niruri after three drying treatments: air, freeze and oven dryings. Water extracts and extracts obtained using different solvent ratios of ethanol and methanol (50, 70, 80 and 100%) were compared. The relationships among the antioxidant, alpha-glucosidase inhibitory activity and metabolite levels of the extracts were evaluated using partial least square analysis (PLS). The solvent selectivity was assessed based on the phytochemical constituents present in the extract and their concentrations quantitatively analyzed using high performance liquid chromatography. The freeze dried P. niruri samples that were extracted with the mixture of ethanol or methanol with low ratio of water showed higher biological activity values compared with the other extracts. The PLS results for the ethanolic with different ratio and water extracts demonstrated that phenolic acids (chlorogenic acid and ellagic acid) and flavonoids were highly linked to strong alpha glucosidase inhibitory and antioxidant activities. PMID- 25800646 TI - Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2. AB - A novel series of macrocyclic compounds were designed and synthesized as multi target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation. PMID- 25800647 TI - Discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors: synthesis, structure-activity relationship analysis and biological evaluation. AB - Phosphorylation of the eukaryotic initiation factor 4E (eIF4E) by mitogen activated protein kinase (MAPK)-interacting kinases (Mnks) is essential for oncogenesis but unnecessary for normal development. Thus, pharmacological inhibition of Mnks may offer an effective and non-toxic anti-cancer therapeutic strategy. Herein, we report the discovery of 4-(dihydropyridinon-3-yl)amino-5 methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors. Docking study of 7a in Mnk2 suggests that the compound is stabilised in the ATP binding site through multiple hydrogen bonds and hydrophobic interaction. Cellular mechanistic studies on MV-4-11 cells with leads 7a, 8e and 8f reveal that they are able to down-regulate the phosphorylated eIF4E, Mcl-1 and cyclin D1, and induce apoptosis. PMID- 25800648 TI - Immediate effects of unilateral restricted ankle motion on gait kinematics in healthy subjects. AB - Correcting a pathological toe walking gait pattern can be achieved by restricting excessive plantarflexion during the swing phase of gait. A common conservative treatment measure is providing the patient with an ankle-foot-orthosis on the affected lower leg. This study examined the lower body gait kinematics and temporal-spatial parameters of fifteen healthy adults when walking freely and with unilateral restricted ankle motion. The latter was achieved by fitting an ankle-foot-orthosis. Specific hip and knee kinematic parameters and temporal spatial parameters were investigated. Differences between the two conditions were calculated by paired Student's t-tests and 95% confidence intervals. Unilateral restricted ankle motion influenced kinematics mainly in the swing phase. Hip and knee peak flexion in the swing phase were increased on the restricted side (hip: 49.2 degrees (SD 4.2 degrees ), knee: 75.9 degrees (SD 6.1 degrees )) compared to walking freely (hip: 43.3 degrees (SD 4.5 degrees ), knee: 66.7 degrees (SD 5.3 degrees )). Peak hip flexion occurred earlier in the swing phase in the restricted condition (85% (SD 2%)) compared to the free-walking condition (96% (SD 5%)). For these parameters, the confidence intervals were different, indicating clinical relevance. Walking with unilateral restricted ankle motion had a negative effect on walking velocity, cadence, step time, and step length. The confidence intervals, however, overlapped. These results might be a reaction to unusual sensory feedback from the feet with the ankle-foot-orthosis or due to increased hip flexor activity compensating for the reduced function of the plantarflexors. The evaluation of the immediate changes in unilateral restricted ankle motion in individuals with healthy gaits can contribute to a more complete understanding on this topic. PMID- 25800649 TI - Increased double support variability in elderly female fallers with vestibular asymmetry. AB - There is a broad consensus on the coupling of deteriorating gait and vestibular asymmetry, which has proved predictive of falls in the elderly. To date, research on this coupling remains inconclusive and has not focused specifically on fallers. In the present study, differences in gait variability were examined in a population of elderly females with fall-related wrist fractures, divided into samples with positive (N=28, 73+/-9 years) and negative head-shaking tests (N=6, 67+/-9 years). Swing, stance, and double support time variability were measured in preferred speed walking using GAITRite((r)) and statistically evaluated in multivariate analysis of covariance with age as covariate. Results showed overall greater gait variability for the positive nystagmus group (p=0.03) despite non significant adjustment of the covariate (p=0.18). In post-hoc analysis, the effect on variability in double support time emerged as a significant and large contributor to this difference (p=0.009, etap(2)=0.20). Conversely, the ability of swing and stance time variability to discriminate between groups was both non significant and small (p=0.25, etap(2)=0.04 and p=0.34, etap(2)=0.03 respectively). We believe that the increased variability might stem from a strategic use of double support to re-stabilize from balance perturbations during gait. To some extent, these results diverge from previous findings and need to be reassessed in future studies. PMID- 25800652 TI - Serum Proteomic Analysis Based on iTRAQ in Miners Exposed to Soil Containing Rare Earth Elements. AB - To explore the toxic effects of rare earth elements (REEs) accumulated in human body, adopting the inductively coupled plasma mass spectrometry (ICP-MS) method, the present study measured REEs and the contents of eight other elements (Ca, Fe, Cu, Na, K, Zn, Mg, and P) in the hair of eight persons exposed to soil containing REEs for a long time as well as in the control group. In addition, proteomic analysis of serum of the two groups was conducted by isobaric tags for relative and absolute quantitation (iTRAQ) technique. Experimental results show that in the hair of the two groups, 15 REEs and eight other elements were detected, in which the content of La, Ce, Pr, Nd, Tb, Ho, Tm, Yb, and Fe in the exposure group is significantly higher than that of the control group, but the content of Ca in the exposure group is significantly lower than that of the control group; analysis yields out 29 differentially expressed proteins, in which 16 proteins are upregulated and 13 proteins are downregulated. Bioinformatics analysis of differentially expressed proteins demonstrates that they participate in various biological processes and five Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, forming an interaction network. Besides, some differentially expressed proteins may be related to neurovirulence, hepatotoxicity, pathological fibrosis, osteoporosis, and anticoagulation caused by REEs. The present experiment investigated the toxic effects of REEs accumulated in human body at the molecular level, which may lay a foundation for the future research of biological effect, threshold limit values, protection from exposure, and reasonable application of REEs. PMID- 25800650 TI - Stereoselective synthesis of UDP-2-(2-ketopropyl)galactose aided by di-tert butylsilylene protecting group. AB - UDP-2-(2-ketopropyl)galactose (1) has been utilized as a valuable probe for profiling proteins modified by O-GlcNAc. In this work, we developed a protocol for efficient synthesis of 1. Thus, 2-methallylgalactose derivative 11, a synthetic intermediate for the compound 1, was prepared by stereoselective iodination and methallylation at C-2 position, through exploitation of 4,6-O-di tert-butylsilylene protecting group. PMID- 25800651 TI - Dissatisfaction of hospital patients, their relatives, and friends: Analysis of accounts collected in a complaints center. AB - OBJECTIVE: This study aimed to analyze complaints of patients, their relatives, and friends who consulted a complaints center based (Espace Patients & Proches (EPP)) in a hospital so as to better understand the reasons that motivated them and their underlying expectations. METHODS: This study was based on the analysis of written accounts of the 253 situations that occurred during the first year of operation of the EPP. The accounts were analyzed qualitatively using an inductive, thematic analytic approach. RESULTS: We identified 372 different types of complaints and 28 main analytic themes. Five clustered themes emerged from the analysis of the interconnections among the core themes: (1) interpersonal relationship (N=160-the number of accounts including a complaint related to this general theme); (2) technical aspects of care (N=106); (3) health-care institution (N=69); (4) billing and insurance; (5) access to information (N=13). CONCLUSION: The main reason for patients, their relatives, and friends going to EPP was related to the quality of the interpersonal relationship with health-care professionals. Such complaints were markedly more frequent than those concerning technical aspects of care. PRACTICE IMPLICATIONS: These results raise important questions concerning changing patient expectations as well as how hospitals integrate complaints into the process of quality health care. PMID- 25800653 TI - Effects of Organic and Inorganic Forms of Manganese, Zinc, Copper, and Chromium on Bioavailability of These Minerals and Calcium in Late-Phase Laying Hens. AB - In the present study, the effects of dietary supplementation of organic and inorganic Mn, Zn, Cu, and Cr mixtures using two different levels (80, 60, 5, and 0.15 mg/kg and 40, 30, 2.5, and 0.07 mg/kg, respectively) on the bioavailability of these trace minerals and Ca in late-phase laying hens were evaluated. Three hundred and sixty laying hens (Barred Rock) at 50 weeks of age were used, and the duration of study was 16 weeks. Each of the four dietary regimes was randomly assigned to six replicates, which included 15 hens each. Organic trace minerals were provided as methionine chelates; inorganic Mn, Zn, and Cr were provided as oxides; and Cu was provided as sulfate. The organic form significantly increased the concentrations of serum Mn, Zn, Cu, and Ca; egg Mn, Zn, Cu, and Cr; and eggshell Zn and Cr compared with the inorganic form. However, the form of trace minerals did not affect the concentrations of serum Cr and eggshell Mn, Cu, and Ca. High-level addition of trace minerals significantly increased serum Mn and Zn; egg Mn, Zn, Cu, and Cr; and eggshell Mn, Zn, and Cu concentrations compared with low-level addition but did not affect serum Cu, Cr, and Ca or eggshell Cr and Ca concentrations. While the organic form reduced the excretion of Mn, Zn, Cu, Cr, and Ca, the high-level supplement increased Mn, Zn, and Cu excretion. The addition level did not affect Cr and Ca excretion. These results demonstrate that dietary supplementation of an organic Mn, Zn, Cu, and Cr mixture increases the bioavailability of Mn, Zn, Cu, Cr, and Ca compared with inorganic sources and that a lower level of trace mineral supplementation results in lower mineral excretion, particularly in an organic form. PMID- 25800654 TI - Boron-Based Drug Design. AB - The use of the element boron, which is not generally observed in a living body, possesses a high potential for the discovery of new biological activity in pharmaceutical drug design. In this account, we describe our recent developments in boron-based drug design, including boronic acid containing protein tyrosine kinase inhibitors, proteasome inhibitors, and tubulin polymerization inhibitors, and ortho-carborane-containing proteasome activators, hypoxia-inducible factor 1 inhibitors, and topoisomerase inhibitors. Furthermore, we applied a closo dodecaborate as a water-soluble moiety as well as a boron-10 source for the design of boron carriers in boron neutron capture therapy, such as boronated porphyrins and boron lipids for a liposomal boron delivery system. PMID- 25800655 TI - Iridium-catalyzed ortho-selective C-H silylation of aromatic compounds directed toward the synthesis of pi-conjugated molecules with Lewis acid-base interaction. AB - We successfully developed an iridium-catalyzed ortho-selective C-H silylation of aromatic compounds. The reaction exhibited a wide substrate scope, and a variety of pi-conjugated molecules were synthesized in good to excellent yields, even in gram scale. Several silyl groups could also be introduced into the products. The experimental results indicated that the regioselectivity could be controlled by a Lewis acid-base interaction between the Lewis acidic silicon atoms of fluorinated hydrosilanes and the Lewis basic nitrogen atoms of aromatic compounds. PMID- 25800657 TI - Erratum to: Can magnifying endoscopy with narrow band imaging be useful for low grade adenomas in preoperative biopsy specimens? PMID- 25800658 TI - Self-reported psychosocial needs and health-related quality of life of colorectal cancer survivors. AB - PURPOSE OF THE RESEARCH: To investigate the prevalence and nature of unmet needs among colorectal cancer (CRC) survivors and the relationship between needs and quality of life (QoL). METHODS AND SAMPLE: Using the Northern Ireland Cancer Registry (NICR) as a sampling frame and working in collaboration with primary care physicians or GPs, the Cancer Survivors Unmet Needs (CaSUN) questionnaire and the Quality of Life in Adult Cancer Survivors Scale (QLACS) were posted to a randomly selected sample of 600 CRC survivors. KEY RESULTS: Approximately 69% (413/600) met eligibility criteria for participating in the study; and 30% (124/413) responded to the survey. A comparative analysis of NICR data between respondents and non-respondents did not indicate any systematic bias except that respondents appeared to be younger (65 years vs. 67 years). Approximately 60% of respondents reported having no unmet needs, with 40% reporting one or more unmet health and social care needs such as fear of recurrence, information needs, difficulty obtaining travel insurance and car parking problems. QoL was significantly lower for CRC survivors who reported an unmet need. Highest scores (poorer QoL) were reported for fatigue, welfare benefits and distress recurrence. CONCLUSIONS: Overall, the majority of CRC survivors who had care needs appeared to have needs that were mainly psychosocial in nature and these unmet needs were related to poorer QoL. PMID- 25800659 TI - Association between histological findings and polarization-sensitive optical coherence tomography analysis of a post-trabeculectomy human eye. PMID- 25800660 TI - The role of endoscopy in inflammatory bowel disease. PMID- 25800662 TI - Easy and cheap way to prepare skin extenders. AB - Skin extender is a very useful method to repair wounds when oedema and skin retraction make a direct suture impossible. We have developed a new, simple and cheap way to prepare skin extenders based only on elastic vessel loops and metal clips stapler commonly used for skin suture and available in any operating room. This simple method can be performed both in the operating room and at the patient bedside, even under local anaesthesia, causes no bleeding and appears to be inexpensive and rapidly usable and should be made readily available in any hospital. PMID- 25800663 TI - Estimating the Dead Space Volume Between a Headform and N95 Filtering Facepiece Respirator Using Microsoft Kinect. AB - N95 filtering facepiece respirator (FFR) dead space is an important factor for respirator design. The dead space refers to the cavity between the internal surface of the FFR and the wearer's facial surface. This article presents a novel method to estimate the dead space volume of FFRs and experimental validation. In this study, six FFRs and five headforms (small, medium, large, long/narrow, and short/wide) are used for various FFR and headform combinations. Microsoft Kinect Sensors (Microsoft Corporation, Redmond, WA) are used to scan the headforms without respirators and then scan the headforms with the FFRs donned. The FFR dead space is formed through geometric modeling software, and finally the volume is obtained through LS-DYNA (Livermore Software Technology Corporation, Livermore, CA). In the experimental validation, water is used to measure the dead space. The simulation and experimental dead space volumes are 107.5-167.5 mL and 98.4-165.7 mL, respectively. Linear regression analysis is conducted to correlate the results from Kinect and water, and R(2) = 0.85. PMID- 25800664 TI - MYC amplification in multiple marker chromosomes and EZH2 microdeletion in a man with acute myeloid leukemia. AB - The role of MYC and EZH2 in acute myeloid leukemia (AML) pathogenesis is poorly understood. Herein we present a case of AML with MYC amplification in marker chromosomes and a microdeletion of chromosome 7 below cytogenetic resolution. The karyotype of the patient's bone marrow aspirate showed three to five marker chromosomes in all dividing cells without other structural or numerical chromosomal abnormalities. Analysis by fluorescence in situ hybridization (FISH) with a probe specific for the human MYC gene revealed amplification of the oncogene localized to the marker chromosomes. Using whole genome single nucleotide polymorphism (SNP) microarray analysis, an approximately 4.4 Mb amplicon containing the MYC gene was identified with an estimated amplification of about 30 copies per leukemic cell and, thus, an average of about 8 copies per marker chromosome. A 6.4 Mb hemizygous microdeletion of chromosome 7 within band q36.1 was also found by SNP microarray analysis in a cellular-equivalent dosage of 50%. The microdeletion spans multiple genes, including EZH2, a gene with well known cancer association. No mutation was found in the remaining EZH2 allele by next generation gene sequencing. The combination of MYC amplification and EZH2 deletion, which has not been described previously in AML, may suggest a synergistic role of the two oncogenes in the pathogenesis of the patient's acute leukemia. PMID- 25800661 TI - Impact of celiac neurolysis on survival in patients with pancreatic cancer. AB - BACKGROUND: Pancreatic cancer (PC) often produces pain that is difficult to control. Celiac neurolysis (CN) is performed with the goal of improving pain control and quality of life while reducing opioid-related side effects. OBJECTIVE: We aimed to evaluate whether CN provides a survival advantage for PC patients. DESIGN: Retrospective case-control study. SETTING: Single tertiary-care referral center. PATIENTS: Review of a prospectively maintained database identified patients with unresectable PC who underwent CN over a 12-year period. Each patient was matched to 2 control patients with unresectable PC. INTERVENTION: CN, which included both celiac plexus neurolysis (CPN) and celiac ganglia neurolysis (CGN). MAIN OUTCOME MEASUREMENTS: Median survival in Kaplan Meier curves and hazard ratios. RESULTS: A total of 417 patients underwent CN and were compared with 840 controls with PC. Baseline characteristics were similar except the CN group had greater weight loss and pain requiring opioids. A mean of 16.6 +/- 5.8 mL of alcohol was administered. For patients who underwent CN, the median survival from the time of presentation was shorter compared with controls (193 vs 246 days; hazard ratio 1.32; 95% confidence interval, 1.13-1.54). There was no difference in survival with unilateral or bilateral injection. However, EUS-guided CN was associated with longer survival compared with non-EUS approaches, and those who received CPN had longer survival compared with CGN. LIMITATIONS: Single center, retrospective. CONCLUSION: Our study suggests that CN is an independent predictor of shortened survival in PC patients. A prospective study is needed to verify the findings and determine whether shortened survival results from CN or from other features such as performance status and tumor related characteristics. It is also imperative to verify our finding that EUS guided CN provides a survival advantage over other approaches and whether CPN prolongs survival compared with CGN. PMID- 25800666 TI - Pilot Study of Exercise Therapy on Painful Diabetic Peripheral Neuropathy. AB - OBJECTIVE: Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes. While the beneficial effect of exercise on diabetes is well established, its effect specifically on painful DPN has not been thoroughly explored. The objective of this pilot study was to examine the effect of aerobic exercise on pain in people with DPN. METHODS: Fourteen sedentary individuals (mean age 57 +/- 5.11 years) with painful DPN were enrolled in a 16-week, supervised aerobic exercise program. The Brief Pain Inventory-Diabetic Peripheral Neuropathy was used to assess pain intensity (worst, least, average, now) and pain interference with daily life (activity, mood, walk, normal work, relationship, sleep, enjoyment of life) pre intervention and postintervention. Body mass index (BMI), maximum oxygen uptake (VO2max ), hemoglobin A1c (HbA1c), and blood pressure were also measured preintervention and postintervention as secondary outcomes of interest. RESULTS: Significant reductions in pain interference were observed with walking (4.93 +/- 3.03 pre to 3.29 +/- 2.89 post, P = 0.016), normal work (5.39 +/- 3.32 pre to 3.79 +/- 3.04 post, P = 0.032), relationship with others (3.96 +/- 3.53 pre to 1.29 +/- 1.27 post, P = 0.006), sleep (5.11 +/- 3.04 pre to 3.5 +/- 3.03 post, P = 0.02), and the overall pain interference (4.65 +/- 2.70 pre to 2.97 +/- 2.22 post, P = 0.013) following the intervention; however, there was no change in pain intensity. VO2max increased significantly postintervention (16.02 +/- 3.84 ml/kg/min pre to 17.18 +/- 4.19 ml/kg/min, P = 0.028), while BMI, HbA1c, and blood pressure remained unchanged. CONCLUSION: These preliminary results suggest that perceived pain interference may be reduced following an aerobic exercise intervention among people with painful DPN, without a change in pain intensity. Further validation by a RCT is needed. PMID- 25800668 TI - High rate of non-susceptibility to metronidazole and clindamycin in anaerobic isolates: Data from a clinical laboratory from Karachi, Pakistan. AB - Due to increasing resistance amongst anaerobic pathogens periodic surveillance of resistance has been recommended in regional/local settings. Anaerobic antimicrobial susceptibility testing is not routinely performed in many laboratories in Pakistan, hence absence of local data may lead to inappropriate empirical therapy in serious cases. 121 clinically significant anaerobic strains (26/121; 21% bacteremic isolates) were isolated and saved from 2010 to 2011. Susceptibility testing against metronidazole, clindamycin, co-amoxiclav, meropenem, piperacillin/tazobactam, linezolid and gatifloxacin was performed by determining minimum inhibitory concentrations (MICs). A high proportion of non susceptible strains to metronidazole (10% of 121 isolates) and clindamycin (12% of 121 isolates) was seen, most noticeable in Bacteroides fragilis. Three Bacteroides species strains were non-susceptible to both metronidazole and clindamycin. One strain of Clostridium species was fully resistant to metronidazole and had intermediate resistance to clindamycin. No resistance to any of the other tested antibiotics was seen. Resistance to metronidazole was higher in bacteremic vs. non bacteremic isolates (p = value 0.07). In our setting where there is a high usage of empirical metronidazole and clindamycin for the treatment of serious anaerobic infections clinicians should be aware of increased resistance to these agents. Periodic surveillance of resistance to anti-anaerobic drugs especially metronidazole and clindamycin should be performed to generate antibiogram and guide appropriate empiric therapy. PMID- 25800665 TI - Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. AB - Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20-25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging-immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies. PMID- 25800667 TI - In/dependent Collaborations: Perceptions and Experiences of African Scientists in Transnational HIV Research. AB - This article examines collaboration in transnational medical research from the viewpoint of African scientists working in partnerships with northern counterparts. It draws on ethnographic fieldwork in an HIV laboratory of an East African state university, with additional data from interviews with scientists working in related research institutions. Collaboration is today the preferred framework for the mechanisms by which northern institutions support research in the south. The concept signals a shift away from the legacy of unequal (post-) colonial power relations, although, amid persisting inequalities, the rhetorical emphasis on equality might actually hinder critical engagement with conflicts of interest and injustice. To collaborate, African scientists engage various strategies: They establish a qualified but flexible, non-permanent workforce, diversify collaborators and research areas, source complementary funding to assemble infrastructures, and maintain prospective research populations to attract transnational clinical trials. Through this labor of collaboration, they sustain their institutions under prevailing conditions of scarcity. PMID- 25800670 TI - The ligand redox behavior and role in 1,2-bis[(2,6-diisopropylphenyl)imino] acenaphthene nickel-TMA(MAO) systems for ethylene polymerization. AB - The BIAN ligands in Brookhart catalysts were proved to be redox-active during the catalyst activation with alkylaluminum or MAO, and the neutral catalytically active species with a radical anionic BIAN rather than the cationic ones with a neutral BIAN ligand were confirmed to be formed in the catalytic system. PMID- 25800669 TI - Failed MILLER Banding Complicated by Pseudoaneurysm: Report of a Case. AB - We present a case in which Minimally Invasive Limited Ligation Endoluminal assisted Revision (MILLER) banding was complicated by the development of a pseudoaneurysm at the site of attempted banding. A patient with a high-flow fistula and symptoms of distal arterial hypoperfusion underwent Miller banding. Six weeks post-Miller banding, the patient's symptoms of hand pain returned gradually and a pseudoaneurysm appeared at the banding site. The remedial surgical procedure revealed a banding suture that had passed through one wall of the vessel and was floating in the pseudoaneurysm cavity. A primary lateral repair of the pseudoaneurysm was performed and the inflow was rebanded over a 4 mm balloon. The patient is now 51 months postpseudoaneurysm repair and the fistula continues to be used for dialysis access. Perforation of the fistula should be suspected when there is more bleeding than usual during the MILLER banding procedure. PMID- 25800671 TI - Position document: IgE-mediated cow's milk allergy. AB - The present document offers an update on the recommendations for managing patients with cow's milk allergy - a disorder that manifests in the first year of life, with an estimated prevalence of 1.6-3% in this paediatric age group. The main causal allergens are the caseins and proteins in lactoserum (beta lactoglobulin, alpha-lactoalbumin), and the clinical manifestations are highly variable in terms of their presentation and severity. Most allergic reactions affect the skin, followed by the gastrointestinal and respiratory systems, and severe anaphylaxis may occur. The diagnosis of cow's milk allergy is based on the existence of a suggestive clinical history, a positive allergy study and the subsequent application of controlled exposure testing, which constitutes the gold standard for confirming the diagnosis. The most efficient treatment for cow's milk allergy is an elimination diet and the use of adequate substitution formulas. The elimination diet must include milk from other mammals (e.g., sheep, goat, etc.) due to the risk of cross-reactivity with the proteins of cow's milk. Most infants with IgE-mediated cow's milk allergy become tolerant in the first few years of life. In those cases where cow's milk allergy persists, novel treatment options may include oral immunotherapy, although most authors do not currently recommend this technique in routine clinical practice. Enough evidence is not there to confirm the efficacy of elimination diets in the mother and infant for preventing the appearance of cow's milk allergy. Likewise, no benefits have been observed with prebiotic and probiotic dietetic supplements in infants for preventing food allergy. PMID- 25800672 TI - Brain self-regulation in criminal psychopaths. AB - Psychopathic individuals are characterized by impaired affective processing, impulsivity, sensation-seeking, poor planning skills and heightened aggressiveness with poor self-regulation. Based on brain self-regulation studies using neurofeedback of Slow Cortical Potentials (SCPs) in disorders associated with a dysregulation of cortical activity thresholds and evidence of deficient cortical functioning in psychopathy, a neurobiological approach seems to be promising in the treatment of psychopathy. The results of our intensive brain regulation intervention demonstrate, that psychopathic offenders are able to gain control of their brain excitability over fronto-central brain areas. After SCP self-regulation training, we observed reduced aggression, impulsivity and behavioral approach tendencies, as well as improvements in behavioral-inhibition and increased cortical sensitivity for error-processing. This study demonstrates improvements on the neurophysiological, behavioral and subjective level in severe psychopathic offenders after SCP-neurofeedback training and could constitute a novel neurobiologically-based treatment for a seemingly change-resistant group of criminal psychopaths. PMID- 25800673 TI - Global variability in gene expression and alternative splicing is modulated by mitochondrial content. AB - Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ~50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotype. PMID- 25800675 TI - Organelle DNA rearrangement mapping reveals U-turn-like inversions as a major source of genomic instability in Arabidopsis and humans. AB - Failure to maintain organelle genome stability has been linked to numerous phenotypes, including variegation and cytosolic male sterility (CMS) in plants, as well as cancer and neurodegenerative diseases in mammals. Here we describe a next-generation sequencing approach that precisely maps and characterizes organelle DNA rearrangements in a single genome-wide experiment. In addition to displaying global portraits of genomic instability, it surprisingly unveiled an abundance of short-range rearrangements in Arabidopsis thaliana and human organelles. Among these, short-range U-turn-like inversions reach 25% of total rearrangements in wild-type Arabidopsis plastids and 60% in human mitochondria. Furthermore, we show that replication stress correlates with the accumulation of this type of rearrangement, suggesting that U-turn-like rearrangements could be the outcome of a replication-dependent mechanism. We also show that U-turn-like rearrangements are mostly generated using microhomologies and are repressed in plastids by Whirly proteins WHY1 and WHY3. A synergistic interaction is also observed between the genes for the plastid DNA recombinase RECA1 and those encoding plastid Whirly proteins, and the triple mutant why1why3reca1 accumulates almost 60 times the WT levels of U-turn-like rearrangements. We thus propose that the process leading to U-turn-like rearrangements may constitute a RecA independent mechanism to restart stalled forks. Our results reveal that short range rearrangements, and especially U-turn-like rearrangements, are a major factor of genomic instability in organelles, and this raises the question of whether they could have been underestimated in diseases associated with mitochondrial dysfunction. PMID- 25800674 TI - Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes. AB - Transcription factors are abundant Sumo targets, yet the global distribution of Sumo along the chromatin and its physiological relevance in transcription are poorly understood. Using Saccharomyces cerevisiae, we determined the genome-wide localization of Sumo along the chromatin. We discovered that Sumo-enriched genes are almost exclusively involved in translation, such as tRNA genes and ribosomal protein genes (RPGs). Genome-wide expression analysis showed that Sumo positively regulates their transcription. We also discovered that the Sumo consensus motif at RPG promoters is identical to the DNA binding motif of the transcription factor Rap1. We demonstrate that Rap1 is a molecular target of Sumo and that sumoylation of Rap1 is important for cell viability. Furthermore, Rap1 sumoylation promotes recruitment of the basal transcription machinery, and sumoylation of Rap1 cooperates with the target of rapamycin kinase complex 1 (TORC1) pathway to promote RPG transcription. Strikingly, our data reveal that sumoylation of Rap1 functions in a homeostatic feedback loop that sustains RPG transcription during translational stress. Taken together, Sumo regulates the cellular translational capacity by promoting transcription of tRNA genes and RPGs. PMID- 25800677 TI - Theophylline-nicotinamide cocrystal formation in physical mixture during storage. AB - Pharmaceutically relevant properties, such as solubility and dissolution rate, of active pharmaceutical ingredients can be enhanced by cocrystal formation. Theophylline and nicotinamide are known to form cocrystals, for example if subjected to solid-state grinding. However, under appropriate conditions, cocrystals can also form in physical mixtures without any mechanical activation. The purpose of this work was to study whether theophylline and nicotinamide could form cocrystals spontaneously, without mechanical activation. Crystalline theophylline and nicotinamide powders were gently mixed manually in a 1:1 molar ratio and stored at different relative humidity and temperature conditions. The solid state of the samples was analyzed by differential scanning calorimetry, Raman spectroscopy and X-ray powder diffractometry. Three different variations of theophylline were used as starting materials, e.g., two size fractions of theophylline anhydrate (large 710 MUm-1 mm and small 180-355 MUm), and monohydrate (recrystallized from water). As a reference, anhydrous theophylline nicotinamide cocrystals were prepared by solid-state grinding. The results of this study indicate that theophylline-nicotinamide cocrystals can form without any mechanical activation from physical mixtures of theophylline and nicotinamide during storage. For anhydrous samples, storage humidity was found to be a critical parameter for cocrystal formation. Increasing temperature was also found to have an accelerating effect on the transformation. The effect of particle size of anhydrous theophylline on the transformation rate could not be completely resolved; DSC and Raman indicated slightly faster transformation with a physical mixture prepared from large size fraction of anhydrous theophylline, but the differences were only minor. Cocrystal formation was also observed in the physical mixture prepared from theophylline monohydrate, but the rate was not as high as with samples prepared from anhydrous material. PMID- 25800676 TI - Effects of radiation type and delivery mode on a radioresistant eukaryote Cryptococcus neoformans. AB - INTRODUCTION: Most research on radioresistant fungi, particularly on human pathogens such as Cryptococcus neoformans, involves sparsely-ionizing radiation. Consequently, fungal responses to densely-ionizing radiation, which can be harnessed to treat life-threatening fungal infections, remain incompletely understood. METHODS: We addressed this issue by quantifying and comparing the effects of densely-ionizing alpha-particles (delivered either by external beam or by (213)Bi-labeled monoclonal antibodies), and sparsely-ionizing (137)Cs gamma rays, on Cryptococcus neoformans. RESULTS: The best-fit linear-quadratic parameters for clonogenic survival were the following: alpha = 0.24 * 10(-2) Gy( 1) for gamma-rays and 1.07 * 10(-2) Gy(-1) for external-beam alpha-particles, and beta = 1.44 * 10(-5) Gy(-2) for both radiation types. Fungal cell killing by radiolabeled antibodies was consistent with predictions based on the alpha particle dose to the cell nucleus and the linear-quadratic parameters for external-beam alpha-particles. The estimated RBE (for alpha-particles vs. gamma rays) at low doses was 4.47 for the initial portion of the alpha-particle track, and 7.66 for the Bragg peak. Non-radiological antibody effects accounted for up to 23% of cell death. CONCLUSIONS: These results quantify the degree of C. neoformans resistance to densely-ionizing radiations, and show how this resistance can be overcome with fungus-specific radiolabeled antibodies. PMID- 25800678 TI - Casein/pectin nanocomplexes as potential oral delivery vehicles. AB - Delivery systems prepared with natural biopolymers are of particular interests for applications in food, pharmaceutics and biomedicine. In this study, nanocomplex particles of sodium caseinate (NaCas) and pectin were fabricated and investigated as potential oral delivery vehicles. Nanocomplexes were prepared with three mass ratios of NaCas/pectin by acidification using glucono-delta lactone and thermal treatment. NaCas/pectin at 1:1 mass ratio resulted in dispersions with the lowest turbidity and the smallest and most uniform nanocomplexes. Thermal treatment at 85 degrees C for 30 min facilitated the formation of stable, compact, and spherical nanocomplexes. Heating not only greatly increased the yield of nanocomplexes but also significantly improved the encapsulation capability of rutin studied as a model compound. Pectin in nanocomplexes delayed the hydrolysis of NaCas by pepsin at gastric conditions and enabled the controlled release of most rutin in simulated intestinal conditions. The nanocomplexes based on food-sourced biopolymers have promising features for oral delivery of nutrients and medicines. PMID- 25800679 TI - Alkyl Aryl Ether Bond Formation with PhenoFluor. AB - An alkyl aryl ether bond formation reaction between phenols and primary and secondary alcohols with PhenoFluor has been developed. The reaction features a broad substrate scope and tolerates many functional groups, and substrates that are challenging for more conventional ether bond forming processes may be coupled. A preliminary mechanistic study indicates reactivity distinct from conventional ether bond formation. PMID- 25800681 TI - The hsa-miR-125a/hsa-let-7e/hsa-miR-99b cluster is potentially implicated in Cystic Fibrosis pathogenesis. AB - BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive disorder implicating the Cystic Fibrosis Transmembrane Regulator (CFTR). Even though CF is mainly considered an inherited monogenic disease, numerous findings over the last few years argue for a more complicated multifactorial disease involving modifier genes. The 19q13.2-19q13.4 region is suspected to contain genetic modifiers that correlate to the severity of CF. METHOD: Here we studied a cohort of p.F508del patients for potential SNPs in the hsa-miR-99b/hsa-let-7e/hsa-miR-125a cluster, which is found within the 19q13.2-19q13.4 region. RESULTS: Three polymorphisms were identified in the hsa-miR-99b/hsa-let-7e/hsa-miR-125a cluster. Using a cell based model, we analysed whether expression of DeltaF508-CFTR influences the expression of mature hsa-miR-99b, hsa-let-7e, and hsa-miR-125a. We found that hsa miR-99b and hsa-miR-125a were significantly increased in DeltaF508-CFTR expressing cells. The three miRNAs appear to be derived from the same precursor but differ in their expression levels suggesting differential maturation of these miRNAs in CF. In silico analysis revealed that two out of the three polymorphisms we identified in a CF p.F508del patients cohort could modulate miRNA maturation and therefore impact on hsa-miR-99b/hsa-let-7e/hsa-miR-125a expression levels. CONCLUSION: Ingenuity Pathway Analysis indicated that hsa-miR-99b and hsa-miR 125a could be associated with the phenotypes manifested by p.F508del patients. Here we provide novel elements in the mechanism of hsa-miR-99b and hsa-miR-125a biogenesis, and for the role of CFTR and DeltaF508-CFTR on the expression of this miRNA cluster. These findings augment existing data implicating miRNAs as putative CF modifiers. PMID- 25800680 TI - Modulation of conformational changes in helix 69 mutants by pseudouridine modifications. AB - Centrally located at the ribosomal subunit interface and mRNA tunnel, helix 69 (H69) from 23S rRNA participates in key steps of translation. Ribosome activity is influenced by three pseudouridine modifications, which modulate the structure and conformational behavior of H69. To understand how H69 is affected by the presence of pseudouridine in combination with sequence changes, the biophysical properties of wild-type H69 and representative mutants (A1912G, U1917C, and A1919G) were examined. Results from NMR and circular dichroism spectroscopy indicate that pH-dependent structural changes of wild-type H69 and the chosen mutants are modulated by pseudouridine and loop sequence. The effects of the mutations on global stability of H69 are negligible; however, pseudouridine stabilizes H69 at low pH conditions. Alterations to induced conformational changes of H69 likely result in compromised function, as indicated by previous biological studies. PMID- 25800682 TI - Oxidation of plastohydroquinone by photosystem II and by dioxygen in leaves. AB - In sunflower leaves linear electron flow LEF=4O2 evolution rate was measured at 20 ppm O2 in N2. PSII charge separation rate CSRII=aII?PAD?(Fm-F)/Fm, where aII is excitation partitioning to PSII, PAD is photon absorption density, Fm and F are maximum and actual fluorescence yields. Under 630 nm LED+720 nm far-red light (FRL), LEF was equal to CSRII with aII=0.51 to 0.58. After FRL was turned off, plastoquinol (PQH2) accumulated, but LEF decreased more than accountable by F increase, indicating PQH2-oxidizing cyclic electron flow in PSII (CEFII). CEFII was faster under conditions requiring more ATP, consistent with CEFII being coupled with proton translocation. We propose that PQH2 bound to the QC site is oxidized, one e- moving to P680+, the other e- to Cyt b559. From Cyt b559 the e- reduces QB- at the QB site, forming PQH2. About 10-15% electrons may cycle, causing misses in the period-4 flash O2 evolution and lower quantum yield of photosynthesis under stress. We also measured concentration dependence of PQH2 oxidation by dioxygen, as indicated by post-illumination decrease of Chl fluorescence yield. After light was turned off, F rapidly decreased from Fm to 0.2 Fv, but further decrease to F0 was slow and O2 concentration dependent. The rate constant of PQH2 oxidation, determined from this slow phase, was 0.054 s(-1) at 270 MUM (21%) O2, decreasing with Km(O2) of 60 MUM (4.6%) O2. This eliminates the interference of O2 in the measurements of CEFII. PMID- 25800683 TI - F-actin distribution and function during sexual development in Eimeria maxima. AB - To determine the involvement of the actin cytoskeleton in macrogametocyte growth and oocyst wall formation, freshly purified macrogametocytes and oocysts were stained with Oregon Green 514 conjugated phalloidin to visualize F-actin microfilaments, while Evans blue staining was used to detect type 1 wall forming bodies (WFB1s) and the outer oocyst wall. The double-labelled parasites were then analysed at various stages of sexual development using three-dimensional confocal microscopy. The results showed F-actin filaments were distributed throughout the entire cytoplasm of mature Eimeria maxima macrogametocytes forming a web-like meshwork of actin filaments linking the type 1 WFBs together into structures resembling 'beads on a string'. At the early stages of oocyst wall formation, F actin localization changed in alignment with the egg-shaped morphology of the forming oocysts with F-actin microfilaments making direct contact with the WFB1s. In tissue oocysts, the labelled actin cytoskeleton was situated underneath the forming outer layer of the oocyst wall. Treatment of macrogametocytes in vitro with the actin depolymerizing agents, Cytochalasin D and Latrunculin, led to a reduction in the numbers of mature WFB1s in the cytoplasm of the developing macrogametocytes, indicating that the actin plays an important role in WFB1 transport and oocyst wall formation in E. maxima. PMID- 25800684 TI - A highly selective two-photon fluorescent probe for the determination of mercury ions. AB - In this work, we developed a new two-photon fluorescent probe, ATD (ATD = amino triphenylamine dendron), by combining a two-photon fluorophore 4-(bis(4-(4 (diphenylamino)styryl)-phenyl)amino) benzaldehyde (TD) with a specific recognition molecule for Hg(2+)- phenyl thiourea (PT) - for the determination of Hg(2+). The designed fluorescent probe emitted at ~455 nm upon one-photon and two photon excitation at 400 nm and 800 nm, respectively. The blue fluorescence obviously dropped with the continuous addition of Hg(2+), and demonstrated a good linearity with the concentration of Hg(2+) in a wide dynamic range of 5 nM-1.0 MUM. The detection limit achieved was 0.49 nM (~0.2 ppb), which is much lower than the standard levels required by the U.S. Environmental Protection Agency (EPA) and World Health Organization (WHO). Furthermore, this probe featured high selectivity for Hg(2+) detection over other metal ions such as Cd(2+), Ag(+), Pd(2+), and so on, due to the specific Hg(2+) recognition by the PT molecule. Meanwhile, the probe demonstrated long-term stability with respect to pH and illumination. As a result, the developed two-photon fluorescent probe, with high sensitivity and selectivity, was successfully applied for the on-site determination of Hg(2+) in environmental water samples. PMID- 25800685 TI - Intravenous glutamine appears to reduce the severity of symptomatic platinum induced neuropathy: a prospective randomized study. AB - The purpose of this study is to evaluate the efficacy of intravenous (IV) glutamine or calcium/magnesium (Ca/Mg) infusion against platinum-induced neuropathy. Patients undergoing platinum-based (oxaliplatin or cisplatin) therapy were randomized to receive IV glutamine or Ca/Mg infusion during four cycles of chemotherapy, from the fifth cycle of therapy to the eighth cycle. The total neuropathy score (TNS) was evaluated at the end of the fourth course of chemotherapy (as baseline) and at the end of the eighth cycle (as end-of treatment). The intent-to-treat analysis of the end point included 29 patients in the glutamine arm and 26 patients in the Ca/Mg arm. The mean TNS of both cohorts increased significantly. The baseline and end-of-treatment TNSs between the two groups were not statistically different. Patients with symptoms at baseline (N = 29) had significantly lower scores at the end of the study in the glutamine group (P = 0.045). Besides, glutamine group patients who initially had only sensory symptoms (N = 23) also had significantly lower scores at the study's end (P = 0.035). Neither IV glutamine nor Ca/Mg infusion prevented further worsening of platinum-induced neuropathy. However, IV glutamine apparently reduced the severity of symptomatic platinum-induced neuropathy. PMID- 25800686 TI - A randomised controlled trial and cost-effectiveness analysis of high-frequency oscillatory ventilation against conventional artificial ventilation for adults with acute respiratory distress syndrome. The OSCAR (OSCillation in ARDS) study. AB - BACKGROUND: Patients with the acute respiratory distress syndrome (ARDS) require artificial ventilation but this treatment may produce secondary lung damage. High frequency oscillatory ventilation (HFOV) may reduce this damage. OBJECTIVES: To determine the clinical benefit and cost-effectiveness of HFOV in patients with ARDS compared with standard mechanical ventilation. DESIGN: A parallel, randomised, unblinded clinical trial. SETTING: UK intensive care units. PARTICIPANTS: Mechanically ventilated patients with a partial pressure of oxygen in arterial blood/fractional concentration of inspired oxygen (P : F) ratio of 26.7 kPa (200 mmHg) or less and an expected duration of ventilation of at least 2 days at recruitment. INTERVENTIONS: Treatment arm HFOV using a Novalung R100((r)) ventilator (Metran Co. Ltd, Saitama, Japan) ventilator until the start of weaning. Control arm Conventional mechanical ventilation using the devices available in the participating centres. MAIN OUTCOME MEASURES: The primary clinical outcome was all-cause mortality at 30 days after randomisation. The primary health economic outcome was the cost per quality-adjusted life-year (QALY) gained. RESULTS: One hundred and sixty-six of 398 patients (41.7%) randomised to the HFOV group and 163 of 397 patients (41.1%) randomised to the conventional mechanical ventilation group died within 30 days of randomisation (p = 0.85), for an absolute difference of 0.6% [95% confidence interval (CI) -6.1% to 7.5%]. After adjustment for study centre, sex, Acute Physiology and Chronic Health Evaluation II score, and the initial P : F ratio, the odds ratio for survival in the conventional ventilation group was 1.03 (95% CI 0.75 to 1.40; p = 0.87 logistic regression). Survival analysis showed no difference in the probability of survival up to 12 months after randomisation. The average QALY at 1 year in the HFOV group was 0.302 compared to 0.246. This gives an incremental cost-effectiveness ratio (ICER) for the cost to society per QALY of L88,790 and an ICER for the cost to the NHS per QALY of L 78,260. CONCLUSIONS: The use of HFOV had no effect on 30-day mortality in adult patients undergoing mechanical ventilation for ARDS and no economic advantage. We suggest that further research into avoiding ventilator-induced lung injury should concentrate on ventilatory strategies other than HFOV. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10416500. PMID- 25800688 TI - Psychosocial correlates of Internet addiction among Jordanian university students. AB - Internet addiction is a significant international mental health problem among university students. The purpose of the current study was to investigate the correlation of Internet addiction with university students' characteristics in Jordan using a descriptive, correlational, cross-sectional design. The Internet Addiction Test, Beck Depression Inventory, and Multidimensional Scale of Perceived Social Support were administered to a random sample of 587 undergraduate university students. The findings demonstrated that university year level, student age, depression, and family support were significant correlates of Internet addiction. The current study should raise awareness in nurses and other health care providers that Internet addiction is a potential mental health problem for this student population. The findings from the current study will help develop appropriate interventions for these students and inform future research. PMID- 25800690 TI - Profiling the immunological characteristics of exacerbation of chronic rhinosinusitis with nasal polyps. PMID- 25800687 TI - Host-pathogen interplay in the respiratory environment of cystic fibrosis. AB - Significant advances have been made in the understanding of disease progression in cystic fibrosis (CF), revealing a complex interplay between host and pathogenic organisms. The diverse CF microbiota within the airway activates an aberrant immune response that is ineffective in clearing infection. An appreciation of how the CF host immune system interacts with these organisms is crucial to understanding the pathogenesis of CF pulmonary disease. Here we discuss the microbial complexity present in the lungs of individuals with CF, review emerging concepts of innate and adaptive immune responses to pathogens that chronically inhabit the CF lung, and discuss therapies that target the aberrant inflammatory response that characterizes CF. A greater understanding of the underlying mechanisms will shed light on pathogenesis and guide more targeted therapies in the future that serve to reduce infection, minimize lung pathology, and improve the quality of life for patients with CF. PMID- 25800693 TI - Identifying inhibitors/enhancers of quantitative real-time PCR in food samples using a newly developed synthetic plasmid. AB - BACKGROUND: Polymerase chain reaction (PCR) has become a common technique offering fast and sensitive analysis of DNA in food/feed samples. However, many substances, either already present in the sample or introduced during sample processing, inhibit PCR and thus underestimate the DNA content. It is therefore necessary to identify PCR inhibition in order to correctly evaluate the sample. RESULTS: We designed and validated a synthetic plasmid DNA that can be used to detect and quantify PCR inhibition. The DNA sequence, appropriate primers and probe, were designed in silico, synthesized and the sequence was inserted into a plasmid vector. The performance of the plasmid was verified via calibration curves and by performing the assay in the presence of various DNAs (crops, fungus, bacterium). The detection of PCR inhibition was assessed using six inhibiting substances with different modes of action, substances used in sample processing (EDTA, ethanol, NaCl, SDS) and food additives (sodium glutamate, tartrazine). The plasmid performance proved to be reproducible and there were no interactions with other DNAs. The plasmid was able to identify the presence of the inhibitors in a wide range of concentrations. CONCLUSION: The presented plasmid DNA is a suitable and inexpensive possibility for evaluating PCR inhibition. PMID- 25800694 TI - Morbidity associated with operative management of bladder stones in spinal cord injured patients. AB - STUDY DESIGN: Retrospective cohort study of spinal cord-injured (SCI) patients undergoing bladder stone removal operations between 1999 and 2013. OBJECTIVES: To determine the morbidity associated with different operative management of bladder stones in SCI patients. SETTING: National Spinal Injuries Unit, Stoke Mandeville Hospital, UK. METHODS: Data on age, sex, level and Frankel classification of spinal cord injury, method of bladder drainage, method of bladder stone removal, complications and length of stay were collected from patient records. Complication was defined as bladder perforation, sepsis or persistent haematuria. Predictors of complications and length of stay were determined using univariate and multivariate regression analyses. RESULTS: Overall, 112 consecutive bladder stone removal operations were performed, one open cystolithotomy and 111 transurethral procedures utilising simple washout, stone punch or electrohydraulic lithotripsy (EHL). Of these procedures, 17% (19/112) had complications; 0/11 (0%) following washout, 5/44 (11%) after stone punch, 3/12 (25%) following EHL and 10/26 (38%) after combined procedures using stone punch and EHL. In a multivariate model, patients with a cervical-level injury and those undergoing a combined procedure were significantly more likely to have a complication (P=0.032 and P=0.046). Length of stay was longer following a complication, the mean was 4.18 days compared with 1.37 days without a complication (P<0.001). Controlling complications and age, use of a combined procedure was associated with significantly longer stay than use of stone punch alone. CONCLUSION: This study provides important outcome data that should guide operative procedure choice and inform patients about possible risks during consent. It sets a benchmark that other centres can evaluate their outcomes against. PMID- 25800695 TI - Pathobiology of radiation myelopathy and strategies to mitigate injury. AB - STUDY DESIGN: This is a narrative review of the literature. OBJECTIVES: The objectives of this study were to review the current concepts underlying the pathobiology of radiation-induced spinal cord injury; to discuss potential biologic strategies to mitigate spinal cord injury following radiation; and to provide an update on the clinical guidelines to prevent injury in the era of image-guided stereotactic body radiotherapy (SBRT). SETTING: This study was conducted in Toronto, Canada. METHODS: A MEDLINE search was performed using the following terms: radiation injury; radiation myelopathy; CNS radiation injury; brain necrosis, radiation; demyelination, radiation; blood-brain barrier, radiation; white matter necrosis; and SBRT. RESULTS AND CONCLUSION: The biologic response of the spinal cord after radiation is a continuously evolving process. Death of vascular endothelial cells and disruption of the blood-spinal cord barrier leads to a complex injury response, resulting in demyelination and tissue necrosis. At present, there is no evidence that the pathobiology of cord injury after SBRT is different from that after standard fractionation. Although permanent myelopathy has become a rare complication following conventional fractionated radiation treatment, cases of radiation myelopathy have re-emerged with the increasing role of spine stereotactic body radiation therapy and reirradiation. Experimental biologic strategies targeting the injury response pathways hold promise in mitigating this dreaded late effect of radiation treatment. PMID- 25800696 TI - Iatrogenic urological triggers of autonomic dysreflexia: a systematic review. AB - STUDY DESIGN: This is a systematic review. OBJECTIVE: The objective of this study was to review the literature on iatrogenic urological triggers of autonomic dysreflexia (AD). SETTING: This study was conducted in an international setting. METHODS: A systematic review was conducted from PubMed search using AD/ autonomic hyperreflexia and spinal cord injury (SCI). Studies selected for review involved iatrogenic urological triggers of AD in individuals with SCI, including original articles, previous practice guidelines, case reports and literature reviews. Studies that did not report AD or blood pressure (BP) assessments during urological procedures were excluded. RESULTS: Forty studies were included for analysis and categorized into four groups: (1) urodynamics and cystometry; (2) cystoscopy and transurethral litholapaxy; (3) extracorporeal shock-wave lithotripsy (ESWL); and (4) other procedures. During urodynamics, the incidence of AD ranged from 36.7% to 77.8%. The symptomatic rate ranged from 50% to 65%, with AD symptoms seen predominantly in cervical SCI patients. The studies imply no consensus regarding the relationship between AD, neurogenic detrusor overactivity and detrusor sphincter dyssynergia. Without anesthesia, the majority of individuals develop AD during cystoscopy, transurethral litholapaxy and ESWL. The effectiveness of different anesthesia methods relies on blocking the nociceptive signals from the lower urinary tract (LUT) below the level of the neurological lesion. Other iatrogenic urological triggers were commonly associated with bladder filling. CONCLUSION: The LUT triggers of episodes of AD are often associated with iatrogenic urological procedures. AD was more prevalent in cervical SCI than in thoracic SCI. To detect this potential life-threatening complication following cervical and high thoracic SCI, routine BP monitoring during urological procedures is highly recommended. PMID- 25800697 TI - Rational design of a chalcogenopyrylium-based surface-enhanced resonance Raman scattering nanoprobe with attomolar sensitivity. AB - High sensitivity and specificity are two desirable features in biomedical imaging. Raman imaging has surfaced as a promising optical modality that offers both. Here we report the design and synthesis of a group of near-infrared absorbing 2-thienyl-substituted chalcogenopyrylium dyes tailored to have high affinity for gold. When adsorbed onto gold nanoparticles, these dyes produce biocompatible SERRS nanoprobes with attomolar limits of detection amenable to ultrasensitive in vivo multiplexed tumour and disease marker detection. PMID- 25800698 TI - Assessing the Critical Parameters of eSMART-MH: A Promising Avatar-Based Digital Therapeutic Intervention to Reduce Depressive Symptoms. AB - PURPOSE: To assess, from the young adults' (YAs') perspectives, the critical parameters (necessity, acceptability, feasibility, fidelity, and safety) of an avatar-based intervention, eSMART-MH, to reduce depressive symptoms. DESIGN AND METHODS: YAs (n = 60) were randomly assigned to eSMART-MH or control and observed for 12 weeks. Qualitative and quantitative data were collected. FINDINGS: Necessity, acceptability, fidelity, and safety of eSMART-MH were supported. Feasibility results were mixed. When benchmarked against usual care, eSMART-MH demonstrated greater feasibility. PRACTICE IMPLICATIONS: eSMART-MH is a promising digital therapeutic for depressive symptoms. Feasibility can be strengthened through "on the go" access via mobile devices and Internet delivery. PMID- 25800699 TI - Blended nanoparticle system based on miscible structurally similar polymers: a safe, simple, targeted, and surprisingly high efficiency vehicle for cancer therapy. AB - A novel blended nanoparticle (NP) system for the delivery of anticancer drugs and its surprisingly high efficacy for cancer chemotherapy by blending a targeting polymer folic acid-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (FA-PEG-b PLGA) and a miscible structurally similar polymer D-alpha-tocopheryl polyethylene glycol 1000 succinate-poly(lactide-co-glycolide) (TPGS-PLGA) is reported. This blended NP system can be achieved through a simple and effective nanoprecipitation technique, and possesses unique properties: i) improved long term compatibility brought by PEG-based polymers; ii) reduced multidrug resistance mediated by P-glycoprotein (P-gp) in tumor cells and increased bioavailability of anticancer drugs by incorporation of TPGS; iii) the regulation of controlled release through polymer ratios and active targeting by FA. Both in vitro cell experiments and in vivo antitumor assays demonstrated the reported blended NP system can achieve the best therapeutic efficiency in an extremely safe, simple and highly efficient process for cancer therapy. Moreover, this NP system is highly efficient in forming NPs with multiple functions, without repeated chemical modification of polymers, which is sometimes complex, inefficient and high cost. Therefore, the development of this novel blended NP concept is extremely meaningful for the application of pharmaceutical nanotechnology in recent studies. PMID- 25800701 TI - Erratum to: The Special Issue on "Computational Molecular Medicine", edited by Rachel Karchin and Melissa S. Cline. PMID- 25800700 TI - Intraoperative Ultrasonography Combined with Indocyanine Green Video-Angiography in Patients with Cerebral Arteriovenous Malformations. AB - BACKGROUND AND PURPOSE: During the operation, accurately identifying the boundary of cerebral arteriovenous malformation (AVM) and discriminating between feeding arteries and draining veins is the key to successful surgical treatment of cerebral AVM. We evaluated the application of intraoperative ultrasonography (IOU) combined with intraoperative indocyanine green video-angiography (IOICGA) in the patients with cerebral AVM. METHODS: The effects of IOU combined with IOICGA on AVM surgery were observed in 12 patients with cerebral AVM. RESULTS: The lesions of cerebral AVM were completely removed in the 12 patients. IOU could clearly visualize the boundary of AVM, so no patients had massive hemorrhage caused by rupture of malformed vessels. IOU also could detect the location of deep vessels and a total of 11 deep vessels were identified in the 12 patients. IOICGA was performed 41 times altogether in the 12 patients, and 31 feeding arteries and 10 draining veins were identified, so there was no massive hemorrhage caused by misjudgment of feeding arteries or draining veins. CONCLUSIONS: IOU combined with IOICGA can identify the boundary of AVM, detect deep vessels, and discriminate between feeding arteries and draining veins, reducing operation difficulty, decreasing mortality and disability rate, and increasing the rate of complete excision. PMID- 25800702 TI - Analysis of human upstream open reading frames and impact on gene expression. AB - The upstream open reading frame (uORF) is a post-transcriptional regulatory element in the 5' untranslated region (5'UTR), which modulates the translation levels of main open reading frame (mORF). Earlier studies showed that disturbed uORF-mediated translation control can result in drastic changes in translation levels of mORF, leading to genetic disorders. To date, there has been no systematic investigation into the relationship between variations in patients and uORF status. Here, taking the advantage of several datasets, including gene ontology (GO) annotations and sequence feature analysis, we have examined uORF impacts in human transcripts. GO annotations indicate that uORF-containing genes are enriched in certain features such as oncogenes and transcription factors. Sequence feature analysis reveals that uORF is a factor for determination of the translation initiation site (TIS) in human transcripts. We show that genes with uORFs have lower protein expression levels than genes without uORFs in multiple human tissues. Moreover, by examining three disease variation databases, we identified uORF-altering mutations from a total of 3,740,225 variations, which are highly suspected to be associated with changed levels of gene expression. For an experimental validation, we found four mutations with significant effects on protein expression but with only modest changes in transcription levels. These findings will provide researchers on related diseases with new insights into the importance of known mutations. PMID- 25800704 TI - Social Media: Portrait of an Emerging Tool in Medical Education. AB - OBJECTIVE: The authors compare the prevalence of challenges and opportunities in commentaries and descriptive accounts versus evaluative studies of social media use in medical education. METHODS: A previously published report of social media use in medical education provided an in-depth discussion of 14 evaluative studies, a small subset of the total number of 99 articles on this topic. This study used the full set of articles identified by that review, including the 58 commentaries and 27 descriptive accounts which had not been previously reported, to provide a glimpse into how emerging tools in medical education are initially perceived. Each commentary, descriptive account, and evaluative study was identified and compared on various characteristics, including discussion themes regarding the challenges and opportunities of social media use in medical education. RESULTS: Themes related to the challenges of social media use in medical education were more prevalent in commentaries and descriptive accounts than in evaluative studies. The potential of social media to affect medical professionalism adversely was the most commonly discussed challenge in the commentaries (53%) and descriptive accounts (63%) in comparison to technical issues related to implementation in the evaluative studies (50%). CONCLUSIONS: Results suggest that the early body of literature on social media use in medical education-like that of previous innovative education tools-comprises primarily commentaries and descriptive accounts that focus more on the challenges of social media than on potential opportunities. These results place social media tools in historical context and lay the groundwork for expanding on this novel approach to medical education. PMID- 25800705 TI - What can qualitative studies reveal about recruitment into psychiatry? AB - OBJECTIVE: Studies examining recruitment problems in psychiatry have been mostly quantitative and limited in their ability to elucidate perceptions and day-to-day influences that may affect recruitment. This review aimed to identify factors on recruitment into psychiatry by appraising available qualitative studies. METHODS: The authors searched MEDLINE, PsycINFO, and Embase using Health Database Advanced Search tool on NHS Evidence. Inclusion criteria were qualitative studies and English-language published papers. The authors appraised 10 qualitative studies and identified common themes. RESULTS: The ten qualitative studies used thematic analysis, phenomenology, and narrative study methods. Populations studied were medical students, foundation doctors, residents/trainees, psychiatrists, and undergraduate psychiatry teachers from the USA, UK, Australia, Canada, and Ghana. The studies highlighted importance of role models, mentorship, and supervision in improving recruitment. Additional factors included stigmatization in mental illness, satisfaction rates, interactive nature, and academic interest within psychiatry. CONCLUSION: The appraised studies were limited in their number and methodology. More qualitative studies are needed to inform policy on recruitment into psychiatry. PMID- 25800706 TI - Structure, synthesis, and applications of TiO2 nanobelts. AB - TiO2 semiconductor nanobelts have unique structural and functional properties, which lead to great potential in many fields, including photovoltaics, photocatalysis, energy storage, gas sensors, biosensors, and even biomaterials. A review of synthetic methods, properties, surface modification, and applications of TiO2 nanobelts is presented here. The structural features and basic properties of TiO2 nanobelts are systematically discussed, with the many applications of TiO2 nanobelts in the fields of photocatalysis, solar cells, gas sensors, biosensors, and lithium-ion batteries then introduced. Research efforts that aim to overcome the intrinsic drawbacks of TiO2 nanobelts are also highlighted. These efforts are focused on the rational design and modification of TiO2 nanobelts by doping with heteroatoms and/or forming surface heterostructures, to improve their desirable properties. Subsequently, the various types of surface heterostructures obtained by coupling TiO2 nanobelts with metal and metal oxide nanoparticles, chalcogenides, and conducting polymers are described. Further, the charge separation and electron transfer at the interfaces of these heterostructures are also discussed. These properties are related to improved sensitivity and selectivity for specific gases and biomolecules, as well as enhanced UV and visible light photocatalytic properties. The progress in developments of near infrared-active photocatalysts based on TiO2 nanobelts is also highlighted. Finally, an outline of important directions of future research into the synthesis, modification, and applications of this unique material is given. PMID- 25800703 TI - Synthesis, antitumor activity, and mechanism of action of 6-acrylic phenethyl ester-2-pyranone derivatives. AB - Based on the scaffolds of caffeic acid phenethyl ester (CAPE) as well as bioactive lactone-containing compounds, 6-acrylic phenethyl ester-2-pyranone derivatives were synthesized and evaluated against five tumor cell lines (HeLa, C6, MCF-7, A549, and HSC-2). Most of the new derivatives exhibited moderate to potent cytotoxic activity. Moreover, HeLa cell lines showed higher sensitivity to these compounds. In particular, compound showed potent cytotoxic activity (IC50 = 0.50-3.45 MUM) against the five cell lines. Further investigation on the mechanism of action showed that induced apoptosis, arrested the cell cycle at G2/M phases in HeLa cells, and inhibited migration through disruption of the actin cytoskeleton. In addition, ADMET properties were also calculated in silico, and compound showed good ADMET properties with good absorption, low hepatotoxicity, and good solubility, and thus, could easily be bound to carrier proteins, without inhibition of CYP2D6. A structure-activity relationship (SAR) analysis indicated that compounds with ortho-substitution on the benzene ring exhibited obviously increased cytotoxic potency. This study indicated that compound is a promising compound as an antitumor agent. PMID- 25800707 TI - US cancer care system in "highly volatile state," cancer group says. PMID- 25800709 TI - Periprocedural management of antithrombotic therapy and open issues in cancer patients. AB - Perioperative management of patients who are receiving anticoagulant or antiplatelet drugs and require surgical or invasive procedure is a dilemma for clinicians. The discontinuation exposes the patient to an exceedingly high risk of thromboembolism while there is an exceedingly high bleeding risk if antithrombotic therapy is continued, strictly related to the type of surgery. This complex management is based on the assessment of thromboembolic and bleeding risk. In this review we analyze the strategies to optimize the perioperative use of antithrombotic drugs with special attention to new oral anticoagulant drugs, also in cancer patients. PMID- 25800710 TI - Barotrauma during apnea testing for the diagnosis of brainstem death. PMID- 25800708 TI - Materials engineering by ameloblasts. AB - Enamel is unique. It is the only epithelial-derived mineralized tissue in mammals and has a distinct micro- and nanostructure with nanofibrous apatite crystals as building blocks. It is synthesized by a highly specialized cell, the ameloblast, which secretes matrix proteins with little homology to any other known amino acid sequence, but which is composed of a primary structure that makes it competent to self-assemble and control apatite crystal growth at the nanometer scale. The end product of ameloblast activity is a marvel of structural engineering: a material optimized to provide the tooth with maximum biting force, withstanding millions of cycles of loads without catastrophic failure, while also protecting the dental pulp from bacterial attack. This review attempts to bring into context the mechanical behavior of enamel with the developmental process of amelogenesis and structural development, since they are linked to tissue function, and the importance of controlling calcium phosphate mineralization at the nanometer scale. The origins of apatite nanofibers, the development of a stiffness gradient, and the biological processes responsible for the synthesis of a hard and fracture-resistant dental tissue are discussed with reference to the evolution of enamel from a fibrous composite to a complex, tough, and damage tolerant coating on dentin. PMID- 25800711 TI - Obstructive sleep apnea and detection of non-adherence to CPAP in OSA: limits of the preanesthesia visit. PMID- 25800712 TI - Forensic intelligence framework. Part II: Study of the main generic building blocks and challenges through the examples of illicit drugs and false identity documents monitoring. AB - The development of forensic intelligence relies on the expression of suitable models that better represent the contribution of forensic intelligence in relation to the criminal justice system, policing and security. Such models assist in comparing and evaluating methods and new technologies, provide transparency and foster the development of new applications. Interestingly, strong similarities between two separate projects focusing on specific forensic science areas were recently observed. These observations have led to the induction of a general model (Part I) that could guide the use of any forensic science case data in an intelligence perspective. The present article builds upon this general approach by focusing on decisional and organisational issues. The article investigates the comparison process and evaluation system that lay at the heart of the forensic intelligence framework, advocating scientific decision criteria and a structured but flexible and dynamic architecture. These building blocks are crucial and clearly lay within the expertise of forensic scientists. However, it is only part of the problem. Forensic intelligence includes other blocks with their respective interactions, decision points and tensions (e.g. regarding how to guide detection and how to integrate forensic information with other information). Formalising these blocks identifies many questions and potential answers. Addressing these questions is essential for the progress of the discipline. Such a process requires clarifying the role and place of the forensic scientist within the whole process and their relationship to other stakeholders. PMID- 25800714 TI - Coordinating with the "Inner GPS". AB - The 2014 Nobel Prize for Physiology or Medicine was awarded for the discoveries that have elucidated the components of the internal positioning system that is centered on the hippocampus and entorhinal cortex. Here I provide a less than objective discussion of the importance of these accomplishments to systems neuroscience. By identifying positioning components like place, direction, distance, borders and the like, the field is given the opportunity to have a shot at piecing together how these components are integrated into the synthetic positioning sense. We are also given what is in my view, the most experimentally accessible and therefore potentially understandable, cognitive representation. Lest we feel too confident in the completeness of our understanding, and to inspire redoubled curiosity, I briefly describe a preliminary observation from our work with the psychosis-inducing drug phencyclidine (PCP). While PCP does not disturb where individual place cells fire, it dramatically discoordinates how these cells discharge together in time. Trying to understand how the positioning component cells are coordinated to provide useful knowledge is an exciting and tenable problem to be working on. PMID- 25800715 TI - "I'm Not Waving, I'm Drowning": An Autoethnographical Exploration of Biographical Disruption and Reconstruction During Recovery From Prescribed Benzodiazepine Use. AB - Benzodiazepines are group of drugs used mainly as sedatives, hypnotics, muscle relaxants, and anti-epileptics. Tapering off benzodiazepines is, for some users, a painful, traumatic, and protracted process. In this article, I use an autoethnographic approach, adopting the metaphor of water, to examine heuristically my experience of iatrogenic illness and recovery. I draw on personal journals and blog entries and former users' narratives to consider the particular form of biographical disruption associated with benzodiazepines and the processes involved in identity reconstruction. I emphasize the role of the online community in providing benzodiazepine users such as myself with a co cultural community through which to share a voice and make sense of our experiences. I explain how the success stories of former users provided me with the hope that I, the "medical victim," could become the "victor" and in the process construct a new life and fresh identity. PMID- 25800713 TI - Forensic analysis of tire rubbers based on their sulfur chemical states. AB - The chemical states of sulfur in 11 tires were analyzed using X-ray absorption near-edge structure (XANES) in order to discriminate between various tire rubbers. All tires had peaks around 2471.5 and 2480.5eV, and the shapes and heights of these peaks differed among tires, suggesting that the sulfur chemical state could be used for discrimination between tire rubbers. Based on t-tests on the results of XANES, 43 of 55 combinations were different at a significance level of 5%. PMID- 25800716 TI - The emergence of mixing methods in the field of evaluation. AB - When and how did the contemporary practice of mixing methods in social inquiry get started? What events transpired to catalyze the explosive conceptual development and practical adoption of mixed methods social inquiry over recent decades? How has this development progressed? What "next steps" would be most constructive? These questions are engaged in this personally narrative account of the beginnings of the contemporary mixed methods phenomenon in the field of evaluation from the perspective of a methodologist who was there. PMID- 25800717 TI - An Effective Model for Prevention and Management of Type 2 Diabetes. AB - We developed and tested a cost-effective model for health promotion capacity building among community health volunteers (CHVs) within culturally and linguistically diverse (CALD) communities. Twenty multilingual CHVs, from CALD communities in Melbourne, underwent 3 days of education and training to deliver face-to-face education programs in their own language. Participants were instructed how to collect anthropometric data, make qualitative observations, and conduct diabetes knowledge questionnaires, before conducting mini education sessions with three members of their own community. Knowledge about diabetes among CHVs increased. CHVs were able to collect anthropomorphic data and knowledge surveys from community participants with greater participation than from outreach programs. Evidence-based data collected by CHVs could be incorporated into health education and promotion programs run by CHVs. Here we confirm that CHVs represent an effective tool for health promotion within CALD communities and have the capacity to incorporate evidence-based collection as part of their health education. PMID- 25800718 TI - Medical Residents' Experiences With Medically Unexplained Illness and Medically Unexplained Symptoms. AB - Patients who present with medically unexplained illnesses or medically unexplained symptoms (MUI/S) tend to be higher utilizers of health care services and have significantly greater health care costs than other patients, which add stress and strain for both the patient and provider. Although MUI/S are commonly seen in primary care, there is not sufficient information available regarding how providers can increase their level of confidence and decrease their level of frustration when working with patients who present with MUI/S. The goal of this article is to present findings from a qualitative phenomenology study, which highlights medical residents' experiences of caring for patients with MUI/S and the personal and professional factors that contributed to their clinical approaches. Results from these studies indicate that residents often experience a lack of confidence in their ability to effectively treat patients with MUI/S, as well as frustration surrounding their encounters with this group of patients. PMID- 25800719 TI - HER2 status in gastroesophageal cancer: a tissue microarray study of 1040 cases. AB - Among patients with gastric cancer (GC) and gastroesophageal cancer (G-EC), HER2 amplification identifies those who may benefit from trastuzumab. HER2 status assessment, however, is influenced by preanalytic, analytic, and postanalytic variables. In a series of 5426 microarray cancer tissue cores obtained from 1040 GC/G-ECs (824 GC, 216 G-EC) and 720 synchronous nodal metastases, we evaluated both the performances of 2 different immunohistochemistry (IHC) protocols and the HER2 status intratumor variability. The prevalence of HER2 amplification and protein overexpression were assessed by chromogenic in situ hybridization and by 2 IHC protocols (CB11 and 4B5). HER2 was amplified in 114 (11%) of 1040 cases; in 6 (5.3%) of 114 cases, gene amplification only involved nodal metastasis. HER2 amplification prevailed in intestinal-type (P = .001) and low-grade (P < .001) tumors, showing no correlation with patients' age/sex, tumor location, stage, and Ming histotype. Overall, 12.5% and 13.7% of cases IHC scored 2+/3+ using the CB11 IHC and the 4B5-IHC protocol, respectively. HER2 amplification was not associated with protein overexpression (score 0/1+) in 11.4% and 6.2% of cases using the CB11-IHC and the 4B5-IHC protocol, respectively. The 4B5-IHC protocol proved more sensitive than CB11-IHC (93.9% versus 88.6%) and just as specific (96.1% versus 96.9%). Tested by chromogenic in situ hybridization, intratumor HER2 status was "substantially" consistent in different tissue cores obtained from the same case (kappa = 0.78). Similar results were obtained for HER2 protein expression (CB11 IHC, kappa = 0.78, and 4B5-IHC, kappa = 0.83). Immunohistochemistry testing, however, fails in identifying about 10% of HER2-amplified cancers, potentially excluding these patients from anti-HER2 therapy. PMID- 25800722 TI - Tumour staging of oesophageal cancer in the Swedish Cancer Registry: A nationwide validation study. AB - BACKGROUND: Tumour stage was introduced to the Swedish Cancer Registry in 2004, but this key variable for prognostic research has not yet been validated. We validated the tumour stage data in surgically treated oesophageal cancer patients. MATERIAL AND METHODS: Completeness and accuracy of tumour stage according to the TNM system ("Tumour Node Metastasis") in the Cancer Registry were compared with a cohort study including comprehensive tumour stage data based on the pathological TNM of almost all patients operated for oesophageal cancer in 2006-2010 in Sweden. RESULTS: Of the 397 patients with pathological TNM data in the comparison cohort, the Cancer Registry reported an overall TNM stage in 390 patients (98.2%), which was based on the pathological TNM of 104 patients (26.2%), the clinical TNM of 183 patients (46.1%), and the pathological or clinical TNM (undefined) of 110 patients (27.7%). The completeness for the separate T, N, and M components was 89.4%, 90.9%, and 85.1%, respectively. The concordance with tumour stage was 98.2%, while it was 51.1%, 70.5%, and 80.4% for the separate T, N, and M components, respectively. While the concordance with tumour stage was high for all TNM assessment groups (98.1-98.4%), the concordance of the T and N components was highest when using pathological TNM (82.7% and 95.2%, respectively), and the concordance of the M component was highest when using clinical TNM (88.5%). CONCLUSION: Although the overall completeness of tumour stage is high, the recording of pathological TNM stage and individual components could be improved within the Swedish Cancer Registry. PMID- 25800720 TI - Adjuvant Chemotherapy in Resected Stage II Non-small Cell Lung Cancer: Evaluating the Impact of Dose Intensity and Time to Treatment. AB - AIMS: Platinum-based adjuvant chemotherapy is the standard of care for resected stage II non-small cell lung cancer (NSCLC). The purpose of this population-based study was to identify factors that predict for receiving adjuvant therapy and to assess the effect of delayed administration and dose reduction on survival. MATERIALS AND METHODS: The British Columbia Cancer Agency provides cancer care to 4.6 million individuals across a large and varied geographical area. A retrospective review was conducted of all referred patients with resected stage II NSCLC between 2005 and 2010. Baseline characteristics, systemic therapy details and outcomes were recorded. RESULTS: Of 258 stage II NSCLC patients, 158 received adjuvant chemotherapy (61%). No-adjuvant versus adjuvant population: men 52%/57%, median age 67/62, Eastern Cooperative Oncology Group (ECOG) <= 1 55%/75%, Charlson comorbidity score (CCS) <= 1 61%/74%, pneumonectomy 11%/26%. In patients who received chemotherapy, treatment details were: cisplatin/carboplatin based 81%/19%, median cycles delivered 4, median time from surgery to adjuvant chemotherapy 8 weeks, 72% received >= 80% (cisplatin < 256 mg/m(2) and carboplatin < AUC 19.2) total planned dose. On multivariate analysis younger age, better ECOG and pneumonectomy were predictive of adjuvant treatment. Overall survival of adjuvant-treated patients was inferior for those with CCS >= 2, age >= 70 and reduced dose intensity on multivariate analysis. The surgery to chemotherapy interval did not affect overall survival. CONCLUSIONS: Pneumonectomy and factors associated with better functional status predicted for receiving adjuvant chemotherapy. For patients who received adjuvant chemotherapy the total platinum dose given affected survival but time from surgery did not. A higher platinum dose delivery was important in maintaining the efficacy of adjuvant chemotherapy for resected stage II NSCLC in this retrospective population-based study. PMID- 25800721 TI - RARgamma is a negative regulator of osteoclastogenesis. AB - Vitamin A is known to influence post-natal bone content, with excess intake being associated with reduced bone mineral density and increased fracture risk. Despite this, the roles retinoids play in regulating osteoclastogenesis, particularly in vivo, remain unresolved. This study therefore aimed to determine the effect of loss of retinoic acid receptors (RAR)alpha or RARgamma on bone mass (analyzed by histomorphometry and dual-energy X-ray absorptiometry) and osteoclastogenesis in mice in vivo. RARgamma null mice had significantly less trabecular bone at 8 weeks of age compared to wildtype littermates. In contrast, no change in trabecular bone mass was detected in RARalpha null mice at this age. Further histomorphometric analysis revealed a significantly greater osteoclast surface in bones from 8-week-old RARgamma null male mice. This in vivo effect was cell lineage autonomous, and was associated with increased osteoclastogenesis in vitro from hematopoietic cells obtained from 8-week-old RARgamma null male mice. The use of highly selective agonists in RANKL-induced osteoclast differentiation of wild type mouse whole bone marrow cells and RAW264.7 cells in vitro showed a stronger inhibitory effect of RARgamma than RARalpha agonists, suggesting that RARgamma is a more potent inhibitor of osteoclastogenesis. Furthermore, NFAT activation was also more strongly inhibited by RARgamma than RARalpha agonists. While RARalpha and RARgamma antagonists did not significantly affect osteoclast numbers in vitro, larger osteoclasts were observed in cultures stimulated with the antagonists, suggesting increased osteoclast fusion. Further investigation into the effect of retinoids in vivo revealed that oral administration of 5mg/kg/day ATRA for 10 days protected against bone loss induced by granulocyte colony-stimulating factor (G-CSF) by inhibiting the pro-osteoclastogenic action of G-CSF. Collectively, our data indicates a physiological role for RARgamma as a negative regulator of osteoclastogenesis in vivo and in vitro, and reveals distinct influences of RARalpha and RARgamma in bone structure regulation. PMID- 25800723 TI - Olfactory response of Anastrepha striata (Diptera: Tephritidae) to guava and sweet orange volatiles. AB - The behavioral responses of virgin and mated female Anastrepha striata Schiner (Diptera: Tephritidae) to guava (Psidium guajava L.) or sweet orange (Citrus sinensis L.) were evaluated separately using multilure traps in two-choice tests in field cages. The results showed that flies were more attracted to guava and sweet orange volatiles than to control (unbaited trap). The physiological state (virgin or mated) of females did not affect their attraction to the fruit volatiles. Combined analysis of gas chromatography coupled with electroantennography (GC-EAD) of volatile extracts of both fruits showed that 1 and 6 compounds from orange and guava, respectively elicited repeatable antennal responses from mated females. The EAD active compounds in guava volatile extracts were identified by gas chromatography-mass spectrometry (GC-MS) as ethyl butyrate, (Z)-3-hexenol, hexanol, ethyl hexanoate, hexyl acetate, and ethyl octanoate. Linalool was identified as the only antennal active compound in sweet orange extracts. In field cage tests, there were no significant differences between the number of mated flies captured by the traps baited with guava extracts and the number caught by traps baited with the 6-component blend that was formulated according to the relative proportions in the guava extracts. Similar results occurred when synthetic linalool was evaluated against orange extracts. From a practical point of view, the compounds identified in this study could be used for monitoring A. striata populations. PMID- 25800726 TI - A longitudinal study of cannabis use initiation among high school students: Effects of social anxiety, expectancies, peers and alcohol. AB - This study identified protective and risk factors of cannabis use initiation, including expectancies and social anxiety. A questionnaire was completed twice by 877 teenagers. Logistic regressions, mediation and moderation analyses were performed. Significant risk factors were alcohol use, peer users, perceptual enhancement, and craving expectancies. Protective factors were negative behavior expectancies and social anxiety. Social anxiety protected from initiation through the mediating role of perceptual enhancement and craving expectancies, whatever the role of peer users and alcohol use. Findings are discussed in terms of risk and protection, in an overall approach including internalizing factors. Results support the identification of an internalizing profile of adolescents for prevention or treatment and the importance of social anxiety and expectancies in intervention. PMID- 25800725 TI - Identification of human papillomavirus-16 E6 variation in cervical cancer and their impact on T and B cell epitopes. AB - The infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for development of cervical cancer. The intra-type variations of HPV have different biological and pathological consequences with respect to disease progression. In the present study, six major Indian variants were experimentally identified in E6 gene of HPV-16 and showed their impact on immunogenicity by in silico methods. Four different phylogenetic lineages were observed in sequences including European (E) prototype, European variant, Asian and American Asian variant classes and complete absence of African phylogenetic lineages. On the prediction of B- and T-cell epitopes, 18 and 23 potent epitopes for MHC-II alleles, 10 potent MHC-I and 15 B-cell epitopes in each reference and variant sequence were identified. Interestingly, the presence of variation H78Y and L83V result in creation of four new epitopes for the HLA-DQA1*0101/DQB1*0501. Out of 15 B-cell predicted epitopes, three most potent epitopes were identified in both reference and variant sequence. Notably the amino acid stretch from amino acid 16 60 and 76-94 are very important for the immunological properties of E6 protein because these regions contain majority of the predicted epitopes. In future, this could control the cervical cancer by targeting these amino acid stretches for the development of HPV-16 vaccine. PMID- 25800727 TI - Health-related quality of life of Asian patients with end-stage renal disease (ESRD) in Singapore. AB - BACKGROUND: This study aimed to identify factors associated with the health related quality of life (HRQOL) of multiethnic Asian end-stage renal disease (ESRD) patients treated with dialysis. The role of dialysis modality was also explored. METHODS: Data used in this study were from two cross-sectional surveys of Singaporean ESRD patients on haemodialysis (HD) or peritoneal dialysis (PD). In both surveys, participants were assessed using the kidney disease quality of life (KDQOL) instrument and questions assessing socio-demographic characteristics. Clinical data including co-morbidity (measured by Charlson comorbidity index [CCI]), albumin level, haemoglobin level, and dialysis-related variables (e.g. dialysis vintage and dialysis adequacy) were retrieved from medical records. The 36-item KDQOL (KDQOL-36) was used to generate three summary scores (physical component summary [PCS], mental component summary [MCS] and kidney disease component summary [KDCS]) and two health utility scores (Short Form 6-dimension [SF-6D] and EuroQol 5-dimension [EQ-5D]). Linear regression analysis was performed to examine the association of factors with each of the HRQOL scale scores. RESULTS: Five hundred and two patients were included in the study (mean age 57.1 years; male 52.4 %; HD 236, PD 266). Mean [standard deviation (SD)] PCS, MCS and KDCS scores were 37.9 (9.7), 46.4 (10.8) and 57.6 (18.1), respectively. Mean (SD) health utility score was 0.66 (0.12) for SF-6D and 0.60 (0.21) for EQ-5D. In multivariate regression analysis, factors found to be significantly associated with better HRQOL included: young (<45 years) or old age (>60 years), low CCI (<5), high albumin (>=37 g/l) and high haemoglobin (>=11 g/dl) with PCS; long dialysis vintage (>=3.5 years) with MCS; old age, Malay ethnicity and PD modality with KDCS; low CCI, high albumin and high haemoglobin with EQ-5D and high albumin with SF-6D. CONCLUSIONS: Clinical characteristics are better predictors of HRQOL in ESRD patients than socio-demographics in Singapore. Dialysis modality has no impact on the health utility of those patients. PMID- 25800728 TI - An audit of diabetes-dependent quality of life in patients with type 2 diabetes mellitus in Malaysia. AB - PURPOSE: The aim of this study was to evaluate and validate the ADDQoL and to assess the impact of diabetes on QoL among the type 2 diabetes mellitus patients in Malaysia. METHODS: The Malay and English versions of the ADDQoL questionnaire were administered to patients attending routine outpatient visits in three primary hospitals and a public clinic. The construct validity of the ADDQoL was validated using confirmatory factor analysis (CFA). The sample comprised 350 Malay respondents who rated the ADDQoL Malay version and 246 non-Malay respondents (Chinese or Indian) who answered using the ADDQoL original English version. RESULTS: CFA confirmed the presence of one-factor structure for both samples. The internal consistency was high with Cronbach's alpha values of 0.945 and 0.907 for the ADDQoL Malay and English versions, respectively. Results showed that for all three ethnicities, the most important domain is 'family life'. Overall, Malay patients stated their 'living conditions' is the most negatively affected, while for Chinese and Indians, diabetes has the greatest impact on their 'freedom to eat'. CONCLUSIONS: The ADDQoL was found to be culturally appropriate, valid and reliable among Malay- and English-speaking type 2 diabetes mellitus patients in Malaysia. PMID- 25800729 TI - Comparative proteomic analysis in Miscanthus sinensis exposed to antimony stress. AB - To explore the molecular basis of Sb tolerance mechanism in plant, a comparative proteomic analysis of both roots and leaves in Miscanthus sinensis has been conducted in combination with physiological and biochemical analyses. M. sinensis seedlings were exposed to different doses of Sb, and both roots and leaves were collected after 3 days of treatment. Two-dimensional gel electrophoresis (2-DE) and image analyses found that 29 protein spots showed 1.5-fold change in abundance in leaves and 19 spots in roots, of which 31 were identified by MALDI TOF-MS and MALDI-TOF-TOF-MS. Proteins involved in antioxidant defense and stress response generally increased their expression all over the Sb treatments. In addition, proteins relative to transcription, signal transduction, energy metabolism and cell division and cell structure showed a variable expression pattern over Sb concentrations. Overall these findings provide new insights into the probable survival mechanisms by which M. sinensis could be adapting to Sb phytotoxicity. PMID- 25800730 TI - Detecting virulence and drug-resistance mycobacterial phenotypes in vivo. AB - Bacterial phenotypes are predominantly studied in culture because detection of their specific metabolic pathways in the host is challenging. Development of stable-isotope breath tests, allowing in situ phenotype analyses, may endow diagnostics with new modalities based upon direct monitoring of in vivo microbial metabolism and host-pathogen phenotypic interactions. PMID- 25800731 TI - Assessment of free light chains in HCV-positive patients with mixed cryoglobulinaemia vasculitis undergoing rituximab treatment. AB - BACKGROUND & AIMS: Mixed cryoglobulinaemia (MC) is an HCV-related lymphoproliferative disorder characterized by the presence of circulating immune complexes called cryoglobulins. Treatment with anti-CD20 monoclonal antibody rituximab is proved to be very useful, especially in patients ineligible to interferon-based antiviral therapy. Recently, free light chain (FLC) kappa/lambda ratio and FLC patterns were associated with MC. The aim of this study was to evaluate changes in FLC-kappa, FCL-lambda, FLC ratio following rituximab treatment in patients with HCV-related MC and to correlate FLC-kappa, FCL-lambda and FLC ratio values with therapy response. PATIENTS AND METHODS: We retrospectively enrolled 46 patients with HCV infection (26 females, 20 males), including 10 patients without signs/symptoms of MC-related vasculitis, 36 with MC vasculitis. Clinical and biological data were recorded at baseline and 6 months after RTX treatment. Nephelometric measurement of serum FLCs was taken. RESULTS: The mean serum FLC-kappa level and FLC ratio were significantly higher in patients with MC, compared to HCV patients without MC and to blood donors. An abnormal FLC ratio at baseline correlated with the presence of cryoglobulins, C4 consumption, higher RF level and higher vasculitis rate. To evaluate the predictive value of FLCs, patients with MC were divided into two groups according to RTX therapy outcome (responders and no/partial responders). Abnormal baseline FLC ratio was significantly associated with no/partial response. CONCLUSIONS: RTX treatment in HCV-related MC induces a reduction in FLC-kappa and RF levels. Moreover, pretreatment FLC ratio, which can be easily assessed by a routine test, may be useful to predict response to this expensive treatment for patients with HCV-related MC ineligible to IFN-based therapy. PMID- 25800732 TI - SDF1-3'A polymorphism is associated with size but not occurrence of abdominal aortic aneurysm in a Chinese population. AB - OBJECTIVE: Previous studies have suggested that stromal-derived factor 1 (SDF1) plays a pivotal role in abdominal aortic aneurysm (AAA) development. The SDF1-3'A polymorphism (G to A, rs1801157), located in the 3' untranslated region, could influence the expression of SDF1. The aim of our study was to investigate the relationship of SDF1-3'A polymorphism with the risk of AAA occurrence and size. METHODS: A total of 205 AAA patients and 216 age- and sex-matched controls were recruited. The SDF1-3'A polymorphism was evaluated by polymerase chain reaction, followed by restriction enzyme analysis. RESULTS: The frequency of A allele was similar between groups. The genotype distribution also displayed no statistically significant differences under both the dominant model (odds ratio [OR], 0.922; P = .678) and the recessive model (OR, 1.617; P = .300). The multiple logistic regression analysis indicated that the association between the polymorphism and AAA remained insignificant when applied to the dominant model. However, AAA patients with GG genotype were more likely to develop aneurysms larger than 50 mm (OR, 0.497; P = .014). AAA patients with SDF1-3'A allele have reduced plasma SDF1alpha levels. In addition, plasma SDF1alpha levels were positively correlated with AAA size. CONCLUSIONS: Our study suggests that SDF1-3'A polymorphism is associated with size but not occurrence of AAA, providing further evidence that SDF1 is implicated in AAA progression. PMID- 25800733 TI - Intussusception risk with 116E rotavirus vaccine in Vellore, South India. PMID- 25800734 TI - The chromatin scaffold protein SAFB1 localizes SUMO-1 to the promoters of ribosomal protein genes to facilitate transcription initiation and splicing. AB - Early steps of gene expression are a composite of promoter recognition, promoter activation, RNA synthesis and RNA processing, and it is known that SUMOylation, a post-translational modification, is involved in transcription regulation. We previously found that SUMO-1 marks chromatin at the proximal promoter regions of some of the most active housekeeping genes during interphase in human cells, but the SUMOylated targets on the chromatin remained unclear. In this study, we found that SUMO-1 marks the promoters of ribosomal protein genes via modification of the Scaffold Associated Factor B (SAFB) protein, and the SUMOylated SAFB stimulated both the binding of RNA polymerase to promoters and pre-mRNA splicing. Depletion of SAFB decreased RNA polymerase II binding to promoters and nuclear processing of the mRNA, though mRNA stability was not affected. This study reveals an unexpected role of SUMO-1 and SAFB in the stimulatory coupling of promoter binding, transcription initiation and RNA processing. PMID- 25800735 TI - SplicePie: a novel analytical approach for the detection of alternative, non sequential and recursive splicing. AB - Alternative splicing is a powerful mechanism present in eukaryotic cells to obtain a wide range of transcripts and protein isoforms from a relatively small number of genes. The mechanisms regulating (alternative) splicing and the paradigm of consecutive splicing have recently been challenged, especially for genes with a large number of introns. RNA-Seq, a powerful technology using deep sequencing in order to determine transcript structure and expression levels, is usually performed on mature mRNA, therefore not allowing detailed analysis of splicing progression. Sequencing pre-mRNA at different stages of splicing potentially provides insight into mRNA maturation. Although the number of tools that analyze total and cytoplasmic RNA in order to elucidate the transcriptome composition is rapidly growing, there are no tools specifically designed for the analysis of nuclear RNA (which contains mixtures of pre- and mature mRNA). We developed dedicated algorithms to investigate the splicing process. In this paper, we present a new classification of RNA-Seq reads based on three major stages of splicing: pre-, intermediate- and post-splicing. Applying this novel classification we demonstrate the possibility to analyze the order of splicing. Furthermore, we uncover the potential to investigate the multi-step nature of splicing, assessing various types of recursive splicing events. We provide the data that gives biological insight into the order of splicing, show that non sequential splicing of certain introns is reproducible and coinciding in multiple cell lines. We validated our observations with independent experimental technologies and showed the reliability of our method. The pipeline, named SplicePie, is freely available at: https://github.com/pulyakhina/splicing_analysis_pipeline. The example data can be found at: https://barmsijs.lumc.nl/HG/irina/example_data.tar.gz. PMID- 25800736 TI - PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression. AB - Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator that catalyzes the trimethylation of H3K27 and is modulated by post-translational modifications (PTMs). However, the precise regulation of EZH2 PTMs remains elusive. We, herein, report that EZH2 is acetylated by acetyltransferase P300/CBP-associated factor (PCAF) and is deacetylated by deacetylase SIRT1. We identified that PCAF interacts with and acetylates EZH2 mainly at lysine 348 (K348). Mechanistically, K348 acetylation decreases EZH2 phosphorylation at T345 and T487 and increases EZH2 stability without disrupting the formation of polycomb repressive complex 2 (PRC2). Functionally, EZH2 K348 acetylation enhances its capacity in suppression of the target genes and promotes lung cancer cell migration and invasion. Further, elevated EZH2 K348 acetylation in lung adenocarcinoma patients predicts a poor prognosis. Our findings define a new mechanism underlying EZH2 modulation by linking EZH2 acetylation to its phosphorylation that stabilizes EZH2 and promotes lung adenocarcinoma progression. PMID- 25800737 TI - Cells deficient in base-excision repair reveal cancer hallmarks originating from adjustments to genetic instability. AB - Genetic instability, provoked by exogenous mutagens, is well linked to initiation of cancer. However, even in unstressed cells, DNA undergoes a plethora of spontaneous alterations provoked by its inherent chemical instability and the intracellular milieu. Base excision repair (BER) is the major cellular pathway responsible for repair of these lesions, and as deficiency in BER activity results in DNA damage it has been proposed that it may trigger the development of sporadic cancers. Nevertheless, experimental evidence for this model remains inconsistent and elusive. Here, we performed a proteomic analysis of BER deficient human cells using stable isotope labelling with amino acids in cell culture (SILAC), and demonstrate that BER deficiency, which induces genetic instability, results in dramatic changes in gene expression, resembling changes found in many cancers. We observed profound alterations in tissue homeostasis, serine biosynthesis, and one-carbon- and amino acid metabolism, all of which have been identified as cancer cell 'hallmarks'. For the first time, this study describes gene expression changes characteristic for cells deficient in repair of endogenous DNA lesions by BER. These expression changes resemble those observed in cancer cells, suggesting that genetically unstable BER deficient cells may be a source of pre-cancerous cells. PMID- 25800738 TI - Two RNA recognition motif-containing proteins are plant mitochondrial editing factors. AB - Post-transcriptional C-to-U RNA editing occurs in plant plastid and mitochondrial transcripts. Members of the Arabidopsis RNA-editing factor interacting protein (RIP) family and ORRM1 (Organelle RNA Recognition Motif-containing protein 1) have been recently characterized as essential components of the chloroplast RNA editing apparatus. ORRM1 belongs to a distinct clade of RNA Recognition Motif (RRM)-containing proteins, most of which are predicted to be organelle-targeted. Here we report the identification of two proteins, ORRM2 (organelle RRM protein 2) and ORRM3 (organelle RRM protein 3), as the first members of the ORRM clade to be identified as mitochondrial editing factors. Transient silencing of ORRM2 and ORRM3 resulted in reduced editing efficiency at ~6% of the mitochondrial C targets. In addition to an RRM domain at the N terminus, ORRM3 carries a glycine rich domain at the C terminus. The N-terminal RRM domain by itself provides the editing activity of ORRM3. In yeast-two hybrid assays, ORRM3 interacts with RIP1, ORRM2 and with itself. Transient silencing of ORRM2 in the orrm3 mutant further impairs the editing activity at sites controlled by both ORRM2 and ORRM3. Identification of the effect of ORRM2 and ORRM3 on RNA editing reveals a previously undescribed role of RRM-containing proteins as mitochondrial RNA editing factors. PMID- 25800739 TI - A model for transcription initiation in human mitochondria. AB - Regulation of transcription of mtDNA is thought to be crucial for maintenance of redox potential and vitality of the cell but is poorly understood at the molecular level. In this study we mapped the binding sites of the core transcription initiation factors TFAM and TFB2M on human mitochondrial RNA polymerase, and interactions of the latter with promoter DNA. This allowed us to construct a detailed structural model, which displays a remarkable level of interaction between the components of the initiation complex (IC). The architecture of the mitochondrial IC suggests mechanisms of promoter binding and recognition that are distinct from the mechanisms found in RNAPs operating in all domains of life, and illuminates strategies of transcription regulation developed at the very early stages of evolution of gene expression. PMID- 25800740 TI - Mechano-chemical kinetics of DNA replication: identification of the translocation step of a replicative DNA polymerase. AB - During DNA replication replicative polymerases move in discrete mechanical steps along the DNA template. To address how the chemical cycle is coupled to mechanical motion of the enzyme, here we use optical tweezers to study the translocation mechanism of individual bacteriophage Phi29 DNA polymerases during processive DNA replication. We determine the main kinetic parameters of the nucleotide incorporation cycle and their dependence on external load and nucleotide (dNTP) concentration. The data is inconsistent with power stroke models for translocation, instead supports a loose-coupling mechanism between chemical catalysis and mechanical translocation during DNA replication. According to this mechanism the DNA polymerase works by alternating between a dNTP/PPi-free state, which diffuses thermally between pre- and post-translocated states, and a dNTP/PPi-bound state where dNTP binding stabilizes the post-translocated state. We show how this thermal ratchet mechanism is used by the polymerase to generate work against large opposing loads (~50 pN). PMID- 25800741 TI - A general approach to high-yield biosynthesis of chimeric RNAs bearing various types of functional small RNAs for broad applications. AB - RNA research and therapy relies primarily on synthetic RNAs. We employed recombinant RNA technology toward large-scale production of pre-miRNA agents in bacteria, but found the majority of target RNAs were not or negligibly expressed. We thus developed a novel strategy to achieve consistent high-yield biosynthesis of chimeric RNAs carrying various small RNAs (e.g. miRNAs, siRNAs and RNA aptamers), which was based upon an optimal noncoding RNA scaffold (OnRS) derived from tRNA fusion pre-miR-34a (tRNA/mir-34a). Multi-milligrams of chimeric RNAs (e.g. OnRS/miR-124, OnRS/GFP-siRNA, OnRS/Neg (scrambled RNA) and OnRS/MGA (malachite green aptamer)) were readily obtained from 1 l bacterial culture. Deep sequencing analyses revealed that mature miR-124 and target GFP-siRNA were selectively released from chimeric RNAs in human cells. Consequently, OnRS/miR 124 was active in suppressing miR-124 target gene expression and controlling cellular processes, and OnRS/GFP-siRNA was effective in knocking down GFP mRNA levels and fluorescent intensity in ES-2/GFP cells and GFP-transgenic mice. Furthermore, the OnRS/MGA sensor offered a specific strong fluorescence upon binding MG, which was utilized as label-free substrate to accurately determine serum RNase activities in pancreatic cancer patients. These results demonstrate that OnRS-based bioengineering is a common, robust and versatile strategy to assemble various types of small RNAs for broad applications. PMID- 25800742 TI - Mycoreovirus genome rearrangements associated with RNA silencing deficiency. AB - Mycoreovirus 1 (MyRV1) has 11 double-stranded RNA genome segments (S1 to S11) and confers hypovirulence to the chestnut blight fungus, Cryphonectria parasitica. MyRV1 genome rearrangements are frequently generated by a multifunctional protein, p29, encoded by a positive-strand RNA virus, Cryphonectria hypovirus 1. One of its functional roles is RNA silencing suppression. Here, we explored a possible link between MyRV1 genome rearrangements and the host RNA silencing pathway using wild-type (WT) and mutant strains of both MyRV1 and the host fungus. Host strains included deletion mutants of RNA silencing components such as dicer-like (dcl) and argonaute-like (agl) genes, while virus strains included an S4 internal deletion mutant MyRV1/S4ss. Consequently, intragenic rearrangements with nearly complete duplication of the three largest segments, i.e. S1, S2 and S3, were observed even more frequently in the RNA silencing deficient strains Deltadcl2 and Deltaagl2 infected with MyRV1/S4ss, but not with any other viral/host strain combinations. An interesting difference was noted between genome rearrangement events in the two host strains, i.e. generation of the rearrangement required prolonged culture for Deltaagl2 in comparison with Deltadcl2. These results suggest a role for RNA silencing that suppresses genome rearrangements of a dsRNA virus. PMID- 25800743 TI - Pathway analysis from lists of microRNAs: common pitfalls and alternative strategy. AB - MicroRNAs (miRNAs) are involved in the regulation of gene expression at a post transcriptional level. As such, monitoring miRNA expression has been increasingly used to assess their role in regulatory mechanisms of biological processes. In large scale studies, once miRNAs of interest have been identified, the target genes they regulate are often inferred using algorithms or databases. A pathway analysis is then often performed in order to generate hypotheses about the relevant biological functions controlled by the miRNA signature. Here we show that the method widely used in scientific literature to identify these pathways is biased and leads to inaccurate results. In addition to describing the bias and its origin we present an alternative strategy to identify potential biological functions specifically impacted by a miRNA signature. More generally, our study exemplifies the crucial need of relevant negative controls when developing, and using, bioinformatics methods. PMID- 25800745 TI - Identification of human MutY homolog (hMYH) as a repair enzyme for 2 hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. PMID- 25800744 TI - Magnesium-binding architectures in RNA crystal structures: validation, binding preferences, classification and motif detection. AB - The ubiquitous presence of magnesium ions in RNA has long been recognized as a key factor governing RNA folding, and is crucial for many diverse functions of RNA molecules. In this work, Mg(2+)-binding architectures in RNA were systematically studied using a database of RNA crystal structures from the Protein Data Bank (PDB). Due to the abundance of poorly modeled or incorrectly identified Mg(2+) ions, the set of all sites was comprehensively validated and filtered to identify a benchmark dataset of 15 334 'reliable' RNA-bound Mg(2+) sites. The normalized frequencies by which specific RNA atoms coordinate Mg(2+) were derived for both the inner and outer coordination spheres. A hierarchical classification system of Mg(2+) sites in RNA structures was designed and applied to the benchmark dataset, yielding a set of 41 types of inner-sphere and 95 types of outer-sphere coordinating patterns. This classification system has also been applied to describe six previously reported Mg(2+)-binding motifs and detect them in new RNA structures. Investigation of the most populous site types resulted in the identification of seven novel Mg(2+)-binding motifs, and all RNA structures in the PDB were screened for the presence of these motifs. PMID- 25800747 TI - Assessing the limits of restraint-based 3D modeling of genomes and genomic domains. AB - Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications. PMID- 25800746 TI - Identification of lncRNA-associated competing triplets reveals global patterns and prognostic markers for cancer. AB - Recent studies have suggested that long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) and indirectly regulate miRNA targets though competing interactions. However, the molecular mechanisms underlying these interactions are still largely unknown. In this study, these lncRNA-miRNA-gene interactions were defined as lncRNA-associated competing triplets (LncACTs), and an integrated pipeline was developed to identify lncACTs that are active in cancer. Competing lncRNAs had sponge features distinct from non-competing lncRNAs. In the lncACT cross-talk network, disease-associated lncRNAs, miRNAs and coding-genes showed specific topological patterns indicative of their competence and control of communication within the network. The construction of global competing activity profiles revealed that lncACTs had high activity specific to cancers. Analyses of clustered lncACTs revealed that they were enriched in various cancer-related biological processes. Based on the global cross-talk network and cluster analyses, nine cancer-specific sub-networks were constructed. H19- and BRCA1/2 associated lncACTs were able to discriminate between two groups of patients with different clinical outcomes. Disease-associated lncACTs also showed variable competing patterns across normal and cancer patient samples. In summary, this study uncovered and systematically characterized global properties of human lncACTs that may have prognostic value for predicting clinical outcome in cancer patients. PMID- 25800751 TI - Resveratrol Ameliorates Diabetes-Induced Cardiac Dysfunction Through AT1R-ERK/p38 MAPK Signaling Pathway. AB - The present study was to determine the preventive effect of resveratrol (Res) on diabetes-induced cardiac dysfunction and the possible signaling pathway involved. Diabetes was induced in rats by injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into three groups (10 rats/group): normal group, diabetes groups with or without Res (80 mg/kg) treatment. Biochemistry, cardiac function and fibrosis were detected. Moreover, pro-inflammatory cytokines were evaluated, and heart tissues were homogenized for western blot analysis to analyze the possible mechanisms. The results indicated that Res might regulate glucose and lipid metabolism, ameliorate cardiac function and fibrosis response in STZ-induced diabetic rats. The protective effects were consistent with the inhibition of inflammatory factors such as TNF-alpha, IL-6 and IL-1beta. In addition, Res favorably shifted STZ-induced AT1R, ERK1/2 and p38 MAPK activation in rat heart. In conclusion, the results suggested that Res attenuated diabetes induced cardiac dysfunction, and the effects were associated with attenuation inflammatory response and down-regulation of AT1R-ERK/p38 MAPK signaling pathway. PMID- 25800749 TI - A set of powerful negative selection systems for unmodified Enterobacteriaceae. AB - Creation of defined genetic mutations is a powerful method for dissecting mechanisms of bacterial disease; however, many genetic tools are only developed for laboratory strains. We have designed a modular and general negative selection strategy based on inducible toxins that provides high selection stringency in clinical Escherichia coli and Salmonella isolates. No strain- or species-specific optimization is needed, yet this system achieves better selection stringency than all previously reported negative selection systems usable in unmodified E. coli strains. The high stringency enables use of negative instead of positive selection in phage-mediated generalized transduction and also allows transfer of alleles between arbitrary strains of E. coli without requiring phage. The modular design should also allow further extension to other bacteria. This negative selection system thus overcomes disadvantages of existing systems, enabling definitive genetic experiments in both lab and clinical isolates of E. coli and other Enterobacteriaceae. PMID- 25800750 TI - Cardiac Fas-Dependent and Mitochondria-Dependent Apoptotic Pathways in a Transgenic Mouse Model of Huntington's Disease. AB - Huntington's disease is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene. Heart disease is the second leading cause of death in patients with Huntington's disease. This study was to evaluate whether cardiac Fas-dependent and mitochondria-dependent apoptotic pathways are activated in transgenic mice with Huntington's disease. Sixteen Huntington's disease transgenic mice (HD) and sixteen wild-type (WT) littermates were studied at 10.5 weeks of age. The cardiac characteristics, myocardial architecture, and two major apoptotic pathways in the excised left ventricle from mice were measured by histopathological analysis, Western blotting, and TUNEL assays. The whole heart weight and the left ventricular weight decreased significantly in the HD group, as compared to the WT group. Abnormal myocardial architecture, enlarged interstitial spaces, and more cardiac TUNEL-positive cells were observed in the HD group. The key components of Fas-dependent apoptosis (TNF alpha, TNFR1, Fas ligand, Fas death receptors, FADD, activated caspase-8, and activated caspase-3) and the key components of mitochondria-dependent apoptosis (Bax, Bax-to-Bcl-2 ratio, cytosolic cytochrome c, activated caspase-9, and activated caspase-3) increased significantly in the hearts of the HD group. Cardiac Fas-dependent and mitochondria-dependent apoptotic pathways were activated in transgenic mice with Huntington's disease, which might provide one of possible mechanisms to explain why patients with Huntington's disease will develop heart failure. PMID- 25800748 TI - Advances in CRISPR-Cas9 genome engineering: lessons learned from RNA interference. AB - The discovery that the machinery of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 bacterial immune system can be re-purposed to easily create deletions, insertions and replacements in the mammalian genome has revolutionized the field of genome engineering and re-invigorated the field of gene therapy. Many parallels have been drawn between the newly discovered CRISPR Cas9 system and the RNA interference (RNAi) pathway in terms of their utility for understanding and interrogating gene function in mammalian cells. Given this similarity, the CRISPR-Cas9 field stands to benefit immensely from lessons learned during the development of RNAi technology. We examine how the history of RNAi can inform today's challenges in CRISPR-Cas9 genome engineering such as efficiency, specificity, high-throughput screening and delivery for in vivo and therapeutic applications. PMID- 25800752 TI - Intraperitoneal chemotherapy: long-term outcomes revive a long-running debate. PMID- 25800754 TI - Deciphering the role of phosphatidylinositol 3-kinase mutations in human epidermal growth factor receptor 2-positive breast cancer. PMID- 25800753 TI - Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. AB - PURPOSE: Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure. PATIENTS AND METHODS: Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level. RESULTS: A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs >= 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively. CONCLUSION: A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings. PMID- 25800757 TI - Palliative care: if it makes a difference, why wait? PMID- 25800755 TI - Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis. AB - PURPOSE: Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. PATIENTS AND METHODS: We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. RESULTS: Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP-treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell-like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1-signature and major histocompatibility complex class II-signature genes, which are known to have a positive impact on prognosis. CONCLUSION: Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management. PMID- 25800758 TI - Polypharmacy: geriatric oncology evaluation should become mainstream. PMID- 25800756 TI - Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a gynecologic oncology group study. AB - PURPOSE: To determine long-term survival and associated prognostic factors after intraperitoneal (IP) chemotherapy in patients with advanced ovarian cancer. PATIENTS AND METHODS: Data from Gynecologic Oncology Group protocols 114 and 172 were retrospectively analyzed. Cox proportional hazards regression models were used for statistical analyses. RESULTS: In 876 patients, median follow-up was 10.7 years. Median survival with IP therapy was 61.8 months (95% CI, 55.5 to 69.5), compared with 51.4 months (95% CI, 46.0 to 58.2) for intravenous therapy. IP therapy was associated with a 23% decreased risk of death (adjusted hazard ratio [AHR], 0.77; 95% CI, 0.65 to 0.90; P = .002). IP therapy improved survival of those with gross residual (<= 1 cm) disease (AHR, 0.75; 95% CI, 0.62 to 0.92; P = .006). Risk of death decreased by 12% for each cycle of IP chemotherapy completed (AHR, 0.88; 95% CI, 0.83 to 0.94; P < .001). Factors associated with poorer survival included: clear/mucinous versus serous histology (AHR, 2.79; 95% CI, 1.83 to 4.24; P < .001), gross residual versus no visible disease (AHR, 1.89; 95% CI, 1.48 to 2.43; P < .001), and fewer versus more cycles of IP chemotherapy (AHR, 0.88; 95% CI, 0.83 to 0.94; P < .001). Younger patients were more likely to complete the IP regimen, with a 5% decrease in probability of completion with each year of age (odds ratio, 0.95; 95% CI, 0.93 to 0.96; P < .001). CONCLUSION: The advantage of IP over intravenous chemotherapy extends beyond 10 years. IP therapy enhanced survival of those with gross residual disease. Survival improved with increasing number of IP cycles. PMID- 25800759 TI - Should the use of surveillance imaging in diffuse large B-cell lymphoma be discontinued? PMID- 25800761 TI - Reply to N.H. Turner et al and L. Dziki et al. PMID- 25800760 TI - Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. AB - PURPOSE: The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma. PATIENTS AND METHODS: We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 * 10(4)/m(2) to 1 * 10(8)/m(2)) of T cells expressing an HER2 specific chimeric antigen receptor with a CD28.zeta signaling domain (HER2-CAR T cells). RESULTS: We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 * 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 * 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing >= 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months). CONCLUSION: This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. PMID- 25800763 TI - Fewer scans, better care. PMID- 25800764 TI - Targeting tumor hypoxia with hypoxia-activated prodrugs. PMID- 25800762 TI - Benefits of Early Versus Delayed Palliative Care to Informal Family Caregivers of Patients With Advanced Cancer: Outcomes From the ENABLE III Randomized Controlled Trial. AB - PURPOSE: To determine the effect of early versus delayed initiation of a palliative care intervention for family caregivers (CGs) of patients with advanced cancer. PATIENTS AND METHODS: Between October 2010 and March 2013, CGs of patients with advanced cancer were randomly assigned to receive three structured weekly telephone coaching sessions, monthly follow-up, and a bereavement call either early after enrollment or 3 months later. CGs of patients with advanced cancer were recruited from a National Cancer Institute cancer center, a Veterans Administration Medical Center, and two community outreach clinics. Outcomes were quality of life (QOL), depression, and burden (objective, stress, and demand). RESULTS: A total of 122 CGs (early, n = 61; delayed, n = 61) of 207 patients participated; average age was 60 years, and most were female (78.7%) and white (92.6%). Between-group differences in depression scores from enrollment to 3 months (before delayed group started intervention) favored the early group (mean difference, -3.4; SE, 1.5; d = -.32; P = .02). There were no differences in QOL (mean difference, -2; SE, 2.3; d = -.13; P = .39) or burden (objective: mean difference, 0.3; SE, .7; d = .09; P = .64; stress: mean difference, -.5; SE, .5; d = -.2; P = .29; demand: mean difference, 0; SE, .7; d = -.01; P = .97). In decedents' CGs, a terminal decline analysis indicated between-group differences favoring the early group for depression (mean difference, -3.8; SE, 1.5; d = -.39; P = .02) and stress burden (mean difference, -1.1; SE, .4; d = -.44; P = .01) but not for QOL (mean difference, -4.9; SE, 2.6; d = -.3; P = .07), objective burden (mean difference, -.6; SE, .6; d = -.18; P = .27), or demand burden (mean difference, -.7; SE, .6; d = -.23; P = .22). CONCLUSION: Early-group CGs had lower depression scores at 3 months and lower depression and stress burden in the terminal decline analysis. Palliative care for CGs should be initiated as early as possible to maximize benefits. PMID- 25800765 TI - Risk-adjusted pathologic margin positivity rate: a problematic quality indicator. PMID- 25800766 TI - Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy and potentially inappropriate medication use among ambulatory senior adults with cancer. AB - PURPOSE: The use of multiple and/or inappropriate medications in seniors is a significant public health problem, and cancer treatment escalates its prevalence and complexity. Existing studies are limited by patient self-report and medical record extraction compared with a pharmacist-led comprehensive medication assessment. PATIENTS AND METHODS: We retrospectively examined medication use in ambulatory senior adults with cancer to determine the prevalence of polypharmacy (PP) and potentially inappropriate medication (PIM) use and associated factors. PP was defined as concurrent use of five or more and less than 10 medications, and excessive polypharmacy (EPP) was defined as 10 or more medications. PIMs were categorized by 2012 Beers Criteria, Screening Tool of Older Person's Prescriptions (STOPP), and the Healthcare Effectiveness Data and Information Set (HEDIS). RESULTS: A total of 248 patients received a geriatric oncology assessment between January 2011 and June 2013 (mean age was 79.9 years, 64% were women, 74% were white, and 87% had solid tumors). Only 234 patients (evaluated by pharmacists) were included in the final analysis. Mean number of medications used was 9.23. The prevalence of PP, EPP, and PIM use was 41% (n = 96), 43% (n = 101), and 51% (n = 119), respectively. 2012 Beers, STOPP, and HEDIS criteria classified 173 occurrences of PIMs, which were present in 40%, 38%, and 21% of patients, respectively. Associations with PIM use were PP (P < .001) and increased comorbidities (P = .005). CONCLUSION: A pharmacist-led comprehensive medication assessment demonstrated a high prevalence of PP, EPP, and PIM use. Medication assessments that integrate both 2012 Beers and STOPP criteria and consider cancer diagnosis, prognosis, and cancer-related therapy are needed to optimize medication use in this population. PMID- 25800767 TI - Reply to V. Pitini et al and L.J. Costa. PMID- 25800769 TI - Reply to N.H. Turner et al and L. Dziki et al. PMID- 25800768 TI - Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial. AB - PURPOSE: Randomized controlled trials have supported integrated oncology and palliative care (PC); however, optimal timing has not been evaluated. We investigated the effect of early versus delayed PC on quality of life (QOL), symptom impact, mood, 1-year survival, and resource use. PATIENTS AND METHODS: Between October 2010 and March 2013, 207 patients with advanced cancer at a National Cancer Institute cancer center, a Veterans Affairs Medical Center, and community outreach clinics were randomly assigned to receive an in-person PC consultation, structured PC telehealth nurse coaching sessions (once per week for six sessions), and monthly follow-up either early after enrollment or 3 months later. Outcomes were QOL, symptom impact, mood, 1-year survival, and resource use (hospital/intensive care unit days, emergency room visits, chemotherapy in last 14 days, and death location). RESULTS: Overall patient-reported outcomes were not statistically significant after enrollment (QOL, P = .34; symptom impact, P = .09; mood, P = .33) or before death (QOL, P = .73; symptom impact, P = .30; mood, P = .82). Kaplan-Meier 1-year survival rates were 63% in the early group and 48% in the delayed group (difference, 15%; P = .038). Relative rates of early to delayed decedents' resource use were similar for hospital days (0.73; 95% CI, 0.41 to 1.27; P = .26), intensive care unit days (0.68; 95% CI, 0.23 to 2.02; P = .49), emergency room visits (0.73; 95% CI, 0.45 to 1.19; P = .21), chemotherapy in last 14 days (1.57; 95% CI, 0.37 to 6.7; P = .27), and home death (27 [54%] v 28 [47%]; P = .60). CONCLUSION: Early-entry participants' patient-reported outcomes and resource use were not statistically different; however, their survival 1-year after enrollment was improved compared with those who began 3 months later. Understanding the complex mechanisms whereby PC may improve survival remains an important research priority. PMID- 25800771 TI - Do we still need proxies for quality control in rectal cancer surgery? PMID- 25800770 TI - Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. AB - PURPOSE: Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts. PATIENTS AND METHODS: A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation. RESULTS: Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for >= 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible. CONCLUSION: Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC. PMID- 25800773 TI - Protein alignment: Exact versus approximate. An illustration. AB - We illustrate solving the protein alignment problem exactly using the algorithm VESPA (very efficient search for protein alignment). We have compared our result with the approximate solution obtained with BLAST (basic local alignment search tool) software, which is currently the most widely used for searching for protein alignment. We have selected human and mouse proteins having around 170 amino acids for comparison. The exact solution has found 78 pairs of amino acids, to which one should add 17 individual amino acid alignments giving a total of 95 aligned amino acids. BLAST has identified 64 aligned amino acids which involve pairs of more than two adjacent amino acids. However, the difference between the two outputs is not as large as it may appear, because a number of amino acids that are adjacent have been reported by BLAST as single amino acids. So if one counts all amino acids, whether isolated (single) or in a group of two and more amino acids, then the count for BLAST is 89 and for VESPA is 95, a difference of only six. PMID- 25800772 TI - Spontaneous resealing of perforated scleral ectasia associated with atypical retinochoroidal coloboma. PMID- 25800774 TI - CD34(+) B-cell progenitors in mobilized peripheral blood apheresis collections: implications for flow cytometric assessment of graft adequacy. PMID- 25800775 TI - Cord blood for brain injury. AB - Recovery from neurological injuries is typically incomplete and often results in significant and permanent disabilities. Currently, most available therapies are limited to supportive or palliative measures, aimed at managing the symptoms of the condition. Because restorative therapies targeting the underlying cause of most neurological diseases do not exist, cell therapies targeting anti inflammatory, neuroprotective and regenerative potential hold great promise. Cord blood (CB) cells can induce repair through mechanisms that involve trophic or cell-based paracrine effects or cellular integration and differentiation. Both may be operative in emerging CB therapies for neurologic conditions, and there are numerous potential applications of CB-based regenerative therapies in neurological diseases, including genetic diseases of childhood, ischemic events such as stroke and neurodegenerative diseases of adulthood. CB appears to hold promise as an effective therapy for patients with brain injuries. In this Review, we describe the state of science and clinical applications of CB therapy for brain injury. PMID- 25800776 TI - Effect of serum choice on replicative senescence in mesenchymal stromal cells. AB - BACKGROUND AIMS: Multipotent mesenchymal stromal cells (MSCs) are promising candidates for innovative cell therapeutic applications. Before their use, however, they usually need to be expanded in vitro with serum-supplemented media. MSCs can undergo replicative senescence during in vitro expansion, but it is not yet clear how serum supplements influence this process. METHODS: In the present study, we compared how media supplemented with fetal bovine serum (FBS) or calf serum (CS) affected morphology, proliferation, differentiation, senescence and other functional characteristics of human umbilical cord-derived MSCs (UC-MSCs). RESULTS: UC-MSCs cultured in both FBS- and CS-containing media were able to differentiate along osteogenic and adipogenic lineages but ultimately reached proliferation arrest. However, senescence-associated characteristics, such as beta-galactosidase activity, reactive oxygen species levels, proliferation rate and gene expression, demonstrate that UC-MSCs grown with FBS have better proliferation potential and differentiation capacity. In contrast, UC-MSCs grown with CS have a higher proportion of apoptotic cells and senescent characteristics. Possible mechanisms for the observed phenotypes include changes in gene expression (Bax, p16, p21 and p53) and cytokine production (interleukin-6 and interleukin-8). CONCLUSIONS: This study demonstrates that FBS-supplemented media provides a better microenvironment for the expansion of UC-MSCs in vitro than CS-supplemented media. This work provides insight into MSCs generation practices for use in basic research and clinical therapies. PMID- 25800777 TI - Mixed Experiences and Perceptions of Psychological Treatment for Chronic Pain in Singapore: Skepticism, Ambivalence, Satisfaction, and Potential. AB - There is little research in Southeast Asia focusing on patients' experiences of seeking psychological treatment for chronic pain. OBJECTIVE: This study aims to understand the experiences of patients seeking psychological treatment for chronic pain in this region. SETTING: Outpatient pain clinic at a tertiary hospital in Singapore. SUBJECTS: People with experiences of attending psychological treatment for chronic pain, including some who were not receiving this type of treatment. STUDY DESIGN AND METHODS: Fifteen inductive semi structured interviews were conducted to explore patients' experiences regarding psychological treatment for their chronic pain. Thematic analysis was then applied. RESULTS: Three main themes were identified: "Expectations and Realities of Health Professionals," "Patients' Attitudes and Beliefs," and "Practical and Social Factors." From the patients' perspectives, an empathetic health professional who was willing to listen contributed to a positive treatment seeking experience. Patients felt that health professionals' lack of knowledge about appropriate treatment contributed to their frustration. Patients could not understand how psychological treatment was related to pain treatment and queried why they were "paying just to talk." Conversely, their experiences were quite positive, and they found psychological treatments helpful when they participated in them. CONCLUSION: Education for both patients and health professionals unfamiliar with psychological treatments for pain may improve access to these treatments. PMID- 25800780 TI - The Miniaturized Multiplane Micro-Transesophageal Echocardiographic Probe: A Comparative Evaluation of Its Accuracy and Image Quality. AB - BACKGROUND: The initial experience with the miniaturized multiplane micro transesophageal echocardiographic probe (MTEE) reported high-quality diagnostic imaging in small infants. The aim of this study was to compare the diagnostic accuracy and image quality of the intraoperative MTEE with the pediatric multiplane transesophageal echocardiographic probe (PTEE). METHODS: Infants weighing <5 kg who underwent intraoperative transesophageal echocardiography were identified. Studies using the MTEE were matched 1:1 with those using the PTEE by cardiac diagnosis. The postoperative transesophageal echocardiograms, obtained using either probe, were reviewed for the presence of 11 cardiac abnormalities. Postoperative transesophageal echocardiograms were compared with predischarge transthoracic echocardiograms to assess accuracy. Using receiver operating characteristic curves, the areas under the curve for the MTEE and PTEE were compared. Two pediatric cardiologists scored six image quality metrics on equal numbers of studies obtained with the MTEE and the PTEE. Composite scores from both reviewers were used to compare image quality. RESULTS: The study included 110 transesophageal echocardiograms per probe type. The mean weight for the MTEE was lower than for the PTEE (3.15 +/- 0.58 vs 3.70 +/- 0.52 kg, P < .001). There was no significant difference in the diagnostic accuracy of the MTEE and PTEE using receiver operating characteristic curves. The numbers of residual anatomic lesions missed by the MTEE and PTEE were similar (19 vs 22, respectively). The composite image quality score was worse for the MTEE compared with the PTEE (81% vs 92%, respectively, P < .0001). CONCLUSIONS: Although the image quality of the MTEE is inferior compared with the PTEE, its diagnostic accuracy in infants weighing <5 kg is comparable. PMID- 25800778 TI - Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells. AB - Germ cell specification is accompanied by epigenetic remodeling, the scale and specificity of which are unclear. Here, we quantitatively delineate chromatin dynamics during induction of mouse embryonic stem cells (ESCs) to epiblast-like cells (EpiLCs) and from there into primordial germ cell-like cells (PGCLCs), revealing large-scale reorganization of chromatin signatures including H3K27me3 and H3K9me2 patterns. EpiLCs contain abundant bivalent gene promoters characterized by low H3K27me3, indicating a state primed for differentiation. PGCLCs initially lose H3K4me3 from many bivalent genes but subsequently regain this mark with concomitant upregulation of H3K27me3, particularly at developmental regulatory genes. PGCLCs progressively lose H3K9me2, including at lamina-associated perinuclear heterochromatin, resulting in changes in nuclear architecture. T recruits H3K27ac to activate BLIMP1 and early mesodermal programs during PGCLC specification, which is followed by BLIMP1-mediated repression of a broad range of targets, possibly through recruitment and spreading of H3K27me3. These findings provide a foundation for reconstructing regulatory networks of the germline epigenome. PMID- 25800779 TI - The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. AB - While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations. PMID- 25800782 TI - miR-30-HNF4gamma and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach. AB - OBJECTIVE: Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) are considered neoplastic precursors of gastric adenocarcinoma and are both marked by gene expression alterations in comparison to normal stomach. Since miRNAs are important regulators of gene expression, we sought to investigate the role of miRNAs on the development of stomach metaplasias. DESIGN: We performed miRNA profiling using a quantitative reverse transcription-PCR approach on laser capture microdissected human intestinal metaplasia and SPEM. Data integration of the miRNA profile with a previous mRNA profile from the same samples was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with selected miRNA mimics and inhibitors was used to evaluate their effects on the expression of putative targets and additional metaplasia markers. RESULTS: We identified several genes as potential targets of miRNAs altered during metaplasia progression. We showed evidence that HNF4gamma (upregulated in intestinal metaplasia) is targeted by miR 30 and that miR-194 targets a known co-regulator of HNF4 activity, NR2F2 (downregulated in intestinal metaplasia). Intestinal metaplasia markers such as VIL1, TFF2 and TFF3 were downregulated after overexpression of miR-30a in a HNF4gamma-dependent manner. In addition, overexpression of HNF4gamma was sufficient to induce the expression of VIL1 and this effect was potentiated by downregulation of NR2F2. CONCLUSIONS: The interplay of the two transcription factors HNF4gamma and NR2F2 and their coordinate regulation by miR-30 and miR 194, respectively, represent a miRNA to transcription factor network responsible for the expression of intestinal transcripts in stomach cell lineages during the development of intestinal metaplasia. PMID- 25800784 TI - Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. AB - OBJECTIVE: Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV. DESIGN: In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks. RESULTS: Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (-3.03 log10 IU/mL vs -3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups. CONCLUSIONS: In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks. TRIAL REGISTRATION NUMBER: NCT01639066. PMID- 25800783 TI - Modulation of HCV reinfection after orthotopic liver transplantation by fibroblast growth factor-2 and other non-interferon mediators. AB - OBJECTIVE: In HCV infected individuals graft infection occurs shortly after orthotopic liver transplantation (OLT). We aimed to describe the composition of the inflammatory response at this time, how it affects the HCV replication cycle and identify novel proviral and antiviral factors. DESIGN: We used a Luminex assay to quantify 50 inflammatory mediators in sera before and shortly after OLT. In vitro grown HCV based on the JFH-1 isolate were used to characterise the effects of patient sera and individual mediators on HCV. RESULTS: Although the mediator composition is highly variable between individuals, sera drawn immediately post-OLT significantly enhance HCV infectivity compared with control sera from before OLT in about half of the cases. Among 27 non-interferon inflammatory mediators fibroblast growth factor (FGF)-2 stood out as it enhanced HCV RNA replication and release of infectious particles. The effect was concentration-dependent and detectable in dividing and non-dividing cells. Moreover, pharmacological inhibition of FGF-2 receptor signalling abrogated the enhancing effect of FGF-2 and inhibited HCV replication in the absence of serum FGF-2 suggesting that HCV replication is dependent on basal activation of the FGF 2 triggered signalling pathway. Finally, in individuals with chronic HCV infection with high viral load, serum FGF-2 was significantly higher compared with those with low viral load. CONCLUSIONS: Although no single mediator may account for this effect, serum shortly post-OLT enhances HCV infection. FGF-2 is a novel endogenous driver of HCV replication and a potential therapeutic target. PMID- 25800785 TI - Patient-led research in amyotrophic lateral sclerosis: Quo vadis? AB - Patient-led trials are steadily claiming their place in modern neurological research. A popular paper on the effects of lithium in amyotrophic lateral sclerosis included a report on a clinical trial in humans. Subsequently, a follow up study using patient-reported data did not confirm the original result, opening a scientific debate on how patient-reported data could contribute to neurological research. This review critically illustrates the major benefits and caveats of the current patient-led trials and presents recent U.S. and UK guidelines, which aim to the optimal incorporation of patient-reported outcomes in a reinvigorated research perspective. PMID- 25800786 TI - Authors' response: Atrial electromechanical coupling: a complementary index for quantifying atrial cardiac electrical heterogeneity in preeclampsia. PMID- 25800787 TI - "Individualized assessment of preterm birth risk using two modified prediction models" from M. Mailath-Pokorny and colleagues. PMID- 25800788 TI - Quality of life and sexual activity during treatment of Bartholin's cyst or abscess with a Word catheter. AB - OBJECTIVES: Cysts and abscesses of the Bartholin glands are a common occurrence in gynecologic or general practice. Little is known about restrictions in patient's daily life and sexual activity during treatment of Bartholin's cysts in general and especially with the Word catheter. This study is to assess the Quality of Life and Sexual Activity during treatment of Bartholin cyst's and abscesses with the Word-catheter. STUDY DESIGN: Between March 2013 and May 2014 30 women were included in the study. Pain before treatment and during catheter insertion and removal was assed using a standardized VAS scale. Health-related quality of life was assessed with the Short-Form-12-Health-Survey. Fallowfield's Sexual Activity Questionnaire was administered to investigate sexual limitations. During treatment patient self-reported to a pain-diary (VAS 0-10). RESULTS: Pain levels decreased from a 3 [0-10] on day 1 to 0 [0-6] on day 6 with the median staying at 0 for the remaining treatment period. Discomfort and pain during sexual activity decreased significantly from initial presentation to end of treatment. The mental component summary score of the SF 12 increased significantly from 46.94+/-10.23 before treatment to 50.58+/-7.16 after treatment (p=0.016); the physical component summary score did not change significantly. CONCLUSIONS: The Word catheter is well tolerated for the treatment of Bartholin's cysts and abscesses with few and no serious side effects and little impingement of sexual health. A more relevant informed consent ahead of treatment, specifically with regard to pain in the first few days after catheter placement, might further increase acceptance of the catheter and adjust patient expectations. PMID- 25800789 TI - Bias in estimating the causal hazard ratio when using two-stage instrumental variable methods. AB - Two-stage instrumental variable methods are commonly used to estimate the causal effects of treatments on survival in the presence of measured and unmeasured confounding. Two-stage residual inclusion (2SRI) has been the method of choice over two-stage predictor substitution (2SPS) in clinical studies. We directly compare the bias in the causal hazard ratio estimated by these two methods. Under a principal stratification framework, we derive a closed-form solution for asymptotic bias of the causal hazard ratio among compliers for both the 2SPS and 2SRI methods when survival time follows the Weibull distribution with random censoring. When there is no unmeasured confounding and no always takers, our analytic results show that 2SRI is generally asymptotically unbiased, but 2SPS is not. However, when there is substantial unmeasured confounding, 2SPS performs better than 2SRI with respect to bias under certain scenarios. We use extensive simulation studies to confirm the analytic results from our closed-form solutions. We apply these two methods to prostate cancer treatment data from Surveillance, Epidemiology and End Results-Medicare and compare these 2SRI and 2SPS estimates with results from two published randomized trials. PMID- 25800790 TI - Ultrasonographic Evaluation of Resistive Index and Renal Artery Stenosis in Patients with Anti-Phospholipid Syndrome: Two Distinct Mechanisms? AB - Renal involvement in anti-phospholipid syndrome (APS) is still relatively unknown and probably underestimated. The described lesions consist of renal artery stenosis (RAS), venous renal thrombosis and glomerular lesions. The resistive index (RI) of intra-renal arteries, expression of the degree of vascular resistance, has been analyzed in different nephropathies and observed to be associated with functional parameters and some histologic features. In contrast, there are no studies on patients with APS. We evaluated the presence of a pathologic RI and RAS in a cohort of patients with APS. The study protocol included ultrasonographic assessment to measure the RI (RIs >0.7 were considered pathologic) and to determine the presence of RAS. We enrolled 36 patients with APS, 13 with primary APS and 23 with the form associated with systemic lupus erythematosus (SLE, secondary APS). As controls, we enrolled 10 anti-phospholipid antibody carriers, 10 patients with SLE without renal involvement and 14 age- and sex-matched healthy patients. A pathologic RI was identified in five patients with APS (13.9%) and in none of the anti-phospholipid antibody carriers (p = 0.00007). Four of the five (80%) patients with a pathologic RI had secondary APS. Three patients, all with primary APS, had RAS. The almost exclusive association of a pathologic RI with secondary APS and of RAS with primary APS suggests the involvement of two pathogenic pathways in the development of these different manifestations. The hypercoagulability status driven by APS could play a central role in the determination of RAS in patients with primary APS, whereas the activation of mTORC (mammalian target of rapamycin complex) pathways could be the pathogenic mechanism inducing development of a pathologic RI. PMID- 25800791 TI - Foreword to the WFUMB guidelines and recommendations on the clinical use of ultrasound elastography. PMID- 25800792 TI - Investigations of possible prodrug structures for 2-(2 mercaptophenyl)tetrahydropyrimidines: reductive conversion from anti-HIV agents with pyrimidobenzothiazine and isothiazolopyrimidine scaffolds. AB - 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) and 3,4 dihydro-2H-benzo[4,5]isothiazolo[2,3-a]pyrimidine are the heterocyclic antiretroviral agents against human immunodeficiency virus type 1 (HIV-1) infection. On the basis of similar structure-activity relationships of anti-HIV activities toward the early-stage of viral infection between these unique scaffolds, the transformations under the bioassay conditions were investigated. The distinctive S-N bond in the isothiazolopyrimidine scaffold was immediately cleaved under reductive conditions in the presence of GSH to generate a thiophenol derivative. A similar rapid conversion of PD 404182 into the same thiophenol derivative was observed, suggesting that pyrimidobenzothiazine and isothiazolopyrimidine scaffolds may work as prodrug forms of the common bioactive thiophenol derivatives. PMID- 25800793 TI - HPIP is upregulated in colorectal cancer and regulates colorectal cancer cell proliferation, apoptosis and invasion. AB - Hematopoietic pre-B cell leukemia transcription factor (PBX)-interacting protein (HPIP) was shown to play a role in cancer development and progression. However, the role of HPIP in colorectal cancer (CRC) is unknown. Here, we report that HPIP is overexpressed in most of CRC patients and predicts poor clinical outcome in CRC. HPIP promotes CRC cell proliferation via activation of G1/S and G2/M checkpoint transitions, concomitant with a marked increase of the positive cell cycle regulators, including cyclin D1, cyclin A, and cyclin B1. HPIP inhibits CRC cell apoptosis accompanied by the decreased levels of BAX and PIG3, the inducers of apoptosis, and the increased level of the apoptosis inhibitor BCL2. HPIP blocks caspase-3-mediated cleavage of PARP, an important apoptosis marker. HPIP promotes CRC cell migration and invasion, and regulates epithelial-mesenchymal transition (EMT), which plays a critical role in cancer cell migration and invasion. Activation of MAPK/ERK1/2 and PI3k/AKT pathways is required for HPIP modulation of CRC cell proliferation, migration and EMT. Moreover, HPIP knockdown suppresses colorectal tumor growth in nude mice. These data highlight the important role of HPIP in CRC cell proliferation and progression and suggest that HPIP may be a useful target for CRC therapy. PMID- 25800795 TI - Breastfeeding Supportive Hospital Practices in the US Differ by County Urbanization Level. AB - BACKGROUND: Breastfeeding rates are lower among infants living in rural areas of the United States, yet there are limited data on whether hospital breastfeeding support differs between rural and urban areas. OBJECTIVE: This study aimed to describe whether maternity care practices supportive of breastfeeding vary by level of urbanization. METHODS: We linked data from the 2007, 2009, and 2011 Maternity Practices in Infant Nutrition and Care (mPINC) surveys with Rural-Urban Continuum Codes to categorize hospital counties as metropolitan urbanized, nonmetropolitan urbanized, less urbanized, and thinly populated. RESULTS: From 2007 to 2011, the average hospital mPINC score, a composite quality score ranging from 0 to 100, increased from 64 to 71 in metropolitan urbanized counties and from 54 to 65 in thinly populated areas. Scores were lowest in thinly populated counties in 2007 and 2009 and in less urbanized counties in 2011. Examination of 2011 mPINC scores by 7 domains of care revealed that hospitals in less urbanized counties had lower scores than those in metropolitan urbanized counties for feeding of breastfed infants, breastfeeding assistance, staff training, and structural and organizational aspects of care delivery; for 3 of these practices, scores were 10 or more points lower-breastfeeding assistance, structural and organizational aspects of care, and staff training. In contrast, hospitals in thinly populated areas had higher scores than in metropolitan areas for mother infant contact and facility discharge care; differences were less than 10 points. CONCLUSION: Interventions that specifically target rural hospitals may reduce the gap in access to hospital maternity care practices supportive of breastfeeding by population density. PMID- 25800796 TI - Myopia and daylight in schools: a neglected aspect of public health? AB - A century ago, it was widely believed that high levels of daylight in classrooms could prevent myopia, and as such, education departments built schools with large windows to try to stop children becoming short-sighted. This practice continued until the 1960s, from which time myopia was believed to be an inherited condition. In the years that followed, less emphasis was placed on preventing myopia. It has since become more common, reaching epidemic levels in east Asia. Recent research strongly suggests that the amount of light children get as they grow determines whether they will develop short sight; however, evidence that daylight in classrooms prevents myopia is lacking. Given the rapid increase in prevalence among school children worldwide, this should be investigated. PMID- 25800794 TI - Cysteine string protein (CSP) and its role in preventing neurodegeneration. AB - Cysteine string protein (CSP) is a member of the DnaJ/Hsp40 family of co chaperones that localises to neuronal synaptic vesicles. Its name derives from the possession of a string of 12-15 cysteine residues, palmitoylation of which is required for targeting to post-Golgi membranes. The DnaJ domain of CSP enables it to bind client proteins and recruit Hsc70 chaperones, thereby contributing to the maintenance of protein folding in the presynaptic compartment. Mutation of CSP in flies, worms and mice reduces lifespan and causes synaptic dysfunction and neurodegeneration. Furthermore, recent studies have revealed that the neurodegenerative disease, adult onset neuronal ceroid lipofuscinosis, is caused by mutations in the human CSPalpha-encoding DNAJC5 gene. Accumulating evidence suggests that the major mechanism by which CSP prevents neurodegeneration is by maintaining the conformation of SNAP-25, thereby facilitating its entry into the membrane-fusing SNARE complex. In this review, we focus on the role of CSP in preventing neurodegeneration and discuss how recent studies of this universal neuroprotective chaperone are being translated into potential novel therapeutics for neurodegenerative diseases. PMID- 25800797 TI - Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hypaconitine is one of the main aconitum alkaloids in traditional Chinese medicines prepared with herbs from the genus Acotinum. These herbs are widely used for the treatment of cardiac insufficiency and arrhythmias. However, Acotinum alkaloids are known for their toxicity as well as their pharmacological activity, especially cardiotoxicity including QT prolongation, and the mechanism of this toxicity is not clear. MATERIAL AND METHODS: In this study, hypaconitine was administered orally to conscious Beagle dogs, and electrocardiograms were recorded by telemetry. Pharmacokinetic studies (6h) were conducted to evaluate the relationship between QT prolongation and exposure level. HEK293 cells stably transfected with KCNH2 (hERG) cDNA were used to examine the effects of hypaconitine on the KCNH2 channel by using the manual patch clamp technique. RESULTS: In the conscious dogs, all doses of hypaconitine induced QTcV (QT interval corrected according to the Van de Water formula) prolongation by more than 23% (67ms) of control in a dose-dependent manner. The maximum QTcV prolongation was observed at 2h after dosing. Maximum prolongation percentages were plotted against plasma concentrations of hypaconitine and showed a strong correlation (R(2)=0.789). In the in vitro study in HEK293 cells, hypaconitine inhibited the KCNH2 currents in a concentration-dependent manner with an IC50 of 8.1nM. CONCLUSION: These data suggest that hypaconitine inhibits KCNH2 potassium channels and this effect might be the molecular mechanism underlying QT prolongation in conscious dogs. PMID- 25800798 TI - Alteration of glutamate/GABA balance during acute alcohol intoxication in rats: effect of Xingnaojing injection. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xingnaojing Injection (XNJI) is a modern Chinese formula came from famous Chinese medicine An Gong Niu Huang Pill. XNJI has been used for treatment of cerebral diseases and stroke in China, and is approved by the State Food and Drug Administration of China for the treatment of acute alcohol intoxication (AAI). XNJI belongs to the ethnopharmacological family of medicines. In this study, we investigated the mechanisms of the XNJI effect on AAI. AIM OF THE STUDY: To investigate the effects of XNJI on glutamate, gamma aminobutyric acid (GABA) and related receptor in lateral hypothalamic area (LHA) of AAI rat. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were implanted with microdialysis probes in LHA. Rats were randomly divided into control, model, 1.36mg/kg XNJI, 0.68mg/kg XNJI and 0.34mg/kg XNJI groups. During microdialysis, baseline samples were collected from 1h to 2.5h; thereafter, the rats were given an intraperitoneal injection of 52% ethanol, 5.2g/kg, or saline for control group. Twenty minutes later, three doses of XNJI was given by unilateral injection respectively, while saline for control and model groups, and samples were collected for the next 4h. The extracellular glutamate and GABA levels were measured in the LHA by a high performance liquid chromatography coupled with fluorescence detector (HPLC-FLU). The expression levels of related receptors N methyl-d-aspartate receptor (NR) subunit NR2A, NR2B and GABAA were analyzed by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Ethanol (5.2g/kg) significantly decreased the extracellular levels of glutamate and increased extracellular GABA in LHA. On the other hand ethanol significantly decreased NR2A and NR2B mRNAs expression, and increase GABAA mRNA expression. XNJI could increase the extracellular level of glutamate and decrease that of GABA; moreover, induced an increase in NR2A and NR2B mRNA expression, and a decrease in GABAA mRNA expression in LHA. CONCLUSIONS: The current changes in glutamate, GABA and mRNA expressions of related receptors in LHA after injection of XNJI suggest that changes in these neurotransmitters and receptors as a potential mechanism of action for AAI. PMID- 25800799 TI - Transcranial direct current stimulation for hyperactivity and noncompliance in autistic disorder. AB - OBJECTIVES: To evaluate the safety, efficacy, and feasibility of inhibitory transcranial direct current stimulation (tDCS) for the treatment of behavioural abnormalities of autistic patients. METHODS: Twelve young adult patients with autistic disorder were enrolled. All subjects presented intellectual disability and most of them had speech impairment. The Aberrant Behavior Checklist (ABC) was administered as the primary outcome measure before and after a 2-week tDCS course. All subjects received 10 daily applications of 20 min/1.5 mA/cathodal (inhibitory) tDCS over the left dorso-lateral pre-frontal cortex. RESULTS: Eight out of 10 study completers improved in their abnormal behaviours, reaching an average reduction of 26.7% of the total ABC score. The remaining two patients showed no changes. In the whole group of completers, among the five subscales contributing to the significant reduction of the total score, the most remarkable and statistically significant change was seen in the subscale assessing hyperactivity and non-compliance (-35.9%, P = 0.002). No adverse effects were reported. CONCLUSIONS: Inhibitory tDCS improved the ABC rating scores for autistic behaviours. Owing to its ease of use, cost-effectiveness and the limited availability of specific treatment strategies, tDCS might be a valid therapeutic option to be tested in autistic patients. PMID- 25800801 TI - Transorbital Ultrasonographic Measurement of Optic Nerve Sheath Diameter in Brain Death. AB - BACKGROUND: Ultrasonographic measurement of optic nerve sheath diameter (ONSD) can successfully be used to estimate intracranial pressure (ICP) elevation. Its utility in corroboration of brain death (BD) was herein studied. METHODS: ONSD was measured in 29 subjects with BD; in 19 comatose patients (with raised ICP in 11), 20 patients with various neurological diseases, and 40 healthy control subjects. The distance between the inner and outer edges of the echolucent lines around hyperechoic area surrounding the optic nerve (ON) was identified as ONSD external (ONSDe) and ONSD internal (ONSDi). RESULTS: Compared to patients with neurological diseases (5.75 +/- .79 mm) or healthy controls (5.98 +/- .63 mm), ONSDe was significantly higher in comatose patients (7.61 +/- .97 and 6.71 +/- 1.07 mm in those with and without raised ICP) and BD subjects (8.34 +/- .66 mm). ONSDi showed similar trends across the groups: 6.09 +/- .71 mm in BD; 5.89 +/- .37 mm in comatose control with elevated ICP; 5.16 +/- .49 mm in comatose control with normal ICP; 4.36 +/- .68 mm in neurological control; 4.69 +/- .67 mm in healthy control. The accuracy of ONSDe measurements in differentiating patients with ICP elevation (n = 40) was .965 as determined by area under the curve (AUC) of receiver-operator characteristics curves. Similarly, accuracy in discrimination of BD was .952. However, ONSDe showed limited yield to identify BD cases among comatose patients with Glasgow coma scale score of 3, where accuracy was .803 (95% CI: .709-.816) and decreased further to .722 (95% CI: .610-.816) when analyses were restricted to comatose patients with ICP elevation. AUC values for ONSDi was similar or lower. CONCLUSION: ONSD is significantly greater in subjects with BD. However, quantification of ONSD cannot discriminate BD subjects from comatose ones with raised ICP with 100% certainty. PMID- 25800800 TI - Diagnostic and therapeutic appropriateness in bone and joint infections: results of a national survey. AB - The impact of infectious diseases (ID) specialist consultation in the management of many types of bacterial infections has been fully demonstrated but not for bone and joint infections (BJIs). Nineteen ID Italian centres collected of data from June 2009 to May 2012. Italian guidelines (2009) were used to determine the appropriateness of the diagnostic and therapeutic process of BJIs before and after consulting an ID specialist. Data on 311 patients were collected: 111 cases of prosthetic joint infection, 99 osteomyelitis, 64 spondylodiscitis and 37 fixation device infection. A significant increase of microbiological investigations, imaging techniques and blood inflammation markers were noted after consulting the ID specialist. Moreover, inappropriateness of treatment duration, dosage, and number of administrations significantly decreased after consultation. Infectious disease specialist intervention in the management of BJIs significantly increases the appropriateness both in performing instrumental and laboratory analysis, but especially in determining the correct therapy. PMID- 25800802 TI - Quantum dynamics of CO-H2 in full dimensionality. AB - Accurate rate coefficients for molecular vibrational transitions due to collisions with H2, critical for interpreting infrared astronomical observations, are lacking for most molecules. Quantum calculations are the primary source of such data, but reliable values that consider all internal degrees of freedom of the collision complex have only been reported for H2-H2 due to the difficulty of the computations. Here we present essentially exact, full-dimensional dynamics computations for rovibrational quenching of CO due to H2 impact. Using a high level six-dimensional potential surface, time-independent scattering calculations, within a full angular momentum coupling formulation, were performed for the de-excitation of vibrationally excited CO. Agreement with experimentally determined results confirms the accuracy of the potential and scattering computations, representing the largest of such calculations performed to date. This investigation advances computational quantum dynamical studies representing initial steps towards obtaining CO-H2 rovibrational quenching data needed for astrophysical modelling. PMID- 25800804 TI - Development of a technical external quality assurance scheme in non gynaecological cytology in UK. AB - Technical external quality assurance (EQA) schemes are well established for histopathology and cervical cytology but, to date, sadly lacking for diagnostic cytology (DC). This timely review redresses the balance by describing the development and evaluation of a technical EQA scheme for DC available to the UK, Europe and beyond. PMID- 25800805 TI - The role of Cytotechnologists in quality assurance and audit in non gynaecological cytology. PMID- 25800806 TI - The impact of HPV triage and test of cure and primary HPV screening on a colposcopy service in England. PMID- 25800807 TI - Strained cyclooctyne as a molecular platform for construction of multimodal imaging probes. AB - Small-molecule-based multimodal and multifunctional imaging probes play prominent roles in biomedical research and have high clinical translation ability. A novel multimodal imaging platform using base-catalyzed double addition of thiols to a strained internal alkyne such as bicyclo[6.1.0]nonyne has been established in this study, thus allowing highly selective assembly of various functional units in a protecting-group-free manner. Using this molecular platform, novel dual modality (PET and NIRF) uPAR-targeted imaging probe: (64)Cu-CHS1 was prepared and evaluated in U87MG cells and tumor-bearing mice models. The excellent PET/NIRF imaging characteristics such as good tumor uptake (3.69%ID/g at 2 h post injection), high tumor contrast, and specificity were achieved in the small animal models. These attractive imaging properties make (64)Cu-CHS1 a promising probe for clinical use. PMID- 25800808 TI - Japan Society of Gynecologic Oncology guidelines 2011 for the treatment of uterine cervical cancer. AB - The second edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine cervical cancer was published in 2011. The guidelines comprise eight chapters and five algorithms. They were prepared by consensus among the members of the Japan Society of Gynecologic Oncology Guidelines Formulation Committee and Evaluation Committee and are based on a careful review of the evidence obtained from the literature, health insurance system, and actual clinical settings in Japan. The highlights of the 2011 revision are (1) the recommended grades have been changed to five stages--A, B, C1, C2, and D; (2) the revisions are consistent with the new International Federation of Gynecology and Obstetrics staging system; (3) the roles are shared between the 'Japanese classification of cervical cancer' and the new guidelines; (4) clinical questions related to adenocarcinoma have been revised; and (5) a clinical question regarding cervical cancer in pregnant patients has been added. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. Each recommendation is accompanied by a classification of recommendation categories. The objective of these guidelines is to update the standard treatment strategies for cervical cancer, thus eliminating unnecessary and insufficient treatment. PMID- 25800810 TI - The nested graft acts by inducing the process of de-senescence of the fibroblasts in chronic venous ulcers. AB - Senescent fibroblasts, which are present in chronic ulcers, are the reason for the wound becoming chronic. In this study, we introduce full-thickness micro skin grafts in the ulcer, a surgical technique known as a 'nested graft', which gave encouraging results leading to complete wound healing in all patients. The assessment of fibroblast cultures taken from the wound before and after treatment and comparison with fibroblasts from healthy skin showed that the fibroblasts taken from the ulcer after the nested graft treatment acquire morpho-functional characteristics overlapping those of fibroblasts from healthy skin. This surgical approach is, therefore, able to lead to the healing of chronic ulcers through the de-senescence of the fibroblasts. PMID- 25800809 TI - Long-term results of definitive concurrent chemoradiotherapy for patients with esophageal submucosal cancer (T1bN0M0). AB - BACKGROUND: The long-term outcomes of definitive concurrent chemoradiotherapy for patients with esophageal submucosal cancer without regional and distant metastasis were retrospectively analyzed. METHODS: Patients with histologically confirmed esophageal submucosal cancers without regional and distant metastasis who received definitive concurrent chemoradiotherapy from 2001 to 2011 were included. Radiation therapy of a median total dose of 60 Gy/30 fractions (range, 54-66 Gy) with elective nodal irradiation of 40 Gy was combined concurrently with 5-furuorouracil-based chemotherapy. RESULTS: Thirty-six patients (33 men and 3 women) aged from 45 to 80 years (median, 67 years) were assessed. All patients had squamous cell carcinoma. With a median follow-up time of 61 months, the 5 year overall survival, disease-free survival, and locoregional failure-free survival rates were 86 % [95 % confidence interval (CI), 74-99 %], 59 % (95 % CI, 42-77 %), and 90 % (95 % CI, 79-100 %), respectively. Late toxicities of grade 3 pleural effusion in 2 patients, grade 4 pericardial effusion in 1 patient, and grade 5 pneumonitis in 1 patient were observed. Metachronous esophageal cancer was observed in 8 patients (22 %). Among them, 6 patients with mucosal legions were salvaged by endoscopic resection. CONCLUSION: Our long-term results of concurrent chemoradiotherapy (CCRT) for patients with esophageal submucosal cancer showed acceptable toxicities and favorable locoregional control and survivals while maintaining organ preservation. PMID- 25800811 TI - Enhancement of bile resistance in Lactobacillus plantarum strains by soy lecithin. AB - This study evaluated the effect of soy lecithin on the bile resistance of Lactobacillus plantarum. Six strains were cultured in MRS broth supplemented with soy lecithin at different concentrations. The strains incubated in MRS broth with 1.0% soy lecithin showed no inhibitory effect on cell growth. After culturing in MRS broth with 0.2-1.0% soy lecithin, the survival rate of harvested cells increased significantly (P < 0.05) in the 0.3% bile challenge compared with the no added soy lecithin group. The cells incubated with 0.6% soy lecithin were able to grow in an MRS broth with a higher bile salt content. The surface hydrophobicity and cell leakage in the bile challenge were assessed to reveal the physical changes caused by the addition of soy lecithin. The cell surface hydrophobicity was enhanced and the membrane integrity in the bile challenge increased after culturing with soy lecithin. A shift in the fatty acid composition was also observed, illustrating the cell membrane change in the soy lecithin culture. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we report for the first time the beneficial effect of adding soy lecithin to an MRS broth on subsequent bile tolerance of Lactobacillus plantarum. Soy lecithin had no inhibitory effect on strain viability but significantly enhanced bile resistance. Surface hydrophobicity and cell integrity increased in strains cultured with soy lecithin. The observed shift in the cell fatty acid composition indicated changes to the cell membrane. As soy lecithin is safe for use in the food industry, its protective effects can be harnessed for the development of bile-sensitive strains with health-benefit functions for use in probiotic products. PMID- 25800812 TI - Cyclic-di-GMP signaling in the Gram-positive pathogen Clostridium difficile. AB - The anaerobic Gram-positive bacterium Clostridium difficile causes intestinal infections responsible for symptoms ranging from mild diarrhea to fulminant colitis. Like other bacteria, C. difficile needs to sense and integrate environmental signals in order to adapt to changes and thrive in its environment. The second messenger cyclic diguanosine monophosphate (c-di-GMP) was recently recognized as a quasi-ubiquitous phenotype coordinator in bacteria. Mostly known to be involved in the transition from motile to sessile and multicellular behaviors in Gammaproteobacteria, c-di-GMP is now known to regulate many other phenotypes from cell morphogenesis to virulence, in many Gram-negative and a few Gram-positive bacteria. Herein, we review recent advances in our understanding of c-di-GMP signaling in the lifecycle of C. difficile. PMID- 25800814 TI - Unilamellar vesicles from amphiphilic graphene quantum dots. AB - Graphene quantum dots (GQDs) have attracted considerable interest due to their unique physicochemical properties and various applications. For the first time it is shown that GQDs surface-functionalized with hydrocarbon chains (i.e., amphiphilic GQDs) self-assemble into unilamellar spherical vesicles in aqueous solution. The amphiphilic GQD vesicles exhibit multicolor luminescence that can be readily exploited for membrane studies by fluorescence spectroscopy and microscopy. The GQD vesicles were used for microscopic analysis of membrane interactions and disruption by the peptide beta-amyloid. PMID- 25800813 TI - Ranking adverse drug reactions with crowdsourcing. AB - BACKGROUND: There is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events. OBJECTIVE: The intent of the study was to rank ADRs according to severity. METHODS: We used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs. RESULTS: There is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy. CONCLUSIONS: ADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making. PMID- 25800815 TI - Radiation-induced skin ulcer and rib fractures following percutaneous coronary intervention (PCI): A case of right back skin ulcer and adjacent rib fractures after single PCI. AB - We experienced a 75-year-old male patient with a refractory and severely painful skin ulcer on the right back. He had suffered from ischemic heart disease and undergone percutaneous coronary intervention 5 months prior to the consultation with us. The characteristic clinical appearance, location of the lesion and his past medical history led us to the diagnosis of radiation-induced skin ulcer. Magnetic resonance imaging, computed tomography as well as bone scintigraphy showed fractures of the right back rib adjacent to the ulcer, which was thought to be attributable to bone damage due to X-ray radiation and/or persistent secondary inflammation of the chronic ulcer. In the published work, there are no other reports of bone fractures associated with radiation dermatitis after coronary interventional radiology. PMID- 25800816 TI - Outpatient treatment for uterine polyps. PMID- 25800817 TI - Asymptomatic, low risk adults should not be screened for coronary heart disease, says US guidance. PMID- 25800818 TI - Successful desensitization of voriconazole in an immunosuppressed pediatric patient. PMID- 25800819 TI - A sequence-based two-level method for the prediction of type I secreted RTX proteins. AB - Many Gram-negative bacteria use the type I secretion system (T1SS) to translocate a wide range of substrates (type I secreted RTX proteins, T1SRPs) from the cytoplasm across the inner and outer membrane in one step to the extracellular space. Since T1SRPs play an important role in pathogen-host interactions, identifying them is crucial for a full understanding of the pathogenic mechanism of T1SS. However, experimental identification is often time-consuming and expensive. In the post-genomic era, it becomes imperative to predict new T1SRPs using information from the amino acid sequence alone when new proteins are being identified in a high-throughput mode. In this study, we report a two-level method for the first attempt to identify T1SRPs using sequence-derived features and the random forest (RF) algorithm. At the full-length sequence level, the results show that the unique feature of T1SRPs is the presence of variable numbers of the calcium-binding RTX repeats. These RTX repeats have a strong predictive power and so T1SRPs can be well distinguished from non-T1SRPs. At another level, different from that of the secretion signal, we find that a sequence segment located at the last 20-30 C-terminal amino acids may contain important signal information for T1SRP secretion because obvious differences were shown between the corresponding positions of T1SRPs and non-T1SRPs in terms of amino acid and secondary structure compositions. Using five-fold cross-validation, overall accuracies of 97% at the full-length sequence level and 89% at the secretion signal level were achieved through feature evaluation and optimization. Benchmarking on an independent dataset, our method could correctly predict 63 and 66 of 74 T1SRPs at the full length sequence and secretion signal levels, respectively. We believe that this study will be useful in elucidating the secretion mechanism of T1SS and facilitating hypothesis-driven experimental design and validation. PMID- 25800820 TI - Prediction of Arteriovenous Fistula Dysfunction: Can it be Taught? AB - Physical examination (PE) is an excellent means of predicting arteriovenous fistula (AVF) dysfunction. Although quick and inexpensive, PE is seldom used as a tool to assess stenosis by general nephrologists, dialysis nurses, and dialysis technicians. Previous studies have demonstrated that PE can be taught to interventional specialists, but the perception remains that it is too complex to be performed by other health care professionals. We hypothesized that the physical exam can be taught to a nonmedical professional, and that, with time, it would be comparable to the physical exam performed by a full-time interventional specialist. An undergraduate student and an interventional specialist (MD) examined AVF for dysfunction in a tertiary care hospital over a 6-month period. PE was performed on patients who were suspected of having dialysis access dysfunction and were referred for angiography and intervention (n = 49). Physical exam findings were categorized blindly by each examiner into four categories of lesion location: inflow, outflow, both, or neither. Data were privately recorded and compared to the gold standard of angiographic results. Potential confounding variables, including age, gender, diabetic status, and location of AVF were recorded. Weighted Cohen's kappa value was used as a measurement of the level of agreement beyond chance between the diagnoses made by physical exam and angiography. The full-time interventional specialist demonstrated correct prediction of lesion location of 89.8% (kappa = 0.850), while the undergraduate student had a correct prediction of 77.6% (kappa = 0.625). The student's performance, however, differed significantly over time. The student correctly predicted the location of the lesion in 6 (42.9%) of the first 14 patients (kappa = 0.082), compared to 32 (91.4%) of the last 35 patients (kappa = 0.855). We suggest that physical exam of AVF can be taught to a nonmedical professional in a short duration of time and the predictive value of the exam can be similar to that of an interventional specialist. PMID- 25800821 TI - The baculovirus expression vector system: A commercial manufacturing platform for viral vaccines and gene therapy vectors. AB - The baculovirus expression vector system (BEVS) platform has become an established manufacturing platform for the production of viral vaccines and gene therapy vectors. Nine BEVS-derived products have been approved - four for human use (Cervarix((r)), Provenge((r)), Glybera((r)) and Flublok((r))) and five for veterinary use (Porcilis((r)) Pesti, BAYOVAC CSF E2((r)), Circumvent((r)) PCV, Ingelvac CircoFLEX((r)) and Porcilis((r)) PCV). The BEVS platform offers many advantages, including manufacturing speed, flexible product design, inherent safety and scalability. This combination of features and product approvals has previously attracted interest from academic researchers, and more recently from industry leaders, to utilize BEVS to develop next generation vaccines, vectors for gene therapy, and other biopharmaceutical complex proteins. In this review, we explore the BEVS platform, detailing how it works, platform features and limitations and important considerations for manufacturing and regulatory approval. To underscore the growth in opportunities for BEVS-derived products, we discuss the latest product developments in the gene therapy and influenza vaccine fields that follow in the wake of the recent product approvals of Glybera((r)) and Flublok((r)), respectively. We anticipate that the utility of the platform will expand even further as new BEVS-derived products attain licensure. Finally, we touch on some of the areas where new BEVS-derived products are likely to emerge. PMID- 25800822 TI - Haemoproteus infected birds have increased lifetime reproductive success. AB - The impact of haematozoan infection on host fitness has received substantial attention since Hamilton and Zuk posited that parasites are important drivers of sexual selection. However, short-term studies testing the assumption that these parasites consistently reduce host fitness in the wild have produced contradictory results. To address this complex issue, we conducted a long-term study examining the relationship between naturally occurring infection with Haemoproteus and Plasmodium, and lifetime reproductive success and survival of Mountain White-crowned Sparrows. Specifically, we tested the hypothesis that birds infected with haematozoan parasites have reduced survival (as determined by overwinter return rates) and reproductive success. Contrary to expectation, there was no relationship between Haemoproteus and Plasmodium infection and reproduction or survival in males, nor was there a relationship between Plasmodium infection and reproduction in females. Interestingly, Haemoproteus infected females had significantly higher overwinter return rates and these females fledged more than twice as many chicks during their lifetimes as did uninfected females. We discuss the impact of parasitic infections on host fitness in light of these findings and suggest that, in the case of less virulent pathogens, investment in excessive immune defence may decrease lifetime reproduction. PMID- 25800824 TI - 14-Deoxy-11,12-dehydroandrographolide exerts anti-influenza A virus activity and inhibits replication of H5N1 virus by restraining nuclear export of viral ribonucleoprotein complexes. AB - The highly pathogenic avian influenza H5N1 virus has become a worldwide public health threat, and current antiviral therapies have limited activity against the emerging, resistant influenza viruses. Therefore, effective drugs with novel targets against influenza A viruses, H5N1 strains in particular, should be developed. In the present study, 14-deoxy-11,12-dehydroandrographolide (DAP), a major component of the traditional Chinese medicine Andrographis paniculata, exerted potent anti-influenza A virus activity against A/chicken/Hubei/327/2004 (H5N1), A/duck/Hubei/XN/2007 (H5N1), A/PR/8/34 (H1N1), A/NanChang/08/2010 (H1N1) and A/HuNan/01/2014 (H3N2) in vitro. To elucidate the underlying mechanisms, a series of experiments was conducted using A/chicken/Hubei/327/2004 (H5N1) as an example. Our results demonstrated that DAP strongly inhibited H5N1 replication by reducing the production of viral nucleoprotein (NP) mRNA, NP and NS1proteins, whereas DAP had no effect on the absorption and release of H5N1 towards/from A549 cells. DAP also effectively restrained the nuclear export of viral ribonucleoprotein (vRNP) complexes. This inhibitory effect ought to be an important anti-H5N1 mechanism of DAP. Meanwhile, DAP significantly reduced the upregulated expression of all the tested proinflammatory cytokines (TNF-alpha, IL 6, IL-8, IFN-alpha, IL-1beta and IFN-beta) and chemokines (CXCL-10 and CCL-2) stimulated by H5N1. Overall results suggest that DAP impairs H5N1 replication at least in part by restraining nuclear export of vRNP complexes, and the inhibition of viral replication leads to a subsequent decrease of the intense proinflammatory cytokine/chemokine expression. In turn, the effect of modification of the host excessive immune response may contribute to overcoming H5N1. To our knowledge, this study is the first to reveal the antiviral and anti inflammatory activities of DAP in vitro against H5N1 influenza A virus infection. PMID- 25800825 TI - Salt as a mitigation option for decreasing nitrogen leaching losses from grazed pastures. AB - BACKGROUND: The main source of nitrogen (N) leaching from grazed pastures is animal urine with a high N deposition rate (i.e. per urine patch), particularly between late summer and early winter. Salt is a potential mitigation option as a diuretic to induce greater drinking-water intake, increase urination frequency, decrease urine N concentration and urine N deposition rate, and thereby potentially decrease N leaching. This hypothesis was tested in three phases: a cattle metabolism stall study to examine effects of salt supplementation rate on water consumption, urination frequency and urine N concentration; a grazing trial to assess effects of salt (150 g per heifer per day) on urination frequency; and a lysimeter study on effects of urine N rate on N leaching. RESULTS: Salt supplementation increased cattle water intake. Urination frequency increased by up to 69%, with a similar decrease in urine N deposition rate and no change in individual urination volume. Under field grazing, sensors showed increased urination frequency by 17%. Lysimeter studies showed a proportionally greater decrease in N leaching with decreased urine N rate. Modelling revealed that this could decrease per-hectare N leaching by 10-22%. CONCLUSIONS: Salt supplementation increases cattle water intake and urination frequency, resulting in a lower urine N deposition rate and proportionally greater decrease in urine N leaching. Strategic salt supplementation in autumn/early winter with feed is a practical mitigation option to decrease N leaching in grazed pastures. PMID- 25800826 TI - Parent-child warmth as a potential mediator of childhood exposure to intimate partner violence and positive adulthood functioning. AB - BACKGROUND AND OBJECTIVES: Links between childhood exposure to intimate partner violence (IPV) and adult functioning are clear, but less research has examined the potential underpinnings of this association, especially the long-term effects of the parent-child relationship on adult well-being. We hypothesized that (i) childhood exposure to IPV would be negatively related to parent-child warmth and positively related to symptoms of psychopathology during adulthood and (ii) the relationship between IPV exposure and positive outcomes in adulthood (i.e., high life satisfaction and low psychopathology) would be mediated by parent-child warmth. DESIGN: Participants included 703 Swedish adults (20-24). METHODS: Participants responded to a self-report survey assessing violence exposure, parental warmth in childhood, and current mental health and well-being. Using multivariate regression and path analysis, models of the relationships between IPV exposure, parent-child warmth, symptoms of psychopathology during adulthood, and life satisfaction were examined. Mediation models were considered exploratory. RESULTS: IPV exposure was related to lower levels of parent-child warmth, higher levels of psychopathology symptoms, and lower life satisfaction. The relationship between IPV exposure and positive outcomes in adulthood was mediated by parent-child warmth. CONCLUSIONS: Warm parent-child interactions may play a key role in long-term positive functioning for those exposed to IPV during childhood. PMID- 25800823 TI - Viral genotype correlates with distinct liver gene transcription signatures in chronic hepatitis C virus infection. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection of the liver with either genotype 1 or genotype 3 gives rise to distinct pathologies, and the two viral genotypes respond differently to antiviral therapy. METHODS: To understand these clinical differences, we compared gene transcription profiles in liver biopsies from patients infected with either gt1 or gt3, and uninfected controls. RESULTS: Gt1-infected biopsies displayed elevated levels of transcripts regulated by type I and type III interferons (IFN), including genes that predict response to IFN alpha therapy. In contrast, genes controlled by IFN-gamma were induced in gt3 infected biopsies. Moreover, IFN-gamma levels were higher in gt3-infected biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes upregulated in gt3 infection were preferentially induced by IFN-gamma. The transcriptional profile of gt3 infection was unaffected by IFNL4 polymorphisms, providing a rationale for the reduced predictive power of IFNL genotyping in gt3 infected patients. CONCLUSIONS: The interactions between HCV genotypes 1 and 3 and hepatocytes are distinct. These unique interactions provide avenues to explore the biological mechanisms that drive viral genotype-specific differences in disease progression and treatment response. A greater understanding of the distinct host-pathogen interactions of the different HCV genotypes is required to facilitate optimal management of HCV infection. PMID- 25800827 TI - Mycophenolate mofetil in primary central nervous system vasculitis. AB - OBJECTIVE: To evaluate the efficacy and safety of mycophenolate mofetil (MMF) in adult primary central nervous system vasculitis (PCNSV). METHODS: We studied a cohort of 163 patients with PCNSV who were seen at the Mayo Clinic from 1983 to 2011. We compared patients treated with MMF and those receiving other therapies. RESULTS: We identified 16 patients treated with MMF. MMF in combination with GCs achieved a favorable response in most patients. A significant proportion of patients treated with MMF had a less severe disability at last follow-up compared to those receiving other therapies (p = 0.023) and cyclophosphamide and prednisone (p = 0.017). No statistically significant differences were observed regarding relapses and ability to discontinue therapy at last follow-up. A trend to a more favorable treatment response was observed in patients treated with MMF compared to those treated with other therapies (p = 0.075). Only 1 patient suspended MMF for severe leukopenia. CONCLUSION: MMF seems to be an effective and safe therapy for adult PCNSV. PMID- 25800829 TI - Bioinformatic approaches to identifying and classifying Rab proteins. AB - The bioinformatic annotation of Rab GTPases is important, for example, to understand the evolution of the endomembrane system. However, Rabs are particularly challenging for standard annotation pipelines because they are similar to other small GTPases and form a large family with many paralogous subfamilies. Here, we describe a bioinformatic annotation pipeline specifically tailored to Rab GTPases. It proceeds in two steps: first, Rabs are distinguished from other proteins based on GTPase-specific motifs, overall sequence similarity to other Rabs, and the occurrence of Rab-specific motifs. Second, Rabs are classified taking either a more accurate but slower phylogenetic approach or a slightly less accurate but much faster bioinformatic approach. All necessary steps can either be performed locally or using the referenced online tools. An implementation of a slightly more involved version of the pipeline presented here is available at RabDB.org. PMID- 25800828 TI - Rab family of GTPases. AB - Rab proteins represent the largest branch of the Ras-like small GTPase superfamily and there are 66 Rab genes in the human genome. They alternate between GTP- and GDP-bound states, which are facilitated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and function as molecular switches in regulation of intracellular membrane trafficking in all eukaryotic cells. Each Rab targets to an organelle and specify a transport step along exocytic, endocytic, and recycling pathways as well as the crosstalk between these pathways. Through interactions with multiple effectors temporally, a Rab can control membrane budding and formation of transport vesicles, vesicle movement along cytoskeleton, and membrane fusion at the target compartment. The large number of Rab proteins reflects the complexity of the intracellular transport system, which is essential for the localization and function of membrane and secretory proteins such as hormones, growth factors, and their membrane receptors. As such, Rab proteins have emerged as important regulators for signal transduction, cell growth, and differentiation. Altered Rab expression and/or activity have been implicated in diseases ranging from neurological disorders, diabetes to cancer. PMID- 25800830 TI - Rab-NANOPS: FRET biosensors for Rab membrane nanoclustering and prenylation detection in mammalian cells. AB - Rab proteins constitute the largest subfamily of Ras-like small GTPases. They are central to vesicular transport and organelle definition in eukaryotic cells. Unlike their Ras counterparts, they are not a hallmark of cancer. However, a number of diseases, including cancer, show a misregulation of Rab protein activity. As for all membrane-anchored signaling proteins, correct membrane organization is critical for Rabs to operate. In this chapter, we provide a detailed protocol for the use of a flow cytometry-based Fluorescence Resonance Energy Transfer (FRET)-biosensors assay, which allows to detect changes in membrane anchorage, subcellular distribution, and of the nanoscale organization of Rab-GTPases in mammalian cell lines. This assay is high-throughput amenable and can therefore be utilized in chemical-genomic and drug discovery efforts. PMID- 25800831 TI - High-throughput assay for profiling the substrate specificity of Rab GTPase activating proteins. AB - Measurement of intrinsic as well as GTPase-Activating Protein (GAP)-catalyzed GTP hydrolysis is central to understanding the molecular mechanism and function of GTPases in diverse cellular processes. For the Rab GTPase family, which comprises at least 60 distinct proteins in humans, putative GAPs have been identified from both eukaryotic organisms and pathogenic bacteria. A major obstacle has involved identification of target substrates and determination of the specificity for the Rab family. Here, we describe a sensitive, high-throughput method to quantitatively profile GAP activity for Rab GTPases in microplate format based on detection of inorganic phosphate released after GTP hydrolysis. The method takes advantage of a well-characterized fluorescent phosphate sensor, requires relatively low protein concentrations, and can in principle be applied to any GAP GTPase system. PMID- 25800832 TI - Measuring Rab GTPase-activating protein (GAP) activity in live cells and extracts. AB - Mammalian cells encode a diverse set of Rab GTPases and their corresponding regulators. In vitro biochemical screening has proven invaluable in assigning particular Rabs as substrates for their cognate GTPase-activating proteins. However, in vitro activity does not always reflect substrate specificity in cells. This method describes a functional test of GAP activity in cells or extracts that takes into account the presence of other factors or conditions that might change observed in vitro specificity. PMID- 25800833 TI - Analysis of the interactions between Rab GTPases and class V myosins. AB - Myosins are actin-based motor proteins that are involved in a wide variety of cellular processes such as membrane transport, muscle contraction, and cell division. Humans have over 40 myosins that can be placed into 18 classes, the malfunctioning of a number of which can lead to disease. There are three members of the human class V myosin family, myosins Va, Vb, and Vc. People lacking functional myosin Va suffer from a rare autosomal recessive disease called Griscelli's Syndrome type I (GS1) that is characterized by severe neurological defects and partial albinism. Mutations in the myosin Vb gene lead to an epithelial disorder called microvillus inclusion disease (MVID) that is often fatal in infants. The class V myosins have been implicated in the transport of diverse cargoes such as melanosomes in pigment cells, synaptic vesicles in neurons, RNA transcripts in a variety of cell types, and organelles such as the endoplasmic reticulum. The Rab GTPases play a critical role in recruiting class V myosins to their cargo. We recently published a study in which we used the yeast two-hybrid system to systematically test myosin Va for its ability to interact with each member of the human Rab GTPase family. We present here a detailed description of this yeast two-hybrid "living chip" assay. Furthermore, we present a protocol for validating positive interactions obtained from this screen by coimmunoprecipitation. PMID- 25800835 TI - Kinetic activation of Rab8 guanine nucleotide exchange factor Rabin8 by Rab11. AB - The Rab family of small GTPases acts as molecular switches that control various stages of vesicular transport. Rab8 functions in exocytic trafficking from the trans-Golgi network (TGN) and recycling endosomes to the plasma membrane. Rabin8 is a major guanine nucleotide exchange factor (GEF) for Rab8. It activates Rab8 by catalyzing its GDP release for subsequent GTP loading. However, how Rabin8 itself is activated in cells is unclear. Recently, it was found that Rabin8 is a downstream effector of Rab11, which controls vesicle exit from the recycling endosomes. Rab11, in its GTP-bound form, stimulates the GEF activity of Rabin8. The Rab11-Rabin8-Rab8 interactions thus couple vesicle generation from the donor compartment to its delivery to plasma membrane. Here we describe the methods we used to express and purify several Rab proteins, and to assay for the effect of Rab11 in the kinetic activation of Rabin8 GEF activity. PMID- 25800834 TI - Assaying the interaction of the Rab guanine nucleotide exchange protein Sec2 with the upstream Rab, a downstream effector, and a phosphoinositide. AB - Rabs are activated by guanine nucleotide exchange proteins, which are in turn controlled by complex regulatory mechanisms. Here we describe several different assays that have been used to delineate the mechanisms by which Sec2p, the exchange factor for the Rab Sec4p, is regulated. These assays assess the interaction of Sec2p with the upstream Rab, Ypt32p, a downstream Sec4p effector, Sec15p, and the lipid, phosphatidylinositol-4-phosphate. PMID- 25800836 TI - Ypt1 and TRAPP interactions: optimization of multicolor bimolecular fluorescence complementation in yeast. AB - Ypt/Rab GTPases are conserved molecular switches that regulate the multiple vesicular transport steps of all intracellular trafficking pathways. They are stimulated by guanine-nucleotide exchange factors (GEFs). In yeast, Ypt1 regulates transport from the endoplasmic reticulum (ER) to two alternative pathways: secretion and autophagy. Ypt1 is activated by TRAPP, a modular multi subunit GEF. Whereas TRAPP I activates Ypt1 to mediate transport through the Golgi, TRAPP III, which contains all the subunits of TRAPP I plus Trs85, activates Ypt1-mediated transport to autophagosomes. The functional pair Ypt31/32 regulates traffic in and out of the trans-Golgi and is activated by TRAPP II, which consists of TRAPP I plus two specific subunits, Trs120 and Trs130. To study the interaction of Ypts with specific TRAPP subunits and interactions between the different subunits of TRAPP, including the cellular sites of these interactions, we have employed a number of approaches. One approach that we have recently optimized for the use in yeast is multicolor bimolecular fluorescence complementation (BiFC). BiFC, which employs split fluorescent tags, has emerged as a powerful approach for determining protein interaction in vivo. Because proteins work in complexes, the ability to determine more than one interaction at a time using multicolor BiFC is even more powerful. Defining the sites of protein interaction is possible by co-localization of the BiFC puncta with compartmental markers. Here, we describe a set of plasmids for multicolor BiFC optimized for use in yeast. We combined their use with a set of available yeast strains that express red fluorescence compartmental markers. We have recently used these constructs to determine Ypt1 and TRAPP interactions in two different processes: intracellular trafficking and autophagy. PMID- 25800837 TI - Identifying a Rab effector on the macroautophagy pathway. AB - Rab GTPases are key regulators of membrane traffic. The Rab GTPase Ypt1 is essential for endoplasmic reticulum (ER)-Golgi traffic, intra-Golgi traffic, and the macroautophagy pathway. To identify effectors on the macroautophagy pathway, known autophagy-related genes (Atg genes) required for macroautophagy were tagged with GFP and screened for mislocalization in the ypt1-2 mutant. At the pre autophagosomal structure (PAS), the localization of the serine/threonine kinase Atg1 was affected in the ypt1-2 mutant. We then used an in vitro binding assay to determine if Atg1 and Ypt1 physically interact with each other and co immunoprecipitation experiments were performed to address if Atg1 preferentially interacts with the GTP-bound form of Ypt1. PMID- 25800838 TI - Functional analysis of Rab27A and its effector Slp2-a in renal epithelial cells. AB - Polarized epithelial cells have two distinct plasma membrane domains, i.e., an apical membrane domain and a basolateral membrane domain, that are the result of polarized trafficking of proteins and lipids. Several members of the Rab-type small GTPases, which are general regulators of membrane trafficking, have been reported to be involved in the regulation of polarized trafficking in epithelial cells, but their precise role in polarized trafficking is poorly understood. In a recent study we used Madin-Darby canine kidney (MDCK) II cells as a model of polarized cells and concluded from the results that Rab27A and its effector synaptotagmin-like protein 2-a (Slp2-a) regulate apical transport of Rab27 bearing vesicles in polarized epithelial cells. Both Rab27A and Slp2-a are uniformly localized at the plasma membrane in subconfluent, non-polarized MDCK II cells, but their expression increases as the cells become polarized, and they are specifically localized at the apical membrane in polarized MDCK II cells (i.e., two-dimensional cell culture). Slp2-a is also localized at the apical membrane of tubular MDCK II cysts (i.e., three-dimensional cell culture) and promotes the formation of a single apical domain in the cysts by regulating polarized trafficking of Rab27-bearing vesicles. In this chapter we describe the assay procedures for analyzing the expression and localization of Rab27A and Slp2-a in non-polarized and polarized renal epithelial cells. PMID- 25800839 TI - Small GTPases in acrosomal exocytosis. AB - Regulated exocytosis employs a conserved molecular machinery in all secretory cells. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) and Rab superfamilies are members of this machinery. Rab proteins are small GTPases that organize membrane microdomains on organelles by recruiting specific effectors that strongly influence the movement, fusion and fission dynamics of intracellular compartments. Rab3 and Rab27 are the prevalent exocytotic isoforms. Many events occur in mammalian spermatozoa before they can fertilize the egg, one of them is the acrosome reaction (AR), a type of regulated exocytosis. The AR relies on the same fusion machinery as all other cell types, which includes members of the exocytotic SNARE and Rab superfamilies. Here, we describe in depth two protocols designed to determine the activation status of small G proteins. One of them also serves to determine the subcellular localization of active Rabs, something not achievable with other methods. By means of these techniques, we have reported that Rab27 and Rab3 act sequentially and are organized in a RabGEF cascade during the AR. Although we developed them to scrutinize the exocytosis of the acrosome in human sperm, the protocols can potentially be extended to study other Ras-related proteins in virtually any cellular model. PMID- 25800840 TI - Rab antibody characterization: comparison of Rab14 antibodies. AB - Rab14 functions in the endocytic recycling pathway, having been implicated in the trafficking of the ADAM10 protease, GLUT4, and components of cell-cell junctions to the plasma membrane. It localizes predominantly to endocytic membranes with a pool also found on trans-Golgi network (TGN) membranes, and is most closely related to the Rab11 subfamily of GTPases. Certain intracellular bacteria such as Legionella pneumophila, Chlamydia trachomatis, and Salmonella enterica utilize Rab14 to promote their maturation and replication. Furthermore, the HIV envelope glycoprotein complex subverts the function of Rab14, and its effector the Rab Coupling Protein (RCP), in order to direct its transport to the plasma membrane. Since the use of antibodies is critical for the functional characterization of cellular proteins and their specificity and sensitivity is crucial in drawing reliable conclusions, it is important to rigorously characterize antibodies prior to their use in cell biology or biochemistry experiments. This is all the more critical in the case of antibodies raised to a protein which belongs to a protein family. In this chapter, we present our evaluation of the specificity and sensitivity of a number of commercially available Rab14 antibodies. We hope that this analysis provides guidance for researchers for antibody characterization prior to its use in cellular biology or biochemistry. PMID- 25800841 TI - Selective visualization of GLUT4 storage vesicles and associated Rab proteins using IRAP-pHluorin. AB - Fluorescence microscopy and fluorescent protein (FP)-tagged GLUT4 molecule have been great tools to characterize GLUT4 localization and dynamics inside the cell. However, it was difficult to distinguish GLUT4 storage vesicles (GSVs) from other intracellular compartments containing GLUT4 in live cells. Here, we describe the use of IRAP-pHluorin and total internal reflection fluorescence (TIRF) microscopy to selectively visualize GSVs and Rab proteins that associate with GSVs. This assay is also valuable to further defining GSV identity by unraveling other GSV associated proteins. PMID- 25800842 TI - 3D time-lapse analysis of Rab11/FIP5 complex: spatiotemporal dynamics during apical lumen formation. AB - Fluorescent imaging of fixed cells grown in two-dimensional (2D) cultures is one of the most widely used techniques for observing protein localization and distribution within cells. Although this technique can also be applied to polarized epithelial cells that form three-dimensional (3D) cysts when grown in a Matrigel matrix suspension, there are still significant limitations in imaging cells fixed at a particular point in time. Here, we describe the use of 3D time lapse imaging of live cells to observe the dynamics of apical membrane initiation site (AMIS) formation and lumen expansion in polarized epithelial cells. PMID- 25800843 TI - In vitro and in vivo characterization of the Rab11-GAP activity of Drosophila Evi5. AB - Small GTPases of the Rab family are master regulators of vesicular trafficking. As such, they control the spatial distribution of various proteins, including proteins involved in cell signaling and the regulation of cell polarity. Misregulation of Rab proteins is associated with a large array of diseases. Surprisingly, the target of some key regulators of Rab proteins, including many GTPase-activating protein (GAP) is still unknown. Identifying the target of a specific GAP requires the combination of both in vitro and in vivo experiments to avoid any misinterpretation. Here is described the methodology we used to characterize the Rab11-GAP activity of Drosophila Evi5. We first focus on the in vitro Rab11 effector pull-down assay we developed and then we detail the in vivo characterization of Rab11 activity during Drosophila border cell migration. PMID- 25800844 TI - Characterization of the role Rab25 in energy metabolism and cancer using extracellular flux analysis and material balance. AB - Rab25, by altering trafficking of critical cellular resources, influences cell metabolism and survival during stress conditions. Overall, perturbations in the vesicular trafficking machinery change cellular bioenergetics that can be directly measured in real time as Oxygen Consumption Rate, OCR (mitochondrial respiration) and Extracellular Acidification Rate, ECAR (glycolysis) by an extracellular flux analyzer (XF96, Seahorse Biosciences, MA). Additionally, overall turnover of glucose, lactate, as well as glutamine and glutamate can be measured biochemically using the YSI2900 Biochemistry Analyzer (YSI Incorporated, Life Sciences, OH). A combination of these two methods allows a precise and quantitative approach to interrogate the role of Rab25 as well as other Rab GTPases in central carbon energy metabolism. PMID- 25800845 TI - Measurement of Rab35 activity with the GTP-Rab35 trapper RBD35. AB - Small GTPase Rab35 functions as a molecular switch for membrane trafficking, specifically for endocytic recycling, by cycling between a GTP-bound active form and a GDP-bound inactive form. Although Rab35 has been shown to regulate various cellular processes, including cytokinesis, cell migration, and neurite outgrowth, its precise roles in these processes are not fully understood. Since a molecular tool that could be used to measure Rab35 activity would be useful for identifying the mechanisms by which Rab35 mediates membrane trafficking, we recently used a RUN domain-containing region of RUSC2 to develop an active Rab35 trapper, and we named it RBD35 (Rab-binding domain specific for Rab35). Because RBD35 specifically interacts with the GTP-bound active form of Rab35 and does not interact with any of the other 59 Rab proteins identified in humans and mice, RBD35 is a useful tool for measuring the level of active Rab35 by pull-down assays and for inhibiting the function of Rab35 by overexpression. In this chapter, we describe the assay procedures for analyzing Rab35 with RBD35. PMID- 25800846 TI - Analysis of connecdenn 1-3 (DENN1A-C) GEF activity for Rab35. AB - Rabs (Ras-related proteins in brain) form the largest family of small GTPases and control numerous aspects of membrane trafficking at multiple cellular sites. Rab GTPases toggle between an inactive GDP-bound state and an active GTP-bound state. Activation of Rab GTPases requires guanine nucleotide exchange factors (GEFs) that interact with inactive GDP-bound Rabs and catalyze the removal of GDP, allowing GTP to bind. The largest single family of GEFs for Rabs is comprised of proteins bearing a DENN (differentially expressed in normal and neoplastic cells) domain. In this chapter we describe a biochemical method that directly measures the exchange activity of DENN domains by monitoring loading of GTP onto a Rab GTPase. Rabs are first purified from bacterial or mammalian sources and are then loaded with GDP. Purified DENN domains or DENN domain-bearing proteins are added in the presence of [(35)S]GTPgammaS and the transfer of [(35)S]GTPgammaS to the Rab is measured by filtering the reaction over nitrocellulose membranes to trap the Rab and thus the associated [(35)S]GTPgammaS. PMID- 25800847 TI - Assay of Rab17 and its guanine nucleotide exchange factor Rabex-5 in the dendrites of hippocampal neurons. AB - Neurons are functionally and morphologically compartmentalized into axons and dendrites, and the localization of specific proteins within these compartments is critical to the proper formation of neuronal networks, which includes neurite morphogenesis and synapse formation. The small GTPase Rab17 is specifically localized in dendrites and is not found in axons, and it regulates the dendrite morphogenesis and postsynaptic development of mouse hippocampal neurons. However, the spatiotemporal regulation of Rab17 is poorly understood. We recently identified Rabex-5, originally described as a Rab5-guanine nucleotide exchange factor (GEF), as a physiological Rab17-GEF that promotes translocation of Rab17 from the cell body to the dendrites of developing hippocampal neurons. Knockdown of Rab17 in mouse hippocampal neurons resulted in reductions in dendrite growth, branch numbers, filopodium density, and active synapse numbers. Knockdown of Rab17-GEF Rabex-5 in hippocampal neurons resulted in decreased targeting of Rab17 to the dendrites, which led to a reduction in dendrite growth. In this chapter we describe the assay procedures for analyzing Rab17 and Rabex-5 in cultured mouse hippocampal neurons, and we particularly focus on the measurement of total dendrite (or axon) length and total dendrite (or axon) branch numbers, filopodium density, number of active synapses, and dendritic Rab17 signals. PMID- 25800848 TI - Methods for analysis of AP-3/Rabin4' in regulation of lysosome distribution. AB - The position of lysosomes in the cytoplasm is important for their ability to fuse with the plasma membrane and release of proteases that are involved in tissue remodeling. Motor-directed bidirectional transport along microtubules is a critical process determining the distribution of lysosomes. How lysosomes are tethered to microtubules is incompletely understood, but a role for small GTPases of rab and arl families has been documented. We recently found that the rab5 and rab4 effector rabip4' interacts with the adaptor complex AP-3 in a rab4-dependent manner on tubular endosomes. We here describe the assays that led to the identification of AP-3 as a rabip4' partner and the role of the complex in regulating the spatial distribution of lysosomes. PMID- 25800849 TI - Determination of Rab5 activity in the cell by effector pull-down assay. AB - Rab5 targets to early endosomes and is a master regulator of early endosome fusion and endocytosis in all eukaryotic cells. Like other GTPases, Rab5 functions as a molecular switch by alternating between GTP-bound and GDP-bound forms, with the former being biologically active via interactions with multiple effector proteins. Thus the Rab5-GTP level in the cell reflects Rab5 activity in promoting endosome fusion and endocytosis and is indicative of cellular endocytic activity. In this chapter, we describe a Rab5 activity assay by using GST fusion proteins with the Rab5 effectors such as Rabaptin-5, Rabenosyn-5, and EEA1 that specifically bind to GTP-bound Rab5. We compare the efficiencies of the three GST fusion proteins in the pull-down of mammalian and fungal Rab5 proteins. PMID- 25800850 TI - Identification of the Rab5 binding site in p110beta: assays for PI3Kbeta binding to Rab5. AB - Isoform-specific signaling by Class IA PI 3-kinases depends in part on the interactions between distinct catalytic subunits and upstream regulatory proteins. From among the class IA catalytic subunits (p110alpha, p110beta, and p110delta), p110beta has unique properties. Unlike the other family members, p110beta directly binds to Gbetagamma subunits, downstream from activated G protein coupled receptors, and to activated Rab5. Furthermore, the Ras-binding domain (RBD) of p110beta binds to Rac and Cdc42 but not to Ras. Defining mutations that specifically disrupt these regulatory interactions is critical for defining their role in p110beta signaling. This chapter describes the approach that was used to identify the Rab5 binding site in p110beta, and discusses methods for the analysis of p110beta-Rab5 interactions. PMID- 25800851 TI - Role of the rab5 guanine nucleotide exchange factor, Rme-6, in the regulation of clathrin-coated vesicle uncoating. AB - Clathrin-coated pits are major ports of entry into eukaryotic cells. Following scission of clathrin-coated pits to form coated vesicles, the peripheral membrane proteins that form the coat need to be removed. Here we describe an assay that provides a measure of the extent of clathrin coat uncoating in intact cells. This assay has been used to investigate rab5-dependent modulation of uncoating. Specifically, it has been used to identify functional differences between rab5 guanine nucleotide exchange factors. PMID- 25800852 TI - Differential effects of overexpression of Rab5 and Rab22 on autophagy in PC12 cells with or without NGF. AB - Macroautophagy selectively recycles damaged or unneeded proteins and organelles by degradation via targeting to the autophagosome. The following method seeks to identify candidate Rab GTPases that likely modulate autophagy in PC12 cells during nerve growth factor (NGF) starvation. This microscopy-based assay is a single cell-based quantification of the presence of autophagosomes by fluorescently labeled markers in response to the overexpression of Rabs and mutants in the presence or absence of NGF. PMID- 25800853 TI - Determining the role of Rab7 in constitutive and ligand-mediated epidermal growth factor receptor endocytic trafficking using single cell assays. AB - RAB proteins are essential for the proper membrane trafficking of a number of proteins. Each of the 60+ RABs that have been identified has a discrete role in coordinating the movement from one subcellular compartment to another. Early attempts at deciphering the roles of individual RAB proteins relied heavily on the use of activating and/or dominant negative mutants (Ceresa, Histol Histopathol 21:987-993, 2006). However, overexpression of mutant proteins can lead to misleading information; high levels of expression can drive low affinity (and possibly, nonphysiological) interactions as well as cause mislocalization. The use of RNAi for transient protein knock down will reveal which membrane trafficking steps absolutely require the attenuated RAB. When determining the role of RAB protein in epidermal growth factor receptor (EGFR) membrane trafficking, there are special considerations. The EGFR undergoes constitutive and ligand-mediated endocytic trafficking. Both affect receptor signaling, but via different mechanisms. Here, we discuss how to experimentally dissect those two processes. PMID- 25800854 TI - Visualizing directional Rab7 and TrkA cotrafficking in axons by pTIRF microscopy. AB - Rab7 GTPase is known to regulate protein degradation and intracellular signaling via endocytic sorting and is also known to be involved in peripheral neurodegeneration. Mutations in the GTP-binding pocket of Rab7 cause Charcot Marie-Tooth type 2B (CMT-2B) neuropathy. It has been suggested that the CMT-2B associated Rab7 mutants may disrupt retrograde survival signaling by degrading the signaling endosomes carrying the nerve growth factor (NGF) and its TrkA receptor. Studying the cotrafficking of Rab7 and retrograde-TrkA endosomes in axons is therefore important to understand how Rab7 mutants affect the NGF signaling in neurons. However, tracking the axonal transport of Rab7 and TrkA with conventional microscopy and assigning the transport directionality in mass neuronal cultures pose some practical challenges. In this chapter, we describe the combination of a single-molecule imaging technique, pseudo-total internal reflection fluorescence (pTIRF) microscopy, with microfluidic neuron cultures that enables the simultaneous tracking of fluorescently labeled Rab7- and TrkA containing endosomes in axons. PMID- 25800856 TI - Monte-Carlo dosimetry for intraoperative radiotherapy using a low energy x-ray source. AB - Intraoperative radiotherapy (IORT) is continuously gaining ground in cancer treatment. However, there is currently no planning system associated with these devices, which precludes patient-specific dose delivery optimization. The objective of this study was the development and validation of a Monte Carlo simulation (MCS)-based dosimetry platform using the IntrabeamTM system. METHODS: After surgical resection of the tumor this system delivers a single dose fraction at the surface of an applicator irradiating the tumor bed through a 50 kV x-ray beam. The GATE MCS platform was used in this study combining the phase space obtained by modeling the x-ray source and the detailed modeling of the additional parts of the IntrabeamTM system. The model was validated by comparing simulated versus experimental measurements of depth dose curves (DDC) and isotropy. A clinical validation study was also carried out using patient computed tomography images. RESULTS: The mean deviation between measured and simulated DDC was 2.9% +/- 4.4% and 5.9% +/- 5.7% for the bare needle and the use of applicators, respectively. A good agreement with experimental measurements was also found in terms of dose isotropy with a maximum difference of 2.04% for the 40 mm diameter applicator. A patient study revealed a mean absolute deviation of 0.06 Gy between simulated and thermoluminescent dosimeters (TLD) measured skin doses. CONCLUSION: This study shows the potential of using the GATE MCS platform to model three dimensional dose distributions of the IntrabeamTM system for use in IORT. PMID- 25800855 TI - Quantitative bead-based flow cytometry for assaying Rab7 GTPase interaction with the Rab-interacting lysosomal protein (RILP) effector protein. AB - Rab7 facilitates vesicular transport and delivery from early endosomes to late endosomes as well as from late endosomes to lysosomes. The role of Rab7 in vesicular transport is dependent on its interactions with effector proteins, among them Rab-interacting lysosomal protein (RILP), which aids in the recruitment of active Rab7 (GTP-bound) onto dynein-dynactin motor complexes to facilitate late endosomal transport on the cytoskeleton. Here we detail a novel bead-based flow cytometry assay to measure Rab7 interaction with the Rab interacting lysosomal protein (RILP) effector protein and demonstrate its utility for quantitative assessment and studying drug-target interactions. The specific binding of GTP-bound Rab7 to RILP is readily demonstrated and shown to be dose dependent and saturable enabling K d and B max determinations. Furthermore, binding is nearly instantaneous and temperature-dependent. In a novel application of the assay method, a competitive small molecule inhibitor of Rab7 nucleotide binding (CID 1067700 or ML282) is shown to inhibit the Rab7-RILP interaction. Thus, the assay is able to distinguish that the small molecule, rather than incurring the active conformation, instead 'locks' the GTPase in the inactive conformation. Together, this work demonstrates the utility of using a flow cytometry assay to quantitatively characterize protein-protein interactions involving small GTPases and which has been adapted to high-throughput screening. Further, the method provides a platform for testing small molecule effects on protein-protein interactions, which can be relevant to drug discovery and development. PMID- 25800858 TI - Hysterectomy and its impact on the calculated incidence of cervical cancer and screening coverage in Denmark. AB - BACKGROUND: The incidence rates of cervical cancer and the coverage in cervical cancer screening are usually reported by including in the denominator all women from the general population. However, after hysterectomy women are not at risk anymore of developing cervical cancer. Therefore, it makes sense to determine the indicators also for the true at-risk populations. We described the frequency of total hysterectomy in Denmark and its impact on the calculated incidence of cervical cancer and the screening coverage. MATERIAL AND METHODS: With data from five Danish population-based registries, the incidence rate of cervical cancer and the screening coverage for women aged 23-64 years on 31 December 2010 were calculated with and without adjustments for hysterectomies undertaken for reasons other than cervical cancer. They were calculated as the number of cases divided by 1) the total number of woman-years from the general population; and 2) the at risk population after exclusion of post-hysterectomy woman-years. Cases were defined as women with cervical cancer (incidence), or as women screened in the recommended interval, with or without adjustment for hysterectomies (coverage). RESULTS AND CONCLUSIONS: In 2010, the all-age prevalence of hysterectomy was estimated at 6%, and >= 16% at age >= 65. This translated into an overall 6% increase in the incidence rate of cervical cancer, from 12.8 (unadjusted) to 13.5 (adjusted) per 100,000 woman-years. The screening coverage increased from 76% (unadjusted) to 79% (adjusted). In Denmark, hysterectomies do not have a large overall impact on the calculated cancer incidence and screening coverage. Nevertheless, at >= 65 years adjusted rates would increase by almost 20% compared to unadjusted rates. This suggests that calculating disease risks per organ-years may have a role in understanding the true burden of the disease in a population at risk of developing that disease. PMID- 25800859 TI - From cesearean scar dehiscence to large incomplete uterine rupture in the second trimester. PMID- 25800857 TI - Predicting radiation-induced valvular heart damage. AB - PURPOSE: To develop a predictive multivariate normal tissue complication probability (NTCP) model for radiation-induced heart valvular damage (RVD). The influence of combined heart-lung irradiation on RVD development was included. MATERIAL AND METHODS: Multivariate logistic regression modeling with the least absolute shrinkage and selection operator (LASSO) was used to build an NTCP model to predict RVD based on a cohort of 90 Hodgkin lymphoma patients treated with sequential chemo-radiation therapy. In addition to heart irradiation factors, clinical variables, along with left and right lung dose-volume histogram statistics, were included in the analysis. To avoid overfitting, 10-fold cross validation (CV) was used for LASSO logistic regression modeling, with 50 reshuffled cycles. Model performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC) and Spearman's correlation coefficient (Rs). RESULTS: At a median follow-up time of 55 months (range 12-92 months) after the end of radiation treatment, 27 of 90 patients (30%) manifested at least one kind of RVD (mild or moderate), with a higher incidence of left sided valve defects (64%). Fourteen prognostic factors were frequently selected (more than 100/500 model fits) by LASSO, which included mainly heart and left lung dosimetric variables along with their volume variables. The averaged cross validated performance was AUC-CV = 0.685 and Rs = 0.293. The overall performance of a final NTCP model for RVD obtained applying LASSO logistic regression to the full dataset was satisfactory (AUC = 0.84, Rs = 0.55, p < 0.001). CONCLUSION: LASSO proved to be an improved and flexible modeling method for variable selection. Applying LASSO, we showed, for the first time, the importance of jointly considering left lung irradiation and left lung volume size in the prediction of subclinical radiation-related heart disease resulting in RVD. PMID- 25800860 TI - [Middle interhemispheric variant of holoprosencephaly and partial 21q monosomy]. PMID- 25800861 TI - Using otolith microchemistry and shape to assess the habitat value of oil structures for reef fish. AB - Over 7500 oil and gas structures (e.g. oil platforms) are installed in offshore waters worldwide and many will require decommissioning within the next two decades. The decision to remove such structures or turn them into reefs (i.e. 'rigs-to-reefs') hinges on the habitat value they provide, yet this can rarely be determined because the residency of mobile species is difficult to establish. Here, we test a novel solution to this problem for reef fishes; the use of otolith (earstone) properties to identify oil structures of residence. We compare the otolith microchemistry and otolith shape of a site-attached coral reef fish (Pseudanthias rubrizonatus) among four oil structures (depth 82-135 m, separated by 9.7-84.2 km) on Australia's North West Shelf to determine if populations developed distinct otolith properties during their residency. Microchemical signatures obtained from the otolith edge using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) differed among oil structures, driven by elements Sr, Ba and Mn, and to a lesser extent Mg and Fe. A combination of microchemical data from the otolith edge and elliptical Fourier (shape) descriptors allowed allocation of individuals to their 'home' structure with moderate accuracy (overall allocation accuracy: 63.3%, range: 45.5-78.1%), despite lower allocation accuracies for each otolith property in isolation (microchemistry: 47.5%, otolith shape: 45%). Site-specific microchemical signatures were also stable enough through time to distinguish populations during 3 separate time periods, suggesting that residence histories could be recreated by targeting previous growth zones in the otolith. Our results indicate that reef fish can develop unique otolith properties during their residency on oil structures which may be useful for assessing the habitat value of individual structures. The approach outlined here may also be useful for determining the residency of reef fish on artificial reefs, which would assist productivity assessments of these habitats. PMID- 25800862 TI - Incorporation of TGF-beta 3 within collagen-hyaluronic acid scaffolds improves their chondrogenic potential. AB - Incorporation of therapeutics in the form of growth factors within biomaterials can enhance their biofunctionality. Two methods of incorporating transforming growth factor-beta 3 within collagen-hyaluronic acid scaffolds are described, markedly improving mesenchymal stem cell-mediated chondrogenic differentiation and matrix production. Such scaffolds offer control over the release of therapeutics, demonstrating their potential for repair of complex chondral defects requiring additional stimuli. PMID- 25800863 TI - Effects of an Integrated Stress Management Program (ISMP) for Psychologically Distressed Students: A Randomized Controlled Trial. AB - PURPOSE: This study aimed to evaluate the effects of an integrated stress management program (ISMP) on college life stress, stress coping, psychological distress, and cortisol among male college students. DESIGN AND METHODS: Out of 137 initially enrolled students, 99 participants were identified as distressed subjects and randomly assigned to either the ISMP or control group. Ultimately, 84 participants (43: experimental, 41: control) completed pretest-posttest. The experimental group received eight 2-hr sessions over 4 weeks. FINDINGS: Stress and psychological distress decreased significantly, whereas stress coping and cortisol did not improve significantly. PRACTICE IMPLICATIONS: Further studies with longer follow-up periods and physiological interventions are required. PMID- 25800864 TI - A first look at women's perspectives on noninvasive prenatal testing to detect sex chromosome aneuploidies and microdeletion syndromes. AB - OBJECTIVE: The aim of this study is to explore women's opinions about the use of noninvasive prenatal testing (NIPT) to assess the risk of sex chromosome aneuploidies and microdeletion syndromes. METHODS: Focus groups were conducted with women who were currently pregnant or had recently delivered. Qualitative analysis using interpretive description was used to generate study findings. RESULTS: Thirty-one women (mean age 32.4 years) participated in the focus groups. Participants were unfamiliar with sex chromosome aneuploidies but expressed support for the use of NIPT to detect these conditions. Participants were uncertain about the utility and actionability of receiving information about microdeletion syndromes with variable or unknown phenotypic expression. Participants voiced their desire to be informed of all conditions assessed by NIPT prior to testing. They considered clinicians to be the key provider of such information, although stated that patients have a responsibility to be knowledgeable prior to testing in order to support informed decision making. CONCLUSIONS: The use of NIPT to identify sex chromosome aneuploidies and microdeletion syndromes will introduce new challenges for clinicians to ensure pregnant women have the information and resources to make informed choices about NIPT when used for these conditions. PMID- 25800865 TI - Initial Ophthalmic Findings in Turkish Children with Autism Spectrum Disorder. AB - Children with autism spectrum disorders (ASD) frequently have ophthalmologic disorders. Due to poor cooperation with ophthalmological examination, ocular abnormalities in such children may be overlooked. We retrospectively studied the records of 324 patients diagnosed as ASD that underwent ophthalmological examination between January 2011 and November 2014 at Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey. Ophthalmic pathology was noted in 26.9% of patients with ASD, of which 22% had significant refractive errors and 8.6% had strabismus. Comprehensive eye examination by a pediatric ophthalmologist is recommended for all children diagnosed as ASD. PMID- 25800868 TI - Phylogenetic uncertainty revisited: Implications for ecological analyses. AB - Ecologists and biogeographers usually rely on a single phylogenetic tree to study evolutionary processes that affect macroecological patterns. This approach ignores the fact that each phylogenetic tree is a hypothesis about the evolutionary history of a clade, and cannot be directly observed in nature. Also, trees often leave out many extant species, or include missing species as polytomies because of a lack of information on the relationship among taxa. Still, researchers usually do not quantify the effects of phylogenetic uncertainty in ecological analyses. We propose here a novel analytical strategy to maximize the use of incomplete phylogenetic information, while simultaneously accounting for several sources of phylogenetic uncertainty that may distort statistical inferences about evolutionary processes. We illustrate the approach using a clade-wide analysis of the hummingbirds, evaluating how different sources of uncertainty affect several phylogenetic comparative analyses of trait evolution and biogeographic patterns. Although no statistical approximation can fully substitute for a complete and robust phylogeny, the method we describe and illustrate enables researchers to broaden the number of clades for which studies informed by evolutionary relationships are possible, while allowing the estimation and control of statistical error that arises from phylogenetic uncertainty. Software tools to carry out the necessary computations are offered. PMID- 25800867 TI - Coping and Well-Being in Parents of Children with Autism Spectrum Disorders (ASD). AB - This study examined psychological well-being and coping in parents of children with ASD and parents of typically developing children. 73 parents of children with ASD and 63 parents of typically developing children completed a survey. Parents of children with ASD reported significantly more parenting stress symptoms (i.e., negative parental self-views, lower satisfaction with parent child bond, and experiences of difficult child behaviors), more depression symptoms, and more frequent use of Active Avoidance coping, than parents of typically developing children. Parents of children with ASD did not differ significantly in psychological well-being and coping when compared as according to child's diagnosis. Study results reinforced the importance of addressing well being and coping needs of parents of children with ASD. PMID- 25800866 TI - Patterns of Sensitivity to Emotion in Children with Williams Syndrome and Autism: Relations Between Autonomic Nervous System Reactivity and Social Functioning. AB - Williams syndrome (WS) and autism spectrum disorder (ASD) are associated with atypical social-emotional functioning. Affective visual stimuli were used to assess autonomic reactivity and emotion identification, and the social responsiveness scale was used to determine the level social functioning in children with WS and ASD contrasted with typical development (TD), to examine syndrome-specific and syndrome-general features. Children with ASD exhibited the highest arousal in response to faces, with a lack of difference in autonomic sensitivity across different emotional expressions, unlike in WS and TD. The WS group demonstrated unique deficits in identifying neutral stimuli. While autonomic responsivity to neutral faces was associated with social functioning in all children, converging profiles characterized children with WS contrasted with TD and ASD. PMID- 25800869 TI - Fluid shear stress promotes proprotein convertase-dependent activation of MT1 MMP. AB - During angiogenesis, endothelial cells (ECs(1)) initiate new blood vessel growth and invade into the extracellular matrix (ECM). Membrane type-1 matrix metalloproteinase (MT1-MMP) facilitates this process and translocates to the plasma membrane following activation to promote ECM cleavage. The N-terminal pro domain within MT1-MMP must be processed for complete activity of the proteinase. This study investigated whether MT1-MMP activation was altered by sphingosine 1 phosphate (S1P) and wall shear stress (WSS), which combine to stimulate EC invasion in three dimensional (3D) collagen matrices. MT1-MMP was activated rapidly and completely by WSS but not S1P. Proprotein convertases (PCs) promoted MT1-MMP processing, prompting us to test whether WSS or S1P treatments increased PC activity. Like MT1-MMP, PC activity increased with WSS, while S1P had no effect. A pharmacological PC inhibitor completely blocked S1P- and WSS-induced EC invasion and MT1-MMP translocation to the plasma membrane. Further, a recombinant PC inhibitor reduced MT1-MMP activation and decreased lumen formation in invading ECs, a process known to be controlled by MT1-MMP. Thus, we conclude that PC and MT1-MMP activation are mechanosensitive events that are required for EC invasion into 3D collagen matrices. PMID- 25800870 TI - Suppression of atherosclerosis by synthetic REV-ERB agonist. AB - The nuclear receptors for heme, REV-ERBalpha and REV-ERBbeta, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBalpha expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID- 25800871 TI - Stronger activation of SREBP-1a by nucleus-localized HBx. AB - We previously showed that hepatitis B virus (HBV) X protein activates the sterol regulatory element-binding protein-1a (SREBP-1a). Here we examined the role of nuclear localization of HBx in this process. In comparison to the wild-type and cytoplasmic HBx, nuclear HBx had stronger effects on SREBP-1a and fatty acid synthase transcription activation, intracellular lipid accumulation and cell proliferation. Furthermore, nuclear HBx could activate HBV enhancer I/X promoter and was more effective on up-regulating HBV mRNA level in the context of HBV replication than the wild-type HBx, while the cytoplasmic HBx had no effect. Our results demonstrate the functional significance of the nucleus-localized HBx in regulating host lipogenic pathway and HBV replication. PMID- 25800872 TI - Intracellular cytoplasm-specific delivery of SH3 and SH2 domains of SLAP inhibits TcR-mediated signaling. AB - Signaling events triggered by T cell receptor (TcR) stimulation are important targets for the development of common therapeutics for various autoimmune diseases. SLAP is a negative regulator of TcR-mediated signaling cascade via targeting TcR zeta chain for degradation through recruiting the ubiquitin ligase c-Cbl. In this study, we generated a transducible form of SH3 and SH2 domains of SLAP (ctSLAPDeltaC) which can be specifically targeted to the cytoplasm of a cell. ctSLAPDeltaC inhibited tyrosine phosphorylation of signaling mediators such as ZAP-70 and LAT involved in T cell activation, and effectively suppressed transcriptional activity of NFAT and NFkappaB upon TcR stimulation. The transduced ctSLAPDeltaC in T cells blocked the secretion of T cell-specific cytokines such as IL-2, IFNgamma, IL-17A, and IL-4 and induced the expression of CD69 and CD25 on effector T cells without influencing the cell viability. Inhibition of TcR-mediated signaling via SLAP blocked the differentiation of naive T cells into Th1, Th2 or Treg cells with different sensitivity, suggesting that qualitative and quantitative intensity of TcR-mediated signaling in the context of polarizing cytokines environment may be a critical factor to determine the differentiation fate of naive T cells. These results suggest that cytoplasm specific transduction of the SH3 and SH2 domains of SLAP has a therapeutic potential of being an immunosuppressive reagent for the treatment of various autoimmune diseases. PMID- 25800874 TI - Identification of APOBEC3B promoter elements responsible for activation by human papillomavirus type 16 E6. AB - Recent cancer genomics studies have identified mutation patterns characteristic of APOBEC3B (A3B) in multiple cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. A3B expression is upregulated by HPV E6/E7 oncoproteins, implying a crucial role for A3B upregulation in HPV-induced carcinogenesis. Here, we explored the molecular mechanisms underlying the activation of the A3B promoter by E6. Luciferase reporter assays with a series of deleted fragments of the human A3B promoter in normal immortalized human keratinocytes (NIKS) identified two functional regions in the promoter: the distal region (from -200 to -51), which is required for basal promoter activity, and the proximal region (from +1 to +45), which exerts an inhibitory effect on gene expression. Each promoter region was found to contain an E6-responsive element(s). Disruption of an AT-rich motif located between +10 and +16 abrogated the proximal-region-mediated activation of the A3B promoter by E6. DNA pull-down assays revealed that a cellular zinc-finger protein, ZNF384, binds to the AT-rich motif in the A3B promoter, and chromatin immunoprecipitation assays confirmed that ZNF384 binds to the A3B promoter in cells. ZNF384 knockdown reduced the A3B mRNA levels in NIKS expressing E6, but not in the parental NIKS, indicating that ZNF384 contributes to A3B upregulation by E6, but not to basal A3B expression. The exogenous expression of ZNF384 led to the activation of the A3B promoter in NIKS. Collectively, these results indicate that E6 activates the A3B promoter through the distal and proximal regions, and that ZNF384 is required for the proximal-region-mediated activation of A3B. PMID- 25800873 TI - REV1 is important for the ATR-Chk1 DNA damage response pathway in Xenopus egg extracts. AB - The translesion DNA synthesis (TLS) polymerase REV1 is implicated in the bypass of the irreparable DNA damage such as interstrand crosslinks (ICLs). However, the potential role of REV1 in DNA damage response (DDR) pathway has not been determined. In this research communication, we provide evidence to demonstrate that REV1 plays a previously unidentified but important role in the ATR-Chk1 checkpoint activation in response to mitomycin C (MMC)-induced ICLs in Xenopus egg extracts. We further pinpointed that REV1 plays a downstream role of a checkpoint protein complex assembly including ATR, ATRIP, TopBP1 and the Rad9 Rad1-Hus1 complex to MMC-induced ICLs on chromatin in the DDR pathway. Notably, domain dissection analysis demonstrates that a C-terminal domain, but not the individual ubiquitin binding motifs, of REV1 is important for the binding of REV1 to MMC-damaged chromatin and the MMC-induced Chk1 phosphorylation. Yet, the ATR Chk1 DDR pathway appears to be dispensable for the preferential association of REV1 to MMC-damaged chromatin. Taken together, REV1 is important for the DDR pathway in Xenopus egg extracts. PMID- 25800875 TI - Assessing community assembly along a successional gradient in the North Adriatic Karst with functional and phylogenetic distances. AB - Recently, two approaches to account for ecological differences in community composition have been developed: one based on trait differences (functional diversity) and another based on evolutionary history (phylogenetic diversity). Combining them allows an integrated view of processes structuring communities. The North Adriatic Karst is covered by species-rich grasslands, but land abandonment has resulted in replacement by woodlands. This creates a successional gradient along which environmental conditions may change, and different community assembly rules may apply. We sampled 56 plant communities in the Karst and used functional-phylogenetic distances to assess assembly along a successional gradient, from grasslands to shrublands and woodlands. We found 146 species, for which we measured functional traits and built a phylogenetic tree. The three successional stages were floristically different, with grasslands having species that are typical of harsher soil conditions and woodlands with species preferring milder soil conditions. All communities had higher functional than phylogenetic distances, implying that closely related species tended to be phenotypically dissimilar. When more importance was given to functional distances, most grasslands and some shrublands were underdispersed; when more importance was given to phylogenetic distances, only one grassland was underdispersed and one woodland was overdispersed. Combining functional and phylogenetic distances provided us with better estimates of ecological differences in a successional gradient, where environmental filters seem to be the dominant force in early stages and competitive exclusion becomes more important in later stages. Taking into account that sucessional stages are assembled by different rules is essential to predicting their behaviour under future environmental scenarios. PMID- 25800876 TI - Neonatal line width in deciduous incisors from Neolithic, mediaeval and modern skeletal samples from north-central Poland. AB - The neonatal line is usually the first accentuated incremental line visible on the enamel. The prenatal environment significantly contributes to the width of the neonatal line, influencing the pace of reaching post-delivery homeostasis by the newborn's organism. Studies of the enamel of the earliest developing deciduous teeth can provide an insight into the prenatal development and the perinatal conditions of children of past human populations, thus being an additional source contributing to consideration of the influence of prenatal and perinatal factors modifying growth processes. The aim of this study was to examine whether the neonatal line, reflecting the conditions of the prenatal and perinatal environment, differed between the Neolithic, the mediaeval and the modern populations from the Kujawy region in north-central Poland. The material consisted of longitudinally ground sections of 57 human deciduous incisors obtained from children aged 1.0-7.5 years representing three archaeological series from Brzesc Kujawski site. All teeth were sectioned in the labio-linqual plane using a diamond blade (Buechler IsoMet 1000). Final specimens were observed with the microscope Delta Optical Evolution 300 at 10* and 40* magnifications. For each tooth, linear measurements of the neonatal line width were performed on its labial surface at the three levels from the cemento-enamel junction. No significant difference was found in the mean neonatal line width depending on the tooth type and archaeological site, although the thickest neonatal line characterised children from the Neolithic series. In all analysed series, the neonatal line width was diversified depending on the child's age at death. The value of Spearman's rank correlation coefficient calculated for the correlation between the child's age at death and the neonatal line width was statistically significant. A clear increase in the width of the neonatal line was thus observed along with a decrease in the child's age at death. PMID- 25800877 TI - Paroxysmal tonic upward gaze of childhood "plus": an oculomotor channelopathy? PMID- 25800878 TI - Epilepsy in childhood and quality of life. PMID- 25800881 TI - Preoperative renin-angiotensin system inhibitors use linked to reduced acute kidney injury: a systematic review and meta-analysis. AB - BACKGROUND: Previous trials of interventions to prevent acute kidney injury (AKI) have been unsuccessful and additional interventions are needed. Existing reviews of preoperative renin-angiotensin system (RAS) inhibitors have suggested harm. We included more recent studies and conducted this meta-analysis to evaluate the risk of postoperative AKI in patients who received preoperative RAS inhibitors. METHODS: A literature search was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through October, 2014. Studies that reported relative risks, odds ratios or hazard ratios comparing the AKI risk in patients who received preoperative RAS inhibitors versus those who did not were included. We performed the prespecified sensitivity analysis including only propensity score-based studies. Mortality risk was evaluated among the studies that reported AKI outcome. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Twenty-four studies (1 randomized controlled trial and 23 cohort studies) with 102 675 patients were included in the analysis to assess the risk of postoperative AKI and preoperative RAS inhibitors use. The pooled RR of AKI in patients receiving RAS inhibitors was 1.05 (95% CI: 0.92-1.20). The meta-analysis of the RCT and 11 studies with propensity score analysis demonstrated the pooled RR of AKI in patients receiving RAS inhibitors of 0.92 (95% CI: 0.85-0.99). Within the selected studies, preoperative RAS inhibitor therapy was not associated with a significant increase or decrease in mortality (RR: 0.93; 95% CI: 0.80-1.09). CONCLUSIONS: Our meta-analysis demonstrates an association between preoperative RAS inhibitor treatment and lower incidence of AKI. PMID- 25800883 TI - Erratum to: Impact of red blood cells count on the relationship between high density lipoproteins and the prevalence and extent of coronary artery disease: a single centre study. PMID- 25800882 TI - Application of an ultra-performance liquid chromatography method with tandem mass spectrometry to pharmacokinetics, tissue distribution and excretion in the study of DAT-230, a novel tubulin-binding agent candidate, in rats. AB - A rapid, sensitive and high-throughput ultra-performance liquid chromatography method with tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of DAT-230 in rat plasma, urine, feces and tissues (heart, liver, spleen, lung, kidney, stomach, intestine and brain). The biological samples were prepared by protein precipitation, and separation was achieved on an ACQUITYTM UPLC BEH C18 column (50 mm * 2.1mm, 1.7 MUm) with a mobile phase that consisted of methanol - 0.2% formic acid water (80:20, v/v) at a flow rate of 0.2 mL/min. The MS/MS ion transitions were monitored at m/z 372.17 -> 357.17 for DAT-230 and m/z 406.08 -> 345.16 for COH-203 (internal standard, IS). The calibration curve was linear in the range of 0.1-5200 ng/mL for all biological matrices (r(2) >= 0.996), and it had the same value for the lower limit of quantification. The validated method was successfully applied to the pharmacokinetics, tissue distribution and excretion study after intravenous administration of a 5mg/kg dose of DAT-230 to healthy Sprague-Dawley rats. The mean pharmacokinetic parameters of t1/2 and AUC0-12 were (1.1 +/- 0.4)h and (861.0 +/- 281.2) ng h/mL, respectively. Tissue distribution results indicated that DAT-230 exhibited rapid distribution and high liver, kidney, spleen, stomach and intestine uptake; these organs were indicated as the major target organs of the drug. In total, 5.3% of the administered DAT-230 was excreted in an unconverted form in urine, feces and bile, which implies that DAT-230 was excreted primarily in the form of metabolites. PMID- 25800884 TI - Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus assessed by follow-up optical coherence tomography in Chinese patients receiving clopidogrel. AB - Cytochrome P450 (CYP) 2C19*2 polymorphism is associated with poor responsiveness to clopidogrel in patients undergoing percutaneous coronary intervention. Despite high frequency of this genetic variant in Chinese patients, its contribution to intra-stent thrombi assessed by optical coherence tomography (OCT) and major adverse cardiac events (MACE) remains unclear. A total of 198 patients who underwent follow-up OCT and simultaneous testing of CYP2C19 genotype by TaqMan assay and P2Y12 reaction unit (PRU) by VerifyNow P2Y12 assay were selected for the study. The patients were divided into three groups: non-carriers (*1/*1), carriers with one CYP2C19*2 allele (*1/*2), carriers with two CYP2C19*2 alleles (*2/*2). OCT data and MACE were compared among the three groups. The mean follow up interval from coronary stent implantation to OCT was 360 +/- 42 days, intra stent thrombi were detected in 50 (25.2 %) patients (16.1 % for *1/*1, 27.8 % for *1/*2 and 43.8 % for *2/*2 carriers, p = 0.007). There were significantly increased PRU values among *1/*1, *1/*2 and *2/*2 carriers (200.4 +/- 36.4 vs. 216.7 +/- 44.6 vs. 242.8 +/- 42.4, p < 0.001), as well as markedly decreased P2Y12 percent inhibition (38.6 +/- 12.6 vs. 31.3 +/- 13.1 vs. 23.8 +/- 9.8 %, p < 0.001). Multivariate logistic regression analysis showed that the presence of CYP2C19 *2/*2 was the only independent predictor for intra-stent thrombi on OCT (OR: 3.488, 95 % CI: 1.992-9.046; p = 0.001), although both *1/*2 and *2/*2 were independent predictors for high on-clopidogrel platelet reactivity. CYP2C19*2/*2 homozygous status is associated with subclinical intra-stent thrombi in clopidogrel-treated Chinese patients. PMID- 25800887 TI - Abstracts from the 30(th) Annual Meeting of the Histiocyte Society Toronto, Ontario, Canada October 28-30, 2014. PMID- 25800885 TI - Telogen effluvium as first clinical presentation of dengue. PMID- 25800889 TI - Sunitinib benefits patients with small-cell lung cancer. PMID- 25800888 TI - Genetic Association Between KIBRA Polymorphism and Alzheimer's Disease with in a Japanese Population. AB - KIBRA plays an important role in synaptic plasticity in human hippocampus related to cognitive function. Functional studies suggest that KIBRA is a potential candidate gene for memory and Alzheimer's disease (AD) risk. A single nucleotide polymorphism, Rs17070145 C allele affects the onset of AD in an age-dependent manner comparing with T/T genotypes and is also associated with risk of substance abuse and relapse. The aim of this case-control study was to investigate whether the rs17070145 polymorphism affected the onset of AD in an age-dependent manner in a Japanese population. We analysed KIBRA and APOE genotypes in 237 young AD cases, 154 age-matched control cases and 160 old AD cases. The analyses were performed by stratifying alcohol consumption and the APOE status. We used single photon emission computed tomography (SPECT) to analyse patients with AD with the rs17070145 polymorphism. The genotypic and allelic frequencies of the young AD group differed significantly from those of control and old AD groups. There was a significant association among high alcohol consumption (HAC-AD group) and the genotypic and allelic frequencies of the rs17070145 polymorphism. Logistic regression analyses demonstrate synergism between the APOE genotype and the rs17070145 C allele to increase the risk of AD in the young group; this was confirmed in the HAC-AD group. The SPECT study revealed hyperperfusion in the C allele carrier group was detected in the right inferior frontal gyrus compared with the T/T group. KIBRA rs17070145 affects specific phenotypes of patients with AD. PMID- 25800890 TI - Aromatase inhibitors may reduce endometrial cancer risk. PMID- 25800892 TI - Mutation patterns in lung cancer never-smokers. PMID- 25800891 TI - Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. METHODS: This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102. FINDINGS: From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30.7 weeks (95% CI 26.7-36.1) versus 27.1 weeks (23.1-31.9) for placebo (hazard ratio 0.98, 95% CI 0.83-1.17, p=0.86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]). INTERPRETATION: In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma. FUNDING: Merck & Co. PMID- 25800894 TI - Minimal residual disease monitoring: a new era for childhood ALL. PMID- 25800895 TI - A lesson from vorinostat in pleural mesothelioma. PMID- 25800896 TI - Failure to improve cancer services in the UK. PMID- 25800893 TI - Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. AB - BACKGROUND: The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia (ALL). We aimed to establish the clinical significance of minimal residual disease in a prospective trial that used sequential minimal residual disease measurements to guide treatment decisions. METHODS: Between June 7, 2000, and Oct 24, 2007, 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children's Research Hospital. We provisionally classified the risk of relapse as low, standard, or high according to patients' baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction, and on week 7 of maintenance treatment. Additional measurements of minimal residual disease were made on weeks 17, 48, and 120 (end of treatment). The primary aim was to establish the association between event-free survival and patients' minimal residual disease levels during remission induction and sequentially post-remission. This trial was registered at ClinicalTrials.gov, number NCT00137111. FINDINGS: Irrespective of the provisional risk classification, 10-year event-free survival was significantly worse for patients with 1% or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels (69.2%, 95% CI 49.6 82.4, n=36 vs 95.5%, 91.7-97.5, n=244; p<0.001 for the provisional low-risk group and 65.1%, 50.7-76.2, n=56 vs 82.9%, 75.6-88.2, n=142; p=0.01 for the provisional standard-risk group). 12 patients with provisional low-risk ALL and 1% or higher minimal residual disease levels on day 19 but negative minimal residual disease (<0.01%) on day 46 were treated for standard-risk ALL and had a 10-year event free survival of 88.9% (43.3-98.4). For the 280 provisional low-risk patients, a minimal residual disease level of less than 1% on day 19 predicted a better outcome, irrespective of the minimal residual disease level on day 46. Of provisional standard-risk patients with minimal residual disease of less than 1% on day 19, the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease (72.7%, 42.5-88.8 vs 84.0%, 76.3-89.4; p=0.06) after receiving the same post-remission treatment for standard-risk ALL. Of patients attaining negative minimal residual disease status after remission induction, minimal residual disease re-emerged in four of 382 studied on week 7, one of 448 at week 17, and one of 437 at week 48; all but one of these six patients died despite additional treatment. By contrast, relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone. INTERPRETATION: Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual disease-guided treatment. Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease. FUNDING: National Institutes of Health and American Lebanese Syrian Associated Charities. PMID- 25800898 TI - The long and short of it: anterior vaginal wall length before and after anterior repair. AB - INTRODUCTION AND HYPOTHESIS: Anterior vaginal wall length (AVL) is on average 6.1 +/- 1.3 cm in women with normal support and lengthened in women with cystocele. We hypothesize that AVL is reduced after anterior repair and that women with larger cystoceles will have greater reduction in AVL. METHODS: Demographic, clinical, and surgical data were collected for women undergoing hysterectomy and anterior repair in whom intraoperative vaginal wall measurements had been made between November 2009 and April 2014. In the operating room, AVL was defined preoperatively as the distance from the hymenal ring to the anterior cervicovaginal junction at the hysterectomy incision site, and postoperatively, from the hymenal ring to the same location on the anterior cuff. During the anterior repair the fibromuscular tissues were plicated using an interrupted technique. RESULTS: Measurements were available for 40 women. Average age was 61.7 +/- 10 years, median parity was 2.5 and median preoperative Pelvic Organ Prolapse Quantification System (POP-Q) point Ba was 3 cm distal to the hymen. On average, AVL was reduced after surgery by 2.5 cm. Mean postoperative AVL was similar to mean AVL in women with normal pelvic support (6.4 +/- 0.8 cm vs 6.1 +/ 1.3 cm, p = 0.15). Longer preoperative AVLs had greater AVL change (R (2) = 0.78, p = <0.0001). CONCLUSIONS: In women undergoing anterior repair, mean AVL was reduced by 28 % and returned to the normal range after surgery. These data highlight a rarely discussed effect of anterior repair, which is restoration of normal anterior vaginal wall length. PMID- 25800897 TI - Epigenetic changes in BRCA1-mutated familial breast cancer. AB - Familial breast cancer occurs in about 10% of breast cancer cases. Germline mutation in BRCA1 is the most penetrant predisposition for the disease. Mutated BRCA1 leads to disease by causing genome instability via multiple mechanisms including epigenetic changes. This review summarizes recent progress in studying the correlation between BRCA1 predisposition and epigenetic alterations in BRCA1 type familial breast cancer. PMID- 25800899 TI - Vaginal mesh for prolapse: a long-term prospective study of 218 mesh kits from a single centre. AB - INTRODUCTION AND HYPOTHESIS: The aim was to assess the long-term surgical outcomes and complications in patients undergoing mesh-augmented vaginal repair of pelvic organ prolapse. METHODS: This is a report of a prospective long-term follow-up experience from the Urogynaecological Service, Counties Manukau District Health Board (CMDHB), Auckland, New Zealand. The subjects were 158 symptomatic women undergoing mesh-augmented prolapse repair (218 kits, Feb 2005 to July 2013) using the Apogee and/or Perigee kits (with IntePro mesh until November 2009, and IntePro Lite mesh thereafter). A dedicated electronic database was used. RESULTS: The median follow-up times were 138 and 105 weeks for the Apogee and Perigee kits, respectively; 56.6% and 48.8% of these kits, respectively, were inserted for recurrent prolapse. Cure rates for prolapse using mesh kits in patients with a history of native tissue POP repair in the same compartment were 90.91% for the anterior compartment (60 of 66) and 95.74% for the posterior compartment (45 of 47). The cumulative mesh extrusion/exposure rate was 15.8% of patients (11.5% of mesh kits) and was significantly higher with the Apogee kit than with the Perigee kit (P = 0.03). The rate of extrusion/exposure was significantly lower with IntePro Lite than with IntePro (P = 0.04 for Perigee and P = 0.0001 for Apogee). There was a significantly higher rate of extrusion/exposure with the Perigee kit in women with previous anterior compartment native tissue repair than with the Apogee kit in women with previous posterior compartment native tissue repair (21.2% versus 6.4%; P = 0.03). Only 8% of extrusions/exposures needed revision of the mesh. A set of significant predictors of mesh extrusion/exposure was identified. Overall success rates were 81.4% (110/135) for the Perigee kit and 74.7% (62/83) for the Apogee kit. CONCLUSIONS: This is one of the longest prospective mesh follow-up studies to date from a single centre and highlights the need for continuing surveillance despite high overall success rates. PMID- 25800900 TI - Missing data frequency and correlates in two randomized surgical trials for urinary incontinence in women. AB - INTRODUCTION AND HYPOTHESIS: Missing data is frequently observed in clinical trials; high rates of missing data may jeopardize trial outcome validity. PURPOSE: We determined the rates of missing data over time, by type of data collected and compared demographic and clinical factors associated with missing data among women who participated in two large randomized clinical trials of surgery for stress urinary incontinence, the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) and the Trial of Midurethral Sling (TOMUS). METHODS: The proportions of subjects who attended and missed each follow-up visit were calculated. The chi-squared test, Fisher's exact test and t test were used to compare women with and without missing data, as well as the completeness of the data for each component of the composite primary outcome. RESULTS: Data completeness for the primary outcome computation in the TOMUS trial (62.3%) was nearly double that in the SISTEr trial (35.7%). The follow-up visit attendance rate decreased over time. A higher proportion of subjects attended all follow-up visits in the TOMUS trial and overall there were fewer missing data for the period that included the primary outcome assessment at 12 months. The highest levels of complete data for the composite outcome variables were for the symptoms questionnaire (SISTEr 100 %, TOMUS 99.8%) and the urinary stress test (SISTEr 96.1%, TOMUS 96.7%). In both studies, the pad test was associated with the lowest levels of complete data (SISTEr 85.1%, TOMUS 88.3%) and approximately one in ten subjects had incomplete voiding diaries at the time of primary outcome assessment. Generally, in both studies, a higher proportion of younger subjects had missing data. This analysis lacked a patient perspective as to the reasons for missing data that could have provided additional information on subject burden, motivations for adherence and study design. In addition, we were unable to compare the effects of the different primary outcome assessment time-points in an identically designed trial. CONCLUSIONS: Missing visits and data increased with time. Questionnaire data and physical outcome data (urinary stress test) that could be assessed during a visit were least prone to missing data, whereas data for variables that required subject effort while away from the research team (pad test, voiding diary) were more likely to be missing. Older subjects were more likely to provide complete data. PMID- 25800901 TI - An ultrasound approach to the posterior compartment and anorectal dysfunction. AB - INTRODUCTION AND HYPOTHESIS: Patients with anorectal dysfunction are common and can be quite challenging to diagnose. The common underlying causes for such conditions are usually anatomical in nature, which may be difficult to fully evaluate by clinical examination alone. The aim of this video was to demonstrate how multicompartmental ultrasound imaging can be utilized clinically in the evaluation of patients with anorectal dysfunction. METHODS: Pertinent ultrasound findings of the common anatomical causes of defecatory dysfunction were discussed in this video. RESULTS: Different ultrasound techniques were shown. CONCLUSION: In conclusion, multicompartmental ultrasound imaging is an easy, cost-efficient, and valuable tool in the evaluation of patients with anorectal dysfunction. PMID- 25800902 TI - Arabic validation of the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: Our aim was to translate then assess the reliability of the culturally adapted Pelvic Organ Prolapse/Incontinence Sexual Function Questionnaire, International Urogynecological Association (IUGA)-Revised (PISQ IR) to assess sexual health among Arabic-speaking women with pelvic floor disorders. METHODS: PISQ-IR was modified to consider cultural characteristics of the Middle East. The final reliability study included 172 women with urinary incontinence (UI) and/or pelvic organ prolapse (POP). Participants completed the questionnaire twice: at enrollment and 2 weeks later. RESULTS: Among sexually active women, good internal consistency was observed for five of the six scales in the adapted instrument: Global Quality (Cronbach's coefficient alpha = 0.86), Condition Impact (alpha = 0.87), Desire (alpha = 0.82), Condition Specific (alpha = 0.74), and Partner Related (alpha = 0.75). Internal consistency was acceptable for the Arousal Orgasm subscale (alpha = 0.66). However, among not sexually active women, internal consistency was poor (alpha <0.6) for all four scales. Lin's concordance correlation coefficient measuring agreement between test and retest measurements [Lin's concordance correlation coefficient (CCC); a value of 1 represents perfect agreement] ranged from 0.81 to 0.87 for the not sexually active scales, except for condition impact (CCC = 0.63.) For sexually active women, CCC was typically stronger, ranging from 0.85 to 0.96. CONCLUSIONS: PISQ IR questionnaire is easy to administer and reliable for assessing sexual function in sexually active Arabic women with POP and UI, but internal consistency is poor for Arabic women not sexually active. PMID- 25800903 TI - Circumferential urethral fistulae in Sub-Saharan Africa, current outcomes and future prospects. AB - INTRODUCTION AND HYPOTHESIS: Circumferential urethral fistula is a severe form of obstetric injury that is recognized to carry a poor prognosis for eventual continence but this has not been quantified before. METHODS: An analysis of 106 women who had undergone primary repair of a circumferential fistula was carried out with particular reference to whether there complete continence or at least some improvement in remaining dry was reported. RESULTS: Of the 106 women, only 25% reported themselves continent; 19% said there was an improvement. Prognosis was not altered by the distance of the fistula from the external urethral meatus, with 10/62 (16% reporting continence if the fistula was <1.5 cm and 10/44 (13%) if >1.5 cm. There was a 13% primary dehiscence rate. CONCLUSIONS: Current methods of primary urethral fiistula repair carry a poor prognosis for eventual continence. Techniques to lengthen the urethra and provide greater support need to be developed for this unfortunate group of women. PMID- 25800904 TI - Three-dimensional analysis of implanted magnetic-resonance-visible meshes. AB - OBJECTIVE: Our primary objective was to develop relevant algorithms for quantification of mesh position and 3D shape in magnetic resonance (MR) images. METHODS: In this proof-of-principle study, one patient with severe anterior vaginal wall prolapse was implanted with an MR-visible mesh. High-resolution MR images of the pelvis were acquired 6 weeks and 8 months postsurgery. 3D models were created using semiautomatic segmentation techniques. Conformational changes were recorded quantitatively using part-comparison analysis. An ellipticity measure is proposed to record longitudinal conformational changes in the mesh arms. The surface that is the effective reinforcement provided by the mesh is calculated using a novel methodology. The area of this surface is the effective support area (ESA). RESULTS: MR-visible mesh was clearly outlined in the images, which allowed us to longitudinally quantify mesh configuration between 6 weeks and 8 months after implantation. No significant changes were found in mesh position, effective support area, conformation of the mesh's main body, and arm length during the period of observation. Ellipticity profiles show longitudinal conformational changes in posterior arms. CONCLUSIONS: This paper proposes novel methodologies for a systematic 3D assessment of the position and morphology of MR visible meshes. A novel semiautomatic tool was developed to calculate the effective area of support provided by the mesh, a potentially clinically important parameter. PMID- 25800905 TI - Anti-fibrotic effects of neferine on carbon tetrachloride-induced hepatic fibrosis in mice. AB - The effects of neferine, a bisbenzylisoquinline alkaloid extracted from the seed embryo of the Chinese traditional medicine Nelumbo nucifera Gaertn, on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice were evaluated. Adult male Kunming mice were administered with CCl4 1 ml/kg via intraperitoneal injection twice a week for 8 weeks. At the beginning of the 9th week, mice were treated with normal saline, colchicine (0.1 mg/kg), and neferine (5, 10, 20 mg/kg) via intraperitoneal injection once a day for 2 weeks. The liver index and histological examination, plasma ALT/AST levels, hydroxyproline and TGF-beta1 content of liver tissue were examined. In the model group, the liver index, the hydroxyproline content of liver tissue and plasma ALT/AST levels were increased, and a high expression of TGF-beta1 was observed. The abnormal changes could be improved by neferine in a dose-dependent manner. Our data showed that neferine had an antifibrosis effect on CCl4-induced hepatic fibrosis in mice, possibly partly due to the decreased expression of TGF-beta1 in the liver. PMID- 25800906 TI - Multidimensional Frailty and Pain in Community Dwelling Elderly. AB - Objective: To examine the relationship between frailty and pain, particularly to analyze whether pain predicts physical, psychological and social frailty, after controlling for the effects of life-course determinants and comorbidity. Design: Cross-sectional. Methods: A nonprobabilistic sample of 252 community dwelling elderly was recruited. Frailty and determinants of frailty were assessed with the Tilburg Frailty Indicator and pain was measured with the Pain Impact Questionnaire. Hierarchical and logistic regression analyses were conducted. Results: In this study, 52.4% of the participants were aged 80 years and over, and 75.8% were women. Pain and frailty were higher in women, and physical frailty was higher in those aged >=80 years. After controlling for the effects of the determinants and comorbidity, pain predicted 5.8% of the variance of frailty, 5.9% of the variance of physical frailty, and 4.0% of the variance of psychological frailty, while the prediction of social frailty was nonsignificant. Overall, a greater pain impact score was associated with the presence of frailty (odds ratio 1.06; 95% CI 1.03-1.10; P < 0.001). Conclusion: Frailty was independently predicted by pain, emphasizing the importance of its treatment, potentially contributing to the prevention of vulnerability, dependency, and mortality. Nonetheless, longitudinal studies are required to better understand the possible association between pain and frailty. PMID- 25800907 TI - Examining the effect of the relationship between falls and mild cognitive impairment on mobility and executive functions in community-dwelling older adults. PMID- 25800908 TI - Innovative approach to measure delirium in hospitalized older adults using the electronic health record. PMID- 25800909 TI - Assisted living facility use by the program of all-inclusive care for the elderly. PMID- 25800910 TI - Reliability and validity of the Persian version of the Falls Efficacy Scale International. PMID- 25800911 TI - Feasibility of a follow-up hip fracture clinic. PMID- 25800912 TI - Braden Scale is not suitable for assessing pressure ulcer risk in individuals aged 80 and older. PMID- 25800914 TI - Studying the association between blood pressure levels and cognitive function in late life: a methodological pitfall? The Osservatorio Epidemiologico Cardiovascolare/Health Examination Survey 2008-2012. PMID- 25800913 TI - Diabetes mellitus risk in older Afro-Caribbeans. PMID- 25800915 TI - Effects of a serious game training on cognitive functions in older adults. PMID- 25800916 TI - Survival trends in very old adults with advanced diffuse large B-cell lymphoma--a population-based study. PMID- 25800917 TI - Loneliness is associated with frailty in community-dwelling elderly adults. PMID- 25800918 TI - Younger Europeans' conceptualizations of successful aging. PMID- 25800919 TI - Drivers with dementia in Japan: required public support under strict legal restrictions. PMID- 25800920 TI - Perceptions of very old adults about informed care in medical encounters. PMID- 25800921 TI - A cutaneous autoimmune blistering disorder related to chronic hepatitis C: bullous pemphigoid. PMID- 25800922 TI - An unusual cause of bilateral lower extremity edema in an older woman. PMID- 25800923 TI - An unusual case of supraventricular tachycardia in a 64-year-old. PMID- 25800926 TI - Improving care for older adults with chronic illnesses and functional impairments: a broader perspective. PMID- 25800924 TI - Colonic stenting as a successful bridge to surgery in a centenarian with obstructing colonic carcinoma. PMID- 25800925 TI - Recurrent encephalopathy induced by metformin in an elderly man. PMID- 25800927 TI - The play of chance may, in some contexts, be consistent. PMID- 25800928 TI - Depression, antidepressants, and bone health in older adults: a systematic review. PMID- 25800929 TI - Response to Mohler and colleagues. PMID- 25800932 TI - Novel system for distant assessment of cataract surgical quality in rural China. AB - BACKGROUND: This study aims to assess the quality of various steps of manual small incision cataract surgery and predictors of quality, using video recordings. DESIGN: This paper applies a retrospective study. PARTICIPANTS: Fifty two trainees participated in a hands-on small incision cataract surgery training programme at rural Chinese hospitals. METHODS: Trainees provided one video each recorded by a tripod-mounted digital recorder after completing a one-week theoretical course and hands-on training monitored by expert trainers. Videos were graded by two different experts, using a 4-point scale developed by the International Council of Ophthalmology for each of 12 surgical steps and six global factors. Grades ranged from 2 (worst) to 5 (best), with a score of 0 if the step was performed by trainers. MAIN OUTCOME MEASURES: Mean score for the performance of each cataract surgical step rated by trainers. RESULTS: Videos and data were available for 49/52 trainees (94.2%, median age 38 years, 16.3% women and 77.5% completing > 50 training cases). The majority (53.1%, 26/49) had performed <= 50 cataract surgeries prior to training. Kappa was 0.57~0.98 for the steps (mean 0.85). Poorest-rated steps were draping the surgical field (mean +/- standard deviation = 3.27 +/- 0.78), hydro-dissection (3.88 +/- 1.22) and wound closure (3.92 +/- 1.03), and top-rated steps were insertion of viscoelastic (4.96 +/- 0.20) and anterior chamber entry (4.69 +/- 0.74). In linear regression models, higher total score was associated with younger age (P = 0.015) and having performed >50 independent manual small incision cases (P = 0.039). CONCLUSIONS: More training should be given to preoperative draping, which is poorly performed and crucial in preventing infection. Surgical experience improves ratings. PMID- 25800933 TI - Significant enhancement of power conversion efficiency for dye sensitized solar cell using 1D/3D network nanostructures as photoanodes. AB - The single-crystalline TiO2 nanorod arrays with rutile phase have attracted much attention in the dye sensitized solar cells (DSSCs) applications because of their superior chemical stability, better electron transport properties, higher refractive index and low production cost. However, it suffers from a low surface area as compared with TiO2 nanoparticle films. In order to enlarge the surface area of TiO2 nanorod arrays, the 1D nanorods/3D nanotubes sample was synthesized using a facile two-step hydrothermal process involving hydrothermal growth 1D/3D nanorods and followed by post-etching treatment. In such bi-layer structure, the oriented TiO2 nanorods layer could provide direct pathway for fast electron transportation, and the 3D nanotubes layer offers a higher surface area for dye loading, therefore, the 1D nanorods/3D nanotubes photoanode exhibited faster electron transport and higher surface area than either 1D or 3D nanostructures alone, and an highest efficiency of 7.68% was achieved for the DSSCs based on 1D nanorods/3D nanotubes photoanode with further TiCl4 treatment. PMID- 25800935 TI - Factors predictive of pelvic lymph node involvement and outcomes in melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study. AB - INTRODUCTION: The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement exist on dissection of pelvic LN. This study aimed at investigating predictors of pelvic LN metastasis and prognostic significance of having metastasis in the pelvic LNs. METHODS: Clinicopathologic data of 740 patients with positive groin sentinel LN who underwent ilioinguinal completion LN dissection at four Italian centre were analysed. Multivariable logistic and Cox regression analysis was used to identify independent predictors of pelvic LN metastasis and to adjust prognostic significance of pelvic LN metastasis. RESULTS: More than a quarter (26%) of patients had positive non-SLNs after inguinal and pelvic lymphadenectomy, which were located in their pelvis in the 12% of cases. Older patients [(OR) 1.69; 95% confidence interval (CI) 1.02-2.78] having thick primary (OR 1.6; 95% CI, 1.01-2.53) and >= 2 positive SLNs (OR 2.5; 95% CI, 1.4-4.47) were more likely to harbour pelvic LN metastasis. Interestingly, 4% of all patients (34% of patients with positive pelvic LNs) had pelvic LN metastasis with negative inguinal LNs. Pelvic LN metastasis was independently associated with higher risk of recurrence and lower survival. 5 year disease free and overall survival was 30% and 50%, respectively, for patients with pelvic LN metastasis. CONCLUSIONS: Pelvic LNs are frequently positive after ilioinguinal lymphadenectomy and it should be considered for all patients, especially those who are older, have thick primary and >= 2 positive SLN. Patients with pelvic LN metastasis have worse prognosis. PMID- 25800936 TI - Development and validation of a terrestrial biotic ligand model for Ni toxicity to barley root elongation for non-calcareous soils. AB - A Terrestrial Biotic Ligand Model (TBLM) for Ni toxicity to barley root elongation (RE) developed from experiments conducted in sand culture was used to predict toxicity in non-calcareous soils. Ca(2+) and Mg(2+) concentrations and pH in sand solution were varied individually and TBLM parameters were computed. EC50 increased as Mg(2+) increased, whereas the effect of Ca(2+) was insignificant. TBLM parameters developed from sand culture were validated by toxicity tests in eight Ni-amended, non-calcareous soils. Additional to Ni(2+) toxicity, toxicity from all solution ions was modelled independently as an osmotic effect and needed to be included for soil culture results. The EC50s and EC10s in soil culture were predicted within twofold of measured results. These are close to the results obtained using parameters estimated from the soil culture data itself. PMID- 25800934 TI - Implications of lymph node retrieval in locoregional rectal cancer treated with chemoradiotherapy: a California Cancer Registry Study. AB - BACKGROUND: In contrast to colon cancer, the implications of reduced lymph node retrieval in rectal cancer are unclear. METHODS: Using the California Cancer Registry, we performed a retrospective cohort study of 4790 patients with stage I - III rectal cancer diagnosed from 2000 to 2007 who underwent tri-modality therapy. Using multivariate Cox proportional hazards models adjusted for age, sex, race, socioeconomic status, T-stage, and lymph node numbers, we evaluated rectal cancer specific survival (RC-SS) in neoadjuvant and adjuvant cohorts in the overall population and amongst those without involved lymph nodes (pN0). RESULTS: Sixty one percent of evaluable patients were treated with neoadjuvant chemoradiation. Although there was no difference in RC-SS between neoadjuvant and adjuvant chemoradiation cohorts, the median number of lymph nodes examined was reduced after neoadjuvant therapy (8 vs. 11, p < 0.0001). Positive lymph nodes were associated with worse RC-SS regardless of sequence, although the effect was numerically stronger for residual lymph nodes in the neoadjuvant cohort. Compared to at least 12, eight or fewer lymph nodes retrieved was associated with worse outcome in both neoadjuvant and adjuvant cohorts. However, no association between reduced lymph nodes examined and RC-SS was seen in the neoadjuvant cohort when the analysis was restricted to pN0 patients. CONCLUSIONS: In this large cohort of rectal cancer patients treated with tri-modality therapy, reduced lymph node retrieval in node negative patients did not provide additional prognostic information in patients treated with neoadjuvant therapy. PMID- 25800937 TI - Bioaccumulation, subcellular distribution and toxicity of sediment-associated copper in the ragworm Nereis diversicolor: The relative importance of aqueous copper, copper oxide nanoparticles and microparticles. AB - The sediment-dwelling ragworm, Nereis diversicolor was exposed to sediment spiked with aqueous Cu (CuAq, CuCl2), CuO nanoparticles (CuONP) or CuO microparticles (CuOMicro) at 150 MUg Cu g(-1) dw sediment for 10d. Exposures to CuAq and CuOMicro caused mortality (62.5 and 37.5%, respectively), whereas mean burrowing time increased during exposure to CuAq and CuONP from 0.12 h (controls) to 19.3 and 12.2 h, respectively. All Cu treatments bioaccumulated, especially CuAq (up to 4 times more than the other treatments). Cu was roughly equally distributed among the five subcellular fractions in controls and worms exposed to CuONP or CuOMicro. In contrast, ~50% of accumulated Cu in CuAq exposed worms was found in metal rich granules and significantly more Cu was present in heat-denatured proteins and organelles than in worms exposed to CuOMicro or in controls. Our results suggest that Cu form affects its bioaccumulation and subsequent toxicity and detoxification in a polychaete like N. diversicolor. PMID- 25800938 TI - Sexual, marital, and general life functioning in couples coping with colorectal cancer: a dyadic study across time. AB - OBJECTIVES: This study evaluated the following: (a) levels of sexual, marital, and general life functioning for both patients and partners; (b) interdependence between both members of the couple; and (c) longitudinal change in sexual, marital, and general life functioning and longitudinal stress-spillover effects in these three domains from a dyadic perspective. METHODS: Couples (n = 102) completed the Maudsley Marital Questionnaire preoperatively and 3 and 6 months postoperatively. Mean scores were compared with norm scores. A multivariate general linear model and a multivariate latent difference score - structural equation modeling (LDS-SEM), which took into account actor and partner effects, were evaluated. RESULTS: Patients and partners reported lower sexual, mostly similar marital, and higher general life functioning compared with norm scores. Moderate to high within-dyad associations were found. The LDS-SEM model mostly showed actor effects. Yet the longitudinal change in the partners' sexual functioning was determined not only by their own preoperative sexual functioning but also by that of the patient. Preoperative sexual functioning did not spill over to the other two domains for patients and partners, whereas the patients' preoperative general life functioning influenced postoperative change in marital and sexual functioning. Health care professionals should examine potential sexual problems but have to be aware that these problems may not spill over to the marital and general life domains. In contrast, low functioning in the general life domain may spill over to the marital and sexual domains. The interdependence between patients and partners implies that a couple-based perspective (e.g., couple-based interventions/therapies) to coping with cancer is needed. PMID- 25800939 TI - Intracranial bacterial infections of oral origin. AB - Brain abscesses are rare but potentially deadly complications of odontogenic infections. This phenomenon has been described mainly in the form of case reports, as large-scale studies are difficult to perform. We compiled a total of 60 previously published cases of such a complication to investigate the predisposing factors, microbiology, and clinical outcomes of intracranial abscesses of odontogenic origin. A systematic review of the literature using the PubMed database was performed. Men accounted for 82.1% of cases, and the mean age was 42.1 years. Caries with periapical involvement and periodontitis were the two most common intra-oral sources, and wisdom tooth extraction was the most common preceding dental procedure. In 56.4% of cases, there were obvious signs of dental disease prior to development of intracranial infection. Commonly implicated microorganisms included Streptococcus viridans (especially the anginosus group), Actinomyces, Peptostreptococcus, Prevotella, Fusobacterium, Aggregatibacter actinomycetemcomitans and Eikenella corrodens. There was an 8.3% mortality rate. Intracranial abscesses can form anywhere within the brain, and appear unrelated to the side of dental involvement. This suggests that hematogenous spread is the most likely route of dissemination. PMID- 25800940 TI - Outcomes of a novel minimalist approach for the treatment of cubital tunnel syndrome. AB - We describe a minimalist approach to perform in situ decompression of the ulnar nerve. Our technique employs a unique small skin incision strategically placed to minimize postoperative scarring over the ulnar nerve and potentially decrease the risk of iatrogenic injury to the medial antebrachial cutaneous nerve. We retrospectively report the outcome of patients who have undergone this procedure at our institution, the Michael E. DeBakey Veterans Affairs Medical Center, from January 1 2007 through November 29 2010. All individuals underwent in situ decompression via the previously described minimalist approach. Outcome variables were Louisiana State University Medical Center (LSU) ulnar neuropathy grade, patient satisfaction, subjective improvement, complications and re-operation rate. A total of 44 procedures were performed in this cohort of 41 patients. Overall, patients' postoperative LSU grades showed a statistically significant improvement (p=0.0019) compared to preoperative grades. Improvement of at least one grade in the LSU scale was observed in 50% of the procedures with a preoperative grade of four or less. Overall procedure satisfaction rate was 88% (39 of 44) with 70% (31 of 44) of the procedures resulting in improvement of symptoms. There were no intraoperative or postoperative complications. One patient required re-operation due to failure of neurological improvement. Our minimalistic approach to perform in situ decompression of the ulnar nerve at the cubital tunnel is both safe and effective. We observed a statistically significant improvement in LSU ulnar neuropathy grades and a success rate comparable to those reported for other more extensive surgical techniques while providing the benefit of a smaller incision, less scarring, decreased risk of iatrogenic nerve injury and minimal complications. PMID- 25800941 TI - Steroid-responsive intracranial germinoma presenting as Holmes' tremor: importance of a tissue diagnosis. AB - Holmes' tremor (rubral or midbrain outflow tremor) refers to a hyperkinetic movement disorder characterized by mild resting and more severe postural and action tremor often with associated brainstem symptoms, dystonia and cerebellar deficits. This syndrome should prompt lesional evaluation with neuroimaging focused on the dorsal midbrain, cerebellar outflow tracts, and thalamus. Herein we report a 26-year-old previously healthy male who presented with 4 years of progressive horizontal diplopia, right Parinaud syndrome, and appendicular ataxia. Neuroimaging revealed a right dorsal midbrain enhancing lesion which completely resolved with intravenous methylprednisolone prompting a diagnosis of neuroinflammatory syndrome. Subsequent clinical and radiographic evaluations, however, revealed steadily progressive left dorsal midbrain syndrome with an expansile enhancing lesion which culminated 4 years from symptom onset with a right upper extremity low-frequency rest, postural and action tremor, ataxic dysarthria, and mild right dystonia with dysdiadochokinesia. Uncomplicated brainstem biopsy confirmed intracranial germinoma and the patient underwent definitive radiation therapy with dramatic radiographic response and partial clinical improvement. This case, which to our knowledge is only the second report of intracranial germinoma presenting as Holmes' tremor, highlights the critical importance of definitive tissue diagnosis in the evaluation of lesional brainstem pathology presenting as Holmes' tremor. Steroid responsiveness can be seen in non inflammatory pathology including intracranial germinoma. Prompt evaluation and appropriate treatment are important as Holmes' tremor responds poorly to symptomatic therapies and response to radiation therapy is favorable for germinomas. PMID- 25800942 TI - WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: liver. AB - The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced these guidelines for the use of elastography techniques in liver disease. For each available technique, the reproducibility, results, and limitations are analyzed, and recommendations are given. Finally, recommendations based on the international literature and the findings of the WFUMB expert group are established as answers to common questions. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of liver diseases. PMID- 25800943 TI - Summarising and validating test accuracy results across multiple studies for use in clinical practice. AB - Following a meta-analysis of test accuracy studies, the translation of summary results into clinical practice is potentially problematic. The sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of a test may differ substantially from the average meta-analysis findings, because of heterogeneity. Clinicians thus need more guidance: given the meta-analysis, is a test likely to be useful in new populations, and if so, how should test results inform the probability of existing disease (for a diagnostic test) or future adverse outcome (for a prognostic test)? We propose ways to address this. Firstly, following a meta-analysis, we suggest deriving prediction intervals and probability statements about the potential accuracy of a test in a new population. Secondly, we suggest strategies on how clinicians should derive post test probabilities (PPV and NPV) in a new population based on existing meta analysis results and propose a cross-validation approach for examining and comparing their calibration performance. Application is made to two clinical examples. In the first example, the joint probability that both sensitivity and specificity will be >80% in a new population is just 0.19, because of a low sensitivity. However, the summary PPV of 0.97 is high and calibrates well in new populations, with a probability of 0.78 that the true PPV will be at least 0.95. In the second example, post-test probabilities calibrate better when tailored to the prevalence in the new population, with cross-validation revealing a probability of 0.97 that the observed NPV will be within 10% of the predicted NPV. PMID- 25800945 TI - Immune Checkpoint Inhibitors for Urologic Cancer: The Tip of the Iceberg? PMID- 25800944 TI - Fifteen-year Outcomes Following Conservative Management Among Men Aged 65 Years or Older with Localized Prostate Cancer. AB - BACKGROUND: To understand the threat posed by localized prostate cancer and the potential impact of surgery or radiation, patients and healthcare providers require information on long-term outcomes following conservative management. OBJECTIVE: To describe 15-yr survival outcomes and cancer therapy utilization among men 65 years and older managed conservatively for newly diagnosed localized prostate cancer. DESIGN, SETTINGS, AND PARTICIPANTS: This is a population-based cohort study with participants living in predefined geographic areas covered by the Surveillance, Epidemiology, and End Results program. The study includes 31 137 Medicare patients aged >=65 yr diagnosed with localized prostate cancer in 1992-2009 who initially received conservative management (no surgery, radiotherapy, cryotherapy, or androgen deprivation therapy [ADT]). All patients were followed until death or December 31, 2009 (for prostate cancer-specific mortality [PCSM]) and December 31, 2011 (for overall mortality). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Competing-risk analyses were used to examine PCSM, overall mortality, and utilization of cancer therapies. RESULTS AND LIMITATIONS: The 15-yr risk of PCSM for men aged 65-74 yr diagnosed with screening-detected prostate cancer was 5.7% (95% confidence interval [CI] 3.7 8.0%) for T1c Gleason 5-7 and 22% (95% CI 16-35%) for Gleason 8-10 disease. After 15 yr of follow-up, 24% (95% CI 21-27%) of men aged 65-74 yr with screening detected Gleason 5-7 cancer received ADT. The corresponding result for men with Gleason 8-10 cancer was 38% (95% CI 32-44%). The major study limitations are the lack of data for men aged <65 yr and detailed clinical information associated with secondary cancer therapy. CONCLUSIONS: The 15-yr outcomes following conservative management of newly diagnosed Gleason 5-7 prostate cancer among men aged >=65 yr are excellent. Men with Gleason 8-10 disease managed conservatively face a significant risk of PCSM. PATIENT SUMMARY: We examined the long-term survival outcomes for a large group of patients diagnosed with localized prostate cancer who did not have surgery, radiotherapy, cryotherapy, or androgen deprivation therapy in the first 6 mo after cancer diagnosis. We found that the 15-yr disease-specific survival is excellent for men diagnosed with Gleason 5-7 disease. The data support conservative management as a reasonable choice for elderly patients with low-grade localized prostate cancer. PMID- 25800946 TI - Evaluation of extraction kits and RT-qPCR systems adapted to high-throughput platform for circulating miRNAs. AB - MicroRNAs regulate gene expression at the post-transcriptional level. Differential expression of miRNAs can potentially be used as biomarkers for early diagnosis and prediction for outcomes. Failure in validation of miRNA profiles is often caused by variations in experimental parameters. In this study, the performance of five extraction kits and three RT-qPCR systems were evaluated using BioMark high-throughput platform and the effects of different experimental parameters on circulating miRNA levels were determined. Differences in the performance of extraction kits as well as varying accuracy, sensitivity and reproducibility in qPCR systems were observed. Normalisation of RT-qPCR data to spike-in controls can reduce extraction bias. However, the extent of correlation for different qPCR systems varies in different assays. At different time points, there was no significant fold change in eight of the plasma miRNAs that we evaluated. Higher level of miRNAs was detected in plasma as compared to serum of the same cohort. In summary, we demonstrated that high-throughput RT-qPCR with pre-amplification step had increased sensitivity and can be achieved with accuracy and high reproducibility through stringent experimental controls. The information provided here is useful for planning biomarker validation studies involving circulating miRNAs. PMID- 25800947 TI - Investigation of an unusual increase in human yersinioses in Creuse, France. AB - OBJECTIVES: To investigate an unusual cluster of Y. enterocolitica 4/O:3/VIII human infections that occurred in Creuse (France) during the summer 2008, and to perform retrospective and prospective analyses of yersiniosis cases to get a better view of the general trend. METHODS: 33 pathogenic Y. enterocolitica strains isolated between 2008 and 2010 in Creuse were subjected to phenotypic and molecular typing. The database of the Yersinia National Reference Laboratory was used to compare the number of human cases over 23 years in Creuse and at the national level. RESULTS: The 33 isolates had three distinct phenotypes and a high genetic diversity, ruling out a unique source of contamination. A long-term analysis of yersiniosis cases in Creuse showed a progressive increase over years, with a peak in 2008 and a subsequent decrease. This trend contrasted with the national cases that showed an opposite pattern. CONCLUSIONS: Local environmental conditions were most likely responsible for a transient expansion of pathogenic Y. enterocolitica strains in Creuse. PMID- 25800948 TI - Cell line-specific oxidative stress in cellular toxicity: A toxicogenomics-based comparison between liver and colon cell models. AB - Imbalance between high reactive oxygen species formation and antioxidant capacity in the colon and liver has been linked to increased cancer risk. However, knowledge about possible cell line-specific oxidative stress-mechanisms is limited. To explore this further, gene expression data from a human liver and colon cell line (HepG2/Caco-2), both exposed to menadione and H2O2 at six time points (0.5-1-2-4-8 and 24h) were compared in association with cell cycle distribution. In total, 3164 unique- and 1827 common genes were identified between HepG2 and Caco-2 cells. Despite the higher number of unique genes, most oxidative stress-related genes such as CAT, OGG1, NRF2, NF-kappaB, GCLC, HMOX1 and GSR were differentially expressed in both cell lines. However, cell-specific regulation of genes such as KEAP1 and GCLM, or of the EMT pathway, which are of pathophysiological importance, indicates that oxidative stress induces different transcriptional effects and outcomes in the two selected cell lines. In addition, expression levels and/or -direction of common genes were often different in HepG2 and Caco-2 cells, and this led to very diverse downstream effects as confirmed by correlating pathways to cell cycle changes. Altogether, this work contributes to obtaining a better molecular understanding of cell line-specific toxicity upon exposure to oxidative stress-inducing compounds. PMID- 25800949 TI - Examination of the use of human sera as an exposure agent for in vitro studies investigating the effects of cigarette smoking on cellular cardiovascular disease models. AB - In vitro models of smoking-related diseases and disease processes are valuable for mechanistic understanding and assessment of novel tobacco products. Many laboratories have used particulate phase or aqueous extracts of cigarette smoke as an exposure system for in vitro models. However, this may not be the most relevant method of exposing cells to smoke and its toxicants. Here we have examined the use of human serum as an exposure system. Cultured human umbilical vein endothelial cells were exposed in vitro to sera (50% dilution in culture media) from human volunteers (9 smokers; 10 non-smokers) for 20 h. Statistically significant differential changes were detected in endothelial migration in an endothelial damage repair model, such that smokers' sera had an inhibitory effect on migration compared with sera from non-smokers (p<0.05). We further observed several statistically-significant differences in cardiovascular disease (CVD) relevant gene expression between cells exposed to smokers' and non-smokers' sera, as well as differences in levels of cytokines secreted from endothelial cells. Our data demonstrate that human sera from smokers and non-smokers can differentially regulate endothelial function. We suggest that human serum provides a relevant exposure medium for in vitro studies assessing the impact of cigarette smoking on CVD risk potential. PMID- 25800950 TI - Distinguishing bipolar II depression from unipolar major depressive disorder: Differences in heart rate variability. AB - OBJECTIVES: Bipolar II (BPII) depression is commonly misdiagnosed as unipolar depression (UD); however, an objective and reliable tool to differentiate between these disorders is lacking. Whether cardiac autonomic function can be used as a biomarker to distinguish BPII from UD is unknown. METHODS: We recruited 116 and 591 physically healthy patients with BPII depression and UD, respectively, and 421 healthy volunteers aged 20-65 years. Interviewer and self-reported measures of depression/anxiety severity were obtained. Cardiac autonomic function was evaluated by heart rate variability (HRV) and frequency-domain indices of HRV. RESULTS: Patients with BPII depression exhibited significantly lower mean R-R intervals, variance (total HRV), low frequency (LF)-HRV, and high frequency (HF) HRV but higher LF/HF ratio compared to those with UD. The significant differences remained after adjusting for age. Compared to the controls, the patients with BPII depression showed cardiac sympathetic excitation with reciprocal vagal impairment, whereas the UD patients showed only vagal impairment. Depression severity independently contributed to decreased HRV and vagal tone in both the patients with BPII depression and UD, but increased sympathetic tone only in those with BPII depression. CONCLUSIONS: HRV may aid in the differential diagnosis of BPII depression and UD as an adjunct to diagnostic interviews. PMID- 25800951 TI - Isn't it time to talk about antiretroviral stewardship? PMID- 25800952 TI - Tuning of PID controllers for integrating systems using direct synthesis method. AB - A PID controller is designed for various forms of integrating systems with time delay using direct synthesis method. The method is based on comparing the characteristic equation of the integrating system and PID controller with a filter with the desired characteristic equation. The desired characteristic equation comprises of multiple poles which are placed at the same desired location. The tuning parameter is adjusted so as to achieve the desired robustness. Tuning rules in terms of process parameters are given for various forms of integrating systems. The tuning parameter can be selected for the desired robustness by specifying Ms value. The proposed controller design method is applied to various transfer function models and to the nonlinear model equations of jacketed CSTR to show its effectiveness and applicability. PMID- 25800953 TI - Analgesia in mice with experimental meningitis reduces pain without altering immune parameters. AB - Intracranial lymphocytic choriomeningitis virus (LCMV) infection is a widely used animal model to study virus-induced cytotoxic T cell (CTL) mediated meningitis and immunopathology. Nevertheless, this model causes severe pain and distress in mice, especially at later stages of the disease. Therefore, new treatment regimens to improve animal welfare have to be developed. In this study, we subcutaneously implanted ALZET(r) osmotic pumps continuously releasing buprenorphine to reduce pain in mice with LCMV-induced meningitis. Thereby, mice treated with buprenorphine demonstrated strongly reduced symptoms of pain. However, the LCMV-specific cytotoxic T cell response and the immune cell infiltration into the central nervous system (CNS) were unchanged in analgesia treated mice indicating that the LCMV-induced immune response was not altered in these mice. Taken together, we demonstrate that in this animal model for meningitis continuous buprenorphine treatment improves animal welfare without affecting the immune response. PMID- 25800954 TI - Dissecting meiotic recombination based on tetrad analysis by single-microspore sequencing in maize. AB - Meiotic recombination drives eukaryotic sexual reproduction and the generation of genome diversity. Tetrad analysis, which examines the four chromatids resulting from a single meiosis, is an ideal method to study the mechanisms of homologous recombination. Here we develop a method to isolate the four microspores from a single tetrad in maize for the purpose of whole-genome sequencing. A high resolution recombination map reveals that crossovers are unevenly distributed across the genome and are more likely to occur in the genic than intergenic regions, especially common in the 5'- and 3'-end regions of annotated genes. The direct detection of genomic exchanges suggests that conversions likely occur in most crossover tracts. Negative crossover interference and weak chromatid interference are observed at the population level. Overall, our findings further our understanding of meiotic recombination with implications for both basic and applied research. PMID- 25800956 TI - A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. AB - Monocytes are recruited from the blood to sites of inflammation, where they contribute to wound healing and tissue repair. There are at least two subsets of monocytes: classical or proinflammatory (CCR2(hi)CX3CR1(low)) and nonclassical, patrolling, or alternative (CCR2(low)CX3CR1(hi)) monocytes. Using spinning-disk confocal intravital microscopy and mice with fluorescent reporters for each of these subsets, we were able to track the dynamic spectrum of monocytes that enter a site of sterile hepatic injury in vivo. We observed that the CCR2(hi)CX3CR1(low) monocytes were recruited early and persisted for at least 48 h, forming a ringlike structure around the injured area. These monocytes transitioned, in situ, from CCR2(hi)Cx3CR1(low) to CX3CR1(hi)CCR2(low) within the ringlike structure and then entered the injury site. This phenotypic conversion was essential for optimal repair. These results demonstrate a local, cytokine driven reprogramming of classic, proinflammatory monocytes into nonclassical or alternative monocytes to facilitate proper wound-healing. PMID- 25800957 TI - A Stable but Highly Reactive Phosphine-Coordinated Borenium: Metal-free Dihydrogen Activation and Alkyne 1,2-Carboboration. AB - Borenium cations have been found to be valuable analogues of boranes as a result of their cationic character which imparts high electrophilicity. Herein, we report the synthesis, characterization, and reactivity of a new type of borenium cation employing a naphthyl bridge and a strong intramolecular P->B interaction. The cation reacts with H2 in the presence of PtBu3 (frustrated Lewis pair (FLP) approach) but also on its own. The mechanism of the reaction between the borenium cation and H2 in the absence of PtBu3 has been investigated using deuterium labeling experiments and DFT calculations. Both experiments and calculations imply the side-on coordination of H2 to the B center, followed by heterolytic splitting and B-C bond cleavage. An uncommon syn 1,2-carboboration has also been observed upon reaction of the borenium ion with 3-hexyne. PMID- 25800955 TI - Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. AB - Splenic myelopoiesis provides a steady flow of leukocytes to inflamed tissues, and leukocytosis correlates with cardiovascular mortality. Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood. Here, we show that red pulp vascular cell adhesion molecule 1 (VCAM-1)(+) macrophages are essential to extramedullary myelopoiesis because these macrophages use the adhesion molecule VCAM-1 to retain HSCs in the spleen. Nanoparticle-enabled in vivo RNAi silencing of the receptor for macrophage colony stimulation factor (M-CSFR) blocked splenic macrophage maturation, reduced splenic VCAM-1 expression and compromised splenic HSC retention. Both, depleting macrophages in CD169 iDTR mice or silencing VCAM-1 in macrophages released HSCs from the spleen. When we silenced either VCAM-1 or M-CSFR in mice with myocardial infarction or in ApoE(-/-) mice with atherosclerosis, nanoparticle-enabled in vivo RNAi mitigated blood leukocytosis, limited inflammation in the ischemic heart, and reduced myeloid cell numbers in atherosclerotic plaques. PMID- 25800958 TI - Facilitation of blood donation amongst haemochromatosis patients. AB - BACKGROUND/OBJECTIVE: The standard medical therapy for haemochromatosis is iron removal by regular phlebotomy. Current guidelines suggest that this blood should be made available through national blood services. Here, we describe a pilot facilitating the process of blood donation amongst uncomplicated haemochromatosis patients. METHODS/MATERIALS: At a dedicated clinic, patients with uncomplicated haemochromatosis interested in becoming blood donors were offered an information leaflet and self-referral application. Upon receipt, members of the local Blood Service contacted them to confirm eligibility to donate. Data on demographics and clinical characteristics, including HFE (high Fe) genotype, co-morbidities, alcohol consumption and body mass index, were collected. RESULTS: Since establishing the clinic, 140 patients have attended (93 male) with median age 57. Most (n = 125; 89%) had uncomplicated haemochromatosis. Of these, 55 were potentially eligible blood donors. Amongst those eligible, there are now 29 regular blood donors, including 23 new. CONCLUSION: There is an interest and willingness to donate blood through the Blood Service amongst uncomplicated haemochromatosis patients undergoing therapeutic phlebotomy. Since the introduction of this facilitation process, we have significantly increased the number of regular donors amongst this cohort. If this process was to be replicated more widely across the UK, this could have a significant impact on the blood donor pool. PMID- 25800959 TI - Intelligent Computation for Optimal Fabrication Condition of a Protein Chip with Ni-Co Alloy-Coated Surface. AB - Based on the principle of immobilized metal affinity chromatography (IMAC), it has been found that a Ni-Co alloy-coated protein chip is able to immobilize functional proteins with a His-tag attached. In this study, an intelligent computational approach was developed to promote the performance and repeatability of a Ni-Co alloy-coated protein chip. This approach was launched out of L18 experiments. Based on the experimental data, the fabrication process model of a Ni-Co protein chip was established by using an artificial neural network, and then an optimal fabrication condition was obtained using the Taguchi genetic algorithm. The result was validated experimentally and compared with a nitrocellulose chip. Consequentially, experimental outcomes revealed that the Ni Co alloy-coated chip, fabricated using the proposed approach, had the best performance and repeatability compared with the Ni-Co chips of an L18 orthogonal array design and the nitrocellulose chip. Moreover, the low fluorescent background of the chip surface gives a more precise fluorescent detection. Based on a small quantity of experiments, this proposed intelligent computation approach can significantly reduce the experimental cost and improve the product's quality. PMID- 25800960 TI - Sex Hormones Predict the Incidence of Erectile Dysfunction: From a Population Based Prospective Cohort Study (FAMHES). AB - INTRODUCTION: The decline of testosterone has been known to be associated with the prevalence of erectile dysfunction (ED), but the causal relationship between sex hormones and ED is still uncertain. AIM: To prove the association between sex hormones and ED, we carried out a prospective cohort study based on our previous cross-sectional study. METHODS: We performed a prospective cohort study of 733 Chinese men who participated in Fangchenggang Area Males Health and Examination Survey from September 2009 to December 2009 and were followed for 4 years. Erectile function was estimated by scores of the five-item International Index of Erectile Dysfunction (IIEF-5) and relative ratios (RRs) were estimated using the Cox proportional hazards regression model. MAIN OUTCOME MEASURES: Data were collected at follow-up visit and included sex hormone measurements, IIEF-5 scores, physical examination, and health questionnaires. RESULTS: Men with the highest tertile of free testosterone (FT) (RR = 0.21, 95% confidence interval [CI]: 0.09-0.46) and the lowest tertile of sex hormone-binding globulin (SHBG) (RR = 0.38, 95% CI: 0.19-0.73) had decreased risk of ED. In young men (aged 21 40), a decreased risk was observed with the increase of FT and bioavailable testosterone (BT) (adjusted RR and 95% CI: 0.78 [0.67-0.92] and 0.75 [0.62-0.95], respectively). Total testosterone (TT) (RR = 0.89, 95% CI: 0.81-0.98) was inversely associated with ED after adjusting for SHBG, while SHBG (RR = 1.04, 95% CI: 1.02-1.06) remained positively associated with ED after further adjusting for TT. Men with both low FT and high SHBG had highest ED risk (adjusted RR = 4.61, 95% CI: 1.33-16.0). CONCLUSIONS: High FT and BT levels independently predicted a decreased risk of ED in young men. Further studies are urgently needed to clarify the molecular mechanisms of testosterone acting on ED. PMID- 25800961 TI - Long-term morbidity of IgA nephropathy in children evaluated with newly proposed remission criteria in Japan. AB - BACKGROUND: The long-term outcome of pediatric IgA nephropathy (IgAN) is unclear. Objective IgAN remission criteria were proposed by the Japanese Society of Nephrology in 2013. METHODS: Children with newly developed IgAN followed for >5 years were analyzed. They were divided into two groups based on histological findings at initial kidney biopsy: the focal mesangial proliferation group (Focal group) and diffuse mesangial proliferation group (Diffuse group). The primary outcome was the remission rate according to the newly proposed IgAN remission criteria. RESULTS: The patients comprised 53 children (31 boys; mean age at IgAN onset, 10.0 years). The Focal and Diffuse groups comprised 21 and 32 patients, respectively. No significant differences in patient characteristics were found between the groups except for steroid administration. The median follow-up period from onset was 9.9 years. Sixteen patients in the Diffuse group and 10 in the Focal group had not achieved remission at the last observation. Patient conditions 2 years after the initial treatment were almost identical to those at the last observation. Multivariate analysis revealed that proteinuria, particularly <0.5 g/g Cr at 2 years, was significantly associated with remission at the last observation regardless of proteinuria status at the start of treatment. CONCLUSIONS: Pediatric IgAN has a prolonged course that is longer than expected regardless of severity at diagnosis. Patient conditions 2 years after initial treatment predicted their conditions at the last observation. Although the final renal function of these patients is presently unclear, children with IgAN should be followed beyond adolescence and further into adulthood. PMID- 25800962 TI - Correlation between P2X7 receptor gene polymorphisms and gout. AB - Not all patients with hyperuricemia will develop acute gouty arthritis, indicating that other initiating factors need to be considered. The P2X7 receptor is an adenosine triphosphate-gated nonselective cation channel that has also been suggested to be a proinflammatory receptor. In the immune system, the P2X7 receptor is involved in the processing and release of various proinflammatory cytokines, including interleukin-1beta (IL-1beta), IL-18 and tumor necrosis factor-alpha (TNF-alpha). IL-1beta is a central cytokine in the initiation of the acute inflammatory response, which plays a key role in the pathogenesis of gout and the pathology of acute gouty arthritis. This review will explore single nucleotide polymorphisms in the P2X7R gene [including rs1718119 (Ala348Thr), rs208294 (His155Tyr), rs3751143 (Glu496Ala), rs28360457 (Arg307Gln) and rs2230911 (Thr357Ser)] and their correlation with the incidence of gout. We conclude that P2X7R gene polymorphisms impact the secretion of IL-1beta and thus play a vital role in the pathogenesis of gout. PMID- 25800963 TI - Immunoglobulin G4-related disease mimicking lymphoma in a Chinese patient. AB - Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by multiorgan fibrosis with IgG4-producing plasma cells, increased IgG4 serum concentration, and responsiveness to steroid therapy. IgG4-RD tends to form tumefactive lesions. As a result, patients are often suspected of having a malignancy such as lymphoma. In this article, a patient with IgG4-RD and the deep vein thrombosis who was initially suspected of lymphoma is reported. The 63-year old man presented with painless salivary swelling and multi-lymphadenopathy, progressively swelling and pain in the left leg. Salivary biopsy showed IgG4+ plasma cells >50 per high-power field and IgG4+/IgG+ plasma cell ratio >40 %. The serum IgG4 level was 4.28 g/L (range 0.03-2.01 mg/dL). Ultrasonography showed that the inferior vena cava was partially occluded, and thrombosis in the left iliac vein. Computed tomography scan revealed plaque-like tissue surrounding the inferior vena cava and abdominal aortic, which is typical for the diagnosis of retroperitoneal fibrosis. The patient was effectively treated with corticosteroids, interventional therapy, and anticoagulant therapy which resulted in a reduction in the swelling of the lymph nodes and left leg. Patient with IgG4 RD and deep vein thrombosis is rare and could be misdiagnosed easily as malignant disease. Accurate diagnosis is critical for disease management. PMID- 25800964 TI - Optimization and kinetic characterization of recombinant 1,3-beta-glucanase production in Escherichia coli K-12 strain BL21/pETSD10 - a bioreactor scale study. AB - The Escherichia coli K-12 strain BL21/pETSD10 was used to produce recombinant endocellular 1,3-beta-glucanase. This enzyme is responsible for the hydrolysis of the glycosidic bond in specific polysaccharides with tracts of unsubstituted beta 1,3-linked glucosyl residues. Conditions for the overproduction were experimentally examined, and the optimal values of the process on a bioreactor scale were found by interpolation of the experimental data. Cell induction was preferred during log-phase with relatively high cell density at OD600 near 1.1 with 0.074 g l(-1) of Isopropyl beta-D-1-thiogalactopyranoside (IPTG). The higher concentration of IPTG favors high enzyme production but with an excess of ballast protein. 1,3-beta-glucanase production was favoured with moderate culture aeration (0.7-0.9 vvm) and moderate stirring (125-150 rev min(-1) ). The highest specific glucanase activity (252 U g(-1) ) was found during validated experiments carried out at aeration at 135 rev min(-1) and stirring at 0.8 vvm. Due to high tonnage industrial applications (i.e. to hemicellulose hydrolysis), the enzymatic preparation did not need to be highly purified. After pretreatment (precipitation with ammonium sulphate and dialysis) of the crude preparation, the enzymatic protein was one of the three main proteins in the preparation. The reaction rate with respect to the substrate (CM-curdlan) was described by the first order reaction equation (k = 1.95 l h(-1 ) g(-1) ). Products formed in the reaction are composed of nine glucose units on average. In the reaction conditions, the preparation showed very good stability (t1/2 = 202 h). SIGNIFICANCE AND IMPACT OF THE STUDY: The results contribute to the knowledge of cultivation parameters of E. coli K-12 strain BL21/pETSD10 on a bioreactor scale to overproduce an enzyme degrading beta-1,3-glucans. The optimal values of protein concentration, specific activity and total glucanase activity as a function of aeration and stirring were evaluated by numerical analysis. The obtained values were validated as positive. The protein degrades some bonds in hemicellulose. Thus, the protein could be applied as one of the degrading components for hemicellulose. PMID- 25800965 TI - Ultrafast intramolecular relaxation and wave-packet motion in a ruthenium-based supramolecular photocatalyst. AB - The hydrogen-evolving photocatalyst [(tbbpy)2 Ru(tpphz)Pd(Cl)2 ](2+) (tbbpy=4,4' di-tert-butyl-2,2'-bipyridine, tpphz=tetrapyrido[3,2-a:2',3'-c:3'',2'' h:2''',3'''-j]phenazine) shows excitation-wavelength-dependent catalytic activity, which has been correlated to the localization of the initial excitation within the coordination sphere. In this contribution the excitation-wavelength dependence of the early excited-state relaxation and the occurrence of vibrational coherences are investigated by sub-20 fs transient absorption spectroscopy and DFT/TDDFT calculations. The comparison with the mononuclear precursor [(tbbpy)2 Ru(tpphz)](2+) highlights the influence of the catalytic center on these ultrafast processes. Only in the presence of the second metal center, does the excitation of a (1) MLCT state localized on the central part of the tpphz bridge lead to coherent wave-packet motion in the excited state. PMID- 25800966 TI - [Tissue engineering and maxillofacial surgery. Report of the scientific meeting held the 10th January 2015 - La Pitie-Salpetriere - Paris]. PMID- 25800968 TI - Switching haemophilia products and inhibitor risk: a United States' perspective. PMID- 25800967 TI - [Mucosal lymphomatoid papulosis: 2 cases]. AB - BACKGROUND: Lymphomatoid Papulosis (LP) is a chronic dermatosis progressing by flare-up. According to the WHO-EORTC classification, LP is a form of CD30+ primitive cutaneous lympho-proliferation. Mucosal lesions are rare, with 15 published cases. We report two new cases of oral localizations, without any cutaneous involvement. PATIENTS AND METHODS: Two women, 32 and 63 years old, presented with an isolated painful oral ulceration, of the maxillary tuberosity and of the inner side of the cheek respectively. The general state of health was preserved. Immunohistochimical analysis of the biopsies showed two Type A LPs. Lesions spontaneously resolved. DISCUSSION: Among the rare published cases, oral localization involved exclusively the tongue and the labial mucosa and almost all patients presented with previous cutaneous lesions. Isolated maxillary tuberosity or cheek involvements were not described yet. PMID- 25800969 TI - Queue for drug registrations grows longer in China. PMID- 25800970 TI - Clinical and psychosocial outcomes of borderline personality disorder in childhood and adolescence: a systematic review. AB - BACKGROUND: While there is a growing body of research on borderline personality disorder (BPD) in children and adolescents, controversy remains regarding the validity and diagnosis of the disorder prior to adulthood. METHOD: MEDLINE, EMBASE, Psych INFO and PubMed databases were systematically searched for articles pertaining to the clinical and psychosocial outcomes (i.e. predictive validity) of BPD first diagnosed in childhood or adolescence (i.e. prior to 19 years of age). All primary empirical studies were included in the review. A narrative synthesis of the data was completed. RESULTS: A total of 8200 abstracts were screened. Out of 214 full-text articles, 18 satisfied the predetermined inclusion criteria. Quality assessment indicated that most studies had high risk of bias in at least one study domain. Consistent with the adult literature, the diagnostic stability of BPD prior to the age of 19 years was low to moderate, and mean-level and rank-order stability, moderate to high. Individuals with BPD symptoms in childhood or adolescence had significant social, educational, work and financial impairment in later life. CONCLUSIONS: Studies indicate that borderline pathology prior to the age of 19 years is predictive of long-term deficits in functioning, and that a considerable proportion of individuals continue to manifest borderline symptoms up to 20 years later. These findings provide some support for the clinical utility of the BPD phenotype in younger populations, and suggest that an early intervention approach may be warranted. Further prospective studies are needed to delineate risk (and protective) factors pertinent to the chronicity of BPD across the lifespan. PMID- 25800972 TI - The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model. AB - We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Abeta were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease. PMID- 25800973 TI - Production of novel vinegar having antioxidant and anti-fatigue activities from Salicornia herbacea L. AB - BACKGROUND: Salicornia herbacea L. is a halophyte that grows in salt marshes and contains significant amounts of salts and minerals. Because it is known as a folk medication to treat diseases, various processed products such as powder, globular type of powder, laver and extract have been developed. However, it is difficult to process as a drink because of its high salinity. In the present study, glasswort vinegar (GV) containing high amounts of organic acids and minerals was developed via two-step fermentation with unpolished rice substrates and investigated its antioxidant and anti-fatigue activities. RESULTS: GV showed various free radical scavenging effects, reducing power, oxidized-LDL inhibition and superoxide dismutase-like activities. Compared with the control group (orally administered 7 g kg(-1) distilled water), the GV supplementation group showed increased running endurance and had higher glycogen accumulation in liver and muscles of rats exhausted by exercise. Furthermore, the GV-administered group demonstrated significantly elevated lactate and ATP metabolism, promoting enzyme activities such as muscle creatine kinase and lactate dehydrogenase, whereas serum fatigue biomarkers such as ammonia, lactate and inorganic acid were markedly decreased. CONCLUSION: These results indicate that GV can be used as a functional food for the development of a dietary beverage to alleviate fatigue. PMID- 25800971 TI - NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism. AB - Drugs targeting the glutamate N-methyl-d-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressant-related effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy 5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking GluN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR. PMID- 25800974 TI - Tenofovir disoproxil fumarate has a substantial efficacy against multidrug resistant strains of hepatitis B virus. AB - BACKGROUND & AIMS: To evaluate the efficacy of tenofovir in chronic hepatitis B (CHB) patients with adefovir resistance (ADF-R) and suboptimal response to adefovir (ADF-S). METHODS: Nucleos(t)ide analogue (NA)-naive patients and patients with previous adefovir failure receiving tenofovir therapy for at least 6 months were included in the study. Biochemical and virological tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure was complete virological response (CVR) (HBVDNA < 20 IU/ml). CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional hazard model was generated to find out factors independently associated with CVR. RESULTS: A total of 165 patients (118 men, mean age 42 +/- 12, 64 HBeAg(+) ) were included in the study. There were 105 patients in NA-naive, 32 patients in ADF-S and 28 patients in ADF-R groups. All patients in the ADF-R group had multidrug resistance patterns. Mean duration of tenofovir treatment was 29 +/- 14 months. CVR rates in NA-naive, ADF-S and ADF-R groups were 65% vs. 75% vs. 58% at 12th month, 77% vs. 87% vs. 79% at 24th month and 83% vs. 94% vs. 79% at 36th month respectively. According to multivariate Cox regression model, HBeAg positivity (HR = 0.56, 95%CI 0.36-0.86, P = 0.008), high baseline HBVDNA level (HR = 0.64, 95%CI 0.55-0.74, P < 0.001) and ADF-R (HR = 0.47, 95%CI 0.28-0.81, P = 0.006) were independent predictors for CVR. Seven patients encountered mild renal dysfunction and were managed by dose adjustments. CONCLUSION: CVR rates during the follow-up show that tenofovir has a decreased, yet still potent in vivo efficacy against multidrug-resistant strains of HBV. PMID- 25800975 TI - Targeted therapies for small cell lung cancer: Where do we stand? AB - Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of targeted therapies based on a better understanding of the molecular basis of the disease is urgently needed. At the genetic level, SCLC appears very heterogenous, although somatic mutations targeting classical oncogenes and tumor suppressors have been reported. SCLC also possesses somatic mutations in many other cancer genes, including transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components. Several avenues have been explored to develop targeted therapies for SCLC. So far, however, there has been limited success with these targeted approaches in clinical trials. Further progress in the optimization of targeted therapies for SCLC will require the development of more personalized approaches for the patients. PMID- 25800977 TI - Mammary gland: From embryogenesis to adult life. AB - The aim of this review is to focus on the molecular factors that ensure the optimal development and maintenance of the mammary gland thanks to their integration and coordination. The development of the mammary gland is supported, not only by endocrine signals, but also by regulatory molecules, which are able to integrate signals from the surrounding microenvironment. A major role is certainly played by homeotic genes, but their incorrect expression during the spatiotemporal regulation of proliferative, functional and differentiation cycles of the mammary gland, may result in the onset of neoplastic processes. Attention is directed also to the endocrine aspects and sexual dimorphism of mammary gland development, as well as the role played by ovarian steroids and their receptors in adult life. PMID- 25800976 TI - Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight. AB - Advanced gastric cancer ranks second as the global leading cause of cancer related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results. PMID- 25800978 TI - Oncofetal expression of Wilms' tumor 1 (WT1) protein in human fetal, adult and neoplastic skeletal muscle tissues. AB - There is increasing evidence that WT1 protein expression is found not only at nuclear, but also at cytoplasmic, level in several developing and neoplastic tissues. In order to better understand the possible role of WT1 protein in human skeletal myogenesis and oncogenesis of rhabdomyosarcoma, we assessed immunohistochemically its comparative expression in a large series of human developing, adult and neoplastic skeletal muscle tissues. The present study shows that WT1 protein is developmentally expressed in the cytoplasm of human myoblasts from the 6 weeks of gestational age. This expression was maintained in the myotubes of developing muscles of the trunk, head, neck, and extremities, while it was down-regulated in fetal skeletal fibers from 20 weeks of gestational age as well as in adult normal skeletal muscle. Notably, WT1 immunostaining disappeared from rhabdomyomas, whereas it was strongly and diffusely re-expressed in all cases (27/27) of embryonal and alveolar rhabdomyosarcoma. The comparative evaluation of the immunohistochemical findings revealed that WT1 cytoplasmic expression in rhabdomyosarcoma may represent an ontogenetic reversal, and this nuclear transcription factor can also be considered an oncofetal protein which can be exploitable as an additional, highly sensitive immunomarker, together with desmin, myogenin and MyoD1, of this tumor. Moreover, our observations support the rationale for the use of WT1 protein-based target therapy in high risk rhabdomyosarcomas in children and adolescents. PMID- 25800979 TI - Presence and distribution of leptin and its receptor in the minor salivary glands of the donkey. AB - Leptin is a hormone widely diffused in the mammalian body in which it plays functions that go far beyond control of appetite and energy metabolism. The finding that it is present in the major salivary glands of various animal species is of interest for the functional implications that it may imply. Since there are no data on the presence of leptin and its receptor in the minor salivary glands, the aim of this study was to demonstrate their presence and distribution in such glands of donkeys. This latter was chosen as species of reference because the monogastric herbivore shows intense salivation during their masticatory activity. Tissue samples were collected from four adult donkeys, of both sexes, following slaughter. Samples were fixed, embedded in paraffin, and processed for immunohistochemical analysis using primary antibodies directed against leptin and its receptor. Controls for non-specific staining were always included. Leptin and its receptor were found in the minor salivary glands. Their distribution was similar to that described in the major salivary glands of animal species that have been investigated to date. We hypothesized that leptin can play a role in regulating gland function, via an autocrine/paracrine mechanism. PMID- 25800981 TI - Comparison of hierarchical and six degrees-of-freedom marker sets in analyzing gait kinematics. AB - The objective of this study was to determine how marker spacing, noise, and joint translations affect joint angle calculations using both a hierarchical and a six degrees-of-freedom (6DoF) marker set. A simple two-segment model demonstrates that a hierarchical marker set produces biased joint rotation estimates when sagittal joint translations occur whereas a 6DoF marker set mitigates these bias errors with precision improving with increased marker spacing. These effects were evident in gait simulations where the 6DoF marker set was shown to be more accurate at tracking axial rotation angles at the hip, knee, and ankle. PMID- 25800980 TI - Immunohistochemical markers of stem/progenitor cells in the developing human kidney. AB - The aim of this study was to better define, by immunohistochemistry, the molecular markers of renal stem/progenitor cells localized in the different niches of ten human preterm kidneys with gestational age ranging from 11 up to 25 weeks. Our data evidence the existence of multiple stem/progenitor pools in different zones of the human developing kidney that are characterized by different phenotypes: capsular stem cells were EMA (MUC1)+, MDM2+, Vimentin+ and Wnt1+; progenitors of the sub-capsular nephrogenic zone were MDM2+ and Wnt1+; cap mesenchymal cells were EMA (MUC1)+, CD15+, vimentin+, Wt1+, CD10+, Bcl2+, Wnt1+ and PAX2+; interstitial progenitor cells were Vimentin+, Wt1+ and alpha1Anti tripsin+. Our data evidence the existence of multiple stem/progenitor cell pools in the fetal and neonatal human kidney. Progenitors of these different pools are characterized by a peculiar phenotype, indicating a different differentiation stage of these renal progenitors. A better knowledge of the molecular markers expressed by renal stem/progenitors might represent a relevant datum for researchers involved in renal regenerative medicine. PMID- 25800982 TI - Is there evidence of sexual reproduction (meiosis) in Acanthamoeba? AB - Evolution of independently breeding species into males and females (gametes) has remained a puzzle. Given the significant advantages of sexual reproduction over asexual reproduction as a long-term species survival strategy; here, we pose the question whether there is some form of meiosis in Acanthamoeba species, which represents our ancient lineage. The recently available Acanthamoeba genome revealed several genes implicated in meiosis in sexual eukaryotes such as Spo11, Mre11, Rad50, Rad51, Rad52, Mnd1, Dmc1, Msh, and Mlh, suggesting that Acanthamoeba is capable of some form of meiosis, inferring the presence of sexual reproduction in Acanthamoeba, and that meiosis evolved early in eukaryotic evolution. PMID- 25800983 TI - Synthesis of Surface Covalent Organic Frameworks via Dimerization and Cyclotrimerization of Acetyls. AB - The formation of additional phenyl rings on surfaces is of particular interest because it allows for the building-up of surface covalent organic frameworks. In this work, we show for the first time that the cyclotrimerization of acetyls to aromatics provides a promising approach to 2D conjugated covalent networks on surfaces under ultrahigh vacuum. With the aid of scanning tunneling microscopy, we have systematically studied the reaction pathways and the products. With the combination of density functional theory calculations and X-ray photoemission spectroscopy, the surface-assisted reaction mechanism, which is different from that in solution, was explored. PMID- 25800984 TI - Prediction of the acoustic and bubble fields in insonified freeze-drying vials. AB - The acoustic field and the location of cavitation bubble are computed in vials used for freeze-drying, insonified from the bottom by a vibrating plate. The calculations rely on a nonlinear model of sound propagation in a cavitating liquid [Louisnard, Ultrason. Sonochem., 19, (2012) 56-65]. Both the vibration amplitude and the liquid level in the vial are parametrically varied. For low liquid levels, a threshold amplitude is required to form a cavitation zone at the bottom of the vial. For increasing vibration amplitudes, the bubble field slightly thickens but remains at the vial bottom, and the acoustic field saturates, which cannot be captured by linear acoustics. On the other hand, increasing the liquid level may promote the formation of a secondary bubble structure near the glass wall, a few centimeters below the free liquid surface. These predictions suggest that rather complex acoustic fields and bubble structures can arise even in such small volumes. As the acoustic and bubble fields govern ice nucleation during the freezing step, the final crystal's size distribution in the frozen product may crucially depend on the liquid level in the vial. PMID- 25800985 TI - Toxicological effects and oxidative stress responses in freshwater snail, Lanistes carinatus, following exposure to chlorpyrifos. AB - Chlorpyrifos is a widely used organophosphorous pesticide in agriculture and environmental health. Laboratory studies of chlorpyrifos have revealed acute lethal toxicity at very low concentration (96-h LC50) of 0.39 MUg L(-1) to the freshwater snail, Lanistes carinatus. Acetylcholinesterase (AChE) inhibition progressed and reached 52% and 78% of the control after 28-d exposure to 0.09 and 0.29 MUg L(-1) chlorpyrifos, respectively. Catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities increased in comparison to control group in the first period of exposure (7-21 d), then decreased relative to the control in the second period of exposure (21-28 d). A significant (p<0.05) glutathione (GSH) depletion was observed in snails exposed to 0.09 and 0.29 MUg L(-1) in comparison to the control, whereas malondialdehyde (MDA) content gradually increased in a dose-dependent manner. This study showed that alterations in antioxidant enzyme activities along with depletion of GSH content and elevation of MDA content can be used as biomarkers in environmental assessment programs. PMID- 25800986 TI - The influence of multiwalled carbon nanotubes on polycyclic aromatic hydrocarbon (PAH) bioavailability and toxicity to soil microbial communities in alfalfa rhizosphere. AB - Carbon nanotubes (CNTs) may affect bioavailability and toxicity of organic contaminants due to their adsorption properties. Recent studies have observed the influence of multiwalled carbon nanotubes (MWNTs) on the fate of polycyclic aromatic hydrocarbons (PAHs) and other organic contaminants. Greenhouse studies (49 d) were conducted with alfalfa plants in two different soil types. Four treatment conditions (0, 25, 50, or 100 mg/kg MWNTs+100 mg/kg PAHs mixture-pyrene and phenanthrene) were tested in order to determine their effects on soil microbial community composition and PAH residues. Microbial community structure in the two highest treatments (50 mg/kg and 100 mg/kg MWNTs) showed a dramatic shift in the presence of MWNTs in sandy loam soil (1% organic matter) in comparison to the control (0 mg/kg MWNTs). Many microbial fatty acid methyl ester (FAMEs) markers (i15:0, 16:1omega5c, 10Me17:0, 10Me16:0) were missing in the control soil. However, there was a lower abundance of these FAMEs in the 25 mg/kg MWNT treatment (except 10Me17:0) and a higher presence of these FAMEs in the 50 mg/kg and 100 mg/kg MWNT treatments compared to control. In contrast, microbial community composition was not influenced by the MWNT treatments in sandy clay loam soil (5.9% organic matter). However, pyrene degradation in sandy clay loam soil significantly increased by 21% in the highest MWNT treatment group (100 mg/kg) and 9.34% in 50 mg/kg MWNT treatment. Under the conditions tested in this study, MWNTs significantly impacted the soil microbial community distribution and PAH degradation and effects were dependent on soil types, specifically organic matter content. PMID- 25800987 TI - Endosulfan affects GnRH cells in sexually differentiated juveniles of the perciform Cichlasoma dimerus. AB - Endosulfan (ES) is an organochlorine pesticide widely used in agriculture despite its high toxicity towards non-target organisms such as fish. It has been demonstrated that ES can cause negative effects on aquatic animals, including disruption of hormonal systems. However, the alterations produced by this pesticide on the reproductive axis of fish prior to sexual maturity, as well as possible modes of action have hardly been studied. This study aimed at assessing the effect of waterborne exposure to the pesticide ES on the reproductive axis during sexual differentiation of juveniles of the South American freshwater cichlid fish Cichlasoma dimerus. No mortality was observed due to ES subchronic exposure (90 days post-fertilization). Exposure to ES did not affect body weight nor morphometric parameters, indicating that larvae nutritional state was not affected. Timing of sexual differentiation, gonadal morphology and sex ratio were likewise not altered by ES. However, ES acted as an endocrine disrupting chemical in this species as the morphometry of gonadotropin-releasing hormones (GnRH) producing cells was altered. Exposure to ES altered nuclear area, cell area and nucleus/cytoplasm ratio of GnRH II neurons, and cell and nuclear area and diameter of GnRH III neurons. Interestingly, in our previous study, exposure before sex differentiation (30 day exposure) caused no alteration to GnRH II and III, and did alter GnRH I and FSH cells. These alterations could lead to changes in circulating hormone levels, especially when fish are exposed for prolonged periods, ultimately impairing reproductive fitness. C. dimerus juveniles can be an interesting biological model to perform toxicological studies with the intent to assess early disruption endpoints in the reproductive axis during development. PMID- 25800989 TI - The Southern states: NPs made an impact in rural and healthcare shortage areas. AB - PURPOSE: To investigate the distribution of nurse practitioners (NPs) in the U.S. Southern region with a focus on rural and underserved areas. Described in this study are the NP characteristics and their workforce distribution relative to rural and health professional shortage areas (HPSAs). DATA SOURCES: METHOD: A questionnaire was administered to NPs in 12 Southern states. Other data sources included (a) the Health Resources and Services Administration, which identified HPSAs; and (b) data from the U.S. Census Bureau, to distinguish urban and rural areas. CONCLUSIONS: Approximately 72% of NPs worked in HPSAs and less than half of the NPs worked in the rural area. Family NPs were more likely to practice in rural and HPSAs. Employment in primary care was more likely to occur in rural and HPSAs. Racial diversity was almost nonexistent within the NP population. IMPLICATION FOR PRACTICE: This research does demonstrate that NPs are practicing in rural and underserved areas as conceived decades ago, but there is still a great demand and gap to fill. To optimize their effectiveness, NPs need to practice to the full extent of their education. Additionally, more research and strategies to help diversify the workforce is needed. PMID- 25800990 TI - Retrospective analysis of prenatal ultrasound of children with Hirschsprung disease. AB - OBJECTIVE: Hirschsprung disease (HD) is a rare gastrointestinal disorder. Our aim was to study the prenatal ultrasound findings of children who were diagnosed with HD after birth. METHODS: The study population included children who suffered from HD between 1990 and 2008. Data of anomaly scan findings in prenatal ultrasound, demographic and post-natal physical abnormalities and treatment were retrieved from medical files and interviews with the parents. RESULTS: Twenty-two patients confirmed histopathological diagnosis of HD at age of 1 day to 15 months. Nineteen fetuses had anomaly scan during pregnancy, which revealed minor sonographic abnormalities in three fetuses; two of them had hyperechogenic bowel. One fetus with hyperechogenic bowel had polyhydramnion, and another had a family history of three brothers with HD. A third fetus had dilated pelvic kidney. None of them had sonographic evidence of bowel dilatation. After birth, six patients (31%) were found to have other structural anomalies: ventriculoseptal defect, atriseptal defect, atrio-ventricular septal defect, and pyloric stenosis. CONCLUSIONS: Abnormal sonographic findings of fetal bowel are absent in the vast majority of fetuses who are diagnosed with HD after birth. In women with a family history of HD, a third trimester anomaly scan may be warranted. PMID- 25800991 TI - Calcium-siRNA nanocomplexes: the importance of reversibility. PMID- 25800992 TI - Erratum to: Neuroendocrine tumours of the female genital tract: a case-based imaging review with pathological correlation. PMID- 25800988 TI - Enhanced osteoclastogenesis by mitochondrial retrograde signaling through transcriptional activation of the cathepsin K gene. AB - Mitochondrial dysfunction has emerged as an important factor in wide ranging human pathologies. We have previously defined a retrograde signaling pathway that originates from dysfunctional mitochondria (Mt-RS) and causes a global nuclear transcriptional reprograming as its end point. Mitochondrial dysfunction causing disruption of mitochondrial membrane potential and consequent increase in cytosolic calcium [Ca(2) ](c) activates calcineurin and the transcription factors NF-kappaB, NFAT, CREB, and C/EBPdelta. In macrophages, this signaling complements receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastic differentiation. Here, we show that the Mt-RS activated transcriptional coactivator heterogeneous ribonucleoprotein A2 (hnRNP A2) is induced by hypoxia in murine macrophages. We demonstrate that the cathepsin K gene (Ctsk), one of the key genes upregulated during osteoclast differentiation, is transcriptionally activated by Mt-RS factors. HnRNP A2 acts as a coactivator with nuclear transcription factors, cRel, and C/EBPdelta for Ctsk promoter activation under hypoxic conditions. Notably, our study shows that hypoxia-induced activation of the stress target factors mediates effects similar to that of RANKL with regard to Ctsk activation. We therefore suggest that mitochondrial dysfunction and activation of Mt-RS, induced by various pathophysiologic conditions, is a potential risk factor for osteoclastogenesis and bone loss. PMID- 25800993 TI - Magnetic Resonance Fingerprinting - a promising new approach to obtain standardized imaging biomarkers from MRI. AB - Current routine MRI examinations rely on the acquisition of qualitative images that have a contrast "weighted" for a mixture of (magnetic) tissue properties. Recently, a novel approach was introduced, namely MR Fingerprinting (MRF) with a completely different approach to data acquisition, post-processing and visualization. Instead of using a repeated, serial acquisition of data for the characterization of individual parameters of interest, MRF uses a pseudo randomized acquisition that causes the signals from different tissues to have a unique signal evolution or 'fingerprint' that is simultaneously a function of the multiple material properties under investigation. The processing after acquisition involves a pattern recognition algorithm to match the fingerprints to a predefined dictionary of predicted signal evolutions. These can then be translated into quantitative maps of the magnetic parameters of interest. MR Fingerprinting (MRF) is a technique that could theoretically be applied to most traditional qualitative MRI methods and replaces them with acquisition of truly quantitative tissue measures. MRF is, thereby, expected to be much more accurate and reproducible than traditional MRI and should improve multi-center studies and significantly reduce reader bias when diagnostic imaging is performed. Key Points * MR fingerprinting (MRF) is a new approach to data acquisition, post-processing and visualization.* MRF provides highly accurate quantitative maps of T1, T2, proton density, diffusion.* MRF may offer multiparametric imaging with high reproducibility, and high potential for multicenter/ multivendor studies. PMID- 25800994 TI - The role of MRI in axillary lymph node imaging in breast cancer patients: a systematic review. AB - OBJECTIVES: To assess whether MRI can exclude axillary lymph node metastasis, potentially replacing sentinel lymph node biopsy (SLNB), and consequently eliminating the risk of SLNB-associated morbidity. METHODS: PubMed, Cochrane, Medline and Embase databases were searched for relevant publications up to July 2014. Studies were selected based on predefined inclusion and exclusion criteria and independently assessed by two reviewers using a standardised extraction form. RESULTS: Sixteen eligible studies were selected from 1,372 publications identified by the search. A dedicated axillary protocol [sensitivity 84.7 %, negative predictive value (NPV) 95.0 %] was superior to a standard protocol covering both the breast and axilla simultaneously (sensitivity 82.0 %, NPV 82.6 %). Dynamic, contrast-enhanced MRI had a lower median sensitivity (60.0 %) and NPV (80.0 %) compared to non-enhanced T1w/T2w sequences (88.4, 94.7 %), diffusion weighted imaging (84.2, 90.6 %) and ultrasmall superparamagnetic iron oxide (USPIO)- enhanced T2*w sequences (83.0, 95.9 %). The most promising results seem to be achievable when using non-enhanced T1w/T2w and USPIO-enhanced T2*w sequences in combination with a dedicated axillary protocol (sensitivity 84.7 % and NPV 95.0 %). CONCLUSIONS: The diagnostic performance of some MRI protocols for excluding axillary lymph node metastases approaches the NPV needed to replace SLNB. However, current observations are based on studies with heterogeneous study designs and limited populations. MAIN MESSAGES: * Some axillary MRI protocols approach the NPV of an SLNB procedure. * Dedicated axillary MRI is more accurate than protocols also covering the breast. * T1w/T2w protocols combined with USPIO enhanced sequences are the most promising sequences. PMID- 25800996 TI - Erratum to: The safety of long-term cryopreservation on slow-frozen early cleavage human embryos. PMID- 25800995 TI - Dysregulation of methylation and expression of imprinted genes in oocytes and reproductive tissues in mice of advanced maternal age. AB - PURPOSE: To evaluate reproductive outcomes in aged compared to young female mice, and determine associated methylation and expression of imprinted genes in reproductive tissues. METHODS: Fetal, placental, and ovarian tissue were collected on d16.5 of pregnancy from young (4-5 weeks) and aged (15 months) mice. Uterine tissue and in vivo matured oocytes were collected from non-pregnant females. Methylation of imprinted genes was determined by restriction enzyme based assays, and transcript abundance of imprinted and nutrient supply genes were analyzed by quantitative PCR (qPCR). RESULTS: Maternal age was associated with fetal growth restriction and placental overgrowth. In maternally aged mice, methylation was minimally dysregulated in fetal tissue, while placental tissue showed aberrant methylation and transcript abundance of imprinted genes. Ovarian methylation and gene expression was severely dysregulated, although oocyte gene expression was only minimally altered. Abundance of Kcnq1 transcripts was significantly (P < 0.05) increased in oocytes obtained from aged females compared to young females. Gene expression was also severely dysregulated in the uterus, including nutrient transport genes. CONCLUSION: Fetal and placental growth abnormalities correspond to aberrant methylation and gene expression in reproductive tissues from maternally aged mice. Significant alterations in gene expression and methylation in the aged ovary suggests that the follicular environment may be compromised. Aberrant methylation and expression of imprinted genes in the aged uterus may contribute to reduced implantation. Maternal age negatively affects imprinted gene methylation and expression in both germ cells and somatic cells of the reproductive tract, contributing to the reduced fertility observed with advanced maternal age. PMID- 25800998 TI - Acute myocardial infarction and inter-hospital transfer. PMID- 25800997 TI - The influence of nonrandom extra-pair paternity on heritability estimates derived from wild pedigrees. AB - Quantitative genetic analysis is often fundamental for understanding evolutionary processes in wild populations. Avian populations provide a model system due to the relative ease of inferring relatedness among individuals through observation. However, extra-pair paternity (EPP) creates erroneous links within the social pedigree. Previous work has suggested this causes minor underestimation of heritability if paternal misassignment is random and hence not influenced by the trait being studied. Nevertheless, much literature suggests numerous traits are associated with EPP and the accuracy of heritability estimates for such traits remains unexplored. We show analytically how nonrandom pedigree errors can influence heritability estimates. Then, combining empirical data from a large great tit (Parus major) pedigree with simulations, we assess how heritability estimates derived from social pedigrees change depending on the mode of the relationship between EPP and the focal trait. We show that the magnitude of the underestimation is typically small (<15%). Hence, our analyses suggest that quantitative genetic inference from pedigrees derived from observations of social relationships is relatively robust; our approach also provides a widely applicable method for assessing the consequences of nonrandom EPP. PMID- 25801000 TI - Optimal use of echocardiography in valvular heart disease evaluation. PMID- 25800999 TI - Basal chordae sites on the mitral valve determine the severity of secondary mitral regurgitation. AB - OBJECTIVES: To evaluate the variation between individuals in terms of basal chordae (BC) attachment sites on the mitral valve (MV) and the influence of this variation on secondary mitral regurgitation (MR) severity. BACKGROUND: BC mediated MV tenting is the main cause of secondary MR. METHODS: In this prospective cross-sectional study, 38 consecutive patients with dilated or ischaemic cardiomyopathy who were due for cardiac transplantation underwent preoperative 3D full volume/colour Doppler echocardiography in sinus rhythm, and MV apparatus geometry, LV volume and MR severity were assessed. The lengths and insertion sites of four BC in the explanted hearts were measured post transplantation before fixation. RESULTS: Multiple linear regression analyses revealed that the anterior leaflet systolic tenting angle and bending angle associated with the distance between the medial and lateral BC insertion sites. By contrast, the posterior leaflet tenting angle associated largely with LV volume indices. The mean longitudinal distance of the four BC from the MV edge was the main determinant of the distal length of the anterior MV from the angulation point. Square root of effective regurgitant orifice area (?EROA) only associated significantly with the mean longitudinal distance of the outer two BC from the MV edge (r=0.509, p=0.001) among pathological parameters, and the central MV tenting area (r=0.524, p=0.001) among echocardiographical parameters. ?EROA did not correlate with LV volume indices, LVEF or BC lengths. CONCLUSIONS: BC insertion sites were associated with systolic anterior MV configuration and secondary MR severity in dilated LV and severe systolic dysfunction. PMID- 25801002 TI - Electrochemical immunosensor with NiAl-layered double hydroxide/graphene nanocomposites and hollow gold nanospheres double-assisted signal amplification. AB - A sensitive electrochemical immunosensor based on NiAl-layered double hydroxide/graphene nanocomposites (NiAl-LDH/G) and hollow gold nanospheres (HGNs) was proposed for chlorpyrifos detection. The NiAl-LDH/G was prepared using a conventional coprecipitation process and reduction of the supporting graphene oxide. Subsequently, the nanocomposites were dispersed with chitosan (CS). The NiAl-LDH/G possessed good electrochemical behavior and high binding affinity to the electrode. The high surface areas of HGNs and the vast aminos and hydroxyls of CS provided a platform for the covalently crosslinking of antibody. Under optimal conditions, the immunosensor exhibited a wide linear range from 5 to 150 MUg/mL and from 150 to 2 MUg/mL, with a detection limit of 0.052 ng/mL. The detection results showed good agreement with standard gas chromatography method. The constructed immunosensor exhibited good reproducibility, high specificity, acceptable stability and regeneration performance, which provided a new promising tool for chlorpyrifos detection in real samples. PMID- 25801001 TI - Longitudinal persistence with secondary prevention therapies relative to patient risk after myocardial infarction. AB - BACKGROUND: Prior studies have demonstrated that patients with high-risk acute myocardial infarction (AMI) are less likely to receive guideline-directed medications during hospitalisation. It is unknown if this paradox persists following discharge. We aimed to assess if persistence with guideline-directed medications post discharge varies by patients' risk following AMI. METHODS: Data were analysed from two prospective, multicentre US AMI registries. The primary outcome was persistence with all prescribed guideline-directed medications (aspirin, beta-blockers, statins, angiotensin-antagonists) at 1, 6 and 12 months post discharge. The association between risk and medication persistence post discharge was assessed using multivariable mixed-effect models. RESULTS: Among 6434 patients with AMI discharged home, 2824 were considered low-risk, 2014 intermediate-risk and 1596 high-risk for death based upon their Global Registry of Acute Coronary Event (GRACE) 6-month risk score. High-risk was associated with a lower likelihood of receiving all appropriate therapies at discharge compared with low-risk patients (relative risk (RR) 0.90; 95% CI 0.87 to 0.94). At 12 months, the rate of persistence with all prescribed therapies was 61.5%, 57.9% and 45.9% among low-risk, intermediate-risk and high-risk patients, respectively. After multivariable adjustment, high-risk was associated with lower persistence with all prescribed medications (RR 0.87; 95% CI 0.82 to 0.92) over follow-up. Similar associations were seen for individual medications. Over the 5 years of the study, persistence with prescribed therapies post discharge improved modestly among high-risk patients (RR 1.05; 95% CI 1.03 to 1.08 per year). CONCLUSIONS: High-risk patients with AMI have a lower likelihood of persistently taking prescribed medications post discharge as compared with low-risk patients. Continued efforts are needed to improve the use of guideline-directed medications in high-risk patients. PMID- 25801003 TI - Impact of alogliptin and pioglitazone on lipid metabolism in islets of prediabetic and diabetic Zucker Diabetic Fatty rats. AB - Prolonged exposure of pancreatic beta (beta) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of beta cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, beta cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARgamma and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARgamma and increased incretin action working in concert to restore GL/FFA cycle in beta cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for beta cell failure. PMID- 25801005 TI - Influence of HIV antiretrovirals on methadone N-demethylation and transport. AB - Drug interactions involving methadone and/or HIV antiretrovirals can be problematic. Mechanisms whereby antiretrovirals induce clinical methadone clearance are poorly understood. Methadone is N-demethylated to 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidine (EDDP) by CYP2B6 and CYP3A4 in vitro, but by CYP2B6 in vivo. This investigation evaluated human hepatocytes as a model for methadone induction, and tested the hypothesis that methadone and EDDP are substrates for human drug transporters. Human hepatocyte induction by several antiretrovirals of methadone N-demethylation, and CYP2B6 and CYP3A4 transcription, protein expression and catalytic activity, and pregnane X receptor (PXR) activation were evaluated. Methadone and EDDP uptake and efflux by overexpressed transporters were also determined. Methadone N-demethylation was generally not significantly increased by the antiretrovirals. CYP2B6 mRNA and activity (bupropion N-demethylation) were induced by several antiretrovirals, as were CYP3A4 mRNA and protein expression, but only indinavir increased CYP3A activity (alfentanil dealkylation). CYP upregulation appeared related to PXR activation. Methadone was not a substrate for uptake (OCT1, OCT2, OCT3, OATP1A2, OATP1B1, OATP1B3, OATP2B1) or efflux (P-gp, BCRP) transporters. EDDP was a good substrate for P-gp, BCRP, OCT1, OCT3, OATP1A2, and OATP1B1. OATP1A2- and OCT3 mediated EDDP uptake, and BCRP-mediated EDDP efflux transport, was inhibited by several antiretrovirals. Results show that hepatocyte methadone N-demethylation resembles expressed and liver microsomal metabolism more than clinical metabolism. Compared with clinical studies, hepatocytes underreport induction of methadone metabolism by HIV drugs. Hepatocytes are not a good predictive model for clinical antiretroviral induction of methadone metabolism and not a substitute for clinical studies. EDDP is a transporter substrate, and is susceptible to transporter-mediated interactions. PMID- 25801004 TI - MK571 inhibits phase-2 conjugation of flavonols by Caco-2/TC7 cells, but does not specifically inhibit their apical efflux. AB - MK571 is a multidrug resistance protein-2 (ABCC2, Mrp2) inhibitor and has been widely used to demonstrate the role of Mrp2 in the cellular efflux of drugs, xenobiotics and their conjugates. Numerous reports have described modulation of Caco-2 cellular efflux and transport of flavonoids in the presence of MK571. Since flavonoids are efficiently conjugated by Caco-2/TC7 cells, we investigated the effects of MK571 on the efflux of flavonoid conjugates. The flavonol aglycones kaempferol, quercetin and galangin were efficiently taken up, conjugated and effluxed by Caco-2/TC7 cells. Apically-applied MK571 caused significant reductions in both the apical and basolateral efflux of flavonol conjugates from Caco-2/TC7 monolayers. MK571 did not significantly alter the apical:basolateral efflux ratio for flavonol conjugates, however, which is not consistent with MK571 specifically inhibiting only apical Mrp2. Since MK571 decreased the total amounts of conjugates formed, and increased cellular flavonol aglycone concentrations, we explored the possibility that MK571 also inhibits phase-2 conjugation of flavonols. MK571 dose-dependently inhibited the intracellular biosynthesis of all flavonol glucuronides and sulphates by Caco-2 cells. MK571 significantly inhibited phase-2 conjugation of kaempferol by cell free extracts of Caco-2, and production of kaempferol-4'-O-glucuronide was competitively inhibited. These data show that MK571, in addition to inhibiting MRP2, is a potential inhibitor of enterocyte phase-2 conjugation. PMID- 25801006 TI - Treatment with angiotensin-(1-9) alleviates the cardiomyopathy in streptozotocin induced diabetic rats. AB - Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. We hypothesized that angiotensin-(1-9) [Ang-(1-9)] attenuates cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Rats were injected with a single intraperitoneal injection of STZ (55 mg/kg body weight) to induced diabetic cardiomyopathy. 4 weeks later, diabetic rats were treated with Ang-(1-9) (200 ng/kg/min), angiotensin type 2 receptor (AT2R) blocker PD123319 (100 ng/kg/min), or Mas antagonist A779 (100 ng/kg/min) for 4 weeks. Although Ang-(1-9) treatment did not affect blood glucose and insulin levels, it significantly attenuated cardiac hypertrophy, reduced cardiac fibrosis and improved ventricular function in STZ-induced diabetic rats. Ang-(1-9) treatment suppressed cardiac NADPH oxidase activity and reduced formation of reactive oxygen species. Ang-(1-9) suppressed NFkappaB activation and reduced myeloperoxidase (MPO) activity and mRNA levels of TNFalpha and IL-1beta in hearts of diabetic rats. In addition, Ang-(1-9) treatment suppressed activity of ACE and reduced angiotensin II (Ang II) formation in hearts of diabetic rats. The beneficial effect of Ang-(1-9) was blunted by coadministration of PD123319 but not by coadministration of A779. Finally, it was found that Ang-(1-9) treatment could alleviate STZ-induced cardiomyopathy in a dose-dependent manner. In conclusions, Ang-(1-9) attenuates cardiac dysfunction in STZ-induced diabetic rats. The Ang-(1-9)/AT2R axis should be investigated as a novel target for treatment of type 1 diabetic cardiomyopathy. PMID- 25801007 TI - Mechanistic basis of a combination D-penicillamine and platinum drugs synergistically inhibits tumor growth in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo. AB - The platinum-based regimen is the front-line treatment of chemotherapy. However, development of platinum resistance often causes therapeutic failure in this disease. We previously have generated an oxaliplatin-resistant subline, named S3, from human cervical carcinoma SiHa cells, and its resistant phenotype was well characterized. In the present study, we aimed to identify the novel therapeutic strategy by combining copper chelator D-penicillamine with oxaliplatin, and to elucidate the underlying mechanisms for overcoming oxaliplatin resistance. As the result, D-penicillamine exerted synergistic killing effects only in S3 cells when combined with oxaliplatin and cisplatin by using Chou-Talalay method. Further study showed that the amounts of platinum DNA adduct formed were positively correlated to the percentage of cell death in S3 cells when co-treated D penicillamine with oxaliplatin and cisplatin. D-penicillamine promoted copper influx transporter hCtr1 expression through upregulation of Sp1. Sp1 overexpression induced p53 translocation from nucleus to cytosol and caused p53 degradation through ubiquitination, which subsequently suppressed the expression of the copper efflux transporter ATP7A. Importantly, co-treatment of cisplatin with D-penicillamine enhanced oxaliplatin-elicited antitumor effect in the oxalipatin-resistant S3 xenograft tumors, but not found in SiHa xenograft model. Notably, Mice received D-penicillamine alone or in combination of D-penicillamine ad oxalipatin, increased hCtrl protein level in S3 xenograft tumor, however, the protein level of ATP7A was decreased. Taken together, this study provides insight into that the co-manipulation of hCtrl and ATP7A by D-penicillamine could increase the therapeutic efficacy of platinum drugs in oxaliplatin resistant tumors, especially in resistant phenotype with downexpression of hCtrl and overexpression of ATP7A. PMID- 25801008 TI - Slow R-warfarin 7-hydroxylation mediated by P450 2C19 genetic variants in cynomolgus monkeys in vivo. AB - Cynomolgus monkeys are widely used as non-human primate species in preclinical studies, due to their close evolutionary relationship to humans. Monkey cytochrome P450 2C19 (formerly known as P450 2C75), highly homologous to human P450 2C19, has been identified to be R-warfarin 7-hydroxylase in cynomolgus monkeys. In the present study, the in vivo pharmacokinetics of stereoselective warfarin and metabolites at a dose of 1.0mg/kg were investigated after oral and intravenous administration of racemic warfarin to fasted male cynomolgus monkeys (n=11, from Indochina, 4-8 years of age, 3.5-7.4kg of body weight), which had been genotyped for P450 2C19 [c.298TT>AA; c.308C>T; and c.334ATC>CTT]. Kinetic parameters for S-warfarin were not different among the homozygous mutant, heterozygous mutant, and wild type groups; however, values of elimination half lives, area under the curves, and total body clearance of R-warfarin in the homozygous mutant group showed one-order differences from those values in the wild type group after oral or intravenous administration. R-Warfarin 7 hydroxylations in vivo in homozygous mutant groups were slow compared to wild type or heterozygous mutant groups. These results demonstrate that inter-animal variations of R-warfarin clearance in cynomolgus monkeys are associated with P450 2C19 genetic variants [p.Phe100Asn, p.Ala103Val, and p.Ile112Leu]. Because some interindividual variability of P450 2C-dependent drug metabolism in cynomolgus monkeys, similarly in humans, is accounted for by polymorphic P450 2C19 variants, genotyping of drug metabolism enzymes should be considered before and after P450 dependent drug metabolism testing and evaluations in cynomolgus monkeys. PMID- 25801010 TI - Spin caloritronics of blue phosphorene nanoribbons. AB - We report a first-principles study of the magnetic properties and spin caloritronics of zigzag-type blue phosphorene nanoribbons (zBPNRs). It is found that the bare zBPNR (0H-zBPNR) or monohydrogenated zBPNR (1H-zBPNR) exhibit spin semiconducting properties arising from the edge electronic states. We further confirm that the py orbitals of the edge P atoms have the main contributions to these states. The spin-semiconducting property has a natural advantage for fabricating perfect thermospin devices with a stronger spin Seebeck effect than charge Seebeck effect at the Fermi level. When a temperature difference is applied, the electric current with the different spin index displays a bipolar behavior, and the spin-filtering efficiency can reach 1200%. By changing the widths of 0H-zBPNR and 1H-zBPNR, the ratio of the spin Seebeck coefficient to the charge Seebeck coefficient at the Fermi level is about 10 at room temperature. PMID- 25801009 TI - Retrospective analysis supports algorithm as efficient diagnostic approach to treatable intellectual developmental disabilities. AB - BACKGROUND: Intellectual developmental disorders (IDD(1)), characterized by a significant impairment in cognitive function and behavior, affect 2.5% of the population and are associated with considerable morbidity and healthcare costs. Inborn errors of metabolism (IEM) currently constitute the largest group of genetic defects presenting with IDD, which are amenable to causal therapy. Recently, we created an evidence-based 2-tiered diagnostic protocol (TIDE protocol); the first tier is a 'screening step' applied in all patients, comprising routinely performed, wide available metabolic tests in blood and urine, while second-tier tests are more specific and based on the patient's phenotype. The protocol is supported by an app (www.treatable-ID.org). OBJECTIVE: To retrospectively examine the cost- and time-effectiveness of the TIDE protocol in patients identified with a treatable IEM at the British Columbia Children's Hospital. METHODS: We searched the database for all IDD patients diagnosed with a treatable IEM, during the period 2000-2009 in our academic institution. Data regarding the patient's clinical phenotype, IEM, diagnostic tests and interval were collected. Total costs and time intervals associated with all testing and physician consultations actually performed were calculated and compared to the model of the TIDE protocol. RESULTS: Thirty-one patients (16 males) were diagnosed with treatable IDD during the period 2000-2009. For those identifiable via the 1st tier (n=20), the average cost savings would have been $311.17 CAD, and for those diagnosed via a second-tier test (n=11) $340.14 CAD. Significant diagnostic delay (mean 9 months; range 1-29 months) could have been avoided in 9 patients with first-tier diagnoses, had the TIDE protocol been used. For those with second-tier treatable IDD, diagnoses could have been more rapidly achieved with the use of the Treatable IDD app allowing for specific searches based on signs and symptoms. CONCLUSION: The TIDE protocol for treatable forms of IDD appears effective reducing diagnostic delay and unnecessary costs. Larger prospective studies, currently underway, are needed to prove that standard screening for treatable conditions in patients with IDD is time- and cost effective, and most importantly will preserve brain function by timely diagnosis enabling initiation of causal therapy. PMID- 25801011 TI - Incremental increase in percentage mouth opening after coronoidectomy in temporomandibular joint ankylosis. AB - The aim of this study was to evaluate the incremental improvement in mouth opening following coronoidectomy. Twenty-three patients with unilateral temporomandibular joint (TMJ) ankylosis (Sawhney types I-III) were assessed preoperatively; physical and radiological examinations were done (panoramic radiography and computed tomography). Data including demographic and clinical parameters were recorded. Patients with bilateral ankylosis, recurrent cases, and those with Sawhney type IV TMJ ankylosis were not included. The improvement in mouth opening was measured after ostectomy, after ipsilateral coronoidectomy, and after contralateral coronoidectomy. The improvements in mouth opening at each stage were analysed using the Student's t-test and Pearson's correlation coefficient. There was a marked improvement in maximal incisal opening (MIO) from 5.7 +/- 4.2mm to 23.7 +/- 5.9 mm after removal of the ankylotic bony mass. MIO was significantly increased after ipsilateral coronoidectomy (31.6 +/- 7.4mm), and after contralateral coronoidectomy, a mean MIO of 39.4 +/- 11.2mm was achieved. At more than 1 year of follow-up, all patients showed improved mouth opening. In conclusion, coronoidectomy plays an important role in improving mouth opening in the treatment of TMJ ankylosis. PMID- 25801012 TI - Effect of the local hemodynamic environment on the de novo development and progression of eccentric coronary atherosclerosis in humans: insights from PREDICTION. AB - BACKGROUND: Eccentric distribution of atheroma has been associated with plaques likely to rupture and cause an acute coronary syndrome, but the factors responsible for the development of eccentricity remain unknown. Endothelial shear stress (ESS) drives plaque formation. We aimed to investigate the role of the local ESS characteristics in the de novo development and progressive worsening of plaque eccentricity in humans. METHODS: Vascular profiling (3-vessel 3D coronary reconstruction by angiography/intravascular ultrasound, and blood flow simulation for ESS computation) was performed in 374 patients at baseline & 6-10 months follow-up. At baseline, we identified (i) disease-free segments (n=2157), and (ii) diseased regions of luminal obstructions (n=408). RESULTS: In disease-free regions, baseline low ESS magnitude (p<0.001), marked ESS circumferential heterogeneity (p=0.001), and their interaction (p=0.026) were associated with an increased probability of de novo eccentric plaque formation at follow-up. In diseased regions, baseline low ESS (odds ratio [OR]: 2.33, p=0.003) and large plaque burden (OR: 2.46, p=0.002) were independent predictors of substantially increasing plaque eccentricity index with worsening lumen encroachment. This combined outcome was more frequent in obstructions with both features vs. all others (33 vs. 12%; p<0.001). The incidence of percutaneous coronary intervention in worsening obstructions with increasing plaque eccentricity was higher (13.3 vs. 4.3%, p=0.011). CONCLUSIONS: The local hemodynamic environment has a critical effect on the development of eccentric coronary plaques at both an early and advanced stage of atherosclerosis. Local ESS assessment could help in predicting sites prone to plaque disruption and acute coronary syndromes in humans. PMID- 25801014 TI - Plasma C20-Sphingolipids predict cardiovascular events independently from conventional cardiovascular risk factors in patients undergoing coronary angiography. AB - AIMS: Sphingolipids are emerging as novel players in the pathogenesis of atherosclerosis and cardiovascular disease. Serine palmitoyltransferase (SPT) catalyzes the first and rate-limiting step in the de novo synthesis of sphingolipids--the condensation of palmitoyl-CoA and L-Serine. In addition to these canonical substrates, SPT can also metabolize other acyl-CoAs and amino acids, thus generating a variety of atypical sphingoid bases. In this study, we investigated the association of these atypical sphingoid bases with the presence of angiographically characterized coronary artery disease (CAD) as well as their ability to predict the incidence of cardiovascular events. METHODS AND RESULTS: 349 subjects, who underwent coronary angiography for the evaluation of established or suspected stable CAD, were enrolled in the study at baseline and followed up for cardiovascular events over a period of 8 years (median 7.7 years). The sphingoid base profile in the extracted plasma sphingolipids were determined by LC/MS after acid-base hydrolysis. Plasma levels of C18SAdiene were found to be significantly lower in CAD patients at baseline, while levels for C16SA, C16SO, C17SO, C18SA, C18SO, and C19SO and 1-deoxy sphingoid bases were not different. In the prospective analysis C20SO significantly predicted cardiovascular events (standardized adjusted HR=1.20, CI 95% [1.03-1.41]; p=0.022) after adjusting for traditional risk factors, the use of lipid-lowering drugs and angiographically-determined CAD at baseline. CONCLUSION: Plasma C20SO levels are independent predictive biomarkers for cardiovascular events, even after adjusting for cardiovascular risk factors including coronary stenosis. PMID- 25801015 TI - Evaluation of thermal comfort, physiological, hematological, and seminal features of buffalo bulls in an artificial insemination station in a tropical environment. AB - This study aimed to assess the variation over time in thermal comfort indices and the behavior of physiological parameters related to thermolysis, blood parameters, and semen in natura of buffalo bulls reared in tropical climate. The study was carried out in an artificial insemination station under a humid tropical climate (Afi according to Koppen). Ten water buffalo bulls (Bubalus bubalis) were used during the 5 months (April to August) of study. The environmental Temperature Humidity Index (THId) and the pen microclimate Temperature Humidity Index (THIp) were calculated. Every 25 days, respiratory rate (RR), heart rate (HR), rectal temperature (RT), and Benezra's thermal comfort index (BTCI) were assessed in the morning and in the afternoon. A blood assay was performed every month, while semen was collected weekly. THIp did not vary over the months (P > 0.05) and was higher in the afternoon than in the morning (77.7 +/- 2.6 versus 81.8 +/- 2.1, P < 0.05). RR, HR, and BTCI significantly increased over the months and were different between the periods of the day (P > 0.05) but within the physiological limits. RT varied between the periods of the day and decreased over the months, being the lowest in August (37.8 +/- 0.7 degrees C), time-impacted hematocrit, mean corpuscular volume, hemoglobin levels, and spermatic gross motility and vigor (P < 0.05). Thus, buffalo bulls reared under a humid tropical climate may have variations in thermal comfort during the hotter periods but are able to efficiently activate thermoregulatory mechanisms and maintain homeothermy, hence preserving their physiological and seminal parameters at normal levels. PMID- 25801013 TI - SKI-II--a sphingosine kinase 1 inhibitor--exacerbates atherosclerosis in low density lipoprotein receptor-deficient (LDL-R-/-) mice on high cholesterol diet. AB - BACKGROUND: Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice. METHODS AND RESULTS: LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-alpha and endothelial adhesion molecules (sICAM-1, sVCAM-1). CONCLUSION: Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia. PMID- 25801016 TI - Treating with liraglutide an obese patient with type 2 diabetes mellitus and hereditary hemochromatosis. PMID- 25801017 TI - Hemophagocytic lymphohistiocytosis in a female patient due to a heterozygous XIAP mutation and skewed X chromosome inactivation. AB - Genetic forms of hemophagocytic lymphohistiocytosis (HLH) are caused by mutations in autosomal recessive genes affecting perforin-dependent cytotoxic function and two X-linked genes affecting distinct cell signaling pathways: SH2D1A and XIAP. HLH caused by mutations in X-linked genes is typically found only in males. Here we report the occurrence of HLH in a female caused by a heterozygous mutation in XIAP. Flow cytometric studies confirmed the absence of XIAP protein expression, while an X chromosome inactivation assay revealed an extreme skewing ratio of 99:1. This finding demonstrates that females are susceptible to X-linked forms of HLH through skewed X chromosome inactivation. PMID- 25801018 TI - Yes, we need PhD immunologists! AB - Constrained research funding prompts some to advocate training fewer PhDs. However, PhD immunologists are critically needed for future health challenges. Rather than discouraging promising young scientists from pursuing doctorates, we should ensure that such training is relevant to many different career possibilities to which PhD immunologists can make valuable contributions. PMID- 25801019 TI - Associations Between Pain, Current Tobacco Smoking, Depression, and Fibromyalgia Status Among Treatment-Seeking Chronic Pain Patients. AB - OBJECTIVE: As smoking impacts physiological pathways in the central nervous system, it is important to consider the association between smoking and fibromyalgia, a pain condition caused predominantly by central nervous system dysfunction. The objectives were to assess the prevalence of current smoking among treatment-seeking chronic pain patients with (FM+) and without (FM-) a fibromyalgia-like phenotype; test the individual and combined influence of smoking and fibromyalgia on pain severity and interference; and examine depression as a mediator of these processes. METHODS: Questionnaire data from 1566 patients evaluated for a range of conditions at an outpatient pain clinic were used. The 2011 Survey Criteria for Fibromyalgia were used to assess the presence of symptoms associated with fibromyalgia. RESULTS: Current smoking was reported by 38.7% of FM+ patients compared to 24.7% of FM- patients. FM+ smokers reported higher pain and greater interference compared to FM+ nonsmokers, FM- smokers, and FM- nonsmokers. There was no interaction between smoking and fibromyalgia. Significant indirect effects of fibromyalgia and smoking via greater depression were observed for pain severity and interference. CONCLUSIONS: Current smoking and positive fibromyalgia status were associated with greater pain and impairment among chronic pain patients, possibly as a function of depression. Although FM+ smokers report the most negative clinical symptomatology (i.e., high pain, greater interference) smoking does not appear to have a unique association with pain or functioning in FM+ patients, rather the effect is additive. The 38.7% smoking rate in FM+ patients is high, suggesting FM+ smokers present a significant clinical challenge. PMID- 25801021 TI - Cilia disassembly with two distinct phases of regulation. AB - Cilia and flagella are dynamic organelles that undergo assembly and disassembly during each cell cycle. They are structurally polarized, and the mechanisms by which these organelles are disassembled are incompletely understood. Here, we show that flagellar resorption occurs in two distinct phases of length-dependent regulation. A CDK-like kinase, encoded by flagellar shortening 1 (FLS1), is required for the normal rate of disassembly of only the distal part of the flagellum. Mechanistically, loss of function of FLS1 prevents the initial phosphorylation of CALK, an aurora-like kinase that regulates flagellar shortening, and induces the earlier onset of the inhibitory phosphorylation of CrKinesin13, a microtubule depolymerase, which is involved in flagellar shortening. In addition, CALK and CrKinesin13 phosphorylation can also be induced by the process of flagellar shortening itself, demonstrating an example of cilia generated signaling not requiring the binding of a ligand or the stimulation of an ion channel. PMID- 25801020 TI - Engraftment of embryonic stem cells and differentiated progeny by host conditioning with total lymphoid irradiation and regulatory T cells. AB - Embryonic stem cells (ESCs) hold promise for the treatment of many medical conditions; however, their utility is limited by immune rejection. The objective of our study is to establish tolerance or promote engraftment of transplanted ESCs as well as mature cell populations derived from ESCs. Luciferase (luc(+)) expressing ESCs were utilized to monitor the survival of the ESCs and differentiated progeny in living recipients. Allogeneic recipients conditioned with fractioned total lymphoid irradiation (TLI) and anti-thymocyte serum (ATS) or TLI plus regulatory T cells (T(reg)) promoted engraftment of ESC allografts after transplantation. Following these treatments, the engraftment of transplanted terminally differentiated endothelial cells derived from ESCs was also significantly enhanced. Our findings provide clinically translatable strategies of inducing tolerance to adoptively transferred ESCs for cell replacement therapy of medical disorders. PMID- 25801022 TI - Spatiotemporal sequestration of miR165/166 by Arabidopsis Argonaute10 promotes shoot apical meristem maintenance. AB - Arabidopsis Argonaute10 (AGO10) specifically sequesters miR165 and miR166 and antagonizes their activity, thus regulating shoot apical meristem (SAM) development. However, where and when this sequestration acts is currently unclear. We show here that AGO10 represses miR165/166 activity in the embryo proper during early embryogenesis, through the apical and central regions of mature embryos, and eventually in the entire adaxial domain and vasculature of the cotyledons and leaf primordia. These locations are essentially identical to regions expressing PHABULOSA and REVOLUTA, mRNA targets of miR165/166. The Arabidopsis genome contains nine MIR165/166 genes. Sequestration of miR165/166 by the MIR165b, MIR166a, MIR166b, and MIR166g promoters efficiently rescues the SAM defect in ago10 mutants. Comparison of the expression patterns of AGO10 and the four MIR165/166 members suggests that AGO10 quenches the non-cell-autonomous activity of any miR165/166 that moves into AGO10-expressing niches. Thus, this study provides insight into how the spatiotemporal regulation of AGO10-miR165/166 activity affects SAM development. PMID- 25801023 TI - Activation of necroptosis in multiple sclerosis. AB - Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-alpha and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS. PMID- 25801025 TI - Manipulation of the quorum sensing signal AI-2 affects the antibiotic-treated gut microbiota. AB - The mammalian gut microbiota harbors a diverse ecosystem where hundreds of bacterial species interact with each other and their host. Given that bacteria use signals to communicate and regulate group behaviors (quorum sensing), we asked whether such communication between different commensal species can influence the interactions occurring in this environment. We engineered the enteric bacterium, Escherichia coli, to manipulate the levels of the interspecies quorum sensing signal, autoinducer-2 (AI-2), in the mouse intestine and investigated the effect upon antibiotic-induced gut microbiota dysbiosis. E. coli that increased intestinal AI-2 levels altered the composition of the antibiotic treated gut microbiota, favoring the expansion of the Firmicutes phylum. This significantly increased the Firmicutes/Bacteroidetes ratio, to oppose the strong effect of the antibiotic, which had almost cleared the Firmicutes. This demonstrates that AI-2 levels influence the abundance of the major phyla of the gut microbiota, the balance of which is known to influence human health. PMID- 25801024 TI - Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. AB - RIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-alpha) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective "hybrid" RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies. PMID- 25801026 TI - Deletion of macrophage Vitamin D receptor promotes insulin resistance and monocyte cholesterol transport to accelerate atherosclerosis in mice. AB - Intense effort has been devoted to understanding predisposition to chronic systemic inflammation because it contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver as well as increasing cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol into the atherosclerotic plaque and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp PPARgamma signaling, and induction of the scavenger receptors CD36 and SR-A1. Bone marrow transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet induced insulin resistance and atherosclerosis in mice. PMID- 25801027 TI - Targeting repulsive guidance molecule A to promote regeneration and neuroprotection in multiple sclerosis. AB - Repulsive guidance molecule A (RGMa) is a potent inhibitor of neuronal regeneration and a regulator of cell death, and it plays a role in multiple sclerosis (MS). In autopsy material from progressive MS patients, RGMa was found in active and chronic lesions, as well as in normal-appearing gray and white matter, and was expressed by cellular meningeal infiltrates. Levels of soluble RGMa in the cerebrospinal fluid were decreased in progressive MS patients successfully treated with intrathecal corticosteroid triamcinolone acetonide (TCA), showing functional improvements. In vitro, RGMa monoclonal antibodies (mAbs) reversed RGMa-mediated neurite outgrowth inhibition and chemorepulsion. In animal models of CNS damage and MS, RGMa antibody stimulated regeneration and remyelination of damaged nerve fibers, accelerated functional recovery, and protected the retinal nerve fiber layer as measured by clinically relevant optic coherence tomography. These data suggest that targeting RGMa is a promising strategy to improve functional recovery in MS patients. PMID- 25801028 TI - The 3D organization of chromatin explains evolutionary fragile genomic regions. AB - Genomic rearrangements are a major source of evolutionary divergence in eukaryotic genomes, a cause of genetic diseases and a hallmark of tumor cell progression, yet the mechanisms underlying their occurrence and evolutionary fixation are poorly understood. Statistical associations between breakpoints and specific genomic features suggest that genomes may contain elusive "fragile regions" with a higher propensity for breakage. Here, we use ancestral genome reconstructions to demonstrate a near-perfect correlation between gene density and evolutionary rearrangement breakpoints. Simulations based on functional features in the human genome show that this pattern is best explained as the outcome of DNA breaks that occur in open chromatin regions coming into 3D contact in the nucleus. Our model explains how rearrangements reorganize the order of genes in an evolutionary neutral fashion and provides a basis for understanding the susceptibility of "fragile regions" to breakage. PMID- 25801029 TI - Cell-autonomous regulation of Mu-opioid receptor recycling by substance P. AB - How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropeptide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post endocytic recycling of the mu-opioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeostatic interaction between the pain and analgesic systems. PMID- 25801030 TI - Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage. AB - MyoD and NeuroD2, master regulators of myogenesis and neurogenesis, bind to a "shared" E-box sequence (CAGCTG) and a "private" sequence (CAGGTG or CAGATG, respectively). To determine whether private-site recognition is sufficient to confer lineage specification, we generated a MyoD mutant with the DNA-binding specificity of NeuroD2. This chimeric mutant gained binding to NeuroD2 private sites but maintained binding to a subset of MyoD-specific sites, activating part of both the muscle and neuronal programs. Sequence analysis revealed an enrichment for PBX/MEIS motifs at the subset of MyoD-specific sites bound by the chimera, and point mutations that prevent MyoD interaction with PBX/MEIS converted the chimera to a pure neurogenic factor. Therefore, redirecting MyoD binding from MyoD private sites to NeuroD2 private sites, despite preserved binding to the MyoD/NeuroD2 shared sites, is sufficient to change MyoD from a master regulator of myogenesis to a master regulator of neurogenesis. PMID- 25801031 TI - Origins and impacts of new mammalian exons. AB - Mammalian genes are composed of exons, but the evolutionary origins and functions of new internal exons are poorly understood. Here, we analyzed patterns of exon gain using deep cDNA sequencing data from five mammals and one bird, identifying thousands of species- and lineage-specific exons. Most new exons derived from unique rather than repetitive intronic sequence. Unlike exons conserved across mammals, species-specific internal exons were mostly located in 5' UTRs and alternatively spliced. They were associated with upstream intronic deletions, increased nucleosome occupancy, and RNA polymerase II pausing. Genes containing new internal exons had increased gene expression, but only in tissues in which the exon was included. Increased expression correlated with the level of exon inclusion, promoter proximity, and signatures of cotranscriptional splicing. Altogether, these findings suggest that increased splicing at the 5' ends of genes enhances expression and that changes in 5' end splicing alter gene expression between tissues and between species. PMID- 25801032 TI - FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-null T ALL cells. AB - Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%-25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo. PMID- 25801033 TI - Dynamic recruitment of functionally distinct Swi/Snf chromatin remodeling complexes modulates Pdx1 activity in islet beta cells. AB - Pdx1 is a transcription factor of fundamental importance to pancreas formation and adult islet beta cell function. However, little is known about the positive- and negative-acting coregulators recruited to mediate transcriptional control. Here, we isolated numerous Pdx1-interacting factors possessing a wide range of cellular functions linked with this protein, including, but not limited to, coregulators associated with transcriptional activation and repression, DNA damage response, and DNA replication. Because chromatin remodeling activities are essential to developmental lineage decisions and adult cell function, our analysis focused on investigating the influence of the Swi/Snf chromatin remodeler on Pdx1 action. The two mutually exclusive and indispensable Swi/Snf core ATPase subunits, Brg1 and Brm, distinctly affected target gene expression in beta cells. Furthermore, physiological and pathophysiological conditions dynamically regulated Pdx1 binding to these Swi/Snf complexes in vivo. We discuss how context-dependent recruitment of coregulatory complexes by Pdx1 could impact pancreas cell development and adult islet beta cell activity. PMID- 25801034 TI - UHRF1 is a sensor for DNA interstrand crosslinks and recruits FANCD2 to initiate the Fanconi anemia pathway. AB - The Fanconi anemia (FA) pathway is critical for the cellular response to toxic DNA interstrand crosslinks (ICLs). Using a biochemical purification strategy, we identified UHRF1 as a protein that specifically interacts with ICLs in vitro and in vivo. Reduction of cellular levels of UHRF1 by RNAi attenuates the FA pathway and sensitizes cells to mitomycin C. Knockdown cells display a drastic reduction in FANCD2 foci formation. Using live-cell imaging, we observe that UHRF1 is rapidly recruited to chromatin in response to DNA crosslinking agents and that this recruitment both precedes and is required for the recruitment of FANCD2 to ICLs. Based on these results, we describe a mechanism of ICL sensing and propose that UHRF1 is a critical factor that binds to ICLs. In turn, this binding is necessary for the subsequent recruitment of FANCD2, which allows the DNA repair process to initiate. PMID- 25801036 TI - Immunotherapeutic approaches for cancer therapy: An updated review. AB - In spite of specific immune effector mechanisms raised against tumor cells, there are mechanisms employed by the tumor cells to keep them away from immune recognition and elimination; some of these mechanisms have been identified, while others are still poorly understood. Manipulation or augmentation of specific antitumor immune responses are now the preferred approaches for treatment of malignancies, and traditional therapeutic approaches are being replaced by the use of agents which potentiate immune effector mechanisms, broadly called "immunotherapy". Cancer immunotherapy is generally classified into two main classes including active and passive methods. Interventions to augment the immune system of the patient, for example, vaccination or adjuvant therapy, actively promote antitumor effector mechanisms to improve cancer elimination. On the other hand, administration of specific monoclonal antibodies (mAbs) against different tumor antigens and adoptive transfer of genetically-modified specific T cells are currently the most rapidly developing approaches for cancer targeted therapy. In this review, we will discuss the different modalities for active and passive immunotherapy for cancer. PMID- 25801035 TI - NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. AB - Innate lymphoid cells (ILCs) are a family of effectors that originate from a common innate lymphoid cell progenitor. However, the transcriptional program that sets the identity of the ILC lineage remains elusive. Here, we show that NFIL3 is a critical regulator of the common helper-like innate lymphoid cell progenitor (CHILP). Cell-intrinsic Nfil3 ablation led to variably impaired development of fetal and adult ILC subsets. Conditional gene targeting demonstrated that NFIL3 exerted its function prior to ILC subset commitment. Accordingly, NFIL3 ablation resulted in loss of ID2(+) CHILP and PLZF(+) ILC progenitors. Nfil3 expression in lymphoid progenitors was under the control of the mesenchyme-derived hematopoietin IL-7, and NFIL3 exerted its function via direct Id2 regulation in the CHILP. Moreover, ectopic Id2 expression in Nfil3-null precursors rescued defective ILC lineage development in vivo. Our data establish NFIL3 as a key regulator of common helper-like ILC progenitors as they emerge during early lymphopoiesis. PMID- 25801037 TI - Antiapoptotic Bcl-2 protein as a potential target for cancer therapy: A mini review. AB - Bcl-2, an antiapoptotic protein, is considered as a potential target in cancer treatment since its oncogenic potential has been proven and is well documented. Antisense technology and RNA interference (RNAi) have been used to reduce the expression of the Bcl-2 gene in many types of cancer cells and are effective as adjuvant therapy along with the chemotherapeutic agents. The lack of appropriate delivery systems is considered to be the main hurdle associated with the RNAi. In this review, we discuss the antiapoptotic Bcl-2 protein, its oncogenic potential, and various approaches utilized to target Bcl-2 including suitable delivery systems employed for successful delivery of siRNA. PMID- 25801038 TI - Synthesis of multifunctional nanocomposites and their application in imaging and targeting tumor cells in vitro. AB - The labeling of cells with nanomaterials for tumor detection is a very important part of various biomedical applications. In this study, multilayer nanocomposites were synthesized to achieve the multiple functions of fluorescence, magnetism, and bioaffinity. Firstly, superparamagnetic Fe3O4 nanoparticles were prepared as a magnetic core. Then, fluorescein isothiocyanate (FITC) was covalently linked to the surface of the silica-coated Fe3O4 core (designated FMNPs). Finally, bovine serum albumin (BSA) was conjugated onto the FMNPs (designated FMNPs-BSA). We also evaluated the feasibility and efficiency of labeling the human liver cancer cell line SMMC-7721 (SMMC-7721) with nanocomposites. SEM, hysteresis loop, EDS, FTIR, fluorescence spectra, and fluorescence microscopy were used to determine the physicochemical properties of nanocomposites. Fluorescence microscopy, SEM-EDS, and TEM were used to determine fluorescence labeling, absorption, and uptake respectively. The results showed that the nanocomposites obtained exhibited fine superparamagnetism, strong fluorescence, and good biological affinity. We succeeded in using the new multilayer nanocomposites to label cells, which had properties of magnetic targeting and fluorescent tracing. PMID- 25801039 TI - Effects of Wharton's jelly cells of the human umbilical cord on acute spinal cord injury in rats, and expression of interleukin-1beta and nerve growth factor in spinal cord tissues. AB - To study the effects of Wharton's jelly cells (WJCs) on acute spinal cord injury (SCI), 81 rats were divided into a sham surgery group, a model group, and a WJC transplantation group (n = 27). Motor functions of the model and WJC transplantation groups were partially recovered, and the recovery was better in the latter group. The WJC transplantation group had integral spinal cord tissues. Compared with the model group, the WJC transplantation group expressed significantly less interleukin-1beta (IL-1beta) and more nerve growth factor (NGF) (P < 0.05). WJC transplantation changed the microenvironment of the SCI site, inhibited IL-1beta expression, increased NGF expression, promoted the recovery of neurological function, and relieved secondary SCI. PMID- 25801040 TI - Silver or gold deposition onto magnetite nanoparticles by using plant extracts as reducing and stabilizing agents. AB - In this paper, we describe an environmentally friendly procedure to produce silver (Ag) or gold (Au)-deposited magnetite nanoparticles by using plant extracts (Ligustrum vulgare) as reducing and stabilizing agents. Firstly, magnetite nanoparticles (~6 nm) with superparamagnetic properties - SPIONs - were synthesized by co-precipitation of Fe(+ 2) and Fe(+ 3) ions. Color changes indicated the differing amounts of Au and Ag ions reduced and deposited on to the SPIONs when the plant extracts were used. UV-vis and transmission electron microscope (TEM) with energy dispersive X-ray (EDX) apparatus confirmed the metallic deposition. Magnetic saturation decreased when the amount of the metallic deposition increased, which was measured by vibrating sample magnetometry (VSM). Due to the molecules coming into contact with - and even remaining on - the surface of the nanoparticles after aggressive washing procedures, the Ag/Au-deposited SPIONs were stable, and almost no agglomeration was observed for months. Fourier Transform Infrared (FTIR) spectra depicted that functional groups such as carboxylic and ketone groups, which are most probably responsible for the reduction and stabilization of Ag/Au- carrying magnetite nanoparticles, originated from the plant extract. The proposed route was facile, viable, and reproducible, and it should be stressed that nanoparticles do contain only safe biomolecules as stabilizing agents on their surfaces. PMID- 25801041 TI - An increased risk of non-Hodgkin lymphoma and chronic lymphocytic leukemia in US patients with Merkel cell carcinoma versus Australian patients: A clinical clue to a different mechanism of pathogenesis? AB - The US and Queensland populations both demonstrate an increased risk of secondary malignancies following the diagnosis of Merkel cell carcinoma (MCC). A recent Queensland study failed to demonstrate a significantly increased risk of developing non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukaemia (CLL) in these patients. In contrast, using the US Surveillance, Epidemiology, and End Results database, we demonstrate there is an increased risk in CLL and NHL following the diagnosis of MCC in the USA. We hypothesise that this difference may be a result of a differing pathogenesis. PMID- 25801043 TI - Peroneus Longus Tendoscopy at the Sole: A Cadaveric Study. AB - PURPOSE: The aim of this study was to investigate the safety of tendoscopy of the peroneus longus (PL) at the sole in a cadaveric model. METHODS: Twelve fresh frozen foot and ankle specimens were used. The locations of the plantar medial and plantar lateral portals were studied. The relationships of the medial and lateral plantar nerves to the tendon sheath of the PL at the sole were also studied. RESULTS: The plantar lateral portal was located on average 11 mm (6 to 16 mm) proximal and 9 mm (6 to 15 mm) plantar to the fifth metatarsal styloid. The plantar medial portal was located on average 1 mm (12 mm proximal to the joint to 7 mm distal to the joint) proximal to the first tarsometatarsal joint. The lateral plantar nerve touched the PLT sheath in 8 specimens. The nerve was separated from the tendon sheath by a thin layer of muscle in 4 specimens. The medial plantar nerve was separated from the tendon sheath of the PL by the flexor digitorum longus and flexor hallucis longus tendons in all specimens. CONCLUSIONS: Tendoscopy of the PL at the sole of the foot is described; however, the lateral plantar nerve can be at risk and the tendoscopy should be performed with caution. CLINICAL RELEVANCE: This cadaveric study provides the anatomic basis of the PL tendoscopy of the sole. PMID- 25801042 TI - Portable microfluidic integrated plasmonic platform for pathogen detection. AB - Timely detection of infectious agents is critical in early diagnosis and treatment of infectious diseases. Conventional pathogen detection methods, such as enzyme linked immunosorbent assay (ELISA), culturing or polymerase chain reaction (PCR) require long assay times, and complex and expensive instruments, which are not adaptable to point-of-care (POC) needs at resource-constrained as well as primary care settings. Therefore, there is an unmet need to develop simple, rapid, and accurate methods for detection of pathogens at the POC. Here, we present a portable, multiplex, inexpensive microfluidic-integrated surface plasmon resonance (SPR) platform that detects and quantifies bacteria, i.e., Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) rapidly. The platform presented reliable capture and detection of E. coli at concentrations ranging from ~10(5) to 3.2 * 10(7) CFUs/mL in phosphate buffered saline (PBS) and peritoneal dialysis (PD) fluid. The multiplexing and specificity capability of the platform was also tested with S. aureus samples. The presented platform technology could potentially be applicable to capture and detect other pathogens at the POC and primary care settings. PMID- 25801044 TI - Arthroscopic Treatment for Anterior Ankle Impingement: A Systematic Review of the Current Literature. AB - PURPOSE: To provide a comprehensive overview of the clinical outcomes of arthroscopic procedures used as a treatment strategy for anterior ankle impingement. METHODS: A systematic literature search of the Medline, Embase (Classic), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases was performed. Studies that met the following inclusion criteria were reviewed: studies reporting outcomes of arthroscopic treatment for anterior ankle impingement; studies reporting on more than 20 patients; a study population with a minimum age of 18 years; and studies in the English, Dutch, German, Italian, or Spanish language. Two reviewers independently performed data extraction. Extracted data consisted of population characteristics, in addition to both primary and secondary outcome measures. The Downs and Black scale was used to assess the methodologic quality of randomized and nonrandomized studies included in this review. RESULTS: Twenty articles were included in this systematic review. Overall, good results were found for arthroscopic treatment in patients with anterior ankle impingement. In the studies that reported patient satisfaction rates, high percentages of good to excellent satisfaction were described (74% to 100%). The percentages of patients who would undergo the same procedure again under the same circumstances were also high (94.3% to 97.5%). Complication rates were low (4.6%), particularly with respect to major complications (1.1%). The high heterogeneity of the included studies made it impossible to compare the results of the studies, including between anterolateral impingement and anteromedial impingement. CONCLUSIONS: Arthroscopic treatment for anterior ankle impingement appears to provide good outcomes with respect to patient satisfaction and low complication rates. However, on the basis of the findings of this study, no conclusion can be made in terms of the effect of the type of impingement or additional pathology on clinical outcome. LEVEL OF EVIDENCE: Level IV, systematic review of Level II and IV studies. PMID- 25801045 TI - Quadrupled Hamstring Graft Strength as a Function of Clinical Sizing. AB - PURPOSE: This study sought to compare the strength of quadrupled hamstring tendon (QHT) grafts of 6 to 9.5 mm in clinical diameter with that of 10-mm bone-patellar tendon-bone (BPTB) grafts. METHODS: Twenty cadaveric semitendinosus and gracilis tendons were combined into QHT grafts. These were sized using a standard graft sizing device and an area micrometer, yielding grafts ranging from 6 to 9.5 mm in diameter. The grafts were tested to failure. Five 10-mm BPTB grafts were also sized and tested. RESULTS: Clinical sizing did predict the strength of the graft but not profoundly. As a material alone, without consideration of fixation in bone tunnels, QHT grafts were stronger than BPTB grafts. Graft strength decreased with size, but a linear relation between strength and diameter (r(2) = 0.715, P < .001) was found to be as good as the expected quadratic fit (r(2) = 0.709). Compared with BPTB grafts, even the smallest QHT grafts (diameter <6.5 mm) were still significantly stronger than 10-mm BPTB grafts (P = .004). The elastic moduli of the QHT and BPTB grafts were 761 +/- 187 MPa and 615 +/- 403 MPa, respectively; elongations at failure were 12.0% +/- 2.0% and 7.5% +/- 1.6%, respectively; and failure stresses were 105 +/- 18 MPa and 50 +/- 14 MPa, respectively. CONCLUSIONS: This work shows that a clinical size of QHT grafts of 6 mm in diameter is not a concern regarding the strength itself. For a possible lower-end prediction of acceptable size, assuming that a gracilis-semitendinosus graft would have only the stress of the weakest measured QHT graft of 88 MPa, a graft of 5.5 mm in diameter would suffice, having more strength in newtons than the average patellar tendon. CLINICAL RELEVANCE: Clinically sized QHT grafts have a higher failure strength than 10-mm patellar tendon grafts. Therefore the strength of the graft cannot account for the higher clinical failure rates of smaller hamstring grafts in active patients in clinical studies. PMID- 25801046 TI - Smoking Predisposes to Rotator Cuff Pathology and Shoulder Dysfunction: A Systematic Review. AB - PURPOSE: To investigate the association of smoking with rotator cuff (RTC) disease and shoulder dysfunction, defined as poor scores on shoulder rating scales. METHODS: A systematic review was performed using a search strategy based on "shoulder AND [smoke OR smoking OR nicotine OR tobacco]." English-language clinical or basic science studies testing the association of smoking and shoulder dysfunction on shoulder rating scales or disease of the soft tissue of the shoulder were included. Level V evidence studies and articles reporting only on surgery outcomes, subjective symptoms, adhesive capsulitis, or presence of fracture or oncologic mass were excluded. RESULTS: Thirteen studies were included, comprising a total of 16,172 patients, of whom 6,081 were smokers. All 4 clinical studies addressing the association between smoking and patient reported shoulder symptoms and dysfunction in terms of poor scores on shoulder rating scales (i.e., Simple Shoulder Test; University of California, Los Angeles shoulder scale; and self-reported surveys) confirmed this correlation with 6,678 patients, of whom 1,723 were smokers. Two of four studies documenting provider reported RTC disease comprised 8,461 patients, of whom 4,082 were smokers, and found a time- and dose-dependent relation of smoking with RTC tears and a correlation of smoking with impingement syndrome. Smoking was also reported in 4 other articles to be associated with the prevalence of larger RTC tears or tears with pronounced degenerative changes in 1,033 patients, of whom 276 were smokers, and may accelerate RTC degeneration, which could result in tears at a younger age. In addition, 1 basic science study showed that nicotine increased stiffness of the supraspinatus tendon in a rat model. CONCLUSIONS: Smoking is associated with RTC tears, shoulder dysfunction, and shoulder symptoms. Smoking may also accelerate RTC degeneration and increase the prevalence of larger RTC tears. These correlations suggest that smoking may increase the risk of symptomatic RTC disease, which could consequently increase the need for surgical interventions. LEVEL OF EVIDENCE: Level IV, systematic review of Level II through IV studies. PMID- 25801047 TI - Clinical Outcomes After Anatomic Double-Bundle Anterior Cruciate Ligament Reconstruction: Comparison of Extreme Knee Hyperextension and Normal to Mild Knee Hyperextension. AB - PURPOSE: The aim of this study was to compare postoperative outcomes after anatomic double-bundle anterior cruciate ligament reconstruction (ACLR) in extreme knee hyperextension versus normal to mild knee hyperextension. METHODS: For 100 patients who underwent anatomic double-bundle ACLR using semitendinosus tendon, we evaluated the side-to-side difference (SSD) in anterior tibial translation (measured on stress radiographs) and rotational stability (assessed by the pivot-shift test) 2 years after surgery. Loss of extension (LOE) was evaluated on lateral radiographs of both knees in full extension, and graft integrity was assessed during second-look arthroscopy 1 to 2 years after surgery. In accordance with the Beighton and Honan criteria, patients with an extension angle less than or equal to 10 degrees in the contralateral uninjured knee composed the group with 10 degrees or less hyperextension (N group), and those with an extension angle of greater than 10 degrees composed the group with more than 10 degrees hyperextension (H group). Postoperative results were compared between these groups. RESULTS: Mean extension angles in the N and H groups were 5.8 degrees +/- 2.9 degrees and 14.7 degrees +/- 3.0 degrees , respectively. The mean SSD in anterior translation was 2.2 +/- 2.9 mm for the N group and 2.8 +/- 2.9 mm for the H group, with no significant difference. The positive ratios on the pivot-shift test were not significantly different between the groups. Mean LOE in the N and H groups was -0.7 degrees +/- 3.7 degrees and 1.3 degrees +/- 3.3 degrees , respectively, with a significant difference (P = .007). During second-look arthroscopy, 6 of 58 knees in the N group and 13 of 42 knees in the H group had superficial graft laceration of the anteromedial bundle graft, with a significant difference (P = .01) seen between groups. CONCLUSIONS: Anatomic double-bundle ACLR for extreme knee hyperextension may attain the same postoperative anterior and rotational stability as seen in knees with normal to mild hyperextension. However, it increased superficial graft laceration. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25801048 TI - Protective effect of molecular hydrogen against oxidative stress caused by peroxynitrite derived from nitric oxide in rat retina. AB - BACKGROUND: Oxidative and nitrative processes have an important role in the pathogenesis of glaucomatous neurodegeneration. Oxidative stress occurs when cellular production of reactive oxygen species outweighs the protective capacity of antioxidant defences. Reactive oxygen species are generated as by-products of cellular metabolism, primarily in the mitochondria. Herein, we present a novel investigation of the effects of molecular hydrogen (H2 ) on retinal cells exposed to oxidative stress. METHODS: We cultured adult rat retinal tissues in an organotypic culture system with a nitric oxide donor, S-nitroso-N acetylpenicillamine, in the presence or absence of H2 . Loss of mitochondrial membrane potential and apoptosis of retinal cells were analysed using a MitoTMRE detection kit and TdT-mediated dUTP nick end labeling (TUNEL) assay, respectively. Tyrosine nitration levels and oxidative stress damage in the retina were evaluated using immunohistochemical staining. Retinal damage was quantified by measuring the numbers of cells in the ganglion cell and inner nuclear layers and the thickness of the retina. RESULTS: H2 suppressed loss of mitochondrial membrane potential and apoptosis in retinal cells. Moreover, H2 decreased the tyrosine nitration level and suppressed oxidative stress damage in retinal cells. S-nitroso-N-acetylpenicillamine treatment decreased the cell numbers in the ganglion cell layer and inner nuclear layer, but the presence of H2 inhibited this reduction. These findings suggest that H2 has a neuroprotective effect against retinal cell oxidative damage, presumably by scavenging peroxynitrite. CONCLUSIONS: H2 reduces cellular peroxynitrite, a highly toxic reactive nitrogen species. Thus, H2 may be an effective and novel clinical tool for treating glaucoma and other oxidative stress-related diseases. PMID- 25801050 TI - An IPTG-inducible derivative of the fission yeast nmt promoter. AB - We here describe an IPTG-inducible system that reveals that the lac repressor alone can function as a potent transmodulator to regulate gene expression in the fission yeast, Schizosaccharomyces pombe. This expression system is a derivative of the Sz. pombe nmt promoter, which normally is strongly repressed by thiamine. With appropriate positioning of a lac operator site (lacO) downstream of the TATA box, we show that gene expression from a chimeric nmt::lacO promoter can be regulated by the lac repressor up to two orders of magnitude in response to IPTG. The chimeric nmt::lacO promoter is rapidly induced and when GFP is used as a reporter; almost full induction is achieved 40 min after the addition of IPTG. Like the wild-type nmt promoter, the chimeric nmt::lacO is repressed by thiamine. This allows expression in a short and defined window, e.g. the S-phase of a synchronized cell population, by first adding IPTG to turn on expression, followed by addition of thiamine to switch off expression. PMID- 25801052 TI - Reply to Jovo Bogdanovic and Vuk Sekulic's Letter to the Editor re: Firas Abdollah, Giorgio Gandaglia, Nazareno Suardi, et al. More Extensive Pelvic Lymph Node Dissection Improves Survival in Patients with Node-positive Prostate Cancer. Eur Urol 2015;67:212-9. PMID- 25801051 TI - Re: Firas Abdollah, Giorgio Gandaglia, Nazareno Suardi, et al. More Extensive Pelvic Lymph Node Dissection Improves Survival in Patients with Node-positive Prostate Cancer. Eur Urol 2015;67:212-9. PMID- 25801053 TI - NAD in RNA: unconventional headgear. AB - Although widely assumed to bear a 5'-terminal triphosphate or monophosphate, recent evidence suggests that the 5' end of bacterial RNA can sometimes bear a modification reminiscent of a eukaryotic cap. A new study has now identified Escherichia coli RNAs that begin with a noncanonical cap resembling the redox cofactor nicotinamide adenine dinucleotide (NAD), as well as a cellular enzyme that can remove it. The biological function of such caps remains to be determined. PMID- 25801054 TI - Parametric excitation of multiple resonant radiations from localized wavepackets. AB - Fundamental physical phenomena such as laser-induced ionization, driven quantum tunneling, Faraday waves, Bogoliubov quasiparticle excitations, and the control of new states of matter rely on time-periodic driving of the system. A remarkable property of such driving is that it can induce the localized (bound) states to resonantly couple to the continuum. Therefore experiments that allow for enlightening and controlling the mechanisms underlying such coupling are of paramount importance. We implement such an experiment in a special optical fiber characterized by a dispersion oscillating along the propagation coordinate, which mimics "time". The quasi-momentum associated with such periodic perturbation is responsible for the efficient coupling of energy from the localized wave-packets (solitons in anomalous dispersion and shock fronts in normal dispersion) sustained by the fiber nonlinearity, into free-running linear dispersive waves (continuum) at multiple resonant frequencies. Remarkably, the observed resonances can be explained by means of a unified approach, regardless of the fact that the localized state is a soliton-like pulse or a shock front. PMID- 25801055 TI - Decoding liver injury: A regulatory role for histone modifications. AB - As a primary metabolic, endocrine, immune-regulatory, and detoxification organ in the human body, the liver is constantly exposed to various stressors. Nutritional, humoral, viral, and/or chemical challenges act either singularly or combinatorially to inflict injuries on the liver. In a complex process of fencing off these injurious signals the liver undergoes profound morphological and functional alterations paralleling a shift in cellular transcriptome. The epigenetic machinery, including histone/DNA modifying enzymes, chromatin remodeling proteins, and non-coding regulatory RNAs, plays an important role in liver injury programming transcriptional events, a clear understanding of which holds the key to devising effective interventional solutions. Here, we summarize recent advances in the studies on epigenetic regulation of liver injury focusing on the role of histone modifications. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 25801056 TI - Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1alpha/Stra13 pathway. AB - 1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1alpha/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1alpha or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1alpha/Stra13 (DEC1) pathway. PMID- 25801057 TI - Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol and dextromethorphan. AB - 1. Although the New World non-human primate, the common marmoset (Callithrix jacchus), is a potentially useful animal model, comprehensive understanding of drug metabolizing enzymes is insufficient. 2. A cDNA encoding a novel cytochrome P450 (P450) 2D8 was identified in marmosets. The amino acid sequence deduced from P450 2D8 cDNA showed a high sequence identity (83-86%) with other primate P450 2Ds. Phylogenetic analysis showed that marmoset P450 2D8 was closely clustered with human P450 2D6, unlike P450 2Ds of miniature pig, dog, rabbit, guinea pig, mouse or rat. 3. Marmoset P450 2D8 mRNA was predominantly expressed in the liver and small intestine among the tissues types analyzed, whereas marmoset P450 2D6 mRNA was expressed predominantly in the liver where P450 2D protein was detected by immunoblotting. 4. By metabolic assays using marmoset P450 2D8 protein heterologously expressed in Escherichia coli, although P450 2D8 exhibits lower catalytic efficiency compared to marmoset and human P450 2D6 enzymes, P450 2D8 mediated O-demethylations of metoprolol and dextromethorphan and bufuralol 1' hydroxylation. 5. These results suggest that marmoset P450 2D8 (also expressed in the extrahepatic tissues) has potential roles in drug metabolism in a similar manner to those of human and marmoset P450 2D6. PMID- 25801058 TI - Effects of four traditional Chinese medicines on the pharmacokinetics of simvastatin. AB - 1. Concomitant traditional Chinese medicines (TCMs) could be the reason for relative poor efficacy of statins in dyslipidemia patients in China. 2. An open label, randomized, 5-period crossover study in healthy Chinese was designed to evaluate the pharmacokinetic interaction and tolerability of multiple doses of certain TCMs on a single dose of simvastatin. In each period, subjects received one of five treatments. In Treatment A, subjects received a single dose of 20 mg simvastatin. In Treatment B, C, D or E, subjects received Tong Xin Luo, Nao Xin Tong, Guan Mai Ning or Yin Xing Ye for 7 days and a single dose of 20 mg simvastatin on Day 7. The washout period was 7 days. 3. The 97.5% confidence interval of the AUC0-48 h geometric mean ratio of simvastatin acid and simvastatin for simvastatin given after multiple oral doses of one of the TCMs versus simvastatin given alone were fully contained within the prespecified bounds of (0.50, 2.00). 4. Exposures to simvastatin acid and simvastatin following a single dose of simvastatin alone were similar to those following coadministration of a single dose of simvastatin with multiple doses of each of the TCM preparations tested. Simvastatin and these TCMs were well tolerated. PMID- 25801059 TI - Characterization of the comparative drug binding to intra- (liver fatty acid binding protein) and extra- (human serum albumin) cellular proteins. AB - 1. This study compared the extent, affinity, and kinetics of drug binding to human serum albumin (HSA) and liver fatty acid binding protein (LFABP) using ultrafiltration and surface plasmon resonance (SPR). 2. Binding of basic and neutral drugs to both HSA and LFABP was typically negligible. Binding of acidic drugs ranged from minor (fu > 0.8) to extensive (fu < 0.1). Of the compounds screened, the highest binding to both HSA and LFABP was observed for the acidic drugs torsemide and sulfinpyrazone, and for beta-estradiol (a polar, neutral compound). 3. The extent of binding of acidic drugs to HSA was up to 40% greater than binding to LFABP. SPR experiments demonstrated comparable kinetics and affinity for the binding of representative acidic drugs (naproxen, sulfinpyrazone, and torsemide) to HSA and LFABP. 4. Simulations based on in vitro kinetic constants derived from SPR experiments and a rapid equilibrium model were undertaken to examine the impact of binding characteristics on compartmental drug distribution. Simulations provided mechanistic confirmation that equilibration of intracellular unbound drug with the extracellular unbound drug is attained rapidly in the absence of active transport mechanisms for drugs bound moderately or extensively to HSA and LFABP. PMID- 25801060 TI - TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain. AB - Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures. PMID- 25801061 TI - Sick man walking: Perception of health status from body motion. AB - An ability to detect subtle signs of sickness in others would be highly beneficial, as it would allow for behaviors that help us avoid contagious pathogens. Recent findings suggest that both animals and humans are able to detect distinctive odor signals of individuals with activated innate immune responses. This study tested whether an innate immune response affects a person's walking speed and whether other people perceive that person as less healthy. 43 subjects watched films of persons who were experiencing experimental immune activation, and rated the walking individuals in the films with respect to health, tiredness, and sadness. Furthermore, the walking speed in the films was analyzed. After LPS injections, participants walked more slowly and were perceived as less healthy and more tired as compared to when injected with placebo. There was also a trend for the subjects to look sadder after LPS injection than after placebo. Furthermore, there were strong associations between walking speed and the appearance of health, tiredness, and sadness. These findings support the notion that walking speed is affected by an activated immune response, and that humans may be able to detect very early signs of sickness in others by merely observing their gait. This ability is likely to aid both a "behavioral immune system", by providing more opportunities for adaptive behaviors such as avoidance, and the anticipatory priming of biochemical immune responses. PMID- 25801062 TI - Antibacterial and anti-biofilm activities of melittin and colistin, alone and in combination with antibiotics against Gram-negative bacteria. AB - In vitro antibacterial and anti-biofilm activities of antimicrobial cationic peptides (AMPs) - melittin and colistin - both alone and in combination with antibiotics were evaluated against clinical isolates of Gram-negative bacteria. Minimum inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) index were determined by the microbroth dilution and chequerboard techniques, respectively. The time-kill curve (TKC) method was used for determining the bactericidal activities of AMPs alone and in combination. Measurements of anti-biofilm activities were performed spectrophotometrically for both inhibition of attachment and 24-hour biofilm formation at MIC or subMIC. According to MIC90 values, the most active agents against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae were colistin, imipenem and ciprofloxacin, respectively. In combination studies, synergistic effects were mostly seen with colistin-imipenem against E. coli and K. pneumoniae (50 and 54%, respectively), colistin-ciprofloxacin against P. aeruginosa (77%). In TKC studies, synergism was observed with almost all expected combinations, even more frequently than chequerboard method. All of the antimicrobial agents were able to inhibit attachment and 24-hour biofilm formation between 0-57% at 1/10 * MIC and 7-73% at 1 * or 1/10 * MIC, respectively. AMPs seem to be a good candidate for antimicrobial chemotherapy with their antibacterial and anti-biofilm activities as a single agent or in combination with antibiotics. PMID- 25801063 TI - Plate selection for fixation of extra-articular distal humerus fractures: A biomechanical comparison of three different implants. PMID- 25801064 TI - Synergistic impact of acute kidney injury and high level of cervical spinal cord injury on the weaning outcome of patients with acute traumatic cervical spinal cord injury. AB - INTRODUCTION: Respiratory neuromuscular impairment severity is known to predict weaning outcome among patients with cervical spinal cord injury; however, the impact of non-neuromuscular complications remains unexplored. This study was to evaluate possible neuromuscular and non-neuromuscular factors that may negatively impact weaning outcome. METHODS: From September 2002 to October 2012, acute traumatic cervical spinal cord injury patients who had received mechanical ventilation for >48h were enrolled and divided into successful (n=54) and unsuccessful weaning groups (n=19). Various neuromuscular, non-neuromuscular factors and events during the intensive care unit stay were extracted from medical charts and electronic medical records. Variables presenting with a significant difference (p<0.2) between these two groups were included in the univariate analysis. Following univariate analysis, those significantly different variables (p<0.05) were subjected to multivariate logistic regression to identify independent predictors of unsuccessful weaning. RESULTS: Compared to successful weaning patients, unsuccessful weaning patients were older; more often had high level of cervical spinal cord injury (C1-3), lower pulse rates, and lower Glasgow Coma Scale score on admission, higher peak blood urea nitrogen, lower trough albumin, and lower trough blood leukocyte counts. Furthermore, unsuccessful weaning patients had a higher incidence of pneumonia, acute respiratory distress syndrome, shock and acute kidney injury during the intensive care unit stay. Multivariate logistic regression analysis revealed acute kidney injury and high level of cervical spinal cord injury were independent risk factors for failure of weaning. Importantly, patients with both risk factors showed a large increase in odds ratio for unsuccessful weaning from mechanical ventilation (p<0.001). CONCLUSIONS: The presence of acute kidney injury during the intensive care unit stay and high level of cervical spinal injury are two independent risk factors that synergistically work together producing a negative impact on weaning outcome. PMID- 25801065 TI - The value of 18-FDG PET/CT in the diagnosis and management of implant-related infections of the tibia: a case series. AB - BACKGROUND: Positron emission tomography (PET) combined with Computerised Tomography (CT) is gaining ground in clinical settings due to its added value of combined metabolic and anatomical imaging. PET/CT has shown promising results in diagnosing both acute and chronic infection of the axial and appendicular skeleton. PET imaging has an advantage in patients with metallic implants because FDG uptake, in contrast to magnetic resonance imaging (MRI) and standard computed tomography (CT), is not hampered by metallic artifacts. The role of PET/CT in the evaluation of implant-related infections involving the tibia in particular has not been thoroughly studied. PURPOSE: To investigate the usefulness of 18-FDG PET/CT in the diagnosis and treatment of implant-related infections of the tibia following osteosynthesis. METHODS: We reviewed 10 patients who underwent internal fixation to the tibia following trauma (4 open fractures, 6 closed fractures) and presented later with clinical signs of a possible implant-related infection. In evaluating the patients we used standard work-up methods (standard radiographs, lab tests) as well as advanced imaging techniques (PET/CT) in order to confirm the diagnosis and decide upon the preferred treatment. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were then calculated for PET/CTs ability to predict presence of infection using intraoperative cultures as the gold standard. RESULTS: PET/CT validated our working diagnosis 9 out of 10 patients. In particular, it helped distinguish between: infected nonunion (n=4), aseptic nonunion (n=1), soft tissue infection (n=2) and chronic osteomyelitis (n=3). The overall sensitivity and specificity of PET/CT for identifying an osseous infection were 85.7% and 100%, respectively. The PPV and NPV were 100% and 75%, respectively. CONCLUSION: PET/CT is a promising imaging modality that can aid in the work up of patients with suspected implant-related infections of the tibia following osteosynthesis, and may be used as a supportive measure in clinical decision making. PMID- 25801066 TI - Influence of access to an integrated trauma system on in-hospital mortality and length of stay. AB - BACKGROUND: Few data are available on population-based access to specialised trauma care and its influence on patient outcomes in an integrated trauma system. We aimed to evaluate the influence of access to an integrate trauma system on in hospital mortality and length of stay (LOS). METHODS: All adults admitted to acute care hospitals for major trauma [International Classification of Diseases Injury Severity Score (ICISS<0.85)] in a Canadian province with an integrated trauma system between 2006 and 2011 were included using an administrative hospital discharge database. The influence of access to an integrated trauma system on in-hospital mortality and LOS was assessed globally and for critically injured patients (ICISS<0.75), according to the type of injury [traumatic brain injury (TBI), abdominal/thoracic, spine, orthopaedic] using logistic and linear multivariable regression models. RESULTS: We identified 22,749 injury admissions. In-hospital mortality was 7% and median LOS was 9 days for all injuries. Overall, 92% of patients were treated within the trauma system. Globally, patients who did not have access had similar mortality and LOS compared to patients who had access. However, we observed a 62% reduction in mortality for critical abdominal/thoracic injuries (odds ratio=0.38; 95% CI, 0.16-0.92) and an 8% increase in LOS for TBI patients (geometric mean ratio=1.08; 95% CI, 1.02-1.14) treated within the trauma system. CONCLUSIONS: Results provides evidence that in a health system with an integrated mature trauma system, access to specialised trauma care is high and the small proportion of patients treated outside the system, have similar mortality and LOS compared to patients treated within the system. This study suggests that the Quebec trauma system performs well in its mandate to offer appropriate treatment to victims of injury that require specialised care. PMID- 25801068 TI - [The role of complementary examinations and home monitoring in patient at risk from apparent life threatening event, apneas and sudden infant death syndrome]. AB - INTRODUCTION: Home apnea monitors detect abnormalities in cardiac and respiratory frequency, but their use in the diagnosis of respiratory -related sleep disturbances in children has not been demonstrated, as was originally thought. OBJECTIVE: To describe the type of patients being monitored, for how long and their outcome. MATERIAL AND METHODS: A retrospective descriptive study was conducted on patients with controlled home cardiorespiratory monitoring from October 2008 to September 2012 in the Outpatient department of a Maternity tertiary hospital. RESULTS: During the study period 88 patients were included, 58% of them were male, with a median age of 15.5 days, and followed up for a period of 4.7 months. The reason for monitoring was in a 20.5% due to a history of sudden death without finding underlying pathology in 20.5%, 25% due to apnea of prematurity, 20.5% due to apparent life-threatening event, and 14.8% due to choking. Other causes accounted for 19.3% (apnea/hypopnea, desaturation and periodic breathing). Of these last three groups, pathological events were observed in 50% of them: reflux disease (9), apnea of prematurity (2), neurological causes (3), and apnea of unknown cause (10). CONCLUSIONS: Suspected infant apnea is a cause for consultation that creates a great deal of concern to the family and the pediatrician. Home monitoring is useful in detecting changes in cardiac and respiratory frequency, but is necessary to limit its indications and ensure proper monitoring of these patients, avoiding the abuse of other tests or treatments. PMID- 25801069 TI - [Expert consensus on the nutritional aspects of initial and follow-on infant formulas]. AB - INTRODUCTION: Infant feeding in the first months/years of life affects the health in the short and long term. Breastfeeding is the perfect food due to its many benefits. However, when breastfeeding is not possible, infant formulas are the best alternative. The aim of this study is to define the role of the supplemented formulas in infant nutrition using the opinion of a panel of experts in infant gastroenterology and nutrition. MATERIAL AND METHODS: A survey, using 62 items, stratified into 5 blocks, was performed by 48 panelists using the Delphi method to achieve a professional criteria consensus on nutritional aspects of infant formulas. RESULTS: A consensus was reached in 64.6% of the items, with a non unified agreement being established as regards the nutritional aspects of infant formulas, and their influence in body and brain development and immune maturity. CONCLUSIONS: According to the experts surveyed, there is consensus as regards the suitable composition of lipids, lactose, calcium, vitamin D, and prebiotics in infant formulas, for a correct cerebral, immune and somatic development. There was no consensus on the not yet well-defined subjects, such as nutritional quality of proteins, use of thickeners, taurine supplementation, probiotic, and symbiotic aspects. More studies are necessary to confirm these subjects. PMID- 25801070 TI - [Inguinal cellulitis-adenitis in group B streptococcal late-onset sepsis]. PMID- 25801071 TI - Experimental proof of nonlocal wavefunction collapse for a single particle using homodyne measurements. AB - A single quantum particle can be described by a wavefunction that spreads over arbitrarily large distances; however, it is never detected in two (or more) places. This strange phenomenon is explained in the quantum theory by what Einstein repudiated as 'spooky action at a distance': the instantaneous nonlocal collapse of the wavefunction to wherever the particle is detected. Here we demonstrate this single-particle spooky action, with no efficiency loophole, by splitting a single photon between two laboratories and experimentally testing whether the choice of measurement in one laboratory really causes a change in the local quantum state in the other laboratory. To this end, we use homodyne measurements with six different measurement settings and quantitatively verify Einstein's spooky action by violating an Einstein-Podolsky-Rosen-steering inequality by 0.042+/-0.006. Our experiment also verifies the entanglement of the split single photon even when one side is untrusted. PMID- 25801072 TI - SBA-15-Oxynitrides as a Solid-Base Catalyst: Effect of Nitridation Temperature on Catalytic Activity. AB - Solid bases, such as SBA-15-oxynitrides, have attracted considerable interest for potential applications as catalysts in important industrial processes. Reported herein is that by simply tuning the temperature of nitridation (ammonolysis), the catalytic activity of these solid bases can be enhanced. Solid-state NMR spectroscopy and XPS studies provided the reasoning behind this change in activity. PMID- 25801067 TI - Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice. AB - Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL 12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4(+), CD8(+) and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy. PMID- 25801073 TI - The association of exercise with both erectile and sexual function in black and white men. AB - INTRODUCTION: There is growing interest in using exercise to treat. Although many studies have highlighted the relationship between better erectile function and exercise, black men have been underrepresented in the literature. AIMS: This study aims to determine whether or not exercise is associated with better erectile as well as sexual function in black men and define a minimum exercise threshold for which better erectile/sexual function is seen in a cross-sectional study. METHODS: Our study population consisted of 295 healthy controls from a case-control study assessing risk factors for prostate cancer conducted at the Durham Veterans Affairs Medical Center, which contained a substantial proportion of black men (n = 93; 32%). Exercise and erectile/sexual function were both determined from self-reported questionnaires. Subjects were stratified into four exercise groups: <3 (sedentary), 3-8.9 (mildly active), 9-17.9 (moderately active), and >=18 (highly active) metabolic equivalents (MET) hours/week. The association between exercise and erectile/sexual function was addressed utilizing multivariable linear regression analyses. MAIN OUTCOME MEASURES: Erectile/sexual function was defined by the validated Expanded Prostate Cancer Index Composite sexual assessment, which was analyzed as a continuous variable (sexual function score). Clinically significant better function was defined as half a standard deviation (SD) (16.5 points). RESULTS: Median sexual function score was 53 (SD = 33). Higher exercise was associated with a better sexual function score (P < 0.001). Importantly, there was no interaction between black race and exercise (P interaction = 0.772), meaning more exercise was linked with better erectile/sexual function regardless of race. Overall, exercise >=18 MET hours/week predicted better erectile/sexual function (P < 0.001) with a clinically significant 17.3-point higher function. Exercise at lower levels was not statistically (P > 0.147) or clinically (<=8.14 points higher function) associated with erectile/sexual function. CONCLUSIONS: In a racially diverse population, exercise >=18 MET hours/week is highly associated with better erectile/sexual function regardless of race. PMID- 25801074 TI - Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid. AB - Understanding how drugs are distributed in perilymph following local applications is important as local drug therapies are increasingly used to treat disorders of the inner ear. The potential contribution of cerebrospinal fluid (CSF) entry to perilymph homeostasis has been controversial for over half a century, largely due to artifactual contamination of collected perilymph samples with CSF. Measures of perilymph flow and of drug distribution following round window niche applications have both suggested a slow, apically directed flow occurs along scala tympani (ST) in the normal, sealed cochlea. In the present study, we have used fluorescein isothiocyanate-dextran as a marker to study perilymph kinetics in guinea pigs. Dextran is lost from perilymph more slowly than other substances so far quantified. Dextran solutions were injected from pipettes sealed into the lateral semicircular canal (SCC), the cochlear apex, or the basal turn of ST. After varying delays, sequential perilymph samples were taken from the cochlear apex or lateral SCC, allowing dextran distribution along the perilymphatic spaces to be quantified. Variability was low and findings were consistent with the injection procedure driving volume flow towards the cochlear aqueduct, and with volume flow during perilymph sampling driven by CSF entry at the aqueduct. The decline of dextran with time in the period between injection and sampling was consistent with both a slow volume influx of CSF (~30 nL/min) entering the basal turn of ST at the cochlear aqueduct and a CSF-perilymph exchange driven by pressure-driven fluid oscillation across the cochlear aqueduct. Sample data also allowed contributions of other processes, such as communications with adjacent compartments, to be quantified. The study demonstrates that drug kinetics in the basal turn of ST is complex and is influenced by a considerable number of interacting processes. PMID- 25801075 TI - Combination therapy - deferasirox and deferoxamine - in thalassemia major patients in emerging countries with limited resources. AB - BACKGROUND: The problem of iron-overload observed in thalassemia patients can be overcome using chelating agents such as deferiprone (Ferroprox((r)) ), deferasirox (Exjade((r)) ) and deferoxamine (Desferal((r)) ). Although these drugs can be used as monotherapy, combined therapy, especially deferiprone with deferoxamine, has led to promising outcomes in various studies. METHODS AND MATERIALS: In this quasi-experimental study, serum ferritin levels were evaluated in 32 beta-thalassemia major patients with severe iron overload before and after receiving combined deferasirox (30-40 mg kg(-1) day(-1) ) and deferoxamine (40 50 mg kg(-1) day(-1) ) 2 days a week. This study was conducted from September 2012 to September 2013 in Southern Iran. RESULTS: The mean of serum ferritin levels significantly reduced from 4031 +/- 1955 to 2416 +/- 1653 ng mL(-1) after 12 months of therapy (P < 0.001). Echocardiograph findings showed significant improvement 1year after end of the study (P < 0.001). No drug toxicity was observed by monitoring serum creatinine, liver enzymes and blood urea nitrogen (BUN) during the study period. We observed no correlation between mean serum ferritin change and age (P = 0.87). In addition, the mean serum ferritin change did not differ between male and female thalassemia patients (P = 0.454). No difference in mean serum ferritin change was observed between patients who had undergone splenectomy compared to those who had not done so (P = 0.307). CONCLUSION: The study suggests that combination chelating therapy with deferasirox and deferoxamine can effectively reduce iron burden in beta thalassemia major patients with heavy iron overload without any significant complications. PMID- 25801076 TI - PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C. AB - BACKGROUND: The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC). AIM: To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. METHODS: Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients. RESULTS: The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI >= 30 (OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26 3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002). CONCLUSION: In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects. PMID- 25801077 TI - A tomato chloroplast-targeted DnaJ protein protects Rubisco activity under heat stress. AB - Photosynthesis is one of the biological processes most sensitive to heat stress in plants. Carbon assimilation, which depends on ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), is one of the major sites sensitive to heat stress in photosynthesis. In this study, the roles of a tomato (Solanum lycopersicum) chloroplast-targeted DnaJ protein (SlCDJ2) in resisting heat using sense and antisense transgenic tomatoes were examined. SlCDJ2 was found to be uniformly distributed in the thylakoids and stroma of the chloroplasts. Under heat stress, sense plants exhibited higher chlorophyll contents and fresh weights, and lower accumulation of reactive oxygen species (ROS) and membrane damage. Moreover, Rubisco activity, Rubisco large subunit (RbcL) content, and CO2 assimilation capacity were all higher in sense plants and lower in antisense plants compared with wild-type plants. Thus, SlCDJ2 contributes to maintenance of CO2 assimilation capacity mainly by protecting Rubisco activity under heat stress. SlCDJ2 probably achieves this by keeping the levels of proteolytic enzymes low, which prevents accelerated degradation of Rubisco under heat stress. Furthermore, a chloroplast heat-shock protein 70 was identified as a binding partner of SlCDJ2 in yeast two-hybrid assays. Taken together, these findings establish a role for SlCDJ2 in maintaining Rubisco activity in plants under heat stress. PMID- 25801078 TI - Large, exophytic mass on the scalp of a newborn. Solitary infantile myofibroma. PMID- 25801079 TI - Infiltrative plaques on the temple. Blastic plasmacytoid dendritic cell neoplasm (BPDCN). PMID- 25801080 TI - Congenital erythematous plaques and papules on the right arm. Eccrine angiomatous hamartoma. PMID- 25801082 TI - Evidence of Amine-CO2 Interactions in Two Pillared-Layer MOFs Probed by X-ray Crystallography. AB - Two pillared-layer metal-organic frameworks (MOFs; PMOF-55 and NH2 -PMOF-55) based on 1,2,4-triazole and terephthalic acid (bdc)/NH2 -bdc ligands were assembled and display framework stabilities, to a certain degree, in both acid/alkaline solutions and toward water. They exhibit high CO2 uptakes and selective CO2 /N2 adsorption capacities, with CO2 /N2 selectivity in the range of 24-27, as calculated by the ideal adsorbed solution theory method. More remarkably, the site and interactions between the host network and the CO2 molecules were investigated by single-crystal X-ray diffraction, which showed that the main interaction between the CO2 molecules and PMOF-55 is due to multipoint supramolecular interactions of C-H???O, C???O, and O???O. Amino functional groups were shown to enhance the CO2 adsorption and identified as strong adsorption sites for CO2 by X-ray crystallography. PMID- 25801081 TI - Cantharidin response. PMID- 25801083 TI - Peripheral blood monocyte and T-lymphocyte activation levels at diagnosis predict long-term survival in head and neck squamous cell carcinoma patients. AB - This study was performed to determine whether peripheral blood (PB) monocyte and/or lymphocyte activation at diagnosis were associated with long-term prognosis in patients with head and neck squamous cell carcinoma (HNSCC), and to what extent such prognostic properties relate to human papilloma virus (HPV) associated tumor infection of the included patients. This was a long-term prospective study describing patient survival in relation to PB T lymphocyte and monocyte activation in patients observed for up to 14 years following diagnosis. Sixty-four patients from a consecutive cohort of newly diagnosed HNSCC patients along with 16 non-cancer control patients were included over a period of almost 2 years. Monocyte responsiveness was assessed at diagnosis (N = 56 HNSCC/16 non cancer controls) by measuring net levels of spontaneous vs lipopolysaccharide induced monocyte chemotactic protein (MCP)-1 secretion in vitro. PB T lymphocyte activation was determined (N = 58 HNSCC/16 controls) by measuring the percentage of T cells expressing CD69 by flow cytometry. Whether HPV infection or not was determined by PCR analysis on formalin fixed paraffin-embedded tumor tissue. Tumor HPV-positive patients had better prognosis than HPV-negative patients. A low net MCP-1 response in monocytes predicted increased survival (Relative risk (RR) = 2.1; Confidence interval (CI): 1.1-4.0; p < 0.05). A low percentage of CD69 positive T lymphocytes also predicted better prognosis (RR = 2.6; CI: 1.3 5.0; p = 0.005). The predictive power of MCP-1 monocyte and CD69 T lymphocyte measures were retained when adjusted for age and gender of the patients and shown to be independent of each other (N = 50 HNSCC/16 controls). The results were similar in HPV tumor-positive and -negative patients. Patients with high monocyte and/or T lymphocyte activation status had low survival with 8% 5 year overall survival (OS) compared to 65% 5 year OS for patients with dual low activation levels (RR = 0.27; CI: 0.14-0.56; p < 0.001), mostly secondary to disease specific survival. Both tumor HPV-positive and -negative HNSCC patients with high percentage of CD69 positive T lymphocytes and/or high monocyte MCP-1 secretion had low long-term survival. The data suggest that the general inflammatory and adaptive immune systems are independently linked to the clinical aggressiveness of both tumor HPV-negative and -positive HNSCC patients. PMID- 25801084 TI - Primary synovial epithelioid sarcoma of the knee: distinctly unusual location leading to its confusion with pigmented villonodular synovitis. AB - Epithelioid sarcoma (ES) is a rare malignant soft tissue tumor occurring in the distal extremities of young adults and is characterized histologically by nodules of epithelioid cells showing central necrosis. Intra-articular ES is extremely rare; only four cases have been reported, but their radiologic and histologic documentation of intra-articular origin have been imprecise. We report the first radiologically and histologically well-documented case of primary synovial ES. A 59-year-old woman presented with pain followed by swelling of her right knee for 6 months. MRI revealed an entirely intra-articular nodular synovial mass in the lateral part of the right knee joint in a background of diffusely thickened synovium. Synovectomy was performed under the clinical impression of pigmented villonodular synovitis (PVNS), a diagnosis erroneously confirmed by the reporting pathologist. The tumor rapidly recurred 3 months afterward and the diagnosis of primary synovial ES was made. Despite above-knee amputation, the tumor continued to spread proximally to the retroperitoneum. She developed multiple lung metastases and died 20 months after initial presentation. The nodular aggregates of tumor cells with central necrosis resulted in diffuse polypoid synovial thickening mimicking tuberculous synovitis and PVNS. The tumor cells showed positive staining for EMA, CK19, CD34, and complete loss of INI1 staining, establishing the diagnosis of primary synovial ES. The ES spread from the synovium to and along the joint capsule, and then extra-articularly into the soft tissue surrounding the knee joint, with lymphovascular permeation. Such pattern of spread calls for radical surgical excision as the treatment of choice. PMID- 25801085 TI - Outcomes of Clostridium difficile infection in hospitalized leukemia patients: a nationwide analysis. AB - BACKGROUND The incidence of Clostridium difficile infection (CDI) has increased among hospitalized patients and is a common complication of leukemia. We investigated the risks for and outcomes of CDI in hospitalized leukemia patients. METHODS Adults with a primary diagnosis of leukemia were extracted from the United States Nationwide Inpatient Sample database, 2005-2011. The primary outcomes of interest were CDI incidence, CDI-associated mortality, length of stay (LOS), and charges. In a secondary analysis, we sought to identify independent risk factors for CDI in leukemia patients. Logistic regression was used to derive odds ratios (ORs) adjusted for potential confounders. RESULTS A total of 1,243,107 leukemia hospitalizations were identified. Overall CDI incidence was 3.4% and increased from 3.0% to 3.5% during the 7-year study period. Leukemia patients had 2.6-fold higher risk for CDI than non-leukemia patients, adjusted for LOS. CDI was associated with a 20% increase in mortality of leukemia patients, as well as 2.6 times prolonged LOS and higher hospital charges. Multivariate analysis revealed that age >65 years (OR, 1.13), male gender (OR, 1.14), prolonged LOS, admission to teaching hospital (OR, 1.16), complications of sepsis (OR, 1.83), neutropenia (OR, 1.35), renal failure (OR, 1.18), and bone marrow or stem cell transplantation (OR, 1.27) were significantly associated with CDI occurrence. CONCLUSIONS Hospitalized leukemia patients have greater than twice the risk of CDI than non-leukemia patients. The incidence of CDI in this population increased 16.7% from 2005 to 2011. Development of CDI in leukemia patients was associated with increased mortality, longer LOS, and higher hospital charges. PMID- 25801086 TI - Development of urea and thiourea kynurenamine derivatives: synthesis, molecular modeling, and biological evaluation as nitric oxide synthase inhibitors. AB - Herein we describe the synthesis of a new family of kynurenamine derivatives with a urea or thiourea moiety, together with their in vitro biological evaluation as inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS, respectively), enzymes responsible for the biogenesis of NO. These compounds were synthesized from a 5-substituted-2-nitrophenyl vinyl ketone scaffold in a five step procedure with moderate to high chemical yields. In general, the assayed compounds show greater inhibition of iNOS than of nNOS, with 1-[3-(2-amino-5 chlorophenyl)-3-oxopropyl]-3-ethylurea (compound 5 n) being the most potent iNOS inhibitor in the series and the most iNOS/nNOS-selective compound. In this regard, we performed molecular modeling studies to propose a binding mode for this family of compounds to both enzymes and, thereby, to elucidate the differential molecular features that could explain the observed selectivity between iNOS and nNOS. PMID- 25801087 TI - No matter how I think, it already hurts: self-stigmatized feelings and face concern of Chinese caregivers of people with intellectual disabilities. AB - This study used mixed-methods design to explore internalized self-stigma among family caregivers (ISFC) of people with intellectual disability (ID) in China, where face culture and collective emotions are emphasized. A total of 120 primary caregivers of people with ID were assessed for ISFC, face concern and psychological distress at the survey phase. Of these caregivers, 10 participated in sequential interviews to provide elaboration for quantitative results. The results highlighted the role of stigmatized feelings instead of cognitive thoughts in hurting caregivers in the Chinese context. Caregivers with higher face concern were more likely to internalize feelings of shame, self-blame and powerlessness and suffered poorer mental health. Low-socioeconomic status group and onset-before-birth group were particularly vulnerable to stigma that require more attention in future studies. Feelings of being marginalized within the family and shame may be more face culture-related concern. Strategies (i.e. withdrawal, compensation, self-compassion and multiple identities) and recommendations for stigma reduction were discussed. PMID- 25801089 TI - Terminally ill patients could benefit from stopping statins, study says. PMID- 25801088 TI - Structural mediation on polycation nanoparticles by sulfadiazine to enhance DNA transfection efficiency and reduce toxicity. AB - Reducing the toxicity while maintaining high transfection efficiency is an important issue for cationic polymers as gene carriers in clinical application. In this paper, a new zwitterionic copolymer, polycaprolactone-g poly(dimethylaminoethyl methyacrylate-co-sulfadiazine methacrylate) (PC-SDZ) with unique pH-sensitivity, was designed and prepared. The incorporation of sulfadiazine into poly(dimethylaminoethyl methacrylate) (PDMAEMA) chains successfully mediates the surface properties including compacter shell structure, lower density of positive charges, stronger proton buffer capability, and enhanced hydrophobicity, which lead to reduction in toxicity and enhancements in stability, cellular uptake, endosome escape, and transfection efficiency for the PC-SDZ2 nanoparticles (NPs)/DNA complexes. Excellent transfection efficiency at the optimal N/P ratio of 10 was observed for PC-SDZ2 NPs/DNA complexes, which was higher than that of the commercial reagent-branched polyethylenimine (PEI). The cytotoxicity was evaluated by CCK8 measurement, and the results showed significant reduction in cytotoxicity even at high concentration of complexes after sulfadiazine modification. Therefore, this work may demonstrate a new way of structural mediation of cationic polymer carriers for gene delivery with high efficiency and low toxicity. PMID- 25801092 TI - In vitro study of biological activities of anthocyanin-rich berry extracts on porcine intestinal epithelial cells. AB - BACKGROUND: Anthocyanins, compounds that represent the major group of flavonoids in berries, are one of the most powerful natural antioxidants. The aim of this study was to evaluate biological activities and comparison of anthocyanin-rich extracts prepared from chokeberry (Aronia melanocarpa), elderberry (Sambucus nigra), bilberry (Vaccinium myrtillus) and blueberry (V. corymbosum) on the porcine intestinal epithelial IPEC-1 cell line. RESULTS: The IC50 values calculated in the antioxidant cell-based dichlorofluorescein assay (DCF assay) were 1.129 mg L(-1) for chokeberry, 1.081 mg L(-1) for elderberry, 2.561 mg L(-1) for bilberry and 2.965 mg L(-1) for blueberry, respectively. We found a significant negative correlation (P < 0.001) between cyanidin glycosides content and IC50 values. Moreover, extracts rich in cyanidin glycosides stimulated proliferation of IPEC-1 cells and did not have cytotoxic effect on cells at an equivalent in vivo concentration. CONCLUSIONS: We found that the chokeberry and elderberry extracts rich in cyanidin glycosides possess better antioxidant and anticytotoxic activities in comparison to blueberry or bilberry extracts with complex anthocyanin profiles. PMID- 25801093 TI - The intracellular location, mechanisms and outcomes of NOD1 signaling. AB - The host has developed an array of systems that enables protection against infection and response to injury, ultimately resulting in the generation of a pro inflammatory response. The most rapid immune response is mediated via the innate immune system, which is comprised of germ line encoded pathogen recognition receptors (PRRs). This PRR mediated system functions by specifically recognizing conserved structures of microbial molecules or products, known as microbial associated molecular patterns (MAMPs), ultimately enabling transduction of signaling cascades, gene transcription and the development of a pro-inflammatory innate immune response. The intracellular PRRs nucleotide-binding oligomerization domain protein 1 (NOD1) and NOD2 will be the focus of this review. A brief overview of NOD1 and NOD2 and recent advances in the field regarding the intracellular location and mechanisms of NOD1 signaling will be discussed. These new findings have broadened our understanding of the mechanisms whereby NOD1 signaling results in the induction of the cellular degradation pathway of autophagy and the development of pro-inflammatory responses that activate the adaptive immune system. PMID- 25801094 TI - Kawasaki disease refractory to standard treatments that responds to a combination of pulsed methylprednisolone and plasma exchange: Cytokine profiling and literature review. AB - We present a case of Kawasaki Disease (KD) that was refractory to plasma exchange (PE), but which finally responded to concurrent intravenous methylprednisolone pulse (IVMP) and PE treatment. To determine direct and indirect evidence for the efficacy of this combination therapy, we analyzed data of patients with refractory KD by review of the literature using medical databases and cytokine profiling. For literature searches, we used the PubmedTM and IchushiTM databases. Search terms used included "Kawasaki disease" and "plasma exchange" to extract articles that described KD cases treated with PE. For cytokine profiling, we measured interleukin (IL)-6, soluble tumor necrosis factor-alpha receptor (sTNF alphaR) type 1 and type 2 before and after PE and PE with IVMP. Our search revealed 201 KD patients treated with PE, of which PE treatment was effective in 188 patients (93.5%), but not in 13 cases (6.5%). All 13 cases were treated successfully with additional treatment. Of the 13 cases, only six (2.5%) had recurrence during the PE treatment period. In our case, cytokine profiling showed PE treatment decreased IL6, while sTNF-alphaR type1 and type2 remained at high levels. PE and IVMP decreased IL-6 and sTNFalpha-R type 1 and type 2 levels. CONCLUSION: PE concurrent with additional anti-inflammatory treatment such as IVMP might be a very promising treatment option for PE refractory patients. PMID- 25801095 TI - Improved pharmacodynamics and pharmacokinetics after i.v. application of peginterferon alfa-2a in hepatitis C null responders. AB - BACKGROUND & AIM: Mechanisms of non-responsiveness to peginterferon alfa-2a are not completely understood. Inadequate plasma levels may contribute to reduced response. The aim of this prospective, multicentre, crossover, Phase 1 study was to evaluate the pharmacokinetics and viral kinetics of intravenous vs. subcutaneous peginterferon alfa-2a in patients with genotype 1 chronic hepatitis C infection who showed null response to previous peginterferon/ribavirin. METHODS: Patients were randomized in four treatment arms to subcutaneous or intravenous peginterferon alfa-2a 180 MUg, once or twice weekly for 2 weeks. After a washout phase of 6 weeks, patients first receiving intravenous administration switched to subcutaneous or vice versa for additional 2 weeks. RESULTS: Intravenous administration of pegylated interferon resulted in a stronger and faster decline in HCV RNA than subcutaneous administration with a maximum decline of 1.17 log10 vs. 0.41 log10 or 1.32 log10 vs. 0.54 log10 after a once or twice weekly application, respectively. Pharmacokinetic studies revealed significantly higher maximum concentration (C(max))(0-12) h and C(max 0-7) d following intravenous administration, irrespective of dosing frequency A rapid rebound in HCV RNA was observed in all treatment arms. Adverse events occurred more frequently following intravenous administration. CONCLUSION: Intravenous administration of peginterferon alfa-2a results in considerably higher plasma concentration and a stronger decline in HCV RNA and offers an interesting approach in order to overcome interferon non-responsive state in patients with full null response to previous peginterferon/ribavirin combination therapy. PMID- 25801097 TI - Neural correlates of early-closure garden-path processing: Effects of prosody and plausibility. AB - Functional magnetic resonance imaging (fMRI) was used to investigate neural correlates of early-closure garden-path sentence processing and use of extrasyntactic information to resolve temporary syntactic ambiguities. Sixteen participants performed an auditory picture verification task on sentences presented with natural versus flat intonation. Stimuli included sentences in which the garden-path interpretation was plausible, implausible because of a late pragmatic cue, or implausible because of a semantic mismatch between an optionally transitive verb and the following noun. Natural sentence intonation was correlated with left-hemisphere temporal activation, but also with activation that suggests the allocation of more resources to interpretation when natural prosody is provided. Garden-path processing was associated with upregulation in bilateral inferior parietal and right-hemisphere dorsolateral prefrontal and inferior frontal cortex, while differences between the strength and type of plausibility cues were also reflected in activation patterns. Region of interest (ROI) analyses in regions associated with complex syntactic processing are consistent with a role for posterior temporal cortex supporting access to verb argument structure. Furthermore, ROI analyses within left-hemisphere inferior frontal gyrus suggest a division of labour, with the anterior-ventral part primarily involved in syntactic-semantic mismatch detection, the central part supporting structural reanalysis, and the posterior-dorsal part showing a general structural complexity effect. PMID- 25801096 TI - A new ent-clerodane diterpenoid from Crassocephalum bauchiense Huch. (Asteraceae). AB - A phytochemical investigation of the whole plant of Crassocephalum bauchiense Huch. resulted in the isolation of a new clerodane diterpenoid, ent-2beta,18,19 trihydroxycleroda-3,13-dien-16,15-olide (1), together with two known flavonoids 3',5-dihydroxy-4',5',6,7,8-pentamethoxyflavone (2) and 4',5-dihydroxy-3',5',6,7,8 pentamethoxyflavone (3). The compounds were tested against the chloroquine sensitive 3D7 strain of Plasmodium falciparum. Compound 2 showed weak activity (IC50 = 10.1 g/mL) whilst compounds 1 and 3 were inactive. The structures of the compounds were elucidated by using detailed spectral analyses, especially (1)H and (13)C NMR, (1)H-(1)H COSY, NOESY, HMBC and HR-ESI-MS. PMID- 25801098 TI - Utilization of a reporter system based on the blue pigment indigoidine biosynthetic gene bpsA for detection of promoter activity and deletion of genes in Streptomyces. AB - The integrative promoter-probe plasmid pBPSA1 was constructed using a promoterless Streptomyces aureofaciens CCM3239 bpsA gene encoding a non-ribosomal peptide synthase for the biosynthesis of a blue pigment, indigoidine. bpsA was also used to prepare pAMR4 plasmid for the deletion of genes in Streptomyces with facile identification of double crossover recombination. PMID- 25801099 TI - Polar Lipid Profile of Nannochloropsis oculata Determined Using a Variety of Lipid Extraction Procedures. AB - Lipid compositions obtained from microalgae species are affected by both the cultivation conditions and the extraction method used. In this study, the extraction of lipids from Nannochloropsis oculata using traditional and modern extraction technologies with several solvents has been compared. Because important polyunsaturated fatty acids are bound to polar lipids, these polar lipids were the main focus of this study. The dominant compounds in the glycolipid fractions were monogalactosyldiglycerides and digalactosyldiglycerides bearing fatty acid chains containing at least one site of unsaturation. Phosphatidylcholine and trimethylhomoserines were detected in the phospholipid fractions. The fatty acid profile comprised large fractions of C16:0, C16:1, C20:5, and C18:3. Extraction of specific compounds was determined by extraction efficiency as well as differences in the selectivity of the method used. The composition derived from a glycolipid fraction was observed to be affected by the method used to a greater extent than the phospholipid fraction. PMID- 25801100 TI - Changes in lumbar multifidus muscle function and nociceptive sensitivity in low back pain patient responders versus non-responders after dry needling treatment. AB - BACKGROUND: Little is known about the physiologic mechanism of dry needling. While some evidence suggests that dry needling may decrease nocioceptive sensitivity and facilitate muscle function, no studies to date have examined these physiologic changes compared to clinical outcomes. OBJECTIVE: To examine changes in lumbar multifidus (LM) muscle function and nociceptive sensitivity after dry needling in patients with LBP and to determine if such changes differ in patients that exhibit improved disability (responders) and those that do not (non-responders). DESIGN: Quasi-experimental study. METHODS: Sixty-six volunteers with mechanical LBP (38 men, age = 41.3 +/- 9.2 years) completed the study. Ultrasound measurements and pain algometry of the LM were taken at baseline and repeated immediately following dry needling treatment to the LM muscles and after one week. The percent change in muscle thickness from rest to contraction was calculated for each time point to represent muscle function. Pressure pain threshold (PPT) was used to measure nociceptive sensitivity. Participants were dichotomized as responders and non-responders based on whether or not they experienced clinical improvement using the modified Oswestry Disability Index after one week. 2 * 3 mixed-model ANOVA were conducted for group (responders vs. non-responders) by time. RESULTS: Patient responders exhibited larger improvements in LM muscle contraction and nociceptive sensitivity 1 week, but not immediately, after dry needling than non-responders. CONCLUSIONS: Our results suggest that there may be lasting and clinically relevant sensorimotor changes that occur in LBP patients that improve with dry needling treatment that partially explain the physiologic mechanism of action. PMID- 25801101 TI - Anthropogenic Trace Compounds (ATCs) in aquatic habitats - research needs on sources, fate, detection and toxicity to ensure timely elimination strategies and risk management. AB - Anthropogenic Trace Compounds (ATCs) that continuously grow in numbers and concentrations are an emerging issue for water quality in both natural and technical environments. The complex web of exposure pathways as well as the variety in the chemical structure and potency of ATCs represents immense challenges for future research and policy initiatives. This review summarizes current trends and identifies knowledge gaps in innovative, effective monitoring and management strategies while addressing the research questions concerning ATC occurrence, fate, detection and toxicity. We highlight the progressing sensitivity of chemical analytics and the challenges in harmonization of sampling protocols and methods, as well as the need for ATC indicator substances to enable cross-national valid monitoring routine. Secondly, the status quo in ecotoxicology is described to advocate for a better implementation of long-term tests, to address toxicity on community and environmental as well as on human health levels, and to adapt various test levels and endpoints. Moreover, we discuss potential sources of ATCs and the current removal efficiency of wastewater treatment plants (WWTPs) to indicate the most effective places and elimination strategies. Knowledge gaps in transport and/or detainment of ATCs through their passage in surface waters and groundwaters are further emphasized in relation to their physico-chemical properties, abiotic conditions and biological interactions in order to highlight fundamental research needs. Finally, we demonstrate the importance and remaining challenges of an appropriate ATC risk assessment since this will greatly assist in identifying the most urgent calls for action, in selecting the most promising measures, and in evaluating the success of implemented management strategies. PMID- 25801102 TI - Optimizing treatments for anxiety by age and genetics. AB - This paper highlights recent human neuroimaging and cross-species developmental and genetic studies that examine how fear regulation varies by age and the individual, especially during the period of adolescence, when there is a peak in the prevalence of anxiety disorders. The findings have significant implications for understanding who may be at risk for anxiety disorders and for whom, and when, an exposure-based therapy may be most effective. We provide proof of concept for targeting treatment to the individual as a function of age and genetics, inferred from mouse and human studies, and suggest optimization of treatment for nonresponders. PMID- 25801104 TI - Simultaneous nitrification and denitrification by novel heterotrophs in remediation of fish processing effluent. AB - Three isolates viz. Lysinibacillus sp. HT13, Alcaligenes sp. HT15 and Proteus sp. HT37 isolated from fish processing effluent and having a C/N ratio of 2, removed 218, 169, and 400 ug cell(-1) day(-1) NH4(+)-N, respectively without subsequent build up of nitrite or nitrate. Ability of the selected isolates in removing NH4(+)-N, NO2(-)-N, and NO3(-)-N was checked in the presence of four commonly reported and tested effluent carbon sources viz. pyruvate, glycerol, methanol, and acetate. Further, when supplemented to fish processing wastewater containing 234 ppm total Kjeldahl's nitrogen, Lysinibacillus sp. HT13, Alcaligenes sp. HT15, and Proteus sp. HT37 could remediate 95.74, 86.17, and 76.6% nitrogen, respectively in 48 h. This is the first report of a Lysinibacillus sp. carrying out aerobically the process of simultaneous nitrification and denitrification. The results demonstrate the potential of the isolates for use in treatment of fish processing effluents and demonstrating the efficient removal of ammonia. PMID- 25801103 TI - SunSmart: evaluation of a pilot school-based sun protection intervention in Hispanic early adolescents. AB - The incidence of melanoma is rising among Hispanic populations in the United States. The purpose of this study is to evaluate the impact of a pilot sun safety educational intervention conducted from 2006 to 2012 on Hispanic early adolescents in a high ultraviolet environment. Nineteen schools with high Hispanic enrollment were recruited from urban neighborhoods in Los Angeles. The analytic sample was restricted to students identifying as Hispanic or Latino (n = 777). A mixed effects linear model was used to test mean changes from pre- to posttest on students' sun protection knowledge, attitudes and behaviors. Significant improvements were observed across several cognitive outcomes related to sun protection, including knowledge of and attitudes toward sun protection and self-efficacy to wear sunscreen. However, changes in sun protective behaviors were not achieved. Although some improvements were observed, future studies should identify the factors that motivate sun protection in this population and develop tailored prevention strategies, as improving the sun safe behaviors of Hispanic youths may aid in reducing the risk of melanoma in adulthood in this population. PMID- 25801105 TI - Endoscopic training in gastroenterology fellowship: adherence to core curriculum guidelines. AB - BACKGROUND: The Gastroenterology Core Curriculum and American Society of Gastrointestinal Endoscopy provide guidelines for endoscopic training. Program adherence to these recommendations is unclear. This study aims to assess endoscopic training experience during fellowship. METHODS: DESIGN: Questionnaire study. SETTING: The questionnaire was circulated to US fellowship programs, with the assistance of the American Gastroenterological Association. PARTICIPANTS: Graduating third-year fellows. RESULTS: Seventy-three fellows returned the questionnaire. Nearly all fellows met the required numbers for esophagoduodenoscopy (98%) and colonoscopy (100%), with fewer meeting requirements for PEG (73%) and non-variceal hemorrhage (75%). The majority of fellows did not meet minimum numbers for variceal banding (40%), esophageal dilation (43%), capsule endoscopy (42%). Fellows rated training in cognitive aspects of endoscopy as 3.86 [1 (inadequate), 5 (excellent)] and reported greatest emphasis on interpreting endoscopic findings and least on virtual colonography. Quality indicators of endoscopy received little emphasis (rating of 3.04; p = 0.00001), with adenoma detection rate being least emphasized. Fifty-six percent of fellows reported having routine endoscopy conferences. Half of the programs have endoscopic simulators, with 15% of fellows being required to use simulation. Following direct hands-on experience, fellows rated external endoscopy courses (64%) as the next most useful experience. CONCLUSIONS: Many fellows do not meet required numbers for several endoscopic procedures, and quality indicators receive little emphasis during training. Most programs do not provide simulation training or hold regular endoscopy conferences. Fellowship programs should perform internal audits and make feasible adjustments. Furthermore, it may be time for professional societies to revisit training guidelines. PMID- 25801106 TI - Systematic review and meta-analysis for laparoscopic versus open colon surgery with or without an ERAS programme. AB - BACKGROUND: In recent years, conventional colorectal resection and its aftercare have increasingly become replaced by laparoscopic surgery and enhanced recovery after surgery (ERAS) pathways, respectively. OBJECTIVE: To ascertain whether combining laparoscopy and ERAS have additional value within colorectal surgery. METHODS: A systematic review with meta-analysis was performed with two primary research questions; does laparoscopy offer an advantage when all patients receive ERAS perioperative care and does ERAS offer advantages in a laparoscopically operated patient population. All randomised and controlled clinical trials were identified using MEDLINE, EMBASE and Cochrane databases. RESULTS: Primary search resulted in 319 hits. After inclusion criteria were applied, three RCTs and six CCTs were included in the meta-analysis. For laparoscopically operated patients with/without ERAS, no differences in morbidity were found and postoperative hospital stay favoured ERAS (MD -2.34 [-3.77, -0.91], Z = 3.20, p = 0.001). When comparing laparoscopy and open surgery within ERAS, major morbidity was significantly reduced in the laparoscopic group (OR 0.42 [0.26, 0.66], Z = 3.73, p = 0.006). Other outcome parameters showed no differences. Quality of included studies was considered moderate to poor overall with small sample sizes. CONCLUSION: When laparoscopy and ERAS are combined, major morbidity and hospital stay are reduced. The reduction in morbidity seems to be due to laparoscopy rather than ERAS, so laparoscopy by itself offers independent advantages beyond ERAS care. Quality of included studies was moderate to poor, so conclusions should be regarded with some reservations. PMID- 25801107 TI - Transanal endoscopic microsurgery as an outpatient procedure is feasible and safe. AB - BACKGROUND: Transanal endoscopic microsurgery (TEM) for the excision of rectal tumor is mostly performed as an inpatient procedure. The aim of this study was to assess the feasibility and safety of TEM resection as an outpatient procedure in selected patients. POPULATION: All first 178 consecutive patients who underwent resection of a rectal tumor using TEM in our institution from April 2011 to September 2013 were included. METHOD: Standardized retrospective chart review was performed. Primary outcome was 30-day mortality and morbidity. Secondary outcomes included unplanned admission and readmission rates, operative and pathologic data. RESULTS: Of the 175 patients who underwent only TEM, 80% (140/175) were discharged the same day of surgery. There was no mortality. Morbidity rate was 31.4%. Ninety-one percent of 154 patients planned as outpatients were discharged the same day. The most common reason for unplanned admission was urinary retention (7/14; 50%). Twelve patients discharged the day of the procedure were readmitted at 30 days. Median operative time was 60 min (10-256 min). All lesions were removed with grossly negative margins with 15 positive microscopic margins on final pathology. A total of 124 adenomatous polyps and 37 malignant lesions were excised. Mean tumor diameter after fixation was 5.0 cm (range 0.5-11 cm). CONCLUSION: Transanal endoscopic microsurgery as an outpatient procedure is feasible and safe in selected patients. The main reason for unplanned admission was urinary retention in our series. PMID- 25801108 TI - Is single port enough in minimally surgery for pneumothorax? AB - BACKGROUND: Video-assisted thoracoscopic surgery is a widespread used procedure for treatment of primary spontaneous pneumothorax patients. In this study, the adaptation of single-port video-assisted thoracoscopic surgery approach to primary spontaneous pneumothorax patients necessitating surgical treatment, with its pros and cons over the traditional two- or three-port approaches are examined. METHODS: Between January 2011 and August 2013, 146 primary spontaneous pneumothorax patients suitable for surgical treatment are evaluated prospectively. Indications for surgery included prolonged air leak, recurrent pneumothorax, or abnormal findings on radiological examinations. Visual analog scale and patient satisfaction scale score were utilized. RESULTS: Forty triple port, 69 double-port, and 37 single-port operations were performed. Mean age of 146 (126 male, 20 female) patients was 27.1 +/- 16.4 (range 15-42). Mean operation duration was 63.59 +/- 26 min; 61.7 for single, 64.2 for double, and 63.8 min for triple-port approaches. Total drainage was lower in the single-port group than the multi-port groups (P = 0.001). No conversion to open thoracotomy or 30-day hospital mortality was seen in our group. No recurrence was seen in single-port group on follow-up period. Visual analog scale scores on postoperative 24th, 48th, and 72nd hours were 3.42 +/- 0.94, 2.46 +/- 0.81, 1.96 +/- 0.59 in the single-port group; significantly lower than the other groups (P = 0.011, P = 0.014, and P = 0.042, respectively). Patient satisfaction scale scores of patients in the single-port group on 24th and 48th hours were 1.90 +/- 0.71 and 2.36 +/- 0.62, respectively, indicating a significantly better score than the other two groups (P = 0.038 and P = 0.046). CONCLUSIONS: This study confirms the competency of single-port procedure in first-line surgical treatment of primary spontaneous pneumothorax. PMID- 25801109 TI - Intracorporeal ileocolic anastomosis in patients with laparoscopic right hemicolectomy. AB - BACKGROUND: Since the introduction of laparoscopic colorectal surgery, there has been a controversy between creating an intracorporeal or extracorporeal ileocolic anastomosis in right hemicolectomy. The purpose is to report our experience in intracorporeal anastomosis following right hemicolectomy in both malignant and benign pathologies. STUDY DESIGN: A retrospective review of a prospectively collected database was conducted at Virgen de la Arrixaca Clinical University Hospital (Murcia) between January 2000 and April 2014. The study includes all surgery patients who received a laparoscopic right hemicolectomy with an intracorporeal ileocolic anastomosis. The criteria for exclusion were conversion to open surgery during the procedure due to technical difficulties during dissect. Tumours considered T4 were not excluded, nor were stage IV patients or those with a history of previous abdominal surgery. RESULTS: There were 173 patients (63 females) aged 67 (range 14-91) years, with body mass index of 27 (17 52) kg/m(2) and ASA 1:2:3:4 of 12:78:68:15; 41% had previous abdominal surgery and 70% had a pre-existing comorbidity. Operating time was 142 (60-270) min. Specimen extraction site incision length was 8.1 (6-11.1) cm. Conversion rate was 9.2%, and there were 39 complications (22.54%) and 9 reoperations (5.2%). Readmission rate was 5.2%. Length of stay was 5.7 (1-35) days. CONCLUSION: The intracorporeal procedure is a safe and feasible alternative for creating an ileocolic anastomosis. It involves a similar rate of complications and may prevent some of the drawbacks presented by extracorporeal anastomosis. PMID- 25801110 TI - Natural orifice transluminal endoscopic surgery in humans: feasibility and safety of transgastric closure using the OTSC system. AB - BACKGROUND: NOTES is a technique in which an operation is performed within the body without a skin incision by using a natural body orifice to provide access. The principal challenge of transgastric NOTES procedures is still the feasibility and safety of access closure. Currently, there are very limited data regarding the closure of transgastric NOTES in humans, and the standard method and device for closure has not been defined. Herein, we evaluate the feasibility and safety of gastric closure after NOTES procedures in humans with the over-the-scope clip (OTSC). METHODS: Review of collected data of patients underwent transgastric NOTES in prospective clinical studies between April 2010 and March 2014 focused on the gastric closure with the OTSC. RESULTS: A total of 43 patients underwent transgastric NOTES: 36 patients with an acute appendicitis, six patients with a prophylactic bilateral salpingo-oophorectomy, and one patient with uterus myomatosus. In all 43 cases, the incision of the gastric wall and the endoscopic access to the abdominal cavity succeeded without any difficulty. After performing transgastric procedures, it was possible to close the access by OTSC in all cases. There were all in all three adverse events: one major (Clavien-Dindo Grade III) and two minor (Clavien-Dindo Grades I and II). CONCLUSION: Even if we could show for the first time in more than 40 consecutive patients that there is a safe approach for closing the transgastric access, it is absolutely necessary that further investigation in clinical settings has to be done to establish clear indications and guidelines for the use of transgastric NOTES. PMID- 25801111 TI - Short- and long-term outcomes of laparoscopic surgery for intestinal Behcet's disease: a comparative study with open surgery. AB - INTRODUCTION: Surgical treatment of intestinal Behcet's disease (BD) is not well established. Specifically, it is still difficult to assess the clinical value of laparoscopic surgery to address this condition. We aimed to evaluate the clinical course and the characteristics of laparoscopic surgery for intestinal BD compared with open surgery. METHODS: We reviewed charts of 91 patients who underwent surgical treatment for intestinal BD between January 1995 and December 2012. We retrospectively compared the laparoscopic group (LG, n = 30) and the open group (OG, n = 61) in terms of patient demographics, clinical features, operative data, postoperative course, complications within 30 days after operation, and long-term follow-up data. RESULTS: There were more females in the LG than in the OG (63.3 vs. 36.1%, p = 0.014), and oral/genital ulcers were more frequent in the LG (76.7 vs. 54.1%, p = 0.038; 60 vs. 36.1%, p = 0.031). Intractability with medical treatment was dominant in the LG (76.7 vs. 45.9%, p = 0.02), while intestinal perforation or fistula were more prevalent in the OG (10 vs. 44.3%, p = 0.001). Most patients received an ileocecectomy or a right hemicolectomy as their first surgery. In the LG, the patients had a shorter operation time (162.0 vs. 228.5 min, p < 0.001) and had less blood loss (61.7 vs. 232.3 ml, p = 0.003). There were no significant differences in postoperative complications, reoperation, mortality, and hospital stay between the groups. During the follow-up period, the mean number of operations was less in the LG than in the OG (1.3 vs. 2.1, p = 0.011). Analysis indicated that 20% of patients in the LG and 50.8% in the OG underwent more than two operations (p = 0.005). CONCLUSION: Laparoscopic surgery is feasible and safe for selected intestinal BD patients. However, there were no better short-term outcomes in LG compared with OG. PMID- 25801112 TI - Vacuum suction fixation versus staple fixation in TAPP laparoscopic hernia repair: introduction of a new technique for mesh fixation. AB - BACKGROUND: Proper mesh fixation is critical for successful TAPP laparoscopic hernia repair. Conventional mesh fixation may cause chronic neuralgia, groin paresthesia or other complications. This study aimed at introducing a new vacuum suction technique for mesh fixation and evaluating its efficacy and safety compared with traditional staple fixation way. METHODS: Clinical data of 242 patients undergoing TAPP from July 2011 to March 2014 were retrospectively analyzed. Patients were divided into vacuum suction fixation group and staple fixation group. The operation time, hospital stay, complications, recurrence, visual analogue scale pain score and cost were evaluated. RESULTS: All surgeries were successful. The operation time of staple group was (42.34 +/- 10.15) min for unilateral hernia and (64.08 +/- 16.01) min for bilateral hernias. The postoperative hospital stay was (2.76 +/- 0.84) days. One recurrence was observed (0.90%). For vacuum group, the operation time was (42.66 +/- 7.76) min and (63.92 +/- 10.49) min, and hospital stay was (2.60 +/- 0.74) days. No recurrence was observed. There was no significant difference in recurrence, operation time, postoperative pain and hospital stay between two groups (P > 0.05). Average cost were (11,714 +/- 726) RMB for vacuum group which was lower than staple group (14,837 +/- 1568) RMB (P < 0.05). The top three complications of staple group were scrotal emphysema (10.81%), scrotal seroma (6.31%) and temporary nerve paresthesia (4.50%) while for vacuum group, they were scrotal seroma (3.82%), temporary nerve paresthesia (3.05%), scrotal emphysema (1.53%) and uroschesis (1.53%). The incidence of scrotal emphysema was lower in vacuum group (P < 0.05). No significant difference was observed in other complications (P > 0.05). CONCLUSION: Both techniques for mesh fixation are safe and effective. There is no significant difference in recurrence, operation time, postoperative pain or hospital stay. The vacuum suction fixation technique is more economical with lower incidence of scrotal emphysema. PMID- 25801113 TI - The effect of rs9939609 FTO gene polymorphism on weight loss after laparoscopic sleeve gastrectomy. AB - PURPOSE: Remarkable differences in weight loss have been observed in obese patients undergoing laparoscopic sleeve gastrectomy (LSG). These high variations might be partly explained by genetic factors. The rs9939609 fat mass and obesity associated gene (FTO) polymorphism has been implicated in the susceptibility of obesity. We aimed to explore the effects of the rs9939609 FTO gene polymorphism on weight loss among severely obese patients applying for LSG. MATERIALS AND METHODS: All individuals were analyzed for the FTO rs9939609 gene polymorphism. A total of 74 morbid obese patients (20 male, 54 female) were operated. Body weight and body mass index (BMI) were measured at before LSG and after surgery at the sixth month. RESULTS: Twenty-eight patients (37.8%) had genotype TT (wild-type allel), 36 patients (48.6%) had genotype TA, and 10 patients (13.5%) had genotype AA. In both wild-type group and mutant group, BMI and weight levels decreased at the sixth month after surgery. Percent of excess weight loss (EWL) at 6 months of follow-up was similar in both groups. There were no differences between the mutant and wild-type groups percent of EWL at the sixth month after applying LSG. CONCLUSION: Our data showed that the rs9939609 FTO gene polymorphism is not a useful genetic test prior to LSG to help clinicians predicting the weight loss for severely obese patients in short-term follow-up. PMID- 25801114 TI - Outcomes of laparoscopic feeding jejunostomy tube placement in 299 patients. AB - BACKGROUND: Jejunostomy catheters for jejunal feeding are an effective method to improve nutritional status in malnourish patients. However, this procedure is commonly being performed using an open approach, which can be associated with more postoperative pain and prolonged recovery. The objective of this study was to assess the outcomes of patients who underwent placement of feeding jejunostomy using a laparoscopic approach. METHODS: A retrospective review was performed of patients who underwent laparoscopic jejunostomy tube placement between 1998 and 2014. Main outcome measures included indication for catheter placement, rate of conversion rate to open surgery, perioperative and late morbidity and in-hospital mortality. RESULTS: Two hundred and ninety-nine consecutive patients underwent laparoscopic jejunostomy during the study period. The mean age was 64 years, and 81% of patients were male. The mean BMI was 26.2 kg/m(2). The most common indications for catheter placement were resectable esophageal cancer (78%), unresectable esophageal cancer (10%) and gastric cancer (6%). There were no conversions to open surgery. The 30-day complication rate was 4.0% and included catheter dislodgement (1%), intraperitoneal catheter displacement (0.7%), catheter blockage (1%) or breakage (0.3%), site infection requiring catheter removal (0.7%) and abdominal wall hematoma (0.3%). The late complication rate was 8.7% and included jejuno-cutaneous fistula (3.7%), jejunostomy tube dislodgement (3.3%), broken or clogged J-tube (1.3%) and small bowel obstruction (0.3%). The 30-day mortality was 0.3% for a patient with stage IV esophageal cancer who died in the postoperative period secondary to respiratory failure. CONCLUSION: In this large consecutive series of feeding jejunostomy, the laparoscopic approach is feasible and safe and associated with a low rate of small bowel obstruction and no intraabdominal catheter-related infection. PMID- 25801115 TI - On the temporal dynamics of sign production: An ERP study in Catalan Sign Language (LSC). AB - This study investigates the temporal dynamics of sign production and how particular aspects of the signed modality influence the early stages of lexical access. To that end, we explored the electrophysiological correlates associated to sign frequency and iconicity in a picture signing task in a group of bimodal bilinguals. Moreover, a subset of the same participants was tested in the same task but naming the pictures instead. Our results revealed that both frequency and iconicity influenced lexical access in sign production. At the ERP level, iconicity effects originated very early in the course of signing (while absent in the spoken modality), suggesting a stronger activation of the semantic properties for iconic signs. Moreover, frequency effects were modulated by iconicity, suggesting that lexical access in signed language is determined by the iconic properties of the signs. These results support the idea that lexical access is sensitive to the same phenomena in word and sign production, but its time-course is modulated by particular aspects of the modality in which a lexical item will be finally articulated. PMID- 25801117 TI - Coiled polymeric growth factor gradients for multi-luminal neural chemotaxis. AB - In the injured adult nervous system, re-establishment of growth-promoting molecular gradients is known to entice and guide nerve repair. However, incorporation of three-dimensional chemotactic gradients in nerve repair scaffolds, particularly in those with multi-luminal architectures, remains extremely challenging. We developed a method that establishes highly tunable three-dimensional molecular gradients in multi-luminal nerve guides by anchoring growth-factor releasing coiled polymeric fibers onto the walls of collagen-filled hydrogel microchannels. Differential pitch in the coiling of neurotrophin-eluting fibers generated sustained chemotactic gradients that appropriately induced the differentiation of Pheochromocytoma (PC12) cells into neural-like cells along an increasing concentration of nerve growth factor (NGF). Computer modeling estimated the stability of the molecular gradient within the luminal collagen, which we confirmed by observing the significant effects of neurotrophin gradients on axonal growth from dorsal root ganglia (DRG). Neurons growing in microchannels exposed to a NGF gradient showed a 60% increase in axonal length compared to those treated with a linear growth factor concentration. In addition, a two-fold increment in the linearity of axonal growth within the microchannels was observed and confirmed by a significant reduction in the turning angle ratios of individual axons. These data demonstrate the ability of growth factor-loaded polymeric coiled fibers to establish three-dimensional chemotactic gradients to promote and direct nerve regeneration in the nervous system and provides a unique platform for molecularly guided tissue repair. PMID- 25801116 TI - In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment. AB - To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype. PMID- 25801119 TI - Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury. AB - Receptor-interacting protein 3 (RIP3) is a key molecular switch in tumor necrosis factor-induced necroptosis requiring the formation of an RIP3-RIP1 complex. We have recently shown that hippocampal cornu ammonis 1 (CA1) neuronal death induced by 20-min global cerebral ischemia/reperfusion (I/R) injury is a form of programmed necrosis. However, the mechanism behind this process is still unclear and was studied here. Global cerebral ischemia was induced by the four-vessel occlusion method and Necrostatin-1 (Nec-1), a specific inhibitor of necroptosis, was administered by intracerebroventricular injection 1h before ischemia. Normally, in the hippocampal CA1 neurons, RIP1 and RIP3 are located in the cytoplasm. However, after I/R injury, RIP3 was upregulated and translocated to the nucleus while RIP1 was not affected. Nec-1 pretreatment prevented hippocampal CA1 neuronal death and I/R induced changes in RIP3. Decreased level of NAD+ in hippocampus and the release of cathepsin-B from lysosomes after I/R injury were also inhibited by Nec-1. Our data demonstrate that Nec-1 inhibits neuronal death by preventing RIP3 upregulation and nuclear translocation, as well as NAD+ depletion and cathepsin-B release. The nuclear translocation of RIP3 has not been reported previously, so this may be an important role for RIP3 during ischemic injury. PMID- 25801122 TI - Rydberg and valence state excitation dynamics: a velocity map imaging study involving the E-V state interaction in HBr. AB - Photoexcitation dynamics of the E((1)Sigma(+)) (v' = 0) Rydberg state and the V((1)Sigma(+)) (v') ion-pair vibrational states of HBr are investigated by velocity map imaging (VMI). H(+) photoions, produced through a number of vibrational and rotational levels of the two states were imaged and kinetic energy release (KER) and angular distributions were extracted from the data. In agreement with previous work, we found the photodissociation channels forming H*(n = 2) + Br((2)P3/2)/Br*((2)P1/2) to be dominant. Autoionization pathways leading to H(+) + Br((2)P3/2)/Br*((2)P1/2) via either HBr(+)((2)Pi3/2) or HBr(+)*((2)Pi1/2) formation were also present. The analysis of KER and angular distributions and comparison with rotationally and mass resolved resonance enhanced multiphoton ionization (REMPI) spectra revealed the excitation transition mechanisms and characteristics of states involved as well as the involvement of the E-V state interactions and their v' and J' dependence. PMID- 25801120 TI - LRIG1, human EGFR inhibitor, reverses multidrug resistance through modulation of ABCB1 and ABCG2. AB - In our previous study, we have found that leucine-rich repeats and immunoglobulin like domains 1(LRIG1) can improve the chemosensitivity in U251 cells whereas the role of LRIG1 in multidrug resistance (MDR) remains unknown. Here, we reported that LRIG1 can reverse MDR by inhibiting epidermal growth factor (EGF) receptor (EGFR) and secondary inhibiting ATP-binding cassette, sub-family B member 1(ABCB1) and ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2). Our data showed that the expression of LRIG1 was significantly higher in O6 methylguanine DNA methyltransferase (MGMT) Promoter Methylation positive glioblastoma tissues compared to MGMT Promoter Methylation negative glioblastoma tissues. In addition, we found that LRIG1 expression was significantly decreased in MDR cells U251/TMZ compared to U251cells. Our results demonstrated that over expression of LRIG1 can reverse the MDR. The expression of ABCB1 and ABCG2 were markedly suppressed when LRIG1 was over-expressed, supporting the negative relationship between LRIG1 level and ABCB1 and ABCG2 level in human specimen. Furthermore, we found that LRIG1 downregulated ABCB1 and ABCG2 through suppressing EGFR expression. In case of EGFR knockdown, the effect of LRIG1 on regulating MDR, ABCB1 and ABCG2 was partially compromised. Our results, for the first time, showed that LRIG1 can reverse MDR in glioblastoma, by negatively regulating EGFR and secondary suppressing the levels of ABCB1 and ABCG2. PMID- 25801118 TI - Corticostriatal BDNF and alcohol addiction. AB - Growth factors, long studied for their involvement in neuronal development and plasticity, also regulate responses to drugs of abuse, including alcohol. This review details the intricate interaction between the Brain-Derived Neurotrophic Factor (BDNF) and alcohol, and provides evidence to suggest that corticostriatal BDNF signaling acts to keep alcohol drinking in moderation. Specifically, we describe studies in rodent models suggesting that moderate consumption of alcohol increases BDNF levels in the dorsal striatum, which in turn act to suppress alcohol intake by activating a Mitogen-Activated Protein Kinase (MAPK)-dependent genomic mechanism. We further provide data to suggest that alcohol intake levels escalate when the endogenous corticostriatal BDNF pathway becomes dysregulated. Finally, we summarize recent studies suggesting that specific microRNAs targeting BDNF mRNA in the medial prefrontal cortex (mPFC) regulate the breakdown of the protective corticostriatal BDNF pathway. PMID- 25801121 TI - Hyperoxia-induced immature brain injury through the TLR4 signaling pathway in newborn mice. AB - Toll-like receptor 4 (TLR4), a pathogen-associated molecular pattern receptor, is known to initiate an inflammatory cascade in response to certain stimuli within the central nervous system (CNS). Although TLR4 activation is known to be a first line response of the innate immune system, whether and how hyperoxia influences TLR4 signaling in an immature brain remains unclear. In this study, TLR4 wild type (W) and TLR4 knock-out(M) mice were exposed to 100% oxygen (the WO2 and MO2 groups, respectively), and control groups were exposed to ambient air (the WA and MA groups, respectively) for 48 h after postnatal-day (PND) 3. Next, neuronal apoptosis was quantified, and Morris water maze assays were conducted. The WO2 mice showed increased TLR4 expression compared with the WA mice, additionally, the expression level of Tumor Necrosis Factor-alpha (TNF-alpha) in the WO2 mice was significantly increased compared with the levels in the WA, MA and MO2 mice. Electron microscopy and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assays showed a significant increase, compared to the WO2 mice, in neuronal apoptosis within the prefrontal cortex and hippocampal CA1 region in the WO2 mice. In contrast, there were no obvious differences in neuronal apoptosis between the MO2 and MA groups. The results of the Morris water maze tests demonstrated marked deficits in learning and memory in the WO2 mice but much milder deficits in the MO2 mice compared to the WA and MA groups, respectively. Moreover, cultured N9 (TLR4 wild-type, derived from ICR/CD1 mice) microglia exposed to hyperoxia showed an immediate increase in the expression of TLR4 mRNA, followed by an increase in the expression of both TNF alpha and reactive oxygen species (ROS), but this increase was abrogated by the loss of TLR4 signaling in TLR4-knockout microglia (primary cells from a C3H/HeJ strain defective in TLR4). Taken together, these data suggest that 1) TLR4 signaling is involved in hyperoxia-induced immune responses in the immature brain and 2) the loss of TLR4 activation may abrogate the neuronal apoptosis and cognitive deficits following hyperoxia exposure in newborn mice. PMID- 25801124 TI - Editorial: Discovery and biosynthesis of natural products with anti-cancer activities. PMID- 25801123 TI - EphB2 activation is required for ependymoma development as well as inhibits differentiation and promotes proliferation of the transformed cell. AB - Our intracranial implantation mouse model of ependymoma clearly demonstrates overexpression of the ephrin receptor EphB2 in Ink4a/Arf((-/-)) supratentorial embryonic neural stem cells (STeNSCs) to be essential for transformation and disease development; however the requirement for and consequence of receptor activation on transformation and neural stem cell function were not examined. We definitively illustrate the necessity for receptor activation in cellular transformation and the importance of implantation site and microenvironment in directing ependymoma development. In vitro assays of EphB2 overexpressing Ink4a/Arf((-/-)) STeNSCs showed no changes in their neural stem cell characteristics (stem cell marker expression and self-renewal) upon receptor activation, but EphB2 driven tumor cells were inhibited significantly in differentiation and exhibited increased tumorsphere formation and cellular proliferation in response to ephrin-B ligand mediated receptor activation. Additionally, we observed substantial differences in the phosphorylation state of several key proteins involved in Ras and p38 MAPK signaling when comparing EphB2 overexpressing Ink4a/Arf((-/-)) STeNSCs and tumor cells with relatively little change in total protein levels. We propose that EphB2 mediated ependymoma development is a multifactorial process requiring microenvironment directed receptor activation, resulting in changes in the phosphorylation status of key regulatory proteins, maintenance of a stem-like state and cellular proliferation. PMID- 25801127 TI - Quantification of morphine, morphine 6-glucuronide, buprenorphine, and the enantiomers of methadone by enantioselective mass spectrometric chromatography in whole blood. AB - PURPOSE: Deaths among drug addicts are frequently caused by intoxication with methadone and/or morphine. These drugs are often used in combination with other drugs, such as buprenorphine. In addition, methadone is generally used as a mixture of R- and S-enantiomers. To date, a method for separation and quantitation of these specific drugs has not been developed. The aim of this study was to develop a sensitive enantioselective method for quantitation of morphine, its active metabolite morphine 6-glucuronide, buprenorphine, and R- and S-methadone, in a single analytical run. METHODS: Whole blood samples were diluted with 0.5 mol/L ammonium carbonate buffer and extracted on a Bond Elut C18 solid-phase extraction column with an automatic solid-phase extraction system. Chromatographic separation was performed on a chiral alpha-1-acid glycoprotein column with an acetonitrile/ammonium acetate buffer (10 mmol/L, pH 7.0, 22:78 v/v) mobile phase. The whole blood concentrations of the drugs were quantified by mass spectrometry using their stable isotope-labeled compounds as internal standards. RESULTS: The method was validated with respect to specificity, linearity, precision, limits of detection, and quantification and matrix effects. The precision (coefficient of variation) was below 15%, and the accuracy was between 90 and 115%. CONCLUSIONS: This method will be useful for routine analyses in forensic laboratories where blood samples are frequently analyzed for drugs of abuse. In some cases, sudden death from methadone overdose is caused by the enantiomeric form of the methadone, which makes the enantiomer separation capability of this method important. PMID- 25801125 TI - The perfect storm: HLA antibodies, complement, FcgammaRs, and endothelium in transplant rejection. AB - The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multifaceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLAs). Despite the clearly detrimental impact of HLA antibodies (HLA-Abs) on graft function and survival, the prevention, diagnosis, and treatment of AMR remain a challenge. The histological manifestations of AMR reflect the signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a 'perfect storm' of inflammation. Characterization of antibody features that are critical for effector functions may help to identify HLA-Abs that are more likely to cause rejection. We also highlight recent advances that may pave the way for new, more effective therapies. PMID- 25801129 TI - Characterization of temperature induced changes in liposomes coated with poly(N isopropylacrylamide-co-methacrylic acid). AB - Positively charged liposomes were coated with the negatively charged and temperature sensitive poly(N-isopropylacrylamide-co-methacrylic acid) by electrostatic deposition. Too low or too high polymer concentrations lead to unstable suspensions. However, intermediate polymer concentrations (0.05-0.2 wt.%) result in relatively stable suspensions of polymer-coated liposomes. At elevated temperatures the thickness of the polymer layer around the coated liposomes increased sharply at 40 degrees C, due to the formation of polymer multilayers. At higher temperatures, a contraction of the adsorbed polymer layer was observed. The uncoated liposomes exhibited an interesting transition in size and intensity of the scattered light when heated, attributed to the transition from the gel to liquid crystalline phase. Rheo-SALS (small angle light scattering under shear conditions) measurements demonstrated that the polymer coating was stable under shear at physiological temperature. It also revealed an anomalous high scattered intensity of the uncoated liposomes compared to the coated liposomes. This discrepancy was diminished at higher temperatures, and can probably be attributed to the change from a non-spherical, polyhedron-like conformation of the uncoated liposomes in the gel phase to a spherical shape above the phase transition. PMID- 25801128 TI - Mechanistic study of the hydrothermal reduction of palladium on the Tobacco mosaic virus. AB - The fundamental mechanisms governing reduction and growth of palladium on the genetically engineered Tobacco mosaic virus in the absence of an external reducer have been elucidated via in situ X-ray absorption spectroscopy. In recent years, many virus-inorganic materials have been synthesized as a means to produce high quality nanomaterials. However, the underlying mechanisms involved in virus coating have not been sufficiently studied to allow for directed synthesis. We combined XAS, via XANES and EXAFS analysis, with TEM to confirm an autocatalytic reduction mechanism mediated by the TMV1Cys surface. This reduction interestingly proceeds via two first order regimes which result in two linear growth regimes as spherical palladium nanoparticles are formed. By combining this result with particle growth data, it was discovered that the first regime describes growth of palladium nanoparticles on the virion while the second regime describes a second layer of larger particles which grew sporadically on the first palladium nanoparticle layer. Subsequent aggregation of free solution based spherical particles and metallized nanorods characterize a third and final regime. At the end of the second reduction regime, the average particle diameter of particles tethered to the TMV1Cys surface are approximately 4.5 nm. The use of XAS to simultaneously monitor the kinetics of biotemplated reactions along with growth of metal nanoparticles will provide insight into the pertinent reduction and growth mechanisms so that nanorod properties can be controlled through their populating nanoparticles. PMID- 25801130 TI - Sunlight responsive WO3/ZnO nanorods for photocatalytic degradation and mineralization of chlorinated phenoxyacetic acid herbicides in water. AB - Highly effective WO3/ZnO nanorods (NRs) were synthesized via a hydrothermal deposition method for degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) under natural sunlight. The structural properties of WO3/ZnO NRs such as morphology, crystal structure, porous properties and light absorption characteristics were investigated in detail. The X-ray diffraction and X-ray photoelectron spectroscopy results indicated that the prepared samples were two-phase photocatalysts consisted of WO3 and ZnO NRs. The UV-vis diffuse reflectance spectroscopy result showed that the addition of WO3 altered the optical properties of the photocatalysts. In contrast with the pure ZnO NRs, commercial anatase TiO2 and commercial WO3, the WO3/ZnO NRs showed excellent sunlight photocatalytic activities in degrading 2,4-D. The optimal WO3 loading and calcination temperature were also determined. Based on the band position, the synergetic effect of WO3 and ZnO NRs was the source of the enhanced photocatalytic activity as validated by PL and terephthalic acid photoluminescence measurements. The reaction intermediates and degradation pathways of 2,4-D were elucidated by a HPLC method. In addition, the extent of mineralization during the 2,4-D degradation was also estimated using total organic carbon (TOC) and ion chromatography (IC) analyses. PMID- 25801126 TI - Emerging preclinical animal models for FSHD. AB - Facioscapulohumeral dystrophy (FSHD) is a unique and complex genetic disease that is not entirely solved. Recent advances in the field have led to a consensus genetic premise for the disorder, enabling researchers to now pursue the design of preclinical models. In this review we explore all available FSHD models (DUX4 dependent and -independent) for their utility in therapeutic discovery and potential to yield novel disease insights. Owing to the complex nature of FSHD, there is currently no single model that accurately recapitulates the genetic and pathophysiological spectrum of the disorder. Existing models emphasize only specific aspects of the disease, highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD. PMID- 25801131 TI - Nitrogen-doped perovskite-type La2Ti2O7 decorated on graphene composites exhibiting efficient photocatalytic activity toward bisphenol A in water. AB - Nitrogen-doped lanthanum titanate decorated on graphene sheets (GR/N-doped La2Ti2O7) used as photocatalyst was prepared by a two-step process. To synthesize GR/N-doped La2Ti2O7, La2Ti2O7 was initially developed under heat treatment in NH3 and subsequently decorated on GR by hydrothermal processing. The resulting GR/N doped La2Ti2O7 was characterized by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. Characterization results indicated that N-doped La2Ti2O7 was approximately 6-8 nm thick with single crystalline perovskite structure and chemically attached onto GR nanosheets by the formation of TiN bond, TiC bond, and oxynitrides. The application of GR/N doped La2Ti2O7 composites to bisphenol A decomposition exhibits high photocatalytic efficiency under irradiation compared with pure La2Ti2O7 materials. This finding was due to the synergistic effect of great adsorption, enhanced light absorption, efficient charge separation and transfer processes in the presence of GR, and reduced band gap energy because of N doping. This study provides new insights into the fabrication and practical application of high performance photocatalysts in wastewater treatment. PMID- 25801132 TI - Determination of molecular orientation and order of N-(6 mercaptoacetylhexyl)quinolinium tricyanoquinodimethanide adsorbed on Ag nanoparticles. AB - The surface-enhanced and tip-enhanced Raman scattering spectra of N-(6 Mercaptoacetylhexyl)quinolinium tricyanoquinodimethanides on silver coated nanosurfaces have been obtained, analyzed using Density Functional Theory Calculations, and a complete list of frequencies and assignments for the molecules are presented. The spectroscopic evidence points to the fact that monolayers of the molecule can be formed through the self-assembly process and the SERS data indicate that the monolayer attach to the silver surface through the nitrile groups. SERS spectroscopy was useful in determining the orientation of the monolayer as well as estimating its order. Deprotection the thiol group thereby terminating the tail of the molecule with a sulfur atom allowed for a selectively oriented monolayer to be formed which permanently bound the molecules to the surface preventing rearrangements. This orientation of AcSC6H12Q-3CNQ on silver a surface allowed the electron pairs of the nitrogen to be available for interaction with a second contact. Based on trigonometric tangent function calculations the tilt angle was calculated to be 38 degrees for the protected molecule and 70 degrees for the deprotected alkane thiol monolayer. PMID- 25801133 TI - Immobilization of fluorescent chemosensor on pyrogenic silica: a promising device for gaseous detection. AB - A new approach to enhance performances of a cyclodextrin-based fluorescent chemosensor combining grafting on a silica matrix and quaternization reaction is presented. The full characterization of new fluorescent hybrid material has clearly revealed the embedding of cyclodextrin inside the siliceous material. Finally, through a comparison with previous aqueous studies, a preliminary test of toluene detection was presented and highlighted the high potential of this approach, which opens attractive perspectives of evolution toward more sensitive and selective VOC's sensing in air or in hot industrial gaseous waste. PMID- 25801134 TI - Effects of oxidation on the defect of reduced graphene oxides in graphene preparation. AB - The relationship between the defects of reduced graphene oxide (RGO) and the oxidation degree of graphite in the preparation of graphene with chemical conversion method has been studied in this work. This study was performed on an artificial graphite through the measurements of X ray diffraction, Raman spectroscopy and particle size analysis. The experimental results have shown that there indeed was a close relationship between the defects and the oxidation degree, which appeared in the form of S-type curve. Also, it was found that a low KMnO4 addition would lead to a partial oxidation of graphite, leaving defects mainly on the edges of RGO; with a high KMnO4 addition, the defects on RGO mostly appeared on the surfaces. PMID- 25801135 TI - Carbon nanotubes/tin oxide nanocomposite-supported Pt catalysts for methanol electro-oxidation. AB - Carbon nanotubes/tin oxide nanocomposite (MWCNTs-SnO2) was obtained via the hydrolysis of SnCl4 in the presence of multi-walled carbon nanotubes (MWCNTs) and subsequent calcinations. And carbon nanotubes/tin oxide nanocomposite-supported Pt catalysts (Pt/MWCNTs-SnO2) were prepared by in-situ liquid phase reduction using H2PtCl6 as a metal precursor. As-prepared catalysts were characterized by X ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM), and their catalytic performances were evaluated by chronoamperometry (CA) and cyclic voltammetry (CV). Desirable catalytic performance for methanol electro-oxidation was observed with a reduced size and an improved dispersion of Pt catalysts on the MWCNTs-SnO2 nanocomposite. The calcination temperature of MWCNTs-SnO2 nanocomposite was a key factor for controlling the catalytic performance of Pt/MWCNTs-SnO2 catalysts. PMID- 25801136 TI - Mapping single macromolecule chains using the colloid deposition method: PDADMAC on mica. AB - Monolayers of the cationic polyelectrolyte poly(diallyldimethylammonium chloride) (PDADMAC) on mica were thoroughly characterized using the streaming potential and the colloid deposition methods. Initially, the stability of the monolayers was determined by performing desorption experiments carried out under diffusion controlled regime. It was shown that the desorption of the polyelectrolyte at the ionic strength range 0.01-0.15 M is negligible over the time of 20 h. The structure of PDADMAC monolayers and orientation of molecules were evaluated using the colloid deposition measurements involving negatively charged polystyrene latex microspheres, 820 nm in diameter. The functional relationships between the polyelectrolyte coverage and latex coverage deposited within 20 h were acquired by direct optical microscope. In this way the influence of ionic strength varied in the range 0.15-0.01 M on the molecule orientation in monolayers was determined. It was shown that for ionic strength of 0.15 M nearly one to one mapping of polyelectrolyte chains by colloid particles can be achieved for PDADMAC coverage below 0.1%. In this way, because of a considerable surface area ratio between the macromolecule and the colloid particle, an enhancement factor of 10(3) can be attained. This behavior was quantitatively interpreted in terms of the random site adsorption model whereas the classical mean-field theory proved inadequate. On the other hand, for lower ionic strength, it was confirmed that an irreversible immobilization of latex particles can only occur at a few closely spaced PDADMAC chains. It was shown that these experimental results were consistent with the side-on adsorption mechanisms of PDADMAC at mica for the above ionic strength. PMID- 25801137 TI - Synthesis, characterization and dye removal capacities of N-doped mesoporous carbons. AB - Nitrogen-doped ordered mesoporous carbons were synthesized by chemical vapor deposition, using acetonitrile as carbon and nitrogen source and SBA-15 as mesoporous silica template. Their porous texture, structural order and surface chemistry were studied as a function of the experimental conditions (acetonitrile stream concentration and deposition time). A non-doped ordered mesoporous carbon was also prepared by the same procedure using propylene as carbon source. Methylene blue, methyl orange and fuchsin acid were selected as probe molecules to investigate the dye adsorption behavior on the ordered mesoporous carbons. Both N-doped and non-doped ordered mesoporous carbons adsorbed large amounts of these three dyes demonstrating the importance of mesoporosity, especially for the adsorption of larger dyes (e.g. fuchsin acid). The presence of nitrogen functional groups was detrimental for the adsorption of the basic dye (methylene blue). On the other hand, the nitrogen functionalities improved the adsorption kinetics for both acid and basic dyes, and the N-doped samples achieved 100% of their maximum adsorption capacities in less than 15 min. PMID- 25801139 TI - Effect of addition of silica- and amine functionalized silica-nanoparticles on the microstructure of calcium silicate hydrate (C-S-H) gel. AB - In this work we study the influence of adding nano-silica (SiO2, NyasilTM) and aminopropyl (-(CH2)3-NH2,) functionalized silica nanoparticles (Stoga) during the synthesis of calcium-silicate-hydrate (C-S-H gel). Characterization by solid state (29)Si NMR and ATR-FTIR spectroscopy showed that the addition of both particle types increases the average length of the silicate chains in C-S-H gel being this effect slightly more important in the case of Stoga particles. In addition, (13)C NMR and XPS confirmed that the aminopropyl chain remains in the final product cleaved to silicon atoms at the end of the silicate chain of C-S-H gel whereas XRD measurements showed that this result in an increment in the basal distance compared with ordinary CSH. In addition, the dynamics of water within the pores of C-S-H gel was analyzed by broadband dielectric spectroscopy. We observed that water confined in C-S-H formed with the addition of nanoparticles is faster than that in plain C-S-H which can be related to a different porous structure in these materials. PMID- 25801138 TI - Synthesis and characterization of pH-responsive and fluorescent poly (amidoamine) dendrimer-grafted cellulose nanocrystals. AB - Poly (amidoamine) (PAMAM) dendrimers have found promising applications in biomedicine and in the encapsulation of inorganic nanoparticles. G6 PAMAM dendrimer-grafted cellulose nanocrystals (CNC-PAMAM) were prepared via a simple carbodiimide-mediated amidation process and they displayed pH-responsive and fluorescent characteristics as confirmed by zeta potential, transmittance, isothermal titration calorimetry (ITC), and fluorescence spectroscopy. Stable aqueous dispersions of CNC-PAMAM were obtained at pH?4 and pH?10, driven by electrostatic repulsion from positive charge and negative charge respectively. However, large aggregates were formed at pH values from 5 to 9 due to electrostatic attraction. In addition, strong blue fluorescent emission was observed, and the fluorescent behaviour of CNC-PAMAM was influenced by the formation of aggregates. The pH-responsive and fluorescent properties of CNC PAMAM may be suitable for their applications in pH-responsive nanodevices, fluorescent-based pH sensors, optical markers, and nanoreactors for the encapsulation of inorganic nanoparticles. PMID- 25801140 TI - Widening Synthesis Bottlenecks: Realization of Ultrafast and Continuous-Flow Synthesis of High-Silica Zeolite SSZ-13 for NOx Removal. AB - Characteristics of zeolite formation, such as being kinetically slow and thermodynamically metastable, are the main bottlenecks that obstruct a fast zeolite synthesis. We present an ultrafast route, the first of its kind, to synthesize high-silica zeolite SSZ-13 in 10 min, instead of the several days usually required. Fast heating in a tubular reactor helps avoid thermal lag, and the synergistic effect of addition of a SSZ-13 seed, choice of the proper aluminum source, and employment of high temperature prompted the crystallization. Thanks to the ultra-short period of synthesis, we established a continuous-flow preparation of SSZ-13. The fast-synthesized SSZ-13, after copper-ion exchange, exhibits outstanding performance in the ammonia selective catalytic reduction (NH3 -SCR) of nitrogen oxides (NOx ), showing it to be a superior catalyst for NOx removal. Our results indicate that the formation of high-silica zeolites can be extremely fast if bottlenecks are effectively widened. PMID- 25801147 TI - Heterotopic Ossification and Peripheral Nerve Entrapment: Ultrasound is a Must use Imaging Modality. PMID- 25801146 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. AB - Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org). PMID- 25801149 TI - Regional survey of entrance surface dose to patients from X-ray examinations in Saudi Arabia. AB - The aim of this study was to evaluate the entrance surface doses (ESDs) to patients undergoing chest and lumbar spine X-ray examinations in Najran, Saudi Arabia. ESD per examination was estimated from X-ray tube output parameters in two hospitals comprising three X-ray units and a sample of 137 radiographs. Hospital mean ESDs estimated range from 0.068 to 0.34 mGy for chest posteroanterior, 0.44-3.42 mGy for lumbar spine anteroposterior and 0.96-7.98 mGy for lumbar spine lateral. The results are useful to national and professional organizations and can be used as a baseline upon which future dose measurements may be compared. PMID- 25801148 TI - Acute kidney injury after transcatheter aortic valve implantation: Impact of contrast agents, predictive factors, and prognostic importance in 203 patients with long-term follow-up. AB - BACKGROUND: Acute kidney injury (AKI) frequently occurs following transcatheter aortic valve implantation (TAVI) and has been related to a worse outcome. We investigated the importance of contrast medium composition, either iso-osmolar (IOCM) or low-osmolar (LOCM) and assessed predictors for AKI after TAVI. METHODS AND RESULTS: We assessed AKI in 203 TAVI patients treated mainly with trans femoral implantation and analgosedation. A total of 100 patients received IOCM and 103 LOCM. AKI was defined according to the Valve Academic Research Consortium. Following TAVI, 39 patients (19.2%) developed AKI; 17.0% of the IOCM and 21.4% of the LOCM group (p=0.43). The only independent predictor for AKI was baseline serum creatinine [odds ratio (OR) 0.26, 95% confidence interval (CI) 0.01-0.64, p=0.002]. Patients with advanced AKI (stages 2 and 3) post-TAVI had significantly higher mortality at 2 years (log rank p<0.001), whereas patients with AKI stage 1 had a similar long-term outcome to non-AKI patients. CONCLUSIONS: Following TAVI, we observed no difference in the occurrence of AKI between IOCM and LOCM. Baseline creatinine was the only independent predictor of AKI, and patients who developed advanced AKI had significantly higher mortality at 2 years. PMID- 25801150 TI - Cell-based biological evaluations of 5-(3-bromo-4 phenethoxybenzylidene)thiazolidine-2,4-dione as promising wound healing agent. AB - Recent studies have focused on prostaglandin E2 (PGE2) because PGE2 regulates vertebrate hematopoietic stem cell induction and engraftment. PGE2 acts through EP2 and EP4 receptors to mediate regeneration and hematopoietic stem cell (HSC) development via the Wnt signaling pathway. Previously we reported that inhibitors of 15-PGDH can control the intracellular levels of PGE2. Therefore, we developed new potent 15-PGDH inhibitor, 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4 dione (TD191), with an IC50 of 4 nM and tested cell-based wound healing effects. This compound significantly increased the level of PGE2 (451 pg/mL) in A549 cells, which was about 7-fold higher than that of control. HaCaT cells exposed to TD191 showed significantly improved wound healing after 48 h in scratch wound healing test, whereas treatment of TD191 to the fibroblast Hs27 cells slightly decreased cell growth compared with control. SCL is a basic helix-loop-helix transcription factor that is an essential for HSC development. By qPCR, SCL expression in HaCaT cells was 2-fold enhanced after addition of TD191, while treatment of TD191 into fibroblast Hs27 cells was not significantly changed the expression levels of the gene. This data provides in vitro evidence that TD191 may have utility for the therapeutic management of wound healing without scar formation. PMID- 25801151 TI - Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors. AB - Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2 methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC50 of 0.95 +/- 0.12 MUM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC50 of 0.62 +/- 0.16 MUM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a go-go-related gene (zERG). PMID- 25801152 TI - A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity. AB - Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC50=5.3 nM, A549 IC50=26 nM). A clear correlation between cellular Mps1 and antiproliferative IC50 values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region. PMID- 25801154 TI - Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice. AB - We herein report the design and synthesis of a novel series of thiophene- and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of beta-hematin polymerization. Tested compounds were 3-71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40 mg/kg/day, while 5/5 mice survived in Thompson test at 160 mg/kg/day. PMID- 25801153 TI - Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new family of anti-oomycete compounds. AB - A novel class of experimental fungicides has been discovered, which consists of special N-thiazol-4-yl-salicylamides. They originated from amide reversion of lead structures from the patent literature and are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Plasmopara viticola (grapevine downy mildew) and Pythium ultimum (damping-off disease). Structure-activity relationship studies revealed the importance of a phenolic or enolic hydroxy function in the beta-position of a carboxamide. An efficient synthesis route has been worked out, which for the first time employs the carbonyldiimidazole-mediated Lossen rearrangement in the field of thiazole carboxylic acids. PMID- 25801155 TI - Ligand selectivity of a synthetic CXCR4 mimetic peptide. AB - The chemokine receptor CXCR4 belongs to the family of seven-transmembrane G protein coupled receptors (GPCRs). It is activated by its natural ligand SDF 1alpha. In addition, CXCR4, along with CCR5, serve as coreceptors during HIV-1 entry into its target cell. Recently, we introduced a CXCR4 mimetic peptide, termed CX4-M1, which presents the three extracellular loops (ECLs) of the receptor. CX4-M1 was shown to selectively bind to gp120 of X4-tropic, that is, CXCR4 using, HIV-1, as well as to peptides that present the V3-loops of these gp120 proteins. Furthermore, CX4-M1 selectively inhibits infection of cells with X4-tropic HIV-1. We have now adapted the sequence of the ECLs presented by CX4-M1 to the recently published crystal structure of CXCR4. The binding behavior, as well as the effect on HIV-1 infection, of the resulting peptide (CX4-Mc) was very similar to CX4-M1, validating retrospectively the original design of CX4-M1. A peptide presenting the ECLs of CCR5 (CR5-M), on the other hand, did neither bind to gp120 from X4-tropic HIV-1, nor did it inhibit infection of cells with X4 tropic HIV-1. Furthermore, we could show that CX4-M1, as well as CX4-Mc, but not CR5-M, are selectively recognized by anti-CXCR4 antibodies, bind to SDF-1alpha, and also inhibit SDF-1alpha signaling, extending the scope of selective functional CXCR4 mimicry through CX4-M1. PMID- 25801156 TI - Acyl-2-aminobenzimidazoles: a novel class of neuroprotective agents targeting mGluR5. AB - Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for treating traumatic brain injury (TBI). Using computational and medicinal methods, the structure-activity relationship of a class of acyl-2-aminobenzimidazoles (1-26) is reported. The new compounds are designed based on the chemical structure of 3,3' difluorobenzaldazine (DFB), a known mGluR5 PAM. Ligand design and prediction of binding affinities of the new compounds have been performed using the site identification by ligand competitive saturation (SILCS) method. Binding affinities of the compounds to the transmembrane domain of mGluR5 have been evaluated using nitric oxide (NO) production assay, while the safety of the compounds is tested. One new compound found in this study, compound 22, showed promising activity with an IC50 value of 6.4 MUM, which is ~20 fold more potent than that of DFB. Compound 22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions. PMID- 25801157 TI - Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis. AB - We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC50's of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC50=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC50=2.24 MUM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide. PMID- 25801158 TI - Structure-activity relationships of benzhydrol derivatives based on 1' acetoxychavicol acetate (ACA) and their inhibitory activities on multiple myeloma cell growth via inactivation of the NF-kappaB pathway. AB - 1'-Acetoxychavicol acetate (ACA), which was isolated from the rhizomes of Zingiberaceae, exhibits various biological actions, including anti-inflammatory, anti-human immunodeficiency virus (HIV), and anti-cancer activities. ACA represents an attractive candidate for the treatment of many cancers. We herein examined the structure-activity relationships of ACA derivatives based on the benzhydrol skeleton in human leukemia cells (HL-60). Our results revealed that the ACA derivatives synthesized (ACA, 1, and 18) had inhibitory effects on the growth of multiple myeloma cells (IM-9 cells) by inactivating the NF-kappaB pathway. PMID- 25801159 TI - Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5. AB - Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC50 value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold. PMID- 25801160 TI - Developing new chemical tools for DNA methyltransferase 1 (DNMT 1): a small molecule activity-based probe and novel tetrazole-containing inhibitors. AB - DNA methylation is an important epigenetic modification catalyzed by DNA methyltransferases (DNMTs). Abnormal expression of endogenous DNMTs in human causes alterations in the genome methylation patterns which subsequently lead to the development of cancers. Thus detection of endogenous DNMT activities and efficient inhibition of DNMTs have important therapeutic significance. In this work, a small molecule activity-based probe (ABP) of DNA methyltransferase 1 (DNMT1), T1, was developed. The probe was a clickable analog of tryptophan and was able to covalently label endogenous DNMT1 and inhibit its enzymatic activity more effectively than previously known DNMT1 inhibitors (RG108 and its maleimide analog 1149). In addition, we also discovered a new type of small molecule DNMT inhibitors based on tetrazole-containing compounds which were analogs of 1149. Among these compounds, which we called Gn, one of them (G6) possessed reasonable inhibitory activity against DNMT1 in both in vitro enzymatic assays and cell growth proliferation experiments. Both T1 and G6 showed effective labeling of endogenous DNMT1 from mammalian cells by using in vitro competitive pull-down and live-cell bioimaging experiments. PMID- 25801161 TI - SiO2 nanoparticles as platform for delivery of 3'-triazole analogues of AZT triphosphate into cells. AB - A system for delivery of analogues of AZT-triphosphates (AZT*TP) based on SiO2 nanoparticles was proposed. For this purpose, a simple and versatile method was developed for the preparation of SiO2~dNTP conjugates using the 'click'-reaction between AZTTP and premodified nanoparticles containing the alkyne groups. The substrate properties of SiO2~AZT*TP were tested using Klenow fragment and HIV reverse transcriptase. The 3'-triazole derivatives of thymidine triphosphate being a part of the SiO2~AZT*TP nanocomposites were shown to be incorporated into the growing DNA chain. It was shown by confocal microscopy that the proposed SiO2~AZT*TP nanocomposites penetrate into cells. These nanocomposites were shown to inhibit the reproduction of POX and Herpes viruses at nontoxic concentrations. PMID- 25801162 TI - Addition of low-dose ketamine to midazolam-fentanyl-propofol-based sedation for colonoscopy: a randomized, double-blind, controlled trial. AB - STUDY OBJECTIVE: To evaluate the effects of low-dose ketamine on midazolam fentanyl-propofol-based sedation for outpatient colonoscopy. DESIGN: Prospective, randomized, double-blinded, placebo-controlled trial. SETTING: Gastroenterology unit at a practice and clinical research center. SUBJECTS: Ninety-seven healthy American Society of Anesthesiology physical status 1 volunteers. INTERVENTIONS: Subjects were randomized to receive midazolam (0.02 mg/kg), fentanyl (1 MUg/kg), and ketamine (0.3 mg/kg) and midazolam (0.02 mg/kg), fentanyl (1 MUg/kg), and placebo (0.9% sodium chloride) in group K and group C, respectively. In both groups, incremental doses of propofol were used to maintain a Ramsay sedation score of 3 to 4. MEASUREMENTS: Values of heart rate, blood pressure, oxygen saturation, and respiratory rate were measured. Procedure times, recovery times, drug doses used, complications associated with the sedation, and physician and patient satisfaction were also recorded. MAIN RESULTS: In group K, mean amount of propofol used and mean induction time (P < .001), the need for the use of jaw thrust maneuver and mask ventilation, and the incidence of disruptive movements were significantly lower (P < .05) and gastroenterologist satisfaction at the beginning of the procedure was significantly superior (P < .05). Mean systolic blood pressures at 4, 6, 8, and 10 minutes (P < .01); diastolic blood pressures at 4, 6, and 8 minutes (P < .05); respiratory rates at 4, 6, 8, 10, 15, 20, and 25 minutes (P < .01); and oxygen saturation at 6, 8, 10, 15, and 20 minutes (P < .05) were significantly lower in group C. Patient satisfaction scores, recovery times, and discharge times were similar. No patient in either group experienced unpleasant dreams or hallucination in the postanesthesia care unit and on the first postoperative day. CONCLUSIONS: Addition of low-dose ketamine to midazolam fentanyl-propofol-based sedation for outpatient colonoscopy resulted in more rapid and better quality of sedation, less propofol consumption, more stable hemodynamic status, and less adverse effects with similar recovery times in adult patients. PMID- 25801163 TI - A simple intervention to reduce the anesthetic pharmacy budget; the effect of price list stickers placed on vaporizers. AB - STUDY OBJECTIVE: The study objective is to investigate the effects of a simple price list sticker placed on vaporizers on anesthetic use and costs. The price list only showed the cost per hour of the annually most expensive drugs, which had a low-cost alternative. DESIGN: The design is a prospective database study with historical controls. SETTING: The setting is at operating rooms. PATIENTS: All patients are undergoing a surgical procedure under anesthesia in both study periods, except cardiothoracic and day care patients. INTERVENTIONS: The intervention is application of a price list sticker on the vaporizers. MEASUREMENTS: Monthly cost and amount of anesthetic agents used during the 9 months before and after the intervention. MAIN RESULTS: After application of the price stickers, the use of both the annually most expensive agents and the anesthetic budget decreased substantially. Most notable was a decrease of 28% in the use of sevoflurane. CONCLUSIONS: Price sticker on vaporizers may be an effective, simple, and cheap method to reduce anesthetic costs. PMID- 25801164 TI - Family Efficacy within Ethnically Diverse Families: A Qualitative Study. AB - Family efficacy, which refers to a family's belief in its ability to produce a desired outcome, has been shown to protect adolescents from risky health behaviors. Few studies have examined family efficacy within diverse populations, however, and understanding of how efficacy is framed and formed within the context of cultural and familial values is limited. This descriptive qualitative study examined sources of family efficacy within ethnically and socioeconomically diverse families, evaluating how such families develop and exercise family efficacy with the intent to protect adolescents from risky health behaviors (i.e., marijuana and alcohol use and early sexual activity). We collected qualitative data via two semi-structured interviews, 4-6 months apart, with 31 adolescents (ages 12-14) and their parent/s, for total of 148 one-on-one interviews. Thematic analysis identified three distinct domains of family efficacy: relational, pragmatic, and value-laden. Prior experiences and cultural background influenced the domain/s utilized by families. Significantly, families that consistently tapped into all three domains were able to effectively manage personal and family difficulties; these families also had family strategies in place to prevent adolescents from risky behaviors. Health professionals could utilize this concept of multidimensional family efficacy to promote health within culturally diverse families. PMID- 25801165 TI - Dietary analysis of full marathon runners over 50 years of age: a retrospective study. AB - AIM: There is little information known about the dietary intakes of older athletes. The purpose of this study was to assess the dietary intakes of full marathon runners over the age of 50 during the 3 days prior to and during a 26.2 mile marathon. METHODS: Participants completed a 3-day food record prior to the marathon and a food recall post-marathon. Dietary records were entered into a nutrient analysis software program and were analyzed for total energy, macronutrients, and micronutrients. RESULTS: The average energy intake based on the 3-day food records was 2670+/-225 kcal/day, which was below the estimated energy requirement of 3140+/-102 kcal/day. The participants consumed 56%, 17% and 27% of energy from carbohydrates, protein and fat, respectively, and these were within the acceptable macronutrient distribution ranges. The participants had a favorable omega-6 to omega-3 ratio of 5:1. The participants were consuming 3920+/ 350 mg/day of sodium which is 70% above the goal of 2300 mg/day. The participants met the dietary reference intakes for only half of the micronutrients. Based on the food recall, 87% of the participants' energy intake was from carbohydrates (213+/-19 g or 852+/-75 kcal) before and during the marathon. CONCLUSION: Marathon runners over the age of 50 have a balanced diet during the 3 days prior to running a 26.2 mile marathon. Carbohydrates were the main source of energy consumed before and during the marathon. PMID- 25801166 TI - Cbx2 targets PRC1 to constitutive heterochromatin in mouse zygotes in a parent-of origin-dependent manner. AB - Polycomb repressive complexes PRC1 and PRC2 regulate expression of genes involved in proliferation and development. In mouse early embryos, however, canonical PRC1 localizes to paternal pericentric heterochromatin (pat-PCH), where it represses transcription of major satellite repeats. In contrast, maternal PCH (mat-PCH) is enriched for H3 lysine 9 tri-methylation (H3K9me3) and Hp1beta. How PRC1 is targeted to pat-PCH, yet excluded from mat-PCH, has remained elusive. Here, we identify a PRC1 targeting mechanism that relies on Cbx2 and Hp1beta. Cbx2 directs catalytically active PRC1 to PCH via its chromodomain (CD(Cbx2)) and neighboring AT-hook (AT(Cbx2)) binding to H3K27me3 and AT-rich major satellites, respectively. CD(Cbx2) prevents AT(Cbx2) from interacting with DNA at PCH marked by H3K9me3 and Hp1beta. Loss-of-function studies show that Hp1beta and not H3K9me3 prevents PRC1 targeting to mat-PCH. Our findings indicate that CD(Cbx2) and AT(Cbx2) separated by a short linker function together to integrate H3K9me3/HP1 and H3K27me3 states. PMID- 25801167 TI - Cotranslational stabilization of Sec62/63 within the ER Sec61 translocon is controlled by distinct substrate-driven translocation events. AB - The ER Sec61 translocon is a large macromolecular machine responsible for partitioning secretory and membrane polypeptides into the lumen, cytosol, and lipid bilayer. Because the Sec61 protein-conducting channel has been isolated in multiple membrane-derived complexes, we determined how the nascent polypeptide modulates translocon component associations during defined cotranslational translocation events. The model substrate preprolactin (pPL) was isolated principally with Sec61alphabetagamma upon membrane targeting, whereas higher order complexes containing OST, TRAP, and TRAM were stabilized following substrate translocation. Blocking pPL translocation by passenger domain folding favored stabilization of an alternate complex that contained Sec61, Sec62, and Sec63. Moreover, Sec62/63 stabilization within the translocon occurred for native endogenous substrates, such as the prion protein, and correlated with a delay in translocation initiation. These data show that cotranslational translocon contacts are ultimately controlled by the engaged nascent chain and the resultant substrate-driven translocation events. PMID- 25801168 TI - High-resolution chromatin dynamics during a yeast stress response. AB - Covalent histone modifications are highly conserved and play multiple roles in eukaryotic transcription regulation. Here, we mapped 26 histone modifications genome-wide in exponentially growing yeast and during a dramatic transcriptional reprogramming-the response to diamide stress. We extend prior studies showing that steady-state histone modification patterns reflect genomic processes, especially transcription, and display limited combinatorial complexity. Interestingly, during the stress response we document a modest increase in the combinatorial complexity of histone modification space, resulting from roughly 3% of all nucleosomes transiently populating rare histone modification states. Most of these rare histone states result from differences in the kinetics of histone modification that transiently uncouple highly correlated marks, with slow histone methylation changes often lagging behind the more rapid acetylation changes. Explicit analysis of modification dynamics uncovers ordered sequences of events in gene activation and repression. Together, our results provide a comprehensive view of chromatin dynamics during a massive transcriptional upheaval. PMID- 25801169 TI - Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. AB - Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. PMID- 25801170 TI - Activation of a primed RING E3-E2-ubiquitin complex by non-covalent ubiquitin. AB - RING ubiquitin ligases (E3) recruit ubiquitin-conjugate enzymes (E2) charged with ubiquitin (Ub) to catalyze ubiquitination. Non-covalent Ub binding to the backside of certain E2s promotes processive polyUb formation, but the mechanism remains elusive. Here, we show that backside bound Ub (Ub(B)) enhances both RING independent and RING-dependent UbcH5B-catalyzed donor Ub (Ub(D)) transfer, but with a more prominent effect in RING-dependent transfer. Ub(B) enhances RING E3s' affinities for UbcH5B-Ub, and RING E3-UbcH5B-Ub complex improves Ub(B)'s affinity for UbcH5B. A comparison of the crystal structures of a RING E3, RNF38, bound to UbcH5B-Ub in the absence and presence of Ub(B), together with molecular dynamics simulation and biochemical analyses, suggests Ub(B) restricts the flexibility of UbcH5B's alpha1 and alpha1beta1 loop. Ub(B) supports E3 function by stabilizing the RING E3-UbcH5B-Ub complex, thereby improving the catalytic efficiency of Ub transfer. Thus, Ub(B) serves as an allosteric activator of RING E3-mediated Ub transfer. PMID- 25801172 TI - Composition, antimicrobial and antioxidant activities of seven essential oils from the North American boreal forest. AB - Essential oils (EOs) were steam-extracted from the needles and twigs of balsam fir, black spruce, white spruce, tamarack, jack pine and eastern white cedar that remained after logging in eastern Canada. These EOs, similarly to that from Labrador tea and other commercial EOs from Chinese cinnamon, clove and lemon eucalyptus, exhibited many common constituent compounds (mainly alpha-pinene, beta-pinene, limonene and bornyl acetate) making up 91% of each oil based on gas chromatography-mass spectrometry analysis. All of these oils exhibited antibacterial properties, especially when examined in closed tube assay compared to the traditional 96-well microliter format. These antimicrobial activities (minimum inhibitory concentration >= 0.2% w/v), comparable to those of exotic EOs, were shown against common pathogenic bacteria and fungi. The antioxidant potential of the boreal samples was determined by the 1,1-diphenyl-2 picrylhydrazyl radical scavenging (concentration providing 50% inhibition >= 7 mg/ml) and reducing power methods. Finally, this investigation revealed some boreal EOs to be potential antimicrobial and antioxidant agents that would notably benefit products in the personal hygiene and care industry. PMID- 25801171 TI - Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. AB - Controlled changes in mitochondrial morphology participate in cellular signaling cascades. However, the molecular mechanisms modifying mitochondrial shape are largely unknown. Here we show that the mitogen-activated protein (MAP) kinase cascade member extracellular-signal-regulated kinase (ERK) phosphorylates the pro fusion protein mitofusin (MFN) 1, modulating its participation in apoptosis and mitochondrial fusion. Phosphoproteomic and biochemical analyses revealed that MFN1 is phosphorylated at an atypical ERK site in its heptad repeat (HR) 1 domain. This site proved essential to mediate MFN1-dependent mitochondrial elongation and apoptosis regulation by the MEK/ERK cascade. A mutant mimicking constitutive MFN1 phosphorylation was less efficient in oligomerizing and mitochondria tethering but bound more avidly to the proapoptotic BCL-2 family member BAK, facilitating its activation and cell death. Moreover, neuronal apoptosis following oxygen glucose deprivation and MEK/ERK activation required an intact MFN1(T562). Our data identify MFN1 as an ERK target to modulate mitochondrial shape and apoptosis. PMID- 25801173 TI - Influence of the scaffold geometry on the spatial and temporal evolution of the mechanical properties of tissue-engineered cartilage: insights from a mathematical model. AB - The production of tissue-engineered cartilage in vitro with inhomogeneous mechanical properties is a problem yet to be solved. Different geometries have been studied to overcome this caveat; however, the reported measurements are limited to average values of some properties and qualitative measures of spatial distributions. We will apply a coupled model to extend knowledge about the introduction of a macrochannel in a scaffold by calculating spatiotemporal patterns for several interest variables related to the remodeling of the mechanical properties. Model parameters were estimated based on experimental data on the temporal patterns of glycosaminoglycans, collagen and compressive Young's modulus for channel-free constructs. The model reproduced the experimental data trends in both geometries, with experimental-numerical correlations between 0.84 and 0.97. The channel had a higher impact on the reduction in spatial heterogeneities and delay of saturation of core properties than in the improvement of average properties. Despite the possible improvement of cell densities for longer periods than 56 days, it is estimated that it will not cause further significant improvements of the mechanical properties. The degrees of spatial heterogeneity of the Young's modulus and permeability in the channeled geometry are 23 and 27 % of the channel-free values. While the average Young's modulus values are in the range of native cartilage, the permeabilities are one to three degrees of magnitude higher than the native cartilage, suggesting that limiting factors such as scaffold porosity and initial permeability are more relevant than scaffold geometry to effectively decrease the tissue permeability. PMID- 25801174 TI - Seizure as the presenting manifestation in Griscelli syndrome type 2. AB - BACKGROUND: Griscelli syndrome is an autosomal recessive disease that is characterized by hypopigmentation of the skin and hair, presence of large clumps of pigment in hair shafts, and accumulation of melanosomes in melanocytes; it resembles Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in the RAB27A gene and has predominant immunologic abnormalities. METHOD: A retrospective case analysis highlighting neurological complications in an individual with Griscelli syndrome type 2. RESULTS: We present a 1-year-old girl with Griscelli syndrome type 2 in an Asian Indian family, confirmed by mutation analysis of the RAB27A gene. She presented with seizures and regression of developmental milestones following a brief febrile illness. Progressive neurological deterioration was associated with refractory status epilepticus. Neurological worsening may have resulted from the accelerated phase of the disease. CONCLUSION: Griscelli syndrome type 2 is a rare primary immunodeficiency state with characteristic silvery hair, partial albinism, and immunological abnormalities. Predominant neurological presentation is rare, but it represents isolated central nervous system hemophagocytosis. PMID- 25801177 TI - The relationship between preterm birth and underweight in Asian women. AB - Although vast improvements have been made in the survival of preterm infants, the toll of preterm birth (PTB) is particularly severe in Asia, with the Indian subcontinent leading the preterm birth rate. Despite the obesity epidemic, maternal underweight remains a common occurrence in developing countries. An association between maternal underweight and preterm birth has been reported in developed countries. A review of epidemiological studies in Asian women in whom association between maternal body mass index (BMI) and risk of PTB was measured, indicated no significant association between low maternal BMI and preterm birth. A hindrance in comparison of these studies is the use of different cut-off point for BMI in defining maternal underweight. As a commentary on published studies it is proposed that that country-specific BMI cut points should be applied for defining underweight for Asian women for the purpose of evaluating the association between maternal underweight and preterm birth. PMID- 25801175 TI - Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis. AB - PURPOSE: Diagnosis of Rett syndrome (RTT) is often delayed. We sought to determine the type of physician who typically makes the RTT diagnosis and to identify risk factors for delayed diagnosis. METHODS: A total of 1085 participants from the multicenter longitudinal RTT natural history study with classic and atypical RTT were recruited between 2006 and 2014. Age of diagnosis, diagnostician, diagnostic criteria, and clinical and developmental data were collected. RESULTS: Among 919 classic and 166 atypical RTT participants, the median diagnosis age was 2.7 years (interquartile range 2.0-4.1) in classic and 3.8 years (interquartile range 2.3-6.9) in atypical RTT. Pediatricians made the diagnosis of classic RTT rarely (5.2%); however, the proportion diagnosed by pediatricians has increased since 2006. Since the first diagnostic criteria, the age of diagnosis decreased among subspecialists but not pediatricians. Odds of a pediatrician making the diagnosis of classic RTT were higher if a child stopped responding to parental interaction, and lower if they possessed gastroesophageal reflux, specific stereotypies, lost babbling, or the ability to follow commands. Delayed acquisition of basic gross motor skills or finger feeding was associated with younger diagnosis; delayed acquisition of higher level fine motor skills, later onset of supportive features, and normal head circumference were associated with late diagnosis. Thirty-three percent with microcephaly before 2.5 years were diagnosed after the median age of 2.7 years. CONCLUSIONS: Age of RTT diagnosis has improved among subspecialists, and pediatricians have made the diagnosis of classic RTT more frequently since 2006. Strategies for educating diagnosticians should incorporate specific risk factors for delayed diagnosis. PMID- 25801178 TI - Evaluation of stability and capsular bag opacification of a new foldable adjustable intraocular lens. AB - BACKGROUND: Incorrect lens power remains one of the most common reasons for intraocular lens explantation/exchange. We evaluated stability and effect on capsular bag opacification of a new foldable modular lens system, with a base component and an optic component in rabbit eyes. METHODS: Bilateral phacoemulsification was performed on six rabbits; one eye received the test lens (Harmoni Modular Lens, ClarVista Medical), whereas the other received a single piece hydrophobic acrylic control lens (SA60AT, Alcon). Slit-lamp examinations were performed at postoperative weeks 1, 2, 3, 4 and 6. All rabbits were sacrificed at week 6. After enucleation, the eyes were examined grossly from the Miyake-Apple view. Following, all globes were sectioned and processed for histopathological examination. RESULTS: The modular lens was stable in all six rabbits. Uveal biocompatibility was similar to or better in the test eyes when compared with control eyes up to 6 weeks postoperatively. Overall, capsular bag opacification was found to be significantly lower in the test eyes when compared with control eyes. At the 6-week gross examination, central posterior capsule opacification was scored as 0.58 +/- 0.73 in the test group, and as 3.00 +/- 1.26 in the control group (paired two samples for means t-test; two-tail P = 0.005). CONCLUSIONS: The Harmoni Modular system remains stable within the capsular bag after implantation. Due to the design of the base component featuring long loops, along with peripheral anterior and posterior square edges, the lens appeared to prevent overall capsular bag opacification in the rabbit model. PMID- 25801179 TI - Touch imprint cytology: a rapid diagnostic tool for oral squamous cell carcinoma. AB - Techniques for intraoperative pathologic examination of oral squamous cell carcinoma are rare in the literature. We evaluated the advantages and limitations of touch imprint cytology for intraoperative diagnosis of oral squamous cell carcinoma. We used 30 incisional biopsies of clinically diagnosed oral squamous cell carcinoma and compared touch imprint cytology to histopathological sections. Touch imprint cytology showed 24 specimens positive for malignancy, two suspicious for malignancy and four inadequate specimens. The accuracy of the test was 93.2%. Touch imprint cytology is an accurate, simple, rapid and cost effective method that aids diagnosis of oral squamous cell carcinoma during operation, but it does not replace incisional biopsy. PMID- 25801176 TI - Blood flow mechanics in cardiovascular development. AB - Hemodynamic forces are fundamental to development. Indeed, much of cardiovascular morphogenesis reflects a two-way interaction between mechanical forces and the gene network activated in endothelial cells via mechanotransduction feedback loops. As these interactions are becoming better understood in different model organisms, it is possible to identify common mechanogenetic rules, which are strikingly conserved and shared in many tissues and species. Here, we discuss recent findings showing how hemodynamic forces potentially modulate cardiovascular development as well as the underlying fluid and tissue mechanics, with special attention given to the flow characteristics that are unique to the small scales of embryos. PMID- 25801180 TI - Comparison of operational characteristics for binary tests with clustered data. AB - Although statistical methodology is well-developed for comparing diagnostic tests in terms of their sensitivity and specificity, comparative inference about predictive values is not. In this paper, we consider the analysis of studies comparing operating characteristics of two diagnostic tests that are measured on all subjects and have test outcomes from multiple sites with varying number of sites among subjects. We have developed a new approach for comparing sensitivity, specificity, positive predictive value, and negative predictive value with simple variance calculation and, in particular, focus on comparing tests using difference of positive and negative predictive values. Simulation studies are conducted to show the performance of our approach. We analyze real data on patients with lung cancer, based on their diagnostic tests, to illustrate the methodology. PMID- 25801181 TI - Exploring the potential of global protein-protein docking: an overview and critical assessment of current programs for automatic ab initio docking. AB - Protein-protein docking is an important computational tool for studying protein protein interactions. A variety of docking programs with different sampling algorithms and scoring functions as well as computational efficiencies have been subsequently developed over the last decades. Here, we have reviewed the trend and performance of current global docking programs through a comprehensive assessment of the 18 docking/scoring protocols of 14 global docking programs on the latest protein docking benchmark 4.0. The effects of docking algorithms, interaction types, and conformational changes on the docking performance were investigated and discussed. The findings are expected to provide a general guideline for the choice of an appropriate docking protocol and offer insights into the optimization and development of docking and scoring algorithms. PMID- 25801183 TI - Erratum to: Association between fat mass, lean mass, and bone loss: the Dubbo osteoporosis epidemiology study. PMID- 25801182 TI - Increased risk of coronary heart disease in patients with hip fracture: a nationwide cohort study. AB - The study indicates that hip fracture is independently associated with increased risk of coronary heart disease. In addition, the highest risk of coronary heart disease following hip fracture appeared within the first year after hip fracture, indicating the need for multidisciplinary care for the patients. INTRODUCTION: Bone and vasculature are modulated through numerous common pathways. However, data on the risk of coronary heart disease (CHD) after hip fracture are scarce. Therefore, we investigated whether hip fracture increased the risk of CHD by conducting a large nationwide cohort study. METHODS: Using universal insurance claims data from 2000 to 2010, we identified a study cohort of 6013 participants newly diagnosed with hip fracture and a control cohort of 23,802 participants. Both cohorts were followed up to the end of 2011 to evaluate the risk of CHD. RESULTS: The overall incidence of CHD was 1.69-fold higher in the hip fracture cohort than it was in the control cohort (29.2 vs. 17.1 per 1000 person-years) with an adjusted hazard ratio of 1.51 (95 % confidence interval [CI] = 1.39 1.65). Sex-, age-, and comorbidity-specific analyses showed a higher relative risk of CHD for both women and men, all age groups, those with and without comorbidities, and patients with hip fracture compared with the control cohort. The highest risk of CHD was within the first year after hip fracture (adjusted HR = 1.72, 95 % CI = 1.45-2.04), and the risk remained high in the following years. CONCLUSION: Hip fracture was independently associated with a subsequent risk of CHD. PMID- 25801184 TI - A case report of osteomalacia unmasking primary biliary cirrhosis. AB - Osteomalacia, a metabolic bone disease characterized by the inability to mineralize new osteoid, can be caused by vitamin D deficiency. We report a patient with symptomatic, biochemical, and imaging evidence of osteomalacia due to vitamin D deficiency, who as a result of work up for bone disease was diagnosed with early primary biliary cirrhosis. Osteomalacia was treated with high-dose vitamin D and serial bone density scans showed evidence of increasing bone mineral density suggesting osteoid mineralization in response to treatment. The diagnosis of cholestatic liver disease should be considered in all patients presenting with osteomalacia due to vitamin D deficiency, particularly if other cholestatic liver enzymes are elevated in addition to alkaline phosphatase. PMID- 25801185 TI - Prevalence of CTX-M-8 and CTX-M-15 type extended-spectrum beta-lactamases between Klebsiella pneumoniae spp. isolated from Zahedan, Southeast Iran. PMID- 25801187 TI - Increased sensitivity to climate change in disturbed ecosystems. AB - Human domination of the biosphere includes changes to disturbance regimes, which push many ecosystems towards early-successional states. Ecological theory predicts that early-successional ecosystems are more sensitive to perturbations than mature systems, but little evidence supports this relationship for the perturbation of climate change. Here we show that vegetation (abundance, species richness and species composition) across seven European shrublands is quite resistant to moderate experimental warming and drought, and responsiveness is associated with the dynamic state of the ecosystem, with recently disturbed sites responding to treatments. Furthermore, most of these responses are not rapid (2-5 years) but emerge over a longer term (7-14 years). These results suggest that successional state influences the sensitivity of ecosystems to climate change, and that ecosystems recovering from disturbances may be sensitive to even modest climatic changes. A research bias towards undisturbed ecosystems might thus lead to an underestimation of the impacts of climate change. PMID- 25801186 TI - Hsp60 response in experimental and human temporal lobe epilepsy. AB - The mitochondrial chaperonin Hsp60 is a ubiquitous molecule with multiple roles, constitutively expressed and inducible by oxidative stress. In the brain, Hsp60 is widely distributed and has been implicated in neurological disorders, including epilepsy. A role for mitochondria and oxidative stress has been proposed in epileptogenesis of temporal lobe epilepsy (TLE). Here, we investigated the involvement of Hsp60 in TLE using animal and human samples. Hsp60 immunoreactivity in the hippocampus, measured by Western blotting and immunohistochemistry, was increased in a rat model of TLE. Hsp60 was also increased in the hippocampal dentate gyrus neurons somata and neuropil and hippocampus proper (CA3, CA1) of the epileptic rats. We also determined the circulating levels of Hsp60 in epileptic animals and TLE patients using ELISA. The epileptic rats showed circulating levels of Hsp60 higher than controls. Likewise, plasma post-seizure Hsp60 levels in patients were higher than before the seizure and those of controls. These results demonstrate that Hsp60 is increased in both animals and patients with TLE in affected tissues, and in plasma in response to epileptic seizures, and point to it as biomarker of hippocampal stress potentially useful for diagnosis and patient management. PMID- 25801188 TI - Sometimes we have to intentionally focus on the details: Incidental encoding and perceptual change decrease recognition memory performance and the ERP correlate of recollection. AB - Prior studies suggest that memory retrieval is based on two independent processes: Recollection and familiarity. Here, we investigated the role of incidental and intentional encoding, and specifically whether perceptual changes between study and test affects behavioral and electrophysiological correlates of both retrieval processes. During retrieval, participants distinguished between identical and changed exemplars as well as novel distractors. Following incidental encoding, participants had difficulty identifying changed exemplars; item and feature recognition increased after intentional encoding, in particular for changed exemplars. Reflecting this increase in memory performance, the ERP correlate of recollection was larger after intentional encoding and for identical item repetitions, whereas the ERP correlate for familiarity was largely unaffected. Pre-response old/new effects corresponding to later aspects of recollection (700-1000 ms relative to stimulus onset) were larger in response compared to stimulus-locked averages, but also of similar magnitude for identical and changed exemplars. These results corroborate previous findings suggesting that the electrophysiological signature of recollection is modulated as a function of memory performance. The role of task characteristics and material retrieved from memory for modulations in familiarity-based retrieval processes is discussed. PMID- 25801190 TI - Why Registered Dietitian Nutritionists Are Not Doing Research-Perceptions, Barriers, and Participation in Research from the Academy's Dietetics Practice Based Research Network Needs Assessment Survey. PMID- 25801189 TI - Usefulness of (11)C-Methionine PET in differential diagnosis of epileptogenic brain neoplasms. PMID- 25801191 TI - The Physical Workload of Surgeons: A Comparison of SILS and Conventional Laparoscopy. AB - BACKGROUND: As extensively reported in the literature, laparoscopic surgery has many advantages for the patient. Surgeons, however, experience increased physical burden when laparoscopic surgery is compared with open surgery. Single-incision laparoscopic surgery (SILS) has been said to further enhance the patient's benefits of endoscopic surgery. Because in this surgical technique only 1 incision is made instead of the 3 to 5, as in conventional laparoscopic surgery (CLS), it is claimed to further reduce discomfort and pain in patients. Yet little is known about its impact on surgeons. This study aims to contribute by indicating the possible differences in physical workload between single-incision laparoscopy and CLS. METHODS: A laparoscopic box trainer was used to simulate a surgical setting. Participants performed 2 series of 3 different tasks in the box: one in the conventional way, the other through SILS. Surface electromyography was recorded from 8 muscles bilaterally. Furthermore, questionnaires on perceived workload were completed. RESULTS: Differences were found in the back, neck, and shoulder muscles, with significantly higher muscle activity in the musculus (M) longissimus, M trapezius pars descendens, and the M deltoideus pars clavicularis. Questionnaires did not indicate any significant differences in perceived workload. CONCLUSION: Performing SILS versus CLS increases the objectively measured physical workload of surgeons particularly in the back, neck, and shoulder muscles. PMID- 25801192 TI - Improving Echo-Guided Procedures Using an Ultrasound-CT Image Fusion System. AB - INTRODUCTION: Image fusion between ultrasound (US) and computed tomography (CT) scan or magnetic resonance can increase operator accuracy in targeting liver lesions, particularly when those are undetectable with US alone. We have developed a modular gel to simulate hepatic solid lesions for educational purposes in imaging and minimally invasive ablation techniques. We aimed to assess the impact of image fusion in targeting artificial hepatic lesions during the hands-on part of 2 courses (basic and advanced) in hepatobiliary surgery. MATERIALS AND METHODS: Under US guidance, 10 fake tumors of various sizes were created in the livers of 2 pigs, by percutaneous injection of a biocompatible gel engineered to be hyperdense on CT scanning and barely detectable on US. A CT scan was obtained and a CT-US image fusion was performed using the ACUSON S3000 US system (Siemens Healthcare, Germany). A total of 12 blinded course attendants, were asked in turn to perform a 10-minute liver scan with US alone followed by a 10-minute scan using image fusion. RESULTS: Using US alone, the expert managed to identify all lesions successfully. The true positive rate for course attendants with US alone was 14/36 and 2/24 in the advanced and basic courses, respectively. The total number of false positives identified was 26. With image fusion, the rate of true positives significantly increased to 31/36 (P < .001) in the advanced group and 16/24 in the basic group (P < .001). The total number of false positives, considering all participants, decreased to 4 (P < .001). CONCLUSIONS: Image fusion significantly increases accuracy in targeting hepatic lesions and might improve echo-guided procedures. PMID- 25801193 TI - Optimized Retroperitoneoscopic Excision of Large (>25 cm) Adult Polycystic Kidneys Using 3-Dimensional Image Reconstruction and Preresection Ultrasound Guided Aspiration: Technique and Early Outcomes. AB - BACKGROUND: Laparoscopic excision of large polycystic kidneys remains a challenging procedure. Most of the literature describes transperitoneal approaches. Alterations in anatomy due to size of kidneys can make vascular and hilar control difficult. Retroperitoneal access with direct control of pedicle avoids risks without dissection for structures anterior to the kidneys. The technique of retroperitoneoscopic excision of massively enlarged kidneys is described with early outcomes. METHODS: Patient DICOM images of kidneys were segmented and reconstructed for 3-dimensional visualization before surgery. Total excision of large polycystic kidneys was performed in 10 patients (11 procedures). After creation of retroperitoneal space, renal pedicle dissection was started with the incision of thinned out Gerota's fascia. Occasionally aspiration of large cysts using ultrasound assistance created space for precise dissection. Following control of vascular pedicle under laparoscopic vision, further aspiration of cysts was accomplished with the help of 3-dimensional reconstructed kidney. Postaspiration, remaining renal specimen was extracted through a small incision using an endobag or as an intact specimen. RESULTS: The operative time was between 180 and 240 minutes (median 200 minutes). Intraoperative blood loss was 100 to 300 mL (median 175 mL). Median time to control pedicle was 12 minutes (range 10-25 minutes). The postoperative periods were uneventful, except for blockage of arteriovenous fistula in 1 patient. Mean hospital stay was 7 days (range 6-14 days). CONCLUSIONS: The retroperitoneasocopic approach to large polycystic kidneys under the guidance of 3-dimensional image reconstruction, occasionally with the assistance of ultrasound aspiration is technically feasible, safe, with good perioperative outcomes. It facilitates early control of vascular pedicle with minimal risk of intraoperative bleeding. PMID- 25801194 TI - Syrian doctors risk arrest and deportation for treating fellow refugees in Lebanon and Jordan. PMID- 25801195 TI - A prospective observational study of trial of labor after cesarean in rural India. AB - OBJECTIVE: To determine the success rate of trial of labor after cesarean (TOLAC) in rural India. METHODS: The present prospective observational study enrolled pregnant women attending Dr Rajendra Prasad Government Medical College, Kangra, India, in 2013. Eligible women had a previous low-segment cesarean delivery and had a singleton pregnancy with cephalic presentation. Women in labor were managed as per the institutional protocol. RESULTS: In total, 482 women were included. TOLAC led to a vaginal delivery in 383 (79.6%) women. Overall, 2 (0.4%) women had scar rupture, and 4 (0.8%) had scar dehiscence. Fetal death was recorded in one woman with scar rupture, for whom peripartum hysterectomy was necessary. Blood loss was significantly lower among the 316 women with normal vaginal delivery than among the 99 who underwent cesarean (P<0.001). Blood transfusion was required in 2 (0.6%) women with normal vaginal delivery and 2 (2.0%) with cesarean delivery (P=0.05). The proportion of neonates who had to be admitted to intensive care did not differ significantly by mode of delivery (P=0.06). CONCLUSION: Under strict supervision, TOLAC is a reasonable option even in rural India. PMID- 25801196 TI - Longitudinal change in quantitative meniscus measurements in knee osteoarthritis- data from the Osteoarthritis Initiative. AB - OBJECTIVE: We aimed to apply 3D MRI-based measurement technology to studying 2 year change in quantitative measurements of meniscus size and position. METHODS: Forty-seven knees from the Osteoarthritis Initiative with medial radiographic joint space narrowing had baseline and 2-year follow-up MRIs. Quantitative measures were obtained from manual segmentation of the menisci and tibia using coronal DESSwe images. The standardized response mean (SRM = mean/SD change) was used as measure of sensitivity to longitudinal change. RESULTS: Medial tibial plateau coverage decreased from 34.8% to 29.9% (SRM -0.82; p < 0.001). Change in medial meniscus extrusion in a central image (SRM 0.18) and in the central five slices (SRM 0.22) did not reach significance, but change in extrusion across the entire meniscus (SRM 0.32; p = 0.03) and in the relative area of meniscus extrusion (SRM 0.56; p < 0.001) did. There was a reduction in medial meniscus volume (10%; p < 0.001), width (7%; p < 0.001), and height (2%; p = 0.08); meniscus substance loss was strongest in the posterior (SRM -0.51; p = 0.001) and weakest in the anterior horn (SRM -0.15; p = 0.31). CONCLUSION: This pilot study reports, for the first time, longitudinal change in quantitative 3D meniscus measurements in knee osteoarthritis. It provides evidence of improved sensitivity to change of 3D measurements compared with single slice analysis. KEY POINTS: * First longitudinal MRI-based measurements of change of meniscus position and size. * Quantitative longitudinal evaluation of meniscus change in knee osteoarthritis. * Improved sensitivity to change of 3D measurements compared with single slice analysis. PMID- 25801197 TI - Metabolic syndrome and the risk of Barrett's oesophagus in white males. AB - BACKGROUND: Few studies have examined the association between metabolic syndrome and Barrett's oesophagus (BO). Whether metabolic syndrome confers a risk greater than the sum of its components is unknown. AIM: To investigate associations between metabolic syndrome, its components and BO in white males. METHODS: We conducted a case-control study among eligible symptomatic patients scheduled for elective oesophagogastroduodenoscopy and a sample of patients eligible for screening colonoscopy recruited at primary care clinics. Metabolic syndrome was defined as the presence of at least three of: high waist-to-hip ratio (WHR), hypertriglyceridaemia, low high-density lipoprotein cholesterol, hypertension or diabetes. We used multivariate logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: There were 244 BO cases, 209 colonoscopy and 615 endoscopy controls. Comparing BO cases with all controls, metabolic syndrome was significantly associated with BO (OR = 1.59, 95% CI 1.05 2.40) and there was a dose effect with increasing number of metabolic syndrome components (Ptrend <0.001); when all five components were present, the OR was 2.61 (95% CI 1.14-5.99). We found that among the components, high WHR, hypertension and hypertriglyceridaemia were associated with increased risk of BO. When we compared cases with the control groups separately, metabolic syndrome was associated with BO for comparisons with endoscopy controls (OR = 1.67, 95% CI 1.10-2.55) but not colonoscopy controls (OR = 0.87, 95% CI 0.49-1.54). Associations with individual components also depended on the comparison group. CONCLUSIONS: Metabolic syndrome is associated with an increased risk of Barrett's oesophagus in men undergoing endoscopy. Metabolic syndrome may confer additional risk of Barrett's oesophagus separate from obesity. PMID- 25801199 TI - Rice bran protein hydrolysates exhibit strong in vitro alpha-amylase, beta glucosidase and ACE-inhibition activities. AB - BACKGROUND: The objective of this study was to systematically examine the in vitro health-promotion activities of rice bran protein hydrolysates. Rice bran proteins were fractioned into albumin, globulin, prolamin and glutelin, which were subjected to hydrolysis by four protease preparations, namely Alcalase, Neutrase, Flavourzyme and Protamax, and the inhibitory activities of the hydrolysates against alpha-amylase, alpha-glucosidase and angiotensin converting enzyme (ACE), were monitored over a hydrolysis period of 240 min. Active peptides in the hydrolysates were isolated by ultra-filtration and ion-exchange chromatography and the peptide sequences of the active fractions were identified by LC-MS/MS. RESULTS: Hydrolysis of the proteins resulted in significant increases in these bioactivities, which were generally correlated with the degree of protein hydrolysis. In general, the highest bioactivities were found with albumin and glutelin hydrolysates, followed by globulin hydrolysates, while prolamin hydrolysates showed the lowest activities. Of the four enzymes used, Alcalase- and Protamax-catalysed hydrolysates generally had the highest activities while Flavourzyme-produced hydrolysates had the lowest activity. The MW < 3 kDa fraction of the Alcalase-catalysed glutelin hydrolysates had the highest beta-glucosidase inhibition activity, which was identified to contain 13 peptides with six to 32 amino acid residues. CONCLUSION: The alpha-amylase and alpha-glucosidase inhibitory activities of albumin and glutelin hydrolysates produced by Alcalase and Protamax were comparable in magnitude to those of the standard anti-diabetic drug acarbose, and had the potential to be developed into a dietary or nutraceutical supplement for the management of diabetes. PMID- 25801200 TI - Can silicon make an excellent drug even better? An in vitro and in vivo head-to head comparison between loperamide and its silicon analogue sila-loperamide. AB - Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila-substitution) at the 4 position of the piperidine ring of 1a (R3 COH->R3 SiOH) leads to sila-loperamide (1b). Sila-loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4-methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila-loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila-loperamide exhibits high unbound clearance (CLu ), leading to a significant decrease in unbound concentration (Cu ) and unbound area under the curve (AUCu ) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties. PMID- 25801201 TI - Sensitive immunosensor for N-terminal pro-brain natriuretic peptide based on N (aminobutyl)-N-(ethylisoluminol)-functionalized gold nanodots/multiwalled carbon nanotube electrochemiluminescence nanointerface. AB - A novel electrochemiluminescence (ECL) immunosensor was developed for the determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) by using N (aminobutyl)-N-(ethylisoluminol) (ABEI)-functionalized gold nanodots/chitosan/multiwalled carbon nanotubes (ABEI/GNDs/chitosan/COOH-MWCNTs) hybrid as nanointerface. First, ABEI/GNDs/chitosan/COOH-MWCNTs hybrid nanomaterials were grafted onto the surface of ITO electrode via the film-forming property of hybrid nanomaterials. The anti-NT-proBNP antibody was connected to the surface of modified electrode by virtue of amide reaction via glutaraldehyde. The obtained sensing platform showed strong and stable ECL signal. When NT-proBNP was captured by its antibody immobilized on the sensing platform via immunoreaction, the ECL intensity decreased. Direct ECL signal changes were used for the determination of NT-proBNP. The present ECL immunosensor demonstrated a quite wide linear range of 0.01-100 pg/mL. The achieved low detection limit of 3.86 fg/mL was about 3 orders of magnitude lower than that obtained with electrochemistry method reported previously. Because of the simple and fast analysis, high sensitivity and selectivity, and stable and reliable response, the present immunosensor has been successfully applied to quantify NT-proBNP in practical plasma samples. The success of the sensor in this work also confirms that ABEI/GNDs/chitosan/COOH-MWCNTs hybrid is an ideal nanointerface to fabricate a sensing platform. Furthermore, the proposed strategy could be applied in the detection of other clinically important biomarkers. PMID- 25801203 TI - The mechanism of CO2 insertion into iridium(I) hydroxide and alkoxide bonds: a kinetics and computational study. AB - The facile insertion of CO2 into iridium(I) hydroxide, alkoxide, and amide bonds was recently reported. In particular, [Ir(cod)(IiPr)(OH)] (IiPr = 1,3 bis(isopropyl)imidazol-2-ylidene) reacted with CO2 in solution and in the solid state in a matter of minutes to give the novel [{Ir(cod)(IiPr)}2(MU kappa(1)O:kappa(2)O,O-CO3)] complex. In the present study, this reaction is probed using kinetics and theoretical studies, which enabled us to analyse its facile nature and to fully elucidate the reaction mechanism with excellent correlation between the two methods. PMID- 25801198 TI - Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing. AB - Insulin-like growth factors (IGFs) are important local regulators during fracture healing. Although IGF1 deficiency is known to increase the risk of delayed union or non-union fractures in the elderly population, the underlying mechanisms that contribute to this defect remains unclear. In this study, IGF1 signaling during fracture healing was investigated in an osteoblast-specific IGF1 receptor (IGF1R) conditional knockout (KO) mouse model. A closed tibial fracture was induced in IGF1R(flox/flox) /2.3-kb alpha1(1)-collagen-Cre (KO) and IGF1R(flox/flox) (control) mice aged 12 weeks. Fracture callus samples and nonfractured tibial diaphysis were collected and analyzed by MUCT, histology, immunohistochemistry, histomorphometry, and gene expression analysis at 10, 15, 21, and 28 days after fracture. A smaller size callus, lower bone volume accompanied by a defect in mineralization, bone microarchitectural abnormalities, and a higher cartilage volume were observed in the callus of these KO mice. The levels of osteoblast differentiation markers (osteocalcin, alkaline phosphatase, collagen 1alpha1) were significantly reduced, but the early osteoblast transcription factor runx2, as well as chondrocyte differentiation markers (collagen 2alpha1 and collagen 10alpha1) were significantly increased in the KO callus. Moreover, increased numbers of osteoclasts and impaired angiogenesis were observed during the first 15 days of fracture repair, but decreased numbers of osteoclasts were found in the later stages of fracture repair in the KO mice. Although baseline nonfractured tibias of KO mice had decreased trabecular and cortical bone compared to control mice, subsequent studies with mice expressing the 2.3-kb alpha1(1)-collagen-Cre ERT2 construct and given tamoxifen at the time of fracture and so starting with comparable bone levels showed similar impairment in fracture repair at least initially. Our data indicate that not only is the IGF1R in osteoblasts involved in osteoblast differentiation during fracture repair, but it plays an important role in coordinating chondrocyte, osteoclast, and endothelial responses that all contribute to the endochondral bone formation required for normal fracture repair. PMID- 25801202 TI - Gait Characteristics in Patients With Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have reduced gait speeds and more frequent falls. We analyzed gait characteristics and fall risk in these patients using video recordings and questionnaires to determine if these patients had any quantitative changes in gait characteristics and to determine if screening for fall risk provided useful information. METHODS: Patients with COPD who had participated in pulmonary rehabilitation completed a short history falls and the Activities-Specific Balance Confidence Scale questionnaire. They performed the Get Up and Go Test. Their typical gait was video recorded and analyzed with Dartfish software. RESULTS: Fourteen patients completed this study. The mean age was 69.7 +/- 6.0 years, and the mean forced expiratory volume in 1 second was 1.01 +/- 0.38 L (36.9% +/- 15.6% predicted). Three patients had a history of falls without significant injury. The mean Activities-Specific Balance Confidence Scale score was 91.8 +/- 14.9, but the scores ranged from 10 to 100. Patients reported decreased balance confidence when "stepping onto or off an escalator while holding onto parcels." The mean time in the Get Up and Go Test was 11.9 +/- 2.0 seconds. Spatiotemporal parameters of gait included mean step length 0.65 +/- 0.6 m, mean double support time 0.36 +/- 0.05 seconds, mean double support time ratio 30.4% +/- 3.1%, average free walking speed 65.3 +/- 6.9 m/min, and number of steps per minute 100.4 +/- 8.8. The speed was significantly slower and the double support time was significantly longer when compared with normal values. CONCLUSIONS: Most patients had good balance confidence scores. Their gait and balance were qualitatively normal using the Tinetti tools for assessment. Therefore, their risk for falls seems low. They had a reduced step length and increased time spent in double support, changes which might represent subtle adaptations to reduced balance. PMID- 25801204 TI - Reducing Health Risk Factors in Workplaces of Low and Middle-Income Countries. AB - OBJECTIVE: To reduce risk factors in workplace settings in low- and middle-income countries. DESIGN AND SAMPLE: Workplace interventions were utilized as part of the Community Interventions for Health program, a nonrandomized, controlled study undertaken in three communities in China, India, and Mexico. Exactly, 45 industrial, 82 health and 101 school workplace settings with a target population of 15,726. Two independent cross-sectional surveys of workers were conducted at baseline and follow-up, after 18-24 months of intervention activities. MEASURES: Culturally appropriate interventions to reduce tobacco use, increase physical activity, and improve dietary intake were delivered in the intervention areas. RESULTS: Exactly, 12,136 adults completed surveys at baseline, and 9,786 at follow-up. In the intervention group, the prevalence of tobacco use reduced significantly in men (-6.0%, p < .001) and the proportion eating five portions of fruit and vegetables daily increased (+6.9%, p < .001) compared with the control group. There were no significant differences between the groups for changes in physical activity or prevalence of overweight. CONCLUSIONS: Workplace interventions improved risk factors in China, India, and Mexico. PMID- 25801205 TI - Higher cognitive ability buffers stress-related depressive symptoms in adolescent girls. AB - Stress has been shown to have a causal effect on risk for depression. We investigated the role of cognitive ability as a moderator of the effect of stressful life events on depressive symptoms and whether this varied by gender. Data were analyzed in two adolescent data sets: one representative community sample aged 11-12 years (n = 460) and one at increased familial risk of depression aged 9-17 years (n = 335). In both data sets, a three-way interaction was found whereby for girls, but not boys, higher cognitive ability buffered the association between stress and greater depressive symptoms. The interaction was replicated when the outcome was a diagnosis of major depressive disorder. This buffering effect in girls was not attributable to coping efficacy. However, a small proportion of the variance was accounted for by sensitivity to environmental stressors. Results suggest that this moderating effect of cognitive ability in girls is largely attributable to greater available resources for cognitive operations that offer protection against stress-induced reductions in cognitive processing and cognitive control which in turn reduces the likelihood of depressive symptomatology. PMID- 25801206 TI - Epigenetic and transcriptional control of Foxp3+ regulatory T cells. AB - Regulatory T cells (Treg cells) present a unique T-cell lineage that plays a key role for the initiation and maintenance of immunological tolerance. Treg cells are characterized by the expression of the forkhead box transcription factor Foxp3, which acts as a lineage-specifying factor and determines the unique properties of these immunosuppressive cells. Work over the past few years has shown that well-defined and precisely controlled events on transcriptional and epigenetic level are required to ensure stable expression of Foxp3 in Treg cells. More recent work suggested that in addition to stable Foxp3 expression, epigenetic modifications of Treg-cell specific genes contribute to the unique phenotype of Treg cells by imprinting their transcriptional program and stabilizing the expression of molecules being essential for the suppressive properties of Treg cells. In this review, we will highlight how Foxp3 expression itself is epigenetically and transcriptionally controlled, how the Treg-cell specific epigenetic signature is achieved, how Foxp3 as transcription factor influences the gene expression programs in Treg cells and how unique properties of Treg-cell subsets are defined by other transcription factors. PMID- 25801208 TI - Functional proteomic biomarkers in cancer. AB - Beyond penetrant germline and somatic mutations, there are substantial challenges in extrapolating phenotypes from linear DNA sequences and transcriptomics. This brings a molecular pathology emphasis to the properties of the main players responsible for executing actions, proteins. The proteomic attribute most frequently determined in pathology is (relative) content, but for many candidate biomarkers this is not the most important feature to understand. In keeping pace with the depth of knowledge of the mechanisms underlying pathologies, we need to ask more sophisticated questions about the state of proteins, for example, their oligomerization status, modification status, and location. This demands hitherto nonroutine approaches to proteomics, which we will discuss in this brief perspective. PMID- 25801207 TI - Etiology and management of dyslipidemia in children with chronic kidney disease and end-stage renal disease. AB - Lipids are essential components of cell membranes, contributing to cell fuel, myelin formation, subcellular organelle function, and steroid hormone synthesis. Children with chronic kidney disease (CKD) and end-stage renal disease (ESRD) exhibit various co-morbidities, including dyslipidemia. The prevalence of dyslipidemias in children with CKD and ESRD is high, being present in 39-65% of patients. Elevated lipid levels in children without renal disease are a risk factor for cardiovascular disease (CVD), while the risk for CVD in pediatric CKD/ESRD is unclear. The pathogenesis of dyslipidemia in CKD features various factors, including increased levels of triglycerides, triglyceride-rich lipoproteins, apolipoprotein C3 (ApoC-III), decreased levels of cholesterylester transfer protein and high-density lipoproteins, and aberrations in serum very low density and intermediate-density lipoproteins. If initial risk assessment indicates that a child with advanced CKD has 2 or more co-morbidities for CVD, first-line treatment should consist of non-pharmacologic management such as therapeutic lifestyle changes and dietary counseling. Pharmacologic treatment of dyslipidemia may reduce the incidence of CVD in children with CKD/ESRD, but randomized trials are lacking. Statins are the only class of lipid-lowering drugs currently approved by the U.S. Food and Drug Administration (FDA) for use in the pediatric population. FDA-approved pediatric labeling for these drugs is based on results from placebo-controlled trial results, showing 30-50% reductions in baseline low-density lipoprotein cholesterol. Although statins are generally well tolerated in adults, a spectrum of adverse events has been reported with their use in both the clinical trial and post-marketing settings. PMID- 25801209 TI - Combined automated NOE assignment and structure calculation with CYANA. AB - The automated assignment of NOESY cross peaks has become a fundamental technique for NMR protein structure analysis. A widely used algorithm for this purpose is implemented in the program CYANA. It has been used for a large number of structure determinations of proteins in solution but was so far not described in full detail. In this paper we present a complete description of the CYANA implementation of automated NOESY assignment, which differs extensively from its predecessor CANDID by the use of a consistent probabilistic treatment, and we discuss its performance in the second round of the critical assessment of structure determination by NMR. PMID- 25801210 TI - Nondestructive diagnostic test for nitrogen nutrition of grapevine (Vitis vinifera L.) based on dualex leaf-clip measurements in the field. AB - Crop nitrogen status is a major issue for crop yield and quality. It is usually assessed by destructive leaf or petiole tissue analysis. A quantitative nondestructive optical estimation of N sufficiency would be a great leap forward toward precision crop management. We therefore calibrated three optical indices against leaf nitrogen content: chlorophyll (Chl), epidermal flavonols, and the nitrogen balance index (NBI), which is the ratio of the former two indices. NBI was the best estimator of leaf N content measured by the Dumas or Kjeldahl method with a root-mean-square error smaller than 2 mg of N g(-1) dry weight, followed by Chl (3 mg g(-1)) and flavonols (4 mg g(-1)). This allowed us to propose the threshold values for the Dualex optical indices that characterize nitrogen supply to grapevines: the first is the threshold below which N supply to the vine can be considered deficient, and the second is the threshold above which N supply is excessive. For a putative optimal N content of 30 mg g(-1) < x < 40 mg g(-1), these thresholds are 30 MUg cm(-2) < x < 40 MUg cm(-2) for Chl and 11 < x < 18 for NBI at flowering. At bunch closure, for N thresholds of 22 < x < 32, Chl is 29 < x < 37 and NBI is 8 < x < 11, in respective units. These values should be verified and refined in the future for various growth regions and cultivars using the specified protocol. The sample size should be 36-60 leaves from a fixed node position, preferably node no. 5 from the tip of the shoot. An alternative to the use of the NBI would be to discard leaves that are not light exposed by checking their flavonol content and to deduce the N sufficiency directly from the Chl values. PMID- 25801212 TI - Mindful brain and EEG-neurophysiology. PMID- 25801211 TI - Can auditory deviant stimuli temporarily suspend cognitive processing? Evidence from patients with anxiety. AB - While anxiety is typically thought to increase distractibility, this notion mostly derives from studies using emotionally loaded distractors presented in the same modality as the target stimuli and tasks involving crosstalk interference. We examined whether pathological anxiety might also increase distractibility for emotionally neutral irrelevant sounds presented prior to target stimuli in a task where these stimuli do not compete for selection. Patients with anxiety and control participants categorized visual digits preceded by task-irrelevant sounds that changed on rare trials (auditory deviance). Both groups exhibited an equivalent increase in response times following a deviant sound but patients showed a reduction of response accuracy, which was entirely due to an increase in response omissions. We conclude that the involuntary capture of attention by unexpected stimuli may, in patients with anxiety, result in a temporary suspension of cognitive activity. PMID- 25801213 TI - Evaluation of a magnetic particles-based chemiluminescence enzyme immunoassay for Golgi protein 73 in human serum. AB - BACKGROUND: Golgi protein 73 (GP73) is regarded as a potential serum biomarker for early diagnosis of hepatocellular carcinoma (HCC). We developed a rapid magnetic particles-based chemiluminescence enzyme immunoassay (MPs-CLEIA) for the determination of serum GP73. METHODS: Fluorescein isothiocyanate (FITC) and alkaline phosphatase (ALP) were used to label 2 different monoclonal antibodies to GP73. Serum GP73 was captured with labeled antibodies and formed a sandwiched immunoreaction. The magnetic particles (MPs) coated with anti-FITC antibody were used as a means of separation of the GP73 protein from other serum proteins. After adding the enzyme substrate solution, the relative light unit (RLU) was measured. A MPs-CLEIA for serum GP73 was established and evaluated. RESULTS: The RLU was directly proportional to the concentration of GP73. The method linearity was 5-600 MUg/l. Limit of the blank was 2.19 MUg/l. The intra- and inter-assay imprecision was <3% and <5%, respectively. The average recoveries were between 95% and 105%. The proposed method showed a good correlation with a commercial ELISA assay (r=0.983, p<0.001). We also evaluated the efficiency of serum GP73 measurement for the diagnosis of HCC using this assay. The area under the receiver operating characteristic curve was 0.822 (95% CI, 0.73-0.89), and the sensitivity and specificity, with cut-off value of 115.6 MUg/l, were 75.4% and 92.1%, respectively. CONCLUSIONS: The proposed method demonstrates an acceptable performance for quantifying serum GP73. This assay could be appropriate for routine use in clinical laboratories. PMID- 25801214 TI - Low protective PON1 lactonase activity in an Arab population with high rates of coronary heart disease and diabetes. AB - BACKGROUND: Recent studies showing that high density lipoproteins (HDL) can effect plaque regression indicate that recent trial failures do not exclude an atheroprotective role of HDL. Instead, they highlight differences between HDL function and measured HDL-cholesterol (HDL-C). PON1 is one key functional activity of HDL. Urban Palestinians have lower HDL-C and a higher incidence and mortality of coronary heart disease than those of Israelis. We hypothesized that the cardioprotective PON1 lactonase and arylesterase activities and PON1 functional genotype may differ between Palestinians and Israelis. METHODS: We measured PON1 activities in a cross-sectional population-based study of Palestinian (n=960) and Israeli (n=694) residents in Jerusalem, 1654 participants in all. RESULTS: Palestinians had high prevalences of obesity and diabetes and low mean concentrations of HDL-cholesterol (0.97 mmol/l in men and 1.19 mmol/l in women). Lactonase and arylesterase activities were lower by 10.8% (p=1.2*10(-14)) and 2.7% (p<0.0005), respectively, in Palestinians as compared to Israelis. The functional genotype distribution, demonstrated by plotting paraoxonase vs lactonase activities, showed a modest between-group difference (p=0.024), with 12.1% RR in Palestinian Arabs vs 8.4% in Israeli Jews, but no overall difference in allele frequencies. Lactonase correlated inversely with age (Spearman's rho= .156), weakly with BMI (-.059), positively with HDL-C (.173) and non-HDL-C (.103), but was not associated with triglycerides or fasting glucose. Palestinians showed consistently lower lactonase activity in logistic regression models adjusted for multiple covariates and for functional genotype (odds ratios of 1.81 and 1.98, respectively, for the lower fifth vs the upper 4 fifths of lactonase activity p<0.0001). CONCLUSION: We showed a lower physiologically significant lactonase PON1 activity in an Arab population, a finding consistent with the high cardiovascular and diabetes risk of Palestinians. PMID- 25801215 TI - Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature. AB - Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated. PMID- 25801216 TI - A1c Gear: Laboratory quality HbA1c measurement at the point of care. AB - INTRODUCTION: HbA1c is an important part of assessing the diabetic control and since the use of point-of-care devices for monitoring HbA1c is increasing, it is important to determine how these devices compare to the central laboratory. METHODS: One hundred and twenty patient samples were analyzed on the Bio-Rad VariantTMII and one POC analyzer (Sakae A1c Gear). Three patient sample pools containing ~5%, ~7%, and ~10% HbA1c levels were run over 20 days. Three reagent lots and three instruments were evaluated for the A1c Gear. RESULTS: The 120 patient samples showed strong correlation (R(2)>0.989) when compared to the VariantTMII with means=8.06% and 7.81%, for Variant IIand A1c Gear, respectively. Changing reagent lots or instruments had no impact for the A1c Gear. The ~5%, ~7%, and ~10% pools within-run and between-run imprecision was between 0.87-1.33% and 1.03-1.32%, and 1.41-2.35% and 1.24-1.89% with total imprecision of 1.67 2.35% and 1.61-2.31% for the A1c Gear and Variant II, respectively. The A1c Gear showed a small negative bias (0.25% HbA1c) across HbA1c measurement ranges of <11.5%. This bias was, however, acceptable and not considered to be clinically significant. CONCLUSIONS: The A1c Gear meets the criteria of total CV <3% leading us to the conclusion that the A1c Gear can give results as precise as the laboratory at the POC. PMID- 25801217 TI - Advanced oxidation protein products decrease the expression of calcium transport channels in small intestinal epithelium via the p44/42 MAPK signaling pathway. AB - Advanced oxidation protein products (AOPPs), novel protein markers of oxidative damage, accumulate in the plasma of patients with inflammatory bowel disease (IBD). Osteoporosis, which is closely related to the regulation of intestinal calcium transport channels (CTCs), is a prevalent extraintestinal complication of IBD and is associated with oxidative stress. However, the underlying mechanisms are unknown. The present study aimed to verify whether AOPPs inhibit CTCs in the small intestinal epithelium and to identify the underlying mechanisms that may contribute to IBD-associated osteoporosis. Normal Sprague-Dawley rats were treated with AOPP-modified rat serum albumin. The calcium ion level in serum was not significantly altered, while the duodenal expression of CTCs (e.g. transient receptor potential vanilloid [TRPV6], calbindin-D9k [CaBP-D9k], plasma membrane Ca(2+)-ATPase 1 [PMCA1], and Na(+)/Ca(2+) exchanger 1 [NCX1]) were decreased. In contrast, the levels of the related hormones that regulate calcium absorption including parathyroid hormone (PTH), 25-(OH)D3, and 1,25-(OH)2D3 were increased, although the trend toward an increase in PTH levels was not significant. In order to further investigate the effects of AOPP exposure, we also evaluated the expression of CTCs (including the voltage-dependent L-type calcium channel [CaV1.3], TRPV6, CaBP-D9k, PMCA1, and NCX1) in cultured human colorectal adenocarcinoma cells (Caco-2). The expression levels of total CTC protein and mRNA, except for CaV1.3, were significantly down-regulated in a concentration- and time-dependent manner. Moreover, phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) was observed in vivo and in vitro. The p44/42 inhibitor U0126 reversed the down-regulation of CTCs induced by AOPPs in the Caco-2 monolayer. Our results indicate that AOPPs down-regulate the expression of CTCs through p44/42 MAPK signaling mechanisms in the small intestinal epithelium. These data provide new insights regarding the molecular basis of AOPP-induced reductions in intestinal CTCs, and are relevant to understanding the mechanisms of IBD-associated osteoporosis. Further studies are needed to explore these mechanisms in greater detail. PMID- 25801218 TI - Assessment of nursing students' stress levels and coping strategies in operating room practice. AB - The aim of this study was to evaluate the stress levels and stress coping strategies of nursing students in their first operating room experience. This descriptive study was done with 126 nursing students who were having an experience in an operating room for the first time. Data were collected by using Personal Information Form, Clinical Stress Questionnaire, and Styles of Coping Inventory. The nursing students mostly had low clinical stress levels (M = 27.56, SD = 10.76) and adopted a self-confident approach in coping with stress (M = 14.3, SD = 3.58). The nursing students generally employed a helpless/self accusatory approach among passive patterns as their clinical stress levels increased, used a self-confident and optimistic approach among active patterns as their average age increased, and those who had never been to an operating room previously used a submissive approach among passive patterns. The results showed that low levels of stress caused the nursing students to use active patterns in coping with stress, whereas increasing levels of stress resulted in employing passive patterns in stress coping. The nursing students should be ensured to maintain low levels of stress and use active patterns in stress coping. PMID- 25801219 TI - Cu2ZnSnS4 absorption layers with controlled phase purity. AB - We report the synthesis and characterization of Cu2ZnSnS4 (CZTS) with controlled phase purity. The precursor was first prepared using sequential electrodeposition of Cu, Zn, and Sn in different orders. The Cu/(Sn+Zn) ratio in each stacking order was also varied. The precursor was subjected to annealing at 200 degrees C and sulfurization at 500 degrees C in a 5%-H2S/Ar atmosphere for the formation of CZTS. The phase evolutions during the electrodeposition and annealing stages, and the final phase formation at the sulfurization stage were examined using both x ray diffractometry and Raman spectroscopy, both of which are shown to be complimentary tools for phase identification. Detailed growth path is therefore reported. We also demonstrate by controlling the stacking order and the Cu/(Sn+Zn) ratio, CZTS with a phase purity as high as 93% is obtained. PMID- 25801220 TI - Patterning of mammalian heterodont dentition within the upper and lower jaws. AB - Mammalian heterodont dentition is differentiated into incisors, canines, premolars, and molars in the mesial-distal direction, in both the upper and lower jaws. Although all the lower teeth are rooted in the mandible, the upper incisors are rooted in the premaxilla and the upper canine and the teeth behind it are in the maxilla. The present study uncovers ontogenetic backgrounds to these shared and differing mesiodistal patterns of the upper and lower dentition. To this end, we examined the dentition development of the house shrew, Suncus murinus, instead of the rodent model animals because the dentition of this primitive eutherian species includes all the tooth classes, and no toothless diastema region. In the shrew, the upper incisor-forming region extended over the medial nasal prominence and the mesial part of the maxillary prominence. Consequently, the maxillary and mandibular prominences were in a mirror-image relationship in terms of the mesiodistally differentiated tooth-forming regions and of the complementary gene expression pattern, with Bmp4 in the mesial and Fgf8 in the distal regions. This suggests shared molecular mechanisms regulating tooth class differentiation between the upper and lower jaws. However, the premaxillary bone appeared within the mesenchyme of the medial nasal prominence, but grew distally beyond the former epithelial boundary with the maxillary prominence to form, finally, the incisive (premaxillary-maxillary) suture just mesial to the canine. Therefore, the developmental locations of the upper incisors are not inconsistent with the classical osteological criterion of the upper canine by comparative odontologists. PMID- 25801221 TI - Expression patterns of Eph genes in the "dual visual development" of the lamprey and their significance in the evolution of vision in vertebrates. AB - Image-forming vision is crucial to animals for recognizing objects in their environment. In vertebrates, this type of vision is achieved with paired camera eyes and topographic projection of the optic nerve. Topographic projection is established by an orthogonal gradient of axon guidance molecules, such as Ephs. To explore the evolution of image-forming vision in vertebrates, lampreys, which belong to the basal lineage of vertebrates, are key animals because they show unique "dual visual development." In the embryonic and pre-ammocoete larval stage (the "primary" phase), photoreceptive "ocellus-like" eyes develop, but there is no retinotectal optic nerve projection. In the late ammocoete larval stage (the "secondary" phase), the eyes grow and form into camera eyes, and retinotectal projection is newly formed. After metamorphosis, this retinotectal projection in adult lampreys is topographic, similar to that of gnathostomes. In this study, we explored the involvement of Ephs in lamprey "dual visual development" and establishment of the image-form vision. We found that gnathostome-like orthogonal gradient expression was present in the retina during the "secondary" phase; i.e., EphB showed a gradient of expression along the dorsoventral axis, while EphC was expressed along the anteroposterior axis. However, no orthogonal gradient expression was observed during the "primary" phase. These observations suggest that Ephs are likely recruited de novo for the guidance of topographical "second" optic nerve projection. Transformations during lamprey "dual visual development" may represent "recapitulation" from a protochordate-like ancestor to a gnathostome-like vertebrate ancestor. PMID- 25801222 TI - A combination of developmental plasticity, parental effects, and genetic differentiation mediates divergences in life history traits between dung beetle populations. AB - The dung beetle, Onthophagus taurus, was introduced <50 years ago from its native Mediterranean range into Western Australia (WA) and the Eastern United States (EUS). The intensity of intra- and interspecific competition for dung as a breeding resource is substantially higher in WA. First, we tested whether differential resource competition in the two exotic ranges is associated with divergences in life history traits, which impact on resource use. We predicted that high levels of resource competition in WA should favor females that produce brood balls more efficiently and of altered size, and produce offspring more readily when a breeding opportunity arises. Furthermore, we predicted that larvae from WA populations may have evolved more efficient development and thus exhibit higher eclosion success, shorter development time, and altered body size under standardized conditions. Second, we examined the likely developmental mechanisms underlying these divergences, that is, genetic differentiation, developmental plasticity, or parental effects in a common garden experiment. Field-collected EUS and WA populations significantly differed, as predicted, in most of the traits examined. However, these differences are facilitated by a complex combination of proximate mechanisms. Developmental plasticity and (grand) parental effects mediated differences related to reproductive performance, whereas genetic differentiation mediated differences in the duration of larval development. Our study highlights that population divergences can be the product of a patchwork of proximate mechanisms, with each mechanism adjusting different traits in a way that the resulting composite phenotype may be better suited to its competitive environment. PMID- 25801223 TI - Insights into Frizzled evolution and new perspectives. AB - The Frizzled proteins (FZDs) are a family of trans-membrane receptors that play pivotal roles in Wnt pathways and thus in animal development. Based on evaluation of the Amphimedon queenslandica genome, it has been proposed that two Fzd genes may have been present before the split between demosponges and other animals. The major purpose of this study is to go deeper into the evolution of this family of proteins by evaluating an extended set of available data from bilaterians, cnidarians, and different basally branching animal lineages (Ctenophora, Placozoa, Porifera). The present study provides evidence that the last common ancestor of metazoans did possess two Fzd genes, and that the last common ancestor of cnidarians and bilaterians may have possessed four Fzd. Furthermore, amino acid analyses revealed an accurate diagnostic motif for these four FZD subfamilies facilitating the assignation of Frizzled paralogs to each subfamily. By highlighting conserved amino acids for each FZD subfamily, our study could also provide a framework for further research on the precise mechanisms that have driven FZD neo-functionalization. PMID- 25801225 TI - Antioxidant, antimicrobial and urease inhibiting activities of methanolic extracts from Cyphostemma digitatum stem and roots. AB - Cyphostemma digitatum stem and roots extracts were investigated for antioxidant, antimicrobial, urease inhibition potential and phytochemical analysis. Phytochemical screening of the roots and stem extract revealed the presence of secondary metabolites including flavonoids, alkaloids, coumarins, saponins, terpenoids, tannins, carbohydrates/reducing sugars and phenolic compounds. The methanolic extracts of the roots displayed highest antioxidant activity (93.518%) against DPPH while the crude methanolic extract of the stem showed highest antioxidant activity (66.163%) at 100 MUg/mL concentration. The methanolic extracts of both stem and roots were moderately active or even found to be less active against the selected bacterial and fungal strains (Tables S2 and S3). The roots extract (methanol) showed significant urease enzyme inhibition activity (IC50 = 41.2 +/- 0.66; 0.2 mg/mL) while the stem extract was found moderately active (IC50 = 401.1 +/- 0.58; 0.2 mg/mL) against thiourea (IC50 = 21.011; 0.2 mg/mL). PMID- 25801226 TI - Clinical evaluation of the safety and efficacy of 10% imidacloprid + 2.5% moxidectin topical solution for the treatment of ear mite (Otodectes cynotis) infestations in dogs. AB - A clinical field investigation was conducted to evaluate the safety and efficacy of 10% imidacloprid/2.5% moxidectin for the treatment of ear mites (Otodectes cynotis) in dogs. The study was a multi-centered, blinded, positive controlled, randomized clinical trial conducted under field conditions with privately owned pets. A total of 17 veterinary clinics enrolled cases for the study. An otoscopic examination was performed to confirm the presence of O. cynotis residing in the ear of the dog prior to enrollment. A single-dog household was enrolled in the study if the dog had 5 or more ear mites and an acceptable physical examination. A multi-dog household was eligible if at least one dog in the household had 5 or more mites and all dogs in the household had acceptable physical exams and met the inclusion criteria. Qualified households were randomly assigned to treatments to receive either 10% imidacloprid+2.5% moxidectin topical solution or topical selamectin solution (positive control product) according to a pre-designated enrollment ratio of 2:1, respectively. If more than one dog in a multiple dog household had adequate numbers of ear mites, one dog was randomly selected to represent the household for efficacy evaluation prior to treatment. Treatments were administered twice per label and dose banding directions for each product approximately 28 days apart (Days 0 and 28), by the dog's owner at the study site. All dogs in a household were treated on the same day and with the same product. The owners completed a post-treatment observation form one day after each treatment. Post-treatment otoscopic examinations were performed by the investigators or attending veterinarian on Days 28 and 56. Physical examinations were performed on Days 0 and 56. One hundred and four (104) households were evaluated for efficacy on SD 28, and 102 households were evaluated for efficacy on SD 56. The dogs' ages ranged from 2 months to 16 years. A total of 247 dogs were evaluated for safety. Percent efficacy was based on the percentage of dogs cleared of ear mites. Mite clearance on Day 28 was 71% for the imidacloprid+moxidectin group and 69% for the selamectin group. Mite clearance on Day 56 was 82% for the imidacloprid+moxidectin group and 74% for the selamectin group. No serious adverse events associated with either product were observed during the study. The study demonstrated that 10% imidacloprid+2.5% moxidectin applied using two topical treatments, 28 days apart, was safe and achieved similar efficacy against O. cynotis as selamectin treatments applied and evaluated under the same conditions. PMID- 25801227 TI - Acute phase protein response in heartworm-infected dogs after adulticide treatment. AB - During the adulticide treatment of Dirofilaria immitis the worms die releasing fragments of parasites and causing pulmonary thromboembolisms which could exacerbate the clinical condition. To determine the utility of acute phase proteins (APPs) to monitor the progression of the treatment, different positive [C-reactive protein (CRP), haptoglobin (hp)] and negative [albumin, paraoxonase 1(PON-1)] APPs were measured in 15 heartworm-infected dogs (5 with high and 10 with low parasite burden) following adulticide treatment. The results showed increased concentrations of CRP, decreased concentrations of haptoglobin and PON 1 in infected dogs before starting the treatment. Progressive but not significant increases were observed in PON-1 activity and albumin concentration along the treatment. After the treatment with doxycycline and ivermectine a decrease in CRP and Hp levels was experienced, which could reflect a reduction of the vascular inflammation caused by the elimination of Wolbachia and reduction of microfilariae. Fifteen days after the first melarsomine injection, marked increases in CRP and Hp were observed, which could be due to pulmonary inflammation and thromboembolism caused by the post-adulticide death of the worms. This increase was greater in dogs with high parasite burden. As the pathology disappeared, there was an improvement in the concentrations of CRP and Hp, returning into reference values in dogs with low parasite burden at the end of the treatment. The measurement of CRP and Hp could be a resource of support to evaluate the magnitude of the post-adulticide complications during the adulticide treatment of D. immitis. PMID- 25801228 TI - Enhanced endothelial progenitor cell mobilization and function through direct manipulation of hypoxia inducible factor-1alpha. AB - Endothelial progenitor cells (EPCs) play a significant role in physiological and pathological hypoxia resistance and neovascularization processes. The ability to mobilize EPCs from bone marrow usually indicates a prognostic endpoint of several vascular diseases. Thus, it is of great value to study possible approaches for activating functional EPCs. The mobilization/homing of EPCs from bone marrow is signalled by stromal-derived factor-1 (SDF-1), which is regulated by the hypoxia inducible factor-1alpha (HIF-1alpha). This study investigated the effects of directly manipulating HIF-1alpha on human EPCs in vitro. EPCs were isolated from human umbilical cord blood. Lentiviral vectors carrying HIF-1alpha and shRNA targeting HIF-1alpha were constructed for gene modification of the EPCs. Results demonstrated that after overexpression of HIF-1alpha by lentiviral transfection, the proliferative capacity of EPCs was elevated while the apoptosis was inhibited and vice versa. On the other hand, the expression of angiogenic-related cytokines including SDF-1 was upregulated on both gene and protein levels when EPCs were transfected with HIF-1alpha. These results indicate that direct HIF-1alpha manipulation over human EPCs is an effective method to promote EPC function and mobilization, thus suggest that drugs or reagents that elevate HIF-1alpha expression are capable of treating ischemic diseases. PMID- 25801229 TI - Photoelectrochemical generation of hydrogen and electricity from hydrazine hydrate using BiVO4 electrodes. AB - This study demonstrates solar driven oxidation of hydrazine hydrate and the simultaneous production of hydrogen and electricity in photoelectrochemical cells and photofuel cells, respectively, using a visible light active molybdenum doped BiVO4 photoelectrode. The developed photoelectrodes exhibited tremendous efficiency towards anodic oxidation of hydrous hydrazine with continuous and stable hydrogen evolution at the Pt cathode under benign pH and zero bias conditions. Significantly, the photofuel cell containing hydrazine hydrate fuel has generated electricity with a high open circuit potential of 0.8 V. The presence of bicarbonate ions in the electrolyte has played a significant role in enhancing the kinetics of photoelectrochemical oxidation of hydrazine and improved the hydrogen and electricity generation efficiency thus avoiding the integration of an oxidation electrocatalyst. In addition, molybdenum doped BiVO4 as a possible photoelectrochemical hydrazine sensor has been investigated and the electrode photocurrent was found to be linearly dependent on the concentration of the hydrazine hydrate in the range of 20-90 mM with a correlation coefficient of 0.9936. PMID- 25801230 TI - Urothelial carcinoma of the bladder in patients aged 30 years or younger: clinicopathological analysis and expression of fibroblast growth factor receptor 3 (FGFR3) of 45 cases. AB - The aim of this study was to demonstrate the clinicopathological features, prognostic outcomes and fibroblast growth factor receptor 3 (FGFR3) protein expression status of a large series (n = 45) of urothelial carcinoma of bladder patients aged 30 or younger, retrospectively. We identified an age gradient (an age of 25, 26 and 27 years), classified patients as <= 25 or >25, <= 26 or >26, <= 27 or >27 years, respectively, and compared variables including recurrence events and FGFR3 expression patterns between different groups. Patients aged 25 years or younger were less likely to experience tumor recurrence (p = 0.046), were more likely to develop smaller size tumors (p = 0.040) and expressed more proportion of negative pattern of FGFR3 protein (p = 0.036). Patients aged 25 years or younger were less likely to develop tumor recurrence and revealed more proportion of negative pattern of FGFR3 expression than those aged 26-30 years did. We identified patients aged 25 years or younger as the true "young" urothelial carcinoma patients, carrying distinct clinical outcomes and molecular tumorigenesis. PMID- 25801231 TI - Pseudomonas aeruginosa preparation plus chemotherapy for advanced non-small-cell lung cancer: a randomized, multicenter, double-blind phase III study. AB - Pseudomonas aeruginosa preparation (PAP) has shown activity in inhibiting the metastasis of cancer and can improve the immune function of cancer patients during chemotherapy. This study aimed to investigate whether PAP can improves the efficacy of chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). A total of 72 subjects with stage IIIB/IV NSCLC were randomized into PAP arm (n = 36) or control arm (n = 36) at a 1:1 ratio. Subjects had vinorelbine and cisplatin combined with 0.5 ml PAP/placebo on d1, followed by 1 ml PAP/placebo injected subcutaneously three times a week. The primary end point was the objective response rate (ORR) and secondary endpoints were time to progression (TTP), overall survival (OS), safety and quality of life (QOL). Sixty-six patients were included in intent-to-treat analysis. After two cycles of treatment, there was a borderline statistically significant improvement in ORR of PAP arm (46.88 vs. 23.53 %, P = 0.0532), and after four cycles of treatment, the ORR in PAP arm was 31.25 versus 14.71 % in control arm (P = 0.1110). Median TTP and OS were 160 and 454 days in PAP arm, 196 and 388 days in control arm, P = 0.4609 and 0.6587, respectively. The 1-year survival rate in PAP and control arms was 53.55 and 50.15 %, respectively. PAP did not result in increased toxicity and or had negative impact on QOL. The results demonstrate the therapeutic potential of PAP for advanced NSCLC. PAP can be used with chemotherapy to improve the response rate. Long-term follow-up might help define whether the combination therapy can result in survival benefit. PMID- 25801232 TI - Wls promotes the proliferation of breast cancer cells via Wnt signaling. AB - The Wnt secretion protein Wntless (Wls)/GPR177 has been reported to be involved in the development of several human cancers. However, the biological significance of Wls in breast cancer progression has not been clarified. In this study, we show for the first time that Wls is an important molecule related to breast cancer. We find that Wls expression is markedly increased in clinical breast tumors compared with adjacent noncancerous tissues. Downregulation of Wls by short-hairpin RNA severely suppressed the proliferation of breast cancer cells. Wls is a core Wnt signaling component, and we show that knockdown of Wls is sufficient to inhibit Wnt secretion and its downstream signaling. Taken together, these results indicate that Wls contributes to the proliferation of breast cancer cells by regulating Wnt signaling. Therefore, Wls could be a novel therapeutic target for inhibiting cell growth in breast cancer. PMID- 25801234 TI - Basal Pain Sensitivity does not Predict the Outcome of Multidisciplinary Chronic Pain Treatment. AB - OBJECTIVES: Individual differences in underlying, "basal" pain sensitivity are large and have clinical implications. Some studies have suggested that basal pain sensitivity may also predict the outcome of pain treatment. Multidisciplinary chronic pain management programs are effective, but treatment success is individually very different. Therefore, identification of predictors of treatment success is important. This study investigated if basal pain sensitivity predicted the outcome of a 4-week outpatient multidisciplinary pain management program. DESIGN: Cohort study. SETTING: Chronic pain outpatient clinic at the Department of Anesthesiology, Intensive Care Medicine and Pain Therapy of the University of Munster. METHODS: Basal pain sensitivity was measured at treatment onset, using comprehensive experimental pain testing (thermal, pressure, and pinprick pain) and the pain sensitivity questionnaire. Primary (clinical pain intensity) and secondary (depression, anxiety, pain-related disability) outcome parameters were assessed at treatment start, at discharge and 6 months later. SUBJECTS: Sixty five adult chronic pain patients with mixed pain diagnoses. RESULTS: There were significant improvements in clinical pain intensity (from 6.1 +/- 2.0 to 5.1 +/- 1.8 [0-10]), depression and anxiety at discharge (all P < 0.001) and of clinical pain intensity (to 5.3 +/- 2.3 [0-10]) and pain-related disability at 6 months (all P < 0.05). However, treatment outcome was not predicted by any of the basal pain sensitivity measures. DISCUSSION: Results show that basal pain sensitivity is not a reliable predictor of treatment outcome in mixed diagnosis multidisciplinary pain management programs, possibly due to the heterogeneity of patients enrolled in such programs. Clinically useful predictors of treatment success in this setting remain to be identified. PMID- 25801233 TI - Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition. AB - The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation. The irradiation of MCF 7 cells alone increased the proportion of cells in the G1 phase in comparison with mock-treated cells. After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase. ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death. Unexpectedly, combining both inhibitors decreased the percentage of senescent cells and increased G2 cell cycle arrest 3 days after treatment. After irradiation, the p21 protein was increased and Chk1 and Chk2 were activated. These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected. Formation of gammaH2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of gammaH2AX, whereas DNA-PK caused persistence of gammaH2AX. Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted. PMID- 25801235 TI - 50 Years in the sun of Burgenstock--on the success factors of a famous conference. AB - The secret of success: This year the famous "Burgenstock Conference" will take place for the 50th time. This conference has become internationally one of the, if not the, most highly regarded conference in chemistry, chemical biology, and physical chemistry. What are the success factors of this conference? These as well as a number of perhaps more hidden figures and facts are discussed. PMID- 25801236 TI - Medicinal chemistry of cannabinoids. AB - The endocannabinoid system comprises the two well characterized Gi/o -protein coupled receptors (cannabinoid receptor 1 (CB1) and CB2), their endogenous lipid ligands, and the enzymes involved in their biosynthesis and biotransformation. Drug discovery efforts relating to the endocannabinoid system have been focused mainly on the two cannabinoid receptors and the two endocannabinoid deactivating enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). This review provides an overview of cannabinergic agents used in drug research and those being explored clinically. PMID- 25801238 TI - Genetic association of CUGBP2 and DNMBP with Alzheimer' s disease in the Chinese Han population. AB - OBJECTIVE: Recently, candidate genetic studies revealed the single nucleotide polymorphisms (SNPs) of CUGBP2 (rs2242451) and DNMBP (rs11190305 and rs3740058) associated with Alzheimer's disease (AD). Due to genetic heterogeneity and different ethnic background, the purpose of our study was to confirm the association between these 3 SNPs with AD risk in the Chinese Han population. METHODS: We investigated 482 sporadic AD (SAD) patients and 813 unrelated cognitive normal controls of the Chinese Han population. The genotypes of the 3 SNPs (rs2242451, rs11190305, rs3740058) were carried out by MassARRAY iPLEX system. RESULTS: The genotype and the allele frequency of rs2242451 were significantly different between AD and control group in total subject (genotype: p=0.019, allele frequency: p=0.022, OR=0.760, 95%CI=0.601- 0.962) with A allele decreasing AD risk. After stratification by age at onset, gender, APOE epsilon4 carrying status and homozygous APOE epsilon4, the protective effect of A allele remained in female and APOE epsilon4epsilon4 non-carrying subgroups. The rs3740058 in DNMBP was significantly differently in genotype between AD and control in APOE epsilon4epsilon4 subgroup, but showed no effect on AD risk, either did rs11190305 polymorphisms in DNMBP. Meta-analysis was performed in rs11190305 and rs3740058 of DNMBP respectively. Positive relationship with AD was found in rs11190305 (OR=1.11, 95%CI=1.01-1.21), but not in rs3740058 (OR=1.05, 95%CI=0.98-1.13). Moreover, the genotypes of these 3 SNPs had no effect on age at onset of AD. CONCLUSION: The A allele of rs2242451 in CUGBP2 might decrease SAD risk in the Chinese Han population. PMID- 25801237 TI - Sensorimotor gating, cannabis use and the risk of psychosis. AB - Sensorimotor gating, measured as the modification of eye blink startle reflexes to loud acoustic stimuli by quieter preceding stimuli, is altered in those with psychosis, their relatives and those at high clinical risk for psychosis. Alterations have also been shown in cannabis users, albeit to a lesser extent, and cannabis is a known risk factor for the onset of psychosis in clinically and genetically susceptible individuals. We examined the interaction between clinical risk for psychosis and cannabis use on sensorimotor gating, both Prepulse Inhibition (PPI) and Prepulse Facilitation (PPF). We tested PPI and PPF in participants with an At Risk Mental State (ARMS) for psychosis and a matched control group. Both groups included a proportion of subjects who had recently used cannabis, as confirmed by urinary drug screening (UDS) on the day of testing. We found that ARMS participants showed reduced PPF and PPI relative to controls, the latter driven by a group by cannabis use interaction, with recent use reducing PPI in ARMS participants but not in controls. When the analysis was limited to UDS-negative participants there was significantly reduced PPF in ARMS subjects relative to controls, but no differences in PPI. Within the ARMS group reduced sensorimotor gating, measured by both PPI and PPF, related to reduced overall level of function. Cannabis use in clinical high risk individuals may increase the risk of psychosis in part through worsening PPI, while PPF is altered in ARMS individuals irrespective of cannabis use. This develops our understanding of cognitive mechanisms leading to the experience of aberrant perceptual phenomena and the subsequent development of psychotic symptoms. PMID- 25801239 TI - Clinicopathologic characteristics and molecular subtypes of microinvasive carcinoma of the breast. AB - Patients with microinvasive carcinoma often have favorable prognosis, but it remains unclear whether this special type of breast cancer represents a distinct morphological entity with its own biological features and clinical behavior distinct from those of ductal carcinoma in situ (DCIS). The study is a retrospective analysis of a large patient cohort from a single institution. One hundred and thirty one microinvasive carcinoma and 451 DCIS cases were collected. ER, PR, HER2, and Ki67 were examined by immunohistochemistry in pathological sections. We assessed the clinicopathologic characteristics, molecular features, and survival status of microinvasive carcinoma and compared to those of DCIS. Microinvasive carcinoma differed from DCIS with respect to tumor size, lymph node status, and initial presentation (P < 0.05). There was a significant difference in nuclear grade among microinvasive carcinoma of different molecular subtype (P < 0.05). The clinicalpathologic features and outcomes of patients with microinvasive carcinoma were similar to those with DCIS. The 5-year OS rate for microinvasive carcinoma and DCIS patients was 99.0 and 99.2%, respectively. A combination of pathologic, clinical, and molecular factors may ultimately reveal more powerful and robust measures for disease classification than any one modality alone. Microinvasive carcinoma does not significantly predict for worse DFS or OS in comparison with patients with DCIS. PMID- 25801240 TI - Insights into the application of let-7 family as promising biomarker in cancer screening. AB - Cancer is a leading cause of death worldwide with its low 5-year survival rate. Studies on the accuracy of let-7 family for human cancers have inconsistent conclusions, leading us to conduct this meta-analysis. This meta-analysis comprised of 11 studies from eight articles involving 805 cancer patients and 483 controls. The pooled parameters were as follows: sensitivity, 77 % (95 % confidence interval (CI) 73-81 %); specificity, 80 % (95 % CI 68-88 %); positive likelihood ratio (PLR), 3.8; negative likelihood ratio (NLR), 0.29; and diagnostic odds ratio (DOR) 13.0. In addition, we plotted the SROC and calculated the area under the curve (AUC) of 0.81 (95 % CI 0.78-0.84), which indicated a relatively high descriptive accuracy. In summary, our data suggested that let-7 family might be applied in noninvasive screening tests for human cancers, which needed to be validated in further large-scale studies. PMID- 25801241 TI - Serum vascular endothelial growth factors C and D as forecast tools for patients with gallbladder carcinoma. AB - Gallbladder carcinoma (GBC) is the most common cancer of the biliary tract. Lymph node metastasis (LNM) is the major diffusion route of GBC and is a prognosis factor. The aim of study was to assess the potential of the serum VEGF-C and VEGF D (sVEGF-C/D) levels to predict the presence of LNM and the survival of GBC patients. The preoperative sVEGF-C/D levels of 31 patients with GBC, 10 patients with cholesterol polyps, and 10 healthy volunteers were measured by enzyme-linked immunoadsorbent assay (ELISA). The sVEGF-C/D levels of patients with GBC were significantly higher than those of people with healthy gallbladders (p < 0.001 and p = 0.001, respectively) and cholesterol polyp (p = 0.032 and p = 0.004, respectively). In GBC, the sVEGF-C levels were associated with LNM (p = 0.011), distant metastasis (p = 0.018), and stage (p = 0.045), but the sVEGF-D levels had a significant association with the tumor depth (p = 0.001), LNM (p = 0.001), distant metastasis (p = 0.047), and stage (p = 0.002). The sVEGF-C/D diagnostic values for the presence of GBC were sensitivity of 71.0 and 74.2 % and specificity of 80.0 and 85.0 %, respectively. With respect to the diagnosis of LNM, the diagnostic values of sVEGF-C/D were as follows: sensitivity 81.2 and 87.5 % and specificity 73.3 and 80.0 %, respectively. The mean survival time with high sVEGF-C was significantly shorter than that with low sVEGF-C (p < 0.001), which was also true for low sVEGF-D (p = 0.032). The preoperative sVEGF-C/D levels might be reliable biomarkers for the presence of disease and LNM in patients with GBC. The sVEGF-C/D levels may be prognosis factors that can predict a poor outcome for GBC patients. PMID- 25801242 TI - Association of TP53 gene polymorphisms with susceptibility of bladder cancer in Bangladeshi population. AB - TP53 is considered to be the most frequently mutated gene in every forms of human cancer. The objective of this study was to evaluate the association of TP53 codon 72 and 248 polymorphisms with the susceptibility and severity of bladder cancer in Bangladeshi population. A case-control study on 102 bladder cancer patients and 140 control subjects was conducted. The genotype analysis was done by polymerase chain reaction-based restriction fragment length polymorphism (PCR RFLP) method. The patients with Pro/Pro genotypes at 72 position were at high risk (odds ratio (OR) = 3.02; 95 % confidence interval (95 % CI) = 1.42 to 6.40) of developing bladder cancer. The cigarette smokers with Pro/Pro genotypes at 72 position were found to have a 3.91-fold increased risk to develop bladder cancer (OR = 3.91; 95 % CI = 1.33 to 11.5). There was no significant association of codon 248 polymorphisms with bladder cancer in the study population. Taken together, these findings indicate an association between p53 codon72 polymorphism and bladder cancer risk in Bangladeshi population. PMID- 25801243 TI - Radical surgery may be not an optimal treatment approach for pulmonary MALT lymphoma. AB - Primary pulmonary MALT lymphoma is a rare disease, and no standard treatments have been defined yet. In this study, 38 consecutive patients from single center were reviewed. Among 25 patients with localized disease, radical surgery were performed in 12 patients, and the other 13 patients had chemotherapy combined with (7 patients) or without (6 patients) radiotherapy. No significant difference in overall survival (OS) was found between patients who received surgery or not; however, patients treated with chemotherapy had superior progression-free survival (PFS) than those treated with upfront surgery (P = 0.032). Among the 12 patients who received radical surgery, 7 were given adjuvant chemotherapy and 1 patient had consolidation radiotherapy. No significant differences in PFS and OS exist between those who received adjuvant treatment or not (P > 0.05). For patients who received chemotherapy, PFS and OS were significantly better for those treated with cyclophosphamide-based therapy than fludarabine-based therapy. At a median follow-up time of 61.1 months, 5- and 10-year PFS rate was 70.0 and 43.0 %, respectively, and 5- and 10-year OS rate was both 81.0 %. In conclusion, we confirmed the indolent behavior and favorable outcome of this disease. In order to preserve lung function and reduce the risks associated with surgery, radiotherapy or rituximab in combination with alkylating drug-based chemotherapy should be considered as first-line option for pulmonary MALT lymphoma. PMID- 25801245 TI - Clinical significance of serum expression of GRObeta in hepatocellular carcinoma. AB - This study aimed to determine whether serum levels of growth-related gene product beta (GRObeta) were associated with clinical parameters in hepatocellular carcinoma (HCC). Using an enzyme-linked immunosorbent assay (ELISA), the serum GRObeta levels of 80 HCC patients, 65 patients with benign diseases of the liver, and 60 healthy volunteers were examined. The association between serum levels of GRObeta and clinical parameters of HCC was analyzed statistically. The serum GRObeta levels were much lower in benign diseases and healthy volunteers than HCC, and associated with tumor node metastasis (TNM) stages, tumor size, vascular thrombosis, capsule, and Edmondson grading of HCC (p < 0.05), but not with gender, age, liver cirrhosis, or the level of AFP (p > 0.05). We have demonstrated that GRObeta, as an oncogene product, contributed to tumorigenesis and metastasis of HCC. PMID- 25801244 TI - Inhibition of mdr1 by G-quadruplex oligonucleotides and reversal of paclitaxel resistance in human ovarian cancer cells. AB - The expression of ATP-dependent efflux pump P-glycoprotein (P-gp) in cancer cells generally results in multidrug resistance (MDR) to chemotherapeutic drugs, which is the main cause of chemotherapy failure in cancer treatment. The intracellular drug levels could be increased by some MDR reversal agents that inhibited the drug efflux activity of P-gp. The synthesized DNA nucleic acids of G-quadruplex represent a novel and unique class of anti-cancer agents. While there was no report on the roles of DNA G-quadruplex oligonucleotides (GQ-ODNs) in the MDR reversal, the present study was performed to investigate the ability of synthesized GQ-ODNs to reverse P-gp-mediated MDR and its mechanism in paclitaxel (PTX)-resistant SKOV3 (SKOV3/PTX) cells and their sensitive cell lines SKOV3. The ability of GQ-ODNs to reverse drug resistance was evaluated by MTS assay. The results showed that GQ-ODNs can reverse PTX resistance effectively. The potential of GQ-ODNs as reversal agents was evaluated with the nude mice tumor xenograft model and showed that the co-administration of the GQ-ODNs and PTX had better effects and was also more evident than treatment with only PTX. The P-gp expression was assessed by the Western blot; it showed that SKOV3/PTX cells showed highly expressed P-gp protein, while their sensitive cells scarcely showed P-gp. The presence of GQ-ODNs efficiently decreased the P-gp expression, showing that GQ-ODNs could reverse P-gp-mediated MDR by decreasing the expression of P gp. This study indicated that GQ-ODNs could effectively reverse P-gp-mediated PTX resistance by inhibiting the expression of P-gp and by the co-administration of GQ-ODNs and PTX that could increase the apoptosis of SKOV3/PTX cells. Thus, the synthesized GQ-ODNs may be a potential inhibitor to overcome drug resistance. PMID- 25801246 TI - Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population. AB - Breast cancer (BC) is the leading cause of cancer-related death among women in 2014. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and MTR reductase (MTRR) are enzymes that play an important role in folate metabolism. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G, and MTRR A66G, alter plasmatic folate and homocysteine concentrations, causing problems during the repairment, synthesis, and methylation of the genetic material. Therefore, it is essential to know how BC risk is associated with histopathological and immunohistochemical characteristics, genotype polymorphisms, and gene expression in a high altitude Ecuadorian mestizo population. DNA was extracted from 195 healthy and 114 affected women. Genotypes were determined by restriction enzymes and genomic sequencing. mRNA was extracted from 26 glandular breast tissue samples, both from cancerous tissue and healthy tissue adjacent to the tumor. Relative gene expression was determined with the comparative Livak method (2(-DeltaDeltaCT)). We found significant association between the rs1801133 (A222V) genotypes and an increased risk of BC development: C/T (odds ratio [OR] = 1.8; 95 % confidence interval [CI] = 1.1-3.2; P = 0.039), T/T (OR = 2.9; 95 % CI = 1.2-7.2; P = 0.025), and C/T + T/T (OR = 1.9; 95 % CI = 1.1-3.3; P = 0.019). Regarding relative gene expression, we found significant mRNA subexpression between the combined genotypes C/T + T/T (rs1801133) and triple negative breast cancer (TNBC) (P = 0.034). In brief, the MTHFR gene and its protein could act as potential predictive biomarkers of BC, especially TNBC among the high altitude Ecuadorian mestizo population. PMID- 25801247 TI - Tumor marker analyses in patients with brain metastases: patterns of practice and implications for survival prediction research. AB - This study aims to explore patterns of practice of tumor marker analyses and potential prognostic impact of abnormal markers in patients with brain metastases from solid tumors. Previously, lactate dehydrogenase (LDH) and albumin were identified as relevant biomarkers. We performed a retrospective analysis of 120 patients with known LDH and albumin treated with whole-brain radiotherapy (WBRT) in two different situations: (1) brain metastases detected at initial cancer diagnosis (n = 46) and (2) brain metastases at later time points (n = 74, median interval 13 months). Twenty-six patients (57 %) from group 1 had at least one tumor marker analyzed, and 11 patients (24 %) had abnormal results. Twenty-two patients (30 %) from group 2 had at least one tumor marker analyzed, and 16 patients (22 %) had abnormal results. When assuming that LDH and albumin would be standard tests before WBRT, additional potential biomarkers were found in 36 % of patients with normal LDH and albumin. Marker positivity rates were for example 80 % for carcinoembryonic antigen (CEA) in colorectal cancer and 79 % for CA 15-3 in breast cancer. Abnormal markers were associated with presence of liver metastases. CA 15-3 values above median predicted shorter survival in patients with breast cancer (median 1.9 vs. 13.8 months, p = 0.1). Comparable trends were not observed for various markers in other tumor types. In conclusion, only a minority of patients had undergone tumor marker analyses. Final group sizes were too small to perform multivariate analyses or draw definitive conclusions. We hypothesize that CA 15-3 could be a promising biomarker that should be studied further. PMID- 25801248 TI - Higher risk of developing a subsequent migraine in adults with nonapnea sleep disorders: A nationwide population-based cohort study. AB - OBJECTIVE: This nationwide population-based cohort study evaluated the effect of nonapnea sleep disorders (NSDs) on the subsequent development of a migraine. METHODS: We identified 46,777 patients aged 20 years and older who were diagnosed with an NSD (ICD-9-CM: 307.4 or 780.5) and without coding for apnea-sleep disorders (ICD-9-CM: 780.51, 780.53, or 780.57) between 2000 and 2002 as the sleep disorder (SD) cohort. A comparison cohort of 93,552 people was enrolled. We calculated the adjusted hazard ratio (aHR) for developing a migraine (ICD-9-CM: 346) after adjusting for age, sex, comorbidity, and drug use. A Kaplan-Meier analysis was used to measure the cumulative incidence of a migraine between 2 curves until the end of 2011. RESULTS: The cumulative incidence of a migraine was significantly higher in the SD cohort. The aHR for developing a migraine in the SD cohort was 3.52 (95% CI=3.28-3.79). The risk of developing a migraine with an NSD was higher in men (aHR=4.31) than in women (aHR=3.35). The age-stratified effect of an NSD on developing a migraine was highest among patients aged 55 years and younger. Higher risks of developing a migraine were observed among the participants without any comorbidity and without any drug treatment for their insomnia. CONCLUSION: The findings of this population-based cohort study indicate a higher risk of developing a subsequent migraine in patients with an NSD, which could be considered an independent, predisposing factor for developing subsequent a migraine in adulthood. PMID- 25801249 TI - Antimicrobial susceptibility of Leptospira isolates from dogs and rats to 12 antimicrobial agents. AB - This study determined the antimicrobial susceptibilities of 67 isolates of Leptospira from dogs (suspect canine cases: n=7 and stray dogs: n=6) and rodents (n=54) in Trinidad to 12 antimicrobial agents using broth microdilution and macrodilution techniques. Commonly used antimicrobial agents such as the penicillin G and ceftriaxone had relatively low minimal inhibitory concentrations (MICs) while doxycycline displayed a relatively higher value but was still considered to be effective. While imipenem was the most effective with low MIC values in vitro, sulphamethoxazole-trimethoprim had the highest i.e. least effective. Based on these results, the drugs commonly used in the treatment of leptospirosis (penicillin G, penicillin-streptomycin, doxycycline and ceftriaxone) in both humans and animals in Trinidad appear to have similar MICs and MBCs in vitro when compared with published reports. The serovar of Leptospira spp. and in most cases the origin of the isolates did not significantly (P>0.05) influence their susceptibilities to the antimicrobial agents tested. PMID- 25801250 TI - Prevalence of Ascaridia galli in white leghorn layers and Fayoumi-Rhode Island red crossbred flock at government poultry farm Dina, Punjab, Pakistan. AB - Poultry farming not only provides high nutritious food but also creates employment opportunity for rural masses. Documented evidences elaborates that helminth parasitism is most deciduous problem of chickens especially in developing world. Ascaridia (A.) galli, a nematode of small intestine, has been considered as the most common and important parasite of chicken. The present study was carried out to investigate prevalence and severity of A. galli in White Leghorn layers (housing type: battery cage and deep litter, 50 each) and Fayoumi Rhode Island Red crossbred (male and female: 50 each) flock rearing at Government Poultry Farm, Dina, Punjab, Pakistan. Two hundred faecal samples were examined by using standard parasitological and McMaster egg counting technique. The overall prevalence was 24.5% at farm, 13% in White leghorn layer (battery cage=2%, deep litter=24%) and 36% in Fayoumi-Rhode Island Red (male=34%, female=38%). It was also observed that White leghorn layer rearing in deep litter had more severe infection (EPG=1920) of A. galli compare with battery cages birds (EPG=500). Parasite prevalence was significantly related with sex (P<0.05) in Fayoumi-Rhode Island Red and male birds had less number of average parasites (0.34+/-0.47) as compared to females (0.38+/-0.490). Additionally, female birds were under serious threat of infection (EPG=2270) compared with its counterpart (EPG=1250). Given the high infection rates, particular attention should be paid to management and provision of feed supplement to White leghorn layer housing in deep litter and female bird of Fayoumi-Rhode Island Red crossbred. PMID- 25801251 TI - Larvicidal activity of few select indigenous plants of North East India against disease vector mosquitoes (Diptera: Culicidae). AB - Mosquitoes are the vectors of several life threatening diseases like dengue, malaria, Japanese encephalitis and lymphatic filariasis, which are widely present in the north-eastern states of India. Investigations on five local plants of north-east India, selected on the basis of their use by indigenous communities as fish poison, were carried out to study their mosquito larvicidal potential against Anopheles stephensi (malaria vector), Stegomyia aegypti (dengue vector) and Culex quinquefasciatus (lymphatic filariasis vector) mosquitoes. Crude Petroleum ether extracts of the roots of three plants viz. Derris elliptica, Linostoma decandrum and Croton tiglium were found to have remarkable larvicidal activity; D. elliptica extract was the most effective and with LC50 value of 0.307 MUg/ml its activity was superior to propoxur, the standard synthetic larvicide. Half-life of larvicidal activity of D. elliptica and L. decandrum extracts ranged from 2-4 days. PMID- 25801252 TI - Inhibition of secretary PLA2--VRV-PL-VIIIa of Russell's viper venom by standard aqueous stem bark extract of Mangifera indica L. AB - The aqueous extract of Mangifera indica is known to possess anti-snake venom activities. However, its inhibitory potency and mechanism of action on multi toxic phospholipases A2s, which are the most toxic and lethal component of snake venom is still unknown. Therefore, this study was carried out to evaluate the modulatory effect of standard aqueous bark extract of M. indica on VRV-PL-VIIIa of Indian Russells viper venom. Mangifera indica extract dose dependently inhibited the GIIB sPLA2 (VRV-PL-VIIIa) activity with an IC50 value of 6.8+/-0.3 MUg/ml. M. indica extract effectively inhibited the indirect hemolytic activity up to 96% at ~40 MUg/ml concentration. Further, M. indica extract at different concentrations (0-50 MUg/ml) inhibited the edema formed in a dose dependent manner. It was found that there was no relieve of inhibitory effect of the extract when examined as a function of increased substrate and calcium concentration. The inhibition was irreversible as evident from binding studies. The in vitro inhibition is well correlated with in situ and in vivo edema inducing activities. As the inhibition is independent of substrate, calcium concentration and was irreversible, it can be concluded that M. indica extracts mode of inhibition could be due to direct interaction of components present in the extract with PLA2 enzyme. In conclusion, the aqueous extract of M. indica effectively inhibits svPLA2 (Snake venom phospholipase A2) enzymatic and its associated toxic activities, which substantiate its anti-snake venom properties. Further in-depth studies are interesting to known on the role and mechanism of the principal inhibitory constituents present in the extract, so as to develop them into potent anti-snake venom and as an anti-inflammatory agent. PMID- 25801253 TI - Regulatory role of GSK3beta in the activation of NF-kappaB and modulation of cytokine levels in Burkholderia pseudomallei-infected PBMC isolated from streptozotocin-induced diabetic animals. AB - Increased susceptibility of diabetics to melioidosis, a disease caused by the Burkholderia pseudomallei bacterium is believed to be attributed to dysfunction of the innate immune system. However, the underlying mechanism of the innate susceptibility is not well-understood. Glycogen synthase kinase-3beta (GSK3beta) plays an important role in the innate inflammatory response caused by bacterial pathogens. The present study was conducted to investigate the effects of GSK3beta inhibition by LiCl on levels of pro- and anti-inflammatory cytokines; and the activity of transcription factor NF-kappaB in B. pseudomallei-infected peripheral blood mononuclear cells (PBMC) derived from diabetic-induced and normal Sprague Dawley rats. In addition, the effects of LiCl on intracellular bacterial counts were also investigated. Infection of PBMC from diabetic and normal rats with B. pseudomallei resulted in elevated levels of cytokines (TNF-alpha, IL-12 and IL 10) and phosphorylation of NF-kappaB in both cell types. Intracellular bacterial counts decreased with time in both cell types during infection. However bacterial clearance was less prominent in diabetic PBMC. Burkholderia pseudomallei infection also caused inactivation (Ser9 phosphorylation) of GSK3beta in normal PBMC, an effect absent in infected diabetic PBMC. Inhibition of GSK3beta by LiCl lowered the levels of pro-inflammatory cytokines (TNF-alpha and IL-12) in both normal and diabetic PBMC. Similarly, phosphorylated NF- kappaB (pNF-kappaB) levels in both cell types were decreased with LiCl treatment. Also, LiCl was able to significantly decrease the intracellular bacterial count in normal as well as diabetic PBMC. Interestingly, the levels of anti-inflammatory cytokine IL-10 in both normal and diabetic PBMC were further elevated with GSK3beta inhibition. More importantly, GSK3beta in infected diabetic PBMC was inactivated as in their non-diabetic counterparts upon LiCl treatment. Taken together, our results suggest that inhibition of dysregulated GSK3beta in diabetic PBMC resulted in the inactivation of NF-kappaB and modulation of inflammatory cytokine levels. This is evidence that dysregulation of GSK3beta is a contributing factor in the molecular basis of innate dysfunction and susceptibility of diabetic host to melioidosis infection. PMID- 25801254 TI - Surveillance of Aedes albopictus Skuse breeding preference in selected dengue outbreak localities, peninsular Malaysia. AB - Entomological surveillance was conducted in order to determine the abundance and to evaluate any changes of biological vectors or ecology, especially in the dengue outbreak areas. The abundance and breeding preference of Aedes albopictus and Aedes aegypti were conducted in selected dengue outbreak localities in three states of peninsular Malaysia namely Selangor, Federal Territory of Kuala Lumpur, and Penang Island using ovitraps and larval survey method. It was determined that Ae. albopictus was predominant in most of the localities and found to breed more outdoor than indoor. A wide range of breeding foci were recorded in this study. It was also determined that ovitrap method was more effective to detect the presence of Aedes mosquitoes when the larval survey was at low rate of infestation. The abundance of Ae. albopictus in dengue outbreak localities emphasis that the vector control programme should also target this species together with the primary dengue vector, Ae. aegypti. PMID- 25801255 TI - Feeding stage, species, body part and sex-specific activity of glutathione S transferase in mosquito. AB - In the present study, the feeding stage, body parts, development and sex specific activity of Glutathione S-transferases (GSTs) were observed in different mosquito species (Aedes aegypti, Culex quinquefasciatus, Anopheles stephensi, An. culicifacies, An. annularis, An. subpictus, An. vagus). GST activity was assayed spectrophotometrically at 23 degrees C, using a UV Max microplate Reader, to measure the rate of conjugation of GSH to CDNB. A significant species-specific difference in the activity of GST was noticed, highest being in unfed Ae. aegypti (41.2 nmol/min/mg) followed by unfed Cx. quinquefasciatus (7.9 nmol/min/mg) and the least in unfed An. stephensi (5.8 nmol/min/mg). In all the species the GST activity was found to be significantly higher in fully fed and gravid stages compared with the unfed, while the enzyme activity was reduced after egg laying either to the level of unfed animals or well below its level in all the experimental species. The GST activity was found to be higher in the abdominal region of all the experimental species in comparison with the other body parts (head and thorax). The GST activity of An. stephensi increased gradually through the larval stages and reached the maximum level in the pupae and remained at that level in the newly emerged adults. However, its activity declined markedly (10 fold) with ageing from 5 to 40 days. A significant sex-related difference in the specific activity of GST was found in An. stephensi where approximately 3.5 fold lower activity was observed in males compared with its females, whereas no significant variation was noticed in Ae. aegypti and Cx. quinquefasciatus. The study corroborates the fact that GSTs are differentially regulated by multiple mechanisms in response to xenobiotics modulation in situation-specific manner such as species, sex, feeding and developmental stage. The knowledge of situation specific modulation of GST will provide a better understanding of GST based insecticide resistance mechanism which is essential for the design of sensitive monitoring methods and for an effective insecticide resistance management. The findings are significant in terms of the methods used to control mosquito vector population. PMID- 25801256 TI - Evaluation of Sumithion L-40 against Aedes aegypti (L.) and Aedes albopictus Skuse. AB - Space spraying of chemical insecticides is still an important mean of controlling Aedes mosquitoes and dengue transmission. For this purpose, the bioefficacy of space-sprayed chemical insecticide should be evaluated from time to time. A simulation field trial was conducted outdoor in an open field and indoor in unoccupied flat units in Kuala Lumpur, to evaluate the adulticidal and larvicidal effects of Sumithion L-40, a ULV formulation of fenitrothion. A thermal fogger with a discharge rate of 240 ml/min was used to disperse Sumithion L-40 at 3 different dosages (350 ml/ha, 500 ml/ha, 750 ml/ha) against lab-bred larvae and adult female Aedes aegypti and Aedes albopictus. An average of more than 80% adult mortality was achieved for outdoor space spray, and 100% adult mortality for indoor space spray, in all tested dosages. Outdoor larvicidal effect was noted up to 14 days and 7 days at a dosage of 500 and 750 ml/ha for Ae. aegypti and Ae. albopictus, respectively. Indoor larvicidal effect was up to 21 days (500 ml/ha) and 14 days (750 ml/ha), respectively, after spraying with larval mortality > 50% against Ae. aegypti. This study concluded that the effective dosage of Sumithion L-40 thermally applied against adult Ae. aegypti and Ae. albopictus indoor and outdoor is 500 and 750 ml/ha. Based on these dosages, effective indoor spray volume is 0.4 - 0.6 ml/m3. Additional indoor and outdoor larvicidal effect will be observed at these application dosages, in addition to adult mortality. PMID- 25801257 TI - An investigation on the diversity of mosquitocidal bacteria and its relationship with incidence of vector borne diseases. AB - Control of mosquitoes is the most important aspect of public health, as mosquitoes transmit many human diseases, including the fatal infection, Japanese encephalitis. This paper addresses the isolation of new mosquitocidal bacteria from soil samples in the Union Territory of Pondicherry, India, where, no clinical cases of vector borne infections have been reported. Bacterial isolates from soil samples were screened for potential mosquitocidal strains and bioassays against mosquito vectors (Culex quinquefasciatus, Anopheles stephensi and Aedes aegypti) were carried out. Genomic DNA of potential mosquitocidal isolates was amplified and species identification was carried out using BLASTn program (NCBI). Phylogenetic analysis of 16S rRNA sequences of mosquitocidal bacteria revealed seven potential isolates. SDS-PAGE results have shown that there was considerable difference in the protein profiles. Numerical analysis revealed 4 distinct groups at similarity level 25%. The relationship between VBDs and prevalence of soil mosquitocidal bacteria in the study sites has elicited considerable interest in the diversity of mosquitocidal bacteria and their application for mosquito borne diseases control. PMID- 25801258 TI - Species clarification of Ogasawara cockroaches which inhabit Japan. AB - The so-called "Ogasawara cockroaches" were examined by morphological observations and by breeding experiments to elucidate their actual taxonomical status. Fourteen groups (isolate) of "Ogasawara cockroaches" collected from Iwoto-A, Iwoto-B, Hahajima, Chichijima, Nishijima, Nakodojima, Tokunoshima-A, Tokunoshima B, Okinawato- A, Okinawa-B, Amamiooshima, Miyakojima, Ishigakijima and Hawaii, were bred and passaged in our laboratory. Cockroaches collected from the field were first reared individually and the sexes of their offspring examined. Cockroaches collected from Iwoto, Tokushima and Okinawa, were found to consist of two groups; those whose offspring were all female and the other whose offspring consist of both male and female. Cross-breeding experiments showed that individuals from the group that did not produce any male but only female offspring were parthenogenetic. On the contrary, the group that have bisexual individuals produced both male and female offspring in a ratio of 1:1. Our results show that the so-called "Ogasawara cockroaches" consist of 2 species, namely, Pycnoscelus surinamensis and Pycnoscelus indicus. There are areas in which both species co-habitated together and there are also areas in which either only one of the two species can be found. The group that reproduces only female offspring and only through parthenogenesis was identified as P. surinamensis. The group that reproduces heterosexually and produce male and female offspring was identified as P. indicus. Thus, the so-called "Ogasawara cockroaches" found in Japan actually consist of 2 species, namely, P. surinamensis and P. indicus, which can be differentiated using the solitary breeding method to demonstrate parthenogenesis in the former and the need for sexual reproduction in the latter. PMID- 25801259 TI - Presence of qacEDelta1 and cepA genes and susceptibility to a hospital biocide in clinical isolates of Klebsiella pneumoniae in Iran. AB - The aim of this study was to evaluate the susceptibility of Klebsiella pneumoniae clinical isolates to antibiotics and to a quaternary ammonium compound (QAC) disinfectant as the concentrations used clinically and to determine the presence of the qacEDelta1 and cepA genes for the first time in Iran. In total, 85 K. pneumoniae isolates were randomly collected from hospitalized patients at the general hospitals in Lorestan, Iran. Antibiotic and antiseptic susceptibility testing was performed according to Clinical and Laboratory Standards Institute recommendations. K. pneumonia isolates were screened by PCR amplification of qacEDelta1 and cepA genes using specific primers and sequence analysis of the amplified regions were also performed. From 85 isolates of K. pneumoniae, 34 (40%) isolates were multidrug resistance (MDR). The evaluation of the susceptibility to the QAC disinfectant revealed that 51 (60%) isolates had reduced susceptibility to QAC disinfectant. The qacEDelta1 gene was detected in 26 isolates (30.6%). While cepA gene was found in 19 isolates (22.3%) of K. pneumonia. Seventy-three percent (19/26) qacEDelta1-positive isolates were detected in the biocide-resistant isolates. Whereas, 63.1% (12/19) cepA-positive isolates were found in the biocide-resistant isolates. Out of qacEDelta1 and cepA positive isolates, 65.4% (17/26) and 42.1% (8/19) were among MDR isolates, respectively. No significant association of biocide resistance with the presence of qacEDelta1 and cepA genes was observed (P>0.05). The results of present study shows that there was a close link between qacEDelta1 gene and antibiotic resistance, but no significant association of biocide resistance with the presence of qacEDelta1 and cepA genes was observed in K. pneumoniae in Iran. PMID- 25801260 TI - Seroprevalence of Toxoplasma gondii infection in pigs in Jilin Province, Northeastern China. AB - In the present study, a total of 1,235 porcine serum samples were collected from 9 counties in Jilin Province (40 degrees 52'~46 degrees 18'N,121 degrees 38'~131 degrees 19'E), northeastern China from August to October 2013, and the seroprevalence of Toxoplasma gondii infection was tested by indirect haemagglutination assay (IHA). The results showed that antibodies to T. gondii were found in 19.1% (95% confidence interval [CI], 16.9% to 21.3%), with higher seroprevalence in the breeding boars (28.6%, 95% CI, 20.0% to 37.2%), and breeding sows (32.0%, 95% CI, 25.2% to 38.9%). No significant difference was found among the slaughter pigs, fattening pigs and the piglets. These results indicated that infection with T. gondii in pigs is widespread in Jilin province, and is of public health concern. PMID- 25801261 TI - Evaluation of dot immunogold filtration assay (DIGFA) for rapid serodiagnosis of eosinophilic meningitis due to Angio-strongylus cantonensis (Nematoda: Metastrongyloidea). AB - Angiostrongylus cantonensis is the most frequent cause of eosinophilic meningitis in humans in Thailand and worldwide. Because of difficulty of recovering the Angiostrongylus larvae from infected patients, detection of parasite-specific antibodies is used to support clinical diagnosis. This study tested serum samples from eosinophilic meningitis patients and individuals at risk of infection with A. cantonensis to evaluate a recently developed simple and rapid dot-immunogold filtration assay (DIGFA) for detection of specific antibodies against A. cantonensis. Purified 31-kDa glycoprotein of A. cantonensis and protein A colloidal gold conjugate were employed to detect the 31-kDa anti-A. cantonensis antibody in patients sera from the parasite endemic areas of northeast Thailand. The results were compared with those obtained by dot-blot enzyme-linked immunosorbent assay (ELISA) with 31-kDa A. cantonensis antigen. The overall positivity rate of DIGFA and dot-blot ELISA for A. cantonensis infection in 98 clinically diagnosed cases from three highly endemic districts in Khon Kaen province were 39.79% and 37.75%, respectively. Among 86 sera of subjects at risk of infection with A. cantonensis, 24.41% were positive by DIGFA and 23.25% by dot blot ELISA. There were good correlation between the visual grading of DIGFA and dot-blot ELISA in both groups of defined sera. DIGFA is as sensitive and specific as dot-blot ELISA for confirming eosinophilic meningitis due to A. cantonensis infection, with advantages of simplicity, rapidity and without the use of specific and expensive equipment, and can be used in field settings. PMID- 25801262 TI - Biology and pathology of caecal nematode Subulura brumpti in Japanese quails (Coturnix coturnix japonica). AB - The occurrence of caecal nematode, Subulura brumpti has become more common in quails being maintained in commercial farms in Tamil Nadu, India. Two trials were carried out to study the biology and pathology of S. brumpti in quails. In the first trial, eight grower quails were divided into two groups (T1 and T2) comprising of four birds each. The birds belonged to the group T1 was infected with 20 cysts collected from beetle and birds of T2 group were kept as control. The beetle was identified as Tenebrionid species. Prevalence of S. brumpti in beetle was 89 per cent and intensity ranged from 1-27 cysts. The eggs of S. brumpti were observed in droppings on 30 - 32 DPI. In the second trial, 16 birds were divided to four groups viz., T1, T2, T3 and T4. The birds of T1, T2, and T3 were infected by gelatin capsule method. All the birds were sacrificed on 30 DPI. The caeca from infected group did not show any gross and histopathological changes. PMID- 25801263 TI - In vitro antiplasmodial activity, macronutrients and trace metals in the medicinal plants: Phyllanthus spp. and Alpinia conchigera Griff. AB - An antiplasmodial screening of Phyllanthus debilis and Phyllanthus urinaria was carried out. The medicinal plants were extracted and evaluated for in vitro antiplasmodial activity against D10 (chloroquine-sensitive, CQS) and Gombak A (chloroquine-resistant, CQR) strains of Plasmodium falciparum. The methanolic crudes from the soxhlet extraction were active against both strains however, P. urinaria (IC50 8.9 MUg/ml with CQR strain) exhibited better anti-malarial activity compared to P. debilis (IC50 12.2 MUg/ml with CQR strain). Furthermore, the methanolic crude of P. urinaria obtained by the cold extraction has good anti malarial activity towards CQS (IC50 4.1 MUg/ml). The concentration of macronutrients (calcium and magnesium) and trace metals (copper, manganese, iron and zinc) from three Phyllanthus species i.e. P. debilis Klein ex Wild., Phyllanthus niruri L., P. urinaria L. and Alpinia conchigera Griff. were determined using microwave digestion method and analyzed by Flame Atomic Absorption Spectroscopy. Standard Reference Material 1547 (peach leaves) was used to validate the method throughout this study. The recovery values were in the range of 80% to 120% which were in very good agreement with the certified values. The three Phyllanthus species and leaves of A. conchigera showed the highest concentration of calcium compared to other metals and macronutrients studied. The significant presence of all the important macronutrients and trace metals which are essential for human health and well-being substantiate their use medicinally in traditional practices. PMID- 25801264 TI - Low efficacy of delthamethrin-treated net against Singapore Aedes aegypti is associated with kdr-type resistance. AB - There has been a worldwide surge in the number and severity of dengue in the past decades. In Singapore, relentless vector control efforts have been put in to control the disease since the 1960's. Space spraying, fogging, chemical treatment and source reduction are some commonly used methodologies for controlling its vectors, particularly Aedes aegypti. Here, as we explored the use of a commercially available delthamethrin-treated net as an alternative strategy and the efficacy of the treated net was found to be limited. Through bioassays and molecular studies, the failure of the treated net to render high mortality rate was found to be associated with the knockdown resistance (kdr) mutation. This is the first report of kdr- mutations in Singapore's Ae. aegypti. At least one point mutation, either homozygous or heterozygous, at amino acid residue V1016G of DIIS6 or F1269C of DIIIS6 was detected in 93% of field strains of Ae. aegypti. Various permutations of wild type and mutant amino acids of the four alleles were found to result in varying degree of survival rate among local field Ae. aegypti when exposed to the deltamethrin treated net. Together with the association of higher survival rate with the presence of both V1016G and F1269C, the data suggest the role of these mutations in the resistance to the deltamethrin. The high prevalence of these mutations were confirmed in a country wide survey where 70% and 72% of the 201 Ae. aegypti analysed possessed the mutations at residues 1016 and 1269 respectively. The highest mutated frequency combination was found to be heterozygous alleles (VG/FC) at both residues 1016 and 1269 (37.8%), followed by homozygous mutation at allele 1269 (24.4%) and homozygous mutation at allele 1016 (22.9%). The kdr- type of resistance among the vector is likely to undermine the effectiveness of pyrethroids treated materials against these mosquitoes. PMID- 25801265 TI - Morphological descriptions on the larvae of Hypopygiopsis fumipennis (Walker, 1856) (Diptera: Calliphoridae). AB - The study on biodiversity of forensically important Diptera in the tropical rain forest in Malaysia is scarce. Thus, a preliminary survey was conducted at a jungle fringe near Kampung Bahagia Bukit Lagong, Sungai Buloh, Selangor. A rat carcass was offered to attract carrion flies and we collected an adult female calliphorid, Hypopygiopsis fumipennis (Walker, 1856) during the fresh stage of carcass decomposition. The female fly was allowed to oviposit on chicken liver in a container and the resulting larvae were reared to the adult stage. Along the developmental process, several individuals from each instar were collected and preserved in 70% ethanol and then processed on the slides. We recorded the duration of development for each instar and described its larval features for the first time. The third instar larvae of H. fumipennis showed accessory oral sclerite present, anterior spiracle with 13-15 papillae, intersegmental spines mostly unicuspid with pointed end, and posterior spiracles heavily sclerotized with inter-slit projections. Some larval differences between H. fumipennis and Hypopygiopsis violacea were noted. PMID- 25801266 TI - In vitro repellent effect of tea tree (Melaleuca alternifolia) and andiroba (Carapa guianensis) oils on Haemotobia irritans and Chrysomya megacephala flies. AB - This study aimed to evaluate the repellent effect of tea tree (Melaleuca alternifolia) and andiroba (Carapa guianensis) essential oils on two species of flies (Haemotobia irritans and Chrysomya megacephala). For the in vitro studies, free-living adult flies were captured and reared in the laboratory. To verify the repellency effect, an apparatus was constructed where H. irritans and C. megacephala were exposed to andiroba and tea tree oils (5.0%), as well as to a known repellent (citronella, 5.0%) to validate the test. The study demonstrated that all three oils used showed in vitro repellent effect against both species of flies. It is possible to conclude that the essential oils (tea tree and andiroba) have repellent effect on these species of flies used in this study. PMID- 25801267 TI - Analysis of structure, function and epitopes of Spirometra erinaceieuropaei casein kinase I. AB - Spirometra erinaceieuropaei casein kinase I (SeCKI) was analyzed using bioinformatical methods to predict its structure and function based on the deduced amino acid sequence from full length cDNA sequence of SeCKI gene with online sites and software programs. The longest open reading frame contains 448 amino acids, 50 kDa and theoretical pI of 4.73, with a complete tubulin domain, a SMART tubulin_C domain and a low complexity region. SeCKI has no signal sequence and no transmembrane domain, but is predicted to be located extracellularly. The secondary structure of SeCKI contains 12 alpha-helixes, 11 beta-strands and 22 coils. SeCKI had 19 potential antigenic epitopes and 25 HLA-I restricted epitopes. Based on phylogenetic analysis of SeCKI sequence, S. erinaceieuropaei has the closest evolutionary status with Hymenolepis microstoma. Information from this study could provide important insights into the identification of diagnostic antigens and molecular targets of anti-sparganum drugs. PMID- 25801268 TI - Cyclosporine A decreases the fluconazole minimum inhibitory concentration of Candida albicans clinical isolates but not biofilm formation and cell growth. AB - Among the genus Candida, Candida albicans is the most abundant species in humans. One of the virulent factors of C. albicans is its ability to develop biofilm. Biofilm forming microbes are characterized by decreasing of its susceptibility to antibiotics and antifungal. The fungicidal effect of fluconazole may be enhanced by cyclosporine A in laboratory engineered C. albicans strains. The aim of this work is to analyze the synergistic effect of cyclosporine A with fluconazole in C. albicans clinical isolates and the effect of cycolsporine A alone in the biofilm formation. Six fluconazole resistant and six sensitive C. albicans clinical isolates were analyzed for its minimum inhibitory concentration (MICs), biofilm formation, and cell growths. A semi-quantitative XTT [2,3-bis(2-methoxy-4 nitro-5- sulfo-phenyl)-2H-tetrazolium-5-carboxanilide] reduction assay was conducted to measure the biofilm formation. Cyclosporine A has synergistic effect with fluconazole that was shown by decreasing MICs of both fluconazole resistant and sensitive C. albicans clinical isolates. However, cyclosporine A alone did not influence the biofilm formation and cell growth of both fluconazole resistant and sensitive C. albicans clinical isolates. These results indicated that cyclosporine A might be a promising candidate of adjuvant therapy for fluconazole against both fluconazole resistant and sensitive C. albicans clinical isolates. PMID- 25801269 TI - Distribution of mosquito larvae in various breeding sites in National Zoo Malaysia. AB - Mosquitoes are principal vectors of major vector-borne diseases. They are widely found throughout urban and rural areas in Malaysia. They are responsible for various vector-borne diseases such as dengue, malaria, filariasis and encephalitis. A total of 158 mosquito larvae specimens were collected from the National Zoo, Malaysia, from 11 types of breeding habitats during the study period from end of May 2007 to July 2007. Aedes albopictus was the predominant species (35.4%), followed by Tripteroides aranoides (26.6%), Lutzia halifaxii (11.4%), Aedes alboscutellatus (10.1%), Aedes caecus (8.9%), Armigeres spp. (4.4%), Malaya genurostris (2.5%) and Culex vishnui (0.6%). It is important to have a mosquito free environment in a public place like the zoo. Routine larval surveillance should be implemented for an effective mosquito control program in order to reduce mosquito population. PMID- 25801270 TI - Dengue serotype surveillance among patients admitted for dengue in two major hospitals in Selangor, Malaysia, 2010-2011. AB - Dengue serotype surveillance is important as any changes in serotype distribution may result in an outbreak or increase in severe dengue cases. This study aimed to determine circulating dengue serotypes in two hospitals in Selangor. Serum samples were collected from patients admitted for dengue at these two major public hospitals i.e. Hospital Sungai Buloh (HSB) and Hospital Tunku Ampuan Rahimah (HTAR) between November 2010 and August 2011 and subjected to real-time RT-PCR using SYBR(r) Green. All four dengue serotypes were detected in samples from both hospitals. The predominating serotype was dengue 1 in samples from both hospitals (HSB, DENV-1; 25.53 % and HTAR, DENV-1; 32.1 %). PMID- 25801271 TI - Identification of Arabidopsis thaliana NRT1/PTR FAMILY (NPF) proteins capable of transporting plant hormones. AB - NRT1/PTR FAMILY (NPF) proteins were originally identified as nitrate or di/tri peptide transporters. Recent studies revealed that this transporter family also transports the plant hormones auxin (indole-3-acetic acid), abscisic acid (ABA), and gibberellin (GA), as well as secondary metabolites (glucosinolates). We developed modified yeast two-hybrid systems with receptor complexes for GA and jasmonoyl-isoleucine (JA-Ile), to detect GA and JA-Ile transport activities of proteins expressed in the yeast cells. Using these GA and JA-Ile systems as well as the ABA system that we had introduced previously, we determined the capacities of Arabidopsis NPFs to transport these hormones. Several NPFs induced the formation of receptor complexes under relatively low hormone concentrations. Hormone transport activities were confirmed for some NPFs by direct analysis of hormone uptake of yeast cells by liquid chromatography-tandem mass spectrometry. Our results suggest that at least some NPFs could function as hormone transporters. PMID- 25801272 TI - Cell cycle reentry from the late S phase: implications from stem cell formation in the moss Physcomitrella patens. AB - Differentiated cells are in a non-dividing, quiescent state, but some differentiated cells can reenter the cell cycle in response to appropriate stimuli. Quiescent cells are generally arrested at the G0/G1 phase, reenter the cell cycle, and progress to the S phase to replicate their genomic DNA. On the other hand, some types of cells are arrested at the different phase and reenter the cell cycle from there. In the moss Physcomitrella patens, the differentiated leaf cells of gametophores formed in the haploid generation contain approximately 2C DNA content, and DNA synthesis is necessary for reentry into the cell cycle, which is suggested to be arrested at late S phase. Here we review various cell division reactivation processes in which cells reenter the cell cycle from the late S phase, and discuss possible mechanisms of such unusual cell cycle reentries with special emphasis on Physcomitrella. PMID- 25801273 TI - Isolation and functional characterization of salt-stress induced RCI2-like genes from Medicago sativa and Medicago truncatula. AB - Salt stress is one of the most significant adverse abiotic factors, causing crop failure worldwide. So far, a number of salt stress-induced genes, and genes improving salt tolerance have been characterized in a range of plants. Here, we report the isolation and characterization of a salt stress-induced Medicago sativa (alfalfa) gene (MsRCI2A), which showed a high similarity to the yeast plasma membrane protein 3 gene (PMP3) and Arabidopsis RCI2A. The sequence comparisons revealed that five genes of MtRCI2(A-E) showed a high similarity to MsRCI2A in the Medicago truncatula genome. MsRCI2A and MtRCI2(A-E) encode small, highly hydrophobic proteins containing two putative transmembrane domains, predominantly localized in the plasma membrane. The transcript analysis results suggest that MsRCI2A and MtRCI2(A-D) genes are highly induced by salt stress. The expression of MsRCI2A and MtRCI2(A-C) in yeast mutants lacking the PMP3 gene can functionally complement the salt sensitivity phenotype resulting from PMP3 deletion. Overexpression of MsRCI2A in Arabidopsis plants showed improved salt tolerance suggesting the important role of MsRCI2A in salt stress tolerance in alfalfa. PMID- 25801274 TI - Pollination system and the effect of inflorescence size on fruit set in the deceptive orchid Cephalanthera falcata. AB - Larger inflorescences in reward-producing plants can benefit plants by increasing both pollinator attraction and the duration of visits by individual pollinators. However, ultimately, inflorescence size is determined by the balance between the benefits of large inflorescences and the increased cost of geitonogamy. At present, little is known about the relationship between inflorescence size and fecundity in deceptive plants. Given that pollinators are likely to leave inflorescences lacking rewards quickly, it seems unlikely that longer pollinator visits and the risk of geitonogamy would be strong selective pressures in these species, which indicates that pollinator attraction might be the most important factor influencing their inflorescence size. Here we examined the pollination ecology of the deceptive orchid Cephalanthera falcata in order to clarify the effects of inflorescence size on the fruit set of this non-rewarding species. Field observations of the floral visitors showed that C. falcata is pollinated by the andrenid bee Andrena aburana, whilst pollination experiments demonstrated that this orchid species is neither autogamous nor apogamous, but is strongly pollinator dependent. Three consecutive years of field observations revealed that fruit set was positively correlated with the number of flowers per inflorescence. These results provide strong evidence that the nectarless orchid C. falcata benefits from producing larger inflorescences that attract a greater number of innate pollinators. Large inflorescences may have a greater positive effect on fruit set in deceptive plants because a growing number of studies suggest that fruit set in reward-producing plants is usually unaffected by display size. PMID- 25801276 TI - Atomic scale investigation of non-equilibrium segregation of boron in a quenched Mo-free martensitic steel. AB - B-added low carbon steels exhibit excellent hardenability. The reason has been frequently attributed to B segregation at prior austenite grain boundaries, which prevents the austenite to ferrite transformation and favors the formation of martensite. The segregation behavior of B at prior austenite grain boundaries is strongly influenced by processing conditions such as austenitization temperatures and cooling rates and by alloying elements such as Mo, Cr, and Nb. Here an local electrode atom probe was employed to investigate the segregation behavior of B and other alloying elements (C, Mn, Si, and Cr) in a Cr-added Mo-free martensitic steel. Similar to our previous results on a Mo-added steel, we found that in both steels B is segregated at prior austenite grain boundaries with similar excess values, whereas B is neither detected in the martensitic matrix nor at martensite martensite boundaries at the given cooling rate of 30K/s. These results are in agreement with the literature reporting that Cr has the same effect on hardenability of steels as Mo in the case of high cooling rates. The absence of B at martensite-martensite boundaries suggests that B segregates to prior austenite grain boundaries via a non-equilibrium mechanism. Segregation of C at all boundaries such as prior austenite grain boundaries and martensite-martensite boundaries may occur by an equilibrium mechanism. PMID- 25801275 TI - Sequence and expression analysis of putative Arachis hypogaea (peanut) Nod factor perception proteins. AB - Peanut, like most legumes, develops a symbiotic relationship with rhizobia to overcome nitrogen limitation. Rhizobial infection of peanut roots occurs through a primitive and poorly characterized intercellular mechanism. Knowledge of the molecular determinants of this symbiotic interaction is scarce, and little is known about the molecules implicated in the recognition of the symbionts. Here, we identify the LysM extracellular domain sequences of two putative peanut Nod factor receptors, named AhNFR1 and AhNFP. Phylogenetic analyses indicated that they correspond to LjNFR1 and LjNFR5 homologs, respectively. Transcriptional analysis revealed that, unlike LjNFR5, AhNFP expression was not induced at 8 h post bradyrhizobial inoculation. Further examination of AhNFP showed that the predicted protein sequence is identical to GmNFR5 in two positions that are crucial for Nod factor perception in other legumes. Analysis of the AhNFP LysM2 tridimensional model revealed that these two amino acids are very close, delimiting a zone of the molecule essential for Nod factor recognition. These data, together with the analysis of the molecular structure of Nod factors of native peanut symbionts previously reported, suggest that peanut and soybean could share some of the determinants involved in the signalling cascade that allows symbiosis establishment. PMID- 25801277 TI - RE: Pleomorphic adenomas: Post-operative radiotherapy is unnecessary following primary incomplete excision: A retrospective review. PMID- 25801278 TI - Dual-Screened Vertical Circulation Wells for Groundwater Lowering in Unconfined Aquifers. AB - A new type of vertical circulation well (VCW) is used for groundwater dewatering at construction sites. This type of VCW consists of an abstraction screen in the upper part and an injection screen in the lower part of a borehole, whereby drawdown is achieved without net withdrawal of groundwater from the aquifer. The objective of this study is to evaluate the operation of such wells including the identification of relevant factors and parameters based on field data of a test site and comprehensive numerical simulations. The numerical model is able to delineate the drawdown of groundwater table, defined as free-surface, by coupling the arbitrary Lagrangian-Eulerian algorithm with the groundwater flow equation. Model validation is achieved by comparing the field observations with the model results. Eventually, the influences of selected well operation and aquifer parameters on drawdown and on the groundwater flow field are investigated by means of parameter sensitivity analysis. The results show that the drawdown is proportional to the flow rate, inversely proportional to the aquifer conductivity, and almost independent of the aquifer anisotropy in the direct vicinity of the well. The position of the abstraction screen has a stronger effect on drawdown than the position of the injection screen. The streamline pattern depends strongly on the separation length of the screens and on the aquifer anisotropy, but not on the flow rate and the horizontal hydraulic conductivity. PMID- 25801279 TI - Diagnostic pathways for obstructive sleep apnoea in the Australian community: observations from pharmacy-based CPAP providers. AB - PURPOSE: Models for the diagnosis of obstructive sleep apnoea (OSA) are evolving in many countries to meet public demand. In Australia, the unregulated sleep industry does not provide a framework to govern or review emerging pathways in the community. The objectives of this study were to (1) describe current diagnostic pathways for OSA in Australia as reported by continuous positive airway pressure (CPAP) providers in community pharmacies and (2) obtain stakeholder feedback on pathways and identify potential areas for practice improvement. METHODS: Semi-structured telephone interviews were conducted with pharmacy-based CPAP practitioners. Participants described diagnostic pathways used in their setting. Subsequently, an expert forum of stakeholders provided feedback on identified pathways during a focus group. RESULTS: Twenty-two telephone interviews were conducted, identifying six key diagnostic pathways. Pathways varied in terms of the diagnostic test used, the practitioner who initiated or interpreted the test and who discussed results with the patient and made treatment recommendations. A nine-member stakeholder group raised medical, ethical and organisational concerns over certain pathways. Concerns included diagnostic tests initiated or interpreted in the absence of an appropriately trained medical practitioner and potential conflicts of interest for CPAP providers offering both diagnostic and treatment services. A best practice framework was proposed to guide practice and translate study findings. Preliminary practice recommendations were subsequently developed. CONCLUSIONS: Diagnostic models have evolved in Australia that raise stakeholder concerns. It is important to address these concerns while still facilitating patient access to services. Development of a practice framework could promote medically appropriate, patient-centred care. PMID- 25801280 TI - The impact of active and former smoking on the severity of obstructive sleep apnea. AB - PURPOSE: Although obstructive sleep apnea (OSA) syndrome is a common disorder; the connection between OSA and smoking habits is still controversial. In this study, we investigated whether active smoking and pack * years of smoking have an impact on the severity of the disease regarding the patients with OSA. METHODS: This study included 964 patients referred to the Sleep Disorders Clinic between 01.01.2007 and 01.03.2013 with an overnight polysomnographic diagnosis of OSA. The correlation between smoking habits and polysomnographic parameters has been studied in detail. RESULTS: There were 684 male (79 %) and 280 female (21 %) patients, 367 (50.6 %) of whom never smoked. Of all, 20.7 % of the smokers were current smokers (n = 150) while 28.2 % were former smokers (n = 208). Active smokers had a mean age of 49.53 (SD 10.17) while former smokers and never smokers had a mean age of 51.37 (SD 10.62), 54.2 (SD 11.56), respectively, which was statistically significant (p < 0.0001). There was a significant male predominance in smoking (p < 0.0001). In addition, male patients displayed more severe OSA than female patients. (p = 0.001). Desaturation time during sleep was found to be significantly longer in the group of former smokers in comparison to never smokers (73.84 SD 97.1-52 SD 85.8) (p = 0.005). Besides, as the apnea hypopnea index increased, the mean pack * years rose significantly (p = 0.01). Severe smokers compared to mild smokers had higher AHI, lower NREM 3, higher NREM1-2 stages (p = 0. 017, p = 0.007, p < 0.001). CONCLUSION: In this study, we found that cigarette smoking was associated with early age disease; heavy smokers had more severe OSA. PMID- 25801282 TI - Perinatal Gjb2 gene transfer rescues hearing in a mouse model of hereditary deafness. AB - Hearing loss is the most widespread sensory disorder, with an incidence of congenital genetic deafness of 1 in 1600 children. For many ethnic populations, the most prevalent form of genetic deafness is caused by recessive mutations in the gene gap junction protein, beta 2, 26 kDa (GJB2), which is also known as connexin 26 (Cx26). Despite this knowledge, existing treatment strategies do not completely recover speech perception. Here we used a gene delivery system to rescue hearing in a mouse model of Gjb2 deletion. Mice lacking Cx26 are characterized by profound deafness from birth and improper development of cochlear cells. Cochlear delivery of Gjb2 using an adeno-associated virus significantly improved the auditory responses and development of the cochlear structure. Using gene replacement to restore hearing in a new mouse model of Gjb2 related deafness may lead to the development of therapies for human hereditary deafness. PMID- 25801281 TI - Periodontitis and obstructive sleep apnea's bidirectional relationship: a systematic review and meta-analysis. AB - PURPOSE: The aim of this study is to evaluate the association between periodontal disease and obstructive sleep apnea (OSA). METHODS: Electronic search using PubMed, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Central Trial Registry, Cochrane Database of Systematic Reviews, Scopus, and Embase was carried out for randomized controlled trials, longitudinal, cohort, case-control, and epidemiological studies on humans, published until October 2014. Manual searches were also performed. The participants considered were adult subjects with OSA and chronic periodontitis. The authors reviewed all articles and extracted data using a customized data abstraction sheet. Methodological quality assessment was carried out using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: Six studies met the inclusion criteria set for this review. They evaluated the association between periodontal disease and OSA and the efficacy of periodontal interventions on OSA occurrence and severity. The periodontal disease outcome measures included clinical attachment loss, periodontal pocket depth, oral hygiene indices, radiographic alveolar bone loss, and salivary cytokines. Meta-analysis of four studies revealed a statistically significant association between periodontal disease and OSA (pooled odds ratio = 1.65, 95 % confidence interval (CI) = 1.11, 2.46, P = 0.01). There is insufficient evidence on the efficacy of periodontal disease interventions. CONCLUSIONS: There is some evidence to a plausible association between periodontal disease and OSA. Evidence on the efficacy of periodontal disease interventions is insufficient. The causal effect relationship of periodontal disease and OSA is debatable. Further research with case-control studies is warranted. PMID- 25801284 TI - Accuracy of dose calculation algorithms for static and rotational IMRT of lung cancer: A phantom study. AB - PURPOSE: To evaluate the dosimetric accuracy of Pencil beam (PB), Anisotropic Analytical Algorithm (AAA) and Collapsed Cone Convolution Superposition (CCCS) in thoracic tumours for various IMRT techniques. METHODS: Step-and-shoot Linac IMRT (IMRT), arc volumetric RapidArc (RA) and Helical Tomotherapy (HT) lung treatments for different clinical situations (mediastinum tumour, single metastasis and multiple metastases) were simulated and calculated with PB/AAA, AAA, CCCS, respectively. Delivery quality assurance plans were first verified in homogeneous media (Cheese phantom and ArcCHECK); then several low-density inhomogeneous phantoms were used: the Multiplug ArcCHECK, the commercial ArcCHECK slightly modified with a low density lung-shape insert and a custom-made slab heterogeneous phantom simulating the thorax region. Absolute doses and planar dose maps were checked to assess the agreement between measured and calculated dose distributions. RESULTS: In total, data referred to 195 point dose measurements and 189 planar measurements were considered. Average point absolute deviations <3% were found for all the delivery techniques/dose algorithms. In small targets completely embedded in very low density media, deviations up to 7 10% and 4-5% were found for PB and AAA/CCCS respectively. Excellent results were found for planar measurements in ArcCHECK configurations, where >= 95% of points satisfy the 3%/3 mm acceptance criteria for all the algorithms. CONCLUSIONS: A satisfactory agreement (<2%) between planned and measured doses was generally found for CCCS and AAA, excepting the very critical situation of a small tumour completely embedded in air. A significant dose overestimation (from few to 5-7%) was confirmed for PB in complex inhomogeneous arrangements. PMID- 25801285 TI - Hypertrophic Olivary Degeneration Secondary to Neuro-Behcet's Disease. PMID- 25801283 TI - New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations. AB - Protein aggregate myopathies (PAMs) define muscle disorders characterized by protein accumulation in muscle fibres. We describe a new PAM in a patient with proximal muscle weakness and hypertrophic cardiomyopathy, whose muscle fibres contained inclusions containing myosin and myosin-associated proteins, and aberrant distribution of microtubules. These lesions appear as intact A- and M bands lacking thin filaments and Z-discs. These features differ from inclusions in myosin storage myopathy (MSM), but are highly similar to those in mice deficient for the muscle-specific RING finger proteins MuRF1 and MuRF3. Sanger sequencing excluded mutations in the MSM-associated gene MYH7 but identified mutations in TRIM63 and TRIM54, encoding MuRF1 and MuRF3, respectively. No mutations in other potentially disease-causing genes were identified by Sanger and whole exome sequencing. Analysis of seven family members revealed that both mutations segregated in the family but only the homozygous TRIM63 null mutation in combination with the heterozygous TRIM54 mutation found in the proband caused the disease phenotype. Both MuRFs are microtubule-associated proteins localizing to sarcomeric M-bands and Z-discs. They are E3 ubiquitin ligases that play a role in degradation of sarcomeric proteins, stabilization of microtubules and myogenesis. Lack of ubiquitin and the 20S proteasome subunit in the inclusions found in the patient suggested impaired turnover of thick filament proteins. Disruption of microtubules in cultured myotubes was rescued by transient expression of wild-type MuRF1. The unique features of this novel myopathy point to defects in homeostasis of A-band proteins in combination with instability of microtubules as cause of the disease. PMID- 25801287 TI - Stressing the recurrent laryngeal nerve during thyroidectomy. AB - BACKGROUND: In thyroidectomy, little has been reported on the differential recurrent laryngeal nerve (RLN) palsy rates between the left and right sides. Even less is known about the potential differences causing these differential rates. This study reports the left versus right RLN palsy rates of total thyroidectomy cases in a single institution, relating them to the comparative stiffness of the left and right porcine RLNs. Computed stress modelling was also used to estimate the differential levels of tension within each RLN. METHODS: For the comparison of the left and right RLN palsy rates, 1926 cases of total thyroidectomy (between 2007 and 2013) from the Monash University Endocrine Surgery Unit were included. Stiffness of porcine RLNs was experimentally determined by measuring nerve extension against incremental increase in load. Additionally, the tension of intraoperatively stretched RLNs was estimated by computer modelling. RESULTS: The left RLN had a palsy rate of 0.9% (18/1926), which was significantly lower (P = 0.025) than the right RLN palsy rate of 1.8% (34/1926). The left porcine RLN was 22% stiffer than the right RLN (P = 0.004). The stress modelling estimated that at the apex of the artificial RLN genu during anteromedial rotation of the thyroid lobe, the right RLN experiences twice the tension experienced by the left RLN. CONCLUSION: The stiffer left RLN and the higher tension generated in the right RLN during thyroidectomy may jointly contribute to the higher right RLN palsy rate. PMID- 25801288 TI - [Neonatal hemochromatosis: Another entity that is no longer orphan. Advances in the diagnosis and management of the main cause of neonatal acute liver failure]. AB - Neonatal hemochromatosis is the most common cause of acute liver failure in the neonatal period. It is associated with high morbidity and mortality due to iron overload in hepatic and extra-hepatic tissues. New evidence has emerged during the last few years as regards its alloimmune etiology, which have had an important repercussion on the diagnosis, treatment and prognosis of these patients. Treatment with immunoglobulins and exchange transfusions has radically changed the prognosis without liver transplant. Another great success has been the preventive use of immunoglobulin in pregnant women with a past history of neonatal hemochromatosis, thus decreasing the rate of disease recurrence up to 70%. This new paradigm has led to an entity with a poor prognosis becoming a curable disease if diagnosed and treated early. Nevertheless, a large widespread ignorance of the disease persists, with medical implications that result in significant health problems, due to the delayed referral of these patients to specialized centers. PMID- 25801286 TI - Glucose, lactate, and shuttling of metabolites in vertebrate retinas. AB - The vertebrate retina has specific functions and structures that give it a unique set of constraints on the way in which it can produce and use metabolic energy. The retina's response to illumination influences its energy requirements, and the retina's laminated structure influences the extent to which neurons and glia can access metabolic fuels. There are fundamental differences between energy metabolism in retina and that in brain. The retina relies on aerobic glycolysis much more than the brain does, and morphological differences between retina and brain limit the types of metabolic relationships that are possible between neurons and glia. This Mini-Review summarizes the unique metabolic features of the retina with a focus on the role of lactate shuttling. PMID- 25801289 TI - Further human evidence for striatal dopamine release induced by administration of ?9-tetrahydrocannabinol (THC): selectivity to limbic striatum. AB - RATIONALE: Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ?9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. OBJECTIVES: The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. METHODS: We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. RESULTS: THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 +/- 0.26 to 2.30 +/- 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. CONCLUSIONS: In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia. PMID- 25801290 TI - Chronic administration of a microencapsulated probiotic enhances the bioavailability of orange juice flavanones in humans. AB - Orange juice (OJ) flavanones are bioactive polyphenols that are absorbed principally in the large intestine. Ingestion of probiotics has been associated with favorable changes in the colonic microflora. The present study examined the acute and chronic effects of orally administered Bifidobacterium longum R0175 on the colonic microflora and bioavailability of OJ flavanones in healthy volunteers. In an acute study volunteers drank OJ with and without the microencapsulated probiotic, whereas the chronic effects were examined when OJ was consumed after daily supplementation with the probiotic over 4 weeks. Bioavailability, assessed by 0-24h urinary excretion, was similar when OJ was consumed with and without acute probiotic intake. Hesperetin-O-glucuronides, naringenin-O-glucuronides, and hesperetin-3'-O-sulfate were the main urinary flavanone metabolites. The overall urinary excretion of these metabolites after OJ ingestion and acute probiotic intake corresponded to 22% of intake, whereas excretion of key colon-derived phenolic and aromatic acids was equivalent to 21% of the ingested OJ (poly)phenols. Acute OJ consumption after chronic probiotic intake over 4 weeks resulted in the excretion of 27% of flavanone intake, and excretion of selected phenolic acids also increased significantly to 43% of (poly)phenol intake, corresponding to an overall bioavailability of 70%. Neither the probiotic bacterial profiles of stools nor the stool moisture, weight, pH, or levels of short-chain fatty acids and phenols differed significantly between treatments. These findings highlight the positive effect of chronic, but not acute, intake of microencapsulated B. longum R0175 on the bioavailability of OJ flavanones. PMID- 25801291 TI - Plasmalogen phospholipids protect internodal myelin from oxidative damage. AB - Reactive oxygen species (ROS) are implicated in a range of degenerative conditions, including aging, neurodegenerative diseases, and neurological disorders. Myelin is a lipid-rich multilamellar sheath that facilitates rapid nerve conduction in vertebrates. Given the high energetic demands and low antioxidant capacity of the cells that elaborate the sheaths, myelin is considered intrinsically vulnerable to oxidative damage, raising the question whether additional mechanisms prevent structural damage. We characterized the structural and biochemical basis of ROS-mediated myelin damage in murine tissues from both central nervous system (CNS) and peripheral nervous system (PNS). To determine whether ROS can cause structural damage to the internodal myelin, whole sciatic and optic nerves were incubated ex vivo with a hydroxyl radical generating system consisting of copper (Cu), hydrogen peroxide (HP), and ortho phenanthroline (OP). Quantitative assessment of unfixed tissue by X-ray diffraction revealed irreversible compaction of myelin membrane stacking in both sciatic and optic nerves. Incubation in the presence of the hydroxyl radical scavenger sodium formate prevented this damage, implicating hydroxyl radical species. Myelin membranes are particularly enriched in plasmalogens, a class of ether-linked phospholipids proposed to have antioxidant properties. Myelin in sciatic nerve from plasmalogen-deficient (Pex7 knockout) mice was significantly more vulnerable to Cu/OP/HP-mediated ROS-induced compaction than myelin from WT mice. Our results directly support the role of plasmalogens as endogenous antioxidants providing a defense that protects ROS-vulnerable myelin. PMID- 25801293 TI - Improving the ability to eliminate wounds and pressure ulcers. AB - Pressure ulcers can be initiated by as little as 2 hours of constant pressure on the ski, that blocks blood circulation causing the skin and underlying tissues to die, leading to an open wound that never heals, but continues to grow in diameter and depth, and frequently jeopardizes patients' lives. Despite the application of many diverse techniques, pressure ulcers remain exceptionally difficult to heal because many ulcer elimination techniques have minimal effects, and although other techniques may appear to be effective, the evidence supporting their efficacy is weak. However, increasing evidence indicates that other techniques, such as the application of platelet-rich plasma, vacuum assisted closure, electrical stimulation, and hyperbaric oxygen therapy are effective and should be substituted for the older techniques. This review describes different standard and novel techniques that have been tested for eliminating pressure ulcers and discusses the relative efficacy of these techniques. PMID- 25801294 TI - Rapid atraumatic sex identification of developmental day 14-16 mice. AB - Embryonic mice have been used widely to study organ development. Days 14-16 are critical for sex organ development and differentiation in mice. Current methods for sex identification are limited. Even the simplest polymerase chain reaction method may injure the embryo. We determined that morphologic analysis of embryonic mammary anlagen could be used for rapid atraumatic sex identification of day 14-16 mice. The accuracy of our method was verified by molecular and anatomical approaches. PMID- 25801292 TI - Detection of oxidative stress-induced carbonylation in live mammalian cells. AB - Oxidative stress is often associated with etiology and/or progression of disease conditions, such as cancer, neurodegenerative diseases, and diabetes. At the cellular level, oxidative stress induces carbonylation of biomolecules such as lipids, proteins, and DNA. The presence of carbonyl-containing biomolecules as a hallmark of these diseases provides a suitable target for diagnostic detection. Here, a simple, robust method for detecting cellular aldehydes and ketones in live cells using a fluorophore is presented. A hydrazine-functionalized synthetic fluorophore serves as an efficient nucleophile that rapidly reacts with reactive carbonyls in the cellular milieu. The product thus formed exhibits a wavelength shift in the emission maximum accompanied by an increase in emission intensity. The photochemical characteristics of the fluorophore enable the identification of the fluorophore-conjugated cellular biomolecules in the presence of unreacted dye, eliminating the need for removal of excess fluorophore. Moreover, this fluorophore is found to be nontoxic and is thus appropriate for live cell analysis. Utility of the probe is demonstrated in two cell lines, PC3 and A549. Carbonylation resulting from serum starvation and hydrogen peroxide-induced stress is detected in both cell lines using fluorescence microscopy and a fluorescence plate reader. The fluorescent signal originates from carbonylated proteins and lipids but not from oxidized DNA, and the majority of the fluorescence signal (>60%) is attributed to fluorophore-conjugated lipid oxidation products. This method should be useful for detecting cellular carbonylation in a high-content assay or high-throughput assay format. PMID- 25801295 TI - Uptake and localization mechanisms of fluorescent and colored lipid probes. Part 3. Protocols for predicting intracellular localization of lipid probes using QSAR models. AB - We provide detailed protocols for applying the QSAR decision-rule models described in Part 2 of this paper. These procedures permit prediction of the intracellular localization of fluorescent probes or of any small molecular xenobiotic whether fluorescent or not. Also included is a set of notes that give practical advice on various possible problems and limitations of the methods, together with a flow chart that provides a graphical algorithmic summary of the QSAR models. PMID- 25801296 TI - The effects of adriamycin on E-cadherin mediated cell-cell adhesion and apoptosis during early kidney development. AB - Adriamycin (ADR) is strongly teratogenic. We investigated the effects of ADR on apoptosis and the intensity of E-cadherin expression in developing kidneys. An experimental group of rats was given 2 mg/kg/day ADR on days 6-9 of gestation and a control group was given saline on the same schedule. Embryos were decapitated on days 13, 15, 17 and 19 of gestation, and processed and embedded in paraffin for routine light microscopy. Kidney specimens were stained with hematoxylin and eosin or periodic acid-Schiff, or immunostained for E-cadherin. Apoptosis was assessed using the TUNEL method. Weight loss and developmental deficiency were determined in embryos of the experimental group. ADR damaged or destroyed tubule epithelial cells, which caused apparent dilatation of the tubule lumen. Also, the brush borders of proximal tubules were damaged and glomerular spaces were dilated. ADR caused apoptosis of kidney tissue by days 15, 17 and 19 of development and E-cadherin expression was up-regulated during kidney development compared to controls. We found that ADR can cause apoptosis and increased E cadherin expression in the developing rat kidney. E-cadherin expression and apoptosis may contribute to the development of ADR nephrotoxicity. PMID- 25801297 TI - Uptake and localization mechanisms of fluorescent and colored lipid probes. Part 2. QSAR models that predict localization of fluorescent probes used to identify ("specifically stain") various biomembranes and membranous organelles. AB - We discuss a variety of biological targets including generic biomembranes and the membranes of the endoplasmic reticulum, endosomes/lysosomes, Golgi body, mitochondria (outer and inner membranes) and the plasma membrane of usual fluidity. For each target, we discuss the access of probes to the target membrane, probe uptake into the membrane and the mechanism of selectivity of the probe uptake. A statement of the QSAR decision rule that describes the required physicochemical features of probes that enable selective staining also is provided, followed by comments on exceptions and limits. Examples of probes typically used to demonstrate each target structure are noted and decision rule tabulations are provided for probes that localize in particular targets; these tabulations show distribution of probes in the conceptual space defined by the relevant structure parameters ("parameter space"). Some general implications and limitations of the QSAR models for probe targeting are discussed including the roles of certain cell and protocol factors that play significant roles in lipid staining. A case example illustrates the predictive ability of QSAR models. Key limiting values of the head group hydrophilicity parameter associated with membrane-probe interactions are discussed in an appendix. PMID- 25801298 TI - Expression of vascular endothelial growth factor receptors and their ligands in rat uterus during the postpartum involution period. AB - Vascular endothelial growth factor (VEGF) and its specific receptors, FLt1/fms, Flk1/KDR and FLt4, play important roles in vasculogenesis, and physiological and pathological angiogenesis. Whether angiogenic growth factors are involved in regulating angiogenic processes during the postpartum involution period (PP) of the rat uterus is unknown. We used immunohistochemistry to analyze the expression levels of VEGF, the fms-like tyrosine kinase 1 (FLt1/fms), the kinase insert domain-containing region 1 (Flk1/KDR), Fms-related tyrosine kinase 4 (FLt4) and vascular endothelial growth inhibitor (VEGI) in the rat uterus during the days 1, 3, 5, 10 and 15 of the PP to determine the temporal and spatial expressions of VEGF and its receptors during the PP. Throughout the PP, cytoplasmic and membrane staining of VEGI, VEGF and their receptors were observed in the lumens, crypts and glandular epithelial cells as well as in connective tissue and vascular endothelial and smooth muscle cells in the endometrium. We found that the intensity of the immunoreactions in the endometrium varied with the morphological changes that occurred during involution. Immunoreactions for VEGI, VEGF and their receptor, Flk1/KDR, in the luminal epithelial cells were stronger than those in the glandular epithelial and stromal cells, particularly during PP 1, 3 and 5, which suggests that these peptides may contribute to re-epithelialization of the endometrium. On the other hand, Flt1/fms immunoreactivity was strong mainly in the stromal cells during the PP. The presence of VEGF and its receptors (FLt1/fms, Flk1/KDR, FLt4) in the stromal cells and blood vessels during the PP suggests that they may contribute to regulating stromal repair and angiogenesis in the involuting uterus of the rat. PMID- 25801299 TI - Identification of genes associated with disc degeneration using bioinformatics. AB - Intervertebral disc degeneration is a common orthopedic disease that has been recognized as the major cause of low back pain. About 80% of the population is affected by this disease. We explored molecular mechanisms of disc degeneration and identified the genes associated with the disease. The transcription profile of GSE34095 was downloaded from Gene Expression Omnibus database with three degenerative disc samples and three healthy disc samples. Gene ontology and pathway enrichment analysis were performed. We constructed a protein-protein interaction (PPI) network and a transcription factor (TF) target network. Differentially expressed genes (DEGs) in normal and disc degeneration samples were identified including 243 up-regulated genes and 351 down-regulated genes. Meanwhile, seven Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were obtained by mapping the 594 DEGs to the KEGG and we found that the calcium signaling pathway was the most significant for developing disc degeneration. The pathways interaction network analysis showed that the adherens junction pathway interacted with other six pathways. In addition, the top five genes, FYN, PRKCD, YWHAB, YWHAZ and AR, with a high degree of interaction of 7, 4, 4, 4 and 4, respectively, were related to the disc degeneration in the PPI network. Furthermore, transcription factors including TFAP2A, E2F4, SP3 and AR had the potential to regulate disc degeneration through the mitogen-activated protein kinase, vascular endothelial growth factor and p53 pathways. The genes and pathways that we identified may be involved in disc degeneration. PMID- 25801300 TI - Experimental comparison of parametric versus nonparametric analyses of data from the cold pressor test. AB - Parametric statistical methods are common in human pain research. They require normally distributed data, but this assumption is rarely tested. The current study analyzes the appropriateness of parametric testing for outcomes from the cold pressor test (CPT), a common human experimental pain test. We systematically reviewed published CPT studies to quantify how often researchers test for normality and how often they use parametric versus nonparametric tests. We then measured the normality of CPT data from 7 independent small to medium cohorts and 1 study of >10,000 subjects. We then examined the ability of 2 common mathematical transformations to normalize our skewed data sets. Lastly, we performed Monte Carlo simulations on a representative data set to compare the statistical power of the parametric t-test versus the nonparametric Wilcoxon Mann Whitney test. We found that only 39% of published CPT studies (47/122) mentioned checking data distribution, yet 72% (88/122) used parametric statistics. Furthermore, among our 8 data sets, CPT outcomes were virtually always nonnormally distributed, and mathematical transformations were largely ineffective in normalizing them. The simulations demonstrated that the nonparametric Wilcoxon Mann-Whitney test had greater statistical power than the parametric t-test for all scenarios tested: For small effect sizes, the Wilcoxon Mann-Whitney test had up to 300% more power. PERSPECTIVE: These results demonstrate that parametric analyses of CPT data are routine but incorrect and that they likely increase the chances of failing to detect significant between group differences. They suggest that nonparametric analyses become standard for CPT studies and that assumptions of normality be routinely tested for other types of pain outcomes as well. PMID- 25801301 TI - Apoptotic-like Leishmania exploit the host's autophagy machinery to reduce T-cell mediated parasite elimination. AB - Apoptosis is a well-defined cellular process in which a cell dies, characterized by cell shrinkage and DNA fragmentation. In parasites like Leishmania, the process of apoptosis-like cell death has been described. Moreover upon infection, the apoptotic-like population is essential for disease development, in part by silencing host phagocytes. Nevertheless, the exact mechanism of how apoptosis in unicellular organisms may support infectivity remains unclear. Therefore we investigated the fate of apoptotic-like Leishmania parasites in human host macrophages. Our data showed--in contrast to viable parasites--that apoptotic like parasites enter an LC3(+), autophagy-like compartment. The compartment was found to consist of a single lipid bilayer, typical for LC3-associated phagocytosis (LAP). As LAP can provoke anti-inflammatory responses and autophagy modulates antigen presentation, we analyzed how the presence of apoptotic-like parasites affected the adaptive immune response. Macrophages infected with viable Leishmania induced proliferation of CD4(+) T-cells, leading to a reduced intracellular parasite survival. Remarkably, the presence of apoptotic-like parasites in the inoculum significantly reduced T-cell proliferation. Chemical induction of autophagy in human monocyte-derived macrophage (hMDM), infected with viable parasites only, had an even stronger proliferation-reducing effect, indicating that host cell autophagy and not parasite viability limits the T-cell response and enhances parasite survival. Concluding, our data suggest that apoptotic-like Leishmania hijack the host cells' autophagy machinery to reduce T cell proliferation. Furthermore, the overall population survival is guaranteed, explaining the benefit of apoptosis-like cell death in a single-celled parasite and defining the host autophagy pathway as a potential therapeutic target in treating Leishmaniasis. PMID- 25801303 TI - Trainable hardware for dynamical computing using error backpropagation through physical media. AB - Neural networks are currently implemented on digital Von Neumann machines, which do not fully leverage their intrinsic parallelism. We demonstrate how to use a novel class of reconfigurable dynamical systems for analogue information processing, mitigating this problem. Our generic hardware platform for dynamic, analogue computing consists of a reciprocal linear dynamical system with nonlinear feedback. Thanks to reciprocity, a ubiquitous property of many physical phenomena like the propagation of light and sound, the error backpropagation-a crucial step for tuning such systems towards a specific task-can happen in hardware. This can potentially speed up the optimization process significantly, offering important benefits for the scalability of neuro-inspired hardware. In this paper, we show, using one experimentally validated and one conceptual example, that such systems may provide a straightforward mechanism for constructing highly scalable, fully dynamical analogue computers. PMID- 25801302 TI - Abnormal pairing of X and Y sex chromosomes during meiosis I in interspecific hybrids of Phodopus campbelli and P. sungorus. AB - Hybrid sterility plays an important role in the maintenance of species identity and promotion of speciation. Male interspecific hybrids from crosses between Campbell's dwarf hamster (Phodopus campbelli) and the Djungarian hamster (P. sungorus) exhibit sterility with abnormal spermatogenesis. However, the meiotic phenotype of these hybrids has not been well described. In the present work, we observed the accumulation of spermatocytes and apoptosis of spermatocyte-like cells in the testes of hybrids between P. campbelli females and P. sungorus males. In hybrid spermatocytes, a high frequency of asynapsis of X and Y chromosomes during the pachytene-like stage and dissociation of these chromosomes during metaphase I (MI) was observed. No autosomal univalency was observed during pachytene-like and MI stages in the hybrids; however, a low frequency of synapsis between autosomes and X or Y chromosomes, interlocking and partial synapsis between autosomal pairs, and gamma-H2AFX staining in autosomal chromatin was observed during the pachytene-like stage. Degenerated MI-like nuclei were frequently observed in the hybrids. Most of the spermatozoa in hybrid epididymides exhibited head malformation. These results indicate that the pairing of X and Y chromosomes is more adversely affected than that of autosomes in Phodopus hybrids. PMID- 25801304 TI - Phytotyping(4D) : a light-field imaging system for non-invasive and accurate monitoring of spatio-temporal plant growth. AB - Integrative studies of plant growth require spatially and temporally resolved information from high-throughput imaging systems. However, analysis and interpretation of conventional two-dimensional images is complicated by the three dimensional nature of shoot architecture and by changes in leaf position over time, termed hyponasty. To solve this problem, Phytotyping(4D) uses a light-field camera that simultaneously provides a focus image and a depth image, which contains distance information about the object surface. Our automated pipeline segments the focus images, integrates depth information to reconstruct the three dimensional architecture, and analyses time series to provide information about the relative expansion rate, the timing of leaf appearance, hyponastic movement, and shape for individual leaves and the whole rosette. Phytotyping(4D) was calibrated and validated using discs of known sizes, and plants tilted at various orientations. Information from this analysis was integrated into the pipeline to allow error assessment during routine operation. To illustrate the utility of Phytotyping(4D) , we compare diurnal changes in Arabidopsis thaliana wild-type Col-0 and the starchless pgm mutant. Compared to Col-0, pgm showed very low relative expansion rate in the second half of the night, a transiently increased relative expansion rate at the onset of light period, and smaller hyponastic movement including delayed movement after dusk, both at the level of the rosette and individual leaves. Our study introduces light-field camera systems as a tool to accurately measure morphological and growth-related features in plants. PMID- 25801307 TI - Towards improving oral health care education and delivery. PMID- 25801305 TI - New insights on the transcriptional regulation of CD69 gene through a potent enhancer located in the conserved non-coding sequence 2. AB - The CD69 type II C-type lectin is one of the earliest indicators of leukocyte activation acting in lymphocyte migration and cytokine secretion. CD69 expression in hematopoietic lineage undergoes rapid changes depending on the cell-lineage, the activation state or the localization of the cell where it is expressed, suggesting a complex and tightly controlled regulation. Here we provide new insights on the transcriptional regulation of CD69 gene in mammal species. Through in silico studies, we analyzed several regulatory features of the 4 upstream conserved non-coding sequences (CNS 1-4) previously described, confirming a major function of CNS2 in the transcriptional regulation of CD69. In addition, multiple transcription binding sites are identified in the CNS2 region by DNA cross-species conservation analysis. By functional approaches we defined a core region of 226bp located within CNS2 as the main enhancer element of CD69 transcription in the hematopoietic cells analyzed. By chromatin immunoprecipitation, binding of RUNX1 to the core-CNS2 was shown in a T cell line. In addition, we found an activating but not essential role of RUNX1 in CD69 gene transcription by site-directed mutagenesis and RNA silencing, probably through the interaction with this potent enhancer specifically in the hematopoietic lineage. In summary, in this study we contribute with new evidences to the landscape of the transcriptional regulation of the CD69 gene. PMID- 25801306 TI - Zinc-binding metallothioneins are key modulators of IL-4 production by basophils. AB - Zinc (Zn) is an essential nutrient, and Zn deficiency causes immunodeficiency and skin disorders. Basophils express FcERI on their surface and release multiple mediators after receptor cross-linking, including large amounts of IL-4. However, the mechanisms involved in the FcERI-mediated regulation of basophil IL-4 production are currently unclear. Here, we show that the Zn-binding metallothionein (MT) proteins are essential for the FcERI-induced basophil production of IL-4. Basophils from MT-I/II(-/-) mice produced significantly less FcERI-induced IL-4 than did wild-type basophils. The MTs were involved in maintaining intracellular Zn levels, thereby regulated the calcineurin activity and nuclear factor of activated T-cell (NFAT)-mediated IL-4 production. These results suggest that the MT-dependent control of Zn homeostasis is a novel mechanism for regulating basophil IL-4 production. PMID- 25801312 TI - Identifying risk factors and protective factors for venous leg ulcer recurrence using a theoretical approach: A longitudinal study. AB - BACKGROUND: The high recurrence rate of chronic venous leg ulcers has a significant impact on an individual's quality of life and healthcare costs. OBJECTIVES: This study aimed to identify risk and protective factors for recurrence of venous leg ulcers using a theoretical approach by applying a framework of self and family management of chronic conditions to underpin the study. DESIGN: Secondary analysis of combined data collected from three previous prospective longitudinal studies. SETTING: The contributing studies' participants were recruited from two metropolitan hospital outpatient wound clinics and three community-based wound clinics. PARTICIPANTS: Data were available on a sample of 250 adults, with a leg ulcer of primarily venous aetiology, who were followed after ulcer healing for a median follow-up time of 17 months after healing (range: 3-36 months). METHODS: Data from the three studies were combined. The original participant data were collected through medical records and self reported questionnaires upon healing and every 3 months thereafter. A Cox proportion-hazards regression analysis was undertaken to determine the influential factors on leg ulcer recurrence based on the proposed conceptual framework. RESULTS: The median time to recurrence was 42 weeks (95% CI 31.9 52.0), with an incidence of 22% (54 of 250 participants) recurrence within three months of healing, 39% (91 of 235 participants) for those who were followed for six months, 57% (111 of 193) by 12 months, 73% (53 of 72) by two years and 78% (41 of 52) of those who were followed up for three years. A Cox proportional hazards regression model revealed that the risk factors for recurrence included a history of deep vein thrombosis (HR 1.7, 95% CI 1.07-2.67, p=0.024), history of multiple previous leg ulcers (HR 4.4, 95% CI 1.84-10.5, p=0.001), and longer duration (in weeks) of previous ulcer (HR 1.01, 95% CI 1.003-1.01, p<0.001); while the protective factors were elevating legs for at least 30min per day (HR 0.33, 95% CI 0.19-0.56, p<0.001), higher levels of self-efficacy (HR 0.95, 95% CI 0.92-0.99, p=0.016), and walking around for at least 3h/day (HR 0.66, 95% CI 0.44 0.98, p=0.040). CONCLUSIONS: Results from this study provide a comprehensive examination of risk and protective factors associated with leg ulcer recurrence based on the chronic disease self and family management framework. These results in turn provide essential steps towards developing and testing interventions to promote optimal prevention strategies for venous leg ulcer recurrence. PMID- 25801313 TI - In memory of Carlos E. Baena-Cagnani. PMID- 25801311 TI - The effects of authentic leadership, six areas of worklife, and occupational coping self-efficacy on new graduate nurses' burnout and mental health: A cross sectional study. AB - BACKGROUND: New nurse burnout has personal and organizational costs. The combined effect of authentic leadership, person-job fit within areas of worklife, and occupational coping self-efficacy on new nurses' burnout and emotional wellbeing has not been investigated. OBJECTIVES: This study tested a model linking authentic leadership, areas of worklife, occupational coping self-efficacy, burnout, and mental health among new graduate nurses. We also tested the validity of the concept of interpersonal strain at work as a facet of burnout. DESIGN: A cross-sectional national survey of Canadian new graduate nurses was conducted. PARTICIPANTS: Registered nurses working in direct patient care in acute care settings with less than 3 years of experience were selected from provincial registry databases of 10 Canadian provinces. A total of 1009 of 3743 surveyed new graduate nurses were included in the final sample (useable response rate 27%). METHODS: Participants received a mail survey package that included a letter of information, study questionnaire, and a $2 coffee voucher. To optimize response rates non-responders received a reminder letter four weeks after the initial mailing, followed by a second survey package four weeks after that. Ethics approval was obtained from the university ethics board prior to starting the study. Descriptive statistics and scale reliabilities were analyzed. Structural equation modelling with maximum likelihood estimation was used to test the fit between the data and the hypothesized model and to assess the factor structure of the expanded burnout measure. RESULTS: The hypothesized model was an acceptable fit for the data (chi(2) (164)=1221.38; chi(2) ratio=7.447; CFI=.921; IFI=.921; RMSEA=.08). All hypothesized paths were significant. Authentic leadership had a positive effect on areas of worklife, which in turn had a positive effect on occupational coping self-efficacy, resulting in lower burnout, which was associated with poor mental health. CONCLUSIONS: Authentic leaders may play an important role in creating positive working conditions and strengthening new nurses' confidence that help them cope with job demands, thereby protecting them from developing burnout and poor mental health. Leadership training to develop supervisors' authentic leadership skills may promote the development of person job fit, thereby increasing occupational self-efficacy and new nurses' wellbeing. PMID- 25801308 TI - Neural response in vestibular organ of Helix aspersa to centrifugation and re adaptation to normal gravity. AB - Gravity plays a key role in shaping the vestibular sensitivity (VS) of terrestrial organisms. We studied VS changes in the statocyst of the gastropod Helix aspersa immediately after 4-, 16-, and 32-day exposures to a 1.4G hypergravic field or following a 7-day recovery period. In the same animals we measured latencies of behavioral "negative gravitaxis" responses to a head-down pitch before and after centrifugation and found significant delays after 16- and 32-day runs. In an isolated neural preparation we recorded the electrophysiological responses of the statocyst nerve to static tilt (+/-19 degrees ) and sinusoids (+/-12 degrees ; 0.1 Hz). Spike sorting software was used to separate individual sensory cells' patterns out of a common trace. In correspondence with behavior we observed a VS decrease in animals after 16- (p < 0.05) and 32-day (p < 0.01) centrifugations. These findings reveal the capability of statoreceptors to adjust their sensitivity in response to a prolonged change in the force of gravity. Interestingly, background discharge rate increased after 16 and 32 days in hypergravity and continued to rise through the recovery period. This result indicates that adaptive mechanisms to novel gravity levels were long lasting, and re-adaptation from hypergravity is a more complex process than just "return to normal". PMID- 25801314 TI - Cryptic biodiversity in the cytogenome of bird-biting blackflies in North Africa. AB - Bird-biting blackflies in the Simulium (Eusimulium) aureum group (Diptera: Simuliidae) are widespread vectors of Leucocytozoon and Trypanosoma parasites. The polytene chromosomes of 619 larvae of the three nominal members of the S. aureum group in North Africa were evaluated cytogenetically for cryptic biodiversity. Seven chromosomal segregates were discovered among 29 populations in Algeria and Morocco. This diversity was based primarily on two chromosomal inversions, which have assumed unique roles in different lineages, including sex linkage, fixation, loss and autosomal polymorphism. Reproductive isolation was demonstrated for six of the seven segregates, doubling the number of species known in the area. Four species were linked with existing names: (a) Simulium mellah Giudicelli & Bouzidi, which is known only from North African high-salinity habitats; (b) Simulium petricolum (Rivosecchi), which is tentatively conspecific with continental European populations; (c) Simulium rubzovianum (Sherban) and its synonym Simulium latinum (Rubtsov), which is widely distributed from North Africa across Europe into Western Asia, and (d) Simulium velutinum (Santos Abreu) and its new synonym Simulium tenerificum Crosskey, which is restricted to North Africa and the Canary Islands. Of the remaining entities, two are new species precinctive to North Africa and one, known only from Morocco, is of undetermined taxonomic status. PMID- 25801316 TI - Adherence to highly active antiretroviral therapy in Hyderabad, India: barriers, facilitators and identification of target groups. AB - We assessed the barriers and facilitators to highly active antiretroviral therapy adherence and determined their prevalence among HIV/AIDS patients in Hyderabad, India. We conducted a cross-sectional study among HIV-infected adults prescribed highly active antiretroviral therapy and receiving care from nine clinics. Depression was screened using Patient Health Questionnaire 9 and facilitators of HIV medication adherence were assessed using an 11-item scale which yielded a total positive attitude to disease score. Prevalence ratios of non-adherence between different categories of potential risk factors were calculated. We compared mean 'facilitators to adherence' scores between the adherent and non adherent population. Multivariable Poisson regression with robust variance was used to identify independent risk factors. Among the 211 respondents, nearly 20% were non-adherent, approximately 8% had either moderately severe or severe depression and mean score for combined facilitators to medication adherence was 33.35 (+/-7.88) out of a possible 44 points. Factors significantly associated with non-adherence included older age, female sex worker, moderate-to-severe depression and the combined facilitators to medication adherence score. These data from a broad range of clinical settings in Hyderabad reveal that key groups to focus on for adherence intervention are female sex workers, older persons and those with depression. PMID- 25801318 TI - NHS trusts' deficits could more than double over next year, leader predicts. PMID- 25801317 TI - Novel chelating agents for iron, manganese, zinc, and copper mixed fertilisation in high pH soil-less cultures. AB - BACKGROUND: Studies about simultaneous fertilisation with several micronutrients have increased in recent years, as Fe, Mn and Zn deficiencies may appear in the same culture conditions. In fertigation, the replacement of sulfates by synthetic chelates is essential in areas with high pH irrigation water and substrates. Ethylenediamine-N-(2-hydroxyphenylacetic acid)-N'-(4-hydroxyphenylacetic acid) (o,p-EDDHA) and ethylenediamine disuccinic acid (EDDS) are novel chelating agents whose efficacy in simultaneous fertilisation of Zn, Mn and Cu is unknown. This work evaluates the effectiveness of both ligands compared to traditional ligands (EDTA, HEEDTA and DTPA) applied as micronutrient chelate mixtures to soybean and navy bean plants grown in soil-less cultures at high pH by analysing the SPAD and micronutrient nutritional status, including the Composition Nutritional Diagnosis (CND) analysis tool. RESULTS: The application of micronutrients using o,p-EDDHA was more effective in providing Mn and Zn than traditional ligands or sulfates. The application using EDDS increased the Zn nutrition. The results are well correlated with the chemical stability of the formulations. CONCLUSION: The combined application of Mn and Zn as o,p-EDDHA chelates can represent a more effective source than traditional chelates in micronutrient fertiliser mixtures in soil-less cultures at a high pH. PMID- 25801319 TI - Hierarchically functionalized magnetic core/multishell particles and their postsynthetic conversion to polymer capsules. AB - The controlled synthesis of hierarchically functionalized core/multishell particles is highly desirable for applications in medicine, catalysis, and separation. Here, we describe the synthesis of hierarchically structured metal organic framework multishells around magnetic core particles (magMOFs) via layer by-layer (LbL) synthesis. The LbL deposition enables the design of multishell systems, where each MOF shell can be modified to install different functions. Here, we used this approach to create controlled release capsules, in which the inner shell serves as a reservoir and the outer shell serves as a membrane after postsynthetic conversion of the MOF structure to a polymer network. These capsules enable the controlled release of loaded dye molecules, depending on the surrounding media. PMID- 25801320 TI - Exploiting the lactose-GM3 interaction for drug delivery. AB - Protein-protein and protein-carbohydrate interactions as a means to target the cell surface for therapeutic applications have been extensively investigated. However, carbohydrate-carbohydrate interactions (CCIs) have largely been overlooked. Here, we investigate the concept of CCI-mediated drug delivery. Lactose-functionalized beta-cyclodextrin (L-beta-CD) hosting doxorubicin (Dox) was evaluated for site-specific delivery to cancer cells via interaction with GM3 , a cell-surface carbohydrate. The host-guest complex was evaluated in B16 melanoma cells, which express exceptionally high levels of GM3 , and acute monocytic leukemia (THP-1) and mouse fibroblast (NIH-3T3) cells, which lack GM3 on the cell surface. Doxorubicin (Dox) was delivered more efficiently into B16 cells compared with NIH-3T3 and THP-1 cells. In B16 cells pretreated with sialidase or sodium periodate, thus preventing CCI formation, drug uptake was significantly decreased. Taken together, the results of these studies strongly support CCI-mediated uptake via the GM3 -lactose interaction as the mechanism of controlled drug delivery. PMID- 25801315 TI - Incident Vertebral Fractures and Risk Factors in the First Three Years Following Glucocorticoid Initiation Among Pediatric Patients With Rheumatic Disorders. AB - Vertebral fractures are an important yet underrecognized manifestation of osteoporosis in children with chronic, glucocorticoid-treated illnesses. Our goal was to determine the incidence and clinical predictors of vertebral fractures in the 3 years following glucocorticoid initiation among pediatric patients with rheumatic disorders. Incident vertebral fractures were evaluated according to the Genant semiquantitative method on lateral radiographs at baseline and then annually in the 3 years following glucocorticoid initiation. Extended Cox models were used to assess the association between vertebral fractures and clinical risk predictors. A total of 134 children with rheumatic disorders were enrolled in the study (mean +/- standard deviation (SD) age 9.9 +/- 4.4 years; 65% girls). The unadjusted vertebral fracture incidence rate was 4.4 per 100 person-years, with a 3-year incidence proportion of 12.4%. The highest annual incidence occurred in the first year (6.0%; 95% confidence interval (CI) 2.9% to 11.7%). Almost one half of the patients with fractures were asymptomatic. Every 0.5 mg/kg increase in average daily glucocorticoid (prednisone equivalents) dose was associated with a twofold increased fracture risk (hazard ratio (HR) 2.0; 95% CI 1.1 to 3.5). Other predictors of increased vertebral fracture risk included: (1) increases in disease severity scores between baseline and 12 months; (2) increases in body mass index Z-scores in the first 6 months of each 12-month period preceding the annual fracture assessment; and (3) decreases in lumbar spine bone mineral density Z-scores in the first 6 months of glucocorticoid therapy. As such, we observed that a clinically significant number of children with rheumatic disorders developed incident vertebral fractures in the 3 years following glucocorticoid initiation. Almost one-half of the children were asymptomatic and thereby would have been undiagnosed in the absence of radiographic monitoring. In addition, discrete clinical predictors of incident vertebral fractures were evident early in the course of glucocorticoid therapy. PMID- 25801321 TI - Inhibitory effects of pain relief drugs on neurological enzymes: implications on their potential neurotoxicity to aquatic animals. AB - Pain relief medications commonly occur in the aquatic environment at measurable levels. While the neurotoxicity of pain relievers to higher vertebrates is currently known, little is known about their effects on aquatic animals. This study investigated the neurotoxicity of pain relievers to aquatic animals. We used three neurological enzymes, cholinesterase (ChE), adenosine triphosphatase (ATPase), and monoamine oxidase (MAO), from a freshwater planarian (Dugesia japonica) and green neon shrimp (Neocaridina denticulata) as biomarkers to examine the effects of pain relievers on in vitro activity. The activity of MAO and ChE, but not ATPase, was significantly inhibited by acetaminophen, but not by other pain relievers examined. It was likely that the inhibitory effects of acetaminophen on shrimp neurological enzymes were more severe than on the planarian. These findings suggest that acetaminophen is potentially neurotoxic to aquatic animals, at least in terms of neurotransmission disturbance. PMID- 25801322 TI - The development of the LC-MS/MS method based on S-9 biotransformation for detection of metabolites of selected beta-adrenolytics in surface water. AB - Pharmaceuticals consumption in Poland is high. One of the most frequently prescribed is cardiovascular drugs. Due to their relatively high hydrophilic properties, they are not completely eliminated during wastewater treatment processes. In contrast to parent compounds, the presence of cardiovascular metabolites is rarely investigated in surface waters. The goal of this paper was to develop the methodology for detection of metabolites of selected beta blockers: metoprolol, bisoprolol and propranolol. These metabolites were obtained by the incubation of parent compounds with S9 rat's liver fraction and used for the development and optimization of the low resolution LC-MS/MS method. Accurate mass spectrometry measurements were applied for validation of this method. The incubation of the parent compound with S9 fraction resulted only in propranolol's metabolites generation. However, on the basis of hydroxypropranolol, theoretically transitions for mono- and dihydroxy-metoprolol and bisoprolol derivatives were generated for MRM mode and applied for surface water analysis. The analysis revealed the presence of some of the target metabolites in the Vistula river. This work is the first one proposing the application of biotrasformation in the methodology of low resolution LC-MS-MS analysis of metabolites of cardiovascular drugs in surface water. PMID- 25801323 TI - Modular Stereoselective Synthesis of (1->2)-C-Glycosides based on the sp(2) sp(3) Suzuki-Miyaura Reaction. AB - This work reports a modular and rapid approach to the stereoselective synthesis of a variety of alpha- and beta-(1->2)-linked C-disaccharides. The key step is a Ni-catalyzed cross-coupling reaction of D-glucal pinacol boronate with alkyl halide glycoside easily prepared from commercially available D-glucal. The products of this sp(2) -sp(3) cross-coupling reaction can be converted to glucopyranosyl, mannopyranosyl, or 2-deoxy-glucopyranosyl C-mannopyranosides by one- or two-step stereoselective oxidative-reductive transformations. To the best of our knowledge, we demonstrated the first synthetic application of a challenging sp(2) -sp(3) Suzuki-Miyaura cross-coupling reaction in carbohydrate chemistry. PMID- 25801324 TI - A Conceptual Model to Promote the Retention of Women with Physical Disabilities in Research. AB - Inadequate participant recruitment and retention practices can affect sample representativeness and thus the generalizability of research findings. Retention of research participants has been examined within the literature to some extent; however, there is no consensus on best practice in achieving acceptable results. Furthermore, there is a gap in understanding how to engage and retain women with physical disabilities (WPDs) in research. To address these oversights, we review (1) the significance of retention as a methodological concern, (2) factors that influence the involvement and retention of participants in research, including individual, population, and health-illness considerations, and (3) particular circumstances impacting the inclusion and retention of WPDs in research. On the basis of a review of the literature and our experience with the Healing Pathways randomized controlled trial (RCT), we present a conceptual model to guide culturally sensitive health research implementation with WPDs, and promote the engagement and retention of this group in RCTs and other forms of interventional health research. PMID- 25801325 TI - Combined inhibitory effects of low temperature and N-acetyl-l-cysteine on the postovulatory aging of mouse oocytes. AB - The postovulatory aging of oocytes eventually affects the development of oocytes and embryos. Oxidative stress is known to accelerate the onset of apoptosis in oocytes and influence their capacity for fertilisation. This study aimed to reveal the roles of temperature and the antioxidant N-acetyl-l-cysteine in preventing the aging of postovulatory mouse oocytes. First, newly ovulated mouse oocytes were cultured at various temperature and time combinations in HCZB medium with varying concentrations of N-acetyl-l-cysteine to assess signs of aging and developmental potential. When cultured in HCZB with 300 MUM N-acetyl-l-cysteine at different temperature and incubation time combinations (namely 25 degrees C for 12 h, 15 degrees C for 24 h and 5 degrees C for 12 h), the increase in the susceptibility of oocytes to activating stimuli was efficiently prevented, and the developmental potential was maintained following Sr2+ activation or in vitro fertilisation. After incubation at either 15 degrees C for 36 h or 5 degrees C for 24 h, oocytes that had decreased blastocyst rates displayed unrecoverable abnormal cortical granule distribution together with decreased BCL2 levels, total glutathione concentrations and glutathione/glutathione disulphide (GSH/GSSG) ratios. In conclusion, postovulatory oocyte aging could be effectively inhibited by appropriate N-acetyl-l-cysteine addition at low temperatures. In addition, a simple method for the temporary culture of mature oocytes was established. PMID- 25801326 TI - [Metamizole]. PMID- 25801327 TI - Persisting allergic patch test reaction to minoxidil manifested as cutaneous lymphoid hyperplasia. PMID- 25801328 TI - Measure your septa release ratios: pheromone release ratio variability affected by rubber septa and solvent. AB - The type of solvent and the volume used to load pheromone components onto rubber septa had significant effects on pheromone release ratios, the variability of those release ratios, and the recoverability of the volatile components during subsequent extraction with hexane. Volatile release ratios of synthetic Oriental fruit moth (OFM) pheromone and additional volatile compounds were determined using a gas chromatograph column as a volatile trap for rapid (<=1 hr) analysis from individual rubber septa. Volatile compound solutions were prepared in hexane, pentane, CH2Cl2, and methyl tert-butyl ether, and a 10, 33, or 100 MUl aliquot of each solution was applied to rubber septa. Septa loaded with 100 MUl of CH2Cl2 emitted significantly (P < 0.05) higher alcohol: acetate (OH:Ac) ratios than septa loaded with the other solvents, which were all similar. Release ratios of the alcohol and acetate components of the OFM pheromone components were assessed over a 3 week period using septa loaded with each solvent. Regardless of loading solvent, the OFM OH:Ac ratios declined logarithmically over 3 weeks; however, the decay slope from septa loaded with CH2Cl2 solutions was different from those of the other three solvents, which were nearly all the same. A high variability in OH:Ac release ratios was measured overall, regardless of the solvent used or the volume it was applied in. Four compounds of near-equal mass: 1-dodecanol, 1-dodecanal, methyl decanoate, and tridecane emitted different release ratios dependent on the solvent, hexane or CH2Cl2, with which a septum was loaded. The more polar and the greater the mass of the test compound, the slower it was emitted from a septum regardless of solvent. These combined results plus comparisons to earlier reports, suggest that researchers should empirically assess the release ratios from septa to be used in bioassays rather than just reporting the type of septum, ratios of compounds applied and solvent used to prepare them. PMID- 25801329 TI - Altering attentional control settings causes persistent biases of visual attention. AB - Attentional control settings have an important role in guiding visual behaviour. Previous work within cognitive psychology has found that the deployment of general attentional control settings can be modulated by training. However, research has not yet established whether long-term modifications of one particular type of attentional control setting can be induced. To address this, we investigated persistent alterations to feature search mode, also known as an attentional bias, towards an arbitrary stimulus in healthy participants. Subjects were biased towards the colour green by an information sheet. Attentional bias was assessed using a change detection task. After an interval of either 1 or 2 weeks, participants were then retested on the same change detection task, tested on a different change detection task where colour was irrelevant, or were biased towards an alternative colour. One experiment included trials in which the distractor stimuli (but never the target stimuli) were green. The key finding was that green stimuli in the second task attracted attention, despite this impairing task performance. Furthermore, inducing a second attentional bias did not override the initial bias toward green objects. The attentional bias also persisted for at least two weeks. It is argued that this persistent attentional bias is mediated by a chronic change to participants' attentional control settings, which is aided by long-term representations involving contextual cueing. We speculate that similar changes to attentional control settings and continuous cueing may relate to attentional biases observed in psychopathologies. Targeting these biases may be a productive approach to treatment. PMID- 25801330 TI - Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir. AB - Lipase mediated desymmetrization of a meso-diol (1,2-cyclopentanedimethanol) allows the synthesis of both enantiomers of some chiral aldehydes, whose behavior in Passerini and Ugi reactions has been explored. Exploiting these two complementary multicomponent reactions and coupling them with a subsequent cyclization process, we observed that 6 out of all 8 possible stereoisomers of peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been proved by the development of a new efficient synthesis of antiviral drug telaprevir. PMID- 25801331 TI - Assessing the welfare of laboratory mice in their home environment using animal based measures--a benchmarking tool. AB - Welfare problems in laboratory mice can be a consequence of an ongoing experiment, or a characteristic of a particular genetic line, but in some cases, such as breeding animals, they are most likely to be a result of the design and management of the home cage. Assessment of the home cage environment is commonly performed using resource-based measures, like access to nesting material. However, animal-based measures (related to the health status and behaviour of the animals) can be used to assess the current welfare of animals regardless of the inputs applied (i.e. the resources or management). The aim of this study was to design a protocol for assessing the welfare of laboratory mice using only animal based measures. The protocol, to be used as a benchmarking tool, assesses mouse welfare in the home cage and does not contain parameters related to experimental situations. It is based on parameters corresponding to the 12 welfare criteria established by the Welfare Quality(r) project. Selection of animal-based measures was performed by scanning existing published, web-based and informal protocols, and by choosing parameters that matched these criteria, were feasible in practice and, if possible, were already validated indicators of mouse welfare. The parameters should identify possible animal welfare problems and enable assessment directly in an animal room during cage cleaning procedures, without the need for extra equipment. Thermal comfort behaviours and positive emotional states are areas where more research is needed to find valid, reliable and feasible animal based measures. PMID- 25801332 TI - Improved genome sequence of the phytopathogenic fungus Rhizoctonia solani AG1-IB 7/3/14 as established by deep mate-pair sequencing on the MiSeq (Illumina) system. AB - The phytopathogenic fungus Rhizoctonia solani AG1-IB of the phylum Basidiomycota affects various economically important crops comprising bean, rice, soybean, figs, cabbage and lettuce. The R. solani isolate 7/3/14 of the anastomosis group AG1-IB was deeply resequenced on the Illumina MiSeq system applying the mate-pair mode to improve its genome sequence. Assembly of obtained sequence reads significantly reduced the amount of scaffolds and improved the genome sequence of the isolate compared to the previous sequencing approach. The genome sequence of the AG1-IB isolate 7/3/14 now provides an up-graded basis to analyze genome features predicted to play a role in pathogenesis and for the development of strategies to antagonize the pathogenic impact of this fungus. PMID- 25801333 TI - Complete genome sequence of the strain Defluviitoga tunisiensis L3, isolated from a thermophilic, production-scale biogas plant. AB - An anaerobic, thermophilic bacterium belonging to the phylum Thermotogae was isolated from a rural, thermophilic biogas plant (54 degrees C) producing methane rich biogas from maize silage, barley, cattle and pig manure. Here we report the first complete genome sequence of the Defluviitoga tunisiensis strain L3, an isolate from the family Thermotogaceae. The strain L3 encodes several genes predicted to be involved in utilization of a large diversity of complex carbohydrates including cellobiose and xylan for the production of acetate, hydrogen (H2) and carbon dioxide (CO2). The genome sequence of D. tunisiensis L3 provides the basis for biotechnological exploitation of genetic determinants playing an important role in thermophilic fermentation processes utilizing renewable primary products. PMID- 25801334 TI - Significance of FBX8 in progression of gastric cancer. AB - F-box only protein 8 (FBX8), a novel component of F-box proteins, has recently been observed in several malignancies. However, its clinical implication in the progression of gastric cancer still remains unclear. The aim of this study was to explore the role of FBX8 in gastric cancer (GC) and analyze its correlation with tumor progression and prognosis. The expression of FBX8 in GC cell lines and matched pairs of fresh gastric cancer tissues were detected by real-time RT-PCR and Western blotting. Immunohistochemistry was used to analyze clinicopathological patterns of FBX8 in 136 cases of clinical paraffin-embedded GC tissues. A series of functional assays were conducted to evaluate the effect of FBX8 on proliferation and invasion in vitro and metastasis in vivo. FBX8 was markedly down-regulated in GC tissues compared to adjacent normal tissues. Patients with low FBX8 had shorter overall survival time and poor prognosis. Knocking down FBX8 obviously promoted proliferation and invasion in BGC823 cells, while over-expression of FBX8 in SGC7901 and AGS cells had the opposite effects. Moreover, FBX8 was sufficient to suppress metastasis in nude mice. Down regulation of FBX8 significantly correlates with invasion, metastasis and poor survival time in GC patients. FBX8 may serve as a promising therapeutic target for inhibition of GC metastasis. PMID- 25801335 TI - Lead selection and characterization of antitubercular compounds using the Nested Chemical Library. AB - Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical LibraryTM using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 MUM and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays. PMID- 25801336 TI - Nucleotide triphosphate promiscuity in Mycobacterium tuberculosis dethiobiotin synthetase. AB - Dethiobiotin synthetase (DTBS) plays a crucial role in biotin biosynthesis in microorganisms, fungi, and plants. Due to its importance in bacterial pathogenesis, and the absence of a human homologue, DTBS is a promising target for the development of new antibacterials desperately needed to combat antibiotic resistance. Here we report the first X-ray structure of DTBS from Mycobacterium tuberculosis (MtDTBS) bound to a nucleotide triphosphate (CTP). The nucleoside base is stabilized in its pocket through hydrogen-bonding interactions with the protein backbone, rather than amino acid side chains. This resulted in the unexpected finding that MtDTBS could utilise ATP, CTP, GTP, ITP, TTP, or UTP with similar Km and kcat values, although the enzyme had the highest affinity for CTP in competitive binding and surface plasmon resonance assays. This is in contrast to other DTBS homologues that preferentially bind ATP primarily through hydrogen bonds between the purine base and the carboxamide side chain of a key asparagine. Mutational analysis performed alongside in silico experiments revealed a gate keeper role for Asn175 in Escherichia coli DTBS that excludes binding of other nucleotide triphosphates. Here we provide evidence to show that MtDTBS has a broad nucleotide specificity due to the absence of the gate-keeper residue. PMID- 25801337 TI - Configuration of ripple domains and their topological defects formed under local mechanical stress on hexagonal monolayer graphene. AB - Ripples in graphene are extensively investigated because they ensure the mechanical stability of two-dimensional graphene and affect its electronic properties. They arise from spontaneous symmetry breaking and are usually manifested in the form of domains with long-range order. It is expected that topological defects accompany a material exhibiting long-range order, whose functionality depends on characteristics of domains and topological defects. However, there remains a lack of understanding regarding ripple domains and their topological defects formed on monolayer graphene. Here we explore configuration of ripple domains and their topological defects in exfoliated monolayer graphenes on SiO2/Si substrates using transverse shear microscope. We observe three-color domains with three different ripple directions, which meet at a core. Furthermore, the closed domain is surrounded by an even number of cores connected together by domain boundaries, similar to topological vortex and anti-vortex pairs. In addition, we have found that axisymmetric three-color domains can be induced around nanoparticles underneath the graphene. This fascinating configuration of ripple domains may result from the intrinsic hexagonal symmetry of two-dimensional graphene, which is supported by theoretical simulation using molecular dynamics. Our findings are expected to play a key role in understanding of ripple physics in graphene and other two-dimensional materials. PMID- 25801338 TI - Liver injury in patients with DRESS: A clinical study of 72 cases. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a syndrome involving multiple systems. Liver injury is the most common visceral manifestation. OBJECTIVE: The purpose of this study was to investigate the types of liver injury and factors associated with DRESS. METHODS: A retrospective cohort study was conducted in Taiwan using a DRESS database compiled from December 2000 to March 2013. RESULTS: Seventy-two cases were included in this study. Among them, 62 (86.1%) cases involved liver injury, 6 of which (9.7%) were liver injury before skin presentation. The distribution of liver injury patterns at initial presentation was 23 cholestatic type (37.1%), 17 mixed type (27.4%), and 12 hepatocellular type (19.4%). Patients with hepatocellular-type injuries were younger, with a median age of 31.5 (P = .044). Individuals with liver function results more than 10 times the upper limit were more likely to have fever (P = .026), took more time to recover, and had fewer eosinophils in the dermis (P = .002). LIMITATIONS: The study was a retrospective cohort study with limited cases. CONCLUSIONS: Liver injury is common in DRESS and frequently associated with atypical lymphocytosis. The cholestatic type is the most common type. Patients with cholestatic-type injuries were older and more frequently had interface changes in skin pathology. PMID- 25801339 TI - Bone Response and Soft Tissue Changes Around Implants With/Without Abutments Supporting Fixed Partial Dentures: Results From a 3-Year, Prospective, Randomized, Controlled Study. AB - BACKGROUND: Diverging opinions exist regarding rough surface abutment usage, and abutment exclusion effects are unstudied. PURPOSE: The study aims to: (1) assess tissue response to oxidized or machined abutments or no abutment; and (2) evaluate immediate implant-loading effects. MATERIALS AND METHODS: In a 2005-2008 parallel-group randomized, clinical trial, 50 partially edentulous subjects received three Branemark TiUniteTM (Nobel Biocare(r), Gothenburg, Sweden) implants. Superstructures were attached via abutments (one with a TiUnite surface - AOX, and one with a machine-milled surface - AM) or directly at implant level (IL). Implants were immediately loaded (test) or unloaded for 3 months (control). Postoperative examinations were done up to 3 years. RESULTS: Forty-seven subjects were reexamined after 3 years. Four and two implants were lost in test and control groups, respectively, during the first year. Thereafter, no implant loss occurred (95.7% survival). After 1 year, mean (SEM) peri-implant marginal bone loss (MBL) was 1.33 (0.08) mm (test) and 1.25 (0.08) mm (control). Between 1 and 3 years, a nonsignificant MBL occurred: 0.36 (0.08) mm (test) and 0.33 (0.06) mm (control). Similar MBL was found at IL (1.81 [0.93] mm) and AOX (1.77 [0.14] mm) after 3 years and was significantly lower at AM (1.42 [0.17] mm) than at IL (groups merged); 42% of the implants displayed mucosal bleeding at 3 years and probing pocket depths varied between 2.13 (0.12) mm and 3.62 (0.15) mm, significantly lower buccally. Bleeding on probing (BoP) in minute amounts was found in 30-45% of the sites and abundant BoP at about 20% of the sites. Soft tissue retracted mostly during year 1 and was more pronounced buccally. Regression analyses revealed significant effects from smoking, periodontal disease, abundant BoP, and a low initial implant stability quotient on MBL. CONCLUSIONS: No further significant MBL was found between 1 and 3 years, irrespective of loading protocol. Use of machined abutments may benefit marginal bone stability over time. PMID- 25801340 TI - Associations between intrauterine bacterial infection, reproductive tract inflammation, and reproductive performance in pasture-based dairy cows. AB - Reproductive tract bacterial infections, particularly those caused by Escherichia coli and Trueperella pyogenes, can have a negative impact on reproductive performance. It has been hypothesized that the presence of E coli early postpartum may increase the risk of isolation of T pyogenes later postpartum. The objective of the present study was to examine associations between intrauterine bacterial infections with E coli and T pyogenes and any bacterial growth (irrespective of bacterial species), purulent vaginal discharge (PVD), cytologic evidence of endometritis (an increased proportion of polymorphonuclear cells [PMNs]), and reproductive performance. Dairy cows (n = 272) from six herds were examined at Days 0 (median, 2 days in milk), 21 and 42 postpartum. From each cow two intrauterine samples were collected via triple-guarded cytobrush at Days 0 and 21. The first cytobrush was used for bacteriologic culture. Escherichia coli and T pyogenes were isolated by culture, and E coli isolates were assigned to one of four phylogenetic groups using a two-step triplex polymerase chain reaction. In addition, T pyogenes was confirmed by polymerase chain reaction. The second cytobrush was used to prepare a cytology slide. Nucleated cells (n = 200) were categorized as epithelial cells, PMNs, or macrophages. Cows were also assessed for body condition score, PVD score, the presence of a CL, and pregnancy. Statistical analysis was performed using multivariable models. There was no association between the presence of E coli at Day 0 and probability of isolation of T pyogenes 3 weeks later; however, E coli positive cows at Day 0 were more likely to be diagnosed with E coli at Day 21 (relative risk [RR] = 2.0, P < 0.01). Escherichia coli at Day 0 or T pyogenes at Day 21 increased the risk of PVD diagnosis 3 weeks later (RR = 1.9; P = 0.04 and RR = 3.0; P = 0.05, respectively). Cows with any bacterial growth at Day 21, irrespective of species, were less likely to conceive within 3 weeks after the start of the seasonal breeding program (RR = 0.8; P = 0.05). Interestingly, cows with 25% PMNs or greater at Day 0 had shorter time to pregnancy (hazard ratio = 1.32; P = 0.05). Intrauterine bacterial infection may impair reproductive performance but the presence of E coli was not associated with isolation of T pyogenes 3 weeks later. Increased endometrial flux of PMNs in cows early postpartum may be a physiological process and improve reproductive performance. PMID- 25801341 TI - Anti-inflammatory flavanol glycosides from Saraca asoca bark. AB - Saraca asoca (Roxb.) de Wilde, a common tree of India, is popularly used in the Ayurvedic and modern herbal systems of medicine for genito-urinary problems of women. Considering the reported antimicrobial or anti-inflammatory effect of S. asoca bark against such infections, we studied the anti-inflammatory activity guided isolation of active compounds from methanol extract. The methanol extract of bark has yielded 10 compounds out of which 3'-deoxyepicatechin-3-O-beta-D glucopyranoside (6) and 3'-deoxycatechin-3-O-alpha-L-rhamnopyranoside (8) have been found to be in vitro and in vivo active. 3',5-Dimethoxy epicatechin (3), 3' deoxyepicatechin-3-O-beta-D-glucopyranoside (6), 3'-deoxycatechin-3-O-alpha-L rhamnopyranoside (8) and epigallocatechin (9) are being reported for the first time from S. asoca. PMID- 25801343 TI - The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline. AB - Experiments on canine lateral saphenous vein segments have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates a segment by diffusion from its microcirculation (vasa vasorum). The effects it causes contrast with those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected - star patterns need darkness, sound patterns, quietness has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance is believed to be responsible for inflammatory and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia. Finally, the shift in the balance caused by the slow physiological increase in plasma noradrenaline concentration in life is believed to be responsible for ageing. PMID- 25801342 TI - Continued maturation of auditory brainstem function during adolescence: A longitudinal approach. AB - OBJECTIVE: Considerable attention has been devoted to understanding development of the auditory system during the first few years of life, yet comparatively little is known about maturation during adolescence. Moreover, the few studies investigating auditory system maturation in late childhood have employed a cross sectional approach. METHODS: To better understand auditory development in adolescence, we used a longitudinal design to measure the subcortical encoding of speech syllables in 74 adolescents at four time points from ages 14 through 17. RESULTS: We find a developmental decrease in the spectral representation of the evoking syllable, trial-by-trial response consistency, and tracking of the amplitude envelope, while timing of the evoked response appears to be stable over this age range. CONCLUSIONS: Subcortical auditory development is a protracted process that continues throughout the first two decades of life. Specifically, our data suggest that adolescence represents a transitional point between the enhanced response during childhood and the mature, though smaller, response of adults. SIGNIFICANCE: That the auditory brainstem has not fully matured by the end of adolescence suggests that auditory enrichment begun later in childhood could lead to enhancements in auditory processing and alter developmental profiles. PMID- 25801344 TI - Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis? AB - The remarkable similarity in inflammatory response and pathology of periodontal disease and rheumatoid arthritis has been recognized for several decades. However, how these two disease may be interrelated has been less clear. During the pathogenesis of rheumatoid arthritis there is a preclinical immunological phase which precedes the clinical manifestation of rheumatoid arthritis. During this phase serum autoantibodies appear many years before the clinical signs and symptoms of rheumatoid arthritis become apparent. To date, the two best studied autoantibodies have been rheumatoid factor and anti-citrullinated protein antibodies (ACPA). Of these the production of ACPA has been considered very important due to their high predictive value in future manifestation of rheumatoid arthritis. Citrullination is a common post-translational modification of proteins based on the enzymatic conversion of arginine into citrulline. Extra articular citrullination and production of ACPA, as a priming immunological experience, is well documented in many tissues including the inflamed gingival tissues associated with periodontal disease. More recently, carbamylation of proteins has also been implicated in the pathogenesis of rheumatoid arthritis in a manner similar to citrullination. Carbamylation is a post translational modification of proteins by an enzyme-independent modification of lysine residues against which autoantibodies are subsequently induced. In this article we hypothesise that, like citrullination, carbamylation of proteins and associated antibody production during the gingival inflammation associated with gingivitis and periodontitis may play a role in the pathogenesis of rheumatoid arthritis. PMID- 25801346 TI - In Situ generation of difluoromethyl diazomethane for [3+2] cycloadditions with alkynes. AB - A novel approach to agrochemically important difluoromethyl-substituted pyrazoles has been developed based on the elusive reagent CF2 HCHN2 , which was synthesized (generated in situ) for the first time and employed in [3+2] cycloaddition reactions with alkynes. The reaction is extremely practical as it is a one-pot process, does not require a catalyst or the isolation of the potentially toxic and explosive gaseous intermediate, and proceeds in a common solvent, namely chloroform, in air. The reaction is also scalable and allows for the preparation of the target pyrazoles on gram scale. PMID- 25801345 TI - Pain Relief due to Transsacrococcygeal Ganglion Impar Block in Chronic Coccygodynia: A Pilot Study. AB - OBJECTIVE: Coccygodynia is a distressing condition that presents with pain around the coccyx. Impar (Walther) ganglion is a sympathetic ganglion located at the end of lumbosacral sympathetic chain. The objective of this study is to share our results and follow up of 34 ganglion impar blocks in 22 patients. DESIGN: Retrospective pilot study. SETTING: Interventional Pain Clinic in the Department of Physical Medicine and Rehabilitation in a university hospital. SUBJECTS: Twenty-two patients with coccygodynia who did not respond to conservative treatment and then presented to interventional pain clinic of a PM&R department in a university hospital METHODS: Pain was evaluated via 10-cm visual analog scale (VAS). VAS values were obtained before, 1 hour and 3 weeks after injection and during this study was conducted. RESULTS: For achieving at least 50% relief of pain, the success rate of a first injection was 82%, but accounted for three technical failures. In patients with a successful outcome, relief lasted for a median duration of 6 months. Relief was reinstated for a median period of 17 months by a second injection in nine patients who presented for repeat treatment. No relief was achieved in two of these patients when they presented for a third treatment. CONCLUSIONS: Ganglion impar block appears to be effective in patients who have coccygodynia resistant to conservative therapy, with high success rates and prolonged duration of effect. Controlled studies are required to reveal the mechanism of this effect. PMID- 25801347 TI - Cannabinoids: Friend or foe? AB - This issue of Clinical Pharmacology & Therapeutics focuses on cannabinoids. Our understanding of these interesting endogenous and synthetic compounds, and their role in the cannabinoid system, has evolved dramatically, in part because of the acquisition of new research tools. Cannabis has been used for centuries by humans for recreational and medicinal purposes, however, there is substantial evidence that cannabis use can expose people to varying complications (e.g., risk of addiction, cognitive impairment), thus, it is important to determine the benefit/risk of cannabis with precision and to implement policy measures based on evidence to maximize the benefits and minimize the harm. Novel cannabinoid drugs are emerging for medicinal use (e.g., dronabinol, nabiximols) and as illicit drugs (e.g., Spice, K2) perpetuating the perception that cannabinoid drugs can be a friend or foe. This special issue will cover these various aspects of cannabinoid pharmacology and therapeutics ranging from basic chemistry, pharmacokinetics, pharmacodynamics, and clinical trial results, to policy and education efforts in this area. PMID- 25801348 TI - Tetracyclines for multidrug-resistant Acinetobacter baumannii infections. AB - Multidrug-resistant (MDR) Acinetobacter baumannii infections have emerged as a serious threat worldwide. As novel agents have yet to be developed, understanding the effectiveness and safety of older antibiotics has become a priority. The purpose of this systematic review was to summarise the available clinical evidence on the use of tetracyclines for the treatment of A. baumannii infections. Ten retrospective studies regarding doxycycline and minocycline for the treatment of 185 A. baumannii infections (of which 65.4% were respiratory infections and 13% were bloodstream infections) in 156 patients were available. In most cases (86.4%), tetracyclines were administered in combination with another agent. The usual dosage of doxycycline or minocycline was 100mg intravenous or per os twice daily (usually with a 200mg loading dose for minocycline). Clinical success was achieved in 120 (76.9%) of 156 patients; in 87 (71.9%) of 121 respiratory infections and in 21 (87.5%) of 24 bloodstream infections. Twenty-two deaths occurred in 100 recorded cases. Microbiological eradication was attained in 72 (71.3%) of 101 available cases and documented microbiological eradication was reached in 59 (66.3%) of 89 available cases. Adverse events were noted in only 1 of 88 cases. Overall, although tetracycline containing regimens showed encouraging results, more data from larger comparative trials are required to establish a role for these antibiotics in the treatment of MDR A. baumannii infections. PMID- 25801349 TI - Injectable Coformulations in Diabetology. AB - Coformulations are a novel pharmaceutical development in diabetology. They are composed of two medicinal products, both of which maintain their distinct pharmacokinetic and pharmacodynamic properties. Currently available coformulations include combinations of basal and rapid-acting insulin, and basal and glucagon-like peptide 1 receptor agonists (GLP1RA). This review describes three coformulations which are in advanced stages of development, or are approved in certain markets. We discuss the basic and clinical pharmacology of these drugs, while describing clinical usage of the commercially available insulin degludec aspart (IDegAsp). PMID- 25801350 TI - The nature of death, coping response and intensity of bereavement following death in the critical care environment. AB - INTRODUCTION: Bereavement, defined as the situation of having recently lost a significant other, is recognised as one of life's greatest stressors and may lead to decrements in health status, psychological morbidity and excess risk of mortality. AIM: The aim of this study was firstly to describe the relationships between the nature of death and bereavement intensity following death in the adult critical care environment and secondly to examine the modifying effects of coping responses on intensity of bereavement reaction. METHOD: Prospective evaluation of the impact of the nature of death and coping responses on bereavement intensity. 78 participants completed a nature of death questionnaire within 2 weeks of bereavement and at 3 and 6 months completed the Core Bereavement Items Questionnaire (CBI-17) and Brief COPE Inventory. RESULTS: At 6 months, univariate variables significantly associated with bereavement intensity were: being unprepared for the death (p<0.001), a drawn out death (p<0.001), a violent death (p=0.007) and if the deceased appeared to suffer more than expected (p=0.03). Multivariate analysis revealed being unprepared for the death appears to account for these relationships. Regarding coping, there were significant increases from 3 to 6 months in both acceptance scales (p=0.01) and planning (p=0.02) on The Brief COPE Inventory. Greater use of emotional support (p=0.02), self-blame (0.003) and denial (p<0.001) were multivariate variables associated with higher bereavement intensity at 6 months. CONCLUSION: The results from this evaluation provide insight into the impact of bereavement after death in the critical care environment and inform potential preventative approaches at the time of death to reduce bereavement intensity. PMID- 25801351 TI - Naive CD8+ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics. AB - Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this 'ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8(+) T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment. PMID- 25801352 TI - Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice. AB - Elevated levels of interleukin (IL)-18 have been reported in a number of allergic diseases. We recently reported that IL-18 in the blood and IL-18Ralpha mRNA in the oesophagus are induced during human eosinophilic oesophagitis (EoE). Additionally, we earlier showed that invariant natural killer T (iNKT) cells are critical to EoE pathogenesis; however, the mechanism of iNKT cell activation in EoE is not well understood. Therefore, the current study focused on the hypothesis that allergen-induced IL-18 may have an important role in iNKT cell mediated EoE pathogenesis. We first validated the human EoE findings of IL-18 in experimental EoE by examining blood levels of IL-18 and oesophageal IL-18Ralpha mRNA levels in aeroallergen- and food allergen-induced experimental mouse models of EoE. We demonstrate that blood IL-18 protein and oesophageal IL-18Ralpha mRNA are induced in the mouse model of EoE and that IL-18Ralpha is expressed by iNKT cells in the oesophagus. Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner. To establish the significance of IL-18 in EoE pathogenesis, we examined DOX-inducible rtTA-CC10-IL-18 bitransgenic mice that induce IL-18 protein expression in the oesophagus. Our analysis indicated that induction of IL-18 in these mice resulted in the development of many of the characteristics of EoE, including oesophageal intraepithelial eosinophilia, increased mast cells, oesophageal remodelling and fibrosis. The current study provides evidence that IL 18 may induce iNKT cell activation to release the eosinophil-activating cytokine IL-5, as IL-5-deficient mice and iNKT cell-deficient (CD1d null) mice do not induce EoE in response to intranasal IL-18 challenge. Taken together, these findings provide evidence that allergen-induced IL-18 has a significant role in promoting IL-5- and iNKT-dependent EoE pathogenesis. PMID- 25801353 TI - Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice. AB - The objective of this study was to determine the extent to which a low level of trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) decreases adiposity and increases browning in overweight mice, its dependence on inflammatory signaling and potential synergistic effects of daily exercise. Young, Sv129 male mice were fed a high-fat diet for 5 weeks to make them fat and glucose intolerant and then switch them to a low-fat diet with or without 0.1% 10,12 CLA, sodium salicylate or exercise for another 7 weeks. 10,12 CLA decreased white adipose tissue (WAT) and brown adipose tissue mass, and increased the messenger RNA and protein levels, and activities of enzymes associated with thermogenesis or fatty acid oxidation in WAT. Mice fed 10,12 CLA had lower body temperatures compared to controls during cold exposure, which coincided with decreased adiposity. Although sodium salicylate decreased 10,12 CLA-mediated increases in markers of inflammation in WAT, it did not affect other outcomes. Exercise had no further effect on the outcomes measured. Collectively, these data indicate that 10,12 CLA mediated reduction of adiposity is independent of inflammatory signaling, and possibly due to up-regulation of fatty acid oxidation and heat production in order to regulate body temperature. Although this low level of 10,12 CLA reduced adiposity in overweight mice, hepatomegaly and inflammation are major health concerns. PMID- 25801355 TI - Visualization of Lymph/Blood Flow in Laparoscopic Colorectal Cancer Surgery by ICG Fluorescence Imaging (Lap-IGFI). AB - PURPOSE: In laparoscopic colorectal cancer (Lap-CRC) surgery, determination of a suitable mesentery division line and the appropriate degree of lymphadenectomy by tracing the blood supply is critical. We performed visualization of the lymph and blood flow by laparoscopic indocyanine green (ICG) fluorescence imaging (Lap IGFI). METHODS: ICG is injected into the submucosa near the tumor via colonoscopy, and the lymph flow is observed. Intestinal blood flow is evaluated by administering ICG intravenously. RESULTS: For lymph flow, visualization of the main lymph node basin helped to determine the surgical division line for cases in which the blood flow was not completely visualized. Lap-IGFI changed the surgical plan of the lymphadenectomy in 23.5 %. In our experience, the metastatic rate of ICG-positive nodes was 10.0 %, and the metastatic rate of ICG-negative nodes was 5.3 %. Furthermore, there were no metastatic nodes that were ICG negative more than 5 cm from the tumor. For blood flow, the blood flow distribution of the intestinal wall from the last branch of the vasa recta of the anastomotic site was clearly visualized and proved useful in choosing the extent of intestinal resection. Lap-IGFI changed the surgical plan of the extensive intestinal resection in 16.7 %. CONCLUSIONS: Lap-IGFI can noninvasively provide detailed lymph and blood flow information and is a useful device to aid in the accurate identification of individual patients' lymph drainage. This helps dictate adequate lymphadenectomy and the extent of intestinal resection in Lap-CRC surgery. PMID- 25801354 TI - Detection of Circulating Tumor Cells at Surgery and at Follow-Up Assessment to Predict Survival After Two-Stage Liver Resection of Colorectal Liver Metastases. AB - BACKGROUND: The presence of circulating tumor cells (CTCs) is negatively associated with survival after resection of colorectal liver metastases (CLM). The current study aimed to determine the prognostic value of CTCs and disseminated tumor cells (DTCs) at the time of surgery and the prognostic value of CTCs at follow-up assessment, for patients scheduled to undergo two-stage hepatectomy with portal vein embolization (PVE) for CLM. METHODS: Samples were collected at surgery (blood and bone marrow) and at follow-up assessment (blood) for the period 2008 through 2011. In this study, CTCs were detected with the CellSearch system, and DTCs were detected using standard immunocytochemical analysis. RESULTS: Of 24 patients, 18 completed both stages, and no patients were lost to follow-up. The median overall survival (OS) was 37 months, and the median recurrence-free survival (RFS) was 7 months. At surgery, CTCs were found in nine patients (38 %), and their presence was associated with reduced OS (p < 0.001) and RFS (p = 0.006). Follow-up CTC status was available for 11 patients. All eight patients with positive CTC status experienced recurrence. Two of three patients with negative CTC status remained recurrence free. In seven patients (32 %), DTCs were detected but were not associated with OS or RFS. CONCLUSIONS: The presence of CTCs at surgery is associated with worse OS and RFS for patients undergoing two-stage hepatectomy with PVE for CLM. Analysis of CTCs should be explored further for their potential to assist in treatment decisions and monitoring for CLM patients. PMID- 25801356 TI - Prognostic Nutritional Index (PNI) Predicts Tumor Recurrence of Very Early/Early Stage Hepatocellular Carcinoma After Surgical Resection. AB - BACKGROUND: Approximately one-quarter of patients with Barcelona Clinic Liver Cancer (BCLC) stage 0/A hepatocellular carcinoma (HCC) suffer from tumor relapse within the first year after surgical resection. Little data is available for inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), in predicting the clinical outcome of patients with very early/early stage HCC who underwent curative surgery. METHODS: A retrospective cohort study of 324 patients with BCLC stage 0/A primary HCC undergoing surgical resection was conducted to investigate the prognostic impacts of NLR, PLR, and PNI. RESULTS: The low-PNI group (<45) had an adverse overall survival (1-year survival rate of 92 vs. 97 %; 5-year survival rate of 57 vs. 82 %; p < 0.001) and disease-free survival (1-year survival rate of 69 vs. 85 %; 5-year survival rate of 39 vs. 63 %; p < 0.001). It was an independent predictor for disease-specific death, and early and late tumor relapses, with hazard ratios of 2.78 (p < 0.001), 1.82 (p = 0.011), and 2.55 (p = 0.013), respectively. Neither NLR nor PLR had any prognostic significance. CONCLUSIONS: The PNI is a significant prognostic factor for OS and DFS of patients with very early/early stage HCC receiving curative surgery. PMID- 25801357 TI - Secondary Cytoreduction in Platinum-Resistant Recurrent Ovarian Cancer: A Single Institution Experience. AB - BACKGROUND: The purpose of this study was to observe the role of secondary cytoreductive surgery in platinum-resistant recurrent ovarian cancer (OC) patients. METHODS: We collected data of patients affected by recurrent OC treated between 1995 and 2013. Inclusion criteria were: invasive epithelial OC histologically documented, cytoreductive surgery and platinum-based chemotherapy at first-line treatment with evidence of complete response to treatment, disease free interval <6 months, and no concomitant neoplasia. Patients considered susceptible of cytoreductive surgery (group A) were compared with a historical series of patients with similar characteristics but not eligible for surgery (group B). RESULTS: Of 122 platinum-resistant patients, 18 met the inclusion criteria for the study and were enrolled. They were compared with a historical series of 18 patients not surgically treated with analogous clinical and pathological features. The most frequent sites of relapse included pelvic and aortic lymph nodes (39 %), peritoneum (33 %), bowel (28 %), and pelvis (22 %). A low rate of intraoperative and postoperative complications was reported. No deaths were recorded. Overall survival was significantly longer in cytoreductive group when compared with the control group (P = 0.035). Median overall survival was 44 months. Estimated 5-year overall survival rates were 57 versus 23.5 % for groups A and B, respectively. CONCLUSIONS: Surgery could represent a useful adjunct to chemotherapy in the management of platinum-resistant recurrent OC patients, carefully selected, in highly selected centers. Larger prospective trials are needed to further confirm our experience. PMID- 25801359 TI - Molecular identification of Cryptosporidium isolates from exotic pet animals in Japan. AB - The Cryptosporidium horse genotype, a zoonotic protozoan parasite first found in a Prezewalski wild horse, has not been found in any other mammal but calves, horses, and humans. Hedgehogs, popular exotic pet animals in Japan, are a reservoir of two zoonotic Cryptosporidum: C. parvum and C. erinacei (previously known as the hedgehog genotype). Recently, after finding Cryptosporidium infection in a four-toed hedgehog (Atelerix albiventris), we identified the isolate genetically as the Cryptosporidium horse genotype. Its subtype (VIbA13) was the same as that of an isolate from a pet shop employee with severe clinical symptoms, as reported previously from sequencing analysis of the partial Cryptosporidum 60kDa glycoprotein gene sequence. The occurrence of this genotype in hedgehog indicates that the horse genotype has broad host specificity. This report is the first of a study identifying isolates from pet reptiles genetically in Japan. The study identified a new host (Teratoscincus scincus) in C. serpentis lizard genotype by sequencing analysis of partial SSU rRNA and actin genes. PMID- 25801360 TI - Pathological changes in cattle naturally infected by Calicophoron daubneyi adult flukes. AB - Local host response and parasite distribution were studied in the forestomachs, abomasum, duodenum and regional lymph nodes of cattle suffering from bovine paramphistomosis. The parasites were found attached, by its ventral sucker, to small conical papillae of the rumen and reticulum. Affected papillae, showed morphological changes denoted by very narrow stalks and expanded heads. Histologically, these changes were characterized by epithelial acanthosis hyperkeratosis of the epithelium. Infiltration of inflammatory cells was often related with the epithelial changes, although it was also found in the duodenal mucosa and submucosa. These cells were arranged as aggregates or follicles but sparse infiltration of eosinophils, globule leukocytes, mast cells or macrophages was also observed in the lamina propria. Tissue damage and inflammatory reaction were more severe in the ruminal atrium, where the largest number of flukes and affected papillae were observed. In contrast, lesions in the ruminal dorsal sac were absent or mild. Statistical correlation between lesion severity and parasite burden was confirmed. PMID- 25801358 TI - Detailed Analysis of Clinicopathologic Factors Demonstrate Distinct Difference in Outcome and Prognostic Factors Between Surgically Treated HPV-Positive and Negative Oropharyngeal Cancer. AB - BACKGROUND: Oropharyngeal cancers (OPC) secondary to human papillomavirus (HPV) infections likely represent a completely different disease compared with conventional head and neck cancers. Our objective was to analyze a surgically treated cohort to determine predictors of outcome in HPV-positive versus HPV negative patients. METHODS: HPV positivity was inferred based on p16 immunohistochemistry. Data was available for 201 patients with OPC treated with surgical resection with/without adjuvant radiotherapy between 1985 and 2005. Subsite distribution was: 66 (33 %) tonsil, 46 (23 %) soft palate, and 89 (44 %) tongue base. Patients were classified into low-, intermediate-, and high-risk groups based on p16 status and smoking history. Outcomes stratified by p16 status and risk groups were determined by the Kaplan-Meier method. Factors predictive of outcome were determined by univariate and multivariate analyses. RESULTS: In this cohort, 30 % had locally advanced disease (pT3/T4) and 71 % had nodal metastasis. The 5-year overall (OS), disease-specific, and recurrence-free survival rates were 60, 76, and 66 %, respectively. There were 22 % low-, 34 % intermediate-, and 44 % high-risk patients. Patients who were p16-positive had better survival compared with p16-negative (OS, 74 vs. 44 %; p < .001). Similarly, low-risk group patients had a better survival compared with intermediate- and high-risk groups (OS, 76, 68, 45 %, respectively, p < .001). Independent predictors of survival in p16-negative patients included margin status, lymphovascular invasion, pN status, and extracapsular spread. In contrast, none of these were predictive in p16 positive patients. CONCLUSIONS: Surgically treated patients with p16-positive OPC have superior survival compared with p16-negative patients. Outcomes in p16 positive and p16-negative OPC are determined by different prognostic factors supporting the notion that these are very different diseases. These should be incorporated into future clinical trials design. PMID- 25801361 TI - A tailored hand exercise program improves function of the rheumatoid hand. PMID- 25801362 TI - After-hours or weekend rehabilitation improves outcomes and increases physical activity but does not affect length of stay: a systematic review. AB - QUESTION: In adults undergoing inpatient rehabilitation, does additional after hours rehabilitation decrease length of stay and improve functional outcome, activities of daily living performance and physical activity? DESIGN: Systematic review with meta-analysis of randomised trials. PARTICIPANTS: Adults participating in an inpatient rehabilitation program. INTERVENTION: Additional rehabilitation provided after hours (evening or weekend). OUTCOME MEASURES: Function was measured with tests such as the Motor Assessment Scale, 10-m walk test, the Timed Up and Go test, and Berg Balance Scale. Performance on activities of daily living was measured with the Barthel index or the Functional Independence Measure. Length of stay was measured in days. Physical activity levels were measured as number of steps or time spent upright. Standardised mean differences (SMD) or mean differences (MD) were used to combine these outcomes. Adverse events were summarised using relative risks (RR). Study quality was assessed using PEDro scores. RESULTS: Seven trials were included in the review. All trials had strong methodological quality, scoring 8/10 on the PEDro scale. Among the measures of function, only balance showed a significant effect: the MD was 14 points better (95% CI 5 to 23) with additional after-hours rehabilitation on a 0-to-56-point scale. The improvement in activities of daily living performance with additional after-hours rehabilitation was of borderline statistical significance (SMD 0.10, 95% CI 0.00 to 0.21). Hospital length of stay did not differ significantly (MD -1.8 days, 95% CI -5.1 to 1.6). Those receiving additional rehabilitation had significantly higher step counts and spent significantly more time upright. Overall, the risk of adverse events was not increased by the provision of after-hours or weekend rehabilitation (RR 0.87, 95% CI 0.70 to 1.10). CONCLUSION: Additional after-hours rehabilitation can increase physical activity and may improve activities of daily living, but does not seem to affect the hospital length of stay. REVIEW REGISTRATION: PROSPERO CRD42014007648. [Scrivener K, Jones T, Schurr K, Graham PL, Dean CM (2015) After hours or weekend rehabilitation improves outcomes and increases physical activity but does not affect length of stay: a systematic review.Journal of Physiotherapy61: 61-67]. PMID- 25801363 TI - Primary-contact physiotherapists manage a minor trauma caseload in the emergency department without misdiagnoses or adverse events: an observational study. AB - QUESTIONS: What proportion of people who are managed by a primary-contact physiotherapy service in an emergency department experience adverse events? For people presenting to the emergency department with minor trauma, does the length of stay differ between those managed by the physiotherapy service and those managed by medical staff? For people presenting to the emergency department with minor trauma, is diagnostic imaging ordered as often by the physiotherapy service as it is by medical staff? DESIGN: Prospective, observational, cohort study. PARTICIPANTS: A consecutive sample of 1320 people presenting to an emergency department and managed by the physiotherapy service was analysed. Where possible, these patients were matched by diagnostic codes - typically for minor trauma including closed fractures of the periphery - to patients who were managed by medical staff in order to generate two matched cohorts for comparison. OUTCOME MEASURES: The outcome measures were adverse events among the patients managed by the physiotherapy service, the average length of stay of each cohort in the emergency department, and the proportion of patients in each cohort who underwent diagnostic imaging studies, including plain radiographs, computerised tomographic scans, and ultrasound imaging studies. RESULTS: No misdiagnoses or adverse events were identified for any patient managed by the physiotherapy service. The patients managed by the physiotherapy service had a significantly reduced length of stay (mean difference 83minutes, 95% CI 75 to 91) and significantly fewer requests for each type of imaging than the matched patients managed by medical staff. CONCLUSION: Primary-contact physiotherapists can manage a minor trauma caseload in the emergency department without adverse events. A physiotherapy service in the emergency department may result in a reduced length of stay and fewer requests for imaging. However, potential confounding of the results for length of stay and imaging must be recognised because matching diagnostic codes may not ensure completely equivalent cohorts. [Sutton M, Govier A, Prince S, Morphett M (2015) Primary-contact physiotherapists manage a minor trauma caseload in the emergency department without misdiagnoses or adverse events: an observational study.Journal of Physiotherapy61: 77-80]. PMID- 25801364 TI - Knee osteoarthritis. PMID- 25801365 TI - Physiotherapy students and clinical educators perceive several ways in which incorporating peer-assisted learning could improve clinical placements: a qualitative study. AB - QUESTION: What are the experiences of students and clinical educators in a paired student placement model incorporating facilitated peer-assisted learning (PAL) activities, compared to a traditional paired teaching approach? DESIGN: Qualitative study utilising focus groups. PARTICIPANTS: Twenty-four physiotherapy students and 12 clinical educators. INTERVENTION: Participants in this study had experienced two models of physiotherapy clinical undergraduate education: a traditional paired model (usual clinical supervision and learning activities led by clinical educators supervising pairs of students) and a PAL model (a standardised series of learning activities undertaken by student pairs and clinical educators to facilitate peer interaction using guided strategies). RESULTS: Peer-assisted learning appears to reduce the students' anxiety, enhance their sense of safety in the learning environment, reduce educator burden, maximise the use of downtime, and build professional skills including collaboration and feedback. While PAL adds to the clinical learning experience, it is not considered to be a substitute for observation of the clinical educator, expert feedback and guidance, or hands-on immersive learning activities. Cohesion of the student-student relationship was seen as an enabler of successful PAL. CONCLUSION: Students and educators perceive that PAL can help to position students as active learners through reduced dependence on the clinical educator, heightened roles in observing practice, and making and communicating evaluative judgments about quality of practice. The role of the clinical educator is not diminished with PAL, but rather is central in designing flexible and meaningful peer-based experiences and in balancing PAL with independent learning opportunities. REGISTRATION: ACTRN12610000859088. [Sevenhuysen S, Farlie MK, Keating JL, Haines TP, Molloy E (2015) Physiotherapy students and clinical educators perceive several ways in which incorporating peer-assisted learning could improve clinical placements: a qualitative study.Journal of Physiotherapy61: 87-92]. PMID- 25801366 TI - Evaluation of observational research reports published in Turkish nursing journals. AB - AIM: The aim of this literature-based descriptive study was to examine the reporting of the observational research studies published in peer-reviewed nursing journals in Turkey. METHODS: Eleven peer-reviewed nursing journals printed on a regular basis in Turkey between 2007 and 2012 were selected. These journals were searched for observational research studies, and 502 studies were selected and examined by using the Strengthening the Reporting of Observational Studies in Epidemiology Statement. RESULTS: Of the 502 studies, 495 were cross sectional, 3 were cohort, and 4 were case controlled. Summary and introduction and aim sections were sufficient in most of the studies. The methods sections of the reports were mostly not reported: 64.3% of the reports did not indicate eligibility/inclusion criteria; sampling method, 67.0%; possible sources of bias, 99.2%; ways to reach sample size, 92.6%. In the results section, the number of individuals participating in each stage of the studies (44.0%) and in other analyses made (39.2%) was not reported. In the discussion section, a main comment about research findings was partly made (97.4%), and limitations of the studies and possible sources of bias were not written in 99.0% of the studies. CONCLUSIONS: This study clearly revealed that the observational research studies published in nursing journals in Turkey did not fulfil the important criteria and needed to be improved. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Information obtained from this study can contribute to improvement of the quality of reporting observational studies in nursing and thus using obtained findings in practice. PMID- 25801367 TI - Element concentrations in urban grass cuttings from roadside verges in the face of energy recovery. AB - Grass from municipal roadside verges is a potential yet largely unused resource for bioenergy recovery, which is mainly due to its unknown elemental composition. Therefore, we measured the concentration of 16 elements (Ca, K, Mg, N, Na, P, S, Al, Cd, Cl, Cr, Cu, Mn, Pb, Si and Zn) in a material from the city of Kassel harvested in different management intensities. The element concentrations were mainly close to reference values of agricultural or nature conservation grassland and usually within the range of literature data. Concentrations of most elements, including heavy metals, were below limiting values. Only N and Cl concentrations in the raw material exceeded the limiting values for combustion, but washing and dewatering of the biomass with the "integrated generation of solid fuel and biogas from biomass" technique resulted in concentrations in the press cake well below the limiting values. Considering the element concentrations of grass from urban roadside verges, utilisation for energy recovery may be possible, provided an appropriate technology is applied. PMID- 25801368 TI - Using synthetic models to simulate aging of Cu contamination in soils. AB - The Bureau Commun de Reference (BCR) sequential extraction scheme and micro synchrotron-based X-ray fluorescence (MU-SXRF) analysis were used to determine the Cu fractionation in a calcareous vineyard soil and a synthetic soil (mixture of seven constituents: calcite, birnessite, ferrihydrite, goethite, lignocellulosic residue, kaolinite, and quartz) at different Cu contamination rates (190, 1270, and 6350 mg kg(-1) of Cu) and aging times (1, 30, 92, and 181 days). The Cu distribution in the spiked vineyard and synthetic soils was different from the original vineyard one and was influenced by the loading level. The newly added Cu was preferentially present in the acid soluble fraction. Aging of the contaminated vineyard and synthetic soils during 6 months led to the redistribution of Cu from the weakly bound acid soluble fraction to the strongly bound reducible one. The evolution with time could satisfactorily be simulated by the Elovich diffusion model for the synthetic soils. It was less significant as less marked in the contaminated vineyard soil than in the synthetic one, even though the trends observed in both were similar. This study supported the hypothesis that "simple" synthetic models could be used to approach the Cu fractionation and its evolution with time in vineyard soils. PMID- 25801369 TI - Nontarget effects of chemical pesticides and biological pesticide on rhizospheric microbial community structure and function in Vigna radiata. AB - Intensive agriculture has resulted in an indiscriminate use of pesticides, which demands in-depth analysis of their impact on indigenous rhizospheric microbial community structure and function. Hence, the objective of the present work was to study the impact of two chemical pesticides (chlorpyrifos and cypermethrin) and one biological pesticide (azadirachtin) at two dosages on the microbial community structure using cultivation-dependent approach and on rhizospheric bacterial communities involved in nitrogen cycle in Vigna radiata rhizosphere through cultivation-independent technique of real-time PCR. Cultivation-dependent study highlighted the adverse effects of both chemical pesticide and biopesticide on rhizospheric bacterial and fungal communities at different plant growth stages. Also, an adverse effect on number of genes and transcripts of nifH (nitrogen fixation); amoA (nitrification); and narG, nirK, and nirS (denitrification) was observed. The results from the present study highlighted two points, firstly that nontarget effects of pesticides are significantly detrimental to soil microflora, and despite being of biological origin, azadirachtin exerted negative impact on rhizospheric microbial community of V. radiata behaving similar to chemical pesticides. Hence, such nontarget effects of chemical pesticide and biopesticide in plants' rhizosphere, which bring out the larger picture in terms of their ecotoxicological effect, demand a proper risk assessment before application of pesticides as agricultural amendments. PMID- 25801370 TI - Mercury transfer from soil to olive trees. A comparison of three different contaminated sites. AB - Mercury contents in soil and olive tree leaves have been studied in 69 plots around three different source areas of this element in Spain: Almaden (Ciudad Real), Flix (Tarragona) and Jodar (Jaen). Almaden was the world's largest cinnabar (HgS) mining district and was active until 2003, Flix is the oldest Spanish chlor-alkali plant (CAP) and has been active from 1898 to the present day and Jodar is a decommissioned CAP that was active for 14 years (1977-1991). Total mercury contents have been measured by high-frequency modulation atomic absorption spectrometry with Zeeman effect (ZAAS-HFM) in the soils and olive tree leaves from the three studied areas. The average soil contents range from 182 MUg kg(-1) in Flix to 23,488 MUg kg(-1) in Almaden, while the average leaf content ranges from 161 MUg kg(-1) in Jodar to 1213 MUg kg(-1) in Almaden. Despite the wide range of data, a relationship between soil-leaf contents has been identified: in Almaden and Jodar, multiplicative (bilogarithmic) models show significant correlations (R = 0.769 and R = 0.484, respectively). Significant correlations were not identified between soil and leaf contents in Flix. The continuous activity of the Flix CAP, which remains open today, can explain the different uptake patterns for mercury, which is mainly atmospheric in origin, in comparison to the other two sites, where activity ceased more than 10 years ago and only soil uptake patterns based on the Michaelis-Menten enzymatic model curve are observed. PMID- 25801371 TI - Biofouling of marbles by oxygenic photosynthetic microorganisms. AB - Phototrophic microorganisms disfigure the surfaces of different types of stone. Stone structure is damaged by the activity of photoautotrophic and other microorganisms. However, to date few, investigations have been undertaken into the relationship between microorganisms and the properties of different types of marble. In this study, biological activity of photoautotrophic microorganisms on three types of marble (Yatagan White, Giallo Anticato and Afyon White) was investigated under laboratory conditions over a short period of time. The three types of marble supported the growth of phototrophic microbial communities on their outer and inner layers, turning their original colour from white to a yellowish green colour. The porosity of the marble types facilitated filamentous microbial growth in the presence of water. Scanning electron microscope analysis revealed the accumulation of aggregates such as small spherical, fibrillar, calcified globular bodies on the inner surfaces of the marbles. This suggests that the microscopic characteristics of particular marble types may stimulate the growth of certain types of microorganisms. PMID- 25801373 TI - Characterization Of Novel Composite Alginate Chitosan-Carrageenan Nanoparticles For Encapsulation Of Bsa As A Model Drug Delivery System. AB - The objective of this research project was to develop a nanoparticle drug delivery system using the biopolymer chitosan as the base component. The nanoparticles were produced through ionotropic gelation by flush mixing chitosan with counterions carrageenan and alginate. The nanoparticles were generated under a range of conditions to determine the effect of pH, chitosan concentration, carrageenan concentration, and alginate concentration on the nanoparticle characteristics of particle diameter, zeta potential, and particle size distribution. The encapsulation and controlled release of BSA from chitosan nanoparticles was also evaluated. The encapsulation of BSA was used as a model system for the controlled drug delivery from composite nanoparticles. The release profile indicated an initial burst in the first few hours of the trial, followed by a slower steady release over time. According to Korsmeyer-Peppas model, the release profile followed fickian diffusion. PMID- 25801372 TI - Estimated human excretion rates of natural estrogens calculated from their concentrations in raw municipal wastewater and its application. AB - Natural estrogens are important endocrine disrupting compounds (EDCs), which may pose adverse effects on our environment. To avoid time-consuming sample preparation and chemical analysis, estimation of their concentrations in municipal wastewater based on their human urine/feces excretion rates has been generally adopted. However, the data of excretion rates available are very limited and show significant difference among countries. In the context of increasing reporting on the concentrations of natural estrogens in municipal wastewater around the world, this study presented a simple method to estimate their human excretion rates based on the concentrations of natural estrogens in raw sewage. The estimated human excretion rates of natural estrogens among ten countries were obtained, which totally covered over 33 million population. Among these, Brazilians had the largest excretion rates with estrone (E1) and 17beta estradiol (E2) as 236.9 and 60 MUg/day/P, respectively, while Iran had the lowest value of 2 MUg/day/P for E1 and 0.5 MUg/day/P for E2. The average estimated human excretion rates of E1, E2, and estriol (E3) are 17.3, 6.4, and 39.7 MUg/day/P, respectively. When the estimated human excretion rates obtained were applied for prediction, the predicted results showed better accuracies than those based on human urinary/feces excretion rates. The method in this study is simple, cost effective and time-saving, which may be widely applied. PMID- 25801375 TI - [Indications and limitations for colloids in interventions and surgery]. AB - BACKGROUND: Over the last few decades colloids have played an important part in the stabilisation of patients with acute need of intravascular volume replacement. After the 6S and the CHEST trials were published in 2012 and the subsequent recommendations of the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) there has been some uncertainty about the current clinical relevance and routine use of colloids. OBJECTIVES: This article summarizes the current evidence and relevance of colloids in the perioperative environment and in the interventional setting on the basis of the recently published German S3-guidelines for volume therapy in adults. RESULTS: In situations of acute volume resuscitation colloids are still appropriate. Only colloids in balanced solutions should be used. Possible side effects, contraindications and the maximum daily dose have to be taken into consideration when administering colloids. PMID- 25801374 TI - [Successful hemodialysis for life-threatening carbamazepine drug overdose: Case based introduction of new guidelines]. AB - BACKGROUND: Over the last decade, there has been a paradigm shift in the extracorporeal treatment of intoxications. The availability of new treatment options, especially new membranes has led to a decrease in the use of techniques like charcoal hemoperfusion, once considered the gold standard to eliminate highly protein bound substances. EXTRIP GUIDELINES: The EXtracorporeal Treatments In Poisoning (EXTRIP) workgroup is a collaborative international effort of pharmacologists, toxicologists, critical care physicians, and nephrologists that is reviewing all available evidence in extracorporeal procedures for the treatment of poisonings in a standardized way to distill treatment recommendations for the physician at the bedside. One of the first available EXTRIP guidelines summarizes treatment recommendations for severe carbamazepine intoxications. CASE REPORT: We report the case of a 43-year-old Caucasian woman with who ingested about 21 g carbamazepine in a suicidal attempt together with alcohol. Combining gastroscopic removal of carbamazepine and multiple dose activated charcoal with intermittent high-flux hemodialysis lowered the initial carbamazepine level of 56.5 mg/l (47 mg/l before dialysis) to 25 mg/l. The patient, who initially required mechanical ventilation could be transferred to the psychiatric ward 24 h after ICU admission. PMID- 25801377 TI - Pediatric Nurse Practitioner Management of Child Anxiety in a Rural Primary Care Clinic With the Evidence-Based COPE Program. AB - INTRODUCTION: Anxiety is the most common mental health disorder in children. Many communities have shortages of mental health providers, and the majority of children with anxiety are not receiving the evidence-based treatment they need. The purpose of this pilot study was to assess the feasibility and effects of a brief seven-session cognitive behavioral skills-building intervention, Creating Opportunities for Personal Empowerment (COPE), which was delivered to anxious children by a pediatric nurse practitioner in a primary care setting. METHODS: A pre-experimental, one-group, pretest and post-test design was used. RESULTS: Children who participated had a significant decrease in anxiety symptoms (13.88 points, SD = 17.96, 95% confidence interval [CI] = -1.13-28.89), as well as an increase in knowledge of cognitive-behavioral coping skills (M = 11.38, CI = 5.99 8.26, p = .00) and improved functioning (at school and at home). Evaluations by parents and children were positive. DISCUSSION: COPE is a promising evidence based intervention for children with anxiety with feasible delivery by pediatric nurse practitioners in primary care. PMID- 25801378 TI - [Validity and applicability of a new method for recording blood pressure]. PMID- 25801376 TI - [Therapeutic hypothermia in 2015 : Influence of the TTM study on the intensive care procedure after cardiac arrest]. AB - BACKGROUND: In the 1960s, Peter Safar et al. postulated the benefit of postcardiac arrest hypothermia after successful cardiopulmonary resuscitation (CPR). However, therapeutic hypothermia postCPR did not become a standard procedure until the first few years of the new millennium. Various noninvasive and invasive cooling methods are available. Generally, more invasive cooling methods are more effective-but also tend to involve more complications. Furthermore, invasive measures need more time and thus may be instituted late in the postCPR process, delaying the cooling efforts in the initial phase. There is ongoing controversy about when best to commence cooling. CURRENT SITUATION: Recent studies of initial out-of-hospital cooling did not show any benefit for the patients compared to starting cooling in the hospital. The exact target temperature is the subject of multiple ongoing discussions. A recent study showed no disadvantage of cooling to 36 C compared to 33 C, which is in the widely accepted standard target temperature range of 32-34 C. Nevertheless, cooling to 32-34 C according to the 2010 guidelines is still the accepted standard procedure unless and until new studies generate more evidence. The European Resuscitation Council has given advance notice of a statement on the optimal target temperature in the near future. Finally, large registry studies have demonstrated the benefit of combining postCPR hypothermia with early percutaneous cardiac interventions (PCI) in acute coronary syndromes, which are often a cause of cardiac arrest. OUTLOOK: Transport of patients after CPR to specialized postcardiac arrest centres with the possibility of acute PCI and cooling, comparable to the transfer of multiple trauma patients to trauma centres, may be beneficial. PMID- 25801379 TI - Deimination level and peptidyl arginine deiminase 2 expression are elevated in astrocytes with increased incubation temperature. AB - Astrocytes respond to environmental cues, including changes in temperatures. Increased deimination, observed in many progressive neurological diseases, is thought to be contributed by astrocytes. We determined the level of deimination and expression of peptidyl arginine deiminase 2 (PAD2) in isolated primary astrocytes in response to changes on either side (31 degrees C and 41 degrees C) of the optimal temperature (37 degrees C). We investigated changes in the astrocytes by using a number of established markers and accounted for cell death with the CellTiter-Blue assay. We found increased expression of glial fibrillary acidic protein, ALDH1L1, and J1-31, resulting from increased incubation temperature and increased expression of TSP1, S100beta, and AQP4, resulting from decreased incubation temperature vs. optimal temperature, suggesting activation of different biochemical pathways in astrocytes associated with different incubation temperatures. Mass spectrometric analyses support such trends. The PAD2 level was increased only as a result of increased incubation temperature with a commensurate increased level of deimination. Actin cytoskeleton and iso[4]LGE, a lipid peroxidase modification, also showed an increase with higher incubation temperature. Altogether, these results suggest that temperature, as an environmental cue, activates astrocytes in a different manner on either side of the optimal temperature and that increase in deimination is associated only with the higher temperature side of the spectrum. PMID- 25801380 TI - "Benign hypermobility"-hyperlax Ehlers-Danlos syndrome. Other comorbidities. PMID- 25801381 TI - Analytical method development for the determination of emerging contaminants in water using supercritical-fluid chromatography coupled with diode-array detection. AB - An analytical method using supercritical-fluid chromatography coupled with diode array detection for the determination of seven emerging contaminants-two pharmaceuticals (carbamazepine and glyburide), three endocrine disruptors (17alpha-ethinyl estradiol, bisphenol A, and 17beta-estradiol), one bactericide (triclosan), and one pesticide (diuron)-was developed and validated. These contaminants were chosen because of their frequency of use and their toxic effects on both humans and the environment. The optimized chromatographic separation on a Viridis BEH 2-EP column achieved baseline resolution for all compounds in less than 10 min. This separation was applied to environmental water samples after sample preparation. The optimized sample treatment involved a preconcentration step by means of solid-phase extraction using C18-OH cartridges. The proposed method was validated, finding recoveries higher than 94 % and limits of detection and limits of quantification in the range of 0.10-1.59 MUg L(-1) and 0.31-4.83 MUg L(-1), respectively. Method validation established the proposed method to be selective, linear, accurate, and precise. Finally, the method was successfully applied to environmental water samples. PMID- 25801382 TI - Determination of lipid content of oleaginous microalgal biomass by NMR spectroscopic and GC-MS techniques. AB - Direct methods based on (1)H NMR spectroscopic techniques have been developed for the determination of neutral lipids (triglycerides and free fatty acids) and polar lipids (glyceroglycolipids/phospholipids) in the solvent extracts of oleaginous microalgal biomasses cultivated on a laboratory scale with two species in different media. The chemical shift assignments observed in the (1)H and (13)C NMR spectra corresponding to unsaturated (C18:N, N = 1-3, C20:3, C20:5, C22:6, epoxy) and saturated (C14-C18) fatty acid ester components in a complex matrix involving overlapped resonances have been unambiguously confirmed by the application of 2D NMR spectroscopy (total correlation spectroscopy and heteronuclear single quantum coherence-total correlation spectroscopy). The study of the effect of a polar lipid matrix on the determination of neutral lipids by an internal reference blending process by a systematic designed experimental protocol has provided absolute quantification. The fatty acid composition of algal extracts was found to be similar to that of vegetable oils containing saturated (C16-C18:0) and unsaturated (C18:N, N = 1-3, C20:N, N = 3-4, C22:6) fatty acids as confirmed by NMR spectroscopy and gas chromatography-mass spectrometry analyses. The NMR methods developed offer great potential for rapid screening of algal strains for generation of algal biomass with the desired lipid content, quality, and potential for biodiesel and value-added polyunsaturated fatty acids in view of the cost economics of the overall cost of generation of the biomass. PMID- 25801384 TI - Inulin supplementation during gestation mitigates acrylamide-induced maternal and fetal brain oxidative dysfunctions and neurotoxicity in rats. AB - Accumulating evidence suggests that the developing brain is more susceptible to a variety of chemicals. Recent studies have shown a link between the enteric microbiota and brain function. While supplementation of non-digestible oligosaccharides during pregnancy has been demonstrated to positively influence human health mediated through stimulation of beneficial microbiota, our understanding on their neuromodulatory propensity is limited. In the present study, our primary focus was to examine whether supplementation of inulin (a well known fructan) during gestation can abrogate acrylamide (ACR)-induced oxidative impairments and neurotoxicity in maternal and fetal brain of rats. Initially, in a dose-determinative study, we recapitulated the impact of ACR exposure during gestation days (GD 6-19) on gestational parameters, extent of oxidative impairments in brain (maternal/fetal), cholinergic function and neurotoxicity. Subsequently, pregnant rats orally (gavage) administered with inulin (IN, 2 g/kg/day in two equal installments) supplements during gestation days (GD 0-19) were exposed to ACR (200 ppm) in drinking water. IN supplements significantly attenuated ACR-induced changes in exploratory activity (reduced open field exploration) measured on GD 14. Further, IN restored the placental weights among ACR exposed dams. Analysis of biochemical markers revealed that IN supplements effectively offset ACR associated oxidative stress not only in the maternal brain, but in the fetal brain as well. Elevated levels of protein carbonyls in maternal brain regions were completely normalized with IN supplements. More importantly, IN supplements significantly augmented the number of Bifidobacteria in the cecum of ACR rats which correlated well with the neurorestorative effect as evidenced by restored dopamine levels in the maternal cortex and fetal brain acetylcholinesterase activity among ACR-exposed dams. Further, IN supplements also conferred significant protection against mitochondrial dysfunction induced by ACR in both milieus. Although the precise mechanism/s by which IN supplements during pregnancy attenuate ACR induced neurotoxic impact merits further investigations, we hypothesize that it may mediate through enhanced enteric microbiota and abrogation of oxidative stress. Further, our study provides an experimental approach to explore the neuroprotective role of prebiotic oligosaccharides during pregnancy in reducing the adverse impact of developmental neurotoxicants. PMID- 25801383 TI - Post-polymerization photografting on methacrylate-based monoliths for separation of intact proteins and protein digests with comprehensive two-dimensional liquid chromatography hyphenated with high-resolution mass spectrometry. AB - Post-polymerization photografting is a versatile tool to alter the surface chemistry of organic-based monoliths so as to obtain desired stationary phase properties. In this study, 2-acrylamido-2-methyl-1-propanesulfonic acid was grafted to a hydrophobic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) monolith to create a strong cation exchange stationary phase. Both single-step and two-step photografting were addressed, and the effects of grafting conditions were assessed. An experimental design has been applied in an attempt to optimize three of the key parameters of the two-step photografting chemistry, i.e. the grafting time of the initiator, the monomer concentration and the monomer irradiation time. The photografted columns were implemented in a comprehensive two-dimensional column liquid chromatography ( (t) LC * (t) LC) workflow and applied for the separation of intact proteins and peptides. A baseline separation of 11 intact proteins was obtained within 20 min by implementing a gradient across a limited RP composition window in the second dimension. (t) LC * (t) LC with UV detection was used for the separation of cytochrome c digest, bovine serum insulin digest and a digest of a complex protein mixture. A semi-quantitative estimation of the occupation of separation space, the orthogonality, of the (t) LC * (t) LC system yielded 75%. The (t) LC * (t) LC setup was hyphenated to a high-resolution Fourier transform ion cyclotron resonance mass spectrometer instrument to identify the bovine serum insulin tryptic peptides and to demonstrate the compatibility with MS analysis. PMID- 25801386 TI - Temporal dynamics of PARK2/parkin and OPTN/optineurin recruitment during the mitophagy of damaged mitochondria. AB - Damaged mitochondria are selectively degraded via autophagy in a regulated pathway known as mitophagy. Parkinson disease-linked proteins PINK1 (PTEN induced putative kinase 1) and PARK2 (parkin RBR E3 ubiquitin protein ligase) are recruited to the outer mitochondrial membrane upon mitochondrial damage, leading to the PARK2-mediated ubiquitination of mitochondrial proteins. Here, we discuss our recent work demonstrating that OPTN (optineurin) is recruited to damaged mitochondria, serving as an autophagy receptor for autophagosome formation around mitochondria. Using high-resolution live-cell imaging, we find that OPTN is recruited to ubiquitinated mitochondria downstream of PARK2, and induces autophagosome assembly around mitochondria via its LC3-interacting region. Mutations in OPTN are linked to both glaucoma and ALS (amyotrophic lateral sclerosis), and an ALS-associated E478G mutation in OPTN's ubiquitin binding domain leads to defective mitophagy and accumulation of damaged mitochondria. Importantly, our results highlight a role for mitophagy defects in ALS pathogenesis, and demonstrate that defects in the same pathway for mitochondrial homeostasis are causal for both familial Parkinson disease and ALS. PMID- 25801385 TI - Vibration inhibits deterioration in rat deep-tissue injury through HIF1-MMP axis. AB - Deep-tissue injury (DTI) is a unique type of pressure ulcer (PU) in which deep tissue damage expands outwards to the superficial skin. DTI progresses rapidly into a severe PU, despite initially appearing as only a bruise or darkened tissue in the superficial skin. Although some DTI detection methods are available, there is currently no strategy for treating deteriorating DTI. This study investigated the efficacy of vibration therapy for preventing DTI deterioration through down regulation of the hypoxia-inducible factor-1 matrix metalloproteinase (MMP) axis in rats. We prepared a conventional PU rat model (PU group) and a DTI deterioration rat model (DTI group). The DTI group was further divided into two groups subjected to vibration and control treatments, respectively. Macroscopic and histological features, hypoxia, oxidative stress, apoptosis, and MMP2 and MMP9 activities in compressed skin were analyzed. Hypoxia, oxidative stress, and MMP activity were enhanced in the DTI group compared with the PU group. Vibration remarkably inhibited DTI deterioration, hypoxia, and the expression/activities of MMP2 and MMP9. These results suggest that vibration therapy can effectively attenuate deterioration of DTI. This report provides the first evidence for a therapeutic treatment for deteriorating DTI. PMID- 25801388 TI - Intradural cement leakage after vertebroplasty. PMID- 25801387 TI - Fibrous dysplasia mimicking vertebral bone metastasis on 18F-FDG PET/computed tomography in a patient with tongue cancer. PMID- 25801390 TI - Foraminal decompression of acute calcified disc herniation in an adult. PMID- 25801389 TI - Does elevated osteopontin level play an important role in the development of scoliosis in bipedal mice? AB - BACKGROUND CONTEXT: Previous studies implied indirectly that an elevated osteopontin (OPN) level might play a key role in the pathomechanism of adolescent idiopathic scoliosis. Nonetheless, up to now, no direct evidence was proposed to determine this issue. PURPOSE: The aim was to determine the role of OPN in the pathomechanism of scoliosis. STUDY DESIGN: This was an experimental study to investigate the role of OPN in a bipedal mouse scoliosis model. METHODS: All procedures were performed under the approval and supervision of the Institutional Animal Care and Use Committee of our university. A new bipedal mouse model with elevated OPN level was established in this study. Amputation of forelimbs and tail was performed on 80 male C3H/HeJ mice at the age of 3 weeks. Then, these mice were randomly divided into two groups: Group A consisted of 40 mice treated with OPN 40 mg/kg daily and Group B consisted of the remaining 40 mice treated with saline. Then, 40 quadruped mice with saline were included in Group C. Body length, X-rays, and computed tomographic scans were obtained at the twentieth week. Then, scoliosis incidence, curve magnitude, and circulating OPN level were compared among groups. RESULTS: Osteopontin level was significantly higher in Group A compared with that in Groups B and C. Spine deformity was identified in 37 mice in Group A, 21 mice in Group B, and 5 mice in Group C. The average Cobb angle was 29.8 degrees in Group A, 20.9 degrees in Group B, and 17.5 degrees in Group C. Although no significant difference of body length was found, significant statistical difference was noted in terms of scoliosis incidence and curve magnitude, among the three groups. CONCLUSIONS: The results of the present study indicated that the elevated OPN level might play an important role in the etiopathogenesis of scoliosis, that is, it not only raises the risk for scoliosis in bipedal mice but also contributes to curve progression. PMID- 25801391 TI - Inferior thyroid arterial injury after percutaneous cervical nucleoplasty. PMID- 25801394 TI - Physics gets its hands dirty. PMID- 25801392 TI - Reprogramming of orientation columns in visual cortex: a domino effect. AB - Cortical organization rests upon the fundamental principle that neurons sharing similar properties are co-located. In the visual cortex, neurons are organized into orientation columns. In a column, most neurons respond optimally to the same axis of an oriented edge, that is, the preferred orientation. This orientation selectivity is believed to be absolute in adulthood. However, in a fully mature brain, it has been established that neurons change their selectivity following sensory experience or visual adaptation. Here, we show that after applying an adapter away from the tested cells, neurons whose receptive fields were located remotely from the adapted site also exhibit a novel selectivity in spite of the fact that they were not adapted. These results indicate a robust reconfiguration and remapping of the orientation domains with respect to each other thus removing the possibility of an orientation hole in the new hypercolumn. These data suggest that orientation columns transcend anatomy, and are almost strictly functionally dynamic. PMID- 25801393 TI - Site-specific dynamics of amyloid formation and fibrillar configuration of Abeta(1-23) using an unnatural amino acid. AB - We identify distinct site-specific dynamics over the time course of Abeta1-23 amyloid formation by using an unnatural amino acid, p-cyanophenylalanine, as a sensitive fluorescent and Raman probe. Our results also suggest the key role of an edge-to-face aromatic interaction in the conformational conversion to form and stabilize beta-sheet structure. PMID- 25801400 TI - Water-based metamaterials: Negative refraction of sound. PMID- 25801401 TI - Van der Waals heterostructures: Mid-infrared nanophotonics. PMID- 25801402 TI - Origami: Folding creases through bending. PMID- 25801403 TI - Colloidal self-assembly: Programmable competitive binding. PMID- 25801404 TI - Biomineralization: Ion binding and nucleation. PMID- 25801405 TI - Material witness: The Turing touch test. PMID- 25801406 TI - Corrigendum: Gated three-terminal device architecture to eliminate persistent photoconductivity in oxide semiconductor photosensor arrays. PMID- 25801407 TI - Determinants of healthcare utilisation and predictors of outcome in colorectal cancer patients from Northern Iran. AB - We aimed to assess healthcare utilisation (HU), its determinants, as well as its relationship with survival in colorectal cancer (CRC) patients. This study was conducted on incident CRC cases from Northern Iran. Information on HU was collected using a valid questionnaire, considering eight diagnostic and four therapeutic services. The results were categorised as good and poor HU. Multivariate logistic regression analysis was used to assess the relationship between HU and other variables. Cox regression analysis was performed to determine major predictors of survival. In total, 227 new cases of CRC were enrolled. HU could be assessed in 218 subjects (96%). Living in rural areas was the strongest variable related to poor HU (adjusted OR, odds ratio = 2.65; CI, confidence interval: 1.30-5.40). The median survival time was 40.5 months. The 1 , 3- and 5-year survival rates were 71%, 52% and 44% respectively. Cox regression analysis showed a significant lower survival rate in patients with poor HU (HR = 2.3; CI: 1.46-3.64). HU was an independent predictor of survival in our CRC patients. Patients' place of residence was a significant determinant of HU. Regarding its effects on patients' outcome, HU and its determinants should be considered in designing CRC controlling programmes in our region and similar high risk populations. PMID- 25801408 TI - Twenty-four-hour heart rate lowering with ivabradine in chronic heart failure: insights from the SHIFT Holter substudy. AB - AIMS: Analysis of 24-h Holter recordings was a pre-specified substudy of SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) for exploring the heart rhythm safety of ivabradine and to determine effects of ivabradine on 24-h, daytime, and night-time heart rate (HR) compared with resting office HR. METHODS AND RESULTS: The 24-h Holter monitoring was performed at baseline and 8 months after randomization to ivabradine (n = 298) or matching placebo (n = 304) titrated maximally to 7.5 mg b.i.d. in patients with baseline HR >=70 b.p.m. Patients received guideline-based optimized heart failure therapy including ACE inhibitors and/or ARBs in 93% and beta-blockers at maximally tolerated doses in 93%. After 8 months, HR over 24 h decreased by 9.5 +/- 10.0 b.p.m. with ivabradine, from 75.4 +/- 10.3 b.p.m. (P < 0.0001), and by 1.2 +/- 8.9 b.p.m. with placebo, from 74.8 +/- 9.7 b.p.m. (P < 0.0001 for difference vs. ivabradine). HR reduction with ivabradine was similar in resting office and in 24 h, awake, and asleep recordings, with beneficial effects on HR variability and no meaningful increases in supraventricular or ventricular arrhythmias. At 8 months, 21.3% on ivabradine vs. 8.5% on placebo had >=1 episode of HR <40 b.p.m. (P < 0.0001). No episode of HR <30 b.p.m. was recorded; 3 (1.2%) patients had RR intervals >2.5 s on ivabradine vs. 4 (1.6%) patients on placebo. No RR intervals >3 s were identified in patients taking ivabradine. CONCLUSION: Ivabradine safely and significantly lowers HR and improves HR variability in patients with systolic heart failure, without inducing significant bradycardia, ventricular arrhythmias, or supraventricular arrhythmias. PMID- 25801409 TI - Epigenetic study identifies genes linked to asthma and allergy. PMID- 25801410 TI - Tackling childhood tuberculosis in Uganda. PMID- 25801411 TI - India revokes patent for COPD drug. PMID- 25801412 TI - Targeting of MEK in lung cancer therapeutics. AB - The MAP-kinase pathway, consisting of the kinases RAS, RAF, MEK, and ERK, is crucial for cell proliferation, inhibition of apoptosis, and migration of cells. Direct inhibition of RAS is not yet possible, whereas inhibition of RAF is already established in malignant melanoma and under investigation in non-small cell lung cancer (NSCLC). Due to their structure and function, the MEK proteins are attractive targets for cancer therapy and are also under investigation in NSCLC. We discuss strategies of targeting the RAS-RAF-MEK-ERK pathway with emphasis on MEK inhibition, either alone or in combination with other targets or conventional chemotherapy. PMID- 25801413 TI - Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. AB - BACKGROUND: Eosinophilic airway inflammation is associated with increased corticosteroid responsiveness in asthma, but direct airway sampling methods are invasive or laborious. Minimally invasive markers for airway eosinophilia could present an alternative method, but estimates of their accuracy vary. METHODS: We did a systematic review and searched Medline, Embase, and PubMed for studies assessing the diagnostic accuracy of markers against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy in patients with asthma or suspected asthma (for inception to Aug 1, 2014). Unpublished results were obtained by contacting authors of studies that did not report on diagnostic accuracy, but had data from which estimates could be calculated. We assessed risk of bias with QUADAS-2. We used meta-analysis to produce summary estimates of accuracy. FINDINGS: We included 32 studies: 24 in adults and eight in children. Of these, 26 (81%) showed risk of bias in at least one domain. In adults, three markers had extensively been investigated: fraction of exhaled nitric oxide (FeNO) (17 studies; 3216 patients; summary area under the receiver operator curve [AUC] 0.75 [95% CI 0.72-0.78]); blood eosinophils (14 studies; 2405 patients; 0.78 [0.74-0.82]); total IgE (seven studies; 942 patients; 0.65 [0.61-0.69]). In children, only FeNO (six studies; 349 patients; summary AUC 0.81 [0.72-0.89]) and blood eosinophils (three studies; 192 patients; 0.78 [0.71-0.85]) had been investigated in more than one study. Induced sputum was most frequently used as the reference standard. Summary estimates of sensitivity and specificity in detecting sputum eosinophils of 3% or more in adults were: 0.66 (0.57-0.75) and 0.76 (0.65-0.85) for FeNO; 0.71 (0.65-0.76) and 0.77 (0.70-0.83) for blood eosinophils; and 0.64 (0.42-0.81) and 0.71 (0.42-0.89) for IgE. INTERPRETATION: FeNO, blood eosinophils, and IgE have moderate diagnostic accuracy. Their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives. FUNDING: None. PMID- 25801415 TI - BODIPY-based probes for the fluorescence imaging of biomolecules in living cells. AB - Fluorescence imaging techniques have been widely used to visualize biological molecules and phenomena. In particular, several studies on the development of small-molecule fluorescent probes have been carried out, because their fluorescence properties can be easily tuned by synthetic chemical modification. For this reason, various fluorescent probes have been developed for targeting biological components, such as proteins, peptides, amino acids, and ions, to the interior and exterior of cells. In this review, we cover advances in the development of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based fluorescent probes for biological studies over the past decade. PMID- 25801416 TI - Risk of psoriasis in patients with childhood asthma: a Danish nationwide cohort study. AB - BACKGROUND: Psoriasis and asthma are disorders driven by inflammation. Psoriasis may carry an increased risk of asthma, but the reverse relationship has not been investigated. OBJECTIVES: To investigate the risk of psoriasis in subjects with childhood asthma in a nationwide Danish cohort. METHODS: Data on all Danish individuals aged 6-14 years at study entry between 1 January 1997 and 31 December 2011 (n = 1,478,110) were linked at an individual level in nationwide registers. Incidence rates per 10,000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by Poisson regression models. RESULTS: There were 21,725 cases of childhood asthma and 6586 incident cases of psoriasis. There were 5697 and 889 incident cases of mild and severe psoriasis, respectively. The incidence rates of overall, mild and severe psoriasis were 4.49, 3.88 and 0.61 for the reference population, and 5.95, 5.18 and 0.83 for subjects with childhood asthma, respectively. The IRRs for overall, mild and severe psoriasis were 3.94 [95% confidence interval (CI) 2.16-7.17], 5.03 (95% CI 2.48-10.21) and 2.27 (95% CI 0.61-8.42) for patients with childhood asthma. CONCLUSIONS: Childhood asthma was associated with a significantly increased risk of psoriasis. Further studies are warranted to determine the clinical significance and effects of therapeutic interventions on this association. PMID- 25801414 TI - Co-transcriptional mRNP formation is coordinated within a molecular mRNP packaging station in S. cerevisiae. AB - In eukaryotes, the messenger RNA (mRNA), the blueprint of a protein-coding gene, is processed and packaged into a messenger ribonucleoprotein particle (mRNP) by mRNA-binding proteins in the nucleus. The steps of mRNP formation - transcription, processing, packaging, and the orchestrated release of the export competent mRNP from the site of transcription for nuclear mRNA export - are tightly coupled to ensure a highly efficient and regulated process. The importance of highly accurate nuclear mRNP formation is illustrated by the fact that mutations in components of this pathway lead to cellular inviability or to severe diseases in metazoans. We hypothesize that efficient mRNP formation is realized by a molecular mRNP packaging station, which is built by several recruitment platforms and coordinates the individual steps of mRNP formation. PMID- 25801417 TI - Outcome of right-sided diaphragmatic hernia repair: a multicentre study. AB - AIM: Right-sided congenital diaphragmatic hernia (R-CDH) occurs in 14 to 25% of all CDH cases. The current literature comparing the outcome of R-CDH vs left CDH (L-CDH) is inconsistent, with some studies reporting higher and others lower mortality in R-CDH compared to L-CDH. The aim of our multicentre study was to analyse characteristics and outcome of R-CDH. METHODS: We retrospectively reviewed the medical records of 178 consecutive infants with CDH who underwent surgical repair of CDH at three European tertiary pediatric surgical centres from three different countries between 2000 and 2009. The analysis focused on demographic data, morbidity and mortality in R-CDH compared with L-CDH. RESULTS: Out of a total of 178 children, 32 (18.0%) right-sided and 146 (82.0 %) left sided cases of CDH were identified. Prenatal diagnosis was made in 8 R-CDH vs 67 L-CDH (25.0 vs 45.9%, p = 0.030). Median gestational age in R-CDH was 39 weeks (range 29-42 weeks) and 39 weeks in L-CDH (range 28-43 weeks, p = 0.943). Median birth weight in R-CDH was 3233 g (range 905-4480 g) and in L-CDH was 3060 g (range 1065-5240 g, p = 0.184). Major associated anomalies were present in 19 R CDH vs 46 L-CDH (59.4 vs 31.5%, p = 0.003). Extracorporeal membrane oxygenation (ECMO) was required in 3 R-CDH vs 19 L-CDH (9.4 vs 13.0%, p = 0.571). A diaphragmatic patch was used in 13 R-CDH and 59 L-CDH (40.6 vs 40.4%, p = 0.982). Fundoplication for GERD was required in 1 R-CDH and 19 L-CDH (3.1 vs 13.0 %, p = 0.109). No significant differences were observed in recurrence rate (9.4 vs 8.9%, p = 0.933). Postoperative mortality rate was significantly higher in R-CDH compared to L-CDH (21.9 vs 8.2%, p = 0.023). In R-CDH, prenatal diagnosis and patch repair correlated with mortality by univariate regression (p = 0.005 and p = 0.019). CONCLUSION: This multicentre study shows that prenatal diagnosis and patch repair were associated with an increased mortality rate in R-CDH. However, the morbidity following repair of R-CDH was not significantly different from that in L-CDH in survivors. PMID- 25801418 TI - The Cholera Toxin B Subunit (CTB) Fused to the Porcine Arterivirus Matrix M and GP5 Envelope Proteins Fails to Enhance the GP5-Specific Antibody Response in Pigs Immunized with Adenovectors. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus of the Arteriviridae family. As the current commercial vaccines are incompletely protective effective against PRRSV infection, we developed a vaccine strategy using replicating but non-disseminating adenovectors (rAdVs) expressing the PRRSV M matrix protein in fusion with the neutralizing major epitope-carrying GP5 envelope protein (Roques et al. in Vet Res 44:17, 2013). Although production of GP5-specific antibodies (Abs) was observed, no PRRSV-specific neutralizing Abs (NAbs) were induced in pigs given the rAdVs expressing M-GP5 or M-GP5m (GP5m being a mutant form of GP5). Nevertheless, partial protection was observed in the M-GP5m-rAdV-inoculated pigs experimentally infected with PRRSV. Here, we determined the impact of the cholera toxin B subunit (CTB, known for its adjuvant effect) in fusion with the C-terminus of M-GP5m on the Ab response to PRRSV. Three-week-old pigs were immunized twice both intramuscularly and intranasally at 3-week intervals with rAdV-expressing the green fluorescent protein (rAdV-GFP), rAdV-M-GP5m, or rAdV-M-GP5m-CTB. Pigs immunized with rAdV-M-GP5m showed a high level of serum GP5-specific Abs (as determined by an indirect ELISA). In contrast, CTB in fusion with M-GP5m had an unexpected severe negative impact on GP5-specific Ab production. PRRSV-specific NAbs could not be detected in any pigs of all groups. PMID- 25801419 TI - Ampelometric Leaf Trait and SSR Loci Selection for a Multivariate Statistical Approach in Vitis vinifera L. Biodiversity Management. AB - High estimated heritability values were recently revealed for mature leaf traits in grape (Vitis vinifera L.), thus redeeming ampelography in the era of molecular markers. The "Organisation Internationale de la Vigne et du Vin (OIV)" set a list of hundreds of descriptors for grapevine in order to standardize ampelographic and ampelometric scores. Therefore, the selection and reduction of the number of OIV codes can represent a major goal for leaner biodiversity assessment studies. The identification of ampelometric traits associated with grape diversity allows to construct Classification Trees with chi squared automatic interaction detection (CHAID) algorithm, a stepwise model-fitting method that produces a tree diagram in which at each step the sample pool is splitted based on the independent variables statistically different for the dependent variable. A collection of 100 table and wine grapevines (Vitis vinifera L.) was characterized and evaluated by means of six microsatellites and twenty-two ampelometric traits on mature leaves. Nine ampelometric traits were selected by principal component analysis and employed to build the classification trees based on CHAID algorithm. The strategy can represent an effective tool for grape biodiversity management, right allocations, and identification of new grape genotypes, implemented by a further microsatellite investigation only when unsolved cases occur, allowing faster and cheaper results. PMID- 25801420 TI - Mobility sensors for hospitalized patients: Quo vadis? PMID- 25801421 TI - Higher strains in the inner region of the meniscus indicate a potential source for degeneration. AB - Complex structural properties of menisci can be characterized in part by their inhomogeneous strain response under compression. This pilot study explored the feasibility to quantify characteristic strain distributions on meniscus cross sections subjected to static compression using electronic speckle pattern interferometry (ESPI). Cross-sectional specimens of 5-mm thickness were harvested from eight human menisci. After application of 20% pre-strain, strain maps in response to 10MUm compression were captured with ESPI. The 10MUm compression induced an aggregate strain of nominally 0.14% and resulted in highly non-uniform strain distributions. Local compressive strain captured by ESPI ranged from 0.03% to 0.7%. The highest strain was in the central region of meniscus cross-sections, and the lowest magnitude of strain was at the femoral surface of the meniscus. After stratifying for age, peak compressive strain in older menisci (71+/-6 years, n=4) was 0.33%+/-0.09, compared to 0.25%+/-0.06 in younger menisci (34+/-9 years, n=4). In conclusion, this study captured for the first time continuous strain distribution maps over entire meniscus cross-sections. The non-uniform strain distributions demonstrated inhomogeneous structural properties. Age related differences in characteristic strain distributions likely represent degenerative changes. As such, ESPI provides a novel strategy of further characterize meniscal function and degeneration. PMID- 25801422 TI - In vivo estimation of perineal body properties using ultrasound quasistatic elastography in nulliparous women. AB - OBJECTIVE: The perineal body must undergo a remarkable transformation during pregnancy to accommodate an estimated stretch ratio of over 3.3 in order to permit vaginal delivery of the fetal head. Yet measurements of perineal body elastic properties are lacking in vivo, whether in the pregnant or non-pregnant state. The objective of this study, therefore, was to develop a method for measuring perineal body elastic modulus and to test its feasibility in young nulliparous women. METHODS: An UltraSONIX RP500 ultrasound system was equipped with elastography software. Approximately 1 Hz free-hand sinusoidal compression loading of the perineum was used to measure the relative stiffness of the perineal body compared to that of a custom reference standoff pad with a modulus of 36.7 kPa. Measurements were made in 20 healthy nulliparous women. Four subjects were invited back for second and third visits to evaluate within- and between-visit repeatability using the coefficient of variation. RESULTS: The mean +/- SD elastic compression modulus of the perineal body was 28.9 +/- 4.7 kPa. Within- and between-visit repeatability averaged 3.4% and 8.3%, respectively. CONCLUSION: Ultrasound elastography using a standoff pad reference provides a valid method for evaluating the elastic modulus of the perineal body in living women. PMID- 25801423 TI - Recent microfluidic devices for studying gamete and embryo biomechanics. AB - The technical challenges of biomechanic research such as single cell analysis at a high monetary cost, labor, and time for just a small number of measurements is a good match to the strengths of microfluidic devices. New scientific discoveries in the fertilization and embryo development process, of which biomechanics is a major subset of interest, is crucial to fuel the continual improvement of clinical practice in assisted reproduction. The following review will highlight some recent microfluidic devices tailored for gamete and embryo biomechanics where biomimicry arises as a major theme of microfluidic device design and function, and the application of fundamental biomechanic principles are used to improve outcomes of cryopreservation. PMID- 25801425 TI - Xenotransplantation literature update, January-February 2015. PMID- 25801426 TI - From the editors. PMID- 25801427 TI - The role of risk analysis in understanding ebola. PMID- 25801424 TI - In vivo cartilage strain increases following medial meniscal tear and correlates with synovial fluid matrix metalloproteinase activity. AB - Meniscal tears are common injuries, and while partial meniscectomy is a frequent treatment option, general meniscus loss is a risk factor for the development of osteoarthritis. The goal of this study was to measure the in vivo tibiofemoral cartilage contact patterns in patients with meniscus tears in relation to biomarkers of cartilage catabolism in the synovial fluid of these joints. A combination of magnetic resonance imaging and biplanar fluoroscopy was used to determine the in vivo motion and cartilage contact mechanics of the knee. Subjects with isolated medial meniscus tears were analyzed while performing a quasi-static lunge, and the contralateral uninjured knee was used as a control. Synovial fluid was collected from the injured knee and matrix metalloproteinase (MMP) activity, sulfated glycosaminoglycan, cartilage oligomeric matrix protein, prostaglandin E2, and the collagen type II cleavage biomarker C2C were measured. Contact strain in the medial compartment increased significantly in the injured knees compared to contralateral control knees. In the lateral compartment, the contact strain in the injured knee was significantly increased only at the maximum flexion angle (105 degrees ). The average cartilage strain at maximum flexion positively correlated with total MMP activity in the synovial fluid. These findings show that meniscal injury leads to loss of normal joint function and increased strain of the articular cartilage, which correlated to elevated total MMP activity in the synovial fluid. The increased strain and total MMP activity may reflect, or potentially contribute to, the early development of osteoarthritis that is observed following meniscal injury. PMID- 25801428 TI - Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and Insulin Resistance in Long-Term Survivors of Pediatric Hematopoietic Stem Cell Transplantation. AB - Allogeneic hematopoietic stem-cell transplantation (alloHSCT) survivors treated with total body irradiation (TBI) exhibit bone deficits and excess adiposity, potentially related to altered mesenchymal stem cell differentiation into osteoblasts or adipocytes. We examined associations among fat distribution, bone microarchitecture, and insulin resistance in alloHSCT survivors after TBI. This was a cross-sectional observational study of 25 alloHSCT survivors (aged 12 to 25 years) a median of 9.7 (4.3 to 19.3) years after alloHSCT compared to 25 age-, race-, and sex-matched healthy controls. Vertebral MR spectroscopic imaging and tibia micro-MRI were used to quantify marrow adipose tissue (MAT) and trabecular microarchitecture. Additional measures included DXA whole-body fat mass (WB-FM), leg lean mass (Leg-LM), trunk visceral adipose tissue (VAT), and CT calf muscle density. Insulin resistance in alloHSCT survivors was estimated by HOMA-IR. AlloHSCT survivors had lower Leg-LM (p < 0.001) and greater VAT (p < 0.01), MAT (p < 0.001), and fat infiltration of muscle (p = 0.04) independent of WB-FM, versus matched controls; BMI did not differ. Survivors had lower bone volume fraction and abnormal microarchitecture including greater erosion and more rod like structure versus controls (all p = 0.04); 14 had vertebral deformities and two had compression fractures. Greater WB-FM, VAT, MAT, and muscle fat infiltration were associated with abnormal trabecular microarchitecture (p < 0.04 for all). AlloHSCT HOMA-IR was elevated, associated with younger age at transplantation (p < 0.01), and positively correlated with WB-FM and VAT (both p < 0.01). In conclusion, the markedly increased marrow adiposity, abnormal bone microarchitecture, and abnormal fat distribution highlight the risks of long-term treatment-related morbidity and mortality in alloHSCT recipients after TBI. Trabecular deterioration was associated with marrow and visceral adiposity. Furthermore, long-term survivors demonstrated sarcopenic obesity, insulin resistance, and vertebral deformities. Future studies are needed to identify strategies to prevent and treat metabolic and skeletal complications in this growing population of childhood alloHSCT survivors. PMID- 25801430 TI - Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation? AB - Graves' disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs. PMID- 25801429 TI - B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance. AB - Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity. PMID- 25801431 TI - T cell-extrinsic CD18 attenuates antigen-dependent CD4+ T cell activation in vivo. AB - The beta2 integrins (CD11/CD18) are heterodimeric leukocyte adhesion molecules expressed on hematopoietic cells. The role of T cell-intrinsic CD18 in trafficking of naive T cells to secondary lymphoid organs and in Ag-dependent T cell activation in vitro and in vivo has been well defined. However, the T cell extrinsic role for CD18, including on APC, in contributing to T cell activation in vivo is less well understood. We examined the role for T cell-extrinsic CD18 in the activation of wild-type CD4(+) T cells in vivo through the adoptive transfer of DO11.10 Ag-specific CD4(+) T cells into CD18(-/-) mice. We found that T cell-extrinsic CD18 was required for attenuating OVA-induced T cell proliferation in peripheral lymph nodes (PLN). The increased proliferation of wild-type DO11.10 CD4(+) T cells in CD18(-/-) PLN was associated with a higher percentage of APC, and these APC demonstrated an increased activation profile and increased Ag uptake, in particular in F4/80(+) APC. Depletion of F4/80(+) cells both reduced and equalized Ag-dependent T cell proliferation in CD18(-/-) relative to littermate control PLN, demonstrating that these cells play a critical role in the enhanced T cell proliferation in CD18(-/-) mice. Consistently, CD11b blockade, which is expressed on F4/80(+) macrophages, enhanced the proliferation of DO11.10 CD4(+) T cells in CD18(+/-) PLN. Thus, in contrast to the T cell-intrinsic essential role for CD18 in T cell activation, T cell-extrinsic expression of CD18 attenuates Ag-dependent CD4(+) T cell activation in PLN in vivo. PMID- 25801432 TI - The STAT5-GATA2 pathway is critical in basophil and mast cell differentiation and maintenance. AB - Transcription factor GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte-monocyte progenitor differentiation, and basophil and mast cell differentiation. However, precise roles of GATA2 in basophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. We observed Gata2 haploinsufficiency for mast cell differentiation, but not for basophil differentiation. We examined the precise role of GATA2 in maintaining the expression of a wide range of genes that are important for performing basophil or mast cell functions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for maintaining Fcer1a mRNA and FcepsilonRIalpha protein expression on both basophils and mast cells, as well as for maintaining Kit mRNA and c-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expression in basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5-GATA2 connection, showing that the STAT5 transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 gene was sufficient to direct basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5-GATA2 pathway is critical for basophil and mast cell differentiation and maintenance. PMID- 25801433 TI - CD13 restricts TLR4 endocytic signal transduction in inflammation. AB - Dysregulation of the innate immune response underlies numerous pathological conditions. The TLR4 is the prototypical sensor of infection or injury that orchestrates the innate response via sequential activation of both cell surface and endocytic signaling pathways that trigger distinct downstream consequences. CD14 binds and delivers LPS to TLR4 and has been identified as a positive regulator of TLR4 signal transduction. It is logical that negative regulators of this process also exist to maintain the critical balance required for fighting infection, healing damaged tissue, and resolving inflammation. We showed that CD13 negatively modulates receptor-mediated Ag uptake in dendritic cells to control T cell activation in adaptive immunity. In this study, we report that myeloid CD13 governs internalization of TLR4 and subsequent innate signaling cascades, activating IRF-3 independently of CD14. CD13 is cointernalized with TLR4, CD14, and dynamin into Rab5(+) early endosomes upon LPS treatment. Importantly, in response to TLR4 ligands HMGB1 and LPS, p-IRF-3 activation and transcription of its target genes are enhanced in CD13(KO) dendritic cells, whereas TLR4 surface signaling remains unaffected, resulting in a skewed inflammatory response. This finding is physiologically relevant as ischemic injury in vivo provoked identical TLR4 responses. Finally, CD13(KO) mice showed significantly enhanced IFNbeta-mediated signal transduction via JAK-STAT, escalating inducible NO synthase transcription levels and promoting accumulation of oxidative stress mediators and tissue injury. Mechanistically, inflammatory activation of macrophages upregulates CD13 expression and CD13 and TLR4 coimmunoprecipitate. Therefore, CD13 negatively regulates TLR4 signaling, thereby balancing the innate response by maintaining the inflammatory equilibrium critical to innate immune regulation. PMID- 25801435 TI - Programmed death ligand 1 on Burkholderia pseudomallei-infected human polymorphonuclear neutrophils impairs T cell functions. AB - Polymorphonuclear neutrophils (PMNs) are terminally differentiated cells that are involved in innate immune responses and form an early line of defense against pathogens. More recently, it has been shown that PMNs have immunosuppressive abilities on other immune cells. However, the effect of PMNs on T cell responses during bacterial infection remains to be determined. In this report, we examined the interaction of PMNs and T cells in response to infection with Burkholderia pseudomallei, the causative agent of human melioidosis. We observed that CD4(+) T cell proliferation and IFN-gamma production in response to polyclonal activators is significantly inhibited by uninfected PMNs, and to a greater extent B. pseudomallei-infected PMNs. Programmed death ligand 1 (PD-L1), a known regulator of T cell activation, is increased in mRNA expression in the blood of patients and upon infection of PMNs in vitro. The increased expression of PD-L1 was correlated with the degree of T cell inhibition in individuals with type 2 diabetes, a major risk factor of melioidosis. In vitro, addition of anti-PD-L1 Abs blocked this inhibitory activity and restored proliferation of CD4(+) T cells and IFN-gamma production, suggesting that PD-L1 on B. pseudomallei-infected PMNs is a regulatory molecule for the functions of T cells and may be involved in pathogenesis versus control of melioidosis. PMID- 25801434 TI - Protection of human myeloid dendritic cell subsets against influenza A virus infection is differentially regulated upon TLR stimulation. AB - The proinflammatory microenvironment in the respiratory airway induces maturation of both resident and infiltrating dendritic cells (DCs) upon influenza A virus (IAV) infection. This results in upregulation of antiviral pathways as well as modulation of endocytic processes, which affect the susceptibility of DCs to IAV infection. Therefore, it is highly relevant to understand how IAV interacts with and infects mature DCs. To investigate how different subsets of human myeloid DCs (MDCs) involved in tissue inflammation are affected by inflammatory stimulation during IAV infection, we stimulated primary blood MDCs and inflammatory monocyte derived DCs (MDDCs) with TLR ligands, resulting in maturation. Interestingly, MDDCs but not MDCs were protected against IAV infection after LPS (TLR4) stimulation. In contrast, stimulation with TLR7/8 ligand protected MDCs but not MDDCs from IAV infection. The reduced susceptibility to IAV infection correlated with induction of type I IFNs. We found that differential expression of TLR4, TRIF, and MyD88 in the two MDC subsets regulated the ability of the cells to enter an antiviral state upon maturation. This difference was functionally confirmed using small interfering RNA and inhibitors. Our data show that different human MDC subsets may play distinct roles during IAV infection, as their capacity to induce type I IFNs is dependent on TLR-specific maturation, resulting in differential susceptibility to IAV infection. PMID- 25801436 TI - Thermal aggregation behaviour of soy protein: characteristics of different polypeptides and sub-units. AB - BACKGROUND: Due to the differences in structure and composition of glycinin and beta-conglycinin, they exhibit different characteristics during heat treatment. In present study, the thermal aggregation behaviour of glycinin, beta-conglycinin and their isolated sub-units was investigated at pH 7.0. RESULTS: Acidic polypeptides, basic polypeptides, alphaalpha' and beta sub-units of soy protein were denatured during the isolation process. The degree of aggregation of protein fractions after heat treatment was in the order: denatured basic polypeptides > native glycinin > denatured beta sub-unit > native beta-conglycinin > denatured acidic polypeptides > denatured alphaalpha' sub-units. Glycinin, beta conglycinin, acidic polypeptides and alphaalpha'/beta sub-units exhibited different changing trends of surface hydrophobicity with increasing temperature. The alphaalpha' sub-units showed higher ability to suppress thermal aggregation of basic polypeptides than beta sub-units during heat treatment. The beta sub units were shown to form soluble aggregates with glycinin after heating. CONCLUSION: The interaction mechanism of alphaalpha' and beta sub-units heated with basic polypeptides was proposed. For the beta sub-units-basic polypeptides mixed system, more hydrophobic chains were binding together and buried inside during heat treatment, which resulted in lower surface hydrophobicity. The alphaalpha' sub-units-basic polypeptides mixed system was considered to be a stable system with higher surface hydrophobicity after being heated. PMID- 25801437 TI - Silicon decorated with amorphous cobalt molybdenum sulfide catalyst as an efficient photocathode for solar hydrogen generation. AB - The construction of viable photoelectrochemical (PEC) devices for solar-driven water splitting can be achieved by first identifying an efficient independent photoanode for water oxidation and a photocathode for hydrogen generation. These two photoelectrodes then must be assembled with a proton exchange membrane within a complete coupled system. Here we report the preparation of a Si/a-CoMoSx hybrid photocathode which shows impressive performance (onset potential of 0.25 V vs RHE and photocurrent jsc of 17.5 mA cm(-2) at 0 V vs RHE) in pH 4.25 phosphate solution and under simulated AM 1.5 solar illumination. This performance is among the best reported for Si photocathodes decorated with noble-metal-free catalysts. The electrode preparation is scalable because it relies on a photoassisted electrodeposition process employing an available p-type Si electrode and [Co(MoS4)2](2-) precursor. Investigation of the mechanism of the Si/a-CoMoSx electrode revealed that under conditions of H2 photogeneration this bimetallic sulfide catalyst is highly efficient in extracting electrons from illuminated Si and subsequently in reducing protons into H2. The Si/a-CoMoSx photocathode is functional over a wide range of pH values, thus making it a promising candidate for the construction of a complete solar-driven water splitting PEC device. PMID- 25801438 TI - Non-aqueous sol-gel synthesis of ultra small persistent luminescence nanoparticles for near-infrared in vivo imaging. AB - Ultra-small ZnGa2 O4 :Cr(3+) nanoparticles (6 nm) that exhibit near-infrared (NIR) persistent luminescence properties are synthesized by using a non-aqueous sol-gel method assisted by microwave irradiation. The nanoparticles are pegylated, leading to highly stable dispersions under physiological conditions. Preliminary in vivo studies show the high potential for these ultra-small ZnGa2 O4 :Cr(3+) nanoparticles to be used as in vivo optical nanotools as they emit without the need for in situ excitation and, thus, avoid the autofluorescence of tissues. PMID- 25801439 TI - Automated functional imaging for assessment of left ventricular mechanics in the presence of left ventricular hypertrophy. AB - BACKGROUND: Increased left ventricular (LV) mass is a well-known independent predictor of cardiovascular morbidity and mortality. Even though these patients have an increased risk of LV diastolic dysfunction; recent data have suggested the presence of subtle LV systolic abnormalities. This study sought to demonstrate if a novel speckle tracking automated functional imaging (AFI) tool would be useful in identifying differences in strain generation between patients with normal and increased LV wall mass. METHODS: Standard measures of LV systolic and diastolic function were collected from 90 patients divided into Group I with LV mass index < 100 g/m(2) and Group II with LV mass index values >= 100 g/m(2). AFI was also obtained to measure peak global LV myocardial strain. RESULTS: As expected, patients with an increased LV mass index had significant LV diastolic abnormalities. However, in addition these patients in Group II not only had significantly lower peak systolic strain values but also significantly lower mitral annular plane systolic excursion (MAPSE) and MA tissue Doppler imaging systolic velocity values than patients in Group I despite having comparable estimates of LV ejection fraction, based on the Simpson's method. CONCLUSION: Based on these results, AFI provides prompt point of care information regarding LV function and mechanics and identifies differences in longitudinal strain generation between patients with normal and increased LV wall mass. Additional studies are now required to prospectively determine if AFI measures of LV function might be useful to identify patients with an increased LV mass that will develop symptomatic systolic or diastolic heart failure. PMID- 25801440 TI - Forensic focused treatment planning: a new standard for forensic mental health systems. AB - Almost no literature addresses treatment planning for the forensic psychiatric patient. In the absence of such guidance, recovery-oriented multifocal treatment planning has been imported into forensic mental health systems from community psychiatric settings, despite the fact that conditions of admission and discharge are vastly different for forensic psychiatry inpatients. We propose that instead of focusing on recovery, forensic treatment planning should prioritize forensic outcomes, such as restoration of trial competence or mitigation of violence risk, as the first steps in a continuum of care that eventually leads to the patient's ability to resolve forensic issues and return to the community for recovery oriented care. Here we offer a model for treatment planning in the forensic setting. PMID- 25801441 TI - Experimental and theoretical study on the hydrogen bonding between dopamine hydrochloride and N,N-dimethyl formamide. AB - The hydrogen bonding between dopamine hydrochloride (DH) and N,N-dimethyl formamide (DMF) were investigated by UV-visible spectra (UV-Vis), cyclic voltammetry (CV) and density functional theory (DFT). It was found that the position of UV-Vis absorption band and the anodic/cathodic peak potentials of DH were all affected by the concentrations of DH in DMF. It was suggested that hydrogen bonding were formed between DH and DMF, which was confirmed by the DFT results. AIM analyses were performed to elucidate the nature of the hydrogen bonding in the mixtures. PMID- 25801442 TI - Bi-anchoring organic sensitizers of type D-(pi-A)2 comprising thiophene-2 acetonitrile as pi-spacer and malonic acid as electron acceptor for dye sensitized solar cell applications. AB - Two new bi-anchoring organic sensitizers of type D-(pi-A)2 comprising the identical pi-spacer (thiophene-2-acetonitrile) and electron acceptor (malonic acid) but different aryl amine as electron donors (diphenylamine and carbazole) were synthesized, characterized and fabricated metal free dye-sensitized solar cell devices. The intra molecular charge transfer property and electrochemical property of these dyes were investigated by molecular absorption, emission, cyclic voltammetric experiments and in addition, quantum chemical calculation studies were performed to provide sufficient driving force for the electron injection into the conduction band of TiO2 which leads to efficient charge collection. Among the fabricated devices, carbazole based device exhibits high current conversion efficiency (eta=4.7%) with a short circuit current density (JSC) 15.3 mA/cm(2), an open circuit photo voltage (VOC) of 0.59 V and a fill factor of 0.44 under AM 1.5 illumination (85 mW/cm(2)) compared to diphenylamine based device. PMID- 25801443 TI - Racemic R,S-venlafaxine hydrochloride-DNA interaction: experimental and computational evidence. AB - The interaction of racemic R,S-venlafaxine hydrochloride (rac-VEN) drug with calf thymus deoxyribonucleic acid (ct-DNA) was studied using various physico-chemical techniques and molecular docking at simulated physiological conditions (pH=7.4). The fluorescence study shows that ct-DNA interacted with rac-VEN and quenched its intrinsic fluorescence in a static quenching process. These results are further supported by UV-Vis spectra. The binding constant of rac-VEN with ct-DNA (0.57 * 10(4)) obtained from the spectroscopic techniques, which is more in keeping with the groove binding with DNA. Furthermore, the competition experiment using Hoechst33258 indicated that rac-VEN may bind to ct-DNA by a minor groove binding mode. In addition, iodide quenching effect on the fluorescence of rac-VEN before and after the interaction with ct-DNA is another evidence to groove binding. The thermodynamic parameters are calculated by van't Hoff equation, which demonstrated that hydrogen bonds and van der Waals interactions played major roles in the binding reaction. Molecular simulation studies carried out by using the AutoDock4 and Spartan 10 programs. From the best docking map, we found that R and S-isomers fit in the A6T7T8/T19A18A17 region in minor groove of B-DNA. Finally, these results indicated that the docking of S-VEN-B-DNA is more stable than R-VEN-B-DNA. PMID- 25801444 TI - Quantum chemical studies on molecular structure, spectroscopic (IR, Raman, UV Vis), NBO and HOMO-LUMO analysis of 1-benzyl-3-(2-furoyl) thiourea. AB - Vibrational and electronic spectra for 1-benzyl-3-(2-furoyl) thiourea were calculated by using density functional method (B3LYP) with different basis sets. The complete assignment of all vibrational modes was performed on basis of the calculated frequencies and comparing with the reported IR and Raman spectra for that thiourea derivative. UV-visible absorption spectra of the compound dissolved in methanol were recorded and analyzed using time dependent density functional theory (TD-DFT). The calculated values for the geometrical parameters of the title compound are consistent with the ones reported from XRD studies. The stability of the molecule, related to hyper-conjugative interactions, and electron delocalization were evaluated using natural bond orbital (NBO) analysis. Intra-molecular interactions were studied by AIM approach. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. Molecular electrostatic potential map was performed by the DFT method. PMID- 25801445 TI - Allergic contact dermatitis caused by Magnolia officinalis bark extract in a facial anti-ageing cream. PMID- 25801447 TI - Oxaliplatin-induced neuropathy: a tale of two electrolytes. PMID- 25801446 TI - Evaluating the Liverpool Care Pathway for care of the terminally ill in rural Australia. AB - PURPOSE: This study evaluates a pilot implementation of the Liverpool Care Pathway (LCP), a clinical tool used to guide the care of dying patients in the last days of life, on the end-of-life care for dying patients in three regions in rural Australia. METHODS: The LCP was implemented at 13 participating sites: nine hospitals (general wards), one community-based palliative care service, and three in-hospital palliative care units. To evaluate the implementation of the LCP, 415 eligible patient records were examined: 223 pre-implementation and 192 post implementation (116 on the LCP and 76 receiving usual care). The primary analysis compared all patients pre-implementation of the LCP versus all patients post implementation. RESULTS: Increases were found post-implementation for communication with other health professionals and with patients or family (pre-69 %, post-87 %; p <= 0.000), use of palliative medications (pre-87 %, post-98 %; p <= 0.000) and frequency of symptom assessments (pre-66 %, post-82 %; p <= 0.000). Fewer blood and radiological investigations were conducted and venous access devices used in the post-implementation groups than in the pre-implementation period. CONCLUSIONS: This study suggests that when rigorously implemented, the LCP improves important components of end-of-life care for dying patients and their families. PMID- 25801448 TI - Subjective Social Status, Mental and Psychosocial Health, and Birth Weight Differences in Mexican-American and Mexican Immigrant Women. AB - Recent Mexican immigrant women on average have an unexpectedly low incidence of low birth weight (LBW). Birth weights decline and LBW incidence increases in post immigrant generations. This pilot project tested the hypothesis that subjective social status (SSS) of pregnant women predicts variation in birth weight between Mexican immigrant and Mexican-American women. 300 low-income pregnant Mexican immigrant and Mexican-American women in South Texas were surveyed for SSS, depression, pregnancy-related anxiety, perceived social stress and self-esteem and subsequent birth weight. No significant difference in SSS levels between pregnant Mexican immigrant and Mexican-American women were found. However, SSS better predicted variation in birth weight across both groups than mental and psychosocial health variables. Results suggest distinct relationships among SSS, mental and psychosocial health that could impact birth weight. They underscore the relevance of a multilevel, biopsychosocial analytical framework to studying LBW. PMID- 25801449 TI - A Qualitative Exploration of Less Acculturated Mexican Mothers' Safety Perceptions of Herbs, Medicines, and Cleaners in the Home. AB - Childhood poisoning is a leading public health concern in our society. The death rate from unintentional poisonings among children has increased by 80% from 2000 to 2009. Immigrant children are also at-risk. A qualitative study, consisting of a pile sort, was conducted among immigrant Mexican mothers to determine their safety perceptions of commonly used medicines, herbs, and cleaners. Participants (N = 35) were selected for semi-structured interviews from a pediatric primary care clinic in the Dallas/Fort Worth Metroplex. Some mothers over-estimated their children's ability to discern the dangers of substances, relied heavily on sensory skills of children, and perceived a medicine as safe after successful use in the past. Other mothers were more cognizant of allergic reactions, ingestion, and the need to store substances carefully. Brief interventions that incorporate culturally-appropriate safety messages are needed to assist Mexican mothers in creating a safe home environment. PMID- 25801450 TI - Understanding Service Utilization Disparities and Depression in Latinos: The Role of Fatalismo. AB - Research demonstrates a disparity between need and utilization of mental health services for Latinos. Cultural variations in perceptions of mental illness may be partially responsible for this discrepancy. Past research with Latinos has shown links between fatalismo, a cultural value similar to external locus of control, and both depression and lower service utilization in medical care, while links to psychiatric care have not been investigated. The current study therefore aimed to explore the associations between fatalismo, depression, and past year mental health service utilization by Latinos. A community sample of 83 Latino adults were recruited during local cultural events. Participants completed self-report measures of depression, fatalism, and past year service utilization. Analyses using structural equation modeling showed fatalismo was directly negatively related to past year medical service utilization (beta = -.35). In contrast, the link between fatalismo and past year mental health service utilization was mediated by self-reported depressive symptoms (indirect beta = .19, p < .001). We conclude that while fatalismo is associated with depression in Latinos, other barriers likely serve as more salient deterrents of service utilization. PMID- 25801451 TI - The suffix priming effect: Further evidence for an early morpho-orthographic segmentation process independent of its semantic content. AB - This work presents the results of a masked lexical decision experiment in which we explore the morphological parsing of Spanish suffixed or pseudosuffixed words through the suffix priming effect. Priming the bases or pseudobases with their suffixed or pseudosuffixed forms is the standard process in experiments aimed at understanding the processes underlying morphological parsing in visual word recognition with masked priming lexical decision (e.g., darkness-DARK; corner CORN). We, however, compare the effect of suffix priming on the lexical decision of suffixed (ero-JORNALERO) and pseudosuffixed words (ero-CORDERO), as well as the effect of orthographic priming on nonsuffixed words (eba-PRUEBA). The results show that in the case of suffixed and pseudosuffixed words, related primes (ero JORNALERO; ero-CORDERO) significantly accelerated response latencies in comparison to unrelated primes (ista-JORNALERO; ura-CORDERO), while for simple words there was no facilitation from the orthographically related prime in comparison to the unrelated prime (eba-PRUEBA; afo-PRUEBA). These results are consistent with the so-called morpho-orthographic segmentation process in the course of visual word recognition, which might also be independent of orthographic and purely semantic factors. Our results also support the view that morphological parsing takes place regardless of whether a stem is present in a word. These results complement findings from studies dealing with CORNER- and BROTHEL-like stimuli. PMID- 25801452 TI - Interaction of metal ions with the His13-His14 sequence relevant to Alzheimer's disease. AB - The interaction of a series of metal ions (i.e., groups 1 and 2, first-row transition metals, and groups 11-14) with the His13-His14 sequence relevant to Alzheimer's disease has been studied using quantum chemical calculations. Metal ions prefer to occupy three coordination sites at two Ndelta of the imidazole rings and one carbonyl oxygen. Simulated IR spectra reveal that vibrational frequency of C-O stretch affords a sensitive probe for understanding the interaction of His13-His14 with metal ions. The relative strength of the interaction of His13-His14 with the representative metal ions follows the order of K(+) < Ca(2+) < Zn(2+) < Cu(2+) < Fe(3+) < Al(3+), which is closely correlated with the available experimental results, providing a vivid physical picture about how metal ions bind to amyloid beta-peptide. IR spectra of the [M.(His13 His14)](n+) complexes could be measured by infrared photodissociation spectroscopic technique and thus afford useful information for the understanding of structure-function relationship and the design of suitable drugs. PMID- 25801454 TI - Randomised controlled trials: the importance of sample size. PMID- 25801453 TI - Virulence of tick-borne encephalitis virus is associated with intact conformational viral RNA structures in the variable region of the 3'-UTR. AB - Tick-borne encephalitis virus (TBEV) is maintained between ticks and mammals in nature and causes severe neurological disease in human. However, the mechanism of viral pathogenicity is unknown. Previously, we showed that the deletion in the variable region of the 3'-untranslated region (UTR) is involved in the pathogenicity of the strains from the Far-Eastern subtype of TBEV. To investigate the detailed function of the variable region, we constructed recombinant TBEV with partial deletions in the region. In a mouse model, the partial deletions drastically increased the virulence of the virus, with no effect on virus multiplication in mouse brain. Furthermore, the mutations did not affect the production of subgenomic flavivirus RNA from the 3'-UTR, and the induction of interferon (IFN) and IFN-stimulated genes. These data suggested that the conformational structure of the variable region is associated with the pathogenicity of the Far-Eastern subtype of TBEV. These findings provide a foundation for further research to identify the pathogenic mechanisms of TBEV. PMID- 25801455 TI - Transdifferentiation of mouse adipose-derived stromal cells into acinar cells of the submandibular gland using a co-culture system. AB - A loss of salivary gland function often occurs after radiation therapy in head and neck tumors, though secretion of saliva by the salivary glands is essential for the health and maintenance of the oral environment. Transplantation of salivary acinar cells (ACs), in part, may overcome the side effects of therapy. Here we directly differentiated mouse adipose-derived stromal cells (ADSCs) into ACs using a co-culture system. Multipotent ADSCs can be easily collected from stromal vascular fractions of adipose tissues. The isolated ADSCs showed positive expression of markers such as integrin beta-1 (CD29), cell surface glycoprotein (CD44), endoglin (CD105), and Nanog. The cells were able to differentiate into adipocytes, osteoblasts, and neural-like cells after 14 days in culture. ADSCs at passage 2 were co-cultured with mouse ACs in AC culture medium using the double chamber (co-culture system) to avoid mixing the cell types. The ADSCs in this co culture system expressed markers of ACs, such as alpha-amylases and aquaporin5, in both mRNA and protein. ADSCs cultured in AC-conditioned medium also expressed AC markers. Cellular proliferation and senescence analyses demonstrated that cells in the co-culture group showed lower senescence and a higher proliferation rate than the AC-conditioned medium group at Days 14 and 21. The results above imply direct conversion of ADSCs into ACs under the co-culture system; therefore, ADSCs may be a stem cell source for the therapy for salivary gland damage. PMID- 25801456 TI - Circumferential electrocautery of the patella in primary total knee replacement without patellar replacement: a meta-analysis and systematic review. AB - The purpose of this meta-analysis and systematic review was to identify and assess whether circumferential electrocautery is useful for improving outcomes after primary total knee replacement(TKR). We searched MEDLINE, EMBASE, PubMed, SpringerLink, Web of Knowledge, OVID CINAHL, OVID EBM and Google Scholar and included articles published through January 2014. A total of 6 articles met the inclusion criteria. Of the 776 cases included in the analysis, 388 cases involved patellar denervation, and 388 cases were designated as the control group. The meta-analysis revealed no significant difference in the incidence of anterior knee pain (AKP, p = 0.18) or in the visual analogue scale score (VAS, p = 0.23) between the two groups. In addition, AKSS Function Score indicated no significant difference between the two groups (p = 0.28). However, the OKS (p = 0.02), patellar score (p = 0.01), AKSS-Knee Score (p = 0.004), range of motion (ROM, p < 0.0001) and WOMAC Score (p = 0.0003) indicated that circumpatellarelectrocautery improved clinical outcomes compared with non-electrocautery. The results indicate that circumferential electrocautery of the patella does not significantly improve AKP compared with non-electrocautery techniques but that circumferential electrocautery significantly improves patients' knee function after surgery. Therefore, we believe that circumferential electrocautery is beneficial to the outcome of primary TKR surgery without patellar replacement. PMID- 25801457 TI - Restraining the pneumococcus. PMID- 25801458 TI - Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. AB - BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) protects against key serotypes that increased after routine immunisation with the seven-valent vaccine (PCV7), but its potential for herd protection and serotype replacement is uncertain. The aim of this study was to analyse the effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction. METHODS: We used a national dataset of electronically reported and serotyped invasive pneumococcal disease cases in England and Wales to estimate incidence rate ratios (IRRs) for vaccine and non vaccine type invasive pneumococcal disease between July, 2013, and June, 2014, versus the pre-PCV13 and pre-PCV7 baseline. Incidence rates were corrected for missing serotype data and changes in surveillance sensitivity over time. An over dispersed Poisson model was used to estimate IRRs and confidence intervals. FINDINGS: Incidence of invasive pneumococcal disease in the epidemiological year 2013/14 decreased by 32% compared with the pre-PCV13 baseline (incidence 10.14 per 100,000 in 2008-10 vs 6.85 per 100,000 in 2013/14; IRR 0.68, 95% CI 0.64 0.72). This was due to an 86% reduction of the serotypes covered by PCV7 (1.46 vs 0.20 per 100,000; IRR 0.14, 0.10-0.18) and a 69% reduction of the additional six serotypes covered by PCV13 (4.48 vs 1.40 per 100,000; IRR 0.31, 0.28-0.35). When compared with the pre-PCV7 baseline, there was a 56% overall reduction in invasive pneumococcal disease (15.63 vs 6.85 per 100,000; IRR 0.44, 95% CI 0.43 0.47). Compared with the pre-PCV13 baseline, the incidence of non-PCV13 serotypes increased (incidence all ages 4.19 vs 5.25 per 100,000; IRR 1.25, 95% CI 1.17 1.35) due to increases across a broad range of serotypes in children younger than 5 years and in people aged 45 years or more. In children younger than 5 years, incidence of non-PCV13 serotypes in 2013/14 was higher than in 2012/13 (age <2 years: 12.03 vs 10.83 per 100,000; age 2-4 years: 4.08 vs 3.63 per 100,000). INTERPRETATION: 8 years of PCV use in England and Wales has reduced the overall incidence of invasive pneumococcal disease by more than 50%. The herd protection induced by PCV7 is continuing, and similar indirect protection is occurring from the additional serotypes covered by PCV13. There is, however, evidence of increasing invasive pneumococcal disease due to non-PCV13 serotypes, particularly in children younger than 5 years in 2014. If this increase continues, the maximum benefit of the PCV13 programme in children might already have been achieved. FUNDING: Public Health England funds national surveillance of invasive pneumococcal disease. PMID- 25801459 TI - The Implant Biologic Pontic Designed Interface: Description of the Technique and Cone-Beam Computed Tomography Evaluation. AB - PURPOSE: The study aims to evaluate clinically the thickness of the alveolar ridge mucosa underneath a zirconia implant-supported restoration with a modified ovate pontic. MATERIALS AND METHODS: Sixty-five patients, 32 women and 33 men (mean age: 65.5 years; range 38-81), were included. A total of 383 implants (303 in the maxilla; 80 in the mandible), supporting 81 full or partial fixed dental prostheses (65 in the maxilla; 16 in the mandible), were either cement- or screw retained. Three years after loading, a total of 219 pontic sites (153 in the maxilla; 66 in the mandible) were measured, and the thickness of the alveolar ridge mucosa between the prosthetic surface and the underlying bone crest were recorded. RESULTS: The overall implant and prosthesis survival rates at 3 years were 98.7% and 100%, respectively. No implant complications were reported, scoring a cumulative implant success rate of 100%. In the maxilla, the overall mean thickness of the alveolar ridge mucosa was 2.32 +/- 0.57 mm. In the mandible, the overall mean thickness of the alveolar ridge mucosa was 2.20 +/- 0.62 mm. There was no statistical difference between the overall mean values in the maxilla and mandible (p = .471). CONCLUSION: This radiologic retrospective study suggests the existence of a physiological barrier, named prosthetic biological width, underneath a novel pontic-designed restoration. PMID- 25801460 TI - Protective effect of hypotaurine against oxidative stress-induced cytotoxicity in rat placental trophoblasts. AB - INTRODUCTION: Hypotaurine is a precursor of taurine and an antioxidant, and is concentrated in fetal plasma compared to maternal plasma. Hypotaurine is significantly decreased in fetal plasma of ezrin (Vil2) knock-out mice, and fetuses show intrauterine growth retardation. The aim of this study was to characterize the mechanism through which cellular hypotaurine level is maintained in placental trophoblasts, and the effect of hypotaurine on oxidative stress induced by hydrogen peroxide (H2O2). METHODS: Hypotaurine transfer from extracellular fluid and antioxidant effect of hypotaurine were analyzed in rat placental trophoblast TR-TBT 18d-1 cells. RESULTS: We found that hypotaurine is concentrated into rat placental trophoblast TR-TBT 18d-1 cells, and the level of hypotaurine was markedly reduced by culture in medium supplemented with dialyzed fetal bovine serum (FBS) instead of normal FBS. The hypotaurine level recovered almost completely when hypotaurine was added to the culture medium, indicating that intracellular hypotaurine is predominantly supplied by transport across the plasma membrane from extracellular fluid rather than by biosynthesis. Hypotaurine showed a cytoprotective effect against H2O2-induced oxidative damage in TR-TBT 18d-1 cells. Hypotaurine treatment of TR-TBT 18d-1 cells increased antioxidant capacity against hydroxyl radical and peroxyl radical. The concentration of intracellular hydroxyl radical induced by H2O2 in TR-TBT 18d-1 cells was significantly reduced by hypotaurine treatment. DISCUSSION: These results indicate that intracellular hypotaurine is mainly supplied to placental trophoblasts by transfer from extracellular fluid across the plasma membrane, and may play a role in cell protection by scavenging reactive oxygen species. PMID- 25801461 TI - A new azaphilone from the entomopathogenic fungus Hypocrella sp. AB - This report describes the isolation of a new azaphilone, designated hypocrellone A (2), together with five known compounds (1, 3-6) from a submerged culture of the entomopathogenic fungus Hypocrella sp. (isolate WYTY-21). The absolute stereostructures of the two compounds (1 and 2) were elucidated based on 1D and 2D NMR spectroscopic and mass spectrometric data combined with the data from various chemical transformations. Hypocrellone A (2) and three (3-6) of the five known compounds were cytotoxic to hepatoma cells (cell line BEL-7404); IC50 values ranged from 6.2 to 17.4 MUM. At 200 MUM, none of the six compounds was toxic to normal human liver cells (cell line HL-7702) or to normal human kidney epithelial cells (cell line HEK-293T). PMID- 25801462 TI - Effects of sulfide on the integration of denitrification with anaerobic digestion. AB - The effects of sulfide on the integration of denitrification with anaerobic digestion using anaerobic effluents of cassava stillage as carbon source were investigated. Batch tests indicated that nitrate reduction efficiencies decreased from 96.5% to 15.8% as sulfide/nitrate (S/NO3(-)-N) ratios increased from 0.27 to 1.60. At low S/NO3(-)-N ratios (0.27-1.08) anaerobic acidogenesis was accelerated. Nitrate was reduced to nitrite via sulfur-based autotrophic denitrification, after which the formed nitrite and residual nitrate were converted to N2 via heterotrophic denitrification. Increases in the S/NO3(-)-N ratio (1.60) caused a shift (76.3%) in the nitrate reduction pathway from denitrification to dissimilatory nitrate reduction to ammonia (DNRA). Sulfide concentrations (S/NO3(-)-N ratio of 1.60) suppressed not only heterotrophic denitrification but also acidogenesis. The potentially toxic effect of sulfide on acid production was mitigated by its rapid oxidation to sulfur, allowing the recovery of acidogenesis. PMID- 25801463 TI - Blunt abdominal trauma: imaging and intervention. AB - Interventional radiology, particularly percutaneous angioembolization, plays an important role in the management of blunt abdominal trauma involving solid organs and pelvic fractures. The traumatic injuries of the central nervous system, heart, and great vessels often lead to death at the site of trauma. Although patients with visceral organ injuries can also die at the site of trauma, these patients often reach the hospital thus giving us an opportunity to treat them with surgical or radiological intervention depending on the clinical condition of the patient. The management of these patients with trauma is now well codified patients who remain unstable despite resuscitation should be shifted either to an operating room for laparotomy if the ultrasound (US) revealed hemoperitoneum or to a interventional room for angioembolization in cases of pelvic fractures. In all other cases, computed tomography is essential. Currently, multidetector computed tomography with contrast is the gold standard imaging modality for the diagnosis of traumatic abdominal injuries; it helps in assessing the extent of injuries, and further management can be planned. PMID- 25801464 TI - A simplified algorithm for diagnosis of spinal cord lesions. AB - Neuroimaging is indispensable for evaluation of Myelopathy not only for localization but also for etiologic determination. MRI is the preferred examination for further characterization of the majority of these conditions. These include traumatic, inflammatory, infections, compressive and neoplastic conditions. This article provides an overview of a variety of pathologies that afflict the spinal cord in an easy to understand format. Their respective imaging manifestations on MRI and differential diagnoses are focused in this review. Early diagnosis and treatment of Myelopathy is critical in preventing or arresting neurological morbidity. PMID- 25801465 TI - WRN translocation from nucleolus to nucleoplasm is regulated by SIRT1 and required for DNA repair and the development of chemoresistance. AB - When defective or absent, Werner syndrome protein (WRN) causes a genetic premature aging disorder called Werner syndrome. Several studies have reported that defects in WRN function are responsible for not only progeria syndrome but also genomic instability via the deregulation of DNA repair, replication, recombination, and telomere stability. Given the importance of WRN in the repair process, we herein investigated the potential role of WRN in drug response by evaluating the DNA repair following exposure to cisplatin in human cancer cell lines. We found that the down-regulation of SIRT1 and inhibition of SIRT1 deacetylase activity blocked the translocation of WRN from the nucleolus to the nucleoplasm in response to genotoxic stresses. In addition, cells expressing low levels of WRN responded favorably to cisplatin, whereas cells expressing high levels responded poorly to cisplatin. The forced expression of WRN protein in chemosensitive cells resulted in an approximately two-fold increase in cell viability in response to cisplatin compared with vector controls and promoted DNA repair, while WRN-deficient cells accumulate unrepaired double-strand breaks following cisplatin exposure. These results suggest that WRN is regulated by SIRT1 and increased expression of WRN might be one of the determinants for the development of chemotherapeutic drug resistance. PMID- 25801466 TI - Interdisciplinary communication and collaboration among physicians, nurses, and unlicensed assistive personnel. AB - PURPOSE: Historically, health care has primarily focused on physician, nurse, and allied healthcare provider triads. Using a phenomenological approach, this study explores the potential for hospital-based interdisciplinary care provided by physicians, nurses, and unlicensed assistive personnel (UAPs). DESIGN: This phenomenological study used a purposive nonprobability, criterion-based, convenience sample from a metropolitan hospital. THEORETICAL FOUNDATION: Malhotra's (1981) Schutzian lifeworld phenomenological orchestra study provided the theoretical basis for the conductorless orchestra model, which guided this study. In an orchestra, each member sees and hears the musical score from a different vantage point or perspective and has a different stock of knowledge or talent; however, members work together to produce a cohesive performance. Like the orchestra, individual talents and perspectives of physicians, nurses, and UAPs can be collaboratively blended to create a symphony: enhanced patient centered care. METHODS: Qualitative semistructured face-to-face, individual interviews were carefully transcribed and coded with the aid of NVivo 9, a qualitative data analysis software program, to discover emergent patterns and themes. FINDINGS: The study suggests that most of the time physicians, nurses, and UAPs operate as separate healthcare providers who barely speak to each other. Physicians see themselves as the primary patient care decision makers. Many physicians acknowledge the importance of nurses' knowledge and expertise. On the other hand, the study indicates a hierarchical, subservient relationship among nurses and UAPs. Physicians and nurses tend to work together or consult each other at times, but UAPs are rarely included in any type of meaningful patient discussion. CONCLUSIONS: Since physicians, nurses, and UAPs each provide portions of patient care, coordination of the various treatments and interventions provided is critical to prevent errors and fragmentation of care. Tensions, misunderstandings, and conflicts caused by differences of opinions and interests can interfere with effective interdisciplinary communications and collaboration. Improving patient safety in the hospital requires addressing the current hierarchical professional structure inherent in healthcare delivery. A hospital patient care model based on the conductorless orchestra model would mitigate hierarchy; recognize physician, nurse, and UAP contributions to care; promote improved communication and collaboration; and enhance patient safety. CLINICAL RELEVANCE: Study results provide additional information supporting interdisciplinary communication and collaboration education and training among physicians, nurses, and UAPs to support positive patient care outcomes. PMID- 25801468 TI - Resident health-related quality of life in Swiss nursing homes. AB - BACKGROUND: Health-related quality of life (HRQOL) levels and their determinants in those living in nursing homes are unclear. The aim of this study was to investigate different HRQOL domains as a function of the degree of cognitive impairment and to explore associations between them and possible determinants of HRQOL. METHOD: Five HRQOL domains using the Minimum Data Set - Health Status Index (MDS-HSI) were investigated in a large sample of nursing home residents depending on cognitive performance levels derived from the Cognitive Performance Scale. Large effect size associations between clinical variables and the different HRQOL domains were looked for. RESULTS: HRQOL domains are impaired to variable degrees but with similar profiles depending on the cognitive performance level. Basic activities of daily living are a major factor associated with some but not all HRQOL domains and vary little with the degree of cognitive impairment. LIMITATIONS: This study is limited by the general difficulties related to measuring HRQOL in patients with cognitive impairment and the reduced number of variables considered among those potentially influencing HRQOL. CONCLUSION: HRQOL dimensions are not all linearly associated with increasing cognitive impairment in NH patients. Longitudinal studies are required to determine how the different HRQOL domains evolve over time in NH residents. PMID- 25801469 TI - A high incidence of chromosome abnormalities in two-cell stage porcine IVP embryos. AB - In pigs, in vitro production is difficult with a high occurrence of polyspermy and low blastocyst formation rates. To test the hypothesis that this may, at least in part, be due to chromosomal errors, we employed whole genome amplification and comparative genomic hybridization, performing comprehensive chromosome analysis to assess both cells of the two-cell stage in vitro porcine embryos. We thus described the incidence, nature and origin of chromosome abnormalities, i.e. whether they derived from incorrect meiotic division during gametogenesis or aberrant mitotic division in the zygote. We observed that 19 out of 51 (37%) of two-cell stage early pig IVP embryos had a chromosome abnormality, mostly originating from an abnormal division in the zygote. Moreover, we frequently encountered multiple aneuploidies and segmental chromosome aberrations. These results indicate that the pig may be particularly sensitive to in vitro production, which may, in turn, be due to incorrect chromosome segregations during meiosis and early cleavage divisions. We thus accept our hypothesis that chromosome abnormality could explain poor IVP outcomes in pigs. PMID- 25801470 TI - Testing the utility of site-specific recombinases for manipulations of genome of moenomycin producer Streptomyces ghanaensis ATCC14672. AB - Streptomyces ghanaensis ATCC14672 is the producer of phosphoglycolipid antibiotics moenomycins that for almost 40 years were used worldwide as an animal feed additive. As the use of moenomycins narrows down (due to bans in the EU and some other countries), it opens the opportunity to develop much-needed antibiotics against Gram-positive human pathogens, such as cocci. It is desirable to develop ATCC14672 strains accumulating only certain members of moenomycin family which would facilitate their purification, analysis and/or chemical modification. Here we tested site-specific recombinases (SSRs) as a tool to manipulate the genome of ATCC14672 and to achieve aforementioned goals. We show that of three SSRs tested--Cre, Dre, and Flp--the first two efficiently catalyzed recombination reactions, while Flp showed no activity in ATCC14672 cells. Cre recombinase can be reused at least three times to modify ATCC14672 genome without detrimental effects, such as large-scale inversions or deletions. Properties of the generated strains and SSRs are discussed. PMID- 25801472 TI - Cardiovascular disease research activity in the Middle East: a bibliometric analysis. AB - OBJECTIVES: The Middle East has a high prevalence of noncommunicable chronic diseases. The objective of this article was to quantify the research activity in cardiovascular disease (CVD) in the Middle East over the last 10 years. METHODS: A Medline search was conducted using medical subject headings and author affiliation to retrieve research articles published from the Middle East between 2003 and 2012 (inclusive). RESULTS: Middle Eastern countries produced only 3% of the total number of CVD research articles in the world. However, the overall trend showed an increase in the number of articles over the years, mainly from Turkey and Iran. Within this region, the ratio of CVD to non-CVD publications was highest in Qatar (0.23). Lebanon ranked first in the number of CVD publications per million persons (PMP) averaging 194.2 publications PMP and Turkey ranked highest in the number of CVD publications per US$1000 gross domestic product (GDP) per capita averaging 954 CVD publications per US$1000 GDP per capita. CONCLUSIONS: Although there has been a drive towards greater publication of CVD papers in the last decade, research activity in the Middle East still lags behinds developed countries. Greater productivity is anticipated to emerge to accompany the recent significant investment in research in Gulf countries. PMID- 25801471 TI - The compensatory renin-angiotensin system in the central regulation of arterial pressure: new avenues and new challenges. AB - Hypertension is a widespread condition that affects millions of people around the world and has a major impact in public health. The classic renin-angiotensin system is a complex system comprised of multiple peptides and pathways that have been the driver of drug development over the years to control hypertension. However, there are still patients whose hypertension is very difficult to control with current drugs and strategies, thus motivating further research in this field. In the past two decades, important discoveries have expanded our knowledge of this system and new pathways are emerging that are helping us understand the complex interaction taking place not only in the periphery, but also in the central nervous system where the renin-angiotensin system is also very active. A new arm, called the ACE2/Ang-(1-7)/Mas receptor axis, was shown to exert antihypertensive properties and serve as a counterbalance to the classic ACE/angiotensin II/AT1 receptor axis, in this way modulating or even counteracting the negative effects of angiotensin II in blood pressure regulation and water retention. Modulation of this new axis through ACE2 activation, ADAM17 regulation or AT1 receptor internalization are some of the novel avenues and challenges that have the potential to become a target for new drug research and development for the treatment of hypertension. PMID- 25801473 TI - The changing landscape in translocator protein (TSPO) function. AB - Translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is an outer mitochondrial membrane protein. TSPO has been shown to cooperate with steroidogenic acute regulatory protein (StAR) and function in the transport of cholesterol into mitochondria. TSPO has also been considered as a structural component of the mitochondrial permeability transition pore (MPTP). However, recent advances have changed these views of TSPO's functions and have prompted a re-evaluation of established concepts. This review summarizes the history of TSPO, key elements of the debate, and functional experiments that have changed our understanding. Moving forward, we examine how this fundamental change impacts our understanding of TSPO and affects the future of TSPO as a therapeutic and diagnostic target. PMID- 25801474 TI - Needs Assessment and Theory-Based Promotion of Voluntary Medical Male Circumcision (VMMC) Among Male Sexually Transmitted Diseases Patients (MSTDP) in China. AB - Voluntary medical male circumcision (VMMC) is an evidence-based biomedical HIV prevention method. It is under-utilized in countries outside Africa, including China. The present single-arm, non-blinded test-of-concept trial was designed to promote VMMC among 179 male sexually transmitted diseases patients (MSTDP) in Shenzhen, China. It was based on behavioral health theories and results of a formative survey. At month 4, 45.5 % of the MSTDP responded positively to the intervention (19.9 % had taken up VMMC and 25.6 % intended to do so in the next 6 months). Adjusted analysis showed that cognitive variables measured at baseline (perceived self-efficacy, subjective norm and behavioral intention) significantly predicted adoption of VMMC during the 4-month follow-up period. Process evaluation involving clinicians of the STD clinics was positive. At month 6, 36.0 % of the circumcised participants used condom less frequently with their regular sex partner. We recommend scaling up the intervention, taking prevention of risk compensation into account. PMID- 25801475 TI - "Please Don't Make Me Ask for Help": Implicit Social Support and Mental Health in Chinese Individuals Living with HIV. AB - China faces a growing HIV epidemic; psychosocial needs of HIV-positive individuals remain largely unaddressed. Research is needed to consider the gap between need for mental healthcare and lack of sufficiently trained professionals, in a culturally acceptable manner. This study assessed explicit and implicit forms of social support and mental health symptoms in 120 HIV positive Chinese. Explicit social support refers to interactions involving active disclosure and discussion of problems and request for assistance, whereas implicit social support refers to the emotional comfort one obtains from social networks without disclosing problems. We hypothesized and found using multiple linear regression, that after controlling for demographics, only implicit, but not explicit social support positively predicted mental health. Future research is warranted on the effects of utilizing implicit social support to bolster mental health, which has the potential to circumvent the issues of both high stigma and low professional resources in this population. PMID- 25801477 TI - Efforts to Find Heterosexual HIV in San Francisco, 2007-2013. AB - Nationally heterosexuals are an HIV prevention priority. In addition to case based HIV surveillance, behavioral surveillance surveys are conducted among heterosexuals living in high AIDS morbidity neighborhoods. We report on risk behaviors and HIV prevalence among "high-risk" heterosexuals in San Francisco. National HIV Behavioral Surveillance System is coordinated by the CDC and implemented in 21 health jurisdictions. The studies were conducted in 2006, 2010 and 2013 in San Francisco. Respondent driven sampling was used to sample participants. Eligible persons were 18-50 years old and had sex with at least one opposite gender partner in the past year. We obtained samples of 371, 421, 165 heterosexuals in 2007, 2010 and 2013, respectively. Some demographics varied across the 3 years. Residential neighborhoods changed, homelessness and healthcare coverage increased. Binge drinking, cocaine and heroin use increased while methamphetamine use declined. There were no changes in numbers of partners, unprotected vaginal intercourse or unprotected anal intercourse. Commercial sex work increased. Even with "fine tuning" of eligibility criteria to attempt to find heterosexual HIV cases, we estimate that HIV prevalence was 0.3, 0.2 and 2.4 % in 2007, 2010 and 2013 respectively. The increase was not statistically significant. For the present, effective prevention among persons in the populations most severely affected by HIV remains the priority, for their own benefit and to prevent transmission to other vulnerable populations to which they may be connected. PMID- 25801476 TI - History of Childhood Abuse, Drinking Motives, Alcohol Use, and Sexual Risk Behavior Among STD Clinic Patients in St. Petersburg, Russia: A Cross-Sectional Study. AB - The relationship between level of childhood abuse (physical and emotional) and sexual risk behavior of sexually transmitted disease clinic patients in St. Petersburg, Russia was examined through path analyses. Mediating variables investigated were: Alcohol Use Disorder Identification Test (AUDIT), drinking motives (for social interaction, to enhance mood, to facilitate sexual encounters), intimate partner violence (IPV), anxiety, and depression symptoms. Results showed a significant indirect effect of childhood abuse on women's sexual risk behavior: higher level of childhood abuse was associated with a greater likelihood of IPV, motivations to drink, leading to higher AUDIT scores and correlated to higher likelihood of having multiple, new or casual sexual partner(s). No significant effect was identified in paths to condom use. Among men, childhood abuse had no significant effect on sexual risk behavior. Reduction in alcohol-related sexual risk behavior may be achieved by addressing the effects of childhood abuse among female participants. PMID- 25801478 TI - Nicorette reborn? E-cigarettes in light of the history of nicotine replacement technology. AB - BACKGROUND: E-cigarettes are currently hotly debated as threatening to re normalize cigarette smoking and make nicotine addiction publicly acceptable once more. In this paper I contextualize the e-cigarette controversy in light of longstanding disagreements about the meaning and significance of nicotine replacement technologies. A concerted effort to develop such technologies first emerged in Sweden at the end of the 1960s, embodying a vital tension. Two competing 'scripts' vied to influence and shape innovative designs. On the one hand, Nicorette chewing gum was conceived as a therapeutic device aiding smoking cessation. On the other hand, it was cast as a cigarette substitute designed to deliver nicotine 'in the right way', thereby advancing the creative destruction of the combustible cigarette as a drug delivery platform. METHOD: Drawing on historical and archival research I outline how these two alternative innovation scripts started out entangled with each other before becoming disentangled, leading to the eventual stabilization of Nicorette gum as a therapeutic product to be deployed in the treatment of smoking as a dependence disorder. RESULTS AND CONCLUSION: While a post-therapeutic future for nicotine replacement was charted by Michael Russell at the beginning of the 1990s, it is only with the rise of e cigarettes after 2003 that such a future has started to verge on reality. E cigarettes can be seen as resurrecting the historically marginalized script of nicotine replacement as dedicated to righting nicotine consumption and freeing it from the wrongful drug delivery of the modern cigarette. PMID- 25801481 TI - Predictors for diagnosing metabolic syndrome among hypertensive patients in a tertiary care centre. AB - Metabolic syndrome (MS) was present in 71% of adult hypertensive subjects according to modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) criteria in a tertiary care health centre. Female gender and higher body mass index (BMI) were predictors for MS among these patients. BMI cut off of 23 (overweight) had sensitivity of 94% and positive predictive value of 75% for diagnosing MS among them. PMID- 25801482 TI - Relationships between the smoking status and plasma fibrinogen, white blood cell count and serum C-reactive protein in Japanese workers. AB - OBJECTIVE: Confirmation of the association between smoking status and biological inflammatory or anticoagulant markers is required in the field of occupational therapy to promote anti-smoking education. The associations between the smoking status and biological markers were clarified. METHODS: The study was performed in 5102 working men aged 30-60 years old. The author measured the plasma fibrinogen, white blood cell count (WBC) and serum high-sensitivity C-reactive protein (CRP) as biomarkers of the smoking status. RESULTS: After adjustment for age, the mean plasma fibrinogen level in never-smokers was significantly lower than that in current smokers. The mean WBC count was also significantly lower in the never smokers than that in current smokers and ex-smokers who had quit within the previous 1 year. Furthermore, the mean log-transformed serum CRP value in never smokers was significantly lower than that in current smokers smoking >=20 cigarettes daily. Spearman's rank correlation coefficients between the plasma fibrinogen and the serum CRP and WBC were 0.561 and 0.243, respectively. The mean plasma fibrinogen, serum CRP and WBC count in the ex-smokers showed a trend toward decreasing as the duration of abstinence became longer. CONCLUSION: Among the three biomarkers, the plasma fibrinogen was the most strongly associated with the smoking status, its value being to be the highest in current smokers smoking >=20 cigarettes daily. The same trend was also observed for the WBC count. PMID- 25801483 TI - Can socioeconomic trajectories during the life influence periodontal disease occurrence in adulthood? Hypotheses from a life-course perspective. AB - Chronic periodontal disease (CPD) is a highly prevalent, multifactorial, bacterially induced inflammatory disease, characterized by pathologic loss of periodontal attachment and alveolar bone with onset mostly in adulthood. While cross-sectional data have demonstrated significant associations between adverse socioeconomic position (SEP) and poor periodontal conditions, there is a gap in the literature on the understanding of how SEPs in different life stages impact on the occurrence of this disease later on. Life-course epidemiology offers different theoretical models to study the pathway of health and illness during the lifespan, and the hypothesis of the present study is that the relationship between SEP and CPD can be explained based on different life-course epidemiology theories: (a) critical period model; (b) critical period with modifier effect model; (c) accumulation of risk model; (d) chain-of-risk model. Under the first theoretical model, the association between SEP and CPD may be explained by an inflammatory hypothesis, considering that childhood adverse socioeconomic backgrounds alter the immunoinflammatory response that leads to disease in adulthood regardless of conditions later in life. The second model postulates that the early life SEP modifies the host immunoinflammatory response, and the risk of disease will be modified over the life-course by socio-behavioural influences. The third, "accumulation of risk model", may explain such relationship taking into account exposures during different periods of life. However, this model does not consider the moment when the exposure occurred, only taking into consideration the number of episodes during the life cycle. Finally, the potential explanation to the role of socioeconomic position on chronic periodontal disease, using a chain-of-risk model, is that early low SEP may cause social stress related to social hierarchies, what may, in turn, trigger endocrine, neural and immune changes, that reflect on elevated levels of cytokines, consequently turning these individuals more likely to develop periodontal disease. To summarize, this paper suggests potential explanations of the relationship between SEP during the lifespan and the occurrence of chronic periodontal disease in adult life, under a life-course framework. Longitudinal studies focusing on such relationship should be conducted, aiming to provide evidence regarding the hypotheses here called in question. PMID- 25801480 TI - The importance of co-stimulation in the orchestration of T helper cell differentiation. AB - Upon their activation, CD4 T cells can differentiate into distinct T helper cell subsets with specialised functions. Different T helper cell subsets produce specific cytokines that mediate beneficial and sometimes detrimental effects, depending on the infection or disease setting. CD4 T-cell priming relies on signals delivered by the T-cell antigen receptor, co-stimulatory receptors and cytokine receptors on the CD4 T-cell surface. Cytokine receptors are well known to deliver instructive signals that direct T helper cell differentiation. However, it is less appreciated that co-stimulatory receptors also exert potent modulatory effects on this process. In this review, we outline the contribution of co-stimulatory and co-inhibitory receptors to the process of T helper cell differentiation, focusing on those pathways for which the underlying mechanisms are best known. Herein, we depict the physiological context of T-cell priming and emphasise the impact of cell-cell communication on directing T helper cell differentiation. PMID- 25801484 TI - Quantum dot-based diabetic foot mapping for diagnosing osteomyelitis and Charcot neuroarthropathy. AB - The location of osteomyelitis is very important in Charcot neuroarthropathy (CN), especially when a physician is considering amputation of the affected extremity. In diabetic CN, the presence of osteomyelitis is likely. Thus, to identify the infected tissue that needs to be removed, the specific area of infection must be correctly identified. Both CN and osteomyelitis have high mortality rates, but osteomyelitis is more life threatening and needs aggressive treatment. We propose a QD-based method for distinguishing CN with sterile inflammation from osteomyelitis that does not require multiple and frequent imaging modalities. The method utilizes two different colored QDs (i.e., red and green). The red QD is attached to a UBI, an antimicrobial peptide, which attaches to bacteria, enabling their detection. The green QD is attached to MDP, which accumulates in areas of inflammation. When these QDs are injected intravenously at the same time, the red QD-UBI accumulates in infected areas and attaches to bacteria, and the green QD MDP accumulates both in areas with sterile inflammation and infected areas. The accumulation of only green QDs in the suspect extremity signifies a sterile inflammation process (CN). However, the accumulation of both the red and green QDs signify infectious and inflammation processes (i.e., osteomyelitis or a soft tissue infection, depending on the location). In the latter case, the treatment needs to be more intensive, with even amputation considered. PMID- 25801485 TI - An insulin based model to explain changes and interactions in human breath holding. AB - Until now oxygen was thought to be the leading factor of hypoxic conditions. Whereas now it appears that insulin is the key regulator of hypoxic conditions. Insulin seems to regulate the redox state of the organism and to determine the breakpoint of human breath-holding. This new hypoxia-insulin hypotheses might have major clinical relevance. Besides the clinical relevance, this hypothesis could explain, for the first time, why the training of the diaphragm, among other factors, results in an increase in breath-holding performance. Elite freedivers/apnea divers are able to reach static breath-holding times to over 6 min. Untrained persons exhibit an unpleasant feeling after more or less a minute. Breath-holding is stopped at the breakpoint. The partial oxygen pressure as well as the carbon dioxide pressure failed to directly influence the breakpoint in earlier studies. The factors that contribute to the breakpoint are still under debate. Under hypoxic conditions the organism needs more glucose, because it changes from the oxygen consuming pentose phosphate (36 ATP/glucose molecule) to the anaerobic glycolytic pathway (2ATP/glucose molecule). Hence insulin, as it promotes the absorption of glucose, is set in the center of interest regarding hypoxic conditions. This paper provides an insulin based model that could explain the changes and interactions in human breath-holding. The correlation between hypoxia and reactive oxygen species (ROS) and their influence on the sympathetic nerve system and hypoxia-inducible factor 1 alpha (HIF-1alpha) is dealt with. It reviews as well the direct interrelation of HIF-1alpha and insulin. The depression of insulin secretion through the vagus nerve activation via inspiration is discussed. Furthermore the paper describes the action of insulin on the carotid bodies and the diaphragm and therefore a possible role in respiration pattern. Freedivers that go over the breakpoint of breath-holding could exhibit seizures and thus the effect of insulin, blood glucose levels and corticosteroids in hippocampal seizures is highlighted. PMID- 25801479 TI - Mycobacterium tuberculosis infection of the 'non-classical immune cell'. AB - Mycobacterium tuberculosis can infect 'non-classical immune cells', which comprise a significant constituency of cells that reside outside of those defined as 'classical immune cells' from myeloid or lymphoid origin. Here we address the influence of specific 'non-classical immune cells' in host responses and their effects in controlling mycobacterial growth or enabling an environment conducive for bacilli persistence. The interaction of M. tuberculosis with epithelial cells, endothelial cells, fibroblasts, adipocytes, glia and neurons and downstream cellular responses that often dictate immune regulation and disease outcome are discussed. Functional integration and synergy between 'classical' and 'non-classical immune cells' are highlighted as critical for determining optimal immune outcomes that favour the host. PMID- 25801486 TI - Neighborhood Crime-Related Safety and Its Relation to Children's Physical Activity. AB - Crime is both a societal safety and public health issue. Examining different measures and aspects of crime-related safety and their correlations may provide insight into the unclear relationship between crime and children's physical activity. We evaluated five neighborhood crime-related safety measures to determine how they were interrelated. We then explored which crime-related safety measures were associated with children's total moderate-to-vigorous physical activity (MVPA) and MVPA in their neighborhoods. Significant positive correlations between observed neighborhood incivilities and parents' perceptions of general crime and disorder were found (r = 0.30, p = 0.0002), as were associations between parents' perceptions of general crime and disorder and perceptions of stranger danger (r = 0.30, p = 0.0002). Parent report of prior crime victimization in their neighborhood was associated with observed neighborhood incivilities (r = 0.22, p = 0.007) and their perceptions of both stranger danger (r = 0.24, p = 0.003) and general crime and disorder (r = 0.37, p < 0.0001). After accounting for covariates, police-reported crime within the census block group in which children lived was associated with less physical activity, both total and in their neighborhood (beta = -0.09, p = 0.005, beta = 0.01, p = 0.02, respectively). Neighborhood-active children living in the lowest crime-quartile neighborhoods based on police reports had 40 min more of total MVPA on average compared to neighborhood-active children living in the highest crime-quartile neighborhoods. Findings suggest that police reports of neighborhood crime may be contributing to lower children's physical activity. PMID- 25801488 TI - Randomized comparison of the i-gel(TM) with the LMA Supreme (TM) in anesthetized adult patients. AB - BACKGROUND: The LMA Supreme(TM) (LMA-S) and i-gel(TM) are two of the most commonly used supraglottic airway devices (SADs) with an inbuilt drain channel. These devices are particularly indicated for performing certain procedures accompanied by high peak airway pressure, such as laparoscopy. This study compared the devices regarding efficacy, safety, ease of use and incidence of adverse events, focusing on the postoperative rate of sore throat, dysphagia or dysphonia and development with time, in patients undergoing laparoscopic cholecystectomy procedures under general anesthesia. METHODS: This was a prospective, randomized, controlled clinical study including 140 patients randomized into 2 groups undergoing elective laparoscopic cholecystectomy to use either i-gel or LMA-S. After the general anesthesia procedure, the speed of insertion, success rates, ease of insertion of the drain tube, leak pressure and tidal volume achieved by the devices were evaluated. The postoperative oropharyngeal discomfort (POPD) during the period of stay of the patients in the recovery room was also recorded. RESULTS: The mean leak pressure was comparable between the two groups (i-gel 28.18 +/- 3.90 cmH2O and LMA-S 27.50 +/- 4 cmH2O, p = 0.09), as well as maximum expiratory tidal volume provided (i-gel 559.60 +/- 45.25 ml and LMA-S 548.95 +/- 56.18 ml, p = 0.12). Insertion times were lower for the i-gel (10 +/- 1.62 s) compared with the LMA-S (11.31 +/- 2.85 s, p = 0.008). Insertion success rate at the first attempt was higher for the LMA-S (95 % compared with i-gel 79 %, p = 0.007). Drain tubes were easier to insert in the LMA-S group (p < 0.001). No differences were found between groups relating to intraoperative complications. Frequency of coughing and visible blood on removal of the device were low and comparable in both groups (p = 0.860 and p = 0.623, respectively). There were no differences relating to the incidence of sore throat, dysphagia or hoarseness at 10 min postoperatively between groups (p = 0.088). The i-gel group complained about a higher sore throat score at 2 h postoperatively (p = 0.009), specifically patients receiving i-gel suffered more from sore throats with 0.24 more points on the visual analog scale (VAS) than patients from the LMA-S group. The i-gel group also reported a lower POPD drop during the first 2 h (p < 0.001). CONCLUSION: No differences were found between i gel and LMA-S regarding leak pressure in the groups of anesthetized patients undergoing laparoscopic cholecystectomy. The LMA-S was easier to insert than the i-gel (based on its better first time success rate) and this device showed better ease of drain tube insertion, although the i-gel was quicker to insert than the LMA-S. The i-gel resulted in higher sore throat scores at 2 h postoperatively and lower POPD reduction during the 2 h period studied in the recovery room was reported. PMID- 25801487 TI - Residential mobility and trajectories of adiposity among adolescents in urban and non-urban neighborhoods. AB - Using data from the 1994-2008 National Longitudinal Study of Adult Health (Add Health), this research examines the relationship between residential mobility and weight gain over time among urban and non-urban young adults. It is theorized that changes in residence act as a barrier to achieving an active lifestyle, which would increase an individual's body mass index (BMI) over time. Relying on linear mixed-effects growth curve models, the results indicate that mobility is protective against weight gain over time after controlling for sociodemographic characteristics. For young adults who are residentially stable in urban neighborhoods, increases in physical activity are associated with a linear decline in BMI. In non-urban areas where respondents are residentially mobile, body weight does not fluctuate as sedentary behavior increases. However, in those areas, weight increases as sedentary behavior increases for those who did not move. Overall, the results suggest that the effect of mobility on weight gain is partially due to the kind of health behaviors that one engages in as well as whether or not one lives in an urban area. Policies geared toward relocating residents (such as Moving to Opportunity), and neighborhood processes that can lead individuals to change residences (such as foreclosures or gentrification) may have adverse health effects depending on whether they are occurring in urban or non-urban areas. PMID- 25801489 TI - Vocal Hygiene Habits and Vocal Handicap Among Conservatory Students of Classical Singing. AB - OBJECTIVES: This study sought to assess classical singing students' compliance with vocal hygiene practices identified in the literature and to explore the relationship between self-reported vocal hygiene practice and self-reported singing voice handicap in this population. The primary hypothesis was that increased attention to commonly recommended vocal hygiene practices would correlate with reduced singing voice handicap. STUDY DESIGN: This is a cross sectional, survey-based study. METHODS: An anonymous survey assessing demographics, attention to 11 common vocal hygiene recommendations in both performance and nonperformance periods, and the Singing Voice Handicap Index 10 (SVHI-10) was distributed to classical singing teachers to be administered to their students at two major schools of music. RESULTS: Of the 215 surveys distributed, 108 were returned (50.2%), of which 4 were incomplete and discarded from analysis. Conservatory students of classical singing reported a moderate degree of vocal handicap (mean SVHI-10, 12; range, 0-29). Singers reported considering all 11 vocal hygiene factors more frequently when preparing for performances than when not preparing for performances. Of these, significant correlations with increased handicap were identified for consideration of stress reduction in nonperformance (P = 0.01) and performance periods (P = 0.02) and with decreased handicap for consideration of singing voice use in performance periods alone (P = 0.02). CONCLUSIONS: Conservatory students of classical singing report more assiduous attention to vocal hygiene practices when preparing for performances and report moderate degrees of vocal handicap overall. These students may have elevated risk for dysphonia and voice disorders which is not effectively addressed through common vocal hygiene recommendations alone. PMID- 25801490 TI - Clonal evolution of acute myeloid leukemia relapsed after 19 years of remission. PMID- 25801491 TI - Investigation of prognostic factors for post-traumatic olfactory dysfunction. AB - BACKGROUND: Post-traumatic olfactory dysfunction is common but has a poor prognosis. The purpose of this study was to analyze the effect of clinical features on improvements in post-traumatic olfactory dysfunction. METHODS: From 2007 to 2013, patients with post-traumatic olfactory dysfunction were enrolled. Olfactory function was assessed using the Sniffin' Sticks test at the first and final visits. Olfactory improvement was defined as a change in olfactory state to an improved level. Variables with a potential effect on improvements in olfactory dysfunction, including age, sex, time from trauma to first visit, initial olfactory function, observation time, and olfactory bulb integrity, were entered into logistic regression analysis. RESULTS: In total, 107 patients were included, with a mean age of 40 years. The mean follow-up period was 9.4 months. Eighteen patients (16.8%) had improvements with regard to olfactory function. No clinical factors were found to influence olfactory recovery in univariate and multivariate analyses (all p > 0.05). In addition, there were no differences in clinical features between the patients with and without olfactory recovery (all p > 0.05). CONCLUSION: No significantly favorable prognostic factors for post-traumatic olfactory recovery were identified, reflecting, to some extent, the poor prognosis of post-traumatic olfactory damage. The results of this study provide useful information that clinical physicians can use when counseling patients with post-traumatic olfactory disorder regarding the prognosis, observation choice, and possible treatment strategy. PMID- 25801492 TI - Rituximab induction therapy, survival benefits, and the increasing selection of radiotherapy as the postinduction treatment in patients with primary mediastinal large B-cell lymphoma. AB - BACKGROUND: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare malignancy that has been reported in young individuals, especially young women. Patients with PMBCL commonly receive rituximab induction. This single-institution study was designed to analyze the clinical benefits of rituximab induction and its impact on postinduction treatments (PITs), especially radiotherapy. METHODS: The benefits of rituximab induction were evaluated by complete response (CR), early treatment failure, relapse, and overall survival (OS) rates. The impact of the induction therapy on the adoption of PIT was evaluated by the proportion of patients who had received at the last follow up any PIT modality [i.e., radiotherapy or hematopoietic stem cell transplantation (HSCT)], radiotherapy alone, HSCT alone, or both modalities. RESULTS: Between 1999 and 2012, 48 PMBCL patients (29 men, 60%) were identified; they had a median age of 31 years. Twenty eight patients received rituximab induction; of these, 23 (82%) patients also underwent fludeoxyglucose-positron emission tomography (FDG-PET) evaluation. Rituximab induction was significantly associated with higher rates of CR and OS, and lower rates of early treatment failure and relapse. Regarding PIT, patients with rituximab induction were more likely to receive radiotherapy alone [with rituximab induction (25%) vs. without rituximab induction (5%)], and patients with FDG-PET evaluation were similarly more likely to receive radiotherapy alone [with FDG-PET evaluation (28.6%) vs. without FDG-PET evaluation (0%)]. In multivariate analysis, age older than 60 years [hazard ratio (HR), 16.697; 95% confidence interval (CI), 1.106-252.022; p = 0.042] and rituximab induction (HR, 0.089; 95% CI, 0.012-0.653; p = 0.017) were significantly associated with OS. CONCLUSION: Rituximab improved the CR and OS rates of patients with PMBCL, but these improvements may be attributable to the increased use of radiotherapy (which may have also resulted from FDG-PET evaluation). PMID- 25801494 TI - From silk spinning in insects and spiders to advanced silk fibroin drug delivery systems. AB - The natural process of silk spinning covers a fascinating versatility of aggregate states, ranging from colloidal solutions through hydrogels to solid systems. The transition among these states is controlled by a carefully orchestrated process in vivo. Major players within the natural process include the control of spatial pH throughout passage of the silk dope, the composition and type of ions, and fluid flow mechanics within the duct, respectively. The function of these input parameters on the spinning process is reviewed before detailing their impact on the design and manufacture of silk based drug delivery systems (DDS). Examples are reported including the control of hydrogel formation during storage or significant parameters controlling precipitation in the presence of appropriate salts, respectively. The review details the use of silk fibroin (SF) to develop liquid, semiliquid or solid DDS with a focus on the control of SF crystallization, particle formation, and drug-SF interaction for tailored drug load. PMID- 25801493 TI - Evaluating a physiologically based pharmacokinetic model for prediction of omeprazole clearance and assessing ethnic sensitivity in CYP2C19 metabolic pathway. AB - PURPOSE: The purpose of this study is to evaluate the ethnicity-specific population models in the SimCYP Simulator(r) for prediction of omeprazole clearance with attention to differences in the CYP2C19 metabolic pathway. METHODS: The SimCYP(r) models incorporating Caucasian, Chinese, and Japanese population-specific demographic, physiological, and enzyme data were applied to simulate omeprazole pharmacokinetics. Published pharmacokinetic data of omeprazole after intravenous or oral administration in Caucasian, Chinese, and Japanese were used for the evaluation. RESULTS: Following oral administration, the ratio of the predicted to observed geometric mean of omeprazole clearance in Caucasian extensive metabolizers (EMs) was 0.88. The ratios in Chinese EMs were 1.16 and 0.99 after intravenous and oral administration, respectively. The ratios in Japanese EMs were 0.88 and 0.71 after intravenous and oral administration, respectively. Significant differences (2-fold) in the observed oral clearance of omeprazole were identified between Caucasian and Asian (Chinese and Japanese) EMs while the observed oral and intravenous clearances of omeprazole were similar between Chinese and Japanese EMs. Physiologically based pharmacokinetics (PBPK) models within SimCYP accurately predicted the difference in the observed oral clearance between Caucasian and Chinese EMs but overpredicted the difference between Caucasians and Japanese EMs due to under-prediction of oral clearance in Japanese EMs. CONCLUSIONS: The PBPK model within SimCYP adequately predicted omeprazole clearance in Caucasian, Chinese, and Japanese EMs and the 2-fold differences in clearance of omeprazole between Caucasian and Asian EMs. This may lead to early identification of ethnic sensitivity in clearance and the need for different dosing regimens in a specific ethnic group for substrates of CYP2C19 which can support the rational design of bridging clinical trials. PMID- 25801495 TI - Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers. AB - To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic Cys). In vitro release studies showed that the peptide was released from the CMD s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2MUM-2mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro. Furthermore, it was shown that the CMD-s-s-peptide conjugates were highly accumulated in tumor tissue in a mouse xenograft model using BxPC-3 cells, and the anti-tumor activity of the conjugate was more effective than that of the free peptide. In addition, the plasma concentrations of peptide were moderately increased and the elimination half-life of the peptide was prolonged after intravenous injection of CMD-s-s-peptide conjugates. These results demonstrated that the conjugate based on thiolated CMD polymer would be potentially useful carriers for the sustained release of the hybrid peptide in vivo. PMID- 25801496 TI - Recent advances in management of diabetic macular edema. AB - Diabetic macular edema (DME) is the leading cause of moderate vision loss in diabetics. Modalities to image and monitor DME have evolved much in the last decade. Systemic control is the most important part of management. Available ocular management options include intravitreal antivascular endothelial growth factor (anti-VEGF) agents, laser, steroids (intravitreal or peribulbar), vitrectomy, topical medications and others. Anti-VEGF agents are increasingly being used in clinical practice with good clinical response and are currently the preferred mode of treatment worldwide. PMID- 25801497 TI - Substance-related coping, HIV-related factors, and mental health among an HIV positive sexual minority community sample. AB - HIV-positive status poses a unique set of social stressors, especially among lesbian, gay, and bisexual (LGB) persons. Among these difficulties are the internalization of HIV-related stigma and poor mental health. Unfortunately, substance use as a coping mechanism is also common, dependent on other demographic factors, among HIV-positive and LGB samples. The present study integrates these bodies of literature by examining main and interactive effects of HIV-related experiences (i.e., disclosure of HIV-positive status, fear of disclosure, HIV-related victimization, and internalized HIV-related stigma) and substance-related coping with discrimination as they impact mental health (i.e., stress, anxiety, depressive symptoms, and suicide and self-injury proneness). Participants were 216 HIV-positive LGB community members from an urban community medical clinic. Prominent results included: (1) robust negative effects of internalized HIV-related stigma on all mental health indicators when controlling for other HIV-related experiences and (2) a significant interaction in which substance-related coping significantly increases suicide proneness, only for those who have disclosed HIV-positive status to family or friends. Results are discussed with respect to theoretical perspectives of internalized stigma, implications for clinical work with LGB persons of HIV-positive status, and future research. PMID- 25801498 TI - Expession patterns of mesenchyme specification genes in two distantly related echinoids, Glyptocidaris crenularis and Echinocardium cordatum. AB - The molecular mechanism of the larval mesenchyme cell specification in echinoids has been well analyzed. However, most of the data have been provided by studies of a single group of echinoids, the order Camarodonta. Little is known about this mechanism in other echinoid orders. We examined the expression patterns of mesenchyme specification genes, micro1, hesC, alx1, tbr, ets1, cyp1, and gcm, in the two non-Camarodonta echinoids, Glyptocidaris crenularis and Echinocardium cordatum. We found that the expression patterns of some genes contained characteristics that were unique to one of the species; others were shared by the two species. Some of the shared characteristics of G. crenularis and E. cordatum are not found in the species belonging to Camarodonta, suggesting the derived status of this order. The expression of ets1 in E. cordatum aboral ectoderm is one of the molecular level modifications possibly related to an evolutionarily novel larval structure, the posterior process. Our results suggest that a considerable number of modifications in the mesenchyme specification mechanisms have been introduced during the echinoid evolution. PMID- 25801499 TI - Ovarian reserve after treatment with alkylating agents during childhood. AB - STUDY QUESTION: What is the effect of different alkylating agents used without pelvic radiation to treat childhood cancer in girls on the ovarian reserve in survivors? SUMMARY ANSWER: Ovarian reserve seems to be particularly reduced in survivors who received procarbazine (in most cases for Hodgkin lymphoma) or high dose chemotherapy; procarbazine but not cyclophosphamide dose is associated with diminished ovarian reserve. WHAT IS KNOWN ALREADY: A few studies have demonstrated diminished ovarian reserve in survivors after various combination therapies, but the individual role of each treatment is difficult to assess. STUDY DESIGN: Prospective cross-sectional study, involving 105 survivors and 20 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and five survivors aged 17-40 years and 20 controls investigated on Days 2-5 of a menstrual cycle or Day 7 of an oral contraceptive pill-free interval. MAIN OUTCOME MEASURES: ovarian surface area (OS), total number of antral follicles (AFC), serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and anti-Mullerian hormone (AMH). MAIN RESULTS AND THE ROLE OF CHANCE: Survivors had a lower OS than controls: 3.5 versus 4.4 cm(2) per ovary (P = 0.0004), and lower AMH levels: 10.7 versus 22 pmol/l (P = 0.003). Ovarian markers (OS, AMH, AFC) were worse in patients who received high-dose compared with conventional-dose alkylating agents (P = 0.01 for OS, P = 0.002 for AMH, P < 0.0001 for AFC). Hodgkin lymphoma survivors seemed to have a greater reduction in ovarian reserve than survivors of leukaemia (P = 0.04 for AMH, P = 0.01 for AFC), sarcoma (P = 0.04 for AMH, P = 0.04 for AFC) and other lymphomas (P = 0.04 for AFC). A multiple linear regression analysis showed that procarbazine but not cyclophosphamide nor ifosfamide dose was associated with reduced OS (P = 0.0003), AFC (P = 0.0007), AMH (P < 0.0001) and higher FSH levels (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: The small percentage of participating survivors (28%) from the total cohort does not allow conclusion on fertility issues because of possible response bias. The association between procarbazine and HL makes it impossible to dissociate their individual impacts on ovarian reserve. The number of controls is small, but ovarian volume and AMH levels in survivors were compared with published normal values and results were unchanged. WIDER IMPLICATIONS OF THE FINDINGS: Early detection and follow-up of compromised ovarian function after cancer therapy should help physicians to counsel young survivors about their fertility window. However, longitudinal follow-up is required to determine the rate of progression from low ovarian reserve to premature ovarian failure. STUDY FUNDING/COMPETING INTERESTS: La Ligue contre le Cancer (grant no., PRAYN7497). The authors have no competing interests to disclose. PMID- 25801500 TI - NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression. AB - Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A) allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors. PMID- 25801501 TI - The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study. AB - Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA. PMID- 25801503 TI - Norwegian elderly patients' need for drug information and attitudes towards medication use reviews in community pharmacies. AB - OBJECTIVES: Medication use review (MUR) is a community pharmacy service in several countries. Knowledge about what patients want from such a service is limited. The aim of this study was therefore to investigate Norwegian elderly patients' need for drug information and their attitudes towards MURs. METHODS: In Norway's two largest cities, 162 patients (72% women; mean age: 78.9 years) who used at least one prescription drug were recruited from 18 senior centres. They were interviewed personally with a structured questionnaire (29 closed and 4 open ended questions). KEY FINDINGS: The average number of prescription drugs used was 4.4. Seventy per cent also used over-the-counter drugs. The main source of drug information was the general practitioner (GP) followed by package inserts and pharmacy staff. For drug-related problems, 62% would contact the GP compared with 24% who preferred the pharmacist. Fifty per cent remembered no information when collecting prescriptions. However, 56% wanted to know more about their medication and 55% were interested in a MUR. The main topics they wished to address were effect/side effects and interactions. Lack of privacy was reported to be a major obstacle in the current situation. CONCLUSIONS: This study shows that community pharmacies in Norway play a minor role regarding drug information to elderly polypharmacy patients. The GP is both their main information source and whom they contact for drug-related problems. However, half of the patients would like to know more about their medication. More than half were positive towards taking part in a MUR. PMID- 25801504 TI - Alzheimer's disease: a financial crisis and the Commonwealth of Pennsylvania. PMID- 25801502 TI - D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats. AB - There is considerable interest in NMDAR modulators to enhance memory and treat neuropsychiatric disorders such as addiction, depression, and schizophrenia. D serine and D-cycloserine, the NMDAR activators at the glycine site, are of particular interest because they have been used in humans without serious adverse effects. Interestingly, D-serine also inhibits some NMDARs active at hyperpolarized potentials (HA-NMDARs), and we previously found that HA-NMDARs within the nucleus accumbens core (NAcore) are critical for promoting compulsion like alcohol drinking, where rats consume alcohol despite pairing with an aversive stimulus such as quinine, a paradigm considered to model compulsive aspects of human alcohol use disorders (AUDs). Here, we examined the impact of D serine and D-cycloserine on this aversion-resistant alcohol intake (that persists despite adulteration with quinine) and consumption of quinine-free alcohol. Systemic D-serine reduced aversion-resistant alcohol drinking, without altering consumption of quinine-free alcohol or saccharin with or without quinine. Importantly, D-serine within the NAcore but not the dorsolateral striatum also selectively reduced aversion-resistant alcohol drinking. In addition, D-serine inhibited EPSCs evoked at -70 mV in vitro by optogenetic stimulation of mPFC NAcore terminals in alcohol-drinking rats, similar to reported effects of the NMDAR blocker AP5. Further, D-serine preexposure occluded AP5 inhibition of mPFC evoked EPSCs, suggesting that D-serine reduced EPSCs by inhibiting HA-NMDARs. Systemic D-cycloserine also selectively reduced intake of quinine-adulterated alcohol, and D-cycloserine inhibited NAcore HA-NMDARs in vitro. Our results indicate that HA-NMDAR modulators can reduce aversion-resistant alcohol drinking, and support testing of D-serine and D-cycloserine as immediately accessible, FDA approved drugs to treat AUDs. PMID- 25801505 TI - A non-invasive platform for functional characterization of stem-cell-derived cardiomyocytes with applications in cardiotoxicity testing. AB - We present a non-invasive method to characterize the function of pluripotent stem cell-derived cardiomyocytes based on video microscopy and image analysis. The platform, called Pulse, generates automated measurements of beating frequency, beat duration, amplitude, and beat-to-beat variation based on motion analysis of phase-contrast images captured at a fast frame rate. Using Pulse, we demonstrate recapitulation of drug effects in stem-cell-derived cardiomyocytes without the use of exogenous labels and show that our platform can be used for high throughput cardiotoxicity drug screening and studying physiologically relevant phenotypes. PMID- 25801506 TI - MicroRNA-302/367 cluster governs hESC self-renewal by dually regulating cell cycle and apoptosis pathways. AB - miR-302/367 is the most abundant miRNA cluster in human embryonic stem cells (hESCs) and can promote somatic cell reprogramming. However, its role in hESCs remains poorly understood. Here, we studied functional roles of the endogenous miR-302/367 cluster in hESCs by employing specific TALE-based transcriptional repressors. We revealed that miR-302/367 cluster dually regulates hESC cell cycle and apoptosis in dose-dependent manner. Gene profiling and functional studies identified key targets of the miR-302/367 cluster in regulating hESC self-renewal and apoptosis. We demonstrate that in addition to its role in cell cycle regulation, miR-302/367 cluster conquers apoptosis by downregulating BNIP3L/Nix (a BH3-only proapoptotic factor) and upregulating BCL-xL expression. Furthermore, we show that butyrate, a natural compound, upregulates miR-302/367 cluster expression and alleviates hESCs from apoptosis induced by knockdown of miR 302/367 cluster. In summary, our findings provide new insights in molecular mechanisms of how miR-302/367 cluster regulates hESCs. PMID- 25801507 TI - Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs. AB - Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs. PMID- 25801508 TI - Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre. AB - The origins of individual fat depots are not well understood, and thus, the availability of tools useful for studying depot-specific adipose tissue development and function is limited. Cre drivers that selectively target only brown adipocyte, subcutaneous white adipocyte, or visceral white adipocyte precursors would have significant value because they could be used to selectively study individual depots without impacting the adipocyte precursors or intrinsic metabolic properties of the other depots. Here, we show that the majority of the precursor and mature subcutaneous white adipocytes in adult C57Bl/6 mice are labeled by Prx1-Cre. In sharp contrast, few to no brown adipocytes or visceral white adipocytes are marked by Prx1-Cre. This suggests that Prx1-Cre-mediated recombination may be useful for making depot-restricted genetic manipulations in subcutaneous white adipocyte precursor cells, particularly when targeting genes with fat-specific functions. PMID- 25801509 TI - Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs. AB - Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patients' motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using MNs derived from SMA patient specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches. PMID- 25801510 TI - [Trail walking test for assessment of motor cognitive interference in older adults. Development and evaluation of the psychometric properties of the procedure]. AB - BACKGROUND: Activities of daily living (ADL), such as walking, often involve the added complexity of walking while doing other activities (i.e. dual task walking). A complex walking task may require a greater motor and mental capacity, resulting in decrements in gait performance not seen for simple walking tasks. AIM: The purpose of this study was to determine if the trail walking test (TWT), the mobile adaptation of the trail making test (TMT), could be a reliable and valid early detection tool to discriminate between non-fallers and fallers. MATERIAL AND METHODS: This study examined dual task costs of a cognitive and a sensorimotor task (walking) in 94 older adults aged 50-81 years (average age M = 67.4 years, SD +/- 7.34). Based on the idea of the paper and pencil TMT, participants walked along a fixed pathway (TWT-1), stepped on targets with increasing sequential numbers (i.e. 1, 2, 3, TWT-2), and increasing sequential numbers and letters (i.e. 1, A, 2, B, 3, C, TWT-3). The dual task costs were calculated for each task. Additionally, the following tests were conducted: TMT, block tapping test (BTT), timed up and go (TUG) test, 30s chair rising test, 10 m walking time test with and without head turns, German physical activity questionnaire (German PAQ-50 +) and the activities-specific balance confidence (ABC-D) scale. RESULTS: The TWT performance times as well as errors increased with increasing age. Reliability coefficients were high (interclass correlation ICC > 0.90). Correlations between the different TWT conditions and potential falls-related predictors were moderate to high (r = -0.430 to 0.699). Of the participants 34 % reported falling in the past year. The stepwise logistic regression analysis revealed that the dual task costs for the numbers and letters (odds ratio OR 1.162, 95 % confidence interval CI 1.058-1.277, p = 0.002), the ABC-D (OR 0.767, 95 % CI 0.651-0.904, p = 0.002) and exercise (OR 1.027, 95 % CI 1.008-1.046, p = 0.006) were significantly related to falls and 91.6 % of cases were correctly classified. CONCLUSION: The results indicate that high-level cognitive processes interfere with automatic processes such as walking. The TWT which converts a relevant fall risk-associated standard neuropsychological test (TMT) with increasing cognitive load into a mobility task, was shown to be a feasible, reliable and valid tool for older adults to discriminate between non fallers and fallers. PMID- 25801512 TI - Effects of inpatient geriatric interventions in a German geriatric hospital: Impact on ADL, mobility and cognitive status. AB - BACKGROUND: Given the demographic changes, the need for effective geriatric intervention is obvious. Geriatric care aims to maintain the highest possible level of independence and quality of life and to reduce the risk of need for care. OBJECTIVES: This study investigated the benefits of geriatric care on functional performance, mobility and cognition. MATERIAL AND METHODS: This study involved a retrospective analysis of clinical data from 646 patients. At hospital admission and discharge functional status was assessed using the Barthel index. Mobility was evaluated by means of the Tinetti test and cognition by the mini mental state examination (MMSE). A follow-up was conducted on 112 patients 2-5 months after hospital discharge. Statistical analysis included t-tests including Cohen's d for effect size and multivariate regression analysis. RESULTS: The mean age of the study population was 81.1 +/- 7.1 years including 439 women (68%) and 207 men (32%). There were significant average improvements for activities of daily living (ADL), mobility and cognition comparing discharge and admission scores. For functional and mobility status, effect sizes were medium to high. Regression analyses showed that ADL improvement was predicted by functional, mobile and cognitive status at admission. Follow-up analyses revealed a high percentage of former patients still living at home and an overall maintenance of ADL levels. CONCLUSION: Geriatric patients seem to experience long-term improvements during geriatric treatment, which appears to fulfill its aim of recovering independence. For a better understanding of relevant factors for the recreation of geriatric patients, further research is needed, e.g. with respect to the impact of the nutritional status. PMID- 25801514 TI - [Interdisciplinarity in gerontology: Theoretical problems and practical challenges]. AB - Philosophy of science is the theoretical background of this article. Firstly, a definition of interdisciplinarity is given, integrating experiences from longitudinal studies in gerontology and arguing for rejecting the large vocable "interdisciplinarity", because of its overloaded meaning. Secondly, science oriented, sociopsychological and practical barriers of interdisciplinary work in gerontology are presented, whereby the central statement is that interdisciplinarity is preconditionally dependent on a "culture of understanding". Thirdly, a model of interdisciplinarity in gerontology is shown. In general, this article does not focus on the question whether gerontology is a multidisciplinary, interdisciplinary or transdisciplinary discipline but how the requirement of interdisciplinarity can be successfully implemented. In conclusion, interdisciplinarity is not established due to the subject (of aging) or a methodological approach but evolves based on reciprocal contact between different disciplines, which can be entitled "fair cooperation." PMID- 25801513 TI - What does delirium cost? An economic evaluation of hyperactive delirium. AB - BACKGROUND: Demographic changes have resulted in an increase in the number of older (> 75 years) multimorbid patients in clinics. In addition to the primary acute diagnoses that lead to hospitalization, this group of patients often has cognitive dysfunctions, such as delirium. According to clinical experience, delirium patients are more time-consuming for clinicians and their function is often poor. The costs caused by delirium patients are currently unknown. In the present study, a retrospective examination of a database was carried out to calculate the costs that arise during the clinical treatment of documented delirium patients. SETTING AND METHODS: The purpose of this retrospective analysis was to collect information recorded by nursing personnel trained in the treatment of delirium and information from a manual documentation matrix for additional time expenditure. In the database analysis anonymous data of previously discharged patients for a time window of 3 months were analyzed. Documented additional expenditure for patients with hyperactive delirium at hospitalization were analyzed by personnel. Material costs, the duration of hospitalization by main diagnosis and age clusters during hospitalization until discharge were also examined. The analysis was performed in a hospital with internal wards. RESULTS: Data for 82 hyperactive delirium patients were examined and an average of approximately 240 min of additional personnel expenditure for these patients was found. These patients were approximately 10 years older (p < 0.01) and were hospitalized for an average of 4.2 days longer (p < 0.01) than non delirium patients. Hyperactive delirium usually developed within the first 5 days of hospitalization and lasted 1.6 days on average. Patients for whom hyperactive delirium was detected early were hospitalized for significantly less time than those for whom it was detected late (6.85 versus 13.61 days, p = 0.002). Additionally, calculated personnel and material costs, including costs affecting the hospitalization period, amounted to approximately 1200 ? per hyperactive delirium patient. This corresponds to approximately 0.3 CMP (casemix points) per patient. CONCLUSION: The calculations of personnel and material costs and duration of hospitalization in patients with hyperactive delirium demonstrated significant additional costs. Early routine detection of delirium can be achieved through training and this approach leads to a shortening of the hospitalization period and lower costs. PMID- 25801517 TI - [Do we want to become gerontologists? Gerontology between professional politics and science]. PMID- 25801515 TI - [Gerontology--Multi-, inter- and transdisciplinarity in theory and practise?]. AB - Given the suggestion to establish gerontology as an independent scientific discipline, the paper discusses the options for further development. It is argued that multidisciplinarity, interdisciplinarity and transdisciplinarity are the only alternatives that should be explicitly highlighted as a special feature of gerontology and that advantages and disadvantages of these alternatives should be discussed further. PMID- 25801518 TI - [Growing old differently: Transdisciplinary perspective]. AB - Growing old differently: the phrase is intended to call something other to mind than merely the fact that images and forms of old age and aging have multiplied and diversified to an enormous extent. The suggestion put forward here is that otherness (as opposed to mere differences) should be positively reinforced. In other words, it is not just a matter of noting different forms of old age and aging but more than this, of seeking out opportunities for aging differently. In order to explore this, the article follows an older strand of theory, which has recently come to be frequently quoted in gerontology: the phenomenology of difference as reasoned analytically by Levinas and Sartre and applied to gerontology by Amery and de Beauvoir. Here, opportunities for aging crucially depend on the way we look at it, how we observe and describe it and not least, how gerontology frames it. A distinction is made between two perspectives and their associated consequences for old age: alienation and alterity. Alienation means looking at old age above all as a disconcerting "other", as a perplexing, problematic deviation from the norm of vitality. Alterity, by contrast, refers to different options for living life in old age: options to be explored and opened up in contradistinction to cultural or academic alienation. Not least, the article appeals for diversity in scholarly approaches and for cross-disciplinary perspectives. PMID- 25801520 TI - Emotional arousal modulation of right temporoparietal cortex in depression depends on parental depression status in women: first evidence. AB - BACKGROUND: Structural and Electroencephalography (EEG) abnormalities in right temporoparietal cortex have been associated with family history of depression (FH). Here we investigate if functional abnormalities in this area, indexed by attenuated responses to emotionally arousing stimuli, are also family-history dependent. METHODS: Neuromagnetic activity for emotional and neutral complex scenes was recorded by Magnetoencephalography (MEG) in 20 depressed patients without, 8 depressed patients with FH, and 15 healthy controls. Emotion-sensitive neuronal steady state responses were cortical source localized and tested for group-by-emotion interactions. RESULTS: The group-by-emotion interaction (F(4, 80)=4.4, p=0.004) was explained by a significant modulation of right temporoparietal cortex activity by emotional arousal in controls and patients without FH. This effect was reduced in FH positive patients. The difference between patient groups remained when clinical variables such as symptom severity were accounted for. LIMITATIONS: All patients were medicated, but differences between patient groups remained after accounting for medication dosage. Further, the sample size was limited, but data-driven resampling statistics showed the robustness of our effects. Finally, the sample consists of female patients only and we cannot generalize our results to male samples. CONCLUSIONS: Patients with FH show impaired recruitment of attention-relevant cortical circuitry by emotional stimuli. The neuroanatomical locus of this effect accords with previous reports on structural abnormalities and electrophysiological deficits at rest in individuals with FH. Our results speak to the relevance of right temporoparietal dysfunction in emotional information processing as a potential endophenotype for depression with FH. PMID- 25801521 TI - A meta-analysis investigating the prevalence and moderators of migraines among people with bipolar disorder. AB - BACKGROUND: Uncertainty exists regarding the prevalence and moderators of migraine comorbidity among people with bipolar disorder (BD). We conducted a meta analysis and meta-regression to investigate the prevalence and moderators of migraine among people with BD. METHOD: Two authors independently searched major electronic databases from inception till 02/2015. Articles were included that reported the prevalence of migraine in people with BD with or without a control group. A random effects meta-analysis and exploratory meta-regression were conducted. RESULTS: Fourteen studies were included encompassing 3976 individuals with BD (mean age 35.5 years, SD 7.6, 29% male). The overall pooled prevalence of migraine was 34.8% (95% CI=25.54-44.69). The prevalence of migraine was higher among people with BD-II (54.17%, 95% CI=31.52-75.95, n=742) compared to BD-I (32.7%, 95% CI=18.16-49.19, n=2138, z=3.97, p<0.0001). The prevalence of migraine was 33.9% (95% CI=26.02-42.44), 39.5% (95% CI=18.81-62.39) and 47.11% (95% CI=22.24-72.77) in North America, Europe and South America respectively. The prevalence of migraine was higher when classified according to recognized criteria at 47.91% (95% CI=32.51-63.5) compared to non-recognized criteria (20.0%, 95% CI=12.44-29.06, z=-8.40, p<0.0001). Meta regression suggests mean age may be a potential moderator. CONCLUSION: Migraine is common and burdensome among people with BD. People with BD-II appear to be particularly affected. Nonetheless, future research is required to better understand these relationships, with a special emphasis toward the course specifiers of comorbid migraine cases of either BD-I vs. BD-II. PMID- 25801522 TI - Mortality of subjects with mood disorders in the Lundby community cohort: a follow-up over 50 years. AB - AIMS: To compare causes of death and mortality among subjects with and without mood disorder in the Lundby Cohort and to analyse additional mental disorders as risk factors for mortality in subjects with mood disorders. BACKGROUND: The Lundby study is a longitudinal study that investigated mental health in an unselected population. The study commenced in 1947; the population was further investigated in 1957, 1972, and 1997. METHODS: Experienced psychiatrists performed semi-structured diagnostic interviews, and best estimate consensus diagnoses of mental disorders were assessed at each field investigation. Subjects with mood disorder (n=508, 195 males, 313 females) were identified until 1997. Causes and dates of death between 1947 and 2011 were obtained from the Swedish cause of death register and were compared between subjects diagnosed with mood disorder and other participants. Mortality was compared between those with mood disorders and the remaining cohort with Cox regression analyses. Other mental disorders were considered as risk factors for death for subjects with mood disorders. RESULTS: The hazard ratio for mortality in mood disorders was HR=1.18. However, the mortality was elevated only for males, HR=1.5. Comorbid anxiety disorders, organic disorders, dementia and psychotic disorders were significant risk factors for death. A total of 6.3% of the participants with mood disorder and 1.2% of the remaining participants committed suicide. CONCLUSIONS: As expected, the suicide rate was higher among participants with mood disorders. Only males with mood disorders had elevated mortality. The impact on mortality from other mental disorders seems to vary between the genders. PMID- 25801523 TI - The bipolar II disorder personality traits, a true syndrome? AB - BACKGROUND: The author was struck by the similarities and commonality of complaints, aside from mood swings, made by Bipolar II patients and started registrating these complaints. This registrational work eventually led to the development of The Bipolar II Syndome Checklist. The aim of this work was to understand how widely the Bipolar II disorder affects the personality, and what disturbing personality traits are the most common? Deliberately, no attempt was made to diagnose psychiatric comorbidities, in the hope that one would get a clearer view of what symptoms, if any, could be considered a natural part of the Bipolar II Disorder. As far as the author knows this is a novel approach. METHOD: 105 Bipolar II patients completed the Bipolar II Syndrome Checklist. The answers to the 44 questions on the list are presented in tables. RESULTS: Symptoms like anxiety, low self esteem, paranoia, extreme hurtfulness, migraine, Post Partum Depression, obsessive traits, alcoholism in the family are amongst the findings which will be presented in greater detail. LIMITATIONS: No control group. Bipolar I patients excluded. The Bipolar II Syndrome Checklist has not been systematically validated. CONCLUSIONS: The results show that Bipolar II Disorder causes multiple symptoms so commonly that it may be justified to describe it as a syndrome, The Bipolar II Syndrome. Also these disturbances commonly lie in families of Bipolar II patients and are in all likelihood, greatly underdiagnosed. The clinical relevance of this study lies in increasing our knowledge and understanding of the nature of the Bipolar II Disorder, which in all probability will increase the diagnostic and treatment accuracy, since clinicians are more likely to scan for other symptoms needing treatment. PMID- 25801524 TI - Epidemiology of Merkel cell carcinoma in New Zealand: a population-based study. PMID- 25801525 TI - Guanidine sulfate-assisted synthesis of hexagonal WO3 nanoparticles with enhanced adsorption properties. AB - Large surface area hexagonal phase WO3 (h-WO3) nanowires were synthesized by a hydrothermal route with the assistance of C2H12N6O4S. They were characterized by XRD, SEM, TEM, BET, FT-IR and XPS. It is shown that C2H12N6O4S not only acts as a stabilizer to facilitate the generation of a metastable hexagonal phase, but also functions as a structure directing agent to assist the construction of nanowires. The obtained h-WO3 possesses a large specific surface area and numerous adsorption functional groups such as -OH groups. These characteristics result in an excellent adsorption performance for the removal of strontium from acidic aqueous solutions. A maximum adsorption capacity of 52.93 mg g(-1) was achieved on the h-WO3 prepared in the presence of C2H12N6O4S. This value is almost two times higher than that of bare h-WO3 (no C2H12N6O4S). The effects of pH, contact time, initial Sr(2+) concentration and ion strength on Sr(2+) removal from the solution by h-WO3 were systematically investigated. The adsorption mechanism involving the combination of electrostatic attraction and ion exchange for the adsorption of Sr(2+) is proposed. Based on our results, h-WO3 with high adsorption capacity and good surface characteristics exhibits great potential for the removal of Sr(2+) from radioactive wastewater. PMID- 25801530 TI - Bad luck and cancer: Does evolution spin the wheel of fortune? PMID- 25801526 TI - The Role of 7,8-Dihydroxyflavone in Preventing Dendrite Degeneration in Cortex After Moderate Traumatic Brain Injury. AB - Our previous research showed that traumatic brain injury (TBI) induced by controlled cortical impact (CCI) not only causes massive cell death, but also results in extensive dendrite degeneration in those spared neurons in the cortex. Cell death and dendrite degeneration in the cortex may contribute to persistent cognitive, sensory, and motor dysfunction. There is still no approach available to prevent cells from death and dendrites from degeneration following TBI. When we treated the animals with a small molecule, 7,8-dihydroxyflavone (DHF) that mimics the function of brain-derived neurotrophic factor (BDNF) through provoking TrkB activation reduced dendrite swellings in the cortex. DHF treatment also prevented dendritic spine loss after TBI. Functional analysis showed that DHF improved rotarod performance on the third day after surgery. These results suggest that although DHF treatment did not significantly reduced neuron death, it prevented dendrites from degenerating and protected dendritic spines against TBI insult. Consequently, DHF can partially improve the behavior outcomes after TBI. PMID- 25801527 TI - An Exploration of the Reliability and Validity of the Spanish Version of the 'Voice and You' (VAY): A Scale for Measuring the Relationship with Voices. AB - The purpose of this study was to adapt the 'Voice and You' Scale (VAY) (Hayward, Denney, Vaughan, & Fowler, 2008) to Spanish and explore its psychometric properties for measuring the perceived relationship with voices. A sample of 50 psychiatric patients with verbal auditory hallucinations (48 had a psychotic disorder and two a borderline personality disorder) was used. Its reliability was calculated using the Cronbach's alpha and test-retest, and concurrent validity by the Pearson correlation coefficient of the VAY with the Beliefs About Voices Questionnaire and the Psychotic Symptom Rating Scales. The results showed that internal consistency of the Spanish version of the VAY ranged from 0.74 to 0.84 on the various subscales, and test-retest reliability varied from 0.74 to 0.83 on three subscales (voice 'dominance', 'intrusiveness' and hearer 'dependence'), and was lower (0.68) on the hearer 'distance' subscale. Concurrent validity was acceptable as significant associations were found with the Beliefs About Voices Questionnaire and the Psychotic Symptom Rating Scales subscales. It is concluded that the Spanish version of the VAY is a reliable and valid instrument that can assist the exploration of voices within relational frameworks across research and clinical domains. KEY PRACTITIONER MESSAGE: The Spanish version of the VAY is a reliable, valid instrument for evaluating the perception a person can have about his or her relationship with the voices and how the person relates to them. Voices that are perceived as relating dominantly and intrusively, and from whom distance is sought, seem to be distressing and cause disturbance. Voices that are related to dependently are perceived as having benevolent intent and are engaged with. Benevolent or neutral voices may be considered as intrusive because of the intensity and frequency with which they are experienced. PMID- 25801532 TI - Nitroxy/azido-functionalized triazoles as potential energetic plasticizers. AB - The synthesis of a series of nitroxy- and azido-functionalized compounds, based on 4-amino-3,5-di(hydroxymethyl)-1,2,4-triazole, for possible use as an energetic plasticizers is described. All compounds were fully characterized. Two of them were further confirmed by X-ray single crystal diffraction. Energetic performance was calculated by using EXPLO5 v6.01 based on calculated heats of formation (Gaussian 03) and experimentally determined densities at 25 degrees C. The results show that the nitration product 1-nitro-3,5-di(nitroxymethyl)-1,2,4 triazole, containing a nitro group and two nitroxy groups, exhibits good detonation properties (D=8574 m s(-1) , P=32.7 GPa). In addition, its low melting point makes it very attractive as an energetic plasticizer in solid propellants. PMID- 25801531 TI - Bismuth sulfide nanoflowers for detection of X-rays in the mammographic energy range. AB - The increased use of diagnostic x-rays, especially in the field of medical radiology, has necessitated a significant demand for high resolution, real-time radiation detectors. In this regard, the photoresponse of bismuth sulfide (Bi2S3), an n-type semiconducting metal chalcogenide, to low energy x-rays has been investigated in this study. In recent years, several types of nanomaterials of Bi2S3 have been widely studied for optoelectronic and thermoelectric applications. However, photoresponse of Bi2S3 nanomaterials for dosimetric applications has not yet been reported. The photosensitivity of Bi2S3 with nanoscale "flower-like" structures was characterized under x-ray tube-potentials typically used in mammographic procedures. Both dark current and photocurrent were measured under varying x-ray doses, field sizes, and bias voltages for each of the tube potentials - 20, 23, 26 and 30 kV. Results show that the Bi2S3 nanoflowers instantaneously responded to even minor changes in the dose delivered. The photoresponse was found to be relatively high (few nA) at bias voltage as low as +1 V, and fairly repeatable for both short and long exposures to mammographic x-rays with minimal or no loss in sensitivity. The overall dose sensitivity of the Bi2S3 nanoflowers was found to be similar to that of a micro ionization chamber. PMID- 25801533 TI - Engineering cortical neuron polarity with nanomagnets on a chip. AB - Intra- and extracellular signaling play critical roles in cell polarity, ultimately leading to the development of functional cell-cell connections, tissues, and organs. In the brain, pathologically oriented neurons are often the cause for disordered circuits, severely impacting motor function, perception, and memory. Aside from control through gene expression and signaling pathways, it is known that nervous system development can be manipulated by mechanical stimuli (e.g., outgrowth of axons through externally applied forces). The inverse is true as well: intracellular molecular signals can be converted into forces to yield axonal outgrowth. The complete role played by mechanical signals in mediating single-cell polarity, however, remains currently unclear. Here we employ highly parallelized nanomagnets on a chip to exert local mechanical stimuli on cortical neurons, independently of the amount of superparamagnetic nanoparticles taken up by the cells. The chip-based approach was utilized to quantify the effect of nanoparticle-mediated forces on the intracellular cytoskeleton as visualized by the distribution of the microtubule-associated protein tau. While single cortical neurons prefer to assemble tau proteins following poly-L-lysine surface cues, an optimal force range of 4.5-70 pN by the nanomagnets initiated a tau distribution opposed to the pattern cue. In larger cell clusters (groups comprising six or more cells), nanoparticle-mediated forces induced tau repositioning in an observed range of 190-270 pN, and initiation of magnetic field-directed cell displacement was observed at forces above 300 pN. Our findings lay the groundwork for high-resolution mechanical encoding of neural networks in vitro, mechanically driven cell polarization in brain tissues, and neurotherapeutic approaches using functionalized superparamagnetic nanoparticles to potentially restore disordered neural circuits. PMID- 25801534 TI - In vivo evaluation of juvenile xanthogranuloma with high-resolution optical coherence tomography and reflectance confocal microscopy and histopathological correlation. PMID- 25801535 TI - Separation of parent homopolymers from poly(ethylene oxide) and polystyrene-based block copolymers by liquid chromatography under limiting conditions of desorption -1. Determination of the suitable molar mass range and optimization of chromatographic conditions. AB - We studied molar mass limits for the LC LCD separation of parent polystyrene (PS) and poly(ethylene oxide) (PEO) homopolymers from PEO/PS based block copolymers and we identified optimized chromatographic conditions. Time delays between barriers and sample injections were 0-2-3'10. Eluent was composed of dimethylformamide (DMF) 40 wt.% and 1-chlorobutane (CLB) 60 wt.%; Barrier 1 (B1), which retained block copolymer, was composed of 100 wt.% CLB and Barrier 2 (B2), which retained PEO, was a mixture of DMF and CLB, which proportions were adjusted to studied block copolymers. With B2 composed of DMF 23 wt.% and CLB 77 wt.%, we obtained successful separation of PS23K-b-PEO35K-b-PS23K (56.5 wt.% of PS, the subscripts indicate the molar mass in kg mol(-1) of each polymer part in the block copolymer) from its parent homopolymers. With B2 adjusted to DMF 30 wt.% and CLB 70 wt.%, PS2.3K-b-PEO3.1K (42.6 wt.% of PS) was also efficiently separated from its parent homopolymers. PMID- 25801536 TI - Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts. AB - Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femurs from rats given a mixture of CBD and Delta(9) -tetrahydrocannabinol (THC) for 8 weeks were markedly increased by CBD. This effect is not shared by THC (the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks postfracture followed by attenuation of the CBD effect at 8 weeks. Using micro computed tomography (MUCT), the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier transform infrared (FTIR) spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes. PMID- 25801537 TI - Verbal naming test for use with older adults: development and initial validation. AB - Naming or word-finding tasks are a mainstay of the typical neuropsychological evaluation, particularly with older adults. However, many older adults have significant visual impairment and there are currently no such word-finding tasks developed for use with older visually impaired populations. This study presents a verbal, non-visual measure of word-finding for use in the evaluation of older adults with possible dysnomia. Stimuli were chosen based on their frequency of usage in everyday spoken language. A 60-item scale was created and given to 131 older Veterans. Rasch analyses were conducted and differential item functioning assessed to eliminate poorly-performing items. The final 55-item scale had a coefficient alpha of 0.84 and correlated with the Neuropsychological Assessment Battery Naming test, r=0.84, p<.01, Delis-Kaplan Executive Function System (D KEFS) Category Fluency, r=0.45, p<.01, and the D-KEFS Letter Fluency, r=0.40, p<.01. ROC analyses found the measure to have sensitivity of 79% and specificity of 85% for detecting dysnomia. Patients with dysnomia performed worse on the measure than patients with intact word-finding, t(84)=8.2, p<.001. Patients with no cognitive impairment performed significantly better than patients with mild cognitive impairment, who performed significantly better than patients with dementia. This new measure shows promise in the neuropsychological evaluation of word-finding ability in older adults with or without visual impairment. Future directions include the development of a shorter version and the generation of additional normative data. PMID- 25801538 TI - Fulminant aspergillosis of the nose and paranasal sinuses: a new clinical entity. 1980. PMID- 25801539 TI - Structural and optical studies of pHEMA encapsulated ZnS:Ni2+ nanoparticles. AB - In this study, ZnS:Ni(2+) nanostructures have been synthesized through chemical precipitation method using poly (2-hydroxyethyl methacrylate) (pHEMA) as capping agent. The structural, morphological and optical properties at different pHEMA concentration of ZnS:Ni(2+) were studied by using X-ray diffraction (XRD), high resolution transmission electron microscopy (HR-TEM), UV-Vis Spectroscopy (UV Vis), fourier transform infrared spectroscopy (FT-IR), Photoluminescence (PL). The Average crystalline size of the nanoparticles was found to be in the range of ~3.59-4.36 nm. The surface morphological analysis reveals that the pHEMA capped nanoparticles showed homogeneous smooth surface. HR-TEM analysis reminds the original size of pHEMA capped nanoparticles. The band gap investigation revealed the size dependent of quantum confined nanoparticles. The immobilized nanoparticles in pHEMA matrix were verified by FT-IR studies. Novel luminescence properties have been observed for uncapped and pHEMA capped ZnS nanoparticles. The optimal capping concentration was successfully determined and its influence on photoluminescence behavior has been thoroughly analyzed. PMID- 25801540 TI - The electronic cigarette: the new source of nickel contact allergy of the 21st century? PMID- 25801541 TI - Emergency endotracheal intubation-related adverse events in bronchial asthma exacerbation: can anesthesiologists attenuate the risk? AB - PURPOSE: Airway management in severe bronchial asthma exacerbation (BAE) carries very high risk and should be performed by experienced providers. However, no objective data are available on the association between the laryngoscopist's specialty and endotracheal intubation (ETI)-related adverse events in patients with severe bronchial asthma. In this paper, we compare emergency ETI-related adverse events in patients with severe BAE between anesthesiologists and other specialists. METHODS: This historical cohort study was conducted at a Japanese teaching hospital. We analyzed all BAE patients who underwent ETI in our emergency department from January 2002 to January 2014. Primary exposure was the specialty of the first laryngoscopist (anesthesiologist vs. other specialist). The primary outcome measure was the occurrence of an ETI-related adverse event, including severe bronchospasm after laryngoscopy, hypoxemia, regurgitation, unrecognized esophageal intubation, and ventricular tachycardia. RESULTS: Of 39 patients, 21 (53.8 %) were intubated by an anesthesiologist and 18 (46.2 %) by other specialists. Crude analysis revealed that ETI performed by an anesthesiologist was significantly associated with attenuated risk of ETI-related adverse events [odds ratio (OR) 0.090, 95 % confidence interval (CI) 0.020-0.41, p = 0.001]. The benefit of attenuated risk remained significant after adjusting for potential confounders, including Glasgow Coma Score, age, and use of a neuromuscular blocking agent (OR 0.058, 95 % CI 0.010-0.35, p = 0.0020). CONCLUSIONS: Anesthesiologist as first exposure was independently associated with attenuated risk of ETI-related adverse events in patients with severe BAE. The skill and knowledge of anesthesiologists should be applied to high-risk airway management whenever possible. PMID- 25801543 TI - Drug fever caused by propofol in the intensive care unit. AB - Few studies have reported that fever is caused by intravenous sedative drugs even though these agents are widely used. We present a case of propofol-induced drug fever. A 57-year-old woman underwent hepatic segmentectomy. Although she was diagnosed with type I glycogen storage disease when in her twenties, her liver function was normal. As the operative hemorrhage was high, the patient was transferred to the intensive care unit (ICU). Her temperature at ICU admission was 35.8 degrees C, and sedation with propofol and dexmedetomidine was initiated. Two hours after admission to the ICU, the patient had a fever of 38 39.5 degrees C. Remittent fever persisted until day 5 after surgery. Because of her persistent fever, pneumonia was suspected and antibiotics were initiated on day 4 after surgery. As the fever persisted after the initiation of antibiotics, drug fever was suspected. On day 5 after surgery, propofol infusion was discontinued and the patient was extubated. Her temperature of 37.7 degrees C at the discontinuation of propofol infusion, and rapidly decreased to 36.1 degrees C in the following 3 h. Propofol-induced drug fever must be considered in cases of fever of unknown origin when patients receive propofol and appear inappropriately well for the degree of fever that they have. PMID- 25801544 TI - Using a hackathon for interprofessional health education opportunities. PMID- 25801542 TI - Fosaprepitant versus ondansetron for the prevention of postoperative nausea and vomiting in patients who undergo gynecologic abdominal surgery with patient controlled epidural analgesia: a prospective, randomized, double-blind study. AB - PURPOSE: Postoperative nausea and vomiting (PONV) is the most common postoperative complication. The postoperative use of opioids is known to increase the incidence. We compared fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, and ondansetron for their preventive effects on PONV in patients who underwent gynecologic abdominal surgery with patient-controlled epidural analgesia. METHODS: This prospective, double-blind, randomized study comprised 44 patients who underwent gynecologic abdominal surgery. They were randomly allocated to receive 150 mg intravenous fosaprepitant (n = 24; NKI group) or 4 mg ondansetron (n = 20; ONS group) before anesthesia, which was maintained with volatile anesthetics, remifentanil, fentanyl, and rocuronium. All patients received postoperative fentanyl by patient-controlled epidural anesthesia. The incidence of nausea and vomiting, complete response rate (i.e., no vomiting and no rescue antiemetic use), rescue antiemetic use, nausea score (0-3), and visual analog scale score (VAS 0-10) for pain were recorded at 2, 24, 48, and 72 h after surgery. RESULTS: No (0 %) patient in the NKI group experienced vomiting after surgery; however, 4-6 (20-30 %) of 20 patients in the ONS group experienced vomiting. This difference was significant at 0-24, 0-48, and 0-72 h. During the study period, no significant differences existed between the NK1 and ONS groups in the incidence of PONV, complete response rate, rescue antiemetic use, nausea score, and VAS score for pain. CONCLUSION: Compared to ondansetron, fosaprepitant more effectively decreased the incidence of vomiting in patients who underwent gynecologic abdominal surgery with patient-controlled epidural analgesia. PMID- 25801545 TI - Personality and attention: Levels of neuroticism and extraversion can predict attentional performance during a change detection task. AB - The present study demonstrates that levels of extraversion and neuroticism can predict attentional performance during a change detection task. After completing a change detection task built on the flicker paradigm, participants were assessed for personality traits using the Revised Eysenck Personality Questionnaire (EPQ R). Multiple regression analyses revealed that higher levels of extraversion predict increased change detection accuracies, while higher levels of neuroticism predict decreased change detection accuracies. In addition, neurotic individuals exhibited decreased sensitivity A' and increased fixation dwell times. Hierarchical regression analyses further revealed that eye movement measures mediate the relationship between neuroticism and change detection accuracies. Based on the current results, we propose that neuroticism is associated with decreased attentional control over the visual field, presumably due to decreased attentional disengagement. Extraversion can predict increased attentional performance, but the effect is smaller than the relationship between neuroticism and attention. PMID- 25801547 TI - Diagnosis, prognosis, and clinical management of mild traumatic brain injury. AB - Concussion and mild traumatic brain injury (TBI) are interchangeable terms to describe a common disorder with substantial effects on public health. Advances in brain imaging, non-imaging biomarkers, and neuropathology during the past 15 years have required researchers, clinicians, and policy makers to revise their views about mild TBI as a fully reversible insult that can be repeated without consequences. These advances have led to guidelines on management of mild TBI in civilians, military personnel, and athletes, but their widespread dissemination to clinical management in emergency departments and community-based health care is still needed. The absence of unity on the definition of mild TBI, the scarcity of prospective data concerning the long-term effects of repeated mild TBI and subconcussive impacts, and the need to further develop evidence-based interventions to mitigate the long-term sequelae are areas for future research that will improve outcomes, reduce morbidity and costs, and alleviate delayed consequences that have only recently come to light. PMID- 25801546 TI - Flexible pulse-controlled fiber laser. AB - Controlled flexible pulses have widespread applications in the fields of fiber telecommunication, optical sensing, metrology, and microscopy. Here, we report a compact pulse-controlled all-fiber laser by exploiting an intracavity fiber Bragg grating (FBG) system as a flexible filter. The width and wavelength of pulses can be tuned independently by vertically and horizontally translating a cantilever beam, respectively. The pulse width of the laser can be tuned flexibly and accurately from ~7 to ~150 ps by controlling the bandwidth of FBG. The wavelength of pulse can be tuned precisely with the range of >20 nm. The flexible laser is precisely controlled and insensitive to environmental perturbations. This fiber based laser is a simple, stable, and low-cost source for various applications where the width-tunable and/or wavelength-tunable pulses are necessary. PMID- 25801548 TI - An assessment of anti-Mullerian hormone in predicting mating outcomes in female hamsters that have undergone natural and chemically-accelerated reproductive aging. AB - In mammals, female fertility declines with age due in part to a progressive loss of ovarian follicles. The rate of follicle decline varies among individuals making it difficult to predict the age of onset of reproductive senescence. Serum anti-Mullerian hormone (AMH) concentrations correlate with the numbers of ovarian follicles, and therefore, AMH could be a useful predictor of female fertility. In women and some production animals, AMH is used to identify which individuals will respond best to ovarian stimulation for assisted reproductive technologies. However, few studies have evaluated AMH's predictive value in unassisted reproduction, and they have yielded conflicting results. To assess the predictive value of AMH in the context of reproductive aging, we prospectively measured serum AMH in 9-month-old Siberian hamsters shortly before breeding them. Female Siberian hamsters experience substantial declines in fertility and fecundity by 9months of age. We also measured serum AMH in 5-month-old females treated with 4 vinylcyclohexene diepoxide (VCD), which selectively destroys ovarian follicles and functionally accelerates ovarian aging. Vehicle-treated 5-month-old females served as controls. AMH concentrations were significantly reduced in VCD-treated females yet many females with low AMH reproduced successfully. On average, both young and old hamsters that littered had higher AMH concentrations than females that did not. However, some females with relatively high AMH concentrations failed to litter, whereas several with low AMH succeeded. Our results suggest that mean AMH concentration can predict mating outcomes on a population or group level, but on an individual basis, a single AMH determination is less informative. PMID- 25801549 TI - Interaction of specific temporal phase relations of circadian neural oscillations and long term photoperiodic responses in Japanese quail, Coturnix coturnix japonica. AB - Specific temporal phase relations of neural oscillations are reported to regulate gonadal activity in many avian species but their interaction with photo-sexual response are still unclear. Hence in the present study, 3week old Japanese quail maintained in short days (experiment 1) received normal saline (SD control) or serotonin precursor 5-HTP and dopamine precursor l-DOPA injections at the interval of 12h (SD 12-h) for 13days. At 37week of age, one subgroup of SD 12-h received these drugs at the interval of 8-h (SD 12-h+8-h). In the second experiment, 3week old quail were injected with 5-HTP and l-DOPA 8h apart (LD 8-h) and then maintained under long days. At the age of 37weeks, one subgroup of these LD quail was retreated with 5-HTP and l-DOPA at the interval of 8h (LD 8-h+8-h). Cloacal gland volume was monitored weekly up to 45weeks of age in both experiments and other reproductive parameters were monitored at 23 and 45week of age. These results indicate that 12-h phase relation of neurotransmitter precursors not only initiates early onset of scotorefractoriness i.e., full development of gonad even under short-day length but maintains it continuously (a long lasting effect) unlike control and the 8-h relation dissipates it, making the quail scotosensitive. On the other hand, the 8-h phase relation suppresses the gonado-stimulatory effect of long days but this effect is transitory. Thus the 12-h phase relation is gonado-stimulatory under short day conditions and the 8-h relation is gonado-inhibitory even under long days, inducing scotorefractoriness and photorefractoriness, respectively, it is suggested that effects of specific temporal phase relation of circadian neural oscillations similar to photoperiodic effects, are not only mediated by HPG axis but may also modulate the classical photoperiodic responses of Japanese quail. PMID- 25801550 TI - Photo quiz. Diarrhea, anasarca, and severe hypoalbuminemia in an AIDS patient. Diagnosis: AIDS-related visceral Kaposi sarcoma (KS) with protein-losing enteropathy (PLE). PMID- 25801552 TI - Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria. AB - The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] MUg . h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] MUg . h/liter, respectively; P >= 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria. PMID- 25801553 TI - Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in healthy adults. AB - The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 * 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 * 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 * 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of sublingual artemether given over 5 days as either 10 3.0-mg or 5 6.0-mg actuations. Frequent blood samples were drawn postdose. Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (>=1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (>=1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing. PMID- 25801554 TI - Exposure to total and protein-unbound rifampin is not affected by malnutrition in Indonesian tuberculosis patients. AB - Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m(2)), malnourished (BMI of <18.5 kg/m(2)), and well-nourished (BMI of >=18.5 kg/m(2)) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0-24 (geometric mean, 59.2 versus 48.2 h . mg/liter; P = 0.02) and higher unbound AUC0-24 (geometric mean, 6.2 versus 4.8 h . mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships. PMID- 25801555 TI - CARB-17 family of beta-lactamases mediates intrinsic resistance to penicillins in Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is commonly resistant to ampicillin, yet the mechanisms underlying this phenomenon are not clear. In this study, a novel class A carbenicillin-hydrolyzing beta-lactamase (CARB) family of beta-lactamases, bla(CARB-17), was identified and found to be responsible for the intrinsic penicillin resistance in V. parahaemolyticus. Importantly, bla(CARB-17)-like genes were present in all 293 V. parahaemolyticus genome sequences available in GenBank and detectable in all 91 V. parahaemolyticus food isolates, further confirming the intrinsic nature of this gene. PMID- 25801557 TI - Population pharmacokinetic analysis of voriconazole from a pharmacokinetic study with immunocompromised Japanese pediatric subjects. AB - A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole. PMID- 25801556 TI - Preliminary clinical study of the effect of ascorbic acid on colistin-associated nephrotoxicity. AB - Nephrotoxicity is a dose-limiting factor of colistin, a last-line therapy for multidrug-resistant Gram-negative bacterial infections. An earlier animal study revealed a protective effect of ascorbic acid against colistin-induced nephrotoxicity. The present randomized controlled study was conducted in 28 patients and aimed to investigate the potential nephroprotective effect of intravenous ascorbic acid (2 g every 12 h) against colistin-associated nephrotoxicity in patients requiring intravenous colistin. Thirteen patients received colistin plus ascorbic acid, whereas 15 received colistin alone. Nephrotoxicity was defined by the RIFLE classification system. Additionally, urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-d glucosaminidase (NAG) were measured as markers of renal damage, and plasma colistin concentrations were quantified. The baseline characteristics, clinical features, and concomitant treatments of the patients in the two groups were comparable. The incidences of nephrotoxicity were 53.8% (7/13) and 60.0% (9/15) in the colistin-ascorbic acid group and the colistin group, respectively (P = 0.956; relative risk [RR], 0.9; 95% confidence interval, 0.47 to 1.72). In both groups, the urinary excretion rates of NGAL and NAG on day 3 or 5 of colistin treatment and at the end of colistin treatment were significantly higher than those at the respective baselines (P < 0.05). However, the urinary excretion rates of these biomarkers at the various times during colistin treatment did not differ significantly between the groups (P > 0.05). The plasma colistin concentrations in the two groups were not significantly different (P > 0.28). The clinical and microbiological outcomes and mortality of the patients in the two groups were not significantly different. This preliminary study suggests that ascorbic acid does not offer a nephroprotective effect for patients receiving intravenous colistin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01501968.). PMID- 25801558 TI - Trends in susceptibility of Escherichia coli from intra-abdominal infections to ertapenem and comparators in the United States according to data from the SMART program, 2009 to 2013. AB - Antimicrobial resistance in Enterobacteriaceae, including resistance to carbapenems, is increasing worldwide. However, using U.S. Study for Monitoring Antimicrobial Resistance Trends (SMART) data for 2009 to 2013, no statistically significant decreasing susceptibility trends were found overall for Escherichia coli isolates from patients with intra-abdominal infections. In the subset of isolates from community-associated infections, susceptibility to levofloxacin decreased significantly and the increasing rate of multidrug-resistant E. coli approached statistical significance. In 2013, ertapenem, imipenem, and amikacin showed the highest susceptibility rates (>=99%) and fluoroquinolones the lowest (<70%). The 10 non-ertapenem-susceptible isolates (0.3% of all E. coli isolates) encoded one or more carbapenemases, extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases, or non-ESBL beta-lactamases. PMID- 25801559 TI - Arbekacin activity against contemporary clinical bacteria isolated from patients hospitalized with pneumonia. AB - Arbekacin is a broad-spectrum aminoglycoside licensed for systemic use in Japan and under clinical development as an inhalation solution in the United States. We evaluated the occurrence of organisms isolated from pneumonias in U.S. hospitalized patients (PHP), including ventilator-associated pneumonia (VAP), and the in vitro activity of arbekacin. Organism frequency was evaluated from a collection of 2,203 bacterial isolates (339 from VAP) consecutively collected from 25 medical centers in 2012 through the SENTRY Antimicrobial Surveillance Program. Arbekacin activity was tested against 904 isolates from PHP collected in 2012 from 62 U.S. medical centers and 303 multidrug-resistant (MDR) organisms collected worldwide in 2009 and 2010 from various infection types. Susceptibility to arbekacin and comparator agents was evaluated by the reference broth microdilution method. The four most common organisms from PHP were Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella spp., and Enterobacter spp. The highest arbekacin MIC among S. aureus isolates from PHP (43% methicillin resistant S. aureus [MRSA]) was 4 MUg/ml. Among P. aeruginosa isolates from PHP, only one had an arbekacin MIC of >16 MUg/ml (MIC50 and MIC90, 1 and 4 MUg/ml), and susceptibility rates for gentamicin, tobramycin, and amikacin were 88.0, 90.0, and 98.0%, respectively. Arbekacin (MIC50, 2 MUg/ml) and tobramycin (MIC50, 4 MUg/ml) were the most potent aminoglycosides tested against Acinetobacter baumannii. Against Enterobacteriaceae from PHP, arbekacin and gentamicin (MIC50 and MIC90, 0.25 to 1 and 1 to 8 MUg/ml for both compounds) were generally more potent than tobramycin (MIC50 and MIC90, 0.25 to 2 and 1 to 32 MUg/ml) and amikacin (MIC50 and MIC90, 1 to 2 and 2 to 32 MUg/ml). Arbekacin also demonstrated potent in vitro activity against a worldwide collection of well characterized MDR Gram-negative and MRSA strains. PMID- 25801560 TI - In vitro activity of polymyxin B plus imipenem, meropenem, or tigecycline against KPC-2-producing Enterobacteriaceae with high MICs for these antimicrobials. AB - We evaluated the in vitro activity of polymyxin B plus imipenem, meropenem, or tigecycline against six KPC-2-producing Enterobacteriaceae strains with high MICs for these antimicrobial agents. Polymyxin B with carbapenems, especially meropenem, were the most active combinations for Klebsiella pneumoniae and Enterobacter cloacae regardless of the polymyxin B concentration used in the time kill assay. This combination was also synergistic against two Serratia marcescens strains that are intrinsically resistant to polymyxins. Polymyxin B and tigecycline also presented synergistic activity in most experiments. PMID- 25801561 TI - N-acetylcysteine selectively antagonizes the activity of imipenem in Pseudomonas aeruginosa by an OprD-mediated mechanism. AB - The modulating effect of N-acetylcysteine (NAC) on the activity of different antibiotics has been studied in Pseudomonas aeruginosa. Our results demonstrate that, in contrast to previous reports, only the activity of imipenem is clearly affected by NAC. MIC and checkerboard determinations indicate that the NAC-based modulation of imipenem activity is dependent mainly on OprD. SDS-PAGE of outer membrane proteins (OMPs) after NAC treatments demonstrates that NAC does not modify the expression of OprD, suggesting that NAC competitively inhibits the uptake of imipenem through OprD. Similar effects on imipenem activity were obtained with P. aeruginosa clinical isolates. Our results indicate that imipenem susceptible P. aeruginosa strains become resistant upon simultaneous treatment with NAC and imipenem. Moreover, the generality of the observed effects of NAC on antibiotic activity was assessed with two additional bacterial species, Escherichia coli and Acinetobacter baumannii. Caution should be taken during treatments, as the activity of imipenem may be modified by physiologically attainable concentrations of NAC, particularly during intravenous and nebulized regimes. PMID- 25801562 TI - Telaprevir and ribavirin interaction: higher ribavirin levels are not only due to renal dysfunction during triple therapy. AB - A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN alpha), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin Cmin) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-alpha plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV coinfected patients were enrolled. The median ribavirin Cmin for triple therapy (4.08 MUg/ml; range, 2.14 to 5.56 MUg/ml) was higher than that observed after telaprevir withdrawal (1.96 MUg/ml; range, 0.41 to 3.45 MUg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN alpha plus ribavirin (1.65 MUg/ml; range, 0.41 to 5.56 MUg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r(2) = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC0-12) (r(2) = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has been registered at ClinicalTrials.gov under registration no. NCT01818856.). PMID- 25801563 TI - In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives. AB - 4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated from Piper peltatum roots. O-Acylation or O-alkylation of compound 1 provides derivatives exhibiting improved stability and significant in vitro antiplasmodial activity. The aim of this work was to study the in vitro inhibition of hemozoin formation, inhibition of isoprenoid biosynthesis in Plasmodium falciparum cultures, and in vivo antimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibited in vitro hemozoin formation by up to 50%. In metabolic labeling studies using [1-(n) (3)H]geranylgeranyl pyrophosphate, diester 2: significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone 8, menaquinone 4, and dolichol 12 in cultures of P. falciparum 3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol 12. P. falciparum in vitro protein synthesis was not affected by compounds 2 or 3. At oral doses of 50 mg per kg of body weight per day, compound 2 suppressed Plasmodium berghei NK65 in infected BALB/c mice by 44%. This in vivo result for derivative 2 represents marked improvement over that obtained previously for natural product 1. Compound 2 was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasma in vitro. However, it was detected after in vitro contact with human blood or blood plasma. Derivatives of 4-nerolidylcatechol exhibit parasite-specific modes of action, such as inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation, and they therefore merit further investigation for their antimalarial potential. PMID- 25801564 TI - Comparative efficacies of tedizolid phosphate, vancomycin, and daptomycin in a rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. AB - Tedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid against Staphylococcus aureus in vitro. The in vivo efficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistant S. aureus strain COL (infection inoculum of 10(7) CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P = 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P = 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (10(8) CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0-24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0-24 for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin. PMID- 25801566 TI - High prevalence of bla(NDM-1) carbapenemase-encoding gene and 16S rRNA armA methyltransferase gene among Acinetobacter baumannii clinical Isolates in Egypt. AB - The main objective of this study was to decipher the molecular mechanism of resistance to carbapenems and aminoglycosides in a large series of 150 Acinetobacter baumannii clinical isolates collected from July 2012 to September 2013 in Egypt. We report for the first time the emergence of bla(NDM-1) and the cooccurrence of 16S rRNA methylase armA with bla(NDM-1) and bla(OXA-23) in Egyptian hospitals. Multilocus sequence typing identified 27 distinct sequence types, 11 of which were novel. PMID- 25801565 TI - Rapid induction of high-level carbapenem resistance in heteroresistant KPC producing Klebsiella pneumoniae. AB - Enterobacteriaceae strains producing the Klebsiella pneumoniae carbapenemase (KPC) have disseminated worldwide, causing an urgent threat to public health. KPC producing strains often exhibit low-level carbapenem resistance, which may be missed by automated clinical detection systems. In this study, eight Klebsiella pneumoniae strains with heterogeneous resistance to imipenem were used to elucidate the factors leading from imipenem susceptibility to high-level resistance as defined by clinical laboratory testing standards. Time-kill analysis with an inoculum as low as 3 * 10(6) CFU/ml and concentrations of imipenem 8- and 16-fold higher than the MIC resulted in the initial killing of 99.9% of the population. However, full recovery of the population occurred by 20 h of incubation in the same drug concentrations. Population profiles showed that recovery was mediated by a heteroresistant subpopulation at a frequency of 2 * 10(-7) to 3 * 10(-6). Samples selected 2 h after exposure to imipenem were as susceptible as the unexposed parental strain and produced the major outer membrane porin OmpK36. However, between 4 to 8 h after exposure, OmpK36 became absent, and the imipenem MIC increased at least 32-fold. Individual colonies isolated from cultures after 20 h of exposure revealed both susceptible and resistant subpopulations. Once induced, however, the high-level imipenem resistance was maintained, and OmpK36 remained unexpressed even without continued carbapenem exposure. This study demonstrates the essential coordination between blaKPC and ompK36 expression mediating high-level imipenem resistance from a population of bacteria that initially exhibits a carbapenem-susceptibility phenotype. PMID- 25801567 TI - Influence of ABCC2 and ABCC4 polymorphisms on tenofovir plasma concentrations in Thai HIV-infected patients. AB - Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged >=18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 +/- 7.2 years. The mean tenofovir plasma concentration was 100.3 +/- 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T -> G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.). PMID- 25801568 TI - Brincidofovir (CMX001) inhibits BK polyomavirus replication in primary human urothelial cells. AB - BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 to 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV; previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary human renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC. The BCV concentrations causing 50 and 90% reductions (EC50 and EC90) in the number of intracellular BKPyV genome equivalents per cell (icBKPyV) were 0.27 MUM and 0.59 MUM, respectively. At 0.63 MUM, BCV reduced viral late gene expression by 90% and halted progeny release. Preinfection treatment for only 24 h reduced icBKPyV similarly to treatment from 2 to 72 h postinfection, while combined pre- and postinfection treatment suppressed icBKPyV completely. After investigating BCV's effects on HUC viability, mean selectivity indices at 50 and 90% inhibition (SI50 and SI90) calculated for cellular DNA replication were 2.7 and 2.9, respectively, those for mitochondrial activity were 8.9 and 10.4, those for total ATP were 8.6 and 8.2, and those for membrane integrity were 25.9 and 16.7. The antiviral and cytostatic effects, but less so the cytotoxic effects, were inversely related to cell density. The cytotoxic effects at concentrations of >=10 MUM were rapid and likely related to BCV's lipid moiety. After carefully defining the antiviral, cytostatic, and cytotoxic properties of BCV in HUCs, we conclude that a preemptive or prophylactic approach in PyVHC is likely to give the best results. PMID- 25801569 TI - Sodium nitrite blocks the activity of aminoglycosides against Pseudomonas aeruginosa biofilms. AB - Sodium nitrite has broad antimicrobial activity at pH 6.5, including the ability to prevent biofilm growth by Pseudomonas aeruginosa on the surfaces of airway epithelial cells. Because of its antimicrobial activity, nitrite is being investigated as an inhaled agent for chronic P. aeruginosa airway infections in cystic fibrosis patients. However, the interaction between nitrite and commonly used aminoglycosides is unknown. This paper investigates the interaction between nitrite and tobramycin in liquid culture, abiotic biofilms, and a biotic biofilm model simulating the conditions in the cystic fibrosis airway. The addition of nitrite prevented killing by aminoglycosides in liquid culture, with dose dependence between 1.5 and 15 mM. The effect was not blocked by the nitric oxide scavenger CPTIO or dependent on efflux pump activity. Nitrite shifted the biofilm minimal bactericidal concentration (MBC-biofilm) from 256 MUg/ml to >1,024 MUg/ml in an abiotic biofilm model. In a biotic biofilm model, the addition of 50 mM nitrite decreased the antibiofilm activity of tobramycin by up to 1.2 log. Respiratory chain inhibition recapitulated the inhibition of aminoglycoside activity by nitrite, suggesting a potential mechanism of inhibition of energy dependent aminoglycoside uptake. In summary, sodium nitrite induces resistance to both gentamicin and tobramycin in P. aeruginosa grown in liquid culture, as an abiotic biofilm, or as a biotic biofilm. PMID- 25801570 TI - ZnO nanoparticles impose a panmetabolic toxic effect along with strong necrosis, inducing activation of the envelope stress response in Salmonella enterica serovar Enteritidis. AB - In this study, we tested the antimicrobial activity of three metal nanoparticles (NPs), ZnO, MgO, and CaO NPs, against Salmonella enterica serovar Enteritidis in liquid medium and on solid surfaces. Out of the three tested metal NPs, ZnO NPs exhibited the most significant antimicrobial effect both in liquid medium and when embedded on solid surfaces. Therefore, we focused on revealing the mechanisms of surface-associated ZnO biocidal activity. Using the global proteome approach, we report that a great majority (79%) of the altered proteins in biofilms formed by Salmonella enterica serovar Enteritidis were downregulated, whereas a much smaller fraction (21%) of proteins were upregulated. Intriguingly, all downregulated proteins were enzymes involved in a wide range of the central metabolic pathways, including translation; amino acid biosynthetic pathways; nucleobase, nucleoside, and nucleotide biosynthetic processes; ATP synthesis coupled proton transport; the pentose phosphate shunt; and carboxylic acid metabolic processes, indicating that ZnO NPs exert a panmetabolic toxic effect on this prokaryotic organism. In addition to their panmetabolic toxicity, ZnO NPs induced profound changes in cell envelope morphology, imposing additional necrotic effects and triggering the envelope stress response of Salmonella serovar Enteritidis. The envelope stress response effect activated periplasmic chaperones and proteases, transenvelope complexes, and regulators, thereby facilitating protection of this prokaryotic organism against ZnO NPs. PMID- 25801571 TI - Evaluation of alpha,beta-unsaturated ketones as antileishmanial agents. AB - In this study, we assessed the antileishmanial activity of 126 alpha,beta unsaturated ketones. The compounds NC901, NC884, and NC2459 showed high leishmanicidal activity for both the extracellular (50% effective concentration [EC50], 456 nM, 1,122 nM, and 20 nM, respectively) and intracellular (EC50, 1,870 nM, 937 nM, and 625 nM, respectively) forms of Leishmania major propagated in macrophages, with little or no toxicity to mammalian cells. Bioluminescent imaging of parasite replication showed that all three compounds reduced the parasite burden in the murine model, with no apparent toxicity. PMID- 25801572 TI - Evolution and dissemination of OqxAB-like efflux pumps, an emerging quinolone resistance determinant among members of Enterobacteriaceae. AB - The OqxAB efflux pump, a plasmid-mediated quinolone resistance (PMQR) determinant, has become increasingly prevalent among members of Enterobacteriaceae over the past decade. To investigate the evolution and dissemination routes of the oqxAB operon, we assessed the prevalence of oqxAB like elements among various Gram-negative bacterial species and analyzed the genotypic and phenotypic characteristics of organisms harboring such elements. With a comprehensive genotyping approach, a chromosome-based oqxAB operon was detectable in all Klebsiella pneumoniae strains tested, including organisms isolated before the year 1984. Sequence and phylogenetic analyses confirmed that the oqxAB operon in K. pneumoniae isolates was genetically closest to their plasmid-borne counterparts recoverable only from Escherichia coli and Salmonella isolates collected from the year 2003 onward. Chromosomal elements with much lower sequence homology were also found among the Enterobacter spp. but not other Gram-negative species. Contrary to the quinolone resistance phenotypes which were consistently observable among organisms with oqxAB-harboring plasmids, chromosomal oqxAB elements generally did not confer quinolone resistance, except for K. pneumoniae strains, which exhibited a typical oqxAB-mediated phenotype characterized by cross-resistance to olaquindox, chloramphenicol, and the quinolones. Gene expression analysis illustrated that such phenotypes were due to elevated expression of the chromosomal oqxAB operon. Furthermore, transposition of the oqxAB operon from the bacterial chromosome to plasmids was found to result in a >80-fold increase in the level of expression of the OqxAB pump, confirming its status as the first constitutively expressed efflux system located in bacterial mobile elements. PMID- 25801573 TI - ClpP-independent function of ClpX interferes with telithromycin resistance conferred by Msr(A) in Staphylococcus aureus. AB - The ABCF family protein Msr(A) confers high resistance to macrolides but only low resistance to ketolides in staphylococci. Mutations in conserved functional regions of ClpX as well as deletion of clpX significantly increased Msr(A) mediated resistance to the ketolide antibiotic telithromycin. ClpX is the chaperone component of the ClpXP two-component proteolytic system. Nevertheless, no changes in resistance were observed in a clpP knockout strain expressing msr(A), demonstrating that ClpX affects Msr(A) independently of ClpP. PMID- 25801574 TI - Imaging-based high-throughput screening assay to identify new molecules with transmission-blocking potential against Plasmodium falciparum female gamete formation. AB - In response to a call for the global eradication of malaria, drug discovery has recently been extended to identify compounds that prevent the onward transmission of the parasite, which is mediated by Plasmodium falciparum stage V gametocytes. Lately, metabolic activity has been used in vitro as a surrogate for gametocyte viability; however, as gametocytes remain relatively quiescent at this stage, their ability to undergo onward development (gamete formation) may be a better measure of their functional viability. During gamete formation, female gametocytes undergo profound morphological changes and express translationally repressed mRNA. By assessing female gamete cell surface expression of one such repressed protein, Pfs25, as the readout for female gametocyte functional viability, we developed an imaging-based high-throughput screening (HTS) assay to identify transmission-blocking compounds. This assay, designated the P. falciparum female gametocyte activation assay (FGAA), was scaled up to a high throughput format (Z' factor, 0.7 +/- 0.1) and subsequently validated using a selection of 50 known antimalarials from diverse chemical families. Only a few of these agents showed submicromolar 50% inhibitory concentrations in the assay: thiostrepton, methylene blue, and some endoperoxides. To determine the best conditions for HTS, a robustness test was performed with a selection of the GlaxoSmithKline Tres Cantos Antimalarial Set (TCAMS) and the final screening conditions for this library were determined to be a 2 MUM concentration and 48 h of incubation with gametocytes. The P. falciparum FGAA has been proven to be a robust HTS assay faithful to Plasmodium transmission-stage cell biology, and it is an innovative useful tool for antimalarial drug discovery which aims to identify new molecules with transmission-blocking potential. PMID- 25801575 TI - In vitro fungicidal activities of anidulafungin, caspofungin, and micafungin against Candida glabrata, Candida bracarensis, and Candida nivariensis evaluated by time-kill studies. AB - Anidulafungin, caspofungin, and micafungin killing activities against Candida glabrata, Candida bracarensis, and Candida nivariensis were evaluated by the time kill methodology. The concentrations assayed were 0.06, 0.125, and 0.5 MUg/ml, which are achieved in serum. Anidulafungin and micafungin required between 13 and 26 h to reach the fungicidal endpoint (99.9% killing) against C. glabrata and C. bracarensis. All echinocandins were less active against C. nivariensis. PMID- 25801577 TI - Chronic overproduction of ghrelin in the hypothalamus leads to temporal increase in food intake and body weight. AB - Ghrelin is known to be a critical stimulator of feeding behavior mainly via actions in the hypothalamus. However, its functional contribution to the control of energy homeostasis under chronic elevated conditions is unknown. Here we show that overproduction of ghrelin via an AAV viral delivery system in the hypothalamus leads to an increase in food intake associated with increases in body weight. However, this increase in food intake is only temporary and is diminished and no longer significant after 3 weeks. Analysis of brain sections of mice 6 weeks after AAV-ghrelin virus injection demonstrates unaltered neuropeptide Y levels but strongly up-regulated pro-opiomelanocortin levels indicating that a compensatory mechanism has been activated to counter regulate the feeding stimulatory actions of ghrelin. This demonstrates that control mechanism exists that is activated under conditions of prolonged high ghrelin levels, which could potentially be utilized to control feeding and the development of obesity. PMID- 25801576 TI - Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesized that analyzing tissues by matching on degree of disease severity would identify different patterns of gene expression from a traditional case control comparison. We analyzed gene expression changes in 4 postmortem central nervous system regions, stratified by severity of motor neuron loss. An overall comparison of cases (n = 6) and controls (n = 3) identified known ALS gene, SOX5, as showing differential expression (log2 fold change = 0.09, p = 5.5 * 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 * 10(-3)), MATR3 (p = 3.46 * 10(-3)), and VEGFA (p = 8.21 * 10(-4)), all implicated in ALS through genetic studies, and changes in other genes in pathways involving RNA processing and immune response. These findings suggest that analysis of gene expression stratified by disease severity can identify major ALS genes and may be more efficient than traditional case-control comparison. PMID- 25801578 TI - A Retrospective Clinical Study with Regard to Survival and Success Rates of Zirconia Implants up to and after 7 Years of Loading. AB - PURPOSE: The study aims to retrospectively investigate the clinical performance of first-generation zirconia implants with a sandblasted surface up to and after 7 years of loading. MATERIALS AND METHODS: Clinical records of patients treated with zirconia implants between 2004 and 2009 were screened. Consequently, adequate patients were invited to a clinical and radiographic investigation to classify each implant according to strict success criteria. RESULTS: Seventy-one patients receiving 161 implants were available for the evaluation. Overall, 36 implants (22.4%) were lost due to early (n = 14) and late failures (n = 4) or fractures (n = 18). All surviving 125 implants fulfilled the success criteria. None of the investigated implants had a history of peri-implant infections. Mean values with regard to gingival index, plaque index, modified sulcus bleeding index, and probing depth were 0.03, 0.23, 0.59, and 2.80 mm, respectively. The radiographically evaluated mean crestal bone loss was 0.97 +/- 0.07 mm. Diameter reduced implants (3.25 mm) showed lower survival (58.5%) compared with implants with a diameter of 4.0 mm (88.9%) and 5.0 mm (78.6%). The overall longitudinal survival rate was 77.3%. CONCLUSIONS: First-generation zirconia implants showed low overall survival and success rates. The evaluated clinical and radiographic parameters were consistent with healthy peri-implant tissues. Additionally, nonfractured failures were not associated with peri-implant infections. PMID- 25801580 TI - Acute compartment syndrome of the hand. PMID- 25801581 TI - Looped versus single-stranded flexor tendon repairs: a cadaveric mechanical study. AB - PURPOSE: To compare the tensile properties of 4-strand modified Kessler flexor tendon repairs using a looped or single-stranded suture. METHODS: We evaluated the mechanical properties of 4-strand Kessler zone II core suture repairs using either looped or single-stranded suture in human flexor digitorum profundus and flexor pollicis longus tendons. Forty repairs were performed on tendons from bilateral cadaveric hands: 20 matched tendons were divided into equal groups of 3 0 looped and 3-0 single-strand repairs and 20 additional matched tendons were divided into equal groups of 4-0 looped and 4-0 single-strand repairs. Repaired tendons were tested in uniaxial tension to failure to determine mechanical properties and failure modes. Data were analyzed to determine the effect of repair type (ie, looped vs single-stranded) for each suture caliber (ie, 3-0 and 4-0). RESULTS: Single-strand repairs with 3-0 suture demonstrated a significantly greater maximum load to failure and a significantly higher force at 2-mm gap compared with repairs with looped 3-0 suture. All 8 looped repairs with 3-0 suture failed by suture pullout whereas 7 of 8 repairs with 3-0 single-stranded suture failed by suture breakage. The mechanical properties of looped versus single-stranded repairs with 4-0 caliber suture were not statistically different. Repairs with 4-0 caliber suture failed by suture breakage in 8 of 10 single strand repairs and failed by suture pullout in 6 of 10 repairs with looped suture. CONCLUSIONS: In a time-0 ex vivo human cadaveric core suture model, the mechanical properties of a 4-strand repair using 3-0 single-stranded suture were significantly better than the same 4-strand repair performed with looped suture. CLINICAL RELEVANCE: Four-strand flexor tendon repairs with 3-0 suture are mechanically superior when performed with single-strand suture versus looped suture. PMID- 25801582 TI - A new triterpenoid bearing octacosanoate from the stems and roots of Clerodendrum philippinum var. simplex (Verbenaceae). AB - A new triterpenoid bearing octacosanoate, named taraxer-3beta-yl octacosanoate (1), together with 13 known compounds (2-14), was isolated from the ethanol extract of the stems and roots of Clerodendrum philippinum var. simplex. The structure of taraxer-3beta-yl octacosanoate (1) was elucidated by extensive spectroscopic analysis. Uncinatone (8) and clerodenone A (10) exhibited inhibition of lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages with IC50 values of 12.50 and 3.18 MUM, respectively. PMID- 25801583 TI - Inhalative IL-10 treatment after bilateral femoral fractures affect pulmonary inflammation in mice. AB - BACKGROUND: Musculoskeletal injuries induce systemic inflammation which often impairs lung function contributing to morbidity. IL-10 has been shown to have a beneficial effect on immune dysfunction and organ damage after different traumatic insults. We sought to investigate the effect of inhalative IL-10 administration on the systemic and pulmonary inflammatory response in a small animal model of bilateral femoral fracture. MATERIALS AND METHODS: Male C57/BL6 mice (6 animals per group) were subjected to bilateral femoral fracture and intramedullary nailing followed by inhalative administration of either 50MUL PBS (Fx group) or 50MUg/kg recombinant mouse IL-10 dissolved in 50MUL PBS (FxIL-10 group). All animals were sacrificed at 6, 24, or 72h after fracture induction. Blood samples were collected and analyzed for IL-6, IL-10, KC, and MCP-1 (CCL2) plasma concentrations by Bio-Plex ProTM assays. Pulmonary infiltration by neutrophils was assessed by myeloperoxidase (MPO) activity (ELISA) and histological analysis of lung tissue. Pulmonary ICAM-1 expression (immunohistochemistry), and pulmonary IL-6 levels (ELISA) were determined. RESULTS: Inhalative IL-10 administration showed a decrease in the pulmonary infiltration by neutrophils. A significant decrease in the expression of the adhesion molecule ICAM-1 after local IL-10 application was observed. In contrast, local IL-10 administration did not show a significant effect on the systemic inflammatory response. CONCLUSION: Our findings suggest that inhalative IL-10 administration may beneficially modulate the pulmonary microenvironment, in which IL-10 effect on the local ICAM-1 expression seems to play a central role. PMID- 25801584 TI - Separation of opiate isomers using electrospray ionization and paper spray coupled to high-field asymmetric waveform ion mobility spectrometry. AB - One limitation in the growing field of ambient or direct analysis methods is reduced selectivity caused by the elimination of chromatographic separations prior to mass spectrometric analysis. We explored the use of high-field asymmetric waveform ion mobility spectrometry (FAIMS), an ambient pressure ion mobility technique, to separate the closely related opiate isomers of morphine, hydromorphone, and norcodeine. These isomers cannot be distinguished by tandem mass spectrometry. Separation prior to MS analysis is, therefore, required to distinguish these compounds, which are important in clinical chemistry and toxicology. FAIMS was coupled to a triple quadrupole mass spectrometer, and ionization was performed using either a pneumatically assisted heated electrospray ionization source (H-ESI) or paper spray, a direct analysis method that has been applied to the direct analysis of dried blood spots and other complex samples. We found that FAIMS was capable of separating the three opiate structural isomers using both H-ESI and paper spray as the ionization source. PMID- 25801586 TI - 27th ASMS Sanibel Conference on Mass Spectrometry--Security and Forensic Applications. PMID- 25801579 TI - Outpatient versus inpatient uterine polyp treatment for abnormal uterine bleeding: randomised controlled non-inferiority study. AB - OBJECTIVE: To compare the effectiveness and acceptability of outpatient polypectomy with inpatient polypectomy. DESIGN: Pragmatic multicentre randomised controlled non-inferiority study. SETTING: Outpatient hysteroscopy clinics in 31 UK National Health Service hospitals. PARTICIPANTS: 507 women who attended as outpatients for diagnostic hysteroscopy because of abnormal uterine bleeding and were found to have uterine polyps. INTERVENTIONS: Participants were randomly assigned to either outpatient uterine polypectomy under local anaesthetic or inpatient uterine polypectomy under general anaesthesia. Data were collected on women's self reported bleeding symptoms at baseline and at 6, 12, and 24 months. Data were also collected on pain and acceptability of the procedure at the time of polypectomy. MAIN OUTCOME MEASURES: The primary outcome was successful treatment, determined by the women's assessment of bleeding at six months, with a prespecified non-inferiority margin of 25%. Secondary outcomes included generic (EQ-5D) and disease specific (menorrhagia multi-attribute scale) quality of life, and feasibility and acceptability of the procedure. RESULTS: 73% (166/228) of women in the outpatient group and 80% (168/211) in the inpatient group reported successful treatment at six months (intention to treat relative risk 0.91, 95% confidence interval 0.82 to 1.02; per protocol relative risk 0.92, 0.82 to 1.02). Failure to remove polyps was higher (19% v 7%; relative risk 2.5, 1.5 to 4.1) and acceptability of the procedure was lower (83% v 92%; 0.90, 0.84 to 0.97) in the outpatient group Quality of life did not differ significantly between the groups. Four uterine perforations, one of which necessitated bowel resection, all occurred in the inpatient group. CONCLUSIONS: Outpatient polypectomy was non inferior to inpatient polypectomy. Failure to remove a uterine polyp was, however, more likely with outpatient polypectomy and acceptability of the procedure was slightly lower. TRIAL REGISTRATION: International Clinical Trials Registry 65868569. PMID- 25801585 TI - Mass Spectrometry Analysis of Pseudomonas aeruginosa Treated with Azithromycin. AB - In microbiology, changes in specialized metabolite production (cell-to-cell signaling metabolites, virulence factors, and natural products) are measured using phenotypic assays. However, advances in mass spectrometry-based techniques including imaging mass spectrometry (IMS) now allow researchers to directly visualize the production of specialized metabolites from microbial colony biofilms. In this study, a combination of IMS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to visualize the effect of the macrolide antibiotic azithromycin (AZM) on colony biofilms of Pseudomonas aeruginosa. Although previous research suggested that AZM may inhibit cell-to-cell signaling of P. aeruginosa and thereby reduce pathogenicity, we observed no clear decrease in specialized metabolite production. PMID- 25801587 TI - Imaging mass spectrometry: enabling a new age of discovery in biology and medicine through molecular microscopy. AB - Imaging mass spectrometry (IMS) has become a valuable tool for the production of molecular maps in samples ranging from solid inorganic materials to biologicals such as cells and tissues. The unique features of IMS are its ability to map a wide variety of different types of molecules, its superb molecular specificity, and its potential for discovery since no target-specific reagents are needed. IMS has made significant contributions in biology and medicine and promises to be a next generation tool in anatomic pathology. PMID- 25801588 TI - Gender differences in the predictors of physical activity among assisted living residents. AB - PURPOSE: To explore gender differences in the predictors of physical activity (PA) among assisted living residents. DESIGN AND METHODS: A cross-sectional design was adopted. A convenience sample of 304 older adults was recruited from four assisted living facilities in Taiwan. Two separate simultaneous multiple regression analyses were conducted to identify the predictors of PA for older men and women. Independent variables entered into the regression models were age, marital status, educational level, past regular exercise participation, number of chronic diseases, functional status, self-rated health, depression, and self efficacy expectations. FINDINGS: In older men, a junior high school or higher educational level, past regular exercise participation, better functional status, better self-rated health, and higher self-efficacy expectations predicted more PA, accounting for 61.3% of the total variance in PA. In older women, better self rated health, lower depression, and higher self-efficacy expectations predicted more PA, accounting for 50% of the total variance in PA. CONCLUSIONS: Predictors of PA differed between the two genders. The results have crucial implications for developing gender-specific PA interventions. CLINICAL RELEVANCE: Through a clearer understanding of gender-specific predictors, healthcare providers can implement gender-sensitive PA-enhancing interventions to assist older residents in performing sufficient PA. PMID- 25801589 TI - Intrathecal haematoma: a rare cause of back pain following epidural blood patch. PMID- 25801590 TI - A correlation of reactive oxygen species accumulation by depletion of superoxide dismutases with age-dependent impairment in the nervous system and muscles of Drosophila adults. AB - The theory that accumulation of reactive oxygen species (ROS) in internal organs is a major promoter of aging has been considered negatively. However, it is still controversial whether overexpression of superoxide dismutases (SODs), which remove ROS, extends the lifespan in Drosophila adults. We examined whether ROS accumulation by depletion of Cu/Zn-SOD (SOD1) or Mn-SOD (SOD2) influenced age related impairment of the nervous system and muscles in Drosophila. We confirmed the efficient depletion of Sod1 and Sod2 through RNAi and ROS accumulation by monitoring of ROS-inducible gene expression. Both RNAi flies displayed accelerated impairment of locomotor activity with age and shortened lifespan. Similarly, adults with nervous system-specific depletion of Sod1 or Sod2 also showed reduced lifespan. We then found an accelerated loss of dopaminergic neurons in the flies with suppressed SOD expression. A half-dose reduction of three pro-apoptotic genes resulted in a significant suppression of the neuronal loss, suggesting that apoptosis was involved in the neuronal loss caused by SOD silencing. In addition, depletion of Sod1 or Sod2 in musculature is also associated with enhancement of age-related locomotion impairment. In indirect flight muscles from SOD-depleted adults, abnormal protein aggregates containing poly-ubiquitin accumulated at an early adult stage and continued to increase as the flies aged. Most of these protein aggregates were observed between myofibril layers. Moreover, immuno-electron microscopy indicated that the aggregates were predominantly localized in damaged mitochondria. These findings suggest that muscular and neuronal ROS accumulation may have a significant effect on age dependent impairment of the Drosophila adults. PMID- 25801592 TI - Characterisation of Acetyl-CoA Thiolase: The First Enzyme in the Biosynthesis of Terpenic Sex Pheromone Components in the Labial Gland of Bombus terrestris. AB - Buff-tailed bumblebees, Bombus terrestris, use a male sex pheromone for premating communication. Its main component is a sesquiterpene, 2,3-dihydrofarnesol. This paper reports the isolation of a thiolase (acetyl-CoA thiolase, AACT_BT), the first enzyme involved in the biosynthetic pathway leading to formation of isoprenoids in the B. terrestris male sex pheromone. Characterisation of AACT_BT might contribute to a better understanding of pheromonogenesis in the labial gland of B. terrestris males. The protein was purified to apparent homogeneity by column chromatography with subsequent stepwise treatment. AACT_BT showed optimum acetyltransferase activity at pH 7.1 and was strongly inhibited by iodoacetamide. The enzyme migrated as a band with an apparent mass of 42.9 kDa on SDS-PAGE. MS analysis of an AACT_BT tryptic digest revealed high homology to representatives of the thiolase family. AACT_BT has 96 % amino acid sequence identity with the previously reported Bombus impatiens thiolase. PMID- 25801593 TI - A systems approach to healthcare: agent-based modeling, community mental health, and population well-being. AB - PURPOSE: Explore whether agent-based modeling and simulation can help healthcare administrators discover interventions that increase population wellness and quality of care while, simultaneously, decreasing costs. Since important dynamics often lie in the social determinants outside the health facilities that provide services, this study thus models the problem at three levels (individuals, organizations, and society). METHODS: The study explores the utility of translating an existing (prize winning) software for modeling complex societal systems and agent's daily life activities (like a Sim City style of software), into a desired decision support system. A case study tests if the 3 levels of system modeling approach is feasible, valid, and useful. The case study involves an urban population with serious mental health and Philadelphia's Medicaid population (n=527,056), in particular. RESULTS: Section 3 explains the models using data from the case study and thereby establishes feasibility of the approach for modeling a real system. The models were trained and tuned using national epidemiologic datasets and various domain expert inputs. To avoid co mingling of training and testing data, the simulations were then run and compared (Section 4.1) to an analysis of 250,000 Philadelphia patient hospital admissions for the year 2010 in terms of re-hospitalization rate, number of doctor visits, and days in hospital. Based on the Student t-test, deviations between simulated vs. real world outcomes are not statistically significant. Validity is thus established for the 2008-2010 timeframe. We computed models of various types of interventions that were ineffective as well as 4 categories of interventions (e.g., reduced per-nurse caseload, increased check-ins and stays, etc.) that result in improvement in well-being and cost. CONCLUSIONS: The 3 level approach appears to be useful to help health administrators sort through system complexities to find effective interventions at lower costs. PMID- 25801591 TI - The effects of piracetam on heroin-induced CPP and neuronal apoptosis in rats. AB - BACKGROUND: Piracetam is a positive allosteric modulator of the AMPA receptor that has been used in the treatment of cognitive disorders for decades. Recent surveys and drug analyses have demonstrated that a heroin mixture adulterated with piracetam has spread rapidly in heroin addicts in China, but its addictive properties and the damage it causes to the central neural system are currently unknown. METHODS: The effect of piracetam on the reward properties of heroin was assessed by conditioned place preference (CPP). Electron microscopy and radioimmunoassay were used to compare the effects of heroin mixed with equivalent piracetam (HP) and heroin alone on neuronal apoptosis and the levels of beta endorphin (beta-EP) in different brain subregions within the corticolimbic system, respectively. RESULTS: Piracetam significantly enhanced heroin-induced CPP expression while piracetam itself didn't induce CPP. Morphological observations showed that HP-treated rats had less neuronal apoptosis than heroin treated group. Interestingly, HP normalized the levels of beta-EP in the medial prefrontal cortex (mPFC) and core of the nucleus accumbens (AcbC) subregions, in where heroin-treated rats showed decreased levels of beta-EP. CONCLUSIONS: These results indicate that piracetam potentiate the heroin-induced CPP and protect neurons from heroin-induced apoptosis. The protective role of HP might be related to the restoration of beta-EP levels by piracetam. Our findings may provide a potential interpretation for the growing trend of HP abuse in addicts in China. PMID- 25801594 TI - Morbidity and mortality of pancreaticoduodenectomy for benign and premalignant pancreatic neoplasms. AB - OBJECTIVES: Patients with benign neoplasms of the pancreas are selected for pancreaticoduodenectomy if there is concern for malignant transformation. This study compares outcomes after pancreaticoduodenectomy for patients with premalignant and malignant pancreatic neoplasms. STUDY DESIGN: This retrospective cohort study included all patients who underwent pancreaticoduodenectomy for histologically confirmed benign/premalignant pancreatic neoplasms and primary pancreatic malignancy reported to National Surgical Quality Improvement Program (NSQIP) from 2005 to 2011. Patient characteristics, intraoperative and postoperative morbidity and mortality were compared. RESULTS: A total of 6085 patients underwent pancreaticoduodenectomy: 744 (12.2 %) for benign/premalignant and 5341 (87.8 %) for malignant pancreatic neoplasms. Patients with benign/premalignant neoplasms were more commonly female, had lower American Society of Anesthesiologists (ASA) class, and were less likely to have major comorbidities (all p <= 0.003). After resection, patients with benign/premalignant neoplasms were more likely to develop organ space infection (13.4 vs. 8.5 %, p < 0.001) and sepsis (12.2 vs. 9.2 %, p = 0.009). Cardiovascular, pulmonary, renal, and other organ system complications (p = 0.12) as well as 30-day mortality (3.0 vs. 2.0 %, p = 0.128) did not differ. CONCLUSIONS: Organ space infection and sepsis are more common after pancreaticoduodenectomy for benign/premalignant neoplasms. Planned improvements in NSQIP data capture should allow for better measurement of this morbidity. A carefully balanced risk and benefit discussion should precede resection in these patients. PMID- 25801595 TI - Chronic abdominal syndrome due to nervous compression. Study of 100 cases and proposed diagnostic-therapeutic algorithm. AB - OBJECTIVE: In the medical literature, thoracic disc protrusion has traditionally been considered a rare occurrence. We hypothesise that the incidence of such protrusions and their abdominal symptoms is higher than is generally believed and that their presence may account for a significant proportion of chronic non visceral abdominal pains. Accordingly, the present study was designed to identify and quantify the symptoms experienced by patients with thoracic disc protrusion and to assess the relative risk of these symptoms being presented, compared to the general population. DESIGN: We conducted a cross-sectional study with a control group. The following comparison groups were analysed: case group, consisting of 100 patients diagnosed with thoracic disc protrusion in our hospital between February 2007 and October 2012, and control group consisting of 100 subjects from the general population, chosen at random. To compare the symptoms observed in each group, the following tests were applied to all study subjects: clinical examination, gastrointestinal-related quality of life (GIQLI) questionnaire and DN4 questionnaire. We also reviewed the subjects' medical records for the previous 3 years. RESULTS: The subjects in the case group had a significantly higher incidence of digestive-urologic symptoms, a poorer gastrointestinal quality of life and greater need of medical care than those in the control group. The differences were statistically significant for all the parameters studied. Almost all the case group subjects suffered chronic abdominal pain and/or digestive-urologic symptoms. We term this group of symptoms "chronic abdominal syndrome due to nervous compression". Nevertheless, in most cases, no neurologic aetiology was suspected, and therefore the treatment given was ineffective. In view of the results obtained, we propose a diagnostic-therapeutic algorithm for such patients. CONCLUSION: Thoracic disc protrusion, as well as having a non-negligible incidence, is often associated with a digestive-urologic clinical syndrome, and this factor should be taken into account in all cases of chronic abdominal pain and other digestive-urologic symptoms when standard tests are negative, so that appropriate treatment may be given. PMID- 25801596 TI - [Postoperative respiratory insufficiency and its treatment]. AB - The development of a postoperative respiratory insufficiency is typically caused by several factors and include patient-related risks, the extent of the procedure and postoperative complications. Morbidity and mortality rates in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are high. It is important to have consistent strategies for prevention and preoperative conditioning is essential primarily for high-risk patients. Treatment of established postoperative lung failure requires early tracheotomy, protective ventilation (tidal volume 6 ml/kg body weight), elevated positive end expiratory pressure (PEEP, 10-20 mmH2O), recurrent bronchoscopy and early patient mobilization. In critical cases an extracorporeal lung assist is considered to be beneficial as a bridge to recovery and for realizing a protective ventilation protocol. Different systems with separate indications are available. The temporary application of a lung assist allows thoracic surgery to be performed safely in patients presenting with insufficient respiratory function. PMID- 25801597 TI - [Unclear space-occupying lesion in the upper left abdomen : A surgical rarity]. PMID- 25801598 TI - [Ablative therapies for locally advanced pancreatic cancer : Use outside clinical studies cannot be recommended due to lack of data]. PMID- 25801599 TI - Biosurfactant production by Pseudomonas strains isolated from floral nectar. AB - AIMS: To screen and identify biosurfactant-producing Pseudomonas strains isolated from floral nectar; to characterize the produced biosurfactants; and to investigate the effect of different carbon sources on biosurfactant production. METHODS AND RESULTS: Four of eight nectar Pseudomonas isolates were found to produce biosurfactants. Phylogenetic analysis based on three housekeeping genes (16S rRNA gene, rpoB and gyrB) classified the isolates into two groups, including one group closely related to Pseudomonas fluorescens and another group closely related to Pseudomonas fragi and Pseudomonas jessenii. Although our nectar pseudomonads were able to grow on a variety of water-soluble and water-immiscible carbon sources, surface active agents were only produced when using vegetable oil as sole carbon source, including olive oil, sunflower oil or waste frying sunflower oil. Structural characterization based on thin layer chromatography (TLC) and ultra high performance liquid chromatography-accurate mass mass spectrometry (UHPLC-amMS) revealed that biosurfactant activity was most probably due to the production of fatty acids (C16:0; C18:0; C18:1 and C18:2), and mono- and diglycerides thereof. CONCLUSIONS: Four biosurfactant-producing nectar pseudomonads were identified. The active compounds were identified as fatty acids (C16:0; C18:0; C18:1 and C18:2), and mono- and diglycerides thereof, produced by hydrolysis of triglycerides of the feedstock. SIGNIFICANCE AND IMPACT OF THE STUDY: Studies on biosurfactant-producing micro-organisms have mainly focused on microbes isolated from soils and aquatic environments. Here, for the first time, nectar environments were screened as a novel source for biosurfactant producers. As nectars represent harsh environments with high osmotic pressure and varying pH levels, further screening of nectar habitats for biosurfactant-producing microbes may lead to the discovery of novel biosurfactants with broad tolerance towards different environmental conditions. PMID- 25801600 TI - SLC24A5 and ASIP as phenotypic predictors in Brazilian population for forensic purposes. AB - Pigmentation is a variable and complex trait in humans and it is determined by the interaction of environmental factors, age, disease, hormones, exposure to ultraviolet radiation and genetic factors, including pigmentation genes. Many polymorphisms of these genes have been associated with phenotypic diversity of skin, eyes and hair color in homogeneous populations. Phenotype prediction from biological samples using genetic information has benefited forensic area in some countries, leading some criminal investigations. Herein, we evaluated the association between polymorphisms in the genes SLC24A5 (rs1426654) and ASIP (rs6058017) with skin, eyes and hair colors, in 483 healthy individuals from Brazilian population for attainable use in forensic practice. The volunteers answered a questionnaire where they self-reported their skin, eye and hair colors. The polymorphic homozygous genotype of rs1426654*A and rs6058017*A in SLC24A5 and ASIP respectively, showed strongest association with fairer skin (OR 47.8; CI 14.1-161.6 and OR 8.6; CI 2.5-29.8); SLC24A5 alone showed associations with blue eyes (OR 20.7; CI 1.2-346.3) and blond hair (OR 26.6; CI 1.5-460.9). Our data showed that polymorphic genotypes (AA), in both genes, are correlated with characteristics of light pigmentation, while the ancestral genotype (GG) is related to darker traits, corroborating with previous studies in European and African populations. These associations show that specific molecular information of an individual may be useful to access some phenotypic features in an attempt to help forensic investigations, not only on crime scene samples but also in cases of face reconstructions in unknown bodies. PMID- 25801601 TI - Odds ratios of treatment response were well approximated from continuous rating scale scores for meta-analysis. AB - OBJECTIVES: To empirically evaluate the performance of methods for estimating odds ratios and their corresponding standard errors from continuous end point data for meta-analysis. STUDY DESIGN AND SETTING: A database of randomized controlled trials of chronic depression treatments was used. Trials that reported both continuous and dichotomous end points for symptom improvement were considered. Odds ratios and standard errors were calculated from the dichotomous data and estimated from the continuous data using currently available methods: Hasselblad and Hedges (HH), Cox and Snell (CS), Furukawa (F), Suissa (S), and Kraemer and Kupfer (KK). Single and meta-analytically pooled observed and estimated values were compared. RESULTS: A total of 26 trials were included. At the trial level, four of five (HH, CS, F, and S) and three of four (HH, F, and S) methods for estimating odds ratios and standard errors performed well, respectively. We found considerable differences in the performance of all methods across trials with more accurate estimates for smaller treatment effects. At the level of meta-analysis, three of four methods (CS, F, and S) performed acceptably. CONCLUSION: Odds ratios and standard errors can be approximated from continuous end points, but we recommend sensitivity and subgroup analyses to test robustness of the findings. PMID- 25801602 TI - Myelodysplastic syndrome with clonal cytogenetic abnormalities followed by fatal erythroid leukemia after 14 years of exposure to hydroxyurea for sickle cell anemia. PMID- 25801603 TI - Phospholipid Ether Linkages Significantly Modulate the Membrane Affinity of the Antimicrobial Peptide Novicidin. AB - The biological activity of antimicrobial peptides is believed to be closely linked to their ability to perturb bacterial membranes. This makes it important to understand the basis of their membrane-binding properties. Here, we present a biophysical analysis of the interactions of the antimicrobial peptide Novicidin (Nc) with ether- and ester-linked C14 phospholipid vesicles below and above the lipid phase transition temperature (t p). These interactions are strongly dependent on whether the lipids contain ether or ester linkages. Nc is in random coil state in solution but undergoes a large increase in alpha-helicity in ether vesicles, and to a much smaller extent in ester vesicles, around the t p. This structure is lost at higher temperatures. Steady-state fluorescence and stopped flow kinetics using fluorophore-labeled Nc reveal that Nc binds more strongly to ether vesicles than to ester vesicles below the t p, while there is no significant difference above the t p. This may reflect ether lipid interdigitation in the gel phase. Isothermal titration calorimetry reveals that partitioning of Nc into both lipids is exothermic and thus enthalpy driven. The higher enthalpy associated with binding to ether lipid may be linked to Nc's higher propensity to form alpha-helical structure in this lipid. The large effect of the ether-ester interchange reveals that membrane-AMP interactions can be strongly modulated by charge-neutral head group changes. PMID- 25801604 TI - Phosphatidylcholine-fatty Alcohols Equilibria in Monolayers at the Air/Water Interface. AB - Monolayers of phosphatidylcholine (PC), tetradecanol (TD), hexadecanol (HD), octadecanol (OD) and eicosanol (E) and their binary mixtures were investigated at the air/water interface. The surface tension values of pure and mixed monolayers were used to calculate pi-A isotherms. The surface tension measurements were carried out at 22 degrees C using a Teflon trough and a Nima 9000 tensiometer. The interactions between phosphatidylcholine and fatty alcohols (tetradecanol, hexadecanol, octadecanol, eicosanol) result in significant deviations from the additivity rule. An equilibrium theory to describe the behavior of monolayer components at the air/water interface was developed in order to obtain the stability constants, Gibbs free energy values and areas occupied by one molecules of PC-TD, PC-HD, PC-OD and PC-E complexes. We considered the equilibrium between the individual components and the complex and established that phosphatidylcholine and fatty alcohols formed highly stable 1:1 complexes. PMID- 25801606 TI - The effects of chronic marijuana use on circadian entrainment. AB - Animal literature suggests a connection between marijuana use and altered circadian rhythms. However, the effect has not yet been demonstrated in humans. The present study examined the effect of chronic marijuana use on human circadian function. Participants consisted of current users who reported smoking marijuana daily for at least a year and non-marijuana user controls. Participants took a neurocognitive assessment, wore actigraphs and maintained sleep diaries for three weeks. While no significant cognitive changes were found between groups, data revealed that chronic marijuana use may act as an additional zeitgeber and lead to increased entrainment in human users. PMID- 25801607 TI - Epidemic history of major genotypes of hepatitis C virus in Uruguay. AB - Worldwide, more than 170 million people are chronically infected with the hepatitis C virus (HCV) and every year die more than 350,000 people from HCV related liver diseases. Recently, HCV was reclassified into seven major genotypes and 67 subtypes. Some subtypes as 1a, 1b and 3a, have become epidemic as a result of the new parenteral transmission routes and are responsible for most HCV infections in Western countries. HCV 1a subtype have been sub-categorized into two separate sub clades. Recent studies based on the analysis of NS5B genome region, reveal that HCV epidemics in Argentina and Brazil are characterized by multiple introductions events of subtypes 1a, 1b and 3a, followed by subsequent local dispersion. There is no data about HCV genotypes circulating in Uruguay and their evolutionary and demographic history. To this end, a total of 153 HCV NS5B gene sequences were obtained from Uruguayan patients between 2005 and 2011. 86 (56%) sequences grouped with subtype 1a, 40 (26%) with subtype 3a and 27 (18%) with subtype 1b. Furthermore, subtype 1a sequences were distributed among both clades, 1 (n=62, 72%) and 2 (n=24, 28%). Four local HCV clades were found: UY 1a(I), UY-1a(II), UY-1a(III) and UY-3a; comprising a 39% of all HCV viruses analyzed in this study. HCV epidemic in Uruguay has been driving by multiple introductions of subtypes 1a, 1b and 3a and by local dissemination of a few country-specific strains. The evolutionary and demographic history of the major Uruguayan HCV clade UY-1a(I) was reconstructed under two different molecular clock rate models and displayed an epidemic history characterized by an initial phase of rapid expansion followed by a more recent reduction of growth rate since 2000-2005. This is the first comprehensive study about the molecular epidemiology and epidemic history of HCV in Uruguay. PMID- 25801605 TI - Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis. AB - Our published research has focused on the role of Goa1p, an apparent regulator of the Candida albicans mitochondrial complex I (CI). Lack of Goa1p affects optimum cell growth, CI activity and virulence. Eukaryotic CI is composed of a core of 14 alpha-proteobacterial subunit proteins and a variable number of supernumerary subunit proteins. Of the latter group of proteins, one (NUZM) is fungal specific and the other (NUXM) is found in fungi, algae and plants, but is not a mammalian CI subunit protein. We have established that NUXM is orf19.6607 and NUZM is orf19.287 in C. albicans. Herein, we validate both subunit proteins as NADH:ubiquinone oxidoreductases (NUO) and annotate their gene functions. To accomplish these objectives, we compared null mutants of each with wild type (WT) and gene-reconstituted strains. Genetic mutants of genes NUO1 (orf19.6607) and NUO2 (orf19.287), not surprisingly, each had reduced oxygen consumption, decreased mitochondrial redox potential, decreased CI activity, increased reactive oxidant species (ROS) and decreased chronological ageing in vitro. Loss of either gene results in disassembly of CI. Transcriptional profiling of both mutants indicated significant down-regulation of genes of carbon metabolism, as well as up-regulation of mitochondrial-associated gene families that may occur to compensate for the loss of CI activity. Profiling of both mutants also demonstrated a loss of cell wall beta-mannosylation but not in a conserved CI subunit (ndh51Delta). The profiling data may indicate specific functions driven by the enzymatic activity of Nuo1p and Nuo2p. Of importance, each mutant is also avirulent in a murine blood-borne, invasive model of candidiasis associated with their reduced colonization of tissues. Based on their fungal specificity and roles in virulence, we suggest both as drug targets for antifungal drug discovery. PMID- 25801608 TI - Time-dependent selection pressure on two arthropod-borne RNA viruses in the same serogroup. AB - Understanding the genetic basis of viral adaptation to taxonomically diverse groups of host species inhabiting different eco-climatic zones is crucial for the discovery of factors underpinning the successful establishment of these infectious pathogens in new hosts/environments. To gain insights into the dynamics of nonsynonymous (dN) and synonymous substitutions (dS) and the ratio between the two (omega=dN/dS), we analyzed the complete nucleotide coding sequence data of the M segment, which encodes glycoproteins of two negative-sense RNA viruses, Akabane virus (AKV) and Schmallenberg virus (SBV) that belong to the same serogroup. While AKV is relatively older and has been circulating in ruminant populations since 1970s, SBV was first reported in 2011. The omega was estimated to be 1.67 and 0.09 for SBV and AKV, respectively, and the estimated mutation rate of SBV is at least 25 times higher than that of AKV. Given the different evolutionary stages of the two viruses, most of the slightly deleterious mutations were likely purged out or kept in low frequency in the AKV genome, whereas positive selection together with the accumulation of slightly deleterious mutations might contribute to such an inflated mutation rate of SBV. The evolutionary distance (d) is nonlinearly and negatively correlated with omega, but is positively correlated with dN and dS. Collectively, the different patterns in omega, dN, dS, and d between AKV and SBV identified in this study provide empirical evidence for a time-dependent selection pressure. PMID- 25801609 TI - Triosephosphate isomerase gene promoter variation: -5G/A and -8G/A polymorphisms in clinical malaria groups in two African populations. AB - TPI1 promoter polymorphisms occur in high prevalence in individuals from African origin. Malaria-patients from Angola and Mozambique were screened for the TPI1 gene promoter variants rs1800200A>G, (-5G>A), rs1800201G>A, (-8G>A), rs1800202T>G, (-24T>G), and for the intron 5 polymorphism rs2071069G>A, (2262G>A). -5G>A and -8G>A variants occur in 47% and 53% in Angola and Mozambique, respectively while -24T>G was monomorphic for the wild-type T allele. Six haplotypes were identified and -8A occurred in 45% of the individuals, especially associated with the GAG haplotype and more frequent in non-severe malaria groups, although not significantly. The arising and dispersion of -5G>A and -8G>A polymorphisms is controversial. Their age was estimated by analyses of two microsatellite loci, CD4 and ATN1, adjacent to TPI1 gene. The -5G>A is older than -8G>A, with an average estimate of approximately 35,000 years. The -8A variant arose in two different backgrounds, suggesting independent mutational events. The first, on the -5G background, may have occurred in East Africa around 20,800 years ago; the second, on the -5A background, may have occurred in West Africa some 7500 years ago. These estimates are within the period of spread of agriculture and the malaria mosquito vector in Africa, which could has been a possible reason for the selection of -8A polymorphism in malaria endemic countries. PMID- 25801610 TI - Elimination of Arsenophonus and decrease in the bacterial symbionts diversity by antibiotic treatment leads to increase in fitness of whitefly, Bemisia tabaci. AB - Bemisia tabaci is an invasive agricultural pest with more than 24 genetic groups harboring different bacterial endosymbionts categorized into obligatory and facultative endosymbionts. Arsenophonus is one of the facultative endosymbionts prevalent in B. tabaci of Indian sub-continent. Not much is known about the functional role of this endosymbiont in its host. Some studies have revealed its involvement in virus transmission by B. tabaci, but how it effects the biology of B. tabaci is unknown. In this study, tetracycline was used to eliminate Arsenophonus from B. tabaci to study its effects with regard to development and other fitness parameters. Bacteria specific 16S Polymerase chain reaction (PCR) was used to ascertain Arsenophonus absence with differential effects on other secondary endosymbionts present in B. tabaci. Our results revealed that Arsenophonus negative (A(-)) whiteflies had more fecundity, increased juvenile developmental time, increased nymphal survival and increased adult life span as compared to control (A(+)) whiteflies. Thus, our results demonstrate that A(+) whiteflies have lesser fitness as compared to A(-) whiteflies. These observations give a new insight about the probable role of Arsenophonus in B. tabaci, that need to be explored further. PMID- 25801611 TI - Toward an era of utilizing methionine overproducing hosts for recombinant protein production in Escherichia coli. AB - Amino acid sequence variants, especially variants containing non-canonical amino acids such as norleucine and norvaline, are a concern during therapeutic protein production in microbial systems. Substitution of methionine residues with norleucine in recombinant proteins produced in Escherichia coli is well known. Continuous feeding of amino acids such as methionine is commonly used in E. coli fermentation processes to control incorporation of norleucine in the recombinant protein. There are several disadvantages associated with continuous feeding during a fermentation process. For example, a continuous feed increases the operational complexity and cost of a manufacturing process and results in dilution of culture medium which could result in lower cell densities and product yields. To overcome the limitations of existing approaches to prevent norleucine incorporation during E. coli fermentations, a new approach using an engineered host was developed that overproduces methionine in the cell to prevent norleucine incorporation without negatively impacting fermentation process performance and product yields. In this commentary, the results on using methionine overproducing hosts for recombinant protein production in E. coli and some "watch outs" when using these hosts for recombinant protein production are discussed. PMID- 25801612 TI - Tumour microenvironment: Driving relapse. PMID- 25801613 TI - Heterogeneity: Explosive beginnings. PMID- 25801620 TI - The role of academic health centres to inform evidence-based integrative oncology practice. PMID- 25801621 TI - The role of academic health centres to inform evidence-based integrative oncology practice. PMID- 25801622 TI - Editorial: Nursing research in the 21st century--who sets the agenda? PMID- 25801618 TI - Caveolae and signalling in cancer. AB - It has been over 20 years since the discovery that caveolar lipid rafts function as signalling organelles. Lipid rafts create plasma membrane heterogeneity, and caveolae are the most extensively studied subset of lipid rafts. A newly emerging paradigm is that changes in caveolae also generate tumour metabolic heterogeneity. Altered caveolae create a catabolic tumour microenvironment, which supports oxidative mitochondrial metabolism in cancer cells and which contributes to dismal survival rates for cancer patients. In this Review, we discuss the role of caveolae in tumour progression, with a special emphasis on their metabolic and cell signalling effects, and their capacity to transform the tumour microenvironment. PMID- 25801619 TI - Metastasis prevention by targeting the dormant niche. AB - Despite considerable advancements that shattered previously held dogmas about the metastatic cascade, the evolution of therapies to treat metastatic disease has not kept up. In this Opinion article, I argue that, rather than waiting for metastases to emerge before initiating treatment, it would be more effective to target metastatic seeds before they sprout. Specifically, I advocate directing therapies towards the niches that harbour dormant disseminated tumour cells to sensitize them to cytotoxic agents. Treatment sensitization, achieved by disrupting reservoirs of leukaemic stem cells and latent HIV, argues that this approach, although unconventional, could succeed in improving patient survival by delaying or even preventing metastasis. PMID- 25801623 TI - Commentary on Jack B, Baldry C, Groves K, Whelan A, Sephton J and Gaunt K (2013) Supporting home care for the dying: an evaluation of healthcare professionals' perspectives of an individually tailored hospice at home service. Journal of Clinical Nursing 22, 2778-2786. PMID- 25801624 TI - The clinical utility of ambulatory blood pressure monitoring (ABPM): a review. AB - The current evidence suggests that ambulatory blood pressure monitoring (ABPM) should be an integral part of the diagnosis and management of hypertension. However, its uptake in routine clinical practice has been variable. This paper reviews the current evidence for the role of ABPM in clinical practice, including in hypotensive disorders and in specific comorbidities. It further discusses the clinical significance of abnormal ambulatory blood pressure patterns and hypertensive syndromes such as white coat, masked and resistant hypertension. PMID- 25801625 TI - Vascular oxidative stress: a key factor in the development of hypertension associated with ethanol consumption. AB - The observation that the excessive consumption of ethyl alcohol (ethanol) is associated with high blood pressure is nearing its centennial mark. Mechanisms linking ethanol consumption and hypertension are complex and not fully understood. It is established that chronic ethanol consumption leads to hypertension and that this process is a multimediated event involving increased sympathetic activity, stimulation of the renin-angiotensin-aldosterone system with a subsequent increase in vascular oxidative stress and endothelial dysfunction. Under physiological conditions, reactive oxygen species (ROS) play an important role as a signaling molecule in the control of vascular tone and endothelial function. Increased ROS bioavailability is associated with important processes underlying vascular injury in cardiovascular disease such as endothelial dysfunction, vascular remodeling, and inflammation. Studies focusing on molecular mechanisms showed a link between overproduction of ROS in the vasculature and ethanol-induced hypertension. Of the ROS generated in vascular cells, superoxide anion (O2(-)) and hydrogen peroxide (H2O2) appear to be especially important. Ethanol-mediated generation of O2(-) and H2O2 in vascular tissues is associated with elevations in intracellular calcium ([Ca(2+)]i), reduced nitric oxide (NO) bioavailability, endothelial dysfunction and vasoconstriction. O2(-) can also act as a vascular signaling molecule regulating signaling pathways that lead to vascular contraction. Thus, through increased generation of ROS and activation of redox-sensitive pathways, ethanol induces vascular dysfunction, a response that might contribute to the hypertension associated with ethanol consumption. The present article reviews the role of ROS in vascular (patho)biology of ethanol. PMID- 25801627 TI - Hypertensive Cardiomyopathy in asymptomatic patients: a neglected diagnosis. AB - Hypertensive Cardiomyopathy diagnosis includes different clinical conditions, on asymptomatic patients, assessed by LV changes in geometry, mass and function, i.e. concentric remodeling, concentric or eccentric hypertrophy and filling impairment or early stage of diastolic dysfunction. Often LA is involved and increases its volume and undergoes to geometrical remodeling. Sometimes it occurs clinical heart failure, the patients became symptomatic, with either a preserved or a reduced LVEF. There is considerable variability in the progression from hypertension to Hypertensive Cardiomyopathy, according to differences in the pressure or volume load and to underlying neurohormonal status; but these differences in LV geometry probably are influenced on genetic basis too. A better comprehension of the mechanisms underlying the development of Hypertensive Cardiomyopathy on hypertensive patients will help to prevent among them the onset of cardiovascular events. PMID- 25801628 TI - The relationship between sugar-sweetened beverages and liver enzymes among healthy premenopausal women: a prospective cohort study. AB - PURPOSE: To prospectively assess the association between sugar-sweetened beverages (SSB), added sugar, and total fructose and serum concentrations of liver enzymes among healthy, reproductive-age women. METHODS: A prospective cohort of 259 premenopausal women (average age 27.3 +/- 8.2 years; BMI 24.1 +/- kg/m(2)) were followed up for up to two menstrual cycles, providing up to eight fasting blood specimens/cycle and four 24-h dietary recalls/cycle. Women with a history of chronic disease were excluded. Alanine and aspartate aminotransferases (ALT and AST, respectively) were measured in serum samples. Linear mixed models estimated associations between average SSB, added sugar, and total fructose intake and log-transformed liver enzymes adjusting for age, race, body mass index, total energy and alcohol intake, and Mediterranean diet score. RESULTS: For every 1 cup/day increase in SSB consumption and 10 g/day increase in added sugar and total fructose, log ALT increased by 0.079 U/L (95 % CI 0.022, 0.137), 0.012 U/L (95 % CI 0.002, 0.022), and 0.031 (0.012, 0.050), respectively, and log AST increased by 0.029 U/L (-0.011, 0.069), 0.007 U/L (0.000, 0.014), and 0.017 U/L (0.004, 0.030), respectively. Women who consumed >=1.50 cups/day (12 oz can) SSB versus less had 0.127 U/L (95 % CI 0.001, 0.254) higher ALT [percent change 13.5 % (95 % CI 0.1, 28.9)] and 0.102 (95 % CI 0.015, 0.190) higher AST [percent change 10.8 % (95 % CI 1.5, 20.9)]. CONCLUSIONS: Sugar-sweetened beverages were associated with higher serum ALT and AST concentrations among healthy premenopausal women, indicating that habitual consumption of even moderate SSB may elicit hepatic lipogenesis. PMID- 25801630 TI - Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. AB - BACKGROUND: Infertility is estimated to affect as many as 186 million people worldwide. Although male infertility contributes to more than half of all cases of global childlessness, infertility remains a woman's social burden. Unfortunately, areas of the world with the highest rates of infertility are often those with poor access to assisted reproductive techniques (ARTs). In such settings, women may be abandoned to their childless destinies. However, emerging data suggest that making ART accessible and affordable is an important gender intervention. To that end, this article presents an overview of what we know about global infertility, ART and changing gender relations, posing five key questions: (i) why is infertility an ongoing global reproductive health problem? (ii) What are the gender effects of infertility, and are they changing over time? (iii) What do we know about the globalization of ART to resource-poor settings? (iv) How are new global initiatives attempting to improve access to IVF? (v) Finally, what can be done to overcome infertility, help the infertile and enhance low-cost IVF (LCIVF) activism? METHODS: An exhaustive literature review using MEDLINE, Google Scholar and the keyword search function provided through the Yale University Library (i.e. which scans multiple databases simultaneously) identified 103 peer-reviewed journal articles and 37 monographs, chapters and reports from the years 2000-2014 in the areas of: (i) infertility demography, (ii) ART in low-resource settings, (iii) gender and infertility in low-resource settings and (iv) the rise of LCIVF initiatives. International Federation of Fertility Societies Surveillance reports were particularly helpful in identifying important global trends in IVF clinic distribution between 2002 and 2010. Additionally, a series of articles published by scholars who are tracking global cross-border reproductive care (CBRC) trends, as well as others who are involved in the growing LCIVF movement, were invaluable. RESULTS: Recent global demographic surveys indicate that infertility remains an ongoing reproductive problem, with six key demographic features. Despite the massive global expansion of ART services over the past decade (2005-2015), ART remains inaccessible in many parts of the world, particularly in sub-Saharan Africa, where IVF clinics are still absent in most countries. For women living in such ART-poor settings, the gender effects of infertility may be devastating. In contrast, in ART-rich regions such as the Middle East, the negative gender effects of infertility are diminishing over time, especially with state subsidization of ART. Furthermore, men are increasingly acknowledging their male infertility and seeking ICSI. Thus, access to ART may ameliorate gender discrimination, especially in the Global South. To that end, a number of clinician-led, LCIVF initiatives are in development to provide affordable ART, particularly in Africa. Without access to LCIVF, many infertile couples must incur catastrophic expenditures to fund their IVF, or engage in CBRC to seek lower-cost IVF elsewhere. CONCLUSIONS: Given the present realities, three future directions for research and intervention are suggested: (i) address the preventable causes of infertility, (ii) provide support and alternatives for the infertile and (iii) encourage new LCIVF initiatives to improve availability, affordability and acceptability of ART around the globe. PMID- 25801631 TI - Reflectance confocal microscopy for monitoring the density of Demodex mites in patients with rosacea before and after treatment. AB - BACKGROUND: Demodex mites seem to serve as a pathogenic trigger in many Demodex associated diseases such as rosacea. In facial skin of patients with rosacea significantly higher numbers of Demodex mites have been shown compared with healthy controls. Reflectance confocal microscopy (RCM) allows the detection and quantification of Demodex mites in vivo noninvasively. It is hypothesized that a reduction of Demodex mites under rosacea therapy can be monitored by RCM. OBJECTIVES: To use RCM to monitor the density of Demodex mites in patients with rosacea before and after treatment. METHODS: In 25 patients with facial rosacea RCM was performed before and after therapy. Mosaics of 5 * 5 mm(2) and 8 * 8 mm(2) were scanned, and the total numbers of mites per follicle and per area were counted, along with the number of follicles per area. RESULTS: In all patients Demodex folliculorum could be detected and quantified using RCM. RCM showed significant differences pre- and post-treatment (P = 0.0053 for 5 * 5 mm(2) and P < 0.001 for 8 * 8 mm(2)). The mean numbers of mites per follicle were 0.63 (range 0.16-2.28) per 8 * 8 mm(2) area and 0.70 (range 0.11-2.20) per 5 * 5 mm(2) area before treatment, and 0.41 (range 0.074-1.75) and 0.51 (range 0.094-1.70), respectively, after treatment. The corresponding mean numbers of mites were 155 (range 45-446) and 86.2 (range 12-286), respectively, before treatment and 96.2 (range 18-363) and 58.5 (range 12-230), respectively, after treatment. CONCLUSIONS: By RCM, a reduction in the density of Demodex mites in facial skin of patients with rosacea under therapy, correlating to clinical improvement, can be quantified and monitored noninvasively. Possible reasons for this therapeutic effect are discussed. PMID- 25801632 TI - Aluminium-catalysed intramolecular hydroamination of aminoalkenes: computational perusal of alternative pathways for aminoalkene activation. AB - A comprehensive computational examination of alternatively plausible mechanistic pathways for the intramolecular hydroamination (HA) of aminoalkenes utilising a recently reported novel phenylene-diamine aluminium amido compound is presented. On the one hand, a proton-assisted concerted N-C/C-H bond-forming pathway to afford the cycloamine in a single step can be invoked, and, on the other, a stepwise sigma-insertive pathway that involves a relatively fast, reversible migratory olefin 1,2-insertion step linked to a less rapid, irreversible Al-C alkyl bond protonolysis. The present study, which employs a sophisticated and reliable computational methodology, supports the prevailing mechanism to be a stepwise sigma-insertive pathway. The predicted effective barrier for turnover limiting aminolysis compares favourably with reported catalytic performance data. Non-competitive kinetic demands militates against the operation of the concerted proton-assisted pathway, which describes N-C bond-forming ring closure triggered by concomitant amino proton delivery at the C[double bond, length as m-dash]C linkage evolving through a six-centre transition state structure. The valuable insights into mechanistic intricacies of aluminium-mediated intramolecular HA reported herein will help guide the rational design of group 13 metal-based HA catalysts. PMID- 25801633 TI - Assessment of the prognostic capacity of pretreatment, interim, and post-therapy (18)F-FDG PET/CT in extranodal natural killer/T-cell lymphoma, nasal type. AB - OBJECTIVE: Although the prognostic value of positron emission tomography/computed tomography (PET/CT) using [(18)F]-fluorodeoxyglucose ((18)F-FDG) has been widely confirmed for diffuse large B cell lymphoma, its value for extranodal natural killer/T-cell lymphoma, nasal type (ENKTL), is still controversial. Therefore, we designed a prospective study to investigate the prognostic value of (18)F-FDG PET/CT in patients with ENKTL. MATERIALS AND METHODS: Thirty-three patients with newly diagnosed, untreated ENKTL, were enrolled in this study. Interim and post therapy PET/CT scans were analyzed by visual evaluation, in accordance with the criteria set forth by the International Harmonization Project. Patients were classified as either positive or negative. Pretreatment maximum standardized uptake values (SUVmax) of (18)F-FDG were recorded in the most (18)F-FDG-intense lesions. The pretreatment (18)F-FDG SUV as well as the interim and post-therapy PET/CT results were assessed for the ability to predict progression-free survival (PFS) and overall survival (OS). RESULTS: On the pretreatment scan, the SUVmax of the indicator lesion was >10.00 in 81.8% of patients who were treatment-resistant and <=10.00 in 86.4% of patients who were treatment non-resistant (mean SUVmax, 12.93 and 8.10, respectively). Univariate analyses revealed that pretreatment SUVmax is a significant predictor (P < 0.01, P < 0.01) of PFS and OS, respectively. Multivariate analyses revealed that pretreatment SUVmax (P < 0.01, P = 0.01) and post-therapy PET/CT result (P < 0.01, P = 0.04) are independent predictors of PFS and OS, respectively. CONCLUSIONS: (18)F-FDG uptakes prior to treatment and post-therapy PET/CT results can predict unfavorable outcomes following treatment in patients with ENKTL, but interim PET/CT results have little value in predicting survival. PMID- 25801634 TI - Is haemodiafiltration more favourable than haemodialysis for treatment of renal anaemia? PMID- 25801629 TI - Resveratrol treatment rescues hyperleptinemia and improves hypothalamic leptin signaling programmed by maternal high-fat diet in rats. AB - PURPOSE: Perinatal high-fat diet is associated with obesity and metabolic diseases in adult offspring. Resveratrol has been shown to exert antioxidant and anti-obesity actions. However, the effects of resveratrol on leptinemia and leptin signaling are still unknown as well as whether resveratrol treatment can improve metabolic outcomes programmed by maternal high-fat diet. We hypothesize that resveratrol treatment in male rats programmed by high-fat diet would decrease body weight and food intake, and leptinemia with changes in central leptin signaling. METHODS: Female Wistar rats were divided into two groups: control group (C), which received a standard diet containing 9 % of the calories as fat, and high-fat group (HF), which received a diet containing 28 % of the calories as fat. Dams were fed in C or HF diet during 8 weeks before mating and throughout gestation and lactation. C and HF male offspring received standard diet throughout life. From 150 until 180 days of age, offspring received resveratrol (30 mg/Kg body weight/day) or vehicle (carboxymethylcellulose). RESULTS: HF offspring had increased body weight, hyperphagia and increased subcutaneous and visceral fat mass compared to controls, and resveratrol treatment decreased adiposity. HF offspring had increased leptinemia as well as increased SOCS3 in the arcuate nucleus of the hypothalamus, which suggest central leptin resistance. Resveratrol treatment rescued leptinemia and increased p-STAT3 content in the hypothalamus with no changes in SOCS3, suggesting improvement in leptin signaling. CONCLUSIONS: Collectively, our data suggest that resveratrol could reverse hyperleptinemia and improve central leptin action in adult offspring from HF mothers attenuating obesity. PMID- 25801626 TI - The role of transforming growth factor beta1 in the regulation of blood pressure. AB - Although human association studies suggest a link between polymorphisms in the gene encoding transforming growth factor (TGF) beta1 and differing blood pressure levels, a causative mechanism for this correlation remains elusive. Recently we have generated a series of mice with graded expression of TGFbeta1, ranging from approximately 10% to 300% compared to normal. We have found that blood pressure and plasma volume are negatively regulated by TGFbeta1. Of note, the 10% hypomorph exhibits primary aldosteronism and markedly impaired urinary excretion of water and electrolytes. We here review previous literature highlighting the importance of TGFbeta signaling as a natriuretic system, which we postulate is a causative mechanism explaining how polymorphisms in TGFbeta1 could influence blood pressure levels. PMID- 25801635 TI - A new chance to beat diabetic kidney disease: innate immunity and MCP-1: a matter of good and bad macrophages? PMID- 25801636 TI - Con: kidney biopsy: an irreplaceable tool for patient management in nephrology. PMID- 25801637 TI - Opponent's comments. PMID- 25801639 TI - Opponent's comments. PMID- 25801638 TI - Pro: urine proteomics as a liquid kidney biopsy: no more kidney punctures! AB - In this article, the benefits of urinary proteomics in comparison with kidney biopsy are discussed. The majority of urinary proteins are generated by the kidney, hence the urinary proteome holds substantial information on the kidney, and assessment of the urinary proteome could be considered a 'liquid biopsy'. The main question is how well the information contained in the urinary proteome can be assessed today, if it is ready to be routinely used, and what are the advantages and possible disadvantages in comparison with current standards. Since chronic kidney disease (CKD) is by far the largest area in nephrology based on the number of patients affected, the focus of this article is on CKD. Substantial progress was made in the last decade in urinary proteomics, and today we have comparable urinary proteome datasets of tens of thousands of subjects available. Clinical proteomics studies in CKD including close to, or even exceeding, 1000 subjects have recently been published, demonstrating a benefit over the current state-of-the-art in diagnosis and especially prognosis. The first large multicentric randomized controlled intervention trial aiming at preventing CKD by employing urinary proteomics-guided intervention has been initiated recently. These data provide ample evidence for the utility and value of urinary proteomics in nephrology. A further consideration is that the purpose of the biopsy, be it 'liquid' or 'solid', is to guide intervention. However, essentially all drug targets are proteins, not microscopic structures. Therefore, obtaining information on the proteome to guide intervention appears to be the most appropriate approach. Presenting more detailed evidence, I argue that urinary proteome analysis can, in most cases, be employed to guide therapeutic intervention, can be repeated multiple times as it is without any direct risk or discomfort and can be considered as a liquid biopsy. PMID- 25801640 TI - Moderator's view: will 'modern' urine proteomics replace 'old-fashioned' renal biopsy? PMID- 25801642 TI - Return of the gonads (retrospective on DOI 10.1002/bies.201200081). PMID- 25801643 TI - Long-acting muscarinic antagonists for the prevention of exacerbations of chronic obstructive pulmonary disease. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD. Current guidelines recommend long acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD. PMID- 25801644 TI - Limiting volume with modern ventilators. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) network low tidal volume study comparing tidal volumes of 12 ml/kg versus 6 ml/kg was published in 2000. The study was stopped early as data revealed a 22% relative reduction in mortality rate when using 6 ml/kg tidal volume. The current generation of critical care ventilators allows the tidal volume to be set during volume targeted, assist/control (volume A/C); however, some ventilators include options that may prevent the tidal volume from being controlled. The purpose of this bench study was to evaluate the delivered tidal volume, when these options are active, in a spontaneously breathing lung model using an electronic breathing simulator. METHODS: Four ventilators were evaluated: CareFusion AVEA (AVEA), Drager Evita(r) XL (Evita XL), Covidien Puritan Bennett(r) 840(TM) (PB 840), and Maquet SERVO-i (SERVO-i). Each ventilator was connected to the Hans Rudolph Electronic Breathing Simulator at an amplitude of 0 cm H2O and then 10 cm H2O. All four ventilators were set to deliver volume A/C, tidal volume 400 ml, respiratory rate 20 bpm, positive end-expiratory pressure 5 cm H2O, peak flowrate 60 L/min. The displayed tidal volume was recorded for each ventilator at the above settings with additional options OFF and then ON. RESULTS: The AVEA has two options in volume A/C: demand breaths and V-sync. When activated, these options allow the patient to exceed the set tidal volume. When using the Evita XL, the option AutoFlow can be turned ON or OFF, and when this option is ON, the tidal volume may vary. The PB 840 does not have any additional options that affect volume delivery, and it maintains the set tidal volume regardless of patient effort. The SERVO-i's demand valve allows additional flow if the patient's inspiratory flowrate exceeds the set flowrate, increasing the delivered tidal volume; this option can be turned OFF with the latest software upgrade. CONCLUSIONS: Modern ventilators have an increasing number of optional settings. These settings may increase the delivered tidal volume and disrupt a low tidal volume strategy. Recognizing how each setting within a mode affects the type of breath delivered is critical when caring for ventilator-dependent patients. PMID- 25801645 TI - The efficacy of crizotinib in patients with ALK-positive nonsmall cell lung cancer. AB - Molecular profiling of nonsmall cell lung cancer (NSCLC) contributes to better understanding the different molecular subtypes of this heterogeneous group of diseases. The discovery of oncogenic ALK rearrangements in NSCLC and the subsequent success in their therapeutic targeting with crizotinib reinforces the benefits of a precision approach to systemic anticancer therapy. In addition, the rapid development of crizotinib from first discovery thorough accelerated US Food and Drug Administration approval, and late stage confirmatory clinical trials, exemplifies the success of the drug development strategy of close collaboration between clinicians, industry and regulatory authorities. In this review we describe the identification of ALK rearranged NSCLC, clinical characteristics of such patients, and clinical outcomes when treated with crizotinib. PMID- 25801646 TI - Molecular-orientation-induced rapid roughening and morphology transition in organic semiconductor thin-film growth. AB - We study the roughening process and morphology transition of organic semiconductor thin film induced by molecular orientation in the model of molecular semiconductor copper hexadecafluorophthalocyanine (F16CuPc) using both experiment and simulation. The growth behaviour of F16CuPc thin film with the thickness, D, on SiO2 substrate takes on two processes divided by a critical thickness: (1) D <= 40 nm, F16CuPc thin films are composed of uniform caterpillar like crystals. The kinetic roughening is confirmed during this growth, which is successfully analyzed by Kardar-Parisi-Zhang (KPZ) model with scaling exponents alpha = 0.71 +/- 0.12, beta = 0.36 +/- 0.03, and 1/z = 0.39 +/- 0.12; (2) D > 40 nm, nanobelt crystals are formed gradually on the caterpillar-like crystal surface and the film growth shows anomalous growth behaviour. These new growth behaviours with two processes result from the gradual change of molecular orientation and the formation of grain boundaries, which conversely induce new molecular orientation, rapid roughening process, and the formation of nanobelt crystals. PMID- 25801647 TI - MnO2 Nanosheets Grown on Nitrogen-Doped Hollow Carbon Shells as a High Performance Electrode for Asymmetric Supercapacitors. AB - A hierarchical hollow hybrid composite, namely, MnO2 nanosheets grown on nitrogen doped hollow carbon shells (NHCSs@MnO2 ), was synthesized by a facile in situ growth process followed by calcination. The composite has a high surface area (251 m(2) g(-1) ) and mesopores (4.5 nm in diameter), which can efficiently facilitate transport during electrochemical cycling. Owing to the synergistic effect of NHCSs and MnO2 , the composite shows a high specific capacitance of 306 F g(-1) , good rate capability, and an excellent cycling stability of 95.2 % after 5000 cycles at a high current density of 8 A g(-1) . More importantly, an asymmetric supercapacitor (ASC) assembled by using NHCSs@MnO2 and activated carbon as the positive and negative electrodes exhibits high specific capacitance (105.5 F g(-1) at 0.5 A g(-1) and 78.5 F g(-1) at 10 A g(-1) ) with excellent rate capability, achieves a maximum energy density of 43.9 Wh kg(-1) at a power density of 408 W kg(-1) , and has high stability, whereby the ASC retains 81.4 % of its initial capacitance at a current density of 5 A g(-1) after 4000 cycles. Therefore, the NHCSs@MnO2 electrode material is a promising candidate for future energy-storage systems. PMID- 25801648 TI - Temperature Dependence of Interband Transitions in Wurtzite InP Nanowires. AB - Semiconductor nanowires (NWs) formed by non-nitride III-V compounds grow preferentially with wurtzite (WZ) lattice. This is contrary to bulk and two dimensional layers of the same compounds, where only zincblende (ZB) is observed. The absorption spectrum of WZ materials differs largely from their ZB counterparts and shows three transitions, referred to as A, B, and C in order of increasing energy, involving the minimum of the conduction band and different critical points of the valence band. In this work, we determine the temperature dependence (T = 10-310 K) of the energy of transitions A, B, and C in ensembles of WZ InP NWs by photoluminescence (PL) and PL excitation (PLE) spectroscopy. For the whole temperature and energy ranges investigated, the PL and PLE spectra are quantitatively reproduced by a theoretical model taking into account contribution from both exciton and continuum states. WZ InP is found to behave very similarly to wide band gap III-nitrides and II-VI compounds, where the energy of A, B, and C displays the same temperature dependence. This finding unveils a general feature of the thermal properties of WZ materials that holds regardless of the bond polarity and energy gap of the crystal. Furthermore, no differences are observed in the temperature dependence of the fundamental band gap energy in WZ InP NWs and ZB InP (both NWs and bulk). This result points to a negligible role played by the WZ/ZB differences in determining the deformation potentials and the extent of the electron-phonon interaction that is a direct consequence of the similar nearest neighbor arrangement in the two lattices. PMID- 25801649 TI - Validation of a new imaging device for telemedical ulcer monitoring. AB - PURPOSE: To clarify whether a new portable imaging device (PID) providing 3D images for telemedical use constitutes a more correct expression of the clinical situation compared to standard telemedical equipment in this case iPhone 4s. METHOD: We investigated intra- and interindividual variability between the new portable camera and the iPhone images vs. clinical assessment as the 'gold standard'. The study included 36 foot ulcers. Four specialists rated the ulcers and filled out a questionnaire, which formed the basis of the evaluation. RESULTS: We found fair to very good intra-rater agreement for the new PID and iPhone, respectively. The gold standard was evaluated by assessing the ulcer twice by two different specialists. Kappa values were moderate to very good with respect to inter-rater agreement except for two variables. The agreement between standard and new equipment compared to the gold standard showed highest agreement with the new PID. CONCLUSION: The new PID is more in accordance with the clinical assessment compared to standard images. It opens for the possibility of using more advanced techniques in a telemedical approach to ulcer treatment and care, including volume measurements. PMID- 25801650 TI - Effect of top soil wettability on water evaporation and plant growth. AB - In general, agricultural soil surfaces being hydrophilic in nature get easily wetted by water. The water beneath the soil moves through capillary effect and comes to the surface of the soil and thereafter evaporates into the surrounding air due to atmospheric conditions such as sunlight, wind current, temperature and relative humidity. To lower the water loss from soil, an experiment was designed in which a layer of hydrophobic soil was laid on the surface of ordinary hydrophilic soil. This technique strikingly decreased loss of water from the soil. The results indicated that the evaporation rate significantly decreased and 90% of water was retained in the soil in 83 h by the hydrophobic layer of 2 cm thickness. A theoretical calculation based on diffusion of water vapour (gas phase) through hydrophobic capillaries provide a meaningful explanation of experimental results. A greater retention of water in the soil by this approach can promote the growth of plants, which was confirmed by growing chick pea (Cicer arietinum) plants and it was found that the length of roots, height of shoot, number of branches, number of leaves, number of secondary roots, biomass etc. were significantly increased upon covering the surface with hydrophobic soil in comparison to uncovered ordinary hydrophilic soil of identical depth. Such approach can also decrease the water consumption by the plants particularly grown indoors in residential premises, green houses and poly-houses etc. and also can be very useful to prevent water loss and enhance growth of vegetation in semi arid regions. PMID- 25801651 TI - A Promising, Single-Dose, Live Attenuated Tetravalent Dengue Vaccine Candidate. PMID- 25801653 TI - Reply to Crawford. PMID- 25801652 TI - Robust and Balanced Immune Responses to All 4 Dengue Virus Serotypes Following Administration of a Single Dose of a Live Attenuated Tetravalent Dengue Vaccine to Healthy, Flavivirus-Naive Adults. AB - BACKGROUND: The 4 serotypes of dengue virus, DENV-1-4, are the leading cause of arboviral disease globally. The ideal dengue vaccine would provide protection against all serotypes after a single dose. METHODS: Two randomized, placebo controlled trials were performed with 168 flavivirus-naive adults to demonstrate the safety and immunogenicity of a live attenuated tetravalent dengue vaccine (TV003), compared with those of a second tetravalent vaccine with an enhanced DENV-2 component (TV005), and to evaluate the benefit of a booster dose at 6 months. Safety data, viremia, and neutralizing antibody titers were evaluated. RESULTS: A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. Compared with TV003, the higher-dose DENV-2 component increased the observed frequency of immunogenicity to DENV-2 in the TV005 trial. Both the first and second doses were well tolerated. Neither vaccine viremia, rash, nor a significant antibody boost were observed following a second dose. CONCLUSIONS: A single subcutaneous dose of TV005 dengue vaccine is safe and induces a tetravalent antibody response at an unprecedented frequency among vaccinees. A second dose has limited benefit and appears to be unnecessary. Studies to confirm these findings and assess vaccine efficacy will now move to populations in regions where DENV transmission is endemic. CLINICAL TRIALS REGISTRATION: NCT01072786 and NCT01436422. PMID- 25801654 TI - The Epithelioid Cell in Tuberculosis is Secretory and Not a Macrophage. PMID- 25801655 TI - Is the band count useful in predicting the presence of septicemia in patients with hematologic malignancies? PMID- 25801656 TI - Differential effects of the computer-tailored FATaintPHAT programme on dietary behaviours according to sociodemographic, cognitive and home environmental factors--CORRIGENDUM. PMID- 25801657 TI - Ganglion cell populations in normal and pathological human cochleae. Implications for cochlear implantation. 1978. PMID- 25801658 TI - International Congress on Mycorrhizae: mycorrhizal symbiosis a key factor for improving plant productivity and ecosystems restoration. PMID- 25801659 TI - Occupational allergic contact urticaria caused by the crustaceans Palaemon serratus and Procambarus clarkii. PMID- 25801660 TI - Towards a second generation of mindfulness-based interventions. PMID- 25801661 TI - Building capacity in academic psychiatry: The Queensland Mental Health Research Alliance. PMID- 25801662 TI - A cross-validation trial of an Internet-based prevention program for alcohol and cannabis: Preliminary results from a cluster randomised controlled trial. AB - OBJECTIVE: Replication is an important step in evaluating evidence-based preventive interventions and is crucial for establishing the generalizability and wider impact of a program. Despite this, few replications have occurred in the prevention science field. This study aims to fill this gap by conducting a cross validation trial of the Climate Schools: Alcohol and Cannabis course, an Internet based prevention program, among a new cohort of Australian students. METHOD: A cluster randomized controlled trial was conducted among 1103 students (Mage: 13.25 years) from 13 schools in Australia in 2012. Six schools received the Climate Schools course and 7 schools were randomized to a control group (health education as usual). All students completed a self-report survey at baseline and immediately post-intervention. Mixed-effects regressions were conducted for all outcome variables. Outcomes assessed included alcohol and cannabis use, knowledge and intentions to use these substances. RESULTS: Compared to the control group, immediately post-intervention the intervention group reported significantly greater alcohol (d = 0.67) and cannabis knowledge (d = 0.72), were less likely to have consumed any alcohol (even a sip or taste) in the past 6 months (odds ratio = 0.69) and were less likely to intend on using alcohol in the future (odds ratio = 0.62). However, there were no effects for binge drinking, cannabis use or intentions to use cannabis. CONCLUSION: These preliminary results provide some support for the Internet-based Climate Schools: Alcohol and Cannabis course as a feasible way of delivering alcohol and cannabis prevention. Intervention effects for alcohol and cannabis knowledge were consistent with results from the original trial; however, analyses of longer-term follow-up data are needed to provide a clearer indication of the efficacy of the intervention, particularly in relation to behavioral changes. PMID- 25801663 TI - Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood. AB - The first order conditional estimation (FOCE) method is still one of the parameter estimation workhorses for nonlinear mixed effects (NLME) modeling used in population pharmacokinetics and pharmacodynamics. However, because this method involves two nested levels of optimizations, with respect to the empirical Bayes estimates and the population parameters, FOCE may be numerically unstable and have long run times, issues which are most apparent for models requiring numerical integration of differential equations. We propose an alternative implementation of the FOCE method, and the related FOCEI, for parameter estimation in NLME models. Instead of obtaining the gradients needed for the two levels of quasi-Newton optimizations from the standard finite difference approximation, gradients are computed using so called sensitivity equations. The advantages of this approach were demonstrated using different versions of a pharmacokinetic model defined by nonlinear differential equations. We show that both the accuracy and precision of gradients can be improved extensively, which will increase the chances of a successfully converging parameter estimation. We also show that the proposed approach can lead to markedly reduced computational times. The accumulated effect of the novel gradient computations ranged from a 10 fold decrease in run times for the least complex model when comparing to forward finite differences, to a substantial 100-fold decrease for the most complex model when comparing to central finite differences. Considering the use of finite differences in for instance NONMEM and Phoenix NLME, our results suggests that significant improvements in the execution of FOCE are possible and that the approach of sensitivity equations should be carefully considered for both levels of optimization. PMID- 25801664 TI - Modality independence of order coding in working memory: Evidence from cross modal order interference at recall. AB - Working memory researchers do not agree on whether order in serial recall is encoded by dedicated modality-specific systems or by a more general modality independent system. Although previous research supports the existence of autonomous modality-specific systems, it has been shown that serial recognition memory is prone to cross-modal order interference by concurrent tasks. The present study used a serial recall task, which was performed in a single-task condition and in a dual-task condition with an embedded memory task in the retention interval. The modality of the serial task was either verbal or visuospatial, and the embedded tasks were in the other modality and required either serial or item recall. Care was taken to avoid modality overlaps during presentation and recall. In Experiment 1, visuospatial but not verbal serial recall was more impaired when the embedded task was an order than when it was an item task. Using a more difficult verbal serial recall task, verbal serial recall was also more impaired by another order recall task in Experiment 2. These findings are consistent with the hypothesis of modality-independent order coding. The implications for views on short-term recall and the multicomponent view of working memory are discussed. PMID- 25801666 TI - Pre-travel counselling in Brazil. PMID- 25801668 TI - US states consider execution by nitrogen gas as lethal injections grind to a halt. PMID- 25801667 TI - Swedish and South African nursing students' descriptions of family. AB - PURPOSE: The purpose of this study was to compare and contrast descriptions of "family" amongst Swedish and South African university nursing students. DESIGN AND METHODS: This qualitative inquiry, using convenience sampling, explored how 232 undergraduate and postgraduate nursing students responded to a two-query, open-response questionnaire designed to elicit a definition of family and a description of who students considered to be members of their own families. Free text responses were analyzed using manifest and qualitative content analysis. FINDINGS: Five categories emerged from the data: Ties of Kinship, Ties of Love, Ties of Influence, Ties of Everyday Life, and Tied by Slipknots. Analysis clarified that students' responses from both countries were addressing the same issues and as such were in general very similar. Contrasting Swedish and South African responses, a noticeable difference in proportions of responses coded into each category was evident. Three conceptualizations of family are offered: for the total sample, Swedish sample, and South African sample. CONCLUSIONS: The study provides data on students' conceptualization of family usable in family research, nursing education, and practice as a basis for comparison, and as a starting point for discussions on the nursing of families, not only in South Africa and Sweden, but also in broader international contexts. CLINICAL RELEVANCE: Because understanding family is important for healthcare providers in their everyday work, awareness about what is meant by family can assist nurses through increasing understanding of the complexities surrounding this issue and encouraging cultural sensitivity and openness to patients' and families' views about who is a family member. PMID- 25801665 TI - Tuberculous and brucellosis meningitis differential diagnosis. AB - BACKGROUND: The Thwaites and Lancet scoring systems have been used in the rapid diagnosis of tuberculous meningitis (TBM). However, brucellar meningoencephalitis (BME) has similar characteristics with TBM. The ultimate aim of this study is to infer data to see if BME should be included in the differential diagnosis of TBM when these two systems suggest the presence of TBM. METHOD: BME and TBM patients from 35 tertiary hospitals were included in this study. Overall 294 adult patients with BME and 190 patients with TBM were enrolled. All patients involved in the study had microbiological confirmation for either TBM or BME. Finally, the Thwaites and Lancet scoring systems were assessed in both groups. RESULTS: The Thwaites scoring system more frequently predicted BME cases (n = 292, 99.3%) compared to the TBM group (n = 182, 95.8%) (P = 0.017). According to the Lancet scoring system, the mean scores for BME and TBM were 9.43 +/- 1.71 and 11.45 +/- 3.01, respectively (P < 0.001). In addition, TBM cases were classified into "probable" category more significantly compared to BME cases, and BME cases were categorized into the "possible" category more frequently. CONCLUSIONS: When the Thwaites or Lancet scoring systems indicate TBM, brucellar etiology should also be taken into consideration particularly in endemic countries. PMID- 25801669 TI - The ideology of convenience. Canned foods in women's magazines (Flanders, 1945 1960). AB - This paper investigates the communication of canned foods in Flanders between 1945 and 1960. It forwards the antinomy between convenience and care as theoretical framework, it uses three women's magazines as source material, and it subjects this material to the technique of close reading. The results show that the discursive construction of canned foods differs according to the ideology of the magazines. Whereas the agrarian periodical discarded canned foods as careless convenience that menaced the idea of the good housewife, the socialist and the commercial publications undeniably accepted them as caring convenience that could facilitate the household chores of working women. The analysis, thus, deals with the ideological aspect of convenience food, an aspect that has only rarely been examined. PMID- 25801670 TI - Therapeutic potential of human umbilical cord blood mesenchymal stem cells on erectile function in rats with cavernous nerve injury. AB - OBJECTIVE: To evaluate the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCBMSCs) on promoting erectile function in a rat model of bilateral cavernous nerve (CN) crush injury. RESULTS: Fifty male Sprague Dawley rats were randomly assigned to sham + PBS group (n = 10), BCNI (bilateral cavernous nerve crush injury) + PBS group (n = 10), BCNI + hUCBMSCs group (n = 30). At day 28 (n = 10) post-surgery, erectile function was examined and histological specimens were harvested. Compared with BCNI + PBS group, hUCBMSC intracavernous injection treatment significantly increased the mean ratio of ICP/MAP, nNOS-positive nerve fibers in the dorsal penile nerve, smooth muscle content, and smooth muscle to collagen ratio in the corpus cavernousum. Electron microscopy revealed few CN and major pelvic ganglion (MPG) lesions in the BCNI + hUCBMSCs group. Injected hUCBMSCs were localized to the sinusoid endothelium of the penis and MPG on day 1, 3, 7, and 28 post-intracavernous injection. CONCLUSION: hUCBMSCs intracavernous injection treatment improves erectile function by inhibiting corpus cavernosum fibrosis and exerting neuroregenerative effects on cell bodies of injured nerves at MPG in a BCNI rat model. PMID- 25801671 TI - Increased biomass saccharification by supplementation of a commercial enzyme cocktail with endo-arabinanase from Bacillus licheniformis. AB - OBJECTIVES: The use of endo-arabinanase from Bacillus licheniformis (ABNase) for sugarcane saccharification has been evaluated by enzyme immobilization and commercial cocktail supplement with the immobilized heterologous protein. RESULTS: Biochemical characterization of the purified ABNase showed that the catalytic activity was strongly inhibited by 5 mM Cu(2+), Zn(2+) or Fe(3+). The optimum pH and temperature for activity were 5.5-6.5 and 35-40 degrees C, respectively. The enzyme stability increased 128-fold when immobilized with glyoxyl agarose, and the hydrolysis of pretreated sugar cane biomass increased by 15 % when a commercial enzyme cocktail was supplemented with immobilized ABNase. CONCLUSION: Pectin hydrolysis by recombinant ABNase plays a role in the effective application of enzymatic cocktails for biomass saccharification. PMID- 25801672 TI - L-Lactic acid fermentation by Enterococcus faecium: a new isolate from bovine rumen. AB - OBJECTIVES: To obtain a novel adaptable stain that can produce enantioselective L lactic acid efficiently, reduce the operational cost of fermentation process and be suitable for scale production. RESULTS: Enterococcus faecium S.156 produced 126 g L-lactic acid/l with high optical purity (99.7 %), high productivity (5.25 g/l.h) and a conversion ratio >90 %. L-lactic acid production remained steady from 32 to 40 degrees C and at pH values from 5.5 to 6.5. O2 made no difference to both biomass growth and the L-lactic acid fermentation. 8 mg folic acid/l combined with 2 mM Fe(2+) substituted for 6 g yeast extract/l, which is a cost saving. CONCLUSIONS: The special characteristics and economic traits of E. faecium S.156 make it suitable for industrial-scale production of L-lactic acid. PMID- 25801673 TI - Deletion of odhA or pyc improves production of gamma-aminobutyric acid and its precursor L-glutamate in recombinant Corynebacterium glutamicum. AB - OBJECTIVES: To enhance gamma-aminobutyric acid (GABA) production in recombinant Corynebacterium glutamicum, metabolic engineering strategies were used to improve the supply of the GABA precursor, L-glutamate. RESULTS: C. glutamicum ATCC13032 co-expressing two glutamate decarboxylase genes (gadB1 and gadB2) was constructed in a previous study Shi et al. (J Ind Microbiol Biotechnol 40:1285-1296, 2013) to synthesize GABA from endogenous L-glutamate. To improve its L-glutamate supply, new strains were constructed here. First, the odhA and pyc genes were deleted separately. Then, a gadB1-gadB2 co-expression plasmid was transferred into DeltaodhA, Deltapyc, and ATCC13032, resulting in recombinant strains SNW201, SNW202, and SNW200, respectively. After fermenting for 72 h, GABA production increased to 29.5 +/- 1.1 and 24.9 +/- 0.7 g/l in SNW201 and SNW202, respectively, which was significantly higher than that in SNW200 (19.4 +/- 2.6 g/l). The GABA conversion ratios of SNW201 and SNW202 reached 0.98 and 0.96 mol/mol, respectively. CONCLUSION: The recombinant strains SNW201 and SNW202 can be used as candidates for GABA production. PMID- 25801674 TI - Intravital two-photon imaging of the gastrointestinal tract. AB - Live imaging of the gastrointestinal tract with two-photon microscopy (TPM) has proven to be a useful tool for mucosal immunologists. It provides deep penetration of live tissues with reduced phototoxicity and photobleaching and thus excels in deciphering dynamic immunological processes that require cell motility and last minutes through hours. The few studies that employed this technique in the gut have uncovered new aspects of mucosal immunity. They focused mainly on adaptive immunity in the small intestine and exposed the details of important interactions among several epithelial and hematopoietic cell types. TPM can be employed either on explanted tissue or intravitally, as has been practiced in our lab. Intravital TPM preserves physiological conditions more faithfully, but it is a demanding technique that requires dedicated personnel. To achieve success, the peristaltic motility of the intestine must be curbed, surgical and photonic damage must be minimized, and tissue degradation must be delayed and controlled for. Here we briefly review published studies that employed intravital TPM in the gut, describe our own technique for imaging the intestinal Peyer's patches (PPs) and villi, and present some observations we made using this technique. PMID- 25801676 TI - Robotics in urological surgery: evolution, current status and future perspectives. AB - CONTEXT: Robotic surgery is rapidly evolving and has become an essential part of surgical practice in several parts of the world. Robotic technology will expand globally and most of the surgeons around the world will have access to surgical robots in the future. It is essential that we are updated about the outcomes of robot assisted surgeries which will allow everyone to develop an unbiased opinion on the clinical utility of this innovation. OBJECTIVE: In this review we aim to present the evolution, objective evaluation of clinical outcomes and future perspectives of robot assisted urologic surgeries. ACQUISITION OF EVIDENCE: A systematic literature review of clinical outcomes of robotic urological surgeries was made in the PUBMED. Randomized control trials, cohort studies and review articles were included. Moreover, a detailed search in the web based search engine was made to acquire information on evolution and evolving technologies in robotics. SYNTHESIS OF EVIDENCE: The present evidence suggests that the clinical outcomes of the robot assisted urologic surgeries are comparable to the conventional open surgical and laparoscopic results and are associated with fewer complications. However, long term results are not available for all the common robotic urologic surgeries. There are plenty of novel developments in robotics to be available for clinical use in the future. CONCLUSION: Robotic urologic surgery will continue to evolve in the future. We should continue to critically analyze whether the advances in technology and the higher cost eventually translates to improved overall surgical performance and outcomes. PMID- 25801675 TI - MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis. AB - Atherosclerosis, a chronic inflammatory disease, is the major cause of life threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR 26a expression was substantially reduced in the aortic intima of ApoE(-/-) mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a, and TRPC6 overexpression abolished the anti apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR 26a for atherosclerosis associated with apoptotic cell death. PMID- 25801677 TI - Intraoperative injection of (99mm)Tc- nanocolloid for localization of nonpalpable intratesticular tumours in organ-sparing surgery. AB - OBJECTIVE: Radical orchidectomy is the standard treatment for malignant testis tumours. Radical orchidectomy results in androgen deprivation, infertility and impaired psychological well-being, especially in synchronous bilateral tumours, metachronous contralateral tumours or tumour in a solitary testis. According to the European Association of Urology Guidelines, if pre-operative testosterone level is normal and the tumour volume is less than 30% of the testicular volume, organ preserving surgery can be performed. For nonpalpable tumours, organ-sparing surgery needs a precise intraoperative localization with high-frequency ultrasound, especially for nonpalpable tumours. MATHERIAL AND METHODS: We report two cases of nonpalpable intratesticular tumours successfully localised using (99mm)Tc nanocolloid injected with intraoperative US and detected with a gamma ray detection probe. CONCLUSIONS: This method is easily reproducible and safe for the patient. This technique could guarantee complete excision of the tumour, especially if the mass is poorly delimited. PMID- 25801680 TI - [Different mummified eyes in ancient Egypt]. PMID- 25801681 TI - [Neuroretinal rim examination: A vintage phenomenon or a revolution?]. PMID- 25801679 TI - [Louis Braille, the blind man who taught to see]. PMID- 25801678 TI - Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus. AB - The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two promoter regulon with allelic variability that produces a quorum-sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentrations by AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum-sensing pathway has fueled tremendous interest in understanding the structure-activity relationships underlying the AIP-AgrC interaction. The defining structural feature of the AIP is a 16-membered, thiolactone-containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the synthesis and functional analysis of AIP analogues featuring enlarged and reduced macrocycles. Notably, this study is the first to interrogate AIP function by using both established cell-based reporter gene assays and newly developed in vitro AgrC-I binding and autophosphorylation activity assays. Based on our data, we present a model for robust agr activation involving a cooperative, three-points-of-contact interaction between the AIP macrocycle and AgrC. PMID- 25801682 TI - A new caffeoylgluconic acid derivative from the nearly ripe fruits of Evodia rutaecarpa. AB - A new caffeoylgluconic acid derivative, trans-caffeoyl-6-O-D-gluconic acid methyl ester (1), together with two known compounds named trans-caffeoyl-6-O-D-glucono gamma-lactone (2) and trans-caffeoyl-6-O-D-gluconic acid (3), was isolated from the nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth.. These compounds were isolated by various separation methods associated with the UPLC-Q-TOF-MS technique. Their structures were elucidated on the basis of extensive spectroscopic methods. PMID- 25801683 TI - Extended-spectrum beta-lactamase-producing Shiga toxin gene (stx1)-positive Escherichia coli O91:H14 carrying blaCTX-M-15 on an IncI1-ST31 plasmid isolated from a human patient in Germany. AB - In 2011, the Shiga toxin- and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli O104:H4 caused a serious outbreak of gastroenteritis in Germany. This strain carried bla(CTX-M-15) and bla(TEM-1) on an IncI1-ST31 plasmid. During screening of individuals at risk for acquisition of the epidemic E. coli O104:H4, we isolated another ESBL-producing and Shiga toxin-positive E. coli belonging to serotype O91:H14 from feces of a human patient. Interestingly, the patient also carried a further ESBL-producing but Shiga toxin-negative E. coli. Both strains harbored bla(CTX-M-15) and bla(TEM-1) on an IncI1-ST31 plasmid, which was indistinguishable regarding size and plasmid restriction pattern from the plasmid of the epidemic E. coli O104:H4 strain. The patient had traveled to India 6 months prior to the isolation of the E. coli strains. This is the first report of an ESBL-producing, Shiga toxin-positive E. coli of serogroup O91. Our data suggest a high propensity of the IncI1-ST31 plasmid to spread in the human and/or animal population. PMID- 25801684 TI - The impact of horizontal gene transfer on targeting the internal transcribed spacer region (ITS) to identify Acinetobacter junii strains. AB - AIMS: Despite electrophoretic patterns of ITS PCR amplicons often suggesting only a single ITS sequence variant is present in strains of Acinetobacter junii, sequence data shows differences in ITS copies between and among them. This paper set out to explain why these ITS variants arise, and whether their presence compromises the reliability of the ITS targeted methods currently available for typing Ac. junii strains. METHODS AND RESULTS: ITS sequences from a number of strains of Ac. junii were either downloaded from public databases or generated here by cloning and sequencing ITS PCR amplicons. ITS copies of Ac. junii strain 97338 were all 666 bp long, with identical sequences. In Ac. junii ATCC 17908(T) /BCRC 14854(T) ), ITS copies were also all identical in their lengths but now were 706/7 bp long. Two sequence variants of these 707 bp ITS were detected. One was identical in its sequence to the nine ITS copies downloaded from the whole genome sequence of Ac. junii CIP 64.5, and those in several other Ac. junii strains. The other 707 bp ITS variant occurred elsewhere only in Ac. junii strain DSM 14968 of those examined. The six ITS copies from the genome sequence of Ac. junii NIPH 182 were all 685 bp, and with identical sequences. Ac. junii strain 178 also possessed this same 685 bp ITS variant, one of six variants detected there. At least five ITS sequence variants were seen in Ac. junii strain 97380, four in strain DSM 14968 and two in the whole genome of strain 107470. CONCLUSIONS: As with those of other Acinetobacter species, such ITS variants arise not from intragenomic recombination events but from the presence of different length indels. These arise from horizontal gene transfers involving ITS fragments of other Acinetobacter species. SIGNIFICANCE AND IMPACT OF THE STUDY: The presence of these indels compromises the reliability of the ITS targeted methods available for typing Acinetobacter junii. It also precludes the value of using ITS sequences as phylogenetic markers in members of the genus Acinetobacter, since the outcomes in both cases depends on which copy variant is chosen. PMID- 25801685 TI - Advances in IL-21 biology - enhancing our understanding of human disease. AB - Cytokines play critical roles in regulating the development and function of immune cells. Cytokines function by binding specific multimeric receptor complexes and activating intracellular signaling pathways that often involve JAKs and STATs. In addition to contributing to immunity, when production of cytokines is perturbed, they can contribute to disease. IL-21 is a pleiotropic cytokine produced predominantly by CD4(+) T cells and NKT cells. Gene-targeting studies in mice and in vitro analyses of human and murine lymphocytes have revealed central roles of IL-21 in regulating effector functions of T cells, NK cells and B cells. However, recent discoveries of loss-of function mutations in IL21 or IL21R in humans have unveiled unexpected roles for IL-21 in immune regulation. This review will focus on recent advances in IL-21 biology that have highlighted its critical role in normal immunity and how dysregulated IL-21 production can lead to immunodeficiency and autoimmune conditions. PMID- 25801686 TI - Multiple sclerosis and HIV-1 infection: case report of a HIV controller. AB - Multiple sclerosis (MS) has been infrequently described in association with human immunodeficiency virus (HIV) infection. Underreporting, missed diagnoses or a true negative association between MS and HIV infection are all possible explanations for the paucity of published cases. Since MS involves inflammation and demyelination of the central nervous system by autoreactive T cells, immunosuppression caused by HIV infection would be expected to confer a reduced risk of MS. This report describes a case of relapsing-remitting MS in a woman with non-progressive HIV-1 infection for 5 years. The patient has stable normal CD4+ cell counts and a low viral load in the absence of combination antitretroviral treatment (cART). She experienced typical neurological symptoms of MS including optic neuritis, trigeminal neuralgia, and transverse myelitis. MRI of the spinal cord demonstrated multiple lesions on T2-weighted images. Immune mechanisms associated with HIV control that may have contributed to the development and relapses of MS in this patient are discussed. PMID- 25801688 TI - [Working group on implant research of the German Society of Surgery]. PMID- 25801687 TI - [Skin and soft tissue complications after orthopedic interventions on tumors : interdisciplinary management]. AB - Interdisciplinary collaboration between orthopedic and plastic surgeons is indicated in reconstructive surgery of the extremities for both traumatic orthopedic fractures with extensive soft tissue damage and musculoskeletal tumor resection. We want to emphasize the need for close cooperation starting in the preoperative planning for reconstruction after tumor resection in order to discuss and establish a unified approach. This is particularly important to establish a joint approach with special consideration of possibly necessary adjuvant therapies. One collaborative approach is for the orthopedic surgeon to resect the tumor and the plastic surgeon to carry out the defect reconstruction for exclusive soft tissue coverage including flap surgery as well as for functional reconstruction depending on the location and extent of tumor resection. Thus, careful preoperative and postoperative communication on the precise location, extent of tumor resection and the therapy timing between the orthopedic surgeon and the plastic surgeon will allow the most effective subsequent repair of the resection site. PMID- 25801689 TI - Genetic and morphological variability of the European mudminnow Umbra krameri (Teleostei, Umbridae) in Serbia and in Bosnia and Herzegovina, a basis for future conservation activities. AB - As a basis for future conservation activities, the genetic and external body morphology variability of the European mudminnow Umbra krameri, a highly endangered fish species in Serbia and in Bosnia and Herzegovina, was determined for existing populations with the use of molecular markers (mitochondrial and microsatellite DNA) and geometric morphometric methods. Mitochondrial DNA cytochrome b gene analysis revealed two previously undescribed haplotypes: Da1 (the Lugomir population from the Danube River basin) and Sa1 (the Bakreni Batar and the Gromizelj populations from the Sava River system), with a corresponding genetic distance of 0.7%. Paired values of FST and DAS distances for microsatellite marker data show that the difference between the Danube and the Sava populations is seven to nine times higher than the difference between the populations within the Sava River system. Geometric morphometric analyses also support a clear separation of the Lugomir population from the Bakreni Batar and the Gromizelj populations. The analysis of the body shape variation, however, indicates a significant difference between the two genetically indistinguishable Sava populations. The observed genetic and phenetic relationships of the analysed mudminnow populations most probably represent a consequence of historical, geographical and ecological factors. These results will offer guidelines for future protection, conservation and sustainable management of this species in the region. PMID- 25801690 TI - Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation. AB - BACKGROUND: Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood. OBJECTIVES: To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring. METHODS: Time-pregnant mice were exposed to LG-SF or sleep control during LG (LG SC) conditions during the last 6 days of gestation. At 24 weeks of age, lipid profiles and metabolic parameters were assessed in the offspring. We performed large-scale DNA methylation analyses using methylated DNA immunoprecipitation (MeDIP) coupled with microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG SC offspring (n=8 mice per group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks. RESULTS: We detected significant increases in body weight (31.7 vs 28.8 g; P=0.001), visceral (642.1 vs 497.0 mg; P=0.002) and subcutaneous (293.1 vs 250.1 mg; P=0.001) fat mass, plasma cholesterol (110.6 vs 87.6 mg dl(-1); P=0.001), triglycerides (87.3 vs 84.1 mg dl(-1); P=0.003) and homeostatic model assessment insulin resistance values (8.1 vs 6.1; P=0.007) in the LG-SF group. MeDIP analyses revealed that 2148 DMRs (LG-SF vs LG-SC; P<0.0001, model-based analysis of tilling-arrays algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome, such as Cartpt, Akt2, Apoe, Insr1 and so on. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response. CONCLUSIONS: Our findings show a major role for epigenomic regulation of pathways associated with the metabolic processes and inflammatory responses in VWAT. LG-SF-induced epigenetic alterations may underlie increases in the susceptibility to obesity and metabolic syndrome in the offspring. PMID- 25801691 TI - Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans. AB - BACKGROUND/OBJECTIVES: Obesity has been associated with both changes in adipose tissue lipid metabolism and inflammation. A key class of lipid-derived signalling molecules involved in inflammation are the prostaglandins. In this study, we aimed to determine how obesity affects the levels of prostaglandins within white adipose tissue (WAT) and determine which cells within adipose tissue produce them. To avoid the effects of cellular stress on prostaglandin levels, we developed a multivariate statistical approach in which metabolite concentrations and transcriptomic data were integrated, allowing the assignment of metabolites to cell types. SUBJECTS/METHODS: Eicosanoids were measured by liquid chromatography-tandem mass spectrometry and mRNA levels using real-time PCR. Eicosanoid levels and transcriptomic data were combined using principal component analysis and hierarchical clustering in order to associate metabolites with cell types. Samples were obtained from C57Bl/6 mice aged 16 weeks. We studied the ob/ob genetically obese mouse model and diet-induced obesity model. We extended our results in mice to a cohort of morbidly obese humans undergoing bariatric surgery. RESULTS: Using our modelling approach, we determined that prostglandin D2 (PGD2) in adipose tissue was predominantly produced in macrophages by the haematopoietic isoform of prostaglandin D synthase (H-Pgds). Analysis of sub fractionated WAT confirmed that H-Pgds was expressed in adipose tissue macrophages (ATMs). Furthermore, H-Pgds expression in ATMs isolated from lean and obese mice was consistent with it affecting macrophage polarisation. Functionally, we demonstrated that H-PGDS-produced PGD2 polarised macrophages toward an M2, anti-inflammatory state. In line with a potential anti-inflammatory role, we found that H-PGDS expression in ATMs was positively correlated with both peripheral insulin and adipose tissue insulin sensitivity in humans. CONCLUSIONS: In this study, we have developed a method to determine the cellular source of metabolites within an organ and used it to identify a new role for PGD2 in the control of ATM polarisation. PMID- 25801693 TI - Analyzing the Influence of a New Dental Implant Design on Primary Stability. AB - BACKGROUND: The macrogeometry of dental implants strongly influences the primary stability and hence the osseointegration process. PURPOSE: Compare the performance of conventional and modified implant models in terms of primary stability. MATERIALS AND METHODS: A total of 36 implants (Neodent(r)) with two different formats (n = 18): Alvim CM (Conical CM, O 4.3 mm * 10 mm in length) and Titamax Ti (Cylindrical HE, O 4.0 mm * 11 mm in length) were inserted into artificial bone blocks. Nine implants from each set were selected to undergo external geometry changes. The primary stability was quantified by insertion torque and resonance frequency using an Osstell device and the pullout test. One way analysis of variance and Tukey's test were used for statistical evaluation. RESULTS: The comparative analysis of the implants showed a significant increase of the insertion torque for the modified Conical CM implants (p = 0.000) and Cylindrical HE (p = 0.043); for the resonance frequency the modified Cylindrical HE showed a lower statistical mean (p = 0.002) when compared to the conventional model, and in the pullout test both modified implants showed significant reduction (p = 0.000). CONCLUSIONS: Within the limitations of this study, the proposed modification showed good stability levels and advantages when compared to the conventional implants. PMID- 25801694 TI - Capsule Commentary on Lee et al., Health Literacy as a Social Determinant of Health in Asian American Immigrants: Findings from a Population-Based Survey in California. PMID- 25801692 TI - Effects of adenotonsillectomy on plasma inflammatory biomarkers in obese children with obstructive sleep apnea: A community-based study. AB - BACKGROUND: Obesity and obstructive sleep apnea syndrome (OSA) are highly prevalent and frequently overlapping conditions in children that lead to systemic inflammation, the latter being implicated in the various end-organ morbidities associated with these conditions. AIM: To examine the effects of adenotonsillectomy (T&A) on plasma levels of inflammatory markers in obese children with polysomnographically diagnosed OSA who were prospectively recruited from the community. METHODS: Obese children prospectively diagnosed with OSA, underwent T&A and a second overnight polysomnogram (PSG) after surgery. Plasma fasting morning samples obtained after each of the two PSGs were assayed for multiple inflammatory and metabolic markers including interleukin (IL)-6, IL-18, plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), adiponectin, apelin C, leptin and osteocrin. RESULTS: Out of 122 potential candidates, 100 obese children with OSA completed the study with only one-third exhibiting normalization of their PSG after T&A (that is, apnea-hypopnea index (AHI) <=1/hour total sleep time). However, overall significant decreases in MCP-1, PAI-1, MMP-9, IL-18 and IL-6, and increases in adropin and osteocrin plasma concentrations occurred after T&A. Several of the T&A-responsive biomarkers exhibited excellent sensitivity and moderate specificity to predict residual OSA (that is, AHI?5/hTST). CONCLUSIONS: A defined subset of systemic inflammatory and metabolic biomarkers is reversibly altered in the context of OSA among community-based obese children, further reinforcing the concept on the interactive pro-inflammatory effects of sleep disorders such as OSA and obesity contributing to downstream end-organ morbidities. PMID- 25801695 TI - Quantity Over Quality: How the Rise in Quality Measures is Not Producing Quality Results. AB - Over the past decade, quality measures (QMs) have been implemented nationally in order to establish standards aimed at improving the quality of care. With the expansion of their role in the Affordable Care Act and pay-for-performance, QMs have had an increasingly significant impact on clinical practice. However, adverse patient outcomes have resulted from adherence to some previously promulgated performance measures. Several of these QMs with unintended consequences, including the initiation of perioperative beta-blockers in noncardiac surgery and intensive insulin therapy for critically ill patients, were instituted as QMs years before large randomized trials ultimately refuted their use. The future of quality care should emphasize the importance of evidence based, peer-reviewed measures. PMID- 25801696 TI - Patient-Centered Models of Care: Closing the Gaps in Physician Readiness. PMID- 25801697 TI - Sustained inhibition of proton-coupled folate transporter by myricetin. AB - Myricetin is a flavonoid that has recently been suggested to interfere with the intestinal folate transport system. To examine that possibility, focusing on its sustained inhibitory effect on proton-coupled folate transporter (PCFT), the uptake of folate was examined in Caco-2 cells, in which PCFT is known to be in operation, in the absence of myricetin in the medium during uptake period after preincubation of the cells with the flavonoid (100 MUM) for 1 h. This pretreatment induced an extensive and sustained reduction in the carrier-mediated component of folate uptake, which was attributable to a reduction in the maximum transport rate (Vmax). Although the affinity of the transporter for folate was increased at the same time as indicated by a reduction in the Michaelis constant (Km), the change in Km was overwhelmed in extent by that in Vmax. Consistent with the finding, folate transport by human PCFT stably expressed in Madin-Darby canine kidney II cells was reduced in a similar manner with simultaneous reductions in Vmax and Km by myricetin pretreatment. Attention may need to be given for a possibility that such a sustained inhibition of PCFT could potentially be a cause of the malabsorption of folate and also antifolate drugs. PMID- 25801698 TI - Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study. AB - Thrombopoietin receptor agonists, which raise platelet counts in patients with chronic immune thrombocytopenia, may be associated with increases in bone marrow (BM) reticulin. Patients with chronic immune thrombocytopenia participating in the Eltrombopag Extended Dosing (EXTEND) study underwent BM biopsies to identify clinically relevant BM fibrosis-related increases. Specimens were centrally reviewed by 2 hematopathologists. Two hundred thirty-two biopsy specimens were collected from 117 patients treated for <=5.5 years. Moderate to marked reticulin fibrosis was found in 2 patients. After withdrawing from the study, the biopsy of 1 patient reverted to normal. There were no other pathologic changes identified among on-treatment specimens, and no pattern of abnormal reticulin deposition associated with eltrombopag treatment was evident. PMID- 25801699 TI - Development and validation of prognostic nomograms for metastatic gastrointestinal stromal tumour treated with imatinib. AB - PURPOSE: Metastatic gastrointestinal stromal tumour (GIST) is generally an incurable disease with variable response to imatinib. We aimed to develop prognostic nomograms to predict overall survival (OS) and progression-free survival (PFS) for patients treated with imatinib. METHODS: Nomograms were developed in a training cohort (n=330) of patients treated in a randomised trial (EORTC-ISG-AGITG 62005 phase III study) using Cox regression models, and validated in patients (n=236) treated in routine clinical care from six referral centres. Nomogram performance was assessed by calculating the c statistic. A classification based on the nomograms' scores was generated to group patients according to risk. RESULTS: Nomogram risk factors for OS and PFS were size of the largest metastasis, tumour genotype, primary tumour mitotic count, haemoglobin and blood neutrophil count at commencement of imatinib. The nomograms predicted survival with a c statistic of 0.75 (training) and 0.62 (validation) for OS, and 0.69 (training) and 0.62 (validation) for PFS. When tested in the validation cohort, the nomograms discriminated well the high and intermediate risk from low risk patients (hazard ratio [HR] for OS 3.83, 95% confidence interval [CI] 1.71 8.56; and 2.48, 95% CI 1.12-5.50; for PFS 2.84, 95% CI 1.66-4.87; and 1.45, 95% CI 0.87-2.41, respectively). CONCLUSION: The nomograms predicted the risk of GIST progression and death with good discrimination of risk groups, and may be of value for patient counselling and risk stratification. PMID- 25801700 TI - RETRA exerts anticancer activity in Ewing's sarcoma cells independent of their TP53 status. AB - Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES. PMID- 25801701 TI - Evaluation of multixenobiotic resistance in dreissenid mussels as a screening tool for toxicity in freshwater sediments. AB - The multixenobiotic defense mechanism (MXR) in aquatic organisms was recognized as a first-line defense system, and its potential use as an early biomarker of exposure to environmental stress has raised attention in the last two decades. To evaluate the relevance of this biomarker in the freshwater mussel Dreissena polymorpha, we studied its responsiveness within laboratory exposures to contaminants sequestered in freshwater sediments affected by moderate anthropogenic impact. The effectiveness of this biomarker was assessed by comparing the MXR-transporter activities determined in bivalves first with toxicity scores recorded with the D. rerio embryo developmental assay. Both bioassays were applied in the sediment contact test format. As a second evaluation approach, MXR activities determined in exposed mussels were compared with sediment-contamination data integrated into toxic units on the basis of acute toxicity to Daphnia magna. In D. polymorpha subjected to acute exposure with moderately polluted sediments, we detected limited (22-33 %) but statistically significant induction of MXR activity. Mean MXR activities significantly correlated with TU values computed for test sediments. MXR activities in mussels showed strong positive correlation with the metal load of sediments and proved to be unrelated to the contamination with polycyclic aromatic compounds. MXR activity in laboratory-exposed mussels showed low variability within treatments and thus reliably reflected even low contaminant differences between the negative reference and moderately polluted harbor sediments. The strong correlation found in this study between the MXR-transporter activity in exposed mussels and environmentally realistic sediment contamination underscores the fairly good sensitivity of this biomarker in laboratory testing conditions to signal the bioavailability of sediment bound contaminants, and it may also anticipate even the incidence of toxicity to biota. PMID- 25801702 TI - Efficacy of the Malva sylvestris L. flowers aqueous extract for functional constipation: A placebo-controlled trial. AB - OBJECTIVE: To evaluate the efficacy of Malva sylvestris L. flowers extract for treatment of FC. METHOD: Adults with FC were allocated to receive the M. sylvestris L. flowers aqueous extract syrup (MSL, 1 g extract/day) or placebo for four weeks. Frequency of constipation symptoms and stool forms were assessed every week. Self-reported improvement was assessed after treatment. RESULTS: Compared with placebo, more increase was observed in defecation frequency (F = 18.8, P < 0.001) and more decrease was observed in frequency of all constipation symptoms by MSL (F = 16.5 to 25.3, all P values <0.001). Also, the MSL group experienced more reduction in frequency of hard stool forms (45.4% vs. 9.1%, P < 0.001) and reported more improvement in all symptoms (all P values <0.01) than placebo. CONCLUSION: The M. sylvestris L. flowers aqueous extract is efficacious and safe for the treatment of FC in adult patients. Investigating the mechanisms of action is warranted. IRCT2014031617032N1. PMID- 25801703 TI - Clock genes control cortical critical period timing. AB - Circadian rhythms control a variety of physiological processes, but whether they may also time brain development remains largely unknown. Here, we show that circadian clock genes control the onset of critical period plasticity in the neocortex. Within visual cortex of Clock-deficient mice, the emergence of circadian gene expression was dampened, and the maturation of inhibitory parvalbumin (PV) cell networks slowed. Loss of visual acuity in response to brief monocular deprivation was concomitantly delayed and rescued by direct enhancement of GABAergic transmission. Conditional deletion of Clock or Bmal1 only within PV cells recapitulated the results of total Clock-deficient mice. Unique downstream gene sets controlling synaptic events and cellular homeostasis for proper maturation and maintenance were found to be mis-regulated by Clock deletion specifically within PV cells. These data demonstrate a developmental role for circadian clock genes outside the suprachiasmatic nucleus, which may contribute mis-timed brain plasticity in associated mental disorders. PMID- 25801705 TI - Specific wiring of distinct amacrine cells in the directionally selective retinal circuit permits independent coding of direction and size. AB - Local and global forms of inhibition controlling directionally selective ganglion cells (DSGCs) in the mammalian retina are well documented. It is established that local inhibition arising from GABAergic starburst amacrine cells (SACs) strongly contributes to direction selectivity. Here, we demonstrate that increasing ambient illumination leads to the recruitment of GABAergic wide-field amacrine cells (WACs) endowing the DS circuit with an additional feature: size selectivity. Using a combination of electrophysiology, pharmacology, and light/electron microscopy, we show that WACs predominantly contact presynaptic bipolar cells, which drive direct excitation and feedforward inhibition (through SACs) to DSGCs, thus maintaining the appropriate balance of inhibition/excitation required for generating DS. This circuit arrangement permits high-fidelity direction coding over a range of ambient light levels, over which size selectivity is adjusted. Together, these results provide novel insights into the anatomical and functional arrangement of multiple inhibitory interneurons within a single computational module in the retina. PMID- 25801704 TI - MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers. AB - Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes. PMID- 25801707 TI - Neisseria meningitidis subverts the polarized organization and intracellular trafficking of host cells to cross the epithelial barrier. AB - Translocation of the nasopharyngeal barrier by Neisseria meningitidis occurs via an intracellular microtubule-dependent pathway and represents a crucial step in its pathogenesis. Despite this fact, the interaction of invasive meningococci with host subcellular compartments and the resulting impact on their organization and function have not been investigated. The influence of serogroup B strain MC58 on host cell polarity and intracellular trafficking system was assessed by confocal microscopy visualization of different plasma membrane-associated components (such as E-cadherin, ZO-1 and transferrin receptor) and evaluation of the transferrin uptake and recycling in infected Calu-3 monolayers. Additionally, the association of N. meningitidis with different endosomal compartments was evaluated through the concomitant staining of bacteria and markers specific for Rab11, Rab22a, Rab25 and Rab3 followed by confocal microscopy imaging. Subversion of the host cell architecture and intracellular trafficking system, denoted by mis-targeting of cell plasma membrane components and perturbations of transferrin transport, was shown to occur in response to N. meningitidis infection. Notably, the appearance of all of these events seems to positively correlate with the efficiency of N. meningitidis to cross the epithelial barrier. Our data reveal for the first time that N. meningitidis is able to modulate the host cell architecture and function, which might serve as a strategy of this pathogen for overcoming the nasopharyngeal barrier without affecting the monolayer integrity. PMID- 25801708 TI - A Triple and Quadruple Therapy with Doxycycline and Bismuth for First-Line Treatment of Helicobacter pylori Infection: A Pilot Study. AB - BACKGROUND: Tetracycline-containing triple therapy has been suggested as an alternative first-line therapy for H. pylori infection. AIM: To evaluate the effect of two dosages of doxycycline (DOX) associated with amoxicillin and esomeprazole with and without bismuth subcitrate as first-line treatment of H. pylori infection. METHODS: Helicobacter pylori-positive patients underwent a 10 day therapy randomized into four groups: Group A received esomeprazole, amoxicillin, and DOX-100 mg b.i.d. (EAD-100), Group B a quadruple therapy with esomeprazole, amoxicillin, DOX-100 mg b.i.d. and bismuth subcitrate (EADB-100), Group C a triple therapy with esomeprazole, amoxicillin, and DOX-200 mg b.i.d. (EAD-200) and Group D a quadruple therapy with esomeprazole, amoxicillin, DOX-200 mg b.i.d., and bismuth subcitrate (EADB-200). Success was accessed by (13)C urea breath test 2 months after the end of treatment. The number of patients to be recruited for each group had to be at least 50 subjects. Treatment success of 80% or less was considered unacceptable. Stopping rules therefore were anytime six failures had occurred. RESULTS: In the EAD-100 group and in EAD-200 group, the recruitment was stopped at the 14th and 15th patient, respectively. Fifty-two patients entered in the EADB-100 group and 51 in the EADB-200 group. Intention to treat eradication was in EADB-100 group 46/52 (88.5%, 95% CI 76.6-95.6); in the EADB-200 group 47/51 (92.1%, 95% CI: 81.1-97.8) (n.s.). Side effects were absent. CONCLUSION: The adjunction of bismuth subcitrate to a triple therapy that includes esomeprazole, amoxicillin, and DOX in patients who are treated for the first time for the H. pylori infection potentiates the therapeutic effect. This regimen, however, deserves to be optimized in terms of duration and dose of DOX. PMID- 25801709 TI - Characterization of plasma membrane associated type II alpha-D-mannosidase and beta-N-acetylglucosaminidase of Aquarius remigis sperm. AB - For successful fertilization to occur, molecules on the surface of male and female gametes must recognize each other in a complementary manner. In some organisms, sperm possess a glycosidase on the plasma membrane overlying the head while eggs have glycoproteins that are recognized by those glycosidases resulting in sperm-egg recognition. In this study, two glycosidases, mannosidase and beta-N acetylglucosaminidase, were identified and biochemically characterized in Aquarius remigis sperm. The mannosidase had a Km of 2.36 +/- 0.19 mM, a Vmax of 27.49 +/- 0.88 pmol/min and a Hill coefficient of 0.94 +/- 0.18 at its optimal pH of 7.0. The mannosidase was extracted most efficiently with CHAPSO but was also efficiently extracted with sodium chloride. Mannosidase activity was effectively inhibited by swainsonine, but not by kifunesine, and was significantly reduced in the presence of Mn(2+) and Mg(2+), but not Zn(2+). N-acetylglucosaminidase had a Km of 0.093 +/- 0.01 mM, a Vmax of 153.80 +/- 2.97 pmol/min and a Hill coefficient of 0.96 +/- 0.63 at its optimal pH of 7.0. N-acetylglucosaminidase was extracted most efficiently with potassium iodide but was also efficiently extracted with Triton X-100 and Zn(2+), but not Ca(2+), Co(2+), Mn(2+) or Mg(2+), significantly inhibited its activity. Taken together, these results indicate that the A. remigis sperm surface contains at least two glycosidases that may recognize complementary glycoconjugates on the surface of water strider eggs. PMID- 25801706 TI - Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. AB - Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in nonneuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and the ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity. PMID- 25801711 TI - Microvascular angina: a women's affair? PMID- 25801710 TI - Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women's Ischemia Syndrome Evaluation. AB - BACKGROUND: Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). Although traditional noninvasive stress imaging is often normal in CMD, cardiac MRI may be able to detect CMD in this population. METHODS AND RESULTS: Vasodilator stress cardiac MRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi-quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression, and sensitivity/specificity. Symptomatic women had lower mean pharmacological stress MPRI compared with reference subjects (1.71+/-0.43 versus 2.23+/-0.37; P<0.0001). Lower MPRI was predictive of >=1 abnormal CRT variables (odds ratio =0.78 [0.70, 0.88], P<0.0001, c-statistic 0.78 [0.68, 0.88]). An MPRI threshold of 1.84 predicted CRT abnormality with sensitivity 73% and specificity 74%. CONCLUSIONS: Noninvasive cardiac MRI MPRI can detect CMD defined by invasive CRT. Further work is aimed to optimize the noninvasive identification and management of CMD patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00832702. PMID- 25801712 TI - Cerebral hyperperfusion and decreased cerebrovascular reactivity correlate with neurologic disease severity in MELAS. AB - OBJECTIVE: To study the mechanisms underlying stroke-like episodes (SLEs) in MELAS syndrome. METHODS: We performed a case control study in 3 siblings with MELAS syndrome (m.3243A>G tRNA(Leu(UUR))) with variable % mutant mtDNA in blood (35 to 59%) to evaluate regional cerebral blood flow (CBF) and arterial cerebrovascular reactivity (CVR) compared to age- and sex-matched healthy study controls and a healthy control population. Subjects were studied at 3T MRI using arterial spin labeling (ASL) to measure CBF; CVR was measured as a change in % Blood Oxygen Level Dependent signal (as a surrogate of CBF) to repeated 10 mmHg step increase in arterial partial pressure of CO2 (PaCO2). RESULTS: MELAS siblings had decreased CVR (p <= 0.002) and increased CBF (p < 0.0026) compared to controls; changes correlated with disease severity and % mutant mtDNA (inversely for CVR: r = -0.82 frontal, r = -0.91 occipital cortex; directly for CBF: r = +0.85 frontal, not for occipital infarct penumbra). Mean CVR was reduced more in frontal (p < 0.001) versus occipital cortex (p = 0.002); mean CBF was increased more in occipital (p = 0.001) than frontal (p = 0.0026) cortices compared to controls. CBF correlated inversely with CVR (r = -0.99 in frontal; not in occipital infarct penumbra) suggesting that increased frontal resting flows are at the expense of flow reserve. INTERPRETATION: MELAS disease severity and mutation load were inversely correlated with Interictal CVR and directly correlated with frontal CBF. These metrics offer further insight into the cerebrovascular hemodynamics in MELAS syndrome and may serve as noninvasive prognostic markers to stratify risk for SLEs. CLASSIFICATION OF EVIDENCE: Class III. PMID- 25801715 TI - SnGa2GeS6: synthesis, structure, linear and nonlinear optical properties. AB - A new sulfide, SnGa2GeS6, has been synthesized, which represents the first member in the quaternary Sn/M/M'/Q (M = Ga, In; M' = Si, Ge; Q = S, Se, Te) system. It adopts a new structure type in the non-centrosymmetric space group Fdd2. In the structure, Sn(2+) is coordinated to a distorted square-pyramid of five S atoms, demonstrating the stereochemical activity of the lone electron pair, while the Ge atom and Ga atom are both tetrahedrally coordinated to four S atoms. The SnS5 square-pyramids and the MS4 (M = Ga, Ge) tetrahedra are connected to each other via corner and edge-sharing to generate a three-dimensional framework. The compound exhibits a powder second harmonic generation signal at 2 MUm whose strength is about one-fourth that of the benchmark material AgGaS2, which may be explained in view of the macroscopic arrangement of the SnS5 square-pyramids and the MS4 tetrahedra. Moreover, based on UV-vis-NIR spectroscopy measurements and the electronic structure calculations, SnGa2GeS6 has two optical transitions at about 1.12 eV and 2.04 eV respectively. PMID- 25801713 TI - Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma. AB - The c-Met protein, a transmembrane receptor tyrosine kinase, is the product of a proto-oncogene. Its only known ligand, hepatocyte growth factor (HGF), regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. The aberrant expression of c-Met is often associated with poor prognosis in multiple cancers, including renal cell carcinoma (RCC). Silencing or inactivation of c-Met leads to decreased viability of cancer cells, thereby making ablation of c-Met signaling an attractive concept for developing novel strategies for the treatment of renal tumors. Naturally-occurring products or substances are the most consistent source of drug development. As such, we investigated the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum) on c-Met expression in RCC cells and demonstrated that PL and its analogs rapidly reduce c-Met protein and RNA levels in RCC cells via ROS dependent mechanism. PL-mediated c-Met depletion coincided with the inhibition of downstream c-Met signaling; namely Erk/MAPK, STAT3, NF-kappaB and Akt/mTOR. As such, PL and PL analogs hold promise as potential therapeutic agents for the treatment of metastatic RCC and the prevention of postoperative RCC recurrence. PMID- 25801714 TI - The mobile revolution--using smartphone apps to prevent cardiovascular disease. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. Mobile technology might enable increased access to effective prevention of CVDs. Given the high penetration of smartphones into groups with low socioeconomic status, health-related mobile applications might provide an opportunity to overcome traditional barriers to cardiac rehabilitation access. The huge increase in low-cost health-related apps that are not regulated by health-care policy makers raises three important areas of interest. Are apps developed according to evidenced-based guidelines or on any evidence at all? Is there any evidence that apps are of benefit to people with CVD? What are the components of apps that are likely to facilitate changes in behaviour and enable individuals to adhere to medical advice? In this Review, we assess the current literature and content of existing apps that target patients with CVD risk factors and that can facilitate behaviour change. We present an overview of the current literature on mobile technology as it relates to prevention and management of CVD. We also evaluate how apps can be used throughout all age groups with different CVD prevention needs. PMID- 25801716 TI - [Cardiac resynchronisation with atrial sensing: Is it feasible?]. AB - In this article the cases of two female patients with heart failure (functional class III) and an intrinsic complete left bundle branch block are reported. Both patients have had an implanted cardioverter defibrillator (ICD) connected to a VDD lead for primary prevention of sudden cardiac death. Atrial sensing was good/acceptable with a physiological frequency histogram and normal PQ time. A system upgrade to cardiac resynchronization therapy device (CRT) was planned. The VDD lead was directly connected to the Bivent ICD. The follow up showed stable measurements and a high biventricular pacing rate. Thus, usage of VDD leads for atrial sensing in CRT seems to be possible in a selected patient population. PMID- 25801718 TI - Differential patterns of functional and structural plasticity within and between inferior frontal gyri support training-induced improvements in inhibitory control proficiency. AB - Ample evidence indicates that inhibitory control (IC), a key executive component referring to the ability to suppress cognitive or motor processes, relies on a right-lateralized fronto-basal brain network. However, whether and how IC can be improved with training and the underlying neuroplastic mechanisms remains largely unresolved. We used functional and structural magnetic resonance imaging to measure the effects of 2 weeks of training with a Go/NoGo task specifically designed to improve frontal top-down IC mechanisms. The training-induced behavioral improvements were accompanied by a decrease in neural activity to inhibition trials within the right pars opercularis and triangularis, and in the left pars orbitalis of the inferior frontal gyri. Analyses of changes in brain anatomy induced by the IC training revealed increases in grey matter volume in the right pars orbitalis and modulations of white matter microstructure in the right pars triangularis. The task-specificity of the effects of training was confirmed by an absence of change in neural activity to a control working memory task. Our combined anatomical and functional findings indicate that differential patterns of functional and structural plasticity between and within inferior frontal gyri enhanced the speed of top-down inhibition processes and in turn IC proficiency. The results suggest that training-based interventions might help overcoming the anatomic and functional deficits of inferior frontal gyri manifesting in inhibition-related clinical conditions. More generally, we demonstrate how multimodal neuroimaging investigations of training-induced neuroplasticity enable revealing novel anatomo-functional dissociations within frontal executive brain networks. PMID- 25801717 TI - Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases. AB - The blood-brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases. PMID- 25801721 TI - The effectiveness of two different laparoscopic surgeries for apical support of pelvic organ prolapse. AB - OBJECTIVE: To evaluate the efficacy of laparoscopic colpo-uterine butterfly suspension and compare it to laparoscopic sacrocervicopexy for apical support in sexually active patients of pelvic organ prolapse. STUDY DESIGN: Twenty-there women with symptomatic prolapse of apical prolapse underwent laparoscopic colpo uterine butterfly suspension and forty-five underwent laparoscopic sacrocervicopexy at the first affiliated of Zhengzhou University between January 2010 and June 2013. They all presented with at least a stage 2 apical prolapse. Pre- and post-operative data referring to pelvic organ prolapse quantification (POP-Q) system were compared. At the same time, validated questionnaire of the Pelvic Floor Distress Inventory (PFDI-20), the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Pelvic organ prolapse urinary Incontinence Sexual Questionnaire (PISQ-12) were included. RESULTS: From 2010 to 2013, 68 patients were included. Only 3 cases lost the follow-up in the Laparoscopic sacrocervicopexy. In the laparoscopic colpo-uterine butterfly suspension, there was no recurrence versus in five the laparoscopic sacrocervicopexy. When considered the operating time and blood loss, the laparoscopic colpo-uterine butterfly suspension was more favorable. Erosion was higher in the laparoscopic sacrocervicopexy compared to the other group (0% vs 21.4%). There was no difference in the postoperative PFDI 20 score (P=0.3079), and PFIQ-7 score (P=0.8889) between the two groups, while the PISQ-12 score was much higher in the laparoscopic colpo-uterine butterfly suspension than the other group (P=0.0076). CONCLUSION: Laparoscopic colpo uterine butterfly suspension is a more effective option for sexually active women with pelvic organ prolapse. PMID- 25801720 TI - Flavonoid metabolites reduce tumor necrosis factor-alpha secretion to a greater extent than their precursor compounds in human THP-1 monocytes. AB - SCOPE: Flavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixtures of metabolites. Using a unique study design, we investigated the potential for singular or additive anti-inflammatory effects of flavonoid metabolites relative to their precursor structures. METHODS AND RESULTS: Six flavonoids, 14 flavonoid metabolites, and 29 combinations of flavonoids and their metabolites (0.1-10 MUM) were screened for their ability to reduce LPS-induced tumor necrosis factor-alpha (TNF-alpha) secretion in THP-1 monocytes. One micromolar peonidin-3-glucoside, cyanidin-3-glucoside, and the metabolites isovanillic acid (IVA), IVA-glucuronide, vanillic acid-glucuronide, protocatechuic acid-3-sulfate, and benzoic acid-sulfate significantly reduced TNF alpha secretion when in isolation, while there was no effect on TNF-alpha mRNA expression. Four combinations of metabolites that included 4-hydroxybenzoic acid (4HBA) and/or protocatechuic acid also significantly reduced TNF-alpha secretion to a greater extent than the precursors or metabolites alone. The effects on LPS induced IL-1beta and IL-10 secretion and mRNA expression were also examined. 4HBA significantly reduced IL-1beta secretion but none of the flavonoids or metabolites significantly modified IL-10 secretion. CONCLUSION: This study provides novel evidence suggesting flavonoid bioactivity results from cumulative or additive effects of circulating metabolites. PMID- 25801722 TI - How singleton breech babies at term are born in France: a survey of data from the AUDIPOG network. AB - Based on data from the AUDIPOG sentinel network between 1994 and 2010, we can say that the rate of singleton breech presentation at term is 3% and remains unchanged despite an external cephalic version rate of 35%. The total cesarean section rate is currently 75%. This rate increased by nearly 20% after the Hannah publication in 2000, regardless of the type of breech and type of maternity unit. The rate of planned cesarean sections increased in particular, going from 40% to 60%, and even reaching 67% for footling breech presentations. The rate is higher in type I maternity units than in type II or III. This cesarean section rate has been stable since 2005 and has even decreased for the Frank breech. The average rate of external cephalic version remains stable at around 23%. The episiotomy rate is 28%. The rate of babies transferred to neonatology units is higher for breech babies at term than for babies presenting cephalically (3.9% compared to 2.9%), but the newborns most often transferred are those born by cesarean section (4.1% compared to 3.4%). PMID- 25801723 TI - Predicting the chance of vaginal delivery after one cesarean section: validation and elaboration of a published prediction model. AB - OBJECTIVE: We aimed to validate a widely used US prediction model for vaginal birth after cesarean (Grobman et al. [8]) and modify it to suit Swedish conditions. STUDY DESIGN: Women having experienced one cesarean section and at least one subsequent delivery (n=49,472) in the Swedish Medical Birth Registry 1992-2011 were randomly divided into two data sets. In the development data set, variables associated with successful trial of labor were identified using multiple logistic regression. The predictive ability of the estimates previously published by Grobman et al., and of our modified and new estimates, respectively, was then evaluated using the validation data set. The accuracy of the models for prediction of vaginal birth after cesarean was measured by area under the receiver operating characteristics curve. RESULTS: For maternal age, body mass index, prior vaginal delivery, and prior labor arrest, the odds ratio estimates for vaginal birth after cesarean were similar to those previously published. The prediction accuracy increased when information on indication for the previous cesarean section was added (from area under the receiver operating characteristics curve=0.69-0.71), and increased further when maternal height and delivery unit cesarean section rates were included (area under the receiver operating characteristics curve=0.74). The correlation between the individual predicted vaginal birth after cesarean probability and the observed trial of labor success rate was high in all the respective predicted probability decentiles. CONCLUSION: Customization of prediction models for vaginal birth after cesarean is of considerable value. Choosing relevant indicators for a Swedish setting made it possible to achieve excellent prediction accuracy for success in trial of labor after cesarean. During the delicate process of counseling about preferred delivery mode after one cesarean section, considering the results of our study may facilitate the choice between a trial of labor or an elective repeat cesarean section. PMID- 25801724 TI - 54G/C polymorphism of SREBF-1 gene is associated with polycystic ovary syndrome. AB - OBJECTIVE: A sterol regulatory element-binding protein (SREBF-1) transcription factor is a major regulator of lipid metabolism, carbohydrate, and plays a key role in energy homeostasis. The 54(G/C) polymorphism of SREBF-1 gene was reported that it is related with metabolic diseases including obesity, type 2 diabetes, and dyslipidemia. Among these, polycystic ovary syndrome (PCOS) is known as a common metabolic-endocrine disorder of women in reproductive ages. STUDY DESIGN: Here, we performed a comparative study of 54(G/C) polymorphism of SREBF-1 gene with PCOS. The 54(G/C) polymorphism of SREBF-1 gene was analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) of total 286 PCOS patients and 149 matched controls of healthy women. Statistical analysis was performed using HapAnalyzer. A p-value under 0.05 was considered statistically significant. RESULTS: There was a strong association between the 54(G/C) polymorphism of SREBF-1 gene and PCOS (OR: 0.65, 95% CI: 0.46-0.90, p: 0.0129). The genotype and allelic frequencies were in Hardy-Weinberg equilibrium (HWE). CONCLUSION: This is the first study on the genetic variation of SREBF-1 gene and PCOS. We concluded that 54(G/C) polymorphism of SREBF-1 gene is associated with PCOS. Therefore, our results suggest that SREBF-1 gene may play a role in genetic predisposition to PCOS, which is helpful in understanding the etiology of PCOS. PMID- 25801725 TI - Survival of pregnancies with small for gestational age detected before 24 weeks gestation. AB - OBJECTIVE: Counselling women where severe growth abnormalities are detected early in the pregnancy is often difficult due to a paucity of outcome data of this specific subset of early onset disease. This study therefore aimed to assess the outcome of pregnancies where an estimated fetal weight less than the third centile were detected prior to 24 weeks gestation. STUDY DESIGN: A retrospective study in two London teaching hospitals, over an eight year period was performed, analysing all pregnancies with an ultrasound estimated fetal weight less than the third centile prior to 24 weeks gestation. Outcome data: intrauterine death, neonatal death, survival to discharge, gestation at delivery and birthweight were collected. RESULTS: Out of 20 pregnancies included in the analysis, six died in utero, two died in the neonatal period and 12 (60%) survived until discharge. Of the livebirths, 67% delivered preterm and 100% percent of livebirths were delivered by Caesarean Section. CONCLUSION: When severe growth abnormalities were detected before 24 weeks, more than half of pregnancies resulted in survival to neonatal discharge. There was an increased incidence of preterm delivery, caesarean section and neonatal unit admission. This information is useful in counselling parents. PMID- 25801726 TI - Parameters influence on acceleration and deceleration capacity based on trans abdominal ECG in early fetal growth restriction at different gestational age epochs. AB - OBJECTIVE: Intrauterine growth restriction (IUGR) is characterized by chronic nutrient deprivation and hypoxemia that alters the autonomous nervous system regulation of fetal heart rate variability (fHRV). Phase-rectified signal averaging (PRSA) is a new algorithm capable to identify periodic and quasi periodic patterns of HR, and which is used to quantify the average acceleration and deceleration capacity (AC/DC) of the heart. The computation of AC/DC depends on the parameters T and s, which we set so that s=T. T and s determine the periodicities that can be detected (the larger T the smaller the frequency of oscillations for which the method is most sensitive). The aim of the study was to evaluate the influence of the parameter T on PRSA computation, based on trans abdominally acquired fetal ECG (ta-fECG), in early IUGR (<34 weeks of gestation) at two different gestational age epochs. STUDY DESIGN: AC/DC were calculated for different T values (1/45) on fetal RR intervals derived from ta-fECG in 22 IUGR and in 37 appropriate for gestational age (AGA) fetuses matched for gestational age, in two gestational age epochs: very preterm group (>=26/<30 weeks), and preterm group (>=30/<34 weeks), respectively. RESULTS: AC/DC were significantly lower in IUGR than in AGA fetuses for all T>=5 values (p<0.05). The best area under the receiver operating characteristic curve (AUC) in identifying IUGR at time of recording was observed for T9 [AUC AC-T9 0.87, 95% confidence interval (CI) 0.77-0.96; and AUC DC-T9 0.89, 95% CI 0.81-0.98), and in range of T 7/15. In the same T interval, AC/DC were significantly lower in very preterm than in preterm IUGR group (p<0.05), while there were no differences in AGA fetuses at two gestational age epochs (p>0.05), respectively. The AUCs of AC-T9 and DC-T9 significantly outperformed that obtained by short-term variation (AUC 0.77, 95% CI 0.65-0.90; p=0.009 and p=0.003, respectively). CONCLUSIONS: Our study shows that within the range of T parameter 1/45, T=9 proved to be the best value to discriminate the AC and DC of the fetal heart rate of IUGR from AGA fetuses prior to 34 weeks of gestation. These significant differences are emphasized in very preterm gestational age epochs. PMID- 25801727 TI - The importance of MTHFR, MTR, MTRR and CSE expression levels in Caucasian women with preeclampsia. AB - OBJECTIVE: Preeclampsia (PE) is a major cause of maternal and perinatal mortality and morbidity. The studies suggest that both polymorphisms and changes of expression in genes encoding enzymes involved in the methionine and homocysteine metabolism (MHM), such as methylenetetrahydrofolate, reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR) and cystathionine gamma-lyase (CSE), could play a role in the development of hypertension during pregnancy. The aim of the study was to determine the expression level of MTHFR, MTR, MTRR and CSE genes in the development of PE in Caucasian women. STUDY DESIGN: The control group consisted of 74 healthy pregnant women and 90 patients with diagnosed pre-eclampsia. Total RNA was isolated from placenta and the mRNA level of examined genes was to determine using real-time PCR. RESULTS: The expression level of MTHFR gene showed no statistically significant difference in the study group as compared to the control group. An increase of mRNA levels for MTR and CTH was observed by 124.7% (p<0.0001) and 26.6% (p>0.05), respectively. However, a decrease of placental expression was noted for MTRR by 50% in preeclamptic women as compared to control group (p<0.0001). CONCLUSIONS: Our findings suggest that the elevated RNA expression of MTR in placenta of preeclamptic patients is probably results of a potential compensation mechanism of the MHM while elevated CSE expression indicates that homocysteine may be eliminated through the alternate transsulfuration pathway. PMID- 25801729 TI - Cracking cavitands: metal-directed scission of phosphinyl-substituted resorcinarenes. AB - Resorcinarene-derived tetramethylene cavitands bearing a diphenylphosphino group grafted to their wider rim undergo facile, directed C-O bond breaking upon reaction with transition-metal ions in the presence of nucleophiles. One possible reaction mechanism involves formation of a P,O-chelate complex, which weakens the adjacent O-CH2 bond, leading to the formation of an oxacarbenium intermediate. PMID- 25801731 TI - The flavivirus NS1 protein's mysteries unveiled?: (Comment on DOI 10.1002/bies.201400182). PMID- 25801728 TI - Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment. AB - Stress induced constant increase of cortisol level may lead to sleep disorder, but the mechanism remains unclear. Here we described a novel model to investigate stress mimicked sleep disorders induced by repetitive administration of corticosterone (CORT). After 7 days treatment of CORT, rats showed significant sleep disturbance, meanwhile, the glucocorticoid receptor (GR) level was notably lowered in locus coeruleus (LC). We further discovered the activation of noradrenergic neuron in LC, the suppression of GABAergic neuron in ventrolateral preoptic area (VLPO), the remarkable elevation of norepinephrine in LC, VLPO and hypothalamus, as well as increase of tyrosine hydroxylase in LC and decrease of glutamic acid decarboxylase in VLPO after CORT treatment. Microinjection of GR antagonist RU486 into LC reversed the CORT-induced sleep changes. These results suggest that GR in LC may play a key role in stress-related sleep disorders and support the hypothesis that repeated CORT treatment may decrease GR levels and induce the activation of noradrenergic neurons in LC, consequently inhibit GABAergic neurons in VLPO and result in sleep disorders. Our findings provide novel insights into the effect of stress-inducing agent CORT on sleep and GRs' role in sleep regulation. PMID- 25801730 TI - Substrate Facet Effect on the Growth of Monolayer MoS2 on Au Foils. AB - MoS2 on polycrystalline metal substrates emerges as an intriguing growth system compared to that on insulating substrates due to its direct application as an electrocatalyst in hydrogen evolution. However, the growth is still indistinct with regard to the effects of the inevitably evolved facets. Herein, we demonstrate for the first time that the crystallography of Au foil substrates can mediate a strong effect on the growth of monolayer MoS2, where large-domain single-crystal MoS2 triangles are more preferentially evolved on Au(100) and Au(110) facets than on Au(111) at relative high growth temperatures (>680 degrees C). Intriguingly, this substrate effect can be weakened at a low growth temperature (~530 degrees C), reflected with uniform distributions of domain size and nucleation density among the different facets. The preferential nucleation and growth on some specific Au facets are explained from the facet dependent binding energy of MoS2 according to density functional theory calculations. In brief, this work should shed light on the effect of substrate crystallography on the synthesis of monolayer MoS2, thus paving the way for achieving batch-produced, large-domain or domain size-tunable growth through an appropriate selection of the growth substrate. PMID- 25801732 TI - How much related to skin wrinkles between facial and body site? Age-related changes in skin wrinkle on the knee assessed by skin bioengineering techniques. AB - BACKGROUND/PURPOSE: Skin aging has been focused the wrinkle on the face than on the body, so most studies have been studied the change in Crow's feet for ages. Only little is known about the age-dependent changes of wrinkles on body sites. The aim of this study was to establish new grading criteria for severity of wrinkles on knees and to investigate the relationship of wrinkle severity with age- and site-dependent. METHODS: The skin on the knee of 38 healthy Korean female volunteers, divided into two groups young and old, were photographed. Standard photograph for body wrinkle was established (grade 0~7), and then visual assessment, skin wrinkle, and skin elasticity were evaluated on Crow's feet and the knee. We examined for any significant differences and the correlation of skin aging parameters with age and two different sites. RESULTS: Skin wrinkle severity with standard photograph and wrinkle parameters (Ra, Rmax, Rz, and Rv) had a significantly positive correlation with age-dependent on the knee (P < 0.001). Also, skin elastic parameters (R2, R5, R6, R7, and Q1) showed a significant negative correlation with age on the knee (P < 0.001). Skin wrinkle severity with standard photograph was highly correlated with all skin wrinkle parameters and skin elastic parameters (R2, R5, R7, and Q1) on the knee (P < 0.001). In addition, all the skin aging parameters on the knee were significantly correlated with Crow's feet (P < 0.01). Skin aging on the knee had the same tendency as the Crow's feet. CONCLUSIONS: This study has shown the new grading criteria of wrinkles on the knee. Skin wrinkle and elasticity on the knee are age-dependent related and aging on the knee is highly related to Crow's feet. Those parameters are using a quantitative method to evaluate body aging. Also, the knee is considered that it could be a suitable site to evaluate body aging. PMID- 25801733 TI - No clinically relevant differences between capillary and venous blood cell counts in adult haematological patients using a nonautomated lancet. PMID- 25801735 TI - Nickel-rich layered lithium transition-metal oxide for high-energy lithium-ion batteries. AB - High energy-density lithium-ion batteries are in demand for portable electronic devices and electrical vehicles. Since the energy density of the batteries relies heavily on the cathode material used, major research efforts have been made to develop alternative cathode materials with a higher degree of lithium utilization and specific energy density. In particular, layered, Ni-rich, lithium transition metal oxides can deliver higher capacity at lower cost than the conventional LiCoO2 . However, for these Ni-rich compounds there are still several problems associated with their cycle life, thermal stability, and safety. Herein the performance enhancement of Ni-rich cathode materials through structure tuning or interface engineering is summarized. The underlying mechanisms and remaining challenges will also be discussed. PMID- 25801738 TI - What does the colour of the tongue tells us in the delivery room? PMID- 25801739 TI - 'Curiouser and curiouser': the role of vitamin D in the prevention of acute respiratory infection. PMID- 25801734 TI - Reduced default mode network suppression during a working memory task in remitted major depression. AB - Insufficient default mode network (DMN) suppression was linked to increased rumination in symptomatic Major Depressive Disorder (MDD). Since rumination is known to predict relapse and a more severe course of MDD, we hypothesized that similar DMN alterations might also exist during full remission of MDD (rMDD), a condition known to be associated with increased relapse rates specifically in patients with adolescent onset. Within a cross-sectional functional magnetic resonance imaging study activation and functional connectivity (FC) were investigated in 120 adults comprising 78 drug-free rMDD patients with adolescent- (n = 42) and adult-onset (n = 36) as well as 42 healthy controls (HC), while performing the n-back task. Compared to HC, rMDD patients showed diminished DMN deactivation with strongest differences in the anterior-medial prefrontal cortex (amPFC), which was further linked to increased rumination response style. On a brain systems level, rMDD patients showed an increased FC between the amPFC and the dorsolateral prefrontal cortex, which constitutes a key region of the antagonistic working-memory network. Both whole-brain analyses revealed significant differences between adolescent-onset rMDD patients and HC, while adult-onset rMDD patients showed no significant effects. Results of this study demonstrate that reduced DMN suppression exists even after full recovery of depressive symptoms, which appears to be specifically pronounced in adolescent onset MDD patients. Our results encourage the investigation of DMN suppression as a putative predictor of relapse in clinical trials, which might eventually lead to important implications for antidepressant maintenance treatment. PMID- 25801740 TI - A Tool for Local Thickness Determination and Grain Boundary Characterization by CTEM and HRTEM Techniques. AB - A new approach for measurement of local thickness and characterization of grain boundaries is presented. The method is embodied in a software tool that helps to find and set sample orientations useful for high-resolution transmission electron microscopic (HRTEM) examination of grain boundaries in polycrystalline thin films. The novelty is the simultaneous treatment of the two neighboring grains and orienting both grains and the boundary plane simultaneously. The same metric matrix-based formalism is used for all crystal systems. Input into the software tool includes orientation data for the grains in question, which is determined automatically for a large number of grains by the commercial ASTAR program. Grain boundaries suitable for HRTEM examination are automatically identified by our software tool. Individual boundaries are selected manually for detailed HRTEM examination from the automatically identified set. Goniometer settings needed to observe the selected boundary in HRTEM are advised by the software. Operation is demonstrated on examples from cubic and hexagonal crystal systems. PMID- 25801741 TI - Substantial clinical benefit of minimally invasive lateral interbody fusion for degenerative spondylolisthesis. AB - PURPOSE: Conventional lumbar arthrodesis for the treatment of degenerative spondylolisthesis (DS) is associated with high complication rates and variable clinical efficacy. Modern minimally invasive (MIS) approaches may reduce the morbidity and produce greater clinical improvement compared to traditional surgical techniques. The objective of this study is to report radiographic outcomes and evaluate clinical improvements in the context of substantial clinical benefit for DS patients treated with a MIS 90 degrees lateral, transpsoas approach for lumbar interbody fusion. METHODS: From 2005 to 2011, 60 consecutive patients were treated with MIS lateral interbody fusion for Grade I or II DS at a single institution. Mean patient age was 68 years, 75 % were female, and 30 % had undergone previous lumbar surgery. A total of 71 levels were treated, supplemental posterior fixation was used in 57 (95 %) cases, and 26 (43 %) patients underwent additional direct posterior decompression. RESULTS: Average follow-up was 20.3 months. Average ORT, EBL, and LOS were 206 min, 83 cc, and 1.29 days, respectively. Complications occurred in 3 (5 %) patients. Transient approach-related thigh/groin pain was observed in 5 (8 %) cases. There were no cases of pseudoarthrosis. At 1 year, LBP improved 71 %, LP improved 68 %, ODI decreased 52 %, and SF-36 PCS and MCS improved 43 and 21 %, respectively. Substantial clinical benefit was met by 94.7 % of patients on NRS LBP, by 84.6 % on NRS LP, by 83.7 % on ODI, and by 66.7 % on SF-36 PCS. Disc height increased 71 % and segmental lordosis increased 27.8 % at treated levels. Foraminal height, width, and volume increased 19.7, 18.0, and 39.6 %, respectively. Slip improved 60.7 % with interbody fusion only and further improved to 69.2 % after the placement of supplemental instrumentation. CONCLUSIONS: MIS lateral interbody fusion in the treatment of DS resulted in significant improvements in clinical and radiographic outcomes, with a low complication rate and a high proportion of patients achieving substantial clinical benefit. PMID- 25801743 TI - Authors' reply to the Letter to the Editor of J. Padulo et al. concerning "Video raster stereography back shape reconstruction: a reliability study for sagittal, frontal, and transversal plane parameters" by Schroeder J, Reer R, Braumann KM (2015), Eur Spine J; 24(2):262-269. DOI: 10.1007/s00586-014-3664-5. PMID- 25801742 TI - Videoassisted anterior surgical approaches to the craniocervical junction: rationale and clinical results. AB - PURPOSE: In this narrative review, we aim to give an update on the anatomic fundamentals of endoscopic assisted surgery to the craniocervical junction (transnasal, transoral and transcervical), and to report on the available clinical results. METHODS: A non-systematic review and reporting on the anatomical and clinical results of endoscopic assisted approaches to the craniocervical junction (CVJ) is performed. RESULTS: Pure endonasal and cervical endoscopic approaches still have some disadvantages, including the learning curve and the lack of 3-dimensional perception of the surgical field. Endoscopically assisted transoral surgery with 30 degrees endoscopes represents an emerging alternative to standard microsurgical techniques for transoral approaches to the anterior CVJ. Used in conjunction with traditional microsurgery and intraoperative fluoroscopy, it provides a safe and improved method for anterior decompression with or without a reduced need for extensive soft palate splitting, hard palate resection, or extended maxillotomy. CONCLUSIONS: Transoral (microsurgical or video-assisted) approach with sparing of the soft palate still remains the gold standard compared to the "pure" transnasal and transcervical approaches due to the wider working channel provided by the former technique. Transnasal endoscopic approach alone appears to be superior when the CVJ lesion exceeds the upper limit of the inferior third of the clivus. Combined transnasal and transoral procedures can be tailored according to the specific pathological and radiological findings. PMID- 25801744 TI - Technical nuances of the minimally invasive extreme lateral approach to treat thoracolumbar burst fractures. AB - PURPOSE: Contemporary minimally invasive techniques have evolved to enable direct access to the anterior spinal column via the extreme lateral approach. We have employed this access approach to treat selected burst fractures. We report our technique. Thoracolumbar burst fractures that require surgical intervention have traditionally been managed with anterior, posterior, or combined approaches. METHODS: We have applied the minimally invasive extreme lateral approach to perform vertebral corpectomy, cage placement, and lateral instrumentation to treat burst fractures. Indications for surgery were incomplete spinal cord injury with persistent neural element compression due to ventral fracture fragments in the canal. We present the technical nuances of this surgical approach for the treatment of thoracolumbar burst fractures with two case illustrations. RESULTS: There were no peri- or intra-operative complications. Both patients in our series remained neurologically intact at their last follow-up (11 and 29 months, respectively), and maintained their correction of kyphosis. CONCLUSION: The minimally invasive extreme lateral approach is an effective treatment option for the management of thoracolumbar burst fractures. PMID- 25801747 TI - Minimal invasive mitral valve surgery does make a difference: Should it be the gold standard for mitral valve repair? PMID- 25801745 TI - Long-term outcomes after surgical and endovascular treatment of spinal dural arteriovenous fistulae. AB - PURPOSE: To examine the validity of our treatment strategy for spinal dural arteriovenous fistulae (SDAVF), based on the treatment results and the long-term outcome. METHODS: This study included 50 SDAVF patients (38 men, 12 women, mean age 63.2 years) with progressive myelopathy. The treatment strategy involved embolization as the initial management tool and surgery if embolization was considered unsuitable. Their medical records were evaluated to identify the treatment results and functional outcomes. The mean follow-up period was 81.2 months (range 27-184 months). RESULTS: Complete obliteration was achieved in 22 (71.0%) of 31 embolized patients and in 18 of 19 (94.7%) operated patients. The initial success rate was significantly lower in embolized than operated patients. At the last follow-up, 33 of the 50 patients (66%) manifested improved gait and 16 (32%) improved micturition. The activity of daily living (ADL) was improved in 33 (66%). When we compared the rates of functional improvement at the last follow up, there was no significant difference between patients treated initially by embolization or surgery. CONCLUSIONS: The long-term outcomes in SDAVF patients treated by multidisciplinary management with first-line embolization were comparable to those in earlier surgical series. However, our results were unable to demonstrate the superiority of endovascular embolization to surgical treatment for SDAVF. For the purpose of justifying endovascular embolization as a first line treatment for SDAVF, it will be necessary to show further improvement in both the initial treatment success and the complication rates. PMID- 25801746 TI - Presence of a high-flow-mediated constriction phenomenon prior to flow-mediated dilation in normal weight, overweight, and obese children and adolescents. AB - PURPOSE: When assessing vasomotor endothelial function by reactive hyperemia, the brachial artery, in some individuals, constricts immediately before beginning to dilate following cuff release. We call this response high-flow-mediated constriction (H-FMC). The aim of this study was to describe the rate of the H-FMC during reactive hyperemia in children and adolescents throughout a range of body mass index (BMI) values, and to investigate differences in flow-mediated dilation (FMD), cardiovascular, and anthropometric measures between subjects with and without H-FMC. METHODS: FMD was assessed in 136 children and adolescents (61 male, 75 female; 13 +/- 3 years) by sonographic imaging of the brachial artery. H FMC was characterized as the lowest point from the baseline brachial artery diameter immediately following reactive cuff release. Independent t tests were used to compare subjects with and without H-FMC. RESULTS: H-FMC was observed in 91 of the 136 participants (66.9%). No significant difference was found between H FMC and non-H-FMC subjects for age (p = 0.602), gender (p = 0.767), height (p = 0.227), or weight (p = 0.171). BMI percentile was nonsignificantly higher (91.8 +/- 4.9th versus 84.6 +/- 22.8th percentile, p = 0.057) and FMD was significantly lower (5.43 +/- 3.41% versus 8.05 +/- 3.97%, p < 0.001) in H-FMC than in non-H FMC subjects. Adding H-FMC to FMD produced no significant difference between H FMC and non-H-FMC individuals (8.03 +/- 3.27% versus 8.05 +/- 3.97%, p = 0.977). CONCLUSIONS: Approximately 67% of participants demonstrated an H-FMC during reactive hyperemia. BMI percentile was nonsignificantly higher and FMD was significantly lower in children and adolescents who displayed this phenomenon. PMID- 25801748 TI - Uric acid levels in patients with schizophrenia on clozapine monotherapy. AB - BACKGROUND: We tested the hypothesis that uric acid levels are higher in subjects with schizophrenia treated with clozapine than in healthy control and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition. METHODS: Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed. RESULTS: There was no difference of fasting uric acid concentrations between clozapine and control groups (4.5 +/- 1.4 vs. 4.3 +/- 1.3 mg/dl, P = 0.87). Regarding the whole group, uric acid levels were significantly higher in men (5.2 +/- 1.2 vs. 3.6 +/- 0.9, P < 0.001). Uric acid levels correlated with weight (R = 0.58, P = 0.003), body mass index (BMI; R = 0.49, P = 0.01), abdominal circumference (R = 0.45, P = 0.03), waist circumference (R = 0.47, P = 0.02), waist-to-hip ratio (R = 0.42, P = 0.04), insulin (R = 0.50, P = 0.01), homoeostasis model assessment of insulin resistance 2 (HOMA2-IR; R = 0.49, P = 0.01), basal metabolic rate (R = 0.56, P = 0.004), lean body mass (R = 0.55, P = 0.005) and body water (R = 0.55, P = 0.005). There were no significant differences of uric acid levels for smoking status, impaired fasting glucose, abdominal obesity, obesity/overweight and dyslipidemia. Uric acid levels did not correlate with age, duration of clozapine treatment, clozapine dose, leg circumference, systolic blood pressure, diastolic blood pressure, total body fat, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine, corrected calcium, glucose and homoeostasis model assessment of insulin resistance 1 (HOMA1-IR). CONCLUSIONS: We did not find significant differences in blood uric acid levels between subjects with schizophrenia and controls. Association with weight, BMI, abdominal and waist circumferences, insulin levels and insulin resistance may support uric acid role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of uric acid than women. PMID- 25801749 TI - Airborne allergic contact dermatitis caused by disulfiram. PMID- 25801751 TI - Key Issues to Consider in Therapy with Muslim Families. AB - We present the key issues to consider in therapy with Muslim families. Following a brief introduction, five themes are presented: self, family dynamics, causation, and coping strategies. The section on "self" includes a discussion of three terms which link the four Islamic models of "self" identified through the review. The family dynamics section pays particular attention to interconnectedness, family roles, and gender. Causation is discussed with reference to supernatural and spiritual causes. On the theme of coping strategies, religious responses are discussed as are the roles of religious leaders, and professional mental health services. Clinical implications from the key themes are also discussed in addition to limitations of the published literature in this area. This includes a discussion of the epistemological and paradigmatic issues related to the research. The review concludes by summarising these issues and presenting areas for further research. PMID- 25801750 TI - Programmed Death-Ligand 1 Expression Predicts Tyrosine Kinase Inhibitor Response and Better Prognosis in a Cohort of Patients With Epidermal Growth Factor Receptor Mutation-Positive Lung Adenocarcinoma. AB - BACKGROUND: The immune checkpoint proteins programmed death-1/ligand (PD-1/PD-L1) play a critical role in immune escape of tumor cells. In models of epidermal growth factor receptor (EGFR)-driven non-small-cell lung cancer (NSCLC), EGFR signal upregulates PD-1/PD-L1. However, data on the clinical significance of PD1/PD-L1 expression in patients with the subtype of NSCLC carrying EGFR mutations remain limited. MATERIALS AND METHODS: Immunohistochemistry was performed to evaluate the expression of PD-1, PD-L1, and CD4+ and CD8+ tumor infiltrating T lymphocytes (TILs). RESULTS: In a cohort of 56 patients, PD-L1 and PD-1 was positive in 53.6% and 32.1% of tumor specimens, respectively. PD-L1(+) patients had a significantly greater disease-control rate (P = .004), in association with longer progression-free survival (P = .001) after EGFR-tyrosine kinase inhibitor (TKI) therapy and overall survival (P = .004), and no correlation between PD-1 positivity and clinical outcomes was observed. PD-L1 expression was not significantly associated with either clinicopathologic features or TILs. CONCLUSIONS: These findings suggest that this subtype of EGFR mutation-positive NSCLC is highly eligible for PD-1/PD-L1 immunotherapy. PD-L1 might represent a favorable biomarker candidate for the response to EGFR-TKIs and outcomes of these patients with NSCLC. PMID- 25801752 TI - Psychiatric disorders as "hidden" contraindications for presurgical VEEG in patients with refractory epilepsy: A retrospective cohort study in a tertiary center. AB - Given the high frequency of psychiatric disorders (PDs) observed among patients with epilepsy, studies have highlighted the necessity of psychiatric evaluation for these patients, especially for those with refractory temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS) who are surgical candidates. Current evidence highlights the safety of video-electroencephalography (VEEG) as a means of investigation in patients with TLE-MTS and PDs. However, the presence of such disorders has still been seen as a contraindication for presurgical evaluation with VEEG in some epilepsy centers mainly because of the risk of negative behavioral events. The present retrospective cohort study performed in a Brazilian tertiary epilepsy center aimed to identify whether the presence of a PD remains a contraindication for presurgical VEEG. Clinical, sociodemographic, and psychiatric data from 41 patients who underwent VEEG as part of their presurgical evaluation were compared to data from 32 patients with refractory TLE-MTS who had not undergone VEEG. Psychiatric diagnoses were determined using the DSM-IV and ILAE criteria. Psychiatric disorders were diagnosed in 34 patients (46.6%). Major depressive disorder was the most frequent PD and was observed in 22 patients (30.1%). Anxiety disorders were observed in 14 patients (19.2%). Of the 41 patients (56.2%) who underwent presurgical VEEG, only 12 (29.2%) were found to have a PD during the presurgical psychiatric evaluation compared to 22 of the 32 (68.7%) who did not undergo VEEG (p=0.001; RR=2.35). The present findings suggest that the presence of a PD alone should not be a contraindication for VEEG monitoring and epilepsy surgery. PMID- 25801753 TI - Diet, exercise, sleep, sexual activity, and perceived stress in people with epilepsy in NE Thailand. AB - The aim of this study was to find out how people with epilepsy in NE Thailand feel about their levels of stress, sleep, diet, exercise habits, and sex lives using a cross-sectional design. Two hundred and three people with epilepsy (PWE) were randomly recruited from a university epilepsy clinic in Khon Kaen and then completed an interview and a questionnaire. A total of 27.6% of the patients believed that diet had an influence on their epilepsy (of those who reported changes, 41.1% stopped consuming alcohol, while 32.1% stopped drinking caffeinated beverages). A total of 47.2% of the patients exercised at least three times per week, while 52.8% exercised two times or less a week. Daytime sleeping was prevalent, with 43.3% saying that they slept during the day frequently or every day. There were 44.3% of the patients who believed that their sex lives changed after the onset of epilepsy, with decreased sexual arousal being most commonly mentioned. A total of 76.4% of the patients said that they had medium or high levels of stress, and epilepsy was listed as the most common reason for their stress (50.2%). Focusing on the problem was the most common method to reduce stress (80.3%). The findings illuminate the need to increase attention towards improving and promoting self-management of epilepsy. As a whole, diet, exercise, sleep, stress reduction, and sex therapy can be valuable tools to improve the quality of life of people with epilepsy. PMID- 25801754 TI - Examining Self-Care Behaviors and Their Associated Factors Among Adolescent Girls With Dysmenorrhea: An Application of Orem's Self-Care Deficit Nursing Theory. AB - PURPOSE: To test a hypothesized model that examines the relationship between selected basic conditioning factors, self-care agency, and self-care behaviors among adolescent girls with dysmenorrhea using Orem's self-care deficit nursing theory as a framework. DESIGN: This was a predictive correlational study conducted with a total of 531 secondary school girls. METHODS: Self-care agency, self-care behaviors, and 11 variables that have been theoretically or empirically justified in previous studies as relevant to basic conditioning factors were selected and collected by means of structured questionnaires. Path analyses were performed to test the hypothesized linkages among variables. FINDINGS: Path analysis revealed that age and received menstrual education had both direct and indirect effects through self-care agency on self-care behaviors. Mother's and father's educational level, pain intensity, and self-medication used when experiencing dysmenorrhea only affected the self-care behaviors directly. CONCLUSIONS: This is the first study that provided information about the relationship between basic conditioning factors, self-care agency, and self-care behaviors among adolescent girls with dysmenorrhea. Knowledge of the factors influencing self-care behaviors in these adolescent girls will assist healthcare professionals in developing effective interventions to promote self-care and ameliorate the adverse impact of this condition. CLINICAL RELEVANCE: Interventional strategies that aim at promoting self-care behaviors among adolescent girls with dysmenorrhea should strengthen girls' self-care agency and should target those with a younger age, higher pain intensity, mother with a higher educational level, father with a lower educational level, and those who do not take self-medication for dysmenorrhea. PMID- 25801755 TI - Abba J. Kastin, the Zeitgeist, and the inception of Peptides. AB - It is wonderful to be able to record the establishment and growth of a professional journal after thirty-five years, and to celebrate the splendid career of Abba J. Kastin as an editor as well as a scientist and educator. Abba is also an enriched human being who is both sophisticated and simple, and we are proud to be life-long friends of his. This Festschrift reviews how we (the Olsons) started our careers as neuropsychologists, our interactions with Abba, reflection of the job as neuroscientists, and discussion of the growth and future of Peptides with the new publishing fads. PMID- 25801756 TI - Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose. AB - The advantage of the new generation IV iron preparations ferric carboxymaltose (FCM), ferumoxytol (FMX), and iron isomaltoside 1000 (IIM) is that they can be administered in relatively high doses in a short period of time. We investigated the physico-chemical properties of these preparations and compared them with those of the older preparations iron sucrose (IS), sodium ferric gluconate (SFG), and low molecular weight iron dextran (LMWID). Mossbauer spectroscopy, X-ray diffraction, and Fe K-edge X-ray absorption near edge structure spectroscopy indicated akaganeite structures (beta-FeOOH) for the cores of FCM, IIM and IS, and a maghemite (gamma-Fe2O3) structure for that of FMX. Nuclear magnetic resonance studies confirmed the structure of the carbohydrate of FMX as a reduced, carboxymethylated, low molecular weight dextran, and that of IIM as a reduced Dextran 1000. Polarography yielded significantly different fingerprints of the investigated compounds. Reductive degradation kinetics of FMX was faster than that of FCM and IIM, which is in contrast to the high stability of FMX towards acid degradation. The labile iron content, i.e. the amount of iron that is only weakly bound in the polynuclear iron core, was assessed by a qualitative test that confirmed decreasing labile iron contents in the order SFG ~ IS > LMWID >= FMX ~ IIM ~ FCM. The presented data are a step forward in the characterization of these non-biological complex drugs, which is a prerequisite to understand their cellular uptake mechanisms and the relationship between the structure and physiological safety as well as efficacy of these complexes. PMID- 25801757 TI - Beyond blood pressure: percutaneous renal denervation for the management of sympathetic hyperactivity and associated disease states. PMID- 25801758 TI - Putting "at-rest" evaluations of the right ventricle to rest: insights gained from evaluation of the right ventricle during exercise in CTEPH patients with and without pulmonary endarterectomy. PMID- 25801759 TI - Differential time trends of outcomes and costs of care for acute myocardial infarction hospitalizations by ST elevation and type of intervention in the United States, 2001-2011. AB - BACKGROUND: Little is known whether time trends of in-hospital mortality and costs of care for acute myocardial infarction (AMI) differ by type of AMI (ST elevation myocardial infarction [STEMI] vs. non-ST-elevation [NSTEMI]) and by the intervention received (percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], or no intervention) in the United States. METHODS AND RESULTS: We conducted a serial cross-sectional study of all hospitalizations for AMI aged 30 years or older using the Nationwide Inpatient Sample, 2001-2011 (1,456,154 discharges; a weighted estimate of 7,135,592 discharges). Hospitalizations were stratified by type of AMI and intervention, and the time trends of in-hospital mortality and hospital costs were examined for each combination of the AMI type and intervention, after adjusting for both patient- and hospital-level characteristics. Compared with 2001, adjusted in-hospital mortality improved significantly for NSTEMI patients in 2011, regardless of the intervention received (PCI odds ratio [OR] 0.68, 95% CI 0.56 to 0.83; CABG OR 0.57, 0.45 to 0.72; without intervention OR 0.61, 0.57 to 0.65). As for STEMI, a decline in adjusted in-hospital mortality was significant for those who underwent PCI (OR 0.83; 0.73 to 0.94); however, no significant improvement was observed for those who received CABG or without intervention. Hospital costs per hospitalization increased significantly for patients who underwent intervention, but not for those without intervention. CONCLUSIONS: In the United States, the decrease in in-hospital mortality and the increase in costs differed by the AMI type and the intervention received. These non-uniform trends may be informative for designing effective health policies to reduce the health and economic burdens of AMI. PMID- 25801760 TI - Pulmonary vascular and right ventricular reserve in patients with normalized resting hemodynamics after pulmonary endarterectomy. AB - BACKGROUND: Patients with normalized mean pulmonary artery pressure (mPAP) after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) do not always regain normal exercise capacity. We evaluated right ventricular function, its interaction with both pulsatile and resistive afterload, and the effect of sildenafil during exercise in these patients. METHODS AND RESULTS: Fourteen healthy controls, 15 CTEPH patients, and 7 patients with normalized resting mPAP (<=25 mm Hg) post-PEA underwent cardiopulmonary exercise testing, followed by cardiac magnetic resonance imaging with simultaneous invasive mPAP measurement during incremental supine cycling exercise. Peak oxygen consumption and peak heart rate were significantly reduced in post-PEA and CTEPH patients compared to controls. The mPAP-cardiac output slope was steeper in post-PEA patients than in controls and similar to CTEPH. Relative to controls, resting right ventricular ejection fraction was reduced in CTEPH, but not in post-PEA patients. In contrast, peak exercise right ventricular ejection fraction was reduced both in post-PEA and CTEPH patients. Exercise led to reduction of pulmonary arterial compliance in all groups. Nevertheless, resting pulmonary arterial compliance values in CTEPH and post-PEA patients were even lower than those in controls at peak exercise. In post-PEA patients, sildenafil did not affect resting hemodynamics nor right ventricular function, but decreased the mPAP/cardiac output slope and increased peak exercise right ventricular ejection fraction. CONCLUSIONS: Exercise intolerance in post-PEA patients is explained by abnormal pulmonary vascular reserve and chronotropic incompetence. The mPAP/cardiac output slope and pulmonary arterial compliance are sensitive measures demonstrating abnormal resistive and pulsatile pulmonary vascular function in post-PEA patients. These abnormalities are partially attenuated with sildenafil. PMID- 25801762 TI - Cross-Cultural Adaptation, Reliability, and Validity of the Turkish Version of the Compliance Questionnaire on Rheumatology in Patients With Behcet's Disease. AB - PURPOSE: The aim of this study was to examine the psychometric properties of the Turkish versionof the Compliance Questionnaire on Rheumatology (CQR-T) for patients with Behcet's disease (BD). METHOD: A sample of 105 Turkish patients with BD participated in this study. The scale was cross-culturally adapted through a process including translation, comparison with versions in other languages, back translation, and pretesting. Construct validity was evaluated by factor analysis, and criterion validity was evaluated using the Morisky Medication Adherence Scale. RESULTS: The CQR-T demonstrated acceptable internal consistency (Cronbach's alpha = .832), adequate test-retest reliability (intraclass correlation coefficient = .630), and correlations with Morisky Medication Adherence Scale scores (r = -.389, p< .001), indicating convergent validity. CONCLUSION: The CQR-T was found to be a valid and reliable instrument for evaluating the compliance of Turkish BD patients with prescribed medications. IMPLICATIONS FOR PRACTICE: The CQR-T might be a helpful tool in two ways: for determining the level of compliance of patients with BD and for adjusting their management and follow-up based on the results. PMID- 25801763 TI - Cross-Cultural Adaptation and Psychometric Assessment of the Liver Disease Symptom Index 2.0 to Measure Health-Related Quality of Life Among Iranian Patients With Chronic Hepatitis B. AB - PURPOSE: There are only a few measures to assess quality of life among patients with liver disorders. The aim of this study was to determine the psychometric properties of the Liver Disease Symptom Index Version 2.0 (LDSI 2.0), a disease specific measure of health-related quality of life (HRQOL), in Persian-speaking patients with chronic hepatitis B. METHOD: Using a cross-sectional design, 312 patients were recruited. Data were collected from the patients using the LDSI 2.0, Chronic Liver Disease Questionnaire, and EuroQol. Convergent and discriminant validity were investigated. Known-groups validity and factor structure of the scale were also determined. Receiver operating characteristics was used to discriminate patients based on their general health status. RESULTS: Significant correlations were found between HRQOL measures. Disease duration, disease stage, and serum aspartate aminotransferase differentiated patients. Factor analysis determined a seven-factor solution that explained 70% of the total variance. Area under the curve in receiver operating characteristics analysis was 0.706; 95% confidence interval = [0.648, 0.764]. CONCLUSIONS: The LDSI2.0 is an appropriate HRQOL scale for use among Iranian patients with chronic hepatitis B based on its solid psychometric properties in this population. PMID- 25801761 TI - Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism. AB - BACKGROUND: Endothelin 1 (ET-1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET-1 peptides, endothelin-like domain peptide (ELDP) and C-terminal pro-ET-1 (CT-proET-1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists. METHODS AND RESULTS: We assessed plasma and urine ELDP and plasma CT-proET-1 in CKD patients with minimal comorbidity. Next, in a randomized double-blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT-proET-1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT-proET-1. Sitaxentan increased both plasma ELDP and CT proET-1 (baseline versus week 6+/-SEM: ELDP, 11.8+/-0.5 versus 13.4+/-0.6 fmol/mL; CT-proET-1, 20.5+/-1.2 versus 23.3+/-1.5 fmol/mL; both P<0.0001). Plasma ET-1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT proET-1 correlated negatively with 24-hour urinary sodium excretion. CONCLUSIONS: ELDP and CT-proET-1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents. CLINICAL TRIAL REGISTRATION: URL: www.clinicalTrials.gov Unique identifier: NCT00810732. PMID- 25801764 TI - Laparoscopic Nephrectomy with Autotransplantation: Safety, Efficacy and Long-Term Durability. AB - PURPOSE: Laparoscopic nephrectomy with autotransplantation is a viable option when renal preservation is required or ureteral reconstruction is impossible. In this study we report on our long-term experience with laparoscopic nephrectomy with autotransplantation. MATERIALS AND METHODS: A retrospective review of data from all patients who underwent laparoscopic nephrectomy with autotransplantation since 2000 revealed data for 52 of 59 patients after study exclusions. Indications for laparoscopic nephrectomy with autotransplantation included ureteral stricture disease (41), renal malignancy (7), ptotic kidney (1), chronic flank pain (1), renal artery aneurysm (1) and renovascular hypertension (1). Followup included ultrasonography, nuclear renography and computerized tomography. Complications analyzed were Clavien-Dindo grade III or higher. RESULTS: A total of 52 patients (30 women, 57.6%) underwent laparoscopic nephrectomy with autotransplantation at a median age of 48 years (range 12 to 76). At a median followup of 73.5 months 47 patients (90.3%) had long-term function of the autotransplanted renal unit including 3 of 4 (75%) solitary kidneys. There were 5 patients (9.7%) who experienced renal unit failure at a median of 15 months. Of these patients 3 required nephrectomy of autotransplant unit secondary to renal vein thrombosis (1 day), pseudoaneurysm (15 months) and chronic pain (48 months). Overall 4 patients had early complications and 8 had late complications. In the tumor group 4 patients had disease progression and all are alive. CONCLUSIONS: Laparoscopic nephrectomy with autotransplantation is an excellent long-term surgical option (greater than 90% success rate with longer than 6-year median followup) for complex ureteral and renal conditions that necessitate preservation of renal parenchyma. However, tumor progression is possible after ex vivo tumor excision. Therefore, careful patient selection and followup are mandatory. This report supports the safety, efficacy and durability of laparoscopic nephrectomy with autotransplantation in experienced hands. PMID- 25801765 TI - Development and Validation of a Novel Robotic Procedure Specific Simulation Platform: Partial Nephrectomy. AB - PURPOSE: We developed a novel procedure specific simulation platform for robotic partial nephrectomy. In this study we prospectively evaluate its face, content, construct and concurrent validity. MATERIALS AND METHODS: This hybrid platform features augmented reality and virtual reality. Augmented reality involves 3 dimensional robotic partial nephrectomy surgical videos overlaid with virtual instruments to teach surgical anatomy, technical skills and operative steps. Advanced technical skills are assessed with an embedded full virtual reality renorrhaphy task. Participants were classified as novice (no surgical training, 15), intermediate (less than 100 robotic cases, 13) or expert (100 or more robotic cases, 14) and prospectively assessed. Cohort performance was compared with the Kruskal-Wallis test (construct validity). Post-study questionnaire was used to assess the realism of simulation (face validity) and usefulness for training (content validity). Concurrent validity evaluated correlation between virtual reality renorrhaphy task and a live porcine robotic partial nephrectomy performance (Spearman's analysis). RESULTS: Experts rated the augmented reality content as realistic (median 8/10) and helpful for resident/fellow training (8.0 8.2/10). Experts rated the platform highly for teaching anatomy (9/10) and operative steps (8.5/10) but moderately for technical skills (7.5/10). Experts and intermediates outperformed novices (construct validity) in efficiency (p=0.0002) and accuracy (p=0.002). For virtual reality renorrhaphy, experts outperformed intermediates on GEARS metrics (p=0.002). Virtual reality renorrhaphy and in vivo porcine robotic partial nephrectomy performance correlated significantly (r=0.8, p <0.0001) (concurrent validity). CONCLUSIONS: This augmented reality simulation platform displayed face, content and construct validity. Performance in the procedure specific virtual reality task correlated highly with a porcine model (concurrent validity). Future efforts will integrate procedure specific virtual reality tasks and their global assessment. PMID- 25801766 TI - Establishing Criteria for Bilateral Pelvic Lymph Node Dissection in the Management of Penile Cancer: Lessons Learned from an International Multicenter Collaboration. AB - PURPOSE: Penile carcinoma with bilateral pelvic lymph node metastasis is a relatively rare condition with poor outcomes. There are little data available on optimal strategies for staging and treating this group of patients. We assessed factors predicting bilateral pelvic lymph node metastasis in patients with penile cancer and confirmed inguinal lymph node metastasis. MATERIALS AND METHODS: Multi institutional data from a total of 4 centers in Europe, the People's Republic of China and the United States were retrospectively analyzed. Patients with penile carcinoma and inguinal lymph node metastasis who underwent bilateral pelvic lymphadenectomy were included in analysis. The Kaplan-Meier and log rank tests were used to express overall survival. Logistic regression was used for multivariate analysis of factors predicting bilateral pelvic lymph node metastasis. Cox regression was done in the multivariable analysis of overall survival. RESULTS: We identified 140 patients with penile carcinoma who had confirmed pelvic lymph node metastasis. Of the patients 83 had bilateral inguinal lymph node metastasis and 64 underwent bilateral pelvic lymphadenectomy. Bilateral pelvic lymph node metastasis was observed in 16 patients (25%). The ROC of the total number of inguinal lymph node metastases and the detection of bilateral pelvic lymph node metastasis had an AUC of 0.76 (p = 0.002) with 95% sensitivity for the cutoff point of 4 inguinal nodes. On logistic regression analysis the detection of 4 or more positive inguinal nodes was the only independent predictor of bilateral pelvic lymph node metastasis (OR 14.0, CI 1.71 115). On Cox regression analysis 4 or more inguinal lymph node metastases, adjuvant chemotherapy, inguinal extraprostatic extension and bilateral procedures were associated with overall survival. CONCLUSIONS: Patients with bilateral inguinal lymph node metastasis who are treated with unilateral pelvic lymphadenectomy should be considered for bilateral pelvic lymphadenectomy in the presence of 4 or more metastatic inguinal nodes. PMID- 25801768 TI - [Analysis of quality management factors associated with the metabolic control of patients with type 2 diabetes mellitus]. PMID- 25801767 TI - Caught in action: selecting peptide aptamers against intrinsically disordered proteins in live cells. AB - Intrinsically disordered proteins (IDPs) or unstructured segments within proteins play an important role in cellular physiology and pathology. Low cellular concentration, multiple binding partners, frequent post-translational modifications and the presence of multiple conformations make it difficult to characterize IDP interactions in intact cells. We used peptide aptamers selected by using the yeast-two-hybrid scheme and in-cell NMR to identify high affinity binders to transiently structured IDP and unstructured segments at atomic resolution. Since both the selection and characterization of peptide aptamers take place inside the cell, only physiologically relevant conformations of IDPs are targeted. The method is validated by using peptide aptamers selected against the prokaryotic ubiquitin-like protein, Pup, of the mycobacterium proteasome. The selected aptamers bind to distinct sites on Pup and have vastly different effects on rescuing mycobacterial proteasome substrate and on the survival of the Bacille Calmette-Guerin, BCG, strain of M. bovis. This technology can be applied to study the elusive action of IDPs under near physiological conditions. PMID- 25801771 TI - Only the mother of all reorganisations can save the NHS. PMID- 25801770 TI - New dog and new tricks: evolving roles for IL-33 in type 2 immunity. AB - IL-33 is a more recently identified member of the IL-1 cytokine family, expressed in the nucleus of epithelial cells and released into the extracellular space following tissue damage. The impact of IL-33 as a regulator of the adaptive immune response has been studied extensively, with an understood role for IL-33 in the effector functions of CD4(+) Th2 cells. IL-33, however, is now being shown to initiate the Th2-polarizing function of DCs, and stimulate the secretion of the type 2-associated cytokines, IL-4, IL-5, and IL-13, from tissue-resident innate-immune cells, especially ILCs and MCs. IL-33 also initiates and perpetuates local inflammatory responses through the recruitment and activation of type 2- and inflammatory-associated effectors, such as eosinophils, basophils, and neutrophils. As such, IL-33 drives and amplifies type 2-dependent immunity, as well as type 2-dependent tissue destruction and inflammation. It is also becoming apparent that IL-33 supports the reparative capacity of macrophage and ILCs, but these functions may also contribute to chronic fibrotic diseases. Herein, we review new developments in the understanding of IL-33 as it functions in Th2 cells and type 2 immunity. This includes a discussion of our evolving understanding of how IL-33 directly and indirectly promotes type 2 immune responses through action on innate cells in immunity and the pathogenesis of atopic and fibrotic diseases. PMID- 25801769 TI - Role for NOD2 in Mycobacterium tuberculosis-induced iNOS expression and NO production in human macrophages. AB - M.tb, which causes TB, is a host-adapted intracellular pathogen of macrophages. Macrophage intracellular PRRs, such as NOD proteins, regulate proinflammatory cytokine production in response to various pathogenic organisms. We demonstrated previously that NOD2 plays an important role in controlling the inflammatory response and viability of M.tb and Mycobacterium bovis BCG in human macrophages. Various inflammatory mediators, such as cytokines, ROS, and RNS, such as NO, can mediate this control. iNOS (or NOS2) is a key enzyme for NO production and M.tb control during infection of mouse macrophages; however, the role of NO during infection of human macrophages remains unclear, in part, as a result of the low amounts of NO produced in these cells. Here, we tested the hypothesis that activation of NOD2 by its ligands (MDP and GMDP, the latter from M.tb) plays an important role in the expression and activity of iNOS and NO production in human macrophages. We demonstrate that M.tb or M. bovis BCG infection enhances iNOS expression in human macrophages. The M.tb-induced iNOS expression and NO production are dependent on NOD2 expression during M.tb infection. Finally, NF kappaB activation is required for NOD2-dependent expression of iNOS in human macrophages. Our data provide evidence for a new molecular pathway that links activation of NOD2, an important intracellular PRR, and iNOS expression and activity during M.tb infection of human macrophages. PMID- 25801772 TI - Two subtle amino Acid changes in a transaminase substantially enhance or invert enantiopreference in cascade syntheses. AB - Amine transaminases (ATAs) are powerful enzymes for the stereospecific production of chiral amines. However, the synthesis of amines incorporating more than one stereocenter is still a challenge. We developed a cascade synthesis to access optically active 3-alkyl-substituted chiral amines by combining two asymmetric synthesis steps catalyzed by an enoate reductase and ATAs. The ATA wild type from Vibrio fluvialis showed only modest enantioselectivity (14 % de) in the amination of (S)-3-methylcyclohexanone, the product of the enoate-reductase-catalyzed reaction step. However, by protein engineering we created two variants with substantially improved diastereoselectivities: variant Leu56Val exhibited a higher R selectivity (66 % de) whereas the Leu56Ile substitution caused a switch in enantiopreference to furnish the S-configured diastereomer (70 % de). Addition of 30 % DMSO further improved the selectivity and facilitated the synthesis of (1R,3S)-1-amino-3-methylcyclohexane with 89 % de at 87 % conversion. PMID- 25801773 TI - Simultaneous stent expansion/balloon deflation technique to salvage failed balloon remodeling. AB - Herniation, with possible embolization, of coils into the parent vessel following aneurysm coiling remains a frequent challenge. For this reason, balloon or stent assisted embolization remains an important technique. Despite the use of balloon remodeling, there are occasions where, on deflation of the balloon, some coils, or even the entire coil mass, may migrate. We report the successful use of a simultaneous adjacent stent deployment bailout technique in order to salvage coil prolapse during balloon remodeling in three patients. Case No 1 was a wide neck left internal carotid artery bifurcation aneurysm, measuring 9 mm*7.9 mm*6 mm with a 5 mm neck. Case No 2 was a complex left superior hypophyseal artery aneurysm, measuring 5.3 mm*4 mm*5 mm with a 2.9 mm neck. Case No 3 was a ruptured right posterior communicating artery aneurysm, measuring 4 mm*4 mm*4.5 mm with a 4 mm neck. This technique successfully returned the prolapsed coil mass into the aneurysm sac in all cases without procedural complications. The closed cell design of the Enterprise VRD (Codman and Shurtleff Inc, Raynham, Massachusetts, USA) makes it ideal for this bailout technique, by allowing the use of an 0.021 inch delivery catheter (necessary for simultaneous access) and by avoiding the possibility of an open cell strut getting caught on the deflated balloon. We hope this technique will prove useful to readers who may find themselves in a similar predicament. PMID- 25801774 TI - Trends in mortality following mechanical thrombectomy for the treatment of acute ischemic stroke in the USA. AB - BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) for the treatment of acute ischemic stroke has been growing in popularity while the therapeutic benefit of MT has been increasingly debated. Our objective was to examine national trends in mortality following MT. METHODS: We analyzed the National Inpatient Sample (2012) and the Nationwide Inpatient Sample (2008-2011) for patients with a primary diagnosis of acute ischemic stroke that received MT. Temporal trends in mortality were examined using Spearman's rank correlation. To account for confounding factors, mortality was further analyzed in binary logistic regression. RESULTS: Hospitals performing MT comprised 8% of all hospitals treating ischemic stroke. The percentage of stroke cases treated with MT increased from 0.6% of cases in 2008 to 1.1% in 2012, totaling 16 307 MT cases in a 5 year period. Inhospital mortality decreased over the study period from 25.4% in 2008 to 16.1% in 2012 (r= 0.081, p<0.001). This finding was supported by regression analysis as each incremental year reduced the odds of mortality by 20% (OR=0.832, p<0.001). Administration of recombinant tissue plasminogen activator was associated with a decrease in the odds of mortality (OR=0.805, p<0.001). CONCLUSIONS: Utilization of MT represents a small percentage of stroke cases, although the trend is increasing. Mortality following MT has been showing a steady decline over the past 5 years. This may be a result of a learning curve, improved patient selection, and/or device improvements. Randomized trials remain essential to evaluate the potential benefit of endovascular devices and identify the most appropriate patients. PMID- 25801776 TI - The mitochondria-plasma membrane contact site. AB - Mitochondria are dynamic organelles that are highly motile and frequently fuse and divide. It has recently become clear that their complex behavior is governed to a large extent by interactions with other cellular structures. This review will focus on a mitochondria-plasma membrane tethering complex that was recently discovered and molecularly analyzed in budding yeast, the Num1/Mdm36 complex. This complex attaches mitochondria to the cell cortex and ensures that a portion of the organelles is retained in mother cells during cell division. At the same time, it supports mitochondrial division and integrates mitochondrial dynamics into cellular architecture. Recent evidence suggests that similar mechanisms might exist also in mammalian cells. PMID- 25801775 TI - Evaluation of an anatomic definition of non-aneurysmal perimesencephalic subarachnhoid hemorrhage. AB - BACKGROUND AND PURPOSE: Perimesencephalic subarachnoid hemorrhage (PSAH) is not consistently defined in the existing literature. The purpose of this study was to test the inter-observer variability and specificity for non-aneurysmal subarachnoid hemorrhage (SAH) of an anatomic definition of PSAH. METHODS: Medical records of all patients who underwent catheter angiography for evaluation of non traumatic SAH between July 2002 and April 2012 were reviewed. Patients with anterior circulation aneurysms were excluded. Three blinded reviewers assessed whether each admission CT scan met the following anatomic criteria for PSAH: (1) center of bleeding located immediately anterior and in contact with the brainstem in the prepontine, interpeduncular, or posterior suprasellar cistern; (2) blood limited to the prepontine, interpeduncular, suprasellar, crural, ambient, and/or quadrigeminal cisterns and/or cisterna magna; (3) no extension of blood into the Sylvian or interhemispheric fissures; (4) intraventricular blood limited to incomplete filling of the fourth ventricle and occipital horns of the lateral ventricles (ie, consistent with reflux); (5) no intraparenchymal blood. RESULTS: 56 patients with non-aneurysmal SAH and 50 patients with posterior circulation or posterior communicating artery aneurysms were identified. Seventeen (16%) of the 106 admission CT scans met the anatomic criteria for PSAH. No aneurysm was identified in this subgroup. Inter-observer agreement was excellent with kappa scores of 0.89-0.96 and disagreement in 2.8% (3/106) of cases. CONCLUSIONS: Our anatomic definition of PSAH correlated with a low risk of brain aneurysm and was applied with excellent inter-observer agreement. PMID- 25801777 TI - Detecting DNA viruses in oral fluids: evaluation of collection and storage methods. AB - Storing saliva for nucleic acid diagnostics is problematic in resource constrained settings. DNA Genotek's OMNIgeneTM.DISCOVER kit aims to stabilise microbial DNA at room temperature. We evaluate this for long-term storage, determining DNA quantity/purity and human herpesvirus 8 (HHV-8) load as indicator. Viral loads and DNA degradation were assayed over 14months in HHV-8 negative saliva spiked with cell-associated and cell-free virus and saliva collected fresh frozen and into kits from 10 HIV-positive patients. Viral loads remained constant for 6-9months, yielding high quantities of DNA: subsequent losses were <=48%. Patient samples, frozen or kit stored, produced pure DNA of comparable concentration. Higher HHV-8 detection in frozen saliva resulted from losses during ethanol precipitation using kits. After 14months, DNA degradation was significant in frozen saliva, but that in kits had integrity similar to fresh samples. Storing frozen saliva is detrimental. This kit is well suited for collection, long-term storage, and assay of viral DNA in resource-constrained settings. PMID- 25801778 TI - Comparison of 2 real-time PCR assays for diagnosis of Pneumocystis jirovecii pneumonia in human immunodeficiency virus (HIV) and non-HIV immunocompromised patients. AB - A total of 120 bronchoalveolar lavage specimens from HIV and non-HIV immunocompromised patients, positive for Pneumocystis jirovecii by an "in house" real-time polymerase chain reaction (PCR), were evaluated by the Bio-Evolution Pneumocystis real-time PCR, a commercial quantitative assay. Patients were classified in 2 categories based on clinical and radiological findings: definite and unlikely Pneumocystis pneumonia (PCP). For the "in house" PCR, cycle threshold 34 was established as cut-off value to discriminate definite PCP from unlikely PCP with 65% and 85% of sensitivity and specificity, respectively. For the Bio-Evolution quantitative PCR, a cut-off value of 2.8*10(5)copies/mL was defined with 72% and 82% of sensitivity and specificity, respectively. Overlapped zones of results for definite and unlikely PCP were observed. Quantitative PCR is probably a useful tool for PCP diagnosis. However, for optimal management of PCP in non-HIV immunocompromised patients, operational thresholds should be assessed according to underlying diseases and other clinical and radiological parameters. PMID- 25801779 TI - Pneumocystis jirovecii in the air surrounding patients with Pneumocystis pulmonary colonization. AB - In this study, Pneumocystis jirovecii was detected and characterized in the air surrounding patients with Pneumocystis pulmonary colonization. Air samples were collected in the rooms of 10 colonized patients using Coriolis(r) MU air sampler at 1m and 5m from the patient's head. P. jirovecii DNA was amplified and genotyped in pulmonary and air samples at the mitochondrial large subunit ribosomal RNA gene. P. jirovecii DNA was detected in 5 of the 10 air samples collected at 1m and in 5 of the 10 other air samples collected at 5m. P. jirovecii genotyping was successful in 4 pairs or triplets of air and pulmonary samples. Full genotype matches were observed in 3 of the 4 pairs or triplets of air and pulmonary samples. These results provide original data supporting P. jirovecii exhalation from colonized patients and emphasize the risk of P. jirovecii nosocomial transmission from this patient population. PMID- 25801780 TI - Evaluation of clinical outcomes in patients with Gram-negative bloodstream infections according to cefepime MIC. AB - Predicted and observed failures at higher cefepime MICs have prompted the Clinical and Laboratories Standards Institute (CLSI) to lower the susceptible breakpoint for Enterobacteriaceae to <=2mg/L, with dose-dependent susceptibility at 4-8mg/L, while the susceptibility breakpoint for nonfermentative organisms remain unchanged at >=8mg/L. The contribution of increasing cefepime MIC to mortality risk in the setting of aggressive cefepime dosing is not well defined. Patients who were treated with cefepime for Gram-negative blood stream infections (GNBSIs), including both Enterobacteriaceae and nonfermentative organisms, were screened for inclusion in this retrospective cohort study. Demographic and microbiologic variables were collected, including pathogen, cefepime MIC, dosage, and interval. The objective was to define a risk-adjusted mortality breakpoint for cefepime MICs. Secondarily, we looked at time to death and length of stay (LOS) postculture. Ninety-one patients were included in the analysis. Overall, 19 patients died and 72 survived. Classification and Regression Tree analysis identified an inhospital mortality breakpoint at a cefepime MIC between 2 and 4mg/L for patients with a modified Acute Physiology and Chronic Health Evaluation II score <=16.5 (4.2% versus 25%, respectively). Multivariate logistic regression revealed increased odds of mortality at a cefepime MIC of 4mg/L (adjusted odds ratio [aOR] 6.47; 95% confidence interval [CI] 1.25-33.4) and 64mg/L (aOR 6.54, 95% CI 1.03-41.4). Those with cefepime MICs >=4mg/L experienced a greater median intensive care unit LOS for survivors (16 versus 2days; P=0.026). Increasing cefepime MIC appears to predict inhospital mortality among patients who received aggressive doses of cefepime for GNBSIs, supporting a clinical breakpoint MIC of 2mg/L. PMID- 25801781 TI - MALDI-TOF identification of Gram-negative bacteria directly from blood culture bottles containing charcoal: Sepsityper(r) kits versus centrifugation-filtration method. AB - Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry has dramatically altered the way microbiology laboratories identify clinical isolates. Direct blood culture (BC) detection may be hampered, however, by the presence of charcoal in BC bottles currently in clinical use. This study evaluates an in-house process for extraction and MALDI-TOF identification of Gram negative bacteria directly from BC bottles containing charcoal. Three hundred BC aliquots were extracted by a centrifugation-filtration method developed in our research laboratory with the first 96 samples processed in parallel using Sepsityper(r) kits. Controls were colonies from solid media with standard phenotypic and MALDI-TOF identification. The identification of Gram-negative bacteria was successful more often via the in-house method compared to Sepsityper(r) kits (94.7% versus 78.1%, P<=0.0001). Our in-house centrifugation filtration method was further validated for isolation and identification of Gram negative bacteria (95%; n=300) directly from BC bottles containing charcoal. PMID- 25801782 TI - Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. PMID- 25801785 TI - Corrigendum. PMID- 25801784 TI - Lymphoid neoplasms. PMID- 25801783 TI - Aberrant SOX11 promoter methylation is associated with poor prognosis in gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is the second most common cause of cancer mortality world-wide. In recent years, aberrant SOX11 expression has been observed in various solid and hematopoietic malignancies, including GC. In addition, it has been reported that SOX11 expression may serve as an independent prognostic factor for the survival of GC patients. Here, we assessed the SOX11 gene promoter methylation status in various GC cell lines and primary GC tissues, and evaluated its clinical significance. METHODS: Five GC cell lines were used to assess SOX11 expression by qRT-PCR. The effect of SOX11 expression restoration after 5-aza-2'-deoxycytidine (5-Aza-dC) treatment on GC growth was evaluated in GC cell line MKN45. Subsequently, 89 paired GC-normal gastric tissues were evaluated for their SOX11 gene promoter methylation status using methylation specific PCR (MSP), and 20 paired GC-normal gastric tissues were evaluated for their SOX11 expression in relation to SOX11 gene promoter methylation. GC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses. RESULTS: Down-regulation of SOX11 mRNA expression was observed in both GC cell lines and primary GC tissues. MSP revealed hyper-methylation of the SOX11 gene promoter in 55.1% (49/89) of the primary GC tissues tested and in 7.9% (7/89) of its corresponding non-malignant tissues. The SOX11 gene promoter methylation status was found to be related to the depth of GC tumor invasion, Borrmann classification and GC differentiation status. Upon 5-Aza-dC treatment, SOX11 expression was found to be up-regulated in MKN45 cells, in conjunction with proliferation inhibition. SOX11 gene promoter hyper-methylation was found to be significantly associated with a poor prognosis and to serve as an independent marker for survival using multivariate Cox regression analysis. CONCLUSIONS: Our results indicate that aberrant SOX11 gene promoter methylation may underlie its down-regulation in GC. SOX11 gene promoter hyper-methylation may serve as a biomarker to predict the clinical outcome of GC. PMID- 25801786 TI - Development of a quantitative real-time PCR assay for direct detection of growth of cellulose-degrading bacterium Clostridium thermocellum in lignocellulosic degradation. AB - AIMS: Currently, there is no direct method for detecting Clostridium thermocellum in the insoluble medium. In this study, a quantitative real-time PCR assay was developed for the direct growth detection of C. thermocellum at the single-cell level in lignocellulosic biomasses. METHODS AND RESULTS: The assay targeted the cipA gene and was able to distinguish C. thermocellum from other species with good reproducibility which quantitative detection limit was 10 cell equivalents (CE) per reaction. OD600-based counting and qPCR quantification of C. thermocellum cultured in soluble medium were compared and an excellent consistency was revealed, indicating the appropriateness of the developed qPCR method. Analysis based on yellow affinity substrate and fermentation products may incorrectly estimate its population. CONCLUSIONS: The developed assay can serve as a specific, sensitive and reproducible method for the detection of C. thermocellum in lignocellulosic biomass at the single-cell level. SIGNIFICANCE AND IMPACT OF THE STUDY: With the ability to rapidly detect C. thermocellum, this method will contribute substantially to the understanding of the lignocellulosic biomass degradation mechanism. Moreover, it can also be applied to detect C. thermocellum growth in certain co-culture system for the understanding of the metabolic interactions. PMID- 25801787 TI - Males are here to stay: fertilization enhances viable egg production by clonal queens of the little fire ant (Wasmannia auropunctata). AB - Evolution of reproduction strategies is affected by both phylogenetic and physiological constraints. Although clonality may benefit females, it may not be selected if a male contribution is necessary to start egg laying and embryo development. In little fire ant, Wasmannia auropunctata, sexual populations employ a typical Hymenopteran system of reproduction. In clonal populations, however, queens and males are produced with only maternal and paternal genomes, respectively, whereas sterile workers are produced sexually. Although this system requires both sexes for worker production, previous work has shown that workers may also be produced clonally by the queens. If so, why are males maintained in this species? Our data suggest that fertilization is necessary to increase the hatching rate of eggs. Although clonal queens can indeed produce both workers and queens without mating, the hatching rate is far below the level necessary to maintain functional colonies. On the other hand, virgin queens from populations exhibiting the original Hymenopteran reproduction system also show low hatching rates, but produce only haploid male eggs. Reasons for the existence of W. auropunctata males have been disputed. However, our data suggest that physiological constraints, such as the requirement for insemination, must be considered in regard to evolution of reproduction systems, in addition to ecological data and theoretical considerations of fitness. PMID- 25801789 TI - Outflow tract ventricular arrhythmias: When and how to treat? PMID- 25801790 TI - Deproteinized Bovine Bone Mineral or Autologous Bone at Dehiscence Type Defects at Implants Installed Immediately into Extraction Sockets: An Experimental Study in Dogs. AB - PURPOSE: The aim of this study was to evaluate bone regeneration at surgically created dehiscence buccal defects at implants placed immediately into extraction sockets (IPIES) of small dimensions filled with autogenous bone or deproteinized bovine bone mineral (DBBM) associated with a collagen membrane. MATERIALS AND METHODS: Eight Labrador dogs were used and implants were placed immediately into the extraction sockets of the second premolar. The buccal wall was subsequently removed to create a standardized defect, 4 mm wide coronally, 2 mm wide apically, and 6 mm high. Autogenous bone particles (AB) or DBBM granules were used to fill the defects. All surgical sites were subsequently covered by a resorbable collagen membrane and a non-submerged healing was allowed. After 4 months, the animals were euthanized and bone blocks harvested and processed for histomorphometric analysis. RESULTS: The bony crest at the buccal aspect (C) was located 2.3 +/- 0.8 mm and 1.7 +/- 0.7 mm apically to the implant shoulder (IS) at the AB and DBBM sites, respectively. The coronal levels of osseointegration at the buccal aspect (B) were located 2.7 +/- 0.7 mm and 2.2 +/- 1.0 mm apically to IS at the AB and DBBM sites, respectively. At the AB sites, the peri-implant mucosa was located 4.3 +/- 0.9 mm, 4.7 +/- 0.9 mm, and 2.0 +/- 1.6 mm coronally to C, B, and IS, respectively. The corresponding values at the DBBM sites were 4.3 +/- 0.6 mm, 4.8 +/- 0.6 mm, and 2.5 +/- 0.8 mm, respectively. No statistically significant differences were found. CONCLUSIONS: The treatment of surgically created buccal defects at IPIES sites using Bio-Oss(r) (Geistlich Biomaterials, Wolhusen, LU, Switzerland) or autogenous bone, concomitantly with a collagen membrane, engenders bone regeneration to a similar extent after 4 months of healing. PMID- 25801791 TI - Identification of Two Loci Associated with Generalized Pustular Psoriasis. PMID- 25801792 TI - Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug Resistant Basal Cell Carcinoma. PMID- 25801793 TI - Common Variants Affecting Susceptibility to Develop Multiple Basal Cell Carcinomas. PMID- 25801788 TI - RNA-stabilizing proteins as molecular targets in cardiovascular pathologies. AB - The stability of mRNA has emerged as a key step in the regulation of eukaryotic gene expression and function. RNA stabilizing proteins (RSPs) contain several RNA recognition motifs, and selectively bind to adenylate-uridylate-rich elements in the 3' untranslated region of several mRNAs leading to altered processing, stability, and translation. These post-transcriptional gene regulations play a critical role in cellular homeostasis; therefore act as molecular switch between 'normal cell' and 'disease state.' Many mRNA binding proteins have been discovered to date, which either stabilize (HuR/HuA, HuB, HuC, HuD) or destabilize (AUF1, tristetraprolin, KSRP) the target transcripts. Although the function of RSPs has been widely studied in cancer biology, its role in cardiovascular pathologies is only beginning to evolve. The current review provides an overall understanding of the potential role of RSPs, specifically HuR mediated mRNA stability in myocardial infarction, hypertension and hypertrophy. Also, the effect of RSPs on various cellular processes including inflammation, fibrosis, angiogenesis, cell-death, and proliferation and its relevance to cardiovascular pathophysiological processes is presented. We also discuss the potential clinical implications of RSPs as therapeutic targets in cardiovascular diseases. PMID- 25801794 TI - Prey size selection and cannibalistic behaviour of juvenile barramundi Lates calcarifer. AB - This study assessed the cannibalistic behaviour of juvenile barramundi Lates calcarifer and examined the relationship between prey size selection and energy gain of cannibals. Prey handling time and capture success by cannibals were used to estimate the ratio of energy gain to energy cost in prey selection. Cannibals selected smaller prey despite its capability of ingesting larger prey individuals. In behavioural analysis, prey handling time significantly increased with prey size, but it was not significantly affected by cannibal size. Conversely, capture success significantly decreased with the increase of both prey and cannibal sizes. The profitability indices showed that the smaller prey provides the most energy return for cannibals of all size classes. These results indicate that L. calcarifer cannibals select smaller prey for more profitable return. The behavioural analysis, however, indicates that L. calcarifer cannibals attack prey of all size at a similar rate but ingest smaller prey more often, suggesting that prey size selection is passively orientated rather than at the predator's choice. The increase of prey escape ability and morphological constraint contribute to the reduction of intracohort cannibalism as fish grow larger. This study contributes to the understanding of intracohort cannibalism and development of strategies to reduce fish cannibalistic mortalities. PMID- 25801795 TI - The effect of activated carbon addition on membrane bioreactor processes for wastewater treatment and reclamation - A critical review. AB - This review concentrates on the effect of activated carbon (AC) addition to membrane bioreactors (MBRs) treating wastewaters. Use of AC-assisted MBRs combines adsorption, biodegradation and membrane filtration. This can lead to advanced removal of recalcitrant pollutants and mitigation of membrane fouling. The relative contribution of adsorption and biodegradation to overall removal achieved by an AC-assisted MBR process can vary, and "biological AC" may not fully develop due to competition of target pollutants with bulk organics in wastewater. Thus periodic replenishment of spent AC is necessary. Sludge retention time (SRT) governs the frequency of spent AC withdrawal and addition of fresh AC, and is an important parameter that significantly influences the performance of AC-assisted MBRs. Of utmost importance is AC dosage because AC overdose may aggravate membrane fouling, increase sludge viscosity, impair mass transfer and reduce sludge dewaterability. PMID- 25801796 TI - Acoustical scattering cross section of gas bubbles under dual-frequency acoustic excitation. AB - The acoustical scattering cross section is a paramount parameter determining the scattering ability of cavitation bubbles when they are excited by the incident acoustic waves. This parameter is strongly related with many important applications of acoustic cavitation including facilitating the reaction of chemical process, boosting bubble sonoluminescence, and performing non-invasive therapy and drug delivery. In present paper, both the analytical and numerical solutions of acoustical scattering cross section of gas bubbles under dual frequency excitation are obtained. The validity of the analytical solution is shown with demonstrating examples. The nonlinear characteristics (e.g., harmonics, subharmonics and ultraharmonics) of the scattering cross section curve under dual-frequency approach are investigated. Compared with single-frequency approach, the dual-frequency approach displays more resonances termed as "combination resonances" and could promote the acoustical scattering cross section significantly within a much broader range of bubble sizes due to the generation of more resonances. The influence of several paramount parameters (e.g., acoustic pressure amplitude, power allocations between two acoustic components, and the ratio of the frequencies) in the dual-frequency system on the predictions of scattering cross section has been discussed. PMID- 25801799 TI - Intercostal artery perforator propeller flap for reconstruction of trunk defects following sarcoma resection. AB - Trunk defects following soft tissue sarcoma resection are usually managed by myocutaneous flaps or free flaps. However, harvesting muscle will cause functional morbidities and some trunk regions lack reliable recipient vessels. The intercostal arteries give off multiple perforators, which distribute widely over the trunk and can supply various pedicle flaps. Our purpose is to use various intercostal artery perforator propeller flaps for trunk oncologic reconstruction. Between November 2013 and July 2014, nine intercostal artery perforator propeller flaps were performed in seven patients to reconstruct the defects following sarcoma resection in different regions of the trunk, including the back, lumbar, chest, and abdomen. Two perforators from intercostal arteries were identified for each flap using Doppler ultrasound probe adjacent to the defect. The perforator with visible pulsation was chosen as the pedicle vessel. An elliptical flap was raised and rotated in a propeller fashion to repair the defects. There were one dorsal intercostal artery perforator flap, four dorsolateral intercostal artery perforator flaps, three lateral intercostal artery perforator flaps, and one anterior intercostal artery perforator flap. The mean skin paddle dimension was 9.38 cm in width (range 6-14 cm) and 21.22 cm in length (range 13-28 cm). All intercostal artery perforator flaps survived completely, except for marginal necrosis in one flap harvested close to the previous flap donor site. The intercostal artery perforator propeller flap provides various and valuable options in our reconstructive armamentarium for trunk oncologic reconstruction. To our knowledge, this is the first case series of using intercostal artery perforator propeller flaps for trunk oncologic reconstruction and clinical application of dorsolateral intercostal artery perforator flaps. PMID- 25801798 TI - Evaluation of the results of simultaneous open rhinoplasty and Abbe flap for the reconstruction of the secondary bilateral cleft and nasal deformity. AB - AIMS: We aimed to evaluate the results of simultaneous rhinoplasty and Abbe flap for the reconstruction of the secondary bilateral cleft and nasal deformity by means of a newly developed software-based method. PATIENTS AND METHODS: A total of 16 patients with the bilateral cleft lip nasal deformity received Abbe flap and simultaneous open rhinoplasty between 2004 and 2010. The mean age of the patients was 21 years, and the average follow-up time was 2.4 years. After the open rhinoplasty procedure, the upper lip was reconstructed with the Abbe flap. Preoperative and postoperative photographs that had been taken laterally were evaluated by using Adobe Photoshop((r)) CS4 and Adobe InDesign((r)) software. The length of the columella and the relative changes of the most anterior point of the upper lip to the vertical plane tangent to the most anterior point of the lower lip were measured in pixels on standardized preoperative and postoperative images. The differences were calculated and compared as a percentage (%). RESULTS: There was no flap loss and associated problems. The measurements of columellar length revealed an average increase of 51.8 +/- 11.3%, while the relative change of the most anterior point of the upper lip revealed an average increase of 68.6 +/- 11.2%. CONCLUSION: The results of the treatment modality were successfully evaluated by a newly developed software-based method. PMID- 25801800 TI - Preoperative color Doppler ultrasound assessment of the lateral thoracic artery perforator flap and its branching pattern. AB - The anatomy of the lateral thoracic artery perforator flap remains controversial, but this region is extremely useful as a reconstructive donor site. In this report, we describe the usefulness of the preoperative color Doppler ultrasound evaluation for the harvesting of the lateral thoracic artery perforator flap, and we clarify its branching pattern. Twenty-seven patients underwent the preoperative color Doppler ultrasound assessment before perforator flaps were harvested. We evaluated the branching pattern and the diameter of the flaps by direct observation. All flaps were successfully transferred, and it was found that the branching pattern of the lateral thoracic perforator is divided into three groups: the superficial branch, the medial branch, and the deep branch. Their appearance ratios were 48.1% (13/27), 14.8% (4/27), and 81.5% (22/27), respectively. The lateral thoracic artery perforator flap has a great deal of anatomical variation, and vessels with relatively small diameters compared to those of other flaps. This is why flaps from this region are not currently popular. This study revealed the superiority of the color Doppler ultrasound for preoperative planning of the lateral thoracic artery perforator flap elevation. Furthermore, the branching pattern and the diameters of the different branches were specified. PMID- 25801801 TI - Recurrent acute and transient psychotic disorder: A pilot study. AB - Acute and transient psychotic disorder (ATPD) is associated with recurrent episodes of illness in 35-45% of cases. However, the course of such relapses and the factors associated with them are unclear. 20 patients with an ICD-10 diagnosis of ATPD (F23.x) who had experienced at least two episodes of illness, and who had been followed up for at least one year, were interviewed and their case records were reviewed. Information pertaining to relapses, their frequency, and the factors associated with them were collected and analyzed. The mean episode frequency was 0.7 episodes per year. Relapse within two years of the first episode (p=0.001) and a later age at onset (p=0.016) were significantly associated with a higher frequency of episodes. Relapse rates were 30% after a second episode and 50% after a third; mean inter-episode intervals decreased with the number of episodes, but not significantly. Patients with a stress-related onset of ATPD tended to have further stress-related relapses. Diagnostic subtypes of ATPD tended to remain stable over time. Though acute and transient psychotic disorder is a recurrent condition, recurrences do not increase significantly over time, and there is no clear evidence for a shortening of the inter-episode period. A later onset of ATPD may be associated with greater illness severity. These results are preliminary and require replication in larger prospective samples. PMID- 25801797 TI - Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials. AB - Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965 27; www.clinicaltrials.gov identifier NCT00635427. PMID- 25801803 TI - A touch of Zen: post-translational regulation of the Leishmania stress response. AB - Across bacterial, archaeal and eukaryotic kingdoms, heat shock proteins (HSPs) are defined as a class of highly conserved chaperone proteins that are rapidly induced in response to temperature increase through dedicated heat shock transcription factors. While this transcriptional response governs cellular adaptation of fungal, plant and animal cells to thermic shock and other forms of stress, early-branching eukaryotes of the kinetoplastid order, including trypanosomatid parasites, lack classical mechanisms of transcriptional regulation and show largely constitutive expression of HSPs, thus raising important questions on the function of HSPs in the absence of stress and the regulation of their chaperone activity in response to environmental adversity. Understanding parasite-specific mechanisms of stress-response regulation is especially relevant for protozoan parasites of the genus Leishmania that are adapted for survival inside highly toxic phagolysosomes of host macrophages causing the various immuno pathologies of leishmaniasis. Here we review recent advances on the function and regulation of chaperone activities in these kinetoplastid pathogens and propose a new model for stress-response regulation through a reciprocal regulatory relationship between stress kinases and chaperones that may be relevant for parasite-adaptive differentiation and infectivity. PMID- 25801802 TI - Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons. AB - Chronic inflammation in the substantia nigra (SN) accompanies conditions with progressive neurodegeneration. This inflammatory process contributes to gradual iron deposition that may catalyze formation of free-radical mediated damage, hence exacerbating the neurodegeneration. This study examined proteins related to iron-storage (ferritin) and iron-export (ferroportin) (aka metal transporter protein 1, MTP1) in a model of neurodegeneration. Ibotenic acid injected stereotactically into the striatum leads to loss of GABAergic neurons projecting to SN pars reticulata (SNpr), which subsequently leads to excitotoxicity in the SNpr as neurons here become vulnerable to their additional glutamatergic projections from the subthalamic nucleus. This imbalance between glutamate and GABA eventually led to progressive shrinkage of the SNpr and neuronal loss. Neuronal cell death was accompanied by chronic inflammation as revealed by the presence of cells expressing ED1 and CD11b in the SNpr and the adjacent white matter mainly denoted by the crus cerebri. The SNpr also exhibited changes in iron metabolism seen as a marked accumulation of inflammatory cells containing ferric iron and ferritin with morphology corresponding to macrophages and microglia. Ferritin was detected in neurons of the lesioned SNpr in contrast to the non-injected side. Compared to non-injected rats, surviving neurons of the SNpr expressed ferroportin at unchanged level. Analyses of dissected SNpr using RT-qPCR showed a rise in ferritin-H and -L transcripts with increasing age but no change was observed in the lesioned side compared to the non-lesioned side, indicating that the increased expression of ferritin in the lesioned side occurred at the post-transcriptional level. Hepcidin transcripts were higher in the lesioned side in contrast to ferroportin mRNA that remained unaltered. The continuous entry of iron-containing inflammatory cells into the degenerating SNpr and their subsequent demise is probably responsible for iron donation in neurodegeneration. This is accompanied by only a slight increase in neuronal ferritin and not ferroportin, which suggests that the iron-containing debris of dying inflammatory cells and degenerating neurons gets scavenged by invading macrophages and activated microglia to prevent an increase in neuronal iron. PMID- 25801804 TI - Relationship between symptom clusters and quality of life in patients at stages 2 to 4 chronic kidney disease in Korea. AB - PURPOSE: This study was conducted to identify the relationship between symptom clusters and quality of life (QOL) in patients with stages 2 to 4 chronic kidney disease (CKD) in Korea. METHODS: Using self-reported questionnaires, data were collected from 143 patients who underwent treatment for CKD at one hospital in Korea. The 17-item Patient Outcome Scale was used to measure symptoms, and the 36 item Short Form Health Survey Instrument Version 2 (SF-36v2) was used to measure the QOL. Data were analyzed using factor analysis to draw symptom clusters. RESULTS: Among five symptom clusters, the energy insufficiency and pain cluster was found to have the highest prevalence and greatest severity. The severity of symptom clusters showed negative correlations with both physical and mental component summary (PCS and MCS) scores. Elderly patients scored low on PCS, whereas younger patients in their 30s and 40s scored low on MCS. Negative correlations were found between symptom clusters and PCS as well as MCS. The severity of symptoms and QOL had stronger relationships with subjective perception of symptoms and psychological factors than with objective clinical indicators. CONCLUSION: As the effects of physical and psychological symptoms on the QOL in patients with stages 2 to 4 CKD were identified in this study, nurses should develop strategic nursing plans focused on symptom clusters and patients' subjective perception of symptoms rather than objective clinical indicators in order to improve the QOL in patients with CKD. PMID- 25801805 TI - Intraductal papillomas on core biopsy can be upgraded to malignancy on subsequent excisional biopsy regardless of the presence of atypical features. AB - Intraductal papillary lesions of the breast constitute a heterogeneous entity, including benign intraductal papilloma (IDP) with or without atypia and malignant papillary carcinoma. Differentiating between these diagnoses can be challenging. We re-evaluated core biopsy specimens that were diagnosed as IDP and the corresponding surgical excision specimens, and assessed the potential risk for the diagnosis to be modified to malignancy based on excision. By sorting the pathology database of the National Cancer Center Hospital, Tokyo, we identified 146 core biopsy cases that were histologically diagnosed as IDP between 1997 and 2013. The re-evaluated diagnosis was IDP without atypia in 79 (54%) patients, IDP with atypia in 66 (45%), and ductal carcinoma in situ (DCIS) in 1 (1%). Among the 34 patients (23%) who underwent surgical excision subsequent to core biopsy, histological diagnosis was upgraded to carcinoma, excluding lobular carcinoma in situ (LCIS), in 14 (41%) cases, including 4 (33%) of 12 IDPs without atypia and 10 (45%) of 22 IDPs with atypia. Complete surgical excision should be kept in mind for all IDPs diagnosed on core biopsy, not only IDPs with atypia but IDPs without atypia, especially when clinical or imaging diagnosis findings cannot rule out the possibility of malignancy, because papillary lesions comprise a variety of morphological appearances. PMID- 25801807 TI - The enhanced photocatalytic activity and self-cleaning properties of mesoporous SiO2 coated Cu-Bi2O3 thin films. AB - Mesoporous SiO2 coated Cu-Bi2O3 thin films (meso-SiO2/Cu-Bi2O3) were prepared on glass substrates using a simple sol-gel/spin-coating method. The structure and optical properties were characterized using X-ray diffraction, X-ray photoelectron spectroscopy, a UV-vis spectrophotometer and a water contact angle meter. The photocatalytic activity and self-cleaning properties of the films were investigated through the degradation of methyl orange and stearic acid, respectively. It was found that the meso-SiO2/Cu-Bi2O3 thin films were highly transparent and showed excellent superhydrophilicity even in the dark. The thin films exhibited enhanced photocatalytic activity and self-cleaning properties compared to pure Bi2O3 films, which was attributed to the cooperation of the interfacial charge transfer between Bi2O3 and surface Cu species as well as the unique mesoporous SiO2 structure. The results showed that the films can be used as promising self-cleaning and antifogging materials. PMID- 25801806 TI - The 2014 ACR annual meeting: a bird's eye view of autoimmunity in 2015. AB - Our understanding of the mechanisms leading to rheumatic diseases is growing at unprecedented pace thanks to the worldwide network of clinical and translational researchers who gather at major scientific meetings to share their progresses. Further, these meetings allow the contamination of unrelated research areas and thus the spreading of ideas, hypotheses, and research tools. The annual meeting of the American College of Rheumatology (ACR) serves this purpose by allowing thousands of rheumatologists, immunologists, health care professionals, and basic scientists to attend the same sessions and present their work. The 2014 ACR meeting was held in Boston, MA, and was attended by over 16,000 participants who had the opportunity to directly witness the presentation of over 3000 abstracts. As such is the case, a full attendance of all update opportunities was not feasible. To fill this gap we arbitrarily selected the abstracts the appeared most interesting in a few fields of interest and we herein discuss the presented data and their further implications. In particular, we were intrigued by research advances in biomarkers for rheumatic diseases, and by advances on Sjogren syndrome, neuropsychiatric systemic lupus erythematosus, fibromyalgia, and B cell mechanisms. While we are well aware of the numerous blind spots that are expected in this type of article, we submit that this is far from a comprehensive overview and refer to the abstract book for a more complete analysis of the presented abstracts. PMID- 25801808 TI - Short-stem hip arthroplasty in osteonecrosis of the femoral head. AB - INTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a locally destructive and complex disorder. Without treatment, infraction of the femoral head is likely. There is also a lack of consensus in the literature about the most appropriate arthroplasty method in patients with progressive ONFH. During the last decade, the number of short-stem prostheses has increased. Some short-stem designs have a metaphyseal anchorage. It is questionable whether ONFH represents a risk factor for failure after implantation of short stems. The aim of this study was to review existing literature regarding the outcome of short-stem arthroplasty in ONFH and to present the pros and cons of short-stem hip arthroplasty in osteonecrosis of the femoral head. MATERIALS AND METHODS: This review summarises existing studies on short-stem hip arthroplasty in osteonecrosis of the femoral head. RESULTS: Few studies have analysed the clinical and radiological outcome of short-stem THA in patients with ONFH. Only a handful of studies present clinical and radiological outcome after implantation of a short-stem arthroplasty in patients with the underlying diagnosis of osteonecrosis of the femoral head. CONCLUSION: The short- to medium-term results show predominantly good outcomes. However, due to differences in the design of short stems and their fixation, it is hard to draw a general conclusion. Short stems with primary diaphyseal fixation do not reveal a high increased risk of failed osseointegration or loosening. For designs with a primary metaphyseal anchorage, an MRI should be conducted to exclude that the ostenecrosis exceeds the femoral neck. PMID- 25801809 TI - Prevention of excessive postoperative sliding of the short femoral nail in femoral trochanteric fractures. AB - INTRODUCTION: Lag screw cut-out is one of the major postoperative complications on femoral trochanteric fractures. However, precise analyses of excessive sliding and lag screw cut-out were limited. The purpose of this study was to investigate the factors that induce this unfavorable event. METHODS: From April 2010 to April 2013, 226 patients were operated in our institute using a short femoral nail. Among them, 177 patients (29 males and 148 females) with a mean age of 84 years (60-97 years), who were followed up >3 months, were included in this study. The postoperative sliding distance, fracture type (AO/OTA classification), tip-apex distance (TAD), reduction pattern in the postoperative X-ray (antero-posterior and lateral views), bone quality (canal flare and cortical indices), walking ability at the time of pre-injury and final follow-up, and complications were investigated retrospectively. RESULTS: The mean sliding distance was 3.7 mm, and one cut-out case (0.6 %) was observed. The sliding distance of the AO/OTA 31-A2 fractures was significantly longer than that of the A1 fractures (p < 0.0001). Regarding the reduction pattern, the sliding distance of the intramedullary type was longer than that of the extramedullary and anatomical types in the lateral view (p < 0.01, p < 0.001, respectively). Further, even in the medial and anatomical types, where the reduction patterns are recommended in the antero posterior view, the sliding distance of the intramedullary type was significantly longer than that of the anatomical type in the lateral view. There was no correlation of bone quality with the sliding distance. CONCLUSIONS: Because the sliding distance increased in the intramedullary type in the lateral view of unstable fractures, an accurate reduction in the lateral view at surgery is important, particularly in unstable fractures. PMID- 25801810 TI - No difference in clinical outcome, bone density and polyethylene wear 5-7 years after standard navigated vs. conventional cementfree total hip arthroplasty. AB - INTRODUCTION: The purpose of this investigation was to compare clinical outcome, component loosening, polyethylene cup wear and periprosthetic bone mineral density between "cup first" navigated and conventional cementless total hip arthroplasty (THA) 5-7 years after surgery. MATERIALS AND METHODS: Fifty patients who received THA with (n = 25) or without (n = 25) the use of an image-free navigation system by a single surgeon were investigated after a mean follow-up of 6.4 (4.8-7.4) years. The Hip Osteoarthritis Outcome Score (HOOS) and the Harris Hip Score (HHS) were obtained; range-of-motion (ROM) was evaluated by a blinded examiner. Radiographic cup inclination, signs of radiographic loosening and polyethylene wear were analysed with the help of digital analysis software on anterio-posterior radiographs by a blinded examiner. Acetabular and femoral periprosthetic bone density was evaluated with the help of dual-energy X-ray absorptiometry. RESULTS: We were unable to find any statistical significant or clinically relevant difference for the HOOS, HHS, ROM and polyethylene wear between the navigated and the conventional THA group 5-7 years after surgery. Cup inclination was more precise in the navigated THA group in relation to the target value of 45 degrees . CONCLUSIONS: Standard "cup first" THA navigation does not improve mid-term functional outcome, bony ingrowth and/or polyethylene wear. New concepts in computer-assisted THA, considering cup and stem as coupled biomechanical partners are needed to justify the effort of navigation in routine operations. PMID- 25801811 TI - Is the cortical thickness index a valid parameter to assess bone mineral density in geriatric patients with hip fractures? AB - INTRODUCTION: Reduced bone quality is a common problem during surgical fixation of geriatric hip fractures. The cortical thickness index (CTI) was proposed to assess the bone mineral density (BMD) of the proximal femur on the basis of plain X-rays. The purpose of this study was to evaluate the inter- and intraobserver reliability of the CTI and to investigate correlation between CTI and BMD in geriatric patients. METHODS: 60 patients (20 pertrochanteric fractures, 20 femoral neck fractures, 20 without fractures) were included. All patients had ap and lateral hip X-rays and measurement of BMD by Dual Energy X-ray Absorptiometry at different areas of the hip. The ap and lateral CTI was measured twice by four blinded observers and correlation between mean CTI and BMD was calculated. RESULTS: Mean ap CTI was 0.52 and mean lateral CTI was 0.45. Inter- and intraobserver reliability was good for ap CTI (ICC 0.71; 0.79) and lateral CTI (ICC 0.65; 0.69). A significant correlation between CTI and overall BMD was found in patients without fractures (r = 0.74; r = 0.67). No significant correlation between CTI and overall BMD was found in patients with proximal femoral fractures. CONCLUSION: The CTI has sufficient reliability for the use in daily practice. It showed significant correlation with BMD in patients without hip fractures. In patients with proximal femoral fractures, no correlation between CTI and BMD was found. We do not recommend the CTI as parameter to assess the BMD of the proximal femur in geriatric patients with hip fractures. PMID- 25801812 TI - Treatment of osteochondral lesions in the elbow: results after autologous osteochondral transplantation. AB - BACKGROUND: Osteochondral lesions in the elbow still remain a challenging field of surgery. In recent years promising clinical results were described for the osteochondral transplantation technique. The aim of this retrospective study was to evaluate the clinical and radiological outcome in the mid-term follow-up of a large cohort of patients following osteochondral transplantation in the elbow. METHODS: 18 patients with advanced osteochondral lesions of the elbow treated by autologous osteochondral autograft cylinders and a minimum follow-up of 36 months were included in the study. The Broberg-Morrey score (BMS) and the American Shoulder and Elbow score (ASES) were used to assess elbow function and pain, respectively. The joint status was analyzed using plain radiographs and MRI scans taken from all patients at recent follow-up. In addition, the ipsilateral knee joint was examined for donor-site morbidity using the Lysholm knee score. RESULTS: 14 patients were evaluated with a mean follow-up of 7 years (range 3-14 years). The mean BMS was 95.1 (range 72-100) points. The ASES score also showed promising results: pain at worst 1.5 (range 0-5) points, pain at rest 0.4 (range 0-5) points, pain lifting loads 2.8 (range 0-8) points, repetitive movement pain 1.5 (range 0-8) points. The range of motion of the injured elbow was free and equal to the contralateral side. Signs of osteoarthritis could be found on plain radiographs in three patients. The MRIs at follow-up showed graft viability in all patients. However, a slight incongruency of the chondral surface could be detected in two patients. The average Lysholm score was 90.9 (range 0-70) points. CONCLUSIONS: Osteochondral transplantation in the elbow leads to both clinical and radiographic good-to-excellent mid-term results and therefore represents a reasonable treatment option for advanced osteochondral lesions in the elbow. LEVEL OF EVIDENCE: Retrospective study; Therapeutic Level IV. PMID- 25801813 TI - Immunotherapy: Soluble ligands--a new approach to cancer therapy. PMID- 25801817 TI - Breast cancer: Shielding the ovaries from chemotherapy in breast cancer. PMID- 25801818 TI - Immunotherapy: Combined immunoradiotherapy reinvigorates antitumour immunity. PMID- 25801820 TI - FBXO4 loss facilitates carcinogen induced papilloma development in mice. AB - Cyclin D1 is frequently overexpressed in esophageal squamous cell carcinoma (ESCC) and is considered a key driver of this disease. Mutations in FBXO4, F-box specificity factor that directs SCF-mediated ubiquitylation of cyclin D1, occur in ESCC with concurrent overexpression of cyclin D1 suggesting a potential tumor suppressor role for FBXO4. To evaluate the contribution of FBXO4-dependent regulation cyclin D1 in esophageal squamous cell homeostasis, we exposed FBXO4 knockout mice to N-nitrosomethylbenzylamine (NMBA), an esophageal carcinogen. Our results revealed that loss of FBXO4 function facilitates NMBA induced papillomas in FBXO4 het (+/-) and null (-/-) mice both by numbers and sizes 11 months after single dose NMBA treatment at 2mg/kg by gavage when compared to that in wt (+/+) mice (P < 0.01). No significant difference was noted between heterozygous or nullizygous mice consistent with previous work. To assess cyclin D1/CDK4 dependence, mice were treated with the CDK4/6 specific inhibitor, PD0332991, for 4 weeks. PD0332991 treatment (150mg/kg daily), reduced tumor size and tumor number. Collectively, our data support a role for FBXO4 as a suppressor of esophageal tumorigenesis. PMID- 25801822 TI - Computational mechanistic elucidation of the intramolecular aminoalkene hydroamination catalysed by iminoanilide alkaline-earth compounds. AB - A comprehensive computational exploration of plausible alternative mechanistic pathways for the intramolecular hydroamination (HA) of aminoalkenes by a recently reported class of kinetically stabilised iminoanilide alkaline-earth silylamido compounds [{N^N}Ae{N(SiMe3)2}?(thf)n] ({N^N} = iminoanilide; Ae = Ca, Sr, Ba) is presented. On the one hand, a proton-assisted concerted N-C/C-H bond-forming pathway to afford the cycloamine in a single step can be invoked and on the other hand, a stepwise sigma-insertive pathway that involves a fast, reversible migratory olefin 1,2-insertion step linked to a less rapid, irreversible metal-C azacycle tether sigma-bond aminolysis. Notably, these alternative mechanistic avenues are equally consistent with reported key experimental features. The present study, which employs a thoroughly benchmarked and reliable DFT methodology, supports the prevailing mechanism to be a stepwise sigma-insertive pathway that sees an initial conversion of the {N^N}Ae silylamido into the catalytically competent {N^N}Ae amidoalkene compound and involves thereafter facile and reversible insertive N-C bond-forming ring closure, linked to irreversible intramolecular Ae-C tether sigma-bond aminolysis at the transient {N^N}Ae alkyl intermediate. Turnover-limiting protonolysis accounts for the substantial primary kinetic isotope effect observed; its DFT-derived barrier satisfactorily matches the empirically determined Eyring parameter and predicts the decrease in rate observed across the series Ca>Sr>Ba correctly. Non competitive kinetic demands militate against the operation of the concerted proton-assisted pathway, which describes N-C bond-forming ring closure triggered by concomitant amino proton delivery at the C=C linkage evolving through a multi centre TS structure. Valuable insights into the catalytic structure-activity relationships are unveiled by a detailed comparison of [{N^N}Ae(NHR)] catalysts. Moreover, the intriguingly opposite trends in reactivity observed in intramolecular (Ca>Sr>Ba) and intermolecular (Ca-8-10-6 M) concentration dependently reduced expression of pro-inflammatory and pro-angiogenic markers in Abeta (1 MUg/mL)-stimulated C6 cells. Moreover, culture medium from PEA-treated C6 cells reduced HUVEC cell proliferation as compared to cells treated with conditioned medium from Abeta-treated C6 cells. Immunocytochemical analysis revealed that PEA treatment inhibited nuclear levels of mitogen-activated protein kinase 1 (the main pro-angiogenic pathway) and cytoplasmic vascular endothelial growth factor in HUVEC cells receiving C6 conditioned medium. Finally, the peroxisome proliferator-activated receptor alpha inhibitor GW6471, added to Abeta treated C6 cells blocked all PEA effects in this model, suggesting that PEA acts through a proliferator-activated receptor alpha-dependent mechanism on astroglial cells. Collectively, these data support the potential therapeutic utility of PEA in AD. PMID- 25801846 TI - A Mo2C/Carbon Nanotube Composite Cathode for Lithium-Oxygen Batteries with High Energy Efficiency and Long Cycle Life. AB - Although lithium-oxygen batteries are attracting considerable attention because of the potential for an extremely high energy density, their practical use has been restricted owing to a low energy efficiency and poor cycle life compared to lithium-ion batteries. Here we present a nanostructured cathode based on molybdenum carbide nanoparticles (Mo2C) dispersed on carbon nanotubes, which dramatically increase the electrical efficiency up to 88% with a cycle life of more than 100 cycles. We found that the Mo2C nanoparticle catalysts contribute to the formation of well-dispersed lithium peroxide nanolayers (Li2O2) on the Mo2C/carbon nanotubes with a large contact area during the oxygen reduction reaction (ORR). This Li2O2 structure can be decomposed at low potential upon the oxygen evolution reaction (OER) by avoiding the energy loss associated with the decomposition of the typical Li2O2 discharge products. PMID- 25801845 TI - Social support decreases depressogenic effect of low-dose interferon alpha treatment in melanoma patients. AB - OBJECTIVE: The most frequent serious psychological side effect of immune therapies is depression. In the present study, we tested whether social support, as a positive environmental effect, is able to moderate depression or anxiety symptoms in melanoma patients during adjuvant low-dose interferon treatment. METHODS: Hundred and twenty-seven melanoma patients with negative psychiatric history were included in our longitudinal study and followed up for one year. Depression and anxiety symptoms were measured six times during treatment: at baseline, at 1st, 3rd, 6th, 9th and 12th month of the therapy. In addition, social support was investigated with the Social Dimension Scale. RESULTS: Depressive symptoms significantly increased during the 12-month follow-up period (p<0.001). However, social support significantly moderated the depressogenic effect of low-dose interferon treatment (p<0.001). Patients with better social support showed attenuated increase of depression. Anxiety showed no significant changes during the low-dose interferon treatment (p=0.230). Social support had no moderating effect on anxiety symptoms (p=0.745) during the follow up. DISCUSSION: Our data provide evidence that social support and interferon alpha treatment significantly interact in the development of depression. In addition, our study emphasises that enhancement of social support can reduce depressogenic side effects and increase compliance during adjuvant interferon treatment, and thus, psychological screening and psychooncological counselling should be incorporated in the treatment protocol. PMID- 25801847 TI - When a foreign adolescent orphan refuses to be treated: Considerations on a clinical case. AB - Providing medical treatment for unaccompanied foreign minors can prove particularly demanding when a patient is not fully compliant. This report describes the case of a 13-year-old boy from Sub-Saharan Africa brought to Italy to receive treatment for a neoplasm. Right from the start, he showed strong oppositional reactions, with aggressive and self-harming behavior. This made it necessary to activate various different psychological, psychiatric, and social support resources, and to adapt the proposed treatments to the patient's willingness and ability to cooperate. Here we outline the assessments and actions (also from the economic and organizational standpoint) that need to be implemented in any scheme to bring young foreign orphans to Italy for specialist medical care. PMID- 25801849 TI - Children and adolescents previously treated with glucocorticoids display lower verbal intellectual abilities. AB - AIM: Perinatal exposure to glucocorticoids has been associated with adverse cerebral effects, but little is known about their effect on cognitive development and exposure later in childhood. This study examined intellectual abilities, memory and behavioural problems in children previously treated with glucocorticoids. METHODS: We evaluated 38 children aged from seven to 16 years, who had been treated with glucocorticoids for rheumatic disease or nephrotic syndrome, together with 42 healthy controls matched for age, gender and parental education. The median cumulative dose of prednisolone equivalents was 158 mg/kg (range 21-723) and the mean time that had elapsed since treatment was three-and-a half (standard deviation 2.2) years. Intellectual abilities were assessed with the Wechsler Intelligence Scale for Children and memory performance and behavioural problems with a pattern recognition memory task and the Child Behaviour Check List. RESULTS: There were no significant differences between the groups in pattern recognition memory, perceptual organisation index or behavioural problems, but patients had a significantly lower verbal comprehension index and this difference was present in both disease groups. There were no significant dose-response relationships regarding verbal intellectual abilities. CONCLUSION: Children and adolescents previously treated with glucocorticoids seemed to have lower intellectual verbal abilities than healthy controls. PMID- 25801848 TI - Nanocomposite membranes based on polybenzimidazole and ZrO2 for high-temperature proton exchange membrane fuel cells. AB - Owing to the numerous benefits obtained when operating proton exchange membrane fuel cells at elevated temperature (>100 degrees C), the development of thermally stable proton exchange membranes that demonstrate conductivity under anhydrous conditions remains a significant goal for fuel cell technology. This paper presents composite membranes consisting of poly[2,2'-(m-phenylene)-5,5' bibenzimidazole] (PBI4N) impregnated with a ZrO2 nanofiller of varying content (ranging from 0 to 22 wt %). The structure-property relationships of the acid doped and undoped composite membranes have been studied using thermogravimetric analysis, differential scanning calorimetry, dynamic mechanical analysis, wide angle X-ray scattering, infrared spectroscopy, and broadband electrical spectroscopy. Results indicate that the level of nanofiller has a significant effect on the membrane properties. From 0 to 8 wt %, the acid uptake as well as the thermal and mechanical properties of the membrane increase. As the nanofiller level is increased from 8 to 22 wt % the opposite effect is observed. At 185 degrees C, the ionic conductivity of [PBI4N(ZrO2 )0.231 ](H3 PO4 )13 is found to be 1.04*10(-1) S cm(-1) . This renders membranes of this type promising candidates for use in high-temperature proton exchange membrane fuel cells. PMID- 25801850 TI - Novel management of postoperative pain using only oral analgesics after LADG. AB - PURPOSE: Managing postoperative pain is important to ensure a good quality of life and fast recovery after surgery. We examined the feasibility of peroral management for the postoperative pain after laparoscopic-assisted distal gastrectomy (LADG). METHODS: Between June 2012 and September 2013, we enrolled 34 patients prospectively to receive peroral tramadol/acetaminophen combination tablets, celecoxib and prochlorperazine maleate after LADG through postoperative day 3 (ORAL group). The postoperative pain was assessed using a visual analogue scale. Postoperative outcomes related to the analgesic methods were compared with those of patients who used epidural anesthesia between January 2010 and December 2011 (EPI group). RESULTS: The ORAL group pain scale scores on postoperative days 1-3 were 3.96, 3.06 and 2.40, respectively. The frequency of additional analgesic use in the ORAL group was significantly lower than in the EPI group (P = 0.006). The rate of urethral catheter reinsertion was 20.6 % in the EPI group (P = 0.054). A multivariate analysis revealed that only epidural anesthesia was a significant risk factor for the need for additional medication four times or more for breakthrough pain (P = 0.048). CONCLUSION: Postoperative pain management using oral analgesics after LADG is feasible and safe, and is an ideal pain treatment associated with few adverse events while providing pain relief not inferior to epidural anesthesia. PMID- 25801851 TI - Opportunistic use of a Foley catheter to provide a common electrocautery with a water-irrigating channel for hepatic parenchymal transection. AB - High-tech surgical energy devices that are used during a single surgery have increased in number and the expense for such disposable units is by no means negligible. We developed a handmade water-irrigating monopolar electrocautery using a Foley catheter to perform liver parenchymal transection. A commonly used 20-24 Fr Foley catheter was cut at a length of about 8 cm. The shaft of the 5 mm ball electrode measuring 13.5 cm in length was then inlaid into the urine drainage channel. The target tissues were cauterized without making an eschar, thereby preventing the adhesion of the electrode to the tissues. A ball electrode with our handmade water irrigation sheath can be made in only a few minutes at a very low cost, using common medical supplies and yielding satisfactory effects comparable to the use of specialized high-tech devices. PMID- 25801852 TI - Assessment of left ventricular function by three-dimensional speckle-tracking echocardiography in well-treated type 2 diabetes patients with or without hypertension. AB - PURPOSE: The aims of this study were to investigate the myocardial deformation in well-treated type 2 diabetes patients with or without hypertension using three dimensional speckle-tracking echocardiography and to explore variables that could affect myocardial deformation. METHODS: We studied 82 patients with type 2 diabetes and controlled blood glucose, including 46 subjects with diabetes alone and 36 subjects with diabetes and well-controlled hypertension, and 40 age- and gender-matched controls. Left ventricular real-time three-dimensional (3D) full volume images were recorded and analyzed using online software. The left ventricular ejection fraction, global longitudinal strain (GLS), global circumferential strain, global area strain, and global radial strain were measured and compared. RESULTS: Despite a similar three-dimensional left ventricular ejection fraction, GLS was significantly lower in patients with diabetes only than in controls (p < 0.001). Patients with diabetes and hypertension showed significantly lower systolic strains in all directions than controls and patients with diabetes only (p < 0.001 and p < 0.05, respectively). Multiple regression analysis revealed that fasting plasma glucose and left ventricular end-diastolic volume were significant factors influencing GLS in both diabetic groups. CONCLUSIONS: Early-stage diabetic patients showed an impaired left ventricular strain that was worsened by coexistent hypertension, although blood glucose and blood pressure were well controlled. Three-dimensional speckle tracking echocardiography was able to detect these subclinical changes. PMID- 25801853 TI - Variability of performance during a 60-min running race. AB - The aim of the present study was to examine the variability of 1-h running performance outside the laboratory, under conditions simulating those of a real competitive event. Twenty-three male recreational runners performed on 3 occasions a 60-min simulated running race attempting to cover as long distance as possible. The races took place in an indoor track, in order to ensure stable environmental conditions. There was no difference in the distance covered between races (12,546.3 +/- 217 m, 12,576 +/- 219.1 m, 12,638.7 +/- 225.3 m for the 1st, 2nd and 3rd races, respectively (mean +/- S(X), F(2, 44) = 1.168, P = 0.32). The coefficient of variation for all participants was 1.5 +/- 0.2 (range: 0.2-3.00). Multiple regression analysis indicated that 83% of the variability in best performance was predicted by determining the speed at the peak volume of oxygen uptake and body mass. In conclusion, performance during 1-h simulated running race in an indoor track was highly reproducible. The present study can be used as low-cost, time-efficient and ecologically valid tool, which could test simultaneously numerous runners' performance under conditions similar to real competitive events. PMID- 25801854 TI - The impact of an antireflux catheter on target volume particulate distribution in liver-directed embolotherapy: a pilot study. AB - PURPOSE: To determine if there are differences in hepatic distribution of embolic particles following infusion with a standard end-hole catheter versus an antireflux microcatheter. MATERIALS AND METHODS: This prospective study included nine patients (age, 48-86 y) enrolled for treatment of hepatocellular carcinoma (n = 6), liver-dominant metastatic disease (n = 2), or intrahepatic cholangiocarcinoma (n = 1) with resin yttrium-90 ((90)Y) microspheres. Before (90)Y treatment, each patient received two same-day sequential lobar infusions of technetium 99m ((99m)Tc) macroaggregated albumin (MAA) via a conventional end hole catheter and an antireflux microcatheter positioned at the same location. Differences in technetium 99m-MAA distribution within tumor and nontarget sites were evaluated by single-photon emission computed tomography (SPECT) on a qualitative and semiquantitative basis. The antireflux microcatheter was used for the ensuing (90)Y treatment, with posttreatment (90)Y positron emission tomography/computed tomography to assess distribution of (90)Y microspheres. RESULTS: Decreases in hepatic nontarget embolization were found in all patients when the antireflux catheter was used. These decreases ranged from a factor of 0.11 to a factor of 0.76 (mean, 0.42; sigma = 0.19), representing a 24%-89% reduction. Increased tumor deposition was also noted in all patients, ranging from a factor of 1.33 to a factor of 1.90 (mean, 1.68; sigma = 0.20), representing a relative increase of 33%-90%. Both findings were statistically significant (P < .05). CONCLUSIONS: Although this pilot study identified differences in the downstream distribution of embolic particles when the antireflux catheter was used, further investigation is needed to determine if these findings are reproducible in a larger patient cohort and, if so, whether they are associated with any clinical impact. PMID- 25801855 TI - Protein contact dermatitis caused by lime in a pastry chef. PMID- 25801856 TI - Exercise: the ultimate medicine. PMID- 25801857 TI - Response to the letter to the editor by Matthew Raider, "hospice in the nursing home: perspective of a medical director". PMID- 25801858 TI - Integrating palliative care in the nursing home: an interprofessional opportunity: response to the letter to the editor - Dr Matthew Raider. PMID- 25801859 TI - Association between Angiotensin-converting enzyme insertion/deletion polymorphisms and frailty among chinese older people. AB - OBJECTIVES: Frailty involves complex mechanisms of cumulative decline in several physiological systems and is associated with adverse events that are determined by genetic and environmental factors. It has been reported that angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms are associated with human performance. However, the relationships between ACE polymorphisms and frailty are poorly understood. Therefore, we used a Chinese community-dwelling cohort to examine these relationships. DESIGN AND SETTING: This study is a part of the Comprehensive Geriatric Assessment and Health Care Service Study, which is a cross-sectional study being conducted in Southwest China. PARTICIPANTS AND MEASUREMENTS: The participants were grouped into frail, pre-frail, and robust groups according to the revised Fried frailty criteria. Frailty scores were obtained based on the number of frailty items present and used to evaluate the levels of frailty. ACE I/D polymorphisms were detected by polymerase chain reaction using specific primer. RESULTS: After the exclusion of participants with missing data, we included 604 community-dwelling Han people (57.9% women, mean age = 70.6 +/- 6.8 years). The frequencies of the I/I, I/D, and D/D genotypes were 45.0%, 45.0%, and 10.0%, respectively. The I/D + D/D genotype (D carriers) exhibited higher frailty scores than did the homozygous I/I group (t = -2.07, P = .039). A greater proportion of the D carriers were classified as frail compared with the homozygous I/I group, but this difference was not statistically significant (15.1% vs 9.9%; chi(2) = -4.57, P = .102). The I/I genotype was associated with a lower frailty score and was significantly associated with reduced risk of prevalent frailty compared with the D-carrying genotypes (adjusted odds ratio 0.689, 95% confidence interval 0.493-0.965; P = .030). CONCLUSIONS: The I/I ACE genotype is associated with a lower risk of frailty and a lower frailty level relative to the D-carrying genotypes among older Han people. PMID- 25801861 TI - Femtosecond mid-infrared study of the dynamics of water molecules in water acetone and water-dimethyl sulfoxide mixtures. AB - We study the vibrational relaxation dynamics and the reorientation dynamics of HDO molecules in binary water-dimethyl sulfoxide (DMSO) and water-acetone mixtures with polarization-resolved femtosecond mid-infrared spectroscopy. For low solute concentrations we observe a slowing down of the reorientation of part of the water molecules that hydrate the hydrophobic methyl groups of DMSO and acetone. For water-DMSO mixtures the fraction of slowed-down water molecules rises much steeper with solute concentration than for water-acetone mixtures, showing that acetone molecules show significant aggregation already at low concentrations. At high solute concentrations, the vibrational and reorientation dynamics of both water-DMSO and water-acetone mixtures show a clear distinction between the dynamics of water molecules donating hydrogen bonds to other water molecules and the dynamics of water donating a hydrogen bond to the S?O/C?O group of the solute. For water-DMSO mixtures both types of water molecules show a very slow reorientation. The water molecules forming hydrogen bonds to the S?O group reorient with a time constant that decreases from 46 +/- 14 ps at XDMSO = 0.33 to 13 +/- 2 ps at XDMSO = 0.95. The water molecules forming hydrogen bonds to the C?O group of acetone show a much faster reorientation with a time constant that decreases from 6.1 +/- 0.2 ps at Xacet = 0.3 to 2.96 +/- 0.05 ps at Xacet = 0.9. The large difference in reorientation time constant of the solute-bound water for DMSO and acetone can be explained from the fact that the hydrogen bond between water and the S?O group of DMSO is much stronger than the hydrogen bond between water and the C?O group of acetone. We attribute the strongly different behavior of water in DMSO-rich and acetone-rich mixtures to their difference in molecular shape. PMID- 25801862 TI - The AJT Report. PMID- 25801860 TI - Solution structures of the DNA-binding domains of immune-related zinc-finger protein ZFAT. AB - ZFAT is a transcriptional regulator, containing eighteen C2H2-type zinc-fingers and one AT-hook, involved in autoimmune thyroid disease, apoptosis, and immune related cell survival. We determined the solution structures of the thirteen individual ZFAT zinc-fingers (ZF) and the tandemly arrayed zinc-fingers in the regions from ZF2 to ZF5, by NMR spectroscopy. ZFAT has eight uncommon bulged-out helix-containing zinc-fingers, and six of their structures (ZF4, ZF5, ZF6, ZF10, ZF11, and ZF13) were determined. The distribution patterns of the putative DNA binding surface residues are different among the ZFAT zinc-fingers, suggesting the distinct DNA sequence preferences of the N-terminal and C-terminal zinc fingers. Since ZFAT has three to five consecutive tandem zinc-fingers, which may cooperatively function as a unit, we also determined two tandemly arrayed zinc finger structures, between ZF2 to ZF4 and ZF3 to ZF5. Our NMR spectroscopic analysis detected the interaction between ZF4 and ZF5, which are connected by an uncommon linker sequence, KKIK. The ZF4-ZF5 linker restrained the relative structural space between the two zinc-fingers in solution, unlike the other linker regions with determined structures, suggesting the involvement of the ZF4 ZF5 interfinger linker in the regulation of ZFAT function. PMID- 25801866 TI - A rare anomaly in the donor vena cava. PMID- 25801867 TI - Laparoscopic sleeve gastrectomy as a weight reduction strategy in obese patients after kidney transplantation. PMID- 25801868 TI - Response to "laparoscopic sleeve gastrectomy as a weight reduction strategy in obese patients after kidney transplantation". PMID- 25801870 TI - Acetaminophen use and risk of myocardial infarction and stroke in a hypertensive cohort. AB - Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and that acetaminophen causes a modest blood pressure rise. There are no randomized trials or studies using verified prescription data of this relationship. We aimed to assess the relationship between verified acetaminophen prescription data and risk of myocardial infarction or stroke in patients with hypertension. We performed a retrospective data analysis using information contained within the UK Clinical Research Practice Datalink. Multivariable Cox proportional hazard models were used to estimate hazard ratios for myocardial infarction (primary end point), stroke, and any cardiovascular event (secondary end points) associated with acetaminophen use during a 10-year period. Acetaminophen exposure was a time-dependent variable. A propensity-matched design was also used to reduce potential for confounding. We included 24,496 hypertensive individuals aged >= 65 years. Of these, 10,878 were acetaminophen-exposed and 13,618 were not. There was no relationship between risk of myocardial infarction, stroke, or any cardiovascular event and acetaminophen exposure on adjusted analysis (hazard ratio, 0.98; 95% confidence interval, 0.76 1.27; hazard ratio, 1.09; 95% confidence interval, 0.86-1.38; and hazard ratio, 1.17; 95% confidence interval, 0.99-1.37; respectively). Results in the propensity-matched sample (n=4000 per group) and when men and women were analyzed separately were similar. High-frequency users (defined as receiving a prescription for >75% of months) were also not at increased risk. After allowance for potentially confounding variables, the use of acetaminophen was not associated with an increased risk of myocardial infarction or stroke in a large cohort of hypertensive patients. PMID- 25801872 TI - Magnitude of blood pressure reduction and clinical outcomes in acute intracerebral hemorrhage: intensive blood pressure reduction in acute cerebral hemorrhage trial study. AB - Evidence supports early intensive blood pressure (BP) lowering in acute intracerebral hemorrhage, but uncertainty persists over whether potential benefits and harms vary according to the magnitude of BP reduction. We aimed to determine whether larger systolic BP (SBP) reductions were associated with better outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). INTERACT2 was an international, open, blinded end point, randomized controlled trial of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated SBP (150-220 mm Hg) assigned to intensive (target SBP <140 mm Hg) or guideline-recommended (SBP <180 mm Hg) treatment. Associations of BP reduction (baseline minus average of achieved SBP) during 3 time periods post randomization (15-60 minutes, 1-24 hours, and 2-7 days) on poor outcome (death or major disability) at 90 days were analyzed in multivariable logistic regression models with odds ratios and 95% confidence intervals. Larger SBP reductions within the first hour after randomization were associated with lower risks of poor outcome: compared with minimal reduction (<10 mm Hg), odds ratios were 0.80 (95% confidence interval, 0.63-1.02) for moderate (10-20 mm Hg) and 0.65 (0.52-0.82) for large (>=20 mm Hg) reductions (P trend <0.01). Similar associations were also observed for SBP reductions during 1 to 24 hours (P<0.01) and 2 to 7 days (P 0.02). No heterogeneity in associations for patients above or below baseline SBP 180 mm Hg was reported (P>0.30). Optimal recovery from intracerebral hemorrhage was observed in hypertensive patients who achieved the greatest SBP reductions (>=20 mm Hg) in the first hour and maintained for 7 days. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079. PMID- 25801871 TI - Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial. AB - Vitamin D deficiency is a risk factor for arterial hypertension, but randomized controlled trials showed mixed effects of vitamin D supplementation on blood pressure (BP). We aimed to evaluate whether vitamin D supplementation affects 24 hour systolic ambulatory BP monitoring values and cardiovascular risk factors. The Styrian Vitamin D Hypertension Trial is a single-center, double-blind, placebo-controlled study conducted from June 2011 to August 2014 at the endocrine outpatient clinic of the Medical University of Graz, Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxyvitamin D levels below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for 8 weeks. Primary outcome measure was 24-hour systolic BP. Secondary outcome measures were 24-hour diastolic BP, N-terminal-pro-B-type natriuretic peptide, QTc interval, renin, aldosterone, 24-hour urinary albumin excretion, homeostasis model assessment insulin resistance, triglycerides, high-density lipoprotein cholesterol, and pulse wave velocity. A total of 188 participants (mean [SD] age, 60.1 [11.3] years; 47% women; 25-hydroxyvitamin D, 21.2 [5.6] ng/mL) completed the trial. The mean treatment effect (95% confidence interval) for 24-hour systolic BP was -0.4 (-2.8 to 1.9) mm Hg (P=0.712). Triglycerides increased significantly (mean change [95% confidence interval], 17 [1-33] mg/dL; P=0.013), but no further significant effects were observed for secondary outcomes. Vitamin D supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on BP and several cardiovascular risk factors, but it was associated with a significant increase in triglycerides. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02136771. PMID- 25801874 TI - Should acetaminophen be added to the list of anti-inflammatory agents that are associated with cardiovascular events? PMID- 25801875 TI - Pediatric interventions using noninvasive vascular health indices. PMID- 25801873 TI - Plasma aldosterone and left ventricular diastolic function in treatment-naive patients with hypertension: tissue-Doppler imaging study. AB - Aldosterone has hypertrophic and profibrotic effects on the heart. The relationship between plasma aldosterone levels and left ventricular diastolic function in hypertension, however, is unclear. The aim of this study was to examine this relationship in treatment-naive hypertensive patients free of comorbidities that could affect left ventricular diastolic filling properties. In 115 patients with primary hypertension who were eating a standard diet and 100 matched normotensive controls, we measured plasma aldosterone and active renin levels and performed both conventional echocardiography and tissue-Doppler imaging for assessment of left ventricular diastolic function. Left ventricular hypertrophy was found in 21% of hypertensive patients, and diastolic dysfunction was detected in 20% by conventional echocardiography and in 58% by tissue-Doppler imaging. Patients with left ventricular diastolic dysfunction at tissue-Doppler imaging were older and more frequently men, had greater body mass index, blood pressure, alcohol intake, left ventricular mass index, relative wall thickness, and lower plasma aldosterone levels than patients with preserved diastolic function. Plasma aldosterone correlated directly with left ventricular mass index in addition to age, body mass index, and systolic blood pressure. Plasma aldosterone was also directly related to e' velocity at tissue-Doppler imaging, but this relationship was lost after multivariate adjustment. In conclusion, plasma aldosterone levels are associated with left ventricular hypertrophy but have no independent relationship with left ventricular diastolic properties in hypertensive patients. PMID- 25801877 TI - Increasing trend in admissions for malignant hypertension and hypertensive encephalopathy in the United States. AB - Malignant hypertension and hypertensive encephalopathy are life-threating manifestations of hypertension. These syndromes primarily occur in patients with a history of poorly controlled hypertension. The purpose of this study was to investigate national trends in hospital admissions for malignant hypertension, hypertensive encephalopathy, and essential hypertension. This was a retrospective cohort study that used the Nationwide Inpatient Sample. We identified all hospitalizations between 2000 and 2011, during which a primary diagnosis of malignant hypertension (ICD 9 code: 401.0), hypertensive encephalopathy (ICD 9 code: 437.2), or essential hypertension (ICD 9 code: 401.9) was recorded. Time series models were estimated for malignant hypertension, hypertensive encephalopathy, essential hypertension and also for the combined series. A piecewise linear regression analyses was performed to investigate whether there were changes in the trends of these series. In addition, we also compared the characteristics of patients with these diagnoses. The estimated number of admissions for both malignant hypertension and hypertensive encephalopathy increased dramatically after 2007, whereas discharges for essential hypertension fell, and there was no change in trend for the combined series. Costs rose substantially for patients with these diagnoses after 2007, but mortality significantly fell for malignant hypertension and mortality for hypertensive encephalopathy did not change. The dramatic increase in the number of hospital admissions for hypertensive encephalopathy and malignant hypertension should have resulted in dramatic increases in morbidity, but it did not. The change is most likely related to changes in coding related to diagnostic-related groups that occurred in 2007. PMID- 25801876 TI - MiR-217 mediates the protective effects of the dopamine D2 receptor on fibrosis in human renal proximal tubule cells. AB - Lack or downregulation of the dopamine D2 receptor (D2R) increases the vulnerability to renal inflammation independent of blood pressure in mice. Common single nucleotide polymorphisms (SNPs) rs6276, 6277, and 1800497 in the human D2R gene are associated with decreased receptor expression/function and hypertension. Human renal proximal tubule cells from subjects carrying these SNPs have decreased D2R expression and increased expression of profibrotic factors and production of extracellular matrix proteins. We tested the hypothesis that the D2R mediates these effects by regulating micro-RNA expression. In cells carrying D2R SNPs, micro-RNAs (miRs)-217, miR-224, miR-335, and miR-1265 were downregulated, whereas miR-1290 was upregulated >4-fold compared with those carrying D2R wild-type alleles. However, only miR-217 was directly regulated by D2R expression. In cells carrying D2R wild-type, miR-217 inhibitor increased the expression of transforming growth factor (TGF)-beta1, matrix metalloproteinase 3, fibronectin 1, and collagen 1a, whereas miR-217 mimic had the opposite effect. In cells carrying D2R SNPs, miR-217 mimic also decreased the expression of TGFbeta1 and its targets. Wnt5a, a miR-217 target, was increased in cells carrying D2R SNPs and decreased by miR-217 mimic but increased by miR-217 inhibitor in both cell types. In cells carrying D2R wild-type, Wnt5a treatment increased TGFbeta1 while silencing Ror2, a Wnt5a receptor, decreased TGFbeta1 and blunted the Wnt5a induced increase in cells carrying D2R wild-type. Our results show that renal proximal tubule cells from subjects carrying D2R SNPs resulting in D2R downregulation have increased TGFbeta1 that is mediated by decreased regulation of the miR-217-Wnt5a-Ror2 pathway. PMID- 25801879 TI - Infectomics and autoinfectomics: a tool to study infectious-induced autoimmunity. AB - The exposome represents all exogenous and endogenous environmental exposures that begin at preconception and carry on throughout life, while the microbiome reflects the microbial component of the exposome. We recently introduced the concept of infectome and autoinfectome as a means of studying the totality of infections throughout life that participate in the induction as well as the progression of autoimmune diseases in an affected individual. The investigation of the autoinfectome could help us understand why some patients develop more than one autoimmune disease, a phenomenon also known as mosaic of autoimmunity. It could also explain the infectious and autoantibody burden of various autoimmune rheumatic diseases. The close interplay between infections and the immune system should be studied over time, long before the onset of autoaggression and autoimmunity. Tracking down each individual's exposure to infectious agents (as defined by the autoinfectome) would be important for the establishment of a causative link between infection and autoimmunity. PMID- 25801880 TI - Mycobacteria and autoimmunity. AB - Mycobacterial infections can cause a variety of different manifestations. The increasing incidence of these infections worldwide brought another medical dilemma: immunological manifestations characterized by the presence of many autoantibodies and concomitant presence of autoimmune diseases. The burden of tuberculosis reactivation that emerged with immunosuppressive therapy worsened with the growing use of biological disease-modifying antirheumatic drugs (DMARDs). This review will address the relationship between the immune system and mycobacteria. PMID- 25801881 TI - 17-beta-estradiol affects BLyS serum levels and the nephritogenic autoantibody network accelerating glomerulonephritis in NZB/WF1 mice. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects fertile women, suggesting sex hormones are involved in disease pathogenesis. B lymphocyte stimulator (BLyS) has been found to be elevated in SLE patients and to drive a lupus-like syndrome in transgenic mice. Our aim was to evaluate the effects of estrogen administration on BLyS and nephritogenic anti C1q and anti-dsDNA antibodies in lupus-prone NZB/WF1 mice. We implanted pellets releasing 17-beta-estradiol (18.8 ug/day) on the back side the ear of 10 NZB/WF1 mice (group 1), and compared them with 10 mice intraperitoneally injected with PBS 200 MUl twice a week (group 2), as controls. We evaluated BLyS, anti-dsDNA and anti-C1q serum levels starting one week after pellet implantation. We also analyzed time to proteinuria onset, proteinuria-free survival and overall survival. Kidneys, spleen, liver and lungs were harvested for histological analysis. Mice were bred until natural death. BLyS serum levels were higher in group 1 than in group 2 mice at each evaluation. Group 1 mice developed nephritogenic antibodies and proteinuria significantly earlier and at higher levels than controls. Direct correlation between BLyS and anti-C1q (R (2 )= 0.6962, p < 0.0001) or anti-dsDNA (R (2 )= 0.5953, p < 0.0001), and between anti C1q and anti-dsDNA autoantibodies (R (2 )= 0.5615, p < 0.0001) were found. Proteinuria-free and global survival rates were significantly lower in group 1 than in controls. Histological analyses showed more severe abnormalities in group 1 mice. Estrogen administration is associated with increased levels of BLyS as well as of anti-C1q and anti-dsDNA antibodies, leading to accelerated glomerulonephritis and disease progression in NZB/WF1 mice. PMID- 25801878 TI - T cells as a therapeutic target in SLE. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion, and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell-targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE. PMID- 25801882 TI - Environmental estrogen bisphenol A and autoimmunity. AB - Over the past few years, there has been evidence of the increasing prevalence of autoimmune diseases. Autoimmune diseases consist of many complex disorders of unknown etiology resulting in immune responses to self-antigens. The immune system, and its function, is under complex and integrated control and its disruption can be triggered by multiple factors. Autoimmunity development is influenced by multiple factors and is thought to be a result of interactions between genetic and environmental factors. Here, we review the role of a specific environmental factor, bisphenol A (BPA), in the pathogenesis of autoimmune diseases. BPA belongs to the group of environmental estrogens that have been identified as risk factors involved in the development of autoimmune diseases. PMID- 25801883 TI - From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis. AB - Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and gammadeltaT cell dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action. PMID- 25801884 TI - Resetting the autoreactive immune system with a therapeutic peptide in lupus. AB - Over the last decade there has been a rapid expansion in the use of peptides as drugs. Nowadays, they are being used therapeutically in such diverse areas as endocrinology, neurology, haematology and some types of allergies. In the field of autoimmunity, a few candidates have emerged. Thus, in the pipeline of novel strategies designed to treat patients with systemic lupus erythematosus, the 21 mer peptide P140/Lupuzor raises hopes for the generation of an efficient, specific and safe treatment. This phosphopeptide has successfully completed a phase IIb clinical trial and will enter into a multi-centre, double-blind, placebo-controlled phase III clinical trial. The phase IIb trial showed that after three months of therapy (three subcutaneous injections of 200 ug peptide/patient in addition to standard of care), Lupuzor improved Systemic Lupus Erythematosus Disease Activity Index score of lupus patients under active treatment by 67.6% versus 41.5% in the placebo group (p < 0.025). After three additional months of follow-up, the improvement rate was 84.2% versus 45.8% (p < 0.025). The side-effect profile was unproblematic and the drug was well tolerated as evidenced by a very low drop-out rate. P140 does not behave as an immunosuppressant, it acts primarily as a fine immunomodulator of autoreactive CD4(+) T cells. Its underlying mechanism of action involves autophagy, a cellular process that implicates lysosomal-dependent recycling of intracellular components and controls the pool of major histocompatibility complex class II-displayed peptides that is presented to CD4(+) T cells. PMID- 25801885 TI - Infections and autoimmunity: role of human cytomegalovirus in autoimmune endothelial cell damage. AB - Molecular mimicry between infectious agents and normal human host cell proteins represents one of the possible mechanisms responsible for autoimmunity. Among infectious agents, human cytomegalovirus (HCMV) is an ideal candidate for involvement in autoimmune disorders because of its lifelong persistence through periods of reactivation and latency and because of the extensive manipulation of innate and adaptive immunity. HCMV has been implicated in the pathogenesis of vascular damage in systemic sclerosis (SSc) and atherosclerosis. Based on our data, which demonstrate a cause-and-effect relationship between HCMV and endothelial cell aggression in SSc and atherosclerosis, we propose that immune responses to particular HCMV proteins may result in autoaggression through a mechanism of molecular mimicry of normally expressed endothelial cell surface molecules. PMID- 25801886 TI - Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses. AB - Anti-citrullinated protein antibodies (ACPA) are a family of rheumatoid arthritis (RA)-specific autoantibodies that recognize the amino acid citrulline, resulting from the post-translational modification of arginine. Peptidyl arginine deiminase, the enzyme responsible for citrullination, is present in humans in different isoforms with different tissue distribution, enzymatic activity and target specificity; nonetheless, the number of proteins citrullinated in physiological or pathological conditions is wide, but not every citrullinated protein is a target for antibodies. In pre-RA patients the immune response to citrullinated antigens is initially restricted, expands with time and, after the onset of the disease, is relatively stable. ACPA are heterogeneous in terms of not only fine specificity but also isotype and IgG subclasses usage. This heterogeneity may be relevant for the immunopathogenesis of RA, conditioning the interaction of antibodies with complement and Fc receptors. PMID- 25801887 TI - Gamma-delta T lymphocytes and 25-hydroxy vitamin D levels as key factors in autoimmunity and inflammation: the case of zoledronic acid-induced acute phase reaction. AB - Zoledronic acid (ZA) infusion for osteoporosis is frequently associated with the onset of an acute phase reaction (APR) secondary to the activation of gammadelta T cell receptor (TCR) lymphocytes (gammadelta T cells) and to low vitamin D levels, similar to what is observed in chronic inflammation and autoimmunity. In this study we investigated whether the phenotype of gammadelta T cells is associated with APR and 25-OH vitamin D (25-OHvD) levels. For flow-cytometry analysis, peripheral blood samples were obtained from 52 osteoporotic women prior to 5 mg ZA intravenous infusion and from nine women (five with APR) one week later. Twenty-six/52 (50%) patients reported APR and APR+ cases had a higher percentage of central memory Th1-like gammadelta T cells. One week after ZA infusion, APR was associated with a decreased percentage of central memory Th1 like gammadelta T cells, an increase in the percentage and activation of effector memory Th1-like gammadelta T cells, and an increase in Th17-like gammadelta T cells. Lower 25-OHvD levels were significantly associated with APR, but no correlation was found between 25-OHvD level and gammadelta T cell percentage or subsets. In conclusion, patients experiencing APR related to ZA infusion have lower 25-OHvD levels and we suggest that the higher percentage of central memory Th1-like gammadelta T cells and the expansion of effector memory Th1-like and Th17-like gammadelta T cells are associated with the occurrence of APR. PMID- 25801888 TI - Oxidatively altered IgG with increased immunoreactivity to beta2-glycoprotein I and its peptide clusters influence human coronary artery endothelial cells. AB - Oxidative stress has been shown to play a role in modifying antibodies in favor of higher auto-immunoreactivity. We studied the immunoreactivity of oxidized IgG (oxIgG) to beta2-glycoprotein I (beta2GPI), six peptide sequences corresponding to amino acid clusters on its different domains, to determine their effects on human coronary artery endothelial cells (HCAEC). Human IgG was purified from seven donors, electro-oxidized and checked for immunoreactivity and avidity to beta2GPI and to peptides by ELISA. Conformational stability and antibody-antigen complex formation of oxIgG was analyzed by fluorescence spectroscopy and dynamic light scattering. Resting and activated sub-confluent HCAEC were stimulated with oxIgG or IgG. Secreted cytokines were measured by ELISA. Immunoreactivity of seven oxIgG samples increased to 7.5-fold against beta2GPI and to 3.8-fold against six peptides as compared to IgG. oxIgG showed low avidity "properties." Conformational changes and exposure of protein hydrophobic regions were confirmed by an elevation in fluorescence (2.4- to 5.0-fold) on bis-ANS dye binding to oxIgG. oxIgG significantly elevated the release of GROalpha and IL-8 in resting and activated states of HCAEC. Oxidation alters IgG in favor of autoreactivity toward whole beta2GPI and corresponding peptides on different domains of beta2GPI and could lead to dysfunction of arterial endothelium by upregulation of chemokines. PMID- 25801889 TI - Severe ASIA syndrome associated with lymph node, thoracic, and pulmonary silicone infiltration following breast implant rupture: experience with four cases. AB - Silicone has been considered biologically inert; thus it has been employed in many medical devices and nowadays is commonly used in plastic surgery for mammary prosthesis. It is well tolerated in most cases. However, autoimmune disorders and siliconomas with granulomatous reactions after silicone implant rupture have been described. We report cases of four women who developed systemic disorders following rupture of silicone breast implants resulting in lymph node and thoracic silicone infiltration. The symptoms in these cases, including arthralgia, myalgia, generalized weakness, severe fatigue, sleeping disturbances, cognitive impairment, memory loss, irritable bowel syndrome, and weight loss, clearly match the criteria of the recently defined autoimmune/inflammatory syndrome induced by adjuvants (ASIA). PMID- 25801890 TI - Extrahepatic manifestations in chronic hepatitis C virus carriers. AB - Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild. PMID- 25801891 TI - A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic regimens in patients with musculoskeletal pain. AB - BACKGROUND: The current mode of therapy for many patients with musculoskeletal pain is unsatisfactory. PURPOSE: We aimed to assess the impact of adding 4000 IU of vitamin D on pain and serological parameters in patients with musculoskeletal pain. MATERIALS AND METHODS: This was a randomized, double-blinded and placebo controlled study assessing the effect of 4000 IU of orally given vitamin D3 (cholecalciferol) (four gel capsules of 1000 IU, (SupHerb, Israel) vs. placebo on different parameters of pain. Eighty patients were enrolled and therapy was given for 3 months. Parameters were scored at three time points: prior to intervention, at week 6 and week 12. Visual analogue scale (VAS) scores of pain perception were recorded following 6 and 12 weeks. We also measured serum levels of leukotriene B4 (LTB4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha) and prostaglandin E2 (PGE2) by ELISA. RESULTS: The group receiving vitamin D achieved a statistically significant larger decline of their VAS measurement throughout the study compared with the placebo group. The need for analgesic 'rescue therapy' was significantly lower among the vitamin D-treated group. TNFalpha levels decreased by 54.3% in the group treated with vitamin D and increased by 16.1% in the placebo group. PGE2 decreased by39.2% in the group treated with vitamin D and increased by 16% in the placebo group. LTB4 levels decreased in both groups by 24% (p < 0.05). CONCLUSION: Adding 4000 IU of vitamin D for patients with musculoskeletal pain may lead to a faster decline of consecutive VAS scores and to a decrease in the levels of inflammatory and pain-related cytokines. PMID- 25801892 TI - Phenotype modifications of T-cells and their shift toward a Th2 response in patients with systemic lupus erythematosus supplemented with different monthly regimens of vitamin D. AB - BACKGROUND: Vitamin D receptor is constitutively expressed on the lymphocyte surface. Recent studies highlight that vitamin D may exert actions on T-cells, inhibiting Th1 and Th17 response and enhancing Th2 and T-regulatory (T-reg) function. METHODS: Thirty-four patients with systemic lupus erythematosus (SLE) were randomly enrolled in a two-year prospective study. In the first year, 16 patients were supplemented with an intensive regimen of cholecalciferol (IR) (300.000 UI of cholecalciferol at baseline and 50.000 UI/monthly as maintenance, 850.000 UI annually), whereas 18 with a standard regimen (SR) (25.000 UI of cholecalciferol monthly, 300.000 UI annually). During the second year, patients were switched to the other arm of treatment. Phenotypic analysis of peripheral T lymphocyte and the quantification of cytokine production from peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry. RESULTS: At baseline, no significant difference between the two groups emerged among main T-cell subtypes. Over two years of treatment, we saw an increase in the number of T-reg cells, in the total amount of CD4+CD45RA+CCR7- T-cells, whereas a significant reduction of CD8+CD28- T-cells was observed. In addition, the analysis of PBMCs from eight patients following the IR showed the reduction of the IFN-gamma/IL-4 ratio (p = 0.01) among CD8+ T-cells after 12 months. CONCLUSIONS: After a long term of monthly treatment with vitamin D in SLE patients, an enhancement of T-reg cells and the production of Th2 cytokines should be expected. PMID- 25801893 TI - A 24-month prospective study on the efficacy and safety of two different monthly regimens of vitamin D supplementation in pre-menopausal women with systemic lupus erythematosus. AB - BACKGROUND: Low vitamin D (vit.D) serum levels are common in patients with systemic lupus erythematosus (SLE) and seem to correlate with higher disease activity. We investigated the effects of different regimens of vit.D supplementation in SLE patients with inactive disease. METHODS: This 24-month prospective study included 34 SLE women who were randomized to receive, together with their ongoing treatment, a standard regimen (SR) of cholecalcipherol (25,000 UI monthly) or an intensive regimen (IR) (300,000 UI initial bolus followed by 50,000 UI monthly) for one year and then were switched to the other regimen in the second year. Patients were seen quarterly for assessment of 25-OH vit.D levels, disease activity, SLE serology and bone metabolism markers. RESULTS: By intra-patient comparison, only the IR was found able to significantly raise vit.D serum levels. After 12 months, values above 30 ng/ml were found in 75% of patients in IR while in only 28% in SR. No significant differences in disease activity and SLE serology were found at any time point between SR and IR. No changes in the mineral metabolism were observed. CONCLUSIONS: The IR was safe and effective in obtaining sufficient levels of vit.D in most SLE patients. However, both regimens of supplementation did not differently affect disease activity nor SLE serology. PMID- 25801894 TI - Value and goals of treat-to-target in systemic lupus erythematosus: knowledge and foresight. AB - Treat-to-target is a therapeutic strategy aimed at improving disease outcome through the achievement of shared treatment goals, which has dramatically ameliorated the prognosis of widespread disorders, such as hypertension or diabetes. Conversely, efforts to delineate treat-to-target in systemic lupus erythematosus (SLE) have failed in pinpointing common goals and treatment strategies, probably because of disease heterogeneity and lack of measurable biomarkers predicting disease course and ensuring a safe treatment tapering during quiescence. Given the detrimental effects of persistent disease activity and protracted corticosteroid therapy on patients' outcome in lupus, disease remission should be pursued whenever possible. Fortunately, clinical remission is currently realistic for a greater number of patients than it was in the past, yet tight monitoring is required in order for patients to benefit from disease- and corticosteroid-free intervals, while minimizing the risk of disease flares. In everyday practice, patients should be brought to the lowest level of disease activity ensuring a significant benefit over a persistently active disease, being either clinical remission or low disease activity. PMID- 25801895 TI - EUROPattern Suite technology for computer-aided immunofluorescence microscopy in autoantibody diagnostics. AB - Antinuclear autoantibodies (ANA) are highly informative biomarkers in autoimmune diagnostics. The increasing demand for effective test systems, however, has led to the development of a confusingly large variety of different platforms. One of them, the indirect immunofluorescence (IIF), is regarded as the common gold standard for ANA screening, as described in a position statement by the American College of Rheumatology in 2009. Technological solutions have been developed aimed at standardization and automation of IIF to overcome methodological limitations and subjective bias in IIF interpretation. In this review, we present the EUROPattern Suite, a system for computer-aided immunofluorescence microscopy (CAIFM) including automated acquisition of digital images and evaluation of IIF results. The system was originally designed for ANA diagnostics on human epithelial cells, but its applications have been extended with the latest system update version 1.5 to the analysis of antineutrophil cytoplasmic antibodies (ANCA) and anti-dsDNA antibodies. PMID- 25801897 TI - TGFbeta Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization. AB - RATIONALE: The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring endothelial cells (ECs) is still unknown. OBJECTIVE: To determine whether SMCs control EC functions through passage of miR-143 and miR 145. METHODS AND RESULTS: We used cocultures of SMCs and ECs under different conditions, as well as intact vessels to assess the transfer of miR-143 and miR 145 from one cell type to another. Imaging of cocultured cells transduced with fluorescent miRNAs suggested that miRNA transfer involves membrane protrusions known as tunneling nanotubes. Furthermore, we show that miRNA passage is modulated by the transforming growth factor (TGF) beta pathway because both a specific transforming growth factor-beta (TGFbeta) inhibitor (SB431542) and an shRNA against TGFbetaRII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and miR-145 modulated angiogenesis by reducing the proliferation index of ECs and their capacity to form vessel-like structures when cultured on matrigel. We also identified hexokinase II (HKII) and integrin beta 8 (ITGbeta8)-2 genes essential for the angiogenic potential of ECs-as targets of miR-143 and miR-145, respectively. The inhibition of these genes modulated EC phenotype, similarly to miR-143 and miR-145 overexpression in ECs. These findings were confirmed by ex vivo and in vivo approaches, in which it was shown that TGFbeta and vessel stress, respectively, triggered miR-143/145 transfer from SMCs to ECs. CONCLUSIONS: Our results demonstrate that miR-143 and miR-145 act as communication molecules between SMCs and ECs to modulate the angiogenic and vessel stabilization properties of ECs. PMID- 25801896 TI - Haptoglobin enhances cardiac transplant rejection. AB - RATIONALE: Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. OBJECTIVE: To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. METHODS AND RESULTS: We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and <=72 hours after transplantation revealed that 22 proteins including haptoglobin, a known antioxidant, are significantly upregulated in our grafts. Through the use of haptoglobin-deficient mice, we show that 80% of haptoglobin-deficient recipients treated with perioperative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited >100-day survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild-type recipients rejected their transplants by 21 days after transplantation. We found that haptoglobin modifies the intra allograft inflammatory milieu by enhancing levels of the inflammatory cytokine interleukin-6 and the chemokine MIP-2 (macrophage inflammatory protein 2) but impair levels of the immunosuppressive cytokine interleukin-10. Haptoglobin also enhances dendritic cell graft recruitment and augments antidonor T-cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. CONCLUSIONS: Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported antioxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions. PMID- 25801899 TI - Incident cancers attributable to alcohol consumption in Germany, 2010. AB - PURPOSE: Germany lacks an up-to-date assessment of the cancer burden attributable to alcohol. Therefore, cancer incidence attributable to this exposure was estimated for colorectal, liver, breast, and upper aerodigestive tract (UADT) cancer. Additionally, the impact of alcohol on UADT cancer was analyzed by smoking status, to account for synergistic interactions between these two risk factors. METHODS: Alcohol consumption and smoking prevalence from a nationwide survey in Germany 2008-2011 were combined with relative risks of incident cancer from meta-analyses to obtain population attributable risks (PARs), indicating the proportion of cancers that could be avoided by eliminating a risk factor. Each PAR was multiplied with the respective cancer incidence for 2010 to calculate the absolute number of attributable cases. RESULTS: In Germany, for the year 2010, approximately 13,000 incident cancer cases could be attributed to alcohol consumption (3% of total cases). PAR was highest for esophageal cancer (men: 47.6% and women: 35.8%) and lowest for colorectal cancer in men (9.7%) and breast cancer in women (6.6%). Among women, moderate consumption levels account for the greatest PAR overall, whereas heavy drinking contributes considerably to overall PAR among men. Additionally, moderate-to-heavy drinking among smokers substantially contributes to the overall PAR of UADT cancers compared to drinking among non-smokers. CONCLUSION: In Germany, a substantial proportion of cases of common cancers can be attributed to alcohol consumption, even when consumed at moderate levels. Alcohol consumption with concurrent tobacco smoking is especially important for cancers of the UADT. These findings strengthen the rationale for prevention measures that address exposure at all levels. PMID- 25801898 TI - Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair. AB - RATIONALE: Optimization of cell therapy for cardiac repair may require the association of different cell populations with complementary activities. OBJECTIVE: Compare the reparative potential of saphenous vein-derived pericytes (SVPs) with that of cardiac stem cells (CSCs) in a model of myocardial infarction, and investigate whether combined cell transplantation provides further improvements. METHODS AND RESULTS: SVPs and CSCs were isolated from vein leftovers of coronary artery bypass graft surgery and discarded atrial specimens of transplanted hearts, respectively. Single or dual cell therapy (300 000 cells of each type per heart) was tested in infarcted SCID (severe combined immunodeficiency)-Beige mice. SVPs and CSCs alone improved cardiac contractility as assessed by echocardiography at 14 days post myocardial infarction. The effect was maintained, although attenuated at 42 days. At histological level, SVPs and CSCs similarly inhibited infarct size and interstitial fibrosis, SVPs were superior in inducing angiogenesis and CSCs in promoting cardiomyocyte proliferation and recruitment of endogenous stem cells. The combination of cells additively reduced the infarct size and promoted vascular proliferation and arteriogenesis, but did not surpass single therapies with regard to contractility indexes. SVPs and CSCs secrete similar amounts of hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, stem cell factor, and stromal cell-derived factor-1, whereas SVPs release higher quantities of angiopoietins and microRNA-132. Coculture of the 2 cell populations results in competitive as well as enhancing paracrine activities. In particular, the release of stromal cell-derived factor-1 was synergistically augmented along with downregulation of stromal cell-derived factor-1-degrading enzyme dipeptidyl peptidase 4. CONCLUSIONS: Combinatory therapy with SVPs and CSCs may complementarily help the repair of infarcted hearts. PMID- 25801900 TI - Measuring the Implementation and Effects of a Coordinated Care Model Featuring Diabetes Self-management Education Within Four Patient-Centered Medical Homes. AB - PURPOSE: The purpose of this study is to measure the implementation and effects of a multisite coordinated care approach that delivered diabetes self-management education (DSME) and diabetes self-management support (DSMS) for disadvantaged patients within 4 patient-centered medical homes (PCMH). METHODS: A total of 173 patients (69.9% African American, 26.0% Caucasian, and 4.1% other) experienced elements of the intervention, which featured DSME and coordinated care. Key informant interviews with PCMH site staff were used to capture, code, and characterize activities related to implementation and sustainability of the intervention. Outcome measures collected at baseline and at 6 months included clinical health indicators, A1C, body mass index (BMI), blood pressure, and lipids, as well as the AADE7 Behaviors. RESULTS: A statistically significant decrease occurred in A1C and BMI within 6 months for participants within 1 PCMH. This improvement among clinical health outcomes was associated with the frequency of services provided (eg, DSME, patient support). CONCLUSION: Integrating and delivering DSME and DSMS within coordinated care settings have the potential to improve PCMH practice and associated clinical health outcomes for populations experiencing health disparities. PMID- 25801903 TI - Politicians set out their stall at health election debate. PMID- 25801902 TI - The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies. AB - BACKGROUND: A few studies have shown aldosterone antagonists (AA) to be effective therapy in patients with resistant hypertension (RH). We performed a meta analysis of randomized and nonrandomized studies of AA in patients with RH. METHODS: We searched PUBMED, EMBASE, and CENTRAL for studies on the use of AA in patients with RH. Meta-analysis was performed using random-effects model. The change in office and ambulatory blood pressures (BP), effects on biochemical profile, change in the number of antihypertensive agents, and adverse events were main outcomes. RESULTS: We included 15 studies (3 randomized controlled trials, 1 nonrandomized comparative study, and 11 single-arm studies) with 1,204 total patients in the meta-analysis. In comparative studies, AA reduced systolic BP (SBP) by 24.26 mm Hg (95% CI: 8.65-39.87, P = 0.002) and diastolic BP (DBP) by 7.79 mm Hg (3.79-11.79, P = 0.0001). Similarly, AA reduced SBP by 22.74 mm Hg (18.21-27.27, P < 0.00001) and DBP by 10.49 mm Hg (8.85-12.13, P < 0.00001) in single-arm studies. AA resulted in significant change in serum electrolytes in single-arm studies but not in comparative studies. Significantly more adverse events were noted in single-arm studies but not in comparative studies. CONCLUSIONS: On the basis of the current meta-analysis, we conclude that AA is safe and effective therapy in patients with RH. PMID- 25801901 TI - Self-Screening and Non-Physician Screening for Hypertension in Communities: A Systematic Review. AB - BACKGROUND: Community-based self-screening may provide opportunities to increase detection of hypertension, and identify raised blood pressure (BP) in populations who do not access healthcare. This systematic review aimed to evaluate the effectiveness of non-physician screening and self-screening of BP in community settings. METHODS: We searched the Cochrane Central Trials Register, Medline, Embase, CINAHL, and Science Citation Index & Conference Proceedings Citation Index-Science to November 2013 to identify studies reporting community-based self screening or non-physician screening for hypertension in adults. Results were stratified by study site, screener, and the cut-off used to define high screening BP. RESULTS: We included 73 studies, which described screening in 9 settings, with pharmacies (22%) and public areas/retail (15%) most commonly described. We found high levels of heterogeneity in all analyses, despite stratification. The highest proportions of eligible participants screened were achieved by mobile units (range 21%-88%) and pharmacies (range 40%-90%). Self-screeners had similar median rates of high BP detection (25%-35%) to participants in studies using other screeners. Few (16%) studies reported referral to primary care after screening. However, where participants were referred, a median of 44% (range 17% 100%) received a new hypertension diagnosis or antihypertensive medication. CONCLUSIONS: Community-based non-physician or self-screening for raised BP can detect raised BP, which may lead to the identification of new cases of hypertension. However, current evidence is insufficient to recommend specific approaches or settings. Studies with good follow-up of patients to definitive diagnosis are needed. PMID- 25801904 TI - MRI as a reliable and accurate method for assessment of posterior hip dislocation in children and adolescents without the risk of radiation exposure. AB - BACKGROUND: Posterior hip dislocation in children and adolescents may involve the non-ossified posterior acetabular wall. Plain radiographs and computed tomography (CT) have been shown to underestimate injury to the unossified acetabulum as well as associated soft-tissue structures. OBJECTIVE: The purpose of this study was to describe findings on radiographs, CT and magnetic resonance imaging (MRI) after posterior hip dislocation in a series of adolescents and to report the intraoperative findings, which are considered the gold standard. Measurements of the posterior wall length using MRI and CT scans were also performed. MATERIAL AND METHODS: After institutional review board approval, 40 patients who sustained a traumatic posterior dislocation of the hip between September 2007 and April 2014 were identified. Inclusion criteria were (1) age younger than 16 years old and (2) availability of MRI obtained following closed reduction of the hip. Eight male patients and one female patient with an average age of 13.2 years (range: 10.1-16.2 years) underwent hip MRI following posterior dislocation. Seven of the nine patients also underwent evaluation by CT. Plain radiographs, CT scans and MRI were evaluated in all patients by a single pediatric radiologist blinded to surgical findings for joint space asymmetry, posterior wall fracture, femoral head fracture, labrum tear, complete or partial ligamentum teres rupture and presence of intra-articular fragments. Six patients underwent surgical treatment and the intraoperative findings were compared with the imaging findings. RESULTS: CT identified all bone injuries but underestimated the involvement of posterior wall fractures. Assessment of the posterior wall size and fracture displacement was possible with MRI. All surgically confirmed soft-tissue injuries, including avulsion of the posterior labrum, were identified preoperatively on MRI. The measurement of posterior wall length was not statistically different using CT and MRI. CONCLUSION: Intraoperative pathological findings at the time of open surgical treatment were universally recognized on MRI but not on CT scans. MRI should be considered for evaluation of the hip following closed reduction for the treatment of a posterior dislocation in children and adolescents as it reliably allows assessment of intra-articular pathology without the risk of radiation exposure. PMID- 25801905 TI - Age- and gender-specific estimates of cumulative CT dose over 5 years using real radiation dose tracking data in children. AB - BACKGROUND: It is necessary to develop a mechanism to estimate and analyze cumulative radiation risks from multiple CT exams in various clinical scenarios in children. OBJECTIVE: To identify major contributors to high cumulative CT dose estimates using actual dose-length product values collected for 5 years in children. MATERIALS AND METHODS: Between August 2006 and July 2011 we reviewed 26,937 CT exams in 13,803 children. Among them, we included 931 children (median age 3.5 years, age range 0 days-15 years; M:F = 533:398) who had 5,339 CT exams. Each child underwent at least three CT scans and had accessible radiation dose reports. Dose-length product values were automatically extracted from DICOM files and we used recently updated conversion factors for age, gender, anatomical region and tube voltage to estimate CT radiation dose. We tracked the calculated CT dose estimates to obtain a 5-year cumulative value for each child. The study population was divided into three groups according to the cumulative CT dose estimates: high, >=30 mSv; moderate, 10-30 mSv; and low, <10 mSv. We reviewed clinical data and CT protocols to identify major contributors to high and moderate cumulative CT dose estimates. RESULTS: Median cumulative CT dose estimate was 5.4 mSv (range 0.5-71.1 mSv), and median number of CT scans was 4 (range 3-36). High cumulative CT dose estimates were most common in children with malignant tumors (57.9%, 11/19). High frequency of CT scans was attributed to high cumulative CT dose estimates in children with ventriculoperitoneal shunt (35 in 1 child) and malignant tumors (range 18-49). Moreover, high-dose CT protocols, such as multiphase abdomen CT (median 4.7 mSv) contributed to high cumulative CT dose estimates even in children with a low number of CT scans. CONCLUSION: Disease group, number of CT scans, and high-dose CT protocols are major contributors to higher cumulative CT dose estimates in children. PMID- 25801906 TI - A bioguided identification of the active compounds that contribute to the antiproliferative/cytotoxic effects of rosemary extract on colon cancer cells. AB - Rosemary extracts have exhibited potential cytostatic or cytotoxic effects in several cancer cell models but their bioactive compounds are yet to be discovered. In this work, the anticancer activity of a rosemary-leaf extract and its fractions were assayed to identify the phenolic compounds responsible for their antiproliferative/cytotoxic effects on a panel of human colon cancer cell lines. Bioguided fractionation of the rosemary-leaf extract was achieved by semi preparative chromatography. The rosemary extract and the compounds in the fractions were characterized and quantified by HPLC-ESI-QTOF-MS. Cellular viability in the presence of these fractions and the whole extract was determined after 24 or 48 h incubations by using an MTT assay. Fractions containing diterpenes or triterpenes were the most active but not as much as the whole extract. In conclusion, carnosic acid, carnosol, 12-methoxycarnosic acid, taxodione, hinokione and betulinic acid were the putative candidates that contributed to the observed antiproliferative activity of rosemary in human colon cancer cells. Whether the effects of the extract and fractions are only cytostatic or cytotoxic needs to be elucidated. Nevertheless, the comparative antiproliferative study on the fractions and whole extract revealed potential synergistic effects between several components in the extract that may deserve further attention. PMID- 25801907 TI - Altered knee joint neuromuscular control during landing from a jump in 10-15 year old children with Generalised Joint Hypermobility. A substudy of the CHAMPS-study Denmark. AB - Generalised Joint Hypermobility (GJH) is considered an intrinsic risk factor for knee injuries. Knee neuromuscular control during landing may be altered in GJH due to reduced passive stability. The aim was to identify differences in knee neuromuscular control during landing of the Single-Leg-Hop-for-Distance test (SLHD) in 25 children with GJH compared to 29 children without GJH (controls), all 10-15years. Inclusion criteria for GJH: Beighton score?5/9 and minimum one hypermobile knee. EMG was recorded from the quadriceps, the hamstring and the calf muscles, presented relative to Maximum Voluntary Electrical activity (MVE). There was no difference in jump length between groups. Before landing, GJH had 33% lower Semitendinosus, but 32% higher Gastrocnemius Medialis activity and 39% higher co contraction of the lateral knee muscles, than controls. After landing, GJH had 36% lower Semitendinosus activity than controls, all significant findings. Although the groups performed equally in SLHD, GJH had a Gastrocnemius Medialis dominated neuromuscular strategy before landing, plausibly caused by reduced Semitendinosus activity. Reduced Semitendinosus activity was seen in GJH after landing, but with no compensatory Gastrocnemius Medialis activity. Reduced pre and post-activation of the Semitendinosus may present a risk factor for traumatic knee injuries as ACL ruptures in GJH with knee hypermobility. PMID- 25801908 TI - Diffusion tensor imaging and tract-based spatial statistics analysis in Friedreich's ataxia patients. AB - INTRODUCTION: Friedreich's ataxia (FRDA) is the most common hereditary ataxia and thinning of the cervical spinal cord is a consistent observation in Magnetic resonance imaging (MRI), although neuropathological examination in FRDA reveals neuronal loss in gray matter (GM) nuclei and degeneration of white matter (WM) tracts in the spinal cord, brainstem and cerebellum. Using diffusion-tensor (DTI) imaging and tract-based spatial statistics (TBSS) we tested the hypothesis that WM damage in FRDA is more extensive than previously described and probably involves normal-appearing WM. METHODS: This transversal study included 21 genetically confirmed FRDA patients and seventeen healthy controls that underwent structural MRI of the brain on a 1.5 T scanner. We quantify the severity of ataxia using SARA scale. DTI was performed and diffusion data were analyzed using FMRIB's Diffusion Toolbox in FSL 4.1 in order to identify Fractional anisotropy (FA) decreases in specific brain regions and also the mean, radial and axial diffusivities (MD, RD, AD). RESULTS: The greatest decreases in FA were in the left superior cerebellar peduncle, left posterior thalamic radiation, major forceps, left inferior fronto-occipital fasciculus and corpus callosum and had a significance level of p < 0.01. No significant correlation between FA, AD, MD and RD values and the clinical findings, SARA scores and genetic expansion was found. CONCLUSION: DTI and TBSS techniques clearly demonstrate the extensive cerebral and cerebellar involvement in FRDA, partially explaining the clinical phenotype of the disease. Further studies are needed with larger samples to correlate clinical, genetic findings and ataxia scores. PMID- 25801909 TI - Brain energy metabolism in early MSA-P: A phosphorus and proton magnetic resonance spectroscopy study. AB - INTRODUCTION: Recently, mutations in the COQ2 gene, encoding for an enzyme involved in coenzyme Q10 biosynthesis, have been suggested to confer susceptibility risk for multiple system atrophy (MSA). Thus, the possible role of mitochondrial dysfunction in the pathophysiology of MSA has emerged. Here, we studied brain energy metabolism in vivo in early MSA-parkinsonism (MSA-P) patients and compared to healthy controls. METHODS: We have used combined phosphorus and proton magnetic resonance spectroscopy to measure high- and low energy phosphates in the basal ganglia of early (Hoehn and Yahr stage I-III), probable MSA-P patients (N = 9) compared to healthy controls (N = 9). RESULTS: No significant changes in the high energy phosphates and other parameters reflecting the energy status of the cells were found in the basal ganglia of MSA-P patients compared to healthy controls. N-acetylaspartate was significantly reduced in MSA P compared to healthy controls and correlated with the Unified Multiple System Atrophy Rating Scale. CONCLUSION: Brain energy metabolism in early MSA-P is not impaired, despite the presence of impaired neuronal integrity. This may imply that mitochondrial dysfunction may not play a primary role in the pathophysiology of MSA, at least in European populations. PMID- 25801910 TI - Senescence-associated inflammatory responses: aging and cancer perspectives. AB - Senescent cells, albeit not proliferating, are metabolically and transcriptionally active, thereby capable of affecting their microenvironment, notably via the production of inflammatory mediators. These mediators maintain and propagate the senescence process to neighboring cells, and then recruit immune cells for clearing senescent cells. Among the inflammatory cues are molecules with pronounced tumor-controlling properties, both growth and invasion factors and inhibitory factors, working directly or via recruited immune cells. These senescence-inflammatory effects also prevail within tumors, mediated by the senescent tumor cells and the senescent tumor stroma. Here, we review the course and impact of senescence-associated inflammatory responses in aging and cancer. We propose that controlling senescence-associated inflammation by targeting specific inflammatory mediators may have a beneficial therapeutic effect in treatment of cancer and aging-related diseases. PMID- 25801912 TI - Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis. AB - We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (? 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients. PMID- 25801911 TI - Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is a hematological cancer associated with an aggressive clinical course. The predominant subtypes of DLBCL display features of chronic or tonic B-cell antigen receptor (BCR) signaling. However, it is not known whether the spatial organization of the BCR contributes to the regulation of pro-survival signaling pathways and cell growth. Here, we show that primary DLBCL tumors and patient-derived DLBCL cell lines contain high levels of phosphorylated Ezrin-Radixin-Moesin (ERM) proteins. The surface BCRs in both activated B cell and germinal B cell subtype DLBCL cells co-segregate with phosphoERM suggesting that the cytoskeletal network may support localized BCR signaling and contribute to pathogenesis. Indeed, ablation of membrane cytoskeletal linkages by dominant-negative mutants, pharmacological inhibition and knockdown of ERM proteins disrupted cell surface BCR organization, inhibited proximal and distal BCR signaling, and reduced the growth of DLBCL cell lines. In vivo administration of the ezrin inhibitor retarded the growth of DLBCL tumor xenografts, concomitant with reduction in intratumor phosphoERM levels, dampened pro-survival signaling and induction of apoptosis. Our results reveal a novel ERM based spatial mechanism that is coopted by DLBCL cells to sustain tumor cell growth and survival. PMID- 25801913 TI - Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. AB - Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM. PMID- 25801915 TI - [Viral meningoencephalitis in inmunocompetent patients: Relevance of HIV infection]. PMID- 25801917 TI - Diabetes: Is altered dopamine turnover the missing link between insulin resistance and cognitive decline? PMID- 25801914 TI - Loss of Dnmt3a and endogenous Kras(G12D/+) cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis. AB - Oncogenic NRAS and KRAS mutations are prevalent in human juvenile and chronic myelomonocytic leukemia (JMML/CMML). However, additional genetic mutations cooperating with oncogenic RAS in JMML/ CMML progression and/or their transformation to acute myeloid leukemia (AML) remain largely unknown. Here we tested the potential genetic interaction of DNMT3A mutations and oncogenic RAS mutations in leukemogenesis. We found that Dnmt3a(-/-) induces multiple hematopoietic phenotypes after a prolonged latency, including T-cell expansion in the peripheral blood, stress erythropoiesis in the spleen and myeloid malignancies in the liver. Dnmt3a(-/-) significantly promoted JMML/CMML progression and shortened the survival of Kras(G12D/+) mice in a cell-autonomous manner. Similarly, downregulating Dnmt3a also promoted myeloid malignancies in Nras(G12D/+) mice. Further studies show that Dnmt3a deficiency rescues Kras(G12D/+)-mediated depletion of hematopoietic stem cells and increases self renewal of Kras(G12D/+) myeloid progenitors (MPs). Moreover, ~33% of animals developed an AML-like disease, which is driven by Kras(G12D/+); Dnmt3a(-/-) MPs. Consistent with our result, COSMIC database mining demonstrates that the combination of oncogenic RAS and DNMT3A mutations exclusively occurred in patients with JMML, CMML or AML. Our results suggest that DNMT3A mutations and oncogenic RAS cooperate to regulate hematopoietic stem and progenitor cells and promote myeloid malignancies. PMID- 25801919 TI - Spinal cord injury (SCI) rehabilitation: systematic analysis of communication from the biopsychosocial perspective. AB - PURPOSE: Communication is powerful predictor of health-related quality of life and overall well-being, yet its role in promoting rehabilitation outcomes in spinal cord injury (SCI) is rarely mentioned. This article systematically analyzes and synthesizes literature from multiple disciplines according to a biopsychosocial perspective, providing an evidence base for clinical practice and clear direction for future research. METHOD: Systematic literature review and analysis, incorporating mapping to International Classification of Functioning, Disability and Health (ICF) codes. RESULTS: In total 4338 entries were retrieved from CINAHL, PsychInfo, Medline, PubMed and SpeechBite databases for the period 1990-2014. A total of 115 treatment and observational studies (quantitative and qualitative) detailed aspects of communication according to structure, function, activity, participation and environmental factors; evident of the complex interactions between communicative function with daily living after SCI. CONCLUSIONS: Communication is a relative strength in SCI, key to empowerment, independence, social interaction, and well-being, yet its potential to enhance SCI rehabilitation outcomes remains largely underexplored and untapped. Through elucidating interactions between communication and functioning, the adapted ICF framework affords clinicians and researchers insight into areas of intervention most likely to result in widespread gains. Conscious consideration should be given to the role of communication, within an integrative, strengths-based, multidisciplinary approach to clinical practice and future research. Implications for Rehabilitation Communication fosters empowerment, independence and greater participation in life roles; recognized as a powerful predictor of health-related quality of life and overall well-being. The ICF framework elucidates influences to communicative function, and components which are influenced by communication, providing valuable insight for clinicians and researchers. Therapeutic and research endeavors guided by existing ICF core sets are at risk of failing to consider communication, thereby limiting rehabilitation outcomes. Tapping the potential of communication as a relative strength within SCI rehabilitation holds considerable promise, within integrative, strengths-based, multidisciplinary approaches to clinical practice and future research. PMID- 25801916 TI - Laminar profile of spontaneous and evoked theta: Rhythmic modulation of cortical processing during word integration. AB - Theta may play a central role during language understanding and other extended cognitive processing, providing an envelope for widespread integration of participating cortical areas. We used linear microelectrode arrays in epileptics to define the circuits generating theta in inferotemporal, perirhinal, entorhinal, prefrontal and anterior cingulate cortices. In all locations, theta was generated by excitatory current sinks in middle layers which receive predominantly feedforward inputs, alternating with sinks in superficial layers which receive mainly feedback/associative inputs. Baseline and event-related theta were generated by indistinguishable laminar profiles of transmembrane currents and unit-firing. Word presentation could reset theta phase, permitting theta to contribute to late event-related potentials, even when theta power decreases relative to baseline. Limited recordings during sentence reading are consistent with rhythmic theta activity entrained by a given word modulating the neural background for the following word. These findings show that theta occurs spontaneously, and can be momentarily suppressed, reset and synchronized by words. Theta represents an alternation between feedforward/divergent and associative/convergent processing modes that may temporally organize sustained processing and optimize the timing of memory formation. We suggest that words are initially encoded via a ventral feedforward stream which is lexicosemantic in the anteroventral temporal lobe; its arrival may trigger a widespread theta rhythm which integrates the word within a larger context. PMID- 25801920 TI - Bladder dysfunction and quality of life for people with multiple sclerosis. AB - PURPOSE: Bladder dysfunction affects 75% of people with multiple sclerosis (MS). People with MS are reluctant to seek treatment for this distressing symptom. This is the first-known study to explore in depth how bladder dysfunction interferes with quality of life for people with MS. METHODS: Nineteen individual semi structured interviews were conducted (M = 8, F = 11). Participants had a definite diagnosis of MS, aged between 37 and 64 years and had at least one bladder dysfunction symptom. The audio-recorded interviews lasted up to 90 min and were transcribed verbatim. RESULTS: Thematic analysis within NVivo10 yielded two key themes: (1) Disruptions and loss and (2) ways of knowing. "Disruptions and Loss" explores how bladder dysfunction interrupted daily living activities and how this contributed to experiencing loss. "Ways of knowing" portrays the types of knowledge that existed around bladder dysfunction. Participants described using their experiential knowledge to self-manage bladder symptoms without advice from healthcare providers. CONCLUSIONS: Bladder dysfunction imposes major disruptions on daily life. People with MS attempt to self-manage their bladder symptoms, despite current barriers to navigating existing healthcare infrastructure. Understanding these barriers and the individual strategies employed by people with MS are the first steps in facilitating independent management of bladder dysfunction. Implications for Rehabilitation Each individual's experience of bladder dysfunction is unique. Healthcare professionals must be prepared to discuss all disruptions and losses associated with bladder dysfunction for people with MS. People with MS have a vast range of knowledge in relation to their own bladder symptoms and healthcare professionals need to explore their existing self management strategies during assessment. People with MS and healthcare professionals need to be educated on the wider health implications relating to bladder dysfunction. PMID- 25801921 TI - Promoting consistent use of the communication function classification system (CFCS). AB - PURPOSE: We developed a Knowledge Translation (KT) intervention to standardize the way speech-language pathologists working in Ontario Canada's Preschool Speech and Language Program (PSLP) used the Communication Function Classification System (CFCS). This tool was being used as part of a provincial program evaluation and standardizing its use was critical for establishing reliability and validity within the provincial dataset. METHOD: Two theoretical foundations - Diffusion of Innovations and the Communication Persuasion Matrix - were used to develop and disseminate the intervention to standardize use of the CFCS among a cohort speech language pathologists. A descriptive pre-test/post-test study was used to evaluate the intervention. Fifty-two participants completed an electronic pre test survey, reviewed intervention materials online, and then immediately completed an electronic post-test survey. RESULTS: The intervention improved clinicians' understanding of how the CFCS should be used, their intentions to use the tool in the standardized way, and their abilities to make correct classifications using the tool. CONCLUSIONS: Findings from this work will be shared with representatives of the Ontario PSLP. The intervention may be disseminated to all speech-language pathologists working in the program. This study can be used as a model for developing and disseminating KT interventions for clinicians in paediatric rehabilitation. IMPLICATIONS FOR REHABILITATION: The Communication Function Classification System (CFCS) is a new tool that allows speech-language pathologists to classify children's skills into five meaningful levels of function. There is uncertainty and inconsistent practice in the field about the methods for using this tool. This study used combined two theoretical frameworks to develop an intervention to standardize use of the CFCS among a cohort of speech-language pathologists. The intervention effectively increased clinicians' understanding of the methods for using the CFCS, ability to make correct classifications, and intention to use the tool in the standardized way in the future. PMID- 25801922 TI - Psychometric properties of self-reported questionnaires for the evaluation of symptoms and functional limitations in individuals with rotator cuff disorders: a systematic review. AB - PURPOSE: To conduct a systematic review of the psychometric properties (reliability, validity and responsiveness) of self-report questionnaires used to assess symptoms and functional limitations of individuals with rotator cuff (RC) disorders. METHODS: A systematic search in three databases (Cinahl, Medline and Embase) was conducted. Data extraction and critical methodological appraisal were performed independently by three raters using structured tools, and agreement was achieved by consensus. A descriptive synthesis was performed. RESULTS: One hundred and twenty articles reporting on 11 questionnaires were included. All questionnaires were highly reliable and responsive to change, and showed construct validity; seven questionnaires also shown known-group validity. The minimal detectable change ranged from 6.4% to 20.8% of total score; only two questionnaires (American Shoulder and Elbow Surgeon questionnaire [ASES] and Upper Limb Functional Index [ULFI]) had a measurement error below 10% of global score. Minimal clinically important differences were established for eight questionnaires, and ranged from 8% to 20% of total score. CONCLUSION: Overall, included questionnaires showed acceptable psychometric properties for individuals with RC disorders. The ASES and ULFI have the smallest absolute error of measurement, while the Western Ontario RC Index is one of the most responsive questionnaires for individuals suffering from RC disorders. IMPLICATIONS FOR REHABILITATION: All included questionnaires are reliable, valid and responsive for the evaluation of individuals with RC disorders. As all included questionnaires showed good psychometric properties for the targeted population, the choice should be made according to the purpose of the evaluation and to the construct being evaluated by the questionnaire. The WORC, a RC-specific questionnaire, appeared to be more responsive. It should therefore be used to evaluate change in time. If the evaluation is time-limited, shorter questionnaires or short versions should be considered (such as Quick DASH or SST). PMID- 25801923 TI - The Arm Function in Multiple Sclerosis Questionnaire (AMSQ): development and validation of a new tool using IRT methods. AB - PURPOSE: We developed the Arm Function in Multiple Sclerosis Questionnaire (AMSQ) to measure arm and hand function in MS, based on existing scales. We aimed at developing a unidimensional scale containing enough items to be used as an itembank. In this study, we investigated reliability and differential item functioning of the Dutch version. METHOD: Patients were recruited from two MS Centers and a Dutch website for MS patients. We performed item factor analysis on the polychoric correlation matrix, using multiple fit-indices to investigate model fit. The graded response model, an item response theory model, was used to investigate item goodness-of-fit, reliability of the estimated trait levels (theta), differential item functioning, and total information. Differential item functioning was investigated for type of MS, gender, administration version, and test length. RESULTS: Factor analysis results suggested one factor. All items showed p-values of the item goodness-of-fit statistic above 0.0016. The reliability was 0.95, and no items showed differential item functioning on any of the investigated variables. CONCLUSION: AMSQ is a unidimensional 31-item questionnaire for measuring arm function in MS. Because of a well fit in a graded response model, it is suitable for further development as a computer adaptive test. Implications for Rehabilitation A new questionnaire for arm and hand function recommended in people with multiple sclerosis (AMSQ). Scale characteristics make the questionnaire suitable for use in clinical practice and research. Good reliability. Further development as a computer adaptive test to reduce burden of (repetitive) testing in patients is feasible. PMID- 25801918 TI - Drug-subphenotype interactions for cancer in type 2 diabetes mellitus. AB - On the basis of data obtained from a prospective cohort of Chinese patients with type 2 diabetes mellitus (T2DM), we discuss cancer subphenotypes (risk factors) in patients with T2DM, which can lead to drug-cancer subphenotype interactions. These subphenotypes include HDL cholesterol levels <1.0 mmol/l, co-occurrence of LDL cholesterol levels <2.8 mmol/l and triglyceride levels <1.7 mmol/l, and co occurrence of LDL cholesterol levels <2.8 mmol/l and albuminuria. The increased risk of cancer associated with low levels of HDL cholesterol, low LDL cholesterol levels plus low triglyceride levels, and low levels of LDL cholesterol plus albuminuria can be reduced by treatment with metformin, renin-angiotensin system (RAS) inhibitors and statins, respectively. Mechanistic studies support the hypothesis that dysregulation of the 5'-AMP-activated protein kinase pathway and crosstalk between the RAS and insulin-like growth factor 1-cholesterol pathways create a cancer-promoting milieu in patients with T2DM. These findings highlight that in Chinese individuals, multiple pathways are implicated in the link between T2DM and cancer, which can generate multiple subphenotypes as well as drug subphenotype interactions. PMID- 25801924 TI - Brain morphology of childhood aggressive behavior: A multi-informant study in school-age children. AB - OBJECTIVE: Few studies have focused on the neuroanatomy of aggressive behavior in children younger than 10 years. Here, we explored the neuroanatomical correlates of aggression in a population-based sample of 6- to 9-year-old children using a multiple-informant approach. METHODS: Magnetic resonance (MR) scans were acquired from 566 children from the Generation R study who participated in the Berkeley Puppet Interview and whose parents had completed the Child Behavior Checklist. Linear regression analyses were used to examine associations between aggression and amygdala and hippocampal volume. We performed surface-based analyses to study the association between aggression and cortical thickness, surface area, and gyrification. RESULTS: Aggressive behavior was associated with smaller amygdala (p < .05) but not hippocampal volume. Aggression was associated with a thinner cortex in the left precentral cortex (p < .01) and in a cluster including the right inferior parietal, supramarginal, and postcentral cortex (p < .001). Gender moderated the association between aggression and cortical thickness in the right medial posterior cortex (p = .001) and the right prefrontal cortex (p < .001). Aggression was associated with decreased gyrification in a large cluster including the right precentral, postcentral, frontal, and parietal cortex (p = .01). Moreover, aggression was associated with decreased gyrification in the right occipital and parietal cortex (p = .02). CONCLUSION: We found novel evidence that childhood aggressive behavior is related to decreased amygdala volume, decreased sensorimotor cortical thickness, and decreased global right hemisphere gyrification. Aggression is related to cortical thickness in regions associated with the default mode network, with negative associations in boys and positive associations in girls. PMID- 25801928 TI - Gait improves after 12 weeks of intensive resistance and functional training in people with mild to moderate dementia. PMID- 25801925 TI - Model-based learning protects against forming habits. AB - Studies in humans and rodents have suggested that behavior can at times be "goal directed"-that is, planned, and purposeful-and at times "habitual"-that is, inflexible and automatically evoked by stimuli. This distinction is central to conceptions of pathological compulsion, as in drug abuse and obsessive-compulsive disorder. Evidence for the distinction has primarily come from outcome devaluation studies, in which the sensitivity of a previously learned behavior to motivational change is used to assay the dominance of habits versus goal-directed actions. However, little is known about how habits and goal-directed control arise. Specifically, in the present study we sought to reveal the trial-by-trial dynamics of instrumental learning that would promote, and protect against, developing habits. In two complementary experiments with independent samples, participants completed a sequential decision task that dissociated two computational-learning mechanisms, model-based and model-free. We then tested for habits by devaluing one of the rewards that had reinforced behavior. In each case, we found that individual differences in model-based learning predicted the participants' subsequent sensitivity to outcome devaluation, suggesting that an associative mechanism underlies a bias toward habit formation in healthy individuals. PMID- 25801929 TI - The spinal cord independence measure. PMID- 25801930 TI - Quaternary organization in a bifunctional prokaryotic FAD synthetase: Involvement of an arginine at its adenylyltransferase module on the riboflavin kinase activity. AB - Prokaryotic FAD synthetases (FADSs) are bifunctional enzymes composed of two modules, the C-terminal module with ATP:riboflavin kinase (RFK) activity, and the N-terminus with ATP:FMN adenylyltransferase (FMNAT) activity. The FADS from Corynebacterium ammoniagenes, CaFADS, forms transient oligomers during catalysis. These oligomers are stabilized by several interactions between the RFK and FMNAT sites from neighboring protomers, which otherwise are separated in the monomeric enzyme. Among these inter-protomer interactions, the salt bridge between E268 at the RFK site and R66 at the FMNAT-module is particularly relevant, as E268 is the catalytic base of the kinase reaction. Here we have introduced point mutations at R66 to analyze the impact of the salt-bridge on ligand binding and catalysis. Interestingly, these mutations have only mild effects on ligand binding and kinetic properties of the FMNAT-module (where R66 is located), but considerably impair the RFK activity turnover. Substitutions of R66 also modulate the ratio between monomeric and oligomeric species and modify the quaternary arrangement observed by single-molecule methods. Therefore, our data further support the cross-talk between the RFK- and FMNAT-modules of neighboring protomers in the CaFADS enzyme, and establish the participation of R66 in the modulation of the geometry of the RFK active site during catalysis. PMID- 25801931 TI - Pseudosaccharin amines as potent and selective KV1.5 blockers. AB - Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects. PMID- 25801933 TI - Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors. AB - This Letter describes the synthesis and antiviral activity study of some glycyrrhizic acid (GL) derivatives against influenza A/H1N1/pdm09 virus in MDCK cells. Conjugation of GL with l-amino acids or their methyl esters, and amino sugar (d-galactose amine) dramatically changed its activity. The most active compounds were GL conjugates with aromatic amino acids methyl esters (phenylalanine and tyrosine) (SI=61 and 38), and S-benzyl-cysteine (SI=71). Thus modification of GL is a perspective route in the search of new antivirals, and some of GL derivatives are potent as anti-influenza A/H1N1 agents. PMID- 25801932 TI - Synthesis and structure-activity relationships of a series of 4-methoxy-3 (piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter. AB - The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1-7, iterative medicinal chemistry efforts led to the identification of ML352 (10m). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold. PMID- 25801934 TI - Disintegration of cruciform and G-quadruplex structures during the course of helicase-dependent amplification (HDA). AB - Unlike chemical damages on DNA, physical alterations of B-form of DNA occur commonly in organisms that serve as signals for specified cellular events. Although the modes of action for repairing of chemically damaged DNA have been well studied nowadays, the repairing mechanisms for physically altered DNA structures have not yet been understood. Our current in vitro studies show that both breakdown of stable non-B DNA structures and resumption of canonical B conformation of DNA can take place during the courses of isothermal helicase dependent amplification (HDA). The pathway that makes the non-B DNA structures repairable is presumably the relieving of the accumulated torsional stress that was caused by the positive supercoiling. Our new findings suggest that living organisms might have evolved this distinct and economical pathway for repairing their physically altered DNA structures. PMID- 25801935 TI - Synthesis of the alkylated active metabolite of tipidogrel. AB - Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented. PMID- 25801936 TI - Synthesis and broad-spectrum antiproliferative activity of diarylamides and diarylureas possessing 1,3,4-oxadiazole derivatives. AB - A series of diarylamides and diarylureas possessing 1,3,4-oxadiazole scaffold was designed and synthesized. Their in vitro antiproliferative activities were tested against a panel of 58 cell lines of nine different cancer types at the NCI, and compared with Sorafenib as a reference compound. Most of the compounds showed strong and broad-spectrum antiproliferative activities. The diarylurea compound 2g possessing 4-chloro-3-(trifluoromethyl)phenyl terminal moiety showed the highest mean % inhibition value of about 100% over the 58-cell line panel at 10MUM concentration. Also compounds 2h, 2l, 2m exhibited mean % inhibition over 90% at 10MUM concentration. The IC50 value of compound 2b over SNB-75 CNS cancer cell line was 0.65MUM. Compound 2h also exerted submicromolar IC50 values of 0.67, 0.80, and 0.87MUM against PC-3 prostate cancer cell line, HCT-116 colon cancer cell line, and ACHN renal cancer cell line, respectively. Compound 2h showed comparable efficacy to Sorafenib. PMID- 25801937 TI - Structure-assisted ligand-binding analysis using fluorogenic photoaffinity labeling. AB - Photoaffinity labeling (PAL) technique using a fluorogenic cross-linker is used to monitor the nucleotide-binding pocket within a protein. A coumarin fluorophore formed in the binding domain due to ultraviolet (UV) irradiation has been shown to accelerate the sequencing of the labeled peptide as well as identification of the labeled site by liquid chromatography (LC)-tandem mass spectrometry (MS), in addition to providing information on the ligand binding state. Selective monitoring of the predefined fluorescence peaks among the numerous digests obtained from high performance liquid chromatography (HPLC) clearly indicates the binding capability of the ligand to the entire protein as well as to the corresponding binding domain under various conditions. In the current study, ligand-binding analysis confirmed by the structural information of the binding state has been demonstrated using fluorogenic ATP/ADP photoactivatable probes under allosteric regulation of multiple substrates in the enzyme glutamate dehydrogenase (GDH). PMID- 25801938 TI - Novel assay to quantify recombination in a calicivirus. AB - Recombination is an important contributor to genomic evolution in many viral families, including the Caliciviridae. While it is known that genomic recombination in caliciviruses contributes to their rapid evolution, the precise molecular mechanisms are poorly understood. The majority of reported recombination events in feline calicivirus (FCV) occur at a "hot spot" between the non-structural protein coding region (open reading frame 1) and structural protein coding region (open reading frame 2). To gain a better understanding of the rate of recombination at this point, we developed a quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay to quantify the rate of recombination between two divergent strains of FCV during co-infection in cell culture. The assay utilised virus-specific primers upstream and downstream of the recombinational "hot spot" that hybridise with only one of the strains in the co infection. Recombinant progeny that shared ORF1 sequence identity with one parental virus and ORF2 sequence identity with the other parental virus, and the site of recombination, was confirmed by sequencing the amplicon generated by the assay. Recombinants were detected in co-infected cells using this assay, but not in cells infected with single strains that were mixed together following infection, thus confirming its specificity. Recombination between two FCVs in co infected cell cultures was estimated to occur at a rate of at least 6.8*10(-6) single direction recombinant genomes per parental virus genome. Further application of this assay will enable factors influencing recombination in caliciviruses to be explored in greater detail, both in vitro and in vivo. PMID- 25801939 TI - Relationship between European eel Anguilla anguilla infection with non-native parasites and swimming behaviour on encountering accelerating flow. AB - The effect of Anguillicola crassus, Pseudodactylogyrus bini and Pseudodactylogyrus anguillae infection on the behaviour of downstream migrating adult European eels Anguilla anguilla as they encountered accelerating water velocity, common at engineered structures where flow is constricted (e.g. weirs and bypass systems), was evaluated in an experimental flume. The probability of reacting to, and rejecting, the velocity gradient was positively related to A. crassus larval, adult and total abundance. High abundance of Pseudodactylogyrus spp. reduced this effect, but A. crassus was the strongest parasitic factor associated with fish behaviour, and abundance was positively related to delay in downstream passage. Delayed downstream migration at hydraulic gradients associated with riverine anthropogenic structures could result in additional energetic expenditure for migrating A. anguilla already challenged by A. crassus infection. PMID- 25801940 TI - Development of Novel Pharmaceutical Agents for Alzheimer's Disease: The Impact of Regulatory Initiatives in Japan and the United States. AB - PURPOSE: The incidence of Alzheimer's disease (AD) has been steadily increasing worldwide. AD is a serious disease that has both societal and economic impacts. The greatest risk factor for AD is aging. Thus, because of the rapidly aging population in Japan, the development of new, effective drugs for AD is urgently needed. The goal of the present article was to analyze the status, clarify the problems, and discuss the scientific and political challenges of disease modifying drug development for AD. METHODS: Public data, official documents, literature, and news releases were surveyed and discussed. FINDINGS: Compared with diabetes mellitus drugs, there is a lack of quantitative surrogate end points among AD drugs. Much AD drug development has focused on amyloid-beta and its associated pathways; however, these drugs have not shown efficacy in Phase III clinical trials. Thus, the US Food and Drug Administration has appealed for a new draft industrial guidance for the development of AD drugs, including those for early-stage AD. In Japan, the Minister of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency have also taken action, including the publication of potential new guidelines for clinical evaluation and development of new AD therapeutics, including drugs. Moreover, scientific initiatives to develop novel AD drugs are ongoing. IMPLICATIONS: The development of quantitative surrogate end points remains necessary to improve the development of AD drugs. Therefore, collaboration among industry, government, and academia should be encouraged. Following the principles of regulatory science, strategies to develop drugs for illnesses with unmet needs can be framed by investigating the effects of past, current, and future AD drug development initiatives. PMID- 25801941 TI - Statistical aspects of psychiatric inpatient care in Japan: Based on a comprehensive nationwide survey of psychiatric hospitals conducted from 1996 to 2012. AB - The aim of this review is to clarify the state of psychiatric admissions and discharges in Japan using statistical data collected from 1996 to 2012. We performed a secondary analysis of nationwide data on psychiatric hospitals, which are collected yearly by the Ministry of Health, Labour and Welfare. The latest national figures for indices defined in the 'Reform Vision of Mental Health and Welfare' (originally released in 2004) were 70.9% for 'discharge rate for newly admitted patients' and 23.3% for 'discharge rate for long-term patients', which have target rates of >=76% and >=29%, respectively. The national discharge rate for newly admitted patients was roughly on the increase, but appeared to reach a plateau in recent years. [Correction added on 17 July 2015, after first online publication: 'on the decline' has been corrected to 'on the increase' in the sentence above.] The national discharge rate for long-term patients was higher in 2012 than in 1999 and appeared to increase throughout the 2000s, although not enough to reach the target. Some improvements in the discharge rate for newly admitted patients indicated some progress in mental health reform, although problems should continue to be addressed in order to reach the targets. As for discharge rates of long-term admissions in local communities, some problems still remain to be solved in order to achieve the goals of the reform vision. PMID- 25801943 TI - Immunogenicity of beta-cells for autologous transplantation in type 1 diabetes. AB - The success of clinical islet transplantation calls for a broader application of this curative treatment for type 1 diabetes mellitus. The toxicity of immunosuppression, limited organ donor supply and high procedural costs are deterrents to expand this therapy to patients with uncomplicated diabetes. The use of pancreatic beta-cell like cells derived from the patient's own induced pluripotent cells (iPSC) holds potential to overcome these barriers. In this review, we discuss the practicality of this regenerative medicine approach and existing evidence regarding the true immunogenicity of iPSC derived cells. PMID- 25801942 TI - Ethanol induces hydroxytyrosol formation in humans. AB - Previous studies in animals have shown an increase of hydroxytyrosol (OHTyr), a potent phenolic antioxidant and a minor metabolite of dopamine (also called 3,4 dihydroxyphenylethanol or DOPET), after ethanol intake. The interaction between ethanol and dopamine metabolism is the probable mechanism involved. The aim of the study was to establish the contribution of the dose of ethanol on OHTyr formation. 24 healthy male volunteers were included. Subjects were distributed in three different cohorts and each volunteer received two doses of ethanol or placebo. Doses of ethanol administered were 6, 12, 18, 24, 30 and 42 g. Study design was double-blind, randomized, crossover and controlled. Hydroxytyrosol, tyrosol (Tyr), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) urinary excretion, ethanol plasma concentrations and drunkenness were evaluated along a 6-h period. Urinary excretion of OHTyr and Tyr increased with ethanol administered dose. A reduction in the ratio DOPAC/OHTyr from placebo to the highest dose was observed, compatible with a shift in the dopamine metabolism to preferently produce OHTyr instead of DOPAC. Also a dose-dependent increase in plasma ethanol concentrations and subjective effects was observed. This study demonstrates an endogenous production of OHTyr and Tyr in relation to ethanol administered dose in humans. Biological effects of both phenols from this source should be investigated in future studies. PMID- 25801944 TI - Burden of soft-tissue and bone sarcoma in routine care: Estimation of incidence, prevalence and survival for health services research. AB - BACKGROUND: Sarcomas constitute a rare group of malignant tumors which can originate from any organ, tissue, bone or cartilage. Due to their heterogeneity, estimates of sarcoma incidence, prevalence and survival are rare. We estimated the burden of sarcoma in Germany from a large unselected cohort of patients from routine healthcare. METHODS: We utilized the AOK PLUS health services research database covering complete medical information on 2,615,865 individuals from the German federal state of Saxony from 2005 to 2012. Persons were defined as sarcoma cases if they had >=4 medical accounts with respective ICD-10 code C49 (soft tissue sarcoma) or C40/C41 (bone sarcoma). We assessed sarcoma burden by calculating five-year prevalences, cumulative incidences, and one- and five-year relative survival rates. RESULTS: Overall 1,468 persons with soft-tissue sarcoma and 671 persons with bone sarcoma were identified. Age-standardized cumulative incidence was 4.5/100,000 persons for soft-tissue and 2.1/100,000 persons for bone sarcoma (European Standard). One- and five-year relative survival was 87.8% and 66.4% for soft-tissue and 91.8% and 52.9% for bone sarcoma, respectively. CONCLUSION: This is the first estimation of the burden of sarcoma based on an unselected sample of routine care data and the first estimation of the burden of sarcoma in Germany. We believe that the proposed methods offer a valuable approach for further outcomes research on cancer. PMID- 25801946 TI - [Gerontology/gerontopsychiatry]. PMID- 25801947 TI - [Novel methods for dementia diagnostics]. AB - Novel diagnostic methods, such as cerebrospinal fluid-based neurochemical dementia diagnostics (CSF-NDD) and [18F] amyloid positron emission tomography (PET) are meanwhile recommended for specific indications by international guidelines for the improved early and differential diagnostics of multigenic (sporadic) Alzheimer's dementia (AD). In the case of CSF-NDD the German neuropsychiatric guidelines have already been validated on the S3 level of evidence (http://www.DGPPN.de) and the additional consideration of [18F] amyloid PET in the current update of the guidelines is to be expected. By means of CSF NDD and/or [18F] amyloid-PET a predictive diagnosis of incipient (preclinical) AD is also possible for patients at high risk for AD who are in prodromal stages, such as mild cognitive impairment (MCI). As accompanying (secondary) preventive therapy of AD cannot be offered a predictive molecular dementia diagnostics is not recommended by the German neuropsychiatric dementia guidelines (http://www.DGPPN.de). However, novel diagnostic approaches, which offer molecular positive diagnostics of AD have already gained high relevance in therapy research as they allow promising preventive treatment avenues to be validated directly in the clinical trial. Moreover, future blood-based dementia diagnostics by means of multiplex assays is becoming increasingly more feasible; however, so far corresponding proteomic or epigenetic assays could not be consistently validated in independent studies. PMID- 25801948 TI - [Gait disorders in geriatric patients. Classification and therapy]. AB - BACKGROUND: Slow walking with reduced body dynamics is a characteristic feature of locomotion in the elderly. Impaired mobility and falls associated with gait disorders significantly contribute to a reduced quality of life in the elderly. OBJECTIVES: A gait disorder is not an inevitable consequence of aging. This article shows that it is worth recognizing specific deficits and differentiating specific aspects in multifactorial disorders because many causes can be well treated. Also provided are the bases for clinical classification and therapeutic principles. METHODS: Review of recent literature and clinical review based on own experience and own scientific results. RESULTS: Common causes of disturbed gait in the elderly are neurological deficits, including sensory deficits (e.g. peripheral neuropathy and vestibulopathy), neurodegeneration (e.g. cerebellar ataxia and parkinsonian syndromes, cognitive impairment (e.g. degenerative dementia), degeneration of joints (e.g. coxarthrosis) and general loss of muscle mass (sarcopenia). Furthermore, a fear of falling also contributes to the gait disorder. Multimodal therapies are often necessary and the principles are presented. CONCLUSION: Identification of deficits is a prerequisite for specific therapy. As physical activity protects against cognitive impairment, reduces the risk of falling and improves overall quality of life, a structured assessment of causes for gait impairment is crucial. PMID- 25801949 TI - [Successful aging: what can neurology and geriatrics contribute?]. AB - The relative proportion of elderly persons in Western societies is rapidly growing, leading to an increasing frequency of age-related neurological diseases (e.g. dementia) and functional impairments (e.g. immobility). This article argues that this development should prompt a new focus in medical care. The key questions should not only be how can we improve treatment of age-related disorders but also how can we prevent age-related disorders in the first place or at least substantially delay their onset? These questions touch on an even more profound question: how can successful aging be accomplished? That is, which factors and processes characterize successful aging both on a system and on a molecular level? Thus, the crucial societal, scientific and medical challenges for Western societies are to develop and implement measures of primary prevention of dysfunctional aging. The disease-centered framework which currently determines most clinical thinking, scientific research and third party funding has to be supplemented by a novel framework of successful aging. This article defines dysfunctional aging as a convergent downstream result of multiple interacting system processes. Each of these detrimental system processes must be targeted by specific measures of geriatric primary prevention. This, in turn, implies that geriatrics does not start in the elderly or with the onset of particular geriatric disorders. Instead, it starts in the daily practice of neurology and other medical disciplines taking care of persons aged 20-40 years who are largely healthy and in the middle of their professional and personal career. Or, in a nutshell, geriatrics starts right in the middle of medical care. PMID- 25801952 TI - Influence of the central diamagnetic cyanidometal on the distant magnetic interaction in cyanide-bridged Fe(III)-M(II)-Fe(III) complexes. AB - To investigate how the central diamagnetic cyanidometal influences the distant magnetic interaction of cyanide-bridged Fe(III)-M(II)-Fe(III) complexes, cis [Cp(dppe)Fe(II)(NC)M(II)(L)2(CN)Fe(II)(dppe) Cp][PF6]2 (M = Os, L = bpy 1; M = Os, L = phen 2; M = Fe, L = bpy 3; M = Fe, L = phen 4), and their one-electron oxidation products 5-7 and two-electron oxidation products 8-11 were synthesized and fully characterized. The cyclic voltammetry of complexes 1-4 suggests that both NC-Os(II)(L)2-CN and NC-Fe(II)(L)2-CN have electronic communication ability. The electronic absorption spectroscopy suggests the presence of the central M(II) to the terminal Fe(III) and the terminal Fe(II) to the terminal Fe(III) metal to metal charge transfers (MMCTs) in 5-7 and the central M(II) to the terminal Fe(III) MMCTs in 8-11. Moreover, for the two-electron oxidation products the MMCT energy increases with the central metal in the order Fe < Os < Ru. The two electron oxidation complexes 8 and 9 exhibit a strong antiferromagnetic coupling (J ~ -26 cm(-1)) between the two distant Fe(III) ions although separated by the diamagnetic cyanidometal NC-Os(II)(L)2-CN bridge. To the best of our knowledge, this is the strongest magnetic coupling between the distant paramagnetic metal ions across a diamagnetic cyanidometal bridge reported by far. For the two electron oxidation complexes 10 and 11 with the diamagnetic NC-Fe(II)(L)2-CN bridge, however, the distant two Fe(III) ions possess only very weak antiferromagnetic coupling (J = -0.15 and -0.19 cm(-1)). Combined with our previous reported results, it could be found that the magnetic coupling strength between the distant Fe(III) ions increases with the diamagnetic cyanidometal bridge in the order of Fe < Ru < Os. PMID- 25801950 TI - CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice. AB - AMD3100 (plerixafor), is a specific CXCR4 antagonist approved by the FDA for mobilizing hematopoietic stem cells from bone marrow to blood for transplantation in cancer. AMD3100 also mobilizes most mature leukocyte subsets to blood; however, their source and trafficking potential have not been fully delineated. Here, we show that a single injection of AMD3100 10 mg/kg into C57Bl/6 mice rapidly mobilizes (peak ~ 2.5 h) the same leukocyte subsets to blood as in humans. Using this model, we found that AMD3100 mobilization of neutrophils, lymphocytes, and monocytes to blood is not reduced by splenectomy or by blockade of lymphocyte egress from lymph node with FTY720, but is coupled to (i) reduced content of each of these cell types in the bone marrow; (ii) reduced T-cell numbers in thymuses; (iii) increased lymphocytes in lymph nodes; and (iv) increased neutrophil and monocyte content in the lung. Direct intrathymic labeling showed that AMD3100 selectively mobilizes naive thymic CD4(+) and CD8(+) T cells to blood. Finally, AMD3100-induced neutrophil mobilization to blood did not reduce neutrophil trafficking to thioglycollate-inflamed peritoneum. Thus, AMD3100 redistributes lymphocytes, monocytes, and neutrophils from primary immune organs to secondary immune organs, peripheral tissues, and blood, without compromising neutrophil trafficking to inflamed sites. PMID- 25801953 TI - An electrochemical DNA biosensor for evaluating the effect of mix anion in cellular fluid on the antioxidant activity of CeO2 nanoparticles. AB - CeO2 nanoparticles are of particular interest as a novel antioxidant for scavenging free radicals. However, some studies showed that they could cause cell damage or death by generating reactive oxygen species (ROS). Up to now, it is not well understood about these paradoxical phenomena. Therefore, many attentions have been paid to the factors that could affect the antioxidant activity of CeO2 nanoparticles. CeO2 nanoparticles would inevitably encounter body fluid environment for its potential medical application. In this work the antioxidant activity behavior of CeO2 nanoparticles is studied in simulated cellular fluid, which contains main body anions (HPO4(2-), HCO3(-), Cl(-) and SO4(2-)), by a method of electrochemical DNA biosensor. We found that in the solution of Cl(-) and SO4(2-), CeO2 nanoparticles can protect DNA from damage by hydroxyl radicals, while in the presence of HPO4(2-) and HCO3(-), CeO2 nanoparticles lose the antioxidant activity. This can be explained by the cerium phosphate and cerium carbonate formed on the surface of the nanoparticles, which interfere with the redox cycling between Ce(3+) and Ce(4+). These results not only add basic knowledge to the antioxidant activity of CeO2 nanoparticles under different situations, but also pave the way for practical applications of nanoceria. Moreover, it also shows electrochemical DNA biosensor is an effective method to explore the antioxidant activity of CeO2 nanoparticles. PMID- 25801954 TI - Edge promoted ultrasensitive electrochemical detection of organic bio-molecules on epitaxial graphene nanowalls. AB - We report the simultaneous electrochemical detection of dopamine (DA), uric acid (UA) and ascorbic acid (AA) on three dimensional (3D) unmodified 'as-grown' epitaxial graphene nanowall arrays (EGNWs). The 3D few layer EGNWs, unlike the 2D planar graphene, offers an abundance of vertically oriented nano-graphitic-edges that exhibit fast electron-transfer kinetics and high electroactive surface area to geometrical area (EAA/GA~134%), as evident from the Fe(CN)6(3-/4-) redox kinetic study. The hexagonal sp(2)-C domains, on the basal plane of the EGNWs, facilitate efficient adsorption via spontaneous pi-pi interaction with the aromatic rings in DA and UA. Such affinity together with the fast electron kinetics enables simultaneous and unambiguous identification of individual AA, DA and UA from their mixture. The unique edge dominant EGNWs result in an unprecedented low limit of detection (experimental) of 0.033 nM and highest sensitivity of 476.2 uA/uM/cm(2), for UA, which are orders of magnitude higher than comparable existing reports. A reaction kinetics based modeling of the edge oriented 3D EGNW system is proposed to illustrate the superior electro-activity for bio-sensing applications. PMID- 25801951 TI - The prognostic significance of beta-catenin, cyclin D1 and PIN1 in minor salivary gland carcinoma: beta-catenin predicts overall survival. AB - Minor salivary gland carcinoma is a rare and heterogeneous type of cancer. Molecular prognostic and predictive markers are sparse. The aim of this study was to identify new prognostic and predictive markers in minor salivary gland carcinoma. 50 tissue samples of carcinomas of the minor salivary glands (adenoid cystic carcinoma n = 23, mucoepidermoid carcinoma n = 12, adenocarcinoma n = 10, carcinoma ex pleomorphic adenoma n = 2, salivary duct carcinoma n = 1, clear cell carcinoma n = 1, basal cell carcinoma n = 1) were immunohistochemically stained for beta-catenin, cyclin D1 and PIN1. Expression patterns were analyzed and correlated to clinical outcome of 37 patients with complete clinical data. High expression of membranous beta-catenin was linked to significantly better overall survival in patients with adenoid cystic carcinoma (log rank test, chi (2) = 13.3, p = .00397, Bonferroni corrected p = .024). PIN1 and cyclin D1 did not show any significant correlation to patients' clinical outcome. Expression of beta catenin in adenoid cystic carcinoma of the minor salivary glands significantly correlates with better overall survival. Hence, evaluation of beta-catenin might serve as a clinical prognostic marker. PMID- 25801955 TI - Aggregation induced Raman scattering of squaraine dye: Implementation in diagnosis of cervical cancer dysplasia by SERS imaging. AB - The extent of squaraine dye aggregation that reflects on surface enhanced Raman signal scattering (SERS) intensity upon adsorption on nano-roughened gold surface has been investigated. Here we have synthesized a serious of six squaraine dyes consisting of two different electron donor moiety i.e. 1,1,2-trimethyl-1H benzo[e]indole and 2-methylbenzo[d]thiazole which modulates the chemisorptions and hydrophobicity being designated as SQ1, SQ2, SQ3, SQ4, SQ5 and SQ6. Interestingly, SQ2 (mono lipoic acid appended), SQ5 and SQ6 (conjugated with hexyl and dodecyl side chain) squaraine derivatives having more tendency of aggregation in DMSO-water mixed solvent showed significant increase of Raman scattering in the fingerprint region when chemisorbed on spherical gold nanoparticles. Two sets of SERS nanotags were prepared with colloidal gold nanoparticle (Au-NPs size: 40 nm) by incorporating Raman reporters SQ2 and SQ5 followed by thiolated PEG encapsulation (SH-PEG, SH-PEG-COOH) denoted as AuNPs SQ2-PEG and AuNPs-SQ5-PEG. Further conjugation of these nanotag with monoclonal antibodies specific to over expressed receptors, EGFR and p16/Ki-67 in cervical cancer cell, HeLa showed prominent SERS mapping intensity and selectivity towards cell surface and nucleus. The fast and accurate recognition obtained by antibody triggered SERS-nanotag has been compared with conventional time consuming immunocytochemistry technique which prompted us to extend further investigation using real patient cervical smear sample for a non-invasive, ultrafast and accurate diagnosis. PMID- 25801956 TI - Mesoporous carbon nitride-tungsten oxide composites for enhanced photocatalytic hydrogen evolution. AB - Composites of mesoporous polymeric carbon nitride and tungsten(VI) oxide show very high photocatalytic activity for the evolution of hydrogen from water under visible light and in the presence of sacrificial electron donors. Already addition of very small amounts of WO3 yields up to a twofold increase in the efficiency when compared to bulk carbon nitrides and their composites and more notably even to the best reported mesoporous carbon nitride-based photocatalytic materials. The higher activity can be attributed to the high surface area and synergetic effect of the carbon nitrides and the WO3 resulting in improved charge separation through a photocatalytic solid-state Z-scheme mechanism. PMID- 25801957 TI - Endurance training facilitates myoglobin desaturation during muscle contraction in rat skeletal muscle. AB - At onset of muscle contraction, myoglobin (Mb) immediately releases its bound O2 to the mitochondria. Accordingly, intracellular O2 tension (PmbO2) markedly declines in order to increase muscle O2 uptake (mVO2). However, whether the change in PmbO2 during muscle contraction modulates mVO2 and whether the O2 release rate from Mb increases in endurance-trained muscles remain unclear. The purpose of this study was, therefore, to determine the effect of endurance training on O2 saturation of Mb (SmbO2) and PmbO2 kinetics during muscle contraction. Male Wistar rats were subjected to a 4-week swimming training (Tr group; 6 days per week, 30 min * 4 sets per day) with a weight load of 2% body mass. After the training period, deoxygenated Mb kinetics during muscle contraction were measured using near-infrared spectroscopy under hemoglobin-free medium perfusion. In the Tr group, the VmO2peak significantly increased by 32%. Although the PmbO2 during muscle contraction did not affect the increased mVO2 in endurance-trained muscle, the O2 release rate from Mb increased because of the increased Mb concentration and faster decremental rate in SmbO2 at the maximal twitch tension. These results suggest that the Mb dynamics during muscle contraction are contributing factors to faster VO2 kinetics in endurance-trained muscle. PMID- 25801958 TI - PI3K/mTOR mediate mitogen-dependent HDAC1 phosphorylation in breast cancer: a novel regulation of estrogen receptor expression. AB - Histone deacetylase 1 (HDAC1) is an important epigenetic controller involved in transcriptional regulation through modification of chromatin structure. Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer. Downregulation of estrogen receptor alpha (ERalpha) expression is one of the mechanisms behind the acquisition of endocrine resistance. Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy. Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer, reversing also acquired hormone resistance. Here we show how mitogens, activating the PI3K/mTOR pathway, trigger the phosphorylation of HDAC1 in breast cancer cells, which is completely dependent on the activity of the p70 S6 kinase (S6K1). Our findings show that S6K1, overexpressed in many breast cancers, controls HDAC1-dependent transcriptional regulation of ERalpha levels upon mitogenic stimuli, controlling HDAC1 recruitment to the ERalpha promoter. Furthermore, cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation. This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease. PMID- 25801959 TI - Ndfip1 represses cell proliferation by controlling Pten localization and signaling specificity. AB - Pten controls a signaling axis that is implicated to regulate cell proliferation, growth, survival, migration, and metabolism. The molecular mechanisms underlying the specificity of Pten responses to such diverse cellular functions are currently poorly understood. Here we report the control of Pten activity and signaling specificity during the cell cycle by Ndfip1 regulation of Pten spatial distribution. Genetic deletion of Ndfip1 resulted in a loss of Pten nuclear compartmentalization and increased cell proliferation, despite cytoplasmic Pten remaining active in regulating PI3K/Akt signaling. Cells lacking nuclear Pten were found to have dysregulated levels of Plk1 and cyclin D1 that could drive cell proliferation. In vivo, transgene expression of Ndfip1 in the developing brain increased nuclear Pten and lengthened the cell cycle of neuronal progenitors, resulting in microencephaly. Our results show that local partitioning of Pten from the cytoplasm to the nucleus represents a key mechanism contributing to the specificity of Pten signaling during cell proliferation. PMID- 25801960 TI - Methuselah regulates longevity via dTOR: a pathway revealed by small-molecule ligands. PMID- 25801961 TI - Nitrogen-Doped Carbon Membrane Derived from Polyimide as Free-Standing Electrodes for Flexible Supercapacitors. AB - Nitrogen-doped carbon materials have attracted great interest in the energy storage due to the better electrochemical performances than the pristine carbon materials. In this work, a heterocyclic polyimide containing benzopyrrole and benzimidazole rings is carbonized to fabricate the free-standing and flexible carbon membrane (CarbonPI ) with a high packing density (0.89 cm(-3)), in which the location of nitrogen atoms in the doped configurations is easily controlled. XPS analysis indicates that quaternary nitrogen is the predominant nitrogen-doped configurations. The high content of nitrogen effectively improves the wettability of the electrode materials. The CarbonPI membrane exhibits excellent volumetric capacitance (159.3 F cm(-3) at 1 A g(-1)), high rate capability (127.5 F cm(-3) at 7 A g(-1)), and long cycle life. TEM images reveal the very slight change of the microstructure of graphitic nanosheet of CarbonPI during the long charge/discharge cycles. PMID- 25801963 TI - Biomolecular assemblies combining two orthogonal copper-mediated ligations in a one-pot reaction. AB - The access to multifunctional biomolecular compounds involves multistep reactions usually with a complicated protection scheme and lengthy separation processes. The development of a strategy combining several orthogonal ligations is highly desirable. Herein, we introduce a new method that involves two orthogonal copper mediated ligations of azide with alkyne, and amine with thioacid. We established compatible conditions to carry out molecular assemblies of three different chemical components in a single one-pot reaction. The effectiveness of the method was demonstrated in the synthesis of biomolecular compounds that are known to target tumor tissue. The simple reaction conditions suggest that this strategy of combining several orthogonal ligations could have wide potential for the chemical synthesis of complex macromolecules. PMID- 25801964 TI - Structural biology turned on its head. AB - NMR spectroscopy and ITC have recently been combined to demonstrate how phosphorylation of the intrinsically disordered eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) induces folding into a stable three dimensional structure. The classical structure-function paradigm is inverted, with phosphorylation-induced folding inhibiting binding to the eukaryotic translation initiation factor 4E (eIF4E) and thereby contributing to regulation of the interaction. PMID- 25801965 TI - Arachis hypogaea PGPR isolated from Argentine soil modifies its lipids components in response to temperature and salinity. AB - The aim of this work was to clarify the mechanism related to plant growth promoting of a bacterial strain (L115) isolated from Arachis hypogaea rhizospheres and the effects of high growth temperature and salinity on phospholipids and fatty acids composition. L115 was isolated from peanut rhizospheres and identified according to the sequence analysis of the 16S rRNA gene. Phenotypic, metabolic and plant growth promoting rhizobacteria (PGPR) characteristics of L115 were tested. Inoculation test in plant growth chamber was performed. In addition, L115 was exposed to a 37 degrees C and 300 mM NaCl and phospholipids and fatty acid composition were evaluated. L115 strain was identified as Ochrobactrum intermedium and was able to increase the peanut shoot and root length as well as dry weight, indicating a PGPR role by being able to produce indole acetic acid and siderophores and present ACC deaminase activity. In addition, L115 showed tolerance to both high growth temperature and 300 mM NaCl. The most striking change was a decreased percentage of 18:1 fatty acid and an increase in 16:0 and 18:0 fatty acids, under high growth temperature or a combination of increased temperature and salinity. The most important change in phospholipid levels was an increase in phosphatidylcholine biosynthesis in all growth conditions. L115 can promote the growth of peanut and can tolerate high growth temperature and salinity modifying the fatty acid unsaturation degree and increasing phosphatidylcholine levels. This work is the first to report the importance of the genus Ochrobactrum as PGPR on peanut growth as well as on the metabolic behaviour against abiotic stresses that occur in soil. This knowledge will be useful for developing strategies to improve the growth of this bacterium under stress and to enhance its bioprocess for the production of inoculants. PMID- 25801966 TI - Bacterial communities in thermophilic H2-producing reactors investigated using 16S rRNA 454 pyrosequencing. AB - In this study, the composition and diversity of the bacterial community in thermophilic H2-producing reactors fed with glucose were investigated using pyrosequencing. The H2-producing experiments in batch were conducted using 0.5 and 2.0 g l(-1) glucose at 550 degrees C. Under the two conditions, the H2 production and yield were 1.3 and 1.6 mol H2 mol glucose(-1), respectively. Acetic, butyric, iso-butyric, lactic and propionic acids were detected in the two reactors. The increase in substrate concentration favored a high H2 yield. In this reactor, a predominance of acetic and iso-butyric acids, 27.7% and 40%, were measured, respectively. By means of pyrosequencing, a total of 323 and 247 operational taxonomic units were obtained, with a predominance of the phylum Firmicutes (68.73-67.61%) for reactors with 0.5 and 2.0 g l(-1) glucose, respectively. Approximately 40.55% and 62.34% of sequences were affiliated with Thermoanaerobacterium and Thermohydrogenium, microorganisms that produce H2 under thermophilic conditions. PMID- 25801967 TI - Identification of BagI as a positive transcriptional regulator of bagremycin biosynthesis in engineered Streptomyces sp. Tu 4128. AB - Bagremycin A and B, two novel antibiotics from Streptomyces sp. Tu 4128, show a moderate activity against fungi, Gram-positive bacteria and tumor cell and have potential application values in the fields of medicine and agriculture. In this study, we obtained a bagI deletion mutant by in-frame deletion. The assays of bagI-deletion and complementation strains revealed that it was essential to bagremycin biosynthesis. Secondly, the impact of bagI mutants on mycelial growth, sporulation and pigment yields was explored throughout secondary metabolism. SEM images displayed that bagI mutation delayed the mycelium growth and sporulation and reduced pigment yields. Moreover, the yields of bagremycin A and B increased 2.5-fold and 2.6-fold in bagI-overexpressed strain compared to WT. Thirdly, we investigated genes associated with bagremycin biosynthesis by real-time fluorescent quantitative PCR (qRT-PCR). Data showed that BagI played a role of transcriptional activator in the course of bagremycin biosynthesis. This provides us new insights into the regulatory network of bagremycin biosynthesis. PMID- 25801968 TI - Generation of the natamycin analogs by gene engineering of natamycin biosynthetic genes in Streptomyces chattanoogensis L10. AB - The polyene antibiotic natamycin is widely used as an antifungal agent in both human therapy and the food industry. Here we obtained four natamycin analogs with high titers, including two new compounds, by engineering of six post-polyketide synthase (PKS) tailoring enzyme encoding genes in a natamycin industrial producing strain, Streptomyces chattanoogensis L10. Precise analysis of S. chattanoogensis L10 culture identified natamycin and two natamycin analogs, 4,5 deepoxy-natamycin and 4,5-deepoxy-natamycinolide. The scnD deletion mutant of S. chattanoogensis L10 did not produce natamycin but increased the titer of 4,5 deepoxy-natamycin. Inactivation of each of scnK, scnC, and scnJ in S. chattanoogensis L10 abolished natamycin production and accumulated 4,5-deepoxy natamycinolide. Deletion of scnG in S. chattanoogensis L10 resulted in production of two new compounds, 4,5-deepoxy-12-decarboxyl-12-methyl-natamycin and its dehydration product without natamycin production. Inactivation of the ScnG associated ferredoxin ScnF resulted in impaired production of natamycin. Bioassay of these natamycin analogs showed that three natamycin analogs remained antifungal activities. We found that homologous glycosyltransferases genes including amphDI and nysDI can partly complement the DeltascnK mutant. Our results here also support that ScnG, ScnK, and ScnD catalyze carboxylation, glycosylation, and epoxidation in turn in the natamycin biosynthetic pathway. Thus this paper provided a method to generate natamycin analogs and shed light on the natamycin biosynthetic pathway. PMID- 25801969 TI - Isolation, characterization, and evaluation of multi-trait plant growth promoting rhizobacteria for their growth promoting and disease suppressing effects on ginger. AB - In this study, 100 PGPR strains isolated from different varieties of ginger (Zingiber officinale Rosc.) were first characterized for their morphological, biochemical, and nutrient mobilization traits in vitro. The PGPR were also screened in vitro for inhibition of Pythium myriotylum causing soft rot in ginger. Results revealed that only five PGPR showed >70% suppression of P. myriotylum. These 5 PGPR viz., GRB (Ginger rhizobacteria) 25--Burkholderia cepacia, GRB35--Bacillus amyloliquefaciens; GRB58--Serratia marcescens; GRB68--S. marcescens; GRB91--Pseudomonas aeruginosa were used for further growth promotion and biocontrol studies in the green house and field. The green house study revealed that GRB35 (B. amyloliquefaciens) and GRB68 (S. marcescens) registered markedly higher sprouting (96.3%) and lower disease incidence (48.1%) and greater rhizome yield (365.6 g pot(-1) and 384.4 g pot(-1), respectively), while control registered the lowest sprouting (66%), maximum soft rot incidence (100%) and lowest rhizome yield (134.4 g pot(-1)). In the field experiments also, GRB68 (S. marcescens) and GRB35 (B. amyloliquefaciens) registered the greatest sprouting (80% each), markedly lower soft rot incidence (5.2% and 7.3%, respectively) and higher yield (5.0 and 4.3 kg(3)m(-2), respectively) compared to chemicals like Streptomycin sulphate (73.0%, 18.5% and 2.3 kg(3)m(-2), respectively), Metalaxyl Mancozeb (73.0%, 14.0% and 3.8 kg(3)m(-2), respectively) and control (73.0%, 25.1% and 2.2 kg 3m(-2), respectively). Overall, the results suggested that for growth promotion and management of soft rot disease in ginger, GRB35 B. amyloliquefaciens and GRB68 S. marcescens could be good alternatives to chemical measures. Since, the latter has been reported to be an opportunistic human pathogen, we recommend the use of B. amyloliquefaciens for integration into nutrient and disease management schedules for ginger cultivation. PMID- 25801970 TI - The rad2 gene of haloarchaeum Halobacterium salinarum is functional in the repair of ultraviolet light induced DNA photoproducts. AB - There are a lot of bacterial and eukaryotic DNA repair gene homologs among sequenced archaeal genomes but there is little information about DNA repair mechanisms and the interaction of involved repair proteins. In order to study DNA repair mechanisms in the third domain of life, we studied these processes in the model archaeon, Halobacterium salinarum. H. salinarum has homologs of eukaryotic nucleotide excision repair genes such as rad2 gene. A functional analysis of rad2 was performed by knocking down of this gene. We introduced an antisense RNA expression vector into the cells and the sensitivity of transformants against ultraviolet light exposure was measured to determine whether rad2 gene performs any role in the repair of the DNA lesions induced by UV light or not. Our data suggests that rad2 is functional in this pathway and knocked down strains were unable to completely repair the UV induced DNA damages. In this study, for the first time antisense RNA is used for functional analysis of a gene in H. salinarum and it is shown that antisense RNA could be used as a reliable genetic tool for understanding of the archaeal genetics. PMID- 25801971 TI - Melting curve analysis of a groEL PCR fragment for the rapid genotyping of strains belonging to the Lactobacillus casei group of species. AB - Lactobacillus casei group (Lcs) consists of three phylogenetically closely related species (L. casei, L. paracasei, and L. rhamnosus), which are widely used in the dairy and probiotic industrial sectors. Strategies to easily and rapidly characterize Lcs are therefore of interest. To this aim, we developed a method according to a technique known as high resolution melting analysis (HRMa), which was applied to a 150 bp groEL gene fragment. The analysis was performed on 53 Lcs strains and 29 strains representatives of species that are commonly present in dairy and probiotic products and can be most probably co-isolated with Lcs strains. DNA amplification was obtained only from Lcs strains, demonstrating the specificity of the groEL primers designed in this study. The HRMa clustered Lcs strains in three groups that exactly corresponded to the species of the L. casei group. A following HRMa separated the 39 L. paracasei strains in two well distinct intraspecific groups, indicating the possible existence of at least two distinct genotypes inside the species. Nonetheless, the phenotypic characterization demonstrated that the genotypes do not correspond to the two L. paracasei subspecies, namely paracasei and tolerans. In conclusion, the melting curve analysis developed in this study is demonstrably a simple, labor-saving, and rapid strategy obtain the genotyping of a bacterial isolate and simultaneously potentially confirm its affiliation to the L. casei group of species. The application of this method to a larger collection of strains may validate the possibility to use the proposed HRMa protocol for the taxonomic discrimination of L. casei group of species. In general, this study suggests that HRMa can be a suitable technique for the genetic typization of Lactobacillus strains. PMID- 25801972 TI - Evaluation of Zygosaccharomyces bailii BCV 08 as a co-starter in wine fermentation for the improvement of ethyl esters production. AB - Zygosaccharomyces bailii BCV 08, a yeast isolated from red wine barrels in Brazil, was evaluated as co-starter in fermentations with Saccharomyces cerevisiae. Z. bailii BCV 08 was preliminarily shown to produce high levels of esters, and the production was optimized in bench and bioreactor scales using grape must. White wine vinifications were conducted with mixed cultures containing different proportions of Z. bailii BCV 08 and an enological strain of S. cerevisiae. In all trials that contained Z. bailii BCV 08, the production of ethyl esters was enhanced in comparison to the vinification control. Our results clearly show the potential of Z. bailii BCV 08 as a mixed starter with S. cerevisiae in order to increase the aromatic complexity of wine. PMID- 25801973 TI - Genetic analysis of plant endophytic Pseudomonas putida BP25 and chemo-profiling of its antimicrobial volatile organic compounds. AB - Black pepper associated bacterium BP25 was isolated from root endosphere of apparently healthy cultivar Panniyur-5 that protected black pepper against Phytophthora capsici and Radopholus similis - the major production constraints. The bacterium was characterized and mechanisms of its antagonistic action against major pathogens are elucidated. The polyphasic phenotypic analysis revealed its identity as Pseudomonas putida. Multi locus sequence typing revealed that the bacterium shared gene sequences with several other isolates representing diverse habitats. Tissue localization assays exploiting green fluorescence protein expression clearly indicated that PpBP25 endophytically colonized not only its host plant - black pepper, but also other distantly related plants such as ginger and arabidopsis. PpBP25 colonies could be enumerated from internal tissues of plants four weeks post inoculation indicated its stable establishment and persistence in the plant system. The bacterium inhibited broad range of pathogens such as Phytophthora capsici, Pythium myriotylum, Giberella moniliformis, Rhizoctonia solani, Athelia rolfsii, Colletotrichum gloeosporioides and plant parasitic nematode, Radopholus similis by its volatile substances. GC/MS based chemical profiling revealed presence of Heneicosane; Tetratetracontane; Pyrrolo [1,2-a] pyrazine-1,4-dione, hexahydro-3-(2-methylpropyl); Tetracosyl heptafluorobutyrate; 1-3-Eicosene, (E)-; 1-Heneicosanol; Octadecyl trifluoroacetate and 1-Pentadecene in PpBP25 metabolite. Dynamic head space GC/MS analysis of airborne volatiles indicated the presence of aromatic compounds such as 1-Undecene;Disulfide dimethyl; Pyrazine, methyl-Pyrazine, 2,5-dimethyl-; Isoamyl alcohol; Pyrazine, methyl-; Dimethyl trisulfide, etc. The work paved way for profiling of broad spectrum antimicrobial VOCs in endophytic PpBP25 for crop protection. PMID- 25801974 TI - Structure and function of a Clostridium difficile sortase enzyme. AB - Sortase enzymes are responsible for covalent anchoring of specific proteins to the peptidoglycan of the cell wall of gram-positive bacteria. In some gram positive bacteria (e.g. Staphylococcus aureus), sortases have been found to be essential for pathogenesis and their inhibitors are under development as potential novel therapeutics. Here we provide the first report on the structural characterisation of the C. difficile sortase. An active site mutant was crystallised and its structure determined to 2.55 A by X-ray diffraction to provide structural insight into its catalytic mechanism. In order to elucidate the role of the sortase in the cell wall biogenesis, a C. difficile sortase knockout strain was constructed by intron mutagenesis. Characterisation of this mutant led to the discovery that the putative adhesin CD0386 is anchored to the peptidoglycan of C. difficile by the sortase SrtB and that an SPKTG peptide motif is involved in the transpeptidation reaction with the C. difficile peptidoglycan. In an animal model for C. difficile infection, the SrtB mutant caused disease at a similar rate of onset as the wild type strain. In conclusion, our detailed study shows that the SrtB enzyme from C. difficile does not play an essential role in pathogenesis. PMID- 25801975 TI - Nitric oxide affects UbcH10 levels differently in type 1 and type 2 diabetic rats. AB - BACKGROUND: Nitric oxide (NO) more effectively inhibits neointimal hyperplasia in type 2 diabetic versus nondiabetic and type 1 diabetic rodents. NO also decreases the ubiquitin-conjugating enzyme UbcH10, which is critical to cell-cycle regulation. This study seeks to determine whether UbcH10 levels in the vasculature of diabetic animal models account for the differential efficacy of NO at inhibiting neointimal hyperplasia. MATERIALS AND METHODS: Vascular smooth muscle cells (VSMCs) harvested from nondiabetic lean Zucker (LZ) and type 2 diabetic Zucker diabetic fatty (ZDF) rats were exposed to high glucose (25 mM) and high insulin (24 nM) conditions to mimic the diabetic environment in vitro. LZ, streptozotocin-injected LZ (STZ, type 1 diabetic), and ZDF rats underwent carotid artery balloon injury (+/-10 mg PROLI/NO), and vessels were harvested at 3 and 14 d. UbcH10 was assessed by Western blotting and immunofluorescent staining. RESULTS: NO more effectively reduced UbcH10 levels in LZ versus ZDF VSMCs; however, addition of insulin and glucose dramatically potentiated the inhibitory effect of NO on UbcH10 in ZDF VSMCs. Three days after balloon injury, Western blotting showed NO decreased free UbcH10 and increased polyubiquitinated UbcH10 levels by 35% in both STZ and ZDF animals. Fourteen days after injury, immunofluorescent staining showed increased UbcH10 levels throughout the arterial wall in all animal models. NO decreased UbcH10 levels in LZ and STZ rats but not in ZDF. CONCLUSIONS: These data suggest a disconnect between UbcH10 levels and neointimal hyperplasia formation in type 2 diabetic models and contribute valuable insight regarding differential efficacy of NO in these models. PMID- 25801976 TI - Viral-induced CD28 loss evokes costimulation independent alloimmunity. AB - BACKGROUND: Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T-cell receptor and CD28 engagement are known to initiate T-cell activation, many human antigen-experienced T-cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28(-) T-cells resulting from viral antigen exposure. MATERIALS AND METHODS: We infected C57BL/6 mice with polyomavirus (a BK virus analog), murine cytomegalovirus (a human cytomegalovirus analog), and gammaherpesvirus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then used mixed lymphocyte reaction (MLR) assays to assess the alloreactive response of these mice against major histocompatibility complex-mismatched cells. RESULTS: We demonstrated that infection with polyomavirus, murine CMV, and HV68 can induce CD28 downregulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against major histocompatibility complex-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T cell expansion is required for the increased alloreactivity. CONCLUSIONS: Virus exposure results in reduced T-cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 downregulation after viral infection may play a seminal role in driving CoBRR. PMID- 25801977 TI - Protein markers related to vascular responsiveness after hemorrhagic shock in rats. AB - BACKGROUND: Vascular hyporesponsiveness is an important pathophysiological feature of some critical conditions such as hemorrhagic shock. Many proteins and molecules are involved in the regulation of the pathologic process, however the mechanism has still remained unclear. Our study was intended to look for the related protein markers involved in the regulation of vascular reactivity after hemorrhagic shock. METHODS: Differential in-gel electrophoresis and tandem mass spectrometry were applied to quantify the differences of protein expression in the superior mesenteric arteries from hemorrhagic shock and normal rats. RESULTS: A total of 2317 differentially expressed protein spots in the superior mesenteric arteries of rats before and after hemorrhagic shock were found, and 146 protein spots were selected for tandem mass spectrometry identification. Thirty-seven differentially expressed proteins were obtained, including 3 uncharacterized proteins and 34 known proteins. Among them, heat shock protein beta-1 and calmodulin were the known proteins involved in the occurrence of vascular hyporesponsiveness. Bioinformatics analysis results showed that 18 proteins were related to vasoconstriction, 11 proteins may be involved in other vascular functions such as regulation of angiogenesis and endothelial cell proliferation. CONCLUSIONS: The changes of vascular responsiveness after hemorrhagic shock in rats may be associated with the upregulation or downregulation of previously mentioned protein expressions. These findings may provide the basis for understanding and further study of the mechanism and treatment targets of vascular hyporeactivity after shock. PMID- 25801979 TI - Calibration of optimal use parameters for an ultraviolet light-emitting diode in eliminating bacterial contamination on needleless connectors. AB - AIMS: Needleless connectors may develop bacterial contamination and cause central line-associated bloodstream infections (CLABSI) despite rigorous application of best-practice. Ultraviolet (UV) light-emitting diodes (LED) are an emerging, increasingly affordable disinfection technology. We tested the hypothesis that a low-power UV LED could reliably eliminate bacteria on needleless central-line ports in a laboratory model of central-line contamination. METHODS AND RESULTS: Needleless central-line connectors were inoculated with Staphylococcus aureus. A 285 nm UV LED was used in calibrated fashion to expose contaminated connectors. Ports were directly applied to agar plates and flushed with sterile saline, allowing assessment of bacterial survival on the port surface and in simulated usage flow-through fluid. UV applied to needleless central-line connectors was highly lethal at 0.5 cm distance at all tested exposure times. At distances >1.5 cm both simulated flow-through and port surface cultures demonstrated significant bacterial growth following UV exposure. Logarithmic-phase S. aureus subcultures were highly susceptible to UV induction/maintenance dosing. CONCLUSIONS: Low power UV LED doses at fixed time and distance from needleless central-line connector ports reduced cultivable S. aureus from >10(6) CFU to below detectable levels in this laboratory simulation of central-line port contamination. SIGNIFICANCE AND IMPACT OF THE STUDY: Low-power UV LEDs may represent a feasible alternative to current best-practice in connector decontamination. PMID- 25801980 TI - Consumption of polyphenol-rich peach and plum juice prevents risk factors for obesity-related metabolic disorders and cardiovascular disease in Zucker rats. AB - Polyphenols from fruits have been implied in the prevention of risk factors for cardiometabolic disorders and cardiovascular disease. The purpose of this study was to investigate if the consumption of peach and plum juice has a protective effect against obesity and metabolic disorders that promote the development of cardiovascular diseases. Obese Zucker and lean rats were fed with peach, plum juice ad libitum or placebo. Body weight gain, biochemical markers and molecular markers for inflammation and cardiovascular disease in heart tissue were quantified. Results show that peach and plum juice consumption protected against a combination of obesity-induced metabolic disorders including hyperglycemia, insulin and leptin resistance, dyslipidemia and low-density lipoprotein oxidation. This was accompanied by a decreased expression of pro-atherogenic and pro-inflammatory biomarkers in plasma and heart tissues including intercellular cell adhesion molecule-1, monocyte chemotactic protein-1, NF-kappaB and foam cell adherence to aortic arches. In addition, peach and plum juice consumption decreased the levels of angiotensin II in plasma and its receptor Agtr1 in heart tissues, suggesting a role of peach and plum polyphenols as peroxisome proliferator-activated receptor-gamma agonists. Furthermore, only plum juice significantly prevented body weight gain and increased the ratio high-density lipoprotein cholesterol/total cholesterol in plasma. This effect is most likely attributed to the plum's higher content of polyphenols (three times that of peach). Altogether, these results imply that cardioprotective effects can be achieved by replacing drinks high in sugar content with fruit juice rich in polyphenols in a diet. PMID- 25801982 TI - Welcome Professor Allan Pacey as the new Editor-in-Chief of Human Fertility. PMID- 25801981 TI - Changes in serum alpha fetoprotein in patients with recurrent hepatocellular carcinoma following hepatectomy. AB - BACKGROUND AND AIM: To study the change in serum alpha fetoprotein (AFP) of patients with recurrent hepatocellular carcinoma (HCC) after curative resection and to analyze its effect on the survival. METHODS: We prospectively collected 981 consecutive patients with post-resectional recurrent HCC between 2005 and 2010 at the Eastern Hepatobiliary Surgery Hospital. According to the change of AFP from the initial stage to recurrent stage, the patients were divided into stable-L (20 ng/mL to 20 ng/mL, n = 296), stable-M (20-400 ng/mL to 20-400 ng/mL, n = 102), stable-H (400 ng/mL to 400 ng/mL, n = 212), decreasing (n = 287), and increasing (n = 84) groups. The overall survival (OS) and recurrence to death survival (RTDS) were analyzed using Kaplan-Meier method. Multivariate analysis was performed by Cox proportional hazards regression. RESULTS: The stable H/increasing and stable-L/decreasing groups had the lowest and highest 5-year OS and RTDS rates (10.8%/18.8% vs 56.3%/55.0%; 3.4%/5.1% vs 37.7%/33.2%; both P < 0.001), while the stable-M group had the lower rates, which were 29.8% and 23.6% (for OS and RTDS: vs stable-L, P < 0.001 and 0.002; vs deceasing, P = 0.001 and 0.012; vs increasing, P = 0.113 and 0.011; vs stable-H, both P < 0.001). Cox regression analysis showed that AFP inconsistency was an independent factor affecting RTDS (decreasing vs stable-L, hazard ratio: 1.10, 95% confidence interval: 0.79-1.54, P = 0.575; increasing vs stable-L, 2.93, 2.06-4.16, P < 0.001). CONCLUSIONS: The AFP inconsistency was an important prognostic factor for recurrent HCC. PMID- 25801978 TI - Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia. AB - An accumulating understanding of the complex pathogenesis of acute myeloid leukemia (AML) continues to lead to promising therapeutic approaches. Among the key aberrant intracellular signaling pathways involved in AML, the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is of major interest. This axis modulates a wide array of critical cellular functions, including proliferation, metabolism, and survival. Pharmacologic inhibitors of components of this pathway have been developed over the past decade, but none has an established role in the treatment of AML. This review will discuss the preclinical data and clinical results driving ongoing attempts to exploit the PI3K/AKT/mTOR pathway in patients with AML and address issues related to negative feedback loops that account for leukemic cell survival. Targeting the PI3K/AKT/mTOR pathway is of high interest for the treatment of AML, but combination therapies with other targeted agents may be needed to block negative feedback loops in leukemia cells. PMID- 25801991 TI - CZT camera: moving beyond classical CAD detection? PMID- 25801993 TI - Superficial anal canal squamous cell carcinoma diagnosed using narrow-band imaging and treated by endoscopic submucosal dissection. PMID- 25801994 TI - [Odontogenic tumor with Liesegang rings]. PMID- 25801995 TI - [Thyroid and squamous cells]. PMID- 25801992 TI - ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment. AB - PURPOSE: To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. METHODS: ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and (64)Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of (64)Cu NOTA-ALT-836-Fab. RESULTS: ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of (64)Cu-NOTA-ALT-836-Fab (5.1 +/- 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 +/- 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. CONCLUSION: (64)Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. PMID- 25801997 TI - Four years of LC-MS/MS method for quantification of 25-hydroxyvitamin D (D2+D3) for clinical practice. AB - Many methods for routine total plasma/serum 25-hydroxyvitamin D (25OHD) measurements are available from automated immunoassays to the most specific LC MS/MS techniques. These last ones are nowadays numerous, still perfectible but more powerful than immunoassays in specific illnesses. We presented a robust method for simple quantification of 25-hydroxyvitamin D(2) (25OHD(2)) and 25 hydroxyvitamin D(3) (25OHD(3)) in human plasma by LC-APCI-MS/MS. This method is reliable and easy to perform for clinical measurements as we report a 4-year of clinical laboratory use. A brief off-line sample pretreatment (protein precipitation with addition of the internal standard) was realized then the supernatant was loaded into 96-well plates and analyzed by an online SPE-LC/MS/MS method on an APCI mode. 25OHD(2) and 25OHD(3) were both measured. The chromatographic system was thought and optimized for providing a dedicated line for this measurement on a shared instrument. The linearity was tested up to 380 nmol/L for both 25OHD(2) and 25OHD(3). The limit of quantification (LOQ) was 7 and 8 nmol/L for 25OHD3 and 25OHD(2), respectively. Routine imprecision and bias were found in agreement with recommended limits for routine testing, CV<=10% and bias<=5%. Since July 2010, our participation to DEQAS was successfully validated. This simple robust online SPE-LC/MS/MS method is suitable for routine measurement of 25OHD(2) and 25OHD(3) in human adult plasma. The assay operates for 4 years and has performed more than 40,000 patient samples on a shared instrument. PMID- 25801996 TI - Comparison of hollow fiber liquid-phase microextraction and ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction for the determination of drugs of abuse in biological samples by gas chromatography-mass spectrometry. AB - Two microextraction techniques based on hollow fiber liquid-phase microextraction (HF-LPME) and ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction (UA-LDS-DLLME) had been applied for the determination of drugs of abuse (methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine, 3,4 methylenedioxyamphetamine, methcathinone, ketamine, meperidine, and methadone) in urine and blood samples by gas chromatography-mass spectrometry. Parameters affecting extraction efficiency have been investigated and optimized for both methods. Under the optimum conditions, linearities were observed for all analytes in the range 0.0030-10 MUg/ml with the correlation coefficient (R) ranging from 0.9985 to 0.9995 for HF-LPME and in the range 0.0030-10 MUg/ml with the R ranging from 0.9985 to 0.9994 for DLLME. The recovery of 79.3-98.6% with RSDs of 1.2-4.5% was obtained for HF-LPME, and the recovery of 79.3-103.4% with RSDs of 2.4-5.7% was obtained for DLLME. The LODs (S/N=3) were estimated to be in the range from 0.5 to 5 ng/ml and 0.5 to 4 ng/ml, respectively. Compared with HF-LPME, the UA LDS-DLLME technique had the advantages of less extraction time, suitability for batches of sample pretreatment simultaneously, and higher extraction efficiency, while HF-LPME has excellent sample clean-up effect, and is a robust and suitable technique for various sample matrices with better repeatability. Both methods were successfully applied to the analysis of drugs of abuse in real human blood sample. PMID- 25801998 TI - Evolution of Multidisciplinary Translational Teams (MTTs): Insights for Accelerating Translational Innovations. AB - There is growing consensus about the factors critical for development and productivity of multidisciplinary teams, but few studies have evaluated their longitudinal changes. We present a longitudinal study of 10 multidisciplinary translational teams (MTTs), based on team process and outcome measures, evaluated before and after 3 years of CTSA collaboration. Using a mixed methods approach, an expert panel of five judges (familiar with the progress of the teams) independently rated team performance based on four process and four outcome measures, and achieved a rating consensus. Although all teams made progress in translational domains, other process and outcome measures were highly variable. The trajectory profiles identified four categories of team performance. Objective bibliometric analysis of CTSA-supported MTTs with positive growth in process scores showed that these teams tended to have enhanced scientific outcomes and published in new scientific domains, indicating the conduct of innovative science. Case exemplars revealed that MTTs that experienced growth in both process and outcome evaluative criteria also experienced greater innovation, defined as publications in different areas of science. Of the eight evaluative criteria, leadership-related behaviors were the most resistant to the interventions introduced. Well-managed MTTs demonstrate objective productivity and facilitate innovation. PMID- 25801999 TI - Hesperidin methyl chalcone - a new cosmetic contact allergen. PMID- 25802000 TI - Spontaneous structural transition in phospholipid-inspired aromatic phosphopeptide nanostructures. AB - Phospholipid membranes could be considered a prime example of the ability of nature to produce complex yet ordered structures, by spontaneous and efficient self-assembly. Inspired by the unique properties and architecture of phospholipids, we designed simple amphiphilic decapeptides, intended to fold in the center of the peptide sequence, with a phosphorylated serine "head" located within a central turn segment, and two hydrophobic "tails". The molecular design also included the integration of the diphenylalanine motif, previously shown to facilitate self-assembly and increase nanostructure stability. Secondary structure analysis of the peptides indeed indicated the presence of stabilized conformations in solution, with a central turn connecting two hydrophobic "tails", and interactions between the hydrophobic strands. The mechanisms of assembly into supramolecular structures involved structural transitions between different morphologies, which occurred over several hours, leading to the formation of distinctive nanostructures, including half-elliptical nanosheets and curved tapes. The phosphopeptide building blocks appear to self-assemble via a particular combination of aromatic, hydrophobic and ionic interactions, as well as hydrogen bonding, as demonstrated by proposed constructed simulated models of the peptides and self-assembled nanostructures. Molecular dynamics simulations also gave insight into mechanisms of structural transitions of the nanostructures at a molecular level. Because of the biocompatibility of peptides, the phosphopeptide assemblies allow for expansion of the library of biomolecular nanostructures available for future design and application of biomedical devices. PMID- 25802001 TI - Take the tube: remodelling of the endosomal system by intracellular Salmonella enterica. AB - Salmonella enterica is a facultative intracellular pathogen residing in a unique host cell-derived membrane compartment, termed Salmonella-containing vacuole or SCV. By the activity of effector proteins translocated by the SPI2-endoced type III secretion system (T3SS), the biogenesis of the SCV is manipulated to generate a habitat permissive for intracellular proliferation. By taking control of the host cell vesicle fusion machinery, intracellular Salmonella creates an extensive interconnected system of tubular membranes arising from vesicles of various origins, collectively termed Salmonella-induced tubules (SIT). Recent work investigated the dynamic properties of these manipulations. New host cell targets of SPI2-T3SS effector proteins were identified. By applying combinations of live cell imaging and ultrastructural analyses, the detailed organization of membrane compartments inhabited and modified by intracellular Salmonella is now available. These studies provided unexpected new details on the intracellular environments of Salmonella. For example, one kind of SIT, the LAMP1-positive Salmonella induced filaments (SIF), are composed of double-membrane tubules, with an inner lumen containing host cell cytosol and cytoskeletal filaments, and an outer lumen containing endocytosed cargo. The novel findings call for new models for the biogenesis of SCV and SIT and give raise to many open questions we discuss in this review. PMID- 25802002 TI - Actl6a protects embryonic stem cells from differentiating into primitive endoderm. AB - Actl6a (actin-like protein 6A, also known as Baf53a or Arp4) is a subunit shared by multiple complexes including esBAF, INO80, and Tip60-p400, whose main components (Brg1, Ino80, and p400, respectively) are crucial for the maintenance of embryonic stem cells (ESCs). However, whether and how Actl6a functions in ESCs has not been investigated. ESCs originate from the epiblast (EPI) that is derived from the inner cell mass (ICM) in blastocysts, which also give rise to primitive endoderm (PrE). The molecular mechanisms for EPI/PrE specification remain unclear. In this study, we provide the first evidence that Actl6a can protect mouse ESCs (mESCs) from differentiating into PrE. While RNAi knockdown of Actl6a, which appeared highly expressed in mESCs and downregulated during differentiation, induced mESCs to differentiate towards the PrE lineage, ectopic expression of Actl6a was able to repress PrE differentiation. Our work also revealed that Actl6a could interact with Nanog and Sox2 and promote Nanog binding to pluripotency genes such as Oct4 and Sox2. Interestingly, cells depleted of p400, but not of Brg1 or Ino80, displayed similar PrE differentiation patterns. Mutant Actl6a with impaired ability to bind Tip60 and p400 failed to block PrE differentiation induced by Actl6a dysfunction. Finally, we showed that Actl6a could target to the promoters of key PrE regulators (e.g., Sall4 and Fgf4), repressing their expression and inhibiting PrE differentiation. Our findings uncover a novel function of Actl6a in mESCs, where it acts as a gatekeeper to prevent mESCs from entering into the PrE lineage through a Yin/Yang regulating pattern. PMID- 25802003 TI - Protective Profile Involving CD23/IgE-mediated NO Release is a Hallmark of Cutaneous Leishmaniasis Patients from the Xakriaba Indigenous Community in Minas Gerais, Brazil. AB - In this study, we described, for the first time, specific aspects of an anti Leishmania immune response in a Brazilian Xakriaba indigenous community. Induction of an intracellular NO pathway, triggered by the binding of IgE to CD23 receptor in IFN-gamma/IL-4 cytokines environment, was evaluated in localized cutaneous leishmaniasis (LCL) carriers and positive Montenegro skin test (MST) individuals without skin lesion (MT(+) SL(-)). Our data demonstrated that the higher frequency of CD23(+) CD14(+) monocytes and the increased serum levels of IgE observed in the LCL group were even higher in LCL carriers with late lesions (LCL>=60). Furthermore, patients with LCL presented increased NO production after Leishmania (Viannia) braziliensis stimulation and this NO profile was independent of the time of the lesion (recent LCL<60 or late LCL>=60). We also showed that the increased frequency of IFN-gamma(+) and IL-4(+) CD4(+) T cells is related to the MT(+) SL(-) group. The results of biomarker signature curves demonstrated that in the MT(+) SL(-) group, the index signature was characterized by DAF-2T(+) CD14(+)/IL-4(+) CD8(+)/IFN-gamma(+) CD4(+)/IL-4(+) CD4(+). On the other hand, the LCL group presented a higher index of DAF-2T(+) CD14(+)/CD23(+) CD14(+)/IL-4(+) CD8(+), associated with a lower index of IFN-gamma(+) CD8(+). Considering the time of lesion, data analysis demonstrated that the main differences observed were highlighted in LCL<60 patients, with a higher index of CD23(+) CD14(+), which was also present in LCL>=60 patients. In conclusion, our data suggest that the protective immune response involving CD23-IgE-mediated NO release is a hallmark of patients with LCL. However, in MT(+) SL(-) individuals, another different leishmanicidal mechanism seems to be involved. PMID- 25802004 TI - Altered cholinergic neurotransmission in Tourette syndrome. PMID- 25802005 TI - Erratum to: Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses. PMID- 25802008 TI - Modeling Field-Induced Quenching in Poly(p-phenylene vinylene) Polymers and Oligomers. AB - Field-induced fluorescence quenching of poly(p-phenylene vinylene) (PPV) oligomers due to nonradiative relaxation through free electron-hole pair (FEHP) states is modeled using singles configuration interaction computations with the intermediate neglect of differential overlap Hamiltonian. The computations find FEHP states with energies that drop linearly with applied field and undergo avoided crossings with the fluorescent state. The coupling between the FEHP and fluorescent state, computed for multiple FEHP states on a variety of oligomer lengths, is found to depend primarily on the field strength required for the state to cross the fluorescent state. The rate of decay to these dark FEHP states is then calculated from Marcus theory, which is modified to take into account dielectric in addition to other bulk measurement considerations. The results predict that individual molecules go from being emissive to fully quenched over a small range of applied field strengths. Phenomenological introduction of inhomogeneous broadening for the energies of the FEHP states leads to a more gradual dependence on applied field. The fluorescence quenching mechanism considered here is found to be important for applied fields above about 1 MV cm( 1), which is similar in magnitude to those present in light-emitting diodes. PMID- 25802006 TI - Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. AB - The aim of present study was to investigate the effect of vitamin U (vit U, S methylmethionine) on oxidative stress, inflammation, and fibrosis within the context of valproic acid (VPA)-induced renal damage. In this study, female Sprague Dawley rats were randomly divided into four groups: Group I consisted of intact animals, group II was given vit U (50 mg/kg/day, by gavage), group III was given VPA (500 mg/kg/day, intraperitonally), and group IV was given VPA + vit U. The animals were treated by vit U 1 h prior to treatment with VPA every day for 15 days. The following results were obtained in vit U + VPA-treated rats: (i) the protective effect of vit U on renal damage was shown by a significant decrease in histopathological changes and an increase in Na(+)/K(+)-ATPase activity; (ii) anti-oxidant property of vit U was demonstrated by a decrease in malondialdehyde levels and xanthine oxidase activity and an increase in glutathione levels, catalase and superoxide dismutase activities; (iii) anti-inflammatory property of vit U was demonstrated by a decrease in tumor necrosis factor-alpha, interleukin 1beta, monocyte chemoattractant protein-1 levels, and adenosine deaminase activity; (iv) anti-fibrotic effect of vit U was shown by a decrease in transforming growth factor-beta, collagen-1 levels, and arginase activity. Collectively, these data show that VPA is a promoter of inflammation, oxidative stress, and fibrosis which resulted in renal damage. Vit U can be proposed as a potential candidate for preventing renal damage which arose during the therapeutic usage of VPA. PMID- 25802009 TI - Z-selective cross metathesis with ruthenium catalysts: synthetic applications and mechanistic implications. AB - Olefin cross metathesis is a particularly powerful transformation that has been exploited extensively for the formation of complex products. Until recently, however, constructing Z-olefins using this methodology was not possible. With the discovery and development of three families of ruthenium-based Z-selective catalysts, the formation of Z-olefins using metathesis is now not only possible but becoming increasingly prevalent in the literature. In particular, ruthenium complexes containing cyclometalated NHC architectures developed in our group have been shown to catalyze various cross metathesis reactions with high activity and, in most cases, near perfect selectivity for the Z-isomer. The types of cross metathesis reactions investigated thus far are presented here and explored in depth. PMID- 25802007 TI - Physiological performance and differential expression profiling of genes associated with drought tolerance in root tissue of four contrasting varieties of two Gossypium species. AB - Root growth in drying soil is generally limited by a combination of mechanical impedance and water stress. As the major function of root tissue is water and nutrient uptake, so it imparts an important role in plant growth and stress management. Previously, we have studied physiological performance and expression profiling of gene associated with drought tolerance in leaf tissue of four cotton varieties. Here, we have further continued our studies with the root tissue of these varieties. The Gossypium hirsutum species JKC-770 is drought-tolerant and KC-2 is drought-sensitive, while Gossypium herbaceum species JKC-717 is drought tolerant and RAHS-187 is drought-sensitive. JKC-770 and JKC-717 the drought tolerant varieties showed a comparatively high glutathione-S-transferase, superoxide dismutase, proline along with their gene expression, and low malondialdehyde content indicating low membrane damage and better antioxidative defense under drought condition. The expression levels of cellulose synthase, xyloglucan:xyloglucosyl transferase, and glycosyl hydrolases suggest modulation in cell wall structure and partitioning of sugars towards osmoprotectants instead of cell wall biosynthesis in tolerant varieties. Heat shock proteins and serine/threonine protein phosphotases show upregulation under drought condition, which are responsible for temperature tolerance and protein phosphorylation, respectively. These effects many metabolic processes and may be playing a key role in drought tolerance and adaptability of JKC-770 towards drought tolerance. The long-term water use efficiency (WUE) estimated in terms of carbon isotope discrimination (?(13)C) in the root tissues showed maximum depletion in the ?(13)C values in JKC-770 variety, while minimum in RAHS-187 under drought stress with reference to their respective control, suggesting a high WUE in JKC-770 variety. PMID- 25802010 TI - Open and closed cortico-subcortical loops: A neuro-computational account of access to consciousness in the distractor-induced blindness paradigm. AB - How the brain decides which information to process 'consciously' has been debated over for decades without a simple explanation at hand. While most experiments manipulate the perceptual energy of presented stimuli, the distractor-induced blindness task is a prototypical paradigm to investigate gating of information into consciousness without or with only minor visual manipulation. In this paradigm, subjects are asked to report intervals of coherent dot motion in a rapid serial visual presentation (RSVP) stream, whenever these are preceded by a particular color stimulus in a different RSVP stream. If distractors (i.e., intervals of coherent dot motion prior to the color stimulus) are shown, subjects' abilities to perceive and report intervals of target dot motion decrease, particularly with short delays between intervals of target color and target motion. We propose a biologically plausible neuro-computational model of how the brain controls access to consciousness to explain how distractor-induced blindness originates from information processing in the cortex and basal ganglia. The model suggests that conscious perception requires reverberation of activity in cortico-subcortical loops and that basal-ganglia pathways can either allow or inhibit this reverberation. In the distractor-induced blindness paradigm, inadequate distractor-induced response tendencies are suppressed by the inhibitory 'hyperdirect' pathway of the basal ganglia. If a target follows such a distractor closely, temporal aftereffects of distractor suppression prevent target identification. The model reproduces experimental data on how delays between target color and target motion affect the probability of target detection. PMID- 25802012 TI - Long-term safety follow-up of a randomized trial of darbepoetin alpha and intravenous iron following autologous hematopoietic cell transplantation. PMID- 25802013 TI - Choroidal thickness and retinal vascular caliber correlations with internal carotid artery Doppler variables. AB - PURPOSE: Decreased retinal arteriolar caliber and increased retinal venular caliber have been associated with increased cardiovascular mortality. This study aimed to evaluate correlations of choroidal thickness and retinal vascular caliber measurements with internal carotid artery (ICA) Doppler ultrasound variables. METHODS: In this cross-sectional and observational study, 43 eyes and ICAs of 43 healthy volunteers were examined. Spectral domain optical coherence tomography was used to measure subfoveal choroidal thickness (SFCT) and retinal vascular caliber. The ICA Doppler ultrasonographic parameters were diameter, flow volume, peak-systolic velocity, end-diastolic velocity, resistance index (RI), and pulsatility index (PI). RESULTS: Negative correlations emerged between ICA RI and SFCT (p = 0.017, r = -0.36) as well as between ICA PI and retinal arteriolar caliber (p = 0.015, r = -0.37). A negative linear correlation appeared between ICA diameter and SFCT (p = 0.005, r = -0.42), although ICA diameter and flow volume showed no association with retinal vessel caliber (p > 0.05). CONCLUSIONS: Choroidal thickness is negatively correlated with ICA diameter and ICA RI, while retinal arteriolar caliber is inversely related with ICA PI in normal volunteers. PMID- 25802014 TI - Coronary CT findings of coronary to bronchial arterial communication in chronic pulmonary disease. AB - To describe the coronary CT findings of coronary-to-bronchial artery communication (CBAC) in chronic pulmonary disease. Coronary CT was performed in 15 patients with chronic pulmonary disease using 64-channel or greater multidetector CT. Among those patients, one or two CBACs were identified. A retrospective analysis of the CT findings was done to determine the originating artery, arterial course of the communications and other associated results. The main underlying pulmonary disease was bronchiectasis (n = 12). The origin of the CBAC was from the left atrial (n = 7) or sinoatrial (SA) nodal (n = 3) branch of the left circumflex artery in nine patients and the SA nodal branch of the right coronary artery in six patients. The CBAC was connected to the left bronchial artery in 11 patients and the right bronchial artery in five patients. The course of the CBAC passed through the interpulmonary venous bare area between reflections of the serous pericardium of the transverse and oblique sinuses in 13 patients. In three patients, it passed through the perivascular space around the left upper or lower pulmonary vein. In one patient, there were two communications one through the interpulmonary venous bare area and the other through the perivascular space around the left lower pulmonary vein. There was no significant coronary arterial stenosis except in two patients. Bronchial arterial hypertrophy was found in all 15 patients. Detailed analysis of coronary CT can be a helpful guide for hemodynamic significance and clinical management including embolotherapy for CBAC in patients of chronic pulmonary disease with hemoptysis. PMID- 25802015 TI - Understanding how domestic abuse is associated with greater depressive symptoms in a community sample of female primary care patients: does loss of belongingness matter? AB - This study examined the relationship between domestic abuse, belongingness, and depressive symptoms in a community sample of 71 female primary care patients. As expected, domestic abuse was associated with greater depressive symptoms. Results from conducting mediation analyses, including bootstrapping techniques, provided strong convergent support for a model in which the hypothesized effect of domestic abuse on depressive symptoms in women is mediated by a loss of belongingness. Noteworthy, even after controlling for content overlap between measures of belongingness and depressive symptoms, the mediation model remained significant. Some implications of the present findings are discussed. PMID- 25802016 TI - Cultural Explanations of Sleep Paralysis in Italy: The Pandafeche Attack and Associated Supernatural Beliefs. AB - The current study examines cultural explanations regarding sleep paralysis (SP) in Italy. The study explores (1) whether the phenomenology of SP generates culturally specific interpretations and causal explanations and (2) what are the beliefs and local traditions associated with such cultural explanations. The participants were Italian nationals from the general population (n = 68) recruited in the region of Abruzzo, Italy. All participants had experienced at least one lifetime episode of SP. The sleep paralysis experiences and phenomenology questionnaire were orally administered to participants. We found a multilayered cultural interpretation of SP, namely the Pandafeche attack, associated with various supernatural beliefs. Thirty-eight percent of participants believed that this supernatural being, the Pandafeche-often referred to as an evil witch, sometimes as a ghost-like spirit or a terrifying humanoid cat-might have caused their SP. Twenty-four percent of all participants sensed the Pandafeche was present during their SP. Strategies to prevent Pandafeche attack included sleeping in supine position, placing a broom by the bedroom door, or putting a pile of sand by the bed. Case studies are presented to illustrate the study findings. The Pandafeche attack thus constitutes a culturally specific, supernatural interpretation of the phenomenology of SP in the Abruzzo region of Italy. PMID- 25802018 TI - Laryngomalacia: Review and Summary of Current Clinical Practice in 2015. AB - Laryngomalacia is the most common cause of stridor in neonates and infants. Associated feeding difficulties are present in approximately half of the children. A definitive diagnosis can generally be made with flexible fiberoptic laryngoscopy. The disorder is most often self-limited with resolution of symptoms within the first 24 months of life, and the majority of children can thus be managed conservatively. The approximately 5%-20% of children with severe or refractory disease may require more aggressive intervention, most commonly in the form of trans-oral supraglottoplasty [1,2]. High success rates and a low rate of complications have been reported for this procedure in otherwise healthy children. Children with syndromes or medical comorbidities are more likely to have complications or persistent symptoms after supraglottoplasty and may require additional interventions. PMID- 25802019 TI - Glucocorticoid safety for treating rheumatoid arthritis. AB - INTRODUCTION: Glucocorticoids (GCs) are often used in the treatment of rheumatoid arthritis and many other inflammatory diseases. Besides strong favorable effects on disease activity, GCs can cause (serious) side effects as well. AREAS COVERED: Side effects of GCs that are ranked as most important by rheumatologists as well as by patients are bone loss and fractures, cardiovascular events, hypertension, and diabetes mellitus. In evaluating these side effects, confounding by indication is a disturbing factor: not only the use of GCs can increase the risk of several side effects, but so can the activity of the underlying disease, which in turn is related to the amount of GCs that is prescribed to the patient. EXPERT OPINION: Generally, side effects predominantly occur in patients with a high disease activity and when used in high doses and for a long period of time. For these patients, caution and monitoring are most warranted. However, monitoring is not only recommended in patients with a high disease activity, and high-dose or long-term use of GCs, but in all GC users, since side effects may also occur in patients treated with low-dose GCs. When detecting possible negative effects in time, they might be managed and serious damage due to side effects might hopefully be prevented. PMID- 25802017 TI - Associations of Trimethylamine N-Oxide With Nutritional and Inflammatory Biomarkers and Cardiovascular Outcomes in Patients New to Dialysis. AB - OBJECTIVES: Trimethylamine N-oxide (TMAO) is a product of metabolism of phosphatidylcholine (lecithin) and carnitine by the intestinal microbiome. Elevated serum concentrations of TMAO have been linked to adverse cardiovascular outcomes in the general population. We examined correlates of serum TMAO and the relations among serum TMAO concentrations, all-cause mortality, and cardiovascular mortality and hospitalizations in a nationally derived cohort of patients new to hemodialysis (HD). METHODS: We quantified serum TMAO by liquid chromatography and online tandem mass spectrometry and assessed nutritional and cardiovascular risk factors in 235 patients receiving HD and measured TMAO in pooled serum from healthy controls. We analyzed time to death and time to cardiovascular death or hospitalization using Cox proportional hazards regression. RESULTS: Serum TMAO concentrations of patients undergoing HD (median, 43 MUM/L; 25th-75th percentile, 28-67 MUM/L) were elevated compared with those with normal or near-normal kidney function (1.41 +/- 0.49 MUM/L). TMAO was directly correlated with serum albumin (Spearman rank correlation, 0.24; 95% CI, 0.12-0.35; P <.001), prealbumin (Spearman rank correlation, 0.19; 95% CI, 0.07 0.31; P = .003), and creatinine (Spearman rank correlation, 0.21; 95% CI, 0.08 0.33; P = .002) and inversely correlated with log C-reactive protein (Spearman rank correlation, -0.18; 95% CI, -0.30 to -0.06; P = .005). Higher serum concentrations of TMAO were not significantly associated with time to death (Spearman rank correlation, 0.84; CI, 0.65-1.09; P = .19) or time to cardiovascular hospitalization or cardiovascular death (Spearman rank correlation, 0.88; CI, 0.57-1.35; P = .55). CONCLUSIONS: Serum TMAO concentrations were markedly elevated and correlated directly with biochemical markers of nutritional status and inversely with markers of inflammation in patients receiving HD. There was no significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations. In patients receiving dialysis-in contrast with the general population-adverse vascular effects of TMAO may be counterbalanced by associations with nutritional or inflammatory status. PMID- 25802020 TI - Within-litter differences in personality and physiology relate to size differences among siblings in cavies. AB - Many aspects of an animal's early life potentially contribute to long-term individual differences in physiology and behaviour. From several studies on birds and mammals it is known that the early family environment is one of the most prominent factors influencing early development. Most of these studies were conducted on highly altricial species. Here we asked whether in the highly precocial cavy (Cavia aperea) the size rank within a litter, i.e. whether an individual is born as the heaviest, the lightest or an intermediate sibling, affects personality traits directly after birth and after independence. Furthermore, we investigated whether individual states (early growth, baseline cortisol and resting metabolic rate) differ between siblings of different size ranks and assessed their relation to personality traits. Siblings of the same litter differed in personality traits as early as three days after birth. Pups born heaviest in the litter were more explorative and in general more risk-prone than their smaller siblings. Physiological state variables were tightly correlated with personality traits and also influenced by the size rank within litter, suggesting that the size relative to littermates constitutes an important factor in shaping an individual's developmental trajectory. Our data add valuable information on how personalities are shaped during early phases of life and indicate the stability of developmentally influenced behavioural and physiological traits. PMID- 25802021 TI - Mechanisms underlying the portion-size effect. AB - The portion-size effect (PSE) refers to the fact that people eat more when served larger portions. This effect is neither obvious nor artifactual. We examine the prevailing explanations (or underlying mechanisms) that have been offered for the PSE. The dominant candidate mechanism is "appropriateness"; that is, people accept the portion that they are served as being of an appropriate size and eat accordingly. Because people do not necessarily finish the portion that they are served, variations on the basic appropriateness mechanism have been suggested. We also consider some evidence that is inconsistent with an appropriateness explanation, including the appearance of the PSE in children as young as two years of age. We also examine other mechanisms that do not rely on appropriateness norms. Visual food cues may assist in assessing appropriateness but may also drive food intake in a more mindless fashion. Larger portions induce larger bites, which may increase intake by reducing oral exposure time and sensory-specific satiety. We consider further research questions that could help to clarify the mechanisms underlying the PSE. PMID- 25802022 TI - Forebrain neuropeptide regulation of pair association and behavior in cooperating cleaner fish. AB - Animals establish privileged relationships with specific partners, which are treated differently from other conspecifics, and contribute to behavioral variation. However, there is limited information on the underlying physiological mechanisms involved in the establishment of these privileged ties and their relationship to individual cooperation levels. The Indo-Pacific bluestreak cleaner wrasse Labroides dimidiatus often forages in mixed-sex pairs when cleaning fish clients. Intra-couple conflicts often arise during a joint client inspection, which may alter the overall quality of cleaning service provided. Here we tested two hypotheses: a) whether intra-pair association (i.e. association index), measured with joint interspecific cleaning and intraspecific behavior, is correlated with neuroendocrine mechanisms involving forebrain neuropeptides arginine vasotocin (AVT) and isotocin (IT) and b) whether these neuropeptide level shifts relate to an individual's interspecific service quality. We found that partner support (number of cleaning interactions and tactile stimulation) received by male cleaners increased with association index. When cleaners inspected clients alone, cleaners' cheating decreased with association index for females but not males. AVT levels did not differ according to sex or association level. Forebrain IT levels increased with association index for males, whereas no relationship was found for females. Finally, cleaner cheating varied between sex and forebrain IT levels. Findings indicate that variation in pairs' relationships influences male and female cleaner fish differently and contributes to the variation of brain neuropeptide levels, which is linked to distinct cooperative outcomes. PMID- 25802023 TI - The role of the mechanical clock in medieval science. AB - The invention and spread of the mechanical clock is a complex and multifaceted historical phenomenon. Some of these facets, such as its social impact, have been widely studied, but their scientific dimensions have often been dismissed. The mechanical clock was probably born as a scientific instrument for driving a model of the universe, and not only natural philosophers but also kings, nobles and other members of the social elites showed an interest in clocks as scientific instruments. Public clocks later spread a new way of telling time based on equal hours, laying the foundations for changes in time consciousness that would accelerate scientific thinking. PMID- 25802011 TI - The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis. AB - Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one's genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However, recent research has also highlighted the hitherto underappreciated involvement of gray matter in multiple sclerosis disease pathophysiology, which may be especially relevant when considering the accumulation of irreversible damage and progressive disability. This review aims at providing a comprehensive overview of the interplay between inflammation, glial/neuronal damage and regeneration throughout the course of multiple sclerosis via the analysis of both white and gray matter lesional pathology. Further, we describe the common pathological mechanisms underlying both relapsing and progressive forms of multiple sclerosis, and analyze how current (as well as future) treatments may interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis. PMID- 25802024 TI - Report of the second Outcome Measures in Myotonic Dystrophy type 1 (OMMYD-2) international workshop San Sebastian, Spain, October 16, 2013. PMID- 25802025 TI - Gut microbiota: Optimal sampling of the intestinal microbiota for research. PMID- 25802026 TI - Computer assisted sperm morphometry in mammals: a review. AB - Computer-assisted sperm morphometry analysis (CASMA or ASMA) systems were developed to reduce the subjectivity of sperm morphology assessement. This review focuses on a complete description of the CASMA technique, including recent developments, factors of variation, results in the different species and possible applications. Techniques to study sperm morphometry include light microscopy, phase-contrast microscopy and, more recently, fluorescence microscopy. Most published studies on sperm morphometry have been centered on the whole sperm heads, although some of them also measured other parts of the sperm structure, such as the nucleus, acrosome, midpiece or flagellum. The independent study of sperm components may be more informative than the traditional assessment of the whole sperm head. Morphometric data provided by the CASMA system may be analyzed using classical statistics although, given the heterogeneity of spermatozoa in the ejaculates, the study of sperm subpopulations using clustering procedures may be more informative. Morphometric results may vary depending on factors intrinsic and extrinsic to the semen donor. Intrinsic factors may include, among others, genetic factors, age and sexual maturity. Extrinsic factors may include those related to the influence of environment on the donor, as well as those related with sample processing and the morphometric analysis itself. Once standardized, this technique may provide relevant information in studies focused on evolutionary biology, sperm formation, sperm quality assessment, including prediction of the potential fertility, semen cryopreservation, or the effect of reprotoxicants. PMID- 25802028 TI - Perspectives on working memory: introduction to the special issue. AB - More than 40 years ago, Baddeley and Hitch (1974) published an article with a wealth of experimentation and theorization on working memory, the small amount of information held in mind and often used within cognitive processes such as language comprehension and production, reasoning, and problem solving. We honor this seminal accomplishment in the present special issue, and take this opportunity to provide an introduction to our perspectives on the origin of the theory of working memory, how it has affected our work, what may be coming in the near future, and how the research articles in the present issue contribute to several related themes within the clearly thriving field of working memory. PMID- 25802027 TI - Glucocerebrosidase and Parkinson disease: Recent advances. AB - Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This hypothesis has been confirmed in GBA mutant mice, PD patient fibroblasts and cells with SNCA overexpression, and offers an important target pathway for future neuroprotection therapy in PD. This article is part of a Special Issue entitled 'Neuronal Protein'. PMID- 25802029 TI - Remembering the melody and timbre, forgetting the key and tempo. AB - The identity of a melody is independent of surface features such as key (pitch level), tempo (speed), and timbre (musical instrument). We examined the duration of memory for melodies (tunes) and whether such memory is affected by changes in key, tempo, or timbre. After listening to previously unfamiliar melodies twice, participants provided recognition ratings for the same (old) melodies as well as for an equal number of new melodies. The delay between initial exposure and test was 10 min, 1 day, or 1 week. In Experiment 1, half of the old melodies were transposed by six semitones or shifted in tempo by 64 beats per minute. In Experiment 2, half of the old melodies were changed in timbre (piano to saxophone, or vice versa). In both experiments, listeners remembered the melodies, and there was no forgetting over the course of a week. Changing the key or tempo from exposure to test had a detrimental impact on recognition after 10 min and 1 day, but not after 1 week. Changing the timbre affected recognition negatively after all three delays. Mental representations of unfamiliar melodies appear to be consolidated after only two presentations. These representations include surface information unrelated to a melody's identity, although information about key and tempo fades at a faster rate than information about timbre. PMID- 25802030 TI - Old World tuberculosis: Evidence from human remains with a review of current research and future prospects. AB - The evidence for TB in archaeological human remains for the Old World is reviewed in published and some unpublished sources. The evidence of Pott's disease was considered specific for TB, with other bone changes, such as rib lesions, as non specific. Limitations of the data are discussed. Most evidence for TB comes from skeletons from the northern hemisphere, particularly in Europe in the late Medieval period (12(th)-16th centuries AD), but there is early evidence in the Near/Middle East and Egypt. Many parts of Africa, Asia and Australasia have very little or no evidence. aDNA analysis has provided data on species and strains of the Mycobacterium tuberculosis complex organisms affecting people in the past. The extant data suggest the first epidemiological transition (Neolithic agriculture and permanent settlements) led to an increase in TB, with later increases in urban environments of the late Medieval period. A number of causative factors were at play. Future research, particularly using biomolecular analysis, has the potential to further contribute to our understanding of the origin and evolution of TB, thus merging the disciplines of palaeopathology and evolutionary medicine. PMID- 25802031 TI - Innovative clinical trial designs to rationalize TB vaccine development. AB - A recent trial of a leading tuberculosis (TB) vaccine candidate in 3000 South African infants failed to show protection over that from BCG alone, and highlights the difficulties in clinical development of TB vaccines. Progression of vaccine candidates to efficacy trials against TB disease rests on demonstration of safety and immunogenicity in target populations and protection against challenge in preclinical models, but immunologic correlates of protection are unknown, and animal models may not be predictive of results in humans. Even in populations most heavily affected by TB the sample sizes required for Phase 2b efficacy trials using TB disease as an endpoint are in the thousands. Novel clinical trial models have been developed to evaluate candidate TB vaccines in selected populations using biologically relevant outcomes and innovative statistical approaches. Such proof of concept studies can be used to more rationally select vaccine candidates for advancement to large scale trials against TB disease. PMID- 25802032 TI - Mycobacterium tuberculosis-specific CD4 T cells are the principal source of IFN gamma in QuantiFERON assays in healthy persons. PMID- 25802033 TI - Development of vaccines against Ornithodoros soft ticks: An update. AB - Ticks are parasites of great medical and veterinary importance since they are vectors of numerous pathogens that affect humans, livestock and pets. Among the argasids, several species of the genus Ornithodoros transmit serious diseases such as tick-borne human relapsing fever (TBRF) and African Swine Fever (ASF). In particular, Ornithodoros erraticus is the main vector of these two diseases in the Mediterranean while O. moubata is the main vector in Africa. The presence of these Ornithodoros ticks in domestic and peridomestic environments may greatly hinder the eradication of TBRF and ASF from endemic areas. In addition, there is a constant threat of reintroduction and spreading of ASF into countries from where it has been eradicated (Spain and Portugal) or where it was never present (the Caucasus, Russia and Eastern Europe). In these countries, the presence of Ornithodoros vectors could have a tremendous impact on ASF transmission and long term maintenance. Therefore, elimination of these ticks from at least synanthropic environments would contribute heavily to the prevention and control of the diseases they transmit. Tick control is a difficult task and although several methods for such control have been used, none of them has been fully effective against all ticks and the problems they cause. Nevertheless, immunological control using anti-tick vaccines offers an attractive alternative to the traditional use of acaricides. The aim of the present paper is to offer a brief overview of the current status in control measure development for Ornithodoros soft ticks, paying special attention to the development of vaccines against O. erraticus and O. moubata. Thus, our contribution includes an analysis of the chief attributes that the ideal antigens for an anti-tick vaccine should have, an exhaustive compilation and analysis of the scant anti-soft tick vaccine trials carried out to date using both concealed and salivary antigens and, finally, a brief description of the new reverse vaccinology approaches currently used to identify new and more effective protective tick antigens. PMID- 25802034 TI - Anaplasma marginale major surface protein 1a: a marker of strain diversity with implications for control of bovine anaplasmosis. AB - Classification of bacteria is challenging due to the lack of a theory-based framework. In addition, the adaptation of bacteria to ecological niches often results in selection of strains with diverse virulence, pathogenicity and transmission characteristics. Bacterial strain diversity presents challenges for taxonomic classification, which in turn impacts the ability to develop accurate diagnostics and effective vaccines. Over the past decade, the worldwide diversity of Anaplasma marginale, an economically important tick-borne pathogen of cattle, has become apparent. The extent of A. marginale strain diversity, formerly underappreciated, has contributed to the challenges of classification which, in turn, likely impacts the design and development of improved vaccines. Notably, the A. marginale surface protein 1a (MSP1a) is a model molecule for these studies because it serves as a marker for strain identity, is both an adhesin necessary for infection of cells and an immuno-reactive protein and is also an indicator of the evolution of strain diversity. Herein, we discuss a molecular taxonomic approach for classification of A. marginale strain diversity. Taxonomic analysis of this important molecule provides the opportunity to understand A. marginale strain diversity as it relates geographic and ecological factors and to the development of effective vaccines for control of bovine anaplasmosis worldwide. PMID- 25802035 TI - [Techniques for quantification of liver fat in risk stratification of diabetics]. AB - CLINICAL/METHODICAL ISSUE: Fatty liver disease plays an important role in the development of type 2 diabetes. Accurate techniques for detection and quantification of liver fat are essential for clinical diagnostics. STANDARD RADIOLOGICAL METHODS: Chemical shift-encoded magnetic resonance imaging (MRI) is a simple approach to quantify liver fat content. METHODICAL INNOVATIONS: Liver fat quantification using chemical shift-encoded MRI is influenced by several bias factors, such as T2* decay, T1 recovery and the multispectral complexity of fat. PERFORMANCE: The confounder corrected proton density fat fraction is a simple approach to quantify liver fat with comparable results independent of the software and hardware used. ACHIEVEMENTS: The proton density fat fraction is an accurate biomarker for assessment of liver fat. PRACTICAL RECOMMENDATIONS: An accurate and reproducible quantification of liver fat using chemical shift encoded MRI requires a calculation of the proton density fat fraction. PMID- 25802036 TI - Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor and is without exception lethal. GBMs modify the immune system, which contributes to the aggressive nature of the disease. Particularly, cells of the monocytic lineage, including monocytes, macrophages and microglia, are affected. We investigated the influence of GBM-derived extracellular vesicles (EVs) on the phenotype of monocytic cells. Proteomic profiling showed GBM EVs to be enriched with proteins functioning in extracellular matrix interaction and leukocyte migration. GBM EVs appeared to skew the differentiation of peripheral blood-derived monocytes to alternatively activated/M2-type macrophages. This was observed for EVs from an established cell line, as well as for EVs from primary cultures of GBM stem-like cells (GSCs). Unlike EVs of non-GBM origin, GBM EVs induced modified expression of cell surface proteins, modified cytokine secretion (e.g., an increase in vascular endothelial growth factor and IL-6) and increased phagocytic capacity of the macrophages. Most pronounced effects were observed upon incubation with EVs from mesenchymal GSCs. GSC EVs also affected primary human microglia, resulting in increased expression of Membrane type 1-matrix metalloproteinase, a marker for GBM microglia and functioning as tumor-supportive factor. In conclusion, GBM derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor-supportive phenotypes observed in patients. PMID- 25802037 TI - A randomised trial comparing the effect of exercise training and weight loss on microvascular function in coronary artery disease. AB - BACKGROUND: Coronary microvascular function is associated with outcome and is reduced in coronary artery disease (CAD) and obesity. We compared the effect of aerobic interval training (AIT) and weight loss on coronary flow reserve (CFR) and peripheral vascular function in revascularised obese CAD patients. METHODS AND RESULTS: Seventy non-diabetic patients (BMI 28-40 kg * m(-2), age 45-75 years) were randomised to 12 weeks' AIT (three weekly sessions lasting 38 min with ~ 16 min at 85-90% of VO2peak) or low energy diet (LED, 800-1000 kcal/day). Per protocol adherence was defined by training-attendance >= 60% and weight loss >= 5%, respectively. CFR was assessed by Doppler echocardiography of the LAD. Peripheral vascular function was assessed by arterial tonometry as reactive hyperaemia index (RHI) and augmentation index. Most participants had impaired CFR with a mean CFR of 2.38 (SD 0.59). Twenty-six AIT and 24 LED participants completed the study per protocol with valid CFR measurements. AIT resulted in a 10.4% improvement in VO2peak and LED in a 10.6% weight loss (between group differences both P<0.001). CFR increased by 0.26 (95%CI 0.04;0.48) after AIT and by 0.39 (95%CI 0.13;0.65) after LED without significant between-group difference (-0.13 (95%CI -0.45;0.20)). RHI and augmentation index remained unchanged after both interventions (P>0.50). Intention-to-treat analyses showed similar results. CONCLUSIONS: 12 weeks' AIT and LED increased CFR by comparable magnitude; thus both interventions might impact prognosis of CAD through improvement of coronary microvascular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01724567. PMID- 25802038 TI - Characterization of aortic dissection as pulsating type and static type during cardiac cycle by electrocardiogram-gated dual-source CT. PMID- 25802047 TI - Special role of corn flour as an ideal carbon source for aerobic denitrification with minimized nitrous oxide emission. AB - Much effort has been made for reducing nitrous oxide (N2O) emission in wastewater treatment processes. This paper presents an interesting way to minimize N2O in aerobic denitrification by strain Pseudomonas stutzeri PCN-1 with help of corn flour as cheaper additional carbon source. Experimental results showed that maximal N2O accumulation by strain PCN-1 was only 0.02% of removed nitrogen if corn flour was used as sole carbon source, which was significantly reduced by 52.07-99.81% comparing with others such as succinate, glucose, acetate and citrate. Sustained release of reducing sugar from starch and continuous expression of nosZ coding for N2O reductase contributed to the special role of corn flour as the ideal carbon source for strain PCN-1. Further experiments in sequencing batch reactors (SBRs) demonstrated similarly efficient nitrogen removal with much less N2O emission due to synergy of the novel strain and activated sludge, which was then confirmed by quantitative PCR analysis. PMID- 25802048 TI - The use of (5Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone for controlling acid mine drainage through the inhibition of Acidithiobacillus ferrooxidans biofilm formation. AB - The aim of this study was to determine whether acid mine drainage (AMD) production can be decreased by (5Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone (furanone C-30) in the presence of Acidithiobacillus ferrooxidans (A. ferrooxidans). The effects of furanone C-30 on A. ferrooxidans biofilm production were determined by crystal violet staining and confocal laser scanning microscopy (CLSM). Biofilm-related gene expression was investigated using real-time RT-PCR. Finally, the effects of furanone C-30 on AMD production were evaluated. The results show that furanone C-30 inhibits the production of extracellular polymeric substances (EPS) and biofilm formation and significantly down-regulates the expression of biofilm-related genes. The decreased EPS production led to reduced pentlandite attachment and biofilm formation on pentlandite. Furthermore, the dissolution of both nickel and copper were inhibited by furanone C-30 without new acid formation. This study provides a promising biochemical method to control AMD. PMID- 25802049 TI - Catalytic hydrothermal upgrading of crude bio-oils produced from different thermo chemical conversion routes of microalgae. AB - This study presents experimental results that compare the use of hydrothermal liquefaction (HTL), alcoholysis (Al), pyrolysis (Py) and hydropyrolysis (HPy) for the production of bio-oil from a microalga (Chlorella pyrenoidosa) and the catalytic hydrothermal upgrading of crude bio-oils produced by these four conversion routes. The yields and compositions of bio-oil, solid residue, and gases were evaluated and compared. HTL resulted in a bio-oil that has a higher energy density and superior fuel properties, such as thermal and storage stabilities, compared with the other three conversion routes. The N in crude bio oils produced from Py and HPy is more easily removed than that in the bio-oils produced from HTL and Al. The upgraded bio-oils contain reduced amounts of certain O-containing and N-containing compounds and significantly increased saturated hydrocarbon contents. All of the upgraded bio-oils have a larger fraction boiling below 350 degrees C than their corresponding crude bio-oils. PMID- 25802050 TI - Enhancement of cell biomass and cell activity of astaxanthin-rich Haematococcus pluvialis. AB - Fed-batch culture and the transformation conditions of Haematococcus pluvialis in a 5L photobioreactor were investigated. Methods of feeding model, low temperature at night and proper feeding time were used to increase both cell biomass and cell activity. Dry cell weight of 1.87 g/L which was 2.0-fold of batch culture and the specific growth rate of 0.43 d(-1) suggested the superduper results of these methods to increase the dry cell weight in the short cultivation time. Furthermore, mixed lights of blue and white (ratio of 3:1) at 7000 xl were used to expedite the morphologic changes of H. pluvialis from green cells to red cyst cells with the yield of 91.8+/-2.53 mg/L. PMID- 25802051 TI - Opioid-Induced Constipation Among Patients with Chronic Noncancer Pain in the United States, Canada, Germany, and the United Kingdom: Laxative Use, Response, and Symptom Burden Over Time. AB - PURPOSE: Estimate rate of laxative inadequate response (LIR) over time among patients with chronic noncancer pain with opioid-induced constipation (OIC). METHODS: A prospective longitudinal study was conducted in United States, Canada, Germany, and United Kingdom. Patients on opioid therapy for >=4 weeks for chronic noncancer pain and OIC completed an Internet-based survey at Baseline and Weeks 2, 4, 6, 8, 12, 16, 20, and 24. 1xLIR was defined as sufficient laxative use (>=1 laxative >= 4 times in past 2 weeks) and inadequate response (<3 bowel movements or >= 1 constipation symptom rated Moderate or greater). 2xLIR was sufficient laxative use of >=2 laxatives from different drug classes and inadequate response. Descriptive statistics and logistic regressions were performed. RESULTS: 489 patients (62% female; 85% white) completed Baseline; 27% reported no laxative use; 25% had insufficient laxative use; 48% had sufficient laxative use. During follow-up, 21-28% of patients had no or insufficient laxative use. Prevalence of 1xLIR was 93% at Baseline and ranged from 59-81% across follow-up; 26% met criteria for 2xLIR (follow-up range: 11-20%). CONCLUSIONS: OIC among noncancer pain patients is a persistent and significant condition with varying utilization and response to laxatives thus increasing the ongoing burden of chronic pain. (c) 2014 Wiley Periodicals, Inc. PMID- 25802052 TI - Nanotubular Heterostructure of Tin Dioxide/Titanium Dioxide as a Binder-Free Anode in Lithium-Ion Batteries. AB - Titanium dioxide (TiO2 ), tin dioxide (SnO2 ), and heterostructured TiO2 /SnO2 nanotube (NT) arrays have been fabricated by template-assisted atomic-layer deposition (ALD) for use as anodes in a lithium-ion battery (LIB). TiO2 NT arrays with 8 nm thick walls showed higher capacity (~250 mA h g(-1) after the 50th cycle at a rate of C/10) than the typical theoretical capacity of bulk TiO2 and a radically improved capacity retention property upon cycling. SnO2 NT arrays with different wall thicknesses (8, 10, 13, and 20 nm) were also fabricated and their electrochemical performances were measured. All of the SnO2 NT arrays showed substantially higher initial irreversible capacity and higher reversible capacity than those of bulk TiO2 . Thinner walls of the SnO2 NTs result in better capacity retention. Heterotubular structures of TiO2 (5 nm)/SnO2 (10 nm)/TiO2 (5 nm) were successfully fabricated, and displayed a sufficiently high capacity (~300 mA h g( 1) after 50 cycles) with exceptionally improved cycling performance up to the 50th cycle. PMID- 25802054 TI - 'IF You Drink Alcohol, THEN You Will Get Cancer': Investigating How Reasoning Accuracy Is Affected by Pictorially Presented Graphic Alcohol Warnings. AB - AIMS: To investigate the cognitive processing of emotive pictorial warnings intended to curb alcohol misuse, using novel methodologies adapted from the reasoning literature to assess whether emotive pictorial warnings alter reasoning. METHOD: In Study 1, individuals completed a version of the Wason selection task-evaluating warnings in which content type (Alcohol and Non Alcohol) and emotional valence (Positive and Negative) were manipulated through imagery. In Study 2, people evaluated the certainty of outcomes described by alcohol-related and non-alcohol-related warnings in the form of If-Then statements. RESULTS: Study 1 found that in alcohol-related warnings, there was no difference in reasoning accuracy between positive and negative content. However, fewer correct responses followed exposure to negative general-health messages. Study 2 suggested that when a warning involves the potential consequences of drinking alcohol, accuracy is improved when the content is negative. However, when considering the consequences of abstinence, accuracy was greatest when the content was positive. This was supported by an inference by content interaction. CONCLUSION: In conclusion, negative imagery should be used with caution in health warnings, and goals carefully considered. In some cases imagery of negative outcomes may improve reasoning, however, its use in alcohol-related messages does not appear to be consistently beneficial. PMID- 25802053 TI - Entrainment of heterogeneous glycolytic oscillations in single cells. AB - Cell signaling, gene expression, and metabolism are affected by cell-cell heterogeneity and random changes in the environment. The effects of such fluctuations on cell signaling and gene expression have recently been studied intensively using single-cell experiments. In metabolism heterogeneity may be particularly important because it may affect synchronisation of metabolic oscillations, an important example of cell-cell communication. This synchronisation is notoriously difficult to describe theoretically as the example of glycolytic oscillations shows: neither is the mechanism of glycolytic synchronisation understood nor the role of cell-cell heterogeneity. To pin down the mechanism and to assess its robustness and universality we have experimentally investigated the entrainment of glycolytic oscillations in individual yeast cells by periodic external perturbations. We find that oscillatory cells synchronise through phase shifts and that the mechanism is insensitive to cell heterogeneity (robustness) and similar for different types of external perturbations (universality). PMID- 25802055 TI - Alcohol-Specific Coping Styles of Adult Children of Individuals with Alcohol Use Disorders and Associations with Psychosocial Functioning. AB - Parental alcohol use disorders (AUDs) have been conceptualized as a chronic stressor that can lead to deleterious long-term outcomes in children of individuals with AUDs. Yet, while many individuals are detrimentally affected by their parents' problematic alcohol use, and go on to manifest psychological problems, others do not. How individuals cope with the stress of having a parent with an AUD is believed to be an important moderator of this differential outcome. This study assessed whether individuals' alcohol-specific coping styles predicted alcohol use, positive or negative life events, and depression, using a sample of 465 college students, of whom 20% were adult children of individuals with alcohol use disorders, colloquially known as adult children of alcoholics (ACOAs), and a battery of well-validated, self-report measures. Participant ACOAs reported less 'engaged' and 'total' alcohol-specific coping strategies and more 'withdrawal' alcohol-specific coping strategies than their non adult children of alcoholics (NACOAs) counterparts. Across participants, women reported more 'engaged', 'tolerant/inactive', and 'total' coping than men. Although ACOAs reported significantly more negative life events, which predicted more passive coping styles, they did not differ significantly from NACOAs on measures of problematic alcohol use or depression, supporting theories of resilience in ACOAs regardless of their alcohol-specific coping styles. For NACOAs, 'tolerant' coping predicted greater depression and alcohol-related problems; 'engaged' coping predicted fewer alcohol problems. Results suggest that ACOAs cope differently with problematic alcohol use among relatives and friends compared with NACOAs and are more likely to experience negative life events. Additionally, alcohol-related coping strategies have more predictive utility in NACOAs than ACOAs. PMID- 25802056 TI - A humoral immune defect distinguishes the response to Staphylococcus aureus infections in mice with obesity and type 2 diabetes from that in mice with type 1 diabetes. AB - Obesity and diabetes are among the greatest risk factors for infection following total joint arthroplasty. However, the underlying mechanism of susceptibility is unclear. We compared orthopedic implant-associated Staphylococcus aureus infections in type 1 (T1D) versus type 2 (T2D) diabetic mouse models and in patients with S. aureus infections, focusing on the adaptive immune response. Mice were fed a high-fat diet to initiate obesity and T2D. T1D was initiated with streptozotocin. Mice were then given a trans-tibial implant that was precoated with bioluminescent Xen36 S. aureus. Although both mouse models of diabetes demonstrated worse infection severity than controls, infection in T2D mice was more severe, as indicated by increases in bioluminescence, S. aureus CFU in tissue, and death within the first 7 days. Furthermore, T2D mice had an impaired humoral immune response at day 14 with reduced total IgG, decreased S. aureus specific IgG, and increased IgM. These changes were not present in T1D mice. Similarly, T2D patients and obese nondiabetics with active S. aureus infections had a blunted IgG response to S. aureus. In conclusion, we report the first evidence of a humoral immune deficit, possibly due to an immunoglobulin class switch defect, in obesity and T2D during exacerbated S. aureus infection which may contribute to the increased infection risk following arthroplasty in patients with T2D and obesity. PMID- 25802058 TI - Roles of reactive oxygen species-degrading enzymes of Francisella tularensis SCHU S4. AB - Francisella tularensis is a facultative intracellular bacterium utilizing macrophages as its primary intracellular habitat and is therefore highly capable of resisting the effects of reactive oxygen species (ROS), potent mediators of the bactericidal activity of macrophages. We investigated the roles of enzymes presumed to be important for protection against ROS. Four mutants of the highly virulent SCHU S4 strain with deletions of the genes encoding catalase (katG), glutathione peroxidase (gpx), a DyP-type peroxidase (FTT0086), or double deletion of FTT0086 and katG showed much increased susceptibility to hydrogen peroxide (H2O2) and slightly increased susceptibility to paraquat but not to peroxynitrite (ONOO(-)) and displayed intact intramacrophage replication. Nevertheless, mice infected with the double deletion mutant showed significantly longer survival than SCHU S4-infected mice. Unlike the aforementioned mutants, deletion of the gene coding for alkyl-hydroperoxide reductase subunit C (ahpC) generated a mutant much more susceptible to paraquat and ONOO(-) but not to H2O2. It showed intact replication in J774 cells but impaired replication in bone marrow-derived macrophages and in internal organs of mice. The live vaccine strain, LVS, is more susceptible than virulent strains to ROS-mediated killing and possesses a truncated form of FTT0086. Expression of the SCHU S4 FTT0086 gene rendered LVS more resistant to H2O2, which demonstrates that the SCHU S4 strain possesses additional detoxifying mechanisms. Collectively, the results demonstrate that SCHU S4 ROS-detoxifying enzymes have overlapping functions, and therefore, deletion of one or the other does not critically impair the intracellular replication or virulence, although AhpC appears to have a unique function. PMID- 25802057 TI - Transcription of TP0126, Treponema pallidum putative OmpW homolog, is regulated by the length of a homopolymeric guanosine repeat. AB - An effective mechanism for introduction of phenotypic diversity within a bacterial population exploits changes in the length of repetitive DNA elements located within gene promoters. This phenomenon, known as phase variation, causes rapid activation or silencing of gene expression and fosters bacterial adaptation to new or changing environments. Phase variation often occurs in surface-exposed proteins, and in Treponema pallidum subsp. pallidum, the syphilis agent, it was reported to affect transcription of three putative outer membrane protein (OMP) encoding genes. When the T. pallidum subsp. pallidum Nichols strain genome was initially annotated, the TP0126 open reading frame was predicted to include a poly(G) tract and did not appear to have a predicted signal sequence that might suggest the possibility of its being an OMP. Here we show that the initial annotation was incorrect, that this poly(G) is instead located within the TP0126 promoter, and that it varies in length in vivo during experimental syphilis. Additionally, we show that TP0126 transcription is affected by changes in the poly(G) length consistent with regulation by phase variation. In silico analysis of the TP0126 open reading frame based on the experimentally identified transcriptional start site shortens this hypothetical protein by 69 amino acids, reveals a predicted cleavable signal peptide, and suggests structural homology with the OmpW family of porins. Circular dichroism of recombinant TP0126 supports structural homology to OmpW. Together with the evidence that TP0126 is fully conserved among T. pallidum subspecies and strains, these data suggest an important role for TP0126 in T. pallidum biology and syphilis pathogenesis. PMID- 25802060 TI - Leaching of Au, Ag, and Pd from waste printed circuit boards of mobile phone by iodide lixiviant after supercritical water pre-treatment. AB - Precious metals are the most attractive resources in waste printed circuit boards (PCBs) of mobile phones. In this work, an alternative process for recovering Au, Ag, and Pd from waste PCBs of mobile phones by supercritical water oxidation (SCWO) pre-treatment combined with iodine-iodide leaching process was developed. In the process, the waste PCBs of mobile phones were pre-treated in supercritical water, then a diluted hydrochloric acid leaching (HL) process was used to recovery the Cu, whose leaching efficiency was approximately 100%, finally the resulting residue was subjected to the iodine-iodide leaching process for recovering the Au, Ag, and Pd. Experimental results indicated that SCWO pre treatment temperature, time, and pressure had significant influence on the Au, Ag, and Pd leaching from (SCWO+HL)-treated waste PCBs. The optimal SCWO pre treatment conditions were 420 degrees C and 60min for Au and Pd, and 410 degrees C and 30min for Ag. The optimum dissolution parameters for Au, Pd, and Ag in (SCWO+HL)-treated PCBs with iodine-iodide system were leaching time of 120min (90min for Ag), iodine/iodide mole ratio of 1:5 (1:6 for Ag), solid-to-liquid ratio (S/L) of 1:10g/mL (1:8g/mL for Ag), and pH of 9, respectively. It is believed that the process developed in this study is environment friendly for the recovery of Au, Ag, and Pd from waste PCBs of mobile phones by SCWO pre-treatment combined with iodine-iodide leaching process. PMID- 25802059 TI - Lung cancer prognosis before and after recurrence in a population-based setting. AB - BACKGROUND: Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management. METHODS: We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non surgically treated patients. RESULTS: Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non-small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients. CONCLUSIONS: This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events. PMID- 25802061 TI - Surface-Tunable Bioluminescence Resonance Energy Transfer via Geometry-Controlled ZnO Nanorod Coordination. AB - The use of ZnO nanorods (NRs) as an effective coordinator and biosensing platform to create bioluminescence resonance energy transfer (BRET) is reported. Herein, a hydrothermal approach is applied to obtain morphologically controlled ZnO NRs, which are directly bound to luciferase (Luc) and carboxy-modified quantum dot (QD) acting as a donor-acceptor pair for BRET. BRET efficiency varies significantly with the geometry of ZnO NRs, which modulates the coordination between hexahistidine-tagged Luc (Luc-His6 ) and QD, owing to the combined effect of the total surface area consisting of (001) and (100) planes and their surface polarities. Unlike typical QD-BRET reactions with metal ions (e.g., zinc ions), a geometry-controlled ZnO NR platform can facilitate the design of surface initiated BRET sensors without being supplemented by copious metal ions: the geometry-controlled ZnO NR platform can therefore pave the way for nanostructure based biosensors with enhanced analytical performance. PMID- 25802062 TI - Development of an Instrument to Measure the Unintended Consequences of EHRs. AB - This article augments the existing body of literature through examining the creation and design of an instrument measuring unintended consequences (UCs) of electronic health records (EHRs). Data from a previous qualitative study that explored nurses' perceptions of EHR effectiveness as a communication system were analyzed using a theoretical model focused on decision making. The qualitative data, informed by the model, were then organized into an instrument seeking to quantitatively measure nurses' experiences with UCs of EHRs. The model assisted in revealing patterns in nurses' perceptions of the effectiveness of the EHR as a communication system that ultimately strengthened the development of the instrument. Instrumentation from qualitative data has long been considered an acceptable and positive approach to scale development. The process for accomplishing this goal has often been omitted from the literature. We contend that other researchers will find this methods article informative for similar undertakings. PMID- 25802064 TI - Standardized outcomes reporting in metabolic and bariatric surgery. PMID- 25802063 TI - Cu and Cr enhanced the effect of various carbon nanotubes on microbial communities in an aquatic environment. AB - Environmental impacts of carbon nanotubes (CNTs) arise both from the characteristics of CNTs as well as from their sorbed contaminants from aquatic environments. In this work, we employed pristine, carboxyl-, hydroxyl- and amino functionalized multi-walled CNTs and pristine single-walled CNTs to quantify and compare their impacts on aquatic microbial communities in the absence and presence of Cu or Cr. Aliquots of samples were set up to 10 and 40 days for culture-dependent analyses, namely, quantitative real-time polymerase chain reaction and denaturing gradient gel electrophoresis. Results revealed that the presence of CNTs or the mixture of CNTs and metals transiently affected microbial communities, and toxicity of CNTs was enhanced with the addition of metals. Meanwhile, functionalized CNTs exhibited stronger toxicity. The major impacts were observed after 10 days of exposure, but the microbial community could recover at 40 days to some extent. Though microbial communities recovered, total microbial numbers continued to decrease with contact time. Analysis of sequence cloned 16S rDNA indicated that Bacillus sp. and Acidithiobacillus sp. were the dominant taxa. Overall, CNTs would have more serious risk to an ecosystem in the presence of metals. PMID- 25802065 TI - Incidence and clinical implications of upper extremity deep vein thrombosis after laparoscopic bariatric procedures. AB - Upper extremity deep vein thrombosis (UEDVT) represents less than 10 % of thromboembolic events, but has been associated with higher incidence of asymptomatic pulmonary embolism. Data regarding UEDVT and its treatment is limited. Our objective was to investigate UEDVT incidence, diagnosis, and treatment in our bariatric patient population. We conducted a retrospective review of patients undergoing laparoscopic bariatric surgery at our institution. Variables analyzed included patient demographics, body mass index (BMI), history of venous thromboembolic event (VTE), type of procedure, and other comorbidities. One thousand five hundred three patients were included in the study. Twenty patients developed VTE events, of which five suffered UEDVT. Although infrequent, awareness of UEDVT is necessary in order to initiate treatment in a timely fashion and to prevent major complications. PMID- 25802066 TI - Bariatric surgery operating room time--size matters. AB - BACKGROUND: The goal of this study was to document the relationship between BMI and the components of bariatric surgical operating room (OR) time. METHODS: The Stanford Translational Research Integrated Database Environment identified all patients who underwent laparoscopic Roux-en-Y gastric bypass procedures at Stanford University Medical Center between May 2008 and November 2013. The 434 patients were divided into 3 groups: group 1 (n = 213) BMI >=35 to <45 kg/m(2), group 2 (n = 188) BMI >=45.0 to <60 kg/m(2), and group 3 (n = 33) BMI >=60 kg/m(2). The primary variable measured was total operating room time, defined as beginning when the patient entered the OR until the moment the patient physically left the OR. Secondary variables were anesthetic induction time, nursing preparation time, operation time, time for emergence from anesthesia, and total length of hospital stay. RESULTS: Increasing BMI was associated with increased total OR time (group 1 = 202 min, group 2 = 215 min, group 3 = 235 min), mainly due to longer operation time (group 1 = 147 min, group 2 = 154 min, group 3 = 163 min). Anesthetic induction (group 1 = 17 min, group 2 = 18 min, group 3 = 23 min) and emergence times (group 1 = 12 min, group 2 = 12 min, group 3 = 22 min) were also significantly longer in the largest patients. CONCLUSIONS: Operating room schedules and plans for resource utilization should recognize that the same bariatric procedure will require more time for patients with BMI >60 kg/m(2) than for smaller bariatric patients. PMID- 25802067 TI - DFT-Aided Vibrational Circular Dichroism Spectroscopy Study of (-)-S-cotinine. AB - The implementation of a strategy comprising the use of vibrational circular dichroism spectroscopy and DFT calculations allows determination of the solution state conformational distribution in (-)-S-cotinine, giving further proof of the extra conformer-discriminating potential of this experimental technique, which may offer unique molecular fingerprints of subtly dissimilar molecular conformers of chiral samples. Natural bond orbital electronic structure calculations of the rotational barrier height between the two main conformers of the species indicate that hyperconjugative effects are the key force governing the conformational equilibrium. The negligible effect of the solvent's polarity over both structure and conformational energy profile supports this result. PMID- 25802068 TI - Variability and stability in the McGurk effect: contributions of participants, stimuli, time, and response type. AB - In the McGurk effect, pairing incongruent auditory and visual syllables produces a percept different from the component syllables. Although it is a popular assay of audiovisual speech integration, little is known about the distribution of responses to the McGurk effect in the population. In our first experiment, we measured McGurk perception using 12 different McGurk stimuli in a sample of 165 English-speaking adults, 40 of whom were retested following a one-year interval. We observed dramatic differences both in how frequently different individuals perceived the illusion (from 0 % to 100 %) and in how frequently the illusion was perceived across different stimuli (17 % to 58 %). For individual stimuli, the distributions of response frequencies deviated strongly from normality, with 77 % of participants almost never or almost always perceiving the effect (<=10 % or >=90 %). This deviation suggests that the mean response frequency, the most commonly reported measure of the McGurk effect, is a poor measure of individual participants' responses, and that the assumptions made by parametric statistical tests are invalid. Despite the substantial variability across individuals and stimuli, there was little change in the frequency of the effect between initial testing and a one-year retest (mean change in frequency = 2 %; test-retest correlation, r = 0.91). In a second experiment, we replicated our findings of high variability using eight new McGurk stimuli and tested the effects of open choice versus forced-choice responding. Forced-choice responding resulted in an estimated 18 % greater frequency of the McGurk effect but similar levels of interindividual variability. Our results highlight the importance of examining individual differences in McGurk perception instead of relying on summary statistics averaged across a population. However, individual variability in the McGurk effect does not preclude its use as a stable measure of audiovisual integration. PMID- 25802069 TI - No demonstrable benefit for coronal alignment outcomes in PSI knee arthroplasty: A systematic review and meta-analysis. AB - AIM: A systematic review and meta-analysis of clinical studies assessing alignment outcomes in patient-specific instrumented (PSI) knee arthroplasty was conducted. MATERIALS AND METHODS: PRISMA compliant data was extracted from literature databases up to January 2014. RESULTS: Twenty-six studies met the inclusion criteria, reporting a total of 1792 knees. Twenty-three studies reported alignment outcomes in the coronal plane, 11 in the sagittal plane. In all but three series, MRI was the preoperative imaging modality. Range of mean postoperative alignment (hip-knee-ankle [HKA] angle) was 176.5 to 181.70. The proportion of three degrees of outliers showed an overall mean of 18.6%. In total, fifteen studies compared alignment outcomes between standard and PSI. From these, four studies showed significantly higher accuracy of coronal plane alignment with PSI (HKA angle). Meta-analysis of seven high-quality comparative studies demonstrated no significant increased accuracy in postoperative mechanical axis (HKA angle) with PSI. Subgroup meta-analysis of both femoral and tibial rotation was not feasible due to a low number of inclusive high-quality series. CONCLUSIONS: PSI knee arthroplasty is shown not to confer increased accuracy in reconstituting the postoperative mechanical axis. Further studies are required to demonstrate both clinical and radiological alignment outcomes in PSI knee arthroplasty with focus upon tibial and femoral rotation. PMID- 25802071 TI - Two functional promoter polymorphisms of neuregulin 1 gene are associated with progressive forms of multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous system (CNS). Spontaneous remyelination happens in most of MS lesions but it is incomplete and inadequate and eventually fails in majority of lesions of damaged areas. According to the fact that the accuracy of this phenomenon depends on distinct temporal expression profiles of molecules, especially growth factors, we decided to study the association of two functional polymorphisms of NRG1 as a myelin-related growth factor which can promote oligodendrocyte proliferation and differentiation in CNS and PNS. SNP rs6994992 and SNP rs7014762 were genotyped by PCR-RFLP and mismatch PCR-RFLP methods, respectively, in 165 subjects with MS and 200 healthy controls. Totally, our results showed no significant difference in the allelic and genotype frequencies of these two NRG1 polymorphisms between MS patients and control group in Iranian population; but statistically significant association was found for the progressive forms of MS (secondary progressive-MS and primary progressive-MS) for functional SNP of rs6994992 polymorphism. Also, considering rs7014762 polymorphism frequencies, significant difference was observed between primary progressive MS group in comparison to the control group. Furthermore, when the samples were stratified by gender, significant association was revealed between male MS subjects and rs7014762 polymorphism. These results indicate that progression of MS disease could be influenced by functional nucleotide variations in NRG1 gene, which might have an impact on remyelination capacity in different patients. PMID- 25802072 TI - Bioenhancements and the telos of medicine. AB - Staggering advances in biotechnology within the past decade have given rise to pharmacological, surgical and prosthetic techniques capable of enhancing human functioning rather than merely treating or preventing disease. Bioenhancement technologies range from nootropics capable of enhancing cognitive abilities to distraction osteogenesis, a surgical technique capable of increasing height through limb lengthening. This paper examines whether the use of bioenhancements falls inside or outside the proper boundaries of healthcare, and if so, whether clinicians have professional responsibilities to administer bioenhancements to patients. After explicating two theoretical approaches to the concept of health, one objectivist and the other constructivist, I contend that clinicians' corresponding professional responsibilities hinge on which philosophical account of health is endorsed, and illustrate how the lack of analytic clarity with respect to this concept can lead to defective positions on the place of bioenhancements in healthcare. With this conceptual framework in place, an account of health as a cluster concept that incorporates both constructivist and objectivist components is developed and defended. PMID- 25802070 TI - Effective suppression of pro-inflammatory molecules by DHCA via IKK-NF-kappaB pathway, in vitro and in vivo. AB - BACKGROUND AND PURPOSE: Dehydrodiconiferyl alcohol (DHCA), a lignan compound isolated from Cucurbita moschata, has previously been shown to contain anti adipogenic and antilipogenic effects on 3T3-L1 cells and mouse embryonic fibroblasts. As some of phytochemicals derived from natural plants show anti inflammatory or antioxidative activities, we determined whether DHCA affects the production of pro-inflammatory mediators and also investigated its underlying mechanisms. EXPERIMENTAL APPROACH: Raw264.7, a murine macrophage cell line, and primary murine macrophages derived from bone marrow cells were treated with LPS in the presence of DHCA. Furthermore, cells were treated with LPS and palmitate in the presence of DHCA to examine its effect on inflammasomes. The production of various pro-inflammatory mediators was examined and the underlying mechanisms investigated using a variety of molecular biological techniques. To test whether DHCA exhibits anti-inflammatory effects in vivo, mouse dextran sodium sulfate (DSS)-induced colitis model was used. KEY RESULTS: DHCA reduced the production of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta and CCL2) and mediators (iNOS, COX-2 and ROS) by down-regulating the activity of I-kappaB kinase and, subsequently, the DNA binding activity of NF-kappaB. Moreover, DHCA effectively suppressed the palmitate-mediated activation of inflammasomes, which resulted in decreased production of IL-1beta. DHCA also showed therapeutic effects in the mouse DSS-induced colitis model by suppressing the production of TNF-alpha and IL 1beta and thus preventing weight loss and colon shrinkage. CONCLUSIONS AND IMPLICATIONS: Our data suggest that DHCA is a novel phytochemical that by regulating key molecules involved in inflammation and oxidative stress might exert a broad range of anti-inflammatory activities. PMID- 25802073 TI - Efficient solutions to hard computational problems by P systems with symport/antiport rules and membrane division. AB - P systems are computing models inspired by some basic features of biological membranes. In this work, membrane division, which provides a way to obtain an exponential workspace in linear time, is introduced into (cell-like) P systems with communication (symport/antiport) rules, where objects are never modified but they just change their places. The computational efficiency of this kind of P systems is studied. Specifically, we present a (uniform) linear time solution to the NP-complete problem, Subset Sum by using division rules for elementary membranes and communication rules of length at most 3. We further prove that such P system allowing division rules for non-elementary membranes can efficiently solve the PSPACE-complete problem, QSAT in a uniform way. PMID- 25802074 TI - Phenotype adjustment promotes adaptive evolution in a game without conflict. AB - Organisms may adjust their phenotypes in response to social and physical environments. Such phenotypic plasticity is known to help or retard adaptive evolution. Here, we study the evolutionary outcomes of adaptive phenotypic plasticity in an evolutionary game involving two players who have no conflicts of interest. A possible example is the growth and sex allocation of a lifelong pair of shrimps entrapped in the body of a sponge. We consider random pair formation, the limitation of total resources for growth, and the needs of male investment to fertilize eggs laid by the partner. We compare the following three different evolutionary dynamics: (1) No adjustment: each individual develops a phenotype specified by its own genotype; (2) One-player adjustment: the phenotype of the first player is specified by its own genotype, and the second player chooses the phenotype that maximizes its own fitness; (3) Two-player adjustment: the first player exhibits an initial phenotype specified by its own genotype, the second player chooses a phenotype given that of the first player, and finally, the first player readjusts its phenotype given that of the second player. We demonstrate that both one-player and two-player adjustments evolve to achieve maximum fitness. In contrast, the dynamics without adjustment fails in some cases to evolve outcomes with the highest fitness. For an intermediate range of male cost, the evolution of no adjustment realizes two hermaphrodites with equal size, whereas the one-player and two-player adjustments realize a small male and a large female. PMID- 25802075 TI - Diabetic nephropathy: Defective podocyte XBP1 signalling in diabetic nephropathy. PMID- 25802076 TI - Chronic kidney disease: Procoagulant microparticles provide a novel pathogenic link between hyperphosphataemia and cardiovascular risk. PMID- 25802077 TI - Chronic kidney disease: Statins in chronic kidney disease: time to move on? AB - Statins reduce the risk of atherosclerotic vascular disease in healthy individuals and those with chronic kidney disease (CKD); however, clinical trials have suggested a minimal effect of statins on CKD progression. The PLANET trials compared the renal effects of rosuvastatin and atorvastatin, but the findings leave many questions unanswered. PMID- 25802078 TI - Heart failure: New data do not SUPPORT triple RAAS blockade. AB - The SUPPORT trial evaluated the effect of adding the angiotensin-receptor blocker olmesartan to a combination of angiotensin-converting-enzyme inhibitors and beta blockers in hypertensive patients with chronic stable heart failure. Unfortunately, this triple renin-angiotensin-aldosterone system blockade was associated with worsening of renal function and increases in cardiac events and mortality. PMID- 25802080 TI - Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development. AB - BACKGROUND: Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development. METHODS: Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology. RESULTS: Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed. CONCLUSIONS: This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes. PMID- 25802081 TI - The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter? A Meta-analysis and Meta-regression of Longitudinal Magnetic Resonance Imaging Studies. AB - BACKGROUND: Deficits in cortical gray matter (GM) have been found in patients with schizophrenia, with evidence of progression over time. The aim of this study was to determine the role of potential moderators of such changes, in particular of the amount and type of antipsychotic medication intake. METHODS: Longitudinal magnetic resonance imaging studies comparing changes in the volume of cortical GM over time between patients with schizophrenia and healthy control subjects published between January 1, 1983, and March 31, 2014, were analyzed. Hedges' g was calculated for each study and volume changes from baseline to follow-up were analyzed. Meta-regression statistics were applied to investigate the role of potential moderators of the effect sizes. RESULTS: Eighteen studies involving 1155 patients with schizophrenia and 911 healthy control subjects were included. Over time, patients with schizophrenia showed a significantly higher loss of total cortical GM volume. This was related to cumulative antipsychotic intake during the interval between scans in the whole study sample. Subgroup meta analyses of studies on patients treated with second-generation antipsychotics and first-generation antipsychotics revealed a different and contrasting moderating role of medication intake on cortical GM changes: more progressive GM loss correlated with higher mean daily antipsychotic intake in patients treated with at least one first-generation antipsychotic and less progressive GM loss with higher mean daily antipsychotic intake in patients treated only with second generation antipsychotics. CONCLUSIONS: These findings add useful information to the controversial debate on the brain structural effects of antipsychotic medication and may have both clinical relevance and theoretical implications. PMID- 25802079 TI - The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys. AB - BACKGROUND: Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. METHODS: We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. RESULTS: AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3 3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine induced accumbens dopamine release. CONCLUSIONS: These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment. PMID- 25802084 TI - Stabilization of a Bimolecular Triplex by 3'-S-Phosphorothiolate Modifications: An NMR and UV Thermal Melting Investigation. AB - Triplexes formed from oligonucleic acids are key to a number of biological processes. They have attracted attention as molecular biology tools and as a result of their relevance in novel therapeutic strategies. The recognition properties of single-stranded nucleic acids are also relevant in third-strand binding. Thus, there has been considerable activity in generating such moieties, referred to as triplex forming oligonucleotides (TFOs). Triplexes, composed of Watson-Crick (W-C) base-paired DNA duplexes and a Hoogsteen base-paired RNA strand, are reported to be more thermodynamically stable than those in which the third strand is DNA. Consequently, synthetic efforts have been focused on developing TFOs with RNA-like structural properties. Here, the structural and stability studies of such a TFO, composed of deoxynucleic acids, but with 3'-S phosphorothiolate (3'-SP) linkages at two sites is described. The modification results in an increase in triplex melting temperature as determined by UV absorption measurements. (1) H NMR analysis and structure generation for the (hairpin) duplex component and the native and modified triplexes revealed that the double helix is not significantly altered by the major groove binding of either TFO. However, the triplex involving the 3'-SP modifications is more compact. The 3'-SP modification was previously shown to stabilise G-quadruplex and i-motif structures and therefore is now proposed as a generic solution to stabilising multi-stranded DNA structures. PMID- 25802086 TI - Nanoscience vs nanotechnology--defining the field. PMID- 25802083 TI - WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides. AB - Peptide vaccines are capable of eliciting immune responses targeting tumor associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNgamma ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials. PMID- 25802088 TI - A conversation with Prof. Zhong Lin Wang, energy harvester. PMID- 25802082 TI - Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy. AB - BACKGROUND: 5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer's disease. However, no data are available as to whether 5-LO is elevated in human tauopathy or if it directly influences tau pathology in a relevant model of the disease. METHODS: We assayed 5-LO levels in brain samples from patients with tauopathy and transgenic tau mice, and we evaluated the effect of 5-LO pharmacologic inhibition on the phenotype of these mice. RESULTS: The 5-LO protein is upregulated in human tauopathy and transgenic tau mice brains. Pharmacologic blockade of 5-LO in tau mice resulted in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism. CONCLUSIONS: These results establish a key role of 5-LO in the development of the tau pathology phenotype and demonstrate it to be a novel viable therapeutic target for the pharmacologic treatment of human tauopathy. PMID- 25802085 TI - Assessing the effects of neoadjuvant chemotherapy on lymphatic pathways to sentinel lymph nodes in cases of breast cancer: Usefulness of the indocyanine green-fluorescence method. AB - BACKGROUNDS: It is not clear how lymphatic pathways to the sentinel lymph node (SLN) change during neoadjuvant chemotherapy (NAC) for breast cancer. METHODS: Using the indocyanine green (ICG)-fluorescence method, we compared lymphatic pathways to the SLN (sentinel lymphatic pathways) and SLN location before and after NAC in 36 patients (38 breasts). RESULTS: Despite that 42.8% of the sentinel lymphatic pathways were changed by NAC, the locations of the SLNs were not affected by NAC. CONCLUSION: These results suggest that the true SLN can be detected even after NAC, and that SLNB can be performed after NAC for clinically node-negative patients. PMID- 25802090 TI - Using local multiplicity to improve effect estimation from a hypothesis generating pharmacogenetics study. AB - We propose a multiple estimation adjustment (MEA) method to correct effect overestimation due to selection bias from a hypothesis-generating study (HGS) in pharmacogenetics. MEA uses a hierarchical Bayesian approach to model individual effect estimates from maximal likelihood estimation (MLE) in a region jointly and shrinks them toward the regional effect. Unlike many methods that model a fixed selection scheme, MEA capitalizes on local multiplicity independent of selection. We compared mean square errors (MSEs) in simulated HGSs from naive MLE, MEA and a conditional likelihood adjustment (CLA) method that model threshold selection bias. We observed that MEA effectively reduced MSE from MLE on null effects with or without selection, and had a clear advantage over CLA on extreme MLE estimates from null effects under lenient threshold selection in small samples, which are common among 'top' associations from a pharmacogenetics HGS. PMID- 25802089 TI - Genetic variation, expression and ontogeny of sulfotransferase SULT2A1 in humans. AB - Sulfotransferases (SULTs) are enzymes involved in the metabolism of several endogenous molecules. The activity and expression exhibit inter- and intra individual variations due to age and genetic variation. The aims of this study were to compare the gene expression of SULT2A1 in fetal and adult livers, to study the intra-individual tissue distribution, and investigate if expression is associated with a SULT2A1 copy number variation polymorphism. In contrast to other drug metabolizing enzyme systems the expression of SULT2A1 did not differ between fetal and adult liver samples and it was not affected by maternal smoking or gestational age. Gene expression in relation to sex could not be assessed as the sex of the fetuses was unknown. SULT2A1 was consistently expressed in livers and adrenals, being seven times more abundant in adrenals, but was absent in the lungs. The SULT2A1 copy number variation was proportional to gene expression in liver and adrenals. Our results show that SULT2A1 is important in the first trimester; particularly in the adrenals. PMID- 25802091 TI - Human antibody technology and the development of antibodies against cytomegalovirus. AB - Cytomegalovirus (CMV) is a virus that causes chronic infections in a large set of the population. It may cause severe disease in immunocompromised individuals, is linked to immunosenescence and implied to play an important role in the pathogenesis of cardiovascular diseases and cancer. Modulation of the immune system's abilities to manage the virus represent a highly viable therapeutic option and passive immunotherapy with polyclonal antibody preparations is already in clinical use. Defined monoclonal antibodies offer many advantages over polyclonal antibodies purified from serum. Human CMV-specific monoclonal antibodies have consequently been thoroughly investigated with respect to their potential in the treatment of diseases caused by CMV. Recent advances in human antibody technology have substantially expanded the breadth of antibodies for such applications. This review summarizes the fundamental basis for treating CMV disease by use of antibodies, the basic technologies to be used to develop such antibodies, and relevant human antibody specificities available to target this virus. PMID- 25802093 TI - Selfish genetic elements and plant genome size evolution. AB - Plants have contributed extensively to our understanding of selfish genetic elements. Most recently, the sequencing of the Arabis alpina genome shows how the co-evolutionary arms race between transposable elements and the silencing machinery employed to control them may drive the evolution of genome size. PMID- 25802094 TI - Natural variation in transcriptional rhythms modulates photoperiodic responses. AB - Recent studies have demonstrated that allelic variation in daily expression profiles of the GIGANTEA gene may account for the variance in plant growth in different accessions. Studying natural variation in daily transcriptional patterns of circadian-clock regulated genes provides new insights into plant adaptive strategies to different geographical regions. PMID- 25802095 TI - Hemorrhoidal arterial ligation with mucopexy: Be careful with the use of acronyms. PMID- 25802096 TI - Air-Stable (CAAC)CuCl and (CAAC)CuBH4 Complexes as Catalysts for the Hydrolytic Dehydrogenation of BH3NH3. AB - The first stable copper borohydride complex [(CAAC)CuBH4] [CAAC = cyclic(alkyl)(amino)carbene] bearing a single monodentate ligand was prepared by addition of NaBH4 or BH3NH3 to the corresponding [(CAAC)CuCl] complex. Both complexes are air-stable and promote the catalytic hydrolytic dehydrogenation of ammonia borane. The amount of hydrogen released reaches 2.8 H2/BH3 NH3 with a turnover frequency of 8400 mol H2 molcat(-1) h(-1) at 25 degrees C. In a fifteen cycle experiment, the catalyst was reused without any loss of efficiency. PMID- 25802097 TI - Reflective writing: the student nurse's perspective on reflective writing and poetry writing. AB - BACKGROUND: Reflective writing is a mandatory part of nurse education but how students develop their skills and use reflection as part of their experiential learning remains relatively unknown. Understanding reflective writing in all forms from the perspective of a student nurse is therefore important. OBJECTIVES: To explore the use of reflective writing and the use of poetry in pre-registered nursing students. DESIGN: A qualitative design was employed to explore reflective writing in pre-registered nursing students. SETTING: A small university in Scotland. PARTICIPANTS: BSc (Hons) Adult and Mental Health Pre-registration Student Nurses. METHODS: Two focus groups were conducted with 10 student nurses during March 2012. Data was analysed thematically using the framework of McCarthy (1999). RESULTS: Students found the process of reflective writing daunting but valued it over time. Current educational methods, such as assessing reflective accounts, often lead to the 'narrative' being watered down and the student feeling judged. Despite this, reflection made students feel responsible for their own learning and research on the topic. Some students felt the use of models of reflection constricting, whilst poetry freed up their expression allowing them to demonstrate the compassion for their patient under their care. CONCLUSIONS: Poetry writing gives students the opportunity for freedom of expression, personal satisfaction and a closer connection with their patients, which the more formal approach to reflective writing did not offer. There is a need for students to have a safe and supportive forum in which to express and have their experiences acknowledged without the fear of being judged. PMID- 25802092 TI - The complement system and adverse pregnancy outcomes. AB - Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the fetal allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child. PMID- 25802098 TI - Primary light-induced reaction steps of reversibly photoswitchable fluorescent protein Padron0.9 investigated by femtosecond spectroscopy. AB - The reversible photoswitching of the photochromic fluorescent protein Padron0.9 involves a cis-trans isomerization of the chromophore. Both isomers are subjected to a protonation equilibrium between a neutral and a deprotonated form. The observed pH dependent absorption spectra require at least two protonating groups in the chromophore environment modulating its proton affinity. Using femtosecond transient absorption spectroscopy, we elucidate the primary reaction steps of selectively excited chromophore species. Employing kinetic and spectral modeling of the time dependent transients, we identify intermediate states and their spectra. Excitation of the deprotonated trans species is followed by excited state relaxation and internal conversion to a hot ground state on a time scale of 1.1-6.5 ps. As the switching yield is very low (Phitrans->cis = 0.0003 +/- 0.0001), direct formation of the cis isomer in the time-resolved experiment is not observed. The reverse switching route involves excitation of the neutral cis chromophore. A strong H/D isotope effect reveals the initial reaction step to be an excited state proton transfer with a rate constant of kH = (1.7 ps)(-1) (kD = (8.6 ps)(-1)) competing with internal conversion (kic = (4.5 ps)(-1)). The deprotonated excited cis intermediate relaxes to the well-known long-lived fluorescent species (kr = (24 ps)(-1)). The switching quantum yield is determined to be low as well, Phicis->trans = 0.02 +/- 0.01. Excitation of both the neutral and deprotonated cis chromophores is followed by a ground state proton transfer reaction partially re-establishing the disturbed ground state equilibrium within 1.6 ps (deuterated species: 5.6 ps). The incomplete equilibration reveals an inhomogeneous population of deprotonated cis species which equilibrate on different time scales. PMID- 25802099 TI - Ambulance Diversion: Ethical Dilema and Necessary Evil. AB - Ambulance diversion presents a dilemma pitting the ethical principles of patient autonomy and beneficence against the principles of justice and nonmaleficence. The guiding priority in requesting ambulance diversion is to maintain the safety of all patients in the emergency department as well as those waiting to be seen. Policies and procedures can be developed that maintain the best possible outcome for patients transported by ambulance during periods of diversion. More importantly, the discussion must focus on addressing the operational inefficiencies within our health systems that lead to conditions such as patient boarding, high waiting room congestion, and ambulance diversion. Addressing these inefficiencies has a greater potential impact on ambulance diversion than simply banning or restricting the practice for practical or ethical considerations. PMID- 25802100 TI - Alvarado score: is it time to develop a clinical-pathological-radiological scoring system for diagnosing acute appendicitis? PMID- 25802101 TI - New-onset diabetes after liver transplantation: Enough attention required! PMID- 25802103 TI - [Non-muscle-invasive high-grade bladder cancer]. AB - BACKGROUND: Non-muscle-invasive bladder cancer with a low-grade differentiation represents a special challenge. METHOD: Although urine cytology is still the most reliable and effective urine-based marker and there are no substantial novel aspects in this field, photodynamic diagnostics have the most important value in transurethral resection of the bladder (TURB) of high-grade T1 tumors and new techniques, such as hybrid knife TURB are coming up. The histopathological assessment of T1 tumors can be supplemented by a description of the exact penetration depth, so-called substaging and the invasion pattern. RESULTS: Intravesicle therapy with Bacillus Calmette-Guerin (BCG) represents the gold standard and a pillar of bladder-preserving therapy and should be planned as maintenance therapy for at least 1 year. With the right risk constellation cystectomy is a safe and proven concept for high-grade bladder cancer, even without proof of muscle invasion. PMID- 25802104 TI - [Comparison of four treatment options for low-risk prostate cancer: Preference based randomized study for the evaluation of four treatment modalities in prostate cancer with low or "early intermediate" risk (PREFERE) - trial AP 65/11 of the AUO]. PMID- 25802105 TI - Mental health and parenting characteristics of caregivers of children with spina bifida. AB - INTRODUCTION: Within the chronic medical illness literature, associations exist between caring for an affected child and parent mental health. The few studies examining both mothers and fathers provide mixed results. The purpose of this study is to examine associations between caregiver anxiety, depression, and parenting variables in caregivers of youth with SB as these relate to marital status, age, education, household income, work status, and child's severity of SB. OBJECTIVE: The aim of this study is to examine associations between anxiety, depression, and parenting variables in caregivers of youth with spina bifida and how they relate to demographic and disease variables. Exploratory analyses examined the relationship between participation in support activities and depressive and anxious symptomatology and parenting characteristics. STUDY DESIGN: Eighty-four primary caregivers (49 mothers) of 51 youth with spina bifida completed measures of depressive and anxious symptomology, parenting stress, parent overprotection, and perceived child vulnerability. RESULTS: There were differences between mothers and fathers on several parenting characteristics; however, these were related more to marital status and employment than to gender of the caretaker per se. In the 33 married/remarried couples for whom both spouses participated, stress for the mothers was correlated with stress for the fathers. This correlation was strongest in the 12 married couples in which the mother works. Higher perceived vulnerability scores were reported in parents of SB patients in the younger age group, especially preschoolers (0-4 years). Parents of children with shunts reported more anxiety, depression and perceived child vulnerability. Both male and female caregivers of younger children reported significantly higher protectiveness scores. Involvement in recreational activities with other families affected by SB was associated with more positive parenting characteristics for mothers. DISCUSSION: Stress and protectiveness were found to be positively correlated (r > 0.6); depression, anxiety, and perceived vulnerability were not (0.3 < r < -0.3). Overall, mothers reported more stress and anxiety than fathers. Higher perceived vulnerability scores were reported in parents of SB patients in the younger age group, especially preschoolers (0-4 years). Parents of children with shunts reported more anxiety, depression and perceived child vulnerability. Both male and female caregivers of younger children reported significantly higher protectiveness scores compared to caregivers of older children. Involvement in recreational activities with other families affected by SB was associated with more positive parenting characteristics for mothers. There were differences between mothers and fathers on several parenting characteristics; however, these were related more to marital status and employment than to gender of the caretaker per se. Limitations to the current study qualify our results and conclusions. Associations do not prove causation. Our measure of parent protection had a lower Cronbach's alpha score for male caregivers (0.68) than female caregivers (0.83), consistent with an examination of the factor structure of the PPS that found the measure to have a poor factor structure and limited reliability in samples with a chronic medical condition. CONCLUSION: Anxiety, depression, and parenting characteristics were differentially impacted by variables such as caregiver and child age, shunt status, and employment status/income for parents of youth with SB. Interventions to improve parenting skills and mental health of these caregivers can be designed to target specific needs of parents. Groups such as the Greater Oklahoma Disabled Sports Association (GODSA) offer real-world support to improve the lives of caregivers of SB children, and should be studied further to optimize outcomes for children. PMID- 25802102 TI - Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. AB - Increased bone marrow adiposity is a common feature of advanced age, obesity and associated metabolic pathologies. Augmented numbers of marrow adipocytes positively correlate with dysregulated bone remodeling, also a well-established complication of metastatic disease. We have shown previously that marrow adiposity accelerates prostate tumor progression in the skeleton and promotes extensive destruction of the bone; however, the factors behind adipocyte-driven osteolysis in the skeletal tumor microenvironment are not currently known. In this study, utilizing in vivo diet-induced models of bone marrow adiposity, we reveal evidence for positive correlation between increased marrow fat content, bone degradation by ARCaP(M) and PC3 prostate tumors, and augmented levels of host-derived CXCL1 and CXCL2, ligands of CXCR2 receptor. We show by in vitro osteoclastogenesis assays that media conditioned by bone marrow adipocytes is a significant source of CXCL1 and CXCL2 proteins. We also demonstrate that both the adipocyte-conditioned media and the recombinant CXCL1 and CXCL2 ligands efficiently accelerate osteoclast maturation, a process that can be blocked by neutralizing antibodies to each of the chemokines. We further confirm the contribution of CXCR2 signaling axis to adiposity-driven osteoclastogenesis by blocking fat cell-induced osteoclast differentiation with CXCR2 antagonist or neutralizing antibodies. Together, our results link CXCL1 and CXCL2 chemokines with bone marrow adiposity and implicate CXCR2 signaling in promoting effects of marrow fat on progression of skeletal tumors in bone. PMID- 25802106 TI - The variations in the AXIN1 gene and susceptibility to cryptorchidism. AB - BACKGROUND: Cryptorchidism is one of the most common congenital anomalies in newborn boys. Although the mechanism responsible for the pathophysiology of cryptorchidism has not yet been well addressed, the Wnt signaling pathway has been involved in the development of cryptorchidism. Axin1 is a central component of the Wnt signaling pathway and may play a critical role in the development of cryptorchidism. OBJECTIVE: We assumed that cryptorchidism risk and the AXIN1 gene may have an association. Thus we picked out three tag SNPs (single nucleotide polymorphisms) in the AXIN1 gene and aimed to investigate whether cryptorchidism risk is associated with polymorphisms in the AXIN1 gene. STUDY DESIGN: The variants were discriminated using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods. A total of 113 cases and 179 controls were recruited to participate in this study, including 92 unilateral cryptorchidism and 21 bilateral cases. In bilateral cases, the position of the testis was decided by the higher one. RESULTS: A significantly increased cryptorchidism risk was found to be associated with both the T allele (p = 2e( 4), OR 1.96, 95% CI 1.37-2.78) and T/T genotype (p = 6e(-4), OR 4.00, 95% CI 1.79 9.09) of rs370681 polymorphism, and, compared with the C/C genotype, a significantly increased cryptorchidism risk was associated with the C/T-T/T genotype (p = 4e(-4), OR 2.44, 95% CI 1.47-4.00) of rs370681 polymorphisms. DISCUSSION: Among the three tag SNPs we have chosen in AXIN1, two SNPs are located in the intron region, the other SNP is located in the synonymous codon region. Evidential research has indicated that introns and other non-protein coding RNAs may have evolved to function as network control molecules in higher organisms. Therefore, we suspected that the tag SNPs may work as controls influencing the conduct of other genes rather than affecting the structure of the protein by influencing the coding of amino acid. There were limitations in our study. One is that we did not test the expression level of Axin1. Secondly, the number of the study subjects is limited. Finally, the molecular mechanisms by which AXIN1 is involved in susceptibility to cryptorchidism should be characterized. CONCLUSIONS: We assessed the impact of the genetic variability of the AXIN1 gene on cryptorchidism. We have offered primary evidence that the T allele and T/T genotype of rs370681 polymorphisms and C/T genotype of rs1805105 polymorphisms in AXIN1 gene are more frequent in patients with cryptorchidism. PMID- 25802108 TI - Commentary to 'Renal damage detected by DMSA despite normal renal ultrasound in children with febrile UTI'. PMID- 25802107 TI - New alternative Mitrofanoff channel based on spiral intestinal lengthening and tailoring. AB - INTRODUCTION: The occasional lack of appendix and the increasing use of the Malone anterograde continence enema (MACE) procedure have expanded the need for alternative Mitrofanoff channels. The Monti procedure does not always provide adequate length, the anastomosis of the double Monti, and the potential kink of the Casale channel is not ideal for smooth catheterisation. We tested the concept of spiral intestinal lengthening and tailoring (SILT), we developed originally for short bowel syndrome, to create a long and straight alternative Mitrofanoff channel (Figure). MATERIAL AND METHODS: After ethical approval five mini-pigs underwent spiral intestinal lengthening and tailoring (SILT) without any previous bowel dilatation procedure. (Mean bowel width was 20.5 +/- 0.57 mm). The spiral line was marked on a 6-8-cm-long ileum approximately 15 mm apart with a 60 degrees angle to the longitudinal axis of the bowel. When the incision was completed, the mesentery was incised perpendicularly where the spiral incision line met the mesentery. The maximum length segment hanging on a single 1.5-cm wide well-vascularised mesentery was detached. The capillary red blood cell velocity (RBCV) and perfusion rate (PR) was measured at the edges of the opened bowel strip by in vivo microscopy using orthogonal polarising spectral imaging (Cytoscan A/R, Cytometrics, Philadelphia, PA, USA). The bowel strips have been reconstructed in spiral fashion over a 12F catheter and were implanted into the bladder. Viability, patency, and microcirculation were assessed 4 weeks later. Conventional microscopy with HE staining was performed. RESULTS: The mean length of the spiral channel (100 +/- 26.4 mm) was longer than could have been achieved with the double Monti or Casale procedure (4 times the bowel width). A 17% and 8.3% reduction was measured in the median values of the RBCV and the PR at the edges of the bowel strip at the primary surgery. All implanted channels remained viable, straight, patent, and easily catheterisable after 4 weeks, with full recovery of the RBCV and PR. The histology showed no necrosis or fibrosis. CONCLUSION: The SILT concept is suitable for creating a long and straight alternative Mitrofanoff channel. DISCUSSION: However, the SILT technique has been reported to be successful in the clinical practice to tailor and lengthen dilated short bowel; in this study we first applied this technique on normal calibre intestine to create long alternative Mitrofanoff channel. The use of an animal model and the relative short-term observation are the limitations of this study. PMID- 25802109 TI - Psychometric evaluation of the negative syndrome of schizophrenia. AB - In this paper, we reviewed the available instruments for assessing the negative syndrome of schizophrenia, describing their strengths and weaknesses. Current instruments were classified into two categories according to their content validity and assessment approach as first- or second-generation instruments. The BPRS, SANS, the SENS and the PANSS belong to the first generation, while the BNSS, the CAINS and the MAP-SR belong to the second generation. The NSA can be considered a transitional instrument between the two. First-generation instruments have more content validity problems than second-generation instruments do, as they do not accurately reflect the currently accepted negative syndrome (they do not include all negative symptoms and signs or they include symptoms from other dimensions). They also have more problems relative to the use of behavioural referents instead of internal experiences of deficits when assessing symptoms, which may lead to measuring functioning instead of negative symptoms. Further research needs to be done in this area in order to ensure the evaluation of primary negative symptoms and internal experiences involved in negative symptoms rather than external behaviours. PMID- 25802110 TI - Utilization of circular dichroism experiment to distinguish acanthoside D and eleutheroside E. AB - Two lignan glycosides, acanthoside D (1) (=liriodendrin, (+)-syringaresinol di-O beta-D-glucopyranoside) and eleutheroside E (2) have been confused each other for so long time, and hard to be distinguished each other. Now, this two compounds need to be defined properly so that all the commercial mistakes and confusions should not be made. They have identical planar structures except for the configurations at C-7 and C-8 in each structure according to the chemistry database, SciFinder((r)). The systematic name of acanthoside D is [(1S,3aR,4S,6aR)-tetrahydro-1H,3H-furo[3,4-c]furan-1,4-diyl]bis(2,6-dimethoxy-4,1 phenylene) bis-beta-D-glucopyranoside (1), and the name of eleutheroside E is [(1R,3aR,4S,6aS)-tetrahydro-1H,3H-furo[3,4-c]furan-1,4-diyl]bis(2,6-dimethoxy-4,1 phenylene) bis-beta-D-glucopyranoside (2). The differences at two chiral centers do not make any differences in the NMR spectra. Thus, the circular dichroism were utilized to dissolve this difficult problem. Acanthoside D (1) showed a positive Cotton effect at 200 nm, whereas eleutheroside E (2) exhibited a negative cotton effect at 200 nm. The absolute structure of acanthoside D was also confirmed by X ray crystallography. PMID- 25802111 TI - Characteristics of Sleep-Disordered Breathing in Etiologic Subtypes of Minor-to Moderate Acute Ischemic Stroke. AB - BACKGROUND: Sleep-disordered breathing (SDB) is frequent in stroke patients. A strong association has been suggested between SDB and atrial fibrillation (AF). In this study, we evaluated the characteristics of SDB in etiologic subtypes of acute ischemic stroke. We also investigated the relationship between SDB and AF in acute ischemic stroke. METHODS: We prospectively enrolled 72 patients with minor-to-moderate acute ischemic stroke. Clinical and laboratory characteristics of population were recorded on admission. SDB was assessed using standard polysomnography within 7 days after stroke onset. RESULTS: Apnea-hypopnea index (AHI) in small-vessel strokes was significantly lower than that in large-artery atherosclerosis strokes (P = .031), cardioembolic strokes (P = .011), and strokes of other or unknown etiology (.008). Desaturation index (DI) in small-vessel strokes was significantly lower than that in cardioembolic strokes and in large artery strokes (P = .008, P = .035). Arousal index (AI) in large-artery strokes was significantly higher than that in small-vessel strokes (P = .013), cardioembolic strokes (P = .007), and strokes of other or unknown etiology (.027). In a multivariate regression model were age (odds ratio [OR], 1.083; 95% confidence interval [CI], 1.022-1.148; P = .007) and DI (OR, 1.037; 95% CI, 1.004 1.071; P = .026) the only significant variables independently associated with AF. CONCLUSIONS: We observed higher AHI, DI, and AI in large-artery strokes that may relate to more severe neurologic deficit in this subgroup. Age and DI were the only independent variables significantly associated with AF in acute ischemic stroke. Higher AHI and DI in cardioembolic strokes may thus mirror more frequent premorbid presence of SDB in patients with AF. PMID- 25802112 TI - EDICH; a Novel Grading Scale for Predicting the 30-Day Case Fatality of Primary Inoperable Intracerebral Hemorrhage. PMID- 25802113 TI - Brain Microbleeds 12 Years after Orthotopic Liver Transplantation in Val30Met Amyloidosis. AB - Unexplained focal neurologic episodes (FNEs) can occur in patients with transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP) after orthotopic liver transplantation (OLT). A patient with Val30Met FAP underwent OLT at age 34 years. Twelve years after transplantation, she presented with recurrent FNEs lasting from 10 minutes to 8 hours each, with nonuniform deficitary clinical features and variably associated with headache. Magnetic resonance imaging showed multiple brain microbleeds and diffuse contrast enhancement of the craniospinal leptomeninges consistent with amyloid deposits. Our observation suggests that microbleeds associated with meningovascular amyloidosis can underlie FNEs in TTR FAP. Moreover, it confirms that OLT does not halt progression of leptomeningeal and vascular amyloid deposition due to TTR production in the choroid plexuses. Such a progression might compromise the good long-term prognosis of patients with TTR-FAP due to increased risk of intracranial hemorrhages. Pharmacologic therapies targeting brain TTR production may modify this scenario. PMID- 25802114 TI - Predictive Ability of a Modified Version of Emergency Department Intracerebral Hemorrhage Grading Scale for Short-term Prognosis of Intracerebral Hemorrhage. PMID- 25802115 TI - From parent to child? Transmission of educational attainment within immigrant families: methodological considerations. AB - One in five U.S. residents under the age of 18 has at least one foreign-born parent. Given the large proportion of immigrants with very low levels of schooling, the strength of the intergenerational transmission of education between immigrant parent and child has important repercussions for the future of social stratification in the United States. We find that the educational transmission process between parent and child is much weaker in immigrant families than in native families and, among immigrants, differs significantly across national origins. We demonstrate how this variation causes a substantial overestimation of the importance of parental education in immigrant families in studies that use aggregate data. We also show that the common practice of "controlling" for family human capital using parental years of schooling is problematic when comparing families from different origin countries and especially when comparing native and immigrant families. We link these findings to analytical and empirical distinctions between group- and individual-level processes in intergenerational transmission. PMID- 25802116 TI - Appraising the suitability of succinimidyl and lipophilic fluorescent dyes to track proliferation in non-quiescent cells by dye dilution. AB - Successful completion of the cell cycle usually results in two identical daughter progeny. This process of generational doubling is termed proliferation and when it occurs in a regulated fashion the benefits range from driving embryonic development to mounting a successful immune response. However when it occurs in a dis-regulated fashion, it is one of the hallmarks of cancer and autoimmunity. These very reasons make proliferation a highly informative parameter in many different biological systems. Conventional flow cytometry (CFC) is a high throughput, fluorescence-based method for measuring the phenotype and function of cells. The application of CFC to measuring proliferation requires a fluorescent dye able to mark live cells so that when they divide, the daughter progeny receives approximately half the fluorescence of the parent. In measurement space, this translates into peaks of fluorescence decreasing by approximately half, each corresponding to a round of division. It is essential that these peaks can be resolved from one another otherwise it is nearly impossible to obtain accurate quantitative proliferation data. Peak resolution is affected by many things, including instrument performance, the choice of fluorescent dye and the inherent properties of the cells under investigation. There are now many fluorescent dyes available for tracking proliferation by dye dilution differing in their chemistry and spectral properties. Here we provide a method for assessing the performance of various candidate dyes with particular emphasis on situations where the cell type is non-quiescent. We have shown previously that even under optimised instrument and labelling conditions, the heterogeneity of non-quiescent cells makes it impossible to obtain an input width below the threshold for peak resolution without reducing the fluorescence distribution using a cell sorter. Moreover, our method also measures how the dye performs post-labelling in terms of loss/transfer to other cells and how the dye is inherited across the cytokinetic plane. All of these factors will affect peak resolution both in non quiescent and primary cell types. PMID- 25802118 TI - Multipotent glia-like stem cells mediate stress adaptation. AB - The neural crest-derived adrenal medulla is closely related to the sympathetic nervous system; however, unlike neural tissue, it is characterized by high plasticity which suggests the involvement of stem cells. Here, we show that a defined pool of glia-like nestin-expressing progenitor cells in the adult adrenal medulla contributes to this plasticity. These glia-like cells have features of adrenomedullary sustentacular cells, are multipotent, and are able to differentiate into chromaffin cells and neurons. The adrenal is central to the body's response to stress making its proper adaptation critical to maintaining homeostasis. Our results from stress experiments in vivo show the activation and differentiation of these progenitors into new chromaffin cells. In summary, we demonstrate the involvement of a new glia-like multipotent stem cell population in adrenal tissue adaptation. Our data also suggest the contribution of stem and progenitor cells in the adaptation of neuroendocrine tissue function in general. PMID- 25802117 TI - Effects of the Fukushima Daiichi nuclear accident on goshawk reproduction. AB - Although the influence of nuclear accidents on the reproduction of top predators has not been investigated, it is important that we identify the effects of such accidents because humans are also top predators. We conducted field observation for 22 years and analysed the reproductive performance of the goshawk (Accipiter gentilis fujiyamae), a top avian predator in the North Kanto area of Japan, before and after the accidents at the Fukushima Daiichi nuclear power plant that occurred in 2011. The reproductive performance declined markedly compared with the pre-accident years and progressively decreased for the three post-accident study years. Moreover, it was suggested that these declines were primarily caused by an increase in the air dose rate of radio-active contaminants measured under the nests caused by the nuclear accidents, rather than by other factors. We consider the trends in the changes of the reproductive success rates and suggest that internal exposure may play an important role in the reproductive performance of the goshawk, as well as external exposure. PMID- 25802119 TI - The Importance of Patient Sex in the Outcomes of Anterior Cruciate Ligament Reconstructions: A Systematic Review and Meta-analysis. AB - BACKGROUND: One of the well-studied epidemiological phenomena of anterior cruciate ligament (ACL) injuries is the 2- to 9-fold increase in the relative risk of ACL rupture in female athletes compared with male athletes. However, the influence of patient sex on the outcome after ACL reconstruction remains unclear, with some authors reporting inferior outcomes in females and others noting no significant difference. PURPOSE: To provide a comprehensive systematic review and meta-analysis to examine the possible association between patient sex and the subjective and objective outcomes after ACL reconstruction. METHODS: This study was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. All studies that reported clinical outcomes after ACL reconstruction in males and females independently were included in the review. A quantitative random-effects meta-analysis was performed to compare outcomes between sexes. For outcomes with considerable heterogeneity, meta-regression was used to identify potential moderators. Articles were evaluated qualitatively when quantitative data were not reported. RESULTS: A total of 135 publications were included in the review. Females had inferior outcomes in instrumented laxity (standardized mean difference [SMD], 0.24; 95% CI, 0.11-0.37), revision rate (relative risk [RR], 1.15; 95% CI, 1.02-1.28), Lysholm score (SMD, -0.33; 95% CI, -0.55 to -0.11), Tegner activity scale (SMD, 0.37; 95% CI, -0.49 to -0.24), and incidence of not returning to sports (RR, 1.12; 95% CI, 1.04-1.21), all of which were statistically significant. Other outcomes were comparable between sexes, including anterior drawer test, Lachman test, pivot-shift test, timed single-legged hop test, single-legged hop test, quadriceps testing, hamstring testing, extension loss, flexion loss, development of cyclops lesion, and International Knee Documentation Committee (IKDC) knee examination score. Females and males were equally likely to develop anterior knee pain and osteoarthritis after ACL reconstruction. The graft rupture and graft failure rates did not differ significantly between sexes. CONCLUSION: There were comparable or inferior results for females compared with males in all outcomes analyzed. No statistically significant sex difference was identified in most of the objective parameters. However, subjective and functional outcomes, including Lysholm score, Tegner activity scale, and ability to return to sports, have been shown to be poorer in females. PMID- 25802120 TI - Time to recanalisation in patients with cerebral venous thrombosis under anticoagulation therapy. AB - BACKGROUND AND PURPOSE: Few studies have investigated the rates of recanalisation after cerebral venous thrombosis (CVT). Our objective was to investigate the recanalisation rate and to identify predictors of recanalisation in patients with CVT. METHODS: We included 102 patients with confirmed first-ever, non-septic CVT. All patients received anticoagulation for 12 months or until complete recanalisation. To assess recanalisation, patients underwent MR venography every 3 months until partial or complete recanalisation or for 12 months after diagnosis. We conducted two parallel analyses of complete recanalisation versus partial and no recanalisation versus any recanalisation. As a secondary objective we explored the influence of recanalisation on outcome and recurrent events. We calculated the probability of recanalisation using Kaplan-Meier analysis and conducted multivariate analysis using a Cox model. RESULTS: The mean age of patients was 33.5+/-11 years (80 (78.4%) women). Survival analysis indicated that 50% of the patients had any recanalisation (grades I, II and III) by 64 days and complete recanalisation (grade III) by 169 days. Adjusted Cox proportional model revealed that age <50 years (HR=11.5 95% CI=1.58 to 84.46, p=0.01) and isolated superior sagittal sinus thrombosis (HR=0.39, 95% CI=0.14 to 1.04, p=0.05) predict complete recanalisation, while age <50 years (HR=4.79; 95% CI=1.69 to 13.5, p=0.003) predicts any recanalisation. Patients with complete recanalisation had a greater chance of good functional outcome (HR=5.17; 95% CI=2.8 to 9.53, p<0.001). CONCLUSIONS: We found that recanalisation occurs over time, until month 11. Complete recanalisation may influence functional outcome. PMID- 25802121 TI - Wounding alters blood chemistry parameters and skin mineralocorticoid receptors in house sparrows (Passer domesticus). AB - Because skin is an important physical barrier against pathogens, the ability to quickly and effectively heal wounds directly impacts an animal's health. The hormone corticosterone (CORT) has many complex effects on immune function and can slow wound healing. It has been suggested that CORT's role during wound healing may be to act as a "brake" on inflammation and cell proliferation. This project aimed to clarify the role of CORT in the healing process by quantifying concentrations of its two intracellular receptors, glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), in the skin of wounded (n = 9) or unwounded (n = 8) house sparrows (Passer domesticus) using radioligand binding assays. We also quantified GR and MR in liver, spleen and pectoralis muscle, as well as several blood chemistry parameters, hypothesizing that wounding would alter whole body energy use. One day post-wounding, wounded birds had higher blood glucose and lower aspartate aminotransferase (a marker indicating muscle damage or catabolism) compared to controls, which may be related to animals' changing metabolic needs in response to lymphocyte and macrophage recruitment at the wound site. Birds had significantly decreased MR, but not GR, in the skin of wounded legs compared to the skin of unwounded legs. There was also a trend towards lower MR in wounded skin compared to unwounded birds. Receptors in the three other tissues did not differ between groups. This study suggests that decreasing the skin's sensitivity to CORT immediately after wounding may be a necessary part of the normal healing process in wild birds. PMID- 25802122 TI - Induction of interleukin-1 beta (IL-1beta) is a critical component of lung inflammation during influenza A (H1N1) virus infection. AB - Cytokine storm during influenza virus infection is recognized as a predictor of morbidity and mortality. To verify the cellular effects of influenza-induced cytokines in primary normal lung cells, human pulmonary microvascular endothelial cells (HMVECs) and lung fibroblast cells (MRC-5 cells) were infected with influenza virus H1N1. H1N1 infection induced the transcription of various genes encoding cytokines and chemokines such as interleukin-1 beta (IL-1beta), IL-6, IL 8, IL-12A, tumor necrosis factor alpha (TNF-alpha), and chemokine (C-C motif) ligand 5 (CCL5) in both endothelial cells and lung fibroblasts. Among them, IL 1beta induction by influenza infection increased the inflammation of lung cells; conversely, blockade of IL-1beta signals with an IL-1beta receptor antagonist or a neutralizing antibody alleviated influenza-driven inflammation. In conclusion, these data suggest that secreted IL-1beta by the endothelial cells contributes to influenza-induced inflammation, and blockade of IL-1beta signals is a potential treatment or therapeutic target for influenza-induced inflammation. PMID- 25802123 TI - Surgical reconstruction for tuberculous airway stenosis: management for patients with concomitant tracheal malacia. AB - OBJECTIVES: Surgical reconstruction is commonly recommended for the treatment of tuberculous airway stenosis. The clinical conditions underlying tuberculous airway stenosis often involve both cicatricial stenosis and malacia. Surgical reconstruction alone may not improve the respiratory symptoms of patients with both types of airway stenosis. This study retrospectively reviewed patients who underwent surgical reconstruction for tuberculous airway stenosis to investigate the most appropriate treatment for this complicated condition. METHODS: Twelve patients with tuberculous airway stenosis underwent surgical reconstruction at our institute from January 2003 to December 2013. The clinical courses of these patients were retrospectively reviewed. RESULTS: The 12 patients were 2 men and 10 women with a mean age of 36 years (range 17-61 years). The site of stenosis was the left main bronchus in six patients, trachea in four patients, and right main bronchus in two patients. The procedure performed was sleeve lobectomy in five patients, bronchial resection in four patients, and tracheal resection in three patients. Additional airway stenting was performed in two patients with concomitant malacia of the lower trachea. The performance status and Hugh-Jones classification improved postoperatively in all patients. The forced expiratory volume in 1 s as a percent of forced vital capacity and percent of forced expiratory volume in 1 s improved significantly. CONCLUSION: Surgical reconstruction is an acceptable treatment for tuberculous airway stenosis. Additional airway stenting may be needed in patients with symptomatic malacia. PMID- 25802125 TI - Gender issues in epilepsy--Difference in management of epilepsy. PMID- 25802124 TI - Early and mid-term outcomes of left ventricular assist device implantation and future prospects. AB - OBJECTIVES: Although implantable left ventricular assist device use as a bridge to heart transplantation is increasing, its permanent use as destination therapy is not permitted in Japan. This retrospective review assessed early and mid-term outcomes of implantable continuous-flow left ventricular assist device compared with extracorporeal pulsatile-flow left ventricular assist device implantation. Issues regarding left ventricular assist device as destination therapy are discussed. METHODS: From January 2009 to September 2013, 72 patients underwent left ventricular assist device implantation at our institute. Forty patients were supported by extracorporeal pulsatile-flow left ventricular assist devices (ex VAD group) and 32 patients with implantable continuous-flow left ventricular assist devices (im-VAD group). RESULTS: The median duration of ventricular assist device support was 563 days. The actuarial survival rates at 1 and 3 years were 92.3 and 79.2 % in the ex-VAD group and 96.4 and 72.3 % in the im-VAD group, respectively. Approximately 50 % of patients in both groups developed cerebrovascular complications within 1 year postoperatively. Six months post implantation, almost 90 % of the ex-VAD group patients suffered exit-site infection compared with about 50 % in the im-VAD group. Readmission rate was 1.74 per patient-year; major causes were driveline exit-site infection (52 %) and cerebrovascular complication (14 %). CONCLUSIONS: Early and mid-term outcomes were satisfactory after both extracorporeal pulsatile-flow left ventricular assist device and implantable continuous-flow left ventricular assist device implantation, although a considerable level of postoperative complications was observed. More data after left ventricular assist device surgery are needed to enable its consideration as a destination therapy option in Japan. PMID- 25802126 TI - Explaining level inversion of the La and Lb States of indole and indole derivatives in polar solvents. AB - Quantum chemical methods are used to study the solvent effects on the spectra of indole and a series of methyl-substituted indoles. We focus on the low-lying L(a) and L(b) states and study their interplay. We find that the solvent mainly affects emission from the L(a) state, by stabilizing its energy in its excited state geometry. The stabilization of the L(a) state increases with increasing solvent polarity, which accounts for the large fluorescence shift observed in indoles and leads to an inversion in the nature of the lowest emitting state, from L(b) in vacuum to L(a) in water. To the best of our knowledge, this is the first theoretical evidence for level inversion done for a series of indoles. The underlying mechanism of level inversion is analyzed in detail. The usual interpretation of level inversion in terms of their static dipole moment is criticized and an improved predictive measurement is suggested. PMID- 25802127 TI - Reversible effects of vitamins C and E combination on cognitive deficits and oxidative stress in the hippocampus of melamine-exposed rats. AB - Previous studies showed that the spatial cognitive deficits of rats were induced by chronic melamine exposure, which was associated with the hippocampal oxidative damage. Currently, we examined the antioxidative effect of vitamins C and E combination on cognitive function in melamine-treated rats. Melamine was oral administrated to male adolescent Wistar at a dosage of 300mg/kg/day for 28days. After that, animals received vitamins C and E at a dose of 150 and 200mg/kg, respectively, intraperitoneally for the next 7days. Cognitive behaviors were investigated using the Morris water maze test. The biochemical indexes were detected in the hippocampal homogenate. The treatment with vitamin complex significantly ameliorated cognitive deficits induced by melamine. ROS, MDA, and NO contents were almost back to normal, while SOD, CAT, GSH-Px, and NOS activities were improved as well. The neural apoptosis in the hippocampus were ameliorated by regulating the expression of anti-apoptotic protein (Bcl-2) and caspase-3. Additionally, histological observation showed that vitamin complex effectively alleviated the injuries of hippocampal neurons. These results suggest that the potential therapeutic for oxidative damage induced neuronal apoptosis after treatment of vitamins C and E combination, which is most likely related to the antioxidative effects. PMID- 25802128 TI - [Disseminated histoplamosis in adolescent mimicking granulomatosis with polyangiitis]. AB - INTRODUCTION: Systemic histoplasmosis is an invasive fungal infection that may mimic primary vasculitis, particularly granulomatosis with polyangiitis (GPA), and was rarely described in adult patients. We reported an immunocompetent patient with disseminated histoplasmosis mimicking GPA who fulfilled European League Against Rheumatism (EULAR)/Pediatric Rheumatology International Trials Organisation (PRINTO)/Pediatric Rheumatology European Society (PRES) validated classification criteria. CASE REPORT: A 6-year old boy presented acute migratory polyarthritis with spontaneous improvement, sinus inflammation, fever, headache and abdominal pain. Serologic test for hepatitis, cytomegalovirus, human immunodeficiency virus, Epstein-Barr virus, toxoplasmosis, dengue virus and antistreptolysin O were all negative. Magnetic resonance imaging (MRI) showed moderate ascites in pelvis and pansinusitis. Antineutrophil cytoplasmic antibodies (c-ANCA) were positive. He had spontaneous remission of the symptoms including fever. At the age of 11 years and 11 months, he had sinusitis, pneumonia and epididymitis. A month later, he was hospitalized and MRI showed left eye proptosis. Cerebrospinal fluid was normal and indirect tests of fungi were negative. Two months later, he had lumbar pain and computer tomography showed a mass in the right kidney and pulmonary nodule in the right lung. He fulfilled EULAR/PRINTO/PRES criteria for GPA, however the renal biopsy showed a focal granulomatous interstitial nephritis with yeast fungal cells compatible with Histoplasma sp. He was treated with liposomal amphotericin B and itraconazole with improvement of signs and symptoms. CONCLUSION: We reported a progressive disseminated histoplasmosis case mimicking GPA. Histoplasmosis infection should be considered in immunocompetent subjects with uncommon clinical manifestations, such as arthritis, nephritis and epididymitis. PMID- 25802129 TI - [Overlap between systemic sclerosis and rheumatoid arthritis: a distinct clinical entity?] AB - INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease of the connective tissue characterized by the triad of vascular injury, autoimmunity (cellular and humoral) and tissue fibrosis. It is estimated that musculoskeletal pain is a common complaint of patients with SSc, ranging from 40 to 80%, and mainly in patients with early diffuse disease. Arthritis, clinically observed, may be a feature seen in the presentation of SSc, often leading to early diagnostic errors with rheumatoid arthritis (RA). In the course of the disease, arthritis is observed in 24 to 97% of patients with SSc. OBJECTIVES: To correlate the occurrence or nonoccurrence of arthritis in patients with SSc of the Midwest region of Brazil with possible distinct clinical and laboratory manifestations observed in three groups of patients. To report the frequency of true association between systemic sclerosis and rheumatoid arthritis in patients with clinically and radiologically observed synovitis. METHODS: Sixty-one SSc patients were subsequently assessed every 3 months within 1 year, in order to clinically observe the occurrence of synovitis and its patterns of progression. Patients were divided into 3 groups: 41 patients with SSc without arthritis, 16 SSc patients with arthritis and 4 patients with overlap of SSc and RA. All patients underwent a radiological examination of the hands at the end of the study. RESULTS: Among all patients evaluated, we found a female predominance (98.7%), mean age of 50.94 years, white color (49.2%), limited form of the disease (47.6%), time of diagnosis between 5 to 10 years (47.6%) and duration of the disease of 8.30 years. Among all patients, 14 (22.9%) had positive rheumatoid factor (RF), while among those with positive RF, only 10 patients had arthritis during one-year follow-up. The antibody anticitrulline (anti-CCP) test was performed in 24 patients, being positive in 4 of them (16.7%), with positivity being observed only in patients with SSc/RA overlap. Comparing the clinical manifestations among the groups of patients, there was a higher incidence of gastritis and cardiac valvulopathy in patients with SSc and arthritis, but not in the others. In the group of patients with SSc/RA overlap and in patients with SSc and arthritis a significant reduction in quality of life was observed, measured by HAQ index, especially in patients with arthritis present during clinical evaluation. We found radiographic changes in 42.6% of patients with SSc. However, in patients with synovitis, radiological changes consistent with rheumatoid arthritis were found in 50% of patients. CONCLUSIONS: While the frequency of clinical arthritis observed in patients with systemic sclerosis was 32.8%, the true overlap between of SSc and RA was 6.6% in this study. We also observed the frequency of positive anti-CCP in 20% of patients with arthritis versus no patients with SSc without arthritis. PMID- 25802130 TI - Behcet's ulcerations in the lower extremity: A case report. AB - Behcet's Disease is a syndrome characterized by recurrent, painful oral aphthous ulcers, in conjunction with 2 or more systemic manifestations - a common systemic manifestation of the disease being cutaneous lesions, which often present as papules that ulcerate to form ulcerations which exhibit the same pathergy phenomenon as pyoderma gangrenosum and are thus difficult to heal. We present a case of a type 2 diabetic male with previously undiagnosed Behcet's Disease who presented to clinic with an atypical lower extremity wound. Due to the atypical nature of the patient's wound, combined with information from the patient regarding the history of the wound and other illnesses he had, the wound was biopsied and the results from the biopsy combined with clinical suspicion yielded a diagnosis of Behcet's Disease. After understanding the nature of the wound, management of the ulceration was adjusted appropriately so as to properly treat the patient with both local wound care and medical management for the disease. Patient was referred to rheumatology for further workup and long-term management of Behcet's Disease. Correct identification and treatment of the systemic disease, as well as the lower extremity ulcerations, in patients with Behcet's Disease are critical to avoid organ and limb-threatening complications. Had the diagnosis of Behcet's not been made in this case, the patient's wound would have been at increased risk of disease-related complications - ranging from non healing ulceration leading to amputation to renal failure to loss of eyesight. PMID- 25802132 TI - Upregulation of Runt-Related Transcription Factor-2 Through CCAAT Enhancer Binding Protein-beta Signaling Pathway in Microglial BV-2 Cells Exposed to ATP. AB - We have shown constitutive expression of the master regulator of osteoblastogenesis, runt-related transcription factor-2 (Runx2), by microglia cells outside bone. Here, we attempted to evaluate the pathological significance of Runx2 in microglial BV-2 cells exposed to ATP at a high concentration. Marked upregulation of Runx2 transcript and protein expression was seen in cells exposed to 1 mM ATP for a period longer than 30 min without inducing cytotoxicity. The Runx2 upregulation by ATP was prevented by extracellular and intracellular Ca(2+) chelators, while thapsigargin upregulated Runx2 expression alone without affecting the upregulation by ATP. A calmodulin antagonist prevented the upregulation by ATP, with calcineurin inhibitors being ineffective. Although ATP markedly increased nuclear levels of nuclear factor of activated T cell-2 (NFAT2), Runx2 promoter activity was not simulated by the introduction of either NFAT1 or NFAT2, but facilitated by that of CCAAT enhancer binding protein-alpha (C/EBPalpha), C/EBPbeta and nuclear factor (erythroid-derived 2)-like-2 (Nrf2). Exposure to ATP up-regulated C/EBPbeta and Nrf2, but not C/EBPalpha, expression, in addition to increasing nuclear levels of respective corresponding proteins. Runx2 upregulation by ATP was deteriorated by knockdown of C/EBPbeta but not by that of Nrf2, however, while exposure to ATP up-regulated matrix metalloproteinase-13 (Mmp13) expression in a Runx2-dependent manner. Overexpression of Runx2 up-regulated Mmp13 expression with promoted incorporation of fluorescent beads into BV-2 cells without ATP. These results suggest that extracellular ATP up-regulates Runx2 expression through activation of the C/EBPbeta signaling in a calmodulin-dependent manner to play a pivotal role in phagocytosis in microglial BV-2 cells. PMID- 25802133 TI - What makes lung cancer invade? PMID- 25802134 TI - Atypical aortic arch branching variants: A novel marker for thoracic aortic disease. AB - OBJECTIVE: To examine the potential of aortic arch variants, specifically bovine aortic arch, isolated left vertebral artery, and aberrant right subclavian artery, as markers for thoracic aortic disease (TAD). METHODS: We screened imaging data of 556 patients undergoing surgery due to TAD for presence of aortic arch variations. Demographic data were collected during chart review and compared with a historical control group of 4617 patients. RESULTS: Out of 556 patients with TAD, 33.5% (186 patients) demonstrated anomalies of the aortic arch, compared with 18.2% in the control group (P < .001). Three hundred seventy (66.5%) had no anomaly of the aortic arch. Bovine aortic arch emerged as the most common anomalous branch pattern with a prevalence of 24.6% (n = 137). Thirty-five patients (6.3%) had an isolated left vertebral artery, and 10 patients (1.8%) had an aberrant right subclavian artery. When compared with the control group, all 3 arch variations showed significant higher prevalence in patients with TAD (P < .001). Patients with aortic aneurysms and anomalous branch patterns had hypertension less frequently (73.5% vs 81.8%; P = .048), but had a higher rate of bicuspid aortic valve (40.8% vs 30.6%; P = .042) when compared with patients with aneurysms but normal aortic arch anatomy. Patients with aortic branch variations were significantly younger (58.6 +/- 13.7 years vs 62.4 +/- 12.9 years; P = .002) and needed intervention for the aortic arch more frequently than patients with normal arch anatomy (46% vs 34.6%; P = .023). CONCLUSIONS: Aortic arch variations are significantly more common in patients with TAD than in the general population. Atypical branching variants may warrant consideration as potential anatomic markers for future development of TAD. PMID- 25802135 TI - Early hemodynamic performance of the third generation St Jude Trifecta aortic prosthesis: A systematic review and meta-analysis. AB - OBJECTIVE: The Trifecta aortic prosthesis is a latest-generation trileaflet stented pericardial valve designed for supra-annular placement in the aortic position. Robust clinical evidence and long-term follow-up data for this new prosthesis are lacking; a systematic review was conducted to assess current evidence. METHODS: A comprehensive search from 6 electronic databases was performed, with time period parameters dating from database inception to January 2014. Results utilizing Trifecta prosthesis for aortic valve replacement (AVR) were identified. RESULTS: A total of 13 studies with 2549 patients undergoing AVR with this prosthesis were included in this review. The mean proportion of patients with aortic stenosis was 82.4%, with a mean gradient of 47.4 mm Hg, and a pooled effective orifice area (EOA) of 0.74 cm(2). Valve sizes of 21 mm and 23 mm were implanted in 71.3% of patients. The pooled rates of 30-day mortality, cerebrovascular accidents, and acute kidney injuries were 2.7%, 1.9%, and 2.6%, respectively. After implantation, the pooled mean gradient decreased to 9.2 mm Hg, whereas discharge EOA increased to 1.8 cm(2), compared with preoperative parameters. Among included studies with significant heterogeneity detected, most patients had satisfactory patient-prosthesis mismatch, with 2.7% having severe mismatch. CONCLUSIONS: The present systematic review demonstrated that short-term AVR with this prosthesis provided excellent early safety and hemodynamic outcomes with acceptable mean gradients and EOA. Long-term follow-up and randomized controlled trials are warranted to confirm the early results. PMID- 25802136 TI - Survival is higher after repeat lung metastasectomy than after a first metastasectomy: Too good to be true? PMID- 25802137 TI - Relationship Between Age and Timely Placement of Vascular Access In Incident Patients on Hemodialysis. AB - BACKGROUND AND PURPOSE: Placement of an arteriovenous fistula (AV) prior to initiating hemodialysis can affect clinical outcomes for patients who subsequently initiate chronic hemodialysis treatments. Age-related variation in receipt of a functioning A TF prior to initiating hemodialysis is not well known. The purpose of this study was to examine age-related rates in use of AVF at the first outpatient hemodialysis treatment among U.S. incident patients on hemodialysis. FINDINGS: Among 526,145 patients identified, the use of AVF outpatient hemodialysis treatment was lower in the youngest (younger than 55 years) and oldest (80 years and older) vs. both 55 to 66-year and 67 to 79-year age groups. These findings persisted after adjusting for demographics, lifestyle behavior, employment and insurance status, physical/functional conditions, and co morbid conditions. CONCLUSIONS: The presence of a functioning AVF at initial hemodialysis treatment varies by age. Modifying healthcare policy and/or expanding the role of nephrology nurses should be considered to address this issue. PMID- 25802138 TI - Neurocognitive functioning of subjects with putative pre-psychotic states and early psychosis. AB - BACKGROUND: The neurocognitive functioning of patients with schizophrenia is likely to decline at the early stage of the illness. More evidence is needed to determine whether deficits in certain domains of neurocognition precede the onset of illness and can predict the onset of psychosis. METHODS: Subjects were recruited from the SOPRES study in Taiwan. A neuropsychological battery including the continuous performance test, Wisconsin Card Sorting Test, Wechsler Adult Intelligence Scale-Third Edition, Trail Making Tests, Mandarin version of the Verbal Fluency Test, and Wechsler Memory Scale-Third Edition, was applied at baseline and 1-year follow-up. Neurocognitive profiles derived from these tests were categorized into 9 domains for comparisons among subjects with different levels of clinical severity. RESULTS: A total of 324 participants, including 49 with first episode psychosis (FEP), 53 with ultra-high risk (UHR), 42 with intermediate risk (IR), 43 with marginal risk (MR), and 137 normal controls completed a baseline assessment and 71% of the participants completed a 1-year follow-up assessment. The profiles of the UHR and IR groups were identical at baseline. Those who converted to FEP later on (UHR+) showed relatively poorer performance than non-converters (UHR-) at baseline. At follow-up the performance of UHR+ was compatible to that of FEP, while UHR- generally improved. CONCLUSIONS: By including subjects with early putative pre-psychotic states, our study clarifies some inconsistencies about the timing and stability of changes in neurocognitive functioning that occur at the start of psychosis; it also raises questions regarding the feasibility of using neurocognitive deficits to predict the risks of transition to psychosis. PMID- 25802139 TI - Education for all ... again! PMID- 25802140 TI - Severity of vasomotor symptoms linked to hip fracture risk. PMID- 25802141 TI - Minimising menopausal side effects whilst treating endometriosis and fibroids. AB - Medical management of endometriosis and fibroids involves manipulation of the hypothalamic-pituitary-gonadal axis to alter the balance of sex hormones thereby inhibiting disease progression and ameliorate symptoms. Unfortunately, resultant menopausal symptoms sometimes limit the tolerability and duration of such treatment. The use of gonadotrophin-releasing hormone agonists to treat these diseases can result in short-term hypoestrogenic and vasomotor side effects as well as long-term impacts on bone health and cardiovascular risk. The routine use of add-back hormone replacement has reduced these risks and increased patient compliance, making this group of drugs more useful as a medium-term treatment option. The estrogen threshold hypothesis highlights the concept of a 'therapeutic window' in which bone loss is minimal but the primary disease is not aggravated. It explains why add-back therapy is appropriate for such patients and helps to explain the basis behind new developments in the treatment of hormonally responsive gynaecological conditions such as gonadotrophin-releasing hormone antagonists and progesterone receptor modulators. PMID- 25802142 TI - Changing the change. PMID- 25802143 TI - Practice observed. PMID- 25802144 TI - Mannose-6-phosphate receptor: a target for theranostics of prostate cancer. AB - The development of personalized and non-invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over-expression of a membrane lectin, the cation-independent mannose 6 phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose-6-phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for in vitro and ex vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic. PMID- 25802145 TI - Can meta-analysis be replaced by best-evidence synthesis in oral oncology systematic review? PMID- 25802146 TI - Preparation of pyranylidene complexes of ruthenium. AB - The reaction of the chloro-complex RuCl(eta(5)-C5H5)(PPh3)[P(OMe)3] with alkylpropiolates HC=CCOOR1 in alcohol R2OH affords pyranylidene derivatives [Ru(eta(5)-C5H5){=C(COOR1)C(H)C(H)C(OR1)O}(PPh3){P(OMe)3}]BPh4 (1, 3) and alkoxycarbene complexes [Ru(eta(5)-C5H5){=C(OR2)(CH2COOR1)}(PPh3){P(OMe)3}]BPh4 (2, 4). A reaction path for the formation of compounds 1-4, involving reactions on a vinylidene intermediate complex, is also discussed. The complexes were characterized spectroscopically (IR and (1)H, (13)C, (31)P NMR) and by X-ray crystal structure determination of [Ru(eta(5) C5H5){=C(COOMe)C(H)C(H)C(OMe)O}(PPh3){P(OMe)3}]BPh4 (1). PMID- 25802147 TI - A RhoA Signaling Pathway Regulates Dendritic Golgi Outpost Formation. AB - The neuronal Golgi apparatus (GA) localizes to the perinuclear region and dendrites as tubulo-vesicular structures designated Golgi outposts (GOPs). Current evidence suggests that GOPs shape dendrite morphology and serve as platforms for the local delivery of synaptic receptors. However, the mechanisms underlying GOP formation remain a mystery. Using live-cell imaging and confocal microscopy in cultured hippocampal neurons, we now show that GOPs destined to major "apical" dendrites are generated from the somatic GA by a sequence of events involving: (1) generation of a GA-derived tubule; (2) tubule elongation and deployment into the dendrite; (3) tubule fission; and (4) transport and condensation of the fissioned tubule. A RhoA-Rock signaling pathway involving LIMK1, PKD1, slingshot, cofilin, and dynamin regulates polarized GOP formation by controlling the tubule fission. Our observations identify a mechanism underlying polarized GOP biogenesis and provide new insights regarding involvement of RhoA in dendritic development and polarization. PMID- 25802148 TI - Dopamine modulates egalitarian behavior in humans. AB - Egalitarian motives form a powerful force in promoting prosocial behavior and enabling large-scale cooperation in the human species [1]. At the neural level, there is substantial, albeit correlational, evidence suggesting a link between dopamine and such behavior [2, 3]. However, important questions remain about the specific role of dopamine in setting or modulating behavioral sensitivity to prosocial concerns. Here, using a combination of pharmacological tools and economic games, we provide critical evidence for a causal involvement of dopamine in human egalitarian tendencies. Specifically, using the brain penetrant catechol O-methyl transferase (COMT) inhibitor tolcapone [4, 5], we investigated the causal relationship between dopaminergic mechanisms and two prosocial concerns at the core of a number of widely used economic games: (1) the extent to which individuals directly value the material payoffs of others, i.e., generosity, and (2) the extent to which they are averse to differences between their own payoffs and those of others, i.e., inequity. We found that dopaminergic augmentation via COMT inhibition increased egalitarian tendencies in participants who played an extended version of the dictator game [6]. Strikingly, computational modeling of choice behavior [7] revealed that tolcapone exerted selective effects on inequity aversion, and not on other computational components such as the extent to which individuals directly value the material payoffs of others. Together, these data shed light on the causal relationship between neurochemical systems and human prosocial behavior and have potential implications for our understanding of the complex array of social impairments accompanying neuropsychiatric disorders involving dopaminergic dysregulation. PMID- 25802149 TI - Steroid Signaling Establishes a Female Metabolic State and Regulates SREBP to Control Oocyte Lipid Accumulation. AB - Disruptions in energy homeostasis severely affect reproduction in many organisms and are linked to several reproductive disorders in humans. As a result, understanding the mechanisms that control nutrient accumulation in the oocyte will provide valuable insights into the links between metabolic disease and reproductive dysfunction. We show that the steroid hormone ecdysone functions in Drosophila to control lipid metabolism and support oocyte production. First, local EcR-mediated signaling induces a stage-specific accumulation of lipids in stage-10 oocytes. EcR induces lipid accumulation by promoting the activation of the lipogenic transcription factor SREBP and by controlling the expression of the low-density lipoprotein (LDL) receptor homolog, LpR2. Second, global signaling via the ecdysone receptor, EcR, establishes a female metabolic state and promotes whole-body triglyceride and glycogen storage at high levels. EcR acts in the CNS to mediate these effects, in part by promoting higher levels of feeding in females. Thus, ecdysone functions at two levels to support reproduction: first by inducing lipid accumulation in the late stages of oocyte development and second by providing a signal that coordinates lipid metabolism in the germline with whole-animal lipid homeostasis. Ecdysone regulation allows females to assess the demands of oogenesis and alter their behavior and metabolic state to support the biosynthetic requirements of oocyte production. PMID- 25802150 TI - Circadian control sheds light on fungal bioluminescence. AB - Bioluminescence, the creation and emission of light by organisms, affords insight into the lives of organisms doing it. Luminous living things are widespread and access diverse mechanisms to generate and control luminescence [1-5]. Among the least studied bioluminescent organisms are phylogenetically rare fungi-only 71 species, all within the ~ 9,000 fungi of the temperate and tropical Agaricales order-are reported from among ~ 100,000 described fungal species [6, 7]. All require oxygen [8] and energy (NADH or NADPH) for bioluminescence and are reported to emit green light (lambdamax 530 nm) continuously, implying a metabolic function for bioluminescence, perhaps as a byproduct of oxidative metabolism in lignin degradation. Here, however, we report that bioluminescence from the mycelium of Neonothopanus gardneri is controlled by a temperature compensated circadian clock, the result of cycles in content/activity of the luciferase, reductase, and luciferin that comprise the luminescent system. Because regulation implies an adaptive function for bioluminescence, a controversial question for more than two millennia [8-15], we examined interactions between luminescent fungi and insects [16]. Prosthetic acrylic resin "mushrooms," internally illuminated by a green LED emitting light similar to the bioluminescence, attract staphilinid rove beetles (coleopterans), as well as hemipterans (true bugs), dipterans (flies), and hymenopterans (wasps and ants), at numbers far greater than dark control traps. Thus, circadian control may optimize energy use for when bioluminescence is most visible, attracting insects that can in turn help in spore dispersal, thereby benefitting fungi growing under the forest canopy, where wind flow is greatly reduced. PMID- 25802152 TI - Functional divergence of type 2 deiodinase paralogs in the Atlantic salmon. AB - Thyroid hormone (TH) is an ancestral signal linked to seasonal life history transitions throughout vertebrates. TH action depends upon tissue-localized regulation of levels of active TH (triiodothyronine, T3), through spatiotemporal expression of thyroid hormone deiodinase (dio) genes. We investigated the dio gene family in juvenile Atlantic salmon (Salmo salar) parr, which prepare for seaward migration in the spring (smoltification) through TH-dependent changes in physiology. We identified two type 2 deiodinase paralogs, dio2a and dio2b, responsible for conversion of thyroxine (T4) to T3. During smoltification, dio2b was induced in the brain and gills in zones of cell proliferation following increasing day length. Contrastingly, dio2a expression was induced in the gills by transfer to salt water (SW), with the magnitude of the response proportional to the plasma chloride level. This response reflected a selective enrichment for osmotic response elements (OREs) in the dio2a promoter region. Transcriptomic profiling of gill tissue from fish transferred to SW plus or minus the deiodinase inhibitor, iopanoic acid, revealed SW-induced increases in cellular respiration as the principal consequence of gill dio2 activity. Divergent evolution of dio2 paralogs supports organ-specific timing of the TH-dependent events governing the phenotypic plasticity required for migration to sea. PMID- 25802151 TI - Stomatal guard cells co-opted an ancient ABA-dependent desiccation survival system to regulate stomatal closure. AB - During the transition from water to land, plants had to cope with the loss of water through transpiration, the inevitable result of photosynthetic CO2 fixation on land [1, 2]. Control of transpiration became possible through the development of a new cell type: guard cells, which form stomata. In vascular plants, stomatal regulation is mediated by the stress hormone ABA, which triggers the opening of the SnR kinase OST1-activated anion channel SLAC1 [3, 4]. To understand the evolution of this regulatory circuit, we cloned both ABA-signaling elements, SLAC1 and OST1, from a charophyte alga, a liverwort, and a moss, and functionally analyzed the channel-kinase interactions. We were able to show that the emergence of stomata in the last common ancestor of mosses and vascular plants coincided with the origin of SLAC1-type channels capable of using the ancient ABA drought signaling kinase OST1 for regulation of stomatal closure. PMID- 25802153 TI - Phenotypic plasticity confers multiple fitness benefits to a mimic. AB - Animal communication is often deceptive; however, such dishonesty can become ineffective if it is used too often, is used out of context, or is too easy to detect [1-3]. Mimicry is a common form of deception, and most mimics gain the greatest fitness benefits when they are rare compared to their models [3, 4]. If mimics are encountered too frequently or if their model is absent, avoidance learning of noxious models is disrupted (Batesian mimicry [3]), or receivers become more vigilant and learn to avoid perilous mimics (aggressive mimicry [4]). Mimics can moderate this selective constraint by imperfectly resembling multiple models [5], through polymorphisms [6], or by opportunistically deploying mimetic signals [1, 7]. Here we uncover a novel mechanism to escape the constraints of deceptive signaling: phenotypic plasticity allows mimics to deceive targets using multiple guises. Using a combination of behavioral, cell histological, and molecular methods, we show that a coral reef fish, the dusky dottyback (Pseudochromis fuscus), flexibly adapts its body coloration to mimic differently colored reef fishes and in doing so gains multiple fitness benefits. We find that by matching the color of other reef fish, dottybacks increase their success of predation upon juvenile fish prey and are therefore able to deceive their victims by resembling multiple models. Furthermore, we demonstrate that changing color also increases habitat-associated crypsis that decreases the risk of being detected by predators. Hence, when mimics and models share common selective pressures, flexible imitation of models might inherently confer secondary benefits to mimics. Our results show that phenotypic plasticity can act as a mechanism to ease constraints that are typically associated with deception. VIDEO ABSTRACT. PMID- 25802154 TI - Integration trumps selection in object recognition. AB - Finding and recognizing objects is a fundamental task of vision. Objects can be defined by several "cues" (color, luminance, texture, etc.), and humans can integrate sensory cues to improve detection and recognition [1-3]. Cortical mechanisms fuse information from multiple cues [4], and shape-selective neural mechanisms can display cue invariance by responding to a given shape independent of the visual cue defining it [5-8]. Selective attention, in contrast, improves recognition by isolating a subset of the visual information [9]. Humans can select single features (red or vertical) within a perceptual dimension (color or orientation), giving faster and more accurate responses to items having the attended feature [10, 11]. Attention elevates neural responses and sharpens neural tuning to the attended feature, as shown by studies in psychophysics and modeling [11, 12], imaging [13-16], and single-cell and neural population recordings [17, 18]. Besides single features, attention can select whole objects [19-21]. Objects are among the suggested "units" of attention because attention to a single feature of an object causes the selection of all of its features [19 21]. Here, we pit integration against attentional selection in object recognition. We find, first, that humans can integrate information near optimally from several perceptual dimensions (color, texture, luminance) to improve recognition. They cannot, however, isolate a single dimension even when the other dimensions provide task-irrelevant, potentially conflicting information. For object recognition, it appears that there is mandatory integration of information from multiple dimensions of visual experience. The advantage afforded by this integration, however, comes at the expense of attentional selection. PMID- 25802156 TI - Use of the Broselow tape in a Mexican emergency department. AB - BACKGROUND: The Broselow tape is one method for rapid weight estimation in pediatric patients undergoing resuscitation, but it does not perform equally in all populations. To date, we are unaware of any study evaluating its use in a Latin American population. OBJECTIVE: To investigate the accuracy of the Broselow tape in a Mexican emergency department (ED). METHODS: We conducted a prospective, observational study of children presenting to a Mexican ED. Patient weight was estimated using the Broselow tape and the estimate compared to their weight measured on a scale. Researchers were blinded to scale weight and Broselow categories. For analysis, the Broselow tape's nine color zones were divided into three weight categories. RESULTS: Of 815 subjects, 356 (43.7%) were female. In children weighing <10 kg, the tape tended to underestimate weight, whereas it overestimated weight in the other two weight categories. The mean percentage difference between the actual weight and the Broselow tape-predicted weight was <3% in each category, although it differed significantly across the three weight categories. Accuracy of the predicted weight to within 10% of actual weight was lowest for children weighing <10 kg, at 46.2% (confidence interval [CI] +/- 6.4%), and greatest for those in the 10-18-kg weight category, at 64.1% (CI +/- 5.1%). However, the correlation of color zones predicted by both methods was highest for subjects <10 kg at 64.4% (CI +/- 6.1%). It was significantly lower in the other weight categories at 54.5% (CI +/- 5.3) for subjects weighing 10-18 kg, and 50.1% (CI +/- 6.4%) for subjects weighing >18 kg. The percentage of children for whom the color code differed by two or more categories was <4% overall and for each weight category. CONCLUSION: The Broselow tape-estimated weight was different from the scale weight by more than 10% in a substantial percentage of Mexican children. Nevertheless, the mean percentage difference was <3%, and Broselow tape color zone estimation was accurate in the majority of subjects, suggesting its use would result in clinically appropriate dosing and equipment estimations. Further research is needed to validate its use in this clinical setting. PMID- 25802157 TI - The Impact of Professionalism on Transfer of Care to the Emergency Department. AB - BACKGROUND: Patient care transfer from Emergency Medical Services (EMS) to the emergency department (ED) providers is a transition point where there are high rates of information degradation and variability in perceptions of handoff quality. OBJECTIVE: To evaluate EMS and ED provider perceptions of information transfer compared to an external observer's objective assessment. METHODS: This evaluation is a review of a quality-improvement database at an academic trauma center. EMS to ED patient transfers were attended by trained external observers who recorded communicated data and evaluated provider professionalism. After handoff, EMS and ED staff rated their own perceptions of the transfer. RESULTS: Trained observers evaluated 1091 patient transfers. The perceived transfer quality was similar between EMS and ED staff, while trained observer ratings were different from EMS (odds ratio [OR] = 13.1; p < 0.001) and ED staff perceptions (OR = 20.2; p < 0.001). The EMS and ED staff perceptions were not influenced by absence of vital signs or demographics, but were affected by the perceived provider professionalism (EMS: OR = 2.4; p < 0.001; ED staff: OR = 1.5; p = 0.03). CONCLUSIONS: This project is the largest evaluation of perceptions of ED transfers of care. During these transfers, significant key clinical information was not passed from EMS to ED staff. This did not have an association with EMS and ED staff transfer perception. Professionalism did affect attitudes concerning quality transfers of are. Future studies should focus on methods to improve information transfer while maximizing the subjective qualities of professional EMS-ED interactions. PMID- 25802155 TI - Stroke Mimics and Acute Stroke Evaluation: Clinical Differentiation and Complications after Intravenous Tissue Plasminogen Activator. AB - BACKGROUND: Intravenous tissue-plasminogen activator remains the only U.S. Food and Drug Administration-approved treatment for acute ischemic stroke. Timely administration of fibrinolysis is balanced with the need for accurate diagnosis. Stroke mimics represent a heterogeneous group of patients presenting with acute onset focal neurological deficits. If these patients arrive within the extended time window for acute stroke treatment, these stroke mimics may erroneously receive fibrinolytics. OBJECTIVE: This review explores the literature and presents strategies for differentiating stroke mimics. DISCUSSION: Clinical outcome in stroke mimics receiving fibrinolytics is overwhelmingly better than their stroke counterparts. However, the risk of symptomatic intracranial hemorrhage remains a real but rare possibility. Certain presenting complaints and epidemiological risk factors may help differentiate strokes from stroke mimics; however, detection of stroke often depends on presence of posterior vs. anterior circulation strokes. Availability of imaging modalities also assists in diagnosing stroke mimics, with magnetic resonance imaging offering the most sensitivity and specificity. CONCLUSION: Stroke mimics remain a heterogeneous entity that is difficult to identify. All studies in the literature report that stroke mimics treated with intravenous fibrinolysis have better clinical outcome than their stroke counterparts. Although symptomatic intracranial hemorrhage remains a real threat, literature searches have identified only two cases of symptomatic intracranial hemorrhage in stroke mimics treated with fibrinolytics. PMID- 25802158 TI - Pediatric Exposures to Electronic Cigarettes Reported to Texas Poison Centers. AB - BACKGROUND: Electronic cigarette use is increasing. There are concerns that pediatric exposures to these products may result in serious adverse affects. OBJECTIVES: This study describes pediatric exposures to electronic cigarettes. METHODS: Cases were electronic cigarette exposures among patients age 5 years or less reported to Texas poison centers during January 2010-June 2014. The distribution by selected variables was determined. RESULTS: Of 203 exposures, two cases were reported in 2010, five in 2011, 20 in 2012, 70 in 2013, and 106 in January-June 2014. Fifty-one percent of the patients were male; 32% of the patients were aged 1 year, and 42% were 2 years of age. Ninety-six percent of the exposures occurred at the patient's own residence. The exposure routes were ingestion (93%), dermal (11%), ocular (3%), and inhalation (2%). Fifty-eight percent of the patients were managed on site. Of the patients seen at a health care facility, 69% were treated or evaluated and released. Eleven percent of the exposures were serious. The most commonly reported clinical effects were vomiting (24%), drowsiness/lethargy (2%), and cough/choke (2%). The most frequent treatments were dilution/irrigation/wash (65%) and food/snack (16%). CONCLUSIONS: Electronic cigarette exposures involving young children reported to poison centers are increasing. Such exposures are likely to involve patients ages 2-3 years, occur at the child's own residence, and occur by ingestion. Further study is needed to determine which subgroups are at risk for serious outcomes and warrant evaluation at a health care facility. PMID- 25802160 TI - Cerebral Air Embolism After Hemodialysis. PMID- 25802159 TI - Determining the utility of metabolic acidosis for trauma patients in the emergency department. AB - BACKGROUND: Metabolic acidosis has been proposed as the gold standard to define shock in trauma patients. Other studies determine the presence of shock by use of serum lactate. However, not all medical centers have the ability to utilize point of-care lactate at bedside. OBJECTIVE: This study seeks to determine the relationship between serum lactate and metabolic acidemia in trauma patients, and if metabolic acidemia can be used to guide therapy. We hypothesized that acidemia would be strongly correlated with lactate levels and would be associated with activation of massive transfusion (MT) in the presence of shock in trauma. METHODS: This was a prospective observational cohort study, level II evidence; this study aids in decision-making. Setting was a Level I academic, urban trauma center. The study took place from July 1, 2012 to March 1, 2013 and included patients who were >=18 years old and required trauma team activation. Observations included baseline demographics (age, gender, type of injury), vital signs, point-of-care arterial blood gas, lactate, and need for MT. RESULTS: One hundred patients were enrolled over the study period. The average age was 34 years, and 82% were male. Forty patients were acidemic (pH < 7.35), and there was a significant difference in lactate levels between the acidemic and non-acidemic groups (p < 0.002). We found a strong correlation between pH and lactate: rs = 0.38, t = -4.03, p < 0.001. In addition, using a logistic regression, we show that pH was associated with activation of MT (p = 0.002). CONCLUSION: This is a prospective observational cohort study with level II evidence. This study demonstrates that acidemia was strongly correlated to serum lactate, lactate levels were higher in the acidemic group, and metabolic acidemia was associated with the activation of MT for trauma patients at our institution. PMID- 25802161 TI - Heat Stroke-Induced Sinoatrial Node Dysfunction. AB - BACKGROUND: Heat stroke has been associated with stress-induced cardiomyopathy and electrocardiogram ST segment elevation and depression. Laboratory studies with dogs have demonstrated heat stroke-induced sinoatrial node dysfunction in the setting of hyperkalemia. No prior case report has described heat stroke induced complete sinoatrial node dysfunction that resolved in the emergency department. CASE REPORT: An 87-year-old female presented to the emergency department with heat stroke and severe bradycardia. Initial electrocardiogram demonstrated complete sinoatrial node dysfunction. The bradycardia responded to external cardiac pacing and the sinoatrial node dysfunction resolved with aggressive cooling. Emergency physicians should be aware that heat stroke can cause complete sinoatrial node dysfunction and that this bradydysthrmia can be treated with aggressive cooling. PMID- 25802162 TI - Syncope in the Pediatric Emergency Department - Can We Predict Cardiac Disease Based on History Alone? AB - BACKGROUND: The American Heart Association recommends a "meticulous history" when evaluating patients with an initial episode of syncope. However, little is known about which historical features are most helpful in identifying children with undiagnosed cardiac syncope. OBJECTIVES: Our objectives were 1) to describe the cardiac disease burden in Emergency Department (ED) syncope presentations, and 2) to identify which historical features are associated with a cardiac diagnosis. METHODS: Using syncope presentations in our ED between May 1, 2009 and February 28, 2013, we 1) performed a cross-sectional study describing the burden of cardiac syncope, and 2) determined the sensitivity and specificity of four historical features identifying cardiac syncope. RESULTS: Of 3445 patients, 44.5% were male presenting at 11.5 +/- 4.5 years of age. Of patients with a cardiac diagnosis (68, ~2%), only 3 (0.09%) were noted to have a previously undiagnosed cardiac cause of syncope: 2 with supraventricular tachycardia and 1 with myocarditis. Among the three cases and 100 randomly selected controls, the respective sensitivity and specificity of the historical features were 67% and 100% for syncope with exercise, 100% and 98% for syncope preceded by palpitations, and 67% and 70% for syncope without prodrome. The presence of at least two features yielded a sensitivity of 100% and specificity of 100%. CONCLUSIONS: Our study, which represents the largest published series of pediatric syncope presenting to the ED, confirms that newly diagnosed cardiac causes of syncope are rare. Using a few specific historical features on initial interview can help guide further work-up more precisely. PMID- 25802163 TI - A Survey of the Competency of Ambulance Service Personnel in the Diagnosis and Management of Sepsis. AB - BACKGROUND: Few studies have evaluated the current status of knowledge of sepsis in ambulance service personnel. OBJECTIVE: Our aim was to ascertain the levels of competency and proficiency of ambulance service personnel in the diagnosis and management of severe sepsis. METHODS: A questionnaire was submitted to a sample of 208 participants in a professional ambulance service conference, and was recovered on site. The study probed eight areas of sepsis diagnosis and management based on modifications of a questionnaire used in a previous study. RESULTS: The term sepsis in Japanese, Haiketsushou, was familiar to 99% of Japanese certified emergency life-saving technicians (ELST) (Group I) and to 92% of noncertified ambulance service personnel (Group II), although 15% of participants in Group I and 44% in Group II ignored the meaning of sepsis. The definition of sepsis as "body's response to infection," "blood poisoning," or "shock due to bacteria in blood" were selected by 17%, 16%, and 37%, respectively, in Group I, and 4%, 6%, and 22%, respectively, in Group II. The mortality associated with sepsis was underestimated by 57% in Group I and 78% in Group II. Vital signs raising a suspicion for sepsis and their pertinent ranges were correctly chosen by only 50% of certified ELST. Hypothermia was prominently undervalued as a sign raising the suspicion of sepsis. CONCLUSIONS: Insufficient knowledge and perception for sepsis in Japanese ambulance services is revealed. A higher level of onsite or formal postgraduate education needs to be provided with a view to improve the prehospital management of sepsis. PMID- 25802164 TI - Lateral rectus myositis presented as binocular diplopia. PMID- 25802165 TI - Correlation between Subclinical Heart Disease and Cardiovascular Risk Profiles in an Urban Emergency Department Population with Elevated Blood Pressures: A Pilot Study. AB - BACKGROUND: Uncontrolled hypertension is a primary risk factor for development of cardiovascular complications. OBJECTIVE: Determine the point prevalence of left ventricular hypertrophy (LVH) and diastolic dysfunction in an urban emergency department (ED) population with elevated blood pressures (BP) and examine correlations between subclinical disease and patient cardiovascular risk profiles. METHODS: A convenience sample of patients with EBP (>140/90 on two measurements) had limited bedside echocardiograms (LBE). Subclinical hypertensive heart disease was classified as the presence of: LVH, abnormal ejection fraction (EF), or diastolic dysfunction. RESULTS: Thirty-nine patients with EBP were enrolled. The mean age was 46 years (SD = 10.9), 59% were women, 21% were smokers, and 92% had a history of hypertension. The average body mass index was 30.7 (SD = 8.7). Patients were 67% African American, 23% Latino, 5% Caucasian, 3% Asian, and 3% Native American. Subclinical disease was found in 39%: 31% had LVH, 15% had diastolic dysfunction, and 8% had abnormal EF. On bivariate analysis, elevated BP (p = 0.039) and blood urea nitrogen (p = 0.016) were correlated with subclinical heart disease. After adjusting for other covariates, receiving oral/intravenous antihypertensive medications in the ED (p = 0.005) was associated with subclinical heart disease. CONCLUSIONS: We found a point prevalence of subclinical heart disease of 39% in this urban ED population, using LBE. Real-time identification of subclinical heart disease at early stages in the ED in conjunction with abnormal renal function can help emergency physicians identify those patients in need of more aggressive therapy and urgent follow-up. PMID- 25802167 TI - MR imaging of the retrorectal-presacral tumors: an algorithmic approach. AB - The retrorectal-presacral space is located posterior to the mesorectum and anterior to the sacrum, and can harbor a heterogeneous group of uncommon masses. Retrorectal-presacral tumors may be classified as congenital, neurogenic, osseous, and miscellaneous. Magnetic resonance imaging (MRI) plays a crucial role in directing appropriate management through accurate diagnosis, detection of complications and anatomic extent. MRI aids in the selection of optimal surgical approach such as anterior, posterior, or combined-based on the lesion extent and relationship to adjacent structures. This article reviews the anatomy of the retrorectal-presacral space and the related tumors, optimal MRI protocol, MRI based approach to differential diagnosis, and finally pertinent reporting pointers and implications of MR imaging findings for surgical management. PMID- 25802168 TI - Protecting elderly travelers from travelers' diarrhea. Do probiotics work? PMID- 25802166 TI - Vancomycin Use in Patients Discharged From the Emergency Department: A Retrospective Observational Cohort Study. AB - BACKGROUND: Infections due to methicillin-resistant Staphylococcus aureus (MRSA) are associated with significant morbidity and mortality and are typically treated with intravenous vancomycin. Given vancomycin's time-dependent mechanism of action, it is unlikely that vancomycin administration in the emergency department (ED) prior to disposition home could be beneficial. STUDY OBJECTIVES: To characterize the indications, dosing, and appropriateness of vancomycin use in patients discharged from the ED. METHODS: This is a single-center retrospective observational cohort study of patients who received vancomycin in an urban, academic, tertiary care ED. The subjects were consecutive adult patients administered intravenous vancomycin in the ED and then discharged home over an 18 month period. Outcomes were measured 1) to characterize patients receiving vancomycin prior to discharge home from the ED; and 2) to identify patients that did not meet indications for appropriate use based on the 2011 Infectious Diseases Society of America guidelines for treating MRSA infections. RESULTS: There were 526 patients that received vancomycin in the ED prior to discharge during the study period. In this cohort, 368 (70%) patients were diagnosed with skin and soft tissue infections. A MRSA risk factor was present in 396 (75%) patients. Prior to discharge, one dose of vancomycin was administered to 357 (68%) patients. Underdosing of vancomycin occurred in 239 (73%) patients. CONCLUSIONS: Vancomycin was given frequently to patients discharged home from the ED, most commonly for conditions where vancomycin was not indicated, such as skin and soft tissue infections. The majority of these patients received a vancomycin dosing strategy that is not only unlikely to lead to clinical improvement, but also has the potential to contribute adversely to the development of antibiotic resistance. Further investigation is needed into the impact of vancomycin use, the emergence of vancomycin resistance, and the role of ED-based antibiotic stewardship. PMID- 25802169 TI - The Janu-faced serotonergic antidepressant nature: mental versus sexual health! PMID- 25802170 TI - Antioxidant, Anti-inflammatory, and Chemoprotective Properties of Acacia catechu Heartwood Extracts. AB - Aqueous extracts of Acacia catechu heartwood are rich source of catechin and epicatechin (gallic acid derivatives), with smaller amounts of flavonoids. Extracts have also been prepared with ethyl acetate, ethanol, and methanol, and the properties of these extracts have been studied and are reviewed. Potent antioxidant activity has been well established in both in vitro and in vivo studies. This antioxidant activity is believed to be responsible for the anti inflammatory, tissue protectant, antineoplastic, and analgesic activities that have been demonstrated and clearly established in animal and cell culture systems. Furthermore, antihyperglycemic, antidiarrheal, antinociceptive, and antipyretic activities have been demonstrated in animal studies. No adverse effects have been observed in animal or human studies or in cell culture systems. In spite of the fact that Acacia products have been used for many years and the general safety of catechins and epicatechins is well documented, few human studies have ever been conducted on the efficacy or safety of A. catechu heartwood extracts. Several studies have shown that a two-ingredient combination product containing A. catechu extract exhibited no adverse effects when administered daily for up to 12 weeks while exhibiting significant anti inflammatory activity in subjects with osteoarthritis of the knee. There is a need for additional human clinical studies with regard to efficacy and safety. PMID- 25802171 TI - Determination of benzene series compounds and chlorobenzenes in water sample by static headspace gas chromatography with flame ionization detection. AB - A simple, efficient, solvent-free, and readily commercially available approach for the determination of eight benzene series compounds and 12 chlorobenzenes in water samples using the static headspace sampling and gas chromatography with flame ionization detection has been described in this paper. The proposed static headspace sampling method was initially optimized, and the optimum experimental conditions explored were 10 mL water sample containing 20% w/v sodium chloride placed in a 20 mL vial and stirred at 70 degrees C for 43 min. The linearity of the method ranged from 1 to 200 MUg/L for 20 analytes, with correlation coefficients ranging between 0.9962 and 0.9994. The limits of detection were in the MUg/L level, ranging between 0.15 and 0.4 MUg/L. The relative recoveries of spiked benzene series and chlorobenzenes with external calibration method at different concentration levels in pure, tap, and sea water samples were 84-113, 78-115 and 85-119%, respectively, with relative standard deviations of 3.8-6.8, 4.1-5.8, and 4.8-5.4% (n = 5), respectively. That this method can be successfully applied to the determination of benzene series compounds and chlorobenzenes in pure, tap, and sea water samples, simultaneously. PMID- 25802174 TI - 2014 Bedford Prize for the 'Most Outstanding Paper'. PMID- 25802173 TI - Novel synthesis of a series of spiro 1,3-indanedione-fused dihydropyridines through the condensation of a tetrone with N-aryl/alkylenamines in presence of solid support silica sulfuric acid. AB - A convenient protocol for the library synthesis of biologically important 1-aryl 2',6-spiro(1',3'-indanedione)-1H-indeno[1,2-b]quinoline-5,7-diones has been developed. In this one-pot reaction protocol a tetrone is condensed with various N-aryl/alkylenamines of 1,3-cyclohexadiones on the surface of a solid-supported acid catalyst silica sulfuric acid under solvent-free condition. The significant advantages of this methodology are the use of solvent-free reaction conditions, operational simplicity of the reaction, good yield of the products with high atom economy, and employment of a recyclable catalyst. All these favorable factors make the present method convenient, economic, and 'benign by design'. PMID- 25802172 TI - A metal-free tandem C-C/C-O bond formation approach to densely functionalized indolyl 4H-chromenes catalyzed by polystyrene-supported p-toluenesulfonic acid under solvent-free conditions. AB - A new environmentally benign and highly convergent protocol for the synthesis of indolyl 4H-chromene derivatives has been developed. This one-pot three-component condensation reaction of salicylaldehyde, cyclic 1,3-diketones, and indole is promoted by PS-PTSA as a reusable heterogeneous acid catalyst under solvent-free conditions. This protocol demonstrates several notable advantages such as that the catalyst is readily available and can be recovered and reused for at least five runs without any significant impact on product yields, high atom economy, excellent yields, and efficiency of producing three new bonds (two C-C and one C O) and one stereo center in a single operation. PMID- 25802175 TI - Predictors of outcome for cognitive behaviour therapy in binge eating disorder. AB - The aim of this naturalistic study was to identify pretreatment predictors of response to cognitive behaviour therapy in treatment-seeking patients with binge eating disorder (BED; N = 304). Furthermore, we examined end-of-treatment factors that predict treatment outcome 6 months later (N = 190). We assessed eating disorder psychopathology, general psychopathology, personality characteristics and demographic variables using self-report questionnaires. Treatment outcome was measured using the bulimia subscale of the Eating Disorder Inventory 1. Predictors were determined using hierarchical linear regression analyses. Several variables significantly predicted outcome, four of which were found to be both baseline predictors of treatment outcome and end-of-treatment predictors of follow-up: Higher levels of drive for thinness, higher levels of interoceptive awareness, lower levels of binge eating pathology and, in women, lower levels of body dissatisfaction predicted better outcome in the short and longer term. Based on these results, several suggestions are made to improve treatment outcome for BED patients. PMID- 25802177 TI - New PET system permits reliable estimates of myocardial blood flow and flow reserve. PMID- 25802176 TI - It's not all in the numbers. PMID- 25802178 TI - Exercise PET: More insight or more complex? PMID- 25802179 TI - Surprises? PMID- 25802180 TI - The counterintuitive effect of a disaster: the need for a long-term perspective. PMID- 25802184 TI - The use of hypnosis in severe brain injury rehabilitation: a case report. PMID- 25802182 TI - Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells. AB - Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but their role in endothelial dysfunction is unknown. Here, we examine how Hcy thiolactone, N-Hcy-protein, and Hcy affect gene expression and molecular pathways in human umbilical vein endothelial cells. We used microarray technology, real time quantitative polymerase chain reaction, and bioinformatic analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We identified 47, 113, and 30 mRNAs regulated by N-Hcy-protein, Hcy-thiolactone, and Hcy, respectively, and found that each metabolite induced a unique pattern of gene expression. Top molecular pathways affected by Hcy-thiolactone were chromatin organization, one-carbon metabolism, and lipid-related processes [-log(P value) = 20-31]. Top pathways affected by N-Hcy-protein and Hcy were blood coagulation, sulfur amino acid metabolism, and lipid metabolism [-log(P value)] = 4-11; also affected by Hcy-thiolactone, [-log(P value) = 8-14]. Top disease related to Hcy thiolactone, N-Hcy-protein, and Hcy was 'atherosclerosis, coronary heart disease' [-log(P value) = 9-16]. Top-scored biological networks affected by Hcy thiolactone (score = 34-40) were cardiovascular disease and function; those affected by N-Hcy-protein (score = 24-35) were 'small molecule biochemistry, neurological disease,' and 'cardiovascular system development and function'; and those affected by Hcy (score = 25-37) were 'amino acid metabolism, lipid metabolism,' 'cellular movement, and cardiovascular and nervous system development and function.' These results indicate that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease. PMID- 25802183 TI - Recombinant rubella vectors elicit SIV Gag-specific T cell responses with cytotoxic potential in rhesus macaques. AB - Live-attenuated rubella vaccine strain RA27/3 has been demonstrated to be safe and immunogenic in millions of children. The vaccine strain was used to insert SIV gag sequences and the resulting rubella vectors were tested in rhesus macaques alone and together with SIV gag DNA in different vaccine prime-boost combinations. We previously reported that such rubella vectors induce robust and durable SIV-specific humoral immune responses in macaques. Here, we report that recombinant rubella vectors elicit robust de novo SIV-specific cellular immune responses detectable for >10 months even after a single vaccination. The antigen specific responses induced by the rubella vector include central and effector memory CD4(+) and CD8(+) T cells with cytotoxic potential. Rubella vectors can be administered repeatedly even after vaccination with the rubella vaccine strain RA27/3. Vaccine regimens including rubella vector and SIV gag DNA in different prime-boost combinations resulted in robust long-lasting cellular responses with significant increase of cellular responses upon boost. Rubella vectors provide a potent platform for inducing HIV-specific immunity that can be combined with DNA in a prime-boost regimen to elicit durable cellular immunity. PMID- 25802185 TI - Multiscale visualization of the structural and characteristic changes of sewage sludge biochar oriented towards potential agronomic and environmental implication. AB - Sewage sludge biochars were obtained at different pyrolysis temperatures from 300 degrees C to 900 degrees C and their macro- and microscale properties were analyzed. The biochar's plant-available nutrients and humus-like substances in the water-extractable phase and fixed nutrients in the solid fraction were evaluated for their potential agronomic implications. FT-IR, Raman, XRD, XPS, and SEM techniques were used to investigate the chemical structure, functional groups, and microcrystal structure on the surface of the biochar. The results revealed minor chemical changes and dramatic mass loss in the biochar obtained at 300-500 degrees C, whereas significant chemical changes in the biochar were obtained at 600-900 degrees C. The concentrations of plant-available nutrients as well as fulvic- and humic-acid-like materials decreased in the biochar samples obtained at higher temperatures. These results implied that the biochar samples pyrolyzed at 300-500 degrees C could be a direct nutrient source and used to neutralize alkaline soil. The surface area and porosity of the biochar samples increased with temperature, which increased their adsorption capacity. Rearrangement occurred at higher temperature 600-900 degrees C, resulting in the biochar becoming increasingly polyaromatic and its graphite-like carbon becoming organized. PMID- 25802186 TI - Short-day aggression is independent of changes in cortisol or glucocorticoid receptors in male Siberian hamsters (Phodopus sungorus). AB - Testosterone mediates aggression in many vertebrates. In some species, aggression remains high during the non-breeding season (e.g., winter), when testosterone levels are low. In Siberian hamsters (Phodopus sungorus), we have demonstrated photoperiodic changes in aggression with hamsters housed in short, "winter-like" days displaying significantly more territorial aggression than long-day animals, despite low levels of testosterone. The mechanisms by which photoperiod regulates aggression, however, remain largely unknown. Adrenocortical hormones (e.g., glucocorticoids) have been implicated in mediating seasonal aggression; circulating concentrations of these hormones have been correlated with aggression in some species. The goal of this study was to examine the role of cortisol and glucocorticoid receptors in mediating photoperiodic changes in aggression in male Siberian hamsters. Males were housed in long or short days and treated with either exogenous cortisol or vehicle. Circulating levels of cortisol, adrenal cortisol content, and aggression were quantified. Lastly, photoperiodic effects on glucocorticoid receptor (GR) protein levels were quantified in limbic brain regions associated with aggression, including medial prefrontal cortex, amygdala, and hippocampus. Short-day hamsters were more aggressive than long-day hamsters, however cortisol treatment did not affect aggression. Photoperiod had no effect on serum or adrenal cortisol or GR levels in the brain regions examined. Taken together, these data suggest that increases in cortisol levels do not cause increases associated with short-day aggression, and further that GR protein levels are not associated with photoperiodic changes in aggression. The results of this study contribute to our understanding of the role of adrenocortical steroids in mediating seasonal aggression. PMID- 25802189 TI - Cannulated, locking blade plates for proximal femoral osteotomy in children and adolescents. AB - BACKGROUND: Proximal femoral osteotomy is the most common major reconstructive surgery in the region of the hip joint in children and adolescents. Given that it may be required across a wide range of ages and indications, appropriate instrumentation is necessary to ensure a technically satisfactory result. Recent developments in fixation include cannulation of the blade plate and locking screw technology. METHODS: We conducted a prospective audit of our first 25 patients who had a unilateral or bilateral proximal femoral osteotomy using a recently available system which combines cannulation and locking plate technology. The principal outcome measures were the radiographic position of the osteotomy at the time of union and surgical adverse events. RESULTS: Forty-five proximal femoral osteotomies were performed in 25 patients, mean age 8 years (range 3-17 years), for a variety of indications, the most common of which was hip subluxation in children with cerebral palsy. All osteotomies were soundly united by 6 weeks in children and by 3 months in adolescents, in the position achieved intra operatively. There were no revision procedures and the technical goals of surgery were achieved in all patients. There was one adverse event, a low-grade peri prosthetic infection, diagnosed at the time of implant removal. CONCLUSIONS: In this prospective audit of our first 25 patients, the new system performed well across a wide range of ages, body weights and surgical indications. Further comparative studies will be required to determine whether it offers additional advantages over more traditional systems. PMID- 25802187 TI - Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B. AB - Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 * 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 * 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 * 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 * 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 * 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 * 10(-71) <= Pmeta <= 9.92 * 10(-7) ). CONCLUSION: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease. PMID- 25802190 TI - Src enhances osteogenic differentiation through phosphorylation of Osterix. AB - Osterix, a zinc-finger transcription factor, is required for osteoblast differentiation and new bone formation during embryonic development. The c-Src of tyrosine kinase is involved in a variety of cellular signaling pathways, leading to the induction of DNA synthesis, cell proliferation, and cytoskeletal reorganization. Src activity is tightly regulated and its dysregulation leads to constitutive activation and cellular transformation. The function of Osterix can be also modulated by post-translational modification. But the precise molecular signaling mechanisms between Osterix and c-Src are not known. In this study we investigated the potential regulation of Osterix function by c-Src in osteoblast differentiation. We found that c-Src activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. The siRNA-mediated knockdown of c-Src decreased the protein levels and transcriptional activity of Osterix. Conversely, Src specific inhibitor, SU6656, decreased the protein levels and transcriptional activity of Osterix. The c-Src interacts with and phosphorylates Osterix. These results suggest that c-Src signaling modulates osteoblast differentiation at least in part through Osterix. PMID- 25802191 TI - Anti-diabetic efficacy of KICG1338, a novel glycogen synthase kinase-3beta inhibitor, and its molecular characterization in animal models of type 2 diabetes and insulin resistance. AB - Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3beta inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-alpha levels. KICG1338 therapy also led to greater beta-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3beta inhibitor. PMID- 25802192 TI - Volatile anesthetic-induced cardiac protection: molecular mechanisms, clinical aspects, and interactions with nonvolatile agents. PMID- 25802193 TI - Variation in tracheal reintubations among patients undergoing cardiac surgery across Washington state hospitals. AB - OBJECTIVES: The objectives of this study were to examine the variation in reintubations across Washington state hospitals that perform cardiac surgery, and explore hospital and patient characteristics associated with variation in reintubation. DESIGN: Retrospective cohort study. SETTING: All nonfederal hospitals performing cardiac surgery in Washington state. PARTICIPANTS: A total of 15,103 patients undergoing coronary artery bypass grafting or valvular surgery between January 1, 2008 and September 30, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient and hospital characteristics were compared between hospitals that had a reintubation frequency >=5% or<5%. Multivariate logistic regression was used to compare the odds of reintubation across the hospitals. The authors tested for heterogeneity of odds of reintubation across hospitals by performing a likelihood ratio test on the hospital factor. After adjusting for patient-level characteristics and procedure type, significant heterogeneity in reintubations across hospitals was present (p = 0.005). This exploratory analyses suggested that hospitals with lower reintubations were more likely to have more acute care days and teaching intensive care units (ICU). CONCLUSIONS: After accounting for patient and procedure characteristics, significant heterogeneity in the relative odds of requiring reintubation was present across 16 nonfederal hospitals performing cardiac surgery in Washington state. The findings suggested that greater hospital volume and ICU teaching status were associated with fewer reintubations. PMID- 25802194 TI - Inflammatory cytokine expression in the quadriceps of rats with posttraumatic knee stiffness: A preliminary study. AB - The primary purpose of this study was to investigate cytokine expression in the quadriceps of rats with posttraumatic knee stiffness (PTKS) and to determine the effect of exercise training on these cytokines at different follow-up time points. The PTKS rats were randomly assigned into two even groups. The treatment group received exercise training, while the control group received no treatment. Quadriceps specimens were harvested randomly from each group at 8, 12, 16, and 20 weeks. RT-qPCR and immunohistochemical analyses were used to assess the protein and mRNA expression levels of the cytokines IL-1, IL-2, TNF-alpha, COX-1, and COX 2. TNF-alpha immunostaining did not differ between the treated and control group tissues, whereas weak immunostaining was observed for all other cytokines in the specimens from the treatment group compared with those from the control group at approximately 12 and 20 weeks. The cytokine levels decreased at approximately 8 weeks in the treatment group, whereas these levels remained elevated or plateaued in the control group. These differences were statistically significant (p<0.05). This study demonstrated that the expression of cytokines IL-1, IL-2, COX-1, and COX-2 increased in the quadriceps of rats with PTKS and that exercise training affected the observed profile trends of these cytokines. PMID- 25802195 TI - Soluble receptor for advanced glycation end products as a potential biomarker to predict weight loss and improvement of insulin sensitivity by a very low calorie diet of obese human subjects. AB - INTRODUCTION: Obesity is associated with low-grade systemic inflammation which is thought to trigger the development of comorbidities such as type 2 diabetes. The soluble receptor for advanced glycation end products (sRAGE) belongs to the innate immune system and has been linked to obesity, recently. The aim of the present study was to examine whether serum sRAGE concentrations are related to the grade of weight loss and improvement of insulin resistance due to a very low calorie diet (VLCD). METHODS: 22 severe obese subjects (Median Body Mass Index (BMI): 44.5kg/m(2)) were included in a dietary intervention study of 6month, consisting of a very low calorie formula diet phase (VLCD: 800kcal/d) for 12 weeks and a following 12 week weight maintenance phase. Fasting glucose, fasting insulin, adiponectin, leptin and sRAGE were determined from sera. Insulin sensitivity was estimated by Homeostasis Model Assessment (HOMA) index and leptin to-adiponectin-ratio (LAR). RESULTS: Mean body weight reduction by VLCD accounted to 21.7kg with a significant improvement of insulin resistance. At baseline, sRAGE serum levels were significantly inversely related to BMI (rS=-0.642, p=0.001) and HOMA (rS=-0.419, p=0.041). Of interest, sRAGE serum levels at baseline were significantly lower in study subjects with greater reduction of BMI (p=0.017). In addition, a significantly greater HOMA reduction was observed in subjects with lower sRAGE serum levels at baseline (p=0.006). Finally, correlation analysis revealed, that changes of sRAGE serum levels were significantly correlated to changes of BMI (rS=-0.650, p=0.022) during intervention. CONCLUSION: Anti-inflammatory sRAGE might be a potential future biomarker to predict weight loss and improvement of insulin resistance by a VLCD whereby lower baseline sRAGE serum levels indicate a better outcome of the dietary intervention. PMID- 25802197 TI - IL-18 polymorphisms in hepatitis B virus related liver disease. AB - Interleukine-18 (IL-18) was originally called interferon (INF-gamma) inducing factor and plays a critical dual role in Th1 polarization and viral clearance. We aimed to explore whether single-nucleotide promoter polymorphisms (SNPs) are associated with the outcome of hepatitis B virus (HBV) infection. 271 HBV infected patients were recruited in this study out of these 109 were spontaneously recovered and 162 were diagnosed to be having persistent HBV infection which includes 48 chronic hepatitis, 84 liver cirrhosis, 30 HCC cases and were compared with 280 healthy controls. IL-18 promoter genotyping was performed with sequence-specific primers. The results demonstrated the significant involvement of genotype AA at position -607 in healthy controls (38.6%) when compared to cases (26.0%) (OR=0.54 (0.385-0.797)) and also associated with spontaneous clearance (37.6%) compared to persistent HBV infections (17.9%) (OR=2.76 (1.582-4.832)). Whereas, genotype CC at position -607 in cases (18.0%) when compared to healthy controls (6.7%) (OR=3.03 (1.734-5.303)) also associated with persistent HBV infections (24.1%) compared to spontaneous clearance (9.2%) (OR=0.31 (0.151-0.67)). And genotype GC at position -137 in cases (49.5%) compared to healthy controls (38.5%) (OR=1.55 (1.11-2.18)). Whereas, genotype GG at position -137 in healthy controls (56.8%) compared to cases (45.4%) (OR=0.63 (0.451-0.885)). No significant difference at position -137 was observed between spontaneous clearance and persistent HBV infections. These polymorphisms of the IL-18 gene promoter region at position -607 and -137 could be associated with different outcomes of HBV infection. The people with allele A at position -607 may be protected against HBV infection; moreover AA genotype is associated with spontaneous clearance. PMID- 25802198 TI - Use of Activated Factor VII in Patients with Diffuse Alveolar Hemorrhage: A 10 Years Institutional Experience. AB - INTRODUCTION: Diffuse alveolar hemorrhage (DAH) is a life-threatening condition with an obscure etiology and pathogenesis. It is associated with many drugs and diseases including chemotherapy, hematopoietic stem cell transplantation, and autoimmune disorders. This retrospective study reports our experience with 23 patients who had DAH and received intravenous recombinant activated Factor VIIa (rFVIIa). METHODS: We performed a retrospective chart review of patients who received intravenous rFVIIa for DAH at a tertiary care university hospital between January 1, 2003 and May 31, 2013. We report demographics, etiology of DAH, frequency and total dose of intravenous rFVIIa, effect of rFVIIa on DAH, and morbidity and mortality. RESULTS: Mean age was 47 +/- 19 years. There were 13 men and 10 women. Nine patients had Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, two had systemic lupus erythematosus, three had Good pasture's syndrome, seven were post-bone marrow transplant, one had idiopathic thrombocytopenic purpura, and one had cryoglobulinemia. Treatment in the ICU was required for 22 patients of whom 18 were intubated and on mechanical ventilation; one patient was treated on general medical service. All patients received 35-120 mcg/kg rFVIIa every 2 h until hemostasis was achieved or treatment was judged to be inadequate. In 22/23 patients, bleeding resolved with rFVIIa therapy. The mean dose to control bleeding was 5 +/- 3 mg. Eight patients died (36 %) of their underlying condition; six of them had received bone marrow transplant, while two had ANCA vasculitis. Deaths were due to multiorgan failure, sepsis, and progressive underlying disease. No overt, clinically obvious adverse thrombotic events were observed with the use of rFVIIa. CONCLUSION: Activated Factor VII can achieve hemostasis in patients with diffuse alveolar hemorrhage. PMID- 25802196 TI - Plasma osteopontin in acute liver failure. AB - BACKGROUND: Osteopontin (OPN) is a novel phosphoglycoprotein expressed in Kupffer cells that plays a pivotal role in activating natural killer cells, neutrophils and macrophages. Measuring plasma OPN levels in patients with acute liver failure (ALF) might provide insights into OPN function in the setting of massive hepatocyte injury. METHODS: OPN levels were measured using a Quantikine(r) ELISA assay on plasma from 105 consecutive ALF patients enrolled by the US Acute Liver Failure Study Group, as well as controls including 40 with rheumatoid arthritis (RA) and 35 healthy subjects both before, and 1 and 3 days after undergoing spine fusion (SF) surgery as a model for acute inflammation. RESULTS: Median plasma OPN levels across all etiologies of ALF patients were elevated 10- to 30-fold: overall median 1055ng/mL; range: 33-19,127), when compared to healthy controls (median in pre-SF patients: 41ng/mL; range 2.6-86.4). RA and SF post op patients had elevated OPN levels (37ng/mL and 198ng/mL respectively), well below those of the ALF patients. Median OPN levels were highest in acetaminophen (3603ng/mL) and ischemia-related ALF (4102ng/mL) as opposed to viral hepatitis (706ng/mL), drug induced liver injury (353ng/mL) or autoimmune hepatitis (436ng/mL), correlating with the degree of hepatocellular damage, as reflected by aminotransferase values (R value: 0.47 for AST, p<0.001). CONCLUSIONS: OPN levels appeared to correlate with degree of liver necrosis in ALF. Very high levels were associated with hyperacute injury and good outcomes. Whether OPN exerts a protective effect in limiting disease progression in this setting remains uncertain. PMID- 25802199 TI - A new approach to sex estimation using the mandibular canine index. AB - Rao et al.'s mandibular canine index (MCI) is a simple odontometric method which uses the mandibular canine as the key to sex estimation. This index is defined as the ratio between the right canine mesiodistal dimension and the mandibular canine arch width. The aim of this study was to contribute to sex estimation using dental techniques by analysing the MCI efficiency, and to propose a new approach for its use. Measurements were taken from 120 plaster casts (70 females) in the 16-30 year age group. Although statistically significant sexual dimorphism was observed in both the mesiodistal dimension and the mandibular canine arch width, the MCI showed a low accuracy in sex classification (54.2% correct identifications). This accuracy was improved to 64.2% using receiver operating characteristics curve analysis. Yet, despite the better accuracy, these results reinforce the idea that the MCI may not be particularly useful in sex prediction, since it may not reflect the same degree of sexual dimorphism as its absolute measures. PMID- 25802201 TI - An ytterbium complex with unique luminescence properties: detecting the temperature based on a luminescence spectrum without the interference of oxygen. AB - We report a novel ytterbium complex [Yb(tta)3DFQZ] which exhibited obviously enhanced two-photon sensitized near-infrared luminescence properties of Yb(3+) compared to the usually reported Yb(3+) complexes, with a two-photon excitation action cross-section of 22 GM under excitation at 860 nm at 298 K. Unlike other lanthanide complexes, [Yb(tta)3DFQZ] under nitrogen exhibited quantum yields for the sensitized Yb(3+) luminescence that increased with increasing temperature. [Yb(tta)3DFQZ] was dispersed in a polymer film to prepare a near-infrared emission sensor that made it possible to conveniently detect the temperature in a range from 178 to 378 K without the influence of O2, via a luminescence spectrum of Yb(3+) in the film. This provided a promising solution to the long-standing problem that complex calculations and complicated structures are usually needed for eliminating the influence of O2 on temperature sensing with a luminescent sensor. PMID- 25802200 TI - MicroRNA Profile in Response to Doxorubicin Treatment in Breast Cancer. AB - Chemotherapy treatment is the standard in triple negative breast cancers, a cancer subgroup which lacks a specific target. The mechanisms leading to the response, as well as any markers that allow the differentiation between responder and non-responder groups prior to treatment are unknown. In parallel, miRNAs can act as oncogenes or tumor suppressors and there is evidence of their involvement in promoting resistance to anticancer drugs. Therefore we hypothesized that changes in miRNA expression after doxorubicin treatment may also be relevant in treatment response. OBJECTIVE: To study miRNAs that are differentially expressed in response to doxorubicin treatment. METHODS: One luminal-A and two triple negative, breast cancer cell lines were exposed to doxorubicin. Microarray analysis was performed to identify the common and differentially modified miRNAs. Genes and pathways that are theoretically regulated by these miRNAs were analyzed. RESULTS: Thirteen miRNAs common to all three lines were modified, in addition to 25 that were specific to triple negative cell lines, and 69 that changed only in the luminal-A cell line. This altered expression pattern seemed to be more strongly related to the breast cancer subgroup than to the treatment. The analysis of target genes revealed that cancer related pathways were the most affected by these miRNAs, moreover many of them had been previously related to chemotherapy resistance; thus suggesting follow-up studies. Additionally, through functional assays, we showed that miR-548c-3p is implicated in doxorubicin treated MCF-7 cell viability, suggesting a role for this miRNA in resistance. PMID- 25802203 TI - Lack of evidence that adherence to standard of care therapy improves survival in subjects with hepatocellular carcinoma in clinical practice. AB - Currently, the BCLC classification, which links tumor stage with treatment option, is the standard system for clinical management of HCC. Thus far, this approach has been considered the standard of care worldwide. This study aimed to evaluate the survival of patients with HCC according to the BCLC Stage, surveillance, and adherence to standards of care. A 3-year prospective study enrolled 92 consecutive patients with HCC in the Gastroenterology Unit of the University of Naples "Federico II". Predictors of the likelihood of death were evaluated by the multivariate Cox model. Forty out of 92 (43%) subjects died during three years of follow up. The overall mortality rate per 100 person-years was 16.7, while the mortality rate for hepatic causes was only 14.2; it was lower in subjects under surveillance (11.4 vs. 28.2), in subjects adherent to standards of care (12.0 vs. 21.1), and in those who were in a better BCLC stage (10.6 vs. 45.8). The multivariate Cox model showed that advanced BCLC stage (HR 4.1, 95% C.I. = 1.8-9.4) was the sole independent predictor of the likelihood of mortality. In this regard, we observed lack of evidence that the adherence to the BCLC recommendations reduces the mortality of patients with HCC; and that the BCLC system cannot be accepted as a "commandment" to be invariably followed in everyday practice. Strategies to help improve adherence to international guidelines for HCC in clinical practice are required. PMID- 25802205 TI - Self-discriminating termination of chiral supramolecular polymerization: tuning the length of nanofibers. AB - Directing the supramolecular polymerization towards a preferred type of organization is extremely important in the design of functional soft materials. Proposed herein is a simple methodology to tune the length and optical chirality of supramolecular polymers formed from a chiral bichromophoric binaphthalene by the control of enantiomeric excess (ee). The enantiopure compound gave thin fibers longer than a few microns, while the racemic mixture favored the formation of nanoparticles. The thermodynamic study unveils that the heterochiral assembly gets preference over the homochiral assembly. The stronger heterochiral binding over homochiral one terminated the elongation of fibrous assembly, thus leading to a control over the length of fibers in the nonracemic mixtures. The supramolecular polymerization driven by pi-pi interactions highlights the effect of the geometry of a twisted pi-core on this self-sorting assembly. PMID- 25802204 TI - Incidental epileptiform discharges in patients of a tertiary centre. AB - OBJECTIVE: This controlled study set out to assess the rate of incidental epileptiform discharges (ED) during routine EEG and the incidence of epilepsy within a 4-year follow-up period in patients without a history of epilepsy. METHODS: We retrospectively analyzed electroencephalography (EEG) recordings of 1750 consecutive patients referred to the Department of Neurology at the Vienna General Hospital between January 1 and December 31, 2009. The incidence of epilepsy in patients with ED and no prior history of epilepsy was compared with a disease control group matched for gender and neuroimaging findings. RESULTS: ED were identified in 26 (4%) of 629 patients without a history of epilepsy. Sixteen (62%) of these patients developed epilepsy during follow-up compared with five (19%) of the disease controls (p=0.01), yielding an adjusted odds ratio of 8.8 (95% CI 2.1-37.7) for developing epilepsy in patients with ED and no prior history of epilepsy. CONCLUSIONS: Incidental ED during routine EEG significantly increase the likelihood of developing epilepsy. SIGNIFICANCE: Patients with incidental ED should be specifically asked for any signs and symptoms suggestive of seizures, since they appear more prone to develop epilepsy. PMID- 25802202 TI - Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion. AB - Runx1 is a transcription factor essential for definitive hematopoiesis, and genetic abnormalities in Runx1 cause leukemia. Runx1 is functionally promiscuous and acts as either an oncogene or tumor suppressor gene in certain epithelial cancers. Recent evidence suggests that Runx1 is an important factor in breast cancer, however, its role remains ambiguous. Here, we addressed whether Runx1 has a specific pathological role during breast cancer progression and show that Runx1 has an oncogenic function. We observed elevated Runx1 expression in a subset of human breast cancers. Furthermore, throughout the course of disease progression in a classical mouse model of breast cancer (i.e., the MMTV-PyMT transgenic model), Runx1 expression increases in the primary site (mammary gland) and is further upregulated in tumors and distal lung metastatic lesions. Ex vivo studies using tumor epithelial cells derived from these mice express significantly higher levels of Runx1 than normal mammary epithelial cells. The tumor cells exhibit increased rates of migration and invasion, indicative of an aggressive cancer phenotype. Inhibition of Runx1 expression using RNA interference significantly abrogates these cancer-relevant phenotypic characteristics. Importantly, our data establish that Runx1 contributes to murine mammary tumor development and malignancy and potentially represents a key disease-promoting and prognostic factor in human breast cancer progression and metastasis. PMID- 25802206 TI - Computed tomography (CT) findings in 88 neurofibromatosis 1 (NF1) patients: Prevalence rates and correlations of thoracic findings. AB - PURPOSE: To evaluate the prevalence rates and the correlations of thoracic computed tomography (CT) findings of neurofibromatosis 1 (NF1) in 88 patients. MATERIALS AND METHODS: Chest CT images of 88 NF1 patients were independently reviewed by three observers, and the CT findings were evaluated. If abnormal findings were present, their number, size, and distribution were recorded. The prevalence rate of each CT finding was calculated, and the correlations between CT findings were analyzed. RESULTS: Of the 88 cases, 13 were positive for cysts, 16 for emphysema, 8 for nodules, 8 for GGNs (ground glass nodules), 13 for mediastinal masses, 20 for scoliosis, 44 for subcutaneous nodules, and 34 for skin nodules. Cysts showed upper and peripheral dominant distributions. Regarding 13 mediastinal masses, 2 were diagnosed as malignant peripheral nerve sheath tumors (MPNSTs), 1 was diagnosed as primary lung cancer, 2 were diagnosed as lateral meningocele, 3 were diagnosed as neurofibromas, and the remaining 7 were considered neurofibromas. There was a significant correlation between the prevalence of subcutaneous nodules and that of skin nodules. Significant positive correlations were also seen between size and number, size and rate of central distribution, and number and rate of central distribution of cysts. CONCLUSION: Various CT findings were found in NF-1 patients, and the prevalence rates of subcutaneous and skin nodules were higher than other findings. Though the prevalence rates of subcutaneous nodules and skin nodules were significantly correlated, the other CT findings in NF-1 occurred independently. The number, size, and distribution of the cysts showed significant positive correlations with each other. PMID- 25802207 TI - Comparative study of three sonoelastographic scores for differentiation between benign and malignant cervical lymph nodes. AB - PURPOSE: The aim of the study was to explore the diagnostic value of three different sonoelastographic scoring systems (labeled S1-S3) for the differentiation between benign and malignant cervical lymph nodes. MATERIALS AND METHOD: The authors propose a six pattern scoring system of the elastographic images with pattern 1 - representing purely soft nodes, pattern 2 - predominantly soft nodes, pattern 3 - predominantly soft nodes with focal had area, pattern 4 - predominantly hard node, pattern 5 - entirely hard node and pattern 6 - node with necrosis. The sonoelastographic images of 50 benign and 70 malignant lymph nodes were assessed. The area under the ROC curve (AUROC) for the differentiation between benign vs. malignant and benign vs. metastatic nodes were analyzed for the three scoring systems. RESULTS: When all the malignant lymph nodes were considered, the S1 score showed an AUROC=0.873 (95%CI [0.805-0.918], where CI=confidence interval; p<0.001), sensibility (Se)=58.57%, and specificity (Sp)=96%. For S2 score the AUROC was 0.890 (95%CI [0.824-0.933], p<0.001), Se=92.86%, and Sp=72%. For S3 score, the AUROC was 0.852 (95%CI [0.778-0.902], p<0.001), Se=64.29%, and Sp=94%). When lymphomatous nodes were excluded, for S1 the AUROC was 0.884 (95%CI [0.809-0.932], p<0.001), Se=64%, and Sp=96%. For S2 the AUROC was 0.894 (95%CI [0.818-0.939], p<0.001), Se=92%, and Sp=72%. For S3, the AUROC was 0.856 (95%CI [0.771-0.911], p<0.001), Se=66%, and Sp=94%. In the S3 scoring system, setting the benign vs. malignant cut off at pattern 3 increases the sensibility (41-65%) with minimal loss of specificity (96-94%). From the gray scale and Doppler criteria, changes of the nodular margins and the presence of the vessels in the cortical part of the lymph node showed both very high sensibility and specificity, the others criteria taken into account had either very good sensibility with low specificity or high specificity and low sensibility. CONCLUSIONS: Our study suggests that there are no significant differences between the three scoring systems in terms of overall diagnostic value. PMID- 25802208 TI - Beyond Sociocultural Influence: Self-monitoring and Self-awareness as Predictors of Women's Interest in Breast Cosmetic Surgery. AB - BACKGROUND: The aim of the present research was to analyze the role of self awareness, self-monitoring, perceived media pressures, and peer attributions on the consideration of breast cosmetic surgery among women. The internalization of thin ideals was taken into account as a key moderating variable. METHODS: Participants were 132 Italian women (mean age = 33.62), who completed a questionnaire aimed at measuring the variables of interest. Path analysis was used to test our hypotheses. RESULTS: The results indicated that perceived media pressure, self-monitoring, and peer attributions influenced participants' interest in breast modification procedures through the internalization of thin ideals. Self-awareness (both private and public) had a direct effect on women's consideration of breast cosmetic surgery. CONCLUSIONS: This research is one of few analyzing how specific aspects of the self could influence women's interest in cosmetic surgery. These findings contribute to the understanding of the reasons that trigger women's interest in cosmetic surgery. Not only sociocultural influences contribute to the development of favorable attitudes toward cosmetic surgery, but also specific aspects of the self have a relevant role. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the table of contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25802209 TI - Sensitive and rapid analytical method for the quantification of glucosamine in human plasma by ultra high performance liquid chromatography with tandem mass spectrometry. AB - A highly sensitive and rapid ultra high performance liquid chromatography with tandem mass spectrometry method has been developed and validated for the determination of glucosamine in human plasma using miglitol as the internal standard. Special attention was paid to achieve the high throughput and sensitivity of the established method, and the absence of a matrix effect on the analytes. The sample preparation procedure involved a simple deproteinization step. The chromatographic separation was achieved on a Waters ACQUITY HSS Cyano column using a mixture of acetonitrile/2 mM ammonium acetate solution containing 0.03% formic acid (80:20, v/v) as the mobile phase with a very short run time of 1.5 min. This method was validated over the concentration range of 10-3000 ng/mL for glucosamine. The intra- and inter-batch precision was <13.9% for the low, medium, and high quality control samples. The established method is highly sensitive with a lower limit of quantification of 10 ng/mL, low enough to determine the circadian rhythm on endogenous glucosamine level in human plasma, which has not been reported in detail until now. The method was successfully applied to characterize the pharmacokinetic profile of glucosamine in healthy volunteers following a single oral administration of 750 or 1500 mg glucosamine hydrochloride. PMID- 25802210 TI - Iranian women and care providers' perceptions of equitable prenatal care: A qualitative study. AB - BACKGROUND: Equity as a basic human right builds the foundation of all areas of primary healthcare, especially prenatal care. However, it is unclear how pregnant women and their care providers perceive the equitable prenatal care. OBJECTIVE: This study aimed to explore Iranian women's and care providers' perceptions of equitable prenatal care. RESEARCH DESIGN: In this study, a qualitative approach was used. Individual in-depth unstructured interviews were conducted with a purposeful sample of pregnant women and their care providers. Data were analyzed using inductive content analysis method. PARTICIPANTS AND RESEARCH CONTEXT: A total of 10 pregnant women and 10 prenatal care providers recruited from six urban health centers across Ahvaz, a south western city in Iran, were participated in the study. ETHICAL CONSIDERATIONS: The study was approved by the Ethics Committee affiliated to Ahvaz Jundishapur University of Medical Sciences. The ethical principles of voluntary participation, confidentiality, and anonymity were considered. FINDINGS: Analysis of participants' interviews resulted in seven themes: guideline-based care, time-saving care, nondiscriminatory care, privacy respecting care, affordable comprehensive care, effective client-provider relationships, and caregivers' competency. CONCLUSION: The findings explain the broader and less discussed dimensions of equitable care that are valuable information for the realization of equity in care. Understanding and focusing on these dimensions will help health policy-makers in designing more equitable healthcare services for pregnant women. PMID- 25802211 TI - Erratum to: Abstracts from the ICBM 2014 Meeting. PMID- 25802213 TI - Assessment of non-Gaussian diffusion with singly and doubly stretched biexponential models of diffusion-weighted MRI (DWI) signal attenuation in prostate tissue. AB - Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Delta = 10, 20 and 40 ms, and b values in the range 0.017-8.2 ms/um(2) . A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Delta = 10 and 20 ms. The lower diffusivity stretching factor (alpha2 ) of the SS model was consistently lower (range ~0.3-0.9) than the higher diffusivity stretching factor (alpha1 , range ~0.7-1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics. PMID- 25802212 TI - Multi-centre reproducibility of diffusion MRI parameters for clinical sequences in the brain. AB - The purpose of this work was to assess the reproducibility of diffusion imaging, and in particular the apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM) parameters and diffusion tensor imaging (DTI) parameters, across multiple centres using clinically available protocols with limited harmonization between sequences. An ice-water phantom and nine healthy volunteers were scanned across fives centres on eight scanners (four Siemens 1.5T, four Philips 3T). The mean ADC, IVIM parameters (diffusion coefficient D and perfusion fraction f) and DTI parameters (mean diffusivity MD and fractional anisotropy FA), were measured in grey matter, white matter and specific brain sub regions. A mixed effect model was used to measure the intra- and inter-scanner coefficient of variation (CV) for each of the five parameters. ADC, D, MD and FA had a good intra- and inter-scanner reproducibility in both grey and white matter, with a CV ranging between 1% and 7.4%; mean 2.6%. Other brain regions also showed high levels of reproducibility except for small structures such as the choroid plexus. The IVIM parameter f had a higher intra-scanner CV of 8.4% and inter-scanner CV of 24.8%. No major difference in the inter-scanner CV for ADC, D, MD and FA was observed when analysing the 1.5T and 3T scanners separately. ADC, D, MD and FA all showed good intra-scanner reproducibility, with the inter-scanner reproducibility being comparable or faring slightly worse, suggesting that using data from multiple scanners does not have an adverse effect compared with using data from the same scanner. The IVIM parameter f had a poorer inter-scanner CV when scanners of different field strengths were combined, and the parameter was also affected by the scan acquisition resolution. This study shows that the majority of diffusion MRI derived parameters are robust across 1.5T and 3T scanners and suitable for use in multi-centre clinical studies and trials. PMID- 25802214 TI - Single-shot single-voxel lactate measurements using FOCI-LASER and a multiple quantum filter. AB - Measurement of tissue lactate using (1) H MRS is often confounded by overlap with intense lipid signals at 1.3 ppm. Single-voxel localization using PRESS is also compromised by the large chemical shift displacement between voxels for the 4.1 ppm (-CH) resonance and the 1.3 ppm -CH3 resonance, leading to subvoxels with signals of opposite phase and hence partial signal cancellation. To reduce the chemical shift displacement to negligible proportions, a modified semi-LASER sequence was written ("FOCI-LASER", abbreviated as fLASER) using FOCI pulses to permit high RF bandwidth even with the limited RF amplitude characteristic of clinical MRI scanners. A further modification, MQF-fLASER, includes a selective multiple-quantum filter to detect lactate and reject lipid signals. The sequences were implemented on a Philips 3 T Achieva TX system. In a solution of brain metabolites fLASER lactate signals were 2.7 times those of PRESS. MQF-fLASER lactate was 47% of fLASER (the theoretical maximum is 50%) but still larger than PRESS lactate. In oil, the main 1.3 ppm lipid peak was suppressed to less than 1%. Enhanced suppression was possible using increased gradient durations. The minimum detectable lactate concentration was approximately 0.5 mM. Coherence selection gradients needed to be at the magic angle to avoid large water signals derived from intermolecular multiple-quantum coherences. In pilot patient measurements, lactate peaks were often observed in brain tumours, but not in cervix tumours; lipids were effectively suppressed. In summary, compared with PRESS, the fLASER sequence yields greatly superior sensitivity for direct detection of lactate (and equivalent sensitivity for other metabolites), while the single-voxel single-shot MQF-fLASER sequence surpasses PRESS for lactate detection while eliminating substantial signals from lipids. This sequence will increase the potential for in vivo lactate measurement as a biomarker in targeted anti-cancer treatments as well as in measurements of tissue hypoxia. PMID- 25802216 TI - Detection of lactate in the striatum without contamination of macromolecules by J difference editing MRS at 7T. AB - Lactate levels are measurable by MRS and are related to neural activity. Therefore, it is of interest to accurately measure lactate levels in the basal ganglia networks. If sufficiently stable, lactate measurements may be used to investigate alterations in dopaminergic signalling in the striatum, facilitating the detection and diagnosis of metabolic deficits. The aim of this study is to provide a J-difference editing MRS technique for the selective editing of lactate only, thus allowing the detection of lactate without contamination of overlapping macromolecules. As a validation procedure, macromolecule nulling was combined with J-difference editing, and this was compared with J-difference editing with a new highly selective editing pulse. The use of a high-field (7T) MR scanner enables the application of editing pulses with very narrow bandwidth, which are selective for lactate. We show that, despite the sensitivity to B0 offsets, the use of a highly selective editing pulse is more efficient for the detection of lactate than the combination of a broad-band editing pulse with macromolecule nulling. Although the signal-to-noise ratio of uncontaminated lactate detection in healthy subjects is relatively low, this article describes the test-retest performance of lactate detection in the striatum when using highly selective J difference editing MRS at 7 T. The coefficient of variation, sigmaw and intraclass correlation coefficients for within- and between-subject differences of lactate were determined. Lactate levels in the left and right striatum were determined twice in 10 healthy volunteers. Despite the fact that the test-retest performance of lactate detection is moderate with a coefficient of variation of about 20% for lactate, these values can be used for the design of new studies comparing, for example, patient populations with healthy controls. PMID- 25802218 TI - Catalytic aerobic oxidation of phenols to ortho-quinones with air-stable copper precatalysts. AB - A range of air-stable copper species was examined for catalytic activity in the catalytic aerobic transformation of phenols into ortho-quinones. Efficient catalysis was obtained with commercially available copper(II) acetate. The stability of all constituents before mixing makes for a practical process that advances previously reported copper(I)-based oxygenations. PMID- 25802215 TI - Cuprizone-induced demyelination and demyelination-associated inflammation result in different proton magnetic resonance metabolite spectra. AB - Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3 CL1/CX3 CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3 CR1(+/-) C57BL/6 mice and wild type CX3 CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3 CR1(-/-) C57BL/6 mice. Second, we show that (1) H MRS metabolite spectra are different when comparing cuprizone-treated CX3 CR1(-/ ) mice showing mild demyelination with cuprizone-treated CX3 CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3 CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3 CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, (1) H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. PMID- 25802220 TI - A comparative study on the potential of epiphytic yeasts isolated from tropical fruits to produce flavoring compounds. AB - In recent years, there has been an increasing interest in identifying and characterizing the yeast flora associated with diverse types of habitat because of the many potential desirable technological properties of these microorganisms, especially in food applications. In this study, a total of 101 yeast strains were isolated from the skins of tropical fruits collected in several locations in the South West Indian Ocean. Sequence analysis of the D1/D2 domains of the large subunit (LSU) ribosomal RNA gene identified 26 different species. Among them, two species isolated from the skins of Cape gooseberry and cocoa beans appeared to represent putative new yeast species, as their LSU D1/D2 sequence was only 97.1% and 97.4% identical to that of the yeasts Rhodotorula mucilaginosa and Candida pararugosa, respectively. A total of 52 Volatile Organic Compounds (VOCs) were detected by Head Space Solid Phase Micro Extraction coupled to Gas Chromatography and Mass Spectroscopy (HS-SPME-GC/MS) from the 26 yeast species cultivated on a glucose rich medium. Among these VOCs, 6 uncommon compounds were identified, namely ethyl but-2-enoate, ethyl 2-methylbut-2-enoate (ethyl tiglate), ethyl 3 methylbut-2-enoate, 2-methylpropyl 2-methylbut-2-enoate, butyl 2-methylbut-2 enoate and 3-methylbutyl 2-methylbut-2-enoate, making them possible yeast species specific markers. In addition, statistical methods such as Principal Component Analysis allowed to associate each yeast species with a specific flavor profile. Among them, Saprochaete suaveolens (syn: Geotrichum fragrans) turned to be the best producer of flavor compounds, with a total of 32 out of the 52 identified VOCs in its flavor profile. PMID- 25802219 TI - Pharmacologic heat shock protein 70 induction confers cytoprotection against inflammation in gliovascular cells. AB - The inhibition of the 90-kDa heat shock protein (HSP90) leads to upregulation of the 70-kDa-inducible HSP70. HSP70 has been previously shown to be neuroprotective and anti-inflammatory. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents in cancer, presumably owing to their ability to upregulate HSP70. However, the effects of HSP90 inhibition in brain inflammation are still unclear. We investigate the effect of a panel of HSP90 inhibitors on endotoxin-activated microglia and eventual protection from brain-derived endothelial cells. Prior studies have shown that GA protects brain cells from oxidative stress. We show here that when astrocytes or microglial BV2 cells were pretreated with GA or other HSP90 inhibitors, endotoxin-induced cell death was reduced in cocultures of BV2 microglia and brain-derived endothelial cells (bEND.3). Endotoxin-stimulated BV2 cells led to increased nitric oxide (NO) and inducible nitric oxide synthase which was prevented by treatment with all HSP90 inhibitors. HSP90 inhibitors also prevented lipopolysaccharide (LPS)-induced BV2 cell death. We also found that HSP90 inhibition blocked nuclear translocation of nuclear factor kappa B and attenuated IkappaBalpha degradation, and inhibited LPS activated JAK-STAT phosphorylation. We show that pharmacologic inhibition of HSP90 with subsequent HSP70 induction protects cells that comprise the cerebral vasculature against cell death owing to proinflammatory stimuli. This approach may have therapeutic potential in neurological conditions with an inflammatory component. PMID- 25802221 TI - Nasolabial symmetry and esthetics in cleft lip and palate: analysis of 3D facial images. AB - OBJECTIVES: To determine the relationship between nasolabial symmetry and esthetics in subjects with orofacial clefts. MATERIAL AND METHODS: Eighty-four subjects (mean age 10 years, standard deviation 1.5) with various types of nonsyndromic clefts were included: 11 had unilateral cleft lip (UCL); 30 had unilateral cleft lip and alveolus (UCLA); and 43 had unilateral cleft lip, alveolus, and palate (UCLAP). A 3D stereophotogrammetric image of the face was taken for each subject. Symmetry and esthetics were evaluated on cropped 3D facial images. The degree of asymmetry of the nasolabial area was calculated based on all 3D data points using a surface registration algorithm. Esthetic ratings of various elements of nasal morphology were performed by eight lay raters on a 100 mm visual analog scale. Statistical analysis included ANOVA tests and regression models. RESULTS: Nasolabial asymmetry increased with growing severity of the cleft (p = 0.029). Overall, nasolabial appearance was affected by nasolabial asymmetry; subjects with more nasolabial asymmetry were judged as having a less esthetically pleasing nasolabial area (p < 0.001). However, the relationship between nasolabial symmetry and esthetics was relatively weak in subjects with UCLAP, in whom only vermilion border esthetics was associated with asymmetry. CONCLUSIONS: Nasolabial symmetry assessed with 3D facial imaging can be used as an objective measure of treatment outcome in subjects with less severe cleft deformity. In subjects with more severe cleft types, other factors may play a decisive role. CLINICAL SIGNIFICANCE: Assessment of nasolabial symmetry is a useful measure of treatment success in less severe cleft types. PMID- 25802222 TI - A 4-year clinical evaluation of direct composite build-ups for space closure after orthodontic treatment. AB - OBJECTIVES: To evaluate the medium-term clinical performance of direct composite build-ups for diastema closures and teeth recontouring using a nano and a nanohybrid composite in combination with three- or two-step etch-and-rinse adhesives following treatment with fixed orthodontic appliances. MATERIALS AND METHODS: A total of 30 patients (mean age, 19.5 years) received 147 direct composite additions for teeth recontouring and diastema closures. A nano and a nanohybrid composite (Filtek Supreme XT and CeramX Duo) were bonded to tooth structure by using a three-step (Scotchbond Multipurpose) or a two-step (XP Bond) etch and rinse adhesive. Ten out of 147 composite build-ups (composite addition) constituted tooth recontouring cases, and the remaining 137 constituted diastema closure cases. The restorations were evaluated by two experienced, calibrated examiners according to modified Ryge criteria at the following time intervals: baseline, 1, 2, 3, and 4 years. RESULTS: The 4-year survival rates were 92.8 % for Filtek Supreme XT/Scotchbond Multi-Purpose Plus and 93 % for CeramX Duo/XP Bond. Only ten restorations failed (5 Filtek Supreme XT and 5 CeramX Duo). Statistical analysis revealed no significant differences between the two composite-adhesive combinations with respect to color match, marginal discoloration, wear/loss of anatomical form, caries formation, marginal adaptation, and surface texture on comparing the five time periods (baseline, 1, 2, 3, and 4 years) CONCLUSIONS: The 4-year survival rates in the present study were favorable. The restorations exhibited excellent scores with regard to color match, marginal adaptation, surface texture, marginal discoloration, wear/loss of anatomical form, and caries formation, after 4 years of clinical evaluation. Clinical relevance An alternative clinical approach for correcting discrepancies in tooth size and form, such as performing direct composite restorations following fixed orthodontic treatment, may be an excellent and minimally invasive treatment. PMID- 25802224 TI - Present status of statin therapy. AB - Statins are cardioprotective agents that reduce the adverse effects of increased low-density lipoprotein cholesterol (LDL-C) levels. For significantly dyslipidemic persons, who are at higher cardiovascular risk, combined statin therapy substantially reduces the mortality risk, thus potentially being an ideal risk-reducing combination with added risk reduction by lifestyle changes. Decisions regarding the initiation of statin therapy for primary prevention where the absolute risk reduction is much less are more difficult, involving LDL-C levels and higher C-reactive protein levels. For significantly dyslipidemic persons, combined intense exercise and statin therapy substantially reduces the mortality risk, thus potentially being an ideal risk-reducing combination. PMID- 25802223 TI - Extraordinarily adaptive properties of the genetically encoded amino acids. AB - Using novel advances in computational chemistry, we demonstrate that the set of 20 genetically encoded amino acids, used nearly universally to construct all coded terrestrial proteins, has been highly influenced by natural selection. We defined an adaptive set of amino acids as one whose members thoroughly cover relevant physico-chemical properties, or "chemistry space." Using this metric, we compared the encoded amino acid alphabet to random sets of amino acids. These random sets were drawn from a computationally generated compound library containing 1913 alternative amino acids that lie within the molecular weight range of the encoded amino acids. Sets that cover chemistry space better than the genetically encoded alphabet are extremely rare and energetically costly. Further analysis of more adaptive sets reveals common features and anomalies, and we explore their implications for synthetic biology. We present these computations as evidence that the set of 20 amino acids found within the standard genetic code is the result of considerable natural selection. The amino acids used for constructing coded proteins may represent a largely global optimum, such that any aqueous biochemistry would use a very similar set. PMID- 25802225 TI - Universal therapeutic targeting of age-related protein quality control system dysfunction in chronic diseases? PMID- 25802226 TI - My approach to patients intolerant to statins. PMID- 25802229 TI - Enumeration of NKG2C+ natural killer cells early following allogeneic stem cell transplant recipients does not allow prediction of the occurrence of cytomegalovirus DNAemia. AB - The role of Natural killer (NK) cells in the control of cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients has not been precisely characterized. The current study is aimed at investigating the potential role of NK cells expressing the activating receptor NKG2C in affording protection against the development of CMV DNAemia in patients exhibiting detectable CMV-specific CD8(+) T-cell responses early following transplantation. A total of 61 nonconsecutive patients were included in the study. Peripheral levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells and CMV pp65/IE 1-specific IFN-gamma-producing CD8(+) T-cells were enumerated by flow cytometry at days +30 and +60 after transplant. Neither the absolute number of NKG2C(+) NK cells, nor that of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cell subsets at day 30 differed significantly between patients with or without subsequent CMV DNAemia. No significant correlation was found between levels of both NKG2C(+) NK-cell populations and the peak CMV DNA load within subsequent episodes of CMV DNAemia. The data indicate that enumeration of NKG2C(+) NK cells early after transplant is unlikely to be helpful in identifying those patients at highest risk of developing CMV DNAemia. Moreover, the data do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia. PMID- 25802228 TI - Alteration of ankle kinematics and muscle activity during heel contact when walking with external loading. AB - PURPOSE: The risk of recurrent ankle sprains could be reduced if the ankle joint is positioned in a more closed pack position (eversion and dorsiflexion) with enhanced co-activation of Tibialis Anterior (TA) and Peroneus Longus (PL) around heel contact in walking. We examined whether such alteration can be induced by augmenting ankle position error in the inversion and plantarflexion directions. METHODS: Fifteen young, healthy subjects participated in this study. They walked on a treadmill while a light weight was affixed to the dorsal-lateral side of the test foot to create afferent error signals in the inversion and plantarflexion directions. We recorded and analyzed subjects' ankle kinematics and electromyographic (EMG) activity of TA and PL before (baseline), during (adaptation), and after (post adaptation) walking with the weight. Our analyses focused on 30 ms before and after heel contact where ankle sprains are most likely to occur. RESULTS: Subjects increased ankle eversion before and after heel contact during the adaptation period. This increase carried over to the post adaptation period following removal of the weight. The weight also induced an increase in the TA activity before heel contact during late adaptation, although this increase did not carry over to the post adaptation period. No significant changes were observed in ankle dorsiflexion, PL activity, and muscle co activation. CONCLUSION: Our error-driven approach is feasible to reduce ankle inversion around heel contact in walking, and may have clinical implication on intervention of recurrent ankle sprains. PMID- 25802227 TI - Effect of aging on hemodynamic response to metaboreflex activation. AB - PURPOSE: The aim of the present investigation was to assess the role of aging on the contribution of diastolic function during metaboreflex activation. In particular, it aimed to determine whether age-related impairment in diastolic function would produce a different hemodynamic response in elderly subjects (EG) as compared to young controls (CTL). METHODS: Hemodynamic response to metaboreflex activation obtained by post-exercise muscle ischemia (PEMI) was gathered in 22 EG and 20 healthy CTL. Subjects also performed a control exercise recovery (CER) test to compare data from the PEMI test. RESULTS: The main results showed that the EG group reached higher mean arterial blood pressure (MAP) increment than the CTL group during the PEMI test (+11.2 +/- 8.6 vs 6.1 +/- 6.4 mmHg in the EG and CTL group, respectively). Moreover, the mechanism by which this response was achieved was different between the two groups. In detail, EG reached the target MAP by increasing systemic vascular resistance (+235.2 +/- 315.1 vs -44.4 +/- 167.7 dynes s(-1) cm(-5) for the EG and the CTL group, respectively), whereas MAP response in the CTL was the result of an increase in cardiac pre-load (-1.5 +/- 11.2 vs 14 +/- 13.7 ml in end-diastolic volume for the EG and the CTL group, respectively), which led to a rise in stroke volume and cardiac output. Moreover, early filling peak velocities showed a higher response in the CTL than EG group. CONCLUSIONS: This study demonstrates that diastolic function is important for normal hemodynamic adjustment during the metaboreflex and to avoid excessive vasoconstriction. PMID- 25802230 TI - The Role of Anti-PD-1/PD-L1 Agents in Melanoma: Progress to Date. AB - The discovery of immune inhibitory checkpoints has revolutionized the approach to the systemic treatment of cancer. The programmed death 1 (PD-1) inhibitory checkpoint, in particular, has played a key role in understanding how certain cancers can evade immune surveillance. Blocking the interaction between the PD-1 receptor and its primary ligand (PD-L1) has demonstrated remarkable anti-cancer activity, and has led to the recent accelerated approval of two anti-PD-1 drugs for use in unresectable and metastatic melanoma in the USA. Results of these therapeutic advances have solidified the role of immunotherapy in the treatment of melanoma, results that may be applicable to the treatment of other cancers. In this review, we discuss the role of the PD-1 pathway in the immune system and the anti-cancer mechanism of action of inhibiting the PD-1/PD-L1 interaction. We also review the efficacy and safety data of currently approved and in-development anti PD-1 agents, and explore the next steps to further improve patient outcomes. PMID- 25802232 TI - Changing antimicrobial resistance patterns and trends of Shigella isolates in Ningbo, Mid-East China, 2005-2013. PMID- 25802233 TI - Cph1p negatively regulates MDR1 involved in drug resistance in Candida albicans. AB - The cph1/cph1 efg1/efg1 double mutant in Candida albicans is defective in filamentous growth and is avirulent in a mouse model. We previously reported that Efg1p but not Cph1p is involved in drug resistance by negatively regulating ERG3 in C. albicans. In the current study, we have found that overexpression of CPH1 in Saccharomyces cerevisiae increases susceptibility to the antifungal drug fluconazole. Furthermore, in C. albicans, null mutation of CPH1 increased the expression of MDR1 as well as decreased susceptibility to fluconazole and voriconazole but not to amphotericin B. These findings indicate that although Efg1p and Cph1p may have the same effects on virulence, they have opposite effects on drug resistance in C. albicans. PMID- 25802231 TI - Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. AB - Ibrutinib (Imbruvica(r)) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. PMID- 25802234 TI - SCD5-induced oleic acid production reduces melanoma malignancy by intracellular retention of SPARC and cathepsin B. AB - A proper balance between saturated and unsaturated fatty acids (FAs) is required for maintaining cell homeostasis. The increased demand of FAs to assemble the plasma membranes of continuously dividing cancer cells might unbalance this ratio and critically affect tumour outgrowth. We unveiled the role of the stearoyl-CoA desaturase SCD5 in converting saturated FAs into mono-unsaturated FAs during melanoma progression. SCD5 is down-regulated in advanced melanoma and its restored expression significantly reduced melanoma malignancy, both in vitro and in vivo, through a mechanism governing the secretion of extracellular matrix proteins, such as secreted protein acidic and rich in cysteine (SPARC) and collagen IV and of their proteases, such as cathepsin B. Enforced expression of SCD5 or supplementation of its enzymatic product, oleic acid, reduced the intracellular pH (pHe > pHi) and, in turn, vesicular trafficking across plasma membranes as well as melanoma dissemination. This intracellular acidification appears also to depend on SCD5-induced reduction of the C2 subunit of the vacuolar H(+) -ATPase, a proton pump whose inhibition changes the secretion profile of cancer cells. Our data support a role for SCD5 and its enzymatic product, oleic acid, in protection against malignancy, offering an explanation for the beneficial Mediterranean diet. Furthermore, SCD5 appears to functionally connect tumour cells and the surrounding stroma toward modification of the tumour microenvironment, with consequences on tumour spread and resistance to treatment. PMID- 25802235 TI - Aerosolized local anaesthetic to reduce postoperative pain. PMID- 25802236 TI - Strengthening Health Systems of Developing Countries: Inclusion of Surgery in Universal Health Coverage. AB - INTRODUCTION: Universal health coverage (UHC) has its roots in the Universal Declaration of Human Rights and has recently gained momentum. Out-of-pocket payments (OPP) remain a significant barrier to care. There is an increasing global prevalence of non-communicable diseases, many of which are surgically treatable. We sought to provide a comparative analysis of the inclusion of surgical care in operating plans for UHC in low- and middle-income countries (LMIC). METHODS: We systematically searched PubMed and Google Scholar using pre defined criteria for articles published in English, Spanish, or French between January 1991 and November 2013. Keywords included "insurance," "OPP," "surgery," "trauma," "cancer," and "congenital anomalies." World Health Organization (WHO), World Bank, and Joint Learning Network for UHC websites were searched for supporting documents. Ministries of Health were contacted to provide further information on the inclusion of surgery. RESULTS: We found 696 articles and selected 265 for full-text review based on our criteria. Some countries enumerated surgical conditions in detail (India, 947 conditions). Other countries mentioned surgery broadly. Obstetric care was most commonly covered (19 countries). Solid organ transplantation was least covered. Cancer care was mentioned broadly, often without specifying the therapeutic modality. No countries were identified where hospitals are required to provide emergency care regardless of insurance coverage. OPP varied greatly between countries. Eighty percent of countries had OPP of 60% or more, making these services, even if partially covered, largely inaccessible. CONCLUSION: While OPP, delivery, and utilization continue to represent challenges to health care access in many LMICs, the inclusion of surgery in many UHC policies sets an important precedent in addressing a growing global prevalence of surgically treatable conditions. Barriers to access, including inequalities in financial protection in the form of high OPP, remain a fundamental challenge to providing surgical care in LMICs. PMID- 25802239 TI - An ESMO-EORTC position paper on the EU clinical trials regulation and EMA's transparency policy: making European research more competitive again. PMID- 25802237 TI - Papillary Thyroid Carcinoma in Children and Adolescents: Long-Term Follow-Up and Clinical Characteristics. AB - BACKGROUND: The aim of this study was to analyze the clinical features and clinical outcomes of papillary thyroid carcinoma (PTC) in the pediatric and adolescent population treated in our institution. METHODS: The subjects were 227 PTC patients 20 years of age or under treated initially between 1979 and 2012. Their mean age at diagnosis was 18-year old (range 7-20 years). Patient characteristics and outcomes in the period before 1999 and the period after 2000 were compared. Cause-specific survival (CSS) rates and disease-free survival (DFS) rates were calculated by the Kaplan-Meier method. RESULTS: Two patients died of their disease and 45 patients had recurrent disease (36 in lymph node, seven in a remnant thyroid, and 11 in the form of distant metastasis). The 10-, 20-, and 30-CSS rates were 99.3, 99.3, and 96.5%, respectively, and the 10-, 20-, and 30-DFS were 83.6, 70.7, and 64.0%, respectively. Gender and preoperative lymph node metastasis were identified as significant factors related to DFS in the multivariate analysis. After the year 2000, there were significantly more patients with a small primary tumor size, significantly more patients without distant metastasis at presentation and significantly more patients without extrathyroidal invasion. CONCLUSION: The number of patients with advanced cancer has been declining in recent years. Lobectomy with prophylactic unilateral central neck dissection is considered acceptable for patients without the risk factors for recurrence. PMID- 25802238 TI - First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)?. AB - BACKGROUND: Papillary renal cell carcinoma (PRCC), type 1 and type 2, represents 10%-15% of renal cell carcinomas (RCC). There is no standard first-line treatment of metastatic PRCC (mPRCC). Anti-angiogenics have shown activity in retrospective studies but no prospective studies in pure papillary histology have been reported, but one with foretinib. PATIENTS AND METHODS: A prospective phase II study evaluated sunitinib in first-line treatment of mPRCC. The primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS: Fifteen and 46 patients, respectively, with type 1 and type 2 mPRCC were enrolled. Using the MSKCC scoring system: 12 (20%), 33 (55%) and 9 (15%) patients were, respectively, in the favourable, intermediate or poor risk group and 7 undetermined. Median follow-up is 51.4 months. In type 1, 2 patients 13% [95% confidence interval (CI) 0.1-30.5] had a partial response (PR), 10 had stable disease (SD) with 5 (33%) >=12 weeks. In type 2, 5 patients 11% (95% CI 1.9-20.3) had a PR, 25 had SD with 10(22%) >=12 weeks. Median PFS was 6.6 months (95% CI 2.8-14.8) in type 1 and 5.5 months (95% CI 3.8-7.1) in type 2. Median OS was 17.8 (95% CI 5.7-26.1) and 12.4 (95% CI 8.2 14.3) months, respectively, in type 1 and 2. Safety was as expected with sunitinib for metastatic RCC. CONCLUSION: Sunitinib showed activity in treatment of type 1 and 2 mPRCC but lower than in clear-cell mRCC. Both PFS and OS are longer in type I PRCC. Sunitinib represents an acceptable option in first-line treatment of mPRCC. PMID- 25802244 TI - Pharmacologic treatment of type 2 diabetes: injectable medications. AB - OBJECTIVE: To review the oral and injectable pharmacologic treatment options for type 2 diabetes. DATA SOURCES: A literature search was conducted using PubMed electronic database for studies published in English between 1993 and September 2014. Search terms included diabetes mellitus, type 2 diabetes, and the individual name for each antidiabetic medication reviewed. In addition, manual searches were performed for cross-references from publications. Package inserts, United States Food and Drug Administration (FDA) Web site, Institute for Safe Medication Practices Web site, American Diabetes Association Web site and scientific session poster presentations, and individual drug company Web pages were also reviewed. STUDY SELECTION AND DATA EXTRACTION: This review focused on information elucidated over the past 10 years to assist prescribers in choosing optimal therapy based on individual patient characteristics. Studies leading to the approval of or raising safety concerns for the antidiabetic medications reviewed in this article were included. DATA SYNTHESIS: In the past 10 years, there have been 4 novel oral antidiabetic medication classes and 10 new injectable agents and insulin products approved by the FDA for the treatment of type 2 diabetes as well as new information regarding the safety and use of several older antidiabetic medication classes. The distinctions were reviewed for each individual agent, and a comparison was completed if there was more than one agent in a particular therapeutic class. Using current information available, select investigational agents in phase III trials or with a pending new drug application were highlighted. CONCLUSION: There are now 9 distinct oral pharmacologic classes and a variety of insulin and noninsulin injectable medications available for the treatment of type 2 diabetes. Metformin remains the first-line treatment option for most patients. When considering options for alternative or additional treatment, prescribers must weigh the benefits and risks using individual patient characteristics. PMID- 25802245 TI - Brain metastasis from colorectal carcinoma: a single cancer centre experience. AB - PURPOSE: Brain metastases (BM) from colorectal cancer (CRC) are rare. As survival increases in patients with metastatic CRC, it is hypothesised that new metastatic patterns will emerge: for instance, as CRC with limited metastatic involvement of the liver and lung can now be successfully resected, we propose that sites, previously rarely involved in metastatic spread, will become more common. The objective of this study was to describe the experience with BM from CRC in a single cancer centre. METHODS: A prospectively compiled database (1988-2012) of patients with CRC treated in a tertiary referral hospital was retrospectively examined. Patients with a histological diagnosis of CRC and radiologically documented BM were included. Clinical information (including patient demographics, primary and metastatic disease factors) was obtained from medical records. RESULTS: Eleven patients (0.3 % of 4219 patients) were identified (8 male, 3 female). The median age at CRC diagnosis was 70 years (range 55-80 years) while the median age at diagnosis of BM was 73 years (range 56-83 years). Three patients diagnosed with synchronous metastases underwent palliative treatment while eight patients had undergone surgical resection of the primary tumour with curative intent a median of 24 months (range 0-48 months) prior to diagnosis of BM. 10/11 patients were symptomatic at diagnosis of BM. All were diagnosed using computed tomography and managed palliatively. The cerebellum was most the frequently involved site. The median overall survival time following diagnosis of BM was 2.5 months (range 2-9 months). Notably, 8/11 patients were diagnosed in the latter 8 years of the study period (between 2004 and 2012). CONCLUSION: With increased survival, improved systemic therapy and aggressive approaches to surgical management of "classical" metastases from CRC, it is likely that a changing pattern of metastases will emerge. As survival rates increase, we propose that metastatic sites, which were previously considered rare (e.g. brain), will now become more common and thus, surgeons must recognise pertinent symptomatology. PMID- 25802246 TI - The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. PMID- 25802247 TI - Novel mutation in GRXCR1 at DFNB25 lead to progressive hearing loss and dizziness. AB - OBJECTIVE: We identified 2 patients in 1 family who had novel mutations in GRXCR1, which caused progressive hearing loss. METHODS: One thousand one hundred twenty Japanese hearing loss patients with sensorineural hearing loss from unrelated families were enrolled in this study. Targeted genomic enrichment with massively parallel sequencing of all known nonsyndromic hearing loss genes was used to identify the genetic causes of hearing loss. RESULTS: In this study, 2 affected individuals with compound heterozygous mutations-c.439C>T (p.R147C) and c.784C>T (p.R262X)-in GRXCR1 were identified. The proband had moderate to severe hearing loss and suffered from dizziness with bilateral canal paralysis. CONCLUSION: Our cases are the first identified in the Japanese population and are consistent with previously reported cases. The frequency of mutations in GRXCR1 seems to be extremely rare. This study underscores the importance of using comprehensive genetic testing for hearing loss. Furthermore, longitudinal audiologic assessment and precise vestibular testing are necessary for a better understanding of the mechanisms of hearing loss and vestibular dysfunction caused by GRXCR1 mutations. PMID- 25802248 TI - Origin of Vocal Fold Stellate Cells in the Human Macula Flava. AB - OBJECTIVES: There is growing evidence that vocal fold stellate cells (VFSCs) in the human maculae flavae are tissue stem cells of the human vocal fold and that the maculae flavae are a stem cell niche. The origin of the cells in the human maculae flavae (CHMF) and the relationship with bone marrow-derived cells were investigated. METHODS: Five human adult vocal fold mucosae were investigated. The CHMF were subcultured and morphological features were assessed. Immunoreactivity to antibodies directed to cytokeratin, desmin, GFAP, vimentin, CD34, CD45, and collagen type I was investigated. RESULTS: Cultured CHMF formed a colony-forming unit, indicating they are mesenchymal stem cells or stromal stem cells in the bone marrow. The CHMF expressed hematopoietic markers (CD34, CD45) and collagen type I, which are the major makers for bone marrow-derived circulating fibrocytes. The cultured CHMF expressed epithelium-associated, muscle-associated, neural-associated, and mesenchymal cell-associated proteins, indicating the CHMF are undifferentiated and express proteins of all 3 germ layers. CONCLUSIONS: The CHMF are undifferentiated cells derived from the differentiation of bone marrow cells. The results of this study are consistent with the hypothesis that the VFSCs are tissue stem cells or progenitor cells of the human vocal fold mucosa. PMID- 25802249 TI - Winter warming delays dormancy release, advances budburst, alters carbohydrate metabolism and reduces yield in a temperate shrub. AB - Global climate models predict an increase in the mean surface air temperature, with a disproportionate increase during winter. Since temperature is a major driver of phenological events in temperate woody perennials, warming is likely to induce changes in a range of these events. We investigated the impact of slightly elevated temperatures (+0.76 degrees C in the air, +1.35 degrees C in the soil) during the non-growing season (October-April) on freezing tolerance, carbohydrate metabolism, dormancy release, spring phenology and reproductive output in two blackcurrant (Ribes nigrum) cultivars to understand how winter warming modifies phenological traits in a woody perennial known to have a large chilling requirement and to be sensitive to spring frost. Warming delayed dormancy release more in the cultivar 'Narve Viking' than in the cultivar 'Titania', but advanced budburst and flowering predominantly in 'Titania'. Since 'Narve Viking' has a higher chilling requirement than 'Titania', this indicates that, in high-chilling requiring genotypes, dormancy responses may temper the effect of warming on spring phenology. Winter warming significantly reduced fruit yield the following summer in both cultivars, corroborating the hypothesis that a decline in winter chill may decrease reproductive effort in blackcurrant. Elevated winter temperatures tended to decrease stem freezing tolerance during cold acclimation and deacclimation, but it did not increase the risk of freeze-induced damage mid winter. Plants at elevated temperature showed decreased levels of sucrose in stems of both cultivars and flower buds of 'Narve Viking', which, in buds, was associated with increased concentrations of glucose and fructose. Hence, winter warming influences carbohydrate metabolism, but it remains to be elucidated whether decreased sucrose levels account for any changes in freezing tolerance. Our results demonstrate that even a slight increase in winter temperature may alter phenological traits in blackcurrant, but to various extents depending on genotype-specific differences in chilling requirement. PMID- 25802250 TI - Making decisions to limit treatment in life-limiting and life-threatening conditions in children: a framework for practice. PMID- 25802251 TI - Choosing two points to add to the 24-2 pattern to better describe macular visual field damage due to glaucoma. AB - BACKGROUND/AIMS: A recent study has shown that the paracentral upper visual field in the macular region is often affected in glaucoma and suggested that two test locations within the central 10 degrees should be added to the Humphrey 24-2 visual field test pattern to detect such damage. This study employed data collected using a different visual field test pattern to determine whether the same two-test locations are supported as the most informative regarding visual field loss. METHODS: A data set of 62 patients with glaucoma and 48 controls had visual field assessments on the Medmont perimeter M700 (Central Threshold or Glaucoma test). Twelve 24-2 locations within central 10 degrees of visual field were derived by interpolation of the nearest neighbours of the Medmont data. The remaining 24 Medmont locations in the central 10 degrees of the glaucomatous set were labelled as abnormal if their thresholds fell outside the lower 5th centile of the age-corrected values for the same location from the control group. All possible pairs of the 24 locations were then assessed for diagnostic power by counting the number of patients that had 0, 1 or 2 abnormal locations in a pair. RESULTS: Overwhelmingly, pairs of locations in the superior macular region were more often abnormal than pairs in the inferior. About 50 pairs of locations had equivalent ability to detect damage, with the best pair having 74% of patients with at least one of the locations as abnormal, and 52% both. CONCLUSIONS: Adding a pair of locations to the superior macular region of the Humphrey Visual Field 24-2 pattern increases the number of abnormal locations identified in individuals with glaucoma. PMID- 25802252 TI - Intravenous immunoglobulin use in managing severe, perioperative peristomal pyoderma gangrenosum following subtotal colectomy with end ileostomy for medically refractory chronic ulcerative colitis. AB - Peristomal pyoderma gangrenosum (PPG) is a rare subtype of pyoderma gangrenosum that is characterized by painful, necrotic ulcerations occurring in the area surrounding an abdominal stoma. PPG is typically seen in younger patients with active inflammatory bowel disease. The etiology and pathogenesis is largely unknown and risk factors are not well defined. Therapy typically involves a combination of aggressive local wound care and systemic medications. Diagnosis and management of PPG can be difficult and data on treatment are limited. We present a case of severe postoperative peristomal recalcitrant to conventional therapy successfully treated with intravenous immune globulin. PMID- 25802253 TI - Floating patella associated with lymphoedema. AB - Ipsilateral injury of more than one component of the knee extensor apparatus is rare. It is mostly associated with previous trauma, surgery, immunosuppression therapy and systemic disease. We present the first documented case of a spontaneous bifocal disruption of the knee extensor apparatus (i.e. floating patella) associated with lymphoedema. This case highlights the importance of considering lymphoedema as another risk factor for rupture of the knee extensor apparatus. It also highlights the importance of assessing all components of the knee extensor apparatus in patients presenting with acute knee injuries. PMID- 25802254 TI - Metastases of lobular breast carcinoma in the terminal ileum and ileocaecal valve. AB - Gastrointestinal (GI) metastases from primary breast carcinoma are rare but more common in invasive lobular carcinoma than invasive ductal carcinoma. The symptoms may be non-specific and the presentation can occur many years after the initial primary breast carcinoma. Radiological and endoscopic findings can be difficult to distinguish from inflammatory bowel disease and primary carcinoma of the GI tract. Histological and immunohistopathology assessment will usually confirm the diagnosis of metastatic breast carcinoma. We report the first case of lobular breast carcinoma metastasizing to the terminal ileum and ileocaecal valve 19 years following treatment for breast cancer in an 82-year-old woman. Staging investigations revealed synchronous metastases in bones and the pleura. A high index of suspicion and awareness of the potential long interval in the presentation of metastatic breast cancer help in making an accurate diagnosis and rapid clinical management. PMID- 25802255 TI - Health policy and cardiovascular medicine: rapid changes, immense opportunities. PMID- 25802256 TI - National heart, lung, and blood institute (NHLBI) strategic visioning: setting an agenda together for the NHLBI of 2025. PMID- 25802257 TI - Development of left atrial thrombus and subsequent cardioembolic stroke in a 21 year-old man with ebstein anomaly who previously underwent pulmonary vein isolation ablation and Cox maze III procedure: significance of left atrial mechanical function. PMID- 25802258 TI - ECG Response: March 24, 2015. PMID- 25802259 TI - MacCallum plaque causes acute myocardial infarction in a young man. PMID- 25802260 TI - A case of coronary-cameral fistulae involving all three major coronary arteries. PMID- 25802261 TI - Letter by Sardovski et al regarding article, "Searching for the culprit vessel in acute myocardial infarction beyond angiography: role of cardiac magnetic resonance". PMID- 25802262 TI - Response to letter regarding article, "Searching for the culprit vessel in acute myocardial infarction beyond angiography: role of cardiac magnetic resonance". PMID- 25802263 TI - Letter by Li and Hong regarding article, "Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer". PMID- 25802265 TI - Correction. PMID- 25802266 TI - Retinal capillary flow and diabetic retinopathy. PMID- 25802264 TI - Response to letter regarding article, "Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer". PMID- 25802267 TI - Author response: retinal capillary flow and diabetic retinopathy. PMID- 25802268 TI - Childhood environmental tobacco smoke exposure: a smoking gun for atherosclerosis in adulthood. PMID- 25802271 TI - Glossopharyngeal nerve contrast enhancement in recent-onset glossopharyngeal neuralgia. PMID- 25802270 TI - Asian and Oceanian Congress of Neurology 2014: intraregional and interregional synergy. PMID- 25802269 TI - Exposure to parental smoking in childhood is associated with increased risk of carotid atherosclerotic plaque in adulthood: the Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: The association between passive smoking exposure in childhood and adverse cardiovascular health in adulthood is not well understood. Using a 26 year follow-up study, we examined whether childhood exposure to passive smoking was associated with carotid atherosclerotic plaque in young adults. METHODS AND RESULTS: Participants were from the Cardiovascular Risk in Young Finns Study (n=2448). Information on childhood exposure to parental smoking was collected in 1980 and 1983. Carotid ultrasound data were collected in adulthood in 2001 or 2007. Childhood serum cotinine levels from 1980 were measured from frozen samples in 2014 (n=1578). The proportion of children with nondetectable cotinine levels was highest among households in which neither parent smoked (84%), was decreased in households in which 1 parent smoked (62%), and was lowest among households in which both parents smoked (43%). Regardless of adjustment for potential confounding and mediating variables, the relative risk of developing carotid plaque in adulthood increased among those children with 1 or both parents who smoked (relative risk, 1.7; 95% confidence interval, 1.0-2.8; P=0.04). Although children whose parents exercised good "smoking hygiene" (smoking parents whose children had nondetectable cotinine levels) had increased risk of carotid plaque compared with children with nonsmoking parents (relative risk, 1.6; 95% confidence interval, 0.6-4.0; P=0.34), children of smoking parents with poor smoking hygiene (smoking parents whose children had detectable serum cotinine levels) had substantially increased risk of plaque as adults (relative risk, 4.0; 95% confidence interval, 1.7-9.8; P=0.002). CONCLUSIONS: Children of parents who smoke have increased risk of developing carotid atherosclerotic plaque in adulthood. However, parents who exercise good smoking hygiene can lessen their child's risk of developing plaque. PMID- 25802272 TI - Metoclopramide-induced facial and palatopharyngeal myoclonus. PMID- 25802273 TI - Predictors of dementia in Parkinson disease: a prospective cohort study. PMID- 25802274 TI - Mirror therapy in unilateral neglect after stroke (MUST trial): a randomized controlled trial. PMID- 25802275 TI - Mystery case: sawtooth waves: another normal variant not to over-read as epileptiform discharges. PMID- 25802276 TI - Teaching video neuroimages: an adult patient with rhythmic movement disorder. PMID- 25802277 TI - Teaching video neuroimages: nonepileptic myoclonus in a neonate following severe hypoxic-ischemic injury. PMID- 25802278 TI - Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. AB - The Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of beta-catenin and thereby induce the expression of key enzymes required for fatty acid beta-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. PMID- 25802279 TI - Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway. AB - The late stage of dry age-related macular degeneration (AMD), or geographic atrophy (GA), is characterized by extensive retinal pigment epithelial (RPE) cell death, and a cure is not available currently. We have recently demonstrated that RPE cells die from necrosis in response to oxidative stress, providing a potential novel mechanism for RPE death in AMD. In this study, we screened U.S. Food and Drug Administration-approved natural compounds and identified gossypol acetic acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces antioxidative response and inhibits accumulation of excessive reactive oxygen species in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) is found to mediate GAA function in antioxidative response and RPE survival upon oxidative stress. Moreover, Forkhead box O3 transcription factor (FoxO3) is further found to be required for GAA-mediated SESN2 expression and RPE survival. Mechanistically, GAA promotes FoxO3 nuclear translocation and binding to the SESN2 enhancer, which in turn increases its transcriptional activity. Taken together, we have identified GAA as a potent inhibitor of oxidative stress induced RPE necrosis by regulating the FoxO3/SESN2 pathway. This study may have significant implications in the therapeutics of age-related diseases, especially GA. PMID- 25802280 TI - Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis. AB - Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes. PMID- 25802282 TI - FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma. AB - On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m(2) over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (>=5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL. PMID- 25802281 TI - The Tomato Defensin TPP3 Binds Phosphatidylinositol (4,5)-Bisphosphate via a Conserved Dimeric Cationic Grip Conformation To Mediate Cell Lysis. AB - Defensins are a class of ubiquitously expressed cationic antimicrobial peptides (CAPs) that play an important role in innate defense. Plant defensins are active against a broad range of microbial pathogens and act via multiple mechanisms, including cell membrane permeabilization. The cytolytic activity of defensins has been proposed to involve interaction with specific lipid components in the target cell wall or membrane and defensin oligomerization. Indeed, the defensin Nicotiana alata defensin 1 (NaD1) binds to a broad range of membrane phosphatidylinositol phosphates and forms an oligomeric complex with phosphatidylinositol (4,5)-bisphosphate (PIP2) that facilitates membrane lysis of both mammalian tumor and fungal cells. Here, we report that the tomato defensin TPP3 has a unique lipid binding profile that is specific for PIP2 with which it forms an oligomeric complex that is critical for cytolytic activity. Structural characterization of TPP3 by X-ray crystallography and site-directed mutagenesis demonstrated that it forms a dimer in a "cationic grip" conformation that specifically accommodates the head group of PIP2 to mediate cooperative higher order oligomerization and subsequent membrane permeabilization. These findings suggest that certain plant defensins are innate immune receptors for phospholipids and adopt conserved dimeric configurations to mediate PIP2 binding and membrane permeabilization. This mechanism of innate defense may be conserved across defensins from different species. PMID- 25802283 TI - A vanG-type locus in Clostridium argentinense. AB - OBJECTIVES: The objective was to study a new vanG-type locus in Clostridium argentinense vanGCar and to determine its impact on glycopeptide susceptibility of the host. METHODS: The whole genome of C. argentinense NCIB 10714 was sequenced using Illumina single-reads sequencing technology. The presence of vanGCar in seven C. argentinense strains was tested by PCR and its expression was tested by quantitative RT-PCR (qRT-PCR). Glycopeptide susceptibility was determined by the Etest procedure. RESULTS: The vanGCar locus contained four genes encoding a carboxypeptidase, a d-alanine:d-serine ligase, a serine transporter and a serine racemase, and was present in the seven C. argentinense studied. An AraC-type transcriptional regulator was found upstream from the genes. C. argentinense NCIB 10714 was susceptible to vancomycin and to teicoplanin. qRT-PCR experiments revealed that vanGCar was not expressed without or with induction by a subinhibitory concentration of vancomycin. CONCLUSIONS: The new vanGCar locus was cryptic in C. argentinense and intrinsic to this species. Emergence of vancomycin resistance in C. argentinense due to decryptification of the vanGCar gene cluster could occur. PMID- 25802284 TI - Vancomycin serum concentrations do not adequately predict tissue exposure in diabetic patients with mild to moderate limb infections. AB - OBJECTIVES: Vancomycin is a common treatment for complicated skin and skin structure infections (cSSSIs) caused by MRSA. This analysis aimed to understand the variability of vancomycin tissue exposure at the site of infection. METHODS: Vancomycin serum and interstitial tissue fluid concentration data for nine patients with cSSSI and normal renal function were derived from an in vivo microdialysis study. Using Pmetrics, the non-parametric population modelling package for R, we co-modelled serum and tissue concentration data. A 5000-patient Monte Carlo simulation was conducted for 1 g of vancomycin every 12 h and every 8 h to calculate the penetration distribution (AUCtissue/fAUCserum) and probability of target attainment (PTA) at an fAUC/MIC target of >=200 in tissue fluid. RESULTS: A three-compartment model fitted the data best. The mean (SD) and median penetration ratios into tissue of the simulated population were 1.91 (4.56) and 0.85, respectively, which were consistent with observed values in the original patients. PTAs for 1 g of vancomycin every 12 h and every 8 h in tissue fluid were 39.6% and 56.6% at an MIC of 1 mg/L. Serum trough concentrations (R(2) = 0.06) and serum AUC exposure (R(2) = 0.002) were poor predictors of vancomycin AUC tissue exposure. CONCLUSIONS: Standard dosages of vancomycin provide a low likelihood of obtaining target pharmacodynamic exposure in the tissue of a lower limb infection. This low likelihood is due to wide variability in vancomycin penetration in the interstitial tissue fluid, which could not be predicted by serum concentrations. PMID- 25802285 TI - Systemic antimycotic and antifungal use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe. PMID- 25802286 TI - Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis. AB - OBJECTIVES: As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. METHODS: Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. RESULTS: Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC <=4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. CONCLUSIONS: Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L. PMID- 25802289 TI - Ethics and research culture. PMID- 25802290 TI - No ethics without meta-ethics - For more Benner and less Beauchamp. PMID- 25802287 TI - A Microarray-Matrix-assisted Laser Desorption/Ionization-Mass Spectrometry Approach for Site-specific Protein N-glycosylation Analysis, as Demonstrated for Human Serum Immunoglobulin M (IgM). AB - We demonstrate a new approach for the site-specific identification and characterization of protein N-glycosylation. It is based on a nano-liquid chromatography microarray-matrix assisted laser desorption/ionization-MS platform, which employs droplet microfluidics for on-plate nanoliter reactions. A chromatographic separation of a proteolytic digest is deposited at a high frequency on the microarray. In this way, a short separation run is archived into thousands of nanoliter reaction cavities, and chromatographic peaks are spread over multiple array spots. After fractionation, each other spot is treated with PNGaseF to generate two correlated traces within one run, one with treated spots where glycans are enzymatically released from the peptides, and one containing the intact glycopeptides. Mining for distinct glycosites is performed by searching for the predicted deglycosylated peptides in the treated trace. An identified peptide then leads directly to the position of the "intact" glycopeptide clusters, which are located in the adjacent spots. Furthermore, the deglycosylated peptide can be sequenced efficiently in a simple collision-induced dissociation-MS experiment. We applied the microarray approach to a detailed site specific glycosylation analysis of human serum IgM. By scanning the treated spots with low-resolution matrix assisted laser desorption/ionization-time-of-flight MS, we observed all five deglycosylated peptides, including the one originating from the secretory chain. A detailed glycopeptide characterization was then accomplished on the adjacent, untreated spots with high mass resolution and high mass accuracy using a matrix assisted laser desorption ionization-Fourier transform-MS. We present the first detailed and comprehensive mass spectrometric analysis on the glycopeptide level for human polyclonal IgM with high mass accuracy. Besides complex type glycans on Asn 395, 332, 171, and on the J chain, we observed oligomannosidic glycans on Asn 563, Asn 402 and minor amounts of oligomannosidic glycans on the glycosite Asn 171. Furthermore, hybrid type glycans were found on Asn 402, Asn 171 and in traces Asn 332. PMID- 25802288 TI - Time of day of cognitive tests might distort shift work study results. PMID- 25802291 TI - Questionable informed consent of vulnerable pregnant research participants in South India - what a staff reminder poster does not say. PMID- 25802292 TI - Multicultural dialogue on dignity from a Japanese perspective. PMID- 25802297 TI - Reassessment of the Genetic Regulation of Fatty Acid Synthesis in Escherichia coli: Global Positive Control by the Dual Functional Regulator FadR. AB - In Escherichia coli, the FadR transcriptional regulator represses the expression of fatty acid degradation (fad) genes. However, FadR is also an activator of the expression of fabA and fabB, two genes involved in unsaturated fatty acid synthesis. Therefore, FadR plays an important role in maintaining the balance between saturated and unsaturated fatty acids in the membrane. We recently showed that FadR also activates the promoter upstream of the fabH gene (L. My, B. Rekoske, J. J. Lemke, J. P. Viala, R. L. Gourse, and E. Bouveret, J Bacteriol 195:3784-3795, 2013, doi:10.1128/JB.00384-13). Furthermore, recent transcriptomic and proteomic data suggested that FadR activates the majority of fatty acid (FA) synthesis genes. In the present study, we tested the role of FadR in the expression of all genes involved in FA synthesis. We found that FadR activates the transcription of all tested FA synthesis genes, and we identified the FadR binding site for each of these genes. This necessitated the reassessment of the transcription start sites for accA and accB genes described previously, and we provide evidence for the presence of multiple promoters driving the expression of these genes. We showed further that regulation by FadR impacts the amount of FA synthesis enzymes in the cell. Our results show that FadR is a global regulator of FA metabolism in E. coli, acting both as a repressor of catabolism and an activator of anabolism, two directly opposing pathways. IMPORTANCE: In most bacteria, a transcriptional regulator tunes the level of FA synthesis enzymes. Oddly, such a global regulator still was missing for E. coli, which nonetheless is one of the prominent model bacteria used for engineering biofuel production using the FA synthesis pathway. Our work identifies the FadR functional dual regulator as a global activator of almost all FA synthesis genes in E. coli. Because FadR also is the repressor of FA degradation, FadR acts both as a repressor and an activator of the two opposite pathways of FA degradation and synthesis. Our results show that there are still discoveries waiting to be made in the understanding of the genetic regulation of FA synthesis, even in the very well-known bacterium E. coli. PMID- 25802296 TI - Membrane Protein Complex ExbB4-ExbD1-TonB1 from Escherichia coli Demonstrates Conformational Plasticity. AB - Iron acquisition at the outer membrane (OM) of Gram-negative bacteria is powered by the proton motive force (PMF) of the cytoplasmic membrane (CM), harnessed by the CM-embedded complex of ExbB, ExbD, and TonB. Its stoichiometry, ensemble structural features, and mechanism of action are unknown. By panning combinatorial phage libraries, periplasmic regions of dimerization between ExbD and TonB were predicted. Using overexpression of full-length His6-tagged exbB exbD and S-tagged tonB, we purified detergent-solubilized complexes of ExbB-ExbD TonB from Escherichia coli. Protein-detergent complexes of ~230 kDa with a hydrodynamic radius of ~6.0 nm were similar to previously purified ExbB4-ExbD2 complexes. Significantly, they differed in electronegativity by native agarose gel electrophoresis. The stoichiometry was determined to be ExbB4-ExbD1-TonB1. Single-particle electron microscopy agrees with this stoichiometry. Two dimensional averaging supported the phage display predictions, showing two forms of ExbD-TonB periplasmic heterodimerization: extensive and distal. Three dimensional (3D) particle classification showed three representative conformations of ExbB4-ExbD1-TonB1. Based on our structural data, we propose a model in which ExbD shuttles a proton across the CM via an ExbB interprotein rearrangement. Proton translocation would be coupled to ExbD-mediated collapse of extended TonB in complex with ligand-loaded receptors in the OM, followed by repositioning of TonB through extensive dimerization with ExbD. Here we present the first report for purification of the ExbB-ExbD-TonB complex, molar ratios within the complex (4:1:1), and structural biology that provides insights into 3D organization. IMPORTANCE: Receptors in the OM of Gram-negative bacteria allow entry of iron-bound siderophores that are necessary for pathogenicity. Numerous iron-acquisition strategies rely upon a ubiquitous and unique protein for energization: TonB. Complexed with ExbB and ExbD, the Ton system links the PMF to OM transport. Blocking iron uptake by targeting a vital nanomachine holds promise in therapeutics. Despite much research, the stoichiometry, structural arrangement, and molecular mechanism of the CM-embedded ExbB-ExbD-TonB complex remain unreported. Here we demonstrate in vitro evidence of ExbB4-ExbD1-TonB1 complexes. Using 3D EM, we reconstructed the complex in three conformational states that show variable ExbD-TonB heterodimerization. Our structural observations form the basis of a model for TonB-mediated iron acquisition. PMID- 25802298 TI - Helicobacter pylori FlhA Binds the Sensor Kinase and Flagellar Gene Regulatory Protein FlgS with High Affinity. AB - Flagellar biogenesis is a complex process that involves multiple checkpoints to coordinate transcription of flagellar genes with the assembly of the flagellum. In Helicobacter pylori, transcription of the genes needed in the middle stage of flagellar biogenesis is governed by RpoN and the two-component system consisting of the histidine kinase FlgS and response regulator FlgR. In response to an unknown signal, FlgS autophosphorylates and transfers the phosphate to FlgR, initiating transcription from RpoN-dependent promoters. In the present study, export apparatus protein FlhA was examined as a potential signal protein. Deletion of its N-terminal cytoplasmic sequence dramatically decreased expression of two RpoN-dependent genes, flaB and flgE. Optical biosensing demonstrated a high-affinity interaction between FlgS and a peptide consisting of residues 1 to 25 of FlhA (FlhANT). The KD (equilibrium dissociation constant) was 21 nM and was characterized by fast-on (kon = 2.9 * 10(4) M(-1)s(-1)) and slow-off (koff = 6.2 * 10(-4) s(-1)) kinetics. FlgS did not bind peptides consisting of smaller fragments of the FlhANT sequence. Analysis of binding to purified fragments of FlgS demonstrated that the C-terminal portion of the protein containing the kinase domain binds FlhANT. FlhANT binding did not stimulate FlgS autophosphorylation in vitro, suggesting that FlhA facilitates interactions between FlgS and other structures required to stimulate autophosphorylation. IMPORTANCE: The high-affinity binding of FlgS to FlhA characterized in this study points to an additional role for FlhA in flagellar assembly. Beyond its necessity for type III secretion, the N-terminal cytoplasmic sequence of FlhA is required for RpoN-dependent gene expression via interaction with the C-terminal kinase domain of FlgS. PMID- 25802300 TI - Combination pertuzumab, trastuzumab, and taxane for metastatic breast cancer after first progression: a single institution's experience. AB - BACKGROUND: The addition of pertuzumab to trastuzumab and taxane therapy was shown to be an effective first-line treatment for patients with HER2-positive metastatic breast cancer. OBJECTIVE: Describe the progression-free survival of pertuzumab, trastuzumab, and taxane therapy for previously treated HER2-positive metastatic breast cancer. METHODS: This case-series reviews 19 patients with metastatic breast cancer receiving treatment with pertuzumab, trastuzumab, taxane after progression and exposure to previous lines of HER2-directed therapy. Progression-free survival and adverse effects such as changes in ejection fraction and episodes of neutropenic fever were assessed. RESULTS: The median progression-free survival of pertuzumab, trastuzumab, taxane therapy for previously treated metastatic breast cancer was 4.1 months. The mean baseline left ventricular ejection fraction change experienced by patients was -1%. Neutropenic fever events were not encountered. CONCLUSIONS: Pertuzumab, trastuzumab, and taxane therapy seems to confer progression-free survival benefit for previously treated metastatic breast cancer. The use of the dual anti-HER2 antibodies, pertuzumab and trastuzumab, in addition to cytotoxic chemotherapy agents for previously treated metastatic breast cancer should be further evaluated. PMID- 25802302 TI - Grassroots volunteers in context: rewarding and adverse experiences of local women working on HIV and AIDS in Kilimanjaro, Tanzania. AB - Many nongovernmental organizations in Africa rely on grassroots volunteers to provide critical health services. Considering context and the interplay of individual, organizational, and societal influences on the experience of volunteers, this paper addresses three questions: What do grassroots volunteers contribute? What organizational processes promote volunteer engagement? What are the positive and negative consequences of volunteering? Eighteen members and staff of the Tanzanian HIV and AIDS NGO, KIWAKKUKI, were selected from 6000+ women volunteers to be interviewed. The interviews were recorded, transcribed, and analyzed for themes. Within KIWAKKUKI, volunteers contributed time and local knowledge, leading to an indigenous educational approach building on local norms and customs. Volunteers' engagement was motivated by the desire to support family members, reverse stigma, and work/socialize with other women. Benefits to volunteers included skills acquisition and community recognition; yet some volunteers also reported negative experiences including burnout, conferred stigma, and domestic violence. Positive organizational processes built on cultural practices such as collective decision-making and singing. The findings point to important considerations about context, including the synergistic effect training can have on local traditions of caring, complications of gender inequity, and how community health planning processes may need to be modified in extremely poor settings. This research also suggests good utility of the research framework (the Bergen Model of Collaborative Functioning) that was used to analyze volunteer engagement for service delivery in sub-Saharan contexts. PMID- 25802299 TI - Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids. AB - Although Staphylococcus aureus is exposed to antimicrobial fatty acids on the skin, in nasal secretions, and in abscesses, a specific mechanism of inducible resistance to this important facet of innate immunity has not been identified. Here, we have sequenced the genome of S. aureus USA300 variants selected for their ability to grow at an elevated concentration of linoleic acid. The fatty acid-resistant clone FAR7 had a single nucleotide polymorphism resulting in an H121Y substitution in an uncharacterized transcriptional regulator belonging to the AcrR family, which was divergently transcribed from a gene encoding a member of the resistance-nodulation-division superfamily of multidrug efflux pumps. We named these genes farR and farE, for regulator and effector of fatty acid resistance, respectively. Several lines of evidence indicated that FarE promotes efflux of antimicrobial fatty acids and is regulated by FarR. First, expression of farE was strongly induced by arachidonic and linoleic acids in an farR dependent manner. Second, an H121Y substitution in FarR resulted in increased expression of farE and was alone sufficient to promote increased resistance of S. aureus to linoleic acid. Third, inactivation of farE resulted in a significant reduction in the inducible resistance of S. aureus to the bactericidal activity of 100 MUM linoleic acid, increased accumulation of [(14)C]linoleic acid by growing cells, and severely impaired growth in the presence of nonbactericidal concentrations of linoleic acid. Cumulatively, these findings represent the first description of a specific mechanism of inducible resistance to antimicrobial fatty acids in a Gram-positive pathogen. IMPORTANCE: Staphylococcus aureus colonizes approximately 25% of humans and is a leading cause of human infectious morbidity and mortality. To persist on human hosts, S. aureus must have intrinsic defense mechanisms to cope with antimicrobial fatty acids, which comprise an important component of human innate defense mechanisms. We have identified a novel pair of genes, farR and farE, that constitute a dedicated regulator and effector of S. aureus resistance to linoleic and arachidonic acids, which are major fatty acids in human membrane phospholipid. Expression of farE, which encodes an efflux pump, is induced in an farR-dependent mechanism, in response to these antimicrobial fatty acids that would be encountered in a tissue abscess. PMID- 25802303 TI - The use of focus groups as a basis for planning and implementing culturally appropriate health promotion among people with diabetes in the Arab community. AB - OBJECTIVE: The main study objective was to identify perceived barriers to achieving glycemic control among the Arab population in Israel, by both members of the Arab community with type 2 diabetes and by primary care teams working with the Arab community. METHODS: A series of six focus groups using qualitative research methodology were conducted in two phases among people with diabetes and primary care professionals treating them. RESULTS: The perception of the disease among people with diabetes was one of low severity. Barriers to adopting a healthy lifestyle and to self-management included awareness of the need, financial considerations regarding medication, and traditional gender roles. Food preparation in family life was identified as a strong cultural determinant. The health literacy needs for more in-depth and accessible educational programs were identified. Primary care staff viewed the needs similarly, with the exception of the need for in-depth instructional materials. CONCLUSION AND PRACTICE IMPLICATIONS: The understanding of the significance of healthy lifestyles and self-management was essential for developing culturally appropriate implementation programs and policy. Consultation with, and involvement of patient groups in needs assessment and planning is essential and should be established in policy that promotes best practice and health promotion in chronic illness. PMID- 25802301 TI - Factors associated with optimized tacrolimus dosing in hematopoietic stem cell transplantation. AB - OBJECTIVE: The primary objective was to analyze the initial tacrolimus concentrations achieved in allogeneic hematopoietic stem cell transplantation patients using the institutional dosing strategy of 1 mg IV daily initiated on day +5. The secondary objectives were to ascertain the tacrolimus dose, days of therapy, and dose changes necessary to achieve a therapeutic concentration, and to identify patient-specific factors that influence therapeutic dose. The relationships between the number of pre-therapeutic days and incidence of graft versus-host disease and graft failure were delineated. METHODS: A retrospective chart review included adult allogeneic hematopoietic stem cell patients who received tacrolimus for graft-versus-host disease prophylaxis in 2012. Descriptive statistics, linear and logistic regression, and graphical analyses were utilized. RESULTS: Ninety-nine patients met the inclusion criteria. The first concentration was subtherapeutic (<10 ng/ml) in 97 patients (98%). The median number of days of tacrolimus needed to achieve a therapeutic trough was 10 with a median of two dose changes. The median therapeutic dose was 1.6 mg IV daily. Approximately 75% of patients became therapeutic on <= 2 mg IV tacrolimus daily. No relationship was found between therapeutic dose and any patient specific factor tested, including weight. No relationship was found between the number of days of therapy required to achieve a therapeutic trough and incidence of graft-versus-host disease or graft failure. CONCLUSION: An initial flat tacrolimus dose of 1 mg IV daily is a suboptimal approach to achieve therapeutic levels at this institution. A dose of 1.6 mg or 2 mg IV daily is a reasonable alternative to the current institutional practice. PMID- 25802304 TI - Pyruvate Is Superior to Citrate in Oral Rehydration Solution in the Protection of Intestine via Hypoxia-Inducible Factor-1 Activation in Rats With Burn Injury. AB - BACKGROUND: Recent studies have suggested that pyruvate-enriched oral rehydration solution (Pyr-ORS) may be superior to the standard bicarbonate-based ORS in the protection of intestine from ischemic injury. The aim of this study was to compare the effects of Pyr-ORS with citrate-enriched ORS (Cit-ORS) on the intestinal hypoxia-inducible factor-1 (HIF-1)-erythropoietin (EPO) signaling pathway for enteral rehydration in a rat model of burn injury. METHODS: Rats were randomly assigned to 4 groups (N = 20, 2 subgroups each: n = 10): scald sham (group SS), scald with no fluid resuscitation (group SN), scald and resuscitation with enteral Cit-ORS (group SC), and scald and resuscitation with enteral Pyr-ORS (group SP). At 2.5 and 4.5 hours after a 35% total body surface area (TBSA) scald, intestinal mucosal blood flow (IMBF), contents of HIF-1, EPO, endothelial nitric oxide synthase (eNOS), nitric oxide (NO), barrier protein (ZO-1), levels of serum diamine oxidase (DAO), and intestinal mucosal histology injury score were determined. RESULTS: Serum DAO activities in the scalded groups were significantly elevated, but less raised in group SP than in group SC, at 2.5 hours and at 4.5 hours after the scald. Further, group SP more profoundly preserved intestinal HIF-1 expression compared with group SC at the 2 time points. Compared with group SC, group SP had markedly elevated intestinal EPO, eNOS, and NO levels at the same time points, respectively (P < .05). Similarly, IMBF and ZO-1 levels were significantly higher in group SP than in group SC. Intestinal mucosal histopathological scores were statistically higher at 2.5 hours and 4.5 hours after scalding but were more attenuated in group SP than in group SC (P < .05). Immunofluorescence expression of intestinal mucosal ZO-1 was consistent with the above changes. The above parameters were also significantly different between groups SC and SN (all P < .05). CONCLUSION: Pyr-ORS provides a superior option to Cit-ORS for the preservation of intestinal blood flow and barrier function and the attenuation of histopathological alterations in enteral resuscitation of rats with burn injury. Its underlying mechanism may be closely related to the pyruvate in activation of intestinal HIF-1-EPO signaling cascades. PMID- 25802306 TI - Primary chemoprevention of breast cancer: Are the adverse effects too burdensome? PMID- 25802307 TI - Mandibular tori. PMID- 25802308 TI - New investment in international health care graduates. PMID- 25802310 TI - Does bilingualism delay dementia? PMID- 25802309 TI - Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months. AB - BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age). METHODS: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. RESULTS: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (>= 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). INTERPRETATION: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01027351. PMID- 25802311 TI - More needed to reduce radon-related cancer. PMID- 25802313 TI - Mass cholera vaccination finally possible. PMID- 25802314 TI - Canada can afford universal pharmacare - no more excuses. PMID- 25802315 TI - Sodium channels open in response to depolarization and then inactivate rapidly. PMID- 25802316 TI - Laminar cortical damage in multiple sclerosis. PMID- 25802317 TI - Where is hippocampal activity in the cascade of Alzheimer's disease biomarkers? PMID- 25802318 TI - Right lateral prefrontal cortex--specificity for inhibition or strategy use? PMID- 25802320 TI - The influence of word characteristics on the vocabulary of children with cochlear implants. AB - The goal of this study was to explore the effects of phonotactic probability, word length, word frequency, and neighborhood density on the words known by children with cochlear implants (CIs) varying in vocabulary outcomes in a retrospective analysis of a subset of data from a longitudinal study of hearing loss. Generalized linear mixed modeling was used to examine the effects of these word characteristics at 3 time points: preimplant, postimplant, and longitudinal follow-up. Results showed a robust effect of neighborhood density across group and time, whereas the effect of frequency varied by time. Significant effects of phonotactic probability or word length were not detected. Taken together, these findings suggest that children with CIs may be able to use spoken language structure in a manner similar to their normal hearing counterparts, despite the differences in the quality of the input. The differences in the effects of phonotactic probability and word length imply a difficulty in initiating word learning and limited working memory ability in children with CIs. PMID- 25802319 TI - The Contribution of Verbal Working Memory to Deaf Children's Oral and Written Production. AB - This study investigated the contribution of verbal working memory to the oral and written story production of deaf children. Participants were 29 severely to profoundly deaf children aged 8-13 years and 29 hearing controls, matched for grade level. The children narrated a picture story orally and in writing and performed a reading comprehension test, the Wechsler Intelligence Scale for Children-Fourth Edition forward digit span task, and a reading span task. Oral and written stories were analyzed at the microstructural (i.e., clause) and macrostructural (discourse) levels. Hearing children's stories scored higher than deaf children's at both levels. Verbal working memory skills contributed to deaf children's oral and written production over and above age and reading comprehension skills. Verbal rehearsal skills (forward digit span) contributed significantly to deaf children's ability to organize oral and written stories at the microstructural level; they also accounted for unique variance at the macrostructural level in writing. Written story production appeared to involve greater verbal working memory resources than oral story production. PMID- 25802322 TI - Dignity and patient-centred care for people with palliative care needs in the acute hospital setting: A systematic review. AB - BACKGROUND: A core concept behind patient-centred approaches is the need to treat people with, and preserve, dignity in care settings. People receiving palliative care are one group who may have particularly sensitive needs in terms of their condition, symptoms and life expectancy. Dignity is more likely to be violated in hospital settings. Given the high percentage of people with palliative care needs who are admitted to hospital during their last year of life, the provision of dignity enhancing and preserving care in that setting is of vital importance. AIM: To examine international evidence relating to dignity and person-centred care for people with palliative care needs in the acute hospital setting. DESIGN: A systematic literature review was conducted, incorporating data extraction, analysis and quality appraisal of included papers. DATA SOURCES: MEDLINE, CINAHL, PsycINFO, ASSIA, EMBASE, Cochrane Database and Web of Science. Inclusion dates: 1 January 2000-1 April 2014. ELIGIBILITY CRITERIA: Adult palliative care, acute care setting, dignity or person-centred care. RESULTS: In all, 33 papers met the inclusion criteria for the review. Papers highlighted the many and varied potential threats to dignity for people with palliative care needs in acute settings, including symptom control and existential distress, approaches and models in care provision and healthcare settings and design. CONCLUSION: Acute hospital staff require adequate training, including symptom control, and the correct environment in which to deliver dignified and person-centred end-of-life care. Specific models/approaches to care can be beneficial, if adequate training regarding implementation is given. The needs of family members also require consideration, particularly following bereavement. PMID- 25802323 TI - Conceptualising psychological distress in families in palliative care: Findings from a systematic review. AB - BACKGROUND: Adult palliative care patients and their family members experience significant psychological distress and morbidity. Psychosocial interventions adopting a systemic approach may provide a cogent model to improve the psychosocial care of families in palliative care. To facilitate design of these interventions, the construct of psychological distress in families in palliative care should be empirically derived. AIM: To ascertain how psychological distress is conceptualised in families receiving palliative care. DESIGN: A systematic review of the literature; this was followed by a thematic analysis and narrative synthesis. DATA SOURCES: Using pre-defined search terms, four electronic databases (MEDLINE, CINAHL, PsycINFO and Behavioural Sciences collections) were searched with no date restrictions imposed. Pre-determined inclusion and exclusion criteria were then applied. RESULTS: A total of 32 papers were included in the review. Two findings emerged from data synthesis. First, distress is conceptualised as a multi-dimensional construct but little consensus exists as to how to capture and measure distress. Second, distress in the families within these studies can be conceptualised using a tiered approach, moving from individual non-interactive depictions of distress through gradations of interaction to convey a systemic account of distress within the family system. Thus, distress shifts from a unitary to a systemic construct. CONCLUSION: Currently, there is a paucity of research examining distress informed by family systems theories. This review proposes that distress in families in palliative care can be conceptualised and illustrated within a tiered model of distress. Further research is merited to advance current explanatory frameworks and theoretical models of distress. PMID- 25802321 TI - The desire to hasten death: Using Grounded Theory for a better understanding "When perception of time tends to be a slippery slope". AB - BACKGROUND: Some patients with advanced and progressive diseases express a desire to hasten death. AIM: This study evaluated the motivations of patients expressing such a desire in a country with prohibitive legislation on euthanasia and physician-assisted suicide. DESIGN: A modified form of Grounded Theory was used. SETTING/PARTICIPANTS: Patients from the departments of palliative medicine in three hospitals in Germany were recruited when they had made a statement or request to hasten death. Participants were interviewed face to face. Recruitment was stopped with 12 participants because of data saturation. RESULTS: Thematic analysis revealed three main motivational themes: self-determination, agony, and time. Expectations toward health professionals, attitudes toward death, and secureness related to the end of life were additional main themes emerging from the analysis. CONCLUSIONS: The desire to hasten death may be used as an extreme coping strategy to maintain control against anticipated agony. Patients expected health professionals to listen to and respect their experiences. Emerging hypotheses included the following: (a) patients try to balance life time and anticipated agony, and the perception of time is distressing in this balancing act; (b) anticipated images of agony and suffering in the dying process occur frequently and are experienced by patients as intrusive; (c) patients expressing a desire to hasten death are in need of more information about the dying process; and (d) patients wanted their caregivers to listen to and respect their wish to hasten death, and they did not expect the caregivers to understand this as an order to actually hasten their death. PMID- 25802325 TI - Health policy and diabetes care: is it time to put politics aside? PMID- 25802324 TI - Surge in newly identified diabetes among medicaid patients in 2014 within medicaid expansion States under the affordable care act. AB - OBJECTIVE: Twenty-six states and the District of Columbia expanded Medicaid in January 2014 pursuant to the Affordable Care Act (ACA); 24 states did not. This created an opportunity to examine the impact of Medicaid expansion on the number of Medicaid patients with newly identified diabetes among enrollees (19-64 years of age) who had laboratory testing through Quest Diagnostics. RESEARCH DESIGN AND METHODS: Newly identified diabetes was defined as an ICD-9 diagnosis code of 250.x (diabetes) or hemoglobin A1c of >6.4% (46 mmol/mol) within the first 6 months of a calendar year and the absence of both in the preceding calendar year within our data repository. RESULTS: We identified 215,398 and 218,890 patients who met our definition of newly diagnosed diabetes within the first 6 months of 2013 (control period) and 2014 (study period), respectively (a 1.6% increase). We identified 26,237 Medicaid-enrolled patients with new diabetes in the control period vs. 29,673 in the study period: an increase of 13%. The number of Medicaid enrolled patients with newly identified diabetes increased by 23% (14,625 vs. 18,020 patients) in the 26 states (and District of Columbia) that expanded Medicaid compared with an increase of 0.4% (11,612 vs. 11,653 patients) in the 24 states that did not expand Medicaid during this period. Similar differences were observed in younger and older adults and for both men and women. CONCLUSIONS: This study suggests that in the states that expanded Medicaid under the ACA, an increased number of Medicaid patients with diabetes are being diagnosed and treated earlier. This could be anticipated to lead to better long-term outcomes. PMID- 25802326 TI - Panobinostat approved for multiple myeloma. PMID- 25802328 TI - Inflammation-associated microRNA-130b down-regulates cytochrome P450 activities and directly targets CYP2C9. AB - Expression of genes involved in absorption, distribution, metabolism, and excretion (ADME) of drugs is impaired in pathophysiologic conditions such as cholestasis and inflammation. The mechanisms of ADME gene down-regulation remain unclear. In our previous study, strongly elevated levels of microRNAs (miRNA) miR 21, miR-34a, and miR-130b in cholestatic liver and of miR-21 and miR-130b during inflammation were observed. Using HepaRG cells, which retain many functional characteristics of human hepatocytes, we investigated the potential of these miRNAs to down-regulate ADME genes. Cells were transfected with the corresponding miRNA mimics, chemically modified double-stranded RNAs that mimic endogenous miRNAs, followed by mRNA profiling by quantitative reverse-transcription polymerase chain reaction. Activities of six cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4) were determined with a liquid chromatography with tandem mass spectrometric cocktail assay. Although miR-21 and miR-34a showed few effects, transfection of miR-130b led to significantly lower expression of nuclear receptors constitutive androstane receptor (CAR) and farnesoid X receptor (FXRalpha), the CYPs 1A1, 1A2, 2A6, 2C8, 2C9, and 2C19, as well as GSTA2. Furthermore, miR-130b negatively affected activity levels of all measured P450s by at least 30%. Reporter gene assays employing the CYP2C9 3' untranslated region (3'-UTR) confirmed direct regulation by miR-130b. These data support miR-130b as a potential negative regulator of drug metabolism by directly and/or indirectly affecting the expression of several ADME genes. This may be of relevance in pathophysiologic conditions such as cholestasis and inflammation, which are associated with increased miR-130b expression. PMID- 25802327 TI - Prediction of gestational age-dependent induction of in vivo hepatic CYP3A activity based on HepaRG cells and human hepatocytes. AB - In pregnant women, CYP3A activity increases by 100% during the third trimester (T3). Due to logistical and ethical constraints, little is known about the magnitude of CYP3A induction during the first trimester (T1) and second trimester (T2). Our laboratory has shown that sandwich-cultured human hepatocytes (SCHH) and HepaRG cells have the potential to predict the magnitude of in vivo induction of CYP3A activity likely to be observed in T1 and T2. Therefore, we incubated SCHH and HepaRG cells with plasma concentrations of various pregnancy-related hormones (PRHs)-individually or in combination-observed during T1, T2, or T3 in pregnant women. Then, CYP3A activity was measured by 1'-OH-midazolam formation. In all three trimesters, only cortisol (C) consistently and significantly induced CYP3A activity, while other individual hormones (progesterone, estradiol, or growth hormones) failed to induce CYP3A activity. At physiologically relevant 1* plasma concentrations, the magnitude of CYP3A induction by C or the combination of all PRHs did not change significantly with gestational age. The pattern of induction of CYP3A activity in SCHH by the hormones was similar to that in HepaRG cells. Based on these data, we conclude that C remains the major inducer of CYP3A activity earlier in gestation. Moreover, we predict that the magnitude of CYP3A induction during T1 and T2 will be similar to that observed during T3 (~100% increase versus postpartum). This prediction is consistent with the observation of similar increases in T2 and T3 oral clearance of indinavir (a CYP3A cleared drug) versus postpartum. PMID- 25802329 TI - Activity of a bacterial cell envelope stress response is controlled by the interaction of a protein binding domain with different partners. AB - The bacterial phage shock protein (Psp) system is a highly conserved cell envelope stress response required for virulence in Yersinia enterocolitica and Salmonella enterica. In non-inducing conditions the transcription factor PspF is inhibited by an interaction with PspA. In contrast, PspA associates with the cytoplasmic membrane proteins PspBC during inducing conditions. This has led to the proposal that PspBC exists in an OFF state, which cannot recruit PspA, or an ON state, which can. However, nothing was known about the difference between these two states. Here, we provide evidence that it is the C-terminal domain of Y. enterocolitica PspC (PspC(CT)) that interacts directly with PspA, both in vivo and in vitro. Site-specific photocross-linking revealed that this interaction occurred only during Psp-inducing conditions in vivo. Importantly, we have also discovered that PspC(CT) can interact with the C-terminal domain of PspB (PspC(CT).PspB(CT)). However, the PspC(CT).PspB(CT) and PspC(CT).PspA interactions were mutually exclusive in vitro. Furthermore, in vivo, PspC(CT) contacted PspB(CT) in the OFF state, whereas it contacted PspA in the ON state. These findings provide the first description of the previously proposed PspBC OFF and ON states and reveal that the regulatory switch is centered on a PspC(CT) partner-switching mechanism. PMID- 25802330 TI - An unprecedented NADPH domain conformation in lysine monooxygenase NbtG provides insights into uncoupling of oxygen consumption from substrate hydroxylation. AB - N-Hydroxylating monooxygenases are involved in the biosynthesis of iron-chelating hydroxamate-containing siderophores that play a role in microbial virulence. These flavoenzymes catalyze the NADPH- and oxygen-dependent hydroxylation of amines such as those found on the side chains of lysine and ornithine. In this work we report the biochemical and structural characterization of Nocardia farcinica Lys monooxygenase (NbtG), which has similar biochemical properties to mycobacterial homologs. NbtG is also active on d-Lys, although it binds l-Lys with a higher affinity. Differently from the ornithine monooxygenases PvdA, SidA, and KtzI, NbtG can use both NADH and NADPH and is highly uncoupled, producing more superoxide and hydrogen peroxide than hydroxylated Lys. The crystal structure of NbtG solved at 2.4 A resolution revealed an unexpected protein conformation with a 30 degrees rotation of the NAD(P)H domain with respect to the flavin adenine dinucleotide (FAD) domain that precludes binding of the nicotinamide cofactor. This "occluded" structure may explain the biochemical properties of NbtG, specifically with regard to the substantial uncoupling and limited stabilization of the C4a-hydroperoxyflavin intermediate. Biological implications of these findings are discussed. PMID- 25802331 TI - A universal stress protein (USP) in mycobacteria binds cAMP. AB - Mycobacteria are endowed with rich and diverse machinery for the synthesis, utilization, and degradation of cAMP. The actions of cyclic nucleotides are generally mediated by binding of cAMP to conserved and well characterized cyclic nucleotide binding domains or structurally distinct cGMP-specific and -regulated cyclic nucleotide phosphodiesterase, adenylyl cyclase, and E. coli transcription factor FhlA (GAF) domain-containing proteins. Proteins with cyclic nucleotide binding and GAF domains can be identified in the genome of mycobacterial species, and some of them have been characterized. Here, we show that a significant fraction of intracellular cAMP is bound to protein in mycobacterial species, and by using affinity chromatography techniques, we identify specific universal stress proteins (USP) as abundantly expressed cAMP-binding proteins in slow growing as well as fast growing mycobacteria. We have characterized the biochemical and thermodynamic parameters for binding of cAMP, and we show that these USPs bind cAMP with a higher affinity than ATP, an established ligand for other USPs. We determined the structure of the USP MSMEG_3811 bound to cAMP, and we confirmed through structure-guided mutagenesis, the residues important for cAMP binding. This family of USPs is conserved in all mycobacteria, and we suggest that they serve as "sinks" for cAMP, making this second messenger available for downstream effectors as and when ATP levels are altered in the cell. PMID- 25802332 TI - Iron-induced Local Complement Component 3 (C3) Up-regulation via Non-canonical Transforming Growth Factor (TGF)-beta Signaling in the Retinal Pigment Epithelium. AB - Dysregulation of iron homeostasis may be a pathogenic factor in age-related macular degeneration (AMD). Meanwhile, the formation of complement-containing deposits under the retinal pigment epithelial (RPE) cell layer is a pathognomonic feature of AMD. In this study, we investigated the molecular mechanisms by which complement component 3 (C3), a central protein in the complement cascade, is up regulated by iron in RPE cells. Modulation of TGF-beta signaling, involving ERK1/2, SMAD3, and CCAAT/enhancer-binding protein-delta, is responsible for iron induced C3 expression. The differential effects of spatially distinct SMAD3 phosphorylation sites at the linker region and at the C terminus determined the up-regulation of C3. Pharmacologic inhibition of either ERK1/2 or SMAD3 phosphorylation decreased iron-induced C3 expression levels. Knockdown of SMAD3 blocked the iron-induced up-regulation and nuclear accumulation of CCAAT/enhancer binding protein-delta, a transcription factor that has been shown previously to bind the basic leucine zipper 1 domain in the C3 promoter. We show herein that mutation of this domain reduced iron-induced C3 promoter activity. In vivo studies support our in vitro finding of iron-induced C3 up-regulation. Mice with a mosaic pattern of RPE-specific iron overload demonstrated co-localization of iron-induced ferritin and C3d deposits. Humans with aceruloplasminemia causing RPE iron overload had increased RPE C3d deposition. The molecular events in the iron-C3 pathway represent therapeutic targets for AMD or other diseases exacerbated by iron-induced local complement dysregulation. PMID- 25802333 TI - Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells. AB - Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors remains troublesome in the treatment of advanced stage chronic myeloid leukemia (CML). The aim of this study was to estimate the reversal effects of down regulation of Na(+)/H(+) exchanger 1 (NHE1) on the chemoresistance of BCR-ABL positive leukemia patients' cells and cell lines. After treatment with the specific NHE1 inhibitor cariporide to decrease intracellular pH (pHi), the heme oxygenase-1 (HO-1) levels of the K562R cell line and cells from IM-insensitive CML patients decreased. HO-1, as a Bcr/Abl-dependent survival molecule in CML cells, is important for the resistance to tyrosine kinase inhibitors in patients with newly diagnosed CML or IM-resistant CML. Silencing PKC-beta and Nrf-2 or treatment with inhibitors of p38 pathways obviously blocked NHE1-induced HO-1 expression. Furthermore, treatment with HO-1 or p38 inhibitor plus IM increased the apoptosis of the K562R cell line and IM-insensitive CML patients' cells. Inhibiting HO-1 enhanced the activation of caspase-3 and poly(ADP-ribose) polymerase-1. Hence, the results support the anti-apoptotic role of HO-1 induced by NHE1 in the K562R cell line and IM-insensitive CML patients and provide a mechanism by which inducing HO-1 expression via the PKC-beta/p38-MAPK pathway may promote tumor resistance to oxidative stress. PMID- 25802334 TI - Molecular and Functional Characterization of RecD, a Novel Member of the SF1 Family of Helicases, from Mycobacterium tuberculosis. AB - The annotated whole-genome sequence of Mycobacterium tuberculosis revealed the presence of a putative recD gene; however, the biochemical characteristics of its encoded protein product (MtRecD) remain largely unknown. Here, we show that MtRecD exists in solution as a stable homodimer. Protein-DNA binding assays revealed that MtRecD binds efficiently to single-stranded DNA and linear duplexes containing 5' overhangs relative to the 3' overhangs but not to blunt-ended duplex. Furthermore, MtRecD bound more robustly to a variety of Y-shaped DNA structures having >=18-nucleotide overhangs but not to a similar substrate containing 5-nucleotide overhangs. MtRecD formed more salt-tolerant complexes with Y-shaped structures compared with linear duplex having 3' overhangs. The intrinsic ATPase activity of MtRecD was stimulated by single-stranded DNA. Site specific mutagenesis of Lys-179 in motif I abolished the ATPase activity of MtRecD. Interestingly, although MtRecD-catalyzed unwinding showed a markedly higher preference for duplex substrates with 5' overhangs, it could also catalyze significant unwinding of substrates containing 3' overhangs. These results support the notion that MtRecD is a bipolar helicase with strong 5' -> 3' and weak 3' -> 5' unwinding activities. The extent of unwinding of Y-shaped DNA structures was ~3-fold lower compared with duplexes with 5' overhangs. Notably, direct interaction between MtRecD and its cognate RecA led to inhibition of DNA strand exchange promoted by RecA. Altogether, these studies provide the first detailed characterization of MtRecD and present important insights into the type of DNA structure the enzyme is likely to act upon during the processes of DNA repair or homologous recombination. PMID- 25802335 TI - Opposing growth regulatory roles of protein kinase D isoforms in human keratinocytes. AB - PKD is a family of three serine/threonine kinases (PKD-1, -2, and -3) involved in the regulation of diverse biological processes including proliferation, migration, secretion, and cell survival. We have previously shown that despite expression of all three isoforms in mouse epidermis, PKD1 plays a unique and critical role in wound healing, phorbol ester-induced hyperplasia, and tumor development. In translating our findings to the human, we discovered that PKD1 is not expressed in human keratinocytes (KCs) and there is a divergence in the expression and function of other PKD isoforms. Contrary to mouse KCs, treatment of cultured human KCs with pharmacological inhibitors of PKDs resulted in growth arrest. We found that PKD2 and PKD3 are expressed differentially in proliferating and differentiating human KCs, with the former uniformly present in both compartments whereas the latter is predominantly expressed in the proliferating compartment. Knockdown of individual PKD isoforms in human KCs revealed contrasting growth regulatory roles for PKD2 and PKD3. Loss of PKD2 enhanced KC proliferative potential while loss of PKD3 resulted in a progressive proliferation defect, loss of clonogenicity and diminished tissue regenerative ability. This proliferation defect was correlated with up-regulation of CDK4/6 inhibitor p15(INK4B) and induction of a p53-independent G1 cell cycle arrest. Simultaneous silencing of PKD isoforms resulted in a more pronounced proliferation defect consistent with a predominant role for PKD3 in proliferating KCs. These data underline the importance and complexity of PKD signaling in human epidermis and suggest a central role for PKD3 signaling in maintaining human epidermal homeostasis. PMID- 25802336 TI - Protein Kinase A (PKA) Phosphorylation of Shp2 Protein Inhibits Its Phosphatase Activity and Modulates Ligand Specificity. AB - Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Src homology 2 domain-containing phosphatase (Shp2) is critical for cardiac function because mutations resulting in loss of Shp2 catalytic activity are associated with congenital cardiac defects and hypertrophy. We identified a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that Shp2 is a component of the protein kinase A anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates PKA phosphorylation of Shp2, which inhibits Shp2 phosphatase activity. We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix alphaB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. Overall, our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic beta-adrenergic stimulation and PKA activation. Therefore, although induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote this compensatory response. PMID- 25802337 TI - Proton transfers in a channelrhodopsin-1 studied by Fourier transform infrared (FTIR) difference spectroscopy and site-directed mutagenesis. AB - Channelrhodopsin-1 from the alga Chlamydomonas augustae (CaChR1) is a low efficiency light-activated cation channel that exhibits properties useful for optogenetic applications such as a slow light inactivation and a red-shifted visible absorption maximum as compared with the more extensively studied channelrhodopsin-2 from Chlamydomonas reinhardtii (CrChR2). Previously, both resonance Raman and low-temperature FTIR difference spectroscopy revealed that unlike CrChR2, CaChR1 under our conditions exhibits an almost pure all-trans retinal composition in the unphotolyzed ground state and undergoes an all-trans to 13-cis isomerization during the primary phototransition typical of other microbial rhodopsins such as bacteriorhodopsin (BR). Here, we apply static and rapid-scan FTIR difference spectroscopy along with site-directed mutagenesis to characterize the proton transfer events occurring upon the formation of the long lived conducting P2 (380) state of CaChR1. Assignment of carboxylic C=O stretch bands indicates that Asp-299 (homolog to Asp-212 in BR) becomes protonated and Asp-169 (homolog to Asp-85 in BR) undergoes a net change in hydrogen bonding relative to the unphotolyzed ground state of CaChR1. These data along with earlier FTIR measurements on the CaChR1 -> P1 transition are consistent with a two-step proton relay mechanism that transfers a proton from Glu-169 to Asp-299 during the primary phototransition and from the Schiff base to Glu-169 during P2 (380) formation. The unusual charge neutrality of both Schiff base counterions in the P2 (380) conducting state suggests that these residues may function as part of a cation selective filter in the open channel state of CaChR1 as well as other low-efficiency ChRs. PMID- 25802338 TI - The Plasmodium Class XIV Myosin, MyoB, Has a Distinct Subcellular Location in Invasive and Motile Stages of the Malaria Parasite and an Unusual Light Chain. AB - Myosin B (MyoB) is one of the two short class XIV myosins encoded in the Plasmodium genome. Class XIV myosins are characterized by a catalytic "head," a modified "neck," and the absence of a "tail" region. Myosin A (MyoA), the other class XIV myosin in Plasmodium, has been established as a component of the glideosome complex important in motility and cell invasion, but MyoB is not well characterized. We analyzed the properties of MyoB using three parasite species as follows: Plasmodium falciparum, Plasmodium berghei, and Plasmodium knowlesi. MyoB is expressed in all invasive stages (merozoites, ookinetes, and sporozoites) of the life cycle, and the protein is found in a discrete apical location in these polarized cells. In P. falciparum, MyoB is synthesized very late in schizogony/merogony, and its location in merozoites is distinct from, and anterior to, that of a range of known proteins present in the rhoptries, rhoptry neck or micronemes. Unlike MyoA, MyoB is not associated with glideosome complex proteins, including the MyoA light chain, myosin A tail domain-interacting protein (MTIP). A unique MyoB light chain (MLC-B) was identified that contains a calmodulin-like domain at the C terminus and an extended N-terminal region. MLC-B localizes to the same extreme apical pole in the cell as MyoB, and the two proteins form a complex. We propose that MLC-B is a MyoB-specific light chain, and for the short class XIV myosins that lack a tail region, the atypical myosin light chains may fulfill that role. PMID- 25802339 TI - Peroxiredoxin II is an antioxidant enzyme that negatively regulates collagen stimulated platelet function. AB - Collagen-induced platelet signaling is mediated by binding to the primary receptor glycoprotein VI (GPVI). Reactive oxygen species produced in response to collagen have been found to be responsible for the propagation of GPVI signaling pathways in platelets. Therefore, it has been suggested that antioxidant enzymes could down-regulate GPVI-stimulated platelet activation. Although the antioxidant enzyme peroxiredoxin II (PrxII) has emerged as having a role in negatively regulating signaling through various receptors by eliminating H2O2 generated upon receptor stimulation, the function of PrxII in collagen-stimulated platelets is not known. We tested the hypothesis that PrxII negatively regulates collagen stimulated platelet activation. We analyzed PrxII-deficient murine platelets. PrxII deficiency enhanced GPVI-mediated platelet activation through the defective elimination of H2O2 and the impaired protection of SH2 domain-containing tyrosine phosphatase 2 (SHP-2) against oxidative inactivation, which resulted in increased tyrosine phosphorylation of key components for the GPVI signaling cascade, including Syk, Btk, and phospholipase Cgamma2. Interestingly, PrxII-mediated antioxidative protection of SHP-2 appeared to occur in the lipid rafts. PrxII deficient platelets exhibited increased adhesion and aggregation upon collagen stimulation. Furthermore, in vivo experiments demonstrated that PrxII deficiency facilitated platelet-dependent thrombus formation in injured carotid arteries. This study reveals that PrxII functions as a protective antioxidant enzyme against collagen-stimulated platelet activation and platelet-dependent thrombosis. PMID- 25802341 TI - The fallopian tube: from back stage to center stage. AB - The recognition that a significant fraction of what historically has been classified as ovarian cancer is, in fact, a malignancy that arises in the fallopian tube mucosa comprises a paradigm shift in our understanding of these neoplasms. New etiologic and management opportunities have been created by this insight, both for women at increased genetic risk of ovarian cancer by virtue of being BRCA1/2 mutation carriers and, perhaps, for women in the general population as well. PMID- 25802340 TI - Dynamic imaging of pancreatic nuclear factor kappaB (NF-kappaB) activation in live mice using adeno-associated virus (AAV) infusion and bioluminescence. AB - Nuclear factor kappaB (NF-kappaB) is an important signaling molecule that plays a critical role in the development of acute pancreatitis. Current methods for examining NF-kappaB activation involve infection of an adenoviral NF-kappaB luciferase reporter into cell lines or electrophoretic mobility shift assay of lysate. The use of adeno-associated viruses (AAVs) has proven to be an effective method of transfecting whole organs in live animals. We examined whether intrapancreatic duct infusion of AAV containing an NF-kappaB-luciferase reporter (AAV-NF-kappaB-luciferase) can reliably measure pancreatic NF-kappaB activation. We confirmed the infectivity of the AAV-NF-kappaB-luciferase reporter in HEK293 cells using a traditional luciferase readout. Mice were infused with AAV-NF kappaB-luciferase 5 weeks before induction of pancreatitis (caerulein, 50 MUg/kg). Unlike transgenic mice that globally express NF-kappaB-luciferase, AAV infused mice showed a 15-fold increase in pancreas-specific NF-kappaB bioluminescence following 12 h of caerulein compared with baseline luminescence (p < 0.05). The specificity of the NF-kappaB-luciferase signal to the pancreas was confirmed by isolating the pancreas and adjacent organs and observing a predominant bioluminescent signal in the pancreas compared with liver, spleen, and stomach. A complementary mouse model of post-ERCP-pancreatitis also induced pancreatic NF-kappaB signals. Taken together these data provide the first demonstration that NF-kappaB activation can be examined in a live, dynamic fashion during pancreatic inflammation. We believe this technique offers a valuable tool to study real-time activation of NF-kappaB in vivo. PMID- 25802342 TI - Executive function in adolescents born <1000 g or <28 weeks: a prospective cohort study. AB - BACKGROUND AND OBJECTIVES: Extremely preterm (EP; <28 weeks) birth and extremely low birth weight (ELBW; <1000 g) are risk factors for poor cognitive outcomes, including in executive function (EF; higher-order cognitive skills necessary for goal-directed, adaptive functioning and important for academic and behavioral emotional outcomes). We aimed to (1) extend the limited data on EF in EP/ELBW survivors in adolescence compared with normal birth weight controls, and (2) determine changes in EF between ages 8 and 17 years in both groups. METHODS: Two hundred twenty-eight EP/ELBW and 166 control adolescents (mean age, 17 years) from a prospective geographical cohort were assessed with multiple EF tasks, and parent- and self-ratings of behavioral EF. The Rey Complex Figure and Behavior Rating Inventory of Executive Function parent report were also administered at age 8 years, enabling examination of change in scores between childhood and adolescence. RESULTS: EP/ELBW adolescents performed more poorly than controls in verbal processing speed, attentional control, cognitive flexibility, and goal setting (effect sizes, -0.7 to -0.2 SD), but not psychomotor reaction time. Group differences were of similar magnitude across tasks. From childhood to late adolescence, EP/ELBW children improved their accuracy of the Rey Complex Figure copy more than controls. According to parents, executive behaviors were largely stable over time in both groups. CONCLUSIONS: Adolescents born EP/ELBW have poorer EF skills across multiple domains than controls. From childhood to late adolescence, different aspects of EF improved, but others did not, underscoring the need for multidomain, longitudinal assessments in this high-risk population. PMID- 25802343 TI - Pediatric palliative care and inpatient hospital costs: a longitudinal cohort study. AB - BACKGROUND: Pediatric palliative care (PPC) improves the quality of life for children with life-limiting conditions, but the cost of care associated with PPC has not been quantified. This study examined the association between inpatient cost and receipt of PPC among high-cost inpatients. METHODS: The 10% most costly inpatients treated at a children's hospital in 2010 were studied, and factors associated with receipt of PPC were determined. Among patients dying during 2010, we compared 2010 inpatient costs between PPC recipients and nonrecipients. Inpatient costs during the 2-year follow up period between PPC recipients and nonrecipients were also compared. Patients were analyzed in 2 groups: those who died and those who survived the 2-year follow-up. RESULTS: Of 902 patients, 86 (10%) received PPC. Technology dependence, older age, multiple chronic conditions, PICU admission, and death in 2010 were independently associated with receipt of PPC. PPC recipients had increased inpatient costs compared with nonrecipients during 2010. Among patients who died during the 2-year follow-up, PPC recipients had significantly lower inpatient costs. Among survivors, PPC recipients had greater inpatient costs. When controlling for patient complexity, differences in inpatient costs were not significant. CONCLUSIONS: The relationship of PPC to inpatient costs is complex. PPC seems to lower costs among patients approaching death. Patients selectively referred to PPC who survive most often do so with chronic serious illnesses that predispose them to remain lifelong high-resource utilizers. PMID- 25802344 TI - Diagnosis of viral infections using myxovirus resistance protein A (MxA). AB - BACKGROUND: Myxoma resistance protein 1 (MxA) is induced during viral infections. MxA testing could be helpful to differentiate between viral and bacterial infections. METHODS: A prospective multicenter cohort study was performed in pediatric emergency departments. MxA blood values were measured in children with confirmed viral or bacterial infections, uninfected controls, and infections of unknown origin. First patients were used to determine MxA threshold for viral infection. The diagnostic performance of MxA was determined by using receiver operating characteristic (ROC) analysis. Sensitivities (Se), specificities (Sp), and positive and negative likelihood ratios (LR+, LR-) were calculated. RESULTS: The study included 553 children; 44 uninfected controls and 77 confirmed viral infections (mainly respiratory syncytial virus and rotavirus) were used to determine an MxA threshold at 200 ng/mL. In the 193 other patients with confirmed infections and uninfected controls (validation group), MxA was significantly higher in patients with viral than in those with bacterial infections and uninfected controls (P < .0001). The area under the ROC curve (AUC) were 0.98, with 96.4% Se and 85.4% Sp, for differentiating uninfected from virus-infected patients and 0.89, with 96.4% Se and 66.7% Sp, for differentiating bacterial and viral infections. MxA levels were significantly higher in patients with clinically diagnosed viral versus clinically diagnosed bacterial infections (P < .001). Some patients with Streptococcus pneumonia infections had high MxA levels. Additional studies are required to elucidate whether this was due to undiagnosed viral coinfections. CONCLUSIONS: MxA is viral infection marker in children, at least with RSV and rotavirus. MxA could improve the management of children with signs of infection. PMID- 25802345 TI - Vitamin B-12, folic acid, and growth in 6- to 30-month-old children: a randomized controlled trial. AB - BACKGROUND: Folate and vitamin B-12 are important for growth. Many children in low- and middle-income countries have inadequate intakes of these nutrients. METHODS: We undertook a randomized, placebo controlled double-blind trial in 1000 North Indian children, 6 to 35 months of age, providing twice the recommended daily allowance of folic acid and/or vitamin B-12, or placebo, daily for 6 months. By using a factorial design, we allocated children in a 1:1:1:1 ratio in blocks of 16. We measured the effect of giving vitamin B-12, folic acid, or the combination of both on linear and ponderal growth. We also identified predictors for growth in multiple linear regression models and effect modifiers for the effect of folic acid or vitamin B-12 supplementation on growth. RESULTS: The overall effect of either of the vitamins was significant only for weight; children who received vitamin B-12 increased their mean weight-for-age z scores by 0.07 (95% confidence interval: 0.01 to 0.13). Weight-for-age z scores and height-for-age z scores increased significantly after vitamin B-12 supplementation in wasted, underweight, and stunted children. These subgrouping variables significantly modified the effect of vitamin B-12 on growth. Vitamin B 12 status at baseline predicted linear and ponderal growth in children not receiving vitamin B-12 supplements but not in those who did (P-interaction < .001). CONCLUSIONS: We provide evidence that poor vitamin B-12 status contributes to poor growth. We recommend studies with larger doses and longer follow-up to confirm our findings. PMID- 25802346 TI - Collaborative care for children with ADHD symptoms: a randomized comparative effectiveness trial. AB - OBJECTIVES: Although many attention-deficit/hyperactivity disorder (ADHD) care models have been studied, few have demonstrated individual-level symptom improvement. We sought to test whether complementing basic collaborative care with interventions that address common reasons for symptom persistence improves outcomes for children with inattention and hyperactivity/impulsivity. METHODS: We conducted a randomized comparative effectiveness trial of 2 care management systems for 6- to 12-year-old children being evaluated for ADHD (n = 156). All participants received care management with decision support. Care managers in the enhanced care arm also were trained in motivational and parent management techniques to help parents engage in their child's treatment, address their own mental health needs, and manage challenging child behaviors. We used multivariable models to assess inattention, hyperactivity/impulsivity, oppositionality, and social skills over 1 year. RESULTS: Both treatment arms generated guideline concordant diagnostic processes in 94% of cases; 40% of children had presentations consistent with ADHD. For the entire sample, there were no differences in symptom trajectories between study arms; mean differences in change scores at 12 months were -0.14 (95% confidence interval -0.34 to 0.07) for inattention; -0.13 (-0.31 to 0.05) for hyperactivity/impulsivity; -0.09 ( 0.28 to 0.11) for oppositionality; and 3.30 (-1.23 to 7.82) for social skills. Among children with ADHD-consistent presentations, enhanced arm participants experienced superior change scores for hyperactivity/impulsivity of -0.36 (-0.69 to -0.03), oppositionality -0.40 (-0.75 to -0.05), and social skills 9.57 (1.85 to 17.28). CONCLUSIONS: Among children with ADHD-consistent presentations, addressing barriers to engagement with care and challenging child behaviors has potential to improve the effectiveness of collaborative care. PMID- 25802347 TI - Assessing sexual symptoms and side effects in adolescents. PMID- 25802348 TI - Case report of GNAS epigenetic defect revealed by a congenital hypothyroidism. AB - Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A includes multihormone resistance syndrome, Albright's hereditary osteodystrophy, and obesity and is caused by mutations in GNAS exon 1 through 13. PHP type 1B (PHP1B), caused by epigenetic changes in the GNAS locus, was initially described as an isolated resistance to PTH. Epigenetic changes in GNAS have also been reported in patients who display mild Albright's hereditary osteodystrophy or mild thyroid-stimulating hormone (TSH) resistance without mutation of GNAS. Here we report a case of PHP caused by epigenetic changes in GNAS in a patient with congenital hypothyroidism. The patient was referred for a positive newborn screening for hypothyroidism (TSH 50 mIU/L). She exhibited severe clinical features of congenital hypothyroidism. The thyroid was in place, and etiologic explorations were negative. TSH was normalized under L-thyroxin, and the symptoms disappeared, except for a macroglossia. In childhood, PHP was suspected in addition to elevated PTH, obesity, brachydactyly, and a rounded face. Sequencing, methylation analysis, and large deletion research were performed in GNAS. No genetic mutations were found. Methylation analysis revealed a broad epigenetic defect without deletion in GNAS consistent with sporadic PHP1B. The multilocus methylation analysis were negative. This finding expands the known onsets of PHP1B and emphasizes the need for a new PHP classification system. This case report has important consequences for the etiologic diagnosis of congenital hypothyroidism because it adds a new cause of the disease. PMID- 25802349 TI - Infectious and autoantibody-associated encephalitis: clinical features and long term outcome. AB - BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority. PMID- 25802351 TI - Mortality after burn injury in children: a 33-year population-based study. AB - OBJECTIVE: To assess the impact of burn injury sustained during childhood on long term mortality and to quantify any increased risk of death attributable to burn injury. METHODS: A population-based cohort study of children younger than 15 years hospitalized for burn injury in Western Australia (1980-2012) and a matched noninjured comparison group. Deidentified extraction of linked hospital morbidity and death records for the period 1980-2012 were provided by the Western Australian Data Linkage System. An inception cohort (1980-2012) of burn cases younger than 15 years of age when hospitalized for a first burn injury (n = 10,426) and a frequency matched noninjured comparison cohort (n = 40,818) were identified. Survival analysis was conducted by using the Kaplan-Meier method and Cox proportional hazards regression. Mortality rate ratios and attributable risk percent adjusted for sociodemographic and preexisting heath factors were generated. RESULTS: The median follow-up time for the pediatric burn cohort was 18.1 years after discharge. The adjusted all-cause mortality rate ratios for burn injury was 1.6 (95% confidence interval: 1.3-2.0); children with burn injury had a 1.6 times greater rate of mortality than those with no injury. The index burn injury was estimated to account for 38% (attributable risk percent) of all recorded deaths in the burn injury cohort during the study period. CONCLUSIONS: Burn injury sustained by children is associated with an increased risk of long term all-cause mortality. Estimates of the total mortality burden based on in hospital deaths alone underestimates the true burden from burn injury. PMID- 25802350 TI - Congenital left paraduodenal hernia causing chronic abdominal pain and abdominal catastrophe. AB - Paraduodenal hernias are the most common type of congenital internal hernia. Because of its overall rare incidence, this entity is often overlooked during initial assessment of the patient. Lack of specific diagnostic criteria also makes diagnosis exceedingly difficult, and the resulting diagnostic delays can lead to tragic outcomes for patients. Despite these perceived barriers to timely diagnosis, there may be specific radiographic findings that, when combined with the appropriate constellation of clinical symptoms, would aid in diagnosis. This patient first presented at 8 years of age with vague symptoms of postprandial emesis, chronic abdominal pain, nausea, and syncope. Over the span of 6 years he was evaluated 2 to 3 times a year with similar complaints, all of which quickly resolved spontaneously. He underwent multiple laboratory, imaging, and endoscopic studies, which were nondiagnostic. It was not until he developed signs of a high grade obstruction and extremis that he was found to have a large left paraduodenal hernia that had volvulized around the superior mesenteric axis. This resulted in the loss of the entire superior mesenteric axis distribution of the small and large intestine and necrosis of the duodenum. In cases of chronic intermittent obstruction without clear etiology, careful attention and consideration should be given to the constellation of symptoms, imaging studies, and potential use of diagnostic laparoscopy. Increased vigilance by primary care and consulting physicians is necessary to detect this rare but readily correctable condition. PMID- 25802352 TI - Fatigue in child chronic health conditions: a systematic review of assessment instruments. AB - BACKGROUND AND OBJECTIVE: Fatigue is common in chronic health conditions in childhood, associated with decreased quality of life and functioning, yet there are limited data to compare assessment instruments across conditions and childhood development. Our objective was to describe fatigue assessment instruments used in children with chronic health conditions and critically appraise the evidence for the measurement properties of identified instruments. METHODS: Data sources included Medline, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO (using the EBSCOhost platform). Study selection included quantitative assessment of fatigue in children with health conditions. Data extraction was as follows: (1) study design, participant and fatigue instruments, (2) measurement properties of fatigue instruments, (3) methodological quality of included studies, and (4) synthesis of the quality of evidence across studies for the measurement properties of fatigue instruments. RESULTS: Twenty fatigue assessment instruments were identified (12 child reports, 7 parent reports, 1 staff report), used in 89 studies. Fatigue was assessed in over 14 health conditions, most commonly in children with cancer and chronic fatigue syndrome. Evidence for the measurement properties of instruments varied, and overall quality was low. Two fatigue instruments demonstrated strong measurement properties for use in children with diverse health conditions and children with cancer. CONCLUSIONS: The review is limited to children younger than 18 years and results are specific to health conditions described, limiting generalizability of findings to other populations. Evidence for the measurement properties of fatigue instruments varied according to the population in which instruments were used and informant. Further evidence is required for assessment of fatigue in younger children, and children with particular health conditions. PMID- 25802353 TI - The frontiers of research about attention-deficit/hyperactivity disorder. PMID- 25802355 TI - New pediatricians: first jobs and future workplace goals. AB - BACKGROUND AND OBJECTIVES: Concern is often expressed about the satisfaction of new physicians and the potential match of their workplace goals with available positions. We studied the interface of desired professional activities with actual initial positions. METHODS: Survey study of all general pediatricians taking the 2012 General Pediatrics Certifying Examination. RESULTS: Of the 5210 who sat for the General Pediatrics Certifying Examination, 5163 (>99%) completed the survey. Of the total respondents, 45% self- identified as general pediatricians (N = 2327). Of those who completed training <2 years ago (N = 1365), most were currently engaged in clinical care (87%; N = 1190). The most important factor, cited most frequently by both men and women, in the choice of their first job was lifestyle and spousal or family considerations. Most (83%; N = 977) reported that the allocation of time for specific duties in their current position was consistent with their goals, with no differences between men and women. Most had no desire for inpatient activity. CONCLUSIONS: Despite concerns about young general pediatricians being able to find positions that meet their career goals, most were in jobs that approximated their desired allocation of professional time and focus of clinical work. PMID- 25802354 TI - Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial. AB - BACKGROUND AND OBJECTIVES: Atopic dermatitis (AD) primarily affects infants and young children. Although topical corticosteroids (TCSs) are often prescribed, noncorticosteroid treatments are needed because compliance with TCSs is poor due to concerns about their side effects. In this longest and largest intervention study ever conducted in infants with mild-to-moderate AD, pimecrolimus 1% cream (PIM) was compared with TCSs. METHODS: A total of 2418 infants were enrolled in this 5-year open-label study. Infants were randomized to PIM (n = 1205; with short-term TCSs for disease flares) or TCSs (n = 1213). The primary objective was to compare safety; the secondary objective was to document PIM's long-term efficacy. Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear). RESULTS: Both PIM and TCSs had a rapid onset of action with >50% of patients achieving treatment success by week 3. After 5 years, >85% and 95% of patients in each group achieved overall and facial treatment success, respectively. The PIM group required substantially fewer steroid days than the TCS group (7 vs 178). The profile and frequency of adverse events was similar in the 2 groups; in both groups, there was no evidence for impairment of humoral or cellular immunity. CONCLUSIONS: Long-term management of mild-to-moderate AD in infants with PIM or TCSs was safe without any effect on the immune system. PIM was steroid-sparing. The data suggest PIM had similar efficacy to TCS and support the use of PIM as a first-line treatment of mild-to moderate AD in infants and children. PMID- 25802356 TI - The right to know and genetic testing. PMID- 25802357 TI - Maternal and neonatal outcomes in nulliparous women undergoing non-medically indicated induction of labour or expectant management at 38-41 weeks gestation. PMID- 25802358 TI - Weight-loss diets only work when you follow them. PMID- 25802359 TI - Perventricular device closure of a doubly committed subarterial ventricular septal defect. AB - A doubly committed subarterial ventricular septal defect (VSD) used to be a contraindication for device closure. Perventricular device closure has been widely applied in China in the past years, but not in a doubly committed subarterial VSD. Chinese surgeons are now beginning to try this procedure also in a doubly committed subarterial VSD in selected patients. The technique of closure of the perimembranous defect has been described previously in this journal, but we hereby present some additional information on this procedure performed in a doubly committed subarterial VSD. PMID- 25802360 TI - Cigarette smoke induces cell motility via platelet-activating factor accumulation in breast cancer cells: a potential mechanism for metastatic disease. AB - Most cancer deaths are a result of metastasis rather than the primary tumor. Although cigarette smoking has been determined as a risk factor for several cancers, its role in metastasis has not been studied in detail. We propose that cigarette smoking contributes to metastatic disease via inhibition of breast cancer cell platelet-activating factor acetylhydrolase (PAF-AH), resulting in PAF accumulation and a subsequent increase in cell motility. We studied several breast cell lines, including immortalized mammary epithelial cells (MCF-10A), luminal A hormone positive MCF-7, basal-like triple negative MDA-MB-468, and claudin-low triple-negative highly metastatic MDA-MB-231 breast tumor cells. We exposed cells to cigarette smoke extract (CSE) for up to 48 h. CSE inhibited PAF AH activity, increased PAF accumulation, and increased cell motility in MDA-MB 231 metastatic triple negative breast cancer cells. The calcium-independent phospholipase A2 (iPLA2) inhibitor, (S) bromoenol lactone ((S)-BEL) was used to prevent the accumulation of PAF and further prevented the increase in cell motility seen previously when cells were exposed to CSE. Thus, iPLA2 or PAF may represent a therapeutic target to manage metastatic disease, particularly in triple-negative breast cancer patients who smoke. PMID- 25802361 TI - High salt diet increases the pressor response to stress in female, but not male ETB-receptor-deficient rats. AB - Acute stress in both rodents and humans causes a transient rise in blood pressure associated with an increase in plasma endothelin-1 (ET-1). High salt (HS) intake also increases ET-1 production, and interestingly, blunts the pressor response to acute air jet stress in rats. We previously reported that female rats lacking functional ETB receptors everywhere except sympathetic nerves (ETB def) had a greater degree of hypertension in response to a HS diet compared to their male counterparts when measured by the tail cuff method. However, we now report that salt-induced hypertension is not different between sexes when measured by telemetry. Therefore, additional experiments were designed to test the hypothesis that female ETB def rats are more sensitive to acute stress when on a HS diet. The pressor response, measured by telemetry, to acute air jet stress was similar between male transgenic control (Tg control) and ETB def rats following chronic HS intake. In contrast, female ETB def rats had a significantly greater pressor response (about twofold higher) than female or male Tg control or male ETB def rats maintained on HS, a finding that cannot be explained by increased vascular reactivity to ET-1 in female rats as we observed that male ETB def rats had a greater pressor response to i.v. infusion of ET-1 compared to females. Furthermore, HS feeding exacerbated the pressor response to ET-1 in both male and female ETB def rats. Given our previous studies demonstrating that the ETA receptor functions to reduce the pressor response to acute stress, these findings further support a role for the ET receptor system in the pressor response to acute stress and that female rats have reduced ETA receptor activity when on a HS diet compared to males. PMID- 25802362 TI - Increased LV apical untwist during preload reduction in healthy humans: an echocardiographic speckle tracking study during lower body negative pressure. AB - We sought to investigate the effect of reduced preload on left ventricle (LV) untwist and early diastolic filling in healthy individuals. Twelve healthy men, 22 (22, 23) years of age, were examined at rest and during applied lower body negative pressure (LBNP) of -20 mmHg and -40 mmHg, respectively. Regional untwist and untwist rate during IVRT were calculated at LV basal, papillary, subpapillary, and apical short axis levels by two dimensional speckle tracking echocardiography. Left ventricle early diastolic filling was assessed by transmitral E-wave (E) peak velocity by pulsed Doppler and flow propagation velocity (Vp) by color M-mode Doppler and early diastolic pulsed Doppler tissue velocities (E') from septal and lateral mitral annulus. From rest to LBNP -40 mmHg, the LV untwist and untwist rate at subpapillary level increased from 2.3 (1.4, 3.5) to 4.5 (3.1, 7.6) degrees and from -36 (-51, -25) to -69 (-127, -42) degrees /s (P < 0.001, P = 0.003), respectively, while apical untwist and untwist rate increased from 3.9 (2.3, 4.3) to 7.6 (6.4, 10.5) degrees and from -51 (-69, 40) to -118 (-170, -84) degrees /s (P < 0.001, P < 0.001), respectively. Since untwist and untwist rate at the basal level were unchanged, this created markedly larger base to apical untwist and untwist rate gradients from rest to LBNP -40 mmHg. E, Vp, and E' were reduced by 34, 32, and 39%, respectively. LV untwist and untwist rate during IVRT were increased at apical levels, which might be a physiological mechanism to minimize the impairment in LV early diastolic filling during preload reduction. PMID- 25802364 TI - Family-focused treatment improves attenuated psychotic symptoms, but does not differ from brief treatment in negative symptoms and social functioning in ultra high risk patients aged 12-35 years. PMID- 25802365 TI - Rates of violent crimes decrease during periods with antipsychotics and mood stabilisers compared to periods without. PMID- 25802363 TI - International Society of Human and Animal Mycology (ISHAM)-ITS reference DNA barcoding database--the quality controlled standard tool for routine identification of human and animal pathogenic fungi. AB - Human and animal fungal pathogens are a growing threat worldwide leading to emerging infections and creating new risks for established ones. There is a growing need for a rapid and accurate identification of pathogens to enable early diagnosis and targeted antifungal therapy. Morphological and biochemical identification methods are time-consuming and require trained experts. Alternatively, molecular methods, such as DNA barcoding, a powerful and easy tool for rapid monophasic identification, offer a practical approach for species identification and less demanding in terms of taxonomical expertise. However, its wide-spread use is still limited by a lack of quality-controlled reference databases and the evolving recognition and definition of new fungal species/complexes. An international consortium of medical mycology laboratories was formed aiming to establish a quality controlled ITS database under the umbrella of the ISHAM working group on "DNA barcoding of human and animal pathogenic fungi." A new database, containing 2800 ITS sequences representing 421 fungal species, providing the medical community with a freely accessible tool at http://www.isham.org/ and http://its.mycologylab.org/ to rapidly and reliably identify most agents of mycoses, was established. The generated sequences included in the new database were used to evaluate the variation and overall utility of the ITS region for the identification of pathogenic fungi at intra-and interspecies level. The average intraspecies variation ranged from 0 to 2.25%. This highlighted selected pathogenic fungal species, such as the dermatophytes and emerging yeast, for which additional molecular methods/genetic markers are required for their reliable identification from clinical and veterinary specimens. PMID- 25802368 TI - From medical students to fellows, a focus on education and training. PMID- 25802369 TI - Bipolar II--not just Bipolar 'lite'. PMID- 25802376 TI - Madness at movies: psychopathology in 1968 Pasolini's Theorem. PMID- 25802366 TI - Network analysis of postharvest senescence process in citrus fruits revealed by transcriptomic and metabolomic profiling. AB - Citrus (Citrus spp.), a nonclimacteric fruit, is one of the most important fruit crops in global fruit industry. However, the biological behavior of citrus fruit ripening and postharvest senescence remains unclear. To better understand the senescence process of citrus fruit, we analyzed data sets from commercial microarrays, gas chromatography-mass spectrometry, and liquid chromatography-mass spectrometry and validated physiological quality detection of four main varieties in the genus Citrus. Network-based approaches of data mining and modeling were used to investigate complex molecular processes in citrus. The Citrus Metabolic Pathway Network and correlation networks were constructed to explore the modules and relationships of the functional genes/metabolites. We found that the different flesh-rind transport of nutrients and water due to the anatomic structural differences among citrus varieties might be an important factor that influences fruit senescence behavior. We then modeled and verified the citrus senescence process. As fruit rind is exposed directly to the environment, which results in energy expenditure in response to biotic and abiotic stresses, nutrients are exported from flesh to rind to maintain the activity of the whole fruit. The depletion of internal substances causes abiotic stresses, which further induces phytohormone reactions, transcription factor regulation, and a series of physiological and biochemical reactions. PMID- 25802367 TI - A Genome-Wide Chronological Study of Gene Expression and Two Histone Modifications, H3K4me3 and H3K9ac, during Developmental Leaf Senescence. AB - The genome-wide abundance of two histone modifications, H3K4me3 and H3K9ac (both associated with actively expressed genes), was monitored in Arabidopsis (Arabidopsis thaliana) leaves at different time points during developmental senescence along with expression in the form of RNA sequencing data. H3K9ac and H3K4me3 marks were highly convergent at all stages of leaf aging, but H3K4me3 marks covered nearly 2 times the gene area as H3K9ac marks. Genes with the greatest fold change in expression displayed the largest positively correlated percentage change in coverage for both marks. Most senescence up-regulated genes were premarked by H3K4me3 and H3K9ac but at levels below the whole-genome average, and for these genes, gene expression increased without a significant increase in either histone mark. However, for a subset of genes showing increased or decreased expression, the respective gain or loss of H3K4me3 marks was found to closely match the temporal changes in mRNA abundance; 22% of genes that increased expression during senescence showed accompanying changes in H3K4me3 modification, and they include numerous regulatory genes, which may act as primary response genes. PMID- 25802385 TI - Investigating the effect of glucose on aortic pulse wave velocity using pancreatic clamping methodology. AB - Aortic stiffness, determined by carotid-femoral pulse wave velocity (cfPWV), independently predicts cardiovascular outcomes. Recent studies suggest that glucose levels influence arterial stiffness indices. It is not clear, however, whether glucose affects cfPWV independently of glucoregulatory hormones. The aim of this study was to utilize a pancreatic clamping approach to determine whether plasma glucose independently predicts cfPWV. Healthy participants (N = 10) underwent pancreatic clamping to control glucose at varying concentrations using a 20% dextrose infusion while suppressing endogenous glucagon, insulin, and growth hormone by octreotide and replacing the hormones intravenously to achieve basal concentrations. Tonometric cfPWV, blood pressure, heart rate, plasma glucose, glucagon, insulin, growth hormone, and vasoactive biomarkers were measured. Plasma glucose levels of 150 mg/dl at 1 hr and 200 mg/dl at 2 hr postbaseline were achieved. There were no significant changes in cfPWV (5.8 m/s at 0 hr, 5.9 m/s at 1 hr, and 5.9 m/s at 2 hr) with increased glucose levels. There were small increases in insulin secretion. A definitive role for glucose in cfPWV modulation was not determined; there is a potential role for insulin as a cfPWV modulator. Continued efforts in clarifying the independent roles of glucose and insulin can elucidate novel vessel-related targets for cardiovascular disease prevention and management in patients with impaired glucose tolerance and diabetes. PMID- 25802387 TI - Carcinoid heart disease. PMID- 25802386 TI - Assessment of the ABC/2 Method of Epidural Hematoma Volume Measurement as Compared to Computer-Assisted Planimetric Analysis. AB - BACKGROUND AND OBJECTIVE: Epidural hematoma volume (EDHV) is an independent predictor of prognosis in patients with epidural hematoma (EDH) and plays a central role in treatment decision making. This study's objective was to determine the accuracy and reliability of the widely used volume measurement method ABC/2 in estimating EDHV by comparing it to the computer-assisted planimetric method. METHODS: A data set of computerized tomography (CT) scans of 35 patients with EDH was evaluated to determine the accuracy of ABC/2 method, using computer-assisted planimetric technique to establish the reference criterion of EDHV for each patient. Another data set was constructed by randomly selecting 5 patients then replicating each case twice to yield 15 patients. Intra and interobserver reliability were evaluated by asking four observers to independently estimate EDHV for the latter data set using the ABC/2 method. RESULTS: Estimation of EDHV using the ABC/2 method showed high intra- and interobserver reliability (intra-class correlation coefficient = .99). These estimates were closely correlated with planimetric measures (r = .99). But the ABC/2 method generally overestimated EDHV, especially in the nonellipsoid-like group. The difference between the ABC/2 measures and planimetric measures was statistically significant (p < .05). CONCLUSIONS: The ABC/2 method could be used for EDHV measurement, which would contribute to treatment decision making as well as clinical outcome prediction. However, clinicians should be aware that the ABC/2 method results in a general volume overestimation. Future studies focusing on justification of the technique to improve its accuracy would be of practical value. PMID- 25802384 TI - Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping. AB - Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease. PMID- 25802388 TI - Lost guidewire protrudes through the heart and chest. PMID- 25802389 TI - Vital exhaustion: ready for prime time? PMID- 25802391 TI - Dynamic auscultation in hypertrophic obstructive cardiomyopathy: what can we learn from a murmur? PMID- 25802392 TI - Intracardiac echocardiography unveils large thrombus on a restenotic TAVR prosthesis more than 6 years after implantation. PMID- 25802393 TI - Transthoracic echocardiogram-guided agitated-saline aortography for post-TAVR peri-prosthetic leak evaluation. PMID- 25802390 TI - The effect of statin therapy on heart failure events: a collaborative meta analysis of unpublished data from major randomized trials. AB - AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not. PMID- 25802396 TI - Correction. PMID- 25802394 TI - Sleep apnoea in acute heart failure: fluid in flux. PMID- 25802397 TI - Correction. PMID- 25802398 TI - Correction. PMID- 25802399 TI - Severe flare as a predictor of poor outcome in ankylosing spondylitis: a cohort study using questionnaire and routine data linkage. AB - OBJECTIVE: To explore severe flare and constant disease pattern (no periods of remission) in AS as predictors of poor outcomes [impaired function, unemployment/early retirement, work impairment, anti-TNF, surgery, frequent general practitioner (GP) visits, depression and anxiety]. METHODS: Three hundred and forty-eight AS patients completed questionnaires about their experience with disease flares. Questionnaire data were linked to electronic medical records to examine visits to GPs and hospital admission data. Outcomes were stratified in two ways: self-reported experience of severe flare and constant disease pattern using the flare illustration tool. RESULTS: The majority of patients (72%, 208/289) experienced flare pre-diagnosis. Severe flares were reported by 58% (202/348) of participants (self-report); of these, 195 responded about earliest flares and 69% (135/195) of severe flare patients experienced flares pre diagnosis. Patients who self-reported severe flares had worse function, disease activity, work impairment and symptoms of anxiety and depression, were less likely to be employed and had more GP encounters per year compared with those who never reported severe flares. Participants who reported constant unremitting disease on the flare illustration tool had worse disease activity, impaired function and work impairment and were more likely to smoke compared with those with intermittent disease. Analysis showed a relationship between self-report of severe flare and subsequent depression, impaired function, increased disease activity and work limitations. CONCLUSION: Severe flare is associated with poor outcomes such as work impairment and impaired function. The onset of severe flare early in the disease course may be a risk factor for later poor outcome and this group could benefit from targeted early aggressive treatment to improve prognosis. PMID- 25802401 TI - Salivary mucins induce a Toll-like receptor 4-mediated pro-inflammatory response in human submandibular salivary cells: are mucins involved in Sjogren's syndrome? AB - OBJECTIVES: A hallmark characteristic of SS patients is the ectopic presence of the mucins MUC5B and MUC7 in the extracellular matrix of salivary glands that have lost apical-basolateral acinar-cell polarity. This study aims to determine whether exogenous salivary mucins induce gene expression of pro-inflammatory cytokines, as well as to evaluate whether the Toll-like receptor-4 (TLR4) pathway is involved in this response. METHODS: Differentiated human submandibular gland (HSG) cells were stimulated with mucins or oligosaccharide residues at different concentrations and for different periods of time. The expression of pro inflammatory cytokines and their receptors was determined by semi-quantitative real time PCR (sqPCR). TLR4-mediated responses induced by mucin were evaluated with the Toll-IL-1 receptor domain containing adaptor protein (TIRAP) inhibitory peptide or using anti-hTLR4 blocking antibody. TLR4-receptor expression was also determined in SS patients, controls and HSG cells. RESULTS: Mucins induced a significant increase in CXCL8, TNF-alpha, IFN-alpha, IFN-beta, IL-6 and IL-1beta, but not B cell activating factor (BAFF). Cytokine induction was mediated by TLR4, as shown using TIRAP or using anti-hTLR4 antibody. Sugar residues present in MUC5B, such as sulpho-Lewis (SO3-3Galbeta1-3GlcNAc), also induced cytokines. Unexpectedly, mucins induced MUC5B, but not MUC7 expression. CONCLUSION: Salivary mucins were recognized by TLR4 in epithelial cells initiating a pro-inflammatory response that could attract inflammatory cells to amplify and perpetuate inflammation and thereby contribute to the development of a chronic state characteristic of SS. The ectopic localization of MUC5B and MUC7 in the salivary gland extracellular matrix from SS patients and the current results reveal the importance of salivary epithelial cells in innate immunity, as well as in SS pathogenesis. PMID- 25802400 TI - The impact of rheumatoid arthritis on work capacity in Chinese patients: a cross sectional study. AB - OBJECTIVE: To evaluate the impact of RA on work capacity and identify factors related to work capacity impairment in patients with RA. METHODS: A cross sectional multicentre study was performed in 21 tertiary care hospitals across China. A consecutive sample of 846 patients with RA was recruited, of which 589 patients of working age at disease onset constituted the study population. Information on the socio-demographic, clinical, working and financial conditions of the patients was collected. Logistic regression analyses were used to identify factors associated with work capacity impairment. RESULTS: The rate of work capacity impairment was 48.0% in RA patients with a mean disease duration of 60 months (interquartile range 14-134 months), including 11.7% leaving the labour force early, 33.6% working reduced hours and 2.7% changing job. Multivariable logistic regression analysis showed that reduced working hours was significantly related to current smoking [odds ratio (OR) 2.07 (95% CI 1.08, 3.97)], no insurance [OR 1.94 (95% CI 1.20, 3.12)], in manual labour [OR 2.66 (95% CI 1.68, 4.20)] and higher HAQ score [OR 2.22 (95% CI 1.36, 3.60)]. There was an association of current smoking [OR 3.75 (95% CI 1.54, 9.15)], in manual labour [OR 2.33 (95% CI 1.17, 4.64)], longer disease duration [OR 1.01 (95% CI 1.00, 1.01)] and lower BMI [OR 0.90 (95% CI 0.82, 0.99)] with leaving the labour force early. CONCLUSION: There is a substantial impact of RA on the work capacity of patients in China. Social-demographic, disease- and work-related factors are all associated with work capacity impairment. PMID- 25802402 TI - The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene. AB - Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder. PMID- 25802404 TI - Effect of metformin on progression of head and neck cancers, occurrence of second primary cancers, and cause-specific survival. AB - BACKGROUND: This study aimed to investigate the effect of metformin on progression of head and neck cancers, occurrence of second primary cancers, and cause-specific survival. METHODS: This study analyzed a retrospective cohort of 1,151 consecutive patients with head and neck squamous cell carcinoma who were treated at our hospital. Patients were divided into three groups: nondiabetic, nonmetformin, and metformin. Clinical characteristics, recurrence of index head and neck cancer, occurrence of second primary cancer, and survival were compared among the different groups. RESULTS: Of 1,151 patients, 99 (8.6%) were included in the metformin group, 79 (6.8%) were in the nonmetformin group, and 973 (84.5%) were in the nondiabetic group. Diabetic status and metformin exposure had no significant impact on index head and neck cancer recurrence or second primary cancer development (p > .2). The nonmetformin group showed relatively lower overall (p = .017) and cancer-specific (p = .054) survival rates than the other groups in univariate analyses, but these results were not confirmed in multivariate analyses. CONCLUSION: Metformin use did not show beneficial effects on index tumor progression, second primary cancer occurrence, and cause-specific survival in patients with head and neck cancer compared with nonmetformin users and nondiabetic patients. PMID- 25802403 TI - Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2. AB - The ETS factor ETV2 (aka ER71) is essential for the generation of the blood and vascular system, as ETV2 deficiency leads to a complete block in blood and endothelial cell formation and embryonic lethality in the mouse. However, the ETV2-mediated gene regulatory network and signaling governing hematopoietic and endothelial cell development are poorly understood. Here, we map ETV2 global binding sites and carry out in vitro differentiation of embryonic stem cells, and germ line and conditional knockout mouse studies to uncover mechanisms involved in the hemangiogenic fate commitment from mesoderm. We show that ETV2 binds to enhancers that specify hematopoietic and endothelial cell lineages. We find that the hemangiogenic progenitor population in the developing embryo can be identified as FLK1(high)PDGFRalpha(-). Notably, these hemangiogenic progenitors are exclusively sensitive to ETV2-dependent FLK1 signaling. Importantly, ETV2 turns on other Ets genes, thereby establishing an ETS hierarchy. Consequently, the hematopoietic and endothelial cell program initiated by ETV2 is maintained partly by other ETS factors through an ETS switching mechanism. These findings highlight the critical role that transient ETV2 expression plays in the regulation of hematopoietic and endothelial cell lineage specification and stability. PMID- 25802405 TI - Breast cancer with brain metastases: clinicopathologic features, survival, and paired biomarker analysis. AB - BACKGROUND: The aim of this study was to describe clinicopathologic features of patients with breast cancer brain metastasis (BCBM); to evaluate survival after diagnosis of BCBM; and to compare estrogen receptor (ER), progesterone receptor (PR), and HER2 expression in the paired primary and brain tumors. MATERIALS AND METHODS: We identified 140 consecutive patients who underwent craniotomy for BCBM (either for diagnostic purpose or with therapeutic intent) at the University of Texas MD Anderson Cancer Center between 2002 and 2009. RESULTS: Most patients had invasive ductal histology (91%), grade 3 tumors (67%), and positive axillary lymph node (64%). Of the tumors, 56% were ER-negative, 62% were PR-negative, 44% were HER2-positive, and 28% were triple negative (TN). Brain metastasis (BM) was solitary in 51% of patients. Median interval from breast cancer diagnosis to BM was 46 months; median survival after BM was 14.1 months. In the univariate analysis, younger age, solitary brain metastasis, and ER or PR positivity in the breast tumors were associated with longer survival. There was a statistical trend toward increased survival in HER2-positive patients compared with HER2-negative patients (18 vs. 11 months). In the multivariate analysis, predictors for longer survival included younger age, solitary brain lesion, and HER2 positivity in the breast cancer. Biomarkers were evaluated in paired primary and brain tumors in 35 patients for ER status, 34 for PR status, and 36 for HER2 status. Discordant rates were 28% for ER, 20% for PR, and 3% for HER2. CONCLUSION: Compared with unselected breast cancer patients at the same institution, patients with breast cancer who had brain metastases had a higher proportion of hormone receptor negative, HER2-positive, and TN tumors. Younger age, solitary brain lesion, and HER2 expression were independent predictors of better survival in patients with BCBM. HER2 status was highly concordant between the paired primary and brain tumors, whereas changes of ER and PR status occurred in a substantial proportion of the patients. These findings are important for making effective treatment decisions for patients with BCBM. PMID- 25802407 TI - Environmental RNAi in herbivorous insects. AB - Environmental RNAi (eRNAi) is a sequence-specific regulation of endogenous gene expression in a receptive organism by exogenous double-stranded RNA (dsRNA). Although demonstrated under artificial dietary conditions and via transgenic plant presentations in several herbivorous insects, the magnitude and consequence of exogenous dsRNA uptake and the role of eRNAi remains unknown under natural insect living conditions. Our analysis of coleopteran insects sensitive to eRNAi fed on wild-type plants revealed uptake of plant endogenous long dsRNAs, but not small RNAs. Subsequently, the dsRNAs were processed into 21 nt siRNAs by insects and accumulated in high quantities in insect cells. No accumulation of host plant derived siRNAs was observed in lepidopteran larvae that are recalcitrant to eRNAi. Stability of ingested dsRNA in coleopteran larval gut followed by uptake and transport from the gut to distal tissues appeared to be enabling factors for eRNAi. Although a relatively large number of distinct coleopteran insect processed plant-derived siRNAs had sequence complementarity to insect transcripts, the vast majority of the siRNAs were present in relatively low abundance, and RNA-seq analysis did not detect a significant effect of plant derived siRNAs on insect transcriptome. In summary, we observed a broad genome wide uptake of plant endogenous dsRNA and subsequent processing of ingested dsRNA into 21 nt siRNAs in eRNAi-sensitive insects under natural feeding conditions. In addition to dsRNA stability in gut lumen and uptake, dosage of siRNAs targeting a given insect transcript is likely an important factor in order to achieve measurable eRNAi-based regulation in eRNAi-competent insects that lack an apparent silencing amplification mechanism. PMID- 25802406 TI - Migrant health in cancer: outcome disparities and the determinant role of migrant specific variables. AB - BACKGROUND: Multiethnic societies face challenges in delivering evidence-based culturally competent health care. This study compared health-related quality of life and psychological morbidity in a hospital-based sample of first-generation migrants and Australian-born Anglo cancer patients, controlling for potential confounders related to migrant status. Further, it explored the relative contribution of ethnicity versus migrant-related variables. METHODS: Eligible participants, recruited via 16 oncology clinics in Australia, included those over the age of 18, diagnosed with cancer (any type or stage) within the previous 12 months and having commenced treatment at least 1 month previously. RESULTS: In total, 571 migrant patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. In multiple linear regression models adjusted for age, sex, education, marital status, socioeconomic status, time since diagnosis, and type of cancer, migrants had clinically significantly worse health-related quality of life (HRQL; 3.6-7.3 points on FACT-G, p < .0001), higher depression and anxiety (both p < .0001), and higher incidence of clinical depression (p < .0001) and anxiety (p = .003) than Anglo-Australians. Understanding the health system (p < .0001 for each outcome) and difficulty communicating with the doctor (p = .04 to .0001) partially mediated the impact of migrancy. In migrant-only analyses, migrant-related variables (language difficulty and poor understanding of the health system), not ethnicity, predicted outcomes. CONCLUSION: Migrants who develop cancer have worse psychological and HRQL outcomes than Anglo-Australians. Potential targets for intervention include assistance in navigating the health system, translated information, and cultural competency training for health professionals. PMID- 25802411 TI - Moments of zeta and correlations of divisor-sums: I. AB - We examine the calculation of the second and fourth moments and shifted moments of the Riemann zeta-function on the critical line using long Dirichlet polynomials and divisor correlations. Previously, this approach has proved unsuccessful in computing moments beyond the eighth, even heuristically. A careful analysis of the second and fourth moments illustrates the nature of the problem and enables us to identify the terms that are missed in the standard application of these methods. PMID- 25802410 TI - Seasonal variation in chemistry, but not morphology, in roots of Quercus robur growing in different soil types. AB - Patterns of root traits among different root orders and their variation across seasons are of considerable importance for soil resource acquisition and partitioning in forest ecosystems. We evaluated whether morphological, anatomical and biochemical traits varied among root orders of Quercus robur (L.) sampled across spring, summer and fall seasons and growing in two different soil types with contrasting site fertility. We found no consistent differences in root diameter and specific root length in relation to soil type or growing season. There was, however, a strong seasonal variation in patterns of nitrogen (N) concentration among root orders. During spring and summer, N concentration was highest in the most distal, absorptive portion of the root system. At the end of the growing season, we observed a sharp decline in the N concentration of these lower-order, absorptive roots and an increase in N concentration of the higher order, transport roots. The specific mechanisms driving the seasonally changing N concentration remain unclear but are likely related to different functions of lower-order roots for absorption and higher-order roots for structure and storage. Future work should identify how common the observed seasonal changes in N concentration are across species and determine what specific environmental cues plants or roots use to trigger shifts in resource allocation within the root branching hierarchy. PMID- 25802408 TI - Comparison of splice sites reveals that long noncoding RNAs are evolutionarily well conserved. AB - Large-scale RNA sequencing has revealed a large number of long mRNA-like transcripts (lncRNAs) that do not code for proteins. The evolutionary history of these lncRNAs has been notoriously hard to study systematically due to their low level of sequence conservation that precludes comprehensive homology-based surveys and makes them nearly impossible to align. An increasing number of special cases, however, has been shown to be at least as old as the vertebrate lineage. Here we use the conservation of splice sites to trace the evolution of lncRNAs. We show that >85% of the human GENCODE lncRNAs were already present at the divergence of placental mammals and many hundreds of these RNAs date back even further. Nevertheless, we observe a fast turnover of intron/exon structures. We conclude that lncRNA genes are evolutionary ancient components of vertebrate genomes that show an unexpected and unprecedented evolutionary plasticity. We offer a public web service (http://splicemap.bioinf.uni-leipzig.de) that allows to retrieve sets of orthologous splice sites and to produce overview maps of evolutionarily conserved splice sites for visualization and further analysis. An electronic supplement containing the ncRNA data sets used in this study is available at http://www.bioinf.uni-leipzig.de/publications/supplements/12-001. PMID- 25802409 TI - Tupaia small RNAs provide insights into function and evolution of RNAi-based transposon defense in mammals. AB - Argonaute proteins comprising Piwi-like and Argonaute-like proteins and their guiding small RNAs combat mobile DNA on the transcriptional and post transcriptional level. While Piwi-like proteins and associated piRNAs are generally restricted to the germline, Argonaute-like proteins and siRNAs have been linked with transposon control in the germline as well as in the soma. Intriguingly, evolution has realized distinct Argonaute subfunctionalization patterns in different species but our knowledge about mammalian RNA interference pathways relies mainly on findings from the mouse model. However, mice differ from other mammals by absence of functional Piwil3 and expression of an oocyte specific Dicer isoform. Thus, studies beyond the mouse model are required for a thorough understanding of function and evolution of mammalian RNA interference pathways. We high-throughput sequenced small RNAs from the male Tupaia belangeri germline, which represents a close outgroup to primates, hence phylogenetically links mice with humans. We identified transposon-derived piRNAs as well as siRNAs clearly contrasting the separation of piRNA- and siRNA-pathways into male and female germline as seen in mice. Genome-wide analysis of tree shrew transposons reveal that putative siRNAs map to transposon sites that form foldback secondary structures thus representing suitable Dicer substrates. In contrast piRNAs target transposon sites that remain accessible. With this we provide a basic mechanistic explanation how secondary structure of transposon transcripts influences piRNA- and siRNA-pathway utilization. Finally, our analyses of tree shrew piRNA clusters indicate A-Myb and the testis-expressed transcription factor RFX4 to be involved in the transcriptional regulation of mammalian piRNA clusters. PMID- 25802412 TI - Number fields and function fields: coalescences, contrasts and emerging applications. AB - The similarity between the density of the primes and the density of irreducible polynomials defined over a finite field of q elements was first observed by Gauss. Since then, many other analogies have been uncovered between arithmetic in number fields and in function fields defined over a finite field. Although an active area of interaction for the past half century at least, the language and techniques used in analytic number theory and in the function field setting are quite different, and this has frustrated interchanges between the two areas. This situation is currently changing, and there has been substantial progress on a number of problems stimulated by bringing together ideas from each field. We here introduce the papers published in this Theo Murphy meeting issue, where some of the recent developments are explained. PMID- 25802413 TI - The autocorrelation of the Mobius function and Chowla's conjecture for the rational function field in characteristic 2. AB - We prove a function field version of Chowla's conjecture on the autocorrelation of the Mobius function in the limit of a large finite field of characteristic 2, extending previous work in odd characteristic. PMID- 25802414 TI - A study in sums of products. AB - We give a general version of cancellation in exponential sums that arise as sums of products of trace functions satisfying a suitable independence condition related to the Goursat-Kolchin-Ribet criterion, in a form that is easily applicable in analytic number theory. PMID- 25802415 TI - A heuristic for the distribution of point counts for random curves over a finite field. AB - How many rational points are there on a random algebraic curve of large genus g over a given finite field Fq? We propose a heuristic for this question motivated by a (now proven) conjecture of Mumford on the cohomology of moduli spaces of curves; this heuristic suggests a Poisson distribution with mean q+1+1/(q-1). We prove a weaker version of this statement in which g and q tend to infinity, with q much larger than g. PMID- 25802416 TI - Shifted convolution and the Titchmarsh divisor problem over ??q[t]. AB - In this paper, we solve a function field analogue of classical problems in analytic number theory, concerning the autocorrelations of divisor functions, in the limit of a large finite field. PMID- 25802417 TI - On a question of Rudnick: do we have square root cancellation for error terms in moment calculations? AB - We answer a question of Rudnick, largely in the negative, as to whether we have square root cancellation for error terms in moment calculations. PMID- 25802418 TI - Moments of zeta functions associated to hyperelliptic curves over finite fields. AB - Let q be an odd prime power, and Hq,d denote the set of square-free monic polynomials D(x)?Fq[x] of degree d. Katz and Sarnak showed that the moments, over Hq,d, of the zeta functions associated to the curves y(2)=D(x), evaluated at the central point, tend, as q->infinity, to the moments of characteristic polynomials, evaluated at the central point, of matrices in USp(2?(d-1)/2?). Using techniques that were originally developed for studying moments of L functions over number fields, Andrade and Keating conjectured an asymptotic formula for the moments for q fixed and q->infinity. We provide theoretical and numerical evidence in favour of their conjecture. In some cases, we are able to work out exact formulae for the moments and use these to precisely determine the size of the remainder term in the predicted moments. PMID- 25802419 TI - After-hours pediatric care compared with emergency department care: a retrospective charge analysis. AB - OBJECTIVE: To compare financial charges between children treated and released from an emergency department (ED) with those evaluated in an after-hours (AH) pediatric clinic. METHODS: Medical records were retrospectively reviewed for 200 children <15 years of age treated in a hospital-based ED and compared with 200 children seen in an AH pediatric clinic. Our main outcome was median overall patient charges by clinic setting. We additionally examined charges by the 6 most common disease diagnoses. RESULTS: Median charges for children treated and released from the ED were $457 [interquartile range (IQR) $320-$628] compared with $140 (IQR $140-$140) for those treated in the AH clinic (P < .01). In addition, median charges were higher for the ED group in the 6 most common disease classes shared between the 2 study groups, both overall and for individual disease class comparison between study groups (all P < .01). We examined the association between charges and clinic setting in multiple quantile regression model while simultaneously adjusting for age, gender, insurance status, and diagnosis. Median costs were $305 (95% CI = $261 to $348; P < .01) more for the ED compared with the AH group. CONCLUSION: We found that financial charges for pediatric health care delivered in an AH clinic were less than those in an ED. We found significantly higher charges for the ED when like diagnoses were compared. Patients should be encouraged to attend AH clinics for urgent care needs when appropriate, which could result in significant cost savings to the health care system. PMID- 25802421 TI - Corrigendum. PMID- 25802420 TI - The extent and patterns of multiple chronic conditions in low-income children. AB - BACKGROUND AND OBJECTIVES: Little is known about the magnitude of multiple chronic conditions (MCC) in children. This study describes the prevalence of and patterns of comorbidities in children receiving Medicaid assistance. METHODS: Diagnoses from 5 years of Medicaid claims data were reviewed and identified 128,044 children with chronic conditions. The relationship between comorbidities and significant urgent health care events was analyzed using logistic regression modeling. RESULTS: More than 15,000 children (12%) had claims for more than 1 condition. The most frequent combination was asthma and allergic rhinitis. Significant health care events ranged from 18% to 51% in children, and the odds of having a significant event increased with each additional condition. Those with >=4 conditions had 4.5 times the odds of a significant event compared with those with 1 condition (P < .0001). CONCLUSION: MCC are prevalent in low-income children and are associated with greater risk for urgent health care use. PMID- 25802423 TI - Case Fatality Rates of Recurrent Thromboembolism and Bleeding in Patients Receiving Direct Oral Anticoagulants for the Initial and Extended Treatment of Venous Thromboembolism: A Systematic Review. AB - BACKGROUND: In patients with venous thromboembolism (VTE), the study of the case fatality rate (CFR) of VTE recurrences and bleeding complications may be of help to balance the risks and benefits of anticoagulant therapy. OBJECTIVE: To investigate the CFR with the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, and edoxaban) in patients with VTE. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials testing the DOACs versus standard initial treatment of VTE (parenteral anticoagulant for >=5 days plus vitamin K antagonists [VKAs] for >=3 months) and DOACs versus placebo or VKA for extended treatment. Two investigators independently extracted the data. A random effects meta-analysis was conducted using StatsDirect software. RESULTS: Overall, 10 trials in 35 029 patients were included. During initial treatment, the rate of recurrent VTE per 100 patient-years (%/yr) and CFR (%) was similar in patients receiving DOACs or standard therapy (4.1%/yr vs 4.4%/yr; P = .21 and 16% vs 13%; P = .61, respectively). However, major bleeding (1.8%/yr vs 3.1%/yr; P = .003), fatal bleeding (0.1%/yr vs 0.3%/yr; P = .02), and CFR (6% vs 10%; P = .18) were lower with DOACs than with standard therapy. During extended treatment, both all-cause mortality and recurrent VTE per 100 patient-years were lower with DOACs than with placebo (0.6%/yr vs 1.1%/yr; P = .01 and 1.9%/yr vs 10.9%/yr; P < .0001, respectively), but there were no statistical differences between treatments on CFR of VTE recurrences (P = .17). No fatal bleeding events were reported during extended treatment. CONCLUSION: The use of DOACs was associated with fewer major and fatal bleedings and corresponding CFR than standard initial treatment of VTE, and fewer recurrent VTEs and mortality than placebo during extended therapy, although the CFR of recurrent VTE was not reduced. PMID- 25802422 TI - Supervised versus non-supervised exercise in patients with recent myocardial infarction: A propensity analysis. AB - BACKGROUND: The influence of supervised versus non-supervised exercise training on outcome in patients with a recent myocardial infarction (MI) is controversial. DESIGN: Longitudinal observational study. METHODS: FRENA is an ongoing registry of stable outpatients with symptomatic coronary, cerebrovascular or peripheral artery disease. We compared the rate of subsequent ischaemic events (MI, ischaemic stroke or lower limb amputation) and the mortality rate in patients with recent MI, according to the use of supervised versus non-supervised exercise training. The influence of physical activity on outcomes was estimated by using propensity score method in multivariate analysis. RESULTS: As of February 2014, 1124 outpatients with recent MI were recruited, of whom 593 (53%) participated in a supervised exercise training programme. Over a mean follow-up of 15 months, 25 patients (3.3%) developed 26 subsequent ischaemic events - 24 MI, one stroke, one lower-limb amputation - and 12 (1.6%) died. The mortality rate (0.15 vs. 2.89 deaths per 100 patient-years; rate ratio = 0.05; 95% confidence interval, 0.01 0.39) was significantly lower in supervised exercise than in non-supervised exercise patients. On propensity score analysis, the rate of the composite outcome was significantly lower in supervised exercise patients (1.80 vs. 6.51 events per 100 patient-years; rate ratio = 0.28; 95% confidence interval, 0.12 0.64). CONCLUSIONS: The use of supervised exercise training in patients with recent MI was associated with a significant decrease in the composite outcome of subsequent ischaemic events and death. PMID- 25802424 TI - The effects of compression gloves on hand symptoms and hand function in rheumatoid arthritis and hand osteoarthritis: a systematic review. AB - OBJECTIVE: to evaluate the effects of compression gloves in adults with rheumatoid arthritis and hand osteoarthritis. DATA SOURCES: Systematic review of randomized controlled trials identified from MEDLINE, CINAHL, AMED, PEDro, OT Seeker, The Cochrane Library, ISI Web of Knowledge, Science Direct and PubMed from their inceptions to January 2015. REVIEW METHODS: Methodological quality of identified trials was evaluated using the PEDro scale by three independent assessors. Effects were summarized descriptively. RESULTS: Four trials (n=8-24; total n=74), comparing night wear of full-length finger compression gloves with placebo gloves, were assessed. Three were of moderate (PEDro score 4-5) and one low (score 3) methodological quality. Effect sizes or standardized mean differences could not be calculated to compare trials due to poor data reporting. In rheumatoid arthritis, finger joint swelling was significantly reduced, but results for pain and stiffness were inconclusive and no differences in grip strength and dexterity were identified. One study reported similar effects in pain, stiffness and finger joint swelling from both compression and thermal placebo gloves. Only one study evaluated gloves in hand osteoarthritis (n=5) with no differences. CONCLUSIONS: All the trials identified were small with a high risk of Type I and II errors. Evidence for the effectiveness of compression gloves worn at night is inconclusive in rheumatoid arthritis and hand osteoarthritis. PMID- 25802425 TI - A comparison between the Static Balance Test and the Berg Balance Scale: validity, reliability, and comparative resource use. AB - OBJECTIVE: Within a sample of acute post-stroke patients, to compare the score on the Berg Balance Scale and the Static Balance Test for validity, inter-rater reliability, and the expenditure of time. DESIGN: Prospective, intra-individual, cross-sectional evaluation study. SETTING: Acute stroke unit of a university hospital in Germany. PARTICIPANTS: A total of 53 patients with acute stroke who did not have other pathology affecting their balance. MAIN OUTCOME MEASURE: For intra-individual comparisons of the Berg Balance Scale and the Static Balance Test, Pearson correlation coefficients were calculated. For inter-rater reliability, Bland Altman plots were drawn and the corresponding mean difference and limits of agreement were calculated. RESULTS: The Static Balance Test took three to five minutes; the Berg Balance Scale 20-30 minutes. There was a high correlation between the scores on the Berg Balance Scale and the Static Balance Test (r = 0.91). For the Berg Balance Scale, the mean difference between the two raters was 0.13 and the limits of agreement were small (-0.25; 0.51). For the Static Balance Test, the mean difference between the two raters was -0.02 and also the limits of agreement (-0.06; 0.02) were even smaller than for the Berg Balance Scale. Both scales showed excellent inter-rater reliability. CONCLUSION: The Static Balance Test was compared with the Berg Balance Scale and turned out to be equally valid, more reliable, and takes much less time. For the moment, the scale can be recommended for the use in acute stroke care, especially for the daily routine therapy. PMID- 25802427 TI - Synergistic Mortality Caused by Plasmodium falciparum During the 1918 Influenza Pandemic. AB - At the end of World War I, British medical officers noted that soldiers infected with malaria were more likely to die during the 1918 influenza pandemic than those without malaria. This synergistic mortality appeared to be specific to Plasmodium falciparum and has not been generally noted since 1920. A possible explanation is that a malaria-induced procoagulant state enhanced the activation of influenza virus to increase inflammation and subsequent severe clinical outcomes. Falciparum proteins bind and likely inhibit antithrombin 3 and other factors. Pathogens interact in ways that may inform pathophysiology studies of remote epidemics. PMID- 25802426 TI - Long-term neurological outcomes in West Nile virus-infected patients: an observational study. AB - The Houston West Nile Cohort (HWNC) was founded in 2002 when West Nile virus (WNV) reached Houston, TX. The long-term outcomes following WNV infection are still mostly unknown, though neurological abnormalities up to 1 year postinfection have been documented. We report an observational study of neurological abnormalities at 1-3 and 8-11 years following WNV infection in the HWNC. We conducted standard neurological examinations at two separate time points to assess changes in neurological status over time. The majority of patients (86%, 30/35) with encephalitis had abnormal neurological exam findings at the time of the first assessment compared with uncomplicated fever (27%, 3/11) and meningitis (36%, 5/14) cases. At the time of the second assessment, 57% (4/7) of West Nile fever (WNF), 33% (2/6) of West Nile meningitis (WNM), and 36% (5/14) of West Nile encephalitis (WNE) had developed new neurological complications. The most common abnormalities noted were tandem gait, hearing loss, abnormal reflexes, and muscle weakness. Long-term neurological abnormalities were most commonly found in patients who experienced primary WNV encephalitis. New abnormalities may develop over time regardless of initial clinical infection. Future studies should aim to differentiate neurological consequences due to WNV neuroinvasive infection versus neurological decline related to comorbid conditions. PMID- 25802428 TI - Decreasing disparities in infant survival using surveillance data from Burkina Faso. AB - We assessed changes in the effect size of risk factors for infant mortality comparing a birth cohort from 2005 to 2010 with a birth cohort from 1993 to 1999 in the Nouna Health and Demographic Surveillance System (HDSS) in Burkina Faso. Single- and three-level Cox proportional hazards regression models were used for analysis. Independent variables among others included year of birth, ethnicity, religion, age of the mother, birth order, death of the mother, being a twin, and distance to the closest health facility. We observed an infant mortality rate of about 51/1,000 person-years. The strongest risk factors were death of the mother and being a twin, which were also the strongest risk factors from the previous analysis period. Compared with the period 1993-1999, the effect of most risk factors decreased, notably ethnicity, religious affiliation, distance to the closest health facility, birth order, and season of birth. The strongest reduction in mortality occurred in the groups with the previously highest infant mortality rates in 1993-1999. PMID- 25802429 TI - Rainfall and sloth births in may, Q fever in July, Cayenne, French Guiana. AB - Q fever in French Guiana is correlated with the rainy season. We found a 1- to 2 month lagged correlation between Q fever incidence and the number of births of three-toed sloth. This result strengthens the hypothesis that the three-toed sloth is the wild reservoir of Q fever in French Guiana. PMID- 25802430 TI - Dot-ELISA Rapid Test Using Recombinant 56-kDa Protein Antigens for Serodiagnosis of Scrub Typhus. AB - We developed a rapid dot-enzyme-linked immunosorbent assay (dot-ELISA) using the combination of recombinant 56-kDa protein antigens that exhibited broad reactivity with serum antibodies against the four most prevalent strains (Karp, Kato, Gilliam, and TA763) of Orientia tsutsugamushi. The assay is rapid (30 minutes), and can be done at room temperature, and results can be read by the naked eye. Only a simple shaker is required to wash the membrane. Sera from 338 patients suspected of being ill with scrub typhus from rural hospitals around Thailand were tested using this dot-ELISA. Seventy-five (22.2%) patients were found to be positive. The sensitivity and specificity of dot-ELISA were determined using the indirect immunofluorescent assay (IFA) test as the gold standard, with the cutoff titer of immunoglobulin peroxidase conjugate M (IgM)/G (IgG) greater than 1:400/1:400. The dot-ELISA had a sensitivity of 98.5%, a specificity of 96.3%, a positive predictive value of 86.7%, and a negative predictive value of 99.6% for the acute-phase specimens. The results indicate that dot-ELISA rapid test using recombinant 56-kDa protein antigen was comparable with the IFA test and may be very useful for the diagnosis of scrub typhus in rural hospitals, where IFA is not available. PMID- 25802432 TI - Molecular Detection of Fastidious and Common Bacteria as Well as Plasmodium spp. in Febrile and Afebrile Children in Franceville, Gabon. AB - Malaria was considered as the main cause of fever in Africa. However, with the roll back malaria initiative, the causes of fever in Africa may change. This study aimed to evaluate the prevalence of bacteria and Plasmodium spp. in febrile and afebrile (controls) children from Franceville, Gabon. About 793 blood samples from febrile children and 100 from controls were analyzed using polymerase chain reaction (PCR) coupled with sequencing. Plasmodium spp. was the microorganism most detected in febrile (74.5%, 591/793) and controls (13%, 13/100), P < 0.0001. Its coinfection with bacteria was found only in febrile children (P = 0.0001). Staphylococcus aureus was the most prevalent bacterium in febrile children (2.8%, 22/793) and controls (3%, 3/100). Eight cases of Salmonella spp. (including two Salmonella enterica serovar Paratyphi) and two of Streptococcus pneumoniae were found only among febrile children. Borrelia spp. was found in 2 controls while Rickettsia felis was detected in 10 children (in 8 febriles and 2 afebriles). No DNA of other targeted microorganisms was detected. Plasmodium spp. remains prevalent while Salmonella spp., Staphylococcus aureus, and Streptococcus pneumoniae were common bacteria in Gabon. Two fastidious bacteria, Rickettsia felis and Borrelia spp., were found. Inclusion of controls should improve the understanding of the causes of fever in sub-Saharan Africa. PMID- 25802433 TI - Triatominae survey (Hemiptera: Reduviidae: Triatominae) in the south-central region of the state of Bahia, Brazil between 2008 and 2013. AB - Triatomine surveillance in rural areas, artificial ecotypes, and natural ecotopes of the cities of Caturama, Ibipitanga, Macaubas, and Seabra in the south-central region of the Brazilian state of Bahia was carried out between 2008 and 2013. Natural infection by Trypanosoma cruzi was evaluated in the specimens collected to monitor vectors of Chagas disease. A total of 1,357 specimens were collected, and four species were identified: Triatoma sordida (83%), Triatoma lenti (16.4%), Triatoma pseudomaculata (0.5%), and Panstrongylus geniculatus (0.1%). Triatoma sordida was found in four cities, only 0.7% in intradomiciliary environments. Triatoma lenti was found only in Macaubas; 8.5% were found in intradomiciliary environments, 88.3% in peridomiciliary environments, and 3.1% in sylvatic environments. Natural infection by T. cruzi was 0.5% for T. sordida and 3.1% T. lenti. All of these cases were found in peridomiciliary environments of Macaubas. As the results show, triatomines were found in intradomiciliary environments in three cities that were surveyed in the south-central region of the state of Bahia. Thus, an epidemiologic survey should be performed to avoid the risk of transmission to the population. PMID- 25802431 TI - Prevalence of Endemic Pig-Associated Zoonoses in Southeast Asia: A Review of Findings from the Lao People's Democratic Republic. AB - The increasing intensification of pork production in southeast Asia necessitates an urgent requirement to better understand the dual impact of pig-associated zoonotic disease on both pig production and human health in the region. Sharing porous borders with five countries and representing many regional ethnicities and agricultural practices, the Lao People's Democratic Republic (Lao PDR) appears well placed to gauge the levels of pig-associated zoonoses circulating in the wider region. Despite this, little is known about the true impact of zoonotic pathogens such as leptospirosis, Trichinella, hepatitis E virus (HEV), Japanese encephalitis (JE), and Taenia solium on human health and livestock production in the country. A comprehensive review of the published prevalences of these five pig-associated zoonoses in Lao PDR has demonstrated that although suspicion remains high of their existence in pig reservoirs across the country, epidemiological data are scarce; only 31 epidemiological studies have been undertaken on these diseases in the past 25 years. A greater understanding of the zoonoses prevalence and subsequent risks associated with pork production in the southeast Asian region could help focus public health and food safety interventions at key points along the value chain, benefiting both livestock producers and the broader animal and human health systems in the region. PMID- 25802434 TI - Population-wide malaria testing and treatment with rapid diagnostic tests and artemether-lumefantrine in southern Zambia: a community randomized step-wedge control trial design. AB - Reducing the human reservoir of malaria parasites is critical for elimination. We conducted a community randomized controlled trial in Southern Province, Zambia to assess the impact of three rounds of a mass test and treatment (MTAT) intervention on malaria prevalence and health facility outpatient case incidence using random effects logistic regression and negative binomial regression, respectively. Following the intervention, children in the intervention group had lower odds of a malaria infection than individuals in the control group (adjusted odds ratio = 0.47, 95% confidence interval [CI] = 0.24-0.90). Malaria outpatient case incidence decreased 17% in the intervention group relative to the control group (incidence rate ratio = 0.83, 95% CI = 0.68-1.01). Although a single year of MTAT reduced malaria prevalence and incidence, the impact of the intervention was insufficient to reduce transmission to a level approaching elimination where a strategy of aggressive case investigations could be used. Mass drug administration, more sensitive diagnostics, and gametocidal drugs may potentially improve interventions targeting the human reservoir of malaria parasites. PMID- 25802435 TI - Meteorological conditions associated with increased incidence of West Nile virus disease in the United States, 2004-2012. AB - West Nile virus (WNV) is a leading cause of mosquito-borne disease in the United States. Annual seasonal outbreaks vary in size and location. Predicting where and when higher than normal WNV transmission will occur can help direct limited public health resources. We developed models for the contiguous United States to identify meteorological anomalies associated with above average incidence of WNV neuroinvasive disease from 2004 to 2012. We used county-level WNV data reported to ArboNET and meteorological data from the North American Land Data Assimilation System. As a result of geographic differences in WNV transmission, we divided the United States into East and West, and 10 climate regions. Above average annual temperature was associated with increased likelihood of higher than normal WNV disease incidence, nationally and in most regions. Lower than average annual total precipitation was associated with higher disease incidence in the eastern United States, but the opposite was true in most western regions. Although multiple factors influence WNV transmission, these findings show that anomalies in temperature and precipitation are associated with above average WNV disease incidence. Readily accessible meteorological data may be used to develop predictive models to forecast geographic areas with elevated WNV disease risk before the coming season. PMID- 25802436 TI - The Influence of Diet on the Use of Near-Infrared Spectroscopy to Determine the Age of Female Aedes aegypti Mosquitoes. AB - Interventions targeting adult mosquitoes are used to combat transmission of vector-borne diseases, including dengue. Without available vaccines, targeting the primary vector, Aedes aegypti, is essential to prevent transmission. Older mosquitoes (>= 7 days) are of greatest epidemiological significance due to the 7 day extrinsic incubation period of the virus. Age-grading of female mosquitoes is necessary to identify post-intervention changes in mosquito population age structure. We developed models using near-infrared spectroscopy (NIRS) to age grade adult female Ae. aegypti. To determine if diet affects the ability of NIRS models to predict age, two identical larval groups were fed either fish food or infant cereal. Adult females were separated and fed sugar water +/- blood, resulting in four experimental groups. Females were killed 1, 4, 7, 10, 13, or 16 days postemergence. The head/thorax of each mosquito was scanned using a near infrared spectrometer. Scans from each group were analyzed, and multiple models were developed using partial least squares regression. The best model included all experimental groups, and positively predicted the age group (< or >= 7 days) of 90.2% mosquitoes. These results suggest both larval and adult diets can affect the ability of NIRS models to accurately assign age categories to female Ae. aegypti. PMID- 25802440 TI - [Clinical use of a new method of inguinal hernia repair]. AB - Surgery is the only treatment for inguinal hernias. The use of allografts has reduced the number recurrences of hernias to 3-14%. However, in any form of alloplasty around implantat develops tissue reaction that causes a number of specific complications. At present, researchers found that in 45-59% of cases of inguinal allogernioplasty leads to a significant disruption of spermatogenic and hormonal functions of the testicle. On the basis of the Surgical Department No 1 (Chernivtsi Emergency Hospital) 61 patients (main group) underwent surgery according to the proposed method (patent of Ukraine for useful model No 81728). The control group included 63 male patients from 19 to 61 years old who underwent inguinal hernia repair by I.L. Lichtenstein. Postoperative recovery periods examined basal activity and disability, pain intensity, the presence of specific complications, length of postoperative hospital stay days, recurrences of hernias. In order to assess reproductive disorders studied the state of blood circulation to the testicular arteries, testicular volume and the level of sex hormones. The prevention of polymeric implant to contact with the components of the spermatic cord reduces the inflammatory response to the structure of the inguinal canal, and the reproductive organs, which leads to a reduction of pain. Also accelerated social and labor rehabilitation of patients, blood circulation is preserved in the testicle and male hormones in the postoperative period. The proposed method prevents the development of recurrences of hernias through the elimination of the deep inguinal ring as one of the weaknesses of the anterior abdominal wall. PMID- 25802437 TI - A prospective multi-center observational study of children hospitalized with diarrhea in Ho Chi Minh City, Vietnam. AB - We performed a prospective multicenter study to address the lack of data on the etiology, clinical and demographic features of hospitalized pediatric diarrhea in Ho Chi Minh City (HCMC), Vietnam. Over 2,000 (1,419 symptomatic and 609 non diarrheal control) children were enrolled in three hospitals over a 1-year period in 2009-2010. Aiming to detect a panel of pathogens, we identified a known diarrheal pathogen in stool samples from 1,067/1,419 (75.2%) children with diarrhea and from 81/609 (13.3%) children without diarrhea. Rotavirus predominated in the symptomatic children (664/1,419; 46.8%), followed by norovirus (293/1,419; 20.6%). The bacterial pathogens Salmonella, Campylobacter, and Shigella were cumulatively isolated from 204/1,419 (14.4%) diarrheal children and exhibited extensive antimicrobial resistance, most notably to fluoroquinolones and third-generation cephalosporins. We suggest renewed efforts in generation and implementation of policies to control the sale and prescription of antimicrobials to curb bacterial resistance and advise consideration of a subsidized rotavirus vaccination policy to limit the morbidity due to diarrheal disease in Vietnam. PMID- 25802438 TI - Sociocultural and structural factors contributing to delays in treatment for children with severe malaria: a qualitative study in southwestern Uganda. AB - Malaria is a leading cause of pediatric mortality, and Uganda has among the highest incidences in the world. Increased morbidity and mortality are associated with delays to care. This qualitative study sought to characterize barriers to prompt allopathic care for children hospitalized with severe malaria in the endemic region of southwestern Uganda. Minimally structured, qualitative interviews were conducted with guardians of children admitted to a regional hospital with severe malaria. Using an inductive and content analytic approach, transcripts were analyzed to identify and define categories that explain delayed care. These categories represented two broad themes: sociocultural and structural factors. Sociocultural factors were 1) interviewee's distinctions of "traditional" versus "hospital" illnesses, which were mutually exclusive and 2) generational conflict, where deference to one's elders, who recommended traditional medicine, was expected. Structural factors were 1) inadequate distribution of health-care resources, 2) impoverishment limiting escalation of care, and 3) financial impact of illness on household economies. These factors perpetuate a cycle of illness, debt, and poverty consistent with a model of structural violence. Our findings inform a number of potential interventions that could alleviate the burden of this preventable, but often fatal, illness. Such interventions could be beneficial in similarly endemic, low-resource settings. PMID- 25802441 TI - [Immediate and long-term results of surgical treatment of benign breast disease]. AB - Sector resection of the breast is the standard surgical treatment of benign breast disease, but often it has unsatisfactory outcomes. The aim of the study was a comparative analysis of the effectiveness of surgical treatment of patients with benign breast diseases after sector resection and after modification of the procedure. Classical sector resection was performed on 45 women, 106 - underwent operations with using of plastic surgery elements. The effectiveness of treatment was defined by the presence of complications in the early postoperative period; the quality of life was studied using questionnaires--The Short Form Medical Study (SF-36) and The Breast Evaluation Questionnaire (BEQ)--before surgery and after 3 and 12 months after surgery. After sector resection was 44% of the complications in the early postoperative period, after the developed techniques - 17%. 3 months after the operation quality of life and aesthetic satisfaction of breast in patients of both groups decreased. 1 year after sector resection the rates of satisfaction of breast aesthetic appearance were significantly lower than the preoperative level. In patients after modified operations at 1 year was observed a significant improvement in well-being and satisfaction of aesthetic appearance of breast. The method of sector resection has a greater number of complications; it leads to deterioration of the aesthetic appearance of the breast in 1 year after surgery. Surgery techniques with elements of mammaplasty have fewer complications and improve quality of life after surgery. PMID- 25802442 TI - [Role of single-nucleotide polymorphism C-1562t of the matrix metaloproteinaza-9 gene in the development of leiomyoma in women with cervical pathology]. AB - 108 women diagnosed with leiomyoma and 84 women without this disease (control group) were examined during the research. Was conducted a comparative analysis of the genotypes distribution between women with cervical pathology of different complexity. The results of the research showed, that there is no connection between the S-1562T polymorphism of the MMP-9 gene and the progression of leiomyoma the course of which is accompanied by false erosion of the cervix (ectopias epithelium) (p>0,521). There is also was not found any connection between the SNP in women with leiomyoma, who undergo conical electrocauterizing excision treatment because of the dysplastic epithelial changes that are considered to be precancerous (p>0,280). PMID- 25802443 TI - Periodontal diseases in patients with vitamin D-resistant rickets. AB - OBJECTIVE: To define the risk of development of periodontal diseases at vitamin D resistant rickets. The material for the study was based on the data from 13 children of 0-18 years with vitamin D-resistant rickets (I group), 68 children with vitamin D-dependent rickets (II group), and the control group included 61 children of the same ages. The patients were divided into 3 age groups: I group of 0-5 years (deciduous/milk teeth occlusion), II group of 6-12 of years (mixed bite), III group of 13-18 years (permanent occlusion). For the qualitative data the differences between the groups were detected by using F criteria but for the quantitative data the differences between the groups were detected by Student's t test for independent selection. Mathematical processing was performed using statistical software SPSS-22. In all three groups the gingivitis of mild and moderate forms were fixed, among them acute course was revealed only in the group of vitamin D-resistant rickets. The rate of chronic, local, catarrhal and generalized gingivitis in the group of vitamin D-resistant rickets was reliably higher in comparison with both vitamin D-dependant rickets and control groups. In addition, a mild form of periodontitis with chronic course was revealed in all three groups the rate of which was reliably higher in the group of vitamin D resistant rickets comparing with the ones of vitamin D-dependant rickets and control groups. CONCLUSION: the rate of inflammatory periodontal diseases in children with vitamin D-resistant rickets is higher than in children with vitamin D-dependent rickets and the control groups. PMID- 25802444 TI - Influence of smoking on audiological characteristics of hearing function. AB - Cigarette smoking and related diseases are global problem of health. Discussion regarding influence of smoking on hearing function has been continued about 20 years. The aim of our study was estimation of relation between smoking and development of cochlear neuritis. Research was conducted at Ltd. National Centre of ENT - Japaridze-Kevanishvili clinic and Ltd.Audiology National Center. The data were collected from September 2011 to December 2013. Cross- sectional observational study was carried out. 600 persons (mean age - 45.4+/-10.4) were enrolled in the research. After filling the informed consent persons were divided into two groups: smokers (300 smokers, apparently healthy persons, mean age 44.3+/-10.6 years) and control group (300 healthy non-smoker persons, mean age 46.5+/-10.2 years). All persons completed a questionnaire, which includes questions about smoking status too. The inclusion criterion in smokers group was a smoking habit during 5 years at least 10 cigarettes per day. Otoscopy and Acoustic impedance test (timpanometry, reflexometry, testing for Eustachian tube conductivity) were used for verification of outer and middle-ear normality. Pure Tone Audiometry was performed for hearing measure and identifies hearing nerve condition. Obtained results were statistically treated by the student's t distribution. For minimal level of significance was taken p<0,05. In smokers group hearing loss was proved in 31.33% (94 persons) and in control group - in 17.34% (52 persons). Hearing-loss vs. normal-hearing ratio amounted hence to 0.46 (P<0.01) in the smokers group and to 0.21 (P<0.01) in the nonsmokers'. Hearing loss in smokers may be provided by different pathological mechanisms. PMID- 25802439 TI - Cutaneous and renal glomerular vasculopathy as a cause of acute kidney injury in dogs in the UK. AB - To describe the signalment, clinicopathological findings and outcome in dogs presenting with acute kidney injury (AKI) and skin lesions between November 2012 and March 2014, in whom cutaneous and renal glomerular vasculopathy (CRGV) was suspected and renal thrombotic microangiopathy (TMA) was histopathologically confirmed. The medical records of dogs with skin lesions and AKI, with histopathologically confirmed renal TMA, were retrospectively reviewed. Thirty dogs from across the UK were identified with clinicopathological findings compatible with CRGV. These findings included the following: skin lesions, predominantly affecting the distal extremities; AKI; and variably, anaemia, thrombocytopaenia and hyperbilirubinaemia. Known causes of AKI were excluded. The major renal histopathological finding was TMA. All thirty dogs died or were euthanised. Shiga toxin was not identified in the kidneys of affected dogs. Escherichia coli genes encoding shiga toxin were not identified in faeces from affected dogs. CRGV has previously been reported in greyhounds in the USA, a greyhound in the UK, without renal involvement, and a Great Dane in Germany. This is the first report of a series of non-greyhound dogs with CRGV and AKI in the UK. CRGV is a disease of unknown aetiology carrying a poor prognosis when azotaemia develops. PMID- 25802445 TI - [Current status on the pathogenesis of progressive myopia]. AB - In the article shown is the modern diagnostic method of progressive myopia pathogenesis. Establishment of possible myopia progress using the ultrasonographic biometry while looking into and into and down contact equator at one and the same point. The research goal is to study the residual deformative changes developed as a result of sclera distraction during reading. We have researched 150 patients. The patients were split in three groups according to the age and myopia type: I group included patients of the age of 5-12 years; the II group had patients of the age of 13-19 years; III group - patients above the 19 years. The used age differentiation is based on the eye anatomic growth criteria. The research was held by the following scheme: all the researches patients underwent the preliminary anesthesia drops instillation; the ultrasonographic biometry catheter was put using one and the same equator point. In the first position they established the front and back axis size, in the second one - the eye size was established in the medial look regime; in the third position - the eye size was established in the reading regime. The data obtained are as follows: among the first group patients, aged from 5 to 12 years, in reading regime the eye size was increased in 93% cases; among the second group patients, aged from 13 to 19 years, in reading regime the eye size was increased in 90% cases; among the third group patients, aged above 19 years - 91% cases. The reason why the sclera capsule distraction during reading regime is that of the extraocular muscles and growth of the intraocular pressure influence the process. Because the sclera is fibrotic membrane, it is characterized with well-marked elasticity, stronger accommodation and the sigh load in the near distance causes sclera capsule distraction. After the contraction the residual deformation stays there. Accumulation of such residual deformations causes the sclera weakness and formation of myopia as a disease. According to the data obtained, it is necessary to work out the certain recommendations, from the sclera nutrition and other medical preparations standpoint. Improvement of the sclera nutrition will slacken the residual changes in sclera, and this will significantly decrease the myopic disease advancing. PMID- 25802446 TI - Aberrant expression of Fcgamma-receptors and Toll like receptor CD180 on monocytes from patients with chronic lymphocytic leukaemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukaemia in the US and in Europe, including Georgia. Patients with CLL are susceptible to infectious diseases as a result of both, the disease progression and chemotherapy that indicates deficiency of immune responses to pathogens, including innate immunity, mediated by monocytes. Monocytes are also often recruited by monoclonal antibodies (mAbs) which express anti-tumour toxicity through Fcgamma-receptor (FcgammaR)-mediated phagocytosis of opsonised leukaemic cells. In this paper we address of monocytes functional status through assessment of the patterns of expression of Fcgamma receptors CD64, CD32, CD16 and CD180 receptor on monocytes from CLL patients and healthy individuals using specific mAbs and flow cytometry. Our data demonstrate that monocytes from peripheral blood of CLL patients lack expression of CD64 and CD16 as well as CD180 that would substantially undermine their ability to contribute to anti-bacterial immune responses. In addition, aberrant expression of CD64 would negatively affect the efficiency of antibody mediated immunotherapies. PMID- 25802447 TI - [The effectiveness of empirical antibiotic therapy of pyelonephritis in patients with type 2 diabetes and without depending on the availability of plasmid mediated resistance genes]. AB - Multi-drug resistance has been increasing in the treatment of urinary tract infections, especially complicated. The prevalence of plasmid-mediated resistance genes among urinary pathogens has nether been studied in Ukraine. So, the aim of our study was to identify the plasmid-mediated resistance genes and to determine their impact on the efficacy of the treatment. A total of 105 adult patients with chronic pyelonephritis were included in the study. Among them, 32 patients were diagnosed with type 2 diabetes mellitus. The diagnosis of pyelonephritis was verified according to the criteria EAU, 2013. Plasmid-mediated resistance genes were determined by polymerase chain reaction (PCR). The prevalence of plasmid mediated resistance mechanisms among patients with pyelonephritis were 44,4%. ESBLs was the most common isolated genes. Favorable clinical response was seen in 11/31 (35,5%) infected with ESBL-producing organisms compared with 59/74 (79,7%) patients with non-ESBL-producing organisms (p<0,05). In 16% of patients with resistance organisms antimicrobial agent was changed. Antibiotic efficiency was reduced in patients with complicated pyelonephritis due to presence of plasmid mediated resistance genes. Therefore, proper management for prescription of antibiotics and also identification of ESBL-producing bacteria in communities are important for prevention. PMID- 25802448 TI - Early repolarization as a predictor of premature ventricular beats. AB - Early repolarization pattern (ERP) is a common ECG variant, characterized by J point elevation manifested either as terminal QRS slurring (the transition from the QRS segment to the ST segment) or notching (a positive deflection inscribed on terminal QRS complex) associated with concave upward ST-segment elevation and prominent T waves in at least two contiguous leads. Aim of this observational study was to compare number of premature ventricular beats in the different groups of patients with early repolarization. The result of this observational study shows that there are: 1,74 fold higher number of premature ventricular beats in 41-74 year subgroup VS 19-40 year subgroup; 1,31 fold higher number of premature ventricular beats in male subgroup VS female subgroup (But this difference is not statistically significant, because t=1,49, p=0,141); 2,85 fold higher number of premature ventricular beats in CAD+ERP subgroup VS ERP without CAD subgroup; 1,74 fold higher number of premature ventricular beats in HF+ERP subgroup VS ERP without HF subgroup; 1,81 fold higher number of premature ventricular beats in CAD+ERP subgroup VS CAD without ERP subgroup; 1,58 fold higher number of premature ventricular beats in HF+ERP subgroup VS HF without ERP subgroup; So, CAD+ERP is very arrhythmogenic condition, after this is HF+ERP, Then Age. This study shows that ERP independently increase number of PVB in different groups (CAD, HF). This is principally new and very important result. Also the number of patients is enough to make this conclusion. PMID- 25802449 TI - Study of CK-MB activity in patients with acute myocardial infarction after percutaneous coronary intervention. AB - The research has been carried out in patients of TSMU Cardiovascular Department of A.Aladashvili University Clinic. 105 patients with acute myocardial infarction have been involved in the study, wich undergoing percutaneous coronary intervention (PCI). For several years coronary angioplasty has been proposed to be an effective method, but in spite of its well developed technique, probability of myocardial injury is still high which appears to have no clinical or electrocardiographic manifestations and is diagnosed only by elevation of cardiac marker level. According to our study data after successful PCI elevation of CK-MB mass was observed in 34.4% patients, majority of those patients had STEMI. In II group the age of patients was higher compared to I group. There were more patients with diabetes mellitus (38.8%), dyslipidemia (86.1%) and patients with low left ventricular ejection fraction (50%). Also there were more patients with previous MI and damage of 3 coronary arteries. Hence age, diabetes mellitus, dyslipidemia, left ventricular ejection fraction <40%, number of damaged coronaries might be considered as predictors of CK-MB elevation after successful PCI. Solid elevation of CK-MB after procedure was also associated with increased hospital complications rate, 30-day and 6 months hospitalization rate and 6 months mortality rate. It should be noted that from 36 patients who developed solid (24 h) elevation of CK-MB after PCI CK-MB mass was increased in all cases, while the concentration was elevated only in 16 cases. It proves that CK-MB mass is more significant criteria of myocardial injury. PMID- 25802450 TI - [Clinical efficacy of calcium channel blockers slow the third generation of lercanidipine in the treatment of patients with arterial hypertension and metabolic disorders (review)]. AB - Arterial hypertension is the most common risk factor in patients with metabolic disorders. In the selection of antihypertensive therapy it is necessary to consider not only the anti-hypertensive and organoprotective effects of drugs and their metabolic effects, which has prognostic value. Calcium antaginists, along. Lercanidipine related to the third generation dihydripyridine calcium antagonist, has been much more selective for the so-called slow calcium channels of vascular smooth muscle cells, which is associated with a good hypertensive, organo and metabolic action. Combination therapy with an ACE inhibitor and a calcium channel blocker is also a justified tactic for the management of patients with high-risk cardiovascular and metabolic disorders. Attention is paid new fixed combinations, including angiotensin converting enzyme inhibitors and calcium antagonists. PMID- 25802451 TI - Vasoplegia in septic shock (review). AB - Vasoplegia is considered as a key factor responsible for the death of patients with septic shock, due to persistent and irreversible hypotension. The latter associated with vascular hyporeactivity to vasoconstrictors is a significant independent prognostic factor of mortality in severe sepsis. Loss of control of the vascular tone occurs through the complex, multifactorial mechanism and implicates deeply disrupted balance between vasoconstrictors and vasodilators. The aim of this review is to discuss in detail the recent suggested alternative mechanisms of vasoplegia in severe sepsis: Overproduction of nitric oxide (NO) by activation of inducible form of nitric oxide synthase (iNOS); up-regulation of prostacyclin (PG12); vasopressin deficiency; significantly elevated levels of circulating endothelin; increased concentrations of vasodilator peptides such as adrenomedulin (AM) and calcitonin gene-related peptide (CGRP); oxidative stress inducing endothelial dysfunction and vascular hyporeactivity to vasoconstrictors; inactivation of catecholamines by oxidation; over-activation of ATP-sensitive potassium channels (KATP channels) during septic shock and their involvement in vascular dysfunction. The review also discusses some therapeutic approaches based on pathogenetic mechanisms of severe sepsis and their efficacy in treatment of patients with septic shock. The loss of vascular tone control occurs through the complex, multifactorial mechanism and implicates deeply disrupted balance between vasoconstrictors and vasodilators in the pathogenesis of septic shock. Overproduction of nitric oxide (NO) by the inducible form of nitric oxide synthase (iNOS); up-regulation of prostacyclin (PG12); vasopressin deficiency; elevated levels of circulating endothelin; increased concentrations of vasodilator peptides such as adrenomedulin (AM) and calcitonin gene-related peptide (CGRP); oxidative stress inducing endothelial dysfunction and vascular hyporeactivity to vasoconstrictors; inactivation of catecholamines by oxidation; over-activation of ATP-sensitive potassium channels (KATP channels) and their involvement in vascular dysfunction - all these factors combined together lead to steady refractory shock with the lethal outcome in patients. PMID- 25802452 TI - [The current knowledge of clinical manifestations of measles]. AB - A comparative study was carried out in children with measles aged 1 month to 18 years. They were admitted to the regional infectious diseases hospital in Karaganda during a measles outbreak in 2014 in Central Kazakhstan. 209 children were included into the study, 66 children were under the age of 1 year and 143 children were aged from 1 year to 18 years. The clinical diagnosis of "measles" was diagnosed according to clinical and epidemiological and serological data. In a comparative study of measles in age aspect, it was found that the highest incidence was in age from 1 year to 3 years and from 11 to 18 years. Measles in children older than 1 year were more severe compared with infants due to severe symptoms of intoxication and catarrhal syndrome. The symptom Bielsko-Filatova and measles enanthema the valuable diagnostic and differential diagnostic symptoms, as a pigmentation remains an important retrospective feature of having had measles before. PMID- 25802453 TI - [The role of lactate acidosis in the development and treatment of various neurologic syndromes in children and adolescents]. AB - The aim of the study was to detect the role of lactate acidosis, also to find the share of mitochondrial insufficiency in development of various neurologic syndromes in children and adolescents. The detection of cellular energetic metabolism and acid based imbalance is also important for finding the specific method of management. We have studied 200 patients with various degree of neurodevelopment delay with epilepsy and epileptic syndromes, headache, vertigo, early strokes, floppy infant syndrome, atrophy of ophthalmic nerve, cataracta, neurosensory deafness, systemic myopathy, cerebral palsy. In 27% of cases with various ages we have detected lactate acidosis and increase level of pyruvate. Mitochondrial insufficiency was seen in 8% of cases which gives us opportunity to find the specific method of treatment in this group of patients. Each patient with neurological symptoms requires correction of parameters of energetic and oxidative metabolism. PMID- 25802454 TI - [On mechanism of functional changes in the organism of teenagers at different levels of locomotor activity]. AB - Comprehensive study of the cardiovascular system functional condition of 15-16 teenagers while in normal daily locomotor activity and in the mode of regular moderate physical activity was performed. The features of cerebral circulation and myocardium functional condition of teenagers are studied depending on initial tonus of the autonomic nervous system and locomotor activity level in the process of continuous step physical activity on tredmil. The condition of regulatory mechanisms, providing adaptation of teenagers in the conditions of modern school was studied. Research results showed, that elasticity of cerebrum arterial vessels, veins tone, venous outflow for teenagers not having regular physical activity, considerably mionectic. More adequate reaction of coronary blood flow in the process of physical activity is educed for the trained teenagers with the balanced autonomic regulation of cardiac rhythm. This group showed a higher level and regulation quality of organism reserve possibilities. PMID- 25802456 TI - [Theoretical and methodological bases of pharmaceutical aid formation (review)]. AB - Pharmacists are required to ensure the quality of services provided to each patient. Good Pharmacy Practice (GPP) is a tool of clarifying and fulfilling this commitment. The role of International Pharmaceutical Federation (FIP) is to guide the national pharmaceutical organizations, which, in turn, should initiate the establishment of national standards. A key element is the obligation imposed by the profession throughout the world - to promote different activities for the benefit of those we serve. GPP is recommended to be considered as a list of occupational tasks, the implementation of which would serve the interests of patients or customers in the pharmacy. Ultimately, the quality of pharmaceutical care system will help to ensure not only the commercial interests of the pharmacy, but also the security requirements as those services and products, as well as professionals and patients. PMID- 25802455 TI - Abdominal organ donation: surgical aspects and recommended practice guidelines for controlled donation of brain-dead donor. AB - The shortage of organ donors along with the increased number of waiting recipients have created the need for new strategies to expand the organ pool from donations after brain death. Organ procurement from brain-dead deceased donors is a complex task. Multiple, complicated operations are performed simultaneously. Very often, this involves numerous physicians and transplant coordinators. An extensive coordination between the thoracic and abdominal surgical teams is crucial for the successful procurement of all suitable organs. The quality of donor organs and the successful recovery therefore depends on a good communication. Organ procurement for transplantation should generally be performed in a calm and dignified atmosphere. The last wishes of the organ donor itself or the relatives must be respected unconditionally. In general, a dignified and respectful treatment of the organ donor is a condition sine qua non for each person involved in the process of organ procurement. The purpose of this article was to focus on the surgical aspects of organ donation after brain death. The proposed recommendations, in cases where they are applicable, are acceptable, however, one should never forget the importance of the ethical side of the issue with respect to the doctor-donating side relationship. PMID- 25802457 TI - [Useage of genetic markers to determine the impact of radiation on the human body]. AB - The timely determination of the fact of radiation impact on the organism is extremely important for preventive and curative interventions. Despite the fact that so far cytogenetic violations are considered to be the best biomarkers to determine the impact of ionizing radiation on the organism, actual problem is to find the optimal combination of different biomarkers. The aim of the work was investigation of the extended set of biomarkers in distant periods of exposure in people previously assigned to the radiation risk group, as well as the identification of genetic disorders in the process of radiotherapy. The object of the study were 37 residents of districts, where at the beginning of this century radioactive sources were discovered, and 6 oncology patients in the course of radiotherapy. Chromosome disorders, the overall level of DNA cells single stranded damage by comet-assay method and a method of level detection of buccal micronuclei in were investigated. The results showed heterogeneity of different organism response to irradiation. Determination of absorbed dose, identification of various genetic disorders in individuals exposed to identical doses of radiation, offers the opportunity to judge the individual biological effect and is very important for individual preventive activities. PMID- 25802458 TI - Effects of immunotoxic and electrolytic lesions of medial septal area on spatial short-term memory in rats. AB - In the present study electrolytic and the immunotoxins (192 IgG saporin and GAT1 SAP) lesions of medial septal area (MS) were used to investigate the importance of cholinergic and GABAergic MS neurons in spatial working memory using spatial alternation task. In our experiments electrolytic lesions destroyed on average 69% of the intact MS. Examination of the AChE stained sections showed that after injections of 192 IgG saporin into the MS, animals exhibited significantly less AChE staining in MS as compared to sections obtained from control animals. Intraseptal GAT1-SAP preferentially reduced GABAergic neurons as compared to cholinergic neurons in the MS. The results of present study indicate that spatial short-term memory is affected only by electrolytic but not 192 IgG saporin or GAT1-SAP lesions. The behavioral testing showed that 192 IgG saporin treated rats, relative to control rats, had a significantly lower level in the number of arms entered during the testing session. However, the groups did not differ in the level of alternation behavior. GAT1-SAP lesioned rats showed that the percent alternation scores and the number of arms that the rat entered in the maze were not significantly different from control rats. These findings indicate that deficits observed after septal electrolytic lesions cannot be accounted solely to the loss of cholinergic or GABAergic septohippocampal projections. To determine more definitively whether septohippocampal projection neurons are required for the spatial short-term memory it would be ideal to produce in future combined lesions of the cholinergic and GABA-ergic septohippocampal projection neurons using 192 IgG-saporin and GAT1-SAP. PMID- 25802459 TI - [Skin defect modeling in experimental animals]. AB - To assess the skin regeneration and explore new medical devices for the treatment of skin defects is necessary to conduct long-term experiments using laboratory animals. Currently, there are many methods for skin trauma modeling but most of them have disadvantages that limit their use. The purpose of this work - the development of an experimental model of the formation of skin defect of various etiologies with the specified parameters of depth and area of damage to the absence of systemic effects on the animal's body. We have developed an installation that allows us to form a skin defect of mechanical, thermal and chemical etiology with area from 1.76 cm2 to 2.0 cm2. The experiment was conducted on 18 male laboratory rats to examine the effectiveness of current method and control the depth and area of the defect. As a result of the new methodology, we were able to carry out simulation skin injuries of different etiology on laboratory animals in the short term and reduce the severity of injuries to extend the life span of animals to monitor the repair processes, as well as to standardize the modeling of injuries according to the criteria of area and depth of the defect. PMID- 25802460 TI - Antinociceptive tolerance to non-steroidal anti-inflammatory drugs microinjected into dorsal hippocampus of rats is due to pharmacological tolerance. AB - Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems, but also on the activation of mechanisms that control emotional processes in limbic brain areas such as the amygdala and the hippocampus. We have recently found that repeated microinjection of non-steroidal anti-inflammatory drugs (NSAIDs) into the dorsal hippocampus of rats for four consecutive days induces antinociceptive tolerance as revealed by a progressive decrease of the latency in the tail-flick and hot plate tests compared to controls treated with saline into the dorsal hippocampus. Here we found that on the first day microinjection of NSAIDs, ketorolac, clodifen and xefocam into the DH produced antinociception as revealed by a latency increase in the TF and HP compared to the baseline control of intact rats and a control group with saline microinjected into the same site as well. Subsequent NSAIDs microinjections, without testing on the second and third days, caused progressively less antinociception, i.e. developed tolerance. After two days resting, by day 7 antinociception was almost completely restored for all the three drugs. Thus we demonstrated that this antinociceptive tolerance is due to pharmacological tolerance to these drugs and not to conditioning by repeating testing or hyperalgesia or other nonspecific mechanisms. PMID- 25802461 TI - IVEU: IT-based collection and reporting of radiological examination parameters. AB - In Germany, each site using ionising radiation in human medicine is assigned to a competent medical authority (CMA) for quality assurance. Duties of these CMAs are, e.g. the inspection of medical aspects of the use of X-rays and nuclear medicine at the sites as well as technical quality assurance of X-ray devices. The CMAs themselves have to report the collected exposure values to the ministries and the Federal Office for Radiation Protection. The IVEU (IT gestutztes Verfahren zur Erfassung von Untersuchungsparametern) Software Framework assists CMAs and radiological departments in collecting and analysing data provided in DICOM headers. PMID- 25802462 TI - A set of patient and staff dose data for validation of Monte Carlo calculations in interventional cardiology. AB - The purpose of this paper is to report a set of experimental values of patient and staff doses in a cardiac catheterisation laboratory using the range of radiographic and geometric parameters from routine clinical practice. The data obtained will be available for validation of Monte Carlo calculations and for training purposes. They will also help optimise radiation protection for patients and staff. Experimental measurements were made with an anthropomorphic phantom, and a monoplane flat detector-based X-ray system was used for interventional cardiology procedures. Standard operational protocols used in clinical practice were applied. Around 1000 patient dose and 5000 staff dose values were measured for different operational conditions (angulations, distances, collimation and wedge filter, magnification, phantom thicknesses, using Copper absorber, etc.). Uncertainties were also estimated. Increase factors of 3-10 for patients and staff doses were measured for the different C-arm angulations. PMID- 25802463 TI - Benefits of an automatic patient dose registry system for interventional radiology and cardiology at five hospitals of the Madrid area. AB - The purpose of this article is to present the results of connecting the interventional radiology and cardiology laboratories of five university hospitals to a unique server using an automatic patient dose registry system (Dose On Line for Interventional Radiology, DOLIR) developed in-house, and to evaluate its feasibility more than a year after its introduction. The system receives and stores demographic and dosimetric parameters included in the MPPS DICOM objects sent by the modalities to a database. A web service provides a graphical interface to analyse the information received. During 2013, the system processed 10 788 procedures (6874 cardiac, 2906 vascular and 1008 neuro interventional). The percentages of patients requiring clinical follow-up due to potential tissue reactions before and after the use of DOLIR are presented. The system allowed users to verify in real-time, if diagnostic (or interventional) reference levels are fulfilled. PMID- 25802464 TI - 210Po in the diet at Seville (Spain) and its contribution to the dose by ingestion. AB - The activity concentrations of (210)Po have been determined in a total of 24 representative diet samples from Seville (south of Spain), inferring from the obtained values the annual intakes of (210)Po by ingestion of the affected population and the corresponding committed effective doses. The annual intakes of (210)Po and, consequently, the corresponding doses of this radionuclide show a high variability in correspondence with the variability in the composition of the analysed samples over time, and their magnitude is comparable with the estimated ones in other regions/countries of the world with similar diet habits (countries where the marine products have a considerable weight in the diets). Committed effective doses by ingestion higher than 0.1 mSv y(-1) have been estimated exclusively for (210)Po, reflecting the importance of this radionuclide and this route of incorporation in the magnitude of the total doses received by the affected population from natural sources. PMID- 25802466 TI - Technological advances in hybrid imaging and impact on dose. AB - New imaging technologies utilising X-rays and radiopharmaceuticals have developed rapidly. Clinical application of computed tomography (CT) has revolutionised medical imaging and plays an enormous role in medical care. Due to technical improvements, spatial, contrast and temporal resolutions have continuously improved. In spite of significant reduction of CT doses during recent years, CT is still a dominating source of radiation exposure to the population. Combinations with single photon emission computed tomography (SPECT) and positron emission tomography (PET) and especially the use of SPECT/CT and PET/CT, provide important additional information about physiology as well as cellular and molecular events. However, significant dose contributions from SPECT and PET occur, making PET/CT and SPECT/CT truly high dose procedures. More research should be done to find optimal activities of radiopharmaceuticals for various patient groups and investigations. The implementation of simple protocol adjustments, including individually based administration, encouraged hydration, forced diuresis and use of optimised voiding intervals, laxatives, etc., can reduce the radiation exposure to the patients. New data about staff doses to fingers, hands and eye lenses indicate that finger doses could be a problem, but not doses to the eye lenses and to the whole body. PMID- 25802465 TI - Be aware of neutrons outside short mazes from 10-MV linear accelerators X-rays in radiotherapy facilities. AB - During the radiation survey of a reinstalled 10-MV linear accelerator in an old radiation treatment facility, high dose rates of neutrons were observed. The area outside the maze entrance is used as a waiting room where patients, their relatives and staff other than those involved in the actual treatment can freely pass. High fluence rates of neutrons would cause an unnecessary high effective dose to the staff working in the vicinity of such a system, and it can be several orders higher than the doses received due to X-rays at the same location. However, the common knowledge appears to have been that the effect of neutrons at 10-MV X-ray linear accelerator facilities is negligible and shielding calculations models seldom mention neutrons for this operating energy level. Although data are scarce, reports regarding this phenomenon are now emerging. For the future, it is advocated that contributions from neutrons are considered already during the planning stage of new or modified facilities aimed for 10 MV and that estimated dose levels are verified. PMID- 25802467 TI - Accuracy of a dose map method assessed in clinical and anthropomorphic phantom situations using Gafchromic films. AB - A dose map method has been integrated on GE x-ray angiographic systems to provide an indication of the local dose distributed on a patient envelope representative of individual patient shapes. Tests have been performed to assess the accuracy of the method by using Gafchromic XR-RV3 films in an anthropomorphic phantom situation and in a clinical situation. Dose values inside different exposed areas have been compared between the film and the dose map method. The dose map results show a good visual agreement for the anthropomorphic phantom situation, and the local doses agreed within better than 15 % compared with the Gafchromic films in both situations. PMID- 25802468 TI - On the estimation of radiation-induced cancer risks from very low doses of radiation and how to communicate these risks. AB - The article is intended to give a short overview of epidemiological data on cancer risks associated with very low absorbed doses of ionising radiation. The linear no-threshold (LNT) approach to estimate cancer risks involves the use of epidemiological data at higher doses (>100 mSv), but is supported by data from lower exposure of more sensitive population groups like fetuses and children and the presence of rare types of cancer. The International Commission on Radiological Protection (ICRP) concludes that the LNT model, combined with a dose and dose-rate effectiveness (reduction) factor (DDREF) of 2 for extrapolation from high doses, should be used. The numerical value of the DDREF is challenged by the findings from some recent epidemiological studies demonstrating risks per unit dose compatible with the risks observed in the higher dose studies. In general there is very limited knowledge about the cancer risk after low absorbed doses (10-100 mSv), as most of epidemiological studies have limitations in detecting small excess risks arising from low doses of radiation against fluctuations in the influence of background risk factors. Even if there may be significant deviations from linearity in the relevant dose range 0-100 mSv, one does not know the magnitude or even the direction of any such deviations. The risks could be lower than those predicted by a linear extrapolation, but they could also be higher. Until more results concerning the effects of low-dose exposure are available, a reasonable radiation protection approach is to consider the risk proportional to the dose. PMID- 25802469 TI - The Accuracy and Efficacy of the Dexcom G4 Platinum Continuous Glucose Monitoring System. AB - BACKGROUND: The purpose of this study was to evaluate the accuracy and efficacy of Dexcom G4 Platinum CGM System. METHODS: Seventy-two subjects enrolled at 4 US centers; 61% were male; 83% had T1DM and17% had T2DM. Subjects wore at least 1 system for up to 7 days. Subjects participated in a total of 36 hours in the clinic to contribute YSI reference glucose measurements with venous blood draws every 15 minutes on study Day 1, Day 4, and Day 7. RESULTS: The overall mean absolute relative difference (ARD) versus YSI was 13% with a median of 10%. Precision ARD was 9% +/- 4% between 2 sensors with a 7% coefficient of variation. The mean ARD versus SMBG was 14% with a median of 11%. One hundred two (94%) sensors lasted 7 days and the systems displayed 97% of their expected glucose readings in average. The time spent in low CGM readings during nighttime hours decreased from the first night use to the 6th night (P < .001) with a small difference in average CGM glucose from 147 +/- 40 mg/dL to 166 +/- 62 mg/dL. There were no serious adverse events or infectious complications reported. CONCLUSIONS: The study showed the Dexcom G4 Platinum CGM System is one of the most accurate CGMs. The significant reduction in nocturnal time spent in a hypoglycemic state observed during this study suggests that a longer term study of CGM use, especially nocturnal use, could be beneficial for patients with hypoglycemia unawareness. PMID- 25802470 TI - Does Visceral Fat Estimated by Dual-Energy X-ray Absorptiometry Independently Predict Cardiometabolic Risks in Adults? AB - BACKGROUND: Abdominal visceral fat, typically measured by computer tomography (CT) or magnetic resonance imaging (MRI), has been shown to correlate with cardiometabolic risks. The purpose of this study was to examine whether a newly developed and validated visceral fat measurement from dual-energy X-ray absorptiometry (DXA) provides added predictive value to the cross-sectional differences of cardiometabolic parameters beyond the traditional anthropometric and DXA adiposity parameters. METHOD: A heterogeneous cohort of 194 adults (81 males and 113 females) with a BMI of 19 to 54 kg/m(2) participated in this cross sectional study. Body composition was measured with a DXA densitometer. Visceral fat was then computed with a proprietary algorithm. Insulin sensitivity index (SI, measured by intravenous glucose tolerance test), blood pressures, and lipid profiles, and peak oxygen uptake were also measured as cardiometabolic risk parameters. RESULTS: DXA-estimated visceral fat mass was associated with HDL cholesterol (regression coefficient [beta] = -5.15, P < .01, adjusted R(2) = .21), triglyceride (beta = 26.01, P < .01, adjusted R(2) = .14), and peak oxygen uptake (beta = -3.15, P < .01, adjusted R(2) = .57) after adjusting for age, gender, and ethnicity. A subanalysis stratifying gender-specific BMI tertiles showed visceral fat, together with ethnicity, was independently associated with SI in overweight men and moderately obese women (second tertile). CONCLUSIONS: Without requiring additional CT or MRI-based measurements, visceral fat detected by DXA might offer certain advantages over the traditional DXA adiposity parameters as means of assessing cardiometabolic risks. PMID- 25802473 TI - Underarousal in Adult ADHD: How Are Peripheral and Cortical Arousal Related? AB - In children and adults with attention deficit/hyperactivity disorder (ADHD), a general slowing of spontaneous electroencephalographic (EEG) brain activity and a decrease of event-related potential amplitudes such as the contingent negative variation (CNV) are observed. Additionally, some studies have reported decreased skin conductance level (SCL) in this clinical population leading to the hypothesis of a peripheral hypoarousal, which may be a target of biofeedback treatment in addition to or instead of neurofeedback. To our knowledge, the relationship between SCL and CNV has not been simultaneously investigated in one experiment. Using the theoretical background of the hypoarousal model, this article aims to gain more insight into the differences and correlations of cortical (CNV) and peripheral (SCL) arousal in adults with ADHD. A sample of 23 adults with ADHD and 22 healthy controls underwent an auditory Go-NoGo task with simultaneous 22-channel EEG and SCL recordings. Reaction time (RT) and reaction time variability (RTV) were also measured to assess task performance. Significantly decreased CNV amplitude and significantly higher RTV were observed in the ADHD group, reflecting cortical underarousal and problems with sustained attention. No significant correlation between peripheral underarousal and cortical underarousal was observed in the ADHD group or the control group. The observed cortical underarousal reflected in the decreased CNV supports the notion of a reduced CNV amplitude as a possible biomarker for ADHD. However, the connection between cortical and peripheral arousal is not as clear as is suggested in previous research investigating both separately. Implications of these results for new treatment options for ADHD such as biofeedback are discussed. PMID- 25802472 TI - Introduction to a thematic issue for WWOX. AB - Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation. PMID- 25802471 TI - Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance and Fasting Glucose Levels. AB - BACKGROUND: Adverse effects of metformin are primarily related to gastrointestinal (GI) intolerance that could limit titration to an efficacious dose or cause discontinuation of the medication. Because some metformin side effects may be attributable to shifts in the GI microbiome, we tested whether a GI microbiome modulator (GIMM) used in combination with metformin would ameliorate the GI symptoms. METHODS: A 2-period crossover study design was used with 2 treatment sequences, either placebo in period 1 followed by GIMM in period 2 or vice versa. Study periods lasted for 2 weeks, with a 2-week washout period between. During the first week, type 2 diabetes patients (T2D) who experienced metformin GI intolerance took 500 mg metformin along with their assigned NM504 (GIMM) or placebo treatment with breakfast and with dinner. In the second week, the 10 subjects took 500 mg metformin (t.i.d.), with GIMM or placebo consumed with the first and third daily metformin doses. Subjects were permitted to discontinue metformin dosing if it became intolerable. RESULTS: The combination of metformin and GIMM treatment produced a significantly better tolerance score to metformin than the placebo combination (6.78 +/- 0.65 [mean +/- SEM] versus 4.45 +/- 0.69, P = .0006). Mean fasting glucose levels were significantly (P < .02) lower with the metformin-GIMM combination (121.3 +/- 7.8 mg/dl) than with metformin-placebo (151.9 +/- 7.8 mg/dl). CONCLUSION: Combining a GI microbiome modulator with metformin might allow the greater use of metformin in T2D patients and improve treatment of the disease. PMID- 25802474 TI - Polymorphisms in the IFNgamma, IL-10, and TGFbeta genes may be associated with HIV-1 infection. AB - OBJECTIVE: This study investigated possible associations between the TNFalpha 308G/A, IFN+874A/T, IL-6-174C/G, IL-10-1082A/G, and TGFbeta-509C/T polymorphisms with HIV-1 infection, in addition to correlation of the polymorphisms with clinical markers of AIDS progression, such as levels of CD4+/CD8+ T lymphocytes and plasma viral load. METHODS: A total of 216 individuals who were infected with HIV-1 and on antiretroviral therapy (ART) and 294 individuals from the uninfected control group were analyzed. RESULTS: All individuals evaluated were negative for total anti-HBc, anti-HCV, anti-T. pallidum, and anti-HTLV-1/2. The polymorphisms were identified by PCR-RFLP. Individuals presenting the IFN+874A allele as well as the AA genotype were more frequent in the HIV-1 infected group compared to the control group (P < 0.05), in addition to having lower levels of CD4+ T lymphocytes. The CD8+ T lymphocytes count was significantly lower in individuals with the IL-10-1082 GG genotype. The TGFbeta-509TT genotype was associated with higher plasma viral load. CONCLUSIONS: The results suggest that the presence of the IFN+874A allele confers susceptibility to HIV-1 infection and a decrease in the number of CD4+ T lymphocytes. In addition, the genotype associated with high serum levels of TGFbeta may be associated with an increase in plasma viral load. PMID- 25802477 TI - Detection of SNCA and FBN1 methylation in the stool as a biomarker for colorectal cancer. AB - AIM: We examined the methylation status of SNCA and FBN1 genes in patients' paired tissue and stool samples for detection of colorectal cancer (CRC). PATIENTS AND METHODS: 89 DNA tissue samples (normal/cancer) and corresponding stool samples were analyzed in our study. In addition, 30 stool samples were collected as healthy controls. RESULTS: The methylation level of those samples was measured by methylation-specific polymerase chain reaction (MSP). The result shows that compared with the paired controls, both SNCA and FBN1 were significantly hypermethylated in CRC patients in tissue samples (P < 0.001). In the stool samples, hypermethylated SNCA and FBN1 were detected to be significantly higher than that in normal stool samples (P < 0.001). The combined sensitivity of at least one positive among the two markers in stool samples was 84.3%, with a specificity of 93.3%. In addition, our experiment suggested that the positive rates of SNCA and FBN1 in Dukes A stage were significantly higher than that of FOBT (P = 0.039; P = 0.006, resp.). CONCLUSION: We concluded that methylation testing of SNCA and FBN1 genes in stool sample may offer a good alternative in a simple, promising, and noninvasive detection of colorectal cancer. PMID- 25802475 TI - Can biomarkers help to diagnose early heart failure with preserved ejection fraction? AB - Early heart failure with preserved ejection fraction (HFpEF) is a frequent disease, but its diagnosis is difficult and relies mostly on the evidence of left ventricular filling pressure (LVFP) elevation during exercise. Several reports have suggested that natriuretic peptides plasma levels reflect exercise-induced increase in LVFP, but they still have significant limitations. In this context, any new laboratory biomarker that can accurately reflect LVFP elevation during exercise is desirable. Recently, cardiotrophin-1, soluble endoglin, ST2, growth differentiation factor 15, galectin-3, and other new laboratory markers associated with LVFP have emerged. However, the current data on the relationship of these biomarkers and diastolic dysfunction are limited to resting conditions. Therefore, their secretion deserves to be tested under the exercise to determine their potential role in making a diagnosis of early HFpEF. PMID- 25802476 TI - The Affymetrix DMET Plus platform reveals unique distribution of ADME-related variants in ethnic Arabs. AB - BACKGROUND: The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus Premier Pack has been designed to genotype 1936 gene variants thought to be essential for screening patients in personalized drug therapy. These variants include the cytochrome P450s (CYP450s), the key metabolizing enzymes, many other enzymes involved in phase I and phase II pharmacokinetic reactions, and signaling mediators associated with variability in clinical response to numerous drugs not only among individuals, but also between ethnic populations. MATERIALS AND METHODS: We genotyped 600 Saudi individuals for 1936 variants on the DMET platform to evaluate their clinical potential in personalized medicine in ethnic Arabs. RESULTS: Approximately 49% each of the 437 CYP450 variants, 56% of the 581 transporters, 56% of 419 transferases, 48% of the 104 dehydrogenases, and 58% of the remaining 390 variants were detected. Several variants, such as rs3740071, rs6193, rs258751, rs6199, rs11568421, and rs8187797, exhibited significantly either higher or lower minor allele frequencies (MAFs) than those in other ethnic groups. DISCUSSION: The present study revealed some unique distribution trends for several variants in Arabs, which displayed partly inverse allelic prevalence compared to other ethnic populations. The results point therefore to the need to verify and ascertain the prevalence of a variant as a prerequisite for engaging it in clinical routine screening in personalized medicine in any given population. PMID- 25802479 TI - Identification of differentially expressed genes associated with prognosis of B acute lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder with high mortality rates. The aim of this study was to validate the expression profile of 45 genes associated with signaling pathways involved in leukemia and to evaluate their association with the prognosis of B-ALL. METHODS: 219 samples of peripheral blood mononuclear cells obtained from 73 B-ALL patients were studied at diagnosis, four, and eight weeks after starting treatment. Gene expression was analyzed by quantitative real-time polymerase chain reaction. RESULTS: Normalized delta Cq values of 23 genes showed differences between B-ALL and controls at diagnosis time (P values < 0.05). There were significant associations between B-ALL patients relapse/death and the expression levels of IL2RA, SORT1, DEFA1, and FLT3 genes at least in one of the times evaluated (P values < 0.05 and odds ratio ranges: 3.73-27). The association between FLT3 deregulation and relapse/death was a constant in the times studied and their overexpression significantly increased the odds of relapse/death in a range of 3.73 and 6.05 among study population (P values < 0.05). CONCLUSIONS: Overexpression of FLT3 and DEFA1 genes retained independent prognostic significance for B-ALL outcome, reflected as increased risks of relapse/death among the study population. PMID- 25802478 TI - MTHFR C677T gene polymorphism and head and neck cancer risk: a meta-analysis based on 23 publications. AB - OBJECTIVE: Conflicting results on the association between MTHFR polymorphism and head and neck cancer (HNC) risk were reported. We therefore performed a meta analysis to derive a more precise relationship between MTHFR C677T polymorphism and HNC risk. METHODS: Three online databases of PubMed, Embase, and CNKI were researched on the associations between MTHFR C677T polymorphism and HNC risk. Twenty-three published case-control studies involving 4,955 cases and 8,805 controls were collected. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the relationship between MTHFR C677T polymorphism and HNC risk. Sensitivity analysis, cumulative analyses, and publication bias were conducted to validate the strength of the results. RESULTS: Overall, no significant association between MTHFR C677T polymorphism and HNC risk was found in this meta analysis (T versus C: OR = 1.04, 95% CI = 0.92-1.18; TT versus CC: OR = 1.15, 95% CI = 0.90-1.46; CT versus CC: OR = 1.00, 95% CI = 0.85-1.17; CT + TT versus CC: OR = 1.01, 95% CI = 0.87-1.18; TT versus CC + CT: OR = 1.11, 95% CI = 0.98-1.26). In the subgroup analysis by HWE, ethnicity, study design, cancer location, and negative significant associations were detected in almost all genetic models, except for few significant risks that were found in thyroid cancer. CONCLUSION: This meta-analysis demonstrates that MTHFR C677T polymorphism may not be a risk factor for the developing of HNC. PMID- 25802480 TI - In vitro sensitivity of paired Leishmania (Viannia) braziliensis samples isolated before meglumine antimoniate treatment and after treatment failure or reactivation of cutaneous leishmaniasis. AB - This study evaluated the in vitro sensitivity of paired Leishmania braziliensis samples isolated from the same patient before pentavalent antimonial treatment (Sample A) and after treatment failure or cutaneous leishmaniasis reactivation (Sample B) in patients undergoing intralesional administration or injections (5 mgSb(V)/kg/d) of meglumine antimoniate. Fourteen samples from 7 patients were studied. After 24 h of drug exposure, 50% lethal dose (LD50) values for promastigotes ranged from 0.37 mg/mL to 5.86 mg/mL for samples obtained before treatment (A) and 0.89 mg/mL to 7.80 mg/mL for samples obtained after treatment (B). After 48 h, LD50 values ranged from 0.37 mg/mL to 5.75 mg/mL and 0.70 mg/mL to 7.68 mg/mL for A and B samples, respectively. After 48 h, LD50 values for amastigotes ranged from 11.7 to 44.3 MUg/mL for A samples and 13.7 to 52.7 MUg/mL for B samples. Of 7 patients, 1 discontinued treatment and 6 were cured after retreatment with amphotericin B (4 cases) or meglumine antimoniate (2 cases). Overall the B samples had higher LD50 values than A samples; however the difference was not significant. These results do not support the hypothesis that low-dose and intralesional treatments induce selection of resistant parasites in vitro and suggest that other factors may influence therapeutic outcome in patients with poor response to initial treatment. PMID- 25802481 TI - Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats. AB - OBJECTIVES: Aluminium, a neurotoxic agent in humans, has been implicated in the pathogenesis of neurodegenerative disorders. In this study, we examined the behavioral and biochemical effects of aluminium in rats with special emphasis on memory centres, namely, hippocampus and frontal cortex. Further, the effect of simvastatin treatment on aluminium intoxication was evaluated. METHODS: Rats were exposed to aluminium chloride (AlCl3) for 60 days. Simvastatin (10 mg/kg/p.o.) and rivastigmine (1 mg/kg/p.o.) were administered daily prior to AlCl3. Behavioral parameters were assessed using Morris water maze test and actophotometer followed by biochemical investigations, namely, acetylcholinesterase (AChE) activity, TNF-alpha level, antioxidant enzymes (GSH, catalase), lipid peroxidation, and nitrite level in hippocampus and frontal cortex. Triglycerides, total cholesterol, LDL, and HDL levels in serum were also determined. KEY FINDINGS: Simvastatin treatment improved cognitive function and locomotor activity in rats. Simvastatin reversed hyperlipidemia and significantly rectified the deleterious effect of AlCl3 on AChE activity. Further, in hippocampus and frontal cortex, aluminium-induced elevation in nitrite and TNF alpha and reduction in antioxidant enzymes were inhibited by simvastatin. CONCLUSION: To conclude, the present study suggests that simvastatin per se protects the neurons in hippocampus and frontal cortex from AlCl3, an environmental toxin. PMID- 25802483 TI - Response to: comment on "serum amyloid a as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis". PMID- 25802482 TI - Increased levels of soluble ST2 in patients with active newly diagnosed ANCA associated vasculitis. AB - OBJECTIVE: ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA associated vasculitides (AAV). METHODS: 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. RESULTS: Newly diagnosed AAV patients had higher sST2 levels than controls (P < 0.01). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (P < 0.001). IL-33 levels were higher in AAV patients than in the control groups (P = 0.002). However, serum IL 33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (P = 0.012). CONCLUSIONS: Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients. PMID- 25802484 TI - ABCB1 transporter and Toll-like receptor 4 in trabecular meshwork cells. AB - PURPOSE: The aqueous humor nourishes the avascular tissues of the anterior segment, and the trabecular meshwork (TM) plays a role in the efflux of endogenous substances and xenobiotics from the aqueous humor. ATP (ATP)-binding cassette (ABC) transporter superfamily members respond to stressors such as hypoxia, cytokine signaling, and aging. The innate immune system within the TM, particularly Toll-like receptor 4 (TLR4) and its ligands, e.g., low-molecular weight hyaluronic acid (LMW-HA) and lipopolysaccharide (LPS), plays a significant role in maintaining a normal environment in the anterior chamber. We hypothesize that the innate immune system may interact with ATP-binding cassette sub-family members ABCB1 (p-glycoprotein and multidrug resistance protein 1) to detoxify xenobiotics from the aqueous humor and in the TM. METHODS: Cell lysates of human TM cells, RAW 264.7 macrophages, and PC12 cells were subjected to western blot analysis. The TM cells were positive for TLR4, ABCB1, and CYP3A5 and were negative for the ABCC1 transporter. Human TM cells and RAW 264.7 macrophages were plated on eight-well chamber slides at 5,000 cells/well overnight in 10% fetal bovine serum (FBS) cell growth medium. The medium was changed to 0.1% FBS 2 h before treatment. Cells were challenged with 1 and 10 mM lactate, 100 ng LMW-HA (20 kDa), 100 ng high-molecular-weight HA (HMW-HA, 1,000 kDa), 100 ng LPS, and/or 100 MUM naloxone for 0.5, 1, 2, and 4 h. Calcein acetyoxymethyl ester (calcein AM; 0.25 MUM) was added for 30 min as the reporting molecule. After calcein AM was administered, it was cleaved by an esterase into a fluorescent product that is normally transported out of the cell by ABCB1. Positive controls were 100 MUM verapamil and 50 MUM digoxin. After the challenge, the TM cells were fixed at 4 degrees C in 3% paraformaldehyde for 15 min, mounted with Vectashield and 4',6 diamidino-2-phenylindole (DAPI) mounting medium, and analyzed by a masked observer using a Leica confocal microscope and software. RESULTS: Verapamil, an ABCB1 inhibitor, significantly (p<0.001) increased fluorescent calcein retention in the cytoplasm of the TM and RAW 264.7 cells compared to the PBS control. Digoxin, an ABCB1 activator, increased calcein efflux (p<0.001). Lactate reduced ABCB1 activity. HMW-HA significantly (p<0.001) reduced ABCB1 activity, whereas LMW-HA decreased ABCB1 activity, and the HA effects were blocked by naloxone (p<0.001), a TLR4 inhibitor. LPS alone did not change ABCB1 activity whereas dephosphorylated LPS significantly (p<0.001) enhanced ABCB1 activity in the TM cells. beta-amyloid significantly reduced ABCB1 activity, and the beta-amyloid effects were blocked by naloxone. CONCLUSIONS: TM cells are responsive to ABCB1 inhibitors and activators. ABCB1 functional activity is affected by TLR4 agonists suggesting that modulation of TLR4 is important in ABCB1 function. The innate immune inflammatory response in the TM may play a role in the ABCB1 detoxification of potentially harmful constituents in the aqueous humor. PMID- 25802485 TI - NYX mutations in four families with high myopia with or without CSNB1. AB - PURPOSE: Mutations in the NYX gene are known to cause complete congenital stationary night blindness (CSNB1), which is always accompanied by high myopia. In this study, we aimed to investigate the association between NYX mutations and high myopia with or without CSNB1. METHODS: Four Chinese families having high myopia with or without CSNB1 and 96 normal controls were recruited. We searched for mutations in the NYX gene using Sanger sequencing. Further analyses of the detected variations in the available family members were performed, and the frequencies of the detected variations in 96 normal controls were determined to verify our deduction. The effect of each variation on the nyctalopin protein was predicted using online tools. RESULTS: Four potential pathogenic variations in the NYX gene were found in four families with high myopia with or without CSNB1. Three of the four variants were novel (c.626G>C; c.121delG; c.335T>C). The previously identified variant, c.529_530delGCinsAT, was found in an isolated highly myopic patient and an affected brother, but the other affected brother did not carry the same variation. Further linkage analyses of this family showed a coinheritance of markers at MYP1. These four mutations were not identified in the 96 normal controls. CONCLUSIONS: Our study expands the mutation spectrum of NYX for cases of high myopia with CSNB1; however, more evidence is needed to elucidate the pathogenic effects of NYX on isolated high myopia. PMID- 25802486 TI - MicroRNA-152 represses VEGF and TGFbeta1 expressions through post-transcriptional inhibition of (Pro)renin receptor in human retinal endothelial cells. AB - PURPOSE: The (pro)renin receptor (PRR), a component of the renin-angiotensin system (RAS), plays an important role in the physiologic and pathophysiological regulation of blood pressure and fluid/electrolyte homeostasis. The RAS including the PRR has been identified in retinal endothelial cells and other ocular tissues. In this study, the potential involvement of miRNAs in the posttranscriptional regulation of PRR was investigated in human retinal endothelial cells (hRECs) under high glucose (HG) conditions. METHODS: miRNA-152 (miR-152) was identified in silico as a potential regulator of PRR, and this was confirmed by quantitative real-time PCR (qRT-PCR) and PRR 3'-untranslated region (UTR) reporter assays. Using RNA interference, both AT1R and PRR were implicated in the HG-mediated induction of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), and transforming growth factor beta1 (TGFbeta1). RESULTS: The downregulation of miR-152 was observed in hRECs and rat retinal tissues under HG conditions. In parallel, PRR (target of miR-152), VEGF, VEGFR-2, and TGFbeta1 at mRNA levels were elevated. However, the transfection of hRECs with miR-152 mimics in HG conditions resulted in the suppression of the PRR expression, as well as reduced VEGF, VEGFR-2, and TGFbeta1 production. This was reversed by transfecting cells with the antisense (antagomir) of miR-152, suggesting the glucose-induced upregulation of VEGF, VEGFR-2, and TGFbeta1 is mediated through PRR, and this regulation is likely achieved through the HG-mediated modulation of miRNAs. CONCLUSIONS: We have demonstrated that miR-152 interacting with PRR regulates downstream VEGF, VRGFR-2, and TGFbeta1 expressions in hRECs in HG conditions. These studies suggest miR-152 and PRR may play a role in the pathogenesis of diabetic retinopathy (DR). PMID- 25802488 TI - A Quantitative Measure of Field Illumination. AB - In this paper, we describe a statistically based algorithm to quantify the uniformity of illumination in an optical light microscopy imaging system that outputs a single quality factor (QF) score. The importance of homogeneous field illumination in quantitative light microscopy is well understood and often checked. However, there is currently no standard automatic quantitative measure of the uniformity of the field illumination. Images from 89 different laser scanning confocal microscopes (LSCMs), which were collected as part of an international study on microscope quality assessment, were used as a "training" set to build the algorithm. To validate the algorithm and verify its robustness, images from 33 additional microscopes, including LSCM and wide-field (WF) microscopes, were used. The statistical paradigm used for developing the quality scoring scale was a regression approach to supervised learning. Three intensity profiles across each image-2 corner-to-corner diagonals and a center horizontal were used to generate pixel-intensity data. All of the lines passed through the center of the image. The intensity profile data then were converted into a single field illumination QF score in the range of 0-100, with 0 having extreme variation, and therefore, essentially unusable, and 100 having no deviation, i.e., straight lines with a constant uniform intensity. Empirically, a QF >= 83 was determined to be the minimum acceptable value based on manufacturer acceptance tests and reasonably achievable values. This new QF is an invaluable metric to ascertain objectively and easily the uniformity of illumination quality, provide a traceable reference for monitoring field uniformity over time, and make a direct comparison among different microscopes. The QF can also be used as an indicator of system failure and the need for alignment or service of the instrument. PMID- 25802487 TI - Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin. AB - PURPOSE: To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members. METHODS: Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next generation sequencing. A minigene splicing assay was used to confirm the splicing defects. RESULTS: In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244-2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin. CONCLUSIONS: In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa. PMID- 25802489 TI - Angiogenesis QTL on Mouse Chromosome 8 Colocalizes with Differential beta Defensin Expression. AB - Identification of genetic factors that modify complex traits is often complicated by gene-environment interactions that contribute to the observed phenotype. In model systems, the phenotypic outcomes quantified are typically traits that maximize observed variance, which in turn, should maximize the detection of quantitative trait loci (QTL) in subsequent mapping studies. However, when the observed trait is dependent on multiple interacting factors, it can complicate genetic analysis, reducing the likelihood that the modifying mutation will ultimately be found. Alternatively, by focusing on intermediate phenotypes of a larger condition, we can reduce a model's complexity, which will, in turn, limit the number of QTL that contribute to variance. We used a novel method to follow angiogenesis in mice that reduces environmental variance by measuring endothelial cell growth from culture of isolated skin biopsies that varies depending on the genetic source of the tissue. This method, in combination with a backcross breeding strategy, is intended to reduce genetic complexity and limit the phenotypic effects to fewer modifier loci. We determined that our approach was an efficient means to generate recombinant progeny and used this cohort to map a novel s.c. angiogenesis QTL to proximal mouse chromosome (Chr.) 8 with suggestive QTL on Chr. 2 and 7. Global mRNA expression analysis of samples from parental reference strains revealed beta-defensins as potential candidate genes for future study. PMID- 25802490 TI - Any Way You Slice It-A Comparison of Confocal Microscopy Techniques. AB - The confocal fluorescence microscope has become a popular tool for life sciences researchers, primarily because of its ability to remove blur from outside of the focal plane of the image. Several different kinds of confocal microscopes have been developed, each with advantages and disadvantages. This article will cover the grid confocal, classic confocal laser-scanning microscope (CLSM), the resonant scanning-CLSM, and the spinning-disk confocal microscope. The way each microscope technique works, the best applications the technique is suited for, the limitations of the technique, and new developments for each technology will be presented. Researchers who have access to a range of different confocal microscopes (e.g., through a local core facility) should find this paper helpful for choosing the best confocal technology for specific imaging applications. Others with funding to purchase an instrument should find the article helpful in deciding which technology is ideal for their area of research. PMID- 25802492 TI - Focus On Light Microscopy. PMID- 25802491 TI - Using Photobleaching to Measure Spindle Microtubule Dynamics in Primary Cultures of Dividing Drosophila Meiotic Spermatocytes. AB - In dividing animal cells, a microtubule (MT)-based bipolar spindle governs chromosome movement. Current models propose that the spindle facilitates and/or generates translocating forces by regionally depolymerizing the kinetochore fibers (k-fibers) that bind each chromosome. It is unclear how conserved these sites and the resultant chromosome-moving mechanisms are between different dividing cell types because of the technical challenges of quantitatively studying MTs in many specimens. In particular, our knowledge of MT kinetics during the sperm-producing male meiotic divisions remains in its infancy. In this study, I use an easy-to-implement photobleaching-based assay for measuring spindle MT dynamics in primary cultures of meiotic spermatocytes isolated from the fruit fly Drosophila melanogaster. By use of standard scanning confocal microscopy features, fiducial marks were photobleached on fluorescent protein (FP)-tagged MTs. These were followed by time-lapse imaging during different division stages, and their displacement rates were calculated using public domain software. I find that k-fibers continually shorten at their poles during metaphase and anaphase A through the process of MT flux. Anaphase chromosome movement is complemented by Pac-Man, the shortening of the k-fiber at its chromosomal interface. Thus, Drosophila spermatocytes share the sites of spindle dynamism and mechanisms of chromosome movement with mitotic cells. The data reveal the applicability of the photobleaching assay for measuring MT dynamics in primary cultures. This approach can be readily applied to other systems. PMID- 25802494 TI - Treatment of refractory Crohn's disease and pyoderma gangrenosum with a combination regimen of rifaximin, gentamicin and metronidazole. AB - The etiology of Crohn's disease (CD) remains controversial. It is hypothesized that CD is the result of an abnormal immune response to the gut flora in genetically susceptible hosts. However, an infectious etiology has not been completely ruled out. Antibiotics have been utilized with some success to modify the course of the disease. Here, we report a patient with CD and pyoderma gangrenosum refractory to standard therapy, including biologics, who achieved remission with a combination of rifaximin, gentamicin and metronidazole. PMID- 25802493 TI - Cardiac tamponade as the initial presentation of systemic lupus erythematosus: a case report and review of the literature. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve any organ system, exhibiting great diversity in presentation. Cardiac tamponade as the initial presentation of childhood onset SLE (cSLE) is rare. We report the case of a 10 year old Afro-Caribbean female who presented with complaints of chest pain, shortness of breath and fever over 4 days. Clinical examination strongly suggested cardiac tamponade which was confirmed by investigations and treated with pericardiocentesis. After a thorough investigation, the underlying diagnosis of SLE was confirmed using the Systemic Lupus International Collaborating Clinics (SLICC) criteria and high dose corticosteroid therapy initiated. A review of recent studies shows that common initial presentations of cSLE include constitutional symptoms, renal disease, musculoskeletal and cutaneous involvement. In presenting this case and reviewing the literature we emphasize the importance of cSLE as a differential diagnosis when presented with pericarditis in the presence or absence of cardiac tamponade. In these patients early diagnosis and treatment is desired and in this regard we also discuss the sensitivity of the SLICC criteria in cSLE. PMID- 25802496 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000362225.]. PMID- 25802495 TI - Peritoneal recurrence of initially controlled hepatocellular carcinoma after living donor liver transplantation. AB - It is well known that the presence of end-stage liver disease increases the risk of developing hepatocellular carcinoma (HCC). Liver transplantation (LT) for patients within the Milan criteria has become a standard treatment for HCC in most developed centers worldwide. However, a major cause of death in cirrhotic patients with HCC after transplantation is tumor recurrence, including peritoneal recurrences, which develops rarely but presents a significant problem with regard to their management. Our experience includes two cases with HCC within the Milan criteria of peritoneal recurrences after living donor LT. Both patients had interventions for HCC in their medical history before LT, and we propose that these might have been a possible cause of the HCC peritoneal recurrence. PMID- 25802497 TI - A unique case of a patient with rectal cancer who developed benign esophageal stenosis after localized rectal radiation and systemic chemotherapy. AB - Acute esophagitis and esophageal strictures typically occur after local radiation therapy to the thoracic field. Toxicity is usually limited to the field of radiation and potentially augmented by concomitant use of chemotherapy, however esophageal stricturing due to chemotherapy alone is exceedingly rare. Gastrointestinal toxicity has been previously reported in the setting of 5 fluorouracil (5-FU)-based chemotherapy with abnormal thymidylate synthase or dihydropyrimidine dehydrogenase activities. We present a unique case of isolated chemotherapy-induced esophageal stricture in the setting of stage IIIa rectal adenocarcinoma which presented shortly after initiation of treatment with 5-FU based chemotherapy in a patient with normal thymidylate synthase and dihydropyrimidine dehydrogenase assays. These findings prompt further investigation of pathways and potential risk factors leading to esophageal toxicity in patients treated with 5-FU-based chemotherapy. PMID- 25802498 TI - Age is no longer a limit: two cases of hepatectomy in patients over 90 years old. AB - Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. The age of patients affected by HCC is considered to be increasing, and several studies have reported significantly higher rates of morbidity and mortality after hepatectomy for HCC in elderly patients. However, other studies have reported that the short- and long-term outcomes of surgery for HCC in elderly patients are similar to those in younger patients. Whether the indications for hepatic resection in elderly patients resemble those in younger patients has thus been questioned. We describe two cases of patients over 90 years old who underwent major hepatectomy for HCC, representing the oldest patients in the world to have done so. PMID- 25802499 TI - The diagnostic challenges of autoimmune pancreatitis. AB - Autoimmune pancreatitis is a rare but important differential diagnosis from pancreatic cancer. This autoimmune disease can mimic pancreatic cancer by its clinical symptoms, including weight loss and jaundice. Furthermore imaging findings may include a mass of the pancreas. Here we present the case of a 67 year-old male patient diagnosed with autoimmune pancreatitis but showing the well known symptoms of pancreatic cancer. This emphasizes the difficulties of histological findings and the importance of the correct diagnostic process. PMID- 25802500 TI - Bilateral Heel Numbness due to External Compression during Obstetric Epidural Analgesia. AB - We describe the case of a 32-year-old woman who developed bilateral heel numbness after obstetric epidural analgesia. We diagnosed her with bilateral neuropathy of the medial calcaneal nerve, most likely due to longstanding pressure on both heels. Risk factors for the development of this neuropathy were prolonged labour with spinal analgesia and a continuation of analgesia during episiotomy. Padded footrests decrease pressure and can possibly prevent this neuropathy. PMID- 25802501 TI - Transient global amnesia and brain tumour: chance concurrence or aetiological association? Case report and systematic literature review. AB - We report a patient presenting with episodes of transient amnesia, some with features suggestive of transient global amnesia (TGA), and some more reminiscent of transient epileptic amnesia. Investigation with neuroimaging revealed an intrinsic lesion in the right amygdala, with features suggestive of low-grade neoplasia. We undertook a systematic review of the literature on TGA and brain tumour. Fewer than 20 cases were identified, some of which did not conform to the clinical diagnostic criteria for TGA. Hence, the concurrence of brain tumour and TGA is very rare and of doubtful aetiological relevance. In some brain tumour associated cases, epilepsy may be masquerading as TGA. PMID- 25802502 TI - Hyperkinetic movement disorder secondary to punctate hemorrhage in lateral ventricle lining. AB - We present the case of an elderly male with hyperkinetic movements of the right arm and leg due to a small hemorrhage in the lateral aspect of the left lateral ventricle atrium. As per our database search, this is a unique presentation of a stroke in this particular location. PMID- 25802503 TI - An unusual presentation of concurrent congenital grouped pigmentation of the retina with albinotic spots. AB - A 10-year-old Japanese girl presented with multiple, small, flat, dark brown clusters of retinal pigment epithelium in both eyes. She had no other symptoms. The appearance was consistent with congenital grouped pigmentation of the retina or bear track spots. A unique co-existing feature was the presence of small, albinotic spots within the entire retina. Fluorescein angiography demonstrated a persistent hypofluorescence correlating with the grouped pigmentation of the retina and granular hyperfluorescence correlating with the albinotic spots. Her mother also showed irregular pigmentation and albinotic spots in both eyes. We describe an extremely rare case of congenital grouped pigmentation and albinotic spots occurring in the retina of the same individual. PMID- 25802505 TI - Peripapillary Choroidal Neovascularization Associated with Optic Nerve Head Drusen Treated with Anti-VEGF Agents. AB - Optic nerve head drusen can be associated with peripapillary choroidal neovascularization, in both the pediatric and adult population. These membranes can involve the macula, causing significant visual loss. Herein, we present a case that required treatment with an anti-VEGF agent. The patient failed to respond to the initial agent, but subsequently responded to a change of agent. Adult patients with macular degeneration involving peripapillary choroidal neovascularization associated with optic nerve head drusen may require individualized treatment plans. PMID- 25802506 TI - Single Bilateral Dexamethasone Implant in Addition to Panretinal Photocoagulation and Oral Azathioprine Treatment in IRVAN Syndrome. AB - The idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) syndrome is a disease characterized by multiple retinal macroaneurysms, neuroretinitis and peripheral capillary nonperfusion. Visual loss may result from either ischemia related complications or macular involvement. Treatment is not always rewarding. We report a case with stage 2 IRVAN syndrome who was successfully treated with a single bilateral intravitreal dexamethasone implant in addition to panretinal photocoagulation and systemic azathioprine treatment. PMID- 25802504 TI - Evaluation of the Response to Ranibizumab Therapy following Bevacizumab Treatment Failure in Eyes with Diabetic Macular Edema. AB - BACKGROUND/AIMS: Bevacizumab and ranibizumab are routinely used to treat diabetic macular edema (DME). We aim to evaluate the usefulness of switching to ranibizumab therapy following bevacizumab treatment failure in eyes with DME. METHODS: We performed a retrospective analysis of a consecutive group of patients with DME who received ranibizumab injections following the failure of bevacizumab injections. The injections were delivered following a pro re nata protocol every 4-6 weeks. The data collected included demographics, systemic and ophthalmic findings, as well as the central subfield thickness according to spectral-domain OCT. RESULTS: Eight eyes (5 patients) were included in the study. The median number of bevacizumab injections prior to the switch to ranibizumab was 4, and the median number of ranibizumab injections during the study was 2. The mean follow-up period was 541 +/- 258 days. The mean central retinal thickness (CRT) (+/-SEM) was 539 +/- 75 MUm before the initiation of bevacizumab treatment, and 524 +/- 43 MUm after the last bevacizumab injection (p = 0.7). It reduced to 325 +/- 26 MUm following the ranibizumab injections (p = 0.0063). The best-corrected visual acuity (BCVA) improved in 4 eyes and remained stable in 4 eyes following the ranibizumab injections. CONCLUSION: A ranibizumab therapy was effective in reducing the CRT in eyes that failed bevacizumab therapy. A BCVA improvement can also occur in these eyes. Switching between anti-vascular endothelial growth factor compounds may be beneficial in eyes with DME. PMID- 25802507 TI - A Case Report of Severe Corneal Toxicity following 0.5% Topical Moxifloxacin Use. AB - Moxifloxacin is a widely used topical antibiotic in various bacterial infections of the eye. Its safety and efficacy have been proved by many studies. We report a case of a rare adverse effect following its use. A 10-year-old female who had presented with acute bacterial conjunctivitis in both eyes with no corneal involvement was started on preservative-free 0.5% topical moxifloxacin four times a day. The child developed a severe form of corneal toxicity in both eyes with circumcorneal congestion and corneal edema following its use. The child's visual acuity had dropped from 20/20 to 20/400 in both the eyes. Topical moxifloxacin was discontinued, following which the cornea cleared dramatically and the visual acuity became normal. This case indicates that though rare, topical moxifloxacin can cause severe keratitis and that more studies need to be conducted to evaluate its safety. PMID- 25802508 TI - Cyclodialysis cleft treatment using a minimally invasive technique. AB - PURPOSE: To report a case of a cyclodialysis cleft that was successfully managed with gas endotamponade and cyclocryotherapy. METHODS: A 37-year-old male victim of a severe blunt ocular trauma was referred to our service for evaluation and treatment of a left eye hypotony. Clinical examination revealed an intraocular pressure of 2 mm Hg, a cyclodialysis cleft extending from the 11 to 1 o'clock positions and a hypotonic maculopathy. Left eye best corrected visual acuity (BCVA) was 3/10. The patient failed to respond to conservative treatment with atropine 1%, so a single bubble of 16% C2F6 was injected into the vitreous cavity, followed by superior quadrant transconjunctival cyclocryotherapy. RESULTS: After gas absorption, the intraocular pressure increased to 11 mm Hg and became steady during the 24 months of follow-up. His hypotonic maculopathy resolved, and the BCVA improved to 9/10. Complete closure of the cyclodialysis cleft was documented with ultrasound biomicroscopy. CONCLUSION: Cryotherapy associated with gas endotamponade is a minimally invasive technique that could be considered for patients with cyclodialysis clefts that fail to respond to medical therapy. PMID- 25802509 TI - A case of a vitreomacular traction-associated macular microhole in an eye with focal choroidal excavation. AB - PURPOSE: It was the aim of this study to report a case of a vitreomacular traction-associated macular microhole (MMH) in an eye with focal choroidal excavation (FCE) detected by spectral-domain optical coherence tomography (SD OCT). PATIENTS AND METHODS: A 38-year-old Japanese female presented to our clinic complaining of metamorphopsia in her left eye. The patient then underwent SD-OCT as well as a routine ophthalmological examination. She had a previous history of a macular hole in her right eye that had been successfully treated by pars plana vitrectomy. RESULTS: Upon initial examination, her best-corrected visual acuity was 20/25 in the left eye with a refractive error of -10.25 diopters. Examination by SD-OCT revealed an MMH with an outer retinal defect adjacent to the FCE. SD OCT also revealed an intraretinal cystoid space in the macula with vitreous attachment around the foveal center. CONCLUSIONS: The findings of this report show that variable changes are likely to be associated with FCE. However, the etiology of FCE has yet to be fully elucidated and careful observation is necessary in cases of FCE. PMID- 25802511 TI - The construction of support vector machine classifier using the firefly algorithm. AB - The setting of parameters in the support vector machines (SVMs) is very important with regard to its accuracy and efficiency. In this paper, we employ the firefly algorithm to train all parameters of the SVM simultaneously, including the penalty parameter, smoothness parameter, and Lagrangian multiplier. The proposed method is called the firefly-based SVM (firefly-SVM). This tool is not considered the feature selection, because the SVM, together with feature selection, is not suitable for the application in a multiclass classification, especially for the one-against-all multiclass SVM. In experiments, binary and multiclass classifications are explored. In the experiments on binary classification, ten of the benchmark data sets of the University of California, Irvine (UCI), machine learning repository are used; additionally the firefly-SVM is applied to the multiclass diagnosis of ultrasonic supraspinatus images. The classification performance of firefly-SVM is also compared to the original LIBSVM method associated with the grid search method and the particle swarm optimization based SVM (PSO-SVM). The experimental results advocate the use of firefly-SVM to classify pattern classifications for maximum accuracy. PMID- 25802510 TI - Antimycobacterial and cytotoxicity activity of microcystins. AB - BACKGROUND: The present work aimed to evaluate the antimycobacterial activity and cytotoxicity of Microcystis aeruginosa toxins, the MC-LR variant and purified extract of [D-Leu(1)] microcystin-LR. METHODS: The antimicrobial activity of M. aeruginosa extract and microcystin was evaluated by resazurin microtiter assay against Mycobacterium tuberculosis, M. terrae, M. chelonae and M. kansasii. The cytotoxicity assay was performed by trypan blue exclusion against the HTC cell line. RESULTS: Antimicrobial activity was observed in the hexanic extract of M. aeruginosa (RST 9501 strain) against M. tuberculosis, including sensitive and resistant strains with minimal inhibitory concentrations (MIC) between 1.93 MUM and 0.06 MUM. The high activity of M. aeruginosa hexanic extract could be attributed to the major presence of the toxins MC-LR and [D-Leu(1)] MC-LR that showed activity at MIC between 53 and 0.42 MUM against tested mycobacterial strains. Even at the highest concentration tested, no toxicity of M. aeruginosa extracts was identified against HTC cells. CONCLUSIONS: These preliminary results suggest that [D-Leu(1)] MC-LR is a promising candidate for the development of a new antimycobacterial agent. PMID- 25802513 TI - Epidermal permeability barrier in the treatment of keratosis pilaris. AB - Objectives. To evaluate and compare the efficacy, safety, hydrating properties, and tolerability of 10% lactic acid (LA) and 5% salicylic acid (SA) in the therapy of keratosis pilaris (KP). Material and Method. Patients with KP were randomized for treatment with either 10% LA or 5% SA creams being applied twice daily for 3 months. The patients were clinically assessed at baseline and after 4, 8, and 12 weeks of treatment and 4 weeks after treatment. The functional properties of the stratum corneum (SC) were determined before treatment, 12 weeks, and follow-up phase by high-frequency conductance and transepidermal water loss (TEWL). Results. At the end of the trial, the mean reduction of the lesions from baseline was statistically significant for 10% LA (66%) and 5% SA (52%). During the treatment, higher conductance values were found on both group and this improvement was maintained until the follow up period. No significant differences in transepidermal water loss were observed after treatment. The adverse effects were limited to mild irritation localized on the skin without systemic side effect. Conclusion. The study demonstrated that 10% LA and 5% SA are beneficial to treat KP with the significantly clearance and marked improvement as by instrumental evaluation. PMID- 25802512 TI - Golden ratio genetic algorithm based approach for modelling and analysis of the capacity expansion of urban road traffic network. AB - This paper presents the modelling and analysis of the capacity expansion of urban road traffic network (ICURTN). Thebilevel programming model is first employed to model the ICURTN, in which the utility of the entire network is maximized with the optimal utility of travelers' route choice. Then, an improved hybrid genetic algorithm integrated with golden ratio (HGAGR) is developed to enhance the local search of simple genetic algorithms, and the proposed capacity expansion model is solved by the combination of the HGAGR and the Frank-Wolfe algorithm. Taking the traditional one-way network and bidirectional network as the study case, three numerical calculations are conducted to validate the presented model and algorithm, and the primary influencing factors on extended capacity model are analyzed. The calculation results indicate that capacity expansion of road network is an effective measure to enlarge the capacity of urban road network, especially on the condition of limited construction budget; the average computation time of the HGAGR is 122 seconds, which meets the real-time demand in the evaluation of the road network capacity. PMID- 25802514 TI - Psychological therapies in patients with irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. AB - Background. Irritable bowel syndrome (IBS) is a poorly understood disease with few effective treatments. Psychosocial factors are believed to contribute to the pathogenesis of IBS. Objective. To evaluate the evidence for psychological therapies in IBS treatment. Methods. We searched six medical databases through February 6, 2014, for randomized controlled trials (RCTs) of psychological therapies for the treatment of IBS. Two independent reviewers identified the RCTs, extracted the data, and assessed trial quality. We used the random-effect model to pool standardized mean difference (SMD) and 95% confidence interval (CI) across trials. Results. 15 RCTs that mostly evaluated cognitive behavioral therapy were included. Psychological therapies were associated with improvement in IBS symptoms severity scales (SMD -0.618; 95% CI: -0.853 to -0.383), IBS Quality of Life (SMD 0.604; 95% CI: 0.440 to 0.768), and abdominal pain (SMD 0.282; 95% CI: -0.562 to -0.001). No statistically significant effect was observed on diarrhea or constipation. Limitations. The trials were at increased risk of bias and the overall sample size was small leading to imprecision. Conclusion. Psychological therapies may improve the quality of life and symptom severity in IBS. The effect size noted is moderate to large and is clinically meaningful. PMID- 25802515 TI - Interval cancers in a population-based screening program for colorectal cancer in catalonia, Spain. AB - Objective. To analyze interval cancers among participants in a screening program for colorectal cancer (CRC) during four screening rounds. Methods. The study population consisted of participants of a fecal occult blood test-based screening program from February 2000 to September 2010, with a 30-month follow-up (n = 30,480). We used hospital administration data to identify CRC. An interval cancer was defined as an invasive cancer diagnosed within 30 months of a negative screening result and before the next recommended examination. Gender, age, stage, and site distribution of interval cancers were compared with those in the screen detected group. Results. Within the study period, 97 tumors were screen-detected and 74 tumors were diagnosed after a negative screening. In addition, 17 CRC (18.3%) were found after an inconclusive result and 2 cases were diagnosed within the surveillance interval (2.1%). There was an increase of interval cancers over the four rounds (from 32.4% to 46.0%). When compared with screen-detected cancers, interval cancers were found predominantly in the rectum (OR: 3.66; 95% CI: 1.51-8.88) and at more advanced stages (P = 0.025). Conclusion. There are large numbers of cancer that are not detected through fecal occult blood test based screening. The low sensitivity should be emphasized to ensure that individuals with symptoms are not falsely reassured. PMID- 25802516 TI - Increased Mercury Levels in Patients with Celiac Disease following a Gluten-Free Regimen. AB - Background and Aim. Although mercury is involved in several immunological diseases, nothing is known about its implication in celiac disease. Our aim was to evaluate blood and urinary levels of mercury in celiac patients. Methods. We prospectively enrolled 30 celiac patients (20 treated with normal duodenal mucosa and 10 untreated with duodenal atrophy) and 20 healthy controls from the same geographic area. Blood and urinary mercury concentrations were measured by means of flow injection inductively coupled plasma mass spectrometry. Enrolled patients underwent dental chart for amalgam fillings and completed a food-frequency questionnaire to evaluate diet and fish intake. Results. Mercury blood/urinary levels were 2.4 +/- 2.3/1.0 +/- 1.4, 10.2 +/- 6.7/2.2 +/- 3.0 and 3.7 +/- 2.7/1.3 +/- 1.2 in untreated CD, treated CD, and healthy controls, respectively. Resulting mercury levels were significantly higher in celiac patients following a gluten-free diet. No differences were found regarding fish intake and number of amalgam fillings. No demographic or clinical data were significantly associated with mercury levels in biologic samples. Conclusion. Data demonstrate a fourfold increase of mercury blood levels in celiac patients following a gluten-free diet. Further studies are needed to clarify its role in celiac mechanism. PMID- 25802517 TI - Development of a machine learning method to predict membrane protein-ligand binding residues using basic sequence information. AB - Locating ligand binding sites and finding the functionally important residues from protein sequences as well as structures became one of the challenges in understanding their function. Hence a Naive Bayes classifier has been trained to predict whether a given amino acid residue in membrane protein sequence is a ligand binding residue or not using only sequence based information. The input to the classifier consists of the features of the target residue and two sequence neighbors on each side of the target residue. The classifier is trained and evaluated on a nonredundant set of 42 sequences (chains with at least one transmembrane domain) from 31 alpha-helical membrane proteins. The classifier achieves an overall accuracy of 70.7% with 72.5% specificity and 61.1% sensitivity in identifying ligand binding residues from sequence. The classifier performs better when the sequence is encoded by psi-blast generated PSSM profiles. Assessment of the predictions in the context of three-dimensional structures of proteins reveals the effectiveness of this method in identifying ligand binding sites from sequence information. In 83.3% (35 out of 42) of the proteins, the classifier identifies the ligand binding sites by correctly recognizing more than half of the binding residues. This will be useful to protein engineers in exploiting potential residues for functional assessment. PMID- 25802518 TI - Expression of P450arom and Estrogen Receptor Alpha in the Oviduct of Chinese Brown Frog (Rana dybowskii) during Prehibernation. AB - One specific physiological phenomenon of Chinese brown frog (Rana dybowskii) is that its oviduct expands prior to hibernation instead of expanding during the breeding period. In this study, we investigated the expression of P450arom and estrogen receptors alpha and beta (ERalpha and ERbeta) in the oviduct of Rana dybowskii during the breeding period and prehibernation. The results of the present study showed that there were significant differences in both oviductal weight and size with values markedly higher in prehibernation than in the breeding period. P450arom was observed in stromal tissue in both the breeding period and prehibernation. ERalpha was expressed in stromal tissue and epithelial cells in both periods, whereas ERbeta could not be detected. The mean protein and mRNA levels of P450arom and ERalpha were significantly higher in prehibernation as compared to the breeding period. Besides, oviductal content of 17beta estradiol was also higher in prehibernation than in the breeding period. These results suggested that estrogen may play autocrine/paracrine roles mediated by ERalpha in regulating the oviductal hypertrophy during prehibernation. PMID- 25802520 TI - Anaplastic thyroid carcinoma: molecular tools for diagnosis and therapy. PMID- 25802522 TI - Fast measurement of methanol concentration in ionic liquids by potential step method. AB - The development of direct methanol fuel cells required the attention to the electrolyte. A good electrolyte should not only be ionic conductive but also be crossover resistant. Ionic liquids could be a promising electrolyte for fuel cells. Monitoring methanol was critical in several locations in a direct methanol fuel cell. Conductivity could be used to monitor the methanol content in ionic liquids. The conductivity of 1-butyl-3-methylimidazolium tetrafluoroborate had a linear relationship with the methanol concentration. However, the conductivity was significantly affected by the moisture or water content in the ionic liquid. On the contrary, potential step could be used in sensing methanol in ionic liquids. This method was not affected by the water content. The sampling current at a properly selected sampling time was proportional to the concentration of methanol in 1-butyl-3-methylimidazolium tetrafluoroborate. The linearity still stood even when there was 2.4 M water present in the ionic liquid. PMID- 25802519 TI - Ejaculate oxidative stress is related with sperm DNA fragmentation and round cells. AB - Oxidative stress (OS) plays an essential role in male infertility aetiology by affecting sperm quality, function, and also the integrity of sperm DNA. The assessment of oxidative stress in semen may be an important tool to improve the evaluation of sperm reproductive capacity. The purpose of this study was the evaluation of any possible relation between the unbalance of oxidative stress caused by superoxide anion in the ejaculate with the presence of sperm DNA fragmentation and high concentration of round cells. 56 semen samples from males from couples suffering from infertility were evaluated according to World Health Organisation (WHO) 2010 guidelines. Oxidative stress levels from N1 (low) to N4 (high) were assessed in ejaculates using oxiSperm; DFI (sperm DNA fragmentation index) as assessed by the SCSA (Sperm Chromatin Structure Assay) was used for evaluation of sperm chromatin integrity. Our data show that high oxidative stress (N3-N4 levels) correlated positively with a DFI >= 30% (P = 0.0379) and round cells >=1.500.000/mL (P = 0.0084). In conclusion, OS increases sperm DNA damage. Thus evaluation of semen OS extent of sperm DNA damage in infertile man could be useful to develop new therapeutic strategies and improve success of assisted reproduction techniques (ART). PMID- 25802523 TI - Determination of the degree of degradation of frying rapeseed oil using fourier transform infrared spectroscopy combined with partial least-squares regression. AB - This rapid method for determining the degree of degradation of frying rapeseed oils uses Fourier-transform infrared (FTIR) spectroscopy combined with partial least-squares (PLS) regression. One hundred and fifty-six frying oil samples that degraded to different degrees by frying potatoes were scanned by an FTIR spectrometer using attenuated total reflectance (ATR). PLS regression with full cross validation was used for the prediction of acid value (AV) and total polar compounds (TPC) based on raw, first, and second derivative FTIR spectra (4000-650 cm(-1)). The precise calibration model based on the second derivative FTIR spectra shows that the coefficients of determination for calibration (R (2)) and standard errors of cross validation (SECV) were 0.99 and 0.16 mg KOH/g and 0.98 and 1.17% for AV and TPC, respectively. The accuracy of the calibration model, tested using the validation set, yielded standard errors of prediction (SEP) of 0.16 mg KOH/g and 1.10% for AV and TPC, respectively. Therefore, the degradation of frying oils can be accurately measured using FTIR spectroscopy combined with PLS regression. PMID- 25802524 TI - Stability-indicating HPLC determination of trandolapril in bulk drug and pharmaceutical dosage forms. AB - A rapid, simple, accurate, precise, economical, robust, and stability indicating reverse phase HPLC-PDA procedure has been developed and validated for the determination of trandolapril. The trandolapril was separated isocratically on Hypersil-Gold C18 column (250 mm * 4.6 mm, 5 MUm) with a mobile phase consisting of 50% acetonitrile and 50% water (containing 0.025% triethylamine, pH 3.0 +/- 0.1), at 25 +/- 2 degrees C. Retention time of the drug was ~4.6 min. The eluted compounds were monitored and identified at 210 nm. The linearity of the method was excellent (r (2) > 0.9999) over the concentration range of 1-24 MUg/mL; the limit of detection (LOD) and limit of quantitation (LOQ) were 0.0566 MUg/mL and 0.1715 MUg/mL, respectively. The overall precision was less than 2%. Mean recovery of trandolapril was more than 99%; no interference was found from the component present in the preparation. Stability studies indicate that the drug was stable to sunlight and UV light. The drug gives 6 different oxidative products on exposure to hydrogen peroxide. Slight degradation was observed in acidic condition. Degradation was higher in the alkaline condition compared to other conditions. The robustness of the method was studied using factorial design experiment. PMID- 25802521 TI - Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. AB - Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC) who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL), antiresorptive agents have been shown to improve bone mineral density (BMD) and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs) in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy. PMID- 25802525 TI - Cytomegalovirus colitis with common variable immunodeficiency and Crohn's disease. AB - Here we present an eleven-year-old male patient who had been diagnosed with common variable immunodeficiency (CVID) three years ago due to recurrent sinopulmonary infections. Two years later he had been diagnosed with Crohn's disease (CD) due to diarrhea episodes which were unresponsive to the treatment. Depending on the active gastrointestinal bleeding and perforation he underwent total colectomy. Despite immunoglobulin and antiviral therapies, general condition of patient deteriorated and he died in the postoperative seventh day. Laboratory analysis was seronegative. CMV inclusion containing cells were detected in postmortem biopsies taken from liver, lungs, and lymph nodes. PMID- 25802526 TI - Isolated rheumatoid nodules: a diagnostic dilemma. AB - We present a 27-year-old male with multiple nonpainful soft tissue masses over several metacarpals, bilateral elbows, the left wrist, and both knees since the age of 4. Physical exam was significant for firm, nonmobile, nodular growths over the extensor surfaces of bilateral elbows and knees and on the 2nd and 5th metacarpal phalangeal joints. Laboratory studies revealed an unremarkable rheumatoid factor, negative ANA screening and normal joint radiographs. Differential diagnosis included subcutaneous granuloma annulare (SGA), seronegative rheumatoid nodule, and calcinosis cutis. Biopsy is the only method to distinguish benign rheumatoid nodules from SGA. This case illustrates the importance of biopsy in diagnosis, an awareness of the potential complications, and the need for good follow-up. PMID- 25802527 TI - A Unique Case of Primary Ewing's Sarcoma of the Cervical Spine in a 53-Year-Old Male: A Case Report and Review of the Literature. AB - Extraskeletal Ewing's sarcoma (EES) is a rare presentation, representing only 15% of all primary Ewing's sarcoma cases. Even more uncommon is EES presenting as a primary focus in the spinal canal. These rapidly growing tumors often present with focal neurological symptoms of myelopathy or radiculopathy. There are no classic characteristic imaging findings and thus the physician must keep a high index of clinical suspicion. Diagnosis can only be definitively made by histopathological studies. In this report, we discuss a primary cervical spine EES in a 53-year-old man who presented with a two-month history of left upper extremity pain and acute onset of weakness. Imaging revealed a cervical spinal canal mass. After undergoing cervical decompression, histopathological examination confirmed a diagnosis of Ewing's sarcoma. A literature search revealed fewer than 25 reported cases of primary cervical spine EES published in the past 15 years and only one report demonstrating this pathology in a patient older than 30 years of age (age = 38). Given the low incidence of this pathology presenting in this age group and the lack of treatment guidelines, each patient's plan should be considered on a case-by-case basis until further studies are performed to determine optimal evidence based treatment. PMID- 25802529 TI - Improvement of In Vitro Osteogenic Potential through Differentiation of Induced Pluripotent Stem Cells from Human Exfoliated Dental Tissue towards Mesenchymal Like Stem Cells. AB - Constraints for the application of MSCs for bone reconstruction include restricted self-renewal and limited cell amounts. iPSC technology presents advantages over MSCs, providing homogeneous cellular populations with prolonged self-renewal and higher plasticity. However, it is unknown if the osteogenic potential of iPSCs differs from that of MSCs and if it depends on the iPSCs originating cellular source. Here, we compared the in vitro osteogenesis between stem cells from human deciduous teeth (SHED) and MSC-like cells from iPSCs from SHED (iPS-SHED) and from human dermal fibroblasts (iPS-FIB). MSC-like cells from iPS-SHED and iPS-FIB displayed fibroblast-like morphology, downregulation of pluripotency markers and upregulation of mesenchymal markers. Comparative in vitro osteogenesis analysis showed higher osteogenic potential in MSC-like cells from iPS-SHED followed by MSC-like cells from iPS-FIB and SHED. CD105 expression, reported to be inversely correlated with osteogenic potential in MSCs, did not display this pattern, considering that SHED presented lower CD105 expression. Higher osteogenic potential of MSC-like cells from iPS-SHED may be due to cellular homogeneity and/or to donor tissue epigenetic memory. Our findings strengthen the rationale for the use of iPSCs in bone bioengineering. Unveiling the molecular basis behind these differences is important for a thorough use of iPSCs in clinical scenarios. PMID- 25802528 TI - The Role of MicroRNAs in Cardiac Stem Cells. AB - Stem cells are considered as the next generation drug treatment in patients with cardiovascular disease who are resistant to conventional treatment. Among several stem cells used in the clinical setting, cardiac stem cells (CSCs) which reside in the myocardium and epicardium of the heart have been shown to be an effective option for the source of stem cells. In normal circumstances, CSCs primarily function as a cell store to replace the physiologically depleted cardiovascular cells, while under the diseased condition they have been shown to experimentally regenerate the diseased myocardium. In spite of their major functional role, molecular mechanisms regulating the CSCs proliferation and differentiation are still unknown. MicroRNAs (miRs) are small, noncoding RNA molecules that regulate gene expression at the posttranscriptional level. Recent studies have demonstrated the important role of miRs in regulating stem cell proliferation and differentiation, as well as other physiological and pathological processes related to stem cell function. This review summarises the current understanding of the role of miRs in CSCs. A deeper understanding of the mechanisms by which miRs regulate CSCs may lead to advances in the mode of stem cell therapies for the treatment of cardiovascular diseases. PMID- 25802532 TI - CSACI position statement: systemic effect of inhaled corticosteroids on adrenal suppression in the management of pediatric asthma. AB - Asthma is a chronic inflammatory disease of the airways that affects a growing number of children and adolescents. Inhaled corticosteroids (ICS) are the mainstay of treatment in persistent asthma, with a stepwise approach to increasing doses of ICS depending on asthma severity and control. ICS have known local and systemic side effects, of which adrenal suppression is still under recognized. The latter is associated with chronic exposure and higher doses, although it has rarely been reported in children receiving low doses for a short period of time. The Canadian Society of Allergy and Clinical Immunology (CSACI) therefore recommends that physicians screen for adrenal suppression in children receiving high doses for more than 6 months and to consider screening those on medium dose if the risk is deemed higher by factors that increase an individual's systemic corticosteroid exposure. Morning serum cortisol level can be used as a screening tool and abnormal results or normal results with a high index of suspicion should be confirmed with low-dose ACTH stimulation tests. PMID- 25802530 TI - The organotypic longitudinal spinal cord slice culture for stem cell study. AB - The objective of this paper is to describe in detail the method of organotypic longitudinal spinal cord slice culture and the scientific basis for its potential utility. The technique is based on the interface method, which was described previously and thereafter was modified in our laboratory. The most important advantage of the presented model is the preservation of the intrinsic spinal cord fiber tract and the ventrodorsal polarity of the spinal cord. All the processes occurring during axonal growth, regeneration, synapse formation, and myelination could be visualized while being cultured in vitro for up to 4-5 weeks after the slices had been isolated. Both pups and adult animals can undergo the same, equally efficient procedures when going by the protocol in question. The urgent need for an appropriate in vitro model for spinal cord regeneration results from a greater number of clinical trials concerning regenerative medicine in the spinal cord injury and from still insufficient knowledge of the molecular mechanisms involved in the neuroreparative processes. The detailed method of organotypic longitudinal spinal cord slice culture is accompanied by examples of its application to studying biological processes to which both the CNS inhabiting and grafted cells are subjected. PMID- 25802533 TI - The effectiveness of computerized cognitive rehabilitation training program in improving cognitive abilities of schizophrenia clients. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of a computer - based training program of attention, memory and executive functions in enhancing neuropsychological performances as well as functional outcome in clients with schizophrenia. METHOD: A total of 15 clinically stable out patients with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for schizophrenia, diagnosed with different types of schizophrenia: paranoid, disorganized, residual, based on DSM- IV-TR were selected to participate in this study. All patients were randomly selected using a conventional sampling method and assigned to 60 hours individual sessions of computer - assisted cognitive remediation (CACR).This was a pre- experimental study with pretest and posttest in a single group. Cognitive functions were checked with Continuous Performance Test (CPT), Wechsler Adult Intelligence Scale (Wds) and Prospective and Retrospective Memory Questionnaire (PRMQ). The symptoms of patients were measured with the Positive and Negative Syndrome Scale (PANSS). Remediation was performed utilizing the Rehacome(r) software. Patients received the cognitive remediation program including attention, concentration and working memory. All participants were followed up after an interval of one month and three months. Data were analyzed using repeated measures analysis. RESULT: After 3 months, the findings showed that patients' scores improved in the time factor. Also, a significant improvement favoring cognitive remediation was found in several cognitive measures including Reaction Time (F = 4015p<.05, Eta = 0.242), Wds (F = 11.806, p<.05,Eta = .48) PRMQ1(F = 3.314, p<.05, Eta = 0.20) PRMQ7(F = 2.85, p<.05, Eta = 0.18). CONCLUSION: Computer-assisted cognitive remediation training program was effective in improving the performance of schizophrenic patients. CACR did not have any effects on the positive and negative symptoms. Long- term follow-up studies are needed to confirm the maintenance of such improvements. PMID- 25802534 TI - A pilot study: the efficacy of virgin coconut oil as ocular rewetting agent on rabbit eyes. AB - Purpose. An open-label pilot study of virgin coconut oil (VCO) was conducted to determine the safety of the agent as ocular rewetting eye drops on rabbits. Methods. Efficacy of the VCO was assessed by measuring NIBUT, anterior eye assessment, corneal staining, pH, and Schirmer value before instillation and at 30 min, 60 min, and two weeks after instillation. Friedman test was used to analyse any changes in all the measurable variables over the period of time. Results. Only conjunctival redness with instillation of saline agent showed significant difference over the period of time (P < 0.05). However, further statistical analysis had shown no significant difference at 30 min, 60 min, and two weeks compared to initial measurement (P > 0.05). There were no changes in the NIBUT, limbal redness, palpebral conjunctiva redness, corneal staining, pH, and Schirmer value over the period of time for each agent (P > 0.05). Conclusion. VCO acts as safe rewetting eye drops as it has shown no significant difference in the measurable parameter compared to commercial brand eye drops and saline. These study data suggest that VCO is safe to be used as ocular rewetting agent on human being. PMID- 25802531 TI - Occupational health hazards among healthcare workers in Kampala, Uganda. AB - OBJECTIVE: To assess the occupational health hazards faced by healthcare workers and the mitigation measures. METHODS: We conducted a cross-sectional study utilizing quantitative data collection methods among 200 respondents who worked in 8 major health facilities in Kampala. RESULTS: Overall, 50.0% of respondents reported experiencing an occupational health hazard. Among these, 39.5% experienced biological hazards while 31.5% experienced nonbiological hazards. Predictors for experiencing hazards included not wearing the necessary personal protective equipment (PPE), working overtime, job related pressures, and working in multiple health facilities. Control measures to mitigate hazards were availing separate areas and containers to store medical waste and provision of safety tools and equipment. CONCLUSION: Healthcare workers in this setting experience several hazards in their workplaces. Associated factors include not wearing all necessary protective equipment, working overtime, experiencing work related pressures, and working in multiple facilities. Interventions should be instituted to mitigate the hazards. Specifically PPE supply gaps, job related pressures, and complacence in adhering to mitigation measures should be addressed. PMID- 25802535 TI - In Vitro Antistaphylococcal Effects of Embelia schimperi Extracts and Their Component Embelin with Oxacillin and Tetracycline. AB - Bacterial infections are in less-developed countries traditionally treated by remedies prepared from medicinal plants. Embelia schimperi (Vatke) is a plant used as a taenicide or disinfectant in Ethiopia, very often taken mixed with another plant species. In the present study, we examined two extracts prepared from seeds and twigs with leaves of E. schimperi and its main present secondary metabolite embelin for their antibacterial combinatory effect with oxacillin and tetracycline against sensitive and resistant Staphylococcus aureus strains. Minimum inhibitory concentrations were determined through the broth microdilution method, whereas the combinatory effect was evaluated through fractional inhibitory concentration sum (SigmaFIC) indices. Results show many positive interactions and synergy occurring in embelin and oxacillin combinations against 4 out of 9 strains (SigmaFIC 0.203-0.477) and for embelin and tetracycline combination against 3 out of 9 strains (SigmaFIC 0.400-0.496). Moreover, the resistance to oxacillin has been overcome in 2 strains and to tetracycline in 3 strains. According to our knowledge, this is the first study showing antimicrobial combinatory effect of E. schimperi as well as of embelin. These findings can be used for the further research targeted on the development of new antistaphylococcal agents. PMID- 25802536 TI - Comparisons of ethanol extracts of chinese propolis (poplar type) and poplar gums based on the antioxidant activities and molecular mechanism. AB - The biological activities of propolis are varied from plant sources and the prominent antioxidant effects of Chinese propolis (poplar type) have been extensively reported. Oxidative stress is associated with inflammation and induces many diseases. In the study, to evaluate antioxidant capacities and clarify the underlying molecular mechanisms of ethanol extracts of Chinese propolis (EECP) and ethanol extracts of poplar gums (EEPG), we analyzed their compositions by HPLC, evaluating their free radical scavenging activities and reducing power by chemical analysis methods. Moreover, we studied the roles of EECP and EEPG on the elimination of ROS and expressions of antioxidant genes (HO 1, TrxR1, GCLM, and GCLC) in RAW264.7 cells. We further investigated the effects of MAPKs on the antioxidant genes expression by specific inhibitors. The nucleus translocation effects of Nrf2 were also measured by confocal microscopy analysis. The results indicated that EECP had higher TPC and FDC values but regarding TFC values were not significant. EECP also possessed more contents of 11 compounds than EEPG. Both phytochemical analysis and cell experiment reflected that EECP exerted stronger antioxidant activities than EEPG. EECP and EEPG enhanced endogenous antioxidant defenses by eliminating reactive oxygen species directly and activating Erk-Nrf2-HO1, GCLM, and TrxR1 signal pathways. PMID- 25802537 TI - Effect of Lactobacillus plantarum Strain K21 on High-Fat Diet-Fed Obese Mice. AB - Recent studies have demonstrated beneficial effects of specific probiotics on alleviating obesity-related disorders. Here we aimed to identify probiotics with potential antiobesity activity among 88 lactic acid bacterial strains via in vitro screening assays, and a Lactobacillus plantarum strain K21 was found to harbor abilities required for hydrolyzing bile salt, reducing cholesterol, and inhibiting the accumulation of lipid in 3T3-L1 preadipocytes. Furthermore, effects of K21 on diet-induced obese (DIO) mice were examined. Male C57Bl/6J mice received a normal diet, high-fat diet (HFD), or HFD with K21 administration (10(9) CFU in 0.2 mL PBS/day) for eight weeks. Supplementation of K21, but not placebo, appeared to alleviate body weight gain and epididymal fat mass accumulation, reduce plasma leptin levels, decrease cholesterol and triglyceride levels, and mitigate liver damage in DIO mice. Moreover, the hepatic expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) related to adipogenesis was significantly downregulated in DIO mice by K21 intervention. We also found that K21 supplementation strengthens intestinal permeability and modulates the amount of Lactobacillus spp., Bifidobacterium spp., and Clostridium perfringens in the cecal contents of DIO mice. In conclusion, our results suggest that dietary intake of K21 protects against the onset of HFD-induced obesity through multiple mechanisms of action. PMID- 25802538 TI - Evaluation of a Patient CAM-with-Chemotherapy Educational Brochure. AB - Biologically active CAM may detrimentally interfere with chemotherapy treatment, so cancer patients require targeted, evidence-based information on chemotherapy CAM integration consequences. The object of this study was to investigate the potential for medical doctor recommendation and patient acceptance of a purpose designed patient educational brochure on the safe use of CAM with chemotherapy. Cancer care doctors (n = 17) were provided a draft version of a patient educational brochure developed by the authors and completed a structured feedback form. Cancer patients receiving treatment (n = 12) were provided with the brochure and completed the local health service consumer testing feedback form. All 17 doctors perceived a need for the brochure and all would recommend the brochure to their patients. Approximately 59% of the doctors indicated they would recommend the brochure to all patients receiving chemotherapy and 41% preferred that only patients using CAM or who enquired about CAM be given the brochure. Cancer patients receiving chemotherapy reported that the brochure information answered their questions and was easy to understand. This evidence-based CAM chemotherapy patient brochure may be a useful adjunct for use by cancer care health professionals to educate patients on the potential dangers of biologically active CAM use with chemotherapy and to provide patients with safe CAM alternatives. PMID- 25802539 TI - Expectancy of stress-reducing aromatherapy effect and performance on a stress sensitive cognitive task. AB - Objective. Stress-reducing therapies help maintain cognitive performance during stress. Aromatherapy is popular for stress reduction, but its effectiveness and mechanism are unclear. This study examined stress-reducing effects of aromatherapy on cognitive function using the go/no-go (GNG) task performance and event related potentials (ERP) components sensitive to stress. The study also assessed the importance of expectancy in aromatherapy actions. Methods. 81 adults were randomized to 3 aroma groups (active experimental, detectable, and undetectable placebo) and 2 prime subgroups (prime suggesting stress-reducing aroma effects or no-prime). GNG performance, ERPs, subjective expected aroma effects, and stress ratings were assessed at baseline and poststress. Results. No specific aroma effects on stress or cognition were observed. However, regardless of experienced aroma, people receiving a prime displayed faster poststress median reaction times than those receiving no prime. A significant interaction for N200 amplitude indicated divergent ERP patterns between baseline and poststress for go and no-go stimuli depending on the prime subgroup. Furthermore, trends for beneficial prime effects were shown on poststress no-go N200/P300 latencies and N200 amplitude. Conclusion. While there were no aroma-specific effects on stress or cognition, these results highlight the role of expectancy for poststress response inhibition and attention. PMID- 25802540 TI - Effects of acupressure on fatigue and depression in hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization: a quasi experimental study. AB - This study was to examine the effects of acupressure on fatigue and depression in HCC patients undergoing TACE. A quasiexperimental study design was used. Patients were evaluated at five time points: before treatment (T1) and 2, 3, 4, and 5 days after treating TACE (T2, T3, T4, and T5). Fatigue and depression were assessed by a VAS fatigue scale and a VAS depression scale at each time point. TFRS and BDI were administered at T1 and T5. Patients' fatigue and depression were significantly higher at T5 than at T1 in two groups. Fatigue and depression increased in both the experimental and control groups' patients over the five days of hospitalization during which TACE and chemotherapy were administered. The experimental group had significantly less fatigue than the control group, with lower subscale scores on physical, psychosocial, daily, and overall fatigue. There were no differences between the groups on depression. At posttest, the experimental group experienced lower physical, psychosocial, daily, and overall fatigue than the control group. Acupressure can improve fatigue in HCC patients during treatment with TACE but did not alleviate depression. Discharge planning should include home care for management of fatigue and depression. PMID- 25802543 TI - Corrigendum to "an emerging translational model to screen potential medicinal plants for nephrolithiasis, an independent risk factor for chronic kidney disease". AB - [This corrects the article DOI: 10.1155/2014/972958.]. PMID- 25802542 TI - Chinese herbal medicine for myelosuppression induced by chemotherapy or radiotherapy: a systematic review of randomized controlled trials. AB - Background. Myelosuppression is one of the major side effects of chemo- and radiotherapy in cancer patients and there are no effective interventions to prevent it currently. Chinese herbal medicine (CHM) may be helpful due to its multidrug targets. Objectives. This study was designed to evaluate effectiveness of CHM on preventing patients from experiencing myelosuppression by chemo- or radiotherapy. Search Methods. Randomized controlled trials (RCTs) were retrieved from seven different databases from the date of database creation to April 2014. We assessed all included studies using Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 and performed statistical analysis using RevMan 5.2.1. Results. Eight RCTs were included (818 patients). Pooled data showed that increase of white blood cells (WBCs) is higher with CHM plus chemotherapy/radiotherapy than with chemotherapy/radiotherapy only. Both CHM compared to placebo and CHM combined with chemotherapy/radiotherapy compared to chemotherapy/radiotherapy lacked significant differences in the peripheral platelets, red blood cells (RBCs), and hemoglobin changes. Conclusions. Our results demonstrated that CHM significantly protected peripheral blood WBCs from a decrease caused by chemotherapy or radiotherapy. There were no significant protective effects on peripheral RBCs, hemoglobin, or platelets, which may be related to low quality and small sample of included studies. PMID- 25802544 TI - Litsea japonica Extract Inhibits Aldose Reductase Activity and Hyperglycemia Induced Lenticular Sorbitol Accumulation in db/db Mice. AB - Aldose reductase (AR) is the first and rate-limiting enzyme of the polyol pathway. AR-dependent synthesis of excess polyols leads to lens opacification in diabetic cataract. The purpose of this study is to investigate the protective effect of Litsea japonica extract (LJE) on diabetes-induced lens opacification and its protective mechanism in db/db mice. Seven-week-old male db/db mice were treated with LJE (100 and 250 mg/kg body weight) once a day orally for 12 weeks. LJE dose dependently inhibited rat lens aldose reductase activity in vitro (IC50 = 13.53 +/- 0.74 ug/mL). In db/db mice, lens was slightly opacified, and lens fiber cells were swollen and ruptured. In addition, lenticular sorbitol accumulation was increased in db/db mice. However, the administration of LJE inhibited these lenticular sorbitol accumulation and lens architectural changes in db/db mice. Our results suggest that LJE might be beneficial for the treatment of diabetes-induced lens opacification. The ability of LJE to suppress lenticular sorbitol accumulation may be mediated by the inhibition of AR activity. PMID- 25802541 TI - Traditional Uses, Phytochemistry, and Pharmacology of Olea europaea (Olive). AB - Aim of the Review. To grasp the fragmented information available on the botany, traditional uses, phytochemistry, pharmacology, and toxicology of Olea europaea to explore its therapeutic potential and future research opportunities. Material and Methods. All the available information on O. europaea was collected via electronic search (using Pubmed, Scirus, Google Scholar, and Web of Science) and a library search. Results. Ethnomedical uses of O. europaea are recorded throughout the world where it has been used to treat various ailments. Phytochemical research had led to the isolation of flavonoids, secoiridoids, iridoids, flavanones, biophenols, triterpenes, benzoic acid derivatives, isochromans, and other classes of secondary metabolites from O. europaea. The plant materials and isolated components have shown a wide spectrum of in vitro and in vivo pharmacological activities like antidiabetic, anticonvulsant, antioxidant, anti-inflammatory, immunomodulatory, analgesic, antimicrobial, antiviral, antihypertensive, anticancer, antihyperglycemic, antinociceptive, gastroprotective, and wound healing activities. Conclusions. O. europaea emerged as a good source of traditional medicine for the treatment of various ailments. The outcomes of phytochemical and pharmacological studies reported in this review will further expand its existing therapeutic potential and provide a convincing support to its future clinical use in modern medicine. PMID- 25802545 TI - Application of acupoints and meridians for the treatment of primary dysmenorrhea: a data mining-based literature study. AB - Background. Dysmenorrhea is a common problem for which acupuncture provides effective analgesia. Although acupoint selection affects the effectiveness of acupuncture, the basic rules of acupoint selection are little understood. This study aims to investigate the principles of acupoint selection and characteristics of acupoints used for primary dysmenorrhea. Methods. PubMed, China National Knowledge Infrastructure, and Chinese Biomedical Database were searched for clinical trials published in English or Chinese from January 1978 to April 2014 evaluating the effect of acupuncture on primary dysmenorrhea, with or without methods of randomization and/or control. Three authors extracted information and two reviewers inputted information on titles, journals, interventions, main acupoints, and outcomes using the self-established Data Excavation Platform of Acupoint Specificity for data mining. Results. Sanyinjiao (SP06), Guanyuan (CV04), and Qihai (CV06) were used most frequently. The most frequently used meridians were Conception Vessel, Spleen Meridian of Foot Taiyin, and Bladder Meridian of Foot Taiyang. 67.24% of acupoints used were specific acupoints. Acupoints on lower limbs were most frequently used. Conclusion. Data mining is a feasible approach to identify the characteristics of acupoint selection. Our study indicated that modern acupuncture treatment for primary dysmenorrhea is based on selection of specific acupoints according to traditional acupuncture theory. PMID- 25802546 TI - UP3005, a Botanical Composition Containing Two Standardized Extracts of Uncaria gambir and Morus alba, Improves Pain Sensitivity and Cartilage Degradations in Monosodium Iodoacetate-Induced Rat OA Disease Model. AB - Osteoarthritis (OA) is a multifactorial disease primarily noted by cartilage degradation in association with inflammation that causes significant morbidity, joint pain, stiffness, and limited mobility. Present-day management of OA is inadequate due to the lack of principal therapies proven to be effective in hindering disease progression where symptomatic therapy focused approach masks the actual etiology leading to irreversible damage. Here, we describe the effect of UP3005, a composition containing a proprietary blend of two standardized extracts from the leaf of Uncaria gambir and the root bark of Morus alba, in maintaining joint structural integrity and alleviating OA associated symptoms in monosodium-iodoacetate- (MIA-) induced rat OA disease model. Pain sensitivity, micro-CT, histopathology, and glycosaminoglycans (GAGs) level analysis were conducted. Diclofenac at 10 mg/kg was used as a reference compound. UP3005 resulted in almost a complete inhibition in proteoglycans degradation, reductions of 16.6% (week 4), 40.5% (week 5), and 22.0% (week 6) in pain sensitivity, statistically significant improvements in articular cartilage matrix integrity, minimal visual subchondral bone damage, and statistically significant increase in bone mineral density when compared to the vehicle control with MIA. Therefore, UP3005 could potentially be considered as an alternative therapy from natural sources for the treatment of OA and/or its associated symptoms. PMID- 25802547 TI - Traditional Herbal Formula Oyaksungi-San Inhibits Adipogenesis in 3T3-L1 Adipocytes. AB - Background. Oyaksungi-san (OYSGS) is a herbal formula that has been used for treating cardiovascular diseases in traditional Asian medicine. Here, we investigated the antiadipogenic effect of OYSGS extract in 3T3-L1 adipose cells. Methods. 3T3-L1 preadipocytes were differentiated into adipocytes with or without OYSGS. After differentiation, we measured Oil Red O staining, glycerol-3 phosphate dehydrogenase (GPDH) activity, leptin production, mRNA, and protein levels of adipogenesis-related factors. Results. OYSGS extract dramatically inhibited intracellular lipid accumulation in the differentiated adipocytes. It also significantly suppressed the (GPDH) activity, triglyceride (TG) content, and leptin production by reducing the expression of adipogenesis-related genes including lipoprotein lipase, fatty acid binding protein 4, CCAAT/enhancer binding protein-alpha (C/EBP-alpha), and peroxisome proliferator-activated receptor gamma (PPAR-gamma). Furthermore, OYSGS clearly enhanced phosphorylation of AMP-activated protein kinase (AMPK) as well as its substrate acetyl CoA (ACC) carboxylase. Conclusions. Our results demonstrate that OYSGS negatively controls TG accumulation in 3T3-L1 adipocytes. We suggest antiadipogenic activity of OYSGS and its potential benefit in preventing obesity. PMID- 25802548 TI - Andrographolide enhances proliferation and prevents dedifferentiation of rabbit articular chondrocytes: an in vitro study. AB - As the main active constituent of Andrographis paniculata that was applied in treatment of many diseases including inflammation in ancient China, andrographolide (ANDRO) was found to facilitate reduction of edema and analgesia in arthritis. This suggested that ANDRO may be promising anti-inflammatory agent to relieve destruction and degeneration of cartilage after inflammation. In this study, the effect of ANDRO on rabbit articular chondrocytes in vitro was investigated. Results showed that not more than 8 MUM ANDRO did no harm to chondrocytes (P < 0.05). DNA content and glycosaminoglycan (GAG) /DNA were, respectively, improved in ANDRO groups comparing to the control (P < 0.05). ANDRO could promote expression of aggrecan, collagen II, and Sox9 genes while downregulating expression of collagen I gene (P < 0.05). Furthermore, hypertrophy that may result in chondrocyte ossification could not be detected in all groups (P > 0.05). The viability assay, hematoxylin-eosin, safranin O, and immunohistochemical staining also showed better performances in ANDRO groups. As to the doses, 3 MUM ANDRO showed the best performance. The results indicate that ANDRO can accelerate proliferation of rabbit articular chondrocytes in vitro and meanwhile maintain the phenotype, which may provide valuable references for further exploration on arthritis. PMID- 25802550 TI - Adaptive thresholding technique for retinal vessel segmentation based on GLCM energy information. AB - Although retinal vessel segmentation has been extensively researched, a robust and time efficient segmentation method is highly needed. This paper presents a local adaptive thresholding technique based on gray level cooccurrence matrix- (GLCM-) energy information for retinal vessel segmentation. Different thresholds were computed using GLCM-energy information. An experimental evaluation on DRIVE database using the grayscale intensity and Green Channel of the retinal image demonstrates the high performance of the proposed local adaptive thresholding technique. The maximum average accuracy rates of 0.9511 and 0.9510 with maximum average sensitivity rates of 0.7650 and 0.7641 were achieved on DRIVE and STARE databases, respectively. When compared to the widely previously used techniques on the databases, the proposed adaptive thresholding technique is time efficient with a higher average sensitivity and average accuracy rates in the same range of very good specificity. PMID- 25802549 TI - A further finite element stress analysis of angled abutments for an implant placed in the anterior maxilla. AB - To systematically measure and compare the stress distribution on the bone around an implant in the anterior maxilla using angled abutments by means of finite element analysis, three-dimensional finite element simplified patient-specific models and simplified models were created and analyzed. Systematically varied angled abutments were simulated, with angulation ranging from 0 degrees to 60 degrees . The materials in the current study were assumed to be homogenous, linearly elastic, and isotropic. Force of 100 N was applied to the central node on the top surface of the abutments to simulate the occlusal force. To simulate axial and oblique loading, the angle of loading was 0 degrees , 15 degrees , and 20 degrees to the long axis of implant, respectively. There was the strong resemblance between the response curves for simplified patient-specific models and simplified models. Response curves under oblique loading were similar in both models. With abutments angulation increased, maximum von Mises stress firstly decreased to minimum point and then gradually increased to higher level. From a biomechanical point of view, favorable peri-implant stress levels could be induced by angled abutments under oblique loading if suitable angulation of abutments was selected. PMID- 25802551 TI - Prevention of lung-to-lung aspiration during emergency thoracic surgery: an experimental study. AB - BACKGROUND: Lung separation is essential for an emergency thoracic surgery for massive hemoptysis. When using a double lumen tube (DLT), a commonly adopted lung separation device during thoracic surgery, a water-tight seal of endobronchial cuff is crucial to prevent lung-to-lung aspiration of blood. In this study, we investigated the fluid sealing characteristics of the endobronchial cuff of a DLT and examined the effect of gel lubrication on the fluid leakage beyond the endobronchial cuff of DLT. METHODS: An artificial tracheobronchial tree was intubated with a DLT. In the first phase of the study, the intra-cuff pressure of endobronchial cuff of DLT was set to 25, 50, or 100 cmH2O (n = 7, each), and the non-dependent bronchus was filled with 5 ml of water. Fluid leakage to the dependent bronchus beyond the endobronchial cuff was collected for 6 h. The time until leakage was first detected and the time until 100% leakage occurred were measured. In the second phase, the endobronchial cuff was coated with either saline (group C, n = 10) or lubricant gel (group GEL, n = 10), and the same parameters were measured. RESULTS: In the first phase of the study, the times to first leakage and 100% leakage at an intra-cuff pressure of 25 cmH2O were 21.0 (7.0 - 59.0) sec and 3.0 (2.0 - 4.0) min, respectively. Higher intra-cuff (50 and 100 cmH2O) resulted in longer time for the first leakage and 100% leakage, but the duration was not long enough for clinical purpose. In the second phase, all the DLTs in group C showed 100% fluid leakage during the 6-hour period. In contrast, in group GEL, fluid leakage beyond the endobronchial cuff was detected only in 50% of the DLTs and none of the DLT showed 100% fluid leakage during the study. Among the DLTs which exhibited fluid leakage, the time to first leakage was 252.0 (171.0-305.0) min and the leakage volume at the end of the study period was 0.3?0.0-1.8?ml. CONCLUSIONS: Endobronchial cuff of DLT cannot prevent fluid leakage beyond the endobronchial cuff, but lubricant gel coating on the endobronchial cuff can effectively reduce the lung-to-lung aspiration. PMID- 25802552 TI - Downregulation of GAUT12 in Populus deltoides by RNA silencing results in reduced recalcitrance, increased growth and reduced xylan and pectin in a woody biofuel feedstock. AB - BACKGROUND: The inherent recalcitrance of woody bioenergy feedstocks is a major challenge for their use as a source of second-generation biofuel. Secondary cell walls that constitute the majority of hardwood biomass are rich in cellulose, xylan, and lignin. The interactions among these polymers prevent facile accessibility and deconstruction by enzymes and chemicals. Plant biomass that can with minimal pretreatment be degraded into sugars is required to produce renewable biofuels in a cost-effective manner. RESULTS: GAUT12/IRX8 is a putative glycosyltransferase proposed to be involved in secondary cell wall glucuronoxylan and/or pectin biosynthesis based on concomitant reductions of both xylan and the pectin homogalacturonan (HG) in Arabidopsis irx8 mutants. Two GAUT12 homologs exist in Populus trichocarpa, PtGAUT12.1 and PtGAUT12.2. Knockdown expression of both genes simultaneously has been shown to reduce xylan content in Populus wood. We tested the proposition that RNA interference (RNAi) downregulation of GAUT12.1 alone would lead to increased sugar release in Populus wood, that is, reduced recalcitrance, based on the hypothesis that GAUT12 synthesizes a wall structure required for deposition of xylan and that cell walls with less xylan and/or modified cell wall architecture would have reduced recalcitrance. Using an RNAi approach, we generated 11 Populus deltoides transgenic lines with 50 to 67% reduced PdGAUT12.1 transcript expression compared to wild type (WT) and vector controls. Ten of the eleven RNAi lines yielded 4 to 8% greater glucose release upon enzymatic saccharification than the controls. The PdGAUT12.1 knockdown (PdGAUT12.1-KD) lines also displayed 12 to 52% and 12 to 44% increased plant height and radial stem diameter, respectively, compared to the controls. Knockdown of PdGAUT12.1 resulted in a 25 to 47% reduction in galacturonic acid and 17 to 30% reduction in xylose without affecting total lignin content, revealing that in Populus wood as in Arabidopsis, GAUT12 affects both pectin and xylan formation. Analyses of the sugars present in sequential cell wall extracts revealed a reduction of glucuronoxylan and pectic HG and rhamnogalacturonan in extracts from PdGAUT12.1-KD lines. CONCLUSIONS: The results show that downregulation of GAUT12.1 leads to a reduction in a population of xylan and pectin during wood formation and to reduced recalcitrance, more easily extractable cell walls, and increased growth in Populus. PMID- 25802553 TI - Dynamic metabolic profiling of the marine microalga Chlamydomonas sp. JSC4 and enhancing its oil production by optimizing light intensity. AB - BACKGROUND: Marine microalgae are among the most promising lipid sources for biodiesel production because they can be grown on nonarable land without the use of potable water. Marine microalgae also harvest solar energy efficiently with a high growth rate, converting CO2 into lipids stored in the cells. Both light intensity and nitrogen availability strongly affect the growth, lipid accumulation, and fatty acid composition of oleaginous microalgae. However, very few studies have systematically examined how to optimize lipid productivity by adjusting irradiance intensity, and the metabolic dynamics that may lead to improved lipid accumulation in microalgae have not been elucidated. Little is known about the mechanism of lipid synthesis regulation in microalgae. Moreover, few studies have assessed the potential of using marine microalgae as oil producers. RESULTS: In this work, a newly isolated marine microalga, Chlamydomonas sp. JSC4, was selected as a potential lipid producer, and the effect of photobioreactor operations on cell growth and lipid production was investigated. The combined effects of light intensity and nitrogen depletion stresses on growth and lipid accumulation were further explored in an effort to markedly improve lipid production and quality. The optimal lipid productivity and content attained were 312 mg L(-1) d(-1) and 43.1% per unit dry cell weight, respectively. This lipid productivity is the highest ever reported for marine microalgae. Metabolic intermediates were profiled over time to observe transient changes during lipid accumulation triggered by combined stresses. Finally, metabolite turnover was also assessed using an in vivo (13)C-labeling technique to directly measure the flow of carbon during lipid biosynthesis under stress associated with light intensity and nitrogen deficiency. CONCLUSIONS: This work demonstrates the synergistic integration of cultivation and dynamic metabolic profiling technologies to develop a simple and effective strategy for enhancing oil production in a marine microalga. The knowledge obtained from this study could be useful in assessing the feasibility of marine microalgae biodiesel production and for understanding the links between dynamic metabolic profiles and lipid biosynthesis during the course of microalgal cultivation. PMID- 25802554 TI - Metastatic carcinoma to the thyroid gland from renal cell carcinoma: role of ultrasonography in preoperative diagnosis. AB - BACKGROUND: Patients with metastases to the thyroid from renal cell carcinoma (RCC) that need surgical management are not many and unfamiliar to clinicians and thyroid endocrinologists. Therefore, little information is available on ultrasonographic features of metastatic carcinoma in the thyroid. The strategic value of ultrasound in preoperative surgical planning for patients with thyroid nodules has become increasingly appreciated. The purposes of this article are to clarify the ultrasound characteristics of metastatic carcinoma to the thyroid from RCC by evaluating many patients in one institute, and to investigate the role of ultrasonography in preoperative diagnosis. METHODS: Ten patients with these carcinomas who had undergone surgical management were investigated clinically and ultrasonographically. Ultrasonographic features to be evaluated were the form of involvement in the thyroid, size, shape, pattern, calcifications, vascularity, and tumor thrombus. Clinical features were previous history of RCC, serum thyroglobulin levels, cytology, preoperative diagnosis, and surgery. RESULTS: Ultrasonographic features of these carcinomas were more likely to involve a solitary, irregular, and solid without calcifications, and prominent intra-tumoral vascularity and tumor thrombus in the vein. These patients tended to be older, and to have relatively late recurrence in the thyroid, RCC in the right kidney as the primary site, and relatively low serum thyroglobulin levels. CONCLUSIONS: Metastatic carcinomas to the thyroid from RCC presented highly characteristic features on ultrasonography. These ultrasonographic features combined with cytological findings and previous medical history of RCC can provide the optimal process for the preoperative diagnosis of such patients. PMID- 25802555 TI - The intestinal fatty acid binding protein-2 Ala54Thr polymorphism is associated with diabetic retinopathy in Chinese population. AB - OBJECTIVE: Endothelial dysfunction which is induced by serum saturated fatty acids increasing is one of pathogenesis of diabetic retinopathy (DR). The intestinal fatty acid binding protein-2 (FABP2) Ala54Thr polymorphism results in serum saturated fatty acids elevating. In the present study, we assessed the association of FABP2 gene polymorphism (Ala54Thr) with DR in Chinese population. MATERIALS/METHODS: In this case-control association study, 810 T2DM patients were recruited. 420 patients with retinal neovascularization, microneurysms and hemorrhages were considered as cases (DR) and 390 patients with T2DM and no clinical signs of retinopathy (DNR), were recruited as controls. Genotypes for FABP2(Ala54Thr) polymorphisms were assessed with the PCR-RFLP method. RESULTS: A significant difference in genotype distribution and allele frequency was observed between cases and controls. Patients with DR had significantly higher frequency of the Ala/Thr + Thr/Thr genotypes compared to DNR group [62.6% vs. 46.2%; OR (95% CI), 1.95 (1.48-2.59); p < 0.001]. The DR group showed a significantly higher frequency of the the Thr allele compared to the DNR group [39.5% vs. 29.4%; OR (95% CI), 1.56 (1.16-2.09); p = 0.003]. Binary logistic analyses showed FFA levels (p = 0.014) and Ala54Thr (p = 0.011) were independent correlates of the presence of DR. CONCLUSIONS: We examined that FABP2 polymophism on the Ala54Thr is significant and independent associated with DR. PMID- 25802556 TI - A highly sensitive novel immunoassay specifically detects low levels of soluble Abeta oligomers in human cerebrospinal fluid. AB - INTRODUCTION: Amyloid beta-protein oligomers play a key role in Alzheimer's disease (AD), but well-validated assays that routinely detect them in cerebrospinal fluid (CSF) are just emerging. We sought to confirm and extend a recent study using the Singulex Erenna platform that reported increased mean CSF oligomer levels in AD. METHODS: We tested four antibody pairs and chose one pair that was particularly sensitive, using 1C22, our new oligomer-selective monoclonal antibody, for capture. We applied this new assay to extracts of human brain and CSF. RESULTS: A combination of 1C22 for capture and 3D6 for detection yielded an Erenna immunoassay with a lower limit of quantification of approximately 0.15 pg/ml that was highly selective for oligomers over monomers and detected a wide size-range of oligomers. Most CSFs we tested had detectable oligomer levels but with a large overlap between AD and controls and a trend for higher mean levels in mild cognitive impairment (MCI) than controls. CONCLUSION: Abeta oligomers are detectable in most human CSFs, but AD and controls overlap. MCI CSFs may have a modest elevation in mean value by this assay. PMID- 25802557 TI - Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. AB - Dementia prevalence increases with age and Alzheimer's disease (AD) accounts for up to 75% of cases. However, significant variability and overlap exists in the extent of amyloid-beta and Tau pathology in AD and non-demented populations and it is clear that other factors must influence progression of cognitive decline, perhaps independent of effects on amyloid pathology. Coupled with the failure of amyloid-clearing strategies to provide benefits for AD patients, it seems necessary to broaden the paradigm in dementia research beyond amyloid deposition and clearance. Evidence has emerged from alternative animal model approaches as well as clinical and population epidemiological studies that co-morbidities contribute significantly to neurodegeneration/cognitive decline and systemic inflammation has been a strong common theme in these approaches. We hypothesise, and discuss in this review, that a disproportionate inflammatory response to infection, injury or chronic peripheral disease is a key determinant of cognitive decline. We propose that detailed study of alternative models, which encompass acute and chronic systemic inflammatory co-morbidities, is an important priority for the field and we examine the cognitive consequences of several of these alternative experimental approaches. Experimental models of severe sepsis in normal animals or moderate acute systemic inflammation in animals with existing neurodegenerative pathology have uncovered roles for inflammatory mediators interleukin-1beta, tumour necrosis factor-alpha, inducible nitric oxide synthase, complement, prostaglandins and NADPH oxidase in inflammation-induced cognitive dysfunction and neuronal death. Moreover, microglia are primed by existing neurodegenerative pathology to produce exaggerated responses to subsequent stimulation with bacterial lipopolysaccharide or other inflammatory stimuli and these insults drive acute dysfunction and negatively affect disease trajectory. Chronic co-morbidities, such as arthritis, atherosclerosis, obesity and diabetes, are risk factors for subsequent dementia and those with high inflammatory status are particularly at risk. Models of chronic co-morbidities, and indeed low grade systemic inflammation in the absence of specific pathology, indicate that interleukin-1beta, tumour necrosis factor-alpha and other inflammatory mediators drive insulin resistance, hypothalamic dysfunction, impaired neurogenesis and cognitive function and impact on functional decline. Detailed study of these pathways will uncover important mechanisms of peripheral inflammation-driven cognitive decline and are already driving clinical initiatives to mitigate AD progression through minimising systemic inflammation. PMID- 25802558 TI - Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study. AB - BACKGROUND: Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. METHODS: This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. RESULTS: Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function. CONCLUSIONS: Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID. PMID- 25802559 TI - The role of regulatory T cells in immune dysfunction during sepsis. AB - BACKGROUND: Although regulatory T cells (Tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about Treg-mediated immunosuppression in the stage of sepsis. This article aimed to review the current literature on the role of Tregs in the pathophysiology of septic response, attempting to investigate the role of Tregs in immune dysfunction during sepsis. DATA SOURCES: A literature search was conducted in January 2014 using the China National Knowledge Infrastructure and PubMed. Articles on the role of Tregs in immune dysfunction during sepsis were identified. RESULTS: The identified articles indicated that Treg levels can be used for the assessment of the course of sepsis. The inhibition of Treg activity can promote the recovery of immune function. CONCLUSION: Since the mechanism of Tregs is complex during the sepsis, more studies are needed. PMID- 25802560 TI - Ultrasound diagnosis of malaria: examination of the spleen, liver, and optic nerve sheath diameter. AB - BACKGROUND: Over 90% of all cases of malaria worldwide occur in Africa. Current methods of diagnosis are time and labor intensive, and could lead to delayed treatment. METHODS: In this study we investigated the effectiveness of measurements of spleen, liver, and optic nerve sheath diameter (ONSD) in identifying patients with malaria or severe malaria through the use of hand-held ultrasound devices. We recruited 40 adult patients with malaria and 16 adult control subjects at two hospitals in Mwanza, Tanzania. Ultrasonographic diagnosis was compared with rapid antigen diagnostic test and peripheral blood smear as the gold standards. An receiver operating characteristic curve test was performed to determine the most optimal diagnostic threshold for malaria and severe malaria, using each of the measurements for liver size, spleen size, and ONSD. The thresholds were determined to be >12 cm for spleen length and >15.1 cm for liver length, whereas ONSD was not significant in this study. RESULTS: The sensitivities for malaria diagnosis were 66.7% and 58.3% for liver and spleen length respectively, suggesting that these measurements may not be suitable for identifying patients with severe malaria. However, the high specificity of 90.9% for spleen length and the acceptable specificity of 75.0% for liver length suggest that these measurements can be used as a method to eliminate false positive diagnoses (i.e. patients who do not have severe malaria but are classified as having it by a test with a high sensitivity), giving a high positive predictive value. CONCLUSIONS: We report a high specificity for spleen size and a moderate specificity for liver size in the ultrasonographic diagnosis of severe malaria. Thus when paired with a highly sensitive method of malaria diagnosis, ultrasonographic measurement of spleen and liver size is promising as part of a diagnostic algorithm for malaria. It could be used to stratify risk in patients diagnosed with malaria and assist in their triage. If no sensitive tests are available, ultrasound might be useful to suggest malaria as a cause of a patient's constellation of clinical symptoms. PMID- 25802561 TI - Evaluation of a simulation-based workshop on clinical performance for emergency physicians and nurses. AB - BACKGROUND: Simulation-based medical education has been growing rapidly and becomes one of the most popular teaching methods for improving patient safety and patient care. The Simulation Subcommittee of the Hong Kong College of Emergency Medicine organized an educational program emphasizing the team training, clinical decision-making and communication skills. This study aimed to evaluate the attitude of the participants toward a new training program and the change in the knowledge on clinical performance in emergency physicians and nurses after attending the educational program. METHODS: A course evaluation form was filled in by the participants at the end of the workshop. An assessment of 20 multiple choice questions with 5 options was administered to the participants before and after the 2-day simulation-based training workshop. RESULTS: A total of 72 doctors and nurses working in the Accident and Emergency Department were enrolled. The average pretest and posttest scores were 12 and 14.3 respectively. The percentage improvement in the mean score of the pretest and posttest was 11.5%. The Chi-square test showed significant improvement in the pretest and posttest score grading (P=0.00). Paired t-test revealed significant difference between the mean scores of the pretest and posttest (P=0.00). CONCLUSIONS: Participants had positive attitude toward this new training program. Significant improvement of the knowledge on clinical performance in healthcare professionals in the Accident and Emergency Department was observed after the participation in this simulation-based educational program. PMID- 25802562 TI - Embryonic natural orifice transluminal endoscopic surgery in the treatment of severe acute pancreatitis complicated by abdominal compartment syndrome. AB - BACKGROUND: The study aimed to estimate the value of embryonal natural orifice transluminal endoscopic surgery (ENOTES) in treating severe acute pancreatitis (SAP) complicated with abdominal compartment syndrome (ACS). METHODS: The patients, who were randomized into an ENOTES group and an operative group, underwent ENOTES and laparotomy, respectively. The results and complications of the two groups were compared. RESULTS: Enterocinesia was observed earlier in the ENOTES group than in the operative group. Acute Physiology and Chronic Health Evaluation II (APACHE II) score of patients in the ENOTES group was lower than that of the operative group on the 1st, 3rd and 5th post-operative day (P<0.05). The cure rate was 96.87% in the ENOTES group, which was statistically different from 78.12% in the operative group (P<0.05). There were significant differences in complications and mortality between the two groups (P<0.01). CONCLUSION: Compared with surgical decompression, ENOTES associated with flexible endoscope therapy is an effective and minimal invasive procedure with less complications. PMID- 25802563 TI - Effect of harmless acute pancreatitis score, red cell distribution width and neutrophil/lymphocyte ratio on the mortality of patients with nontraumatic acute pancreatitis at the emergency department. AB - BACKGROUND: Harmless acute pancreatitis score (HAPS), neutrophile/lymphocyte ratio and red blood cell distribution width (RDW) are used to determine the early prognosis of patients diagnosed with nontraumatic acute pancreatitis in the emergency department (ED). METHODS: Patients diagnosed with acute pancreatitis (K 85.9) in the ED according to the ICD10 coding during one year were included in the study. Patients with chronic pancreatitis and those who had missing data in their files were excluded from the study. Patients who did not have computed tomography (CT) in the ED were not included in the study. RESULTS: Ultimately, 322 patients were included in the study. The median age of the patients was 53.1 (IQR=36-64). Of the patients, 68.1% (n=226) had etiological causes of the biliary tract. The mortality rate of these patients within the first 48 hours was 4.3% (n=14). In the logistic regression analysis performed by using Balthazar classification, HAPS score, RDW, neutrophile/lymphocyte ratio, age, diabetes mellitus and systolic blood pressure, the only independent variable in determining mortality was assigned as Balthazar classification (OR: 15; 95% CI: 3.5 to 64.4). CONCLUSIONS: HAPS, neutrophile/lymphocyte ratio and RDW were not effective in determining the mortality of nontraumatic acute pancreatitis cases within the first 48 hours. The only independent variable for determining the mortality was Balthazar classification. PMID- 25802564 TI - Effect of low-dose glucocorticoid on corticosteroid insufficient patients with acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: This study aimed to investigate the prevalence rate of critical illness-related corticosteroid insufficiency (CIRCI) and the effect of low-dose glucocorticoid on prognosis of CIRCI in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Since January 2010 to December 2012, 385 patients, who met the criteria of AECOPD, were enrolled in the Intensive Care Unit (ICU) of the First People's Hospital and Municipal Central Hospital of Xiangtan City. The AECOPD patients complicated with CIRCI screened by an adrenalcorticotrophic hormone test within 12 hours after admission to ICU were divided into a treatment group (n=32) and a control group (n=31) for a prospective, randomized and controlled clinical trial. Hydrocortisone (150 mg/d) or normal saline was injected intravenously for 7 days. The patients were followed up for 28 days after injection. The endpoint included 28-day survival time, non-shock time, ICU stay and the period of non-mechanical ventilation. The markers of inflammation C-reactive protein, tumor necrosis factor-alpha, interleukin 6 and procalcitonin were measured at baseline and 7 days after treatment. The variables were analyzed by Student's t test, the non-parametric statistical test, the Chi-square test or the Kaplan-Meier method with SPSS18.0 statistic software. A P value <0.05 was considered statistically significant. RESULTS: Totally 63 patients were diagnosed with CIRCI by an adrenalcorticotrophic hormone test and the prevalence rate was 16.4%. The shock rate of the AECOPD patients complicated with CIRCI was higher than that of the AECOPD patients without CIRCI (23.8% vs. 8.7%, P<0.01). Kaplan-Meier analysis revealed that the 28-day survival time of the treatment group was obviously longer than that of the control group (P<0.05). Compared with the control group, shock-free days within 28 days was longer in the treatment group (18.2+/-9.5 vs. 25.8+/-4.1, P<0.05). Treatment with low-dose glucocorticoid obviously decreased the markers of infection and inflammation (P<0.01), such as C-reactive protein (13.2+/-5.5 mg/L vs. 8.3+/-3.1 mg/L for the control group; 13.5+/-5.9 mg/L vs. 5.1+/-2.3 mg/L for the treatment group), tumor necrosis factor-alpha (26.1+/-16.2 MUg/L vs. 17.5+/-11.7 MUg/L for the control group; 25.0+/-14.8 MUg/L vs. 10.4+/ 7.8 MUg/L for the treatment group) and procalcitonin (3.88 MUg/L vs. 2.03 MUg/L for the control group; 3.77 MUg/L vs. 1.26 MUg/L for the treatment group). Furthermore, the markers in the treatment group decreased more obviously than those in the control group (P<0.01). CONCLUSION: The prevalence rate of CIRCI was higher in the patients with AECOPD in the department of critical medicine, and low-dose glucocorticoid treatment for one week reduced the 28-day mortality, shock time and markers of infection and inflammation. PMID- 25802565 TI - Prognostic value of CD4(+)CD25(+) Tregs as a valuable biomarker for patients with sepsis in ICU. AB - BACKGROUND: Sepsis is a common complication of infections, burns, traumas, surgeries, poisonings, and post-cardiopulmonary resuscitation. The present study aimed to investigate prognostic value of CD4(+)CD25(+) regulatory T cells (Treg) in peripheral blood of patients with sepsis. METHODS: Periphery blood from 28 patients diagnosed with sepsis was collected on day 1 and 7 after hospitalization in the ICU of Shanghai Changzheng Hospital between December 2013 to April 2014. The blood was used for analyses of Treg ratio using flow cytometry and for analyses of blood routine test, C-reactive protein (CRP), bilirubin, procalcitonin (PCT), and coagulation. APACHE II and sequential organ failure assessment (SOFA) scores were also investigated. The results were compared between two outcome groups of survival or death to evaluate prognostic value for sepsis. RESULTS: The patients had an average age of 60.36+/-15.03 years, APACHE II score 16.68+/-7.00, and SOFA score 7.18+/-3.78. Among the 28 patients, 12 had severe trauma (42.9%), 10 had septic shock (35.7%), and 9 (32.2%) died. The median ratio of Tregs was 2.10% (0.80%, 3.10%) in the survival group vs. 1.80% (1.15%, 3.65%) in the death group (Z=-0.148, P=0.883) on day 1; however it was significantly changed to 0.90% (0.30%, 2.80%) vs. 5.70% (2.60%, 8.30%) (Z=-2.905, P=0.004). CONCLUSION: With better prospects for clinical application, dynamic monitoring of Tregs ratio in peripheral blood has potential value in predicting prognosis of sepsis. PMID- 25802566 TI - The risk of wound infection after simple hand laceration. AB - BACKGROUND: This prospective observational study aimed to determine the infection rate of simple hand laceration (SHL), and to compare infection rates between patients who were prescribed antibiotics and those who were not. METHODS: The study was performed at two urban hospitals enrolling 125 emergency department (ED) patients with SHL. Exclusion criteria included patients with lacerations for more than 12 hours, immunocompromized patients, patients given antibiotics, and patients with gross contamination, bites or crush injuries. Wound infection was defined as clinical infection at a follow-up visit (10-14 days) or wound was treated with antibiotics. Patient satisfaction was also measured using a visual analogue scale 1-10, asking the patients about wound appearance. Demographic data and wound characteristics were compared between the infected and non-infected wounds. The infection rates were also compared between patients who received prophylactic antibiotics and those who did not. The results were presented with medians and quartiles or percentages with 95% confidence intervals (CI). RESULTS: In the 125 patients SHL [median age: 28 (18, 43); range: 1-102 years old; 36% female], 44 (35%, 95% CI: 27%-44%) were given antibiotics in the ED. Wound infection was reported in 6 patients (4.8%, 95% CI: 2%-10%). Age, gender, history of diabetes and wound closure were not associated with wound infection (P>0.05). The infection rate was not significantly different between patients with or without antibiotic prophylaxis [7% (3/44), 95% CI: 2%-10% vs. 4% (3/81), 95% CI: 1%-11%, P=0.66]. Patient's satisfaction with appearance of infected and non infected wounds were significantly different [7.5 (6, 8) vs. 9 (8, 10), P=0.01]. CONCLUSION: Approximately 5% of simple hand lacerations become infected. Age, gender, diabetes, prophylactic antibiotics and closure technique do not affect the risk of infection. PMID- 25802567 TI - Trauma patterns in patients attending the Emergency Department of Jazan General Hospital, Saudi Arabia. AB - BACKGROUND: Modern civilization and the sharp rise in living standards have led to dramatic changes in trauma pattern in Saudi Arabia. This study aimed to describe the different patterns of injuries of patients attending the Emergency Department of Jazan General Hospital (JGH) in the southwest corner of Saudi Arabia. METHODS: A total number of 1 050 patients were enrolled in the study. A pre-organized data sheet was prepared for each patient attended the Emergency Department of JGH from February 2012 to January 2013. It contains data about socio-demographics, trauma data, clinical evaluation results, investigations as well as treatment strategies. RESULTS: The mean age of the patients was 25.3+/ 16.8 years. Most (45.1%) of the patients were at age of 18-30 years. Males (64.3%) were affected by trauma more common than females. More than half (60.6%) of the patients were from urban areas. The commonest kind of injury was minor injury (60%), followed by blunt trauma (30.9%) and then penetrating trauma (9.1%). The mean time from the incident to arrival at hospital was 41.3+/-79.8 minutes. The majority (48.2%) of the patients were discharged after management of trivial trauma, whereas 2.3% were admitted to ICU, 7.7% transferred to inpatient wards, and 17.7% observed and subsequently discharged. The mortality rate of the patients was 2.6%. CONCLUSION: Trauma is a major health problem, especially in the young population in Saudi Arabia. Blunt trauma is more frequent than penetrating trauma, with road traffic accidents accounting for the majority. PMID- 25802568 TI - Acute intoxication cases admitted to the emergency department of a university hospital. AB - BACKGROUND: This study aimed to describe the clinical and socio-demographic aspects of acute poisoning in 2010 in Duzce City, Northwest Anatolian Region of Turkey. METHODS: Acute poisoning was due to the intentional ingestion of drugs in young and adult people (>=16), who were treated at the Emergency Service of Duzce University Medical Hospital, Turkey from January 1, 2010 to December 31, 2010. In this retrospective and descriptive study, 95 patients were diagnosed with intoxications and 30 of them intentionally ingested drugs to commit suicide. Records of the patients diagnosed with intoxication were obtained from the Clinical Archive of the hospital. Their diagnoses were established according to the International Statistical Classification of Diseases and Related Health Problems. Codes X60-X84 of this classification were used to classify self infringed drug injuries and drug poisoning. RESULTS: In this series, 35 (36.8%) patients were male and 60 patients (63.2%) female. The male/female ratio was 1.0/1.7. The mean age of the patients was 33.1+/-14.2 years; 17 (17.9%) patients were below 20 years old and 9 (9.5%) were older than 50 years. Of these patients, 29 (30.5%) were single, 7 (7.4%) divorced or separated, and 59 (62.1%) married. Their mean time for admission to the emergency service after the incident was 208+/-180 (15-660) minutes. The mean time for admission to the emergency service for patients with food intoxication after the incident was 142+/-160 minutes, for those with drug intoxication 173+/-161 minutes, for those with carbon monoxide (CO) intoxication 315+/-209 minutes, and for those with undefined intoxication 289+/-166 minutes (P=0.005). Most of the intoxication cases occurred in winter (41.1%, 39 of 95 patients). Admissions to the emergency service were most common in December and April (21 and 16 of 95 patients, respectively). Sixty-five (68.4%) cases were involved in non-deliberate poisoning, whereas 30 (31.6%) were involved in deliberate poisoning. Twenty-six of the 95 patients with acute poisonings had mortality risk at admission, however only one died from CO intoxication in the emergency service (1.1%). Suicide attempts were more common in females than in males (21 of 30 patients, 70%, P<0.05). CONCLUSION: In Duzce City of Turkey, most intoxication cases occurred in winter, especially in December. They had non-deliberate poisoning, but deliberate poisoning in suicide attempts was more common in females than in males. PMID- 25802569 TI - Relationship between intubation rate and continuous positive airway pressure therapy in the prehospital setting. AB - BACKGROUND: To determine whether the prehospital use of continuous positive airway pressure (CPAP) therapy is associated with a reduced rate of endotracheal intubation in patients with an acute respiratory disorder brought to the emergency department (ED). METHODS: We reviewed medical records of patients with acute respiratory distress who had been treated with CPAP in the Mobile Intensive Care Unit (MICU) from January 2010 to December 2011. These records were compared with those of patients who received standardized care without CPAP in the MICU from January 2004 to December 2004. Categorical variables were summarized as frequencies and compared between groups using Fisher's exact test or the Chi square test. Continuous variables were summarized as medians (interquartile range), and comparison between the groups was made using Wilcoxon's rank-sum test. The relationship between CPAP and intubation rate was determined using multivariable logistic regression analysis of propensity scores. The results were presented as odds ratio (OR), 95% confidence interval (CI), and P value for test effect. The adequacy of the model was calibrated using Hosmer and Lemeshow's goodness-of-fit test. P<0.05 was considered statistically significant. RESULTS: The records of 785 patients were reviewed. Of the 215 patients treated with CPAP in the MICU, 13% were intubated after admission. In contrast, of the 570 patients who did not receive CPAP, 28% were intubated after ED admission. Unadjusted logistic regression analysis showed that patients who had been treated with CPAP were less likely to be intubated than those without CPAP treatment (OR=0.37, 95%CI, 0.24-0.57, P<0.0001). With propensity scores adjusted, multivariate logistic regression analysis showed that CPAP treatment was associated with a 62% reduction of intubation (OR=0.384, 95%CI, 0.25-0.60, P<0.0001). CONCLUSIONS: In patients with acute respiratory disorder, there was a relationship between CPAP therapy and the decreased intubation rate. CPAP therapy was feasible in prehospital management of patients with respiratory distress. PMID- 25802570 TI - Regulatory effects of hydrogen sulfide on alveolar epithelial cell endoplasmic reticulum stress in rats with acute lung injury. AB - BACKGROUND: The present study was undertaken to examine the regulatory effect of hydrogen sulfide (H2S) on endoplasmic reticulum stress in alveolar epithelial cells of rats with acute lung injury (ALI) induced by oleic acid (OA). METHODS: Seventy-two male Sprague Dawley (SD) rats were divided into control group, oleic acid-induced ALI group (OA group), oleic acid-induced ALI with sodium hydrosulfide (NaHS) pretreatment group (OA+NaHS group), and sodium hydrosulfide treatment group (NaHS group). Rats of each group were further subdivided into 3 subgroups. Index of quantitative assessment of histological lung injury (IQA), wet/dry weight ratio (W/D) and H2S level of lung tissues were measured. The expressions of endoplasmic reticulum stress markers including glucose-regulated protein 78 (GRP78) and alpha-subunit of eukaryotic translation initiation factor 2 (elF2alpha) in lung tissues were measured by immunohistochemical staining and Western blotting. RESULTS: The IQA score and W/D ratio of lung tissues at the three time points significantly increased in rats injected with OA, but significantly decreased in other rats injected with OA and NaHS. The level of H2S in lung tissue at the three time points significantly decreased in rats injected with OA, but significantly increased in other rats injected with both OA and NaHS. GRP78 and elF2alpha decreased in rats injected with OA, but increased in other rats injected with both OA and NaHS, especially at 4-hour and 6-hour time points. CONCLUSION: The results suggested that H2S could promote alveolar epithelial cell endoplasmic reticulum stress in rats with ALI. PMID- 25802571 TI - Lingual angioedema after alteplase treatment in a patient with acute ischemic stroke. AB - BACKGROUND: In recent years, thrombolytic therapy has become the main treatment of ischemic stroke. But the increasing use of alteplase in ischemic stroke has made some complications more evident. Angioedema is a rare but potentially life threatening complication of alteplase treatment. Only a few studies have examined the incidence of angioedema after treatment with alteplase for stroke. METHODS: A 75-year-old man complaining of right hemiparesis was admitted to our emergency department. He was diagnosed as having acute ischemic stroke, and alteplase infusion was given two hours after the onset of stroke symptoms. Immediately after the completion of infusion he was noted to have a large swollen tongue. RESULTS: His neurological symptoms resolved gradually within 4 hours, whereas his upper extremity strength improved to 4/5 and lower extremity 5/5. Lingual edema resolved within 16 hours without any complication. He died from presumed nosocomial infection 5 days later. CONCLUSIONS: Lingual angioedema may appear as a possible complication in patients who were treated with alteplase. The management of these patients should be very careful. PMID- 25802572 TI - Development of Stabilimax NZ From Biomechanical Principles. AB - BACKGROUND: Traditionally, spinal degeneration and injury have been associated with abnormal intervertebral motion; thus, treatment for lowback pain has centered on prevention of motion through spinal fusion. Although the rate of successful spinal fusions is improving, complications such as adjacent-level syndrome emphasize the need to develop alternatives for treating spinal degeneration. In an effort to improve the clinical outcomes associated with such treatment, we hypothesized that spinal stabilization and a consequent reduction in symptoms is achievable without the harsh restrictions to spinal motion imposed by fusion. This idea was based on the principle of the neutral zone and the neutral zone hypothesis of back pain. DEVELOPMENT: Performance requirements for a novel device were determined through a series of biomechanical experiments. From these data, the Stabilimax NZ was developed to provide stabilization to a degenerated or surgically destabilized spine while maintaining the maximum possible total range of motion. Applied Spine Technologies Inc has tested 70 bilateral assemblies of the final design of the Stabilimax NZ, and all exceeded the biomechanical, static, fatigue, wear, and histological requirements necessary to initiate clinical investigation. DISCUSSION: The Stabilimax NZ device has been systematically designed and tested under protocols developed by Applied Spine Technologies in conjunction with Panjabi, Patwardhan, and Goel. The device decreased the neutral zone in destabilized spines while maintaining substantial range of motion. CLINICAL RELEVANCE: Development testing has been submitted to the US Food and Drug Administration and permission obtained to initiate an investigational device exemption trial to clinically investigate the efficacy of the Stabilimax NZ device. PMID- 25802573 TI - The first 18 months following food and drug administration approval of lumbar total disc replacement in the United States: reported adverse events outside an investigational device exemption study environment. AB - BACKGROUND: Introduction of a new surgical technology may result in higher rates of adverse events compared with rates reported in the study performed to gain regulatory approval. The purpose of our study was to describe the incidence of reported adverse events during the first 18 months following US Food and Drug Administration (FDA) approval of the first lumbar arthroplasty device available in the United States and to discern data trends. METHODS: Reports of adverse events submitted to the FDA in patients receiving the Charite artificial disc were reviewed and pooled by similarity. We analyzed 135 medical device reports filed with the FDA regarding the Charite artificial disc between October 26, 2004, and April 26, 2006. Sixteen reports were excluded for lack of information regarding cause or because described events were vague or unrelated to the procedure. RESULTS: Rate of adverse events reported to the FDA as a percentage of devices of which the device manufacturer was aware had been dispensed at 6, 12, and 18 months following approval was 0.58%, 2.34%, and 2.13%, respectively. The adverse event reported most frequently through 18 months was anterior migration with reoperation (0.65%); other reported adverse events were, in decreasing order, sizing and malposition errors resulting in reoperation (0.36%), posterior element fracture resulting in reoperation (0.30%), major vascular injury requiring a blood transfusion (0.23%), and subsidence requiring reoperation (0.20%). Three non-device-related patient deaths were reported following FDA approval. The reported rate of sizing/malposition errors leading to reoperation of 0.36% was the same rate as that seen in the investigational device exemption (IDE) study of the Charite artificial disc. All other reported rates were lower than rates of the same events reported in the study. CONCLUSIONS: Medical device reporting is an important yet highly anecdotal and incomplete event-tracking process. However, it is the principal means available in the United States for obtaining information on the clinical performance of a device after its approval for sale and does provide some data, albeit imperfect, in this regard. The cumulative medical device reports through the 18 months following FDA approval, measured against the number of devices dispensed, suggests a rate of adverse events that either tracks or is somewhat less than that reported in the IDE study. This suggests that a repeat of the "cage rage," a "lumbar arthroplasty rage," has not yet occurred. PMID- 25802574 TI - Surgical treatment for discogenic low-back pain: lumbar arthroplasty results in superior pain reduction and disability level improvement compared with lumbar fusion. AB - BACKGROUND: The US Food and Drug Administration approved the Charite artificial disc on October 26, 2004. This approval was based on an extensive analysis and review process; 20 years of disc usage worldwide; and the results of a prospective, randomized, controlled clinical trial that compared lumbar artificial disc replacement to fusion. The results of the investigational device exemption (IDE) study led to a conclusion that clinical outcomes following lumbar arthroplasty were at least as good as outcomes from fusion. METHODS: The author performed a new analysis of the Visual Analog Scale pain scores and the Oswestry Disability Index scores from the Charite artificial disc IDE study and used a nonparametric statistical test, because observed data distributions were not normal. The analysis included all of the enrolled subjects in both the nonrandomized and randomized phases of the study. RESULTS: Subjects from both the treatment and control groups improved from the baseline situation (P < .001) at all follow-up times (6 weeks to 24 months). Additionally, these pain and disability levels with artificial disc replacement were superior (P < .05) to the fusion treatment at all follow-up times including 2 years. CONCLUSIONS: The a priori statistical plan for an IDE study may not adequately address the final distribution of the data. Therefore, statistical analyses more appropriate to the distribution may be necessary to develop meaningful statistical conclusions from the study. A nonparametric statistical analysis of the Charite artificial disc IDE outcomes scores demonstrates superiority for lumbar arthroplasty versus fusion at all follow-up time points to 24 months. PMID- 25802575 TI - Complications of Lumbar Artificial Disc Replacement Compared to Fusion: Results From the Prospective, Randomized, Multicenter US Food and Drug Administration Investigational Device Exemption Study of the Charite Artificial Disc. AB - BACKGROUND: Previous reports of lumbar total disc replacement (TDR) have described significant complications. The US Food and Drug Administration (FDA) investigational device exemption (IDE) study of the Charite artificial disc represents the first level I data comparison of TDR to fusion. METHODS: In the prospective, randomized, multicenter IDE study, patients were randomized in a 2:1 ratio, with 205 patients in the Charite group and 99 patients in the control group (anterior lumbar interbody fusion [ALIF] with BAK cages). Inclusion criteria included confirmed single-level degenerative disc disease at L4-5 or L5 S1 and failure of nonoperative treatment for at least 6 months. Complications were reported throughout the study. RESULTS: The rate of approach-related complications was 9.8% in the investigational group and 10.1% in the control group. The rate of major neurological complications was similar between the 2 groups (investigational = 4.4%, control = 4.0%). There was a higher rate of superficial wound infection in the investigational group but no deep wound infections in either group. Pseudarthrosis occurred in 9.1% of control group patients. The rate of subsidence in the investigational group was 3.4%. The reoperation rate was 5.4% in the investigational group and 9.1% in the control group. CONCLUSIONS: The incidence of perioperative and postoperative complications for lumbar TDR was similar to that of ALIF. Vigilance is necessary with respect to patient indications, training, and correct surgical technique to maintain TDR complications at the levels experienced in the IDE study. PMID- 25802576 TI - Kineflex (centurion) lumbar disc prosthesis: insertion technique and 2-year clinical results in 100 patients. AB - BACKGROUND: The Kineflex lumbar disc is a mechanical, unconstrained, re-centering disc prosthesis developed in South Africa. The first implantation took place in October 2002. We present a single-center, prospective, longitudinal study of the first 100 patients treated with the Kineflex lumbar disc. Our objective was to evaluate the insertion technique, clinical outcomes, and patient satisfaction at 2 years postimplantation in 100 consecutive patients with 132 (68 single- and 32 2-level) Kineflex lumbar disc replacements. METHODS: We determined the exact central placement of all disc implants in the coronal and midsagittal planes. We measured clinical outcome with the Oswestry disability index (ODI), our own questionnaire, and the time needed to return to work. All patients received radiological and clinical follow-up assessments for 2 years after the index procedure. RESULTS: Forty-three patients were female. The mean age of the patients at operation was 44.9 years (range, 23-63 years). Postoperative hospitalization averaged 2.8 days (range, 2 to 8 days). All patients who were employed before surgery returned to work 31 +/- 16.8 days after the operation. Fifty-six percent of operated disc levels had intervertebral disc heights of less than 5 mm. A 2-year clinical outcome was available for 98 of the 100 patients (58 excellent, 30 good, 7 fair, 3 poor). The ODI score improved from 47.8 +/- 16.0 preoperatively to 14.2 +/- 14.0 (P < .01) at 2 years. At 2 years, 95% of disc implants were radiologically in the ideal position. The insertion technique, with a released prosthetic mechanism for final placement, allowed ideal placement in the sagittal plane in 98% of discs. The radiographic placement accuracy achieved was equal in patients with preoperative intervertebral disc height below and above 5 mm. CONCLUSIONS: Good short-term clinical results were achieved with the Kineflex disc in a heterogeneous patient group with a high number of patients with advanced disc degeneration, severe disc space narrowing, and lumbar flat back deformity. In this cohort, accurate implant placement could be achieved in our first 100 patients. CLINICAL RELEVENCE: This is the first report on the Kineflex mechanical lumbar disc prosthesis. PMID- 25802577 TI - Nubac disc arthroplasty: preclinical studies and preliminary safety and efficacy evaluations. AB - BACKGROUND: Disc arthroplasty is gaining popularity for treatment of low-back pain caused by degenerative disc disease (DDD). It can involve total disc replacement or partial disc or nucleus replacement (or augmentation). Compared with total disc replacement, nucleus replacement is less invasive, has less surgical risk, has faster postoperative recovery, and doesn't "burn bridges" should further surgery be required. However, nucleus replacement has a high risk of implant expulsion because the device is not fixed to the vertebrae. Nubac is the first polyetheretherketone (PEEK)-on-PEEK articulated disc arthroplasty device designed to optimally restore the lumbar anatomy and biomechanics. METHODS: ISO 10993 standards were used to evaluate the biocompatibility of the PEEK material. Chemical and thermal-mechanical tests and in vivo study assessed PEEK's biostability after exposure to high g irradiation and harsh oxidative conditions. Biomechanical tests to evaluate kinematic properties and anatomical restoration of the implanted lumbar motion segments and implant expulsion risk assessments were performed with a human cadaveric model. Because of the novelty of PEEK-on-PEEK as a self-mating articulating material, extensive wear tests were conducted with unidirectional and coupled motions. Static and fatigue strength also were tested. Animal study with a baboon model was conducted with gross, radiographic, biomechanical, and histological evaluations at 6 and 12 months postoperatively. Preliminary clinical data were collected through a prospective multicenter cohort study. RESULTS: PEEK demonstrated exceptional biocompatibility and biodurability. Nubac restored disc height and motion segment range of motion. The unique articulating design of the Nubac demonstrated low risk of implant expulsion in a human cadaveric model. Wear tests showed that the Nubac has minimal wear and compares favorably to other disc arthroplasty materials. The Nubac also had excellent static and fatigue properties for the intended application. The animal study showed that the Nubac caused no adverse local or systematic tissue reaction and there was no detectable wear debris. The preliminary clinical data showed no major intraoperative vascular and neurological complications. There was significant Visual Analog Scale and Oswestry Disability Index score improvement. CONCLUSIONS: The preclinical data supported the design rationale, and the preliminary clinical data (level II evidence) on safety and efficacy were encouraging. CLINICAL RELEVANCE: The Nubac could be a viable first surgical option for patients with back pain caused by DDD. PMID- 25802578 TI - Anatomic Facet Replacement System (AFRS) Restoration of Lumbar Segment Mechanics to Intact: A Finite Element Study and In Vitro Cadaver Investigation. AB - BACKGROUND: Many decompression procedures involve complete or partial facetectomy. Spinal fusion usually stabilizes the motion segment after complete facetectomies. However, problems with fusion, such as adjacent-level degeneration, have increased interest in motion- preservation technologies. Facet arthroplasty may become an important posterior motion-preservation device, but its biomechanical literature is sparse. METHODS: We conducted an in vitro investigation and finite element study to compare the biomechanical effects of an artificial facet system to the intact spine. In the in vitro study, we tested human osteo-ligamentous segments (L3-S1) in intact, injured, and artificial facet repaired conditions. For the finite element study, we used a 3-dimensional ligamentous L3-S1 segment model. We simulated destabilization in the intact model by removing the facets across the L4-L5 functional unit, then repaired it with appropriately sized facet implants and compared the ranges of motion, facet loads, disc pressures, and device loads. We also analyzed a finite element model with a rigid posterior pedicle-rod fixation system. We subjected the cadaveric specimens and the models to 400 N of follower load plus a 10 Nm moment in extension, flexion, bending, and rotation. We used a novel technique to apply the follower load in the finite element models such that preload induced minimal vertebral rotation during the range of motion. RESULTS: The predicted ranges of motion for the intact and implanted models were consistent with cadaver data. After destabilization and facet replacement, the artificial facet system restored motion in all loading modes to intact values. The implant facet loads were similar to intact facet loads in extension and axial rotation, but less in lateral bending. The intradiscal pressure at the implanted level for the facet replacement device was similar to the intact pressure, whereas with the rigid system the intradiscal pressure was up to 70% less than the intact pressure. The maximum von-Mises stress predicted in the facet replacement construct was 85 MPa in extension at the bone-pedicle screw interface, compared with 174 MPa in the rigid system. Contact stresses at implant mating surfaces were minimal. CONCLUSIONS: The artificial facet system replicated natural facet kinematics. The cadaveric ranges of motion and the predicted finite element-based data indicated that the implant can "restore" the normal function of the segment after artificial facet replacement. CLINICAL RELEVANCE: Compared to rigid posterior pedicle-rod fixation, the artificial facet system restored the intact mechanics at the implanted level and may prevent adjacent-level degeneration. PMID- 25802580 TI - Two- to 3-Year Follow-Up of ProDisc-L: Results From a Prospective Randomized Trial of Arthroplasty Versus Fusion. AB - BACKGROUND: Although total disc replacement has been performed for years outside the United States, relatively little available data address clinical outcomes, particularly data from prospective studies. We report the 24- to 36-month follow up of one center's experience with the ProDisc-L artificial disc as part of a prospective, randomized trial comparing total disc arthroplasty to combined anterior-posterior lumbar fusion. METHODS: The study involved clinical results for 157 patients from a single center enrolled in the US Food and Drug Administration-regulated trial comparing ProDisc-L to fusion. Only patients who had reached a minimum 24-month follow-up were included in the study. Patients were randomized to receive total disc replacement or circumferential fusion at 1 or 2 lumbar disc levels from L3 to S1, with specific inclusion and exclusion criteria. Data were collected preoperatively and at 6 weeks to 36 months postoperatively. The primary clinical outcome measures were Visual Analog Scale (VAS) scores to assess pain and Oswestry Disability Index (ODI) scores to measure function. RESULTS: The VAS and ODI scores in both treatment groups improved significantly as early as the 6-week followup visit and remained significantly improved throughout the 36-month follow-up period. Although a tendency was observed for the ProDisc-L scores to indicate more favorable outcome, the differences were not statistically significant. The proportion of patients who would have the same procedure again was greater in the total disc replacement group at all follow-up intervals, and significantly greater at the 6- month, 12 month, 24-month, and 36-month follow-up visits. CONCLUSIONS: The results of this study indicate that the total disc replacement with ProDisc-L produces improvements in pain and function that are at least as good as those provided by circumferential fusion. During the long-term follow-up of 24 and 36 months, outcomes did not become less favorable compared with the early outcomes. CLINICAL RELEVANCE: We found that results of total disc replacement were at least as good as those achieved with combined instrumented anterior-posterior fusion for the treatment of painful disc degeneration. Favorable results were maintained during 24- and 36-month follow-up. PMID- 25802579 TI - Finite element study of matched paired posterior disc implant and dynamic stabilizer (360 degrees motion preservation system). AB - BACKGROUND: Anterior lumbar disc replacements are used to restore spinal alignment and kinematics of a degenerated segment. Compared to fusion of the segment, disc replacements may prevent adjacent segment degeneration. To resolve some of the deficiencies of anterior lumbar arthroplasty, such as the approach itself, difficulty of revision, and postoperative facet pain, 360 degrees motion preservation systems based on posterior disc and posterior dynamic system (PDS) designs are being pursued. These systems are easier to revise and address all the pain generators in a motion segment, including the nerves, facets, and disc. However, biomechanics of the 360 degrees posterior motion preservation system, including the contributions of the 2 subsystems (disc and PDS), are sparsely reported in the literature.nds. METHODS: An experimentally validated 3 dimensional finite element model of the ligamentous L3-S1 segment was used to investigate the differences in biomechanical behavior of the lumbar spine. A single-level 360 degrees posterior motion preservation system and its individual components in various orientations were simulated and compared with an intact model. Appropriate posterior surgical procedures were simulated. The PDS, a curved device with male and female components, was attached to the pedicle screws. The finite element models were subjected to 400 N of follower load plus 10Nm moment in extension and flexion. RESULTS: The PDS restored flexion/extension motion to normal. The artificial disc led to increases in range of motion (ROM) compared with the intact model. ROM for the 360 degrees system at the implanted and adjacent levels were similar to those of the respective intact levels. ROM was similar whether the discs were placed (a) both parallel to the midsagittal plane, (b) both angled 20 degrees to the midsagittal plane, and (c) one at 20 degrees and one parallel to the midsagittal plane. However, the stresses were slightly higher in the nonparallel disc configuration than in the parallel disc configuration, both in flexion and extension modes. CONCLUSIONS: Posterior disc replacement with PDS restored the kinematics of the spine at all levels to near normal. In addition, placing the discs in a nonparallel configuration with respect to the midsagittal plane does not affect the functionality of the discs compared with parallel placement. Posterior disc replacement alone is not sufficient to restore the segment biomechanics to normal levels. CLINICAL RELEVANCE: Finite element analysis results show that, unlike implants for fusion, PDS and posterior discs together (360 degrees motion preservation system) are needed to preserve ROM. Such systems will prevent adjacent level degeneration and address pain from various spinal components, including facets. PMID- 25802581 TI - Optimal intervertebral sealant properties for the lumbar spinal disc: a finite element study. AB - BACKGROUND: In the lumbar spinal column, an annular disruption may be sealed after annulotomy to prevent further prolapse and instability. We investigated the biomechanical effects of various material properties of an injectable sealant. METHODS: We used a 3-dimensional, nonlinear, osteoligamentous, experimentally validated finite-element model of the L3-L5 spine segment to study annulotomies of varying sizes and locations in the L3-L4 annulus followed by replacement with isotropic sealants (plugs) with a Young's modulus of 0.4, 2.0, 4.0, 6.0, and 40.0 MPa. Annulotomies in the region of the posterior longitudinal ligament were studied with and without the ligament in place. Intact, destabilized, and repaired models were subjected to 400 N compression and 12.7 Nm moment in all loading modes to compute plug forces, plug stresses, motion characteristics, and annulus bulge. RESULTS: Changes in sealant stiffness minimally affected the overall motion characteristics of the segment. Increases in shear stress and von Mises stress were proportional to the stiffness of the sealant. The von Mises stress was inversely proportional to plug size. Removal of portions of the posterior longitudinal ligament did not significantly alter motion between spinal segments or stress in the annulus fibrosus. Removal of portions of the ligament increased the disc bulge when plugs were less stiff. Intradiscal pressure decreased when an annulotomy was created. The sealant generally restored nucleus pressure to a degree proportionate to sealant stiffness. CONCLUSIONS: Minimizing sealant stresses as well as expulsion and separation forces should lead to a minimal Young's modulus. Sealant materials with a Young's modulus close to 6 MPa are most appropriate. The allowable variation in material properties is reduced with increased annulotomy size. Removal of posterior longitudinal ligament only allows increased sealant bulge when the sealant's modulus of elasticity is very low. This removal does not affect spinal unit biomechanics or annulus stress in annulotomy or annulotomy with sealant repair. PMID- 25802583 TI - Osteopenia and total disc prosthesis subsidence: inclusion/exclusion criteria for total disc replacement. AB - BACKGROUND: Prosthetic subsidence is an adverse event of disc arthroplasty with a total disc prosthesis. Factors affecting prosthetic subsidence are (1) the size of the prosthetic endplate (footprint), (2) amount of load applied to the spine, and (3) compressive strength of the vertebral bone. The size of the prosthetic endplate has been addressed adequately in the development of the current generation of total disc prostheses. However, little information is available on the relation between osteopenia (low bone mineral density [BMD]) and prosthetic subsidence. We evaluated the relation between osteopenia and compressive strength of vertebral bone and propose an inclusion/exclusion guideline for disc arthroplasty in the presence of osteopenia. METHODS: This study was based on previously published data by C.K. Lee on bone mineral density, contact surface area, and applied load that emphasized the critical contact surface area required to prevent subsidence. The study included 35 cadaveric vertebral bones (representing ages 38-68) that were evaluated via quantitative computed tomography for BMD and subjected to nondestructive and destructive tests for compressive strength of the vertebral bones. The relationship of osteopenia to prosthetic subsidence was evaluated from the data. RESULTS: Patients with average BMD (0.137 g/cm(3)) require a minimum contact surface area of 6.5 cm(2) for the physiologic load of 2500 N. Patients with a BMD of up to 1 SD below the average will require 9.1 cm(2) of contact area for the same load. Patients with a BMD of up to 2 SD below the average will require 13 cm(2) of contact area. DISCUSSION: The average endplate surface area of small disc prostheses is about 6.5-8 cm(2), which is enough to tolerate normal physiologic load for patients with normal BMD. Patients with BMD of 2 SD below the average will require a disc prosthesis with an endplate surface area greater than 12.75 cm(2) to tolerate normal physiologic load. The largest size of prosthetic endplate of the currently available disc prostheses is about 11 cm(2); therefore, patients with BMD below 2 SD will have a high risk of subsidence, and these patients should be excluded for disc arthroplasty. Patients with BMD between -1.5 SD and -2.0 SD may be included for disc arthroplasty only when they can receive the large size of prosthesis with greater than 10.5 cm(2) prosthetic endplates. CONCLUSIONS: All patients should be evaluated preoperatively with BMD measurement. Patients with a BMD of up to 1.5 SD below the average can be included for total disc arthroplasty. Patients with BMD of 2 SD below the average should be excluded for total disc arthroplasty, and patients with BMD of 1.5-2 SD below the average should be carefully evaluated for the appropriate size of the prosthesis prior to the surgery. PMID- 25802582 TI - Stress Reduction in Adjacent Level Discs via Dynamic Instrumentation: A Finite Element Analysis. AB - BACKGROUND: Conventional (rigid) fusion instrumentation is believed to accelerate the degeneration of adjacent discs by increasing stresses caused by motion discontinuity. Fusion instrumentation that employs reduced rod stiffness and increased axial motion, or dynamic instrumentation, may partially alleviate this problem, but the effects of this instrumentation on the stresses in the adjacent disc are unknown. We used a finiteelement model to calculate and compare the stresses in the adjacent-level disc that are induced by rigid and dynamic posterior lumbar fusion instrumentation. METHODS: A 3-dimensional finite-element model of the lumbar spine was obtained that simulated flexion and extension. The L5-S1 segment of this model was fused, and the L4-L5 segment was fixed with rigid or dynamic instrumentation. The mechanical properties of the dynamic instrumentation were determined by laboratory testing and then used in the finite element model. Peak stresses in the lumbar discs were calculated and compared. RESULTS: The reduced-stiffness component of the dynamic instrumentation was associated with a 1% to 2% reduction in peak compressive stresses in the adjacent level disc (at 45 degrees flexion), and the increased axial motion component of this instrumentation reduced peak disc stress by 8% to 9%. Areas of disc tissue exposed to 80% of peak stresses of 6.17 MPa were 47% less for discs adjacent to dynamic instrumentation than for those adjacent to rigid instrumentation. CONCLUSIONS: Reduced stiffness and increased axial motion of dynamic posterior lumbar fusion instrumentation designs result in an approximately 10% cumulative stress reduction for each flexion cycle. The effect of this stress reduction over many cycles may be substantial. CLINICAL RELEVANCE: The cumulative effect of this reduced amplitude and distribution of peak stresses in the adjacent disc may partially alleviate the problem of adjacent-level disc degeneration. PMID- 25802584 TI - Lumbar disc replacement for junctional decompensation after fusion surgery: clinical and radiological outcome at an average follow-up of 33 months. AB - BACKGROUND: Failed fusion surgery remains difficult to treat. Few published data on disc replacement surgery after failed fusion procedures exist. Our objective was to evaluate outcomes of junctional lumbar disc replacement after previous fusion surgery and to correlate outcome with radiological changes to parameters of sagittal balance. METHODS: Out of a single-center prospective registry of 290 patients with 404 lumbar disc replacements, 27 patients had had a previous lumbar fusion operation on 1 to 4 lumbar segments and had completed a mean follow- up of 33 months (range: 18-56). We correlated the clinical outcome measures (patient satisfaction, 10-point pain score, and Oswestry Disability Index [ODI] score) to parameters of spinal sagittal alignment (sacral tilt, pelvic tilt, pelvic incidence, and lumbar lordosis). RESULTS: Postoperative hospital stay averaged 3.3 days (range: 2-8). Previously-employed patients went back to their jobs with a mean of 32 days (range: 21-42) after the procedure. At the latest follow-up, 1 of the patients considered the outcome to be poor, 3 fair, 8 good, and 15 excellent. Twenty-four patients "would undergo the operation again." Average pain score decreased from 9.1 +/- 1.0 (SD) to 3.2 +/- 2.1 (P < .01). Average ODI decreased from 50.2 +/- 9.9 preoperatively to 21.7 +/- 14.2 (P <= .01). We found the change in pelvic tilt to be an independent predictor of better clinical outcome by multivariate analysis (P < .05). CONCLUSIONS: In patients with junctional failure adjacent to a previous posterolateral fusion, disc replacement at the junctional level(s), compared with osteotomy and fusion surgery, offers the advantage of maintaining segmental mobility and correcting the flat-back deformity through a single approach with less operative time and blood loss. Early- to intermediate-term results are promising. The influence of changes in spinal sagittal alignment on clinical outcome needs to be addressed in future research. CLINICAL RELEVANCE: This is the first study on "junctional disc replacement patients" correlating clinical outcome to changes in spinal/pelvic alignment. PMID- 25802585 TI - Benefits of the paraspinal muscle-sparing approach versus the conventional midline approach for posterior nonfusion stabilization: comparative analysis of clinical and functional outcomes. AB - BACKGROUND: The influence of approach on outcomes of posterior nonfusion stabilization has not been described. This paper analyzes the influence of surgical approach on functional outcome with nonfusion stabilization. METHODS: We performed a prospective consecutive cohort outcome analysis of 88 patients who had undergone posterior nonfusion stabilization of the lumbar spine at 178 levels using the Dynesys system (Zimmer Spine, Inc, Warsaw, Indiana). Patients needing decompression (n = 42) were operated through a midline approach using microscopic laminotomy/foraminotomy with or without discectomy, followed by posterior nonfusion stabilization with Dynesys. None of the patients had a complete laminectomy. Patients not needing decompression (n = 46) underwent the procedure via the bilateral paraspinal muscle-sparing approach and were subsequently stabilized. Clinical and functional outcomes data were collected using the visual analog scale (VAS), Treatment Intensity Score (TIS), Oswestry Disability Index (ODI), and SF-36. Average follow-up was 18 months (range, 12-36 mo). RESULTS: All outcome measures in both groups showed significant improvement at last follow-up. Between the groups a significant difference was apparent in the reduction of the TIS when measured at 1 week and 6 weeks. The preoperative, 1-week, and 6-week values were 66, 48, and 40, respectively (P < 0.05), for the midline group and 80, 32, and 28 (P < 0.05) for the paraspinal group. This trend continued through 3 to 6 months after the procedure but did not reach statistical significance. In the paraspinal group, pain scores showed a nonsignificant trend toward lower values in the first month, compared with values in the midline group. Patients reported excellent to fair results, with the exception of three patients in the midline group and two in the paraspinal group, who rated the procedure as fair. CONCLUSIONS: Significantly fewer patients required postoperative narcotics in the paraspinal group than in the midline group. This improvement in early outcomes suggests a significant early benefit to the less tissue-destructive muscle sparing approach in posterior nonfusion stabilization procedures. PMID- 25802586 TI - The learning curve in foraminal endoscopic discectomy: experience needed to achieve a 90% success rate. AB - BACKGROUND: We sought to construct a general methodology for objectively quantifying the learning curve associated with any surgical technique and to determine the number of cases needed to achieve a success rate of 90% for the technique of transforaminal endoscopic lumbar discectomy. To our knowledge, no other studies have observed the learning curve of endoscopic lumbar discectomy by transforaminal approach. METHODS: We studied the learning curve of 1 orthopedic surgeon who had had experience performing open spine surgery and knee and shoulder arthroscopic surgery, but not endoscopic spine surgery. We studied 144 patients who had an endoscopic lumbar discectomy by transforaminal approach (using the Yeung Endoscopic Surgery System). We evaluated results with modified MacNab criteria and used a questionnaire to determine the patients' satisfaction with the surgery. The average follow-up period was 24 months. We used an algorithm, analyzing the patient outcome and the surgical time evolution, to determine the case at which a success rate of 90% good/excellent results was reached. RESULTS: The cut for the calculated learning curve was placed at case no. 72; i.e., the results in the first 72 cases were 75% good/excellent, 18% fair, and 7% poor, and the results in the following 72 cases were 90.3% good/excellent, 9.7% fair, and 0% poor. CONCLUSIONS: A methodology to calculate the learning curve of a surgical procedure was developed. A learning curve of 72 cases was needed to reach the goal of 90% of good/excellent results for transforaminal endoscopic lumbar discectomy. CLINICAL RELEVANCE: The method developed to establish the learning curve of a surgical procedure, based on outcome and surgical time, may be used to assess any new procedure. With respect to the transforaminal endoscopic technique, the determination of a specific number of cases (72) needed to master (achieve 90% excellent/ good results) could help orient surgeons willing to adopt this technique. PMID- 25802587 TI - The Evolution and Advancement of Endoscopic Foraminal Surgery: One Surgeon's Experience Incorporating Adjunctive Techologies. AB - BACKGROUND: Endoscopic spine surgery has evolved gradually through improvements in endoscope design, instrumentation, and surgical techniques. The ability to visualize and treat painful pathology endoscopically through the foramen has opened the door for the diagnosis and treatment of degenerative conditions of the lumbar spine (from T10 to S1). Other endoscopic techniques for treating a painful disc have been focused on a posterior approach and has been compared with micro lumbar discectomy. These procedures have not been more effective than open microdiscectomy but are less invasive, have less surgical morbidity, and allow for more rapid surgical recovery. Spinal decompression and fusion was the fallback procedure when nonsurgical treatment or discectomy failed to relieve sciatica and back pain. Foraminal endoscopic surgery, however, provides a truly minimally invasive alternative approach to the pathoanatomy of the lumbar spine because it preserves the multifidus muscle, maintains motion, and eliminates or, at worst, delays the need for fusion. METHODS: The following developments helped facilitate the evolution of a transforaminal endoscopic surgery procedure for disc herniations from a foraminal disc decompression, also known as percutaneous endoscopic lumbar discectomy, to a more complete foraminal surgical technique that can address spinal stenosis and spinal instability. This expanded capability gives foraminal endoscopic surgery distinct advantages and flexibility for certain painful degenerative conditions compared with open surgery. Advancement of the technique occurred when needle trajectory and placement was refined to better target each type of herniation with precise needle and cannula positioning directed at the herniation. New instrumentation and inclusion of a biportal technique also facilitated removal of extruded, migrated, and sequestered disc herniations. The further development of foraminoscopes with larger working channels and high speed burrs to remove bone more efficiently, along with recognition of foraminal pathoanatomy in the foramen, led to the identification and treatment of other painful degenerative conditions of the lumbar spine such as failed back surgery syndrome, recurrent disc herniations, lateral foraminal stenosis, degenerative spondylolisthesis, and isthmic spondylolisthesis. A summary of the endoscopic techniques currently used and trademarked by the author as the YESS technique include: (1) a published protocol for optimal needle and instrument placement calculated by lines drawn on the skin from the C-arm image; (2) evocative chromodiscography by the operating surgeon with nonionic radiologic contrast and indigo carmine dye to confirm concordant pain production and to stain tissue in contact with the injectate; (3) selective endoscopic discectomy, which targets the removal of loose degenerative nucleus stained differentially by indigo carmine dye; (4) thermal annuloplasty, a visualized radiofrequency thermal modulation of disc and annular defects guided by vital tissue staining; (5) endoscopic foraminoplasty, a decompression of the lateral and subarticular recess, including disc and foraminal degenerative and isthmic spondylolisthesis; (6) visually and radiologically guided exploration of the epidural space; (7) probing the hidden zone of MacNab for normal nerves (and branches of spinal nerves known as furcal nerves) versus anomalous autonomic nerves in the foramen; and (8) a uniportal and biportal technique for inside-out removal of extruded and sequestered nucleus pulposus. RESULTS: Endoscopic foraminal surgical procedures are not limited to disc decompression. The approaches and techniques allow access to the lumbar spine for treatment of conditions ranging from discogenic pain to failed back surgery syndrome (most commonly caused by residual or recurrent disc herniation and lateral recess stenosis). More than 3000 patients have undergone endoscopic posterolateral surgical exploration and decompression by the author since 1991. The first 80 patients reported formed the basis for expansion of techniques as new instruments and adjunctive therapy methods were added to selective endoscopic discectomy and thermal annuloplasty. New anatomic and pathoanatomic conditions were reported as they were encountered. CONCLUSIONS: New skills will become desirable and necessary for the spine surgeon to keep up with endoscopic technology in spine care. The emphasis is on visualization of painful pathoanatomy and preservation of mobility. A new focus is on nucleus replacement, annular repair, annular reinforcement, biologics, and even transforaminal interbody fusion as the procedure of last resort. The transforaminal surgical approach to the lumbar spine can allow for minimally invasive access without negatively affecting and destabilizing the multifidus muscle. PMID- 25802588 TI - Soft stabilization with an artificial intervertebral ligament in grade I degenerative spondylolisthesis: comparison with instrumented posterior lumbar interbody fusion. AB - BACKGROUND: The purpose of this retrospective study was to evaluate the efficacy of soft stabilization with an artificial intervertebral ligament after microdecompression for the treatment of grade I degenerative spondylolisthesis. METHODS: From a total of 54 patients with degenerative spondylolisthesis who were treated surgically from May 2000 to April 2003, 36 patients who showed grade I spondylolisthesis without evidence of concomitant disc herniation necessitating discectomy were enrolled in the study. After decompression, the patients had undergone either soft stabilization with an artificial intervertebral ligament (n = 17) or instrumented posterior lumbar interbody fusion (PLIF; n = 19). RESULTS: The average follow-up period was 24 months for the PLIF group and 16 months for the soft stabilization group. In the PLIF group, preoperative mean scores of 60% on the Oswestry Disability Index, 8.8 on the visual analog scale (VAS) for low back pain, and 9.3 on the VAS for leg pain improved to 28%, 4.1, and 2.6, respectively, after surgery. Corresponding scores in the soft stabilization group were 55%, 8.4, and 8.9, improving to 25%, 4.1, and 2.2 after surgery. There were no significant differences between the 2 groups in any of these clinical parameters. Patients' subjective improvement rates and satisfaction with the surgical procedure were higher in the soft stabilization group, but the differences were not significant. Mean operation time and mean blood loss were significantly lower in the soft stabilization group than in the PLIF group. In the soft stabilization group, there were 3 cases of progression of slippage in patients who had had preoperative slippage of more than 20%; there was 1 dural tear in the PLIF group. CONCLUSIONS: Patients with grade I degenerative spondylolisthesis who received soft stabilization with an artificial intervertebral ligament after microdecompression had clinical outcomes similar to those of patients who received PLIF. Since soft stabilization can be done in a much less invasive way than fusion, if slippage is 20% or less, soft stabilization with an artificial ligament is a viable alternative to fusion for patients who are elderly or who have significant comorbidities that make a prolonged operation inadvisable. LEVEL OF EVIDENCE: This study was a retrospective comparative study with a very limited population (level III evidence). PMID- 25802589 TI - Biomechanical behavior of a new nucleus prosthesis made of knitted titanium filaments. AB - BACKGROUND: One of the greatest challenges in the development of a nucleus prosthesis is to minimize the risk of implant expulsion. At the same time, the physiological flexibility, compressive behavior, and height of the disc should be restored. In this biomechanical in vitro study we investigated the ability of a new nucleus prosthesis made of knitted titanium filaments to meet these challenges. METHODS: Flexibility, axial deformation, and height of six bovine lumbar spine segments were measured in the intact condition, after implantation of the new prosthesis, and during and after complex cyclic loading (100,000 cycles). For this purpose, six new prostheses preformed according to the shape of the bovine nucleus pulposus were manufactured. Flexibility was tested in the three main planes under pure moment loads of 7.5 Nm. Axial deformation was measured under application of an axial force of 1000 N. Radiographs taken before and after cyclic testing were used to assess implant migration and expulsion. RESULTS: In lateral bending, the intact range of motion (RoM) could almost be restored after implantation. However, in axial rotation, the RoM increased slightly with the implant. This was also the case in extension, with an increase from -2.9 degrees to -6.4 degrees , whereas in flexion, RoM decreased from 4.3 degrees to 3.2 degrees . In all loading planes, cyclic loading caused the RoM to increase asymptotically by 0.1 degrees to 1.8 degrees . The axial deformation of the specimens was nearly equivalent in all tested states, as was their height. Cyclic loading did not cause implant expulsion. CONCLUSIONS: In this feasibility study, the new knitted nucleus prosthesis showed promising results in segmental flexibility, axial deformability, height, and implant expulsion. However, further study is needed for other factors, such as wear and fatigue behavior. PMID- 25802590 TI - Adjacent segment disease in a patient with klippel-feil syndrome and radiculopathy: surgical treatment with two-level disc replacement. AB - Klippel-Feil syndrome (KFS) is a complex congenital condition characterized by improper segmentation of cervical motion segments that could contribute to undesirable adjacent segment degeneration. KFS patients have a strong tendency to present with disease in the adjacent segments. When this condition is present, anterior decompression followed by total disc replacement can be performed safely and can lead to good clinical results. This treatment has theoretical advantages compared with anterior decompression and fusion. Comparative studies and long term follow-up are needed. Complications associated with fusion include loss of a motion segment, disc height loss, subsidence of the graft, progressive degenerative changes at the adjacent level, graft-related complications, and graft-site complications. Such new technologies as motion preservation spine arthroplasty represent attempts to avoid these complications. Here we present a case report of a 62-year-old female patient with type I congenital fusion at the C5-6 level, with a history of neck pain and right radiculopathy at C5-7. X-rays and MRI show evidence of adjacent segment degeneration at levels above and below congenital fusion. The patient's preoperative visual analog score (VAS) for neck pain was 7 out of a possible 10, her score for right upper extremity pain was 8 out of 10, and her Neck Disability Index (NDI) was 32%. Surgical treatment consisted of anterior decompression and total disc replacement at both levels. At 1-year follow-up, the patient's VAS for neck pain was 2 out of 10, her VAS score for right upper extremity pain was 1 of 10, and her NDI was 9%. PMID- 25802591 TI - A comparison of the degree of lateral recess and foraminal enlargement with facet preservation in the treatment of lumbar stenosis with standard surgical tools versus a novel powered filing instrument: a cadaver study. AB - BACKGROUND: The SurgiFile (SurgiFile, Inc., Carlsbad, California) is a specialized tool designed for the treatment of lateral recess and foraminal stenosis that allows surgeons to internally expand and decompress the entire length of the neural foramen while preserving the integrity of the overlying facet complex. METHODS: We used two cadaveric specimens in this study. After they removed the lamina and spinous processes of L2, L3, L4, and L5 from the dorsal spine, fellowship-trained spinal surgeons used the standard tools and the SurgiFile to the best of their experience and ability on alternating sides of each level to decompress the lateral recess and neural foramen while still preserving at least 50% of the dorsal facet complex. Using preoperative and postoperative fine-cut CT scans with axial and sagittal reconstructions, we evaluated the degree of decompression and the amount of preserved facet complex using analytical tests and recording the measurements. RESULTS: The difference between the proximal recess and lateral foramen of the groups was statistically significant in the axial CT images. On sagittal reconstruction CT images, the difference between the two groups was significant (P < 0.05, Wilcoxon) only for the lateral foramen. Although a strong trend toward better area change was evident for the proximal recess measurements in the experimental tool sides, this did not achieve statistical significance. Macroscopic and CT scans measurements showed that the amount of facetectomy for adequate decompression with the SurgiFile was less than the amount achieved with the standard tools. CONCLUSIONS: For the treatment of spinal stenosis, this novel powered-file instrument provides surgeons with a new means of decompressing the lateral recess and neural foramina. In this cadaveric study, procedures performed with the SurgiFile tool showed a statistically superior degree of decompression as compared with the standard surgical instruments and techniques. PMID- 25802593 TI - Clinical symposium I: pedicle-based posterior non-fusion stabilization. PMID- 25802592 TI - Posterior Dynamic Stabilization as a Salvage Procedure for Lumbar Facet Degeneration Following Total Disc Arthroplasty: Case report. AB - Following an L5-S1 SB Charite disc III implantation, a 37-year-old female patient developed intractable radicular pain in the left L5 distribution. The patient underwent a minimally invasive foraminotomy, and her symptoms improved significantly. However, following recurrence of radicular pain, she showed signs of an L5-S1 facet degeneration and recurrent nerve root compression from hypertrophied synovium. A partial facetectomy was then performed to completely decompress the L5 root with supplemental posterior dynamic stabilization using a pedicle-based flexible titanium rod system. To date, the patient remains free of symptoms. Although posterolateral fusion would have been a viable option, the application of a posterior dynamic system permitted segmental motion preservation. PMID- 25802594 TI - Who should decide how new medical technology is utilized? Completing the algorithm with existing resources. PMID- 25802595 TI - In Vivo Assessment of Bone Graft/Endplate Contact Pressure in a Caprine Interbody Pseudarthrosis Model: A Preliminary Biomechanical Characterization of the Fusion Process for the Development of a Microelectromechanical Systems (MEMS) Biosensor. AB - BACKGROUND: In this preliminary study we used a goat model to quantify pressure at an interbody bone graft interface. Although the study was designed to assess fusion status, the concept behind the technology could lead to early detection of implant failure and potential hazardous complications related to motion preservation devices. The purpose of this study was to investigate the feasibility of in vivo pressure monitoring as a strategy to determine fusion status. METHODS: Telemetric pressure transducers were implanted, and pressure at the bone graft interfaces of cervical interbody fusion autografts placed into living goats (Groups A and B) was evaluated. Group A constituted the 4-month survival group and Group B the 6-month survival group. One goat served as the study control (Group C) and was not implanted with a pressure transducer. An additional six cadaveric goat cervical spines (Group D) were obtained from a local slaughterhouse and implanted with bone grafts and ventral plates and used for in vitro biomechanical comparison to the specimens from Groups A and B. RESULTS: All goats demonstrated an increase in interface pressure within the first 10 days postoperatively, with the largest relative change in pressure occurring between the sixth and ninth days. The goats from Groups A and B had a 200% to 400% increase in relative pressure. CONCLUSIONS: Although this was a pilot study to assess pressure as an indicator for a fusion or pseudarthrosis, the preliminary data suggest that early bone healing is detectable by an increase in pressure. Thus, pressure may serve as an indicator of fusion status by detecting altered biomechanical parameters. PMID- 25802596 TI - Twelve-Month Follow-up of Lumbar Spine Range of Motion Following Intervertebral Disc Replacement Using Radiostereometric Analysis. AB - BACKGROUND: Many clinical studies have focused on clinical pain scores and less on kinematics following intervertebral disc replacement. Although flexion and extension of the motion segment can be measured on lateral X-rays, measuring lateral bending and axial rotation of the device is extremely difficult on plain radiography. This study was designed to measure, using radiostereometric analysis (RSA), the postoperative range of motion of the spinal segment following placement of ProDisc-L interbody device (Synthes Spine, West Chester, Pennsylvania). METHODS: Twelve patients (15 discs) with a ProDisc-L intervertebral disc replacement were followed postoperatively at 1.5, 3, 6, and 12 months with both clinical and RSA examinations. For follow-up RSA analysis, 4 to 5 tantalum beads were inserted into the vertebrae adjacent to the surgical level during surgery. Standing biplanar films were collected during follow-up, and the ranges of motion (ROM) (sagittal and coronal bending) of the adjacent vertebrae were determined by RSA. RESULTS: Based on the clinical surveys, this group of patients had similar outcomes compared to larger clinical populations. The flexion/extension ROM with the disc replacement averaged 2.5 degrees at 6 weeks and increased over the follow-up period to 6.6 degrees at 6 months. The lateral bending ROM with the disc replacement remained consistent over the 4 time points and averaged 3.0 degrees . The motion at the level of the L4-5 vertebrae following disc replacement was greater across all time points than the motion at the L5-S1 level for both sagittal (5.9 degrees versus 2.1 degrees ) and coronal (4.2 degrees versus 0.6 degrees ) bending. CONCLUSIONS: In this study, the amount of RSA-measured segmental flexion/extension ROM for those with disc replacement was similar to other studies using plain radiography. In lateral bending, the amount of motion with disc replacement was less than the typical 6 degrees -16 degrees reported for normal ROM. CLINICAL RELEVANCE: This is the first published study evaluating the in vivo kinematics of artificial disc replacement using RSA. PMID- 25802597 TI - Does vertebral endplate morphology influence outcomes in lumbar disc arthroplasty? Part I: an initial assessment of a novel classification system of lumbar endplate morphology. AB - BACKGROUND: The influence of lumbar endplate morphology on the clinical and radiographic outcomes of lumbar disc arthroplasty has not been evaluated to the best of our knowledge. STUDY DESIGN AND OBJECTIVE: In this observational study of 80 patients, the objective was to formulate a reproducible and valid lumbar endplate classification system to be used in evaluating lumbar total disc replacement patients. METHODS: A novel vertebral endplate morphology classification system was formulated after review of data related to 80 patients enrolled in a prospective, randomized clinical trial in conjunction with an application for a US Food and Drug Administration investigational device exemption. Intraobserver and interobserver analyses of the classification system were performed on the same 80 patients utilizing the classification system. RESULTS: The initial review of the radiographs revealed 5 types of endplates: Type I (n = 82) flat endplates; Type II (n = 26) posterior lip; Type III (n = 5) central concavity; Type IV (n = 4) anterior sloping endplate; and Type V (n = 2) combination of Types I-IV. The intraobserver kappa was 0.66 and the interobserver kappa was 0.51. These kappa values indicate "substantial" to "moderate" reproducibility, respectively. CONCLUSIONS: In this study, we propose a lumbar endplate classification system to be used in the preoperative assessment of patients undergoing lumbar disc arthroplasty. The classification can function as a basis for comparison and discussion among arthroplasty clinicians, and serve as a possible exclusionary screening tool for disc arthroplasty. Special consideration should be given to Type II endplates to optimize proper positioning and functioning of a total disc replacement (TDR) implant. Further outcome studies are warranted to assess the clinical significance of this classification system. The key points of our study are: (1) We present a novel lumbar vertebral endplate classification system; (2) Five types of endplates were identified and classified; (3) Intraobserver and interobserver reliability were classified as substantial and moderate, respectively; and (4) The classification system used may assist in the preoperative evaluation of patients for total disc replacement. LEVEL OF EVIDENCE: A systematic review of cohort studies (level 2a). PMID- 25802598 TI - Anterior cervical corpectomy and fusion accelerates degenerative disease at adjacent vertebral segments. AB - BACKGROUND: Anterior cervical corpectomy provides the most direct and thorough surgical approach for anterior decompression when spinal cord compression is found directly behind the vertebral body. However, anterior cervical fusion has been shown to be associated with the development of new degenerative changes at levels immediately adjacent to the fused segments. Th e incidence of adjacent segment disease (ASD) following anterior cervical corpectomy has not been widely reported. We set out to determine the incidence of clinical ASD following anterior cervical corpectomy. METHODS: We retrospectively reviewed all available medical charts and radiographic studies of all cases of anterior cervical corpectomy performed at the Barrow Neurological Institute over a 4-year period with a minimum 24-month follow-up. Factors assessed included the success of arthrodesis, the presence of degenerative changes on serial follow-up radiographs, and the development of new neurological symptoms. RESULTS: Seventy six patients met the criteria for inclusion: 54 had undergone a 1-level corpectomy, 18 underwent a 2-level corpectomy, and 4 underwent a 3- or 4-level corpectomy. Arthrodesis was performed with either allograft or autograft and anterior cervical plating. All patients achieved successful fusion. Follow-up was available for a minimum of 2 years in all cases, with a mean length of 3.6 years. Sixteen patients (21%) eventually developed radiological and clinical evidence of degenerative changes at adjacent levels. In 10 of 11 patients who developed clinical symptoms within 2 years, the changes represented progression of pre existing, asymptomatic degenerative disease. Five patients developed degenerative changes more than 5 years after surgery; these were all associated with an unrelated new insult to the cervical spine such as trauma. CONCLUSIONS: Anterior cervical corpectomy with fixation can accelerate degenerative changes identified preoperatively at adjacent, asymptomatic levels of the cervical spine. LEVEL OF EVIDENCE: Retrospective cohort study (level 2b). PMID- 25802599 TI - Mechanical and biomechanical characterization of a polyurethane nucleus replacement device injected and cured in situ within a balloon. AB - BACKGROUND: The DASCOR device has recently been introduced as an innovative nucleus replacement alternative for the treatment of low-back pain caused by degenerative intervertebral disc disease. The purpose of this study was to characterize, through a series of preclinical mechanical bench and biomechanical tests, the effectiveness of this device. METHODS: A number of samples were created using similar preparation methods in order to characterize the nucleus replacement device in multiple mechanical bench tests, using ASTM-guided protocols, where appropriate. Mechanical bench testing included static testing to characterize the device's compressive, shear properties, and fatigue testing to determine the device's compressive fatigue strength, wear, and durability. Biomechanical testing, using human cadaveric lumbar spines, was also conducted to determine the ability of the device to restore multidirectional segmental flexibility and to determine its resulting endplate contact stress. RESULTS: The static compressive and shear moduli of the nucleus replacement device were determined to be between 4.2-5.6 MPa and 1.4-1.9 MPa, respectively. Similarly, the ultimate compressive and shear strength were 12,400 N and 6,993 N, respectively. The maximum axial compressive fatigue strength of the tested device that was able to withstand a runout without failure was determined to be approximately 3 MPa. The wear assessment determined that the device is durable and yielded minimal wear rates of 0.29mg/Mc. Finally, the biomechanical testing demonstrated that the device can restore the multidirectional segmental flexibility to a level seen in the intact condition while concurrently producing a uniform endplate contact stress. CONCLUSIONS: The results of the present study provided a mechanical justification supporting the clinical use of the nucleus replacement device and also help explain and support the positive clinical results obtained from two European studies and one US pilot study. CLINICAL RELEVANCE: Nucleus replacement devices are rapidly emerging to address specific conditions of degenerative disc disease. Preclinical testing of such devices is paramount in order to potentially ensure successful clinical outcomes post implantation. PMID- 25802600 TI - Modified muscle-sparing paraspinal approach for stabilization and interlaminar decompression: a minimally invasive technique for pedicle screw-based posterior nonfusion stabilization. AB - INTRODUCTION: Though Wiltse developed the paraspinal muscle-splitting approach to the spine, the exact location of where and how to split the paraspinal musculature when performing this approach remains unclear. This type of approach may be particularly useful for posterior nonfusion stabilization as significantly less damage occurs with this approach than with a muscle-stripping approach. METHODS: We use the term "modified muscle-sparing approach" to describe our technique for following the natural cleavage plane between the multifidus and longissimus muscles to access the spine. We review the rationale behind this methodology and describe technical aspects of this approach and also demonstrate the technique on video. RESULTS: We use this technique routinely for our posterior nonfusion pedicle screw stabilization approach. CONCLUSIONS: The modified muscle-sparing approach is a useful approach for insertion of pedicle screw-based posterior nonfusion stabilization. The approach can be readily performed with little blood loss and with little muscle damage. Decompression can also be performed through the same incision if needed. PMID- 25802601 TI - Electromagnetic navigation in minimally invasive spine surgery: results of a cadaveric study to evaluate percutaneous pedicle screw insertion. AB - BACKGROUND: This cadaveric study compared efficacy and safety of an electromagnetic (EM) guidance system versus conventional fluoroscopy for percutaneous pedicle screw fixation. As percutaneous pedicle screw fixation becomes increasingly common in spinal surgery, intraoperative imaging systems that maximize efficiency while minimizing radiation exposure and inaccurate trajectories will be progressively more important. Published studies have validated the safety of percutaneous screw fixation using conventional fluoroscopic guidance and frameless optical stereotaxy, though EM guidance systems have not been evaluated for percutaneous placement in the lumbosacral spine. The aim of the study was to evaluate the clinical applicability of an EM system for minimally invasive spine fusion in the lumbosacral spine. METHODS: Five human cadaveric specimens underwent bilateral lumbosacral percutaneous screw fixation from L1 to S1 using conventional anteroposterior (AP) and lateral fluoroscopic techniques on one side and 2-dimesional (2D) EM guidance on each matching side. Intraoperative efficiency was evaluated, and pedicle, vertebral, and critical breach rates were assessed on postoperative computed tomography (CT). RESULTS: Overall mean fluoroscopy time per screw was 58.9 +/- 44.7 seconds for conventional fluoroscopy compared to 27.4 +/- 13.5 seconds for electromagnetic guidance (P = .0003). Pedicle, vertebral, and critical breach rates for the L1-S1 were 32.1%, 10.7%, and 25.0% for conventional fluoroscopy and 42.8%, 10.7%, and 14.1% for electromagnetic guidance (difference not statistically significant [ns]). In comparing critical breaches in the lumbar spine (L1-L5), there was a significant difference between 2-D EM guidance (0) and CF guidance (6) (P = .02). CONCLUSIONS: Two-dimensional EM navigation provides a modality for lumbosacral percutaneous pedicle screw fixation that is more efficient and safer than conventional fluoroscopy. This data provides a foundation for further clinical trials of this technology. LEVEL OF EVIDENCE: Level 5 - Bench Research. PMID- 25802603 TI - Basic science symposium I: bone graft substitutes. PMID- 25802602 TI - Iliac bars lever reduction and fixation system used in the treatment of spondylolisthesis. AB - BACKGROUND: The purpose of the current study was to use the Iliac Bars Lever Reduction and Fixation System (IBLRFS) for Grades 1 and 2 spondylolytic spondylolisthesis, evaluate its stability and reductive efficacy, and examine the complications. METHODS: Between April 2005 and August 2006, 44 patients with Grades 1 and 2 spondylolytic spondylolisthesis were treated surgically: 21 patients underwent posterior Iliac Bars Lever Reduction and Fixation (IBRLFS), 23 patients were treated with traditional stabilization and reduction systems (SRS). The follow-up periods ranged from 1 to 2 years (mean, 1 year and 2 months). The clinical outcome, fusion rate, average percentile degree of displacement, displacement angle, sacral inclination, ratio of intervertebral height, and complications were evaluated. Operating time, blood loss, and duration of hospital stay were compared. RESULTS: There were no statistically significant differences between the 2 groups in blood loss, recovery rate, and radiographic results. However, there were statistically significant differences in operating time (P < .05), duration of hospital stay (P < .05). There were no cases of nonunion in the two groups. In the IBLRFS group, preoperatively, the average percentile degree of displacement, displacement angle, sacral inclination, and ratio of intervertebral height were 23.48% +/- 5.36%, 2.2 degrees +/- 1.1 degrees , 29.4 degrees +/- 6.5 degrees , and 0.68 +/- 0.21, respectively. Postoperatively, the respective measurements were 6.47% +/- 1.49%, 10.3 degrees +/- 3.3 degrees , 42.6 degrees +/- 8.1 degrees , and 0.85 +/- 0.12. No patients experienced major complications. In the SRS group, preoperatively, the average percentile degree of displacement, displacement angle, sacral inclination, and ratio of intervertebral height were 21.78% +/- 5.16%, 2.3 degrees +/- 1.0 degrees , 26.4 degrees +/- 8.5 degrees , and 0.62 +/- 0.25, respectively. Postoperatively, the respective measurements were 6.34% +/- 2.01%, 9.8 degrees +/- 2.1 degrees , 44.1 degrees +/- 7.6 degrees , and 0.79 +/- 0.23. One patient experienced a badly placed screw in the right pedicle of lumbar 4. CONCLUSIONS: This kind of new fixation system (IBLRFS) was shown to be useful in the treatment of spondylolisthesis, and its use was associated with minimal complications after 14 months of mean follow-up. LEVEL OF EVIDENCE: Therapeutic, case studies (level 4). PMID- 25802604 TI - Silicon Matrix Calcium Phosphate as a Bone Substitute: Early Clinical and Radiological Results in a Prospective Study With 12-Month Follow-up. AB - INTRODUCTION: Autograft has been the "gold standard" for orthopedic bone grafting applications, but with some clinical challenges. Here we present the rationale and clinical outcomes supporting the use of a bone substitute material that consists of a mixture of two calcium phosphates (HA and beta-TCP), which are integrated into a silicon xerogel matrix, promoting nanocrystalline apatite layers on the surface of the material following implantation into a physiological environment. METHODS: Twenty-four patients with a median age of 53.80 (36-81) years underwent lumbar spinal fusion for degenerative disease, selected by clinical presentation, X-rays, and MRI findings. Subjects were evaluated preoperatively and postoperatively at 1, 3, 6, and 12 months. The outcome assessment consisted of visual analog scale (VAS), Oswestry Disability Index (ODI), and radiological assessment analyzing the state of fusion on X-ray and CT evaluation by 3 independent radiologists. RESULTS: All patients completed 12 month follow-up. The mean VAS decreased from 9.3 (+/- 0.9) to 2.4 (+/- 1.6) and the mean ODI decreased from 55.0 (+/- 9.2) to 19.3 (+/- 11.4) at 12-month follow up. Three months after surgery, 10 patients (41.67%) had solid fusion based on analysis of CT scans and dynamic radiographs. At 6 months postoperatively, the fusion rate had increased to 75% (18 patients). Twelve months after surgery, 95.83% of patients had solid fusion (23 patients). CONCLUSIONS: The clinical results from this study of silicon matrix calcium phosphate are consistent with previous in vitro studies indicating that this material stimulates formation of a bioactive layer and provides an effective bone graft material for lumbar fusion applications. In comparison with previous studies involving rhBMP-2, silicon matrix calcium phosphate provided a lower fusion rate at 3- and 6-month follow-up points, but after 12 months, the fusion rate was similar, with no statistical differences and lower overall costs. No clinically relevant adverse events were associated with either the cage or graft material. With increasing evidence of high rates of enhanced fusion development in this spinal application, additional research is encouraged, including longer periods of followup, to further confirm the efficacy of silicon matrix calcium phosphate as a safe and effective bone graft substitute. PMID- 25802605 TI - Early Clinical & Radiographic Results of NFix II Posterior Dynamic Stabilization System. AB - BACKGROUND: Complications associated with rigid posterior instrumented fusions of the lumbar spine include pseudarthrosis, accelerated adjacent-segment disease, hardware failure, and iatrogenic fixed sagittal imbalance. Posterior pedicle screw/rod-based dynamic stabilization systems, in which semirigid rods or cords are used to restrict or control, rather than completely eliminate spinal segmental motion, aim to reduce or eliminate these fusion-associated drawbacks. In this study, we analyzed the early radiographic and clinical outcomes of patients treated with the NFix II System (N Spine, Inc., San Diego, California), a novel pedicle screw/ rod-based system used as a nonfusion posterior dynamic stabilization system, and compared our results to those of similar systems currently in use. METHODS: Seven sites participated in a retrospective assessment of 40 consecutive patients who underwent dynamic stabilization of the lumbar spine with the NFix II System at a single level. (One patient underwent 2 single level dynamic constructs at noncontiguous levels (L3-4 and L5-S1).) Patients were included based on the presence of spinal stenosis, degenerative spondylolisthesis, adjacent segment degeneration, recurrent disc herniation, symptomatic degenerative disc disease, and degenerative scoliosis requiring dynamic stabilization at 1 level with or without instrumented rigid fusion at a contiguous level. Participants were evaluated preoperatively, with planned postoperative assessments at 3 and 6 weeks (1 center assessed patients at 4 weeks), 3 months, 6 months, and 12 months. The primary clinical outcome measures at each assessment were visual analogue scale (VAS) scores to measure back pain, and Oswestry Disability Index (ODI)(1) scores to measure function. Radiographic outcome measurements included evidence of instrumentation failure and range of motion (ROM) based on postoperative flexion-extension radiographs at 3, 6, and 12 months. RESULTS: Forty patients (15males, 25 females) with a mean age of 55 years (range 21-81) were included. Average follow-up was 8.1 months (range 6-12). The mean VAS score improved from 7.6 preoperatively to 3.3 postoperatively (P < .001), and the ODI score from 47.3 to 22.8 (P < .001). Eighty percent of patients were severely disabled or worse (ODI >= 41) preoperatively, which was reduced to 13% postoperatively. Of the 10 patients with more than 6 months' follow-up, only 4 demonstrated adequate flexion/extension effort. ROM measurements in those 4 patients showed that on average 53% of preoperative segmental motion was retained at the dynamically stabilized level 6 months postoperatively. There were no instrumentation-related complications. CONCLUSIONS: Results of this limited study indicate that the NFix II System when used as a nonfusion device for dynamic stabilization produces significant improvements in pain and function at short term follow-up with outcomes comparable to other dynamic stabilization systems. The use of this system was not associated with an increased risk of instrumentation failure. The small number of patients with postoperative severe disability or worse compares favorably to long-term published data on posterolateral fusion. Lastly, in this small sample, ROM was preserved at 6-month follow-up. CLINICAL RELEVANCE: Posterior pedicle screw/rod dynamic stabilization using the NFix II System seems very effective in improving pain and function scores, at least in the short term (mean postoperative ODI of 22.8). Preservation of ROM is also possible. Longerterm follow-up is necessary to assess sustained clinical improvement, hardware complications, and maintenance in segmental ROM. The NFix II System may be considered an effective alternative to existing dynamic stabilization systems. This device is cleared by the US Food and Drug Administration for use as an adjunct to fusion and has the European CE Marking for use in both fusion and nonfusion applications. PMID- 25802606 TI - Two-Year Results of a Randomized Controlled Clinical Trial Comparing ProDisc-C and Anterior Cervical Discectomy and Fusion. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a well-accepted procedure for the treatment of cervical radiculopathy. Hilibrand et al. reported that adjacent segment disease is known to occur at a rate of 2.9% per year after cervical fusion. Developers of cervical disc replacements postulate that maintaining more normal motion may reduce the rate of adjacent segment disease. The purpose of this study was to compare the 2-year efficacy and safety of ACDF and cervical total disc replacement surgery. METHODS: Eighty-seven patients from 2 sites of this 13 multicenter trial were randomized to treatment with either ACDF or cervical disc replacement surgery with the ProDisc-C (Synthes, Inc., West Chester, Pennsylvania) implant. Patient outcomes were assessed via neck disability index (NDI), visual analog pain scale (VAS), and health survey SF-36 (QualityMetric, Lincoln, Rhode Island). Forty-three patients were treated with ACDF using allograft and plating, and 44 were treated with cervical disc replacement. The average age was 44 (23 to 61) years. All surgical procedures were single level. RESULTS: At all measured time points, both groups showed statistically significant improvement over their preoperative baseline with regard to NDI, VAS arm and neck pain levels, SF-36 mental composite score (MCS), and physical composite score (PCS) (P < .05). At 24 months, the disc replacement group showed results equivalent to the ACDF group with regard to NDI, VAS arm and neck pain, and SF-36 MCS. At 24 months, the disc replacement group showed significantly greater improvement in SF- 36 PCS as compared to the ACDF group (P = .0359). Of note, there was a trend toward greater patient satisfaction in the disc replacement group as compared to the ACDF group (83% versus 71%, P = .144). CONCLUSIONS: This study indicates that the tested disc replacement device achieves 2-year results ranging from equivalent to superior in comparison to ACDF in the treatment of symptomatic cervical disc disease. Long-term maintenance of these results has not yet been determined. PMID- 25802607 TI - Prognostic factors related to motion dynamics following cervical arthroplasty with a bryan disc: average 2-year follow-up. AB - BACKGROUND: This is a retrospective study to assess the prognostic factors influencing the postoperative motion dynamics and clinical outcome following cervical arthroplasty with a Bryan disc. METHODS: Twenty-seven patients (30 levels) consecutively underwent cervical arthroplasty using a Bryan disc (Medtronic Sofamor Danek, Memphis, Tennessee). Motion dynamics and clinical outcome (visual analogue score (VAS) and neck disability index (NDI) score) were examined preoperatively and at 1 month, 1 year, and final follow-up (average: 25 months). The prognostic factors influencing clinical outcome and postoperative motion dynamics were assessed. RESULTS: At last follow-up, mean VAS and NDI scores were significantly decreased from 8.33 +/- 1.52 to 1.10 +/- 0.99 (P = .001) and from 25.0 +/- 15.9 to 9.2 +/- 5.9 (P = .001), respectively. In a comparative study of pre- and postoperative motion changes at operated segments, mean segmental range of motion (ROM) increased from 6.96 degrees +/- 2.03 degrees to 8.93 degrees +/- 3.53 degrees (P = .014), and mean segmental angle decreased from 2.85 degrees +/- 3.27 degrees to 1.21 degrees +/- 5.93 degrees (P = .126). Mean global angle increased significantly from 14.54 degrees +/- 10.32 degrees to 18.36 degrees +/- 11.10 degrees (P = .003), and ROM increased non-significantly from 40.25 degrees +/- 13.51 degrees to 41.56 degrees +/- 12.53 degrees (P = .654). At upper and lower segments, ROMs did not change significantly postoperatively. The heights of functional segment units showed no change postoperatively (3.51 +/- 0.21 to 3.49 +/- 0.22, P = .701). No significant relationships were found between VAS and NDI improvement and changes in ROMs or segmental angles at last follow-up. Statistically, the postoperative functional segment unit (FSU) ROM decreased as the age of the patients increased (Spearman r = 0.391, P = .048). The gender and preoperative segmental ROM did not influence FSU ROM. CONCLUSIONS: Our results demonstrate that cervical arthroplasty with the Bryan disc for the treatment of cervical degenerative provides a good clinical outcome and preserves motion postoperatively. The age of the patients and the preoperative segmental ROM significantly affect the postoperative FSU ROM. These factors however do not relate to the clinical outcome. The relationship between long-term outcome and these variables should be verified by a larger cohort study. PMID- 25802608 TI - Is Degenerative Spondylolisthesis a Contraindication for Total Disc Replacement? Kineflex Lumbar Disc Replacement in 7 Patients With 24-Month Follow-up. AB - BACKGROUND: Degenerative spondylolisthesis is associated with a significant segmental kyphosis at the level of the listhesis. We treated 7 disc spaces with Grade 2 listhesis and/or kyphosis of the slipped disc level with Kineflex disc replacement. METHODS: Out of a single-center prospective registry, involving 310 lumbar disc replacement patients, 7 patients underwent a single-level Kineflex disc replacement at the level of a degenerative spondylolisthesis with either segmental kyphosis or a Grade 2 slip. Preoperative and follow-up radiological parameters studied were: pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis L1-S1, degree of segmental listhesis, segmental lordosis, and range of motion (ROM). Clinical outcome measures were Visual Analog Scale pain score (VAS), Oswestry Disability Index (ODI), and patient satisfaction. RESULTS: Five replacements were performed at the L4-L5 level, and 2 were performed at a L3-4 level, above a pre-existing L4-S1 posterolateral fusion. Mean age was 50 (32-62) years. Average follow-up was 23.8 +/- 13.1 months. Six of 7 patients considered their outcome as good or excellent. The mean VAS score decreased from 8.4 +/- 1.9 to 2.7 +/- 2.2 (P < .01). The ODI decreased from 45.2 +/- 9.9 preoperatively to 19.7 +/- 12.8 (P < .01). There were increases in lumbar lordosis (from 47.4o +/- 10.6 to 61.3o +/- 8.0 (P < .03)), in segmental lordosis (from 0.17 degrees +/- 7.0 degrees to 16.4 degrees +/- 2.0 degrees (P < .03)), and in sacral slope (from 34.5 degrees +/- 4.8 degrees to 40.7 degrees +/- 4.5 degrees (P < .03)). There were decreases in pelvic tilt (from 22.6 degrees +/- 6.3 degrees to 15.5 degrees +/- 5.9 degrees (P < .05)), and degree of segmental listhesis (from 24.4% +/- 7.7 to 3.7% +/- 3.4 (P < .03)). Pelvic incidence and ROM did not change. CONCLUSIONS: Disc replacement resulted in significant improvement in clinical outcome and excellent sagittal balance and slip correction. However, the influence of improved sagittal spinal alignment on clinical outcomes needs to be investigated in larger studies including a control group. CLINICAL RELEVANCE: This study is the first focused on disc replacement in degenerative spondylolisthesis. PMID- 25802609 TI - Does Vertebral Endplate Morphology Influence Outcomes in Lumbar Total Disc Arthroplasty? Part II: Clinical and Radiographic Results as Evaluated Utilizing the Vertebral Endplate Yue-Bertagnoli (VEYBR) Classification. AB - STUDY DESIGN: This study was a prospective study with a minimum patient follow-up of 2 years. Objective The purpose of this study was to evaluate the clinical usefulness of a vertebral endplate classification system (VEYBR) in predicting outcomes following lumbar arthroplasty. BACKGROUND: In the present study, our previously described endplate classification system was evaluated to determine its clinical usefulness in patients undergoing lumbar arthroplasty. METHODS: The patient cohort in this study consisted of 80 patients who had been enrolled in the US FDA ProDisc clinical trial. Radiographs were classified using the VEYBR classification. The preoperative categories (Types I to V) were then correlated with the patients' visual analogue scores (VAS) and Oswestry Disability Index (ODI) scores and radiographic outcomes at an average follow-up point of 28 months. RESULTS: The rank order of total change in VAS based on preoperative VEYBR classification was Type IV, III, I II, and V, with Type IV having the greatest improvement in VAS and Type V having the least improvement. The rank order of total change in ODI was Type IV, II, III, I, and V. We found no differences in clinical outcomes among the 5 vertebral endplate types. Type II endplates had least optimal sagittal positioning. CONCLUSIONS: Although not statistically significant, there was a strong trend for Type V endplates to have the least improvements in VAS and Oswestry clinical outcome scores. Knowledge and use of the endplate classification system did lead to consistent implant placement across endplate classes which may indicate the usefulness of this classification system in preoperative planning, especially for physicians in the "learning curve" phase of this procedure. LEVEL OF EVIDENCE: Case series (Level IV). PMID- 25802610 TI - The functional anaesthetic discogram: description of a novel diagnostic technique and report of 3 cases. AB - BACKGROUND: The diagnostic evaluation of patients with presumed discogenic low back pain is controversial; recent studies have brought the specificity of the traditional technique, provocative lumbar discography, into question. One of the explanations for the relative lack of predictability in treatment outcomes for patients with discogenic low back pain may be a corresponding lack of certainty in the diagnosis. PURPOSE: A new diagnostic technique is described for the evaluation of patients with presumptive discogenic low back pain; the cases of 3 patients in whom the technique was used are presented. STUDY DESIGN/SETTING: Case report; university practice. METHODS: A technique is described in which an anaesthetic catheter is placed into putative symptomatic lumbar discs, the patient elicits his or her typical pain via a position or activity, and anaesthetic or placebo is delivered to the disc. The effect of the injected substance on the patient's pain is then noted. RESULTS: In one patient, the new test was confirmatory of the results of the provocative discogram; in two patients, the test results were divergent. CONCLUSIONS: These case studies and technical description are presented as a first step in examining this method of preoperative assessment. Further study of the technique will allow us to make more definitive recommendations with regards to its validity and utility. LEVEL OF EVIDENCE: Level 4 - Case Series. PMID- 25802611 TI - Screening for nuclear replacement candidates in patients with lumbar degenerative disc disease. AB - BACKGROUND: Nuclear replacement is an emerging surgical treatment for degenerative disc disease (DDD) and low back pain (LBP). While clinical experience is most extensive with the prosthetic disc nucleus PDN (Raymedica, Minneapolis, Minnesota), strict indications apply for the implantation of this device. The purpose of this study was to ascertain what percentage of patients treated surgically for degenerative disc disease with other surgical procedures would have been candidates for nuclear replacement implantation. METHODS: The charts and films of 85 consecutive patients with failed conservative management for LBP treated surgically with fusion, disc replacement, or annuloplasty were retrospectively reviewed. There were 53 patients with 1-level disease and 32 with 2-level disease, accounting for 117 treated levels. Patients with the following radiographic contraindications to nuclear replacement were serially eliminated: (1) Schmorl's nodes and > 50% collapse of the disc space, (2) irregular/convex endplates on the MRI, (3) complete tears and large annular defects (ie, both incomplete tears and complete tears were eliminated, but patients with local annular deficiency were deemed eligible for nuclear replacement), and (4) a BMI > 30. RESULTS: Fifty-nine levels (50.4%) had no radiographic contraindications to treatment with a nuclear replacement device. Twelve levels in 10 patients with a BMI > 30 were excluded. Overall, 47 out of 117 levels (40.2%) had no contraindications to a prosthetic nucleus device. The L5-S1 level was the most commonly treated level (55 out of 117, 47%), but only 25.5% had no radiographic contraindications, and overall only 21.8% of the levels were suitable for a nuclear replacement device. Upper lumbar levels (L3-4 and L4-5) had no radiographic contraindications in a higher percentage of cases (68.8% and 72.7%, respectively). The inclusion of the BMI criteria reduced these percentages to 50% and 59.1%, respectively. CONCLUSIONS: The surgeon has to assess endplate integrity, disc height, endplate shape, annular integrity, and BMI when offering nuclear replacement as treatment for patients with DDD. PMID- 25802613 TI - The combined use of a posterior dynamic transpedicular stabilization system and a prosthetic disc nucleus device in treating lumbar degenerative disc disease with disc herniations. AB - BACKGROUND: Prosthetic replacement of spinal discs is emerging as a treatment option for degenerative disc disease. Posterior dynamic transpedicular stabilization (PDTS) and prosthetic disc nucleus (PDN) devices have been used sporadically in spinal surgery. METHODS: This was a prospective study of 13 patients averaging 40.9 years of age with degenerative disc disease who underwent posterior placement of a PDN with a PDTS. The Oswestry low-back pain disability questionnaire and visual analog scale (VAS) for pain were used to assess patient outcomes at the 3rd, 6th, and 12th postoperative months. Lumbar range of motion was evaluated using a bubble inclinometer preoperatively and at 12 months postoperatively. Radiological parameters including lumbar lordosis angle (LL), segmental lordosis angle (alpha), disc height at the operated level (DHo), and disc height of the adjacent level (DHu) were evaluated. A typical midline posterior approach for complete discectomy was followed by the simultaneous placement of the PDN with PDTS. RESULTS: Both the Oswestry and VAS scores showed significant improvement postoperatively (P < .05). There were no significant differences in LL, alpha, DHo, and DHu parameters. We observed complications in 3 patients including 2 patients who had the PDN device embedded into the adjacent corpus; 1 had massive endplate degeneration, and the other experienced interbody space infection. In 1 patient, the PDN device migrated to one side in the vertebral space. CONCLUSION: The use of a PDN in combination with posterior dynamic instrumentation can help to restore the physiologic motion of the anterior and posterior column and could help to establish posterior dynamic instrumentation as an important treatment of degenerative disc disease. Theoretically this concept is superior, but practically we need more advanced technology to replace disc material. Because this study examined the combination of the PDN and stabilization instrumention, the results cannot be compared with those reported in the literature for either PDN alone or dynamic screws alone. LEVEL OF EVIDENCE: Prospective cohort study with good follow-up (level 1b). PMID- 25802612 TI - Basic Science Symposium II: MEMS Technology. PMID- 25802614 TI - Measurement of paradoxical and coupled motions following lumbar total disc replacement. AB - BACKGROUND: Maintenance of segmental motion following lumbar total disc replacement (LTDR) is one of the theoretical advantages of spinal arthroplasty. This in vivo study examined paradoxical and coupled motions during sagittal plane movements following disc arthroplasty and compared these motions with those measured following lumbar discectomy. METHODS: Ten patients following LTDR using ProDisc-L (Synthes, Inc., West Chester, Pennsylvania) and 8 patients following lumbar discectomy (LD) were enrolled. At 1-month, 1-year and 2-year postoperative time-points, patients performed flexion/extension starting from a neutral position, and the intervertebral rotations were determined with radiostereometric analysis. The amount of intended and coupled motion was compared in each group and at each postoperative time. The frequency of paradoxical motion was compared between the 2 groups, and the effects of intended motion, operative-level, number of levels, and postoperative time-point were examined. RESULTS: The intended and coupled motions following LTDR and LD did not change over time and did not differ from each other for the flexion and total sagittal movements. The sagittal range of motion (ROM) of LTDR was significantly smaller than that of LD in extension ( 0.6 degrees +/- 1.1 degrees vs -2.2 degrees +/- 1.6 degrees ). LTDR exhibited a significantly higher rate of paradoxical motion when compared to LD (26.4% vs 6.7%). In LTDR, the rate of paradoxical motion at 1 month (40%) was significantly higher than at 1-year (21.1%) or at 2-year (25.0%). The presence of paradoxical motion was significantly less frequent at L4-5 (19.2%) when compared to L5-S1 (31.3%) or L2-3 (36.4%). CONCLUSION: The overall sagittal ROM of LTDR was 3.5 degrees +/- 2.4 degrees and not significantly different than LD. The current study did not demonstrate a difference in coupled motions between LTDR and LD. The rate of paradoxical motion was significantly higher in LTDR than in LD. In LTDR, there was a significantly lower rate of paradoxical motion seen at L4-5 and significantly higher rate seen in the earlier postoperative period. LEVEL OF EVIDENCE: Prospective cohort study with good follow-up (level 1b). PMID- 25802616 TI - Clinical Symposium II: Interspinous-based Dynamic Stabilization. PMID- 25802617 TI - Ethical considerations of authorship. PMID- 25802615 TI - Comparison of 2-Level Versus 1-Level Total Disc Replacement: Results From a Prospective FDA-Regulated Trial. AB - BACKGROUND: Fusion has been the traditional surgery for painful disc degeneration unresponsive to nonoperative care. Fusion rates may decline in multilevel procedures. Also, fusion may force additional stress onto adjacent discs. This effect may be amplified in multilevel procedures. Single-level total disc replacement (TDR) has been found to be as effective as fusion. There have been few published reports addressing 2-level TDR. The purpose of this study was to compare results of TDR at 2 levels to 1-level procedures. METHODS: This report included the first consecutive 86 patients who had reached 24-month follow-up from among those enrolled in the ProDisc-L investigational device exemption (IDE) study of patients undergoing TDR at 1 level (N = 54) or at 2 levels (N = 32). Clinical outcome measures included visual analog scales (VAS) assessing pain, Oswestry Disability Index, satisfaction measured by VAS, and responses to the question regarding whether the patient would have the same surgery again. RESULTS: Operative time and length of hospitalization were significantly less in the 1-level cases compared to 2 levels (61.6 min vs 97.8 min; and 1.89 days vs 2.44 days; P < .05). There was a trend for less blood loss in single-level cases (59.0 mL vs 79.2 mL) (.05 < P < .09). VAS and Oswestry scores were significantly improved in both groups postoperatively (by approximately 50%). At no follow-up were there significant differences in VAS, Oswestry, or patient satisfaction scores between the single- and 2-level patients. At all follow-ups, the mean satisfaction in both groups was greater than 7.5 on a scale of 0 to 10. CONCLUSIONS: Patients undergoing 2-level TDR improved significantly postoperatively based on VAS and Oswestry scores, and there were no significant differences in outcome scores when comparing 1- and 2-level TDR. CLINICAL RELEVANCE: This study suggests that 2-level TDR can be undertaken in appropriately selected patients and achieve results similar to singlelevel cases. PMID- 25802619 TI - In vitro assessment of serum-saline ratios for fluid simulator testing of highly modular spinal implants with articulating surfaces. AB - BACKGROUND: The increasing complexity of articulating spinal implants prohibits the use of serum-supplemented simulator fluid testing because multicomponent interfaces retain residual protein and preclude gravimetric measurement. Our original hypothesis was that simulator testing of a posterior dynamic stabilization implant that has metal-on-metal articulating bearings will not produce dramatically different wear debris when tested using pure saline versus testing in saline supplemented with 20% serum. METHODS: This hypothesis was tested using simulator testing of 12 dynamic stabilization spinal implants, 6 in 100% saline and 6 in 20%-serum saline. Gravimetric and particle analysis were performed after every million cycles up to 10 million cycles, with flexion of 11.3 degrees /extension of 5.6 degrees coupled with axial rotation of +/- 4 degrees . RESULTS: The mean gravimetric weight loss was approximately 200 mg over 10 million cycles for the implants tested in 100% saline, while the mean weight loss for those tested in 20%-serum saline was below the method detection limits (< 10 mg over 10 million cycles). For the 100%-saline and 20%-serum simulator fluids, the average particle size over the course of 0 to 10 million cycles remained relatively constant at 0.2 um-dia (saline) and 3.2 um-dia (20%-serum saline). Testing in 100% saline generated > 1000-fold more particles, compared to testing in 20% serum-supplemented saline. Energy-dispersive X-ray (EDAX) analyses of particles demonstrated that the 100% saline debris was composed of Co-Cr-P-O (Cr-Co metal oxides), and for the 20%-serum saline debris only bulk metal Co-Cr was detected. CONCLUSION: Our initial hypothesis was not supported. There were significant differences in gravimetric wear, average size, and type of wear debris that were mechanistically attributable to the type of simulator fluid used. The over-protective effect of serum proteins appears to underscore the importance of using both saline and serum when establishing upper and lower bounds of predictive implant debris generation modeling, where saline represents a worst-case scenario and as little as 20% serum masks all weight loss completely in highly modular articulating implants. CLINICAL RELEVANCE: Clinical Relevance = 5 (Oxford Centre for Evidence-based Medicine Levels of Evidence). Study findings are limited to a greater understanding of the science associated with predictive wear testing of articulating spinal implants. PMID- 25802618 TI - Biomechanical evaluation of pedicle screw-based dynamic stabilization devices for the lumbar spine: a systematic review. AB - STUDY DESIGN: This study is a systematic review of published biomechanical studies involving pedicle screw-based posterior dynamic stabilization devices (PDS) with a special focus on kinematics and load transmission through the functional spine unit (FSU). METHODS: A literature search was performed via the PubMed online database from 1990 to 2008 using the following key words: "biomechanics," "lumbar dynamic stabilization," "Graf system," "Dynesys," and "posterior dynamic implant." Citations were limited to papers describing biomechanics of pedicle screw-based PDS devices currently available for clinical use. Studies describing clinical experience, radiology, and in vivo testing were excluded from the review. Parameters measured included kinematics of the FSU (range of motion (ROM), neutral zone (NZ), and location of the center of rotation) and load transmission through the disk, facets, and instrumentation. RESULTS: A total of 27 publications were found that concerned the biomechanical evaluation of lumbar pedicle screw-based dynamic stabilization instrumentation. Nine in vitro experimental studies and 4 finite element analyses satisfied the inclusion criteria. The Dynesys implant was the most investigated pedicle screw based PDS system. In vitro cadaveric studies mainly focused on kinematics comparing ROM of intact versus instrumented spines whereas finite element analyses allowed analysis of load transmission at the instrumented and adjacent levels. CONCLUSION: Biomechanical studies demonstrate that pedicle screw-based PDS devices limit intervertebral motion while unloading the intervertebral disk. The implant design and the surgical technique have a significant impact on the biomechanical behavior of the instrumented spinal segment. The posterior placement of such devices results in non-physiologic intervertebral kinematics with a posterior shift of the axis of rotation. Biomechanical studies suggest that the difference at the adjacent level between investigated dynamic devices and rigid stabilization systems may not be as high as reported. Finally, additional investigations of semirigid devices are needed to further evaluate their biomechanical properties compared to soft stabilization PDS systems. PMID- 25802620 TI - The parallax effect in the evaluation of range of motion in lumbar total disc replacement. AB - BACKGROUND: Range of motion (ROM) has been shown to influence clinical outcomes of total disc replacement (TDR). While the parallax effect in image acquisition has been shown in the literature to influence the accuracy of a variety of measurements, this concept has not been investigated in the assessment of ROM analysis following TDR. We performed an evaluation of the influence of radiograph beam angle on "by hand" and on "gold standard" flexionextension ROM measurements in lumbar total disc replacement. The purpose of this study is to determine (1) the influence of X-ray beam angle on index level angle (ILA) measurements in lumbar TDR using the keel method, and (2) whether the out-of-plane radiographic beam effects cause a difference between true and calculated range of motion. METHODS: Eight blinded orthopaedic surgeons used the keel method to calculate ROM measurements from radiographs of a flexible Sawbones model (Pacific Research Laboratories, Inc., Vashon, Washington) implanted with a ProDisc-L device (Synthes Spine, West Chester, Pennsylvania). Radiographs were obtained at beam angles of 0 degrees , 5 degrees , 10 degrees , and 15 degrees in the sagittal plane from the device center. Calculations were compared to measurements obtained by a validated digitized software method (Quantitative Motion Analysis, QMA, Medical Metrics, Inc., Houston, Texas). Inter- and intraobserver precision and accuracy were determined. RESULTS: Compared with QMA, the radiographic keel method had an average error of 3.7 degrees . No significant effect of variation in beam angle on interobserver precision (N = 16, P = .92) or accuracy (N = 16, P = 0.86) or intraobserver precision (N = 8, P = .09) or accuracy (N = 8, P = 0.07) of ROM measurements was identified. Repeat testing with QMA also revealed no effect of parallax and resulted in nearly identical ROM measurements. CONCLUSIONS: Accuracy and precision of the keel method to determine ROM from index level angle measurements after TDR was not affected by increases in X-ray beam angles up to 15 degrees from the device center. CLINICAL RELEVANCE: Our study demonstrates that range of motion measurements are not influenced by parallax effect when using the keel method to determine index level angle measurements in lumbar total disc replacement. PMID- 25802621 TI - Surgeons' perceptions of spinal navigation: analysis of key factors affecting the lack of adoption of spinal navigation technology. AB - BACKGROUND: Computer-assisted spinal navigation allows for real time localization of surgical instruments in multiple views. Its use decreases radiation exposure and clears the surgical field of the C-arm fluoroscope. Despite these advantages, spinal navigation has yet to gain general acceptance among spine surgeons. The purpose of this study is to survey spine surgeons about their opinions on the strengths and weaknesses of spinal navigation. METHODS: Spine surgeons from the membership of the Spine Arthroplasty Society (SAS) and the Society for Minimally Invasive Spine Surgery (SMISS) were surveyed regarding their current use of spinal navigation and their perceptions of the strengths and weaknesses of spinal navigation (N = 147). Responses were analyzed using 2-sided chi-square tests. RESULTS: Most spine surgeons (63.4%) have only superficial experience with spinal navigation, and 76.2% of surgeons rarely use spinal navigation in their cases. Spine surgeons have the most experience with virtual fluoroscopy spinal navigation systems (35.9%). Surgeons considered longer operating times (63.5%), increased cost (48.3%), lack of necessity (40.7%), unreliable navigation accuracy (37.9%), and too many intraoperative glitches (35.2%) to be the major weaknesses of spinal navigation. Surgeons considered decreased radiation exposure to the surgeon (76.1%), increased screw placement accuracy (65.7%), decreased radiation exposure to the patient (41.8%), and keeping the C-arm away from the operating field (29.1%) to be the greatest advantages of spinal navigation. Among the types of procedures surgeons believe are most likely to benefit from spinal navigation are minimally invasive instrumentation and fusion (72.5%) and complex open deformity (55.6%). CONCLUSION: Most spine surgeons have only superficial experience in spinal navigation. The most commonly selected weaknesses of spinal navigation are increased operative time, cost, and lack of necessity. Increased fluoroscopy and MIS use in the future may shift focus from weaknesses to the strengths of spinal navigation, including decreased radiation exposure and elimination of the C-arm from the operative field. PMID- 25802622 TI - Basic Science Symposium III: Animal Models for Orthopaedic Implant Evaluation. PMID- 25802624 TI - Osteochondroma arising from the thoracic transverse process. AB - The incidence of osteochondroma is rare and only 2% of such tumors are found in the spine area. When they are found in the vertebral column, less than 1% of all osteochondromas and few tumors occur in the thoracic vertebrae. An osteochondroma arising from the transverse process of the vertebra is even rarer, especially following from the thoracic transverse process. Here we report a giant solitary osteochondroma arising from the thoracic transverse process of T8 vertebra and involving the corresponding transverse process and rib. A 28-year-old man presented with a progressive thoracic node, and neuroradiological evaluation of the spine showed a giant mass lesion involving the transverse process of T8 vertebra and concomitant corresponding facet joint and rib on the left side. At surgery, a firm and cartilaginous tumor originating from the transverse process was radically excised and surgical curettage of the lesion was performed. It is concluded that accurate and prompt diagnosis requires a high index of suspicion followed by surgical treatment to prevent severe morbidity in cases of primary spinal column tumors. The histological examination of this patient revealed the lesion was osteochondroma. The best choice of treatment for spinal osteochondromas is surgical excision or curettage and spinal stabilization, if necessary. PMID- 25802623 TI - 100 consecutive cases of degenerative lumbar conditions using a non-threaded locking screw system with a 90-degree locking cap. AB - BACKGROUND: This prospective study analyzes the perioperative outcomes and long term fusion success of 100 consecutive lumbar degenerative cases. The cases were managed using a non-threaded locking screw system, in conjunction with polyetheretherketone (PEEK) cages, for posterior lumbar interbody fusion (PLIF) procedures. These 100 cases were compared to another prospective study treating patients with the same inclusion and exclusion criteria using conventional plate based pedicle screw spinal instrumentation augmented with carbon fiber interbody cages. METHODS: A total of 167 operative levels were treated in 100 patients (51 single-level, 39 two-level and 10 three-level cases). Eleven cases were revisions and 67 patients received interbody fusion cages. Patients had an average of 22.8 +/- 4.0 months followup. RESULTS: There was one instrumentation failure but no significant subsidence at the interbody fusion level. The disc space height was restored as part of the surgical procedure at the interbody cage levels: from 7.5 +/- 2.3 mm preoperative to 9.0 +/- 2.1 mm postoperative. There were 2 cases of pseudarthrosis (2 / 100 = 2%). The average operative time for 1-level cases was 111 +/- 25 minutes; for 2-level cases it was 132.4 +/- 21.8 minutes; and for 3 level cases it was 162.6 +/- 33 minutes. Blood loss averaged 800 +/- 473 cc for 1 level cases, 1055 +/- 408 cc for 2 levels, and 1155 +/- 714 cc for 3 levels. The length of stay was similar between the 3 groups (4.4 +/- 1.2 days for single level cases, 4.7 +/- 1.1 for 2 levels, and 5.0 +/- 1.1 for 3 levels; P > .05). There were 3 incidental durotomies, and 4 other patients developed infections postoperatively that required reoperation. CONCLUSION: The disc and foraminal heights can be restored and maintained with a unilateral cage and pedicle screw construct. Unilateral transforaminal lumbar interbody fusion using a PEEK cage combined with a non-threaded locking pedicle screw and rod system results in similar fusion rates to those achieved using the bilateral Brantigan interbody fusion cage or a single BAK Vista implant. When compared to the bilateral Brantigan cages, decreased operative time (P < .001), decreased blood loss (P < .001) and reduced incidence of dural tears (P < .001) are advantages of using a non-threaded locking screw system and single PEEK interbody cage for lumbar degenerative conditions without compromising subsequent fusion rates. PMID- 25802625 TI - Prospective, Randomized, Multicenter FDA IDE Study of CHARITE Artificial Disc versus Lumbar Fusion: Effect at 5-year Follow-up of Prior Surgery and Prior Discectomy on Clinical Outcomes Following Lumbar Arthroplasty. AB - BACKGROUND: Candidates for spinal arthrodesis or arthroplasty often present with a history of prior surgery such as laminectomy, laminotomy or discectomy. In this study, lumbar arthroplasty patients with prior surgery, and in particular patients with prior discectomy, were evaluated for their clinical outcomes at the 5-year time point. METHODS: Randomized patients from the 5-year CHARITE investigational device exemption (IDE) study were divided as follows: 1) fusion prior surgery (excluding prior decompression with fusion) group (FSG); 2) fusion prior discectomy group (FDG); 3) fusion no prior surgery group (FNG); 4) arthroplasty prior surgery group (ASG); 5) arthroplasty prior discectomy group (ADG); and 6) arthroplasty no prior surgery group (ANG). The 5-year clinical outcomes included visual analog scale (VAS), Oswestry Disability Index 2.0 (ODI), patient satisfaction, and work status. RESULTS: In the arthroplasty group, all subgroups had statistically significant VAS improvements from baseline (VAS change from baseline: ASG = -36.6 +/- 29.6, P < 0.0001; ADG = -40.2 +/- 30.9, P = 0.0002; ANG = -36.5 +/- 34.6, P < 0.0001). There was no statistical difference between subgroups (P = 0.5587). In the fusion group, VAS changes from baseline were statistically significant for the FNG and FSG subgroups, but not for the FDG patients (FNG = -46.3 +/- 28.8, P < 0.0001; FSG = -24.2 +/- 36.4, P = 0.0444; FDG = -26.7 +/- 38.7, P = 0.2188). A trend of decreased VAS improvements was observed for FSG versus FNG (P = 0.0703) subgroups. Similar findings and trends were observed in ODI scores (Changes in ODI from baseline: ASG = -20.4 +/- 23.8, P < 0.0001; ANG = -26.6+/-21.1, P < 0.0001; ADG= -17.6 +/- 28.6, P = 0.0116; FSG = 14.5 +/- 21.2, P = 0.0303; FNG= -32.5 +/- 22.6, P < 0.0001; FDG = -10.7 +/- 9.4, P = 0.0938). The greatest improvement in work status from preoperative to postoperative was seen in the ADG subgroup (28% increase in part- and full-time employment), while the FDG subgroup showed the greatest reduction in work status (17% decrease). CONCLUSIONS: Arthroplasty patients with prior surgery or prior discectomy had similar clinical outcomes as arthroplasty patients without prior surgery, while fusion patients with prior surgery or prior discectomy showed trends of lowered clinical outcomes compared to fusion patients without prior surgery or discectomy. PMID- 25802626 TI - Overview of the Role of Statistic Analysis in the Design of Spine-related Studies. PMID- 25802627 TI - Co-culture of Adult Mesenchymal Stem Cells and Nucleus Pulposus Cells in Bilaminar Pellets for Intervertebral Disc Regeneration. AB - BACKGROUND: Our goal is to optimize stem cell-based tissue engineering strategies in the context of the intervertebral disc environment. We explored the benefits of co-culturing nucleus pulposus cells (NPC) and adult mesenchymal stem cells (MSC) using a novel spherical bilaminar pellet culture system where one cell type is enclosed in a sphere of the other cell type. Our 3D system provides a structure that exploits embryonic processes such as tissue induction and condensation. We observed a unique phenomenon: the budding of co-culture pellets and the formation of satellite pellets that separate from the main pellet. METHODS: MSC and NPC co-culture pellets were formed with three different structural organizations. The first had random organization. The other two had bilaminar organization with either MSC inside and NPC outside or NPC inside and MSC outside. RESULTS: By 14 days, all co-culture pellets exhibited budding and spontaneously generated satellite pellets. The satellite pellets were composed of both cell types and, surprisingly, all had the same bilaminar organization with MSC on the inside and NPC on the outside. This organization was independent of the structure of the main pellet that the satellites stemmed from. CONCLUSION: The main pellets generated satellite pellets that spontaneously organized into a bilaminar structure. This implies that structural organization occurs naturally in this cell culture system and may be inherently favorable for cell-based tissue engineering strategies. The occurrence of budding and the organization of satellite pellets may have important implications for the use of co-culture pellets in cell-based therapies for disc regeneration. CLINICAL RELEVANCE: From a therapeutic point of view, the generation of satellite pellets may be a beneficial feature that would serve to spread donor cells throughout the host matrix and restore normal matrix composition in a sustainable way, ultimately renewing tissue function. PMID- 25802628 TI - L5 - s1 segmental kinematics after facet arthroplasty. AB - BACKGROUND: Facet arthroplasty is a motion restoring procedure. It is normally suggested as an alternative to rigid fixation after destabilizing decompression procedures in the posterior lumbar spine. While previous studies have reported successful results in reproducing normal spine kinematics after facet replacement at L4-5 and L3-4, there are no data on the viability of facet replacement at the lumbosacral joint. The anatomy of posterior elements and the resulting kinematics at L5-S1 are distinctly different from those at superior levels, making the task of facet replacement at the lumbosacral level challenging. This study evaluated the kinematics of facet replacement at L5-S1. METHODS: Six human cadaveric lumbar spines (L1-S1, 46.7 +/- 13.0 years) were tested in the following sequence: (1) intact (L1-S1), (2) complete laminectomy and bilateral facetectomy at L5-S1, and (3) implantation of TFAS-LS (Lumbosacral Total Facet Arthroplasty System, Archus Orthopedics, Redmond, Washington) at L5-S1 using pedicle screws. Specimens were tested in flexion (8Nm), extension (6Nm), lateral bending (LB, +/- 6Nm), and axial rotation (AR, +/- 5Nm). The level of significance was alpha = .017 after Bonferroni correction for three comparisons: (1) intact vs. destabilized, (2) destabilized vs. reconstructed, and (3) intact vs. reconstructed. RESULTS: Laminectomy-facetectomy at L5-S1 increased the L5-S1 angular range of motion (ROM) in all directions. Flexion-extension (F-E) ROM increased from 15.3 +/- 2.9 to 18.7 +/- 3.5 degrees (P < .017), LB from 8.2 +/- 1.8 to 9.3 +/- 1.6 degrees (P < .017), and AR from 3.7 +/- 2.0 to 5.9 +/- 1.8 degrees (P < .017). The facet arthroplasty system decreased ROM compared to the laminectomy-facetectomy condition in all tested directions (P < .017). The facet arthroplasty system restored the L5-S1 ROM to its intact levels in LB and AR (P > .017). F-E ROM after the facet arthroplasty system implantation was smaller than the intact value (10.1 +/- 2.2 vs. 15.3 +/- 2.9 degrees, P < .017). The load-displacement curves after the facet arthroplasty system implantation at L5-S1 were sigmoidal, and quality of motion measures were similar to intact, demonstrating graded resistance to angular motion in F-E, LB and AR. CONCLUSIONS: The facet arthroplasty system was able to restore stability to the lumbosacral segment after complete laminectomy and bilateral facetectomy, while also allowing near normal kinematics in all planes. While F-E ROM after the facet arthroplasty system implantation was smaller than the intact value, it was within the physiologic norms for L5-S1. These results are consistent with previous studies of facet arthroplasty at L3-L4 and L4-L5 and demonstrate that TFAS technology can be adapted to the lumbosacral joint with functionality comparable to its application in superior lumbar levels. PMID- 25802629 TI - Survivorship of coflex Interlaminar-Interspinous Implant. AB - BACKGROUND: The purpose of this study was to determine the indications for implantation of the coflex device (Paradigm Spine, LLC, New York, New York), assess long-term complications, and evaluate the long-term clinical outcomes of patients. METHODS: A total of 127 patients underwent placement of a coflex implant for various indications by one orthopaedic spine surgeon. The mean follow up was 6.3 years. The original indications for implantation were determined based upon the data provided in the case report forms. Preoperatively and postoperatively, patients were asked to grade their low-back and leg pain using the visual analog scale (VAS) and the pain severity scale: no pain (0), mild pain (1), moderate pain (2), or severe pain (3). Patients were queried about their satisfaction with the surgical procedure. Follow-up radiographs were taken to determine any device-related issues. RESULTS: The most prevalent diagnoses for implantation were spinal stenosis (19.7%) and spinal stenosis with lumbar disc herniation (35.4%). The mean severity of low-back pain was decreased by 33% (from moderate to mild) at the 2-year follow-up (P < .001) and at the 5-year follow-up (from moderate to mild, P < .001). The mean severity of leg pain was decreased by 66% (from severe to mild) at the 2-year follow-up (P < .001) and at the 5-year follow-up (from severe to mild, P < .001). At the mean follow-up period of 6.3 years, a patient satisfaction query demonstrated that 7% were unsatisfied, 46% were satisfied, and 46% were very satisfied with their clinical outcome. Based on the follow-up radiographs, 92 of patients had no devicerelated issues and 8% had device-related issues. CONCLUSION: The data provided have demonstrated that the coflex implant provides pain relief for patients with low-back pain and leg pain. The most common indications for implantation were spinal stenosis and spinal stenosis with lumbar disc herniation. There were very few device-related complications. CLINICAL SIGNIFICANCE: Using coflex is a safe and viable option in the selection of instrumentation for spinal stabilization. PMID- 25802631 TI - Kinematics of total facet replacement (TFAS-TL) with total disc replacement. AB - BACKGROUND: Total disc replacement (TDR) and total facet replacement (TFR) have been the focus of recent kinematics evaluations. Yet their concurrent function as a total joint replacement of the lumbar spine's 3-joint complex has not been comprehensively reported. This study evaluated the effect of a TFR specifically designed to replace the natural facets and supplement the function with the natural disc and with TDR. The ability to replace degenerated facets to complement a pre-existing or simultaneously implanted TDR may allow surgeons to completely address degenerative pathologies of the 3-joint complex of the lumbar spine. We hypothesized that TFR would reproduce the biomechanical function of the natural facets when implanted in conjunction with TDR. METHODS: Lumbar spines (L1 5, 51.3 +/- 14.2 years, N = 6) were tested sequentially as follows: (1) intact, (2) after TDR implantation, and (3) after TFR implantation in conjunction with TDR, all at L3-4. Specimens were tested in flexion-extension (+ 8 Nm to - 6 Nm), lateral bending (+/- 6 Nm), and axial rotation (+/- 5 Nm). A 400 N compressive follower preload was applied during flexion-extension tests. Three-dimensional segmental motion was recorded and analyzed using analysis of variance in Systat (Systat Software Inc., Chicago, Illinois) and multiple comparisons with Bonferroni correction. RESULTS: The TDR implantation (TDR + natural facets) allowed similar lateral bending (P = .66), but it generally increased flexion extension (P = .06) and axial rotation (P < .05) range of motion (ROM) at the implanted level compared to intact. The TFR + TDR (following replacement of the natural facets with TFR) decreased ROM to levels similar to intact in lateral bending (P = .70) and axial rotation (P = .23). The TFR + TDR flexion-extension ROM was reduced in comparison to intact and TDR + natural facets (P < .05). CONCLUSIONS: The TFR with TDR was able to restore stability to the lumbar segment after bilateral facetectomy, while allowing near-normal motions in all planes. PMID- 25802630 TI - Evaluation of Perivascular Adhesion Formation in New Zealand White Rabbits Using Oxiplex and DuraSeal Xact Adhesion Barrier System. AB - BACKGROUND: Adhesion formation after spine surgery is a result of normal wound healing that may place patients at increased risk for complications during revision surgery. Preventing adhesions could reduce the risk of complications during revision surgery, and possibly reduce the need for revision procedures. This study evaluates the ability of DuraSeal Xact Adhesion Barrier System (DSX) (Covidien, Mansfield, Massachusetts) and Oxiplex/SP gel (OX) (FzioMed, San Luis Obispo, California) to affect the extent and severity of postoperative perivascular adhesion development in an anterior spinal surgical rabbit model. METHODS: We determined the extent and severity of postoperative adhesion development 34 days after surgery in 12 male New Zealand White rabbits randomly assigned to intraoperative treatment with either DSX or OX, or to an untreated control group. Adhesion severity and extent were scored on scale from 0 (none) to 3 (severe). RESULTS: The extent and severity of adhesions in the DSX group were significantly less than in the untreated control group. The DSX group mean extent score was 1.3 +/- 0.5 (vs 2.5, P = .01) and the mean severity score was 1.25 +/- 0.5 (vs 2.8, P = .005). The extent and severity of adhesions in the OX group were not significantly different from the control group. CONCLUSION: In this study, we found DSX to be the most effective compound in preventing adhesion formation after anterior spine surgery. CLINICAL RELEVANCE: Extrapolating these results in rabbits to humans, less scarring between the major blood vessels could decrease the rate of complications in revision spine procedures. PMID- 25802632 TI - Does core mobility of lumbar total disc arthroplasty influence sagittal and frontal intervertebral displacement? Radiologic comparison with fixed-core prosthesis. AB - BACKGROUND: An artificial disc prosthesis is thought to restore segmental motion in the lumbar spine. However, it is reported that disc prosthesis can increase the intervertebral translation (VT). The concept of the mobile-core prosthesis is to mimic the kinematic effects of the migration of the natural nucleus and therefore core mobility should minimize the VT. This study explored the hypothesis that core translation should influence VT and that a mobile core prosthesis may facilitate physiological motion. METHODS: Vertebral translation (measured with a new method presented here), core translation, range of motion (ROM), and distribution of flexion-extension were measured on flexion-extension, neutral standing, and lateral bending films in 89 patients (63 mobile-core [M]; 33 fixed-core [F]). RESULTS: At L4-5 levels the VT with M was lower than with F and similar to the VT of untreated levels. At L5-S1 levels the VT with M was lower than with F but was significantly different compared to untreated levels. At M levels a strong correlation was found between VT and core translation; the VT decreases as the core translation increases. At F levels the VT increases as the ROM increases. No significant difference was found between the ROM of untreated levels and levels implanted with either M or F. Regarding the mobility distribution with M and F we observed a deficit in extension at L5-S1 levels and a similar distribution at L4-5 levels compared to untreated levels. CONCLUSION: The intervertebral mobility was different between M and F. The M at L4-5 levels succeeded to replicate mobility similar to L4-5 untreated levels. The M at L5-S1 succeeded in ROM, but failed regarding VT and mobility distribution. Nevertheless M minimized VT at L5-S1 levels. The F increased VT at both L4-5 and L5-S1. CLINICAL RELEVANCE: This study validates the concept that the core translation of an artificial lumbar disc prosthesis minimizes the VT. PMID- 25802633 TI - Twenty-four month follow-up for reporting results of spinal implant studies: Is this guideline supported by the literature? AB - BACKGROUND: Traditionally, spine societies and journals have set guidelines requiring a minimum 24-month follow-up for reporting results of surgical implant studies. However, the basis for this particular time period is not clear. The purpose of this study was to analyze prospective spinal implant studies reporting data at multiple specific follow-up periods to determine if there were significant changes in the clinical outcome throughout the 24-month follow-up period. METHODS: A comprehensive literature search was conducted using PubMed as well as searching the FDA web page. Studies were evaluated to identify those meeting the inclusion criteria: involved at least 100 patients receiving a spinal implant with data reported at multiple pre-defined time periods post-operatively for at least 24-months. Data recorded from each study included, number of patients, diagnoses, implant used, outcome measures used, and the results reported. The primary outcome data were analyzed in the current study to determine the amount of change in scores, with particular focus on the six and 24 month follow-up periods. RESULTS: Only 7 studies met the inclusion criteria. All seven studies were FDA-regulated trials published since 1997. Six addressed the treatment of symptomatic disc degeneration and 1 involved patients with neurogenic claudication due to stenosis. The outcome measures in the studies varied but pain and function were frequently assessed. In none of the studies was there a significant deterioration in results between the 6 and 24-month follow-up periods. In fact, the only changes during the follow-up periods were slight, not statistically significant, improvements, with the exception of 1 scale in 1 study where a slight, not statistically significant, decrease in the extent of improvement on a physical function assessment was noted between 6 and 24 months. These results suggest a great deal of stability in the mean scores for various outcome measures between the 6 and 24 months in patients receiving spinal implants. CONCLUSIONS: Although long-term follow-up is certainly desirable for any clinical outcome study, there appears to be no significant change in outcome measures between the 6-month and 24-month follow-ups. These results support that earlier dissemination of results may be appropriate without producing overly optimistic reports. PMID- 25802635 TI - A brief summary of 15 years of research on beta-tricalcium phosphates. PMID- 25802636 TI - Anterior cervical arthrodesis using an osteoconductive scaffold: The use of beta tricalcium phosphate with local bone marrow aspirate in over 100 patients. PMID- 25802634 TI - Osteoconductive carriers for integrated bone repair. AB - Successful bone repair is judged in achieving restitution of space and mechanical integrity, and in regaining function. When the biology or anatomy are insufficient to attain a full repair, therapeutic use of graft material has been used to omit compliance features such as strain tolerance, reduced stiffness, and attenuated strength, and instead promote primary or membranous-type bone formation within the physical approximation of a graft material. The challenge of most conductive materials is that they emerge from a static platform and in placement force the living system to adapt to placement, dimension, different properties, and eventually are only successful in degradation and replacement, or in integration. The synergy and interdependency between adhesion, ECM, and proteolysis are important concepts that must be understood to engineer scaffolds capable of holding up to standards which are more than cell decoration. Moreover, the reactive specificity to loading, degradation, therapeutic delivery during absorption remains a key aim of both academic and industrial designs. Achieving conductivity comes with challenges of best fit integration, delivery, and in integrated modeling. The more liquid is the delivery, the more modular the components, and adaptive the matrix to meeting the intended application, the more likely that the conductivity will not be excluded by the morphology of the injury site. Considerations for osteoconductive materials for bone repair and replacement have developed conceptually and advanced parallel with a better understanding of not only bone biology but of materials science. First models of material replacements utilized a reductionist-constructionist logic; define the constituents of the material in terms of its morphology and chemical composition, and then engineer material with similar content and properties as a means of accommodating a replacement. Unfortunately for biologic systems, empiric formulation is insufficient to promote adequate integration in a timely fashion. Future matrices will need to translate their biological surfaces as more than a scaffold to be decorated with cells. Conductivity will be improved by formulations that enhance function, further extended from understanding what composition best suits cell attachment, and be adopted by conveniences of delivery that meet those criteria. PMID- 25802637 TI - Foreword. PMID- 25802638 TI - The fundamentals of biotribology and its application to spine arthroplasty. AB - The biological effect of wear of articulating surfaces is a continued concern with large joint replacements and, likewise, of interest for total disc replacements. There are a number of important biotribological testing parameters that can greatly affect the outcome of a wear study in addition to the implant design and material selection. The current ASTM and ISO wear testing standards/guides for spine arthroplasty leave many choices as testing parameters. These factors include but are not limited to the sequence of kinematics and load, phasing, type of lubricant, and specimen preparation (sterilization and artificial aging). The spinal community should critically assess wear studies and be cognizant of the influence of the selected parameters on the test results. PMID- 25802639 TI - Metal wear particles: What we know, what we do not know, and why. AB - The importance of wear particle characterization for orthopaedic implants has long been established in the hip and knee arthroplasty literature. With the increasing use of motion preservation implants in the spine, the characterization of wear debris, particularly metallic nature, is gaining importance. An accurate morphological analysis of wear particles provides for both a complete characterization of the biocompatibility of the implant material and its wear products, and an in-depth understanding of the wear mechanisms, ion release, and associated corrosive activity related to the wear particles. In this paper, we present an overview of the most commonly-used published protocols for the isolation and characterization of metal wear particles, and highlight the limitations and uncertainties inherent to metal particle analysis. PMID- 25802642 TI - What standards can (and can't) tell us about a spinal device. AB - Standards are important tools in evaluating and predicting the performance of medical devices prior to implantation. There are three types of standards that are available: a material specification, a standard test method, and a standard test guide. Each of these types of standards is defined with examples of how each is used to facilitate evaluation of medical devices. The standards development process is also described: this is a complex process, requiring the involvement of a multidisciplinary team, usually consisting of engineers, scientists, and clinicians who represent healthcare, academia, government, and industry. Finally, standards have a clear and defined role in the development of medical devices, and the benefits, strengths, as well as the limitations in this role are discussed. PMID- 25802643 TI - Incidence of dysphagia comparing cervical arthroplasty and ACDF. AB - STUDY DESIGN: Retrospective cohort from randomized prospective clinical trial. OBJECTIVE: Evaluate incidence of dysphagia between instrumented ACDF and a no profile cervical disc arthroplasty. SUMMARY OF BACKGROUND DATA: Dysphagia is a well-known complication following anterior cervical discectomy and fusion (ACDF) and the etiology is multifactorial. One potential source for postoperative dysphagia involves the anterior profile of the implant used. Hence, a no-profile cervical disc arthroplasty could theoretically have fewer soft tissue adhesions and a lower incidence of dysphagia. The purpose of this study is to compare the incidence of dysphagia at least 1 year postoperatively following ACDF with anterior plating and a no-profile cervical disc arthroplasty. METHODS: A cohort of 87 patients meeting the inclusion criteria for the prospective, randomized, multicenter IDE trial of ProDisc-C versus ACDF were evaluated for dysphagia. Forty-five patients were randomized to receive cervical arthroplasty and 42 patients were randomized to the ACDF and plate group. The Bazaz-Yoo dysphagia questionnaire was administered in a blinded fashion after completion of at least 12 months follow-up. RESULTS: Follow-up averaged 18.2 months and included 76 (87%) of the 87 enrolled, with 38 of the original 45 in the arthroplasty group and 38 of the original 42 in the ACDF group. Six of 38 (15.8%) in the arthroplasty group versus 16 of 38 (42.1%) in the ACDF group reported ongoing dysphagia complaints. This was found to be statistically significant (P = .03). CONCLUSION: This study suggests a significantly lower rate of dysphagia with a no profile cervical disc arthroplasty compared to instrumented ACDF for single level disc disease between C3-7. Though there are many potential etiologies, we hypothesize this is related to the lack of anterior hardware in the retropharyngeal space. Operative technique, operating time, and significant midline retraction did not seem to result in more dysphagia complaints. Future studies comparing cervical disc arthroplasty and no-profile fusion devices may help delineate the effect that anterior instrumentation profile has on postoperative dysphagia. PMID- 25802641 TI - Retrieval analysis of motion preserving spinal devices and periprosthetic tissues. AB - This article reviews certain practical aspects of retrieval analysis for motion preserving spinal implants and periprosthetic tissues as an essential component of the overall revision strategy for these implants. At our institution, we established an international repository for motion-preserving spine implants in 2004. Our repository is currently open to all spine surgeons, and is intended to be inclusive of all cervical and lumbar implant designs such as artificial discs and posterior dynamic stabilization devices. Although a wide range of alternative materials is being investigated for nonfusion spine implants, many of the examples in this review are drawn from our existing repository of metal-on polyethylene, metal-on-metal lumbar total disc replacements (TDRs), and polyurethane-based dynamic motion preservation devices. These devices are already approved or nearing approval for use in the United States, and hence are the most clinically relevant at the present time. This article summarizes the current literature on the retrieval analysis of these implants and concludes with recommendations for the development of new test methods that are based on the current state of knowledge of in vivo wear and damage mechanisms. Furthermore, the relevance and need to evaluate the surrounding tissue to obtain a complete understanding of the biological reaction to implant component corrosion and wear is reviewed. PMID- 25802640 TI - A review of the biologic effects of spine implant debris: Fact from fiction. AB - BACKGROUND: Biologic-reactivity to implant-debris is the primary determinant of long-term clinical performance. The following reviews: 1) the physical aspects of spinal-implant debris and 2) the local and systemic biologic responses to implant debris. METHODS: Methods included are: 1) gravimetric wear analysis; 2) SEM and LALLS; 3) metal-ion analysis; 4) ELISA, toxicity testing, patch testing; and 5) metal-lymphocyte transformation testing (metal-LTT). RESULTS: Wear and corrosion of spine-implants produce particles and ions. Particles (0.01-1000 MUm) are generally submicron ( <1 um). Wear rates of metal-on-polymer and metal-on-metal disc arthroplasties are approximately 2-20 and 1 mm(3)/yr, respectively. Metal-on metal total disc replacement components have significant increases in circulating metal (less than 10-fold that of controls at 4 ppb-Co and 3 ppb-Cr or ng/mL). Debris reactivity is local and systemic. Local inflammation is caused primarily by ingestion of debris by local macrophages, which produce pro-inflammatory cytokines TNFalpha, IL-1beta, IL-6, and PGE2. Systemic responses associated with implant-debris have been limited to hypersensitivity reactions. Elevated amounts of in the liver, spleen, etc of patients with failed TJA have not been associated with remote toxicological or carcinogenic pathology to date. Implant debris are differentially bioreactive. Greater numbers are pro-inflammatory; the smaller sized debris are more bioreactive by virtue of their greater numbers (dose) for a given amount of implant mass loss (one 100-MUm-diameter particle is equivalent in mass to 1 million 1-MUm-diameter particles). Elongated particles are pro inflammatory (ie, aspect ratio of greater than 3). Metal particles are more proinflammatory than polymers, ceteris paribus. CONCLUSION: Spinal arthroplasty designs have been in use for more than 20 years internationally; therefore, concerns about neuropathology, toxicity, and carcinogenicity are mitigated. Debris-induced inflammation still depends on the individual and the type of debris. The consequence of debris-induced inflammation is continued; vigilance by physicians is recommended monitoring of spinal implants using physical exams and testing of metal content and bioreactivity, as is planning for the likelihood of revision in younger individuals. PMID- 25802644 TI - Initial clinical experience with a next-generation artificial disc for the treatment of symptomatic degenerative cervical radiculopathy. AB - BACKGROUND: A feasibility trial was conducted to evaluate the initial safety and clinical use of a next-generation artificial cervical disc (M6-C artificial cervical disc; Spinal Kinetics, Sunnyvale, CA) for the treatment of patients with symptomatic degenerative cervical radiculopathy. A standardized battery of validated outcome measures was utilized to assess condition-specific functional impairment, pain severity, and quality of life. METHODS: Thirty-six consecutive patients were implanted with the M6-C disc and complete clinical and radiographic outcomes for 25 patients (mean age, 44.5 +/- 10.1 years) with radiographically confirmed cervical disc disease and symptomatic radiculopathy unresponsive to conservative medical management are included in this report. All patients had disc-osteophyte complex causing neural compression and were treated with discectomy and artificial cervical disc replacement at either single level (n = 12) or 2-levels (n = 13). Functional impairment was evaluated using the Neck Disability Index (NDI). Evaluation of arm and neck pain severity utilized a standard 11-point numeric scale, and health-related quality of life was evaluated with the SF-36 Health Survey. Quantitative radiographic assessments of intervertebral motion were performed using specialized motion analysis software, QMA (Quantitative Motion Analysis; Medical Metrics, Houston, TX). All outcome measures were evaluated pre-treatment and at 6 weeks, 3, 6, 12, and 24 months. RESULTS: The mean NDI score improved from 51.6 +/- 11.3% pre-treatment to 27.9 +/ 16.9% at 24 months, representing an approximate 46% improvement (P <.0001). The mean arm pain score improved from 6.9 +/- 2.5 pre-treatment to 3.9 +/- 3.1 at 24 months (43%, P =.0006). The mean neck pain score improved from 7.8 +/- 2.0 pre treatment to 3.8 +/- 3.0 at 24 months (51%, P <.0001). The mean PCS score of the SF-36 improved from 34.8 +/- 7.8 pre-treatment to 43.8 +/- 9.3 by 24 months (26%, P =.0006). Subgroup analyses found that patients treated at single level and those with a shorter duration of symptoms showed better functional results. By 24 months, the mean range of motion (ROM) value at the treated level had returned to approximately pretreatment levels (12.2 degrees vs 11.1 degrees ). There were no serious device-related adverse events, surgical re-interventions or radiographic evidence of heterotopic ossification, device migration, or expulsion in this study group. CONCLUSIONS: These findings indicate substantial clinical improvement for all function, pain, and quality of life outcomes in addition to maintenance of ROM and increase in disc height at the treated level(s). The findings also exhibit an acceptable safety profile, as indicated by the absence of serious adverse events and reoperations following arthroplasty with a next generation artificial cervical disc replacement device. PMID- 25802645 TI - Clinical performance of an elastomeric lumbar disc replacement: Minimum 12 months follow-up. AB - BACKGROUND: Elastomeric disc replacements have been developed to restore normal shock absorption and physiologic centers of rotation to the degenerated disc. The Physio-L Artificial Lumbar Disc is an elastomeric disc which uses a compliant polycarbonate-polyurethane core with enhanced endurance properties. The objective of this study was to evaluate the safety and efficacy of the Physio-L through a 12-month follow-up period in a prospective, nonrandomized clinical trial. METHODS: Twelve patients who met the inclusion/exclusion criteria were enrolled in the study. Eight patients received a single implant (L5-S1) and 4 received a 2 level implantation (L4-5 and L5-S1). Patients were assessed preoperatively and postoperatively at 6 weeks and 3, 6, and 12 months. Primary outcomes included the VAS, ODI, a radiographic analysis of implant condition, incidence of major complications, and reoperations. Secondary outcomes included SF-36, ROM at index and adjacent levels and disc height. RESULTS: All patients completed the 12-month follow-up evaluations. Through 12 months, the Physio-L devices have remained intact with no evidence of subsidence, migration, or expulsion. VAS low-back pain and ODI scores improved significantly at all follow-up periods compared to preoperative scores. The range of motion of 13.3 degrees +/- 5.5 degrees at the index level was considered normal. Overall, patients were satisfied with an average score of 83.5 +/- 26.8 mm. When comparing the device to other artificial discs, the current device showed a clinically relevant improvement in both ODI and VAS scores at all follow-up time points. Statistically significant improvements in both scores were observed at 12 months (P < .05). CONCLUSION: The Physio-L is safe and efficacious, as demonstrated by improved pain relief and functional recovery without any implant failures, significant device related complications, or adverse incidents. The clinical results for VAS and ODI were superior to other marketed artificial lumbar discs such as the Charite and ProDisc-L at the same follow-up timeframes. PMID- 25802646 TI - Cement leakage and filling pattern study of low viscous vertebroplastic versus high viscous confidence cement. AB - BACKGROUND: Vertebral augmentation has recently evolved as a medical procedure for the treatment of vertebral compression fractures, the most common type of skeletal fractures related to osteoporosis. METHODS: This study compared the cement leakage and filling behavior of 2 existing delivery systems (Confidence and Vertebroplastic; DePuy Spine, Raynham, MA). The Confidence system with the high viscosity cement has been recently introduced in an attempt to curtail cement leakage. RESULTS: The comparison was performed using an established benchmark model wherein the cement leakage, filling behavior can be assessed. A double-conduit introducer needle was used to deliver the cement and to measure the intravertebral pressure while delivering the cement. There were 5 experimental groups in this study: 3 low-viscosity groups, whose cement was injected at 3.5, 6.5, and 9.5 minutes after admixing the powder and monomer, and 2 high-viscosity groups injected at 3.5 and 6.5 minutes. The mass of leaked cement generally decreased with delaying the start of the injection. Specifically, for the low-viscosity, the average smallest leakage mass obtained was 2.6 +/- 1.2g when the cement was delivered at 9.5 minutes. If delivered after 3.5 minutes, the mass of cement leak was 4.0 +/- 1.2g. The high-viscosity system has showed improved results in curtailing cement leakage, as compared to low viscosity. Specifically, if injected after 3.5 and 6.5 minutes, the cement leakage amounts were 1.5 +/- 1.2g and 0.92 +/- 0.6g, respectively. Similarly, the uniformity of cement filling increased when the delivery was delayed and when the high-viscosity system was applied. Furthermore, there were no significance changes in the intravertebral pressures between the low- and high-viscous groups. No correlation between the leakage mass and the IV pressures was noted. CONCLUSION: The cement thickness and timing of delivery are key in controlling the intravertebral cement filling and physician may want to explore the use of low- or high-viscous cement for different fractures. The thickness of the cement has no significant impact on the intravertebral pressures. PMID- 25802647 TI - Value and cost in less invasive spinal fusion surgery: lessons from a community hospital. PMID- 25802648 TI - Two-year clinical and radiographic success of minimally invasive lateral transpsoas approach for the treatment of degenerative lumbar conditions. AB - BACKGROUND: The lateral transpsoas approach to interbody fusion is a less disruptive but direct-visualization approach for anterior/anterolateral fusion of the thoracolumbar spine. Several reports have detailed the technique, the safety of the approach, and the short term clinical benefits. However, no published studies to date have reported the long term clinical and radiographic success of the procedure. MATERIALS AND METHODS: The current study is a retrospective chart review of prospectively collected clinical and radiographic outcomes in 62 patients having undergone the Anterolateral transpsoas procedure at a single institution for anterior column stabilization as treatment for degenerative conditions, including degenerative disk disease, spondylolisthesis, scoliosis, and stenosis. Only patients who were a minimum of 2 years postoperative were included in this evaluation. Clinical outcomes measured included visual analog pain scales (VAS) and Oswestry disability index (ODI). Radiographic outcomes included identification of successful arthrodesis. RESULTS: Sixty-two patients were treated with lateral interbody fusion between 2003 and December 2006. Twenty six patients (42%) were single-level, 13 (21%) 2-level, and 23 (37%) 3- or more levels. Forty-five (73%) included supplemental posterior pedicle fixation, 4 (6%) lateral fixation, and 13 (21%) were stand-alone. Pain scores (VAS) decreased significantly from preoperative to 2 years follow-up by 37% (P < .0001). Functional scores (ODI) decreased significantly by 39% from preoperative to 2 years follow-up (P < .0001). Clinical success by ODI-change definition was achieved in 71% of patients. Radiographic success was achieved in 91% of patients, with 1 patient with pseudarthrosis requiring posterior revision. CONCLUSION: The lateral transpsoas approach is similar to a traditional anterior lumbar interbody fusion, in that access is obtained through a retroperitoneal, direct-visualization exposure, and a large implant can be placed in the interspace to achieve disk height and alignment correction. The 2 years plus clinical and radiographic success rates are similar to or better than those reported for traditional anterior and posterior approach procedures, which, coupled with significant short-term benefits of minimal morbidity, make the lateral approach a safe and effective treatment option for anterior/anterolateral lumbar fusions. PMID- 25802649 TI - Clinical and radiographic outcomes after minimally invasive transforaminal lumbar interbody fusion. AB - OBJECTIVE: To evaluate outcomes after minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). BACKGROUND: MI-TLIF is a relatively novel technique for treating symptomatic spondylolisthesis and degenerative disc disease of the lumbar spine. It has become a popular option for lumbar arthrodesis largely because of its potential to minimize iatrogenic trauma to the soft tissue, paraspinous muscles as well as to neural elements. METHODS: Literature search using PubMed database. RESULTS: Eight retrospective clinical studies and 1 prospective clinical study were identified. No randomized studies were found. The indications for surgery were low-back pain and/or radicular symptoms secondary to spondylolisthesis and/or degenerative disc disease. Analysis of radiographic outcomes demonstrated a fusion rate greater than 90% in the vast majority of patients. Patients also experienced a significant improvement in functional outcome parameters at a mean follow-up of 20 months. Comparison of functional outcomes of MI-TLIF patients to a similar matched cohort of patients who underwent conventional open TLIF did not demonstrate any statistically significant difference between both cohorts. CONCLUSION: For carefully selected patients, MI-TLIF has a very favorable long term outcome that is comparable to conventional open TLIF, with the added benefit of decreased adjacent tissue injury. PMID- 25802652 TI - Meta-analysis. PMID- 25802650 TI - Presacral retroperitoneal approach to axial lumbar interbody fusion: a new, minimally invasive technique at L5-S1: Clinical outcomes, complications, and fusion rates in 50 patients at 1-year follow-up. AB - BACKGROUND: The presacral retroperitoneal approach to an axial lumbar interbody fusion (ALIF) is a percutaneous, minimally invasive technique for interbody fusion at L5-S1 that has not been extensively studied, particularly with respect to long-term outcomes. OBJECTIVE: The authors describe clinical and radiographic outcomes at 1-year follow-up for 50 consecutive patients who underwent the presacral ALIF. METHODS: Our patients included 24 males and 26 females who underwent the presacral ALIF procedure for interbody fusion at L5-S1. Indications included mechanical back pain and radiculopathy. Thirty-seven patients had disc degeneration at L5-S1, 7 had previously undergone a discectomy, and 6 had spondylolisthesis. A 2-level L4-S1 fusion was performed with a transforaminal lumbar interbody fusion at L4-5 in 15 patients. AxiaLIF was performed as a stand alone procedure in 5 patients and supplemented with pedicle screws in 45 patients. Pre- and postoperative visual analog scale (VAS) and Oswestry Disability Index (ODI) scores were evaluated and complications were tracked. Fusion was evaluated by an independent neuro-radiologist. RESULTS: At 1-year follow-up, VAS and ODI scores had significantly improved by 49% and 50%, respectively, versus preoperative scores. By high-resolution computer tomography (CT) scans, fusion was achieved in 44 (88%) patients, developing bone occurred in 5 (10%), and 1 (2%) patient had pseudoarthrosis. One patient suffered a major operative complication-a bowel perforation with a pre-sacral abscess that resolved with treatment. CONCLUSION: Our initial 50 patients who underwent presacral ALIF showed clinical improvement and fusion rates comparable with other interbody fusion techniques; its safety was reflected by low complication rates. Its efficacy in future patients will continue to be monitored, and will be reported in a 2-year follow-up study of fusion. PMID- 25802651 TI - Fusion after minimally disruptive anterior lumbar interbody fusion: Analysis of extreme lateral interbody fusion by computed tomography. AB - BACKGROUND: Less invasive fusion approaches, such as extreme lateral interbody fusion (XLIF), have proliferated, but few reports have critically assessed fusion rates. To date, no studies have reported computed tomography (CT) documented fusion rates following XLIF. METHODS: An institutional review board-approved prospective radiographic and CT assessment of minimally disruptive anterior lumbar interbody fusion (mini-ALIF) fusions performed through the XLIF approach. Sixty-six patients (88 operative levels) were examined 12 months after XLIF to determine the rate and quality of anterior lumbar fusion. RESULTS: Eighty five of the 88 levels (96.6%) were judged fused by CT. Sixty-four of the 66 patients (97.0%) were judged fused by CT. Patient satisfaction at 12 months after surgery was high, with 89.4% reportedly "satisfied or very satisfied" with their results. No revisions were necessary for pseudarthrosis. CONCLUSION: Mini-ALIF using an XLIF approach reliably results in anterior lumbar fusion. PMID- 25802653 TI - Results from a randomized controlled study between total disc replacement and fusion compared with results from a spine register. AB - BACKGROUND: Difficulties in performing randomized controlled trials (RCTs) to evaluate new treatment options are increasing. Higher costs and patient unwillingness are the main obstacles. A spinal surgery register has been in use in Sweden for 11 years. Our aim was to determine whether this register can provide the same information as an RCT and whether register data compare favorably with RCT data, making RCTs unnecessary. If not the case, was patient selection or follow-up frequency the cause of any differences? MATERIALS AND METHODS: We compared baseline data and outcome, retrieved from our register, between 2 surgical groups, total disc replacement (TDR) and fusion at 1 or 2 levels, performed for degenerative disc disease. One hundred fifty-two patients were part of an RCT, whereas four hundred fifty-five patients had been treated according to an active decision. These 2 subgroups were the subjects for comparison. RESULTS: The 2 subgroups were not similar at baseline. Patients who were fused in the non-RCT subgroup were older, had a higher Oswestry Disability Index, and were more frequently smokers than the other patients. The outcome for the non-RCT group showed larger differences in favor of TDR than the RCT did. The nonresponders in the non-RCT group showed worse life quality and disability at baseline, and patients who answered the 1-year follow-up questionnaire but not the 2-year follow-up questionnaire had an inferior clinical result compared with the other patients at 1 year. CONCLUSION: Data from our register showed results similar to the RCT, but a register cannot fully replace an RCT study when evaluating a new treatment option if the RCT has narrower selection than just the diagnosis. In this RCT comparing TDR with posterior fusion, the normal exclusion criteria for TDR were used. These were not registered, so the register could not prevent a possible selection bias, which might also be caused by the nonresponders. PMID- 25802655 TI - Retroperitoneal lymphocele after lumbar total disc replacement: a case report and review of literature. AB - BACKGROUND: Retroperitoneal lymphoceles (RPLs) caused by injury to the lymphatics are commonly seen after pelvic lymphadenectomy, renal transplantation, and gynecologic tumor resection surgeries. Degenerative disc disease still remains the major cause of low-back pain. Anterior lumbar spinal procedures, such as anterior lumbar interbody fusion and anterior lumbar arthroplasty, have been increasingly performed for treatment of axial back pain. RPLs, as an approach related complication, though infrequent, have been reported after anterior lumbar spinal surgery. We report a case of RPL after total disc replacement of the lumbar spine. To our knowledge, there has been no prior report of RPL after total disc replacement managed by percutaneous aspiration only. METHODS: A 49-year-old woman who underwent total disc replacement at the L4-5 level presented with a postoperative complication of RPL. The imaging findings, clinical course, and treatment are discussed, and a review of literature is presented. RESULTS: The patient presented with significant abdominal swelling and discomfort at 4 weeks after surgery without any signs or symptoms of infection. Investigations showed an RPL. She was treated by multiple aspirations under ultrasound guidance. At 12 months' follow-up, the patient had no further abdominal symptoms and had gone back to her routine activities and work with significant improvement in back pain. CONCLUSIONS: RPL is an uncommon complication after anterior lumbar surgery and can be managed effectively if detected and diagnosed early. Although repeated aspiration is associated with high recurrence and infection, it is a safe and minimally invasive procedure to manage RPL. PMID- 25802654 TI - Bone grafting options for lumbar spine surgery: a review examining clinical efficacy and complications. AB - BACKGROUND: Iliac crest harvest has been considered the "gold standard" at producing successful arthrodesis of the lumbar spine but is also associated with many donor-site morbidities. Many alternatives have been used to avoid iliac crest harvest, including autologous bone from other donor sites, allogeneic bone, ceramics, and recombinant human bone morphogenetic proteins (rhBMPs). This review will highlight the properties and preparations of these graft types and their potential complications and reported clinical efficacy. METHODS: A Medline search was conducted via PubMed by use of the following terms in various combinations: lumbar fusion, freeze-dried allograft, fresh-frozen allograft, autograft, iliac crest, demineralized bone matrix, rhBMP-2, rhBMP-7, scoliosis, bone marrow aspirate, HEALOS, coralline hydroxyapatite, beta tricalcium phosphate, synthetic, ceramics, spinal fusion, PLF, PLIF, ALIF, and TLIF. Only articles written in English were assessed for appropriate material. Related articles were also assessed depending on the content of articles found in the original literature search. CONCLUSIONS: Although iliac crest remains the gold standard, reported success with alternative approaches, especially in combination, has shown promise. Stronger evidence with limited sources of potential bias is necessary to provide a clear picture of their clinical efficacy. PMID- 25802658 TI - Cost comparison of patients with 3-level artificial total lumbar disc replacements versus 360 degrees fusion at 3 contiguous lumbar vertebral levels: an analysis of compassionate use at 1 site of the US investigational device exemption clinical trial. AB - BACKGROUND: We sought to evaluate the difference between hospital service costs of 2 treatment options for patients diagnosed with 3-level degenerative disc disease (DDD) in the lumbar spine. In this retrospective analysis, itemized billing records of hospital stay for patients with 3-level DDD treated with artificial disc replacement (ADR) were compared with those treated with circumferential fusion (standard of care). METHODS: Sequential 3-level DDD patients treated with either ADR (ProDisc-L; Synthes, West Chester, Pennsylvania) or circumferential fusion during the period from January 2004 to October 2005 were included. Surgeries were performed at the same hospital for all patients. The ADR-treated patients were participating in the investigational device exemption clinical trial as part of the compassionate-use arm. Patients treated with fusion at the same institution during this same time interval were evaluated. Itemized billing records were collected at least 1 year after the index surgery. Costs according to hospital service categories were compared between ADR-treated and fusion-treated patients by use of analysis of variance and multivariate statistical techniques. RESULTS: There were 43 consecutive patients treated for 3-level DDD between January 2004 and October 2005. Of these, 21 underwent 3-level ADR and 22 had a 3-level fusion procedure. There was a mean of 3 fewer hospital days for patients treated with ADR (4.77 +/- 1.11 days) than for those treated with fusion (8.00 +/- 1.82 days) (P < .0001). The cost of hospital services for ADR-treated patients was 49% less excluding instrumentation costs and 54% less when accounting for instrumentation. The pattern of cost was similar when workers' compensation patients were analyzed separately. CONCLUSIONS: ADR-treated 3-level patients benefited from significantly lower costs from their in-hospital stay compared with those treated by fusion. Hospital service costs were 49% (54% when instrumentation was included in the costs) less for ADR patients than for fusion patients. PMID- 25802656 TI - Clinical outcomes after posterior dynamic transpedicular stabilization with limited lumbar discectomy: Carragee classification system for lumbar disc herniations. AB - BACKGROUND: The observed rate of recurrent disc herniation after limited posterior lumbar discectomy is highest in patients with posterior wide annular defects, according to the Carragee classification of type II (fragment-defect) disc hernia. Although the recurrent herniation rate is lower in both type III (fragment-contained) and type IV (no fragment-contained) patients, recurrent persistent sciatica is observed in both groups. A higher rate of recurrent disc herniation and sciatica was observed in all 3 groups in comparison to patients with type I (fragment-fissure) disc hernia. METHODS: In total, 40 single-level lumbar disc herniation cases were treated with limited posterior lumbar microdiscectomy and posterior dynamic stabilization. The mean follow-up period was 32.75 months. Cases were selected after preoperative magnetic resonance imaging and intraoperative observation. We used the Carragee classification system in this study and excluded Carragee type I (fragment-fissure) disc herniations. Clinical results were evaluated with visual analog scale scores and Oswestry scores. Patients' reherniation rates and clinical results were evaluated and recorded at 3, 12, and 24 months postoperatively. RESULTS: The most common herniation type in our study was type III (fragment-contained), with 45% frequency. The frequency of fragment-defects was 25%, and the frequency of no fragment-contained defects was 30%. The perioperative complications observed were as follows: 1 patient had bladder retention that required catheterization, 1 patient had a superficial wound infection, and 1 patient had a malpositioned transpedicular screw. The malpositioned screw was corrected with a second operation, performed 1 month after the first. Recurrent disc herniation was not observed during the follow-up period. CONCLUSIONS: We observed that performing discectomy with posterior dynamic stabilization decreased the risk of recurrent disc herniations in Carragee type II, III, and IV groups, which had increased reherniation and persistent/continuous sciatica after limited lumbar microdiscectomy. Moreover, after 2 years' follow-up, we obtained improved clinical results. PMID- 25802657 TI - Clinical outcomes of degenerative lumbar spinal stenosis treated with lumbar decompression and the Cosmic "semi-rigid" posterior system. AB - BACKGROUND: Although some investigators believe that the rate of postoperative instability is low after lumbar spinal stenosis surgery, the majority believe that postoperative instability usually develops. Decompression alone and decompression with fusion have been widely used for years in the surgical treatment of lumbar spinal stenosis. Nevertheless, in recent years several biomechanical studies have shown that posterior dynamic transpedicular stabilization provides stabilization that is like the rigid stabilization systems of the spine. Recently, posterior transpedicular dynamic stabilization has been more commonly used as an alternative treatment option (rather than rigid stabilization with fusion) for the treatment of degenerative spines with chronic instability and for the prevention of possible instability after decompression in lumbar spinal stenosis surgery. METHODS: A total of 30 patients with degenerative lumbar spinal stenosis (19 women and 11 men) were included in the study group. The mean age was 67.3 years (range, 40-85 years). Along with lumbar decompression, a posterior dynamic transpedicular stabilization (dynamic transpedicular screw-rigid rod system) without fusion was performed in all patients. Clinical and radiologic results for patients were evaluated during follow-up visits at 3, 12, and 24 months postoperatively. RESULTS: The mean follow-up period was 42.93 months (range, 24-66 months). A clinical evaluation of patients showed that, compared with preoperative assessments, statistically significant improvements were observed in the Oswestry and visual analog scale scores in the last follow-up control. Compared with preoperative values, there were no statistically significant differences in radiologic evaluations, such as segmental lordosis angle (alpha) scores (P = .125) and intervertebral distance scores (P = .249). There were statistically significant differences between follow-up lumbar lordosis scores (P = .048). There were minor complications, including a subcutaneous wound infection in 2 cases, a dural tear in 2 cases, cerebrospinal fluid fistulas in 1 case, a urinary tract infection in 1 case, and urinary retention in 1 case. We observed L5 screw loosening in 1 of the 3-level decompression cases. No screw breakage was observed and no revision surgery was performed in any of these cases. CONCLUSIONS: Posterior dynamic stabilization without fusion applied to lumbar decompression leads to better clinical and radiologic results in degenerative lumbar spinal stenosis. To avoid postoperative instability, especially in elderly patients who undergo degenerative lumbar spinal stenosis surgery with chronic instability, the application of decompression with posterior dynamic transpedicular stabilization is likely an important alternative surgical option to fusion, because it does not have fusion related side effects, is easier to perform than fusion, requires a shorter operation time, and has low morbidity and complication rates. PMID- 25802659 TI - Navigation-assisted fluoroscopy in minimally invasive direct lateral interbody fusion: a cadaveric study. AB - BACKGROUND: Minimally invasive surgery (MIS) is dependent on intraoperative fluoroscopic imaging for visualization, which significantly increases exposure to radiation. Navigation-assisted fluoroscopy (NAV) can potentially decrease radiation exposure and improve the operating room environment by reducing the need for real-time fluoroscopy. The direct lateral interbody fusion (DLIF) procedure is a technique for MIS intervertebral lumbar and thoracic interbody fusions. This study assesses the use of navigation for the DLIF procedure in comparison to standard fluoroscopy (FLUORO), as well as the accuracy of the NAV MIS DLIF procedure. METHODS: Three fresh whole-body cadavers underwent multiple DLIF procedures at the T10-L5 levels via either NAV or FLUORO. Radiation exposure and surgical times were recorded and compared between groups. An additional cadaver was used to evaluate the accuracy of the NAV system for the DLIF procedure by measuring the deviation error as the surgeon worked further from the anterior superior iliac spine tracker. RESULTS: Approach, discectomy, and total fluoroscopy times for FLUORO were longer than NAV (P < .05). In contrast, the setup time was longer in NAV (P = .005). Cage insertion and total operating times were similar for both. Radiation exposure to the surgeon for NAV was significantly less than FLUORO (P < .05). Accuracy of the NAV system was within 1 mm for L2-5. CONCLUSION: Navigation for the DLIF procedure is feasible. Accuracy for this procedure over the most common levels (L2-5) is likely sufficient for safe clinical application. Although initial setup times were longer with NAV, simultaneous anteroposterior and lateral imaging with the NAV system resulted in overall surgery times similar to FLUORO. Navigation minimizes fluoroscopic radiation exposure. CLINICAL SIGNIFICANCE: Navigation for the DLIF procedure is accurate and decreases radiation exposure without increasing the overall surgical time. PMID- 25802660 TI - Results at 24 months from the prospective, randomized, multicenter Investigational Device Exemption trial of ProDisc-C versus anterior cervical discectomy and fusion with 4-year follow-up and continued access patients. AB - BACKGROUND: Cervical total disk replacement (TDR) is intended to address pain and preserve motion between vertebral bodies in patients with symptomatic cervical disk disease. Two-year follow-up for the ProDisc-C (Synthes USA Products, LLC, West Chester, Pennsylvania) TDR clinical trial showed non-inferiority versus anterior cervical discectomy and fusion (ACDF), showing superiority in many clinical outcomes. We present the 4-year interim follow-up results. METHODS: Patients were randomized (1:1) to ProDisc-C (PDC-R) or ACDF. Patients were assessed preoperatively, and postoperatively at 6 weeks and 3, 6, 12, 18, 24, 36, and 48 months. After the randomized portion, continued access (CA) patients also underwent ProDisc-C implantation, with follow-up visits up to 24 months. Evaluations included Neck Disability Index (NDI), Visual Analog Scale (VAS) for pain/satisfaction, and radiographic and physical/neurologic examinations. RESULTS: Randomized patients (103 PDC-R and 106 ACDF) and 136 CA patients were treated at 13 sites. VAS pain and NDI score improvements from baseline were significant for all patients (P < .0001) but did not differ among groups. VAS satisfaction was higher at all time points for PDC-R versus ACDF patients (P = .0499 at 48 months). The percentage of patients who responded yes to surgery again was 85.6% at 24 months and 88.9% at 48 months in the PDC-R group, 80.9% at 24 months and 81.0% at 48 months in the ACDF group, and 86.3% at 24 months in the CA group. Five PDC-R patients (48 months) and no CA patients (24 months) had index-level bridging bone. By 48 months, approximately 4-fold more ACDF patients required secondary surgery (3 of 103 PDC-R patients [2.9%] vs 12 of 106 ACDF patients [11.3%], P = .0292). Of these, 6 ACDF patients (5.6%) required procedures at adjacent levels. Three CA patients required secondary procedures (24 months). CONCLUSIONS: Our 4-year data support that ProDisc-C TDR and ACDF are viable surgical options for symptomatic cervical disk disease. Although ACDF patients may be at higher risk for additional surgical intervention, patients in both groups show good clinical results at longer-term follow-up. PMID- 25802661 TI - Intracranial subdural hematoma as a cause of postoperative delirium and headache in cervical laminoplasty: A case report and review of the literature. AB - OBJECTIVES: To describe a rare case of acute intracranial subdural hematoma as a cause of postoperative delirium and headache following cervical spine surgery. SUMMARY OF BACKGROUND DATA: Headache is uncommon following spinal surgery, but can be observed in cases of accidental tearing of the dura during surgery. The causes of headache after surgery are thought to include dural tear and CSF leakage. On the other hand, intracranial subdural hematoma can be a cause of headache and cognitive dysfunction. However, only 4 cases as a postoperative complication of spinal surgery have been reported in the literature. METHODS: A 55-year-old man underwent re-explorative surgery due to postoperative hematoma causing hemiplegia following cervical laminoplasty. During this operation, accidental dural tear occurred and induced CSF leakage. On the following day, headache and delirium were noted. CSF leakage continued despite intraoperative repair of the dural laceration. Cranial CT at that time clearly demonstrated subdural hematoma. RESULTS: We reexplored the surgical site and attempted to stop the CSF leakage with meticulous suturing of the dural sac under microscopic observation. The intracranial subdural hematoma was carefully observed under consultation with a specialist neurosurgeon. Following this reexploration, the headache and delirium gradually improved, with spontaneous resolution of intracranial hematoma over a two-month period of observation. CONCLUSIONS: We have reported a rare case of acute intracranial subdural hematoma caused by CSF leakage following cervical spine surgery. This report demonstrates the possibility of intracranial hematoma as a cause of postoperative cognitive dysfunction or headache, especially when accidental tearing of the dura has occurred in spinal surgery. PMID- 25802662 TI - Lumbar extraforaminal decompression: A technical note and retrospective study looking at potential complications as an outpatient procedure. AB - BACKGROUND: Lumbar disc herniation and stenosis that results in compression of a nerve root lateral to the foramen is defined as extraforaminal. In recent years the recognition of such pathology has increased with technology and greater awareness. Various approaches and techniques have been developed for extraforaminal decompression in the lumbar region. The purpose of this study was two fold: 1) Determine the safety of treating patients operatively via a paramedian muscle splitting approach on an outpatient basis, and 2) Highlight the technical aspects of the approach to the extraforaminal region. METHODS: One hundred consecutive extraforaminal decompressions were performed from 1992 to 2007 by a single surgeon. A retrospective review was performed consisting of chart reviews. Summary statistics and the Pierson Chi-square test were used to analyze the data. The primary outcome measure was the need for hospital admission or readmission following surgical decompression. RESULTS: Seven of 100 patients (7%) were required to remain in the hospital for twenty-three hour observation due to Medicare requirements. Five (5%) of the patients originally scheduled for an outpatient procedure were converted to inpatient status due to postoperative pain. All were released within 2 days (average 1.25 days). Only one (1%) patient was readmitted for urinary retention that resolved without incident. There was no significant difference (P = 0.137) in complication rate between our control and those that underwent extraforaminal decompression. CONCLUSIONS: Extraforaminal lumbar decompression as an outpatient procedure can be done safely without the need for hospital admission. PMID- 25802663 TI - Measurement of occlusion of the spinal canal and intervertebral foramen by intervertebral disc bulge. AB - BACKGROUND: Disc protrusion has been proposed to be a possible cause of both pain and stenosis in the lower spine. No previous study has described the amount of disc occlusion of the spinal canal and intervertebral foramen that occurs under different loading conditions. The objective of this study was to quantitatively assess the percent occlusion of the spinal canal and intervertebral foramen by disc bulge under different loading conditions. METHODS: Spinal canal depth and foraminal width were measured on computed tomography-scanned images of 7 human lumbar spine specimens. In vitro disc bulge measurements were completed by use of a previously described method in which single functional spinal units were subjected to 3 separate load protocols in a spine test machine and disc bulge was recorded with an optoelectric motion system that tracked active light-emitting diodes placed on the posterior and posterolateral aspects of the intervertebral disc. Occlusion was defined as percentage of encroachment into area of interest by maximum measured disc bulge at corresponding point of interest (the spinal canal is at the posterior point; the intervertebral foramen is at the posterolateral point). RESULTS: The mean spinal canal depth and mean foraminal width were 19 4 +/- mm and 5 +/- 2 mm, respectively. Mean spinal canal occlusion under a 250-N axial load, +/- 2.5 Nm of flexion/extension, and +/- 2.5 Nm of lateral bend was 2.5% +/- 1.9%, 2.5% +/- 1.6%, and 1.5% +/- 0.8%, respectively. Mean intervertebral foramen occlusion under a 250-N axial load, +/- 2.5 Nm of flexion/extension, and +/- 2.5 Nm of lateral bend was 7.8% +/- 4.7%, 9.5% +/- 5.7%, and 11.3% +/- 6.2%, respectively. CONCLUSION: Percent occlusion of the spinal canal and intervertebral foramen is dependent on magnitude and direction of load. Exiting neural elements at the location of the intervertebral foramen are the most vulnerable to impingement and generation of pain. PMID- 25802664 TI - Biomechanical evaluation of a spherical lumbar interbody device at varying levels of subsidence. AB - BACKGROUND: Ulf Fernstrom implanted stainless steel ball bearings following discectomy, or for painful disc disease, and termed this procedure disc arthroplasty. Today, spherical interbody spacers are clinically available, but there is a paucity of associated biomechanical testing. The primary objective of the current study was to evaluate the biomechanics of a spherical interbody implant. It was hypothesized that implantation of a spherical interbody implant, with combined subsidence into the vertebral bodies, would result in similar ranges of motion (RoM) and facet contact forces (FCFs) when compared with an intact condition. A secondary objective of this study was to determine the effect of using a polyetheretherketone (PEEK) versus a cobalt chrome (CoCr) implant on vertebral body strains. We hypothesized that the material selection would have a negligible effect on vertebral body strains since both materials have elastic moduli substantially greater than the annulus. METHODS: A finite element model of L3-L4 was created and validated by use of ROM, disc pressure, and bony strain from previously published data. Virtual implantation of a spherical interbody device was performed with 0, 2, and 4 mm of subsidence. The model was exercised in compression, flexion, extension, axial rotation, and lateral bending. The ROM, vertebral body effective (von Mises) strain, and FCFs were reported. RESULTS: Implantation of a PEEK implant resulted in slightly lower strain maxima when compared with a CoCr implant. For both materials, the peak strain experienced by the underlying bone was reduced with increasing subsidence. All levels of subsidence resulted in ROM and FCFs similar to the intact model. CONCLUSIONS: The results suggest that a simple spherical implant design is able to maintain segmental ROM and provide minimal differences in FCFs. Large areas of von Mises strain maxima were generated in the bone adjacent to the implant regardless of whether the implant was PEEK or CoCr. PMID- 25802666 TI - Hybrid dynamic stabilization with posterior spinal fusion in the lumbar spine. AB - BACKGROUND: Instrumented lumbar arthrodesis has been established as the gold standard in the care of patients with degenerative disc disease. However, spinal fusion results in the elimination of motion of the functional spinal unit and has been implicated in the development of adjacent-level degeneration. Motion preserving devices such as the dynamic rod allow for stabilization of a pathologic motion segment above a fused segment and create a transitional zone (index level) that decreases the loads applied to the supra-adjacent normal segment. METHODS: After institutional review board approval, 28 patients were included in this prospective, consecutive, nonrandomized clinical trial. Each subject was consented for dynamic stabilization. There was no attempt at fusion at the dynamic level. The cohort underwent a posterior lateral spinal fusion with single- or 2-level transforaminal lumbar interbody fusion by use of a cage, with superior-level posterior dynamic instrumentation. Functional clinical outcomes were measured with a 100-point visual analog scale, Oswestry Disability Index, and Short Form 36 questionnaire. Radiographic measurements, fusion evaluation, complications, and screw loosening were recorded. RESULTS: A minimum of 24 months' follow-up data included 22 patients. No device failure or screw breakage was identified. Postoperative range of motion averaged 2.5 degrees at the index level, and the superior adjacent-level range of motion remained unchanged (P > .05). Disc height was preserved at all levels (P > .05). Of 180 screws, 6 (3%) showed radiographic loosening. Functional outcomes showed significant improvement in mean postoperative visual analog scale score by 24.7 points (P < .01) and Oswestry Disability Index by 27.6 points (P < .01), as well as the Short Form 36 physical (P < .01) and mental (P < .05) components from baseline to 2-year follow up. CONCLUSIONS: Our preliminary results at 2 years are satisfactory. CLINICAL RELEVANCE: Ultimately, further follow-up will assess the potential for this treatment to delay adjacent-level changes in the long term. PMID- 25802665 TI - Cost-utility analysis of posterior minimally invasive fusion compared with conventional open fusion for lumbar spondylolisthesis. AB - BACKGROUND: The utility and cost of minimally invasive surgical (MIS) fusion remain controversial. The primary objective of this study was to compare the direct economic impact of 1- and 2-level fusion for grade I or II degenerative or isthmic spondylolisthesis via an MIS technique compared with conventional open posterior decompression and fusion. METHODS: A retrospective cohort study was performed by use of prospective data from 78 consecutive patients (37 with MIS technique by 1 surgeon and 41 with open technique by 3 surgeons). Independent review of demographic, intraoperative, and acute postoperative data was performed. Oswestry disability index (ODI) and Short Form 36 (SF-36) values were prospectively collected preoperatively and at 1 year postoperatively. Cost utility analysis was performed by use of in-hospital micro-costing data (operating room, nursing, imaging, laboratories, pharmacy, and allied health cost) and change in health utility index (SF-6D) at 1 year. RESULTS: The groups were comparable in terms of age, sex, preoperative hemoglobin, comorbidities, and body mass index. Groups significantly differed (P < .01) regarding baseline ODI and SF-6D scores, as well as number of 2-level fusions (MIS, 12; open, 20) and number of interbody cages (MIS, 45; open, 14). Blood loss (200 mL vs 798 mL), transfusions (0% vs 17%), and length of stay (LOS) (6.1 days vs 8.4 days) were significantly (P < .01) lower in the MIS group. Complications were also fewer in the MIS group (4 vs 12, P < .02). The mean cost of an open fusion was 1.28 times greater than that of an MIS fusion (P = .001). Both groups had significant improvement in 1-year outcome. The changes in ODI and SF-6D scores were not statistically different between groups. Multivariate regression analysis showed that LOS and number of levels fused were independent predictors of cost. Age and MIS were the only predictors of LOS. Baseline outcomes and MIS were predictors of 1-year outcome. CONCLUSION: MIS posterior fusion for spondylolisthesis does reduce blood loss, transfusion requirements, and LOS. Both techniques provided substantial clinical improvements at 1 year. The cost utility of the MIS technique was considered comparable to that of the open technique. LEVEL OF EVIDENCE: Level III. PMID- 25802667 TI - Novel indication for posterior dynamic stabilization: Correction of disc tilt after lumbar total disc replacement. AB - BACKGROUND: The increase in total disc replacement procedures performed over the last 5 years has increased the occurrence of patients presenting with postoperative iatrogenic deformity requiring revision surgery. Proposed salvage treatments include device retrieval followed by anterior lumbar interbody fusion or posterior fusion. We propose a novel approach for the correction of disc tilt after total disc replacement using a posterior dynamic stabilization system. METHODS: Pedicle screws can be inserted either in an open manner or percutaneously by standard techniques under fluoroscopy. The collapsed side is expanded, and the convex side is compressed. Universal spacers are placed bilaterally, with the spacer on the collapsed side being taller by 6 mm. Cords are threaded through the spacers and pulled into place with the tensioning instrument. Extra tension is applied to the convex side, and the wound is closed by standard techniques. RESULTS: Three patients presenting with tilted total disc replacement devices underwent corrective surgery with posterior dynamic stabilization. Radiographs confirmed correction of deformity in all cases. CONCLUSIONS/LEVEL OF EVIDENCE: This technical note presents a novel indication for posterior dynamic stabilization and describes its surgical application to the correction of disc tilt after total disc replacement. This is level V evidence. PMID- 25802668 TI - A comparison of the shock-absorbing properties of cervical disc prosthesis bearing materials. AB - BACKGROUND DATA: Cervical arthroplasty offers theoretical advantages over traditional spinal fusion, including elimination of adjacent segment disease and elimination of the risk of pseudoarthrosis formation. Initial studies of cervical arthroplasty have shown promising results, however, the ideal design characteristics for disc replacement constructs have not been determined. The current study seeks to quantify the differences in the shock absorption characteristics of three commonly used materials in cervical disc arthroplasty. METHODS: Three different nucleus materials, polyurethane (PU), polyethylene (PE) and a titanium-alloy (Ti) were tested in a humidity- and temperature-controlled chamber. Ten of each nucleus type underwent three separate mechanical testing protocols to measure 1) dynamic stiffness, 2) quasi-static stiffness, 3) energy absorption, and 4) energy dissipation. The results were compared using analysis of variance. RESULTS: PU had the lowest mean dynamic stiffness (435 +/- 13 N/mm, P < .0001) and highest energy absorption (19.4 +/- 0.1 N/mm, P < .0001) of all three nucleus materials tested. PU was found to have significantly higher energy dissipation (viscous damping ratio 0.017 +/- 0,001, P < .0001) than the PE or TI nuclei. PU had the lowest quasi-static stiffness (598 +/- 23 N/mm, P < .0001) of the nucleus materials tested. A biphasic response curve was observed for all of the PU nuclei tests. CONCLUSIONS: Polyurethane absorbs and dissipates more energy and is less stiff than either polyethylene or titanium. LEVEL OF EVIDENCE: Basic Science/Biomechanical Study. CLINICAL RELEVANCE: This study characterizes important differences in biomechanical properties of materials that are currently being used for different cervical disc prostheses. PMID- 25802669 TI - Use of a quantitative pedicle screw accuracy system to assess new technology: Initial studies on O-arm navigation and its effect on the learning curve of percutaneous pedicle screw insertion. AB - BACKGROUND: A quantitative screw accuracy system is proposed that allows for high fidelity discrimination between various methods of pedicle screw insertion. Our purpose was to study the utility of a quantitative screw accuracy scoring system to assess new imaging technologies and their effects on the minimally invasive spine learning curve. METHODS: By use of a hypothetical "perfect screw," a scoring system is proposed that may be used to compare the position of a small number of screws inserted according to a desired optimal position. This study incorporates a retrospective review of imaging studies for 10 patients who underwent percutaneous pedicle screw placement with either navigation-assisted O arm imaging or navigation-assisted C-arm imaging. For the learning-curve portion of the study, 2 cadaveric adult torsos were used for instrumentation. Computed tomography imaging studies were used in both studies to assess screw position in the pedicle and vertebral body in relation to an optimal screw by use of a quantitative scoring system to rate accuracy. RESULTS: The quantitative scoring system allowed a statistically significant accuracy difference to be ascertained between 2 different technologies using fewer data points than previously published methods. When this screw scoring system is applied to minimally invasive percutaneous pedicle screw insertion, an optimal screw position can be achieved with greater accuracy through navigation-assisted technology (O-arm with computer-assisted navigation). When the O-arm with computer-assisted navigation was used by a novice surgeon learning the technique of percutaneous screw insertion, screws were inserted in a shorter period without loss of accuracy. In contrast, use of the traditional C-arm fluoroscopy leads to a loss of accuracy with faster insertion times. Increased accuracy can be seen clinically when compared with fluoroscopic navigation. CONCLUSIONS: The use of a quantitative scoring system allows for rapid assessment of screw accuracy. As additional technologies and new teaching techniques for pedicle screw insertion are developed, this scoring system may be useful as an early assessment tool. PMID- 25802670 TI - Three-dimensional assessment of the intervertebral kinematics after Mobi-C total disc replacement at the cervical spine in vivo using the EOS stereoradiography system. AB - BACKGROUND: Because 3-dimensional computed tomography and magnetic resonance imaging analysis of the spinal architecture is done with the patient in the supine position, stereoradiography may be more clinically relevant for the measurement of the relative displacements of the cervical vertebrae in vivo in the upright position. The innovative EOS stereoradiography system was used for measuring the relative angular displacements of the cervical vertebrae in a limited population to determine its feasibility. The precision and accuracy of the method were investigated. METHODS: In 9 patients with 16 Mobi-C prostheses (LDR Medical, Troyes, France) and 12 healthy subjects, EOS stereoradiography of the lower cervical spine (C3-7) was performed in the neutral upright position of the neck, flexion, extension, left and right lateral bending, and left and right axial rotation. The angular displacements were measured from the neutral position to every other posture. The random error was studied in terms of reproducibility. In addition, an in vitro protocol was performed in 6 specimens to investigate accuracy. RESULTS: The reproducibility and the accuracy variables varied similarly between 1.2 degrees and 3.2 degrees depending on the axis and direction of rotation under consideration. The Mobi-C group showed less mobility than the control group, whereas the pattern of coupling was similar. CONCLUSIONS: Overall, the feasibility of dynamic EOS stereoradiography was shown. The prosthesis replicates the pattern of motion of the normal cervical spine. PMID- 25802671 TI - Surgical results of dynamic nonfusion stabilization with the Segmental Spinal Correction System for degenerative lumbar spinal diseases with instability: Minimum 2-year follow-up. AB - BACKGROUND: When spinal fusion is applied to degenerative lumbar spinal disease with instability, adjacent segment disorder will be an issue in the future. However, decompression alone could cause recurrence of spinal canal stenosis because of increased instability on operated segments and lead to revision surgery. Covering the disadvantages of both procedures, we applied nonfusion stabilization with the Segmental Spinal Correction System (Ulrich Medical, Ulm, Germany) and decompression. METHODS: The surgical results of 52 patients (35 men and 17 women) with a minimum 2-year follow-up were analyzed: 10 patients with lumbar spinal canal stenosis, 15 with lumbar canal stenosis with disc herniation, 20 with degenerative spondylolisthesis, 6 with disc herniation, and 1 with lumbar discopathy. RESULTS: The Japanese Orthopaedic Association score was improved, from 14.4 +/- 5.3 to 25.5 +/- 2.8. The improvement rate was 76%. Range of motion of the operated segments was significantly decreased, from 9.6 degrees +/- 4.2 degrees to 2.0 degrees +/- 1.8 degrees . Only 1 patient had adjacent segment disease that required revision surgery. There was only 1 screw breakage, but the patient was asymptomatic. CONCLUSIONS: Over a minimum 2-year follow-up, the results of nonfusion stabilization with the Segmental Spinal Correction System for unstable degenerative lumbar disease were good. It is necessary to follow up the cases with a focus on adjacent segment disorders in the future. PMID- 25802673 TI - Complications with axial presacral lumbar interbody fusion: A 5-year postmarketing surveillance experience. AB - BACKGROUND: Open and minimally invasive lumbar fusion procedures have inherent procedural risks, with posterior and transforaminal approaches resulting in significant soft-tissue injury and the anterior approach endangering organs and major blood vessels. An alternative lumbar fusion technique uses a small paracoccygeal incision and a presacral approach to the L5-S1 intervertebral space, which avoids critical structures and may result in a favorable safety profile versus open and other minimally invasive fusion techniques. The purpose of this study was to evaluate complications associated with axial interbody lumbar fusion procedures using the Axial Lumbar Interbody Fusion (AxiaLIF) System (TranS1, Wilmington, North Carolina) in the postmarketing period. METHODS: Between March 2005 and March 2010, 9,152 patients underwent interbody fusion with the AxiaLIF System through an axial presacral approach. A single-level L5-S1 fusion was performed in 8,034 patients (88%), and a 2-level (L4-S1) fusion was used in 1,118 (12%). A predefined database was designed to record device- or procedure-related complaints via spontaneous reporting. The complications that were recorded included bowel injury, superficial wound and systemic infections, transient intraoperative hypotension, migration, subsidence, presacral hematoma, sacral fracture, vascular injury, nerve injury, and ureter injury. RESULTS: Complications were reported in 120 of 9,152 patients (1.3%). The most commonly reported complications were bowel injury (n = 59, 0.6%) and transient intraoperative hypotension (n = 20, 0.2%). The overall complication rate was similar between single-level (n = 102, 1.3%) and 2-level (n = 18, 1.6%) fusion procedures, with no significant differences noted for any single complication. CONCLUSIONS: The 5-year postmarketing surveillance experience with the AxiaLIF System suggests that axial interbody lumbar fusion through the presacral approach is associated with a low incidence of complications. The overall complication rates observed in our evaluation compare favorably with those reported in trials of open and minimally invasive lumbar fusion surgery. PMID- 25802672 TI - Motion-preserving technologies for degenerative lumbar spine: The past, present, and future horizons. AB - Over the past few decades, remarkable advancements in the understanding of the origin of low-back pain and lumbar spinal disorders have been achieved. Spinal fusion is generally considered the "gold standard" in the treatment of low-back pain; however, fusion is also associated with accelerated degeneration of adjacent levels. Spinal arthroplasty and dynamic stabilization technologies, as well as the continuous improvement in diagnosis and surgical interventions, have opened a new era of treatment options. Recent advancements in nonfusion technologies such as motion-preservation devices and posterior dynamic stabilization may change the gold standard. These devices are designed with the intent to provide stabilization and eliminate pain while preserving motion of the functional spinal unit. The adaption of nonfusion technologies by the surgical community and payers for the treatment of degenerative spinal conditions will depend on the long-term clinical outcome of controlled randomized clinical studies. Although the development of nonfusion technology has just started and the adoption is very slow, it may be considered a viable option for motion preservation in coming years. This review article provides technical and surgical views from the past and from the present, as well as a glance at the future endeavors and challenges in instrumentation development for lumbar spinal disorders. (c) 2011 SAS - The International Society for the Advancement of Spine Surgery. Published by Elsevier Inc. All rights reserved. PMID- 25802674 TI - Letter to the editor: Novel indication for posterior dynamic stabilization: correction of disc tilt after lumbar total disc replacement. PMID- 25802675 TI - Preclinical and clinical experience with a viscoelastic total disc replacement. AB - BACKGROUND: The purpose of this study is to describe the mechanical durability and the clinical and radiographic outcomes of a viscoelastic total disc replacement (VTDR). The human intervertebral disc is a complex, viscoelastic structure, permitting and constraining motion in 3 axes, thus providing stability. The ideal disc replacement should be viscoelastic and deformable in all directions, and it should restore disc height and angle. METHODS: Mechanical testing was conducted to validate the durability of the VTDR, and a clinical study was conducted to evaluate safety and performance. Fifty patients with single-level, symptomatic lumbar degenerative disc disease at L4-5 or L5-S1 were enrolled in a clinical trial at 3 European sites. Patients were assessed clinically and radiographically for 2 years by the Oswestry Disability Index (ODI), a visual analog scale (VAS), and independent radiographic analyses. RESULTS: The VTDR showed a fatigue life in excess of 50 million cycles (50-year equivalent) and a physiologically appropriate level of stiffness, motion, geometry, and viscoelasticity. We enrolled 28 men and 22 women in the clinical study, with a mean age of 40 years. Independent quantitative radiographic assessment indicated that the VTDR restored and maintained disc height and lordosis while providing physiologic motion. Mean ODI scores decreased from 48% preoperatively to 23% at 2 years' follow-up. Mean VAS low-back pain scores decreased from 7.1 cm to 2.9 cm. Median scores indicated that half of the patient population had ODI scores below 10% and VAS low-back pain scores below 0.95 cm at 2 years. CONCLUSIONS: The VTDR has excellent durability and performs clinically and radiographically as intended for the treatment of symptomatic lumbar degenerative disc disease. CLINICAL RELEVANCE: The VTDR is intended to restore healthy anatomic properties and stability characteristics to the spinal segment. This study is the first to evaluate a VTDR in a 50-patient, multicenter European study. PMID- 25802676 TI - Kineflex lumbar artificial disc versus Charite lumbar total disc replacement for the treatment of degenerative disc disease: A randomized non-inferiority trial with minimum of 2 years' follow-up. AB - BACKGROUND: The Kineflex lumbar artificial disc replacement device (SpinalMotion, Mountain View, California) is a semiconstrained, posterior center of rotation, metal-on-metal intervertebral disc prosthesis. We performed a prospective, randomized, non-inferiority trial comparing the Kineflex Disc with the Food and Drug Administration (FDA)-approved Charite device (DePuy Spine, Raynham, Massachusetts). Our objective was to evaluate the Kineflex Disc's safety and efficacy using validated outcomes measures-the visual analog scale (VAS) and the Oswestry Disability Index (ODI). METHODS: Sixty-four patients were randomized to receive either the Kineflex Disc or Charite device and were then followed up for up to 3 years. Patients completed VAS and ODI questionnaires and were evaluated clinically and radiologically for complication or device failure. Results were analyzed in terms of change in mean VAS score and ODI from baseline, as well as with a comparison of clinical success as defined by FDA investigational device exemption criteria. Non-inferiority was defined as a difference of less than 18 points in the VAS score and difference of less than 10 units on the ODI scale, in keeping with a previously established minimum clinically important difference. RESULTS: The mean improvement for the Kineflex Disc group at 24 months was 56.80 for the VAS score and 37.30 for the ODI. Similarly, the mean improvement in the Charite group was 54.43 for the VAS score and 38.40 for the ODI. At 2 years of follow-up, no difference was found in VAS scores between the two groups. The Kineflex Disc group was therefore found to be non-inferior (mean difference, 2.37; 95% confidence interval, -12.5 to 17.3; P = .004). In addition, at 24 months, 83% of patients in the Kineflex Disc group and 85% of patients in the Charite group met FDA-defined criteria for clinical success, with no difference between groups (P = .802). CONCLUSIONS: This level I evidence shows the Kineflex Disc to be non-inferior to the Charite device in terms of pain reduction (VAS score) and FDA-defined clinical success at 24 months' follow-up. Both devices showed a high degree of safety. PMID- 25802678 TI - Effects of preoperative education on spinal surgery patients. AB - BACKGROUND: Preoperative patient education (PE) has been used by many institutions to deal with patient anxiety, pain control, and overall satisfaction. Although the literature suggests PE's effectiveness in joint reconstruction, data are missing in spinal surgery. METHODS: We retrospectively analyzed patients having elective spinal surgery who underwent PE (spine pre-care class) from October 2009 to March 2010. Of the 155 patients surveyed, 77 (49.7%) attended the class whereas 78 (50.3%) did not. RESULTS: Of the participants in the pre-care class, 96% were satisfied with their pain management versus 83% in the control group (P =.02). There was also a trend for better overall satisfaction in the pre-care class group (91% vs 85%; P > .05, multiple regression analysis). Elderly women tend to be less satisfied with pain management and overall treatment. CONCLUSIONS: Implementation of PE has had a positive impact on patient satisfaction, especially in terms of pain management. PMID- 25802677 TI - Vertebral augmentation treatment of painful osteoporotic compression fractures with the Kiva VCF Treatment System. AB - BACKGROUND: Vertebral compression fractures (VCFs) can cause significant pain and functional impairment, and their cumulative effect can lead to progressive morbidity. This single-arm, prospective feasibility trial, conducted at 4 clinical sites, was undertaken to evaluate the clinical outcomes associated with the use of an innovative vertebral augmentation device, the Kiva VCF Treatment System (Benvenue Medical, Santa Clara, California), in the management of symptomatic VCFs associated with osteoporosis. METHODS: Vertebral augmentation treatment was performed for persistent back pain symptoms in 57 patients (mean age, 71.9 +/- 10.4 years), including 46 women, with radiologically confirmed VCFs; 36 of these patients (63%) had reached 12 months of follow-up at this data analysis. There were 51 one-level cases, 5 two-level cases, and 1 three-level case, representing 64 treated levels. Back pain severity and condition-specific functional impairment were evaluated with a standard 100-mm visual analog scale and the Oswestry Disability Index (ODI), respectively, before device implantation as well as at 6 weeks, 3 months, and 12 months. RESULTS: Marked clinical improvements were realized in back pain severity and functional impairment through 12 months of follow-up. The mean back pain score on the visual analog scale improved from 79.3 +/- 17.2 before treatment to 21.9 +/- 21.3, 21.9 +/- 24.6, and 23.2 +/- 23.3 at 6 weeks, 3 months, and 12 months, respectively. The mean decrease at 12 months was 49.9 +/- 30.3 mm, or approximately 66% (P < .0001). Similarly, the mean ODI score improved from 68.1% +/- 16.9% before treatment to 27.4% +/- 17.2%, 23.8% +/- 18.7%, and 23.3% +/- 15.5% at 6 weeks, 3 months, and 12 months, respectively, representing a mean change of 39.2 +/- 19.6 percentage points, or approximately 63%, at 12 months. Overall clinical success rates based on a 30% improvement in pain severity or greater and maintenance or improvement in the ODI were 91%, 88%, and 89% at 6 weeks, 3 months, and 12 months, respectively. The vertebral augmentation procedure required injection of a mean of 2.2 +/- 0.12 mL of cement per vertebral body. There were 5 levels (8%) where cement extravasation was identified radiographically, and none were related to clinical symptoms. CONCLUSIONS: These pilot findings are encouraging, suggesting robust and durable clinical improvement after this novel vertebral augmentation procedure in patients with painful VCFs. PMID- 25802680 TI - Response to editorial regarding a novel surgical treatment option in which posterior dynamic stabilization is used to correct coronal plane tilt of a lumbar total disc replacement. PMID- 25802679 TI - An attempt at clinically defining and assessing minimally invasive surgery compared with traditional "open" spinal surgery. AB - BACKGROUND: The goal of this editorial and literature review is to define the term "minimally invasive surgery" (MIS) as it relates to the spine and characterize methods of measuring parameters of a spine MIS technique. METHODS: This report is an analysis of 105,845 cases of spinal surgery in unmatched series and 95,161 cases in paired series of open compared with MIS procedures performed by the same surgeons to develop quantitative criteria to analyze the success of MIS. RESULTS: A lower rate of deep infection proved to be a key differentiator of spinal MIS. In unmatched series the infection rate for 105,845 open traditional procedures ranged from 2.9% to 4.3%, whereas for MIS, the incidence of infection ranged from 0% to 0.22%. For matched paired series with the open and MIS procedures performed by the same surgeons, the rate of infection in open procedures ranged from 1.5% to 10%, but for spine MIS, the rate of deep infection was much lower, at 0% to 0.2%. The published ranges for open versus MIS infection rates do not overlap or even intersect, which is a clear indication of the superiority of MIS for one specific clinical outcome measure (MIS proves superior to open spine procedures in terms of lower infection rate). CONCLUSIONS: It is difficult, if not impossible, to validate that an operative procedure is "less invasive" or "more minimally invasive" than traditional surgical procedures unless one can establish a commonly accepted definition of MIS. Once a consensus definition or precise definition of MIS is agreed upon, the comparison shows a higher infection rate with traditional spinal exposures versus MIS spine procedures. PMID- 25802684 TI - Hospitalization as a teachable moment for cigarette smoking cessation. PMID- 25802681 TI - Influence of vitamin C supplementation on oxidative stress and neutrophil inflammatory response in acute and regular exercise. AB - Exercise induces a multitude of physiological and biochemical changes in blood affecting its redox status. Tissue damage resulting from exercise induces activation of inflammatory cells followed by the increased activity of myeloperoxidase (MPO) in circulation. Vitamin C readily scavenges free radicals and may thereby prevent oxidative damage of important biological macromolecules. The aim of this study was to examine the effect of vitamin C supplementation on oxidative stress and neutrophil inflammatory response induced by acute and regular exercise. Experiment was conducted on acute exercise group (performing Bruce Treadmill Protocol (BTP)) and regular training group. Markers of lipid peroxidation, malondialdehyde (MDA), MPO activity, and vitamin C status were estimated at rest and after BTP (acute exercise group) and before and after vitamin C supplementation in both groups. Our results showed increased postexercise Asc in serum independently of vitamin supplementation. They also showed that vitamin C can significantly decrease postexercise MDA level in both experimental groups. Increased postexercise MPO activity has been found in both groups and was not affected by vitamin C supplementation. We concluded that vitamin C supplementation can suppress lipid peroxidation process during exercise but cannot affect neutrophil inflammatory response in either exercise group. PMID- 25802683 TI - Urinary F2-isoprostanes and metabolic markers of fat oxidation. AB - Metabolomic studies of increased fat oxidation showed increase in circulating acylcarnitines C2, C8, C10, and C12 and decrease in C3, C4, and C5. We hypothesize that urinary F2-isoprostanes reflect intensity of fatty acid oxidation and are associated with circulating C2, C8, C10, and C12 directly and with C3, C4, and C5 inversely. Four urinary F2-isoprostane isomers and serum acylcarnitines are quantified using LC-MS/MS within the Insulin Resistance Atherosclerosis Study nondiabetic cohort (n = 682). Cross-sectional associations between fasting urinary F2-isoprostanes (summarized as a composite index) and the selected acylcarnitines are examined using generalized linear models. F2 isoprostane index is associated with C2 and C12 directly and with C5 inversely: the adjusted beta coefficients are 0.109, 0.072, and -0.094, respectively (P < 0.05). For these acylcarnitines and for F2-isoprostanes, the adjusted odds ratios (ORs) of incident diabetes are calculated from logistic regression models: the ORs (95% CI) are 0.77 (0.60-0.97), 0.79 (0.62-1.01), 1.18 (0.92-1.53), and 0.51 (0.35-0.76) for C2, C12, C5, and F2-isoprostanes, respectively. The direction of the associations between urinary F2-isoprostanes and three acylcarnitines (C2, C5, and C12) supports our hypothesis. The inverse associations of C2 and C12 and with incident diabetes are consistent with the suggested protective role of efficient fat oxidation. PMID- 25802685 TI - The cost of postgraduate medical education and continuing medical education: re examining the status fifty years back. AB - The subject of the cost and value of medical education is becoming increasingly important. However, this subject is not a new one. Fifty years ago, Mr. DH Patey, Dr. OF Davies, and Dr. John Ellis published a report on the state of postgraduate medical education in the UK. The report was wide-ranging, but it made a considerable mention of cost. In this short article, I have presented the documentary research that I conducted on their report. I have analyzed it from a positivist perspective and have concentrated on the subject of cost, as it appears in their report. The authors describe reforms within postgraduate medical education; however, they are clear from the start that the issue of cost can often be a barrier to such reforms. They state the need for basic facilities for medical education, but then outline the financial barriers to their development. The authors then discuss the costs of library services for education. They state that the "annual spending on libraries varies considerably throughout the country." The authors also describe the educational experiences of newly graduated doctors. According to them, the main problem is that these doctors do not have time to attend formal educational events, and that this will not be possible until there is "a more graduated approach to responsible clinical work," something which is not possible without financial investment. While concluding their report, the authors state that the limited money invested in postgraduate medical education and continuing medical education has been well spent, and that this has had a dual effect on improving medical education as well as the standards of medical care. PMID- 25802682 TI - The loss of cellular junctions in epithelial lung cells induced by cigarette smoke is attenuated by corilagin. AB - Cigarette smoke (CS) contains over 4700 compounds, many of which can affect cellular redox balance through free radicals production or through the modulation of antioxidant enzymes. The respiratory tract is one of the organs directly exposed to CS and it is known that CS can damage the integrity of lung epithelium by affecting cell junctions and increasing epithelium permeability. In this study, we have used a human lung epithelial cell line, Calu-3, to evaluate the effect of CS on lung epithelial cell junctions levels, with special focus on the expression of two proteins involved in intercellular communication: connexins (Cx) 40 and 43. CS exposure increased Cx40 gene expression but not of Cx43. CS also induced NFkappaB activation and the formation of 4HNE-Cxs adducts. Since corilagin, a natural polyphenol, is able to inhibit NFkappaB activation, we have determined whether corilagin could counteract the effect of CS on Cxs expression. Corilagin was able to diminish CS induced Cx40 gene expression, 4HNE-Cx40 adducts formation, and NFkappaB activation. The results of this study demonstrated that CS induced the loss of cellular junctions in lung epithelium, possibly as a consequence of Cx-4HNE adducts formation, and corilagin seems to be able to abolish these CS induced alterations. PMID- 25802686 TI - Results of an inpatient smoking cessation program: 3-month cessation rate and predictors of success. AB - BACKGROUND: Hospitalization presents smokers with an opportunity to initiate smoking cessation. We studied the effect of inpatient counseling and follow-up after discharge on smoking cessation and assessed predictors of successful cessation. METHODS: This study included a total of 125 patients (118 male and 7 female) who were admitted to departments of neurology, cardiology, and pulmonology. They were referred to the smoking cessation clinic, and participated between September 2011 and February 2013. A counseling service lasting about thirty minutes was provided by the third-year family medicine residents during hospitalization. The follow-up counseling services, which were either by telephone or in-person physician counseling were provided at 1 week, 4 weeks, and 3 months. Smoking habits and nicotine dependency data were gathered using questionnaires, and patient information was collected from electronic medical records. RESULTS: The average age in the study was 57.9 +/- 10.2 years and duration of smoking was 35.9 +/- 11.7 years. Daily tobacco consumption was 23.5 +/- 13.2 cigarettes. The smoking cessation rate after 3 months was 42.4%. The only differences between patients in the successful cessation and failed groups were cause of admission (P = 0.039) and total number of counseling sessions after discharge (P < 0.001). In a multivariate analysis, smoking cessation was more likely when patients experienced more instances of follow-up after discharge (1-2 visits: odds ratio [OR], 8.186; 95% confidence interval [CI], 1.060 to 63.239; >=3 visits: OR, 121.873; 95% CI, 14.462 to 1,027.055). CONCLUSION: Smoking cessation counseling during hospitalization and further follow-up by telephone or outpatient counseling after discharge contributed to an increased smoking cessation rate. The smoking cessation rate also tended to increase with total counseling numbers. PMID- 25802687 TI - Association between Metabolic Syndrome and Microalbuminuria in Korean Adults. AB - BACKGROUND: We conducted a population-based cross-sectional study of Korean adults to evaluate the association between metabolic syndrome and microalbuminuria as a marker for early-stage chronic kidney disease. METHODS: A total of 8,497 adults (3,625 men and 4,872 women) who participated in the Korea National Health and Nutrition Examination Survey between 2011 and 2012 were included. Metabolic syndrome was defined according to recommendation from a joint interim statement of international organizations published in 2009. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio of 30 to 300 mg/g. The association between metabolic syndrome and microalbuminuria was evaluated using logistic regression analysis with adjustment for covariates while considering sampling weights and the complex survey design. RESULTS: The prevalence of microalbuminuriain subjects with metabolic syndrome was 11% for men and 14.4% for women, whereas the prevalence in subjects without metabolic syndrome was 3.1% for men and 6.7% for women. Metabolic syndrome was significantly associated with an increased risk of microalbuminuriain both women (odds ratio, 2.79; 95% confidence interval, 2.01 to 3.88) and men (odds ratio, 3.00; 95% confidence interval, 2.11 to 4.27). All components of the metabolic syndrome were associated with a significantly increased risk of microalbuminuria with the strongest association for high blood pressure. The risk of microalbuminuria increased in a dose-dependent manner (P-value for trend < 0.001) with the number of metabolic syndrome components observed for both sexes. CONCLUSION: These findings suggest that metabolic syndrome is a risk factor for chronic kidney disease from an early stage. PMID- 25802688 TI - Weight Control Methods Related to Cotinine-Verified Smoking among Korean Adult Women: Korea National Health and Nutrition Examination Survey, 2008-2011. AB - BACKGROUND: Korean women are known to have a very low smoking rate. However, the actual smoking rate among Korean women is higher than 10% and may continue to increase gradually. In addition, some Korean women use extreme weight control methods that have potentially harmful effects. This study was conducted to elucidate weight control methods related to cotinine-verified smoking among Korean adult women. METHODS: This cross-sectional study involved 4,189 women aged >=19 years who had attempted weight control during the past 1 year from the Korea National Health and Nutrition Examination Survey, 2008-2011. Smoking status was assessed using both self-report questionnaires and assays of urinary cotinine, and weight control methods were investigated using self-report questionnaires. RESULTS: The smoking rate based on the measurement of urinary cotinine was 12.4% +/- 0.8% among Korean women. Cotinine-verified smokers were more likely to attempt fasting (odds ratio, 2.19; 95% confidence intervals, 1.03 to 4.67), taking prescription diet-pills (odds ratio, 2.37; 95% confidence intervals, 1.47 to 3.82), and taking nonprescription diet-pills (odds ratio, 3.46; 95% confidence intervals, 1.71 to 6.98), and were less likely to attempt eating less food or modifying dietary patterns (odds ratio, 0.71; 95% confidence intervals, 0.51 to 0.99) compared to non-smokers. CONCLUSION: Korean adult women's smoking is independently related to a high likelihood of using weight control methods with potentially harmful effects, such as fasting and taking diet-pills, and a low likelihood of choosing weight control methods, including dietary modification, that require constant effort for a prolonged time. PMID- 25802689 TI - Suicidal ideation in underweight adults who attempt to lose weight: Korea national health and nutrition examination survey, 2007-2012. AB - BACKGROUND: Being underweight has been related to health risks. However, little is known about the relationship between suicidal ideation and attempting to lose weight. This study was conducted to examine if there is an association between suicidal ideation and attempting to lose weight among underweight adults. METHODS: A cross-sectional study of 1,122 underweight adults (range, 19 to 69 years) was conducted based on the Korea National Health and Nutrition Examination Survey, 2007-2012. We examined suicidal ideation, doctor-diagnosed depression, depressive mood, stress, physical activity, health-related behavior, comorbidity, and socioeconomic status by weight loss attempts. Logistic regression analysis was performed to examine the association between suicidal ideation and weight loss attempts. The following covariates were controlled for: age, sex, physical activity, alcohol problem, marital status, education, income, occupation, self perception of body image, chronic disease, and body mass index. RESULTS: There were 101 subjects in the weight loss attempt group and 1,021 in the non-attempt group. The attempt group had a higher risk of suicidal ideation (odds ratio [OR], 2.47; 95% confidence interval [CI], 1.35 to 4.53) and depressive symptoms (OR, 2.17; 95% CI, 1.19 to 3.98). After depressive symptoms were added to the covariates, the risk of suicidal ideation was also significant (OR 2.11, 95% CI: 1.03 to 4.35). The two groups did not significantly differ in doctor-diagnosed depression and stress. CONCLUSION: Weight loss attempts were associated with suicidal ideation in underweight Korean adults. PMID- 25802690 TI - The Relationship between a Spouse's Alcohol Use Disorder and Family Communication. AB - BACKGROUND: Alcohol use disorder (AUD) affects not only an individual's health but also their family. This study was conducted to examine effects of a spouse's AUD on family functioning and family communication. METHODS: We conducted a cross sectional study using data from 890 participants (445 couples) in a Korean family cohort in primary care. Participants with Alcohol Use Disorders Identification Test in Korea scores of 8 or greater were classified into an AUD group. Family functioning was classified into three groups (balanced, midrange, and extreme) using the Family Adaptability and Cohesion Scale (FACES)-III questionnaire, and then reclassified into two groups (appropriate and extreme groups) for binominal analyses. Family communication was classified into three groups (high, moderate, and low) using the Family Communication Scale, FACES-IV, and also reclassified into two groups (good and poor). RESULTS: There was no significant difference in adaptability and cohesion between both male and female participants with a spouse with AUD and participants with a spouse without AUD. Using multivariate logistic regression to adjust for potential confounders, there was no significant difference in family type and communication between the two groups in males. However, there was a significant decrease in family communication (odds ratio, 2.14; 95% confidence interval, 1.29 to 3.58) in females with a spouse with AUD compared to females with a spouse without AUD, even after adjusting for the participant's own AUD. CONCLUSION: In females, family communication is significantly worse when spouses have AUD. This suggests that a husband's alcohol consumption has negative effects on his wife's family communication. PMID- 25802691 TI - Changes in the degree of patient expectations for patient-centered care in a primary care setting. AB - BACKGROUND: To date, the medical environment has been undergoing continual changes. It is therefore imperative that clinicians recognize the changing trends in the degree of patient expectations for patient-centered care. We conducted this study to examine changes in the degree of patient expectations for patient centered care and the related socio-demographic factors in a primary care setting over a 5-year period. METHODS: We evaluated patients' attitudes toward patient centered care using the Patient-Practitioner Orientation Scale, which provides 'sharing' and 'caring' scores. The study included 359 and 468 patients in phase I (March-July, 2005) and II (March-July, 2010). We also examined the relationship of their changes to their socio-demographic factors. RESULTS: In phase II, as compared with phase I, the 'sharing' score was higher (3.67 +/- 0.68 vs. 3.82 +/- 0.44; P < 0.001) and 'caring' one was lower (4.01 +/- 0.57 vs. 3.67 +/- 0.58; P = 0.001). Further, 'sharing' and 'caring' scores were associated with age, monthly income, education level, marital status, and the functional health status of patients. CONCLUSION: These results would be of help for providing patient centered care for patients because it makes clinicians are aware of the degree to which patients' expect it. PMID- 25802692 TI - Great toenail dystrophy: a single-center experience and review of the literature. AB - BACKGROUND: There have been a few reported cases of congenital great toenail dystrophy (GTND), described as a congenital malalignment of the great toenails. However, acquired GTDN is rare, and has not been documented extensively. This study aimed to describe the clinical features of 21 patients with acquired GTND. METHODS: Twenty-one patients with acquired GTND who visited Yeouido St. Mary's Hospital between June 2005 and August 2012 were retrospectively reviewed. RESULTS: The mean patient age was 43.1 years (range, 17 to 88 years), and the cohort predominantly comprised women (18/21). In our experience, all acquired GTND patients presented with yellow or yellow-brownish chromonychia, onychotrophy, and onycholysis. Conservative treatment with tape methods and grinding, as well as nail extraction, was provided and yielded little improvement in any case. CONCLUSION: This study provides initial data on the nail changes affecting the great toenail, such as yellowish chromonychia, onychomadesis, and onycholysis. These data may help physicians to distinguish various nail disorders, including onychomycosis, congenital malalignment of the great toenails, and yellow nail syndrome. PMID- 25802693 TI - Presence of both Mesenchymal and Carcinomatous Features in an In-vitro Model of Ovarian Carcinosarcoma Derived from Patients' Ascitic Fluid. AB - We have refined the technique for isolating and propagating cultures of primary ovarian carcinosarcoma cells (OSCs) derived from ascites, which allowed the cells to obtain the biphasic features of carcinosarcoma in cell culture conditions (presence of both carcinoma and mesenchymal morphologic types). This protocol involves a simple yet rapid method for the growth and propagation of ascites OSC in a basal culture medium. Autologous ascitic fluid was used as source of growth factors, and minimal manipulation was involved to establish the culture. The methodology allowed for the direct application of multiple molecular, cellular, and functional analyses within a few weeks of initial cell isolation, with the further potential of retrospective analyses of archived cells and tissues. PMID- 25802694 TI - Erythrocyte indices in Pre-school Nigerian Children with Sickle Cell Anaemia in Steady State. AB - BACKGROUND: Sickle cell disease is a genetic haemoglobinopathy with consequent haemolysis and anaemia. It is of interest to study its effect on red cell indices beside haemoglobin concentration. OBJECTIVES: The objective of the study is to determine the values of red cell indices in preschool-age children with sickle cell anaemia. METHODS: we conducted a cross-sectional study including 97 children with sickle cell anaemia aged six months to five years and 97 age-and sex-matched healthy controls with haemoglobin genotype AA (Hb AA). The red cell indices such as packed cell volume, haemoglobin concentration, mean corpuscular volume, red blood cell count, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration were investigated, using an auto analyzer. RESULTS: The mean PCV, haemoglobin concentration and red blood cell count were significantly higher in HbAA controls (p = 0.000 in each case). The mean MCV was higher among HbSS subjects but it was only among females and when the result was analyzed irrespective of gender that the difference was statistically significant (p < 0.05). CONCLUSION: Children with sickle cell anaemia in steady state have lower values of all red cell parameters and higher values of MCV, compared to haemoglobin phenotype AA controls. PMID- 25802695 TI - GDP versus ESHAP Regimen in Relapsed and/or Refractory Hodgkin lymphoma: A Comparison Study. AB - BACKGROUND: Despite multiple published studies reporting result of salvage regimens for relapsed and refractory Hodgkin's lymphoma, there are no comparisons of different combinations. PATIENTS AND METHODS: A Total of 44 patients identified with refractory or relapsed Hodgkin's Lymphoma were considered eligible for this study. The Patients were randomly divided into two groups of 22, one of which were treated with GDP regimen (gemcitabine, dexamethasone and cisplatin) and the other with EHSAP regimen (etoposide, methyl prednisolone, cisplatin and cytarabine) in a prospective manner. The results of each group were compared. RESULTS: There were 27.3% complete response, 31.8% more than 50% response, and 40.9% no response with GDP. ESHAP results were 29.5%, 24% and 45.5%, respectively. CONCLUSION: There is no significant difference in response rate between GDP and ESHAP regimens as salvage chemotherapy in refractory or relapsed Hodgkin's Lymphoma. PMID- 25802696 TI - Study of SFRP1 and SFRP2 methylation status in patients with de novo Acute Myeloblastic Leukemia. AB - INTODUCTION: Acute myeloid leukemia (AML) is a heterogeneous group of hematologic malignancies with abundant changeability in the pathogenesis. DNA methylation of CpG islands within the promoters of specific genes may play roles in tumor initiation and progression. Secreted frizzled-related proteins (SFRPs) are negative regulator of the Wnt signaling pathway. In the present study, we examined the methylation status of SFRP1 and SFRP2 genes in patients with AML. METHODS: Isolated DNA from peripheral blood of 43 AML patients and 25 healthy subjects as a control group was treated with sodium bisulfite was treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction (MSP) with primers specific for methylated and unmethylated promoter sequences of the SFRP1 & -2 genes. We used Mann-Whitney u-tests to investigate the correlation between SFRP1 and SFRP2 genes hypermethylation and clinical parameters. RESULTS: The frequency of aberrant hypermethylation of SFRP1 and SFRP2 genes in patients with AML was determined 30.2% (13/43) and 20.9% (9/43), respectively. In addition, for all subjects in control group, methylation of SFRP1 and SFRP2 genes were negative. Patients with M0 subtype of FAB-AML had the highest incidence of hypermethylation of SFRP1 (P = 0.028) and SFRP2 (P = 0.004). CONCLUSION: The present study showed that, like many solid tumors, methylation of SFRP genes also occurs in AML. Therefore, the methylation of these genes may play a role in the initiation of leukmogenesis. PMID- 25802697 TI - Inflammatory Rheumatologic disorders in patients with Myelodysplastic Syndromes: A cross-sectional study. AB - BACKGROUND: The aim of this study was to determine the prevalence and characteristics of rheumatologic manifestations associated with MDS. METHODS: Eighty patients with MDS were evaluated by history and physical examination for inflammatory rheumatologic disorders from Jan 2013 to May 2014. Patients who had any signs or symptoms of rheumatologic disorders underwent evaluation by laboratory tests. Patients with and without inflammatory rheumatic disorders were compared for their characteristics. RESULTS: Of 80 participants with MDS, 9 (11.3%) patients were diagnosed as having rheumatic disorders. MDS patients with or without rheumatologic disorder were similar in demographic and hematologic parameters, except age which was lower in patients with rheumatologic disorders. (p=0.016). In younger patients, refractory cytopenia and refractory cytopenia with multilinage dysplasia were more prevalent. CONCLUSION: The findings of this study indicate that rheumatologic manifestations may be present in MDS patients. Younger patients are more prone to the occurrence of MDS and rheumatic disorders. PMID- 25802698 TI - Outcome of rapamycin therapy for post-transplant-lymphoproliferative disorder after kidney transplantation: case series. AB - BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are a complication of chronic immunosuppressive therapy in solid organ transplantation with a high mortality rate. Alternative treatments such as rapamycin have been explored. METHODS: A detailed retrospective analysis was performed according to data collected from 13 patients with PTLD. At the time of PTLD diagnosis, immunosuppressive therapy was decreased and rapamycin administered. Overall survival, disease-free survival of patients and graft survival were determined. RESULTS: Among 590 kidney transplant recipients, 13 adult patients with PTLD were included in this study. The mean age of the patients was 42.15 (range: 25-58) years at the time of PTLD diagnosis, and 9 patients were male. Histology was distributed in 9 diffuse large B cell, 1 Malt lymphoma, 1 Burkitt lymphoma, 2 Hodgkin-like PTLD. The response rate to rapamycin alone was 30.8%. The mean overall survival period was 23.38 months and 11 patients are still alive. In total, 10 patients (76.9%) achieved a complete remission with functioning graft in 11 (84.6%) patients. CONCLUSION: Despite the retrospective focus and limited number of patients, this study provides promising results regarding the effectiveness of stopping calcineurin inhibitors and switching to rapamycin for patients with PTLD. PMID- 25802700 TI - Myeloid Sarcoma of the peritoneum at older ages: A case report and review of literature. AB - Myeloid sarcoma or granulocytic sarcoma (GS) is a rare disease with poor prognosis. It is characterized by the occurrence of tumor masses at an extra medullary tissue. It is composed of myeloblastic cells and usually occurs in association with acute myeloid leukemia. Because of its nonspecific clinical and radiologic findings, its diagnosis might be challenging. It might be more commonly found in patients with specific cytogenetic abnormalities, particularly with the t (8; 21) translocation and less frequently the inv (16) type. We report a case of GS in a 62 years old man without particular previous pathologies, which brutally presented as an ascites and generalized edema. The laparoscopy showed involvement of greater omentum and peritoneum. The histologic examination of greater omentum showed granulocytic sarcoma. The bone marrow aspiration was normal. We started treatment of patient by standard acute myeloid leukemia's chemotherapy. PMID- 25802699 TI - Involvement of MicroRNA in T-Cell Differentiation and Malignancy. AB - MicroRNAs are 19-22 nucleotide RNAs involved in such important processes as development, proliferation, differentiation and apoptosis. Different miRNAs are uniquely expressed in lymphoid T cells, and play a role indevelopment and differentiation of various subtypes by targeting their target genes. Recent studies have shown that aberrant miRNA expression may be involved in T cell leukemogenesis and lymphogenesis, and may function as tumor suppressor (such as miR-451, miR-31, miR-150, and miR-29a) or oncogene (e.g. miR-222, miR-223, miR-17 92, miR-155). MiRNAs can be used as new biomarkers for prognosis and diagnosis or as an index of disease severity in T-cell leukemia and lymphoma. This article presents a review of studies in recent years on the role of miRNAs in T-cell development and their aberrant expression in pathogenesis of T-cell leukemia and lymphoma. Characterizing miRNAs can help recognize their role as new important molecules with prognostic and therapeutic applications. PMID- 25802702 TI - Identification of the serotypes of bacterial meningitis agents; implication for vaccine usage. AB - BACKGROUND AND OBJECTIVES: Bacterial meningitis is one of the most serious infections and should be treated as emergency. As it has significant morbidity and mortality throughout the world, every country should have precise information regarding the etiological agents of disease and populations at risk to design public health prevention strategy. In the present study in addition of evaluation of common etiological agents (Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae) in bacterial meningitis cases, we sero-grouped or serotyped the obtained agents in order to predict the usefulness of existing vaccines against bacterial meningitis. MATERIALS AND METHODS: Cerebrospinal fluid of 182 suspected meningitis patients were collected, from which 114 cases were approved by biochemical, microbiological and molecular tests as bacterial meningitis. The isolated bacteria were serogrouped or serotyped to determine the dominant serotypes. RESULTS: Streptococcus pneumoniae accounted for 36%, Haemophilus influenza for 26% and Neisseria meningitidis for 14% of cases. From 13 serogroups of N. meningitides the most frequent serogroups, were meningococcus group B (51%), C(24%) A (18%), Z(2%), W135 (1%) and 3% was not identified. In H. influenzae group only serotype b (100%) have been identified and in pneumococcal meningitis the most common serotype among our cases were 18C (44%) followed by14 (17%), 19A (13%), 6A (9%), 7F (4%), 4(3%), 3 (3%), 9V (2%), 8 (2%), 23f (2%), 5 (1%). CONCLUSION: Since there is no nationwide mass immunization program for common agents of bacterial meningitis in Iran, the result of this study can be used to improve the existing vaccines to cover the detected serotypes and consequently reduce the incidence of bacterial meningitis. PMID- 25802703 TI - Colonization of Mycoplasma hominis and Ureaplasma urealyticum in pregnant women and their transmission to offspring. AB - BACKGROUND AND OBJECTIVES: Mycoplasma hominis and Ureaplasma urealyticum are important opportunistic pathogens that cause urogenital infections and accelerated newborn delivery in pregnant women. Moreover genital mycoplasmas have been implicated in different neonatal diseases such as pneumonia, sepsis and meningitis. This study was conducted to find out the prevalence and transmission rate of these two organisms in pregnant women and their neonates. MATERIALS AND METHODS: Nasotracheal and pharyngeal specimens of 165 newborns hospitalized at Neonatal Intensive Care Unit (NICU) of Rasoul Akram Hospital (during 2010 - 2011) were assessed by PCR to detect M. hominis and U. urealyticum. Moreover, PCR of vaginal specimens from their mothers were obtained to determine the prevalence of these organisms in pregnant women and rate of transmission to their newborns. Data were analyzed using SPSS software. RESULTS: Totally, the results of PCR were positive in 33 newborns (20%). Vaginal colonization among the mothers was found to be 15% (25/165) for U. urealyticum and 15% (25/165) for M. hominis. The transmission rate to their infants was 72% and 60% for U. urealyticum and M. hominis, respectively. CONCLUSION: These data indicate that vertical transmission of mycoplasma and ureaplasma are prevalent in newborns. Since these organisms cause serious infections in neonates, it would be better to perform screening tests in pregnant women before the delivery in order to prevent transmission to neonates and consequent infections and morbidities among them. PMID- 25802701 TI - Penicillin-Resistant trend of Streptococcus pneumoniae in Asia: A systematic review. AB - The high prevalence of resistance to penicillin by Streptococcus pneumoniaeis considered as a great concern, particularly in Asian countries. The aim of this study was to investigate the changing trend of penicillin-resistant S. pneumoniae (PRSP) in Asia over a 20 years period. A review of the literature was conducted using the PubMed database, Google Scholar, Scopus, two Persian scientific search engines "Scientific Information Database" (www.sid.ir), and "Mag Iran" (www.magiran.com) through 1993 to 2013. Our study provides a unique chance to investigate the changing trend in PSSP in Asia over a 20 years period. Susceptibility rates among different centers in each country varied widely. In Malaysia, the PSSP rate decreased from 97.2% in 1995-1996 to 69% in 2000. In Singapore, PSSP levels decreased from 72.6% in 1997 to 30.5% in 2007-2008. In Iran, PSSP ranged from 0% to 100%. In Taiwan, the rate of PSSP was 60.3% in 1995 and <50% in other years. In Lebanon, the rate of PSSP was less than 50% (ranging from 30.1% to 50%) in all published data. In Hong Kong, the level of penicillin susceptibility decreased from 71.1% during 1993-1995 to less 42% in 2007. Continuous surveillance of resistance data from clinical isolates as well as implementation of strict infection control policies is recommended. More studies are needed for better evaluation PSSP rate in some Asian countries such as Vietnam, Singapore, Philippines, Pakistan, Nepal, Kuwait, Korea and Indonesia. PMID- 25802705 TI - Resistance of nanobacteria isolated from urinary and kidney stones to broad spectrum antibiotics. AB - BACKGROUND AND OBJECTIVE: Nanoscopic life forms called Nanobacteria or calcifying nanoparticles (CNP) are unconventional agents. These novel organisms are very small (0.1 to 0.5 microns) and possess unusual properties such as high resistance to heat and routine antimicrobial agents. Nanobacteria are 100 times smaller than bacteria and protected by a shell of apatite, so they could be as candidate for emerging and progress of in vivo pathological calcification. In this study, the inhibitory effect of broad-spectrum antibiotics on growth of these new forms of life has been investigated. MATERIAL AND METHODS: Powdered urinary and kidney stones were demineralized with HCl and neutralized with appropriate buffers and became filtered. Finally suspension was incubated in DMEM medium with Fetal Bovine Serum (FBS) and broad-spectrum antibiotics (100U/ml for penicillin and 100MUg/ml for streptomycin) for 60 days. RESULTS: In the presence of broad spectrum antibiotics, Scanning Electron Micrographs (SEM) showed a spherical shape of these nanobacteria. Also, Energy Dispersive X-ray spectroscopy (EDS) showed a pick for calcium and phosphor. Transmission Electron Microscopy (TEM) results illustrated cover around the nanobacteria. CONCLUSION: The growth of calcifying nanoparticles after adding the broad-spectrum antibiotics may be due to their apatite hard shells supporting them against penetration of the antibiotics. PMID- 25802704 TI - Shigella flexneri: a three-year antimicrobial resistance monitoring of isolates in a Children Hospital, Ahvaz, Iran. AB - BACKGROUND AND OBJECTIVES: Shigellosis is an acute gastroenteritis that is one of the most common causes of morbidity and mortality in children with diarrhea in developing countries. The purpose of this study was to describe the distribution of Shigella serogroups and serotypes and their antibacterial drug resistance profiles. MATERIALS AND METHODS: Fecal samples of all children suffering from shigellosis who had been admitted to Abuzar Children's Hospital in Ahvaz, southwestern Iran, from September 2008 to August 2010 were examined. Antibiotics susceptibility testing was performed according to the Kirby Bauer disk diffusion method. RESULTS: Shigella flexneri was the predominant serogroup and being identified in 87 isolates (49.8%). The most common S. flexneri serotypes were type 2 (57.5%) and type 1 (21.8%). High rates of resistance were observed to trimethoprime-sulfamethpxazole (85%) and ampicillin (87.5%). CONCLUSION: S. flexneri and its serotypes was the most frequently isolated Shigella species from southwest of Iran, Ahvaz. Identification of predominant S. flexneri serotypes in developing countries can help in prioritizing strategies such as development of effective vaccines. PMID- 25802707 TI - Isolation and molecular identification of biodegrading Mycobacteria from water supplies of Iranian hospitals. AB - BACKGROUND AND OBJECTIVES: Some microorganisms, mainly members of two genera including Pseudomonas and Mycobacterium, were found to be capable of transforming and degrading of polluting agents. We herein report the isolation of a few mycobacteria with the ability to biodegrade organic and inorganic compounds from water supplies of Iranian hospitals. MATERIALS AND METHODS: The water samples were collected from hospital water supplies. Isolation processes were done according to standard methods. The colonies were subcultured on Lowenstein-Jensen medium to obtain a pure culture. The identification and characterization of the isolates were based on conventional and molecular methods including direct sequence analysis of almost full length of 16S rRNA gene. RESULTS: The almost complete 16S rRNA gene sequences of the studied strains revealed that the isolates WP16, AW18-1 and AW18-3 were identified as M. fredriksbergense, AW18-2 as M. austroafricanum, AW27-2 as M. obuenseand AW27-6 as M. phocaicum.The relationship between our isolates and standard strains of Mycobacterium was supported by a phylogenetic tree of 16S rRNA gene. CONCLUSION: In the current study we were able to isolate and characterize six mycobacteria with capability of transforming and degrading polluting agents from Iranian hospital environments. This is indeed the first report on isolation and characterization of mycobacteria with degrading capability of polluting agents from Iranian hospitals. It can be considered as a pioneer study to open up a new horizon in the study of microbial diversity in Iran with an objective-based and applied approach to tackle environmental challenges. PMID- 25802706 TI - Isolation of Mycobacterium fortuitum from fish tanks in Alborz, Iran. AB - INTRODUCTION: Fish mycobacteriosis is caused by the non-tuberculous mycobacteria. Infected fish are normally the primary source of infection, although non tuberculous Mycobacteria can be found in the environment. The present study was designed to investigate the few recently found suspected cases of mycobacteriosis in Iranian ornamental fish tanks. MATERIALS AND METHODS: Pathological specimens including granolumas from autopsied fish were used to inoculate Lowenstein-Jensen medium. Genomic material was extracted from all acid-fast positive cultures. The mycobacterial identity of bacterial isolates was authenticated using a PCR assessment targeting a 543 bp-long stretch of 16Sr RNA gene. Further more, a PCR assessment targeting a 294 bp-long stretch of heat shock protein hsp65 was performed and the amplicons were sequenced to identify the isolates. RESULTS: Characteristic mycobacterial bacilli were identified both in light and fluorescent microscopy of bacterial culture from all the suspected specimens. PCR amplification of DNA templates from all isolates successfully resulted in production of the expected products. Existence of Mycobacterium fortuitum was confirmed by comparison analysis of nucleotide sequencing at hsp65 gene. CONCLUSION: The present work clearly shows mycobacteria are important in pathology of ornamental fish diseases. People who are keeping fish as pet in their homes should be cantioned about the bacterial contamination risks arise from close contact with exotic ornamental species of fish. PMID- 25802708 TI - Molecular typing of methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates from Shiraz teaching hospitals by PCR-RFLP of coagulase gene. AB - BACKGROUND AND OBJECTIVES: To investigate coagulase gene polymorphism of MRSA and MSSA isolates from Shiraz teaching hospitals from 2011 to 2012. MATERIALS AND METHODS: A total of 302 isolates of Staphylococcus aureus were collected from clinical specimens in three major teaching hospitals and confirmed on the basis of morphological characteristics and biochemical tests. The isolates were subjected to molecular typing on the basis of coagulase enzyme gene polymorphism by PCR-RFLP. RESULTS: There were 27 and 28 different RFLP patterns for AluI and HaeIII restriction enzymes respectively. This study showed that the discriminatory power of coagulase gene typing by Hae III enzyme was more than that of Alu I enzyme. CONCLUSION: PCR-RFLP method is rapid, reproducible, simple and efficient for typing Staphylococcus aureus isolated from clinical specimens. This study showed that Hae III discriminatory power is better than Alu I for typing Staphylococcus aureus isolates. PMID- 25802709 TI - Distribution of Malassezia species on healthy human skin in Bosnia and Herzegovina: correlation with body part, age and gender. AB - BACKGROUND AND OBJECTIVES: The genus Malasezia currently includes fourteen species that have been isolated from healthy and diseased human and animal skin. However, there were differences with respect to the species most commonly isolated, not only in patients with various skin diseases but also between healthy individuals. The aim of this study was to analyze the prevalence of Malassezia species from clinically normal skin of the scalp and trunk of healthy individuals and to examine if the range of species varies according to body site, gender and age. MATERIALS AND METHODS: The study was conducted at the Department of Dermatovenerology, University Clinical Center in Sarajevo, Bosnia and Herzegovina from December 2012 to May 2013. One hundred healthy men and women with no skin diseases and aged from <1 to 82 years were studied. The samples were obtained by scraping the skin surface from the upper and middle part of trunk and from scalps of all subjects and then incubated on modified Dixon agar. The yeasts isolated were identified by their morphological and physiological properties according to Guillot et al. method. RESULTS: M. sympodialis was the predominant species on trunk skin in older subjects, M. restricta on scalp skin in age groups 21-35 years, while M. globosa was identified as common species in adults (36-50 years), both from scalp skin and trunk skin. From the trunk skin M. furfur was the most frequent in children. CONCLUSION: This study confirmed that cutaneous Malassezia microbiota in healthy subjects varies by body part and age but not by gender. PMID- 25802710 TI - Comparison of salivary Candida profile in patients with fixed and removable orthodontic appliances therapy. AB - BACKGROUND AND OBJECTIVES: Long-term usage of fixed and removable orthodontic appliances creates a favorable environment for the augmentation of oral normal microflora particularly Candida species, which can increases the risk of periodontal lesions. The aim of this study was to assess quantitative and qualitative alterations in the carrier rate of Candida spp. after placement of fixed and removable orthodontic appliances on permanent dentition. MATERIALS AND METHODS: Patients enrolled in this study were children aged 7-18 years, who having fixed or removable orthodontic appliances, attended in orthodontics clinic for periodical provision. Six months after beginning of their orthodontic therapy, saliva samples were collected and cultured on Sabouraud dextrose agar for identification and enumerating of isolated Candida colonies. Candida species were identified using the germ tube test and API 20C AUX identification system. Data was analyzed with T-test and Chi square using SPSS 17 software. RESULTS: The average number of Candida colonies isolated from saliva in patients with fixed orthodontic was more than patients with removable appliance (P=0.001). Also frequency of non-albicans Candida species was higher in patients with fixed orthodontic appliances in compare with fixed group (p=0.001). CONCLUSIONS: The results suggest that fixed orthodontic appliances treatment promotes an increase in salivary Candida carriers particularly non-albicans Candida species in compare with removable ones. This can indicate a more cautious approach when providing fixed orthodontic treatments for immunocompromised children regarding the increased possibility of candidal infection. PMID- 25802711 TI - Effect of Rhus coriaria L. water extract on five common oral bacteria and bacterial biofilm formation on orthodontic wire. AB - BACKGROUND AND OBJECTIVES: Recently, use of herbal medicine and plant extracts as a substitute for commercially available chemical drugs for control of infectious diseases such as dental caries and periodontal disease has become increasingly popular. The present study was aimed to evaluate the effect of Rhus coriaria L. water extract on five common oral bacteria and bacterial biofilm formation on orthodontic wire. MATERIALS AND METHODS: For primary assessment of the antibacterial properties of Rhus coriaria L. water extract, the well-plate method in BHIA (Brain Heart Infusion Agar, Merck, Germany) medium was used Using macrodilution method, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the extract against each microorganism were determined. The effect of Rhus coriaria L. on bacterial biofilm formation on orthodontic wire was assessed using viable cell count in biofilm medium (BM) containing 3% sucrose. In the final phase, after fixation of samples in alcohol and glutaraldehyde, samples were prepared for SEM (Scanning Electron Microscopy) analysis. RESULTS: The diameter of the zone of growth inhibition was proportionate to the tested concentrations of the extract. The lowest MIC (0.390 mg/ml) and MBC (1.5 mg/ml ) of the Rhus coriaria L. were found to be against Streptococcus sobrinus ATCC 27607. Rhus coriaria L. water extract decreased bacterial biofilm formation on orthodontic wire at MIC and 1/8 of MIC by S. sanguinis ATCC 10556, S. sobrinus ATCC 27607, S. salivarius ATCC 9222, S. mutans ATCC 35608 and E. faecalis CIP 55142 by24.2%-43%, 68.5%-91.6%, 10.6%-79.1%, 22.2% 86.1% and 40.6%-76.4%, respectively. CONCLUSION: Based on the results, Rhus coriaria L. water extract had significant antibacterial properties against five common oral bacteria and was able to inhibit bacterial biofilm formation on orthodontic wire. Further investigations are recommended for widespread clinical use of this extract. PMID- 25802712 TI - Survey on O157:H7 enterohemorrhagic Escherichia coli (EHEC) in cattle in Golestan province, Iran. AB - BACKGROUND AND OBJECTIVES: A diverse group of Escherichia coli are known as enterohemorrhagic Escherichia coli (EHEC) including O157:H7 and non-O157 EHEC. Enterohemorrhagic strains are related to sever clinical conditions in humans including hemorrhagic colitis and hemolytic uremic syndrome, and most of the recorded outbreaks occurred due to O157: H7 E. coli. The aim of the present study was to investigate the presence of O157:H7 E. coli among healthy cattle in Golestan province. MATERIALS AND METHODS: Fecal samples were collected from 180 clinically healthy cattle in Golestan province. After primary enrichment, samples were streaked on sorbitol MacConkey agar supplemented with cefixime and potassium tellurite (CT-SMAC). Non-sorbitol fermenting (NSF) Escherichia coli isolates were subjected to serotyping using commercial O157 antisera and rfb O157 gene PCR. Isolates were additionally tested for major virulence factors of EHEC including stx1, stx2, eae and ehly by multiplex-PCR. RESULTS: Eighteen NSF isolates were recovered from CT-SMAC confirmed as E. coli in biochemical tests. None of the obtained isolates belonged to O157 serogroup. Overall, two isolates harbored the tested virulence genes; one isolate possessed stx2 and ehly, and the other one carried stx2, eae and ehly. CONCLUSION: The results of this study indicated that cattle in Golestan province could be the reservoir for non-O157 EHEC. PMID- 25802713 TI - Development of a PCR assay to detect mycoplasma contamination in cord blood hematopoietic stem cells. AB - BACKGROUND AND OBJECTIVES: Contamination of cell lines and biological products is one of the major problems of cell culture techniques. Rapid detection of mycoplasma contamination in cell culture is an important part of quality control standards in related laboratories. The aim of this study was to evaluate the efficacy of PCR in detection of myroplasma as contaminants in cell cultures and other biological products. METHOD: PCR assays were optimized for 16 S rRNA target gene. Also the utilized PCR method was evaluated in terms of sensitivity and specificity. Finally, a simple DNA extraction and PCR analysis of 164 cell culture of adipose tissue derived mesenchymal stem cells were performed. RESULTS: A 715 bp product was amplified and subsequently was confirmed by sequencing. The technique could detect 10 copies of the target DNA. No cross-reactivity with genomic DNA of other microorganisms was observed. CONCLUSIONS: The PCR technique in this study was based on 16S rRNA gene. It was highly sensitive and specific since it was able to detected Mycoplasma contamination in cell cultures. PMID- 25802714 TI - Phosphate solubilization characteristics of efficient nitrogen fixing soil Azotobacter strains. AB - BACKGROUND AND OBJECTIVES: Azotobacter is a diazotroph bacterium reported to possess various plant growth-promoting characteristics.The aim of this study was to isolate Azotobacter strains capable of fixing nitrogen and effectively hydrolyzing both organic and inorganic Pi compounds. MATERIALS AND METHODS: In this study, soil samples collected from a diverse range of slightly alkaline soil types were screened for Azotobacter isolates. The inorganic and organic phosphate solubilization potentials of twenty competent phosphate solubilizing Azotobacter isolates were assessed.Variations were noted in the solubilization potentials. RESULT: Three isolates, identified as Azotobacter vinelandii strains O2, O4 and O6, were able to fix atmospheric N2 effectively. The nitrogenase activity of these isolates ranged between 158.6 and 326.4 C2H4h(-1)vial(-1) (ethylene). Bacterial growth rates and phosphate solubilization activities were measured quantitatively under various environmental conditions. A close association was evident between phosphate solubilizing ability and growth rate as an indicator of active metabolism. All three phosphate solubilizing bacteria (PSB) were able to withstand temperature as high as 45 degrees C, high concentration of NaCl (upto 5%) and a wide range of initial pH from 5 to 10 while hydrolyzing phosphate compounds actively. CONCLUSION: Azotobacter vinelandii strains O2, O4 and O6 are superior candidates for biofertilizers that may result in the reduction of chemical nitrogen and phosphate fertilizers leading to increase crop production. PMID- 25802715 TI - Phytoplanktons and DNA barcoding: Characterization and molecular analysis of phytoplanktons on the Persian Gulf. AB - BACKGROUND AND OBJECTIVES: Phytoplanktons are organisms with a very high diversities and global distribution in different habitats. The high distribution of phytoplankton is due to ecological flexibility and their ability to tolerate different climatic conditions and environmental stress. Phytoplankton is the most sensitive biological indicators of water resources. The purpose of this study was to identify the phytoplankton species with emphasis on DNA bar-coding method. The study of phytoplankton variation and the identification of their species composition can provide useful information about the water quality. MATERIALS AND METHODS: In this research project, a clone library of the ribosomal small subunit RNA gene (18S rDNA) in the nuclear genome was constructed by PCR using A and SSU inR1 primers, and then, after examining the clones, selected clones were sequenced. RESULTS: Eleven analyzed sequences were identified correctly and characterized by a similarity search of the GenBank database using BLAST (NCBI). In this study, we revealed a wide range of taxonomic groups in the Alveolata (Ciliphora and Dinophyceae), Stramenopiles (Bacillariophyta and Bicosoecida), Rhodophyta and Haptophyceae. Moreover, we found species of fungi and Metazoa (Arthropoda). Most of the sequences were previously unknown but could still be assigned to important marine phyla. CONCLUSION: Clone library of 18S rDNA is an accurate method to identify marine specimens and it is recommended as an efficient method for phylogenic studies in marine environments. There seems to be a high diversity and abundance of small eukaryotes in the marine regions of Persian Gulf. PMID- 25802716 TI - New risk factors for obesity and diabetes: Environmental chemicals. PMID- 25802719 TI - Intracellular free fatty acid upholds beta-cell glucose competence: The role of peroxisome proliferator-activated receptor delta and mitochondrial metabolism. PMID- 25802718 TI - Present status of clinical deployment of glucokinase activators. AB - Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the beta-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of beta-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials. PMID- 25802720 TI - Mitochondrial reactive oxygen species in the pathogenesis of early diabetic nephropathy. PMID- 25802717 TI - Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence. AB - A significant proportion of patients with type 2 diabetes mellitus have a low testosterone level relative to reference ranges based on healthy young men. Only a small number of these patients suffer from classical hypogonadism as a result of recognizable hypothalamic-pituitary-gonadal axis pathology. The cut-off value of the serum testosterone level in men without obvious hypothalamic-pituitary gonadal axis pathology is controversial. It is unclear to what extent a low serum testosterone level causally leads to type 2 diabetes and/or the metabolic syndrome. From a theoretical standpoint, there can be complex interactions among the hypothalamic-pituitary-gonadal axis, body composition and insulin resistance, which can be further influenced by intrinsic and extrinsic factors to give rise to metabolic syndrome, glucose intolerance, and low-grade inflammation to increase the risk of cardiovascular disease. Although a low serum testosterone level frequently coexists with cardiometabolic risk factors and might serve as a biomarker, more studies are required to clarify the causal, mediating or modifying roles of low serum testosterone level in the development of adverse clinical outcomes. Currently, there are insufficient randomized clinical trial data to evaluate the effects of testosterone replacement therapy on meaningful clinical outcomes. The risk-to-benefit ratio of testosterone therapy in high-risk subjects, such as those with type 2 diabetes, also requires elucidation. The present article aims to review the current evidence on low serum testosterone levels in patients with type 2 diabetes, and its implications on cardiovascular risk factors, metabolic syndrome and adverse clinical outcomes. PMID- 25802722 TI - Heel bone strength is related to lifestyle factors in Okinawan men with type 2 diabetes mellitus. AB - AIMS/INTRODUCTION: Although male diabetic patients have an increased risk of fracture, there is little information about this in the literature. The association between heel bone stiffness and the lifestyle of male patients with diabetes was evaluated. MATERIALS AND METHODS: The study included 108 participants with type 2 diabetes mellitus patients and 168 age-adjusted, healthy male volunteers. None of the participants had a history of osteoporosis or other severe diseases. Heel bone stiffness was examined by quantitative ultrasound, and each participant completed a health interview survey questionnaire. Bone stiffness was taken as an indicator of bone strength. Stepwise regression analysis was used to investigate associations between bone stiffness and lifestyle-related factors, such as sunlight exposure, intake of milk or small fish, regular exercise, cigarette smoking, consumption of alcohol, and number of remaining teeth. RESULTS: Bone stiffness showed a significant negative association with cigarette smoking [standardized coefficient (SC) = -0.297, F value (F) = 10.059] and age (SC = -0.207, F = 7.565) in diabetic patients. Bone stiffness showed a significant negative association with age (SC = -0.371, F = 12.076) and height (SC = -0.193, F = 7.898), as well as a significant positive association with sunlight exposure (SC = 0.182, F = 9.589) and intake of small fish (SC = 0.170, F = 7.393) in controls. CONCLUSIONS: These findings suggest that cigarette smoking and age are negatively associated with bone stiffness in Okinawan male patients with type 2 diabetes mellitus. PMID- 25802723 TI - Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease. AB - AIMS/INTRODUCTION: To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease. MATERIALS AND METHODS: Liver biopsy specimens were obtained from 72 patients with non alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method. RESULTS: The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = -0.45, P < 0.001; grade r = -0.54, P < 0.001; stage r = -0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = -0.22, P < 0.05) and grade (coefficient = -0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = -0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = -0.62, P = 0.059). CONCLUSIONS: Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle. PMID- 25802721 TI - Therapeutic efficacy of bone marrow-derived mononuclear cells in diabetic polyneuropathy is impaired with aging or diabetes. AB - AIMS/INTRODUCTION: Recent studies have shown that cell transplantation therapies, such as endothelial precursor cells, bone marrow-derived mononuclear cells (BM MNCs) and mesenchymal stem cells, are effective on diabetic polyneuropathy through ameliorating impaired nerve blood flow in diabetic rats. Here, we investigated the effects of BM-MNCs transplantation in diabetic polyneuropathy using BM-MNCs derived from adult (16-week-old) diabetic (AD), adult non-diabetic (AN) or young (8-week-old) non-diabetic (YN) rats. MATERIALS AND METHODS: BM-MNCs of AD and AN were isolated after an 8-week diabetes duration. The BM-MNCs were characterized using flow cytometry analysis of cell surface markers and reverse transcription polymerase chain reaction of several cytokines. BM-MNCs or saline were injected into hind limb muscles. Four weeks later, the thermal plantar test, nerve conduction velocity, blood flow of the sciatic nerve and capillary-to muscle fiber ratio were evaluated. RESULTS: The number of CD29(+)/CD90(+) cells that host mesenchymal stem cells in BM-MNCs decreased in AD compared with AN or YN, and transcript expressions of basic fibroblast growth factor and nerve growth factor in BM-MNCs decreased in AD compared with AN or YN. Impaired thermal sensation, decreased blood flow of the sciatic nerve and delayed nerve conduction velocity in 8-week-diabetic rats were significantly ameliorated by BM-MNCs derived from YN, whereas BM-MNCs from AD or AN rats did not show any beneficial effect in these functional tests. CONCLUSIONS: These results show that cytokine production abilities and the mesenchymal stem cell population of BM-MNCs would be modified by aging and metabolic changes in diabetes, and that these differences could explain the disparity of the therapeutic efficacy of BM-MNCs between young and adult or diabetic and non-diabetic patients in diabetic polyneuropathy. PMID- 25802724 TI - Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study. AB - AIMS/INTRODUCTION: Recent data have shown that ectopic fat accumulation in the liver worsens hepatic glucose metabolism, suggesting that fatty liver in patients with type 2 diabetes is a therapeutic target. Glucagon-like peptide (GLP)-1 improves fatty liver, but the effect of dipeptidyl peptidase-4 inhibitor on fatty liver is still unclear. The present pilot study determined the effects of 12-week treatment with sitagliptin, a dipeptidyl peptidase-4 inhibitor, on liver fat content in type 2 diabetes with fatty liver. We also evaluated intramyocellular lipid (IMCL) and glucose kinetics during oral glucose tolerance test (OGTT) before and after the treatment. MATERIALS AND METHODS: The study participants were seven type 2 diabetes patients with fatty liver who were studied at baseline and 12 weeks after sitagliptin treatment. Intrahepatic lipid (IHL) and IMCL were assessed by (1)H magnetic resonance spectroscopy. Glucose kinetics was assessed during double-tracer OGTT (U-[(13)C]-glucose orally and 6,6-[(2)H2]-glucose intravenously). RESULTS: Sitagliptin significantly reduced glycated hemoglobin (from 7.1 +/- 0.2 to 6.5 +/- 0.3%, P < 0.005), but had no effects on IHL and IMCL. The glucose level diminished, whereas GLP-1 concentration increased during OGTT at the end of treatment. These changes were not accompanied by significant changes in insulin or glucagon levels. However, long-term sitagliptin treatment partially decreased the rate of appearance of oral glucose during OGTT, but did not affect endogenous glucose production or the rate of disappearance. CONCLUSIONS: It was found that 12-week sitagliptin treatment improved glycated hemoglobin and glucose excursion during OGTT in type 2 diabetes with fatty liver, independent of changes in lipid accumulation in the liver. This trial was registered with the Japan Clinical Trials Registry (UMIN-CTR000005666). PMID- 25802725 TI - Response to the dipeptidyl peptidase-4 inhibitors in Japanese patients with type 2 diabetes might be associated with a diplotype of two single nucleotide polymorphisms on the interleukin-6 promoter region under a certain level of physical activity. AB - AIMS/INTRODUCTION: Muscle-derived interleukin-6 (IL-6) has been reported to promote glucagon-like peptide-1 (GLP-1) secretion, and we explored the association of single nucleotide polymorphisms (SNPs) in the human IL-6 promoter region with the responsiveness to dipeptidyl peptidase-4 inhibitors (DPP-4Is), drugs that increase circulating GLP-1. MATERIALS AND METHODS: The present observational study enrolled Japanese patients with type 2 diabetes who took a DPP-4I over 3 months, and most of the clinical information was collected retrospectively. We defined non-responders as those having less than a 0.2% decrease of the glycated hemoglobin level at 3 or 4 months after starting DPP-4I treatment. Physical activity was retrospectively estimated by the Japanese short version of International Physical Activity Questionnaire. RESULTS: We studied 316 patients whose physical activity corresponding to the season of the DPP-4I administration was estimated. The non-responder rate was 29.7%. We analyzed rs1800796 and rs2097677, both are suggested to be functional in Japanese. Multivariate analysis for all patients showed that the adjusted odds ratio for the non-responder risk of the diplotype rs1800796 G/*-rs2097677 A/* against C/C G/G (OR_G*A*) was 0.445 (P = 0.068). When patients were stratified by the International Physical Activity Questionnaire into low (n = 149) and moderate/high (n = 167) activity groups, however, OR_G*A* in each group was 1.58 (P = 0.615) and 0.153 (P = 0.003), respectively. CONCLUSIONS: The diplotype rs1800796 G/*-rs2097677 A/* might contribute to responsiveness to DPP-4Is in Japanese patients with type 2 diabetes under a certain level of physical activity. However, further investigation is warranted to confirm this. PMID- 25802726 TI - Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone (Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1): A multicenter, randomized, open-label, non-inferiority trial. AB - AIMS/INTRODUCTION: To assess the efficacy and safety of sitagliptin compared with alpha-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. MATERIALS AND METHODS: In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20-79 years with type 2 diabetes who had glycated hemoglobin 6.9-8.8% on stable metformin (500-1,500 mg/day) or pioglitazone (15-30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an alpha-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. RESULTS: After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were -0.70% in sitagliptin and -0.21% in the alpha-glucosidase inhibitor groups respectively; between-group difference was -0.49% (95% confidence interval -0.66 to -0.32, P < 0.0001), meeting the predefined non-inferiority criterion (0.25%) and showing statistical significance. This statistical significance also continued after 24 weeks. Although sitagliptin did not affect bodyweight, alpha-glucosidase inhibitors decreased bodyweight significantly from baseline (-0.39 kg; P = 0.0079). Gastrointestinal disorders were significantly lower with sitagliptin than with an alpha-glucosidase inhibitor (6 [10.3%] patients vs 23 [39.7%]; P = 0.0003). Minor hypoglycemia occurred in two patients (3.5%) in each group. CONCLUSIONS: Sitagliptin showed greater efficacy and better tolerability than an alpha-glucosidase inhibitor when added to stable doses of metformin or pioglitazone. These findings support the use of sitagliptin in Japanese patients with type 2 diabetes inadequately controlled by insulin-sensitizing agents. This trial was registered with UMIN (no. 000004675). PMID- 25802727 TI - Vildagliptin vs liraglutide as a second-line therapy switched from sitagliptin based regimens in patients with type 2 diabetes: A randomized, parallel-group study. AB - INTRODUCTION: A step-up strategy for dipeptidyl peptidase (DPP)-4 inhibitor-based regimens has not yet been established. In addition, similarities and differences between DPP-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists remain to be elucidated in humans. We investigated the pleiotropic effects of vildagliptin vs liraglutide in patients with type 2 diabetes on sitagliptin-based regimens in an open-label, randomized, clinical trial. MATERIALS AND METHODS: A total of 122 patients with type 2 diabetes that was inadequately controlled by sitagliptin-based regimens were randomly assigned to either vildagliptin (50 mg, twice daily) or liraglutide treatment (0.9 mg, once daily) for 12 weeks. The primary outcomes were glycated hemoglobin and body mass index. RESULTS: Both vildagliptin and liraglutide significantly lowered glycated hemoglobin within 12 weeks after switching from sitagliptin, but liraglutide produced a greater reduction (-0.67 +/- 0.12% vs -0.36 +/- 0.53%). Liraglutide lowered body mass index, whereas vildagliptin did not affect body mass index. Vildagliptin lowered fasting C-peptide immunoreactivity, but liraglutide did not. Vildagliptin increased serum levels of adiponectin, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, whereas liraglutide had no effect on these levels. Quality of life, assessed using the diabetes treatment satisfaction questionnaire, was not impaired in either group. The most common adverse events were gastrointestinal symptoms, which occurred with similar frequencies in both groups. CONCLUSIONS: Vildagliptin-mediated improvements in glycemic control did not correlate with indices for insulin secretion and insulin sensitivity. Switching from sitagliptin to liraglutide is useful in managing hyperglycemia and weight. Each agent exerts unique pleiotropic effects. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. 000004953). PMID- 25802728 TI - Efficacy and safety of lixisenatide in Japanese patients with type 2 diabetes mellitus inadequately controlled by sulfonylurea with or without metformin: Subanalysis of GetGoal-S. AB - AIMS/INTRODUCTION: This was a subanalysis of Japanese patients included in the glucagon-like peptide-1 receptor agonist AVE0010 in patients with type 2 diabetes mellitus for glycemic control and safety evaluation (GetGoal-S) study - a 24 week, randomized, placebo-controlled study of lixisenatide in patients with type 2 diabetes mellitus inadequately controlled by sulfonylurea with or without metformin. MATERIALS AND METHODS: In GetGoal-S, 127 Japanese patients received the once-daily prandial glucagon-like peptide-1 receptor agonist lixisenatide 20 MUg/day or a matching placebo. The primary outcome was change in glycated hemoglobin. RESULTS: At week 24, lixisenatide significantly reduced mean glycated hemoglobin (least squares mean difference vs the placebo -1.1% [12 mmol/mol, P < 0.0001]), and significantly more lixisenatide patients reached glycated hemoglobin targets of <7% (53 mmol/mol) and <=6.5% (48 mmol/mol) vs the placebo. Lixisenatide produced statistically significant reductions in 2-h postprandial plasma glucose (least squares mean difference vs the placebo -8.51 mmol/L, P < 0.0001) and glucose excursion vs the placebo, and significantly reduced fasting plasma glucose (least squares mean difference vs the placebo -0.65 mmol/L, P = 0.0454). Bodyweight decreased with both lixisenatide and the placebo (least squares mean change -1.12 kg for lixisenatide, -1.02 kg for placebo). The overall incidence of adverse events was similar for lixisenatide and the placebo (84.2 and 82.4%, respectively), the most frequent being gastrointestinal disorders (52.6% for lixisenatide vs 29.4% for placebo). The incidence of symptomatic hypoglycemia was higher with lixisenatide vs the placebo (17.1 and 9.8%, respectively), with no cases of severe symptomatic hypoglycemia in either group. CONCLUSIONS: In the Japanese subpopulation of the GetGoal-S study, lixisenatide produced a significant and clinically relevant improvement in glycated hemoglobin, with a pronounced improvement in postprandial plasma glucose, and a good safety and tolerability profile. PMID- 25802729 TI - Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: A 52-week open label study. AB - AIMS/INTRODUCTION: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor under development for the treatment of type 2 diabetes. Our aim was to examine its efficacy and safety as monotherapy or in combination with commonly used oral antihyperglycemic drugs in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: Patients on diet/exercise alone or diet/exercise plus an oral antihyperglycemic drug (sulfonylurea, glinide, alpha-glucosidase inhibitor, biguanide, thiazolidinedione or dipeptidyl peptidase-4 inhibitor) were randomized to either 100 or 200 mg canagliflozin while continuing prior therapy. Patients were treated for 52 weeks in an open-label manner. RESULTS: Canagliflozin significantly reduced hemoglobin A1c, fasting plasma glucose and bodyweight in all the study groups. Improvements were apparent by 4 weeks of treatment, and were maintained for 52 weeks. The reduction in hemoglobin A1c ranged from -0.80 to -1.06%, and from -0.93 to -1.26% in the 100 and 200 mg canagliflozin groups, respectively. Drug-related adverse events occurred in approximately one-third of patients, and included hypoglycemia/asymptomatic hypoglycemia and pollakiuria. Hypoglycemia/asymptomatic hypoglycemia was most common in patients treated with a sulfonylurea. Most adverse events were classified as mild or moderate in severity. CONCLUSIONS: The results of the present study confirmed that treatment with canagliflozin resulted in significant reductions in glycemic control and bodyweight that were maintained for 52 weeks of treatment irrespective of whether it was administered as monotherapy or in combination with another oral antihyperglycemic drug. Canagliflozin was well tolerated, with a low incidence of drug-related adverse events. This trial was registered with ClinicalTrials.gov (no. NCT01387737). PMID- 25802731 TI - Cardiovascular autonomic function analysis using approximate entropy from 24-h heart rate variability and its frequency components in patients with type 2 diabetes. AB - AIMS/INTRODUCTION: The principal aim of the present study was to investigate the cardiovascular autonomic system status of diabetes patients using approximate entropy (ApEn) extracted from 24-h heart rate variability (HRV) and its frequency components. MATERIALS AND METHODS: A total of 29 healthy controls and 63 type 2 diabetes patients were included. Participants' 24-h HRV signals were recorded, and decomposed and reconstructed into four frequency components: high, low, very low and ultra low. The total 24-h HRV and its four components were divided into 24 1-h segments. ApEn values were extracted and statistically analyzed. Four traditional HRV indices, namely standard deviation of the RR intervals, root mean square of successive differences, coefficient of variance of RR intervals and ratio of low to high power of HRV, were also calculated. RESULTS: The low frequency component contained the most abundant non-linear information, so was potentially most suitable for studying the cardiovascular system status with non linear methods. ApEn values extracted from low- and high-frequency components of healthy controls were higher than those of diabetes patients. Except for root mean square of successive differences, standard deviation of the RR intervals, low to high power of HRV and coefficient of variance of RR intervals of healthy controls were all higher than those of diabetes patients. CONCLUSIONS: The results showed that ApEn contained information on disorders of autonomic system function of diabetes patients as traditional HRV indices in time and frequency domains. ApEn and three traditional indices showed accordance to some degree. Non linear information in subcomponents of HRV was shown, which is potentially more effective for distinguishing healthy individuals and diabetes patients than that extracted from the total HRV. Compared with diabetes patients, the cardiovascular system of healthy controls showed information of higher complexity, and better regulation function in response to changes of environment. PMID- 25802732 TI - Simple self-reported behavioral or psychological characteristics as risk factors for future type 2 diabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 14. AB - AIMS/INTRODUCTION: Depression, anger, sleep disorders and cognitive impairment are regarded as presenting a high risk for diabetes. We investigated whether responses to single statements on a self-report questionnaire on the presence of each of these four factors were associated with the development of type 2 diabetes. MATERIALS AND METHODS: We investigated 3,211 Japanese individuals without diabetes. Cumulative incidence rate and hazard ratios (HRs) for future type 2 diabetes over 7-13 years were evaluated according to the presence of lack of perseverance, anger, memory loss or sleep disorders. RESULTS: Results of Cox regression analysis showed that lack of perseverance (age- and sex-adjusted HR 1.41, 95% confidence interval 1.07-1.84), anger, (HR 1.51, 95% confidence interval 1.07-2.12) or memory loss (HR 1.47, 95% confidence interval 1.14-1.90) was predictive of the development of diabetes. Even after adjustment for metabolic factors including glycemic measurements, anger was significantly associated with an increased risk of future diabetes. Individuals with both anger and memory loss had a 1.94-fold (95% confidence interval 1.19-3.15) increased risk of type 2 diabetes than those without those two symptoms. CONCLUSIONS: Responses to a simple self-report questionnaire as to whether individuals were aware of anger or memory loss were associated with the development of type 2 diabetes independent of traditional risk factors for diabetes in this cohort of Japanese individuals. PMID- 25802730 TI - Combined use of basal insulin analog and acarbose reduces postprandial glucose in patients with uncontrolled type 2 diabetes. AB - AIMS/INTRODUCTION: Early initiation of basal insulin therapy is recommended for normalizing fasting blood glucose in type 2 diabetes mellitus. However, basal insulin treatment might not adequately control postprandial glucose levels. The present study evaluated whether the combination of the alpha-glucosidase inhibitor, acarbose, and basal insulin improved blood glucose control under daily life treatment conditions in a large sample of Korean patients. MATERIALS AND METHODS: The present study was a multicenter, prospective, observational study under daily-life treatment conditions. A total of 539 patients with type 2 diabetes who were treated with basal insulin and additional acarbose were enrolled and followed up for 20 weeks. Changes in hemoglobin A1c, fasting and postprandial blood glucose were evaluated at baseline and at the end of the observation period. The physician and patient satisfaction of the combination treatment and safety were assessed. RESULTS: Hemoglobin A1c decreased by 0.55 +/- 1.05% from baseline (P < 0.0001). Fasting and postprandial blood glucose levels were reduced by 0.89 +/- 3.79 and 2.59 +/- 4.77 mmol/L (both P < 0.0001). The most frequently reported adverse drug reactions were flatulence (0.37%) and abnormal gastrointestinal sounds (0.37%), and all were mild in intensity and transient. In the satisfaction evaluation, 79.0% of physicians and 77.3% of patients were 'very satisfied' or 'satisfied' with the combined basal insulin and acarbose therapy. CONCLUSIONS: Combination therapy of basal insulin and acarbose in patients with type 2 diabetes improved glucose control, and had no drug specific safety concerns, suggesting that the treatment might benefit individuals who cannot control blood glucose with basal insulin alone. PMID- 25802733 TI - A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy. AB - The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non diabetic kidney disease as being crucial in all stages of diabetic nephropathy. PMID- 25802735 TI - Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene. AB - BACKGROUND: Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5 hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF). METHODS: We sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis. RESULTS: The known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations. Upon analyzing over 15,000 normal control chromosomes, only SLC29A4 c.86A > G was found in 23 alleles (0.14%), while neither c.412G > A (<0.007%) nor c.978 T > G (<0.007%) were observed in all chromosomes analyzed, emphasizing the rareness of the three alterations. Expression of mutations PMAT p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP(+)), while mutation p.Asp29Gly had reduced transport activity only towards MPP(+). At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members. CONCLUSIONS: Our findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD. PMID- 25802736 TI - Heterogeneous responses and cross reactivity between the major peanut allergens Ara h 1, 2,3 and 6 in a mouse model for peanut allergy. AB - BACKGROUND: The relative contribution and the relation between individual peanut allergens in peanut allergic responses is still matter of debate. We determined the individual contribution of peanut proteins to B, T cell and allergic effector responses in a mouse model for peanut allergy. METHODS: Mice were immunized and challenged by oral gavage with peanut protein extract or isolated allergens Ara h 1, 2, 3 and 6 followed by assessment of food allergic manifestations. In addition, T cell responses to the individual proteins were measured by an in vitro dendritic cell-T cell assay. RESULTS: Sensitization with the individual peanut proteins elicited IgE responses with specificity to the allergen used as expected. However, cross reactivity among Ara h 1, 2, 3 and 6 was observed. T cell re-stimulations with peanut extract and individual peanut proteins also showed cross reactivity between Ara h 1, 2, 3 and 6. Despite the cross reactivity at the IgE level, only Ara h 2 and 6 were able to elicit mast cell degranulation after an oral challenge. However, after systemic challenge, Ara h 1, 2 and 6 and to lesser extent Ara h 3 were able to elicit anaphylactic responses. CONCLUSIONS: Ara h 1, 2, 3 and 6 sensitize via the intra-gastric route, but differ in their capacity to cause allergic effector responses. Interestingly, extensive cross reactivity at T cell and antibody level is observed among Ara h 1, 2, 3 and 6, which may have important implications for the diagnosis and therapy of peanut allergy. Awareness about the relative contribution of individual peanut allergens and cross reactivity between these allergens is of importance for current research in diagnostics and therapeutics for and the mechanism of peanut allergy. PMID- 25802738 TI - Burkholderia pseudomallei in cystic fibrosis and treatment complications. AB - A healthy 29-year-old Australian man with cystic fibrosis (CF) grew B urkholderia pseudomallei on a routine sputum culture 1 month after returning from holiday in Thailand. He underwent a 12-month treatment regime with multiple antibiotics resulting in a number of adverse events. Sputum cultures were cleared of the pathogen and remain negative 8 years post-treatment. There were no clinical sequelae and no deterioration in lung function. Few reports have been published to date on melioidosis in CF patients. The proposed management for this infection includes multiple antibiotics regimens for prolonged periods of time, which may result in adverse events. Optimal treatment and length of treatment are currently determined on an individual basis. PMID- 25802739 TI - Anaphylaxis caused by tipepidine hibenzate, a central antitussive drug. AB - Tipepidine hibenzate, a central antitussive drug, is widely used in the management of cough and is generally safe and well tolerated. We present here a case of anaphylaxis caused by this drug. When the patient had caught a cold over the previous 10 years, she had received medications, including tipepidine hibenzate, from her family doctor. However, this time, she developed dyspnea, skin eruption, and anaphylactic shock after taking a Chinese herbal medicine and this drug. After her conditions improved due to adequate treatment, she was referred to our hospital to confirm the causative drug. Double-blind placebo controlled oral challenge tests were performed after obtaining informed consent. Oral challenge with one-third tablet dose of tipepidine hibenzate caused a positive reaction. Urinary leukotriene E4 rose during the challenge with tipepidine hibenzate, but not with control. Clinicians should keep in mind that common antitussive drug use can cause anaphylactic reactions in very rare cases and can be harmful. PMID- 25802737 TI - Clinical examination findings as prognostic factors in low back pain: a systematic review of the literature. AB - BACKGROUND: There is a strong tradition of performing a clinical examination of low back pain (LBP) patients and this is generally recommended in guidelines. However, establishing a pathoanatomic diagnosis does not seem possible in most LBP patients and clinical tests may potentially be more relevant as prognostic factors. The aim of this review of the literature was to systematically assess the association between low-tech clinical tests commonly used in adult patients with acute, recurrent or chronic LBP and short- and long-term outcome. METHODS: MEDLINE, Embase, and MANTIS were searched from inception to June 2012. Prospective clinical studies of adult patients with LBP with or without leg pain and/or signs of nerve root involvement or spinal stenosis, receiving non-surgical or no treatment, which investigated the association between low-tech clinical tests and outcome were included. Study selection, data extraction and appraisal of study quality were performed independently by two reviewers. RESULTS: A total of 5,332 citations were retrieved and screened for eligibility, 342 articles were assessed as full text and 49 met the inclusion criteria. Due to clinical and statistical heterogeneity, qualitative synthesis rather than meta-analysis was performed. Associations between clinical tests and outcomes were often inconsistent between studies. In more than one third of the tests, there was no evidence of the tests being associated with outcome. Only two clinical tests demonstrated a consistent association with at least one of the outcomes: centralization and non-organic signs. CONCLUSIONS: For most clinical tests in LBP there is not consistent evidence for an association with outcome. Centralization and non-organic signs are exceptions from that. None of the other clinical tests have been investigated in confirmatory studies and study quality is generally low. There is a need for hypothesis testing studies designed specifically to investigate the prognostic value of the clinical tests, and a need for standardization of the performance and interpretation of tests. PMID- 25802740 TI - Treatment associated Mantle Cell Lymphoma with Cyclophosphamide therapy for Granulomatosis with Polyangiitis. AB - We present a case of a 68-year-old woman who developed mantle cell lymphoma in the setting of long-term cyclophosphamide therapy and relapsing granulomatosis with polyangiitis (Wegener's granulomatosis, GPA). Adverse outcomes associated with cyclophosphamide therapy are well documented; however, the development of non-Hodgkin's lymphoma appears rare. Cumulative dose of cyclophosphamide (>36 g) is a significant risk factor in the development of serious long-term adverse outcomes and is particularly relevant to this case in which maintenance cyclophosphamide therapy was continued, following induction, for 2 years total, on account of patient preference. This case study will highlight the patient's initial diagnosis, treatment response, relapse and subsequent complications of therapy. PMID- 25802741 TI - Malignant pleural mesothelioma presenting as a spontaneous pneumothorax. AB - Malignant pleural mesothelioma (MPM) is thought to arise from the mesothelial cells that line the pleural cavities. Most patients initially experience the insidious onset of chest pain or shortness of breath and have a history of asbestos exposure. MPM rarely presents as spontaneous pneumothorax. We report two male patients who presented with a spontaneous hydropneumothorax. One was exposed to asbestos and the other was not. Computed tomography showed tiny nodules with pleural thickness. They both underwent pleural effusion cytology and/or pleural biopsy. Therefore, the pathological diagnosis of MPM was obtained in both cases. We also reviewed 16 Japanese MPM cases with pneumothorax including our two patients. More than half of the patients suffered from pneumothorax repeatedly. We emphasize the need to obtain a pathological diagnosis of pleural effusion cytology and/or pleural biopsy in older patients presenting with a spontaneous hydropneumothorax. PMID- 25802742 TI - Intractable pneumothorax managed by talc pleurodesis and bronchial occlusion with spigots. AB - Three cases of inoperable secondary spontaneous pneumothorax were diagnosed in patients with chronic obstructive pulmonary disease. Two cases initially underwent bronchial occlusion with endobronchial Watanabe spigot (EWS), while one underwent talc poudrage with pleuroscopy. As air leaks were not stopped completely in all cases with the initial procedures, we performed additional interventional treatments: pleuroscopic talc poudrage in cases when bronchial occlusion was performed first; and bronchial occlusion with EWS for a case that initially underwent talc pleurodesis. The air leaks ceased in all cases without complication. We successfully removed chest tubes 2-10 days after secondary procedure, which was 10-23 days after the first procedure. The combination of talc pleurodesis and bronchial occlusion with EWS, when a single, initial interventional treatment fails, can be considered in cases of intractable, inoperable secondary pneumothorax. PMID- 25802743 TI - Mediastinitis and pericarditis after endobronchial ultrasound-guided transbronchial needle aspiration. AB - A 73-year-old man was admitted to our hospital for further investigation of multiple lung nodules and lymphadenopathy that were observed on chest radiography. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed to sample the lower paratracheal lymph node (4R), leading to a definitive diagnosis of squamous cell carcinoma of the lung. About 2 weeks after EBUS-TBNA, the patient had a high temperature, anterior chest pain, tachycardia, and hypotension. The diagnosis of infectious mediastinitis and pericarditis as complications of EBUS-TBNA, which were successfully treated with systemic antibiotics, was made after examinations. EBUS-TBNA is minimally invasive and useful for the diagnosis of hilar and mediastinum lesions particularly in determining the extent of lung cancer. With the increased employment of this method, critical complications may also increase. Clinicians should be aware of the rare but critical complications associated with EBUS-TBNA. PMID- 25802744 TI - Mycobacterium phocaicum and Mycobacterium avium-intracellulare in a patient with hot tub lung. AB - A 77-year-old woman who used her spa pool at least twice a day to relieve pain from osteoarthritis, developed progressive breathlessness, impaired pulmonary function, and radiographic changes consistent with hypersensitivity pneumonitis like lung disease. M ycobacterium avium-intracellulare complex (MAC) was cultured from bronchoalveolar lavage fluid. Transbronchial biopsies revealed non necrotizing granulomatous inflammation. Sputum and spa pool water cultured M ycobacterium phocaicum but not MAC. She stopped using the spa pool and was treated with oral prednisone, which led to symptomatic, pulmonary function, and radiographic improvement. This is the first case of hypersensitivity pneumonitis like granulomatous lung disease associated with exposure to M . phocaicum in spa pool water. PMID- 25802745 TI - Metachronous tracheal squamous cell carcinoma treated with Nd: YAG laser. AB - Tracheal squamous cell carcinoma detected early in a high-risk patient has been treated twice with local neodymium-yttrium aluminium garnet laser therapy with good result so far. Ongoing bronchoscopic monitoring continues. PMID- 25802746 TI - The value of spirometry and exercise challenge test to diagnose and monitor children with asthma. AB - Asthma is defined as a chronic inflammatory disease of the airways with characteristic symptoms including recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. It may result in abnormalities of ventilator function, which can be assessed by different pulmonary function tests. In this case report, we present a 15-year-old boy with asthma and illustrate the value and limitations of spirometry and exercise challenge test in daily practice. PMID- 25802747 TI - A case of multiple pulmonary cavernous hemangioma. AB - A 61-year-old male who originally visited a different hospital, underwent a health checkup in which multiple lung nodules were detected. Multiple well defined small nodules were observed in both lungs, with lesions reaching the arteries. Metastatic lung cancer, with unknown origin, was suspected. A computed tomography-guided percutaneous lung biopsy was performed; however, a pathological diagnosis could not be established. Then the patient was referred to our hospital for surgical lung biopsy. Macroscopically, the nodule was dark-red in color and solid without a capsule. Microscopically, the nodule was composed of dilated vascular spaces lined by flattened bland cells. They were positive for CD34, but were negative for TTF-1, consistent with lesions of endothelial origin. Microscopic and immunohistochemical findings supported the diagnosis of multiple pulmonary cavernous hemangiomas. After diagnosis, the lesions were left untreated and thereafter showed no signs of deterioration. PMID- 25802748 TI - Bronchial stenosis secondary to epidermolysis bullosa successfully treated with bronchoscopic balloon dilatation. AB - Epidermolysis bullosa rarely affects lower airways. We present a case of lower airway involvement and stenosis successfully managed with flexible bronchoscopy and balloon dilation. PMID- 25802749 TI - Challenges inherent to the diagnosis of antibody-mediated rejection in lung transplantation. AB - A bilateral sequential lung transplant was performed on a young female with cystic fibrosis-related bronchiectasis. She had negative prospective T- and B cell crossmatch, and no known donor-specific antibodies. Post-transplantation, she developed bilateral pulmonary infiltrates of uncertain etiology, compounded by persistent tachycardia and questionable medication adherence. Despite aggressive intervention for suspected cellular rejection with high-dose intravenous corticosteroid, immunoglobulin, and anti-thymocyte globulin, her condition deteriorated to ultimately require ventilatory support. The eventual discovery of eplet donor-recipient mismatches on related DQB1 alleles raised the diagnosis of antibody-mediated rejection. Before plasmapheresis could be instituted, the patient rapidly succumbed to respiratory failure. Postmortem examination confirmed features of atypical allograft rejection, without evidence of classic acute cellular rejection. This is an unconventional case of antibody mediated lung allograft rejection - an entity that is currently a difficult diagnostic and therapeutic challenge. Prevention of donor-specific antibodies by correct donor-recipient matching, and optimizing adherence post-transplantation are most important. PMID- 25802753 TI - Update on uveitis management. PMID- 25802752 TI - An eleven-year retrospective study of endogenous bacterial endophthalmitis. AB - Purpose. To determine the clinical features, microbial profiles, treatment outcomes, and prognostic factors for endogenous bacterial endophthalmitis (EBE). Methods. The medical records of 27 eyes of 21 patients diagnosed with EBE for 11 years were reviewed. Collected data included age, site of infection, visual acuities (VAs), microbial profiles, and treatment regimen. Results. The mean age was 68.5 years. Gram-positive organisms accounted for 76.2%, while gram-negative ones accounted for 19.0%. Staphylococcus aureus was the most common causative organism (52.3%) of which 72.7% was methicillin-resistant S. aureus. A final VA of >=20/40 was achieved in 44% and 20/200 or better was in 64%. Eyes with initial VA of >=20/200 (P = 0.003) and focal involvements (P = 0.011) had significantly better final VA. Initial VA (P = 0.001) and the interval between onset of ocular symptoms and intravitreal antibiotic injection (P = 0.097) were associated with final VA in eyes receiving intravitreal antibiotics. Conclusions. EBE is generally associated with poor visual outcome; however the prognosis may depend on initial VA, extent of ocular involvement, and an interval between onset of ocular symptoms and intravitreal antibiotic injection. Early diagnosis and early intravitreal injection supplement to systemic antibiotics might lead to a relatively good visual outcome. PMID- 25802754 TI - Comment on "the ocular surface chemical burns". PMID- 25802751 TI - Future therapies of wet age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population, and the prevalence of the disease increases exponentially with every decade after the age of 50 years. While VEGF inhibitors are promising drugs for treating patients with ocular neovascularization, there are limitations to their potential for improving vision in AMD patients. Thus, future therapies are required to have the potential to improve visual outcomes. This paper will summarize the future strategies and therapeutic targets that are aimed at enhancing the efficacy and duration of effect of antiangiogenic strategies. PMID- 25802755 TI - Awareness and perception of plant-based diets for the treatment and management of type 2 diabetes in a community education clinic: a pilot study. AB - Objective. To assess awareness, barriers, and promoters of plant-based diet use for management of type 2 diabetes (T2D) for the development of an appropriate educational program. Design. Cross-sectional study of patients and healthcare providers. Setting. Regional Diabetes Education Centre in ON, Canada. Participants. n = 98 patients attending the Diabetes Education Centre and n = 25 healthcare providers. Variables Measures. Patient questionnaires addressed demographics, health history, and eating patterns, as well as current knowledge, confidence levels, barriers to, promoters of, and interests in plant-based diets. Staff questionnaires addressed attitudes and current practice with respect to plant-based diets. Analysis. Mean values, frequency counts, and logistic regression (alpha = 0.05). Results. Few respondents (9%) currently followed a plant-based diet, but 66% indicated willingness to follow one for 3 weeks. Family eating preferences and meal planning skills were common barriers to diet change. 72% of healthcare providers reported knowledge of plant-based diets for diabetes management but low levels of practice. Conclusions and Implications. Patient awareness of the benefits of a plant-based diet for the management of diabetes remains suboptimal and may be influenced by perception of diabetes educators and clinicians. Given the reported willingness to try (but low current use of) plant based diets, educational interventions targeting patient and provider level knowledge are warranted. PMID- 25802756 TI - The safety and efficacy of an enzyme combination in managing knee osteoarthritis pain in adults: a randomized, double-blind, placebo-controlled trial. AB - This randomized, double-blind, placebo-controlled, and comparator-controlled trial evaluated the safety and efficacy of an enzyme combination, as Wobenzym, in adults with moderate-to-severe osteoarthritis (OA) of the knee. Adults (n = 150) received Wobenzym, diclofenac (a nonsteroidal anti-inflammatory drug, NSAID), or placebo for 12 weeks. Improvement in pain scores (Lequesne Functional Index) did not differ between subjects treated with Wobenzym or diclofenac, and both treatment groups improved compared to placebo (P < 0.05). Reduction in total WOMAC scores (secondary outcome measure) did not differ between Wobenzym and diclofenac, although only diclofenac emerged as different from placebo (P < 0.05). The median number of rescue medication (paracetamol) tablets consumed was less in the Wobenzym group compared to placebo (P < 0.05), while there was no difference between diclofenac and placebo. Adverse events were similar in frequency in Wobenzym and placebo groups (7.2% and 9.1% of subjects, resp.) and higher in diclofenac group (15.6%). Wobenzym is comparable to the NSAID diclofenac in relieving pain and increasing function in adults with moderate-to severe painful knee OA and reduces reliance on analgesic medication. Wobenzym is associated with fewer adverse events and, therefore, may be appropriate for long term use. PMID- 25802757 TI - Facile Synthesis, Characterization, and In Vitro Antimicrobial Screening of a New Series of 2,4,6-Trisubstituted-s-triazine Based Compounds. AB - A series of new 2,4,6-trisubstituted-s-triazine was synthesized, assessed for antimicrobial activity, and characterized by FTIR, (1)HNMR, (13)CNMR, and elemental analysis. The tested compounds, 4d, 4g, 4h, 4k, and 4n, have shown considerable in vitro antibacterial efficacy with reference to the standard drug ciprofloxacin (MIC 3.125 MUgmL(-1) against B. subtilis, E. coli, and K. pneumoniae). It was observed that compounds 4d and 4h displayed equipotent antibacterial efficacy against B. subtilis (MIC 3.125 MUgmL(-1)) and S. aureus (MIC 6.25 MUgmL(-1)). The studies demonstrated that the para fluorophenylpiperazine substituted s-triazine (4n) was potent and exhibited broad spectrum antibacterial activity against S. epidermidis, K. pneumoniae, and P. aeruginosa with MIC of 6.25 MUgmL(-1) and for E. coli, it showed an MIC of 3.125 MUgmL(-1) equipotent with reference to the standard drug. Among all the compounds under investigation, compound 4g also demonstrated significant antifungal activity (3.125 MUgmL(-1)) against C. albicans. PMID- 25802758 TI - Disease-modifying drugs reduce cortical lesion accumulation and atrophy progression in relapsing-remitting multiple sclerosis: results from a 48-month extension study. AB - Cortical lesions (CLs) and atrophy are pivotal in multiple sclerosis (MS) pathology. This study determined the effect of disease modifying drugs (DMDs) on CL development and cortical atrophy progression in patients with relapsing remitting MS (RRMS) over 48 months. Patients (n = 165) were randomized to sc IFN beta-1a 44 MUg, im IFN beta-1a 30 MUg, or glatiramer acetate 20 mg. The reference population comprised 50 DMD-untreated patients with RRMS. After 24 months, 43 of the untreated patients switched to DMDs. The four groups of patients were followed up for an additional 24 months. At 48 months the mean standard deviation number of new CLs was significantly lower in patients treated with sc IFN beta-1a (1.4 +/- 1.0, range 0-5) compared with im IFN beta-1a (2.3 +/- 1.3, range 0-6, P = 0.004) and glatiramer acetate (2.2 +/- 1.5, range 0-7, P = 0.03). Significant reductions in CL accumulation and new white matter and gadolinium-enhancing lesions were also observed in the 43 patients who switched to DMDs after 24 months, compared with the 24 months of no treatment. Concluding, this study confirms that DMDs significantly reduce CL development and cortical atrophy progression compared with no treatment. PMID- 25802759 TI - Perceived cause, environmental factors, and consequences of falls in adults with cerebral palsy: a preliminary mixed methods study. AB - Objective. Describe perceived cause, environmental influences, and consequences of falls or near-falls in ambulant adults with cerebral palsy (CP). Methods. Adults with CP completed postal surveys and follow-up semistructured interviews. Surveys sought information on demographic data, self-nominated Gross Motor Function Classification Score (GMFCS-E&R), falls, and near-falls. Interviews gathered additional information on falls experiences, near-falls, and physical and psychosocial consequences. Results. Thirty-four adults with CP participated. Thirty-three participants reported at least one fall in the previous year. Twenty six participants reported near-falls. Most commonly, falls occurred indoors, at home, and whilst engaged in nonhazardous ambulation. Adults with CP experienced adverse falls consequences, lower limb injuries predominant (37%), and descriptions of fear, embarrassment, powerlessness, and isolation. Discussion. Adults with CP may experience injurious falls. Further investigation into the impact of falls on health-related quality of life and effective remediation strategies is warranted to provide comprehensive falls prevention programs for this population. PMID- 25802760 TI - Velocity during Strength and Power Training of the Ankle Plantar and Dorsiflexor Muscles in Older Patients Attending Day Hospital Rehabilitation. AB - Power training has been proposed as a more effective type of resistance training for older adults for functional performance. It is not yet known whether older adults respond appropriately to instructions for power versus strength training. The purpose of this study was to determine the velocity during strength and power training, with elastic resistance bands, in older adults attending a geriatric rehabilitation day program. It was hypothesized that power training would be faster than strength training, but that there would be large interindividual differences. Nine older patients (70 to 86 years) performed power and strength training of the ankle dorsiflexor and plantar flexor muscles using elastic resistance bands. Training sessions were filmed to assess the velocity of training. Power training occurred at faster velocities as compared to strength training (P < 0.01) for both muscle groups. However, a wide variation was observed between participants in the training velocities. Older adults attending geriatric rehabilitation do have the potential to develop faster contractions during power training as compared to strength training. Nevertheless, the actual velocities achieved differed between individuals. This could explain some of the mixed findings of studies on power training. Hence, researchers should monitor velocity when comparing different types of resistance training. PMID- 25802761 TI - Calcium Alginate-Neusilin US2 Nanocomposite Microbeads for Oral Sustained Drug Delivery of Poor Water Soluble Drug Aceclofenac Sodium. AB - The aim of the present study was to formulate and investigate the calcium alginate- (CA-) Neusilin US2 nanocomposite microbeads containing preconcentrate of aceclofenac sodium (ACF-Na) liquid microemulsion (L-ME) for enhancement of oral bioavailability. The preconcentrate L-ME is prepared by using Labrafac PG, Labrasol, and Span 80 as oil, surfactant, and cosurfactant, respectively. The solid CA nanocomposite microbeads of L-ME prepared by microemulsification internal gelation technique using sodium alginate (SA) gelling agent, Neusilin US2 as adsorbent, and calcium chloride as crosslinking agent. L-ME has good thermodynamic stability; globule size was found to be 32.4 nm with polydispersity index 0.219 and -6.32 mV zeta potential. No significant interactions of excipients, drug in the formulations observed by FT-IR, DSC and XPRD. The concentration of SA and Neusilin US2 influences the flow properties, mean particle size, mechanical strength, drug entrapment efficiency, and percentage of drug release. All the formulations show minimum drug release in simulated gastric fluid (SGF) pH 1.2 for initial 2 h, maximum drug release in pH 6.8 phosphate buffer solution (PBS) at 6 h, followed by sustaining in simulated intestinal fluid (SIF) of pH 7.4 up to 12 h. The interaction of SA with Neusilin US2 creates a thick thixotropic gel network structure which acts as barrier to control the release of drug in the alkaline pH environment. Neusilin US2 is a novel filler used to convert L-ME into solid nanocomposite microbeads to enhance dissolution rate of poor water soluble drugs sustaining the drug release for prolonged period of time. PMID- 25802762 TI - Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. AB - Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 * 10(9) aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-gamma EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC. PMID- 25802765 TI - Isolated perforation of left coronary cusp after blunt chest trauma. AB - Left coronary cusp perforation is an extremely rare consequence of blunt chest trauma. A 22-year-old male presented after a motor vehicle accident with dyspnea. Transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) showed moderate to severe aortic regurgitation with prolapsing right coronary cusp. In the operating room he was found to have a left coronary cusp tear near the annulus and an enlarged right cusp. The patient recovered well after successful aortic valve replacement with a mechanical valve. Traumatic aortic regurgitation with left cusp perforation is serious and surgical intervention may be lifesaving if performed timely. PMID- 25802764 TI - Effects of trace metal profiles characteristic for autism on synapses in cultured neurons. AB - Various recent studies revealed that biometal dyshomeostasis plays a crucial role in the pathogenesis of neurological disorders such as autism spectrum disorders (ASD). Substantial evidence indicates that disrupted neuronal homeostasis of different metal ions such as Fe, Cu, Pb, Hg, Se, and Zn may mediate synaptic dysfunction and impair synapse formation and maturation. Here, we performed in vitro studies investigating the consequences of an imbalance of transition metals on glutamatergic synapses of hippocampal neurons. We analyzed whether an imbalance of any one metal ion alters cell health and synapse numbers. Moreover, we evaluated whether a biometal profile characteristic for ASD patients influences synapse formation, maturation, and composition regarding NMDA receptor subunits and Shank proteins. Our results show that an ASD like biometal profile leads to a reduction of NMDAR (NR/Grin/GluN) subunit 1 and 2a, as well as Shank gene expression along with a reduction of synapse density. Additionally, synaptic protein levels of GluN2a and Shanks are reduced. Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor. Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis. PMID- 25802767 TI - Right atrial metastatic melanoma with unknown primaries. AB - A 54-year-old male with history of anemia and rheumatoid arthritis presented with a three-month history of dyspnea on exertion and lower extremity edema. Patient was referred for a transthoracic echocardiogram that revealed a large right atrial mass with reduced ejection fraction of 40% and an incidental large liver mass. Subsequent cardiac MRI revealed a lobulated right atrial mass measuring 5.4 cm * 5.3 cm with inferior vena cava compression and adjacent multiple large liver lesions confirmed to be malignant melanoma through biopsy. Interestingly, no primaries were found in the patient. PET/CT imaging displayed hypermetabolic masses within the right atrium and liver that likely represent metastases, as well as bilateral pleural effusions, most likely due to heart failure. Preoperative coronary angiogram demonstrated perfusion to the mass by a dense network of neovasculature arising from the mid right coronary artery. The cardiac melanoma was surgically removed, and the right atrium was reconstructed with a pericardial patch. After surgery, all cardiac chambers appeared normal in size and function with associated moderate tricuspid regurgitation. The patient is currently being administered ipilimumab for systemic therapy of metastatic melanoma. PMID- 25802766 TI - Myocarditis leading to severe dilated cardiomyopathy in a patient with dengue Fever. AB - Background. Majority of dengue fever cases follow a benign self-limiting course but recently rare presentations and complications are increasingly seen due to rising burden of disease. Cardiac involvement in dengue fever with fatal outcome is a very rare complication. We report a case of 44-year-old patient who presented with symptoms of severe acute congestive heart secondary to myocarditis induced cardiomyopathy caused by dengue virus infection. Case Presentation. A 44 year-old man presented to ER with the complaints of high fever, fatigue, and shortness of breath. Patient was lethargic and blood pressure was low when he was brought to the ER. CXR showed cardiomegaly with pulmonary congestion and echocardiography revealed dilated left ventricle and ejection fraction of 10%. Patient condition worsened and he got admitted to the ICU because of acute hypoxic respiratory failure. Despite aggressive measures, patient died on day 5. Conclusion. Dilated cardiomyopathy is a rare complication of dengue myocarditis. Early recognition of acute DCM caused by dengue myocarditis is imperative in the management of dengue fever as early detection and management of cardiac failure can improve the survival of patient. PMID- 25802763 TI - Neuraminidase inhibition primes short-term depression and suppresses long-term potentiation of synaptic transmission in the rat hippocampus. AB - Neuraminidase (NEU) is a key enzyme that cleaves negatively charged sialic acid residues from membrane proteins and lipids. Clinical and basic science studies have shown that an imbalance in NEU metabolism or changes in NEU activity due to various pathological conditions parallel with behavior and cognitive impairment. It has been suggested that the decreases of NEU activity could cause serious neurological consequences. However, there is a lack of direct evidences that modulation of endogenous NEU activity can impair neuronal function. Using combined rat entorhinal cortex/hippocampal slices and a specific inhibitor of NEU, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NADNA), we examined the effect of downregulation of NEU activity on different forms of synaptic plasticity in the hippocampal CA3-to-CA1 network. We show that NEU inhibition results in a significant decrease in long-term potentiation (LTP) and an increase in short term depression. Synaptic depotentiation restores LTP in NADNA-pretreated slices to the control level. These data suggest that short-term NEU inhibition produces the LTP-like effect on neuronal network, which results in damping of further LTP induction. Our findings demonstrate that downregulation of NEU activity could have a major impact on synaptic plasticity and provide a new insight into the cellular mechanism underlying behavioral and cognitive impairment associated with abnormal metabolism of NEU. PMID- 25802768 TI - Management of an intruded tooth and adjacent tooth showing external resorption as a late complication of dental injury: three-year follow-up. AB - Treatment and prognosis of intrusive luxation can vary depending on the age of the patient, type of dentition, stage of root development, and time and severity of the trauma. Some studies have demonstrated that intrusions of up to 3.0 mm have an excellent prognosis, whereas teeth with severe intrusion or teeth that are intruded more than 6.0 mm present an unfavorable prognosis because of the occurrence of inflammatory resorption and pulp necrosis. The aim of this case report is to present an 11-year-old male patient with complete intrusion of the permanent maxillary left lateral incisor, associated with the adjacent central tooth presenting external resorption, treated by immediate surgical repositioning and root canal treatment with a favorable prognosis. After long-term (3-year) clinical and radiographic follow-up, the teeth appeared normal and the patient was pleased with the outcome. PMID- 25802769 TI - An unusual cause of pulmonary nodules in the emergency department. AB - We report a 51-year-old woman who presented to the emergency department with left sided pleuritic chest pain 2 weeks after subtotal hysterectomy and bilateral salpingo-oophorectomy for a leiomyomatous uterus. Computed tomography scan of the chest revealed bilateral pulmonary nodules. Biopsy showed cytologically bland spindle cells without overt malignant features. Immunohistochemistry confirmed smooth muscle phenotype, in keeping with a clinicopathologic diagnosis of benign metastasizing leiomyoma (BML). BML does not frequently come to the attention of the emergency physician because it is rare and usually asymptomatic. When symptomatic, its clinical presentation depends on the site(s) of metastasis, number, and size of the smooth muscle tumors. Emergent presentations of BML are reviewed. PMID- 25802770 TI - Detecting foreign bodies in a head laceration. AB - Open wounds represent a potential area of medicolegal risk if foreign bodies are not identified prior to wound closure. The importance of imaging of lacerations was underscored by a recent case where a 20-year-old male collided with a friend's mouth on a trampoline sustaining a simple, superficial scalp laceration. The wound was evaluated in typical fashion including irrigation and local exploration and was prepared for closure. The friend was then evaluated and noted to have multiple extensive dental fractures. An increased index of suspicion generated further evaluation of the first patient's wound. Plain radiography obtained of the first patient's skull was noted to have bony foreign bodies consistent with teeth, which were then removed after further exploration. Superficial wounds are common and complications arising from retained foreign bodies are a potential source of substantial morbidity and consequently medical litigation. This case serves as a reminder to be vigilant and maintain a high index of suspicion regarding the potential for foreign body. PMID- 25802771 TI - A rare cause of acute Dysphagia: abscess of the base of the tongue. AB - Dysphagia represents a difficulty in passage of solid or liquid foods from the oral cavity into the stomach and is considered as an alarm symptom of gastrointestinal system. It often indicates an organic disease and needs to be explained. In this paper, a case of 61-year-old man with posterior tongue abscess is presented. PMID- 25802772 TI - Acute Pancreatitis and Splenic Vein Thrombosis due to Hypertriglyceridemia. AB - Acute pancreatitis (AP) is a condition characterised by the activation of the normally inactive digestive enzymes due to an etiological factor and digestion of the pancreatic tissues, resulting in extensive inflammation and leading to local, regional, and systemic complications in the organism. It may vary from the mild edematous to the hemorrhagic and severely necrotising form. The most common causes are biliary stones and alcohol abuse. In this case study, we would like to present a patient with AP due to hypertriglyceridemia (HPTG), which is a rare cause of pancreatitis, and splenic vein thrombosis, which is a rare complication of pancreatitis. PMID- 25802774 TI - Pneumonia by Listeria monocytogenes: A Common Infection by an Uncommon Pathogen. AB - Infections by Listeria monocytogenes typically occur in infants, the elderly, pregnant women, and immunosuppressed subjects. Pulmonary infections in adults are extremely uncommon and only few reports can be found in the literature. We here report a case of Listeria pneumonia in an 85-year-old female patient and we discuss our diagnostic and therapeutic approach. Despite being rare and in most cases difficult to be identified, Listeria pneumonia should always be considered in immunosuppressed patients, presenting with fever and symptoms from the lower respiratory system. PMID- 25802773 TI - Acute viral hepatitis e is associated with the development of myocarditis. AB - Myocarditis, an inflammatory disease of heart muscle, is an important cause of dilated cardiomyopathy worldwide. Viral infection is an important cause of myocarditis. This condition presents with various symptoms, ranging from minimally symptomatic cases to fatal arrhythmia and cardiogenic shock, and may develop chronic myocarditis and dilated cardiomyopathy in some patients. We report the case of a 26-year-old patient with acute viral hepatitis E who developed symptomatic myocarditis. As far as we could search, this is probably the 3rd case report of this rare association. PMID- 25802775 TI - A case of nephrotic syndrome, showing evidence of response to saquinavir. AB - The treatment of primary nephrotic syndrome such as minimal change nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis nephropathy remains challenging. Whilst most cases of idiopathic nephrotic syndrome respond to steroid therapy and experience a limited number of relapses prior to complete remission, some cases suffer from frequent relapses and become steroid dependent or are primarily steroid resistant. Treatment options are limited to immunosuppressive drugs with significant side effect profiles. New modalities targeting novel pathways in the pathogenesis of nephrotic syndrome are actively sought. Here we report the case of a patient with steroid dependent focal segmental glomerulosclerosis (FSGS) nephrotic syndrome with a favourable response to a novel proteasome inhibitor saquinavir. PMID- 25802776 TI - Deep brain stimulation for pantothenate kinase-associated neurodegeneration. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is usually associated with dystonia, which is typically severe and progressive over time. Pallidal stimulation (GPi DBS) has been carried out in selected cases of PKAN with drug resistant dystonia with variable results. We report a 30-month follow-up study of a 30-year-old woman with PKAN-related dystonia treated with GPi DBS. Postoperatively, the benefit quickly became evident, as the patient exhibited a marked improvement in her dystonia, including her writing difficulty. This result has been maintained up to the present. GPi DBS should be considered in dystonic PKAN patients provided fixed contractures and/or pyramidal symptoms are not present. PMID- 25802777 TI - Posterior reversible encephalopathy syndrome as presenting form of very early systemic sclerosis. AB - Introduction. Posterior Reversible Encephalopathy Syndrome (PRES) is an increasingly recognized clinical and radiological entity with a wide spectrum of symptoms. Its mechanism depends on failure of the blood-brain barrier due to high systemic blood pressure (BP) and loss of integrity of vascular endothelium related with different triggers. Methods. We aim to report a case of PRES induced by arterial hypertension and very early systemic sclerosis (SSc) not previously known. Results. A 64-year-old female was admitted due to 1-week pulsating headache more prominent on frontal scalp, accompanied by phonophobia, photophobia, and facial flushing. Neurological exam revealed brisk deep tendon reflex. Brain magnetic resonance imaging (MRI) showed subcortical lesions mainly located in posterior regions. BP was monitored and episodic arterial hypertension was detected. In laboratory tests positive anti-topoisomerase I antibodies were detected. BP was controlled with angiotensin-converting-enzyme inhibitors and headache improved. In a new MRI a month later improvement of white matter lesions was observed. Capillaroscopy showed "active pattern," considered typical of SSc. Conclusion. In SSc anti-endothelial cell antibodies impair vascular endothelium and liberation of vasoconstrictors leads to BP increasing and disruption of blood brain barrier autoregulation mechanisms. PRES can be the first manifestation of very early SSc and this entity should be considered even in absence of skin lesions or Raynaud phenomenon. PMID- 25802779 TI - An unexpected presentation of haemoperitoneum in a pregnant woman. AB - In the majority of tertiary centres the Emergency Room or Assessment Unit is the gateway to the rest of the hospital. It is the location where critical decisions are formulated depending on whether a patient's condition is serious enough to warrant admission and, at times, emergency surgery. On occasion this decision can be straightforward based solely on the patient's presentation, observations, and basic investigations. This case highlights that although the decision and initial management may be apparent, often the diagnosis can be unexpected and that the diagnostic challenge is often outside the scope of a brief Emergency Room assessment. Corpus luteal cyst rupture is a common phenomenon but often not the cause of significant morbidity as it was in this case, especially in the absence of any associated risk factors. PMID- 25802778 TI - Crossed-brain representation of verbal and nonverbal functions. AB - A 74-year-old, left-handed man presented with a rapidly evolving loss of strength in his right leg associated with difficulty in walking. MR images disclosed an extensive left hemisphere tumor. A neuropsychological examination revealed that language was broadly normal but that the patient presented with severe nonlinguistic abnormalities, including hemineglect (both somatic and spatial), constructional defects, and general spatial disturbances; symptoms were usually associated with right hemisphere pathologies. No ideomotor apraxia was found. The implications of crossed-brain representations of verbal and nonverbal functions are analyzed. PMID- 25802780 TI - Diagnosis of pentalogy of cantrell in the first trimester using transvaginal sonography and color Doppler. AB - We report the prenatal diagnosis of Cantrell syndrome in the first trimester. During a routine transabdominal ultrasonographic examination, a midline supraumbilical abdominal wall defect including herniated liver and ectopia cordis with a large omphalocele containing the intestines and cystic hygroma was incidentally identified at the 12th week of gestation. A transvaginal sonography examination revealed a severe lumbosacral scoliosis in addition to the inability to visualize the abdominal aorta which was indicative of a severe intracardiac defect. The parents opted for pregnancy to be terminated. In this case report, we discuss the complementary role of transvaginal sonography and Doppler imaging in the diagnosis of Cantrell syndrome in early pregnancy. PMID- 25802781 TI - Mullerian cyst of the vagina masquerading as a cystocele. AB - Mullerian cysts are usually small, ranging from 0.1 to 2 cm in diameter. Rarely, they may be enlarged and mistaken for other structures, such as a cystocele or urethral diverticulum. We report on a female with symptomatic vaginal wall prolapse, diagnosed as a vaginal Mullerian cyst, which was originally misdiagnosed as a cystocele. The mass was soft and could be compressed manually without difficulty. Perineal ultrasonography and cystoscopy revealed no relationship between the cyst and the lower urinary tract, suggesting independence of the lesion. We performed surgical treatment with complete excision of the mass via a vaginal approach under spinal anaesthesia. The pathology result confirmed a benign Mullerian cyst lined with mucinous and squamous epithelium. When evaluating an anterior vaginal cyst, assessment of the lesion via history taking and pelvic examination is important to confirm both lesion size and location. Perineal ultrasonography performed with an empty bladder is useful to differentiate such vaginal cysts and to define their communication, if any, with adjacent organs. PMID- 25802782 TI - Serous tubal intraepithelial carcinoma: an incidental finding at the time of prophylactic bilateral salpingo-oophorectomy. AB - Background. Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion for high-grade pelvic serous carcinoma. The incidence of STIC is estimated to occur in 0.6% to 6% of women who are BRCA positive or have a strong family history of breast or ovarian cancer. Case. A 56-year-old woman underwent robotic assisted sacrocolpopexy, rectocele repair, and concurrent bilateral salpingo oophorectomy for recurrent stage 3 pelvic organ prolapse and reported family history of ovarian cancer. Histopathologic examination of her left fallopian tube revealed STIC. Conclusion. We report this rare occurrence of STIC in a patient undergoing surgery primarily for pelvic organ prolapse and having a family history of ovarian cancer. Possible management options include observation with annual physical exam and CA-125, surgical staging, or empiric chemotherapy. However, due to the lack of consensus regarding management options, referral to a gynecologic oncologist is recommended. PMID- 25802783 TI - Lower lid ectropion in hypohidrotic ectodermal dysplasia. AB - We report a case of a lower lid ectropion with ectodermal dysplasia and ectropion blepharoplasty surgery experience. A 14-year-old Han nationality male patient with typical characteristics of hypohidrotic ectodermal dysplasia presented to our clinic for his right lower lid eversion. The patient was diagnosed as having hypohidrotic ectodermal dysplasia and underwent an uneventful blepharoplasty surgery. The lower lid maintained normal position during the 10-month follow-up period. Patients with ectodermal dysplasia could firstly visit ophthalmologist for their ectropion and blepharoplasty surgery could be useful for the disease. PMID- 25802784 TI - Vertebral Stenting and Vertebroplasty Guided by an Angiographic 3D Rotational Unit. AB - Introduction. Use of interventional imaging systems in minimally invasion procedures such as kyphoplasty and vertebroplasty gives the advantage of high resolution images, various zoom levels, different working angles, and intraprocedure image processing such as three-dimensional reconstructions to minimize complication rate. Due to the recent technological improvement of rotational angiographic units (RAU) with flat-panel detectors, the useful interventional features of CT have been combined with high-quality fluoroscopy into one single machine. Intraprocedural 3D images offer an alternative way to guide needle insertion and the safe injection of cement to avoid leakages. Case Report. We present the case of a 72-year-old female patient with insidious lumbar pain. Computed tomography revealed a wedge-shaped osteoporotic compression fracture of T10 vertebrae, which was treated successfully with the installation of vertebral stenting system and vertebroplasty with methacrylate guided with a rotational interventional imaging system. Conclusion. Rotational angiographic technology may provide a suitable place for the realization of high-quality minimally invasive spinal procedures, such as kyphoplasty, vertebroplasty, and vertebral stenting. New software programs available nowadays offer the option to make three-dimensional reconstructions with no need of CT scans with the same degree of specificity. PMID- 25802785 TI - Total knee arthroplasty in a patient with bilateral congenital dislocation of the patella treated with a different method in each knee. AB - We have operated total knee arthroplasty in a patient with bilateral congenital dislocation of the patella treated with a different method in each knee. PMID- 25802786 TI - Enteric duplication cyst located at the posterior tongue: a rare case report and review of the literature. AB - The lingual localization of an enteric duplication is extremely rare but may present with respiratory and feeding problems that require emergency intervention. A 7-month-old boy was brought to our clinic with feeding difficulties and tongue swelling. Physical examination showed a cystic lesion located near the left side of the tongue base that caused tongue protrusion to the contralateral side. During surgery, a 3-cm diameter opaque thick-walled cyst was found to be very closely adherent to the base of tongue, which was excised in its entirety. Following surgery, the patient fed during the early postoperative period and no complications were observed other than hypersalivation. On histological examination, a cystic lesion lined with intestinal mucosa and goblet cells was found. We present the rare case of a duplication cyst of the posterior tongue, with a literature review. PMID- 25802788 TI - Subacute sclerosing panencephalitis in a child with recurrent febrile seizures. AB - Subacute sclerosing panencephalitis (SSPE) is a devastating disease of the central nervous system (CNS) caused by persistent mutant measles virus infection. The diagnosis of SSPE is based on characteristic clinical and EEG findings and demonstration of elevated antibody titres against measles in cerebrospinal fluid. Subacute sclerosing panencephalitis can have atypical clinical features at the onset. Herein, we report an unusual case of subacute sclerosing panencephalitis in a child with recurrent febrile seizures. The disease progressed with an appearance of myoclonic jerks, periodic high amplitude generalized complexes on EEG, and elevated titers of measles antibodies in cerebrospinal fluid leading to the final diagnosis of subacute sclerosing panencephalitis. PMID- 25802787 TI - Multiple epithelioid hemangiomas with orbital involvement. AB - Epithelioid hemangioma, also known as angiolymphoid hyperplasia with eosinophilia, is a cutaneous angioproliferative lesion that follows a benign clinical course. It is most frequently localized in the skin of the head and neck region; although it may sometimes arise deeper in soft tissues, orbital involvement is rare. Here we describe a patient who developed multiple epithelioid hemangiomas, including an intraorbital lesion. The histopathological parallels with other reactive and neoplastic lesions as well as therapeutic options are discussed. PMID- 25802789 TI - A case of multicentric carcinoid in a patient with psoriatic spondyloarthropathy. AB - We describe the first case of a patient presenting with multicentric carcinoid occurring in the lung and subsequently in the rectum, with chronic psoriatic arthritis. Although reports have been published regarding carcinoid syndrome occurring alongside rheumatoid arthritis, no reports have been made on such a case. Initial presentation of carcinoid syndrome in this patient was insidious and atypical with few symptoms, including shortness of breath and long standing abdominal bloating. Several years later a sudden change in bowel habit prompted a colonoscopy with biopsy that revealed a carcinoid rectal polyp. The case we report describes a rare presentation of carcinoid syndrome in chronic psoriatic arthropathy. PMID- 25802790 TI - Tongue necrosis as an initial manifestation of giant cell arteritis: case report and review of the literature. AB - Giant cell arteritis (GCA) is a systemic vasculitis of medium and large arteries that mainly affects the external carotid artery. It is a diagnosis of the elderly that typically presents as low-grade fever, temporal tenderness, claudication of the jaw, and in some patients vision loss. In cases where GCA presents with atypical manifestations, the diagnosis may be more difficult, causing a delay in both diagnosis and treatment and ultimately leading to irreversible complications. In this paper, we present an atypical presentation of GCA with symptoms of neck swelling and lingual pain in an elderly female. These symptoms progressed to bilateral necrosis and eventual dislodgement of the tongue. Lingual necrosis is a severe potential complication in GCA. In patients presenting with lingual swelling, pain, and discoloration, GCA should be suspected and prompt therapy should be initiated to avoid irreversible complications. PMID- 25802791 TI - Endometriosis of the Vermiform Appendix within a Hernia Sac Infiltrating the Pubic Bone. AB - Purpose. Appendicular endometriosis mimicking appendicitis is a rare finding. Inguinal tumor in the course of appendicular endometriosis located within an inguinal hernia sac and infiltrating the periosteum of the pubic bone has not yet been described. Case Report. This paper describes a case of a rapidly enlarging, solid, unmovable, very painful upon palpation inguinal tumor, in a 36-year-old nulliparous woman. During surgery, a hard (approximately 4 cm in diameter) tumor infiltrating the periosteum of the right pubic bone and continuous with the inguinal hernia sac was dissected. The distal segment of the vermiform appendix was an element of the dissected tumor. Histological examination revealed endometriosis of the distal vermiform appendix. After 6 months of hormone treatment, she was referred for reoperation due to tumor recurrence. Once again histological examination of the resected tissue revealed endometriosis. There was no further recurrence of the disease with goserelin therapy. In addition to the case report, we present a review of the literature about endometriosis involving the vermiform appendix and the inguinal canal (Amyand's hernia). Conclusion. This case expands the list of differential diagnoses of nodules found in the inguinal region of women. PMID- 25802792 TI - Pneumatosis cystoides intestinalis after cetuximab chemotherapy for squamous cell carcinoma of parotid gland. AB - Pneumatosis intestinalis, defined as gas in the bowel wall, is often first identified on abdominal radiographs or computed tomography (CT) scans. It is a radiographic finding and not a diagnosis, as the etiology varies from benign conditions to fulminant gastrointestinal disease. We report here a case of pneumatosis intestinalis associated with cetuximab therapy for squamous cell carcinoma of head and neck. The patient underwent laparotomy based on the CT scan and the result was pneumatosis intestinalis without any signs of necrotizing enterocolitis. PMID- 25802793 TI - A lethal complication after transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. AB - Background. The current standard of care for patients with large or multinodular noninvasive hepatocellular carcinoma is conventional transarterial chemoembolization (TACE). TACE may also be performed with drug-eluting beads, but serious complications of this procedure have been reported. Methods. Aim of this report is to present a patient affected by multifocal HCC who underwent TACE with drug-eluting bead (DEB-TACE). Results. Following the procedure the patient developed a hepatic abscess and biliobronchial fistula resulting in adult respiratory distress syndrome and death. Conclusion. We speculate that DEB-TACE has a prolonged effect on the tumor and the surrounding liver, resulting in progressive enlargement of the necrotic area. This activity that can extend to the surrounding healthy hepatic tissues may continue indefinitely. PMID- 25802794 TI - Iliac Vein Compression Syndrome due to Bladder Distention Caused by Urethral Calculi. AB - We report a rare case of iliac vein compression syndrome caused by urethral calculus. A 71-year-old man had a history of urethral stenosis. He complained of bilateral leg edema and dysuria for 1 week. Physical examination revealed bilateral distention of the superficial epigastric veins, so obstruction of both common iliac veins or the inferior vena cava was suspected. Plain abdominal computed tomography showed a calculus in the pendulous urethra, distention of the bladder (as well as the right renal pelvis and ureter), and compression of the bilateral common iliac veins by the distended bladder. Iliac vein compression syndrome was diagnosed. Bilateral iliac vein compression due to bladder distention (secondary to neurogenic bladder, benign prostatic hyperplasia, or urethral calculus as in this case) is an infrequent cause of acute bilateral leg edema. Detecting distention of the superficial epigastric veins provides a clue for diagnosis of this syndrome. PMID- 25802795 TI - Portal vein thrombosis. AB - Portal vein thrombosis (PVT) is the blockage or narrowing of the portal vein by a thrombus. It is relatively rare and has been linked with the presence of an underlying liver disease or prothrombotic disorders. We present a case of a young male who presented with vague abdominal symptoms for approximately one week. Imaging revealed the presence of multiple nonocclusive thrombi involving the right portal vein, the splenic vein, and the left renal vein, as well as complete occlusion of the left portal vein and the superior mesenteric vein. We discuss pathogenesis, clinical presentation, and management of both acute and chronic thrombosis. The presence of PVT should be considered as a clue for prothrombotic disorders, liver disease, and other local and general factors that must be carefully investigated. It is hoped that this case report will help increase awareness of the complexity associated with portal vein thrombosis among the medical community. PMID- 25802796 TI - Giant dissecting aortic aneurysm in an asymptomatic young male. AB - Giant aortic aneurysm is defined as aneurysm in the aorta greater than 10 cm in diameter. It is a rare finding since most patients will present with complications of dissection or rupture before the size of aneurysm reaches that magnitude. Etiological factors include atherosclerosis, Marfan's syndrome, giant cell arteritis, tuberculosis, syphilis, HIV-associated vasculitis, hereditary hemorrhagic telangiectasia, and medial agenesis. Once diagnosed, prompt surgical intervention is the treatment of choice. Although asymptomatic unruptured giant aortic aneurysm has been reported in the literature, there has not been any case of asymptomatic giant dissecting aortic aneurysm reported in the literature thus far. We report a case of giant dissecting ascending aortic aneurysm in an asymptomatic young male who was referred to our institution for abnormal findings on physical exam. PMID- 25802797 TI - Women, drug dependency and consequences: a study from a developing country. AB - Introduction. Addiction in women can expose them to malnutrition, high blood pressure, cancer, and some other dangerous diseases like hepatitis, AIDS, or other sexual transmitted diseases. The aim of this study was to assess illegal sexual relations in three groups of women. Methods. This is a cross-sectional study that was done on 236 girls and young women aged 16-25 years in 2012 in three groups: vulnerable women who have substance dependency (crimes that had made women incarcerated were considered as vulnerability in this study), invulnerable women who have substance dependency (substance dependent women without a history of incarceration), and a control group (women with no history of substance dependency or being in prison). Results. 43.8% of vulnerable women who have substance dependency had extramarital sexual relations; this percentage was 55.8% in invulnerable women who have substance dependency and 1.4% in the control group. Crystal and methamphetamine abuse was higher in addicts who had extramarital sexual relations and alcohol abuse was correlated with unsafe sexual intercourse (r = 0.36, P = 0.001). There was a statistically significant difference in extramarital sexual relation based on marital status (P < 0.001). Conclusions. Poverty, drug dependency, divorce, and alcohol consumption make women prone to other high risk behaviors that need more attention. PMID- 25802798 TI - The most cited papers in osteoporosis and related research. AB - Osteoporosis is a systemic disease of the bone that affects millions of people and causes burden for both the affected individual and health systems and societies worldwide. Since the 1970s much research has been done in the field of osteoporosis. The number of citations of a paper reflects its influence and importance to the field. Thomson ISI Web of Science database was searched to retrieve a list of the fifty most cited articles related to osteoporosis and its research. The fifty most cited articles in absolute numbers in the field of osteoporosis were cited from 877 to 3056 times (mean 1141 +/- 537). Most papers were published in the basic science category (n = 23). 395 authors contributed; a single paper had between one and 62 authors (mean: 10.02 +/- 9.9 authors). 12 authors (3.04%) contributed between 7 and 4 papers; 340 authors (86.1%) were at least named once. Corresponding authors were from eight countries with most contributions from the United States (n = 34, 68%). The majority of papers were published in the 1990s (n = 29). The list of 50 most cited papers presents citation classics in the field of osteoporosis and related research. PMID- 25802799 TI - The effects of uric Acid, serum vitamin d3, and their interaction on Parkinson's disease severity. AB - Objectives. In current study, the relationships between serum vitamin D3 levels and serum UA concentrations as well as their interaction with severity of PD were evaluated in a sample of Iranian PD patients. Method. In a cross sectional study at the one of the main referral hospitals in central region of Iran, during September to November 2011, 112 patients were recruited. Severity of PD was evaluated sing H&R stages and UPDRS. Results. The Spearman rank correlation coefficient suggests the negative significant association between serum vitamin D3 and UPDRS in patients aged >62 (r = -0.34, P < 0.05). No statistically significant association was observed between the UA levels and severity of PD (represented by H&Y categories) in different levels of serum vitamin D3 not only in total sample but also in separate age and sex groups. The linear regression coefficients suggested positive association between UA and serum vitamin D3 with UPDRSIII scores while negative relationship between UA and serum vitamin D3 interaction with UPDRSIII; however it was only statistically significant in age group <=62 (P < 0.05). Conclusion. Our study revealed a negative correlation between interaction of serum vitamin D3 and UA with severity of PD; other studies are required to confirm our findings. PMID- 25802801 TI - Age, growth and natural mortality of coney (Cephalopholis fulva) from the southeastern United States. AB - Coney (Cephalopholis fulva) sampled from recreational and commercial vessels along the southeastern coast of the United States in 1998-2013 (n = 353) were aged by counting opaque bands on sectioned sagittal otoliths. Analysis of otolith edge type (opaque or translucent) revealed that annuli formed in January-June with a peak in April. Coney were aged up to 19 years, and the largest fish measured 430 mm in total length (TL). The weight-length relationship was ln(W) = 3.03 * ln(TL) - 18.05 (n = 487; coefficient of determination [r (2)] = 0.91), where W = whole weight in kilograms and and TL = total length in millimeters. Mean observed sizes at ages 1, 3, 5, 10, and 19 years were 225, 273, 307, 338, and 400 mm TL, respectively. The von Bertalanffy growth equation for coney was Lt = 377 (1 - e ((-0.20(t+3.53)))). Natural mortality (M) estimated by Hewitt and Hoenig's longevity-based method which integrates all ages was 0.22. Age-specific M values, estimated with the method of Charnov and others, were 0.40, 0.30, 0.26, 0.22, and 0.20 for ages 1, 3, 5, 10, and 19, respectively. PMID- 25802800 TI - Characterization of four new monoclonal antibodies against the distal N-terminal region of PrP(c). AB - Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. They are characterized by the accumulation in the central nervous system of a pathological form of the host-encoded prion protein (PrP(C)). The prion protein is a membrane glycoprotein that consists of two domains: a globular, structured C-terminus and an unstructured N-terminus. The N-terminal part of the protein is involved in different functions in both health and disease. In the present work we discuss the production and biochemical characterization of a panel of four monoclonal antibodies (mAbs) against the distal N-terminus of PrP(C) using a well-established methodology based on the immunization of Prnp (0/0) mice. Additionally, we show their ability to block prion (PrP(Sc)) replication at nanomolar concentrations in a cell culture model of prion infection. These mAbs represent a promising tool for prion diagnostics and for studying the physiological role of the N-terminal domain of PrP(C). PMID- 25802802 TI - Orangutans modify facial displays depending on recipient attention. AB - Primate facial expressions are widely accepted as underpinned by reflexive emotional processes and not under voluntary control. In contrast, other modes of primate communication, especially gestures, are widely accepted as underpinned by intentional, goal-driven cognitive processes. One reason for this distinction is that production of primate gestures is often sensitive to the attentional state of the recipient, a phenomenon used as one of the key behavioural criteria for identifying intentionality in signal production. The reasoning is that modifying/producing a signal when a potential recipient is looking could demonstrate that the sender intends to communicate with them. Here, we show that the production of a primate facial expression can also be sensitive to the attention of the play partner. Using the orangutan (Pongo pygmaeus) Facial Action Coding System (OrangFACS), we demonstrate that facial movements are more intense and more complex when recipient attention is directed towards the sender. Therefore, production of the playface is not an automated response to play (or simply a play behaviour itself) and is instead produced flexibly depending on the context. If sensitivity to attentional stance is a good indicator of intentionality, we must also conclude that the orangutan playface is intentionally produced. However, a number of alternative, lower level interpretations for flexible production of signals in response to the attention of another are discussed. As intentionality is a key feature of human language, claims of intentional communication in related primate species are powerful drivers in language evolution debates, and thus caution in identifying intentionality is important. PMID- 25802804 TI - Evolution of a research field-a micro (RNA) example. AB - Background. Every new scientific field can be traced back to a single, seminal publication. Therefore, a bibliometric analysis can yield significant insights into the history and potential future of a research field. This year marks 21 years since that first ground-breaking microRNA (miRNA) publication. Here, we make the case that the miRNA field is mature, utilising bibliometrics. Methods. Utilising the Web of ScienceTM (WoS) database publication and citation information, we charted the history of miRNA-related publications, describing and dissecting contributions by publication type (plus category, pay-per-view or open access), journal (highlighting dominant journals), by country, citations and languages. Results. We found that the United States of America (USA) publishes the most miRNA papers, followed by China and Germany. Significantly, publications attributed to the USA also receive the most citations per publication, followed by a close grouping of England, Germany and France. We also describe the relevance and acceptance of the miRNA field to different research areas, through its uptake in areas from oncology to plant sciences. Exploring the recent momentous change in publishing, we find that although pay-per view articles vastly out-number open-access articles, the citation rate of pay-per-view articles is currently less than double that of open-access. Conclusions. We believe the trends described here represent the typical evolution of a research field. By analysing publications, citations and distribution patterns, key moments in the evolution of this research area are recognised, indicating the maturation of the miRNA field and providing guidance for future research endeavours. PMID- 25802803 TI - Web party effect: a cocktail party effect in the web environment. AB - In goal-directed web navigation, labels compete for selection: this process often involves knowledge integration and requires selective attention to manage the dizziness of web layouts. Here we ask whether the competition for selection depends on all web navigation options or only on those options that are more likely to be useful for information seeking, and provide evidence in favor of the latter alternative. Participants in our experiment navigated a representative set of real websites of variable complexity, in order to reach an information goal located two clicks away from the starting home page. The time needed to reach the goal was accounted for by a novel measure of home page complexity based on a part of (not all) web options: the number of links embedded within web navigation elements weighted by the number and type of embedding elements. Our measure fully mediated the effect of several standard complexity metrics (the overall number of links, words, images, graphical regions, the JPEG file size of home page screenshots) on information seeking time and usability ratings. Furthermore, it predicted the cognitive demand of web navigation, as revealed by the duration judgment ratio (i.e., the ratio of subjective to objective duration of information search). Results demonstrate that focusing on relevant links while ignoring other web objects optimizes the deployment of attentional resources necessary to navigation. This is in line with a web party effect (i.e., a cocktail party effect in the web environment): users tune into web elements that are relevant for the achievement of their navigation goals and tune out all others. PMID- 25802805 TI - Captive chimpanzee foraging in a social setting: a test of problem solving, flexibility, and spatial discounting. AB - In the wild, primates are selective over the routes that they take when foraging and seek out preferred or ephemeral food. Given this, we tested how a group of captive chimpanzees weighed the relative benefits and costs of foraging for food in their environment when a less-preferred food could be obtained with less effort than a more-preferred food. In this study, a social group of six zoo housed chimpanzees (Pan troglodytes) could collect PVC tokens and exchange them with researchers for food rewards at one of two locations. Food preference tests had revealed that, for these chimpanzees, grapes were a highly-preferred food while carrot pieces were a less-preferred food. The chimpanzees were tested in three phases, each comprised of 30 thirty-minute sessions. In phases 1 and 3, if the chimpanzees exchanged a token at the location they collected them they received a carrot piece (no travel) or they could travel >=10 m to exchange tokens for grapes at a second location. In phase 2, the chimpanzees had to travel for both rewards (>=10 m for carrot pieces, >=15 m for grapes). The chimpanzees learned how to exchange tokens for food rewards, but there was individual variation in the time it took for them to make their first exchange and to discover the different exchange locations. Once all the chimpanzees were proficient at exchanging tokens, they exchanged more tokens for grapes (phase 3). However, when travel was required for both rewards (phase 2), the chimpanzees were less likely to work for either reward. Aside from the alpha male, all chimpanzees exchanged tokens for both reward types, demonstrating their ability to explore the available options. Contrary to our predictions, low-ranked individuals made more exchanges than high-ranked individuals, most likely because, in this protocol, chimpanzees could not monopolize the tokens or access to exchange locations. Although the chimpanzees showed a preference for exchanging tokens for their more-preferred food, they appeared to develop strategies to reduce the cost associated with obtaining the grapes, including scrounging rewards and tokens from group mates and carrying more than one token when travelling to the farther exchange location. By testing the chimpanzees in their social group we were able to tease apart the social and individual influences on their decision making and the interplay with the physical demands of the task, which revealed that the chimpanzees were willing to travel farther for better. PMID- 25802806 TI - Additive global cerebral blood flow normalization in arterial spin labeling perfusion imaging. AB - To determine how different methods of normalizing for global cerebral blood flow (gCBF) affect image quality and sensitivity to cortical activation, pulsed arterial spin labeling (pASL) scans obtained during a visual task were normalized by either additive or multiplicative normalization of modal gCBF. Normalization by either method increased the statistical significance of cortical activation by a visual stimulus. However, image quality was superior with additive normalization, whether judged by intensity histograms or by reduced variability within gray and white matter. PMID- 25802808 TI - Honey bee success predicted by landscape composition in Ohio, USA. AB - Foraging honey bees (Apis mellifera L.) can routinely travel as far as several kilometers from their hive in the process of collecting nectar and pollen from floral patches within the surrounding landscape. Since the availability of floral resources at the landscape scale is a function of landscape composition, apiculturists have long recognized that landscape composition is a critical determinant of honey bee colony success. Nevertheless, very few studies present quantitative data relating colony success metrics to local landscape composition. We employed a beekeeper survey in conjunction with GIS-based landscape analysis to model colony success as a function of landscape composition in the State of Ohio, USA, a region characterized by intensive cropland, urban development, deciduous forest, and grassland. We found that colony food accumulation and wax production were positively related to cropland and negatively related to forest and grassland, a pattern that may be driven by the abundance of dandelion and clovers in agricultural areas compared to forest or mature grassland. Colony food accumulation was also negatively correlated with urban land cover in sites dominated by urban and agricultural land use, which does not support the popular opinion that the urban environment is more favorable to honey bees than cropland. PMID- 25802807 TI - GROM-RD: resolving genomic biases to improve read depth detection of copy number variants. AB - Amplifications or deletions of genome segments, known as copy number variants (CNVs), have been associated with many diseases. Read depth analysis of next generation sequencing (NGS) is an essential method of detecting CNVs. However, genome read coverage is frequently distorted by various biases of NGS platforms, which reduce predictive capabilities of existing approaches. Additionally, the use of read depth tools has been somewhat hindered by imprecise breakpoint identification. We developed GROM-RD, an algorithm that analyzes multiple biases in read coverage to detect CNVs in NGS data. We found non-uniform variance across distinct GC regions after using existing GC bias correction methods and developed a novel approach to normalize such variance. Although complex and repetitive genome segments complicate CNV detection, GROM-RD adjusts for repeat bias and uses a two-pipeline masking approach to detect CNVs in complex and repetitive segments while improving sensitivity in less complicated regions. To overcome a typical weakness of RD methods, GROM-RD employs a CNV search using size-varying overlapping windows to improve breakpoint resolution. We compared our method to two widely used programs based on read depth methods, CNVnator and RDXplorer, and observed improved CNV detection and breakpoint accuracy for GROM-RD. GROM-RD is available at http://grigoriev.rutgers.edu/software/. PMID- 25802810 TI - Long-term atmospheric deposition of nitrogen, phosphorus and sulfate in a large oligotrophic lake. AB - We documented significantly increasing trends in atmospheric loading of ammonium (NH4) and nitrate/nitrite (NO2/3) and decreasing trends in total phosphorus (P) and sulfate (SO4) to Flathead Lake, Montana, from 1985 to 2004. Atmospheric loading of NO2/3 and NH4 increased by 48 and 198% and total P and SO4 decreased by 135 and 39%. The molar ratio of TN:TP also increased significantly. Severe air inversions occurred periodically year-round and increased the potential for substantial nutrient loading from even small local sources. Correlations between our loading data and various measures of air quality in the basin (e.g., particulate matter <10 um in size, aerosol fine soil mass, aerosol nutrient species, aerosol index, hectares burned) suggest that dust and smoke are important sources. Ammonium was the primary form of N in atmospheric deposition, whereas NO3 was the primary N form in tributary inputs. Atmospheric loading of NH4 to Flathead Lake averaged 44% of the total load and on some years exceeded tributary loading. Primary productivity in the lake is colimited by both N and P most of the year; and in years of high atmospheric loading of inorganic N, deposition may account for up to 6.9% of carbon converted to biomass. PMID- 25802809 TI - Association of academic stress with sleeping difficulties in medical students of a Pakistani medical school: a cross sectional survey. AB - Introduction. Medicine is one of the most stressful fields of education because of its highly demanding professional and academic requirements. Psychological stress, anxiety, depression and sleep disturbances are highly prevalent in medical students. Methods. This cross-sectional study was undertaken at the Combined Military Hospital Lahore Medical College and the Institute of Dentistry in Lahore (CMH LMC), Pakistan. Students enrolled in all yearly courses for the Bachelor of Medicine and Bachelor of Surgery (MBBS) degree were included. The questionnaire consisted of four sections: (1) demographics (2) a table listing 34 potential stressors, (3) the 14-item Perceived Stress Scale (PSS-14), and (4) the Pittsburgh Quality of Sleep Index (PSQI). Logistic regression was run to identify associations between group of stressors, gender, year of study, student's background, stress and quality of sleep. Results. Total response rate was 93.9% (263/280 respondents returned the questionnaire). The mean (SD) PSS-14 score was 30 (6.97). Logistic regression analysis showed that cases of high-level stress were associated with year of study and academic-related stressors only. Univariate analysis identified 157 cases with high stress levels (59.7%). The mean (SD) PSQI score was 8.1 (3.12). According to PSQI score, 203/263 respondents (77%) were poor sleepers. Logistic regression showed that mean PSS-14 score was a significant predictor of PSQI score (OR 1.99, P < 0.05). Conclusion. We found a very high prevalence of academic stress and poor sleep quality among medical students. Many medical students reported using sedatives more than once a week. Academic stressors contributed significantly to stress and sleep disorders in medical students. PMID- 25802811 TI - Size class structure, growth rates, and orientation of the central Andean cushion Azorella compacta. AB - Azorella compacta (llareta; Apiaceae) forms dense, woody, cushions and characterizes the high elevation rocky slopes of the central Andean Altiplano. Field studies of an elevational gradient of A. compacta within Lauca National Park in northern Chile found a reverse J-shape distribution of size classes of individuals with abundant small plants at all elevations. A new elevational limit for A. compacta was established at 5,250 m. A series of cushions marked 14 years earlier showed either slight shrinkage or small degrees of growth up to 2.2 cm yr(-1). Despite their irregularity in growth, cushions of A. compacta show a strong orientation, centered on a north-facing aspect and angle of about 20 degrees from horizontal. This exposure to maximize solar irradiance closely matches previous observations of a population favoring north-facing slopes at a similar angle. Populations of A. compacta appear to be stable, or even expanding, with young plants abundant. PMID- 25802812 TI - Ecological correlates to cranial morphology in Leporids (Mammalia, Lagomorpha). AB - The mammalian order Lagomorpha has been the subject of many morphometric studies aimed at understanding the relationship between form and function as it relates to locomotion, primarily in postcranial morphology. The leporid cranial skeleton, however, may also reveal information about their ecology, particularly locomotion and vision. Here we investigate the relationship between cranial shape and the degree of facial tilt with locomotion (cursoriality, saltation, and burrowing) within crown leporids. Our results suggest that facial tilt is more pronounced in cursors and saltators compared to generalists, and that increasing facial tilt may be driven by a need for expanded visual fields. Our phylogenetically informed analyses indicate that burrowing behavior, facial tilt, and locomotor behavior do not predict cranial shape. However, we find that variables such as bullae size, size of the splenius capitus fossa, and overall rostral dimensions are important components for understanding the cranial variation in leporids. PMID- 25802813 TI - Estimating relative risk of within-lake aquatic plant invasion using combined measures of recreational boater movement and habitat suitability. AB - Effective monitoring, prevention and impact mitigation of nonindigenous aquatic species relies upon the ability to predict dispersal pathways and receiving habitats with the greatest risk of establishment. To examine mechanisms affecting species establishment within a large lake, we combined observations of recreational boater movements with empirical measurements of habitat suitability represented by nearshore wave energy to assess the relative risk of Eurasian watermilfoil (Myriophyllum spicatum) establishment. The model was evaluated using information from a 17 year (1995-2012) sequence of M. spicatum presence and absence monitoring. M. spicatum presence was not specifically correlated with recreational boater movements; however its establishment appears to be limited by wave action in Lake Tahoe. Of the sites in the "High" establishment risk category (n = 37), 54% had current or historical infestations, which included 8 of the 10 sites with the highest relative risk. Of the 11 sites in the "Medium" establishment risk category, 5 had current or historical M. spicatum populations. Most (76%) of the sites in the "Low" establishment risk category were observed in locations with higher wave action. Four sites that received zero boater visits from infested locations were occupied by M. spicatum. This suggests that the boater survey either represents incomplete coverage of boater movement, or other processes, such as the movement of propagules by surface currents or introductions from external sources are important to the establishment of this species. This study showed the combination of habitat specific and dispersal data in a relative risk framework can potentially reduce uncertainty in estimates of invasion risk. PMID- 25802814 TI - How much biomass do plant communities pack per unit volume? AB - Aboveground production in terrestrial plant communities is commonly expressed in amount of carbon, or biomass, per unit surface. Alternatively, expressing production per unit volume allows the comparison of communities by their fundamental capacities in packing carbon. In this work we reanalyzed published data from more than 900 plant communities across nine ecosystems to show that standing dry biomass per unit volume (biomass packing) consistently averages around 1 kg/m(3) and rarely exceeds 5 kg/m(3) across ecosystem types. Furthermore, we examined how empirical relationships between aboveground production and plant species richness are modified when standing biomass is expressed per unit volume rather than surface. We propose that biomass packing emphasizes species coexistence mechanisms and may be an indicator of resource use efficiency in plant communities. PMID- 25802815 TI - A pilot study to evaluate the magnitude of association of the use of electronic personal health records with patient activation and empowerment in HIV-infected veterans. AB - The HITECH Act signed into law in 2009 requires hospitals to provide patients with electronic access to their health information through an electronic personal health record (ePHR) in order to receive Medicare/Medicaid incentive payments. Little is known about who uses these systems or the impact these systems will have on patient outcomes in HIV care. The health care empowerment model provides rationale for the hypothesis that knowledge from an electronic personal health record can lead to greater patient empowerment resulting in improved outcomes. The objective was to determine the patient characteristics and patient activation, empowerment, satisfaction, knowledge of their CD4, Viral Loads, and antiretroviral medication, and medication adherence outcomes associated with electronic personal health record use in Veterans living with HIV at the San Francisco VA Medical Center. The participants included HIV-Infected Veterans receiving care in a low volume HIV-clinic at the San Francisco VA Medical Center, divided into two groups of users and non-users of electronic personal health records. The research was conducted using in-person surveys either online or on paper and data abstraction from medical records for current anti-retroviral therapy (ART), CD4 count, and plasma HIV-1 viral load. The measures included the Patient Activation Measure, Health Care Empowerment Inventory, ART adherence, provider satisfaction, current CD4 count, current plasma viral load, knowledge of current ART, knowledge of CD4 counts, and knowledge of viral load. In all, 40 participants were recruited. The use of electronic personal health records was associated with significantly higher levels of patient activation and levels of patient satisfaction for getting timely appointments, care, and information. ePHR was also associated with greater proportions of undetectable plasma HIV-1 viral loads, of knowledge of current CD4 count, and of knowledge of current viral load. The two groups differed by race and computer access. There was no difference in the current CD4, provider satisfaction, Health Care Empowerment Inventory score, satisfaction with provider-patient communication, satisfaction with courteous and helpful staff, knowledge of ART, or ART adherence. The use of electronic personal health records is associated with positive clinical and behavioral characteristics. The use of these systems may play a role in improving the health of people with HIV. Larger studies are needed to further evaluate these associations. PMID- 25802817 TI - Detection of Legionella spp. by a nested-PCR assay in air samples of a wastewater treatment plant and downwind distances in Isfahan. AB - BACKGROUND: Wastewater contains a variety of pathogens and bio -aerosols generated during the wastewater treatment process, which could be a potential health risk for exposed individuals. This study was carried out to detect Legionella spp. in the bio -aerosols generated from different processes of a wastewater treatment plant (WWTP) in Isfahan, Iran, and the downwind distances. MATERIALS AND METHODS: A total of 54 air samples were collected and analyzed for the presence of Legionella spp. by a nested- polymerase chain reaction (PCR) assay. A liquid impingement biosampler was used to capture bio -aerosols. The weather conditions were also recorded. RESULTS: Legionella were detected in 6% of the samples, including air samples above the aeration tank (1/9), belt filter press (1/9), and 250 m downwind (1/9). CONCLUSION: The result of this study revealed the presence of Legionella spp. in air samples of a WWTP and downwind distance, which consequently represent a potential health risk to the exposed individuals. PMID- 25802816 TI - Patterns of evolution of MHC class II genes of crows (Corvus) suggest trans species polymorphism. AB - A distinguishing characteristic of genes that code for the major histocompatibility complex (MHC) is that alleles often share more similarity between, rather than within species. There are two likely mechanisms that can explain this pattern: convergent evolution and trans-species polymorphism (TSP), in which ancient allelic lineages are maintained by balancing selection and retained by descendant species. Distinguishing between these two mechanisms has major implications in how we view adaptation of immune genes. In this study we analyzed exon 2 of the MHC class IIB in three passerine bird species in the genus Corvus: jungle crows (Corvus macrorhynchos japonensis) American crows (C. brachyrhynchos) and carrion crows (C. corone orientalis). Carrion crows and American crows are recently diverged, but allopatric, sister species, whereas carrion crows and jungle crows are more distantly related but sympatric species, and possibly share pathogens linked to MHC IIB polymorphisms. These patterns of evolutionary divergence and current geographic ranges enabled us to test for trans-species polymorphism and convergent evolution of the MHC IIB in crows. Phylogenetic reconstructions of MHC IIB sequences revealed several well supported interspecific clusters containing all three species, and there was no biased clustering of variants among the sympatric carrion crows and jungle crows. The topologies of phylogenetic trees constructed from putatively selected sites were remarkably different than those constructed from putatively neutral sites. In addition, trees constructed using non-synonymous substitutions from a continuous fragment of exon 2 had more, and generally more inclusive, supported interspecific MHC IIB variant clusters than those constructed from the same fragment using synonymous substitutions. These phylogenetic patterns suggest that recombination, especially gene conversion, has partially erased the signal of allelic ancestry in these species. While clustering of positively selected amino acids by supertyping revealed a single supertype shared by only jungle and carrion crows, a pattern consistent with convergence, the overall phylogenetic patterns we observed suggest that TSP, rather than convergence, explains the interspecific allelic similarity of MHC IIB genes in these species of crows. PMID- 25802818 TI - A study of psychological well-being in people with multiple sclerosis and their primary caregivers. AB - BACKGROUND: Multiple sclerosis (MS) is the most common disabling disease of the central nervous system. In these patients, fatigue is the most common symptom that causes disorder in the work, social activities and daily functions of the patients. Given the assumption that MS reduces the patients' psychological well being, this study aimed at assessing the psychological well-being of both the patients and their primary caregivers. MATERIALS AND METHODS: Current research as a descriptive study was conducted on 200 MS patients and 200 primary caregivers. For data collection, the Reef questionnaire was used to determine psychological well-being of these individuals. Data were analyzed using SPSS software. RESULTS: According to the obtained results, the mean duration of MS was estimated 6.37 years. The psychological well-being score of the people with MS and their primary caregivers was slightly higher than average. The total score of psychological well-being in primary caregivers was higher than the patients. CONCLUSION: The mean score of psychological well-being subscales was significantly different in patients and their caregivers. Regarding the autonomy subscale, there was a significant different in patients with MS, that is, it was lower than average. In terms of two subscales of "positive relationship with others" and "personal growth," there was no difference between people with MS and the primary caregivers, and for other subscales, the mean score of caregivers was higher than the patients. PMID- 25802819 TI - Practical approach to electrodiagnosis of the carpal tunnel syndrome: A review. AB - Despite being the most common entrapment neuropathy and the most common reason for referral to the electromyography (EMG) laboratory, the diagnosis of carpal tunnel syndrome (CTS) continues to be challenging due to a large number of electrodiagnostic (EDX) tests available. We present a flowchart and propose a practical approach to the diagnosis of CTS using the available literature and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) guidelines and the Practice Parameter for Electrodiagnostic Studies in Carpal Tunnel Syndrome. PMID- 25802820 TI - Peripheral communications of intercostobrachial nerve Peripheral communications of the intercostobrachial nerve in relation to the alar thoracic artery. AB - The intercostobrachial nerve (ICBN) is often encountered during axillary dissection for axillary lymph node dissection (ALND) for diagnostic and therapeutic surgery for mastectomy. The present report is a case observed in the Department of Anatomy at Vardhman Mahavir Medical College, Delhi during routine dissection of the upper extremity of a male cadaver for first year undergraduate medical students. On the right side, the medial cord of brachial plexus gave two medial cutaneous nerves of arm. Both the nerves were seen communicating with the branches of the ICBN. The ICBN and one of its branches were surrounding the termination of an alar thoracic artery. These peripheral neural connections of the ICBN with the branches of the medial cord can be a cause of sensory impairment during axillary procedures done for mastectomy or exploration of long thoracic nerves. The alar thoracic artery found in relation to the ICBN could further be a cause of vascular complications during such procedures. PMID- 25802821 TI - Comparison of the findings of endothelial specular microscopy before and after corneal cross-linking. AB - BACKGROUND: To report the long-term findings of corneal cross-linking (CXL) with riboflavin drops on the corneal endothelial cell. MATERIALS AND METHODS: In this prospective non-randomized study, we aim to assess the long-term safety of CXL on the corneal endothelium for the treatment of progressive keratoconus, by endothelial specular microscopy. A total of 68 eyes of 42 keratoconus patients were selected. We checked the corneal thickness (with ultrasonic pachymetry), endothelial cell density, pleomorphism, and polymegathism (with specular microscopy) of the endothelial cells, before CXL and one year after this procedure. RESULTS: The mean +/- SD of the preoperative and postoperative corneal thicknesses were 470 +/- 40 MUm and 469.8 +/- 42 MUm, respectively (p-value = 0.591). The mean +/- SD of the preoperative and postoperative endothelial cell densities were 2753 +/- 230 cells/mm[2] and 2699 +/- 210 cells/mm,[2] respectively (p-value = 0.004). We found reduction in the endothelial cell density after CXL, but this reduction was less significant in a corneal thickness of less than 400 MUm (which was treated with hypo-osmolar riboflavin 0.1% drops) compared to the corneal thickness of more than 450 MUm. We did not find any significant differences in the cell shapes (pleomorphism) (p-value = 0.517), but the cell sizes (polymegathism) were changed after the procedure (p-value = 0.021). CONCLUSION: We found a significant decrease in endothelial corneal cell density after CXL, but this reduction was low; also the size of these cells increased after CXL. We believe that other parameters besides the corneal thickness may be the determinant factors for the changing of cell density and cell size in corneal endothelial cells. PMID- 25802823 TI - The value of transcranial Doppler derived pulsatility index for diagnosing cerebral small-vessel disease. AB - BACKGROUND: The pulsatility index (PI), measured by transcranial Doppler (TCD) ultrasonography, can reflect vascular resistance induced by cerebral small-vessel disease (SVD). We evaluated the value of TCD-derived PI for diagnosing SVD as compared with magnetic resonance imaging (MRI). MATERIALS AND METHODS: Fifty-six consecutive cases with SVD (based on MRI) and 48 controls with normal MRI underwent TCD. Based on MRI findings, patients were categorized into five subgroups of preventricular hyperintensity (PVH), deep white matter hyperintensity (DWMH), lacunar, pontin hyperintensity (PH), and PVH+DWMH+lacunar. The sensitivity and specificity of TCD in best PI cut-off points were calculated in each group. RESULTS: The sensitivity and specificity of TCD in comparison with MRI with best PI cut-off points were as follows: In PVH with PI = 0.83, the sensitivity and specificity was 90% and 98%, respectively. In DWMH with PI = 0.79, the sensitivity and specificity was 75% and 87.5%, respectively. In lacunar with PI = 0.80, the sensitivity and specificity was 73% and 90%, respectively. In PH with PI = 0.69, the sensitivity and specificity was 92% and 87.5%, respectively. And, in PVH+DWMH+lacunar subgroup with PI = 0.83, the sensitivity and specificity was 90% and 96%, respectively. CONCLUSIONS: Increased TCD derived PI can accurately indicate the SVD. Hence, TCD can be used as a non-invasive and inexpensive method for diagnosing SVD, and TCD-derived PI can be considered as a physiologic index of the disease as well. PMID- 25802824 TI - Increase in intraocular pressure is less with propofol and remifentanil than isoflurane with remifentanil during cataract surgery: A randomized controlled trial. AB - BACKGROUND: This double-blinded, randomized clinical trial was designed to evaluate intraocular pressure (IOP) change in cataract surgery using the combination of propofol and remifentanil or the combination of isoflurane and remifentanil. MATERIALS AND METHODS: One hundred sixty patients were randomly allocated to a maintenance anesthetic consisting of remifentanil + isoflurane (group I), normal saline + isoflurane (group II), propofol + remifentanil (group III) or normal saline + propofol (group IV). IOP was measured at seven predefined time points, baseline (T0), 3 min after the start of continuous remifentanil infusion (T2), after induction of anesthesia (T3), immediately after laryngoscopy and intubation (T4), 5 min after laryngoscopy (T5), immediately after the block of continuous remifentanil infusion (T6) and 3 min after T6 (T7). Outcomes included IOP, systole blood pressure (SBP) and diastole blood pressure (DBP), mean arterial pressure (MAP) and heart rate (HR). RESULTS: The mean of IOP in Group III was lower than other groups and in group IV was higher than other groups. At time point T4 and T5 differences in the mean of IOP between groups III and IV was significantly different (P > 0.05). The trend in changes in the mean of IOP was statistically significant among groups (P value = 0.01). The trends in changes in the mean of SBP, DBP and MAP were not significantly different among groups (P value = 0.41). HR in group III was significantly lower than other groups. The trend in changes in the mean of HR was significantly different among groups (P value = 0.002). CONCLUSION: Propofol with remifentanil was more effective than placebo or adding remifentanil to isoflurane in management of IOP in cataract surgery. PMID- 25802822 TI - Neurotrophic factors and their effects in the treatment of multiple sclerosis. AB - Neurotrophins are small molecules of polypeptides, which include nerve growth factor (NGF) family, glial cell line-derived neurotrophic factor (GDNF) family ligands, and neuropoietic cytokines. These factors have an important role in neural regeneration, remyelination, and regulating the development of the peripheral and central nervous systems (PNS and CNS, respectively) by intracellular signaling through specific receptors. It has been suggested that the pathogenesis of human neurodegenerative disorders may be due to an alteration in the neurotrophic factors and their receptors. The use of neurotrophic factors as therapeutic agents is a novel strategy for restoring and maintaining neuronal function during neurodegenerative disorders such as multiple sclerosis. Innate and adaptive immune responses contribute to pathology of neurodegenerative disorders. Furthermore, autoimmune and mesenchymal stem cells, by the release of neurotrophic factors, have the ability to protect neuronal population and can efficiently suppress the formation of new lesions. So, these cells may be an alternative source for delivering neurotrophic factors into the CNS. PMID- 25802825 TI - Which one is more efficient on propofol 2% injection pain? Magnesium sulfate or ondansetron: A randomized clinical trial. AB - BACKGROUND: Painful sensation has been reported after propofol injection in most of the patients but no definite mechanism for this painful sensation has been proposed yet. The present randomized clinical trial compares analgesic effect of ondansetron, magnesium sulphate (MS) and placebo on patients after propofol 2% injection. MATERIALS AND METHODS: The present randomized clinical trial with parallel design was performed on 90 patients American Society of Anesthesiologists I-II undergoing general anesthesia within vitrectomy operation with propofol induction. Subjects were randomly allocated into three groups with 30 patients each: (1) MS group (2) ondansetron group and (3) normal saline (NS) group as placebo group. Anesthesia induction and maintenance were the same between groups. Pain intensity of propofol injection in subjects was assessed by a four-point scale (none 0, mild 1, moderate 2 and severe 3) at four time intervals (5, 10, 20 and 25 s) after injection. RESULTS: MS and ondansetron had significant impacts on pain reduction after propofol 2% injection in comparison with NS as placebo. Comparing two trial groups did not have any significant priority for analgesic impact. CONCLUSION: Using ondansetron or MS had no priority on each other on declining propofol injection induced pain. PMID- 25802827 TI - Life-threatening misdiagnosis of bulbar onset myasthenia gravis as a motor neuron disease: How much can one rely on exaggerated deep tendon reflexes. AB - The autoimmune disease myasthenia gravis (MG), can mimic a variety of neurological disorders leading to a delay in diagnosis and treatment. On occasions, misdiagnosis of MG could lead to unnecessary therapeutic interventions. We report the case of a 50 year-old man, in whom MG was mistaken for motor neuron disease (MND). Subsequently, correct diagnosis and optimal management resulted in saving his life and significant improvement in his functional status. We discuss the importance of considering MG as one of the potential differential diagnoses among cases of new onset or recurrent unexplained bulbar symptoms, despite exaggerated deep tendon reflexes. Also, a literature review on the misdiagnosis of MG and the potential pitfalls in MG diagnosis are discussed. PMID- 25802826 TI - Molecular detection of metallo-beta-lactamase gene blaVIM-1 in imipenem-resistant Pseudomonas aeruginosa strains isolated from hospitalized patients in the hospitals of Isfahan. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic human pathogen that causes serious problems, especially in people, who have immunodeficiency. In recent times, metallo-beta-lactamase (MBLs) resistance in this bacterium has led to some difficulties in treating bacterial infections. The metallo-beta-lactamase family of genes, including blaVIM-1, is being reported with increasing frequency worldwide. The aim of this study is the detection of the metallo-beta-lactamase gene blaVIM-1 in imipenem-resistant P. aeruginosa (IRPA) strains isolated from hospitalized patients. MATERIALS AND METHODS: In this study, 106 P. aeruginosa samples were isolated from various nosocomial infections. The isolates were identified, tested for susceptibility to various antimicrobial agents by the Kirby-Bauer disk diffusion method, and all the imipenem-resistant isolates were screened for the presence of MBLs by using the combined disk (IMP-EDTA). The minimal inhibitory concentration (MIC) of imipenem was determined by E-test on the Mueller-Hinton agar. To detect the blaVIM-1 gene, the isolates were subjected to a polymerase chain reaction (PCR). RESULTS: Of all the P. aeruginosa isolates, 62 (58.5%) were found to be imipenem-resistant P. aeruginosa (MIC >=32 MUg/ml). Twenty-six (42%) of the imipenem-resistant isolates were MBL positive. None of these isolates carried the blaVIM-1 gene using the PCR assay. CONCLUSION: The results demonstrated the serious therapeutic threat of the MBL-producing P. aeruginosa populations. The rate of imipenem resistance due to MBL was increased dramatically. Early detection and infection-control practices are the best antimicrobial strategies for this organism. None of MBL-producing isolates in this study carry the blaVIM-1 gene; therefore, another gene in the MBL family should be investigated. PMID- 25802828 TI - The investigation of correlation between Iminoral concentration and neurotoxic levels after kidney transplantation. AB - BACKGROUND: Neurotoxicity side effects related to cyclosporine kinetics could lead to dysfunction of kidney graft and patient outcome after transplantation. The aim of this study was evidence-based pharmacotherapy of kidney transplant recipients and to investigate neurotoxic levels of Iminoral. MATERIALS AND METHODS: The results of 2239 cyclosporine trough levels obtained from 743 patients were studied. Seventy-five adult kidney recipients who received Iminoral were studied for neurotoxicity symptoms. Demographic, clinical, hematology and biochemical data were recorded in d-base and analyzed using SPSS application for windows. RESULTS: The mean value related to cyclosporine C0 was 246.3 MUg/l. In the 48% the signs of neurotoxicity such as tremor and headache were noted, but only in 9% the levels of cyclosporine C0 were >400 MUg/l. Further studies on 75 patients showed that the incidence of neurotoxic side effects were as follows: Tremor in 35, headache in 24 and anxiety in 34 recipients of kidney. The prescribed drug regimens from the day of transplant in most patients were based on mycophenolic acid or cellcept, pulse therapy using methylprednisolone (daily from kidney transplant up to 3 days after transplant), cyclosporine or Iminoral plus other drugs related to each individual. Administrations of ganciclovir, thymoglobulin, clotrimazol and prednisolone were also distinguished with immunosuppressant-based therapy simultaneously. CONCLUSION: Evidence-based study related to pharmacotherapy of Iminoral showed that clinical presentation related to neurotoxic side effects such as tremor, headache and anxiety might be due to many factors such as polypharmacy. Planning immunosuppression to individual patients based on programmed therapeutic Iminoral monitoring, avoiding polypharmacy in terms of removal or drug minimization and focusing on first week after transplant seem to be a realistic option. PMID- 25802829 TI - Do pregnant women have a higher risk for venous thromboembolism following air travel? AB - International travel has become increasingly common and accessible, and it is part of everyday life in pregnant women. Venous thromboembolism (VTE) is a serious public health disorder that occurs following long-haul travel, especially after air travel. The normal pregnancy is accompanied by a state of hypercoagulability and hypofibrinolysis. Thus, it seems that pregnant women are at a higher risk of VTE following air travel, and, if they have preexisting risk factors, this risk would increase. There is limited data about travel-related VTE in pregnant women; therefore, in the present study, we tried to evaluate the pathogenesis of thrombosis, association of thrombosis and air travel, risk factors and prevention of VTE in pregnant women based on available evidences. Pregnancy is associated with a five- to 10-fold increased risk of VTE compared with nonpregnant women; however, during the postpartum period, this risk would increase to 20-80-fold. Furthermore, the risk of thrombosis is higher in individuals with preexisting risk factors, and the most common risk factor for VTE during pregnancy is a previous history of VTE. Pregnant women are at a higher risk for thrombosis compared with other women. Thus, the prevention of VTE and additional risk factors should be considered for all pregnant women who travel by plane. PMID- 25802830 TI - Circadian type, chronic fatigue, and serum IgM in the shift workers of an industrial organization. AB - BACKGROUND: Night shift workers are more vulnerable to immune-related diseases. Immunoglobulin M (IgM) is a potent activator of complement, and complement has a crucial role in defense against bacterial infections. Circadian type is known as an effective agent on vulnerability and adaptation with shift work due to non compliance with shift stress. The objective of this study was to investigate the correlation of circadian type and chronic fatigue with the serum concentration of IgM in a group of shift workers. MATERIALS AND METHODS: This cross-sectional study was performed in an industrial organization in Isfahan, Iran. The study population consisted of 221 male employees working at night shifts who were selected by random cluster sampling. The following questionnaires were used: composite morningness (Torsvall and Akerstedt), circadian type (Folkard), and chronic fatigue (Barton and colleagues). The serum concentration of IgM was measured by the nephelometric method. The data were analyzed with the Pearson coefficient correlation and the path analysis for finding the pattern of the structural equations to evaluate the direct and indirect relationships between variables, using the SPSS 15 and LISREL 8.5 statistical software. RESULTS: Significant correlation was documented between morningness, flexibility, languidness, and chronic fatigue with the serum concentration of IgM (P < 0.01). CONCLUSION: The results showed that the shift workers with morningness and languidness experienced more problems during the working hours due to more tiredness, and had decreased serum concentration of IgM. Correct management of shift work may attenuate fatigue in workers and also improve many health issues experienced by the shift workers. PMID- 25802831 TI - Pentacam topographic changes after collagen cross-linking in patients with keratoconus. AB - BACKGROUND: Corneal cross-linking (CXL) with riboflavin and ultra-violet A is less invasive in comparison with other procedures such as penetrating keratoplasty. Hence, we planned this study to evaluate the efficacy of CXL in disease progression and to compare keratoconus indices before and 1 year after cross-linking by Pentacam. MATERIALS AND METHODS: In this prospective clinical trial, we enrolled 37 eyes of 37 patients suffering from keratoconus who were candidates for CXL. All eyes were examined before and one 1 year after surgery with a slit lamp and Pentacam for corneal topography. To compare the mean of each Pentacam parameter and index before and 1 year after the surgery, we used paired t-test. RESULTS: There were 23 males and 14 females. The mean age was 21.5 years 18-30 years). At the 12(th) month examination, the corneal thickness had decreased (P = 0.0068) and the Index of Height Decentration (IHD) had increased (P = 0.016). There were no statistically significant differences in other indices and parameters 1 year after CXL. CONCLUSION: Most of the parameters and indices had not changed during 1 year after CXL. The procedure seems to be effective in stopping the disease progression at least for 12 months after surgery. PMID- 25802832 TI - Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation. AB - Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs. PMID- 25802833 TI - Effect of salinity on biomass yield and physiological and stem-root anatomical characteristics of purslane (Portulaca oleracea L.) accessions. AB - 13 selected purslane accessions were subjected to five salinity levels 0, 8, 16, 24, and 32 dS m(-1). Salinity effect was evaluated on the basis of biomass yield reduction, physiological attributes, and stem-root anatomical changes. Aggravated salinity stress caused significant (P < 0.05) reduction in all measured parameters and the highest salinity showed more detrimental effect compared to control as well as lower salinity levels. The fresh and dry matter production was found to increase in Ac1, Ac9, and Ac13 from lower to higher salinity levels but others were badly affected. Considering salinity effect on purslane physiology, increase in chlorophyll content was seen in Ac2, Ac4, Ac6, and Ac8 at 16 dS m(-1) salinity, whereas Ac4, Ac9, and Ac12 showed increased photosynthesis at the same salinity levels compared to control. Anatomically, stem cortical tissues of Ac5, Ac9, and Ac12 were unaffected at control and 8 dS m(-1) salinity but root cortical tissues did not show any significant damage except a bit enlargement in Ac12 and Ac13. A dendrogram was constructed by UPGMA based on biomass yield and physiological traits where all 13 accessions were grouped into 5 clusters proving greater diversity among them. The 3-dimensional principal component analysis (PCA) has also confirmed the output of grouping from cluster analysis. Overall, salinity stressed among all 13 purslane accessions considering biomass production, physiological growth, and anatomical development Ac9 was the best salt-tolerant purslane accession and Ac13 was the most affected accession. PMID- 25802834 TI - Immunohistological analysis of ABCD3 expression in Caucasian and African American prostate tumors. AB - In a previously published study, we showed that expression of the ABCD3 gene increased with increasing metastatic potential in a panel of prostate cancer cell lines derived from African American and Caucasian American men. Given importance of identifying biomarker(s) that can distinguish indolent versus aggressive prostate tumors, we conducted an immunohistochemical analysis of ABCD3 expression Caucasian and African American prostate tumors. ABCD3 expression in each patient population was compared with clinicopathologic characteristics, Gleason score, and age. ABCD3 expression increased with increasing Gleason score (P = 0.0094), age (P = 0.0014), and pathology grade (P = 0.0007) in Caucasian patients. Interestingly, in the AA patients, ABCD3 expression highly increased to the same degree in both low and high Gleason score tumors. Similarly, ABCD3 expression was elevated to the same degree in BPH derived from AA. Our findings demonstrate that increased ABCD3 expression correlates with Gleason Score in CA prostate tumors. However, in AA prostate tumors, ABCD3 expression was higher and was sustained in both low Gleason and high Gleason AA tumors. While the functional role of ABCD3 in prostate cancer is not completely elucidated, this gene warrants further study as a potential biomarker for aggressive prostate. PMID- 25802835 TI - Bone marrow pathology predicts mortality in chronic hemodialysis patients. AB - INTRODUCTION: A bone marrow biopsy is a useful procedure for the diagnosis and staging of various hematologic and systemic diseases. The objective of this study was to investigate whether the findings of bone marrow studies can predict mortality in chronic hemodialysis patients. METHODS: Seventy-eight end-stage renal disease patients on maintenance hemodialysis underwent bone marrow biopsies between 2000 and 2011, with the most common indication being unexplained anemia followed by unexplained leukocytosis and leukopenia. RESULTS: The survivors had a higher incidence of abnormal megakaryocyte distribution (P = 0.001), band and segmented cells (P = 0.021), and lymphoid cells (P = 0.029) than the nonsurvivors. The overall mortality rate was 38.5% (30/78), and the most common cause of mortality was sepsis (83.3%) followed by respiratory failure (10%). In multivariate Cox regression analysis, both decreased (OR 3.714, 95% CI 1.671 8.253, P = 0.001) and absent (OR 9.751, 95% CI 2.030-45.115, P = 0.004) megakaryocyte distribution (normal megakaryocyte distribution as the reference group), as well as myeloid/erythroid ratio (OR 1.054, CI 1.012-1.098, P = 0.011), were predictive of mortality. CONCLUSION: The results of a bone marrow biopsy can be used to assess the pathology, and, in addition, myeloid/erythroid ratio and abnormal megakaryocyte distribution can predict mortality in chronic hemodialysis patients. PMID- 25802836 TI - Bioaccessible antioxidants in milk fermented by Bifidobacterium longum subsp. longum strains. AB - Bifidobacterium longum subsp. longum is among the dominant species of the human gastrointestinal microbiota and could thus have potential as probiotics. New targets such as antioxidant properties have interest for beneficial effects on health. The objective of this study was to evaluate the bioaccessibility of antioxidants in milk fermented by selected B. longum subsp. longum strains during in vitro dynamic digestion. The antioxidant capacity of cell extracts from 38 strains, of which 32 belong to B. longum subsp. longum, was evaluated with the ORAC (oxygen radical absorbance capacity) method. On the basis of screening and gene sequence typing by multilocus locus sequence analysis (MLSA), five strains were chosen for fermenting reconstituted skim milk. Antioxidant capacity varied among the strains tested (P = 0.0009). Two strains of B. longum subsp. longum (CUETM 172 and 171) showed significantly higher ORAC values than the other bifidobacteria strains. However, there does not appear to be a relationship between gene sequence types and antioxidant capacity. The milk fermented by each of the five strains selected (CUETM 268, 172, 245, 247, or PRO 16-10) did not have higher initial ORAC values compared to the nonfermented milk samples. However, higher bioaccessibility of antioxidants in fermented milk (175-358%) was observed during digestion. PMID- 25802837 TI - Activity of alpha1-antitrypsin and some lysosomal enzymes in the blood serum of patients with chronic obstructive pulmonary disease after smoking cessation. AB - The activity of alpha1-antitrypsin (AAT) and the lysosomal enzymes, cathepsin D (CTS D), arylsulfatase (ASA), and acid phosphatase, (AcP) was determined in patients with COPD (GOLD category A). Moreover, the diagnostic usefulness of these parameters in blood serum was assessed along with establishing whether smoking cessation affects these parameters. The study included 70 patients with COPD who ceased smoking (study group) and two control groups of 33 subjects each: nonsmokers without COPD (control I) and patients with COPD who continued smoking (control II). In control I, blood was taken once and in control II, at the start of the experiment and after the 1st, 2nd, and 3rd months. AAT in the patients exhibited higher activity than in the healthy subjects at all time points. AAT activity in the patients before the start of the experiment was ~80% higher (P < 0.001) than in control I. No statistically significant differences in CTS D, ASA, and AcP activity were found. COPD involves increased AAT activity and unchanged activities of the assessed lysosomal enzymes. Three-month tobacco abstinence does not affect these parameters in peripheral blood. Determining the AAT levels in blood serum can be used in the diagnostics of COPD. PMID- 25802838 TI - Cardiac function in a long-term follow-up study of moderate and severe porcine model of chronic myocardial infarction. AB - BACKGROUND: Novel therapies need to be evaluated in a relevant large animal model that mimics the clinical course and treatment in a reasonable time frame. To reliably assess therapeutic efficacy, knowledge regarding the translational model and the course of disease is needed. METHODS: Landrace pigs were subjected to a transient occlusion of the proximal left circumflex artery (LCx) (n = 6) or mid left anterior descending artery (LAD) (n = 6) for 150 min. Cardiac function was evaluated before by 2D echocardiography or 3D echocardiography and pressure volume loop analysis. At 12 weeks of follow-up the heart was excised for histological analysis and infarct size calculations. RESULTS: Directly following AMI, LVEF was severely reduced compared to baseline in the LAD group (-17.1 +/- 1.6%, P = 0.009) compared to only a moderate reduction in the LCx group (-5.9 +/- 1.5%, P = 0.02) and this effect remained unchanged during 12 weeks of follow-up. CONCLUSION: Two models of chronic MI, representative for different patient groups, can reproducibly be created through clinically relevant ischemia reperfusion of the mid-LAD and proximal LCx. PMID- 25802839 TI - Prediction of antimicrobial peptides based on sequence alignment and support vector machine-pairwise algorithm utilizing LZ-complexity. AB - This study concerns an attempt to establish a new method for predicting antimicrobial peptides (AMPs) which are important to the immune system. Recently, researchers are interested in designing alternative drugs based on AMPs because they have found that a large number of bacterial strains have become resistant to available antibiotics. However, researchers have encountered obstacles in the AMPs designing process as experiments to extract AMPs from protein sequences are costly and require a long set-up time. Therefore, a computational tool for AMPs prediction is needed to resolve this problem. In this study, an integrated algorithm is newly introduced to predict AMPs by integrating sequence alignment and support vector machine- (SVM-) LZ complexity pairwise algorithm. It was observed that, when all sequences in the training set are used, the sensitivity of the proposed algorithm is 95.28% in jackknife test and 87.59% in independent test, while the sensitivity obtained for jackknife test and independent test is 88.74% and 78.70%, respectively, when only the sequences that has less than 70% similarity are used. Applying the proposed algorithm may allow researchers to effectively predict AMPs from unknown protein peptide sequences with higher sensitivity. PMID- 25802840 TI - Autologous bone marrow mesenchymal stem cells associated with tantalum rod implantation and vascularized iliac grafting for the treatment of end-stage osteonecrosis of the femoral head. AB - Tantalum rod implantation with vascularized iliac grafting has been reported to be an effective method for the treatment of young patients with osteonecrosis of the femoral head (ONFH) to avert the need for total hip arthroplasty (THA). However, there have been unsatisfactory success rates for end-stage ONFH. The authors describe a modified technique using bone marrow mesenchymal stem cells (BMMSCs) associated with porous tantalum rod implantation combined with vascularized iliac grafting for the treatment of end-stage ONFH. A total of 24 patients (31 hips) with end-stage ONFH were treated with surgery; ARCO IIIc stage was observed in 19 hips and ARCO IV stage was observed in 12 hips. All patients were followed for a mean time of 64.35 +/- 13.03 months (range 26-78). Operations on only five hips were converted to THA. The joint-preserving success rate of the entire group was 89.47% for ARCO stage IIIc and 75% for ARCO stage IV. The mean Harris hip score of the 31 hips improved significantly from 38.74 +/- 5.88 points (range 22-50) to 77.23 +/- 14.75 points (range 33-95). This intervention was safe and effective in delaying or avoiding total hip replacement for end-stage ONFH. PMID- 25802841 TI - Effects of modified multistage field test on performance and physiological responses in wheelchair basketball players. AB - A bioenergetical analysis of manoeuvrability and agility performance for wheelchair players is inexistent. It was aimed at comparing the physiological responses and performance obtained from the octagon multistage field test (MFT) and the modified condition in "8 form" (MFT-8). Sixteen trained wheelchair basketball players performed both tests in randomized condition. The levels performed (end-test score), peak values of oxygen uptake (VO2peak), minute ventilation (VEpeak), heart rate (HRpeak), peak and relative blood lactate (Delta[Lact(-)] = peak--rest values), and the perceived rating exertion (RPE) were measured. MFT-8 induced higher VO2peak and VEpeak values compared to MFT (VO2peak: 2.5 +/- 0.6 versus 2.3 +/- 0.6 L . min(-1) and VEpeak: 96.3 +/- 29.1 versus 86.6 +/- 23.4 L . min(-1); P < 0.05) with no difference in other parameters. Significant relations between VEpeak and end-test score were correlated for both field tests (P < 0.05). At exhaustion, MFT attained incompletely VO2peak and VEpeak. Among experienced wheelchair players, MFT-8 had no effect on test performance but generates higher physiological responses than MFT. It could be explained by demands of wheelchair skills occurring in 8 form during the modified condition. PMID- 25802842 TI - Polymorphic basal rates of continuous subcutaneous insulin infusion among Taiwanese children with type 1 diabetes. AB - INTRODUCTION: The basal dose of insulin, proportion of total daily insulin, and circadian variation during continuous subcutaneous insulin infusion (CSII) therapy among children with type 1 diabetes mellitus (T1D) have not been fully elucidated. MATERIALS AND METHODS: A total of 45 childhood patients with T1D receiving CSII therapy at Pediatrics Department of Chang Gung Memorial Hospital between 2004 and 2012 were analyzed. Patients were classified according to Tanner stage. RESULTS: HbA1c was significantly reduced in all Tanner groups within three months of CSII therapy (from 67 mmol/mol (8.3%) to 54 mmol/mol (7.1%), P < 0.05). The actual basal proportion of total daily insulin use was 34-40%. The circadian distribution of basal insulin differed markedly between the five Tanner groups. Basal insulin requirement was highest between 3:00 and 7:00 h in Tanner stages 1 2. In stages 3-4, a lower nocturnal basal insulin that increased gradually until daytime was noted. Adolescents (stage 5) displayed a high insulin peak between 6:00 and 11:00 h, and a smaller peak between 19:00 and 23:00 h. CONCLUSIONS: A smaller proportion of basal insulin to total daily insulin use, as well as varied circadian patterns of insulin use, characterized these children with T1D. PMID- 25802843 TI - Metabolomic profiling in perinatal asphyxia: a promising new field. AB - Metabolomics, the latest "omic" technology, is defined as the comprehensive study of all low molecular weight biochemicals, "metabolites" present in an organism. As a systems biology approach, metabolomics has huge potential to progress our understanding of perinatal asphyxia and neonatal hypoxic-ischaemic encephalopathy, by uniquely detecting rapid biochemical pathway alterations in response to the hypoxic environment. The study of metabolomic biomarkers in the immediate neonatal period is not a trivial task and requires a number of specific considerations, unique to this disease and population. Recruiting a clearly defined cohort requires standardised multicentre recruitment with broad inclusion criteria and the participation of a range of multidisciplinary staff. Minimally invasive biospecimen collection is a priority for biomarker discovery. Umbilical cord blood presents an ideal medium as large volumes can be easily extracted and stored and the sample is not confounded by postnatal disease progression. Pristine biobanking and phenotyping are essential to ensure the validity of metabolomic findings. This paper provides an overview of the current state of the art in the field of metabolomics in perinatal asphyxia and neonatal hypoxic ischaemic encephalopathy. We detail the considerations required to ensure high quality sampling and analysis, to support scientific progression in this important field. PMID- 25802844 TI - Ethnic-specific genetic association of variants in the corticotropin-releasing hormone receptor 1 gene with nicotine dependence. AB - Twin and family studies indicate that smoking addiction is highly influenced by genetic factors. Variants in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been associated with alcoholism and depression. In this study, we tested five single nucleotide polymorphisms (SNPs) in CRHR1 for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom test for ND (FTND) in 2,037 subjects from 602 families of either European American (EA) or African American (AA) ancestry. Association analysis of the five SNPs revealed a significant association of rs171440 with SQ in the AA sample and with SQ and FTND in the pooled AA and EA samples. Haplotype-based association analysis indicated significant association of haplotypes C-C (56.9%) and T-C (38.9%), formed by SNPs rs171440 and rs1396862, with SQ in the AA sample, C-C-G (47.6%) with SQ, and T-C G (42.3%), formed by SNPs rs171440, rs1396862, and rs878886, with SQ and FTND in the pooled AA and EA samples. However, none of these associations remained significant after correction for multiple testing. Together, our results provide suggestive evidence for the involvement of CRHR1 in ND, which warrants further investigation using larger independent samples. PMID- 25802846 TI - Normal and pathological placental angiogenesis. PMID- 25802845 TI - Effectiveness of hyaluronic acid administration in treating adhesive capsulitis of the shoulder: a systematic review of randomized controlled trials. AB - INTRODUCTION: Adhesive capsulitis (AC) of the shoulder presents with an insidious onset of pain and progressive limitation of shoulder movement. OBJECTIVES: To investigate whether intra-articular hyaluronic acid (HA) administration alone is superior to conventional therapies and whether the addition of intra-articular HA administration to conventional therapies improves clinical outcomes in patients with AC. METHODS: The PubMed, EMBASE, CINAHL, and Cochrane Library electronic databases were searched without language restrictions in July 2014 with a priori defined inclusion and exclusion criteria. RESULTS: Four randomized controlled trials (273 participants, 278 shoulders) were included in this review. Two trials compared intra-articular HA administration with conventional therapies and 2 trials evaluated intra-articular HA administration as an addition to conventional therapies. Pain and shoulder function/disability outcomes in the HA injection group were not superior to those achieved in the conventional therapy groups. No significant differences in pain or shoulder function/disability outcomes were noted between the groups with and without adjunctive HA administration. CONCLUSIONS: Intra-articular HA administration alone is not superior to conventional AC treatments, and the addition of intra-articular HA administration to conventional therapies does not provide significant added benefits. HA administration in AC patients who are receiving conventional therapies should be evaluated to avoid unnecessary medical expenditure. PMID- 25802849 TI - A novel fixation system for acetabular quadrilateral plate fracture: a comparative biomechanical study. AB - This study aims to assess the biomechanical properties of a novel fixation system (named AFRIF) and to compare it with other five different fixation techniques for quadrilateral plate fractures. This in vitro biomechanical experiment has shown that the multidirectional titanium fixation (MTF) and pelvic brim long screws fixation (PBSF) provided the strongest fixation for quadrilateral plate fracture; the better biomechanical performance of the AFRIF compared with the T-shaped plate fixation (TPF), L-shaped plate fixation (LPF), and H-shaped plate fixation (HPF); AFRIF gives reasonable stability of treatment for quadrilateral plate fracture and may offer a better solution for comminuted quadrilateral plate fractures or free floating medial wall fracture and be reliable in preventing protrusion of femoral head. PMID- 25802847 TI - Novel candidate key drivers in the integrative network of genes, microRNAs, methylations, and copy number variations in squamous cell lung carcinoma. AB - The mechanisms of lung cancer are highly complex. Not only mRNA gene expression but also microRNAs, DNA methylation, and copy number variation (CNV) play roles in tumorigenesis. It is difficult to incorporate so much information into a single model that can comprehensively reflect all these lung cancer mechanisms. In this study, we analyzed the 129 TCGA (The Cancer Genome Atlas) squamous cell lung carcinoma samples with gene expression, microRNA expression, DNA methylation, and CNV data. First, we used variance inflation factor (VIF) regression to build the whole genome integrative network. Then, we isolated the lung cancer subnetwork by identifying the known lung cancer genes and their direct regulators. This subnetwork was refined by the Bayesian method, and the directed regulations among mRNA genes, microRNAs, methylations, and CNVs were obtained. The novel candidate key drivers in this refined subnetwork, such as the methylation of ARHGDIB and HOXD3, microRNA let-7a and miR-31, and the CNV of AGAP2, were identified and analyzed. On three large public available lung cancer datasets, the key drivers ARHGDIB and HOXD3 demonstrated significant associations with the overall survival of lung cancer patients. Our results provide new insights into lung cancer mechanisms. PMID- 25802850 TI - Black stain and dental caries: a review of the literature. AB - Black stain is characterized as a dark line or an incomplete coalescence of dark dots localized on the cervical third of the tooth. Over the last century, the etiology of black stain has been the subject of much debate. Most of the studies concerning this issue were conducted in pediatric population. According to the reviewed articles published between 2001 and 2014, the prevalence of black stain varies from 2.4% to 18% with equal sex distribution. The majority of the authors confirm the correlation between the presence of black stain and lower caries experience. The microflora of this deposit is dominated by Actinomyces spp. and has lower cariogenic potential than nondiscolored dental plaque. Iron/copper and sulfur complexes are thought to be responsible for the dark color. In patients with black stain saliva has higher calcium concentrations and higher buffering capacity. Factors such as dietary habits, socioeconomic status, and iron supplementation may be contributing to the formation of black stain. PMID- 25802848 TI - Cementless hydroxyapatite coated hip prostheses. AB - More than twenty years ago, hydroxyapatite (HA), calcium phosphate ceramics, was introduced as a coating for cementless hip prostheses. The choice of this ceramic is due to its composition being similar to organic apatite bone crystals. This ceramic is biocompatible, bioactive, and osteoconductive. These qualities facilitate the primary stability and osseointegration of implants. Our surgical experience includes the implantation of more than 4,000 cementless hydroxyapatite coated hip prostheses since 1990. The models implanted are coated with HA in the acetabulum and in the metaphyseal area of the stem. The results corresponding to survival and stability of implants were very satisfactory in the long-term. From our experience, HA-coated hip implants are a reliable alternative which can achieve long term survival, provided that certain requirements are met: good design selection, sound choice of bearing surfaces based on patient life expectancy, meticulous surgical technique, and indications based on adequate bone quality. PMID- 25802851 TI - MALDI-TOF MS and CD spectral analysis for identification and structure prediction of a purified, novel, organic solvent stable, fibrinolytic metalloprotease from Bacillus cereus B80. AB - The ability to predict protein function from structure is becoming increasingly important; hence, elucidation and determination of protein structure become the major steps in proteomics. The present study was undertaken for identification of metalloprotease produced by Bacillus cereus B80 and recognition of characteristics that can be industrially exploited. The enzyme was purified in three steps combining precipitation and chromatographic methods resulting in 33.5% recovery with 13.1-fold purification of enzyme which was detected as a single band with a molecular mass of 26 kDa approximately in SDS-PAGE and zymogram. The MALDI-TOF MS showed that the enzyme exhibited 70-93% similarity with zinc metalloproteases from various strains Bacillus sp. specifically from Bacillus cereus group. The sequence alignment revealed the presence of zinc binding region VVVHEMCHMV in the most conserved C terminus region. Secondary structure of the enzyme was obtained by CD spectra and I-TASSER. The enzyme kinetics revealed a Michaelis constant (Km) of 0.140 MUmol/ml and Vmax of 2.11 MUmol/min. The application studies showed that the enzyme was able to hydrolyze various proteins with highest affinity towards casein followed by BSA and gelatin. The enzyme exhibited strong fibrinolytic, collagenolytic, and gelatinolytic properties and stability in various organic solvents. PMID- 25802852 TI - Use of adipose-derived mesenchymal stem cells in keratoconjunctivitis sicca in a canine model. AB - Keratoconjunctivitis sicca (KCS) or dry eye disease (DED) is an immune-mediated multifactorial disease, with high level of prevalence in humans and dogs. Our aim in this study was to investigate the therapeutic effects of allogeneic adipose derived mesenchymal stromal cells (Ad-MSCs) implanted around the lacrimal glands in 12 dogs (24 eyes) with KCS, which is refractory to current available treatments. Schirmer tear test (STT) and ocular surface integrity were assessed at 0 (before treatment), 3, 6, and 9 months after treatment. Average STT values and all clinical signs showed a statistically significant change (P < 0.001) during the follow-up with reduction in all ocular parameters scored: ocular discharge, conjunctival hyperaemia, and corneal changes, and there were no signs of regression or worsening. Implanted cells were well tolerated and were effective reducing clinical signs of KCS with a sustained effect during the study period. None of the animals showed systemic or local complications during the study. To our knowledge, this is the first time in literature that implantation of allogeneic Ad-MSCs around lacrimal glands has been found as an effective therapeutic alternative to treat dogs with KCS. These results could reinforce a good effective solution to be extrapolated to future studies in human. PMID- 25802853 TI - Genitourethral reconstruction. PMID- 25802854 TI - Maternal glucose during pregnancy and after delivery in women with gestational diabetes mellitus on overweight status of their children. AB - OBJECTIVE: To examine the association of maternal glycemia during pregnancy and after delivery with anthropometry in the offspring of mothers with gestational diabetes mellitus (GDM). METHODS: A total of 1,263 GDM mothers and their children finished the health survey at 1-5 years after delivery. RESULTS: Offspring of GDM mothers who were diagnosed with diabetes during pregnancy had higher prevalence of overweight, higher mean weight for height Z scores, and higher mean BMI for age Z scores at 1-5 years old than the offspring of GDM mothers who were diagnosed with impaired glucose tolerance (IGT) during pregnancy. Offspring of GDM mothers who developed diabetes 1-5 years after delivery had higher mean values of Z scores for weight for height and BMI for age at 1-5 years old than the offspring of GDM mothers who had normal glucose or prediabetes after delivery. CONCLUSIONS: Offspring of GDM mothers who were diagnosed with diabetes during pregnancy or after delivery had an increased risk of childhood overweight or weight gain at 1-5 years old compared with children of GDM mothers with IGT during pregnancy or with normal glucose or prediabetes after delivery. PMID- 25802855 TI - Clostridium butyricum combined with Bifidobacterium infantis probiotic mixture restores fecal microbiota and attenuates systemic inflammation in mice with antibiotic-associated diarrhea. AB - Antibiotic-associated diarrhea (AAD) is one of the most common complications of most types of antibiotics. Our aim was to determine the efficacy of Clostridium butyricum, Bifidobacterium infantis, and their mixture for AAD treatment in mice. AAD models were administered with single probiotic strain and probiotic mixture for short term and long term to evaluate the changes of the composition and diversity of intestinal microbiota, histopathology of the colon, and the systemic inflammation. Our data indicated that long-term probiotic therapy, but not short term course, exerted beneficial effects on the restoration of the intestinal microbiota, the recovery of the tissue architecture, and attenuation of systemic inflammation. All predominant fecal bacteria reached normal level after the long term probiotic mixture treatment, while IL-10, IFN-gamma, and TNF-alpha also returned to normal level. However, the efficacy for AAD was time dependent and probiotic strain specific. Short-term administration of probiotic strains or mixture showed no apparent positive effects for AAD. In addition, the beneficial effects of C. butyricum combined with B. infantis probiotic mixture were superior to their single strain. This research showed that supplementation with C. butyricum combined with B. infantis probiotic mixture may be a simple and effective method for AAD treatment. PMID- 25802856 TI - Age-related impairment of quality of joint motion in vibroarthrographic signal analysis. AB - Aging is associated with degenerative changes in articular surfaces leading to quantitative and qualitative impairment of joint motion. Therefore, the aim of this study is to evaluate an age-related quality of the patellofemoral joint (PFJ) motion in the vibroarthrographic (VAG) signal analysis. Two hundred and twenty individuals were enrolled in this study and divided into five groups according to age. The VAG signals were collected during flexion/extension knee motion using an acceleration sensor and described using four parameters (VMS, P1, P2, and H). We observed that values of parameters VMS, P1, and P2 increase in accordance with the age, but H level decreases. The most significant differences were achieved between the youngest and the oldest participants' groups. Moreover, we show that parameters VMS, P1, and P2 positively correlate with age, contrary to negatively associated H parameter. Our results suggest that the impairment of joint motion is a result of age-related osteoarticular degenerative changes. PMID- 25802857 TI - Diagnosis of Neisseria gonorrhoeae using molecular beacon. AB - Neisseria gonorrhoeae is an important sexually transmitted diseases (STD) causing pathogen worldwide. Due to absence of an affordable diagnostic assay, routine screening of gonococcal infection becomes impossible in developing countries where infection rates are maximum. Treatment is given on the basis of symptoms alone which leads to spread of infection. Thus, development of a rapid, sensitive, specific, and PCR based visual diagnostic assay suitable for developing countries, required for better disease management, is aimed at in present study. Endocervical swabs were collected from patients visiting gynecology department of various hospitals in Delhi. In-house PCR based assay was developed and modified to visual assay using molecular beacon for end-point detection. It was evaluated against Roche AMPLICOR NG kit and rmp gene. Specificity of beacon was confirmed by competition experiments. Diagnostic test was 98.21% specific and 99.59% sensitive whereas negative and positive predicted value were 99.40% and 98.78%, respectively. We also observed that twice the concentration (2X) of premix was stable at 4 degrees C for 4 months and dry swab samples gave concordant results with that of wet swabs. These features make the test best suitable for routine diagnosis of genital infections in developing countries. PMID- 25802858 TI - Impact of plasma Epstein-Barr virus-DNA and tumor volume on prognosis of locally advanced nasopharyngeal carcinoma. AB - This retrospective study aims to examine the association of plasma Epstein-Barr virus- (EBV-) DNA levels with the tumor volume and prognosis in patients with locally advanced nasopharyngeal carcinoma (NPC). A total of 165 patients with newly diagnosed locally advanced NPC were identified from September 2011 to July 2012. EBV-DNA was detected using fluorescence quantitative polymerase chain reaction (PCR) amplification. The tumor volume was calculated by the systematic summation method of computer software. The median copy number of plasma EBV-DNA before treatment was 3790 copies/mL. The median gross tumor volume of the primary nasopharyngeal tumor (GTVnx), the lymph node lesions (GTVnd), and the total GTV before treatment were 72.46, 23.26, and 106.25 cm(3), respectively; the EBV-DNA levels were significantly correlated with the GTVnd and the total GTV (P < 0.01). The 2-year overall survival (OS) rates in patients with positive and negative pretreatment plasma EBV-DNA were 100% and 98.4% (P = 1.000), and the disease-free survival (DFS) rates were 94.4% and 80.8% (P = 0.044), respectively. These results indicate that high pretreatment plasma EBV-DNA levels in patients with locally advanced NPC are associated with the degree of lymph node metastasis, tumor burden, and poor prognosis. PMID- 25802860 TI - Evaluation of pediatric manual wheelchair mobility using advanced biomechanical methods. AB - There is minimal research of upper extremity joint dynamics during pediatric wheelchair mobility despite the large number of children using manual wheelchairs. Special concern arises with the pediatric population, particularly in regard to the longer duration of wheelchair use, joint integrity, participation and community integration, and transitional care into adulthood. This study seeks to provide evaluation methods for characterizing the biomechanics of wheelchair use by children with spinal cord injury (SCI). Twelve subjects with SCI underwent motion analysis while they propelled their wheelchair at a self-selected speed and propulsion pattern. Upper extremity joint kinematics, forces, and moments were computed using inverse dynamics methods with our custom model. The glenohumeral joint displayed the largest average range of motion (ROM) at 47.1 degrees in the sagittal plane and the largest average superiorly and anteriorly directed joint forces of 6.1% BW and 6.5% BW, respectively. The largest joint moments were 1.4% body weight times height (BW * H) of elbow flexion and 1.2% BW * H of glenohumeral joint extension. Pediatric manual wheelchair users demonstrating these high joint demands may be at risk for pain and upper limb injuries. These evaluation methods may be a useful tool for clinicians and therapists for pediatric wheelchair prescription and training. PMID- 25802859 TI - Biodiversity and gamma-aminobutyric acid production by lactic acid bacteria isolated from traditional alpine raw cow's milk cheeses. AB - "Nostrano-cheeses" are traditional alpine cheeses made from raw cow's milk in Trentino-Alto Adige, Italy. This study identified lactic acid bacteria (LAB) developing during maturation of "Nostrano-cheeses" and evaluated their potential to produce gamma-aminobutyric acid (GABA), an immunologically active compound and neurotransmitter. Cheese samples were collected on six cheese-making days, in three dairy factories located in different areas of Trentino and at different stages of cheese ripening (24 h, 15 days, and 1, 2, 3, 6, and 8 months). A total of 1,059 LAB isolates were screened using Random Amplified Polymorphic DNA-PCR (RAPD-PCR) and differentiated into 583 clusters. LAB strains from dominant clusters (n = 97) were genetically identified to species level by partial 16S rRNA gene sequencing. LAB species most frequently isolated were Lactobacillus paracasei, Streptococcus thermophilus, and Leuconostoc mesenteroides. The 97 dominant clusters were also characterized for their ability in producing GABA by high-performance liquid chromatography (HPLC). About 71% of the dominant bacteria clusters evolving during cheeses ripening were able to produce GABA. Most GABA producers were Lactobacillus paracasei but other GABA producing species included Lactococcus lactis, Lactobacillus plantarum, Lactobacillus rhamnosus, Pediococcus pentosaceus, and Streptococcus thermophilus. No Enterococcus faecalis or Sc. macedonicus isolates produced GABA. The isolate producing the highest amount of GABA (80.0+/-2.7 mg/kg) was a Sc. thermophilus. PMID- 25802861 TI - Simultaneous channel and feature selection of fused EEG features based on Sparse Group Lasso. AB - Feature extraction and classification of EEG signals are core parts of brain computer interfaces (BCIs). Due to the high dimension of the EEG feature vector, an effective feature selection algorithm has become an integral part of research studies. In this paper, we present a new method based on a wrapped Sparse Group Lasso for channel and feature selection of fused EEG signals. The high dimensional fused features are firstly obtained, which include the power spectrum, time-domain statistics, AR model, and the wavelet coefficient features extracted from the preprocessed EEG signals. The wrapped channel and feature selection method is then applied, which uses the logistical regression model with Sparse Group Lasso penalized function. The model is fitted on the training data, and parameter estimation is obtained by modified blockwise coordinate descent and coordinate gradient descent method. The best parameters and feature subset are selected by using a 10-fold cross-validation. Finally, the test data is classified using the trained model. Compared with existing channel and feature selection methods, results show that the proposed method is more suitable, more stable, and faster for high-dimensional feature fusion. It can simultaneously achieve channel and feature selection with a lower error rate. The test accuracy on the data used from international BCI Competition IV reached 84.72%. PMID- 25802862 TI - Biocheese: a food probiotic carrier. AB - This review describes some aspects related to the technological barriers encountered in the development and stability of probiotic cheeses. Aspects concerning the viability of probiotic cultures in this matrix are discussed and the potential of cheese as a biofunctional food carrier is analyzed, outlying some points related to health and safety. In general, the manufacture of probiotic cheese should have little change when compared with the elaboration of cheese in the traditional way. The physicochemical and technological parameters influencing the quality of these products have also to be measured so as to obtain a process optimization. PMID- 25802863 TI - Endoscopic ultrasound-guided therapies in pancreatic neoplasms. AB - Endoscopic ultrasound (EUS) has evolved from being primarily a diagnostic modality into an interventional endoscopic tool for the management of both benign and malignant gastrointestinal illnesses. EUS-guided therapy has garnered particular interest as a minimally invasive approach for the treatment of pancreatic cancer, a disease often complicated by its aggressive course and poor survival. The potential advantage of an EUS-guided approach revolves around real time imaging for targeted therapy of a difficult to reach organ. In this review, we focus on EUS-guided therapies for pancreatic neoplasms. PMID- 25802866 TI - Retracted: Microfluidic method of pig oocyte quality assessment in relation to different follicular size based on lab-on-chip technology. PMID- 25802864 TI - Vitamin A-deficient diet accelerated atherogenesis in apolipoprotein E(-/-) mice and dietary beta-carotene prevents this consequence. AB - Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE(-/ )). ApoE(-/-) mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing betac isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietary betac fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary betac, as a sole source of retinoids, can compensate for vitamin A deficiency. PMID- 25802865 TI - Characterization of bone marrow mononuclear cells on biomaterials for bone tissue engineering in vitro. AB - Bone marrow mononuclear cells (BMCs) are suitable for bone tissue engineering. Comparative data regarding the needs of BMC for the adhesion on biomaterials and biocompatibility to various biomaterials are lacking to a large extent. Therefore, we evaluated whether a surface coating would enhance BMC adhesion and analyze the biocompatibility of three different kinds of biomaterials. BMCs were purified from human bone marrow aspirate samples. Beta tricalcium phosphate (beta TCP, without coating or coated with fibronectin or human plasma), demineralized bone matrix (DBM), and bovine cancellous bone (BS) were assessed. Seeding efficacy on beta-TCP was 95% regardless of the surface coating. BMC demonstrated a significantly increased initial adhesion on DBM and beta-TCP compared to BS. On day 14, metabolic activity was significantly increased in BMC seeded on DBM in comparison to BMC seeded on BS. Likewise increased VEGF-synthesis was observed on day 2 in BMC seeded on DBM when compared to BMC seeded on BS. The seeding efficacy of BMC on uncoated biomaterials is generally high although there are differences between these biomaterials. Beta-TCP and DBM were similar and both superior to BS, suggesting either as suitable materials for spatial restriction of BMC used for regenerative medicine purposes in vivo. PMID- 25802868 TI - Scenarios approach to the electromagnetic exposure: the case study of a train compartment. AB - Previous studies identified the train compartment as the place where people can experience the highest exposure levels (still below the international guideline limits) to electromagnetic fields in the radiofrequency range. Here a possible scenario of a train compartment has been reproduced and characterized, both numerically and experimentally. A good agreement between the simulated electric field distributions and measurements has been found. Results indicate that the higher values of exposure in specific positions inside the train compartment depend on the number of active cell phones, the bad coverage condition, the cell orientation, and the presence of metallic walls. This study shows that the proposed approach, based on the scenarios characterization, may efficiently support the assessment of the individual electromagnetic exposure. PMID- 25802867 TI - Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: a systematic review. AB - Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10-15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS. PMID- 25802869 TI - Acute myocardial infarction: a comparison of the risk between physicians and the general population. AB - Physicians in Taiwan have a heavy workload and a stressful workplace, both of which may contribute to cardiovascular disease. However, the risk of acute myocardial infarction (AMI) in physicians is not clear. This population-based cohort study used Taiwan's National Health Insurance Research Database. We identified 28,062 physicians as the case group and randomly selected 84,186 nonmedical staff patients as the control group. We used a conditional logistic regression to compare the AMI risk between physicians and controls. Subgroup analyses of physician specialty, age, gender, comorbidities, area, and hospital level were also done. Physicians have a higher prevalence of HTN (23.59% versus 19.06%, P < 0.0001) and hyperlipidemia (21.36% versus 12.93%, P < 0.0001) but a lower risk of AMI than did the controls (adjusted odds ratio (AOR): 0.57; 95% confidence interval (CI): 0.46-0.72) after adjusting for DM, HTN, hyperlipidemia, and area. Between medical specialty, age, and area subgroups, differences in the risk for having an AMI were nonsignificant. Medical center physicians had a lower risk (AOR: 0.42; 95% CI: 0.20-0.85) than did local clinic physicians. Taiwan's physicians had higher prevalences of HTN and hyperlipidemia, but a lower risk of AMI than did the general population. Medical center physicians had a lower risk than did local clinic physicians. Physicians are not necessary healthier than the general public, but physicians, especially in medical centers, have a greater awareness of disease and greater access to medical care, which permits timely treatment and may prevent critical conditions such as AMI induced by delayed treatment. PMID- 25802871 TI - Resveratrol prevents cardiovascular complications in the SHR/STZ rat by reductions in oxidative stress and inflammation. AB - The cardioprotective effects of resveratrol are well established in animal models of metabolic disease but are yet to be investigated in a combined model of hypertension and diabetes. This study investigated the ability of resveratrol's antioxidant and anti-inflammatory effects to prevent cardiovascular complications in the spontaneously hypertensive streptozotocin-induced diabetic rat. Diabetes was induced in eight-week-old male spontaneously hypertensive rats via a single intravenous injection of streptozotocin. Following this, resveratrol was administered orally for an eight-week period until the animals were sixteen weeks of age. Upon completion of the treatment regime assessments of oxidative stress, lipid peroxidation, inflammation, and cardiovascular function were made. Resveratrol administration to hypertensive-diabetic animals did not impact upon blood glucose or haemodynamics but significantly reduced oxidative stress, lipid peroxidation, and inflammatory cytokines. Reductions in systemic levels of oxidative stress and inflammation conferred improvements in vascular reactivity and left ventricular pump function and electrophysiology. This study demonstrates that resveratrol administration to hypertensive diabetic animals can elicit cardioprotective properties via antioxidant and anti-inflammatory effects. The observed preservation of cardiovascular function was independent of changes in blood glucose concentration and haemodynamics, suggesting that oxidative stress and inflammation are key components within the pathological cascade associated with hypertension and diabetes. PMID- 25802872 TI - Synthesis, characterization, and antibacterial activities of novel sulfonamides derived through condensation of amino group containing drugs, amino acids, and their analogs. AB - Novel sulfonamides were developed and structures of the new products were confirmed by elemental and spectral analysis (FT-IR, ESI-MS, (1)HNMR, and (13)CNMR). In vitro, developed compounds were screened for their antibacterial activities against medically important gram (+) and gram (-) bacterial strains, namely, S. aureus, B. subtilis, E. coli, and K. pneumoniae. The antibacterial activities have been determined by measuring MIC values (MUg/mL) and zone of inhibitions (mm). Among the tested compounds, it was found that compounds 5a and 9a have most potent activity against E. coli with zone of inhibition: 31 +/- 0.12 mm (MIC: 7.81 MUg/mL) and 30 +/- 0.12 mm (MIC: 7.81 MUg/mL), respectively, nearly as active as ciprofloxacin (zone of inhibition: 32 +/- 0.12 mm). In contrast, all the compounds were totally inactive against the gram (+) B. subtilis. PMID- 25802870 TI - Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. AB - Polyphenolic compounds are plant nutraceuticals showing a huge structural diversity, including chlorogenic acids, hydrolyzable tannins, and flavonoids (flavonols, flavanones, flavan-3-ols, anthocyanidins, isoflavones, and flavones). Most of them occur as glycosylated derivatives in plants and foods. In order to become bioactive at human body, these polyphenols must undergo diverse intestinal transformations, due to the action of digestive enzymes, but also by the action of microbiota metabolism. After elimination of sugar tailoring (generating the corresponding aglycons) and diverse hydroxyl moieties, as well as further backbone reorganizations, the final absorbed compounds enter the portal vein circulation towards liver (where other enzymatic transformations take place) and from there to other organs, including behind the digestive tract or via blood towards urine excretion. During this transit along diverse tissues and organs, they are able to carry out strong antiviral, antibacterial, and antiparasitic activities. This paper revises and discusses these antimicrobial activities of dietary polyphenols and their relevance for human health, shedding light on the importance of polyphenols structure recognition by specific enzymes produced by intestinal microbial taxa. PMID- 25802874 TI - Endoscopic/external approaches in otorhinolaryngology and head and neck surgery. PMID- 25802873 TI - Biofilm-forming Staphylococcus epidermidis expressing vancomycin resistance early after adhesion to a metal surface. AB - We investigated biofilm formation and time of vancomycin (VCM) resistance expression after adhesion to a metal surface in Staphylococcus epidermidis. Biofilm-forming Staphylococcus epidermidis with a VCM MIC of 1 MUg/mL was used. The bacteria were made to adhere to a stainless steel washer and treated with VCM at different times and concentrations. VCM was administered 0, 2, 4, and 8 hours after adhesion. The amount of biofilm formed was evaluated based on the biofilm coverage rates (BCRs) before and after VCM administration, bacterial viability in biofilm was visually observed using the fluorescence staining method, and the viable bacterial count in biofilm was measured. The VCM concentration required to decrease BCR significantly compared with that of VCM-untreated bacteria was 4 MUg/mL, even in the 0 hr group. In the 4 and 8 hr groups, VCM could not inhibit biofilm growth even at 1,024 MUg/mL. In the 8 hr group, viable bacteria remained in biofilm at a count of 10(4) CFU even at a high VCM concentration (1,024 MUg/mL). It was suggested that biofilm-forming Staphylococcus epidermidis expresses resistance to VCM early after adhesion to a metal surface. Resistance increased over time after adhesion as the biofilm formed, and strong resistance was expressed 4-8 hours after adhesion. PMID- 25802875 TI - A Micropolymorphism Altering the Residue Triad 97/114/156 Determines the Relative Levels of Tapasin Independence and Distinct Peptide Profiles for HLA-A(*)24 Allotypes. AB - While many HLA class I molecules interact directly with the peptide loading complex (PLC) for conventional loading of peptides certain class I molecules are able to present peptides in a way that circumvents the PLC components. We investigated micropolymorphisms at position 156 of HLA-A(*)24 allotypes and their effects on PLC dependence for assembly and peptide binding specificities. HLA A(*)24:06(156Trp) and HLA-A(*)24:13(156Leu) showed high levels of cell surface expression while HLA-A(*)24:02(156Gln) was expressed at low levels in tapasin deficient cells. Peptides presented by these allelic variants showed distinct differences in features and repertoire. Immunoprecipitation experiments demonstrated all the HLA-A(*)24/156 variants to associate at similar levels with tapasin when present. Structurally, HLA-A(*)24:02 contains the residue triad Met97/His114/Gln156 and a Trp156 or Leu156 polymorphism provides tapasin independence by stabilizing these triad residues, thus generating an energetically stable and a more peptide receptive environment. Micropolymorphisms at position 156 can influence the generic peptide loading pathway for HLA-A(*)24 by altering their tapasin dependence for peptide selection. The trade-off for this tapasin independence could be the presentation of unusual ligands by these alleles, imposing significant risk following hematopoietic stem cell transplantation (HSCT). PMID- 25802877 TI - Genetic counselors and Genomic Counseling in the United Kingdom. PMID- 25802878 TI - Genetics and genomic medicine in Colombia. PMID- 25802876 TI - Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis. AB - In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed. This disturbed balance is also the case in rheumatoid arthritis (RA). Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes. However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors. Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs. However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood. Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity. A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures. PMID- 25802879 TI - A slowly progressive form of limb-girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics. AB - Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of gamma-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability. PMID- 25802880 TI - Variability in pathogenicity prediction programs: impact on clinical diagnostics. AB - Current practice by clinical diagnostic laboratories is to utilize online prediction programs to help determine the significance of novel variants in a given gene sequence. However, these programs vary widely in their methods and ability to correctly predict the pathogenicity of a given sequence change. The performance of 17 publicly available pathogenicity prediction programs was assayed using a dataset consisting of 122 credibly pathogenic and benign variants in genes associated with the RASopathy family of disorders and limb-girdle muscular dystrophy. Performance metrics were compared between the programs to determine the most accurate program for loss-of-function and gain-of-function mechanisms. No one program correctly predicted the pathogenicity of all variants analyzed. A major hindrance to the analysis was the lack of output from a significant portion of the programs. The best performer was MutPred, which had a weighted accuracy of 82.6% in the full dataset. Surprisingly, combining the results of the top three programs did not increase the ability to predict pathogenicity over the top performer alone. As the increasing number of sequence changes in larger datasets will require interpretation, the current study demonstrates that extreme caution must be taken when reporting pathogenicity based on statistical online protein prediction programs in the absence of functional studies. PMID- 25802881 TI - A positive genotype-phenotype correlation in a large cohort of patients with Pseudohypoparathyroidism Type Ia and Pseudo-pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene. AB - Maternally inherited inactivating GNAS mutations are the most common cause of parathyroid hormone (PTH) resistance and Albright hereditary osteodystrophy (AHO) leading to pseudohypoparathyroidism type Ia (PHPIa) due to Gsalpha deficiency. Paternally inherited inactivating mutations lead to isolated AHO signs characterizing pseudo-pseudohypoparathyroidism (PPHP). Mutations are distributed throughout the Gsalpha coding exons of GNAS and there is a lack of genotype phenotype correlation. In this study, we sequenced exon 1-13 of GNAS in a large cohort of PHPIa- and PPHP patients and identified 58 different mutations in 88 patients and 27 relatives. Thirty-three mutations including 15 missense mutations were newly discovered. Furthermore, we found three hot spots: a known hotspot (p.D190MfsX14), a second at codon 166 (p.R166C), and a third at the exon 5 acceptor splice site (c.435 + 1G>A), found in 15, 5, and 4 unrelated patients, respectively. Comparing the clinical features to the molecular genetic data, a significantly higher occurrence of subcutaneous calcifications in patients harboring truncating versus missense mutations was demonstrated. Thus, in the largest cohort of PHPIa patients described to date, we extend the spectrum of known GNAS mutations and hot spots and demonstrate for the first time a correlation between the genetic defects and the expression of a clinical AHO feature. PMID- 25802882 TI - Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next generation sequencing. AB - Tumor suppressor genes BRCA1 and BRCA2 are the two main breast and ovarian cancer susceptibility genes, and their genetic testing has been used to evaluate the risk of hereditary breast and ovarian cancer (HBOC). While several studies have reported the prevalence of BRCA1 and BRCA2 mutations in Japanese populations, there is insufficient information about deleterious mutations compared with western countries. Moreover, because many rare variants are found in BRCA1 and BRCA2, both of which encode large proteins, it is difficult to sequence all coding regions using the Sanger method for mutation detection. In this study, therefore, we performed next-generation sequencing (NGS) analysis of the entire coding regions of BRCA1 and BRCA2 in 135 breast and/or ovarian cancer patients. Deleterious BRCA1 and BRCA2 mutations were detected in 10 patients (7.4%) by NGS analysis. Of these, one mutation in BRCA1 and two in BRCA2 had not been reported previously. Furthermore, a BRCA2 mutation found in a proband was also identified in two unaffected relatives. These data suggest the utility of screening BRCA1 and BRCA2 mutations by NGS in clinical diagnosis. PMID- 25802883 TI - Personalized treatment of Sezary syndrome by targeting a novel CTLA4:CD28 fusion. AB - Matching molecularly targeted therapies with cancer subtype-specific gene mutations is revolutionizing oncology care. However, for rare cancers this approach is problematic due to the often poor understanding of the disease's natural history and phenotypic heterogeneity, making treatment of these cancers a particularly unmet medical need in clinical oncology. Advanced Sezary syndrome (SS), an aggressive, exceedingly rare variant of cutaneous T-cell lymphoma (CTCL) is a prototypical example of a rare cancer. Through whole genome and RNA sequencing (RNA-seq) of a SS patient's tumor we discovered a highly expressed gene fusion between CTLA4 (cytotoxic T lymphocyte antigen 4) and CD28 (cluster of differentiation 28), predicting a novel stimulatory molecule on the surface of tumor T cells. Treatment with the CTLA4 inhibitor ipilimumab resulted in a rapid clinical response. Our findings suggest a novel driver mechanism for SS, and cancer in general, and exemplify an emerging model of cancer treatment using exploratory genomic analysis to identify a personally targeted treatment option when conventional therapies are exhausted. PMID- 25802884 TI - Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia. Patients with PCD have diverse clinical phenotypes that include chronic upper and lower respiratory tract infections, situs inversus, heterotaxy with or without congenital heart disease, and male infertility, among others. In this report, the carrier frequencies for eleven mutations in eight PCD-associated genes (DNAI1, DNAI2, DNAH5, DNAH11, CCDC114, CCDC40, CCDC65, and C21orf59) that had been found in individuals of Ashkenazi Jewish descent were investigated in order to advise on including them in existing clinical mutation panels for this population. Results showed relatively high carrier frequencies for the DNAH5 c.7502G>C mutation (0.58%), the DNAI2 c.1304G>A mutation (0.50%), and the C21orf59 c.735C>G mutation (0.48%), as well as lower frequencies for mutations in DNAI1, CCDC65, CCDC114, and DNAH11 (0.10-0.29%). These results suggest that several of these genes should be considered for inclusion in carrier screening panels in the Ashkenazi Jewish population. PMID- 25802887 TI - Structural, optical, and magnetic properties of NiMoO4 nanorods prepared by microwave sintering. AB - We report on the structural, optical, and magnetic properties of alpha,beta NiMoO4 nanorods synthesized by annealing the NiMoO4:nH2O precursor at 600 degrees C for 10 minutes in a domestic microwave. The crystalline structure properties of alpha,beta-NiMoO4 were investigated using X-ray diffraction (XRD), Fourier transform infrared (FTIR), and Raman (FT-Raman) spectroscopies. The particle morphologies and size distributions were identified by field emission microscopy (FE-SEM). Experimental data were obtained by magnetization measurements for different applied magnetic fields. Optical properties were analyzed by ultraviolet-visible (UV-vis) and photoluminescence (PL) measurements. Our results revealed that the oxygen atoms occupy different positions and are very disturbed in the lattice and exhibit a particular characteristic related to differences in the length of the chemical bonds (Ni-O and Mo-O) of the cluster structure or defect densities in the crystalline alpha,beta-NiMoO4 nanorods, which are the key to a deeper understanding of the exploitable physical and chemical properties in this study. PMID- 25802885 TI - Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. AB - Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results. PMID- 25802889 TI - Pick's Theorem in two-dimensional subspace of R3. AB - In the Euclidean space R(3), denote the set of all points with integer coordinate by Z(3). For any two-dimensional simple lattice polygon P, we establish the following analogy version of Pick's Theorem, k(I(P) + (1/2)B(P) - 1), where B(P) is the number of lattice points on the boundary of P in Z(3), I(P) is the number of lattice points in the interior of P in Z(3), and k is a constant only related to the two-dimensional subspace including P. PMID- 25802888 TI - Assessment of two school-based programs to prevent universal eating disorders: media literacy and theatre-based methodology in Spanish adolescent boys and girls. AB - AIMS: To evaluate the long-term effects of two school-based prevention programs administered to a universal mixed-sex sample of school-going adolescents on disturbed eating attitudes, aesthetic ideal internalization, and other eating disorder risk factors, when compared to a control group. METHODS: Participants were 200 adolescents aged 12-15 selected by means of incidental sampling from second-year compulsory secondary education at schools. An interactive multimedia media literacy program (ML + NUT, Media Literacy and Nutrition) and a program focused on the same topics using dramatic arts (Theatre Alive) were applied and compared with a control group. Pretest, posttest (1 month later), and 5- and 13 month follow-up measurements were taken. Analyses were conducted with two-way mixed 3 * 3 ANCOVA (group * phase) adjusted by baseline levels, body mass index, and sex. RESULTS: Participants in both experimental groups showed significantly higher self-esteem scores than the control group over time. The ML + NUT group also presented lower aesthetic ideal internalization scores than the control group. DISCUSSION: Both programs can benefit students' self-esteem. Moreover, ML + NUT program was useful in reducing thin-ideal internalization. However, differences in body dissatisfaction and disordered eating attitudes were not found. The programs may be protective on the core psychological variables, which are essential to adaptive adolescent development. PMID- 25802890 TI - Comparison of the proseal, supreme, and i-gel SAD in gynecological laparoscopic surgeries. AB - We compared proseal, supreme, and i-gel supraglottic airway devices in terms of oropharyngeal leak pressures and airway morbidities in gynecological laparoscopic surgeries. One hundred and five patients undergoing elective surgery were subjected to general anesthesia after which they were randomly distributed into three groups. Although the oropharyngeal leak pressure was lower in the i-gel group initially (mean +/- standard deviation; 23.9 +/- 2.4, 24.9 +/- 2.9, and 20.9 +/- 3.5, resp.), it was higher than the proseal group and supreme group at 30 min of surgery after the trendelenburg position (25.0 +/- 2.3, 25.0 +/- 1.9, and 28.3 +/- 2.3, resp.) and at the 60 min of surgery (24.2 +/- 2.1, 24.8 +/- 2.2, and 29.5 +/- 1.1, resp.). The time to apply the supraglottic airway devices was shorter in the i-gel group (12.2 (1.2), 12.9 (1.0), and 6.7 (1.2), resp., P = 0.001). There was no difference between the groups in terms of their fiber optic imaging levels. pH was measured at the anterior and posterior surfaces of the pharyngeal region after the supraglottic airway devices were removed; the lowest pH values were 5 in all groups. We concluded that initial oropharyngeal leak pressures obtained by i-gel were lower than proseal and supreme, but increased oropharyngeal leak pressures over time, ease of placement, and lower airway morbidity are favorable for i-gel. PMID- 25802892 TI - A study of depression and quality of life in patients of lichen planus. AB - The precise cause of lichen planus is unknown, but the disease seems to be immunologically mediated. It is a psychocutaneous disorder. Due to scarcity of Indian studies in this field, we decided to study in patients of lichen planus the prevalence of depression and quality of life with comparison of the same in both the genders. Patients diagnosed as having lichen planus by consultant dermatologist were enrolled after informed consent and ethics approval. 45 patients were screened, of which 35 who satisfied the criteria were taken up for the study. A semistructured proforma was designed to collect the necessary information with administration of dermatology life quality index and Beck's depression inventory. While 25% were depressed with females being more affected than males, quality of life was impaired in more than 90% patients. Impairment was maximum due to symptoms and illness feelings, disturbed daily activities, or work and time consumption in treatment. There was a strong association between depression and impairment in quality of life in both the genders. This study helps in early identification of psychological problems in lichen planus patients and in planning their future course of management, hence reducing the lack of productivity and improving the prognosis and quality of life. PMID- 25802891 TI - Lung cancer prediction using neural network ensemble with histogram of oriented gradient genomic features. AB - This paper reports an experimental comparison of artificial neural network (ANN) and support vector machine (SVM) ensembles and their "nonensemble" variants for lung cancer prediction. These machine learning classifiers were trained to predict lung cancer using samples of patient nucleotides with mutations in the epidermal growth factor receptor, Kirsten rat sarcoma viral oncogene, and tumor suppressor p53 genomes collected as biomarkers from the IGDB.NSCLC corpus. The Voss DNA encoding was used to map the nucleotide sequences of mutated and normal genomes to obtain the equivalent numerical genomic sequences for training the selected classifiers. The histogram of oriented gradient (HOG) and local binary pattern (LBP) state-of-the-art feature extraction schemes were applied to extract representative genomic features from the encoded sequences of nucleotides. The ANN ensemble and HOG best fit the training dataset of this study with an accuracy of 95.90% and mean square error of 0.0159. The result of the ANN ensemble and HOG genomic features is promising for automated screening and early detection of lung cancer. This will hopefully assist pathologists in administering targeted molecular therapy and offering counsel to early stage lung cancer patients and persons in at risk populations. PMID- 25802893 TI - Induced resistance in Solanum lycopersicum by algal elicitor extracted from Sargassum fusiforme. AB - Tomato (Solanum lycopersicum) production relies heavily on the use of chemical pesticides, which is undesired by health- and environment-concerned consumers. Environment-friendly methods of controlling tomato diseases include agroecological practices, organic fungicides, and biological control. Plants' resistance against pathogens is induced by applying agents called elicitors to the plants and would lead to disease prevention or reduced severity. We investigated the ability of a novel elicitor extracted from the brown sea algae (Sargassum fusiforme) to elicit induced resistance in tomato. The studied elicitor induced hypersensitive cell death and O2 (-) production in tomato tissues. It significantly reduced severities of late blight, grey mold, and powdery mildew of tomato. Taken together, our novel elicitor has not shown any direct antifungal activity against the studied pathogens, concluding that it is an elicitor of induced resistance. PMID- 25802896 TI - Solution-based nanosensors for in-field detection with the naked eye. AB - Nanomaterials are revolutionising analytical applications with low-cost tests that enable detecting a target molecule in a few steps and with the naked eye. With this approach, non-experts can perform analyses on-site and without utilising electronic readers. This is advantageous in point-of-care diagnostics, in-field measurements and analyses performed in resource-constrained settings. Here we review the main strategies adopted for detecting analytes with the naked eye and at the point of need using plasmonic nanosensors, catalytic nanoparticles and fluorescent nanomaterials. Examples of the detection of ions, glucose, small molecules, peptides and proteins with the nanosensors are explained in detail. PMID- 25802894 TI - Digital radiography for determination of primary tooth length: in vivo and ex vivo studies. AB - BACKGROUND: Methods for determining the root canal length of the primary tooth should yield accurate and reproducible results. In vitro studies show some limitations, which do not allow their findings to be directly transferred to a clinical situation. AIM: To compare the accuracy of radiographic tooth length obtained from in vivo digital radiograph with that obtained from ex vivo digital radiograph. METHOD: Direct digital radiographs of 20 upper primary incisors were performed in teeth (2/3 radicular resorption) that were radiographed by an intraoral sensor, according to the long-cone technique. Teeth were extracted, measured, and mounted in a resin block, and then radiographic template was used to standardise the sensor-target distance (30 cm). The apparent tooth length (APTL) was obtained from the computer screen by means of an electronic ruler accompanying the digital radiography software (CDR 2.0), whereas the actual tooth length (ACTL) was obtained by means of a digital calliper following extraction. Data were compared to the ACTL by variance analysis and Pearson's correlation test. RESULTS: The values for APTL obtained from in vivo radiography were slightly underestimated, whereas those values obtained from ex vivo were slightly overestimated. No significance was observed (P <= 0.48) between APTL and ACTL. CONCLUSION: The length of primary teeth estimated by in vivo and ex vivo comparisons using digital radiography was found to be similar to the actual tooth length. PMID- 25802895 TI - Gold nanoparticles as a substrate in bio-analytical near-infrared surface enhanced Raman spectroscopy. AB - As biospectroscopy techniques continue to be developed for screening or diagnosis within a point-of-care setting, an important development for this field will be high-throughput optimization. For many of these techniques, it is therefore necessary to adapt and develop parameters to generate a robust yet simple approach delivering high-quality spectra from biological samples. Specifically, this is important for surface-enhanced Raman spectroscopy (SERS) wherein there are multiple variables that can be optimised to achieve an enhancement of the Raman signal from a sample. One hypothesis is that "large" diameter (>100 nm) gold nanoparticles provide a greater enhancement at near-infrared (NIR) and infrared (IR) wavelengths than those <100 nm in diameter. Herein, we examine this notion using examples in which SERS spectra were acquired from MCF-7 breast cancer cells incubated with 150 nm gold nanoparticles. It was found that 150 nm gold nanoparticles are an excellent material for NIR/IR SERS. Larger gold nanoparticles may better satisfy the theoretical restraints for SERS enhancement at NIR/IR wavelengths compared to smaller nanoparticles. Also, larger nanoparticles or their aggregates are more readily observed via optical microscopy (and especially electron microscopy) compared to smaller ones. This allows rapid and straightforward identification of target areas containing a high concentration of nanoparticles and facilitating SERS spectral acquisition. To some extent, these observations appear to extend to biofluids such as blood plasma or (especially) serum; SERS spectra of such biological samples often exhibit a low signal-to-noise ratio in the absence of nanoparticles. With protein rich biofluids such as serum, a dramatic SERS effect can be observed; although this might facilitate improved spectral biomarker identification in the future, it may not always improve classification between control vs. cancer. Thus, use of "large" gold nanoparticles are a good starting point in order to derive informative NIR/IR SERS analysis of biological samples. PMID- 25802898 TI - Collisional relaxation of apocarotenals: identifying the S* state with vibrationally excited molecules in the ground electronic state S(0)*. AB - In recent work, we demonstrated that the S* signal of beta-carotene observed in transient pump-supercontinuum probe absorption experiments agrees well with the independently measured steady-state difference absorption spectrum of vibrationally hot ground state molecules S0* in solution, recorded at elevated temperatures (Oum et al., Phys. Chem. Chem. Phys., 2010, 12, 8832). Here, we extend our support for this "vibrationally hot ground state model" of S* by experiments for the three terminally aldehyde-substituted carotenes beta-apo-12' carotenal, beta-apo-4'-carotenal and 3',4'-didehydro-beta,psi-caroten-16'-al ("torularhodinaldehyde") which were investigated by ultrafast pump-supercontinuum probe spectroscopy in the range 350-770 nm. The apocarotenals feature an increasing conjugation length, resulting in a systematically shorter S1 lifetime of 192, 4.9 and 1.2 ps, respectively, in the solvent n-hexane. Consequently, for torularhodinaldehyde a large population of highly vibrationally excited molecules in the ground electronic state is quickly generated by internal conversion (IC) from S1 already within the first picosecond of relaxation. As a result, a clear S* signal is visible which exhibits the same spectral characteristics as in the aforementioned study of beta-carotene: a pronounced S0 -> S2 red-edge absorption and a "finger-type" structure in the S0 -> S2 bleach region. The cooling process is described in a simplified way by assuming an initially formed vibrationally very hot species S0** which subsequently decays with a time constant of 3.4 ps to form a still hot S0* species which relaxes with a time constant of 10.5 ps to form S0 molecules at 298 K. beta-Apo-4'-carotenal behaves in a quite similar way. Here, a single vibrationally hot S0* species is sufficient in the kinetic modeling procedure. S0* relaxes with a time constant of 12.1 ps to form cold S0. Finally, no S0* features are visible for beta-apo-12'-carotenal. In that case, the S1 -> S0 IC process is expected to be roughly 20 times slower than S0* relaxation. As a result, no spectral features of S0* can be found, because there is no chance that a detectable concentration of vibrationally hot molecules is accumulated. PMID- 25802899 TI - Dr. Douglas E. Wigle. PMID- 25802897 TI - Energy flow between spectral components in 2D broadband stimulated Raman spectroscopy. AB - We introduce a general theoretical description of non resonant impulsive femtosecond stimulated Raman spectroscopy in a multimode harmonic model. In this technique an ultrashort actinic pulse creates coherences of low frequency modes and is followed by a paired narrowband Raman pulse and a broadband probe pulse. Using closed-time-path-loop (CTPL) diagrams, the response on both the red and the blue sides of the broadband pulse with respect to the narrowband Raman pulse is calculated, the process couples high and low frequency modes, which share the same ground state. The transmitted intensity oscillates between the red and the blue side, while the total number of photons is conserved. The total energy of the probe signal is periodically modulated in time by the coherence created in the low frequency modes. PMID- 25802900 TI - A community college model to support nursing workforce diversity. AB - Community College of Allegheny County (CCAC), Allegheny Campus, is situated on the North Side of Pittsburgh. The neighborhood is 60% African American. At the time of the Health Resources and Services Administration (HRSA) application, approximately one third of the students admitted to the program were African American, less than one third of whom successfully completed it. With the aid of HRSA funding, CCAC developed a model that significantly improved the success rate of disadvantaged students. Through the formation of a viable cohort, the nursing faculty nurtured success among the most at-risk students. The cohort was supported by a social worker, case managers who were nursing faculty, and tutors. Students formed study groups, actively participated in community activities, and developed leadership skills through participation in the Student Nurse Association of Pennsylvania. This article provides the rationale for the Registered Nurse (RN) Achievement Model, describes the components of RN Achievement, and discusses the outcomes of the initiative. PMID- 25802901 TI - Madness in civilisation. PMID- 25802902 TI - John Evans. PMID- 25802903 TI - Future of advanced practice public health nursing education. AB - The objective of this study was to conduct an assessment of the need for advanced practice, master's-prepared public health nurses in Michigan. A cross-sectional design was used to conduct interviews with former students, community leaders, and faculty. Content was analyzed qualitatively for themes. Participants were enthusiastic about the practice environment, but funding was a major concern. Almost all participants thought jobs were available and that public health nursing was cost-effective, yet there was concern about the aging work force and the need for higher education. Other disciplines serving in public health roles and hospitals were identified as competition to the public health nurse. Epidemiology, prevention, community assessment/program planning, health policy/law/ethics, leadership, health services, informatics, research, and grant writing were noted as skills needed. The results of this study are favorable for the future of advanced practice public health nursing practice and education. PMID- 25802904 TI - Steven Hsiao: in memoriam. PMID- 25802905 TI - Authors reply. PMID- 25802906 TI - Management of patent ductus arteriosus in preterm infants-where do we stand? A UK national perspective. PMID- 25802907 TI - Cryoglobulins mimicking platelet recovery in a mantle cell lymphoma patient treated with chemoimmunotherapy. PMID- 25802908 TI - Digestion. PMID- 25802909 TI - To serve patients. PMID- 25802911 TI - Sodium phenylbutyrate coated granules (Pheburane). Defective urea synthesis: a welcome formulation. AB - Compared with Ammonaps granules, Pheburane coated granules mask the unpleasant taste of sodium phenylbutyrate. A more precise dosing device is provided with the coated granules than with the uncoated granules (Ammonaps). PMID- 25802913 TI - First-line treatment of acute lymphoblastic leukaemia in children. PMID- 25802910 TI - Canagliflozin (Invokana). A "me-too" of the dangerous dapagliflozin. AB - Currently, metformin is the only oral hypoglycaemic drug with reasonably well established efficacy in preventing the complications of type 2 diabetes. Canagliflozin is the second renal sodium-glucose cotransporter 2 (SGLT2) inhibitor to be authorised in the European Union, after dapagliflozin. Initial evaluation of canagliflozin included no controlled clinical trials designed to determine its efficacy in preventing the clinical complications of diabetes. The eight available placebo-controlled trials show a moderate hypoglycaemic effect (mean HbA1c decline: -0.7%), similar to that of dapagliflozin. This effect is reduced in patients with renal failure. Canagliflozin has the same adverse effects as dapagliflozin, due to their shared mechanism of action: they include urogenital infections, arterial hypotension, dehydration, and altered renal function. As with dapagliflozin, questions remain as to the long-term risk of fractures and malignancies. A risk of cardiovascular toxicity in some patients cannot be ruled out. In practice, canagliflozin and dapagliflozin share many properties, particularly an unfavourable harm-benefit balance, and neither drug should be used. PMID- 25802914 TI - Common stem--pris. PMID- 25802916 TI - Drugs that promote dental caries. AB - Dental caries result from erosion of tooth enamel or cementum by acidic substances produced by bacteria found in dental plaque. Caries can lead to pulp necrosis and tooth loss. Risk factors include certain dietary habits, poor oral hygiene, and dry mouth. Diabetes and Sjogren's syndrome can also promote dental caries. Psychotropic substances such as cocaine, methamphetamine, heroin and cannabis can promote dental caries. Many medicinal drugs facilitate the formation of dental caries, through various mechanisms; they include formulations with a high sugar content; drugs that cause dry mouth (especially antimuscarinics); drugs that lower the buccal pH (inhaled powders, etc.); and drugs that cause demineralisation (tetracyclines, etc.). In practice, patients (and parents) should be informed that some drugs can increase the risk of dental caries. They should be encouraged to adapt and reinforce dental hygiene, and advised to visit a dentist regularly. PMID- 25802917 TI - Mechanism and causes of tooth decay. PMID- 25802918 TI - Choosing not to take bromocriptine. AB - In a survey of women not wishing to breastfeed, conducted in a French maternity hospital, 89% of those who received balanced information chose not to take bromocriptine to prevent puerperal lactation. PMID- 25802919 TI - Pregabalin: major weight gain. PMID- 25802920 TI - Hospital readmission for adverse drug reactions. AB - Two studies show that some hospital readmissions for adverse drug reactions are due to the same drug and the same adverse effect. PMID- 25802921 TI - Acute pancreatitis linked to isotretinoin. PMID- 25802922 TI - Prevention of migraine attacks. First-choice treatments. PMID- 25802923 TI - Sciatica and epidural corticosteroid injections. AB - According to trials conducted in hundreds of patients with sciatica, epidural corticosteroid injections have no demonstrated efficacy beyond the placebo effect, either in the short-term or the long-term. However, they expose patients to a risk of sometimes serious neurological adverse effects. PMID- 25802924 TI - The reorganisation of European pharmacovigilance. Part 2. From spontaneous reports to agency reviews and decisions. AB - Despite the fact that adverse effects are vastly under-reported, spontaneous reporting remains the foundation of pharmacovigilance. A small series of properly documented cases, when very specific, can suffice to constitute a signal. In France, reporting adverse effects to Regional Pharmacovigilance Centres (CRPVs) permits high-quality analysis of pharmacovigilance signals, so that they can be brought to the attention of the national agency responsible for making decisions about drugs, the French Health Products Agency (ANSM). The ANSM can use this information to protect patients by implementing the measures within its power or by initiating a European referral. When a decision taken at the national level concerns a drug marketed in several Member States of the European Union, a "harmonisation" procedure results in a decision taken at community level, applicable in all Member States. This means that a safety issue raised by a single Member State sometimes leads to a decision that protects the population of the entire European Union. But it also means that other European decisions can compel national agencies to allow back onto the market a drug that they sought to withdraw in order to protect their citizens. Negotiations with other Member States, the European Medicines Agency (EMA) and the European Commission must be supported by robust data: this is yet another reason for each country to have its own effective national pharmacovigilance database, the contents of which should be publicly accessible. This is unfortunately not yet the case in France in 2014. It also provides another good reason for healthcare professionals and patients to report adverse effects, so that the details can be recorded in national and European databases. PMID- 25802925 TI - Encouraging spontaneous reporting of adverse effects. AB - One priority when organising surveillance of health products is to remove barriers to reporting adverse effects. One way to encourage reporting is by providing regular feedback, as practised by the German drug bulletin arznei telegramm, for example. PMID- 25802926 TI - NATIONAL INSTITUTIONS AND SUBNATIONAL DEVELOPMENT IN AFRICA. AB - We investigate the role of national institutions on subnational African development in a novel framework that accounts for both local geography and cultural-genetic traits. We exploit the fact that the political boundaries on the eve of African independence partitioned more than 200 ethnic groups across adjacent countries subjecting similar cultures, residing in homogeneous geographic areas, to different formal institutions. Using both a matching type and a spatial regression discontinuity approach we show that differences in countrywide institutional structures across the national border do not explain within-ethnicity differences in economic performance, as captured by satellite images of light density. The average noneffect of national institutions on ethnic development masks considerable heterogeneity partially driven by the diminishing role of national institutions in areas further from the capital cities. PMID- 25802927 TI - Contributions of BrCl, Br2, BrOCl, Br2O, and HOBr to regiospecific bromination rates of anisole and bromoanisoles in aqueous solution. AB - When bromide-containing waters are chlorinated, conventional wisdom typically assumes HOBr is the only active brominating agent. Several additional and often overlooked brominating agents (including BrCl, Br2, BrOCl, Br2O) can form in chlorinated waters, albeit at generally lower concentrations than HOBr. The extent to which these additional brominating agents influence bromination rates of disinfection byproduct precursors is, however, poorly understood. Herein, the influence of BrCl, Br2, BrOCl, Br2O, and HOBr toward rates of sequential bromination of anisole was quantified. Conditions affecting bromine speciation (e.g., pH, concentrations of chloride, bromide, and chlorine) were varied, and regiospecific second-order rate constants were calculated for reactions of each brominating agent with anisole, 2-bromoanisole, and 4-bromoanisole. The regioselectivity of anisole bromination changed with pH, consistent with the participation of more than one brominating agent. Under conditions representative of chlorinated drinking water, contributions to bromination rates decreased as BrCl > BrOCl > HOBr > Br2O (Br2 negligible). The second-order rate constant determined for net bromination of anisole by HOBr is up to 3000-times less than reported in previous studies (which assumed HOBr was the only active brominating agent). Accordingly, models that assume HOBr is the only kinetically relevant brominating agent in solutions of free bromine may be insufficient for reactions involving modestly nucleophilic organic compounds. PMID- 25802928 TI - Absolute quantification of the total and antidrug antibody-bound concentrations of recombinant human alpha-glucosidase in human plasma using protein G extraction and LC-MS/MS. AB - The administration of protein-based pharmaceuticals can cause the in vivo formation of antidrug antibodies (ADAs), which may reduce the efficacy of the therapy by binding to the protein drug. An accurate determination of the total and ADA-bound concentrations of the drug gives information on the extent of this immune response and its consequences and may help develop improved therapeutic regimens. We present an absolute quantitative method to differentiate between total, free, and ADA-bound drug for recombinant human alpha acid glucosidase (rhGAA) in plasma from patients suffering from Pompe's disease. LC-MS/MS quantification of a signature peptide after trypsin digestion of plasma samples before and after an extraction of the total IgG content of plasma with protein G coated beads was used to determine the total and the ADA-bound fractions of rhGAA in samples from Pompe patients after enzyme infusion. The methods for total and ADA-bound rhGAA allow quantitation of the drug in the range of 0.5 to 500 MUg/mL using 20 MUL of plasma and met the regular bioanalytical validation requirements, both in the absence and presence of high levels of anti-rhGAA antibodies. This demonstrates that the ADA-bound rhGAA fraction can be accurately and precisely determined and is not influenced by sample dilution, repeated freezing and thawing, or extended benchtop or frozen storage. In samples from a patient with a reduced response to therapy due to ADAs, high ADA-bound concentrations of rhGAA were found, while in the samples from a patient lacking ADAs, no significant ADA bound concentrations were found. Since protein G captures the complete IgG content of plasma, including all antidrug antibodies, the described extraction approach is universally applicable for the quantification of ADA-bound concentrations of all non-IgG-based biopharmaceuticals. PMID- 25802929 TI - Folates Induce Colorectal Carcinoma HT29 Cell Line Proliferation Through Notch1 Signaling. AB - Folic acid (FA) consumption at high levels has been associated with colon cancer risk. Several mechanisms have been proposed to explain this association. The Notch signal pathway has been implicated in the regulation of cellular proliferation. Our aim was to demonstrate that high concentrations of FA or its reduced form, 5-methyltetrahydrofolic acid (5-MTHF), increase colorectal carcinoma HT29 cell proliferation through an increase of Notch1 activation and to prove if the inhibition of Notch1 activation by gamma secretase inhibitor, reduce the effect of folic acid. HT29 cells were cultured in high (400 nM), low (20 nM), or 0 nM FA or 5-MTHF concentrations during 96 h with or without DAPT (gamma secretase inhibitor). Cell proliferation was determined by the methylthiazole tetrazolium method, and Notch1-intracellular domain (NICD) was analyzed by flow cytometry. HT29 cells exposed to 400 nM FA or 5-MTHF showed higher proliferation rate than those exposed to 20 nM of FA or 5-MTHF (P < 0.01) during 96 h. NICD expression increased at higher FA or 5-MTHF concentrations compared with lower concentrations (P < 0.01). This effect on proliferation was partially reversible when we blocked Notch1 activation with the inhibitor of gamma-secretase (P < 0.05).These data suggest that high concentration of FA and 5-MTHF induce HT29 cell proliferation activating Notch1 pathway. PMID- 25802930 TI - Quantitative magnetic resonance imaging evidence for altered structural remodeling of the temporal lobe in West syndrome. AB - OBJECTIVE: To explore the structure-function relation of the temporal lobe in newly diagnosed West syndrome of unknown cause (uWS). METHODS: Quantitative magnetic resonance imaging (three-dimensional [3D] structural MRI and diffusion tensor imaging [DTI]) was analyzed using voxel-based morphometry (VBM) and tract based spatial statistics (TBSS) in 22 patients and healthy age-matched controls. The electrophysiologic responsiveness of the temporal lobe was measured using the N100 auditory event-related potential (aERP) to a repeated 1,000 Hz tone. Neurocognitive function was assessed using the Bayley Scales of Infant Development, Second Edition (BSID-II). Tests followed first-line treatment with vigabatrin (17 patients) or high-dose oral prednisolone (5 patients). RESULTS: Total temporal lobe volume was similar in patients and controls. Patients had a smaller temporal stem (TS) (p < 0.0001) and planum temporale (PT) (p = 0.029) bilaterally. TS width asymmetry with a larger right-sided width in controls was absent in patients (p = 0.033). PT asymmetry was present in both groups, being larger on the right (p = 0.048). VBM gray matter volume was increased at the left temporal lobe (superior and middle temporal gyri, the peri-rhinal cortex, and medial temporal lobe) (p < 0.005, family wise error-corrected). VBM gray matter volume correlated with the duration of infantile spasms (Pearson's r = -0.630, p = 0.009). DTI metrics did not differ between patients and controls on TBSS. Mean BSID-II scores were lower (p < 0.001) and auditory N100 ERP attenuated less in patients than in controls (p = 0.002). SIGNIFICANCE: The functional networking and white matter development of the temporal lobe are impaired following infantile spasms. Treatment may promote structural plasticity within the temporal lobe following infantile spasms, manifest as increased gray matter volume on VBM. It remains to be investigated further whether this predicts patients' long-term cognitive difficulties. PMID- 25802935 TI - The dark side of medicine. PMID- 25802932 TI - A pilot study of nimotuzumab plus single agent chemotherapy as second- or third line treatment or more in patients with recurrent, persistent or metastatic cervical cancer. AB - Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m(2) as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m(2)) or cisplatin (50 mg/m(2)) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were 163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer. PMID- 25802933 TI - The Use of a Dynamic Elastomeric Fabric Orthosis in Supporting the Management of Athletic Pelvic and Groin Injury. AB - CONTEXT: Athletic pelvic and groin injuries are a common yet challenging problem. Pelvic belts have been successfully used to reduce pain and improve function but are not a practical solution for athletes. Therefore, there is scope to explore the use of a more dynamic intervention developed to aid in the management of this type of injury. OBJECTIVES: To undertake a preliminary investigation into the effectiveness of a dynamic elastomeric fabric orthosis (DEFO) in supporting the management of athletic pelvic and groin injury. DESIGN: A case series with an AB design. Daily assessments were undertaken over 15 days; the onset of intervention was randomized with a minimum baseline period of 6 d. Follow-up assessment was undertaken after 1 mo. SETTINGS: Community and university. PARTICIPANTS: 8 athletes presenting with pelvic or groin injury confirmed through clinical screening. INTERVENTION: A bespoke DEFO. MAIN OUTCOME MEASURES: Force produced on bilateral resisted hip adduction and self-scored pain (using a numerical rating scale of 0-10) at rest and during an active straight-leg raise and a broad jump. RESULTS: In 7 cases a significant improvement was observed on at least 1 measure (2-SD method, celeration line, and/or the point of nonoverlapping data). The remaining case showed minimal symptoms during testing. PMID- 25802936 TI - Are antidepressants safe in the first trimester of pregnancy? AB - Antidepressants have been linked to cardiac malformations when used early in pregnancy, particularly the first trimester. However, recent analyses suggest that the overall risk of malformations is very low. When determining appropriate therapy for pregnant women or women who plan to become pregnant, providers should consider the growing body of evidence compared with the potential harm caused if maternal medical conditions are not treated. PMID- 25802938 TI - A rare cause of hearing loss in a child. AB - Neurofibromatosis type 2 is a rare genetic disease affecting the central and peripheral nervous systems and characterized by schwannomas, meningiomas, and ependymomas. Prompt symptom recognition, diagnosis, and proper referrals can increase treatment effectiveness and decrease the mortality risk of this life threatening disease. PMID- 25802931 TI - Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells. AB - Mouse embryonic stem cells (ES cells) can proliferate indefinitely. To identify potential signals involved in suppression of self-renewal, we previously screened a kinase/phosphatase expression library in ES cells, and observed that inhibition of Dual Leucine zipper-bearing Kinase (DLK) increased relative cell numbers. DLK protein was detected in both the pluripotent and differentiated states of mouse ES cells while DLK kinase activity increased upon differentiation. Overexpression of DLK in mouse ES cells displayed reductions in relative cell/colony numbers and Nanog expression, suggesting a suppressive role of DLK in self-renewal. By examining protein sequences of DLK, we identified 2 putative Akt phosphorylation sites at S584 and T659. Blocking PI3K/Akt signaling with LY-294002 enhanced DLK kinase activity dramatically. We found that Akt interacts with and phosphorylates DLK. Mutations of DLK amino acid residues at putative Akt phosphorylation sites (S584A, T659A, or S584A and T659A) diminished the level of DLK phosphorylation. While the mutated DLKs (S584A, T659A, or S584A and T659A) were expressed, a further reduction in cell/colony numbers and Nanog expression appeared in mouse ES cells. In addition, these mutant DLKs (S584A, T659A, or S584A and T659A) exhibited more robust kinase activity and cell death compared to wild type DLK or green fluorescence (GFP) controls. In summary, our results show that DLK functions to suppress self-renewal of mouse ES cells and is restrained by Akt phosphorylation. PMID- 25802939 TI - When exercise causes exertional rhabdomyolysis. AB - Exertional rhabdomyolysis is a clinical condition caused by intense, repetitive exercise or a sudden increase in exercise in an untrained person, although rhabdomyolysis can occur in trained athletes. In many cases, the presentation of early, uncomplicated rhabdomyolysis is subtle, but serious complications such as renal failure, compartment syndrome, and dysrhythmias may arise if severe exertional rhabdomyolysis is undiagnosed or untreated. Management is further complicated by the lack of concrete management guidelines for treating rhabdomyolysis and returning patients to activity. PMID- 25802940 TI - An introduction to cost analysis. AB - This article describes the basics of cost accounting for healthcare providers and how these concepts relate to decision making in medical practice. By understanding cost accounting and cost analysis, providers can be better prepared to compete and survive in a changing healthcare environment. PMID- 25802941 TI - Community health centers at the crossroads: growth and staffing needs. AB - In response to increased demand for primary care services under the Affordable Care Act, the national network of community health centers (CHCs) will play an increasingly prominent role. CHCs have a broad staffing model that includes extensive use of physician assistants (PAs), nurse practitioners (NPs), and certified nurse midwives (CNMs). Between 2007 and 2012, the number of PAs, NPs, and CNMs at CHCs increased by 61%, compared with 31% for physicians. However, several policy and payment issues jeopardize CHCs' ability to expand their workforce and meet the current and rising demand for care. PMID- 25802942 TI - What caused this patient's chest pain and refractory hypotension? PMID- 25802943 TI - Orthopedic uses of stem cell therapy. AB - The treatment of musculoskeletal disorders is gaining importance as the population ages. In addition to the complications brought on by prolonged life expectancy, the growing epidemic of obesity is contributing to joint degradation. Cell-based tissue engineering has the potential to advance the current treatment for musculoskeletal disorders. This article reviews the various forms of arthritis and describes stem cell therapy as a promising treatment option. PMID- 25802944 TI - Abdominal pain after air travel. PMID- 25802945 TI - Breathing easier at the end of the day. PMID- 25802946 TI - Comparison of different numerical treatments for x-ray phase tomography of soft tissue from differential phase projections. AB - X-ray imaging of soft tissue is made difficult by their low absorbance. The use of x-ray phase imaging and tomography can significantly enhance the detection of these tissues and several approaches have been proposed to this end. Methods such as analyzer-based imaging or grating interferometry produce differential phase projections that can be used to reconstruct the 3D distribution of the sample refractive index. We report on the quantitative comparison of three different methods to obtain x-ray phase tomography with filtered back-projection from differential phase projections in the presence of noise. The three procedures represent different numerical approaches to solve the same mathematical problem, namely phase retrieval and filtered back-projection. It is found that obtaining individual phase projections and subsequently applying a conventional filtered back-projection algorithm produces the best results for noisy experimental data, when compared with other procedures based on the Hilbert transform. The algorithms are tested on simulated phantom data with added noise and the predictions are confirmed by experimental data acquired using a grating interferometer. The experiment is performed on unstained adult zebrafish, an important model organism for biomedical studies. The method optimization described here allows resolution of weak soft tissue features, such as muscle fibers. PMID- 25802947 TI - Lower Lid Laxity is Negatively Correlated with Improvement of the Ocular Surface Disease Index in Dry Eye Treatment. AB - PURPOSE: To compare the responses to dry eye treatment of patients sorted by the degree of lower lid laxity. METHODS: Sixty patients were grouped into three groups according to the degree of lower lid laxity. Tear break-up time (TBUT), Schirmer test (ST) scores, ocular surface disease index (OSDI) scores, and changes in OSDI score in each group were compared, before and at 3 months after treatment. RESULTS: TBUT, ST, and OSDI scores were not different among the three groups at baseline. TBUT improved in each group at 3 months after treatment, and no differences between groups were found. ST scores were not increased after treatment, while OSDI were improved to 22.57 +/- 5.243, 31.16 +/- 11.353, and 37.85 +/- 13.342 in the no, moderate, and high laxity groups, respectively; these improvements were statistically significant (p = 0.003, <0.001, <0.001, respectively). Patients with greater than moderate lower lid laxity saw the smallest improvement in response to dry eye treatment, as assessed by change in OSDI score (p = 0.005 versus moderate laxity group, p = 0.005 versus no laxity group). CONCLUSIONS: Lower lid laxity is one of the factors contributing to the responses to dry eye treatment assessed by change in OSDI score, independent of TBUT and ST scores. PMID- 25802949 TI - LMX, Breach Perceptions, Work-Family Conflict, and Well-Being: A Mediational Model. AB - Despite research advances, work-family scholars still lack an understanding of how leadership constructs relate to an employee's ability to effectively manage the work-family interface. In addition, there remains a need to examine the process through which leadership and work-family conflict influence well-being outcomes. Using a sample of 312 workers, a mediated process model grounded in social exchange theory is tested wherein the authors seek to explain how leaders shape employee perceptions, which, in turn, impact organizational fulfillment of expectations (i.e., psychological contract breach), work-family conflict, and well-being. A fully latent structural equation model was used to test study hypotheses, all of which were supported. Building on existing theory, findings suggest that the supervisor plays a critical role as a frontline representative for the organization and that work-family conflict is reduced and well-being enhanced through a process of social exchange between the supervisor and worker. PMID- 25802948 TI - Acceleration of Biochar Surface Oxidation during Composting? AB - Biochar composting experiments were performed to determine whether composting is a suitable method to accelerate biochar surface oxidation for increasing its reactivity. To assess the results, surface properties of Terra Preta (Brazil) and ancient charcoal pit (Northern Italy) biochars were additionally investigated. Calculation of O/C ratios by energy-dispersive X-ray spectroscopy demonstrated the anticipated increasing values from fresh biochars (0.13) to composted biochars (0.40), and finally charcoal pit biochars (0.54) and ancient Terra Preta biochars (0.64). By means of Fourier transformation infrared microscopy, formation of carboxylic and phenolic groups on biochars surface could be detected. Carboxylic acids of three composted biochars increased up to 14%, whereas one composted biochar showed a 21% lower proportion of carboxylic acids compared to the corresponding fresh biochar. Phenolic groups increased by 23% for the last mentioned biochar, and on all other biochars phenolic groups decreased up to 22%. Results showed that biochar surface oxidation can be accelerated through composting but still far away from ancient biochars. PMID- 25802950 TI - Treatment cost of non-small cell lung cancer in three European countries: comparisons across France, Germany, and England using administrative databases. AB - INTRODUCTION: Lung cancer is a highly prevalent condition with non-small cell lung cancer (NSCLC), representing ~ 80%. Given its high prevalence and poor survival rates, it is important to understand costs associated with NSCLC treatment. OBJECTIVES: To carry out an incidence-based study in three European countries: France, Germany, and the UK, to estimate the cost of NSCLC treatment. METHODS: Three similar administrative databases were accessed; Hospital Episode Statistics (England), Gesundheitsforen Leipzig (Germany), French Hospital Discharge system (France), using ICD-9/10 codes and treatment/surgery algorithms to identify NSCLC patients. An incidence population of NSCLC patients was obtained using an index year (ranging from 2007-2008), ensuring the absence of prior lung cancer (12-months). Data were extracted on treatment information, patient characteristics, and disease staging. Average NSCLC treatment costs were estimated by age and severity. For England, 20,081 patients were identified, for France, 15,061, and for Germany, 1038. RESULTS: In-patient length of stay was 8.9, 8.7, and 10.1 days for France, England, and Germany, respectively, for the first year. Average total costs for the 2-year follow-up period for France, England, and Germany were ?25,063, ?17,777, and ?32,500, respectively. Sub-group analyses showed higher costs for younger patients and those with metastatic disease. CONCLUSION: Considerable differences in average treatment costs were observed. In-patient costs dominate in the first year of treatment in all countries. The study highlights the costly nature of NSCLC. PMID- 25802951 TI - What Are the Characteristics of Home Exercise Programs That Older Adults Prefer?: A Cross-Sectional Study. AB - OBJECTIVE: The aim of this study was to examine the preferences of older adults toward the structure and delivery of home exercise programs for the prevention of falls as well as the perceived benefits of and barriers to program adherence. METHODS: A two-wave cross-sectional telephone survey of community-dwelling older adults was conducted in Victoria, Australia. Respondents were categorized as current, previous, or nonparticipants of a home exercise program in the last 6 yrs. Thematic analysis of open-response questions examining the preferences of current and previous participants toward participation in, and delivery of, home exercise programs for falls preventions was performed. RESULTS: A total of 245 respondents completed the follow-up survey. The respondents were classified as current (n = 54), previous (n = 22), or nonparticipants (n = 169) of a home exercise program in the last 6 yrs. Program adherence was influenced by the perceived effect of programs on physical and mental health, participant autonomy, and how well the program structure complemented individual exercise and lifestyle preferences. CONCLUSIONS: Adherence to home exercise programs for falls prevention is influenced by personal preferences toward program structure and delivery as well as perceived benefits of and barriers to program participation. To optimize participant adherence, service providers need to consider personal preferences and some flexibility in the program being delivered. PMID- 25802952 TI - Effect of Electrical Stimulation and Vibration Therapy on Skeletal Muscle Trophism in Rats with Complete Spinal Cord Injury. AB - OBJECTIVE: The goals of this work were to analyze the skeletal muscle changes after complete spinal cord injury (SCI) in rats and to compare the effects of electrical stimulation and whole-body vibration on prevention of muscle hypotrophy in these animals. DESIGN: Seven-week-old male Wistar rats were divided into four groups: (1) sham operation (sham, n = 12), (2) SCI (n = 10), (3) SCI + electrical stimulation (n = 9), and (4) SCI + whole-body vibration (n = 9). Complete SCI was generated by surgical transection of the cord at the T10 level. Therapies were initiated 3 days after the surgery and continued for 30 days at a frequency of 3 days per week, 20 mins per day. The animals were killed on day 33 after injury for subsequent analyses. RESULTS: SCI caused a significant decrease in muscle mass and fibers, perimeter measurements, and mechanical resistance to traction as well as an increase in fibrotic tissue. Electrical stimulation, but not whole-body vibration, resulted in significant partial muscle hypotrophy prevention. CONCLUSIONS: Electrical stimulation may be a potentially beneficial therapeutic modality to prevent muscle hypotrophy after SCI. PMID- 25802953 TI - Effect of strengthening versus balance-proprioceptive exercises on lower extremity function in patients with juvenile idiopathic arthritis: a randomized, single-blind clinical trial. AB - OBJECTIVE: The aim of this study was to investigate the effects of two exercise programs on lower extremity function in patients with juvenile idiopathic arthritis. DESIGN: Thirty patients with juvenile idiopathic arthritis participated in this study. Pain, passive range of motion, muscle strength, balance, and functional abilities were assessed with the Numeric Rating Scale, goniometer, handheld dynamometer, Flamingo Balance Test, Functional Reach Test, 10-meter walking test, 10-stair climbing test, and Childhood Health Assessment Questionnaire. Participants were randomly assigned to the strengthening exercise group (group 1, n = 15) or the proprioceptive-balance exercise group (group 2, n = 15). RESULTS: Intragroup analysis showed statistically significant improvements in all outcome measures except muscle strength in the hip and ankle after strengthening exercises in group 1. However, statistically significant improvements were found in all outcome measures after the proprioceptive-balance exercises in group 2. Intergroup analysis showed statistically significant improvement in all outcome measures in group 2 except for the Numeric Rating Scale, Childhood Health Assessment Questionnaire, and passive range of motion scores and hip extension and knee flexion muscle strengths. CONCLUSIONS: This study demonstrates that exercise treatment significantly improves musculoskeletal symptoms in patients with juvenile idiopathic arthritis. However, balance proprioceptive exercises prove to be effective more than strengthening exercises for improving lower extremity function such as walking, climbing stairs, and balance in patients with juvenile idiopathic arthritis. PMID- 25802954 TI - Improved Walking Claudication Distance with Transcutaneous Electrical Nerve Stimulation: An Old Treatment with a New Indication in Patients with Peripheral Artery Disease. AB - OBJECTIVE: The aim of this study was to determine whether 45 mins of transcutaneous electrical nerve stimulation before exercise could delay pain onset and increase walking distance in peripheral artery disease patients. DESIGN: After a baseline assessment of the walking velocity that led to pain after 300 m, 15 peripheral artery disease patients underwent four exercise sessions in a random order. The patients had a 45-min transcutaneous electrical nerve stimulation session with different experimental conditions: 80 Hz, 10 Hz, sham (presence of electrodes without stimulation), or control with no electrodes, immediately followed by five walking bouts on a treadmill until pain occurred. The patients were allowed to rest for 10 mins between each bout and had no feedback concerning the walking distance achieved. RESULTS: Total walking distance was significantly different between T10, T80, sham, and control (P < 0.0003). No difference was observed between T10 and T80, but T10 was different from sham and control. Sham, T10, and T80 were all different from control (P < 0.001). There was no difference between each condition for heart rate and blood pressure. CONCLUSIONS: Transcutaneous electrical nerve stimulation immediately before walking can delay pain onset and increase walking distance in patients with class II peripheral artery disease, with transcutaneous electrical nerve stimulation of 10 Hz being the most effective. PMID- 25802955 TI - Combining Afferent Stimulation and Mirror Therapy for Improving Muscular, Sensorimotor, and Daily Functions After Chronic Stroke: A Randomized, Placebo Controlled Study. AB - OBJECTIVE: Mirror therapy (MT) combined with mesh glove (MG) afferent stimulation (MT + MG) has been suggested as an effective intervention for motor recovery in patients with stroke. This study aimed to further determine the treatment effects of the MT + MG approach on muscular properties, sensorimotor functions, and daily function. DESIGN: This was a single-blind, randomized, placebo-controlled study. Forty-eight participants with chronic stroke were recruited from medical centers and were randomly assigned to the MT, MT + MG, and MT with sham MG stimulation (MT + sham) groups. The intervention consisted of 1.5 hrs/day, 5 days/wk for 4 wks. Primary outcomes were the Fugl-Meyer Assessment and muscular properties (muscle tone and stiffness). Secondary outcomes included measures of sensorimotor and daily functions. RESULTS: Compared with the MT and MT + sham groups, the MT + MG group demonstrated improved muscular properties. The MT + MG and MT + sham groups showed greater improvement in manual dexterity and daily function than the MT group did. No beneficial effects on the Fugl-Meyer Assessment and other sensorimotor outcomes were found for the MT + MG group. CONCLUSIONS: Although no significant group differences were found in the Fugl-Meyer Assessment, MT + MG induced distinctive effects on muscular properties, manual dexterity, and daily function. PMID- 25802956 TI - Compartment syndrome with mononeuropathies after anterior cruciate ligament reconstruction. AB - Compartment syndrome rarely follows anterior cruciate ligament reconstruction. However, when it does, it may result in mononeuropathies that are amenable to neurolysis. The authors of this study present an 18-yr-old woman who sustained a right anterior cruciate ligament tear and underwent uneventful anterior cruciate ligament reconstruction using femoral and popliteal nerve blocks. Postoperatively, she developed compartment syndrome requiring emergent fasciotomies. At 11 wks after fasciotomy, results of electrophysiologic tests showed evidence of severe fibular and tibial neuropathies. Magnetic resonance images showed extensive tricompartmental myonecrosis. Fibular and tibial neurolysis as well as decompression were performed, followed by intensive outpatient rehabilitation. At the 6-mo follow-up, she reported resolution of pain as well as significant improvement in sensation, strength, and function. Early recognition and intervention are crucial to prevent serious neurologic damage. Excessive tourniquet pressure and anesthetic nerve blocks may have been responsible. PMID- 25802957 TI - Magnetic Resonance Imaging Analysis of Deep Cervical Flexors in Patients with Ossification of the Posterior Longitudinal Ligament and Clinical Implication. AB - OBJECTIVE: The purpose of this study was to analyze the cross-sectional area (CSA) of deep cervical flexors as measured by magnetic resonance imaging in ossification of the posterior longitudinal ligament (OPLL) patients with neck pain and, by implication, how this may relate to recruitment of the deep cervical flexors and sternocleidomastoid. DESIGN: A retrospective case-control study was conducted. All 72 subjects were imaged using plain radiography, computed tomography, and magnetic resonance imaging. RESULTS: There was a more limited cervical range of motion in the OPLL group than that in the control group. Cervical lordosis, T1 slope, and thoracic inlet angle values were significantly lower in the OPLL group than in the control group. Bilateral CSAs of the longus colli muscle and longus capitis muscle of the OPLL group were smaller than those of the control group. In addition, bilateral CSAs of the sternocleidomastoid of the OPLL subjects were greater than those of healthy subjects. CONCLUSIONS: The authors found that the OPLL patients with chronic neck pain had lesser lordotic cervical alignment, smaller deep cervical flexor CSAs, and larger sternocleidomastoid CSAs than the control group did. The authors' theory is that the sternocleidomastoids in these OPLL patients have compensatorily hypertrophied in response to presumably atrophied deep cervical flexors. PMID- 25802958 TI - Treadmill Training Improves Forward and Backward Gait in Early Parkinson Disease. AB - OBJECTIVE: The aim of this study was to examine effects of treadmill training (TT) and lasting duration of training effects on forward walking (FW) and backward walking (BW) gait in Parkinson disease (PD). DESIGN: Twenty-six early PD patients undertook a 12-wk intensive TT program using FW. A repeated-measures design compared GAITRite-measured FW and BW gait before TT, within 1 wk, and at 4 and 12 wks after TT. RESULTS: Twenty-three PD patients, after completing TT, walked forward and backward with increased velocity, enlarged stride length, prolonged swing phase, and decreased double support phase; improvements occurred within 1 wk and remained at 4 and 12 wks after training (P < 0.01 or < 0.001). In addition, trends toward reduced posttraining swing time variability and stride length variability occurred in both directions and sustained for 12 wks. Posttraining FW and BW gait improvements were comparable. BW deficits, regardless of training, constantly exceeded FW deficits. Cadence did not differ before and after training in FW (P = 0.195) and BW (P = 0.229) and between FW and BW irrespective of TT (P = 0.124). CONCLUSIONS: A 12-wk TT program improves the 12 wk duration of FW and BW gait and can be considered a part of a rehabilitation strategy to overcome gait disturbances in early PD. PMID- 25802959 TI - Happiness, Pain Intensity, Pain Interference, and Distress in Individuals with Physical Disabilities. AB - OBJECTIVES: The aim of this study was to examine how the construct of happiness is related to pain intensity, pain interference, and distress in individuals with physical disabilities. DESIGN: This study involves cross-sectional analyses of 471 individuals with a variety of health conditions reporting at least mild pain. RESULTS: The first hypothesis that happiness mediates the relationship between pain intensity and two outcomes, pain interference and distress, was not supported. The second hypothesis was supported by a good fitting model (chi2(10) = 12.83, P = 0.23, root-mean-square error of approximation = 0.025) and indicated that pain intensity significantly mediated the effect of happiness on pain interference (indirect effect: beta = -0.13, P < 0.001) and on distress (indirect effect: beta = 0.10, P = 0.01). Happiness showed a significant direct effect on pain intensity (beta = -0.20, P < 0.001). A third model exploring the happiness components meaning, pleasure, and engagement fitted well (chi2(4) = 9.65, P = 0.05, root-mean-square error of approximation = 0.055). Pain intensity acted as a significant mediator but only mediated the effect of meaning on pain interference (indirect effect: beta = -0.07, P = 0.05) and on distress (indirect effect via pain interference: beta = -0.04, P = 0.05). Only meaning (beta = -0.10, P = 0.05), but neither pleasure nor engagement, had a significant direct effect on pain intensity. CONCLUSIONS: Participants who reported greater happiness reported lower pain interference and distress through happiness' effects on pain intensity. Experiencing meaning and purpose in life seems to be most closely (and negatively) associated with pain intensity, pain interference, and distress. Findings from this study can lay the groundwork for intervention studies to better understand how to more effectively decrease pain intensity, pain interference, and distress. PMID- 25802960 TI - Effect of High Interval Training in Acute Myocardial Infarction Patients with Drug-Eluting Stent. AB - OBJECTIVE: Peak oxygen uptake (VO2peak) is a strong predictor of survival in cardiac patients. The aims of this study were to compare the effects of high interval training (HIT) to moderate continuous training (MCT) on VO2peak and to identify the safety of HIT in acute myocardial infarction patients with drug eluting stent. DESIGN: Twenty-eight acute myocardial infarction patients with drug-eluting stent were randomized to either HIT at 85%-95 % of heart rate reserve or MCT at 70%-85% of heart rate reserve, 3 days a week for 6 wks at a cardiac rehabilitation clinic. Primary outcome was VO2peak at baseline and after cardiac rehabilitation. RESULTS: Both HIT and MCT groups showed significant increases in VO2peak and heart rate recovery after 6 wks of training. The 22.16% improvement in VO2peak in the HIT group was significantly greater than the 8.48% improvement in the MCT group (P = 0.021). There were no cardiovascular events related to both HIT and MCT. CONCLUSIONS: HIT is more effective than MCT for improving VO2peak in acute myocardial infarction patients with drug-eluting stent. These findings may have important implications for more effective exercise training in cardiac rehabilitation program. PMID- 25802961 TI - Low-Intensity Wheelchair Training in Inactive People with Long-Term Spinal Cord Injury: A Randomized Controlled Trial on Propulsion Technique. AB - OBJECTIVE: The objective of this study was to investigate the effects of a low intensity wheelchair training on propulsion technique in inactive people with long-term spinal cord injury. DESIGN: Participants in this multicenter nonblinded randomized controlled trial were inactive manual wheelchair users with spinal cord injury for at least 10 yrs (N = 29), allocated to exercise (n = 14) or no exercise. The 16-wk training consisted of wheelchair treadmill propulsion at 30% 40% heart rate reserve or equivalent in rate of perceived exertion, twice a week, 30 mins per session. Propulsion technique was assessed at baseline as well as after 8, 16, and 42 wks during two submaximal treadmill-exercise blocks using a measurement wheel attached to a participant's own wheelchair. Changes over time between the groups were analyzed using Mann-Whitney U tests on difference scores (P < 0.05/3). RESULTS: Data of 16 participants could be analyzed (exercise: n = 8). Significant differences between the exercise and control groups were only found in peak force after 8 wks (respective medians, -20 N vs. 1 N; P = 0.01; r(u) = 0.78). CONCLUSIONS: Significant training effects on propulsion technique were not found in this group. Perhaps, substantial effects require a higher intensity or frequency. Investigating whether more effective and feasible interventions exist might help reduce the population's risk of upper-body joint damage during daily wheelchair propulsion. PMID- 25802962 TI - "Numb Chin" Syndrome: Mental Nerve Mononeuropathy Resulting From a Synovial Temporomandibular Cyst. PMID- 25802963 TI - Re: Cancer rehabilitation education during physical medicine and rehabilitation residency. PMID- 25802964 TI - Reappraisal on the Role of Ultrasound Imaging for Lateral Hip Pain in a Case with Tensor Fascia Lata Tear. PMID- 25802965 TI - Mechanical Compression of the Iliopsoas Muscle by a Large Vertebral Osteophyte, Presenting with Abdominal and Lumbar Pain. PMID- 25802966 TI - Surface peroneal nerve stimulation in lower limb hemiparesis: effect on quantitative gait parameters. AB - OBJECTIVE: The objective of this study was to evaluate possible mechanisms for functional improvement and compare ambulation training with surface peroneal nerve stimulation vs. usual care via quantitative gait analysis. DESIGN: This study is a randomized controlled clinical trial. SETTING: The setting of this study is a teaching hospital of an academic medical center. PARTICIPANTS: One hundred ten chronic stroke survivors (>12 wks poststroke) with unilateral hemiparesis participated in this study. INTERVENTIONS: The subjects were randomized to a surface peroneal nerve stimulation device or usual care intervention. The subjects were treated for 12 wks and followed up for 6-mo posttreatment. MAIN OUTCOME MEASURES: Spatiotemporal, kinematic, and kinetic parameters of gait were the main outcome measures. RESULTS: Cadence (F3,153 = 5.81, P = 0.012), stride length (F3,179 = 20.01, P < 0.001), walking speed (F3,167 = 18.2, P < 0.001), anterior-posterior ground reaction force (F3,164 = 6.61, P = 0.004), peak hip power in preswing (F3,156 = 8.76, P < 0.001), and peak ankle power at push-off (F3,149 = 6.38, P = 0.005) all improved with respect to time. However, peak ankle ankle dorsiflexion in swing (F3,184 = 4.99, P = 0.031) worsened. In general, the greatest change for all parameters occurred during the treatment period. There were no significant treatment group * time interaction effects for any of the spatiotemporal, kinematic, or kinetic parameters. CONCLUSIONS: Gait training with peroneal nerve stimulation and usual care was associated with improvements in peak hip power in preswing and peak ankle power at push-off, which may have resulted in improved cadence, stride length, and walking speed; however, there were no differences between treatment groups. Both treatment groups also experienced a decrease in peak ankle ankle dorsiflexion in swing, although the clinical implications of this finding are unclear. PMID- 25802967 TI - Diagnostic Algorithm for Patients With Suspected Giant Cell Arteritis. AB - BACKGROUND: To identify clinical and laboratory factors contributing to the diagnosis of giant cell arteritis (GCA) and develop a diagnostic algorithm for the evaluation of GCA. METHODS: Retrospective review of 213 consecutive cases of temporal artery biopsy (TAB) seen at a single academic center over a 10-year period (2000-2009). Pathologic specimens were re-reviewed and agreement between the original and second readings was assessed. A composite clinical suspicion score was created by adding 1 point for each of the following criteria: anterior extracranial circulation ischemia, new onset headache, abnormal laboratory results (erythrocyte sedimentation rate, C-reactive protein (CRP), or platelet count), jaw claudication, abnormal or tender superficial temporal artery, constitutional symptoms, and polymyalgia rheumatica; one point was subtracted if a comorbid condition could explain a criterion. RESULTS: Of the 204 TABs analyzed, pathologic findings were confirmatory in 49 (24.0%) and suggestive in 12 (5.9%). TAB-positive patients were more likely to be older (age 75.2 +/- 7.8 vs 69.7 +/- 11.0 years, P = 0.0002), complain of jaw claudication (relative-risk = 3.26, P = 0.0014), and have thrombocytosis (relative-risk = 3.3, P = 0.0072) and elevated CRP (relative-risk = 1.8, P = 0.037). None of the patients with a clinical score less than 2 had a positive TAB. Diabetes mellitus and kidney disease were often the explanation for the symptoms and abnormal clinical finding(s) that led to a negative TAB. CONCLUSIONS: We propose a clinical algorithm that is highly predictive for a positive TAB and can be valuable in the evaluation process of suspected cases of GCA. PMID- 25802969 TI - Ethanol dehydration in HZSM-5 studied by density functional theory: evidence for a concerted process. AB - Dehydration over acidic zeolites is an important reaction class for the upgrading of biomass pyrolysis vapors to hydrocarbon fuels or to precursors for myriad chemical products. Here, we examine the dehydration of ethanol at a Bronsted acid site, T12, found in HZSM-5 using density functional theory (DFT). The geometries of both cluster and mixed quantum mechanics/molecular mechanics (QM:MM) models are prepared from the ZSM-5 crystal structure. Comparisons between these models and different DFT methods are conducted to show similar results among the models and methods used. Inclusion of the full catalyst cavity through a QM:MM approach is found to be important, since activation barriers are computed on average as 7 kcal mol(-1) lower than those obtained with a smaller cluster model. Two different pathways, concerted and stepwise, have been considered when examining dehydration and deprotonation steps. The current study shows that a concerted dehydration process is possible with a lower (4-5 kcal mol(-1)) activation barrier while previous literature studies have focused on a stepwise mechanism. Overall, this work demonstrates that fairly high activation energies (~50 kcal mol(-1)) are required for ethanol dehydration. A concerted mechanism is favored over a stepwise mechanism because charge separation in the transition state is minimized. QM:MM approaches appear to provide superior results to cluster calculations due to a more accurate representation of charges on framework oxygen atoms. PMID- 25802968 TI - Qualitative evaluation of a text messaging intervention to support patients with active tuberculosis: implementation considerations. AB - BACKGROUND: Tuberculosis (TB) remains a major global public health problem and mobile health (mHealth) interventions have been identified as a modality to improve TB outcomes. TextTB, an interactive text-based intervention to promote adherence with TB medication, was pilot-tested in Argentina with results supporting the implementation of trials at a larger scale. OBJECTIVE: The objective of this research was to understand issues encountered during pilot testing in order to inform future implementation in a larger-scale trial. METHODS: A descriptive, observational qualitative design guided by a sociotechnical framework was used. The setting was a clinic within a public pulmonary-specialized hospital in Argentina. Data were collected through workflow observation over 115 days, text messages (n=2286), review of the study log, and stakeholder input. Emerging issues were categorized as organizational, human, technical, or sociotechnical considerations. RESULTS: Issues related to the intervention included workflow issues (eg, human, training, security), technical challenges (eg, data errors, platform shortcomings), and message delivery issues (eg, unintentional sending of multiple messages, auto-confirmation problems). System/contextual issues included variable mobile network coverage, electrical and Internet outages, and medication shortages. CONCLUSIONS: Intervention challenges were largely manageable during pilot-testing, but need to be addressed systematically before proceeding with a larger-scale trial. Potential solutions are outlined. Findings may help others considering implementing an mHealth intervention to anticipate and mitigate certain challenges. Although some of the issues may be context dependent, other issues such as electrical/Internet outages and limited resources are not unique issues to our setting. Release of new software versions did not result in solutions for certain issues, as specific features used were removed. Therefore, other software options will need to be considered before expanding into a larger-scale endeavor. Improved automation of some features will be necessary, however, a goal will be to retain the intervention capability to be interactive, user friendly, and patient focused. Continued collaboration with stakeholders will be required to conduct further research and to understand how such an mHealth intervention can be effectively integrated into larger health systems. PMID- 25802970 TI - Enforcement of alcohol-impaired driving laws in the United States: a national survey of state and local agencies. AB - OBJECTIVES: Enforcement of alcohol-impaired driving laws is an important component of efforts to prevent alcohol-involved motor vehicle fatalities. Little is known about the use of drinking-driving enforcement strategies by state and local law enforcement agencies or whether the use of strategies differs by agency and jurisdiction characteristics. METHODS: We conducted two national surveys, with state patrol agencies (n = 48) and with a sample of local law enforcement agencies (n = 1,082) selected according to state and jurisdiction population size. We examined 3 primary enforcement strategies (sobriety checkpoints, saturation patrols, and enforcement of open container laws) and tested whether use of these strategies differed by jurisdiction and agency characteristics across state and local law enforcement agencies RESULTS: Most state patrol agencies reported conducting sobriety checkpoints (72.9%) and saturation patrols (95.8%), whereas less than half (43.8%) reported enforcing open container laws. In contrast, a lower proportion of local law enforcement agencies reported using these alcohol-impaired driving enforcement strategies (41.5, 62.7, and 41.1%, respectively). Sobriety checkpoint enforcement was more common in states in the dry South region (vs. wet and moderate regions). Among local law enforcement agencies, agencies with a full-time alcohol enforcement officer and agencies located in areas where drinking-driving was perceived to be very common (vs. not/somewhat common) were more likely to conduct multiple types of impaired driving enforcement. CONCLUSIONS: Recommended enforcement strategies to detect and prevent alcohol-impaired driving are employed in some jurisdictions and underutilized in others. Future research should explore the relationship of enforcement with drinking and driving behavior and alcohol-involved motor vehicle fatalities. PMID- 25802971 TI - Awareness tool for safe and responsible driving (OSCAR): a potential educational intervention for increasing interest, openness and knowledge about the abilities required and compensatory strategies among older drivers. AB - OBJECTIVE: This pilot study aimed to verify the impact of the awareness tool for safe and responsible driving (OSCAR) on older adults' (1) interest, openness, and knowledge about the abilities and compensatory strategies required for safe driving; (2) awareness of changes that have occurred in their own driving abilities; and (3) actual utilization of compensatory strategies. METHODS: A preexperimental design, including a pretest (T0) and posttest (T1) 8 to 10 weeks after exposure to the intervention, was used with 48 drivers aged between 67 and 84. The participants had a valid driving license and drove at least once a week. RESULTS: Overall, the results demonstrate that OSCAR increased interest, openness, and knowledge about the abilities and compensatory strategies of older drivers (P <.01). After exposure to OSCAR, the majority of the participants confirmed that changes had occurred in at least one of their abilities. Moreover, half of the older drivers reported having started using 6 or more compensatory strategies. CONCLUSION: In summary, in addition to increasing older adults' interest, openness, and knowledge to discussion about driving, OSCAR also improved awareness of the changes that could negatively impact safe driving and enhanced utilization of compensatory strategies. While promoting safe driving and the prevention of crashes and injuries, this intervention could ultimately help older adults maintain or increase their transportation mobility. More studies are needed to further evaluate OSCAR and identify ways to improve its effectiveness. PMID- 25802974 TI - The fan-beam short-scan FBP algorithm is not exact. AB - The fan-beam short-scan filtered backprojection (FBP) algorithm is popular in the computed tomography (CT) industry and in clinical applications. This paper points out that the fan-beam short-scan FBP algorithm is not exact, even in an ideal noiseless situation. The error depends on the focal length of the imaging geometry. When the focal length is long enough, the error is small and can therefore be ignored. PMID- 25802975 TI - Surface Modification of CoO(x) Loaded BiVO4 Photoanodes with Ultrathin p-Type NiO Layers for Improved Solar Water Oxidation. AB - Photoelectrochemical (PEC) devices that use semiconductors to absorb solar light for water splitting offer a promising way toward the future scalable production of renewable hydrogen fuels. However, the charge recombination in the photoanode/electrolyte (solid/liquid) junction is a major energy loss and hampers the PEC performance from being efficient. Here, we show that this problem is addressed by the conformal deposition of an ultrathin p-type NiO layer on the photoanode to create a buried p/n junction as well as to reduce the charge recombination at the surface trapping states for the enlarged surface band bending. Further, the in situ formed hydroxyl-rich and hydroxyl-ion-permeable NiOOH enables the dual catalysts of CoO(x) and NiOOH for the improved water oxidation activity. Compared to the CoO(x) loaded BiVO4 (CoO(x)/BiVO4) photoanode, the ~6 nm NiO deposited NiO/CoO(x)/BiVO4 photoanode triples the photocurrent density at 0.6 V(RHE) under AM 1.5G illumination and enables a 1.5% half-cell solar-to-hydrogen efficiency. Stoichiometric oxygen and hydrogen are generated with Faraday efficiency of unity over 12 h. This strategy could be applied to other narrow band gap semiconducting photoanodes toward the low-cost solar fuel generation devices. PMID- 25802972 TI - Cholera toxin B: one subunit with many pharmaceutical applications. AB - Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in unsanitary conditions. The major virulence factor is cholera toxin (CT), which consists of two subunits: the A subunit (CTA) and the B subunit (CTB). CTB is a 55 kD homopentameric, non-toxic protein binding to the GM1 ganglioside on mammalian cells with high affinity. Currently, recombinantly produced CTB is used as a component of an internationally licensed oral cholera vaccine, as the protein induces potent humoral immunity that can neutralize CT in the gut. Additionally, recent studies have revealed that CTB administration leads to the induction of anti-inflammatory mechanisms in vivo. This review will cover the potential of CTB as an immunomodulatory and anti-inflammatory agent. We will also summarize various recombinant expression systems available for recombinant CTB bioproduction. PMID- 25802973 TI - Further evidence for staphylococcal food poisoning outbreaks caused by egc encoded enterotoxins. AB - Staphylococcal food poisoning represents the most prevalent foodborne intoxication worldwide. It is caused by oral intake of enterotoxins preformed by Staphylococcus aureus in food. The relevance of newly described enterotoxins in outbreaks of staphylococcal food poisoning is controversially discussed. Although the staphylococcal enterotoxins SEG, SEI, SEM, SEN, and SEO elicit emesis in a monkey feeding assay, there has been no conclusive proof of their emetic activity in humans. In this study, we provide further evidence suggesting that one of these enterotoxins or a combination of SEG, SEI, SEM, SEN, and SEO cause staphylococcal food poisoning. We investigated two outbreaks registered with the Swiss Federal Office of Public Health, in which only Staphylococcus aureus strains harboring the egc cluster, including seg, sei, sem, sen, and seo linked to typical signs of staphylococcal food poisoning were isolated. The outbreaks were caused by consumption of raw goat cheese and semi-hard goat cheese, and were linked to strains assigned to CC45 (agr type I) and CC9 (agr type II), respectively. These outbreaks provide further evidence that newly-described staphylococcal enterotoxins are likely to cause staphylococcal food poisoning in humans. PMID- 25802976 TI - Mechanisms and therapeutic potential of inhibiting drug efflux transporters. AB - INTRODUCTION: The ATP-binding cassette transporters are among the largest transmembrane protein families in humans and are expressed in a wide variety of tissues. By promoting outward transport, they protect cells from the accumulation of undesirable substrates. This protection might lead to suboptimal concentration of chemotherapeutics in the tumor cells, resulting in therapy resistance and poor disease prognosis. In the past decades, a considerable effort was made to reverse multidrug resistance (MDR). AREAS COVERED: We briefly summarize the present knowledge on the clinical efficacy of MDR reversing agents in various types of cancer and discuss their availability in a non-cancerous disease (rheumatoid arthritis). The classical and novel pharmacological approaches directly inhibiting the transporters' function and their extensive investigations in human clinical studies are also mentioned. Furthermore, the article highlights the methodological concerns raised by these investigations. EXPERT OPINION: The development of chemotherapeutics lacking transporter-inducing effects, gene therapy approaches, nanomedicinal formulations and the identification of natural compounds to modulate transporter function are intriguing but face serious delivery challenges. Understanding and mapping molecular mechanisms of drug resistance will make it easier to design clinical treatment regimes that avoid escalation of MDR, by utilizing collateral sensitivity. PMID- 25802977 TI - The role of short- and long-term cognitive empathy activation in preventing cyberbystander reinforcing cyberbullying behavior. AB - The long- versus short-term effectiveness of empathy activation on reducing bystander behavior reinforcing cyberbullying was tested. The focus was on limiting the frequency of forwarding a message ridiculing a peer. Experimental research on adolescent students was conducted in conditions simulating online contact. The results confirmed the significance of cognitive empathy activated immediately prior to decision making on limiting involvement in reinforcing cyberbullying behavior. The long-term impact of empathy was markedly limited. PMID- 25802978 TI - One-pot Sonogashira coupling-cyclization toward regioselective synthesis of benzosultams. AB - A one-pot method for the Sonogashira coupling and cyclization of 2 bromobenzenesulfonamides and terminal alkynes is presented. This method allows access to a variety of substituted benzosultams regioselectively in excellent yields. The reasons for regioselectivity are interpreted through density functional theory (DFT) studies. PMID- 25802979 TI - The epidemiology of common mental disorders from age 20 to 50: results from the prospective Zurich cohort Study. AB - BACKGROUND: There are only a small number of prospective studies that have systematically evaluated standardised diagnostic criteria for mental disorder for more than a decade. The aim of this study is to present the approximated overall and sex-specific cumulative incidence of mental disorder in the Zurich cohort study, a prospective cohort study of 18-19 years olds from the canton of Zurich, Switzerland, who were followed through age 50. METHOD: A stratified sample of 591 participants were interviewed with the Structured Psychopathological Interview and Rating of the Social Consequences of Psychological Disturbances for Epidemiology, a semi-structured interview that uses a bottom-up approach to assess the past-year presence of 15 psychiatric syndromes. Seven interview waves took place between 1979 and 2008. Approximated cumulative incidence was estimated using Kaplan-Meier methods. RESULTS: Rates of mental disorder were considerably higher than those generally reported in cross-sectional surveys. We found rates ranging from 32.5% for major depressive disorder to 1.2% for Bipolar I disorder. The cumulative probability of experiencing any of the mental disorders assessed by age 50 was 73.9%, the highest reported to date. We also found that rates differed by sex for most disorders, with females generally reporting higher rates of mood, anxiety and phobic disorder, and males reporting higher rates of substance- and alcohol-related disorders. CONCLUSIONS: These findings confirm those of other long-term prospective studies that indicate the nearly universal nature of disturbances of emotion and behaviour across the life span. Greater community awareness of the normative nature of these experiences is warranted. An important area of future research is study long-term course and stability to determine who among those with such disturbances suffer from chronic disabling mental disorders. Such longitudinal studies may aid in directing services and intervention efforts where they are most needed. PMID- 25802981 TI - Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. PMID- 25802980 TI - Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. AB - This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ? 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work. PMID- 25802983 TI - Different Muscle-Recruitment Strategies Among Elite Breaststrokers. AB - PURPOSE: To investigate electromyographical (EMG) profiles characterizing the lower-limb flexion-extension in an aquatic environment in high-level breaststrokers. METHODS: The 2-dimensional breaststroke kick of 1 international- and 2 national-level female swimmers was analyzed during 2 maximal 25-m swims. The activities of biceps femoris, rectus femoris, gastrocnemius, and tibialis anterior were recorded. RESULTS: The breaststroke kick was divided in 3 phases, according to the movements performed in the sagittal plane: push phase (PP) covering 27% of the total kick duration, glide phase (GP) 41%, and recovery phase (RP) 32%. Intrasubject reproducibility of the EMG and kinematics was observed from 1 stroke cycle to another. In addition, important intersubject kinematic reproducibility was noted, whereas muscle activities discriminated the subjects: The explosive PP was characterized by important muscle-activation peaks. During the recovery, muscles were likewise solicited for swimmers 1 (S1) and 2 (S2), while the lowest activities were observed during GP for S2 and swimmer 3 (S3), but not for S1, who maintained major muscle solicitations. CONCLUSIONS: The main muscle activities were observed during PP to perform powerful lower-limb extension. The most-skilled swimmer (S1) was the only 1 to solicit her muscles during GP to actively reach better streamlining. Important activation peaks during RP correspond to the limbs acting against water drag. Such differences in EMG strategies among an elite group highlight the importance of considering the muscle parameters used to effectively control the intensity of activation among the phases for a more efficient breaststroke kick. PMID- 25802982 TI - Arc expression identifies the lateral amygdala fear memory trace. AB - Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity. PMID- 25802985 TI - "Hirnsymptome bei Carcinomatose" - Hermann Oppenheim and an Early Description of a Paraneoplastic Neurological Syndrome. AB - Paraneoplastic neurological syndromes belong to the most enigmatic and fascinating disorders. Their remarkable clinical spectrum ranges from sensory neuronopathy to cerebellar degeneration or limbic encephalitis. We retrace the clinical and pathological description of a forgotten case published by Hermann Oppenheim in 1888, which to our knowledge represents the first report of a paraneoplastic neurological syndrome. The young Oppenheim used thorough observation and good clinical judgment to suggest a causal link between the seemingly mere association of an underlying malignancy and a neurological syndrome, decades before Denny-Brown's identification of sensory neuronopathy in 1948 and a century before the discovery of "anti-Hu" antibodies. Oppenheim anticipated that scientific progress was required to prove this link, and he indicated his finding as "a pointer for future observers." In this way, he leaves the reader with the fascinating question of which observations during our current neurology practice could be the next "pointers" in medical research. PMID- 25802984 TI - Anhedonia, but not irritability, is associated with illness severity outcomes in adolescent major depression. AB - OBJECTIVES: Unlike adult major depressive disorder (MDD) which requires anhedonia or depressed mood for diagnosis, adolescent MDD can be sufficiently diagnosed with irritability in the absence of the former symptoms. In addition, the current Diagnostic and Statistical Manual of Mental Disorders (DSM) schema does not account for the interindividual variability of symptom severity among depressed adolescents. This practice has contributed to the high heterogeneity and diagnostic complexity of adolescent MDD. Here, we sought to examine relationships between two core symptoms of adolescent MDD - irritability and anhedonia, assessed both quantitatively and categorically - and other clinical correlates among depressed adolescents. METHODS: Ninety adolescents with MDD (51 females), ages 12-20, were enrolled. Anhedonia and irritability scores were quantified by summing related items on the Children's Depression Rating Scale-Revised and the Beck Depression Inventory. Extremes of score distribution were defined as high or low irritability/anhedonia subgroups. A significance level of p=0.01 was set to adjust for the five comparisons. RESULTS: Despite all subjects exhibiting moderate to severe MDD, both irritability and anhedonia scores manifested a full and normally distributed severity range including the lowest values possible. However, only anhedonia severity was associated with more severe clinical outcomes, including greater overall illness severity (p<0.001), suicidality scores (p<0.001), episode duration (p=0.006), and number of MDD episodes (p=0.01). Similarly, only the high-anhedonia subgroup manifested more severe outcomes; specifically, greater illness severity (p<0.0001), number of MDD episodes (p=0.01), episode duration (p=0.01), and suicidality scores (p=0.0001). CONCLUSIONS: Our findings suggest the significance of anhedonia as a hallmark of adolescent MDD and the need to incorporate dimensional analyses. These data are preliminary, and future prospective studies are needed to better characterize the syndrome of adolescent MDD. PMID- 25802987 TI - Anionic metal-organic framework for adsorption and separation of light hydrocarbons. AB - The reaction of nickel(II) sulfate with 4,4',4"-s-triazine-2,4,6-triyltribenzoate in dimethyl sulfoxide afforded a hexanuclear nickel(II)-based anionic 2-fold interpenetrated metal-organic framework exhibiting the ability to adsorb and separate light hydrocarbons and canted antiferromagnetism. PMID- 25802986 TI - Obesogens beyond Vertebrates: Lipid Perturbation by Tributyltin in the Crustacean Daphnia magna. AB - BACKGROUND: The analysis of obesogenic effects in invertebrates is limited by our poor knowledge of the regulatory pathways of lipid metabolism. Recent data from the crustacean Daphnia magna points to three signaling hormonal pathways related to the molting and reproductive cycles [retinoic X receptor (RXR), juvenile hormone (JH), and ecdysone] as putative targets for exogenous obesogens. OBJECTIVE: The present study addresses the disruptive effects of the model obesogen tributyltin (TBT) on the lipid homeostasis in Daphnia during the molting and reproductive cycle, its genetic control, and health consequences of its disruption. METHODS: D. magna individuals were exposed to low and high levels of TBT. Reproductive effects were assessed by Life History analysis methods. Quantitative and qualitative changes in lipid droplets during molting and the reproductive cycle were studied using Nile red staining. Lipid composition and dynamics were analyzed by ultra-performance liquid chromatography coupled to a time-of-flight mass spectrometer. Relative abundances of mRNA from different genes related to RXR, ecdysone, and JH signaling pathways were studied by qRT PCR. RESULTS AND CONCLUSIONS: TBT disrupted the dynamics of neutral lipids, impairing the transfer of triacylglycerols to eggs and hence promoting their accumulation in adult individuals. TBT's disruptive effects translated into a lower fitness for offspring and adults. Co-regulation of gene transcripts suggests that TBT activates the ecdysone, JH, and RXR receptor signaling pathways, presumably through the already proposed interaction with RXR. These findings indicate the presence of obesogenic effects in a nonvertebrate species. PMID- 25802988 TI - Continuous germanene layer on Al(111). AB - Germanene, a 2D honeycomb structure similar to silicene, has been fabricated on Al(111). The 2D germanene layer covers uniformly the substrate with a large coherence over the Al(111) surface atomic plane. It is characterized by a (3 * 3) superstructure with respect to the substrate lattice, shown by low energy electron diffraction and scanning tunnelling microscopy. First-principles calculations indicate that the Ge atoms accommodate in a very regular atomic configuration with a buckled conformation. PMID- 25802990 TI - Uncompromised treatment efficacy in elderly patients with hepatocellular carcinoma: a propensity score analysis: erratum. AB - [In the article "Uncompromised Treatment Efficacy in Elderly Patients With Hepatocellular Carcinoma: A Propensity Score Analysis", which appeared in Volume 93, Issue 28 of Medicine, one of the authors' affiliations, National Yang-Ming University School of Medicine, Taipei, Taiwan, was omitted. The article has since been corrected online.]. PMID- 25802989 TI - Comparison of Visual Function in Older Eyes in the Earliest Stages of Age-related Macular Degeneration to Those in Normal Macular Health. AB - PURPOSE: To compare the ability of several visual functional tests in terms of the strength of their associations with the earliest phases of age-related macular degeneration (AMD), which bears on their potential to serve as functional endpoints in evaluating treatments for early AMD and prevention strategies. MATERIALS AND METHODS: Eyes from adults >=60 years old were identified as being in normal macular health or in the earliest stages of AMD (steps 2, 3 or 4) through grading of color stereo-fundus photos by an experienced grader masked to all other study variables who used the 9-step Age-Related Eye Disease Study (AREDS) classification system for AMD severity. Visual function was assessed using the following tests: best-corrected visual acuity, low luminance visual acuity, spatial contrast sensitivity, macular cone-mediated light sensitivity and rod-mediated dark adaptation. RESULTS: A total of 1260 eyes were tested from 640 participants; 1007 eyes were in normal macular health (defined as step 1 in AREDS system) and 253 eyes had early AMD (defined as steps 2, 3 or 4). Adjusting for age and gender, early AMD eyes had two times the odds of having delayed rod mediated dark adaptation than eyes in normal macular health (p = 0.0019). Visual acuity, low luminance acuity, spatial contrast sensitivity and macular light sensitivity did not differ between normal eyes and early AMD eyes. CONCLUSIONS: Eyes in the earliest phases of AMD were two times more likely to have delayed rod mediated dark adaptation, as assessed by the rod-intercept, as compared to older eyes in normal macular health, whereas there was no difference in early AMD versus normal eyes in tests of visual acuity, low luminance acuity, macular light sensitivity and spatial contrast sensitivity. PMID- 25802991 TI - Magnetic skyrmion logic gates: conversion, duplication and merging of skyrmions. AB - Magnetic skyrmions, which are topological particle-like excitations in ferromagnets, have attracted a lot of attention recently. Skyrmionics is an attempt to use magnetic skyrmions as information carriers in next generation spintronic devices. Proposals of manipulations and operations of skyrmions are highly desired. Here, we show that the conversion, duplication and merging of isolated skyrmions with different chirality and topology are possible all in one system. We also demonstrate the conversion of a skyrmion into another form of a skyrmion, i.e., a bimeron. We design spin logic gates such as the AND and OR gates based on manipulations of skyrmions. These results provide important guidelines for utilizing the topology of nanoscale spin textures as information carriers in novel magnetic sensors and spin logic devices. PMID- 25802993 TI - A message to the proponents of animal experimentation: the truth shall make you free. PMID- 25802994 TI - Human embryonal carcinoma cells in serum-free conditions as an in vitro model system of neural differentiation. AB - Serum is generally regarded as an essential component of many eukaryotic cell culture media, despite the fact that serum composition varies greatly and may be the source of a wide range of artefacts. The objective of this study was to assess serum-free growth conditions for the human embryonal carcinoma cell line, NT2/D1. These cells greatly resemble embryonic stem cells. In the presence of retinoic acid (RA), NT2/D1 cells irreversibly differentiate along the neuronal lineage. We have previously shown that the early phases of neural induction of these cells by RA involve the up-regulation of SOX3 gene expression. Our goal was to compare RA-induced differentiation of NT2/D1 cells in serum-containing and serum-free media, by using SOX3 protein levels as a marker of differentiation. We found that NT2/D1 cells can be successfully grown under serum-free conditions, and that the presence or absence of serum does not affect the level of SOX3 protein after a 48-hour RA induction. However, six days of RA treatment resulted in a marked increase in SOX3 protein levels in serum-free media compared to serum containing media, indicating that serum might have an inhibitory effect on the expression of this neural differentiation marker. This finding is important for both basic and translational studies that hope to exploit cell culture conditions that are free of animal-derived products. PMID- 25802995 TI - A step forward in the quality control testing of inactivated rabies vaccines - extensive evaluation of European vaccines by using alternative methods to the in vivo potency tests. AB - The mouse challenge test still remains the reference method for the potency determination of human and animal inactivated rabies vaccines, and it is still widely used throughout the world. This test suffers from many disadvantages - it is expensive and time consuming, uses a large number of mice, causes significant animal distress, and suffers from high variability. Recently, the European Pharmacopoeia has recognised the use of a serological potency assay (SPA) as an alternative method to the challenge test. This new test is based on the determination of rabies neutralising antibody titres in vaccinated mice, by using the modified Rapid Fluorescent Focus Inhibition Test (mRFFIT). With the objective of adopting this new method for the batch release of inactivated rabies vaccines, we evaluated its performance on a large collection of rabies vaccines currently assessed in our laboratory. The Fluorescent Antibody Virus Neutralisation test (FAVNt) was used in parallel with the mRFFIT, and the results were compared to the mouse challenge test. Our results demonstrate that the SPA is capable of estimating the potency of vaccines formulated with a potency margin well above the minimum of 1IU/dose. For low potency vaccines, this new method demonstrated some limitations, due to the recurrent invalidation of the assay. We have also demonstrated the superior sensitivity of the FAVNt when compared to the mRFFIT, and the importance of minimising the risk of detecting non-responders in vaccinated mice. PMID- 25802996 TI - Better science with human cell-based organ and tissue models. AB - At present, animal-based models are the major test systems for assessing the tolerability and safety of chemical substances for regulatory purposes, and also for pivotal efficacy testing in pharmaceutical development. In spite of the high genetic similarity between many laboratory animals and humans, animal models are very poor predictors of human health effects and pathophysiological processes. Thus, models and testing strategies that are more relevant to human biology, are needed for these purposes. The best predictability is achieved with human organotypic models that mimic the microenvironment of human tissues. During their development, such models have to be characterised at the structural, genetic and functional levels, and compared to the respective human tissues. Their predictivity should be confirmed by using known reference chemicals with corresponding human data. The use of these methods in safety assessment and biomedical research, combined with the knowledge gained of the underlying biological processes on gene and protein expression, as well as on cellular signalling, will ultimately lead to better human science and animal welfare. PMID- 25802997 TI - Toxicity assessment of tobacco products in vitro. AB - Driven by new regulatory demands to demonstrate risk reduction, the toxicity assessment of tobacco products increasingly employs innovative in vitro methods, including biphasic cell and tissue cultures exposed to whole cigarette smoke at the air-liquid interface, cell transformation assays, and genomic analyses. At the same time, novel tobacco products are increasingly compared to traditional cigarettes. This overview of in vitro toxicology studies of tobacco products reported in the last five years provides evidence to support the prioritisation of in vitro over in vivo methods by industry and their recommendation by regulatory authorities. PMID- 25802999 TI - 15. Comparative substitution. PMID- 25802992 TI - RNA Export through the NPC in Eukaryotes. AB - In eukaryotic cells, RNAs are transcribed in the nucleus and exported to the cytoplasm through the nuclear pore complex. The RNA molecules that are exported from the nucleus into the cytoplasm include messenger RNAs (mRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), micro RNAs (miRNAs), and viral mRNAs. Each RNA is transported by a specific nuclear export receptor. It is believed that most of the mRNAs are exported by Nxf1 (Mex67 in yeast), whereas rRNAs, snRNAs, and a certain subset of mRNAs are exported in a Crm1/Xpo1-dependent manner. tRNAs and miRNAs are exported by Xpot and Xpo5. However, multiple export receptors are involved in the export of some RNAs, such as 60S ribosomal subunit. In addition to these export receptors, some adapter proteins are required to export RNAs. The RNA export system of eukaryotic cells is also used by several types of RNA virus that depend on the machineries of the host cell in the nucleus for replication of their genome, therefore this review describes the RNA export system of two representative viruses. We also discuss the NPC anchoring-dependent mRNA export factors that directly recruit specific genes to the NPC. PMID- 25803000 TI - Likelihood ratios in assessing the safety of new medicines. PMID- 25802998 TI - Participation of Brazil in the World Congresses on Alternatives and Animal Use in the Life Sciences: an increase in commitment to the Three Rs. AB - Many Brazilian researchers have long been interested in the development and use of alternative methods. Most of their research groups work in isolation, due to the lack of funding for collaborative studies. Despite these problems, since the Third World Congress on Alternatives and Animal Use in the Life Sciences, Brazilian researchers have strongly participated, not only by presenting posters and oral presentations, but also by being involved in the World Congress Committees. The Brazilian Center for the Validation of Alternative Methods (BraCVAM) must play an important role in the development and validation of alternative methods, through the active participation of the National Network of Alternative Methods (ReNaMA). In Brazil, Law 11,794/2008 regulates the use of animals in experimentation and education, and Law 9,605/1998 clearly states that use of the original animal test is not permitted, if an alternative method is available. Therefore, given the current legal framework, it is very important that all the Ministries involved with animal use, and the organisations responsible for funding researchers, strive to increase the financial support of those groups that are involved in the development and use of alternative methods in Brazil. PMID- 25803001 TI - The cost of standing strong for replacement. AB - The testimonies of these individuals largely speak for themselves. The responses point to the importance of specific institutions or research groups that focus on the development and use of alternatives, and these should, of course, be better supported. Those who find themselves outside such institutions or teams, are more likely to feel stranded and isolated. Then again, Liz did have the support of a research group dedicated to replacement, but she has still had a significant struggle to find funding. The interviews with some of these particular young researchers indeed pointed toward a tangible 'cost' in terms of having to steer their career on the often difficult path toward the use of non-animal based methods. PMID- 25803002 TI - The use of animals in experiments - not because of lack of empathy? PMID- 25803003 TI - A novel polynorbornene-based chemosensor for the fluorescence sensing of Zn2+ and Cd2+ and subsequent detection of pyrophosphate in aqueous solutions. AB - A hydroxyquinoline functionlized polynorbornene (P1) was designed and synthesized. In an aqueous solution, P1 shows a "turn-on" fluorescence response for Zn(2+) and Cd(2+) with a 50 nm blue shift. Furthermore, both P1-Zn(2+) and P1 Cd(2+) complexes were found to respond to pyrophosphate (PPi) over other important biological anions via a fluorescence quenching effect. P1 is also capable of monitoring intracellular Zn(2+) and PPi in real time. PMID- 25803004 TI - Synthesis and aggregation behaviour of luminescent mesomorphic zinc(II) complexes with 'salen' type asymmetric Schiff base ligands. AB - A new series of photoluminescent Zn(II)-salen type asymmetric Schiff base complexes, [ZnL], H2L = [N,N'-bis-(4-n-alkoxysalicylidene)-1,2-diaminopropane] (n = 12, 14 and 16) have been accessed and their mesomorphic and photophysical properties investigated. Though the ligands are non-mesomorphic, coordination to Zn(2+) ion induces liquid crystalline behaviour. The complexes exhibited a lamello-columnar phase (Coll) as characterized by a variable temperature powder X ray diffraction (XRD) study. Intense blue emissions were observed for the complexes at room temperature in solution, in the solid state and in the mesophase. Aggregation properties of the complexes were explored in different solvents through absorption and photoluminescence studies. While de-aggregation to monomers occurred in coordinating solvents due to axial coordination to Zn(II), aggregates were formed in the solution of non-coordinating solvents. Density functional theory (DFT) computation carried out on a representative complex using a GAUSSIAN 09 program at the B3LYP level suggested a distorted square planar geometry. The results of a time-dependent DFT (TD-DFT) spectral correlative study showed the electronic properties of the complex molecule to be in compliance with the spectral data. PMID- 25803006 TI - System-level factors as predictors of adherence to clinical appointment schedules in antiretroviral therapy in Cambodia. AB - Adherence to clinical appointment schedules by patients on antiretroviral therapy (ART) is necessary for the prevention of medication interruptions, viral rebound, and the development of drug resistance. An observational study conducted in 2010, Enablers and Adherence to Antiretroviral Therapy in Cambodia, sought to identify factors that predict on-time clinical appointment attendance by patients on ART. Clinical data, including appointment attendance across five consecutive visits, were collected from hospital records on a random sample of ART patients at government referral hospitals (RHs) in Battambang Province, Cambodia. Interviews were conducted to obtain quantitative information from patients on their experiences of support services provided by local NGOs and RHs. This information was used to identify ART patient care and support system factors that could potentially enable patients to adhere to clinical appointment schedules. These factors included adherence counseling, support groups, home-based care (HBC) services, and support provided for transportation to ART appointments. Bivariate and multivariable logistic regression analysis was done to assess relationships between system variables and the ART appointment adherence outcome. Of the 289 study participants, 20.4% had missed at least one of the five appointments in the study period. The hospital source of ART services, participation in a hospital based support group, receiving a loan from a microfinance institution, and the frequency of adherence counseling were found to be associated with ART appointment adherence. No significant associations were found between other support system factors such as HBC, transportation support, food/monetary support, and appointment adherence. PMID- 25803007 TI - [Institutional Prevalence and Context of Severe Sleep Disorders in Psychosomatic Rehabilitation]. AB - BACKGROUND: In cases of burnout, chronic fatigue, depression, somatization, overtaxation, or impairment in wellbeing and work capacity, the cause can be sleep problems. Goal of the present study was to estimate the prevalence of sleep problems in psychosomatic inpatients. METHOD: Included were 1325 unselected patients from a psychosomatic rehabilitation hospital. They filled in the SCL-90, the PSQI and were assessed in respect to their clinical, social and occupational status. RESULTS: At admission 13.4% of patients had a PSQI score of 5 at maximum (no sleep problem), 34.6% 6 to 10 (moderate sleep problem) und 52.1% over 10 (severe sleep problem). At discharge there was a reduction of sleep problems with 32.7% of patients over 10. Sleep problems were significantly associated with more severe mental problems, older age, women, lower socioeconomic status, and also incapacity to work or early retirement. CONCLUSIONS: Mental disorders can cause sleep problems and sleep problems mental disorders and incapacity to work, with a negative interaction. The high rate of severe sleep problems in rehabilitation patients shows that this problem is in need of special diagnostic and therapeutic attention. Also, the equipment of hospitals and the qualification of therapists should allow adequate care. PMID- 25803008 TI - Influenza vaccines for preventing acute otitis media in infants and children. AB - BACKGROUND: Acute otitis media (AOM) is one of the most common infectious diseases in children. It has been reported that 64% of infants have an episode of AOM by the age of six months and 86% by one year. Although most cases of AOM are due to bacterial infection, it is commonly triggered by a viral infection. In most children it is self limiting, but it does carry a risk of complications. Since antibiotic treatment increases the risk of antibiotic resistance, influenza vaccines might be an effective way of reducing this risk by preventing the development of AOM. OBJECTIVES: To assess the effectiveness of influenza vaccine in reducing the occurrence of acute otitis media (AOM) in infants and children. SEARCH METHODS: We searched CENTRAL (2014, Issue 6), MEDLINE (1946 to July week 1, 2014), EMBASE (2010 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014), Web of Science (1955 to July 2014) and reference lists of articles to July 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing influenza vaccine with placebo or no treatment in infants and children aged younger than six years old. We included children of either sex and of any ethnicity, with or without a history of recurrent AOM. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, assessed trial quality and extracted data. We performed statistical analyses using the random effects and fixed-effect models and expressed the results as risk ratio (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, with 95% confidence intervals (CI). MAIN RESULTS: We included 10 trials (six trials in high-income countries and four multicentre trials in high-, middle and low-income countries) involving 16,707 children aged six months to six years. Eight trials recruited participants from a healthcare setting. Nine trials (and all five trials that contributed to the primary outcome) declared funding from vaccine manufacturers. Four trials reported adequate allocation concealment and nine trials reported adequate blinding of participants and personnel. Attrition was low for all trials included in the analysis.The primary outcome showed a small reduction in at least one episode of AOM over at least six months of follow-up (five trials, 4736 participants: RR 0.80, 95% CI 0.67 to 0.96; RD 0.04, 95% CI -0.07 to -0.02; NNTB 25, 95% CI 15 to 50).The subgroup analyses (i.e. number of courses, settings, seasons or types of vaccine administered) showed no differences.There was a reduction in the use of antibiotics in vaccinated children (two trials, 1223 participants: RR 0.70, 95% CI 0.59 to 0.83; RD -0.15, 95% CI -0.30 to -0.00).There was no significant difference in the utilisation of health care for the one trial that provided sufficient information to be included. The use of influenza vaccine resulted in a significant increase in fever (six trials, 10,199 participants: RR 1.15, 95% CI 1.06 to 1.24; RD 0.02, 95% CI -0.00 to 0.05) and rhinorrhoea (six trials, 10,563 children: RR 1.17, 95% CI 1.07 to 1.29; RD 0.09, 95% CI 0.01 to 0.16) but no difference in pharyngitis. No major adverse events were reported.Compared to the protocol, the review included a subgroup analysis of AOM episodes by season, and changed the types of influenza vaccine from a secondary outcome to a subgroup analysis. AUTHORS' CONCLUSIONS: Influenza vaccine results in a small reduction in AOM. The observed reduction with the use of antibiotics needs to be considered in the light of current recommended practices aimed at avoiding antibiotic overuse. Safety data from these trials are limited. The benefits may not justify the use of influenza vaccine without taking into account the vaccine efficacy in reducing influenza and safety data. The quality of the evidence was high to moderate. Additional research is needed. PMID- 25803009 TI - Distyrylbenzene-aldehydes: identification of proteins in water. AB - Three different, water soluble, aldehyde-appended distyrylbenzene (DSB) derivatives were prepared. Their interaction with different albumin variants (human, porcine, bovine, lactalbumin, ovalbumin) was investigated (pH 11). All three fluorophores exhibit graded, protein-dependent fluorescence turn-on at slightly differing wavelengths. Linear discriminant analysis (LDA) differentiated all of the investigated albumins and was used to discern commercially available protein shakes. The three DSB derivatives barely react with the constituting amino acids but cysteine. In the proteins significant fluorescence signals are generated, probably due to a combination of imine/N,S-aminal formation and hydrophobic interactions between the DSBs and the proteins. PMID- 25803010 TI - Effect of interpolation on parameters extracted from seating interface pressure arrays. AB - Interpolation is a common data processing step in the study of interface pressure data collected at the wheelchair seating interface. However, there has been no focused study on the effect of interpolation on features extracted from these pressure maps, nor on whether these parameters are sensitive to the manner in which the interpolation is implemented. Here, two different interpolation paradigms, bilinear versus bicubic spline, are tested for their influence on parameters extracted from pressure array data and compared against a conventional low-pass filtering operation. Additionally, analysis of the effect of tandem filtering and interpolation, as well as the interpolation degree (interpolating to 2, 4, and 8 times sampling density), was undertaken. The following recommendations are made regarding approaches that minimized distortion of features extracted from the pressure maps: (1) filter prior to interpolate (strong effect); (2) use of cubic interpolation versus linear (slight effect); and (3) nominal difference between interpolation orders of 2, 4, and 8 times (negligible effect). We invite other investigators to perform similar benchmark analyses on their own data in the interest of establishing a community consensus of best practices in pressure array data processing. PMID- 25803013 TI - Inflammatory bowel disease: Appreciating disability and impact of disease. PMID- 25803014 TI - Re: RP Myers, H Shah, KW Burak, et al. An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol 2015;29(1):19-34. PMID- 25803015 TI - Tissue sampling using a submucosal tunnelling technique for indefinite gastric amyloidosis. PMID- 25803016 TI - Patient preference and willingness to pay for transient elastography versus liver biopsy: A perspective from British Columbia. AB - BACKGROUND: The cost of liver biopsy (LB) is publicly funded in British Columbia, while the cost of transient elastography (FibroScan [FS], Echosens, France) is not. Consequently, there is regional variation regarding FS access and monitoring of liver disease progression. OBJECTIVE: To evaluate patient preference for FS versus LB and to assess the willingness to self-pay for FS. METHODS: Questionnaires were distributed in clinic and via mail to LB-experienced and LB naive patients who underwent FS at Vancouver General Hospital, Vancouver, British Columbia. RESULTS: The overall response rate was 76%. Of the 422 respondents, 205 were LB-experienced. The mean age was 53.5 years, 50.2% were male, 54.7% were Caucasian, 38.2% had hepatitis C and 26.3% had an annual household income >$75,000. Overall, 95.4% of patients preferred FS to LB. FS was associated with greater comfort than LB, with the majority reporting no discomfort during FS (84.1% versus 7.8% for LB), no discomfort after (96.2% versus 14.6% LB) and no feelings of anxiety after FS explanation (78.2% versus 12.7% LB). FS was also associated with greater speed, with the majority reporting short test duration (97.2% versus 48.3% LB) and short wait for the test result (95.5% versus 30.2% LB). Most (75.3%) respondents were willing to self-pay for FS, with 26.3% willing to pay $25 to $49. Patients with unknown liver disease preferred LB (OR [FS preference] 0.20 [95% CI 0.07 to 0.53]). CONCLUSIONS: FS was the preferred method of assessing liver fibrosis among patients, with the majority willing to self pay. To ensure consistency in access, provincial funding for FS is needed. However, LB remains the procedure of choice for individuals with an unknown diagnosis. PMID- 25803017 TI - Living with inflammatory bowel disease: A Crohn's and Colitis Canada survey. AB - BACKGROUND: Despite improvements in therapies for inflammatory bowel diseases (IBDs), patient quality of life continues to be significantly impacted. OBJECTIVE: To assess the impact of IBD on patients and families with regard to leisure, relationships, mental well-being and financial security, and to evaluate the quality and availability of IBD information. METHODS: An online survey was advertised on the Crohn's and Colitis Canada website, and at gastroenterology clinics at the University of Alberta Hospital (Edmonton, Alberta) and University of Calgary Hospital (Calgary, Alberta). RESULTS: The survey was completed by 281 IBD patients and 32 family members. Among respondents with IBD, 64% reported a significant or major impact on leisure activities, 52% a significant or major impact on interpersonal relationships, 40% a significant or major impact on financial security, and 28% a significant or major impact on planning to start a family. Patient information needs emphasized understanding disease progression (84%) and extraintestinal symptoms (82%). There was a strong interest in support systems such as health care insurance (70%) and alternative therapies (66%). The most common source of information for patients was their gastroenterologist (70%); however, most (70%) patients preferred to obtain their information from the Crohn's and Colitis Canada website. CONCLUSIONS: The impact of IBD on interpersonal relationships and leisure activities was significant among IBD patients and their families. Understanding the disease, but also alternative treatment options, was of high interest. Currently, there is a discrepancy between interest in information topics and their availability. Respondents reported a strong desire to obtain information regarding disease progression, especially extraintestinal symptoms. PMID- 25803018 TI - Randomized controlled trial comparing outcomes of video capsule endoscopy with push enteroscopy in obscure gastrointestinal bleeding. AB - BACKGROUND: Optimal management of obscure gastrointestinal bleeding (OGIB) remains unclear. OBJECTIVE: To evaluate diagnostic yields and downstream clinical outcomes comparing video capsule endoscopy (VCE) with push enteroscopy (PE). METHODS: Patients with OGIB and negative esophagogastroduodenoscopies and colonoscopies were randomly assigned to VCE or PE and followed for 12 months. End points included diagnostic yield, acute or chronic bleeding, health resource utilization and crossovers. RESULTS: Data from 79 patients were analyzed (VCE n=40; PE n=39; 82.3% overt OGIB). VCE had greater diagnostic yield (72.5% versus 48.7%; P<0.05), especially in the distal small bowel (58% versus 13%; P<0.01). More VCE-identified lesions were rated possible or certain causes of bleeding (79.3% versus 35.0%; P<0.05). During follow-up, there were no differences in the rates of ongoing bleeding (acute [40.0% versus 38.5%; P not significant], chronic [32.5% versus 45.6%; P not significant]), nor in health resource utilization. Fewer VCE-first patients crossed over due to ongoing bleeding (22.5% versus 48.7%; P<0.05). CONCLUSIONS: A VCE-first approach had a significant diagnostic advantage over PE-first in patients with OGIB, especially with regard to detecting small bowel lesions, affecting clinical certainty and subsequent further small bowel investigations, with no subsequent differences in bleeding or resource utilization outcomes in follow-up. These findings question the clinical relevance of many of the discovered endoscopic lesions or the ability to treat most of these effectively over time. Improved prognostication of both patient characteristics and endoscopic lesion appearance with regard to bleeding behaviour, coupled with the impact of therapeutic deep enteroscopy, is now required using adapted, high-quality study methodologies. PMID- 25803019 TI - Dysphagia among adult patients who underwent surgery for esophageal atresia at birth. AB - BACKGROUND: Clinical experiences of adults who underwent surgery for esophageal atresia at birth is limited. There is some evidence that suggests considerable long-term morbidity, partly because of dysphagia, which has been reported in up to 85% of adult patients who undergo surgery for esophageal atresia. The authors hypothesized that dysphagia in this population is caused by dysmotility and/or anatomical anomalies. OBJECTIVE: To determine the motor and anatomical causes of dysphagia. METHODS: A total of 41 adults, followed at the Esophageal Atresia Clinic at Hopital Saint-Luc (Montreal, Quebec), were approached to particpate in the present prospective study. Evaluation was completed using upper endoscopy, manometry and barium swallow for the participants who consented. The medical charts of respondents were systematically reviewed from the neonatal period to 18 years of age to assess medical and surgical history. RESULTS: All 41 patients followed at the clinic consented and were included in the study. Dysphagia was present in 73% of patients. Esophagogastroduodenoscopy was performed in 32 patients: hiatal hernia was present in 62% (n=20); esophageal diverticulum in 13% (n=4); macroscopic Barrett esophagus in 31% (n=10); and esophagitis in 19% (n=6). Histological esophagitis was present in 20% and intestinal metaplasia in 10%. There were no cases of dysplagia or adenocarcinoma. Esophageal manometry was performed on 56% of the patients (n=23). Manometry revealed hypomotility in 100% of patients and included an insufficient number of peristaltic waves in 96%, nonpropagating peristalsis in 78% and low-wave amplitude in 95%. Complete aperistalsis was present in 78%. The lower esophageal sphincter was abnormal in 12 (52%) patients, with incomplete relaxation the most common anomaly. Of the 41 patients, 29 (71%) consented to a barium swallow, which was abnormal in 13 (45%). The anomalies found were short esophageal dilation in 28%, delay in esophageal emptying in 14%, diverticula in 14% and stenosis in 7% of patients. There was more than one anomaly in 14% of patients. CONCLUSION: Dysphagia was a highly prevalent symptom in adults who underwent surgery for esophageal atresia. The present study is the first to demonstrate that motor and anatomical abnormalities may be implicated in causes of dysphagia in this population. Furthermore, these anomalies may be demonstrated with simple investigations such as endoscopy, manometry and barium swallow. PMID- 25803020 TI - Does the level of reproductive knowledge specific to inflammatory bowel disease predict childlessness among women with inflammatory bowel disease? AB - BACKGROUND: Women with inflammatory bowel disease (IBD) may choose to remain childless due to a lack of IBD-specific reproductive knowledge. OBJECTIVES: To examine the effects of IBD-specific reproductive knowledge and discussion of family planning with a physician on childlessness among women with IBD. METHODS: Female IBD patients 18 to 45 years of age completed the Crohn's and Colitis Pregnancy Knowledge questionnaire (CCPKnow), and answered questions regarding reproductive history, plans to have children and discussion of family planning with a physician. CCPKnow scores were grouped according to poor (0 to 7), adequate (8 to 10), good (11 to 13) and very good (14 to 17). RESULTS: Of 434 eligible women, 248 (57.1%) completed the questionnaires. Of these 248 women, 51.6% were childless and, among these, 12.9% were voluntarily childless and 12.1% were trying to become pregnant. Childless women had a lower median CCPKnow score than women with children (6.0 versus 8.0; P=0.001). After adjusting for current age and marital status, each one point increase in the CCPKnow score corresponded to 8% lower odds of childlessness (OR 0.92 [95% CI 0.86 to 0.99]), 9% lower odds of voluntary childlessness (OR 0.91 [95% CI 0.79 to 1.0]) and 20% higher odds of trying to become pregnant (OR 1.2 [95% CI 1.0 to 1.4]). Discussion of family planning with a gastroenterologist corresponded to 72% lower odds of a poor CCPKnow score (OR 0.28 [95% CI 0.15 to 0.53]) and of voluntary childlessness (OR 0.28 [95% CI 0.057 to 1.3]). CONCLUSION: In the present study, higher IBD specific reproductive knowledge lowered the odds of childlessness among women with IBD. Discussion of family planning with a physician was associated with higher CCPKnow scores and lower odds of voluntary childlessness. PMID- 25803022 TI - A time study of physicians' work in a German university eye hospital to estimate unit costs. AB - BACKGROUND: Technical efficiency of hospital services is debated since performance has been heterogeneous. Staff time represents the main resource in patient care and its inappropriate allocation has been identified as a key factor of inefficiency. The aim of this study was to analyse the utilisation of physicians' work time stratified by staff groups, tasks and places of work. A further aim was to use these data to estimate resource use per unit of output. METHODS: A self-reporting work-sampling study was carried during 14-days at a University Eye Hospital. Staff costs of physicians per unit of output were calculated at the wards, the operating rooms and the outpatient unit. RESULTS: Forty per cent of total work time was spent in contact with the patient. Thirty per cent was spent with documentation tasks. Time spent with documentation tasks declined monotonically with increasing seniority of staff. Unit costs were 56 ? per patient day at the wards, 77 ? and 20 ? per intervention at the operating rooms for inpatients and outpatients, respectively, and 33 ? per contact at the outpatient unit. Substantial differences in resources directly dedicated to the patient were found between these locations. CONCLUSION: The presented data provide unprecedented units costs in inpatient Ophthalmology. Future research should focus on analysing factors that influence differences in time allocation, such as types of patients, organisation of care processes and composition of staff. PMID- 25803021 TI - Tax-deductible provisions for gluten-free diet in Canada compared with systems for gluten-free diet coverage available in various countries. AB - Celiac disease affects 1% of the North American population, with an estimated 350,000 Canadians diagnosed with this condition. The disease is triggered by the ingestion of gluten, and a lifelong, strict gluten-free diet (GFD) is the only currently available treatment. Compliance with a strict GFD is essential not only for intestinal mucosal recovery and alleviation of symptoms, but also for the prevention of complications such as anemia, osteoporotic fractures and small bowel lymphoma. However, a GFD is difficult to follow, socially inconvenient and expensive. Different approaches, such as tax reduction, cash transfer, food provision, prescription and subsidy, have been used to reduce the additional costs of the GFD to patients with celiac disease. The current review showed that the systems in place exhibit particular advantages and disadvantages in relation to promoting uptake and compliance with GFD. The tax offset system used in Canada for GFD coverage takes the form of a reimbursement of a cost previously incurred. Hence, the program does not help celiac patients meet the incremental cost of the GFD - it simply provides some future refund of that cost. An ideal balanced approach would involve subsidizing gluten-free products through controlled vouchers or direct food provision to those who most need it, independently of 'ability or willingness to pay'. Moreover, if the cost of such a program is inhibitive, the value of the benefits could be made taxable to ensure that any patient contribution, in terms of additional taxation, is directly related to ability to pay. The limited coverage of GFD in Canada is concerning. There is an unmet need for GFD among celiac patients in Canada. More efforts are required by the Canadian medical community and the Canadian Celiac Association to act as agents in identifying ways of improving resource allocation in celiac disease. PMID- 25803023 TI - How does B-value affect HARDI reconstruction using clinical diffusion MRI data? AB - BACKGROUND: A number of imaging factors can affect the orientation distribution function (ODF) reconstruction in high angular resolution diffusion imaging (HARDI). The aim of this study was to investigate the effect of the b-value on the HARDI reconstruction and to seek for the appropriate b-value for ODF reconstruction from clinical HARDI data. METHODS: Diffusion MRI data with various b-values were collected on a GE 3T MRI scanner. To reconstruct the diffusion ODF and fiber ODF, decomposition-based spherical polar Fourier imaging and deconvolution-based constrained spherical deconvolution approaches were applied separately. The full width at half maximum (FWHM) of the ODF and the angular difference of the peaks extracted from ODF were measured to investigate the effect of b-value on the ODF reconstruction. Visual inspection of the ODF was used to evaluate the reconstructions. RESULTS: The FWHM of the ODFs in the corpus callosum, which was chosen as the region of interest (ROI), decreased with increasing b-values. The differences in the FWHM for the diffusion ODF and the fiber ODF between the b-values of 2000 s/mm2 and 2500 s/mm2 were not significant. The angular differences of the ODF between 2000 s/mm2 and 2500 s/mm2 were lowest in both single-directional and two-directional situations. The ODFs became sharper and crossing-fiber situations were detected with an increase in b-value. B = 2000 s/mm2 and above revealed most of the two-way or three-way crossing-fiber structures. CONCLUSIONS: Considering both the signal-to-noise ratio and the acquisition time, b = 2000 s/mm2 is the basic requirement for ODF reconstruction using current HARDI methods on clinical data. This study can provide a useful reference for researchers and clinicians attempting to set appropriate scan protocols for specific HARDI experiments. PMID- 25803024 TI - Effect of cold plasma on glial cell morphology studied by atomic force microscopy. AB - The atomic force microscope (AFM) is broadly used to study the morphology of cells. The morphological characteristics and differences of the cell membrane between normal human astrocytes and glial tumor cells are not well explored. Following treatment with cold atmospheric plasma, evaluation of the selective effect of plasma on cell viability of tumor cells is poorly understood and requires further evaluation. Using AFM we imaged morphology of glial cells before and after cold atmospheric plasma treatment. To look more closely at the effect of plasma on cell membrane, high resolution imaging was used. We report the differences between normal human astrocytes and human glioblastoma cells by considering the membrane surface details. Our data, obtained for the first time on these cells using atomic force microscopy, argue for an architectural feature on the cell membrane, i.e. brush layers, different in normal human astrocytes as compared to glioblastoma cells. The brush layer disappears from the cell membrane surface of normal E6/E7 cells and is maintained in the glioblastoma U87 cells after plasma treatment. PMID- 25803025 TI - Belief in a just what? Demystifying just world beliefs by distinguishing sources of justice. AB - People's Belief in a Just World (BJW) plays an important role in coping with misfortune and unfairness. This paper demonstrates that understanding of the BJW concept, and its consequences for behavior, is enhanced if we specify what (or who) the source of justice might be. We introduce a new scale, the 5-Dimensional Belief in a Just Treatment Scale (BJT5), which distinguishes five causal dimensions of BJW (God, Nature, Other People, Self, Chance). We confirm the 5 factor structure of the BJT5. We then address whether the BJW should be considered a uni- and/or multi-dimensional construct and find support for our multi-dimensional approach. Finally, we demonstrate convergent and discriminant validity with respect to important correlates of BJW as well as action in response to important negative life events and societal attitudes. This work illustrates the importance of distinguishing causal dimensions with regard to who distributes justice. PMID- 25803026 TI - Comparative transcriptome profiling of the maize primary, crown and seminal root in response to salinity stress. AB - Soil salinity is a major constraint to crop growth and yield. The primary and lateral roots of Arabidopsis thaliana are known to respond differentially to a number of environmental stresses, including salinity. Although the maize root system as a whole is known to be sensitive to salinity, whether or not different structural root systems show differential growth responses to salinity stress has not yet been investigated. The maize primary root (PR) was more tolerant of salinity stress than either the crown root (CR) or the seminal root (SR). To understand the molecular mechanism of these differential growth responses, RNA Seq analysis was conducted on cDNA prepared from the PR, CR and SR of plants either non-stressed or exposed to 100 mM NaCl for 24 h. A set of 444 genes were shown to be regulated by salinity stress, and the transcription pattern of a number of genes associated with the plant salinity stress response differed markedly between the various types of root. The pattern of transcription of the salinity-regulated genes was shown to be very diverse in the various root types. The differential transcription of these genes such as transcription factors, and the accumulation of compatible solutes such as soluble sugars probably underlie the differential growth responses to salinity stress of the three types of roots in maize. PMID- 25803029 TI - Effects of harvest on the sustainability and leaf productivity of populations of two palm species in Maya homegardens. AB - Traditional management practices are usually thought to be sustainable. The Maya manage Sabal (Arecaceae) palms in homegardens, using their leaves for thatching. The sustainability of such production systems depends on the long-term persistence of palm populations, whereas resource availability also depends on the number of leaves on individual palms. We examined how leaf harvest affects Sabal yapa and S. mexicana population growth rates (lambda) and leaf production, comparing traditional and alternative harvest regimes in terms of sustainability and productivity. Demographic, harvest and leaf production data were recorded for three years in two homegardens. We used general integral projection models linked to leaf-production models to describe population dynamics and productivity. Harvest had no effect on S. yapa's vital rates or on lambda, but it changed the growth rate of individuals of S. mexicana, with a negligible impact on lambda. Homegardens affected lambda values, reflecting the species' ecological affinities. S. mexicana, introduced from mesic forests, required watering and shade; therefore, its population declined rapidly in the homegarden that lacked both water and shade. The lambda of the xerophilic S. yapa was slightly larger without watering than with watering. Palms usually compensated for leaf extraction, causing the number of leaves harvested per individual to increase with harvest intensity. Nevertheless, traditional management is relatively mild, allowing standing leaves to accumulate but reducing the homegarden's yield. Apparently, the Maya do not seek to maximize annual production but to ensure the availability of large numbers of leaves in homegardens. These leaves may then be used when the entire roof of a hut needs to be replaced every few years. PMID- 25803028 TI - Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and L-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer's disease. AB - This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer's disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7MUm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients 'at risk' from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification. PMID- 25803027 TI - Mitochondrial physiology in the major arbovirus vector Aedes aegypti: substrate preferences and sexual differences define respiratory capacity and superoxide production. AB - Adult females of Aedes aegypti are facultative blood sucking insects and vectors of Dengue and yellow fever viruses. Insect dispersal plays a central role in disease transmission and the extremely high energy demand posed by flight is accomplished by a very efficient oxidative phosphorylation process, which take place within flight muscle mitochondria. These organelles play a central role in energy metabolism, interconnecting nutrient oxidation to ATP synthesis, but also represent an important site of cellular superoxide production. Given the importance of mitochondria to cell physiology, and the potential contributions of this organelle for A. aegypti biology and vectorial capacity, here, we conducted a systematic assessment of mitochondrial physiology in flight muscle of young adult A. aegypti fed exclusively with sugar. This was carried out by determining the activities of mitochondrial enzymes, the substrate preferences to sustain respiration, the mitochondrial bioenergetic efficiency and capacity, in both mitochondria-enriched preparations and mechanically permeabilized flight muscle in both sexes. We also determined the substrates preferences to promote mitochondrial superoxide generation and the main sites where it is produced within this organelle. We observed that respiration in A. aegypti mitochondria was essentially driven by complex I and glycerol 3 phosphate dehydrogenase substrates, which promoted distinct mitochondrial bioenergetic capacities, but with preserved efficiencies. Respiration mediated by proline oxidation in female mitochondria was strikingly higher than in males. Mitochondrial superoxide production was essentially mediated through proline and glycerol 3 phosphate oxidation, which took place at sites other than complex I. Finally, differences in mitochondrial superoxide production among sexes were only observed in male oxidizing glycerol 3 phosphate, exhibiting higher rates than in female. Together, these data represent a significant step towards the understanding of fundamental mitochondrial processes in A. aegypti, with potential implications for its physiology and vectorial capacity. PMID- 25803030 TI - Cardiovascular complications secondary to Graves' disease: a prospective study from Ukraine. AB - BACKGROUND: Graves' disease (GD) is a common cause of hyperthyroidism resulting in development of thyrotoxic heart disease (THD). OBJECTIVES: to assess cardiovascular disorders and health related quality of life (HRQoL) in patients with THD secondary to GD. PATIENTS AND METHODS: All patients diagnosed with THD secondary to GD between January 2011 and December 2013 were eligible for this study. Clinical assessment was performed at baseline and at the follow-up visit after the restoring of euthyroid state. HRQoL was studied with a questionnaire EQ 5D-5L. RESULTS: Follow-up data were available for 61 patients, but only 30 patients with THD secondary to GD were consented to participate in investigation of their HRQoL. The frequency of cardiovascular complications was significantly reduced as compared before and after the antithyroid therapy as follows: resting heart rate (122 vs. 74 bpm), blood pressure: systolic (155 vs. 123 mm Hg), diastolic (83 vs. 66 mm Hg), supraventricular premature contractions (71% vs. 7%), atrial fibrillation (72% vs. 25%), congestive heart failure (69% vs. 20%), thyrotoxic cardiomyopathy (77% vs. 26%), all p<0.01. Anti-TSH receptor antibodies were determined as independent predictor of left ventricular geometry changes, (b coefficient = 0.04, 95%CI 0.01-0.07, p = 0.02). HRQoL was improved in all domains and self-rated health increased from 43 to 75 units by visual analogue score (p<0.001). CONCLUSIONS: Restoring of euthyroid state in patients with GD is associated with significant elimination of cardiovascular disorders and improvement of HRQoL. To our knowledge this is the first study evaluating Ukrainian patients with THD secondary to GD with focus on HRQoL. PMID- 25803031 TI - Tissue-engineered regeneration of completely transected spinal cord using induced neural stem cells and gelatin-electrospun poly (lactide-co glycolide)/polyethylene glycol scaffolds. AB - Tissue engineering has brought new possibilities for the treatment of spinal cord injury. Two important components for tissue engineering of the spinal cord include a suitable cell source and scaffold. In our study, we investigated induced mouse embryonic fibroblasts (MEFs) directly reprogrammed into neural stem cells (iNSCs), as a cell source. Three-dimensional (3D) electrospun poly (lactide co-glycolide)/polyethylene glycol (PLGA-PEG) nanofiber scaffolds were used for iNSCs adhesion and growth. Cell growth, survival and proliferation on the scaffolds were investigated. Scanning electron microscopy (SEM) and nuclei staining were used to assess cell growth on the scaffolds. Scaffolds with iNSCs were then transplanted into transected rat spinal cords. Two or 8 weeks following transplantation, immunofluorescence was performed to determine iNSC survival and differentiation within the scaffolds. Functional recovery was assessed using the Basso, Beattie, Bresnahan (BBB) Scale. Results indicated that iNSCs showed similar morphological features with wild-type neural stem cells (wt-NSCs), and expressed a variety of neural stem cell marker genes. Furthermore, iNSCs were shown to survive, with the ability to self-renew and undergo neural differentiation into neurons and glial cells within the 3D scaffolds in vivo. The iNSC-seeded scaffolds restored the continuity of the spinal cord and reduced cavity formation. Additionally, iNSC-seeded scaffolds contributed to functional recovery of the spinal cord. Therefore, PLGA-PEG scaffolds seeded with iNSCs may serve as promising supporting transplants for repairing spinal cord injury (SCI). PMID- 25803033 TI - A novel nonsense mutation in the MIP gene linked to congenital posterior polar cataracts in a Chinese family. AB - PURPOSE: To detect the causative mutation for congenital posterior polar cataracts in a five-generation Chinese family and further explore the potential pathogenesis of this disease. METHODS: Coding exons, with flanking sequences of five candidate genes, were screened using direct DNA sequencing. The identified mutations were confirmed by restriction fragment length polymorphism (RFLP) analysis. A full-length wild-type or an Y219* mutant aquaporin0 (AQP0) fused with an N-terminal FLAG tag, was transfected into HEK293T cells. For co-localization studies, FLAG-WT-AQP0 and Myc-Y219*-AQP0 constructs were co-transfected. Quantitative real-time RT-PCR, western blotting and immunofluorescence studies were performed to determine protein expression levels and sub-cellular localization, respectively. RESULTS: We identified a novel nonsense mutation in MIP (c.657 C>G; p.Y219*) (major intrinsic protein gene) that segregates with congenital posterior polar cataract in a Chinese family. This mutation altered a highly conserved tyrosine to a stop codon (Y219*) within AQP0.When FLAG-WT-AQP0 and FLAG-Y219*-AQP0 expression constructs were singly transfected into HEK 293T cells, mRNA expression showed no significant difference between the wild-type and the mutant, while Y219*-AQP0 protein expression was significantly lower than that of wild-type AQP0. Wild-type AQP0 predominantly localized to the plasma membrane, while the mutated protein was abundant within the cytoplasm of HEK293T cells. However, when FLAG-WT-AQP0 andMyc-MU-AQP0were co-expressed, both proteins showed high fluorescence in the cytoplasm. CONCLUSIONS: The novel nonsense mutation in the MIP gene (c.657 C>G) identified in a Chinese family may cause posterior polar cataracts. The dominant negative effect of the mutated protein on the wild-type protein interfered with the trafficking of wild-type protein to the cell membrane and both the mutant and wild-type protein were trapped in the cytoplasm. Consequently, both wild-type and mutant protein lost their function as a water channel on the cell membrane, and may result in a cataract phenotype. Our data also expands the spectrum of known MIP mutations. PMID- 25803034 TI - Autonomously folding protein fragments reveal differences in the energy landscapes of homologous RNases H. AB - An important approach to understanding how a protein sequence encodes its energy landscape is to compare proteins with different sequences that fold to the same general native structure. In this work, we compare E. coli and T. thermophilus homologs of the protein RNase H. Using protein fragments, we create equilibrium mimics of two different potential partially-folded intermediates (I(core) and I(core+1)) hypothesized to be present on the energy landscapes of these two proteins. We observe that both T. thermophilus RNase H (ttRNH) fragments are folded and have distinct stabilities, indicating that both regions are capable of autonomous folding and that both intermediates are present as local minima on the ttRNH energy landscape. In contrast, the two E. coli RNase H (ecRNH) fragments have very similar stabilities, suggesting that the presence of additional residues in the I(core+1) fragment does not affect the folding or structure as compared to I(core). NMR experiments provide additional evidence that only the I(core) intermediate is populated by ecRNH. This is one of the biggest differences that has been observed between the energy landscapes of these two proteins. Additionally, we used a FRET experiment in the background of full length ttRNH to specifically monitor the formation of the I(core+1) intermediate. We determine that the ttRNH I(core+1) intermediate is likely the intermediate populated prior to the rate-limiting barrier to global folding, in contrast to E. coli RNase H for which I(core) is the folding intermediate. This result provides new insight into the nature of the rate-limiting barrier for the folding of RNase H. PMID- 25803032 TI - Smad4 loss synergizes with TGFalpha overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis. AB - AIMS: While overexpression of TGFalpha has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFalpha develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-beta signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFalpha and TGF-beta signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. METHODS: The MT-TGFalpha mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFalpha;p48-Cre (STP). After TGFalpha overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFalpha, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (alpha-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. RESULTS: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFalpha mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. CONCLUSION: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer. PMID- 25803035 TI - Facilitative-competitive interactions in an old-growth forest: the importance of large-diameter trees as benefactors and stimulators for forest community assembly. AB - The role of competition in tree communities is increasingly well understood, while little is known about the patterns and mechanisms of the interplay between above- and belowground competition in tree communities. This knowledge, however, is crucial for a better understanding of community dynamics and developing adaptive near-natural management strategies. We assessed neighbourhood interactions in an unmanaged old-growth European beech (Fagus sylvatica) forest by quantifying variation in the intensity of above- (shading) and belowground competition (crowding) among dominant and co-dominant canopy beech trees during tree maturation. Shading had on average a much larger impact on radial growth than crowding and the sensitivity to changes in competitive conditions was lowest for crowding effects. We found that each mode of competition reduced the effect of the other. Increasing crowding reduced the negative effect of shading, and at high levels of shading, crowding actually had a facilitative effect and increased growth. Our study demonstrates that complementarity in above- and belowground processes enable F. sylvatica to alter resource acquisition strategies, thus optimising tree radial growth. As a result, competition seemed to become less important in stands with a high growing stock and tree communities with a long continuity of anthropogenic undisturbed population dynamics. We suggest that growth rates do not exclusively depend on the density of potential competitors at the intraspecific level, but on the conspecific aggregation of large-diameter trees and their functional role for regulating biotic filtering processes. This finding highlights the potential importance of the rarely examined relationship between the spatial aggregation pattern of large-diameter trees and the outcome of neighbourhood interactions, which may be central to community dynamics and the related forest ecosystem services. PMID- 25803037 TI - Large genomic fragment deletions and insertions in mouse using CRISPR/Cas9. AB - ZFN, TALENs and CRISPR/Cas9 system have been used to generate point mutations and large fragment deletions and insertions in genomic modifications. CRISPR/Cas9 system is the most flexible and fast developing technology that has been extensively used to make mutations in all kinds of organisms. However, the most mutations reported up to date are small insertions and deletions. In this report, CRISPR/Cas9 system was used to make large DNA fragment deletions and insertions, including entire Dip2a gene deletion, about 65kb in size, and beta-galactosidase (lacZ) reporter gene insertion of larger than 5kb in mouse. About 11.8% (11/93) are positive for 65kb deletion from transfected and diluted ES clones. High targeting efficiencies in ES cells were also achieved with G418 selection, 46.2% (12/26) and 73.1% (19/26) for left and right arms respectively. Targeted large fragment deletion efficiency is about 21.4% of live pups or 6.0% of injected embryos. Targeted insertion of lacZ reporter with NEO cassette showed 27.1% (13/48) of targeting rate by ES cell transfection and 11.1% (2/18) by direct zygote injection. The procedures have bypassed in vitro transcription by directly co-injection of zygotes or co-transfection of embryonic stem cells with circular plasmid DNA. The methods are technically easy, time saving, and cost effective in generating mouse models and will certainly facilitate gene function studies. PMID- 25803038 TI - Pigment-based chemotaxonomy--a quick alternative to determine algal assemblages in large shallow eutrophic lake? AB - Pigment-based chemotaxonomy and CHEMTAX software have proven to be a valuable phytoplankton monitoring tool in marine environments, but are yet underdeveloped to determine algal assemblages in freshwater ecosystems. The main objectives of this study were (1) to compare the results of direct microscopy and CHEMTAX in describing phytoplankton community composition dynamics in a large, shallow and eutrophic lake; (2) to analyze the efficiency of the pigment-based method to detect changes in phytoplankton seasonal dynamics and during rapid bloom periods; (3) to assess the suitability of specific marker pigments and available marker pigment:chlorophyll a ratios to follow seasonal changes in eutrophic freshwater environment. A 5-year (2009-2013) parallel phytoplankton assessment by direct microscopy and by CHEMTAX was conducted using published marker pigment:chlorophyll a ratios. Despite displaying some differences from microscopy results, the pigment-based method successfully described the overall pattern of phytoplankton community dynamics during seasonal cycle in a eutrophic lake. Good agreement between the methods was achieved for most phytoplankton groups - cyanobacteria, chlorophytes, diatoms and cryptophytes. The agreement was poor in case of chrysophytes and dinoflagellates. Our study shows clearly that published marker pigment:chlorophyll a ratios can be used to describe algal class abundances, but they need to be calibrated for specific freshwater environment. Broader use of this method would enable to expand monitoring networks and increase measurement frequencies of freshwater ecosystems to meet the goals of the Water Framework Directive. PMID- 25803039 TI - Exploring early and late Toxoplasma gondii strain RH infection by two-dimensional immunoblots of chicken immunoglobulin G and M profiles. AB - Toxoplasma gondii is an intracellular apicomplexan parasite infecting warm blooded vertebrate hosts, with only early infection stage being contained with drugs. But diagnosis differencing early and late infection was not available. In the present investigation, 2-dimensional immunobloting was used to explore early and late infections in chickens. The protein expression of T. gondii was determined by image analysis of the tachyzoites proteome separated by standard one and conventional two-dimentional gel polyacrylamide electrophoresis (2D- PAGE). Pooled gels were prepared from tachyzoites of T. gondii. A representative gel spanning a pH range of 3-10 of the tachyzoite proteome consisted of 1306 distinct polypeptide spots. Two-dimensional electrophoresis (2-DE) combined with 2-DE immunoblotting was used to resolve and compare immunoglobulins (Igs) M & G patterns against Toxoplasma gondii strain RH (mouse virulent strain). Total tachyzoite proteins of T. gondii were separated by two-dimensional gel electrophoresis and analyzed by Western blotting for their reactivity with the 7 and 56 days post-infection (dpi) SPF chicken antisera. Different antigenic determinant patterns were detected during analysis with M and G immunoglobulins. Of the total number of polypeptide spots analyzed (1306 differentially expressed protein spots), 6.97% were identified as having shared antigenic polypeptide spots on immunoblot profiles with IgG and IgM antibodies regardless the time after infection. Furthermore, some of the immunoreactive polypeptide spots seemed to be related to the stage of infection. Interestingly, we found natural antibodies to toxoplasmic antigens, in addition to the highly conserved antigenic determinants that reacted with non-specific secondary antibody; goat anti-chicken IgG antibodies conjugated with horseradish peroxidase. In conclusion, unique reactive polypeptide spots are promising candidates for designation of molecular markers to discriminate early and late chicken infection. PMID- 25803036 TI - Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. AB - Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study. PMID- 25803040 TI - The UII/UT system mediates upregulation of proinflammatory cytokines through p38 MAPK and NF-kappaB pathways in LPS-stimulated Kupffer cells. AB - The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-alpha, and IL-1beta by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor kappaB (NF-kappaB) p65 subunit in KCs and enhanced the binding activity of NF-kappaB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-kappaB. PMID- 25803041 TI - Btk29A-mediated tyrosine phosphorylation of armadillo/beta-catenin promotes ring canal growth in Drosophila oogenesis. AB - Drosophila Btk29A is the ortholog of mammalian Btk, a Tec family nonreceptor tyrosine kinase whose deficit causes X-linked agammaglobulinemia in humans. The Btk29AficP mutation induces multiple abnormalities in oogenesis, including the growth arrest of ring canals, large intercellular bridges that allow the flow of cytoplasm carrying maternal products essential for embryonic development from the nurse cells to the oocyte during oogenesis. In this study, inactivation of Parcas, a negative regulator of Btk29A, was found to promote Btk29A accumulation on ring canals with a concomitant increase in the ring canal diameter, counteracting the Btk29AficP mutation. This mutation markedly reduced the accumulation of phosphotyrosine on ring canals and in the regions of cell-cell contact, where adhesion-supporting proteins such as DE-cadherin and beta-catenin ortholog Armadillo (Arm) are located. Our previous in vitro and in vivo analyses revealed that Btk29A directly phosphorylates Arm, leading to its release from DE cadherin. In the present experiments, immunohistological analysis revealed that phosphorylation at tyrosine 150 (Y150) and Y667 of Arm was diminished in Btk29AficP mutant ring canals. Overexpression of an Arm mutant with unphosphorylatable Y150 inhibited ring canal growth. Thus Btk29A-induced Y150 phosphorylation is necessary for the normal growth of ring canals. We suggest that the dissociation of tyrosine-phosphorylated Arm from DE-cadherin allows dynamic actin to reorganize, leading to ring canal expansion and cell shape changes during the course of oogenesis. PMID- 25803042 TI - T-cell activation and early gene response in dogs. AB - T-cells play a crucial role in canine immunoregulation and defence against invading pathogens. Proliferation is fundamental to T-cell differentiation, homeostasis and immune response. Initiation of proliferation following receptor mediated stimuli requires a temporally programmed gene response that can be identified as immediate-early, mid- and late phases. The immediate-early response genes in T-cell activation engage the cell cycle machinery and promote subsequent gene activation events. Genes involved in this immediate-early response in dogs are yet to be identified. The present study was undertaken to characterise the early T-cell gene response in dogs to improve understanding of the genetic mechanisms regulating immune function. Gene expression profiles were characterised using canine gene expression microarrays and quantitative reverse transcription PCR (qRT-PCR), and paired samples from eleven dogs. Significant functional annotation clusters were identified following stimulation with phytohemagluttinin (PHA) (5MUg/ml), including the Toll-like receptor signaling pathway and phosphorylation pathways. Using strict statistical criteria, 13 individual genes were found to be differentially expressed, nine of which have ontologies that relate to proliferation and cell cycle control. These included, prostaglandin-endoperoxide synthase 2 (PTGS2/COX2), early growth response 1 (EGR1), growth arrest and DNA damage-inducible gene (GADD45B), phorbol-12 myristate-13-acetate-induced protein 1 (PMAIP1), V-FOS FBJ murine osteosarcoma viral oncogene homolog (FOS), early growth response 2 (EGR2), hemogen (HEMGN), polo-like kinase 2 (PLK2) and polo-like kinase 3 (PLK3). Differential gene expression was re-examined using qRT-PCR, which confirmed that EGR1, EGR2, PMAIP1, PTGS2, FOS and GADD45B were significantly upregulated in stimulated cells and ALAS2 downregulated. PTGS2 and EGR1 showed the highest levels of response in these dogs. Both of these genes are involved in cell cycle regulation. This study provides a comprehensive analysis of the early T-cell gene response to activation in dogs. PMID- 25803044 TI - Muscle histidine-containing dipeptides are elevated by glucose intolerance in both rodents and men. AB - OBJECTIVE: Muscle carnosine and its methylated form anserine are histidine containing dipeptides. Both dipeptides have the ability to quench reactive carbonyl species and previous studies have shown that endogenous tissue levels are decreased in chronic diseases, such as diabetes. DESIGN AND METHODS: Rodent study: Skeletal muscles of rats and mice were collected from 4 different diet intervention studies, aiming to induce various degrees of glucose intolerance: 45% high-fat feeding (male rats), 60% high-fat feeding (male rats), cafeteria feeding (male rats), 70% high-fat feeding (female mice). Body weight, glucose tolerance and muscle histidine-containing dipeptides were assessed. Human study: Muscle biopsies were taken from m. vastus lateralis in 35 males (9 lean, 8 obese, 9 prediabetic and 9 newly diagnosed type 2 diabetic patients) and muscle carnosine and gene expression of muscle fiber type markers were measured. RESULTS: Diet interventions in rodents (cafeteria and 70% high-fat feeding) induced increases in body weight, glucose intolerance and levels of histidine containing dipeptides in muscle. In humans, obese, prediabetic and diabetic men had increased muscle carnosine content compared to the lean (+21% (p>0.1), +30% (p<0.05) and +39% (p<0.05), respectively). The gene expression of fast-oxidative type 2A myosin heavy chain was increased in the prediabetic (1.8-fold, p<0.05) and tended to increase in the diabetic men (1.6-fold, p = 0.07), compared to healthy lean subjects. CONCLUSION: Muscle histidine-containing dipeptides increases with progressive glucose intolerance, in male individuals (cross sectional). In addition, high-fat diet-induced glucose intolerance was associated with increased muscle histidine-containing dipeptides in female mice (interventional). Increased muscle carnosine content might reflect fiber type composition and/or act as a compensatory mechanism aimed at preventing cell damage in states of impaired glucose tolerance. PMID- 25803043 TI - Accumulation of glucosylceramide in the absence of the beta-glucosidase GBA2 alters cytoskeletal dynamics. AB - Glycosphingolipids are key elements of cellular membranes, thereby, controlling a variety of cellular functions. Accumulation of the simple glycosphingolipid glucosylceramide results in life-threatening lipid storage-diseases or in male infertility. How glucosylceramide regulates cellular processes is ill defined. Here, we reveal that glucosylceramide accumulation in GBA2 knockout-mice alters cytoskeletal dynamics due to a more ordered lipid organization in the plasma membrane. In dermal fibroblasts, accumulation of glucosylceramide augments actin polymerization and promotes microtubules persistence, resulting in a higher number of filopodia and lamellipodia and longer microtubules. Similar cytoskeletal defects were observed in male germ and Sertoli cells from GBA2 knockout-mice. In particular, the organization of F-actin structures in the ectoplasmic specialization and microtubules in the sperm manchette is affected. Thus, glucosylceramide regulates cytoskeletal dynamics, providing mechanistic insights into how glucosylceramide controls signaling pathways not only during sperm development, but also in other cell types. PMID- 25803046 TI - What drives the occurrence of the melioidosis bacterium Burkholderia pseudomallei in domestic gardens? AB - Melioidosis is an often fatal infectious disease affecting humans and animals in tropical regions and is caused by the saprophytic environmental bacterium Burkholderia pseudomallei. Domestic gardens are not only a common source of exposure to soil and thus to B. pseudomallei, but they also have been found to contain more B. pseudomallei than other environments. In this study we addressed whether anthropogenic manipulations common to gardens such as irrigation or fertilizers change the occurrence of B. pseudomallei. We conducted a soil microcosm experiment with a range of fertilizers and soil types as well as a longitudinal interventional study over three years on an experimental fertilized field site in an area naturally positive for B. pseudomallei. Irrigation was the only consistent treatment to increase B. pseudomallei occurrence over time. The effects of fertilizers upon these bacteria depended on soil texture, physicochemical soil properties and biotic factors. Nitrates and urea increased B. pseudomallei load in sand while phosphates had a positive effect in clay. The high buffering and cation exchange capacities of organic material found in a commercial potting mix led to a marked increase in soil salinity with no survival of B. pseudomallei after four weeks in the potting mix sampled. Imported grasses were also associated with B. pseudomallei occurrence in a multivariate model. With increasing population density in endemic areas these findings inform the identification of areas in the anthropogenic environment with increased risk of exposure to B. pseudomallei. PMID- 25803047 TI - Epethelial presence of Trueperella pyogenes predicts site-level presence of cranial abscess disease in white-tailed deer (Odocoileus virginianus). AB - Cranial/intracranial abscess disease is an emerging source of significant mortality for male white-tailed deer (Odocoileus virginianus). Most cases of cranial/intracranial abscess disease are associated with infection by the opportunistic pathogen Trueperella pyogenes although the relationship between the prevalence of the bacteria and occurrence of disease is speculative. We examined 5,612 hunter-harvested deer from 29 sites across all physiographic provinces in Georgia for evidence of cranial abscess disease and sampled the forehead, lingual, and nasal surfaces from 692 deer. We used polymerase chain reaction (PCR) to determine presence of T. pyogenes from these samples. We found T. pyogenes prevalence at a site was a predictor for the occurrence of cranial abscess disease. Prevalence of T. pyogenes did not differ between samples from the nose or tongue although prevalence along the forehead was greater for males than females (p = 0.04), particularly at sites with high occurrence of this disease. Socio-sexual behaviors, bacterial prevalence, or physiological characteristics may predispose male deer to intracranial/cranial abscess disease. Determination of factors that affect T. pyogenes prevalence among sites may help explain the occurrence of this disease among populations. PMID- 25803045 TI - StartReact effects support different pathophysiological mechanisms underlying freezing of gait and postural instability in Parkinson's disease. AB - INTRODUCTION: The pathophysiology underlying postural instability in Parkinson's disease is poorly understood. The frequent co-existence with freezing of gait raises the possibility of shared pathophysiology. There is evidence that dysfunction of brainstem structures contribute to freezing of gait. Here, we evaluated whether dysfunction of these structures contributes to postural instability as well. Brainstem function was assessed by studying the StartReact effect (acceleration of latencies by a startling acoustic stimulus (SAS)). METHODS: We included 25 patients, divided in two different ways: 1) those with postural instability (HY = 3, n = 11) versus those without (HY<3, n = 14); and 2) those with freezing (n = 11) versus those without freezing (n = 14). We also tested 15 matched healthy controls. We tested postural responses by translating a balance platform in the forward direction, resulting in backward balance perturbations. In 25% of trials, the start of the balance perturbation was accompanied by a SAS. RESULTS: The amplitude of automatic postural responses and length of the first balance correcting step were smaller in patients with postural instability compared to patients without postural instability, but did not differ between freezers and non-freezers. In contrast, the StartReact effect was intact in patients with postural instability but was attenuated in freezers. DISCUSSION: We suggest that the mechanisms underlying freezing of gait and postural instability in Parkinson's disease are at least partly different. Underscaling of automatic postural responses and balance-correcting steps both contribute to postural instability. The attenuated StartReact effect was seen only in freezers and likely reflects inadequate representation of motor programs at upper brainstem level. PMID- 25803048 TI - Public awareness of melioidosis in Thailand and potential use of video clips as educational tools. AB - BACKGROUND: Melioidosis causes more than 1,000 deaths in Thailand each year. Infection occurs via inoculation, ingestion or inhalation of the causative organism (Burkholderia pseuodmallei) present in soil and water. Here, we evaluated public awareness of melioidosis using a combination of population-based questionnaire, a public engagement campaign to obtain video clips made by the public, and viewpoints on these video clips as potential educational tools about the disease and its prevention. METHODS: A questionnaire was developed to evaluate public awareness of melioidosis, and knowledge about its prevention. From 1 March to 31 April 2012, the questionnaire was delivered to five randomly selected adults in each of 928 districts in Thailand. A video clip contest entitled "Melioidosis, an infectious disease that Thais must know" was run between May and October 2012. The best 12 video clips judged by a contest committee were shown to 71 people at risk from melioidosis (diabetics). Focus group interviews were used to evaluate their perceptions of the video clips. RESULTS: Of 4,203 Thais who completed our study questionnaire, 74% had never heard of melioidosis, and 19% had heard of the disease but had no further knowledge. Most participants in all focus group sessions felt that video clips were beneficial and could positively influence them to increase adherence to recommended preventive behaviours, including drinking boiled water and wearing protective gear if in contact with soil or environmental water. Participants suggested that video clips should be presented in the local dialect with simple words rather than medical terms, in a serious manner, with a doctor as the one presenting the facts, and having detailed pictures of each recommended prevention method. CONCLUSIONS: In summary, public awareness of melioidosis in Thailand is very low, and video clips could serve as a useful medium to educate people and promote disease prevention. PRESENTED IN PART: World Melioidosis Congress 2013, Bangkok, Thailand, 18-20 September 2013 (abstract OS VII-04). PMID- 25803049 TI - Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions. AB - The biological nitrogen cycle involves step-wise reduction of nitrogen oxides to ammonium salts and oxidation of ammonia back to nitrites and nitrates by plants and bacteria. Neither process has been thought to have relevance to mammalian physiology; however in recent years the salivary bacterial reduction of nitrate to nitrite has been recognized as an important metabolic conversion in humans. Several enteric bacteria have also shown the ability of catalytic reduction of nitrate to ammonia via nitrite during dissimilatory respiration; however, the importance of this pathway in bacterial species colonizing the human intestine has been little studied. We measured nitrite, nitric oxide (NO) and ammonia formation in cultures of Escherichia coli, Lactobacillus and Bifidobacterium species grown at different sodium nitrate concentrations and oxygen levels. We found that the presence of 5 mM nitrate provided a growth benefit and induced both nitrite and ammonia generation in E.coli and L.plantarum bacteria grown at oxygen concentrations compatible with the content in the gastrointestinal tract. Nitrite and ammonia accumulated in the growth medium when at least 2.5 mM nitrate was present. Time-course curves suggest that nitrate is first converted to nitrite and subsequently to ammonia. Strains of L.rhamnosus, L.acidophilus and B.longum infantis grown with nitrate produced minor changes in nitrite or ammonia levels in the cultures. However, when supplied with exogenous nitrite, NO gas was readily produced independently of added nitrate. Bacterial production of lactic acid causes medium acidification that in turn generates NO by non-enzymatic nitrite reduction. In contrast, nitrite was converted to NO by E.coli cultures even at neutral pH. We suggest that the bacterial nitrate reduction to ammonia, as well as the related NO formation in the gut, could be an important aspect of the overall mammalian nitrate/nitrite/NO metabolism and is yet another way in which the microbiome links diet and health. PMID- 25803051 TI - Genomic, proteomic and morphological characterization of two novel broad host lytic bacteriophages PhiPD10.3 and PhiPD23.1 infecting pectinolytic Pectobacterium spp. and Dickeya spp. AB - Pectinolytic Pectobacterium spp. and Dickeya spp. are necrotrophic bacterial pathogens of many important crops, including potato, worldwide. This study reports on the isolation and characterization of broad host lytic bacteriophages able to infect the dominant Pectobacterium spp. and Dickeya spp. affecting potato in Europe viz. Pectobacterium carotovorum subsp. carotovorum (Pcc), P. wasabiae (Pwa) and Dickeya solani (Dso) with the objective to assess their potential as biological disease control agents. Two lytic bacteriophages infecting stains of Pcc, Pwa and Dso were isolated from potato samples collected from two potato fields in central Poland. The PhiPD10.3 and PhiPD23.1 phages have morphology similar to other members of the Myoviridae family and the Caudovirales order, with a head diameter of 85 and 86 nm and length of tails of 117 and 121 nm, respectively. They were characterized for optimal multiplicity of infection, the rate of adsorption to the Pcc, Pwa and Dso cells, the latent period and the burst size. The phages were genotypically characterized with RAPD-PCR and RFLP techniques. The structural proteomes of both phages were obtained by fractionation of phage proteins by SDS-PAGE. Phage protein identification was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Pulsed field gel electrophoresis (PFGE), genome sequencing and comparative genome analysis were used to gain knowledge of the length, organization and function of the PhiPD10.3 and PhiPD23.1 genomes. The potential use of PhiPD10.3 and PhiPD23.1 phages for the biocontrol of Pectobacterium spp. and Dickeya spp. infections in potato is discussed. PMID- 25803050 TI - Streptococcus pneumoniae induces autophagy through the inhibition of the PI3K I/Akt/mTOR pathway and ROS hypergeneration in A549 cells. AB - The present study focused on the action mechanism of S. pneumoniae (Sp) in inducing autophagy in human alveolar epithelial cells. Sp, a gram-positive extracellular bacterium, activates autophagy with considerably increased microtuble-associated protein light chain 3 (LC3) punctation in A549 cells. The accumulation of typical autophagosomes and conjugation of LC3 to phosphatidylethanolamine were observed in Sp-infected cells as an indication of autophagy. Using the pneumolysin (PLY) mutant, we successfully demonstrated that PLY is involved in initiating autophagy without affecting the expression levels of PI3K-III and Beclin1. PLY-mediated autophagy depends on the inhibition of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Furthermore, Sp could also lead to the reactive oxygen species (ROS) hypergeneration in A549 cells. Taken together, Sp infection-induced autophagy is PLY-mediated through ROS hypergeneration and mTOR inhibition. PI3K-I and rapamycin (autophagy inducers) enhanced bacterial clearance, whereas wortmannin (autophagy inhibitor) and acetylcysteine (ROS inhibitor) reduced intracellular bacteria clearance. Thus, Sp-induced autophagy represents a host-protective mechanism, providing new insight into the pathogenesis of respiratory tract Sp infection. PMID- 25803052 TI - Association between tooth loss and cognitive function among 3063 Chinese older adults: a community-based study. AB - BACKGROUND: Oral health has been found to be associated with cognitive function in basic research and epidemiology studies. Most of these studies had no comprehensive clinical diagnosis on cognitive function. This study firstly reported the association between tooth loss and cognitive function among Chinese older population. METHODS: The study included 3,063 community dwelling older adults aged 60 or above from the Shanghai Aging Study. Number of teeth missing was obtained from self-reporting questionnaire and confirmed by trained interviewers. Participants were diagnosed as "dementia", "mild cognitive impairment (MCI)", or "cognitive normal" by neurologists using DSM-IV and Petersen criteria. Multivariate logistic regression model was applied to examine the association between number of teeth missing and cognitive function. RESULTS: The study participants had an average of 10.2 teeth lost. Individuals with dementia lost 18.7 teeth on average, much higher than those with MCI (11.8) and cognitive normal (9.3) (p<0.001). After adjusted for sex, age, education year, living alone, body mass index, cigarette smoking, alcohol drinking, anxiety, depression, heart disease, hypertension, diabetes, and APOE-epsilon4, tooth loss of >16 were significantly associated with dementia with an OR of 1.56 (95%CI 1.12 2.18). CONCLUSION: Having over 16 missing teeth was associated with severe cognitive impairment among Chinese older adults. Poor oral health might be considered as a related factor of neurodegenerative symptom among older Chinese population. PMID- 25803053 TI - Splice variants of activation induced deaminase (AID) do not affect the efficiency of class switch recombination in murine CH12F3 cells. AB - Activation Induced Deaminase (AID) triggers the antigen-driven antibody diversification processes through its ability to edit DNA. AID dependent DNA damage is also the cause of genetic alterations often found in mature B cell tumors. A number of splice variants of AID have been identified, for which a role in the modulation of its activity has been hypothesized. We have thus tested two of these splice variants, which we find catalytically inactive, for their ability to modulate the activity of endogenous AID in CH12F3 cells, a murine lymphoma cell line in which Class Switch Recombination (CSR) can be induced. In contrast to full-length AID, neither these splice variants or a catalytically impaired AID mutant affect the efficiency of Class Switch Recombination. Thus, while a role for these splice variants at the RNA level remains possible, it is unlikely that they exert any regulatory effect on the function of AID. PMID- 25803054 TI - Long term effects of below-the-knee angioplasty in diabetic patients with critical ischemia of lower limbs referred to Sina Hospital during 2010-2011. AB - Despite significant advances in the treatment of diabetic foot ulcers and below the-knee critical ischemia, there are ongoing efforts to achieve a method with low complication, high success rate and persistence of long-term effects. The aim of the study was to examine the outcome of angioplasty in patients with below-the knee critical ischemia referred to Hospital. MATERIAL AND METHODS: This semi experimental study conducted on diabetics patients treated with PTA (Percutaneous transluminal angioplasty) with critical ischemia of lower limbs referred to Sina Hospital. After discharge, the patients were followed weekly for the first month and then monthly up to 12 months. The procedure short-term effects were examined through evaluation of wound healing as well as patients' recovery and pain relief, after one month. Given the distribution type, parametric and non parametric test were used to compare the results before and after treatment. Pearson's correlation coefficient was used to determine the correlation between variables. RESULTS: Twenty four patients participated in this study. The mean ankle-brachial index (ABI) at baseline was 0.55 +/- 0.17. A month after angioplasty, the index increased statistically significant to 0.93 +/- 0.16. The mean health score expressed by the patients at baseline was 5.48 +/- 1.39. A month after angioplasty, it was significantly increased (6.32 +/- 1.24). The mean pain score before enrollment was 6.68 +/- 2.52 (according to VAS scale). There was a significant decrease over time (3.45 +/- 1.13). The overall mean score of all patients at Rutherford Classification was 3.88 +/- 0.63 at baseline. During the 1st month and 6th month follow-up, it was changed to Class 0 that was statistically significant in the first month. CONCLUSIONS: This study represents the mid-term outcomes of PTA. Although PTA treatment was associated with improved pain scores, satisfaction with health, classification of limb ischemia and diabetic foot ulcers, the effects only remain short-term and mid-term. However, long-term efficacy of PTA needs to be investigated further. PMID- 25803055 TI - The efficacy of alcohol-antibiotic lock therapy for treatment of catheter related bloodstream infections in patients receiving home parenteral nutrition. AB - In patients with chronic gastrointestinal tract failure, requiring access to the venous system, the subsequent catheter re-insertion are leading to large veins thrombosis impeding or preventing the insertion of another catheter and exposing patients to the risk of complications. Understanding the pathophysiology of catheter-related infections, enabled to use methods allowing to eradicate the source of infection without removal and replacement of central catheter with a new one. In our center, for many years we have been using an alternative method involving implementation of the alcohol-antibiotic lock in the treatment of infections. This method is based on the assumption that the destruction of biofilm with concentrated alcohol will enable antibiotic penetration and killing other microorganisms. Treatment with alcohol-antibiotic lock lasts from 8 to 10 days and involves filling the catheter with 96% alcohol followed by a solution of the antibiotic of high concentration. The aim of the study was to evaluate the efficacy of treatment of catheter-related bloodstream infections with two methods (catheter replacement with a new one and the alcohol-antibiotic lock therapy) in patients receiving home parenteral nutrition (HPN). MATERIAL AND METHODS: 428 HPN in the period from 1 January 2005 to 31 December 2010. Among which 240 (56%) of women with an average age of 56.5 +/- 16 years and 188 (44%) of men with an average age of 54 +/- 17 years. The indications to HPN were as follows: short bowel syndrome in 298 (70%) patients, multilevel obstruction of the gastrointestinal tract in 52 (12%), postoperative gastrointestinal fistulas in 48 (11.2%), malabsorption syndrome in 17 (4%), motility disorders in 6, cachexia in 4 and radiation enteritis in 3 patients. RESULTS: In 247 (57.5%) from 428 patients, no episode of catheter-related bloodstream infection was found, while 181 were diagnosed with 352 episodes of catheter-related bloodstream infections. In 40 (9.4%) from 428 patients, 168 (47.8%) episodes have been found - almost a half. The mean duration of treatment of patients receiving home parenteral nutrition, starting from the first episode of catheter-related bloodstream infection, in 48 patients treated with the lock was equal to 1053+748 days, and in 133 patients treated with catheter replacement was equal to 952+709 days (t test p = 0.62). CONCLUSIONS: The survival time of patients treated with alcohol antibiotic lock is the same as in patients treated with the catheter removal and insertion of the new one. The use of alcohol-antibiotic lock to treat catheter related bloodstream infections in order to eradicate selected microorganisms that colonize the lumen and cause an infection, is as effective as catheter replacement with a new one. PMID- 25803056 TI - The prognostic role of comorbidities in older patients qualified for emergency abdominal surgery. AB - Until now, the literature about the influence of specific comorbid conditions on outcome of emergency abdominal surgery in polish elderly patients is scars. The aim of the study was to determine the prognostic role of comorbidities in patients qualified for emergency abdominal surgery. MATERIAL AND METHODS: One hundred and eighty four consecutive patients(98 female and 86 male). 65 years of age were prospectively enrolled. The mean age was 76.9 +/- 5.8 (range 65-100) years old. RESULTS: Only 16% of patients did not have any preoperative comorbidity. The 30-day mortality was 24.5% (45 patients). The 30-day morbidity was experienced by the 58.7% (108 patients), including 40 patients (21.7%) with minor complications and 68 patients (37%) with major complications, according to the Clavien-Dindo complications scale. The dysrhythmia (odds ratio 1.6, 95% CI 1.2-2.6, p=0.02), vascular disease (odds ratio 2.1, 95% CI 1.4- 3.1, p=0.02) and renal disease (odds ratio 1.4, 95% CI 1.2-2.8, p=0.01) were independent risk factors of 30-day morbidity. The vascular disease was also the independent risk factor of 30-day postoperative death in the multivariate regression analysis (odds ratio 1.9, 95% CI 1.3-2.8, p=0.001). CONCLUSIONS: Preoperative comorbidities are common among elderly patients qualified for emergency abdominal surgery. However, only some of them (the dysrhythmia, the vascular disease and the renal disease) are independent risk factors of postoperative adverse outcomes. Therefore, number of comorbidies alone should not be the reason for a limited treatment. PMID- 25803057 TI - Iatrogenic bile duct injury. A significant surgical problem. Assessment of treatment outcomes in the department's own material. AB - Iatrogenic bile duct injuries (BDI) are still a challenging diagnostic and therapeutic problem. With the introduction of the laparoscopic technique for the treatment of cholecystolithiasis, the incidence of iatrogenic BDI increased. The aim of the study was a retrospective analysis of 69 patients treated at the department due to iatrogenic BDI in the years 2004-2014. MATERIAL AND METHODS: In this paper, we presented the results of a retrospective analysis of 69 patients treated at the Department due to iatrogenic BDI in the years 2004-2014. The data were analysed in terms of age, sex, type of biliary injury, clinical symptoms, the type of repair surgery, the time between the primary surgery and the BDI management, postoperative complications and duration of hospital stay. RESULTS: 82.6% of BDI occurred during laparoscopic cholecystectomy, 8.7% occurred during open cholecystectomy, whereas 6 cases of BDI resulted from surgeries conducted for other indications. In order to assess the degree of BDI, Bismuth and Neuhaus classifications were used (for open and laparoscopic cholecystectomy respectively). 84.1% of patients with confirmed BDI, were transferred to the Department from other hospitals. The average time between the primary surgery and reoperation was 6.2 days (SD 4). The most common clinical symptom was biliary fistula observed in 78.3% of patients. In 28 patients, unsuccessful attempts to manage BDI were made prior to the admission to the Department in other centres. The repair procedure was mainly conducted by laparotomy (82.6%) and by the endoscopic approach (15.9%). Hepaticojejunostomy was the most common type of reconstruction following BDI (34.7%). CONCLUSIONS: The increase in the rate of iatrogenic bile duct injury remains a challenging surgical problem. The management of BDI should be multidisciplinary treatment. Referring patients with both suspected and confirmed iatrogenic BDI to tertiary centres allows more effective treatment to be implemented. PMID- 25803058 TI - Evaluation of the learning curve for intraoperative neural monitoring of the recurrent laryngeal nerves in thyroid surgery. AB - Intraoperative neuromonitoring facilitates identification of the recurrent laryngeal nerves (RLN) and allows for predicting their postoperative function. Nevertheless, the outcome of thyroid surgery monitoring is affected by both the experience of the operator and his mastering of the technique. The aim of the study was the assessment of the learning curve for intraoperative RLN neuromonitoring. MATERIAL AND METHODS: The prospective analysis included 100 consecutive thyroid operations performed by a single surgeon during implementation of RLN neuromonitoring in a district surgical ward in Staszow. RLN neuromonitoring was performed in keeping with the recommendations of the International Neural Monitoring Study Group using a C2 NerveMonitor (Inomed, Germany). The outcomes of initial 50 procedures (group I: 08/2012-07/2013) were compared with the results of subsequent 50 operations (group II: 08/2013 07/2014). The evaluation included demographic and intraoperative data along with predictive value of the method and complications. RESULTS: In group II as compared to group I, a significant reduction of operative time was noted (102.1 +/- 19.4 vs 109.9 +/- 19; p = 0.045), along with an increased percentage of identified RLNs (99% vs 89.2%; p = 0.006), a decreased percentage of correction requiring technical errors (8% vs 24%; p = 0.029), an improved negative predictive (99% vs 89.3%; p < 0.001) and positive value (75% vs 55.6%; p < 0.001), as well as a decreased percentage of RLN injuries (3% vs 14%; p = 0.006). CONCLUSIONS: Mastering the technique of intraoperative RLN neuromonitoring in thyroid surgery requires the surgeon to perform independently approximately 50 monitored procedures, what allows for achieving the predictive value of the method that is comparable to outcomes published by referral centers. PMID- 25803059 TI - Foreign body in the gastrointestinal tract leading to small bowel obstruction- case report and literature review. AB - The presence of a foreign body in the gastrointestinal tract constitutes a common pathology, considering surgical clinical practice. The management of the ingestion of a foreign body depends on many factors. The study presented a case of a 33-year-old female patient subjected to surgical treatment, due to deliberate swallowing of a balloon. The above-mentioned was the amateur equivalent of intragastric balloon insertion, inducing weight loss. This is a rare cause of a foreign body ingestion, seldomly found in literature data. The patient reported to the Emergency Department on the second day after ingestion with symptoms of mechanical subobstruction, and after initial diagnostics, was qualified for surgery. The postoperative period proved uneventful. The study illustrated the often unfavourable access to false data on the internet, which may stimulate towards the above-mentioned behaviour. PMID- 25803060 TI - A successful resection of two giant mediastinal neurogenic tumors. AB - We reported two cases of the giant mediastinal neurogenic tumors. Patients were women in middle age. In both cases the chest X-ray and CT (computed tomography) demonstrated the huge mass in a pleural cavity without intraspinal invasion. Radical procedures with removal of the giant tumors were performed. The postoperative treatment course was uneventful. The pathology showed schwannoma and neurofibroma. The follow up examination (6-24 months) showed no recurrence of the disease. PMID- 25803062 TI - The use of the laser-Doppler method in surgery. PMID- 25803061 TI - Spontaneous pneumoperitoneum in a patient after ventilation therapy. AB - Free gas in the peritoneal cavity is not always associated with gastrointestinal perforation. The study presented a case of a 72-year old male patient with peritoneal emphysema, which developed after ventilation therapy. Suspecting gastrointestinal perforation the patient was subjected to laparotomy, which did not show perforation. The patient was diagnosed with spontaneous pneumoperitoneum. The patient died, due to cardiopulmonary and neurological disturbances. Withdrawal from non-therapeutic laparotomy may prove crucial in similar cases. PMID- 25803063 TI - The efficiency of burn wounds debridement with use of hydrosurgery--our experiences. AB - The aim of the study was to present experience of doctors from the Center for Burns Treatment in Siemianowice Slaskie who use a Versajet system. MATERIAL AND METHODS: Debridement with the use of a water jet was applied in 70 patients with IIb degrees /III degrees thermal burns in the period between 2009-2013. The corresponding evaluation involved duration of operation, locations, wound surfaces and technique of debridement after operation. Microbiological tests were also performed before and after debridement. RESULTS AND CONCLUSIONS: In the paper, its authors draw attention to the short time of debridement. The application of a water jet allows precise debridement, particularly in hardly accessible places, preparation of wounds to be covered with autologous split thickness skin graft, protection of healthy tissues. PMID- 25803064 TI - Groin hernia surgery in northern Ghana--humanitarian mission of Polish surgeons in Tamale. AB - Availability of surgical care in Africa is severely limited. This is due to the lack of surgeons and a small number of public hospitals. Only 25 out of 100,000 patients with inguinal hernia undergo a surgical treatment. As many as 65% of inguinal hernia repairs are performed urgently because of incarceration. Among patients with incarceration who do not reach the hospital there is recorded as many as 87 deaths per 100 cases. In order to improve the availability of treatment of inguinal hernia in Africa, humanitarian medical missions involving surgeons from Europe are organized. During regular visits to selected centers in Africa, they also carry out intensified treatment of patients and training of the local staff. The aim of the study was to present the experience of Polish surgeons from the humanitarian medical mission in Tamale in northern Ghana undertaken in fall of 2014. MATERIAL AND METHODS: Surgical repair was performed in 87 patients (74 men - 85% and 13 women - 15%) between the ages of 26 to 70 years (mean 52.8 years; SD 10.3), who underwent a total of 98 inguinal hernia repairs under local anesthesia. RESULTS: Lichtenstein procedure was performed in 93 and Desarda technique in 5 patients. Patients reported the long-term presence of hernia symptoms - from one to 7 years (mean 3.4 years, SD 1.4). In most patients, hernia occurred more than 3 years earlier (61 patients; 70%). There were no intraoperative complications. All patients were discharged the next day after surgery. There was one wound infection in postoperative period which required mesh explantation. CONCLUSIONS: Inguinal hernia commonly found in Ghana is a major issue for the inefficient health care system. Humanitarian medical missions can help to improve the treatment results, as long as they are carried out periodically and allow for training of local personnel. Scarce equipment of medical facilities in Ghana is not a significant difficulty in performing the Lichtenstein repair under the local anesthesia. PMID- 25803065 TI - Comparison of the effectiveness of the treatment using standard methods and negative pressure wound therapy (NPWT) in patients treated with open abdomen technique. AB - Open abdomen technique is a surgical treatment in which the fascia and skin are left open in order to reduce the value of the intra-abdominal pressure. According to the World Society of the Abdominal Compartment Syndrome (WSACS) normal values of the intra-abdominal pressure are between 5 and 7 mm Hg. Intra-abdominal hypertension occurs when the pressure value is equal to or exceeds 12 mm Hg. The aim of the study was to compare the results of the open abdomen treatment using standard methods and negative pressure wound therapy. MATERIAL AND METHODS: The study was in the form of a retrospective analysis of the documentation of the patients treated with open abdomen technique. The study included 37 patients treated in the Department of General and Endocrine Surgery and Gastroenterological Oncology and in the Department of Anesthesiology and Intensive Care of the Medical Sciences since 2009-2012. Patients were divided into two groups: group 1 (n = 20) was treated with standard surgical procedures (laparostomy, repeated peritoneal cavity lavage) and group 2 (n =17) was treated using negative pressure wound therapy (NPWT). The analysed clinical data included the period of hospitalization and clinical outcome (survival vs death), the occurrence of enteroatmospheric fistulae, cyclical determination of the quantitative C-reactive protein levels. RESULTS: The number of deaths during hospitalization in the group treated with NPWT was lower than in the group treated with standard methods (3 vs 9). The number of fistulae during hospitalization in the group treated with NPWT dropped as compared to the group treated using standard procedures (18% vs 70%). The decrease in the CRP levels was recorded in the group treated with NPWT and its increase - in the group treated with standard methods. CONCLUSIONS: The use of NPWT in patients requiring open abdomen treatment is reasonable due to the positive results with respect to survival rates and the decrease in the number of gastrointestinal fistulae. It is necessary to train the physicians in using this type of therapy in the form of workshops and in the clinical setting. PMID- 25803066 TI - Evaluation of the early results of a loop stoma with a plastic rod in comparison to a loop stoma made with a skin bridge. AB - Loop stoma allows reducing the percentage of anastomotic leak and re-operation caused by this complication. Our department has performed the loop stoma on a skin bridge since 2011. The aim of the study was to evaluate the early results of treatment after the skin bridge loop stoma creation in comparison with the stoma made on a plastic rod. Both groups had 20 patients. MATERIAL AND METHODS: The study involved 40 patients with ileostomy, operated 2010-2013. We evaluated 20 patients with a loop ileostomy on a plastic rod, compared to 20 other patients with a skinbridge ileostomy. The study included 24 men and 16 women. Median age was 68.3. All evaluated patients were previously operated due to rectal cancer. RESULTS: It has been shown that the surgical site infection is more common in the group with a plastic rod (5 vs 1 patient). Inflammation of the skin around the stoma occurred in 18 patients (90%) in the first group, while no such complication was found in patients in the second group. The average number of exchanged ostomy wafers was 2.9 per week in the first group of patients, and 1,1 in the second group (p 0.05). CONCLUSIONS: The creation of the skin bridge stoma allows for tight fit of the ostomy appliance immediately after surgery completion. The equipment has stable and long-lasting contact with the skin, no skin inflammatory changes occur. Also the surgical site infection rates are lower in this group of patients. As perioperative patient does not require an increased number of ostomy appliance, the cost of treatment can be considered as an important aspect. PMID- 25803068 TI - Complex interventional treatment of extensive consequences of necrotizing pancreatitis--case report. AB - The paper presents description of the effective treatment of patients with extensive consequences of necrotizing pancreatitis. The strategy of treatment was to extend access to necrotic areas ("step-up approach"). Applied endoscopic transmural access (transgastric), percutaneous access (transperitoneal) and surgical access. The cooperation endoscopist, surgeon and interventional radiologist gave very beneficial clinical effects in patients with extensive complications of acute pancreatitis. PMID- 25803067 TI - Inflammatory myofibroblastic tumor within ileal intussusception as the cause of recurrent abdominal pain in a 57-year old patient. AB - The study presented a rare case of inflammatory myofibroblastic tumor (IMT) in a 57-year old male patient who presented with recurrent abdominal pain. He was diagnosed to have a tumor of the small intestine within ileal intussusception, demonstrated by CT enterography. The patient underwent surgery to remove the tumor with a margin of healthy tissue. Histopathological and immunohistochemical examination results enabled to diagnose IMT. IMT is a rare tumor that occurs mainly in children and young adults. Its etiology remains to be fully understood. Due to the differentiated histology it can be found in many organs and soft tissues, being responsible for different, non-specific clinical and radiological symptoms. Due to the rarity of this tumor a clear treatment protocol has not yet been established. However, given the tendency to recur with possible distant metastases an important element of treatment consists in long-term clinical patient observation. PMID- 25803069 TI - Laparoscopy-assisted total gastrectomy with D2 lymphadenectomy and Roux-en-Y reconstruction--case report. AB - We report a case of patient with stage IIIb gastric cancer qualified for laparoscopy-assisted gastrectomy and our first impressions about this procedure. Total gastrectomy with complete omentectomy and extended lymphadenectomy (D2) was performed laparoscopically. The intestinal continuity was restored in a Roux-en-Y mode extracorporeally through the abdominal access system. The orogastric tube with anvil of the circular stapler was transorally introduced into the esophagus. Subsequently, intracorporeal stapling esophagojejunostomy was performed. There were no complications after the operation and the patient was discharged in good shape. Oncological radicality was sufficient and patient has undergone chemotherapy treatment. PMID- 25803070 TI - The importance of prerehabilitation in the reduction of postoperative complications of elderly patients undergoing abdominal operations--systematic review. PMID- 25803071 TI - Are there anamnestic risk factors for iron deficiency in pregnancy? Results from a feasibility study. AB - The conditions of iron deficiency are highly incident in pregnancy with elevated risks for preterm birth and low birth weight. In our recent study, we found 6% of participants having anemia, whereas between 39% and 47% showed iron deficiency without anemia. In many countries in prenatal care solely hemoglobin (Hb) measurement is applied. For the gynecologists till date there is no indication to determine other markers (e.g., serum-ferritin). As iron deficiency results from an imbalance between intake and loss of iron, our aim was to find out if the risk of iron deficiency conditions can be estimated by a diet history protocol as well as questionnaires to find about iron loss. We found that the risk of having iron deficiency in upper gestational week (>=21) increased by a factor of five. Thus, additional diagnostics should be done in this group by now. Using the questionnaire as a screening instrument, we further estimated the probability of disease in terms of a positive likelihood ratio (LR+). The positive LR for the group below 21th week of gestation is 1.9 thus, increasing the post-test probability to 52% from 36% as before. Further research based on higher sample sizes will show if the ratios can be increased further. PMID- 25803072 TI - How effective is ultrasound-based screening for trisomy 18 without the addition of biochemistry at the time of late first trimester? AB - Trisomy 18 (T18) remains the second most common aneuploidy. It is associated with multiple congenital anomalies and causes intrauterine fetal demise in the most severe cases. OBJECTIVES: To examine the screening performance of ultrasound based protocols for detecting T18, we aimed to determine the most common signs and their prevalence in fetuses with T18 to develop logistic regression model. METHODS: This was a prospective study based on singleton pregnancies examined at gestation 11+0 to 13+6. The referrals constituted 6210 patients. Scan protocol enclosed a systematic review of the entire early fetal anatomy, including fetal cardiac evaluation and sonographic signs of aneuploidy. RESULTS: Our study population comprised 5650 pregnancies: 5613 cases with a normal karyotype and 37 cases with T18. The mean nuchal translucency (NT) thickness in the subgroup of euploidy was 1.7 and in the subgroup of T18 it was 5.4. No statistically significant differences were found in terms of maternal age. One case of T18 (2.7%) demonstrated no markers of aneuploidy as opposed to 5111 cases of euploidy (91.1%). Extracardiac malformations were identified in 13 cases of T18 (35.1%) and in 48 cases of euploidy (0.8%). Congenital heart defects were observed in 26 cases of T18 (70.3%) and in 27 cases of euploidy (0.5%). CONCLUSIONS: Our results showed good screening performance of ultrasound-based risk calculation models. When the first trimester pattern of T18 is considered, an increased NT, tricuspid regurgitation, single umbilical artery, omphalocele and right dominant heart should be specifically searched for. PMID- 25803073 TI - Altered cardiovascular autonomic function in young normotensive offspring of hypertensive parents - Is obesity an additional risk factor? AB - BACKGROUND: A study was undertaken to analyze the nature and magnitude of autonomic dysregulation that starts early in the offspring of a hypertensive parent and also whether obesity in them add an additional risk for future hypertension. METHODS: Forty normotensive subjects aged 18-25 years with at least one hypertensive parent constitute the study group. The study group was divided into obese and non-obese depending on their body mass index (non-obese with BMI 18.50-24.99 kg/m2; obese with BMI>=30 kg/m2). Twenty age-matched normotensive, without parental history subjects constitute the control group. Anthropometric parameters, heart rate, systolic and diastolic pressures were recorded. Heart rate variability indices like total power, LF, HF, LF/HF, SDNN, RMSSD, and PNN50% were studied. One-way ANOVA was used for simultaneous multiple group comparison followed by post hoc Tukey's test for groupwise comparison. The Pearson correlation coefficient was used to assess the relationship between BMI and other variables. RESULTS: Subjects who were obese with parental history of hypertension showed significantly higher heart rate, diastolic blood pressure, LF, LF/HF ratio and reduced total power, HF, SDNN, RMSSD, and PNN50% compared to the other groups with normal BMI. HF and all the time domain indices showed negative correlation and LF a positive correlation with BMI. CONCLUSIONS: In the obese offspring of hypertensive parents, HRV markers, which represent a vagal dominance were reduced substantially, and indices of sympathetic activity were increased. So obesity in a normotensive offspring of a hypertensive parent is an additional risk factor for the future development of hypertension as it further dysregulates the autonomic control of the heart. PMID- 25803074 TI - Atheromic and lymphoplasmacytic effects of Mangifera indica methanolic leaf extract on the heart of chinchilla rabbits. AB - BACKGROUND: The aim of this study was to evaluate the effect of methanol extract of Mangifera indica on serum concentration of creatine kinase, total white blood cell (WBC) count and lymphocyte counts and the micro-anatomical architecture of the heart in chinchilla rabbits in order to find its safe and toxic levels. A total of 24 Chinchilla rabbits aged 10-14 weeks, divided into four experimental groups were orally administered the doses of none, 500, 1000 and 1500 mg/kg body weight of the methanol extract of M. indica, respectively, for 28 days. METHODS: The modified International Federation of Clinical Chemistry (IFCC) method was used to estimate the serum concentration of creatine kinase (CK (-MB)) while the haematology auto-analyser was used to estimate the total WBC count and lymphocyte count. The estimated values were subjected to analysis of variance using the SPSS software application (version 16) and expressed as mean+/-standard deviation. Tissue sections were stained by phosphotungstic acid haematoxylin and haematoxylin and eosin staining techniques. RESULTS: The result showed significant increases in serum concentrations of CK (-MB) (12.05+/-3.11-21.55+/ 9.93 U/L) and total WBC count (5.33+/-0.66-6.51+/-0.38 103/MUL) when the control group was compared with the treated groups (p<0.05). A significant dose-dependent decrease in the weight of the heart (0.053+/-0.00-0.041+/-0.003 kg) was also observed (p<0.05). An insignificant increase was observed in the lymphocyte count (4.47+/-0.94-5.18+/-0.76 103/MUL) in the blood when compared with the control group (p>0.05). Significant differences were also observed in the body weight of the treated groups (p<0.05). The histopathological findings include atheroma, attenuated vasculature, lymphoplasmacytic infiltrates, necrotic and fibrotic vascular walls. CONCLUSIONS: Thus, M. indica is indicated to have some health benefits at 500 mg/kg and shows toxicity on the micro-architecture of the heart at a concentration of >=1000 mg/kg. PMID- 25803076 TI - Secretory sphingomyelinase in health and disease. AB - Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn2+ ions for activation and is glycosylated mainly with high mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann Pick disease B. Thus, lower serum/plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target. PMID- 25803077 TI - The pseudo-atomic structure of an RND-type tripartite multidrug efflux pump. AB - Microorganisms encode several classes of transmembrane molecular pumps that can expel a wide range of chemically distinct toxic substances. These machines contribute to the capacity of the organisms to withstand harsh environments, and they help to confer resistance against clinical antimicrobial agents. In Gram negative bacteria, some of the pumps comprise tripartite assemblies that actively transport drugs and other harmful compounds across the cell envelope. We describe recent structural and functional data that have provided insights into the architecture and transport mechanism of the AcrA-AcrB-TolC pump of Escherichia coli. This multidrug efflux pump is powered by proton electrochemical gradients through the activity of AcrB, a member of the resistance/nodulation/cell division (RND) transporter family. Crystallographic data reveal how the small protein AcrZ binds to AcrB in a concave surface of the transmembrane domain, and we discuss how this interaction may affect the efflux activities of the transporter. PMID- 25803079 TI - Whole blood thromboelastometry profiles in women with preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is a pregnancy complication characterized by high blood pressure and significant amounts of protein in the urine. Various coagulation abnormalities have been described in pregnant women with PE. The aim of the present case-control study was to evaluate whole blood thromboelastometry profiles, performed by ROTEM((r)), in women with PE in order to better characterize the PE-related discoagulopathy. METHODS: Standard ROTEM((r)) (Tem International GmbH, Munich, Germany) parameters evaluating clot initiation [clotting time (CT)], propagation [clot formation time (CFT); alpha-angle], stability [maximum clot firmness (MCF)] and lysis [maximum lysis (ML)] in INTEM, EXTEM, NATEM, and FIBTEM assays were performed in 30 consecutive pregnant women with PE at diagnosis. Sixty (1:2 ratio with cases) healthy pregnant women, matched for gestational age (+/- 2 weeks) with the cases, acted as controls. Platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, antithrombin and D-Dimer were also evaluated. RESULTS: Preeclamptic women showed a significantly more rapid propagation phase in EXTEM assay than controls (CFT 62 +/- 15 vs. 75 +/- 15 s and alpha-angle 78 +/- 4 vs. 75 +/- 4 degrees , p<0.01 in both cases). Moreover, MCF was significantly higher and ML significantly lower in women with PE than in healthy pregnant women (p=0.001 for all comparisons). CONCLUSIONS: ROTEM((r)) profiles in women with PE were characterized by an increased tissue factor driven clot propagation capability. In addition, higher clot stability due both to the increase in clot firmness and the decrease in blood fibrinolysis was observed. Larger studies are needed to identify the clinical relevance of ROTEM((r)) alterations in women with PE. PMID- 25803080 TI - Potentiometric measurement of urinary iodine concentration in patients with thyroid diseases with and without previous exposure to non-radioactive iodine. AB - BACKGROUND: Extensive application of measurement of urinary iodine concentration (UIC) in several benign and malignant thyroid diseases could profit by the availability of rapid and inexpensive measuring techniques. Aim of this study was to apply a simple and inexpensive commercially available potentiometric method for the quantification of UIC based on iodine-specific ion-selective electrodes (ISE) in patients with thyroid diseases. METHODS: This retrospective study included patients with differentiated thyroid cancer (n=286) and patients with hyperthyroidism of different etiologies (n=203). Within the whole sample (n=489) 20 patients had previously (1 week-6 months) been exposed to iodine overload, either from contrast media (n=8) or amiodarone (n=12). RESULTS: In patients not exposed to iodine, the histogram showed that the distribution of UIC violated normality. The peak of the curve occurred between 5.0 MUmol/L and 6.0 MUmol/L. Variability was sizeable (percent coefficient of variation, %CV: 66%, 95% confidence interval: 1.48-18.72 MUmol/L). The group of exposed patients could be easily distinguished from not exposed patients (median UIC: 47.5 MUmol/L vs. 5.42 MUmol/L). UIC was significantly correlated to urinary creatinine concentration, but normalization to urinary creatinine increased the inter-subject variability of UIC (%CV=96% vs. 66%). In test-retest studies (n=25) the intra-class correlation coefficient was 0.73 for UIC, 0.82 for creatinine and 0.64 for the UIC: creatinine ratio. CONCLUSIONS: Iodine-specific ISE-based potentiometric methods can be successfully applied as an alternative to existing methods in patients with thyroid diseases. The promising characteristics of the method need to be confirmed in future larger prospective studies. PMID- 25803075 TI - Molecular mechanisms of erythrocyte aging. AB - Anemia and hemorrhagic shock are leading causes of morbidity and mortality worldwide, and transfusion of human blood products is the ideal treatment for these conditions. As human erythrocytes age during storage in blood banks they undergo many biochemical and structural changes, termed the red blood cell 'storage lesion'. Specifically, ATP and pH levels decrease as metabolic end products, oxidative stress, cytokines, and cell-free hemoglobin increase. Also, membrane proteins and lipids undergo conformational and organizational changes that result in membrane loss, viscoelastic changes and microparticle formation. As a result, transfusion of aged blood is associated with a host of adverse consequences such as decreased tissue perfusion, increased risk of infection, and increased mortality. This review summarizes current research detailing the known parts of the erythrocyte storage lesion and their physiologic consequences. PMID- 25803078 TI - The contribution of methionine to the stability of the Escherichia coli MetNIQ ABC transporter-substrate binding protein complex. AB - Despite the ubiquitous role of ATP-binding cassette (ABC) importers in nutrient uptake, only the Escherichia coli maltose and vitamin B12 ABC transporters have been structurally characterized in multiple conformations relevant to the alternating access transport mechanism. To complement our previous structure determination of the E. coli MetNI methionine importer in the inward facing conformation (Kadaba et al. (2008) Science 321, 250-253), we have explored conditions stabilizing the outward facing conformation. Using two variants, the Walker B E166Q mutation with ATP+EDTA to stabilize MetNI in the ATP-bound conformation and the N229A variant of the binding protein MetQ, shown in this work to disrupt methionine binding, a high affinity MetNIQ complex was formed with a dissociation constant measured to be 27 nm. Using wild type MetQ containing a co-purified methionine (for which the crystal structure is reported at 1.6 A resolution), the dissociation constant for complex formation with MetNI is measured to be ~40-fold weaker, indicating that complex formation lowers the affinity of MetQ for methionine by this amount. Preparation of a stable MetNIQ complex is an essential step towards the crystallographic analysis of the outward facing conformation, a key intermediate in the uptake of methionine by this transport system. PMID- 25803081 TI - Establishing objective analytical quality requirements in the IgE specific assay: a message in a bottle. PMID- 25803082 TI - Atypical hemolytic uremic syndrome: from diagnosis to treatment. AB - Thrombotic microangiopathy (TMA) is a relatively rare condition but a medical urgency requiring immediate intervention to avoid irreversible organ damage or death. Symptoms on presentation include microangiopathic haemolytic anaemia, thrombocytopenia and organ damage. The most frequent direct causes of TMA are thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). The most common form of HUS is related to Shiga toxin producing Escherichia coli (STEC) infection while approximately 10% of cases are due to dysregulation of the complement pathway (atypical haemolytic uremic syndrome, aHUS). Optimal treatment regimens differ depending on the underlying cause; however, differential diagnosis may be difficult. The most accurate method of diagnosis is based on exclusion and should consider, beyond the symptoms common to TMA, ADAMTS13 activity levels and STEC infection status. For the management of TTP, plasma exchange (PE) is the most important acute intervention and is associated with lower mortality and better outcomes than plasma infusion. In most patients with STEC-HUS, the course of disease is self-limiting although management of acute kidney injury is often required. Until recently, the management of aHUS consisted of early and intensive PE, although this was mostly ineffective in protecting from subsequent organ damage. Eculizumab, an inhibitor of the alternative complement pathway, produces a rapid and sustained inhibition of the TMA process, with significant improvements in long-term clinical outcomes. Due to the significant improvement achieved, eculizumab has subsequently been approved as first-line therapy when an unequivocal diagnosis of aHUS has been made. PMID- 25803083 TI - Optimizing the use of the "state-of-the-art" performance criteria. AB - The organizers of the first EFLM Strategic Conference "Defining analytical performance goals" identified three models for defining analytical performance goals in laboratory medicine. Whereas the highest level of model 1 (outcome studies) is difficult to implement, the other levels are more or less based on subjective opinions of experts, with models 2 (based on biological variation) and 3 (defined by the state-of-the-art) being more objective. A working group of the German Society of Clinical Chemistry and Laboratory Medicine (DGKL) proposes a combination of models 2 and 3 to overcome some disadvantages inherent to both models. In the new model, the permissible imprecision is not defined as a constant proportion of biological variation but by a non-linear relationship between permissible analytical and biological variation. Furthermore, the permissible imprecision is referred to the target quantity value. The biological variation is derived from the reference interval, if appropriate, after logarithmic transformation of the reference limits. PMID- 25803084 TI - The role of telomeres and vitamin D in cellular aging and age-related diseases. AB - Aging is a complex biological process characterized by a progressive decline of organ functions leading to an increased risk of age-associated diseases and death. Decades of intensive research have identified a range of molecular and biochemical pathways contributing to aging. However, many aspects regarding the regulation and interplay of these pathways are insufficiently understood. Telomere dysfunction and genomic instability appear to be of critical importance for aging at a cellular level. For example, age-related diseases and premature aging syndromes are frequently associated with telomere shortening. Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. Here we review existing knowledge about the link between telomere biology and cellular aging with a focus on the role of vitamin D. We searched the literature up to November 2014 for human studies, animal models and in vitro experiments that addressed this topic. PMID- 25803085 TI - Tumor markers assay by the Lumipulse G. PMID- 25803086 TI - Double bias: estimation of causal effects from length-biased samples in the presence of confounding. AB - Length bias in survival data occurs in observational studies when, for example, subjects with shorter lifetimes are less likely to be present in the recorded data. In this paper, we consider estimating the causal exposure (treatment) effect on survival time from observational data when, in addition to the lack of randomization and consequent potential for confounding, the data constitute a length-biased sample; we hence term this a double-bias problem. We develop estimating equations that can be used to estimate the causal effect indexing the structural Cox proportional hazard and accelerated failure time models for point exposures in double-bias settings. The approaches rely on propensity score-based adjustments, and we demonstrate that estimation of the propensity score must be adjusted to acknowledge the length-biased sampling. Large sample properties of the estimators are established and their small sample behavior is studied using simulations. We apply the proposed methods to a set of, partly synthesized, length-biased survival data collected as part of the Canadian Study of Health and Aging (CSHA) to compare survival of subjects with dementia among institutionalized patients versus those recruited from the community and depict their adjusted survival curves. PMID- 25803087 TI - Nursing students' experiences with high-fidelity simulation. AB - Research has revealed the effectiveness of simulation for facilitating student development of self-efficacy, knowledge, clinical judgment, and proficiency in technical skills. This grounded theory study was conducted to describe the experience of nursing students in high-fidelity simulation and develop a model which explicates the experience of nursing students in simulation. Focus group interviews were conducted with three cohorts of students enrolled in a baccalaureate nursing program who experienced simulation four to twelve times per academic year. Five prominent themes emerged during analysis Emotional Processing; Anxiety; Making Connections; Fidelity; and Learning. The Simulation Learning Model - Student Experience (SLM-SE) was developed to illustrate the student's multi-dimensional experience of learning through high-fidelity simulation. Findings from this study suggest that students are better equipped to learn through increasing confidence and experience, continued reflection-on action and enhanced peer-to-peer interaction. Recommendations for future research include developing strategies to optimize students' experiences for learning in simulation. PMID- 25803088 TI - H-CLAP: hierarchical clustering within a linear array with an application in genetics. AB - In most cases where clustering of data is desirable, the underlying data distribution to be clustered is unconstrained. However clustering of site types in a discretely structured linear array, as is often desired in studies of linear sequences such as DNA, RNA or proteins, represents a problem where data points are not necessarily exchangeable and are directionally constrained within the array. Each position in the linear array is fixed, and could be either "marked" (i.e., of interest such as polymorphic or substitute sites) or "non-marked." Here we describe a method for clustering of those marked sites. Since the cluster generating process is constrained by discrete locality inside such an array, traditional clustering methods need adjustment to be appropriate. We develop a hierarchical Bayesian approach. We adopt a Markov clustering algorithm, revealing any natural partitioning in the pattern of marked sites. The resulting recursive partitioning and clustering algorithm is named hierarchical clustering in a linear array (H-CLAP). It employs domain-specific directional constraints directly in the likelihood construction. Our method, being fully Bayesian, is more flexible in cluster discovery compared to a standard agglomerative hierarchical clustering algorithm. It not only provides hierarchical clustering, but also cluster boundaries, which may have their own biological significance. We have tested the efficacy of our method on data sets, including two biological and several simulated ones. PMID- 25803089 TI - Effect of Withania somnifera (Ashwagandha) root extract on amelioration of oxidative stress and autoantibodies production in collagen-induced arthritic rats. AB - BACKGROUND: Rheumatoid arthritis is an inflammatory autoimmune disorder. Withania somnifera Dunal (Solanaceae) (WS), is a common medicinal plant used in traditional systems of medicine for the treatment of arthritis, and is an ingredient of anti-arthritic polyherbal formulations such as Habb-e-Asgand(r) and ArthritinTM. In the present study, we evaluated the antioxidant and anti arthritic activity of aqueous extract of WS root (WSAq) in collagen-induced arthritic (CIA) rats. METHODS: CIA rats were treated by using three doses of WSAq (100, 200, 300 mg/kg b. wt., orally) and methotrexate (MTX, 0.25 mg/kg b. wt. i.p.) as a standard reference drug for 20 days. The anti-arthritic effect was assayed by measuring the arthritic index, autoantibodies such as rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (a-CCP), anti-nuclear antibody (ANA), anti-collagen type II antibody (a-CII) and inflammatory marker like C-reactive protein (CRP). The oxidative stress parameters were also measured. RESULTS: Treatment with WSAq resulted in a dose-dependent reduction in arthritic index, autoantibodies and CRP (p < 0.05) with maximum effect at dose of 300 mg/kg b. wt. and the results were comparable to that of MTX-treated rats. Similarly, oxidative stress in CIA rats was ameliorated by treatment with different doses of WSAq, as evidenced by a decrease in lipid peroxidation and glutathione-S-transferase activity and an increase in the glutathione content and ferric-reducing ability of plasma (p < 0.05). CONCLUSIONS: The results showed that WSAq exhibited antioxidant and anti-arthritic activity and reduced inflammation in CIA rats and suggests the potential use of this plant in the treatment of arthritis. PMID- 25803090 TI - Effect of daily drinking of Aloe vera gel extract on plasma total antioxidant capacity and oral pathogenic bacteria in healthy volunteer: a short-term study. AB - BACKGROUND: The aim of this study was to investigate the effect of Aloe vera gel extract on plasma total antioxidant capacity (TAC) and oral pathogenic bacteria in healthy volunteer. METHODS: Fifty-three healthy volunteers were participated and interviewed for history of allergy, current systemic diseases and medications. Participants were received 250 mL of A. vera gel extract daily for 14 consecutive days. At days 0 and 15 of the experiment, blood samples were collected and analyzed for biochemical markers. The plasma TAC was evaluated by ferric reducing ability of plasma technique. The biochemical markers, including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total protein (TP), serum albumin (ALB), serum globulin (GLB), total bilirubin (TB), blood urea nitrogen (BUN), serum creatinine (Cr) and creatinine clearance (CrCl) were measured. The antibacterial effect of A. vera gel extract against Lactobacillus spp. and Streptococcus mutans was also investigated. Statistical analysis was performed using paired t-test to compare between baseline and 14 days post-intervention. RESULTS: Neither allergy nor side effects of A. vera gel extract was detected. After 14 days of A. vera gel extract consumption, plasma TAC was significantly greater than that of baseline (p = 0.001). ALP, TB, TP and GLB were significantly increased (p < 0.05) which were still within normal range. AST, ALT, ALB, BUN, Cr and CrCl were not significantly different. A. vera gel extract significantly reduced the number of Lactobacillus spp. (p < 0.05), not S. mutans. CONCLUSIONS: Our data revealed that A. vera gel extract significantly increased plasma TAC, and decreased the number of Lactobacillus spp. without any clinical side effects. PMID- 25803091 TI - Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations. AB - Data on frequency of pharmacogenetic polymorphisms in the UK population are limited. However, availability of whole genome sequencing data on 94 UK controls of European ethnicity from the 1000 genomes project together with similar data on other populations provides a valuable new source of data in this area and allows direct comparison of allele frequencies with those for other European populations. The ethnic diversity of the UK population also needs to be considered, and 1000 genomes includes data on South Asians, the most common ethnic group in the UK after White Europeans. Allele frequencies for polymorphisms in genes relevant to phase I and phase II drug metabolism for UK, Finnish, Spanish and South Asian populations were obtained from the literature and 1000 genomes. Generally there was good agreement between the literature and 1000 genomes reports. CYP2D6*4, the most common CYP2D6 poor metabolizer allele among Europeans, appears more common in the UK than in Spain and Finland, whereas, as suggested previously, CYP2C19*2 and CYP2C9*2 appear more common in Finland and Spain, respectively, than in the UK. South Asians show low frequencies of CYP2C9*2 and CYP2C19*17 but higher frequencies of CYP2C19*2 compared with UK residents of European ethnicity. Though personalizing drug treatment on the basis of individual genotype rather than ethnicity may be more appropriate, differences in allele frequencies across continents should be considered when designing clinical trials of new drugs. PMID- 25803093 TI - Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects. AB - BACKGROUND: Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor and a CYP3A4 enzyme substrate. This study assessed the safety, tolerability, and pharmacokinetics of bosutinib when coadministered with the CYP3A4 inducer rifampin in 24 healthy men. METHODS: Subjects received single oral doses of bosutinib 500 mg (Days 1 and 14) and once-daily oral doses of rifampin 600 mg (Days 8-17); serial blood samples were analyzed. RESULTS: Bosutinib exposures were reduced following concomitant administration of rifampin vs. bosutinib alone, measured by peak plasma concentration (C(max); 112 vs. 16.0 ng/mL; 86% reduction), total area under the concentration-time curve (AUC; 2740 vs. 207 ng.h/mL; 92% reduction), and AUC to the last measurable concentration at time T (2440 vs. 158 ng.h/mL; 94% reduction). Median time to C(max) and mean half life were shorter for bosutinib plus rifampin vs. single-agent bosutinib. Oral clearance increased approximately 13-fold; the volume of distribution increased from 9560 to 72,900 L. Treatment-emergent adverse events appeared less frequently with bosutinib plus rifampin (59%) vs. single-agent bosutinib (79%); diarrhea was reported in 11 (46%) vs. 4 (18%) subjects, respectively. CONCLUSIONS: Concomitant use of potent or moderate CYP3A inducers with bosutinib should be avoided because of the effects of drug-drug interaction observed between bosutinib and rifampin. PMID- 25803094 TI - Minor contribution of biliary excretion in lithium elimination in rats. AB - BACKGROUND: Lithium, which is often used for the treatment of bipolar disorders, is mainly recovered into urine after being orally administered. Due to the fact that it is completely absorbed via the gastrointestinal tract, it remains unknown whether biliary excretion is involved in the lithium disposition. In this study, we examined biliary excretion of lithium in rats and compared these with renal excretion. MATERIALS AND METHODS: After the injection of lithium chloride to femoral vein, plasma levels and excretion into urine and bile of lithium were evaluated. RESULTS: After its intravenous administration as a bolus, the plasma concentration of lithium decreased time-dependently. Until 60 min, 6.47% and 0.694% of injected lithium were excreted into urine and bile, respectively. The biliary clearance of lithium was calculated to be 0.0779 mL/min/kg, and this was 11.3% of the renal clearance. CONCLUSIONS: These findings suggest the low ability of the liver to eliminate lithium from plasma in comparison with the kidney in rats. PMID- 25803095 TI - Quantitative photoacoustics to measure single cell melanin production and nanoparticle attachment. AB - Photoacoustics can be used as a label-free spectroscopic method of identifying pigmented proteins and characterizing their intracellular concentration over time in a single living cell. The authors use a microscopic laser irradiation system with a 5 ns, Q-switched laser focused onto single cells in order to collect photoacoustic responses of melanoma cells from the HS936 cell line and gold nanoparticle labeled breast cancer cells from the T47D cell line. The volume averaged intracellular concentration of melanin is found to range from 29-270 mM for single melanoma cells and the number of gold nanoparticles (AuNP) is shown to range from 850-5900 AuNPs/cell. Additionally, the melanin production response to UV-A light stimulus is measured in four melanoma cells to find a mass production rate of 5.7 pg of melanin every 15 min. PMID- 25803096 TI - An effective support system of emergency medical services with tablet computers. AB - BACKGROUND: There were over 5,000,000 ambulance dispatches during 2010 in Japan, and the time for transportation has been increasing, it took over 37 minutes from dispatch to the hospitals. A way to reduce transportation time by ambulance is to shorten the time of searching for an appropriate facility/hospital during the prehospital phase. Although the information system of medical institutions and emergency medical service (EMS) was established in 2003 in Saga Prefecture, Japan, it has not been utilized efficiently. The Saga Prefectural Government renewed the previous system in an effort to make it the real-time support system that can efficiently manage emergency demand and acceptance for the first time in Japan in April 2011. OBJECTIVE: The objective of this study was to evaluate if the new system promotes efficient emergency transportation for critically ill patients and provides valuable epidemiological data. METHODS: The new system has provided both emergency personnel in the ambulance, or at the scene, and the medical staff in each hospital to be able to share up-to-date information about available hospitals by means of cloud computing. All 55 ambulances in Saga are equipped with tablet computers through third generation/long term evolution networks. When the emergency personnel arrive on the scene and discern the type of patient's illness, they can search for an appropriate facility/hospital with their tablet computer based on the patient's symptoms and available medical specialists. Data were collected prospectively over a three-year period from April 1, 2011 to March 31, 2013. RESULTS: The transportation time by ambulance in Saga was shortened for the first time since the statistics were first kept in 1999; the mean time was 34.3 minutes in 2010 (based on administrative statistics) and 33.9 minutes (95% CI 33.6-34.1) in 2011. The ratio of transportation to the tertiary care facilities in Saga has decreased by 3.12% from the year before, 32.7% in 2010 (regional average) and 29.58% (9085/30,709) in 2011. The system entry completion rate by the emergency personnel was 100.00% (93,110/93,110) and by the medical staff was 46.11% (14,159/30,709) to 47.57% (14,639/30,772) over a three-year period. Finally, the new system reduced the operational costs by 40,000,000 yen (about $400,000 US dollars) a year. CONCLUSIONS: The transportation time by ambulance was shorter following the implementation of the tablet computer in the current support system of EMS in Saga Prefecture, Japan. The cloud computing reduced the cost of the EMS system. PMID- 25803097 TI - The physics of proton therapy. AB - The physics of proton therapy has advanced considerably since it was proposed in 1946. Today analytical equations and numerical simulation methods are available to predict and characterize many aspects of proton therapy. This article reviews the basic aspects of the physics of proton therapy, including proton interaction mechanisms, proton transport calculations, the determination of dose from therapeutic and stray radiations, and shielding design. The article discusses underlying processes as well as selected practical experimental and theoretical methods. We conclude by briefly speculating on possible future areas of research of relevance to the physics of proton therapy. PMID- 25803098 TI - Selection pressure in CD8+ T-cell epitopes in the pol gene of HIV-1 infected individuals in Colombia. A bioinformatic approach. AB - One of the main characteristics of the human immunodeficiency virus is its genetic variability and rapid adaptation to changing environmental conditions. This variability, resulting from the lack of proofreading activity of the viral reverse transcriptase, generates mutations that could be fixed either by random genetic drift or by positive selection. Among the forces driving positive selection are antiretroviral therapy and CD8+ T-cells, the most important immune mechanism involved in viral control. Here, we describe mutations induced by these selective forces acting on the pol gene of HIV in a group of infected individuals. We used Maximum Likelihood analyses of the ratio of non-synonymous to synonymous mutations per site (dN/dS) to study the extent of positive selection in the protease and the reverse transcriptase, using 614 viral sequences from Colombian patients. We also performed computational approaches, docking and algorithmic analyses, to assess whether the positively selected mutations affected binding to the HLA molecules. We found 19 positively-selected codons in drug resistance-associated sites and 22 located within CD8+ T-cell epitopes. A high percentage of mutations in these epitopes has not been previously reported. According to the docking analyses only one of those mutations affected HLA binding. However, algorithmic methods predicted a decrease in the affinity for the HLA molecule in seven mutated peptides. The bioinformatics strategies described here are useful to identify putative positively selected mutations associated with immune escape but should be complemented with an experimental approach to define the impact of these mutations on the functional profile of the CD8+ T-cells. PMID- 25803100 TI - Both ERK1 and ERK2 are required for enterovirus 71 (EV71) efficient replication. AB - It has been demonstrated that MEK1, one of the two MEK isoforms in Raf-MEK-ERK1/2 pathway, is essential for successful EV71 propagation. However, the distinct function of ERK1 and ERK2 isoforms, the downstream kinases of MEKs, remains unclear in EV71 replication. In this study, specific ERK siRNAs and selective inhibitor U0126 were applied. Silencing specific ERK did not significantly impact on the EV71-caused biphasic activation of the other ERK isoform, suggesting the EV71-induced activations of ERK1 and ERK2 were non-discriminative and independent to one another. Knockdown of either ERK1 or ERK2 markedly impaired progeny EV71 propagation (both by more than 90%), progeny viral RNA amplification (either by about 30% to 40%) and protein synthesis (both by around 70%), indicating both ERK1 and ERK2 were critical and not interchangeable to EV71 propagation. Moreover, suppression of EV71 replication by inhibiting both early and late phases of ERK1/2 activation showed no significant difference from that of only blocking the late phase, supporting the late phase activation was more importantly responsible for EV71 life cycle. Taken together, this study for the first time identified both ERK1 and ERK2 were required for EV71 efficient replication and further verified the important role of MEK1-ERK1/2 in EV71 replication. PMID- 25803102 TI - Correction Factors for Photocell Sprint Timing With Flying Start. AB - PURPOSE: A review of published studies monitoring sprint performance reveals considerable variation in start distance behind the initial timing gate. The aim of the current study was to generate correction factors across varying flying start distances used in sprint testing with photocells. METHODS: Forty-four well trained junior soccer players (age 18.2 +/- 1.0 y, height 175 +/- 8 cm, body mass 68.4 +/- 8.9 kg) performed sprint testing on an indoor sprint track. They were allocated to 3 groups based on sprint-performance level. Times for 10- and 200-m sprint with foot placement ranging from 0.5 to 15 m back from the initial timing gate were recorded twice for each athlete. RESULTS: Correction-factor equation coefficients were generated for each of the 3 analyzed groups derived from the phase-decay equation y = (y0 - PL) * exp(-k * x) + PL, where y = time difference (0.5-m flying start as reference), x = flying-start distance, y0 is the y value when time is zero, PL (plateau) is the y value at infinite times, and k is the rate constant, expressed in reciprocal of the x-axis time units; if x is in seconds, then k is expressed in inverse seconds. R2 was >=.998 across all athlete groups and sprint distances, demonstrating excellent goodness of fit. Within group time differences were significant (P < .05) across all flying-start distance checkpoints for all groups. Between-groups time-saving differences up to 0.04 s were observed between the fastest and the slowest groups (P < .05). CONCLUSIONS: Small changes in flying-start distances can cause time differences larger than the typical gains made from specific training, or even the difference between the fastest and slowest elite team-sport athletes. The presented correction factors should facilitate more meaningful comparisons of published sprint-performance results. PMID- 25803099 TI - Human papillomavirus and tonsillar and base of tongue cancer. AB - In 2007, human papillomavirus (HPV) type 16 was recognized as a risk factor by the International Agency for Research on Cancer, for oropharyngeal squamous cell carcinoma (OSCC), where tonsillar and base of tongue cancer (TSCC and BOTSCC) dominate. Furthermore, patients with HPV-positive TSCC and BOTSCC, had a much better clinical outcome than those with corresponding HPV-negative cancer and other head and neck cancer. More specifically, survival was around 80% for HPV positive TSCC and BOTSCC vs. 40% five-year disease free survival, for the corresponding HPV-negative tumors with conventional radiotherapy and surgery, while this could not be observed for HPV-positive OSCC at other sites. In addition, the past 20-40 years in many Western Countries, the incidence of HPV positive TSCC and BOTSCC has risen, and >70% are men. This has resulted in a relative increase of patients with HPV-positive TSCC and BOTSCC that may not need the intensified chemo-radiotherapy (with many more severe debilitating side effects) often given today to patients with head and neck cancer. However, before tapering therapy, one needs to enable selection of patients for such treatment, by identifying clinical and molecular markers that together with HPV-positive status will better predict patient prognosis and response to therapy. To conclude, there is a new increasing group of patients with HPV-positive TSCC and BOTSCC with good clinical outcome, where options for better-tailored therapy are needed. For prevention, it would be of benefit to vaccinate both girls and boys against HPV16 infection. For potential future screening the ways to do so need optimizing. PMID- 25803101 TI - Changes of CD4+CD25+ cells ratio in immune organs from chickens challenged with infectious bursal disease virus strains with varying virulences. AB - In the current study, we investigate changes in CD4+CD25+ cells in chickens during infectious bursal disease virus (IBDV) infection. The percentage of CD4+CD25+ cells in lymph organs, e.g., the thymus, spleen, bursa of Fabricius and peripheral blood, during the first 1-5 days post infection (dpi) was assessed by flow cytometry. The data revealed a remarkable decrease in the percentage of CD4+CD25+ cells in the thymus from 1 to 5 dpi and in the spleen during early infection. An increase of the percentage of CD4+CD25+ cells among peripheral blood lymphocytes was observed during the first two days of IBDV infection. Additionally, CD4+CD25+ cells infiltrated the bursa along with CD4+ cells after IBDV infection. Quantitative reverse transcription polymerase chain reaction (qRT PCR) was used to measure the mRNA levels of immune-related cytokines in IBDV infected thymus and bursa of Fabricius tissues. The data revealed that IBDV caused a significant increase in interleukin (IL)-10 mRNA levels, with the Harbin 1 strain (vvIBDV) inducing higher IL-10 expression than the Ts strain. Taken together, our data suggest that chicken CD4+CD25+ cells may participate in IBDV pathogenicity by migrating from their sites of origin and storage, the thymus and spleen, to the virally targeted bursa of Fabricius during IBDV infection. PMID- 25803104 TI - Wilson's disease: a comprehensive review of the molecular mechanisms. AB - Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches. PMID- 25803105 TI - Primary biliary cirrhosis is a generalized autoimmune epithelitis. AB - Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice. PMID- 25803106 TI - Cholinergic transactivation of the EGFR in HaCaT keratinocytes stimulates a flotillin-1 dependent MAPK-mediated transcriptional response. AB - Acetylcholine and its receptors regulate numerous cellular processes in keratinocytes and other non-neuronal cells. Muscarinic acetylcholine receptors are capable of transactivating the epidermal growth factor receptor (EGFR) and, downstream thereof, the mitogen-activated protein kinase (MAPK) cascade, which in turn regulates transcription of genes involved in cell proliferation and migration. We here show that cholinergic stimulation of human HaCaT keratinocytes results in increased transcription of matrix metalloproteinase MMP-3 as well as several ligands of the epidermal growth factor family. Since both metalloproteinases and the said ligands are involved in the transactivation of the EGFR, this transcriptional upregulation may provide a positive feed-forward loop for EGFR/MAPK activation. We here also show that the cholinergic EGFR and MAPK activation and the upregulation of MMP-3 and EGF-like ligands are dependent on the expression of flotillin-1 which we have previously shown to be a regulator of MAPK signaling. PMID- 25803107 TI - High-resolution chromosome ideogram representation of currently recognized genes for autism spectrum disorders. AB - Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors to access convenient visual images of the location and distribution of ASD genes. Meaningful correlations of the observed phenotype in patients with suspected/confirmed ASD gene(s) at the chromosome region or breakpoint band site can be made to inform diagnosis and gene-based personalized care and provide genetic counselling for families. PMID- 25803110 TI - Effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease. A systematic review. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from breathlessness, deconditioning, and reduced health-related quality of life (HRQL) despite best medical management. Opioids may relieve breathlessness at rest and on exertion in COPD. OBJECTIVES: We aimed to estimate the efficacy and safety of opioids on refractory breathlessness, exercise capacity, and HRQL in COPD. METHODS: This was a systematic review and metaanalysis using Cochrane methodology. We searched Cochrane Central Register of Controlled Trials, MEDLINE, and Embase up to 8 September, 2014 for randomized, double-blind, placebo controlled trials of any opioid for breathlessness, exercise capacity, or HRQL that included at least one participant with COPD. Effects were analyzed as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random effect models. MEASUREMENTS AND MAIN RESULTS: A total of 16 studies (15 crossover trials and 1 parallel-group study, 271 participants, 95% with severe COPD) were included. There were no serious adverse effects. Breathlessness was reduced by opioids overall: SMD, -0.35 (95% CI, -0.53 to -0.17; I(2), 48.9%), by systemic opioids (eight studies, 118 participants): SMD, -0.34 (95% CI, -0.58 to 0.10; I(2), 0%), and less consistently by nebulized opioids (four studies, 82 participants): SMD, -0.39 (95% CI, -0.71 to -0.07; I(2), 78.9%). The quality of evidence was moderate for systemic opioids and low for nebulized opioids on breathlessness. Opioids did not affect exercise capacity (13 studies, 149 participants): SMD, 0.06 (95% CI, -0.15 to 0.28; I(2), 70.7%). HRQL could not be analyzed. Findings were robust in sensitivity analyses. Risk of study bias was low or unclear. CONCLUSIONS: Opioids improved breathlessness but not exercise capacity in severe COPD. PMID- 25803111 TI - [The labour climate in the area of justice as a basis for behavioural change in offenders]. PMID- 25803108 TI - Favourable IFNL3 genotypes are associated with spontaneous clearance and are differentially distributed in Aboriginals in Canadian HIV-hepatitis C co-infected individuals. AB - Canadian Aboriginals are reported to clear Hepatitis C (HCV) more frequently. We tested the association of spontaneous clearance and three single nucleotide polymorphisms (SNPs) near the Interferon-lambda 3 (IFNL3) gene (rs12979860, rs8099917, functional variant rs8103142) and compared the SNP frequencies between HIV-HCV co-infected whites and Aboriginals from the Canadian Co-infection Cohort. HCV treatment-naive individuals with at least two HCV RNA tests were included (n = 538). A spontaneous clearance case was defined as someone with two consecutive HCV RNA-negative tests, at least six months apart. Data were analyzed using Cox proportional hazards adjusted for sex and ethnicity. Advantageous variants and haplotypes were more common in Aboriginals than Caucasians: 57% vs. 46% had the rs12979860 CC genotype, respectively; 58% vs. 48%, rs8103142 TT; 74% vs. 67%, the rs12979860 C allele; and 67% vs. 64% the TCT haplotype with three favourable alleles. The adjusted Hazard Ratios (95% CI) for spontaneous clearance were: rs12979860: 3.80 (2.20, 6.54); rs8099917: 5.14 (2.46, 10.72); and rs8103142: 4.36 (2.49, 7.62). Even after adjusting for rs12979860, Aboriginals and females cleared HCV more often, HR (95% CI) = 1.53 (0.89, 2.61) and 1.42 (0.79, 2.53), respectively. Our results suggest that favourable IFNL3 genotypes are more common among Aboriginals than Caucasians, and may partly explain the higher HCV clearance rates seen among Aboriginals. PMID- 25803112 TI - [Extrapulmonary tuberculosis]. AB - Up to 25% of tuberculosis cases present extrapulmonary involvement. This is produced by haematogenous and lymphatic spread of the M. tuberculosis bacillus to other organs. The most common locations are the lymph nodes, pleura and the osteoarticular system. The problem with these types of tuberculosis is the difficulty in establishing a definitive diagnosis, since the clinical symptoms and results of imaging tests may be vague. It is often necessary to resort to invasive diagnostic testing such as ultrasound or CAT-guided FNAB, used to collect biological samples for diagnosis. Despite the growing use of and advances in recent years of molecular methods for early detection of mycobacteria DNA, cultures continue to be the gold standard that enable a firm microbiological diagnosis to be made. Treatment for these types of tuberculosis do not differ from treatment regimens for pulmonary forms of the same disease. The same antibiotic regimens for 6 months are recommended, and any extension of this period is advisable solely in tuberculosis affecting the central nervous system and in Pott's disease. PMID- 25803109 TI - Recent developments of engineered translational machineries for the incorporation of non-canonical amino acids into polypeptides. AB - Genetic code expansion and reprogramming methodologies allow us to incorporate non-canonical amino acids (ncAAs) bearing various functional groups, such as fluorescent groups, bioorthogonal functional groups, and post-translational modifications, into a desired position or multiple positions in polypeptides both in vitro and in vivo. In order to efficiently incorporate a wide range of ncAAs, several methodologies have been developed, such as orthogonal aminoacyl-tRNA synthetase (AARS)-tRNA pairs, aminoacylation ribozymes, frame-shift suppression of quadruplet codons, and engineered ribosomes. More recently, it has been reported that an engineered translation system specifically utilizes an artificially built genetic code and functions orthogonally to naturally occurring counterpart. In this review we summarize recent advances in the field of ribosomal polypeptide synthesis containing ncAAs. PMID- 25803113 TI - [Laboral health in Penitentiary Center of Chile: a look from policies of human resources]. AB - This article examines the influence of human resources policies on occupational health variables, such as engagement and job satisfaction, with regard to Chilean prison employees. 80 workers at the Women's Prison of Iquique were evaluated and results show that 77% and 88 % have a moderate to high score in terms of engagement and job satisfaction respectively. The 24% variation in engagement of the workers studied can be explained by policies aimed at promoting personal interests, while 32% of the variation in job satisfaction could be explained by policies of self-efficacy and personal interests. The above data permits the assertion to be made that human resources policies have a role that is relevant and necessary to modify and improve the occupational health conditions of these public sector workers. PMID- 25803115 TI - [The management committee of the 10th Congress on Prison Health in Barcelona]. PMID- 25803114 TI - [Obesity and anthropometric indicators in a sample of males with Acute Coronary Syndrome in a health area with inclusion of inmates: case-control study]. AB - OBJECTIVES: Obesity is a cardiovascular risk factor with a high epidemic burden on ischemic heart disease. The aim of this study was to analyze the anthropometric indicators of obesity in a sample of males who have had an Acute Coronary Syndrome (ACS) diagnosed in a prison referral hospital, and a control group. MATERIAL AND METHODS: Cross-sectional case-control study in a Health Area with inclusion of a penitentiary center. The participants in this study were 204 males, 102 cases and one control selected for each case (n=102). We measured weight, height waist circumference (WC), umbilical waist (UW) and hip circumference. We calculated body mass index (BMI) and other anthropometric indicators: waist to-hip-ratios (WHR and UWHR), waist to-height-ratios (WHtR and UWHtR). We obtained the areas under the receiver operating characteristic curves (AUC), the odds ratio (OR) and the correlations in the infarcted people. RESULTS: Obesity was more prevalent in ACS (31.4% vs 9.1%; OR: 4.7). Other indicators show a discriminatory association. BMI (AUC: 0.699; OR: 3.9), WC (AUC: 0.750; OR: 6.3), UW (AUC: 0.777; OR: 10), inverse height (AUC: 0.619; OR: 2.1), WHR (AUC: 0.832; OR: 11.6); UWHR (AUC: 0.857; OR: 15.6), UWHtR (AUC: 0.800; OR: 8.9). In ACS the correlations for both WC and UW with waist to-height-ratios (WHtR and UWHtR) were strong (all r >=0.90; p < 0.001). DISCUSSION: The anthropometric indicators of obesity are clearly associated with ACS. UW is the simple measurement with the best association. BMI is most weakly associated. UWHtR presents high discriminatory power and the best anthropometric correlation of risk that supports its use for the identification of males at risk of myocardial infarction in the general population and prison. PMID- 25803116 TI - [Reply to the letter of director: a concerning the management committee of the 10th Congress on Prison Health in Barcelona]. PMID- 25803117 TI - [A case of self harm in a psychotic patient]. PMID- 25803118 TI - Short-term and Long-term Postoperative Safety of Off-Pump versus On-Pump Coronary Artery Bypass Grafting for Coronary Heart Disease: A Meta-analysis for Randomized Controlled Trials. AB - OBJECTIVE: The aim was to compare the short-term (30 days after surgery) and long term (over 6 months' follow-up) postoperative safety of off-pump and on-pump coronary artery bypass grafting (CABG) for patients with coronary heart disease (CHD). METHODS: Relevant randomized controlled trials (RCTs) were obtained from PubMed, Embase, Springer, Ovid, and Cochrane library up to July 2013. Odds ratios (ORs) with their 95% confidence intervals (CIs) were used to access effect sizes. RESULTS: Seven RCTs involving 9,128 patients were included. Results suggested no significant difference in all the short-term outcomes (mortality, OR = 0.90, 95% CI: 0.69 to 1.16, p = 0.41; myocardial infarction, OR = 0.95, 95% CI: 0.79 to 1.15, p = 0.61; stroke, OR = 0.78, 95% CI: 0.56 to 1.07, p = 0.12; renal failure, OR = 0.84, 95% CI: 0.60 to 1.18, p = 0.43; revascularization: OR = 1.95, 95% CI: 0.79 to 4.85, p = 0.15) and some long-term outcomes (mortality, OR = 1.02, 95% CI: 0.86 to 1.22, p = 0.81; myocardial infarction, OR = 0.86, 95% CI: 0.70 to 1.04, p = 0.12; stroke, OR = 0.89, 95% CI: 0.67 to 1.19, p = 0.44) between off pump and on-pump CABG. However, off-pump CABG had a significantly higher revascularization rate (OR = 1.45; 95% CI: 1.02 to 2.06; p = 0.04) than on-pump CABG in long-term follow-up. CONCLUSION: Short-term postoperative safety was similar between off-pump and on-pump CABG. A high revascularization rate was the drawback of off-pump CABG for CHD patients in long-term follow-up. PMID- 25803119 TI - Conversion to Total Cavopulmonary Connection Improves Functional Status Even in Older Patients with Failing Fontan Circulation. AB - BACKGROUND: Facing longer follow-up of patients after Fontan operation, Fontan conversion was proposed to treat failing Fontan circulation. We reviewed our patients who reached up to 42 years of age. METHODS: Fifteen consecutive patients underwent Fontan conversion to extracardiac conduit combined with biatrial maze procedure between October 2006 and January 2014. Mean age at conversion was 30.9 +/- 5.6 years and mean interval from primary Fontan palliation to conversion was 23.2 +/- 3.3 years. RESULTS: There was one early death. Ten of 14 survivors were extubated within 24 hours, and 11 were discharged from intensive care unit (ICU) within 7 days. The impaired left ventricular function, presented in four patients prior to surgery, improved from EF 43.8 to 54.8% (p = 0.02). During follow-up time of 3.6 +/- 2.3 years after conversion, there was no late death and no reoperation. Two patients developed recurrent atrial arrhythmia. Older age at Fontan procedure, lower left ventricular function, higher New York Heart Association (NYHA) class, and anatomy other than tricuspid atresia emerged as risk factors for longer ICU stay. CONCLUSION: Fontan conversion improved the functional status in almost all patients. A concomitant maze procedure effectively eliminated atrial arrhythmia. This procedure provides a benefit even for older patients if all additional cardiac pathologies are addressed. PMID- 25803120 TI - Retrograde Autologous Priming as a Safe and Easy Method to Reduce Hemodilution and Transfusion Requirements during Cardiac Surgery. AB - BACKGROUND: During the last decades many efforts have been made to reduce transfusion requirements and adverse clinical effects during cardiopulmonary bypass (CPB). The minimal extracorporeal circulation (MECC) system and the technique of retrograde autologous priming (RAP) of a conventional CPB circuit have been associated with decreased hemodilution. Our study aimed to compare conventional CPB (cCPB), RAP, and the ROCsafe MECC (Terumo Europe N.V., Leuven, Belgium) system in elective coronary artery bypass patients. PATIENTS AND METHODS: Data were retrospectively collected on three cohorts of 30 adult CPB patients. Patients were operated using cCPB, RAP, and the ROCsafe MECC system. RESULTS: The three groups were comparable in demographic data. The priming volume in the ROCsafe and RAP group was significantly less compared with the conventional priming group (p <0.05). The mean time of extracorporeal circulation and aortic cross-clamp time (p <0.05) were significantly shorter in the ROCsafe group. The levels of hemoglobin (Hb) and hematocrit (Hct) during CPB and postoperatively showed significant differences between the three groups (p < 0.05) and resulted in significantly higher blood transfusion requirements (p < 0.05). Lactate, serum creatinine, troponin, and creatine kinase-myocardial band (CK-MB) levels did not differ significantly among the three groups (p >0.05). There was also no statistically significant difference in ventilation time, intensive care unit (ICU) stay, overall hospital stay, and postoperative complications (p >0.05). CONCLUSION: In conclusion, RAP is compared with cCPB and MECC a safe and low-cost technique in reducing the priming volume of the CPB system, causes less hemodilution, and reduces the need for intra- and postoperative blood transfusion. PMID- 25803121 TI - Significant human impact on the flux and delta(34)S of sulfate from the largest river in North America. AB - Riverine dissolved sulfate (SO4(2-)) flux and sulfur stable isotope composition (delta(34)S) yield information on the sources and processes affecting sulfur cycling on different spatial and temporal scales. However, because pristine preindustrial natural baselines of riverine SO4(2-) flux and delta(34)S cannot be directly measured, anthropogenic impact remains largely unconstrained. Here we quantify natural and anthropogenic SO4(2-) flux and delta(34)S for North America's largest river, the Mississippi, by means of an exhaustive source compilation and multiyear monitoring. Our data and analysis show that, since before industrialization to the present, Mississippi River SO4(2-) has increased in flux from 7.0 to 27.8 Tg SO4(2-) yr(-1), and in mean delta(34)S from -5.00/00, within 95% confidence limits of -14.80/00 to 4.10/00 (assuming normal distribution for mixing model input parameters), to -2.7 +/- 1.60/00, reflecting an impressive footprint of bedrocks particular to this river basin and human activities. Our first-order modern Mississippi River sulfate partition is 25 +/- 6% natural and 75% +/- 6% anthropogenic sources. Furthermore, anthropogenic coal usage is implicated as the dominant source of modern Mississippi River sulfate, with an estimated 47 +/- 5% and 13% of total Mississippi River sulfate due to coal mining and burning, respectively. PMID- 25803122 TI - Controlling the ionic current rectification factor of a nanofluidic/microfluidic interface with symmetric nanocapillary interconnects. AB - The current rectification factor can be tailored by changing the degree of asymmetry between the fluid baths on opposite sides of a nanocapillary membrane (NCM). A symmetric device with symmetric fluid baths connected to opposite sides of the NCM did not rectify ionic current; while a NCM connected between fluid baths with a 32-fold difference in cross-sectional area produced a rectification factor of 75. The data suggests that the primary mechanism for the current rectification is the change in cross-sectional area of the fluid baths and the polarity dependent propagation of the enriched and depleted concentration polarization (CP) zones into these regions. An additional contribution to the increasing rectification factor with increasing bath asymmetry appears to be a result of electroconvection in the macropore, with inside diameters (IDs) of 625 and 850-MUm. Power spectral density (PSD) analysis reveals chaotic oscillations that are consistent with electroconvection in the I-t data of the 625 and 850-MUm ID macropore devices. In the ON state, current rectification keeps ionic transport toward the NCM high, increasing the speed of processes like sample enrichment. A simple means is provided to fabricate fluidic diodes with tailored current rectification factors. PMID- 25803123 TI - 1,1/1,2 Isomerisation in Lewis base adducts of B2cat2. AB - Reaction of bis-catecholatodiborane and 1 or 2 equivalents of 1,5 diazabicyclo[4.3.0]non-5-ene or 4-picoline yields Lewis acid-base adducts. Recrystallisation enabled identification of an unexpected isomerisation from the 1,1-isomer to the 1,2-isomer. This observation was probed computationally with significantly different dipole moments calculated for the two effectively isoenergetic isomeric forms. PMID- 25803124 TI - Current State and Future Challenges of Mass Spectrometry Imaging for Clinical Research. AB - The ability of mass spectrometry imaging (MSI) to localize panels of biomolecules in tissues, without prior knowledge of their presence and in a label-free manner, has led to a rapid and substantial impact in clinical and pharmacological research, uncovering biomolecular changes associated with disease and providing low cost imaging of pharmaceuticals. This Feature article will give an introduction to the capabilities and role of MSI in the clinical analysis of patient tissues and discusses those improvements that are necessary for the progression of MSI toward routine clinical application. PMID- 25803125 TI - Correction to "Reversible interconversion of CO2 and formate by a molybdenum containing formate dehydrogenase". PMID- 25803127 TI - Direct evidence for secondary interactions in planar and nonplanar aromatic pi conjugates and their photophysical characteristics in solid-state assemblies. AB - Direct evidence for non-covalent secondary interactions in planar and nonplanar aromatic pi-conjugates and their solid-state assemblies is established. A series of horizontally, vertically, and radially expanded oligo(phenylenevinylene)s (H OPVs, V-OPVs, and R-OPVs, respectively) were designed with a fixed pi-core and variable alkyl chain lengths on the periphery. Single-crystal structures of the OPVs were resolved to trace the secondary interactions that direct the solid state self-organization and molecular packing of the chromophores. The H-OPVs were found to be planar, and they did not show any secondary interactions in the crystal lattices. The V-OPVs and R-OPVs were found to be nonplanar and to exhibit multiple CH/pi hydrogen-bonding interactions among aryl hydrogen donors and acceptors. The enthalpies of the melting and crystallization transitions revealed that the planar H-OPVs are highly crystalline compared with the nonplanar R-OPVs and V-OPVs. Polarized light microscopy studies revealed the formation of one dimensional nematic mesophases in H-OPVs. The absolute solid-state photoluminescence quantum yields (PLQYs) of the OPVs were determined using an integrating sphere setup. The highly packed H-OPVs showed low PLQYs compared with those of the weakly packed V-OPVs and R-OPVs. Time-resolved fluorescence decay measurements revealed that the excited-state decay dynamics of highly packed H OPVs was much faster with respect to their low PLQYs. The decay profiles were found to be relatively slow (with higher life time (tau)) in the V-OPVs and R OPVs. A field-effect transistor (FET) device was constructed for an OPV sample that showed a hole carrier mobility in the range of 10(-5) cm(2) V(-1) s(-1). The present investigation thus provides a new opportunity to trace the role of secondary interactions on pi-conjugated mesophase self-assemblies and their solid state emission and FET devices, more specifically based on OPV chromophores. PMID- 25803126 TI - Product Formation by the Promiscuous Lanthipeptide Synthetase ProcM is under Kinetic Control. AB - Lanthipeptides are natural products that belong to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs). They contain characteristic lanthionine (Lan) or methyllanthionine (MeLan) structures that contribute to their diverse biological activities. Despite its structurally diverse set of 30 substrates, the highly substrate-tolerant lanthipeptide synthetase ProcM is shown to display high selectivity for formation of a single product from selected substrates. Mutation of the active site zinc ligands to alanine or the unique zinc ligand Cys971 to histidine resulted in a decrease of the cyclization rate, especially for the second cyclization of the substrates ProcA1.1, ProcA2.8, and ProcA3.3. Surprisingly, for ProcA3.3 these mutations also altered the regioselectivity of cyclization resulting in a new major product. ProcM was not able to correct the ring topology of incorrectly cyclized intermediates and products, suggesting that thermodynamic control is not operational. Collectively, the data in this study suggest that the high regioselectivity of product formation is governed by the selectivity of the initially formed ring. PMID- 25803128 TI - Asymmetric Robinson-type annulation reaction between beta-ketoamides and alpha,beta-unsaturated ketones. AB - Enantioselective Robinson-type annulation reaction between beta-ketoamide and alpha,beta-unsaturated ketone was developed by utilizing the amino acid derived primary-secondary diamine catalysts. The less reactive acyclic beta-ketoamides employed as both electrophile and nucleophile are reported in this asymmetric tandem reaction. A number of chiral cyclohexenone derivatives containing an amide group were obtained in high yields and good selectivities. PMID- 25803129 TI - Effects of caffeic and 5-caffeoylquinic acids on cell viability and cellular uptake in human colon adenocarcinoma cells. AB - Colorectal cancer is a major cause of morbidity and mortality throughout the world. Issues related to the role of diet in cancer prevention and treatment are featured each year, and, in this context, consumption of hydroxycinanmic acids is associated with reduced risk of chronic diseases including cancer. Therefore, the aim of this study was to evaluate the cellular uptake of caffeic and 5 caffeoylquinic acids and their effects on cell viability, cell cycle, and apoptosis in human colon adenocarcinoma cells (HT-29). HT-29 cells were incubated with different concentrations of caffeic and 5-caffeoylquinic acids (1.25 uM to 80.0 uM) from 0.5 to 96 h. Cellular uptake was analyzed by HPLC and LCMS. Cell viability, cell cycle, and apoptosis was measured, respectively, using MTT method and flow cytometry. Caffeic and 5-caffeoylquinic acids are absorbed, isomerized, and metabolized by HT-29 cells. Both compounds were able to reduce HT-29 cell viability, promoting specific changes in the cell cycle and increased the apoptosis rate. Caffeic acid and 5-caffeoylquinic acid showed inhibitory effects on cell growth, suggesting a modulation of the cell cycle with an increase in apoptosis in human colon adenocarcinoma cells. PMID- 25803130 TI - Sulfido and cysteine ligation changes at the molybdenum cofactor during substrate conversion by formate dehydrogenase (FDH) from Rhodobacter capsulatus. AB - Formate dehydrogenase (FDH) enzymes are attractive catalysts for potential carbon dioxide conversion applications. The FDH from Rhodobacter capsulatus (RcFDH) binds a bis-molybdopterin-guanine-dinucleotide (bis-MGD) cofactor, facilitating reversible formate (HCOO(-)) to CO2 oxidation. We characterized the molecular structure of the active site of wildtype RcFDH and protein variants using X-ray absorption spectroscopy (XAS) at the Mo K-edge. This approach has revealed concomitant binding of a sulfido ligand (Mo=S) and a conserved cysteine residue (S(Cys386)) to Mo(VI) in the active oxidized molybdenum cofactor (Moco), retention of such a coordination motif at Mo(V) in a chemically reduced enzyme, and replacement of only the S(Cys386) ligand by an oxygen of formate upon Mo(IV) formation. The lack of a Mo=S bond in RcFDH expressed in the absence of FdsC implies specific metal sulfuration by this bis-MGD binding chaperone. This process still functioned in the Cys386Ser variant, showing no Mo-S(Cys386) ligand, but retaining a Mo=S bond. The C386S variant and the protein expressed without FdsC were inactive in formate oxidation, supporting that both Mo-ligands are essential for catalysis. Low-pH inhibition of RcFDH was attributed to protonation at the conserved His387, supported by the enhanced activity of the His387Met variant at low pH, whereas inactive cofactor species showed sulfido-to oxo group exchange at the Mo ion. Our results support that the sulfido and S(Cys386) ligands at Mo and a hydrogen-bonded network including His387 are crucial for positioning, deprotonation, and oxidation of formate during the reaction cycle of RcFDH. PMID- 25803131 TI - Differential regulation of autophagy and cell viability by ceramide species. AB - The present studies sought to determine whether the anti-folate pemetrexed (Alimta) and the sphingosine-1-phosphate receptor modulator FTY720 (Fingolimod, Gilenya) interacted to kill tumor cells. FTY720 and pemetrexed interacted in a greater than additive fashion to kill breast, brain and colorectal cancer cells. Loss of p53 function weakly enhanced the toxicity of FTY720 whereas deletion of activated RAS strongly or expression of catalytically inactive AKT facilitated killing. Combined drug exposure reduced the activity of AKT, p70 S6K and mTOR and activated JNK and p38 MAPK. Expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the interaction between FTY720 and pemetrexed. Treatment of cells with FTY720 and pemetrexed increased the numbers of early autophagosomes but not autolysosomes, which correlated with increased LC3II processing and increased p62 levels, suggestive of stalled autophagic flux. Knock down of ATG5 or Beclin1 suppressed autophagosome formation and cell killing. Knock down of ceramide synthase 6 suppressed autophagosome production and cell killing whereas knock down of ceramide synthase 2 enhanced vesicle formation and facilitated death. Collectively our findings argue that pemetrexed and FTY720 could be a novel adjunct modality for breast cancer treatment. PMID- 25803132 TI - Characteristics and viral propagation properties of a new human diploid cell line, Walvax-2, and its suitability as a candidate cell substrate for vaccine production. AB - Human diploid cell strains (HDCSs), possessing identical chromosome sets known to be free of all known adventitious agents, are of great use in developing human vaccines. However it is extremely difficult to obtain qualified HDCSs that can satisfy the requirements for the mass production of vaccines. We have developed a new HDCS, Walvax-2, which we derived from the lung tissue of a 3-month-old fetus. We established primary, master and working cell banks successfully from reconstituted frozen cells. Observations during the concurrent propagation of Walvax-2 and MRC-5 cells revealed differences in terms of growth rate, cell viability and viral sensitivities. Specifically, Walvax-2 cells replicated more rapidly than MRC-5 cells, with Walvax-2 cells attaining the same degree of confluence in 48 hours as was reached by MRC-5 cells in 72 hours. Moreover, Walvax-2 cells attained 58 passages of cell doublings whereas MRC-5 reached 48 passages during this period. We also assessed the susceptibility of these cells to rabies, hepatitis A, and Varicella viruses. Analysis of virus titers showed the Walvax-2 cells to be equal or superior to MRC-5 cells for cultivating these viruses. Furthermore, in order to characterize the Walvax-2 cell banks, a series of tests including cell identification, chromosomal characterization, tumorigenicity, as well as tests for the presence of microbial agents, exogenous viruses, and retroviruses, were conducted according to standard international protocols. In conclusion, results from this study show that Walvax-2 cell banks are a promising cell substrate and could potentially be used for the manufacturing of HDCVs. PMID- 25803133 TI - Predictive Analysis Between Topographic, Pachymetric and Wavefront Parameters in Keratoconus, Suspects and Normal Eyes: Creating Unified Equations to Evaluate Keratoconus. AB - PURPOSE: To perform prediction analysis between topographic, pachymetric and wavefront parameters in keratoconus, suspects, and normal cases and to look at the possibility of a unified equation to evaluate keratoconus. METHODS: This cross-sectional, observational study was done in cornea services of a specialty hospital. Fifty eyes of 50 candidates with a diagnosis of normal, keratoconus suspect, and keratoconus were included in each group (total 150 eyes). All eyes underwent detailed analysis on Scheimplug + Placido device (Sirius, CSO, Italy). Main parameters evaluated were topographic [maximum keratometry (Max Km), average keratometry and astigmatism at 3, 5, and 7 mm], pachymetric [central and minimum corneal thickness (MCT) and their difference, corneal volume] and corneal aberrations [higher order aberrations root-mean-square (HOARMS), coma, spherical, residual].Central tendency, predictive fits and regression models, were computed. RESULTS: The measured variables had a significant difference in mean between the three groups (Kruskal-Wallis, p < 0.001). Max Km, MCT, and HOARMS had significant fits with other topographic, pachymetric and wavefront parameters, respectively. Inter-relations between these three (Max Km, MCT, and HOARMS) were also stronger for keratoconus (R(2) from 0.75 to 0.33) compared to suspect/normal eyes (R(2) from 0.15 to 0.003). These three variables (Max Km, MCT and HOARMS) were used as representative variables to create the unified equations. The equation for the pooled data was (Kmax = 59.5 + 2.3 * HOARMS-0.03 * MCT; R(2)= 0.7, p < 0.001). CONCLUSIONS: Major variables used for grading keratoconus (MaxKm, MCT, HOARMS) can be linked by linear regression equations to predict the pathology's behavior. PMID- 25803134 TI - The CROES global percutaneous nephrolithotomy study revisited. PMID- 25803136 TI - Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale. AB - Patients with delirium may fail to respond to standard therapies. Sixteen patients with management-refractory hyperactive delirium responded to adjunctive valproic acid, with complete resolution of hyperactive delirium in 13 cases. A rationale for using valproic acid in such circumstances is discussed. PMID- 25803137 TI - High altitude medicine and biology in China. PMID- 25803135 TI - Prevalence of hereditary angioedema in untested first-degree blood relatives of known subjects with hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurring attacks of nonpruritic, nonpitting edema caused by an inherited deficiency or dysfunction of C1 esterase inhibitor (C1 INH). Symptoms can present years before an accurate diagnosis is made. The objective of this study, the Angioedema Clinical Epidemiology Testing Initiative for the Study of Hereditary Angioedema, was to determine the prevalence and clinical manifestations of HAE in untested first-degree blood relatives of known patients with HAE. Patients with a confirmed diagnosis of HAE recruited first-degree relatives who had not been evaluated for HAE. Enrolled subjects underwent complement testing (C4, C1 INH antigen, and functional C1 INH). If the lab tests were abnormal, the enrolled subjects returned to the site for a follow-up visit and questionnaire. Overall, 31 patients with HAE and 46 first-degree relatives enrolled in the study. Of 46 enrolled relatives, 30 (65%) had lab test results that ruled out a diagnosis of HAE, two (4%) were categorized as "HAE not ruled out," and 14 (30%) were newly diagnosed with HAE. Of 14 newly diagnosed subjects, nine (64%) reported having experienced symptoms that may have been related to HAE, such as swelling in the throat, face, or extremities or abdominal pain. When reported, median age of symptom onset in these 14 subjects was nine years whereas newly diagnosed asymptomatic subjects had a median chronological age of six years. These 14 subjects reported a historic mean standard deviation rate of 2.51 (5.59) swelling episodes per month with a mean standard deviation duration of 1.6 (0.74) days. This study's findings reinforce the importance of testing family members of patients with HAE to detect this hereditary condition. PMID- 25803140 TI - Exaggerated hypoxic pulmonary vasoconstriction without susceptibility to high altitude pulmonary edema. AB - BACKGROUND: Abnormally high pulmonary artery pressure (PAP) in hypoxia due to exaggerated hypoxic pulmonary vasoconstriction (HPV) is a key factor for development of high-altitude pulmonary edema (HAPE). It was shown that about 10% of a healthy Caucasian population has an exaggerated HPV that is comparable to the response measured in HAPE-susceptible individuals. Therefore, we hypothesized that those with exaggerated HPV are HAPE-susceptible. METHODS AND RESULTS: We screened 421 healthy Caucasians naive to high altitude for HPV using Doppler echocardiography for assessment of systolic PAP in normobaric hypoxia (PASPHx; Po2 corresponding to 4500 m). Subjects with exaggerated HPV and matched controls were exposed to 4559 m with an identical protocol that causes HAPE in 62% of HAPE S. Screening revealed 39 subjects with exaggerated HPV, of whom 33 (PASPHx 51+/-6 mmHg) ascended within 24 hours to 4559 m. Four (13%) of them developed HAPE during the 48 h-stay. This incidence is significantly lower than the recurrence rate of 62% previously observed in HAPE-S in the same setting. None of the control subjects (PASPHx 33+/-5 mmHg) developed HAPE. CONCLUSION: An exaggerated HPV cannot be considered a surrogate maker for HAPE-susceptibility although excessively elevated PAP is a hallmark in HAPE, while a normal HPV appears to protect from HAPE in this study. PMID- 25803142 TI - Acute normobaric hypoxia reduces body temperature in humans. AB - Anapyrexia is the regulated decrease in body temperature during acute exposure to hypoxia. This study examined resting rectal temperature (Trec) in adult humans during acute normobaric hypoxia (NH). Ten subjects breathed air consisting of 21% (NN), 14% (NH14), and 12% oxygen (NH12) for 30 min each in thermoneutral conditions while Trec and blood oxygen saturation (Spo2) were measured. Linear regression indicated that Spo2 was progressively lower in NH14 (p=0.0001) and NH12 (p=0.0001) compared to NN, and that Spo2 in NH14 was different than NH12 (p=0.00001). Trec was progressively lower during NH14 (p=0.014) and in NH12 (p=0.0001) compared to NN. The difference in Trec between NH14 and NH12 was also significant (p=0.0287). Spo2 was a significant predictor of Trec such that for every 1% decrease in Spo2, Trec decreased by 0.15 degrees C (p=0.0001). The present study confirmed that, similar to many other species, human adults respond to acute hypoxia exposure by lowering rectal temperature. PMID- 25803144 TI - Longest survival in a crevasse. PMID- 25803145 TI - Reciprocity in computer-human interaction: source-based, norm-based, and affect based explanations. AB - Individuals often apply social rules when they interact with computers, and this is known as the Computers Are Social Actors (CASA) effect. Following previous work, one approach to understand the mechanism responsible for CASA is to utilize computer agents and have the agents attempt to gain human compliance (e.g., completing a pattern recognition task). The current study focuses on three key factors frequently cited to influence traditional notions of compliance: evaluations toward the source (competence and warmth), normative influence (reciprocity), and affective influence (mood). Structural equation modeling assessed the effects of these factors on human compliance with computer request. The final model shows that norm-based influence (reciprocity) increased the likelihood of compliance, while evaluations toward the computer agent did not significantly influence compliance. PMID- 25803141 TI - Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not in males. AB - Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lower rat brain serotonin levels, and impair brain bioenergetics in both humans and rats. We therefore examined the effect of hypobaric hypoxia on depression-like behavior in rats. After a week of housing at simulated altitudes of 20,000 ft, 10,000 ft, or sea level, or at local conditions of 4500 ft (Salt Lake City, UT), Sprague Dawley rats were tested for depression like behavior in the forced swim test (FST). Time spent swimming, climbing, or immobile, and latency to immobility were measured. Female rats housed at altitude display more depression-like behavior in the FST, with significantly more immobility, less swimming, and lower latency to immobility than those at sea level. In contrast, males in all four altitude groups were similar in their FST behavior. Locomotor behavior in the open field test did not change with altitude, thus validating immobility in the FST as depression-like behavior. Hypobaric hypoxia exposure therefore induces depression-like behavior in female rats, but not in males. PMID- 25803143 TI - Diffuse alveolar hemorrhage from systemic lupus erythematosus misdiagnosed as high altitude pulmonary edema. AB - A 26-year-old woman presented with dyspnea and dry cough soon after arriving on the Qinghai-Tibet Plateau (3650 m). Chest radiograph showed diffuse patchy infiltrates. The initial diagnosis was high altitude pulmonary edema (HAPE). However, the patient had no sputum or moist rales, and supplemental oxygen and intravenous aminophylline produced no improvement. Chest HRCT revealed symmetric and diffuse ground glass opacities. Further examination found anemia, leukopenia, urine abnormalities, and increased erythrocyte sedimentation rate. Antibodies for ds-DNA and ANA were positive. Hemoptysis and arthralgia developed after a few days. Finally the patient was diagnosed with diffuse alveolar hemorrhage secondary to systemic lupus erythemetosus. CONCLUSION: When considering a diagnosis of HAPE, careful attention to physical signs, and a clinical course that is atypical for HAPE should prompt evaluation for other disease processes; HRCT can be useful in this setting. PMID- 25803147 TI - The nasal cycle and age. AB - CONCLUSION: The reciprocal nature of the nasal cycle declined with age in keeping with other published data, suggesting that studies of the nasal cycle may be a useful measure of central nervous system (CNS) disease and aging. OBJECTIVES: The aim of this study was to investigate changes in the nasal cycle with age. METHODS: In one male subject changes in nasal airflow were measured by anterior rhinomanometry to determine the reciprocal nature of the 'nasal cycle' at age 28 and again at age 66 years. RESULTS: Significant reciprocity was demonstrated in the historical study (age 28 years) with correlation coefficients for the 3 study days of -0.81, -0.83 and -0.79. compared with the current study (age 66 years) where non-significant correlation coefficients of 0.02 and -0.43 were obtained. PMID- 25803148 TI - Highly efficient electron transport obtained by doping PCBM with graphdiyne in planar-heterojunction perovskite solar cells. AB - Organic-inorganic perovskite solar cells have recently emerged at the forefront of photovoltaics research. Here, for the first time, graphdiyne (GD), a novel two dimension carbon material, is doped into PCBM layer of perovskite solar cell with an inverted structure (ITO/PEDOT:PSS/CH3NH3PbI(3-x)Cl(x)/PCBM:GD/C60/Al) to improve the electron transport. The optimized PCE of 14.8% was achieved. Also, an average power conversion efficiency (PCE) of PCBM:GD-based devices was observed with 28.7% enhancement (13.9% vs 10.8%) compared to that of pure PCBM-based ones. According to scanning electron microscopy, conductive atomic force microscopy, space charge limited current, and photoluminescence quenching measurements, the enhanced current density and fill factor of PCBM:GD-based devices were ascribed to the better coverage on the perovskite layer, improved electrical conductivity, strong electron mobility, and efficient charge extraction. Small hysteresis and stable power output under working condition (14.4%) have also been demonstrated for PCBM:GD based devices. The enhanced device performances indicated the improvement of film conductivity and interfacial coverage based on GD doping which brought the high PCE of the devices and the data repeatability. In this work, GD demonstrates its great potential for applications in photovoltaic field owing to its networks with delocalized pi-systems and unique conductivity advantage. PMID- 25803149 TI - Role of the ehxA gene from Escherichia coli serotype O82 in hemolysis, biofilm formation, and in vivo virulence. AB - Enterohemorrhagic Escherichia coli (EHEC) strains cause serious gastrointestinal disease, which can lead to potentially life-threatening systemic complications such as hemolytic uremic syndrome. Although the ehx gene is established as a major virulence factor of EHEC, the role of this gene in colonization and biofilm formation remains to be elucidated. We constructed recombinant isogenic mutants of the ehxA locus of E. coli HLJ1122 (serotype O82) using the lambda Red homologous recombination system. Significantly higher levels of adherence to human epithelial cells (HEp-2) cells were observed for strain HLJ1122 compared with the mutant strain HLJ1122-DeltaehxA (P < 0.05). Strain HLJ1122 also exhibited significantly higher levels of biofilm formation than strain HLJ1122 DeltaehxA (P < 0.05). Mice infected with strain HLJ1122 showed severe destruction of the intestinal and gastric mucosa; in contrast, mice infected with HLJ1122 DeltaehxA showed limited intestinal pathology, displaying minimal inflammatory infiltrates compared with mock-infected mice. These results showed the multifunctional role of Ehx in E. coli virulence. PMID- 25803150 TI - Parasitoid wasps indirectly suppress seed production by stimulating consumption rates of their seed-feeding hosts. AB - In parasitoid-herbivore-plant food chains, parasitoids may be simultaneously linked with both herbivore hosts and plants, as occurs when herbivores attacked by parasitoids continue to consume plants although they are destined to die. This peculiar property may cause parasitoids to confer a differential trophic cascading effect on plants than that known for typical predators. We hypothesized that larval koinobiont parasitoids would confer an immediate negative effect on plant seed production by stimulating consumption of their seed-predator hosts. We tested this hypothesis in an alpine parasitic food chain of plant seeds, pre dispersal seed predators (tephritid fly larvae) and koinobiont parasitoids using field observations, a field experiment and a microcosm study. We first compared observed seed production in (i) non-infected capitula, (ii) capitula infected only by seed predators (tephritid flies) and (iii) capitula infected by both seed predators and their parasitoids in five Asteraceae species. Consistent with our hypothesis, seed loss in the capitula with both seed predators and parasitoids was significantly greater than in the capitula infested only by seed predators. This effect was replicated in a controlled field experiment focusing on the most common parasitoid-seed predator-plant interaction chain in our system, in which confounding factors (e.g. density and phenology) were excluded. Here, we show that parasitoids indirectly decreased plant seed production by changing the behaviour of seed predators. In a microcosm study, we show that larval parasitoids significantly extended the growth period and increased the terminal size of their host tephritid maggots. Thus, parasitoids suppressed plant seed production by stimulating the growth and consumption of the fly maggots. In contrast to the typical predator-induced trophic cascade, we highlight the significance of parasitoids indirectly decreasing plant fitness by stimulating consumption by seed predators. Future studies on trophic interactions should consider the net effect of both increased consumption by seed predators and their death after development of parasitoids. PMID- 25803151 TI - Technology and Plastic Surgery: Potential Pitfalls for Patient Confidentiality and Proposed Solutions. PMID- 25803153 TI - Reconstructive Surgery for Breast Cancer Patients: Have Improved Treatment Modalities Outpaced Current Legislation? PMID- 25803152 TI - Is There a Right Way to Interpret SPY? Normalization of Indocyanine Green Angiography Readings in a Burn Model. PMID- 25803154 TI - The Impact of Deferoxamine on Vascularity and Soft-Tissue Biomechanics in a Rat TRAM Flap Model. PMID- 25803155 TI - Hemothorax in a Patient Undergoing Breast Augmentation Surgery. PMID- 25803156 TI - Eccrine Porocarcinoma: A Wolf in Sheep's Clothing. PMID- 25803157 TI - Forgotten Functionality. PMID- 25803158 TI - The Pythagorean Theorem as a Tool for Preoperative Planning of a Concealed Scar in Augmentation Mammaplasty with Round Implants. PMID- 25803159 TI - Medial Thigh Lift in the Massive Weight Loss Population: Outcomes and Complications. PMID- 25803160 TI - Reply: The Pythagorean Theorem as a Tool for Preoperative Planning of a Concealed Scar in Augmentation Mammaplasty with Round Implants. PMID- 25803161 TI - Reply: Medial Thigh Lift in the Massive Weight Loss Population: Outcomes and Complications. PMID- 25803162 TI - The Role of Estrogen in the Modulation of Autologous Fat Graft Outcomes. PMID- 25803163 TI - Reply: Psychological Impact of Breast Asymmetry on Adolescents: A Prospective Cohort. PMID- 25803164 TI - Optima: A Model for HIV Epidemic Analysis, Program Prioritization, and Resource Optimization. AB - Optima is a software package for modeling HIV epidemics and interventions that we developed to address practical policy and program problems encountered by funders, governments, health planners, and program implementers. Optima's key feature is its ability to perform resource optimization to meet strategic HIV objectives, including HIV-related financial commitment projections and health economic assessments. Specifically, Optima allows users to choose a set of objectives (such as minimizing new infections, minimizing HIV-related deaths, and/or minimizing long-term financial commitments) and then determine the optimal resource allocation (and thus program coverage levels) for meeting those objectives. These optimizations are based on the following: calibrations to epidemiological data; assumptions about the costs of program implementation and the corresponding coverage levels; and the effects of these programs on clinical, behavioral, and other epidemiological outcomes. Optima is flexible for which population groups (specified by behavioral, epidemiological, and/or geographical factors) and which HIV programs are modeled, the amount of input data used, and the types of outputs generated. Here, we introduce this model and compare it with existing HIV models that have been used previously to inform decisions about HIV program funding and coverage targets. Optima has already been used in more than 20 countries, and there is increasing demand from stakeholders to have a tool that can perform evidence-based HIV epidemic analyses, revise and prioritize national strategies based on available resources, set program coverage targets, amend subnational program implementation plans, and inform the investment strategies of governments and their funding partners. PMID- 25803166 TI - Biomechanical Evaluation of Interfragmentary Compression At Tibia Plateau Fractures In Vitro Using Different Fixation Techniques: A CONSORT-Compliant Article: Erratum. AB - [In the article "Biomechanical Evaluation of Interfragmentary Compression At Tibia Plateau Fractures In Vitro Using Different Fixation Techniques: A CONSORT compliant" article, which appeared in Volume 94, Issue 1 of Medicine, a line denoting dual authorship was omitted. K. Kojima and B. Gueorguiev contributed equally to the article.]. PMID- 25803167 TI - Cyclosporine for the Treatment of HLTV-1-Induced HAM/TSP: An Experience from a Case Report: Erratum. AB - [In the article "Cyclosporine for the Treatment of HLTV-1-Induced HAM/TSP: An Experience from a Case Report", which appeared in Volume 94, Issue 1 of Medicine, a word in the title was misspelled. The correct title is "Cyclosporine for the Treatment of HTLV-1-Induced HAM/TSP: An Experience from a Case Report".]. PMID- 25803168 TI - Hepatic resection as a safe and effective treatment for hepatocellular carcinoma involving a single large tumor, multiple tumors, or macrovascular invasion: erratum. AB - [In the article "Hepatic Resection as a Safe and Effective Treatment for Hepatocellular Carcinoma Involving a Single Large Tumor, Multiple Tumors, or Macrovascular Invasion", which appeared in Volume 94, Issue 3 of Medicine, the word "disorder" was incorrectly substituted for the word "pathology" in the first sentence of the Definitions section. Also, in Figure 3, the y-axis incorrectly read "Overall survival (%)". It should have read "Disease-free survival (%)".]. PMID- 25803169 TI - Conversational assessment in memory clinic encounters: interactional profiling for differentiating dementia from functional memory disorders. AB - OBJECTIVES: In the UK dementia is under-diagnosed, there is limited access to specialist memory clinics, and many of the patients referred to such clinics are ultimately found to have functional (non-progressive) memory disorders (FMD), rather than a neurodegenerative disorder. Government initiatives on 'timely diagnosis' aim to improve the rate and quality of diagnosis for those with dementia. This study seeks to improve the screening and diagnostic process by analysing communication between clinicians and patients during initial specialist clinic visits. Establishing differential conversational profiles could help the timely differential diagnosis of memory complaints. METHOD: This study is based on video- and audio recordings of 25 initial consultations between neurologists and patients referred to a UK memory clinic. Conversation analysis was used to explore recurrent communicative practices associated with each diagnostic group. RESULTS: Two discrete conversational profiles began to emerge, to help differentiate between patients with dementia and functional memory complaints, based on (1) whether the patient is able to answer questions about personal information; (2) whether they can display working memory in interaction; (3) whether they are able to respond to compound questions; (4) the time taken to respond to questions; and (5) the level of detail they offer when providing an account of their memory failure experiences. CONCLUSION: The distinctive conversational profiles observed in patients with functional memory complaints on the one hand and neurodegenerative memory conditions on the other suggest that conversational profiling can support the differential diagnosis of functional and neurodegenerative memory disorders. PMID- 25803171 TI - Ciliated muconodular papillary tumors of the lung: a clinicopathologic analysis of 10 cases. AB - Ciliated muconodular papillary tumors (CMPTs) are rare peripheral nodules of the lung first described in 2002. Because of their rarity and nonstandardized diagnostic terminology, CMPTs have been poorly recognized among pathologists. To better characterize these lesions, we undertook a detailed clinicopathologic and immunohistochemical study of 10 archival cases. Ten CMPTs occurred in 7 men and 3 women with a median age of 62 years. All were small peripheral nonendobronchial nodules with a mean diameter of 1.0 cm. All but 1 tumor were incidentally detected by computed tomography-based screening, all of which were radiologically interpreted as adenocarcinomas. Although limited surgery treated all but 1 CMPT, they followed a benign course with no recurrence at a mean follow-up of 43 months (range: 2 to 88 mo). Histologically, CMPTs showed glandular and/or papillary architecture, comprising a vaguely organized mixture of nonatypical ciliated columnar cells, mucous cells, and basal cells, often enveloped by copious intra alveolar mucin. Micropapillary tufts of ciliated cells and seemingly discontinuous growth along alveolar walls were occasionally present, mimicking adenocarcinomas. Ciliated cells and basal cells were immunopositive for TTF-1 and p40, respectively, whereas mucous cells lacked HNF4alpha expression. CMPTs are rare, likely benign, underrecognized processes of the lung that should be distinguished from adenocarcinomas. PMID- 25803174 TI - A Measure of Barriers Toward Medical Disclosure Among Health Professionals in the United Arab Emirates. AB - BACKGROUND: There has been a growing awareness that patients are subject to injuries that can be prevented as a direct consequence of health care. Error disclosure is an effective technique to restore the lost trust with the health care system. OBJECTIVE: The current study aimed to develop a valid and reliable scale to determine the factors facilitating the disclosure of health professionals in health organizations. METHODS: This study had a cross-sectional design that consisted of 722 responses (response rate of 68.3%) from 1 private and 1 public hospital in Sharjah, United Arab Emirates. The data collection tool included 23 items rated on a Likert scale ranging from 5, strongly agree, to 1, strongly disagree.The internal consistency was established through calculating the split-half reliability for part 1 (12 items), which had a Cronbach coefficient of 0.65, and part 2 (11 items), which had a Cronbach coefficient of 0.62. Scale validity was assessed with the Kaiser-Meyer-Olkin measure of sampling adequacy, which had a value of 0.62, and the Bartlett test of sphericity (approximated chi = 13012.2, P = 0.0001) supported the factorability of the correlation matrix. The varimax rotation revealed 5 components that explained 77.8% of the total variance. RESULTS: The varimax rotation revealed 21 items loaded on the following 5 factors: fear of disclosure and provider image consequences (factor 1), apology (factor 2), organizational culture toward patient safety (factor 3), professional ethics and transparency (factor 4), as well as patient and provider education (factor 5). CONCLUSIONS: The disclosure of medical mistakes requires preliminary considerations to effectively and compassionately disclose these events to patients. The validity and reliability of the results support the use of this scale at hospitals as part of the health care providers' disclosure processes. PMID- 25803173 TI - Medication Administration Errors in an Adult Emergency Department of a Tertiary Health Care Facility in Ghana. AB - OBJECTIVES: This study determined the incidence, types, clinical significance, and potential causes of medication administration errors (MAEs) at the emergency department (ED) of a tertiary health care facility in Ghana. METHODS: This study used a cross-sectional nonparticipant observational technique. Study participants (nurses) were observed preparing and administering medication at the ED of a 2000 bed tertiary care hospital in Accra, Ghana. The observations were then compared with patients' medication charts, and identified errors were clarified with staff for possible causes. RESULTS: Of the 1332 observations made, involving 338 patients and 49 nurses, 362 had errors, representing 27.2%. However, the error rate excluding "lack of drug availability" fell to 12.8%. Without wrong time error, the error rate was 22.8%. The 2 most frequent error types were omission (n = 281, 77.6%) and wrong time (n = 58, 16%) errors. Omission error was mainly due to unavailability of medicine, 48.9% (n = 177). Although only one of the errors was potentially fatal, 26.7% were definitely clinically severe. The common themes that dominated the probable causes of MAEs were unavailability, staff factors, patient factors, prescription, and communication problems. CONCLUSIONS: This study gives credence to similar studies in different settings that MAEs occur frequently in the ED of hospitals. Most of the errors identified were not potentially fatal; however, preventive strategies need to be used to make life saving processes such as drug administration in such specialized units error free. PMID- 25803175 TI - The Safety Stand-down: A Technique for Improving and Sustaining Hand Hygiene Compliance Among Health Care Personnel. AB - OBJECTIVES: Hand hygiene (HH) is critical to prevent health care-acquired infections. However, compliance by health care workers remains between 30% and 70% at most institutions. Most efforts to improve compliance have proven ineffective. The objective of this study was to determine whether a safety stand down can improve HH compliance. METHODS: We adapted and borrowed from the military an approach known as a stand-down. A mandatory Hand-Hygiene Leadership Safety Summit was called for all hospital leaders-physicians and nonphysicians. Four days later, a hospital-wide 15-minute-long safety stand-down occurred, during which all nonessential activity was suspended and action plans to improve HH compliance were discussed. All medical sections and hospital departments were required to submit written action plans. After the stand-down, HH compliance monitoring was increased, and noncompliers were required to speak to senior hospital administration. RESULTS: Compliance increased from less than 65% to greater than 95% (P < 0.001) and has been sustained for 31/2 years. CONCLUSIONS: A health care safety stand-down can be an effective method to rapidly change and sustain culture change regarding HH in the inpatient hospital setting. PMID- 25803172 TI - Competency-based assessment for clinical supervisors: design-based research on a web-delivered program. AB - BACKGROUND: Clinicians need to be supported by universities to use credible and defensible assessment practices during student placements. Web-based delivery of clinical education in student assessment offers professional development regardless of the geographical location of placement sites. OBJECTIVE: This paper explores the potential for a video-based constructivist Web-based program to support site supervisors in their assessments of student dietitians during clinical placements. METHODS: This project was undertaken as design-based research in two stages. Stage 1 describes the research consultation, development of the prototype, and formative feedback. In Stage 2, the program was pilot tested and evaluated by a purposeful sample of nine clinical supervisors. Data generated as a result of user participation during the pilot test is reported. Users' experiences with the program were also explored via interviews (six in a focus group and three individually). The interviews were transcribed verbatim and thematic analysis conducted from a pedagogical perspective using van Manen's highlighting approach. RESULTS: This research succeeded in developing a Web-based program, "Feed our Future", that increased supervisors' confidence with their competency-based assessments of students on clinical placements. Three pedagogical themes emerged: constructivist design supports transformative Web based learning; videos make abstract concepts tangible; and accessibility, usability, and pedagogy are interdependent. CONCLUSIONS: Web-based programs, such as Feed our Future, offer a viable means for universities to support clinical supervisors in their assessment practices during clinical placements. A design based research approach offers a practical process for such Web-based tool development, highlighting pedagogical barriers for planning purposes. PMID- 25803176 TI - Impact of Inpatient Harms on Hospital Finances and Patient Clinical Outcomes. AB - OBJECTIVE: The aim of this study was to determine the impact of all-cause inpatient harms on hospital finances and patient clinical outcomes. RESEARCH DESIGN: A retrospective analysis of inpatient harm from 24 hospitals in a large multistate health system was conducted during 2009 to 2012 using the Institute of Healthcare Improvement Global Trigger Tool for Measuring Adverse Events. Inpatient harms were detected and categorized into harm (F-I), temporary harm (E), and no harm. RESULTS: Of the 21,007 inpatients in this study, 15,610 (74.3%) experienced no harm, 2818 (13.4%) experienced temporary harm, and 2579 (12.3%) experienced harm. A patient with harm was estimated to have higher total cost ($4617 [95% confidence interval (CI), $4364 to 4871]), higher variable cost ($1774 [95% CI, $1648 to $1900]), lower contribution margin (-$1112 [95% CI, $1378 to -$847]), longer length of stay (2.6 d [95% CI, 2.5 to 2.8]), higher mortality probability (59%; odds ratio, 1.4 [95% CI, 1.0 to 2.0]), and higher 30 day readmission probability (74.4%; odds ratio, 2.9 [95% CI, 2.6 to 3.2]). A patient with temporary harm was estimated to have higher total cost ($2187 [95% CI, $2008 to $2366]), higher variable cost ($800 [95% CI, $709 to $892]), lower contribution margin (-$669 [95% CI, -$891 to -$446]), longer length of stay (1.3 d [95% CI, 1.2 to 1.4]), mortality probability not statistically different, and higher 30-day readmission probability (54.6%; odds ratio, 1.2 [95% CI, 1.1 to 1.4]). Total health system reduction of harm was associated with a decrease of $108 million in total cost, $48 million in variable cost, an increase of contribution margin by $18 million, and savings of 60,000 inpatient care days. CONCLUSIONS: This all-cause harm safety study indicates that inpatient harm has negative financial outcomes for hospitals and negative clinical outcomes for patients. PMID- 25803170 TI - MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition. AB - CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy. PMID- 25803177 TI - MRI simulation: end-to-end testing for prostate radiation therapy using geometric pelvic MRI phantoms. AB - To clinically implement MRI simulation or MRI-alone treatment planning requires comprehensive end-to-end testing to ensure an accurate process. The purpose of this study was to design and build a geometric phantom simulating a human male pelvis that is suitable for both CT and MRI scanning and use it to test geometric and dosimetric aspects of MRI simulation including treatment planning and digitally reconstructed radiograph (DRR) generation.A liquid filled pelvic shaped phantom with simulated pelvic organs was scanned in a 3T MRI simulator with dedicated radiotherapy couch-top, laser bridge and pelvic coil mounts. A second phantom with the same external shape but with an internal distortion grid was used to quantify the distortion of the MR image. Both phantoms were also CT scanned as the gold-standard for both geometry and dosimetry. Deformable image registration was used to quantify the MR distortion. Dose comparison was made using a seven-field IMRT plan developed on the CT scan with the fluences copied to the MR image and recalculated using bulk electron densities. Without correction the maximum distortion of the MR compared with the CT scan was 7.5 mm across the pelvis, while this was reduced to 2.6 and 1.7 mm by the vendor's 2D and 3D correction algorithms, respectively. Within the locations of the internal organs of interest, the distortion was <1.5 and <1 mm with 2D and 3D correction algorithms, respectively. The dose at the prostate isocentre calculated on CT and MRI images differed by 0.01% (1.1 cGy). Positioning shifts were within 1 mm when setup was performed using MRI generated DRRs compared to setup using CT DRRs.The MRI pelvic phantom allows end-to-end testing of the MRI simulation workflow with comparison to the gold-standard CT based process. MRI simulation was found to be geometrically accurate with organ dimensions, dose distributions and DRR based setup within acceptable limits compared to CT. PMID- 25803178 TI - Development and Evaluation of a Simple, Multifactorial Model Based on Landing Performance to Indicate Injury Risk in Surfing Athletes. AB - PURPOSE: To develop and evaluate a multifactorial model based on landing performance to estimate injury risk for surfing athletes. METHODS: Five measures were collected from 78 competitive surfing athletes and used to create a model to serve as a screening tool for landing tasks and potential injury risk. In the second part of the study, the model was evaluated using junior surfing athletes (n = 32) with a longitudinal follow-up of their injuries over 26 wk. Two models were compared based on the collected data, and magnitude-based inferences were applied to determine the likelihood of differences between injured and noninjured groups. RESULTS: The study resulted in a model based on 5 measures--ankle dorsiflexion range of motion, isometric midthigh-pull lower-body strength, time to stabilization during a drop-and-stick (DS) landing, relative peak force during a DS landing, and frontal-plane DS-landing video analysis--for male and female professional surfers and male and female junior surfers. Evaluation of the model showed that a scaled probability score was more likely to detect injuries in junior surfing athletes and reported a correlation of r = .66, P = .001, with a model of equal variable importance. The injured (n = 7) surfers had a lower probability score (0.18 +/- 0.16) than the noninjured group (n = 25, 0.36 +/- 0.15), with 98% likelihood, Cohen d = 1.04. CONCLUSIONS: The proposed model seems sensitive and easy to implement and interpret. Further research is recommended to show full validity for potential adaptations for other sports. PMID- 25803179 TI - Correction: Rasmussen, B.B., et al. Global and phylogenetic distribution of quorum sensing signals, acyl homoserine lactones, in the family of vibrionaceae. Mar. Drugs 2014, 12, 5527-5546. AB - The authors wish to make the following corrections to this paper [1]: Due to duplicated and missing data in Table 3, Page 5533, replace: [...]. PMID- 25803182 TI - Characterization of particles from ferrate preoxidation. AB - Studies were conducted evaluating the nature of particles that result from ferrate reduction in a laboratory water matrix and in a natural surface water with a moderate amount of dissolved organic carbon. Particle characterization included size, surface charge, morphology, X-ray photoelectron spectroscopy, and transmission Fourier transform infrared spectroscopy. Characteristics of ferrate resultant particles were compared to particles formed from dosing ferric chloride, a common water treatment coagulant. In natural water, ferrate addition produced significantly more nanoparticles than ferric addition. These particles had a negative surface charge, resulting in a stable colloidal suspension. In natural and laboratory matrix waters, the ferrate resultant particles had a similar charge versus pH relationship as particles resulting from ferric addition. Particles resulting from ferrate had morphology that differed from particles resulting from ferric iron, with ferrate resultant particles appearing smoother and more granular. X-ray photoelectron spectroscopy results show ferrate resultant particles contained Fe2O3, while ferric resultant particles did not. Results also indicate potential differences in the mechanisms leading to particle formation between ferrate reduction and ferric hydrolysis. PMID- 25803181 TI - Extracorporeal membrane oxygenation as bridge-to-decision in acute heart failure due to systemic light-chain amyloidosis. AB - PATIENT: Female, 58. FINAL DIAGNOSIS: Acute hear failure. SYMPTOMS: Dispnoea * edema * fatigue. MEDICATION: - CLINICAL PROCEDURE: Bone marrow biopsy * endomyocardial biopsy * abdominal subcutaneous fat biopsy under ECMO support. SPECIALTY: Cardiology. OBJECTIVE: Rare disease. BACKGROUND: Cardiac amyloidosis results from the amyloid deposition in heart tissue, either in the context of a systemic disease or as a localized form. Several pro-amyloid proteins can produce amyloid deposits in the heart. Each of these amyloidoses has characteristic clinical (cardiac and extracardiac) features, and a specific diagnosis and treatment. CASE REPORT: A 58-year-old woman who presented with acute heart failure and echocardiographic findings strongly suggestive of infiltrative cardiomyopathy needed percutaneous veno-arterial extracorporeal membrane oxygenation (ECMO) as bridge-to-decision. Amyloid deposition was found on endomyocardial and bone marrow biopsies. Bone marrow plasma cell infiltrate with acute renal lesion and hypercalcemia confirmed the diagnosis of multiple myeloma associated systemic light-chain amyloidosis (AL). Refractory shock with multi organic failure syndrome persisted and no improvements in left ventricular function and structure were seen. After extensive discussion by a multidisciplinary team, and with the patients' family, she was not considered eligible for high-dose chemotherapy and/or autologous stem cell transplantation, heart transplantation, or sequential heart with autologous stem cell transplantation. The patient died a few hours after ECMO withdrawal. During the 14 days of ECMO support no major bleeding or thrombotic complications occurred. CONCLUSIONS: The clinician must consider a diagnosis of cardiac amyloidosis in patients with heart failure, a restrictive type of cardiomyopathy with ventricular hypertrophy in the absence of valve abnormalities, or uncontrolled arterial hypertension. Although developments in chemotherapy have greatly improved the outcomes in AL amyloidosis, the prognosis of patients with severe cardiac involvement remains very poor. ECMO is potentially a reliable bridge-to diagnosis and bridge-to-decision in these patients. An experienced ECMO team, careful patient selection, and rigorous management protocols with objective criteria to wean or stop ECMO are needed. PMID- 25803180 TI - Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells. AB - The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula). Kalkitoxin exhibited N-methyl-D-aspartate (NMDA)-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed that kalkitoxin generated a delayed form of colon tumor cell cytotoxicity in 7-day clonogenic cell survival assays. Cell line and exposure time-dependent cytostatic/cytotoxic effects were previously observed with mitochondria-targeted inhibitors of hypoxia-inducible factor-1 (HIF 1). The transcription factor HIF-1 functions as a key regulator of oxygen homeostasis. Therefore, we investigated the ability of kalkitoxin to inhibit hypoxic signaling in human tumor cell lines. Kalkitoxin potently and selectively inhibited hypoxia-induced activation of HIF-1 in T47D breast tumor cells (IC50 5.6 nM). Mechanistic studies revealed that kalkitoxin inhibits HIF-1 activation by suppressing mitochondrial oxygen consumption at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Further studies indicate that kalkitoxin targets tumor angiogenesis by blocking the induction of angiogenic factors (i.e., VEGF) in tumor cells. PMID- 25803183 TI - The Swedish alpha1-Antitrypsin Screening Study: Health Status and Lung and Liver Function at Age 34. AB - RATIONALE: All Swedish newborn infants were screened for alpha1-antitrypsin (AAT) deficiency between 1972 and 1974. The cohort of 127 individuals with severe AAT deficiency (PiZZ) and 54 with moderate AAT deficiency (PiSZ) has been followed up regularly. OBJECTIVES: To compare smoking habits, quality of life, respiratory symptoms, and lung and liver function at the age of 34 years in this cohort and among 300 age-matched control subjects randomly selected from the Swedish population registry. METHODS: The study participants answered a questionnaire on smoking habits and symptoms; underwent spirometry, including FEV1 and FVC; and provided blood samples. Health-related quality of life was assessed by using the St. George's Respiratory Questionnaire (SGRQ). MEASUREMENTS AND MAIN RESULTS: One hundred sixteen PiZZ, 48 PiSZ, and 229 control subjects (normal AAT level [PiMM]) answered the questionnaire. Eighty-eight PiZZ (76%), 36 PiSZ (75%), and 144 PiMM (63%) subjects had never smoked (P = 0.02). No significant differences were found in lung function parameters between the protease inhibitor (Pi) subgroups, nor were any discovered between the smoking subgroups. In all Pi subgroups, the symptom score on the SGRQ was significantly lower in ever-smokers than in never smokers (P = 0.01 for PiZZ, P = 0.009 for PiSZ, and P = 0.01 for PiMM). The mean plasma levels of liver enzymes and albumin were within normal range in all Pi subgroups. However, the mean gamma-glutamyl transpeptidase and albumin levels were significantly higher in the PiZZ than in the PiMM subjects (P < 0.05). CONCLUSIONS: In this population-based study, no differences in lung function or symptoms were found between subjects with AAT deficiency and control subjects, but smoking frequency was significantly lower among the subjects with AAT deficiency than in the controls at age 34 years. PMID- 25803184 TI - Advantages and disadvantages of educational email alerts for family physicians: viewpoint. AB - BACKGROUND: Electronic knowledge resources constitute an important channel for accredited Continuing Medical Education (CME) activities. However, email usage for educational purposes is controversial. On the one hand, family physicians become aware of new information, confirm what they already know, and obtain reassurance by reading educational email alerts. Email alerts can also encourage physicians to search Web-based resources. On the other hand, technical difficulties and privacy issues are common obstacles. OBJECTIVE: The purpose of this discussion paper, informed by a literature review and a small qualitative study, was to understand family physicians' knowledge, attitudes, and behavior in regard to email in general and educational emails in particular, and to explore the advantages and disadvantages of educational email alerts. In addition, we documented participants' suggestions to improve email alert services for CME. METHODS: We conducted a qualitative descriptive study using the "Knowledge, Attitude, Behavior" model. We conducted semi-structured face-to-face interviews with 15 family physicians. We analyzed the collected data using inductive deductive thematic qualitative data analysis. RESULTS: All 15 participants scanned and prioritized their email, and 13 of them checked their email daily. Participants mentioned (1) advantages of educational email alerts such as saving time, convenience and valid information, and (2) disadvantages such as an overwhelming number of emails and irrelevance. They offered suggestions to improve educational email. CONCLUSIONS: The advantages of email alerts seem to compensate for their disadvantages. Suggestions proposed by family physicians can help to improve educational email alerts. PMID- 25803185 TI - Ultrahigh-speed optical coherence tomography utilizing all-optical 40 MHz swept source. AB - We present an ultrahigh-speed optical coherence tomography (OCT) based on an all optical swept-source with an A-scan rate of 40 MHz. The inertia-free swept source, which has its output power of 41.2 mW and tuning range of 40 nm and high scan linearity in wavenumber with Pearson's correlation coefficients r of 0.9996, consists of a supercontinuum laser, an optical band-pass filter, a linearly chirped fiber Bragg grating, an erbium-doped fiber amplifier, and two buffer stages. With sensitivity of 87 dB, high-speed OCT imaging of biological tissue in vivo is also demonstrated. PMID- 25803187 TI - Quantitative photoacoustic tomography using illuminations from a single direction. AB - Quantitative photoacoustic tomography is an emerging imaging technique aimed at estimating optical parameters inside tissues from photoacoustic images, which are formed by combining optical information and ultrasonic propagation. This optical parameter estimation problem is ill-posed and needs to be approached within the framework of inverse problems. It has been shown that, in general, estimating the spatial distribution of more than one optical parameter is a nonunique problem unless more than one illumination pattern is used. Generally, this is overcome by illuminating the target from various directions. However, in some cases, for example when thick samples are investigated, illuminating the target from different directions may not be possible. In this work, the use of spatially modulated illumination patterns at one side of the target is investigated with simulations. The results show that the spatially modulated illumination patterns from a single direction could be used to provide multiple illuminations for quantitative photoacoustic tomography. Furthermore, the results show that the approach can be used to distinguish absorption and scattering inclusions located near the surface of the target. However, when compared to a full multidirection illumination setup, the approach cannot be used to image as deep inside tissues. PMID- 25803186 TI - Review of short-wave infrared spectroscopy and imaging methods for biological tissue characterization. AB - We present a review of short-wave infrared (SWIR, defined here as ~1000 to 2000 nm) spectroscopy and imaging techniques for biological tissue optical property characterization. Studies indicate notable SWIR absorption features of tissue constituents including water (near 1150, 1450, and 1900 nm), lipids (near 1040, 1200, 1400, and 1700 nm), and collagen (near 1200 and 1500 nm) that are much more prominent than corresponding features observed in the visible and near-infrared (VIS-NIR, defined here as ~400 to 1000 nm). Furthermore, the wavelength dependence of the scattering coefficient has been observed to follow a power-law decay from the VIS-NIR to the SWIR region. Thus, the magnitude of tissue scattering is lower at SWIR wavelengths than that observed at VIS or NIR wavelengths, potentially enabling increased penetration depth of incident light at SWIR wavelengths that are not highly absorbed by the aforementioned chromophores. These aspects of SWIR suggest that the tissue spectroscopy and imaging in this range of wavelengths have the potential to provide enhanced sensitivity (relative to VIS-NIR measurements) to chromophores such as water and lipids, thereby helping to characterize changes in the concentrations of these chromophores due to conditions such as atherosclerotic plaque, breast cancer, and burns. PMID- 25803189 TI - High-resolution mobility analysis of charge-reduced electrosprayed protein ions. AB - Many mobility studies (IMS) of electrospray ions with charge states z reduced to unity have shown a singular ability to analyze large protein complexes and viruses, though with wide mobility peaks (fwhm ~ 20%). Here we confirm that this limitation arises primarily when early charge reduction precedes drop evaporation (suppressing secondary atomization by the usual sequence of many Coulomb explosions). By drying before neutralizing, we achieve a protein fwhm of ~3.7%. A positively biased electrospraying capillary is coaxial with a cylindrical charge reduction (CR) chamber coated with radioactive Ni-63 (10 mCi) that fills the CR chamber with a bipolar ionic atmosphere. A screen interposed between the spraying capillary and the CR chamber limits penetration of the neutralizing anions into the electrospray (ES) chamber, precluding destabilization of the ES tip, even when brought very close to the grid to enhance ion transmission. As ES cations cross the grid, driven by their own space charge, they recombine with CR ions reducing their charge state as well as space charge dispersion. The setup is tested with the protein ovalbumin (MW ~ 44.3 kDa) and its clusters up to the tetramer, by analyzing the charge-reduced ions with a differential mobility analyzer (DMA). At gas sample flow rates of ~1 L/min, the dominant peaks are singly charged (z = 1). They are widened by clustering of involatile solution impurities, depending on spray quality and solution cleanness, with fwhm as small as 3.7% achieved in desalted and acidified solutions. When using sharp nanospray capillaries, the grid may be removed, resulting in ~2-fold increased ion transmission. In the absence of the grid, however, spray stability and quality are often compromised, even with capillary tip diameters as small as 30 MUm. PMID- 25803190 TI - Vesicular exocytosis and microdevices - microelectrode arrays. AB - Among all the analytical techniques capable of monitoring exocytosis in real time at the single cell level, electrochemistry (particularly amperometry at a constant potential) using ultramicroelectrodes has been demonstrated to be an important and convenient tool for more than two decades. Indeed, because the electrochemical sensor is located in the close vicinity of the emitting cell ("artificial synapse" configuration), much data can be gathered from the whole cell activity (secretion frequency) to the individual vesicular release (duration, fluxes or amount of molecules released) with an excellent sensitivity. However, such a single cell analysis and its intrinsic benefits are at the expense of the spatial resolution and/or the number of experiments. The quite recent development of microdevices/microsystems (and mainly the microelectrode arrays (MEAs)) offers in some way a complementary approach either by combining spectroscopy-microscopy or by implementing a multianalysis. Such developments are described and discussed in the present review over the 2005-2014 period. PMID- 25803188 TI - Dynamics of protein kinases: insights from nuclear magnetic resonance. AB - Protein kinases are ubiquitous enzymes with critical roles in cellular processes and pathology. As a result, researchers have studied their activity and regulatory mechanisms extensively. Thousands of X-ray structures give snapshots of the architectures of protein kinases in various states of activation and ligand binding. However, the extent of and manner by which protein motions and conformational dynamics underlie the function and regulation of these important enzymes is not well understood. Nuclear magnetic resonance (NMR) methods provide complementary information about protein conformation and dynamics in solution. However, until recently, the large size of these enzymes prevented researchers from using these methods with kinases. Developments in transverse relaxation optimized spectroscopy (TROSY)-based techniques and more efficient isotope labeling strategies are now allowing researchers to carry out NMR studies on full length protein kinases. In this Account, we describe recent insights into the role of dynamics in protein kinase regulation and catalysis that have been gained from NMR measurements of chemical shift changes and line broadening, residual dipolar couplings, and relaxation. These findings show strong associations between protein motion and events that control kinase activity. Dynamic and conformational changes occurring at ligand binding sites and other regulatory domains of these proteins propagate to conserved kinase core regions that mediate catalytic function. NMR measurements of slow time scale (microsecond to millisecond) motions also reveal that kinases carry out global exchange processes that synchronize multiple residues and allosteric interconversion between conformational states. Activating covalent modifications or ligand binding to form the Michaelis complex can induce these global processes. Inhibitors can also exploit the exchange properties of kinases by using conformational selection to form dynamically quenched states. These investigations have revealed that kinases are highly dynamic enzymes, whose regulation by interdomain interactions, ligand binding, and covalent modifications involve changes in motion and conformational equilibrium in a manner that can be correlated with function. Thus, NMR provides a unique window into the role of protein dynamics in kinase regulation and catalysis with important implications for drug design. PMID- 25803191 TI - Strawberry as a health promoter: an evidence based review. AB - Since a high intake of fruits and vegetables is inversely related to the incidence of several degenerative diseases, the importance of a balanced diet in relation to human health has received increased consumer attention worldwide. Strawberries (Fragaria X ananassa, Duch.) are a rich source of a wide variety of nutritive compounds such as sugars, vitamins, and minerals, as well as non nutritive, bioactive compounds such as flavonoids, anthocyanins and phenolic acids. All of these compounds exert a synergistic and cumulative effect on human health promotion and in disease prevention. Strawberry phenolics are indeed able (i) to detoxify free radicals blocking their production, (ii) to modulate the expression of genes involved in metabolism, cell survival and proliferation and antioxidant defense, and (iii) to protect and repair DNA damage. The overall objective of the present review is to update and discuss the key findings, from recent in vivo studies, on the effects of strawberries on human health. Particular attention will be paid to the molecular mechanisms proposed to explain the health effects of polyphenols against the most common diseases related to oxidative stress driven pathologies, such as cancer, cardiovascular diseases, type II diabetes, obesity and neurodegenerative diseases, and inflammation. PMID- 25803192 TI - The role of oxidative stress in corneal diseases and injuries. AB - In various corneal injuries (such as chemical burns or irradiation of corneas with UVB radiation) and ocular diseases (e.g. dry eye disease, keratokonus, bullous keratopathy, Fuchs' endothelial dystrophy), the expressions of malondialdehyde (a marker of lipid peroxidation) and nitrotyrosine (a marker of oxidative stress) appeared in cells of individual corneal layers and conjunctival cells (dry eye disease). This is in contrast to healthy corneas in which negligible levels of malondialdehyde and no expressions of nitrotyrosine are present. The injured or diseased corneas reveal decreased capacity of antioxidants (enzymatic as well as non-enzymatic), whereas the levels of pro oxidants (e.g. oxidases that generate reactive oxygen species) remain at physiological levels or even increase, leading to the antioxidant/prooxidant imbalance and oxidative stress. Oxidative stress in the cornea stimulates generation of pro-inflammatory cytokines, proteolytic enzymes and enzymes that generate nitric oxide (nitric oxide synthases). An abundant amout of reactive oxygen species and nitric oxide lead to the formation of toxic reactive products contributing to tissue damage. This review aims to summarize immunohistochemical changes in severe corneal injuries and diseases in which oxidative stress has been proved. PMID- 25803194 TI - Transformation assay in Bhas 42 cells: a model using initiated cells to study mechanisms of carcinogenesis and predict carcinogenic potential of chemicals. AB - Transformation assays using cultured cells have been applied to the study of carcinogenesis. Although various cell systems exist, few cell types such as BALB/c 3T3 subclones and Syrian hamster embryo cells have been used to study chemically induced two-stage carcinogenesis. Bhas 42 cells were established as a clone by the transfection with the v-Ha-ras gene into mouse BALB/c 3T3 A31-1-1 cells and their subsequent selection based on their sensitivity to 12-O tetradecanoylphorbol-13-acetate. Using Bhas 42 cells, transformed foci were induced by the treatment with nongenotoxic carcinogens, most of which act as tumor promoters. Therefore, Bhas 42 cells were considered to be a model of initiated cells. Subsequently, not only nongenotoxic carcinogens but also genotoxic carcinogens, most of which act as tumor initiators, were found to induce transformed foci by the modification of the protocol. Furthermore, transformation of Bhas 42 cells was induced by the transfection with genes of oncogenic potential. We interpret this high sensitivity of Bhas 42 cells to various types of carcinogenic stimuli to be related to the multistage model of carcinogenesis, as the transfection of v-Ha-ras gene further advances the parental BALB/c 3T3 A31-1-1 cells toward higher transforming potential. Thus, we propose that Bhas 42 cells are a novel and sensitive cell line for the analysis of carcinogenesis and can be used for the detection of not only carcinogenic substances but also gene alterations related to oncogenesis. This review will address characteristics of Bhas 42 cells, the transformation assay protocol, validation studies, and the various chemicals tested in this assay. PMID- 25803193 TI - PRIMA-1Met induces apoptosis in Waldenstrom's Macroglobulinemia cells independent of p53. AB - PRIMA-1Met has shown promising preclinical activity in various cancer types. However, its effect on Waldenstrom's Macroglobulinemia (WM) cells as well as its exact mechanism of action is still elusive. In this study, we evaluated the anti- tumor activity of PRIMA-1Met alone and in combination with dexamethasone or bortezomib in WM cell lines and primary samples. Treatment of WM cells with PRIMA 1Met resulted in induction of apoptosis, inhibition of migration and suppression of colony formation. Upon PRIMA-1Met treatment, p73 was upregulated and Bcl-xL was down-regulated while no significant change in expression of p53 was observed. Furthermore, siRNA knockdown of p53 in WM cell line did not influence the PRIMA 1Met-induced apoptotic response whereas silencing of p73 inhibited latter response in WM cells. Importantly, combined treatment of BCWM-1 cells with PRIMA 1Met and dexamethasone or bortezomib induced synergistic reduction in cell survival. Our study provides insights into the mechanisms of anti-WM activity of PRIMA-1Met and supports further clinical evaluation of PRIMA-1Met as a potential novel therapeutic intervention in WM. PMID- 25803196 TI - An updated review on cancer risk associated with incretin mimetics and enhancers. AB - Incretin-based therapies, including the use of incretin mimetics of glucagon-like peptide-1 receptor (GLP-1R) agonists and incretin enhancers of dipeptidyl peptidase 4 (DPP-4) inhibitors, are widely used by clinicians for glucose lowering in patients with type 2 diabetes mellitus. These agents have benefits of a lower risk of hypoglycemia, being neutral for body weight for DPP-4 inhibitors and having a potential for weight reduction with GLP-1R agonists. They may also have a neutral or beneficial cardiovascular effect. Despite these benefits, an increased risk of cancer (especially pancreatic cancer and thyroid cancer) associated with incretin-based therapies has been reported. In this article, we reviewed related literature of experimental animal and observational human studies, clinical trials, and meta-analyses published until December 15, 2014. Current studies suggested a probable role of GLP-1R activation on the development of pancreatic cancer and thyroid cancer in rodents, but such an effect in humans is not remarkable due to the lower or lack of expression of GLP-1R on human pancreatic ductal cells and thyroid tissues. Findings in human studies are controversial and inconclusive. In the analyses of the US Food and Drug Administration adverse events reporting system, a significantly higher risk of pancreatic cancer was observed for GLP-1R agonists and DPP-4 inhibitors, but a significantly higher risk of thyroid cancer was only observed for GLP-1R agonists. Such a higher risk of pancreatic cancer or thyroid cancer could not be similarly demonstrated in other human observational studies or analyses of data from clinical trials. With regards to cancers other than pancreatic cancer and thyroid cancer, available studies supported a neutral association in humans. Some preliminary studies even suggested a potentially beneficial effect on the development of other cancers with the use of incretins. Based on current evidence, continuous monitoring of the cancer issues related to incretin-based therapies is required, even though the benefits may outweigh the potential cancer risk in the general patients with type 2 diabetes mellitus. PMID- 25803195 TI - A review and meta-analysis of outdoor air pollution and risk of childhood leukemia. AB - Leukemia is the most frequent malignant disease affecting children. To date, the etiology of childhood leukemia remains largely unknown. Few risk factors (genetic susceptibility, infections, ionizing radiation, etc.) have been clearly identified, but they appear to explain only a small proportion of cases. Considerably more uncertain is the role of other environmental risk factors, such as indoor and outdoor air pollution. We sought to summarize and quantify the association between traffic-related air pollution and risk of childhood leukemia, and further examined results according to method of exposure assessment, study quality, leukemia subtype, time period, and continent where studies took place. After a literature search yielded 6 ecologic and 20 case-control studies, we scored the studies based on the Newcastle-Ottawa Scale. The studies assessed residential exposure to pollutants from motorized traffic by computing traffic density in the neighboring roads or vicinity to petrol stations, or by using measured or modeled nitrogen dioxide and benzene outdoor air levels. Because heterogeneity across studies was observed, random-effects summary odds ratios (OR) and 95% confidence intervals (CI) were reported. Whenever possible we additionally conducted stratified analyses comparing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Limiting the analysis to high-quality studies (Newcastle-Ottawa Scale >= 7), those using traffic density as the exposure assessment metric showed an increase in childhood leukemia risk in the highest exposure category (OR = 1.07, 95% CI 0.93-1.24). However, we observed evidence of publication bias. Results for NO2 exposure and benzene showed an OR of 1.21 (95% CI 0.97-1.52) and 1.64 (95% CI 0.91-2.95) respectively. When stratifying by leukemia type, the results based upon NO2 were 1.21 (95% CI 1.04 1.41) for ALL and 1.06 (95% CI 0.51-2.21) for AML; based upon benzene were 1.09 (95% CI 0.67-1.77) for ALL and 2.28 (95% CI 1.09-4.75) for AML. Estimates were generally higher for exposures in the postnatal period compared to the prenatal period, and for European studies compared to North American studies. Overall, our results support a link between ambient exposure to traffic pollution and childhood leukemia risk, particularly due to benzene. PMID- 25803198 TI - Changes in Peripheral Refractive Profile after Orthokeratology for Different Degrees of Myopia. AB - PURPOSE: The purpose of this study was to evaluate the effect of orthokeratology for different degrees of myopia correction in the relative location of tangential (F(T)) and sagittal (F(S)) power errors across the central 70 degrees of the visual field in the horizontal meridian. METHODS: Thirty-four right eyes of 34 patients with a mean age of 25.2 +/- 6.4 years were fitted with Paragon CRT (Mesa, AZ) rigid gas permeable contact lenses to treat myopia (-2.15 +/- 1.26D, range: -0.88 to -5.25D). Axial and peripheral refraction were measured along the central 70 degrees of the horizontal visual field with the Grand Seiko WAM5500 open-field auto-refractor. Spherical equivalent (M), as well as tangential (FT) and sagittal power errors (FS) were obtained. Analysis was stratified in three groups according to baseline spherical equivalent: Group 1 [M(Baseline) = -0.88 to -1.50D; n = 11], Group 2 [M(Baseline) = -1.51 to -2.49D; n = 11], and Group 3 [M(Baseline) = -2.50 to -5.25D; n = 12]. RESULTS: Spherical equivalent was significantly more myopic after treatment beyond the central 40 degrees of the visual field (p < 0.001). FT became significantly more myopic for all groups in the nasal and temporal retina with 25 degrees (p <= 0.017), 30 degrees (p <= 0.007) and 35 degrees (p <= 0.004) of eye rotation. Myopic change in FS was less consistent, achieving only statistical significance for all groups at 35 degrees in the nasal and temporal retina (p <= 0.045). CONCLUSIONS: Orthokeratology changes significantly FT in the myopic direction beyond the central 40 degrees of the visual field for all degrees of myopia. Changes induced by orthokeratology in relative peripheral M, FT and FS with 35 degrees of eye rotation were significantly correlated with axial myopia at baseline. PMID- 25803197 TI - Oritavancin for acute bacterial skin and skin structure infections. AB - INTRODUCTION: Inpatient treatment of acute bacterial skin and skin structure infections (ABSSSIs) exerts a significant economic burden on the healthcare system. Oritavancin is a concentration-dependent, rapid bactericidal agent approved for the treatment of ABSSSIs. Its prolonged half-life with one-time intravenous (i.v.) dosing offers a potential solution to this burden. In addition, oritavancin represents an alternative therapy for Streptococci and multidrug-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Animal models have also shown promising results with oritavancin for other disease states including those that require long courses of i.v. THERAPY: AREAS COVERED: This review covers oritavancin's basic chemistry, spectrum of activity, pharmacodynamics/pharmacokinetics and efficacy in clinical trials, and provides expert opinion on future directions. To compose this review, a search of PubMed was performed, and articles written in the English language were selected based on full text availability. EXPERT OPINION: If oritavancin is proven to be a cost effective strategy for outpatient treatment and prevents complications of prolonged i.v. therapy, it will be sought as an alternative antibiotic therapy for ABSSSIs. In addition, further clinical data demonstrating efficacy in Gram positive infections requiring prolonged therapy such as endocarditis and osteomyelitis could support oritavancin's success in the current market. PMID- 25803199 TI - The flavan-isoflavan rearrangement: bioinspired synthetic access to isoflavonoids via 1,2-shift-alkylation sequence. AB - An approach to 2-substituted isoflavonoids is reported based on the 1,2-shift of the aryl group in the catechin skeleton followed by the in situ alkylation. Synthesis of (-)-equol, a natural isoflavan with estrogenic activities, was achieved. PMID- 25803201 TI - Anxiety in Huntington's Disease. AB - Anxiety is common in Huntington's disease (HD), though it has been under researched. The authors conducted a systematic review of anxiety in HD. The prevalence of anxiety in manifest HD ranged from 13% to 71%. No significant difference in anxiety between manifest and premanifest HD carriers was revealed. Anxiety appears to be associated with depression, suicide, irritability, quality of life (QoL), pain, illness beliefs, and coping styles but does not seem to be linked with measures of disease progression. From the few pilot studies available, interventions that show promise include olanzapine and psychosocial approaches. Improved assessment, more exploration of the nature of anxiety in HD, and evaluation of anxiety interventions are required. PMID- 25803202 TI - Probing the intrinsic failure mechanism of fluorinated amorphous carbon film based on the first-principles calculations. AB - Fluorinated amorphous carbon films exhibit superlow friction under vacuum, but are prone to catastrophic failure. Thus far, the intrinsic failure mechanism remains unclear. A prevailing view is that the failure of amorphous carbon film results from the plastic deformation of substrates or strong adhesion between two contacted surfaces. In this paper, using first-principles and molecular dynamics methodology, combining with compressive stress-strain relation, we firstly demonstrate that the plastic deformation induces graphitization resulting in strong adhesion between two contacted surfaces under vacuum, which directly corresponds to the cause of the failure of the films. In addition, sliding contact experiments are conducted to study tribological properties of iron and fluorinated amorphous carbon surfaces under vacuum. The results show that the failure of the film is directly attributed to strong adhesion resulting from high degree of graphitization of the film, which are consistent with the calculated results. PMID- 25803203 TI - Associations Between the Rotter Incomplete Sentences Blank and Measures of Personality and Psychopathology. AB - The Rotter Incomplete Sentences Blank (RISB; Rotter, Lah, & Rafferty, 1992) is a sentence completion test intended to detect psychological maladjustment. To investigate the construct validity of the measure, we investigated what aspects of personality and psychopathology are correlated with the RISB and also tested the incremental validity of the RISB in a combined sample of clinical (n = 72) and undergraduate participants (n = 69). Interrater reliability of the RISB was good (intraclass correlation > .80). The RISB overall adjustment score discriminated between clinical and undergraduate participants, and high scores on the RISB were associated with higher negative affect, more anxiety and depression, irrational thinking, and interpersonal problems. The incremental validity of the RISB was modest, but it did explain variance in satisfaction with life and personality disorder symptoms above and beyond an extracted measure of general psychological distress. Our findings support the construct validity of the RISB. PMID- 25803204 TI - Mothers' use of information and communication technologies for information seeking. AB - Previous studies have revealed that information and communication technologies (ICTs) play a crucial role in parenting. Utilizing a national sample of mothers, the current study addresses mothers' information-seeking behaviors using ICTs utilizing the sense-making theoretical approach. Specifically, the study explored mothers' gap-bridging activities via online information venues including blogs, discussion boards/chatrooms, e-mailed newsletters, and online courses. Further, the associations were examined between mothers' demographic characteristics and their patterns of gap-bridging activities using online information venues. Latent class analysis revealed five latent classes: limited gap bridging, active gap bridging, problem identifiers, perspective explorers, and reassurance seekers. The "limited gap bridging" latent class was the most common class across online information venues. The other latent classes illustrate a more complex picture of mothers' gap-bridging activities depending on their needs. Mothers' demographic characteristics were associated with their patterns of gap-bridging activities. Implications of these findings for future research are discussed. PMID- 25803206 TI - Control of Forster energy transfer in the vicinity of metallic surfaces and hyperbolic metamaterials. AB - Optical cavities, plasmonic structures, photonic band crystals and interfaces, as well as, generally speaking, any photonic media with homogeneous or spatially inhomogeneous dielectric permittivity (including metamaterials) have local densities of photonic states, which are different from that in vacuum. These modified density of states environments are known to control both the rate and the angular distribution of spontaneous emission. In the present study, we question whether the proximity to metallic and metamaterial surfaces can affect other physical phenomena of fundamental and practical importance. We show that the same substrates and the same nonlocal dielectric environments that boost spontaneous emission, also inhibit Forster energy transfer between donor and acceptor molecules doped into a thin polymeric film. This finding correlates with the fact that in dielectric media, the rate of spontaneous emission is proportional to the index of refraction n, while the rate of the donor-acceptor energy transfer (in solid solutions with a random distribution of acceptors) is proportional to n(-1.5). This heuristic correspondence suggests that other classical and quantum phenomena, which in regular dielectric media depend on n, can also be controlled with custom-tailored metamaterials, plasmonic structures, and cavities. PMID- 25803200 TI - From marrow to matrix: novel gene and cell therapies for epidermolysis bullosa. AB - Epidermolysis bullosa encompasses a group of inherited connective tissue disorders that range from mild to lethal. There is no cure, and current treatment is limited to palliative care that is largely ineffective in treating the systemic, life-threatening pathology associated with the most severe forms of the disease. Although allogeneic cell- and protein-based therapies have shown promise, both novel and combinatorial approaches will undoubtedly be required to totally alleviate the disorder. Progress in the development of next-generation therapies that synergize targeted gene-correction and induced pluripotent stem cell technologies offers exciting prospects for personalized, off-the-shelf treatment options that could avoid many of the limitations associated with current allogeneic cell-based therapies. Although no single therapeutic avenue has achieved complete success, each has substantially increased our collective understanding of the complex biology underlying the disease, both providing mechanistic insights and uncovering new hurdles that must be overcome. PMID- 25803208 TI - Indirect-to-direct band gap crossover in few-layer MoTe2. AB - We study the evolution of the band gap structure in few-layer MoTe2 crystals, by means of low-temperature microreflectance (MR) and temperature-dependent photoluminescence (PL) measurements. The analysis of the measurements indicate that in complete analogy with other semiconducting transition metal dichalchogenides (TMDs) the dominant PL emission peaks originate from direct transitions associated with recombination of excitons and trions. When we follow the evolution of the PL intensity as a function of layer thickness, however, we observe that MoTe2 behaves differently from other semiconducting TMDs investigated earlier. Specifically, the exciton PL yield (integrated PL intensity) is identical for mono and bilayer, decreases slightly for trilayer, and it is significantly lower in the tetralayer. The analysis of this behavior and of all our experimental observations is fully consistent with mono and bilayer MoTe2 being direct band gap semiconductors with tetralayer MoTe2 being an indirect gap semiconductor and with trilayers having nearly identical direct and indirect gaps. This conclusion is different from the one reached for other recently investigated semiconducting transition metal dichalcogenides for which monolayers are found to be direct band gap semiconductors, and thicker layers have indirect band gaps that are significantly smaller (by hundreds of meV) than the direct gap. We discuss the relevance of our findings for experiments of fundamental interest and possible future device applications. PMID- 25803207 TI - Efficacy of C1 esterase inhibitor concentrate in treatment of cutaneous attacks of hereditary angioedema. AB - BACKGROUND: Although treatment with C1 esterase inhibitor (C1-INH) concentrate is well established for hereditary angioedema (HAE) attacks in general, data that assess its efficacy for cutaneous attack treatment are sparse. OBJECTIVE: To assess efficacy of plasma-derived, nanofiltered C1-INH concentrate for cutaneous attack treatment by comparing treated attacks from the uncontrolled I.M.P.A.C.T.2 study with historical data for untreated attacks. METHODS: Cutaneous attack data from patients with HAE who were treated for cutaneous edema with 20 IU/kg body weight C1-INH concentrate in the uncontrolled I.M.P.A.C.T.2 study (38 patients) were compared with data from untreated patients from an historical data base (46 patients) and included subset analyses for facial edema (treated group, 21 patients; untreated group, 33 patients) and peripheral edema (30 patients in each group). Average attack duration (AAD) per patient was the efficacy end point used to compare treated and untreated patients. Differences were assessed with a Wilcoxon test (primary analysis) and a log-rank test; AAD per patient was analyzed descriptively and graphically with Kaplan-Meier curves. RESULTS: The AAD per patient of all cutaneous attacks or facial and peripheral cutaneous attack subsets was significantly faster with C1-INH treatment than without treatment (Wilcoxon and log-rank tests, both p < 0.0001 for all comparisons). Mean AADs per patient for all, facial, and peripheral attacks were 2.04, 1.45, and 2.16 days, respectively, in the C1-INH-treated group, and were 3.74, 4.45, and 2.98 days, respectively, in the untreated group. Kaplan-Meier curves corroborated the observed group differences. CONCLUSION: Treatment of cutaneous HAE attacks (all attacks or facial and peripheral attack subsets) with 20 IU/kg C1-INH concentrate provided faster attack resolution compared with no treatment. PMID- 25803209 TI - Tricholoma matsutake fruit bodies secrete hydrogen peroxide as a potent inhibitor of fungal growth. AB - Tricholoma matsutake is an ectomycorrhizal fungus that dominates the microbial communities in the soil of pine and spruce forests. The mycorrhizas of this fungus have antimicrobial activity, although factors responsible for the antimicrobial activity have not been fully elucidated. The present study shows that fruit bodies of T. matsutake secreted hydrogen peroxide (H2O2), which was produced by pyranose oxidase, and that the H2O2 thus secreted strongly inhibited the growth of mycelia of the phytopathological fungus Rhizoctonia solani. These findings suggest that fruit bodies of T. matsutake have antifungal activity and that the pyranose oxidase plays an important role in the antifungal activity. PMID- 25803210 TI - A new take on term pregnancy. PMID- 25803211 TI - Colostrum versus formula supplementation for glucose stabilization in newborns of diabetic mothers. AB - The purpose of this article is to describe practice change designed to facilitate breastfeeding while maintaining glucose stabilization in infants born to diabetic mothers. Postpractice change outcomes of newborn blood glucose levels, formula supplementation, and colostrum feeds are specifically addressed. There were no significant differences between glucose values for infants given formula supplementation versus those fed colostrum. Postpractice change, admissions to the neonatal intensive care unit (NICU) for glucose stabilization decreased and exclusive breastfeeding increased. PMID- 25803214 TI - Knowledge and attitudes toward breastfeeding in an African American male population. AB - OBJECTIVE: To measure knowledge and attitudes toward breastfeeding among African American men. DESIGN: Cross-sectional survey. SETTING: Three barbershops in Dallas, Texas. PARTICIPANTS: African American adult men (N = 81). METHODS: Surveys were completed by African American men to evaluate their knowledge, attitudes, and involvement in breastfeeding. RESULTS: One half of the participants were age 26 to 40. Eighty-five percent were U.S.-born, and others were born in several African countries. Education varied from some high school to postgraduate. Most had some college or a degree (78%). One half were fathers (51%), and most were single (61%). Most had witnessed breastfeeding (85%), and 58% preferred their infants to be breastfed. Only 47% knew that breastfeeding helps prevent infant infections, and 15% knew it can prevent breast cancer in the mother. Significant differences were found when comparing knowledge and attitudes by place of birth and age. Almost one half of men age 18 to 25 (43%) and age 25 to 40 (48%) felt that breastfeeding should not occur in public compared to only 4% of men older than 40 (p = .005). CONCLUSION: Overall, we found that African American men were supportive of breastfeeding, knew that breastfeeding was best for infants, and had positive attitudes toward breastfeeding. However, we found consistent gaps in knowledge about the actual health benefits to mothers and infants and conflicting attitudes toward breastfeeding. Results emphasize the need for health education efforts to improve attitudes toward breastfeeding in public. PMID- 25803215 TI - Current resources for evidence-based practice, November/December 2013. PMID- 25803217 TI - Does home attachment contribute to strengthen sense of coherence in times of war? Perspectives of Jewish Israeli mothers. AB - The perceptions of home, the significance attached to the home, and the reasons for the decision to continue living at home despite past and potentially future threats were investigated among Jewish Israeli mothers whose homes were exposed to long-term rocket attacks. Findings showed that the mothers expressed a firm attachment to their homes and to their physical and social surroundings and indicated that home attachment, in terms of thoughts, feelings, and behaviors connected to home, contributed to the strengthening of their sense of coherence due to the comprehension, management, and the meaning that they accorded the situation. These components of sense of coherence served as assets and coping resources that helped the women handle their stressful situations. PMID- 25803216 TI - Genomics in pregnancy. PMID- 25803213 TI - Maternal satisfaction with administering infant interventions in the neonatal intensive care unit. AB - OBJECTIVE: To examine mothers' satisfaction with administering interventions for their preterm infants and with the helpfulness of the study nurse by comparing massage with auditory, tactile, visual, and vestibular stimulation (ATVV intervention), kangaroo care, and education about equipment needed at home and to explore whether mother and infant characteristics affected maternal satisfaction ratings. DESIGN: Three-group experimental design. SETTING: Four neonatal intensive care units (NICUs) (two in North Carolina, two in Illinois). PARTICIPANTS: Two hundred and eight (208) preterm infants and their mothers. METHODS: When the infant was no longer critically ill, mother/infant dyads were randomly assigned to ATVV, kangaroo care, or the education group all taught by study nurses. At discharge and 2 months corrected age, mothers completed questionnaires. RESULTS: All groups were satisfied with the intervention and with nurse helpfulness, and the degree of satisfaction did not differ among them. Intervention satisfaction, but not nurse helpfulness, was related to recruitment site. Older, married, and minority mothers were less satisfied with the intervention but only at 2 months. Higher anxiety was related to lower intervention satisfaction at discharge and lower ratings of nurse helpfulness at discharge and 2 months. More depressive symptoms were related to lower nurse helpfulness ratings at 2 months. CONCLUSIONS: Mothers were satisfied with interventions for their infants regardless of the intervention performed. Maternal satisfaction with the intervention was related to recruitment site, maternal demographic characteristics, and maternal psychological distress, especially at 2 months. Thus, nursing interventions that provide mothers with a role to play in the infant's care during hospitalization are particularly likely to be appreciated by mothers. PMID- 25803218 TI - Physiological Activity of Spinal Cord in Children: An 18F-FDG PET-CT Study. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate, in a pediatric population, F-Fluoro-deoxy-glucose (F-FDG) metabolic activity of normal spinal cord and to assess the correlation with demographic, clinical, and environmental variables. SUMMARY OF BACKGROUND DATA: F-FDG uptake of normal spinal cord is variable in children. The knowledge of physiological metabolism of spinal cord is essential to distinguish normal from pathological findings by positron emission tomography-computed tomography (PET-CT). METHODS: We retrospectively evaluated F FDG positron emission tomography-computed tomography scans from a total of 167 pediatric patients (97 males; 3.9-18.9 yr) divided into 4 age groups (0-4.9 yr, 5 9.9 yr, 10-14.9 yr, and 15-18.9 yr), excluding those submitted to previous or recent therapeutic procedures influencing spinal cord metabolism or with central nervous system diseases. Spinal cord was divided into 3 levels (C1-C7; D1-D6; and D7-L1), and maximum standardized uptake value (SUVmax) of each cord level was measured. Correlations between SUVmax and spinal cord level, age, body weight, sex, type of disease, and season were statistically assessed. RESULTS: Median SUVmax was similar and significantly (P < 0.01) higher at C1-C7 and D7-L1 levels than at D1-D6 level and it significantly (P < 0.01) increased with age in all spinal cord levels. A positive and significant association between SUVmax and body weight, female sex, and Hodgkin lymphoma was found. No significant association with season was observed. By multivariate analysis, only weight and female sex remained significant. CONCLUSION: Knowledge of physiological F-FDG spinal cord activity in children is essential for a correct interpretation of positron emission tomography-computed tomography, especially in oncologic pediatric patients to avoid potential pitfalls. LEVEL OF EVIDENCE: N/A. PMID- 25803219 TI - Diagnostic Accuracy of Lumbosacral Spine Magnetic Resonance Image Reading by Chiropractors, Chiropractic Radiologists, and Medical Radiologists. AB - STUDY DESIGN: A cross-sectional diagnostic accuracy study was conducted in 2 sessions. OBJECTIVE: It is important to know whether it is possible to accurately detect "specific findings" on lumbosacral magnetic resonance (MR) images and whether the results of different observers are comparable. SUMMARY OF BACKGROUND DATA: Health care providers frequently use magnetic resonance imaging in the diagnostic process of patients with low back pain. The use of MR scans is increasing. This leads to an increase in costs and to an increase in risk of inaccurately labeling patients with an anatomical diagnosis that might not be the actual cause of symptoms. METHODS: A set of 300 blinded MR images was read by medical radiologists, chiropractors, and chiropractic radiologists in 2 sessions. Each assessor read 100 scans in round 1 and 50 scans in round 2. The reference test was an expert panel.For all analyses, the magnetic resonance imaging findings were dichotomized into "specific findings" or "no specific findings." For the agreement, percentage agreement and kappa values were calculated and for validity, sensitivity, and specificity. Sensitivity analysis was done for classifications A and B (prevalence of 31% and 57%, respectively). RESULTS: The intraobserver kappa values for chiropractors, chiropractic radiologists, and medical radiologists were 0.46, 0.49, and 0.69 for A and 0.55, 0.75, and 0.64 for B, respectively.The interobserver kappa values were lowest for chiropractors (0.28 for A, 0.37 for B) and highest for chiropractic radiologists (0.50 for A, 0.49 for B).The sensitivities of the medical radiologists, chiropractors, and chiropractic radiologists were 0.62, 0.71, and 0.75 for A and 0.70, 0.74, 0.84 for B, respectively.The specificities of medical radiologists, chiropractic radiologists, and chiropractors were 0.82, 0.77, and 0.70 for A and 0.74, 0.52, and 0.61 for B, respectively. CONCLUSION: Agreement and validity of MR image readings of chiropractors and chiropractic and medical radiologists is modest at best. This study supports recommendations in clinical guidelines against routine use of magnetic resonance imaging in patients with low back pain. LEVEL OF EVIDENCE: 3. PMID- 25803220 TI - Predictors of Vertebral Artery Injury in Isolated C2 Fractures Based on Fracture Morphology Using CT Angiography. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To determine C2 fracture patterns associated with vertebral artery injury (VAI) as assessed by computed tomography angiography. SUMMARY OF BACKGROUND DATA: The incidence of C2 fracture hospitalizations has increased significantly in the last decade. The vertebral arteries are susceptible to injury as each courses through the C2 transverse foramen. Early screening for VAI to institute antithrombotic treatment is critical to prevent ischemic neurological sequelae. Imaging-based fracture classification schemes to determine which patterns are predictors of VAI in isolated C2 fractures using computed tomography angiography have not been described. METHODS: Cervical spine computed tomographic (CT) scans at a level I trauma center were reviewed for isolated C2 fractures from 2004 to 2014 under institutional board review approval. Exclusion criteria included penetrating injury or additional cervical/occipital fractures. Fractures were classified using multiplanar CT scans into type I/II/IIa/III spondylolisthesis, type I/IIA/IIB/IIC/III dens, transverse foramen (displacement/comminution/intraforaminal fragments), and miscellaneous vertebral body fractures. Corresponding CT angiograms were assessed for VAI on the basis of the Denver grading criteria. Fisher exact test and Student t test were performed to determine predictors of VAI on the basis of fracture type. RESULTS: Sixty seven patients met inclusion criteria. Fracture pattern analysis revealed that the majority were dens fractures (50.8%) and traumatic spondylolisthesis (41.8%); 29.9% had miscellaneous coronal/sagittal fractures and 22.4% were a combination.VAI was identified in 37.3% of patients with isolated C2 fractures, and 88% of patients had transverse foramen involvement. Fracture patterns significantly associated with VAI were type III dens and transverse foramen fractures with intraforaminal fragments, with or without comminution. CONCLUSION: The C2 fracture pattern most associated with VAI was comminuted transverse foramen fracture with intraforaminal fragments. Transverse foramen fracture alone was not found to be significant. These results help stratify patients with isolated C2 fractures who are at high VAI risk and should be further evaluated with computed tomography angiography. LEVEL OF EVIDENCE: 3. PMID- 25803221 TI - Proximal Junctional Failure After Long-Segment Instrumentation for Degenerative Lumbar Kyphosis With Ankylosing Spinal Disorder. AB - STUDY DESIGN: Case report. OBJECTIVE: We report a case of proximal junctional failure at the ankylosed, but not the mobile, junction after segmental instrumented fusion for degenerative lumbar kyphosis with ankylosing spinal disorder. SUMMARY OF BACKGROUND DATA: Proximal junctional failure (PJF) and proximal junctional kyphosis (PJK) are important complications that occur subsequent to long-segment instrumentation for correction of adult spinal deformity. Thus far, most studies have focused on the mobile junction as a site at which PJK/PJF can occur, and little is known about the relationship between PJK/PJF and ankylosing spinal disorders such as diffuse idiopathic skeletal hyperostosis. METHODS: The patient was an 82-year-old female with degenerative lumbar kyphosis. She had abnormal confluent hyperostosis in the anterior longitudinal ligaments from Th5 to Th10. The patient was treated operatively with spinal instrumented fusion from Th10 to the sacrum. RESULTS: Four weeks subsequent to initial surgery, the patient developed progressive lower extremity paresis caused by the uppermost instrumented vertebrae fracture (Th10) and adjacent subluxation (Th9). Extension of fusion to Th5 with decompression at Th9 Th10 was performed. However, the patient showed no improvement in neurological function. CONCLUSION: PJF can occur at the ankylosing site above the uppermost instrumented vertebrae after long-segment instrumentation for adult spinal deformity. PJF in the ankylosed spine may cause severe fracture instability and cord deficit. The ankylosed spine should be integrated into the objective determination of materials contributing to the appropriate selection of fusion levels. LEVEL OF EVIDENCE: 3. PMID- 25803222 TI - "Surprise" Loading in Flexion Increases the Risk of Disc Herniation Due to Annulus-Endplate Junction Failure: A Mechanical and Microstructural Investigation. AB - STUDY DESIGN: Microstructural investigation of compression-induced herniation of the flexed lumbar disc. OBJECTIVE: To provide a microstructural analysis of the mechanisms of annular wall failure in healthy discs subjected to flexion and a rate of compression comparable with the maximum rate at which the muscles of the spinal column can generate a force. SUMMARY OF BACKGROUND DATA: Clinical evidence indicates the involvement of the endplate in herniation. It is known that both an elevated rate of compression and a flexed posture are necessary to cause disc failure either within the midspan of the annulus or at the annular-endplate interface. However, the question of what effect a sudden or "surprise" loading might have on the mode of failure is, as yet, unanswered. METHODS: Twenty-four healthy mature ovine lumbar motion segments were compressed to failure in high physiological flexion (10o). This occurred over approximately 5 mm of crosshead displacement in 0.75 seconds that resulted in a displacement rate of 400 mm/min (defined as a "surprise" rate) and was intended to simulate the maximum rate at which the muscles of the spinal column can generate a force. The damaged discs were then analyzed microstructurally. RESULTS: Fifty-eight percent of discs suffered annular-endplate junction rupture, 25% suffered midspan annular rupture, and the balance of 17% endplate fracture. Microstructural analysis indicated that annular rupture initiated at the endplate apical ridge in the mid-to-outer region of the annulus in both annular-endplate and midspan annulus rupture. CONCLUSION: Motion segments subjected to a "surprise" loading rate are likely to fail via some form of annular rupture. Failure under such sudden loading occurs mostly via rupture of the annular-endplate junction and is thought to arise from a rate induced mechanostructural imbalance between the annulus and the endplate. LEVEL OF EVIDENCE: N/A. PMID- 25803224 TI - Conventional and novel imaging modalities in osteoarthritis: current state of the evidence. AB - PURPOSE OF REVIEW: Imaging modalities are currently an inseparable part of osteoarthritis diagnosis. In this review, we describe the current state of evidence regarding conventional and novel imaging modalities in evaluation of osteoarthritis. Modalities including radiography (qualitative and semi quantitative assessments), ultrasonography, computed tomography [CT; conventional multidetector CT (MDCT), cone-beam CT (CBCT) and four-dimensional CT (4DCT)], MRI (MRI; semi-quantitative, quantitative and compositional) and PET and their applications are reviewed. RECENT FINDINGS: Radiography is the modality of choice for initial assessment of osteoarthritis. However, due to its low sensitivity and specificity, numerous recent investigations have proposed MRI as a powerful addition to detect and grade osteoarthritis features, which are not apparent in radiography. Semi-quantitative MRI measurements are feasible to perform in routine clinical practice. Quantitative and compositional MRI measurements have extended the amount of information an MRI examination can provide regarding the three-dimensional shape and tissue composition of articular cartilage. 4DCT and CBCT are introduced as imaging examinations that may reveal biomechanical cartilage abnormalities in osteoarthritis joint by dynamic and weight-bearing evaluations, respectively. Recent PET studies may unveil the underlying metabolic activities that can be associated with osteoarthritis. SUMMARY: In addition to the established role of radiographs, MRI is the advanced modality of choice for detection and quantification of various osteoarthritis features. 4DCT and CBCT may have specified applications when diagnosis of underlying motion abnormality or dynamic changes in weight-bearing situation is suspected. Future studies should elucidate the specific clinical applications of ultrasonography and PET. PMID- 25803225 TI - Osteoarthritis research: current state of the evidence. PMID- 25803228 TI - Recent advances in electrochemiluminescence. AB - The great success of electrochemiluminescence (ECL) for in vitro diagnosis (IVD) and its promising potential in light-emitting devices greatly promote recent ECL studies. More than 45% of ECL articles were published after 2010, and the first international meeting on ECL was held in Italy in 2014. This critical review discusses recent vibrant developments in ECL, and highlights novel ECL phenomena, such as wireless ECL devices, bipolar electrode-based ECL, light-emitting electrochemical swimmers, upconversion ECL, ECL resonance energy transfer, thermoresponsive ECL, ECL using shape-controlled nanocrystals, and ECL as an ion selective electrode photonic reporter, a paper-based microchip, and a self powered microfluidic ECL platform. We also comment on the latest progress in bioassays, light-emitting devices and, the computational approach for the ECL mechanism study. Finally, perspectives and key challenges in the near future are addressed (198 references). PMID- 25803227 TI - Post-traumatic stress syndrome in a large sample of older adults: determinants and quality of life. AB - OBJECTIVES: The aims of this study are to assess in a sample of older adults consulting in primary care practices the determinants and quality of life associated with post-traumatic stress syndrome (PTSS). METHOD: Data used came from a large sample of 1765 community-dwelling older adults who were waiting to receive health services in primary care clinics in the province of Quebec. PTSS was measured with the PTSS scale. Socio-demographic and clinical characteristics were used as potential determinants of PTSS. Quality of life was measured with the EuroQol-5D-3L (EQ-5D-3L) EQ-Visual Analog Scale and the Satisfaction With Your Life Scale. Multivariate logistic and linear regression models were used to study the presence of PTSS and different measures of health-related quality of life and quality of life as a function of study variables. RESULTS: The six-month prevalence of PTSS was 11.0%. PTSS was associated with age, marital status, number of chronic disorders and the presence of an anxiety disorder. PTSS was also associated with the EQ-5D-3L and the Satisfaction with Your Life Scale. CONCLUSION: PTSS is prevalent in patients consulting in primary care practices. Primary care physicians should be aware that PTSS is also associated with a decrease in quality of life, which can further negatively impact health status. PMID- 25803226 TI - A mobile telehealth intervention for adults with insulin-requiring diabetes: early results of a mixed-methods randomized controlled trial. AB - BACKGROUND: The role of technology in health care delivery has grown rapidly in the last decade. The potential of mobile telehealth (MTH) to support patient self management is a key area of research. Providing patients with technological tools that allow for the recording and transmission of health parameters to health care professionals (HCPs) may promote behavior changes that result in improved health outcomes. Although for some conditions the evidence of the effectiveness of MTH is clear, to date the findings on the effects of MTH on diabetes management remain inconsistent. OBJECTIVE: This study aims to evaluate an MTH intervention among insulin-requiring adults with diabetes to establish whether supplementing standard care with MTH results in improved health outcomes-glycated hemoglobin (HbA1c), blood pressure (BP), health-related quality of life (HRQoL), diabetes self-management behaviors, diabetes health care utilization, and diabetes self efficacy and illness beliefs. An additional objective was to explore the acceptability of MTH and patients' perceptions of, and experience, using it. METHODS: A mixed-method design consisting of a 9-month, two-arm, parallel randomized controlled trial (RCT) was used in combination with exit qualitative interviews. Quantitative data was collected at baseline, 3 months, and 9 months. Additional intervention fidelity data, such as participants' MTH transmissions and contacts with the MTH nurse during the study, were also recorded. RESULTS: Data collection for both the quantitative and qualitative components of this study has ended and data analysis is ongoing. A total of 86 participants were enrolled into the study. Out of 86 participants, 45 (52%) were randomized to the intervention group and 36 (42%) to the control group. Preliminary data on MTH training sessions and MTH usage by intervention participants are presented in this paper. We expect to publish complete study results in 2015. CONCLUSIONS: The range of data collected in this study will allow for a comprehensive evaluation of processes and outcomes. The early results presented suggest that MTH usage decreases over time and that MTH participants would benefit from attending more than one training session. TRIAL REGISTRATION: ClinicalTrials.gov NCT00922376; http://clinicaltrials.gov/ct2/show/NCT00922376 (Archived by WebCite at http://www.webcitation.org/6Vu4nhLI6). PMID- 25803230 TI - Procalcitonin as Biomarker of Infection: Implications for Evaluation and Treatment. AB - Procalcitonin (PCT) is a quickly measurable marker, assumed to have high sensitivity and specificity for sepsis and infection. A literature search was conducted to evaluate PCT ability as a diagnostic and prognostic tool in infectious processes and its ability to monitor the antibiotic therapy. PCT level is increased in bacterial and fungal infections, but not in viral infections, with a significantly higher level in patients with bacteremia compared with uninfected patients (2.5 vs. 0.3 ng/mL; P < 0.0001). A PCT value of <=0.1 ng/mL discards bacteremia and microbiological tests (negative predictive value of 96.3%), >0.1 ng/mL needs microbiological tests, and >1.0 ng/mL is indicative of bacteremia. Antibiotic treatment algorithms guided by PCT decreased the need for antibiotic treatment in approximately 50%. PCT is a promising test in clinical practice to decide the introduction of antibiotic therapy in addition to the existing tools, without neglecting the clinical assessment, with a significant decrease in costs. PMID- 25803229 TI - MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN. AB - Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR-21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC. PMID- 25803231 TI - Treatment for IgG and IgA paraproteinaemic neuropathy. AB - BACKGROUND: Paraproteinaemic neuropathy refers to those neuropathies associated with a monoclonal gammopathy or paraprotein. The most common of these present with a chronic, predominantly sensory, symmetrical neuropathy, similar to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but with relatively more sensory involvement, both clinically and neurophysiologically. The optimal treatment for neuropathies associated with IgG and IgA monoclonal gammopathy of uncertain significance is not known. This is an update of a review first published in 2007. OBJECTIVES: To assess the effects of any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. SEARCH METHODS: On 18 January 2014 we searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, CENTRAL, MEDLINE and EMBASE. We also checked bibliographies for controlled trials of treatments for IgG or IgA paraproteinaemic peripheral neuropathy. We checked clinical trials registries for ongoing studies in November 2014. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) and quasi-RCTs using any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. We excluded people with IgM paraproteins. We excluded people where the monoclonal gammopathy was considered secondary to an underlying disorder. We included participants of any age with a diagnosis of monoclonal gammopathy of uncertain significance with a paraprotein of the IgG or IgA class and a neuropathy. Included participants were not required to fulfil specific electrophysiological diagnostic criteria. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology to select studies, extract data and analyse results. One trial author provided additional data and clarification. MAIN RESULTS: We identified one RCT, with 18 participants, that fulfilled the predetermined inclusion criteria. The trial compared plasma exchange to sham plasma exchange in participants with IgG or IgA paraproteinaemic neuropathy over a three-week follow-up period. We identified four other studies but these were not RCTs or quasi-RCTs. The included RCT did not report our predefined primary outcome measure, change in disability six months after randomisation. The trial revealed a modest benefit of plasma exchange in the weakness component of the Neuropathy Disability Score (NDS, now the Neuropathy Impairment Score); the mean improvement with plasma exchange was 17 points (95% confidence interval (CI) 5.2 to 28.8 points) versus 1 point (95% CI -7.7 to 9.7 points) in the sham exchange group at three weeks' follow-up (mean difference (MD) 16.00; 95% CI 1.37 to 30.63, low quality evidence). There was no statistically significant difference in the overall NDS (MD 18.00; 95% CI -2.03 to 38.03, low quality evidence), vibration thresholds or neurophysiological indices. Adverse events were not reported. The trial was at low risk of bias overall, although limitations of trial size and duration reduce the quality of the evidence in support of its conclusions. AUTHORS' CONCLUSIONS: The evidence from RCTs for the treatment of IgG or IgA paraproteinaemic neuropathy is currently inadequate. More RCTs of treatments are required. These should have adequate follow-up periods and contain larger numbers of participants, perhaps through multicentre collaboration, considering the relative infrequency of this condition. Observational or open trial data provide limited support for the use of treatments such as plasma exchange, cyclophosphamide combined with prednisolone, intravenous immunoglobulin, and corticosteroids. These interventions show potential therapeutic promise but the potential benefits must be weighed against adverse effects. Their optimal use and the long-term benefits need to be considered and validated with well-designed RCTs. PMID- 25803236 TI - Leading the way: changing the focus from teaching to learning in large subjects with limited budgets. AB - To lead positive change in the teaching practice of teams that service large numbers of diverse students from multiple degree programs provides many challenges. The primary aim of this study was to provide a clear framework on which to plan the process of change that can be utilized by academic departments sector wide. Barriers to change were reduced by adapting and utilizing Kotter's principals of change specifically by creating a sense of urgency and defining a clear goal designed to address the problem. Changing attitudes involved training staff in new teaching and learning approaches and strategies, and creating a collaborative, supportive team-based teaching environment within which the planned changes could be implemented and evaluated. As a result senior academics are now directly involved in delivering sections of the face-to-face teaching in the new environment. Through promoting positive change we enabled deeper student engagement with the theoretical concepts delivered in lectures as evidenced by favorable student evaluations, feedback, and improved final exam results. A collaborative team-based approach that recognizes the importance of distributed leadership combined with a clearly articulated change management process were central to enabling academics to design, try, and evaluate the new teaching and learning practices. Our study demonstrates that a concerted focus on "change management" enabled teaching team members to adopt a major shift in the teaching and learning approach that resulted in measurable improvements in student learning. PMID- 25803232 TI - Optimization of multi-pulse sequences for nonlinear contrast agent imaging using a cMUT array. AB - Capacitive micromachined ultrasonic transducer (cMUT) technology provides advantages such as wide frequency bandwidth, which can be exploited for contrast agent imaging. Nevertheless, the efficiency of traditional multi-pulse imaging schemes, such as pulse inversion (PI), remains limited because of the intrinsic nonlinear character of cMUTs. Recently, a new contrast imaging sequence, called bias voltage modulation sequence (BVM), has been specifically developed for cMUTs to suppress their unwanted nonlinear behavior. In this study, we propose to optimize contrast agent detection by combining the BVM sequence with PI and/or chirp reversal (CR). An aqueous dispersion of lipid encapsulated microbubbles was exposed to several combinations of multi-pulse imaging sequences. Approaches were evaluated in vitro using 9 inter-connected elements of a cMUT linear array (excitation frequency of 4 MHz; peak negative pressure of 100 kPa). For sequences using chirp excitations, a specific compression filter was designed to compress and extract several nonlinear components from the received microbubble responses. A satisfactory cancellation of the nonlinear signal from the source is achieved when BVM is combined with PI and CR. In comparison with PI and CR imaging modes alone, using sequences incorporating BVM increases the contrast-to-tissue ratio by 10.0 dB and 4.6 dB, respectively. Furthermore, the combination of BVM with CR and PI results in a significant increase of the contrast-to-noise ratio (+29 dB). This enhancement is attributed to the use of chirps as excitation signals and the improved preservation of several nonlinear components contained within the contrast agent response. PMID- 25803237 TI - Training-Load Distribution in Endurance Runners: Objective Versus Subjective Assessment. AB - PURPOSE: To assess the distribution of exercise intensity in long-distance recreational athletes (LDRs) preparing for a marathon and to test the hypothesis that individual perception of effort could provide training responses similar to those provided by standardized training methodologies. METHODS: Seven LDRs (age 36.5 +/- 3.8 y) were followed during a 5-mo training period culminating with a city marathon. Heart rate at 2.0 and 4.0 mmol/L and maximal heart rate were used to establish 3 intensity training zones. Internal training load (TL) was assessed by training zones and TRIMPi methods. These were compared with the session-rating of-perceived-exertion (RPE) method. RESULTS: Total time spent in zone 1 was higher than in zones 2 and 3 (76.3% +/- 6.4%, 17.3% +/- 5.8%, and 6.3% +/- 0.9%, respectively; P = .000 for both, ES = 0.98, ES = 0.99). TL quantified by session RPE provided the same result. The comparison between session-RPE and training zones-based methods showed no significant difference at the lowest intensity (P = .07, ES = 0.25). A significant correlation was observed between TL RPE and TL TRIMPi at both individual and group levels (r = .79, P < .001). There was a significant correlation between total time spent in zone 1 and the improvement at the running speed of 2 mmol/L (r = .88, P < .001). A negative correlation was found between running speed at 2 mmol/L and the time needed to complete the marathon (r = -.83, P < .001). CONCLUSIONS: These findings suggest that in recreational LDRs most of the training time is spent at low intensity and that this is associated with improved performances. Session-RPE is an easy-to-use training method that provides responses similar to those obtained with standardized training methodologies. PMID- 25803238 TI - The prevalence and causes of visual impairment and blindness among older adults in the city of Lodz, Poland: erratum. AB - [In the article "The Prevalence and Causes of Visual Impairment and Blindness Among Older Adults in the City of Lodz, Poland", which appeared in Volume 94, Issue 5 of Medicine, the authors' affiliation line was omitted. The affiliation line should read as follows: From the Department of Ophthalmology and Visual Rehabilitation (MSN), and the Department of Geriatrics (JS), Medical University of Lodz, Lodz, Poland.]. PMID- 25803239 TI - Preparation and characterization of thin-film composite membrane with nanowire modified support for forward osmosis process. AB - Internal concentration polarization (ICP) in forward osmosis (FO) process is a characteristic problem for asymmetric thin-film composite (TFC) FO membrane which leads to lower water flux. To mitigate the ICP effect, modification of the substrates' properties has been one of the most effective methods. A new polyethersulfone-based ultrafiltration membrane with increased surface porosity and high water flux was recently produced by incorporating Zn2GeO4 nanowires. The composite membrane was used as a substrate for the fabrication of TFC FO membrane, by coating a thin layer of polyamide on top of the substrate. The substrate and the nanowires were characterized by a range of techniques such as SEM, XRD, and contact angle goniometry. The water permeability and molecular weight cut-offs (MWCO) of the substrate; and the FO performance of the TFC membrane were also determined. The Zn2GeO4-modified membrane showed ~45% increase in water permeability and NaCl salt rejection of 80% under RO mode. In FO mode, the ratio of water flux to reverse solute flux was also improved. However, lower FO flux was obtained which could be due to ICP. The result shows that Zn2GO4 nanowire may be used as a modifier to the substrate to improve the quality of the polyamide layer on the substrate to improve the flux and selectivity, but not as effective in reducing ICP. This work demonstrates that the incorporation of nanomaterials to the membrane substrate may be an alternative approach to improve the formation of polyamide skin layer to achieve better FO performance. PMID- 25803240 TI - Regional air quality management aspects of climate change: impact of climate mitigation options on regional air emissions. AB - We investigate the projected impact of six climate mitigation scenarios on U.S. emissions of carbon dioxide (CO2), sulfur dioxide (SO2), and nitrogen oxides (NOX) associated with energy use in major sectors of the U.S. economy (commercial, residential, industrial, electricity generation, and transportation). We use the EPA U.S. 9-region national database with the MARKet Allocation energy system model to project emissions changes over the 2005 to 2050 time frame. The modeled scenarios are two carbon tax, two low carbon transportation, and two biomass fuel choice scenarios. In the lower carbon tax and both biomass fuel choice scenarios, SO2 and NOX achieve reductions largely through pre-existing rules and policies, with only relatively modest additional changes occurring from the climate mitigation measures. The higher carbon tax scenario projects greater declines in CO2 and SO2 relative to the 2050 reference case, but electricity sector NOX increases. This is a result of reduced investments in power plant NOX controls in earlier years in anticipation of accelerated coal power plant retirements, energy penalties associated with carbon capture systems, and shifting of NOX emissions in later years from power plants subject to a regional NOX cap to those in regions not subject to the cap. PMID- 25803241 TI - Montelukast inhibits pentylenetetrazol-induced seizures in rats. AB - BACKGROUND: Montelukast is an antiinflammatory drug with an antioxidant property. In this study, we aimed to reveal whether montelukast has a preventive effect against seizures and post-seizure oxidative stress in pentylenetetrazol (PTZ) induced seizures in rats. MATERIAL AND METHODS: Of the 48 male Sprague-Dawley rats used in the study, 24 were assigned to EEG recordings (group A) and 24 were assigned to behavioral studies (group B). In group A, the electrodes were implanted on dura over the left frontal cortex for EEG recording. After 10 days, in group A, i.p. saline, 25, 50, or 100 mg/kg montelukast+35 mg/kg PTZ was administered to the rats. EEG was recorded and spike percentage was evaluated. In group B, i.p. saline, 25, 50, or 100 mg/kg montelukast+70 mg/kg PTZ was administered to the rats. Racine's Convulsion Scale (RCS) and onset times of first myoclonic jerk (FMJ) was used to evaluate the seizures. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined in the brain tissue of animals. RESULTS: Animals treated with 50 or 100 mg/kg montelukast had significantly lower RCS and significantly increased FMJ onset time compared to the saline-treated animals. Moreover, groups given 25, 50, or 100 mg/kg montelukast had significantly lower MDA and higher SOD levels compared to the saline-treated group. The differences were more pronounced in the 100 mg/kg montelukast-pretreated group (p<0.001). CONCLUSIONS: Montelukast showed anticonvulsant action and led to amelioration of oxidative stress markers in PTZ induced seizures in rats. PMID- 25803242 TI - Luminescent optical detection of volatile electron deficient compounds by conjugated polymer nanofibers. AB - Optical detection of volatile electron deficient analytes via fluorescence quenching is demonstrated using ca. 200 nm diameter template-synthesized polyfluorene nanofibers as nanoscale detection elements. Observed trends in analyte quenching effectiveness suggest that, in addition to energetic factors, analyte vapor pressure and polymer/analyte solubility play an important role in the emission quenching process. Individual nanofibers successfully act as luminescent reporters of volatile nitroaromatics at sub-parts per million levels. Geometric factors, relating to the nanocylindrical geometry of the fibers and to low nanofiber substrate coverage, providing a less crowded environment around fibers, appear to play a role in providing access by electron deficient quencher molecules to the excited states within the fibers, thereby facilitating the pronounced fluorescence quenching response. PMID- 25803244 TI - Contrast Enema for Hirschsprung Disease Investigation: Diagnostic Accuracy and Validity for Subsequent Diagnostic and Surgical Planning. AB - INTRODUCTION: A targeted Hirschsprung disease (HD) diagnostic is necessary, as it determines a specific approach primarily based on surgical resection of the affected aganglionic colonic segment. The aim of this study was to evaluate the diagnostic accuracy of a contrast enema (CE) for HD diagnosis and to determine whether it should be performed before or after rectal biopsies (RBs). METHODS: A retrospective observational study of children undergoing RB for HD investigation was performed. In the performed CE, the occurrence and the level of a colonic caliber change (CCC) were recorded and its concordance with the histologically assessed level of aganglionosis by RB and the odds ratio were calculated. RESULTS: A total of 107 cases were included. Sensitivity and specificity for a CCC in CE were 74.1% and 94.6%. A CCC present in CE was associated with a 50-fold increased probability for a histologically proven HD. The overall concordance between a CCC and the histologically assessed level of aganglionosis was high (kappa 0.642, p = 0.003), being correct in 94.4% of cases when the CCC was located in the rectosigmoid, but only in 50% of cases when it was located in more proximal segments. By performing a CE only after HD diagnosis confirmation by RB would avoid 67.5% of CE with no loss of diagnostic accuracy. CONCLUSION: We confirm that CE is a valuable tool for HD diagnosis; however, it should only be performed for subsequent diagnostic and surgical planning following histological confirmation of HD by RB. On the basis of this, an algorithm for an optimized investigation and management of HD is presented. PMID- 25803245 TI - Do timing of injection and status of the suction drain effect postoperative pain scores after intra-articular bupivacaine injection in arthroscopic ACL reconstruction? AB - OBJECTIVE: The aim of this study was to determine if the timing of intra articular local anesthetic injection and the status of the suction drain affect variable pain scores after ACL reconstruction. METHODS: The study included 40 patients undergoing arthroscopic ACL reconstruction randomized into 4 groups. Patients in Group 1 received intra-articular 20 ml of 0.25% bupivacaine 20 minutes before the start of the operation (preemptive: PE), Group 2 at the end of the operation with the suction drain opened (DO). Group 3 also received intra articular bupivacaine at the end of the operation and the drain was kept closed for one hour postoperatively (DC). Group 4 did not receive any intra-articular injection (control group: CG) and served as the control group. Visual analog scale (VAS) scores and additional analgesic requirements were recorded. RESULTS: The PE group had the lowest and the control group the highest VAS scores at the second postoperative hour. At the fourth postoperative hour, VAS scores were significantly higher in the DC group than the DO group (p<0.05). At the sixth postoperative hour, the PE and DC groups had significantly lower VAS scores than the other groups (p<0.05). At Hour 12, the PE and control groups had higher VAS scores than the DO and DC groups. VAS scores were not different among groups at Hour 24. The interval to first analgesic requirement was significantly shorter in the control group and longer in the PE group in comparison to the other two groups (p<0.001). CONCLUSION: Intra-articular bupivacaine injection at different stages of the operation yielded variable VAS scores in the postoperative period. Closing the drain after intra-articular injection resulted in an early onset analgesic effect without shortening the duration. PMID- 25803243 TI - Spatial Variation in the Healthy Human Lung Microbiome and the Adapted Island Model of Lung Biogeography. AB - RATIONALE: The lung microbiome is spatially heterogeneous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (URT; "adapted island model of lung biogeography"), rather than differences in regional bacterial growth conditions. OBJECTIVES: To determine if the lung microbiome is spatially varied in healthy adults. METHODS: Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage [BAL]), then in the right upper lobe, left upper lobe, and supraglottic space (by protected-specimen brush). Bacterial 16S ribosmal RNA-encoding genes were sequenced using MiSeq (Illumina, San Diego, CA). MEASUREMENTS AND MAIN RESULTS: There were no significant differences between specimens collected by BAL and protected-specimen brush. Spatially separated intrapulmonary sites, when compared with each other, did not contain consistently distinct microbiota. On average, intrasubject variation was significantly less than intersubject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, intersubject variability, and similarity to source community), right upper lobe microbiota more closely resembled those of the URT than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the URT (P < 0.05). CONCLUSIONS: In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. BAL of a single lung segment is an acceptable method of sampling the healthy lung microbiome. Clinical trial registered with www.clinicaltrials.gov (NCT02392182). PMID- 25803246 TI - Arthroscopic stabilization of anterior shoulder instability using a single anterior portal. AB - OBJECTIVE: The aim of this study was to compare the effects of the use of a single anterior portal in the arthroscopic surgery treatment of traumatic anterior shoulder instability with those in the literature. METHODS: The study included 72 patients (60 males, 12 females; mean age: 23.9 years) who underwent surgery using a single arthroscopic anterior portal for the treatment of traumatic anterior shoulder instability between 2002 and 2011. Clinical outcomes were assessed using the Rowe and Oxford scales, forward flexion range and external rotation limitation. Redislocation was considered failure. RESULTS: Mean follow-up was 49.3 months. Bankart lesion was determined in 38 patients and Bankart and SLAP lesions in 34. An average of 3.7 (range: 2 to 5) anchors were used. Redislocation was observed in 4 (5.6%) patients in the postoperative period. Postoperative Rowe and Oxford scores were 93.4 and 42.6, respectively. CONCLUSION: Instability surgery performed using a single arthroscopic anterior portal provided findings comparable with the literature regarding clinical outcomes, postoperative shoulder movements and low recurrence rates, emphasizing the importance of appropriate patient selection rather than the number of the portals. The use of a single portal is less invasive and reduces the surgical period. PMID- 25803247 TI - Results of midshaft clavicle fractures treated with expandable, elastic and locking intramedullary nails. AB - OBJECTIVE: The aim of the study was to present the results of osteosynthesis with elastic expandable intramedullary nail for clavicle fractures. METHODS: The study included 17 patients (11 males, 6 females; mean age 36.4 years, range: 21 to 54 years) who underwent surgery for a displaced clavicle fracture and had a shortening of more than 2 cm. The Constant Score and DASH (Disabilities of The Arm, Shoulder and Hand) scoring were used to determine the functional status of the patients. RESULTS: Mean operation time was 30.4 (range: 25 to 42) minutes and mean follow-up period was 10.3 (range: 8 to 19) months. Mean union time was 15.8 (range: 9 to 20) weeks. A superficial infection was treated with wound debridement and antibiotherapy in one patient. No patient suffered from neurovascular compromise, deep infection or implant irritation. Implant fracture developed at 2 months after surgery in one patient treated for Type B1 clavicle fracture and healed without any other intervention. There was no statistically significant shortening (p>0.05). In the final follow-up, the mean Constant Score was 94.3 (range: 86 to 97), and mean DASH score was 11.8 (range: 7.3 to 17.4). CONCLUSION: Expandable elastic locking intramedullary nail appears to provide minimal complication and high success rate for the surgical treatment of non comminuted displaced clavicle shaft fractures. Additional studies with large series are necessary for further investigation. PMID- 25803248 TI - Reconstruction of fingertip defects with digital artery perforator flap. AB - OBJECTIVE: The aim of this study was to present our findings for the use of the digital artery perforator (DAP) flap in the covering of digital pulp defects. METHODS: The study included 15 patients who underwent reconstruction of the fingertip using a DAP flap between July 2007 and February 2012. The blood supply of the perforator island flap was based on the distal and either radial or ulnar sides of the digit. Donor sites were closed using skin grafting in all cases. Static two-point discrimination (s2PD) and Semmes-Weinstein monofilament (SWM) testing was performed at the final follow-up to determine extension loss and sensorial improvement. RESULTS: Mean follow-up was 22 (range: 7 to 62) months. Flaps size was between 2 x 1 cm and 2.5 x 1.5 cm. Temporary venous congestion was observed in 12 of the 15 patients and was without complication. All patients returned to their normal daily activities and work within an average of 39 (range: 30 to 45) days. Mean two-point discrimination was 5.3 mm and SWM test results were between 3.61 and 4.56 at the final follow-up. CONCLUSION: The DAP flap appears to be a reliable procedure with several advantages as a single-stage operating procedure, easy to harvest, good sensory recovery and preservation of digital arteries. PMID- 25803249 TI - Choosing the most efficacious scoring method for carpal tunnel syndrome. AB - OBJECTIVE: The aim of this study was to determine the most efficacious hand specific questionnaire to determine functionality in patients with carpal tunnel syndrome. METHODS: The study included 89 patients who underwent open carpal tunnel release surgery within three years prior to the study. A visual analog scale was used to assess the intensity of pain and paresthesia symptoms. Each participant completed the Boston Carpal Tunnel Questionnaire (BCTQ), the Michigan Hand Outcome Questionnaire (MHQ), the quick form of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and the Duruoz Hand Index (DHI). The BCTQ, pain and paresthesia results were assumed as gold standards. Correlations between the MHQ, QuickDASH, and the DHI were analyzed. A correlation analysis between the variables was tested using Spearman's rho test or Pearson's test for variables. RESULTS: The QuickDASH was well correlated with pain, paresthesia and the BCTQ (p<0.001). The questionnaires complied with each other. CONCLUSION: In addition to its complicated scoring, the MHQ contained detailed subparameters with similar questions and takes a long time to complete. Further studies may confirm the effective usage of the DHI. The easier QuickDASH questionnaire appears to be more practical for carpal tunnel release patients. PMID- 25803250 TI - Positional alterations of the Kambin's triangle and foraminal areas in the lumbosacral region. AB - OBJECTIVE: The aim of this anatomical study was to compare the effects of the prone and lateral decubitus positions in endoscopic disc surgery on the Kambin's triangle (KT) and neural foramina zones in the lumbosacral region. METHODS: The study included 32 healthy volunteers (16 females and 16 males). Bilateral KT areas (KTA) and neural foraminal areas (FA) of the L4-L5 and L5-S1 levels in the prone and lateral decubitus positions were calculated depending on the freehand region of interest measurements on magnetic resonance images. KTA and FA values for each side and level in the prone and lateral decubitus positions were compared. RESULTS: Mean left KTA value in the prone and right lateral decubitus positions was 0.58 cm(2) and 0.69 cm(2), respectively, for L4-L5; and 0.69 cm(2) and 0.78 cm(2), respectively, for L5-S1 levels. Mean right KTA values in the prone and left lateral decubitus positions were 0.54 cm(2) and 0.65 cm(2) for L4 L5; and 0.69 cm(2) and 0.81 cm(2) for L5-S1, respectively. The differences in the KTA between prone and lateral decubitus positions for both levels and both sides were statistically significant (p=0.05). Only the difference in the FA between the prone and lateral decubitus positions at L5-S1 level on the right side was statistically significant (p=0.05). CONCLUSION: The KTA is wider in the lateral decubitus position than in the prone position at the levels of L4-L5 and L5-S1. PMID- 25803251 TI - Lateral versus medial approach for intra-articular knee injections. AB - OBJECTIVE: The aim of this study was to determine whether the medial or the lateral mid-patellar approach is the most reliable for intra-articular knee injections. METHODS: The study included 76 knees of 76 patients divided into 2 groups. The first group consisted of 38 patients with a knee injury and resultant knee effusion. The second group included 38 patients without any known knee pathology. Patients were matched according to age and gender. The medial joint opening (medial patellofemoral angle) was calculated on a T1-weighted transverse image by measuring the anatomic angle between the femur and the patella. The lateral joint opening (lateral patellofemoral angle) was calculated in a similar way. RESULTS: The medial patellofemoral angle was significantly higher than the lateral patellofemoral angle in both groups (p<0.001). CONCLUSION: The medial patellofemoral angle is significantly higher than the lateral patellofemoral angle in both healthy knees and knees with effusion. Therefore, the medial approach appears to be more accurate for intra-articular knee injection due to the medial joint's larger opening. PMID- 25803252 TI - Measurement of the knee joint line in Turkish population. AB - OBJECTIVE: The aim of the present study was to determine the knee joint line level by its distance to the adductor tubercle and the apex of the fibular head in the Turkish population. METHODS: The study included 117 knees of 108 patients (63 males, 45 females; mean age: 31.3 years, range: 16 to 82 years). Femoral width and the distance from the apex of the fibular head to the joint line as well as the distance from the adductor tubercle to the joint line were measured on anteroposterior radiographs. RESULTS: Mean femoral width was 87.2 mm. The average distance from the adductor tubercle to the joint line was 47.9 mm and from the fibular head to the joint line was 20.5 mm. A linear correlation was found between the distance from the adductor tubercle to the joint line and femoral width, with a ratio of 0.55. There was no significant correlation between the distance from the fibular head to the joint line and femoral width. CONCLUSION: There was a linear correlation between the femoral width and the adductor tubercle-joint line distance irrespective of any factors such as age, gender and height. Therefore, the adductor tubercle can be used as a reliable landmark to determine the joint line level for easy evaluation and measurement during surgery. PMID- 25803253 TI - Peroneal nerve palsy secondary to prolonged squatting in seasonal farmworkers. AB - OBJECTIVE: The aim of this study was to evaluate the follow-up and treatment results of peroneal nerve palsy secondary to prolonged squatting for working and to determine an approach for its treatment and prevention. METHODS: The study retrospectively evaluated 16 patients (7 males, 9 females; mean age: 23.6 years) diagnosed with peroneal nerve palsy due to squatting for work. Clinical and neurological evaluations were performed and weight and height were measured. Lesion site was determined using electrophysiological testing. After diagnosis, medical and orthotic treatment was initiated and rest was advised. Patients were followed until motor symptoms were resolved. RESULTS: Clinical and neurophysiological evaluations were consistent with isolated peroneal nerve palsy. The left side was affected in seven patients, the right side in seven and both sides in two. Average onset of the symptoms was 3.3 (range: 1 to 6) weeks and average daily squatting period was 6.8 (range: 6 to 8) hours. Average healing time was 7.4 (range: 3 to 16) weeks. None of the patients was obese or overweight. All patients healed with conservative treatment and no surgical treatment was necessary. CONCLUSION: Working conditions and duties should be considered in the evaluation of peroneal nerve palsy. In peroneal nerve palsy secondary to squatting, healing should be expected with conservative treatment, resting and close follow-up. PMID- 25803254 TI - Improvement of popliteal angle with semitendinosus or gastrocnemius tenotomies in children with cerebral palsy. AB - OBJECTIVE: The aim of this study was to determine the efficacy of semitendinosus and gastrocnemius tenotomies on popliteal angle presenting knee flexion spasticity in children with cerebral palsy (CP). METHODS: The study included 44 patients (25 males, 19 females; mean age: 8.1 years, range: 4 to 14 years) with spastic CP who underwent surgery for knee flexion spasticity. A total of 78 semitendinosus tenotomies and 28 associated gastrocnemius tenotomies were performed. Popliteal angle was measured under general anesthesia before and after surgery. Patients were divided into groups according to age (younger and older than 7 years), severity of deformity and type of CP. RESULTS: Mean popliteal angles decreased by 14.3o (30.1%) following semitendinosus tenotomy and by 6.1o (12%) following gastrocnemius tenotomy (p=0.0001). The change in popliteal angle was not statistically significant according to age, severity of flexion spasticity, and type of CP palsy. There was a significant difference following gastrocnemius tenotomy between groups with a popliteal angle of greater or lesser than 50o (p=0.0001). CONCLUSION: Semitendinosus and gastrocnemius tenotomies improved popliteal angle by 30.1% and 12%, respectively. Age, preoperative popliteal angle or anatomical disease classification did not a significantly affect popliteal angle. PMID- 25803255 TI - A bibliometric analysis of orthopedic publications originating from Turkey. AB - OBJECTIVE: The objective of this study was to analyze the research productivity originating in Turkey using articles published in the top 40 orthopedic journals according to the Journal Citation Reports for 2013. METHODS: All scientific papers published in English and included in the Science Citation Index Expanded between 1980 and 2013 were analyzed using the "Web of Science". The number of publications per million (PmP) was calculated. All selected journals were analyzed for the numbers of articles, authorships, institutions and 100 most frequently cited papers. RESULTS: From a total of 130,494 articles published worldwide, the United States ranked first according to output. Turkey ranked 14th in the number of orthopedic publications and 26th out of 30 countries in the PmP index. 2012 produced the greatest number of publications worldwide and 2008 for Turkey. Gunal I., Yazici M. and Ozturk C. were the most frequent contributors. Hacettepe University, Istanbul University and Ankara University were the most frequent intuitions among all Turkish publications. The Archives of Orthopaedic and Trauma Surgery was the most frequently published journal in this period with a rate of 16.3%. There was a total of 9,085 (8,765; excluding self-citations) citations of the 1,398 publications published in Turkey until December 2013, with a citation-to-work ratio of 7.47 and an h-index of 34. CONCLUSION: With the newly established universities, as well as training and research clinics, the approach of increasing number of orthopedics and traumatology clinics and specialists to scientific activities would be more fruitful in the light of these data. PMID- 25803256 TI - Compliance, persistence, and preference outcomes of postmenopausal osteoporotic women receiving a flexible or fixed regimen of daily risedronate: A multicenter, prospective, parallel group study. AB - OBJECTIVE: The aim of this study was to examine the level of compliance and persistence in patients with postmenopausal osteoporosis (OP) receiving daily risedronate (5 mg) with either fixed dosing of three different timing regimens (A: before breakfast; B: in-between meals; C: before bedtime) or with flexible dosing and the effect on urinary N-terminal telopeptide of Type 1 collagen (NTX 1). METHODS: The study included 448 patients with postmenopausal OP. Patients were randomly assigned into six treatment groups each with a permutation of the treatment sequence (ABC, BCA, etc.) in the crossover phase (3 x 1 week) and randomized to 23 weeks of either the daily flexible (either regimen A, B or C) or fixed timing (only regimen A, B, or C) in the patient's preference phase. Urinary NTX-1 was tested. RESULTS: A total of 433 patients participated in the patient's preference phase (49.7% preferred flexible and 50.3% fixed timing). There was no significant difference between the proportion of responders who were both compliant and persistent in the flexible (54.4%) and fixed regimens (53.7%) (p=0.8803). A significant difference between the flexible and fixed regimens was seen in persistence in favor of the flexible regimen (p=0.0306). There was no significant difference between the flexible and fixed regimens in terms of compliance (p=0.4611). Change in urinary NTX-1 did not show any difference between the two regimens. At the final visit, 51% of patients in the flexible and 55% in the fixed regimen group considered the used risedronate regimen as excellent or very good (p=0.1440). CONCLUSION: A flexible dosing with daily risedronate appears be a valuable option in terms of compliance and persistence for patients with postmenopausal OP. PMID- 25803258 TI - The effect of HIF stabilizer on distraction osteogenesis. AB - OBJECTIVE: The aim of this study was to investigate the effect of an orally applicable hypoxia-inducible factor (HIF) stabilizer on distraction osteogenesis (DO) in a rat model. METHODS: The study included 24 Wistar albino rats undergoing osteotomy of the left tibia diaphysis. Rats were divided equally into experiment and control groups. Tibias were fixed using an external fixator. HIF stabilizer was administered to the experiment group. On the 5th postoperative day, distraction with increased rate (0.4 mm twice a day) was commenced and continued for 10 days. Histological and immunohistochemical evaluation was performed. RESULTS: Vascular endothelial growth factor levels of the experiment group were higher than those of the control group (p<0.05). The experiment group had slightly better intramembranous ossification quality than the control group on both Day 16 and 30. Endochondral ossification rates were better in the experiment group on Day 16. CONCLUSION: Vascular endothelial growth factor levels increased and stimulated angiogenesis in the presence of HIF pathway activation by oral administration of HIF stabilizer during DO. The biomechanical features of the distraction and angiogenesis should be coupled to achieve adequate bone homeostasis. PMID- 25803257 TI - Relationship between pedographic analysis and the Manchester scale in hallux valgus. AB - OBJECTIVE: The aim of this study was to evaluate the correlation between the Manchester scale and foot pressure distribution in patients with hallux valgus deformity. METHODS: The study included 152 feet of 87 patients with hallux valgus and a control group of 391 feet of 241 individuals without hallux valgus deformity. The severity of hallux valgus was determined using the Manchester scale grading system. Plantar loading patterns in 10 foot areas were determined for all participants. RESULTS: According to the Manchester scale, 72% of the participants had no, 12.9% mild, 10.7% moderate and 4.4% severe deformity. The Manchester scale grade was highly correlated with both hallux valgus angle and first intermetatarsal angle (p=0.00). Significant differences between the four grades were present for mean pressure under the hallux and the first and second metatarsal heads only (p=0.00). The load distribution under these areas was higher as the hallux valgus progressed from mild to more severe. In all groups, the highest pressure was observed under the second metatarsal head. CONCLUSION: The Manchester scale was strongly associated with both the hallux valgus angle and the first intermetatarsal angle. The progression from mild to moderate and severe deformation is associated with peak pressure raise at the hallux, first and second metatarsal heads. The Manchester scale appears to be a useful tool to provide information for the degree of deformity and the pressure under painful foot areas. PMID- 25803260 TI - Arthroscopic treatment of bilateral snapping scapula syndrome: a case report and review of the literature. AB - Snapping scapula syndrome represents a rare entity in shoulder surgery. Clinically, it presents as shoulder pain and loud crepitus during shoulder movement. Moreover, glenohumeral bursitis can cause additional pain. Snapping scapula syndrome is caused by an increased angulation of the superomedial part of the scapula combined with bursitis. Other common causes such as subscapular osteochondroma or rib fracture non-unions were excluded. We report a 24-year-old female patient with persisting shoulder pain and disturbing crepitus during movement of the left shoulder. Radiographic examination revealed increased angulation of the superomedial scapula on both sides and MRI, bursitis of the left shoulder. The patient was successfully treated with minimally invasive arthroscopic trimming of the prominent osseous formation at the left scapula combined with bursectomy. Additionally, specific pain-adapted physiotherapeutic exercises of both shoulders were performed. The patient had a pain-free shoulder movement without crepitus on both sides at the 6th month follow-up. PMID- 25803259 TI - Biomechanical effects of daily physical activities on the lower limb. AB - OBJECTIVE: The aim of this study was to determine the joint torques on the lower extremity during the daily physical activity movements of sit-to-stand, crouch down-stand up, and stair climbing without using an external device. METHODS: The study subject was a healthy 26-year-old male without any physical problems. A link-segment model was prepared according to the subject's individual anthropometric characteristics and transferred to the MATLAB((r)) program. Joint torques were calculated using SimMechanicsTM software. Motions were recorded by one digital video camera as the subject performed the movements (sit-to-stand from 20 cm and 40 cm height, crouch down-stand up, and climbing 10 cm and 20 cm high step) and the joint's position data was obtained using a digitization process. In addition, the vertical ground reaction forces were measured using a force plate in order to test the accuracy of the link-segment model. Lower extremity joint torques were calculated. RESULTS: Maximum joint torques occurred in the knee joint. The knee and the ankle joints were the most loaded joint during the high step movement. The highest torques of the knee and ankle joint were 157.2 Nm and 146 Nm, respectively, during the movements. Knee joint torque and the ankle joint torque increased when the sitting height increased. The hip joint experienced the least amount of load during the movements. CONCLUSION: The knee joint has enough strength against high torques during extension and flexion movement. Joint torques can be successfully calculated using a simulation process involving an inverse dynamics method without an external device mounted on the limbs. The obtained data can be used in the design of prosthetics and orthotics and for structural analysis of the bones. PMID- 25803261 TI - Lumbar plexopathy following transforaminal interbody fusion: a rare complication. AB - Postoperative radiculopathy has previously been reported as a common complication of transforaminal lumbar interbody fusion (TLIF). However, no data has been published on lumbar plexopathy following TLIF. We present a rare case of lumbar plexopathy occurring following TLIF (L5-S1) in a patient with spondylolisthesis. Although initially a diagnostic challenge, sinister causes of neuropathy such as bleeding or neoplastic growths were excluded by imaging. A diagnosis of acute lumbar plexopathy of left L2 to L4 was eventually made after electromyographic studies was performed in consultation with a senior neurologist. The patient was treated supportively with good functional recovery. PMID- 25803263 TI - Recurrent anterior hip dislocation in a patient with myasthenia gravis: a case report. AB - Traumatic anterior hip dislocation is a rare condition compared to posterior dislocation and recurrent anterior hip dislocation is encountered even less. Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by various degrees of muscle weakness. Closed reduction is the first choice of treatment for traumatic, non-recurring hip dislocation. We report a 59-year-old female with myasthenia gravis who underwent surgical intervention for recurrent anterior hip dislocation after failure of closed reduction. To our knowledge, this is the first case with recurrent anterior hip dislocation and myasthenia gravis in the literature. PMID- 25803262 TI - Spinal gas accumulation causing lumbar discogenic disease: a case report. AB - Vacuum disc phenomenon is seen frequently with degenerative disc disease and is characterized by the collection of gas in the disc space. Although the accumulation of gas within the disc space does not have clinical significance, symptoms may develop when occurring within the spinal canal. We present a 60-year old female patient with low back and left leg pain occurring for 3 months before admission to our clinic. Straight leg raise test was 50 degrees in the left leg. Magnetic resonance imaging showed a narrowing of the L5-S1 disc space with vacuum disc phenomenon and hypointense cystic mass in T1 and T2-weighted images. The decision for surgery was made and left L5-S1 hemilaminectomy and foraminotomy was performed. The cyst wall was adherent to the root and dura mater and was partially excised. The patient was pain-free on the first postoperative day. In cases of gas accumulation in the spinal canal, discogenic pain may occur. Surgical therapy is still an acceptable method for the treatment of vacuum disc phenomenon and accumulation of gas within the spinal canal. PMID- 25803264 TI - Posterior tibial nerve as a tendon transfer for drop foot reconstruction: a devastating complication. AB - Iatrogenic peripheral nerve injuries can result from numerous medical procedures, particularly transection, stretching, compression, injections, heat, radiation, and the use of anticoagulant agents. Late diagnosis may lead to atrophy of the motor endplate and result in poor outcomes. We report a case in which the posterior tibial nerve was accidentally sectioned as the posterior tibial tendon for transfer to the anterior tibial tendon in the reconstruction of drop foot. This iatrogenic complication ultimately required foot amputation. Physicians must be aware of the anatomy of the posterior tibial nerve in order to avoid such complications. PMID- 25803265 TI - Glucose-responsive polymer vesicles templated by alpha-CD/PEG inclusion complex. AB - Polymeric nanoparticles with glucose-responsiveness are of great interest in developing a self-regulated drug delivery system. In this work, glucose responsive polymer vesicles were fabricated based on the complexation between a glucosamine (GA)-containing block copolymer PEG45-b-P(Asp-co-AspGA) and a phenylboronic acid (PBA)-containing block copolymer PEG114-b-P(Asp-co-AspPBA) with alpha-CD/PEG45 inclusion complex as the sacrificial template. The obtained polymer vesicles composed of cross-linked P(Asp-co-AspGA)/P(Asp-co-AspPBA) layer as wall and PEG chains as both inner and outer coronas. The vesicular morphology was observed by transmission electron microscopy (TEM), and the glucose responsiveness was investigated by monitoring the variations of hydrodynamic diameter (Dh) and light scattering intensity (LSI) in the polymer vesicle solution with glucose using dynamic light scattering (DLS). Vancomycin as a model drug was encapsulated in the polymer vesicles and sugar-triggered drug release was carried out. This kind of polymer vesicle may be a promising candidate for glucose-responsive drug delivery. PMID- 25803267 TI - Vapor-liquid equilibrium and polarization behavior of the GCP water model: Gaussian charge-on-spring versus dipole self-consistent field approaches to induced polarization. AB - We developed the Gaussian charge-on-spring (GCOS) version of the original self consistent field implementation of the Gaussian Charge Polarizable water model and test its accuracy to represent the polarization behavior of the original model involving smeared charges and induced dipole moments. For that purpose we adapted the recently proposed multiple-particle-move (MPM) within the Gibbs and isochoric-isothermal ensembles Monte Carlo methods for the efficient simulation of polarizable fluids. We assessed the accuracy of the GCOS representation by a direct comparison of the resulting vapor-liquid phase envelope, microstructure, and relevant microscopic descriptors of water polarization along the orthobaric curve against the corresponding quantities from the actual GCP water model. PMID- 25803266 TI - Impact of mHealth chronic disease management on treatment adherence and patient outcomes: a systematic review. AB - BACKGROUND: Adherence to chronic disease management is critical to achieving improved health outcomes, quality of life, and cost-effective health care. As the burden of chronic diseases continues to grow globally, so does the impact of non adherence. Mobile technologies are increasingly being used in health care and public health practice (mHealth) for patient communication, monitoring, and education, and to facilitate adherence to chronic diseases management. OBJECTIVE: We conducted a systematic review of the literature to evaluate the effectiveness of mHealth in supporting the adherence of patients to chronic diseases management ("mAdherence"), and the usability, feasibility, and acceptability of mAdherence tools and platforms in chronic disease management among patients and health care providers. METHODS: We searched PubMed, Embase, and EBSCO databases for studies that assessed the role of mAdherence in chronic disease management of diabetes mellitus, cardiovascular disease, and chronic lung diseases from 1980 through May 2014. Outcomes of interest included effect of mHealth on patient adherence to chronic diseases management, disease-specific clinical outcomes after intervention, and the usability, feasibility, and acceptability of mAdherence tools and platforms in chronic disease management among target end-users. RESULTS: In all, 107 articles met all inclusion criteria. Short message service was the most commonly used mAdherence tool in 40.2% (43/107) of studies. Usability, feasibility, and acceptability or patient preferences for mAdherence interventions were assessed in 57.9% (62/107) of studies and found to be generally high. A total of 27 studies employed randomized controlled trial (RCT) methods to assess impact on adherence behaviors, and significant improvements were observed in 15 of those studies (56%). Of the 41 RCTs that measured effects on disease-specific clinical outcomes, significant improvements between groups were reported in 16 studies (39%). CONCLUSIONS: There is potential for mHealth tools to better facilitate adherence to chronic disease management, but the evidence supporting its current effectiveness is mixed. Further research should focus on understanding and improving how mHealth tools can overcome specific barriers to adherence. PMID- 25803271 TI - Conformational features of secondary N-cyclopropyl amides. AB - NMR studies in conjunction with ab initio calculations revealed unexpected conformational behavior of N-cyclopropylacetamide (1). This secondary amide displays 16-19% E-rotamer (cis) around the carbonyl-nitrogen bond in apolar solvents, in contrast to other aliphatic secondary acetamides in which significant E-rotamer populations are rare due to steric contacts between the substituents on the amide bond. In addition, 1 adopts an ortho conformation around the N-cPr bond instead of the anti conformation generally preferred by secondary acetamides. This distinct conformational behavior was also observed for other secondary N-cyclopropyl amides. PMID- 25803269 TI - Maternal Smoking Dysregulates Protein Expression in Second Trimester Human Fetal Livers in a Sex-Specific Manner. AB - CONTEXT: Maternal smoking during pregnancy has adverse effects on the offspring (eg, increased likelihood of metabolic syndrome and infertility), which may involve alterations in fetal liver function. OBJECTIVE: Our aim was to analyze, for the first time, the human fetal liver proteome to identify pathways affected by maternal smoking. DESIGN: Fetal liver proteins extracted from elective second trimester pregnancy terminations (12-16 weeks of gestation) were divided in four balanced groups based on sex and maternal smoking. SETTING AND PARTICIPANTS: Livers were collected from 24 morphologically normal fetuses undergoing termination for nonmedical reasons and analyzed at the Universities of Aberdeen and Glasgow. MAIN OUTCOME MEASURES: Protein extracts were resolved by 2D-PAGE and analyzed with SameSpots software. Ingenuity pathway analysis was used to investigate likely roles of dysregulated proteins identified by tandem liquid chromatography/mass spectroscopy. RESULTS: Significant expression differences between one or more groups (fetal sex and/or maternal smoking) were found in 22 protein spots. Maternal smoking affected proteins with roles in post translational protein processing and secretion (ERP29, PDIA3), stress responses and detoxification (HSP90AA1, HSBP1, ALDH7A1, CAT), and homeostasis (FTL1, ECHS1, GLUD1, AFP, SDHA). Although proteins involved in necrosis and cancer development were affected in both sexes, pathways affecting cellular homeostasis, inflammation, proliferation, and apoptosis were affected in males and pathways affecting glucose metabolism were affected in females. CONCLUSIONS: The fetal liver exhibits marked sex differences at the protein level, and these are disturbed by maternal smoking. The foundations for smoke-induced post-natal diseases are likely to be due to sex-specific effects on diverse pathways. PMID- 25803268 TI - Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial. AB - CONTEXT AND OBJECTIVE: The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy. DESIGN: This was a phase 3, prospective, open-label study. SETTING AND PARTICIPANTS: Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long term extension phase. OUTCOME MEASURES: Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up. RESULTS: Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy. CONCLUSIONS: Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP. PMID- 25803270 TI - Comparative efficacy and safety of OADs in management of GDM: network meta analysis of randomized controlled trials. AB - OBJECTIVE: We conducted a network meta-analysis to evaluate the efficacy and safety of oral antidiabetic drugs (OADs) for gestational diabetes. DATA SOURCES: We searched PubMed, the Cochrane Library, ClinicalTrials.gov, and related reviews from inception to October 2014. STUDY SELECTION: We included randomized clinical trials comparing efficacy and safety between different OADs or OADs vs insulin in patients with gestational diabetes. DATA SYNTHESIS: We included 18 randomized clinical trials. Traditional and network meta-analyses were performed to compare different OADs or OADs vs insulin. Traditional meta-analyses confirmed that there was no significant difference in maternal fasting blood glucose or glycated hemoglobin levels in patients treated with insulin, metformin, and glyburide. Compared to insulin, metformin was associated with lower maternal weight gain (weighted mean difference [WMD], -1.49 kg; 95% confidence interval [CI], -2.26 to -0.31), shorter gestational age (WMD, -0.16 wk; 95% CI, -0.30 to -0.03), and increased incidence of premature birth (odds ratio [OR], 1.63; 95% CI, 1.07 to 2.48). Compared to insulin, glyburide was associated with higher neonatal birth weight (WMD, 130.68 g; 95% CI, 55.98 to 205.38), increased incidence of neonatal hypoglycemia (OR, 2.64; 95% CI, 1.59 to 4.38), and increased incidence of macrosomia (OR, 3.09; 95% CI, 1.59 to 6.04). Network meta-analysis revealed that glyburide was associated with higher maternal weight gain, higher neonatal birth weight, increased incidence of neonatal hypoglycemia, and increased incidence of macrosomia than was metformin. CONCLUSION: Both metformin and glyburide are suitable for use in the management of gestational diabetes because of good glycemic control. However, glyburide treatment is associated with increased risk of neonatal hypoglycemia, high maternal weight gain, high neonatal birth weight, and macrosomia. PMID- 25803272 TI - Increased expression of interferon signaling genes in the bone marrow microenvironment of myelodysplastic syndromes. AB - INTRODUCTION: The bone marrow (BM) microenvironment plays an important role in the pathogenesis of myelodysplastic syndromes (MDS) through a reciprocal interaction with resident BM hematopoietic cells. We investigated the differences between BM mesenchymal stromal cells (MSCs) in MDS and normal individuals and identified genes involved in such differences. MATERIALS AND METHODS: BM-derived MSCs from 7 MDS patients (3 RCMD, 3 RAEB-1, and 1 RAEB-2) and 7 controls were cultured. Global gene expression was analyzed using a microarray. RESULT: We found 314 differentially expressed genes (DEGs) in RCMD vs. control, 68 in RAEB vs. control, and 51 in RAEB vs. RCMD. All comparisons were clearly separated from one another by hierarchical clustering. The overall similarity between differential expression signatures from the RCMD vs. control comparison and the RAEB vs. control comparison was highly significant (p = 0), which indicates a common transcriptomic response in these two MDS subtypes. RCMD and RAEB simultaneously showed an up-regulation of interferon alpha/beta signaling and the ISG15 antiviral mechanism, and a significant fraction of the RAEB vs. control DEGs were also putative targets of transcription factors IRF and ICSBP. Pathways that involved RNA polymerases I and III and mitochondrial transcription were down regulated in RAEB compared to RCMD. CONCLUSION: Gene expression in the MDS BM microenvironment was different from that in normal BM and exhibited altered expression according to disease progression. The present study provides genetic evidence that inflammation and immune dysregulation responses that involve the interferon signaling pathway in the BM microenvironment are associated with MDS pathogenesis, which suggests BM MSCs as a possible therapeutic target in MDS. PMID- 25803273 TI - Studying memory encoding to promote reliable engagement of the medial temporal lobe at the single-subject level. AB - The medial temporal lobe (MTL)-comprising hippocampus and the surrounding neocortical regions-is a targeted brain area sensitive to several neurological diseases. Although functional magnetic resonance imaging (fMRI) has been widely used to assess brain functional abnormalities, detecting MTL activation has been technically challenging. The aim of our study was to provide an fMRI paradigm that reliably activates MTL regions at the individual level, thus providing a useful tool for future research in clinical memory-related studies. Twenty young healthy adults underwent an event-related fMRI study consisting of three encoding conditions: word-pairs, face-name associations and complex visual scenes. A region-of-interest analysis at the individual level comparing novel and repeated stimuli independently for each task was performed. The results of this analysis yielded activations in the hippocampal and parahippocampal regions in most of the participants. Specifically, 95% and 100% of participants showed significant activations in the left hippocampus during the face-name encoding and in the right parahippocampus, respectively, during scene encoding. Additionally, a whole brain analysis, also comparing novel versus repeated stimuli at the group level, showed mainly left frontal activation during the word task. In this group analysis, the face-name association engaged the HP and fusiform gyri bilaterally, along with the left inferior frontal gyrus, and the complex visual scenes activated mainly the parahippocampus and hippocampus bilaterally. In sum, our task design represents a rapid and reliable manner to study and explore MTL activity at the individual level, thus providing a useful tool for future research in clinical memory-related fMRI studies. PMID- 25803275 TI - Dynamics to equilibrium in network games: individual behavior and global response. AB - Various social contexts can be depicted as games of strategic interactions on networks, where an individual's welfare depends on both her and her partners' actions. Whereas much attention has been devoted to Bayes-Nash equilibria in such games, here we look at strategic interactions from an evolutionary perspective. To this end, we present the results of a numerical simulations program for these games, which allows us to find out whether Nash equilibria are accessible by adaptation of player strategies, and in general to identify the attractors of the evolution. Simulations allow us to go beyond a global characterization of the cooperativeness at equilibrium and probe into individual behavior. We find that when players imitate each other, evolution does not reach Nash equilibria and, worse, leads to very unfavorable states in terms of welfare. On the contrary, when players update their behavior rationally, they self-organize into a rich variety of Nash equilibria, where individual behavior and payoffs are shaped by the nature of the game, the social network's structure and the players' position within the network. Our results allow to assess the validity of mean-field approaches we use to describe the dynamics of these games. Interestingly, our dynamically-found equilibria generally do not coincide with (but show qualitatively the same features of) those resulting from theoretical predictions in the context of one-shot games under incomplete information. PMID- 25803274 TI - Functional roles of three cutin biosynthetic acyltransferases in cytokinin responses and skotomorphogenesis. AB - Cytokinins (CKs) regulate plant development and growth via a two-component signaling pathway. By forward genetic screening, we isolated an Arabidopsis mutant named grow fast on cytokinins 1 (gfc1), whose seedlings grew larger aerial parts on MS medium with CK. gfc1 is allelic to a previously reported cutin mutant defective in cuticular ridges (dcr). GFC1/DCR encodes a soluble BAHD acyltransferase (a name based on the first four enzymes characterized in this family: Benzylalcohol O-acetyltransferase, Anthocyanin O hydroxycinnamoyltransferase, anthranilate N-hydroxycinnamoyl/benzoyltransferase and Deacetylvindoline 4-O-acetyltransferase) with diacylglycerol acyltransferase (DGAT) activity in vitro and is necessary for normal cuticle formation on epidermis in vivo. Here we show that gfc1 was a CK-insensitive mutant, as revealed by its low regeneration frequency in vitro and resistance to CK in adventitious root formation and dark-grown hypocotyl inhibition assays. In addition, gfc1 had de-etiolated phenotypes in darkness and was therefore defective in skotomorphogenesis. The background expression levels of most type-A Arabidopsis Response Regulator (ARR) genes were higher in the gfc1 mutant. The gfc1-associated phenotypes were also observed in the cutin-deficient glycerol-3 phosphate acyltransferase 4/8 (gpat4/8) double mutant [defective in glycerol-3 phosphate (G3P) acyltransferase enzymes GPAT4 and GPAT8, which redundantly catalyze the acylation of G3P by hydroxyl fatty acid (OH-FA)], but not in the cutin-deficient mutant cytochrome p450, family 86, subfamily A, polypeptide 2/aberrant induction of type three 1 (cyp86A2/att1), which affects the biosynthesis of some OH-FAs. Our results indicate that some acyltransferases associated with cutin formation are involved in CK responses and skotomorphogenesis in Arabidopsis. PMID- 25803278 TI - Correction: The dynamic process of interspecific interactions of competitive nitrogen capture between intercropped wheat (Triticum aestivum L.) and faba bean (Vicia faba L.). PMID- 25803279 TI - Time of first arrival in electrochemical collision experiments as a measure of ultralow concentrations of analytes in solution. AB - In electrochemical collision experiments, the frequency of collisions of nanoparticles (NPs) with an ultramicroelectrode (UME) is a measure of the solution concentration of NPs. The time of first arrival is evaluated as a measure of ultralow (sub-femtomolar) concentration of analytes in solution. This is the time from the beginning of the experiment until the moment of observation of the first electrochemically detectable collision event. Theoretical equations are developed relating the time of the first arrival and the concentration of analyte species in solution for the cases when the species is transferred by diffusion alone and with electrophoretic migration. These equations are supported by experimental data. According to analysis of the results, the time of first arrival can be used successfully to estimate the order of magnitude of the analyte concentration with the precision of analysis being affected by the inherent stochasticity of the analyte movement and its initial position near the electrode. The use of the multiplexed parallel detection based on simultaneous measurement of a series of time of first arrival values will allow both faster and more precise determination of ultralow concentrations of analytes in solution. PMID- 25803277 TI - Restoration of spermatogenesis and male fertility using an androgen receptor transgene. AB - Androgens signal through the androgen receptor (AR) to regulate male secondary sexual characteristics, reproductive tract development, prostate function, sperm production, bone and muscle mass as well as body hair growth among other functions. We developed a transgenic mouse model in which endogenous AR expression was replaced by a functionally modified AR transgene. A bacterial artificial chromosome (BAC) was constructed containing all AR exons and introns plus 40 kb each of 5' and 3' regulatory sequence. Insertion of an internal ribosome entry site and the EGFP gene 3' to AR allowed co-expression of AR and EGFP. Pronuclear injection of the BAC resulted in six founder mice that displayed EGFP production in appropriate AR expressing tissues. The six founder mice were mated into a Sertoli cell specific AR knockout (SCARKO) background in which spermatogenesis is blocked at the meiosis stage of germ cell development. The AR EGFP transgene was expressed in a cyclical manner similar to that of endogenous AR in Sertoli cells and fertility was restored as offspring were produced in the absence of Sertoli cell AR. Thus, the AR-EGFP transgene under the control of AR regulatory elements is capable of rescuing AR function in a cell selective, AR null background. These initial studies provide proof of principle that a strategy employing the AR-EGFP transgene can be used to understand AR functions. Transgenic mice expressing selective modifications of the AR-EGFP transgene may provide crucial information needed to elicit the molecular mechanisms by which AR acts in the testis and other androgen responsive tissues. PMID- 25803276 TI - Regulation of human hepatic drug transporter activity and expression by diesel exhaust particle extract. AB - Diesel exhaust particles (DEPs) are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe) may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC) uptake transporters organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC) efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 MUg/mL and relevant to environmental exposure situations. By contrast, 25 MUg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT) 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP), whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP). Treatment by 25 MUg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a reference activator of the aryl hydrocarbon receptor (AhR) pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute to their systemic effects through impairing hepatic transport of endogenous compound or drug substrates of these transporters. PMID- 25803280 TI - Integrated analyses resolve conflicts over squamate reptile phylogeny and reveal unexpected placements for fossil taxa. AB - Squamate reptiles (lizards and snakes) are a pivotal group whose relationships have become increasingly controversial. Squamates include >9000 species, making them the second largest group of terrestrial vertebrates. They are important medicinally and as model systems for ecological and evolutionary research. However, studies of squamate biology are hindered by uncertainty over their relationships, and some consider squamate phylogeny unresolved, given recent conflicts between molecular and morphological results. To resolve these conflicts, we expand existing morphological and molecular datasets for squamates (691 morphological characters and 46 genes, for 161 living and 49 fossil taxa, including a new set of 81 morphological characters and adding two genes from published studies) and perform integrated analyses. Our results resolve higher level relationships as indicated by molecular analyses, and reveal hidden morphological support for the molecular hypothesis (but not vice-versa). Furthermore, we find that integrating molecular, morphological, and paleontological data leads to surprising placements for two major fossil clades (Mosasauria and Polyglyphanodontia). These results further demonstrate the importance of combining fossil and molecular information, and the potential problems of estimating the placement of fossil taxa from morphological data alone. Thus, our results caution against estimating fossil relationships without considering relevant molecular data, and against placing fossils into molecular trees (e.g. for dating analyses) without considering the possible impact of molecular data on their placement. PMID- 25803282 TI - Spots, damn'd spots and gammaH2AX foci. PMID- 25803281 TI - Trichophyton rubrum is inhibited by free and nanoparticle encapsulated curcumin by induction of nitrosative stress after photodynamic activation. AB - Antimicrobial photodynamic inhibition (aPI) utilizes radical stress generated from the excitation of a photosensitizer (PS) with light to destroy pathogens. Its use against Trichophyton rubrum, a dermatophytic fungus with increasing incidence and resistance, has not been well characterized. Our aim was to evaluate the mechanism of action of aPI against T. rubrum using curcumin as the PS in both free and nanoparticle (curc-np) form. Nanocarriers stabilize curcumin and allow for enhanced solubility and PS delivery. Curcumin aPI, at optimal conditions of 10 MUg/mL of PS with 10 J/cm2 of blue light (417 +/- 5 nm), completely inhibited fungal growth (p<0.0001) via induction of reactive oxygen (ROS) and nitrogen species (RNS), which was associated with fungal death by apoptosis. Interestingly, only scavengers of RNS impeded aPI efficacy, suggesting that curcumin acts potently via a nitrosative pathway. The curc-np induced greater NO expression and enhanced apoptosis of fungal cells, highlighting curc np aPI as a potential treatment for T. rubrum skin infections. PMID- 25803286 TI - Research highlights: translating chips. AB - Microfluidic and microfabricated systems are providing key functionalities in diagnostic and therapeutic scenarios, translating beyond the research laboratory to pre-clinical animal studies and clinical studies with patients. Here, we highlight a recent study making use of miniaturization and automation in the development of a smartphone-integrated point-of-care diagnostic to detect antibodies to infectious diseases in a global health setting. We also review an intraocular implanted diagnostic system for glaucoma that relies on imaging the location of a fluid meniscus in a microchannel to readout pressure within the eye. Developments in low-cost and highly functional consumer electronic systems (e.g. smartphones in both highlighted works) has led to a continuing trend to incorporate such technologies with microfluidic fluid handling capabilities to achieve complete diagnostic solutions. We conclude with another implanted microdevice that delivers drug locally to tumors through electroosmotic flow and electromigration of charged drug species, which allows high drug concentrations near a tumor or resected tumor site while preventing high systemic levels associated with significant side-effects. The maturity of microsystem components are now allowing integration into fully functional systems that are poised to reach the clinic in a variety of forms - diagnostic to therapeutic. PMID- 25803283 TI - Effect of acute inspiratory muscle exercise on blood flow of resting and exercising limbs and glucose levels in type 2 diabetes. AB - To evaluate the effects of inspiratory loading on blood flow of resting and exercising limbs in patients with diabetic autonomic neuropathy. Ten diabetic patients without cardiovascular autonomic neuropathy (DM), 10 patients with cardiovascular autonomic neuropathy (DM-CAN) and 10 healthy controls (C) were randomly assigned to inspiratory muscle load of 60% or 2% of maximal inspiratory pressure (PImax) for approximately 5 min, while resting calf blood flow (CBF) and exercising forearm blood flow (FBF) were measured. Reactive hyperemia was also evaluated. From the 20 diabetic patients initially allocated, 6 wore a continuous glucose monitoring system to evaluate the glucose levels during these two sessions (2%, placebo or 60%, inspiratory muscle metaboreflex). Mean age was 58 +/- 8 years, and mean HbA1c, 7.8% (62 mmol/mol) (DM and DM-CAN). A PImax of 60% caused reduction of CBF in DM-CAN and DM (P<0.001), but not in C, whereas calf vascular resistance (CVR) increased in DM-CAN and DM (P<0.001), but not in C. The increase in FBF during forearm exercise was blunted during 60% of PImax in DM-CAN and DM, and augmented in C (P<0.001). Glucose levels decreased by 40 +/- 18.8% (P<0.001) at 60%, but not at 2%, of PImax. A negative correlation was observed between reactive hyperemia and changes in CVR (Beta coefficient = -0.44, P = 0.034). Inspiratory muscle loading caused an exacerbation of the inspiratory muscle metaboreflex in patients with diabetes, regardless of the presence of neuropathy, but influenced by endothelial dysfunction. High-intensity exercise that recruits the diaphragm can abruptly reduce glucose levels. PMID- 25803284 TI - Hypertriglyceridemia is a potential preoperative predictor for biochemical recurrence after radical prostatectomy. AB - OBJECTIVES: Many previous studies have suggested that the outcome of prostate cancer (PCa) may be closely related to abnormal lipid metabolism. Therefore, in this study, we evaluated the preoperative lipid profiles of patients with clinically localized prostate cancer (PCa) who underwent radical prostatectomy (RP), with particular emphasis on the relationship between these profiles and biochemical recurrence (BCR). PATIENTS AND METHODS: We evaluated 715 consecutive men with clinically localized PCa who underwent RP at our institution between January 2011 and December 2013. We defined hypertriglyceridemia as a fasting serum triglyceride (TG) level greater than 200 mg/dL. We used the Kaplan-Meier method to predict BCR-free survival and applied the log-rank test to determine the statistical significance between survival curves. Cox proportional hazard ratio (HR) models were used to identify the significant predictors of BCR according to clinicopathological variables. RESULTS: Of 663 patients who underwent RP for clinically localized PCa, 66 (10.0%) showed BCR during a median follow-up period of 21 months. Patients without BCR had higher levels of serum TG, and patients with hypertriglyceridemia were significantly more likely to achieve BCR-free survival in the Kaplan-Meier analysis (log-rank test, P = 0.009). In the multivariable analysis, the presence of hypertriglyceridemia (HR 0.22), pathologic Gleason score (>= 8; HR 2.85), pathologic T stage (>= pT3; HR 3.44), and a positive surgical margin (HR, 2.39) were still significant BCR predictors. CONCLUSIONS: We found that preoperative hypertriglyceridemia was associated with a lower risk of BCR after RP in patients with clinically localized PCa. Our results could help to clarify the currently conflicting evidence on the relationship between serum lipid profiles, particularly the presence of hypertriglyceridemia, and the risk of BCR in PC a patients after surgery. PMID- 25803285 TI - Effects of TiO2 and Co3O4 nanoparticles on circulating angiogenic cells. AB - BACKGROUND AND AIM: Sparse evidence suggests a possible link between exposure to airborne nanoparticles (NPs) and cardiovascular (CV) risk, perhaps through mechanisms involving oxidative stress and inflammation. We assessed the effects of TiO2 and Co3O4 NPs in human circulating angiogenic cells (CACs), which take part in vascular endothelium repair/replacement. METHODS: CACs were isolated from healthy donors' buffy coats after culturing lymphomonocytes on fibronectin-coated dishes in endothelial medium for 7 days. CACs were pre-incubated with increasing concentration of TiO2 and Co3O4 (from 1 to 100 MUg/ml) to test the effects of NP characterized by Transmission Electron Microscopy - on CAC viability, apoptosis (caspase 3/7 activation), function (fibronectin adhesion assay), oxidative stress and inflammatory cytokine gene expression. RESULTS: Neither oxidative stress nor cell death were associated with exposure to TiO2 NP (except at the highest concentration tested), which, however, induced a higher pro-inflammatory effect compared to Co3O4 NPs (p<0.01). Exposure to Co3O4 NPs significantly reduced cell viability (p<0.01) and increased caspase activity (p<0.01), lipid peroxidation end-products (p<0.05) and pro-inflammatory cytokine gene expression (p<0.05 or lower). Notably, CAC functional activity was impaired after exposure to both TiO2 (p<0.05 or lower) and Co3O4 (p<0.01) NPs. CONCLUSIONS: In vitro exposure to TiO2 and Co3O4 NPs exerts detrimental effects on CAC viability and function, possibly mediated by accelerated apoptosis, increased oxidant stress (Co3O4 NPs only) and enhancement of inflammatory pathways (both TiO2 and Co3O4 NPs). Such adverse effects may be relevant for a potential role of exposure to TiO2 and Co3O4 NPs in enhancing CV risk in humans. PMID- 25803287 TI - Clinical utility and limitations of intraoperative monitoring of visual evoked potentials. AB - OBJECTIVES: During surgeries that put the visual pathway at risk of injury, continuous monitoring of the visual function is desirable. However, the intraoperative monitoring of the visual evoked potential (VEP) is not yet widely used. We evaluate here the clinical utility of intraoperative VEP monitoring. METHODS: We analyzed retrospectively 46 consecutive surgeries in 2011-2013. High luminance stimulating devices delivered flash stimuli on the closed eyelid during intravenous anesthesia. We monitored VEP features N75 and P100 and took patients' preoperative and postoperative visual function from patient charts. Postoperative ophthalmologic workup was performed in 25 (54%) patients and preoperatively in 28 (61%) patients. RESULTS: VEP recordings were feasible in 62 of 85 eyes (73%) in 46 patients. All 23 eyes without VEP had impaired vision. During surgery, VEPs remained stable throughout surgery in 50 eyes. In 44 of these, visual function did not deteriorate and three patients (6 eyes) developed hemianopia. VEP decreased transiently in 10 eyes and visual function of all was preserved. VEPs were lost permanently in 2 eyes in two patients without new postoperative visual impairment. CONCLUSIONS: Satisfactory intraoperative VEP monitoring was feasible in all patients except in those with severe visual impairment. Preservation of VEPs predicted preserved visual function. During resection of lesions in the visual cortex, VEP monitoring could not detect new major visual field defects due to injury in the posterior visual pathway. Intraoperative VEPs were sensitive enough to detect vascular damage during aneurysm clipping and mechanical manipulation of the anterior visual pathway in an early reversible stage. Intraoperative VEP monitoring influenced surgical decisions in selected patients and proved to be a useful supplement to the toolbox of intraoperative neurophysiological monitoring. PMID- 25803288 TI - Characterization of potent fusion inhibitors of influenza virus. AB - New inhibitors of influenza viruses are needed to combat the potential emergence of novel human influenza viruses. We have identified a class of small molecules that inhibit replication of influenza virus at picomolar concentrations in plaque reduction assays. The compound also inhibits replication of vesicular stomatitis virus. Time of addition and dilution experiments with influenza virus indicated that an early time point of infection was blocked and that inhibitor 136 tightly bound to virions. Using fluorescently labeled influenza virus, inhibition of viral fusion to cellular membranes by blocked lipid mixing was established as the mechanism of action for this class of inhibitors. Stabilization of the neutral pH form of hemagglutinin (HA) was ruled out by trypsin digestion studies in vitro and with conformation specific HA antibodies within cells. Direct visualization of 136 treated influenza virions at pH 7.5 or acidified to pH 5.0 showed that virions remain intact and that glycoproteins become disorganized as expected when HA undergoes a conformational change. This suggests that exposure of the fusion peptide at low pH is not inhibited but lipid mixing is inhibited, a different mechanism than previously reported fusion inhibitors. We hypothesize that this new class of inhibitors intercalate into the virus envelope altering the structure of the viral envelope required for fusion to cellular membranes. PMID- 25803289 TI - Depth profilometry via multiplexed optical high-coherence interferometry. AB - Depth Profilometry involves the measurement of the depth profile of objects, and has significant potential for various industrial applications that benefit from non-destructive sub-surface profiling such as defect detection, corrosion assessment, and dental assessment to name a few. In this study, we investigate the feasibility of depth profilometry using an Multiplexed Optical High-coherence Interferometry MOHI instrument. The MOHI instrument utilizes the spatial coherence of a laser and the interferometric properties of light to probe the reflectivity as a function of depth of a sample. The axial and lateral resolutions, as well as imaging depth, are decoupled in the MOHI instrument. The MOHI instrument is capable of multiplexing interferometric measurements into 480 one-dimensional interferograms at a location on the sample and is built with axial and lateral resolutions of 40 MUm at a maximum imaging depth of 700 MUm. Preliminary results, where a piece of sand-blasted aluminum, an NBK7 glass piece, and an optical phantom were successfully probed using the MOHI instrument to produce depth profiles, demonstrate the feasibility of such an instrument for performing depth profilometry. PMID- 25803290 TI - Measurement of the effect of physical exercise on the concentration of individuals with ADHD. AB - Attention Deficit Hyperactivity Disorder (ADHD) mainly affects the academic performance of children and adolescents. In addition to bringing physical and mental health benefits, physical activity has been used to prevent and improve ADHD comorbidities; however, its effectiveness has not been quantified. In this study, the effect of physical activity on children's attention was measured using a computer game. Intense physical activity was promoted by a relay race, which requires a 5-min run without a rest interval. The proposed physical stimulus was performed with 28 volunteers: 14 with ADHD (GE-EF) and 14 without ADHD symptoms (GC-EF). After 5 min of rest, these volunteers accessed the computer game to accomplish the tasks in the shortest time possible. The computer game was also accessed by another 28 volunteers: 14 with ADHD (GE) and 14 without these symptoms (GC). The response time to solve the tasks that require attention was recorded. The results of the four groups were analyzed using D'Agostino statistical tests of normality, Kruskal-Wallis analyses of variance and post-hoc Dunn tests. The groups of volunteers with ADHD who performed exercise (GE-EF) showed improved performance for the tasks that require attention with a difference of 30.52% compared with the volunteers with ADHD who did not perform the exercise (GE). The (GE-EF) group showed similar performance (2.5% difference) with the volunteers in the (GC) group who have no ADHD symptoms and did not exercise. This study shows that intense exercise can improve the attention of children with ADHD and may help their school performance. PMID- 25803293 TI - Comparison of Superior Rectus and Peripheral Lamellar Corneal Traction Suture during Trabeculectomy. AB - PURPOSE: To compare the efficacy and safety of two different traction suture (superior rectus traction suture and peripheral lamellar corneal traction suture) in patients undergoing trabeculectomy. METHODS: This retrospective trial compared outcomes of 385 eyes that underwent trabeculectomy with superior rectus traction suture (SRTS group; 206 eyes; 53.3%) and peripheral lamellar corneal traction suture (CTS group; 179 eyes; 46.7%). Qualified surgical success is defined as an intraocular pressure (IOP) between 6 and 21 mm Hg with or without topical anti glaucoma medication. RESULTS: After a follow-up of 24 months, the difference of IOP was significant (p = 0.042). The mean number of anti-glaucoma medications was 3.5 +/- 0.6 and 3.5 +/- 0.5 preoperatively (p = 1.000), whereas 0.18 +/- 0.32 and 0.10 +/- 0.39 at 24 months (p = 0.028). The 24-month qualified surgical success rates were 88.3% and 94.4% for both groups (p = 0.035; log-rank test). The difference between the two groups in regard to maximal bleb area is statistically significant (p = 0.011), with CTS group exhibiting more diffuse bleb area. The difference between the two groups in regard to the vascularity at the central and peripheral part of bleb is statistically significant (p = 0.019; p = 0.023, respectively). Encysted blebs was seen in 27 (13.1%) eyes in SRTS group and in 12 (6.7%) eyes in CTS group (p = 0.041). CONCLUSION: The use of superior rectus traction suture is significantly associated with a lower success rate than corneal traction suture, suggesting that surgeons should use a corneal fixation suture if at all possible. PMID- 25803291 TI - Chronic ethanol exposure produces time- and brain region-dependent changes in gene coexpression networks. AB - Repeated ethanol exposure and withdrawal in mice increases voluntary drinking and represents an animal model of physical dependence. We examined time- and brain region-dependent changes in gene coexpression networks in amygdala (AMY), nucleus accumbens (NAC), prefrontal cortex (PFC), and liver after four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure in C57BL/6J mice. Microarrays were used to compare gene expression profiles at 0-, 8-, and 120-hours following the last ethanol exposure. Each brain region exhibited a large number of differentially expressed genes (2,000-3,000) at the 0- and 8-hour time points, but fewer changes were detected at the 120-hour time point (400-600). Within each region, there was little gene overlap across time (~20%). All brain regions were significantly enriched with differentially expressed immune-related genes at the 8-hour time point. Weighted gene correlation network analysis identified modules that were highly enriched with differentially expressed genes at the 0- and 8 hour time points with virtually no enrichment at 120 hours. Modules enriched for both ethanol-responsive and cell-specific genes were identified in each brain region. These results indicate that chronic alcohol exposure causes global 'rewiring' of coexpression systems involving glial and immune signaling as well as neuronal genes. PMID- 25803292 TI - Sodium montmorillonite/amine-containing drugs complexes: new insights on intercalated drugs arrangement into layered carrier material. AB - Layered drug delivery carriers are current targets of nanotechnology studies since they are able to accommodate pharmacologically active substances and are effective at modulating drug release. Sodium montmorillonite (Na-MMT) is a clay that has suitable properties for developing new pharmaceutical materials due to its high degree of surface area and high capacity for cation exchange. Therefore Na-MMT is a versatile material for the preparation of new drug delivery systems, especially for slow release of protonable drugs. Herein, we describe the intercalation of several amine-containing drugs with Na-MMT so we can derive a better understanding of how these drugs molecules interact with and distribute throughout the Na-MMT interlayer space. Therefore, for this purpose nine sodium montmorillonite/amine-containing drugs complexes (Na-MMT/drug) were prepared and characterized. In addition, the physicochemical properties of the drugs molecules in combination with different experimental conditions were assessed to determine how these factors influenced experimental outcomes (e.g. increase of the interlayer spacing versus drugs arrangement and orientation). We also performed a molecular modeling study of these amine-containing drugs associated with different Na-MMT/drug complex models to analyze the orientation and arrangement of the drugs molecules in the complexes studied. Six amine-containing drugs (rivastigmine, doxazosin, 5-fluorouracil, chlorhexidine, dapsone, nystatin) were found to successfully intercalate Na-MMT. These findings provide important insights on the interlayer aspect of the molecular systems formed and may contribute to produce more efficient drug delivery nanosystems. PMID- 25803294 TI - Tandem differential mobility spectrometry with ion dissociation in air at ambient pressure and temperature. AB - Proton-bound dimers were dissociated to protonated monomers in air at ambient pressure and temperature using electric fields of ultrahigh Field Asymmetric Ion Mobility Spectrometry (ultraFAIMS) with the onset of dissociation for ethyl acetate as 96 Td and for dimethyl methyl phosphonate as 170 Td. Ions then were measured by differential mobility spectrometry (DMS). Fragment ions were formed with propyl acetate at electric fields of 90 Td or greater. The dissociation in ultraFAIMS of ions, with compensation fields near zero, to form smaller ions with new compensation fields, provided a method to improve peak capacity in DMS without gas modifiers. These findings also lay the foundation for a triple stage DMS with a centre stage for ion dissociation or fragmentation. PMID- 25803296 TI - Composition of glycosaminoglycans in elasmobranchs including several deep-sea sharks: identification of chondroitin/dermatan sulfate from the dried fins of Isurus oxyrinchus and Prionace glauca. AB - Shark fin, used as a food, is a rich source of glycosaminoglyans (GAGs), acidic polysaccharides having important biological activities, suggesting their nutraceutical and pharmaceutical application. A comprehensive survey of GAGs derived from the fin was performed on 11 elasmobranchs, including several deep sea sharks. Chondroitin sulfate (CS) and hyaluronic acid (HA) were found in Isurus oxyrinchus, Prionace glauca, Scyliorhinus torazame, Deania calcea, Chlamydoselachus anguineus, Mitsukurina owatoni, Mustelus griseus and Dasyatis akajei, respectively. CS was only found from Chimaera phantasma, Dalatias licha, and Odontaspis ferox, respectively. Characteristic disaccharide units of most of the CS were comprised of C- and D-type units. Interestingly, substantial amount of CS/dermatan sulfate (DS) was found in the dried fin (without skin and cartilage) of Isurus oxyrinchus and Prionace glauca. 1H-NMR analysis showed that the composition of glucuronic acid (GlcA) and iduronic acid (IdoA) in shark CS/DS was 41.2% and 58.8% (Isurus oxyrinchus), 36.1% and 63.9% (Prionace glauca), respectively. Furthermore, a substantial proportion of this CS/DS consisted of E , B- and D-type units. Shark CS/DS stimulated neurite outgrowth of hippocampal neurons at a similar level as DS derived from invertebrate species. Midkine and pleiotrophin interact strongly with CS/DS from Isurus oxyrinchus and Prionace glauca, affording Kd values of 1.07 nM, 6.25 nM and 1.70 nM, 1.88 nM, respectively. These results strongly suggest that the IdoA-rich domain of CS/DS is required for neurite outgrowth activity. A detailed examination of oligosaccharide residues, produced by chondroitinase ACII digestion, suggested that the IdoA and B-type units as well as A- and C-type units were found in clusters in shark CS/DS. In addition, it was discovered that the contents of B type units in these IdoA-rich domain increased in a length dependent manner, while C- and D-type units were located particularly in the immediate vicinity of the IdoA-rich domain. PMID- 25803298 TI - Correction: the early origin of the antarctic marine fauna and its evolutionary implications. AB - [This corrects the article DOI: 10.1371/journal.pone.0114743.]. PMID- 25803295 TI - Validation of serological tests for the detection of antibodies against Treponema pallidum in nonhuman primates. AB - There is evidence to suggest that the yaws bacterium (Treponema pallidum ssp. pertenue) may exist in non-human primate populations residing in regions where yaws is endemic in humans. Especially in light of the fact that the World Health Organizaiton (WHO) recently launched its second yaws eradication campaign, there is a considerable need for reliable tools to identify treponemal infection in our closest relatives, African monkeys and great apes. It was hypothesized that commercially available serological tests detect simian anti-T. pallidum antibody in serum samples of baboons, with comparable sensitivity and specificity to their results on human sera. Test performances of five different treponemal tests (TTs) and two non-treponemal tests (NTTs) were evaluated using serum samples of 57 naturally T. pallidum-infected olive baboons (Papio anubis) from Lake Manyara National Park in Tanzania. The T. pallidum particle agglutination assay (TP-PA) was used as a gold standard for comparison. In addition, the overall infection status of the animals was used to further validate test performances. For most accurate results, only samples that originated from baboons of known infection status, as verified in a previous study by clinical inspection, PCR and immunohistochemistry, were included. All tests, TTs and NTTs, used in this study were able to reliably detect antibodies against T. pallidum in serum samples of infected baboons. The sensitivity of TTs ranged from 97.7-100%, while specificity was between 88.0-100.0%. The two NTTs detected anti-lipoidal antibodies in serum samples of infected baboons with a sensitivity of 83.3% whereas specificity was 100%. For screening purposes, the TT Espline TP provided the highest sensitivity and specificity and at the same time provided the most suitable format for use in the field. The enzyme immune assay Mastblot TP (IgG), however, could be considered as a confirmatory test. PMID- 25803297 TI - Advantages of the phosphatidylserine-recognizing peptide PSP1 for molecular imaging of tumor apoptosis compared with annexin V. AB - A number of peptide-based indicators have been identified and reported as potential apoptosis probes, offering great promise for early assessment of therapeutic efficacy in several types of cancer. Direct comparison of the newly developed probes with previously used ones would be an important step in assessing possible applications. Here, we compared the newly identified peptide based phosphatidylserine (PS) indicator PSP1 (CLSYYPSYC) with annexin V, a common probe for molecular imaging of apoptotic cells, with respect to PS binding kinetics, apoptotic cell-targeting ability, and the efficacy of homing to apoptotic tumor cells in a mouse model after treatment with the anticancer agent camptothecin. Our results indicate that PSP1 efficiently targeted apoptotic cells and generated apoptosis/tumor-specific signals after cancer treatment in the animal model, whereas a similar dose of annexin V showed weak signals. The formation of a stable complex of PSP1 with PS might be one reason for the efficient in vivo targeting. We suggest that PSP1 has potential advantages for in vivo apoptotic cell imaging and could serve as a platform for the development of de novo peptide-based probes for apoptosis. PMID- 25803299 TI - Antimicrobial Resistance and Plasmid Profile of Bacterial Strains Isolated from the Urbanized Eltsovka-1 River (Russia). AB - Antimicrobial resistance and plasmid profile of Gram-positive and Gram-negative bacterial strains isolated from the urbanized Eltsovka-1 River (Russia) were investigated. Sequencing of the 16S rRNA of of G+ strains showed 99-100% identity to that of Bacillus aerophilus, Bacillus altitudinis, Bacillus amyloliquefaciens, Bacillus anthrancis, Bacillus barbaricus, Bacillus cereus, Bacillus flexus, Bacillus indriensis, Bacillus stratosphericus, Bacillus subtilis subsp. subtilis, Bacillus thuringiensis, Streptomyces albidoflavus, Streptomyces albus, Streptomyces exfoliatus, Streptomyces odorifer, and Streptomyces sampsonii. Sequencing of the 16S rRNA of G-strains was similar in 99-100% to that of Aeromonas bestiarum, Aeromonas encheleia, Aeromonas hydrophila, A. hydrophila subsp. anaerogenes, A. hydrophila subsp. dhakensis, Aeromonas media, Aeromonas molluscorum, Aeromonas popoffii, Aeromonas salmonicida subsp. masoucida, A. salmonicida subsp. pectinolytica, A. salmonicida subsp. salmonicida, Aeromonas punctata, Aeromonas sobria, and Shewanella putrefaciens. The highest percentage (88.4%) of strains was resistant to polymyxin B followed by 69% to lincomycin, 61.5% to benzilpenicillin, 57.7% to ampicillin, and 50% to carbenicillin. A low level of resistance (4%) was found to kanamycin (8%), to streptomycin (11.5%), to neomycin and tetracycline, and (15%) to erythromycin. No resistance was found to gentamycin, monomycin, and chloroamphenicol. The majority (80.7%) of strains was multidrug-resistant. Ninety-two percent of all strains carried plasmid DNA of various sizes. PMID- 25803301 TI - Why do you dance? Development of the Dance Motivation Inventory (DMI). AB - Dancing is a popular form of physical exercise and studies have show that dancing can decrease anxiety, increase self-esteem, and improve psychological wellbeing. The aim of the current study was to explore the motivational basis of recreational social dancing and develop a new psychometric instrument to assess dancing motivation. The sample comprised 447 salsa and/or ballroom dancers (68% female; mean age 32.8 years) who completed an online survey. Eight motivational factors were identified via exploratory factor analysis and comprise a new Dance Motivation Inventory: Fitness, Mood Enhancement, Intimacy, Socialising, Trance, Mastery, Self-confidence and Escapism. Mood Enhancement was the strongest motivational factor for both males and females, although motives differed according to gender. Dancing intensity was predicted by three motivational factors: Mood Enhancement, Socialising, and Escapism. The eight dimensions identified cover possible motives for social recreational dancing, and the DMI proved to be a suitable measurement tool to assess these motives. The explored motives such as Mood Enhancement, Socialising and Escapism appear to be similar to those identified in other forms of behaviour such as drinking alcohol, exercise, gambling, and gaming. PMID- 25803300 TI - B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens. AB - Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naive wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naive wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients. PMID- 25803303 TI - Strengthening the detection of and early response to public health emergencies: lessons from the West African Ebola epidemic. AB - Mark Siedner and colleagues reflect on the early response to the Ebola epidemic and lessons that can be learned for future epidemics. PMID- 25803304 TI - Update on osteoporosis from the 2014 Santa Fe Bone symposium. AB - The 2014 Santa Fe Bone Symposium provided a setting for the presentation and discussion of the clinical relevance of recent advances in the fields of osteoporosis and metabolic bone disease. The format included oral presentations of abstracts by endocrinology fellows, plenary lectures, panel discussions and breakout sessions, with ample opportunities for informal discussions before and after scheduled events. Topics addressed in these proceedings included a review of the important scientific publications in the past year, fracture prevention in patients with dysmobility and immobility, fracture liaison services for secondary fracture prevention, management of pre-menopausal osteoporosis, the role of bone microarchitecture in determining bone strength, measurement of microarchitecture in clinical practice and methods to improve the quality of bone density testing. This is a report of the proceedings of the 2014 Santa Fe Bone Symposium. PMID- 25803302 TI - Analysis and prediction of the critical regions of antimicrobial peptides based on conditional random fields. AB - Antimicrobial peptides (AMPs) are potent drug candidates against microbes such as bacteria, fungi, parasites, and viruses. The size of AMPs ranges from less than ten to hundreds of amino acids. Often only a few amino acids or the critical regions of antimicrobial proteins matter the functionality. Accurately predicting the AMP critical regions could benefit the experimental designs. However, no extensive analyses have been done specifically on the AMP critical regions and computational modeling on them is either non-existent or settled to other problems. With a focus on the AMP critical regions, we thus develop a computational model AMPcore by introducing a state-of-the-art machine learning method, conditional random fields. We generate a comprehensive dataset of 798 AMPs cores and a low similarity dataset of 510 representative AMP cores. AMPcore could reach a maximal accuracy of 90% and 0.79 Matthew's correlation coefficient on the comprehensive dataset and a maximal accuracy of 83% and 0.66 MCC on the low similarity dataset. Our analyses of AMP cores follow what we know about AMPs: High in glycine and lysine, but low in aspartic acid, glutamic acid, and methionine; the abundance of alpha-helical structures; the dominance of positive net charges; the peculiarity of amphipathicity. Two amphipathic sequence motifs within the AMP cores, an amphipathic alpha-helix and an amphipathic pi-helix, are revealed. In addition, a short sequence motif at the N-terminal boundary of AMP cores is reported for the first time: arginine at the P(-1) coupling with glycine at the P1 of AMP cores occurs the most, which might link to microbial cell adhesion. PMID- 25803305 TI - APOE epsilon4 Genotype and the Risk for Subjective Cognitive Impairment in Elderly Persons. AB - The authors compared the risk for subjective cognitive impairment (SCI) between carriers of the apolipoprotein E epsilon4 (APOE epsilon4) allele (cases) and APOE epsilon4 noncarriers (controls). SCI was assessed by a validated self-reported questionnaire. The authors used multivariable logistic regression analyses to compute odds ratios and 95% confidence intervals adjusted for age, sex, education, and marital status. Data were available on 114 participants (83 women; 47 APOE epsilon4 carriers; mean age, 69 years). The risk for SCI was significantly higher among cases than controls, particularly for those 70 years of age and older. These findings should be considered preliminary until confirmed by a prospective cohort study. PMID- 25803308 TI - Helical mesoporous silica as an inorganic heterogeneous chiral trigger for asymmetric autocatalysis with amplification of enantiomeric excess. AB - Mesoporous silica has been used as a heterogeneous support for catalysts; however, asymmetric induction by the helicity of inorganic mesoporous silica itself has not yet been achieved. P- and M-helical mesoporous silica was found to act as a chiral inorganic trigger for asymmetric autocatalysis to afford (S) and (R)-pyrimidyl alkanol with >99.5% ee, respectively. PMID- 25803306 TI - Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. AB - The insertion of precise genetic modifications by genome editing tools such as CRISPR-Cas9 is limited by the relatively low efficiency of homology-directed repair (HDR) compared with the higher efficiency of the nonhomologous end-joining (NHEJ) pathway. To enhance HDR, enabling the insertion of precise genetic modifications, we suppressed the NHEJ key molecules KU70, KU80 or DNA ligase IV by gene silencing, the ligase IV inhibitor SCR7 or the coexpression of adenovirus 4 E1B55K and E4orf6 proteins in a 'traffic light' and other reporter systems. Suppression of KU70 and DNA ligase IV promotes the efficiency of HDR 4-5-fold. When co-expressed with the Cas9 system, E1B55K and E4orf6 improved the efficiency of HDR up to eightfold and essentially abolished NHEJ activity in both human and mouse cell lines. Our findings provide useful tools to improve the frequency of precise gene modifications in mammalian cells. PMID- 25803309 TI - Assessing Interpersonal Subtypes in Depression. AB - The context-free diagnoses outlined by the Diagnostic and Statistical Manual of Mental Disorders might not provide enough information to represent the heterogeneity observed in depressed patients. Interpersonal factors have been linked to depression in a mutually influencing pathoplastic relationship where certain problems, like submissiveness, are related to symptom chronicity. This study evaluated interpersonal pathoplasticity in a range of depressive presentations. We examined archival data collected from 407 participants who met criteria for major depressive disorder (MDD), dysthymic disorder (DD), or subthreshold depression (sD). Latent profile analysis (LPA) identified 5 interpersonal subtypes (vindictive, intrusive, socially avoidant, exploitable, and cold). Apart from gender, the subtypes did not differ significantly on demographic characteristics, psychiatric comorbidity, or self-report depression severity. Socially avoidant participants were more likely to meet criteria for a clinical depression diagnosis (MDD or DD), whereas vindictive participants were more likely to have sD. Our results indicate that interpersonal problems could account for heterogeneity observed in depression. PMID- 25803312 TI - Moral license in video games: when being right can mean doing wrong. AB - Research on video game violence has found largely consistent evidence that violence in video games tends to be associated with an increase in antisocial behavior. However, this body of work has mostly ignored one prominent feature of many violent games: moral decision making. It is possible that the influence of video game violence could change when moral decisions are brought into the context. One way video games change behavior is through changes in players' self perceptions, a process called identity simulation. In addition, a perspective called moral license predicts that these effects should not necessarily be consistent across behaviors, in that people should try to balance selfishness with keeping the moral high ground across many behaviors. Therefore, moral choices (or immoral choices) in a video game may predict less moral (or more moral) behaviors right after the game. However, later behavior may revert yet again, creating a cycle of pro- and antisocial behaviors. The present experiment asks participants to make moral choices in a video game, and then measures their behavior on two subsequent tasks. Results indicate that taking what participants perceive to be the more moral mind-set in the video game predicts more antisocial behavior on the first task, but more pro-social behavior on the next task. These results support identity simulation and moral license processes in a video game and moral behavior context, and indicate that there may be greater complexity in video game violence effects than previously understood. PMID- 25803307 TI - Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium. AB - We have previously shown that Annexin A8 (ANXA8) is strongly associated with the basal-like subgroup of breast cancers, including BRCA1-associated breast cancers, and poor prognosis; while in the mouse mammary gland AnxA8 mRNA is expressed in low-proliferative isolated pubertal mouse mammary ductal epithelium and after enforced involution, but not in isolated highly proliferative terminal end buds (TEB) or during pregnancy. To better understand ANXA8's association with this breast cancer subgroup we established ANXA8's cellular distribution in the mammary gland and ANXA8's effect on cell proliferation. We show that ANXA8 expression in the mouse mammary gland was strong during pre-puberty before the expansion of the rudimentary ductal network and was limited to a distinct subpopulation of ductal luminal epithelial cells but was not detected in TEB or in alveoli during pregnancy. Similarly, during late involution its expression was found in the surviving ductal epithelium, but not in the apoptotic alveoli. Double-immunofluorescence (IF) showed that ANXA8 positive (+ve) cells were ER alpha negative (-ve) and mostly quiescent, as defined by lack of Ki67 expression during puberty and mid-pregnancy, but not terminally differentiated with ~15% of ANXA8 +ve cells re-entering the cell cycle at the start of pregnancy (day 4.5). RT-PCR on RNA from FACS-sorted cells and double-IF showed that ANXA8+ve cells were a subpopulation of c-kit +ve luminal progenitor cells, which have recently been identified as the cells of origin of basal-like breast cancers. Over expression of ANXA8 in the mammary epithelial cell line Kim-2 led to a G0/G1 arrest and suppressed Ki67 expression, indicating cell cycle exit. Our data therefore identify ANXA8 as a potential mediator of quiescence in the normal mouse mammary ductal epithelium, while its expression in basal-like breast cancers may be linked to ANXA8's association with their specific cells of origin. PMID- 25803313 TI - Chemoselective formation of unsymmetrically substituted ethers from catalytic reductive coupling of aldehydes and ketones with alcohols in aqueous solution. AB - A well-defined cationic Ru-H complex catalyzes reductive etherification of aldehydes and ketones with alcohols. The catalytic method employs environmentally benign water as the solvent and cheaply available molecular hydrogen as the reducing agent to afford unsymmetrical ethers in a highly chemoselective manner. PMID- 25803317 TI - The impact of attentional allocation capacities on nonword repetition in children with specific language impairment. AB - This study aimed at directly assessing the hypothesis that attentional allocation capacity influences poor nonword repetition (NWR) performances in children with specific language impairment (SLI), using an attention demanding visual search task given concurrently with the NWR task. Twenty-one children with SLI, 21 typically developing children matched on age and 21 typically developing children matched on nonword span performed an immediate serial recall task of nonwords. The nonword lists were presented either alone or concurrently with the visual search task. Overall, results revealed a resource-sharing trade-off between the two tasks. Children with SLI were affected to the same extent as their span matched controls by the necessity to allocate their attentional resources between the two tasks. Interestingly, nonword processing strategies seemed to differ among groups: age-matched controls allocated a larger part of their attentional resources to the encoding stage, whereas nonword recall was more attention demanding in children with SLI and younger controls. PMID- 25803314 TI - Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells. AB - Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 MUM) and higher concentrations (10 MUM, 100 MUM, 240 MUM and 480 MUM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 MUM, 10 MUM and 100 MUM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 MUM and 480 MUM concentrations and the cytokinesis block proliferation index between 0.6 MUM and 240 MUM concentrations. On the other hand, glibenclamide changed the cell proliferation kinetics when used at 480 MUM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug. PMID- 25803316 TI - Neonatal Abstinence Syndrome: Influence of a Combined Inpatient/Outpatient Methadone Treatment Regimen on the Average Length of Stay of a Medicaid NICU Population. AB - Prescription opioid and heroin abuse have been increasing steadily year after year, and continue to be a serious national problem. A sequela of the increase in opioid abuse has been an increase in the number of infants born with opioid dependence. These infants often require costly, prolonged stays in the neonatal intensive care unit (NICU) for drug withdrawal treatment. The authors studied a population of infants from a large Medicaid health plan who were born with neonatal abstinence syndrome (NAS) secondary to in utero opioid exposure to assess the average length of stay in the NICU, and to determine the variables that may account for differences in interinstitutional lengths of stay. The overall average length of stay for NAS was 21.1 days for the 139 infants included in the study. Analysis of the medication used for treatment revealed that infants who were treated with a combined inpatient/outpatient regimen with methadone had an average length of stay of 11.4 days versus 25.1 days for infants who were treated entirely as inpatients (P<0.001), a 55% reduction in average length of stay. In 2009 there were an estimated 13,600 cases of NAS in the United States at a cost of $53,000 per case. A 55% reduction in length of stay corresponds to $396 million in annual savings for the treatment of NAS. Development of successful combined inpatient/outpatient management programs for NAS warrants further consideration. PMID- 25803320 TI - Transparent organic photodetector using a near-infrared absorbing cyanine dye. AB - Organic photodetectors are interesting for low cost, large area optical sensing applications. Combining organic semiconductors with discrete absorption bands outside the visible wavelength range with transparent and conductive electrodes allows for the fabrication of visibly transparent photodetectors. Visibly transparent photodetectors can have far reaching impact in a number of areas including smart displays, window-integrated electronic circuits and sensors. Here, we demonstrate a near-infrared sensitive, visibly transparent organic photodetector with a very high average visible transmittance of 68.9%. The transmitted light of the photodetector under solar irradiation exhibits excellent transparency colour perception and rendering capabilities. At a wavelength of 850 nm and at -1 V bias, the photoconversion efficiency is 17% and the specific detectivity is 10(12) Jones. Large area photodetectors with an area of 1.6 cm(2) are demonstrated. PMID- 25803318 TI - Improved visualization of intracranial vessels with intraoperative coregistration of rotational digital subtraction angiography and intraoperative 3D ultrasound. AB - INTRODUCTION: Ultrasound can visualize and update the vessel status in real time during cerebral vascular surgery. We studied the depiction of parent vessels and aneurysms with a high-resolution 3D intraoperative ultrasound imaging system during aneurysm clipping using rotational digital subtraction angiography as a reference. METHODS: We analyzed 3D intraoperative ultrasound in 39 patients with cerebral aneurysms to visualize the aneurysm intraoperatively and the nearby vascular tree before and after clipping. Simultaneous coregistration of preoperative subtraction angiography data with 3D intraoperative ultrasound was performed to verify the anatomical assignment. RESULTS: Intraoperative ultrasound detected 35 of 43 aneurysms (81%) in 39 patients. Thirty-nine intraoperative ultrasound measurements were matched with rotational digital subtraction angiography and were successfully reconstructed during the procedure. In 7 patients, the aneurysm was partially visualized by 3D-ioUS or was not in field of view. Post-clipping intraoperative ultrasound was obtained in 26 and successfully reconstructed in 18 patients (69%) despite clip related artefacts. The overlap between 3D-ioUS aneurysm volume and preoperative rDSA aneurysm volume resulted in a mean accuracy of 0.71 (Dice coefficient). CONCLUSIONS: Intraoperative coregistration of 3D intraoperative ultrasound data with preoperative rotational digital subtraction angiography is possible with high accuracy. It allows the immediate visualization of vessels beyond the microscopic field, as well as parallel assessment of blood velocity, aneurysm and vascular tree configuration. Although spatial resolution is lower than for standard angiography, the method provides an excellent vascular overview, advantageous interpretation of 3D-ioUS and immediate intraoperative feedback of the vascular status. A prerequisite for understanding vascular intraoperative ultrasound is image quality and a successful match with preoperative rotational digital subtraction angiography. PMID- 25803322 TI - Recent developments in alkene hydro-functionalisation promoted by homogeneous catalysts based on earth abundant elements: formation of C-N, C-O and C-P bond. AB - This Perspective article provides an overview of the recent advancements in the field of intra- and inter-molecular C-N, C-O and C-P bond formation by hydroamination, hydroalkoxylation, hydrophosphination, hydrophosphonylation or hydrophosphinylation of unactivated alkenes, including allenes, 1,3-dienes and strained alkenes, promoted by (chiral) homogeneous catalysts based on earth abundant elements of the s and p blocks, the first row transition metals and the rare-earth metals. The relevant literature from 2009 until late 2014 has been covered. PMID- 25803321 TI - Elevated salivary alpha amylase in adolescent sexual abuse survivors with posttraumatic stress disorder symptoms. AB - OBJECTIVE: Little is known regarding neuroendocrine responses in adolescent girls with posttraumatic stress disorder (PTSD) who have experienced sexual abuse. Therefore, we collected saliva samples three times daily for 3 days to assess concentrations of salivary alpha amylase (sAA) - a surrogate marker for autonomic nervous system (ANS) activity and, in particular, sympathetic activity - in sexually abused adolescent girls. METHODS: Twenty-four girls (mean age: 15+/-1.4 years) who had experienced recent sexual abuse (i.e., sexual abuse occurred 1-6 months prior to study enrollment) and 12 healthy comparison subjects (mean age: 14.8+/-1.3 years) completed a structured interview and assessments to ascertain symptoms of posttraumatic stress, then collected saliva at home upon awakening, 30 minutes after waking, and at 5 p.m. on three consecutive school days. RESULTS: For sexually abused girls, total PTSD symptoms were associated with higher overall morning levels of sAA (r[20]=0.51, p=0.02), a finding driven by intrusive symptoms (r[20]=0.43, p<0.05) and hyperarousal symptoms (r[20]=0.58, p=0.01). There were no significant differences in diurnal sAA secretion between the sexually abused girls and healthy comparison adolescents. CONCLUSIONS: Overall morning concentrations of sAA in sexually abused girls are associated with overall PTSD severity as well as symptoms of hyperarousal and intrusive symptoms, possibly reflecting symptom-linked increases in ANS tone. These data raise the possibility that alterations in ANS activity are related to the pathophysiology of sexual abuse-related PTSD in adolescent girls, and may inform therapeutic interventions (e.g., antiadrenergic medications). PMID- 25803324 TI - A participatory approach to designing and enhancing integrated health information technology systems for veterans: protocol. AB - BACKGROUND: The Department of Veterans Affairs (VA) has developed health information technologies (HIT) and resources to improve veteran access to health care programs and services, and to support a patient-centered approach to health care delivery. To improve VA HIT access and meaningful use by veterans, it is necessary to understand their preferences for interacting with various HIT resources to accomplish health management related tasks and to exchange information. OBJECTIVE: The objective of this paper was to describe a novel protocol for: (1) developing a HIT Digital Health Matrix Model; (2) conducting an Analytic Hierarchy Process called pairwise comparison to understand how and why veterans want to use electronic health resources to complete tasks related to health management; and (3) developing visual modeling simulations that depict veterans' preferences for using VA HIT to manage their health conditions and exchange health information. METHODS: The study uses participatory research methods to understand how veterans prefer to use VA HIT to accomplish health management tasks within a given context, and how they would like to interact with HIT interfaces (eg, look, feel, and function) in the future. This study includes two rounds of veteran focus groups with self-administered surveys and visual modeling simulation techniques. This study will also convene an expert panel to assist in the development of a VA HIT Digital Health Matrix Model, so that both expert panel members and veteran participants can complete an Analytic Hierarchy Process, pairwise comparisons to evaluate and rank the applicability of electronic health resources for a series of health management tasks. RESULTS: This protocol describes the iterative, participatory, and patient-centered process for: (1) developing a VA HIT Digital Health Matrix Model that outlines current VA patient-facing platforms available to veterans, describing their features and relevant contexts for use; and (2) developing visual model simulations based on direct veteran feedback that depict patient preferences for enhancing the synchronization, integration, and standardization of VA patient facing platforms. Focus group topics include current uses, preferences, facilitators, and barriers to using electronic health resources; recommendations for synchronizing, integrating, and standardizing VA HIT; and preferences on data sharing and delegation within the VA system. CONCLUSIONS: This work highlights the practical, technological, and personal factors that facilitate and inhibit use of current VA HIT, and informs an integrated system redesign. The Digital Health Matrix Model and visual modeling simulations use knowledge of veteran preferences and experiences to directly inform enhancements to VA HIT and provide a more holistic and integrated user experience. These efforts are designed to support the adoption and sustained use of VA HIT to support patient self management and clinical care coordination in ways that are directly aligned with veteran preferences. PMID- 25803323 TI - New somatic mutations and WNK1-B4GALNT3 gene fusion in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignant neoplasia. Oncogene activation occurs in more than 70% of the cases. Indeed, about 40% of PTCs harbor mutations in BRAF gene, whereas RET rearrangements (RET/PTC oncogenes) are present in about 20% of cases. Finally, RAS mutations and TRK rearrangements account for about 5% each of these malignancies. We used RNA Sequencing to identify fusion transcripts and mutations in cancer driver genes in a cohort of 18 PTC patients. Furthermore, we used targeted DNA sequencing to validate identified mutations. We extended the screening to 50 PTC patients and 30 healthy individuals. Using this approach we identified new missense mutations in CBL, NOTCH1, PIK3R4 and SMARCA4 genes. We found somatic mutations in DICER1, MET and VHL genes, previously found mutated in other tumors, but not described in PTC. We identified a new chimeric transcript generated by the fusion of WNK1 and B4GALNT3 genes, correlated with B4GALNT3 overexpression. Our data confirmed PTC genetic heterogeneity, revealing that gene expression correlates more with the mutation pattern than with tumor staging. Overall, this study provides new data about mutational landscape of this neoplasia, suggesting potential pharmacological adjuvant therapies against Notch signaling and chromatin remodeling enzymes. PMID- 25803325 TI - Corneal collagen cross-linking for treating keratoconus. AB - BACKGROUND: Keratoconus is a condition of the eye that affects approximately 1 in 2000 people. The disease leads to a gradual increase in corneal curvature and decrease in visual acuity with consequent impact on quality of life. Collagen cross-linking (CXL) with ultraviolet A (UVA) light and riboflavin (vitamin B2) is a relatively new treatment that has been reported to slow or halt the progression of the disease in its early stages. OBJECTIVES: The objective of this review was to assess whether there is evidence that CXL is an effective and safe treatment for halting the progression of keratoconus compared to no treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2014), EMBASE (January 1980 to August 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to August 2014), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to August 2014), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organisation International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 August 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) where CXL with UVA light and riboflavin was used to treat people with keratoconus and was compared to no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed trial quality, and extracted data using standard methodological procedures expected by Cochrane. Our primary outcomes were two indicators of progression at 12 months: increase in maximum keratometry of 1.5 dioptres (D) or more and deterioration in uncorrected visual acuity of more than 0.2 logMAR. MAIN RESULTS: We included three RCTs conducted in Australia, the United Kingdom, and the United States that enrolled a total of 225 eyes and analysed 219 eyes. The total number of people enrolled was not clear in two of the studies. Only adults were enrolled into these studies. Out of the eyes analysed, 119 had CXL (all using the epithelium-off technique) and 100 served as controls. One of these studies only reported comparative data on review outcomes. All three studies were at high risk for performance bias (lack of masking), detection bias (only one trial attempted to mask outcome assessment), and attrition bias (incomplete follow-up). It was not possible to pool data due to differences in measuring and reporting outcomes. We identified a further three unpublished trials that potentially had enrolled a total of 195 participants.There was limited evidence on the risk of progression. Analysis of the first few participants followed up to one year in one study suggested that eyes given CXL were less likely to have an increase in maximum keratometry of 1.5 D or more at 12 months compared to eyes given no treatment, but the confidence intervals (CI) were wide and compatible with no effect or more progression in the CXL group (risk ratio (RR) 0.12, 95% CI 0.01 to 2.00, 19 eyes). The same study reported the number of eyes with an increase of 2 D or more at 36 months in the whole cohort with a RR of 0.03 favouring CXL (95% CI 0.00 to 0.43, 94 eyes). Another study reported "progression" at 18 months using a different definition; people receiving CXL were less likely to progress, but again the effect was uncertain (RR 0.14, 95% CI 0.01 to 2.61, 44 eyes). We judged this to be very low quality evidence due to the risk of bias of included studies, imprecision, indirectness and publication bias but noted that the size of the potential effect was large.On average, treated eyes had a less steep cornea (approximately 2 D less steep) (mean difference (MD) -1.92, 95% CI -2.54 to -1.30, 94 eyes, 1 RCT, very low-quality evidence) and better uncorrected visual acuity (approximately 2 lines or 10 letters better) (MD -0.20, 95% CI -0.31 to -0.09, 94 eyes, 1 RCT, very low-quality evidence) at 12 months. None of the studies reported loss of 0.2 logMAR acuity. The data on corneal thickness were inconsistent. There were no data available on quality of life or costs. Adverse effects were not uncommon but mostly transient and of low clinical significance. In one trial, 3 out of 12 participants treated with CXL had an adverse effect including corneal oedema, anterior chamber inflammation, and recurrent corneal erosions. In one trial at 3 years 3 out of 50 participants experienced adverse events including mild diffuse corneal oedema and paracentral infiltrate, peripheral corneal vascularisation, and subepithelial infiltrates and anterior chamber inflammation. No adverse effects were reported in the control groups. AUTHORS' CONCLUSIONS: The evidence for the use of CXL in the management of keratoconus is limited due the lack of properly conducted RCTs. PMID- 25803326 TI - Efficacy of intense pulsed light for the treatment of burn scar dyschromias: a pilot study to assess patient satisfaction, safety, and willingness to pay. AB - INTRODUCTION: No treatment algorithms exist to reliably treat burn scar dyschromias. Intense pulsed light (IPL) has been used successfully to treat hyperpigmentation disorders, but has not been studied extensively in the treatment of burn scars. The purpose of this investigation was to assess clinical efficacy and patient satisfaction with IPL for the treatment of burn scar dyschromia. METHODS: Patients with burn scar dyschromias were treated using the Lume 1 platform (Lumenis) to target pigmented lesions, using fluences between 10 and 22 joules/cm and filters ranging from 560 to 650 nm. At the conclusion of the study, providers assessed changes in burn scar dyschromia, whereas patients were queried regarding satisfaction and perceived efficacy, using a 1 to 5 Likert scale. The patients, who were not charged for the IPL treatment, were queried regarding willingness to pay. RESULTS: Twenty patients (mean age, 35.4 years; mean total body surface area, 27.6%; mean composite Fitzpatrick score, 3.9) underwent IPL treatment of burn scar dyschromias, an average of 3.2 years after injury. Mean fluence was 15.4 J/cm (range, 10-22 J/cm), and the most common filter used was 590 nm (range, 560-650 nm). Mean area treated was 90.7 cm, with a range of 4 to 448 cm. Complications included pain (4), hyperpigmentation (1), and blistering (2). Sixteen patients noted mild to moderate improvement, reporting a 4.5 for efficacy and a 4.4 for satisfaction. Regarding willingness to pay, patients would spend a mean of U.S. $7429 to completely remove their scars, but only a median of U.S. $350 to get the actual results that they received. Mean length of follow-up was 3.8 months, with a standard deviation of 2.2 months. CONCLUSIONS: Patients perceived IPL as an efficacious modality in the treatment of burn scar dyschromia, with a high level of satisfaction, despite the potential for morbidity. However, we are reluctant to recommend IPL for routine treatment of burn scar dyschromias, given only minimal improvement observed, potential for complications, and a willingness to pay that is lower than the cost of providing care. PMID- 25803327 TI - Human Embryonic Stem Cell-Derived Endothelial Precursor Cell Conditioned Medium Reduces the Thickness of the Capsule Around Silicone Implants in Rats. AB - BACKGROUND: We postulated that the fibrotic capsule around a silicone implant could be induced by ischemic conditions, based on previous reports that hypoxia is an important microenvironmental factor in the development of tissue fibrosis. OBJECTIVE: This study aimed to determine the effect of human embryonic stem cell (hESC)-derived endothelial precursor cell (EPC) conditioned medium (CM), which has strong angiogenic potential, on the development of capsule around the silicone implant in a rat model. METHODS AND MATERIALS: Three groups had a mini silicone implant with a smooth surface inserted. In 2 experimental groups, hESC EPC CM was administered into the subcutaneous pocket either 1 or 2 times. After 2 months, the capsules were harvested and analyzed by histologic examination. RESULTS: There was a significant reduction in the thickness of the peri-implant capsules (P < 0.05) between the control and experimental groups. There is no tendency that hESC-EPC CM reduces inflammatory reaction in early postoperative periods. The experimental group showed increased angiogenesis compared to the control group (P < 0.05). CONCLUSIONS: Tissue hypoxia around the implant may be another cause for the peri-implant capsule. A preventive or therapeutic strategy to decrease capsular contracture by relieving the ischemic condition around the implant can be investigated in the future. PMID- 25803330 TI - Clown with folded arms: Walt Kuhn. PMID- 25803331 TI - Putting Chagas disease on the US radar screen. PMID- 25803332 TI - Nudging medical practice change one regulation at a time. PMID- 25803342 TI - Harnessing RNA interference for therapy: the silent treatment. PMID- 25803343 TI - Naltrexone extended-release plus bupropion extended-release for treatment of obesity. PMID- 25803344 TI - A piece of my mind. The absence of something. PMID- 25803345 TI - Endovascular therapy for atherosclerotic intracranial arterial stenosis: back to the drawing board. PMID- 25803347 TI - Surveillance of adverse psychiatric medication events. PMID- 25803348 TI - Systemic corticosteroid therapy for acute sinusitis. AB - CLINICAL QUESTION: Are oral or parenteral corticosteroids associated with improved clinical outcomes in patients with acute sinusitis compared with placebo or nonsteroidal anti-inflammatory drugs (NSAIDs)? BOTTOM LINE: Oral corticosteroids combined with antibiotics may be associated with modest benefit for short-term relief of symptoms in adults with severe symptoms of acute sinusitis compared with antibiotics alone. Oral corticosteroids as monotherapy are not associated with improved clinical outcomes in adults with clinically diagnosed acute sinusitis. PMID- 25803350 TI - Salary differences between male and female registered nurses in the United States. PMID- 25803349 TI - Evaluating hyponatremia. PMID- 25803351 TI - Coronary artery disease screening using coronary computed tomography angiography. PMID- 25803352 TI - Coronary artery disease screening using coronary computed tomography angiography- reply. PMID- 25803353 TI - Duty hour reforms and patient outcomes. PMID- 25803354 TI - Treatment to prevent hepatitis B virus reactivation in patients with lymphoma receiving chemotherapy. PMID- 25803355 TI - Duty hour reforms and patient outcomes--reply. PMID- 25803346 TI - Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial. AB - IMPORTANCE: Intracranial stenosis is one of the most common etiologies of stroke. To our knowledge, no randomized clinical trials have compared balloon-expandable stent treatment with medical therapy in symptomatic intracranial arterial stenosis. OBJECTIVE: To evaluate the efficacy and safety of the balloon expandable stent plus medical therapy vs medical therapy alone in patients with symptomatic intracranial stenosis (>=70%). DESIGN, SETTING, AND PATIENTS: VISSIT (the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy) trial is an international, multicenter, 1:1 randomized, parallel group trial that enrolled patients from 27 sites (January 2009-June 2012) with last follow-up in May 2013. INTERVENTIONS: Patients (N = 112) were randomized to receive balloon-expandable stent plus medical therapy (stent group; n = 59) or medical therapy alone (medical group; n = 53). MAIN OUTCOMES AND MEASURES: PRIMARY OUTCOME MEASURE: a composite of stroke in the same territory within 12 months of randomization or hard transient ischemic attack (TIA) in the same territory day 2 through month 12 postrandomization. A hard TIA was defined as a transient episode of neurological dysfunction caused by focal brain or retinal ischemia lasting at least 10 minutes but resolving within 24 hours. Primary safety measure: a composite of any stroke, death, or intracranial hemorrhage within 30 days of randomization and any hard TIA between days 2 and 30 of randomization. Disability was measured with the modified Rankin Scale and general health status with the EuroQol-5D, both through month 12. RESULTS: Enrollment was halted by the sponsor after negative results from another trial prompted an early analysis of outcomes, which suggested futility after 112 patients of a planned sample size of 250 were enrolled. The 30 day primary safety end point occurred in more patients in the stent group (14/58; 24.1% [95% CI, 13.9%-37.2%]) vs the medical group (5/53; 9.4% [95% CI, 3.1% 20.7%]) (P = .05). Intracranial hemorrhage within 30 days occurred in more patients in the stent group (5/58; 8.6% [95% CI, 2.9%-19.0%]) vs none in the medical group (95% CI, 0%-5.5%) (P = .06). The 1-year primary outcome of stroke or hard TIA occurred in more patients in the stent group (21/58; 36.2% [95% CI, 24.0-49.9]) vs the medical group (8/53; 15.1% [95% CI, 6.7-27.6]) (P = .02). Worsening of baseline disability score (modified Rankin Scale) occurred in more patients in the stent group (14/58; 24.1% [95% CI, 13.9%-37.2%]) vs the medical group (6/53; 11.3% [95% CI, 4.3%-23.0%]) (P = .09).The EuroQol-5D showed no difference in any of the 5 dimensions between groups at 12-month follow-up. CONCLUSIONS AND RELEVANCE: Among patients with symptomatic intracranial arterial stenosis, the use of a balloon-expandable stent compared with medical therapy resulted in an increased 12-month risk of added stroke or TIA in the same territory, and increased 30-day risk of any stroke or TIA. These findings do not support the use of a balloon-expandable stent for patients with symptomatic intracranial arterial stenosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00816166. PMID- 25803358 TI - Why physicians err in diagnosis. PMID- 25803356 TI - Treatment to prevent hepatitis B virus reactivation in patients with lymphoma receiving chemotherapy--reply. PMID- 25803359 TI - JAMA patient page. Hypoglycemia. PMID- 25803360 TI - Effects of porosity and mixed convection on MHD two phase fluid flow in an inclined channel. AB - The present study deals with the flow and heat transfer analysis of two immiscible fluids in an inclined channel embedded in a porous medium. The channel is divided in two phases such that a third grade fluid occupies the phase I and a viscous fluid occupies the phase II. Both viscous and third grade fluids are electrically conducting. A constant magnetic field is imposed perpendicular to the channel walls. The mathematical model is developed by using Darcy's and modified Darcy's laws for viscous and third grade fluids respectively. The transformed ordinary differential equations are solved numerically using a shooting method. The obtained results are presented graphically and influence of emerging parameters is discussed in detail. PMID- 25803361 TI - Task-driven image acquisition and reconstruction in cone-beam CT. AB - This work introduces a task-driven imaging framework that incorporates a mathematical definition of the imaging task, a model of the imaging system, and a patient-specific anatomical model to prospectively design image acquisition and reconstruction techniques to optimize task performance. The framework is applied to joint optimization of tube current modulation, view-dependent reconstruction kernel, and orbital tilt in cone-beam CT. The system model considers a cone-beam CT system incorporating a flat-panel detector and 3D filtered backprojection and accurately describes the spatially varying noise and resolution over a wide range of imaging parameters in the presence of a realistic anatomical model. Task-based detectability index (d') is incorporated as the objective function in a task driven optimization of image acquisition and reconstruction techniques. The orbital tilt was optimized through an exhaustive search across tilt angles ranging +/- 30 degrees . For each tilt angle, the view-dependent tube current and reconstruction kernel (i.e. the modulation profiles) that maximized detectability were identified via an alternating optimization. The task-driven approach was compared with conventional unmodulated and automatic exposure control (AEC) strategies for a variety of imaging tasks and anthropomorphic phantoms. The task driven strategy outperformed the unmodulated and AEC cases for all tasks. For example, d' for a sphere detection task in a head phantom was improved by 30% compared to the unmodulated case by using smoother kernels for noisy views and distributing mAs across less noisy views (at fixed total mAs) in a manner that was beneficial to task performance. Similarly for detection of a line-pair pattern, the task-driven approach increased d' by 80% compared to no modulation by means of view-dependent mA and kernel selection that yields modulation transfer function and noise-power spectrum optimal to the task. Optimization of orbital tilt identified the tilt angle that reduced quantum noise in the region of the stimulus by avoiding highly attenuating anatomical structures. The task driven imaging framework offers a potentially valuable paradigm for prospective definition of acquisition and reconstruction protocols that improve task performance without increase in dose. PMID- 25803363 TI - Acute Thoracic Findings in Oncologic Patients. AB - Cancer is the second most common cause of mortality in the United States, with >500,000 deaths reported annually. Acute or emergent findings in this group of patients can be a life-threatening phenomenon that results from malignancy or as a complication of therapy. In many cases, these events can be the first clinical manifestation of malignant disease. Oncologic emergencies have been classified as metabolic, hematologic, and structural emergencies. Within the thorax, most acute oncologic findings involve the lungs and airways in the form of drug toxicity, pulmonary infections, or malignant airway compression; the cardiovascular system in the form of pulmonary embolism, superior vena cava syndrome, cardiac tamponade, or massive hemoptysis; the mediastinum in the form of esophageal perforation, acute mediastinitis, or esophagorespiratory fistula; and the osseous spine and spinal cord in the form of invasion and cord compression. Given the life-threatening nature of many of these disease processes, awareness of such complications is critical to making an accurate diagnosis and formulating appropriate treatment strategies. PMID- 25803362 TI - A Real-Time Case Study in Driver Science: Physiological Strain and Related Variables. AB - This case study was conducted as an attempt to quantify racecar-driver core body temperature and heart rate (HR) in real time on a minute-by-minute basis and to expand the volume of work in the area of driver science. Three drivers were observed during a 15-lap, 25-min maximal event. Each driver competed in the closed-wheel, closed-cockpit sports-car category. Data on core body temperature and HR were collected continuously using the HQ Inc. ingestible core probe system and HR monitoring. Driver 1 pre- and postrace core temperatures were 37.80 degrees C and 38.79 degrees C, respectively. Driver 2 pre- and postrace core temperatures were 37.41 degrees C and 37.99 degrees C. Driver 1 pre- and postrace HRs were 102 and 161 beats/min. Driver 2 pre- and postrace HRs were 94.3 and 142 beats/min. Driver 1's physiological strain index (PSI) at the start was 3.51. Driver 2's PSI at the start was 3.10. Driver 1 finished with a PSI of 7.04 and driver 2 with a PSI of 3.67. Results show that drivers are continuously challenged minute by minute. In addition, before getting into their cars, the drivers already experience physiological and thermal challenges. The data suggest that drivers are getting hot quickly. In longer events, this represents the potential for severe heat injury. Investigating whether the HRs observed are indicative of work or evidence of a thermoregulatory-associated challenge is a direction for future work. The findings support the value of real-time data collection and offer strong evidence for the expansion of research on driver athletes. PMID- 25803365 TI - Association of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Shares Genetic and Cytokine Profiles With Other Autoinflammatory Diseases: Erratum. AB - [In the article "Association of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Shares Genetic and Cytokine Profiles With Other Autoinflammatory Diseases", which appeared in Volume 93, Issue 27 of Medicine, one of Orietta M. Borghi's affiliations was omitted. The article should have stated that Orietta M. Borghi is associated with the IRCCS Istituto Auxologico Italiano, Milano, Italy as well as the Dipartimento di Scienze Cliniche e di Comunita, Universita di Milano.]. PMID- 25803366 TI - A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma: erratum. AB - [In the article "A Metabolic Phenotype Based on Mitochondrial Ribosomal Protein Expression as a Predictor of Lymph Node Metastasis in Papillary Thyroid Carcinoma", which appeared in Volume 94, Issue 2 of Medicine, several abbreviations were left undefined in figure and table legends. The article has since been corrected online.]. PMID- 25803367 TI - Statistics Commentary Series: Commentary #10-Dealing With Drop-Outs. PMID- 25803364 TI - Association of cord blood levels of lead, arsenic, and zinc and home environment with children neurodevelopment at 36 months living in Chitwan Valley, Nepal. AB - BACKGROUND: Inconsistent results continue to be reported from studies linking low level prenatal lead exposure and child development. Because of limited earlier epidemiological studies with birth cohort follow up design, it still remains inconclusive that either the associations of cord blood level of toxic, and essential elements, and postnatal raising environment on neurodevelopment of children remains constant throughout childhood or change over time. AIMS: This study aims to investigate the influence of in utero toxic [lead (Pb) and arsenic (As)] and essential elements [zinc (Zn)] levels on neurodevelopment of 36 months children in Chitwan valley, Nepal taking the postnatal environment into account. STUDY DESIGNS AND SUBJECTS: In this birth cohort study, participants (N=100 mother-infants' pairs) were recruited in Chitwan district, Nepal. We measured Pb, As and Zn concentrations in cord blood. Postnatal raising environment (i.e., Home score or home environment hereafter) was evaluated using Home Observation for Measurement of Environment (HOME) scale. Neurodevelopment of children at 36 months of age (n=70) were assessed using Bayley Scale of Infant Development, Second Edition (BSID II). Multivariate regression was performed (n=70) to see the association of in utero toxic and essential elements level and home environment with neurodevelopment score adjusted for covariates. RESULTS: Cord blood levels of Pb, As and Zn were not associated with any BSID II cluster scores of 36 months children. The children with relatively superior HOME score and concurrent nutritional status (weight at 36 months) showed better cognitive development (i.e., MDI scores) and motor functions than their counterparts, respectively. CONCLUSION: In this general population in Nepal, prenatal Pb, As and Zn levels are not important determinants of the neurodevelopment of 36- month-old children while a consistent beneficial effect of a stimulating home environment on neurodevelopmental indicators is continued. PMID- 25803369 TI - Monitoring of International Diabetes Federation-recommended Clinical Diabetes Indicators in a Public Health Centre in Southwest Trinidad. AB - OBJECTIVES: To examine availability of International Diabetes Federation (IDF) recommended diabetes indicators in the medical charts of patients in active care at a public health centre in southwest Trinidad and Tobago, and to determine clinical status of the patient population according to Caribbean Health Research Council/Pan American Health Organization (CHRC/PAHO) guidelines for disease control. METHODS: Data were extracted from the medical records of consecutive patients with diagnosed diabetes who presented for routine care at the health centre over a seven-month period. The three most recent dates and results for the following clinical indicators were extracted: glycated haemoglobin (HbA1c), blood pressure, lipid panel, random blood sugar and weight. RESULTS: Data were extracted from 486 patient medical records (91% of patients who presented for care). The majority of records, 366 (76%), had one of three recommended IDF indicators of HbA1c, blood pressure or low-density lipoprotein (LDL) in the past year, 58 (12%) had two, 55 (11%) had three and seven (1%) had no indicators recorded. Random blood sugar and blood pressure were recorded in 93% of records, while only 20% had an HbA1c reported in the past year. The vast majority of patients did not meet guidelines for control of blood sugar, blood pressure or cholesterol. Due to a non-standardized HbA1c assay, rate of controlled HbA1c, based on CHRC/PAHO clinical guidelines, could not be determined. CONCLUSIONS: Although availability of indicators suggests an increase from prior audits reported in the literature, current reporting patterns challenge optimal patient management and future systematic evaluation of trends in diabetes care and outcomes. PMID- 25803370 TI - Cervical Smears at Public Health Centres in Eastern Trinidad: Coverage and Follow up, 2009-2010. AB - BACKGROUND: The objective was to examine the cervical screening programme at selected health centres in the Eastern Regional Health Authority (ERHA), Trinidad and Tobago, specifically regarding Pap smear coverage, frequency distribution of abnormal smears and the adequacy of follow-up of abnormal smears, according to the Caribbean Frameworks for Developing National Screening and Clinical Guidelines for Cervical Cancer Prevention and Control. METHODS: A retrospective analysis of secondary data from five health centres in the ERHA over the two-year period 2009-2010 was conducted. Data were entered into Microsoft Excel, cleaned and imported into SPSS (v 12) for analysis. Descriptive and Chi-squared analyses were carried out. RESULTS: The cumulative cervical screening coverage for the years 2009 and 2010 was 2600 Pap smears for a population of 28 811 women (9% coverage). The proportion of cervical smears done per age group ranged from 1.6% to 8.6% in 2009 and from 1.9% to 12.9% in 2010. The proportion of Pap smears for the target population, 25-49 years, stood at 11% in 2009 and 13.2% in 2010. The distribution of abnormal Pap smears (n = 155) was: atypical squamous cell of undetermined significance (ASCUS), 68.4%; low-grade squamous intra-epithelial lesion (LSIL), 14.2%; atypical squamous cells - high-grade squamous intra epithelial lesion cannot be excluded (ASC-H), 4.5%; atypical glandular cells of undetermined significance (AGUS), 1.3% and invasive squamous cervical carcinoma, 0.6%. Human papillomavirus was detected in 7.7% of the study population. More than half of the women with abnormal smears did not follow-up on recommendations for further care and there was a significant loss to follow-up especially among the women who were referred for repeat Pap smear. The significant predictor to whether follow-up care occurred or not was age (p < 0.05). CONCLUSION: The cervical screening services in the ERHA in Trinidad did not provide adequate coverage to the target population or adequate follow-up care for women with abnormal smears in 2009 and 2010. PMID- 25803371 TI - Neurodevelopmental Outcome of Childhood Cancer Survivors Treated at the Eric Williams Medical Sciences Complex. AB - OBJECTIVE: To investigate the neurodevelopmental outcome of childhood cancer survivors treated at the Eric Williams Medical Sciences Complex (EWMSC). METHODS: Study participants were children treated at EWMSC from January 2003 to March 31, 2012 for various childhood cancers. All had completed treatment and were in remission. The McCarthy Scales of Children's Abilities (MSCA) was administered. The study was conducted from December 2011 to March 31, 2012. RESULTS: Twenty-six children were evaluated, a response rate of 74%. There were 12 males and 14 females. Ages ranged from 3.25 to 9.00 years. Four (15.4%) children scored a general cognitive index (GCI) < 68. One child (3.8%) scored a GCI > 132. The children's mean estimated mental age was found to be significantly lower than their mean actual age (p = 0.0086). Children treated for solid tumours had the least difference between their actual ages and estimated mental ages (p = 0.0301). The mean GCI for the genders was 97.4 for females and 81.0 for males; this difference was statistically significant (p = 0.0302). Age at diagnosis, type and length of treatment were not found to significantly affect development. CONCLUSION: The paediatric cancer survivors in this survey were found to have delays in their development. This group of children should have their development closely monitored. This would ensure that any delays in development can be discovered early and appropriate interventions instituted, so that childhood cancer survivors are adequately prepared for adult life beyond cancer. PMID- 25803368 TI - Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. AB - Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense-a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality. PMID- 25803373 TI - HIV-1 Antiretroviral Drug Resistance in Pregnant Women in Jamaica: A Preliminary Report. AB - This preliminary report sought to provide insight into the genetic diversity of human immunodeficiency virus drug resistance (HIVDR) in Jamaica. This was done by investigating the genetic diversity associated with drug resistance in pregnant women living with HIV attending antenatal clinics in Kingston, Jamaica. Blood samples were collected and viral RNA were extracted and analysed. The protease and reverse transcriptase (Pro-RT) genes were amplified using the nested polymerase chain reaction (PCR) method. Polymerase chain reaction amplicons were obtained for nine of 16 patients (56%), of which five (55%) were antiretroviral (ARV) drug naive and four (45%) were treatment experienced. Three minor protease resistant-conferring mutations (A71AT, A71V, A71T) and five mutations conferring high to low-level resistance (K219EK, T69S, K103S, G190A and K103N) were detected in the RT region. More than 50% of the resistance mutations found were detected in ARV drug naive individuals, implying that viruses are being transmitted with the ARV resistance. These preliminary results will inform the health practitioners of the level of drug resistance that is being transmitted as well as strengthen the need to initiate a national baseline survey on HIVDR in Jamaica. PMID- 25803372 TI - Evalution of Serum Lipid Profiles in Turkish Children Aged Two to Eighteen Years. AB - OBJECTIVE: The purpose of this study was to evaluate dyslipidaemia in children according to age, gender, percentiles, mother's education level, breastfeeding duration and areas of residence. METHODS: A total of 285 children (137 girls; 148 boys), aged between two and 18 years, were enrolled in this cross-sectional, epidemiologic study. Lipid profiles were assessed and its relation with sociodemographic features was evaluated. RESULTS: Dyslipidaemia prevalence was 37.4% (n = 107). High very low-density lipoprotein cholesterol (VLDL-C) and low high-density lipoprotein cholesterol (HDL-C) levels are related with percentiles of the children (p = 0.006, p = 0.03, respectively). Gender was a significant factor for VLDL-C, which was higher in girls than boys (p = 0.04). Total cholesterol levels were high in 14 children (4.9%); 72 of the study group (25.3%) had high triglyceride levels; HDL-C levels were low in 52 children (18.2%). CONCLUSION: All the parameters of dyslipidaemia are not so high in our region. However, as early detection of dyslipidaemia should begin in childhood, we should perform periodic checks to prevent cardiovascular risks. PMID- 25803374 TI - Relationship between Leukopenia and Intercellular Adhesion Molecules in Graves' Disease. AB - OBJECTIVE: Changes in soluble intercellular adhesion molecule-1 (sICAM-1) and E selectin levels as well as leukocyte count were examined in this study to explore the relationship between leukopenia and ICAMs in Graves' disease (GD). METHODS: Fasting blood samples were obtained from 37 GD patients with normal leukocytes and 32 GD patients with leukopenia. Enzyme-linked immunosorbent assay (ELISA) was performed to determine serum sICAM-1 and E-selectin levels for comparison. The same analyses were repeated for the GD patients with leukopenia after glucocorticoid treatment (15 mg/day to 30 mg/day prednisone). RESULTS: The ELISA results showed that E-selectin levels were higher in GD patients with leukopenia than those with normal leukocytes (p < 0.05), but these levels decreased after glucocorticoid (prednisone) treatment (p < 0.05). No significant change in sICAM 1 levels was observed (p = 0.12). Correlation analysis showed that leukocyte count and E-selectin were negatively correlated (r = -0.778; p < 0.05). CONCLUSION: E-selectin may have an important function in GD with leukopenia, and glucocorticoids (prednisone) could decrease E-selectin level, which may be a new therapy target for GD with leukopenia. PMID- 25803376 TI - Underestimated Prevalence of Chronic Heart Failure among the Elderly Residing in Care Homes in Aruba. AB - OBJECTIVE: Diagnosing chronic heart failure (CHF) is important, since subsequent treatments by medication and cardiac intervention improve quality of life. However, accurate CHF diagnosis in the elderly residing in care homes (residents) is hampered by suboptimal diagnostic tools, co-morbidity and physician's unawareness of CHF. We sought to estimate the CHF prevalence among Aruban residents. METHODS: All eligible residents were clinically assessed and screened for CHF signs and symptoms. The diagnosis of CHF was made by final judgment of a cardiologist. Plasma B-type-natriuretic peptide (BNP) levels were determined. RESULTS: Of the 235 residents, 184 (78%) were excluded, mostly because of decreased cognition. The remaining 51 included residents with a mean age of 78 +/ 8 years; 57% was female, 59% had diabetes mellitus Type 2 and 71% had renal dysfunction (< 60 mL/min/1.73 m2). Sixteen (31%) had CHF, of which five (31%) were aware of their diagnosis and 11 (69%) were being diagnosed for the first time. Two (29%) residents were previously incorrectly diagnosed with CHF. Most residents with CHF (94%) also had renal dysfunction and 75% had diabetes mellitus Type 2. At a BNP cut-off value of 100 pg/mL, the sensitivity, specificity and predictive values of positive and negative tests were 0.75, 0.69, 0.52 and 0.86, respectively. CONCLUSION: The CHF prevalence in Aruba residents is high (31%) and underestimated. The high CHF prevalence may be related to the high occurrence of diabetes mellitus Type 2 in Arubans. The use of BNP at a cut-off value of 100 pg/mL adds value to the diagnostic work-up of CHF in the elderly residing in care homes. PMID- 25803375 TI - Level of Caregiver Burden in Jamaican Stroke Caregivers and Relationship between Selected Sociodemographic Variables. AB - OBJECTIVE: This study sought to determine the level of caregiver burden present in Jamaican stroke caregivers and to investigate the relationship between caregiver burden and selected sociodemographic variables. METHOD: The Bakas Caregiving Outcomes Scale and a demographic sheet were administered to the caregivers. The stroke survivors completed the Barthel Index and the Geriatric Depression Scale. Interview administration was used for all tools. RESULTS: A total of 48 caregivers with their stroke survivors participated in this study. Preliminary findings showed that caregivers of stroke survivors in Jamaica are experiencing some level of burden with scores ranging from 21 to 62 (mean = 43.64 +/- 8.73). Lower burden scores indicate greater burden. Caregivers of female stroke survivors had significantly greater levels of burden (43.5 +/- 8.87) than those caring for male survivors [44.4 +/- 8.3] (p = 0.03). There were no significant correlations between caregiver burden and age of the stroke survivor; however, a low correlation was found between depression and caregiver burden (r = -0.33, p = 0.02). Female survivors were found to have significantly higher levels of depression than males (16.72 +/- 6.21 vs 11.34 +/- 7.31, p < 0.01) and caregivers of survivors who had higher depression scores experienced more burden. CONCLUSION: Preliminary findings point to depressive symptoms and functional status in the stroke survivor as being a significant contributor to caregiver burden; however, further data collection and analysis need to be completed before more definitive conclusions can be made. PMID- 25803379 TI - Development and Validation of a Measure of Attitudes toward Fluffy Women. AB - BACKGROUND: There is an absence of research on the newly evolved term "fluffy" which describes body image and personality features among women. Research on "fluffiness" among Caribbean peoples has been limited by the lack of valid and reliable measures of the concept. OBJECTIVE: This project addresses this problem by exploring the internal consistency reliability and the concurrent and discriminant validity of the Attitudes toward Fluffy Women Scale (ATFW) using a mixture of past and present students from The University of the West Indies (UWI), Mona, and the University of Technology (UTech), Kingston. METHOD: Past or present students from The UWI, Mona, and UTech, Kingston, were recruited for the study through the use of convenience sampling. A total of 80 students (38 males, 47.5%; 42 females, 52.5%) participated in the study. RESULTS: Overall, the ATFW was found to have an acceptable degree of internal consistency reliability (alpha = 0.90). The scale also had reasonably good concurrent validity as evidenced by moderate correlations with scores on the Attitudes Toward Obese Persons Scale (r = -0.42) and acceptable discriminant validity as demonstrated through low correlations with a Bogardus Social Distance Scale designed to assess prejudice toward people living with the human immunodeficiency virus [HIV] (r = 0.29). This pattern of scores suggests that the majority of the stable variance underlying the ATFW assesses the "fluffy" concept (17.6%) while a smaller degree of the variability (8%) measures a conceptually similar but distinct concept. CONCLUSION: The Attitudes toward Fluffy Women scale was found to be a reliable and valid scale for assessing the attitudes of young adults toward fluffy women. PMID- 25803378 TI - A Radiographic Correlation between Renal and Pulp Stones. AB - AIM: The purpose of this study was to determine the correlation between pulp stones and renal stones. This study also aims to report associations between the presence of pulp stone and gender, age, tooth type, dental arches and sides. PATIENTS AND METHODS: Data were collected through radiographic examination of bitewing radiographs of 116 kidney stone patients and a similar number of age matched controls, referred to the Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Erciyes University. Two oral radiologists examined the radiographs to identify pulp stones. The Chi-squared and Mann Whitney U tests were used to investigate the correlations between the presence of pulp chamber calcification and age, gender, dental status and kidney stone. RESULTS: Pulp chamber opacities were detected in 199 (19.3%) out of the 1031 examined teeth, and in 84 (72.4%) out of the 116 kidney stone patients. There was no statistically significant difference between the study and control group (p = 0.882). The occurrence of pulp stones was significantly higher in molars than premolars and similar prevalences were found between dental arches and sides. CONCLUSION: In this study, no correlation was found between the presence of pulp stones and kidney stones in the investigated group. Therefore, the presence of pulp stones does not seem to be correlated with that of kidney stones. PMID- 25803380 TI - Child Sexual Abuse and Continuous Influence of Cultural Practices: A Review. AB - AIM: To provide information on the possible influence of cultural practices in perpetuating child sexual abuse and to examine documented examples of these cultural influences. METHODS: A computer literature search was done of Medline, Science Direct, PSYCInfo, Embase and PubMed for keywords. There were also manual searches in the library of journals that are not accessible online. Keywords for searches included: sexual abuse, child abuse, psychopathology, name of countries (eg Jordan, China and Morocco), culture and cultural practices. RESULTS: There is documented evidence of cultural practices that continue to fuel the persistently high level of child sexual abuse across the globe. The definition has evolved to now include simple genital-genital and non-genital contact such as oral-genital contacts, exhibitionism and pornography. CONCLUSIONS: Cultural practices are no longer restricted to one geographical collection of people due to migratory influence, as these practices may also spread to different groups who intermingle. There are few empirical studies of child sexual abuse in the Caribbean, but one factor that could be used as a proxy is age of first sexual activity. The World Bank reports that this age is youngest in the Caribbean and is likely to be significantly influenced by child sexual abuse. PMID- 25803382 TI - Reasons for Non-vaccination among Patients Who Acquired Measles: Lessons from the Local Measles Epidemics in Japan. AB - A survey was conducted at a private general hospital, exploring the reasons why children with measles had missed opportunities for vaccination during the local measles epidemics that occurred in Japan between 1999 and 2003. The answers from parents/guardians of confirmed measles patients (n = 120) indicated the following: more than half of the parents/guardians were too busy or forgot to have their children immunized and 32% refrained from immunization due to anti vaccine views. Healthcare workers should consider that parents/guardians who are willing to immunize their children may miss opportunities to do so because they are busy, and not because of anti-vaccine attitudes. Healthcare workers should keep in mind that it is important to provide honest information on the potential risks and benefits of the vaccine, while informing parents/guardians of the vaccination schedule. PMID- 25803381 TI - Can We Afford Total Joint Replacements in Jamaica? PMID- 25803383 TI - Monoclonal Antibodies in Cancer Therapy: Mechanisms, Successes and Limitations. AB - Rituximab was the first chemotherapeutic monoclonal antibody (CmAb) approved for clinical use in cancer therapeutics in 1997 and has significantly improved the clinical outcomes in non-Hodgkin's lymphoma. Since then, numerous CmAbs have been developed and approved for the treatment of various haematologic and solid human cancers. In this review, the classification, efficacy and significantly reduced toxicity of CmAbs available for use in the United States of America are presented. Finally, the limitations of CmAbs and future considerations are explored. PMID- 25803384 TI - Toward Understanding the Biology of Crime in Trinidad and Tobago. AB - Serious crime is a scourge within Trinidad and Tobago's borders and seems to be escalating yearly with no resolution in sight. It is commonplace for governments to view/implement policies targeting crime based on sociological and psychological paradigms. What is most often overlooked, however, is that crime has unique biological underpinnings, which, if characterized, could lead toward clinical interventions that could mitigate its incidence within the population. PMID- 25803385 TI - Ischaemic Priapism and Glucose-6-Phosphate Dehydrogenase Deficiency: A Mechanism of Increased Oxidative Stress? AB - Ischaemic priapism is a devastating urological condition that has the potential to cause permanent erectile dysfunction. The disorder has been associated with numerous medical conditions and the use of pharmacotherapeutic agents. The aetiology is idiopathic in a number of cases. There are two prior case reports of the association of ischaemic priapism and glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report on a third case of priapism associated with G6PD deficiency and review recently described molecular mechanisms of increased oxidative stress in the pathophysiology of ischaemic priapism. The case report of a 32-year old Afro-Caribbean male with his first episode of major ischaemic priapism is described. Screening for common causes of ischaemic priapism, including sickle cell disease was negative. Glucose-6-phosphate dehydrogenase deficiency was discovered on evaluation for priapism. Penile aspiration was performed and erectile function was good post treatment.Glucose-6-phosphate dehydrogenase deficiency is a cause for ischaemic priapism and should be a part of the screening process in idiopathic causes of the disorder. Increased oxidative stress occurs in G6PD deficiency and may lead to priapism. PMID- 25803386 TI - A Papilloma-like Atypical Gingival Enlargement Treated Using Nd:YAG Laser Surgery: Report of a Case. AB - Gingival overgrowths can occur due to various factors, such as inflammation, or rarely without a reason and are significant in periodontology. Here, we describe the diagnosis and treatment of a 33-year old female with a papilloma-like atypical enlargement of the gingiva attached to the molar vestibular region of her lower jaw. After the patient's medical history was taken and the clinical examination done, the enlargement was surgically removed with a Nd:YAG laser and evaluated histopathologically. There was an inflamed, oedematous and vascularized stroma with a thick spongy squamous epithelium layer. After six months, there were no problems at the surgical area and recurrence was not observed. PMID- 25803387 TI - Colonic Carcinoma Associated with Malakoplakia. AB - Malakoplakia is an unusual chronic inflammatory response first described in the genitourinary tract by Michaelis and Gutmann in 1902. It is now known to occur in other locations including the gastrointestinal tract, skin, lungs and the central nervous system. Malakoplakia has been frequently misdiagnosed clinically as a malignant lesion. Similarly, when it occurs in the gastrointestinal tract (eg colon) in association with adenocarcinoma, it may lead to clinical and radiological overstaging of the tumour. PMID- 25803388 TI - Large Cell Neuroendocrine Carcinoma of the Ovary and Its Skin Metastases: A Case Report and Review of the Literature. AB - Large cell neuroendocrine carcinoma in the gynaecological organs affects the uterine cervix and ovary. Large cell neuroendocrine carcinoma of the ovary is extremely rare, and prognosis is quite poor even when diagnosed at an early stage. These tumours respond poorly to standard chemotherapy regimens. The clinical observation of skin metastasis in patients with epithelial ovarian cancer is relatively uncommon, occurring in only 3.5% of patients. These lesions are observed mostly in skin of the abdominal wall adjacent to the primary ovarian tumours. Metastatic skin lesions on extremities are much more rare; it is reported that only 12% of epithelial ovarian carcinoma skin metastases occur on the limbs. Skin metastasis due to large cell neuroendocrine carcinoma of the ovary has not been previously reported. We report the case of a large cell neuroendocrine tumour of the ovary with skin metastases on extremities appearing two months after surgery in a 68-year old woman. PMID- 25803389 TI - 'Green Apple' Heart Failure. AB - We report here the clinical case of an Afro-Caribbean patient referred for complete atrioventricular block for whom a diagnosis of hereditary cardiac amyloidosis was eventually confirmed. Hereditary cardiac amyloidosis is an emerging threat in the Caribbean, and the main goal of this report is to raise the awareness of the disease among physicians. PMID- 25803390 TI - A Rare Case of Port-a-Cath Migration into the Mediastinum. AB - Port-a-cath is commonly used in patients who require frequent administration of intravenous medications. We describe a rare case of port-a-cath migration into the mediastinum 16 months after its insertion. PMID- 25803391 TI - Primary Intestinal-type Adenocarcinoma of the Nasal Cavity: A Case Report. AB - We report a rare case of sinonasal intestinal-type adenocarcinoma in the nasal cavity. A 31-year old man represented with headache and epistaxis. We identified a malignant tumour, which is a rare pathology, with detailed physical examination, anterior rhinoscopy, computed tomography scan, magnetic resonance imaging and histopathologic examination. Endoscopic excision of the tumour was performed. After three years of follow-up of the patient in our clinic, there was no sign of any recurrence. PMID- 25803392 TI - Oral Health Status and Treatment Needs of Rastafarians in the Jamaican Population. PMID- 25803393 TI - Coexistence of Heterotopic Ossification of the Elbow and Vitamin D Deficiency Following Stroke: Can Calcium and Vitamin D Treatment Aggravate Ossification? PMID- 25803394 TI - Iron Deficiency among Jamaican Adolescents. AB - OBJECTIVES: To raise awareness of significant iron deficiency anaemia occurring in Jamaican secondary school students. METHODS: Haematological screening of students in the fifth and sixth forms of 14 secondary schools in the parishes of Manchester and Clarendon, Jamaica, was done. Samples were subject to haemoglobin electrophoresis, examination of haematological indices, and haemoglobin, alpha 2 (HbA2) levels where indicated. RESULTS: Of 13 172 students with normal haemoglobin (AA) genotype aged 15-19 years, haemoglobin levels below 10 g/dL occurred in 0.36% of males and in 3.79% females. These subjects had low mean red cell volumes, low mean cell haemoglobin and high red cell distribution width, characteristic of iron deficiency, which was confirmed by dramatic increases in haemoglobin level following iron supplementation. Most revealed classic symptoms, histories of poor diets and pica, which generally resolved on iron supplementation. CONCLUSIONS: Iron deficiency, even in the absence of anaemia, is known to limit physical and mental functions and may impair intellectual performance in these high school students. Significant anaemia could be detected by incorporating a blood test into the school medical assessments performed on entry to secondary schools. There is a need for simple oral iron medications to be available at health centres. PMID- 25803395 TI - Penile Carcinoma in Northern Trinidad and Tobago. AB - OBJECTIVE: To determine the current incidence as well as general and ethnic trends of penile carcinoma in northern Trinidad and Tobago. METHODS: A retrospective analysis was conducted on all cases of penile carcinoma presenting in north and east Trinidad, as well as Tobago over an eight-year period. RESULTS: There were 19 cases from October 2003 to February 2012 with an age range of 42-96 years, mean of 59 years; peak age of presentation was 41-50 years and the number of cases presenting per year varied from one to four, with an average of three new cases yearly. Of 19 cases, 63% (12) originated from Port-of-Spain General Hospital (POSGH), 26% (5) from Sangre Grande (SGH) and 11% (2) from Tobago (TRH). There were 14 (74%) patients of African descent, three mixed and two of East Indian descent. There were four associated inflammatory lesions, five with ulcers, five verrucous lesions and two (10.5%) with human papillomavirus (HPV). One case presented with metastatic disease to the groin with erosion into the common femoral artery resulting in a blow-out of the vessel. The patient had the vessel oversewn and an extra-anatomic bypass done. He later had an above-knee amputation due to graft infection and failure. CONCLUSION: The incidence of penile carcinoma in north Trinidad and in Tobago is low and has halved in the past two decades. It stands at 0.6 cases per 100 000 males with the peak age group being 41-50 years, and with 95% of cases occurring between 41 and 80 years. There is a statistically significant association with active infection and being Afro-Caribbean. The decreasing incidence may be attributed to better hygiene, a higher rate of circumcision and low HPV rates in our population. PMID- 25803396 TI - Impaired Bronchoprotection Is Not Induced by Increased Smooth Muscle Mass in Chronic Treatment In Vivo with Formoterol in Asthmatic Mouse Model. AB - OBJECTIVE: Inhaling beta2-adrenoceptor agonist is first-line asthma treatment, which is used for both acute relief of and prevention of bronchoconstriction. However, chronic use of beta-agonists results in impaired bronchoprotection and increasing occurrences of severe asthma exacerbation, even death in clinical practice. The mechanism of beta-adrenoceptor hyposensitivity has not been thoroughly elucidated thus far. Bronchial smooth muscle contraction induces airway narrowing and also mediates airway inflammation. Moreover, bronchial smooth muscle mass significantly increases in asthmatics. We aim to establish an asthmatic model that demonstrated that formoterol induced impaired bronchoprotection and to see whether increased smooth muscle mass play a role in it. METHODS: We combined routine allergen challenging (seven weeks) with repeated application of formoterol, formoterol plus budesonide or physiological saline in allergen-sensitized BALB/c mouse. The bronchoprotection mediated by beta-agonist was measured in five consecutive weeks. Smooth muscle mass was shown by morphometric analysis, and alpha-actin expression was detected by western blot. RESULTS: The trend of bronchoprotection was wavy in drug interventional groups, which initially increased and then decreased. Chronic treatment with formoterol significantly impaired bronchoprotection. According to the morphometric analysis and alpha-actin expression, no significant difference was detected in smooth muscle mass in all groups. CONCLUSION: This experiment successfully established that a chronic asthmatic mouse model, which manifested typical features of asthmatic patients, when treated chronically with formoterol, resulted in a loss of bronchoprotection. No significant difference was detected in smooth muscle mass in all groups, which implied some subcellular signalling changes may be the key points. PMID- 25803397 TI - Influence of pea protein aggregates on the structure and stability of pea protein/soybean polysaccharide complex emulsions. AB - The applications of plant proteins in the food and beverage industry have been hampered by their precipitation in acidic solution. In this study, pea protein isolate (PPI) with poor dispersibility in acidic solution was used to form complexes with soybean soluble polysaccharide (SSPS), and the effects of PPI aggregates on the structure and stability of PPI/SSPS complex emulsions were investigated. Under acidic conditions, high pressure homogenization disrupts the PPI aggregates and the electrostatic attraction between PPI and SSPS facilitates the formation of dispersible PPI/SSPS complexes. The PPI/SSPS complex emulsions prepared from the PPI containing aggregates prove to possess similar droplet structure and similar stability compared with the PPI/SSPS emulsions produced from the PPI in which the aggregates have been previously removed by centrifugation. The oil droplets are protected by PPI/SSPS complex interfacial films and SSPS surfaces. The emulsions show long-term stability against pH and NaCl concentration changes. This study demonstrates that PPI aggregates can also be used to produce stable complex emulsions, which may promote the applications of plant proteins in the food and beverage industry. PMID- 25803398 TI - Syntheses of nickel (II) complexes from novel semicarbazone ligands with chloroformylarylhydrazine, benzimidazole and salicylaldehyde moieties. AB - This study addressed the design and syntheses of diverse ligands, which were then successfully treated with Ni (II) ion to afford a series of nickel complexes. alpha-Chloroformylarylhydrazine hydrochlorides contain two different functional groups. One is a strong nucleophile, and the other is a good electrophile. Therefore, it can be designed to react with several reagents to obtain diverse derivatives which can be used as ligands for metal complexes. Furthermore, benzimidazole and salicylaldehyde can provide electron donor sites, N and O electron donors, separately. Hence, the starting materials alpha chloroformylarylhydrazine hydrochlorides were first treated with 2-(aminomethyl) benzimidazole (7) to give the corresponding semicarbazides. Then, the semicarbazides 8 reacted with various substituted salicylaldehydes to afford the desired substituted-salicylaldehyde 2-aryl-4-substituted semicarbazones, which could coordinate with nickel (II) ion to give the corresponding nickel complexes. PMID- 25803399 TI - Emergency department burden of constipation in the United States from 2006 to 2011. AB - OBJECTIVES: Although constipation is typically managed in an outpatient setting, there is an increasing trend in the frequency of constipation-related hospital visits. The aim of this study was to analyze trends related to chronic constipation (CC) in the United States with respect to emergency department (ED) visits, patient and hospital characteristics, and associated costs. METHODS: Data from 2006 to 2011, in which constipation (The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes 564.00 564.09) was the primary discharge diagnosis, were obtained from the National Emergency Department Sample (NEDS). RESULTS: Between 2006 and 2011, the frequency of constipation-related ED visits increased by 41.5%, from 497,034 visits to 703,391 visits, whereas the mean cost per patient rose by 56.4%, from $1,474 in 2006 to $2,306 in 2011. The aggregate national cost of constipation-related ED visits increased by 121.4%, from $732,886,977 in 2006 to $1,622,624,341 in 2011. All cost data were adjusted for inflation and reported in 2014 dollars. Infants (<1 year old) had the highest rate of constipation-related ED visits in both 2006 and 2011. The late elders (85+ years) had the second highest constipation-related ED visit rate in 2006; however, the 1- to 17-year-old age group experienced a 50.7% increase in constipation-related ED visit rate from 2006 to 2011 and had the second highest constipation-related ED visit rate in 2011. CONCLUSIONS: The frequency of and the associated costs of ED visits for constipation are significant and have increased notably from 2006 to 2011. PMID- 25803400 TI - Familial risk of inflammatory bowel disease: a population-based cohort study 1977 2011. AB - OBJECTIVES: Estimates of familial risk of inflammatory bowel diseases (IBDs), Crohn's disease (CD), and ulcerative colitis (UC) are needed for counseling of patients and could be used to target future prevention. We aimed to provide comprehensive population-based estimates of familial risk of IBD. METHODS: The study encompassed the entire Danish population during 1977-2011 (N=8,295,773; 200 million person-years). From national registries, we obtained information on diagnosis date of IBD (N=45,780) and family ties. Using Poisson regression, we estimated incidence rate ratios (IRRs) of IBD in relatives of IBD cases compared with individuals with relatives of the same type without IBD. RESULTS: The risk of CD was significantly increased in first-degree (IRR, 7.77; 95% confidence interval (CI), 7.05-8.56), second-degree (IRR, 2.44; 95% CI, 2.01-2.96), and third-degree relatives (IRR, 1.88; 95% CI, 1.30-2.71) to patients with CD, and was less pronounced in relatives to UC cases. Likewise, the risk of UC was increased in first-degree (IRR, 4.08; 95% CI, 3.81-4.38), second-degree (IRR, 1.85; 95% CI, 1.60-2.13), and third-degree relatives (IRR, 1.51; 95% CI, 1.07 2.12) of UC cases, and less pronounced in relatives of CD cases. IRRs increased with two or more IBD-affected relatives and were modified by age, with the highest family-related IRR observed in early life. CONCLUSIONS: The risk of IBD is significantly increased in first -, second-, and third-degree relatives of IBD affected cases, with up to 12% of all IBD cases being family cases. The risk is particularly pronounced in young individuals. PMID- 25803401 TI - Status of Competency-Based Medical Education in Endoscopy Training: A Nationwide Survey of US ACGME-Accredited Gastroenterology Training Programs. AB - OBJECTIVES: The Accreditation Council for Graduate Medical Education (ACGME) emphasizes the importance of medical trainees meeting specific performance benchmarks and demonstrating readiness for unsupervised practice. The aim of this study was to examine the readiness of Gastroenterology (GI) fellowship programs for competency-based evaluation in endoscopic procedural training. METHODS: ACGME accredited GI program directors (PDs) and GI trainees nationwide completed an online survey of domains relevant to endoscopy training and competency assessment. Participants were queried about current methods and perceived quality of endoscopy training and assessment of competence. Participants were also queried about factors deemed important in endoscopy competence assessment. Five point Likert items were analyzed as continuous variables by an independent t-test and chi(2)-test was used for comparison of proportions. RESULTS: Survey response rate was 64% (94/148) for PDs and 47% (546/1,167) for trainees. Twenty-three percent of surveyed PDs reported that they do not have a formal endoscopy curriculum. PDs placed less importance (1-very important to 5-very unimportant) on endoscopy volume (1.57 vs. 1.18, P<0.001), adenoma detection rate (2.00 vs. 1.53, P<0.001), and withdrawal times (1.96 vs. 1.68, P=0.009) in determining endoscopy competence compared with trainees. A majority of PDs report that competence is assessed by procedure volume (85%) and teaching attending evaluations (96%). Only a minority of programs use skills assessment tools (30%) or specific quality metrics (28%). Specific competencies are mostly assessed by individual teaching attending feedback as opposed to official documentation or feedback from a PD. PDs rate the overall quality of their endoscopy training and assessment of competence as better than overall ratings by trainees. CONCLUSIONS: Although the majority of PDs and trainees nationwide believe that measuring specific metrics is important in determining endoscopy competence, most programs still rely on procedure volume and subjective attending evaluations to determine overall competence. As medical training transitions from an apprenticeship model to competency-based education, there is a need for improved endoscopy curricula which are better suited to demonstrate readiness for unsupervised practice. PMID- 25803403 TI - Breath Methane Excretion Is not An Accurate Marker of Colonic Methane Production in Irritable Bowel Syndrome. AB - OBJECTIVES: The role of colonic methane production in functional bowel disorders is still uncertain. In small samples of irritable bowel syndrome (IBS) patients, it was shown that methane breath excretion correlates with clinical presentation and delayed gastrointestinal transit time. The aim of this study was to evaluate the relationship between intestinal production and breath excretion of CH4 and to correlate CH4 production with the presence and the severity of symptoms, in a large cohort of IBS patients and in a group of healthy volunteers. METHODS: A group of 103 IBS patients and a group of 28 healthy volunteers were enrolled. The presence and severity of symptoms and gastrointestinal transit were evaluated in all subjects, who underwent breath H2/CH4 measurement for 7 h after lactulose to identify breath excretors of these gases; H2 and CH4 were also measured in rectal samples to identify colonic producers. Cumulative H2 and CH4 excretion and production were evaluated by the area under the time-concentration curve calculation (AUC). RESULTS: In IBS patients, CH4 was detected in rectal samples in 48 patients (47%), but only 27 of them (26% of the 103 enrolled patients) excreted this gas with breath. In CH4 producers, the prevalence and severity of symptoms and gastrointestinal transit time were not significantly different with respect to non-producers. IBS subtypes were homogeneously represented in CH4 producers and in non-producers. Healthy volunteers, compared with IBS patients, showed a significantly lower prevalence of CH4 excretion, whereas no difference was found in the prevalence of colonic CH4 production; moreover, in healthy volunteers compared with IBS, CH4 breath excretion and CH4 production were not different in quantitative terms. CONCLUSION: Our data show that colonic CH4 production is not associated with clinical presentation in IBS patients and does not correlate with symptom severity or with gastrointestinal transit time. Clinical inferences based on breath CH4 excretion should undergo an in-depth revision, as this method is not a good marker of CH4 colonic production. PMID- 25803405 TI - Benchmarking multiple fragmentation methods on an orbitrap fusion for top-down phospho-proteoform characterization. AB - Top-down analysis of intact proteins by mass spectrometry provides an ideal platform for comprehensive proteoform characterization, in particular, for the identification and localization of post-translational modifications (PTM) co occurring on a protein. One of the main bottlenecks in top-down proteomics is insufficient protein sequence coverage caused by incomplete protein fragmentation. Based on previous work on peptides, increasing sequence coverage and PTM localization by combining sequential ETD and HCD fragmentation in a single fragmentation event, we hypothesized that protein sequence coverage and phospho-proteoform characterization could be equally improved by this new dual fragmentation method termed EThcD, recently been made available on the Orbitrap Fusion. Here, we systematically benchmark the performance of several (hybrid) fragmentation methods for intact protein analysis on an Orbitrap Fusion, using as a model system a 17.5 kDa N-terminal fragment of the mitotic regulator Bora. During cell division Bora becomes multiply phosphorylated by a variety of cell cycle kinases, including Aurora A and Plk1, albeit at distinctive sites. Here, we monitor the phosphorylation of Bora by Aurora A and Plk1, analyzing the generated distinctive phospho-proteoforms by top-down fragmentation. We show that EThcD and ETciD on a Fusion are feasible and capable of providing richer fragmentation spectra compared to HCD or ETD alone, increasing protein sequence coverage, and thereby facilitating phosphosite localization and the determination of kinase specific phosphorylation sites in these phospho-proteoforms. Data are available via ProteomeXchange with identifier PXD001845. PMID- 25803402 TI - Pregnancy and postpartum bowel changes: constipation and fecal incontinence. AB - Pregnancy and the postpartum period are often associated with many gastrointestinal complaints, including nausea, vomiting, and heartburn; however, the most troublesome complaints in some women are defecatory disorders such as constipation and fecal incontinence, especially postpartum. These disorders are often multifactorial in etiology, and many studies have looked to see what risk factors lead to these complications. This review discusses the current knowledge of pelvic floor and anorectal physiology, especially during pregnancy, and reviews the current literature on causes and treatments of postpartum bowel symptoms of constipation and fecal incontinence. PMID- 25803404 TI - Childhood lead exposure in an industrial town in China: coupling stable isotope ratios with bioaccessible lead. AB - Fingerprinting based on stable isotopes of lead (Pb) in blood and environmental media helps to identify Pb exposure pathways in children. However, previous studies used stable isotopes of total Pb in media. In this study, a wire rope production town in China (Zhuhang) was selected for investigating the effectiveness of using isotope ratios in bioaccessible Pb to identify childhood Pb exposure pathways. Blood Pb levels of 115 children in Zhuhang were 1.7-20.4 MUg dL(-1), averaging 6.1 +/- 3.2 MUg dL(-1) (mean +/- standard deviation), and were ~1.6 times the national average in China (3.9 +/- 1.8 MUg dL(-1)). Among different environmental media (housedust, soil, PM10, vegetables, rice, and drinking water), housedust (695 +/- 495 mg kg(-1)) and vegetables [0.36 +/- 0.40 mg (kg of fresh weight)(-1)] contained elevated Pb concentrations. The isotope ratios ((207)Pb/(206)Pb and (208)Pb/(206)Pb) of total Pb were the highest in housedust (0.8587 +/- 0.0039 and 2.1049 +/- 0.0087) but lower than blood Pb ratios (0.8634 +/- 0.0027 and 2.1244 +/- 0.0061). When using bioaccessible Pb in housedust (0.8639 +/- 0.0018 and 2.1171 +/- 0.0036), the isotope ratios overlapped with blood Pb ratios, suggesting that incidental ingestion of housedust was the predominant contributor to children's blood Pb. Coupling the stable isotope technique with bioaccessible Pb is more reliable for identifying Pb exposure pathways than total Pb determinations. PMID- 25803406 TI - An intermetallic Au24Ag20 superatom nanocluster stabilized by labile ligands. AB - An intermetallic nanocluster containing 44 metal atoms, Au24Ag20(2 SPy)4(PhC=C)20Cl2, was successfully synthesized and structurally characterized by single-crystal analysis and density funtional theory computations. The 44 metal atoms in the cluster are arranged as a concentric three-shell Au12@Ag20@Au12 Keplerate structure having a high symmetry. For the first time, the co-presence of three different types of anionic ligands (i.e., phenylalkynyl, 2 pyridylthiolate, and chloride) was revealed on the surface of metal nanoclusters. Similar to thiolates, alkynyls bind linearly to surface Au atoms using their sigma-bonds, leading to the formation of two types of surface staple units (PhC=C Au-L, L = PhC=C(-) or 2-pyridylthiolate) on the cluster. The co-presence of three different surface ligands allows the site-specific surface and functional modification of the cluster. The lability of PhC=C(-) ligands on the cluster was demonstrated, making it possible to keep the metal core intact while removing partial surface capping. Moreover, it was found that ligand exchange on the cluster occurs easily to offer various derivatives with the same metal core but different surface functionality and thus different solubility. PMID- 25803408 TI - Reconstruction of the pediatric midface following oncologic resection. AB - BACKGROUND: Sarcoma is the most common midface malignancy in children. While first-line treatment in adults is resection, the challenges associated with resection and reconstruction of these tumors in children often lead to radiation therapy as primary treatment. This report highlights the feasibility and efficacy of midface reconstruction in the pediatric population after resection. In most cases, the same principles utilized in reconstructing midface defects in adults hold for the pediatric population. PATIENTS AND METHODS: From 2008 to 2013 seven pediatric patients underwent resection and reconstruction for maxillary sarcomas. These patients ranged in age from 18 months to 20 years. Five patients were reconstructed with six microvascular free flaps. Two patients received pedicled flaps. Follow-up ranged from 15 months to 4.5 years. Reconstructive, oncological, and functional outcomes were analyzed. RESULTS: Seven patients underwent eight reconstructions for sarcomas of the maxilla. Flaps utilized included vertical rectus abdominis, anterolateral thigh, fibula, and temporoparietal fascia. One flap was complicated by venous thrombosis but was successfully salvaged after thrombectomy and revision using vein graft. One patient developed recurrence after initial flap placement and required salvage resection and a second free flap. Six patients were judged to have good facial symmetry and tolerated a regular oral diet with normal or near-normal dental occlusion. CONCLUSIONS: Standard primary therapy for sarcomas of the maxilla in the pediatric population consists of nonsurgical management. However, a radiation-first approach is associated with significant morbidity and makes surgical salvage more difficult. Based on our experience, microsurgical reconstruction of the pediatric midface is safe and effective, and should be considered a first-line treatment option for midface sarcomas in children. In general, there is no significant area of departure between the principles that govern midface reconstruction in adults and children. PMID- 25803410 TI - Reverse Dorsoradial Flaps for Thumb Coverage Show Increased Sensory Recovery with Smaller Flap Sizes. AB - BACKGROUND: Reverse homodigital dorsoradial (RHD) flap has been developed to repair soft-tissue defects of the thumb. However, few articles have reported this flap with long-term follow-up. This retrospective study was designed to evaluate the RHD flap and investigate factors affecting sensory recovery. METHODS: From February 2010 to February 2011, 19 patients were treated consecutively with RHD flap without neurorrhaphy. At final follow-up, flap sensibility was assessed by Semmes-Weinstein (SW) monofilament, moving two-point discrimination (M-2PD), and static two-point discrimination (S-2PD) tests. Patient satisfaction, active range of-motion of the joints, patient complications, and cold intolerance severity score questionnaire were sequentially evaluated. The patients were divided into two groups based on the S-2PD results and another two groups based on flap size. RESULTS: The mean SW monofilament sensitivity and M-2PD and S-2PD scores on the flap were 4.01 g and 9.26 mm, and 10.63 mm, respectively. Highly positive correlations existed between the flap size and the M-2PD and S-2PD scores. Moreover, in the respective groups based on S-2PD scores and flap size, no statistical difference was found among age, sex, and follow-up time, but the flap size and S-2PD scores were statistically different. CONCLUSIONS: RHD flap without neurorrhaphy is a recommendable technique for relatively small-sized thumb-defect reconstruction, which can achieve a satisfactory sensory recovery. PMID- 25803411 TI - Competencies, milestones, and entrustable professional activities: what they are, what they could be. PMID- 25803409 TI - Impact of Timing of Admission and Microvascular Reconstruction on Free Flap Success Rates in Traumatic Upper Extremity Defects. AB - BACKGROUND: Despite a growing body of knowledge, the timing of microsurgical reconstruction for the upper extremity remains a controversial topic. Most of the available literature deals with lower extremity reconstruction and the few reports on microsurgical reconstruction of the upper extremity are mostly concerned with infection rates and rarely consider thrombosis and changes in coagulation parameters. METHODS: We performed a retrospective review of all free flaps performed for upper extremity reconstruction at our institution from 2000 to 2010. Only acute, isolated traumatic defects of the upper extremity requiring a free flap for reconstruction were included in this study. A review of medical records was performed to assess, among others, comorbidities, timing of reconstruction, and platelet levels. RESULTS: A total of 41 patients were included in this study, 70% of whom were male. Mean age at the time of surgery was 40.8 +/- 15.4 years. Patients who were directly referred to our hospital underwent reconstruction significantly faster than those who were transferred secondarily (p = 0.0001). The number of surgical revisions as well as the flap loss rate was higher in patients undergoing reconstruction more than 1 week after trauma (p = 0.09 and 0.033, respectively). A significantly higher platelet count was seen in the patients undergoing delayed reconstruction (p = 0.002). CONCLUSION: In our study, early microsurgical reconstruction of the upper extremity yielded better results in terms of lower rates of surgical revisions and flap loss. This might be partly because of a trauma-induced thrombocythemia, with a maximum level of platelets in the 2nd week post trauma. We, therefore, advocate a timely coverage of these defects along with an anticoagulatory regimen including some form of platelet inhibition. PMID- 25803412 TI - Patient-centered instruction: the cornerstone of surgical education. PMID- 25803407 TI - Adherence Determinants in Cystic Fibrosis: Cluster Analysis of Parental Psychosocial, Religious, and/or Spiritual Factors. AB - RATIONALE: Cystic fibrosis is a progressive disease requiring a complex, time consuming treatment regimen. Nonadherence may contribute to an acceleration of the disease process. Spirituality influences some parental healthcare behaviors and medical decision-making. OBJECTIVES: We hypothesized that parents of children with cystic fibrosis, when classified into groups based on adherence rates, would share certain psychosocial and religious and/or spiritual variables distinguishing them from other adherence groups. METHODS: We conducted a multisite, prospective, observational study focused on parents of children younger than 13 years old at two cystic fibrosis center sites (Site 1, n= 83; Site 2, n = 59). Religious and/or spiritual constructs, depression, and marital adjustment were measured by using previously validated questionnaires. Determinants of adherence included parental attitude toward treatment, perceived behavioral norms, motivation, and self-efficacy. Adherence patterns were measured with the Daily Phone Diary, a validated instrument used to collect adherence data. Cluster analysis identified discrete adherence patterns, including parents' completion of more treatments than prescribed. MEASUREMENTS AND MAIN RESULTS: For airway clearance therapy, four adherence groups were identified: median adherence rates of 23%, 52%, 77%, and 120%. These four groups differed significantly for parental depression, sanctification of their child's body, and self-efficacy. Three adherence groups were identified for nebulized medications: median adherence rates of 35%, 82%, and 130%. These three groups differed significantly for sanctification of their child's body and self-efficacy. CONCLUSIONS: Our results indicated that parents in each group shared psychosocial and religious and/or spiritual factors that differentiated them. Therefore, conversations about adherence likely should be tailored to baseline adherence patterns. Development of efficacious religious and/or spiritual interventions that promote adherence by caregivers of children with cystic fibrosis may be useful. PMID- 25803413 TI - Developing practical wisdom in customer service. PMID- 25803415 TI - On leadership and service during medical training. PMID- 25803414 TI - Undergraduate anatomy teaching: evaluations and conclusions. PMID- 25803416 TI - Artist's statement: seedling. PMID- 25803417 TI - Medicine and the arts. Jane by George Bilgere. Commentary on "Jane". PMID- 25803419 TI - The day life's snooze button broke. PMID- 25803421 TI - Cosolute effects on amyloid aggregation in a nondiffusion limited regime: intrinsic osmolyte properties and the volume exclusion principle. AB - The effects of cosolutes on amyloid aggregation kinetics in vivo are critical and not fully understood. To explore the effects of cosolute additives, the in vitro behavior of destabilizing and stabilizing osmolytes with polymer cosolutes on the aggregation of a model amyloid, human insulin, is probed using experiments coupled with an amyloid aggregation reaction model. The destabilizing osmolyte, guanidine hydrochloride (GuHCl), induces biphasic behavior on the amyloid aggregation rate exhibited by an enhancement of the aggregation kinetics at low concentrations of GuHCl (<0.6 M) and a reduction in kinetics at higher GuHCl concentrations. Stabilizing osmolytes, glycerol, sorbitol and trimethylamine N oxide, slow the rate of aggregation by reducing the rate of monomer unfolding. Polymer cosolutes, polyvinylpyrrolidone 3.5 kDa and 40 kDa, delay amyloid aggregation mainly through a decrease in the nucleation reaction. These results are in good agreement with the volume exclusion principle for polymer crowding and supports the need to include conformational rearrangement of monomers prior to nucleation. Using fluorescence correlation spectroscopy, we demonstrate that amyloid aggregation is nondiffusion limited, except during fibril accumulation in the presence of high concentrations of long chain polymers. Lastly, the neutral surface area of osmolytes correlates well with the time to initiate fibril formation, tlag, which implicates an intrinsic osmolyte property underlying preferential interactions. PMID- 25803422 TI - Fast surface diffusion of amorphous o-terphenyl and its competition with viscous flow in surface evolution. AB - Surface self-diffusion coefficients have been measured for the model molecular glass o-terphenyl (OTP) through surface-grating decay driven by capillarity. The decay mechanism transitions from viscous flow at high temperatures to surface diffusion at low temperatures; for 1000 nm wavelength gratings, the transition occurs at Tg + 11 K. The surface diffusion of OTP is 10(8) times faster than bulk diffusion at Tg and even faster at lower temperatures because of its weaker temperature dependence. At Tg, OTP has approximately the same bulk diffusivity as the previously studied molecular liquid indomethacin, but its surface diffusion is 100 times faster. While the molecular glass-formers exhibit transitions from viscous flow to surface diffusion as the mechanism of capillarity-driven surface flattening, polystyrenes and silicates show no such transition under comparable conditions, suggesting slower surface diffusion on these materials and a general dependence of surface diffusion on intermolecular forces. The velocity of surface crystal growth on molecular glasses is proportional to surface diffusivity, indicating a common kinetic barrier for both processes for temperatures below Tg. PMID- 25803420 TI - Multiple comorbidities of 21 psychological disorders and relationships with psychosocial variables: a study of the online assessment and diagnostic system within a web-based population. AB - BACKGROUND: While research in the area of e-mental health has received considerable attention over the last decade, there are still many areas that have not been addressed. One such area is the comorbidity of psychological disorders in a Web-based sample using online assessment and diagnostic tools, and the relationships between comorbidities and psychosocial variables. OBJECTIVE: We aimed to identify comorbidities of psychological disorders of an online sample using an online diagnostic tool. Based on diagnoses made by an automated online assessment and diagnostic system administered to a large group of online participants, multiple comorbidities (co-occurrences) of 21 psychological disorders for males and females were identified. We examined the relationships between dyadic comorbidities of anxiety and depressive disorders and the psychosocial variables sex, age, suicidal ideation, social support, and quality of life. METHODS: An online complex algorithm based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision, was used to assign primary and secondary diagnoses of 21 psychological disorders to 12,665 online participants. The frequency of co-occurrences of psychological disorders for males and females were calculated for all disorders. A series of hierarchical loglinear analyses were performed to examine the relationships between the dyadic comorbidities of depression and various anxiety disorders and the variables suicidal ideation, social support, quality of life, sex, and age. RESULTS: A 21-by-21 frequency of co-occurrences of psychological disorders matrix revealed the presence of multiple significant dyadic comorbidities for males and females. Also, for those with some of the dyadic depression and the anxiety disorders, the odds for having suicidal ideation, reporting inadequate social support, and poorer quality of life increased for those with two-disorder comorbidity than for those with only one of the same two disorders. CONCLUSIONS: Comorbidities of several psychological disorders using an online assessment tool within a Web-based population were similar to those found in face-to-face clinics using traditional assessment tools. Results provided support for the transdiagnostic approaches and confirmed the positive relationship between comorbidity and suicidal ideation, the negative relationship between comorbidity and social support, and the negative relationship comorbidity and quality of life. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN121611000704998; http://www.anzctr.org.au/trial_view.aspx?ID=336143 (Archived by WebCite at http://www.webcitation.org/618r3wvOG). PMID- 25803424 TI - pH-regulated ionic conductance in a nanochannel with overlapped electric double layers. AB - Accurately and rapidly analyzing the ionic current/conductance in a nanochannel, especially under the condition of overlapped electric double layers (EDLs), is of fundamental significance for the design and development of novel nanofluidic devices. To achieve this, an analytical model for the surface charge properties and ionic current/conductance in a pH-regulated nanochannel is developed for the first time. The developed model takes into account the effects of the EDL overlap, electroosmotic flow, Stern layer, multiple ionic species, and the site dissociation/association reactions on the channel walls. In addition to good agreement with the existing experimental data of nanochannel conductance available from the literature, our analytical model is also validated by the full model with the Poisson-Nernst-Planck and Navier-Stokes equations. The EDL overlap effect is significant at small nanochannel height, low salt concentration, and medium low pH. Neglecting the EDL overlap effect could result in a wrong estimation in the zeta potential and conductance of the nanochannel in a single measurement. PMID- 25803423 TI - Deep-red emissive BODIPY-chlorin arrays excitable with green and red wavelengths. AB - We report here the synthesis and characterization of BODIPY-chlorin arrays containing a chlorin subunit, with tunable deep-red (641-685 nm) emission, and one or two BODIPY moieties, absorbing at 504 nm. Two types of arrays were examined: one where BODIPY moieties are attached through a phenylacetylene linker at the 13- or 3,13-positions of chlorin, and a second type where BODIPY is attached at the 10-position of chlorin through an amide linker. Each of the examined arrays exhibits an efficient (>=0.80) energy transfer from BODIPY to the chlorin moiety in both toluene and DMF and exhibits intense fluorescence of chlorin upon excitation of BODIPY at ~500 nm. Therefore, the effective Stokes shift in such arrays is in the range of 140-180 nm. Dyads with BODIPY attached at the 10-position of chlorin exhibit a bright fluorescence in a range of solvents with different polarities (i.e., toluene, MeOH, DMF, and DMSO). In contrast to this, some of the arrays in which BODIPY is attached at the 3- or at both 3,13 positons of chlorin exhibit significant reduction of fluorescence in polar solvents. Overall, dyads where BODIPY is attached at the 10-position of chlorin exhibit ~5-fold brighter fluorescence than corresponding chlorin monomers, upon excitation at 500 nm. PMID- 25803425 TI - Discovery of Potent Inhibitors of Schistosoma mansoni NAD+ Catabolizing Enzyme. AB - The blood fluke Schistosoma mansoni is the causative agent of the intestinal form of schistosomiasis (or bilharzia). Emergence of Schistosoma mansoni with reduced sensitivity to praziquantel, the drug currently used to treat this neglected disease, has underlined the need for development of new strategies to control schistosomiasis. Our ability to screen drug libraries for antischistosomal compounds has been hampered by the lack of validated S. mansoni targets. In the present work, we describe a virtual screening approach to identify inhibitors of S. mansoni NAD(+) catabolizing enzyme (SmNACE), a receptor enzyme suspected to be involved in immune evasion by the parasite at the adult stage. Docking of commercial libraries into a homology model of the enzyme has led to the discovery of two in vitro micromolar inhibitors. Further structure-activity relationship studies have allowed a 3-log gain in potency, accompanied by a largely enhanced selectivity for the parasitic enzyme over the human homologue CD38. PMID- 25803426 TI - The source of the river as a nursery for microbial diversity. AB - Bacteria are highly diverse and ubiquitous organisms that play a key role as drivers for ecosystem processes. The application of NGS (next-generation sequencing technologies) for 16S analysis has been broadly used for understanding bacterioplankton composition and structure. Most of studies conducted on aquatic ecosystems with 16S NGS have been in seawater and lakes. A few studies using NGS have been conducted in river environments and have suggested the presence of a bacterial seed-bank. We performed 16S highly variable V4 region high-throughput analysis in the Sinos River, which is located in one of most important Brazilian industrial centers. This region has several contrasts in its environmental characteristics, presenting a longitudinal gradient of eutrophication and making it a remarkable study site for observing the dynamics of bacterioplankton. We demonstrated consistent evidence for the existence of a bacterial seed-bank and its longitudinal persistence. Seasonal shifts reinforce the importance of the source of the river in maintaining the bacterial seed-bank that spreads throughout the river. Therefore, the preservation of the source of the river is important not only for hydrologic reasons but also to maintain the microbial composition and the ecological integrity of the river. PMID- 25803427 TI - Quantifying the shape of aging. AB - In Biodemography, aging is typically measured and compared based on aging rates. We argue that this approach may be misleading, because it confounds the time aspect with the mere change aspect of aging. To disentangle these aspects, here we utilize a time-standardized framework and, instead of aging rates, suggest the shape of aging as a novel and valuable alternative concept for comparative aging research. The concept of shape captures the direction and degree of change in the force of mortality over age, which-on a demographic level-reflects aging. We 1) provide a list of shape properties that are desirable from a theoretical perspective, 2) suggest several demographically meaningful and non-parametric candidate measures to quantify shape, and 3) evaluate performance of these measures based on the list of properties as well as based on an illustrative analysis of a simple dataset. The shape measures suggested here aim to provide a general means to classify aging patterns independent of any particular mortality model and independent of any species-specific time-scale. Thereby they support systematic comparative aging research across different species or between populations of the same species under different conditions and constitute an extension of the toolbox available to comparative research in Biodemography. PMID- 25803429 TI - Acquisition versus consolidation of auditory perceptual learning using mixed training regimens. AB - Learning is considered to consist of two distinct phases-acquisition and consolidation. Acquisition can be disrupted when short periods of training on more than one task are interleaved, whereas consolidation can be disrupted when a second task is trained after the first has been initiated. Here we investigated the conditions governing the disruption to acquisition and consolidation during mixed-training regimens in which primary and secondary amplitude modulation tasks were either interleaved or presented consecutively. The secondary task differed from the primary task in either task-irrelevant (carrier frequency) or task relevant (modulation rate) stimulus features while requiring the same perceptual judgment (amplitude modulation depth discrimination), or shared both irrelevant and relevant features but required a different judgment (amplitude modulation rate discrimination). Based on previous literature we predicted that acquisition would be disrupted by varying the task-relevant stimulus feature during training (stimulus interference), and that consolidation would be disrupted by varying the perceptual judgment required (task interference). We found that varying the task relevant or -irrelevant stimulus features failed to disrupt acquisition but did disrupt consolidation, whereas mixing two tasks requiring a different perceptual judgment but sharing the same stimulus features disrupted both acquisition and consolidation. Thus, a distinction between acquisition and consolidation phases of perceptual learning cannot simply be attributed to (task-relevant) stimulus versus task interference. We propose instead that disruption occurs during acquisition when mixing two tasks requiring a perceptual judgment based on different cues, whereas consolidation is always disrupted regardless of whether different stimulus features or tasks are mixed. The current study not only provides a novel insight into the underlying mechanisms of perceptual learning, but also has practical implications for the optimal design and delivery of training programs that aim to remediate perceptual difficulties. PMID- 25803428 TI - Cytotoxic helix-rich oligomer formation by melittin and pancreatic polypeptide. AB - Conversion of amyloid fibrils by many peptides/proteins involves cytotoxic helix rich oligomers. However, their toxicity and biophysical studies remain largely unknown due to their highly dynamic nature. To address this, we chose two helical peptides (melittin, Mel and pancreatic polypeptide, PP) and studied their aggregation and toxicity. Mel converted its random coil structure to oligomeric helical structure upon binding to heparin; however, PP remained as helix after oligomerization. Interestingly, similar to Parkinson's associated alpha-synuclein (AS) oligomers, Mel and PP also showed tinctorial properties, higher hydrophobic surface exposure, cellular toxicity and membrane pore formation after oligomerization in the presence of heparin. We suggest that helix-rich oligomers with exposed hydrophobic surface are highly cytotoxic to cells irrespective of their disease association. Moreover as Mel and PP (in the presence of heparin) instantly self-assemble into stable helix-rich amyloidogenic oligomers; they could be represented as models for understanding the biophysical and cytotoxic properties of helix-rich intermediates in detail. PMID- 25803431 TI - Development of a Summarized Health Index (SHI) for use in predicting survival in sea turtles. AB - Veterinary care plays an influential role in sea turtle rehabilitation, especially in endangered species. Physiological characteristics, hematological and plasma biochemistry profiles, are useful references for clinical management in animals, especially when animals are during the convalescence period. In this study, these factors associated with sea turtle surviving were analyzed. The blood samples were collected when sea turtles remained alive, and then animals were followed up for surviving status. The results indicated that significantly negative correlation was found between buoyancy disorders (BD) and sea turtle surviving (p < 0.05). Furthermore, non-surviving sea turtles had significantly higher levels of aspartate aminotranspherase (AST), creatinine kinase (CK), creatinine and uric acid (UA) than surviving sea turtles (all p < 0.05). After further analysis by multiple logistic regression model, only factors of BD, creatinine and UA were included in the equation for calculating summarized health index (SHI) for each individual. Through evaluation by receiver operating characteristic (ROC) curve, the result indicated that the area under curve was 0.920 +/- 0.037, and a cut-off SHI value of 2.5244 showed 80.0% sensitivity and 86.7% specificity in predicting survival. Therefore, the developed SHI could be a useful index to evaluate health status of sea turtles and to improve veterinary care at rehabilitation facilities. PMID- 25803432 TI - Mapping mid-cell: MapZ shows the way. PMID- 25803430 TI - Preoperative flexible bronchoscopy in patients with persistent ground-glass nodule. AB - There are no accurate data on the diagnostic value of preoperative flexible bronchoscopy (FB) for persistent ground-glass nodule (GGN) of the lung. We evaluated the value of preoperative FB in patients with suspected GGN-type lung cancer. We retrospectively searched a database for subjects who had 'ground-glass opacity', 'non-solid nodule', 'part-solid nodule', or 'sub-solid nodule' on chest computed tomography reports between February 2004 and March 2012. Patients who had infiltrative ground-glass opacity lesions, mediastinal lymphadenopathy, or pleural effusion, focal ground-glass opacity lesions >3 cm, and were lost to follow-up were excluded. We assessed the diagnostic value of preoperative FB in patients with persistent GGNs who underwent surgical resection. In total, 296 GGNs were evaluated by FB in 264 patients with persistent GGNs who underwent preoperative FB and surgical resection. The median size of the GGNs was 18 mm; 135 (46%) were pure GGN and 161 (54%) were part-solid GGN. No visible tumor or unsuspected endobronchial metastasis was identified by preoperative FB. Only 3 (1%, 3/208) GGNs were identified preoperatively as malignant by bronchial washing cytology; all were part-solid GGNs. No other etiology was identified by FB. Of the GGNs, 271 (91%) were subsequently confirmed as malignant and 25 (9%) were confirmed as benign at surgical resection. Consequently, the overall diagnostic sensitivity and negative predictive value of preoperative FB on a per-nodule basis was 1% (3/271) and 8% (25/293), respectively. The preoperative FB did not change the surgical strategy. Preoperative FB did not add much to the evaluation of persistent GGNs of the lung. Routine preoperative FB may have limited value in surgical candidates with small persistent pure GGNs. PMID- 25803433 TI - Use of 5-alpha-reductase inhibitors did not increase the risk of cardiovascular diseases in patients with benign prostate hyperplasia: a five-year follow-up study. AB - BACKGROUND: This nationwide population-based study investigated the risk of cardiovascular diseases after 5-alpha-reductase inhibitor therapy for benign prostate hyperplasia (BPH) using the National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: In total, 1,486 adult patients newly diagnosed with BPH and who used 5-alpha-reductase inhibitors were recruited as the study cohort, along with 9,995 subjects who did not use 5-alpha-reductase inhibitors as a comparison cohort from 2003 to 2008. Each patient was monitored for 5 years, and those who subsequently had cardiovascular diseases were identified. A Cox proportional hazards model was used to compare the risk of cardiovascular diseases between the study and comparison cohorts after adjusting for possible confounding risk factors. RESULTS: The patients who received 5-alpha-reductase inhibitor therapy had a lower cumulative rate of cardiovascular diseases than those who did not receive 5-alpha-reductase inhibitor therapy during the 5-year follow-up period (8.4% vs. 11.2%, P=0.003). In subgroup analysis, the 5-year cardiovascular event hazard ratio (HR) was lower among the patients older than 65 years with 91 to 365 cumulative defined daily dose (cDDD) 5-alpha-reductase inhibitor use (HR=0.63, 95% confidence interval (CI) 0.42 to 0.92; P=0.018), however there was no difference among the patients with 28 to 90 and more than 365 cDDD 5-alpha-reductase inhibitor use (HR=1.14, 95% CI 0.77 to 1.68; P=0.518 and HR=0.83, 95% CI 0.57 to 1.20; P=0.310, respectively). CONCLUSIONS: 5-alpha reductase inhibitor therapy did not increase the risk of cardiovascular events in the BPH patients in 5 years of follow-up. Further mechanistic research is needed. PMID- 25803434 TI - The functions of atrial strands interdigitating with and penetrating into sinoatrial node: a theoretical study of the problem. AB - The sinoatrial node (SAN)-atrium system is closely involved with the activity of heart beating. The impulse propagation and phase-locking behaviors of this system are of theoretical interest. Some experiments have revealed that atrial strands (ASs) interdigitate with and penetrate into the SAN, whereby the SAN-atrium system works as a complex network. In this study, the functions of ASs are numerically investigated using realistic cardiac models. The results indicate that the ASs penetrating into the central region of the SAN play a major role in propagating excitation into the atrium. This is because the threshold SAN-AS coupling for an AS to function as an alternative path for propagation is lower at the center than at the periphery. However, ASs penetrating into the peripheral region have a great effect in terms of enlarging the 1:1 entrainment range of the SAN because the automaticity of the SAN is evidently reduced by ASs. Moreover, an analytical formula for approximating the enlargement of the 1:1 range is derived. PMID- 25803437 TI - Phytoplankton succession in recurrently fluctuating environments. AB - Coastal marine systems are affected by seasonal variations in biogeochemical and physical processes, sometimes leading to alternating periods of reproductive growth limitation within an annual cycle. Transitions between these periods can be sudden or gradual. Human activities, such as reservoir construction and interbasin water transfers, influence these processes and can affect the type of transition between resource loading conditions. How such human activities might influence phytoplankton succession is largely unknown. Here, we employ a multispecies, multi-nutrient model to explore how nutrient loading switching mode might affect phytoplankton succession. The model is based on the Monod relationship, predicting an instantaneous reproductive growth rate from ambient inorganic nutrient concentrations whereas the limiting nutrient at any given time was determined by Liebig's Law of the Minimum. When these relationships are combined with population loss factors, such as hydraulic displacement of cells associated with inflows, a characterization of a species' niche can be achieved through application of the R* conceptual model, thus enabling an ecological interpretation of modeling results. We found that the mode of reversal in resource supply concentrations had a profound effect. When resource supply reversals were sudden, as expected in systems influenced by pulsed inflows or wind-driven mixing events, phytoplankton were characterized by alternating succession dynamics, a phenomenon documented in inland water bodies of temperate latitudes. When resource supply reversals were gradual, as expected in systems influenced by seasonally developing wet and dry seasons, or annually occurring periods of upwelling, phytoplankton dynamics were characterized by mirror-image succession patterns. This phenomenon has not been reported previously in plankton systems but has been observed in some terrestrial plant systems. These findings suggest that a transition from alternating to "mirror-image" succession patterns might arise with continued coastal zone development, with crucial implications for ecosystems dependent on time-sensitive processes, e.g., spawning events and migration patterns. PMID- 25803435 TI - Laryngoscope and a new tracheal tube assist lightwand intubation in difficult airways due to unstable cervical spine. AB - PURPOSE: The WEI Jet Endotracheal Tube (WEI JET) is a new tracheal tube that facilitates both oxygenation and ventilation during the process of intubation and assists tracheal intubation in patients with difficult airway. We evaluated the effectiveness and usefulness of the WEI JET in combination with lightwand under direct laryngoscopy in difficult tracheal intubation due to unstable cervical spine. METHODS: Ninety patients with unstable cervical spine disorders (ASA I III) with general anaesthesia were included and randomly assigned to three groups, based on the device used for intubation: lightwand only, lightwand under direct laryngoscopy, lightwand with WEI JET under direct laryngoscopy. RESULTS: No statistically significant differences were detected among three groups with respect to demographic characteristics and C/L grade. There were statistically significant differences between three groups for overall intubation success rate (p = 0.015) and first attempt success rate (p = 0.000). The intubation time was significantly longer in the WEI group (110.8+/-18.3 s) than in the LW group (63.3+/-27.5 s, p = 0.000) and DL group (66.7+/-29.4 s, p = 0.000), but the lowest SpO2 in WEI group was significantly higher than other two groups (p<0.01). The WEI JET significantly reduced successful tracheal intubation attempts compared to the LW group (p = 0.043). The severity of sore throat was similar in three groups (p = 0.185). CONCLUSIONS: The combined use of WEI JET under direct laryngoscopy helps to assist tracheal intubation and improves oxygenation during intubation in patients with difficult airway secondary to unstable spine disorders. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC 14005141. PMID- 25803436 TI - Involvement of Eyelid Pressure in Lid-Wiper Epitheliopathy. AB - OBJECTIVES: To determine whether eyelid pressure is involved in the development of lid-wiper epitheliopathy (LWE). METHODS: Study 1: The eyelid pressure was measured with a blepharo-tensiometer, and the degree of LWE was assessed in 79 eyes of 43 non-contact lens (CL) wearers. Study 2: The movements of the eyelids and displacement of the eyes during spontaneous blinking were photographed with a high-speed camera. The eyelid pressure was also measured in 34 normal eyes of 19 non-CL wearers who were not part of Study 1. RESULTS: Study 1: Upper-LWE was detected in 24 of 79 eyes (30.4%), and no significant difference was detected in the eyelid pressure between any grade of upper-LWE. Lower-LWE was detected in 41 of 79 eyes (51.9%), and the eyelid pressure (27.9 +/- 2.8 mmHg) in eyes with grade 3 LWE was significantly higher than that with grade 0 LWE (19.7 +/- 1.3 mmHg; p < 0.05). Study 2: The lower eyelid pressure was significantly correlated with the length of the horizontal movement of the lower eyelids (p < 0.05) and also with the degree of posterior movement of the eye globe (p < 0.05). CONCLUSIONS: The higher pressure from the eyelid may be one of the causes for the development of lower-LWE. PMID- 25803438 TI - Obesity and risk of bladder cancer: a dose-response meta-analysis of 15 cohort studies. AB - BACKGROUND: Epidemiological studies have reported inconsistent association between obesity and risk of bladder cancer, and the dose-response relationship between them has not been clearly defined. METHODS: We carried out a meta analysis to summarize available evidence from epidemiological studies on this point. Relevant articles were identified by searching the PubMed and Web of Science databases through September 30, 2014. We pooled the relative risks from individual studies using random-effect model, and the dose-response relationship was estimated by using restricted cubic spline model. RESULTS: Fifteen cohort studies with 38,072 bladder cancer cases among 14,201,500 participants were included. Compared to normal weight, the pooled relative risks and corresponding 95% confidence intervals of bladder cancer were 1.07(1.01-1.14) and 1.10(1.06 1.14) for preobese and obesity, with moderate (I2 = 37.6%, P = 0.029) and low (I2 = 15.5%, P = 0.241) heterogeneities between studies, respectively. In a dose response meta-analysis, body mass index (BMI) was associated with bladder cancer risk in a linear fashion (P(non-linearity) = 0.467) and the risk increased by 4.2% for each 5 kg/m2 increase. No significant publication bias was found (P = 0.912 for Begg's test, P = 0.712 for Egger's test). CONCLUSIONS: Findings from this dose-response meta-analysis suggest obesity is associated with linear increased risk of bladder cancer. PMID- 25803439 TI - Integrating solid-state NMR and computational modeling to investigate the structure and dynamics of membrane-associated ghrelin. AB - The peptide hormone ghrelin activates the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. This 28-residue peptide is acylated at Ser3 and is the only peptide hormone in the human body that is lipid-modified by an octanoyl group. Little is known about the structure and dynamics of membrane associated ghrelin. We carried out solid-state NMR studies of ghrelin in lipid vesicles, followed by computational modeling of the peptide using Rosetta. Isotropic chemical shift data of isotopically labeled ghrelin provide information about the peptide's secondary structure. Spin diffusion experiments indicate that ghrelin binds to membranes via its lipidated Ser3. Further, Phe4, as well as electrostatics involving the peptide's positively charged residues and lipid polar headgroups, contribute to the binding energy. Other than the lipid anchor, ghrelin is highly flexible and mobile at the membrane surface. This observation is supported by our predicted model ensemble, which is in good agreement with experimentally determined chemical shifts. In the final ensemble of models, residues 8-17 form an alpha-helix, while residues 21-23 and 26-27 often adopt a polyproline II helical conformation. These helices appear to assist the peptide in forming an amphipathic conformation so that it can bind to the membrane. PMID- 25803440 TI - Value of dynamic susceptibility contrast perfusion MRI in the acute phase of transient global amnesia. AB - PURPOSE: Transient global amnesia (TGA) is a transitory, short-lasting neurological disorder characterized by a sudden onset of antero- and retrograde amnesia. Perfusion abnormalities in TGA have been evaluated mainly by use of positron emission tomography (PET) or single-photon emission computed tomography (SPECT). In the present study we explore the value of dynamic susceptibility contrast perfusion-weighted MRI (PWI) in TGA in the acute phase. METHODS: From a MRI report database we identified TGA patients who underwent MRI including PWI in the acute phase and compared these to control subjects. Quantitative perfusion maps (cerebral blood flow (CBF) and volume (CBV)) were generated and analyzed by use of Signal Processing In NMR-Software (SPIN). CBF and CBV values in subcortical brain regions were assessed by use of VOI created in FIRST, a model based segmentation tool in the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL). RESULTS: Five TGA patients were included (2 men, 3 women). On PWI, no relevant perfusion alterations were found by visual inspection in TGA patients. Group comparisons for possible differences between TGA patients and control subjects showed significant lower rCBF values bilaterally in the hippocampus, in the left thalamus and globus pallidus as well as bilaterally in the putamen and the left caudate nucleus. Correspondingly, significant lower rCBV values were observed bilaterally in the hippocampus and the putamen as well as in the left caudate nucleus. Group comparisons for possible side differences in rCBF and rCBV values in TGA patients revealed a significant lower rCBV value in the left caudate nucleus. CONCLUSIONS: Mere visual inspection of PWI is not sufficient for the assessment of perfusion changes in TGA in the acute phase. Group comparisons with healthy control subjects might be useful to detect subtle perfusion changes on PWI in TGA patients. However, this should be confirmed in larger data sets and serial PWI examinations. PMID- 25803441 TI - Assessing the stability and safety of procedure during endoscopic submucosal dissection according to sedation methods: a randomized trial. AB - BACKGROUND: Although endoscopic submucosal dissection (ESD) is routinely performed under sedation, the difference in ESD performance according to sedation method is not well known. This study attempted to prospectively assess and compare the satisfaction of the endoscopists and patient stability during ESD between two sedation methods. METHODS: One hundred and fifty-four adult patients scheduled for ESD were sedated by either the IMIE (intermittent midazolam/propofol injection by endoscopist) or CPIA (continuous propofol infusion by anesthesiologist) method. The primary endpoint of this study was to compare the level of satisfaction of the endoscopists between the two groups. The secondary endpoints included level of satisfaction of the patients, patient's pain scores, events interfering with the procedure, incidence of unintended deep sedation, hemodynamic and respiratory events, and ESD outcomes and complications. RESULTS: Level of satisfaction of the endoscopists was significantly higher in the CPIA Group compared to the IMIE group (IMIE vs. CPIA; high satisfaction score; 63.2% vs. 87.2%, P=0.001). The incidence of unintended deep sedation was significantly higher in the IMIE Group compared to the CPIA Group (IMIE vs. CPIA; 17.1% vs. 5.1%, P=0.018) as well as the number of patients showing spontaneous movement or those requiring physical restraint (IMIE vs. CPIA; spontaneous movement; 60.5% vs. 42.3%, P=0.024, physical restraint; 27.6% vs. 10.3%, P=0.006, respectively). In contrast, level of satisfaction of the patients were found to be significantly higher in the IMIE Group (IMIE vs. CPIA; high satisfaction score; 85.5% vs. 67.9%, P=0.027). Pain scores of the patients, hemodynamic and respiratory events, and ESD outcomes and complications were not different between the two groups. CONCLUSION: Continuous propofol and remifentanil infusion by an anesthesiologist during ESD can increase the satisfaction levels of the endoscopists by providing a more stable state of sedation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01806753. PMID- 25803442 TI - Shrimp serine proteinase homologues PmMasSPH-1 and -2 play a role in the activation of the prophenoloxidase system. AB - Melanization mediated by the prophenoloxidase (proPO) activating system is a rapid immune response used by invertebrates against intruding pathogens. Several masquerade-like and serine proteinase homologues (SPHs) have been demonstrated to play an essential role in proPO activation in insects and crustaceans. In a previous study, we characterized the masquerade-like SPH, PmMasSPH1, in the black tiger shrimp Penaeus monodon as a multifunctional immune protein based on its recognition and antimicrobial activity against the Gram-negative bacteria Vibrio harveyi. In the present study, we identify a novel SPH, known as PmMasSPH2, composed of an N-terminal clip domain and a C-terminal SP-like domain that share high similarity to those of other insect and crustacean SPHs. We demonstrate that gene silencing of PmMasSPH1 and PmMasSPH2 significantly reduces PO activity, resulting in a high number of V. harveyi in the hemolymph. Interestingly, knockdown of PmMasSPH1 suppressed not only its gene transcript but also other immune-related genes in the proPO system (e.g., PmPPAE2) and antimicrobial peptides (e.g., PenmonPEN3, PenmonPEN5, crustinPm1 and Crus-likePm). The PmMasSPH1 and PmMasSPH2 also show binding activity to peptidoglycan (PGN) of Gram positive bacteria. Using a yeast two-hybrid analysis and co-immunoprecipitation, we demonstrate that PmMasSPH1 specifically interacted with the final proteinase of the proPO cascade, PmPPAE2. Furthermore, the presence of both PmMasSPH1 and PmPPAE2 enhances PGN-induced PO activity in vitro. Taken together, these results suggest the importance of PmMasSPHs in the activation of the shrimp proPO system. PMID- 25803443 TI - Mechanisms explaining nursery habitat association: how do juvenile snapper (Chrysophrys auratus) benefit from their nursery habitat? AB - Nursery habitats provide elevated survival and growth to the organisms that associate with them, and as such are a crucial early life-stage component for many fishes and invertebrates. The exact mechanisms by which these benefits are afforded to associated organisms, however, are often unclear. Here we assessed potential explanations of the nursery function of structurally complex habitats for post-settlement snapper, Chrysophrys auratus, in New Zealand. Specifically, we deployed Artificial Seagrass Units (ASUs) and used a combination of video observation, netting and diet analysis of associated post-settlement snapper as well describing potential prey within the micro-habitats surrounding ASUs. We did not observe any predation attempts and few potential predators, suggesting that for snapper the nursery value of structurally complex habitats is not as a predation refuge. The diet of post-settlement snapper mostly consisted of calanoid and cyclopoid copepods, which were most commonly sampled from within the water column. Nearly all suspected feeding events were also observed within the water column. When considering the velocity of water flow at each ASU, plankton sampling revealed a greater availability of copepods with increasing current strength, while netting and video observation demonstrated that the abundance of snapper was highest at sites with intermediate water velocity. This study highlights that the interaction between water flow and food availability may represent an important trade-off between energy expenditure and food intake for post-settlement snapper. Structurally complex habitats may mediate this relationship, allowing snapper to access sites with higher food availability while reducing swimming costs. This mechanism may have broader relevance, potentially explaining the importance of estuarine nursery habitats for other species. PMID- 25803444 TI - On the automaticity of the evaluative priming effect in the valent/non-valent categorization task. AB - It has previously been argued (a) that automatic evaluative stimulus processing is critically dependent upon feature-specific attention allocation and (b) that evaluative priming effects can arise in the absence of dimensional overlap between the prime set and the response set. In line with both claims, research conducted at our lab revealed that the evaluative priming effect replicates in the valent/non-valent categorization task. This research was criticized, however, because non-automatic, strategic processes may have contributed to the emergence of this effect. We now report the results of a replication study in which the operation of non-automatic, strategic processes was controlled for. A clear-cut evaluative priming effect emerged, thus supporting initial claims concerning feature-specific attention allocation and dimensional overlap. PMID- 25803445 TI - Ultrasound echo-intensity predicts severe pancreatic affection in cystic fibrosis patients. AB - BACKGROUND: Pancreatic destruction affects the majority of patients with cystic fibrosis. We aimed to relate ultrasound findings to exocrine pancreatic function and cystic fibrosis genotype. METHODS: Patients with cystic fibrosis and a matched group of healthy controls were included. We performed transabdominal ultrasound, and recorded echo intensities of the pancreas and parenchymal characteristics according to endoscopic ultrasound based Rosemont criteria. RESULTS: We included 39 patients and 29 healthy controls. The cystic fibrosis patients were grouped according to exocrine pancreatic function; Cystic fibrosis, insufficient (n = 20) and sufficient (n = 19). Echo intensity measures and visual score demonstrated hyper-echogenicity in the pancreas insufficient group compared to the pancreas sufficient groups (p<0.001). Ductal and parenchymal changes were not prevalent in any of the groups. CONCLUSION: The hyper-echoic pancreas was the most frequent ultrasonographic finding in exocrine pancreas insufficient cystic fibrosis patients. Pancreatic echo levels correlated to pancreatic phenotype. PMID- 25803447 TI - Persistent Postconcussive Symptoms Are Accompanied by Decreased Functional Brain Oxygenation. AB - Diagnostic methods are considered a major concern in the determination of mild traumatic brain injury. The authors examined brain oxygenation patterns in subjects with severe and minor persistent postconcussive difficulties and a healthy control group during working memory tasks in prefrontal brain regions using functional near-infrared spectroscopy. The results demonstrated decreased working memory performances among concussed subjects with severe postconcussive symptoms that were accompanied by decreased brain oxygenation patterns. An association appears to exist between decreased brain oxygenation, poor performance of working memory tasks, and increased symptom severity scores in subjects suffering from persistent postconcussive symptoms. PMID- 25803448 TI - Prevalence of Taenia saginata Larvae (Cysticercus bovis) in Feedlot Cattle Slaughtered in a Federal Inspection Type Abattoir in Northwest Mexico. AB - The prevalence of bovine cysticercosis was established using routine postmortem inspection of 52,322 feedlot cattle slaughtered at 1 Federal Inspection Type abattoir (TIF 301) located in the Mexicali Valley in Baja California, Mexico. The study included 31,393 animals (60.0%) purchased and transported to Baja California from stocker operations located in 17 states of Mexico and 20,929 animals (40.0%) native to Baja California. A total of 208 carcasses showed lesions suggestive of cysticercosis, and 109 were confirmed as positive for the parasite with a prevalence of 0.21%, equivalent to 2.1 cases/1000 carcasses inspected, 2.8 cases/1000 carcasses for cattle purchased in other states, and 1.0 cases/1000 carcasses for cattle native from Baja California. The sensitivity of the postmortem inspection, when compared to a gold standard of stereoscopic microscopy, was 52.4%. The prevalence of cysticercosis was 2.8 times higher in cattle from other states compared with those native to Baja California. Cysticerci were most frequently found in the heart, followed by liver and masseter muscles. In cattle from other states, 96.6% of cysticerci were classified as calcified and <4% as viable; in cattle native to Baja California, 29% of cysticerci were classified as calcified and 71% as viable. The prevalence of bovine cysticercosis established at TIF 301 was found to be 28% lower than a previous report for Baja California. However, given the sensitivity of the postmortem inspection calculated between 10% and 50%, it is possible that an undetermined number of carcasses pass as being free of cysticerci and that the meat reached both domestic and international wholesale markets, increasing the possibility of human infection and causing substantial economic loss through condemnation of infected meat and trade restrictions for endemic regions. PMID- 25803446 TI - Minireview: 12-Lipoxygenase and Islet beta-Cell Dysfunction in Diabetes. AB - The insulin producing islet beta-cells have increasingly gained attention for their role in the pathogeneses of virtually all forms of diabetes. Dysfunction, de-differentiation, and/or death of beta-cells are pivotal features in the transition from normoglycemia to hyperglycemia in both animal models of metabolic disease and humans. In both type 1 and type 2 diabetes, inflammation appears to be a central cause of beta-cell derangements, and molecular pathways that modulate inflammation or the inflammatory response are felt to be prime targets of future diabetes therapy. The lipoxygenases (LOs) represent a class of enzymes that oxygenate cellular polyunsaturated fatty acids to produce inflammatory lipid intermediates that directly and indirectly affect cellular function and survival. The enzyme 12-LO is expressed in all metabolically active tissues, including pancreatic islets, and has received increasing attention for its role in promoting cellular inflammation in the setting of diabetes. Genetic deletion models of 12-LO in mice reveal striking protection from metabolic disease and its complications and an emerging body of literature has implicated its role in human disease. This review focuses on the evidence supporting the proinflammatory role of 12-LO as it relates to islet beta-cells, and the potential for 12-LO inhibition as a future avenue for the prevention and treatment of metabolic disease. PMID- 25803451 TI - Correction: HPLC-MS/MS analyses show that the near-starchless aps1 and pgm leaves accumulate wild type levels of ADPglucose: further evidence for the occurrence of important ADPglucose biosynthetic pathway(s) alternative to the pPGI-pPGM-AGP pathway. PMID- 25803449 TI - Characterization of stimulus-secretion coupling in the human pancreatic EndoC betaH1 beta cell line. AB - AIMS/HYPOTHESIS: Studies on beta cell metabolism are often conducted in rodent beta cell lines due to the lack of stable human beta cell lines. Recently, a human cell line, EndoC-betaH1, was generated. Here we investigate stimulus secretion coupling in this cell line, and compare it with that in the rat beta cell line, INS-1 832/13, and human islets. METHODS: Cells were exposed to glucose and pyruvate. Insulin secretion and content (radioimmunoassay), gene expression (Gene Chip array), metabolite levels (GC/MS), respiration (Seahorse XF24 Extracellular Flux Analyzer), glucose utilization (radiometric), lactate release (enzymatic colorimetric), ATP levels (enzymatic bioluminescence) and plasma membrane potential and cytoplasmic Ca2+ responses (microfluorometry) were measured. Metabolite levels, respiration and insulin secretion were examined in human islets. RESULTS: Glucose increased insulin release, glucose utilization, raised ATP production and respiratory rates in both lines, and pyruvate increased insulin secretion and respiration. EndoC-betaH1 cells exhibited higher insulin secretion, while plasma membrane depolarization was attenuated, and neither glucose nor pyruvate induced oscillations in intracellular calcium concentration or plasma membrane potential. Metabolite profiling revealed that glycolytic and TCA-cycle intermediate levels increased in response to glucose in both cell lines, but responses were weaker in EndoC-betaH1 cells, similar to those observed in human islets. Respiration in EndoC-betaH1 cells was more similar to that in human islets than in INS-1 832/13 cells. CONCLUSIONS/INTERPRETATION: Functions associated with early stimulus-secretion coupling, with the exception of plasma membrane potential and Ca2+ oscillations, were similar in the two cell lines; insulin secretion, respiration and metabolite responses were similar in EndoC betaH1 cells and human islets. While both cell lines are suitable in vitro models, with the caveat of replicating key findings in isolated islets, EndoC betaH1 cells have the advantage of carrying the human genome, allowing studies of human genetic variants, epigenetics and regulatory RNA molecules. PMID- 25803453 TI - Scents and sensibility. PMID- 25803452 TI - Conservation thinning in secondary forest: negative but mild effect on land molluscs in closed-canopy mixed oak forest in Sweden. AB - Secondary succession is changing the character of many temperate forests and often leads to closed-canopy stands. In such forests set aside for conservation, habitat management alternatives need to be tested experimentally, but this is rarely done. The Swedish Oak Project compares two often debated alternatives: minimal intervention and non-traditional active management (conservation thinning) on plots of each type replicated at 25 sites. We study responses of several taxa, and here report results for land molluscs. They are considered to be sensitive to more open, drier forest and we predicted a negative effect of the thinning (26% reduction of the basal area; mean value for 25 experimental forests). We sampled molluscs in the litter in ten 20 x 25 cm subplots, and by standardised visual search, in each plot. In total, we recorded 53 species of snails and slugs (24 369 individuals) and the mean species richness in plots was 17. Two seasons after thinning, mean (+/- SE) species richness had decreased by 1.4 (+/- 0.9) species in thinning plots, but increased by 0.7 (+/- 1.0) species in minimal intervention plots, a significant but small change with considerable variation among sites. In matched comparisons with minimal intervention, thinning reduced the overall abundance of molluscs. Most species responded negatively to thinning - but only five of the 53 species were significantly affected, and reproduction seemed to be negatively affected in only one species. An ordination analysis did not reveal any particular change in the species community due to thinning. Thus, the negative effect of conservation thinning on land molluscs was apparently mild - one reason was that many trees, shrubs and other forest structures remained after the treatment. Conservation thinning may be recommended, since other taxa are favoured, but minimal intervention is also a useful form of management for molluscs and saproxylic taxa. PMID- 25803455 TI - Theatre: Rekindling an old flame. PMID- 25803450 TI - Superinfection between influenza and RSV alternating patterns in San Luis Potosi State, Mexico. AB - The objective of this paper is to explain through the ecological hypothesis superinfection and competitive interaction between two viral populations and niche (host) availability, the alternating patterns of Respiratory Syncytial Virus (RSV) and influenza observed in a regional hospital in San Luis Potosi State, Mexico using a mathematical model as a methodological tool. The data analyzed consists of community-based and hospital-based Acute Respiratory Infections (ARI) consultations provided by health-care institutions reported to the State Health Service Epidemiology Department from 2003 through 2009. PMID- 25803461 TI - Origin of life: Primordial soup that cooks itself. PMID- 25803462 TI - Inorganic materials: The quest for new functionality. PMID- 25803463 TI - Supramolecular sensing: Enzyme activity with a twist. PMID- 25803464 TI - Protein engineering: The power of four. PMID- 25803465 TI - Surface chemistry: A step in the right direction. PMID- 25803466 TI - Supramolecular ferroelectrics. AB - Supramolecular chemistry uses non-covalent interactions to coax molecules into forming ordered assemblies. The construction of ordered materials with these reversible bonds has led to dramatic innovations in organic electronics, polymer science and biomaterials. Here, we review how supramolecular strategies can advance the burgeoning field of organic ferroelectricity. Ferroelectrics - materials with a spontaneous and electrically reversible polarization - are touted for use in non-volatile computer memories, sensors and optics. Historically, this physical phenomenon has been studied in inorganic materials, although some organic examples are known and strong interest exists to extend the search for ferroelectric molecular systems. Other undiscovered applications outside this regime could also emerge. We describe the key features necessary for molecular and supramolecular dipoles in organic ferroelectrics and their incorporation into ordered systems, such as porous frameworks and liquid crystals. The goal of this Review is to motivate the development of innovative supramolecular ferroelectrics that exceed the performance and usefulness of known systems. PMID- 25803467 TI - Stepwise growth of surface-grafted DNA nanotubes visualized at the single molecule level. AB - DNA nanotubes offer a high aspect ratio and rigidity, attractive attributes for the controlled assembly of hierarchically complex linear arrays. It is highly desirable to control the positioning of rungs along the backbone of the nanotubes, minimize the polydispersity in their manufacture and reduce the building costs. We report here a solid-phase synthesis methodology in which, through a cyclic scheme starting from a 'foundation rung' specifically bound to the surface, distinct rungs can be incorporated in a predetermined manner. Each rung is orthogonally addressable. Using fluorescently tagged rungs, single molecule fluorescence studies demonstrated the robustness and structural fidelity of the constructs and confirmed the incorporation of the rungs in quantitative yield (>95%) at each step of the cycle. Prototype structures that consisted of up to 20 repeat units, about 450 nm in contour length, were constructed. Combined, the solid-phase synthesis strategy described and its visualization through single molecule spectroscopy show good promise for the production of custom-made DNA nanotubes. PMID- 25803468 TI - Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. AB - A minimal cell can be thought of as comprising informational, compartment-forming and metabolic subsystems. To imagine the abiotic assembly of such an overall system, however, places great demands on hypothetical prebiotic chemistry. The perceived differences and incompatibilities between these subsystems have led to the widely held assumption that one or other subsystem must have preceded the others. Here we experimentally investigate the validity of this assumption by examining the assembly of various biomolecular building blocks from prebiotically plausible intermediates and one-carbon feedstock molecules. We show that precursors of ribonucleotides, amino acids and lipids can all be derived by the reductive homologation of hydrogen cyanide and some of its derivatives, and thus that all the cellular subsystems could have arisen simultaneously through common chemistry. The key reaction steps are driven by ultraviolet light, use hydrogen sulfide as the reductant and can be accelerated by Cu(I)-Cu(II) photoredox cycling. PMID- 25803469 TI - Prediction and accelerated laboratory discovery of previously unknown 18-electron ABX compounds. AB - Chemists and material scientists have often focused on the properties of previously reported compounds, but neglect numerous unreported but chemically plausible compounds that could have interesting properties. For example, the 18 valence electron ABX family of compounds features examples of topological insulators, thermoelectrics and piezoelectrics, but only 83 out of 483 of these possible compounds have been made. Using first-principles thermodynamics we examined the theoretical stability of the 400 unreported members and predict that 54 should be stable. Of those previously unreported 'missing' materials now predicted to be stable, 15 were grown in this study; X-ray studies agreed with the predicted crystal structure in all 15 cases. Among the predicted and characterized properties of the missing compounds are potential transparent conductors, thermoelectric materials and topological semimetals. This integrated process-prediction of functionality in unreported compounds followed by laboratory synthesis and characterization-could be a route to the systematic discovery of hitherto missing, realizable functional materials. PMID- 25803470 TI - Inducing and quantifying forbidden reactivity with single-molecule polymer mechanochemistry. AB - Forbidden reactions, such as those that violate orbital symmetry effects as captured in the Woodward-Hoffmann rules, remain an ongoing challenge for experimental characterization, because when the competing allowed pathway is available the reactions are intrinsically difficult to trigger. Recent developments in covalent mechanochemistry have opened the door to activating otherwise inaccessible reactions. Here we report single-molecule force spectroscopy studies of three mechanically induced reactions along both their symmetry-allowed and symmetry-forbidden pathways, which enables us to quantify just how 'forbidden' each reaction is. To induce reactions on the ~0.1 s timescale of the experiments, the forbidden ring-opening reactions of benzocyclobutene, gem-difluorocyclopropane and gem-dichlorocyclopropane require approximately 130 pN less, 560 pN more and 1,000 pN more force, respectively, than their corresponding allowed analogues. The results provide the first experimental benchmarks for mechanically induced forbidden reactions, and in some cases suggest revisions to prior computational predictions. PMID- 25803471 TI - Combined biomass valorization and hydrogen production in a photoelectrochemical cell. AB - In a typical hydrogen-producing photoelectrochemical cell (PEC), water reduction at the cathode (producing hydrogen) is accompanied by water oxidation at the anode (producing oxygen). This anode reaction is, however, not kinetically favourable. Here we investigate the possibility of utilizing solar energy for biomass conversion by performing the oxidation of 5-hydroxymethylfurfural (HMF) into 2,5-furandicarboxylic acid (FDCA) at the anode of a PEC. HMF is a key intermediate in biomass conversion, and FDCA is an important monomer for the production of numerous polymers. Using 2,2,6,6-tetramethylpiperidine-1-oxyl as a mediator, we obtained a near-quantitative yield and 100% Faradaic efficiency at ambient conditions without the use of precious-metal catalysts. This reaction is also thermodynamically and kinetically more favourable than water oxidation. Our results suggest that solar-driven biomass conversion can be a viable anode reaction that has the potential to increase both the efficiency and the utility of PECs constructed for solar-fuel production. PMID- 25803473 TI - Highly emissive platinum(II) metallacages. AB - Light-emitting materials, especially those with tunable wavelengths, attract considerable attention for applications in optoelectronic devices, fluorescent probes, sensors and so on. Many species evaluated for these purposes either emit as a dilute solution or on aggregation, with the former often self-quenching at high concentrations, and the latter falling dark when aggregation is disrupted. Here we preserve emissive behaviour at both low- and high-concentration regimes for two discrete supramolecular coordination complexes (SCCs). These tetragonal prismatic SCCs are self-assembled on mixing a metal acceptor, Pt(PEt3)2(OSO2CF3)2, with two organic donors, a pyridyl-decorated tetraphenylethylene and one of two benzene dicarboxylate species. The rigid organization of these fluorescence-active ligands imparts an emissive behaviour to dilute solutions of the resulting assemblies. Furthermore, on aggregation the prisms exhibit variable-wavelength visible-light emission, including rare white light emission in tetrahydrofuran. The favourable photophysical properties and solvent-dependent aggregation behaviour provide a means to tune emission wavelengths. PMID- 25803474 TI - Quantum dynamical resonances in low-energy CO(j = 0) + He inelastic collisions. AB - In molecular collisions, long-lived complexes may be formed that correspond to quasi-bound states in the van der Waals potential and give rise to peaks in the collision energy-dependent cross-sections. They are known as 'resonances' and their experimental detection remains difficult because their signatures are extremely challenging to resolve. Here, we show a complete characterization of quantum-dynamical resonances occurring in CO-He inelastic collisions with rotational CO(j = 0->1) excitation. Crossed-beam scattering experiments were performed at collision energies as low as 4 cm(-1), equivalent to a temperature of 4 K. Resonance structures in the measured cross-sections were identified by comparison with quantum-mechanical calculations. The excellent agreement found confirms that the potential energy surfaces describing the CO-He van der Waals interaction are perfectly suitable for calculating state-to-state (de)excitation rate coefficients at the very low temperatures needed in chemical modelling of the interstellar medium. We also computed these rate coefficients. PMID- 25803472 TI - Iterative design of a helically folded aromatic oligoamide sequence for the selective encapsulation of fructose. AB - The ab initio design of synthetic molecular receptors for a specific biomolecular guest remains an elusive objective, particularly for targets such as monosaccharides, which have very close structural analogues. Here we report a powerful approach to produce receptors with very high selectivity for specific monosaccharides and, as a demonstration, we develop a foldamer that selectively encapsulates fructose. The approach uses an iterative design process that exploits the modular structure of folded synthetic oligomer sequences in conjunction with molecular modelling and structural characterization to inform subsequent refinements. Starting from a first-principles design taking size, shape and hydrogen-bonding ability into account and using the high predictability of aromatic oligoamide foldamer conformations and their propensity to crystallize, a sequence that binds to beta-D-fructopyranose in organic solvents with atomic-scale complementarity was obtained in just a few iterative modifications. This scheme, which mimics the adaptable construction of biopolymers from a limited number of monomer units, provides a general protocol for the development of selective receptors. PMID- 25803476 TI - Erratum: Catalytic enantioselective synthesis of indanes by a cation-directed 5 endo-trig cyclization. PMID- 25803477 TI - Quantum caesium. PMID- 25803475 TI - Two-stage directed self-assembly of a cyclic [3]catenane. AB - Interlocked molecules possess properties and functions that depend upon their intricate connectivity. In addition to the topologically trivial rotaxanes, whose structures may be captured by a planar graph, the topologically non-trivial knots and catenanes represent some of chemistry's most challenging synthetic targets because of the three-dimensional assembly necessary for their construction. Here we report the synthesis of a cyclic [3]catenane, which consists of three mutually interpenetrating rings, via an unusual synthetic route. Five distinct building blocks self-assemble into a heteroleptic triangular framework composed of two joined Fe(II)3L3 circular helicates. Subcomponent exchange then enables specific points in the framework to be linked together to generate the cyclic [3]catenane product. Our method represents an advance both in the intricacy of the metal templated self-assembly procedure and in the use of selective imine exchange to generate a topologically complex product. PMID- 25803480 TI - Photoluminescence performance enhancement of ZnO/MgO heterostructured nanowires and their applications in ultraviolet laser diodes. AB - Vertically aligned ZnO/MgO coaxial nanowire (NW) arrays were prepared on sapphire substrates by metal-organic chemical vapor deposition combined with a sputtering system. We present a comparative investigation of the morphological and optical properties of the produced heterostructures with different MgO layer thicknesses. Photoluminescence measurements showed that the optical performances of ZnO/MgO coaxial NWs were strongly dependent on the MgO layer thickness. The intensity of deep-level emission (DLE) decreased monotonously with the increase of MgO thickness, while the enhancement of ultraviolet (UV) emission showed a critical thickness of 15 nm, achieving a maximum intensity ratio (~226) of IUV/IDLE at the same time. The significantly improved exciton emission efficiency of the coaxial NW structures allows us to study the surface passivation effect, photogenerated carrier confinement and transfer in terms of energy band theory. More importantly, we achieved an ultralow threshold (4.5 mA, 0.58 A cm(-2)) electrically driven UV lasing action based on the ZnO/MgO NW structures by constructing an Au/MgO/ZnO metal/insulator/semiconductor diode, and the continuous-current-driven diode shows a good temperature tolerance. The results obtained on the unique optical properties of ZnO/MgO coaxial NWs shed light on the design and development of ZnO-based UV laser diodes assembled with nanoscale building blocks. PMID- 25803479 TI - Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse model of idiopathic autism. AB - Autism spectrum disorders are characterized by impaired social and communicative skills and repetitive behaviors. Emerging evidence supported the hypothesis that these neurodevelopmental disorders may result from a combination of genetic susceptibility and exposure to environmental toxins in early developmental phases. This study assessed the effects of prenatal exposure to chlorpyrifos (CPF), a widely diffused organophosphate insecticide endowed with developmental neurotoxicity at sub-toxic doses, in the BTBR T+tf/J mouse strain, a validated model of idiopathic autism that displays several behavioral traits relevant to the autism spectrum. To this aim, pregnant BTBR mice were administered from gestational day 14 to 17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent assessment of early developmental milestones, including somatic growth, motor behavior and ultrasound vocalization. To evaluate the potential long-term effects of CPF, two different social behavior patterns typically altered in the BTBR strain (free social interaction with a same-sex companion in females, or interaction with a sexually receptive female in males) were also examined in the two sexes at adulthood. Our findings indicate significant effects of CPF on somatic growth and neonatal motor patterns. CPF treated pups showed reduced weight gain, delayed motor maturation (i.e., persistency of immature patterns such as pivoting at the expenses of coordinated locomotion) and a trend to enhanced ultrasound vocalization. At adulthood, CPF associated alterations were found in males only: the altered pattern of investigation of a sexual partner, previously described in BTBR mice, was enhanced in CPF males, and associated to increased ultrasonic vocalization rate. These findings strengthen the need of future studies to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders. PMID- 25803478 TI - Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset. AB - Mycobacterial antigens are not exclusively presented to T-cells by classical HLA class Ia and HLA-class II molecules, but also through alternative antigen presentation molecules such as CD1a/b/c, MR1 and HLA-E. We recently described mycobacterial peptides that are presented in HLA-E and recognized by CD8+ T cells. Using T-cell cloning, phenotyping, microbiological, functional and RNA expression analyses, we report here that these T-cells can exert cytolytic or suppressive functions, inhibit mycobacterial growth, yet express GATA3, produce Th2 cytokines (IL-4,-5,-10,-13) and activate B-cells via IL-4. In TB patients, Mtb specific cells were detectable by peptide-HLA-E tetramers, and IL-4 and IL-13 were produced following peptide stimulation. These results identify a novel human T-cell subset with an unorthodox, multifunctional Th2 like phenotype and cytolytic or regulatory capacities, which is involved in the human immune response to mycobacteria and demonstrable in active TB patients' blood. The results challenge the current dogma that only Th1 cells are able to inhibit Mtb growth and clearly show that Th2 like cells can strongly inhibit outgrowth of Mtb from human macrophages. These insights significantly expand our understanding of the immune response in infectious disease. PMID- 25803482 TI - L-arginine pretreatment reduces intestinal mucositis as induced by 5-FU in mice. AB - Beneficial effects of L-arginine on immune responses and bowel function have been reported. Mucositis is a side effect of chemotherapy treatment that affects approximately 40% of patients. This complication is characterized by inflammation that affects the gastrointestinal tract, increasing permeability and causing abdominal pain, nausea, vomiting, and diarrhea, which worsen the patient's nutritional status and increases morbimortality. The aim of this study was to evaluate the effect of pretreating with 2% L-arginine supplementation in water on mucositis as induced by 5-fluorouracil (5-FU; a single dose of 200 mg/kg body weight) in Swiss male mice. The effect of L-arginine on weight, intestinal permeability, morphology, and the histopathological score of the small intestine (from 0 to 12), oxidative stress, myeloperoxidase (MPO), and N acetylglucosaminidase (NAG) activities were evaluated. Intestinal length improvement was observed, in addition to the partial recovery of the mucosal architecture. L-arginine attenuated the histopathological score and MPO activity. There was also an improvement in intestinal permeability, despite weight loss after 5-FU administration. In conclusion, L-arginine can positively impact intestinal mucositis by promoting partial mucosal recovery, reducing inflammation and improving intestinal permeability. PMID- 25803483 TI - Testing and treating the missing millions with tuberculosis. AB - In a Guest Editorial on World TB Day, Madhukar Pai and Puneet Dewan identify programmatic and policy changes needed to end TB by 2035. PMID- 25803481 TI - Climate drivers on malaria transmission in Arunachal Pradesh, India. AB - The present study was conducted during the years 2006 to 2012 and provides information on prevalence of malaria and its regulation with effect to various climatic factors in East Siang district of Arunachal Pradesh, India. Correlation analysis, Principal Component Analysis and Hotelling's T2 statistics models are adopted to understand the effect of weather variables on malaria transmission. The epidemiological study shows that the prevalence of malaria is mostly caused by the parasite Plasmodium vivax followed by Plasmodium falciparum. It is noted that, the intensity of malaria cases declined gradually from the year 2006 to 2012. The transmission of malaria observed was more during the rainy season, as compared to summer and winter seasons. Further, the data analysis study with Principal Component Analysis and Hotelling's T2 statistic has revealed that the climatic variables such as temperature and rainfall are the most influencing factors for the high rate of malaria transmission in East Siang district of Arunachal Pradesh. PMID- 25803484 TI - Anaerobic degradation of dairy wastewater in intermittent UASB reactors: influence of effluent recirculation. AB - This work studied the influence of effluent recirculation upon the kinetics of anaerobic degradation of dairy wastewater in the feedless phase of intermittent upflow anaerobic sludge bed (UASB) reactors. Several laboratory-scale tests were performed with different organic loads in closed circuit UASB reactors inoculated with adapted flocculent sludge. The data obtained were used for determination of specific substrate removal rates and specific methane production rates, and adjusted to kinetic models. A high initial substrate removal was observed in all tests due to adsorption of organic matter onto the anaerobic biomass which was not accompanied by biological substrate degradation as measured by methane production. Initial methane production rate was about 45% of initial soluble and colloidal substrate removal rate. This discrepancy between methane production rate and substrate removal rate was observed mainly on the first day of all experiments and was attenuated on the second day, suggesting that the feedless period of intermittent UASB reactors treating dairy wastewater should be longer than one day. Effluent recirculation expressively raised the rate of removal of soluble and colloidal substrate and methane productivity, as compared with results for similar assays in batch reactors without recirculation. The observed bed expansion was due to the biogas production and the application of effluent recirculation led to a sludge bed contraction after all the substrates were degraded. The settleability of the anaerobic sludge improved by the introduction of effluent recirculation this effect being more pronounced for the higher loads. PMID- 25803485 TI - Correction: Musosal effects for tenofovir 1% gel. PMID- 25803488 TI - Iridium-catalyzed selective hydrogenation of 3-hydroxypyridinium salts: a facile synthesis of piperidin-3-ones. AB - The selective hydrogenation of 3-hydroxypyridinium salts has been achieved using a homogeneous iridium catalyst, providing a direct access to 2- and 4-substituted piperidin-3-one derivatives with high yields, which are important organic synthetic intermediates and the prevalent structural motifs in pharmaceutical agents. Mild reaction conditions, high chemoselectivity, and easy scalability make this reaction highly practical for the synthesis of piperidin-3-ones. PMID- 25803486 TI - Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells. AB - Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive MITF interactome identifying novel cofactors involved in transcription, DNA replication and repair, and chromatin organisation. We show that MITF interacts with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF associated regulatory elements (MAREs) at active enhancers. Combinations of MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus defining both a signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of the regulatory elements they occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1 interplay thus plays an essential role in transcription regulation in melanoma. PMID- 25803489 TI - Ebolavirus classification based on natural vectors. AB - According to the WHO, ebolaviruses have resulted in 8818 human deaths in West Africa as of January 2015. To better understand the evolutionary relationship of the ebolaviruses and infer virulence from the relationship, we applied the alignment-free natural vector method to classify the newest ebolaviruses. The dataset includes three new Guinea viruses as well as 99 viruses from Sierra Leone. For the viruses of the family of Filoviridae, both genus label classification and species label classification achieve an accuracy rate of 100%. We represented the relationships among Filoviridae viruses by Unweighted Pair Group Method with Arithmetic Mean (UPGMA) phylogenetic trees and found that the filoviruses can be separated well by three genera. We performed the phylogenetic analysis on the relationship among different species of Ebolavirus by their coding-complete genomes and seven viral protein genes (glycoprotein [GP], nucleoprotein [NP], VP24, VP30, VP35, VP40, and RNA polymerase [L]). The topology of the phylogenetic tree by the viral protein VP24 shows consistency with the variations of virulence of ebolaviruses. The result suggests that VP24 be a pharmaceutical target for treating or preventing ebolaviruses. PMID- 25803487 TI - In vitro generation of human pluripotent stem cell derived lung organoids. AB - Recent breakthroughs in 3-dimensional (3D) organoid cultures for many organ systems have led to new physiologically complex in vitro models to study human development and disease. Here, we report the step-wise differentiation of human pluripotent stem cells (hPSCs) (embryonic and induced) into lung organoids. By manipulating developmental signaling pathways hPSCs generate ventral-anterior foregut spheroids, which are then expanded into human lung organoids (HLOs). HLOs consist of epithelial and mesenchymal compartments of the lung, organized with structural features similar to the native lung. HLOs possess upper airway-like epithelium with basal cells and immature ciliated cells surrounded by smooth muscle and myofibroblasts as well as an alveolar-like domain with appropriate cell types. Using RNA-sequencing, we show that HLOs are remarkably similar to human fetal lung based on global transcriptional profiles, suggesting that HLOs are an excellent model to study human lung development, maturation and disease. PMID- 25803490 TI - Patient perspectives and preferences for communication of medical imaging risks in a cancer care setting. AB - PURPOSE: To identify opportunities for improving patient-centered communication about diagnostic imaging tests that involve the use of radiation in a cancer care setting. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Patient knowledge, information sources, and communication preferences were assessed in six focus groups during 2012. The groups consisted of patients undergoing treatment for metastatic colorectal carcinoma, women treated within the past 6 months for early stage breast carcinoma, men undergoing surveillance after testicular cancer treatment, parents of patients treated for stage I-III neuroblastoma, patients in a thoracic oncology survivorship program, and participants in a lung cancer screening program. A multidisciplinary research team performed thematic content analysis of focus group transcripts. High-level findings were summarized during consensus conferences. RESULTS: Although they were aware of the long-term risk of cancer from exposure to ionizing radiation, most participants reported that their health care provider did not initiate discussion about benefits and risks of radiation from imaging tests. Most patients obtained information by means of self directed internet searches. Participants expressed gratitude for tests ("That CT saved my daughter's life," "I'd rather have the radiation dosage than being opened up"), yet they expressed concern about having to initiate discussions ("If you don't ask, nobody is going to tell you anything") and the desire to be offered information concerning the rationale for ordering specific imaging examinations, intervals for follow-up imaging, and testing alternatives. Participants believed that such information should be available routinely and that conversation with their personal physician or endorsed, readily available reference materials were ideal methods for information exchange. Understanding imaging radiation risks and active participation in decision making about imaging were especially important to cancer survivors. CONCLUSION: A substantial gap exists between patient expectations and current practices for providing information about medical imaging tests that involve the use of radiation. PMID- 25803492 TI - In vitro reconstitution of co-translational D1 insertion reveals a role of the cpSec-Alb3 translocase and Vipp1 in photosystem II biogenesis. AB - Photosystem II (PS II) is a multi-subunit complex localized in the thylakoid membrane that performs the light-dependent photosynthetic charge separation. The PS II reaction centre comprises, among others, the D1 protein. De novo synthesis and repair of PS II require efficient mechanisms for transport and insertion of plastid encoded D1 into the thylakoid membrane. To elucidate the process of D1 insertion, we used an in vitro translation system derived from pea chloroplasts to reconstitute the D1 insertion. Thereby, truncated D1 encoding psbA mRNAs lacking a stop codon were translated in the presence of thylakoid membranes and the translation was stalled by addition of chloramphenicol. The generated ribosome nascent chain complexes (RNCs) were tightly associated with the thylakoids. Subsequently, these D1 insertion intermediates were enriched from solubilized thylakoids by sucrose cushion centrifugation. Immunological analyses demonstrated the presence of the cpSec translocase, Alb3, cpFtsY, cpSRP54 and Vipp1 (vesicle-inducing protein in plastids 1) in the enriched D1 insertion intermediates. A complex formation between cpSecY, Alb3, cpFtsY and Vipp1 in thylakoid membranes was shown by gel filtration chromatography, BN (Blue Native)/SDS-PAGE and co-immunoprecipitation experiments. Furthermore, a stimulating effect of recombinant Vipp1 on the formation of a D1 insertion intermediate was observed in vitro. These results suggest a co-operative function of these proteins in D1 insertion. PMID- 25803494 TI - Selected papers from ICPLA 2014. Editorial. PMID- 25803493 TI - Assessing the effects of data selection and representation on the development of reliable E. coli sigma 70 promoter region predictors. AB - As the number of sequenced bacterial genomes increases, the need for rapid and reliable tools for the annotation of functional elements (e.g., transcriptional regulatory elements) becomes more desirable. Promoters are the key regulatory elements, which recruit the transcriptional machinery through binding to a variety of regulatory proteins (known as sigma factors). The identification of the promoter regions is very challenging because these regions do not adhere to specific sequence patterns or motifs and are difficult to determine experimentally. Machine learning represents a promising and cost-effective approach for computational identification of prokaryotic promoter regions. However, the quality of the predictors depends on several factors including: i) training data; ii) data representation; iii) classification algorithms; iv) evaluation procedures. In this work, we create several variants of E. coli promoter data sets and utilize them to experimentally examine the effect of these factors on the predictive performance of E. coli sigma70 promoter models. Our results suggest that under some combinations of the first three criteria, a prediction model might perform very well on cross-validation experiments while its performance on independent test data is drastically very poor. This emphasizes the importance of evaluating promoter region predictors using independent test data, which corrects for the over-optimistic performance that might be estimated using the cross-validation procedure. Our analysis of the tested models shows that good prediction models often perform well despite how the non-promoter data was obtained. On the other hand, poor prediction models seems to be more sensitive to the choice of non-promoter sequences. Interestingly, the best performing sequence-based classifiers outperform the best performing structure-based classifiers on both cross-validation and independent test performance evaluation experiments. Finally, we propose a meta-predictor method combining two top performing sequence-based and structure-based classifiers and compare its performance with some of the state-of-the-art E. coli sigma70 promoter prediction methods. PMID- 25803495 TI - Stability of Growth Factors in Autologous Serum Eyedrops After Long-Term Storage. AB - PURPOSE: The purpose of this study is to assess the stability of the growth factors (GF) in autologous serum eyedrops under different storage conditions. METHODS: The concentration of epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta1), platelet-derived growth factor AB (PDGF-AB), and albumin was measured in fresh and defrosted samples of autologous serum under different storage conditions. The fresh and defrosted samples were cooled at 4 degrees C, and they were studied immediately after preparation, or after defrosting, and after 1, 2, 3, and 4 weeks. The concentration of GF was also assessed after 1, 3, 6, and 9 months at -20 degrees C. We also investigated how the different storage conditions influence the biological effects of autologous serum on conjunctival and corneal cell cultures. RESULTS: The concentration of EGF, TGF-beta1, PDGF-AB, and albumin remained stable over the 4 weeks at 4 degrees C, both in fresh and in defrosted samples. Likewise, no statistically significant differences were found between the GF concentration in fresh samples and after 1, 3, 6, and 9 months of freezing at -20 degrees C. Moreover, no differences were found on the cell proliferation and differentiation between cultured cells with fresh or defrosted samples after 4 weeks at 4 degrees C or after 1, 3, 6, or 9 months at 20 degrees C. CONCLUSIONS: Long-term storage of autologous serum eyedrops at -20 degrees C does not affect the concentration of GF, simplifies clinical logistics, and reduces the frequency of blood extractions from the patients. PMID- 25803496 TI - Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution. AB - Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy. PMID- 25803498 TI - A Banff Component Scoring-based Histologic Assessment of Bortezomib-based Antibody-mediated Rejection Therapy. AB - BACKGROUND: Histology remains a cornerstone for antibody-mediated rejection (AMR) diagnosis. Little data exist supporting histology for assessing therapeutic responses. This study evaluates histologic components in assessing AMR therapeutic responses. METHODS: Antibody-mediated rejection was diagnosed using Antibody Working Group criteria and Banff component scoring, and C4d staining data were analyzed. Statistics included independent and paired samples t test, chi(2), Fisher exact, or the Wilcoxon-signed rank test. Fifty-five AMR patients were analyzed. Early AMR was defined as occurring within 6 months after transplantation and treated with a single rituximab dose and 4 bortezomib doses preceded by plasmapheresis. Allograft biopsies were performed within 48 hours of treatment; repeat biopsy was performed 14 to 21 days later. RESULTS: Early AMR demonstrated histologic improvement in mean scores for acute Banff components glomerulitis (g), C4d, g+ peritubular capillaritis (ptc) and acute composite score, but showed deterioration in chronic Banff components tubular atrophy and interstitial fibrosis. Late AMR showed improved mean scores for acute Banff components tubulitis, interstitial inflammation, g, ptc, g + ptc, C4d, and acute composite score, but chronic scores did not change. Significant changes in distribution of Banff scores after treatment were observed for g, C4d, tubular atrophy, and interstitial fibrosis scores in early AMR patients and tubulitis, interstitial inflammation, g, ptc, and C4d in late AMR. CONCLUSIONS: These results show that: (1) Banff component scoring provides insights into histologic responses to AMR therapy and may provide a potential endpoint for clinical AMR trials. (2) Early and late AMR demonstrate differences in acute and chronic Banff components at the time of the AMR diagnostic biopsy, as well as differential responses to AMR therapy. PMID- 25803499 TI - Synergistic Effect of Neutral Protease and Clostripain on Rat Pancreatic Islet Isolation. AB - BACKGROUND: Islet isolation currently requires collagenase, neutral protease and other components. Thermolysin (TL) from Bacillus thermoproteolyticus is the gold standard neutral protease. However, we speculated that neutral protease derived from Clostridium histolyticum (Ch; ChNP) would be biologically superior for islet isolation. Tryptic-like activity has also been reported to be important. Therefore, we focused on clostripain (CP), since it is one of the main proteases in Clostridium histolyticum which possesses tryptic-like activity. We then examined the synergistic effects of highly purified ChNP and CP on rat islet isolation. METHODS: The same amount of collagenase was used in all four groups (TL, ChNP, TL+CP and ChNP+CP; n = 12/group). The efficiency was evaluated by the islet yield and function. An immunohistochemical analysis, in vitro digestion assay for each enzyme component and evaluation of the activation of endogenous exocrine proteases during islet isolation were also performed. RESULTS: The islet yield of the TL group was significantly higher than that of the ChNP group (P < 0.01). The islet yield was dose dependently increased in the ChNP+CP group, but was decreased in the TL + CP group. The islet yield in the ChNP + CP group was significantly higher than that in the TL group, but their islet function was similar. Different specificities for laminin, especially laminin-511, were observed in the TL, ChNP, and CP groups. CONCLUSIONS: Clostripain had a strong synergistic effect with ChNP, but not with TL. Therefore, ChNP and CP, in combination with collagenase derived from the same bacteria, may effectively increase the isolation efficiency without affecting the quality of islets. PMID- 25803497 TI - Sex differences in mania phenotype and ethanol consumption in the lateral hypothalamic kindled rat model. AB - Sex differences have been observed in mania phenotypes in humans. However the mechanisms underlying this difference are poorly understood. Activating the lateral hypothalamus is implicated in manic-like behaviors in rodents. Using newly established lateral hypothalamus kindled (LHK) rat mania model, we investigated sex differences of manic-like behaviors and its correlation with voluntary ethanol intake. We stimulated the lateral hypothalamus bilaterally in the male and female Wistar rats over five consecutive days. We recorded and quantified kindling-induced behaviors for each individual animal. We also assessed ethanol consumption using a two-bottle choice ethanol drinking as well as circadian locomotor activity counts daily throughout the experiment. We found notable sex differences in several aspects of manic-like behaviors during kindling. Males exhibited a significantly increased locomotor activity during the light phase, and reduced rest interval. On the other hand, females displayed significantly higher ethanol consumption and more frequent rearing behavior. However, no sex differences were present in the duration of sexual, feeding or grooming behaviors or in dark-phase activity counts. The excessive alcohol intake in LHK female rats is reminiscent of clinically reported sex differences in bipolar patients while the other phenotypic sex differences such as rearing and locomotor activity are less clearly described in clinical studies. Overall, our results lend further evidence for the validity of the LHK rat as a useful model to study brain region-specific molecular changes during mania and its correlation with alcohol use disorders. PMID- 25803502 TI - Complete surface coverage of ZnO nanorod arrays by pulsed electrodeposited CuInS2 for visible light energy conversion. AB - Well-aligned ZnO nanorods were uniformly coated with a layer of CuInS2 nanoparticle photosensitizers using a tailored sequential pulsed electrodeposition. The formation of CuInS2-ZnO heterojunction with well-matched band energy alignment and the superior electron mobility in ZnO nanorods led to a remarkable 3.75 times improved photoelectrochemical performance of the electrode under visible light irradiation. PMID- 25803501 TI - Therapeutic drug levels of second generation antipsychotics in youth: a systematic review. AB - OBJECTIVE: In children and adolescents, the prevalence rate of mental illness is claimed to be as high as 10-20%. Effective pharmacological treatments are available for use in children, adolescents, and adults; however, most of what is known about the effects of these treatments has been confirmed in clinical studies involving adults only. Second generation antipsychotic drugs (SGAs) are the most common class of antipsychotic medication used in pediatric populations, and these drugs are increasingly being used for disorders other than psychosis. Many SGAs are routinely used in pediatric care, and the vast majority of use in this population is off label. Children, adolescents, and adults differ in age, weight, height, and metabolism, which may lead to pharmacokinetic differences in how drugs ultimately affect target tissues. The aim of this review is to summarize and evaluate the literature that investigated blood plasma levels of SGAs in youth. METHODS: Plasma levels were assessed in relation to their administered dose, indication, and therapeutic range (if known). Studies were limited to those evaluating oral administration only. A systematic electronic database search for peer-reviewed articles published between 2000 and 2013 was conducted. Twenty-one articles were included in the review. Additional articles for discussion were also included throughout the article. RESULTS: The only SGA that may require routine therapeutic drug monitoring (TDM) in youth given the current body of research is clozapine. Highly variable results were seen in studies of aripiprazole, olanzapine, and risperidone, indicating that more research is needed on plasma levels with these drugs. Quetiapine maintained a similar profile to that found in adults, with no dosage adjustments or indications of TDM. CONCLUSION: TDM may be indicated in any circumstance in which cytochrome P450 inhibitors or inducers are coprescribed. Further research is required for establishing a sounder safety profile for SGA use in the pediatric population. PMID- 25803500 TI - Repeat Kidney Transplantation After Failed First Transplant in Childhood: Past Performance Informs Future Performance. AB - BACKGROUND AND OBJECTIVES: Kidney transplant graft survival is almost uniformly superior for initial transplants compared to repeat transplants. We investigate the association between first second kidney transplant graft survival in patients who underwent initial transplant during their pediatric years whether age at second transplant is associated with outcome. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a retrospective analysis of Organ Procurement and Transplantation Network data from October 1987 to May 2009 examining second kidney graft survival in 2281 patients who received their first transplant at younger than 18 years using Kaplan-Meier statistics. Factors associated with second graft survival were identified using a multivariable Cox proportional hazards model. RESULTS: Patients with first kidney graft survival of less than 5 years had better second graft survival compared to patients with first graft survival of 30 days to 5 years (P < 0.01). Patients with first kidney graft survival less than 30 days had similar second kidney graft outcomes(P = 0.50) as those with longer than 5 years first kidney graft survival, demonstrating that very early first graft loss is not associated with poor second transplant outcome. Patients 15 to 20 years of age at second transplant have lower second graft survival compared to other age groups; P less than 0.01, regardless of other recipient/donor characteristics and recurrent disease. CONCLUSIONS: Poor second transplant outcomes are identified among patients with previous pediatric kidney transplant with first graft survival longer than 30 days, but shorter than 5 years, and those receiving second transplants at a high-risk age category (15 20 years). These groups may benefit from increased attention both before and after transplantation. PMID- 25803503 TI - Management of intra-abdominal abscesses in children with Crohn's disease: a 12 year, retrospective single-center review. AB - BACKGROUND: Intra-abdominal abscesses (IAA) are complications of Crohn's disease, which often result in hospitalization, surgery, and increased cost. Initial management may include medical therapy, percutaneous drainage (PD), or surgery, although the optimal management of IAA in children is unclear. METHODS: Retrospective review of all pediatric patients with Crohn's disease who developed an IAA from January 1, 2000 to April 30, 2012. Three groups, based on initial IAA treatment modality (medical, PD, and surgery), were compared. RESULTS: Thirty cases of IAA were identified (mean age at IAA diagnosis, 15.4 +/- 2.6 yr, 67% female, median Crohn's disease duration, 2.6 mo). Computed tomography was the most common initial (93%) and follow-up (47%) imaging. The average time to follow up imaging was 8.5 days. For initial management, 18 received medical therapy, 10 PD, and 2 had surgery. The medical therapy group received more computed tomography scans for follow-up imaging than the PD group (12 [67%] versus 2 [20%], P = 0.046). There were no significant differences in abscess characteristics or management of posttreatment course between these 2 groups. Surgical resection occurred in 3 patients (17%) in the medical group and 2 (20%) in the PD group during index hospitalization. No significant differences were identified among treatment groups for readmissions, complications, or abscess recurrence. By 1 year, 12 of the 18 medically managed patients (67%) had surgery, and 6 of the 10 patients (60%) treated with initial PD ultimately had surgery. CONCLUSIONS: The majority of patients with IAA require definitive surgical treatment, and there were no clear predictors of those who did not. PMID- 25803505 TI - Transition readiness skills acquisition in adolescents and young adults with inflammatory bowel disease: findings from integrating assessment into clinical practice. AB - BACKGROUND: Almost 80% of adult gastroenterologists report inadequacies in the preparation of patients transferred from pediatrics. To improve transition to adult care, it is important to identify the specific deficits that patients are demonstrating before transfer. We present data from a clinic-wide assessment of transition readiness skill acquisition in adolescents/young adults with IBD. METHODS: A total of 195 patients (age, 16-25 yr) with IBD completed the Transition Readiness Assessment Questionnaire. Patient age, diagnosis, time since diagnosis, physician global assessment, and patient and parent disease management confidence ratings were extracted from the medical record. Transition Readiness Assessment Questionnaire scores were compared with a benchmark established by an interdisciplinary, multi-institutional Transition Task Force. RESULTS: Only 5.6% of older adolescents/young adults on the verge of transfer to adult care met our institutional benchmark (3.5% of adolescents, 7.3% of young adults). Patients reported mastery of 9.10 +/- 4.68 out of 20 Transition Readiness Assessment Questionnaire items. Transition readiness was associated with older age (r = 0.27, P < 0.001) and female gender (F(1,192) = 13.81, P < 0.001) but not time since diagnosis, physician global assessment, or confidence ratings. Deficits in health care utilization/self-advocacy (e.g., understanding insurance, scheduling appointments/following up on referrals), and self-management (e.g., filling/reordering prescriptions) were observed. CONCLUSIONS: Most patients on the verge of transferring to adult care are not demonstrating transition readiness. Deficits observed represent modifiable behaviors. Using data-driven assessments to guide interventions to enhance transition readiness may minimize the retention of young adult patients in pediatrics and result in patients who are better prepared for adult care. PMID- 25803504 TI - Efficacy and safety of adalimumab 80 mg weekly in luminal Crohn's disease. AB - BACKGROUND: In case of a loss of response to adalimumab, some patients with Crohn's disease may derive benefit from increasing the dosing frequency to 40 mg weekly. Efficacy and safety of adalimumab 80 mg weekly remain unknown. METHODS: From February 2011 to September 2012, all adults who had active Crohn's disease, defined at least by Crohn's disease activity index >150 and 1 objective sign of inflammation, and required an adalimumab dose escalation to 80 mg weekly were enrolled in a prospective multicenter cohort study. Crohn's disease activity index and C-reactive protein levels were recorded during the first 14 weeks following adalimumab optimization and at 6 months. All adverse events were recorded. RESULTS: Forty-two patients were included. The median age was 33 years, and the median disease duration was 8.6 years. Adalimumab was associated with steroids in 28% of cases and with immunomodulators in 10% of patients. Within the 14 weeks after adalimumab optimization, 14 patients (33.3%) achieved clinical remission (Crohn's disease activity index <150), and 23 patients (54.8%) had a clinical response. Clinical improvement was associated with a drop in the C reactive protein level from 18 to 5 mg/L (P = 0.0008). After a median follow-up of 14.5 months, 5 patients underwent major abdominal surgery. Adverse events were reported in 13 patients (31%). CONCLUSIONS: Adalimumab 80 mg weekly seems to be well-tolerated and may be effective in inducing clinical remission in patients with luminal Crohn's disease who failed to respond to 40 mg weekly or 80 mg every other week. PMID- 25803506 TI - Alpha-1 antitrypsin and granulocyte colony-stimulating factor as serum biomarkers of disease severity in ulcerative colitis. AB - BACKGROUND: Initial assessment of patients with ulcerative colitis (UC) is challenging and relies on apparent clinical symptoms and measurements of surrogate markers (e.g., C-reactive protein [CRP] or similar acute phase proteins). As CRP only reliably identifies patients with severe disease, novel biomarkers are currently needed for identification of patients with mild or moderate disease activity. Using a commercially available platform, we aimed at identifying serum biomarkers that are able to grade the disease severity. METHODS: Serum samples from 65 patients with UC with varying disease activity (Mayo score) and from 40 healthy controls were analyzed by multiplex enzyme linked immunosorbent assay for 78 potential disease biomarkers. Using the statistical software SIMCA-P+ and GraphPad Prism, multivariate statistical analyses were conducted to identify a limited number of biomarkers to assess disease severity. RESULTS: Alpha-1 antitrypsin (AAT) differentiated between mild and moderate UC (area under the curve [AUC] = 0.79) with a sensitivity of 0.90 and a specificity of 0.70, thereby exceeding the predictive ability of CRP (AUC = 0.52). Combining alpha-1 antitrypsin and granulocyte colony-stimulating factor produced a predictive model with an AUC of 0.72 when differentiating mild and moderate UC, and an AUC of 0.96 when differentiating moderate and severe UC, the latter being as reliable as CRP. CONCLUSIONS: Alpha-1 antitrypsin is identified as a potential serum biomarker of mild-to-moderate disease activity in UC. With the ability to differentiate between mild, moderate, and severe stages of UC using a simple serum biomarker that is already commercially available, clinicians can initiate individualized treatment regimens at an earlier stage before endoscopic examinations are available. PMID- 25803508 TI - Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model. AB - BACKGROUND: IL-23/T(H)17 inflammatory responses are regarded as central to the pathogenesis of inflammatory bowel disease, but clinically IL-17A antibodies have shown low efficacy and increased infections in Crohn's disease. Hence, we decided to closely examine the role of the IL-23/T(H)17 axis in 3 models of colitis. METHODS: IL-17A(-/-) and IL-17Ra(-/-) T cells were transferred into Rag1 and RaW mice to assess the role of IL-17A-IL-17Ra signaling in T cells during colitis. In Winnie mice with spontaneous colitis due to an epithelial defect, we studied the progression of colitis in the absence of IL-17A and the efficacy of neutralizing antibodies against the IL-17A or IL-23p19 cytokines. RESULTS: In transfer colitis models, IL-17A-deficient T cells failed to ameliorate disease, and IL-17Ra deficient T cells were more colitogenic than wild-type T cells. In Winnie mice with an epithelial defect and spontaneous T(H)17-dominated inflammation, genetic deficiency of IL-17A did not suppress initiation of colitis but limited colitis progression. Furthermore, inhibition of IL-17A by monoclonal antibodies did not reduce colitis severity. In contrast, neutralizing IL-23 using an anti-p19 antibody significantly alleviated both emerging and established colitis, downregulating T(H)17 proinflammatory cytokine expression and diminishing neutrophil infiltration. CONCLUSIONS: Our results support clinical studies showing that IL-17 neutralization is not therapeutic but that targeting IL-23 suppresses intestinal inflammation. Effects of IL-23 distinct from its effects on maturation of IL-17A-producing lymphocytes may underlie the protection from inflammatory bowel disease conveyed by hypomorphic IL-23 receptor polymorphisms and contribute to the efficacy of IL-23 neutralizing antibodies in inflammatory bowel disease. PMID- 25803507 TI - Pulse Wave Velocity, Intima Media Thickness, and Flow-mediated Dilatation in Patients with Normotensive Normoglycemic Inflammatory Bowel Disease. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) have increased risk for atherosclerosis. The cause of increased cardiovascular risk is not fully understood. Chronic inflammatory process may predispose to atherosclerosis. We aimed primarily to investigate subclinical atherosclerosis in patients with IBD, by measuring carotid femoral pulse wave velocity (PWV), carotid intima media thickness, and flow-mediated dilatation compared with matched normal controls. METHODS: Patients with IBD were recruited among individuals proven to have Crohn's disease (CD) and ulcerative colitis (UC). To exclude any interference of confounding factors for endothelial dysfunction or atherosclerosis, we studied a specifically selected group with no additional cardiovascular risk. PWV, carotid intima media thickness, and flow-mediated dilatation levels were measured in all patients and controls. RESULTS: The carotid femoral PWV levels were 8.13 +/- 1.61 m/sec in the patients with UC, 8.16 +/- 1.74 m/sec in the patients with CD, and 6.85 +/- 0.95 m/sec in the healthy subjects. The levels of carotid femoral PWV were significantly higher in patients with CD and UC than control group (P < 0.001). Flow-mediated dilatation levels were significantly decreased in patients with UC and CD (9.6% +/- 5.1% versus 108% +/- 4.4%) when compared with control subjects (15.1% +/- 9.7%) (P = 0.004). No significant difference in carotid intima media thickness was detected between UC, CD, and control groups (P = 0.152). CONCLUSIONS: This study suggests that patients with IBD without traditional cardiovascular risk factors have increased risk of endothelial dysfunction and atherosclerosis. PMID- 25803511 TI - Motionless electromagnetic phase stepping versus mechanical phase stepping in x ray phase-contrast imaging with a compact source. AB - X-ray phase contrast imaging based on grating interferometers detects the refractive index distribution of an object without relying on radiation attenuation, thereby having the potential for reduced radiation absorption. These techniques belong to the broader category of optical wavefront measurement, which requires stepping the phase of the interference pattern to obtain a pixel-wise map of the phase distortion of the wavefront. While phase stepping traditionally involves mechanical scanning of a grating or mirror, we developed electromagnetic phase stepping (EPS) for imaging with compact sources to obviate the need for mechanical movement. In EPS a solenoid coil is placed outside the x-ray tube to shift its focal spot with a magnetic field, causing a relative movement between the projection of the sample and the interference pattern in the image. Here we present two embodiments of this method. We verified experimentally that electromagnetic and mechanical phase stepping give the same results and attain the same signal-to-noise ratios under the same radiation dose. We found that the relative changes of interference fringe visibility were within 3.0% when the x ray focal spot was shifted by up to 1.0 mm in either direction. We conclude that when using x-ray tube sources, EPS is an effective means of phase stepping without the need for mechanical movement. PMID- 25803510 TI - Circulating 20S proteasome is independently associated with abdominal muscle mass in hemodialysis patients. AB - Protein-energy wasting is highly prevalent in hemodialysis patients, and it contributes to patient morbidity and mortality. The ubiquitin-proteasome system is the major pathway for intracellular protein degradation and it is involved in the regulation of basic cellular processes. However, the role of this system in the determination of nutritional status is largely unknown. To examine a relationship between protein-energy wasting and the ubiquitin-proteasome system, a cross-sectional study of 76 hemodialysis patients was performed. Plasma concentrations of 20S proteasome were studied to evaluate its association with muscle and fat mass, which were investigated by abdominal muscle and fat areas measured using computed tomography and by creatinine production estimated using the creatinine kinetic model. Plasma 20S proteasome concentrations significantly and negatively correlated with abdominal muscle areas and creatinine production (rho = -0.263, P < 0.05 and rho = -0.241, P < 0.05, respectively), but not abdominal subcutaneous and visceral fat areas. Multiple regression analyses showed that 20S proteasome was a significant independent predictor of abdominal muscle area (P < 0.05). In conclusion, plasma 20S proteasome concentrations were independently associated with abdominal muscle mass in hemodialysis patients. Our findings indicate a relationship between circulating 20S proteasomes and muscle metabolism in these patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000012341. PMID- 25803509 TI - Lambda red mediated gap repair utilizes a novel replicative intermediate in Escherichia coli. AB - The lambda phage Red recombination system can mediate efficient homologous recombination in Escherichia coli, which is the basis of the DNA engineering technique termed recombineering. Red mediated insertion of DNA requires DNA replication, involves a single-stranded DNA intermediate and is more efficient on the lagging strand of the replication fork. Lagging strand recombination has also been postulated to explain the Red mediated repair of gapped plasmids by an Okazaki fragment gap filling model. Here, we demonstrate that gap repair involves a different strand independent mechanism. Gap repair assays examining the strand asymmetry of recombination did not show a lagging strand bias. Directly testing an ssDNA plasmid showed lagging strand recombination is possible but dsDNA plasmids did not employ this mechanism. Insertional recombination combined with gap repair also did not demonstrate preferential lagging strand bias, supporting a different gap repair mechanism. The predominant recombination route involved concerted insertion and subcloning though other routes also operated at lower frequencies. Simultaneous insertion of DNA resulted in modification of both strands and was unaffected by mutations to DNA polymerase I, responsible for Okazaki fragment maturation. The lower efficiency of an alternate Red mediated ends-in recombination pathway and the apparent lack of a Holliday junction intermediate suggested that gap repair does not involve a different Red recombination pathway. Our results may be explained by a novel replicative intermediate in gap repair that does not involve a replication fork. We exploited these observations by developing a new recombineering application based on concerted insertion and gap repair, termed SPI (subcloning plus insertion). SPI selected against empty vector background and selected for correct gap repair recombinants. We used SPI to simultaneously insert up to four different gene cassettes in a single recombineering reaction. Consequently, our findings have important implications for the understanding of E. coli replication and Red recombination. PMID- 25803512 TI - Web-based telemonitoring and delivery of caregiver support for patients with Parkinson disease after deep brain stimulation: protocol. AB - BACKGROUND: The increasing number of patients, the high costs of management, and the chronic progress of the disease that prevents patients from performing even simple daily activities make Parkinson disease (PD) a complex pathology with a high impact on society. In particular, patients implanted with deep brain stimulation (DBS) electrodes face a highly fragile stabilization period, requiring specific support at home. However, DBS patients are followed usually by untrained personnel (caregivers or family), without specific care pathways and supporting systems. OBJECTIVE: This projects aims to (1) create a reference consensus guideline and a shared requirements set for the homecare and monitoring of DBS patients, (2) define a set of biomarkers that provides alarms to caregivers for continuous home monitoring, and (3) implement an information system architecture allowing communication between health care professionals and caregivers and improving the quality of care for DBS patients. METHODS: The definitions of the consensus care pathway and of caregiver needs will be obtained by analyzing the current practices for patient follow-up through focus groups and structured interviews involving health care professionals, patients, and caregivers. The results of this analysis will be represented in a formal graphical model of the process of DBS patient care at home. To define the neurophysiological biomarkers to be used to raise alarms during the monitoring process, neurosignals will be acquired from DBS electrodes through a new experimental system that records while DBS is turned ON and transmits signals by radiofrequency. Motor, cognitive, and behavioral protocols will be used to study possible feedback/alarms to be provided by the system. Finally, a set of mobile apps to support the caregiver at home in managing and monitoring the patient will be developed and tested in the community of caregivers that participated in the focus groups. The set of developed apps will be connected to the already existing WebBioBank Web-based platform allowing health care professionals to manage patient electronic health records and neurophysiological signals. New modules in the WebBioBank platform will be implemented to allow integration and data exchange with mobile health apps. RESULTS: The results of this project will provide a novel approach to long-term evaluation of patients with chronic, severe conditions in the homecare environment, based on caregiver empowerment and tailored applications developed according to consensus care pathways established by clinicians. CONCLUSIONS: The creation of a direct communication channel between health care professionals and caregivers can benefit large communities of patients and would represent a scalable experience in integrating data and information coming from a clinical setting to those in home monitoring. PMID- 25803514 TI - Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. AB - Metabolic acidosis has been implicated in the development of coagulopathy, although the specific mechanisms have not been well characterized. We sought to explore whether resuscitation of injured patients with a balanced crystalloid solution affects coagulation, as measured by endogenous thrombin potential (ETP) and thromboelastography (TEG). We performed an exploratory analysis of a subset of subjects enrolled in a randomized trial comparing the effect of resuscitation with isotonic saline versus Plasma-Lyte A (PLA) on acidosis and electrolyte abnormalities. We collected plasma at admission and 6 h later for subsequent ETP and TEG analysis and compared subjects receiving isotonic saline to those receiving PLA. Among 18 evaluated subjects, baseline characteristics, including ETP and TEG parameters, were similar between the two arms. At 6 h, subjects receiving isotonic saline were more acidemic. At 6 h, there were no differences in ETP parameters between groups; however, TEG results showed the time from initial clot formation to an amplitude of 20 mm (K) was shorter (3.8 +/- 2.1 vs. 7.2 +/- 2.8 s) and the rapidity of fibrin build-up and cross-linking (alpha angle) was significantly greater (41 +/- 8 vs. 24 +/- 15 deg) for the PLA group than in the isotonic saline group. Relative to PLA, isotonic saline does not alter thrombin generation, but isotonic saline and PLA may differentially impact clotting factor availability. The shorter time to reach prespecified clot amplitude and the increased rate of fibrin generation imply faster amplification of clotting factors with PLA without effect on latency time or clot strength. PMID- 25803515 TI - Antithrombotic therapy in a patient with mild haemophilia A and atrial fibrillation: case report and brief review of the literature. AB - The remarkable advances made in recent decades in the treatment of haemophilia have resulted in a longer life expectancy for haemophilia patients. The care of diseases related to ageing in these patients is becoming of great interest. We briefly discuss the current possibilities for antithrombotic therapy in patients with haemophilia describing the case of a 67-year-old patient with mild haemophilia A and atrial fibrillation requiring antithrombotic therapy. PMID- 25803516 TI - Prenatal diagnosis in a family with purfura fulminans. PMID- 25803517 TI - Plasminogen activator inhibitor type 1 deficiency revealed by severe bleeding after prostatectomy in a 76-year-old male. PMID- 25803518 TI - Achilles' heel of Aristotle. PMID- 25803520 TI - Shear wave elastography plaque characterization with mechanical testing validation: a phantom study. AB - Determining plaque vulnerability is critical when selecting the most suitable treatment for patients with atherosclerotic plaque. Currently, clinical non invasive ultrasound-based methods for plaque characterization are limited to visual assessment of plaque morphology and new quantitative methods are needed. In this study, shear wave elastography (SWE) was used to characterize hard and soft plaque mimicking inclusions in six common carotid artery phantoms by using phase velocity analysis in static and dynamic environments. The results were validated with mechanical tensile testing. In the static environment, SWE measured a mean shear modulus of 5.8 +/- 0.3 kPa and 106.2 +/- 17.2 kPa versus 3.3 +/- 0.5 Pa and 98.3 +/- 3.4 kPa measured by mechanical testing in the soft and hard plaques respectively. Furthermore, it was possible to measure the plaques' shear moduli throughout a simulated cardiac cycle. The results show good agreement between SWE and mechanical testing and indicate the possibility for in vivo arterial plaque characterization using SWE. PMID- 25803519 TI - Factor X deficiency associated with compound heterozygosity involving a novel missense mutation at codon 38 from Val (GTC) to Leu (CTC) in exon 2. PMID- 25803521 TI - Assessment of Accelerometers for Measuring Upper-Extremity Physical Activity. AB - OBJECTIVE: The overarching goal of this study was to examine the use of triaxial accelerometers in measuring upper-extremity motions to monitor upper-extremity exercise compliance. There were multiple questions investigated, but the primary objective was to investigate the correlation between visually observed arm motions and triaxial accelerometer activity counts to establish fundamental activity counts for the upper extremity. STUDY DESIGN: Cross-sectional, basic research. SETTING: Clinical laboratory. PARTICIPANTS: Thirty healthy individuals age 26 +/- 6 y, body mass 24 +/- 3 kg, and height 1.68 +/- 0.09 m volunteered. INTERVENTION: Participants performed 3 series of tasks: activities of daily living (ADLs), rehabilitation exercises, and passive shoulder range of motion at 5 specific velocities on an isokinetic dynamometer while wearing an accelerometer on each wrist. Participants performed exercises with their dominant arm to examine differences between sides. A researcher visually counted all arm motions to correlate counts with physical activity counts provided by the accelerometer. MAIN OUTCOME MEASURE: Physical activity counts derived from the accelerometer and visually observed activity counts recorded from a single investigator. RESULTS: There was a strong positive correlation (r = .93, P < .01) between accelerometer physical activity counts and visual activity counts for all ADLs. Accelerometers activity counts demonstrated side-to-side difference for all ADLs (P < .001) and 5 of the 7 rehabilitation activities (P < .003). All velocities tested on the isokinetic dynamometer were shown to be significantly different from each other (P < .001). CONCLUSION: There is a linear relationship between arm motions counted visually and the physical activity counts generated by an accelerometer, indicating that arm motions could be potentially accounted for if monitoring arm usage. The accelerometers can detect differences in relatively slow arm-movement velocities, which is critical if attempting to evaluate exercise compliance during early phases of shoulder rehabilitation. These results provide fundamental information that indicates that triaxial accelerometers have the potential to objectively monitor and measure arm activities during rehabilitation and ADLs. PMID- 25803522 TI - Hepatosplenic cat scratch disease in immunocompetent adults: report of 3 cases and review of the literature. AB - [In the article "Hepatosplenic Cat Scratch Disease in Immunocompetent Adults: Report of 3 Cases and Review of the Literature", the author name Asuncion Lopez, MD was left out of the list of author names. The correct list of author names is given below.]. PMID- 25803523 TI - [A recently acknowledged state with great variation in severity. NMDAR encephalitis frequently misinterpreted as psychiatric illness]. AB - Since first described less than ten years ago, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is now recognized as one of the most common causes of autoimmune encephalitis. The disorder is more common in women (80%), where it is frequently associated with an underlying ovarian teratoma. Most patients with anti-NMDAR encephalitis develop a multi-stage illness that progresses from initially psychiatric symptoms to subsequent mnemonic disturbances, seizures, dyskinesias, catatonia and even coma. Since the neurological and psychiatric symptoms can be highly variable upon presentation, the disease is probably under diagnosed. Outcome is likely to be improved with prompt diagnosis and early treatment. Here we describe a hospital-based case series of six patients that illustrate the wide clinical spectrum of the condition. The series also includes one severely ill patient with treatment-refractory disease who was hospitalized with invasive ventilation for seven months, and eventually responded to a combination of rituximab, cyclophosphamide and bortezomib. PMID- 25803524 TI - [Percutaneous coronary intervention can be done on an outpatient basis. Patient Safe method for early discharge--if the criteria are met]. AB - Due to technical and medical advances, the complication rate associated with elective percutaneous coronary intervention (PCI) has decreased considerably during the past decades. Accordingly, patients might be scheduled for same-day discharge without exposing them to an increased risk. We conducted a retrospective single-center study to test such an approach. Overall, we noted no difference in the 30-day complication rate in a total of 128 angina patients undergoing elective PCI before and after implementation of a same-day discharge policy. The only variable associated with an increased complication rate was PCI of >2 coronary segments. These patients as well as those with PCI of left main or bifurcational stenoses, femoral access and reduced well-being are recommended to stay at the hospital according to routines at our institution. In summary, our data indicate that same-day discharge after elective PCI is safe provided that suitable patients are identified by appropriate criteria. PMID- 25803525 TI - [Who am I? Today's Swedish doctors in search of an identity]. PMID- 25803527 TI - [EDS, a "fashionable diagnosis" that deserves attention]. PMID- 25803528 TI - [Speaking! Physician shortage in primary care--Higher salary to general practitioners, where needed]. PMID- 25803529 TI - [New Swedish standard gives values for blood pressure in children--better opportunities to detect and treat children with hypertension]. AB - High blood pressure in children predicts hypertension in adulthood. Blood pressure should therefore be measured during childhood and adolescence, and if necessary treated at an early stage. The first Swedish standard for blood pressures in 6 to 16-year-old boys and girls is now available and recommended for screening or follow-up programs. PMID- 25803530 TI - [Put a "brake" on the diagnoses in psychiatry]. PMID- 25803531 TI - [Negative trend can be reversed in the metropolitan areas of this initiative]. PMID- 25803532 TI - [Ingemar Engstrom, Swedish Society of Medicine: The wallet should not determine access to new and effective drugs]. PMID- 25803533 TI - [A psychiatric hospital for 40 million people--residents]. PMID- 25803534 TI - [SYLF: How do we stop the discrimination?]. PMID- 25803535 TI - [The existence of "Abusive Head Trauma" scientifically determined]. PMID- 25803536 TI - [Beta lactam antibiotics and the question of dose regimen for severe infection. Prolonged infusion theoretically appealing--yet no evidence of clinical benefit]. AB - Patients with severe sepsis/septic shock have a high mortality. Beta-lactam antibiotics are normally first line treatment. This antimicrobial class has been associated with time-dependent efficacy. It is therefore plausible that administration as prolonged infusion will increase the therapeutic effect, as compared to short term bolus injections, which is the most common practice today. We have reviewed 14 randomized controlled studies to investigate whether prolonged infusion provides lower mortality and/or increased clinical cure. In summary, convincing advantages with prolonged infusion could not be found, however randomized studies are heterogeneous, and it cannot be excluded that some subgroups of critically ill patients could benefit from such treatment. PMID- 25803538 TI - The Effects of Dementia and Long-Term Care Services on the Deterioration of Care needs Levels of the Elderly in Japan: Erratum. AB - [In the article "The Effects of Dementia and Long-Term Care Services on the Deterioration of Care-needs Levels of the Elderly in Japan", which appeared in Volume 94, Issue 7 of Medicine, the acknowledgments section was omitted. It should have read as follows: The authors report no conflicts of interest. H. Lin is a recipient of a scholarship from Otsuka Toshimi Scholarship Foundation (Osaka, Japan). This study was supported by a Health and Labour Sciences Research Grant for Research on Research on Dementia from the Ministry of Health, Labour and Welfare, Japan [H26-Ninchisho-001] and JSPS Grant-in-Aid for Scientific Research (A) (25253033).]. PMID- 25803537 TI - Sputum glucose and glycemic control in cystic fibrosis-related diabetes: a cross sectional study. AB - Cystic fibrosis-related diabetes affects up to half of cystic fibrosis patients and is associated with increased mortality and more frequent pulmonary exacerbations. However, it is unclear to what degree good glycemic control might mitigate these risks and clinical outcomes have not previously been studied in relation to glucose from the lower airways, the site of infection and CF disease progression. We initially hypothesized that diabetic cystic fibrosis patients with glycosylated hemoglobin (HbA(1c)) > 6.5% have worse pulmonary function, longer and more frequent exacerbations and also higher sputum glucose levels than patients with HbA(1c) <= 6.5% or cystic fibrosis patients without diabetes. To test this, we analyzed spontaneously expectorated sputum samples from 88 cystic fibrosis patients. The median sputum glucose concentration was 0.70 mM (mean, 4.75 mM; range, 0-64.6 mM). Sputum glucose was not correlated with age, sex, body mass index, diabetes diagnosis, glycemic control, exacerbation frequency or length, or pulmonary function. Surprisingly, sputum glucose was highest in subjects with normal glucose tolerance, suggesting the dynamics of glycemic control, sputum glucose and pulmonary infections are more complex than previously thought. Two-year mean HbA(1c) was positively correlated with the length of exacerbation admission (p < 0.01), and negatively correlated with measures of pulmonary function (p < 0.01). While total number of hospitalizations for exacerbations were not significantly different, subjects with an HbA(1c) > 6.5% were hospitalized on average 6 days longer than those with HbA(1c) <= 6.5% (p < 0.01). Current clinical care guidelines for cystic fibrosis-related diabetes target HbA(1c) <= 7% to limit long-term microvascular damage, but more stringent glycemic control (HbA(1c) <= 6.5%) may further reduce the short-term pulmonary complications. PMID- 25803539 TI - Visceral adipose tissue area as an independent risk factor for elevated liver enzyme in nonalcoholic Fatty liver disease: erratum. AB - [In the article "Visceral Adipose Tissue Area as an Independent Risk Factor for Elevated Liver Enzyme in Nonalcoholic Fatty Liver Disease", which appeared in Volume 94, Issue 9 of Medicine, Dr. Min Sun Kwak's name was spelled incorrectly in the byline. The article has since been corrected online.]. PMID- 25803540 TI - The high prevalence of hypovitaminosis d in china: a multicenter vitamin d status survey: erratum. AB - [In the article "The High Prevalence of Hypovitaminosis D in China: A Multicenter Vitamin D Status Survey", which appeared in Volume 94, Issue 8 of Medicine, several corrections were required regarding various manufacturer locations. The article has since been corrected online.]. PMID- 25803542 TI - Endometrial injury in women undergoing assisted reproductive techniques. AB - BACKGROUND: Implantation of an embryo within the endometrial cavity is a critical step in assisted reproductive techniques (ART). Previous research has suggested that endometrial injury - intentional damage to the endometrium - can increase the probability of pregnancy in women undergoing ART. OBJECTIVES: To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing ART. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American Caribbean Health Sciences Literature (LILACS) and ClinicalTrials.gov. The original search was performed in November 2011, and further searches were done in March 2014 and January 2015. SELECTION CRITERIA: Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing ART, versus no intervention or a sham procedure. DATA COLLECTION AND ANALYSIS: Two independent review authors screened studies and extracted data which were checked by a third review author. Two review authors independently assessed risk of bias. We contacted and corresponded with study investigators as required and analysed data using risk ratio (RR) and a random-effects model. We assessed the quality of the evidence by using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria. MAIN RESULTS: We included 14 trials that included 1063 women in the intervention groups and 1065 women in the control groups. Thirteen studies compared endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle versus no injury, and one study compared endometrial injury on the day of oocyte retrieval versus no injury. Overall, eight of the 14 included studies were deemed to be at high risk of bias in at least one domain.In studies comparing endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle versus no intervention or a sham procedure, endometrial injury was associated with an increase in live birth or ongoing pregnancy rate: RR 1.42, 95% confidence interval (CI) 1.08 to 1.85; P value 0.01; nine RCTs; 1496 women; I2 = 53%; moderate-quality evidence. In other words, moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with endometrial injury. A sensitivity analysis removing the studies at high risk of bias showed no difference in effect.There was no evidence of an effect on miscarriage, however the evidence is of low-quality: RR 0.99, 95% CI 0.63 to 1.53; P value 0.06; eight RCTs; 500 clinical pregnancies; I2 = 10%; low-quality evidence.Endometrial injury was also associated with an increased clinical pregnancy rate: RR 1.34, 95% CI 1.21 to 1.61; P value 0.002; 13 RCTs; 1972 women; I2 = 45%; moderate-quality evidence. This suggests that if 30% of women achieve clinical pregnancy without endometrial injury, between 33% and 48% will achieve clinical pregnancy with this intervention.Endometrial injury was associated with increased pain, however the evidence was of very low quality. One study reported pain on a VAS scale: MD 4.60, 95% CI 3.98 to 5.22; P value < 0.00001; one RCT; 158 women. Two studies reported the number of pain complaints after the procedure; one recorded no events in either group, and the other reported that endometrial injury increased pain complaints: OR 8.65, 95% CI 2.49 to 30.10; P value 0.0007; one RCT; 101 women.Results from the only randomised controlled trial (RCT) comparing endometrial injury on the day of oocyte retrieval versus no injury, reported that this endometrial injury markedly decreased live birth (RR 0.31, 95% CI 0.14 to 0.69; P value 0.004; 156 women; low-quality evidence) and clinical pregnancy (RR 0.36, 95% CI 0.18 to 0.71; P value 0.003; one RCT; 156 women; low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence indicates that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle is associated with an improvement in live birth and clinical pregnancy rates in women with more than two previous embryo transfers. There is no evidence of an effect on miscarriage, multiple pregnancy or bleeding. The procedure is mildly painful. Endometrial injury on the day of oocyte retrieval is associated with a reduction of clinical and ongoing pregnancy rates.Although current evidence suggests some benefit of endometrial injury, we need evidence from well-designed trials that avoid instrumentation of the uterus in the preceding three months, do not cause endometrial damage in the control group, stratify the results for women with and without recurrent implantation failure (RIF) and report live birth. PMID- 25803544 TI - Interpreting the Australian dietary guideline to "limit" into practical and personalised advice. AB - Food-based dietary guidelines shift the focus from single nutrients to whole diet. Guideline 3 of the Australian Dietary Guidelines (ADG) recommends "limiting" discretionary foods and beverages (DF)-Those high in saturated fat, added sugars, salt, and/or alcohol. In Australia, DF contribute 35% of total energy intake. Using the ADG supporting documents, the aim of this study was to develop a food-based educational toolkit to help translate guideline 3 and interpret portion size. The methodology used to produce the toolkit is presented here. "Additional energy allowance" is specific to gender, age, height and physical activity level, and can be met from core foods, unsaturated fats/oils/spreads and/or DF. To develop the toolkit, additional energy allowance was converted to serves equaling 600 kJ. Common DF were selected and serves were determined based on nutrient profile. Portion sizes were used to calculate number of DF serves. A consumer brochure consisting of DF, portion sizes and equivalent number of DF serves was developed. A healthcare professional guide outlines the methodology used. The toolkit was designed to assist dietitians and consumers to translate guideline 3 of the ADF and develop a personalized approach to include DF as part of the diet. PMID- 25803543 TI - Anaesthetic and sedative agents used for electrical cardioversion. AB - BACKGROUND: Electrical cardioversion is an effective procedure for restoring normal sinus rhythm in the hearts of patients with irregular heart rhythms. It is important that the patient is not fully conscious during the procedure, as it can be painful and distressing. The drug used to make patients unaware of the procedure should rapidly achieve the desired level of sedation, should wear off quickly and should not cause cardiovascular or respiratory side effects. OBJECTIVES: We aimed to compare the safety, effectiveness and adverse events associated with various anaesthetic or sedative agents used in direct current cardioversion for cardiac arrhythmia in both elective and emergency settings.We sought answers to the following specific questions.* Which drugs deliver the best outcomes for patients undergoing electrical cardioversion?* Does using a particular agent confer advantages or disadvantages?* Is additional analgesic necessary to prevent pain? SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) on 27 March 2014. Our search terms were relevant to the review question and were not limited by outcomes. We also carried out searches of clinical trials registers and forward and backward citation tracking. SELECTION CRITERIA: We considered all randomized controlled trials and quasi-randomized and cluster-randomized studies with adult participants undergoing electrical cardioversion procedures in the elective or emergency setting. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data, consulting with a third review author for disagreements. We used standard Cochrane methodological procedures, including assessment of risk of bias for all studies. MAIN RESULTS: We included 23 studies with 1250 participants that compared one drug with one or more other drugs. Of these comparisons, 19 studies compared propofol with another drug. Seven of these compared propofol with etomidate (four of which combined the drugs with remifentanil or fentanyl), five midazolam, six thiopentone and two sevoflurane. Three studies compared etomidate with thiopentone, and three etomidate with midazolam. Two studies compared thiopentone with midazolam, one thiopentone with diazepam and one midazolam with diazepam. Drug doses and the time over which the drugs were given varied between studies. Although all studies were described as randomized, limited information was provided about the methods used for selection and group allocation. A high level of performance bias was observed across studies, as study authors had not attempted to blind the anaesthetist to group allocation. Similarly, study authors had rarely provided sufficient information on whether outcome assessors had been blinded.Included studies presented outcome data for hypotension, apnoea, participant recall, success of cardioversion, minor adverse events of nausea and vomiting, pain at injection site and myoclonus, additional analgesia and participant satisfaction. We did not pool the data from different studies in view of the multiple drug comparisons, differences in definitions and reporting of outcomes, variability of endpoints and high or unclear risk of bias across studies. AUTHORS' CONCLUSIONS: Few studies reported statistically significant results for our relevant outcomes, and most study authors concluded that both, or all, agents compared in individual studies were adequate for cardioversion procedures. It is our opinion that at present, there is no evidence to suggest that current anaesthetic practice for cardioversion should change. PMID- 25803546 TI - Maternal fish oil supplementation in pregnancy: a 12 year follow-up of a randomised controlled trial. AB - A number of trials have been undertaken to assess whether the intake of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) during pregnancy can influence the neurological development of the offspring, yet no consensus from these trials has been reached. We aimed to investigate the long-term effects (12 years) of fish oil supplementation in pregnancy on neurodevelopment, including cognition, language and fine motor skills. In a follow up of a previously published randomised controlled trial of 98 pregnant women, their children were assessed at 12 years of age using a battery of neurodevelopmental assessments. Fifty participants were assessed at 12 years, with 25 participant's mothers receiving fish oil supplementation, and 25 receiving control capsules. There were no significant differences for any of the assessment measures completed. Our data indicate that fish oil supplementation during pregnancy does not influence the cognition, language or fine motor skills of children in late primary school (12 years of age). PMID- 25803545 TI - Can we translate vitamin D immunomodulating effect on innate and adaptive immunity to vaccine response? AB - Vitamin D (VitD), which is well known for its classic role in the maintenance of bone mineral density, has now become increasingly studied for its extra-skeletal roles. It has an important influence on the body's immune system and modulates both innate and adaptive immunity and regulates the inflammatory cascade. In this review our aim was to describe how VitD might influence immune responsiveness and its potential modulating role in vaccine immunogenicity. In the first instance, we consider the literature that may provide molecular and genetic support to the idea that VitD status may be related to innate and/or adaptive immune response with a particular focus on vaccine immunogenicity and then discuss observational studies and controlled trials of VitD supplementation conducted in humans. Finally, we conclude with some knowledge gaps surrounding VitD and vaccine response, and that it is still premature to recommend "booster" of VitD at vaccination time to enhance vaccine response. PMID- 25803548 TI - mQTL.NMR: an integrated suite for genetic mapping of quantitative variations of (1)H NMR-based metabolic profiles. AB - High-throughput (1)H nuclear magnetic resonance (NMR) is an increasingly popular robust approach for qualitative and quantitative metabolic profiling, which can be used in conjunction with genomic techniques to discover novel genetic associations through metabotype quantitative trait locus (mQTL) mapping. There is therefore a crucial necessity to develop specialized tools for an accurate detection and unbiased interpretability of the genetically determined metabolic signals. Here we introduce and implement a combined chemoinformatic approach for objective and systematic analysis of untargeted (1)H NMR-based metabolic profiles in quantitative genetic contexts. The R/Bioconductor mQTL.NMR package was designed to (i) perform a series of preprocessing steps restoring spectral dependency in collinear NMR data sets to reduce the multiple testing burden, (ii) carry out robust and accurate mQTL mapping in human cohorts as well as in rodent models, (iii) statistically enhance structural assignment of genetically determined metabolites, and (iv) illustrate results with a series of visualization tools. Built-in flexibility and implementation in the powerful R/Bioconductor framework allow key preprocessing steps such as peak alignment, normalization, or dimensionality reduction to be tailored to specific problems. The mQTL.NMR package is freely available with its source code through the Comprehensive R/Bioconductor repository and its own website ( http://www.ican institute.org/tools/ ). It represents a significant advance to facilitate untargeted metabolomic data processing and quantitative analysis and their genetic mapping. PMID- 25803549 TI - A dicationic iminophosphane. AB - A novel dicationic system containing a PN fragment has been synthesized and structurally characterized. According to the solid-state analysis and theoretical investigation, the dicationic iminophosphane resonance form is the most appropriate description for the dication. However, the contribution from the phosphorus mononitride resonance form is not negligible. PMID- 25803547 TI - Associations between orosensory perception of oleic acid, the common single nucleotide polymorphisms (rs1761667 and rs1527483) in the CD36 gene, and 6-n propylthiouracil (PROP) tasting. AB - Orosensory perception of dietary fat varies in individuals, thus influencing nutritional status. Several studies associated fat detection and preference with CD36 or 6-n-propylthiouracil (PROP) sensitivity. Other studies have not confirmed the latter association. We analyzed the relationship between orosensory perception of oleic acid, two CD36 variants, and PROP tasting. Thresholds of oleic acid perception were assessed in 64 subjects using a modification of the three-alternative forced-choice procedure. Subjects were classified for PROP taster status and genotyped for TAS2R38 and CD36 (SNPs: rs1761667 and rs1527483). Subjects homozygous for GG of the rs1761667 polymorphism showed higher sensitivity to oleic acid than AA subjects. The capability to detect oleic acid was directly associated with TAS2R38 or PROP responsiveness. PROP non-tasters had a lower papilla density than tasters, and those with genotype GG of the rs1761667 polymorphism had lower oleic acid thresholds than PROP non-tasters with genotype AA. In conclusion, results showed a direct association between orosensory perception of oleic acid and PROP tasting or rs1761667 polymorphism of CD36, which play a significant role in PROP non-tasters, given their low number of taste papillae. Characterization of individual capability to detect fatty acids may have important nutritional implications by explaining variations in human fat preferences. PMID- 25803552 TI - Photolysis of an amphiphilic assembly by calixarene-induced aggregation. AB - Photosensitizers generally show great tendency for self-aggregation in aqueous media, leading to quenched fluorescence and lower photosensitizing ability. Herein, we report that amphiphilic anthracene is highly photoreactive after aggregation induced by p-sulfonatocalix[4]arene in water. The formation of a host guest supramolecular assembly and the photolysis of the anthryl core are identified by UV-vis and NMR spectroscopy, dynamic light scattering, and transmission electron microscopy. Additionally, the assembly exhibited efficient photolysis with visible light in the presence of exogenous photosensitizers. This approach could be extended to various photoresponsive self-assemblies and applications in phototherapy and the design of photodegradable materials. PMID- 25803550 TI - Short- and long-term major cardiovascular adverse events in carotid artery interventions: a nationwide population-based cohort study in Taiwan. AB - INTRODUCTION: Carotid artery stenosis is one of the leading causes of ischemic stroke. Carotid artery stenting has become well-established as an effective treatment option for carotid artery stenosis. For this study, we aimed to determine the efficacy and safety of carotid stenting in a population-based large cohort of patients by analyzing the Taiwan National Healthcare Insurance (NHI) database. METHODS: 2,849 patients who received carotid artery stents in the NHI database from 2004 to 2010 were identified. We analyzed the risk factors of outcomes including major adverse cardiovascular events including death, acute myocardial infarction, and cerebral vascular accidents at 30 days, 1 year, and overall period and further evaluated cause of death after carotid artery stenting. RESULTS: The periprocedural stroke rate was 2.7% and the recurrent stroke rate for the overall follow-up period was 20.3%. Male, diabetes mellitus, and heart failure were significant risk factors for overall recurrent stroke (Hazard Ratio (HR) = 1.35, p = 0.006; HR = 1.23, p = 0.014; HR = 1.61, p < 0.001, respectively). The periprocedural acute myocardial infarction rate was 0.3%. Age and Diabetes mellitus were the significant factors to predict periprocedural myocardial infarction (HR = 3.06, p = 0.019; HR = 1.68, p < 0.001, respectively). Periprocedural and overall mortality rates were 1.9% and 17.3%, respectively. The most significant periprocedural mortality risk factor was acute renal failure. Age, diabetes mellitus, acute or chronic renal failure, heart failure, liver disease, and malignancy were factors correlated to the overall period mortality. CONCLUSION: Periprocedural acute renal failure significantly increased the mortality rate and the number of major adverse cardiovascular events, and the predict power persisted more than one year after the procedure. Age and diabetes mellitus were significant risk factors to predict acute myocardial infarction after carotid artery stenting. PMID- 25803553 TI - [Genetics in ophthalmology. Basis for new insights and therapeutic options]. PMID- 25803551 TI - Midkine-a protein localization in the developing and adult retina of the zebrafish and its function during photoreceptor regeneration. AB - Midkine is a heparin binding growth factor with important functions in neuronal development and survival, but little is known about its function in the retina. Previous studies show that in the developing zebrafish, Midkine-a (Mdka) regulates cell cycle kinetics in retinal progenitors, and following injury to the adult zebrafish retina, mdka is strongly upregulated in Muller glia and the injury-induced photoreceptor progenitors. Here we provide the first data describing Mdka protein localization during different stages of retinal development and during the regeneration of photoreceptors in adults. We also experimentally test the role of Mdka during photoreceptor regeneration. The immuno-localization of Mdka reflects the complex spatiotemporal pattern of gene expression and also reveals the apparent secretion and extracellular trafficking of this protein. During embryonic retinal development the Mdka antibodies label all mitotically active cells, but at the onset of neuronal differentiation, immunostaining is also localized to the nascent inner plexiform layer. Starting at five days post fertilization through the juvenile stage, Mdka immunostaining labels the cytoplasm of horizontal cells and the overlying somata of rod photoreceptors. Double immunolabeling shows that in adult horizontal cells, Mdka co-localizes with markers of the Golgi complex. Together, these data are interpreted to show that Mdka is synthesized in horizontal cells and secreted into the outer nuclear layer. In adults, Mdka is also present in the end feet of Muller glia. Similar to mdka gene expression, Mdka in horizontal cells is regulated by circadian rhythms. After the light-induced death of photoreceptors, Mdka immuonolabeling is localized to Muller glia, the intrinsic stem cells of the zebrafish retina, and proliferating photoreceptor progenitors. Knockdown of Mdka during photoreceptor regeneration results in less proliferation and diminished regeneration of rod photoreceptors. These data suggest that during photoreceptor regeneration Mdka regulates aspects of injury-induced cell proliferation. PMID- 25803554 TI - [Inherited retinal or optic nerve disorders - five steps to diagnosis]. AB - An early diagnosis of inherited retinal or optic nerve disorders is often delayed due to unspecific clinical signs, multiple clinical manifestations and striking genetic heterogeneity of the underlying molecular defects. This study represents a retrospective analysis of findings in 4,021 patients with inherited retinal or optic nerve disorders seen between 1986 and 2014 (1,171 with follow-up). In addition to the basic ophthalmological examination, electrophysiological tests (ERG, n = 2,088, since 1986; EOG, n = 381, since 1986; VEP n = 595, since 1986; mfERG, n = 819, since 1998) and non-invasive retinal imaging (fundus autofluorescence (FAF, n = 1,784, since 2002), near-infrared autofluorescence (NIA, n = 1,091, since 2006), spectral domain OCT (SD-OCT, n = 848, since 2008) and three-wavelengths multicolour spectral reflection imaging (MC, n = 366, since 2013) were performed at least once. Molecular DNA testing was done in 383 patients between 2006 and 2014. Based on these data an efficient diagnostic strategy is suggested: 1) inclusion of inherited retinal and optic nerve disorders into the differential diagnosis of visual loss or visual field defects with undefined causes; 2) non-invasive retinal imaging; 3) electrophysiological tests; 4) DNA testing to confirm the initial clinical diagnosis; 5) examination in specialised centres, therapy and follow-up. In recent years, the spectrum of diagnostic techniques has continuously expanded. Importantly, non-invasive retinal imaging has become the primary diagnostic tool and DNA testing based on state-of-the-art high throughput techniques increases the identification of associated gene mutations. In conclusion, a structured process in the diagnostic procedure of inherited retinal and optic nerve disorders greatly reduces a diagnostic delay, enables an earlier counselling and therapy and avoids further unnecessary diagnostic tests. PMID- 25803555 TI - [Genotype-phenotype correlation in patients with PRPH2-mutations]. AB - BACKGROUND: The peripherin-2 (PRPH2) gene encodes a photoreceptor-specific transmembrane-protein called peripherin-2 which is critical for the formation and maintenance of rod and cone outer segments. Over 90 different disease-causing mutations in PRPH2 have been identified which cause a variety of forms of macular degeneration and also retinopathia pigmentosa. PATIENTS/MATERIAL AND METHODS: This study is a retrospective observational study of 3 patients ascertained over a 5 month period in the ophthalmogenetic consultation of the university ophthalmic clinic. So far, the patients were followed for 8 months at least. Data examined included clinical history, pedigree analysis, ophthalmological examination, fundus photography, autofluorescence imaging, optical coherence tomography, Arden colour test, Goldmann perimetry and detailed electrophysiological assessment. Blood samples were taken for DNA extraction and mutation analysis of PRPH2 and ABCA4, BEST1, C1QTNF5, CDH3, CNGB3, ELOVL4, FSCN2, PROM1, RDH12, RP1L1, RPGR, TIMP3 was performed. RESULTS: All patients had presented with clinically evident maculopathy and visual acuities in the range of 1/50 Metervisus to 0.8 p [dec.]. All had specific electroretinogrammes. All PRPH2 mutations were autosomal dominant. One family was heterozygous for a previously reported missense mutation in the PRPH2 gene c.514C>T, p.R172W. The other patient was heterozygous for a so far non-described PRPH2 deletion and frameshift mutation c.74_77delGGTT, p.W25SfsX12 leading most likely to a truncated, dysfunctional protein. All patients showed a significant, inter-individual phenotypical variability. CONCLUSION: The data add to the documented phenotypical variability of PRPH2 mutations and describe the c.74_77delGGTT, p.W25SfsX12 mutation within PRPH2 for the first time. FAF, OCT and electrophysiological exams are helpful tools for diagnosis and evaluation of macular disease due to PRPH2 mutations. PMID- 25803556 TI - [Congenital cranial dysinnervation disorders (CCDD)]. AB - Knowledge about hereditary eye diseases has been substantially increased by means of genetic testing during the last decade. This has resulted in a new classification of a number of disease patterns, which are characterised by non progressive restrictive disorders of the oculomotor system, formerly classified as "congenital fibrosis syndromes". Based on the results of genetic testing, these ocular motility disorders are now referred to as "congenital cranial dysinnervation disorders" (CCDDs). They are caused by an impaired innervation of extraocular muscles because of a dysgenesis of the nuclei of the affected cranial nerves in the brainstem and pons and not by primary fibrosis of the extraocular muscles. In this review, congenital fibrosis of the extraocular muscles (CFEOM), Duane syndrome, horizontal gaze palsy with progressive scoliosis, congenital ptosis and Moebius syndrome are presented and basic principles of intracellular transport mechanisms and kinesins are discussed. PMID- 25803557 TI - [Horizontal gaze palsy with progressive scoliosis]. PMID- 25803558 TI - [The revised newest IC3D classification of corneal dystrophies]. AB - PURPOSE: This report suggests how corneal dystrophies (CDs) should be diagnosed at the slit lamp and specifies the new IC(3)D classification of CDs in 2015 which incorporates new information. METHODS: IC(3)D reviewed all peer-reviewed articles on CDs 2008 to 6/2014. Corneal dystrophy templates and anatomic classifications were updated. RESULTS: To detect landmarks for correct classification of CDs, opacity patterns and opacity units are determined at the slit lamp. Opacity patterns are described as (1) horizontal extension, (2) vertical extension ("depth") and clarity of the (3) cornea in between. Horizontal extension is assessed using a broad beam, vertical extension using a bright, thin slit lamp beam in high magnification. For assessment of opacity units, examination using retroillumination with dilated pupil is indispensable! This is especially true for epithelial and endothelial CDs. With a better review of the cellular origin of CDs, a new anatomic classification is proposed: 1. epithelial and subepithelial; 2. epithelial-stromal transforming growth factor beta-induced (TGFBI); 3. stromal; 4. endothelial dystrophies. Epithelial recurrent erosion dystrophies include three epithelial dystrophies (Franceschetti CD, dystrophia Smolandiensis, and dystrophia Helsinglandica) and are differentiated against TGFBI dystrophies, also associated with recurrent epithelial erosion. The chromosome locus of Thiel-Behnke CD is only located on 5q31. The entity previously called Thiel-Behnke on chromosome 10q24 may be a unique corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is an autosomal recessive disorder. The autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to be a unique entity and most cases appear to be similar to other reported dystrophies, particularly posterior polymorphous corneal dystrophy (PPCD). CONCLUSIONS: The 2015 revision of IC(3)D classification includes an updated anatomic classification more accurately describing TGFBI dystrophies to affect multiple layers. Some entities, e.g., Grayson Wilbrandt, Meretoja syndrome, and CHED2 are removed. All authors and reviewers should adhere to this classification of CDs! PMID- 25803559 TI - Significantly Different Covalent Binding of Oxidative Metabolites, Acyl Glucuronides, and S-Acyl CoA Conjugates Formed from Xenobiotic Carboxylic Acids in Human Liver Microsomes. AB - Xenobiotic carboxylic acids may be metabolized to oxidative metabolites, acyl glucuronides, and/or S-acyl-CoA thioesters (CoA conjugates) in vitro, e.g., in hepatocytes, and in vivo. These metabolites can potentially be reactive species and bind covalently to tissue proteins and are generally considered to mediate adverse drug reactions in humans. Acyl glucuronide metabolites have been the focus of reactive metabolite research for decades, whereas drug-CoA conjugates, which have been shown to be up to 40-70 times more reactive, have been given much less attention. In an attempt to dissect the contribution of different pathways to covalent binding, we utilized human liver microsomes supplemented with NADPH, uridine 5'-diphosphoglucuronic acid (UDPGA), or CoA to evaluate the reactivity of each metabolite separately. Seven carboxylic acid drugs were included in this study. While ibuprofen and tolmetin are still on the market, ibufenac, fenclozic acid, tienilic acid, suprofen, and zomepirac were stopped before their launch or withdrawn. The reactivities of the CoA conjugates of ibuprofen, ibufenac, fenclozic acid, and tolmetin were higher compared to those of their corresponding oxidative metabolites and acyl glucuronides, as measured by the level of covalent binding to human liver microsomal proteins. The highest covalent binding was observed for ibuprofenyl-CoA and ibufenacyl-CoA, to levels of 1000 and 8600 pmol drug eq/mg protein, respectively. In contrast and in agreement with the proposed P450-mediated toxicity for these drug molecules, the reactivities of oxidative metabolites of suprofen and tienilic acid were higher compared to the reactivities of their conjugated metabolites, with NADPH-dependent covalent binding of 250 pmol drug eq/mg protein for both drugs. The seven drugs all formed UDPGA-dependent acyl glucuronides, but none of these resulted in covalent binding. This study shows that, unlike studies with hepatocytes or in vivo, human liver microsomes provide an opportunity to investigate the reactivity of individual metabolites. PMID- 25803561 TI - Identification of Relationships Between Patients Through Elements in a Data Warehouse Using the Familial, Associational, and Incidental Relationship (FAIR) Initiative: A Pilot Study. AB - BACKGROUND: Over the last several years there has been widespread development of medical data warehouses. Current data warehouses focus on individual cases, but lack the ability to identify family members that could be used for dyadic or familial research. Currently, the patient's family history in the medical record is the only documentation we have to understand the health status and social habits of their family members. Identifying familial linkages in a phenotypic data warehouse can be valuable in cohort identification and in beginning to understand the interactions of diseases among families. OBJECTIVE: The goal of the Familial, Associational, & Incidental Relationships (FAIR) initiative is to identify an index set of patients' relationships through elements in a data warehouse. METHODS: Using a test set of 500 children, we measured the sensitivity and specificity of available linkage algorithm identifiers (eg, insurance identification numbers and phone numbers) and validated this tool/algorithm through a manual chart audit. RESULTS: Of all the children, 52.4% (262/500) were male, and the mean age of the cohort was 8 years old (SD 5). Of the children, 51.6% (258/500) were identified as white in race. The identifiers used for FAIR were available for the majority of patients: insurance number (483/500, 96.6%), phone number (500/500, 100%), and address (497/500, 99.4%). When utilizing the FAIR tool and various combinations of identifiers, sensitivity ranged from 15.5% (62/401) to 83.8% (336/401), and specificity from 72% (71/99) to 100% (99/99). The preferred method was matching patients using insurance or phone number, which had a sensitivity of 72.1% (289/401) and a specificity of 94% (93/99). Using the Informatics for Integrating Biology and the Bedside (i2b2) warehouse infrastructure, we have now developed a Web app that facilitates FAIR for any index population. CONCLUSIONS: FAIR is a valuable research and clinical resource that extends the capabilities of existing data warehouses and lays the groundwork for family-based research. FAIR will expedite studies that would otherwise require registry or manual chart abstraction data sources. PMID- 25803562 TI - Minimally invasive characterization of covalent monolayer sheets using tip enhanced Raman spectroscopy. AB - Synthetic covalent monolayer sheets and their subclass, two-dimensional polymers are of particular interest in materials science because of their special dimensionality which renders them very different from any bulk matter. However, structural analysis of such entities is rather challenging, and there is a clear need for additional analytical methods. The present study shows how tip-enhanced Raman spectroscopy (TERS) can be performed on monomer monolayers and the covalent sheets prepared from them by [4 + 4]-cycloaddition to explore rather complex structural and mechanistic issues. TERS is a surface analytical method that combines the high lateral resolution of scanning probe microscopy (SPM) with a greatly enhanced Raman scattering intensity. The high spatial resolution (<60 nm) and the significantly improved sensitivity (contrast factor of >4000) compared to confocal Raman microscopy provides new insights into the formation of this new and exciting material, namely significant consumption of the reactive units (anthracenes) and exclusion of the alternative [4 + 2]-cycloaddition. Moreover, due to the high lateral resolution, it was possible to find a first spectroscopic hint for step growth as the dominant mechanism in the formation of these novel monolayer sheets. In addition, TERS was used to get first insights into the phase behavior of a comonomer mixture. PMID- 25803560 TI - Routine serum creatinine measurements: how well do we perform? AB - BACKGROUND: The first aim of the study was to investigate the accuracy and intra laboratory variation of serum creatinine measurements in clinical laboratories in Flanders. The second purpose was to check the effect of this variation in serum creatinine concentration results on the calculated estimated glomerular filtration rate (eGFR) and the impact on classification of patients into a chronic kidney disease (CKD) stage. METHODS: 26 routine instruments were included, representing 13 different types of analyzers from 6 manufacturers and covering all current methodologies (Jaffe, compensated Jaffe, enzymatic liquid and dry chemistry methods). Target values of five serum pools (creatinine concentrations ranging from 35 to 934 MUmol/L) were assigned by the gold standard method (ID-GC/MS). RESULTS: Intra-run CV (%) (n = 5) and bias (%) from the target values were higher for low creatinine concentrations. Especially Jaffe and enzymatic dry chemistry methods showed a higher error. The calculated eGFR values corresponding with the reported creatinine concentration ranges resulted in a different CKD classification in 47% of cases. CONCLUSIONS: Although most creatinine assays claim to be traceable to the gold standard (ID-GC/MS), large inter-assay differences still exist. The inaccuracy in the lower concentration range is of particular concern and may lead to clinical misinterpretation when the creatinine-based eGFR of the patient is used for CKD staging. Further research to improve harmonization between methods is required. PMID- 25803564 TI - Structure and dynamics of ionic micelles: MD simulation and neutron scattering study. AB - Fully atomistic molecular dynamics (MD) simulations have been carried out on sodium dodecyl sulfate (SDS), an anionic micelle, and three cationic (CnTAB; n = 12, 14, 16) micelles, investigating the effects of size, the form of the headgroup, and chain length. They have been used to analyze neutron scattering data. MD simulations confirm the dynamical model of global motion of the whole micelle, segmental motion (headgroup and alkyl chain), and fast torsional motion associated with the surfactants that is used to analyze the experimental data. It is found that the solvent surrounding the headgroups results in their significant mobility, which exceeds that of the tails on the nanosecond time scale. The middle of the chain is found to be least mobile, consolidating the micellar configuration. This dynamical feature is similar for all the ionic micelles investigated and therefore independent of headgroup form and charge and chain length. Diffusion constants for global and segmental motion of the different micelles are consistent with experimentally obtained values as well as known structural features. This work provides a more realistic model of micelle dynamics and offers new insight into the strongly fluctuating surface of micelles which is important in understanding micelle dispersion and related functionality, like drug delivery. PMID- 25803563 TI - ACR Appropriateness Criteria((r)) induction and adjuvant therapy for N2 non-small cell lung cancer. AB - The integration of chemotherapy, radiation therapy (RT), and surgery in the management of patients with stage IIIA (N2) non-small-cell lung carcinoma is challenging. The American College of Radiology (ACR) Appropriateness Criteria Lung Cancer Panel was charged to update management recommendations for this clinical scenario. The Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. There is limited level I evidence to guide patient selection for induction, postoperative RT (PORT), or definitive RT. Literature interpretation is complicated by inconsistent diagnostic procedures for N2 disease, disease heterogeneity, and pooled analysis with other stages. PORT is an appropriate therapy following adjuvant chemotherapy in patients with incidental pN2 disease. In patients with clinical N2 disease who are potential candidates for a lobectomy, both definitive and induction concurrent chemotherapy/RT are appropriate treatments. In N2 patients who require a pneumonectomy, definitive concurrent chemotherapy/RT is most appropriate although induction concurrent chemotherapy/RT may be considered in expert hands. Induction chemotherapy followed by surgery +/- PORT may also be an option in N2 patients. For preoperative RT and PORT, 3-dimensional conformal techniques and intensity modulated RT are most appropriate. PMID- 25803565 TI - Synthesis of 21,23-selenium- and tellurium-substituted 5-porphomethenes, 5,10 porphodimethenes, 5,15-porphodimethenes, and porphotrimethenes and their interactions with mercury. AB - The 3+1 condensation of symmetrical 16-Selena/telluratripyrranes with symmetrical selenophene-2,5-diols/tellurophene-2,5-diols in the presence of BF3-etheratre or BF3-methanol followed by oxidation with DDQ gave 5,10-porphodimethenes, whereas the process with unsymmetrical selenophene-2,5-diols/tellurophene-2,5-diols gave 5-porphomethenes. In addition, the reaction of unsymmetrical 16 Selena/telluratripyrranes with symmetrical selenophene-2,5-diols/tellurophene-2,5 diols gave the corresponding porphotrimethenes, whereas the process with unsymmetrical selenophene-2,5-diols/tellurophene-2,5-diols gave the 5,15 porphodimethenes. The structures of different products were characterized by IR, (1)H and (13)C NMR, (1)H-(1)H COSY, CHN analysis, and mass spectrometry. The binding of mercury with the calix[4]phyrins mentioned above had been observed in the decreasing order of porphodimethenes > porphomethenes > porphotrimethenes by UV-vis and (1)H NMR spectroscopy. PMID- 25803566 TI - Picodiscs for facile protein-glycolipid interaction analysis. AB - Protein interactions with glycolipids are implicated in diverse cellular processes. However, the study of protein-glycolipid complexes remains a significant experimental challenge. Here, we describe a powerful new assay that combines electrospray ionization mass spectrometry (ESI-MS) and picodiscs, which are composed of human sphingolipid activator protein saposin A and a small number of phospholipids, to display glycolipids in a lipid environment for protein glycolipid interaction studies in aqueous solution. Time-resolved measurements of enzyme catalyzed hydrolysis of glycolipid substrates and the detection of low, moderate, and high affinity protein-glycolipid interactions serve to demonstrate the reliability and versatility of the assay. PMID- 25803567 TI - A split-face comparison of facial hair removal with the long-pulsed alexandrite laser and intense pulsed light system. AB - BACKGROUND: Undesirable hair growth presents a significant problem for many patients. Photoepilation has become a very popular procedure in esthetic and cosmetic practice. Among the systems used are the long-pulsed alexandrite laser (755 nm) (ALX) and intense pulsed light (IPL). OBJECTIVE: To compare the safety and efficacy of long-pulsed ALX and IPL for hair removal. PATIENTS AND METHODS: This comparative study was carried out in the outpatient Department of Dermatology and Venereology, Al-Sadir Teaching Hospital, Al Najaf City during the period from June 2009 to July 2010. Thirty-five patients were included; thirty of them completed the study. They received six treatment sessions with the ALX on the left side of the face and IPL on the right side of face with 4-week intervals between sessions. Response to treatment on both sides of the face was assessed at 1, 3, and 6 treatment sessions. Hair-free intervals and patient's satisfaction were recorded in each visit. RESULTS: After six treatment sessions, IPL-treated sides showed longer median hair-free intervals compared with ALX-treated sides. Reduction in hair counts was significantly larger on the IPL compared with that on the ALX-treated sides at 1, 3, and 6 sessions. Three patients (10%) developed postinflammatory hyperpigmentation, one of them on the left side and the others on the right side. It was more severe on the right side and both the patients were of skin type IV. Slight stinging and burning sensation at time of the treatment were recorded in all patients. All reported side effects were transient and tolerated by the patients except postinflammatory hyperpigmentation which persisted and was decreasing gradually toward the end of the study. CONCLUSIONS: The results of this study suggested that IPL is more effective in reducing excessive facial hair growth, with longer hair-free intervals and greater patient satisfaction than the ALX. PMID- 25803568 TI - Treatment of periorbital syringoma by the pinhole method using a carbon dioxide laser in 29 Asian patients. AB - BACKGROUND: Pinhole method has been used to treat various types of scars and dermal tumors by making multiple small holes in target tissues of the deep dermis using an ablative 10,600-nm carbon dioxide (CO2) laser. OBJECTIVES: We prospectively investigated the efficacy and safety of using a CO2 laser to treat periorbital syringomas via the pinhole method. METHODS: A total of 29 patients with periorbital syringomas were treated with two sessions of CO2 laser treatment using the pinhole method at two-month intervals. Laser fluences were delivered under the following settings: pulse duration of 200 MUs, frequency of 50 Hz, on time of 0.04, and an off time of 0.01. RESULTS: Among the 29 patients, 13 patients (44.8%) presented with small discrete papular syringomas, 10 (34.5%) had plaque-type lesions, and six (20.7%) had mixed lesions. Evaluation of the clinical results at 2 months after the second treatment session revealed marked clinical improvement (51-75%) in 10 of the 29 patients (34.5%), moderate clinical improvement (26-50%) in eight (27.6%), near-total improvement (>= 75%) in seven (24.1%), and minimal improvement (0-25%) in four patients (13.8%). CONCLUSIONS: Our observations indicated that application of the pinhole method using a CO2 laser exerts positive therapeutic effects in Asian patients with periorbital syringomas. PMID- 25803569 TI - Removal of a toothpick penetrated into foot by Er:YAG laser ablation. AB - Although rare, foot injuries caused by toothpicks can result in serious complications such as severe pain, local inflammation and infection in several days, and a delayed granulamatous foreign-body reaction in weeks or months. For this reason they should be removed from the tissue in the early phase. Here, we report case of penetration injury caused by a toothpick treated using Er: YAG laser ablation. PMID- 25803570 TI - Inflammatory morphea mimicking an acquired port-wine stain initially treated with pulsed-dye laser. AB - The early inflammatory lesions of morphea may present with erythema or violaceous patches and plaques before evolving into areas of sclerosis. They have been misdiagnosed as acquired port-wine stains (PWSs). We report a previously well 7 year-old Chinese girl presenting with early facial morphea mimicking an acquired PWS with unusual histologic features of perineural inflammation. The presence of cutaneous perineural inflammation may be seen in a small percentage of cases of morphea and appears to be a feature of early inflammatory morphea. We report this case to highlight the importance in recognizing this entity and summarize the reported cases of inflammatory morphea mimicking acquired PWSs. PMID- 25803571 TI - A prospective, split-face, randomized study of the efficacy and safety of a novel fractionated intense pulsed light treatment for melasma in Asians. AB - BACKGROUND: Intense pulsed light (IPL) has been reported to effectively treat melasma in previous studies, but an aggravation of pigmentation was noted. Fractionated IPL is a novel technique in which microsecond-domain fractionated pulses are delivered to the target area. OBJECTIVE: To compare the safety and efficacy of low-fluency, frequently scheduled fractionated IPL and conventional IPL for melasma treatment. MATERIALS AND METHODS: This was a 14-week, split-face study in which 30 Asian women were treated with weekly fractionated IPL on one side of the face and biweekly conventional IPL on the other side. RESULTS: The non-inferiority of a weekly fractionated IPL regimen to a biweekly conventional IPL regimen was verified by a lower margin of the 95% confidence interval for the difference in the Melasma Area and Severity Index (MASI) change from baseline of 2.61 for each side. This value was greater than the previously determined non inferiority margin of -2.68 (P < 0.025). On the fractionated IPL side, the modified MASI score decreased continuously, but in the conventional IPL group, the MASI score rebounded during the treatment course. CONCLUSION: Fractionated IPL shows moderate efficacy as a melasma treatment and is therefore a good alternative to conventional IPL as there is no indication of melasma exacerbation. Fractionated IPL can also be used as a maintenance treatment for melasma. PMID- 25803572 TI - Lycopene inhibits the isomerization of beta-carotene during quenching of singlet oxygen and free radicals. AB - The present study aimed to investigate the influence of singlet oxygen and radical species on the isomerization of carotenoids. On the one hand, lycopene and beta-carotene standards were incubated with 1,4-dimethylnaphthalene-1,4 endoperoxide that produced singlet oxygen in situ. (13Z)- and (15Z)-beta-carotene were preferentially generated at low concentrations of singlet oxygen, while high concentrations resulted in formation of (9Z)-beta-carotene. The addition of different concentrations of lycopene led to the same isomerization progress of beta-carotene, but resulted in a decreased formation of (9Z)-beta-carotene and retarded degradation of (all-E)-beta-carotene. On the other hand, isomerization of beta-carotene and lycopene was induced by ABTS-radicals, too. As expected from the literature, chemical quenching was observed especially for lycopene, while physical quenching was preferred for beta-carotene. Mixtures of beta-carotene and lycopene resulted in a different isomerization progress compared to the separate beta-carotene model. As long as lycopene was present, almost no isomerization of beta-carotene was triggered; after that, strong formation of (13Z)-, (9Z)-, and (15Z)-beta-carotene was initiated. In summary, lycopene protected beta-carotene against isomerization during reactions with singlet oxygen and radicals. These findings can explain the pattern of carotenoid isomers analyzed in fruits and vegetables, where lycopene containing samples showed higher (all-E)/(9Z)-beta carotene ratios, and also in in vivo samples such as human blood plasma. PMID- 25803574 TI - From unsuccessful H2-activation with FLPs containing B(Ohfip)3 to a systematic evaluation of the Lewis acidity of 33 Lewis acids based on fluoride, chloride, hydride and methyl ion affinities. AB - The possibility of obtaining frustrated Lewis pairs (FLPs) suitable for H2 activation based on the Lewis acid B(Ohfip)3 1 (Ohfip = OC(H)(CF3)2) was investigated. In this context, the crystal structure of 1 as well as the crystal structure of the very weak adduct 1.NCMe was determined. When reacting solutions of 1 with H2 (1 bar) and selected phosphanes, amines, pyridines and N heterocyclic carbenes, dihydrogen activation was never observed. Without H2, adduct formation with 1 was observed to be an equilibrium process, regardless of the Lewis base adduct. Thus, the thermodynamics of H2 activation of 1 in comparison with the well-known B(C6F5)3 was analyzed using DFT calculations in the gas phase and different solvents (CH2Cl2, ortho-difluorobenzene and acetonitrile). These investigations indicated that FLP chemistry based on 1 is considerably less favored than that with B(C6F5)3. This is in agreement with control NMR experiments indicating hydride transfer from [H-B(Ohfip)3](-) upon reaction with B(C6F5)3, giving [H-B(C6F5)3](-) and B(Ohfip)3 in toluene and also MeCN. Induced by these unsuccessful reactions, the Lewis acidity towards HSAB hard and soft ions was investigated for gaining a deeper insight. A unified reference system based on the trimethylsilyl compounds Me3Si-Y (Y = F, Cl, H, Me) and their respective ions Me3Si(+)/Y(-) calculated at the G3 level was chosen as the anchor point. The individual ion affinities were then assessed based on subsequent isodesmic reactions calculated at a much less expensive level (RI )BP86/SV(P). This method was validated by systematic calculations of smaller reference systems at the frozen core CCSD(T) level with correlation effects extrapolated to a full quadruple-zeta basis. Overall, 33 common and frequently used Lewis acids were ranked with respect to their FIA, CIA, HIA and MIA (fluoride/chloride/hydride/methyl ion affinity). PMID- 25803575 TI - Mad2 and BubR1: chemotherapeutic coordinators in gastric cancer. PMID- 25803573 TI - Design and Synthesis of a Screening Library Using the Natural Product Scaffold 3 Chloro-4-hydroxyphenylacetic Acid. AB - The fungal metabolite 3-chloro-4-hydroxyphenylacetic acid (1) was utilized in the generation of a unique drug-like screening library using parallel solution-phase synthesis. A 20-membered amide library (3-22) was generated by first converting 1 to methyl (3-chloro-4-hydroxyphenyl)acetate (2), then reacting this scaffold with a diverse series of primary amines via a solvent-free aminolysis procedure. The structures of the synthetic analogues (3-22) were elucidated by spectroscopic data analysis. The structures of compounds 8, 12, and 22 were confirmed by single X-ray crystallographic analysis. All compounds were evaluated for cytotoxicity against a human prostate cancer cell line (LNCaP) and for antiparasitic activity toward Trypanosoma brucei brucei and Plasmodium falciparum and showed no significant activity at 10 MUM. The library was also tested for effects on the lipid content of LNCaP and PC-3 prostate cancer cells, and it was demonstrated that the fluorobenzyl analogues (12-14) significantly reduced cellular phospholipid and neutral lipid levels. PMID- 25803576 TI - The art of war: beyond memory-one strategies in population games. AB - We show that the history of play in a population game contains exploitable information that can be successfully used by sophisticated strategies to defeat memory-one opponents, including zero determinant strategies. The history allows a player to label opponents by their strategies, enabling a player to determine the population distribution and to act differentially based on the opponent's strategy in each pairwise interaction. For the Prisoner's Dilemma, these advantages lead to the natural formation of cooperative coalitions among similarly behaving players and eventually to unilateral defection against opposing player types. We show analytically and empirically that optimal play in population games depends strongly on the population distribution. For example, the optimal strategy for a minority player type against a resident TFT population is ALLC, while for a majority player type the optimal strategy versus TFT players is ALLD. Such behaviors are not accessible to memory-one strategies. Drawing inspiration from Sun Tzu's the Art of War, we implemented a non-memory-one strategy for population games based on techniques from machine learning and statistical inference that can exploit the history of play in this manner. Via simulation we find that this strategy is essentially uninvadable and can successfully invade (significantly more likely than a neutral mutant) essentially all known memory-one strategies for the Prisoner's Dilemma, including ALLC (always cooperate), ALLD (always defect), tit-for-tat (TFT), win-stay-lose-shift (WSLS), and zero determinant (ZD) strategies, including extortionate and generous strategies. PMID- 25803578 TI - Characterization, identification and application of lactic Acid bacteria isolated from forage paddy rice silage. AB - There has been growing interest to develop forage rice as a new feed resource for livestock. This study was to characterize the natural population of lactic acid bacteria (LAB) and select potentially excellent strains for paddy rice silage preparation in China. One hundred and twenty-six strains were isolated and screened from paddy rice silage prepared using a small-scale fermentation system, and ninety-nine of these isolates were considered to be LAB based on their Gram positive and catalase-negative morphology and the production of most of their metabolic products as lactic acid. These isolates were divided into eight groups (A-H) on the basis of their morphological and biochemical characteristics. The Group A to H strains were identified as Lactobacillus (L.) plantarum subsp. plantarum (species ratio: 8.1%), L. casei (5.1%), Leuconostoc (Ln.) pseudomesenteroides (11.1%), Pediococcus (P.) pentosaceus (24.2%), Enterococcus (E.) mundtii (12.1%), Lactococcus (Lc.) garvieae (15.2%), E. faecium (9.1%) and Lc. lactis subsp. lactis (15.2%) based on sequence analyses of their 16S rRNA and recA genes. P. pentosaceus was the most abundant member of the LAB population in the paddy rice silage. A selected strain, namely L. casei R 465, was found to be able to grow under low pH conditions and to improve the silage quality with low pH and a relatively high content of lactic acid. This study demonstrated that forage paddy rice silage contains abundant LAB species and its silage can be well preserved by inoculation with LAB, and that strain R 465 can be a potentially excellent inoculant for paddy rice silage. PMID- 25803579 TI - Local Variability of Parameters for Characterization of the Corneal Subbasal Nerve Plexus. AB - PURPOSE: The corneal subbasal nerve plexus (SNP) offers high potential for early diagnosis of diabetic peripheral neuropathy. Changes in subbasal nerve fibers can be assessed in vivo by confocal laser scanning microscopy (CLSM) and quantified using specific parameters. While current study results agree regarding parameter tendency, there are considerable differences in terms of absolute values. The present study set out to identify factors that might account for this high parameter variability. MATERIALS AND METHODS: In three healthy subjects, we used a novel method of software-based large-scale reconstruction that provided SNP images of the central cornea, decomposed the image areas into all possible image sections corresponding to the size of a single conventional CLSM image (0.16 mm2), and calculated a set of parameters for each image section. In order to carry out a large number of virtual examinations within the reconstructed image areas, an extensive simulation procedure (10,000 runs per image) was implemented. RESULTS: The three analyzed images ranged in size from 3.75 mm2 to 4.27 mm2. The spatial configuration of the subbasal nerve fiber networks varied greatly across the cornea and thus caused heavily location-dependent results as well as wide value ranges for the parameters assessed. Distributions of SNP parameter values varied greatly between the three images and showed significant differences between all images for every parameter calculated (p < 0.001 in each case). CONCLUSIONS: The relatively small size of the conventionally evaluated SNP area is a contributory factor in high SNP parameter variability. Averaging of parameter values based on multiple CLSM frames does not necessarily result in good approximations of the respective reference values of the whole image area. This illustrates the potential for examiner bias when selecting SNP images in the central corneal area. PMID- 25803577 TI - Safety and efficacy of at-home robotic locomotion therapy in individuals with chronic incomplete spinal cord injury: a prospective, pre-post intervention, proof-of-concept study. AB - BACKGROUND: The compact Motorized orthosis for home rehabilitation of Gait (MoreGait) was developed for continuation of locomotion training at home. MoreGait generates afferent stimuli of walking with the user in a semi-supine position and provides feedback about deviations from the reference walking pattern. OBJECTIVE: Prospective, pre-post intervention, proof-of-concept study to test the feasibility of an unsupervised home-based application of five MoreGait prototypes in subjects with incomplete spinal cord injury (iSCI). METHODS: Twenty five (5 tetraplegia, 20 paraplegia) participants with chronic (mean time since injury: 5.8 +/- 5.4 (standard deviation, SD) years) sensorimotor iSCI (7 ASIA Impairment Scale (AIS) C, 18 AIS D; Walking Index for Spinal Cord Injury (WISCI II): Interquartile range 9 to 16) completed the training (45 minutes / day, at least 4 days / week, 8 weeks). Baseline status was documented 4 and 2 weeks before and at training onset. Training effects were assessed after 4 and 8 weeks of therapy. RESULTS: After therapy, 9 of 25 study participants improved with respect to the dependency on walking aids assessed by the WISCI II. For all individuals, the short-distance walking velocity measured by the 10-Meter Walk Test showed significant improvements compared to baseline (100%) for both self selected (Mean 139.4% +/- 35.5% (SD)) and maximum (Mean 143.1% +/- 40.6% (SD)) speed conditions as well as the endurance estimated with the six-minute walk test (Mean 166.6% +/- 72.1% (SD)). One device-related adverse event (pressure sore on the big toe) occurred in over 800 training sessions. CONCLUSIONS: Home-based robotic locomotion training with MoreGait is feasible and safe. The magnitude of functional improvements achieved by MoreGait in individuals with iSCI is well within the range of complex locomotion robots used in hospitals. Thus, unsupervised MoreGait training potentially represents an option to prolong effective training aiming at recovery of locomotor function beyond in-patient rehabilitation. TRIAL REGISTRATION: German Clinical Trials Register (DKRS) DRKS00005587. PMID- 25803580 TI - Identification of candidate odorant receptors in Asian corn borer Ostrinia furnacalis. AB - In lepidopteran insects, odorant receptors are involved in the perception of sex pheromones and general odorants. In the Asian corn borer, Ostrinia furnacalis, although several pheromone receptors have been identified, no general odorant receptor has been reported. In this study, an RNA sequencing analysis was carried out to identify the whole repertoire of the odorant receptors expressed in the antennae of O. furnacalis. Among 12 million reads obtained from the antennae of male and female moths, 52 candidate odorant receptors were identified, including 45 novel ones. Expression levels of candidate odorant receptors were estimated by read mapping and quantitative reverse transcription PCR. These analyses confirmed that the expression of the previously identified pheromone receptors was highly male biased. In contrast, none of the newly identified odorant receptors showed male-biased expression. Three of the newly identified odorant receptors showed female-biased expression. Two of them were the most highly expressed odorant receptors in the female antennae, suggesting that they may be involved in the detection of odorants important for the induction of female-specific behaviors such as oviposition site selection. In addition, candidate genes of 21 ionotropic receptors, 5 gustatory receptors, 2 sensory neuron membrane proteins, and 26 odorant degrading enzymes were identified. Our results provide a basis for further analysis of the chemosensory system in the Ostrinia species. PMID- 25803581 TI - Stromally expressed beta-catenin modulates Wnt9b signaling in the ureteric epithelium. AB - The mammalian kidney undergoes cell interactions between the epithelium and mesenchyme to form the essential filtration unit of the kidney, termed the nephron. A third cell type, the kidney stroma, is a population of fibroblasts located in the kidney capsule, cortex and medulla and is ideally located to affect kidney formation. We found beta-catenin, a transcriptional co-activator, is strongly expressed in distinctive intracellular patterns in the capsular, cortical, and medullary renal stroma. We investigated beta-catenin function in the renal stroma using a conditional knockout strategy that genetically deleted beta-catenin specifically in the renal stroma cell lineage (beta-cats-/-). beta cats-/- mutant mice demonstrate marked kidney abnormalities, and surprisingly we show beta-catenin in the renal stroma is essential for regulating the condensing mesenchyme cell population. We show that the population of induced mesenchyme cells is significantly reduced in beta-cats-/- mutants and exhibited decreased cell proliferation and a specific loss of Cited 1, while maintaining the expression of other essential nephron progenitor proteins. Wnt9b, the key signal for the induction of nephron progenitors, was markedly reduced in adjacent ureteric epithelial cells in beta-cats-/-. Analysis of Wnt9b-dependent genes in the neighboring nephron progenitors was significantly reduced while Wnt9b independent genes remained unchanged. In contrast mice overexpressing beta catenin exclusively in the renal stroma demonstrated massive increases in the condensing mesenchyme population and Wnt9b was markedly elevated. We propose that beta-catenin in the renal stroma modulates a genetic program in ureteric epithelium that is required for the induction of nephron progenitors. PMID- 25803582 TI - Analysis of antibody aggregate content at extremely high concentrations using sedimentation velocity with a novel interference optics. AB - Monoclonal antibodies represent the most important group of protein-based biopharmaceuticals. During formulation, manufacturing, or storage, antibodies may suffer post-translational modifications altering their physical and chemical properties. Such induced conformational changes may lead to the formation of aggregates, which can not only reduce their efficiency but also be immunogenic. Therefore, it is essential to monitor the amount of size variants to ensure consistency and quality of pharmaceutical antibodies. In many cases, antibodies are formulated at very high concentrations > 50 g/L, mostly along with high amounts of sugar-based excipients. As a consequence, all routine aggregation analysis methods, such as size-exclusion chromatography, cannot monitor the size distribution at those original conditions, but only after dilution and usually under completely different solvent conditions. In contrast, sedimentation velocity (SV) allows to analyze samples directly in the product formulation, both with limited sample-matrix interactions and minimal dilution. One prerequisite for the analysis of highly concentrated samples is the detection of steep concentration gradients with sufficient resolution: Commercially available ultracentrifuges are not able to resolve such steep interference profiles. With the development of our Advanced Interference Detection Array (AIDA), it has become possible to register interferograms of solutions as highly concentrated as 150 g/L. The other major difficulty encountered at high protein concentrations is the pronounced non-ideal sedimentation behavior resulting from repulsive intermolecular interactions, for which a comprehensive theoretical modelling has not yet been achieved. Here, we report the first SV analysis of highly concentrated antibodies up to 147 g/L employing the unique AIDA ultracentrifuge. By developing a consistent experimental design and data fit approach, we were able to provide a reliable estimation of the minimum content of soluble aggregates in the original formulations of two antibodies. Limitations of the procedure are discussed. PMID- 25803583 TI - slc7a6os gene plays a critical role in defined areas of the developing CNS in zebrafish. AB - The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes. PMID- 25803584 TI - Effect of in vitro syncytium formation on the severity of human metapneumovirus disease in a murine model. AB - Human metapneumovirus (HMPV) is an important cause of acute respiratory tract infections (ARTI) in children, elderly individuals and immunocompromised patients. In vitro, different HMPV strains can induce variable cytopathic effects ranging from large multinucleated syncytia to focal cell rounding. In this study, we investigated the impact of different in vitro phenotypes of two HMPV strains on viral replication and disease severity in a BALB/c mouse model. We first generated two recombinant GFP-expressing HMPV viruses: C-85473, a syncytium inducing strain (rC-85473) belonging to the A1 subtype and CAN98-75, a focal cell rounding-inducing strain (rCAN98-75) of the B2 subtype. We subsequently exchanged the F genes of both strains to create the chimeric viruses rC-85473_F and rCAN98 75_F. We demonstrated that the F protein was the sole protein responsible for the syncytium phenotype and that viruses carrying a syncytium-inducing F protein replicated to significantly higher titers in vitro. In vivo, however, the virulence and replicative capacity of the different HMPV strains did not appear to be solely dependent on the F gene but also on the viral background, with the strains containing the C-85473 background inducing more weight loss as well as increased lung viral titers, pro-inflammatory cytokines and inflammation than strains containing the CAN98-75 background. In conclusion, the F protein is the main determinant of syncytium formation and replication kinetics in vitro, although it is not the only factor implicated in HMPV disease severity in mice. PMID- 25803585 TI - Thrombospondin1 deficiency attenuates obesity-associated microvascular complications in ApoE-/- mice. AB - Obesity is associated with insulin resistance and the increased development of vascular complications. Previously, we have demonstrated that thrombospondin1 (TSP1) regulates macrophage function and contributes to obesity associated inflammation and insulin resistance. However, the role of TSP1 in the development of obesity associated vascular complications is not clear. Therefore, in the current study, we investigated whether TSP1 deficiency protects mice from obesity associated micro as well as macro-vascular complications in ApoE-/- mice. In this study, male ApoE-/- mice and ApoE-/-TSP1-/- mice were fed with a low-fat (LF) or a high-fat (HF) diet for 16 weeks. We found that body weight and fat mass increased similarly between the ApoE-/-TSP1-/- mice and ApoE-/- mice under HF feeding conditions. However, as compared to obese ApoE-/- mice, obese ApoE-/-TSP1 /- mice had improved glucose tolerance, increased insulin sensitivity, and reduced systemic inflammation. Aortic atherosclerotic lesion formation was similar in these two groups of mice. In contrast, albuminuria was attenuated and kidney fibrosis was reduced in obese ApoE-/-TSP1-/- mice compared to obese ApoE-/ mice. The improved kidney function in obese ApoE-/-TSP1-/- mice was associated with decreased renal lipid accumulation. Together, these data suggest that TSP1 deficiency did not affect the development of obesity associated macro-vascular complication, but attenuated obesity associated micro-vascular complications. PMID- 25803586 TI - Computerized assessment of communication for cognitive stimulation for people with cognitive decline using spectral-distortion measures and phylogenetic inference. AB - Therapeutic communication and interpersonal relationships in care homes can help people to improve their mental wellbeing. Assessment of the efficacy of these dynamic and complex processes are necessary for psychosocial planning and management. This paper presents a pilot application of photoplethysmography in synchronized physiological measurements of communications between the care-giver and people with dementia. Signal-based evaluations of the therapy can be carried out using the measures of spectral distortion and the inference of phylogenetic trees. The proposed computational models can be of assistance and cost effectiveness in caring for and monitoring people with cognitive decline. PMID- 25803588 TI - Developing a generic model for total quality management in higher education in Saudi Arabia. AB - The field of higher education has been progressing at a rapid pace in the Kingdom of Saudi Arabia over the past decade, with doubling the number of government and private universities and colleges. Quality and accreditation are of great importance to higher education institutes world-wide. Thus, developing a generic model for quality management in higher education is badly needed in the country. PMID- 25803587 TI - Relating sub-surface ice features to physiological stress in a climate sensitive mammal, the American pika (Ochotona princeps). AB - The American pika (Ochotona princeps) is considered a sentinel species for detecting ecological effects of climate change. Pikas are declining within a large portion of their range, and ongoing research suggests loss of sub-surface ice as a mechanism. However, no studies have demonstrated physiological responses of pikas to sub-surface ice features. Here we present the first analysis of physiological stress in pikas living in and adjacent to habitats underlain by ice. Fresh fecal samples were collected non-invasively from two adjacent sites in the Rocky Mountains (one with sub-surface ice and one without) and analyzed for glucocorticoid metabolites (GCM). We also measured sub-surface microclimates in each habitat. Results indicate lower GCM concentration in sites with sub-surface ice, suggesting that pikas are less stressed in favorable microclimates resulting from sub-surface ice features. GCM response was well predicted by habitat characteristics associated with sub-surface ice features, such as lower mean summer temperatures. These results suggest that pikas inhabiting areas without sub-surface ice features are experiencing higher levels of physiological stress and may be more susceptible to changing climates. Although post-deposition environmental effects can confound analyses based on fecal GCM, we found no evidence for such effects in this study. Sub-surface ice features are key to water cycling and storage and will likely represent an increasingly important component of water resources in a warming climate. Fecal samples collected from additional watersheds as part of current pika monitoring programs could be used to further characterize relationships between pika stress and sub-surface ice features. PMID- 25803589 TI - Validity and reliability of bilingual English-Arabic version of Schutte self report emotional intelligence scale in an undergraduate Arab medical student sample. AB - BACKGROUND: The psychological construct of emotional intelligence (EI), its theoretical models, measurement instruments and applications have been the subject of several research studies in health professions education. AIM: The objective of the current study was to investigate the factorial validity and reliability of a bilingual version of the Schutte Self Report Emotional Intelligence Scale (SSREIS) in an undergraduate Arab medical student population. METHODS: The study was conducted during April-May 2012. A cross-sectional survey design was employed. A sample (n = 467) was obtained from undergraduate medical students belonging to the male and female medical college of King Saud University, Riyadh, Saudi Arabia. Exploratory and confirmatory factor analysis was performed using SPSS 16.0 and AMOS 4.0 statistical software to determine the factor structure. Reliability was determined using Cronbach's alpha statistics. RESULTS: The results obtained using an undergraduate Arab medical student sample supported a multidimensional; three factor structure of the SSREIS. The three factors are Optimism, Awareness-of-Emotions and Use-of-Emotions. The reliability (Cronbach's alpha) for the three subscales was 0.76, 0.72 and 0.55, respectively. CONCLUSION: Emotional intelligence is a multifactorial construct (three factors). The bilingual version of the SSREIS is a valid and reliable measure of trait emotional intelligence in an undergraduate Arab medical student population. PMID- 25803590 TI - Assessment of educational games for health professions: a systematic review of trends and outcomes. AB - BACKGROUND: Traditional lecturing used in teaching has the lowest retention rate; the use of games as part of an instruction method may enhance retention and reinforce learning by creating a dynamic educational environment. This study aims to systematically review the literature on educational games for the health professions to identify trends and investigate assessment tools used to measure its learning outcomes. METHODS: Seven databases were used in the search: ERIC, Education Research Complete, Medline, Medline Complete, Academic Search Complete, The Cochrane Library and PubMed. RESULTS: The search identified 2865 papers; among them, 1259 were excluded and 22 were evaluated. The selection incorporated five full papers which focused directly on the health professionals. Two studies involved the use of board games and two studies involved card games, crossword puzzles and one study involved a team quiz competition. Overall, studies lacked a strong link between the use of games for both instructional and assessment purposes. CONCLUSION: Gaming makes a positive impact on the teaching/learning process. However, existing assessment methodologies have been not fully captured the learning that may occur in these games. Robust research is needed to address the use of games that have been assessed objectively. PMID- 25803591 TI - Faculty development for learning and teaching of medical professionalism. AB - INTRODUCTION: Professionalism must be explicitly taught, but teaching professionalism is challenging, because medical teachers are not prepared to teach this content area. AIM: This study aims at designing and evaluating a faculty development programme on learning and teaching professionalism in the Arabian context. Programme development: The study used a participatory design, where four authors and 28 teachers shared the responsibility in programme design in three steps: orientation workshop for teachers, vignette development, and teaching professionalism to students. The workshop provided the cognitive base on the salient attributes of professionalism in the Arabian context. After the workshop, authors helped teachers to develop a total of 32 vignettes in various clinical aspects, portraying a blend of professionalism dilemmas. A battery of seven questions/triggers was suggested to guide students' reflection. PROGRAMME EVALUATION: The programme was evaluated with regard to its "construct" and its "outcomes". The programme has fulfilled the guiding principles for its design and it has emerged from a genuine professionalism framework from local scholarly studies in the Arabian context. Programme outcomes were evaluated at the four levels of Kirkpatrick's model; reaction, learning, behaviour, and results. DISCUSSION: The study communicates a number of context-specific issues that should be considered when teaching professionalism in Arabian culture with respect to teachers and students. Three lessons were learned from developing vignettes, as reported by the authors. This study advocates the significance of transforming faculty development from the training discourse of stand-alone interventions to mentorship paradigm of the communities of learning. CONCLUSION: A three-step approach (orientation workshop, vignettes development, and teaching professionalism) proved effective for faculty development for learning and teaching of professionalism. Professionalism can be taught using vignettes that demonstrate professionalism dilemmas in a particular context. PMID- 25803592 TI - Problem-based learning in undergraduate medical education in Saudi Arabia: time has come to reflect on the experience. AB - BACKGROUND: Problem-based learning (PBL) is being increasingly used in many undergraduate medical schools worldwide due to its recognized advantages. OBJECTIVES: To explore views of medical students in the Kingdom of Saudi Arabia (KSA) about the appropriateness of the PBL concepts and process. Differences in students' views were examined as well. METHODS: This is a cross-sectional, questionnaire-based study conducted in two medical colleges in Riyadh, Saudi Arabia, during the period from April to June 2012. RESULTS: One hundred seventy four undergraduate medical students participated in the study. Majority of the participants supported the concept of PBL and thought it is a beneficial learning strategy. However, only about half of them consider the problems used in tutorials are relevant for the local setting. Significant differences have been identified between the gender, schools, and study level of participants and their views on the process of PBL tutorials. About 35% of participants either undecided or will not recommend medical schools that adopt PBL curriculums for their friends. CONCLUSIONS: The majority of participants were satisfied with PBL approach and valued its importance in their learning process. Specific concerns have been expressed about relevance of some aspects of PBL. Underlying factors should be further explored in order to improve the outcomes of PBL curriculum in the local Saudi setting. PMID- 25803593 TI - A lesson learned from Middle East respiratory syndrome (MERS) in Saudi Arabia. AB - Middle East respiratory syndrome (MERS) caused by novel Corona virus hit Kingdom of Saudi Arabia (KSA) and resulted in hundreds of mortality and morbidity, fears and psychosocial stress among population, economic loss and major political change at Ministry of Health (MoH). Although MERS discovered two years ago, confusion still exists about its origin, nature, and consequences. In 2003, similar virus (SARS) hit Canada and resulted in a reform of Canada's public health system and creation of a Canadian Agency for Public Health, similar to the US Centers for Disease Control (CDC). The idea of Saudi CDC is attractive and even "sexy" but it is not the best option. Experience and literature indicate that the best option for KSA is to revitalize national public health systems on the basis of comprehensive, continuing, and integrated primary health care (PHC) and public health (PH). This article proposes three initial, but essential, steps for such revitalization to take place: political will and support, integration of PHC and PH, and on-job professional programs for the workforce. In addition, current academic and training programs for PHC and PH should be revisited in the light of national vision and strategy that aim for high quality products that protect and promote healthy nation. Scientific associations, medical education research chair, and relevant academic bodies should be involved in the revitalization to ensure quality of process and outcomes. PMID- 25803594 TI - Cultural challenges to implementation of formative assessment in Saudi Arabia: an exploratory study. AB - BACKGROUND/PURPOSE: This study investigates challenges that students and faculty face to implement assessment for learning; and the activities, capabilities, enablers, and indicators which could impact performance. METHOD: The study is a mixed methods research, cross-sectional, exploratory study. The study was organized through two phases of data collection and analysis (QUAL -> quan). Based on qualitative focus group discussions (FGD), we first gathered data through field notes. Later, we engaged in analysis using techniques drawn from qualitative data including categorization, theme identification, and connection to existing literature. Based on this analysis, we developed a questionnaire that could provide quantitative measures based on the qualitative FGD. We then administered the questionnaire, and the quantitative data were analyzed to quantitatively test the qualitative findings. Twenty-four faculty and 142 students from the 4th and 5th clinical years participated voluntarily. Their perception of FA and the cultural challenges that hinder its adoption were evaluated through a FGD and a questionnaire. RESULTS: The mean score of understanding FA concept was equal in faculty and students (p = 0.08). The general challenge that scored highest was the need to balance work and academic load in faculty and the need to balance study load and training and mental anxiety in students. There was no difference between faculty and students in perceiving "learning is teacher-centered" (p = 0.481); and "past learning and assessment experience" (p = 0.322). There was a significant difference between them regarding interaction with opposite gender (p <0.001). Students showed higher value as regards the "gap between learning theories and assessment practice", "grade as a priority", and "discrimination by same faculty gender". CONCLUSION: The authors suggested a "Framework of Innovation in Endorsing Assessment for Learning". It emphasizes a holisitic approach through all levels of the System: Government, Accreditation Bodies, Policy makers; Institution, and Classroom levels. PMID- 25803595 TI - Division of Human Listeria monocytogenes Pulsed-Field Gel Electrophoresis (PFGE) Types Belonging to Lineage I (Serovar 4b, 1/2b, and 3b) into PFGE Groups. AB - The 63 pulsed-field gel electrophoresis (PFGE) types identified among 427 clinical isolates of Listeria monocytogenes that were characterized in a previous study by serotyping and PFGE (AscI) could be further divided into 17 PFGE groups. While the 63 PFGE types, all part of lineage I, were established based on the number and distribution of all bands in each DNA profile, the 17 PFGE groups were based on the configuration of small bands with sizes <145.5 kb. The 30 PFGE types of L. monocytogenes serovar 4b isolates (n=334) were divided into 8 PFGE groups; the 32 PFGE types of serovar 1/2b isolates (n=90) and the serovar 3b isolates (n=3, 1 PFGE type) were divided into 9 PFGE groups. An association was observed between PFGE groups and serovars. L. monocytogenes isolates belonging to PFGE groups I, J, Q, R, X, Z, O-4, and O-5 all shared serovar 4b, whereas isolates from PFGE groups D, G, O, P, T, U, O-1, O-2, and O-3 shared serovar 1/2b. Small fragments <33.3 kb were nonvisible in all L. monocytogenes isolates. From the results of the present study, a procedure for accelerating the identification of PFGE types when analyzing new PFGE profiles can be suggested. Therefore, we propose a stepwise procedure to PFGE profiling by first identifying the PFGE group using the smaller band patterns <145.5 kb, and then determining PFGE types based on the band patterns >145.5 kb. PMID- 25803597 TI - Differentiating the functional contributions of resting connectivity networks to memory decision-making: fMRI support for multistage control processes. AB - Neural substrates of memory control are engaged when participants encounter unexpected mnemonic stimuli (e.g., a new word when told to expect an old word). The present fMRI study (n = 18) employed the likelihood cueing recognition task to elucidate the role of functional connectivity (fcMRI) networks in supporting memory control processes engaged by these unexpected events. Conventional task evoked BOLD analyses recovered a memory control network similar to that previously reported, comprising medial prefrontal, lateral prefrontal, and inferior parietal regions. These were split by their differential affiliation to distinct fcMRI networks ("conflict detection" and "confirmatory retrieval" networks). Subsequent ROI analyses clarified the functional significance of this connectivity differentiation, with "conflict" network-affiliated regions specifically sensitive to cue strength, but not to response confidence, and "retrieval" network-affiliated regions showing the opposite pattern. BOLD time course analyses corroborated the segregation of memory control regions into "early" conflict detection and "late" retrieval analysis, with both processes underlying the allocation of memory control. Response specificity and time course findings were generalized beyond task-recruited ROIs to clusters within the large scale fcMRI networks, suggesting that this connectivity architecture could underlie efficient processing of distinct processes within cognitive tasks. The findings raise important parallels between prevailing theories of memory and cognitive control. PMID- 25803598 TI - Occipital cortex of blind individuals is functionally coupled with executive control areas of frontal cortex. AB - In congenital blindness, the occipital cortex responds to a range of nonvisual inputs, including tactile, auditory, and linguistic stimuli. Are these changes in functional responses to stimuli accompanied by altered interactions with nonvisual functional networks? To answer this question, we introduce a data driven method that searches across cortex for functional connectivity differences across groups. Replicating prior work, we find increased fronto-occipital functional connectivity in congenitally blind relative to blindfolded sighted participants. We demonstrate that this heightened connectivity extends over most of occipital cortex but is specific to a subset of regions in the inferior, dorsal, and medial frontal lobe. To assess the functional profile of these frontal areas, we used an n-back working memory task and a sentence comprehension task. We find that, among prefrontal areas with overconnectivity to occipital cortex, one left inferior frontal region responds to language over music. By contrast, the majority of these regions responded to working memory load but not language. These results suggest that in blindness occipital cortex interacts more with working memory systems and raise new questions about the function and mechanism of occipital plasticity. PMID- 25803599 TI - Auditory perceptual category formation does not require perceptual warping. AB - Categorical perception occurs when a perceiver's stimulus classifications affect their ability to make fine perceptual discriminations and is the most intensively studied form of category learning. On the basis of categorical perception studies, it has been proposed that category learning proceeds by the deformation of an initially homogeneous perceptual space ("perceptual warping"), so that stimuli within the same category are perceived as more similar to each other (more difficult to tell apart) than stimuli that are the same physical distance apart but that belong to different categories. Here, we present a significant counterexample in which robust category learning occurs without these differential perceptual space deformations. Two artificial categories were defined along the dimension of pitch for a perceptually unfamiliar, multidimensional class of sounds. A group of participants (selected on the basis of their listening abilities) were trained to sort sounds into these two arbitrary categories. Category formation, verified empirically, was accompanied by a heightened sensitivity along the entire pitch range, as indicated by changes in an EEG index of implicit perceptual distance (mismatch negativity), with no significant resemblance to the local perceptual deformations predicted by categorical perception. This demonstrates that robust categories can be initially formed within a continuous perceptual dimension without perceptual warping. We suggest that perceptual category formation is a flexible, multistage process sequentially combining different types of learning mechanisms rather than a single process with a universal set of behavioral and neural correlates. PMID- 25803600 TI - The Timing of Regular Sequences: Production, Perception, and Covariation. AB - The temporal structure of behavior provides information that allows the tracking of temporal regularity in the sensory and sensorimotor domains. In turn, temporal regularity allows the generation of predictions about upcoming events and to adjust behavior accordingly. These mechanisms are essential to ensure behavior beyond the level of mere reaction. However, efficient temporal processing is required to establish adequate internal representations of temporal structure. The current study used two simple paradigms, namely, finger-tapping at a regular self-chosen rate (spontaneous motor tempo) and ERPs of the EEG (EEG/ERP) recorded during attentive listening to temporally regular and irregular "oddball" sequences to explore the capacity to encode and use temporal regularity in production and perception. The results show that specific aspects of the ability to time a regular sequence of events in production covary with the ability to time a regular sequence in perception, probably pointing toward the engagement of domain-general mechanisms. PMID- 25803601 TI - Malnutrition and Dysphagia in long-term care: a systematic review. AB - Determining the co-occurrence of malnutrition and dysphagia is important to understand the extent to which swallowing impairment contributes to poor food intake in long-term care (LTC). This review investigated the impact of dysphagia on malnutrition in LTC by synthesizing the results of published literature. Seven electronic databases were used to search for English-language publications reporting malnutrition and dysphagia in LTC facilities from 1946 to 2013. Fourteen studies were eligible for inclusion. Overall, the literature on the co occurrence of malnutrition and dysphagia in LTC shows a paucity of high-quality evidence. Articles reviewed lacked consistent definitions for both conditions. Methods used to confirm each diagnosis also differed and were of questionable validity. Based on a review of the literature, evidence of the existence of concurrent concerns with respect to malnutrition and dysphagia emerges. The reported frequency of participants in LTC with dysphagia ranges from 7% to 40%, while the percentage of those who were malnourished ranges from 12% to 54%. Due to discrepancies used to describe and measure these conditions, it is difficult to determine the exact prevalence of either condition separately, or in combination. Consequently, the impact of dysphagia on malnutrition must be considered and studied using valid definitions and measures. PMID- 25803602 TI - Use of song as an effective teaching strategy for nutrition education in older adults. AB - The objective of this study was to explore whether singing an educational song would be effective in improving older adults' knowledge about nutrition. We used a randomized controlled design to determine whether singing an educational song would result in increased nutrition knowledge in a low-income population of older adults compared to a control group of similar adults who did not sing the song. Eighteen congregate nutrition sites were randomly assigned to the treatment or control group. Analysis via independent samples t -test showed the knowledge gain mean scores for the treatment group were significantly ( P < 0.05) greater than those of the control group. This study supports a unique new approach to increasing nutrition knowledge of older adults by using music. PMID- 25803596 TI - Cognitive network neuroscience. AB - Network science provides theoretical, computational, and empirical tools that can be used to understand the structure and function of the human brain in novel ways using simple concepts and mathematical representations. Network neuroscience is a rapidly growing field that is providing considerable insight into human structural connectivity, functional connectivity while at rest, changes in functional networks over time (dynamics), and how these properties differ in clinical populations. In addition, a number of studies have begun to quantify network characteristics in a variety of cognitive processes and provide a context for understanding cognition from a network perspective. In this review, we outline the contributions of network science to cognitive neuroscience. We describe the methodology of network science as applied to the particular case of neuroimaging data and review its uses in investigating a range of cognitive functions including sensory processing, language, emotion, attention, cognitive control, learning, and memory. In conclusion, we discuss current frontiers and the specific challenges that must be overcome to integrate these complementary disciplines of network science and cognitive neuroscience. Increased communication between cognitive neuroscientists and network scientists could lead to significant discoveries under an emerging scientific intersection known as cognitive network neuroscience. PMID- 25803603 TI - A descriptive study of nasogastric tube feeding among geriatric inpatients in Malaysia: utilization, complications, and caregiver opinions. AB - The strong emphasis on feeding in Asian cultures may influence decisions for nasogastric (NG) tube feeding in geriatric inpatients. We evaluated the utility, complications, and opinions of caregivers toward NG tube feeding in an acute geriatric ward in a teaching hospital in Kuala Lumpur. Consecutive patients aged 65 years and older receiving NG tube feeding were included. Sociodemographic, clinical, and laboratory indices were recorded. Opinion on NG tube feeding were evaluated through face-to-face interviews with caregivers, recruited through convenience sampling. Of 432 patients admitted, 96 (22%), age +/- standard deviation = 80.8 +/- 7.4 years, received NG tube feeding. The complication and mortality rates were 69% and 38%, respectively. Diabetes (odds ratio [95% confidence interval] = 3.34 [1.07, 10.44], aspiration pneumonia (8.15 [2.43, 27.24]), impaired consciousness (3.13 [1.05, 9.36]), and albumin <=26 g/dl (4.43 [1.46, 13.44]) were independent predictors of mortality. Other relatives were more likely than spouses (23.5 [3.59, 154.2]) and caregivers with tertiary education more likely than those with no formal education ( 18 [1.23, 262.7]) to agree to NG feeding. Sixty-four percent of caregivers felt NG tube feeding was appropriate at the end of life, mostly due to the fear of starvation. NG tube feeding is widely used in our setting, despite high complication and mortality rates, with likely influences from cultural emphasis on feeding. PMID- 25803604 TI - Impact of a program of Tai Chi plus behaviorally based dietary weight loss on physical functioning and coronary heart disease risk factors: a community-based study in obese older women. AB - This study employed a quasi-experimental design in a community-based study translating the results of our recent findings on the combined effects of Tai Chi and weight loss on physical function and coronary heart disease (CHD) risk factors. A 16-week intervention was conducted to assess the impact of Tai Chi plus a behavioral weight loss program (TCWL, n = 29) on obese (body mass index [BMI] = 35.4 +/- 0.8 kg/m2) older (68.2 +/- 1.5 yr.) women compared to a control group (CON, n = 9, BMI = 38.0 +/- 1.5 kg/m2, 65.6 +/- 2.7 yr.), which was asked to maintain their normal lifestyle. The TCWL group lost weight (1.6 +/- 2.9 kg, P = 0.006) while the CON group did not (1.2 +/- 1.9 kg, P = 0.106). Physical functioning as measured by the short physical performance battery improved in TCWL when compared to the CON group (beta = 1.94, 95% Confidence Interval [CI]: 1.12, 2.76, P < 0.001). TCWL also improved in sit-and-reach flexibility (beta = 2.27, 95% CI: -4.09, -0.46, P = 0.016), body fat mass (BMI, beta = -0.65, 95% CI: -1.03, -0.26, P = 0.002), waist circumference (beta = -1.78, 95% CI: -2.83, 0.72, P = 0.002), systolic blood pressure (beta = -16.41, 95% CI: -21.35, -11.48, P < 0.001), and diastolic blood pressure (beta = -9.52, 95% CI: -12.65, -6.39, P < 0.001). Thus, TCWL intervention may represent an effective strategy to improve physical function and ameliorate CHD risk in the older adult population. PMID- 25803605 TI - Eat Smart, Live Strong intervention increases fruit and vegetable consumption among low-income older adults. AB - This study evaluated the impact of a four-session interactive nutrition education program-Eat Smart, Live Strong (ESLS)-on the consumption of fruit and vegetables by low-income older adults. A pre-post quasi-experimental design study was conducted with a longitudinal sample of 614 low-income Supplemental Nutrition Assistance Program (SNAP) participants and those eligible for SNAP, aged 60 to 80 years, in 17 intervention and 16 comparison senior centers in Michigan. The study compared participants' self-reports of their consumption of fruit and vegetables using a modified version of the University of California Cooperative Extension Food Behavior Checklist. ESLS increased participants' average daily consumption of fruit by 0.2 cups (P < 0.05) and vegetables by 0.31 cups (P < 0.01). ESLS, a four-session, cognitive-behavioral nutrition education program is an effective curriculum for helping low-income older adults eat more fruit and vegetables. PMID- 25803606 TI - beta-arrestin regulates estradiol membrane-initiated signaling in hypothalamic neurons. AB - Estradiol (E2) action in the nervous system is the result of both direct nuclear and membrane-initiated signaling (EMS). E2 regulates membrane estrogen receptor alpha (ERalpha) levels through opposing mechanisms of EMS-mediated trafficking and internalization. While beta-arrestin-mediated mERalpha internalization has been described in the cortex, a role of beta-arrestin in EMS, which underlies multiple physiological processes, remains undefined. In the arcuate nucleus of the hypothalamus (ARH), membrane-initiated E2 signaling modulates lordosis behavior, a measure of female sexually receptivity. To better understand EMS and regulation of ERalpha membrane levels, we examined the role of beta-arrestin, a molecule associated with internalization following agonist stimulation. In the present study, we used an immortalized neuronal cell line derived from embryonic hypothalamic neurons, the N-38 line, to examine whether beta-arrestins mediate internalization of mERalpha. beta-arrestin-1 (Arrb1) was found in the ARH and in N-38 neurons. In vitro, E2 increased trafficking and internalization of full length ERalpha and ERalphaDelta4, an alternatively spliced isoform of ERalpha, which predominates in the membrane. Treatment with E2 also increased phosphorylation of extracellular-signal regulated kinases 1/2 (ERK1/2) in N-38 neurons. Arrb1 siRNA knockdown prevented E2-induced ERalphaDelta4 internalization and ERK1/2 phosphorylation. In vivo, microinfusions of Arrb1 antisense oligodeoxynucleotides (ODN) into female rat ARH knocked down Arrb1 and prevented estradiol benzoate-induced lordosis behavior compared with nonsense scrambled ODN (lordosis quotient: 3 +/- 2.1 vs. 85.0 +/- 6.0; p < 0.0001). These results indicate a role for Arrb1 in both EMS and internalization of mERalpha, which are required for the E2-induction of female sexual receptivity. PMID- 25803608 TI - Wild type beta-2 microglobulin and DE loop mutants display a common fibrillar architecture. AB - Beta-2 microglobulin (beta2m) is the protein responsible for a pathologic condition known as dialysis related amyloidosis. In recent years an important role has been assigned to the peptide loop linking strands D and E (DE loop) in determining beta2m stability and amyloid propensity. Several mutants of the DE loop have been studied, showing a good correlation between DE loop geometrical strain, protein stability and aggregation propensity. However, it remains unclear whether the aggregates formed by wild type (wt) beta2m and by the DE loop variants are of the same kind, or whether the mutations open new aggregation pathways. In order to address this question, fibrillar samples of wt and mutated beta2m variants have been analysed by means of atomic force microscopy and infrared spectroscopy. The data here reported indicate that the DE loop mutants form aggregates with morphology and structural organisation very similar to the wt protein. Therefore, the main effect of beta2m DE loop mutations is proposed to stem from the different stabilities of the native fold. Considerations on the structural role of the DE loop in the free monomeric beta2m and as part of the Major Histocompatibility Complex are also presented. PMID- 25803607 TI - Mapping biodiversity and setting conservation priorities for SE Queensland's rainforests using DNA barcoding. AB - Australian rainforests have been fragmented due to past climatic changes and more recently landscape change as a result of clearing for agriculture and urban spread. The subtropical rainforests of South Eastern Queensland are significantly more fragmented than the tropical World Heritage listed northern rainforests and are subject to much greater human population pressures. The Australian rainforest flora is relatively taxonomically rich at the family level, but less so at the species level. Current methods to assess biodiversity based on species numbers fail to adequately capture this richness at higher taxonomic levels. We developed a DNA barcode library for the SE Queensland rainforest flora to support a methodology for biodiversity assessment that incorporates both taxonomic diversity and phylogenetic relationships. We placed our SE Queensland phylogeny based on a three marker DNA barcode within a larger international rainforest barcode library and used this to calculate phylogenetic diversity (PD). We compared phylo- diversity measures, species composition and richness and ecosystem diversity of the SE Queensland rainforest estate to identify which bio subregions contain the greatest rainforest biodiversity, subregion relationships and their level of protection. We identified areas of highest conservation priority. Diversity was not correlated with rainforest area in SE Queensland subregions but PD was correlated with both the percent of the subregion occupied by rainforest and the diversity of regional ecosystems (RE) present. The patterns of species diversity and phylogenetic diversity suggest a strong influence of historical biogeography. Some subregions contain significantly more PD than expected by chance, consistent with the concept of refugia, while others were significantly phylogenetically clustered, consistent with recent range expansions. PMID- 25803610 TI - Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-kappaB and TGF-beta1/Smad pathways in db/db diabetic mice. AB - Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively) once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-alpha, interleukin-1beta, and active nuclear factor kappaB (NF kappaB). APF treatment also reduced type I and IV collagen, transforming growth factor-beta1 (TGF-beta1), and TGF-beta1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-kappaB and TGF-beta1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of alpha-smooth muscle actin, collagen I, TGF-beta1 and NF-kappaB in mesangial cells cultured with high glucose concentrations. Our findings indicate that treatment with multi component herbal therapeutic formulations may be a useful approach for the treatment of diabetic nephropathy. PMID- 25803609 TI - The bactofilin cytoskeleton protein BacM of Myxococcus xanthus forms an extended beta-sheet structure likely mediated by hydrophobic interactions. AB - Bactofilins are novel cytoskeleton proteins that are widespread in Gram-negative bacteria. Myxococcus xanthus, an important predatory soil bacterium, possesses four bactofilins of which one, BacM (Mxan_7475) plays an important role in cell shape maintenance. Electron and fluorescence light microscopy, as well as studies using over-expressed, purified BacM, indicate that this protein polymerizes in vivo and in vitro into ~3 nm wide filaments that further associate into higher ordered fibers of about 10 nm. Here we use a multipronged approach combining secondary structure determination, molecular modeling, biochemistry, and genetics to identify and characterize critical molecular elements that enable BacM to polymerize. Our results indicate that the bactofilin-determining domain DUF583 folds into an extended beta-sheet structure, and we hypothesize a left-handed beta-helix with polymerization into 3 nm filaments primarily via patches of hydrophobic amino acid residues. These patches form the interface allowing head to-tail polymerization during filament formation. Biochemical analyses of these processes show that folding and polymerization occur across a wide variety of conditions and even in the presence of chaotropic agents such as one molar urea. Together, these data suggest that bactofilins are comprised of a structure unique to cytoskeleton proteins, which enables robust polymerization. PMID- 25803612 TI - The nicotinic receptor Alpha7 impacts the mouse lung response to LPS through multiple mechanisms. AB - The nicotinic acetylcholine receptor alpha7 (alpha7) is expressed by neuronal and non-neuronal cells throughout the body. We examined the mechanisms of the lung inflammatory response to intranasal (i.n.) lipopolysaccharide (LPS) regulated by alpha7. This was done in mice using homologous recombination to introduce a point mutation in the alpha7 receptor that replaces the glutamate residue 260 that lines the pore with alanine (alpha7E260A), which has been implicated in controlling the exceptional calcium ion conductance of this receptor. The alpha7E260A mice exhibit normal inflammatory cell recruitment to the blood in response to i.n. LPS administration. This differs from the alpha7knock-out (alpha7KO) in which upstream signaling to initiate the recruitment to the blood following i.n. LPS is significantly impaired. While hematopoietic cells are recruited to the bloodstream in the alpha7E260A mouse, they fail to be recruited efficiently into both the interstitium and alveolar spaces of the lung. Bone marrow reconstitution experiments demonstrate that the responsiveness of both CD45+ and CD45- cells of the alpha7E260A mouse are impaired. The expression of several pro-inflammatory cytokine and chemokine RNAs including TNFalpha, IL 1alpha, Ccl2 and Cxcl10 are decreased in the alpha7E260A mouse. However, there is a substantial increase in IL-13 expression by CD45- lung interstitial cells in the alpha7E260A mouse. Our results support the conclusion that alpha7 functional pleiotropy contributes to modulating the tissue response to an inflammatory insult through impacting upon a variety of mechanisms reflecting the individual cell composition of the lung. PMID- 25803611 TI - A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies. AB - Tauopathies are a group of disorders leading to cognitive and behavioral impairment in the aging population. While four-repeat (4R) Tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and Alzheimer's disease, three-repeat (3R) Tau is the most abundant splice, in Pick's disease. A number of transgenic models expressing wild-type and mutant forms of the 4R Tau have been developed. However, few models of three-repeat Tau are available. A transgenic mouse model expressing three-repeat Tau was developed bearing the mutations associated with familial forms of Pick's disease (L266V and G272V mutations). Two lines expressing high (Line 13) and low (Line 2) levels of the three-repeat mutant Tau were analyzed. By Western blot, using antibodies specific to three-repeat Tau, Line 13 expressed 5-times more Tau than Line 2. The Tau expressed by these mice was most abundant in the frontal-temporal cortex and limbic system and was phosphorylated at residues detected by the PHF-1, AT8, CP9 and CP13 antibodies. The higher-expressing mice displayed hyperactivity, memory deficits in the water maze and alterations in the round beam. The behavioral deficits started at 6-8 months of age and were associated with a progressive increase in the accumulation of 3R Tau. By immunocytochemistry, mice from Line 13 displayed extensive accumulation of 3R Tau in neuronal cells bodies in the pyramidal neurons of the neocortex, CA1-3 regions, and dentate gyrus of the hippocampus. Aggregates in the granular cells had a globus appearance and mimic Pick's-like inclusions. There were abundant dystrophic neurites, astrogliosis and synapto-dendritic damage in the neocortex and hippocampus of the higher expresser line. The hippocampal lesions were moderately argyrophilic and Thioflavin-S negative. By electron microscopy, discrete straight filament aggregates were detected in some neurons in the hippocampus. This model holds promise for better understanding the natural history and progression of 3R tauopathies and their relationship with mitochondrial alterations and might be suitable for therapeutical testing. PMID- 25803613 TI - N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus. AB - An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro desoxyglucose ([18F]-FDG)-MUPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole brain [18F]-FDG-MUPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L group was accelerated by about 6 days relative to controls. The effect of N acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of MUPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus. PMID- 25803614 TI - ICan: an integrated co-alteration network to identify ovarian cancer-related genes. AB - BACKGROUND: Over the last decade, an increasing number of integrative studies on cancer-related genes have been published. Integrative analyses aim to overcome the limitation of a single data type, and provide a more complete view of carcinogenesis. The vast majority of these studies used sample-matched data of gene expression and copy number to investigate the impact of copy number alteration on gene expression, and to predict and prioritize candidate oncogenes and tumor suppressor genes. However, correlations between genes were neglected in these studies. Our work aimed to evaluate the co-alteration of copy number, methylation and expression, allowing us to identify cancer-related genes and essential functional modules in cancer. RESULTS: We built the Integrated Co alteration network (ICan) based on multi-omics data, and analyzed the network to uncover cancer-related genes. After comparison with random networks, we identified 155 ovarian cancer-related genes, including well-known (TP53, BRCA1, RB1 and PTEN) and also novel cancer-related genes, such as PDPN and EphA2. We compared the results with a conventional method: CNAmet, and obtained a significantly better area under the curve value (ICan: 0.8179, CNAmet: 0.5183). CONCLUSION: In this paper, we describe a framework to find cancer-related genes based on an Integrated Co-alteration network. Our results proved that ICan could precisely identify candidate cancer genes and provide increased mechanistic understanding of carcinogenesis. This work suggested a new research direction for biological network analyses involving multi-omics data. PMID- 25803617 TI - Synthesis, characterization and theoretical studies of nonlinear optical crystal Sr2B5O9(OH).H2O. AB - Strontium borate Sr2B5O9(OH).H2O (space group C2, No. 5) has been synthesized in high yields using a facile hydrothermal method. The UV-Vis-NIR diffuse reflectance spectrum shows that it has a wide transparency range extending from UV to NIR with the short-wavelength cut off edge below 190 nm. Second-harmonic generation (SHG) has been measured with a 1064 nm laser using the Kurtz and Perry technique, which shows that Sr2B5O9(OH).H2O is phase matchable and the powder SHG effect is approximately 3 times that of KDP. It also has a high thermal stability up to 500 degrees C which has been identified by TG, DSC and variable temperature PXRD. These properties make it possible for application as a UV nonlinear optical (NLO) material. Based on the electronic band structure, the optical refractive indices, birefringence, and SHG coefficients of Sr2B5O9(OH).H2O are calculated, which are consistent with experiments. In addition, the electronic structure, SHG-weighted electron density and real-space atom-cutting analyses are performed to elucidate the origin of its NLO properties. PMID- 25803615 TI - IKK2 inhibition using TPCA-1-loaded PLGA microparticles attenuates laser-induced choroidal neovascularization and macrophage recruitment. AB - The inhibition of NF-kappaB by genetic deletion or pharmacological inhibition of IKK2 significantly reduces laser-induced choroid neovascularization (CNV). To achieve a sustained and controlled intraocular release of a selective and potent IKK2 inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3 thiophenecarboxamide (TPCA-1) (MW: 279.29), we developed a biodegradable poly lactide-co-glycolide (PLGA) polymer-delivery system to further investigate the anti-neovascularization effects of IKK2 inhibition and in vivo biosafety using laser-induced CNV mouse model. The solvent-evaporation method produced spherical TPCA-1-loaded PLGA microparticles characterized with a mean diameter of 2.4 1/4m and loading efficiency of 80%. Retrobulbar administration of the TPCA-1-loaded PLGA microparticles maintained a sustained drug level in the retina during the study period. No detectable TPCA-1 level was observed in the untreated contralateral eye. The anti-CNV effect of retrobulbarly administrated TPCA-1 loaded PLGA microparticles was assessed by retinal fluorescein leakage and isolectin staining methods, showing significantly reduced CNV development on day 7 after laser injury. Macrophage infiltration into the laser lesion was attenuated as assayed by choroid/RPE flat-mount staining with anti-F4/80 antibody. Consistently, laser induced expressions of Vegfa and Ccl2 were inhibited by the TPCA-1-loaded PLGA treatment. This TPCA-1 delivery system did not cause any noticeable cellular or functional toxicity to the treated eyes as evaluated by histology and optokinetic reflex (OKR) tests; and no systemic toxicity was observed. We conclude that retrobulbar injection of the small molecule IKK2 inhibitor TPCA-1, delivered by biodegradable PLGA microparticles, can achieve a sustained and controllable drug release into choroid/retina and attenuate laser-induced CNV development without causing apparent systemic toxicity. Our results suggest a potential clinical application of TPCA-1 delivered by microparticles in treatment of CNV in the patients with age-related macular degeneration and other retinal neovascularization diseases. PMID- 25803616 TI - A novel pre-clinical murine model to study the life cycle and progression of cervical and anal papillomavirus infections. AB - BACKGROUND: Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disease has long been sought. We chose to investigate whether the newly discovered mouse papillomavirus, MmuPV1, could infect mucosal tissues in Foxn1nu/Foxn1nu mice. METHODS: The vaginal and anal canals of Foxn1nu/Foxn1nu mice were gently abraded using Nonoxynol-9 and "Doctor's BrushPicks" and MmuPV1 was delivered into the vaginal tract or the anal canal. RESULTS: Productive vaginal, cervical and anal infections developed in all mice. Vaginal/cervical infections could be monitored by vaginal lavage. Dysplasias were evident in all animals. CONCLUSIONS: Anogenital tissues of a common laboratory mouse can be infected with a papillomavirus unique to that animal. This observation will pave the way for fundamental virological and immunological studies that have been challenging to carry out heretofore due to lack of a suitable model system. PMID- 25803619 TI - Iridium-catalyzed dehydrogenative silylation of azulenes based on regioselective C-H bond activation. AB - Use of an iridium catalyst allowed the efficient dehydrogenative functionalization of C-H bonds of azulenes with the production of hydrogen as the sole byproduct. The reaction occurred with excellent chemo- and regioselectivities to provide 2-silylazulenes even without any directing groups. Effective conjugation through the 2-position of the azulene ring was demonstrated by the unique stimuli-responsiveness against an acid-base reaction. PMID- 25803618 TI - Unravelling the hidden ancestry of American admixed populations. AB - The movement of people into the Americas has brought different populations into contact, and contemporary American genomes are the product of a range of complex admixture events. Here we apply a haplotype-based ancestry identification approach to a large set of genome-wide SNP data from a variety of American, European and African populations to determine the contributions of different ancestral populations to the Americas. Our results provide a fine-scale characterization of the source populations, identify a series of novel, previously unreported contributions from Africa and Europe and highlight geohistorical structure in the ancestry of American admixed populations. PMID- 25803621 TI - Collagen II regulates chondroycte integrin expression profile and differentiation. AB - Collagen II is the major fibril-forming collagen in cartilage. Complete absence of collagen II in mice is not compatible with life and in humans mutations in the COL2A1 gene lead to osteochondrodysplasias with diverse phenotypes. However, mechanistic studies on how chondrocytes respond to a lack of collagen II in their extracellular matrix are limited. Primary mouse chondrocytes were isolated from knee joints of newborn mice and transfected with siRNA targeting Col2alpha1 to suppress collagen II expression. The expression of integrin receptors and matrix proteins was investigated by RT-PCR and immunoblots. The localization of matrix components was evaluated by immunostaining. Signaling pathways and the differentiation state of chondrocytes was monitored by RT-PCR and flow cytometry. We demonstrate that in the absence of collagen II chondrocytes start to produce collagen I. Some binding partners of collagen II are partially lost from the matrix while other proteins, e.g. COMP, were still found associated with the newly formed collagen network. The lack of collagen II induced changes in the expression profile of integrins. Further, we detected alterations in the Indian hedgehog/parathyroid hormone-related protein (Ihh/PTHrP) pathway that were accompanied by changes in the differentiation state of chondrocytes. Collagen II seems not to be essential for chondrocyte survival in culture but it plays an important role in maintaining chondrocyte differentiation. We suggest that a crosstalk between extracellular matrix and cells via integrins and the Ihh/PTHrP pathway is involved in regulating the differentiation state of chondrocytes. PMID- 25803622 TI - Selection of animal models for pre-clinical strategies in evaluating the fracture healing, bone graft substitutes and bone tissue regeneration and engineering. AB - In vitro assays can be useful in determining biological mechanism and optimizing scaffold parameters, however translation of the in vitro results to clinics is generally hard. Animal experimentation is a better approximation than in vitro tests, and usage of animal models is often essential in extrapolating the experimental results and translating the information in a human clinical setting. In addition, usage of animal models to study fracture healing is useful to answer questions related to the most effective method to treat humans. There are several factors that should be considered when selecting an animal model. These include availability of the animal, cost, ease of handling and care, size of the animal, acceptability to society, resistance to surgery, infection and disease, biological properties analogous to humans, bone structure and composition, as well as bone modeling and remodeling characteristics. Animal experiments on bone healing have been conducted on small and large animals, including mice, rats, rabbits, dogs, pigs, goats and sheep. This review also describes the molecular events during various steps of fracture healing and explains different means of fracture healing evaluation including biomechanical, histopathological and radiological assessments. PMID- 25803620 TI - Differential responses of normal human melanocytes to intra- and extracellular dsRNA. AB - Viral factor has been implicated in the etiopathogenesis of vitiligo. To elucidate the effects of viral double-stranded RNA (dsRNA) on melanocytes and to explore the underlying mechanisms, primary cultured normal human melanocytes were treated with synthetic viral dsRNA analog poly(I:C). The results demonstrated that poly(I:C)-triggered apoptosis when transfected into melanocytes, while extracellular poly(I:C) did not have that effect. Intracellular poly(I:C)-induced melanocyte death was decreased by RIG-I or MDA5 siRNA, but not by TLR3 siRNA. Both intracellular and extracellular poly(I:C) induced the expression of IFNB, TNF, IL6, and IL8. However, extracellular poly(I:C) demonstrated a much weaker induction capacity of cytokine genes than intracellular poly(I:C). Further analysis revealed that phosphorylation of TBK1, IRF3, IRF7, and TAK1 was differentially induced by intra- or extracellular poly(I:C). NFkappaB inhibitor Bay 11-7082 decreased the induction of all the cytokines by poly(I:C), suggesting the ubiquitous role of NFkappaB in the process. Poly(I:C) treatment also induced the phosphorylation of p38 and JNK in melanocytes. Both JNK and p38 inhibitors showed suppression on the cytokine induction by intra- or extracellular poly(I:C). However, only the JNK inhibitor decreased the intracellular poly(I:C) induced melanocyte death. Taken together, this study provides the possible mechanism of viral factor in the pathogenesis of vitiligo. PMID- 25803623 TI - An inflammatory equine model demonstrates dynamic changes of immune response and cartilage matrix molecule degradation in vitro. AB - The molecular aspects of inflammation were investigated in equine articular cartilage explants using quantitative proteomics. Articular cartilage explants were stimulated with interleukin (IL)-1beta in vitro for 25 days, and proteins released into cell culture media were chemically labeled with isobaric mass tags and analyzed by liquid chromatography-tandem mass spectrometry. A total of 127 proteins were identified and quantified in media from explants. IL-1beta stimulation resulted in an abundance of proteins related to inflammation, including matrix metalloproteinases, acute phase proteins, complement components and IL-6. Extracellular matrix (ECM) molecules were released at different time points, and fragmentation of aggrecan and cartilage oligomeric matrix protein was observed at days 3 and 6, similar to early-stage OA in vivo. Degradation products of the collagenous network were observed at days 18 and 22, similar to late-stage OA. This model displays a longitudinal quantification of released molecules from the ECM of articular cartilage. Identification of dynamic changes of extracellular matrix molecules in the secretome of equine explants stimulated with IL-1beta over time may be useful for identifying components released at different time points during the spontaneous OA process. PMID- 25803624 TI - Authors' reply: No vaginal bleeding does not indicate no bleeding: still valid for Bakri balloon and also for "holding the cervix". PMID- 25803625 TI - Early Changes in Corneal Epithelial Thickness after Cataract Surgery--Pilot Study. AB - PURPOSE: To assess early variations in central and paracentral corneal epithelial and non-epithelial thicknesses after uneventful clear corneal incision phacoemulsification. MATERIALS AND METHODS: Twenty patients with a senile cataract underwent coaxial phacoemulsification through a 2.75-mm-wide corneal incision created at 180 degrees in a prospective cohort pilot study. Corneal sublayer thickness measurements were obtained with Fourier-domain optical coherence tomography (FD-OCT, Cirrus HD-OCT, Carl Zeiss Meditec, Inc., Dublin, CA) before and after 1 week and 1 month postoperatively. Central measurements were performed in the middle of the FD-OCT scan and in the 3-mm corneal diameter (paracentral 180 degrees and 0 degrees locations). Epithelial, non-epithelial and total corneal pachymetry were measured at the central and paracentral locations. RESULTS: No significant changes in epithelial thickness were seen 1 week postoperatively. However, 1 month postoperatively, the central, 180 degrees , and 0 degrees paracentral epithelial thicknesses (52.7 +/- 3.8, 53.1 +/- 5.4, and 52.7 +/- 5.3 um, respectively) decreased significantly (p < 0.01) compared to preoperatively (57.2 +/- 4.8, 58.0 +/- 5.7, 56.6 +/- 5.3 um, respectively). The 1 week central, 180 degrees , and 0 degrees paracentral non-epithelial corneal thicknesses (515.5 +/- 39.6, 534.3 +/- 45.6, and 521.3 +/- 36.9 um) were significantly (p < 0.01) higher than preoperatively (486.2 +/- 34.7, 498.2 +/- 33.8, 497.5 +/- 32.3 um, respectively). The non-epithelial corneal thickness increase was significantly (p = 0.02) greater after 1 week in the central (29.3 +/- 17.2 um) and the 180 degrees paracentral (36.1 +/- 28.7 um) locations than at the 0 degrees paracentral location (23.8 +/- 16.5 um). CONCLUSIONS: Immediate postoperative corneal edema following phacoemulsification irregularly affects the cornea at the sublayer level. The initial central and paracentral non-epithelial thickening is compensated by subsequent central and paracentral epithelial thinning. These initial changes occurred more markedly closest to the main incision over the entrance pupil, which may have visual implications. PMID- 25803626 TI - Perioperative synbiotics decrease postoperative complications in periampullary neoplasms: a randomized, double-blind clinical trial. AB - Periampullary neoplasms are rapidly progressive tumors with a poor prognosis and high morbidity and mortality rates, which have a negative influence on patient outcomes. Some probiotics and prebiotics have the ability to protect the intestinal barrier and prevent bacterial translocation, infection, and postoperative complications. We evaluated the use of synbiotics in a prospective, double-blind study of patients undergoing surgery for periampullary neoplasms (PNs) and assessed the effect of these agents on nutritional status, postoperative complications, antibiotic use, length of hospital stay, and mortality. Patients were randomized to receive probiotics and prebiotics synbiotics--group S [Lactobacillus acidophilus 10, 1 * 10(9)CFU, Lactobacillus rhamnosus HS 111, 1 * 10(9) CFU, Lactobacillus casei 10, 1 * 10(9) CFU, Bifidobacterium bifidum, 1 * 10(9)CFU, and fructooligosaccharides (FOS) 100 mg]- or placebo-controls--group C, twice daily, for a total of 14 days. Risk, clinical status, and postoperative complication rates were assessed. Twenty-three patients were allocated to each group. The incidence of postoperative infection was significantly lower in group S (6 of 23 patients, 26.1%) than in group C (16 of 23 patients, 69.6%) (P = 0.00). Duration of antibiotic therapy was also shorter in group S (mean = 9 days vs. 15 days in group C; P = 0.01). Noninfectious complications were less common in group S (6 of 23 vs. 14 of 23 patients in group C; P = 0.03). Mean length of hospital stay was 12 +/- 5 days in group S vs. 23 +/ 14 days in group C (P = 0.00). No deaths occurred in group S, whereas 6 deaths occurred in group C (P = 0.02). Perioperative administration of synbiotics reduces postoperative mortality and complication rates in patients undergoing surgery for PNs. PMID- 25803628 TI - Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment? AB - Sepsis is a clinical syndrome characterized by systemic inflammation, usually in response to infection. The signs and symptoms are very similar to Systemic Inflammatory Response Syndrome (SIRS), which typically occur consequent to trauma and auto-immune diseases. Common treatments of sepsis include administration of antibiotics and oxygen. Oxygen is administered due to ischemia in tissues, which results in the production of free radicals. Poor utilization of oxygen by the mitochondrial electron transport chain can increase oxidative stress during ischemia and exacerbate the severity and outcome in septic patients. This course of treatment virtually mimics the conditions seen in ischemia-reperfusion disorders. Therefore, this review proposes that the mechanism of free radical production seen in sepsis and SIRS is identical to the oxidative stress seen in ischemia-reperfusion injury. Specifically, this is due to a biochemical mechanism within the mitochondria where the oxidation of succinate to fumarate by succinate dehydrogenase (complex II) is reversed in sepsis (hypoxia), leading to succinate accumulation. Oxygen administration (equivalent to reperfusion) rapidly oxidizes the accumulated succinate, leading to the generation of large amounts of superoxide radical and other free radical species. Organ damage possibly leading to multi-organ failure could result from this oxidative burst seen in sepsis and SIRS. Accordingly, we postulate that temporal administration with anti-oxidants targeting the mitochondria and/or succinate dehydrogenase inhibitors could be beneficial in sepsis and SIRS patients. PMID- 25803627 TI - Characterization of the avian Trojan gene family reveals contrasting evolutionary constraints. AB - "Trojan" is a leukocyte-specific, cell surface protein originally identified in the chicken. Its molecular function has been hypothesized to be related to anti apoptosis and the proliferation of immune cells. The Trojan gene has been localized onto the Z sex chromosome. The adjacent two genes also show significant homology to Trojan, suggesting the existence of a novel gene/protein family. Here, we characterize this Trojan family, identify homologues in other species and predict evolutionary constraints on these genes. The two Trojan-related proteins in chicken were predicted as a receptor-type tyrosine phosphatase and a transmembrane protein, bearing a cytoplasmic immuno-receptor tyrosine-based activation motif. We identified the Trojan gene family in ten other bird species and found related genes in three reptiles and a fish species. The phylogenetic analysis of the homologues revealed a gradual diversification among the family members. Evolutionary analyzes of the avian genes predicted that the extracellular regions of the proteins have been subjected to positive selection. Such selection was possibly a response to evolving interacting partners or to pathogen challenges. We also observed an almost complete lack of intracellular positively selected sites, suggesting a conserved signaling mechanism of the molecules. Therefore, the contrasting patterns of selection likely correlate with the interaction and signaling potential of the molecules. PMID- 25803629 TI - Process improvement: a multi-registry database abstraction success story. AB - BACKGROUND: The St. Joseph Hospital/Marshfield Clinic Cardiac Database Registry submits data to the National Cardiovascular Data Registry (NCDR) and to the Society of Thoracic Surgeons (STS) National Database. Delayed chart abstraction is problematic, since hospital policy prohibits patient care clarifications made to the medical record more than 1 month after hospital discharge. This can also lead to late identification of missed care opportunities and untimely notification to providers. Our institution was 3.5 months behind in retrospective postdischarge case abstraction. A process improvement plan was implemented to shorten this delay to 1 month postdischarge. METHODS: Daily demand of incoming cases and abstraction capacity were determined for 4 employees. Demand was matched to capacity, with the remaining time allocated to reducing backlog. RESULTS: Daily demand of new cases was 17.1 hours. Daily abstraction capacity was 24 hours, assuming 6 hours of effective daily abstraction time per employee, leaving 7 hours per day for backlogged case abstraction. The predicted time to reach abstraction target was 10 weeks. This was accomplished after 10 weeks, as predicted, leading to a 60% reduction of backlogged cases. CONCLUSION: The delay of postdischarge chart abstraction was successfully shortened from 3.5 months to 1 month. We intend to maintain same-day abstraction efficiency without reaccumulating substantial backlog. PMID- 25803630 TI - Updated and expanded study of polycythemia vera and other myeloproliferative neoplasms in the tri-county area. AB - INTRODUCTION: The results of a 2001-2005 polycythemia vera (PV) investigation in Eastern Pennsylvania revealed a disease cluster plus underreporting and false reporting to the Pennsylvania Cancer Registry (PCR). PURPOSE: The objectives of this study were 1) to assess PV reporting to the PCR in 2006-2009, 2) to determine whether a cancer cluster persisted, and 3) to determine whether other myeloproliferative neoplasms (MPNs), including essential thrombocytopenia (ET), were subject to similar reporting problems. METHODS: Cases were identified from: 1) PCR records from the Tri-County, 2) reviewing billing records at Tri-County hematologist/oncologist offices, and 3) self-identification. An expert panel of physicians reviewed medical records and determined "true," "false," or "indeterminate" cases reported to the PCR. The analyses were conducted to determine sensitivity and positive predictive value (PPV) of case reporting to the PCR, estimate cancer incidence rates, and evaluate the presence of cancer clusters. RESULTS: Of 290 cases identified, 90% were from the original PCR, 9% from billing records, and 1% from self-report. Fifty-five cases consented to participate, and medical records were obtained for 44. The expert panel determined that 45% were true cases, 32% were false cases, and 23% were indeterminate. PV had 100% (95% CI, 59-100) sensitivity, but only 47% PPV (95% CI, 20-70): ET had 78% (95% CI, 47-99) sensitivity and 100% PPV (95% CI, 59-100). Low participation and chart review rates led to rates with wide confidence intervals. We did not identify any PV cancer clusters, but we did identify a cluster of 9 ET cases in the Wilkes-Barre, Pennsylvania area. CONCLUSION: The current study was limited by the low response rate (22%) from MPN patients in the Tri-County area. This study identified 47% PPV for PV reporting and 100% PPV for ET. PMID- 25803632 TI - Cancers coded as tongue not otherwise specified: relevance to surveillance of human papillomavirus-related cancers. AB - Data from US population-based cancer registries have shown increasing incidence rates for cancer of the base of the tongue, interpreted as related to the epidemic of human papillomavirus (HPV) infection, but rates could be underestimated due to miscoding of some base of tongue cancers to tongue "not otherwise specified" (NOS). Tongue NOS was the most commonly coded subsite among incident (2000-2011) invasive cancers of the oral tongue (tongue excluding base of tongue and lingual tonsil which together comprise the posterior one-third of the tongue) in the 18 Surveillance, Epidemiology and End Results (SEER) Program registries combined and in the Connecticut SEER registry. All 173 cases of tongue NOS cancer in the Connecticut SEER registry diagnosed in selected years were reviewed. Only 5% were recoded to base of tongue, decreasing from over time from 8% to 2%, resulting in minimal impact on the incidence rate for base of tongue cancer in Connecticut. Most (76%) of the 173 tongue NOS cases were recoded to anterior two-thirds of tongue NOS, ruling out base of tongue as the actual site but resulting in underestimation of incidence rates for anterior two-thirds NOS in Connecticut. Similar studies are needed on tongue NOS cancers in other US cancer registries, along with studies on the HPV status of tumors at specific subsites of the oral tongue, to enhance surveillance and interpretation of trends in cancer incidence in relation to the HPV epidemic. PMID- 25803631 TI - Exclusion of progressive brain disorders of childhood for a cerebral palsy monitoring system: a public health perspective. AB - BACKGROUND: Cerebral palsy (CP) is defined by its nonprogressive features. Therefore, a standard definition and list of progressive disorders to exclude would be useful for CP monitoring and epidemiologic studies. METHODS: We reviewed the literature on this topic to 1) develop selection criteria for progressive brain disorders of childhood for public health surveillance purposes, 2) identify categories of disorders likely to include individual conditions that are progressive, and 3) ascertain information about the relative frequency and natural history of candidate disorders. RESULTS: Based on 19 criteria that we developed, we ascertained a total of 104 progressive brain disorders of childhood, almost all of which were Mendelian disorders. DISCUSSION: Our list is meant for CP surveillance programs and does not represent a complete catalog of progressive genetic conditions, nor is the list meant to comprehensively characterize disorders that might be mistaken for cerebral palsy. The criteria for progressive disorders that we developed could be applied by public health investigators in the future, as more children with very rare conditions are followed and new candidate disorders are identified. PMID- 25803633 TI - Decision counseling and participation in a pancreas cancer registry. AB - Cancer registries play a vital role in research, as they provide important data that can be used to assess disease etiology and risk. Specialty registries can help to address the need for information on defined cancer types. However, achieving high rates of participation in such registries is problematic.We studied the impact of decision support on patient participation in a hospital based pancreas cancer registry, the Jefferson Pancreas Tumor Registry (JPTR). In this study, we assembled a nonrandomized cohort of 40 patients, of whom 20 were exposed to the intervention and 20 were exposed to routine recruiting methods. Patients in the control group were invited to join the JPTR; while those in the intervention group were also invited to join the JPTR, and received decision support related to participation. Registry participation was assessed at 90 days. At baseline, patient gender, race, and stage of pancreatic cancer did not vary significantly between study groups. Overall, participation in the intervention group was significantly higher (P = 0.01) than in the control group (55% and 10%, respectively). In the intervention group, altruism was the major factor motivating patient participation, while patient concerns related to treatment recovery, registration time and complexity, and the confidentiality of registry data discouraged participation. PMID- 25803634 TI - What increased registry outreach may mean for cutaneous melanoma surveillance: impact of changes in Iowa. AB - BACKGROUND: Cutaneous melanoma (CM) is underreported to cancer registries, in part due to insufficient reporting in the nonhospital setting. The objective of this study was to better understand the impact of dermatologist and private pathology laboratory reporting on CM rates. METHODS: We examined the impact of targeted casefinding in private pathology laboratories and dermatology offices by the State Health Registry of Iowa (SHRI) on CM incidence, as well as the characteristics of nonhospital reported cases. RESULTS: Over the 39-year period (1973-2011), 22,541 cases of CM were captured by the SHRI; 16,183 (72%) were invasive melanoma cases and 6,358 (28%) were in situ cases. The incidence of invasive melanoma increased 3.6 fold between the time periods of 1973-1975 and 2009-2011 (6.6 vs. 24 per 100,000 person-years, respectively). If case reporting from private pathology laboratories and dermatology offices was not conducted, the 2009-2011 invasive CM rate would have decreased to 19.1. The ratio of invasive to in situ cases declined from 8:1 from 1973-1987 to less 2:1 from 2007 2011. Age at diagnosis also significantly increased across time periods, while the proportion of females declined. From 2007-2011, the majority (55%) of nonhospital cases were in situ, and 90% of the invasive cases were localized. A higher percentage of urban residents were attributed to nonhospital-based reporting sources compared to hospital-based sources (57% vs 45%, P < .0001) CONCLUSIONS: Electronic health records and incentivized Meaningful Use for reporting may provide an efficient method for nonhospital based providers to easily and accurately report CM cases to registries. PMID- 25803635 TI - Alcohol Abuse Mediates the Association between Baseline T/C Ratio and Anger Expression in Intimate Partner Violence Perpetrators. AB - The imbalance between testosterone (T) and cortisol (C) levels has been proposed as a possible marker of risk for intimate partner violence (IPV). Moreover, it could be related to a high probability of adopting risky behaviors such as alcohol abuse which, in turn, promotes the onset of IPV. This study tested the potential mediating effect of alcohol consumption on the relationship between baseline T/C ratio and anger expression in IPV perpetrators and non-violent controls. Alcohol consumption was higher in the former than controls. A high baseline T/C ratio was only associated with high anger expression in IPV perpetrators, and this association was mediated by high alcohol consumption. Thus, alcohol abuse may act as a catalytic factor in this relationship, high consumption promoting the onset of IPV. These findings contribute to the development of effective treatment and prevention programs, which could introduce the use of biological markers for preventing the onset, development and recidivism of IPV. PMID- 25803636 TI - Psychotropic medication use among adolescents and young adults with an autism spectrum disorder: parent views about medication use and healthcare services. AB - OBJECTIVE: Psychotropic medications are frequently used to treat mental health and behavioral issues in adolescents and adults with an autism spectrum disorder (ASD). Although parents of individuals with ASD frequently take on medication management for their child, there is limited literature on parent perspectives of their child's medication use or their views about the healthcare services they receive, particularly in adulthood. The current study examined and compared parents of adolescents and of young adults with ASD regarding their child's psychotropic medication use and their views about healthcare services. METHODS: One hundred parents of adolescents and young adults with ASD (ages 12-30 years) completed an online survey about their experience with their child's healthcare services and medication use. RESULTS: Parents of young adults were less likely to use nonpharmacological services before using a psychotropic medication than were parents of adolescents. Parents of young adults were also less likely to believe that their prescribing healthcare provider had adequate expertise in ASD, and were less satisfied with how their prescriber monitored their child's medication use. CONCLUSION: Findings highlight the need to build capacity among healthcare providers supporting individuals with ASD as they transition into adulthood. There is also a need for improved medication monitoring and increased awareness of the different mental health challenges that individuals with ASD encounter as they age. PMID- 25803640 TI - Imidazol-2-ylidene-N'-phenylureate ligands in alkali and alkaline earth metal coordination spheres--heterocubane core to polymeric structural motif formation. AB - The synthesis and isolation of two potassium, one lithium and two calcium complexes of imidazol-2-ylidene-N'-phenylureate ligands [Im(R)NCON(H)Ph] [(R = tBu (1a); Mes (1b) and Dipp (1c); Mes = mesityl, Dipp = 2,6-diisopropylphenyl] are described. Potassium complexes, [{kappa(2)-(Im(Mes)NCONPh)K}4] (2b) and [{kappa(3)-(Im(Dipp)NCONPh)K}2{KN(SiMe3)2}2]n (2c), were prepared in good yields by the reactions of 1b and 1c, respectively, with potassium bis(trimethyl)silyl amide at ambient temperature in toluene. Lithium complex [{(2,6-tBu2-4-Me C6H2O)Li(Im(tBu)NCON(H)Ph)}2{Im(tBu)NCON(H)Ph}] (3a) was isolated by a one-pot reaction between 1a and LiCH2SiMe3, followed by the addition of 2,6-tBu2-4-Me C6H2OH in toluene. Calcium complex [{kappa(2)-(Im(tBu)NCONPh)Ca{N(SiMe3)2} {KN(SiMe3)2}]n (4a) was isolated by the one-pot reaction of 1a with [KN(SiMe3)2] and calcium diiodide in THF at ambient temperature. The solid-state structures of ligand 1a and complexes 2b, 2c, 3a and 4a were confirmed by single-crystal X-ray diffraction analysis. It was observed that potassium was coordinated to the oxygen atom of urea group and to the nitrogen atom of the imidazolin-2-imine group, in the solid-state structure of 2b. In complex 4a, the calcium ion was ligated to the monoanionic imidazol-2-ylidene-N'-phenylureate ligand in a bi dentate (kappa(2)) fashion through the oxygen and nitrogen atoms of the isocyanate building block leaving the imidazolin-2-imine fragment uncoordinated. In the solid state of the potassium complex 2c, tri-dentate (kappa(3)) coordination from the imidazol-2-ylidene-N'-phenylureate ligand was observed through the oxygen and nitrogen atoms of the isocyanate building block and of the imidazolin-2-imine fragment. In contrast, in the dimeric lithium complex 3a, the neutral imidazol-2-ylidene-N'-phenylureate ligand was bound to the lithium centre in a mono-dentate fashion (kappa(1)) through an oxygen atom of the isocyanate moiety. It is to be noted that in each complex thus observed, the elongated carbon-nitrogen bond distances indicate substantial electron delocalisation from the imidazole ring to the ureate group present in ligand 1. PMID- 25803638 TI - beta-HPV 5 and 8 E6 disrupt homology dependent double strand break repair by attenuating BRCA1 and BRCA2 expression and foci formation. AB - Recent work has explored a putative role for the E6 protein from some beta-human papillomavirus genus (beta-HPVs) in the development of non-melanoma skin cancers, specifically beta-HPV 5 and 8 E6. Because these viruses are not required for tumor maintenance, they are hypothesized to act as co-factors that enhance the mutagenic capacity of UV-exposure by disrupting the repair of the resulting DNA damage. Supporting this proposal, we have previously demonstrated that UV damage signaling is hindered by beta-HPV 5 and 8 E6 resulting in an increase in both thymine dimers and UV-induced double strand breaks (DSBs). Here we show that beta HPV 5 and 8 E6 further disrupt the repair of these DSBs and provide a mechanism for this attenuation. By binding and destabilizing a histone acetyltransferase, p300, beta-HPV 5 and 8 E6 reduce the enrichment of the transcription factor at the promoter of two genes critical to the homology dependent repair of DSBs (BRCA1 and BRCA2). The resulting diminished BRCA1/2 transcription not only leads to lower protein levels but also curtails the ability of these proteins to form repair foci at DSBs. Using a GFP-based reporter, we confirm that this reduced foci formation leads to significantly diminished homology dependent repair of DSBs. By deleting the p300 binding domain of beta-HPV 8 E6, we demonstrate that the loss of robust repair is dependent on viral-mediated degradation of p300 and confirm this observation using a combination of p300 mutants that are beta-HPV 8 E6 destabilization resistant and p300 knock-out cells. In conclusion, this work establishes an expanded ability of beta-HPV 5 and 8 E6 to attenuate UV damage repair, thus adding further support to the hypothesis that beta-HPV infections play a role in skin cancer development by increasing the oncogenic potential of UV exposure. PMID- 25803641 TI - Development of estimation models of bone height considering the potential presence of anterior extension of the mandibular canal. AB - PURPOSE: To evaluate the presence of the anterior extension (AE) of the mandibular canal and to measure the bone height (BH) at different points along the extension. MATERIALS AND METHODS: Cone-beam computed tomography examinations of 108 patients were bilaterally evaluated regarding the presence of the AE, and linear measurements of the AE and BH were obtained. For comparisons between sides and genders, Student t test was applied. Variations in BH measurements were assessed by a 2-way analysis of variance. Through a simple linear regression analysis, formulas were determined for calculations of the BH in the AE. RESULTS: A right AE was detected in 76.9% and left AE in 77.8% of the samples. In the majority of the cases, the extension was of the rectilinear type. The mean length of the AE was 8.5 mm, and there was no statistically significant difference observed in relation to gender or side. It was observed that the BH increases as it approaches the midline. CONCLUSION: The AE of the mandibular canal must be evaluated during presurgical planning. The formulae presented in this study provide a method to calculate BH values in the interforaminal region and can be used to assist in presurgical planning, especially in the cases in which the identification of the hipodense site, which corresponds to the AE, is not evident. PMID- 25803639 TI - Silver-zinc redox-coupled electroceutical wound dressing disrupts bacterial biofilm. AB - Pseudomonas aeruginosa biofilm is commonly associated with chronic wound infection. A FDA approved wireless electroceutical dressing (WED), which in the presence of conductive wound exudate gets activated to generate electric field (0.3-0.9V), was investigated for its anti-biofilm properties. Growth of pathogenic P. aeruginosa strain PAO1 in LB media was markedly arrested in the presence of the WED. Scanning electron microscopy demonstrated that WED markedly disrupted biofilm integrity in a setting where silver dressing was ineffective. Biofilm thickness and number of live bacterial cells were decreased in the presence of WED. Quorum sensing genes lasR and rhlR and activity of electric field sensitive enzyme, glycerol-3-phosphate dehydrogenase was also repressed by WED. This work provides first electron paramagnetic resonance spectroscopy evidence demonstrating that WED serves as a spontaneous source of reactive oxygen species. Redox-sensitive multidrug efflux systems mexAB and mexEF were repressed by WED. Taken together, these observations provide first evidence supporting the anti-biofilm properties of WED. PMID- 25803643 TI - Model-based correction for scatter and tailing effects in simultaneous 99mTc and 123I imaging for a CdZnTe cardiac SPECT camera. AB - An advantage of semiconductor-based dedicated cardiac single photon emission computed tomography (SPECT) cameras when compared to conventional Anger cameras is superior energy resolution. This provides the potential for improved separation of the photopeaks in dual radionuclide imaging, such as combined use of (99m)Tc and (123)I . There is, however, the added complexity of tailing effects in the detectors that must be accounted for. In this paper we present a model-based correction algorithm which extracts the useful primary counts of (99m)Tc and (123)I from projection data. Equations describing the in-patient scatter and tailing effects in the detectors are iteratively solved for both radionuclides simultaneously using a maximum a posteriori probability algorithm with one-step-late evaluation. Energy window-dependent parameters for the equations describing in-patient scatter are estimated using Monte Carlo simulations. Parameters for the equations describing tailing effects are estimated using virtually scatter-free experimental measurements on a dedicated cardiac SPECT camera with CdZnTe-detectors. When applied to a phantom study with both (99m)Tc and (123)I, results show that the estimated spatial distribution of events from (99m)Tc in the (99m)Tc photopeak energy window is very similar to that measured in a single (99m)Tc phantom study. The extracted images of primary events display increased cold lesion contrasts for both (99m)Tc and (123)I. PMID- 25803642 TI - Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial. AB - BACKGROUND: Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus like particle (VLP) candidate vaccine in human volunteers. METHODS AND FINDINGS: Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated. CONCLUSIONS: Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT01168401. PMID- 25803646 TI - Ultrasound-Guided Subclavian Vein Catheterization: A Systematic Review and Meta Analysis. AB - OBJECTIVE: Although ultrasound guidance for subclavian vein catheterization has been well described, evidence for its use has not been comprehensively appraised. Thus, we conducted a systematic review and meta-analysis to determine whether ultrasound guidance of subclavian vein catheterization reduces catheterization failures and adverse events compared to the traditional "blind" landmark method. All forms of ultrasound were included (dynamic 2D ultrasound, static 2D ultrasound, and Doppler). DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL (from inception to September 2014). STUDY SELECTION: Randomized controlled trials of ultrasound compared to landmark technique for subclavian catheterization in adult populations were considered. Outcomes of interest included safety and failure of catheterization. DATA EXTRACTION: Adverse event data were analyzed according to Peto's method and expressed as odd ratios and 95% CIs. Failure of catheterization was analyzed with inverse variance random effects modeling and expressed as risk ratios and 95% CI. DATA SYNTHESIS: Six hundred and one studies were reviewed and 10 met inclusion criteria (n = 2,168 participants). Six used dynamic 2D ultrasound (n = 719), one used static 2D ultrasound (n = 821), and three used Doppler-guided insertion techniques (n = 628). Overall complication rates were reduced with ultrasound use compared to the landmark group (odd ratio, 0.53; 95% CI, 0.41-0.69). Subgroup analysis demonstrated that dynamic 2D ultrasound reduced inadvertent arterial puncture, pneumothorax, and hematoma formation. No difference in failure of catheterization was noted between the ultrasound group and the landmark method (risk ratio, 0.85; 95% CI, 0.48 1.51). Subgroup analysis of dynamic 2D ultrasound demonstrated a significant decrease in failed catheterization (risk ratio, 0.24; 95% CI, 0.06-0.92). CONCLUSIONS: Ultrasound-guided subclavian catheterization reduced the frequency of adverse events compared with the landmark technique. Our findings support the use of dynamic 2D ultrasound for subclavian catheterization to reduce adverse events and failed catheterization. PMID- 25803644 TI - Effects of corticosterone and dietary energy on immune function of broiler chickens. AB - An experiment was conducted to investigate the effects of dietary energy level on the performance and immune function of stressed broiler chickens (Gallus gallus domesticus). A total of 96 three-day-old male broiler chickens (Ross * Ross) were divided into two groups. One group received a high energy (HE) diet and the other group received a low energy (LE) diet for 7 days. At 5 days of age, the chickens from each group were further divided into two sub-groups and received one of the following two treatments for 3 days: (1) subcutaneous injection of corticosterone, twice per day (CORT group; 2 mg of CORT/kg BW in corn oil) and (2) subcutaneous injection of corn oil, twice per day (Control/Sham treatment group). At 10 days of age, samples of blood, duodenum, jejunum, and ileum were obtained. Compared with the other three groups, the LE group treated with CORT had the lowest average daily gain (ADG) and the poorest feed conversion ratio (FCR, P < 0.05). Furthermore, CORT treatment decreased the relative weight (RW) of the bursa independent of the dietary energy level, but it decreased the RW of the thymus only in the chickens fed the LE diet. By contrast, CORT administration decreased the RW of the spleen only in the chickens fed the HE diet (P < 0.05). The plasma total protein, albumin, tumor necrosis factor alpha, interleukin 2 and immunoglobulin G (IgG) levels were affected by the CORT treatment (P < 0.05); however, these factors were not significantly affected by the dietary energy level. Toll-like receptor-5 mRNA level was down-regulated by CORT injection in the duodenum and ileum (P < 0.05) and showed a trend of down-regulation in the jejunum (P=0.0846). The present study showed that CORT treatment induced immunosuppressive effects on the innate immune system of broiler chickens, which were ameliorated by consumption of higher dietary energy. PMID- 25803647 TI - Critical Care Delivery: The Importance of Process of Care and ICU Structure to Improved Outcomes: An Update From the American College of Critical Care Medicine Task Force on Models of Critical Care. AB - In 2001, the Society of Critical Care Medicine published practice model guidelines that focused on the delivery of critical care and the roles of different ICU team members. An exhaustive review of the additional literature published since the last guideline has demonstrated that both the structure and process of care in the ICU are important for achieving optimal patient outcomes. Since the publication of the original guideline, several authorities have recognized that improvements in the processes of care, ICU structure, and the use of quality improvement science methodologies can beneficially impact patient outcomes and reduce costs. Herein, we summarize findings of the American College of Critical Care Medicine Task Force on Models of Critical Care: 1) An intensivist-led, high-performing, multidisciplinary team dedicated to the ICU is an integral part of effective care delivery; 2) Process improvement is the backbone of achieving high-quality ICU outcomes; 3) Standardized protocols including care bundles and order sets to facilitate measurable processes and outcomes should be used and further developed in the ICU setting; and 4) Institutional support for comprehensive quality improvement programs as well as tele-ICU programs should be provided. PMID- 25803648 TI - Hypothermia for Traumatic Brain Injury in Children-A Phase II Randomized Controlled Trial. AB - OBJECTIVES: To perform a pilot study to assess the feasibility of performing a phase III trial of therapeutic hypothermia started early and continued for at least 72 hours in children with severe traumatic brain injury. DESIGN: Multicenter prospective randomized controlled phase II trial. SETTING: All eight of the PICUs in Australia and New Zealand and one in Canada. PATIENTS: Children 1 15 years old with severe traumatic brain injury and who could be randomized within 6 hours of injury. INTERVENTIONS: The control group had strict normothermia to a temperature of 36-37 degrees C for 72 hours. The intervention group had therapeutic hypothermia to a temperature of 32-33 degrees C for 72 hours followed by slow rewarming at a rate compatible with maintaining intracranial pressure and cerebral perfusion pressure. MEASUREMENTS AND MAIN RESULTS: Of 764 children admitted to PICU with traumatic brain injury, 92 (12%) were eligible and 55 (7.2%) were recruited. There were five major protocol violations (9%): three related to recruitment and consent processes and two to incorrect temperature management. Rewarming took a median of 21.5 hours (16-35 hr) and was performed without compromise in the cerebral perfusion pressure. There was no increase in any complications, including infections, bleeding, and arrhythmias. There was no difference in outcomes 12 months after injury; in the therapeutic hypothermia group, four (17%) had a bad outcome (pediatric cerebral performance category, 4-6) and three (13%) died, whereas in the normothermia group, three (12%) had a bad outcome and one (4%) died. CONCLUSIONS: Early therapeutic hypothermia in children with severe traumatic brain injury does not improve outcome and should not be used outside a clinical trial. Recruitment rates were lower and outcomes were better than expected. Conventional randomized controlled trials in children with severe traumatic brain injury are unlikely to be feasible. A large international trials group and alternative approaches to trial design will be required to further inform practice. PMID- 25803649 TI - Treatment of Highly Virulent Extraintestinal Pathogenic Escherichia coli Pneumonia With Bacteriophages. AB - OBJECTIVE: To study the effect of bacteriophage treatment on highly virulent extraintestinal Escherichia coli pneumonia in mice and compare it with conventional antimicrobial treatment. DESIGN: Animal investigation. SETTING: University research laboratory. SUBJECTS: Pathogen-free 8-week-old Balb/cJRj male mice. INTERVENTIONS: Two bacteriophages (536_P1 and 536_P7) were isolated from sewage using strain 536, a highly virulent extraintestinal E. coli. Their in vitro and in vivo efficacy against strain 536 and a ventilator-associated pneumonia E. coli were tested. The first group of mice were infected by intranasal instillation of bioluminescent strain 536 and received 536_P1 intranasally, ceftriaxone, or control. The second group of mice was infected with the ventilator-associated pneumonia strain and received 536_P7. Adaptation of 536_P7 to this clinical isolate was also evaluated in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: In vivo efficacy of bacteriophage and antibiotic treatment were assessed by recording bioluminescence for short-time periods and by recording body weight and survival of mice for longer periods. Both treatments improved survival compared with control (100% vs 0%), and in vivo bioluminescence recordings showed a similar rapid decrease of emitted light, suggesting prompt bacterial clearance. The majority of mice infected by the ventilator-associated pneumonia strain were not rescued by treatment with 536_P7; however, in vitro adaptation of this bacteriophage toward the ventilator-associated pneumonia strain led to isolate a variant which significantly improved in vivo treatment efficacy (animal survival increased from 20% to 75%). CONCLUSIONS: Bacteriophage treatment was as effective as antibiotherapy to provide 100% survival rate in a lethal model of highly virulent E. coli pneumonia. Adaptation of a bacteriophage is a rapid solution to improve its efficacy toward specific strains. These results suggest that phage therapy could be a promising therapeutic strategy for ventilator-associated pneumonia. PMID- 25803650 TI - Prehospital Hypotension Is Associated With Altered Inflammation Dynamics and Worse Outcomes Following Blunt Trauma in Humans. AB - OBJECTIVE: To define the impact of prehospital hypotension on the dynamic, systemic acute inflammatory response to blunt trauma. DESIGN: Retrospective study. SETTINGS: Tertiary care institution. PATIENTS: Twenty-two hypotensive blunt trauma patients matched with 28 normotensive blunt trauma patients. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: From a cohort of 472 blunt trauma survivors studied following institutional review board approval, two stringently matched subcohorts were derived. Twenty-two patients who sustained prehospital hypotension following blunt trauma (15 males and 7 females; age, 45 +/- 3.8; Injury Severity Score, 20.7 +/- 1.8) were matched with 28 normotensive trauma patients (20 males and 8 females; age, 46.1 +/- 2.5; Injury Severity Score, 20.8 +/- 1.3). Serial blood samples (three samples within the first 24 hr and then from days 1 to 7 postinjury) were assessed for 24 inflammatory mediators using Luminex, and No2-/No3- was measured using the nitrate reductase/Griess assay. Two-way analysis of variance was used to compare groups. Dynamic Bayesian Network inference was used to infer causal relationships based on probabilistic measures. Statistically significant differences were observed in ICU length of stay, total length of stay, days on mechanical ventilator, and Marshall Multiple Organ Dysfunction score between hypotensive and normotensive patients. Shock markers (shock index, pH, lactate, and base deficit) were significantly altered in hypotensive patients. Plasma levels of chemokines (monocyte chemotactic protein-1/CCL2, inducible protein-10/CXCL10, macrophage inflammatory protein 1alpha/CCL3, and interleukin-8/CCL8) and cytokines (interleukin-6, interleukin 10, interleukin-17, granulocyte-macrophage colony-stimulating factor, interleukin 1beta, and interleukin-7) as well as soluble interleukin-2 receptor-alpha were significantly elevated over the first 7 days postinjury in the hypotensive versus normotensive patients. Dynamic Bayesian Network suggested that the chemokines monocyte chemotactic protein-1/CCL2 and monokine induced by gamma interferon/CXCL9 in the hypotensive and normotensive patients, respectively, affect plasma interleukin-6 levels differentially in the initial 24 hours postinjury. CONCLUSIONS: Studies in stringently matched patient cohorts suggest that an episode of prehospital hypotension post trauma leads to early, dynamic reprogramming of systemic inflammation (including differential upstream regulation of interleukin-6), which is associated with worse outcomes. PMID- 25803651 TI - Determination of Lung Volume and Hemodynamic Changes During High-Frequency Ventilation Recruitment in Preterm Neonates With Respiratory Distress Syndrome. AB - OBJECTIVES: To evaluate the changes in end-expiratory lung volume during an oxygenation-guided stepwise recruitment procedure in elective high-frequency ventilation. We hypothesized that high continuous distending pressure impedes pulmonary blood flow as evidenced by reduced lung volume measurements using respiratory inductive plethysmography. Changes in oxygenation, ventilation, and peripheral perfusion were evaluated as secondary outcomes. DESIGN: A prospective, single center, observational, nonrandomized study. SETTING: The study was conducted in a neonatal ICU in Italy. PATIENTS: High-frequency ventilated preterm infants with respiratory distress syndrome. INTERVENTIONS: During the recruitment procedure, end-expiratory lung volume measured by respiratory inductive plethysmography, oxygen saturation, perfusion index, regional cerebral and perirenal tissue oxygenation, heart rate, transcutaneous PCO2, and tidal volume were simultaneously recorded at each airway pressure step. MEASUREMENTS AND MAIN RESULTS: In 12 preterm newborns (gestational age, 27.4 +/- 0.2 wk; birth weight, 979 +/- 198 g), high-frequency ventilation was initiated at a continuous distending pressure of 10 cm H2O and incrementally increased by 1-2 cm H2O every 2-5 minutes until FIO2 was less than or equal to 0.25. End-expiratory lung volume progressively increased during the initial recruitment, but decreased at the maximum airway pressure in nine patients, indicative of a reduction in pulmonary perfusion. At the end of recruitment, tidal volume was significantly higher (p = 0.002) and oxygenation was significantly improved (p = 0.002); however, mean perfusion index, postductal saturation, and mean renal tissue oxygenation values were significantly reduced (p < 0.05) compared with baseline. Mean cerebral tissue oxygenation and mean transcutaneous PCO2 values were reduced but failed to reach significance. CONCLUSIONS: High distending lung pressures increased oxygenation but decreased peripheral perfusion with no adverse cerebral side effects. Coupled with the reduction in respiratory inductive plethysmography derived lung volume, high continuous distending pressure had adverse cardiopulmonary effects. Incorporation of lung volume and hemodynamic and oxygenation variables may guide optimum lung volume determination during high frequency ventilation recruitment procedure while preventing adverse effects on the pulmonary circulation. PMID- 25803652 TI - Temporal Changes in the Influence of Hospitals and Regional Healthcare Networks on Severe Sepsis Mortality. AB - OBJECTIVES: There is systematic variation between hospitals in their care of severe sepsis, but little information on whether this variation impacts sepsis related mortality, or how hospitals' and health-systems' impacts have changed over time. We examined whether hospital and regional organization of severe sepsis care is associated with meaningful differences in 30-day mortality in a large integrated health care system, and the extent to which those effects are stable over time. DESIGN: In this retrospective cohort study, we used risk- and reliability-adjusted hierarchical logistic regression to estimate hospital- and region-level random effects after controlling for severity of illness using a rich mix of administrative and clinical laboratory data. SETTING: One hundred fourteen U.S. Department of Veterans Affairs hospitals in 21 geographic regions. PATIENTS: Forty-three thousand seven hundred thirty-three patients with severe sepsis in 2012, compared to 33,095 such patients in 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median hospital in the worst quintile of performers had a risk-adjusted 30-day mortality of 16.7% (95% CI, 13.5%, 20.5%) in 2012 compared with the best quintile, which had a risk-adjusted mortality of 12.8% (95% CI, 10.7%, 15.3%). Hospitals and regions explained a statistically and clinically significant proportion of the variation in patient outcomes. Thirty day mortality after severe sepsis declined from 18.3% in 2008 to 14.7% in 2012 despite very similar severity of illness between years. The proportion of the variance in sepsis-related mortality explained by hospitals and regions was stable between 2008 and 2012. CONCLUSIONS: In this large integrated healthcare system, there is clinically significant variation in sepsis-related mortality associated with hospitals and regions. The proportion of variance explained by hospitals and regions has been stable over time, although sepsis-related mortality has declined. PMID- 25803653 TI - Effect of Early Intervention on Long-Term Outcomes of Critically Ill Cancer Patients Admitted to ICUs. AB - OBJECTIVES: The objective of this observational study was to evaluate whether early intervention was associated with improved long-term outcomes in critically ill patients with cancer. DESIGN: Retrospective analysis with prospectively collected data. SETTING: A university-affiliated, tertiary referral hospital. PATIENTS: Consecutive critically ill cancer patients who were managed by a medical emergency team before ICU admission between January 2010 and December 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 525 critically ill cancer patients were admitted to the ICU with respiratory failure (41.7%) and severe sepsis or septic shock (40.6%) following medical intervention by a medical emergency team. Of 356 ICU survivors, 161 (45.2%) received additional treatment for cancer after ICU discharge. Mortality was 66.1% at 6 months and 72.8% at 1 year. Median time from physiological derangement to intervention before ICU admission was significantly shorter in 1 year survivors (1.3 hr; interquartile range, 0.5-4.8 hr) than it was in nonsurvivors (2.9 hr; interquartile range, 0.8-9.6 hr) (p< 0.001). Additionally, the early intervention (<= 1.5 hr) group had a lower 30-day mortality rate than the late intervention (> 1.5 hr) group (29.0% vs 55.3%; p < 0.001) and a similar difference in mortality rate was observed up to 1 year. Other factors associated with 1-year mortality were illness severity, performance status, malignancy status, presence of more than three abnormal physiological variables, time from derangement to ICU admission, and the need for mechanical ventilation. Even after adjusting for potential confounding factors, early intervention was significantly associated with 1-year mortality (adjusted hazard ratio, 0.456; 95% CI, 0.348 0.597; p < 0.001). CONCLUSION: Early intervention for clinical derangement on general wards was significantly associated with long-term outcomes in critically ill cancer patients. PMID- 25803654 TI - Effects and Clinical Characteristics of Intracranial Pressure Monitoring-Targeted Management for Subsets of Traumatic Brain Injury: An Observational Multicenter Study. AB - OBJECTIVES: To evaluate the efficacy of traumatic brain injury management guided by intracranial pressure monitoring and to explore the specific subgroups for which intracranial pressure monitoring might be significantly associated with improved outcomes based on a classification of the various traumatic brain injury pathophysiologies using the clinical features and CT scans. DESIGN: Retrospective observational multicenter study. SETTING: Twenty-two hospitals (16 level I trauma centers and six level II trauma centers) in nine provinces in China. PATIENTS: Moderate or severe traumatic brain injury patients who were more than 14 years old. INTERVENTIONS: Intracranial pressure monitoring. MEASUREMENTS AND MAIN RESULTS: All data were collected by physicians from medical records. The 6-month mortality and favorable outcome were assessed with the Glasgow Outcome Scale Extended score. An intracranial pressure monitor was inserted into 838 patients (58.1%). The mean duration of intracranial pressure monitoring was 4.44 +/- 3.65 days. The significant predictors of intracranial pressure monitoring included the mechanism of injury, a Glasgow Coma Scale score of 9-12 at admission that dropped to a score of 3-8 within 24 hours after injury, a Marshall CT classification of III-IV, the presence of a major extracranial injury, subdural hematoma, intraparenchymal lesions, trauma center level, and intracranial pressure monitoring utilization of hospital. The intracranial pressure monitoring and no intracranial pressure monitoring groups did not significantly differ in terms of complications. For the total sample, the placement of intracranial pressure monitoring was not associated with either 6-month mortality (16.9% vs 20.5%; p = 0.086) or 6-month unfavorable outcome (49.4% vs 45.8%; p = 0.175). For patients with a Glasgow Coma Scale score of 3-8 at admission, intracranial pressure monitoring was also not significantly associated with 6-month mortality (20.9% vs 26.0%; p = 0.053) or an unfavorable outcome (56.9% vs 55.5%; p = 0.646). Multivariate logistic regression analyses showed that intracranial pressure monitoring resulted in a significantly lower 6-month mortality for patients who had a Glasgow Coma Scale score of 3-5 at admission (adjusted odds ratio, 0.57; 95% CI, 0.36-0.90; adjusted p = 0.016), those who had a Glasgow Coma Scale score of 9-12 at admission that dropped to 3-8 within 24 hours after injury (adjusted odds ratio, 0.28; 95% CI, 0.08-0.96; adjusted p = 0.043), and those who had a probability of death at 6 months greater than 0.6 (adjusted odds ratio, 0.55; 95% CI, 0.32-0.94; adjusted p = 0.029). CONCLUSIONS: There were multiple differences between the intracranial pressure monitoring and no intracranial pressure monitoring groups regarding patient characteristics, injury severity, characteristics of CT scan, and hospital type. Intracranial pressure monitoring in conjunction with intracranial pressure-targeted therapies is significantly associated with lower mortality in some special traumatic brain injury subgroups. The prospective randomized controlled trials specifically investigating these subgroups will be required to further characterize the effects of intracranial pressure monitoring on behavioral outcomes in patients with traumatic brain injury. PMID- 25803655 TI - Effects of Proanthocyanidins on Adhesion, Growth, and Virulence of Highly Virulent Extraintestinal Pathogenic Escherichia coli Argue for Its Use to Treat Oropharyngeal Colonization and Prevent Ventilator-Associated Pneumonia. AB - OBJECTIVE: In the context of increasing microbial resistance and limited new antimicrobials, we aimed to study the antimicrobial effects of cranberry proanthocyanidin extracts on Escherichia coli growth, adhesion to epithelial cells, and lung infection. DESIGN: Experimental in vitro and in vivo investigation. SETTING: University research laboratory. SUBJECTS: Seventy-eight 6 to 8-week-old male Balb/C mice. INTERVENTIONS: In vitro, the effect of increasing concentrations of cranberry proanthocyanidin on bacterial growth of different clinical E. coli isolates was evaluated. Ex vivo, adhesion of E. coli to fresh human buccal epithelial cells was measured in the presence or absence of cranberry proanthocyanidin using microscopy. In vivo, lung bacterial count, pulmonary immune response (neutrophil murine chemokine keratinocyte-derived cytokine measurement and polymorphonuclear recruitment in bronchoalveolar lavage fluid), and lethality were evaluated in a pneumonia mouse model with E. coli precultured with or without cranberry proanthocyanidin. E. coli isolates originated from ventilated ICU patients with respiratory tract colonization or ventilator- associated pneumonia. They differed in number of virulence genes. MEASUREMENTS AND MAIN RESULTS: A significant inhibition of bacterial growth was observed with increasing concentration of cranberry proanthocyanidin, affecting both time to maximal growth and maximal growth rate (p<0.0001 for both). The minimal concentration at which this effect occurred was 250 MUg/mL. Cranberry proanthocyanidin significantly reduced E. coli adhesion to fresh buccal epithelial cells by up to 80% (p<0.001). Bacterial counts in homogenized lungs and bronchoalveolar lavage fluid were decreased after cranberry proanthocyanidin exposition (p<0.05 and p<0.01, respectively). Cranberry proanthocyanidin also decreased KC concentrations and polymorphonuclear cell recruitment in bronchoalveolar lavage fluid (p<0.05 for both). At identical inoculum, mortality was reduced by more than half in mice inoculated with E. coli exposed to cranberry proanthocyanidin (p<0.01). CONCLUSION: Cranberry proanthocyanidins exhibit potent effects on growth, adhesion, and virulence of oropharyngeal and lung isolates of E. coli, suggesting that cranberry proanthocyanidin could be of clinical interest to reduce oropharyngeal colonization and prevent lung infection. PMID- 25803656 TI - Joint reconstruction of non-overlapping magnetic particle imaging focus-field data. AB - The focus field is a key component to enable clinical applications in magnetic particle imaging (MPI). Due to physiological constraints, the method of choice is to place the focus of a small acquisition volume at various static positions in space and acquire the full field-of-view using a multi-station approach. In the first experiments, overlapping drive-field patches were used and boundary artifacts between drive-field patches were reduced using image processing. In this work we show that artifact-free reconstruction of non-overlapping focus field data is feasible by using a joint reconstruction algorithm. This enables maximum scanning efficiency in multi-station focus-field experiments, which is key for reaching sufficiently short acquisition times to image the human heart. PMID- 25803657 TI - The Effect of Target Position on the Accuracy of Cervical-Spine-Rotation Active Joint-Position Sense. AB - CONTEXT: The cervical spine can be divided into upper and lower units, each making a different contribution to the magnitude of rotation and proprioception. However, few studies have examined the effect of the cervical-rotation positions on proprioception. OBJECTIVE: To compare cervical-spine rotation active joint position sense (AJPS) near midrange of motion (mid-ROM; 30 degrees ) and near end ROM (60 degrees ). DESIGN: Cross-sectional study. SETTING: Human performance research laboratory. PARTICIPANTS: 53 military helicopter pilots (age 28.4 +/- 6.2 y, height 175.3 +/- 9.3 cm, weight 80.1 +/- 11.8 kg). MAIN OUTCOME MEASURES: A motion-analysis system was used to record cervical-rotation kinematics. Subjects sat in a chair wearing a headband and blindfold. First, they actively rotated the head right or left to a target position (30 degrees /60 degrees ), with real-time verbal cues provided by the tester. Subjects held the target position for 5 s and then returned to the start position. After this, they replicated the target position as closely as possible. Five trials were performed in both directions to both target positions (R30/R60/L30/L60). Order of direction/position was randomized. The difference between target and replicated positions was calculated and defined as absolute error (AE), and the mean of 5 trials was used for analyses. Wilcoxon signed-ranks tests were used to compare AJPS at the different target positions (P < .0125 with Bonferroni adjustments). RESULTS: End-ROM AEs were significantly more accurate than mid-ROM AEs (P = .001). CONCLUSION: Cervical-spine-rotation AJPS is more accurate near end-ROM than mid-ROM. Both target positions should be used to examine cervical-spine rotation AJPS of both the upper and lower units. PMID- 25803658 TI - Intermediate hosts of Angiostrongylus cantonensis in Tenerife, Spain. AB - The nematode Angiostrongylus cantonensis is the causative agent of human angiostrongyliasis, the main clinical manifestation of which is eosinophilic meningitis. Although this parasite has been found recently in its definitive rat host in Tenerife (Canary Islands, Spain), showing a widespread distribution over the north-east part of the island, there are no available data regarding which snail and/or slug species are acting as intermediate hosts on this island. Consequently, the objective of this work was to determine the possible role of three mollusc species, Plutonia lamarckii, Cornu aspersum and Theba pisana, as intermediate hosts of A. cantonensis in Tenerife. Between 2011 and 2014, 233 molluscs were collected from five biotopes where rats had been found previously to harbor either adult worms or antibodies against A. cantonensis, and the identification was carried out on the basis of morphological features and a LAMP technique. The prevalence of A. cantonensis larvae in the mollusc samples, based on morphological identification, was 19.3%, whereas 59 out of the 98 individuals (60.2%) analyzed by LAMP were positive. Positive results were obtained for the three mollusc species analyzed and two of the positive samples, both obtained from P. lamarckii, were confirmed as positive by 18S rRNA and ITS1 PCR. Sequence analysis of 18S rRNA PCR products showed 100% similarity with previously published A. cantonensis sequences. These results may be relevant from a public health point of view, since all the biotopes from which the samples were obtained were in inhabited areas or areas with human activity, but it is also important from the perspective of a possible transmission to other accidental hosts, such as dogs and horses, animals that are present in some of the areas analyzed. PMID- 25803659 TI - A review and comparison of methods for recreating individual patient data from published Kaplan-Meier survival curves for economic evaluations: a simulation study. AB - BACKGROUND: In general, the individual patient-level data (IPD) collected in clinical trials are not available to independent researchers to conduct economic evaluations; researchers only have access to published survival curves and summary statistics. Thus, methods that use published survival curves and summary statistics to reproduce statistics for economic evaluations are essential. Four methods have been identified: two traditional methods 1) least squares method, 2) graphical method; and two recently proposed methods by 3) Hoyle and Henley, 4) Guyot et al. The four methods were first individually reviewed and subsequently assessed regarding their abilities to estimate mean survival through a simulation study. METHODS: A number of different scenarios were developed that comprised combinations of various sample sizes, censoring rates and parametric survival distributions. One thousand simulated survival datasets were generated for each scenario, and all methods were applied to actual IPD. The uncertainty in the estimate of mean survival time was also captured. RESULTS: All methods provided accurate estimates of the mean survival time when the sample size was 500 and a Weibull distribution was used. When the sample size was 100 and the Weibull distribution was used, the Guyot et al. method was almost as accurate as the Hoyle and Henley method; however, more biases were identified in the traditional methods. When a lognormal distribution was used, the Guyot et al. method generated noticeably less bias and a more accurate uncertainty compared with the Hoyle and Henley method. CONCLUSIONS: The traditional methods should not be preferred because of their remarkable overestimation. When the Weibull distribution was used for a fitted model, the Guyot et al. method was almost as accurate as the Hoyle and Henley method. However, if the lognormal distribution was used, the Guyot et al. method was less biased compared with the Hoyle and Henley method. PMID- 25803660 TI - Enhancement of fluorescent properties of near-infrared dyes using clickable oligoglycerol dendrons. AB - Near-infrared (NIR) fluorescent dyes are gaining increased attention due to their potential to serve as molecular probes for in vivo imaging. Here, we demonstrate that oligoglycerol dendrons effectively enhance the fluorescence properties of an NIR dye by increasing the solubility in water and the prevention of aggregate formation. First- and second-generation oligoglycerol dendrons were conjugated to an NIR dye via a dipolar-cycloaddition (click) reaction. The two new dye conjugates exhibited enhanced NIR fluorescent emission and considerably higher fluorescent quantum yields than the dye alone. The high photostability measured for one of the oligoglycerol-linked dyes, in comparison to commonly used fluorogenic dyes such as Cy5 and Cy7, was validated using fluorescence microscopy of macrophages. PMID- 25803661 TI - Comparison of the sensitivity and specificity of 5 image sets of dual-energy computed tomography for detecting first-pass myocardial perfusion defects compared with positron emission tomography. AB - [In the article "Comparison of the Sensitivity and Specificity of 5 Image Sets of Dual-Energy Computed Tomography for Detecting First-Pass Myocardial Perfusion Defects Compared With Positron Emission Tomography", the authors did not list their funding. The funding line should read as follows: "This study was supported by the National Basic Research Program of China (973 Program, No. 303-01-001 0018).".]. PMID- 25803662 TI - Post-transplant malignancy in liver transplantation: a single center experience. AB - [In the article "Post-Transplant Malignancy in Liver Transplantation: A Single Center Experience", the acting editor's name was incorrectly given as Cheng-Maw Ho. The actual acting editor of the article was Haijun Zhang.]. PMID- 25803663 TI - Extra- and intracranial cerebral vasculitis in giant cell arteritis: an observational study. AB - [An uncorrected version of "Extra- and Intracranial Cerebral Vasculitis in Giant Cell Arteritis: An Observational Study" was originally posted in Volume 93, Issue 28 of Medicine. The article has since been corrected and reposted in the issue.]. PMID- 25803664 TI - Experimentally derived delta13C and delta15N discrimination factors for gray wolves and the impact of prior information in Bayesian mixing models. AB - Stable isotope analysis of diet has become a common tool in conservation research. However, the multiple sources of uncertainty inherent in this analysis framework involve consequences that have not been thoroughly addressed. Uncertainty arises from the choice of trophic discrimination factors, and for Bayesian stable isotope mixing models (SIMMs), the specification of prior information; the combined effect of these aspects has not been explicitly tested. We used a captive feeding study of gray wolves (Canis lupus) to determine the first experimentally-derived trophic discrimination factors of C and N for this large carnivore of broad conservation interest. Using the estimated diet in our controlled system and data from a published study on wild wolves and their prey in Montana, USA, we then investigated the simultaneous effect of discrimination factors and prior information on diet reconstruction with Bayesian SIMMs. Discrimination factors for gray wolves and their prey were 1.970/00 for delta13C and 3.040/00 for delta15N. Specifying wolf discrimination factors, as opposed to the commonly used red fox (Vulpes vulpes) factors, made little practical difference to estimates of wolf diet, but prior information had a strong effect on bias, precision, and accuracy of posterior estimates. Without specifying prior information in our Bayesian SIMM, it was not possible to produce SIMM posteriors statistically similar to the estimated diet in our controlled study or the diet of wild wolves. Our study demonstrates the critical effect of prior information on estimates of animal diets using Bayesian SIMMs, and suggests species-specific trophic discrimination factors are of secondary importance. When using stable isotope analysis to inform conservation decisions researchers should understand the limits of their data. It may be difficult to obtain useful information from SIMMs if informative priors are omitted and species-specific discrimination factors are unavailable. PMID- 25803665 TI - Influence of personal social network and coping skills on risk for suicidal ideation in Chinese university students. AB - BACKGROUND: Personal social network and coping skills have important influences on suicidality of young people and such influences must be understood in the context of other factors. This study aims to assess the influences of social contacts and coping skills on risk for suicidal ideation and to disentangle their possible pathways using a large sample of university students from China. METHODS: 5972 students, randomly selected from 6 universities in China, completed the questionnaire survey for the study. Logistic regression was performed to estimate individual effect of social contacts and coping skills on risk for suicidal ideation. A partial least squares path model (PLSPM) was used to probe possible paths of their effects in the context of psychopathology. RESULTS: Of the 5972 students, 16.39% reported the presence of suicidal ideation. Poor social contacts were significantly associated with an increased risk for suicidal ideation. The influence of coping skills varied by coping styles adapted toward problems. A high score of skills on seeking guidance and support, problem solving as well as seeking alternative rewards was associated with a reduced risk of suicidal ideation; whereas a high score of acceptance or resignation, emotional discharge as well as logical analysis was associated with a significantly increased risk. Modeling the data with PLSPM indicated that the avoidance coping skills conferred the most important dimensional variable in suicidal ideation prediction, followed by the approach coping skills and social network. CONCLUSIONS: Poor social contacts and deficient coping skills are strong risk factors for suicidal ideation in young students. Prevention program focusing on these problems may have an enduring effect on reducing suicidal behavior in this population. PMID- 25803666 TI - Effects of Nordic Walking and Pilates exercise programs on blood glucose and lipid profile in overweight and obese postmenopausal women in an experimental, nonrandomized, open-label, prospective controlled trial. AB - OBJECTIVE: Cardiometabolic effects of physical exercise depend on its intensity, duration, and type. The aim of this study was to compare the effects of two exercise models, Nordic Walking (NW) and Pilates, on postmenopausal women. METHODS: The study comprised 196 overweight or obese women: 20 were advised to maintain their previous level of physical activity (control group) whereas the others started either an NW exercise program (n = 88) or a Pilates exercise program (n = 88). Blood was collected twice for testing: before the program commenced and after it had ended. RESULTS: Of the 196 women who enrolled in the study, 147 (75%) completed the study; among those women, 69 (47%) completed a 10 week NW exercise program, 58 (39%) completed a 10-week Pilates exercise program, and 20 (14%) were in the control group. After 10 weeks, women in the NW group showed a significant reduction in body weight (6.4%), body mass index (6.4%), blood glucose (3.8%), total cholesterol (10.4%), non-high-density lipoprotein (HDL) cholesterol (16.7%), low-density lipoprotein cholesterol (12.8%), and triglycerides (10.6%), as well as an increase in HDL cholesterol (9.6%). Significantly smaller-although still favorable-changes, except for glucose and HDL cholesterol levels, were observed in the Pilates group (decreases of 1.7%, 1.7%, 1.6%, 5.3%, 8.3%, 7.5%, and 6% and an increase of 3.1%, respectively). Nevertheless, at the end of the study, the percentage of women with target concentrations of the lipid fractions had significantly increased in both exercise groups. No significant changes in the studied parameters were found in the control group. On multiple regression analysis, type of exercise program was an independent predictor of amplitude changes in most of the studied parameters. CONCLUSIONS: Exercise training in accordance with the NW model causes statistically and clinically more significant changes in glucose and basic blood lipid levels than do Pilates and dietary intervention alone. PMID- 25803667 TI - Life course exposure to smoke and early menopause and menopausal transition. AB - OBJECTIVE: Early age at menopause is associated with increased risk of cardiovascular disease, stroke, osteoporosis, and all-cause mortality. Cigarette smoke exposure in adulthood is an established risk factor for earlier age at natural menopause and may be related to age at the menopausal transition. Using data from two US birth cohorts, we examined the association between smoke exposure at various stages of the life course (prenatal exposure, childhood exposure to parental smoking, and adult smoke exposure) and menopause status in 1,001 women aged 39 to 49 years at follow-up. METHODS: We used logistic regression analysis (adjusting for age at follow-up) to estimate odds ratios (ORs) and 95% confidence intervals (CI) relating smoke exposure to natural menopause and the menopausal transition. RESULTS: The magnitudes of the associations for natural menopause were similar but not statistically significant after adjustment for confounders among (i) women with prenatal smoke exposure who did not smoke on adult follow-up (OR, 2.7; 95% CI, 0.8-9.4) and (ii) current adult smokers who were not exposed prenatally (OR, 2.8; 95% CI, 0.9-9.0). Women who had been exposed to prenatal smoke and were current smokers had three times the risk of experiencing earlier natural menopause (adjusted OR, 3.4; 95% CI, 1.1 10.3) compared with women without smoke exposure in either period. Only current smoking of long duration (>26 y) was associated with the timing of the menopausal transition. CONCLUSIONS: Our data suggest that exposure to smoke both prenatally and around the time of menopause accelerates ovarian aging. PMID- 25803668 TI - Midlife women's symptom cluster heuristics: evaluation of an iPad application for data collection. AB - OBJECTIVE: This study aims to elicit midlife women's heuristics about symptom clusters they were experiencing, as identified by the Computerized Symptom Capture Tool for Menopause (C-SCAT M). METHODS: Women aged 40 to 60 years who were experiencing symptoms that they associated with menopause were recruited through flyers posted on campus and in clinics. Women completed the C-SCAT M application (app), using an iPad, by identifying and drawing symptom clusters they experienced during the last 24 hours, indicating relationships among symptoms, prioritizing the clusters and symptoms within them, making causal attributions, and identifying exacerbating and ameliorating factors. They were asked to prioritize the clusters and a symptom within each cluster. While women were completing the app, they were asked to "think aloud" about their experience using the app. Data generated from the C-SCAT M app were transmitted securely to an Amazon Web Services account and saved as screen images and Excel files to preserve both graphical images and text elicited from the app. Qualitative data were saved in verbatim phrases. Conventional content analysis was used to analyze qualitative data. RESULTS: Thirty women completed the app. Most women (77%) stated that the final diagrams were very/extremely accurate in depicting their symptoms and their connections. Women reported between 1 and 22 symptoms (median, 11). Hot flashes, waking up during the night, night sweats, and early morning awakening were the most commonly reported symptoms. Women rated hot flashes as their most bothersome symptom, followed by waking up during the night and fatigue. They reported more than 300 different bivariate relationships between their symptoms and more than 150 unique causal paths. They believed that hot flashes caused several symptoms, especially sleep disruption, and most could describe the time order of their symptoms. Women reported clusters consisting of 2 to 18 symptoms. Women also named each cluster based on their response to their symptoms ("really annoying"), time of occurrence ("night problem"), and symptoms included in the cluster ("hot flash"). They attributed their clusters to menopause, life demands, and other symptoms, among other causes. Management strategies that women used included over-the-counter preparations, sleep, rest, and other lifestyle changes. Some women requested for a copy of their final symptom cluster diagram to discuss with their healthcare providers. CONCLUSIONS: Use of the C-SCAT M affords women an opportunity to depict their symptoms and clusters and the relationships between them and to provide narrative data about their heuristics. Women's unsolicited comments about using the cluster diagram to facilitate conversations (about their symptoms) with their healthcare providers suggest the potential value of modifying the C-SCAT M and evaluating its use in a healthcare setting. PMID- 25803670 TI - Effects of self-reported age at nonsurgical menopause on time to first fracture and bone mineral density in the Women's Health Initiative Observational Study. AB - OBJECTIVE: Menopause is a risk factor for fracture; thus, menopause age may affect bone mass and fracture rates. We compared bone mineral density (BMD) and fracture rates among healthy postmenopausal women with varying ages at self reported nonsurgical menopause. METHODS: We compared hazard ratios for fractures and differences in BMD among 21,711 postmenopausal women from the Women's Health Initiative Observational Study cohort who had no prior hysterectomy, oophorectomy, or hormone therapy and had varying self-reported ages at menopause (<40, 40-49, or >=50 y). RESULTS: Before multivariable adjustments, we found no differences in absolute fracture risk among menopause age groups. After multivariable adjustments for known risk factors for fracture, women who underwent menopause before age 40 years had a higher fracture risk at any site compared with women who underwent menopause at age 50 years or older (hazard ratio, 1.21; 95% CI, 1.02 to 1.44; P = 0.03). In a subset with BMD measurements (n = 1,351), whole-body BMD was lower in women who reported menopause before age 40 years than in women who reported menopause at ages 40 to 49 years (estimated difference, -0.034 g/cm; 95% CI, -0.07 to -0.004; P = 0.03) and women who reported menopause at age 50 years or older (estimated difference, -0.05 g/cm; 95% CI, -0.08 to -0.02; P < 0.01). Left hip BMD was lower in women who underwent menopause before age 40 years than in women who underwent menopause at age 50 years or older (estimated difference, -0.05 g/cm; 95% CI, -0.08 to -0.01; P = 0.01), and total spine BMD was lower in women who underwent menopause before age 40 years than in women who underwent menopause at age 50 years or older (estimated difference, -0.11 g/cm; 95% CI, -0.16 to -0.06; P < 0.01) and women who underwent menopause at ages 40 to 49 years (estimated difference, -0.09 g/cm; 95% CI, -0.15 to -0.04; P < 0.01). CONCLUSIONS: In the absence of hormone therapy, younger age at menopause may be a risk factor contributing to decreased BMD and increased fracture risk in healthy postmenopausal women. Our data suggest that menopause age should be taken into consideration, along with other osteoporotic risk factors, when estimating fracture risk in postmenopausal women. PMID- 25803669 TI - Associations between body mass index and sexual functioning in midlife women: the Study of Women's Health Across the Nation. AB - OBJECTIVE: This study aims to examine baseline and longitudinal associations between body mass index (BMI) and sexual functioning in midlife women. METHODS: Midlife women (N = 2,528) from the Study of Women's Health Across the Nation reported on sexual functioning and underwent measurements of BMI annually beginning in 1995-1997, with follow-up spanning 13.8 years. Associations between baseline levels and longitudinal changes in BMI and sexual desire, arousal, intercourse frequency, and ability to climax were assessed with generalized linear mixed-effects models. Models were adjusted for demographic variables, depressive symptoms, hormone therapy use, alcohol intake, menopause status, smoking status, and health status. RESULTS: Mean BMI increased from 27.7 to 29.1 kg/m2, whereas all sexual functioning variables declined across time (P values <= 0.001). Higher baseline BMI was associated with less frequent intercourse (P = 0.003; 95% CI, -0.059 to -0.012). Although overall change in BMI was not associated with changes in sexual functioning, years of greater-than-expected BMI increases relative to women's overall BMI change trajectory were characterized by less frequent intercourse (P < 0.001; 95% CI, -0.106 to -0.029) and reduced sexual desire (P = 0.020; 95% CI, -0.078 to -0.007). CONCLUSIONS: Although women's overall BMI change across 13.8 years of follow-up was not associated with overall changes in sexual functioning, sexual desire and intercourse frequency diminished with years of greater-than-expected weight gain. Results suggest that adiposity and sexual functioning change concurrently from year to year. Further research should explore the impact of weight management interventions as a strategy for preserving sexual functioning in midlife women. PMID- 25803671 TI - Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all cause mortality. AB - OBJECTIVE: Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland. METHODS: A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (<=1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population. RESULTS: Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older. CONCLUSIONS: In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years. PMID- 25803673 TI - Stereocontrol in nucleophilic substitution reactions at silicon: the role of permutation in generating silicon-centered chirality. AB - Intramolecular isomerization in pentacoordinate compounds can play an essential role for the adjustment of defined stereochemical information. Here, we present a conclusive mechanism of a stereocontrolled reaction on chiral dimethoxysilanes that opens new aspects in understanding the origin of creating silicon-centered chirality during a nucleophilic substitution process. By combining experimental, structural, and quantum chemical methods, we were able to disclose an interconversion process, based on consecutive Berry-type motions, as the most plausible mechanism for describing the stereochemical outcome in suchlike substitution reactions. PMID- 25803672 TI - Variant rs1801157 in the 3'UTR of SDF-1beta does not explain variability of healthy-donor G-CSF responsiveness. AB - The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3'UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3'UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism. In a cohort of 515 healthy stem cell donors we attempted to reproduce the correlation of the CXCL12 3'UTR SNP and mobilization responses and tested the role of miR941 in this context. The SNP was distributed with the expected frequency. Mobilization efficiency for CD34+ cells in WT, heterozygous and homozygous SNP individuals was indistinguishable, even after controlling for gender. miR941 expression in non-hematopoietic bone marrow cells was undetectable and miR941 did not interact with the 3' UTR of CXCL12. Proposed effects of the SNP rs1801157 on G-CSF responsiveness cannot be confirmed in a larger cohort. PMID- 25803674 TI - The use of micro-plasma radiofrequency technology in secondary skin graft contraction: 2 case reports. AB - Secondary skin graft contraction leading to cosmetic deformity remains a great challenge. These two case reports present serious skin graft contraction and the treatment with micro-plasma radiofrequency technology. Two patients presented with complaints of post-burn depigmentation on the forehead and the hand, respectively, and received dermabrasion and thin split-thickness skin grafting. Then, many localized contraction lesions occurred after 4 weeks. The treatment selected was non-surgical removal using micro-plasma radiofrequency technology with the following energy parameters: a roller tip at 80 watts, three passes in different directions. No complications were observed. The contracted skin was ablated without affecting the pigment distribution. The consequents were that the color, appearance, and texture of the grafted skin matched the adjacent skin well and had better patient acceptance. PMID- 25803675 TI - Long-term patient-reported functional and cosmetic outcomes following severe traumatic foot and ankle wound reconstruction with acellular dermal matrix. AB - BACKGROUND: The prevalence of acellular dermal matrices in reconstructive surgery has increased through the last decade with satisfying outcomes. Long-term follow up and effectiveness studies could enable appropriate use of these devices and challenge the current gold-standard treatments. This paper presents functional and cosmetic long-term outcomes on the Integra((r)) Dermal Regeneration Template (IDRT) for treating traumatic soft-tissue defects of the foot and ankle. METHODS: All adult patients who underwent severe traumatic foot and ankle reconstruction with Integra((r)) since 2004 were retrospectively included. Results were evaluated using standardized outcome instruments. RESULTS: Twenty-one reconstructions were evaluated 4.5 +/- 2.5 years after foot and ankle injury. Major complications inducing a second application included 1 hematoma and 1 infection. Seven patients (35%) had good or excellent Foot and Ankle Ability Measures. Subjectively, when asked to compare current function with pre-injury status, the mean response was 66 +/- 23%. The Observer Scar Assessment Scale scored 17 +/- 5 points (possible range, 5-50), while the Patient Scar Assessment Scale scored 30 +/- 11 points (possible range, 6-60). CONCLUSIONS: Long-term functional and cosmetic outcomes 4.5 years after severe traumatic foot and ankle wounds treated with IDRTs were rated fair in the great majority of patients. Nevertheless, because complications and surgical revisions were few, potential benefits might be underestimated because of the initial combined injuries and their sequelae. In this way, for appropriately selected patients with severe traumatic foot and ankle soft-tissue defects, including subacute coverage, it appears that this treatment may be a viable first option. PMID- 25803676 TI - A case of generalized bromhidrosis following whole-body depilatory laser. AB - BACKGROUND: Laser treatment is a widespread method for hair removal. Despite its very common use, side effects remain relatively rare and transient. OBJECTIVE: Axillary hyperhidrosis and bromhidrosis have already been reported in the literature after depilatory lasers. We report here a novel side effect of total body bromhidrosis following hair removal laser. RESULTS: A 27-year-old man, phototype 3 underwent four sessions of total body depilatory laser, combining pulsed alexandrite and pulsed diode lasers. A few days afterwards, a generalized foul odor was noted and was resistant to regular deodorants and Aluminum chloride based antiperspirants. Possible mechanisms include the activation of dormant bacteria in the skin flora, sweat gland dysfunction, altered skin flora, sweat gland hormone receptor disturbances, and genetic factors. CONCLUSION: Total body bromhidrosis and hyperhidrosis are potential complications of total body laser hair removal. PMID- 25803677 TI - Comparison of topical anesthesia and subcutaneous infiltration anesthesia with regard to effect of plasma skin regeneration system. AB - The plasma skin regeneration (PSR) system is a safe device for skin regeneration, which is usually carried out under local anesthetic to control the pain. Topical anesthesia and subcutaneous infiltration anesthesia are the common and safe anesthetizations. This study was undertaken to evaluate the effects of PSR after using topical anesthetization as compared with subcutaneous infiltration anesthesia, thereby inquiring into the effect of subcutaneous infiltration anesthesia in PSR and increasing electivity for clinical work. 14 Sprague Dawley rats were randomly utilized in this experiment. After adequate sedation and depilation, the rat's back was randomly divided into three experimental regions marked as A, B, and C. A and B were treated with lidocaine cream and lidocaine hydrochloride, respectively, before PSR. C was treated solely with PSR without any anesthesia. Biopsies were taken from all treatment sites at 4 and 30 days after treatment to observe the skin necrosis and thickness of new collagen fiber. Histopathologic examination was performed by observers blinded to the treatment conditions. In this analysis, there was a statistically significant reduction (P < 0.01) in the skin necrosis and thickness of new collagen fiber in the topical anesthesia group compared with that in the other two groups, while a statistically significant increase (P < 0.01) in the subcutaneous infiltration anesthesia group. The results suggest that subcutaneous infiltration anesthesia group showed a deeper range of tissue effects via the treatment of PSR as compared with the topical anesthesia and the control groups. Meanwhile, the effect of the topical anesthesia was the lowest. So we conclude that subcutaneous infiltration anesthesia for PSR treatment was superior to that of the topical anesthesia. PMID- 25803678 TI - Nd:YAG Q-switched laser for the treatment of a hemicorporal epidermal nevus: A safe and effective option. AB - Epidermal nevi are benign proliferations of the epidermis for which different treatments have been used with disappointing results due to their recurrences and anesthetic scars. Topical therapies have generally been ineffective and surgical treatment provides more definitive results, but with high risk of scarring. In recent years, multiple laser modalities have been described for the treatment of these lesions. In the literature, there are no reported cases of treatment of these lesions with Neodymium-doped Yttrium aluminum garnet (Nd:YAG) laser. We present the case of a 3-year-old patient with a hemicorporal epidermal nevus treated with Nd:YAG laser at an early stage with good results. PMID- 25803679 TI - Effectiveness of low-fluence and short-pulse intense pulsed light in the treatment of melasma: A randomized study. AB - BACKGROUND: Various treatment protocols for melasma have been suggested in the literature, but the efficacy and safety of treatment varies according to the report. OBJECTIVE: To investigate the selective photothermolytic effect of fluence-dependent intense pulsed light (IPL) in the treatment of melasma. METHODS: Twenty Korean adults with melasma were enrolled, randomly assigned to two groups and treated at fluences of 10 or 13 J/cm(2) of IPL weekly over 6 weeks. Subjects were evaluated at baseline and weekly during the 6 weeks of treatment and at 3 weeks following the final treatment. Melanin and erythema indices were scored using a spectrophotometer. RESULTS: The modified Melasma Area Severity Index (MASI) score of 20 patients at inclusion was 11.6 (+/- 0.9). Both 10J and 13J IPL treatment groups had decreased modified MASI scores from 2 weeks onward at statistically significant levels. Both 10J and 13J IPL treatment groups showed decreased melanin indices with statistically significant differences from 3 weeks onward. The effect of IPL on melasma was slightly greater in patients treated with 13J of IPL than in those treated with 10J over the entire duration of the study. The erythema index was transiently increased in weeks 1-3, but after 4 weeks it decreased to sub-baseline levels. CONCLUSION: We suggest that a low-fluence IPL protocol could provide more effective treatment for melasma with minimal side effects in Asian skin. PMID- 25803680 TI - Laser therapy of a dermal nevus in the esthetic zone of the nasal tip: A case report and comprehensive literature review. AB - This case report demonstrates the ablation of a dermal nevus using a diode laser in the esthetically very demanding facial area of the nasal tip. The clinical outcome shows good results and a high level of patient satisfaction. Due to effective wound granulation and healing, elaborate skin grafts could be avoided. The application of the contact laser ensures safe treatment in highly perfused areas thanks to haptic feedback and good coagulative effect. The method should therefore be considered as an alternative to other ablative procedures for benign lesions in the facial area. PMID- 25803681 TI - Gp120/CD4 blocking antibodies are frequently elicited in ART-naive chronically HIV-1 infected individuals. AB - Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naive chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine. PMID- 25803682 TI - Refining hypertension surveillance to account for potentially misclassified cases. AB - Administrative health data have been used in hypertension surveillance using the 1H2P method: the International Classification of Disease (ICD) hypertension diagnosis codes were recorded in at least 1 hospitalization or 2 physician claims within 2 year-period. Accumulation of false positive cases over time using the 1H2P method could result in the overestimation of hypertension prevalence. In this study, we developed and validated a new reclassification method to define hypertension cases using regularized logistic regression with the age, sex, hypertension and comorbidities in physician claims, and diagnosis of hypertension in hospital discharge data as independent variables. A Bayesian method was then used to adjust the prevalence estimated from the reclassification method. We evaluated the hypertension prevalence in data from Alberta, Canada using the currently accepted 1H2P method and these newly developed methods. The reclassification method with Bayesian adjustment produced similar prevalence estimates as the 1H2P method. This supports the continued use of the 1H2P method as a simple and practical way to conduct hypertension surveillance using administrative health data. PMID- 25803683 TI - Comparative study of state-of-the-art myoelectric controllers for multigrasp prosthetic hands. AB - A myoelectric controller should provide an intuitive and effective human-machine interface that deciphers user intent in real-time and is robust enough to operate in daily life. Many myoelectric control architectures have been developed, including pattern recognition systems, finite state machines, and more recently, postural control schemes. Here, we present a comparative study of two types of finite state machines and a postural control scheme using both virtual and physical assessment procedures with seven nondisabled subjects. The Southampton Hand Assessment Procedure (SHAP) was used in order to compare the effectiveness of the controllers during activities of daily living using a multigrasp artificial hand. Also, a virtual hand posture matching task was used to compare the controllers when reproducing six target postures. The performance when using the postural control scheme was significantly better (p < 0.05) than the finite state machines during the physical assessment when comparing within-subject averages using the SHAP percent difference metric. The virtual assessment results described significantly greater completion rates (97% and 99%) for the finite state machines, but the movement time tended to be faster (2.7 s) for the postural control scheme. Our results substantiate that postural control schemes rival other state-of-the-art myoelectric controllers. PMID- 25803684 TI - DeepSAGE based differential gene expression analysis under cold and freeze stress in seabuckthorn (Hippophae rhamnoides L.). AB - Seabuckthorn (Hippophae rhamnoides L.), an important plant species of Indian Himalayas, is well known for its immense medicinal and nutritional value. The plant has the ability to sustain growth in harsh environments of extreme temperatures, drought and salinity. We employed DeepSAGE, a tag based approach, to identify differentially expressed genes under cold and freeze stress in seabuckthorn. In total 36.2 million raw tags including 13.9 million distinct tags were generated using Illumina sequencing platform for three leaf tissue libraries including control (CON), cold stress (CS) and freeze stress (FS). After discarding low quality tags, 35.5 million clean tags including 7 million distinct clean tags were obtained. In all, 11922 differentially expressed genes (DEGs) including 6539 up regulated and 5383 down regulated genes were identified in three comparative setups i.e. CON vs CS, CON vs FS and CS vs FS. Gene ontology and KEGG pathway analysis were performed to assign gene ontology term to DEGs and ascertain their biological functions. DEGs were mapped back to our existing seabuckthorn transcriptome assembly comprising of 88,297 putative unigenes leading to the identification of 428 cold and freeze stress responsive genes. Expression of randomly selected 22 DEGs was validated using qRT-PCR that further supported our DeepSAGE results. The present study provided a comprehensive view of global gene expression profile of seabuckthorn under cold and freeze stresses. The DeepSAGE data could also serve as a valuable resource for further functional genomics studies aiming selection of candidate genes for development of abiotic stress tolerant transgenic plants. PMID- 25803685 TI - Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation. AB - Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH* scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH*. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media. PMID- 25803686 TI - CD105 expression on CD34-negative spindle-shaped stromal cells of primary tumor is an unfavorable prognostic marker in early breast cancer patients. AB - Several studies have confirmed that the breast tumor microenvironment drives cancer progression and metastatic development. The aim of our research was to investigate the prognostic significance of the breast tumor microenvironment in untreated early breast cancer patients. Therefore, we analyzed the association of the expression of alpha-SMA, FSP, CD105 and CD146 in CD34-negative spindle-shaped stromal cells, not associated with the vasculature, in primary breast tumors with classical prognostic marker levels, metastatic recurrence, local relapse, disease free survival, metastasis-free survival and the overall survival of patients. In the same way, we evaluated the association of the amount of intra-tumor stroma, fibroblasts, collagen deposition, lymphocytic infiltration and myxoid changes in these samples with the clinical-pathological data previously described. This study is the first to demonstrate the high CD105 expression in this stromal cell type as a possible independent marker of unfavorable prognosis in early breast cancer patients. Our study suggests that this new finding can be useful prognostic marker in the clinical-pathological routine. PMID- 25803688 TI - Lambs fed fresh winter forage rape (Brassica napus L.) emit less methane than those fed perennial ryegrass (Lolium perenne L.), and possible mechanisms behind the difference. AB - The objectives of this study were to examine long-term effects of feeding forage rape (Brassica napus L.) on methane yields (g methane per kg of feed dry matter intake), and to propose mechanisms that may be responsible for lower emissions from lambs fed forage rape compared to perennial ryegrass (Lolium perenne L.). The lambs were fed fresh winter forage rape or ryegrass as their sole diet for 15 weeks. Methane yields were measured using open circuit respiration chambers, and were 22-30% smaller from forage rape than from ryegrass (averages of 13.6 g versus 19.5 g after 7 weeks, and 17.8 g versus 22.9 g after 15 weeks). The difference therefore persisted consistently for at least 3 months. The smaller methane yields from forage rape were not related to nitrate or sulfate in the feed, which might act as alternative electron acceptors, or to the levels of the potential inhibitors glucosinolates and S-methyl L-cysteine sulfoxide. Ruminal microbial communities in forage rape-fed lambs were different from those in ryegrass-fed lambs, with greater proportions of potentially propionate-forming bacteria, and were consistent with less hydrogen and hence less methane being produced during fermentation. The molar proportions of ruminal acetate were smaller and those of propionate were greater in forage rape-fed lambs, consistent with the larger propionate-forming populations and less hydrogen production. Forage rape contained more readily fermentable carbohydrates and less structural carbohydrates than ryegrass, and was more rapidly degraded in the rumen, which might favour this fermentation profile. The ruminal pH was lower in forage rape fed lambs, which might inhibit methanogenic activity, shifting the rumen fermentation to more propionate and less hydrogen and methane. The significance of these two mechanisms remains to be investigated. The results suggest that forage rape is a potential methane mitigation tool in pastoral-based sheep production systems. PMID- 25803687 TI - Genome-wide scan of gastrointestinal nematode resistance in closed Angus population selected for minimized influence of MHC. AB - Genetic markers associated with parasite indicator traits are ideal targets for study of marker assisted selection aimed at controlling infections that reduce herd use of anthelminthics. For this study, we collected gastrointestinal (GI) nematode fecal egg count (FEC) data from post-weaning animals of an Angus resource population challenged to a 26 week natural exposure on pasture. In all, data from 487 animals was collected over a 16 year period between 1992 and 2007, most of which were selected for a specific DRB1 allele to reduce the influence of potential allelic variant effects of the MHC locus. A genome-wide association study (GWAS) based on BovineSNP50 genotypes revealed six genomic regions located on bovine Chromosomes 3, 5, 8, 15 and 27; which were significantly associated ( log10 p=4.3) with Box-Cox transformed mean FEC (BC-MFEC). DAVID analysis of the genes within the significant genomic regions suggested a correlation between our results and annotation for genes involved in inflammatory response to infection. Furthermore, ROH and selection signature analyses provided strong evidence that the genomic regions associated BC-MFEC have not been affected by local autozygosity or recent experimental selection. These findings provide useful information for parasite resistance prediction for young grazing cattle and suggest new candidate gene targets for development of disease-modifying therapies or future studies of host response to GI parasite infection. PMID- 25803689 TI - A 'mystery client' evaluation of adolescent sexual and reproductive health services in health facilities from two regions in Tanzania. AB - Unwelcoming behaviours and judgemental attitudes have long been recognised as a barrier to young people's access to reproductive health services. Over the last decade youth friendly reproductive health services have been promoted and implemented world-wide. However, long term evidence of the impact of these programmes is lacking. We report the results of a large mystery client evaluation of adolescent sexual and reproductive health services in Tanzania, a country that has had a long established youth friendly policy. Forty-eight visits made to thirty-three health facilities were conducted by twelve young people (six in each region) trained to perform three different scripted scenarios (i.e., condom request, information on sexually transmitted infections and family planning). The study revealed barriers in relation to poor signage and reception for services. In addition health workers demonstrated paternalistic attitudes as well as lack of knowledge about adolescent sexual and reproductive health services. In some cases, health workers discouraged young people from using services such as condoms and family planning methods. Lack of confidentiality and privacy were also noted to be common challenges for the young people involved. Intervention strategies that focus on changing health workers' mind-set in relation to adolescent sexual and reproductive health are crucial for ensuring quality provision of sexual and reproductive health services to young people. The study identified the importance of reception or signs at the health units, as this can facilitate young people's efforts in seeking sexual and reproductive health services. Likewise, improvement of health workers knowledge of existing policy and practice on sexual and reproductive health services and youth friendly services is much needed. PMID- 25803690 TI - Clinical outcomes and microbiological characteristics of severe pneumonia in cancer patients: a prospective cohort study. AB - INTRODUCTION: Pneumonia is the most frequent type of infection in cancer patients and a frequent cause of ICU admission. The primary aims of this study were to describe the clinical and microbiological characteristics and outcomes in critically ill cancer patients with severe pneumonia. METHODS: Prospective cohort study in 325 adult cancer patients admitted to three ICUs with severe pneumonia not acquired in the hospital setting. Demographic, clinical and microbiological data were collected. RESULTS: There were 229 (71%) patients with solid tumors and 96 (29%) patients with hematological malignancies. 75% of all patients were in septic shock and 81% needed invasive mechanical ventilation. ICU and hospital mortality rates were 45.8% and 64.9%. Microbiological confirmation was present in 169 (52%) with a predominance of Gram negative bacteria [99 (58.6%)]. The most frequent pathogens were methicillin-sensitive S. aureus [42 (24.9%)], P. aeruginosa [41(24.3%)] and S. pneumonia [21 (12.4%)]. A relatively low incidence of MR [23 (13.6%)] was observed. Adequate antibiotics were prescribed for most patients [136 (80.5%)]. In multivariate analysis, septic shock at ICU admission [OR 5.52 (1.92-15.84)], the use of invasive MV [OR 12.74 (3.60-45.07)] and poor Performance Status [OR 3.00 (1.07-8.42)] were associated with increased hospital mortality. CONCLUSIONS: Severe pneumonia is associated with high mortality rates in cancer patients. A relatively low rate of MR pathogens is observed and severity of illness and organ dysfunction seems to be the best predictors of outcome in this population. PMID- 25803692 TI - Low elastin content of carotid plaques is associated with increased risk of ipsilateral stroke. AB - OBJECTIVES: Atherosclerotic plaques with a low content of connective tissue proteins are believed to have an increased risk of rupture and to give rise to clinical events. The aim of the present study was to investigate if the content of elastin, collagen and of the matrix metalloproteinase (MMP) -1, -3, -9 and -12 in plaques removed at surgery can be associated with the occurrence of ipsilateral symptoms. METHODS: The atherosclerotic plaques of 221 patients undergoing carotid endarterectomy were analyzed and their composition was related to the incidence of preoperative, intraoperative and postoperative neurological events. RESULTS: Elastin, collagen and MMP-12 contents were lower in males and diabetic patients. Elastin (P .010), MMP-3 (P .008) and MMP-9 (P < .0001) were lower, while MMP-1 (P .004) and MMP-9 (P .002) were higher in plaques of patients with preoperative symptoms, even after correction for the time between the occurrence of symptoms and surgery. Elastin and MMP-12 decreased (r = -0.17, P .009 and r = -.288, P <.0001 respectively) while MMP-1 (r = 0.17, P .012) and MMP 9 (r = .21 P <.0001) increased with age. After a mean follow-up time of 39.6 +/- 16.6 months, 7.7% of patients had suffered one or multiple ipsilateral neurological events. Patients with plaque elastin levels lower than the median (52 mg/g) had increased post-operative incidence of ipsilateral stroke (P for trend 0.009 using Log Rank Chi-square test). This finding was confirmed when controlling for age, gender, hypertension, diabetes, smoking, pre-operative symptoms and statin usage in a Cox Proportional Hazard model (hazard ratio 7.38, 95% C.I. 1.50-36.31). CONCLUSIONS: These observations support the concept that elastin may be important for plaque stability, and suggest that a low plaque content of elastin is associated with a higher risk for ipsilateral stroke. PMID- 25803691 TI - Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition. AB - Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma. PMID- 25803694 TI - Development and evaluation of a web-based assent for adolescents considering an HIV vaccine trial. AB - HIV vaccine trials with minors will likely require parental permission and informed assent from adolescents. For this to be a valid process, the information needs to be presented in a manner that promotes adolescent comprehension. Previous studies suggest that adolescent comprehension of assent is often insufficient. We developed an interactive web-based assent that included interspersed quiz questions for a hypothetical HIV vaccine trial. Efficacy of the web-based assent was compared to a standard paper assent with and without interspersed questions. One hundred twenty teen participants, ages 15-17 years, from five community organizations were randomized to self-administered web-based assent (n=60) or investigator-administered paper assent with (n=29) or without (n=31) interspersed quiz questions. After reviewing the assent, participants completed a 27-item comprehension test. Comprehension scores were compared between groups. The mean number of correctly answered questions were 21.2 for the full paper group and 21.1 for the web-based group (t118=-0.08, p=0.94). Scores were 20.2 for the paper without interspersed questions sub-group and 22.1 for the paper with interspersed questions sub-group (t58=1.96, p=0.055). Participants in the web-based group performed as well on the comprehension test as those in the paper group, and those in the paper with questions sub-group performed better than those in the paper without questions sub-group, suggesting that interspersed quiz questions may improve understanding of a traditional paper assent. The minimal investigator time and standardized administration of the web-based assent as well as ability to tailor the assent discussion to topics identified by incorrect comprehension test responses are advantages worthy of further investigation. PMID- 25803695 TI - Enteral nutrition formulations for acute pancreatitis. AB - BACKGROUND: Acute pancreatitis is a common and potentially lethal disease with increasing incidence. Severe cases are characterised by high mortality, and despite improvements in intensive care management, no specific treatment relevantly improves clinical outcomes of the disease. Meta-analyses suggest that enteral nutrition is more effective than conventional treatment consisting of discontinuation of oral intake with use of total parenteral nutrition. However, no systematic review has compared different enteral nutrition formulations for the treatment of patients with acute pancreatitis. OBJECTIVES: To assess the beneficial and harmful effects of different enteral nutrition formulations in patients with acute pancreatitis. SEARCH METHODS: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Specialised Register of Clinical Trials, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 7), MEDLINE (from inception to 20 August 2013), EMBASE (from inception to 2013, week 33) and Science Citation Index-Expanded (from 1990 to August 2013); we conducted full-text searches and applied no restrictions by language or publication status. SELECTION CRITERIA: We considered randomised clinical trials assessing enteral nutrition in patients with acute pancreatitis. We allowed concomitant interventions if they were received equally by all treatment groups within a trial. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. We performed the analysis using Review Manager 5 (Review Manager 2013) and both fixed-effect and random-effects models. We expressed results as risk ratios (RRs) for dichotomous data, and as mean differences (MDs) for continuous data, both with 95% confidence intervals (CIs). Analysis was based on an intention-to-treat principle. MAIN RESULTS: We included 15 trials (1376 participants) in this review. We downgraded the quality of evidence for many of our outcomes on the basis of high risk of bias. Low quality evidence suggests that immunonutrition decreases all-cause mortality (RR 0.49, 95% CI 0.29 to 0.80). The effect of immunonutrition on other outcomes from a subset of the included trials was uncertain. Subgrouping trials by type of enteral nutrition did not explain any variation in effect. We found mainly very low-quality evidence for the effects of probiotics on the main outcomes. One eligible trial in this comparison reported a higher rate of serious adverse events leading to increased organ failure and mortality due to low numbers of events and low risk of bias. When we excluded this study as a post hoc sensitivity analysis, risks of mortality (RR 0.30, 95% CI 0.10 to 0.84), organ failure (RR 0.74, 95% CI 0.59 to 0.92) and local septic complications (RR 0.40, 95% CI 0.22 to 0.72) were lower with probiotics. In one trial assessing immunonutrition with probiotics and fibres, no deaths occurred, but hospital stay was shorter with immunonutrition (MD -5.20 days, 95% CI -8.73 to -1.67). No deaths were reported following semi-elemental enteral nutrition (EN), and the effect on length of hospital stay was small (MD 0.30 days, 95% CI -0.82 to 1.42). Fibre-enriched formulations reduced the number of other local complications (RR 0.52, 95% CI 0.32 to 0.87) and length of hospital stay (MD -9.28 days, 95% CI 13.21 to -5.35) but did not significantly affect all-cause mortality (RR 0.23, 95% CI 0.03 to 1.84) and other outcomes. Very low-quality evidence from the subgroup of trials comparing EN versus no intervention showed a decrease in all cause mortality with EN (RR 0.50, 95% CI 0.29 to 0.86). AUTHORS' CONCLUSIONS: We found evidence of low or very low quality for the effects of immunonutrition on efficacy and safety outcomes. The role of supplementation of enteral nutrition with potential immunomodulatory agents remains in question, and further research is required in this area. Studies assessing probiotics yielded inconsistent and almost contrary results, especially regarding safety and adverse events, and their findings do not support the routine use of EN enriched with probiotics in routine clinical practice. However, further research should be carried out to try to determine the potential efficacy or harms of probiotics. Lack of trials reporting on other types of EN assessed and lack of firm evidence regarding their effects suggest that additional randomised clinical trials are needed. The quality of evidence for the effects of any kind of EN on mortality was low, and further studies are likely to have an impact on the finding of improved survival with EN versus no nutritional support. Evidence remains insufficient to support the use of a specific EN formulation. PMID- 25803693 TI - High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats. AB - There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05), and promoted a 20% (P<0.05) increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05), and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05). In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05) and a 20% decrease in cross sectional area (P<0.05). HIIT also increased brain natriuretic peptide by 50% (P<0.05), in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease. PMID- 25803696 TI - Maintaining economic value of ecosystem services whilst reducing environmental cost: a way to achieve freshwater restoration in China. AB - Freshwater fisheries are central to food security in China and this remains one of the most important priorities for the growing human population. Thus, combining ecosystem restoration with economics is pivotal in setting successful conservation in China. Here, we have developed a practical management model that combines fishery improvement with conservation. For six years, a ban on fertilizer and a reduction of planktivorous fish stocking along with the introduction of both mandarin fish Siniperca chuatsi and Chinese mitten crab Eriocheir sinensis was apparent in Wuhu Lake, a highly eutrophic lake located in the middle reaches of the Yangtze River. Annual fish yield decreased slightly after the change in management, whereas fisheries income increased 2.6 times. Mandarin fish and Chinese mitten crab accounted for only 16% of total fisheries production but for 48% of total fisheries income. During this six year period, water clarity increased significantly from 61 cm to 111 cm. Total nitrogen, total phosphorus and chlorophyll decreased significantly from 1.14 to 0.84 mg/L, 0.077 to 0.045 mg/L, and 21.45 to 11.59 MUg/L respectively, and macrophyte coverage increased by about 30%. Our results showed that the ecological status of shallow lakes could be rapidly reversed from eutrophic to oligotrophic using simple biomanipulation, whilst maintaining fisheries economic value. It also offers a better approach to shallow fisheries lake management in Asia where traditionally the stocking of Chinese carp and use of fertilizers is still popular. PMID- 25803698 TI - Correction: Antihypertensive medication classes used among Medicare beneficiaries initiating treatment in 2007-2010. PMID- 25803697 TI - Efficacy of a parainfluenza virus 5 (PIV5)-based H7N9 vaccine in mice and guinea pigs: antibody titer towards HA was not a good indicator for protection. AB - H7N9 has caused fatal infections in humans. A safe and effective vaccine is the best way to prevent large-scale outbreaks in the human population. Parainfluenza virus 5 (PIV5), an avirulent paramyxovirus, is a promising vaccine vector. In this work, we generated a recombinant PIV5 expressing the HA gene of H7N9 (PIV5 H7) and tested its efficacy against infection with influenza virus A/Anhui/1/2013 (H7N9) in mice and guinea pigs. PIV5-H7 protected the mice against lethal H7N9 challenge. Interestingly, the protection did not require antibody since PIV5-H7 protected JhD mice that do not produce antibody against lethal H7N9 challenge. Furthermore, transfer of anti-H7 serum did not protect mice against H7N9 challenge. PIV5-H7 generated high HAI titers in guinea pigs, however it did not protect against H7N9 infection or transmission. Intriguingly, immunization of guinea pigs with PIV5-H7 and PIV5 expressing NP of influenza A virus H5N1 (PIV5 NP) conferred protection against H7N9 infection and transmission. Thus, we have obtained a H7N9 vaccine that protected both mice and guinea pigs against lethal H7N9 challenge and infection respectively. PMID- 25803699 TI - Red Light-Regulated Reversible Nuclear Localization of Proteins in Mammalian Cells and Zebrafish. AB - Protein trafficking in and out of the nucleus represents a key step in controlling cell fate and function. Here we report the development of a red light inducible and far-red light-reversible synthetic system for controlling nuclear localization of proteins in mammalian cells and zebrafish. First, we synthetically reconstructed and validated the red light-dependent Arabidopsis phytochrome B nuclear import mediated by phytochrome-interacting factor 3 in a nonplant environment and support current hypotheses on the import mechanism in planta. On the basis of this principle we next regulated nuclear import and activity of target proteins by the spatiotemporal projection of light patterns. A synthetic transcription factor was translocated into the nucleus of mammalian cells and zebrafish to drive transgene expression. These data demonstrate the first in vivo application of a plant phytochrome-based optogenetic tool in vertebrates and expand the repertoire of available light-regulated molecular devices. PMID- 25803702 TI - Media debates and 'ethical publicity' on social sex selection through preimplantation genetic diagnosis (PGD) technology in Australia. AB - This paper offers a critical discourse analysis of media debate over social sex selection in the Australian media from 2008 to 2014. This period coincides with a review of the National Health and Medical Research Council's Ethical Guidelines on the Use of Assisted Reproductive Technology in Clinical Practice and Research (2007), which underlie the regulation of assisted reproductive clinics and practice in Australia. I examine the discussion of the ethics of pre-implatation genetic diagnosis (PGD) within the media as 'ethical publicity' to the lay public. Sex selection through PGD is both exemplary of and interconnected with a range of debates in Australia about the legitimacy of certain reproductive choices and the extent to which procreative liberties should be restricted. Major themes emerging from media reports on PGD sex selection in Australia are described. These include: the spectre of science out of control; ramifications for the contestation over the public funding of abortion in Australia; private choices versus public authorities regulating reproduction; and the ethics of travelling overseas for the technology. It is concluded that within Australia, the issue of PGD sex selection is framed in terms of questions of individual freedom against the principle of sex discrimination - a principle enshrined in legislation - and a commitment to publically-funded medical care. PMID- 25803700 TI - Endocytosis of a functionally enhanced GFP-tagged transferrin receptor in CHO cells. AB - The endocytosis of transferrin receptor (TfR) has served as a model to study the receptor-targeted cargo delivery system for cancer therapy for many years. To accurately evaluate and optically measure this TfR targeting delivery in vitro, a CHO cell line with enhanced green fluorescent protein (EGFP)-tagged human TfR was established. A chimera of the hTfR and EGFP was engineered by fusing EGFP to the amino terminus of hTfR. Data were provided to demonstrate that hTfR-EGFP chimera was predominantly localized on the plasma membrane with some intracellular fluorescent structures on CHO cells and the EGFP moiety did not affect the endocytosis property of hTfR. Receptor internalization occurred similarly to that of HepG2 cells expressing wild-type hTfR. The internalization percentage of this chimeric receptor was about 81 +/- 3% of wild type. Time-dependent co localization of hTfR-EGFP and PE-conjugated anti-hTfR mAb in living cells demonstrated the trafficking of mAb-receptor complexes through the endosomes followed by segregation of part of the mAb and receptor at the late stages of endocytosis. The CHO-hTfR cells preferentially took up anti-hTfR mAb conjugated nanoparticles. This CHO-hTfR cell line makes it feasible for accurate evaluation and visualization of intracellular trafficking of therapeutic agents conjugated with transferrin or Abs targeting the hTfRs. PMID- 25803701 TI - Characterisation of the small RNAs in the biomedically important green-bottle blowfly Lucilia sericata. AB - BACKGROUND: The green bottle fly maggot, Lucilia sericata, is a species with importance in medicine, agriculture and forensics. Improved understanding of this species' biology is of great potential benefit to many research communities. MicroRNAs (miRNA) are a short non-protein coding regulatory RNA, which directly regulate a host of protein coding genes at the translational level. They have been shown to have developmental and tissue specific distributions where they impact directly on gene regulation. In order to improve understanding of the biology of L. sericata maggots we have performed small RNA-sequencing of their secretions and tissue at different developmental stages. RESULTS: We have successfully isolated RNA from the secretions of L. sericata maggots. Illumina small RNA-sequencing of these secretions and the three tissues (crop, salivary gland, gut) revealed that the most common small RNA fragments were derived from ribosomal RNA and transfer RNAs of both insect and bacterial origins. These RNA fragments were highly specific, with the most common tRNAs, such as GlyGCC, predominantly represented by reads derived from the 5' end of the mature maggot tRNA. Each library also had a unique profile of miRNAs with a high abundance of miR-10-5p in the maggot secretions and gut and miR-8 in the food storage organ the crop and salivary glands. The pattern of small RNAs in the bioactive maggot secretions suggests they originate from a combination of saliva, foregut and hindgut tissues. Droplet digital RT-PCR validation of the RNA-sequencing data shows that not only are there differences in the tissue profiles for miRNAs and small RNA fragments but that these are also modulated through developmental stages of the insect. CONCLUSIONS: We have identified the small-RNAome of the medicinal maggots L. sericata and shown that there are distinct subsets of miRNAs expressed in specific tissues that also alter during the development of the insect. Furthermore there are very specific RNA fragments derived from other non coding RNAs present in tissues and in the secretions. This new knowledge has applicability in diverse research fields including wound healing, agriculture and forensics. PMID- 25803703 TI - Compressive viscoelasticity of freshly excised mouse skin is dependent on specimen thickness, strain level and rate. AB - Although the skin's mechanical properties are well characterized in tension, little work has been done in compression. Here, the viscoelastic properties of a population of mouse skin specimens (139 samples from 36 mice, aged 5 to 34 weeks) were characterized upon varying specimen thickness, as well as strain level and rate. Over the population, we observed the skin's viscoelasticity to be quite variable, yet found systematic correlation of residual stress ratio with skin thickness and strain, and of relaxation time constants with strain rates. In particular, as specimen thickness ranged from 211 to 671 MUm, we observed significant variation in both quasi-linear viscoelasticity (QLV) parameters, the relaxation time constant (tau1 = 0.19 +/- 0.10 s) and steady-state residual stress ratio (Ginfinity = 0.28 +/- 0.13). Moreover, when tau1 was decoupled and fixed, we observed that Ginfinity positively correlated with skin thickness. Second, as steady-state stretch was increased (lambdainfinity from 0.22 to 0.81), we observed significant variation in both QLV parameters (tau1 = 0.26 +/- 0.14 s, Ginfinity = 0.47 +/- 0.17), and when tau1 was fixed, Ginfinity positively correlated with stretch level. Third, as strain rate was increased from 0.06 to 22.88 s-1, the median time constant tau1 varied from 1.90 to 0.31 s, and thereby negatively correlated with strain rate. These findings indicate that the natural range of specimen thickness, as well as experimental controls of compression level and rate, significantly influence measurements of skin viscoelasticity. PMID- 25803704 TI - Longitudinal Impact on Quality of Life for School-aged Children with Amblyopia Treatment: Perspective from Children. AB - BACKGROUND: To evaluate the longitudinal impact on health-related quality of life (HRQOL) during amblyopia treatment for school-aged children from children's perspective. METHODS: School-aged children prescribed amblyopia treatment for the first time were recruited into the current study. Using a questionnaire, subjects' HRQOL was assessed before patching treatment, and at 8 weeks and 16 weeks after the commencement of patching treatment. Evaluation of visual function and psychosocial aspect was included in the questionnaire. Visual acuity and demographic data of the subjects were recorded. RESULTS: Forty-four children, aged 7-12 years, with anisometropic amblyopia were included in the study. Visual acuity in the amblyopic eye improved 1.90 (0.41-3.74) and 3.98 (2.22-5.11) lines at follow-up weeks 8 and 16, respectively. Both the total score and subscales of the questionnaire were reduced at the first follow-up and recovered at the second follow-up. Scores at week 16 were higher than those before treatment in the psychosocial aspect (p = 0.003), and lower in the visual function aspect (p < 0.001), without significant difference in total score (p = 0.207). Visual acuity in the amblyopic eye and psychosocial expectations for treatment were the most important factors that influenced HRQOL during treatment. CONCLUSIONS: From the children's perspective, the impacts on visual function and psychosocial aspect were significant in the first two months of treatment, and could be adapted during therapy for school-aged children. More attention should be paid to negative effects of treatment on daily life and study at the stage of amblyopia treatment for school-aged children. Meanwhile, necessary precautions should be taken to help reduce the impacts. PMID- 25803706 TI - Open hardware: a role to play in wireless sensor networks? AB - The concept of the Internet of Things is rapidly becoming a reality, with many applications being deployed within industrial and consumer sectors. At the 'thing' level-devices and inter-device network communication-the core technical building blocks are generally the same as those found in wireless sensor network implementations. For the Internet of Things to continue growing, we need more plentiful resources for building intelligent devices and sensor networks. Unfortunately, current commercial devices, e.g., sensor nodes and network gateways, tend to be expensive and proprietary, which presents a barrier to entry and arguably slows down further development. There are, however, an increasing number of open embedded platforms available and also a wide selection of off-the shelf components that can quickly and easily be built into device and network gateway solutions. The question is whether these solutions measure up to built for-purpose devices. In the paper, we provide a comparison of existing built-for purpose devices against open source devices. For comparison, we have also designed and rapidly prototyped a sensor node based on off-the-shelf components. We show that these devices compare favorably to built-for-purpose devices in terms of performance, power and cost. Using open platforms and off-the-shelf components would allow more developers to build intelligent devices and sensor networks, which could result in a better overall development ecosystem, lower barriers to entry and rapid growth in the number of IoT applications. PMID- 25803705 TI - Behavioral functionality of mobile apps in health interventions: a systematic review of the literature. AB - BACKGROUND: Several thousand mobile phone apps are available to download to mobile phones for health and fitness. Mobile phones may provide a unique means of administering health interventions to populations. OBJECTIVE: The purpose of this systematic review was to systematically search and describe the literature on mobile apps used in health behavior interventions, describe the behavioral features and focus of health apps, and to evaluate the potential of apps to disseminate health behavior interventions. METHODS: We conducted a review of the literature in September 2014 using key search terms in several relevant scientific journal databases. Only English articles pertaining to health interventions using mobile phone apps were included in the final sample. RESULTS: The 24 studies identified for this review were primarily feasibility and pilot studies of mobile apps with small sample sizes. All studies were informed by behavioral theories or strategies, with self-monitoring as the most common construct. Acceptability of mobile phone apps was high among mobile phone users. CONCLUSIONS: The lack of large sample studies using mobile phone apps may signal a need for additional studies on the potential use of mobile apps to assist individuals in changing their health behaviors. Of these studies, there is early evidence that apps are well received by users. Based on available research, mobile apps may be considered a feasible and acceptable means of administering health interventions, but a greater number of studies and more rigorous research and evaluations are needed to determine efficacy and establish evidence for best practices. PMID- 25803707 TI - Global coverage measurement planning strategies for mobile robots equipped with a remote gas sensor. AB - The problem of gas detection is relevant to many real-world applications, such as leak detection in industrial settings and landfill monitoring. In this paper, we address the problem of gas detection in large areas with a mobile robotic platform equipped with a remote gas sensor. We propose an algorithm that leverages a novel method based on convex relaxation for quickly solving sensor placement problems, and for generating an efficient exploration plan for the robot. To demonstrate the applicability of our method to real-world environments, we performed a large number of experimental trials, both on randomly generated maps and on the map of a real environment. Our approach proves to be highly efficient in terms of computational requirements and to provide nearly-optimal solutions. PMID- 25803709 TI - Vitamin D, vitamin D binding protein, and longitudinal outcomes in COPD. AB - BACKGROUND: Associations between Vitamin D3 [25(OH)D], vitamin D binding protein (VDBP) and chronic obstructive pulmonary disease (COPD) are previously reported. We aimed to further investigate these associations on longitudinal outcomes. METHODS: 426 COPD patients from western Norway, GOLD stage II-IV, aged 40-76, were followed every six-month from 2006 through 2009 with spirometry, bioelectrical impedance measurements and registration of exacerbation frequency. Serum 25(OH)D and VDBP levels were determined at study-entry by high-performance liquid chromatography coupled with mass spectrometry and enzyme immunoassays respectively. Yearly change in lung function and body composition was assessed by generalized estimating equations (GEE), yearly exacerbation rate by negative binomial regression models, and 5 years all-cause mortality by Cox proportional hazard regression. RESULTS: 1/3 of the patients had vitamin D deficiency (<20ng/mL) and a greater decline in both FEV1 and FVC, compared to patients with normal levels; for FEV1 this difference only reached statistical significance in the 28 patients with the lowest levels (<10ng/mL, p = 0.01). Neither 25(OH)D nor VDBP levels predicted exacerbation rate, change in fat free mass index or risk of death. CONCLUSION: Severe vitamin D deficiency may affect decline in lung function parameters in COPD. Neither 25(OH)D nor VDBP levels did otherwise predict markers of disease progression. PMID- 25803708 TI - Extract from Rumex acetosa L. for prophylaxis of periodontitis: inhibition of bacterial in vitro adhesion and of gingipains of Porphyromonas gingivalis by epicatechin-3-O-(4beta->8)-epicatechin-3-O-gallate (procyanidin-B2-Di-gallate). AB - BACKGROUND: The aerial parts of Rumex acetosa L. have been used in traditional European medicine for inflammatory diseases of the mouth epithelial tissue. The following study aimed to investigate the influence of a proanthocyanidin-enriched extract from R. acetosa extract against the adhesion of Porphyromonas gingivalis (P. gingivalis), a pathogen strongly involved in chronic and aggressive periodontitis. A further goal was to define the bioactive lead structures responsible for a potential antiadhesive activity and to characterize the underlying molecular mechanisms of the antiadhesive effects. METHODOLOGY: An extract of R. acetosa (RA1) with a defined mixture of flavan-3-ols, oligomeric proanthocyanidins and flavonoids, was used. Its impact on P. gingivalis adhesion to KB cells was studied by flow cytometry, confocal laser scanning microscopy and in situ adhesion assay using murine buccal tissue. RA1 and its compounds 1 to 15 were further investigated for additional effects on gingipain activity, hemagglutination and gene expression by RT-PCR. PRINCIPAL FINDINGS: RA1 (5 to 15 MUg/mL) reduced P. gingivalis adhesion in a dose-dependent manner to about 90%. Galloylated proanthocyanidins were confirmed to be responsible for this antiadhesive effect with epicatechin-3-O-gallate-(4beta,8)-epicatechin-3'-O gallate (syn. procyanidin B2-di-gallate) being the lead compound. Ungalloylated flavan-3-ols and oligomeric proanthocyanidins were inactive. RA1 and the galloylated proanthocyanidins strongly interact with the bacterial virulence factor Arg-gingipain, while the corresponding Lys-gingipain was hardly influenced. RA1 inhibited also hemagglutination. In silico docking studies indicated that epicatechin-3-O-gallate-(4beta,8)-epicatechin-3'-O-gallate interacts with the active side of Arg-gingipain and hemaglutinin from P. gingivalis; the galloylation of the molecule seems to be responsible for fixation of the ligand to the protein. In conclusion, the proanthocyanidin-enriched extract RA1 and its main active constituent procyanidin B2-di-gallate protect cells from P. gingivalis infection by inhibiting bacterial adhesion to the host cell. RA1 and procyanidin B2-di-gallate appear to be promising candidates for future cytoprotective preparations for oral mouth care products. PMID- 25803710 TI - Correlated variability in the breathing pattern and end-expiratory lung volumes in conscious humans. AB - In order to characterize the variability and correlation properties of spontaneous breathing in humans, the breathing pattern of 16 seated healthy subjects was studied during 40 min of quiet breathing using opto-electronic plethysmography, a contactless technology that measures total and compartmental chest wall volumes without interfering with the subjects breathing. From these signals, tidal volume (VT), respiratory time (TTOT) and the other breathing pattern parameters were computed breath-by-breath together with the end expiratory total and compartmental (pulmonary rib cage and abdomen) chest wall volume changes. The correlation properties of these variables were quantified by detrended fluctuation analysis, computing the scaling exponenta. VT, TTOT and the other breathing pattern variables showed alpha values between 0.60 (for minute ventilation) to 0.71 (for respiratory rate), all significantly lower than the ones obtained for end-expiratory volumes, that ranged between 1.05 (for rib cage) and 1.13 (for abdomen) with no significant differences between compartments. The much stronger long-range correlations of the end expiratory volumes were interpreted by a neuromechanical network model consisting of five neuron groups in the brain respiratory center coupled with the mechanical properties of the respiratory system modeled as a simple Kelvin body. The model-based alpha for VT is 0.57, similar to the experimental data. While the alpha for TTOT was slightly lower than the experimental values, the model correctly predicted alpha for end expiratory lung volumes (1.045). In conclusion, we propose that the correlations in the timing and amplitude of the physiological variables originate from the brain with the exception of end-expiratory lung volume, which shows the strongest correlations largely due to the contribution of the viscoelastic properties of the tissues. This cycle-by-cycle variability may have a significant impact on the functioning of adherent cells in the respiratory system. PMID- 25803712 TI - Complete series of chiral paramagnetic molecular conductors based on tetramethyl bis(ethylenedithio)-tetrathiafulvalene (TM-BEDT-TTF) and Chloranilate-bridged heterobimetallic honeycomb layers. AB - Electrocrystallization of enantiopure (S,S,S,S)- and (R,R,R,R)-tetramethyl bis(ethylenedithio)-tetrathiafulvalene (TM-BEDT-TTF) donors, as well as the racemic mixture, in the presence of potassium cations and the tris(chloranilato)ferrate(III) [Fe(Cl2An)3](3-) paramagnetic anion afforded a complete series of chiral magnetic molecular conductors formulated as beta [(S,S,S,S)-TM-BEDT-TTF]3PPh4[K(I)Fe(III)(Cl2An)3].3H2O (1), beta-[(R,R,R,R)-TM BEDT-TTF]3PPh4[K(I)Fe(III)(Cl2An)3].3H2O (2), and beta-[(rac)-TM-BEDT TTF]3PPh4[K(I)Fe(III)(Cl2An)3].3H2O (3). Compounds 1-3 are isostructural and crystallize in triclinic space groups (P1 for 1 and 2, P-1 for 3) showing a segregated organic-inorganic crystal structure, where anionic honeycomb layers obtained by self-assembling of the Lambda and Delta enantiomers of the paramagnetic complex with potassium cations alternate with organic layers where the chiral donors are arranged in the beta packing motif. Compounds 1-3 show a molecular packing strongly influenced by the topology of the inorganic layers and behave as molecular semiconductors with room-temperature conductivity values of ca. 3 * 10(-4) S cm(-1). The magnetic properties are dominated by the paramagnetic S = 5/2 [Fe(Cl2An)3](3-) anions whose high-spin character is confirmed by magnetic susceptibility measurements. The correlation between crystal structure and conducting behavior has been studied by means of tight binding band structure calculations which support the observed conducting properties. PMID- 25803711 TI - Multimodal holographic microscopy: distinction between apoptosis and oncosis. AB - Identification of specific cell death is of a great value for many scientists. Predominant types of cell death can be detected by flow-cytometry (FCM). Nevertheless, the absence of cellular morphology analysis leads to the misclassification of cell death type due to underestimated oncosis. However, the definition of the oncosis is important because of its potential reversibility. Therefore, FCM analysis of cell death using annexin V/propidium iodide assay was compared with holographic microscopy coupled with fluorescence detection - "Multimodal holographic microscopy (MHM)". The aim was to highlight FCM limitations and to point out MHM advantages. It was shown that the annexin V+/PI- phenotype is not specific of early apoptotic cells, as previously believed, and that morphological criteria have to be necessarily combined with annexin V/PI for the cell death type to be ascertained precisely. MHM makes it possible to distinguish oncosis clearly from apoptosis and to stratify the progression of oncosis. PMID- 25803713 TI - [Challenges in Traffic for Blind and Visually Impaired People and Strategies for their Safe Participation]. AB - BACKGROUND: Blind and visually impaired people experience special risks and hazards in road traffic. This refers to participation as a driver, bicycle rider and pedestrian. MATERIAL AND METHODS: These risks are shown by a review of international research studies and a study by the author, where 45 people with Usher syndrome were asked about their accident rates and causes as driver, bicycle rider and pedestrian. In addition, basic legal information has been worked out to demonstrate the visual conditions of people with visual impairment for participation in road traffic. RESULTS: The research studies show that blind and visually impaired persons are particularly exposed to experience high risks in traffic. These risks can be reduced through acquisition of skills and coping strategies such as training in orientation and mobility. CONCLUSIONS: People with visual impairment need special programmes which help to reduce traffic hazards. PMID- 25803714 TI - CH3CO + O2 + M (M = He, N2) Reaction Rate Coefficient Measurements and Implications for the OH Radical Product Yield. AB - The gas-phase CH3CO + O2 reaction is known to proceed via a chemical activation mechanism leading to the formation of OH and CH3C(O)OO radicals via bimolecular and termolecular reactive channels, respectively. In this work, rate coefficients, k, for the CH3CO + O2 reaction were measured over a range of temperature (241-373 K) and pressure (0.009-600 Torr) with He and N2 as the bath gas and used to characterize the bi- and ter-molecular reaction channels. Three independent experimental methods (pulsed laser photolysis-laser-induced fluorescence (PLP-LIF), pulsed laser photolysis-cavity ring-down spectroscopy (PLP-CRDS), and a very low-pressure reactor (VLPR)) were used to characterize k(T,M). PLP-LIF was the primary method used to measure k(T,M) in the high pressure regime under pseudo-first-order conditions. CH3CO was produced by PLP, and LIF was used to monitor the OH radical bimolecular channel reaction product. CRDS, a complementary high-pressure method, measured k(295 K,M) over the pressure range 25-600 Torr (He) by monitoring the temporal CH3CO radical absorption following its production via PLP in the presence of excess O2. The VLPR technique was used in a relative rate mode to measure k(296 K,M) in the low-pressure regime (9-32 mTorr) with CH3CO + Cl2 used as the reference reaction. A kinetic mechanism analysis of the combined kinetic data set yielded a zero pressure limit rate coefficient, kint(T), of (6.4 +/- 4) * 10(-14) exp((820 +/- 150)/T) cm(3) molecule(-1) s(-1) (with kint(296 K) measured to be (9.94 +/- 1.3) * 10(-13) cm(3) molecule(-1) s(-1)), k0(T) = (7.39 +/- 0.3) * 10(-30) (T/300)(-2.2+/-0.3) cm(6) molecule(-2) s(-1), and kinfinity(T) = (4.88 +/- 0.05) * 10(-12) (T/300)( 0.85+/-0.07) cm(3) molecule(-1) s(-1) with Fc = 0.8 and M = N2. A He/N2 collision efficiency ratio of 0.60 +/- 0.05 was determined. The phenomenological kinetic results were used to define the pressure and temperature dependence of the OH radical yield in the CH3CO + O2 reaction. The present results are compared with results from previous studies and the discrepancies are discussed. PMID- 25803715 TI - Structure of the low pH conformation of Chandipura virus G reveals important features in the evolution of the vesiculovirus glycoprotein. AB - Chandipura virus (CHAV), a member of the vesiculovirus genus, is an emerging human pathogen. As for other rhabdoviruses, CHAV entry into susceptible cells is mediated by its single envelope glycoprotein G which is both involved in receptor recognition and fusion of viral and cellular membranes. Here, we have characterized the fusion properties of CHAV-G. As for vesicular stomatitis virus (VSV, the prototype of the genus) G, fusion is triggered at low pH below 6.5. We have also analyzed the biochemical properties of a soluble form of CHAV-G ectodomain (CHAV-Gth, generated by thermolysin limited-proteolysis of recombinant VSV particles in which the G gene was replaced by that of CHAV). The overall behavior of CHAV-Gth is similar to that previously reported for VSV-Gth. Particularly, CHAV-Gth pre-fusion trimer is not stable in solution and low-pH induced membrane association of CHAV-Gth is reversible. Furthermore, CHAV-Gth was crystallized in its low pH post-fusion conformation and its structure was determined at 3.6A resolution. An overall comparison of this structure with the previously reported VSV-Gth post-fusion conformation, shows a high structural similarity as expected from the comparison of primary structure. Among the three domains of G, the pleckstrin homology domain (PHD) appears to be the most divergent and the largest differences are confined to the secondary structure of the major antigenic site of rhabdoviruses. Finally, local differences indicate that CHAV has evolved alternate structural solutions in hinge regions between PH and fusion domains but also distinct pH sensitive switches. Globally the comparison between the post fusion conformation of CHAV and VSV-G highlights several features essential for the protein's function. It also reveals the remarkable plasticity of G in terms of local structures. PMID- 25803717 TI - Ultrasensitive colorimetric detection of 17beta-estradiol: the effect of shortening DNA aptamer sequences. AB - We report a strategy enabling ultrasensitive colorimetric detection of 17beta estradiol (E2) in water and urine samples using DNA aptamer-coated gold nanoparticles (AuNPs). Starting from an established sensor format where aggregation is triggered when target-bound aptamers dissociate from AuNP surfaces, we demonstrated that step-change improvements are easily accessible through deletion of excess flanking nucleotides from aptamer sequences. After evaluating the lowest energy two-dimensional configuration of the previously isolated E2 binding 75-mer aptamer (KD ~25 nM), new 35-mer and 22-mer aptamers were generated with KD's of 14 and 11 nM by simply removing flanking nucleotides on either side of the inner core. The shorter aptamers were found to improve discrimination against other steroidal molecules and to improve colorimetric sensitivity for E2 detection by 25-fold compared with the 75-mer to 200 pM. In comparing the response of all sequences, we find that the excess flanking nucleotides suppress signal transduction by causing target-bound aptamers to remain adhered to AuNPs, which we confirm via surface sensitive electrochemical measurements. However, comparison between the 22-mer and 35-mer systems show that retaining a small number of excess bases is optimal. The performance advances we achieved by specifically considering the signal transduction mechanism ultimately resulted in facile detection of E2 in urine, as well as enabling environmental detection of E2 at levels approaching biological relevance. PMID- 25803716 TI - Fluorescent image analysis of HIV-1 and HIV-2 uncoating kinetics in the presence of old world monkey TRIM5alpha. AB - Uncoating of Human Immunodeficiency Virus type 1 (HIV-1) and type 2 (HIV-2) conical cores is an important early step for establishment of infection. In Old World Monkey (OWM) cells, the TRIM5alpha cellular factor potently suppresses an early step of infection by HIV-1. Previously, biochemical studies using whole cell lysates of infected cells revealed that OWM TRIM5alpha accelerates the uncoating of HIV-1, leading to premature reverse transcription. In the present study, we re-evaluated uncoating kinetics of HIV-1 in the presence of OWM TRIM5alpha by using an in situ uncoating assay, which allowed us to differentiate productive HIV-1 entry from simple (non-productive) endocytosis. Results showed that the uncoating kinetics of HIV-1 was indeed accelerated in the presence of OWM TRIM5alpha. Furthermore, we adapted an in situ uncoating assay to HIV-2, which showed wide variations in TRIM5alpha sensitivity among different isolates. HIV-2 isolate GH123, whose infectivity was suppressed by cynomolgus monkey (CM) TRIM5alpha, showed accelerated uncoating in the presence of CM TRIM5alpha. In contrast, mutant HIV-2 ASA, whose infectivity was unaltered by CM TRIM5alpha, showed no change in uncoating kinetics in the presence of CM TRIM5alpha. These results confirmed and further extended the previous notion that accelerated uncoating is associated with restriction activity of TRIM5alpha against lentiviruses. PMID- 25803718 TI - Evaluation of the diagnostic accuracy of a new dengue IgA capture assay (Platelia Dengue IgA Capture, Bio-Rad) for dengue infection detection. AB - Considering the short lifetime of IgA antibodies in serum and the key advantages of antibody detection ELISAs in terms of sensitivity and specificity, Bio-Rad has just developed a new ELISA test based on the detection of specific anti-dengue IgA. This study has been carried out to assess the performance of this Platelia Dengue IgA Capture assay for dengue infection detection. A total of 184 well characterized samples provided by the French Guiana NRC sera collection (Laboratory of Virology, Institut Pasteur in French Guiana) were selected among samples collected between 2002 and 2013 from patients exhibiting a dengue-like syndrome. A first group included 134 sera from confirmed dengue-infected patients, and a second included 50 sera from non-dengue infected patients, all collected between day 3 and day 15 after the onset of fever. Dengue infection diagnoses were all confirmed using reference assays by direct virological identification using RT-PCR or virus culture on acute sera samples or on paired acute-phase sera samples of selected convalescent sera. This study revealed: i) a good overall sensitivity and specificity of the IgA index test, i.e., 93% and 88% respectively, indicating its good correlation to acute dengue diagnosis; and ii) a good concordance with the Panbio IgM capture ELISA. Because of the shorter persistence of dengue virus-specific IgA than IgM, these results underlined the relevance of this new test, which could significantly improve dengue diagnosis accuracy, especially in countries where dengue virus is (hyper-) endemic. It would allow for additional refinement of dengue diagnostic strategy. PMID- 25803720 TI - Microbiological screening is necessary to distinguish carriers of plasmid mediated AmpC beta-lactamase-producing enterobacteriaceae and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae because of clinical similarity. AB - OBJECTIVES: Plasmid-mediated AmpC beta-lactamase-producing (pAmpC) Enterobacteriaceae are increasing worldwide, difficult to identify and often confounded with extended-spectrum beta-lactamase (ESBL) producers. The low prevalence precludes routine universal admission screening. Therefore, we evaluated potential risk factors for carriage of pAmpC-producing Enterobacteriaceae that would allow targeted screening to improve yield and reduce cost. PATIENTS AND METHODS: We performed a case control study at a tertiary care center from 1/2006 to 12/2010. Cases were adult patients in whom pAmpC-producing Enterobacteriaceae were isolated; controls were chosen among carriers of ESBL-producing Enterobacteriaceae. Both infected and colonized patients were included. RESULTS: Over five years, we identified 40 pAmpC producers in 39 patients among 16,247 screened consecutive isolates of Enterobacteriaceae. The pAmpC prevalence was low (0.25%), but more than 30% of pAmpC carriers received incorrect empirical antibiotic treatment. When compared with 39 ESBL controls, pAmpC carriage was associated with clinically confirmed infections in 74% (versus 51%) (p=0.035), mainly of the urinary tract, previous antibiotic exposure in 63% (versus 36%) (p=0.035) and carriage of a nasogastric tube in 23% (versus 0%) (p=0.002). In the multivariate regression analysis only clinically confirmed infections remained significantly associated with pAmpC carriage (OR 1.44 (95%CI 1.15-2.57)). No other clinical and blood test-associated risk factor allowed discrimination of pAmpC-carrying patients from ESBL controls. The type of acquisition - nosocomial versus community-acquired - was also non informative for resistance type, as 46% of pAmpC- and 44% of ESBL-producing Enterobacteriaceae were community-acquired. CONCLUSIONS: This study could not identify a clinical profile that would allow targeted screening for pAmpC producing Enterobacteriaceae when compared to ESBL carriers. Because empiric antimicrobial therapy was inappropriate in more than 30%, rapid identification of pAmpC carriers is needed. New microbiological methods are therefore required to simplify rapid and reliable detection of pAmpC carriers. PMID- 25803719 TI - Detection and characterisation of Lactobacillus spp. in the bovine uterus and their influence on bovine endometrial epithelial cells in vitro. AB - Bacterial infections and inflammation of the uterus are common in dairy cattle after parturition. In particular, pathogenic bacteria that cause endometritis have been the focus of research in cattle reproduction in the last ten years. The aim of the present study was to identify commensal lactobacilli in the bovine uterus and to examine their influence on the synthesis of pro-inflammatory factors in bovine endometrial epithelial cells in vitro. Lactobacillus species were isolated from healthy bovine uteri and further characterised. Bovine endometrial epithelial cells in the second passage (n = 5 animals) were co cultured with the autochthonous isolates L. buchneri, L. ruminis and L. amylovorus as well as with a commercially available L. vaginalis in different multiplicities of infection (MOI = 1, 5 and 10, respectively). Endometrial epithelial cells cultured without bacteria served as controls. At distinct points in time (2, 4 and 6 h) total RNA was extracted from co-cultured epithelial cells and subjected to reverse transcription quantitative PCR of pro-inflammatory factors. Furthermore, the release of such factors by co-cultured epithelial cells was measured by ELISA or EIA after 24 and 48 h. L. ruminis and L. amylovorus induced increased interleukin (IL) IL1A, IL6, IL8 and prostaglandin-endoperoxide synthase 2 mRNA levels and the release of IL8 and prostaglandin F(2alpha) in endometrial epithelial cells compared with control cells. In contrast, L. buchneri did not significantly influence the expression and release of these factors. Toll-like receptors 2 and 6 transcripts were found unchanged in co cultured and untreated epithelial cells in vitro. However, endometrial epithelial cells of each animal showed individual differences in the response to bacterial load. These results suggest that Lactobacillus species are present in the bovine uterus, revealing immunomodulatory properties. PMID- 25803722 TI - Effect of remote aryl substituents on the conformational equilibria of 2,2-diaryl 1,3-dioxanes: importance of electrostatic interactions. AB - The conformational preference of a variety of 2,2-diaryl-1,3-dioxanes bearing remote substituents on the phenyl rings has been studied via equilibration of configurationally isomeric 2,2-diaryl-cis-4,6-dimethyl-1,3-dioxane epimers, X-ray crystallography, (1)H NOESY analysis, and B3LYP/6-311+G* calculations. When the aryl ring bears a remote electron-withdrawing substituent, the isomer having both the higher dipole moment and the electron-withdrawing group in the equatorial phenyl ring and/or an electron-donating group in the axial ring has the lower energy. These results differ from the conclusions reported in a previous study of similar systems. The conformational energy differences of para-substituted 2,2 diaryl-1,3-dioxanes are linearly related to the Hammett sigma values with a slope (rho) of 0.6. In addition, there is a trend toward longer bond lengths between the C(2) ketal center and the aryl ring as the electron-withdrawing nature of the para-substituent is increased. Electrostatic interactions, rather than a hyperconjugative anomeric effect, appear to be responsible for the conformational behavior of such molecules. PMID- 25803721 TI - Complete protection of mice against lethal murine cytomegalovirus challenge by immunization with DNA vaccines encoding envelope glycoprotein complex III antigens gH, gL and gO. AB - Human cytomegalovirus infects the majority of humanity which may lead to severe morbidity and mortality in newborns and immunocompromised adults. Humoral and cellular immunity are critical for controlling CMV infection. HCMV envelope glycoprotein complexes (gC I, II, III) represent major antigenic targets of antiviral immune responses. The gCIII complex is comprised of three glycoproteins, gH, gL, and gO. In the present study, DNA vaccines expressing the murine cytomegalovirus homologs of the gH, gL, and gO proteins were evaluated for protection against lethal MCMV infection in the mouse model. The results demonstrated that gH, gL, or gO single gene immunization could not yet offer good protection, whereas co-vaccination strategy apparently showed effects superior to separate immunization. Twice immunization with gH/gL/gO pDNAs could provide mice complete protection against lethal salivary gland-derived MCMV (SG-MCMV) challenge, while thrice immunization with pgH/pgL, pgH/pgO or pgL/pgO could not provide full protection. Co-vaccination with gH, gL and gO pDNAs elicited robust neutralizing antibody and cellular immune responses. Moreover, full protection was also achieved by simply passive immunization with anti-gH/gL/gO sera. These data demonstrated that gCIII complex antigens had fine immunogenicity and might be a promising candidate for the development of HCMV vaccines. PMID- 25803724 TI - Unusual variants of intravascular malignant hematopoietic neoplasms: a report of 4 cases and review of the literature. AB - Intravascular lymphoma (IVL) is a rare and fatal disease, typically of B-cell origin. Most of the reported cases have been for primary IVL, and only a minority of cases are of recurrent IVL. In addition, recurrent IVL occurring after treatment of anaplastic large T-cell lymphoma (ALCL) by contrast is extraordinarily rare. In this article, we present 3 cases of recurrent cutaneous IVL (2 men and 1 woman) and compare these with 1 case of primary IVL. The patients ranged in age from 56 to 73 years and were encountered in the routine dermatopathology and consultative practices of one of the authors. In 2 of the cases, the patients had intravascular cutaneous ALCL. In regard to the remaining 2 patients, 1 patient had a recurrent intravascular cutaneous follicular lymphoma in the context of a history of diffuse large B-cell lymphoma. The fourth patient had a primary intravascular ALCL because there was no antecedent history. In all cases, the skin biopsies showed large aggregates of atypical cells within the blood vessels. Phenotypic studies revealed variable staining results with CD29 and CD54 in cases of recurrent IVL compared with those of primary IVL. Recurrent cutaneous IVL represents a somewhat heterogeneous group of lymphoproliferative disorders with a distinct variant being in the context of intravascular ALCL; the mechanisms of intravascular localization in recurrent IVL are likely different from those of primary IVL. PMID- 25803725 TI - Perforating lichen nitidus. AB - Transepidermal elimination and/or perforation of the epidermis is seen in a variety of conditions but has only rarely been reported in association with lichen nitidus. We describe a case of lichen nitidus with the unique finding of epidermal perforation, a feature that made the usual straightforward diagnosis of lichen nitidus much more difficult. PMID- 25803723 TI - Abnormal development of tapetum and microspores induced by chemical hybridization agent SQ-1 in wheat. AB - Chemical hybridization agent (CHA)-induced male sterility is an important tool in crop heterosis. To demonstrate that CHA-SQ-1-induced male sterility is associated with abnormal tapetal and microspore development, the cytology of CHA-SQ-1 treated plant anthers at various developmental stages was studied by light microscopy, scanning and transmission electron microscopy, in situ terminal deoxynucleotidyl transferasemediated dUTP nick end-labelling (TUNEL) assay and DAPI staining. The results indicated that the SQ-1-treated plants underwent premature tapetal programmed cell death (PCD), which was initiated at the early uninucleate stage of microspore development and continued until the tapetal cells were completely degraded; the process of microspore development was then blocked. Microspores with low-viability (fluorescein diacetate staining) were aborted. The study suggests that premature tapetal PCD is the main cause of pollen abortion. Furthermore, it determines the starting period and a key factor in CHA-SQ-1 induced male sterility at the cell level, and provides cytological evidence to further study the mechanism between PCD and male sterility. PMID- 25803727 TI - A dual-responsive "turn-on" bifunctional receptor: a chemosensor for Fe3+ and chemodosimeter for Hg2+. AB - Synthesis of L1-L3, their thorough characterization by spectral as well as structural studies and use in selective photochemical detection of Fe(3+) and Hg(2+) at ppb level have been described. Notably, these exhibit bifunctional behaviour toward Fe(3+) (CHEF) and Hg(2+) (chemodosimetric) which has been unequivocally established by various studies. PMID- 25803726 TI - Cutaneous epithelioid osteoblastoma. AB - Epithelioid osteoblastomas (EOB) typically arise in the axial skeleton of young adults, but there are rare case reports of the lesion arising in soft tissue. To date, only 1 case has been reported in the skin, and it has been debated in the literature if that case was truly a neoplasm. With the availability of the new osteoblastic marker SAT2B, the authors present a case of an EOB with confirmed osteoblastic differentiation arising in the tattooed skin of a 32-year-old army veteran. Despite the rarity of the neoplasm, 2 other cases of soft tissue EOB are reported in the literature, also involving military servicemembers. The identification of this unique tumor solely in military personnel is likely due to the relatively high proportion of young males represented in the military, the demographic most likely to develop osteoblastomas. Less likely, the authors postulate the possible existence of an occupational risk factor for soft tissue EOB in military service. PMID- 25803728 TI - Neural stimulation and recording with bidirectional, soft carbon nanotube fiber microelectrodes. AB - The development of microelectrodes capable of safely stimulating and recording neural activity is a critical step in the design of many prosthetic devices, brain-machine interfaces, and therapies for neurologic or nervous-system-mediated disorders. Metal electrodes are inadequate prospects for the miniaturization needed to attain neuronal-scale stimulation and recording because of their poor electrochemical properties, high stiffness, and propensity to fail due to bending fatigue. Here we demonstrate neural recording and stimulation using carbon nanotube (CNT) fiber electrodes. In vitro characterization shows that the tissue contact impedance of CNT fibers is remarkably lower than that of state-of-the-art metal electrodes, making them suitable for recording single-neuron activity without additional surface treatments. In vivo chronic studies in parkinsonian rodents show that CNT fiber microelectrodes stimulate neurons as effectively as metal electrodes with 10 times larger surface area, while eliciting a significantly reduced inflammatory response. The same CNT fiber microelectrodes can record neural activity for weeks, paving the way for the development of novel multifunctional and dynamic neural interfaces with long-term stability. PMID- 25803730 TI - Comparative effectiveness of different oral antibiotics regimens for treatment of urinary tract infection in outpatients: an analysis of national representative claims database. AB - [An uncorrected version of "Comparative Effectiveness of Different Oral Antibiotics Regimens for Treatment of Urinary Tract Infection in Outpatients: An Analysis of National Representative Claims Database" was originally posted in Volume 93, Issue 28 of Medicine. The article has since been corrected and reposted in the issue.]. PMID- 25803731 TI - Hepatic angiomyolipoma mimicking hepatocellular carcinoma: magnetic resonance imaging and clinical pathological characteristics in 9 cases. AB - [In the article "Hepatic Angiomyolipoma Mimicking Hepatocellular Carcinoma: Magnetic Resonance Imaging and Clinical Pathological Characteristics in 9 Cases", which appeared in Volume 93, Issue 28 of Medicine, the corresponding author's name, Yong-Ping Yang, M.D., was omitted from the author list.]. PMID- 25803729 TI - A biologically plausible computational theory for value integration and action selection in decisions with competing alternatives. AB - Decision making is a vital component of human and animal behavior that involves selecting between alternative options and generating actions to implement the choices. Although decisions can be as simple as choosing a goal and then pursuing it, humans and animals usually have to make decisions in dynamic environments where the value and the availability of an option change unpredictably with time and previous actions. A predator chasing multiple prey exemplifies how goals can dynamically change and compete during ongoing actions. Classical psychological theories posit that decision making takes place within frontal areas and is a separate process from perception and action. However, recent findings argue for additional mechanisms and suggest the decisions between actions often emerge through a continuous competition within the same brain regions that plan and guide action execution. According to these findings, the sensorimotor system generates concurrent action-plans for competing goals and uses online information to bias the competition until a single goal is pursued. This information is diverse, relating to both the dynamic value of the goal and the cost of acting, creating a challenging problem in integrating information across these diverse variables in real time. We introduce a computational framework for dynamically integrating value information from disparate sources in decision tasks with competing actions. We evaluated the framework in a series of oculomotor and reaching decision tasks and found that it captures many features of choice/motor behavior, as well as its neural underpinnings that previously have eluded a common explanation. PMID- 25803732 TI - Prior to the Oral Therapy, What Do We Know About HCV-4 in Egypt: A Randomized Survey of Prevalence and Risks Using Data Mining Computed Analysis. AB - [In the article "Prior to the Oral Therapy, What Do We Know About HCV-4 in Egypt: A Randomized Survey of Prevalence and Risks Using Data Mining Computed Analysis" which appeared in Volume 93, Issue 28 of Medicine, Abd Elrazek Abd Elrazek's name incorrectly appeared as Abd Elrazek M. Aly Abd Elrazek.]. PMID- 25803733 TI - Pulmonary Fibrosis in Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis: A Series of 49 Patients and Review of the Literature: Erratum. AB - [In Figure 1 of the article "Pulmonary Fibrosis in Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis: A Series of 49 Patients and Review of the Literature", which appeared in Volume 93, Issue 24 of Medicine, the descriptions for panels B and C were originally reversed. The article has since been corrected and reposted in the issue.]. PMID- 25803734 TI - Relation Between VE/VCO2 Slope and Maximum Phonation Time in Chronic Heart Failure Patients. AB - [In the article "Relation Between VE/VCO2 Slope and Maximum Phonation Time in Chronic Heart Failure Patients", which appeared in Volume 93, Issue 29 of Medicine, the acting editor's name, Salvatore Patane, was incorrectly spelled as Salvatore Patane. Salvatore Patane's name also incorrectly appeared online as an author of the paper. He was the editor of the paper, but not an author.]. PMID- 25803735 TI - Predictive Accuracy of Amyloid Imaging for Progression From Mild Cognitive Impairment to Alzheimer Disease With Different Lengths of Follow-up: A Systematic Review. AB - [In the article "Predictive Accuracy of Amyloid Imaging for Progression From Mild Cognitive Impairment to Alzheimer Disease With Different Lengths of Follow-up: A Systematic Review", which appeared in Volume 93, Issue 27 of Medicine, the title was given incorrectly. The article was a meta-analysis and not a systematic review. The correct title is "Predictive Accuracy of Amyloid Imaging for Progression From Mild Cognitive Impairment to Alzheimer Disease With Different Lengths of Follow-up: A Meta-analysis".]. PMID- 25803736 TI - Shared investment projects and forecasting errors: setting framework conditions for coordination and sequencing data quality activities. AB - In this paper, we investigate the impact of inaccurate forecasting on the coordination of distributed investment decisions. In particular, by setting up a computational multi-agent model of a stylized firm, we investigate the case of investment opportunities that are mutually carried out by organizational departments. The forecasts of concern pertain to the initial amount of money necessary to launch and operate an investment opportunity, to the expected intertemporal distribution of cash flows, and the departments' efficiency in operating the investment opportunity at hand. We propose a budget allocation mechanism for coordinating such distributed decisions The paper provides guidance on how to set framework conditions, in terms of the number of investment opportunities considered in one round of funding and the number of departments operating one investment opportunity, so that the coordination mechanism is highly robust to forecasting errors. Furthermore, we show that-in some setups-a certain extent of misforecasting is desirable from the firm's point of view as it supports the achievement of the corporate objective of value maximization. We then address the question of how to improve forecasting quality in the best possible way, and provide policy advice on how to sequence activities for improving forecasting quality so that the robustness of the coordination mechanism to errors increases in the best possible way. At the same time, we show that wrong decisions regarding the sequencing can lead to a decrease in robustness. Finally, we conduct a comprehensive sensitivity analysis and prove that-in particular for relatively good forecasters-most of our results are robust to changes in setting the parameters of our multi-agent simulation model. PMID- 25803738 TI - Three bonding modes of bis(2-picolyl)phenylphosphine at iron: isolation of a dinuclear iron complex featuring dearomatized pyridine moieties. AB - The coordination ability of the bis(2-picolyl)phenylphosphine (NPN) compound has been probed toward the iron precursor [Fe{N(SiMe3)2}2]. By a careful control of the experimental conditions we were able to isolate and characterize three complexes displaying different coordination modes of the NPN ligand as revealed in particular by X-ray diffraction, and multinuclear solution and solid state NMR analyses. It is shown that NPN can be used as a proton-responsive ligand with enough flexibility to allow the formation of the dinuclear complex [Fe{P(CH2(C5H4N))(CH(C5H4N))}(N(SiMe3)2)]2 with two NPN ligands spanning the two metal centres. PMID- 25803737 TI - AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell proliferation. AB - Autophagy-promoting proteins and stimuli are often associated with inhibition of cell proliferation; in this context, we recently described a key role for the pro autophagic protein AMBRA1. Indeed, AMBRA1, through its direct interaction with the protein phosphatase PP2A, tightly regulates the stability of the oncoprotein and pro-mitotic factor c-Myc. Moreover, the AMBRA1-mediated regulation of c-Myc affects both cell proliferation rate and tumorigenesis. Interestingly, AMBRA1/PP2A activity is under the control of the master regulator of autophagy and cell growth, the protein kinase mTOR. Besides the mechanistic details of this regulation pathway which we dissected previously, any possible interplay(s) between AMBRA1 and its interactor BECLIN 1 was not investigated in this scenario. Here we show that both AMBRA1 and BECLIN 1 affect c-Myc regulation, but through two different pathways. Nevertheless, these two pro-autophagic proteins are, together with PP2A, in the same macromolecular complex, whose functional significance of which will be addressed in future studies. PMID- 25803739 TI - Minimizing the risk of hemorrhagic stroke during anticoagulant therapy for atrial fibrillation. AB - INTRODUCTION: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC's most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications. AREAS COVERED: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke. EXPERT OPINION: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding. PMID- 25803741 TI - DFT study of the energetic and noncovalent interactions between imidazolium ionic liquids and hydrofluoric acid. AB - In this work, we evaluated the energetic interactions between imidazolium ionic liquids (ILs) and hydrofluoric acid, as well as the cation-anion interactions in ILs. We used DFT calculations that include dispersion corrections employing the PBE and M06 functionals. We tested 22 ILs, including [C4MIM][PF6], [C4MIM][NTf2], and [C4MIM][CH3COO], obtaining interaction energies in the range of -27 to -13 kcal/mol with the PBE functional. The NCI (noncovalent interaction) index developed by Yang and collaborators ( J. Am. Chem. Soc. 2010 , 132 , 6498 - 6506 ; J. Chem. Theory Comput. 2011 , 7 , 625 - 632 ) also was used for mapping the key noncovalent interactions (hydrogen bonds, van der Waals, and steric repulsions) between the anions and cations of ILs and also for interactions of ILs with hydrofluoric acid (HF). The results obtained show that the anions have a stronger effect with respect to cations in their capacity for interacting with hydrofluoric acid, and the strongest interaction energies occur in systems where the key noncovalent interactions are mainly hydrogen bonds. The [C4MIM][PF6], [C4MIM][NTf2], and [C4MIM][BF4] ionic liquids displayed the weakest cation-anion interactions. PMID- 25803743 TI - Relationship Between Muscle Fiber Type and Reactive Balance: A Preliminary Study. AB - The authors' objective was to quantify the relationship between type II muscle fiber composition and recovery latency from controlled perturbations. Thirty healthy adults performed a Thorstensson test to indirectly determine muscle fiber composition of the knee extensors. On a subsequent day, reactive balance was measured by assessing latency time required to accommodate three controlled perturbations via computerized dynamic posturography. The proportion of type II fibers had a negative correlation with latency caused by a large backward perturbation (r = -.62, p = .001). These data may indicate a higher percentage of type II fibers in the knee extensors are associated with better reactive balance. Further investigation is warranted, in particular as it pertains to populations at risk for balance impairment. PMID- 25803744 TI - Scandinavian Journal of Gastroenterology - the editors-in-chief. AB - The SJG has enjoyed a sequence of active and dynamic editors-in-chief following the initial period with Professor Myren in charge. This paper gives a short overview of the subsequent editors including their clinical and scientific merits. PMID- 25803740 TI - MTHFR 677C>T polymorphism and the risk of breast cancer: evidence from an original study and pooled data for 28031 cases and 31880 controls. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) acts at an important metabolic point in the regulation of cellular methylation reaction. It assists in the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter aids in remethylation of homocysteine to de novo methionine that is required for DNA synthesis. The objective of this study was to examine the effect of MTHFR 677 C>T polymorphism on the risk of breast cancer in the Indian sub continent. METHODS AND RESULTS: We genotyped 677 C>T locus in 1096 individuals that were classified into cases (N=588) and controls (N=508). Genotype data were analyzed using chi-square test. No significant difference was observed in the distribution of genotypes between cases and controls in north Indian (P = 0.932), south Indian (P = 0.865), and pooled data (P = 0.680). To develop a consensus regarding the impact of 677C>T polymorphism on breast cancer risk, we also conducted a meta-analysis on 28031 cases and 31880 controls that were pooled from sixty one studies. The overall summary estimate upon meta-analysis suggested no significant correlation between the 677C>T substitution and breast cancer in the dominant model (Fixed effect model: OR = 0.97, P=0.072, Random effects model: OR = 0.96, P = 0.084) or the recessive model (Fixed effect model: OR = 1.05, P = 0.089; Random effects model: OR= 1.08, P= 0.067). CONCLUSION: 677 C>T substitution does not affect breast cancer risk in the Indo-European and Dravidian populations of India. Analysis on pooled data further ruled out association between the 677 C>T polymorphism and breast cancer. Therefore, 677 C>T substitution does not appear to influence the risk of breast cancer. PMID- 25803742 TI - Genomic characterization of Burkholderia pseudomallei isolates selected for medical countermeasures testing: comparative genomics associated with differential virulence. AB - Burkholderia pseudomallei is the causative agent of melioidosis and a potential bioterrorism agent. In the development of medical countermeasures against B. pseudomallei infection, the US Food and Drug Administration (FDA) animal Rule recommends using well-characterized strains in animal challenge studies. In this study, whole genome sequence data were generated for 6 B. pseudomallei isolates previously identified as candidates for animal challenge studies; an additional 5 isolates were sequenced that were associated with human inhalational melioidosis. A core genome single nucleotide polymorphism (SNP) phylogeny inferred from a concatenated SNP alignment from the 11 isolates sequenced in this study and a diverse global collection of isolates demonstrated the diversity of the proposed Animal Rule isolates. To understand the genomic composition of each isolate, a large-scale blast score ratio (LS-BSR) analysis was performed on the entire pan genome; this demonstrated the variable composition of genes across the panel and also helped to identify genes unique to individual isolates. In addition, a set of ~550 genes associated with pathogenesis in B. pseudomallei were screened against the 11 sequenced genomes with LS-BSR. Differential gene distribution for 54 virulence-associated genes was observed between genomes and three of these genes were correlated with differential virulence observed in animal challenge studies using BALB/c mice. Differentially conserved genes and SNPs associated with disease severity were identified and could be the basis for future studies investigating the pathogenesis of B. pseudomallei. Overall, the genetic characterization of the 11 proposed Animal Rule isolates provides context for future studies involving B. pseudomallei pathogenesis, differential virulence, and efficacy to therapeutics. PMID- 25803747 TI - Ultrasound-guided forearm nerve blocks in kids: a novel method for pain control in the treatment of hand-injured pediatric patients in the emergency department. AB - OBJECTIVES: Ultrasound-guided forearm nerve blocks have been shown to safely reduce pain for emergency procedures in the adult emergency department (ED). Although ultrasonography is widely used for forearm nerve blocks in the adult ED and in the pediatric operating room, no study to date has examined its use in the pediatric emergency setting. METHODS: We conducted a prospective nonblinded descriptive study of ultrasound-guided ulnar, median, and radial nerve blocks in a convenience sample of pediatric patients with hand injuries requiring procedural intervention who presented to a freestanding pediatric ED. RESULTS: The mean initial pain score for the sample was 5.8, and the mean postprocedure score was 0.8, with a mean on the 10-point visual pain scale of 5 (interquartile range [IQR], 3-6; P = 0.04). Seven patients reported complete resolution of their pain that was signified by a score of 0. The mean time to completion for ulnar nerve block was 79 seconds (IQR, 67-103 seconds). The mean time to completion for median nerve block was 76 seconds (IQR, 70-112 seconds). The mean time to completion for radial nerve block was 69 seconds (IQR, 60-100 seconds). No immediate complications, including vascular puncture, carpal tunnel injury, or direct nerve injection, were noted during the study. At 1-year follow-up, no adverse effects were reported. CONCLUSIONS: Ultrasound-guided forearm nerve blocks are effective for pediatric patients in the ED. The procedure provides effective analgesia and facilitates care while minimizing iatrogenic risk. PMID- 25803745 TI - Growth factor dependent regulation of centrosome function and genomic instability by HuR. AB - The mRNA binding protein HuR is over expressed in cancer cells and contributes to disease progression through post-transcriptional regulation of mRNA. The regulation of HuR and how this relates to glioma is the focus of this report. SRC and c-Abl kinases regulate HuR sub-cellular trafficking and influence accumulation in the pericentriolar matrix (PCM) via a growth factor dependent signaling mechanism. Growth factor stimulation of glioma cell lines results in the associate of HuR with the PCM and amplification of centrosome number. This process is regulated by tyrosine phosphorylation of HuR and is abolished by mutating tyrosine residues. HuR is overexpressed in tumor samples from patients with glioblastoma and associated with a reduced survival. These findings suggest HuR plays a significant role in centrosome amplification and genomic instability, which contributes to a worse disease outcome. PMID- 25803748 TI - Methicillin-resistant Staphylococcus aureus: decolonization and prevention prescribing practices for children treated with skin abscesses/boils in a pediatric emergency department. AB - OBJECTIVE: This study aimed to describe methicillin-resistant Staphylococcus aureus (MRSA) eradication/prevention practices of clinicians managing patients with skin and soft tissue infections (SSTIs), specifically, in those patients undergoing abscess incision and drainage (I&D) in a pediatric emergency department (ED). METHODS: A retrospective cohort study was performed for children aged 0 to 18 years old undergoing I&D of cutaneous abscess between January 1, 2011, and December 31, 2011, in the Cincinnati Children's Hospital Medical Center ED. RESULTS: Five hundred seventy-five patients underwent abscess I&D during our study period. Approximately 25% of our population had previous history of MRSA, SSTI, or boil/abscess; in addition, 26% of our population had a household family member with a previous history of MRSA, SSTI, or boil/abscess. Wound cultures were obtained in 399 (69%) of 575 of I&D abscesses, and of these, 57% of the I&D abscesses grew MRSA. Of all patients, only 3.7% (21 patients) had documentation of MRSA eradication/prevention instructions for patient/family. CONCLUSIONS: Methicillin-resistant S aureus eradication/prevention discussions are not commonly included in discharge instructions for patients undergoing abscess I&D. Given the significant proportion with previous MRSA infection, the ED may be a setting to provide instructions to patients/families with recurrent infections. PMID- 25803750 TI - Association between medication and intestinal intussusception in children: a case crossover study. AB - OBJECTIVES: This study aimed to assess the association between the appearance of intussusception in children and medication intake in the immediately preceding period (2-15 days). METHODS: A case-crossover design was used. We selected cases of children admitted with a diagnosis of intussusception (International Classification of Diseases, Ninth Revision, 860) to the major hospitals in the city of Valencia, Spain, from 2006 to 2009. We then estimated the association between the episode of intussusception and the intake of prescription medication during the preceding 2, 7, and 15 days (case period) and for the same time window 1, 2, 3, and 4 months prior (control period). Data on previous drug administration were obtained from the Pharmaceutical Service Manager System. RESULTS: A total of 95 cases (65.3% boys and 34.7% girls) were selected; 76.6% were younger than the age of 2 years. The association between intussusception and prior drug use varied depending on the exposure window: 15-day odds ratio (OR), 1.45 (95% confidence interval [95% CI], 0.86-2.43); 7-day OR, 1.46 (95% CI, 0.80 2.67); and 2-day OR, 2.26 (95% CI, 1.10-4.64). These associations were greater for children aged younger than 2 years and were usually due to the recent administration (preceding 2 days) of antibiotics (OR, 8.00; 95% CI, 1.47-43.7). CONCLUSIONS: Intussusception was more common among boys aged younger than 2 years. A positive and significant association was observed when drugs were administered 2 to 7 days before the onset of symptoms in children younger than the age of 2 years. PMID- 25803749 TI - Cervical spine imaging in hospitalized children with traumatic brain injury. AB - OBJECTIVES: The purposes of this study, in children with traumatic brain injury (TBI), to describe cervical spine imaging practice, to assess for recent changes in imaging practice, and to determine whether cervical spine computed tomography (CT) is being used in children at low risk for cervical spine injury. METHODS: The setting was children's hospitals participating in the Pediatric Health Information System database, from January 2001 to June 2011. Participants were children (younger than 18 y) with TBI who were evaluated in the emergency department, admitted to the hospital, and received a head CT scan on the day of admission. The primary outcome measures were cervical spine imaging studies. This study was exempted from institutional review board assessment. RESULTS: A total of 30,112 children met study criteria. Overall, 52% (15,687/30,112) received cervical spine imaging. The use of cervical spine radiographs alone decreased between 2001 (47%) and 2011 (23%), with an annual decrease of 2.2% (95% confidence interval [CI], 1.1%-3.3%), and was largely replaced by an increased use of CT, with or without radiographs (8.6% in 2001 and 19.5% in 2011, with an annual increase of 0.9%; 95% CI, 0.1%-1.8%). A total of 2545 children received cervical spine CT despite being discharged alive from the hospital in less than 72 hours, and 1655 of those had a low-risk mechanism of injury. CONCLUSIONS: The adoption of CT clearance of the cervical spine in adults seems to have influenced the care of children with TBI, despite concerns about radiation exposure. PMID- 25803751 TI - High-fidelity simulation in pediatric emergency medicine: a national survey of facilitator comfort and practice. AB - OBJECTIVES: High-fidelity simulation (HFS) is widely used in pediatric emergency medicine (PEM) training and a competent facilitator is vital for effective learning. This survey describes the characteristics, comfort, practices, and need of PEM physicians as HFS facilitators. METHODS: A descriptive cross-sectional survey was electronically distributed to Pediatric Emergency Research Canada physician members, representing 14 academic pediatric emergency departments nationally. RESULTS: The response rate was 66.6% (92/138); 63% (56/89) of PEM physicians taught HFS. Junior attending physicians (P = 0.011) and those with an education focus (P = 0.005) were more comfortable in using HFS. Sixty-eight percent (38/56) described their facilitator training as formal. Generally, facilitators felt comfortable in running simulations (weighted mean scale, 1.53 [<2 = comfortable] on a 5-point rating scale). Facilitators with formal training used verbal confidentiality agreements more frequently (P = 0.008), spent less time running the scenario (P < 0.05) and spent more time in debriefing (P < 0.05) than those without formal training. Sixty-three percent (n = 56) of facilitators identified debriefing as the most stressful aspect of HFS. Their main barrier to HFS teaching was lack of protected teaching time (mean scale, 2.02 [>2 = barrier]). Seventy-six percent (35/46) of respondents desired online and printable facilitator information. Seventy percent (35/51) thought the ideal time for formal facilitator training was during fellowship. CONCLUSIONS: High-fidelity simulation is a widely used educational modality, and more attention must be paid to the needs of the facilitator in order to optimize the educational experience. Standardized facilitator training, focused particularly on effective debriefing techniques, would help improve facilitator comfort with HFS. PMID- 25803752 TI - BD Veritor System Respiratory Syncytial Virus Rapid Antigen Detection Test: Point of-Care Results in Primary Care Pediatric Offices Compared With Reverse Transcriptase Polymerase Chain Reaction and Viral Culture Methods. AB - BACKGROUND: During respiratory syncytial virus season, many children present to pediatric offices and urgent care medical facilities with cough, tachypnea, intercostal retraction, wheezing, as well as disturbed appetite and sleep. Identification of the responsible viral pathogen is quite difficult because several pathogens can produce similar signs and symptoms. METHODS: Nasopharyngeal specimens were collected from symptomatic sick children younger than 6 years, in 8 geographically representative primary care pediatric practices during a 4-month RSV season. Institutional review board approval and signed parental consent were obtained. The primary objective of the study was the estimation of the sensitivity and specificity of the Becton Dickinson (BD) Veritor RSV point-of care (POC) assay as compared with reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Of 523 specimens, 58.3% (n = 305) were from patients younger than 2 years. The BD Veritor RSV POC assay sensitivity and specificity are 81.6% (146/179) and 99.1% (341/344), respectively. When compared with RT-PCR, the BD Veritor RSV POC assay false positive was 0.9% (3/344, with a 95% confidence interval of 0.3%-2.5%) and the false negative was 18.4% (33/179, with a 95% confidence interval of 13.4%-24.5%). The BD Veritor RSV POC assay identified more true positive specimens (n = 146) than viral cell culture (n = 134 positive specimens). CONCLUSIONS: In 8 participating primary care pediatric offices with 523 evaluable subjects, POC BD Veritor RSV tests performed better than viral cell culture results when RT-PCR was the reference standard. PMID- 25803753 TI - Effect of adjusting pulse durations of functional electrical stimulation cycling on energy expenditure and fatigue after spinal cord injury. AB - The purpose of the current study was to determine the effects of three different pulse durations (200, 350, and 500 microseconds [P200, P350, and P500, respectively]) on oxygen uptake (VO2), cycling performance, and energy expenditure (EE) percentage of fatigue of the knee extensor muscle group immediately and 48 to 72 h after cycling in persons with spinal cord injury (SCI). A convenience sample of 10 individuals with motor complete SCI participated in a repeated-measures design using a functional electrical stimulation (FES) cycle ergometer over a 3 wk period. There was no difference among the three FES protocols on relative VO2 or cycling EE. Delta EE between exercise and rest was 42% greater in both P500 and P350 compared with P200 (p = 0.07), whereas recovery VO2 was 23% greater in P350 compared with P200 (p = 0.03). There was no difference in the outcomes of the three pulse durations on muscle fatigue. Knee extensor torque significantly decreased immediately after (p < 0.001) and 48 to 72 h after (p < 0.001) FES leg cycling. Lengthening pulse duration did not affect submaximal or relative VO2 or EE, total EE, and time to fatigue. Greater recovery VO2 and delta EE were noted in P350 and P500 compared with P200. An acute bout of FES leg cycling resulted in torque reduction that did not fully recover 48 to 72 h after cycling. PMID- 25803755 TI - Cognitive Fusion and Pain Experience in Young People. AB - OBJECTIVES: Acceptance and Commitment Therapy (ACT) has been shown to be an effective treatment for chronic pain in young people. Cognitive fusion is a key concept of ACT that is hypothesized to contribute to distress and suffering. In this study, we sought to: (1) test hypothesized associations between cognitive fusion and pain intensity, disability, and catastrophizing; and (2) examine the function of cognitive fusion as a possible mediator between catastrophizing and disability. METHODS: A community sample of 281 young people (11 to 20 y) completed measures assessing cognitive fusion, pain intensity, disability, and pain catastrophizing. RESULTS: Cognitive fusion was positively related to pain intensity (r=0.24, P<0.01), disability (r=0.32, P<0.001), and pain catastrophizing (r=0.47, P<0.001). Moreover, cognitive fusion was found to mediate the association between pain catastrophizing and disability (beta=0.01, 95% confidence interval=0.002-0.024, 5000 bootstrap resamples). DISCUSSION: The findings indicate that cognitive fusion is moderately to strongly associated with pain-related outcomes, which support the need for further research to (1) better understand the relationship between cognitive fusion and adjustment to chronic pain, and (2) determine whether the benefits of treatments such as ACT are mediated, at least in part, by reductions in cognitive fusion. PMID- 25803756 TI - Factors Associated With Disability and Sick Leave in Early Complex Regional Pain Syndrome Type-1. AB - OBJECTIVE: Factors influencing disability and work absence in complex regional pain syndrome type-1 (CRPS)-1 have not been thoroughly described in the literature. We sought to determine whether demographic variables, work-related factors, CRPS clinical severity ratings, pain scores, or psychological variables were associated with disability and sick leave in early CRPS-1. METHODS: A total of 66 CRPS-1 patients were recruited within 12 weeks of CRPS onset. Patients completed measures of pain, depression, anxiety, stress, pain catastrophizing, and pain-related fear. A physical examination was conducted to assess signs and symptoms of CRPS and to calculate a CRPS severity score. Demographic details, clinical details, treatments, work type, and work status were recorded. RESULTS: In multivariate analyses, the following factors were associated with greater disability: higher pain scores, more restricted ankle or wrist extension, and higher levels of depression. Among the 49 who were either working or studying before developing CRPS, 28 had stopped work or study at the time of assessment. Multivariate analyses showed that sick leave was more likely among those whose CRPS was triggered by more severe injuries, whose work was more physically demanding, among those with higher disability scores, and there was also a significant effect of depression on sick leave, which was mediated by disability. DISCUSSION: Although the study was cross-sectional and so cannot differentiate cause from effect, results suggest that even in the early stages of CRPS, a cycle of pain, disability, depression, and work absence can emerge. Treatments aimed to prevent this cycle may help prevent adverse long-term outcomes. PMID- 25803757 TI - Transcutaneous Electrical Nerve Stimulation in Patients With Knee Osteoarthritis: Evidence From Randomized-controlled Trials. AB - OBJECTIVES: Transcutaneous electrical nerve stimulation (TENS) has been reported to relieve pain and improve function in patients with knee osteoarthritis. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of TENS for the management of knee osteoarthritis. METHODS: We searched Embase, PubMed, CENTRAL, SIGLE, PEDro, and clinicaltrials.gov, up to June 2014 for literature related to TENS used for the treatment of knee osteoarthritis. Two authors independently screened the searched records based on the title and abstract. Information including the authors, study design, mean age, sex, study population, stimulation frequency (of TENS), outcome measures, and follow-up periods were extracted by the 2 authors. RESULTS: Eighteen trials were included in the qualitative systematic review, and 14 were included in the meta-analysis. TENS significantly decreased pain (standard mean difference, -0.79; 95% confidence interval [CI], -1.31 to -0.27; P<0.00001) compared with control groups. There was no significant difference in the Western Ontario and McMaster Universities Osteoarthritis Index (standard mean differences, -0.13; 95% CI, 0.35 to 0.1; P=0.09) or the rate of all-cause discontinuation (risk ratio, 0.77; 95% CI, 0.48 to 1.22; P=0.94) between the TENS and control groups. DISCUSSION: TENS might relieve pain due to knee osteoarthritis. Further randomized-controlled trials should focus on large-scale studies and a longer duration of follow-up. PMID- 25803759 TI - Ultrasound-guided Versus Fluoroscopy-controlled Lumbar Transforaminal Epidural Injections: A Prospective Randomized Clinical Trial. AB - OBJECTIVES: Recently, most lumbar spine injections have been administered under ultrasound (US) guidance; however, there is no standard method for US-guided lumbar transforaminal epidural injection (TFEI). In this study, we evaluated the accuracy, effect on pain relief, and safety of US-guided lumbar TFEI. METHODS: A total of 80 patients with low back pain and radicular pain were enrolled. The patients were randomly assigned to either the fluoroscopy (FL) group or the US group. The FL-guided approaches were performed under standardized procedures using the C-arm, whereas the US-guided injections were performed with an US device with a linear probe, and were verified by FL. The needle tip reached the lateral side of the lamina in the axis view and the middle of the adjacent facet joints in the parasagittal view. Afterward, the needle was advanced slightly deeper until the loss-of-resistance test was positive. RESULTS: The success ratio of the US-guided interventions was 85%. The operation time in the US group (518+/ 103 s) was shorter than the FL group (929+/-228 s) (P<0.05). In addition, the radiation dosage in the US group (2640+/-906 MUGy m2) was lower than in the FL group (8992+/-2132 MUGy m2). There was no significant difference in pain relief between the US and FL groups. No serious complication was observed in any of the patients in either group. DISCUSSION: Lumbar TFEI under US guidance was feasible, safe, and required less radiation to achieve the same benefit as the FL-guided interventions. PMID- 25803758 TI - Pharmacogenetic Testing for Analgesic Adverse Effects: Pediatric Case Series. AB - OBJECTIVES: Genetic variants in pharmacokinetic genes can alter the effectiveness and increase the risks of using analgesics to treat pain. The purpose of this retrospective study is to describe the clinical experiences that led to pharmacogenetic testing of pediatric pain management program patients for alterations in the CYP2D6, CYP2C19, and CYP2C9 genes and correlate the analgesic efficacy and adverse analgesic effects with the gene-specific findings and Metabolic Reserve (MR) index. MATERIALS AND METHODS: Nineteen patients were referred for pharmacogenetic testing between February 2010 and December 2013 due to analgesic ineffectiveness or adverse analgesic effects. CYP2D6, CYP2C19, and CYP2C9 functional status was inferred from genotyping; and MR calculated. Data from the available inpatient and outpatient medical records from January 2007 to May 2014 for these patients were reviewed and extracted to characterize patient analgesic response phenotype. RESULTS: Significant CYP2D6 genetic variants were identified in 16 of the 19 (84%) patients: 4 were ultra-rapid metabolizers, 8 were deficient, 3 were poor metabolizers, and 1 was CYP2D6 null metabolizer. Of the 3 patients with functional CYP2D6 status, 2 were CYP2C19 null metabolizers. The MR scores ranged from 3.0 to 7.0, with a bimodal distribution with high frequencies corresponding to 4.0/4.5 and 7.0. DISCUSSION: Clinical evaluation of analgesic ineffectiveness and adverse effects led to the high likelihood of identifying patients with CYP2D6, CYP2C19, and CYP2C9 alleles associated with alterations in analgesic metabolism. Further research is needed to integrate pharmacogenetic and clinical information into anticipatory guidance for pharmacogenetic testing and analgesic prescribing to children with pain. PMID- 25803760 TI - Design, implementation, and first-year outcomes of a value-based drug formulary. AB - BACKGROUND: Value-based insurance design attempts to align drug copayment tier with value rather than cost. Previous implementations of value-based insurance design have lowered copayments for drugs indicated for select "high value" conditions and have found modest improvements in medication adherence. However, these implementations have generally not resulted in cost savings to the health plan, suggesting a need for increased copayments for "low value" drugs. Further, previous implementations have assigned equal copayment reductions to all drugs within a therapeutic area without assessing the value of individual drugs. Aligning the individual drug's copayment to its specific value may yield greater clinical and economic benefits. In 2010, Premera Blue Cross, a large not-for profit health plan in the Pacific Northwest, implemented a value-based drug formulary (VBF) that explicitly uses cost-effectiveness analyses after safety and efficacy reviews to estimate the value of each individual drug. Concurrently, Premera increased copayments for existing tiers. OBJECTIVE: To describe and evaluate the design, implementation, and first-year outcomes of the VBF. METHODS: We compared observed pharmacy cost per member per month in the year following the VBF implementation with 2 comparator groups: (1) observed pharmacy costs in the year prior to implementation, and (2) expected costs if no changes were made to the pharmacy benefits. Expected costs were generated by applying autoregressive integrated moving averages to pharmacy costs over the previous 36 months. We used an interrupted time series analysis to assess drug use and adherence among individuals with diabetes, hypertension, or dyslipidemia compared with a group of members in plans that did not implement a VBF. RESULTS: Pharmacy costs decreased by 3% compared with the 12 months prior and 11% compared with expected costs. There was no significant decline in medication use or adherence to treatments for patients with diabetes, hypertension, or dyslipidemia. CONCLUSIONS: The VBF and copayment changes enabled pharmacy plan cost savings without negatively affecting utilization in key disease states. PMID- 25803761 TI - Accuracy of pharmacy benefit manager medication formularies in an electronic health record system and the Epocrates mobile application. AB - BACKGROUND: Physicians commonly use formulary medication coverage information generated by electronic heath records (EHRs) and the Epocrates mobile drug database application when making medication selection decisions. Nonformulary selections may lead to higher out-of-pocket patient costs and nonadherence with prescribed regimens. Nonformulary selections also contribute to higher overall health plan spending. However, the accuracy of these systems compared with actual insurance coverage is not known. OBJECTIVE: To assess the accuracy of formulary status icons generated by an EHR system and the Epocrates mobile application for patients with Alabama Medicaid and Blue Cross Blue Shield of Alabama (BCBS), the primary insurance providers in the state of Alabama. METHODS: Patients of all ages who had a chart review performed at the outpatient family medicine or pediatric clinics at the University of Alabama at Birmingham Huntsville Medical Regional Campus from May to October 2013 were included in this retrospective analysis. Patients who were not insured by either Alabama Medicaid or BCBS were excluded. Patients who did not have new medications added at the time of the visit were also excluded. For each medication prescribed, the formulary status provided in the EHR system and Epocrates was compared with the actual Medicaid and BCBS formularies published online, and the accuracy of the 2 databases was determined. RESULTS: A total of 1,529 medication records were analyzed. The EHR and Epocrates provided accurate formulary information for 93.1% and 89.4% of medications, respectively. Formulary information generated by the EHR was 96.3% accurate for Medicaid patients and 80.1% accurate for BCBS patients. Epocrates was 88.2% accurate for Medicaid patients and 94.4% accurate for BCBS patients. A total of 936 medication records from the pediatric clinic were analyzed, and the majority of these patients (88.4%) had Medicaid insurance. In this population, the EHR was more accurate (96.9%) than Epocrates (86.6%). Of the small number of pediatric medication records (n = 109) associated with patients who had BCBS, Epocrates was more accurate (92.7%) than the EHR (83.5%). In family medicine, 593 medication records were analyzed. Again, for Medicaid patients, the EHR was more accurate (95.3%) than Epocrates (91.5%). For those with BCBS, Epocrates was more accurate (95.3%) than the EHR (78.2%). When over-the-counter (OTC) medications (n = 232) were analyzed separately from prescription medications, it was found that overall the EHR was 90.5% accurate, and Epocrates was 41.4% accurate. It is important to note that when only prescription medications were analyzed, the accuracy rates were high (93.6% for the EHR and 98.0% for Epocrates). CONCLUSIONS: Formulary information generated by the EHR system and the Epocrates mobile application is a useful tool for physicians when prescribing medications, but neither source is completely accurate. Prescribers should be particularly cautious when making OTC formulary decisions using the Epocrates mobile application, since the formulary information provided for these medications was found to be the least accurate. PMID- 25803762 TI - Consumer choice between common generic and brand medicines in a country with a small generic market. AB - BACKGROUND: Generic medicines offer an opportunity for governments to contain pharmaceutical expenditures, since generics are generally 10%-80% lower in price than brand medicines. Belgium has a small generic market that takes up 15% of the total pharmaceutical market in packages sold. OBJECTIVE: To determine the knowledge of consumers about the different available packages of a common over the-counter medicine (acetaminophen) with regard to price advantage, quality, and effectiveness in a country with a small generic market. METHODS: We conducted an online survey in the general Flemish population using a questionnaire with 25 statements. The questionnaire also contained 2 informative interventions. First, we showed the price per package and per tablet that the patient would pay in the pharmacy. Second, we provided the respondent with general information about generic medication (equivalence, effectiveness, price, and recognition). Before and after the interventions, we probed for preferences and knowledge about the different packages. Multivariate logistic models were used to examine the independent effects of consumer characteristics on responses to the survey statements. RESULTS: We obtained a sample of 1,636 respondents. The general attitude towards generic medication was positive-only 5% would rather not use a generic. Nevertheless, only 17% of the respondents were able to recognize a generic medicine. Older consumers (aged 60 years and above) were more often confused about the different packages (OR = 2.59, 95% CI = 1.76-3.80, P <= 0.001). Consumers without a higher education degree tended to be more doubtful about the difference in effectiveness and quality between the different brands (OR = 0.59, 95% CI = 0.44-0.79, P <= 0.001). Consumer recognition of the name of the active substance of acetaminophen was poor. When different brands were displayed, possible price advantage seemed to be an important motive to switch to a cheaper brand. Consumers generally found medicines to be too expensive; however, consumers with medical or paramedical training had a different opinion. CONCLUSIONS: Two main recommendations can be made to increase the knowledge and enhance the trust in cheaper equivalent medicines. First, highlighting the name of the active substance on the label of medicine packages can reduce confusion and avoid health risks, especially among older consumers. Second, new investments or reallocation of budgets should be considered in order to provide consumers with authoritative information on the bioequivalence and price differences between the different available brands. This would be a cost-effective and potentially cost-saving investment for health care payers. PMID- 25803763 TI - Evaluation of the influence of a pharmacist-led patient-centered medication therapy management and reconciliation service in collaboration with emergency department physicians. AB - BACKGROUND: The implementation of the Patient Protection and Affordable Care Act is anticipated to increase the frequency of emergency department (ED) visits. Therefore, there is a critical need to improve the quality of care transitions among ED patients from ED to outpatient services. OBJECTIVE: To evaluate the effect of systematic implementation of a pharmacist-led patient-centered approach to medication therapy management and reconciliation service (MRS) in the ED on patient utilization of available health care services. METHODS: A single institution prospective randomized cohort study with 90-day postvisit observation randomized patients into 2 groups: (1) medication therapy management reconciliation service following a patient-centered approach (MRS) or (2) usual care provided by the institution (non-MRS). To align patient enrollment with availability of other primary care services, subjects were enrolled during weekday daytime hours. Data for the 90 days before and after the index ED visit were matched in all analyses. Generalized estimating equations evaluated any primary care (PC), urgent care (UC), and ED visits during the 90 days post-index ED visit, adjusted by age and sex and weighted by survival time. Generalized linear models evaluated the average number of ED visits during that period, adjusted by age and sex and weighted by survival time. Data were analyzed for all adult patients (ADLTS), aged >= 18 years, and the subpopulation taking 1 or more prescribed daily medication at the time of the index ED visit (ADLTS1+)-the patients expected to receive greatest benefit from an MRS program. RESULTS: ADLTS MRS patients were 1.9 more likely than non-MRS patients to visit their PC providers (mean difference 0.15, P less than 0.001). Similarly, ADLTS1+ MRS patients were 1.5 times more likely to visit their PC providers (mean difference 0.10, P = 0.026). Although ADLT MRS patients were less likely to visit the UC, this was not significant. However, ADLTS1+ MRS patients were significantly less likely than non-MRS patients (OR = 0.5, 95% CI = 0.3-0.9) to visit the UC. No significant difference was seen in ED visits. CONCLUSIONS: The implementation of a patient-centered approach to medication therapy management and reconciliation improved the odds of patients visiting their PC providers, a positive first step in transitioning patients toward an appropriate use of PC services. PMID- 25803764 TI - Treatment patterns, health care resource utilization, and costs in U.S. patients diagnosed with chronic hepatitis C infection who received telaprevir or boceprevir. AB - BACKGROUND: Chronic hepatitis C (CHC) is associated with substantial morbidity and mortality, with the future burden of disease predicted to significantly increase. The recent addition of 2 direct-acting antiviral (DAA) protease inhibitors, telaprevir and boceprevir, to peginterferon alfa (PEG) and ribavirin (RBV) therapy has been shown to significantly improve sustained virologic response rates and thus has become standard of care. While the efficacy and safety of DAAs has been assessed in the clinical trial setting, less is known about real-world use of these new therapies. OBJECTIVES: To (a) evaluate the treatment patterns, health care utilization, and costs of CHC patients receiving DAA-based therapies in the United States using a retrospective analysis of a large administrative claims database and (b) evaluate factors associated with therapy noncompletion using multivariable analyses. METHODS: Adult patients with >= 1 claim for CHC and a prescription filled for boceprevir or telaprevir were selected from a de-identified U.S.-based claims database. The date of the first fill for a DAA after May 13, 2011 (date of first DAA availability) was defined as the index date, and patients were categorized into either the telaprevir or boceprevir cohort. Patients were required to have continuous eligibility and no claims for hepatitis B during the 6 months before (baseline) and 12 months following (study period) the index date. Baseline characteristics and study period treatment patterns, health care utilization, and costs were described. Factors associated with therapy noncompletion were examined using multivariable logistic regression, and adjusted health care costs were compared between the DAA cohorts using multivariable analyses. RESULTS: A total of 871 telaprevir and 284 boceprevir patients were identified. DAA patients were aged 54 years on average and more often were male (60%, n = 688). Approximately 25% (n = 216) of telaprevir and 18% (n = 52) of boceprevir patients had cirrhosis, and 9% (n = 82) of telaprevir and 7% (n = 20) of boceprevir patients had decompensated cirrhosis at baseline. Less than 1% (n = 9) of patients were HIV co-infected. Approximately 54% (n = 470) of telaprevir and 74% (n = 210) of boceprevir patients did not complete the minimum duration of therapy as per the prescribing information (telaprevir: 12 weeks of triple + 12 weeks of dual; boceprevir: 3 weeks of lead in + 24 weeks of triple). In multivariable analyses, females (vs. males) and patients taking boceprevir (vs. telaprevir) were more likely to not complete therapy (P = 0.011). CHC patients experienced high medical and drug-related resource utilization. Telaprevir patients had numerically higher study period unadjusted medical (boceprevir: $16,927; telaprevir: $19,519) and drug costs (boceprevir: $59,953; telaprevir: $76,497) than boceprevir patients; however, after adjusting for baseline characteristics, only drug costs remained significantly different (P less than 0.001). CONCLUSIONS: These results indicate that a large proportion of CHC patients receiving telaprevir or boceprevir did not complete minimum duration of therapy as per the prescribing information. CHC patients on a DAA regimen also experienced high resource utilization and high medical and drug costs. PMID- 25803765 TI - Cost and effectiveness of biologics for rheumatoid arthritis in a commercially insured population. AB - BACKGROUND: Administrative claims contain detailed medication, diagnosis, and procedure data, but the lack of clinical outcomes for rheumatoid arthritis (RA) historically has limited their use in comparative effectiveness research. A claims-based algorithm was developed and validated to estimate effectiveness for RA from data for adherence, dosing, and treatment modifications. OBJECTIVE: To implement the claims-based algorithm in a U.S. managed care database to estimate biologic cost per effectively treated patient. METHODS: The cohort included patients with RA aged 18-63 years in the Optum Research Database who initiated biologic treatment between January 2007 and December 2010 and were continuously enrolled 6 months before through 12 months after the first claim for the biologic (the index date). Patients were categorized as effectively treated by the claims based algorithm if they met all of the following 6 criteria in the 12-month post index period: (1) a medication possession ratio >= 80% for subcutaneous biologics, or at least as many infusions as specified in U.S. labeling for intravenous biologics; (2) no increase in biologic dose; (3) no switch in biologics; (4) no new nonbiologic disease-modifying antirheumatic drug; (5) no new or increased oral glucocorticoid treatment; and (6) no more than 1 glucocorticoid injection. Drug costs (all biologics) and administration costs (intravenous biologics) were obtained from allowed amounts on claims. Biologic cost per effectively treated patient was defined as total 1-year biologic cost divided by the number of patients categorized by the algorithm as effectively treated with that index biologic. Sensitivity analysis was conducted to examine the total health care costs per effectively treated patient during the first year of biologic therapy. RESULTS: A total of 5,474 individuals were included in the analysis. The index biologic was categorized as effective by the algorithm for 28.9% of patients overall, including 30.6% for subcutaneous biologics and 22.1% for intravenous biologics. The index biologic was categorized as effective in the first year for 32.7% of etanercept (794/2,425), 32.3% of golimumab (40/124), 30.2% of abatacept (89/295), 27.7% of adalimumab (514/1,857), and 19.0% of infliximab (147/773) patients. Mean 1-year biologic cost per effectively treated patient, as defined in the algorithm, was lowest for etanercept ($43,935), followed by golimumab ($49,589), adalimumab ($52,752), abatacept ($62,300), and infliximab ($101,402). The rank order in the sensitivity analysis was the same, except for golimumab and etanercept. CONCLUSIONS: Using a claims-based algorithm in a large commercial claims database, etanercept was the most effective and had the lowest biologic cost per effectively treated patient with RA. PMID- 25803766 TI - Best practices: an electronic drug alert program to improve safety in an accountable care environment. AB - BACKGROUND: The accountable care organization (ACO), one of the most promising and talked about new models of care, focuses on improving communication and care transitions by tying potential shared savings to specific clinical and financial benchmarks. An important factor in meeting these benchmarks is an ACO's ability to manage medications in an environment where medical and pharmacy care has been integrated. The program described in this article highlights the critical components of Marshfield Clinic's Drug Safety Alert Program (DSAP), which focuses on prioritizing and communicating safety issues related to medications with the goal of reducing potential adverse drug events. PROGRAM DESCRIPTION: Once the medication safety concern is identified, it is reviewed to evaluate whether an alert warrants sending prescribers a communication that identifies individual patients or a general communication to all physicians describing the safety concern. Instead of basing its decisions regarding clinician notification about drug alerts on subjective criteria, the Marshfield Clinic's DSAP uses an internally developed scoring system. The scoring system includes criteria developed from previous drug alerts, such as level of evidence, size of population affected, severity of adverse event identified or targeted, litigation risk, available alternatives, and potential for duration of medication use. Each of the 6 criteria is assigned a weight and is scored based upon the content and severity of the alert received. OBSERVATIONS: In its first 12 months, the program targeted 6 medication safety concerns involving the following medications: topiramate, glyburide, simvastatin, citalopram, pioglitazone, and lovastatin. Baseline and follow-up prescribing data were gathered on the targeted medications. Follow-up review of prescribing data demonstrated that the DSAP provided quality up-to-date safety information that led to changes in drug therapy and to decreases in potential adverse drug events. In aggregate, nearly 10,000 total potential adverse drug events were identified with baseline data from the DSAP initiatives, and nearly 8,000 were resolved by changes in prescribing. IMPLICATIONS: Implications and additional thoughts from The Working Group on Optimizing Medication Therapy in Value-Based Healthcare were provided for the following categories: leveraging electronic health records, importance of data collection and reassessment, preventing alert fatigue utilizing various techniques, relevance to ACO quality measurement, and limitations of a retrospective system. RECOMMENDATIONS: While health information technologies have been recognized as a cornerstone for an ACO's success, additional research is needed on comparing these types of technological innovations. Future research should focus on reviewing comparable scoring criteria and alert systems utilized in a variety of ACOs. In addition, an examination of different data mining procedures used within different electronic health record platforms would prove useful to ACOs looking to improve the care of not only the subpopulations with specific metrics associated with them, but their patient population as a whole. The authors also highlight the need for additional research on health information exchanges, including the cost and resource requirements needed to successfully participate in these types of networks. PMID- 25803767 TI - Role of pharmacy services in accountable care organizations. AB - BACKGROUND: The accountable care organization (ACO) model being adopted across the United States aims to improve patient care and reduce costs. Little is known about whether commercial ACO contracts include accountability for prescription drug spending or how ACOs are engaging outpatient pharmacies and managing prescription drug use. OBJECTIVE: To explore how ACOs are addressing drug spending and pharmacy services-a potentially important determinant of quality and total spending. METHODS: We used data from 2 waves of the National Survey of Accountable Care Organizations (N = 270), a survey completed by ACOs that were established prior to July 2013. ACO executives were asked about ACO engagement of pharmacy services, pharmacy-related health information technology capabilities, and ACO accountability for prescription drug spending. RESULTS: Among ACOs with commercial contracts, 77% reported being held responsible for prescription spending by their largest contract. Considering all ACOs (Medicare, Medicaid, and/or commercial contracts), 45% reported at least 1 contract included prescription drug spending responsibility. Nearly half of ACOs reported a formal relationship with a pharmacy; 26% included a pharmacy within the ACO; and 19% had contracted pharmacy services. On average, compared with those that do not, ACOs that engage pharmacies have a broader range of services and provider types, commercial and public contracts, and greater experience with payment reform. CONCLUSIONS: Management of pharmacy services and prescription spending will likely influence commercial ACO contract success. Given the broad potential impact of prescription use on overall spending and quality, payers might encourage integration of pharmacy services in ACOs through prescribing quality and prescription spending performance measures. PMID- 25803769 TI - Predicting adolescent problematic online game use from teacher autonomy support, basic psychological needs satisfaction, and school engagement: a 2-year longitudinal study. AB - Problematic online game use (POGU) has become a serious global public health concern among adolescents. However, its influencing factors and mediating mechanisms remain largely unknown. This study provides the first longitudinal design to test stage-environment fit theory empirically in POGU. A total of 356 Chinese students reported on teacher autonomy support, basic psychological needs satisfaction, school engagement, and POGU in the autumn of their 7th-9th grade years. Path analyses supported the proposed pathway: 7th grade teacher autonomy support increased 8th grade basic psychological needs satisfaction, which in turn increased 9th grade school engagement, which ultimately decreased 9th grade POGU. Furthermore, 7th grade teacher autonomy support directly increased 9th grade school engagement, which in turn decreased 9th grade POGU. These findings suggest that teacher autonomy support is an important protective predictor of adolescent POGU, and basic psychological needs satisfaction and school engagement are the primary mediators in this association. PMID- 25803770 TI - Minimally invasive septal myectomy for the treatment of hypertrophic obstructive cardiomyopathy and intrinsic mitral valve disease. AB - OBJECTIVE: Transaortic left ventricular septal myectomy described by Morrow is a classical procedure for the treatment of systolic anterior motion of the mitral apparatus associated with hypertrophic obstructive cardiomyopathy (HOCM). We aimed to review our results of transmitral septal myectomy and mitral valve repair/replacement in patients with intrinsic mitral valve disease associated with HOCM, operated on through a minimally invasive approach. METHODS: Between 2005 and 2014, 19 patients [7 men (37%); mean (SD) age, 69.4 (14.5) years] were treated with minimally invasive approach for degenerative mitral regurgitation and HOCM. Preoperative peak left ventricular outflow tract (LVOT) gradient was 66 (24) mm Hg. Severe mitral regurgitation was diagnosed in 16 cases (84%). New York Heart Association functional class III to IV heart failure was present in 13 patients (68%). RESULTS: Fifteen patients (79%) underwent mitral valve replacement, and four patients (21%) underwent mitral valve repair. Left ventricular outflow tract obstruction was corrected directly in all patients via the mitral valve with septal myectomy/myotomy, avoiding aortotomy in majority of the patients. No significant prolongation of extracorporeal circulation/aortic cross-clamping times was observed (P = 0.41 and P = 0.67, respectively) when compared with a similar population without HOCM. No iatrogenic ventricular septal defect developed in treated patients. No hospital mortality occurred. Resting LVOT gradient reduced at discharge to 13 (22) mm Hg (P = 0.025). CONCLUSIONS: Transmitral left ventricular septal myectomy in patients with degenerative mitral valve disease is quite a simple, feasible, and effective technique and does not require aortotomy in most cases. It can be performed with low early mortality and satisfactory resolution of LVOT obstruction in a minimally invasive setting. PMID- 25803768 TI - Challenges to integrating pharmacogenetic testing into medication therapy management. AB - Some have proposed the integration of pharmacogenetic (PGx) testing into medication therapy management (MTM) to enable further refinement of treatments to reduce risk of adverse responses and improve efficacy. PGx testing involves the analysis of genetic variants associated with therapeutic or adverse response and may be useful in enhancing the ability to identify ineffective and/or harmful drugs or drug combinations. This "enhanced" MTM might also reduce patient concerns about side effects and increase confidence that the medication is effective, addressing 2 key factors that impact patient adherence: concern and necessity. However, the feasibility and effectiveness of the integration of PGx testing into MTM in clinical practice has not yet been determined. In this commentary, we consider some of the challenges to the integration and delivery of PGx testing in MTM services. PMID- 25803771 TI - A minimally invasive, algorithm-based approach for anomalous aortic origin of a coronary artery. AB - OBJECTIVE: Operative repair for anomalous aortic origin of a coronary artery (AAOCA) has been described using various innovative techniques. Common to each series is the use of a full sternotomy. As demand for minimally invasive approaches to adult cardiac surgery has increased, the upper hemisternotomy has emerged as a safe and effective technique for aortic valve and root replacement. This report reviews our results and describes the application of an upper hemisternotomy to an algorithm-based surgical approach for AAOCA. METHODS: From January 2012 to March 2013, the aortic root was approached via a 7-cm skin incision and upper hemisternotomy for all patients undergoing repair of an AAOCA. The type of repair performed was in accordance with a predefined surgical algorithm. The anomalous vessel had a slit-like ostium and followed a supracommissural intramural course in three patients with symptomatic anomalous right coronary artery. These patients underwent coronary unroofing. In contrast, a patient with an anomalous left coronary artery presented without an intramural segment and underwent vessel translocation and reimplantation. RESULTS: All patients underwent AAOCA repair according to our surgical algorithm and via an upper hemisternotomy. The median length of stay was 4 days. All patients had resolution of symptoms, and there were no reported complications at a median follow-up of 16.5 months. CONCLUSIONS: This series describes a minimally invasive approach to AAOCA repair. When used in conjunction with a defined surgical algorithm, this technique enables a safe and effective repair in all forms of AAOCA without concomitant coronary artery disease. PMID- 25803772 TI - Outcomes of repeat mitral valve surgery in patients with pulmonary hypertension. AB - OBJECTIVE: We sought to study the outcomes of redo-mitral valve surgery in patients with pulmonary hypertension. METHODS: We reviewed data on redo mitral valve surgery in patients with pulmonary hypertension measured by Swan-Ganz catheter (mean pulmonary artery pressure >= 25 mm Hg or systolic pulmonary artery pressure >= 40 mm Hg). RESULTS: Between 1996 and 2010, 637 patients underwent 658 redo mitral valve operations; 138 of them had pulmonary hypertension. The mean patient age was 61.3 (13.9) years, with mean left ventricular ejection fraction of 47.6% (13.2%). The mean systolic pulmonary artery pressure was 61.5 (16.8) mm Hg, and mean pulmonary artery pressure was 40.8 (11.6) mm Hg. Patients had one (71%, 98/138), two (23.9%, 33/138), and three (5.1%, 7/138) previous mitral valve operations. Thirty-day mortality was 10.1% (14/138). Multivariate predictors of 30-day mortality were chronic renal failure [odds ratio (OR), 8.041; P = 0.022], peripheral vascular disease (OR, 5.976; P = 0.025), previous mitral valve replacement (OR, 9.034; P = 0.014), and increasing age (OR, 1.077; P = 0.013). The severity of pulmonary hypertension did not impact 30-day (P = 0.314) or late mortality (P = 0.860). Kaplan-Meier survival rates at 1, 3, and 5 years were 76.6% (n = 99), 65.7% (n = 62), and 55.9% (n = 41), respectively. CONCLUSIONS: Patients with pulmonary hypertension that undergo redo mitral valve surgery have a 55.9% 5-year survival rate. Increasing age, chronic renal insufficiency, peripheral vascular disease, and preexisting mitral valve prosthesis are associated with early mortality. The severity of pulmonary hypertension does not affect operative mortality rates, but it may decrease 1-, 3-, and 5-year survival. PMID- 25803773 TI - Does paravertebral blockade facilitate immediate extubation after totally endoscopic robotic mitral valve repair surgery? AB - OBJECTIVE: Immediate extubation of select patients in the operating room after cardiac surgery has been shown to be safe and may result in improved hemodynamics and decreased cost perioperatively. The aim of this study was to evaluate whether the addition of paravertebral blockade (PVB) to general anesthesia facilitates extubation in the operating room in patients undergoing totally endoscopic robotic mitral valve repair (TERMR). METHODS: A review of 65 consecutive patients who underwent TERMR between January 2012 and June 2013 at a single institution was conducted. Patients were divided into two groups, one group that received PVB and general anesthesia and a second group that received general anesthesia alone. The data analyzed included quantities of anesthetic administered during surgery and the location of extubation after surgery. RESULTS: A total of 34 patients received PVB and general anesthesia, whereas 31 received general anesthesia alone. The two groups had similar demographic and surgical data. Patients in the PVB and general anesthesia group were more likely to be extubated in the operating room (67.6%, n = 23 vs 41.9%, n = 13, P = 0.048) and required less intraoperative fentanyl (3.41 MUg/kg vs 4.90 MUg/kg, P = 0.006). There were no adverse perioperative events in either group related to PVB or extubation. CONCLUSIONS: The addition of PVB to general anesthesia for perioperative pain control facilitated extubation in the operating room in patients undergoing TERMR. Paravertebral blockade allowed for lower intraoperative fentanyl dosing, which may account for the increased incidence of immediate extubation. A detailed prospective study is warranted. PMID- 25803774 TI - Left ventricular mass regression after two alternative sutureless aortic bioprostheses. AB - OBJECTIVE: Left ventricular (LV) hypertrophy in aortic stenosis (AS) constitutes a risk factor for cardiac morbidity and mortality. The aim of this study was to investigate the degree of LV mass regression after aortic valve replacement (AVR) with two alternative sutureless self-expanding strategies: Perceval S (Sorin Group, Saluggia, Italy) (P) and 3f Enable (Medtronic, ATS Medical, Minneapolis, MN USA) (E) aortic bioprostheses. METHODS: Between March 2010 and December 2011, 129 patients with symptomatic AS underwent AVR with the Perceval S or 3f Enable bioprostheses in two cardiac surgery departments (Massa, Italy; Nuremberg, Germany). We analyzed 45 patients in group P and 19 in group E undergoing isolated AVR with a 6-month follow-up. The LV mass was calculated using the Devereux formula and was indexed to body surface area. RESULTS: Baseline patient characteristics showed no significant differences between the two groups. There were no in-hospital deaths. Two patients in group P died at follow-up versus zero in group E (P = 0.49). Mean LV mass index decreased from 146.6 (78) g/m at baseline to 123.3 (63) g/m at follow-up (P < 0.001) in group P and from 146.1 (47.6) g/m to 118.1 (39.8) g/m (P = 0.003) in group E, with no significant difference between the two groups (P = 0.315). This effect was accompanied by significant clinical improvement. CONCLUSIONS: In isolated AS, AVR with sutureless bioprostheses is associated with a significant regression in LV mass at 6-month follow-up. No significant differences were present between the two alternative sutureless strategies. However, regression needs an evaluation with long-term echocardiographic examinations. PMID- 25803776 TI - Hierarchical line-defect patterns in wrinkled surfaces. AB - We demonstrate a novel approach for controlling the formation of line-defects in wrinkling patterns by introducing step-like changes in the Young's modulus of elastomeric substrates supporting thin, stiff layers. Wrinkles are formed upon treating the poly(dimethylsiloxane) (PDMS) substrates by UV/Ozone (UVO) exposure in a uniaxially stretched state and subsequent relaxation. Line defects such as minutiae known from fingerprints are a typical feature in wrinkling patterns. The position where these defects occur is random for homogenous substrate elasticity and film thickness. However, we show that they can be predetermined by using PDMS substrates consisting of areas with different cross-linking densities. While changing the cross-linking density is well known to influence the wrinkling wavelength, we use this parameter in this study to force defect formation. The defect formation is monitored in situ using light microscopy and the mechanical parameters/film thicknesses are determined using imaging AFM indentation measurements. Thus the observed wrinkle-wavelengths can be compared to theoretical predictions. We study the density and morphology of defects for different changes in elasticity and compare our findings with theoretical considerations based on a generalized Swift-Hohenberg-equation to simply emulate the observed pattern-formation process, finding good agreement. The fact that for suitable changes in elasticity, well-ordered defect patterns are observed is discussed with respect to formation of hierarchical structures for applications in optics and nanotechnology. PMID- 25803775 TI - Impacts of intraoperative flow on graft patency of sequential and individual saphenous vein grafts. AB - OBJECTIVE: We sought to delineate the predictor of saphenous vein graft (SVG) failure and to evaluate the impact of sequential grafting of SVG on graft flow as the significant predictor of patency. METHODS: Angiograms and clinical records of 439 patients who underwent coronary artery bypass grafting with aortocoronary SVG were reviewed. Of these, 708 distal anastomoses were created by 480 SVGs. Of 349 patients who underwent isolated coronary artery bypass grafting, operation was performed with an off-pump technique in 347 patients (99%). For 90 patients, a combined procedure on cardiopulmonary bypass was performed. A postoperative angiography was performed in 230 SVGs for clinical reasons. Insufficient flow (IF) was defined as a graft flow of 20 mL/min or less, measured by transit-time Doppler flowmetry during operation. RESULTS: In 480 SVGs, 44 (9.2%) presented IF, and 24 SVGs presented partial or total occlusion. Six of the nine failed individual SVG had IF, whereas none of the failed sequential SVG was associated with IF. Univariate and multivariate logistic regression analyses demonstrated that IF (P = 0.002; odds ratio, 6.63) and sequential grafting (P = 0.004; odds ratio, 2.51) were significantly correlated with a failure of the SVG. The patency rate of sequential SVG to the most distal target was 78/93 (83.9%), which was significantly lower than 9/139 (93.5%) of the individual SVG (P = 0.02) and 7/113 (93.8%) of the sequential SVG to proximal targets (P = 0.02). CONCLUSIONS: When both targets seem to have sufficient demand, avoidance of sequential grafting would be reasonable. Moreover, the important target should be grafted by individual grafting or sequential proximal anastomosis. PMID- 25803777 TI - Effects of zinc sulfate supplementation on cell-mediated immune response in head and neck cancer patients treated with radiation therapy. AB - Zinc deficiency is an important factor that impairs cellular immunity and contributes to low T lymphocyte counts in head and neck cancers. Persistent T lymphopenia is clinically relevant in terms of tumor persistence and/or recurrence. The primary objective was to evaluate the impact of zinc sulfate supplementation on the absolute numbers of circulating T lymphocytes and T lymphocyte subpopulations. The secondary objectives were to evaluate overall survival, progression-free survival, and the adverse events of zinc sulfate. Seventy-two head and neck cancer patients were enrolled in a randomized, double blind, placebo-controlled trial. Zinc sulfate 50 mg in 10 cc and an identically appearing placebo were self-administered 3 times daily at meal times. Blood samples were obtained for complete blood count, total T lymphocytes and T lymphocyte subpopulations before radiation therapy as baselines, at the fifth week during radiation therapy, and at the first month after completion of radiation therapy. The baseline characteristics of patients, tumors, and treatments and the baseline lymphocyte parameters were not significantly different between the 2 groups. Zinc sulfate supplementation during head and neck radiation therapy showed no increase in absolute numbers of circulating T lymphocytes, T lymphocyte subpopulations, or survival with acceptable side effects. PMID- 25803779 TI - Glacial ice and atmospheric forcing on the Mertz Glacier Polynya over the past 250 years. AB - The Mertz Glacier Polynya off George V Land, East Antarctica, is a source of Adelie Land Bottom Water, which contributes up to ~25% of the Antarctic Bottom Water. This major polynya is closely linked to the presence of the Mertz Glacier Tongue that traps pack ice upstream. In 2010, the Mertz Glacier calved a massive iceberg, deeply impacting local sea ice conditions and dense shelf water formation. Here we provide the first detailed 250-year long reconstruction of local sea ice and bottom water conditions. Spectral analysis of the data sets reveals large and abrupt changes in sea surface and bottom water conditions with a ~70-year cyclicity, associated with the Mertz Glacier Tongue calving and regrowth dynamics. Geological data and atmospheric reanalysis, however, suggest that sea ice conditions in the polynya were also very sensitive to changes in surface winds in relation to the recent intensification of the Southern Annular Mode. PMID- 25803778 TI - Glycosylation of phenolic compounds by the site-mutated beta-galactosidase from Lactobacillus bulgaricus L3. AB - beta-Galactosidases can transfer the galactosyl from lactose or galactoside donors to various acceptors and thus are especially useful for the synthesis of important glycosides. However, these enzymes have limitations in the glycosylation of phenolic compounds that have many physiological functions. In this work, the beta-galactosidase from Lactobacillus bulgaricus L3 was subjected to site-saturation mutagenesis at the W980 residue. The recombinant pET-21b plasmid carrying the enzyme gene was used as the template for mutation. The mutant plasmids were transformed into Escherichia coli cells for screening. One recombinant mutant, W980F, exhibited increased yield of glycoside when using hydroquinone as the screening acceptor. The enzyme was purified and the effects of the mutation on enzyme properties were determined in detail. It showed improved transglycosylation activity on novel phenolic acceptors besides hydroquinone. The yields of the glycosides produced from phenol, hydroquinone, and catechol were increased by 7.6% to 53.1%. Moreover, it generated 32.3% glycosides from the pyrogallol that could not be glycosylated by the wild-type enzyme. Chemical structures of these glycoside products were further determined by MS and NMR analysis. Thus, a series of novel phenolic galactosides were achieved by beta-galactosidase for the first time. This was a breakthrough in the enzymatic galactosylation of the challenging phenolic compounds of great values. PMID- 25803780 TI - Comparison of Gebauer SLc and Moria CBm Carriazo-Barraquer ALK Microkeratomes for Descemet's Stripping Automated Endothelial Keratoplasty Preparation. AB - PURPOSE: We compared the hand-guided Moria Carriazo-Barraquer (CBm) microkeratome with the fully automatic SLc microkeratome for Descemet's stripping automated endothelial keratoplasty (DSAEK)-lamella preparation and storage, vis-a-vis accuracy, endothelial cell loss (ECL), and lamellar surface roughness (LSR). METHODS: A total of 18 human corneas were dissected with both the 300 MUm CBm multi-use (n = 9) and the 300 um SLc (n = 9) single-use heads, after which they were incubated for 6 d in a 5% dextran medium. Before preparation (0 h) and 1, 24, and 144 h after dissection, ECL and corneal thickness (CT) were measured by ultrasound pachymetry (USP) and optical coherence tomography (OCT). LSR was assessed by scanning electron microscopy (SEM) and evaluated by three masked observers. RESULTS: Prior to cutting, CTs did not differ significantly between OCT or USP measurements, with a high correlation between the two modalities (r(2)= 0.94, p < 0.0001). One hour after preparation the anterior lamella showed a significantly higher dissection depth with the CBm (429.4 +/- 21.8 um) than the SLc (311.7 +/- 54.8 um, p = 0.0006), with the variance of the SLc system showing a trend towards higher values (p = 0.07). Anterior and posterior lamellae swelled significantly in the subsequent culture period. Both groups showed a significant ECL 1 h after preparation (p < 0.0001) with no significant difference between the systems (1 h: p = 0.44; CBm: - 9.4%, SLc: -11.7%), which stabilized over 144 h (144 h CBm: -13.9%, 144 h SLc: -10.3%). LSR did not differ significantly between both systems (p = 0.60). CONCLUSIONS: The SLc system agrees more with the designated cutting depth than the CBm. The dissection produced a comparable LSR and a ~10% ECL independently of the system. Further incubation of the prepared lamellae led to a swelling, but no further ECL. PMID- 25803781 TI - Exome analysis reveals differentially mutated gene signatures of stage, grade and subtype in breast cancers. AB - Breast cancers exhibit highly heterogeneous molecular profiles. Although gene expression profiles have been used to predict the risks and prognostic outcomes of breast cancers, the high variability of gene expression limits its clinical application. In contrast, genetic mutation profiles would be more advantageous than gene expression profiles because genetic mutations can be stably detected and the mutational heterogeneity widely exists in breast cancer genomes. We analyzed 98 breast cancer whole exome samples that were sorted into three subtypes, two grades and two stages. The sum deleterious effect of all mutations in each gene was scored to identify differentially mutated genes (DMGs) for this case-control study. DMGs were corroborated using extensive published knowledge. Functional consequences of deleterious SNVs on protein structure and function were also investigated. Genes such as ERBB2, ESP8, PPP2R4, KIAA0922, SP4, CENPJ, PRCP and SELP that have been experimentally or clinically verified to be tightly associated with breast cancer prognosis are among the DMGs identified in this study. We also identified some genes such as ARL6IP5, RAET1E, and ANO7 that could be crucial for breast cancer development and prognosis. Further, SNVs such as rs1058808, rs2480452, rs61751507, rs79167802, rs11540666, and rs2229437 that potentially influence protein functions are observed at significantly different frequencies in different comparison groups. Protein structure modeling revealed that many non-synonymous SNVs have a deleterious effect on protein stability, structure and function. Mutational profiling at gene- and SNV-level revealed differential patterns within each breast cancer comparison group, and the gene signatures correlate with expected prognostic characteristics of breast cancer classes. Some of the genes and SNVs identified in this study show high promise and are worthy of further investigation by experimental studies. PMID- 25803784 TI - American Geriatrics Society care of lesbian, gay, bisexual, and transgender older adults position statement: American Geriatrics Society Ethics Committee. AB - There is ample evidence that lesbian, gay, bisexual, and transgender (LGBT) individuals face discrimination in the healthcare setting. Providing high-quality health care for older LGBT adults will require active steps by organizations, institutions, advocacy groups, and health professionals that create an environment that is free from discrimination. This position statement that the American Geriatrics Society (AGS) Ethics Committee developed addresses the vision of the AGS for the care of LGBT older adults and specific steps that can be taken to ensure that they receive the care that they need. PMID- 25803783 TI - Branched-chain amino acids and arginine improve performance in two consecutive days of simulated handball games in male and female athletes: a randomized trial. AB - The central nervous system plays a crucial role in the development of physical fatigue. The purpose of this study is to investigate the effect of combined supplementation of branched-chain amino acids (BCAA) and arginine on intermittent sprint performance in simulated handball games on 2 consecutive days. METHODS: Fifteen male and seven female handball players consumed 0.17 g/kg BCAA and 0.04 g/kg arginine together (AA trial), or placebo (PB trial) before exercise. Each trial contained two 60-min simulated handball games on consecutive days. The game was consisted of 30 identical 2-min blocks and a 20 m all-out sprint was performed at the end of each block. The performance, measured by percentage changes of sprint time between day 1 and 2, was significantly better in the AA trial (first half: AA trial: -1.34 +/- 0.60%, PB trial: -0.21 +/- 0.69%; second half: AA trial: -1.68 +/- 0.58%, PB trial: 0.49 +/- 0.42%). The average ratings of perceive exertion throughout the 2-day trial was significantly lower in the AA trial (14.2 +/- 0.3) than the PB trial (15.1 +/- 0.4). Concurrently, post exercise tryptophan/BCAA ratio on both days in the AA trial was significantly lower than the baseline. This study showed that BCAA and arginine supplementation could improve performance in intermittent sprints on the second consecutive day of simulated handball games in well-trained athletes by potentially alleviating central fatigue. PMID- 25803782 TI - PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3 AWA)-induced autophagy to apoptosis in prostate cancer cells. AB - An active medicinal component of plant origin with an ability to overcome autophagy by inducing apoptosis should be considered a therapeutically active lead pharmacophore to control malignancies. In this report, we studied the effect of concentration-dependent 3-AWA (3-azido withaferin A) sensitization to androgen independent prostate cancer (CaP) cells which resulted in a distinct switching of 2 interrelated conserved biological processes, i.e. autophagy and apoptosis. We have observed 3 distinct parameters which are hallmarks of autophagy in our studies. First, a subtoxic concentration of 3-AWA resulted in an autophagic phenotype with an elevation of autophagy markers in prostate cancer cells. This led to a massive accumulation of MAP1LC3B and EGFP-LC3B puncta coupled with gradual degradation of SQSTM1. Second, higher toxic concentrations of 3-AWA stimulated ER stress in CaP cells to turn on apoptosis within 12 h by elevating the expression of the proapoptotic protein PAWR, which in turn suppressed the autophagy-related proteins BCL2 and BECN1. This inhibition of BECN1 in CaP cells, leading to the disruption of the BCL2-BECN1 interaction by overexpressed PAWR has not been reported so far. Third, we provide evidence that pawr-KO MEFs exhibited abundant autophagy signs even at toxic concentrations of 3-AWA underscoring the relevance of PAWR in switching of autophagy to apoptosis. Last but not least, overexpression of EGFP-LC3B and DS-Red-BECN1 revealed a delayed apoptosis turnover at a higher concentration of 3-AWA in CaP cells. In summary, this study provides evidence that 3-AWA is a strong anticancer candidate to abrogate protective autophagy. It also enhanced chemosensitivity by sensitizing prostate cancer cells to apoptosis through induction of PAWR endorsing its therapeutic potential. PMID- 25803786 TI - Early hospital readmission of nursing home residents and community-dwelling elderly adults discharged from the geriatrics service of an urban teaching hospital: patterns and risk factors. AB - OBJECTIVES: To compare rates and risk factors for early hospital readmission for nursing home residents and community-dwelling older adults. DESIGN: Retrospective cohort study. SETTING: Geriatric inpatient service at a large urban hospital. PARTICIPANTS: Nursing home residents (n=625) and community-dwelling individuals (n=413) aged 65 and older admitted over a 1-year period. MEASUREMENTS: Thirty-day readmissions. RESULTS: There were 1,706 hospital admissions within the 1-year study period involving 1,038 individuals. The 30-day readmission rate was higher for subjects discharged to a nursing home than those discharged to the community (34.4% vs 22.6%, P<.001). Chronic kidney disease and pressure ulcers were associated with greater risk of readmission in both groups. Chronic obstructive pulmonary disease was a risk factor for readmission only in community-dwelling individuals. Congestive heart failure and dementia were associated with greater risk of readmission only in nursing home residents. Readmission rates varied between individual nursing homes by more than a factor of 2. Risk of readmission was 30% lower in nursing home residents cared for by hospitalist than nonhospitalist geriatricians. CONCLUSION: Higher rates of hospital readmission for individuals discharged to nursing homes than to the community and differing patterns of risk factors for readmission indicate the importance of customized interventions to reduce readmission rates for two distinct elderly populations. PMID- 25803785 TI - Associations between sleep-disordered breathing, nocturnal hypoxemia, and subsequent cognitive decline in older community-dwelling men: the Osteoporotic Fractures in Men Sleep Study. AB - OBJECTIVES: To determine whether sleep-disordered breathing (SDB), a group of disorders common in older adults characterized by breathing pauses during sleep often accompanied by hypoxemia, is associated with cognitive decline. DESIGN: Population-based longitudinal study. SETTING: Six centers in the United States. PARTICIPANTS: Community-dwelling older men (N=2,636; aged 76.0+/-5.3) without probable mild cognitive impairment or dementia followed for 3.4+/-0.5 years. MEASUREMENTS: SDB was measured using in-home polysomnography: nocturnal hypoxemia (>=1% of sleep time with oxygen saturation (SaO2)<90%, oxygen desaturation index (ODI: number of oxygen desaturations of >=3% per hour of sleep)) and apnea hypopnea index (AHI, number of apneas and hypopneas at >=3% desaturation per hour of sleep). Cognitive decline was measured using the Modified Mini-Mental State Examination (3MS) and the Trail-Making Test Part B (Trails B) at baseline and two follow-up points. Associations between predictors and cognitive decline were examined using linear mixed models adjusted for multiple confounders. Models were further adjusted for potential mediators (sleep duration, sleep fragmentation, resting SaO2). RESULTS: Nocturnal hypoxemia was related to greater decline on the 3MS. Men with 1% or more of sleep time with SaO2 less than 90% had an adjusted annualized decline of 0.43 points, compared with 0.25 for men in the reference group (P=.003). For each 5-point increase in ODI, there was an average annualized decline of 0.36 points (P=.01). Results were robust to further adjustment for potential mediators. The association between AHI and cognitive decline did not reach significance. No associations were seen with SDB and decline on the Trails B. CONCLUSION: In older community-dwelling men, there was a modest association between nocturnal hypoxemia and global cognitive decline, suggesting the importance of overnight oxygenation for cognitive function. PMID- 25803787 TI - Awareness and completion of advance directives in older Korean-American adults. AB - There has been growing concern about racial and ethnic disparities in completion rates of advance directives (ADs) in community-dwelling older populations. Although differences in AD completion rates between non-Hispanic whites and African Americans have been reported, not much is known about the awareness and completion of ADs in other groups of ethnic minorities. Using a sample of community-dwelling Korean-American older adults (n=675) as a target, factors associated with their awareness and completion of ADs were explored. Guided by Andersen's behavioral health model, predisposing (age, sex, marital status, education), need (chronic conditions, functional disability), and enabling (health insurance, acculturation) variables were included in the separate logistic regression models of AD awareness and AD completion. In both models, acculturation was found to be a significant predictor; those who were more acculturated were more likely to be aware of ADs and to have completed ADs. This study contributes to the knowledge about the role of acculturation in explaining AD awareness and completion in Korean-American older adults and provides recommendations for possible AD educational interventions for this older adult minority population. PMID- 25803789 TI - Trends in attention-deficit/hyperactivity disorder drug consumption in children and adolescents in Slovenia from 2001 to 2012: a drug use study from a national perspective. AB - OBJECTIVE: In most Eastern and Central European countries, except Germany, there is a lack of drug consumption studies for attention-deficit/hyperactivity disorder (ADHD). The main purpose of the present study was to present the pattern and the evolution of national ADHD drug consumption in Slovenia. METHODS: The national consumption data for the period 2001-2012 and medication costs were obtained from the database of the Health Insurance Institute of Slovenia. A defined daily dose (DDD) per 1000 inhabitants per day and the total medication cost in euro were extracted. Only immediate-release methylphenidate (IR-MPH), methylphenidate-osmotic release oral delivery system (OROS-MPH) and atomoxetine (ATX) have been approved for ADHD in Slovenia and are included in this study. Amphetamines have not been available in Slovenia. RESULTS: ADHD drug consumption increased in Slovenia from 0.0537 DDD/1000 inhabitants/day in 2001 to 0.0687 DDD/1000 inhabitants/day in 2006 and to 0.3076 DDD/1000 inhabitants/day in 2012. The rise was largely because of an increase in OROS-MPH consumption and increase in ATX consumption, whereas the consumption of IR-MPH decreased rapidly. During the study period, the total cost of the medicines increased 31-fold. From 2007 to 2010, the total cost of ADHD medicines increased 14-fold and from 2010 to 2012 the cost increased by 11.4% only. CONCLUSIONS: When new drugs are licensed in a jurisdiction, their prescription rates increase rapidly. The changes in the pattern of prescribing medicines are evident in Slovenia, primarily in the increase of OROS-MPH and ATX prescriptions and in the rapid decrease of IR-MPH prescriptions. Results indicate a need for appropriate interventions in Slovenia. PMID- 25803790 TI - Bronsted acid-catalyzed intramolecular nucleophilic substitution of the hydroxyl group in stereogenic alcohols with chirality transfer. AB - The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote SN1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future. PMID- 25803791 TI - Synthetic Strategies for Engineering Intravenous Hemostats. AB - While there are currently many well-established topical hemostatic agents for field administration, there are still limited tools to staunch bleeding at less accessible injury sites. Current clinical methods to restore hemostasis after large volume blood loss include platelet and clotting factor transfusion, which have respective drawbacks of short shelf life and risk of viral transmission. Therefore, synthetic hemostatic agents that can be delivered intravenously and encourage stable clot formation after localizing to sites of vascular injury are particularly appealing. In the past three decades, platelet substitutes have been prepared using drug delivery vehicles such as liposomes and PLGA nanoparticles that have been modified to mimic platelet properties. Additionally, structural considerations such as particle size, shape, and flexibility have been addressed in a number of reports. Since platelets are the first responders after vascular injury, platelet substitutes represent an important class of intravenous hemostats under development. More recently, materials affecting fibrin formation have been introduced to induce faster or more stable blood clot formation through fibrin cross-linking. Fibrin represents a major structural component in the final blood clot, and a fibrin-based hemostatic mechanism acting downstream of initial platelet plug formation may be a safer alternative to platelets to avoid undesired thrombotic activity. This Review explores intravenous hemostats under development and strategies to optimize their clotting activity. PMID- 25803792 TI - Community-based intervention packages for reducing maternal and neonatal morbidity and mortality and improving neonatal outcomes. AB - BACKGROUND: While maternal, infant and under-five child mortality rates in developing countries have declined significantly in the past two to three decades, newborn mortality rates have reduced much more slowly. While it is recognised that almost half of the newborn deaths can be prevented by scaling up evidence-based available interventions (such as tetanus toxoid immunisation to mothers, clean and skilled care at delivery, newborn resuscitation, exclusive breastfeeding, clean umbilical cord care, and/or management of infections in newborns), many require facility-based and outreach services. It has also been stated that a significant proportion of these mortalities and morbidities could also be potentially addressed by developing community-based packaged interventions which should also be supplemented by developing and strengthening linkages with the local health systems. Some of the recent community-based studies of interventions targeting women of reproductive age have shown variable impacts on maternal outcomes and hence it is uncertain if these strategies have consistent benefit across the continuum of maternal and newborn care. OBJECTIVES: To assess the effectiveness of community-based intervention packages in reducing maternal and neonatal morbidity and mortality; and improving neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2014), World Bank's JOLIS (25 May 2014), BLDS at IDS and IDEAS database of unpublished working papers (25 May 2014), Google and Google Scholar (25 May 2014). SELECTION CRITERIA: All prospective randomised, cluster-randomised and quasi-randomised trials evaluating the effectiveness of community-based intervention packages in reducing maternal and neonatal mortality and morbidities, and improving neonatal outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed trial quality and extracted the data. Data were checked for accuracy. MAIN RESULTS: The review included 26 cluster-randomised/quasi-randomised trials, covering a wide range of interventional packages, including two subsets from three trials. Assessment of risk of bias in these studies suggests concerns regarding insufficient information on sequence generation and regarding failure to adequately address incomplete outcome data, particularly from randomised controlled trials. We incorporated data from these trials using generic inverse variance method in which logarithms of risk ratio (RR) estimates were used along with the standard error of the logarithms of RR estimates.Our review showed a possible effect in terms of a reduction in maternal mortality (RR 0.80; 95% confidence interval (CI) 0.64 to 1.00, random-effects (11 studies, n = 167,311; random-effects, Tau2 = 0.03, I2 20%). However, significant reduction was observed in maternal morbidity (average RR 0.75; 95% CI 0.61 to 0.92; four studies, n = 138,290; random-effects, Tau2 = 0.02, I2 = 28%); neonatal mortality (average RR 0.75; 95% CI 0.67 to 0.83; 21 studies, n = 302,646; random-effects, Tau2 = 0.06, I2 = 85%) including both early and late mortality; stillbirths (average RR 0.81; 95% CI 0.73 to 0.91; 15 studies, n = 201,181; random-effects, Tau2 = 0.03, I2 = 66%); and perinatal mortality (average RR 0.78; 95% CI 0.70 to 0.86; 17 studies, n = 282,327; random-effects Tau2 = 0.04, I2 = 88%) as a consequence of implementation of community-based interventional care packages.Community-based intervention packages also increased the uptake of tetanus immunisation by 5% (average RR 1.05; 95% CI 1.02 to 1.09; seven studies, n = 71,622; random-effects Tau2 = 0.00, I2 = 52%); use of clean delivery kits by 82% (average RR 1.82; 95% CI 1.10 to 3.02; four studies, n = 54,254; random-effects, Tau2 = 0.23, I2 = 90%); rates of institutional deliveries by 20% (average RR 1.20; 95% CI 1.04 to 1.39; 14 studies, n = 147,890; random-effects, Tau2 = 0.05, I2 = 80%); rates of early breastfeeding by 93% (average RR 1.93; 95% CI 1.55 to 2.39; 11 studies, n = 72,464; random-effects, Tau2 = 0.14, I2 = 98%), and healthcare seeking for neonatal morbidities by 42% (average RR 1.42; 95% CI 1.14 to 1.77, nine studies, n = 66,935, random-effects, Tau2 = 0.09, I2 = 92%). The review also showed a possible effect on increasing the uptake of iron/folic acid supplementation during pregnancy (average RR 1.47; 95% CI 0.99 to 2.17; six studies, n = 71,622; random-effects, Tau2 = 0.26; I2 = 99%).It has no impact on improving referrals for maternal morbidities, healthcare seeking for maternal morbidities, iron/folate supplementation, attendance of skilled birth attendance on delivery, and other neonatal care-related outcomes. We did not find studies that reported the impact of community-based intervention package on improving exclusive breastfeeding rates at six months of age. We assessed our primary outcomes for publication bias and observed slight asymmetry on the funnel plot for maternal mortality. AUTHORS' CONCLUSIONS: Our review offers encouraging evidence that community-based intervention packages reduce morbidity for women, mortality and morbidity for babies, and improves care-related outcomes particularly in low- and middle-income countries. It has highlighted the value of integrating maternal and newborn care in community settings through a range of interventions, which can be packaged effectively for delivery through a range of community health workers and health promotion groups. While the importance of skilled delivery and facility based services for maternal and newborn care cannot be denied, there is sufficient evidence to scale up community-based care through packages which can be delivered by a range of community-based workers. PMID- 25803795 TI - Meaningfully incorporating staff input to enhance frontline engagement. AB - Nurses play a critical role in care transformation. To achieve transformation, frontline staff must be engaged in their work, committed to their organization's mission, and capable of delivering high-quality care. Data from the Advisory Board Survey Solutions show that nurses are both the least engaged and most disengaged among all frontline staff. To identify the most promising opportunities for driving engagement, researchers from The Advisory Board Company analyzed engagement survey responses from more than 343,000 employees at 575 healthcare organizations. This article describes 3 strategies for addressing 1 of the greatest opportunities identified from the data: ensuring that nurses feel that their ideas and suggestions are valued by the organization. PMID- 25803788 TI - Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy. AB - Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them "tolerogenic," which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility. PMID- 25803793 TI - Psychological therapies (remotely delivered) for the management of chronic and recurrent pain in children and adolescents. AB - BACKGROUND: Chronic pain is common during childhood and adolescence and is associated with negative outcomes such as increased severity of pain, reduced function (e.g. missing school), and low mood (e.g. high levels of depression and anxiety). Psychological therapies, traditionally delivered face-to-face with a therapist, are efficacious at reducing pain intensity and disability. However, new and innovative technology is being used to deliver these psychological therapies remotely, meaning barriers to access to treatment such as distance and cost can be removed or reduced. Therapies delivered with technological devices, such as the Internet, computer-based programmes, smartphone applications, or via the telephone, can be used to deliver treatment to children and adolescents with chronic pain. OBJECTIVES: To determine the efficacy of psychological therapies delivered remotely compared to waiting-list, treatment-as-usual, or active control treatments, for the management of chronic pain in children and adolescents. SEARCH METHODS: We searched four databases (CENTRAL, MEDLINE, EMBASE, and PsycINFO) from inception to June 2014 for randomised controlled trials of remotely delivered psychological interventions for children and adolescents (0 to 18 years of age) with chronic pain. We searched for chronic pain conditions including, but not exclusive to, headache, recurrent abdominal pain, musculoskeletal pain, and neuropathic pain. We also searched online trial registries for potential trials. A citation and reference search for all included studies was conducted. SELECTION CRITERIA: All included studies were randomised controlled trials that investigated the efficacy of a psychological therapy delivered remotely via the Internet, smartphone device, computer-based programme, audiotapes, or over the phone in comparison to an active, treatment-as-usual, or waiting-list control. We considered blended treatments, which used a combination of technology and face-to-face interaction. We excluded interventions solely delivered face-to-face between therapist and patient from this review. Children and adolescents (0 to 18 years of age) with a primary chronic pain condition were the target of the interventions. Each comparator arm, at each extraction point had to include 10 or more participants. DATA COLLECTION AND ANALYSIS: For the analyses, we combined all psychological therapies. We split pain conditions into headache and mixed (non-headache) pain and analysed them separately. Pain, disability, depression, anxiety, and adverse events were extracted as primary outcomes. We also extracted satisfaction with treatment as a secondary outcome. We considered outcomes at two time points: first immediately following the end of treatment (known as 'post-treatment'), and second, any follow-up time point post treatment between 3 and 12 months (known as 'follow-up'). We assessed all included studies for risk of bias. MAIN RESULTS: Eight studies (N = 371) that delivered treatment remotely were identified from our search; five studies investigated children with headache conditions, one study was with children with juvenile idiopathic arthritis, and two studies included mixed samples of children with headache and mixed (i.e. recurrent abdominal pain, musculoskeletal pain) chronic pain conditions. The average age of children receiving treatment was 12.57 years.For headache pain conditions, we found one beneficial effect of remotely delivered psychological therapy. Headache severity was reduced post treatment (risk ratio (RR) = 2.65, 95% confidence interval (CI) 1.56 to 4.50, z = 3.62,p < 0.01, number needed to treat to benefit (NNTB) = 2.88). For mixed pain conditions, we found only one beneficial effect: psychological therapies reduced pain intensity post-treatment (standardised mean difference (SMD) = -0.61, 95% CI -0.96 to -0.25, z = 3.38, p < 0.01). No effects were found for reducing pain at follow-up in either analysis. For headache and mixed conditions, there were no beneficial effects of psychological therapies delivered remotely for disability post-treatment and a lack of data at follow-up meant no analyses could be run. Only one analysis could be conducted for depression outcomes. We found no beneficial effect of psychological therapies in reducing depression post treatment for headache conditions. Only one study presented data in children with mixed pain conditions for depressive outcomes and no data were available for either condition at follow-up. Only one study presented anxiety data post treatment and no studies reported follow-up data, therefore no analyses could be run. Further, there were no data available for adverse events, meaning that we are unsure whether psychological therapies are harmful to children who receive them. Satisfaction with treatment is described qualitatively.'Risk of bias' assessments were low or unclear. We judged selection, detection, and reporting biases to be mostly low risk for included studies. However, judgements made on performance and attrition biases were mostly unclear. AUTHORS' CONCLUSIONS: Psychological therapies delivered remotely, primarily via the Internet, confer benefit in reducing the intensity or severity of pain after treatment across conditions. There is considerable uncertainty around these estimates of effect and only eight studies with 371 children contribute to the conclusions. Future studies are likely to change the conclusions reported here. All included trials used either behavioural or cognitive behavioural therapies for children with chronic pain, therefore we cannot generalise our findings to other therapies. However, satisfaction with these treatments was generally positive. Larger trials are needed to increase our confidence in all conclusions regarding the efficacy of remotely delivered psychological therapies. Implications for practice and research are discussed. PMID- 25803794 TI - Opportunistic pathogens and elements of the resistome that are common in bottled mineral water support the need for continuous surveillance. AB - Several differences concerning bacterial species, opportunistic pathogens, elements of the resistome as well as variations concerning the CFU/mL counts were identified in some of the five most marketed bottled mineral water from Araraquara city, Sao Paulo, Brazil. Two out of five brands tested were confirmed as potential source of opportunistic pathogens, including Mycobacterium gordonae, Ralstonia picketti and Burkholderia cepacia complex (Bcc). A total of one hundred and six isolates were recovered from four of these bottled mineral water brands. Betaproteobacteria was predominant followed by Alphaproteobacteria, Gammaproteobacteria and Firmicutes. Ninety percent of the bacteria isolated demonstrated resistance to seventeen of the nineteen antimicrobials tested. These antimicrobials included eight different classes, including 3rd and 4th generation cephalosporins, carbapenems and fluoroquinolones. Multidrug resistant bacteria were detected for fifty-nine percent of isolates in three water brands at counts up to 103 CFU/ml. Of major concern, the two bottled mineral water harboring opportunistic pathogens were also source of elements of the resistome that could be directly transferred to humans. All these differences found among brands highlight the need for continuous bacteriological surveillance of bottled mineral water. PMID- 25803796 TI - Going beyond benchmarks: zero harm for every patient, every time. AB - In this Magnet(r) Perspectives, the author discusses how preventing harm and protecting patients are cornerstones of nursing excellence. PMID- 25803797 TI - Applying Lean Six Sigma for innovative change to the post-anesthesia care unit. AB - Many healthcare organizations are building or renovating patient care facilities. Using Lean Six Sigma methods, nurse leaders can eliminate unnecessary waste and improve work and patient care environments. Starting with a key department like the post-anesthesia care unit is a good way to expose staff and leaders to the potential of Lean. PMID- 25803798 TI - Complexity, flow, and antifragile healthcare systems: implications for nurse executives. AB - As systems evolve over time, their natural tendency is to become increasingly more complex. Studies in the field of complex systems have generated new perspectives on the application of management strategies in health systems. Much of this research appears as a natural extension of the cross-disciplinary field of systems theory. In this article, I further discuss the concept of fragility, its impact on system behavior, and ways to reduce it. PMID- 25803799 TI - The influence of emerging administrative scientists: an interview with Anne Miller. AB - This department highlights emerging nursing leaders and scientists demonstrating promise in advancing innovation and patient care leadership in practice, policy, research, education, and theory. This interview profiles Anne Miller, PhD, BA, assistant professor jointly appointed to the Center of Interdisciplinary Health Workforce Studies and the School of Nursing at Vanderbilt University Medical Center. PMID- 25803800 TI - The perceived value of certification by Magnet(r) and non-Magnet nurses. AB - OBJECTIVE: The aim of this study is to compare the barriers to certification and the perceived value of certification by nurses in a Magnet(r)-recognized and a non-Magnet-recognized organization. BACKGROUND: Magnet recognition promotes certification as a component of professional practice. It is not known if nurses in Magnet and non-Magnet organizations hold different values toward certification. METHODS: An electronic survey obtained perceptions of certification values and barriers of nurses practicing at a Magnet-recognized facility (n = 202) and a non-Magnet-recognized facility (n = 103). RESULTS: There was no difference between nurses from a Magnet-recognized facility and nurses from a non-Magnet-recognized facility on intrinsic or extrinsic certification value perceptions. However, as a group, certified nurses reported higher intrinsic value perceptions than noncertified nurses. CONCLUSIONS: Nurses' intrinsic and extrinsic perceived values of certification do not differ by the Magnet recognition status of the facility. Strategies to improve certification rates should focus on targeting the extrinsic values of certification. PMID- 25803801 TI - The relationship between work complexity and nurses' participation in decision making in hospitals. AB - OBJECTIVE: The aim of this study is to examine the relationship between work complexity and nurses' participation in decision making in hospital nursing units. BACKGROUND: Increasing nurses' participation in decision making has been used as a way to manage work complexity; however, the work of nurses in acute care hospitals has become highly complex, and strategies used to manage this complexity have not been fully explored. METHODS: The relationship between work complexity and nurse participation in decision making was examined using data from the Outcomes Research in Nursing Administration project. The sample included 3,718 RNs in 278 medical-surgical units in 143 hospitals. RESULTS: When work complexity increased, nurses' participation in decision making decreased. CONCLUSIONS: When nurses have limited input into decision making, the information available to the care team may be incomplete. Barriers to nurses' participation in decision making should be explored and interventions developed so that nurses may be full participants in decision making affecting both patients and the work environment. PMID- 25803802 TI - Educational gaps and solutions for early-career nurse managers' education and participation in quality improvement. AB - OBJECTIVE: The objective of this study was to examine early-career frontline nurse managers' (FLNMs') reported educational preparedness and participation in quality improvement (QI). BACKGROUND: Frontline nurse managers are vitally important for leading QI. However, it is not well known if they have adequate knowledge and skills to lead this important function. METHODS: We examined cross sectional survey data from 42 FLNMs using descriptive statistics. RESULTS: About 30% of FLNMs reported being very prepared across 12 measured QI skills by schools or employers and 35% reported participating in a specific clinical effort to improve patient care on their unit more than once a month. More than 50% reported having good organizational support for QI, but only about 30% reported being rewarded for their contributions to QI. CONCLUSION: Our study highlights opportunities for development in QI for FLNMs and offers some solutions for nurse executives that can bridge the educational gaps. PMID- 25803803 TI - Clinical nurse specialists' perceptions of work patterns, outcomes, desires, and emerging trends. AB - OBJECTIVE: This study explored clinical nurse specialists' (CNSs') perceptions of work patterns, outcomes, desires, and emerging trends in practice. BACKGROUND: Clinical nurse specialists transform patient care toward high-quality, cost effective outcomes, but the role includes multiple dimensions contributing to role confusion. METHODS: Using qualitative methods, 12 CNSs were interviewed for perceptions of their role in healthcare today. Data reduction and confirmability strategies were used in data analysis. RESULTS: Work patterns included office activities, patient rounds, working with nurses, attending meetings, and supporting quality improvement initiatives. Outcomes included safer patient care, getting patients the resources they need, transforming nurses, and meeting the quality metrics. An emerging trend was increased involvement in research. CONCLUSIONS: Clinical nurse specialists perceive the role to be important in driving change and transforming nursing care towards high-quality clinical outcomes. PMID- 25803804 TI - Accuracy of harm scores entered into an event reporting system. AB - This quality improvement project evaluated the accuracy of harm scores entered into an event reporting system by inpatient nursing staff at a National Cancer Institute-designated comprehensive cancer center. Nurses scored 10 safety scenarios using 2 versions of the Agency for Healthcare Research and Quality scale to determine interrater reliability. Results indicated inconsistency in the way nurses scored the scenarios, suggesting that the event reporting system may not accurately portray the severity of harm in patient safety events. Nurse executives can use this information to guide the development and implementation of incident reporting systems. PMID- 25803805 TI - Increasing nurse certification rates using a multimodal approach. AB - The attainment of specialty nursing certification can be beneficial for nurses, patients, and the healthcare organization alike. Barriers may prevent nurses from seeking specialty certification, which may impede healthcare organizations from increasing certification rates among nursing staff. The purpose of this article is to share the process and outcomes of 1 medical center's multimodal plan designed to prepare and support nurses seeking specialty certification in pediatric nursing practice. PMID- 25803806 TI - Regulatory components of the alternative complement pathway in endothelial cell cytoplasm, factor H and factor I, are not packaged in Weibel-Palade bodies. AB - It was recently reported that factor H, a regulatory component of the alternative complement pathway, is stored with von Willebrand factor (VWF) in the Weibel Palade bodies of endothelial cells. If this were to be the case, it would have therapeutic importance for patients with the atypical hemolytic-uremic syndrome that can be caused either by a heterozygous defect in the factor H gene or by the presence of an autoantibody against factor H. The in vivo Weibel-Palade body secretagogue, des-amino-D-arginine vasopressin (DDAVP), would be expected to increase transiently the circulating factor H levels, in addition to increasing the circulating levels of VWF. We describe experiments demonstrating that factor H is released from endothelial cell cytoplasm without a secondary storage site. These experiments showed that factor H is not stored with VWF in endothelial cell Weibel-Palade bodies, and is not secreted in response in vitro in response to the Weibel-Palade body secretagogue, histamine. Furthermore, the in vivo Weibel Palade body secretagogue, DDAVP does not increase the circulating factor H levels concomitantly with DDAVP-induced increased VWF. Factor I, a regulatory component of the alternative complement pathway that is functionally related to factor H, is also located in endothelial cell cytoplasm, and is also not present in endothelial cell Weibel-Palade bodies. Our data demonstrate that the factor H and factor I regulatory proteins of the alternative complement pathway are not stored in Weibel-Palade bodies. DDAVP induces the secretion into human plasma of VWF- but not factor H. PMID- 25803807 TI - Elevated serum levels of mannose-binding lectin and diabetic nephropathy in type 2 diabetes. AB - OBJECTIVE: Inflammation and complement activation initiated by mannose-binding lectin (MBL) may be implicated in the pathogenesis of diabetic vascular complications. We investigated serum MBL levels in type 2 diabetes with diabetic nephropathy (DN) and with persistent normoalbuminuria. METHOD: Serum MBL levels were determined in 242 type 2 diabetes with overt nephropathy and 242 type 2 diabetes with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The prediction value of MBL was compared with HbA1c, Hs-CRP and with other known predictors. Multivariate analyses were performed using logistic regression models. RESULTS: The serum MBL levels were significantly higher in diabetes with DN as compared to with persistent normoalbuminuria (P<0.0001). Multivariate logistic regression analysis adjusted for common factors showed that serum MBL levels>=2950ug/L was an independent indictor of DN (OR=7.55; 95%CI: 3.44-19.04). Based on the ROC curve, the optimal cutoff value of serum MBL levels as an indicator for diagnosis of DN was projected to be 2950ug/L, which yielded a sensitivity of 77.2% and a specificity of 80.8%, with the area under the curve at 0.809 (95%CI, 0.769 0.848). CONCLUSION: Our findings suggested that MBL may be involved in the pathogenesis of DN in type 2 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing nephropathy complications. PMID- 25803808 TI - Programmed death 1 regulates memory phenotype CD4 T cell accumulation, inhibits expansion of the effector memory phenotype subset and modulates production of effector cytokines. AB - Memory phenotype CD4 T cells are found in normal mice and arise through response to environmental antigens or homeostatic mechanisms. The factors that regulate the homeostasis of memory phenotype CD4 cells are not clear. In the present study we demonstrate that there is a marked accumulation of memory phenotype CD4 cells, specifically of the effector memory (T(EM)) phenotype, in lymphoid organs and tissues of mice deficient for the negative co-stimulatory receptor programmed death 1 (PD-1). This can be correlated with decreased apoptosis but not with enhanced homeostatic turnover potential of these cells. PD-1 ablation increased the frequency of memory phenotype CD4 IFN-gamma producers but decreased the respective frequency of IL-17A-producing cells. In particular, IFN-gamma producers were more abundant but IL-17A producing cells were more scarce among PD 1 KO T(EM)-phenotype cells relative to WT. Transfer of peripheral naive CD4 T cells suggested that accumulated PD-1 KO T(EM)-phenotype cells are of peripheral and not of thymic origin. This accumulation effect was mediated by CD4 cell intrinsic mechanisms as shown by mixed bone marrow chimera experiments. Naive PD 1 KO CD4 T cells gave rise to higher numbers of TEM-phenotype lymphopenia-induced proliferation memory cells. In conclusion, we provide evidence that PD-1 has an important role in determining the composition and functional aspects of memory phenotype CD4 T cell pool. PMID- 25803809 TI - Regional gray matter density associated with cognitive reflectivity-impulsivity: evidence from voxel-based morphometry. AB - When faced with a problem or choice, humans can use two different strategies: "cognitive reflectivity," which involves slow responses and fewer mistakes, or "cognitive impulsivity," which comprises of quick responses and more mistakes. Different individuals use these two strategies differently. To our knowledge, no study has directly investigated the brain regions involved in reflectivity impulsivity; therefore, this study focused on associations between these cognitive strategies and the gray matter structure of several brain regions. In order to accomplish this, we enrolled 776 healthy, right-handed individuals (432 men and 344 women; 20.7 +/- 1.8 years) and used voxel-based morphometry with administration of a cognitive reflectivity-impulsivity questionnaire. We found that high cognitive reflectivity was associated with greater regional gray matter density in the ventral medial prefrontal cortex. Our finding suggests that this area plays an important role in defining an individual's trait associated with reflectivity and impulsivity. PMID- 25803810 TI - Potentiation of epidermal growth factor-mediated oncogenic transformation by sialidase NEU3 leading to Src activation. AB - We previously demonstrated that sialidase NEU3, a key glycosidase for ganglioside degradation, is up-regulated in various human cancers, leading to increased cell invasion, motility and survival of cancer cells possibly through activation of EGF signaling. Its up-regulation is also important for promotion of the stage of colorectal carcinogenesis in vivo in human NEU3 transgenic mice treated with azoxymethane for the induction of aberrant crypt foci in the colon mucosa, accompanied by enhanced phosphorylation of EGF receptor (EGFR). To address whether the activation of EGF signaling by the sialidase is associated with oncogenic transformation, we here analyzed the effects of overexpression of NEU3 and EGFR in NIH-3T3 cells. When NEU3 was stably transfected with or without EGFR, it was associated with significant increases in clonogenic growth, clonogenicity on soft agar and in vivo tumor growth in nude mice either with or without the receptor overexpression in the presence of EGF, compared with the levels in their vector controls. Despite the fact that the endogenous level of EGFR is known to be extremely low in these cells, NEU3 significantly enhanced the phosphorylation of Akt and ERK, as well as that of the receptor. The NEU3-mediated activation was largely abrogated by the EGFR inhibitor AG1478 or PD153035, but significant clonogenic growth still remained. NEU3 was then found to activate Src kinase, and the clonogenicity was completely suppressed by an Src inhibitor, PP2. The activity-null mutants failed to activate Src and EGFR, indicating that ganglioside modulation by NEU3 may be necessary for the activation. NEU3 and Src were co-immunoprecipitated with EGFR in NEU3- and EGFR- transfected cells. These findings identify NEU3 as an essential participant in tumorigenesis through the EGFR/Src signaling pathway and a potential target for inhibiting EGFR-mediated tumor progression. PMID- 25803811 TI - Screening of drugs to treat 8p11 myeloproliferative syndrome using patient derived induced pluripotent stem cells with fusion gene CEP110-FGFR1. AB - Induced pluripotent stem (iPS) cells provide powerful tools for studying disease mechanisms and developing therapies for diseases. The 8p11 myeloproliferative syndrome (EMS) is an aggressive chronic myeloproliferative disorder (MPD) that is caused by constitutive activation of fibroblast growth factor receptor 1. EMS is rare and, consequently, effective treatment for this disease has not been established. Here, iPS cells were generated from an EMS patient (EMS-iPS cells) to assist the development of effective therapies for EMS. When iPS cells were co cultured with murine embryonic stromal cells, EMS-iPS cells produced more hematopoietic progenitor and hematopoietic cells, and CD34+ cells derived from EMS-iPS cells exhibited 3.2-7.2-fold more macrophage and erythroid colony forming units (CFUs) than those derived from control iPS cells. These data indicate that EMS-iPS cells have an increased hematopoietic differentiation capacity, which is characteristic of MPDs. To determine whether a tyrosine kinase inhibitor (TKI) could suppress the increased number of CFUs formed by EMS-iPS-induced CD34+ cells, cells were treated with one of four TKIs (CHIR258, PKC 412, ponatinib, and imatinib). CHIR258, PKC 412, and ponatinib reduced the number of CFUs formed by EMS-iPS-induced CD34+ cells in a dose-dependent manner, whereas imatinib did not. Similar effects were observed on primary peripheral blood cells (more than 90% of which were blasts) isolated from the patient. This study provides evidence that the EMS-iPS cell line is a useful tool for the screening of drugs to treat EMS and to investigate the mechanism underlying this disease. PMID- 25803813 TI - Enhanced ferroelectric-nanocrystal-based hybrid photocatalysis by ultrasonic-wave generated piezophototronic effect. AB - An electric field built inside a crystal was proposed to enhance photoinduced carrier separation for improving photocatalytic property of semiconductor photocatalysts. However, a static built-in electric field can easily be saturated by the free carriers due to electrostatic screening, and the enhancement of photocatalysis, thus, is halted. To overcome this problem, here, we propose sonophotocatalysis based on a new hybrid photocatalyst, which combines ferroelectric nanocrystals (BaTiO3) and semiconductor nanoparticles (Ag2O) to form an Ag2O-BaTiO3 hybrid photocatalyst. Under periodic ultrasonic excitation, a spontaneous polarization potential of BaTiO3 nanocrystals in responding to ultrasonic wave can act as alternating built-in electric field to separate photoinduced carriers incessantly, which can significantly enhance the photocatalytic activity and cyclic performance of the Ag2O-BaTiO3 hybrid structure. The piezoelectric effect combined with photoelectric conversion realizes an ultrasonic-wave-driven piezophototronic process in the hybrid photocatalyst, which is the fundamental of sonophotocatalysis. PMID- 25803814 TI - Identifying the environmental conditions favouring West Nile Virus outbreaks in Europe. AB - West Nile Virus (WNV) is a globally important mosquito borne virus, with significant implications for human and animal health. The emergence and spread of new lineages, and increased pathogenicity, is the cause of escalating public health concern. Pinpointing the environmental conditions that favour WNV circulation and transmission to humans is challenging, due both to the complexity of its biological cycle, and the under-diagnosis and reporting of epidemiological data. Here, we used remote sensing and GIS to enable collation of multiple types of environmental data over a continental spatial scale, in order to model annual West Nile Fever (WNF) incidence across Europe and neighbouring countries. Multi model selection and inference were used to gain a consensus from multiple linear mixed models. Climate and landscape were key predictors of WNF outbreaks (specifically, high precipitation in late winter/early spring, high summer temperatures, summer drought, occurrence of irrigated croplands and highly fragmented forests). Identification of the environmental conditions associated with WNF outbreaks is key to enabling public health bodies to properly focus surveillance and mitigation of West Nile virus impact, but more work needs to be done to enable accurate predictions of WNF risk. PMID- 25803817 TI - Analysis of the hypersensitivity of the (29)Si NMR chemical shift of the pentacoordinate silicon compounds to the temperature effect. N (Silylmethyl)acetamides. AB - Theoretical investigation of the phenomenon of hypersensitivity of the (29)Si NMR chemical shift, delta, in the pentacoordinate silicon compounds to the temperature effect has been performed by the example of N-(silylmethyl)acetamides MeC(O)NMeCH2SiX3 (X = Me, 1; OMe, 2; F, 3) and MeC(O)NMeCH2SiMe2F (4) with the use of experimental dynamic NMR (DNMR) (29)Si data. It is based on the following: (i) the analysis of the potential energy surface of molecules 1-4 in polar solvents and the energetics of interconversion between their possible isomeric forms; (ii) the calculations of delta at different temperatures taking into account the dependence of the dielectric constant (epsilon) of the medium on T, and (iii) the isolation of dynamic, geometrical, and polar contributions to the temperature drift of delta. The results obtained allowed us to give a consistent explanation of the DNMR (29)Si spectra of acetamides 1-4 and to elucidate the nature of an unusual effect of T on delta. PMID- 25803815 TI - Field application of SD bioline malaria Ag Pf/Pan rapid diagnostic test for malaria in Greece. AB - Greece, a malaria-free country since 1974, has experienced re-emergence of Plasmodium vivax autochthonous malaria cases in some agriculture areas over the last three years. In early 2012, an integrated control programme (MALWEST Project) was launched in order to prevent re-establishment of the disease. In the context of this project, the rapid diagnostic tests (RDT) of SD Bioline Malaria Ag Pf/Pan that detects hrp-2 and pan-LDH antigens were used. The aim of this study was to assess the field application of the RDT for the P. vivax diagnosis in comparison to light microscopy and polymerase chain reaction (PCR). A total of 955 samples were tested with all three diagnostic tools. Agreement of RDT against microscopy and PCR for the diagnosis of P. vivax was satisfactory (K value: 0.849 and 0.976, respectively). The sensitivity, specificity and positive predictive value of RDT against PCR was 95.6% (95% C.I.: 84.8-99.3), 100% (95% C.I.: 99.6 100.0) and 100% (95% CI: 91.7-100.0) respectively, while the sensitivity, specificity and positive predictive value of RDT against microscopic examination was 97.4% (95% C.I.: 86.1-99.6), 99.4% (95% C.I.: 98.6-99.8) and 86.1% (95% CI: 72.1-94.7), respectively. Our results indicate that RDT performed satisfactory in a non-endemic country and therefore is recommended for malaria diagnosis, especially in areas where health professionals lack experience on light microscopy. PMID- 25803816 TI - Anaplastic lymphoma kinase gene copy number gain in inflammatory breast cancer (IBC): prevalence, clinicopathologic features and prognostic implication. AB - BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, and its molecular pathogenesis still remains to be elucidated. This study aimed to evaluate the prevalence and implication of anaplastic lymphoma kinase (ALK) copy number change in IBC patients. METHODS: We retrospectively collected formalin-fixed, paraffin-embedded tumor tissues and medical records of IBC patients from several institutes in Korea. ALK gene copy number change and rearrangement were assessed by fluorescence in situ hybridization (FISH) assay, and ALK expression status was evaluated by immunohistochemical (IHC) staining. RESULTS: Thirty-six IBC patients including those with HER2 (+) breast cancer (16/36, 44.4%) and triple-negative breast cancer (13/36, 36.1%) were enrolled in this study. ALK copy number gain (CNG) was observed in 47.2% (17/36) of patients, including one patient who harbored ALK gene amplification. ALK CNG (+) patients showed significantly worse overall survival compared to ALK CNG (-) patients in univariate analysis (24.9 months vs. 38.1 months, p = 0.033). Recurrence free survival (RFS) after curative mastectomy was also significantly shorter in ALK CNG (+) patients than in ALK CNG (-) patients (n = 22, 12.7 months vs. 43.3 months, p = 0.016). Multivariate Cox regression analysis with adjustment for HER2 and ER statuses showed significantly poorer RFS for ALK CNG (+) patients (HR 5.63, 95% CI 1.11-28.44, p = 0.037). CONCLUSION: This study shows a significant presence of ALK CNG in IBC patients, and ALK CNG was associated with significantly poorer RFS. PMID- 25803819 TI - Regional personality differences in Great Britain. AB - Recent investigations indicate that personality traits are unevenly distributed geographically, with some traits being more prevalent in certain places than in others. The geographical distributions of personality traits are associated with a range of important political, economic, social, and health outcomes. The majority of research on this subject has focused on the geographical distributions and macro-level correlates of personality across nations or regions of the United States. The aim of the present investigation was to replicate and extend that past work by examining regional personality differences in Great Britain. Using a sample of nearly 400,000 British residents, we mapped the geographical distributions of the Big Five Personality traits across 380 Local Authority Districts and examined the associations with important political, economic, social, and health outcomes. The results revealed distinct geographical clusters, with neighboring regions displaying similar personality characteristics, and robust associations with the macro-level outcome variables. Overall, the patterns of results were similar to findings from past research. PMID- 25803818 TI - Methylation-associated partial down-regulation of mesothelin causes resistance to anti-mesothelin immunotoxins in a pancreatic cancer cell line. AB - Anti-mesothelin Pseudomonas exotoxin A-based recombinant immunotoxins (RITs) present a potential treatment modality for pancreatic ductal adenocarcinoma (PDAC). To study mechanisms of resistance, the sensitive PDAC cell line KLM-1 was intermittently exposed to the anti-mesothelin SS1-LR-GGS RIT. Surviving cells were resistant to various anti-mesothelin RITs (IC50s >1 MUg/ml), including the novel de-immunized RG7787. These resistant KLM-1-R cells were equally sensitive to the anti-CD71 HB21(Fv)-PE40 RIT as KLM-1, indicating resistance was specific to anti-mesothelin RITs. Mesothelin gene expression was partially down-regulated in KLM-1-R, resulting in 5-fold lower surface protein levels and decreased cellular uptake of RG7787 compared to KLM-1. Bisulfite sequencing analysis found that the mesothelin promoter region was significantly more methylated in KLM-1-R (59 +/- 3.6%) compared to KLM-1 (41 +/- 4.8%), indicating hypermethylation as a mechanism of mesothelin downregulation. The DNA methyltransferase inhibitor 5 azacytidine restored original mesothelin surface expression to more than half in KLM-1-R and increased sensitivity to RG7787 (IC50 = 722.4 +/- 232.6 ng/ml), although cells remained significantly less sensitive compared to parental KLM-1 cells (IC50 = 4.41 +/- 0.38 ng/ml). Mesothelin cDNA introduction in KLM-1-R led to 5-fold higher surface protein levels and significantly higher RG7887 uptake compared to KLM-1. As a result, the original sensitivity to RG7787 was fully restored (IC50 = 4.49 +/- 1.11 ng/ml). A significantly higher RG7787 uptake was thus required to reach the original cytotoxicity in resistant cells, hinting that intracellular RIT trafficking is also a limiting factor. RNA deep sequencing analysis of KLM-1 and KLM-1-R cells supported our experimental findings; compared to KLM-1, resistant cells displayed differential expression of genes linked to intracellular transport and an expression pattern that matched a more general hypermethylation status. In conclusion, resistance to anti-mesothelin RITs in KLM 1 is linked to a methylation-associated down-regulation of mesothelin, while aberrations in RIT trafficking could also play a role. PMID- 25803820 TI - MiR-20a promotes cervical cancer proliferation and metastasis in vitro and in vivo. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that are critical regulators of various diseases. MicroRNA-20a (miR-20a) has previously significantly altered in a range of cancers. In this study, we detected the relationship between miR-20a and the development of cervical cancer by qRT-PCR, we found that the expression level of miR-20a was significantly higher in cervical cancer patients than in normal controls, the aberrant expression of miR-20a was correlated with lymph node metastasis, histological grade and tumor diameter. Then we successfully established the stable anti-miR-20a cervical cancer cell lines by lentivirus. Inhibited miR-20a prevented tumor progression by modulating cell cycle, apoptosis, and metastasis in vitro and in vivo. TIMP2 and ATG7 were proved to be direct targets of miR-20a, using luciferase assay and western blot. These results indicate that miR-20a suppresses the proliferation, migration and invasion of cervical cancer cell through targeting ATG7 and TIMP2. Our results support the involvement of miR-20a in cervical tumorigenesis, especially lymph node metastasis. We propose that miRNAs might be used as therapeutic agent for cervical cancer. PMID- 25803822 TI - Of ammonia and orotic acid and their importance for clinical neuropediatrics. PMID- 25803823 TI - Optical coherence tomography opens a new era in the afferent visual system evaluation. PMID- 25803821 TI - ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines. AB - The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple negative (TN) breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation. Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies. PMID- 25803812 TI - A new set of ESTs from chickpea (Cicer arietinum L.) embryo reveals two novel F box genes, CarF-box_PP2 and CarF-box_LysM, with potential roles in seed development. AB - Considering the economic importance of chickpea (C. arietinum L.) seeds, it is important to understand the mechanisms underlying seed development for which a cDNA library was constructed from 6 day old chickpea embryos. A total of 8,186 ESTs were obtained from which 4,048 high quality ESTs were assembled into 1,480 unigenes that majorly encoded genes involved in various metabolic and regulatory pathways. Of these, 95 ESTs were found to be involved in ubiquitination related protein degradation pathways and 12 ESTs coded specifically for putative F-box proteins. Differential transcript accumulation of these putative F-box genes was observed in chickpea tissues as evidenced by quantitative real-time PCR. Further, to explore the role of F-box proteins in chickpea seed development, two F-box genes were selected for molecular characterization. These were named as CarF box_PP2 and CarF-box_LysM depending on their C-terminal domains, PP2 and LysM, respectively. Their highly conserved structures led us to predict their target substrates. Subcellular localization experiment revealed that CarF-box_PP2 was localized in the cytoplasm and CarF-box_LysM was localized in the nucleus. We demonstrated their physical interactions with SKP1 protein, which validated that they function as F-box proteins in the formation of SCF complexes. Sequence analysis of their promoter regions revealed certain seed specific cis-acting elements that may be regulating their preferential transcript accumulation in the seed. Overall, the study helped in expanding the EST database of chickpea, which was further used to identify two novel F-box genes having a potential role in seed development. PMID- 25803824 TI - Applications of optical coherence tomography in pediatric clinical neuroscience. AB - For nearly two centuries, the ophthalmoscope has permitted examination of the retina and optic nerve-the only axons directly visualized by the physician. The retinal ganglion cells project their axons, which travel along the innermost retina to form the optic nerve, marking the beginning of the anterior visual pathway. Both the structure and function of the visual pathway are essential components of the neurologic examination as it can be involved in numerous acquired, congenital and genetic central nervous system conditions. The development of optical coherence tomography now permits the pediatric neuroscientist to visualize and quantify the optic nerve and retinal layers with unprecedented resolution. As optical coherence tomography becomes more accessible and integrated into research and clinical care, the pediatric neuroscientist may have the opportunity to utilize and/or interpret results from this device. This review describes the basic technical features of optical coherence tomography and highlights its potential clinical and research applications in pediatric clinical neuroscience including optic nerve swelling, optic neuritis, tumors of the visual pathway, vigabatrin toxicity, nystagmus, and neurodegenerative conditions. PMID- 25803826 TI - Use of genome-wide association studies for cancer research and drug repositioning. AB - Although genome-wide association studies have identified many risk loci associated with colorectal cancer, the molecular basis of these associations are still unclear. We aimed to infer biological insights and highlight candidate genes of interest within GWAS risk loci. We used an in silico pipeline based on functional annotation, quantitative trait loci mapping of cis-acting gene, PubMed text-mining, protein-protein interaction studies, genetic overlaps with cancer somatic mutations and knockout mouse phenotypes, and functional enrichment analysis to prioritize the candidate genes at the colorectal cancer risk loci. Based on these analyses, we observed that these genes were the targets of approved therapies for colorectal cancer, and suggested that drugs approved for other indications may be repurposed for the treatment of colorectal cancer. This study highlights the use of publicly available data as a cost effective solution to derive biological insights, and provides an empirical evidence that the molecular basis of colorectal cancer can provide important leads for the discovery of new drugs. PMID- 25803825 TI - Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity. AB - Immunological heterogeneity has long been the major challenge in developing broadly effective vaccines to protect humans and animals against bacterial and viral infections. Enterotoxigenic Escherichia coli (ETEC) strains, the leading bacterial cause of diarrhea in humans, express at least 23 immunologically different colonization factor antigens (CFAs) and two distinct enterotoxins [heat labile toxin (LT) and heat-stable toxin type Ib (STa or hSTa)]. ETEC strains expressing any one or two CFAs and either toxin cause diarrhea, therefore vaccines inducing broad immunity against a majority of CFAs, if not all, and both toxins are expected to be effective against ETEC. In this study, we applied the multiepitope fusion antigen (MEFA) strategy to construct ETEC antigens and examined antigens for broad anti-CFA and antitoxin immunogenicity. CFA MEFA CFA/I/II/IV [CVI 2014, 21(2):243-9], which carried epitopes of seven CFAs [CFA/I, CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)] expressed by the most prevalent and virulent ETEC strains, was genetically fused to LT-STa toxoid fusion monomer 3xSTaA14Q-dmLT or 3xSTaN12S-dmLT [IAI 2014, 82(5):1823-32] for CFA/I/II/IV STaA14Q-dmLT and CFA/I/II/IV-STaN12S-dmLT MEFAs. Mice intraperitoneally immunized with either CFA/I/II/IV-STa-toxoid-dmLT MEFA developed antibodies specific to seven CFAs and both toxins, at levels equivalent or comparable to those induced from co-administration of the CFA/I/II/IV MEFA and toxoid fusion 3xSTaN12S-dmLT. Moreover, induced antibodies showed in vitro adherence inhibition activities against ETEC or E. coli strains expressing these seven CFAs and neutralization activities against both toxins. These results indicated CFA/I/II/IV-STa-toxoid dmLT MEFA or CFA/I/II/IV MEFA combined with 3xSTaN12S-dmLT induced broadly protective anti-CFA and antitoxin immunity, and suggested their potential application in broadly effective ETEC vaccine development. This MEFA strategy may be generally used in multivalent vaccine development. PMID- 25803829 TI - Understanding bond formation in polar one-step reactions. Topological analyses of the reaction between nitrones and lithium ynolates. AB - The mechanism of the reaction between nitrones and lithium ynolates has been studied using DFT methods at the M06-2X/cc-pVTZ/PCM=THF level. After the formation of a starting complex an without energy barrier, in which the lithium atom is coordinated to both nitrone and ynolate, the reaction takes place in one single kinetic step through a single transition structure. However, the formation of C-C and C-O bonds takes place sequentially through a typical two-stage, one step process. A combined study of noncovalent interactions (NCIs) and electron localization function (ELFs) of selected points along the intrinsic reaction coordinate (IRC) of the reaction confirmed that, in the transition structure, only the C-C bond is being formed to some extent, whereas an electrostatic interaction is present between carbon and oxygen atoms previous to the formation of the C-O bond. Indeed, the formation of the second C-O bond only begins when the first C-C bond is completely formed without formation of any intermediate. Once the C-C bond is formed and before the C-O bond formation starts the RMS gradient norm dips, approaching but not reaching 0, giving rise to a hidden intermediate. PMID- 25803827 TI - Cadherin expression, vectorial active transport, and metallothionein isoform 3 mediated EMT/MET responses in cultured primary and immortalized human proximal tubule cells. AB - BACKGROUND: Cultures of human proximal tubule cells have been widely utilized to study the role of EMT in renal disease. The goal of this study was to define the role of growth media composition on classic EMT responses, define the expression of E- and N-cadherin, and define the functional epitope of MT-3 that mediates MET in HK-2 cells. METHODS: Immunohistochemistry, microdissection, real-time PCR, western blotting, and ELISA were used to define the expression of E- and N cadherin mRNA and protein in HK-2 and HPT cell cultures. Site-directed mutagenesis, stable transfection, measurement of transepithelial resistance and dome formation were used to define the unique amino acid sequence of MT-3 associated with MET in HK-2 cells. RESULTS: It was shown that both E- and N cadherin mRNA and protein are expressed in the human renal proximal tubule. It was shown, based on the pattern of cadherin expression, connexin expression, vectorial active transport, and transepithelial resistance, that the HK-2 cell line has already undergone many of the early features associated with EMT. It was shown that the unique, six amino acid, C-terminal sequence of MT-3 is required for MT-3 to induce MET in HK-2 cells. CONCLUSIONS: The results show that the HK-2 cell line can be an effective model to study later stages in the conversion of the renal epithelial cell to a mesenchymal cell. The HK-2 cell line, transfected with MT-3, may be an effective model to study the process of MET. The study implicates the unique C-terminal sequence of MT-3 in the conversion of HK-2 cells to display an enhanced epithelial phenotype. PMID- 25803830 TI - The development of a plant risk evaluation (PRE) tool for assessing the invasive potential of ornamental plants. AB - Weed Risk Assessment (WRA) methods for evaluating invasiveness in plants have evolved rapidly in the last two decades. Many WRA tools exist, but none were specifically designed to screen ornamental plants prior to being released into the environment. To be accepted as a tool to evaluate ornamental plants for the nursery industry, it is critical that a WRA tool accurately predicts non invasiveness without falsely categorizing them as invasive. We developed a new Plant Risk Evaluation (PRE) tool for ornamental plants. The 19 questions in the final PRE tool were narrowed down from 56 original questions from existing WRA tools. We evaluated the 56 WRA questions by screening 21 known invasive and 14 known non-invasive ornamental plants. After statistically comparing the predictability of each question and the frequency the question could be answered for both invasive and non-invasive species, we eliminated questions that provided no predictive power, were irrelevant in our current model, or could not be answered reliably at a high enough percentage. We also combined many similar questions. The final 19 remaining PRE questions were further tested for accuracy using 56 additional known invasive plants and 36 known non-invasive ornamental species. The resulting evaluation demonstrated that when "needs further evaluation" classifications were not included, the accuracy of the model was 100% for both predicting invasiveness and non-invasiveness. When "needs further evaluation" classifications were included as either false positive or false negative, the model was still 93% accurate in predicting invasiveness and 97% accurate in predicting non-invasiveness, with an overall accuracy of 95%. We conclude that the PRE tool should not only provide growers with a method to accurately screen their current stock and potential new introductions, but also increase the probability of the tool being accepted for use by the industry as the basis for a nursery certification program. PMID- 25803828 TI - Prevention of biofilm formation and removal of existing biofilms by extracellular DNases of Campylobacter jejuni. AB - The fastidious nature of the foodborne bacterial pathogen Campylobacter jejuni contrasts with its ability to survive in the food chain. The formation of biofilms, or the integration into existing biofilms by C. jejuni, is thought to contribute to food chain survival. As extracellular DNA (eDNA) has previously been proposed to play a role in C. jejuni biofilms, we have investigated the role of extracellular DNases (eDNases) produced by C. jejuni in biofilm formation. A search of 2791 C. jejuni genomes highlighted that almost half of C. jejuni genomes contains at least one eDNase gene, but only a minority of isolates contains two or three of these eDNase genes, such as C. jejuni strain RM1221 which contains the cje0256, cje0566 and cje1441 eDNase genes. Strain RM1221 did not form biofilms, whereas the eDNase-negative strains NCTC 11168 and 81116 did. Incubation of pre-formed biofilms of NCTC 11168 with live C. jejuni RM1221 or with spent medium from a RM1221 culture resulted in removal of the biofilm. Inactivation of the cje1441 eDNase gene in strain RM1221 restored biofilm formation, and made the mutant unable to degrade biofilms of strain NCTC 11168. Finally, C. jejuni strain RM1221 was able to degrade genomic DNA from C. jejuni NCTC 11168, 81116 and RM1221, whereas strain NCTC 11168 and the RM1221 cje1441 mutant were unable to do so. This was mirrored by an absence of eDNA in overnight cultures of C. jejuni RM1221. This suggests that the activity of eDNases in C. jejuni affects biofilm formation and is not conducive to a biofilm lifestyle. These eDNases do however have a potential role in controlling biofilm formation by C. jejuni strains in food chain relevant environments. PMID- 25803833 TI - Charge Hopping Dynamics along a Disordered Chain in Quantum Environments: Comparative Study of Different Rate Kernels. AB - This work presents a computational study of charge hopping dynamics along a one dimensional chain with Gaussian site energy disorder and linearly coupled quantum bath. Time-dependent square displacements are calculated directly from numerical solutions of Pauli master equations, for five different rate kernels: exact Fermi golden rule (FGR) rate expression, stationary phase interpolation (SPI) approximation, semiclassical (SC) approximation, classical Marcus rate expression, and Miller-Abrahams expression. All results demonstrate diffusive behavior in the steady state limit. The results based on the FGR rate expression show that the charge transport in the quantum bath can be much more sensitive to the disorder than the prediction from the classical Marcus expression. While the SPI approximation captures this general trend reasonably well, the SC approximation tends to be unreliable at both quantitative and qualitative levels and becomes even worse than the classical Marcus expression under certain conditions. These results offer useful guidance in the choice of approximate rate kernels for larger-scale simulations and also demonstrate significant but fragile positive effects of quantum environments on the charge hopping dynamics. PMID- 25803832 TI - Host phenology and geography as drivers of differentiation in generalist fungal mycoparasites. AB - The question as to why parasites remain generalist or become specialist is a key unresolved question in evolutionary biology. Ampelomyces spp., intracellular mycoparasites of powdery mildew fungi, which are themselves plant pathogens, are a useful model for studies of this issue. Ampelomyces is used for the biological control of mildew. Differences in mycohost phenology promote temporal isolation between sympatric Ampelomyces mycoparasites. Apple powdery mildew (APM) causes spring epidemics, whereas other powdery mildew species on plants other than apple cause epidemics later in the season. This has resulted in genetic differentiation between APM and non-APM strains. It is unclear whether there is genetic differentiation between non-APM Ampelomyces lineages due to their specialization on different mycohosts. We used microsatellites to address this question and found no significant differentiation between non-APM Ampelomyces strains from different mycohosts or host plants, but strong differentiation between APM and non-APM strains. A geographical structure was revealed in both groups, with differences between European countries, demonstrating restricted dispersal at the continent scale and a high resolution for our markers. We found footprints of recombination in both groups, possibly more frequent in the APM cluster. Overall, Ampelomyces thus appears to be one of the rare genuine generalist pathogenic fungi able to parasitize multiple hosts in natural populations. It is therefore an excellent model for studying the evolution of pathogens towards a generalist rather than host-specific strategy, particularly in light of the tritrophic interaction between Ampelomyces mycoparasites, their powdery mildew fungal hosts and the mildew host plants. PMID- 25803834 TI - Universal Length Dependence of Rod-to-Seed Exciton Localization Efficiency in Type I and Quasi-Type II CdSe@CdS Nanorods. AB - A critical step involved in many applications of one-dimensional seeded CdSe@CdS nanorods, such as luminescent solar concentrators, optical gains, and photocatalysis, is the localization of excitons from the light-harvesting CdS nanorod antenna into the light-emitting CdSe quantum dot seed. We report that the rod-to-seed exciton localization efficiency decreases with the rod length but is independent of band alignment between the CdSe seed and CdS rod. This universal dependence can be well modeled by the competition between exciton one-dimensional diffusion to the CdSe seed and trapping on the CdS rod. This finding provides a rational approach for optimizing these materials for their various device applications. PMID- 25803831 TI - ATG18 and FAB1 are involved in dehydration stress tolerance in Saccharomyces cerevisiae. AB - Recently, different dehydration-based technologies have been evaluated for the purpose of cell and tissue preservation. Although some early results have been promising, they have not satisfied the requirements for large-scale applications. The long experience of using quantitative trait loci (QTLs) with the yeast Saccharomyces cerevisiae has proven to be a good model organism for studying the link between complex phenotypes and DNA variations. Here, we use QTL analysis as a tool for identifying the specific yeast traits involved in dehydration stress tolerance. Three hybrids obtained from stable haploids and sequenced in the Saccharomyces Genome Resequencing Project showed intermediate dehydration tolerance in most cases. The dehydration resistance trait of 96 segregants from each hybrid was quantified. A smooth, continuous distribution of the anhydrobiosis tolerance trait was found, suggesting that this trait is determined by multiple QTLs. Therefore, we carried out a QTL analysis to identify the determinants of this dehydration tolerance trait at the genomic level. Among the genes identified after reciprocal hemizygosity assays, RSM22, ATG18 and DBR1 had not been referenced in previous studies. We report new phenotypes for these genes using a previously validated test. Finally, our data illustrates the power of this approach in the investigation of the complex cell dehydration phenotype. PMID- 25803836 TI - Space-Time Covariation of Mortality with Temperature: A Systematic Study of Deaths in France, 1968-2009. AB - BACKGROUND: The temperature-mortality relationship has repeatedly been found, mostly in large cities, to be U/J-shaped, with higher minimum mortality temperature (MMT) at low latitudes being interpreted as indicating human adaptation to climate. OBJECTIVES: Our aim was to partition space with a high resolution grid to assess the temperature-mortality relationship in a territory with wide climate diversity, over a period with notable climate warming. METHODS: The 16,487,668 death certificates of persons > 65 years of age who died of natural causes in continental France (1968-2009) were analyzed. A 30-km * 30-km grid was placed over the map of France. Generalized additive model regression was used to assess the temperature-mortality relationship for each grid square, and extract the MMT and the RM25 and RM25/18 (respectively, the ratios of mortality at 25 degrees C/MMT and 25 degrees C/18 degrees C). Three periods were considered: 1968-1981 (P1), 1982-1995 (P2), and 1996-2009 (P3). RESULTS: All temperature-mortality curves computed over the 42-year period were U/J-shaped. MMT and mean summer temperature were strongly correlated. Mean MMT increased from 17.5 degrees C for P1 to 17.8 degrees C for P2 and to 18.2 degrees C for P3 and paralleled the summer temperature increase observed between P1 and P3. The temporal MMT rise was below that expected from the geographic analysis. The RM25/18 ratio of mortality at 25 degrees C versus that at 18 degrees C declined significantly (p = 5 * 10-5) as warming increased: 18% for P1, 16% for P2, and 15% for P3. CONCLUSIONS: Results of this spatiotemporal analysis indicated some human adaptation to climate change, even in rural areas. PMID- 25803838 TI - Analysis of oligomer proanthocyanidins in different barley genotypes using high performance liquid chromatography-fluorescence detection-mass spectrometry and near-infrared methodologies. AB - Proanthocyanidins are a class of polyphenols present in many foodstuffs (i.e., tea, cocoa, berries, etc.) that may reduce the risk of several chronic diseases. Barley, with sorghum, rice, and wheat, are the only cereals that contain these compounds. Because of that, two barley genotypes, named waxy and non-waxy, were analyzed by normal-phase high-performance liquid chromatography-fluorescence detection-mass spectrometry (NP-HPLC-FLD-MS). Total proanthocyanidin content ranged between 293.2 and 652.6 MUg/g of flour. Waxy samples reported the highest content (p < 0.05) of proanthocyanidins. Dimer compounds were the principal proanthocyanidin constituents of barley samples. Moreover, the possibility to use near-infrared (NIR) spectroscopy as a rapid method to discriminate between waxy and non-waxy samples and to predict quantitatively proanthocyanidins in barley samples was evaluated. Partial least squares (PLS) models were built to predict the proanthocyanidin constituent, obtaining determination coefficients (R(2)) ranging from 0.92 to 0.97, in test set validation. Because of that, this study highlights that NIR spectroscopy technology with multivariate calibration analysis could be successfully applied as a rapid method to determine proanthocyanidin content in barley. PMID- 25803835 TI - Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. AB - Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia. PMID- 25803839 TI - The human footprint in Mexico: physical geography and historical legacies. AB - Using publicly available data on land use and transportation corridors we calculated the human footprint index for the whole of Mexico to identify large scale spatial patterns in the anthropogenic transformation of the land surface. We developed a map of the human footprint for the whole country and identified the ecological regions that have most transformed by human action. Additionally, we analyzed the extent to which (a) physical geography, expressed spatially in the form of biomes and ecoregions, compared to (b) historical geography, expressed as the spatial distribution of past human settlements, have driven the patterns of human modification of the land. Overall Mexico still has 56% of its land surface with low impact from human activities, but these areas are not evenly distributed. The lowest values are on the arid north and northwest, and the tropical southeast, while the highest values run along the coast of the Gulf of Mexico and from there inland along an east-to-west corridor that follows the Mexican transversal volcanic ranges and the associated upland plateau. The distribution of low- and high footprint areas within ecoregions forms a complex mosaic: the generally well-conserved Mexican deserts have some highly transformed agro-industrial areas, while many well-conserved, low footprint areas still persist in the highly-transformed ecoregions of central Mexico. We conclude that the spatial spread of the human footprint in Mexico is both the result of the limitations imposed by physical geography to human development at the biome level, and, within different biomes, of a complex history of past civilizations and technologies, including the 20th Century demographic explosion but also the spatial pattern of ancient settlements that were occupied by the Spanish Colony. PMID- 25803840 TI - Diurnal and seasonal variations in carbon dioxide exchange in ecosystems in the Zhangye oasis area, Northwest China. AB - Quantifying carbon dioxide exchange and understanding the response of key environmental factors in various ecosystems are critical to understanding regional carbon budgets and ecosystem behaviors. For this study, CO2 fluxes were measured in a variety of ecosystems with an eddy covariance observation matrix between June 2012 and September 2012 in the Zhangye oasis area of Northwest China. The results show distinct diurnal variations in the CO2 fluxes in vegetable field, orchard, wetland, and maize cropland. Diurnal variations of CO2 fluxes were not obvious, and their values approached zero in the sandy desert, desert steppe, and Gobi ecosystems. Additionally, daily variations in the Gross Primary Production (GPP), Ecosystem Respiration (Reco) and Net Ecosystem Exchange (NEE) were not obvious in the sandy desert, desert steppe, and Gobi ecosystems. In contrast, the distributions of the GPP, Reco, and NEE show significant daily variations, that are closely related to the development of vegetation in the maize, wetland, orchard, and vegetable field ecosystems. All of the ecosystems are characterized by their carbon absorption during the observation period. The ability to absorb CO2 differed significantly among the tested ecosystems. We also used the Michaelis-Menten equation and exponential curve fitting methods to analyze the impact of Photosynthetically Active Radiation (PAR) on the daytime CO2 flux and impact of air temperature on Reco at night. The results show that PAR is the dominant factor in controlling photosynthesis with limited solar radiation, and daytime CO2 assimilation increases rapidly with PAR. Additionally, the carbon assimilation rate was found to increase slowly with high solar radiation. The light response parameters changed with each growth stage for all of the vegetation types, and higher light response values were observed during months or stages when the plants grew quickly. Light saturation points are different for different species. Nighttime Reco increases exponentially with air temperature. High Q10 values were observed when the vegetation coverage was relatively low, and low Q10 values occurred when the vegetables grew vigorously. PMID- 25803841 TI - Sickness absence from work among persons with new physician-diagnosed carpal tunnel syndrome: a population-based matched-cohort study. AB - BACKGROUND: Carpal tunnel syndrome is common among employed persons. Data on sickness absence from work in relation to carpal tunnel syndrome have been usually based on self-report and derived from clinical or occupational populations. We aimed to determine sickness absence among persons with physician diagnosed carpal tunnel syndrome as compared to the general population. METHODS: In Skane region in Sweden we identified all subjects, aged 17-57 years, with new physician-made diagnosis of carpal tunnel syndrome during 5 years (2004-2008). For each subject we randomly sampled, from the general population, 4 matched reference subjects without carpal tunnel syndrome; the two cohorts comprised 5456 and 21,667 subjects, respectively (73% women; mean age 43 years). We retrieved social insurance register data on all sickness absence periods longer than 2 weeks from 12 months before to 24 months after diagnosis. Of those with carpal tunnel syndrome 2111 women (53%) and 710 men (48%) underwent surgery within 24 months of diagnosis. We compared all-cause sickness absence and analyzed sickness absence in conjunction with diagnosis and surgery. RESULTS: Mean number of all cause sickness absence days per each 30-day period from 12 months before to 24 months after diagnosis was significantly higher in the carpal tunnel syndrome than in the reference cohort. A new sickness absence period longer than 2 weeks in conjunction with diagnosis was recorded in 12% of the women (n = 492) and 11% of the men (n = 170) and with surgery in 53% (n = 1121) and 58% (n = 408) of the surgically treated, respectively; median duration in conjunction with surgery was 35 days (IQR 27-45) for women and 41 days (IQR 28-50) for men. CONCLUSIONS: Persons with physician-diagnosed carpal tunnel syndrome have substantially more sickness absence from work than age and sex-matched persons from the general population from 1 year before to 2 years after diagnosis. Gender differences were small. PMID- 25803842 TI - Redefining the septal L-strut in septal surgery. AB - In septal surgery, the surgeon preserves the L-strut, the portion anterior to a vertical line drawn from the rhinion to the anterior nasal spine (ANS) and at least a 1-cm width of the dorsal and caudal septal segment, to decrease the potential for loss of the tip and dorsal nasal support. However, nasal tip collapse and saddle deformities occur occasionally. We utilized a mechanical approach to determine the safe width size for the L-strut in contact with the maxillary crest. Five L-strut models were designed based on computed tomography data (80 patients) and previous studies (55 patients). All L-strut models connected the perpendicular plate of the ethmoid bone (PPE) and the maxillary crest and were assumed to be fixed to the PPE and maxillary crest. An approximated daily load was applied to the dorsal portion of the L-strut. Finite element analyses were performed to compare the stress, strain, and displacement distribution of all L-strut models. According to the differences in the contact area between the caudal L-strut and maxillary crest, there are significant differences in terms of the stress, strain, and displacement distribution in the L-strut. High stresses occurred at the inner corner of the L-strut when 60 - 100% of the strut was in contact with the maxillary crest. High stresses also occurred at the inferior portion of the caudal L-strut when 20 - 40% of the caudal strut was in contact with maxillary crest. We conclude that it is important to preserve the 1-cm width L-strut caudal segment, which corresponds to the portion posterior to a vertical line drawn from the rhinion to the ANS. In particular, we must maintain more than 40% of the contact area between the L-strut and the maxillary crest when the septal cartilage in the caudal portion of the L-strut is harvested. PMID- 25803845 TI - Brand discrimination: an implicit measure of the strength of mental brand representations. AB - While mental associations between a brand and its marketing elements are an important part of brand equity, previous research has yet to provide a sound methodology to measure the strength of these links. The following studies present the development and validation of an implicit measure to assess the strength of mental representations of brand elements in the mind of the consumer. The measure described in this paper, which we call the Brand Discrimination task, requires participants to identify whether images of brand elements (e.g. color, logo, packaging) belong to a target brand or not. Signal detection theory (SDT) is used to calculate a Brand Discrimination index which gives a measure of overall recognition accuracy for a brand's elements in the context of its competitors. A series of five studies shows that the Brand Discrimination task can discriminate between strong and weak brands, increases when mental representations of brands are experimentally strengthened, is relatively stable across time, and can predict brand choice, independently and while controlling for other explicit and implicit brand evaluation measures. Together, these studies provide unique evidence for the importance of mental brand representations in marketing and consumer behavior, along with a research methodology to measure this important consumer-based brand attribute. PMID- 25803844 TI - Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa. AB - Two lineages of Salmonella enterica serovar Typhimurium (S. Typhimurium) of multi locus sequence type ST313 have been linked with the emergence of invasive Salmonella disease across sub-Saharan Africa. The expansion of these lineages has a temporal association with the HIV pandemic and antibiotic usage. We analysed the whole genome sequence of 129 ST313 isolates representative of the two lineages and found evidence of lineage-specific genome degradation, with some similarities to that observed in S. Typhi. Individual ST313 S. Typhimurium isolates exhibit a distinct metabolic signature and modified enteropathogenesis in both a murine and cattle model of colitis, compared to S. Typhimurium outside of the ST313 lineages. These data define phenotypes that distinguish ST313 isolates from other S. Typhimurium and may represent adaptation to a distinct pathogenesis and lifestyle linked to an-immuno-compromised human population. PMID- 25803843 TI - Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region. AB - The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2 q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function. PMID- 25803847 TI - Effect of the transient pharmacological inhibition of Mapk3/1 pathway on ovulation in mice. AB - Mitogen-activated protein kinase 3/1 (Mapk3/1) pathway is critical for LH signal transduction during ovulation. However, the mechanisms remain incompletely understood. We hypothesized that Mapk pathway regulates ovulation through transcriptional regulation of ovulatory genes. To test this hypothesis we used immature mice superovulated with equine and human chorionic gonadotropins (eCG and hCG) and PD0325901, to inhibit hCG-induced Mapk3/1 activity. Mice received either the inhibitor PD0325901 (25 MUg/g, i.p.) or vehicle at 2h before hCG stimulation. Administration of the inhibitor abolished Mapk3/1 phosphorylation in granulosa cells. While vehicle-treated mice ovulated normally, there were no ovulations in inhibitor-treated mice. First, we analyzed gene expression in granulosa cells at 0h, 1h and 4h post-hCG. There was expected hCG-driven increase in mRNA abundance of many ovulation-related genes including Ptgs2 in vehicle treated granulosa cells, but not (P<0.05) in inhibitor-treated group. There was also reduced mRNA and protein abundance of the transcription factor, early growth response 1 (Egr1) in inhibitor-treated granulosa cells. We then used GRMO2 cell line to test if Egr1 is recruited to promoter of Ptgs2 followed by chromatin immunoprecipitation with either Egr1 or control antibody. Enrichment of the promoter regions in immunoprecipitants of Egr1 antibody indicated that Egr1 binds to the Ptgs2 promoter. We then knocked down Egr1 expression in mouse primary granulosa cells using siRNA technology. Treatment with Egr1-siRNA inhibited Egr1 transcript accumulation, which was associated with reduced expression of Ptgs2 when compared to control-siRNA treated granulosa cells. These data demonstrate that transient inhibition of LH-stimulated MAPK3/1 activity abrogates ovulation in mice. We conclude that Mapk3/1 regulates ovulation, at least in part, through Egr1 and its target gene, Ptgs2 in granulosa cells of ovulating follicles in mice. PMID- 25803846 TI - Elevational gradients in beta-diversity reflect variation in the strength of local community assembly mechanisms across spatial scales. AB - Despite long-standing interest in elevational-diversity gradients, little is known about the processes that cause changes in the compositional variation of communities (beta-diversity) across elevations. Recent studies have suggested that beta-diversity gradients are driven by variation in species pools, rather than by variation in the strength of local community assembly mechanisms such as dispersal limitation, environmental filtering, or local biotic interactions. However, tests of this hypothesis have been limited to very small spatial scales that limit inferences about how the relative importance of assembly mechanisms may change across spatial scales. Here, we test the hypothesis that scale dependent community assembly mechanisms shape biogeographic beta-diversity gradients using one of the most well-characterized elevational gradients of tropical plant diversity. Using an extensive dataset on woody plant distributions along a 4,000-m elevational gradient in the Bolivian Andes, we compared observed patterns of beta-diversity to null-model expectations. beta-deviations (standardized differences from null values) were used to measure the relative effects of local community assembly mechanisms after removing sampling effects caused by variation in species pools. To test for scale-dependency, we compared elevational gradients at two contrasting spatial scales that differed in the size of local assemblages and regions by at least an order of magnitude. Elevational gradients in beta-diversity persisted after accounting for regional variation in species pools. Moreover, the elevational gradient in beta-deviations changed with spatial scale. At small scales, local assembly mechanisms were detectable, but variation in species pools accounted for most of the elevational gradient in beta diversity. At large spatial scales, in contrast, local assembly mechanisms were a dominant force driving changes in beta-diversity. In contrast to the hypothesis that variation in species pools alone drives beta-diversity gradients, we show that local community assembly mechanisms contribute strongly to systematic changes in beta-diversity across elevations. We conclude that scale-dependent variation in community assembly mechanisms underlies these iconic gradients in global biodiversity. PMID- 25803849 TI - Prevalence of dental caries and fissure sealants in a Portuguese sample of adolescents. AB - INTRODUCTION: The aims of this study were to assess the prevalence of dental caries and the DMFT index, as well as the distribution pattern of pit and fissure sealants on permanent teeth in a Portuguese sample of adolescents, and to assess whether the existing usage of sealants and socio-demographic factors are correlated to caries prevalence on the examined sample. MATERIALS AND METHODS: A cross-sectional study was designed with a sample of 447 adolescents aged 12 to 18 years old, attending a public school in Satao, Portugal. A self-administered questionnaire with questions about oral health behaviours and socio-economic status was answered by adolescents in the classroom. Clinical examination of oral health status and assessment of fissure sealants were accomplished by only one trained member of the research team. RESULTS: We obtained a DMFT index of 3.32 (2.92), which indicates a moderate level of prevalence of dental caries. When considering a DMFT = 0, we found significant statistical differences between the parents' level of education (<= 4th grade = 26.3 vs 5th-12th grade = 18.8 vs <12th grade = 43.3, p = 0.001), gender (male = 27.3 vs female = 19.6, p = 0.04), age (<= 15 years = 27.1 vs <15 years = 18.5, p = 0.02), presence of fissure sealants (yes = 30.6 vs no = 13.5, p = 0.001) and experience of dental pain (no = 25.4 vs yes = 16.8, p = 0.02). When analyzing the prevalence of fissure sealants, we verified that 58.8% of adolescents had at least one fissure sealant applied. Significant statistical differences were found when analyzing the presence of fissure sealants related with parents' educational level (<9th grade, OR = 1.56 CI95% = 1.05-2.54), gender (female, OR = 1.86 CI95% = 1.19-2.98), experience of dental pain (yes, OR = 0.62 CI95% = 0.39-0.97) and presence of dental caries (yes, OR = 0.35 CI95% = 0.19-0.65). CONCLUSIONS: The moderate level of caries prevalence reveals the need of improvement of primary prevention interventions among Portuguese adolescents. The establishment of a more targeted preventive program with better and more effective oral health education is essential, having into account socio-demographic aspects. PMID- 25803848 TI - The epidemiology of hepatitis C virus in the Maghreb region: systematic review and meta-analyses. AB - OBJECTIVE: To systematically review and synthesize available epidemiological data on hepatitis C virus (HCV) prevalence and incidence in the Maghreb region and to estimate the country-specific population-level HCV prevalence. METHODS: We conducted a systematic review of HCV antibody prevalence and incidence in the Maghreb countries as outlined by the PRISMA guidelines. Meta-analyses were conducted using DerSimonian-Laird random-effect models with inverse variance weighting to pool HCV prevalence estimates among general population groups. RESULTS: We identified 133 HCV prevalence measures and two HCV incidence measures. Among high risk groups, HCV prevalence ranged between 22% and 94% among people who inject drugs, 20% and 76% among dialysis patients, and 2% and 51% among hemophiliacs. Among intermediate-risk groups, considerable but widely variable HCV prevalence was found. Most common risk factors cited across studies were the duration of dialysis, number of transfusions, and having a history of surgery or dental work. The national HCV prevalence in Algeria was estimated at 0.3% (95%CI: 0.1-0.5), Libya 1.2% (95%CI: 1.1-1.3), Mauritania 1.1% (95%CI: 0 2.3), Morocco 0.8% (95%CI: 0.5-1.2), and Tunisia 0.6% (95%CI: 0.5-0.8). CONCLUSIONS: HCV prevalence in the Maghreb region of the Middle East and North Africa is comparable to that in developed countries of about 1%. HCV exposures appear often to be linked to medical care and are suggestive of ongoing transmission in such settings. Injecting drug use appears also to be a major, though not dominant, contributor to HCV transmission. Further research is needed to draw a more thorough understanding of HCV epidemiology, especially in the countries with limited number of studies. HCV prevention policy and programming in these countries should focus on the settings of exposure. PMID- 25803850 TI - Blockade of the SNARE protein syntaxin 1 inhibits glioblastoma tumor growth. AB - Glioblastoma (GBM) is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1) function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM. PMID- 25803851 TI - Multi-generational drinking of bottled low mineral water impairs bone quality in female rats. AB - BACKGROUND: Because of reproductions and hormone changes, females are more sensitive to bone mineral loss during their lifetime. Bottled water has become more popular in recent years, and a large number of products are low mineral water. However, research on the effects of drinking bottled low mineral water on bone health is sparse. OBJECTIVE: To elucidate the skeletal effects of multi generational bottled water drinking in female rats. METHODS: Rats continuously drank tap water (TW), bottled natural water (bNW), bottled mineralized water (bMW), or bottled purified water (bPW) for three generations. RESULTS: The maximum deflection, elastic deflection, and ultimate strain of the femoral diaphysis in the bNW, bMW, and bPW groups and the fracture strain in the bNW and bMW groups were significantly decreased. The tibiae calcium levels in both the bNW and bPW groups were significantly lower than that in the TW group. The tibiae and teeth magnesium levels in both the bNW and bPW groups were significantly lower than those in the TW group. The collagen turnover markers PICP (in both bNW and bPW groups) were significantly lower than that in the TW group. In all three low mineral water groups, the 1,25-dihydroxy-vitamin D levels were significantly lower than those in the TW group. CONCLUSION: Long-term drinking of low mineral water may disturb bone metabolism and biochemical properties and therefore weaken biomechanical bone properties in females. Drinking tap water, which contains adequate minerals, was found to be better for bone health. To our knowledge, this is the first report on drinking bottled low mineral water and female bone quality on three generation model. PMID- 25803853 TI - Causes of death in a contemporary cohort of patients with invasive aspergillosis. AB - Information regarding the processes leading to death in patients with invasive aspergillosis (IA) is lacking. We sought to determine the causes of death in these patients, the role that IA played in the cause, and the timing of death. The factors associated with IA-related mortality are also analyzed. We conducted a multicenter study (2008-2011) of cases of proven and probable IA. The causes of death and whether mortality was judged to be IA-related or IA-unrelated were determined by consensus using a six-member review panel. A multivariate analysis was performed to determine risk factors for IA-related death. Of 152 patients with IA, 92 (60.5%) died. Mortality was judged to be IA-related in 62 cases and IA-unrelated in 30. The most common cause of IA-related death was respiratory failure (50/62 patients), caused primarily by Aspergillus infection, although also by concomitant infections or severe comorbidities. Progression of underlying disease and bacteremic shock were the most frequent causes of IA-unrelated death. IA-related mortality accounted for 98% and 87% of deaths within the first 14 and 21 days, respectively. Liver disease (HR 4.54; 95% CI, 1.69-12.23) was independently associated with IA-related mortality, whereas voriconazole treatment was associated with reduced risk of death (HR 0.43; 95% CI, 0.20-0.93). In conclusion, better management of lung injury after IA diagnosis is the main challenge for physicians to improve IA outcomes. There are significant differences in causes and timing between IA-related and IA-unrelated mortality and these should be considered in future research to assess the quality of IA care. PMID- 25803854 TI - Genotyping on ALDH2: comparison of four different technologies. AB - OBJECTIVES: This study aimed to compare the accuracy and performance of four genotyping methods for detecting single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase-2 (ALDH2), which is the principal enzyme involved in alcohol metabolism. DESIGN AND METHODS: We genotyped rs671 of ALDH2 in 96 coronary heart disease (CHD) patients with four methods including high resolution melting analysis (HRM), TaqMan allelic discrimination assay (TaqMan), allele specific PCR (AS-PCR) and pyrosequencing. Meanwhile, we compared the accuracy and performance of these methods. RESULTS: All selected patients were successfully genotyped with referred methods. The results of these four assays showed 100% concordant results and had 100% accuracy as verified by Sanger sequencing. CONCLUSIONS: All of the referred methods can be used for genotyping ALDH2 rs671 with the same accuracy compared to Sanger sequencing. In small size of clinical samples, HRM and AS-PCR outperform over others due to their lower cost and less hands-on operation, which are suitable for clinical application. PMID- 25803852 TI - Relationships among parvalbumin-immunoreactive neuron density, phase-locked gamma oscillations, and autistic/schizophrenic symptoms in PDGFR-beta knock-out and control mice. AB - Cognitive deficits and negative symptoms are important therapeutic targets for schizophrenia and autism disorders. Although reduction of phase-locked gamma oscillation has been suggested to be a result of reduced parvalbumin immunoreactive (putatively, GABAergic) neurons, no direct correlations between these have been established in these disorders. In the present study, we investigated such relationships during pharmacological treatment with a newly synthesized drug, T-817MA, which displays neuroprotective and neurotrophic effects. In this study, we used platelet-derived growth factor receptor-beta gene knockout (PDGFR-beta KO) mice as an animal model of schizophrenia and autism. These mutant mice display a reduction in social behaviors; deficits in prepulse inhibition (PPI); reduced levels of parvalbumin-immunoreactive neurons in the medical prefrontal cortex, hippocampus, amygdala, and superior colliculus; and a deficit in of auditory phase-locked gamma oscillations. We found that oral administration of T-817MA ameliorated all these symptoms in the PDGFR-beta KO mice. Furthermore, phase-locked gamma oscillations were significantly correlated with the density of parvalbumin-immunoreactive neurons, which was, in turn, correlated with PPI and behavioral parameters. These findings suggest that recovery of parvalbumin-immunoreactive neurons by pharmacological intervention relieved the reduction of phase-locked gamma oscillations and, consequently, ameliorated PPI and social behavioral deficits. Thus, our findings suggest that phase-locked gamma oscillations could be a useful physiological biomarker for abnormality of parvalbumin-immunoreactive neurons that may induce cognitive deficits and negative symptoms of schizophrenia and autism, as well as of effective pharmacological interventions in both humans and experimental animals. PMID- 25803855 TI - ShapeR: an R package to study otolith shape variation among fish populations. AB - ShapeR is an open source software package that runs on the R platform and is specifically designed to study otolith shape variation among fish populations. The package extends previously described software used for otolith shape analysis by allowing the user to automatically extract closed contour outlines from a large number of images, perform smoothing to eliminate pixel noise, choose from conducting either a Fourier or Wavelet transform to the outlines and visualize the mean shape. The output of the package are independent Fourier or Wavelet coefficients which can be directly imported into a wide range of statistical packages in R. The package might prove useful in studies of any two dimensional objects. PMID- 25803856 TI - MD-2 determinants of nickel and cobalt-mediated activation of human TLR4. AB - Recent findings unexpectedly revealed that human TLR4 can be directly activated by nickel ions. This activation is due to the coordination of nickel by a cluster of histidine residues on the ectodomain of human TLR4, which is absent in most other species. We aimed to elucidate the role of MD-2 in the molecular mechanism of TLR4/MD-2 activation by nickel, as nickel binding site on TLR4 is remote from MD-2, which directly binds the endotoxin as the main pathological activator of TLR4. We identified MD-2 and TLR4 mutants which abolished TLR4/MD-2 receptor activation by endotoxin but could nevertheless be significantly activated by nickel, which acts in synergy with LPS. Human TLR4/MD-2 was also activated by cobalt ions, while copper and cadmium were toxic in the tested concentration range. Activation of TLR4 by cobalt required MD-2 and was abolished by human TLR4 mutations of histidine residues at positions 456 and 458. We demonstrated that activation of TLR4 by nickel and cobalt ions can trigger both the MyD88-dependent and the -independent pathway. Based on our results we propose that predominantly hydrophobic interactions between MD-2 and TLR4 contribute to the stabilization of the TLR4/MD-2/metal ion complex in a conformation that enables activation. PMID- 25803857 TI - A novel method for measuring anterior segment area of the eye on ultrasound biomicroscopic images using photoshop. AB - PURPOSE: To describe a novel method for quantitative measurement of area parameters in ocular anterior segment ultrasound biomicroscopy (UBM) images using Photoshop software and to assess its intraobserver and interobserver reproducibility. METHODS: Twenty healthy volunteers with wide angles and twenty patients with narrow or closed angles were consecutively recruited. UBM images were obtained and analyzed using Photoshop software by two physicians with different-level training on two occasions. Borders of anterior segment structures including cornea, iris, lens, and zonules in the UBM image were semi automatically defined by the Magnetic Lasso Tool in the Photoshop software according to the pixel contrast and modified by the observers. Anterior chamber area (ACA), posterior chamber area (PCA), iris cross-section area (ICA) and angle recess area (ARA) were drawn and measured. The intraobserver and interobserver reproducibilities of the anterior segment area parameters and scleral spur location were assessed by limits of agreement, coefficient of variation (CV), and intraclass correlation coefficient (ICC). RESULTS: All of the parameters were successfully measured by Photoshop. The intraobserver and interobserver reproducibilities of ACA, PCA, and ICA were good, with no more than 5% CV and more than 0.95 ICC, while the CVs of ARA were within 20%. The intraobserver and interobserver reproducibilities for defining the spur location were more than 0.97 ICCs. Although the operating times for both observers were less than 3 minutes per image, there was significant difference in the measuring time between two observers with different levels of training (p<0.001). CONCLUSION: Measurements of ocular anterior segment areas on UBM images by Photoshop showed good intraobserver and interobserver reproducibilties. The methodology was easy to adopt and effective in measuring. PMID- 25803858 TI - Correction: Activity-based funding of hospitals and its impact on mortality, readmission, discharge destination, severity of illness, and volume of care: a systematic review and meta-analysis. PMID- 25803859 TI - MiR-519d-3p suppresses invasion and migration of trophoblast cells via targeting MMP-2. AB - Our study was approved by the Medical Ethics Committee of Tang Du Hospital, Fourth Military Medical University and complied strictly with national ethical guidelines. Preeclampsia (PE) is a specific clinical disorder characterized by gestational hypertension and proteinuria and is a leading cause of maternal and perinatal mortality worldwide. The miR-519d-3p is upregulated in the maternal plasma of patients with PE which indicates a possible association between this microRNA and the pathogenesis of PE. No studies to date have addressed the effect of miR-519d-3p on the invasion and migration of trophoblast cells. In our study, we found that miR-519d-3p expression was elevated in placental samples from patients with PE. In vitro, overexpression of miR-519d-3p significantly inhibited trophoblast cell migration and invasion, whereas transfection of a miR-519d-3p inhibitor enhanced trophoblast cell migration and invasion. Luciferase assays confirmed that matrix metalloproteinase-2 (MMP-2) is a direct target of miR-519d 3p. Quantitative real-time PCR and western blot assays showed that overexpression of miR-519d-3p downregulated MMP-2 mRNA and protein expression. Knockdown of MMP 2 using a siRNA attenuated the increased trophoblast migration and invasion promoted by the miR-519d-3p inhibitor. In placentas from patients with PE or normal pregnancies, a negative correlation between the expression of MMP-2 and miR-519d-3p was observed using the Pearson correlation and linear regression analysis. Our present findings suggest that upregulation of miR-519d-3p may contribute to the development of PE by inhibiting trophoblast cell migration and invasion via targeting MMP-2; miR-519d-3p may represent a potential predictive and therapeutic target for PE. PMID- 25803860 TI - Nutritional status and nosocomial infections among adult elective surgery patients in a Mexican tertiary care hospital. AB - BACKGROUND: Controversy exists as to whether obesity constitutes a risk-factor or a protective-factor for the development of nosocomial Infection (NI). According to the obesity-paradox, there is evidence that moderate obesity is a protective factor. In Mexico few studies have focused on the nutritional status (NS) distribution in the hospital setting. OBJECTIVES: The aim of this study was to estimate the distribution of NS and the prevalence of nosocomial infection NI among adult elective surgery (ES) patients and to compare the clinical and anthropometric characteristics and length of stays (LOS) between obese and non obese patients and between patients with and without NI. METHODS: We conducted a cross-sectional study with a sample (n = 82) adult ES patients (21-59 years old) who were recruited from a tertiary-care hospital. The prevalences of each NS category and NI were estimated, the assessments were compared between groups (Mann-Whitney, Chi-squared or the Fisher's-exact-test), and the association between preoperative risk-factors and NI was evaluated using odds ratios. RESULTS: The distribution of subjects by NS category was: underweight (3.66%), normal-weight (28.05%), overweight (35.36%), and obese (32.93%). The prevalence of NI was 14.63%. The LOS was longer (p<0.001) for the patients who developed NI. The percentages of NI were: 33.3% in underweight, 18.52% in obese, 17.39% in normal-weight, and 6.90% in overweight patients. CONCLUSION: The prevalence of overweight and obesity in adult ES patients is high. The highest prevalence of NI occurred in the underweight and obese patients. The presence of NI considerably increased the LOS, resulting in higher medical care costs. PMID- 25803862 TI - High peripheral blood th17 percent associated with poor lung function in cystic fibrosis. AB - People with cystic fibrosis (CF) have been reported to make lung T cell responses that are biased towards T helper (Th) 2 or Th17. We hypothesized that CF-related T cell regulatory defects could be detected by analyzing CD4+ lymphocyte subsets in peripheral blood. Peripheral blood mononuclear cells from 42 CF patients (6 months-53 years old) and 78 healthy controls (2-61 years old) were analyzed for Th1 (IFN-gamma+), Th2 (IL-4+), Th17 (IL-17+), Treg (FOXP3+), IL-10+ and TGF-beta+ CD4+ cells. We observed higher proportions of Treg, IL-10+ and TGF-beta+ CD4+ cells in CF adults (>= 18 years old), but not children/adolescents, compared with controls. Within the CF group, high TGF-beta+% was associated with chronic Pseudomonas aeruginosa lung infection (p < 0.006). We observed no significant differences between control and CF groups in the proportions of Th1, Th2 or Th17 cells, and no association within the CF group of any subset with sex, CFTR genotype, or clinical exacerbation. However, high Th17% was strongly associated with poor lung function (FEV1 % predicted) (p = 0.0008), and this association was strongest when both lung function testing and blood sampling were performed within one week. Our results are consistent with reports of CF as a Th17 disease and suggest that peripheral blood Th17 levels may be a surrogate marker of lung function in CF. PMID- 25803861 TI - Alcohol use disorder with and without stimulant use: brain morphometry and its associations with cigarette smoking, cognition, and inhibitory control. AB - OBJECTIVE: Little is known about the effects of polysubstance use and cigarette smoking on brain morphometry. This study examined neocortical brain morphometric differences between abstinent polysubstance dependent and alcohol-only dependent treatment seekers (ALC) as well as light drinking controls (CON), the associations of cigarette smoking in these polysubstance users (PSU), and morphometric relationships to cognition and inhibitory control. METHODS: All participants completed extensive neuropsychological assessments and 4 Tesla brain magnetic resonance imaging. PSU and ALC were abstinent for one month at the time of study. Parcellated morphological data (volume, surface area, thickness) were obtained with FreeSurfer methodology for the following bilateral components: dorso-prefrontal cortex (DPFC), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and insula. Regional group differences were examined and structural data correlated with domains of cognition and inhibitory control. RESULTS: PSU had significantly smaller left OFC volume and surface area and trends to smaller right DPFC volume and surface area compared to CON; PSU did not differ significantly from ALC on these measures. PSU, however, had significantly thinner right ACC than ALC. Smoking PSU had significantly larger right OFC surface area than non-smoking PSU. No significant relationships between morphometry and quantity/frequency of substance use, alcohol use, or age of onset of heavy drinking were observed. PSU exhibited distinct relationships between brain structure and processing speed, cognitive efficiency, working memory and inhibitory control that were not observed in ALC or CON. CONCLUSION: Polysubstance users have unique morphometric abnormalities and structure-function relationships when compared to individuals dependent only on alcohol and light drinking controls. Chronic cigarette smoking is associated with structural brain irregularities in polysubstance users. Further elucidation of these distinctive characteristics could help inform the development of targeted and thus potentially more effective treatments in this large but understudied population. PMID- 25803863 TI - Dissecting out the complex Ca2+-mediated phenylephrine-induced contractions of mouse aortic segments. AB - L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by alpha1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that alpha1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by alpha1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between alpha1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein. PMID- 25803864 TI - Lysophosphatidylcholine acyltransferase1 overexpression promotes oral squamous cell carcinoma progression via enhanced biosynthesis of platelet-activating factor. AB - BACKGROUND: The relevance of lysophosphatidylcholine acyltransferase1 (LPCAT1), a cytosolic enzyme in the remodeling pathway of phosphatidylcholine metabolism, in oral squamous cell carcinoma (OSCC) is unknown. We investigated LPCAT1 expression and its functional mechanism in OSCCs. METHODS: We analyzed LPCAT1 mRNA and protein expression levels in OSCC-derived cell lines. Immunohistochemistry was performed to identify correlations between LPCAT1 expression levels and primary OSCCs clinicopathological status. We established LPCAT1 knockdown models of the OSCC-derived cell lines (SAS, Ca9-22) for functional analysis and examined the association between LPCAT1 expression and the platelet-activating factor (PAF) concentration and PAF-receptor (PAFR) expression. RESULTS: LPCAT1 mRNA and protein were up-regulated significantly (p<0.05) in OSCC-derived cell lines compared with human normal oral keratinocytes. Immunohistochemistry showed significantly (p<0.05) elevated LPCAT1 expression in primary OSCCs compared with normal counterparts and a strong correlation between LPCAT1-positive OSCCs and tumoral size and regional lymph node metastasis. In LPCAT1 knockdown cells, cellular proliferation and invasiveness decreased significantly (p<0.05); cellular migration was inhibited compared with control cells. Down-regulation of LPCAT1 resulted in a decreased intercellular PAF concentration and PAFR expression. CONCLUSION: LPCAT1 was overexpressed in OSCCs and correlated with cellular invasiveness and migration. LPCAT1 may contribute to tumoral growth and metastasis in oral cancer. PMID- 25803865 TI - A novel expansin protein from the white-rot fungus Schizophyllum commune. AB - A novel expansin protein (ScExlx1) was found, cloned and expressed from the Basidiomycete fungus Schizophylum commune. This protein showed the canonical features of plant expansins. ScExlx1 showed the ability to form "bubbles" in cotton fibers, reduce the size of avicel particles and enhance reducing sugar liberation from cotton fibers pretreated with the protein and then treated with cellulases. ScExlx1 was able to bind cellulose, birchwood xylan and chitin and this property was not affected by different sodium chloride concentrations. A novel property of ScExlx1 is its capacity to enhance reducing sugars (N-acetyl glucosamine) liberation from pretreated chitin and further added with chitinase, which has not been reported for any expansin or expansin-like protein. To the best of our knowledge, this is the first report of a bona fide fungal expansin found in a basidiomycete and we could express the bioactive protein in Pichia pastoris. PMID- 25803866 TI - Probabilistic models to describe the dynamics of migrating microbial communities. AB - In all but the most sterile environments bacteria will reside in fluid being transported through conduits and some of these will attach and grow as biofilms on the conduit walls. The concentration and diversity of bacteria in the fluid at the point of delivery will be a mix of those when it entered the conduit and those that have become entrained into the flow due to seeding from biofilms. Examples include fluids through conduits such as drinking water pipe networks, endotracheal tubes, catheters and ventilation systems. Here we present two probabilistic models to describe changes in the composition of bulk fluid microbial communities as they are transported through a conduit whilst exposed to biofilm communities. The first (discrete) model simulates absolute numbers of individual cells, whereas the other (continuous) model simulates the relative abundance of taxa in the bulk fluid. The discrete model is founded on a birth death process whereby the community changes one individual at a time and the numbers of cells in the system can vary. The continuous model is a stochastic differential equation derived from the discrete model and can also accommodate changes in the carrying capacity of the bulk fluid. These models provide a novel Lagrangian framework to investigate and predict the dynamics of migrating microbial communities. In this paper we compare the two models, discuss their merits, possible applications and present simulation results in the context of drinking water distribution systems. Our results provide novel insight into the effects of stochastic dynamics on the composition of non-stationary microbial communities that are exposed to biofilms and provides a new avenue for modelling microbial dynamics in systems where fluids are being transported. PMID- 25803867 TI - Assessing the independent contribution of maternal educational expectations to children's educational attainment in early adulthood: a propensity score matching analysis. AB - BACKGROUND: Parental educational expectations have been associated with children's educational attainment in a number of long-term longitudinal studies, but whether this relationship is causal has long been debated. The aims of this prospective study were twofold: 1) test whether low maternal educational expectations contributed to failure to graduate from high school; and 2) compare the results obtained using different strategies for accounting for confounding variables (i.e. multivariate regression and propensity score matching). METHODOLOGY/PRINCIPAL FINDINGS: The study sample included 1,279 participants from the Quebec Longitudinal Study of Kindergarten Children. Maternal educational expectations were assessed when the participants were aged 12 years. High school graduation-measuring educational attainment-was determined through the Quebec Ministry of Education when the participants were aged 22-23 years. Findings show that when using the most common statistical approach (i.e. multivariate regressions to adjust for a restricted set of potential confounders) the contribution of low maternal educational expectations to failure to graduate from high school was statistically significant. However, when using propensity score matching, the contribution of maternal expectations was reduced and remained statistically significant only for males. CONCLUSIONS/SIGNIFICANCE: The results of this study are consistent with the possibility that the contribution of parental expectations to educational attainment is overestimated in the available literature. This may be explained by the use of a restricted range of potential confounding variables as well as the dearth of studies using appropriate statistical techniques and study designs in order to minimize confounding. Each of these techniques and designs, including propensity score matching, has its strengths and limitations: A more comprehensive understanding of the causal role of parental expectations will stem from a convergence of findings from studies using different techniques and designs. PMID- 25803868 TI - Assessment of condyle and glenoid fossa morphology using CBCT in South-East Asians. AB - INTRODUCTION: Proper imaging allows practitioners to evaluate an asymptomatic tempormandibular joint (TMJ) for potential degenerative changes prior to surgical and orthodontic treatment. The recently developed cone-beam computed tomography (CBCT) allows measurement of TMJ bony structures with high accuracy. A study was undertaken to determine the morphology, and its variations, of the mandibular condyle and glenoid fossa among Malay and Chinese Malaysians. METHODS: CBCT was used to assess 200 joints in 100 subjects (mean age, 30.5 years). i-CAT CBCT software and The Mimics 16.0 software were employed to measure the volume, metrical size, position of each condyle sample and the thickness of the roof of the glenoid fossa (RGF). RESULTS: No significant gender differences were noted in thickness of the RGF and condylar length; however condylar volume, width, height and the joint spaces were significantly greater among males. With regards to comparison of both TMJs, the means of condylar volume, width and length of the right TMJ were significantly higher, while the means of the left condylar height and thickness of RGF were higher. When comparing the condylar measurements and the thickness of RGF between the two ethnic groups, we found no significant difference for all measurements with exception of condylar height, which is higher among Chinese. CONCLUSION: The similarity in measurements for Malays and Chinese may be due to their common origin. This information can be clinically useful in establishing the diagnostic criteria for condylar volume, metrical size, and position in the Malaysian East Asians population. PMID- 25803869 TI - Selenium alleviates porcine nephrotoxicity of ochratoxin A by improving selenoenzyme expression in vitro. AB - Ochratoxin A (OTA), a mycotoxin, is a potent nephrotoxin in humans and animals. Selenium (Se) is an essential micronutrient for humans and animals, and plays a key role in antioxidant defense. To date, little is known about the effect of Se on OTA-induced nephrotoxicity. In this study, the protective effects of selenomethionine against OTA-induced nephrotoxicity were investigated using the porcine kidney 15 (PK15) cells as a model. The results showed that OTA induced nephrotoxicity in a dose-dependent manner. Se at 0.5, 1, 2 and 4 MUM had significant protective effects against OTA-induced nephrotoxicity. Furthermore, selenomethionine enhanced the activity and mRNA and protein expression of glutathione peroxidase 1 (GPx1), mRNA expression of GPx4, and mRNA expression of thioredoxin reductase 1 in the presence and absence of OTA. Among them, promoting effect of selenomethionine on GPx1 was maximal. Knock-down of GPx1 by using a GPx1-specific siRNA eliminated the protective effects of selenomethionine against OTA-induced nephrotoxicity. The results suggest that selenomethionine alleviates OTA-induced nephrotoxicity by improving selenoenzyme expression in PK15 cells. Therefore, selenomethionine supplementation may be an attractive strategy for protecting humans and animals from the risk of kidney damage induced by OTA. PMID- 25803870 TI - Identification and validation of potential biomarkers for the detection of dysregulated microRNA by qPCR in patients with colorectal adenocarcinoma. AB - Colorectal cancer represents a lethal disease that has raised concern and has attracted significant attention. Adenocarcinoma is the most common type of colorectal cancer (CRC). MicroRNAs are thought to be potential biomarkers of CRC. Many researchers have focused on the expression pattern of miRNAs in CRC. However, previous studies did not pay particular attention to the effects of the degree of differentiation of the cancer with respect to the miRNA expression profile. First, this study compared the expression level of 1547 miRNAs by qRT PCR in Colorectal adenocarcinoma tissues to that in paired normal tissues. In all, 93 miRNAs were identified that were significantly dysregulated in Colorectal adenocarcinoma relative to normal tissues (P<0.05). Then, we analyzed their potential as cancer biomarkers by ROC analysis, and the result revealed that three miRNAs with high sensitivity and specificity are suitable as biomarkers for the diagnosis of CRC (the value of the AUC was greater than 0.7). Interestingly, previous reports of 23 of these miRNAs have been scarce. Furthermore, we wanted to analyze the difference between well- and moderately differentiated cancers, and as expected, 58 miRNAs showed significant dysregulation. Importantly, 32 miRNAs were able to not only distinguish cancer tissues from normal tissues, but they were also able to identify well- and moderately differentiated cancers. In conclusion, the degree of differentiation has an important influence on the miRNA expression pattern. To avoid misdiagnoses and missed diagnoses, tumors of different degrees of differentiation should be treated differently when miRNAs are used as cancer biomarkers. PMID- 25803871 TI - Optimal strategies for controlling riverine tsetse flies using targets: a modelling study. AB - BACKGROUND: Tsetse flies occur in much of sub-Saharan Africa where they transmit the trypanosomes that cause the diseases of sleeping sickness in humans and nagana in livestock. One of the most economical and effective methods of tsetse control is the use of insecticide-treated screens, called targets, that simulate hosts. Targets have been ~1 m2, but recently it was shown that those tsetse that occupy riverine situations, and which are the main vectors of sleeping sickness, respond well to targets only ~0.06 m2. The cheapness of these tiny targets suggests the need to reconsider what intensity and duration of target deployments comprise the most cost-effective strategy in various riverine habitats. METHODOLOGY/PRINCIPAL FINDINGS: A deterministic model, written in Excel spreadsheets and managed by Visual Basic for Applications, simulated the births, deaths and movement of tsetse confined to a strip of riverine vegetation composed of segments of habitat in which the tsetse population was either self-sustaining, or not sustainable unless supplemented by immigrants. Results suggested that in many situations the use of tiny targets at high density for just a few months per year would be the most cost-effective strategy for rapidly reducing tsetse densities by the ~90% expected to have a great impact on the incidence of sleeping sickness. Local elimination of tsetse becomes feasible when targets are deployed in isolated situations, or where the only invasion occurs from populations that are not self-sustaining. CONCLUSION/SIGNIFICANCE: Seasonal use of tiny targets deserves field trials. The ability to recognise habitat that contains tsetse populations which are not self-sustaining could improve the planning of all methods of tsetse control, against any species, in riverine, savannah or forest situations. Criteria to assist such recognition are suggested. PMID- 25803872 TI - Identification of a microRNA signature for the diagnosis of fibromyalgia. AB - BACKGROUND: Diagnosis of fibromyalgia (FM), a chronic musculoskeletal pain syndrome characterized by generalized body pain, hyperalgesia and other functional and emotional comorbidities, is a challenging process hindered by symptom heterogeneity and clinical overlap with other disorders. No objective diagnostic method exists at present. The aim of this study was to identify changes in miRNA expression profiles (miRNome) of these patients for the development of a quantitative diagnostic method of FM. In addition, knowledge of FM patient miRNomes should lead to a deeper understanding of the etiology and/or symptom severity of this complex disease. METHODS: Genome-wide expression profiling of miRNAs was assessed in Peripheral Blood Mononuclear Cells (PBMCs) of FM patients (N=11) and population-age-matched controls (N=10) using human v16 miRbase 3D-Gene microarrays (Toray Industries, Japan). Selected miRNAs from the screen were further validated by RT-qPCR. Participating patients were long term sufferers (over 10 years) diagnosed by more than one specialist under 1990 American College of Rheumatology criteria. RESULTS: Microarray analysis of FM patient PBMCs evidenced a marked downregulation of hsa-miR223-3p, hsa-miR451a, hsa-miR338-3p, hsa-miR143-3p, hsa-miR145-5p and hsa-miR-21-5p (4-fold or more). All but the mildest inhibited miRNA, hsa-miR-21-5p, were validated by RT-qPCR. Globally, 20% of the miRNAs analyzed (233/1212) showed downregulation of at least 2-fold in patients. This might indicate a general de-regulation of the miRNA synthetic pathway in FM. No significant correlations between miRNA inhibition and FM cardinal symptoms could be identified. However, the patient with the lowest score for mental fatigue coincided with the mildest inhibition in four of the five miRNAs associated with the FM-group. CONCLUSIONS: We propose a signature of five strikingly downregulated miRNAs (hsa-miR223-3p, hsa-miR451a, hsa-miR338-3p, hsa-miR143-3p and hsa-miR145-5p) to be used as biomarkers of FM. Validation in larger study groups is required before the results can be transferred to the clinic. PMID- 25803873 TI - Calnexin is essential for survival under nitrogen starvation and stationary phase in Schizosaccharomyces pombe. AB - Cell fate is determined by the balance of conserved molecular mechanisms regulating death (apoptosis) and survival (autophagy). Autophagy is a process by which cells recycle their organelles and macromolecules through degradation within the vacuole in yeast and plants, and lysosome in metazoa. In the yeast Schizosaccharomyces pombe, autophagy is strongly induced under nitrogen starvation and in aging cells. Previously, we demonstrated that calnexin (Cnx1p), a highly conserved transmembrane chaperone of the endoplasmic reticulum (ER), regulates apoptosis under ER stress or inositol starvation. Moreover, we showed that in stationary phase, Cnx1p is cleaved into two moieties, L_Cnx1p and S_Cnx1p. Here, we show that the processing of Cnx1p is regulated by autophagy, induced by nitrogen starvation or cell aging. The cleavage of Cnx1p involves two vacuolar proteases: Isp6, which is essential for autophagy, and its paralogue Psp3. Blocking autophagy through the knockout of autophagy-related genes (atg) results in inhibition of both, the cleavage and the trafficking of Cnx1p from the ER to the vacuole. We demonstrate that Cnx1p is required for cell survival under nitrogen-starvation and in chronological aging cultures. The death of the mini_cnx1 mutant (overlapping S_cnx1p) cells is accompanied by accumulation of high levels of reactive-oxygen species (ROS), a slowdown in endocytosis and severe cell-wall defects. Moreover, mutant cells expressing only S_Cnx1p showed cell wall defects. Co-expressing mutant overlapping the L_Cnx1p and S_Cnx1p cleavage products reverses the death, ROS phenotype and cell wall defect to wild type levels. As it is involved in both apoptosis and autophagy, Cnx1p could be a nexus for the crosstalk between these pro-death and pro-survival mechanisms. Ours, and observations in mammalian systems, suggest that the multiple roles of calnexin depend on its sub-cellular localization and on its cleavage. The use of S. pombe should assist in further shedding light on the multiple roles of calnexin. PMID- 25803877 TI - [Medicaid eligibility]. PMID- 25803874 TI - Ectopic expression of a Neospora caninum Kazal type inhibitor triggers developmental defects in Toxoplasma and Plasmodium. AB - Regulated proteolysis is known to control a variety of vital processes in apicomplexan parasites including invasion and egress of host cells. Serine proteases have been proposed as targets for drug development based upon inhibitor studies that show parasite attenuation and transmission blockage. Genetic studies suggest that serine proteases, such as subtilisin and rhomboid proteases, are essential but functional studies have proved challenging as active proteases are difficult to express. Proteinaceous Protease Inhibitors (PPIs) provide an alternative way to address the role of serine proteases in apicomplexan biology. To validate such an approach, a Neospora caninum Kazal inhibitor (NcPI-S) was expressed ectopically in two apicomplexan species, Toxoplasma gondii tachyzoites and Plasmodium berghei ookinetes, with the aim to disrupt proteolytic processes taking place within the secretory pathway. NcPI-S negatively affected proliferation of Toxoplasma tachyzoites, while it had no effect on invasion and egress. Expression of the inhibitor in P. berghei zygotes blocked their development into mature and invasive ookinetes. Moreover, ultra-structural studies indicated that expression of NcPI-S interfered with normal formation of micronemes, which was also confirmed by the lack of expression of the micronemal protein SOAP in these parasites. Our results suggest that NcPI-S could be a useful tool to investigate the function of proteases in processes fundamental for parasite survival, contributing to the effort to identify targets for parasite attenuation and transmission blockage. PMID- 25803875 TI - Prevalence and associated factors of myopia in high-school students in Beijing. AB - PURPOSE: To evaluate prevalence and associated factors for myopia in high school students in Beijing. METHODS: Grade 10 and 11 high school students were randomly selected from nine randomly selected districts of Beijing. The students underwent non-cylcoplegic auto-refractometry and an interview. RESULTS: Out of 4798 eligible students, 4677 (93.4%) students (mean age:16.9+/-0.7years;range:16-18 years) participated. Mean refractive error of right eyes and left eyes was 2.78+/-2.29 diopters and -2.59+/-2.50 diopters, respectively. Prevalence of myopia (defined as <= -1.00 diopters in the worse eye) was 80.7% (95% Confidence Interval (CI): 79.6-81.8%). Out of 3773 students with myopia, 1525 (40.4%) wore glasses daily. In multiple logistic regression analysis, a higher prevalence of myopia was associated with female sex (odds ratio (OR) = 1.31;95%CI:1.11-1.55), Han ethnicity (OR = 1.64;95%CI:1.28-2.11), attending key schools (OR = 1.48;95%CI:1.24,1.77), higher family income (OR = 1.37;95%CI:1.09-1.71), longer time spent for near work (OR = 1.43;95%CI:1.06-1.93), shorter near work distance (OR = 1.87;95%CI:1.55-2.26), lower frequency of active rest during studying (OR = 1.40;95%CI:1.16-1.70), and parental myopia (OR = 2.28;95%CI:1.80-2.87). The interaction between distance from near work and time spent for near work was statistically (P = 0.03) significant. In multiple logistic regression analysis, higher prevalence of high myopia (<=-6.0 diopters) was associated with studying in key schools (OR = 1.38;95%CI:1.05,1.81), lower frequency of active rest during studying (OR = 1.40;95%CI:1.09,1.79), and a higher number of myopic parents (OR = 2.66;95%CI:2.08,3.40). CONCLUSIONS: A prevalence of about 80% for myopia and a prevalence of about 10% for high myopia in students aged 16 to 18 years and attending classes of grade 10 and 11 in a Chinese metropolitan region is another example of the high prevalence of moderate and high myopia in metropolitan areas of China. With this young myopic generation getting older, myopia as cause for visual impairment and blindness may further increase in importance. Future studies may address whether active rests during studying with looking into the distance are preventive against myopia development or progression. PMID- 25803878 TI - [My academic career at Hadassah, Jerusalem]. PMID- 25803876 TI - Prevalence and risk factors of restless legs syndrome among Chinese adults in a rural community of Shanghai in China. AB - AIMS: The primary objective of this study was to investigate the prevalence and risk factors of restless legs syndrome (RLS) in an adult Chinese population living in a rural community. We also aimed to determine the predictive diagnostic value of the 4-item screening questionnaire for RLS in this population. METHODS: This study was designed as a 2-phase survey. In phase 1 we performed a face-to face interview of eligible individuals living in a rural community in Shanghai using a 4-item screening questionnaire. In phase 2, sleep specialists performed a phone interview of the individuals who screened positive to diagnosis RLS. RESULTS: Forty-one RLS cases were confirmed among 2941 eligible individuals 18 years of age or older in the study community. The prevalence of RLS was 1.4% (95% confidence interval (CI) = 1.0-1.9%), with a significantly higher rate observed in females (1.9% [95%CI =1.3-2.7%]) than that in males (0.9% [95%CI = 0.5-1.5%], p = 0.019). The prevalence rate increased significantly with age, from 0.2% (95% CI = 0.08-0.6%) in those 18-39 years old to 4.1% (95% CI = 2.1-7.9%) in those >= 70 years old (p < 0.001). The multivariate logistic regression analysis indicated that gastritis, anemia and hypertension were risk factors for RLS. The sensitivity and specificity of the 4-item screening questionnaire used in this study were 63.4% and 97.5%, respectively. CONCLUSION: RLS prevalence is relatively low among Chinese adults living in rural Shanghai. Furthermore, population-based studies with a larger sample size and a longitudinal follow-up may help to determine the risk factors of RLS and potential interventions for RLS. PMID- 25803879 TI - Reply by authors. PMID- 25803880 TI - Analysis of the contributing factors to airway hyperresponsiveness by a forced oscillation technique in patients with asthma. AB - BACKGROUND: Forced oscillation technique (FOT) is increasingly used to obtain much information on the state of the respiratory system. However, there are little data about FOT parameters on methacholine provocation test in adult asthma. This study was designed to determine the physiological implications of FOT parameters during methacholine provocation and analyze the major contributing factors to airway hyperresponsiveness (AHR) in asthma. METHODS: Spirometry and FOT were performed in 22 asthmatic patients and 21 normal control subjects before and after provocation with a maximal dose of methacholine. RESULTS: In asthmatic patients, the percent increase in resistance at 5 Hz (R5) and resistance at 20 Hz (R20) after the methacholine provocation was 70 [45-93] % and 16 [5-23] %. The percent change in R20 was not significantly correlated with the percent change in FVC or FEV1. Similarly, the percent change in R5 was not significantly correlated with the percent change in FEV1, but was significantly correlated with the percent change in FVC. Moreover, the percent change in R5 was significantly correlated with the closing index (r = 0.55, p = 0.01). In addition, AHR to methacholine was closely correlated with the percent change in R5 (r = -0.71, p = 0.001). CONCLUSIONS: Simultaneous measurement of FOT and bronchial challenge test provide meaningful information, and greater change in R5 may represent exaggerated response of small airways in asthmatic patients. This study will provide new insights into the physiological implications of each FOT parameter in asthmatic patients. PMID- 25803881 TI - Sensory hypersensitivity in children with high-functioning pervasive developmental disorder. AB - BACKGROUND: Studies have shown that children with pervasive developmental disorder (PDD) have high rates of sensory hypersensitivity. In addition, a few recent studies suggested that sensory hypersensitivity was related to anxiety or depression. However, most studies had methodological limitations because they included children with mental retardation and did not examine broadband psychopathology. Therefore, the purpose of this study was to examine the prevalence of sensory hypersensitivity in children with high-functioning PDD (HFPDD) and the correlation among sensory hypersensitivity, various characteristics, and broadband psychopathology. METHODS: We assessed 132 children with HFPDD (aged 6-15 years, 75% male) that were divided into sensory hypersensitivity (HS) and sensory non-hypersensitivity (non-HS) groups. A logistic regression model was used to examine correlations among sensory hypersensitivity, age, gender, PDD subtypes, socioeconomic status, and broadband psychopathology, including symptoms of anxiety and depression. RESULTS: Of the 132 children with HFPDD, 65.9% (n = 87) were categorized as HS and 34.1% (n = 45) as non-HS. The most common sensory hypersensitivity was auditory. Logistic regression analyses revealed that sensory hypersensitivity in HFPDD was significantly associated with autistic disorder and symptoms of anxiety and depression. CONCLUSIONS: Majority of children with HFPDD exhibited sensory hypersensitivity. Our findings suggested that sensory hypersensitivity may be a core feature of HFPDD and is possibly correlated to symptoms of anxiety and depression. We propose that sensory hypersensitivity in children with PDD should be aggressively assessed. PMID- 25803882 TI - Correlation between right medial temporal lobe atrophy and persecutory delusions in patients with dementia of the Alzheimer's type demonstrated on VSRAD advance. AB - BACKGROUND: The relationship between focal brain atrophy and delusions in patients with Dementia of the Alzheimer's Type (DAT) is not well understood. Few studies have been reported on the association between medial temporal atrophy (MTA) and persecutory delusions in patients with DAT. We investigated the relationship between MTA and persecutory delusions in patients with DAT using voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) advance software, which allows us to quantify the laterality and the degree of MTA on magnetic resonance imaging (MRI) scans. METHODS: Thirty-one patients diagnosed with DAT were recruited and scanned with a 1.5 tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z score (Z-score) on the target VOI, with higher scores indicating more severe. These DAT patients were divided into a group with (D group: n = 13) and without (ND group: n = 18) persecutory delusions. RESULTS: In the D group, the mean the bilateral, right, and left Z-scores were 2.45, 2.69, and 2.19, respectively. These mean Z-scores of the ND group were 2.00, 2.00, and 1.95, respectively. The right Z-scores for the D group were significantly higher than those for the ND group (p < 0.05). CONCLUSIONS: These findings suggest that right MTA could contribute to the development of persecutory delusions in patients with DAT. PMID- 25803883 TI - Cerebral infarction in the left hemisphere compared with the right hemisphere increases the risk of aspiration pneumonia. AB - BACKGROUND: Aspiration pneumonia (AP) following cerebral infarction (CI) has been considered as one of its most serious complications. Nevertheless, there are no reports on the association between the type or location of CI and the incidence of AP. In addition, the association between dysphagia, which leads to aspiration, and the type or location of CI has never been investigated. Therefore we hypothesized that the laterality of CI affects the development of both dysphagia and AP. METHODS: We performed a retrospective cohort study to examine the association between the laterality of CI and the incidence of dysphagia and AP in 133 patients. RESULTS: AP was found in 6.0% of the group with left CI and in 0.8% of the group with right CI. A univariate logistic regression analysis revealed that left CI was a significant predictor of AP (hazard ratio, 8.81; 95% confidence interval, 1.07-72.59; p = 0.043). Left CI was a significant predictor of AP even after adjusting for age, sex, CI type, or presence of diabetes mellitus. In addition, although the frequency of dysphagia as the direct cause of AP did not differ according to laterality, the frequency of AP that ensued from dysphagia in the left CI group was greater than that observed in the right CI group. CONCLUSIONS: The group with left CI from the motor cortex to the internal capsule complicated by dysphagia exhibited a high risk of AP. PMID- 25803884 TI - Increased annexin A2 expression in the placenta of women with acute worsening of preeclampsia. AB - BACKGROUND: The aims of present study were to investigate the expression of Annexin A2 in the placenta of patients with preeclampsia (PE) and correlate these data with acute worsening of clinical symptoms. METHODS: Placentas were collected from uncomplicated normal pregnancies (n = 9), PE cases without emergency termination of pregnancy (group 1, n = 6), and PE cases with acute worsening of symptoms necessitating immediate pregnancy termination (group 2, n = 7). Immunohistochemistry data were analyzed quantitatively, and placental mRNA expression was measured by Real-time PCR. RESULTS: Group 2 had a significantly shorter interval between diagnosis and pregnancy termination compared with group 1 (p = 0.002). Birth weight and placental weight in group 2 were significantly lower compared with the normal group (p = 0.006 and p = 0.03, birth weight and placental weight, respectively), whereas there were no differences in gestational age at delivery between the three groups or the severity of high blood pressure and proteinuria between the PE groups. Placental expression of Annexin A2 as determined by immunohistochemistry was significantly higher in both PE groups compared with the uncomplicated pregnancy group (p < 0.001 and p < 0.001, groups 1 and 2, respectively). Placental Annexin A2 mRNA expression was significantly elevated in group 2 compared with the normal group (p = 0.002) but did not change in group 1. CONCLUSIONS: This study is the first to demonstrate increased placental Annexin A2 mRNA expression during the acute phase of PE. Immunohistochemical staining of placental Annexin A2 was high, regardless of PE phase. These findings suggest that worsening of PE might alter Annexin A2 expression at the transcription level. PMID- 25803885 TI - Fibrosing cholestatic hepatitis after successful interferon and ribavirin therapy for recurrent hepatitis C post living related liver transplantation: a case report. AB - A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed. PMID- 25803886 TI - [2-KGA metabolism coupling respiratory chain in Ketogulonigenium vulgare--a review]. AB - 2-keto-L-gulonate (2-KGA) is the key intermediate of vitamin C, which can be biosynthesized by Ketogulonigenium vulgare. There are five reactions related to 2 KGA metabolism, including: (1) Oxidation of D-sorbitol to L-sorbose; (2) Oxidation of L-sorbose to L-sorbosone; (3) Oxidation of L-sorbosone (Pyranose form) to 2-KGA; (4) Oxidation of L-sorbosone (Furanose form) to vitamin C, and (5) Reduction of 2-KGA to L-idonate. L-sorbose/L-sorbosone dehydrogenase (SSDH) is responsible for the reaction of 1 through 3, L-sorbose dehydrogenase (SDH) is responsible for the reaction of 2 and 3, L-sorbosone dehydrogenase (SNDH) is responsible for the reaction of 3 and 4, aldehyde dehydrogenase (ALDH) is responsible for the reaction of 3, 2-KGA reductase (2-KGR) is responsible for the reaction of 5. Enzymes of SDH, SSDH and ALDH belong to Quinoprotein Type I that uses PQQ as the only prosthetic group. SNDH belongs to Quinoprotein Type II that is quinohemoprotein assembling heme c and PQQ. They are all soluble in the periplasm and coupled with the respiratory chain. The substrate respiration to generate ATP directly on the outside cellular membrane means this strain can use the substrate quickly in the natural environment for the necessary bioenergy. PMID- 25803887 TI - [Transmembrane transport of inorganic mercury in microorganisms--a review]. AB - Methylmercury (CH3Hg+, or MeHg) is the most poisonous form of mercury (Hg) because it can enter into human bodies through the consumption of Hg-contaminated fish and shellfish. A first step toward bioaccumulation of MeHg in aquatic foods is the methylation of inorganic mercury, a process that is predominantly mediated by anaerobic bacteria, such as sulfate reducing bacteria and iron reducing bacteria. Many researches have confirmed that microbial methylation of mercury is an intracellular reaction. Therefore, MeHg production rates are not only related to the presence and productivity of methylating bacteria and also the biouptake of Hg to these anaerobic bacteria. To understand the pathways of Hg biouptake is indispensable to elucidate the mechanisms of microbial methylation. In this review, we systematically evaluated the current state of knowledge regarding the four pathways of mercury biouptake, Mer-based transport system, passive diffusion, facilitated diffusion and active transport. In the future, facilitated diffusion and active transport of inorganic mercury to the cytoplasm of microbial cells should be emphasized. PMID- 25803888 TI - [Bacterial diversity in littoral wetland of Wuliangsuhai Lake]. AB - OBJECTIVE: The aim of this study was to analyze the bacterial diversity of land water transition zone in littoral wetland of Wuliangsuhai Lake, and to study the effect of eutrophic substrate on the bacterial composition. METHODS: The denaturing gradient gel electrophoresis (DGGE) with PCR-amplified 16S rDNA fragments was used to determine bacterial diversity, and the ordination technique of canonical correspondence analysis (CCA) was used to evaluate its effects on bacterial community composition. RESULTS: DGGE result shows that the microbial quantity decreased gradually from eutrophic lake sediment to desert soil. Diversity index analysis shows that the Shannon-Wiener index (H), Evenness index (E), richness index (S) and Simpson index (Ds) decreased gradually from water to land (eutrophic lake sediment > swamp sediment > saline soil > desert soil). Based on the sequencing results, there are 3 phyla in 4 samples, including Proteobacteria (78.6%), Acidobacteria (7.1%), Bacteroidetes (14.3%), Proteobacteria (52.6%) were dominant species, in which the Epsilon proteobacteria were predominant subgroup. The results of CCA suggest that that NH4+ -N, total nitrogen, organic carbon, total soluble salt, Cl- and K+ have most significant influenced the distribution of bands related species. CONCLUSION: The bacterial community structure of transition zone in Wuliangsuhai wetland differed significantly, and eutrophic relative factors had a strong impact on the bacterial community structure. This work presented a certain reference for the preliminary understanding of the bacterial composition and diversity and provided a scientific foundation for the research of spatial heterogeneity in this transition zone. PMID- 25803889 TI - [Transcriptional regulation of bkd gene cluster in Bacillus thuringiensis]. AB - OBJECTIVE: In order to determine the effect of bkdR deletion on Cry protein production. We analyzed the transcriptional regulation of bkd gene cluster and the phenotype of bkdR mutant. METHODS: Sequence of bkd gene cluster in Bacillus thuringiensis was analyzed by sequence alignment. RT-PCRwas used to reveal the transcriptional units of the bkd gene cluster. bkdR insertion mutant was constructed by homologous recombination. Transcriptional activity was analyzed by promoter fusions with lacZ gene. Comparison of the CrylAc protein production was determined by protein quantitation. RESULTS: The bkd gene cluster was composed of eight genes. The ptb-bkdB formed one transcriptional unit. The transcriptional activity of ptb sharply decreased in sigL and bkdR mutants. Deletion of bkdR decreased the motility of cells, but no effect on growth, sporulation efficiency and Cry protein production. The bkd gene cluster is controlled by Sigma 54 and activated by BkdR. Deletion of bkdR has no effect on Cry protein production, but decreased the motility of the cells. CONCLUSION: The bkd gene cluster is controlled by Sigma 54 and activated by BkdR. Deletion of bkdR has nb effect on Cry protein production, but decreased the motility of the cells. It suggested that deletion of bkdR do not affect the Cry protein production the same as sigL mutant. It means decreasing of Cry protein productioninsigL mutant was not caused by only one EBP mutation, but might be multiple roles. PMID- 25803890 TI - [Expression of cry1Ac gene directed by PexsYpromoter of the exsY gene encoding component protein of exosporium basal layer in Bacillus thuringiensis]. AB - OBJECTIVE: To discover new elements for cry gene expression, PexsY, which is the promoter of the exosporium basal layer structural gene exsY, was used to express cry1Ac gene in Bacillus thuringiensis. METHODS: We used be ta- galactosidase assays by promoter-lacZ fusion to analyze the transcriptional activity of exsY promoter and truncated exsY promoter. The cry1Ac gene was directed by the non-cry gene promoter PexsY and was then expressed in Bacillus thuringiensis HD73. Transmission electron microscope (TEM) was used to observe the formation of crystal inclusion. The CrylAc yieldswere evaluated by protein quantification and SDS-PAGE analysis. Bioassays against Ostriniafurnacalis were used for the functional verification. RESULTS: Beta-galactosidase assays showed that the exsY promoter had a strong transcriptional activity in the acrystalliferous mutant strain HD73- on the late sporulation phase. Cry1Ac expression products directed by the PexsY could form diamond crystals. SDS-PAGE analysis showed that the cry1Ac gene directed by the cry8E promoter has the highest protein yield among the four promoters while the cry1Ac gene under the direction of PexsYorcry3A promoters showed similar protein yields. The bioassay results showed that the Cry1Ac protein directed by the PexsY promoter was toxic against Ostrinia furnacalis. CONCLUSION: The cry1Ac gene under the direction ofthe non-cry gene promoter PexsY was able to express the Cry proteins at the late sporulation phase and could form crystal inclusion in a B. thuringiensis strain. Our finding provides applicationpotential for the genetically modification of engineered Bt strains. PMID- 25803891 TI - [Carbohydrate metabolism and lactic acid biosynthesis of Lactococcus lactis subsp. lactis KLDS4.0325]. AB - OBJECTIVE: We aimed to study the carbohydrate metabolism and lactic acid biosynthesis of Lactococcus lactis KLDS4. 0325. METHODS: Whole genome shot gun strategy was used for genome sequencing of strain L. lactis KLDS 4. 0325. Then, using bioinformatics method, we compared a series of protein-coding genes involved in transporting extracellular carbohydrate, sugar metabolism and lactic acid biosynthesis of strain L. lactis KLDS4. 0325 with other 9 reference strains. RESULTS: In L. lactis KLDS4. 0325 genome, where possesses more key enzyme coding genes related to the whole pathway of sugar metabolism than reference strains. CONCLUSION: In gene level, therefore, strain L. lactis KLDS4. 0325 shows a remarkable characteristic by utilizing various sugar to produce lactic acid, is a lactic acid bacteria with industrial potential of high yield L-lactic acid. PMID- 25803892 TI - [Identification of a kojic-acid producing Aspergillus flavus F52]. AB - OBJECTIVE: We identified an endophytic fungus of Vigna unguiculata, as well as the influence of carbon sources on the production of kojic acid by the isolated fungus. METHODS: This kojic acid producer was identified as Aspergillus flavus F52 according to morphological characteristics and ITS region of rDNA. The metabolite of strain F52 was obtained by recrystallization, and identified as kojic acid based on the spectral data of NMR, HR-ESI/MS and IR. The fungus was cultivated in medium containing various carbon sources, and the production of kojic acid in the fermentation broth was quantified by high performance liquid chromatography. RESULTS: The complex carbon source which was composed of glucose and sucrose was preferential, whereas the presence of lactose was not beneficial to the production of kojic acid. The content of kojic acid in the fermentation broth reached 24.44 g/L. CONCLUSION: Aspergillus flavus F52 might be a potent producer of kojic acid for commercial use. PMID- 25803893 TI - [Screening and optimization of cholesterol conversion strain]. AB - OBJECTIVE: Bacterial strain SE-1 capable of transforming cholesterol was isolated from soil and characterized. The transformation products were identified. Fermentation conditions were optimized for conversion. METHODS: Cholesterol was used as sole carbon source to isolate strain SE-1. Morphology, physiological and biochemical characteristics of strain SE-1 were studied. 16S rRNA gene was sequenced and subjected to phylogenetic analysis. Fermentation supernatants were extracted with chloroform, the transformation products were analyzed by silica gel thin layer chromatography and Sephadex LH20. Their structures were identified by 1H-NMR and 13C-NMR. Fermentation medium including carbon and nitrogen, methods of adding substrates and fermentation conditions for Strain SE-1 were optimized. RESULTS: Strain SE-1 was a Gram-negative bacterium, exhibiting the highest homologs to Burkholderia cepacia based on the physiological analysis. The sequence analysis of 16S rRNA gene of SE-1 strain and comparison with related Burkholderia show that SE-1 strain was very close to B. cepacia (Genbank No. U96927). The similarity was 99%. The result of silica gel thin layer chromatography shows that strain SE-1 transformed cholesterol to two products, 7beta-hydroxycholesterol and the minor product was 7-oxocholesterol. The optimum culture conditions were: molasses 5%, (NH4 )2SO4 0.3%, 4% of inoculation, pH 7.5 and 36 degrees C. Under the optimum culture condition, the conversion rate reached 34.4% when concentration of cholesterol-Tween 80 was 1 g/L. Cholesterol 7beta-hydroxylation conversion rate under optimal conditions was improved by 20.8%. CONCLUSION: Strain SE-1 isolated from soil is capable of converting cholesterol at lab-scale. PMID- 25803895 TI - [Heterologous expression and characterization of L200F/D215K mutant of homoserine dehydrogenase from Corynebacterium pekinense AS1.299]. AB - OBJECTIVE: To obtain a new homoserine dehydrogenase with better properties from Corynebacterium pekinense by the spatial structure transfromation. METHODS: Double mutants L200F/D215A, L200F/D215E, L200F/D215G and L200F/D215K were constructed by site-directed mutagenesis and expressed in E. coli BL21. L200F/D215K was characterized for its highest catalytic efficiency and compared with that of L200F. RESULTS: The Vmax of L200F/D215K was 36.92 U/mg, 1.24 times as that of L200F. The optimum reaction temperature of L200F/D215K was 37 degrees C, 2 degrees C higher than that of L200F. The optimum pH of L200F/D215K was 7.5, the same as that of L200F. The half-life time of L200F/D215K under optimum temperature was 4.16 h and was 1.12 times as that of L200F. Both L200F/D215K and L200F had good resistance to organic solvents and metal ions. CONCLUSION: Through the spatial structure transformation, the enzymatic activity was increased, and the enzymology properties was optimized. PMID- 25803894 TI - [Sequence characterization and differential expression of a glutathione S transferase gene vv-gto1 from Volvariella volvacea]. AB - OBJECTIVE: Based on the analysis of omics data of Volvariella volvacea, a gene encoding glutathione S- transferase (GSTs) named vv-gtol was obtained. To reveal the role of GSTs in the growth and development in edible fungi, the structure, the sequence characters and the expression profile of a GST gene vv-gto1 of Volvariella volvacea were analyzed. METHODS: ZOOM software was used to map sequencing read (reads) from genome and transcriptome against the splicing sequence of genome, to confirm the complete length and the accuracy of the gene sequence, and to visualize gene structure. The MEGA 5.1 was used to do the multiple sequence alignment and phylogenetic tree analysis. Real time fluorescent quantitative PCR was used to determine the expression levels of vv-gtol at different growth periods of Volvariella volvacea. RESULTS: The full sequence of vv-gtol covered 2083 bp, containing 11 exons and 10 introns, and encoded a protein with 356 amino acids. 5'UTR was 305 bp which contains one intron region, and 3'UTR was 86bp. Two intron retentions could be recognized during RNA processing, and the transcripts formed by the intron retention could not translate the correct conservative functional domains. The full-length of vv-gtol had more than 50 accurate positioning genome sequencing reads, suggesting that genome sequencing and assembly results are accurate and reliable. The phylogenetic tree showed that GTO1 of Volvariella volvacea belonged to the subclass I of the Omega class of glutathione S-transferase superfamily, and had the closest relationship with GTO1 and GTO2 in Phanerochaete chrysosporium. The analysis of digital gene expression profiling, fluorescence quantitative PCR and proteomics showed that vv-gtol had the highest expression level in the heterokaryotic hyphae. CONCLUSIONS: This is the first time to obtain a gene encoding glutathione S-transferase from Volvariella volvacea which belongs to Omega class. Our study showed that the gene may play an important role during the special biological functions of heterokaryotic hyphae. This study also suggested that Volvariella volvacea heterokaryotic hyphae in H1521 had stronger resistance ability than other samples. In addition, vv-gto1 could form different alternative splicesome to regulate gene transcription and translation, and ultimately affect the function of the protein. PMID- 25803897 TI - [Adaptation of Acidianus hospitalis W1 to oligotrophic and acidic hot spring environments]. AB - OBJECTIVE: To study the adaptation of A. hospitalis W1 to oligotrophic and acidic hot spring environments at the whole genome level. METHODS: We annotated the gene functions and constructed metabolic pathways of strain W1 by using different databases, such as NCBI non-redundant database (NRDB), UniProt, Sulfolobus protein database and Kyoto Encyclopedia of Genes and Genomes (KEGG). The metabolic pathways were polished according to the results of comparative genomics. RESULTS: Strain W1 grew autotrophically by fixing CO2 as carbon source through 3-hydroxypropionate/4-hydroxybutyrate or dicarboxylate-4-hydroxybutyrate cycle, and gained energy for growth by oxidation of reduced inorganic sulfur compounds (RISCs). Strain W1 differenced from A. ambivalens because its genome did not possess sulfur-metabolizing genes encoding sulfite: acceptor oxidoreductase, adenosine phosphosulfate reductase, sulfate adenylyl transferase and phosphoadenosine phosphosulfate reductase. Glucose was metabolized by strain W1 through non- phosphorylated Entner-Doudoroff pathway and tricarboxylic acid cycle. In addition, the sugar and amino acids transporters, as well as related hydrolysis enzymes were identified in the genome. These results suggest that strain W1 could also grow facultative autotrophically. Strain W1 cannot use H2 as electron donor due to lack of hydrogenase encoding genes. CONCLUSION: The versatile metabolic patterns afforded A. hospitalis W1 the ability to adapt to oligotrophic and acidic hot spring environments. Furthermore, the unique metabolic features of strain W1 will help to better understand the metabolic diversities of Acidianus. PMID- 25803896 TI - [Characterization of Candida albicans ferric reductase genes in response to environmental stresses]. AB - OBJECTIVE: Ferric reductases play a central role in iron acquisition and mobilization in C. albicans. This study focuses on stress response strategies exhibited by several ferric reductase genes through function and expression analyses. METHODS: Northern blot analysis was used to examine ferric reductase genes expression levels in different iron deficiency. We constructed ferric reductase-null mutants by a PCR-based homologous recombination, and examined the effects of gene deletion on cell-surface ferric reductase activity and growth ability under different conditions. Sub-cellular localization of Frpl-GFP fusion was imaged and analyzed by confocal laser scanning fluorescence microscopy. RESULTS: FRE10 was highly expressed at acidic pH, compared to that at alkaline pH, whereas the expression of FRE2 was just the opposite. Deletion of FRE10 resulted in a significant decreased surface reductase activity at acidic pH, with 75.5% down-regulation compared to wild-type levels. The fre2delta/delta mutant showed significantly attenuated growth ability and cell-surface ferric reductase activity at alkaline pH. Sub-cellular localization revealed that the green fluorescence was accumulated in the vacuoles. CONCLUSION: The expression of both FRE10 and FRE2 is induced in a pH-dependent manner. FRE2 encodes a major cell surface ferric reductase under alkaline pH condition. Frp1 localizes to the vacuole, and might support mobilization and transport of vacuolar ferric iron stores. PMID- 25803898 TI - [Inhibitory effects of biochanin A on the efflux pump of methicillin-resistant Staphylococcus aureus (MRSA)]. AB - OBJECTIVE: To study the inhibitory effect of biochanin A on efflux system of Methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Inhibitory effects of biochanin A on efflux system of Strain MRSA41577 were evaluated using double dilution method, two plate method and fluorescence spectrophotometry. Real time PCR and SDS-PAGE were applied to detect the expression of MRSA41577 norA and to analyze the changes of MRSA41577 efflux protein before and after dosing biochanin A in association with liquid chromatography mass spectrometry to determinate protein variation. RESULTS: Biochanin A alone had no inhibitory effect on MRSA41577, but it showed synergy effect with ciprofloxacin in inhibition MRSA41577 in which 40pg/mL biochanin A decreased the minimum inhibitory concentration (MIC) value of ciprofloxacin from 64 microg/mL to 8 microgg/mL. Biochanin A significantly increased the accumulation of ciprofloxacin in MRSA41577 in a time-dependent manner. At 15 min, biochanin A increased ciprofloxacin in MRSA41577 by 83%, which is similar to that of reserpine (positive control). Further mechanism studies indicated that biochanin A could reduce the expression of nor A in ciprofloxacin-treated MRSA41577. After incubated with biochanin A and ciprofloxacin for 16 h, the relative expression of nor A of MRSA41577 was reduced by 65%. SDS-PAGE analysis showed that the total protein profiles of MRSA41577 were significantly changed after treatment with biochanin A for 16h, in which both norA protein and efflux system ABC transporter ATP-binding protein were significantly decreased. CONCLUSION: Biochanin A could inhibit Methicillin-resistant Staphylococcus aureus efflux system through reducing pathogen' s expression of nor A and norA protein. PMID- 25803899 TI - [NF-kappaB-induced gp96 up-regulation promotes hepatocyte growth, cell cycle progression and transition]. AB - OBJECTIVE: To investigate the mechanism of gp96 raised during hepatitis B virus (HBV) infection and the pathological mechanism. METHODS: The mechanism of NF-KB activating gp96 expression was determined by bioinformatics analysis, luciferase reporter assay, real-time PCR and Western blot. The effect of over-expression and knockdown gp96 expression by transfection or RNA interference on hepatocyte proliferation, apoptosis and cell cycle was examined by CCK-8 and flow cytometry. The role of gp96 for HCC development was determined by epithelial-mesenchymal transition (EMT) and colony formation assay. RESULTS: NF-kB significantly increased the gp96 expression by binding to the NF-kappaB binding site. Over expression and knockdown studies both show that gp96 promoted hepatocyte proliferation, inhibited apoptosis, and induced G0/G1 to S phase cell cycle progression. Moreover, gp96 induced epithelial-mesenchymal transition and increased colony formation ability of hepatocytes. CONCLUSION: Our results therefore provide insights in chronic HBV infection-induced gp96 expression, and indicate that elevated gp96 may contribute to HCC development during chronic inflammation. PMID- 25803900 TI - [Overexpression, purification and characterization of phospholipase C from Acinetobacter calcoaceticus]. AB - OBJECTIVE: In this study, we constructed two recombinant Escherichia coli strains to produce phospholipase C (PLC) from Acinetobacter calcoaceticus. The recombinant enzymes were purified to homogeneity and characterized. [Methods] We cloned the PLC encoding gene plc1, plc2 from genome DNA of A. calcoaceticus ATCC17902. The amplified fragments were inserted into pET28a(+ to obtain expression plasmids. E. coli BL21 (DE3) harboring the above plasmids were cultivated and induced with isopropyl-beta-D-thiogalactopyranoside to express PLCs. The recombinant PLCs were purified by affinity chromatography and their catalytic properties were characterized. RESULTS: Two PLCs from A. calcoaceticus were cloned and functional expressed in E. coli. The recombinant enzymes have activities of 31,160 +/- 418 U/mg for PLC1 and 13640 +/- 354 U/mg for PLC2, when using p-nitrophenyl phosphorycholine as substrate. The purified PLC1 and PLC2 exhibited optimum temperature at 65 degrees C and 50 degrees C, respectively. Their optimal pH were 8 and 7.5, respectively. PLC2 was stable under 40 degrees C and pH at 8, whereas the residual activity of PLC1 was less than 25% in the same condition. Mg2+ and Ca2+ stimulated two enzymes activity, whereas Zn2. stimulated PLC1 and inhibited PLC2. PLC1 and PLC2 hydrolyzed phosphatidylinositol. CONCLUSION: It is the first time to express and characterize the PLC gene from A. calcoaceticus ATCC17902. These research results provide reference for the study of food-safety microbiological PLC. PMID- 25803902 TI - [Internet addiction disorder in children]. PMID- 25803901 TI - [Quantitation of intestinal Fusobacterium and butyrate- producing bacteria in patients with colorectal adenomas and colorectal cancer]. AB - OBJECTIVE: To compare the abundance of 16S rRNA gene of intestinal Fusobacterium and butyrate-producing bacteria in patients with colorectal adenomas patients and colorectal cancer and to reveal the correlation between the target bacteria and the development of colorectal cancer. METHODS: Feces were collected from colorectal cancer patients (n=19), colorectal adenomas patients (n=12) and healthy subjects (n=19). Bacteria genome DNA from the fecal samples was used to quantitate the Fusobacterium, two butyrate-producing bacteria Eubacterium rectal, Faecalibacterium prausnitzii and total bacteria by real-time polymerase chain reaction. Then the variation of the target bacteria among different groups were assayed using Mann-Whitney U test. RESULTS: The abundance of Fusobacterium was significantly higher in colorectal cancer patients than that in healthy subjects (P = 0.000) and colorectal adenomas patients (P = 0.013), and it was significantly higher in colorectal cancer patients than that in colorectal adenomas patients (P = 0.002). F. prausnitzii was significantly lower in colorectal adenomas patients compared to healthy subjects (P = 0.033). The total bacteria count was significantly lower in the colorectal adenomas samples than that in the healthy samples (P = 0.002). There was no significantly difference of E. rectal between the three groups. CONCLUSIONS: The shifts in the colonic bacterial population may potentially contribute to the development of colorectal cancer. PMID- 25803903 TI - [A girl showing congenital heart defects and psychomotor developmental delay]. PMID- 25803904 TI - [Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy]. AB - Glycosylphosphatidylinositol (GPI) is a glycolipid, which anchors 150 or more types of proteins to the cell surface. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins (GPI-APs). Many inherited GPI deficiencies (IGDs) have been recently found using whole-exome sequencing. Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death. The major symptoms of IGDs include intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms vary in severity depending upon the degree of the defect and/or position in the pathway of the affected gene. We clarified a mechanism of hyperphosphatasia, which is characterized by elevated release of tissue nonspecific alkaline phosphatase. Hyperphosphatasia is observed in some patients with IGDs, such as hyperphosphatasia mental retardation syndrome or Mabry syndrome, caused by mutations in genes in the later stage of GPI biosynthesis. The possibility of IGD should be considered in patients with seizures and intellectual disability. The presence of hyperphosphatasia is strong evidence of IGD. Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD. PMID- 25803905 TI - [Electroencephalographic characteristics in patients with febrile status epilepticus]. AB - OBJECTIVE: This study was undertaken to investigate the electroencephalographic (EEG) characteristics in patients with febrile status epilepticus. METHODS: Medical records and EEG findings were retrospectively examined in 14 patients with febrile status epilepticus, who were transferred to the Shiga University Hospital between November, 2009 and March, 2012. RESULTS: Mean time to the initial EEG examination from the cessation of febrile status epilepticus was 3.4 hours. delta waves were seen in 9 of 11 patients during awake or forced awake state, and these slow waves disappeared on or after the 2nd day. Slow waves were predominantly detected in the occipital and frontal leads in 4 and 2 patients, respectively, while diffuse slowing was seen in 4 patients. Spindle/hump waves were observed in 10 of 11 patients, but not detected in the 3 patients because only awake recordings were available. CONCLUSIONS: EEGs in the postictal state of febrile status epilepticus show slow waves, but improve early, then normal EEG sleep pattern such spindle/hump waves are commonly recognized thereafter. PMID- 25803906 TI - [Effects of topiramate on headache in children with epilepsy]. AB - OBJECTIVES: The purpose of the present study was to evaluate the efficacy and safety of topiramate (TPM) on inter-ictal headache in children with epilepsy. METHODS: Patients were interviewed regarding whether they suffered from headaches. Data obtained from each patient included seizure frequency. Inter ictal headache was defined as a headache beginning outside an hour before or after the seizure. The study group included 85 outpatients (42 valproate-treated, 34 carbamazepine-treated, 6 combination therapy, 3 other) between 5 and 15 years old. For children with headache, TPM was administered twice daily at a total initial dose of 0.5 mg/kg/day, up to 3.0 mg/kg/day in accordance with symptoms. RESULTS: Of 85 patients, 18 (21.2%) patients (8 valproate-treated, 6 carbamazepine-treated, 3 combination therapy, and 1 other) complained of inter ictal headache. Seizure frequency was significantly higher in children with headache (2.6 times/year) than in children without headache (0.9 times/year; p < 0.0001). The responder rate (rate of patients with a > 50% reduction in headache frequency or degree) was 13/18 (72%). Six children (33.3%) achieved complete cessation for the entire 6 months. Mean dose of TPM was significantly lower in responders (1.1 mg/kg/day) than in non-responders (2.7 mg/kg/day; p < 0.001). CONCLUSIONS: Headache is encountered more frequently in patients with frequent seizures. In addition, TPM represents a useful addition to the treatments available for headache in children with epilepsy. The effective dose of TPM for headache may be lower than that for seizure. PMID- 25803907 TI - [A nationwide survey on the uses of melatonin and ramelteon in Japanese children]. AB - OBJECTIVE: We carried out a questionnaire survey to investigate the uses of melatonin and ramelteon in Japanese children. METHODS: We sent a questionnaire to councilors of the Japanese Society of Child Neurology by e-mail, and sent the same questionnaire to members of the Japanese Society of Pediatric Psychiatry and Neurology by postal mail. RESULTS: During the first phase of the survey, 220 responses were obtained, and 45% of the respondents prescribed melatonin. Imported supplements and chemical reagents were used by 64% and 29% of melatonin prescribers, respectively. Some prescribed melatonin without patient consent or institutional approval. In patients with pervasive developmental disorder, cerebral palsy, attention-deficit hyperactivity disorder, Rett syndrome, and visual disturbance, melatonin was prescribed by 37%, 29%, 10%, 6%, and 6% of the respondents, respectively. In terms of sleep disorders, melatonin was prescribed by 49% and 42% of respondents in patients with circadian rhythm disorders and insomnia, respectively. Ramelteon was prescribed by 52% of respondents. Regarding types of target diseases and sleep disorders, the use of ramelteon differed little from that of melatonin. In the second phase of the survey on the use of melatonin, 23 doctors prescribed the drug for 254 patients. The daily effective dose ranged from 0.2 mg to 8 mg in patients aged 2 months to 37 years. In more than 60% of the patients who took melatonin, PDD was diagnosed. In the patients with melatonin for insomnia, 90% and 25% had difficulty falling asleep and disorders in circadian rhythm, respectively. CONCLUSIONS: Both melatonin and ramelteon were widely prescribedin Japanese children. Melatonin tended to be used without sufficient ethical consideration in Japan, indicating the necessity of melatonin as medicine. Then, careful determination of an applicable dose are required in future studies. PMID- 25803908 TI - [Effectiveness of continuous infusion of tizanidine (Ternelin) via a feeding tube for patients with the mixed type of tetraplegia]. AB - OBJECTIVE: Severe muscle hypertonia in patients with the mixed type of tetraplegia may be associated with significant deterioration in the quality of life of the patients. Intermittent use of oral muscle relaxant drugs, for example, Tizanidine (Ternelin), which is a fast-acting muscle relaxant, can provide relief from the severe hypertonia in these patients, but only for short durations. METHODS: We conducted a retrospective study of the effect of continuous infusion of tizanidine via a feeding tube on the severe systemic muscle hypertonia in patients with the mixed type of tetraplegia. We mixed tizanidine with milk or other enteral nutrients and administered the mixture via a naso-duodenal tube at a constant infusion rate several hours to 5 patients with the mixed type of tetraplegia showing severe uncontrolled systemic hypertonia under intermittent treatment with oral muscle relaxant drugs. RESULTS: Significant relief from the systemic muscle hypertonia was obtained in 4 of the 5 patients with improvement of the quality of life of the patients, e. g., they could get adequate sleep. There were no serious side effects in any of the cases. CONCLUSION: We consider that continuous infusion of tizanidine via a feeding tube would be useful for the treatment of severe systemic hypertonia in patients in whom the symptom cannot be adequately controlled by intermittent use of oral muscle relaxant drugs. PMID- 25803909 TI - [A clinical study on high-dose erythropoietin therapy for acute encephalopathy or encephalitis]. AB - OBJECTIVE: We performed high-dose erythropoietin therapy (hEPO) for acute encephalopathy or encephalitis (AE), and evaluated its safety and efficacy. METHODS: We performed hEPO in AE patients with widespread lesions demonstrated by diffusion-weighted imaging, and prospectively investigated changes in hemoglobin levels, adverse events, changes in images, and developmental quotients. RESULTS: All four patients showed neither an increase in the hemoglobin level nor adverse event possibly related to hEPO. One patient with acute encephalitis showed resolution of the lesion and normal developmental quotient. Two patients who had acute encephalopathy with febrile convulsive status epilepticus showed mild cerebral atrophy in the recovery phase;one had a normal developmental quotient. The patient with acute necrotizing encephalopathy including a brainstem lesion avoided acute-phase death. CONCLUSION: Two patients showed no sequelae despite images indicating widespread abnormality. hEPO could be performed safely in patients with AE, however further trials are necessary concerning its efficacy. PMID- 25803910 TI - [Long-term prognosis of children with cerebrovascular disease]. AB - OBJECTIVE: Reports of the prognosis of cerebrovascular disease (CVD) in children have not been common. We investigated the prognoses in 71 children with CVD, which were composed of 43 and 28 patients, suffering from hemorrhagic stroke (HS) and ischemic stroke (IS), respectively. They were followed for at least one year after the stroke event. METHODS: The average age of onset was 9 years 8 months in HS and 6 years 8 months in IS, the present ages being 13 years 5 months and 12 years 5 months, respectively. The medical records were reviewed, and the clinical courses during the acute stage and the state of sequelae were investigated. RESULTS: The etiologies were rupture of the arteriovenous malformation in 29 cases in HS, and traumatic brain damage, during rewarming from hypothermia therapy or during operations such as for heart diseases in IS. An age-related characteristic was seen in the heart diseases operation group. The main damaged regions were the frontal lobe, temporal lobe, parietal lobe, and cerebellum in HS, and the middle cerebral arterial area, basal ganglia, and frontal lobe in IS. The damage in the infra-tentorial area was more frequent in HS than in IS. The sequelae comprised physical disabilities in 39 cases with HS and 25 cases with IS, mental disabilities in 11/11, epilepsy in 4/7, and higher brain dysfunction such as attention deficit in 31/26. Severe disabilities were low as one case each. CONCLUSION: The etiology, region, and sequelae differed between HS and IS in children. PMID- 25803911 TI - [Long-term outcome of childhood hypoxic-ischemic encephalopathy]. AB - OBJECTIVE: To propose an adequate rehabilitation program for children suffering from hypoxic-ischemic encephalopathy (HIE) based on estimated outcomes. METHODS: Participants were 42 children, 28 boys and 14 girls, who suffered from HIE after neonatal period. We divided them into three groups; favorable (GMFCS level 1 or 2), moderate (level 3 or 4), and unfavorable (level 5), and compared the extent of brain lesions on MRI, age of onset, and complications among the groups. RESULTS: The number of children in favorable, moderate, and unfavorable groups was 10, 10 and 22, respectively. All children in favorable and moderate groups showed focal cerebral lesions on MRI. In contrast, most children in unfavorable group (19/22) had diffuse brain damage and the rest were infantile onset with focal cerebral lesions. The etiology and situation of HIE did not differ among three groups. Three children in moderate group whose onsets were earlier than 5 months showed lesions similar to those in neonatal HIE; in bilateral basal ganglia, thalamus, and perirolandic cortex. In favorable group, 7 children were able to walk independently within 5 months after the insult, but 9 had moderate or severe mental retardation and 3 showed severe visual impairment. A majority of unfavorable group developed scoliosis or hip dislocation, and underwent tracheostomy or gastrostomy. Five children who had stayed acute hospitals for longer than 6 months developed irreversible complications such as joint contractures before discharge. CONCLUSIONS: Children with focal cerebral lesions need continual rehabilitation and education for mental retardation and visual impairment, even if they can walk within several months after HIE. Those with diffuse brain damage need sufficient rehabilitation as early as possible to avoid developing secondary complications. MR image, age of onset, and clinical course were of great prognostic value to make appropriate long-term rehabilitation and education programs. PMID- 25803912 TI - [A family with creatine transporter deficiency diagnosed with urinary creatine/creatinine ratio and the family history: the third Japanese familial case]. AB - Creatine transporter deficiency (CRTR-D) is an X-linked disorder characterized by hypotonia, developmental delay, and seizures. We report the third Japanese family with CRTR-D. The proband was an 8-year-old boy who presented with hypotonia, severe intellectual disability and two episodes of seizures associated with/without fever. Among 7 siblings (4 males, 3 females), the eldest brother had severe intellectual disability, epilepsy, and sudden death at 17 years of age, while 18-year-old third elder brother had severe intellectual disability, autism, and drug-resistant epilepsy. The proband's urinary creatine/creatinine ratio was increased. A reduced creatine peak on brain magnetic resonance spectroscopy and a known pathogenic mutation in the SLC6A8 gene (c.1661 C > T;p.Pro554Leu) confirmed the diagnosis of CRTR-D. The same mutation was found in the third elder brother. Their mother was a heterozygote. Symptoms of CRTR-D are non-specific. Urinary creatine/creatinine ratio should be measured in patients with hypotonia, developmental delay, seizure and autism whose family history indicates an X linked inheritance. PMID- 25803913 TI - [Energy expenditure measured by the flow-through indirect calorimetry in children with severe motor and intellectual disabilities]. PMID- 25803915 TI - Politicizing science: conceptions of politics in science and technology studies. AB - This essay examines five ideal-typical conceptions of politics in science and technology studies. Rather than evaluating these conceptions with reference to a single standard, the essay shows how different conceptions of politics serve distinct purposes: normative critique, two approaches to empirical description, and two views of democracy. I discuss each conception of politics with respect to how well it fulfills its apparent primary purpose, as well as its implications for the purpose of studying a key issue in contemporary democratic societies: the politicization of science. In this respect, the essay goes beyond classifying different conceptions of politics and also recommends the fifth conception as especially conducive to understanding and shaping the processes whereby science becomes a site or object of political activity. The essay also employs several analytical distinctions to help clarify the differences among conceptions of politics: between science as 'political' (adjective) and science as a site of 'politics' (noun), between spatial-conceptions and activity-conceptions of politics, between latent conflicts and actual conflicts, and between politics and power. The essay also makes the methodological argument that the politics of science and technology is best studied with concepts and methods that facilitate dialogue between actors and analysts. The main goal, however, is not to defend a particular view of politics, but to promote conversation on the conceptions of politics that animate research in social studies of science and technology. PMID- 25803914 TI - [Low dose L-dopa therapy and SST improved communication skill in a female autistic child]. PMID- 25803916 TI - 'The artist's piece is already in the stone': constructing creativity in paleontology laboratories. AB - Laboratory technicians are typically portrayed as manual workers following routine procedures to produce scientific data. However, technicians in vertebrate paleontology laboratories often describe their work in terms of creativity and artistry. Fossil specimens undergo extensive preparation--including rock removal, damage repair, and reconstruction of missing parts--to become accessible to researchers. Technicians called 'fossil preparators' choose, apply, and sometimes invent these preparation methods. They have no formal training, no standard protocols, and few publications to consult on techniques. Despite the resulting diversity of people and practices, preparators and their work are usually absent from research publications, making them 'invisible technicians' in Steven Shapin's sense. But preparators reject the view of their work as predictable or simple; in particular, many preparators value art training, the aesthetics of prepared fossils, and the process of creative problem-solving in their work. Based on interviews and participant observation and drawing from literature in science studies, sociology of work, and anthropology of craft, I ask why these technicians compare themselves with artists and how this portrayal affects scientific practice and social order in laboratories. I argue that associating artistry and creativity with their work distances preparators from ideas of unskilled technical work and technicians' low status, thus improving their social role in the laboratory community and preserving their power over laboratory practices. PMID- 25803917 TI - Sustaining cyborgs: sensing and tuning agencies of pacemakers and implantable cardioverter defibrillators. AB - Recently there has been a renewed interest in cyborgs, and particularly in new and emerging fusions of humans and technologies related to the development of human enhancement technologies. These studies reflect a trend to follow new and emerging technologies. In this article, I argue that it is important to study 'older' and more familiar cyborgs as well. Studying 'the old' is important because it enables us to recognize hybrids' embodied experiences. This article addresses two of these older hybrids: pacemakers and implantable cardioverter defibrillators inserted in the bodies of people suffering from heart-rhythm disturbances. My concern with hybrid bodies is that internal devices seem to present a complex and neglected case if we wish to understand human agency. Their 'users' seem to be passive because they cannot exert any direct control over the working of their devices. Technologies inside bodies challenge a longstanding tradition of theorizing human-technology relations only in terms of technologies external to the body. Cyborg theory is problematic as well because most studies tend to conceptualize the cyborg merely as a discursive entity and silence the voices of people living as cyborgs. Inspired by feminist research that foregrounds the materiality of the lived and intimate relations between bodies and technologies, I argue that creating these intimate relations requires patients' active involvement in sustaining their hybrid bodies. Based on observations of these monitoring practices in a Dutch hospital and interviews with patients and technicians, the article shows that heart cyborgs are far from passive. On the contrary, their unique experience in sensing the entangled agencies of technologies and their own heart plays a crucial role in sustaining their hybrid bodies. PMID- 25803918 TI - Trust in standards: transitioning clinical exome sequencing from bench to bedside. AB - Clinical exome sequencing is a genetic technology making the transition from a laboratory research tool to a routine clinical technique used to diagnose patients. Standards help make this transition by offering authoritative shortcuts for time-intensive tasks, but each shortcut means that something is lost during abstraction. In clinical exome sequencing, reliance on standards may obscure the match between a patient's phenotype and genotype. Based on three years of observations, I show how a clinical exome sequencing team decides when to trust standards and when to develop workarounds. I argue that the match between phenotype and genotype is circumscribed by the team's reliance on specific standards and that trusting in standards means trusting in experts' appropriate use of standards, generating a workflow of reflexive standardization. PMID- 25803919 TI - Nanotechnology researchers' collaboration relationships: a gender analysis of access to scientific information. AB - Women are underrepresented in science, technology, engineering, and mathematics fields, particularly at higher levels of organizations. This article investigates the impact of this underrepresentation on the processes of interpersonal collaboration in nanotechnology. Analyses are conducted to assess: (I) the comparative tie strength of women's and men's collaborations, (2) whether women and men gain equal access to scientific information through collaborators, (3) which tie characteristics are associated with access to information for women and men, and (4) whether women and men acquire equivalent amounts of information by strengthening ties. Our results show that the overall tie strength is less for women's collaborations and that women acquire less strategic information through collaborators. Women and men rely on different tie characteristics in accessing information, but are equally effective in acquiring additional information resources by strengthening ties. This article demonstrates that the underrepresentation of women in science, technology, engineering, and mathematics has an impact on the interpersonal processes of scientific collaboration, to the disadvantage of women scientists. PMID- 25803920 TI - Reviving a ghost in the history of technology: the social construction of the recumbent bicycle. AB - Recumbent bicycles have never truly been associated with international cycling. Conventional safety (upright) bicycles have long been at the center of the cycling world, for both sport and transportation. This is despite the fact that recumbent bicycles are faster, more comfortable, and more efficient than the upright bicycles. The aim of this article is to explain the historical and social perspectives that led to the rejection of the recumbent bicycle by utilizing the theory of Social Construction of Technology (SCOT) and Bijker's two power theory, providing a contrast with the adoption of the safety bicycle. PMID- 25803921 TI - Infrastructure and the state in science and technology studies. PMID- 25803922 TI - Subject matter: human behavior, psychological expertise, and therapeutic lives. PMID- 25803923 TI - [Meeting session dedicated to pediatrics]. PMID- 25803924 TI - [Pediatric medicine in 2013]. AB - Three specific characteristics must be taken into account in our management of the pediatric patient: each child is a developing person and therefore vulnerable, and is also part of a family. Our reflections and practices must be guided by these three characteristics. The following aspects are dealt with here: -Healthcare organization must emphasize the importance of collaborative networks, -All child-oriented preventive actions and screening programs have a dual aim: to preserve the health of the individual concerned, and also to improve public health. One must never forget that children's current health status will determine the health of tomorrow's adults. The resources provided by the government be therefore commensurate with these objectives. -Management of common diseases but also specific and complex health disorders such as chronic diseases and disabilities, -The need to provide pertinent answers to lifestyle questions posed not only by the child and his/her family, but also by other pediatric professionals, -Specific pediatric research and knowledge dissemination. PMID- 25803925 TI - [Pediatrics at an academic medical center: organization of university pediatric services]. AB - Pediatric medicine is one of the most important activities of any teaching hospital. Its internal organization depends on the size of the hospital and must take into account not only its missions of advice, reference and proximity, but also economic issues. Regional networking with general hospitals, private clinics and community pediatricians is necessary, if only to regulate use of the emergency department. The activity of pediatric units fluctuates over time and is not always controllable, involving both rapid turnover and extended stays. Cost of health is often underestimated or unadapted, and many units are in financial deficit despite their best efforts. University pediatrician training is highly demanding in order to ensure the quality of recruitment, but it must be sufficiently flexible if it is to attract a suficient number of candidates. As with other specialties, research is relatively easy to evaluate, contrary to teaching and clinical activity. PMID- 25803926 TI - [Pediatric emergency care in pediatric hospitals in France]. AB - Emergency medicine has evolved considerably over the last 25 years in France, driven by major sociological and epidemiological upheavals, and is now a high level and academic specialty. Pediatric emergency units were originally modeled on adult emergency services and now meet the same efficiency criteria. However, the reduction in care supply, together with the simultaneous increase in demand, has created significant deficiencies. This is particularly true in pediatric teaching hospitals, which deal with the highest volume of patients but are subject to cost-cutting and eficiency measures. The main problems are the lack of flow management upstream and inadequate hospital capacity downstream. Solutions have been proposed to mitigate these issues but more efforts are needed. PMID- 25803927 TI - [Pediatric private practice: stakes, difficulties and future perspectives]. AB - Paediatrics is the medicine of the developing human being, the future adult. In France, this role is mainly ensured by private-practice pediatricians. The pediatrician's field of action is highly varied, sometimes going far beyond organic medicine to cover children's emotional, educational and sociocultural environment, with the overriding aim of helping them to make the best use of their skills and to become healthy, well integrated adults. Unfortunately, there is a lack of private practice pediatricians in France and their geographic distribution is highly uneven. Private practice must be reorganized to ensure that all children have access to a pediatrician. PMID- 25803928 TI - [Meeting session dedicated to HIV infection]. PMID- 25803930 TI - [Towards eradication of human immunodeficiency virus (HIV)?]. AB - Antiretroviral therapy has led to massive improvement in the prognosis of HIV infected patients. In France, more than 80% of patients have suppressed HIV viremia and prolonged survival. However, current antiretroviral strategies are unable to eradicate HIV, and treatment therefore has to be maintained for life, raising issues of long-term toxicity, comorbidities, resistance, and cost. Several factors explain our inability to eradicate HIV including viral latency in long-lived memory T cells, the persistence of immune activation despite suppression of viral replication in plasma, and persistent low-level viral replication in different compartments. Various international research strategies are currently addressing these issues with the ultimate aim of finding a cure. PMID- 25803929 TI - [Expanded testing and early treatment of HIV]. PMID- 25803931 TI - [Humanitarian and health day. Presentation]. PMID- 25803932 TI - [The Raoul Follereau Foundation]. PMID- 25803933 TI - [Handicap International]. PMID- 25803934 TI - [Health initiatives of the International Red Cross]. PMID- 25803935 TI - [Emergencies and first aid of the French Red Cross]. PMID- 25803937 TI - [Access to care and prevention, a priority of the Secours Populaire in France]. PMID- 25803936 TI - [The Chain of Hope]. PMID- 25803938 TI - [Humanitarian medicine as a model for humanitarian action]. AB - Humanitarian action is undergoing profound changes. Beyond the emergency relief phase, it is becoming involved in the processes that enable victims to regain their autonomy and, more recently, in prevention and risk-reduction policies. This trend is similar to that experienced by humanitarian medicine which, after focusing on emergency situations, is now involved in rehabilitation and prevention programs. The concept of resilience is perfectly suited to each phase of humanitarian interventions. Moreover, local communities are increasingly seeking to achieve their humanitarian emancipation. This trend must be anticipated, specifically by profiling future aid workers, and is similar to that faced by humanitarian medicine. PMID- 25803939 TI - [The french Maternity and Pediatric Hospital in Kaboul (Afghanistan): Making the impossible possible]. PMID- 25803940 TI - [The Research Center and the Fight Against Sickle Cell Anemia of Bamako: an example of a North-South public private partnership]. PMID- 25803941 TI - [Spontaneous models of human diseases in dogs: ichthyoses as an example]. AB - Ichthyoses encompass a heterogeneous group of genodermatoses characterized by abnormal desquamation over the entire body due to defects of the terminal differentiation of keratinocytes and desquamation, which occur in the upper layer of the epidermis. Even though in humans more than 40 genes have already been identified, the genetic causes of several forms remain unknown and are difficult to identify in Humans. Strikingly, several purebred dogs are also affected by specific forms of ichthyoses. In the Golden retriever dog breed, an autosomal recessive form of ichthyosis, resembling human autosomal recessive congenital ichthyoses, has recently been diagnosed with a high incidence. We first characterized the disease occurring in the golden retriever breed and collected cases and controls. A genome-wide association study on 40 unrelated Golden retriever dogs, using the canine 49.000 SNPs (single nucleotide polymorphisms) array (Affymetrix v2), followed by statistical analyses and candidate gene sequencing, allowed to identify the causal mutation in the lipase coding PNPLA1 gene (patatin-like phospholipase domain-containing protein). Screening for alterations in the human ortholog gene in 10 autosomal recessive congenital ichthyoses families, for which no genetic cause has been identified thus far, allowed to identify two recessive mutations in the PNPLA1 protein in two families. This collaborative work between "human" and "canine" geneticists, practicians, histopathologists, biochemists and electron microscopy experts not only allowed to identify, in humans, an eighth gene for autosomal recessive congenital ichthyoses, but also allowed to highlight the function of this as-yet unknown skin specific lipase in the lipid metabolism of the skin barrier. For veterinary medicine and breeding practices, a genetic test has been developed. These findings illustrate the importance of the discovery of relevant human orthologous canine genetic diseases, whose causes can be tracked in dog breeds more easily than in humans. Indeed, due to the selection and breeding practices applied to purebred dogs, the dog constitutes a unique species for unravelling phenotype/genotype relationships and providing new insights into human genetic diseases. This work paves the way for the identification of rare gene variants in humans that may be responsible for other keratinisation and epidermal barrier defects. PMID- 25803942 TI - [Neonatal medicine, past and present]. AB - This review deals with early neonatal medicine and its rapid development as a medical specialty, starting with the birth of neonatology in the early 19th century. Shaffer first used the term neonatology in 1963 to cover neonatal disorders and their treatment. Between the early 19th century and the 1950s, neonatal care was ensured by obstetricians, whose main goal was to reduce neonatal mortality. After the second world war, and especially the 1960s, the development of neonatal physiology and pathophysiology provided insights into neonatal diseases and their treatment, including respiratory distress, jaundice, malnutrition, and prevention of respiratory distress and brain complications, etc. Currently, neonatal mortality, regardless of birth weight, is below 2/1000, and the survival rate of premature infants, regardless of gestational age and birth weight, exceeds 85%. This represents a resounding success, despite the associated costs, ethical issues, and inevitable morbidity. PMID- 25803943 TI - Participation and occupation: the need for a human rights perspective. PMID- 25803944 TI - "Do-Live-Well": a Canadian framework for promoting occupation, health, and well being. AB - BACKGROUND: Occupational therapists can bring a unique and valuable perspective to the national dialogue on health promotion. Current approaches have a narrow focus on diet and exercise; a broader focus on occupation has the potential to enrich understanding regarding forces that contribute to health and well-being. PURPOSE: A new "Do-Live-Well" framework will be presented that is grounded in evidence regarding the links between what people do every day and their health and well-being. KEY ISSUES: Elements of the framework include eight different dimensions of experience and five key activity patterns that impact health and well-being outcomes. Personal and social forces that shape activity engagement also affect the links to health and well-being. IMPLICATIONS: The framework is designed to facilitate individual reflection, community advocacy, and system level dialogue about the impact of day-to-day occupations on the health and well being of Canadians. PMID- 25803945 TI - Uncovering the theoretical underpinnings of an interprofessional preschool intervention program: Tumbling Together. AB - BACKGROUND: Intervention programs are rarely tailored for children with self regulation and communication challenges. Therefore, clinicians develop their own programs as is the case with the preschool program Tumbling Together. This program combines occupational therapy, speech-language therapy, and gymnastics. PURPOSE: The aim of this study was to take an in-depth look at the program to answer the following questions: (a) What are the fundamental concepts of the program? and (b) What is the underlying theoretical model that illustrates the relationships between concepts? METHOD: The qualitative research method of grounded theorizing using situational analysis was employed. FINDINGS: Fourteen main concepts of the program were identified and informed the development of a theoretical model. IMPLICATIONS: A theoretical model incorporating Tumbling Togethers concepts is a first step in evaluating its efficacy. Although the concepts involved are not novel, their unique combination forms a promising intervention approach for this population. PMID- 25803946 TI - Video methodologies in research: unlocking the complexities of occupation. AB - BACKGROUND: Video methods are used by numerous academic disciplines researching human action. Occupational therapists and scientists have primarily employed video data to enumerate subcomponents of occupational behaviour, to conduct reliability tests, and to study clinical reasoning. There is a gap in the literature using video data to explore complex dimensions of typical occupational behaviour. PURPOSE: This paper aims to encourage the use of video methodology beyond its current state in research on occupation. KEY ISSUES: Drawing on recent theoretical developments in the literature and empirical illustrations from a video-based project with migrants, this paper demonstrates thepotential contributions of video data to understandings of identity, the physical environment, the stream of occupations, and collective occupations. The paper also discusses the unique advantages and richness of collecting video data in comparison to interviews and traditional observations. The challenges in employing video methodologies are discussed. IMPLICATIONS: Video research offers unprecedented opportunities to study human occupation in incommensurable detail as it unfolds through sociocultural and physical environments. PMID- 25803947 TI - Coping strategies associated with participation and quality of life in older adults. AB - BACKGROUND: It is important to understand the coping strategies that optimize or restrict participation or quality of life, especially for older adults. PURPOSE: The purpose of this study was to examine the associations between, on the one hand, problem- and emotion-focused coping strategies used to deal with aging limitations or health problems and, on the other hand, participation and quality of life. METHOD: A cross-sectional design was used with 82 community-dwelling participants aged 65 and older. FINDINGS: Participants used both problem-focused (distancing, self-control) and emotion-focused (seeking social support, planful problem solving, positive appraisal) coping strategies to deal with aging limitations or health problems. Only a few moderately significant associations were found except for escape-avoidance coping strategies, which were significantly associated with lower participation and quality of life. IMPLICATIONS: Before developing interventions to improve or maintain older adults' participation and quality of life, more studies are needed to better understand coping strategies used by older adults to deal with aging limitations or health problems and especially escape-avoidance strategies. PMID- 25803948 TI - An occupation-based video feedback intervention for improving self-awareness: protocol and rationale. AB - BACKGROUND: Impaired self-awareness can limit rehabilitation outcomes for people with traumatic brain injury (TBI). Video feedback on occupational performance has been found to improve self-awareness after TBI when delivered according to specific principles. PURPOSE: The purpose of this article is to describe an occupation-based video feedback intervention found to be effective in a randomized controlled trial to assist with translation into clinical practice. KEY ISSUES: The intervention uses therapist-mediated video feedback on clients' occupational performance, aiming to facilitate self-reflection on performance and improve self-awareness. This paper describes the theoretical background, intervention principles, and protocol of the intervention. IMPLICATIONS: Therapists can use video feedback intervention, incorporating the principles in this article, to improve people's intellectual awareness and ability to recognize and correct errors during task performance after TBI without a negative impact on emotional status. PMID- 25803949 TI - Peer support as a catalyst for recovery: a mixed-methods study. AB - BACKGROUND: Peer support involves people in recovery from mental illness supporting their peers. PURPOSE: This mixed-methods pilot randomized control trial with qualitative interviews aimed to (a) compare peer support worker (PSW) and mental health worker (MHW) client outcomes and (b) provide estimates to inform the design of a larger study. METHOD: Fifteen adults living with a mental illness and receiving services at a community health team were randomly assigned to a PSW or a MHW group. The Quality of Life Interview-Brief Version was administered at baseline and after 6 months of intervention. Participants completed a semi-structured exit interview. FINDINGS: While both groups improved from baseline to 6 months, the PSW group did not improve more than the MHW group. Interviews highlighted therapeutic alliance and boundaries. IMPLICATIONS: This research adds to existing literature that PSWs produce outcomes similar to nonpeer staff and struggle with boundaries related to their unique role. PMID- 25803950 TI - Falling litigation rates in the US: could Ireland adopt similar measures. PMID- 25803951 TI - Children's television and nutrition. PMID- 25803952 TI - Referral letters to the emergency department: is the medication list accurate? AB - Medication errors are common when patients transfer across healthcare boundaries. This study was designed to investigate the quality of information on medicines provided by general practitioners (GPs) on emergency department (ED) referral letters. A convenience sample of referral letters to the ED of a teaching hospital was reviewed. The medication list and/or patient's drug allergy status were noted. Medicines reconciliation including patient (or carer) interview was conducted to determine the patient's actual home medication list. This was compared with the GP list and any discrepancies were identified and addressed. A total of 92 referral letters were included in the analysis of which 60 were computer-generated and 32 were hand-written. GPs provided dose and frequency of administration information in 47 (51%) of the letters sampled i.e. 44 (71%) computer-generated versus 3 (10%) hand-written; p < 0.001. In addition, the patient was taking their medicines exactly as per the GP list in 20 (22%) of cases. The patient's drug allergy status was documented in 13 (14%) of the letters. PMID- 25803953 TI - Can you die from obstructive sleep apnoea syndrome (OSAS)? AB - Studies suggest an independent association between Obstructive Sleep Apnoea Syndrome (OSAS) and cardiovascular death. The purpose of our study is to examine doctors' awareness of this association and to determine whether this correlates with recording of OSAS on death certificates. We contacted the Central Statistics Office (CSO) and obtained relevant mention of OSAS on death certificates. We surveyed doctors on their view of OSAS-related deaths, CSO data from 2008-2011 reveal two deaths with OSAS documented as a direct cause and 52 deaths with OSAS as a contributory cause. Seventy-five doctors' surveyed (41%) believe OSAS can be a direct cause of death and 177 (96%) believe OSAS can be an indirect cause of death. Only 22 (12%) had putdown OSAS as a cause of death. OSAS is seldom recorded on death certificates. This is at odds with epidemiological forecasts and contrary to an opinion poll from a selection of doctors. PMID- 25803954 TI - Sickle cell disease: time for a targeted neonatal screening programme. AB - Ireland has seen a steady increase in paediatric sickle cell disease (SCD). In 2005, only 25% of children with SCD were referred to the haemoglobinopathy service in their first year. A non-funded screening programme was implemented. This review aimed to assess the impact screening has had. All children referred to the haemoglobinopathy service born in Ireland after 2005 were identified. Data was collected from the medical chart and laboratory system. Information was analysed using Microsoft Excel. 77 children with SCD were identified. The median age at antibiotic commencement in the screened group was 56 days compared with 447 days in the unscreened group, p = < 0.0003. 22 (28%) of infants were born in centre's that do not screen and 17 (81%) were over 6 months old at referral, compared with 14 (21%) in the screened group. 6 (27%) of those in the unscreened group presented in acute crisis compared with 2 (3%) in the screened population. The point prevalence of SCD in Ireland is 0.2% in children under 15 yr of African and Asian descent. We identified delays in referral and treatment, which reflect the lack of government funded support and policy. We suggest all maternity units commence screening for newborns at risk of SCD. It is a cost effective intervention with a number needed to screen of just 4 to prevent a potentially fatal crisis. PMID- 25803955 TI - Hospital to home paediatric enteral nutrition--parents need support. AB - This study assessed the provision of education and support to parents of children on home enteral nutrition (HEN), current dietetic support available and perceived challenges facing parents and carers. From the 39 responses (13%), 29 (83%, n = 35) parents suggested services for HEN need improvement. 29 (74%, n = 39) parents wanted more structured follow up and 22 (56%) would like one person to co ordinate HEN, education and discharge. 7 parents (18%) reported a need for further education of health care professionals (HCP). Hospital dietitians were the most common HCPs reported to provide support to patients following discharge. Specialist paediatric HEN dietetic services working in a dedicated HEN team, who would provide accurate training and education and liaise with both parents and community care services post discharge should be in place. This would facilitate transfer to community care, reduce hospital re-admissions, outpatient department attendances and costs. PMID- 25803956 TI - Expanding access to rheumatology care: the rheumatology general practice toolbox. AB - Management guidelines for many rheumatic diseases are published in specialty rheumatology literature but rarely in general medical journals. Musculoskeletal disorders comprise 14% of all consultations in primary care. Formal post-graduate training in rheumatology is limited or absent for many primary care practitioners. Primary care practitioners can be trained to effectively treat complex diseases and have expressed a preference for interactive educational courses. The Rheumatology General Practice (GP) Toolbox is an intensive one day course designed to offer up to date information to primary care practitioners on the latest diagnostic and treatment guidelines for seven common rheumatic diseases. The course structure involves a short lecture on each topic and workshops on arthrocentesis, joint injection and DXA interpretation. Participants evaluated their knowledge and educational experience before, during and after the course. Thirty-two primary care practitioners attended, who had a median of 13 (IQR 6.5, 20) years experience in their specialty. The median number of educational symposia attended in the previous 5 years was 10 (IQR-5, 22.5), with a median of 0 (IQR 0, 1) in rheumatology. All respondents agreed that the course format was appropriate. Numerical improvements were demonstrated in participant's confidence in diagnosing and managing all seven common rheumatologic conditions, with statistically significant improvements (p < 0.05) in 11 of the 14 aspects assessed. The Rheumatology Toolbox is an effective educational method for disseminating current knowledge in rheumatology to primary care physicians and improved participant's self-assessed competence in diagnosis and management of common rheumatic diseases. PMID- 25803958 TI - Access to diagnostics in primary care and the impact on a primary care led health service. AB - We undertook a postal survey of GPs to establish their current access to radiological and endoscopic tests. More than one fifth of GPs do not have direct access to abdominal (n = 42, 21.4%) or pelvic (n = 49, 24.6%) ultrasound in the public system. Where access is available public patients have an average 14 week waiting period. In stark contrast in the private system virtually all GPs have direct access (n = 159, 99.2% and n = 156, 98.8% respectively for abdominal and pelvic ultrasound) with an average wait of just over four days. Direct access to CT scan in the public system is available to the minority of GPs, e.g. n = 31, 18.4% for chest scan, in the public system; even where available, there is an average 12 week wait for this. In comparison 151 (88.6%) GPs have access to CT chest scanning in the private sector with an average waiting time of 5.4 working days. Such limited access to diagnostics impacts on the delivery of a quality service. PMID- 25803957 TI - Acute stroke unit improves stroke management-four years on from INASC. AB - The Irish Heart Foundation carried out the Irish National Audit of Stroke Care (INASC) in 2008. Management practices were significantly poorer than those in the UK Sentinel audits. Since then an acute stroke unit has been established in University Hospital Limerick. A stroke database was established. 12 key indicators of stroke management audited by INASC were identified. Results were compared to those in INASC. 89 stroke patients were admitted. 8 of the 12 key indicators scored significantly better than in INASC. 92.5% had a brain scan within 24hrs (INASC-40%, p = < 0.001). 100% of ischaemic strokes received anti thrombotics (INASC-85%, p = 0.001). 94% had rehab goals agreed by MDT (22% in INASC p = 0.0000). 55% were treated in stroke unit (2% in INASC, p = 0.0000). MDT input improved with regard to physiotherapy (87% vs 43% in INASC, p = < 0.02) and SALT (74% vs 26%, p = < 0.02). Stroke management has significantly improved from 2008, however some deficiencies remain. PMID- 25803959 TI - Chronic kidney disease and obesity in Ireland: comparison of self-reported coronary artery disease in population study with clinic attendees. AB - Obesity is a growing issue in Ireland. The link between obesity, CKD and CAD has not previously been described in the Irish population. The prevalence of obesity and CKD was compared across 3 groups: population based estimates with self reported CAD, population based estimates without self-reported CAD (SLAN-07) and a random selection of cardiology outpatients with CAD. The SLAN-07 is a representative survey of 1207 randomly selected participants >= 45 years. Validated methods measured parameters including waist circumference, blood pressure and markers of renal function specifically glomerular filtration rate (eGFR) and albumin: creatinine ratio. The Cardiology clinic surveyed a random selection of 126 participants >= 45 years with CAD. Similar parameters were measured using the validated methods utilised in SLAN-07 study. Prevalence of obesity and renal disease was significantly higher in both CAD groups. At population level, risk factors were modelled using logistic regression to compare odds of participants with self-reported CAD with those without. Age, hypertension, obesity, elevated waist circumference, renal disease and diabetes are significantly associated with existing CAD. Obesity and CKD are more frequent in patients with CAD. Routine evaluation is essential to facilitate more intensive management of these risk factors. PMID- 25803960 TI - New hazards in paediatric poisoning presentations. AB - Accidental ingestion is an important preventable cause of childhood morbidity. All accidental ingestion presentations (n = 478) to a tertiary paediatric ED from January 2010 to December 2011 were analysed. These results were compared with a similar study in the same institution ten years previously in 2001 and showed that while accidental ingestions constituted a higher proportion of presentations (0.5% in this study v 0.45% in 2001), fewer had investigations performed (21% v 35%) and fewer were admitted (7% v 20%). Accidental ingestions account for 0.5% of presentations and are an important focus of home safety information for parents and guardians. Paracetamol (n = 67, 14%) and liquid detergent capsules (n = 44, 9.2%) were the two most common substances implicated in these presentations, and have the potential to cause severe morbidity and mortality. PMID- 25803961 TI - Sweet syndrome revealing systemic lupus erythematosus. AB - Sweet Syndrome is an acute inflammatory skin eruption which is rare in children. We report a case of childhood Systemic Lupus Erythematosus (SLE) that presented with Sweet syndrome. This case is a unique presentation of a common disorder which provides a new facet for the differential diagnosis of SLE in children. It is also the first paediatric case to be reported in a Caucasian child. PMID- 25803962 TI - Erdheim-Chester disease. PMID- 25803963 TI - The role of oximetry in patients with obstructive sleep apnea. PMID- 25803965 TI - Relation of cuspal asymmetry to development of aortic stenosis in adults with tricuspid aortic valves. AB - BACKGROUND AND AIM OF THE STUDY: The contribution of aortic valve (AV) cusp asymmetry to the future development of aortic stenosis (AS) has not been studied. METHODS: Of the 412,458 patients that underwent echocardiography between January 2003 and January 2011 at the Cleveland Clinic, 34,326 with aortic stenosis (AS) were identified from the Echocardiography Database. Among these patients, 5,830 had undergone echocardiography on more than one occasion. The review identified 71 patients who had tricuspid AV without stenosis, sclerosis or calcification, who met the study criteria, and who ultimately developed AS at a mean of 56.5 +/- 19.4 months after the initial echocardiogram. Comprehensive echocardiographic AV cusp measurements taken from these echocardiograms were compared to those of 71 age- and gender-matched control subjects without AS. RESULTS: In the AS group, 11 patients (15.4%) had three equal-sized AV cusps, six (8.4%) had two equal-sized cusps, and 54 (76.1%) had three different-sized cusps. In the control group, 70 subjects (98.6%) had three equal-sized AV cusps, none had two equal-sized cusps, and one subject (1.4%) had three different-sized cusps. The average asymmetry index (AIx; %) among all the corresponding cusp measurements was significantly larger in the AS group (p = 0.000). Among the 71 AS patients, 32 developed mild AS, 30 moderate AS, and nine severe AS. The average AIx did not differ significantly based on AS severity. CONCLUSION: The presence of asymmetry among AV cusps is strongly associated with the future development of AS. The present data suggest that a non-laminar flow secondary to an asymmetric valve may predispose the AV to become stenotic. PMID- 25803964 TI - The role of inorganic pyrophosphate in aortic valve calcification. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve (AV) calcification is a major cause of morbidity and mortality, yet the molecular mechanisms involved are poorly understood. Hence, an ex vivo model of calcification in intact AVs was developed in order to test the role of orthophosphate and pyrophosphate (PPi), both of which factors are known to influence vascular calcification. METHODS: Porcine AV leaflets were cultured in serum-free medium under static conditions for eight days, over which time leaflet architecture and viability were preserved. Calcification was measured as the incorporation of 45Ca, with confirmation by Alizarin Red staining. RESULTS: Calcification required both a high phosphate concentration (3.8 mM) and removal of PPi with alkaline phosphatase or inorganic pyrophosphatase. Calcification occurred predominantly on the fibrosa and was arrested by the bisphosphonate etidronate, a non-hydrolyzable analog of PPi. Leaflets released PPi into the medium, and this was enhanced by MLS38949, a specific inhibitor of tissue non-specific alkaline phosphatase (TNAP). Furthermore, leaflets synthesized PPi from extracellular ATP, which was reduced by beta,gamma-methylene-ATP, an inhibitor of ectonucleotide pyrophosphorylase phosphodiesterase (NPP1). CONCLUSION: The ex vivo AV calcification model developed in the present study showed that extracellular PPi, produced by valvular tissue, is a potent inhibitor of valvular calcification. In addition to synthesis, hydrolysis by TNAP also controls PPi levels and calcification. The results suggest that a decreased synthesis or increased hydrolysis of pyrophosphate may contribute to valvular calcification, and that bisphosphonates or inhibitors of TNAP are potential preventive strategies of the process. TNAP are potential preventive strategies. PMID- 25803966 TI - Relationship between bicuspid aortic valve phenotype, valvular function, and ascending aortic dimensions. AB - BACKGROUND AND AIM OF THE STUDY: Bicuspid aortic valve (BAV) is known to be associated with aortic valve dysfunction and ascending aorta (AA) dilatation. However, the relationship between BAV morphology and AA dimensions remains unclear. Thus, the study aim was to characterize the aortic valve function and AA dimensions according to the presence of raphe and BAV phenotype. METHODS: A total of 164 patients with BAV who underwent aortic valve surgery between October 2007 and November 2012 was investigated. BAV was classified as either type I (anterior posterior orientation) or type II (right-left orientation), and subdivided as raphe+ (presence of raphe) and raphe-(no raphe). RESULTS: Type I BAV was present in 103 patients (62.8%), and raphe+ in 100 (61.0%). Patients with raphe+ were typically younger than those with raphe-, and male gender was more predominant (88.0% and 53.1%, respectively, p < 0.05). Aortic regurgitation was more common in patients with type I and raphe+ BAV, and aortic stenosis in patients with type II and raphe- BAV. In patients with raphe+, the diameters of aortic annulus related to the body surface area (BSA) were larger, and the diameters of the tubular portion of AA indexed to BSA were smaller than in patients with raphe- (p < 0.05). CONCLUSION: BAV morphology is helpful for predicting the type of aortic valve dysfunction and the location of AA dilatation. PMID- 25803967 TI - Long-term outcomes after aortic valve repair and associated aortic root reconstruction. AB - BACKGROUND AND AIM OF THE STUDY: The advantages of aortic valve repair and root reconstruction include the maintenance of natural valve hemodynamics and an avoidance of prosthetic valve-related complications. However, the general acceptance of valve reconstruction currently may be limited by a paucity of long term follow up data from only a few centers. The study aim was to supplement existing outcome information for aortic valve repair. METHODS: Between 2003 and 2012, a total of 150 consecutive patients (119 males, 31 females; mean age 51.1 years) with significant aortic regurgitation and aortic root enlargement underwent aortic valve repair and associated root reconstruction. The same prospective selection criteria and systematic valve repair approaches were followed throughout the study. Root management consisted of either root remodeling or reimplantation with Dacron prostheses. Kaplan-Meier techniques were used to assess major end-points of all-cause mortality, reoperation, and repair failure. Univariable log-rank testing identified any associations between risk factors and major events. RESULTS: The early mortality rate was 2.7% (n = 4), and early repair failure rate 3.3% (n = 5). At a mean follow up of 43.6 months (1st, 3rd percentile, 17.8, 78.0 months), the survival rate was 93% and freedom from reoperation 91%. Univariable risk factors for mortality included advanced preoperative NYHA class and a requirement for root replacement. Repair failure and reoperation were associated with bicuspid valve anatomy, subcommissural annuloplasty, leaflet resection with pericardial patching, and Gore-Tex leaflet reinforcement. CONCLUSION: The present data, acquired from a prospective cohort of patients undergoing aortic valve repair and root reconstruction, reinforced the satisfactory late results obtained with valve reconstruction. These findings also support a broader application of aortic valve repair in future patients. PMID- 25803968 TI - Aortic interleaflet triangles reshaping: hydrodynamic, kinematic and morphological effects in in-vitro analysis. AB - BACKGROUND AND AIM OF THE STUDY: Subcommissural triangles reshaping is a reparative technique used to remodel the ventriculo-aortic junction. The study aim was to evaluate, by means of in-vitro testing, the effects of this technique on hemodynamics, leaflet kinematics and aortic root functional unit morphology. METHODS: Twenty-one porcine aortic roots were tested in a pulsatile mock loop under basal conditions and after subcommissural triangles reshaping performed at 50% of the interleaflet triangles height. During each test, hydrodynamic quantities, high-speed digital videos and echocardiographic images were recorded. RESULTS: The comparison between pre- and post-surgery data showed a statistically significant increase in coaptation height (p < 0.01) and length (p < 0.01). Significant reductions were found in the virtual basal ring diameter (p < 0.01), sinus of Valsalva diameters (p < 0.01), maximum leaflet opening (p < 0.01), leaflet opening before rapid valve closing time (p < 0.01) and maximum opening area (p < 0.01). An opened valve time reduction (p <0.01) was observed due to an opening time reduction (p < 0.01), offset by a closed valve time increase (p < 0.01). A slow closing period increase (p < 0.07) and a rapid closing phase reduction (p < 0.01), were also highlighted without influence on the total closing time. A statistical, but not clinically significant, increase in pressure drop across the valve (p < 0.01) and an effective orifice area reduction (p < 0.01) were observed. CONCLUSION: Subcommissural triangles reshaping performed at 50% of the interleaflet triangles' height determines an increase in leaflet coaptation by remodeling the ventriculo-aortic junction. Some hydrodynamic and kinematic changes also occur, without any acute clinically threatening alterations. PMID- 25803969 TI - Comparison of myocardial tagging and feature tracking in patients with severe aortic stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Transcatheter aortic valve implantation (TAVI) has become an effective treatment for severe aortic stenosis (AS) in patients considered to be at high surgical risk. However, data relating to myocardial function and deformation in these patients are rare. Cardiovascular magnetic resonance (CMR) tagging has been established as non-invasive technique for the accurate measurement of myocardial motion. However, additional tagging datasets are necessary and the post-processing procedure is time-consuming. Recently, the novel technique of feature tracking (FT) was introduced, with which myocardial strain can be derived directly from balanced steady-state free precession (bSSFP) cine sequences. The study aim was to compare tagging with FT in patients with high-grade AS and who had been considered for TAVI. METHODS: Thirty patients with severe AS underwent cardiac magnetic resonance imaging at 1.5 T (Philips Achieva). A stack of serial short-axis slices was used to assess left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and LV mass and function. TomTec 2D Cardiac Performance Analysis software was used to derive myocardial deformation parameters from three short-axis cine views (basal, medial and apical levels) using bSSFP. All patients also underwent myocardial tagging on identical short-axis views, and data acquired from FT and tagging were compared. RESULTS: The mean left ventricular ejection fraction (LVEF), LVEDV and LVESV (57 +/- 14%, 158 +/- 58 ml, and 74 +/- 48 ml, respectively) were all normal. All patients demonstrated concentric hypertrophy of the left ventricle with an increased basal septal thickness (16 +/- 3 mm), LV mass (126 +/- 40 g) and indexed LV mass (68 +/- 23 g/m2, papillary muscles excluded). Bland-Altman analysis revealed a reasonable agreement between basal and medial circumferential strain (cc), and a good correlation was observed between tagging and FT for the derived basal and medial cc (Pearson's correlation coefficient 0.83 for basal, 0.74 for medial). Basal rotation was impaired compared to previous studies in patients with AS, but medial and apical rotations were comparable. The apical peak diastolic rotation velocity was faster compared to earlier analyses. Rotation, peak systolic and end-diastolic rotation velocity did not demonstrate any correlation or acceptable agreement between FT and tagging. The inter observer agreement as assessed by the intra- class correlation coefficient for FT showed good results for the cc (basal 0.94, medial 0.83, apical 0.75). CONCLUSION: To the present authors' knowledge, this is the first study to assess myocardial motion using tagging and FT in patients with AS prior to TAVI. A reasonable agreement was found for the basal and medial cc between both techniques. Estimated cc-values using FT were systematically higher than those with tagging, but this might have been due to the different techniques employed. Although FT is a promising method to assess cc, further studies including the evaluation of standard values--and investigations with different diseases are necessary. PMID- 25803971 TI - Aortic dilation rates in patients with biscuspid aortic valve: correlations with cusp fusion phenotype. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the pattern and rate of aortic dilation in patients with isolated non-surgical bicuspid aortic valve (BAV) with left-right fusion (L-R) and right-non coronary fusion (R-N). Although the etiology and optimal management of aortic dilation associated with BAV remain the subject of debate, recent data have suggested that L-R and R-N cusp fusion phenotypes represent distinct pathological entities. METHODS: Consecutive patients with BAV and at least two echocardiographic assessments made between 2006 and 2012 were reviewed. Patients with hemodynamically significant valvular disease, aortic aneurysm (> 50 mm) or unrepaired aortic coarctation were excluded. Longitudinal analyses of the aortic annulus, sinuses of Valsalva, sinotubular junction and ascending aortic diameters were performed using mixed effect models. RESULTS: A total of 590 echocardiographic studies was analyzed in 212 patients (mean age 33 +/- 14 years), of which 147 had L-R phenotype and 65 had R-N phenotype. The median follow up was 3.6 years. Baseline aortic diameters at the sinuses of Valsalva were larger in patients with L-R compared to R-N fusion (33.8 +/- 5.3 mm versus 30.8 +/- 4.8 mm; p < 0.001). At this level, the rate of aortic dilation was higher with L-R versus R-N fusion (0.41 +/- 0.11 mm/year versus 0.01 +/- 0.08 mm/year; p < 0.001). The rate of proximal ascending aortic dilation was also higher with L-R versus R-N fusion (0.58 +/- 0.08 mm/year versus 0.18 +/- 0.09 mm/year; p < 0.001). CONCLUSION: Aortic dilation rates vary according to the pattern of BAV cusp fusion, with faster rates of aortic sinus and ascending aortic dilation associated with the L-R compared to R-N phenotype. PMID- 25803970 TI - 'Paradoxical' low-flow, low-gradient severe aortic valve stenosis: an entity with limited improvement following transcatheter aortic valve implantation. AB - BACKGROUND AND AIM OF THE STUDY: The aim of this single-center observational study was to determine the outcome of patients with 'paradoxical' low-flow, low gradient aortic valve stenosis (PLF-LG-AS) after transcatheter aortic valve implantation (TAVI). METHODS: Based on pre-procedural echocardiographic data, a total of 150 patients with severe aortic valve stenosis (AS) (indexed aortic valve area (AVA) <= 0.6 cm2/m2) who underwent TAVI at the authors' institution were allocated retrospectively to three groups: Group 1: PLF-LG-AS (ejection fraction (EF) >= 50%, indexed stroke volume (SV) <= 35 ml/m2, mean AV gradient < 40 mmHg; n = 30); Group 2: Classical low-flow, low-gradient AS (CLF-LG-AS: EF < 50%, SV <= 35 ml/m2, mean AV gradient < 40 mmHg; n = 21); and Group 3: High gradient AS (HG-AS: EF < or >= 50%, mean AV gradient >= 40 mmHg; n = 99). RESULTS: PLF-LG-AS was associated with an increased relative wall thickness (RWT) and a higher post-procedural systolic blood pressure (sBP) and pulse pressure (PP) (RWT 60.6 +/- 15.3%, sBP 144 +/- 14 mmHg, PP 79 +/- 15 mmHg) compared to patients with HG-AS or CLF-LG-AS: (RWT 52 +/- 13% and 40 +/- 9%, p < 0.001; sBP 138 +/- 15 mmHg and 125 +/- 25 mmHg, p = 0.006; PP 68 +/- 16 mmHg and 60 +/- 21 mmHg, p = 0.01). These patients experienced less improvement in a 6-min walk test (improvement for PLF-LG-AS 14 +/- 84 m, for CLF-LG-AS 86 +/- 83 m, for HG-AS 87 +/- 66 m; intergroup p < 0.007). PLF-LG-AS and CLF-LG-AS were also associated with significantly increased one-year overall mortality (PLF-LG-AS 31%, CLF-LG-AS 19%, HG-AS 6%; p = 0.001) and cardiovascular mortality (PLF-LG-AS 20%, CLF-LG-AS 19%, HG-AS 3%; p = 0.002). CONCLUSION: Patients with PLF-LG-AS may represent a subgroup with a worse clinical outcome after TAVI. PMID- 25803972 TI - The use of intra-aortic balloon pump in patients undergoing heart valve replacement: outcome and risk analysis. AB - BACKGROUND AND AIM OF THE STUDY: Intra-aortic balloon pump (IABP) in heart valve surgical patients is associated with a higher mortality than coronary artery bypass grafting (CABG). The study aim was to analyze the early outcome of heart valve surgical patients requiring IABP support, and to assess the risk factors for early mortality. METHODS: Among a cohort of 5,786 patients undergoing heart valve replacement without CABG, 81 (1.4%) required IABP support. Data from these latter patients were collected and analyzed retrospectively, and univariate and multivariate logistic regression were applied to identify risk factors for early mortality in patients requiring IABP support. RESULTS: IABP was inserted in 30 patients intraoperatively, and in 51 patients postoperatively. The overall mortality was 50.6%. Mortality in the intraoperative IABP subgroup was significantly lower than in the postoperative IABP subgroup (26.7% versus 64.7%, p = 0.001). The independent risk factors for early mortality were: age increasing by 10 years (OR 1.906, 95% CI: 1.165-3.116, p = 0.010) and pulmonary hypertension (OR 4.153, 95% CI: 1.380-12.499, p = 0.011). Intraoperative IABP insertion (OR 0.297, 95% CI: 0.100-0.876, p = 0.028) was identified as a protective factor compared to postoperative insertion. CONCLUSION: The mortality of patients requiring IABP support after heart valve replacement was high. The efficacy of intraoperative IABP insertion was better than a postoperative mandatory use. Clearly, more attention should be paid to older patients or those with pulmonary hypertension, who may benefit less from IABP. PMID- 25803973 TI - Aortic dimensions in relation to bicuspid and tricuspid aortic valve pathology. AB - BACKGROUND AND AIM OF THE STUDY: The relationship between aortic valve pathology and the aortic root and ascending aortic dimensions in cardiac surgery patients is unclear, and its clarification was the objective of this study. METHODS: The severity of valve pathology, whether aortic valve stenosis (AS) or aortic valve regurgitation (AR), and the aortic dimensions (aortic root and ascending aorta) were prospectively evaluated with echocardiography in 500 consecutive patients with tricuspid aortic valve (TAV) or bicuspid aortic valve (BAV) who had undergone surgery due to aortic valve and/or ascending aortic disease. RESULTS: The distribution of valve pathology was similar in TAV and BAV patients when the aorta was non-dilated. However, when the aorta was dilated, AS was seen predominantly in BAV patients (n = 76) compared to TAV patients (n = 2). In TAV and BAV patients with non-dilated aortas, an increased severity of valve pathology was associated with smaller dimensions of the aortic root and the ascending aorta. In TAV and BAV patients with dilated aortas, an increase in the severity of AR was associated with a decreasing dimension of the ascending aorta but an increasing dimension of the aortic root. In BAV patients with aneurysm, the severity of AS was associated with a decreased dimension of the aortic root and the ascending aorta. CONCLUSION: Patients with AS and ascending aortic dilatation almost exclusively have a BAV. An increasing severity of valve pathology was related to decreasing dimensions of the aortic root and the ascending aorta, and the pattern was strikingly similar in TAV and BAV patients. The high frequency of ascending aortic dilatations in BAV patients cannot be explained by the valve pathology. PMID- 25803974 TI - Surgical reconstruction of aortic root in Marfan syndrome patients: a systematic review. AB - BACKGROUND AND AIM OF THE STUDY: Several recent studies have compared the clinical results of valve-sparing (VS) surgery and composite valve graft (CVG) surgery in the aortic root reconstruction of Marfan syndrome (MS) patients. The study aim was to investigate whether it is appropriate to preserve the native aortic valve in root surgery of MFS patients when taking the short-term and long term prognoses into consideration. METHOD: A thorough literature search of PubMed, Embase and Cochrane library was conducted to identify studies comparing the outcomes of VS and CVG surgery in MFS patients. The Newcastle-Ottawa Scale evaluation scheme was used to assess the methodological quality of the included articles. Data were extracted from reports and analyzed using Revman 5.0, supplied by Cochrane collaboration. RESULT: Six clinical trials incorporating 539 patients were included. Compared to CVG, VS surgery was associated with a lower risk for re-exploration (RR 0.48, 95% CI 0.24-0.97; p = 0.04), thromboembolic events (RR 0.17, 95% CI 0.05-0.57; p = 0.004) and endocarditis (RR 0.31, 95% CI 0.11-0.94; p = 0.04). Despite an inherent incidence of aortic regurgitation, VS surgery resulted in an elevation of long-term survival rate; however, no statistical differences were found between groups with regards to reoperation (RR 1.07, 95% CI 0.35-3.27; p = 0.91). CONCLUSION: Root reconstruction with VS surgery can effectively improve the prognosis of MFS patients and provide a promising alternative for surgical treatment. However, the results must be interpreted with caution due to the retrospective nature of the included studies; large-scale prospective control trials are needed to confirm these findings. PMID- 25803976 TI - Transcatheter mitral repair and replacement: state of the art and future directions. AB - Many patients affected by severe mitral regurgitation (MR) do not currently undergo surgery, mainly because of the high surgical risk due to old age, impaired left ventricular function and comorbidities. Consequently, many transcatheter devices are emerging with the purpose of treating MR in a less invasive fashion, using different approaches and addressing different anatomic targets. The most widely used device in the clinical setting at present is the MitraClip system (Abbott Vascular, Inc., Menlo Park, CA, USA), which 'clips' the mitral leaflets together to force coaptation, and has shown optimal safety and acceptable clinical results, despite the high-risk profile of the patients in which it is commonly used. Other repair technologies include percutaneous neochordae implantation, direct and indirect annuloplasty, and reshaping of the left ventricle, but these are still undergoing limited clinical trials or preclinical experience. The combination of different repair techniques is likely to be required to achieve good long-lasting results. Transcatheter mitral valve implantation is also under development, and has already been carried out successfully in the context of valve-in-valve, whereas in the native scenario it remains an open challenge because of the particular anatomic and physiologic features of the mitral complex; hence, various prostheses using different concepts are emerging, and the first human cases have already been treated. Because data on the safety, efficacy and durability of all transcatheter mitral therapies are still limited, they are currently reserved to high-risk and inoperable patients, and their application requires an integrated Heart-Team approach. However, they represent the natural evolution of surgery and promise to expand treatment options and improve patient outcomes in the near future. PMID- 25803975 TI - Valvuloplasty with a paclitaxel-eluting balloon prevents restenosis in an experimental animal model of aortic stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Restenosis occurs invariably within 12 months following balloon valvuloplasty (BAV) in calcific aortic valve disease (CAVD), and is a limiting factor of this treatment. Cellular proliferation secondary to balloon injury is thought to play a pivotal role in the mechanism of restenosis. The study aim was to investigate the potential role of a paclitaxel-eluting valvuloplasty balloon to mitigate the progression of restenosis in an animal model of CAVD. METHODS: Fifty-three rabbits were fed with an aortic stenosis (AS) inducing diet (cholesterol 0.5% plus vitamin D3 50,000 IU/day) for three months. The surviving animals (n = 40) underwent echocardiographic and invasive assessments, followed by valvuloplasty, randomly using either a paclitaxel-coated (3 MUg/mm2) or a plain balloon. At one month after BAV, the surviving animals (n = 28) underwent repeat assessments, followed by histology and micro-computed tomography (MicroCT) analysis of the aortic valve. RESULTS: The baseline and post BAV transvalvular gradients, aortic valve area (AVA), left ventricular stroke work loss (SWL) and aortic valve resistance (AVR) were similar between the groups (14 rabbits were assigned to paclitaxel-eluting, and 14 to plain balloon). Significant differences between the groups were observed at one-month post-BAV, which was suggestive of diminished restenosis in the paclitaxel-balloon group (mean maximum transvalvular pressure gradient 7.7 +/- 7.7 versus 3.6 +/- 3.7 mmHg, p = 0.08; AVA 0.91 +/- 0.59 versus 0.55 +/- 0.22 cm2, p = 0.04; SWL 3.5 +/- 4.0 versus 8.6 +/- 8.0%, p = 0.047; AVR 86 +/- 71 versus 177 +/- 137 dynes/s/cm( 5), p = 0.039). Histology demonstrated decreased leaflet thickness (0.60 +/- 0.15 versus 0.71 +/- 0.17 mm, p = 0.03), proliferating cell nuclear antigen (PCNA) staining (grade 1.53 +/- 0.04 versus 2.24 +/- 0.55, p = 0.049), and calcification in the paclitaxel-balloon group. CONCLUSION: Use of a paclitaxel-eluting valvuloplasty balloon in an animal model of AS resulted in attenuated restenosis, secondary to decrease in valve proliferation and calcification. PMID- 25803977 TI - Ruptured giant mitral valve aneurysm: an unexpected finding in a diabetic patient with dyspnea and new-onset atrial fibrillation. AB - Mitral valve aneurysm (MVA) is a rare valve disease. The case is reported of pathologically proven MVA in a 61-year-old diabetic male with chronic alcoholic liver disease who presented with dyspnea and new-onset atrial fibrillation, without clinical elements of current or recent infection. Transthoracic echocardiography revealed a 'cystic' formation of the anterior mitral leaflet (AML) with mild mitral regurgitation (MR) and aortic regurgitation (AR) hitting the AML. Transesophageal echocardiography (TEE) showed clearly that the formation on the AML was a valve aneurysm, and depicted the site of aneurysm rupture with an additional jet of MR through the rupture. Following mitral valve replacement, pathology of the excised valve showed chronic bacterial endocarditis with calcified bacterial colonies, myxomatous changes with fibrinoid dissection of lamina fibrosa, and neovascularization of the leaflet. The mechanisms of MVA formation are discussed, together with its potential complications, diagnostic modalities and therapeutic strategies. The present case emphasizes that MVA is often a remnant of endocarditis, even when the latter is clinically silent and undiagnosed. The importance of chronic AR directed towards the AML as a predisposing condition for MVA formation is also underlined in this case. The superiority of TEE in providing a full exploration of the mitral valve morphology is verified. PMID- 25803978 TI - Balloon pulmonary valvuloplasty in adults: immediate and long-term outcomes. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to determine the immediate and long-term outcomes of balloon pulmonary valvuloplasty (BPV) in a large cohort of adult patients (aged >= 18 years) with congenital valvular pulmonic stenosis. METHODS: A retrospective data analysis was conducted of the immediate and long term outcomes of adult patients who had undergone BPV between 2000 and 2012 at a single tertiary care center. RESULTS: A total of 132 patients (mean age 27.7 years; 95% CI 21.12-34.76) underwent BPV, with a mean follow up period of 5.7 years (95% CI 4.37-6.98). Intervention resulted in successful BPV (> 50% reduction in baseline gradient) in 124 patients (94%), and a partially successful BPV (20-50% reduction in baseline gradient) in eight patients (6%). The mean right ventricular (RV) systolic pressure was decreased from 90.6 mmHg (95% CI 84.90-96.33) to 50.9 mmHg (95% CI 47.17-54.61) (p < 0.001), and the pulmonary valve (PV) gradient was reduced from 70.7 mmHg (95% CI 65.12-76.22) to 29.0 mmHg (95% CI 25.83-32.23) (p < 0.001). The mean percentage difference in PV gradient in both genders was 60.23% in males and 57.44% in females (95% CI 55.33-65.12 and 55.32-61.56, respectively) (p > 0.05). Pulmonary valve regurgitation was reported in 17.4% of patients, and was not related to either successful outcome or balloon size. The gradient reductions were maintained after five and 10 years of follow up. Two patients (1.5%) developed restenosis that required repeat BPV. There was no referral for urgent surgery. CONCLUSION: BPV in adults produced excellent long term clinical results, there being no gender-related difference in outcome. In addition, the need for reintervention was very low. PMID- 25803980 TI - Over 5,100 attend EMS World Expo 2014 in Nashville, TN. Attendees descended on "Music City" for five days of education, exhibits and networking. PMID- 25803979 TI - Comprehensive hemodynamic performance and frequency of patient-prosthesis mismatch of the St. Jude Medical Trifecta bioprosthetic aortic valve. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the performance of a new stented pericardial bioprosthesis, the Trifecta (St. Jude Medical, St. Paul, MN, USA), for aortic valve replacement (AVR) with respect to valvular hemodynamics and frequency of patient-prosthesis mismatch (PPM). PPM has been reported in a wide range of bioprosthetic valves following AVR, and has been associated with multiple adverse outcomes. It was hypothesized that the Trifecta aortic valve would have superior hemodynamics and an acceptable incidence of PPM following AVR. METHODS: A prospective cohort study was performed between January 2010 and May 2012, following 75 patients (mean age 71.9 _ 11.1 years) who had undergone AVR with a Trifecta valve for aortic stenosis (88%) or regurgitation (12%) at the authors' institutions. Intraoperative three-dimensional and Doppler transesophageal echocardiography were used to evaluate hemodynamic variables before and after AVR, as well as pre-discharge. RESULTS: Echocardiographic evaluation showed a preoperative average mean gradient (MG) of 40.6 +/- 21.6 mmHg, an average peak gradient (PG) of 72.1 +/- 19.4 mmHg, and an average effective orifice area index (EOAI) of 0.39 +/- 0.20 cm2/m2. Postoperative mean pressure gradient measurements showed a postoperative average MG of 8.76 +/- 3.75 mmHg (p < 0.001), an average PG of 19.4 +/- 8.6 mmHg (p < 0.001), and EOAI of 1.09 +/- 0.36 cm2/m2 (p < 0.001), which demonstrated a significantly improved hemodynamic performance across all valve sizes. Postoperative MG versus measured EOAI demonstrated a fairly linear relationship (R2 = 0.0703), rather than a rapid increase in MG with EOAI < 0.85 and < 0.65, as was seen with previous valve designs. Severe PPM (defined as EOAI <= 0.65 cm2/m2) was found in four patients (6%), while moderate PPM (EOAI > 0.65 and < 0.85 cm2/m2) was seen in 11 patients (16%). CONCLUSION: The Trifecta pericardial valve demonstrated excellent hemodynamic performance at all valve sizes, and resulted in very low postoperative transvalvular pressure gradients and PPM, without the need for aortic root enlargement. PMID- 25803981 TI - Air traffic control. With patients' airways or the skies above, keep control of your scene. PMID- 25803982 TI - Evidence-based EMS: endotracheal Intubation. What does all the evidence really say about ETI before the hospital? PMID- 25803983 TI - The nose knows. A novel approach to preoxygenating the high-risk patient. PMID- 25803984 TI - Surgical cricothyrotomies in prehospital care. Surgical airway placement is indicated when you cannot intubate or ventilate. AB - Managing the airway does not mean intubation, it means managing the airway. Allowing a patient to breathe on their own with appropriate positioning, bag valve ventilation and blind insertion devices are all airway management options. The surgical cricothyrotomy is a rare and life-saving procedure when managing patients who are in a "can't intubate, can't ventilate" situation. These patients will die without aggressive and rapid intervention. While not all surgical cricothyrotomies provide a definitive airway, the needle cricothyrotomy is an ineffective means for ventilation and its use is discouraged. Understand the techniques used in your program and that are within your scope of practice as an EMS provider. Provide your patient the best opportunity for survival by knowing your program's surgical airway procedure thoroughly, and practice it regularly. PMID- 25803985 TI - Mobile integrated healthcare: Part 1.Strategic planning for rapid implementation. How to work with stakeholders to deploy an MIH program. PMID- 25803986 TI - Are paramedic program educators overworked and underresourced? National assessment of paramedic educator workload. PMID- 25803987 TI - Duty to react. When you're needed, don't turn a blind eye. PMID- 25803988 TI - Nuclear morphometry in flat epithelial atypia of the breast as a predictor of malignancy: a digital image-based histopathologic analysis. AB - OBJECTIVE: To identify morphometric features unique to flat epithelial atypia associated with cancer using digital image analysis. STUDY DESIGN: Cases with diagnosis of flat epithelial atypia were retrieved and divided into 2 groups: flat epithelial atypia associated with invasive or in situ carcinoma (n = 31) and those without malignancy (n = 27). Slides were digitally scanned. Nuclear features were analyzed on representative images at 20x magnification using digital morphometric software. RESULTS: Parameters related to nuclear shape and size (diameter, perimeter) were similar in both groups. However, cases with malignancy had significantly higher densitometric green (p = 0.02), red (p = 0.03), and grey (p = 0.02) scale levels as compared to cases without cancer. A mean grey densitometric level > 119.45 had 71% sensitivity and 70.4% specificity in detecting cases with concomitant carcinoma. CONCLUSION: Morphometry of features related to nuclear staining appears to be useful in predicting risk of concurrent malignancy in patients with flat epithelial atypia, when added to a comprehensive histopathologic evaluation. PMID- 25803989 TI - Automated labeling of cancer textures in larynx histopathology slides using quasi supervised learning. AB - OBJECTIVE: To evaluate the performance of a quasi-supervised statistical learning algorithm, operating on datasets having normal and neoplastic tissues, to identify larynx squamous cell carcinomas. Furthermore, cancer texture separability measures against normal tissues are to be developed and compared either for colorectal or larynx tissues. STUDY DESIGN: Light microscopic digital images from histopathological sections were obtained from laryngectomy materials including squamous cell carcinoma and nonneoplastic regions. The texture features were calculated by using co-occurrence matrices and local histograms. The texture features were input to the quasi-supervised learning algorithm. RESULTS: Larynx regions containing squamous cell carcinomas were accurately identified, having false and true positive rates up to 21% and 87%, respectively. CONCLUSION: Larynx squamous cell carcinoma versus normal tissue texture separability measures were higher than colorectal adenocarcinoma versus normal textures for the colorectal database. Furthermore, the resultant labeling performances for all larynx datasets are higher than or equal to that of colorectal datasets. The results in larynx datasets, in comparison with the former colorectal study, suggested that quasi-supervised texture classification is to be a helpful method in histopathological image classification and analysis. PMID- 25803990 TI - Immunohistochemical and histopathological changes in the skin of rats after maneb application. AB - OBJECTIVE: To determine the immunohistochemical and histopathological changes in facial skin after exposure to maneb (manganese ethylene bisdithiocarbamate), a fungicidal dithiocarbamate pesticide. STUDY DESIGN: In the experimental group maneb was administered by inhalation to 10 male Wistar albino rats for 5 days each week for 3 weeks. As a biological control, the control group (n = 10) received distilled water by spray for the same time period. The experiment was terminated after 3 weeks. Sections of rat facial skin were examined histopathologically. RESULTS: In the experimental group, microscopic examination of facial skin revealed degeneration of the epidermis, detection of mild inflammatory reaction, and vascular dilation in the connective tissue. Hair follicles and degenerative changes were observed in the deeper parts. In the experimental group, dilation of the blood vessels in the dermis and hemorrhage were supported by an increase in CD34 expression. In addition, a reduction in the number of melanocytes (hypopigmentation) was observed in the hair follicles and epidermis, along with a decrease in the expression of CD117. CONCLUSION: Epidermal degeneration, intradermal cell infiltration, vascular changes, and reduction in the number of melanocytes in the follicle and content of cytokeratin in both the epidermis and hair follicle keratinocytes were detected after maneb application. These findings may have important implications in the association with main signaling pathways, including keratinocyte proliferation and differentiation. Disruption of these pathways may cause some dermatoses. PMID- 25803991 TI - Clival dedifferentiated chordoma: a case report. AB - BACKGROUND: Chordoma is a rare, slowly growing tumor arising from notochordal rests and occurring in several anatomical locations with different clinical patterns of presentation. Dedifferentiation or sarcomatous transformation in a chordoma is a known but rarely recorded event. CASE: We report the case of a 58 year-old man diagnosed with chordoma of the clivus who, over the course of 5 years, showed histological and immunohistochemical evidence of progressive dedifferentiation in the tumor. CONCLUSION: Sarcomatous transformation in chordomas is seen less frequently in the clival region. A high degree of suspicion and extensive sampling are essential for diagnosis, especially in recurrent tumors. PMID- 25803992 TI - Multifocal blue nevus of the prostate: a case report. AB - BACKGROUND: Blue nevus of the prostate is rare and is most commonly discovered incidentally in patients presenting with classic symptoms of prostatic hyperplasia. Only 32 cases have been reported to date in the literature. We describe the first case of multifocal blue nevus of the prostate gland. CASE: A 69-year-old man presented with obstructive urinary symptoms. The preoperative clinical and radiological fndings had shown a massive increase in the volume of the prostate. Suprapubic prostatectomy was performed with good postoperative course. The histopathological examination disclosed benign hyperplasia with large areas characterized by abundant fibromuscular component. In the context of this hyperplasia were observed a dozen foci of pigmented cells measuring 0.1-1 cm in diameter. Histochemical and immunohistochemical stains confirmed the pigment as melanin. CONCLUSION: A review of the literature shows that the blue nevus of the prostate is an incidental finding and is most often associated with a benign disease of the prostate, as indeed occurred in our case. All the cases reported are monofocal. Ours is the first reported multifocal case and, as the material has not been fully sampled, consists of at least 12 different outbreaks of varying sizes. Even in our case blue nevus was asymptomatic, and the patient showed no symptoms related to the same blue nevus. PMID- 25803993 TI - Small cell carcinoma of the bladder associated with schistosomiasis: a case report. AB - BACKGROUND: Smoking and occupational exposure to bladder cancer carcinogens are the major risk factors for bladder cancer development in industrialized countries, where urothelial carcinoma is the most common histologic type, accounting for >90% of cases. In Africa and the Middle East, with highly prevalent chronic infection by Schistosoma haematobium (S. haematobium), urinary bladder squamous cell carcinoma is the most prevalent histologic type of bladder cancer, followed by transitional cell carcinoma. Small cell carcinoma accounts for <1% of all primary bladder malignancies. It has the same demographic and clinical features as conventional urothelial carcinoma, and to our knowledge there is no data regarding its association with S. haematobium infection. CASE: We report on the clinicopathological characteristics of a 62-year-old, African man who presented with gross hematuria and advanced disease, resulting in a diagnosis of small cell carcinoma of the bladder associated with S. haematobium infection. He was treated with neoadjuvant chemotherapy followed by cystoprostatectomy, and remains alive after 19 months of follow-up. CONCLUSION: We cannot rule out the possibility that a parasitic infection played a major role in the pathogenesis of small cell bladder carcinoma in this particular case. PMID- 25803994 TI - Metastatic lung adenocarcinoma to the kidney diagnosed by urine cytology: a case report. AB - BACKGROUND: Although lung cancer is the solid tumor which most frequently metastasizes to the kidney, metastatic pulmonary adenocarcinoma detected by urine cytology examination is exceedingly rare. CASE: A 52-year-old woman presented with gross hematuria. Urine cytology revealed numerous crowded, overlapped 3 dimensional clusters with occasional papillary and luminal formations. The tumor nuclei were uniformly enlarged with smooth oval contours, regular nuclear membranes, finely granular chromatin, and prominent nucleoli. Numerous clear, intracytoplasmic vacuoles were noted. Urine fluorescence in situ hybridization (FISH) examination was abnormal. Positive immunohistochemical thyroglobulin transcription factor-1 and Napsin-A staining of a renal calyx biopsy confirmed the diagnosis of metastatic lung cancer. CONCLUSION: Although rare, metastatic lung adenocarcinoma in urine has characteristic cytomorphologic findings which appear distinct from the more commonly encountered urothelial carcinoma. Differentiation from other metastatic malignancies may be more problematic and will likely require immunohistochemical confirmation. Metastatic lung cancer may also cause abnormal urine FISH results and thus may be misdiagnosed as urothelial cancer. Therefore, this ancillary testing modality must be employed with caution in the setting of metastatic disease. PMID- 25803995 TI - Histological evidence of traditional serrated adenoma originating from a goblet cell hyperplastic polyp: a case report. AB - BACKGROUND: Serrated polyps of the colorectum are now considered to be a heterogeneous group of polyps. There is debate about the progression of these serrated polyps in a continuous spectrum. We report a case of traditional serrated adenoma (TSA) in the rectum arising from a goblet cell hyperplastic polyp (HP). CASE: A 44-year-old, Chinese man presented with abdominal discomfort of 3 months' duration. Colonoscopy revealed a pedunculated polyp about 10 mm in diameter in the rectum. The polyp was removed by conventional snare polypectomy. Histopathologic examination showed that TSA and goblet cell HP coexisted in the polyp. Follow-up colonoscopy revealed no recurrence 6 months after the polypectomy. CONCLUSION: This case provides histological evidence that TSA originates from a goblet cell HP, and also suggests that HPs should not be considered as non-neoplastic lesions without malignant potential. PMID- 25803996 TI - Expression of iNOS and NF-kappaB in melasma: an immunohistochemical study. AB - OBJECTIVE: To investigate the role of inducible nitric oxide synthases (iNOS) and nuclear factor-kappa B (NF-kappaB) in the pathogenesis of melasma through their immunohistochemical (IHC) co-localization in skin of melasma and to correlate their expression with the clinical and the histopathological data. STUDY DESIGN: This prospective case-control study was conducted on 34 female patients with melasma and 30 age- and gender-matched healthy subjects as a control group for evaluation of IHC expression of iNOS and NF-kappaB in melasma. RESULTS: There were significant differences between lesional and perilesional skin regarding iNOS intensity, iNOS histo-score (H-score), NF-kappaB intensity, and NF-kappaB H score (p < 0.001 for all). There were significant associations between the higher values of H-scores for both iNOS and NF-kappaB and positive family history (p = 0.002 and p = 0.001, respectively) and very severe melasma areas and severity index score (p < 0.001 and p = 0.001, respectively). There was a positive correlation between H-score values of both iNOS and NF-kappaB (r = +0.604 and p < 0.001). CONCLUSION: The IHC co-localization and direct correlation of both iNOS and NF-kappaB in melasma could provide evidence about their role as co-players in melanogenesis and might provide new targets for a more efficient treatment for melasma. PMID- 25803998 TI - Splendore-Hoeppli phenomenon on fine needle aspiration cytology of subcutaneous inflammatory lesions. AB - OBJECTIVE: To put forth the importance of Splendore-Hoeppli (SH) material on fine needle aspiration cytology (FNAC) smears from subcutaneous inflammatory lesions. STUDY DESIGN: This is a retrospective study that analyzes 33 cases of subcutaneous inflammatory lesions, diagnosed on FNAC over a 2.5-year period (January 2011-July 2013). Giemsa- and Papanicolaou (Pap)-stained smears were retrieved and reviewed. RESULTS: The cytological counterpart of SH material can be seen as acellular, dense, nonfibrillary homogenous bodies of varying sizes and shapes, purple to blue on Giemsa-stained and greenish on Pap-stained smears, respectively. Of the 33 cases, 15 showed the presence of SH material on the smears; 11/15 cases with SH material were positive for fungus. Of the 18/33 cases that were negative for SH material, there were 7 acid-fast bacilli-positive tuberculous lesions, 8 nonspecific inflammatory lesions, and 3 fungal infections. None of the cases showed actinomycete filaments or clumps of bacterial colonies. Histopathology was available in 4 cases. CONCLUSION: SH material should be recognized on cytology smears as it is an indicator of a specific etiology and also helps rule out nonspecific inflammatory and tuberculous lesions. PMID- 25803997 TI - Nicotine-induced ICAM-1 and VCAM-1 expression in mouse cardiac vascular endothelial cell via p38 MAPK signaling pathway. AB - OBJECTIVE: To explore the link between cigarette smoking and thromboembolic events and to investigate cigarette smoking as a major risk factor in the etiology of atherosclerosis. STUDY DESIGN: We determined the effect of nicotine on the expression of adhesion molecules, intercellular adhesion molecule (ICAM 1), and vascular cell adhesion molecule (VCAM-1) in mouse cardiac vascular endothelial cells and the involvement of important known intermediaries, namely p38 mitogen-activated protein kinase (MAPK) signaling pathway. RESULTS: Our results indicate that nicotine can enhance the expression of ICAM-1 and VCAM-1 on mouse cardiac vascular endothelial cell via p38 MAPK signaling pathway, resulting in increased expression of the cellular adhesion molecules ICAM-1 and VCAM-1. CONCLUSION: We demonstrate that 10(-6) M nicotine maximally enhances mouse cardiac vascular endothelial cell expression of ICAM-1 and VCAM-1 at 8 hours. Our results provide a putative mechanism by which nicotine stimulates expression of these adhesion molecules via p38 MAPK signaling pathway. PMID- 25804000 TI - Parallel increase in secretory activity between N-glycosylated and nonglycosylated alpha-amylase without protein synthesis after short-term beta adrenergic receptor activation in isolated rat parotid acinar cells. AB - OBJECTIVE: To investigate comparisons of the secretory activity between N glycosylated and nonglycosylated alpha-amylase, and alpha-amylase synthetic activity, after beta-adrenergic receptor activation in rat parotid acinar cells in vitro. STUDY DESIGN: Rat parotid acinar cells were incubated in the presence or absence of (-)-isoproterenol. For beta-adrenergic blocking experiments, acinar cells were pretreated with (+/-)-propranolol prior to adding agonist. After the time indicated, the "released amylase" and "total amylase" were obtained. Western blotting was applied to identify and quantify the N-glycosylated and nonglycosylated alpha-amylase. Amylase activity was also measured. RESULTS: The potent beta-adrenergic agonist (-)-isoproterenol induced a dramatic increase (2-3 fold) of alpha-amylase secretion for 30 minutes (p < 0.05 vs. control), while the effect was completely abolished when cells were pretreated with (+/-)-propranolol for 15 minutes. Moreover, the N-glycosylated level of released and total amylase among groups was measured accordingly. Our data showed the N-glycosylated level ratios (released amylase/total amylase) did not differ among groups, which indicated that the N-glycosylated form of alpha-amylase was not secreted more easily than the nonglycosylated one after stimulation. Interestingly, the total amylase concentration remained unchanged after stimulation within 30 minutes, which might indicate no alpha-amylase synthesized within the time indicated. CONCLUSION: Our findings suggest a parallel increase in secretory activity between N-glycosylated and nonglycosylated alpha-amylase after beta-adrenergic receptor activation. There seems to be a dissociation of alpha-amylase synthesis from secretion within 30 minutes. PMID- 25803999 TI - Body mass index, selected dietary factors, and acne severity: are they related to in situ expression of insulin-like growth factor-1? AB - OBJECTIVE: To evaluate the possible role of insulin-like growth factor (IGF)-1 in acne vulgaris (AV) pathogenesis through its immunohistochemical localization in acne skin biopsies and to investigate the relationship of its expression with body mass index (BMI), selected dietary factors, and acne severity. STUDY DESIGN: Using the standard immunohistochemical techniques, we examined 60 acne cases and 40 gender- and age-matched, healthy subjects, representing the control group. RESULTS: IGF-1 was overexpressed in AV lesions as compared to in normal skin, both in epidermis and pilo-sebaceous units (p < 0.0001 for both). There was significant association between strong intensity of IGF-1 and high BMI values (>= 30) in AV cases as compared to controls, with high (>= 30) and low (< 30) BMI values, both in epidermis (p < 0.0001 for both) and pilosebaceous units (p <0.0001 for both). Strong IGF-1 intensity was significantly associated with higher mean values of BMI (p = 0.01) and severe AV (p = 0.04). Significant associations between high BMI values and acne severity (p = 0.001) and acne aggravation by dairy products intake (p = 0.03) were demonstrated. CONCLUSION: IGF-1 may play a role in AV pathogenesis through its role in keratinocyte proliferation, sebaceous lipogenesis, and androgen synthesis. The significant association between strong IGF-1, high BMI, and severe acne underscores the value of dietary intervention in the management of AV. PMID- 25804001 TI - Effects of adnexal torsion on the Fallopian tube in rats: a histologic and immunohistochemical study. AB - OBJECTIVE: To investigate histopathological and immunohistochemical changes in the Fallopian tube structure following ovarian torsion. STUDY DESIGN: Thirty fertile, female, adult Wistar albino rats, weighing 200-220 g, were randomly divided into 3 equal groups (n = 10): sham, torsion, and detorsion. In the torsion and detorsion groups, bilateral adnexal torsion (3-hour ischemia) was carried out. Bilateral adnexal detorsion (3-hour reperfusion) was performed in the detorsion group. Fallopian tube sections were stained hematoxylin and eosin, periodic acid-Schiff, Mallory-Azan and immunohistochemically-stained desmin, alpha smooth actin, and CD68 antibodies. RESULTS: In the sections of the ischemic group, degeneration of epithelium, loss of cilia, dilation of blood vessels, and hemorrhages were observed. Image analysis of the studied Fallopian section revealed a significant decrease in density of desmin in the torsion group. Moreover, strong positive cytoplasmic CD68 expression was observed in the torsion group. CONCLUSION: The use of effective antiinflammatory treatments may contribute to the conservative surgery in preservation of ovarian reserve and tubal structure. PMID- 25804002 TI - Paraganglioma of the urinary bladder: a challenging diagnosis in transurethral resection specimens: a case report. AB - BACKGROUND: Urinary bladder paraganglioma is a rare neoplasm that originates from embryonic rests of chromaffin cells in the sympathetic plexus of the detrusor muscle, and which occasionally can be observed in transurethral resection specimens. Artifactual changes due to the procedure may frequently simulate an advanced urothelial carcinoma. CASE: A 65-year-old woman presented with episodic macroscopic hematuria. No symptoms of hyperadrenergic stimulation were referred. Cystoscopic examination revealed a protruding mass on the left side of the bladder. Transurethral resection (TUR) was performed, and histological examination revealed a tissue organized in solid nests delineated by delicate fibrovascular septa. There were artifactual changes that consisted of cautery effect and absence of orientation of the fragments. The tumor infiltrated the muscle layer and part of the muscularis mucosae of the bladder. No necrosis or mitoses were observed. On immunohistochemical staining, the tumor cells were negative for epithelial membrane antigen, cytokeratin 7, and carcinoembryonic antigen and positive for chromogranin A, NSE, and PGP9.5. Immunohistochemistry for S-100 highlighted sustentacular cells. CONCLUSION: It is essential to consider the diagnosis of urinary bladder paraganglioma on TUR specimens in order to avoid inappropriate treatment. PMID- 25804004 TI - Diagnosis of histoplasmosis on lymph node fine needle aspiration cytology utilizing Giemsa stain: a report of three cases. AB - BACKGROUND: Histoplasmosis is a fungal infection caused by Histoplasma capsulatum; it mostly occurs in immunocompromised individuals. Disseminated histoplasmosis may affect almost all systems. The lymph node is frequently involved in the reticuloendothelial dissemination. Histoplasmosis of the lymph node can mimic tuberculosis clinically and cytomorphologically. Fine needle aspiration cytology (FNAC) is an effective method for differentiating the two. The histoplasma yeast forms are small and usually intracellular and are likely to be overlooked in Papanicolaou (Pap)-stained smears. Air-dried Giemsa-stained smears can identify them easily and clearly because of their large size and bright purple-to-blue color as compared with fixed Pap-stained smears. CASES: We report 3 cases of lymph node histoplasmosis diagnosed on cytology seen over a period of 2 years. CONCLUSION: Lymph node FNAC is a rapid, cost-effective, reliable diagnostic toolfor histoplasmosis. It can obviate the need of surgical biopsy and hasten the initiation of treatment. PMID- 25804003 TI - Fat-forming solitary fibrous tumor of the kidney: a case report. AB - BACKGROUND: Solitary fibrous tumor (SFT) arises in many parts of the body, but rarely in the kidney. To the best of our knowledge this is the second report of a fat-forming SFT in the kidney. CASE: We present a case of a fat-containing SFT at the parihilar region of the kidney in a 64-year-old man complaining of epigastric pain. The tumor was initially diagnosed as angiomyolipoma at hematoxylin and eosin stains. However, by immunohistochemistry the tumor was reclassified as a fat-forming SFT. CONCLUSION: SFT arises in many sites, but rarely in the kidney. There is also a subset of these tumors that have a variable amount of adipocytic component that should be differentiated from angiomyolipoma. That subset of tumors affects mainly middle-aged adults of either gender and has a wide anatomic distribution. Recurrence is infrequent, and morphologically malignant examples are extremely rare. PMID- 25804005 TI - Reproducibility of the cobas 4800 HPV test in the "grey zone". PMID- 25804006 TI - Tech support. New capabilities play a big role in a difficult ice rescue. PMID- 25804007 TI - Improving prehospital care around the world. How three countries are improving quality and innovating paramedic service. PMID- 25804008 TI - Is it time to stop chilling? Induced therapeutic hypothermia doesn't appear to have the prehospital effect we thought it did. AB - The evidence is quite clear that ITH in the prehospital setting is of dubious benefit. But what is the harm in continuing the practice? Well, prehospital ITH most likely takes away from more beneficial therapies such as high-quality CPR, rapid defibrillation, recognition of ST-segment elevation myocardial infarction (STEMI), and similar essential treatments. Several studies have shown prehospital ITH, in many cases, delays hospital transport. When the initial studies of ITH were released, I was immediately on the ITH bandwagon. Interestingly, the American Heart Association (AHA) has never recommended prehospital ITH. Even the position paper on ITH by the National Association of EMS Physicians (NAEMSP) was cautious, saying, "A lack of evidence on induced hypothermia in the prehospital setting currently precludes recommending this treatment modality as standard of care for all emergency medical services (EMS) patients resuscitated from cardiac arrest. A systematic review of ITH recently published states, "In cardiac arrest, the initiation of therapeutic hypothermia in the out-of-hospital environment has not been shown to improve neurologic outcomes, although studies to date have been limited. We now know that caution Fxercised by the AHA and preMSP was appropriate. One medmy mentors in residency and ays said, "Never be the first- Univtor to prescribe a new drug or of Mlast doctor to prescribe an old is th" Lik" many things in EMS, EMS tms something that was put in Practe with good intent but lim- scientific evidence. We now P ITH is probably not a good ice and it is time to abandon it. However, we should still carry chilled IV fluids for hyperthermia, excited delirium and to main- tainormothermia in patients in cardiac arrest where transport times are long. PMID- 25804009 TI - Is your shore line overloaded? Always be alert for a warm cord: it's never OK. PMID- 25804010 TI - Mobile integrated healthcare: Part 2. MIH-CP outcome measures. PMID- 25804011 TI - Partners in rhyme. Allen was a natural caregiver--he showed it on his first day. PMID- 25804012 TI - Electroconvulsive therapy during pregnancy as a possible cause of Mobius syndrome: additional clinical observation. AB - Mobius syndrome is a rare congenital disease with a prevalence of between 0.0002 and 0.002% of births. Minimum diagnostic criteria for this disease include congenital unilateral or bilateral facial and abducens nerve paresis. Occasionally, the cranial nerves V and VIII are affected. If cranial VIII is affected, the person experiences hearing loss. Other findings in these patients that are not part of the diagnostic criteria include the involvement of other cranial nerves, malformations of orofacial structures, reductive limb anomalies, and defects of the chest wall. We herein report a newborn case with Mobius syndrome. PMID- 25804013 TI - A case of L-2 hydroxyglutaric aciduria presenting as febrile seizure. AB - L-2 hydroxyglutaric aciduria (L2HGA) is a rare, infantile-onset, autosomal recessive organic aciduria affecting exclusively the central nervous system. A case is reported here of L2HGA presenting with macrocephaly and febrile seizure. Although there have been reports of epilepsy associated with L2HGA, to the best of our knowledge this is the second case in literature of febrile seizure in a patient with L2HGA. This report suggests that detailed neurological evaluation of macrocephalic children with febrile convulsion is important. Moreover, metabolic and genetic investigations may be necessary for these kinds of patients. PMID- 25804014 TI - Holoprosencephaly spectrum among Egyptian patients: clinical and cytogenetic study. AB - We report 24 patients with holoprosencephaly (HPE) spectrum screened for Del 7q36 and subtelomere 13q. They were divided according to the type of HPE into: 6 alobar, 15 semilobar, 1 lobar and 2 middle interhemispheric variant (MIH). All patients presented with global developmental delay. Microcephaly was in 83.3% and midfacial developmental defects were in the form of; cyclopia, arrhinia and agnathia in 2 patients (8.3%), premaxillary agenesis in 2 patients (8.3%), cleft lip and palate in 7 patients (29.2%), hypotelorism in 8 patients (33.3%) and hypertelorism in 9 patients (37.5%). The neurological deficits were as follows: abnormal tone and spasticity were present in all of them with exceptional of a single patient with MIH who presented with hypotonia and was able to walk independently at the age of 3 years, athetoid and/or dystonic movements of limbs in 22 patients, seizures in twelve patients (50%) and abnormal EEG in 15 patients (62.5%). Poor temperature regulation was found in 50% of patients and diabetes insipidus was documented in 3 patients (12.5%). The MRI showed complete or partial fusion of basal ganglia and thalami in 21 patients (87.5%) and 19 patients (79.2%) respectively, fused mesencephalon in 8 patients (33.3%), incomplete separation of mesencephalon from diencephalon in 4 patients (16.7%), dorsal cyst in 10 patients (41.7%), abnormal gyral pattern anteriorly in 15 patients (62.5%), anterior located sylvian fissures in 22 patients (99.7%), complete or partial agenesis of the corpus callosum (ACC) in all patients and Dandy-Walker malformation (DWM) in three patients (12.5%). A small occipital cephalocele was detected clinically and radiological as atretic type in MIH patient. Karyotype analysis demonstrated 47, XY+13 in a patient with alobar holoprosencephaly, 46, XY,t(12;13) (q13q24.1;q14q33) in a semilobar case associated with DWM, 46, XY, del(13)(q34) in one semilobar case and three cases had del 7q36 using FISH technique in two semilobar cases and one lobar case. Conclusion: This study highlights the clinical spectrum in patients with HPE and report a case of HPE and DWM associated with t(12;13). Neuroimaging delineated the pathogenesis underlying developmental defects in HPE. Accurate molecular diagnosis is crucial for further understanding of the pathogenesis of HPE. PMID- 25804015 TI - Dental findings in Hamamy syndrome. AB - This paper highlights features of dental rehabilitation of patients with Hamamy syndrome. A 10-year-old boy patient with Hamamy syndrome reported pain in the maxillary left central incisor, and all mandibular incisors. Intraoral clinical and radiographical examination showed enamel hypoplasia, severe dilacerated maxillary left central incisor and mandibular incisors, malocclusion, delayed eruption of teeth, taurodontism, and loss of lamina dura. Root canal treatment, strip crown and composite restorations were performed. PMID- 25804016 TI - Glycogen storage disease type 1b: an early onset severe phenotype associated with a novel mutation (IVS4) in the glucose 6-phosphate translocase (SLC37A4) gene in a Turkish patient. AB - Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders that include types Ia and Ib. GSD-Ib is caused by a deficiency in the glucose-6-phosphate transporter (G6PT) caused by a mutation in the SLC37A4 gene coding for G6PT. Glycogen storage disease is characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver and chronic neutropenia. Herein we describe a 4 month-old Turkish patient with early onset and severe typical clinical features of GSD-1b in which a novel mutation in the SLC37A4 gene was detected. After the bone marrow examination parenteral antibiotic therapy and subcutaneous granulocyte colony-stimulating factor (G-CSF) were started. Due to the severe neutropenia the patient had developed nosocomial sepsis and the dose of G-CSF was increased. After 2 months later from the initial treatment of the G-CSF he developed splenomegaly and urinary complications. Despite maximal therapy he had an extremely poor quality of life and life-threatening complications due to impaired bone marrow function. As the patient required continual hospitalization he was schedule for bone marrow transplantation. PMID- 25804017 TI - Fryns anophthalmia-plus syndrome: two rare cases. AB - Fryns anophthalmia-plus syndrome is a rare syndrome with clinical diversity primarily including anophthalmia/microphthalmia, facial clefts, cleft lip/palate, ear and nasal deformities. Here we present two different cases of APS with anopthalmia/microphthalmia, cleft palate, low set ears, ventriculomegaly and one of which had intestinal non-fixation anomaly not described in the literature before. PMID- 25804018 TI - Follow up of a family with asymptomatic compound long QT syndrome mutations. AB - Long QT syndromes (LQTS) are a cause of syncope and sudden death and present as a long QT interval on the surface ECG. The mortality of the condition may be quite variable among affected individuals. Hundreds of mutations in more than ten genes are identified as responsible for almost all patients with LQTS. Compound mutations are reported in different series as 4.5 and 7.9% and are associated with poor outcome. Beta blockers are the mainstay of therapy. The use of intracardiac defibrillators (ICD) is widely considered in patients at high risk for sudden death. Herein, we report a case of LQTS with compound mutations of KCNQ1 and SCN5a. Although ICD implantation was advised due to high cardiac event risk, the patient followed with beta blocker treatment for 15 years without any syncope or palpitations. PMID- 25804019 TI - A patient with duplication (7)(p15.3p22.3) and deletion (7)(p22.3pter) characterized by array-CGH. AB - We report a patient with neurodevelopmental delay, hypotonia, congenital cardiac anomaly and dysmorphic features such as macrocephaly, a large anterior fontanel, prominent forehead, short neck, downslanted and short palpebral fissures, hypertelorism, wide nasal bridge, straight, thin nose with asymmetric narrow inverted nostrils, micrognathia, low-set dysplastic ears. 7p15.3-p22.3 duplication and a 7p22.3-pter deletion were characterized by array-CGH analysed after karyotyping and FISH studies. The patient's distinctive features are consistent with the phenotypic features of 7p duplication. The genes involved in these regions are discussed for their possible relation to our patient's phenotype. PMID- 25804020 TI - Case report: partial trisomy 4q27q35 syndrome. AB - Partial trisomy 4q is a rare chromosomal abnormality which results in variable clinical features, often including growth and developmental delay, mental retardation and dysmorphic features. We herein report a newborn with the diagnosis of partial trisomy 4q with Hirschsprung's disease who was monitored in neonatal intensive care unit. This is the first report of partial trisomy 4q27q35 with accompanying Hirschsprung's disease. PMID- 25804021 TI - Results of fifteen-year follow-up from a single center: findings and risks for tumor development in isolated hemihyperplasia cases. AB - Isolated hemihyperplasia is abnormal asymmetric growth of one or more parts of the body without any underlying disease. The risk for the development of embryonal tumor is increased in the subjects with isolated hemihyperplasia. The study presented here retrospectively evaluated the clinical data and the risk for tumor development in the cases with isolated hemihyperplasia. 24 cases with isolated hemihyperplasia were retrospectively evaluated. An extremity segment has been involved in 16.7%, an extremity has been entirely involved in 37.5%, more than one extremity have been involved on the same side in 16.7%, and definitely half of the body including the face has been involved in 25% of the patients, whereas one side of the face has been involved in only one case. Wilms tumor in the left abdomen (4.2%) was developed in one case. Isolated hemihyperplasia is a rare clinical picture that enhances the risk for the development of embryonal tumors. PMID- 25804023 TI - A new de novo mutation in a non-hot spot region at the DMD gene in a Mexican family. AB - In this report we present the analysis of a sporadic case of DMD and his family. In the present case, a deletion of exons 18-47 is presented which predicts abolition of the reading frame and is located between the well-known deletion hot spots of the DMD gene. This mutation was not previously reported in the Leiden database (LOVD). Both MLPA and segregation analysis with short tandem repeat markers elucidated the status of the mother, sister and the younger brother of the proband, who were not carriers of the mutation. This case provides a description of a new pathogenic variant presented as de novo mutation in a DMD patient. Haplotype analysis and complete gene screening may improve genetic counseling in cases of germline mosaicism and de novo mutations. PMID- 25804022 TI - De novo partial trisomy distal 4q: a case report. AB - We present a case of de novo distal partial trisomy 4q with firstly described chronic cholecystitis, rarely seen hypothyroidism, and bilateral membranous choanal atresia. The patient, a 10-month-old baby girl had dysmorphic facial features as well as neuromotor retardation, congenital hypothyroidism, atrial septal defect (ASD), white matter atrophy in cranial MRI, grade 2 dilatation in pelvicalyceal system of the left kidney, and bilateral ureteral reflux. In peripheral blood chromosome analysis 46, XX, dup(4) (q21q35) karyotype was detected. In FISH analysis using 4p/4q subtelomeric probe; 3 signals for 4 q region and 2 signals for 4p region were observed. In chromosome analyses of her healthy parents, no anomaly was detected. Herein we present a case of de novo partial distal trisomy 4q syndrome to contribute to the literature since it is rarely seen and this is the first patient with partial trisomy distal 4q syndrome presented with chronic cholecystitis and the second patient with hypothyroidism. PMID- 25804025 TI - A male newborn with Simpson-Golabi-Behmel syndrome, presenting with metopic synostosis, anal atresia, and total anomalous pulmonary venous return. AB - Simpson-Golabi-Behmel syndrome is a clinical condition described by Simpson, characterized with multiple congenital anomalies and caused by Glypican 3 (GPC3) mutations of the X-linked gene. Typical findings such as overgrowth, hypoplastic changes of hands and feet, visceromegaly, cleft palate and macrocephalic distinctive facial features and multiple organ anomalies might be observed. GPC3 mutation is claimed to generally cause metopic synostosis. This case was reported because even though a lot of anomalies accompanying Simpson-Golabi-Behmel syndrome had been noticed, combination of metopic synostosis, has not been reported before. PMID- 25804024 TI - A twin sibling with Prader-Willi syndrome caused by uniparental disomy conceived after in vitro fertilization. AB - The use of assisted reproductive technologies (ART) has increased gradually in the treatment of infertility worldwide. On the other hand ART has been found to be associated with an increased risk of congenital malformations including imprinting defects as well. Although a number of imprinting syndromes have been reported to be related with ART, no case with uniparental disomy (UPD) caused Prader-Willi syndrome (PWS) [OMIM ID: 176270] has been reported in the literature. Here we present a dizygotic twin in which one of them was born with maternal UPD15 following ART. The proband was a 2-year-old boy who had feeding difficulties, generalized hypotonia, frontal bossing, broad forehead, small hands and feet. Laboratory investigations revealed minimal dilatation in 3rd and 4th ventricles and corpus callosum hypoplasia in magnetic resonance imaging, supravalvular pulmonary stenosis in echocardiography and pelvicaliectasia in the USG examinations. Methylation and microsatellite markers analyses showed maternal UPD for chromosome 15. Here we report, for the first time UPD caused PWS patient born after ART. PMID- 25804026 TI - Giant cell tumor of distal phalanx in an adolescent with Goltz-Gorlin syndrome. AB - We report on a unique case of a young female patient with the Goltz-Gorlin syndrome who developed a giant cell tumor of bone in the distal phalanx of the thumb. This case is noteworthy because of the combination of some unusual features. Firstly, it is only the fifth case report on the association of giant cell tumor of bone and the Goltz-Gorlin syndrome. Also the localization of the lesion in the bones of the hand and the presentation at adolescent age is rarely seen. PMID- 25804027 TI - Single median maxillary central incisor syndrome and its clinical importance. PMID- 25804028 TI - [Light-induced retinal damage and the protective approach by antioxidants]. PMID- 25804029 TI - [Protection effect of astaxanthin against light-induced retinal damage in rat]. AB - PURPOSE: To clarify the protective effect of astaxanthin (AST) against light induced retinal damage in rats. METHODS: Albino rats were divided into three groups: a group treated orally with 1 mg/kg AST daily (group H), a group treated with 0.2 mg/kg AST (group L), and a control group (group C). Rats were administered AST in groups H and L and olive oil in group C followed by a 12-hour exposure to 3000-lux white light. After exposure for 7 days, the protective effect of AST was evaluated functionally by electroretinogram (ERG) and histologically by measuring outer nuclear layer (ONL) thickness and by counting rate of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stained cells. RESULTS: After exposure to light, the b-wave amplitudes were significantly preserved in the AST groups compared to group C, Further the rate of the residual amplitude was higher in group H than in group L. The ONL thicknesses were significantly thicker in AST-treated rats compared to group C. The rates of TUNEL stained cells were significantly lower in the following order: group H, L and C. CONCLUSION: AST may have a protective effect against light induced retinal damage in albino rats. PMID- 25804030 TI - [Clinical features of 19 cases of Fisher syndrome]. AB - PURPOSE: To determine the clinical symptoms of Fisher syndrome (FS). METHODS: We performed a retrospective study of 19 patients who had been diagnosed as having FS. RESULTS: The study involved 19 patients (13 men and 6 women) whose mean age of onset was 42.0 years. Ophthalmoplegia included 16 cases of abducens nerve palsy, 2 cases of total external ophthalmoplegia, and 1 combined case of abducens nerve palsy and impaired eye elevation. Although all cases of abducens nerve palsy were bilateral, in 5 cases the degree of the affliction was asymmetric. Other neurologic symptoms included 5 cases of nystamus, 5 cases of pain on eye movement, 5 cases of pupillary defects, 6 cases of blepharoptosis, 2 cases of facial palsy, 9 cases of dysesthesia in the limbs, 3 cases of ataxia and 1 case of bulbar palsy. Anti-GQ1b antibodies were detected in 74% of the patients. Sixteen patients were followed without treatment while 1 patient, was given oral vitamin B12 and 2 patients received intravenous immunoglobulin. Double vision improved in all cases, and the mean duration of double vision was approximately 70 days. CONCLUSIONS: FS develops in people of all ages and is more common in men. Also, abducens nerve palsy is common in FS. While it is rare to observe the triad of ophthalmoplegia, ataxia and areflexia, the frequency in which the disorder is complicated by neurologic symptoms other than the triad is high. Double vision has a good prognosis and improves even without treatment. PMID- 25804031 TI - [Prone position ultrasound biomicroscopy for two plateau iris configuration cases with decreased corneal endothelial cells after laser iridotomy]. AB - BACKGROUND: To report a possibility of mechanical injury following laser iridotomy (LI) via the iris surface to the corneal endothelium possibly causing bullous keratopathy. CASE: Subjects were two patients with plateau iris configuration who had been given LI bilaterally. One eye of each patient showed serious decrease in cellular density of the corneal endothelium. Cataract surgery was carried out in these two eyes. We performed ultrasound biomicroscopy in supine and prone positions for eight directions and specular microscopy for nine directions. Data were compared before and after the surgery. Significant endothelial loss was observed in the lower part of cornea in the two eyes. In the same area, the angular part of the plateau iris was attached to the cornea above the Schwalbe line was also shown in prone position. After the cataract surgery, the attachment was relieved, and the cellular density value of endothelium was increased in the lower area while the value was decreased in other areas. Thereafter, the endothelial decrease stopped. CONCLUSION: The contact between the iris root and the corneal endothelium might be one cause of bullous keratopathy in eyes with plateau iris following LI. PMID- 25804032 TI - [Prospects for improving the management tactics for patients with gastroesophageal reflux disease complicated by Barrett's esophagus]. AB - The paper presents the new principles relative to adequate diagnosis, management tactics, and rational treatment regimens in patients with gastroesophageal reflux disease (GERD) complicated by the development of Barrett's esophagus. The paper contains up-to-date, mainly original information on the pathological physiology, clinical picture, and principles of diagnosis of this form of GERD. It outlines data on approaches to the early diagnosis and prevention of neoplastic progression in Barrett's esophagus, by taking into account recent advances in pharmacotherapy. PMID- 25804033 TI - [Capabilities of 99mTc-pyrphotech single-photon emission computed tomography in combination with myocardial perfusion scintigraphy in the evaluation of inflammatory changes in the heart of patients with persistent atrial fibrillation]. AB - AIM: To estimate the capabilities of 99mTc-pyrphotech single-photon emission computed tomography (SPECT) in the diagnosis of myocardial inflammatory changes in patients with persistent atrial fibrillation (AF). SUBJECTS AND METHODS: Nineteen patients (11 males and 8 females, mean age 47.46 +/- 9.92 years) with persistent idiopathic AF underwent preoperative complete clinical and instrumental examination. 99mTc-pyrphotech SPECT was performed to identify foci of myocardial inflammatory changes. After completing 99mTC-pyrphotech scanning, resting myocardial perfusion scintigraphy with 99mTC-methoxyisobutylisonitrile (99mTc-MIBI) was performed in accordance with the standard protocol. The scintigrams obtained in both studies were then combined using the applied programs Jet Stream Workspace Release 2.5 (Philips) and the application Fusion. During invasive intervention, endomyocardial samples were intraoperatively taken from all the patients for histological and immunohistochemical examinations. RESULTS: Abnormal 99mTc-pyrphotech myocardial accumulation was found in 7 (36.8%) of the examinees, multiple foci in 3 cases and single foci in 4. Analysis of perfusion scintigrams indicated that the mean abnormal accumulation of 99mTc-MIBI in the left ventricle was 3.75 +/- 0.88% (maximum 9%). Histological examination of endomyocardial samples from 19 patients with persistent AF verified myocarditis in 4 (21%) patients and myocardial sclerosis concurrent with other abnormalities in 15 (78.9%) patients. CONCLUSION: Latent lymphocytic or polymorphic cellular myocarditis of viral etiology is a cause of idiopathic AF in 20% of the cases. 99mTc-pyrphotech scintigraphy may be one of the primary noninvasive diagnostic techniques for the detection of myocardial inflammation in this form of arrhythmia. PMID- 25804034 TI - [Estimation of central blood pressure and arterial stiffness in pregnant women with different forms of hypertension]. AB - AIM: To estimate central (aortic) blood pressure (BP) and arterial stiffness and their prognostic value in the development of preeclampsia (PE) in pregnant women with different forms of hypertension. SUBJECTS AND METHODS: The study included 106 patients with chronic hypertension, 21 with the latter concurrent with PE, 63 with gestational hypertension, 10 with PE, and 100 without hypertension. All the women underwent 24-hour BP monitoring by an oscillometric method to estimatecentral (aortic) BP and arterial stiffness at 16-22 weeks' gestation. RESULTS: The highest average daily central systolic and diastolic BP was in the pregnant women with PE. ROC analysis showed that the average daily aortic systolic BP greater than 115 mm Hg was most significant for the prediction of PE. The highest values of arterial stiffness (augmentation index, stiffness, maximum rate of blood pressure rise) were detected in the pregnant women with PE in the presence of chronic hypertension. CONCLUSION: 24-four BP monitoring inpregnant women can provide additional characteristics that reflect the stiffness of the aorta and peripheral arteries, which may be used to predict PE. PMID- 25804035 TI - [Trends in hospitalizations of patients with acute coronary syndrome and indicators of the atmospheric state in Moscow in 2009-2012]. AB - AIM: To identify the meteorological factors or their combinations, which are most significant for the development of acute coronary syndrome (ACS) in different seasons. SUBJECTS AND METHODS: A Statistica package was used to make an exploration analysis of the data of the A.S. Puchkov Central Emergency Medical Care Station on 63,412 admissions of patients diagnosed with acute myocardial infarction (AMI) to Moscow hospitals in 2009-2012 and those of the Hydrometeorology Center of Russia on weather conditions in the period under study. RESULTS: Among the 63,412 patients, there were more men than women (p < 0.000005). Two long frost periods and three long abnormal heat periods were recorded in 2009-2012. In summer, the number of patients with a prehospital diagnosis of AMI was an average 19-22% less than in the other seasons. There was no peak in the number of hospitalizations during the abnormally hot summer of 2010. Air temperature proved to be a factor that was most strongly associated with the trend in AMI hospitalizations in men (MS = 1011.52, MSor = 27.27; p < 0.00005) and women (MS = 895.36, MSor = 25.37; p < 0.00005). The number of hospitalizations was negatively associated with daily average temperature in its positive range. In summer, the interdaily temperature difference turned out to be statistically significant; the highest number of hospitalizations was noted when it grew 6 degrees C colder. On days off, the number of admitted patients was 25% less than that on weekdays. CONCLUSION: The trend in hospitalizations for a referral diagnosis of AMI has a significant seasonal component. Their number was minimal in summer, including in the abnormally hot summer of 2010. Air temperature is the most important factor. Positive temperature was found to be strongly negatively correlated with diagnosed AMI hospitalizations. PMID- 25804036 TI - [Associations of the prevalence of cardiovascular diseases with a high level of depression in the open population of an average urbanized Siberian town]. AB - AIM: To reveal an association of the prevalence of coronary heart disease (CHD) and metabolic syndrome (MS) with a high level of depression in the open population of 25-64-year-old men in an average urbanized Siberian town. SUBJECTS AND METHODS: The survey was conducted on a representative sample formed from the voting list of 25-64-year-old men in one of the administrative districts of Tyumen. The standard WHO MONICA-psychosocial questionnaire was used to study associations of the prevalence of CHD and MS with a high level of depression within cardiologic screening. RESULTS: The age-adjusted prevalence of depression was 4.6% (a high rate) and 19% (a moderate rate) in the 25-64-year-old men of the average urbanized town of West Siberia. With advancing age, the high level of depression increased, peaking in a 55-64-year-old group. In high depression and CHD in the 25-64-year-old men, the odds ratio (OR) was 21.07 for high depression and 39.84 for a definite CHD form. High depression was significantly more common in MS patients in the open population of 25-64-year-old people of the average urbanized Siberian town and in the 55-64 year old age group. An association was found between high depression and a combination of MS components: a concurrence of abdominal obesity, hypertriglyceridemia, and lower high-density lipoprotein cholesterol (OR 13.13). CONCLUSION: The epidemiological criteria revealed by standardized survey methods for psychosocial factors, depression in particular, should be used during the preventive examinations of a male population and during the selection of able-bodied people with cardiovascular disease to undergo in depth examination and follow-up. PMID- 25804037 TI - [Use of high-frequency chest wall oscillation in an exacerbation of chronic pyo obstructive bronchitis in adult patients with cystic fibrosis]. AB - AIM: To evaluate the efficiency of high-frequency chest wall oscillation in the treatment of an exacerbation of chronic pyo- obstructive bronchitis in adult patients with cystic fibrosis (CF). SUBJECTS AND METHODS: A simple open-label comparative study enrolled 31 patients with CF. C-reactive protein (CRP), spirometric indicators (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow), hemoglobin oxygen saturation, anthropometric data, six-minute walk test, and dyspnea rating by the MRC scale were assessed before treatment and on the last day of hospitalization. All the patients received conventional drug therapy; the study group patients (n=15) had the latter in combination with vibration-compression therapy for 15 minutes twice daily at a vibration frequency of 9-12 Hz and at an amplitude of 6-9 bars; the treatment cycle lasted 12-14 days. RESULTS: Both groups showed significant changes in spirometric and pulsometric readings, 6-minute walk test results, and MRC score. Body mass index increased and CRP decreased in the majority of patients in both groups. There were significant group differences in functional and anthropometric changes: 10.0 +/- 4.6 and 6.9 +/- 3.6% for FEV1 (p = 0.04) and 9.5 +/- 4.8 and 5.9 +/- 3.8% for FVC (p = 0.03) in the study and control groups, respectively. CONCLUSION: Incorporation of vibration-compression therapy (Vest vibro drainage) into the combination treatment of adult patients with CF results in significantly improved bronchial patency and more effective abolishment of an exacerbation. PMID- 25804038 TI - [Chronic lymphocytic leukemia accompanied by renal failure]. AB - AIM: To evaluate the efficiency and safety of monotherapy with bendamustine (B) and therapy with B in combination with rituximab (B + R) in patients with chronic lymphocytic leukemia (CLL) accompanied by renal failure (RF). SUBJECTS AND METHODS: The prospective pilot study included 8 patients (6 men, 2 women) with CLL concurrent with RF. The patients' median age was 63 years (51-77 years). The Binet classification stage of CLL corresponded to B in 2 cases and C in 6. The mean (+/- standard error) pretreatment concentration of creatinine was 218 +/- 92 MUmol/l and the glomerular filtration rate (GFR) was 33 +/- 20 ml/min. The efficiency of monotherapy with B (n=5) and combination therapy with B + R (n=3) was evaluated. In progressive CLL, therapy was performed in specific treatment naive patients (n = 5) and in pretreated patients refractory to alkylating agents (cyclophosphan, chlorambucil) (n = 3). A total of cycles of B and B + R were carried out. RESULTS: After B monotherapy, one of the 5 cases achieved a complete remission, 3 a partial remission, and 1 a nodular partial remission. Three patients developed recurrence. In the B monotherapy group, the cumulative risk of recurrence was 70% at a median follow-up of 22 months and at a maximum follow-up of 27 months. In the B + R therapy group, all the 3 patients achieved a complete remission. The median follow-up was 7 months; the maximum follow-up was 1 year. There were no deaths or recurrences. During B monotherapy and B + R combination therapy, there was improved kidney function: the mean concentration of creatinine decreased from 218 +/- 92 to 140 +/- 57 MUmol/l (p < 0.05); GFR increased from 33 +/- 20.0 to 54 +/- 25 ml/min; the mean increment was 20 ml/min (p < 0.01). Mild and moderate anemia and thrombocytopenia were most common during B and B + R therapies. Neutropenia with mild infection complications, as well as nonhematologic complications were detected in some cases. The drugs were observed to have no nephrotoxic effects. CONCLUSION: The performed pilot prospective indicated that the B + R combination therapy was effective in patients with RF associated CLL. No toxic effect of B on kidney function was seen. During B therapy, there was better kidney function manifesting itself as a statistically and clinically important decrease in creatinine concentrations and a statistically and clinically important increase in GFR as compared to the baseline values. PMID- 25804039 TI - [Etoricoxib in the treatment of active sacroiliitis in patients with axial spondyloarthritis, including ankylosing spondylitis]. AB - AIM: To study a trend in active sacroiliitis (ASI) in patients with axial spondyloarthritis (axSpA) during different short-term regimens using etoricoxib (ET) 90 mg. SUBJECTS AND METHODS: Forty patients with axSpA, including 30 with ankylosing spondyloarthritis), and ASI (sacroiliac joint (SIJ) osteitis as evidenced by magnetic resonance imaging) were examined and then randomized to 2 groups: 1) 20 patients who took ET 90 mg four days or more a week; 2) 20 patients who received ET 90 mg 3 days or less a week. Osteitis was measured in 4 quadrants of each SIJ (0-3 scores). Its main criterion was considered to be a decrease in total osteitis activity (TOA) 12 week later. RESULTS: In all the patients (n = 40), TOA decreased from 6.5 (4; 9) to 2 (0; 5) scores (p < 0.0001). In Group 1 (n = 20), that reduced from 6.5 (4; 8.5) to 0 (0; 3) scores (p < 0.0001). In Group 2 (n = 20), that did from 6.5 (4; 10) to 4 (1; 8) scores (p = 0.49). At 12 weeks, in in Groups 1 and 2, the difference in final TOA achieved no statistical significance (p=0.056). In these groups, there were 19 (95%) and 14 (70%) treatment-responsive patients, respectively. CONCLUSION: The intake of ET 90 mg for 12-weeks is associated with a reduction in the degree of ASI in patients with axSpA. The use of ET 4 times or more a week is more effective in diminishing osteitis than that of ET 3 days or less. PMID- 25804041 TI - [The prevalence of anxiety and depression in different regions of the Russian Federation and its association with sociodemographic factors (according to the data of the ESSE-RF study)]. AB - AIM: To study the prevalence of anxiety and depression by psychometric methods (the Hospital Anxiety and Depression Scale (HADS) in different regions of the Russian Federation (RF), which are characterized by various climatic, geographic, economic, and demographic indicators. SUBJECTS AND METHODS: The investigation used the data of the multicenter epidemiological survey of cardiovascular diseases in different regions of the Russian Federation--the ESSE-RF study. The subjects of the study were representative samples from unorganized male and female populations aged 25-64 years from 10 RF regions. The survey included a total 16,877 people (6244 men and 10,623 women). All the examinees were interviewed using a standard questionnaire. An analysis involved their gender, age, education level, place and region of residence, and income and morbidity level. The HADS validated in Russia was used to rate the level of anxiety/depression. RESULTS: The total prevalence of higher anxiety and depression averaged 46.3 and 25.6%, respectively. Respondents with clinical anxiety/depression constituted more than one third of those who had a higher level of these conditions. In the examined population, the moderate level of anxiety/depression was 7.5 +/- 0.06 and 5.1 +/- 0.04, respectively. The population of Volgograd, Samara, Saint Petersburg, and Tomsk had the similar values of the moderate level of anxiety/depression (p > 0.05). The lowest level of anxiety/ depression (p < 0.0001) was seen in the dwellers of Tyumen (5.9 +/- 0.1 and 3.4 +/- 0.1, respectively) and the highest in the Republic of North Ossetia-Alania (NOA) (8.4 +/- 0.1 and 6.8 +/- 0.1, respectively). These regions showed the lowest and highest prevalence of higher anxiety (22% in Tyumen and 59.8% in the Republic of NOA (p < 0.0001). CONCLUSION: All the 10 selected RF regions differing in demographic, economic, climatic, and geographical parameters are characterized by a high level of anxiety that remains statistically significant after adjusting for gender and age, so are parameters, such as income and morbidity levels are present in only 4 of the 10 regions. PMID- 25804040 TI - [Ursodeoxycholic acid-enhanced efficiency and safety of statin therapy in patients with liver, gallbladder, and/or biliary tract diseases: the RACURS study]. AB - AIM: To evaluate the efficiency and safety of using statins in combination with ursodeoxycholic acid (UDCA) in patients with this or another liver disease at high risk for cardiovascular events (CVE). SUBJECTS AND METHODS: A register of 262 patients at high risk for CCE who needed statin therapy and have concomitant chronic liver and biliary tract diseases was created in 5 cities of the Russian Federation. RESULTS: After addition of statins or adjustment of their doses, the patients were recommended to include UDCA into their therapy. Six months after stabilization of the dose of statins, the whole group showed a significant reduction in the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. Assessment of the laboratory parameters responsible for the safety of statin intake revealed no deterioration in the trend in the activity of alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, lactate dehydrogenase, as well as an increase in the serum level of bilirubin. The data obtained using a special questionnaire indicated that 196 patients had taken UDCA and 56 had not. The UDCA and non-UDCA subgroups did not differ in age, weight, or baseline lipid metabolic disturbances. An additional analysis showed that by the end of 6 months, the goal levels of LDL cholesterol in the UDCA and non-UDCA groups were reached in 37 and 20%, respectively (p = 0.01). CONCLUSION: UDCA added to statin therapy in patients at high risk for CVE and concurrent liver diseases contributes to an additional reduction in total cholesterol and LDL cholesterol and prevents enhanced hepatic transaminase activities. PMID- 25804042 TI - [Cognitive and emotional impairments in patients with protracted anxiety-phobic disorders]. AB - AIM: To study cognitive and emotional impairments in patients with anxiety-phobic disorders (APDs), to comparatively analyze the clinical manifestations of acute (less than one-year) and protracted (1-to-5-year) forms of this disease, and to evaluate the efficacy of noofen used to treat this pathology. SUBJECTS AND METHODS: Sixty-two patients aged 18 to 50 years with APDs were examined. The investigators collected clinical history data, performed neurological examination, and assessed autonomic disorders in accordance with the questionnaire to reveal their signs, anxiety using the Hamilton anxiety rating scale, memory impairment employing the methods developed by A.R. Luria, attention disorders applying the test of variables of attention, and diagnosed emotional intelligence using the Mayer-Salovey-Caruso emotional intelligence test. Noofen 1000 mg/day was used to treat the patients. RESULTS: Protracted APDs were shown to be characterized by the higher degree of psychosomatic symptoms and by more pronounced impairments in attention, memory, and emotional intelligence. The data of posttreatment clinical and psychological studiesare indicative of improvements in 73.3% of cases. CONCLUSION: The findings may lead to the conclusion that noofen is highly effective in the treatment of patients with protracted APDs. PMID- 25804043 TI - [Association of T174M polymorphism of the angiotensinogen gene with the higher risk of cerebral stroke in women]. AB - AIM: To study the association of M235T (rs699) and T174M (rs4762) polymorphisms of the angiotensinogen (AGT) gene with the risk of cerebral stroke (CS) in the Russians of the Central Chernozem Region. MATERIALS AND METHODS: A total of 638 DNA samples obtained from 353 patients with CS and 285 sex- and age-matched healthy individuals were examined. The polymorphisms were genotyped by polymerase chain reaction (T174M) and TaqMan allelic discrimination (M235T) assays. RESULTS: Heterozygous AGT 174TM genotype carriers were found to be at a higher risk for CS (odd ratio (OR) = 1.52; 95% confidence interval (CI), 1.08-2.15; p = 0.02). A gender-stratified analysis showed that the mutant 174M allele (OR = 1.86; 95% CI, 1.14-3.03, p = 0.01) and variant 174TM and 174MM genotypes (OR = 1.86; 95% CI, 1.09-3.20; p = 0.02) were associated with the higher risk of cerebral stroke in women. CONCLUSION: The association of AGT T174M polymorphism with the risk of CS was first found; but the higher risk of the disease in the carriers of variant alleles and genotypes was observed in the women only. PMID- 25804044 TI - [Direct human DNA damage by unfavorable environmental and climatic factors]. AB - AIM: To study the impact of simulated climatic conditions of the 2010 summer in Moscow on the telomere repeats of chromosomes in human blood cells. MATERIALS AND METHODS: The climatic conditions of July-August 2010 in Moscow were simulated at the Medical Technical Complex, Institute of Biomedical Problems, Russian Academy of Sciences. The relative length of the telomeric repeats of blood cell chromosomes from 6 apparently healthy volunteers was measured by quantitative real-time polymerase chain reaction. RESULTS: These conditions were ascertained to lead to a statistically significant decline in the length of telomere repeats in the terminal portions of chromosomes by 15%. CONCLUSION: Environmental changes and abnormal temperature rises may result in oxidative stress accompanied by telomere shortening, which can be, in turn, a factor of premature aging. PMID- 25804045 TI - [Nephrotic syndrome in a female patient with Rapunzel syndrome]. AB - The Rapunzel syndrome is a rare complication of gastric trichobezoar, which may be long insidious. Systemic hair eating gradually leads to bezoar growth, gastritis, gastric mucosal ulcerations, and evacuatory disorders. The Rapunzel syndrome may cause acute and chronic bowel obstruction, peritonitis, pancreatitis, appendicitis, anemia, hypoalbuminemia, and allergic manifestations. Neither proteinuria nor nephrotic syndrome is depicted in any of the 38 Rapunzel syndrome cases described in the literature. The authors present the first case of gastric trichobezoar extending to the small bowel (its total length was 118 cm), which gave rise to chronic recurrent partial bowel obstruction, causing intoxication nephrotic syndrome in a 20-year-old women with trichotillomania. The nephrotic syndrome became a reason for her admission to a nephrology department and had specific features: it was unaccompanied by hypercholesterolemia, it rapidly regressed and completely disappeared after surgical removal of the trichobezoar weighing 1980 g. PMID- 25804046 TI - [Efficacy of a fixed-dose combination of perindopril and amlodipine in the treatment of hypertensive patients. A clinical case]. AB - The paper describes a clinical case of the efficacy of a fixed-dose combination of perindopril and amlodipine used in a hypertensive patient. It shows its clinical effectiveness with no impact on blood lipid and glucose levels. 24-hour blood pressure monitoring revealed a reduction in daily blood pressure, including its variability, in pulse wave propagation velocity and central aortic pressure. PMID- 25804047 TI - [Cough: differential diagnosis and rational pharmacotherapy]. AB - This publication deals with topical problems in the management of patients with cough. It presents its epidemiology and clinical classification, an analysis of its causes, a list of required diagnostic techniques, and areas of pharmacotherapy. Emphasis is laid on the differential diagnosis of different abnormalities and diseases, the leading clinical sign of which is cough. The authors provide the detailed characteristics of medicaments for its treatment and the principles of rational antitussive and mucoactive pharmacotherapy. PMID- 25804048 TI - [Immunomodulators for the prevention and treatment of acute respiratory infections: efficacy of azoximer bromide]. AB - The review gives the results of a many-sided study of the basic properties of the therapeutic molecule of azoximer bromide (polyoxidonium). It analyzes our experience with the immunomodulator used to treat acute respiratory infections. Polyoxidonium has marked immunomodulatory (including interferon-producing) activity and a nonspecific protective effect against a broad range of pathogens, which is based on the regulation of systemic immunity rather than the direct inhibition of microorganisms. In addition, the drug has antitoxic and antioxidant properties. Azoximer bromide is used in combination with etiotropic therapy in the acute phase of disease and as monotherapy for rehabilitation or immunoprophylaxis of respiratory infections. PMID- 25804049 TI - [Antiplatelet therapy with acetylsalicylic acid: approaches to reducing the frequency of gastrointenstinal adverse reactions]. AB - Acetylsalicylic acid (ASA) is highly effective in preventing cardiovascular events, but associated with increased risk for digestive adverse reactions. The paper provides an update on the epidemiology, mechanisms, and risk factors of esophagogastroduodeno- and enteropathies during long-term low-dose ACA therapy. It outlines the key principles of their prevention. PMID- 25804050 TI - [Magnesium deficiency in cardiology]. AB - The paper considers the consequences and causes of magnesium deficiency in patients with cardiovascular diseases. The features of magnesium metabolism in atherosclerosis, hypertension, and heart failure are described. Prospects of magnesium therapy in cardiology practice are discussed. PMID- 25804051 TI - [Hypolipidemic and pleiotropic effects of a combination of simvastatin and ezetimibe in patients with different types of hyperlipidemia]. AB - The review considers trials dealing with the efficiency of combination hypolipidemic therapy with simvastatin and ezetimibe. Its synergistic potentiating effect can cause a considerable decrease in the level of total cholesterol, low-density lipoproteins, triglycerides, and C-reactive protein, which are important participants in the atherogenic process. This effect promotes the achievement of hypolipidemic therapeutic goals in many cases when this cannot be attained by high-dose statin monotherapy. The authors consider the results of trials of combination hypolipidemic therapy with simvastatin and ezetimibe performed as basic ones done in both previous and recent years. PMID- 25804052 TI - [The ghrelin-obestatin system in health and disease]. AB - The role of the ghrelin--obestatin system in health and disease is multifaceted and new ample evidence has been recently accumulated. Ghrelin was discovered much earlier than obestatin so the biological, physiological and pathophysiological, pharmacological aspects of its activity could be studied far better than obestatin. There is no question that these hormones are not antagonists and they are a uniform system. However, there is a need for further studies of the role of this system in the body's vital functions in health and disease. The paper analyzes the accumulated information on the ghrelin--obestatin system in health and disease, assesses the possibility of their use in clinical practice, and pays attention to the unsolved problems to be explored and solved. PMID- 25804053 TI - [The modern concepts of pyoderma gangrenosum]. AB - The review provides an update on pyoderma ganrenosum, a rare chronic disease from a group of neutrophilic dermatoses. It considers its pathogenesis, its association with background visceral disease, and the specific features of skin and visceral involvement. Major and minor diagnostic criteria and differential treatment approaches are given. PMID- 25804054 TI - [Mastocytosis. Review of the literature and description of clinical cases]. AB - The term mastocytosis (MC) encompasses a group of rare diseases characterized by the tumorous proliferation of clonal mast cells and the infiltration of one or several organs. The clinical picture of MC is extremely diverse from skin lesions that can spontaneously regress to the aggressive disease forms associated with organ dysfunction and short survival. Nowadays, the 2008 WHO classification identifies 7 MC subtypes. The disease is diagnosed on the basis of its clinical manifestations and detection of tumorous mast cell infiltrations via morphological, immunohistochemical, immunophenotypic, genetic, and molecular examinations. Abnormal mast cells are characterized by the atypical morphology and pathological expression of CD25 and CD2 antigens. Enhanced serum tryptase activity is a common sign in all MC subtypes. More than 90% of the patients have D816V KIT mutations in the mast cells. This paper reviews the literature. Three cases are described as a clinical example in patients with different MC subtypes. PMID- 25804055 TI - [Aging and pain: specific features of neuropathy treatment in the elderly]. AB - The changes in the somatosensory system in aging and peripheral neuropathies are similar. Higher pain sensitivity thresholds in the presence of axonopathy are accompanied by paradoxically decreased pain tolerance associated with neuroplastic changes in the spinal cord and brain. The symptomatic treatment of neuropathic pain syndrome with antidepressants, anticonvulsants, and opioids is related to the lower quality of life in elderly patients and to the high risk of severe side effects. The pathogenetic treatment of polyneuropathies frequently increases the intensity of neuropathic pain at its beginning; however, it can recover the function of an axon and reduce the degree of deficiency states. The paper discusses methods for increasing the safety of treatment for neuropathic pain in elderly patients, a relationship between the pathogenesis of nervous system aging and distal diabetic polyneuropathy, and ways of their correction. PMID- 25804056 TI - Nodulation competitiveness of Ensifer meliloti alfalfa nodule isolates and their potential for application as inoculants. AB - Alfalfa (Medicago sativa) is a widely cultivated legume, which enters into nitrogen-fixing symbiosis with Ensifer (Sinorhizobium) spp. In this study, an autochthonous rhizobial population of Ensifer sp. occupying alfalfa nodules grown in arable soil was used as the basis for selection of potential inoculants. Alfalfa nodule isolates were identified as Ensifer meliloti by partial 16S rDNA, recA, atpD and nodC nucleotide sequencing. The sampled isolates displayed different symbiotic performance and diversity in the number of plasmids and molecular weight. Isolates that were the most efficient in symbiotic nitrogen fixation were tagged with a constitutively expressed gusA gene carried by a stable plasmid vector pJBA21Tc and used in competition experiments in soil under greenhouse conditions. Two E. meliloti strains LU09 and LU12, which effectively competed with indigenous soil rhizobia, were selected. The metabolic profiles of these selected strains showed differences in the use of carbon and energy sources. In addition, the LU09 strain exhibited bacteriocin production and LU12 mineral phosphate solubilization, which are valuable traits for soil survival. These strains may be considered as potential biofertilizers for alfalfa cultivation. PMID- 25804057 TI - Agrobacterium-mediated transformation of three freshwater microalgal strains. AB - Microalgal transformation has gained interest in recent years. Agrobacterium mediated transformation remains as the most efficient method for the development of transgenic plants and microalgae due to its wide host range, inexpensive procedure and transfer of large segments of DNA. In the present study, three different microalgal species were isolated from freshwater environment and identified based on the morphological characteristics and ITS-2 region amplification. Agrobacterium-mediated transformation was successful for the isolates Chlorella sp., Ankistrodesmus sp and Scenedesmus bajacalifornicus. Gene integration and expression was confirmed by PCR amplification of hptII and GUS histochemical assay. A. tumifaciens contamination was checked by amplification of npt II gene (kanamycin resistant) which lies outside the T-border. Based on GUS assay, transformation efficiencies were found to be 12.25% for Chlorella sp. 2.96% for Scenedesmus bajacalifornicus and 3.5% for Ankistrodesmus sp. PMID- 25804059 TI - Compartmentalization in penicillin G biosynthesis by Penicillium chrysogenum PQ 96. AB - The arrangement of organelles in the sub-apical productive non-growing vacuolated hyphal cells of the high- and the low-penicillin-pro- ducing strains Penicillium chrysogenum was compared using transmission electron microscopy. In the productive cells of the high-yielding strain the endoplasmic reticulum and the polyribosomes with associated peroxisomes are frequently arranged at the periphery of the cytoplasm and around the vacuoles. At the high activity of penicillin G biosynthesis the immuno-label of the cytosolic isopenicillin N synthase is concentrated at the polyribosomes arranged in the peripheral cytoplasm and along the tonoplast as well as around the peroxisomes. On the basis of the obtained results the compartmentalization of the pathway of penicillin G biosymthesis is discussed. The obtained results support the phenylacetic acid detoxification hypothesis of penicillin G biosynthesis. PMID- 25804058 TI - Evaluation of the time period for which real-time polymerase chain reaction detects dead bacteria. AB - Real-time polymerase chain reaction (PCR) is currently widely used for the diagnosis of infections. We evaluated the time after treatment during which real time PCR can detect dead bacteria. The presence of bacterial DNA was identified by real-time PCR through methicillin-resistant Staphylococcus (MRS)-PCR and universal PCR. Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and Escherichia coli were each killed with alcohol, antibiotics, or heat treatment in vitro. The detection periods of MRS-PCR for MRSA treated by alcohol, vancomycin, linezolid, and heat were found to be less than 16, 8, 12, and 8 weeks, respectively. The detection period of universal PCR for S. epidermidis treated by alcohol, cefazolin, and heat was less than 20, 20, and 4 weeks, whereas that for E. coli was 8, 20, and 4 weeks, respectively. The presence of detectable bacterial DNA in infected arthroplasty patients before and after successful treatment was also assessed by MRS- and universal PCR. MRS-PCR was positive in 6 patients before treatment and all became negative after a mean interval of 20.8 weeks (95% confidential interval, 13.2 to 33.7) after treatment. Universal PCR detected remnant bacterial DNA in 4 patients at a mean of 15.2 weeks (95% CI, 12.4 to 18.0) after treatment and was negative in 7 patients at a mean of 17.3 weeks (95% CI, 10.6 to 24.0) after treatment. Our studies revealed that real-time PCR detects dead bacteria for several weeks, but this capability decreases with time and is likely lost by 20 weeks after treatment. PMID- 25804060 TI - In vitro study of biofilm growth on biologic prosthetics. AB - Biologic prosthetics are increasingly used for the repair of abdominal wall hernia defects but can become infected as a result of peri- or early post operative bacterial contamination. Data evaluating biofilm formation on biologic prosthetics is lacking. The aim of this study was to investigate the influence of different biologic prosthetics on the growth behavior of two different bacterial species and their ability to form biofilms. Methicillin resistant Staphylococcus aureus (MRSA) or Pseudomrnonas aeruginosa were incubated on disks of two biologic prosthetics-human acellular dermis (ADM), and porcine small intestinal submucosa (SIS). The bacteria were allowed to attach to the prosthetics and propagate into mature biofilms for 24 hours at 370C. Images of biofilms were obtained using confocal microscopy and scanning electron microscopy (SEM). The number of viable cells and the biofilm biomass were quantified by colony forming units (CFUs) and crystal violet staining respectively. Analysis of variance was performed to compare the mean values for the different prosthetics. Each biologic matrix had a distinct surface characteristic. SEM visualized mature biofilms characterized by highly organized multi-cellular structures on surface of both biologic prosthetics. Quantification of bacterial growth over time showed that ADM had the lowest CFUs and biofilm biomass at 24 hours post-inoculation compared to SIS for both bacterial strains. MRSA and P. aeruginosa can form mature biofilms on biologic prosthetics but the relative abundance of the biofilm varies on different prosthetic constructs. Biologic material composition and manufacturing methods may influence bacterial adherence. PMID- 25804061 TI - Bioprotective potential of bacteriocinogenic Enterococcus gallinarum strains isolated from some Nigerian fermented foods, and of their bacteriocins. AB - Enterococcus gallinarum strains isolated from some Nigerian fermented foods were found to produce bacteriocins. The bacteriocins had a broad spectrum of activity against both Gram-positive and negative bacteria. The effects of the bacteriocins and bacteriocinogenic organ- isms on Staphylococcus aureus infections in rats were evaluated. Sprague-Dawley rats were infected with S. aureus MTCC 737 and treated with E. gallinarum T71 and different concentrations of the bacteriocins from E. gallinarum W211 and T71. Staphylococcus aureus infection caused significant upregulation of aspartate aminotransferase and alanine aminotransferase levels in sera of the infected rats. Moreover, gelatin zymography revealed that infected gastric tissues showed elevated matrix metalloproteinase-9 activity. Bacteriocin treatments reduced the MMP-9 activity and inhibited the expressions of both Tumour Necrosis Factor Alpha (TNF-alpha) and Interleukin-1 Beta (IL-1beta) dose dependently, pointing to a potential role of the bacteriocins in attenuating inflammatory responses to Staphylococcus aureus infec- tion. Gastric and GIT damage caused by staphylococcal infection were reduced in the Enterococcus gallinarum T71 and bacteriocin-treated groups also dose dependently. We conclude that these bacteriocins may have useful biomedical applications. PMID- 25804062 TI - Synthetic amphibian peptides and short amino-acids derivatives against planktonic cells and mature biofilm of Providencia stuartii clinical strains. AB - Over the last decade, the growing number of multidrug resistant strains limits the use of many of the currently available chemotherapeutic agents. Furthermore, bacterial biofilm, due to its complex structure, constitutes an effective barrier to conventional antibiotics. The in vitro activities of naturally occurring peptide (Citropin 1.1), chemically engineered analogue (Pexiganan), newly designed, short amino-acid derivatives (Pal-KK-NH2, Pal-KKK-NH2, Pal-RRR-NH2) and six clinically used antimicrobial agents (Gatifloxacin, Ampicilin, Cefotaxime, Ceftriaxone, Cefuroxime and Cefalexin) were investigated against planktonic cells and mature biofilm of multidrug-resistant Providencia stuartii strains, isolated from urological catheters. The MICs, MBCs values were determined by broth microdilution technique. Inhibition of biofilm formation by antimicrobial agents as well as biofilm susceptibility assay were tested using a surrogate model based on the Crystal Violet method. The antimicrobial activity of amino-acids derivatives and synthetic peptides was compared to that of clinically used antibiotics. For planktonic cells, MICs of peptides and antibiotics ranged between 1 and 256 MUg/ml and 256 and >= 2048 MUg/ml, respectively. The MBCs values of Pexiganan, Citropin 1.1 and amino-acids derivatives were between 16 and 256 MUg/ml, 64 and 256 MUg/ml and 16 and 512 MUg/ml, respectively. For clinically used antibiotics the MBCs values were above 2048 MUg/ml. All of the tested peptides and amino-acids derivatives, showed inhibitory activity against P. stuartii biofilm formation, in relation to their concentrations. Pexiganan and Citropin 1.1 in concentration range 32 and 256 MUg/ml caused both strong and complete suppression of biofilm formation. None of the antibiotics caused complete inhibition of biofilm formation process. The biofilm susceptibility assay verified the extremely poor antibiofilm activity of conventional antibiotics compared to synthetic peptides. The obtained results showed that synthetic peptides are generally more potent and effective than clinically used antibiotics. PMID- 25804063 TI - Antiquorum from freshwater zoosporic isolated fungi: maximization of some ameliorative factors. AB - Many bacteria detect their critical cell numbers through a mechanism known as quorum sensing (QS). Acyl homoserine lactones (AHLs) mediated QS systems have been shown to operate in important human pathogens. The aim of this study was to evaluate the inhibitory effect generated by zoosporic freshwater fungi on AHLs production. A potent strain of zoosporic fungi, Leptolegniella keratinophilum, was isolated after extended screening study. A new cheap medium was used to support the anti-AHLs activities. Statistical strategy depending on two levels factorial model and three levels quadratic model were applied to guide a production maximization process. The three levels Box-Behnken model possessed the ability to optimize the significant nutritional and cultural conditions and to predict the maximum that can be achieved. In the course of study, we reached 88% anti-AHLs activity, while the initial activity was 63%. There was no previous maximization methodology for either the experimental medium, or the fungi. The results suggest that freshwater zoosporic fungi can be potentially used against bacterial infections. PMID- 25804064 TI - Sulphate reducing activity detected in soil samples from Antarctica, Ecology Glacier Forefield, King George Island. AB - We determined sulphate-reducing activities in media inoculated with soils and with kettle lake sediments in order to investigate their potential in geomicrobiological processes in low-temperature, terrestrial maritime Antarctic habitats. Soil and sediment samples were collected in a glacier valley abandoned by Ecology Glacier during the last 30 years: from a new formed kettle lake sediment and forefield soil derived from ground moraine. Inoculated with these samples, liquid Postgate C and minimal media supplemented with various carbon sources as electron donors were incubated for 8 weeks at 4 degrees C. High rates of sulphate reduction were observed only in media inoculated with soil. No sulphate reduction was detected in media inoculated with kettle lake sediments. In soil samples culture media calcite and elemental sulphur deposits were observed, demonstrating that sulphate-reducing activity is associated with a potential to mineral formation in cold environments. Cells observed on scanning microscopy (SEM) micrographs of post-culture-soil deposits could be responsible for sulphate-reducing activity. PMID- 25804066 TI - Measles outbreak among Roma people in Wroclaw, Poland, 2012. AB - A measles outbreak that affected mainly the Roma ethnic group has been observed in Wroclaw, southwest Poland, in spring/summer 2012. There were 15 confirmed measles cases occurring among young Roma people aged from 0 to 16 years including a newborn infant, born by a mother who showed measles symptoms immediately after delivery. Measles virus transmission into the general Polish population was restricted to two contact cases. Initiation of the outbreak by MeV importation from Romania has been confirmed by detection of MeV variant "D4-Maramures" circulating in Romania from 2011 to 2012. The outbreak experience highlights once more the still existing prob- lem of immunity gaps in Roma groups moving throughout Europe with a high susceptibility among children and adolescents including young women of child-bearing age. PMID- 25804065 TI - Relationship between measles outbreaks based on genetic analysis of measles virus genomes detected in patients in Poland between 2006 and 2012. AB - This study describes the molecular characterization of 56 MeV strains obtained from 56 patients in Poland from 2006 to 2012. The C-terminal fragment of nucleoprotein gene was analysed. It has been found out during 2006 and 20012 MeV strains circulating in Poland belonged to genotypes D4, D5, D6 and B3. The D4 strains isolated in Poland were different from any other D4 strain circulating at the same time in Europe, whereas all other MeV strains isolated during 2007-2012 were related to strains from other countries. The present data suggest that after 2006 the MeV strains were imported. PMID- 25804067 TI - Production of ligninolytic enzymes by cultures of white rot fungi. AB - Some Basidiomycota were chosen for studies of key ligninases synthesis (25 degrees C, 30 days) in modified medium (shaken or not cultures) with added wheat straw. Liquid Czapek medium with straw yielded a higher amount of laccase than peroxidase, ground straw induced enzyme worse than chopped straw. With peroxidase the reverse dependencies were observed. Laccase of Lentinus edodes synthesized two enzyme isoforms (ca 30 and 16 kDa). In T. versicolor culture active laccase protein with highest molecular mass ca 65 kDa was found. P. sajor-caju yielded three different peroxidase isoforms. Ligninase biosynthesis depended on strain, straw fragmentation extent, culture method and growth medium. PMID- 25804068 TI - Identification of some yeasts by fatty acid profiles. AB - 178 yeasts isolated from various foods were identified using ID32 C strip; Saccharomyces cerevisiae (47), Rhodotorula mucilaginosa (19), Candida kefyr (33), Candida krusei (37), Candida lusitaniae (28), Cndida lipolytica (14). The yeasts were harvested, saponified, derivatized, and extracted, and fatty acid analysis was performed by Gas Chromatography Mass Spectrometry. The yeast lipids contained Decanoic acid (C10:0), Luaric acid (C12:0), Myristoleic acid (C14:1), Myristic acid (C14:0), Pentadecanoic acid (C15:0), Palmitoleic acid C16:1), Pamitic acid (C16:0), Heptadecenoic acid (C17:1), Linoleic acid (C18:2), Linolenic acid (C18:3), Oleic acid (C18:1) and Stearic acid (C 18:0). The differences in the composition of these fatty acids could be used to identify the species as an accurate, efficient and relatively rapid method. PMID- 25804069 TI - [Evaluation of ITS-PCR and PCR MP techniques for Streptococcus agalactiae genetic differentiation]. AB - INTRODUCTION: The aim of this study was to evaluate the usefulness of ITS-PCR and PCR MP methods for genotyping of S. agalactiae strains isolated from women in reproductive age. METHODS: In the course of the study 250 strains of S. agalactiae were isolated and their serotype was identified. The ITS-PCR and PCR MP methods allowed to differentiate 20 strains and then the correlation between the serotypes of the tested isolates and their geno- type was evaluated. RESULTS: Among 250 strains of S. agalactiae the following serotypes were identified as the most common: III (54%), Ia (17%) and V (12%). Also other serotypes have been found: IV (8%), Ib (5%) and II (4%). PCR MP has a higher discriminative power than the ITS-PCR and it allowed for the efficient differentiation of strains. There is no direct relationship between genotypes and serotypes ofS. agalactiae. CONCLUSIONS: PCR MP is useful in the differentiation of S. agalactiae. Exactly as in the case of RAPD and PFGE methods, PCR MP can be used for thediagnosis and analysis of GBS isolates colonization. This method is also used for successful genotyping of other microbial species, often closely related ones, as well as in epidemiological studies. PMID- 25804070 TI - [Evaluation of usefulness of the enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to lipopolysaccharides of Enterohemorrhagic Escherichia coli (EHEC) strains in patients with gastrointestinal disorders and patients with hemolytic uremic syndrome]. AB - INTRODUCTION: Enterohemorrhagic Escherichia coli (EHEC) strains are an important zoonotic food-borne and waterborne pathogens causing diarrhea and the severe hemolytic uremic syndrome (HUS) in humans. The aim of the study was to evaluate the usefulness of enzyme immunoassay ELISA for detection of antibodies to the lipopolysaccharides (LPS) of EHEC in patients with gastrointestinal disorders and patients with hemolytic-uremic syndrome. MATERIAL AND METHODS: Sera obtained from 526 patients with gastrointestinal disorders, 26 patients with HUS and 74 patients with different bacterial gastroenteritis infections were screened by an LPS-based ELISA. The LPS antigens of EHEC belonging to serogroups O26, O103, O104, O111, O121, O145, and O157 were obtained by modified Boivin's method. Additionally, to determine the cut-off level, the 122 sera from healthy people were tested. Cellular extract from E. coli O14 were used to remove by absorption antibodies to the Enterobacteriaceae Common Antigen (ECA). RESULTS: Generally, seroprevalence of antibodies to the LPS of different EHEC serogroups in patients with gastrointestinal disorders was low. Additionally, interpretation of the some positive results was difficult to the fact of many serological mutual interactions. Particularly a lot of cross-reactions were seen in the group of sera obtained from patients with different bacterial gastroenteritis infections. The study showed also that in most cases the absorption of antibodies to the ECA had no significant effect on the cross-reactions observed in ELISA. On the other hand, the very high level of antibodies to the LPS antigen of E. coli O26 was found in 5 patients, to E. coli O157 in 4 patients, to E. coli O104 and O145 in 3 patients and E. coli O111 in 2 patients with HUS. Analysis of antibody levels in paired sera taken 2-3 weeks apart obtained from six HUS patients showed a rapid decline of antibody levels to the LPS antigens. CONCLUSIONS: The results showed the usefulness of the ELISA with lipopolysaccharides antigens to serodiagnosis of infection caused by EHEC. Due to the possibility of cross- -reaction there is a need to develop more specific antigens, based on the recombinant proteins of verotoxin-producing Escherichia coli. PMID- 25804071 TI - [Comparison of phenotypic methods for the detection of beta-lactamases MBL in strains from the Enterobacteriaceae family and non-fermentative bacilli isolated from clinical specimens]. AB - INTRODUCTION: Bacterial resistance is growing because of treatment a broad spectrum antibio- tics. Gram-negative pathogens which producing carbapenemase are a one of major problem in many hospitals. Rapid detection those strains provide an early inhibition of infection and control the expansion of microorganisms. The aim of work was to characterize the frequency of appearance MBLs in specific groups of Gram-negative bacilli which are resistant or intermediate to at least one of carbapenems. METHODS: Bacterial isolates were collected from Baby Jesus Clinical Hospital from 2003 to 2009. Pathogens were isolated from urine, blood, fluids, swab of the wound, pharyngeal swab. They were identified by the ID 32 E (bioMerieux, France) and Vitek2. Antimicrobial resistance was marked by the ATB G 5 and ATB UR (bioMerieux, France). Detection of metalo-beta-lactamases was tested by disk diffusion test recommended by the EUCAST. The DDS test using imipenem, ceftazidime, ethylenediaminetetraacetic acid (EDTA) and 2-mercaptopropionic acid (2-MPA). Positive test was reading as enlargement of inhibition zone about imipenem- or ceftazidime-impregnated disk. RESULTS: Of the 88 isolates, 32 come fromEnterobacteriaceae and 56 from non-fermentative bacilli. All strains were tested of production of MBL by disk diffusion test. This method used two inhibitors: ethylenediaminetetraacetic acid and 2-mercaptopropionic acid. As a result of EDTA there was 45 MBL positive strains. In apply 2-MPA there was 55 MBL positive strains. Both the EDTA and 2-MPA disk test showing the highest percentage of positive result in Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and Pseudomonas putida. CONCLUSIONS: Resistance to carbapenems in the non-fermentative bacilli occurs more often than in the Enterobacteriaceae. Method with 2-mercaptopropionic acid was more effective to detect metallo-beta-lactamases than EDTA. Concerns especially bacilli from Enterobacteriaceae. PMID- 25804072 TI - [Evaluation of Bordetella pertussis strains toxicity in vitro using CHO cell lines]. AB - INTRODUCTION: Whooping cough is still a significant disease with regular outbreaks despite the decades of mass vaccination and good immunization coverage. The aim of this study was to evaluate the capacity of Bordetella pertussis toxicity testing among strains harbouring different alleles of the pertussis toxin promoter ptxP using hamster ovary cell line CHO (Hamster Ovary). METHODS: The study assessed the limits of detection of high and low Ptx levels producing strains using a reference preparation ofpertussis toxin and B. pertussis strains that increased toxicity in vitro has been previously correlated with ptxP3 allele presence. RESULTS: The presence of the strong agglomerates on CHO cell line confirmed the higher toxicity of B. pertussis strains isolated in France. Preliminary toxicity study with use of selected strains of B. pertussis differing by ptxP1 and ptxP3 promdter alleles with respect to relevant reference preparation indicate lower toxicity of strains B. pertussis isolated in Poland. CONCLUSIONS: The toxicity measured on CHO line will be used to assess the virulence of all available B. pertussis strains isolated in Poland. PMID- 25804073 TI - [Frequency of antibodies to the recombinant protein P39 of C. jejuni in patients with gastrointestinal disorders and reactive arthritis in Poland]. AB - INTRODUCTION: Campylobacterjejuni is has been found to be the leading cause of bacterial gastroenteritis worldwide. Clinical manifestation on enterocolitis caused by C. jejuni are diarrhea, fever, abdominal pain and in some patients, fecal blood. After C. jejuni infection, squeals may occur such as reactive arthritis. The aim of the study was to investigate the frequency of antibodies to the recombinant protein P39 sticks C. jejuni in patients with gastrointestinal disorders and reactive arthritis in Poland. MATERIAL AND METHODS: Serum samples collected from 46 patients with bacteriology confir- med infection caused by Campylobacter jejuni, 472 sera from patients with gastrointestinal disorders, 97 serum samples obtained from patients with reactive arthritis and 84 sera from healthy adults and children. Sera were screened for anti-P39 C. jejuni recombinant protein IgA, IgG andIgM antibodies by using the home-made ELISA. Protein P39 C. jejuni was expressing in E. coli BL21 (DE3) using the pET-30 Ek/LIC expression vector. Purification was accomplished by immobilized metal (Ni2+) affinity column chromatography (His Bind Resign, Novagen). RESULTS: SDS PAGE and Coomassie brilliant blue staining confirmed a high purity of the recombinant P39 protein preparation with an expected molecular mass of 39 kDa. The results of ELISA with the P39 recombinant protein revealed that IgA antibodies in diagnostically significant level (x + 2SD) were found in 18.8%, IgM in 14.8% and IgG in 7.8% of sera obtained from patients with of gastrointestinal disorders. On the other hand, antibodies to recombinant P39 protein in sera obtained from patients with reactive arthritis were found in more than twice the percentage than in patients with gastrointestinal disorders (IgA in 34.0%, IgG in 26.8% and IgM in 19.6%). CONCLUSIONS: In conclusion, based on the data obtained, C. jejuni may be important factor in triggering the gastrointestinal disorder and reactive arthritis in humans in Poland. PMID- 25804074 TI - [Resistance to azithromycin of Neisseria gonorrhoeae strains isolated in Poland in 2012-2013 years]. AB - INTRODUCTION: Azithromycin is one of the most commonly used macrolide antibiotics. As other macrolides it inhibits bacterial proteins synthesis by binding with V domene of bacterial 23S rRNA. Resistance to azithromycin can be related to: 1. Mutations in gene encoding 23S rRNA. Significant effect on azithromycin MIC (minimal inhibitory concentration) is not observed when the mutation occurs only in 1 allele. In case of mutations occurring in 4 alleles, more common mutation C2611T is associated with MIC 2-16 mg/L and the second mutation A2059T results in high level resistance to azithromycin MIC > 256 mg/l 2. Over- production of membrane pumps proteins MtrCDE and MacAB, that remove antibiotics from bacterial cells. The mechanism is not able to cause azithromycin resistance itself but coexisting with other mechanisms of resistance can additionally increase MIC. 3. Synthesis of 23S rRNA methylases ErmB, ErmF, ErmC, ErmA. These enzymes cause demethylation of adenine (A2058) in V domain of 23S rRNA. The mechanism was common in the past, but it has been replaced by mutations in in V domain of 23S rRNA. Nowadays 23S rRNA methylases are very rare in N. gonorhoeae. METHODS: Sixty five Neisseria gonorrhoeae strains isolated from patients of the Department of Dermatology and Venereology in Warsaw in the second half of 2012 and first of 2013 were investigated. The strains were cultured on chocolate agar plates in a 5% CO2 atmosphere at 37 degrees C and identified by colony morphology, Gram staining and oxidase reaction, followed by carbohydrate utilization test. Azithromycin susceptibility was determined by E-Tests (bioMerieux). Bacteria were incubated at 37 degrees C in 5% CO2 for 24 h on chocolate agar plates. Tests were performed according to producers recommendations. The results (sensitive or resistant) were interpreted according to EUCAST recommendations. RESULTS: The MIC of azithromycin in investigated strains ranged from 0,064 to 4 mg/L, MIC50 = 0.5 mg/L, MIC90 = 2 mg/L. It was shown that only 38.5% of the strains were sensitive to azithromycin according to EUCAST criteria from 2014 year and 89.3% of the strains were sensitive to azithromycin according to CDC criteria from 2014 year. CONCLUSIONS: The percentage of azithromycin resistant Neisseria gonorrhoeae strains is increasing in Poland and the antibiotic should not be used in monotherapy as gonorrhoea patients. It should only be used in combination with ceftriaxone or cefixime. PMID- 25804075 TI - [HCV inection in pregnancy]. AB - The prevalence of anti-HCV antibodies in pregnant women ranges from 0.1% to 3.6% worldwide. In Poland, one work was published on the prevalence of HCV antibodies in pregnant women. Based on studies conducted by Aniszewska et al. in 544 women, the percentage of anti-HCV antibodies was estimated at 2.02%. Since 2011, the NIPH-NIH performs "Preliminary programme of routine HCV testing among pregnant women" within the Swiss-Polish Cooperation Programme, co-financed by the Ministry of Health, with the aim to, i.a. estimate the prevalence of HCV infection in the population of pregnant women. The transmission of the virus from mother to fetus is now considered to be the most common route leading to infections in children and infants. According to available data, the risk of vertical transmission from infected mother is relatively low and ranges from 1.8% to 5%. Transmission of HCV can occur both in the prenatal period as well as during the labor. Irrespective of the numerous studies on the transmission of the virus from mother to child, its mechanism has not been completely understood. Exclusively the factors favoring this route of infection are known. The main risk factor for vertical transmission is the presence of viral RNA in maternal peripheral blood. Other risk factors include: the presence of viral RNA in PBMC, HIV coinfection, significant increase in ALT in a year preceding pregnan- cy and during labor in women infected with HCV, extended time between the rupture of membranes and delivery as well as female gender of the baby. The impact of amniocentesis and cesarean delivery as risk factors for vertical transmission of HCV are still discussed. Breastfeeding by mothers infected with HCV is safe and does not lead to transmission of infection to the baby. As ribavirin and interferon, which are used in therapeutic regimens, cannot be administered during pregnancy, it is important to perform testing for HCV prior to a planned pregnancy. This gives the opportunity to cure the infection and eliminate the vertical route of HCV transmission. PMID- 25804076 TI - [Gut microbiome and its dysbiosis as an important factor influencing the human health condition]. AB - Human organism consists of not only from numerous of eukaryotic cells but also from thousands of microorganisms. The most complicated is the microflora of gastrointestinal tract. Numerous studies indicates that the complex network of interactions between the host organism and its microbiome can have a very significant impact on the health condition of the host. These interactions can affect not only to gastrointestinal tract but can be related to different processes and organs. Disturbance of the homeostasis, e.g. after antibiotic course, can therefore have significant health implications Therefore, very important is the deepest exploring of the network of these interactions and dependencies. PMID- 25804077 TI - [Problematic issues and prospects of development of information and telecommunication technologies in the medical service of the Armed Forces]. AB - Medical information systems composed of many specialized modules help in synchronous solving of diagnostic, therapeutic, administrative, financial, statistical, and other tasks. According to the authors, the creation of a single information space of the medical service, integrating it into a single information space of the Defense Ministry of the Russian Fedaration, development and widespread use of telemedicine technology will significantly accelerate the integration in the daily activities of military hospitals of the latest achievements in medical science and practices consistent with the objectives of improving the military health care and improvement of the quality and accessibility of health care. PMID- 25804078 TI - [The basis of modern technologies in management of health care system]. AB - For the development of national heaIth care it is required to implement modern and effective methods and forms of governance. It is necessary to clearly identify transition to process management followed by an introduction of quality management care. It is necessary to create a complete version of the three-level health care system based on the integration into the system "Clinic - Hospital - Rehabilitation", which will ensure resource conservation in general throughout the industry. The most important task is purposeful comprehensive management training for health care--statesmen who have the potential ability to manage. The leader must possess all forms of management and apply them on a scientific basis. Standards and other tools of health management should constantly improve. Standards should be a teaching tool and help to improve the quality and effectiveness of treatment processes, the transition to the single-channel financing--the most advanced form of payment for the medical assistance. This type of financing requires managers to new management approaches, knowledge of business economics. One of the breakthrough objectives is the creation of a new type of health care organizations, which as lead locomotives for a rest. PMID- 25804079 TI - [Political and organizational-legal frameworks for cooperation between countries of the Asia-Pacific region in the field of military medicine]. AB - A framework for cooperation in the field of military medicine in the Asia-Pacific region is considered. Expert Working Group on Military Medicine in cooperation with the Association of Southeast Asian dialogue partners (including Russia) was formed to discuss the most important issues in the field of military medicine, to share practical experience of military physicians, standardization and unification of medical equipment, medicines, levels and standards of medical services and other issues in order to enhance cooperation of military medical services of the participating countries. From 2014 to 2016, the Russian Federation and the Kingdom of Thailand are co-chairs of the expert group. PMID- 25804080 TI - [Bilateral massive pulmonary embolism: clinical observation and literature review]. AB - The description of successful surgical treatment of a patient with bilateral massive pulmonary embolism (with the defeat of the equity and segmental branches), thrombosis of the right atrium and patent foramen ovale is given. The authors emphasize that determining predictors of successful surgical treatment of bilateral pulmonary embolism in a patient with high risk of death are the following: a) operational emergency diagnosis of disease; b) time from the beginning of clinical manifestations till embolectomy (within 1 hour); c) the maximum total removal of blood clots from the pulmonary artery and its branches. Dynamic 12 months observation showed a significant decrease of pulmonary perfusion deficiency, improvement of functional parameters of right heart chambers, absence of thromboembolism relapses. PMID- 25804081 TI - [Our experience of the clinical use of desflurane]. AB - Despite the widespread use of inhalational anaesthetics in modern medical practice it is still unable to create an "ideal" anesthetic, which meets the following requirements--maximum performance, security, and manageability. Desflurane is an inhalational anaesthetic, which first appeared on Russian market in 2013, according to the specifications meet the above-mentioned requirements. The results of the use of Desflurane during anaesthesia in 157 patients of the Cancer Department and Department of Oral and Maxillofacial Surgery at the Burdenko Main Military Clinical Hospital are given. The main advantages are the rapid achievement of Desflurane required depth of anaesthesia, minimal effects on the cardiovascular system, good handling, fast and safe awakening of the patient after surgery, which can make it "anaesthetic of choice" for long surgical procedures and outpatient surgery. PMID- 25804082 TI - [Diagnosis and treatment of achalasia cardiae]. AB - Achalasia is a progressive oesophageal motility disorder of unstudied aetiology involving the smooth muscle layer of the oesophagus. Insufficient knowledge of the pathogenesis of achalasia and the lack of clear treatment approaches has led to an increase of advanced disease forms. Common clinical manifestations of the disease are: incomplete LES relaxation, non-specific initial manifestations and as a result late medical seeking. Occurrence of achalasia cardiae is significantly low, therefore it is important to analyse the available clinical data. The article presents an experience of treatment of 30 patients over the last 16 years of observation. The average age of patients was 50, 5 years; insignificant male predominance is noted. III or IV disease state was diagnosed in 86.7% of patients; this diagnosis was confirmed by esophagogastroduodenoscopy. In the group of 24 patients who underwent attempted endoscopic dilatation of the cardiae, most of the included patients with stage II and III disease. Immediate good and satisfactory results of endoscopic treatment were obtained in 20 patients (83.3%), in 4 cases (16.7%) developed recurrent disease. PMID- 25804083 TI - [Status and development prospects of radiological health in the Navy]. AB - More than 7.5 thousands of people work as military and civilian personnel and have an access to a lot of sources of ionizing radiation on ships and vessels, at coastal units and institutions of the Navy. This fact determines the importance of radiation safety and medical preventive measures on naval fleets. The article analyses the state of radiation-hygienic measures, outlines the conceptual basis for the development of radiation hygiene in the Navy. Substantiated reconstruction tasks effectiveness of health control and state sanitary and epidemiological supervision of radiation safety, provides information about the optimal set of instruments for radiation monitoring equipment radiobiological laboratories and centres of state sanitary and epidemiological supervision at various levels. PMID- 25804084 TI - [Illustration of military medicine on the pages of mass printed media during the First World War]. AB - The article analyses some of illustrations dedicated to the military medical topics on the pages of some Russian magazines and newspapers (magazine "Ogonek" newspaper "Petrograd's paper" and its annexes), its place among the images of the war, formed in the mass consciousness by periodical subjects. It is concluded that with the beginning of the First World War medical illustrations were finally approved as a recognizable symbol of the war. Mass printed media played a significant role in its entrenchment. PMID- 25804085 TI - [D.P.Zuikhin and his contribution to the establishment and development of the system of medical maintenance of nuclear submarines personnel]. AB - A highly qualified physician, an outstanding leader, a scientist Dmitry Zuikhin (1924-1988) was directly involved into establishment of a system of medical support for submariners in the sea and on shore, he proved the necessity of forces and means for the medical service fleet. He was a pioneer in this challenging and new field of naval medicine. His energy, perseverance and determination helped to establish in the early 1960 a system of medical support for nuclear submarines personnel, which was subsequently implemented in all associations and connections of nuclear submarines of the Northern and Pacific fleets. PMID- 25804086 TI - ["Podmoskovie"--health resort institution of the Federal Drug Control Service of the Russian Federation celebrates the 20th anniversary]. AB - The article is dedicated to the 20th anniversary of the Federal government health resort institution of the Federal Drug Control Service of the Russian Federation (FGI "Health resort "Podmoskovie" of the Federal Drug Control Service of the Russian Federation). In this health resort were developed treatment programs for patients with abnormalities of the cardiovascular, respiratory and digestive systems; methods of ultrasonic, laser and magnetic therapy, atmospheric hypoxic, herbal medicine, speleotherapy are employed. Widely used natural healing factors of Ruza district of the Moscow region such as climate therapy, treatment with mineral water group of X type of Smolensk from own wells and balneo-mudtherapy. Over the past 20 years 70 000 patients received an appropriate treatment in this health resort. PMID- 25804087 TI - The Effect of Duration of Penile Traction Therapy in Patients Undergoing Intralesional Injection Therapy for Peyronie's Disease. AB - PURPOSE: The concomitant use of penile traction therapy with interferon alpha-2b has been previously described. We present an update on our clinical experience to assess the benefit and duration of daily traction. MATERIALS AND METHODS: A retrospective review of patients who underwent interferon alpha-2b therapy between 2001 and 2012 was performed. Charts were reviewed and data collected regarding various patient demographics, vascular parameters, objective length and curvature measurements, and use of penile traction therapy. Penile traction therapy was further stratified according to duration of daily use. RESULTS: A total of 112 patients underwent a median of 12 interferon alpha-2b injections (range 6 to 24). Daily use of penile traction therapy was reported by 31% of patients. There were no differences in patient demographics, initial vascular status, pretreatment stretched penile length, erect circumference and curvature between patients who followed a penile traction therapy regimen and those who did not. Overall, the use of penile traction therapy did not effect change in penile circumference (with therapy +3.2 mm [SD 6.5] vs no therapy +2.1 mm [SD 7.4], p=0.45), change in curvature (with therapy -8.1 degrees [SD 16.0] vs no therapy 9.9 degrees [SD 11.8], p=0.49) or change in stretched penile length (with therapy +2.4 mm [SD 0.9] vs no therapy +1.3 mm [SD 0.8], p=0.56). Men who used penile traction therapy 3 or more hours per day gained significantly greater stretched penile length compared to those who did not use penile traction therapy (4.4 mm [SD 0.5] vs 1.3 mm [SD 0.8], p=0.04). CONCLUSIONS: Routine penile traction therapy during intralesional injection with interferon alpha-2b for Peyronie's disease may result in a small but subjectively meaningful improvement in stretched penile length, without affecting curvature, if used for at least 3 hours a day. PMID- 25804089 TI - Exploratory behavior and recognition memory in medial septal electrolytic, neuro- and immunotoxic lesioned rats. AB - In the present study, the effect of the medial septal (MS) lesions on exploratory activity in the open field and the spatial and object recognition memory has been investigated. This experiment compares three types of MS lesions: electrolytic lesions that destroy cells and fibers of passage, neurotoxic - ibotenic acid lesions that spare fibers of passage but predominantly affect the septal noncholinergic neurons, and immunotoxin - 192 IgG-saporin infusions that only eliminate cholinergic neurons. The main results are: the MS electrolytic lesioned rats were impaired in habituating to the environment in the repeated spatial environment, but rats with immuno- or neurotoxic lesions of the MS did not differ from control ones; the MS electrolytic and ibotenic acid lesioned rats showed an increase in their exploratory activity to the objects and were impaired in habituating to the objects in the repeated spatial environment; rats with immunolesions of the MS did not differ from control rats; electrolytic lesions of the MS disrupt spatial recognition memory; rats with immuno- or neurotoxic lesions of the MS were normal in detecting spatial novelty; all of the MS lesioned and control rats clearly reacted to the object novelty by exploring the new object more than familiar ones. Results observed across lesion techniques indicate that: (i) the deficits after nonselective damage of MS are limited to a subset of cognitive processes dependent on the hippocampus, (ii) MS is substantial for spatial, but not for object recognition memory - the object recognition memory can be supported outside the septohippocampal system; (iii) the selective loss of septohippocampal cholinergic or noncholinergic projections does not disrupt the function of the hippocampus to a sufficient extent to impair spatial recognition memory; (iv) there is dissociation between the two major components (cholinergic and noncholinergic) of the septohippocampal pathway in exploratory behavior assessed in the open field - the memory exhibited by decrements in exploration of repeated object presentations is affected by either electrolytic or ibotenic lesions, but not saporin. PMID- 25804088 TI - Effects of Duloxetine on Urethral Continence Reflex and Bladder Activity in Rats with Cerebral Infarction. AB - PURPOSE: We investigated the effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on the sneeze induced continence reflex and on bladder function in rats with cerebral infarction. MATERIALS AND METHODS: Using urethane anesthesia the effect of duloxetine (1 mg/kg intravenously) on the amplitude of urethral responses during sneezing as well as urethral baseline pressure at the mid urethra was evaluated in normal female adult rats and cerebral infarction rats. Tilt leak point pressure was also measured. In normal and cerebral infarction rats continuous cystometry was evaluated before and after duloxetine injection. RESULTS: In cerebral infarction rats urethral baseline pressure was 43% lower than in normal rats but the amplitude of urethral responses during sneezing did not differ in the 2 groups. Duloxetine increased the amplitude of urethral responses during sneezing and urethral baseline pressure by 31% and 21%, respectively, in normal rats but did not affect either in cerebral infarction rats. Also, in cerebral infarction rats leak point pressure was 29% lower compared with normal rats. Duloxetine increased leak point pressure in normal rats but not in cerebral infarction rats. Cerebral infarction reduced intercontraction intervals without affecting the amplitude of bladder contractions compared with normal rats. Duloxetine prolonged intercontraction intervals in cerebral infarction rats but not in normal rats. CONCLUSIONS: These results suggest that cerebral infarction induces not only bladder overactivity but also stress urinary incontinence, which may account for mixed incontinence in patients with cerebral infarction. After cerebral infarction duloxetine reduced bladder overactivity but failed to enhance active urethral closure mechanisms during sneezing, suggesting that disorganization of the brain network after cerebral infarction might influence the effect of duloxetine on lower urinary tract function. PMID- 25804090 TI - Serum omentin levels in adolescent girls with anorexia nervosa and obesity. AB - It is believed that omentin is secreted by stromal cells of adipose tissue and modulates insulin sensitivity. Data from a few studies have shown lower serum omentin in obese children and higher in anorexia nervosa. However, to date, there is lack of research on serum omentin concentrations in adolescent patients in a wide range of body mass index (BMI) and insulin resistance. In this cross sectional study omentin-1 serum concentrations were evaluated using commercially available ELISA kit in 47 Polish girls with restrictive anorexia nervosa (AN), 50 with simple obesity (OB) and 39 healthy controls (C). The mean serum omentin-1 concentration in girls with AN was statistically significantly higher than that of C and OB girls. Statistically significant (P<0.0001) negative correlations between the serum concentrations of omentin-1 and body weight (r=-0.73), BMI (r= 0.75), standard deviation score for body mass index (BMI-SDS) (r=-0.75), insulin (r=-0.81) and HOMA-IR index (r=-0.82) were seen in the entire examined population. We conclude, that omentin-1 is the nutritional marker reflecting body weight and insulin resistance. Our findings support the hypothesized role of omentin in maintenance of body weight and regulation of appetite and suggest the adaptation of its secretion to body weight and glucose metabolism. PMID- 25804091 TI - The protective influence of selenium on oxidant disturbances in brain of rats exposed to lithium. AB - For more than sixty years lithium carbonate has been used in medicine. However, during its administration different side effects including oxidative stress can occur. Selenium belongs to essential elements possessing antioxidant properties. This study aimed at evaluating if selenium could be used as a protective adjuvant in lithium therapy. The experiment was performed on four groups of Wistar rats: I (control), II (Li), III (Se), IV (Li + Se) treated with saline, lithium carbonate (2.7 mg Li/kg b.w.), sodium selenite (0.5 mg Se/kg b.w.) and lithium carbonate (2.7 mg Li/kg b.w.) + sodium selenite (0.5 mg Se/kg b.w.), respectively. All substances were administered as water solutions by stomach tube for 3 or 6 weeks. Catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as malonyldialdehyde (MDA) were determined in brain homogenates. Lithium slightly enhanced MDA and depressed CAT and SOD after 6 weeks as well as GPx after 3 weeks. Selenium co-administration showed tendency to restore the disturbed parameters. Selenium alone and given with lithium significantly increased GPx vs. Li-treated group after 3 weeks. Having regarded the outcomes of this study, the research on application of selenium during lithium treatment seems to be worth continuation. PMID- 25804092 TI - Hepatocyte transplantation attenuates the course of acute liver failure induced by thioacetamide in Lewis rats. AB - Acute liver failure (ALF) is a clinical syndrome resulting from widespread damage of hepatocytes, with extremely high mortality rate. Urgent orthotopic liver transplantation was shown to be the most effective therapy for ALF but this treatment option is limited by scarcity of donor organs. Therefore, hepatocyte transplantation (Tx) has emerged as a new therapeutical measure for ALF, however, the first clinical applications proved unsatisfactory. Apparently, extensive preclinical studies are needed. Our aim was to examine if hepatocytes isolated from transgenic "firefly luciferase" Lewis rats into the recipient liver would attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Untreated Lewis rats after TAA administration showed a profound decrease in survival rate; no animal survived 54 h. The rats showed marked increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, in plasma level of bilirubin and ammonia (NH(3)), and in a significant decrease in plasma albumin. Hepatocyte Tx attenuated the course of TAA-induced ALF Lewis rats which was reflected by improved survival rate and reduced degree of liver injury showing as lowering of elevated plasma ALT, AST, NH(3) and bilirubin levels and increasing plasma albumin. In addition, bioluminescence imaging analyses have shown that in the TAA-damaged livers the transplanted hepatocyte were fully viable throughout the experiment. In conclusion, the results show that hepatocyte Tx into the liver can attenuate the course of TAA-induced ALF in Lewis rats. This information should be considered in attempts to develop new therapeutic approaches to the treatment of ALF. PMID- 25804093 TI - Endogenous LPS alters liver GH/IGF system gene expression and plasma lipoprotein lipase in goats. AB - Endotoxin lipopolysaccharide (LPS) affects the ruminant health and animal performance. The main purposes of this study were to investigate the potential effects of GH/IGF system and lipoprotein lipase (LPL) concentration on resistance the circulating LPS concentration increased in liver with high concentrate diet treatment. Non-lactating goats were randomly allocated to two groups: a high concentrate diet (HCD) or a low-concentrate diet (LCD) in cross over design and the blood collection at different time points after feeding at the end of the experiment. The average rumen pH was significantly reduced (P<0.05), but the duration with pH was not more than 120 min in the HCD group. The plasma LPL concentration was significantly raised (P<0.05). However, from 2 h onwards, LPS concentration was significantly reduced (P<0.01) in the HCD group compared with LCD group. In addition, the plasma IGF1 concentration and the hepatic insulin like growth factor-1 receptor (IGF1R) mRNA expression were markedly reduced (P<0.05). However, growth hormone (GH) secretion at 15, 30, and 45 min after feeding and growth hormone receptor (GHR) mRNA expression in the liver was significantly increased (P<0.05) in HCD group. The correlation analysis showed that the plasma LPL concentration was positively correlated with hepatic GHR mRNA expression (P<0.05). Conversely, the plasma LPS concentration was negatively correlated with LPL concentration (P<0.05). These findings reveal that alterations in GH/IGF system function in response to a high-concentrate diet are accompanied by corresponding changes in systemic LPL in non-lactating goats' liver in presence of endogenous LPS stress. PMID- 25804094 TI - ROS scavenger decreases basal perfusion pressure, vasoconstriction and NO synthase activity in pulmonary circulation during pulmonary microembolism. AB - Two mechanisms contribute in the development of pulmonary hypertension in pulmonary embolism (PE) - obstruction of pulmonary blood vessels and vasoconstriction. We hypothesize that hypoxia, increased shear stress and/or activation of gathered leukocytes in the PE may cause a release of reactive oxygen species (ROS). Therefore our aim was to determine the influence of the ROS scavenger Tempol on pulmonary hypertension and to describe NO synthase activity and production of NO oxidative products (NOx) after PE. In general anesthesia sephadex microspheres suspended in PSS were applied in right jugular vein as the pulmonary microembolism. Than we measured in isolated salt solution-perfused lungs the changes in perfusion pressure, activity of NO synthase and NOx plasma concentration in 7 groups of rats: C: control group (n=5), CN: C + sodium nitroprusside (SN) (n=5), EN: PE + SN (n=5), ETN: Tempol + PE + SN (n=5), CL: C + L-NAME (n=5), EL: PE + L-NAME (n=5), ETL: Tempol + PE + L-NAME (n=5). Tempol was applied intraperitoneally before PE. Animals that received Tempol (groups TN, TL) had significantly lower basal perfusion pressure than those which did not receive Tempol (EN, EL). Overall we measured a higher decrease of perfusion pressure than in the control group (C) after application of SN. Administration of L-NAME after PE (EL) increased the pressure more than in the control group (NL). NOx concentration was higher after PE. We found that preventive administration of Tempol decreases the increase in perfusion pressure after PE. PE increased NO release and concentration of NOx. PMID- 25804095 TI - Role of NO/cGMP signaling pathway in cardiac ischemic tolerance of chronically hypoxic rats. AB - It has been suggested that increase in acute nitric oxide (NO) or cyclic guanosine monophosphate production may be involved in cardioprotection induced by chronic hypoxia (CH). We studied the effect of NO donor molsidomine and phosphodiesterase type 5 inhibitor sildenafil on myocardial ischemia/reperfusion (I/R) injury in rats adapted to CH. Male Wistar rats were exposed to continuous hypoxia in a normobaric chamber (10 % O(2), 4 weeks). Rats received either saline, molsidomine (10 mg/kg body weight, i.v.) or sildenafil (0.7 mg/kg body weight, i.v.) 30 min before ischemia. Control rats were kept under normoxia and treated in a corresponding manner. Adaptation to CH increased the myocardial ischemic tolerance. Acute treatment with either molsidomine or sildenafil significantly reduced infarct size in normoxic rats and further enhanced cardioprotection induced by CH. However, the cardioprotective effect of CH on I/R injury was not additive to the cardioprotection provided by the drugs. PMID- 25804096 TI - Renal sympathetic denervation improves cardiac dysfunction in rats with chronic pressure overload. AB - Varied causative and risk factors can lead to cardiac dysfunction. Cardiac dysfunction often evolves into heart failure by cardiac remodeling due to autonomic nervous system disturbance and neurohumoral abnormalities, even if the detriment factors are removed. Renal sympathetic nerve activity plays a pivotal regulatory role in neurohumoral mechanisms. The present study was designed to determine the therapeutic effects of renal sympathetic denervation (RSD) on cardiac dysfunction, fibrosis, and neurohumoral response in transverse aortic constriction (TAC) rats with chronic pressure overload. The present study demonstrated that RSD attenuated myocardial fibrosis and hypertrophy, and structural remodeling of the left atrium and ventricle, up-regulated cardiac beta adrenoceptor (beta-AR, including beta(1)AR and beta(2)AR) and sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) while down-regulated angiotensin II type 1 receptor (AT(1)R), and decreased plasma B-type natriuretic peptide (BNP), norepinephrine (NE), angiotensin II (Ang II), and arginine vasopressin (AVP) levels in TAC rats with chronic pressure overload. We conclude that RSD attenuates myocardial fibrosis, the left atrial enlargement, and the left ventricular wall hypertrophy; inhibits the overdrive of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and AVP system in TAC rats with chronic pressure overload. RSD could be a promising non-pharmacological approach to control the progression of cardiac dysfunction. PMID- 25804097 TI - Hydrogen sulfide improves the endothelial dysfunction in renovascular hypertensive rats. AB - As a novel gasotransmitter, hydrogen sulfide (H(2)S) has vasodilating and antihypertensive effects in cardiovascular system. Thus, we hypothesized that H(2)S might have beneficial effects on thoracic endothelial function in two kidney one-clip (2K1C) rats, a model of renovascular hypertension. Sodium hydrosulfide (NaHS, 56 micromol/kg/day) was administrated intra-peritoneally from the third day after the 2K1C operation. Along with the development of hypertension, the systolic blood pressure (SBP) was measured before the operation and each week thereafter. The oxidative stress was determined by measurement of malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity and protein expression of oxidative stress-related proteins (AT(1)R, NADPH oxidase subunits). Acetylcholine (ACh)-induced vasorelaxation and angiotensin II (Ang II) induced vasocontraction were performed on isolated thoracic aorta. The SBP was significantly increased from the first week after operation, and was lowered by NaHS. NaHS supplementation ameliorated endothelial dysfunction. The protein expression of oxidative stress-related proteins were downregulated, while SOD activity upregulated. In conclusion, improvement of endothelial function is involved in the antihypertensive mechanism of H(2)S. The protective effect of H(2)S is attributable to suppression of vascular oxidative stress that involves inhibition of Ang II-AT(1)R action, downregulation of oxidases, as well as upregulation of antioxidant enzyme. PMID- 25804098 TI - Effect of homocysteine on survival of human glial cells. AB - Several neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, or vascular dementia and cognitive impairment, are associated with mild hyperhomocysteinemia. Hyperhomocysteinemia is defined as an increase of the homocysteine (Hcy) level beyond 10 microM. Although the adverse effect of Hcy on neurons is well documented, knowledge about the impact of this amino acid on glial cells is missing. Therefore, with the aim to evaluate the neurotoxic properties of Hcy on glial cells, we used a glioblastoma cell line as a study model. The viability of cells was assayed biochemically and cytologically. At a concentration around 50 microM in the culture medium D,L-Hcy induced cell death. It is noteworthy that Hcy induces cell death of human glial cells at concentrations encountered during mild hyperhomocysteinemia. Therefore, we propose that Hcy-induced impairment of neuronal functions along with damage of glial cells may contribute to the etiopathogenesis of neurodegenerative diseases associated with hyperhomocysteinemia. PMID- 25804099 TI - Polymorphisms associated with low bone mass and high risk of atraumatic fracture. AB - Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures. In the pathogenesis of osteoporosis, except environment and internal factors, such as hormonal imbalance and genetic background, are also in play. In this study candidate genes for osteoporosis were classified according to metabolic or hormonal pathways, which regulate bone mineral density and bone quality (estrogen, RANKL/RANK/OPG axis, mevalonate, the canonical circuit and genes regulating the vitamin D system). COL1A1 and/or COL1A2 genes, which encode formation of the procollagen 1 molecule, were also studied. Mutations in these genes are well-known causes of the inborn disease 'osteogenesis imperfecta'. In addition to this, polymorphisms in COL1A1 and/or COL1A2 have been found to be associated with parameters of bone quality in adult subjects. The authors discuss the perspectives for the practical utilization of pharmacogenetics (identification of single candidate genes using PCR) and pharmacogenomics (using genome wide association studies (GWAS) to choose optimal treatment for osteoporosis). Potential predictors of antiresorptive therapy efficacy include the following well established genes: ER, FDPS, Cyp19A1, VDR, Col1A1, and Col1A2, as well as the gene for the canonical (Wnt) pathway. Unfortunately, the positive outcomes seen in most association studies have not been confirmed by other researchers. The controversial results could be explained by the use of different methodological approaches in individual studies (different sample size, homogeneity of investigated groups, ethnic differences, or linkage disequilibrium between genes). The key pitfall of association studies is the low variability (7-10 %) of bone phenotypes associated with the investigated genes. Nevertheless, the identification of new genes and the verification of their association with bone density and/or quality (using both PCR and GWAS), remain a great challenge in the optimal prevention and treatment of osteoporosis. PMID- 25804100 TI - Slow breathing training reduces resting blood pressure and the pressure responses to exercise. AB - Slow breathing training reduces resting blood pressure, probably by modifying central autonomic control, but evidence for this is lacking. The pressor response to static handgrip exercise is a measure of autonomic control and the aim of this study was to determine whether slow breathing training modulates the pressor responses to exercise of untrained muscles. Twenty hypertensive patients trained for 8 weeks, 10 with unloaded slow breathing (Unloaded) and 10 breathing against an inspiratory load of 20 cm H(2)O (Loaded). Ten subjects were untrained controls. Subjects performed a 2 min handgrip pressor test (30 % MVC) pre- and post-training, and blood pressure and heart rate (HR) were measured before the contraction, at the end and following 2 min recovery. Resting systolic (sBP) and HR were reduced as a result of training, as reported previously. After training there was both a smaller pressor response to hand grip exercise and a more rapid recovery of sBP and HR compared to pre-training. There were no changes in the Controls and no differences between the Unloaded and Loaded groups. Combining the two training groups, the sBP response to handgrip exercise after training was reduced by 10 mm Hg (95 % CI: -7, -13) and HR by 5 bpm (95 % CI: -4, -6), all p<0.05. These results are consistent with slow breathing training modifying central mechanisms regulating cardiovascular function. PMID- 25804101 TI - The microRNA-23a has limited roles in bone formation and homeostasis in vivo. AB - Recent studies have demonstrated that some microRNAs (miRNAs) inhibit bone formation by inhibiting the translation of specific genes. Several in vitro studies have suggested that miR-23a inhibits osteogenic differentiation by suppressing the translation of Runx2, a transcription factor essential for osteoblastogenesis, and of Satb2, a member of the special AT-rich binding protein family. In the present study, we used a gain-of-function approach to determine the roles of miR-23a in bone formation and homeostasis in vivo. The miR-23a transgenic (Tg) mice grew normally and their body size and weight were similar to those of wild-type (WT) littermates. Bone structure and morphology were similar in Tg and WT mice. Furthermore, the numbers of osteoblasts and osteoclasts, as well as their activities in bone were similar between Tg and WT mice. Our results indicate that miR-23 has limited roles in bone formation and maintenance in vivo in mice. PMID- 25804102 TI - Changes in the composition of fatty acids and lipofuscin-like pigments during development of rat heart. AB - Postnatal heart development is characterized by critical periods of heart remodeling. In order to characterize the changes in the lipophilic fraction induced by free radicals, fatty acids and their oxidized products, lipofuscin like pigments (LFP), were investigated. Fatty acids were analyzed by gas chromatography and LFP were studied by fluorescence techniques. A fluorophore characterized by spectral methods was further resolved by HPLC. Major changes in the composition of fatty acids occurred immediately after birth and then during maturation. Fluorescence of LFP changed markedly on postnatal days 1, 4, 8, and 14, and differed from the adult animals. LFP comprise several fluorophores that were present since fetal state till adulthood. No new major fluorophores were formed during development, just the abundances of individual fluorophores have been modulated which produced changes in the shape of the spectral arrays. HPLC resolved the fluorophore with excitation maximum at 360 nm and emission maximum at 410 nm. New chromatographically distinct species appeared immediately on postnatal day 1, and then on days 30 and 60. Consumption of polyunsaturated fatty acids immediately after birth and subsequent formation of LFP suggests that oxidative stress is involved in normal heart development. PMID- 25804103 TI - Impaired PI3K/Akt signaling as a potential cause of failure to precondition rat hearts under conditions of simulated hyperglycemia. AB - The aim of the study was to evaluate the impact of simulated acute hyperglycemia (HG) on PI3K/Akt signaling in preconditioned and non-preconditioned isolated rat hearts perfused with Krebs-Henseleit solution containing normal (11 mmol/l) or elevated (22 mmol/l) glucose subjected to ischemia-reperfusion. Ischemic preconditioning (IP) was induced by two 5-min cycles of coronary occlusion followed by 5-min reperfusion. Protein levels of Akt, phosphorylated (activated) Akt (P-Akt), as well as contents of BAX protein were assayed (Western blotting) in cytosolic fraction of myocardial tissue samples taken prior to and after 30 min global ischemia and 40-min reperfusion. In "normoglycemic" conditions (NG), IP significantly increased P-Akt at the end of long-term ischemia, while reperfusion led to its decrease together with the decline of BAX levels as compared to non-preconditioned hearts. On the contrary, under HG conditions, P Akt tended to decline in IP-hearts after long-term ischemia, and it was significantly higher after reperfusion than in non-preconditioned controls. No significant influence of IP on BAX levels at the end of I/R was observed under HG conditions. It seems that high glucose may influence IP-induced activation of Akt and its downstream targets, as well as maintain persistent Akt activity that may be detrimental for the heart under above conditions. PMID- 25804104 TI - Recombinant human tissue non-specific alkaline phosphatase successfully counteracts lipopolysaccharide induced sepsis in mice. AB - Sepsis is a life threatening condition that arises when the body's response to an infection injures its own tissues and organs. Sepsis can lead to shock, multiple organ failure and death especially if not recognized early and treated promptly. Molecular mechanisms underlying the systemic inflammatory response syndrome associated with sepsis are still not completely defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. In this study we investigated a possibility of combating sepsis in a mouse model by intravenous treatment with recombinant human tissue non-specific alkaline phosphatase (rhTNAP) derived from transgenic rabbit milk. We induced sepsis in mice by intraperitoneal injection of LPS and three hours later treated experimental group of mice by intravenous injection with rhTNAP derived from transgenic rabbits. Such treatment was proved to be physiologically effective in this model, as administration of recombinant rhTNAP successfully combated the decrease in body temperature and resulted in increased survival of mice (80 % vs. 30 % in a control group). In a control experiment, also the administration of bovine intestinal alkaline phosphatase by intravenous injection proved to be effective in increasing survival of mice treated with LPS. Altogether, present work demonstrates the redeeming effect of the recombinant tissue non-specific AP derived from milk of genetically modified rabbits in combating sepsis induced by LPS. PMID- 25804105 TI - Proton partial breast irradiation in the supine position: Treatment description and reproducibility of a multibeam technique. AB - PURPOSE: Proton-accelerated partial breast irradiation (APBI) is early in its developmental phase without standardized treatment parameters. We report an approach to multibeam proton APBI using a universally available supine setup and deliberate beam arrangement strategy to limit the total area of skin receiving a full dose while being robust for interfraction variation. METHODS AND MATERIALS: Thirty-three American Society for Radiation Oncology consensus suitable/cautionary APBI candidates were treated using a passively scattered proton beam between 2010 and 2014 to 34 Gy relative biological effectiveness in 10 fractions twice daily. All patients were immobilized in a Vac-Lok cradle, typically with the arm down, and adducted to mound the breast and facilitate multiple, optimal en face beams. Radiopaque wires were placed on the surgical scar and 3 markers separate from the scar were placed elsewhere on the breast. All markers were used for each setup and removed before treatment. Marker displacement, wire rotation, and wire displacement were recorded from 10 random patients (100 orthogonal films). A 15-mm expansion was made to the tumor bed to obtain a clinical target volume, and followed by a 5-mm skin contraction and exclusion of the chest wall. A radial planning target volume margin of 5 mm was used. RESULTS: Across 100 pretreatment images, median displacement of 3 distinct skin set-up markers was 3, 4, and 3 mm. Displacement of the scar wire in the X and Y direction was 0 and 1 mm, respectively. Among 28 verification scans performed, only 1 resulted in adaptive planning because of the initial presence of an air pocket in the lumpectomy cavity that resolved spontaneously during treatment. CONCLUSIONS: APBI proton treatment using a supine approach was largely reproducible. Inter-fraction variation demonstrates 5-mm radial planning margins were adequate; however, outliers do occur and films should be reviewed critically and in real time. This technique is straightforward and could be used at any proton facility without the need for specialized equipment. PMID- 25804106 TI - [A potentially fatal intoxication with colchicine]. AB - BACKGROUND: Approximately ten times a year the Dutch National Poisons Information Centre (NVIC) is consulted regarding a colchicine intoxication or overdose. CASE DESCRIPTION: An 18-year old woman was admitted to the intensive care unit after a suicide attempt with a potentially lethal dosage of colchicine tablets (0.5 mg/kg body weight). After a few hours the patient developed abdominal pain and vomited. Over subsequent days she developed anaemia, thrombocytopenia and a paralytic ileus. Treatment mainly comprised intensive supportive care, including sedation, ventilation and repeated administration of activated charcoal. After a week she gradually began to recover and was able to leave IC 10 days after ingestion. CONCLUSION: Early recognition and treatment of colchicine intoxication is crucial to preventing a fatal outcome. Complete recovery is possible if extensive supportive treatment is given. PMID- 25804107 TI - [Healthcare-associated infections on readmission: 1 in 3 is linked to previous hospital admission]. AB - OBJECTIVE: To gain insight into the prevalence of healthcare-associated (HAI) infections in hospital patients in the Netherlands, and their link with previous hospital admission. DESIGN: Cross-sectional study. METHOD: This prevalence study was carried out in 36 hospitals at 42 locations in the Netherlands in March 2014. All inpatients at the time of the study were evaluated for the presence of an HAI, according to the standard protocol and in accordance with internationally determined definitions. It was subsequently determined whether the HAI had been acquired during the current admission or was linked to a previous recent admission. Readmission had to have taken place within a predetermined time period. RESULTS: A total of 9,420 patients were evaluated for the presence of an HAI; 470 (5.0%) HAI were reported, of which almost 36% was linked to a previous admission. Two-thirds of the HAI were post-operative surgical-site infections. Almost 88% of the patients with HAI were treated with antibiotics, versus 32% of the patients without HAI. CONCLUSION: Registration of HAI on admission to hospital provides insight into the frequency of HAI that become apparent after discharge. There is no insight into the treatment frequency of HAI by general practitioners. An inventory of the treatment frequency of HAI in primary care is advised, to evaluate infection-prevention policy in hospitals and to optimise primary care. PMID- 25804108 TI - [Disciplinary verdicts in cases of child abuse; lessons for paediatricians]. AB - OBJECTIVE: To give an overview of disciplinary cases regarding action taken by paediatricians and paediatric residents in cases of (suspected) child abuse and to discuss the considerations of the disciplinary board in these cases. DESIGN: Retrospective, descriptive study. METHOD: We considered all disciplinary cases instigated from 2001 to 2013 against paediatricians or paediatric residents and selected complaints regarding action taken in cases of (suspected) child abuse. We divided these complaints into six categories and studied the considerations of the disciplinary board in these cases. RESULTS: From 33 disciplinary cases instigated from 2001 to 2013, we selected 76 complaints regarding action taken by paediatricians or paediatric residents in cases of (suspected) child abuse. The majority of these complaints concerned the reporting or requesting of information in the context of (suspected) child abuse. All of the complaints in the category 'unwarranted reporting of child abuse' were declared unfounded by the disciplinary judge. CONCLUSION: The disciplinary board declared all complaints unfounded in cases where the paediatrician or paediatric resident had followed the Dutch national protocol regarding reporting of child abuse and domestic violence. The disciplinary board examines whether action was taken in accordance with reasonable standards of professional competence and considers that paediatricians have an important role in identifying child abuse. PMID- 25804109 TI - [A former bodybuilder with a swelling on the forearm]. AB - A 56-year-old man came to the general practitioner with a solitary compressible swelling on his left forearm, which enlarged during exercise. The patient reported a history of bodybuilding and he worked as a plasterer. Physical examination revealed primary varicose of the upper extremity, a rare localisation of a common vascular disease. PMID- 25804110 TI - [A man with swollen fingers]. AB - A 28-year-old man was referred to our hospital because of localised swelling of his fingers, with suspicion of arthritis of the proximal interphalangeal (PIP) joints. At physical examination we observed a swelling, superficial to the PIP joints. Ultrasonography revealed a hypo-echoic structure above the extensor tendon, typical for knuckle pads. PMID- 25804111 TI - [Referral for mammography often not according to guideline]. AB - OBJECTIVE: To analyse the percentage of women with a family history of breast cancer referred by general practitioners (GPs) for a screening mammography in accordance with the Dutch Breast Cancer Guideline produced by the Netherlands Comprehensive Cancer Centre (IKNL). DESIGN: Prospective cohort study. METHOD: Women referred by their GP between December 2011 and December 2012 for mammography, with the indication "family history of breast cancer", were invited to take part in this study. A trained radiology laboratory assistant carried out a structured questionnaire to assess their risk on the basis of the categories of the 2008 IKNL guideline "Family history of breast/ovarian cancer". Based on the presence of certain risk factors, the women were allocated to one of the following groups: "referral for mammography", "referral to a clinical geneticist" or "no referral indicated". RESULTS: 242 women were referred by their GPs to the Radiology Department for mammography on the basis of family history; we included 210 women in our study. Their ages ranged from 25 to 77 years (mean age: 48 years). Forty-five patients (21%) were referred for mammography in accordance with the guideline. Twenty-two patients (10%) should have been referred to a clinical geneticist according to the guideline, whereas 143 patients (68%) did not meet the criteria for a screening mammography outside the screening programme. CONCLUSION: In only 21% of patients referred by their GPs for a screening mammography, with "family history" given as the reason, this referral was in accordance with the standard of the Dutch College of General Practitioners (NHG) or the IKNL guideline. Screening outside the breast cancer screening programme was not indicated according to the guideline for the majority of the women. Referral of 10% of the women referred should have been to a clinical geneticist; this figure rises to as many as 20% using the 2012 IKNL guideline. PMID- 25804112 TI - [The Dutch College of General Practitioners' practice guideline 'Problem drinking']. AB - The Dutch College of General Practitioners' practice guideline "Problem drinking" contains recommendations for the (early) recognition, diagnosis and treatment of problem drinking and includes recommendations for young people and the management of acute alcohol intoxication. In daily practice problems with alcohol manifest themselves mainly as indirect signals and aspecific symptoms. The practice guideline recommends asking about alcohol use in every case where symptoms cannot be directly explained. General practitioners are usually able treat patients with a drinking problem themselves. Short-term interventions by the general practitioner and practice nurse are effective in the reduction of alcohol use. 'E mental health' is an aid that can be used in the diagnosis and treatment of problem alcohol use. PMID- 25804113 TI - [Adrian Stokes and 'trench jaundice']. AB - On the day that Great Britain declared war on Germany in 1914, the Irish physician and bacteriologist Adrian Stokes travelled to London to volunteer. One week later he left for France with the first British troops as an officer with the Royal Army Medical Corps. He spent most of the First World War attached to No. 1 Mobile Bacteriological Laboratory at the Remy Siding British-Canadian field hospital in Flanders. In April 1916, he was confronted with an outbreak of trench jaundice, also known as epidemic jaundice (Weil's disease). Conditions in the trenches contributed to the hundred cases identified by Stokes in a short period. In 1917, he was the first to publish (in The Lancet) the finding that the bacterium Spirochaeta icterohaemorrhagiae, the causative agent of epidemic jaundice, could be isolated from the kidneys of rats. A subsequent rat control campaign in the trenches successfully curbed the disease. PMID- 25804114 TI - [The NHG guideline 'Sleep problems and sleeping pills']. AB - The Dutch College of General Practitioners' (NHG) guideline 'Sleep problems and sleeping pills' provides recommendations for the diagnosis and treatment of the most prevalent sleep problems and for the management of chronic users of sleeping pills. The preferred approach for sleeplessness is not to prescribe medication but to give information and behavioural advice. Practice assistants of the Dutch Association of Mental Health and Addiction Care are also expected to be able to undertake this management. The GP may consider prescribing sleeping pills for a short period only in cases of severe insomnia with considerable distress. Chronic users of sleeping pills should be advised by the GP to stop using them or to reduce the dose gradually (controlled dose reduction). The GP may refer patients with suspected obstructive sleep apnoea (OSA) to a pulmonary or ear, nose and throat specialist or neurologist for further diagnosis depending on the regional arrangements. The GP may then consider the cardiovascular risk factors commonly present with OSA. In patients with restless legs syndrome (RLS) who continue to experience major distress despite being given advice without the prescription of medication, the GP may consider prescribing a dopamine agonist. PMID- 25804115 TI - [Putting sleep disorders in context]. AB - The new guidelines show many improvements when compared to the previous set. However, there still are several shortcomings. These mainly involve a lack of discussion of the increasing problem of sleep deprivation in western societies, and a non-consistent use of the terms "fatigue" and "excessive daytime sleepiness". PMID- 25804116 TI - Academic productivity and contributions to the literature among spine surgery fellowship faculty. AB - BACKGROUND CONTEXT: No previous study has considered academic productivity and contributions to the literature among the faculty members of spine fellowship programs. PURPOSE: We sought to evaluate the total number of publications and measures of academic impact among faculty at spine surgical fellowship programs between 2011 and the present. STUDY DESIGN: This study is based on a review of data publicly available on PubMed and Scopus. PATIENT SAMPLE: Physicians listed as faculty at a spine fellowship program in the directory of the North American Spine Society (NASS). OUTCOME MEASURES: The outcome measures were the number of publications between January 1, 2011 and August 31, 2014 and the h-index for 1996 to present (h-tot) and 2011 to present (h-pres) for faculty members. METHODS: Fellowship programs and their characteristics were obtained from the directory of the NASS. Program-specific features, including academic affiliation, number of participating faculty, location, number of fellowship positions, dedicated research time, and presence of a research requirement for fellows, were abstracted. The number of publications for faculty at each program between January 1, 2011 and August 31, 2014 and the h-tot and h-pres were obtained from Scopus. Multivariable linear regression was used to identify statistically significant factors associated with increased academic productivity. RESULTS: Among 75 fellowship programs, with 282 faculty members, there were 55 (73%) with academic affiliation. The average number of publications per faculty member (2011 2014) was 5.5 (standard deviation, 8.4; range, 0-54). The mean h-tot for programs was 13.6 (8.7, 0-37), and mean h-pres was 3.0 (2.2, 0-8.2). Academic affiliation (regression coefficient, 22.1; 95% confidence interval: 7.2, 37.0), and the number of fellows in a program (7.0, 0.9-13.2) was significantly associated with the total number of publications. Similar findings were encountered for average h tot and h-pres. CONCLUSIONS: The descriptive statistics presented can help surgeons benchmark their performance and that of their fellowship, compared with others in the field. Determinations regarding characteristics associated with academic productivity may also help programs' fashion future strategic initiatives. PMID- 25804117 TI - FISH in triple-negative breast cancer: a possible strategy for the future? PMID- 25804118 TI - SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString). AB - BACKGROUND: Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers. MATERIALS & METHODS: A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2). RESULTS: SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%). CONCLUSION: Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC. PMID- 25804119 TI - Lgr5 expression, cancer stem cells and pancreatic cancer: results from biological and computational analyses. AB - AIMS: To determine the relationship between Lgr5 and other stemness markers and pathologic features in pancreatic ductal adenocarcinoma (PDAC) samples. MATERIALS & METHODS: In 69 samples, Lgr5 was analyzed by qRT-PCR together with a panel of 29 genes. Bioinformatic analysis was carried out to identify a possible pathway regulating Lgr5 expression in PDAC. RESULTS: Lgr5 expression was not associated with the expression of tested cancer stem cell markers. Moreover, it was not an independent predictor of survival neither at univariate analysis (p = 0.21) nor at multivariate analysis (p = 0.225). CONCLUSION: Based on the lack of correlation between Lgr5 and tested cancer stem cell markers, Lgr5 does not seem to be a potential stemness marker or prognostic factor in PDAC. PMID- 25804120 TI - Techniques for intraoperative radiation therapy for early-stage breast carcinoma. AB - Intraoperative radiation therapy (IORT) is a method of accelerated partial breast irradiation developed to replace other longer courses of radiotherapy with a single radiation session administered at the time of breast-conserving surgery. The purpose of this review is to summarize the advantages and disadvantages of breast IORT techniques that are currently available, as well to consider potential alternative techniques for breast IORT or ultra-short course breast radiotherapy. Furthermore, we highlight the published outcomes for the IORT treatment approaches including: electron therapy, superficial photon therapy and other techniques. Potential future directions of IORT are explored including novel IORT techniques utilizing intraoperative brachytherapy with in-room imaging and rapid treatment planning. PMID- 25804121 TI - Patient pathway for breast cancer: turning points and future aspirations. AB - Improved survival from breast cancer can be attributed to a number of advances in the patient pathway from screening to advanced disease. The benefit of population screening has been established with national programs implemented. There has been improvement in the methodology of diagnostic assessment, relating to imaging techniques, methods of obtaining histological evidence and evaluation of lymph node status. Sentinel node biopsy is now routine, as is oncoplastic surgery. New forms and improved adjuvant systemic therapies are being explored. The prognosis of breast cancer can be more reliably evaluated to provide individualized information and to personalize treatments. Developments have also been seen in other areas improving the treatment and care of patients with advanced disease. PMID- 25804122 TI - Desmoplastic small round cell tumor 20 years after its discovery. AB - Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy. PMID- 25804123 TI - PET-based molecular imaging in personalized oncology: potential of the assessment of therapeutic outcome. AB - Molecular imaging techniques allow an individualization and optimization of therapy on a patient basis noninvasively. The availability of new hybrid scanners, like PET-computed tomography and PET-MRI allow the combined assessment of changes in morphology and function and are a unique tool for personalized cancer treatment. In particular, it is crucial to identify nonresponders as soon as possible for therapy guidance. The choice of the appropriate therapy and optimal treatment duration can help to avoid side effects and save costs. Furthermore, the development of new specific tracers will enable a more accurate assessment of a therapeutic result. Numerous peptides targeting receptor-active tumors are in development with a high potential in a large spectrum of tumors for theranostic approaches. PMID- 25804124 TI - Biomechanical effects of microbubbles: from radiosensitization to cell death. AB - Ultrasound-stimulated microbubbles have been demonstrated to mechanically perturb cell membranes, resulting in the activation of biological signaling pathways that significantly enhance the effects of radiation. The underlying mechanism involves augmented ceramide production following both microbubble stimulation and irradiation, leading to rapid and extensive endothelial apoptosis and tumor cell death as a result of vascular collapse. Endothelial cells are particularly sensitive to ceramide-induced cell death due to an enriched presence of sphingomyelinase in their membranes. In tumors, this consequent rapid vascular shutdown translates to an overall increase in tumor responses to radiation treatments. This review summarizes the groundwork behind endothelial-based radiation enhancement with ultrasound-stimulated microbubbles, and presents ongoing research on the use of microbubbles as therapeutic agents in cancer therapy. PMID- 25804125 TI - Risk of fatal pulmonary events in patients with advanced non-small-cell lung cancer treated with EGF receptor tyrosine kinase inhibitors: a comparative meta analysis. AB - We performed a meta-analysis of fatal pulmonary events associated with erlotinib, gefitinib or afatinib in patients with non-small-cell lung cancer (NSCLC). Eligible studies included randomized trials of patients with NSCLC on the three drugs describing events of high-grade pulmonary events. The relative risk of high grade interstitial lung disease, pneumonitis, pneumonia, pulmonary embolism and hemoptysis were 4.18 (95% CI: 2.49-7.01; p < 0.00001), 1.94 (95% CI: 0.93-4.06; p = 0.08), 1.28 (95% CI: 0.92-1.77; p = 0.14), 1.6 (95% CI: 0.81-3.18 p = 0.17), 1.00 (95% CI: 0.14-7.08 p = 0.35), respectively. Our meta-analysis has demonstrated that erlotinib, gefitinib and afatinib are associated with an increased risk of high-grade interstitial lung disease in patients with NSCLC. PMID- 25804126 TI - Cosmic radiation and cancer: is there a link? AB - Cosmic radiation can cause genetic and cytogenetic damage. Certain occupations including airline pilots and cabin crew are acknowledged to have a greater exposure to cosmic radiation. In a systematic search of MEDLINE, performed from 1990 to 2014, we analyzed clinical studies using the keywords: cosmic radiation, cancer, chromosome aberration, pilots and astronauts. Increased incidence of skin cancers among airline cabin crew has been reported in a number of studies and appears to be the most consistent finding. However, as with other cancers, it is unclear whether increased exposure to cosmic radiation is a factor in the increased incidence or whether this can be explained by lifestyle factors. Further research is needed to clarify the risk of cancer in relation to cosmic radiation. PMID- 25804127 TI - Immunohistochemical protein expression profiling of growth- and apoptotic-related factors in relation to umbilical cord length. AB - INTRODUCTION: Umbilical cord (UC) alterations are related to fetal and neonatal deaths and late neurological complications. Abnormal UC length has been recognized as the most significant abnormality linked to unfavorable outcomes. Despite its importance, causal factors resulting in abnormally long or short UCs have yet to be established. The factors that govern UC length are largely unknown. Furthermore, there is a paucity of studies that assess molecular processes involved in the establishment of UC length. We hypothesize that UC length abnormalities in UC length are associated with altered protein expression patterns of known cell growth and/or apoptosis regulators. In this study we analyze diverse protein expression patterns in different UC cell types found in UCs of normal and abnormal length. METHODS: An analytical observational study was carried out on fetal autopsies; diagnosed abnormal length UCs were compared to normal controls by gestational age. Immunohistochemical analysis of expression levels of growth and pro- and anti-apoptotic factors was performed. RESULTS: We performed immunohistochemistry antibody tests against FAS, BAX, Ki67, cMyc, FGF2, TGFBR3, VEGF, Bcl2, p57 and IGF2 and analyzed UC cell expression patterns. We found significant differences in specific long and/or short cord cell types in comparison to those in normal cords. DISCUSSION: Factors that determine UC length are still largely unknown; however, this study demonstrates significant specific cell type differences in protein expression patterns of several genes related to cell proliferation. This preliminary study provides strong supporting data to continue the search for molecular factors that determine UC length. PMID- 25804128 TI - ABCG8 polymorphisms and renal disease in type 2 diabetic patients. AB - BACKGROUND AND AIM: Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. METHODS: Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabetic patients for the purpose of validation. RESULTS: In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. CONCLUSIONS: A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabetic patients. PMID- 25804129 TI - Meta-analysis: Tobacco smoking may enhance the risk of acute pancreatitis. AB - BACKGROUND AND AIM: Questions remain unclear about the association of smoking status and the development of acute pancreatitis (AP). We performed a meta analysis of observational studies explore this association. METHODS: A computerized literature search was performed in MEDLINE and EMBASE through November 30, 2014. We also searched the reference lists of pertinent articles. We used a random-effects model to calculate the summary relative risks (SRRs) and their corresponding 95% confidence intervals (CIs). RESULTS: A total of 3690 incident cases of AP included 12 observational studies (6 case-control and 6 prospective cohort/nested case-control studies) were identified. Compared with never smokers, the summary RR estimates were 1.54 (95% CI, 1.31-1.80) for ever smokers, 1.71 (95% CI, 1.37-2.14) for current smokers, and 1.21 (95% CI, 1.02 1.43) for former smokers. Smoking is found to be a potential risk factor for alcohol use, idiopathic factors and drugs related AP, but not for gallstone related AP, in the ever and current smokers. A dose-response effect of tobacco use on the risk was ascertained: current smokers had a 40% (95% CI, 30%-51%) increased risk of AP for every additional 10 cigarettes per day. CONCLUSION: The present analysis suggests that smokers have an elevated risk of AP development. Further studies, however, are warranted before definitive conclusions can be drawn. PMID- 25804130 TI - Bacteria-mimicking nanoparticle surface functionalization with targeting motifs. AB - In recent years, surface modification of nanocarriers with targeting motifs has been explored to modulate delivery of various diagnostic, sensing and therapeutic molecular cargo to desired sites of interest in in vitro bioengineering platforms and in vivo pathologic tissue. However, most surface functionalization approaches are often plagued by complex chemical modifications and effortful purifications. To resolve such challenges, this study demonstrates a unique method to immobilize antibodies that can act as targeting motifs on the surfaces of nanocarriers, inspired by a process that bacteria use for immobilization of the host's antibodies. We hypothesized that alkylated Staphylococcus aureus protein A (SpA) would self-assemble with micelles and subsequently induce stable coupling of antibodies to the micelles. We examined this hypothesis by using poly(2 hydroxyethyl-co-octadecyl aspartamide) (PHEA-g-C18) as a model polymer to form micelles. The self-assembly between the micelles and alkylated SpA became more thermodynamically favorable by increasing the degree of substitution of octadecyl chains to PHEA-g-C18, due to a positive entropy change. Lastly, the mixing of SpA PA-coupled micelles with antibodies resulted in the coating of micelles with antibodies, as confirmed with a fluorescence resonance energy transfer (FRET) assay. The micelles coated with antibodies to VCAM-1 or integrin alphav displayed a higher binding affinity to substrates coated with VCAM-1 and integrin alphavbeta3, respectively, than other controls, as evaluated with surface plasmon resonance (SPR) spectroscopy and a circulation-simulating flow chamber. We envisage that this bacteria-inspired protein immobilization approach will be useful to improve the quality of targeted delivery of nanoparticles, and can be extended to modify the surface of a wide array of nanocarriers. PMID- 25804131 TI - Enhanced photoelectrochemical aptasensing platform based on exciton energy transfer between CdSeTe alloyed quantum dots and SiO2@Au nanocomposites. AB - High-efficient exciton energy transfer between CdSeTe alloyed quantum dots and SiO2@Au nanocomposites was applied to develop an enhanced photoelectrochemical aptasensing platform with ultrahigh sensitivity, good selectivity, reproducibility and stability. PMID- 25804132 TI - Thermoelectric fabrics: toward power generating clothing. AB - Herein, we demonstrate that a flexible, air-permeable, thermoelectric (TE) power generator can be prepared by applying a TE polymer (e.g. poly(3,4 ethylenedioxythiophene):poly(4-styrenesulfonate)) coated commercial fabric and subsequently by linking the coated strips with a conductive connection (e.g. using fine metal wires). The poly(3,4-ethylenedioxythiophene):poly(4 styrenesulfonate) coated fabric shows very stable TE properties from 300 K to 390 K. The fabric device can generate a TE voltage output (V) of 4.3 mV at a temperature difference (DeltaT) of 75.2 K. The potential for using fabric TE devices to harvest body temperature energy has been discussed. Fabric-based TE devices may be useful for the development of new power generating clothing and self-powered wearable electronics. PMID- 25804134 TI - Goodwill in the NHS is a one-way street. AB - The NHS runs on goodwill. Every day thousands of nurses, midwives and healthcare support workers work extra hours, skip breaks and go the extra mile to keep the health service running. In return, you may receive a 'thank you' from your manager or expressions of gratitude from patients, but rarely will you see any extra in your pay packet. PMID- 25804133 TI - The effects of folic acid on global DNA methylation and colonosphere formation in colon cancer cell lines. AB - Folate and its synthetic form, folic acid (FA), are essential vitamins for the regeneration of S-adenosyl methionine molecules, thereby maintaining adequate cellular methylation. The deregulation of DNA methylation is a contributing factor to carcinogenesis, as alterations in genetic methylation may contribute to stem cell reprogramming and dedifferentiation processes that lead to a cancer stem cell (CSC) phenotype. Here, we investigate the potential effects of FA exposure on DNA methylation and colonosphere formation in cultured human colorectal cancer (CRC) cell lines. We show for the first time that HCT116, LS174T, and SW480 cells grown without adequate FA demonstrate significantly impaired colonosphere forming ability with limited changes in CD133, CD166, and EpCAM surface expression. These differences were accompanied by concomitant changes to DNA methyltransferase (DNMT) enzyme expression and DNA methylation levels, which varied depending on cell line. Taken together, these results demonstrate an interaction between FA metabolism and CSC phenotype in vitro and help elucidate a connection between supplemental FA intake and CRC development. PMID- 25804135 TI - Payroll errors causing hardship as trusts try to recoup large sums. AB - Payroll errors that result in nurses being overpaid - sometimes by thousands of pounds - and then pressured by their employers to repay the sums are on the increase, the RCN has warned. PMID- 25804136 TI - Dame Donna to join RCN as new head of nursing. AB - A senior nurse who contributed to former prime minister Gordon Brown's commission on the future of nursing and who assisted the Victoria Climbie inquiry has been appointed as the RCN's head of nursing. PMID- 25804137 TI - College seeks 'exceptional nurse leader' to fill chief executive post. AB - A worldwide search is on for a new general secretary and chief executive of the RCN to succeed Peter Carter when he leaves the college in October. PMID- 25804138 TI - Call for NMC to drop Cafferkey investigation. AB - A petition calling on the Nursing and Midwifery Council to end its investigation into nurse Pauline Cafferkey has attracted 1,090 signatures. PMID- 25804140 TI - 'Only legislation can ensure safe staffing levels in Welsh hospitals'. AB - Safe nurse staffing levels in Welsh hospitals can only be achieved through legislation, not by health boards being directed to use an acuity tool. PMID- 25804139 TI - Barts is paying the price for its job cuts, says RCN. AB - The decision to place England's largest NHS trust in special measures after cutting hundreds of jobs and wages should serve as a cautionary tale for other trusts, the RCN has said. PMID- 25804141 TI - Tablet made for the Ebola zone is safe by design. AB - A tablet computer that can be sterilised in chlorine will enable nurses fighting Ebola in Sierra Leone to record patients' notes quickly and accurately. PMID- 25804143 TI - Confusion reigns on who cleans up. AB - Guidance on the cleaning responsibilities of nursing and domestic staff must be communicated clearly, the RCN said. PMID- 25804144 TI - Smarter procurement could save NHS millions each year. AB - A campaign that could save the NHS millions through procuring medical supplies more efficiently has been launched. PMID- 25804145 TI - Hospital's patient safety board game is serious fun. AB - Staff at South Tees Hospitals NHS Foundation Trust have developed a board game about patient safety. PMID- 25804146 TI - Inquiry finds link between patient suicide and inexperienced staff. AB - Suicide by patients under observation should be a 'never event', say researchers who have found a direct link between the number of inpatient deaths and inexperienced staff. PMID- 25804147 TI - The importance of healthy eating for all NHS staff. AB - With an estimated 700,000 of the NHS's 1.3 million staff being overweight or obese, promoting healthy lifestyles among health service workers is a top priority for the government. PMID- 25804153 TI - Care homes. AB - Essential facts: About 450,000 mainly older people live in more than 17,000 care and nursing homes in England. Following concerns about mistreatment and the standard of care some residents receive, the Care Quality Commission (CQC) introduced a new inspection regime for care homes in October last year. A recent report on almost 10,000 care homes in England found that one in five failed to meet national standards for safety and care. PMID- 25804154 TI - 'Revalidation is not rocket science'. AB - The new code of conduct takes effect at the end of this month. The Code's standards underpin revalidation, the new system for nurses and midwives due to be introduced at the end of this year. In this interview, NMC chief executive Jackie Smith says revalidation will be a straightforward and positive experience for registrants who are 'organised' and who do not delay their preparation. PMID- 25804155 TI - Fighting for MND specialists. AB - Awareness of motor neurone disease (MND) is rising, but many patients struggle to get the care they need. MND specialist nurses provide support and help people navigate the system. Gordon Aikman has campaigned successfully for funding to double the number of nurses in Scotland. PMID- 25804168 TI - Living lung - lung viewer. AB - Living Lung is a real-time, three-dimensional medical education and patient communication tool that features detailed, colour, anatomical respiratory models. PMID- 25804169 TI - Nurse awards are a wonderful showcase for nursing excellence. AB - Our profession has had more than its fair share of bad publicity lately so I was delighted to get an opportunity to celebrate nursing as chair of the judging panel for the Nursing Standard Nurse Awards. PMID- 25804170 TI - Minister didn't say government won't support safe staffing bill. AB - I am afraid your report on the progress of the safe nurse staffing levels bill, 'Minimum staffing ratios failed to gain Welsh Government support' (News March 11) may give an unnecessarily pessimistic picture of the situation. PMID- 25804171 TI - New training model is too general - and where will we find the mentors? AB - The Shape of Caring review was tasked with ensuring the education of nurses and healthcare assistants is fit for purpose. Although there were some good recommendations from review chair Lord Willis (News and Analysis March 18), I am concerned by his '2+1+1' model of nurse training. PMID- 25804173 TI - No nursing care is 'basic' and our new code recognises this. AB - I recently received my copy of the new Nursing and Midwifery Council code. The Code is set out clearly and simply, identifies what good nursing and midwifery practice looks like, and promotes and insists on practice that puts the interests of patients and service users first. PMID- 25804177 TI - Developing a nurse-led clinic using transformational leadership. AB - Nurses are at the forefront of implementing and managing change, given constantly changing healthcare services and the increase in demand for health care. Therefore, it is important to identify the best style of leadership to engage nurses in implementing service-led improvements. This article explores the effects of transformational leadership in bringing about service-led improvements in health care, using the example of setting up a nurse-led acupuncture clinic to optimise the care of patients with chronic pain. Transformational leadership was used throughout the project - from the initial local planning, training and development, through to liaising with the appropriate staff and deciding on an evaluation strategy. Transformational leadership proved to be an effective way to engage and empower nurses and other members of the chronic pain team to enable them to achieve the project aims. PMID- 25804175 TI - Exceptional work of hospital staff should not be overlooked. AB - On February 20, my partner Lynda Hughes passed away after spending seven months on ward A7 at the University Hospital of Wales. During this time, I witnessed an exceptional level of care from the nursing and auxiliary staff, which I spoke about at Lynda's funeral in accordance with her wishes. Lynda had great respect for the special people who sought to help her, and wanted me to acknowledge this. PMID- 25804178 TI - Qualitative research. AB - Qualitative research has an important role in helping nurses and other healthcare professionals understand patient experiences of health and illness. Qualitative researchers have a large number of methodological options and therefore should take care in planning and conducting their research. This article offers a brief overview of some of the key issues qualitative researchers should consider. PMID- 25804179 TI - Caring for older people experiencing agitation. AB - Agitation commonly affects older adults, particularly those living in care homes and in hospital settings. Agitation can be distressing to experience, may be associated with poorer health outcomes and can present a challenge to staff in keeping the person and those around them safe. This article examines why agitation can occur in older people and discusses current best practice, focusing on communication and non-pharmaceutical interventions. Agitation is commonly associated with dementia and delirium. This article indicates how these conditions can affect the older person and their interactions with the surrounding environment. A case study is used to illustrate application in practice. PMID- 25804180 TI - Gout. AB - Gout predominantly affects people aged between 40 and 60 years and frequently occurs alongside diabetes, cardiovascular disease, hypertension and reduced renal function. I was interested to read this article because of my work caring for older people. PMID- 25804181 TI - A force for progress. AB - I work for the Leeds Cancer Centre as a nurse consultant for clinical research and as a Cancer Research UK senior nurse. I am also the operations manager for the National Institute for Health Research (NIHR) Leeds Clinical Research Facility. Here I manage a team of about 50 clinical and administrative staff to deliver 200 cancer clinical trials each year. PMID- 25804183 TI - A solid basis for improvement. AB - A two-day training plan delivered to ward-based staff at a West Midlands trust has had a major effect on the care of patients with cognitive impairment and dementia. PMID- 25804184 TI - Are you the nursing 'type'? AB - Research from a psychological consultancy company has found nurses tend to score lower than the general population for resilience. PMID- 25804185 TI - Student life - how to avoid plagiarism. AB - Academic assessments are a challenging part of nurse education. Students are expected to review and analyse literature from many sources and integrate this evidence into their assignments. PMID- 25804186 TI - Use of greater omentum in the surgical treatment of a synovial cyst in a cat. AB - A 13-year-old cat was diagnosed with a synovial cyst originating from the glenohumeral joint. The cat presented with severe front limb lameness and a non painful fluctuating swelling on the medial aspect of the humerus. Radiographic examination showed severe bilateral shoulder osteoarthritis with osteophyte formation. The mass was surgically resected and histopathology confirmed the diagnosis of a synovial cyst. Three weeks postoperatively the cyst recurred. Surgical resection was repeated followed by omentalisation of the defect. Throughout the following 3 months the cyst did not recur. Unfortunately, for reasons unrelated to the presented disease, the cat was euthanized shortly afterwards, therefore making a long-term follow-up impossible. PMID- 25804187 TI - Synthesis and biological evaluations of a series of thaxtomin analogues. AB - Thaxtomins are a unique family of phytotoxins with unique 4-nitroindole and diketopiperazine fragments possessing potential herbicidal activities. This work presents the total synthesis of natural product thaxtomin C and its analogues. The extensive structure-activity relationship study screens four effective compounds, including thaxtomin A and thaxtomin C. It is indicated that 4-nitro indole fragment is essential for phytotoxicity, while benzyl and m-hydroxybenzyl substituents on the diketopiperazine ring are favorable for the efficacy. The N methylations on indole and diketopiperazine show weak influence on the herbicidal activities. The four selected compounds show effective herbicidal activities against Brassica campestris, Amaranthus retroflexus, and Abutilon theophrasti, which are comparable or better than dichlobenil, even at a dosage of 187.5 g ha( 1). Moreover, these four compounds show good crop-selective properties to different crops and exhibit moderate protoporphyrinogen oxidase (PPO) enzyme inhibition. The antifungal results indicate that thaxtomin C displays inhibition to a wide range of fungi. PMID- 25804188 TI - Treatment of cachexia: An overview of recent developments. AB - Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients' skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article is to summarise clinical trials published over the last two years. Therapeutic approaches discussed here include appetite stimulants like megestrol acetate, l-carnitine, or melatonin, anti inflammatory drugs like thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1alpha as well as ghrelin and the ghrelin agonist anamorelin, nutritional support, and anabolics like enobosarm and testosterone. PMID- 25804189 TI - Prevalence of Whipple's disease in north-western Italy. AB - Whipple's disease (WD) is a rare systemic infection due, in genetically susceptible individuals, to Tropheryma whipplei, a heterogeneous Gram-positive actinobacteria. Although it has already been recognised that WD affects mainly middle-aged Caucasian men, the prevalence of WD is virtually unknown. The annual incidence of WD in the general population is said to be less than 1 per 1,000,000, but scientific evidence for these figures is still lacking. On the basis of the number of patients recorded with a diagnosis of Whipple's disease in the regional registers for rare diseases of Lombardia, Liguria and Piemonte-Valle d'Aosta regions, we studied the prevalence of WD in the north-western part of Italy. Forty-six patients with Whipple's disease were recorded in these regions (13 females; mean age at diagnosis 52.1 +/- 11.1 years). Since 16,130,725 inhabitants live in these four regions, prevalence of WD in the general population is 3/10(6) and almost 30% of the patients are females. WD is certainly a rare disease but it also affects women in a considerable proportion of cases. PMID- 25804190 TI - Examining exposure reciprocity in a resin based composite using high irradiance levels and real-time degree of conversion values. AB - OBJECTIVE: Exposure reciprocity suggests that, as long as the same radiant exposure is delivered, different combinations of irradiance and exposure time will achieve the same degree of resin polymerization. This study examined the validity of exposure reciprocity using real time degree of conversion results from one commercial flowable dental resin. Additionally a new fitting function to describe the polymerization kinetics is proposed. METHODS: A Plasma Arc Light Curing Unit (LCU) was used to deliver 0.75, 1.2, 1.5, 3.7 or 7.5 W/cm(2) to 2mm thick samples of Tetric EvoFlow (Ivoclar Vivadent). The irradiances and radiant exposures received by the resin were determined using an integrating sphere connected to a fiber-optic spectrometer. The degree of conversion (DC) was recorded at a rate of 8.5 measurements a second at the bottom of the resin using attenuated total reflectance Fourier Transform mid-infrared spectroscopy (FT MIR). Five specimens were exposed at each irradiance level. The DC reached after 170s and after 5, 10 and 15 J/cm(2) had been delivered was compared using analysis of variance and Fisher's PLSD post hoc multiple comparison tests (alpha=0.05). RESULTS: The same DC values were not reached after the same radiant exposures of 5, 10 and 15 J/cm(2) had been delivered at an irradiance of 3.7 and 7.5 W/cm(2). Thus exposure reciprocity was not supported for Tetric EvoFlow (p<0.05). SIGNIFICANCE: For Tetric EvoFlow, there was no significant difference in the DC when 5, 10 and 15J/cm(2) were delivered at irradiance levels of 0.75, 1.2 and 1.5 W/cm(2). The optimum combination of irradiance and exposure time for this commercial dental resin may be close to 1.5 W/cm(2) for 12s. PMID- 25804191 TI - An MMP-inhibitor modified adhesive primer enhances bond durability to carious dentin. AB - OBJECTIVES: To evaluate the effect of adding a matrix metalloproteinase (MMP) inhibitor (BB94, Batimastat) to the primer of a three-step etch and rinse adhesive system on caries-affected dentin (CaD) MMP activity, and to assess the effect of such an inclusion on the chemical content of the CaD-adhesive interface. METHODS: Caries-infected dentin (CiD) was excavated selectively from freshly extracted human carious teeth using a chemo-mechanical agent. Each tooth was sectioned into three slabs through the CaD retained cavity. These were treated with either Optibond FL "OB" (Kerr, Orange, USA) without MMP inhibitor, or with 500 MUM BB94 prior to the application of OB primer and bond, or with OB primer that contained 5 MUM BB94. In situ zymography and Raman micro-spectroscopy were used to investigate MMP activity and the changes in the chemical content at the CaD/adhesive interface, respectively. RESULTS: Data showed the use of OB adhesive with BB94 resulted in immediate interfacial MMP inhibition, by direct application (93.3%) and by means of a drug delivery system (80%), as demonstrated by in situ zymography. Raman imaging revealed 33% higher resin infiltration into MMP-inhibited adhesive interfaces (SE 3.88). SIGNIFICANCE: Through competitive inhibition by batimastat (BB94), a proportion of the MMPs found in CaD were inhibited immediately and irreversibly. Such a competitive mechanism brings the adhesive primer close to the collagen matrix and enhances the dental adhesive wettability, which is a proposed mechanism to explain the presence of more resin within the hybrid layer. PMID- 25804193 TI - Coinfection with multiple strains of bovine papular stomatitis virus. AB - Bovine papular stomatitis virus (BPSV) infects cattle and, occupationally, humans. Prevalent subclinical infections, frequent reinfections, and virus persistence in healthy animals compound a poorly understood, but likely complex, scenario of BPSV perpetuation and transmission in nature. Here, we report the isolation of multiple BPSV strains coinfecting a single animal. Whole-genome analysis of isolated BPSV strains revealed genomic variability likely affecting virus virulence and infectivity. Further, incongruent phylogenetic relationships between viruses suggested genomic recombination. These results have significant implications for parapoxvirus infection biology and virus evolution in nature. PMID- 25804194 TI - The study of the electronic structure of some N-heterocyclic carbenes (NHCs) by variable energy photoelectron spectroscopy. AB - The photoionization of three N-heterocyclic carbenes (NHCs) has been studied in the valence and core regions using synchrotron radiation. We observed different variations in the relative band intensities with photon energy for the NHCs in the valence ionization region. This is due to the intra-ring interactions between the C=C bond, nitrogen and carbene lone pairs in the heterocyclic ring of NHCs. In the core ionization region we observed chemical shifts which are consistent with the relative electron affinities of atoms and intramolecular electron density shifts. The core electron binding energies calculated via the unrestricted DeltaDFT (B3LYP and M06-2X) approach are in very good agreement with the experiment. The shake-up portion of the core photoionization spectra is adequately described by the time-dependent DFT calculations relying on the CAM B3LYP functional. PMID- 25804192 TI - Bloodstream infection in paediatric cancer centres--leukaemia and relapsed malignancies are independent risk factors. AB - In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 paediatric cancer patients (58% males; median age 8.3 years, interquartile range (IQR) 3.8-14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63% of all patients and Ports in 20%. One hundred forty-two patients (18%; 95% CI 16 to 21%) experienced at least one BSI (179 BSIs in total; bacteraemia 70%, bacterial sepsis 27%, candidaemia 2%). In 57%, the BSI occurred in inpatients, in 79% after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16%) was an independent risk factor for all BSI and for Gram-positive BSI. CONCLUSION: This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles. WHAT IS KNOWN: * Paediatric cancer patients face an increased risk of nosocomial bloodstream infections (BSIs). * In most cases, these BSIs are associated with the use of a long-term central venous catheter (Broviac, Port), severe and prolonged immunosuppression (e.g. neutropenia) and other chemotherapy induced alterations of host defence mechanisms (e.g. mucositis). What is New: * This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. * It describes the epidemiology of nosocomial BSI in paediatric cancer patients mainly outside the stem cell transplantation setting during conventional intensive therapy and argues for prospective surveillance programmes to target and evaluate preventive bundle interventions. PMID- 25804195 TI - Combination of total Astragalus extract and total Panax notoginseng saponins strengthened the protective effects on brain damage through improving energy metabolism and inhibiting apoptosis after cerebral ischemia-reperfusion in mice. AB - OBJECTIVE: To explore the effects and molecular mechanisms of the combination between total Astragalus extract (TAE) and total Panax notoginseng saponins (TPNS) against cerebral ischemia-reperfusion injury. METHODS: C57BL/6 mice were randomly divided into sham-operated group, model group, TAE (110 mg/kg) group, TPNS (115 mg/kg) group, TAE-TPNS combination group and Edaravone (4 mg/kg) group, treated for 4 days, then, cerebral ischemia-reperfusion injury was established by bilateral common carotid artery (CCA) ligation for 20 min followed by reperfusion for 1 and 24 h. RESULTS: TPNS could increase adenosine triphosphate (ATP) level, TAE and TAE-TPNS combination increased ATP, adenosine diphosphate (ADP) contents and Na+-K+-ATPase activity, and the effects of TAE-TPNS combination were stronger than those of TAE or TPNS alone after reperfusion for 1 h. After reperfusion for 24 h, TAE, TPNS and TAE-TPNS combination significantly increased neurocyte survival rate and decreased the apoptosis rate as well as down-regulated the expression of phosphorylated c-June N-terminal kinase1/2 (p-JNK1/2), cytochrome C (Cyt C), cysteine aspartic acid-specific protease (Caspase)-9 and Caspase-3. Furthermore, the effects in TAE-TPNS combination were better than those in TAE or TPNS alone. CONCLUSION: The combination of TAE 110 mg/kg and TPNS 115 mg/kg could strengthen protective effects on cerebral ischemia injury, the mechanism underlying might be related to improving jointly the early energy metabolism, and relieving the delayed apoptosis via inhibiting the mitochondrial apoptosis pathway of JNK signal transduction. PMID- 25804196 TI - Qualitative analysis of a sulfur-fumigated Chinese herbal medicine by comprehensive two-dimensional gas chromatography and high-resolution time of flight mass spectrometry using colorized fuzzy difference data processing. AB - OBJECTIVE: To investigate the chemical transformation of volatile compounds in sulfur-fumigated Radix Angelicae Sinensis. METHODS: A comprehensive two dimensional gas chromatography (GC*GC) and high-resolution time-of-flight mass spectrometry (HR-TOF/MS) with colorized fuzzy difference (CFD) method was used to investigate the effect of sulfur-fumigation on the volatile components from Radix Angelicae Sinensis. RESULTS: Twenty-five compounds that were found in sun-dried samples disappeared in sulfur-fumigated samples. Seventeen volatile components including two sulfur-containing compounds were newly generated for the first time in volatile oils of sulfur-fumigated Radix Angelicae Sinensis. CONCLUSION: The strategy can be successfully applied to rapidly and holistically discriminate sun dried and sulfur-fumigated Radix Angelicae Sinensis. GC*GC-HR-TOF/MS based CFD is a powerful and feasible approach for the global quality evaluation of Radix Angelicae Sinensis as well as other herbal medicines. PMID- 25804197 TI - Matrine and CYC116 synergistically inhibit growth and induce apoptosis in multiple myeloma cells. AB - OBJECTIVE: To investigate whether CYC116 can potentiate matrine-dependent growth inhibition and apoptosis in multiple myeloma (MM) cells. METHODS: The dose response relationship of matrine to dexamethasone-resistant and dexamethasone sensitive MM cells was first established. Myeloma RPMI8226 cells were treated with matrine alone or combined with CYC116 for 24 h. Cell proliferation was measured using an MTT assay and apoptosis induction was evaluated by flow cytometry. Activation of the caspase pathway and expression of apoptosis regulator proteins were detected by Western blotting. RESULTS: Matrine significantly induced growth arrest and apoptosis in both drug-resistant and drug sensitive MM cells. Treatment with the combination of matrine and CYC116 had a stronger cytotoxic effect on MM cells than did single drug treatments. Enhanced apoptosis observed following the combined treatment of matrine and CYC116 was associated with higher levels of activation of caspase-9, caspase-3, and poly adenosine diphosphate ribose polymerase (PARP) and down-regulation of the anti apoptotic proteins Bcl-2 and Mcl-1 and the signaling proteins p-Akt and nuclear factor kappaB (NF-kappaB). CONCLUSION: CYC116 enhances the growth inhibitory and apoptotic effects of matrine on MM cells. PMID- 25804198 TI - The application of biotechnology in medicinal plants breeding research in China. AB - Breeding is not only an important area of medicinal plants research but also the foundation for the superior varieties acquirement of medicinal plants. The rise of modern biotechnology provides good opportunities and new means for medicinal plants breeding research in China. Biotechnology shows its technical advantages and new development prospects in breeding of new medicinal plants varieties with high and stable yield, good quality, as well as stress-resistance. In this paper, we describe recent advances, problems, and development prospects about the application of modern biotechnology in medicinal plants breeding research in China. PMID- 25804200 TI - Quantification of tetrabromo benzoic acid and tetrabromo phthalic acid in rats exposed to the flame retardant Uniplex FPR-45. AB - The first withdrawal of certain polybrominated diphenyl ethers flame retardants from the US market occurred in 2004. Since then, use of brominated non-PBDE compounds such as bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEH-TEBP) and 2 ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) in commercial formulations has increased. Assessing human exposure to these chemicals requires identifying metabolites that can potentially serve as their biomarkers of exposure. We administered by gavage a dose of 500 mg/Kg bw of Uniplex FRP-45 (>95 % BEH-TEBP) to nine adult female Sprague-Dawley rats. Using authentic standards and mass spectrometry, we positively identified and quantified 2,3,4,5-tetrabromo benzoic acid (TBBA) and 2,3,4,5-tetrabromo phthalic acid (TBPA) in 24-h urine samples collected 1 day after dosing the rats and in serum at necropsy, 2 days post exposure. Interestingly, TBBA and TBPA concentrations correlated well (R (2) = 0.92). The levels of TBBA, a known metabolite of EH-TBB, were much higher than the levels of TBPA both in urine and serum. Because Uniplex FRP-45 was technical grade and EH-TBB was present in the formulation, TBBA likely resulted from the metabolism of EH-TBB. Taken together, our data suggest that TBBA and TBPA may serve as biomarkers of exposure to non-PBDE brominated flame retardant mixtures. Additional research can provide useful information to better understand the composition and in vivo toxicokinetics of these commercial mixtures. PMID- 25804202 TI - Statistically-based DLVO approach to the dynamic interaction of colloidal microparticles with topographically and chemically heterogeneous collectors. AB - Electrostatic surface heterogeneity on the order of a few nanometers is common in colloidal and bacterial systems, dominating adhesion and aggregation and inducing deviations from classical DLVO theory based on a uniform distribution of surface charge. Topographical heterogeneity and roughness also strongly influence adhesion. In this work, a model is introduced to quantify the spatial fluctuations in the interaction of microparticles in a flowing suspension with a wall aligned parallel to the flow. The wall contains nanoscale chemical and topographical heterogeneities ("patches") that are randomly distributed and produce localized attraction and repulsion. These attractive and repulsive regions induce fluctuations in the trajectories of the flowing particles that are critical to particle capture by the wall. The statistical distribution of patches is combined with mean-field DLVO calculations between a particle and two homogeneous surfaces: one with the surface potential of the patches and one with the potential of the underlying wall. These surface potentials could be obtained in experiments from zeta potential measurements for the bare wall and for one saturated with patches. This simple model reproduces the mean DLVO interaction force or energy vs. particle-wall separation distance, its variance, and particle adhesion thresholds from direct simulations of particle trajectories over patchy surfaces. The predictions of the model are consistent with experimental findings of significant microparticle deposition onto patchy, net-repulsive surfaces whose apparent zeta potential has the same sign as that of the particles. Deposition is significantly enhanced if the patches protrude even slightly from the surface. The model predictions are also in agreement with the observed variation of the adhesion threshold with the shear rate in published studies of dynamic microparticle adhesion on patchy surfaces. PMID- 25804203 TI - Alternative food and biological control by generalist predatory mites: the case of Amblyseius swirskii. PMID- 25804199 TI - Prenatal exposure to bisphenol A impacts neuronal morphology in the hippocampal CA1 region in developing and aged mice. AB - Bisphenol A (BPA), a widely used raw component of polycarbonate plastics and epoxy resins, has been reported to induce developmental neurotoxicity in offspring born to dams exposed to low doses of BPA; however, the toxicity mechanism remains elusive. To study the effects of in utero BPA exposure on neuronal morphology, we studied spine density and dendritic growth in the hippocampal CA1 of aged mice and developing mice prenatally exposed to low doses of BPA. Pregnant mice were orally administered BPA at a low dose of 0, 40, or 400 MUg/kg body weight/day on gestational days 8.5-17.5/18.5. Mouse progenies were euthanized at 3 weeks or 14 months, and their brains were analyzed for dendritic arborization of GFP-expressing neurons or spine densities of Golgi-stained neurons in the hippocampal CA1. Regardless of the dose, in utero BPA exposure reduced spine densities in the hippocampal CA1 of the 14-month-old mice. In the developing brain from the 3-week-old mice born to dams exposed to BPA at a dose of 400 MUg/kg body weight/day, overall length and branching number of basal dendrites but not apical dendrites were decreased. In utero low doses of BPA exposure disrupts hippocampal CA1 neuronal morphology during development, and this disruption is believed to persist in adulthood. PMID- 25804204 TI - Highly sensitive detection of quantal dopamine secretion from pheochromocytoma cells using neural microelectrode array electrodeposited with polypyrrole graphene. AB - For the measurement of events of dopamine (DA) release as well as the coordinating neurotransmission in the nerve system, a neural microelectrode array (nMEA) electrodeposited directionally with polypyrrole graphene (PG) nanocomposites was fabricated. The deposited graphene significantly increased the surface area of working electrode, which led to the nMEA (with diameter of 20 MUm) with excellent selectivity and sensitivity to DA. Furthermore, PG film modification exhibited low detection limit (4 nM, S/N = 3.21), high sensitivity, and good linearity in the presence of ascorbic acid (e.g., 13933.12 MUA mM(-1) cm(-2) in the range of 0.8-10 MUM). In particular, the nMEA combined with the patch-clamp system was used to detect quantized DA release from pheochromocytoma cells under 100 mM K(+) stimulation. The nMEA that integrates 60 microelectrodes is novel for detecting a large number of samples simultaneously, which has potential for neural communication research. PMID- 25804201 TI - Gene expression profiling to investigate tyrosol-induced lifespan extension in Caenorhabditis elegans. AB - PURPOSE: We have previously reported that tyrosol (TYR) promotes lifespan extension in the nematode Caenorhabditis elegans, also inducing a stronger resistance to thermal and oxidative stress in vivo. In this study, we performed a whole-genome DNA microarray in order to narrow down the search for candidate genes or signaling pathways potentially involved in TYR effects on C. elegans longevity. METHODS: Nematodes were treated with 0 or 250 MUM TYR, total RNA was isolated at the adult stage, and derived cDNA probes were hybridized to Affymetrix C. elegans expression arrays. Microarray data analysis was performed, and relative mRNA expression of selected genes was validated using qPCR. RESULTS: Microarray analysis identified 208 differentially expressed genes (206 over expressed and two under-expressed) when comparing TYR-treated nematodes with vehicle-treated controls. Many of these genes are linked to processes such as regulation of growth, transcription, reproduction, lipid metabolism and body morphogenesis. Moreover, we detected an interesting overlap between the expression pattern elicited by TYR and those induced by other dietary polyphenols known to extend lifespan in C. elegans, such as quercetin and tannic acid. CONCLUSIONS: Our results suggest that important cellular mechanisms directly related to longevity are influenced by TYR treatment in C. elegans, supporting our previous notion that this phenol might act on conserved genetic pathways to increase lifespan in a whole organism. PMID- 25804205 TI - Induction of spermatogenesis by rhFSH for azoospermia due to spermatogenic dysfunction with maturation arrest: five case series. AB - When sperm cannot be retrieved from the testes of patients with azoospermia due to spermatogenic dysfunction (ASD), there is no rational way for the patient to become a biological father. We investigated the possibility of inducing spermatogenesis in such patients by hormonal therapy with recombinant human follicle-stimulating hormone (rhFSH) alone. Twenty-six ASD patients who could not obtain spermatozoa by microdissection testicular sperm extraction (micro-TESE) were confirmed to have arrested spermatogenesis at the late stage of maturation arrest. They were subsequently treated with 75-150 IU two times/week rhFSH alone for 12 months. The primary endpoint was the appearance of sperm in ejaculate, and we followed the patients to determine the outcome of inseminating their partners. After rhFSH treatment, mature spermatozoa were found in the ejaculate in five of 26 (19.2%) patients, all of whom showed histology of non-uniform type maturation arrest. Intracytoplasmic sperm injection of the mature spermatozoa resulted in two ongoing clinical pregnancies (insemination success rate, 40.0%). Recombinant human follicle-stimulating hormone treatment can be used as an advanced assisted reproductive technology to improve spermatogenesis in some azoospermic patients with maturation arrest of spermatogenesis and is a potential treatment option after unsuccessful micro-TESE. PMID- 25804206 TI - Rotational open-wedge osteotomy improves treatment outcomes for patients older than eight years with Legg-Calve-Perthes disease in the modified lateral pillar B/C border or C group. AB - PURPOSE: Since 2003, we have been performing rotational open-wedge osteotomy (ROWO) for older children with severe Legg-Calve-Perthes disease (LCPD). We compared the treatment outcomes before and after the introduction of ROWO for patients aged >= eight years, classified in the modified lateral pillar B/C border or C group. METHODS: Before the introduction of ROWO, conservative treatment (non-weight bearing [NWB]) was performed for all cases between 1986 and 2002, whereby there were 34 hips (NWB group). The median patient age, at the first visit, was 9.1 years. According to the lateral pillar classification, 21 hips were categorized into the B/C border group and the others into the C group. Meanwhile, 14 consecutive hips underwent ROWO combined with NWB between 2003 and 2008 (ROWO+NWB group). The median patient age, at the first visit, was 9.1 years. Six hips were in the lateral pillar B/C border group and the others were classified into the C group. There were no significant differences in pre treatment patients' demographic data. RESULTS: At the latest follow-up, according to the Stulberg classification, there were 19 class II hips, 13 class III hips, and two class IV hips in the NWB group. In the ROWO+NWB group, there were 12 class II hips, two class III hips, and no class IV hips. CONCLUSIONS: The application of ROWO combined with NWB in the treatment of older children with severe LCPD improved their outcomes, compared to those obtained by NWB treatment alone. PMID- 25804207 TI - Modern teaching of military surgery: why and how to prepare the orthopaedic surgeons before deployment? The French experience. AB - PURPOSE: Improved survival of combat casualties in modern conflicts is especially due to early access to damage control resuscitation and surgery in forward surgical facilities. In the French Army, these small mobile units are staffed with one general surgeon and one orthopaedic surgeon who must be able to perform any kind of trauma or non trauma emergency surgery. METHODS: This concept of forward surgery requires a solid foundation in general surgery which is no longer provided by the current surgical programs due to an early specialization of the residents. Obviously a specific training is needed in war trauma due to the special pathology and practice, but also in humanitarian care which is often provided in military field facilities. RESULTS: To meet that demand the French Military Health Service Academy created an Advanced Course for Deployment Surgery (ACDS), also called CACHIRMEX (Cours Avance de CHIRurgie en Mission EXterieure). Since 2007 this course is mandatory for young military surgeons before their first deployment. Orthopaedic trainees are particularly interested in learning war damage control orthopaedic tactics, general surgery life-saving procedures and humanitarian orthopaedic surgery principles in austere environments. CONCLUSION: Additional pre-deployment training was recently developed to improve the preparation of mobile surgical teams, as well as a continuing medical education for any active-duty or reserve surgeon to be deployed. PMID- 25804209 TI - Involve children with life limiting conditions in decisions to stop treatment, says new guidance. PMID- 25804208 TI - Participation of sex hormones in multifactorial pathogenesis of adolescent idiopathic scoliosis. AB - PURPOSE: In order to verify the potential association between the aetiopathogenesis of adolescent idiopathic scoliosis (AIS) and the process of sexual maturation, we determined the concentrations of oestrogens in pre- and postmenarcheal girls affected by this condition. AIS, occurring mostly in pubescent girls, is one of the most frequent forms of faulty posture. Therefore, it was assumed that the multifactorial pathomechanism of AIS involves significant deficiency of oestrogens. METHODS: The diagnosis of AIS was established on the basis of physical examination and analyses of radiograms. Concentrations of FSH, LH, oestrogens, progesterone, osteocalcin and RANKL were determined by ELISA. The activity of alkaline phosphatase (AP) was measured by kinetic method. The study included pre- and postmenarcheal girls with AIS and corresponding groups of scoliosis-free controls. RESULTS: In premenarcheal scoliotic girls, the levels of FSH, LH and oestradiol were lower; the levels of progesterone, oestrone and oestriol were higher; and the concentrations of oestrone and oestriol were similar compared to premenarcheal controls. Higher levels of RANKL, osteocalcin and AP were observed in premenarcheal adolescents with AIS compared to controls. The concentrations of FSH, LH, oestradiol, and progesterone in postmenarcheal girls with scoliosis were lower, oestrone were slightly lower and oestriol did not differ compared with the control group. Significantly higher levels of RANKL, osteocalcin and AP were observed in postmenarcheal scoliotic adolescents compared with controls. CONCLUSIONS: There is an interdependence between the concentration of oestradiol and development of scoliosis. Determination of estradiol may have diagnostic value in the screening of spinal pathologies associated with AIS. PMID- 25804210 TI - Avoidable waste of research related to inadequate methods in clinical trials. AB - OBJECTIVE: To assess the waste of research related to inadequate methods in trials included in Cochrane reviews and to examine to what extent this waste could be avoided. A secondary objective was to perform a simulation study to re estimate this avoidable waste if all trials were adequately reported. DESIGN: Methodological review and simulation study. DATA SOURCES: Trials included in the meta-analysis of the primary outcome of Cochrane reviews published between April 2012 and March 2013. DATA EXTRACTION AND SYNTHESIS: We collected the risk of bias assessment made by the review authors for each trial. For a random sample of 200 trials with at least one domain at high risk of bias, we re-assessed risk of bias and identified all related methodological problems. For each problem, possible adjustments were proposed that were then validated by an expert panel also evaluating their feasibility (easy or not) and cost. Avoidable waste was defined as trials with at least one domain at high risk of bias for which easy adjustments with no or minor cost could change all domains to low risk. In the simulation study, after extrapolating our re-assessment of risk of bias to all trials, we considered each domain rated as unclear risk of bias as missing data and used multiple imputations to determine whether they were at high or low risk. RESULTS: Of 1286 trials from 205 meta-analyses, 556 (43%) had at least one domain at high risk of bias. Among the sample of 200 of these trials, 142 were confirmed as high risk; in these, we identified 25 types of methodological problem. Adjustments were possible in 136 trials (96%). Easy adjustments with no or minor cost could be applied in 71 trials (50%), resulting in 17 trials (12%) changing to low risk for all domains. So the avoidable waste represented 12% (95% CI 7% to 18%) of trials with at least one domain at high risk. After correcting for incomplete reporting, avoidable waste due to inadequate methods was estimated at 42% (95% CI 36% to 49%). CONCLUSIONS: An important burden of wasted research is related to inadequate methods. This waste could be partly avoided by simple and inexpensive adjustments. PMID- 25804211 TI - Mortality estimates from ovarian age distributions of the tsetse fly Glossina pallidipes Austen sampled in Zimbabwe suggest the need for new analytical approaches. AB - Mortality estimates are central to understanding tsetse fly population dynamics, but are difficult to acquire from wild populations. They can be obtained from age distribution data but, with limited data, it is unclear whether the assumptions required to make the estimates are satisfied and, if not, how violations affect the estimates. We evaluate the assumptions required for existing mortality estimation techniques using long-term longitudinal ovarian dissection data from 144,106 female tsetse, Glossina pallidipes Austen, captured in Zimbabwe between 1988 and 1999. At the end of the hot-dry season each year, mean ovarian ages peaked, and maximum-likelihood mortality estimates declined to low levels, contrary to mark-recapture estimates, suggesting violations of the assumptions underlying the estimation technique. We demonstrate that age distributions are seldom stable for G. pallidipes at our study site, and hypothesize that this is a consequence of a disproportionate increase in the mortality of pupae and young adults at the hottest times of the year. Assumptions of age-independent mortality and capture probability are also violated, the latter bias varying with capture method and with pregnancy and nutritional status. As a consequence, mortality estimates obtained from ovarian dissection data are unreliable. To overcome these problems we suggest simulating female tsetse populations, using dynamical modelling techniques that make no assumptions about the stability of the age distribution. PMID- 25804212 TI - Cognitive Aging in Parents of Children with Disabilities. AB - OBJECTIVE: This study examines the cognitive functioning of parents of children with disabilities, specifically, whether there is an evidence of accelerated cognitive aging among these parents. In addition, the study investigates the moderating influences of two variables: parents' gender and stress from negative parenting experience. METHOD: The analyses utilize data from the National Survey of Midlife in the United States (2005). The analytic sample consisted of two groups of parents, who completed the cognitive battery, the interview, and the mail-back survey: 128 parents who had children with childhood-onset disabilities and 512 matched comparison parents who had only nondisabled children. RESULTS: Age differences in episodic memory were more pronounced among mothers of children with disabilities than among mothers with nondisabled children, especially among mothers with higher levels of negative parenting experience. In contrast, there were no interaction effects of parenting status, age, and negative parenting experience among fathers. DISCUSSION: The results show that parenting children with disabilities over a prolonged period of time jeopardizes cognitive function (especially memory) among older mothers, possibly via the mechanism of heightened parenting stress due to higher levels of negative parenting experience. PMID- 25804214 TI - Defining competence in obstetric epidural anaesthesia for inexperienced trainees. AB - BACKGROUND: Cumulative sum (CUSUM) analysis has been used for assessing competence of trainees learning new technical skills. One of its disadvantages is the required definition of acceptable and unacceptable success rates. We therefore monitored the development of competence amongst trainees new to obstetric epidural anaesthesia in a large public hospital. METHODS: Obstetric epidural data were collected prospectively between January 1996 and December 2011. Success rates for inexperienced trainees were calculated retrospectively for (1) the whole database, (2) for each consecutive attempt and (3) each trainee's individual overall success rate. Acceptable and unacceptable success rates were defined and CUSUM graphs generated for each trainee. Competence was assessed for each trainee and the number of attempts to reach competence recorded. RESULTS: Mean (sd) success rate for all inexperienced trainees was 76.8 (0.1%), range 63-90%. Consecutive attempt success rate produced a learning curve with a mean success rate commencing at 58% on attempt 1. After attempt 10 the attempt number had no effect on subsequent success rates. From these results, the acceptable and unacceptable success rates were set at 65 and 55% respectively. CUSUM graphs demonstrated 76 out of 81 trainees competent after a mean of 46 (22) attempts. CONCLUSIONS: CUSUM is useful for assessing trainee epidural competence. Trainees require approximately 50 attempts, as defined by CUSUM, to reach competence. PMID- 25804216 TI - Suicide and Self-Determination. PMID- 25804215 TI - Epithelioid mammary myofibroblastoma mimicking invasive lobular carcinoma. AB - A case of a 53-year-old woman with the epithelioid variant of mammary myofibroblastoma, which was initially misinterpreted as invasive lobular carcinoma, is presented. A needle core biopsy of the 1.6 cm mass showed interlacing bundles of epithelioid myofibroblasts amid dense fibrous tissue associated with lobular carcinoma in situ of the classical type. Most epithelioid cells showed nuclear atypia, and a few exhibited signet-ring cytology. Immunoreactivity for estrogen and progesterone receptors further compounded the deception, and the neoplasm was misinterpreted as invasive lobular carcinoma. Excisional biopsy showed a circumscribed stromal tumor with foci suspicious for invasive lobular carcinoma. The latter was excluded by cytokeratin negativity throughout the tumor. The overall histopathological appearance and immunostaining pattern was confirmatory of myofibroblastoma. This case report emphasizes the potential for mistaking epithelioid myofibroblastoma for invasive lobular carcinoma--particularly in the setting of limited sampling, hormone-receptor immunoreactivity of the lesional cells, and synchronous lobular carcinoma in situ. PMID- 25804213 TI - Role of the PhoP-PhoQ gene regulatory system in adaptation of Yersinia pestis to environmental stress in the flea digestive tract. AB - The Yersinia pestis PhoPQ gene regulatory system is induced during infection of the flea digestive tract and is required to produce adherent biofilm in the foregut, which greatly enhances bacterial transmission during a flea bite. To understand the in vivo context of PhoPQ induction and to determine PhoP-regulated targets in the flea, we undertook whole-genome comparative transcriptional profiling of Y. pestis WT and DeltaphoP strains isolated from infected fleas and from temperature-matched in vitro planktonic and flow-cell biofilm cultures. In the absence of PhoP regulation, the gene expression program indicated that the bacteria experienced diverse physiological stresses and were in a metabolically less active state. Multiple stress response genes, including several toxin antitoxin loci and YhcN family genes responsible for increased acid tolerance, were upregulated in the phoP mutant during flea infection. The data implied that PhoPQ was induced by low pH in the flea gut, and that PhoP modulated physiological adaptation to acid and other stresses encountered during infection of the flea. This adaptive response, together with PhoP-dependent modification of the bacterial outer surface that includes repression of pH 6 antigen fimbriae, supports stable biofilm development in the flea foregut. PMID- 25804219 TI - [Herpesvirus detection in clinically healthy West African mud turtles (Pelusioscastaneus)]. AB - OBJECTIVE: First description of a herpesvirus in West African mud turtles. MATERIALS AND METHODS: A herpesvirus was detected in two clinically healthy West African mud turtles (Pelusios castaneus) by PCR during a quarantine exam. The animals had been imported from Togo, West Africa to Germany for the pet trade. RESULTS: Analysis of a portion of the genome of the detected virus showed that it is a previously unknown virus related to other chelonid herpesviruses. The virus was named pelomedusid herpesvirus 1. DISCUSSION: This case highlights the importance of testing for infectious agents during quarantine, even in clinically healthy animals. PMID- 25804217 TI - Canadian Men's Self-Management of Chronic Diseases: A Literature Analysis of Strategies for Dealing With Risks and Promoting Wellness. AB - This article reviews the qualitative research on men's self-management of mental and physical chronic diseases, with emphasis on strategies for dealing with risks and promoting wellness. Using Bardin's method of document analysis, it was focused on the findings of Canadian qualitative studies published in French or English from 2005 to 2011. Boltanski's theory on social uses of the body inspired the analysis. Living with a chronic disease threatens men's sense of masculinity and self-image, as well as their perceived ability to fulfill expected social roles. Social images of men's bodies influence how men express their emotions, attributes, and attitudes, or acknowledge the need for and seek social affirmation. Self-management has been documented in Canadian qualitative literature as a complex phenomenon influenced by the social environment, personal capacities, feelings, perceptions, and potentials. The extent of how all these features interact within the scope of men's mental and physical health and illness experiences was partially revealed in this study. The findings underscore the social invisibility of men's bodies, especially those of men facing social inequities. Attending to principles of social justice can ensure that future research on men's health will amplify the range of men's voices and allow them to be heard. Recommendations address also the international scientific community interested in advancing men's health research, especially in those countries that lack a national men's health policy. PMID- 25804218 TI - The Role of Marital Status in Physical Activity Among African American and White Men. AB - Racial differences in physical activity among men are well documented; however, little is known about the impact of marital status on this relationship. Data from the National Health and Examination Survey (NHANES) 1999-2006 was used to determine whether the association of race and physical activity among men varied by marital status. Marital status was divided into two categories: married and unmarried. Physical activity was determined by the number of minutes per week a respondent engaged in household/yard work, moderate and vigorous activity, or transportation (bicycling and walking) over the past 30 days. The sample included 7,131 African American (29%) and White(71%) men aged 18 years and older. All models were estimated using logistic regression. Because the interaction term of race and marital status was statistically significant (p < .001), the relationship between race, physical activity, and marital status was examined using a variable that reflects the different levels of the interaction term. After adjusting for age, income, education, weight status, smoking status, and self-rated health, African American married men had lower odds (odds ratio = 0.53, 95% confidence interval = [0.46-0.61], p < .001) of meeting federal physical activity guidelines compared with White married men. Possible dissimilarities in financial and social responsibilities may contribute to the racial differences observed in physical activity among African American and White married men. PMID- 25804220 TI - Mr. right versus Mr. right now: A discounting-based approach to promiscuity. AB - Research has begun to examine how individuals discount delayed sex. However, these tasks have not evaluated the dimension of sexual behavior associated with promiscuity (i.e., choices between partners). The current study assessed choices between hypothetical sexual partners within a delay discounting paradigm. Participants first completed a preference assessment featuring pictures of hypothetical sexual partners. These rankings were then used to present hypothetical choices between immediate sex with a less preferred partner or sex with the most-preferred partner after a series of delays. These choices titrated through the partner rankings from the preference assessment. Data were well fit by the hyperboloid model of discounting. Area under the curve (AUC) measures were calculated for all participants' discounting of sex. AUC was higher for those with more sexual partners and was correlated with measures of sexual risk behavior. PMID- 25804221 TI - Exploring the underlying structure of mental disorders: cross-diagnostic differences and similarities from a network perspective using both a top-down and a bottom-up approach. AB - BACKGROUND: It has been suggested that the structure of psychopathology is best described as a complex network of components that interact in dynamic ways. The goal of the present paper was to examine the concept of psychopathology from a network perspective, combining complementary top-down and bottom-up approaches using momentary assessment techniques. METHOD: A pooled Experience Sampling Method (ESM) dataset of three groups (individuals with a diagnosis of depression, psychotic disorder or no diagnosis) was used (pooled N = 599). The top-down approach explored the network structure of mental states across different diagnostic categories. For this purpose, networks of five momentary mental states ('cheerful', 'content', 'down', 'insecure' and 'suspicious') were compared between the three groups. The complementary bottom-up approach used principal component analysis to explore whether empirically derived network structures yield meaningful higher order clusters. RESULTS: Individuals with a clinical diagnosis had more strongly connected moment-to-moment network structures, especially the depressed group. This group also showed more interconnections specifically between positive and negative mental states than the psychotic group. In the bottom-up approach, all possible connections between mental states were clustered into seven main components that together captured the main characteristics of the network dynamics. CONCLUSIONS: Our combination of (i) comparing network structure of mental states across three diagnostically different groups and (ii) searching for trans-diagnostic network components across all pooled individuals showed that these two approaches yield different, complementary perspectives in the field of psychopathology. The network paradigm therefore may be useful to map transdiagnostic processes. PMID- 25804223 TI - Leukemic blast cells and controversies in models of hematopoiesis. AB - Classical and up-to-date models of hematopoietic lineage determination are briefly reviewed with the focus on myeloid-based models challenging the existence of the common progenitor for T cells, B cells and NK cells. The analysis of immunophenotype of leukemic blast cells seems to be a promising approach for interpreting some controversies in the schemes of normal hematopoiesis. The literature data as well as our own findings in the patients with various types of acute leukemias are in favor of the concept postulating that common myeloid lymphoid progenitors giving rise to T and B cell branches retain the myeloid potential. The similarity of some immunophenotypic features of blast cells in pro B acute lymphoblastic leukemia and acute monoblastic leukemia is consistent with monocyte origin postulated in the studies of normal hematopoiesis. Study of acute leukemias may be the challenging area of research allowing for new insight into the origin of hematopoietic cell lineages. PMID- 25804224 TI - Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives. AB - In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high pathogenetic importance in the lung carcinogenesis and can be identified in biological samples with high accuracy and reliability using highly sensitive mass spectrometry methods (TOF/TOF, TOF/MS, MS/MS). The appearance of DNA adducts in blood or tissues is the result of the interaction of carcinogenic factors, such as tobacco constituents, and the body reaction which is determined by individual characteristics of metabolic and repair systems. So, DNA adducts may be considered as a cumulative mirror of heterogeneous response of different individuals to smoking carcinogens, which finally could determine the risk for lung cancer. This review is devoted to analysis of the role of DNA adducts in lung carcinogenesis in order to demonstrate their usefulness as cancer associated markers. Currently, there are some serious limitations impeding the widespread use of DNA adducts as cancer biomarkers, due to failure of standardization of mass spectrometry analysis in order to correctly measure the adduct level in each individual. However, it is known that all DNA adducts are immunogenic, their accumulation over some threshold concentration leads to the appearance of long-living autoantibodies. Thus, detection of an informative pattern of autoantibodies against DNA adducts using innovative multiplex ELISA immunoassay may be a promising approach to find lung cancer at an early stage in high-risk groups (smokers, manufacturing workers, urban dwellers). PMID- 25804222 TI - Glucocorticoid signaling in the heart: A cardiomyocyte perspective. AB - Heart failure is one of the leading causes of death in the Western world. Glucocorticoids are primary stress hormones that regulate a vast array of biological processes, and synthetic derivatives of these steroids have been mainstays in the clinic for the last half century. Abnormal levels of glucocorticoids are known to negatively impact the cardiovascular system; however, surprisingly little is known about the direct role of glucocorticoid signaling in the heart. The actions of glucocorticoids are mediated classically by the glucocorticoid receptor (GR). In certain cells, such as cardiomyocytes, glucocorticoid occupancy and activation of the mineralocorticoid receptor (MR) may also contribute to the observed response. Recently, there has been a surge of reports investigating the in vivo function of glucocorticoid signaling in the heart using transgenic mice that specifically target GR or MR in cardiomyocytes. Results from these studies suggest that GR signaling in cardiomyocytes is critical for the normal development and function of the heart. In contrast, MR signaling in cardiomyocytes participates in the development and progression of cardiac disease. In the following review, we discuss these genetic mouse models and the new insights they are providing into the direct role cardiomyocyte glucocorticoid signaling plays in heart physiology and pathophysiology. This article is part of a Special Issue entitled 'Steroid Perspectives'. PMID- 25804225 TI - Long-term administration of prolactin or testosterone induced similar precancerous prostate lesions in rats. AB - Evidence indicates that prolactin plays a crucial role in the normal function and development of the prostate, but abnormal high levels of the hormone are associated with hyperplasia and cancer of the gland. AIMS: The present study was designed to describe the progressive specific histological abnormalities in the prostate of rats with chronic hyperprolactinemia. MATERIAL AND METHODS: Prolactin was administered during 4; 12 or 24 weeks, and the resulting prostatic alterations were compared with control rats, and also with those treated with testosterone, or the combination of prolactin + testosterone. RESULTS: Rats treated with prolactin, testosterone or prolactin + testosterone expressed precancerous histological abnormalities in the dorsolateral and ventral portions of the prostate as early as in 4 weeks of treatment, but in all cases the malignancy increased after 12 or 24 weeks of treatment. CONCLUSION: Our study confirms that chronic hyperprolactinemia is a cause of prostate precancerous pathologies. PMID- 25804226 TI - Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin. AB - AIM: To study indices of energy metabolism, content of K(+) and Mg(++) both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. METHODS: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains - by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. RESULTS: It has been determined that development of drug resistance causes the decrease of K(+), Mg(++), glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor's loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. CONCLUSION: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance. PMID- 25804227 TI - In vitro and in vivo evaluation of 2-chloroethylnitrosourea derivatives as antitumor agents. AB - AIM: To evaluate potential of Naphthal-NU, Napro-NU and 5-Nitro-naphthal-NU, 2 chloroethylnitrosourea compounds with substituted naphthalimide in the pre clinical studies. MATERIALS AND METHODS: In vitro cytotoxicity of three nitrosoureas was determined in human and mouse tumor cell lines by MTT assays. In vivo anti-tumor potential was evaluated in Sarcoma-180 (S-180) and Ehrlich's carcinoma (EC) solid tumors. Apoptosis in S-180 cells was analyzed by using Annexin V-Propidium Iodide (PI). Histological analysis of liver and kidney was performed at optimum dose (50 mg/kg). Expression status of CD4(+), CD8(+) and CD25(+) cells in treated mouse were also examined. RESULTS: Significant tumor growth retardation by the compounds was noted in early and advanced disease groups, as the life span of drug treated mice increased considerably. Drug induced killing was observed by induction of apoptosis. Naphthal-NU and 5-Nitro naphthal-NU were effective to normalize the tumor induced structural abnormalities of liver and kidney. The compounds have no immunotoxic effect on CD4(+) and CD8(+) T cells and down regulate CD4(+)CD25(+) regulatory T cells. CONCLUSION: Overall data holds promise for the antitumor activity with lower toxicity of the compounds that can be utilized for the treatment of human malignant tumors. PMID- 25804228 TI - The antitumor efficacy of cisplatin in combination with triptorelin and exemestane therapy for an ovarian cancer ascites model in Wistar rats. AB - AIM: To study antitumor activity of triptorelin - agonist of gonadotropin releasing hormone and exemestane - inhibitor of aromatase in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant transplantable ascites ovarian tumor (OT); to assess tumor response to treatment and VEGF expression in tumor cells under different combinations of cytostatic and hormonal drugs. MATERIALS AND METHODS: 36 female Wistar rats, which underwent intraperitoneal transplantation of ascites OT (5*10(6) cells per animal), have been involved in the study. Rats were distributed into 4 groups (9 rats in each group): group 1 - animals, which received combination of cisplatin and triptorelin; group 2 - rats treated with combination of cisplatin and exemestane; group 3 - animals, which were administered with combination of cisplatin, triptorelin and exemestane; group 4 - rats, which received combination of triptorelin and exemestane. Histological study with assessment of treatment pathomorphosis in OT and immunohistochemical study have been carried out to analyze VEGF expression in OT cells. Survival of animals has been evaluated. RESULTS: Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly higher rates of treatment pathomorphosis (10.1 +/- 0.1% and 16.2 +/- 0.3%, respectively) and antiangiogenic activity in OT (21.4 +/- 1.4% and 15.0 +/- 1.3%, respectively), as well as the highest survival of animals (100.0 and 85.7%, respectively) as compared with the same in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured (22.2%), and among rats, which received cisplatin and exemestane, one animal (11.1%) was cured. CONCLUSIONS: Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the transplantable malignant ascites OT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination. PMID- 25804229 TI - Redox-regulation of gelatinases during growth of cisplatin-sensitive and resistant Guerin carcinoma. AB - Study was aimed to analyze the dynamics of changes and study interrelations between content of ferritin, transferrin, active gelatinases (MMP-2 and -9) in blood serum and tumor tissue, free iron, rate of superoxide radicals generation in tumor, activity of NADPH-oxidase and iNOS in neutrophils rats with sensitive and resistant strains of Guerin carcinoma (GC). MATERIALS AND METHODS: In order to obtain resistant tumor, 12 courses of cisplatin chemotherapy have been carried out on rats bearing GC. Levels of transferrin and free iron were determined by analysis of EPR spectra from computerized radiospectrometer EPR -RE-1307 at temperature of liquid nitrogen. Rate of superoxide radicals and nitric oxide generation in tumor and neutrophils of blood was determined by EPR using spin traps at room temperature. Content of ferritin in tumor homogenate and blood serum of rats with GC was determined by ELISA method using corresponding kits. Concentration of active forms of MMP-2 and -9 in obtained samples was determined using method of zymography. RESULTS: Unregulated generation of superoxide radicals and NO by mitochondria of tumor cells and NADPH-oxidase and iNOS neutrophils via oxidation of iron-containing proteins causes the accumulation of "free iron" complexes in blood and tumor tissue of rats able to evoke oxide induced damages of macromolecules. It has been shown that for resistant strain of carcinoma, as compared with sensitive one, significantly higher concentrations of active forms of MMP-2 and -9 in blood serum of rats are typical. Dynamics of gelatinases activity changes in tumor tissue corresponds in general with dynamics of changes in serum. In tumor tissue of rats the indices of gelatinases activity positively correlate with rate of superoxide radicals generation, content of "free iron" complexes, ferritin and activity of transferrin. Cytostatic agent increased levels of reactive oxygen species (ROS) and self-amplify rate of superoxide radicals generation. In turn, activation of MMPs via superoxide depending regulation allows tumor cells to facilitate migration, invasion and finally - formation of metastatic centers. Mentioned above tumor "oxide phenotype" determines high level of its aggressiveness and forms corresponding level of drug resistance. CONCLUSIONS: Thus, high levels of superoxide radicals oxidize transport proteins and form free iron pool. Iron ions, via Haber - Weiss mechanism, initiate generation of the hydroxyl radicals, which also enhance oxidation processes. PMID- 25804230 TI - Peculiarities of DNA damage caused by exogenous nitric oxide combined with fractionated low dose ionizing radiation in normal and tumor cells. AB - The aim of this study was to investigate the reaction of normal and tumor cells to genotoxic effect of widespread environmental factors - exogenous nitric oxides and ionizing radiation. METHODS: The animals were treated with NO (125 mg/m(3)) and low dose ionizing radiation (10 acute exposures with 0.1 Gy each). Genotoxicity was estimated in vivo in rats peripheral blood lymphocytes, bone marrow cells and tumor cells of Guerin carcinoma. DNA damages were assessed by alkaline single-cell gel electrophoresis. RESULTS: Exogenous nitric oxides as well as irradiation caused significant increase of DNA damage in all types of investigated cells. The genotoxic effect increased in the order: peripheral blood lymphocytes < bone marrow cells < Guerin carcinoma cells. The greatest genotoxic effect was registered in Guerin carcinoma cells on terminal phase of tumor growth in rats exposed to NO and low dose ionizing radiation. CONCLUSIONS: Long-term exposure to common environmental factors (exogenous nitric oxides and ionizing radiation) capable to induce DNA damage in different cells. Severity of the genotoxic effect depends on cell type and nature of impacting factors. NO caused more significant DNA damage than low dose ionizing radiation but the highest level of DNA damage was observed after their joint action. Obtained results confirm the real threat of cancer risk increase under combined action of common environmental factors of different nature. PMID- 25804231 TI - Polymorphism of DNA mismatch repair genes in endometrial cancer. AB - Endometrial cancer (EC) is the second most common malignancy associated with hereditary non-polyposis colorectal cancer (HNPCC) family. The development of HNPCC is associated with defects in DNA mismatch repair (MMR) pathway resulting in microsatellite instability (MSI). MSI is present in a greater number of EC than can be accounted for by inherited MMR mutations, therefore alternative mechanisms may underline defective MMR in EC, including polymorphic variation. AIM: We checked the association between EC occurrence and two polymorphisms of MMR genes: a 1032G>A (rs4987188) transition in the hMSH2 gene resulting in a Gly22Asp substitution and a -93G>A (rs1800734) transition in the promoter of the hMLH1 gene. MATERIAL AND METHODS: These polymorphisms were genotyped in DNA from peripheral blood lymphocytes of 100 EC patients and 100 age-matched women by restriction fragment length polymorphism PCR. RESULTS: A positive association (OR 4.18; 95% CI 2.23-7.84) was found for the G/A genotype of the -93G>A polymorphism of the hMLH1 gene and EC occurrence. On the ot-her hand, the A allele of this polymorphism was associated with decreased EC occurrence. The Gly/Gly genotype slightly increased the effect of the -93G>A-G/A genotype (OR 4.52; CI 2.41-8.49). Our results suggest that the -93G>A polymorphism of the hMLH1 gene singly and in combination with the Gly322Asp polymorphism of the hMSH2 gene may increase the risk of EC. PMID- 25804232 TI - CD8 and CD45RO T lymphocytes in bone marrow of gastric cancer patients: correlation with disseminated tumor cells and disease outcome. AB - AIM: To evaluate the association between the presence of CD8 and CD45RO T lymphocytes in bone marrow (BM), disseminated tumor cells (DTCs), tumor hypoxia and their impact on disease outcome. MATERIAL AND METHODS: 91 naive gastric cancer (GC) patients were enrolled into the study. DTCs, CD8- and CD45RO-positive T lymphocytes in BM were detected using immunocytochemistry. All patients were thoroughly informed about the study that was approved by the local ethics committee. Statistical analyses were done using NCSS2000/PASS2000 and Prism, version 4.03 software packages. RESULTS: It was detected that 80.5 and 81.3% of patients had CD8- and CD45RO-positive T cells in BM, respectively. When DTCs were detected in BM, the number of patients with CD8-and CD45RO-positive T cells in BM were 86.1 and 84.4%, respectively. It was also determined that the number of patients with DTCs in BM with categories M0 and M1 and with CD8- and CD45RO positive T cells in BM were 86.2 and 85.7%, 85.7 and 80.0%, respectively. The association between DTCs in BM and presence of CD8 and CD45RO T cells lymphocytes in BM was not found. At the same time it was shown the association between presence of CD8 and CD45RO T lymphocytes and survival. The presence of CD8- and CD45RO-positive T cells in BM were accompanied with significantly longer overall survival of patients compared to that of patients without CD8- and CD45RO positive T cells in BM. CONCLUSION: Patients with the presence of CD8- and CD45RO positive T cells in BM demonstrated better survival of GC patients than those with the absence of these cells in BM. It may be suggested that tumor cells in BM are controlled in a dormant state by T cells in BM, in particular by CD8-positive T cells. PMID- 25804233 TI - The role of cardiac biomarkers as predictors of trastuzumab cardiotoxicity in patients with breast cancer. AB - AIM: Identification of patient with increased risk of cardiotoxicity would allow not only prevention and early diagnosis of chemotherapy related cardiotoxicity but also administration of optimal dose and duration of chemotherapy. MATERIALS AND METHODS: Fifty-two women with HER2(+) breast cancer treated with trastuzumab were included in this study. Patients were prospectively followed with routine cardiac evaluation. Before and after administration of trastuzumab blood samples for NT-proBNP were also taken. RESULTS: The median age was 48.5 year (range: 26 74). Hypertension and obesity were two most common co-morbidities. The median duration application of trastuzumab was 52 weeks. During median 14.5 (3-33) months follow-up cardiac adverse events occurred in 5 (9.6%) patients and 2 out of 5 was grade III-IV heart failure. Both patients had preserved left ventricular ejection fraction and no symptom of heart failure before trastuzumab but older than 65 years old and had diabetes mellitus and obesity. High level of NT-proBNP (> 300 ng/ml) was observed in both patients and heart failure recovery was not observed. There was statistically significant difference regarding body mass index (p = 0.004) and diabetes mellitus (p = 0.002) between patients with and without cardiotoxicity. CONCLUSION: Although, cardiac biomarkers still cannot replace routine cardiac monitoring, natriuretic peptides may provide additional tool for detection of patients with high risk of cardiotoxicity and early detection of cardiotoxicity. PMID- 25804234 TI - SD44+/CD24- markers of cancer stem cells in patients with breast cancer of different molecular subtypes. AB - AIM: To determine frequency of tumors with immunohistochemical markers of cancer stem cells (CSC) CD44+/CD24- in patients with breast cancer (BC) of different molecular subtype and to evaluate their prognostic value. OBJECT: Surgical material of 132 patients with BC stage I-II, age from 23 to 75 years, mean age - 50.2 +/- 3.1 years was studied. METHODS: Clinical, immunohistochemical (expression CD44+/CD24-), morphological, statistical. RESULTS: BC is characterized by heterogeneity of molecular subtypes and expression of markers (CD44+/CD24-). Immunohistochemical study of expression of CSC markers in surgical material has detected their expression in 34 (25.4%) patients with BC of different molecular subtypes. The highest frequency of cells with expression of CSC marker was observed in patients with basal molecular subtype (44.8% patients). Most of BC patients with phenotype CD44+/CD24 had stage I of tumor process (34.3%). Statistical processing of data has showen that Yule colligation coefficient equaled 0.28 (r > 0.05) that argues poor correlation between stage of tumor process and number of tumors with positive expression of CSC markers. Statistical processing of data has showen high correlation between presence of cells with expression of CSC markers and metastases of BC in regional lymph nodes (Yule colligation coefficient equals 0.943; r < 0.5). Difference in overall survival of patients with BC of basal molecular subtype depending on expression of CSC CD44+/CD24- markers was detected. Survival of patients with basal BC was reliably higher at lack in tumors of cells with CSC markers CD44+/CD24- and, correspondingly, lower at presence of such cells (r < 0.05). In patients with BC of luminal (A and B), HER-2-positive subtypes, significant change in survival of patients depending on expression of CSC markers was not determined (r > 0.05). CONCLUSION: Significance of tumor cells with markers CD44+/CD24- within the limits of molecular subtype of BC may be additional criterion for advanced biological characteristic of BC, and in patients with BC of basal molecular subtype - for predictive evaluation of individual potential of tumor to aggressive clinical course. PMID- 25804235 TI - The immunophenotype of adult T acute lymphoblastic leukemia in Morocco. AB - BACKGROUND: There is paucity of detailed studies of adult T cell acute lymphoblastic leukemia (T-ALL) in developing countries reflecting the condition of these patients including clinical and biological features. OBJECTIVE: This study was carried out to analyze the immunophenotypic characteristics of 40 Moroccan patients with T-ALL and its association with biological and clinical features. PATIENTS AND METHODS: Between 2006 and 2009, 130 adult patients diagnosed with acute lymphoblastic leukemia (ALL) were immunophenotyped by 3 color flow cytometry using a panel of monoclonal antibodies. Cases presenting features of a T-lineage phenotype were subjected to detailed analysis including immunophenotypic, clinical and biological parameters. RESULTS: Proportion of T ALL among ALL Moroccan patients was 31.0%. Median age of patients was 28 years. Twenty-nine patients were females and 11 were males. 45.0% of patients (18/40) had features of immature T-ALL stages (pro-T and pre-T ALL), 30.0% (12/40) of CD1a+ cortical T-ALL stage and 25.0% (10/40) had a characteristic phenotype of medullary T-ALL. The frequencies of progenitor cell markers CD10, CD34 and TdT expression were 14.0; 57.5% and 50.0% respectively. The aberrant expression of B lineage associated antigen CD79a were positive in 20.5% of the cases and the aberrant expression of myeloid antigens CD13 and/or CD33 was found in 22 (55.0%) cases. No significant association was encountered between TdT, CD34 or myeloid antigens positivity and high risk features at presentation as age, sex, and white blood cells. However, myeloid antigens (CD13 and/or CD33) was significantly associated with T-cell maturation stages (p = 0.009). CONCLUSION: To the best of our knowledge, this is the first report from North Africa of immunophenotypic study on adult T-ALL. Our findings indicate that the proportion of T-ALL among ALL in Morocco is similar to that reported in others Mediterranean countries like France and Italy and that myeloid-associated antigens expression is frequently associated with immature immunophenotype. PMID- 25804236 TI - Functional activity of CD34-positive cells in chronic myeloid leukemia patients with different response to imatinib therapy. AB - INTRODUCTION: It is believed that the reason of the leukemic clone cell resistance to treatment with tyrosine kinase inhibitors during chronic myeloid leukemia (CML) is mutations in the genome of an early bone marrow progenitor cells that are CD34-positive. Such cells, regardless of treatment, acquire ability to proliferation and differentiation. This leads to the re-expansion of the CD34(+) cells. AIM: to determine the CD34 antigen expression in bone marrow and peripheral blood cells in CML patients with different response to imatinib therapy using the results of hematopoietic cells culturing and the data of flow cytometry. METHODS: Bone marrow aspirate from 39 patients who were treated with imatinib was studied with cytogenetic, flow cytometry and culture methods in vitro. RESULTS: In patients with an optimal response to imatinib therapy the number of colonies was 1.8 times lower than the number of those in the group of patients with a suboptimal response to therapy. In turn, in patients with failure of imatinib therapy the number of colonies was the highest and was 2.1 times higher than the patients with optimal response. The results of cytometric studies have shown that the number of CD34(+) cells in bone marrow was significantly higher compared to the number of CD34(+) cells in peripheral blood cells and increased with the acquisition of leukemic cells the resistance to imatinib. There was a direct correlation between the number of colonies and clusters in semisolid agar in vitro and the number of CD34(+) cells in the bone marrow of patients. CONCLUSIONS: The correlation between the number of CD34(+) cells and the number of cell aggregates in semisolid agar in vitro indicates the prognostic value of the method for determining CD34(+) cells in the patient bone marrow. The parallel increase of their number in the peripheral blood will allow developing express methods for the detection of individual patient response to imatinib therapy. PMID- 25804237 TI - Peripheral blood lymphocyte phenotype of ZAP-70+ and ZAP-70- patients with B-cell chronic lymphocytic leukaemia. AB - BACKGROUND: Up to now, the immune status of chronic lymphocytic leukemia (CLL) patients in association with the expression of zeta-chain-associated protein kinase 70 (ZAP-70) in leukemic cells has not been evaluated. AIM: The aim of this work was the study of the peripheral blood (PB) T-lymphocyte phenotypes in ZAP-70 positive (ZAP-70(+)) and ZAP-70-negative (ZAP-70(-)) untreated patients with CLL. MATERIALS AND METHODS: ZAP-70-, CD25-, CD3-, CD4-, and CD8-positive lymphocytes were enumerated by flow cytometry in PB of 120 untreated CLL patients. CD8+, CD3+CD4+ and CD3+CD25+ cells were counted for the non-leukemic lymphocytes. RESULTS: The patients were distributed into two groups: the ZAP-70(+) group of high CLL progression (n = 61), and the ZAP-70(-) group of low CLL progression (n = 59). In the ZAP-70(+) group, the ratio CD4/CD8 (0.33 +/- 0.62; p = 0.001) and the numbers of the CD3+ (34.8 +/- 8.1%; p = 0.01), CD3+CD4+ (24.4% +/- 4.8; p = 0.001), and CD3+CD25+ (6.2 +/- 0.91%; p = 0.001) lymphocytes were reduced and the percentage of the CD8+ cells (73.1 +/- 4.6%; p = 0.0001) was above the norm. In the ZAP-70(-) group, the number of the CD3+CD4+ cells (36.9 +/- 6.1%; p = 0.001) was within the norm, but the numbers of the CD8+ (11.3 +/- 1.1%; p = 0.0001) and CD3+ (41.2 +/- 5.3%; p = 0.05) lymphocytes were reduced; the ratio CD4/CD8 (3.26 +/- 0.88; p = 0.001) and the percentage of the CD3+CD25+ cells (27.1 +/- 3.4%; p = 0.0001) were above the norm. CONCLUSIONS: Our data show that the increased CD4/CD8 ratio, caused by the reduced number of the CD8+ lymphocytes, and the increased number of CD3+CD25+ cells are characteristic for the ZAP-70(-) group (slow progressing) of untreated CLL patients. In ZAP-70(+) patients, the CD4/CD8 ratio was significantly below the norm indicating an active disease process. Results of our study contribute to identification of CLL patients with different prognosis in routine diagnostic/prognostic procedures. PMID- 25804238 TI - Expression profiling of SCN8A and NDUFC2 genes in colorectal carcinoma. AB - AIM: The expression differences of SCN8A (which encodes type VIII alpha subunit of voltage gated sodium channel) and NDUFC2 (which encodes C2 subunit of Complex I enzyme in oxidative phosphorylation) genes were evaluated in paired colorectal cancer (CRC) tissues which was relied on our partial transcriptome analysis data in cancer cell lines. MATERIALS AND METHODS: A total of 62 paired tissues of CRC patients (34 male, 28 female) were included in the study. The mRNA levels of SCN8A and NDUFC2 genes were determined by using real-time PCR (qRT-PCR and semiquantitative PCR). RESULTS: SCN8A gene expression level was significantly lower in tumor tissues (p = 0.0128) and in the patients with the age below 45 years (p = 0.0049). There were also meaningful relationships between the gender, grade of CRC, tumor location, histopathological classification, and SCN8A expression. There was no NDUFC2 differential expression. However, the tumors taken from right colon had significantly lower NDUFC2 expression. CONCLUSION: Although the voltage gated sodium channels (VGSCs) and Complex I (CI) were associated to a number of diseases including different types of cancers, the different subunits of CI and individual members of VGSCs seem to be cancer type specific in varying proportions. PMID- 25804239 TI - Self-assembled multi-ring formations of glutamine and a possible link to erythema gyratum repens. AB - In the body L-glutamine is abundant and required for the proliferation of cells. Indeed human physiology is dependent upon having and maintaining the correct glutamine levels for a range of functions including neurological signalling and a healthy immune system. However, during tumourigenesis cell proliferation demands elevated levels of glutamine, which can ultimately lead to muscle atrophy. In some cases the skin provides the first indications of the underlying disease and erupts in a wave of complicated pattern formations. One such skin marker is erythema gyratum repens. We investigated the pattern formations associated with concentrations of glutamine in aqueous solutions at levels higher than that of a normal biological functionality. We find remarkable similarities between the patterns of erythema gyratum repens and the unusual self-assembled patterns of glutamine. The findings may lead to new therapeutics and understanding for those working in oncology and toxicology. Utilising the formations associated with glutamine could also assist in bio-functionalising micro and nanoparticles for high efficacy. PMID- 25804240 TI - Anti-herpesviral activity of curcumin may attenuate the development of Alzheimer's disease. PMID- 25804241 TI - Hierarchical Multinomial Modeling Approaches: An Application to Prospective Memory and Working Memory. AB - Hierarchical extensions of multinomial processing tree (MPT) models have been developed to deal with heterogeneity in participants or items. In this study, the beta-MPT model ( J. B. Smith & Batchelder, 2010 ) and the latent-trait approach ( Klauer, 2010 ) were used to estimate individual model parameters for prospective and retrospective components of prospective memory (PM), which requires remembering to perform an action in the future. The data from two experiments investigating the relationship between PM and working memory ( R. E. Smith & Bayen, 2005 , Experiment 1; R. E. Smith, Persyn, & Butler, 2011 ) were reanalyzed using the two hierarchical modeling approaches, both of which provide parameter estimates for individual participants. The results showed a positive correlation of the prospective component of PM with working-memory span and provide the first direct comparisons of the two hierarchical extensions of an MPT model. PMID- 25804242 TI - Distractor Locations Influence Multiple Object Tracking Beyond Interobject Spacing: Evidence From Equidistant Distractor Displacements. AB - Human observers are able to keep track of several independently moving objects among other objects. Within theories of multiple object tracking (MOT), distractors are assumed to influence tracking performance only by their distance toward the next target. In order to test this assumption, we designed a variant of the MOT paradigm that involved spatially arranged target-distractor pairs and sudden displacements of distractors during a brief flash. Critically, these displacements maintained target-distractor spacing. Our results show that displacing distractors hurts tracking performance (Experiment 1). Importantly, target-distractor confusions occur within target-distractor pairs with displaced distractors (Experiment 2). This displacement effect increases with an increasing displacement angle (Experiment 3) but is equal at different distances between target and distractor (Experiment 4). This finding illustrates that distractors influence tracking performance beyond pure interobject spacing. We discuss how inhibitory processes as well as relations between targets and distractors might interfere with target tracking. PMID- 25804243 TI - The Role of Shape in Semantic Memory Organization of Objects: An Experimental Study Using PI-Release. AB - Visual information contributes fundamentally to the process of object categorization. The present study investigated whether the degree of activation of visual information in this process is dependent on the contextual relevance of this information. We used the Proactive Interference (PI-release) paradigm. In four experiments, we manipulated the information by which objects could be categorized and subsequently be retrieved from memory. The pattern of PI-release showed that if objects could be stored and retrieved both by (non-perceptual) semantic and (perceptual) shape information, then shape information was overruled by semantic information. If, however, semantic information could not be (satisfactorily) used to store and retrieve objects, then objects were stored in memory in terms of their shape. The latter effect was found to be strongest for objects from identical semantic categories. PMID- 25804244 TI - Exploring the Boundaries of the Number-Temporal Order Association. AB - Past research has shown that numbers are associated with order in time such that performance in a numerical comparison task is enhanced when number pairs appear in ascending order, when the larger number follows the smaller one. This was found in the past for the integers 1-9 ( Ben-Meir, Ganor-Stern, & Tzelgov, 2013 ; Muller & Schwarz, 2008 ). In the present study we explored whether the advantage for processing numbers in ascending order exists also for fractions and negative numbers. The results demonstrate this advantage for fraction pairs and for integer-fraction pairs. However, the opposite advantage for descending order was found for negative numbers and for positive-negative number pairs. These findings are interpreted in the context of embodied cognition approaches and current theories on the mental representation of fractions and negative numbers. PMID- 25804245 TI - One-step duplex polymerase chain reaction for the detection of swinepox and vaccinia viruses in skin lesions of swine with poxvirus-related disease. AB - Infection of pigs with swinepox virus (SWPV) was reported in Brazil in 2011. SWPV causes a systemic pustular disease in pigs and the symptoms are clinically indistinguishable from those caused by vaccinia virus (VACV) infection. Pigs infected with VACV have been reported in various countries; however, VACV is endemic in Brazil, India and other countries, where it affects mainly dairy cows, dairy buffaloes and dairy workers causing localized pustules. The transmission of VACV to other susceptible hosts has also been detected in Brazil. Therefore, VACV should be investigated as a possible etiologic agent of pustular skin disorders in pigs. This work describes the development of a one-step duplex assay to detect swinepox and vaccinia viruses simultaneously in skin lesions of pigs with generalized pustular disease. The investigation of VACV infection in pigs is important in countries where this zoonosis is endemic and should be differentiated from SWPV infection. PMID- 25804247 TI - Saskatchewan movement disorders program. AB - We review the Saskatchewan Movement Disorders Program, which started in 1968 and has had the dual goals of patient care and research. The clinics are structured to collect research-worthy data including videos, longitudinal follow-up, and autopsy studies of patients seen in the clinics. At every clinic visit, the patient is evaluated by one or both authors. A total of 25% to 30% of the deceased come to autopsy. Frozen half-brain and formalin-fixed remnants from autopsy are preserved in our laboratories. Patients not seen in our clinic are not included in research, which makes it different from brain banks. So far, 515 cases have come to autopsy. So far, there have been 17 collaborating scientific teams from Canada, the United States, Europe, and Japan. The collaborators are not charged for access to our resources. This program offers a unique opportunity to study multiple aspects of movement disorder patients seen in clinical practice. PMID- 25804249 TI - Altered autonomic nervous system reactivity to pain in trigeminal neuralgia. AB - BACKGROUND: In the past two decades, there has been increasing evidence to suggest that trigeminal neuralgia (TN) may be linked to a dysfunction of the autonomic nervous system (ANS). The aim of the present study was to formally test this hypothesis by comparing the reactivity of the ANS to experimental pain in a population of TN patients and healthy controls. METHODS: Twelve patients diagnosed with classical TN and 12 healthy controls participated in the study. Cardiac activity was assessed while participants were instructed to rest and again during a cold pressor test (CPT). Heart rate variability analyses were performed off-line to obtain parasympathetic (high-frequency) and sympathetic (low-frequency) indices. RESULTS: At baseline, ANS measures did not differ between healthy controls and TN patients, and both groups showed a similar increase in heart rate during the CPT (all p values >0.05). However, TN patients showed a greater increase in cardiac sympathetic activity and a greater decrease in cardiac parasympathetic activity during CPT compared with healthy controls (all p values <0.05). Importantly, changes in sympathetic reactivity, from baseline to CPT, were negatively associated with the number of pain paroxysms experienced each day by TN patients in the preceding week (r=-.58, p<0.05). CONCLUSIONS: These results suggest that TN, like many other short-lasting, unilateral facial pain conditions, is linked to ANS alterations. Future studies are required to determine if the altered ANS response observed in TN patients is a cause or a consequence of TN pain. PMID- 25804250 TI - A survey of the use of empiric novel anticoagulants during investigation of stroke. PMID- 25804248 TI - Canadian perspectives on the clinical actionability of neuroimaging in disorders of consciousness. AB - BACKGROUND: Acquired brain injury is a critical public health and socioeconomic problem in Canada, leaving many patients in vegetative, minimally conscious, or locked-in states, unresponsive and unable to communicate. Recent advances in neuroimaging research have demonstrated residual consciousness in a few exemplary patients with acquired brain injury, suggesting potential misdiagnosis and changes in prognosis. Such progress, in parallel with research using multimodal brain imaging technologies in recent years, has promising implications for clinical translation, notwithstanding the many challenges that impact health care and policy development. This study explored the perspectives of Canadian professionals with expertise either in neuroimaging research, disorders of consciousness, or both, on the potential clinical applications and implications of imaging technology. METHODS: Twenty-two professionals from designated communities of neuroimaging researchers, ethicists, lawyers, and practitioners participated in semistructured interviews. Data were analyzed for emergent themes. RESULTS: The five most dominant themes were: (1) validation and calibration of the methods; (2) informed consent; (3) burdens on the health care system; (4) implications for the Canadian health care system; and (5) possibilities for improved prognosis. CONCLUSIONS: Movement of neuroimaging from research into clinical care for acquired brain injury will require careful consideration of legal and ethical issues alongside research reliability, responsible distribution of health care resources, and the interaction of technological capabilities with patient outcome. PMID- 25804251 TI - Preparation of Inulin Powder from Jerusalem Artichoke (Helianthus tuberosus L.) Tuber. AB - The complete procedure for the production of inulin powder from Jerusalem artichoke tubers (JAT) was investigated. The procedure consists of isolation of inulin from JAT, elimination of color from the inulin extract and solidification. Washed tubers were first sliced, dried in a 60 degrees C oven for 10 h and then milled and sieved into a powder. Inulin was isolated from the JAT powder by hot water extraction using an accelerated solvent extractor (ASE). The effects of temperature and time for the extraction were investigated. The highest extraction efficiency was obtained at the extraction temperature of 80 degrees C for 20 min. The color of the extract was eliminated using ion exchange process with diethylaminoethyl cellulose as the sorbent. The inulin powder was subsequently obtained by freeze drying. Inulin content and inulin profiles were monitored to evaluate the efficiencies of the complete procedure. The inulin content was indirectly determined by spectrophotometry from free and total fructose measurements using potassium iodide. The inulin profile was monitored using high performance anion exchange chromatography equipped with integrated pulse amperometric detection (HPAEC-PAD). The proposed method provided the inulin production yield of 92.5%. The present procedure is fast, simple and effective for production of inulin powder from JAT. In addition, infrared spectra and some physico-chemical properties of the obtained inulin powder were determined and compared with the standard inulin. PMID- 25804252 TI - Bioactive carbazole alkaloids from the stems of Clausena lansium. AB - Seven new carbazole alkaloids, claulansines L-R (1-7), and six known analogues (8 13) were isolated from the stems of Clausena lansium. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, and NMR experiments (HSQC, HMBC, and NOE experiment). Compound 7 showed moderate anti inflammatory activities. Compounds 3, 5, 6, 8, and 12 exhibited moderate hepatoprotective activities. PMID- 25804253 TI - Variation of anatomical structures related to biventricular pacing procedures and cannulation of the coronary sinus. AB - The success of biventricular pacing procedures is at least partially related to the ability to implant leads into the heart. Lead placement into the coronary sinus can be particularly challenging because of variations in the coronary venous anatomy. We examined the anatomy of the coronary sinus and the Thebesian valve. Forty-three (22 male, 21 female) embalmed adult cadavers were used to determine the internal diameter of the coronary sinus ostium, the presence of a membranous or fenestrated Thebesian valve, and the percent occlusion of the coronary sinus ostium by the Thebesian valve, if present. An 8-French (F) guiding catheter was used to simulate coronary sinus cannulation. The average internal diameter of the coronary sinus ostium was 11.44 +/- 3.21 mm. A Thebesian valve was present in 74 % of the cadavers, and the majority (84 %) of those valves were membranous. In the presence of a Thebesian valve, the opening at the ostium was reduced to 7.47 +/- 2.69 mm. The percent occlusion of the coronary sinus ostium by the Thebesian valve varied from 8.26 to 100 %. The average cannulation distance (length of catheter travel into the coronary sinus from the coronary sinus ostium) was 69 +/- 18 mm. Statistical analyses revealed no gender differences in the measurement data for either the coronary sinus or Thebesian valve. The most common presentation is a membranous Thebesian valve. Most frequently, the percent occlusion ranged between 41 and 50 %. The cannulation distance was greater in males than in females. PMID- 25804254 TI - Oral tacrolimus treatment of pruritus in prurigo nodularis. PMID- 25804255 TI - Angiomatoid fibrous histiocytoma: comparison of fluorescence in situ hybridization and reverse transcription polymerase chain reaction as adjunct diagnostic modalities. AB - Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the extremities of children and young adults. Although it has characteristic histologic features of a lymphoid cuff surrounding nodules of ovoid cells with blood-filled cystic cavities, diagnosis is often difficult due to its morphologic heterogeneity and lack of specific immunoprofile. Angiomatoid fibrous histiocytoma is associated with recurrent chromosomal translocations, leading to characteristic EWSR1-CREB1, EWSR1-ATF1, and, rarely, FUS-ATF1 gene fusions; fluorescence in situ hybridization (FISH), detecting EWSR1 or FUS rearrangements, and reverse transcription-polymerase chain reaction (RT-PCR) for EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts have become routine ancillary tools. We present a large comparative series of FISH and RT-PCR for AFH. Seventeen neoplasms (from 16 patients) histologically diagnosed as AFH were assessed for EWSR1 rearrangements or EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts. All 17 were positive for either FISH or RT-PCR or both. Of 16, 14 (87.5%) had detectable EWSR1-CREB1 or EWSR1 ATF1 fusion transcripts by RT-PCR, whereas 13 (76.5%) of 17 had positive EWSR1 rearrangement with FISH. All 13 of 13 non-AFH control neoplasms failed to show EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts, whereas EWSR1 rearrangement was present in 2 of these 13 cases (which were histopathologically myoepithelial neoplasms). This study shows that EWSR1-CREB1 or EWSR1-ATF1 fusions predominate in AFH (supporting previous reports that FUS rearrangement is rare in AFH) and that RT-PCR has a comparable detection rate to FISH for AFH. Importantly, cases of AFH can be missed if RT-PCR is not performed in conjunction with FISH, and RT PCR has the added advantage of specificity, which is crucial, as EWSR1 rearrangements are present in a variety of neoplasms in the histologic differential diagnosis of AFH, that differ in behavior and treatment. PMID- 25804256 TI - Cytomorphologic features and ultrasonographic characteristics of thyroid nodules with Hurthle cells. AB - This study was designed to evaluate the ultrasonographic and histopathologic features of nodules composed predominantly of Hurthle cells detected during cytological examination. Fifty-seven patients with thyroid nodules composed predominantly of Hurthle cells on fine needle aspiration cytology were retrospectively analyzed. Patients were evaluated by thyroid ultrasonography (US), and biopsy samples taken by US-guided fine needle aspiration cytology were assessed histopathologically. There were 57 patients and 57 nodules with Hurthle cells in cytological examination; 49 (86%) were classified as Bethesda 1, and 8 (14%) were classified as Bethesda 3. Histopathologically, 45 (78.9%) nodules were benign and 12 (21.1%) were malignant. Nuclear groove, transgressing blood vessel, and absence of colloid were observed with a higher frequency in malignant nodules compared to benign nodules (P < .05). There were no specific morphological features (nodule echogenity, presence of microcalsification, presence of cystic areas, absence of halo, margin irregularity, and increased blood flow) predicting malignancy in the US evaluation of nodules including Hurthle cells. Nuclear groove, transgressing blood vessel, and absence of colloid on cytomorphological evaluation are indicative of malignancy in nodules containing Hurthle cells. PMID- 25804258 TI - Six proud years: building a solid foundation to advance applied materials science and interfaces research. PMID- 25804259 TI - First detection of Macrorhabdus ornithogaster in wild Eurasian Siskins (Carduelis spinus) in Germany. A case study. AB - OBJECTIVE: The colonization of the gastric ascomycetous yeast Macrorhabdus (M.) ornithogaster could be associated with a chronic wasting disease in several bird species in captivity. The prevalence and clinical relevance of M. ornithogaster in wild birds is unknown in detail. MATERIAL AND METHODS: In the wintering season 2012/13 injured Eurasian Siskins (Carduelis spinus, n = 8) from the area of Hannover, Lower Saxony, Germany were examined microbiologically and pathologically. RESULTS: In six out of eight injured Eurasian Siskins M. ornithogaster were detected. The yeast was diagnosed microscopically in wet smears from the gastric isthmus and/or in faecal samples. Histopathological examination (n = 4) of the macroscopically slightly enlarged proventriculus in infected birds demonstrated the growth of M. ornithogaster in the mucosal surface and in the ducts of the glands without an inflammatory reaction. As a possible sign of a lowered fitness, all six infected siskins had a reduced body weight (mean: 11.8 +/- 1.64 g) in the lower normal weight range compared to the two injured Eurasian Siskins without M. ornithogaster (15.0 g) as well as to data from the literature. Concurrent intestinal bacterial infections comprised Escherichia coli, Clostridium perfringens or Salmonella Typhimurium, that are regarded as an abnormal bacterial flora for Eurasian Siskins. CONCLUSION AND CLINICAL RELEVANCE: Infections with M. ornithogaster can be found in the wild population of Eurasian Siskins in Germany. The frequent occurrence of secondary bacterial infections associated with M. ornithogaster infections should be considered in the treatment and rehabilitation of finches. PMID- 25804257 TI - Nanoscale electron transport measurements of immobilized cytochrome P450 proteins. AB - Gold nanopillars, functionalized with an organic self-assembled monolayer, can be used to measure the electrical conductance properties of immobilized proteins without aggregation. Measurements of the conductance of nanopillars with cytochrome P450 2C9 (CYP2C9) proteins using conducting probe atomic force microscopy demonstrate that a correlation exists between the energy barrier height between hopping sites and CYP2C9 metabolic activity. Measurements performed as a function of tip force indicate that, when subjected to a large force, the protein is more stable in the presence of a substrate. This agrees with the hypothesis that substrate entry into the active site helps to stabilize the enzyme. The relative distance between hopping sites also increases with increasing force, possibly because protein functional groups responsible for electron transport (ETp) depend on the structure of the protein. The inhibitor sulfaphenazole, in addition to the previously studied aniline, increased the barrier height for electron transfer and thereby makes CYP2C9 reduction more difficult and inhibits metabolism. This suggests that P450 Type II binders may decrease the ease of ETp processes in the enzyme, in addition to occupying the active site. PMID- 25804260 TI - QCT/FEA predictions of femoral stiffness are strongly affected by boundary condition modeling. AB - Quantitative computed tomography-based finite element models of proximal femora must be validated with cadaveric experiments before using them to assess fracture risk in osteoporotic patients. During validation, it is essential to carefully assess whether the boundary condition (BC) modeling matches the experimental conditions. This study evaluated proximal femur stiffness results predicted by six different BC methods on a sample of 30 cadaveric femora and compared the predictions with experimental data. The average stiffness varied by 280% among the six BCs. Compared with experimental data, the predictions ranged from overestimating the average stiffness by 65% to underestimating it by 41%. In addition, we found that the BC that distributed the load to the contact surfaces similar to the expected contact mechanics predictions had the best agreement with experimental stiffness. We concluded that BC modeling introduced large variations in proximal femora stiffness predictions. PMID- 25804261 TI - The prevalence of premature loss of primary teeth and its impact on malocclusion in the Eastern Province of Saudi Arabia. AB - OBJECTIVES: The present study was designed to determine the prevalence of premature loss of primary teeth and its effect on malocclusion in Eastern Province, Saudi Arabia. MATERIALS AND METHODS: This is an observational, cross sectional study that included 307 male children aged 9-11 years old. Clinical examinations were performed using a disposable sharp explorer, a UNC periodontal probe and a dental mirror. The samples were examined clinically to detect the following traits: Angle's classification of malocclusion, overjet, overbite, anterior open-bite, lateral open-bite, midline shift and cross-bite. Additionally, a dental caries examination was performed using WHO methods. Questionnaires in Arabic were coded and sent to the students' parents. RESULTS: The mean DMFT was 5.61 (SD = 3.01). The d-component was the highest, with a mean of 4 (SD = 2.83). Of the 307 children, it was found that 204 (66.4%) had a high DMFT score, which is defined as a score above 4. It was found that 156/307 (51%) children had premature loss of deciduous teeth. CONCLUSION: A high prevalence of premature loss of teeth was found in this study. This finding emphasizes the importance of increasing awareness levels about this issue and focuses attention on the need for more preventive efforts to maintain healthy and normal dentitions that would improve the masticatory function and aesthetics of individuals and the whole population. In addition, the findings emphasize the importance of the early detection of premature loss of primary teeth to prevent future malocclusion. PMID- 25804262 TI - Augmentation of cardiac sympathetic tone by percutaneous low-level stellate ganglion stimulation in humans: a feasibility study. AB - Modulation of human cardiac mechanical and electrophysiologic function by direct stellate ganglion stimulation has not been performed. Our aim was to assess the effect of low-level left stellate ganglion (LSG) stimulation (SGS) on arrhythmias, hemodynamic, and cardiac electrophysiological indices. Patients undergoing ablation procedures for arrhythmias were recruited for SGS. A stimulating electrode was placed next to the LSG under fluoroscopy and ultrasound imaging; and SGS (5-10 Hz, 10-20 mA) was performed. We measured hemodynamic, intracardiac and ECG parameters, and activation recovery intervals (ARIs) (surrogate for action potential duration) from a duodecapolar catheter in the right ventricular outflow tract. Five patients underwent SGS (3 males, 45 +/- 20 years). Stimulating catheter placement was successful, and without complication in all patients. SGS did not change heart rate, but increased mean arterial blood pressure (78 +/- 3 mmHg to 98 +/- 5 mmHg, P < 0.001) and dP/dt max (1148 +/- 244 mmHg/sec to 1645 +/- 493 mmHg/sec, P = 0.03). SGS shortened mean ARI from 304 +/- 23 msec to 283 +/- 17 msec (P < 0.001), although one patient required parasympathetic blockade. Dispersion of repolarization (DOR) increased in four patients and decreased in one, consistent with animal models. QT interval, T-wave duration and amplitude at baseline and with SGS were 415 +/- 15 msec versus 399 +/- 15 msec (P < 0.001); 201 +/- 12 msec versus 230 +/- 28 msec; and 0.2 +/- 0.09 mV versus 0.22 +/- 0.08 mV, respectively. At the level of SGS performed, no increase in arrhythmias was seen. Percutaneous low-level SGS shortens ARI in the RVOT, and increases blood pressure and LV contractility. These observations demonstrate feasibility of percutaneous SGS in humans. PMID- 25804263 TI - Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an "obesogenic" diet. AB - Obesity and related comorbidities are becoming increasingly prevalent globally. In mice preconception paternal exposure to a high fat diet (HFD) impairs the metabolic and reproductive health of male offspring, despite their control diet (CD) consumption. However, offspring share lifestyle, including diet, with parents. We assessed if male offspring from HFD fathers have a heightened susceptibility to HFD-induced metabolic and reproductive derangements. This 2 * 2 design saw founder males (F0) and their offspring (F1) fed either a HFD or a nutritionally matched CD. Regardless of paternal diet, HFD fed male offspring had greater total body weight and adiposity. Offspring sired by a HFD male and fed a HFD were the heaviest, had the greatest adiposity and had the greatest concentration of serum cholesterol, triglyceride, HDL, and NEFA compared with CD sired/fed littermates. A synergistic increase in serum insulin was unmasked by both father/son HFD consumption, concomitant with increased sera glucose. Either a paternal or offspring HFD was associated with similar reductions to offspring sperm motility. Whereas sperm ROS concentrations and sperm-oocyte binding saw detrimental effects of both F0 HFD and F1 HFD with an interaction evident between both, culminating in the most impaired sperm parameters in this group. This indicates that metabolic and fertility disturbances in male offspring sired by HFD fathers are exacerbated by a "second-hit" of exposure to the same obesogenic environment postnatally. If translatable to human health, this suggests that adverse reproductive and metabolic outcomes may be amplified across generations through a shared calorie dense diet, relevant to the current worldwide obesity epidemic. PMID- 25804264 TI - Effect of pregnancy on the uterine vasoconstrictor response to exercise in rats. AB - A major maternal adaptation in pregnancy is the large increase in uteroplacental blood flow that supplies the growing fetus with oxygen and nutrients. The impact of gestation on the dynamic uterine vasoconstrictor response to exercise in the rat, a common model for pathophysiological disorders in pregnancy remains unknown. We hypothesized that rats exhibit a robust uterine vasoconstrictor response to acute exercise that is attenuated in late pregnancy. Pregnant (P, N = 12) and nonpregnant (NP, N = 8) rats were instrumented chronically with a ultrasonic transit-time flowprobe and carotid arterial catheter to directly measure uterine artery blood flow (UtBF) and blood pressure (BP), respectively, at day 20 of gestation for 5 min of treadmill exercise (7 m/min; 6% grade). Preexercise UtBF [P, 2.1 (SD1.6) vs. NP, 0.5 (SD0.3) mL/min P < 0.01) and uterine artery conductance (UtC) [P, 2.1(SD1.7) vs. NP, 0.4 (SD0.2) mL/min * mmHg(-1) * 10(-2), P < 0.01] were higher in pregnant rats, whereas preexercise BP was lower in the pregnant rats [P, 111 (SD13) vs. NP, 126 (SD13) mmHg, P = 0.02]. Preexercise heart rate was similar [P, 457 (SD30) vs. NP, 454 (SD42), P = 0.3]. Exercise initiated rapid and sustained decreases in UtBF [Delta-47% (SD12)] and UtC [Delta-49% (SD12)] that were attenuated in the pregnant rats [UtBF, Delta-25% (SD20) and UtC, Delta-30% (SD20), P = 0.02]. The BP and heart rate responses to exercise were unaffected in late pregnancy (interaction term, P = 0.3). In rats, dynamic exercise induces a uterine vasoconstrictor response that is blunted during late gestation, a response that we observed previously in pregnant rabbits. PMID- 25804265 TI - Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury. AB - Neonatal seizures have been associated with cerebrovascular endothelial injury and neurological disabilities. In a piglet model, the long-term loss of endothelial regulation of cerebral blood flow coincides with the surge of brain derived circulating endothelial cells (BCECs) in blood. We hypothesized that BCECs could serve as a noninvasive biomarker of cerebrovascular injury in neonates with seizures. In a prospective pilot feasibility study, we enrolled newborn infants with confirmed diagnoses of perinatal asphyxia and intraventricular hemorrhage (IVH); both are commonly associated with seizures. Infants without clinical evidence of cerebrovascular injuries were representative of the control group. BCECs were detected in the CD45-negative fraction of peripheral blood mononuclear cells by coexpression of CD31 (common endothelial antigen) and GLUT1 (blood-brain barrier antigen) via automated flow cytometry method. In Infants with asphyxia (n = 12) and those with IVH grade III/IV (n = 5), the BCEC levels were 9.9 +/- 0.9% and 19.0 +/- 2.0%, respectively. These levels were significantly higher than the control group (n = 27), 0.9 +/- 0.2%, P < 0.001. BCECs in infants with cerebrovascular insults with documented clinical seizures (n = 10; 16.8 +/- 1.3%) were significantly higher than infants with cerebrovascular insults with subclinical or no seizures (n = 7; 9.5 +/- 1.2%); P < 0.001. BCEC levels decreased with seizure control. BCECs levels were elevated in infants with seizures caused by severe IVH and perinatal asphyxia. We suggest that monitoring BCEC levels in peripheral blood can potentially offer a biological marker that reflects cerebrovascular insult and recovery. Further studies with a larger number of patients are required to support these findings. PMID- 25804267 TI - Women who take n-3 long-chain polyunsaturated fatty acid supplements during pregnancy and lactation meet the recommended intake. AB - The aim of the current study was to estimate total intake and dietary sources of eicosapentaenoic acid (EPA), docosapentanoic (DPA), and docosahexaenoic acid (DHA) and compare DHA intakes with the recommended intakes in a cohort of pregnant and lactating women. Twenty-four-hour dietary recalls and supplement intake questionnaires were collected from 600 women in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort at each trimester of pregnancy and 3 months postpartum. Dietary intake was estimated in 2 ways: by using a commercial software program and by using a database created for APrON. Only 27% of women during pregnancy and 25% at 3 months postpartum met the current European Union (EU) consensus recommendation for DHA. Seafood, fish, and seaweed products contributed to 79% of overall n-3 long-chain polyunsaturated fatty acids intake from foods, with the majority from salmon. The estimated intake of DHA and EPA was similar between databases, but the estimated DPA intake was 20%-30% higher using the comprehensive database built for this study. Women who took a supplement containing DHA were 10.6 and 11.1 times more likely to meet the current EU consensus recommendation for pregnancy (95% confidence interval (CI): 6.952-16.07; P<0.001) and postpartum (95% CI: 6.803-18.14; P<0.001), respectively. Our results suggest that the majority of women in the cohort were not meeting the EU recommendation for DHA during pregnancy and lactation, but taking a supplement significantly improved the likelihood that they would meet recommendations. PMID- 25804266 TI - Hyperglycemia abolishes the protective effect of ischemic preconditioning in glomerular endothelial cells in vitro. AB - In preclinical investigations, ischemic preconditioning (IPC) protects kidneys from ischemia/reperfusion injury. The direct effects of IPC on glomerular endothelial cells have not been studied in detail. Most investigations of IPC have focused on healthy cells and animals, and it remains unknown whether IPC is renoprotective in the setting of medical comorbidities such as diabetes. In this study, we determined the preventive potential of IPC in healthy glomerular endothelial cell monolayers, and compared these results to monolayers cultured under hyperglycemic conditions. We exposed glomerular endothelial monolayers to 1 h of IPC 24 h prior to oxygen-glucose deprivation (OGD), an in vitro model of ischemia/reperfusion injury. Glomerular endothelial monolayer integrity was assessed by measuring transendothelial electrical resistance, albumin flux, and cell survival. We found that IPC protected healthy but not hyperglycemic glomerular endothelial monolayers from ischemia/reperfusion injury. Furthermore, not only was the protective effect of IPC lost in the setting of hyperglycemia, but IPC was actually deleterious to the integrity of hyperglycemic glomerular endothelial cell monolayers. PMID- 25804268 TI - Omega-3 fatty acids in the management of autism spectrum disorders: findings from an open-label pilot study in Singapore. AB - The goal of this open-label trial was to examine the efficacy and safety of a 12 week omega-3 fatty acids supplementation among children suffering with Autism Spectrum Disorders (ASD). A total of 41 children and adolescents aged 7-18 years (36 boys, 5 girls; mean age = 11.66, s.d. = 3.05) diagnosed with ASD participated in the study. At post-treatment, participants showed significant improvements on all subscales of the Social Responsiveness Scale (P < 0.01) and the Social and Attention Problems syndrome scales of the Child Behavior Checklist (P < 0.05). Blood fatty acid levels were significantly correlated with changes in the core symptoms of ASD. Baseline levels of blood fatty acid levels were also predictive of response to the omega-3 treatment. Omega-3 fatty acids supplementation was well-tolerated and did not cause any serious side effects. Our findings lend some preliminary support for the use of omega-3 fatty acids supplementation in addressing ASD. Future randomized controlled trials of omega-3 fatty acids in ASD with blood fatty acid measurements with a larger sample and longer follow-up period is warranted. PMID- 25804269 TI - Dietary sodium intake and prediction of cardiovascular events. AB - BACKGROUND/OBJECTIVES: The association of dietary sodium and cardiovascular disease (CVD), as well as the reduction of sodium intake in the prevention of CVD, has been under debate. To study whether sodium consumption has a role as a risk factor for fatal and non-fatal CVD. SUBJECTS/METHODS: A well-defined population-based cohort of 1045 subjects collected between 1991 and 1993 (mean age 51.4 years) was used with approximately 19 years' follow-up. At the baseline, 716 subjects filled in a 1-week food follow-up diary, which was used to calculate the daily sodium intake (mg/1000 kcal). RESULTS: The baseline sodium intake correlated significantly with age (rs=0.117, P=0.002), BMI (rs=0.216, P=0.000), waist circumference (rs=0.268, P=0.000), smoking (rs=0.144, P=0.000), alcohol consumption (rs=0.111, P=0.003), systolic blood pressure (rs=0.106, P=0.005) and low-density lipoprotein (LDL) cholesterol (rs=0.081, P=0.033). Those who had cardiovascular events in the follow-up consumed more sodium at the baseline (mean 2010.4 mg/1000 kcal/day, s.d. 435.2, n=101) compared with the subjects without events (mean 1849.9 mg/1000 kcal/day, s.d. 361.2, n=589; t-test; P=0.001). The incidence of cardiovascular events was greater in the highest quartile (22.1%) than in the lower quartiles (first 11.0%, second 9.9% and third 15.6%; X(2); P=0.005). Cox regression analysis showed that sodium intake as a continuous variable predicts CVD events (P=0.031) independently when age, sex, smoking, alcohol consumption, systolic blood pressure, LDL cholesterol and waist circumference were added as covariates. This predictive role is seen especially in the group of subjects on hypertensive medication (P=0.001). CONCLUSIONS: Dietary sodium intake is a significant independent predictor of cardiovascular events in the study population. PMID- 25804270 TI - Energy intake adaptations to acute isoenergetic active video games and exercise are similar in obese adolescents. AB - BACKGROUND/OBJECTIVES: Although the impact of passive video games (PVGs) on energy intake has been previously explored in lean adolescents, data are missing on the nutritional adaptations to passive and active video games (AVGs) in obese adolescents. It is also unknown whether isoenergetic AVGs and exercise (EX) differently affect food consumption in youth. SUBJECTS/METHODS: Nineteen obese adolescent boys (12-15 years old) had to complete four 1-hour sessions in a crossover manner: control (CON; sitting on a chair), PVG (boxing game on Xbox 360), AVG (boxing game on Xbox Kinect 360) and EX (cycling). The EX was calibrated to generate the same energy expenditure as the AVG session. Energy expenditure was measured using a K4b2 portable indirect calorimeter. Ad libitum food intake (buffet-style meal) and appetite sensations (visual analogue scales) were assessed after the sessions. RESULTS: As expected, mean energy expenditure was similar between AVG (370+/-4 kcal) and EX (358+/-3 kcal), both of which were significantly higher than PVG (125+/-7 kcal) and CON (98+/-5 kcal) (P<0.001). However, ad libitum food intake after the sessions was not significantly different between CON (1174+/-282 kcal), PVG (1124+/-281 kcal), AVG (1098+/-265 kcal) and EX (1091+/-290 kcal). Likewise, the energy derived from fat, carbohydrate and protein was not significantly different between sessions, and appetite sensations were not affected. CONCLUSIONS: Energy intake and food preferences after an hour of AVG or PVG playing remain unchanged, and isoenergetic sessions of AVG and EX at moderate intensity induce similar nutritional responses in obese adolescent boys. PMID- 25804271 TI - Appraising nutrient availability of household food supplies using Block Dietary Screeners for individuals. AB - BACKGROUND/OBJECTIVE: The growing interest in environmental influences on obesity risk has spawned the development of tools for appraising home food availability. These tools reveal good reliability but tend to be limited in scope and burdensome to use. This cross-sectional study investigated the feasibility of using food categories and scoring algorithms from valid food frequency questionnaires for individuals (that is, Block Dietary Fat and Fruit-Vegetable Fiber Screeners) to estimate nutrient availability in household food supplies. SUBJECTS/METHODS: Screeners were compared with household food inventories from 100 two-parent families with ?1 children ?12 years of age. Inventoried foods were coded to match Screener food groups, and amounts available were converted to total adult daily equivalent servings to express the greatest possible frequency at which each food group could be eaten/day/household. Scoring algorithms were converted to express all scores on a per-day basis. For the most conservative assessment, the highest point was used for day ranges for the Fruit-Vegetable Fiber Screener and the lowest range point was used for the Fat Screener. RESULTS: Spearman's rank-order correlations (r?0.76) showed that the Fruit-Vegetable-Fiber Screener ranked households well for fruit/vegetable servings, vitamin C and dietary fiber. The Fat Screener and household inventory were positively correlated (r?0.58) for total fat, saturated fat and cholesterol. Concordance of household inventories and the Fruit-Vegetable-Fiber Screener, as determined by kappa with quadratic weighting, were strong and significant. Fat Screener concordance was moderate. CONCLUSIONS: Results indicate that it is feasible to use the efficient, valid Block Dietary Screeners for individuals to appraise household food supplies. PMID- 25804272 TI - Socio-demographic correlates and trends in low-calorie sweetener use among adults in the United States from 1999 to 2008. AB - BACKGROUND/OBJECTIVES: Replacing added sugars in beverages and foods with low calorie sweeteners (LCSs) is one strategy to reduce calories and manage body weight. There are few studies on LCS consumption by product category and by consumer socio-demographic status. SUBJECTS/METHODS: Data for a representative sample of 22 231 adults were obtained from five cycles of the National Health and Nutrition Examination Survey (1999-2008 NHANES). A single 24-h recall was used to identify consumers of LCS beverages, foods and tabletop sweeteners. Time-trend analyses were conducted for total LCS consumption and for LCS beverages. RESULTS: Approximately 30% of US adults consumed some type of LCS, with 19.5% consuming LCS beverages, 11.4% consuming tabletop LCS and 4.6% consuming LCS foods. LCS consumption by product category peaked at different ages, with older adults more likely to consume tabletop LCS and LCS foods. In age-adjusted analyses, LCS consumers in every product category were more likely to be women, 45-65 years old, non-Hispanic whites, US-born adults, college graduates and with higher household incomes. Predictors of LCS consumption were not altered upon adjustment for body mass index and diabetes status. LCS consumption from all sources and from LCS beverages increased between 1999 and 2008. CONCLUSIONS: LCS use was more common among populations with a lower burden of obesity and related chronic disease, specifically, non-Hispanic whites and those with more education/higher incomes. The reasons for this observed paradox are complex and merit additional research. PMID- 25804273 TI - Inter- and intraindividual correlations of background abundances of (2)H, (18)O and (17)O in human urine and implications for DLW measurements. AB - BACKGROUND/OBJECTIVES: The method of choice for measuring total energy expenditure in free-living individuals is the doubly labeled water (DLW) method. This experiment examined the behavior of natural background isotope abundance fluctuations within and between individuals over time to assess possible methods of accounting for variations in the background isotope abundances to potentially improve the precision of the DLW measurement. SUBJECTS/METHODS: In this work, we measured natural background variations in (2)H, (18)O and (17)O in water from urine samples collected from 40 human subjects who resided in the same geographical area. Each subject provided a urine sample for 30 consecutive days. Isotopic abundances in the samples were measured using Off-Axis Integrated Cavity Output Spectroscopy. RESULTS: Autocorrelation analyses demonstrated that the background isotopes in a given individual were not temporally correlated over the time scales of typical DLW studies. Using samples obtained from different individuals on the same calendar day, cross-correlation analyses demonstrated that the background variations of different individuals were not correlated in time. However, the measured ratios of the three isotopes (2)H, (18)O and (17)O were highly correlated (R(2)=0.89-0.96). CONCLUSIONS: Although neither specific timing of DLW water studies nor intraindividual comparisons were found to be avenues for reducing the impact of background isotope abundance fluctuations on DLW studies, strong inter-isotope correlations within an individual confirm that use of a dosing ratio of 80/00:10/00 (0.6 p.p.m.: p.p.m.) optimizes DLW precision. Theoretical implications for the possible use of (17)O measurements within a DLW study require further study. PMID- 25804274 TI - Coffee but not green tea consumption is associated with prevalence and severity of hepatic steatosis: the impact on leptin level. AB - BACKGROUND/OBJECTIVES: Most of the studies that have investigated the association between coffee consumption and hepatic steatosis have been experimental and small scale clinical studies. As a result, epidemiological studies are scarce. To clear the association, we conducted a cross-sectional study and investigated the effects of coffee consumption with those of green tea consumption. SUBJECTS/METHODS: We analyzed 1024 Japanese male workers. The diagnosis of hepatic steatosis was based on ultrasonography. We divided coffee and green tea consumption into the following three categories: non-drinker; 1-2 cups/day and ?3 cups/day. To investigate the association between hepatic steatosis and coffee or green tea consumption, we calculated the odds ratio (OR) and adjusted the means of leptin levels on each severity of hepatic steatosis. RESULTS: A total of 265 of our subjects (25.9%) were diagnosed with hepatic steatosis. The ORs of the group of subjects who drank >3 cups of coffee/day was significantly lower compared with that of the noncoffee drinker group (OR 0.59, 95% confidence intervals 0.38-0.90, P=0.03). Although there was a significant difference between coffee consumption and leptin level only in the asymptomatic group, we found a decreasing trend in the asymptomatic and moderate-severe hepatic steatosis group. We did not find the same relationships in green tea consumption. CONCLUSIONS: Although we did not find an association between hepatic steatosis and green tea consumption, coffee may have beneficial effects on hepatic steatosis. In addition, we produced one possible hypothesis that coffee consumption negatively associates with leptin levels in hepatic steatosis. PMID- 25804276 TI - Acquired night blindness due to bad eating patterns. AB - We report a case of acquired night blindness in a developed country (Spain) without risk factors for nutritional deficiency disease or family history of hereditary retinal disease. A 76-year-old woman presented with acquired night blindness of 6-month progression. After a thorough inquiry about eating patterns she becomes suspicious of vitamin A low dietary intake, which is analytically confirmed and successfully treated. Despite being very uncommon in our environment and even more in patients without digestive problems, in a patient reporting acquired night blindness vitamin A deficiency should not be discarded until eating patterns have been investigated. It might be especially relevant in certain socioeconomic situations and eating disorders such as bulimia or anorexia nervosa. PMID- 25804275 TI - Dietary patterns and bone mineral density in Brazilian postmenopausal women with osteoporosis: a cross-sectional study. AB - BACKGROUND/OBJECTIVES: The aim of this study was to investigate the association between dietary patterns and bone mineral density (BMD) in postmenopausal women with osteoporosis. SUBJECTS/METHODS: This cross-sectional study included 156 postmenopausal and osteoporotic Brazilian women aged over 45 years. BMD of lumbar spine, total femur (TF), femoral neck and of total body (TB), as well as body composition (fat and lean mass), was assessed by dual-energy X-ray absorptiometry. Body mass index and lifestyle information were also obtained. Dietary intake was assessed by using a 3-day food diary. Dietary patterns were obtained by principal component factor analysis. Adjusted multiple linear regression analysis was applied in order to evaluate the predictive effect of dietary patterns on BMD. Significance was set at P<0.05. RESULTS: Five patterns were retained: 'healthy', 'red meat and refined cereals', 'low-fat dairy', 'sweet foods, coffee and tea' and 'Western'. The 'sweet foods, coffee and tea' pattern was inversely associated with TF BMD (beta=-0.178; 95% CI: -0.039 to -0.000) and with TB BMD (beta=-0.320; 95% CI: -0.059 to -0.017) even after adjusting for energy and calcium intake, lean mass, age and postmenopausal time. CONCLUSIONS: A concomitant excessive consumption of sweet foods and caffeinated beverages appears to exert a negative effect on BMD even when the skeleton already presents some demineralization. Food and beverage intake is a modifiable factor that should not be neglected in the treatment of individuals with osteoporosis. PMID- 25804277 TI - Effects of human milk and formula on postprandial glycaemia and insulinaemia. AB - BACKGROUND/OBJECTIVES: Consumption of formula in place of human milk may produce differences in postprandial glycaemia and insulinaemia that contribute to metabolic programming in the first year of life. The objective of the current study was to determine glycaemic and insulinaemic responses to human milk compared with a typical commercial formula, and then compare 11 other formulas. SUBJECTS/METHODS: On separate mornings in random order, 10 healthy breastfeeding mothers consumed 25 g available carbohydrate portions of their own milk, a formula and reference food (25 g glucose on two occasions). In the second study, 10 different healthy subjects consumed 25 g available carbohydrate portions of 11 different commercial formulas and three reference foods (25 g glucose on three occasions). Fingerpick blood samples were taken at regular intervals over 2 h, and the glycaemic index (GI) and insulin index determined according to a standardised protocol. RESULTS: There were no significant differences in postprandial glycaemia or insulinaemia after human milk vs a typical formula (P = 0.3). Both produced a low GI (mean +/- s.e.m.: 38 +/- 7 vs 34 +/- 7, respectively) and high insulin index (87 +/- 14 vs 94 +/- 16). The GI and insulin indices of the other formulas ranged from 18 +/- 3 to 67 +/- 6 and 53 +/- 9 to 209 +/- 33, respectively. CONCLUSIONS: Human milk and a typical formula elicit similar postprandial glycaemic and insulinaemic responses, but there is a wide range of responses to other formulas. PMID- 25804278 TI - Virgin olive oil, palm olein and coconut oil diets do not raise cell adhesion molecules and thrombogenicity indices in healthy Malaysian adults. AB - BACKGROUND/OBJECTIVES: Effects of high-protein diets that are rich in saturated fats on cell adhesion molecules, thrombogenicity and other nonlipid markers of atherosclerosis in humans have not been firmly established. We aim to investigate the effects of high-protein Malaysian diets prepared separately with virgin olive oil (OO), palm olein (PO) and coconut oil (CO) on cell adhesion molecules, lipid inflammatory mediators and thromobogenicity indices in healthy adults. METHODS: A randomized cross-over intervention with three dietary sequences, using virgin OO, PO and CO as test fats, was carried out for 5 weeks on each group consisting of 45 men and women. These test fats were incorporated separately at two-thirds of 30% fat calories into high-protein Malaysian diets. RESULTS: For fasting and nonfasting blood samples, no significant differences were observed on the effects of the three test-fat diets on thrombaxane B2 (TXB2), TXB2/PGF1alpha ratios and soluble intracellular and vascular cell adhesion molecules. The OO diet induced significantly lower (P<0.05) plasma leukotriene B4 (LTB4) compared with the other two test diets, whereas PGF1alpha concentrations were significantly higher (P<0.05) at the end of the PO diet compared with the OO diet. CONCLUSION: Diets rich in saturated fatty acids from either PO or CO and high in monounsaturated oleic acid from virgin OO do not alter the thrombogenicity indices-cellular adhesion molecules, thromboxane B2 (TXB2) and TXB2/prostacyclin (PGF1alpha) ratios. However, the OO diet lowered plasma proinflammatory LTB4, whereas the PO diet raised the antiaggregatory plasma PGF1alpha in healthy Malaysian adults. This trial was registered at clinicaltrials.gov as NCT 00941837. PMID- 25804280 TI - Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy. AB - Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long lasting NS consenting to rituximab (375 mg/m(2)) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximab treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN. PMID- 25804279 TI - Utility of HLA Antibody Testing in Kidney Transplantation. AB - HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor-specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes. PMID- 25804281 TI - Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy. AB - Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P<0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P<0.001; for Klotho: r=-0.49, P<0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD. PMID- 25804282 TI - Loss of Klotho in CKD Breaks One's Heart. PMID- 25804284 TI - An enzymatically-sensitized sequential and concentric energy transfer relay self assembled around semiconductor quantum dots. AB - The ability to control light energy within de novo nanoscale structures and devices will greatly benefit their continuing development and ultimate application. Ideally, this control should extend from generating the light itself to its spatial propagation within the device along with providing defined emission wavelength(s), all in a stand-alone modality. Here we design and characterize macromolecular nanoassemblies consisting of semiconductor quantum dots (QDs), several differentially dye-labeled peptides and the enzyme luciferase which cumulatively demonstrate many of these capabilities by engaging in multiple sequential energy transfer steps. To create these structures, recombinantly expressed luciferase and the dye-labeled peptides were appended with a terminal polyhistidine sequence allowing for controlled ratiometric self-assembly around the QDs via metal-affinity coordination. The QDs serve to provide multiple roles in these structures including as central assembly platforms or nanoscaffolds along with acting as a potent energy harvesting and transfer relay. The devices are activated by addition of coelenterazine H substrate which is oxidized by luciferase producing light energy which sensitizes the central 625 nm emitting QD acceptor by bioluminescence resonance energy transfer (BRET). The sensitized QD, in turn, acts as a relay and transfers the energy to a first peptide-labeled Alexa Fluor 647 acceptor dye displayed on its surface. This dye then transfers energy to a second red-shifted peptide-labeled dye acceptor on the QD surface through a second concentric Forster resonance energy transfer (FRET) process. Alexa Fluor 700 and Cy5.5 are both tested in the role of this terminal FRET acceptor. Photophysical analysis of spectral profiles from the resulting sequential BRET-FRET-FRET processes allow us to estimate the efficiency of each of the transfer steps. Importantly, the efficiency of each step within this energy transfer cascade can be controlled to some extent by the number of enzymes/peptides displayed on the QD. Further optimization of the energy transfer process(es) along with potential applications of such devices are finally discussed. PMID- 25804283 TI - Anti-phospholipase A2 Receptor Antibody and Immunosuppression in Membranous Nephropathy: More Evidence for Pathogenicity of Anti-phospholipase A2 Receptor Autoantibodies. PMID- 25804285 TI - Introduction to metrology series. PMID- 25804286 TI - Oligomeric interface modifiers in hybrid polymer solar cell prototypes investigated by fluorescence voltage spectroscopy. AB - Carboxylated oligothiophenes were evaluated as interfacial modifiers between the organic poly(3-hexylthiophene) (P3HT) and inorganic TiO2 layers in bilayer hybrid polymer solar cells. Carboxylated oligothiophenes can be isolated using conventional purification techniques resulting in pure, monodisperse molecules with 100% carboxylation. Device prototypes using carboxylated oligothiophenes as interfacial modifiers showed improved performance in the open-circuit voltage and fill factor over devices using unmodified oligothiophenes as interfacial modifiers. X-ray photoelectron spectroscopy (XPS) studies supported the idea that interface layer adhesion was improved by functionalizing oligothiophenes with a carboxyl moiety. Wide-field fluorescence images revealed that devices made using carboxylated oligothiophenes had fewer aggregates in the P3HT layers atop the modified TiO2 surface. Hysteresis seen in the fluorescence intensity as a function of applied bias, obtained from In-Device Fluorescence Voltage Spectroscopy (ID-FVS), was found to be a diagnostic criterion of the quality of the hybrid interface modification. The best interfaces were found using oligothiophenes functionalized with carboxylates, which created smooth layers on TiO2, and showed no hysteresis, suggesting elimination of interfacial charge traps. However, this hysteresis could be re-introduced by increasing the scan rate of the applied bias, suggesting that smooth P3HT layers created by carboxylated oligothiophene interface modifiers were necessary but not sufficient for sustaining improved photovoltaic properties especially during long-term device operation. PMID- 25804287 TI - An entomological review of invasive mosquitoes in Europe. AB - Among the invasive mosquitoes registered all over the world, Aedes species are particularly frequent and important. As several of them are potential vectors of disease, they present significant health concerns for 21st century Europe. Five species have established in mainland Europe, with two (Aedes albopictus and Aedes japonicus) becoming widespread and two (Ae. albopictus and Aedes aegypti) implicated in disease transmission to humans in Europe. The routes of importation and spread are often enigmatic, the ability to adapt to local environments and climates are rapid, and the biting nuisance and vector potential are both an ecomonic and public health concern. Europeans are used to cases of dengue and chikungunya in travellers returning from the tropics, but the threat to health and tourism in mainland Europe is substantive. Coupled to that are the emerging issues in the European overseas territorities and this paper is the first to consider the impacts in the remoter outposts of Europe. If entomologists and public health authorities are to address the spread of these mosquitoes and mitigate their health risks they must first be prepared to share information to better understand their biology and ecology, and share data on their distribution and control successes. This paper focusses in greater detail on the entomological and ecological aspects of these mosquitoes to assist with the risk assessment process, bringing together a large amount of information gathered through the ECDC VBORNET project. PMID- 25804288 TI - Evidence that the presence of psychosis in non-psychotic disorder is environment dependent and mediated by severity of non-psychotic psychopathology. AB - BACKGROUND: Evidence suggests that in affective, non-psychotic disorders: (i) environmental exposures increase risk of subthreshold psychotic experiences (PEs) and strengthen connectivity between domains of affective and subthreshold psychotic psychopathology; and (ii) PEs are a marker of illness severity. METHOD: In 3021 adolescents from the Early Developmental Stages of Psychopathology cohort, we tested whether the association between PEs and presence of DSM-IV mood disorder (MD)/obsessive-compulsive disorder (OCD) would be moderated by risk factors for psychosis (cannabis use, childhood trauma and urbanicity), using the interaction contrast ratio (ICR) method. Furthermore, we analysed whether the interaction between environment and PEs was mediated by non-psychotic psychopathology. RESULTS: The association between PEs and MD/OCD was moderated by urbanicity (ICR = 2.46, p = 0.005), cannabis use (ICR = 3.76, p = 0.010) and, suggestively, trauma (ICR = 1.91, p = 0.063). Exposure to more than one environmental risk factor increased the likelihood of co-expression of PEs in a dose-response fashion. Moderating effects of environmental exposures were largely mediated by the severity of general non-psychotic psychopathology (percentage explained 56-68%, all p < 0.001). Within individuals with MD/OCD, the association between PEs and help-seeking behaviour, as an index of severity, was moderated by trauma (ICR = 1.87, p = 0.009) and urbanicity (ICR = 1.48, p = 0.005), but not by cannabis use. CONCLUSIONS: In non-psychotic disorder, environmental factors increase the likelihood of psychosis admixture and help-seeking behaviour through an increase in general psychopathology. The findings are compatible with a relational model of psychopathology in which more severe clinical states are the result of environment-induced disturbances spreading through a psychopathology network. PMID- 25804289 TI - Juvenile xanthogranuloma--a rare cause of unilateral orbital swelling in an elderly patient. AB - OBJECTIVE: To report the clinical and pathologic features of an elderly patient with a unilateral orbital swelling and proptosis caused by Juvenile Xanthogranuloma diagnosed and confirmed by orbital biopsy. DESIGN: Interventional case report. PARTICIPANTS: One patient. INTERVENTION: Steroids (Medrol dose pack) and radiation. MAIN OUTCOME MEASURES: Unusual clinical presentation and pathological features of Juvenile Xanthogranuloma in the orbit. CONCLUSIONS: Juvenile Xanthogranuloma affecting one orbit is very rare with unilateral involvement in an elderly patient. Steroids and radiation therapy were very effective in treatment and provided impressive results. PMID- 25804291 TI - Nanocomposite heterojunctions as sunlight-driven photocatalysts for hydrogen production from water splitting. AB - Hydrogen production via photocatalytic water splitting using sunlight has enormous potential in solving the worldwide energy and environmental crisis. The key challenge in this process is to develop efficient photocatalysts which must satisfy several criteria such as high chemical and photochemical stability, effective charge separation and strong sunlight absorption. The combination of different semiconductors to create composite materials offers a promising way to achieve efficient photocatalysts because doing so can improve the charge separation, light absorption and stability of the photocatalysts. In this review article, we summarized the most recent studies on semiconductor composites for hydrogen production under visible light irradiation. After a general introduction about the photocatalysis phenomenon, typical heterojunctions of widely studied heterogeneous semiconductors, including titanium dioxide, cadmium sulfide and graphitic carbon nitride are discussed in detail. PMID- 25804290 TI - Synthesis and characterization of S-nitrosoglutathione-oligosaccharide-chitosan as a nitric oxide donor. AB - OBJECTIVES: The aim of this work is to synthesize a novel stable and biodegradable nitric oxide (NO) donor polymer based on a chitosan backbone. This polymer needed to be linked to glutathione (GSH), which was nitrosated in a second step. This polymer has been developed as an NO delivery platform that could be further evaluated for an oral delivery in Crohn's disease. METHODS: The new polymer (named S-nitrosoglutathione-oligosaccharide-chitosan or SNOC) was obtained using a two-step procedure involving the linkage of GSH to chitosan via an amidine reaction followed by a post-nitrosation with NaNO2. The GSH linkage was assessed using NMR, FTIR and an Ellman's test, whereas the final NO amount was determined by the Griess and Saville method. RESULTS: Polymers with different numbers of NO groups were obtained (159.04 +/- 64.16 umol/g of polymer for SNOC G1 and 525.08 +/- 151.35 umol/g of polymer for SNOC G2) depending on the procedure used for production. When tested in an Ussing chamber, SNOC G2 had a sustained release of NO and nitrites for at least 6 h. CONCLUSION: We believe that this type of polymer is adapted for the development of various formulations, including microparticles. PMID- 25804292 TI - Cobalt phosphate modified TiO2 nanowire arrays as co-catalysts for solar water splitting. AB - Cobalt phosphate (Co-Pi) is photo-electrodeposited on TiO2 nanowire arrays in Co(2+) containing phosphate buffer. The resulting composite photoanode shows a generally enhanced photocurrent near the flat band potential region, and represents a 2.3 times improved photoconversion efficiency compared to that of pristine TiO2 in a neutral electrolyte. A negative effect on the photocurrent generation is also observed when loading TiO2 with a relatively thick Co-Pi layer, which is demonstrated to be due to the poor photohole transfer kinetics in the Co-Pi layer. Moreover, we find that Co-Pi can facilitate the photoelectrochemical performance of TiO2 over a wide pH range from 1-14. This improved activity is studied in detail by optical and electrochemical analyses. It is suggested that the mechanism of the overpotential-demanding water oxidation reaction is changed to a facile pathway by the Co-based electrocatalyst. At the same time, the more significant band bending is induced by the Co-Pi catalyst decreasing the charge recombination. This work provides a feasible route to reduce the external power needed to drive water splitting by coupling an electrocatalyst with a photocatalyst, as well as mechanistic insights important for other Co-Pi modified photoelectrodes for solar-driven water splitting. PMID- 25804293 TI - Unraveling the charge transfer/electron transport in mesoporous semiconductive TiO2 films by voltabsorptometry. AB - In this work, we demonstrate that chronoabsorptometry and more specifically cyclic voltabsorptometry are particularly well suited techniques for acquiring a comprehensive understanding of the dynamics of electron transfer/charge transport within a transparent mesoporous semiconductive metal oxide film loaded with a redox-active dye. This is illustrated with the quantitative analysis of the spectroelectrochemical responses of two distinct heme-based redox probes adsorbed in highly-ordered mesoporous TiO2 thin films (prepared from evaporation-induced self-assembly, EISA). On the basis of a finite linear diffusion-reaction model as well as the establishment of the analytical expressions governing the limiting cases, it was possible to quantitatively analyse, predict and interpret the unusual voltabsorptometric responses of the adsorbed redox species as a function of the potential applied to the semiconductive film (i.e., as a function of the transition from an insulating to a conductive state or vice versa). In particular, we were able to accurately determine the interfacial charge transfer rates between the adsorbed redox species and the porous semiconductor. Another important and unexpected finding, inferred from the voltabsorptograms, is an interfacial electron transfer process predominantly governed by the extended conduction band states of the EISA TiO2 film and not by the localized traps in the bandgap. This is a significant result that contrasts those previously observed for dye-sensitized solar cells formed of randomly sintered TiO2 nanoparticles, a behaviour that was ascribed to a particularly low density of localized surface states in EISA TiO2. The present methodology also provides a unique and straightforward access to an activation-driving force relationship according to the Marcus theory, thus opening new opportunities not only to investigate the driving-force effects on electron recombination dynamics in dye sensitized solar cells but also to study the electron transfer/transport mechanisms in heterogeneous photoelectrocatalytic systems combining nanostructured semiconductor electrodes and heterogeneous redox-active catalysts. PMID- 25804294 TI - Using comparative genomics to develop a molecular diagnostic for the identification of an emerging pest Drosophila suzukii. AB - Drosophila suzukii (Spotted Wing Drosophila) has recently become a serious invasive pest of fruit crops in the USA, Canada, and Europe, leading to substantial economic losses. D. suzukii is a direct pest, ovipositing directly into ripe or ripening fruits; in contrast, other Drosophilids utilize decaying or blemished fruits and are nuisance pests at worst. Immature stages of D. suzukii are difficult to differentiate from other Drosophilids, posing problems for research and for meeting quarantine restrictions designed to prevent the spread of this pest in fruit exports. Here we used a combined phylogenetic and bioinformatic approach to discover genetic markers suitable for a species diagnostic protocol of this agricultural pest. We describe a molecular diagnostic for rapid identification of single D. suzukii larva using multiplex polymerase chain reaction. Our molecular diagnostic was validated using nine different species of Drosophila for specificity and 19 populations of D. suzukii from different geographical regions to ensure utility within species. PMID- 25804295 TI - Treatment of a diaphyseal long-bone defect with autologous bone grafts and platelet-rich plasma in a rabbit model. AB - INTRODUCTION: Large bone defects are a therapeutic challenge to surgeons and are often associated with a high morbidity. The use of autologous cancellous bone graft represents an essential therapeutic option and is considered the gold standard. However, the use of platelet-rich plasma (PRP) for improving bone defect healing has been discussed controversially. The aim of this study was to evaluate the treatment of a diaphyseal long-bone defect in a rabbit model with a combination of PRP and autologous cancellous bone. MATERIAL AND METHODS: A monocortical long-bone defect in the radial diaphysis of 24 New Zealand white rabbits was filled either with autologous cancellous graft as a control group or with autologous cancellous graft combined with autologous PRP. Histomorphometrical and radiological analysis as well as quantification of platelets and growth factors were performed. The animals were euthanatized after three and six weeks according to the study arms. RESULTS: A significant improvement in bone healing was observed histomorphometrically in the PRP group in the central area of the defect zone (p <0.01) as well as the cortical defect zone (p <0.01). The radiological findings were in accordance with the histomorphometrical results. Comparing native blood and PRP, an enrichment of growth factors and platelets was detectable in the PRP. CONCLUSION: Within this animal study, the combination of PRP and autologous cancellous bone grafts improved bone healing significantly compared to the sole application of autologous bone. Therefore, further efforts should be initiated to establish the composite of PRP and autologous bone for bone healing disorders in clinical use. PMID- 25804296 TI - Synthesis and structures of soluble magnesium and zinc carboxylates containing intramolecular NH...O hydrogen bonds in nonpolar solvents. AB - Readily soluble magnesium and zinc carboxylates [M(Ln)2(H2O)4] (MLn2) (M = Mg, Zn; L1 = O2C-2-Ar3CCONH-6-n-BuCONHC6H3; L2 = O2C-2-Ar3CCONHC6H4; Ar = 4-t-BuC6H4) containing intramolecular NH...O hydrogen bonds in nonpolar solvents were synthesized and their molecular structures were determined by X-ray analysis. The complexes were crystallized in the trans or cis configuration. The M-O bond distances were dependent on the mode of the hydrogen bonds. (1)H NMR spectral measurements revealed a fast trans-cis isomerization of MLn2 in CDCl3, which was converted into a unique fac-[M(Ln)3(H2O)3]- (fac-[MLn3]-) by the addition of equimolar [Ln]-. The theoretical calculations supported the existence of the facial configuration. The coordinated water molecules of MLn2 were detected by (1)H NMR spectroscopy and the acidity was estimated in the order of ML12 > ML22. Calcium afforded only the dinuclear complex, [Ca2(L1)2(H2O)5(1,4-dioxane)] (Ca2L14), which showed a low hydrolytic activity. PMID- 25804298 TI - Cardiovascular mortality in chronic kidney disease patients: potential mechanisms and possibilities of inhibition by resin-based phosphate binders. AB - Cardiovascular mortality has been considered as the most important risk associated with chronic kidney disease. The mechanisms underlying this include inflammation, poor control of serum phosphate, high serum calcium, increased calcification of the arteries and cardiac valves, hyperlipidemia, diabetes, severe anemia, uric acid accumulation and others. Elevated phosphate levels have been strongly associated with increased mortality, thus phosphate-binding drugs have long been used to control the increase serum phosphate levels. However, phosphate-binding drugs differ considerably and recently numerous publications suggest differences between agents in the effects on overall mortality. The resin based phosphate binders, comprising sevelamer and colestilan, not only reduce serum phosphate but also do not raise serum calcium. In addition, they reduce serum LDL-C, inflammation, uric acid and high Hba1c values. These differences suggest that not all phosphate binders may be equal in the context of cardiovascular mortality in this patient population. PMID- 25804297 TI - A pragmatic randomized controlled trial to evaluate the effectiveness of a facilitated exercise intervention as a treatment for postnatal depression: the PAM-PeRS trial. AB - BACKGROUND: Postnatal depression affects about 10-15% of women in the year after giving birth. Many women and healthcare professionals would like an effective and accessible non-pharmacological treatment for postnatal depression. METHOD: Women who fulfilled the International Classification of Diseases (ICD)-10 criteria for major depression in the first 6 months postnatally were randomized to receive usual care plus a facilitated exercise intervention or usual care only. The intervention involved two face-to-face consultations and two telephone support calls with a physical activity facilitator over 6 months to support participants to engage in regular exercise. The primary outcome was symptoms of depression using the Edinburgh Postnatal Depression Scale (EPDS) at 6 months post randomization. Secondary outcomes included EPDS score as a binary variable (recovered and improved) at 6 and 12 months post-randomization. RESULTS: A total of 146 women were potentially eligible and 94 were randomized. Of these, 34% reported thoughts of self-harming at baseline. After adjusting for baseline EPDS, analyses revealed a -2.04 mean difference in EPDS score, favouring the exercise group [95% confidence interval (CI) -4.11 to 0.03, p = 0.05]. When also adjusting for pre-specified demographic variables the effect was larger and statistically significant (mean difference = -2.26, 95% CI -4.36 to -0.16, p = 0.03). Based on EPDS score a larger proportion of the intervention group was recovered (46.5% v. 23.8%, p = 0.03) compared with usual care at 6 months follow-up. CONCLUSIONS: This trial shows that an exercise intervention that involved encouragement to exercise and to seek out social support to exercise may be an effective treatment for women with postnatal depression, including those with thoughts of self harming. PMID- 25804299 TI - Medial orbital wall landmarks in three different North American populations. AB - PURPOSE: We sought to measure the medial orbital wall foramina distances in two previously unstudied populations, to describe a new bony medial wall feature, and to validate the accuracy of a new coordinate measurement device within the orbit. METHODS: Dried, well-preserved, complete human skulls without orbital defects were studied. Age, gender, birthplace, ethnicity, and laterality of the orbit were recorded for each skull. Supranumerary ethmoidal foramina were recorded, and the fronto-ethmoidal groove depth was measured. The distances between the anterior lacrimal crest (ALC) - anterior ethmoidal foramen (AEF), AEF - posterior ethmoidal foramen (PEF), and PEF - optic canal (OC) were measured first by surgical ruler and wire and then by the Microscribe coordinate measurement device. RESULTS: One hundred and forty-six orbits were studied. Fifty-seven orbits were of European or Caucasian descent, 68 orbits of African American descent, 2 orbits of West African descent, 11 orbits of Eskimo descent, and 8 orbits of unknown origin. No significant differences existed between the manual and Microscribe measurements for the ALC-AEF, AEF-PEF, and PEF-OF distances (p < 0.0001). A significant frontoethmoidal groove was observed in 27/146 (19%) orbits, in 6/57 (11%) Caucasian orbits, in 17/70 (24%) African American orbits, and in 4/11 (36%) Eskimo orbits. Supranumerary ethmoidal foramina were found in 50/146 orbits (34.2%) and in 17/27 (63%) orbits with a significant frontoethmoidal grooves. CONCLUSIONS: No significant differences in medial wall foramina distances exist between African American and Caucasian orbits; however, a frontoethmoidal groove occurs more commonly in African American orbits. This groove often occurs in the presence of supernumerary ethmoidal foramina. The Microscribe coordinate measurement system represents a valid tool to measure distances within the orbit. PMID- 25804301 TI - Evaluation of a hearing screening questionnaire for use with Ecuadorian school aged children. AB - OBJECTIVE: The purpose of this study was to evaluate the accuracy of a teacher administered hearing screening questionnaire to detect hearing loss among first grade Ecuadorian children in public schools. DESIGN: A cross-sectional design was used to compare screening results from the teacher-administered questionnaire and pure-tone audiometry. STUDY SAMPLE: Children were randomly selected from 117 schools. The study was conducted in two phases to accommodate different school calendars in the country. Data for both screening methods were available for 4616 children. RESULTS: For Phase 1, almost 90% who failed the questionnaire passed audiometry; and, 85% who failed audiometry passed the questionnaire. A revised questionnaire was used for Phase 2 and 70% who failed the questionnaire passed audiometry; and 85% who failed audiometry, passed the questionnaire. Of the 27 children identified in Phase 2 as having hearing loss at the time screening was done, 88.9% failed audiometry, but only 22.2% failed the questionnaire. CONCLUSIONS: Because there was little agreement between the questionnaire and the audiometry, it was recommended that the questionnaire not be used to screen Ecuadorian children for hearing loss. The results of this evaluation of the school hearing screening program provided the Ecuadorian government with important information to guide policy decisions. PMID- 25804300 TI - The efficacy of adjuvant immunochemotherapy with OK-432 after curative resection of gastric cancer: an individual patient data meta-analysis of randomized controlled trials. AB - BACKGROUND: OK-432 has been used as a cancer treatment for 40 years, and the immunostimulatory effects of OK-432 therapy have been intensely investigated in Japan. Recently, it has received attention as a possible booster for cancer vaccine treatments. Our previous meta-analysis based on summary measures revealed a significant improvement in the survival of patients with curatively resected gastric cancer. However, it is impossible to exclude the possibility of bias due to several prognostic factors. METHODS: We collected individual data for patients with stage III or stage IV gastric cancer after curative resection from 14 trials that were identified in a previous meta-analysis. Immunochemotherapy with OK-432 was compared with treatment with standard chemotherapy on an intention-to-treat basis. The primary end point was overall survival. Stratified survival analyses were performed with the trial as the stratification factor. Subgroup analyses were also performed according to the potential prognostic factors, which included pathological factors, splenectomy, and delayed-type hypersensitivity. RESULTS: There were 796 and 726 patients in the OK-432 and control groups, respectively. The median overall survival was 42.6 months for the OK-432 group and 32.3 months for the control group. The overall hazard ratio was 0.88 (95 % confidence interval 0.77-1.00, p = 0.050). No factor showed a statistically significant interaction in the subgroup analyses. CONCLUSIONS: The results suggest that immunochemotherapy treatment with OK-432 could have a borderline significant effect for patients with stage III or stage IV gastric cancer after curative resection. PMID- 25804302 TI - Observation of polarized gain from aligned colloidal nanorods. AB - In recent years, colloidal semiconductor nanorods have attracted great interest for polarized spontaneous emission. However, their polarized gain has not been possible to achieve so far. In this work we show the highly polarized stimulated emission from the densely packed ensembles of core-seeded nanorods in a cylindrical cavity. Here CdSe/CdS dot-in-rods were coated and aligned on the inner wall of a capillary tube, providing optical feedback for the nanorod gain medium. Results show that the polarized gain originates intrinsically from the aligned nanorods and not from the cavity and that the optical anisotropy of the nanorod ensemble was amplified with the capillary tube, resulting in highly polarized whispering gallery mode lasing. The highly polarized emission and lasing, together with easy fabrication and flexible incorporation, make this microlaser a promising candidate for important color conversion and enrichment applications including liquid crystal display backlighting and laser lighting. PMID- 25804303 TI - Assessment of human gingival fibroblast interaction with dental implant abutment materials. AB - The biocompatibility of dental implant abutment materials depends on numerous factors including the nature of the material, its chemical composition, roughness, texture, hydrophilicity and surface charge. The aim of the present study was to compare the viability and adhesion strength of human gingival fibroblasts (HGFs) grown on several dental materials used in implant prosthodontics. Surfaces of the tested materials were assessed using an optical imaging profiler. For material toxicity and cellular adhesion evaluation, primary human gingival fibroblast cells were used. To evaluate the strength of cellular adhesion, gingival fibroblasts were cultured on the tested materials and subjected to lateral shear forces by applying 300 and 500 rpm shaking intensities. Focal adhesion kinase (FAK) expression and phosphorylation in cells grown on the specimens were registered by cell-based ELISA. There was a tendency of fibroblast adhesion strength to decrease in the following order: sandblasted titanium, polished titanium, sandblasted zirconium oxide, polished zirconium oxide, gold-alloy, chrome-cobalt alloy. Higher levels of total as well as phospho FAK protein were registered in HGFs grown on roughened titanium. Material type and surface processing technique have an impact on gingival fibroblast interaction with dental implant abutment materials. PMID- 25804304 TI - Synthesis of functionalized Pluronic-b-poly(epsilon-caprolactone) and the comparative study of their pendant groups on the cellular internalization behavior. AB - This study focuses on the synthesis of Pluronic-b-poly(epsilon-caprolactone) bearing benzyl-oxycarbonylmethyl and carboxylic groups and the comparative study to investigate the influence of the different pendant groups on the cellular behavior. The functionalized Pluronic-b-poly(epsilon-caprolactone) bearing two kinds of pendant groups are synthesized via ring-opening polymerization of epsilon-caprolactone and 6-(benzyl-oxycarbonyl methyl)-epsilon-caprolactone and followed by deprotection respectively. The structure of the copolymers is confirmed and the polymeric micelles are formed by an emulsion/solvent evaporation technique. The critical micelle concentrations are improved compared with Pluronic F127, the morphologies of the micelles are spherical with the diameter on nano scale and good colloidal stability. The copolymers have good cytocompatibility and the comparative study reveals that cellular internalization, digesting by lysosome and intracellular distribution are affected by the pendant groups, moreover, the endocytosis pathway is determined by the pendant groups. Therefore, the definite internalization mechanism is beneficial for the design of polymeric micellar carriers to achieve intra- or extracellular modes of drug delivery and provide better access to either cell membrane or intracellular organelles. PMID- 25804305 TI - Novel nano-composite biomimetic biomaterial allows chondrogenic and osteogenic differentiation of bone marrow concentrate derived cells. AB - In clinical orthopedics suitable materials that induce and restore biological functions together with the right mechanical properties are particularly needed for the regeneration of osteochondral lesions. For this purpose, the ideal scaffold should possess the right properties with respect to degradation, cell binding, cellular uptake, non-immunogenicity, mechanical strength, and flexibility. In addition, it should be easy to handle and serve as a template for chondrocyte and bone cells guiding both cartilage and bone formation. The aim of the present study was to estimate the chondrogenic and osteogenic capability of bone marrow concentrated derived cells seeded onto a novel nano-composite biomimetic material. These properties have been evaluated by means of histological, immunohistochemical and electron microscopy analyses. The data obtained demonstrated that freshly harvested cells obtained from bone marrow were able, once seeded onto the biomaterial, to differentiate either down the chondrogenic and osteogenic pathways as evaluated by the expression and production of specific matrix molecules. These findings support the use, for the repair of osteochondral lesions, of this new nano-composite biomimetic material together with bone marrow derived cells in a "one step" transplantation procedure. PMID- 25804306 TI - Development and preparation of a low-immunogenicity porcine dermal scaffold and its biocompatibility assessment. AB - Acellular dermal matrix (ADM) has been widely used in repair and reconstruction of tissue defect. Therapeutic effect of porcine ADM (PADM) is inferior to that of human ADM (HADM). Relatively high immunogenicity and the resulting strong inflammatory response are major issue in application of PADM. We therefore treated reticular layer PADM (Rl-PADM) with matrix metalloproteinase-7 (MMP-7) and obtained a low-immunogenicity porcine dermal scaffold (LIPDS). Highly immunogenic components, tissue structure, cytocompatibility, and postgrafting histological changes of LIPDS were further investigated. Compared with Rl-PADM, LIPDS showed that the epithelial root sheath, cell debris, laminin, and type IV collagen were almost entirely removed, the structure remained normal, and the interfibrous space was relatively enlarged. Cytocompatibility of LIPDS was similar to that of HADM but superior to Rl-PADM. With regard to the extent of tissue ingrowth in terms of host fibroblasts infiltration and vascularization, LIPDS exhibited clear advantages over Rl-PADM after they had been subcutaneously transplanted in a rat model. In addition, no excessive inflammatory response was observed in LIPDS group up to 28 days postgraft, and the morphosis of collagenous fibers kept essentially normal. However, there were stronger inflammatory response and obvious collagen spallation in Rl-PADM group. The processes of integration and remodeling after the LIPDS grafting were similar to those of a normal wound healing response. The LIPDS graft was vascularized at a relatively high speed. Thus, as an implantable scaffold material, LIPDS is a superior template for guiding tissue regeneration and remodeling. PMID- 25804308 TI - ROS and endothelial nitric oxide synthase (eNOS)-dependent trafficking of angiotensin II type 2 receptor begets neuronal NOS in cardiac myocytes. AB - Angiotensin II (Ang II), a potent precursor of hypertrophy and heart failure, upregulates neuronal nitric oxide synthase (nNOS or NOS1) in the myocardium. Here, we investigate the involvement of type 1 and 2 angiotensin receptors (AT1R and AT2R) and molecular mechanisms mediating Ang II-upregulation of nNOS. Our results showed that pre-treatment of left ventricular (LV) myocytes with antagonists of AT1R or AT2R (losartan, PD123319) and ROS scavengers (apocynin, tiron or PEG-catalase) blocked Ang II-upregulation of nNOS. Surface biotinylation or immunocytochemistry experiments demonstrated that AT1R expression in plasma membrane was progressively decreased (internalization), whereas AT2R was increased (membrane trafficking) by Ang II. Inhibition of AT1R or ROS scavengers prevented Ang II-induced translocation of AT2R to plasma membrane, suggesting an alignment of AT1R-ROS-AT2R. Furthermore, Ang II increased eNOS-Ser(1177) but decreased eNOS-Thr(495), indicating concomitant activation of eNOS. Intriguingly, ROS scavengers but not AT2R antagonist prevented Ang II-activation of eNOS. NOS inhibitor (L-NG-Nitroarginine Methyl Ester, L-NAME) or eNOS gene deletion (eNOS( /-)) abolished Ang II-induced membrane trafficking of AT2R, nNOS protein expression and activity. Mechanistically, S-nitrosation of AT2R was increased by sodium nitroprusside (SNP), a NO donor. Site-specific mutagenesis analysis reveals that C-terminal cysteine 349 in AT2R is essential in AT2R translocation to plasma membrane. Taken together, we demonstrate, for the first time, that Ang II upregulates nNOS protein expression and activity via AT1R/ROS/eNOS-dependent S nitrosation and membrane translocation of AT2R. Our results suggest a novel crosstalk between AT1R and AT2R in regulating nNOS via eNOS in the myocardium under pathogenic stimuli. PMID- 25804307 TI - Reliable femoral chronic total occlusion model using a thin biodegradable polymer coated copper stent in a porcine model. AB - Chronic total occlusions (CTOs) are common in patients with peripheral arterial disease (PAD). This study aimed to examine the feasibility and reliability of a CTO induced by a thin biodegradable polymer (polyglycolic acid) coated copper stent in a porcine femoral artery. Novel thin biodegradable polymer coated copper stents (9 mm long) were crimped on an angioplasty balloon (4.5 mm diameter * 12 mm length) and inserted into the femoral artery. Histopathologic analysis was performed 35 days after stenting. In five of six stented femoral arteries, severe in-stent restenosis and total occlusion with collateral circulation were observed without adverse effects such as acute stent thrombosis, leg necrosis, or death at 5 weeks. Fibrous tissue deposition, small vascular channels, calcification, and inflammatory cells were observed in hematoxylin-eosin, Carstair's, and von Kossa tissue stains; these characteristics were similar to pathological findings associated with CTOs in humans. The neointima volume measured by micro-computed tomography was 93.9 +/- 4.04 % in the stented femoral arteries. CTOs were reliably induced by novel thin biodegradable polymer coated copper stents in porcine femoral arteries. Successful induction of CTOs may provide a practical understanding of their formation and application of an interventional device for CTO treatment. PMID- 25804312 TI - Structures and photophysical properties of copper(I) complexes bearing diphenylphenanthroline and bis(diphenylphosphino)alkane: the effect of phenyl groups on the phenanthroline ligand. AB - A series of copper(I) complexes bearing 2,9-dimethyl-4,7-diphenyl-1,10 phenanthroline (dmpp) and a diphosphine ligand have been prepared. The diphosphine ligands used have two, three or four methylene carbons between the two phosphorus atoms. The crystallographic study has revealed that two of the three complexes have the mononuclear structure bearing dmpp and a bidentate diphosphine ligand, and one is a diphosphine-bridged binuclear complex. The photoluminescence of the complexes in solution was studied and compared with the previously reported complexes bearing 2,9-dimethyl-1,10-phenanthroline (dmp). It was found that the two phenyl groups on the phenanthroline ligand have a marked effect on the photophysical properties of the complexes; the intensity of the emission of the complexes is greatly enhanced by the phenyl groups. The photophysics of the complexes is discussed with the results of DFT and TDDFT calculations. PMID- 25804311 TI - Default mode network dissociation in depressive and anxiety states. AB - The resting state brain networks, particularly the Default Mode Network (DMN), have been found to be altered in several psychopathological conditions such as depression and anxiety. In this study we hypothesized that cortical areas of the DMN, particularly the anterior regions--medial prefrontal cortex and anterior cingulate cortex--would show an increased functional connectivity associated with both anxiety and depression. Twenty-four healthy participants were assessed using Hamilton Depression and Anxiety Rating Scales and completed a resting-state functional magnetic resonance imaging scan. Multiple regression was performed in order to identify which areas of the DMN were associated with anxiety and depression scores. We found that the functional connectivity of the anterior portions of DMN, involved in self-referential and emotional processes, was positively correlated with anxiety and depression scores, whereas posterior areas of the DMN, involved in episodic memory and perceptual processing were negatively correlated with anxiety and depression scores. The dissociation between anterior and posterior cortical midline regions, raises the possibility of a functional specialization within the DMN in terms of self-referential tasks and contributes to the understanding of the cognitive and affective alterations in depressive and anxiety states. PMID- 25804309 TI - Hypo-metabolism of the rostral anterior cingulate cortex associated with working memory impairment in 18 cases of schizophrenia. AB - Working memory (Work-Mem), the capacity to hold and manipulate information, activates the anterior cingulate cortex (ACC), especially its caudal subregion. Impaired Work-Mem and structural and functional abnormalities of the ACC are reported in schizophrenia. This study aims to elucidate the pathogenesis of Work Mem dysfunction in schizophrenia by comparing metabolite concentrations across ACC subregions. This retrospective study of 18 schizophrenia cases and 10 matched controls used proton magnetic resonance spectroscopic imaging ((1)H-MRSI, TR/TE = 1800/35 ms, 0.5 cm(3) spatial resolution) to test whether the Work-Mem Index of the Wechsler Adult Intelligence Scale, third edition is associated with differences in the rostral to caudal ACC ratios of N-acetylaspartate (NAA) and creatine (Cr). Higher caudal:rostral ACC Cr (but not NAA) concentrations were associated with decreased Work-Mem Index in cases (r = -0.6, p = 0.02), with a similar trend in controls (r = -0.56, p = 0.10), although caudal:rostral ACC Cr correlated with NAA in cases and controls (r = 0.67 and 0.62, p < 0.05 for both). NAA and Cr ratios did not correlate with myo-inositol, excluding gliosis as the underlying process. Subjects' sex and age had no effects on these relationships. The findings suggest that rostral ACC energy hypo-metabolism, possibly arising from neurodevelopmental processes, is associated with working memory impairment in schizophrenia. Changes in the rostral (not the expected caudal) subregion underscore the interconnections between the ACC subregions and may offer laboratory markers for treatment trials, etiology studies, and perhaps even enhanced identification of prodromal "at risk" subjects. PMID- 25804310 TI - Exposure to childhood trauma is associated with altered n-back activation and performance in healthy adults: implications for a commonly used working memory task. AB - Previous research suggests that a history of early life stress (ELS) impacts working memory (WM) in adulthood. Despite the widespread use of WM paradigms, few studies have evaluated whether ELS exposure, in the absence of psychiatric illness, also impacts WM-associated brain activity in ways that might improve sensitivity to these ELS effects or provide insights into the mechanisms of these effects. This study evaluated whether ELS affects WM behavioral performance and task-associated activity by acquiring 3T functional images from 27 medication free healthy adults (14 with ELS) during an N-back WM task that included 0- and 2 back components. Whole brain voxel-wise analysis was performed to evaluate WM activation, followed by region of interest analyses to evaluate relationships between activation and clinical variables. ELS was associated with poorer accuracy during the 2-back (79% +/- 19 vs. 92% +/- 9, p = 0.049); accuracy and response time otherwise did not differ between groups. During the 0-back, ELS participants demonstrated increased activation in the superior temporal gyrus/insula, left inferior parietal lobule (IPL) (both corrected p < 0.001), and middle temporal and parahippocampal gyrus (MTG/PHG)(corrected p < 0.010). During the 2-back, ELS was associated with greater activation in the IPL, MTG/PHG and inferior frontal gyrus (corrected p < 0.001), with a trend towards precuneus activation (p = 0.080). These findings support previous research showing that ELS is associated with impaired neurobehavioral performance and changes in brain activation, suggesting recruitment of additional cognitive resources during WM in ELS. Based on these findings, ELS screening in future WM imaging studies appears warranted. PMID- 25804313 TI - Arterial stiffness is not associated with bone parameters in an elderly hyperhomocysteinemic population. AB - Several studies have observed positive associations between bone disease and cardiovascular disease. A potential common pathway is hyperhomocysteinemia; however, to date, there is a lack of data regarding hyperhomocysteinemic populations. Therefore, we examined both cross-sectionally and longitudinally, whether there is an association between bone parameters and arterial stiffness in a hyperhomocysteinemic population, and investigated the potential common role of homocysteine (hcy) level on these associations. Cross-sectional and longitudinal data of the B-PROOF study were used (n = 519). At both baseline and 2-year follow up we determined bone measures-incident fractures and history of fractures, bone mineral density (BMD) and quantitative ultrasound (QUS) measurement. We also measured arterial stiffness parameters at baseline-pulse wave velocity, augmentation index and aortic pulse pressure levels with applanation tonometry. Linear regression analysis was used to examine these associations and we tested for potential interaction of hcy level. The mean age of the study population was 72.3 years and 44.3 % were female. Both cross-sectionally and longitudinally there was no association between arterial stiffness measures and BMD or QUS measurements or with incident fractures (n = 16) within the 2-3 years of follow up. Hcy level did not modify the associations and adjustment for hcy did not change the results. Arterial stiffness was not associated with bone parameters and fractures, and hcy neither acted as a pleiotropic factor nor as a mediator. The potential association between bone and arterial stiffness is therefore not likely to be driven by hyperhomocysteinemia. PMID- 25804314 TI - Investigating histomorphometric relationships at the human femoral midshaft in a biomechanical context. AB - Cortical bone histomorphometry utilised in human and animal bone biology studies has demonstrated that osteon densities and their geometric properties may be in a relationship with biomechanical load application. Further research is required to investigate mutual links between bone histological variables to elucidate their usefulness in future biomechanical studies. Here, a series of correlations exploring bone biology relationships at the human midshaft femur were performed using a large sample. Mean intact, fragmentary and total osteon population densities, Haversian canal diameter and area, osteon area, as well as osteocyte lacunae density were measured along the sub-periosteal cortex in sections removed from the posterior midshaft aspect of modern human male (n = 233) and female (n = 217) femora (total n = 450). Parametric and non-parametric correlations between the histology variables were sought in the entire sample, as well as within age and sex sub-groups. Several significant positive and negative correlations explaining a large proportion of data variation were found. Haversian canal area, diameter, and osteon area were positively correlated. As the density of osteocyte lacunae increased, Haversian canals and osteons became smaller. As osteons increased in density, so did osteocyte lacunae, but Haversian canal and osteon area became smaller. Results were consistent across age and sex groups. Findings suggest that an increased rate of bone remodelling is associated with a decrease in geometrical properties of osteons. An increased density of osteocyte lacunae and osteons indicates the involvement of bone maintenance cells in remodelling potentially induced by mechanical stimuli. Future histomorphometry studies will benefit from examining multiple bone histology variables due to many mutual bone biology relationships that exist at the human midshaft femur. PMID- 25804316 TI - The relationship between four health-related quality-of-life indicators and use of mammography and Pap test screening in US women. AB - PURPOSE: Limited evidence is available to explain the role of four components of health-related quality of life (HRQoL) on breast and cervical cancer screening. The objective of this study was to determine the relationship between four HRQoL aspects and use of mammography and Pap test screening in US women. METHODS: Data were obtained from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). The outcome variables were receiving mammogram <2 versus >=2 years in women aged 50-74 years, and receiving Pap test <3 versus >=3 years in women aged 18-64 years. Eight logistic regression models were conducted to test the role of four HRQoL aspects (general health status, physical HRQoL, mental HRQoL, and activity limitation) on the two screening variables, after adjusting for covariates. Statistical analysis accounted for the complex sampling design of the BRFSS, and the a priori alpha error was set at p <= 0.05. RESULTS: Among respondents, approximately 74 and 78 % of the women received mammography and Pap test, respectively. Three HRQoL aspects (general health status, physical HRQoL, and activity limitation) were significantly associated with mammography use (all p values < 0.05), whereas two HRQoL aspects (general health status and physical HRQoL) were significantly associated with Pap test (p values <= 0.05). All significant relationships demonstrated higher cancer screening rates among individuals with better HRQoL. CONCLUSIONS: HRQoL is an important factor associated with use of mammography and Pap test. Future studies should explore the mechanisms associated with an individual's HRQoL and use HRQoL assessment as an avenue to influence adherence to use of mammography and Pap tests. PMID- 25804317 TI - Impact of Malnutrition on the Outcome of Critically Ill Children. AB - OBJECTIVE: To assess the impact of nutritional status on outcomes like mortality rate, length of mechanical ventilation and length of Pediatric Intensive Care Unit (PICU) stay, in critically ill children. METHODS: In this retrospective study conducted at a tertiary care center, records of 332 critically ill children between 1 mo to 15 y of age for whom anthropometric parameters were available were included. Anthropometric parameters for the study subjects were used to assess the nutritional status using the WHO growth charts as the reference. The study subjects were categorized as non-malnourished, moderately, and severely malnourished, defined by Body mass index (BMI) for age 0 to -2 SD, -2 to -3 SD and less than -3 SD of WHO growth charts, respectively. Various outcomes like mortality, duration of PICU stay and duration of mechanical ventilation were assessed in the 3 groups based on the nutritional status. RESULTS: The prevalence of malnutrition in the index study was 51.2 % with an overall mortality of 38.8 %. No difference was found between mortality rates and proportion of ventilated children in the three study groups. However, more children who were severely malnourished had significantly prolonged ICU stay (>7 d) as well as duration of mechanical ventilation (>7 d). When the outcome variables were compared after adjusting for PIM2 scores, there were increasing odds of mortality, ventilation, prolonged PICU stay and duration of mechanical ventilation with increasing severity of malnutrition. CONCLUSIONS: After stabilization of the initial critical phase, PICU outcome is influenced by the nutritional status of the children. PMID- 25804319 TI - Larval trematode infections in Galba truncatula (Gastropoda, Lymnaeidae) from the Brenne Regional Natural Park, central France. AB - Adult Galba truncatula ( >= 4 mm in shell height) were collected from 135 habitats for 3 years (2012-2014) to identify parasite species via the study of cercariae, and to determine the prevalence of each digenean infection in relation to the type of snail habitat (six types). A total of 323 infected snails and ten digenean species were noted in the bodies of 11,025 G. truncatula after their dissection. Snails with Calicophoron daubneyi and/or Fasciola hepatica were found in 20.7% and 12.5% of the habitats, respectively, and most of these infected snails were collected from rainwater-draining furrows and pools in meadows. The percentages were lower for snails with Echinostoma revolutum (9.6% of habitats) and Haplometra cylindracea (7.4%), and were less than 5% for those parasitized by any of the other five species of digenean. The highest prevalence of all digenean infections was noted in pools (9.4%), followed by furrows located in meadows (8.3%) and ponds (5.1%). The prevalence noted for each digenean infection varied with the type of habitat. In furrows located in meadows, the infection rate of C. daubneyi in snails (3.5%) was significantly higher than that of F. hepatica (2.2%). In pools, values greater than 1.5% were noted for C. daubneyi, H. cylindracea and Opistoglyphe ranae. In ponds, E. revolutum was the dominant species (prevalence, 2.5%). Parasite species richness in G. truncatula was greater in the Brenne Natural Regional Park than in the nearby region of Limousin (ten instead of eight). The distribution and prevalence of each parasite species were dependent on the type and location of each snail habitat. PMID- 25804318 TI - Stem Cell Therapy in Neonatal Diseases. AB - Common complications in neonates occur in almost every organ system in the neonatal intensive care unit. While a number of them have short-term effects, a few of them also have long-term consequences. Among the latter are bronchopulmonary dysplasia and necrotizing enterocolitis in premature neonates, and hypoxic ischemic encephalopathy in borderline preterm and term neonates. While medical advances have improved our understanding of the pathogenesis, therapies to effectively prevent and/or significantly ameliorate the severity of these disorders, and to decrease their associated mortality and morbidity have not been found. One promising approach to make a potential impact in the outcomes of these neonatal conditions is the use stem cells, specifically, mesenchymal stem cells. The authors briefly review the potential role of stem cell therapy in the above-mentioned neonatal diseases. They focus primarily on human clinical trials. PMID- 25804315 TI - Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. AB - Osteoclasts are cells derived from bone marrow macrophages and are important in regulating bone resorption during bone homeostasis. Understanding what drives osteoclast differentiation and activity is important when studying diseases characterized by heightened bone resorption relative to formation, such as osteoporosis. In the last decade, studies have indicated that reactive oxygen species (ROS), including superoxide and hydrogen peroxide, are crucial components that regulate the differentiation process of osteoclasts. However, there are still many unanswered questions that remain. This review will examine the mechanisms by which ROS can be produced in osteoclasts as well as how it may affect osteoclast differentiation and activity through its actions on osteoclastogenesis signaling pathways. In addition, the contribution of ROS to the aging-associated disease of osteoporosis will be addressed and how targeting ROS may lead to the development of novel therapeutic treatment options. PMID- 25804320 TI - Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis. AB - INTRODUCTION AND OBJECTIVES: Recent studies have identified several genetic variants associated with coronary artery disease. Some of these genetic variants are not associated with classical cardiovascular risk factors and the mechanism of such associations is unclear. The aim of the study was to determine whether these genetic variants are related to subclinical atherosclerosis measured by carotid intima media thickness, carotid stiffness, and ankle brachial index. METHODS: A cross-sectional study nested in the follow-up of the REGICOR cohort was undertaken. The study included 2667 individuals. Subclinical atherosclerosis measurements were performed with standardized methods. Nine genetic variants were genotyped to assess associations with subclinical atherosclerosis, individually and in a weighted genetic risk score. A systematic review and meta-analysis of previous studies that analyzed these associations was undertaken. RESULTS: Neither the selected genetic variants nor the genetic risk score were significantly associated with subclinical atherosclerosis. In the meta-analysis, the rs1746048 (CXCL12; n = 10581) risk allele was directly associated with carotid intima-media thickness (beta = 0.008; 95% confidence interval, 0.001 0.015), whereas the rs6725887 (WDR12; n = 7801) risk allele was inversely associated with this thickness (beta = -0.013; 95% confidence interval, -0.024 to -0.003). CONCLUSIONS: The analyzed genetic variants seem to mediate their association with coronary artery disease through different mechanisms. Our results generate the hypothesis that the CXCL12 variant appears to influence coronary artery disease risk through arterial remodeling and thickening, whereas the WDR12 risk variant could be related to higher plaque vulnerability. PMID- 25804321 TI - Beneficial Effects of Renal Denervation on Pulmonary Vascular Remodeling in Experimental Pulmonary Artery Hypertension. AB - INTRODUCTION AND OBJECTIVES: Activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system is closely associated with pulmonary arterial hypertension. We hypothesized that renal denervation decreases renin angiotensin-aldosterone activity and inhibits the progression of pulmonary arterial hypertension. METHODS: Twenty-two beagles were randomized into 3 groups. The dogs' pulmonary dynamics were measured before and 8 weeks after injection of 0.1mL/kg dimethylformamide (control dogs) or 2mg/kg dehydromonocrotaline (pulmonary arterial hypertension and pulmonary arterial hypertension + renal denervation dogs). Eight weeks after injection, neurohormone levels and pulmonary tissue morphology were measured. RESULTS: Levels of plasma angiotensin II and endothelin-1 were significantly increased after 8 weeks in the pulmonary arterial hypertension dogs and were higher in the lung tissues of these dogs than in those of the control and renal denervation dogs (mean [standard deviation] angiotensin II: 65 [9.8] vs 38 [6.7], 46 [8.1]; endothelin-1: 96 [10.3] vs 54 [6.2], 67 [9.4]; P < .01). Dehydromonocrotaline increased the mean pulmonary arterial pressure (16 [3.4] mmHg vs 33 [7.3] mmHg; P < .01), and renal denervation prevented this increase. Pulmonary smooth muscle cell proliferation was higher in the pulmonary arterial hypertension dogs than in the control and pulmonary arterial hypertension + renal denervation dogs. CONCLUSIONS: Renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental pulmonary arterial hypertension. The effect of renal denervation may contribute to decreased neurohormone levels. PMID- 25804322 TI - Atmospheric transport of radioactive debris to Norway in case of a hypothetical accident related to the recovery of the Russian submarine K-27. AB - The Russian nuclear submarine K-27 suffered a loss of coolant accident in 1968 and with nuclear fuel in both reactors it was scuttled in 1981 in the outer part of Stepovogo Bay located on the eastern coast of Novaya Zemlya. The inventory of spent nuclear fuel on board the submarine is of concern because it represents a potential source of radioactive contamination of the Kara Sea and a criticality accident with potential for long-range atmospheric transport of radioactive particles cannot be ruled out. To address these concerns and to provide a better basis for evaluating possible radiological impacts of potential releases in case a salvage operation is initiated, we assessed the atmospheric transport of radionuclides and deposition in Norway from a hypothetical criticality accident on board the K-27. To achieve this, a long term (33 years) meteorological database has been prepared and used for selection of the worst case meteorological scenarios for each of three selected locations of the potential accident. Next, the dispersion model SNAP was run with the source term for the worst-case accident scenario and selected meteorological scenarios. The results showed predictions to be very sensitive to the estimation of the source term for the worst-case accident and especially to the sizes and densities of released radioactive particles. The results indicated that a large area of Norway could be affected, but that the deposition in Northern Norway would be considerably higher than in other areas of the country. The simulations showed that deposition from the worst-case scenario of a hypothetical K-27 accident would be at least two orders of magnitude lower than the deposition observed in Norway following the Chernobyl accident. PMID- 25804323 TI - Reply to letter to the editor. PMID- 25804324 TI - Effect of locally injected autologous platelet-rich plasma on second intention wound healing of acute full-thickness skin defects in dogs. AB - OBJECTIVES: Second intention wound healing may be impaired by wound and host factors and thus more advanced therapies are required for a fast and satisfactory outcome. Platelet-rich plasma (PRP), rich in growth factors and cytokines essential for tissue repair, could improve wound healing. The purpose of this experimental study was to evaluate the effect of locally injected autologous PRP on second intention healing of acute full-thickness skin defects in dogs. METHODS: Three 2 x 2 cm full-thickness skin defects were created bilaterally on the dorsolateral area of the trunk of six Beagle dogs. The wounds of one randomly selected side received PRP treatment, whereas the contralateral wounds were left untreated (controls). Wound healing was evaluated by planimetry, laser-Doppler flowmetry measurements of tissue perfusion, and histologically. RESULTS: The rate of wound healing did not differ significantly between the two groups. Tissue perfusion was significantly higher in the PRP-treated group (p = 0.008) compared to controls on day 10. Histological evaluation revealed a trend towards greater collagen production and a significantly better collagen orientation (p = 0.019) in PRP-treated wounds on day 20. CLINICAL SIGNIFICANCE: Locally injected autologous PRP does not accelerate the healing process, but increases tissue perfusion and may promote the formation of organized collagen bundles in acute full-thickness skin defects in dogs. PMID- 25804325 TI - Life satisfaction and mental health problems (18 to 35 years). AB - BACKGROUND: Previous research has found that mental health is strongly associated with life satisfaction. In this study we examine associations between mental health problems and life satisfaction in a birth cohort studied from 18 to 35 years. METHOD: Data were gathered during the Christchurch Health and Development Study, which is a longitudinal study of a birth cohort of 1265 children, born in Christchurch, New Zealand, in 1977. Assessments of psychiatric disorder (major depression, anxiety disorder, suicidality, alcohol dependence and illicit substance dependence) using DSM diagnostic criteria and life satisfaction were obtained at 18, 21, 25, 30 and 35 years. RESULTS: Significant associations (p < 0.01) were found between repeated measures of life satisfaction and the psychiatric disorders major depression, anxiety disorder, suicidality, alcohol dependence and substance dependence. After adjustment for non-observed sources of confounding by fixed effects, statistically significant associations (p < 0.05) remained between life satisfaction and major depression, anxiety disorder, suicidality and substance dependence. Overall, those reporting three or more mental health disorders had mean life satisfaction scores that were nearly 0.60 standard deviations below those without mental health problems. A structural equation model examined the direction of causation between life satisfaction and mental health problems. Statistically significant (p < 0.05) reciprocal associations were found between life satisfaction and mental health problems. CONCLUSIONS: After adjustment for confounding, robust and reciprocal associations were found between mental health problems and life satisfaction. Overall, this study showed evidence that life satisfaction influences mental disorder, and that mental disorder influences life satisfaction. PMID- 25804326 TI - Wavelet transform analysis to assess oscillations in pial artery pulsation at the human cardiac frequency. AB - Pial artery adjustments to changes in blood pressure (BP) may last only seconds in humans. Using a novel method called near-infrared transillumination backscattering sounding (NIR-T/BSS) that allows for the non-invasive measurement of pial artery pulsation (cc-TQ) in humans, we aimed to assess the relationship between spontaneous oscillations in BP and cc-TQ at frequencies between 0.5 Hz and 5 Hz. We hypothesized that analysis of very short data segments would enable the estimation of changes in the cardiac contribution to the BP vs. cc-TQ relationship during very rapid pial artery adjustments to external stimuli. BP and pial artery oscillations during baseline (70s and 10s signals) and the response to maximal breath-hold apnea were studied in eighteen healthy subjects. The cc-TQ was measured using NIR-T/BSS; cerebral blood flow velocity, the pulsatility index and the resistive index were measured using Doppler ultrasound of the left internal carotid artery; heart rate and beat-to-beat systolic and diastolic blood pressure were recorded using a Finometer; end-tidal CO2 was measured using a medical gas analyzer. Wavelet transform analysis was used to assess the relationship between BP and cc-TQ oscillations. The recordings lasting 10s and representing 10 cycles with a frequency of ~1 Hz provided sufficient accuracy with respect to wavelet coherence and wavelet phase coherence values and yielded similar results to those obtained from approximately 70cycles (70s). A slight but significant decrease in wavelet coherence between augmented BP and cc TQ oscillations was observed by the end of apnea. Wavelet transform analysis can be used to assess the relationship between BP and cc-TQ oscillations at cardiac frequency using signals intervals as short as 10s. Apnea slightly decreases the contribution of cardiac activity to BP and cc-TQ oscillations. PMID- 25804327 TI - The role of tissue resection length in the determination of post-operative eyelid position for Muller's muscle-conjunctival resection surgery. AB - PURPOSE: To investigate the relationships between pre-operative marginal reflex distance (MRD), tissue resection length, phenylephrine response, and change in MRD with surgery for a cohort of individuals undergoing Muller's muscle conjunctival resection (MMCR) surgery. METHODS: All cases of MMCR surgery performed over a 13-year period at a single institution were screened for entry. Individuals with adequate photographic documentation and follow up were included. Patients with previous or concurrent upper eyelid, orbital or eyebrow disease of surgery were excluded. Marginal reflex distance (MRD) was calculated based on photographs utilizing public domain software. Data was plotted for inspection and appropriate statistical tests were performed. RESULTS: During the study period 198 eyes fit criteria for analysis. A loose association between tissue resection length and change in MRD with surgery was found (r = 0.176, p < 0.05); this relationship was not significant in ANOVA analysis (p = 0.367). There was a strong association between MRD change with surgery and pre-operative MRD (r = 0.498, p < 0.01). Approximately 28% of the sample responded to 2.5% phenylephrine drop instillation with a greater than 2 mm increase in MRD. The response to phenylephrine was strongly associated with pre-operative MRD (r = -0.441, p < 0.01). A regression on change in MRD with surgery with tissue resection, phenylephrine response >2 mm and pre-operative MRD as variables revealed a model with pre-operative MRD as the only significant predictor (p < 0.01). CONCLUSION: Tissue resection length and phenylephrine response play small roles relative to pre-operative MRD in the determination of change in MRD with MMCR surgery. PMID- 25804328 TI - Amphipaniculosides A-D, triterpenoid glycosides, and amphipaniculoside E, an aliphatic alcohol glycoside from the leaves of Amphilophium paniculatum. AB - Four new triterpenoids; One oleanane-, one ursane- and two cycloartane-type triterpenoids, named amphipaniculosides A-D, in addition to one new aliphatic alcohol glycoside, named amphipaniculoside E, were isolated from the 1-BuOH fraction of the leaves of Amphilophium paniculatum (L.) Kunth., together with five known compounds, (+)-lyoniresinol 3alpha-O-beta-D-glucopyranoside, (-) lyoniresinol 3alpha-O-beta-D-glucopyranoside, acteoside (verbascoside), isoacteoside (isoverbascoside), and luteolin 7-O-beta-D-glucopyranoside. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments ((1)H, (13)C, DEPT, COSY, ROESY, HSQC, HMBC) in combination with HR ESI-MS and by comparisons of their physical and spectroscopic data with literature values. PMID- 25804329 TI - Supersonic Shear Imaging and Transient Elastography With the XL Probe Accurately Detect Fibrosis in Overweight or Obese Patients With Chronic Liver Disease. AB - BACKGROUND & AIMS: Assessment of the severity of liver fibrosis is an important step in evaluating patients with chronic liver disease and determining their prognosis. We compared liver stiffness measurements (LSMs) made by supersonic shear imaging (SSI) with those of transient elastography (TE)-XL for their ability to determine the degree of liver fibrosis in overweight or obese patients with chronic liver disease. METHODS: We performed a prospective study of 258 patients with chronic hepatitis of different etiologies and a body mass index greater than 25, evaluated at the University of Miami from October 2013 to December 2014. Liver stiffness was measured using the TE-XL probe and SSI of the right and left lobes during the same clinic visit, and comparisons were made for fibrosis stage in 124 biopsy-proven patients. In addition, further analysis was performed on a subgroup of 102 chronic hepatitis C virus (HCV)-positive patients for whom biopsy data were available. RESULTS: Reliable LSMs were obtained from 96.1%, 94.6%, and 72.1% of patients using the TE-XL probe, SSI of the right lobe, and SSI of the left lobe, respectively. TE-XL, SSI of the right lobe, and SSI of the left lobe detected severe fibrosis (fibrosis stages 3-4), with area under the receiver operating characteristic curve (AUROC) values of 0.955, 0.954, and 0.910, respectively, compared with results from histologic analysis for the 124 biopsy-proven patients included in the study; these values were 0.952, 0.949, and 0.917, respectively, for the 102 biopsy-proven patients with HCV infection. TE XL, SSI of the right lobe, and SSI of the left lobe detected fibrosis stage 4 with AUROC values of 0.920, 0.930, and 0.910, respectively, compared with histologic analysis, in all 124-biopsy proven patients, and with AUROC values of 0.907, 0.914, and 0.887, respectively, in the 102 biopsy-proven patients with chronic HCV infection. CONCLUSIONS: SSI and the TE-XL probe each accurately quantify liver fibrosis in overweight or obese patients with chronic liver disease, including those with HCV infection, when compared with data obtained from histologic analysis. SSI data obtained from the right lobe and the TE-XL probe can be used to evaluate fibrosis with similar accuracy. PMID- 25804330 TI - Colon Cancer Presenting as an Upper Gastrointestinal Bleed. PMID- 25804331 TI - Safety and Feasibility of Using the Second-Generation Pillcam Colon Capsule to Assess Active Colonic Crohn's Disease. AB - BACKGROUND & AIMS: The second-generation Pillcam Colon Capsule Endoscope (PCCE-2; Given Imaging Ltd, Yoqneam, Israel) is an ingestible capsule for visualization of the colon. We performed a multicenter pilot study to assess its safety and feasibility in evaluating the severity of Crohn's disease (CD). METHODS: In a prospective study, 40 patients with active colonic CD underwent PCCE-2 and optical colonoscopy procedures. Using both techniques, we generated values for the Crohn's Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for CD, and global evaluation of lesion severity. In the first stage of the study, we calculated the correlation between PCCE-2 and optical colonoscopy scores. In the second stage, we performed interobserver agreement analysis for a random subset of 20 PCCE-2 recordings, graded in duplicate by 2 independent readers. RESULTS: There was substantial agreement between PCCE-2 and optical colonoscopy in the measurement of the CDEIS (intraclass correlation coefficient [ICC], 0.65; 95% confidence interval [CI], 0.43-0.80). There was substantial interobserver agreement between 2 independent PCCE-2 readers for the CDEIS (ICC, 0.67; 95% CI, 0.35-0.86) and the Simple Endoscopic Score for CD (ICC, 0.66; 95% CI, 0.32-0.85). However, the PCCE-2 scoring systematically underestimated the severity of disease compared with optical colonoscopy; based on our results, PCCE 2 detected colonic ulcerations with 86% sensitivity and 40% specificity. No adverse events were observed and PCCE-2 was better tolerated than colonoscopy. CONCLUSIONS: PCCE-2 is feasible, safe, and well tolerated for the assessment of mucosal CD activity in selected populations. Larger studies are needed to assess its operating characteristics further. European clinical trials database number: 2014-003854-15. PMID- 25804333 TI - Multi-criteria group decision making for evaluating the performance of e-waste recycling programs under uncertainty. AB - This paper presents a multi-criteria group decision making approach for effectively evaluating the performance of e-waste recycling programs under uncertainty in an organization. Intuitionistic fuzzy numbers are used for adequately representing the subjective and imprecise assessments of the decision makers in evaluating the relative importance of evaluation criteria and the performance of individual e-waste recycling programs with respect to individual criteria in a given situation. An interactive fuzzy multi-criteria decision making algorithm is developed for facilitating consensus building in a group decision making environment to ensure that all the interest of individual decision makers have been appropriately considered in evaluating alternative e waste recycling programs with respect to their corporate sustainability performance. The developed algorithm is then incorporated into a multi-criteria decision support system for making the overall performance evaluation process effectively and simple to use. Such a multi-criteria decision making system adequately provides organizations with a proactive mechanism for incorporating the concept of corporate sustainability into their regular planning decisions and business practices. An example is presented for demonstrating the applicability of the proposed approach in evaluating the performance of e-waste recycling programs in organizations. PMID- 25804332 TI - Analysis of a single Helicobacter pylori strain over a 10-year period in a primate model. AB - Helicobacter pylori from different individuals exhibits substantial genetic diversity. However, the kinetics of bacterial diversification after infection with a single strain is poorly understood. We investigated evolution of H. pylori following long-term infection in the primate stomach; Rhesus macaques were infected with H. pylori strain USU101 and then followed for 10 years. H. pylori was regularly cultured from biopsies, and single colony isolates were analyzed. At 1-year, DNA fingerprinting showed that all output isolates were identical to the input strain; however, at 5-years, different H. pylori fingerprints were observed. Microarray-based comparative genomic hybridization revealed that long term persistence of USU101 in the macaque stomach was associated with specific whole gene changes. Further detailed investigation showed that levels of the BabA protein were dramatically reduced within weeks of infection. The molecular mechanisms behind this reduction were shown to include phase variation and gene loss via intragenomic rearrangement, suggesting strong selective pressure against BabA expression in the macaque model. Notably, although there is apparently strong selective pressure against babA, babA is required for establishment of infection in this model as a strain in which babA was deleted was unable to colonize experimentally infected macaques. PMID- 25804334 TI - Impact of compost process conditions on organic micro pollutant degradation during full scale composting. AB - Knowledge about the effects of oxygen concentration, nutrient availability and moisture content on removal of organic micro-pollutants during aerobic composting is at present very limited. Impact of oxygen concentration, readily available nitrogen content (NH4(+), NO3(-)), and moisture content on biological transformation of 15 key organic micro-pollutants during composting, was therefore investigated using bench-scale degradation experiments based on non sterile compost samples, collected at full-scale composting facilities. In addition, the adequacy of bench-scale composting experiments for representing full-scale composting conditions, was investigated using micro-pollutant concentration measurements from both bench- and full-scale composting experiments. Results showed that lack of oxygen generally prevented transformation of organic micro-pollutants. Increasing readily available nitrogen content from about 50 mg N per 100 g compost to about 140 mg N per 100 g compost actually reduced micro-pollutant transformation, while changes in compost moisture content from 50% to 20% by weight, only had minor influence on micro pollutant transformation. First-order micro-pollutant degradation rates for 13 organic micro-pollutants were calculated using data from both full- and bench scale experiments. First-order degradation coefficients for both types of experiments were similar and ranged from 0.02 to 0.03 d(-1) on average, indicating that if a proper sampling strategy is employed, bench-scale experiments can be used to represent full-scale composting conditions. PMID- 25804335 TI - [Incidence of urinary tract infections after cardiac surgery: comparative study accordind to catheterization device]. AB - INTRODUCTION: Urinary tract infections (UTI) associated with urethral catheterization are the second cause of nosocomial infections in Intensive care units. We confirm a UTI when we get a result of 100,000 CFU/ml with at least one microorganism in a urine culture. MAIN OBJECTIVE: Compare and determine the incidence of UTI in cardiac surgery postpoperative patients according to the catheterization device. METHODS: A prospective, randomized analytical observational study of patients in the immediate cardiac surgery postoperative period. One group was probed with catheter Foley and one was inserted the catheter BIPFoley-Bactiguard(r) (CBF). The CBF is coated with noble metals (silver, gold and palladium) and biocompatible antimicrobial properties, covering the entire surface of the device and prevents the formation of biofilm, microbial adherence and colonization. RESULTS: 116 cases, 59.5% (69 cases) were negative for UTI and 40.5% (47 cases) were positive. Out of the positive UTI results, 25% were carriers of catheter Foley and 15.5% of CBF. Most common etiologic microorganisms: Escherichia coli 29.8% Klebsiella pneumonia 29.8%, Klebsiella oxytoca 9%. CONCLUSION: With the data we have observed that patients catheterized BIPfoley-Bactiguard(r) are infected to a lesser extent than Foley carriers. PMID- 25804336 TI - Validation and impact analysis of prognostic clinical prediction rules for low back pain is needed: a systematic review. AB - OBJECTIVES: To identify prognostic forms of clinical prediction rules (CPRs) related to the nonsurgical management of adults with low back pain (LBP) and to evaluate their current stage of development. STUDY DESIGN AND SETTING: Systematic review using a sensitive search strategy across seven databases with hand searching and citation tracking. RESULTS: A total of 10,005 records were screened for eligibility with 35 studies included in the review. The included studies report on the development of 30 prognostic LBP CPRs. Most of the identified CPRs are in their initial phase of development. Three CPRs were found to have undergone validation--the Cassandra rule for predicting long-term significant functional limitations and the five-item and two-item Flynn manipulation CPRs for predicting a favorable functional prognosis in patients being treated with lumbopelvic manipulation. No studies were identified that investigated whether the implementation of a CPR resulted in beneficial patient outcomes or improved resource efficiencies. CONCLUSION: Most of the identified prognostic CPRs for LBP are in the initial phase of development and are consequently not recommended for direct application in clinical practice at this time. The body of evidence provides emergent confidence in the limited predictive performance of the Cassandra rule and the five-item Flynn manipulation CPR in comparable clinical settings and patient populations. PMID- 25804337 TI - High-level soluble expression of a bacterial N-acyl-d-glucosamine 2-epimerase in recombinant Escherichia coli. AB - N-Acyl-d-glucosamine 2-epimerase (AGE) is an important enzyme for the biocatalytic synthesis of N-acetylneuraminic acid (Neu5Ac). Due to the wide range of biological applications of Neu5Ac and its derivatives, there has been great interest in its large-scale synthesis. Thus, suitable strategies for achieving high-level production of soluble AGE are needed. Several AGEs from various organisms have been recombinantly expressed in Escherichia coli. However, the soluble expression level was consistently low with an excessive formation of inclusion bodies. In this study, the effects of different solubility-enhancement tags, expression temperatures, chaperones and host strains on the soluble expression of the AGE from the freshwater cyanobacterium Anabaena variabilis ATCC 29413 (AvaAGE) were examined. The optimum combination of tag, expression temperature, co-expression of chaperones and host strain (His6-tag, 37 degrees C, GroEL/GroES, E. coli BL21(DE3)) led to a 264-fold improvement of the volumetric epimerase activity, a measure of the soluble expression, compared to the starting conditions (His6-maltose-binding protein-tag, 20 degrees C, without chaperones, E. coli BL21(DE3)). A maximum yield of 22.5mg isolated AvaAGE per liter shake flask culture was obtained. PMID- 25804338 TI - Economic burden of common variable immunodeficiency: annual cost of disease. AB - OBJECTIVES: In the context of the unknown economic burden imposed by primary immunodeficiency diseases, in this study, we sought to calculate the costs associated with the most prevalent symptomatic disease, common variable immunodeficiency (CVID). METHODS: Direct, indirect and intangible costs were recorded for diagnosed CVID patients. Hidden Markov model was used to evaluate different disease-related factors and Monte Carlo method for estimation of uncertainty intervals. RESULTS: The total estimated cost of diagnosed CVID is US$274,200/patient annually and early diagnosis of the disease can save US$6500. Hospital admission cost (US$25,000/patient) accounts for the most important expenditure parameter before diagnosis, but medication cost (US$40,600/patients) was the main factor after diagnosis primarily due to monthly administration of immunoglobulin. CONCLUSION: The greatest cost-determining factor in our study was the cost of treatment, spent mostly on immunoglobulin replacement therapy of the patients. It was also observed that CVID patients' costs are reduced after diagnosis due to appropriate management. PMID- 25804340 TI - Viral-related diseases of the head and neck. PMID- 25804341 TI - Epstein-Barr virus (EBV)-associated lymphoid lesions of the head and neck. AB - Epstein Barr virus (EBV)-related lymphoproliferative processes occur in the head and neck ranging from reactive processes such as infectious mononucleosis to high grade malignant lymphomas. EBV is a ubiquitous herpes virus that infects more than 90% of adults worldwide, and is generally transferred though saliva. Primary infection can occur throughout life. EBV is the first virus linked to malignancies, both epithelial and lymphoid. Both T and B cell lymphomas can be associated with EBV and evidence shows that an individual's response to the acute EBV infection may be critical in the development of subsequent lymphoma. Currently, in situ hybridization for EBER is the most sensitive available test to detect EBV and should be routinely performed in lymphoproliferative lesions of the head and neck. Immunohistochemistry for EBV related proteins, such as LMP1, is much less sensitive than EBER in situ hybridization, but can help determine latency patterns of EBV infection. Although relatively rare, primary EBV-related lymphomas must be considered in the differential of atypical lymphoid proliferations in the head and neck. We present selected EBV-related disorders of the head and neck discussing etiology as well as differential diagnosis. PMID- 25804342 TI - Human papillomavirus-related head and neck squamous cell carcinoma variants. AB - During the last few decades, a phenotypically distinct type of head and neck squamous cell carcinoma (SCC), which is etiologically related to human papillomavirus (HPV), has emerged, and its prevalence continues to increase. The tumors are site-specific with special predilection for the oropharynx. They are morphologically and molecularly distinct and are responsive to different types of treatment modalities, with excellent clinical outcome, in spite of early lymph node metastasis. Microscopically, the carcinomas are nonkeratinizing SCCs. More recently, other variants that are believed to be etiologically related to HPV are reported. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in these HPV-related variants. This review is an attempt to answer some of these questions based on information derived from available yet limited number of publications. The variants to be discussed include nonkeratinizing SCC (NKSCC), NKSCC with maturation (hybrid type), keratinizing SCC (KSSC), basaloid squamous carcinoma (BSCC), undifferentiated carcinoma (UC), papillary SCC (PSCC), small cell carcinoma, adenosquamous carcinoma (AdSCC), and spindle cell (sarcomatoid) carcinoma. PMID- 25804339 TI - Final results of EFC6663: a multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia. AB - Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. One hundred and sixty five patients were enrolled and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months, respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures. PMID- 25804343 TI - The pathology of HPV-related head and neck cancer: implications for the diagnostic pathologist. AB - A subset of head and neck squamous cell carcinomas are caused by the human papillomavirus (HPV). This HPV-related form of head and neck squamous cell carcinoma (HPV-HNSCC) has captured the attention of the oncology community for its rising incidence, its link to non-traditional risk factors, and its divergent clinical behavior. To diagnose this special form of head and neck squamous cell carcinoma is to provide important prognostic information and, in some instances, redirect clinical therapy. The diagnosis of HPV-HNSCC is aided by a strong appreciation for its characteristic microscopic findings and by an awareness of aberrant features that set apart a growing list of HPV-HNSCC morphologic variants. This review will delineate the microscopic appearance of HPV-HNSCC, spotlight ways in which the misinterpretation of these microscopic features can lead to diagnostic confusion, offer recommendations for appropriate terminology when diagnosing HPV-HNSCC, and provide examples of specific diagnostic scenarios where HPV testing can inform the diagnostic process. PMID- 25804344 TI - Lymphoepithelial-like carcinomas of the head and neck. AB - Lymphoepithelial-like carcinomas (LELC) of the head and neck represent malignant neoplasms that are histologically similar to nasopharyngeal carcinoma (NPC), nonkeratinizing undifferentiated type but arise in locations other than the nasopharynx. The most common location for LELC in the head and neck is the salivary glands, in particular the parotid gland. However, LELC may arise in other sites including the oropharynx (tonsils, base of tongue), sinonasal tract, larynx, and middle ear/temporal bone. Unlike the nonkeratinizing undifferentiated type of NPC which is etiologically linked to Epstein-Barr virus (EBV), LELCs are not uniformly associated with EBV. The differential diagnosis for LELC varies per site and depending on the site of occurrence may include lymphoepithelial sialadenitis, sinonasal undifferentiated carcinoma (SNUC), and large cell neuroendocrine carcinoma. Treatment general includes combined (multimodality) therapy including surgical resection, neck dissection, radiation therapy and/or chemotherapy. The prognosis may vary per site overall favorable owing to a good response to therapy. PMID- 25804346 TI - The role of marriage in the causal pathway from economic conditions early in life to mortality. AB - This paper analyzes the interplay between early-life conditions and marital status, as determinants of adult mortality. We use individual data from Dutch registers (years 1815-2000), combined with business cycle conditions in childhood as indicators of early-life conditions. The empirical analysis estimates bivariate duration models of marriage and mortality, allowing for unobserved heterogeneity. Results show that conditions around birth and school going ages are important for marriage and mortality. Men typically enjoy a protective effect of marriage, whereas women suffer during childbearing ages. However, having been born under favorable economic conditions reduces female mortality during childbearing ages. PMID- 25804345 TI - The laboratory domestication of Caenorhabditis elegans. AB - Model organisms are of great importance to our understanding of basic biology and to making advances in biomedical research. However, the influence of laboratory cultivation on these organisms is underappreciated, and especially how that environment can affect research outcomes. Recent experiments led to insights into how the widely used laboratory reference strain of the nematode Caenorhabditis elegans compares with natural strains. Here we describe potential selective pressures that led to the fixation of laboratory-derived alleles for the genes npr-1, glb-5, and nath-10. These alleles influence a large number of traits, resulting in behaviors that affect experimental interpretations. Furthermore, strong phenotypic effects caused by these laboratory-derived alleles hinder the discovery of natural alleles. We highlight strategies to reduce the influence of laboratory-derived alleles and to harness the full power of C. elegans. PMID- 25804348 TI - Exercise oscillatory ventilation: ventilation-perfusion abnormality in heart failure. PMID- 25804347 TI - Clinical outcomes of weekly cisplatin chemoradiotherapy for patients with pyriform sinus cancer. AB - BACKGROUND: Pyriform sinus squamous cell carcinoma (SCC) has one of the worst prognoses of all upper aerodigestive tract cancers. Improving clinical outcomes for patients with hypopharyngeal SCC has been particularly challenging for head and neck surgeons and oncologists. METHODS: We investigated 30 patients with pyriform sinus SCC to verify the effectiveness of weekly cisplatin chemotherapy with concurrent radiotherapy. Cisplatin was administered at a dose of 40 mg/m(2) on weeks 1, 2, 3, 5, 6, and 7 during definitive radiotherapy with the aim of preserving the larynx. RESULTS: All 30 patients achieved definitive radiotherapy at a median dose of 70 Gy (range 64-70 Gy). Cisplatin was administrated concomitantly a median of five times (range 2-6 times). Persistent or recurrent primary disease was observed in four patients (13 %). Persistent or recurrent nodal metastasis was observed in five patients (17 %). Nine salvage surgeries were performed for eight patients, of whom seven survived without any evidence of disease. Post-operative complications were observed in two patients (22 %). The 5 year overall survival and locoregional control rates were 87 and 96 %, respectively. The 5-year laryngeal preservation rate was 74 %. CONCLUSIONS: The regimen of weekly cisplatin CRT may be effective for pyriform sinus SCC; however, there were problems with strong selection bias in the current study due to the large number of T2 patients. Salvage surgery was safe and was able to improve the survival rate. This chemoradiation regimen was considered successful in preserving laryngeal function. PMID- 25804349 TI - Risk of heart failure- and cardiac death gradually increases with more right ventricular pacing. AB - BACKGROUND: Right ventricular pacing (RVP) is associated with an increased risk of heart failure (HF) events. However, the extent and shape of this association is hardly assessed. OBJECTIVE: We quantified whether the undesired effects of RVP are confirmed in an unselected population of first bradycardia pacemaker recipients. Furthermore, we studied the shape of the association between RVP and HF death and cardiac death. METHODS: Cumulative percentage RVP (%RVP) was measured in 1395 patients. Using multivariable Cox regression analysis with %RVP as time-dependant co-variate we evaluated the association between %RVP and HF- and cardiac death, both unadjusted and adjusted for confounders, including age, gender, pacemaker-indication, cardiac disease, HF at baseline, diabetes, hypertension, atrio-ventricular synchrony, usage of beta-blocking drugs, anti arrhythmic medication, HF medication, and prior atrial fibrillation/flutter. Non linear associations were evaluated with restricted cubic splines. RESULTS: During a mean follow-up of 5.8 (SD 1.1) years 104 HF deaths and 144 cardiac deaths were observed. %RVP was significantly associated with HF- and cardiac death in both unadjusted (p<0.001 and p<0.001, respectively) and adjusted analyses (p=0.046 and p=0.009, respectively). Our results show a linear association between %RVP and HF and cardiac death. We observed a constant increase of 8% risk of HF death per 10% increase in RVP. A model incorporating various non-linear transformations of %RVP using restrictive cubic splines showed no improved model fit over linear associations. CONCLUSION: This long-term, prospective study observed a significant, though linear association between %RVP and risk of HF death and/or cardiac death in unselected bradycardia pacing recipients. PMID- 25804350 TI - Reference values for left and right ventricular trabeculation and non-compacted myocardium. AB - BACKGROUND: Since the differentiation between physiological and pathological trabeculation is challenging, we assessed its distribution in a reference population of selected healthy volunteers. METHODS: We studied 117 subjects (58 males) stratified into age tertiles and by gender. Cardiovascular magnetic resonance images were acquired using a standard SSFP-sequence. Left and right ventricular (LV/RV) end-diastolic (EDV), end-systolic (ESV) and trabeculated volumes indexed to the body surface area as well as ejection fraction (EF) were quantified in short-axis views. The maximum non-compacted-to-compacted (NC/C) ratio was measured in long-axis views. RESULTS: The trabeculated volumes were significantly larger in men than in women and decreased with age. The correlation between both was moderate (r=0.46; p<0.001). LV trabeculated volume was positively associated with EDV and ESV (r=0.74; r=0.59; both p<0.001) and negatively with EF (r=-0.27; p<0.005). It was no independent predictor for EF. The maximum NC/C ratio was >2.3 in 46.2% and >2.5 in 37.6% of the subjects, which is regarded as abnormal in current literature. The fraction of subjects with a maximum NC/C ratio >2.3 and the mean maximum NC/C ratio differed significantly between gender but not between age groups. An increasing NC/C ratio was associated with a significant decrease in EF (r=-0.21; p<0.05). CONCLUSION: A considerable amount of healthy volunteers fulfils the current diagnostic criteria of LV noncompaction with female subjects showing a higher fraction of false positive results than males. LV trabeculated volume is more pronounced in young subjects and declines with age. The use of age- and gender-specific reference values as provided in this study may facilitate the delineation of physiological and pathological findings. PMID- 25804351 TI - Classification of obsessive compulsive disorder by EEG complexity and hemispheric dependency measurements. AB - In the present study, both single channel electroencephalography (EEG) complexity and two channel interhemispheric dependency measurements have newly been examined for classification of patients with obsessive-compulsive disorder (OCD) and controls by using support vector machine classifiers. Three embedding entropy measurements (approximate entropy, sample entropy, permutation entropy (PermEn)) are used to estimate single channel EEG complexity for 19-channel eyes closed cortical measurements. Mean coherence and mutual information are examined to measure the level of interhemispheric dependency in frequency and statistical domain, respectively for eight distinct electrode pairs placed on the scalp with respect to the international 10-20 electrode placement system. All methods are applied to short EEG segments of 2 s. The classification performance is measured 20 times with different 2-fold cross-validation data for both single channel complexity features (19 features) and interhemispheric dependency features (eight features). The highest classification accuracy of 85 +/-5.2% is provided by PermEn at prefrontal regions of the brain. Even if the classification success do not provided by other methods as high as PermEn, the clear differences between patients and controls at prefrontal regions can also be obtained by using other methods except coherence. In conclusion, OCD, defined as illness of orbitofronto striatal structures [Beucke et al., JAMA Psychiatry70 (2013) 619-629; Cavedini et al., Psychiatry Res.78 (1998) 21-28; Menzies et al., Neurosci. Biobehav. Rev.32(3) (2008) 525-549], is caused by functional abnormalities in the pre frontal regions. Particularly, patients are characterized by lower EEG complexity at both pre-frontal regions and right fronto-temporal locations. Our results are compatible with imaging studies that define OCD as a sub group of anxiety disorders exhibited a decreased complexity (such as anorexia nervosa [Toth et al., Int. J. Psychophysiol.51(3) (2004) 253-260] and panic disorder [Bob et al., Physiol. Res.55 (2006) S113-S119]). PMID- 25804352 TI - A P300 brain-computer interface based on a modification of the mismatch negativity paradigm. AB - The P300-based brain-computer interface (BCI) is an extension of the oddball paradigm, and can facilitate communication for people with severe neuromuscular disorders. It has been shown that, in addition to the P300, other event-related potential (ERP) components have been shown to contribute to successful operation of the P300 BCI. Incorporating these components into the classification algorithm can improve the classification accuracy and information transfer rate (ITR). In this paper, a single character presentation paradigm was compared to a presentation paradigm that is based on the visual mismatch negativity. The mismatch negativity paradigm showed significantly higher classification accuracy and ITRs than a single character presentation paradigm. In addition, the mismatch paradigm elicited larger N200 and N400 components than the single character paradigm. The components elicited by the presentation method were consistent with what would be expected from a mismatch paradigm and a typical P300 was also observed. The results show that increasing the signal-to-noise ratio by increasing the amplitude of ERP components can significantly improve BCI speed and accuracy. The mismatch presentation paradigm may be considered a viable option to the traditional P300 BCI paradigm. PMID- 25804353 TI - Evaluation of the Relationship between Selected Reticulocyte Parameters and Inflammation determined by Plasma C-reactive Protein in Dogs. AB - Anaemia secondary to inflammatory disease is one of the main causes of anaemia in veterinary and human medicine and impairment of iron homeostasis due to the release of pro-inflammatory cytokines is one of the aetiological mechanisms involved. Because reticulocytes are recently produced cells, reticulocyte indices are early indicators of iron deficiency anaemia in man and dogs and reticulocyte indices may be affected during the course of inflammatory processes earlier than indices related to mature red blood cells. The aim of this study was to evaluate the possible influence of inflammation on reticulocyte parameters including concentration, mean reticulocyte volume, volume distribution width, percentage of microcytic reticulocytes, percentage of macrocytic reticulocytes, mean reticulocyte haemoglobin content (CHr), haemoglobin distribution width, cell haemoglobin concentration, mean percentage of hypochromic reticulocytes, percentage of reticulocytes with low CHr and immature reticulocyte factor medium and high, and on white blood cell concentration by using C-reactive protein (CRP) as an inflammatory biomarker. Samples from 175 diseased dogs and 16 healthy dogs were included in the study. The diseased dogs were grouped according to plasma CRP and ferritin concentrations, the presence and type of anaemia and different aetiopathological categories. Dogs with high plasma CRP concentrations had lower CHr (median 23.3 pg) and percentage of reticulocytes with high CHr (median 35.5%) and higher percentage of reticulocytes with low CHr (median 14.6%) compared with dogs without inflammation (median 24.9 pg, median 50.9% and median 7.8%, respectively) and healthy dogs (median 25.1 pg, median 50.0% and median 6.1%, respectively), with no differences between the last two groups. Reticulocyte parameters, particularly those related to haemoglobin concentration, are therefore affected by inflammatory conditions in anaemic and in non-anaemic dogs. PMID- 25804354 TI - US Military Child and Adolescent Psychiatry Training Programs and Careers of Military Child Psychiatrists. AB - Military child and adolescent psychiatry (CAP) fellowship programs offer educational experiences universal to all civilian training programs in the USA. They also offer unique training opportunities not found in civilian CAP fellowships in order to prepare graduates to serve the needs of military families. Military-specific curricula and exposures prepare trainees to address various issues faced by military families, in contending with frequent military moves, parental deployments, and disrupted social ties. Curricula are also designed to provide the psychiatrist with a greater understanding of the rigors of military service. CAP training and subsequent assignments prepare military psychiatrists for diverse career paths in the military environment. CAP military careers often include duties in addition to treating patients. Administrative roles, academic teaching positions, as well as school consultation positions are all career options available to military CAP. PMID- 25804355 TI - Stable mammalian producer cell lines for structural biology. AB - The mammalian cell lines HEK293 and CHO have become important expression hosts in structural biology. Generating stable mammalian cell lines remains essential for studying the function and structure of recombinant proteins, despite the emergence of highly efficient transient transfection protocols. Production with stable cell lines can be scaled up easily and high volumetric product yield can be achieved. Protein structure reports of the past two years that used stable cell lines were surveyed for this review. Well-established techniques and novel approaches for generating stable cell lines and stable cell pools are presented, including cell sorting, site-specific recombination, transposons, the Lentivirus system and phage integrases. Host cell line optimization by endoglycosidase overexpression and sequence-specific genome engineering is highlighted. PMID- 25804357 TI - Does bariatric surgery influence diabetic retinopathy? PMID- 25804356 TI - Potential Benefits of Prophylactic Cholecystectomy in Patients Undergoing Bariatric Bypass Surgery. AB - BACKGROUND: In patients with morbid obesity, laparoscopic Roux-en-Y gastric bypass (LRYGB) is the treatment of choice. Patients with gallstones routinely undergo cholecystectomy at the same time as LRYGB. Although the risk of developing gallstones afterwards is high, prophylactic cholecystectomy during LRYGB remains controversial. Therefore, we conducted a retrospective study to evaluate the risk associated with prophylactic cholecystectomy and risk factors for developing gallstones after LRYGB. METHODS: Data for patients on whom we consecutively performed LRYGB in 2003-2008 were extracted from the prospective bariatric database. The primary endpoint of the study was detection of newly developed gallstones by ultrasonography, and the secondary endpoint was evaluation of the incidence of post-LRYGB cholecystectomy (questionnaire). RESULTS: Of 117 patients who underwent LRYGB, 20 (17 %) had a previous and 26 (22 %) had a concomitant cholecystectomy. Of the 71 LRYGB patients remaining who had not had their gallbladders removed, 22 (34 %) developed gallstones, with 11 (17 %) requiring emergency cholecystectomy before the study began. Seven (10 %) patients were lost to follow-up, and 53 (75 %) underwent abdominal ultrasound during follow-up, which detected stones in another 11 (17 %) patients up to end of the study period. CONCLUSIONS: Nearly 50 % of our patients had either experienced gallstones before LRYGB or developed gallstones after LRYGB. In the group with new gallstone development, 50 % required emergency cholecystectomy. These results, together with the reported better quality of life after a combined procedure and the reported economic benefits, support the use of concomitant prophylactic cholecystectomy in patients undergoing LRYGB. PMID- 25804358 TI - Involvement of AMPA receptors in the antidepressant-like effects of dextromethorphan in mice. AB - Dextromethorphan (DM) is an antitussive with rapid acting antidepressant potential based on pharmacodynamic similarities to ketamine. Building upon our previous finding that DM produces antidepressant-like effects in the mouse forced swim test (FST), the present study aimed to establish the antidepressant-like actions of DM in the tail suspension test (TST), another well-established model predictive of antidepressant efficacy. Additionally, using the TST and FST, we investigated the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the antidepressant-like properties of DM because accumulating evidence suggests that AMPA receptors play an important role in the pathophysiology of depression and may contribute to the efficacy of antidepressant medications, including that of ketamine. We found that DM displays antidepressant-like effects in the TST similar to the conventional and fast acting antidepressants characterized by imipramine and ketamine, respectively. Moreover, decreasing the first-pass metabolism of DM by concomitant administration of quinidine (CYP2D6 inhibitor) potentiated antidepressant-like actions, implying DM itself has antidepressant efficacy. Finally, in both the TST and FST, pretreatment with the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro 1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide) significantly attenuated the antidepressant-like behavior elicited by DM. Together, the data show that DM exerts antidepressant-like actions through AMPA receptors, further suggesting DM may act as a safe and effective fast acting antidepressant drug. PMID- 25804359 TI - The serotonin 5-HT1A receptor agonist tandospirone improves executive function in common marmosets. AB - Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40 mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1-0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1 0.3mg/kg) or haloperidol (0.1-0.3mg/kg) did not improve animals' performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1 0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor. PMID- 25804360 TI - Cortical gyrification and its relationships with cortical volume, cortical thickness, and cognitive performance in healthy mid-life adults. AB - Across species, greater cortical gyrification, or folding of the cortex, has been shown to be associated with higher cognitive abilities and is thought to reflect an evolutionary process aimed at maximizing the number of cerebral computational units while minimizing the energy and communication costs of larger brains. Relatively little is known about the significance of individual variation in gyrification in humans and how it relates to other aspects of cerebral structure and function. In the current study, we examined relationships between cortical gyrification and (i) cortical volume, (ii) cortical thickness, and (iii) executive functions. Participants were middle-aged healthy adults (44-48 years old, n=396) in a community-based sample. T1-weighted 3D structural magnetic resonance imaging scans were acquired in a Fast Field Echo sequence. Cortical gyrification, volume, and thickness were measured through the semi-automated software FreeSurfer. Results showed that cortical gyrification was strongly and positively related to cortical volume, but was negatively related to cortical thickness in many regions of the cortex. In addition, frontal gyrification was positively related to performance in working memory and mental flexibility tasks. These results support the view that greater cortical gyrification is related both to bigger brain volumes and better cognitive function, but not to greater cortical thickness. The results provide evidence of functional relevance of cortical gyrification development, and show that it can be a useful index to investigate structure-cognition relationships. PMID- 25804361 TI - Distal motor deficit contributions to postural instability and gait disorder in Parkinson's disease. AB - Clinical subtypes in Parkinson's disease (PD) are often based on the presence of clustered motor symptoms. In contrast to the tremor dominant (TD) subtype, the postural instability and gait disorder (PIGD) subtype is characterized by predominantly axial motor involvement and increased cognitive impairment. It is, however, unclear if subtypes represent distinct underlying neuropathological mechanisms or reflect more severe disease progression. We aimed to clarify the validity of PD subtypes by investigating behavioral outcomes at multiple levels. Therefore, spatiotemporal kinematics of gait, upper and lower limb repetitive movements in combination with a balance and cognitive assessment were recorded in 73 patients with PD. We classified patients as PIGD (n=43), TD (n=22) or indeterminate (n=8) while 'off' medication and recruited 20 age-matched controls. Surprisingly, differences between PIGD and TD were more prominent during repetitive distal motor tasks than during gait. Gait impairment in PIGD was only shown by reduced step length and gait speed. However, motor scaling and coordination of distal movements were more affected in PIGD than in TD patients. PIGD patients also had impaired postural control compared to TD patients as shown by lower mini-BESTest scores. There were no cognitive differences between patient subgroups. Distal movement was not significantly different in TD patients from controls, except for greater movement asymmetry. The results indicate a widespread impairment within PIGD with more pronounced distal than axial motor deficits. This suggests involvement of different neurotransmitter systems in the neuropathology of PD subtypes, which are at least partially independent of disease progression. PMID- 25804362 TI - Cumulative effects of anodal and priming cathodal tDCS on pegboard test performance and motor cortical excitability. AB - Transcranial direct current stimulation (tDCS) protocols applied over the primary motor cortex are associated with changes in motor performance. This transcranial magnetic stimulation (TMS) study examines whether cathodal tDCS prior to motor training, combined with anodal tDCS during motor training improves motor performance and off-line learning. Three study groups (n=36) were trained on the grooved pegboard test (GPT) in a randomized, between-subjects design: SHAM-sham stimulation prior and during training, STIM1-sham stimulation prior and atDCS during training, STIM2-ctDCS stimulation prior and atDCS during training. Motor performance was assessed by GPT completion time and retested 14 days later to determine off-line learning. Cortical excitability was assessed via TMS at baseline (T0), prior training (T1), after training (T2), and 60 min after training (T3). Motor evoked potentials (MEP) were recorded from m. abductor pollicis brevis of the active left hand. GPT completion time was reduced for both stimulated groups compared to SHAM. For STIM2 this reduction in time was significantly higher than for STIM1 and further off-line learning occurred after STIM2. After ctDCS at T1, MEP amplitude and intracortical facilitation was decreased and intracortical inhibition was increased. After atDCS at T2, an opposite effect was observed for STIM1 and STIM2. For STIM2 these neuromodulatory effects were retained until T3. It is concluded that application of atDCS during the training improves pegboard performance and that additional priming with ctDCS has a positive effect on off-line learning. These cumulative behavioral gains were indicated by the preceding neuromodulatory changes. PMID- 25804364 TI - Diaphyseal Fracture of the Radius. PMID- 25804363 TI - The prognostic value of concurrent phrenic nerve palsy in newborn babies with neonatal brachial plexus palsy. AB - PURPOSE: To investigate the prognostic value of concurrent phrenic nerve palsy for predicting spontaneous motor recovery in neonatal brachial plexus palsy. METHODS: We reviewed the records of 366 neonates with brachial plexus palsy. The clinical and follow-up data of patients with and without phrenic nerve palsy were compared. RESULTS: Of 366 newborn babies with neonatal brachial plexus palsy, 21 (6%) had concurrent phrenic nerve palsy. Sixteen of these neonates had upper-type palsy and 5 had total-type palsy. Poor spontaneous motor recovery was observed in 13 neonates with concurrent phrenic nerve palsy (62%) and in 129 without concurrent phrenic nerve palsy (39%). Among neonates born via vertex delivery, poor motor recovery was observed in 7 of 9 (78%) neonates with concurrent phrenic nerve palsy and 115 of 296 (39%) without concurrent phrenic nerve palsy. CONCLUSIONS: Concurrent phrenic nerve palsy in neonates with brachial plexus palsy has prognostic value in predicting poor spontaneous motor recovery of the brachial plexus, particularly after vertex delivery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25804365 TI - Foot web free flaps for single-stage reconstruction of hand webs. AB - PURPOSE: To present a method for reconstructing the digital web in posttraumatic defects using a free tissue transfer of the web from the foot and to present the functional and aesthetic results. METHODS: Nine web free flaps were performed; 8 were used to reconstruct posttraumatic web losses and 1 was used to reconstruct a defect resulting from to infection. All cases involved the first (3) or second (6) webs of the hand. Web flaps were taken from the foot first web (2 patients), from the second (6 cases), and from the third (1 case) in a patient with congenital syndactyly of second foot web space. The donor site was managed by skin grafting from the instep (1 case), creation of a syndactyly (7 cases), or both (1 case). RESULTS: All flaps survived without complications. Finger abduction and flexion-extension were similar to the contralateral side. No functional limitations, pain, or contracture were reported. One donor site healed with hypertrophic scars; otherwise, no donor site complications occurred. On a visual analog scale (0-10), the patient assessed appearance of the hand and the donor foot as 9.0 and 9.0, respectively, on average. One web was not well positioned in the first operation and required revision. CONCLUSIONS: The foot web free flap reconstructs the hand web by replacing it with a similar functional subunit rather than attempting to recreate the complex geometry, and allows for full function and excellent appearance of the hand. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25804366 TI - Audit of transoral laser-assisted microsurgical resection of early laryngeal cancer. AB - OBJECTIVE: This study aimed to report our current practice of transoral laser microsurgery for early glottic cancer against the standards outlined by the ENT UK Head and Neck Group and assess the oncological outcome. METHOD: A retrospective review of case notes of patients diagnosed with early glottic cancer (tumour stages Tis, T1 and T2) who underwent transoral laser microsurgery as a primary curative treatment. The minimum follow-up period was two years. RESULTS: Thirty-one patients had transoral laser microsurgery for early glottic cancer during the study period. Eighty-four per cent of cases were discussed by a multidisciplinary team prior to transoral laser microsurgery. Complete circumferential excision was achieved in 77 per cent of cases. Sixty-five per cent of specimens were subjected to histological analysis; they complied with standard pathology reporting for margins. Within 12 months of transoral laser microsurgery, there were 10 residual cases and 2 recurrences. Kaplan-Meier survival analysis gave disease-free survival rates of 96.8 per cent at 18 months and 93.5 per cent at 24 months. The laryngectomy-free survival rate was 96.8 per cent at two years. CONCLUSION: The findings of this audit are encouraging and have highlighted areas for further discussions, recommendations, training and education. PMID- 25804367 TI - Investigation of properties of Mg(n) clusters and their hydrogen storage mechanism: a study based on DFT and a global minimum optimization method. AB - The global minimum structures of Mgn clusters have been determined using the so called "kick method". With the improved DFT method of B3PW91 functional and Grimme's dispersion correction, a series of the most stable structure of Mgn have been found and a novel Mg9 structure has been located. Subsequently, the chemisorption of hydrogen onto Mg clusters was systemically studied. Considering the average adsorption energies and the ratio of Mg and H, we developed a function that can describe the relation between average adsorption energy and number of Mg and H atoms. Our results may be helpful in the future for developing different kinds of gas chemisorption materials. PMID- 25804368 TI - Syntheses, crystal structure, Hirshfeld surfaces, fluorescence properties, and DFT analysis of benzoic acid hydrazone Schiff bases. AB - Two hydrazone Schiff base analogues, namely, (E)-N'-(4-hydroxy-3 methoxybenzylidene)benzohydrazide (3a) and (E)-N'-(4 methoxybenzylidene)benzohydrazide (3b), were synthesized using a mild, efficient method and characterized by (1)H NMR, mass spectrometry, elemental analysis, and single-crystal X-ray diffraction. X-ray analysis of a single crystal of 3a revealed a tetragonal, space group I4(1)/a structure, with an E-configuration around the azomethine (C8N2) double bond. In this structure, the NH and OH groups act as proton donors and the >CO and N groups as proton acceptors, and these facilitate hydrogen bond formation in the crystal state. Plausible intermolecular interactions were studied using 3D Hirshfeld surfaces and related 2D fingerprint plots. The optimized geometry, vibrational frequencies, Mulliken charge distribution, molecular electrostatic potential (MEP) maps, frontier molecular orbitals (FMOs), and associated energies of the ground state and the first single excited state were calculated using density functional theory (DFT) and time dependant DFT calculations using the B3LYP/6-311G method. Vibrational frequencies calculated in the gaseous phase compared with experimental values measured in the solid state and showed good agreement with each other. The chemical reactivities of 3a and 3b were predicted by mapping MEP surface over optimized geometries and comparing these with MEP map generated over crystal structures. Mulliken charge distribution analysis and MEP map of 3a and 3b revealed that N(1), O(1), O(2) and O(3) atoms could act as electron donors and coordinate with metals and that these represented the most suitable sites for electrophilic attack. In fluorescence spectra, the absorption and emission spectra of 3a and 3b were similar in different polar solvents with few exceptions. In addition, both compounds exhibited dual emission spectra in acetone due to keto-enol tautomerism induced by photoexcitation. PMID- 25804370 TI - Rivaroxaban in the Treatment of Heparin-Induced Thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition and it is associated with increased in vivo thrombin generation that needs to be treated with non-heparin anticoagulants such as direct thrombin inhibitors (DTIs). DTIs require parenteral administration and are associated with a non negligible risk of major bleeding. We describe a case of HIT treated with rivaroxaban, a direct oral factor Xa inhibitor which could be used to inhibit the generation of thrombin, instead of DTIs. A 68 year-old man with a thrombosis confined to the internal gastrocnemius and soleal veins developed HIT during enoxaparin 80 mg twice a day. Enoxaparin was stopped and rivaroxaban 20 mg once a day was started. Platelet count returned to base line after 6 days from enoxaparin withdrawal. After 3 months rivaroxaban was stopped and the patient had an uneventful course. This case report supports the hypothesis that rivaroxaban may be candidate for treatment of HIT, and larger studies are justified. PMID- 25804371 TI - Biosafety evaluations of well-dispersed mesoporous silica nanoparticles: towards in vivo-relevant conditions. AB - This study aimed to investigate how mesoporous silica nanoparticles (MSNs), especially focussing on their surface functional groups, interacted with Raw 264.7 macrophages, as well as with zebrafish embryos. Upon introducing nanoparticles into a biological milieu, adsorption of proteins and biomolecules onto the nanoparticle surface usually progresses rapidly. Nanoparticles bound with proteins can result in physiological and pathological changes, but the mechanisms remain to be elucidated. In order to evaluate how protein corona affected MSNs and the subsequent cellular immune responses, we experimented in both serum and serum-deprived conditions. Our findings indicated that the level of p-p38 was significantly elevated by the positively charged MSNs, whereas negatively charged MSNs resulted in marked ROS production. Most significantly, our experiments demonstrated that the presence of protein efficiently mitigated the potential nano-hazard. On the other hand, strongly positively charged MSNs caused 94% of the zebrafish embryos to die. In that case, the toxicity caused by the quaternary ammonium ligands on the surface of those nanoparticles was exerted in a dose-dependent manner. In summary, these fundamental studies here provide valuable insights into the design of better biocompatible nanomaterials in the future. PMID- 25804372 TI - Influence of associated lesions of the intrinsic ligaments on distal radius fractures outcome. AB - INTRODUCTION: We aimed to evaluate the influence of associated scapholunate (SL) and/or lunotriquetral ligament (LT) injury on the outcome of distal radius fractures. MATERIALS AND METHODS: This prospective study included 40 patients with surgically treated distal radius fracture. Wrist arthroscopy was used to identify associated lesions of the scapholunate and lunotriquetral ligaments and classify them according to Geissler. Patients were divided in two groups by presence (injured group) or absence (intact group) of associated injury of the SL and/or LT ligament. The patient-rated wrist evaluation (PRWE) and the disabilities of the arm, shoulder and hand (DASH) questionnaires were used to evaluate disability 3 and 6 months after injury. Grip strength was also evaluated. RESULTS: Wrist arthroscopy identified SL and/or LT injury in 15 patients (37.5 %). Mean total PRWE score for the intact group was 26.64 at 3 months and 16.22 at 6 months, and 50.47 (at 3 months) and 20.7 (at 6 months) for the group with ligament injury. Mean DASH scores were 26.03 and 13 at 3 and 6 months for the intact group, and 49.5 and 24.11 for the injured group. Mann Whitney test results showed significant difference for the PRWE and DASH scores and the grip strength for the two examined groups. CONCLUSIONS: Patients with distal radius fracture with associated intrinsic ligament injury had worse outcomes than did patients without associated ligamentous injury. Associated injuries of the SL and LT ligament should be considered when treating distal radius fractures, and wrist arthroscopy should be incorporated into the operative protocol. PMID- 25804373 TI - Is procrastination a vulnerability factor for hypertension and cardiovascular disease? Testing an extension of the procrastination-health model. AB - Personality is an important epidemiological factor for understanding health outcomes. This study investigated the associations of trait procrastination with hypertension and cardiovascular disease (HT/CVD) and maladaptive coping by testing an extension of the procrastination-health model among individuals with and without HT/CVD. Individuals with self-reported HT/CVD (N = 182) and healthy controls (N = 564), from a community sample, completed an online survey including measures of personality, coping, and health outcomes. Logistic regression analysis controlling for demographic and higher order personality factors found that older age, lower education level and higher procrastination scores were associated with HT/CVD. Moderated mediation analyses with bootstrapping revealed that procrastination was more strongly associated with maladaptive coping behaviours in participants with HT/CVD than the healthy controls, and the indirect effects on stress through maladaptive coping were larger for the HT/CVD sample. Results suggest procrastination is a vulnerability factor for poor adjustment to and management of HT/CVD. PMID- 25804374 TI - Communication avoidance, coping and psychological distress of women with breast cancer. AB - This study examined the relationship between communication avoidance of cancer related topics with psychological distress, and the mediating role of coping strategies, in women with breast cancer. Women diagnosed with breast cancer (N = 338) completed an online survey including measures of self- and perceived-partner communication avoidance, psychological distress (depression, anxiety and stress), and coping strategies. Linear regression analyses indicated that women's and perceived-partner's communication avoidance was associated with anxiety, depression, and stress in the cancer-affected women. Bootstrapping analyses showed significant mediation effects of self- and perceived-partner communication avoidance on all distress outcomes through greater disengagement coping, and on anxiety through lower engagement coping. Emotionally valenced topics (i.e., disease progression and sexuality) were most avoided and practical issues were least avoided. Enhancing couple communication about cancer and women's adaptive coping skills (i.e., discourage use of disengagement coping strategies and promote use of engagement coping strategies) may be important targets for psychosocial intervention. PMID- 25804375 TI - Perioperative alendronate, risedronate, calcitonin and indomethacin treatment alters femoral stem fixation and periprosthetic bone mineral density in ovariectomized rats. AB - BACKGROUND: Many factors affect implant stability and periprosthetic bone mineral density (BMD) following total joint arthroplasty. We asked whether perioperative alendronate, risedronate, calcitonin and indomethacine administration altered (1) femoral stem shear strength and periprosthetic bone mineral density BMD in ovariectomized rats and (2) whether there were differences in the effect of these drugs. METHODS: Thirty overiectomized rats were divided into five groups and implanted with intramedullary mini-cortical screws in the femur. Four groups were treated with alendronate, risedronate, salmon calcitonin and indomethacin for 4 weeks preoperatively and 8 weeks postoperatively. RESULTS: Although alendronate and risedronate increased the periprosthetic BMD more than calcitonin, they did not alter implant fixation compared to calcitonin. Indomethacin significantly decreased the BMD around the stem and implant stability compared to all other groups. CONCLUSIONS: This study showed that perioperative treatment with bisphosphonates and calcitonin improved the BMD around the stems and implant stability. Although bisphosphonates increased the BMD more than calcitonin, there was no difference in implant stability. Indomethacin markedly decreased the periprosthetic BMD and implant stability. The main clinical significance of our study was the finding about the need to strictly avoid long-term use of high-dose nonsteroidal antiinflammatory drugs for patients who have major joint arthritis and a previous history of arthroplasty. PMID- 25804376 TI - Approach to metastatic carcinoma of unknown primary in the head and neck: squamous cell carcinoma and beyond. AB - Metastatic carcinoma to cervical lymph nodes presenting as an unknown primary is quite common. In most cases, the primary site is ultimately identified. Carcinomas that remain of unknown primary after a thorough search are uncommon. This review will focus on those cases that initially present as unknown primaries, since this is the setting in which pathologists first encounter these cases and in which they play an important role in guiding patient management. Most are squamous cell carcinomas, the majority of which are human papillomavirus (HPV)-related and originate in the palatine tonsils and base of tongue. HPV related oropharyngeal squamous cell carcinomas are increasing in incidence and have unique clinical and pathologic features that make them particularly likely to present as an unknown primary. Understanding these features has led to improved detection of the primary tumors. Further, even when the primary tumor is not found, prognosis is very dependent on characterization of the tumor HPV status. Papillary thyroid carcinomas may also initially present without a known or clinically detectable primary, either as a neck mass or incidentally in a neck dissection performed for another indication. The latter is a very indolent disease. Finally, primary salivary gland carcinomas may mimic an unknown primary and need to be distinguished from cutaneous metastases to the parotid gland, which may present without a recognized skin tumor. Here, we review the clinical and pathologic features of these entities and provide a systematic approach to their diagnosis. PMID- 25804377 TI - Mutant allele tumor heterogeneity (MATH) and head and neck squamous cell carcinoma. AB - Intra-tumor heterogeneity, variation between individual tumor cells within a patient's tumor, is increasingly seen as a critical mechanism underlying treatment resistance and therapeutic failure. Despite this growing awareness, few methods to assess intra-tumor heterogeneity exist outside the research laboratory, especially in the absence of a known marker. Mutant allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative method to assess genetic heterogeneity based on tumor next generation exome sequencing. The quantitative aspect of MATH has allowed it to be verified as an actionable biomarker in a retrospective HNSCC data set with available exome sequencing and clinical data. In addition, it was also capable of stratifying patient outcome after controlling for other high-risk features such as p53 mutation, HPV status, and advanced tumor stage. Future work will explore the predictive power of MATH in larger data sets such as The Cancer Genome Atlas and examine the underlying cellular mechanisms responsible for intra-tumor heterogeneity. PMID- 25804378 TI - Myoepithelial neoplasms of soft tissue: an updated review of the clinicopathologic, immunophenotypic, and genetic features. AB - Myoepithelial tumors in skin and soft tissue are uncommon but have been increasingly characterized over the past decade. Men and women are equally affected across all age groups and lesions arise most frequently on the extremities and limb girdles. Approximately 20 % of cases occur in pediatric patients, in whom they are frequently malignant. Similar to their salivary gland counterparts, myoepithelial tumors of soft tissue demonstrate heterogeneous morphologic and immunophenotypic features. Tumors are classified as mixed tumor/chondroid syringoma, myoepithelioma, and myoepithelial carcinoma; in soft tissue, tumors having at least moderate cytologic atypia are classified as malignant. Mixed tumor and myoepithelioma show a benign clinical course, with recurrence in up to 20 % (typically secondary to incomplete excision), and do not metastasize. In contrast, myoepithelial carcinoma shows more aggressive behavior with recurrence and metastasis in up to 40-50 % of cases. The majority of myoepithelial neoplasms typically coexpress epithelial antigens (cytokeratin and/or EMA) and S-100 protein; GFAP and p63 are frequently positive and a subset of malignant neoplasms lose INI1 expression. Up to 45 % of myoepitheliomas and myoepithelial carcinomas harbor EWSR1 gene rearrangements, unlike mixed tumor/chondroid syringoma which is characterized by PLAG1 gene rearrangement. While mixed tumor/chondroid syringoma are likely related to primary salivary myoepithelial tumors, soft tissue myoepithelioma and myoepithelial carcinoma appear to be pathologically distinct neoplasms. PMID- 25804379 TI - When thyroid carcinoma goes bad: a morphological and molecular analysis. AB - Thyroid carcinomas of follicular epithelial derivation are common and generally well-behaved malignancies with excellent cure and survival rates. However, a subset of these carcinomas, whether well-differentiated, poorly differentiated, or anaplastic, is highly aggressive, manifesting with local invasion, recurrence, and distant metastasis. The recognition of dedifferentiation is of paramount importance. In addition, the challenge for Pathologists is to identify the rare aggressive differentiated carcinomas so that treatment may be tailored appropriately. Thus, histological subtyping and documentation of other aggressive features such as widespread invasion and angioinvasion are critical. Mutational analyses in the past decade have delineated the molecular alterations responsible for thyroid carcinogenesis and progression, allowing greater sub-classification and prognostication of thyroid carcinomas. This review article highlights important aggressive morphologic features and molecular mutations associated with thyroid carcinoma. PMID- 25804381 TI - Modulated excitation extended X-ray absorption fine structure spectroscopy. AB - The sensitivity of extended X-ray absorption fine structure spectroscopy (EXAFS) for minute structural changes can be enhanced by combination with the modulated excitation approach and making use of phase sensitive analysis. A modulated EXAFS experiment of a reversible periodic Pd to PdO partial oxidation has been simulated in order to understand the effect of the phase sensitive analysis on the shape and meaning of the resulting phase-resolved EXAFS spectra. In particular, the simulation comprises either a synchronous or a delayed sinusoidal variation of the EXAFS parameters, i.e. coordination number (N), interatomic distance (R) and Debye-Waller factor (sigma(2)), of first Pd-Pd, first Pd-O, and second Pd-(O)-Pd coordination shells. The effect of these variations on the resulting phase-resolved Fourier transform EXAFS spectra is discussed. The results of the simulation are validated by an in situ EXAFS experiment at the Pd K-edge over 1.6 wt% Pd/Al2O3 undergoing reversible partial oxidation in a H2vs. O2 modulation at 573 K. It is shown that phase sensitive detection (PSD) is able to separate the minor contribution at ca. 2.8 A corresponding to the growth of the Pd-(O)-Pd shell that is otherwise hidden under the static signal of the Pd-Pd shell of reduced Pd particles. The fitting of the phase-resolved EXAFS spectra suggests that the fast H2 to O2 switch leads the partial oxidation of the Pd surface with the formation of a PdO shell covering a metallic Pd core. Therefore, the dynamics of the full system can be described with greater detail than in conventional EXAFS. The intention of this work is to provide the tools and therefore a solid guidance to qualitatively and quantitatively understand the nature of the shape of phase-resolved FT-EXAFS spectra that may prove helpful in the analysis of a wide range of functional materials. PMID- 25804380 TI - IgG4 related disease of the head and neck. AB - IgG4 related disease of the head and neck region represents one of the more common manifestations of IgG4 related disease. Involvement of the submandibular and parotid glands, the orbit and thyroid represent some of the more common sites involved by IgG4 related disease. Eosinophilic angiocentric fibrosis, Mikulicz disease and Riedel thyroiditis are also members of the family of IgG4 related disease. Clinically, the disease is characterized by tumefactive lesions, often multicentric, that show a swift response to immunosuppressive therapy. An elevated serum IgG4 represents the only validated blood based biomarker. However, elevated serum IgG4 is detected in only half the patients with this disease. Histology continues to represent the gold standard for the diagnosis of IgG4 related disease: storiform-type fibrosis and obliterative phlebitis constitute characteristic features of this disease. A definitive diagnosis of IgG4 related disease also requires the presence of elevated numbers of IgG4 positive plasma cells as well as an IgG4 to IgG ratio of greater than 40 %. In isolation, elevated numbers of IgG4 positive plasma cells represents a non-specific feature, detected in a variety of other inflammatory as well as neoplastic diseases. Attention to the clinical context, histological features, as well as an elevated IgG4 to IgG ratio is critical to avoiding overdiagnosis of IgG4 related disease. PMID- 25804382 TI - Electronic structure of graphene nanoribbons doped with nitrogen atoms: a theoretical insight. AB - The electronic structure of graphene nanoribbons doped with a graphitic type of nitrogen atoms has been studied using B3LYP, B2PLYP and CAS methods. In all but one case the restricted B3LYP solutions were unstable and the CAS calculations provided evidence for the multiconfigurational nature of the ground state with contributions from two dominant configurations. The relative stability of the doped nanoribbons depends mostly on the mutual position of the dopant atoms and notably less on the position of nitrogen atoms within the nanoribbon. N-graphitic doping affects cationic states much more than anionic ones due the participation of the nitrogen atoms in the stabilization of the positive charge, resulting in a drop in ionization energies (IPs) for N-graphitic doped systems. Nitrogen atoms do not participate in the negative charge stabilization of anionic species and, therefore, the doping does not affect the electron affinities (EAs). The unrestricted B3LYP method is the method of choice for the calculation of IPs and EAs. Restricted B3LYP and B2PLYP produces unreliable results for both IPs and EAs while CAS strongly underestimates the electron affinities. This is also true for the reorganization energies where restricted B3LYP produces qualitatively incorrect results. Doping changes the reorganization energy of the nanoribbons; the hole reorganization energy is generally higher than the corresponding electron reorganization energy due to the participation of nitrogen atoms in the stabilization of the positive charge. PMID- 25804383 TI - Oxidized LDL and NO synthesis--Biomarkers of endothelial dysfunction and ageing. AB - Oxidized LDL (oxLDL) and nitric oxide (NO) exert contradictory actions within the vascular endothelium microenvironment influencing key events in atherogenesis. OxLDL and NO are so far regarded as representative parameters of oxidative stress and endothelial dysfunction, new targets in prevention, diagnosis and therapy of cardiovascular diseases, and also as candidate biomarkers in evaluating the human biological age. The aim of this review is to explore recent literature on molecular mechanisms and pathophysiological relationships between LDL oxidation, NO synthesis and vascular endothelium function/dysfunction in ageing, focusing on the following aspects: (1) the impact of metabolic status on both LDL oxidation and NO synthesis in relation with oxidative stress, (2) the use of oxidized LDL and NO activity as biomarkers in human studies reporting on cardiovascular outcomes, and (3) evidences supporting the importance of oxidized LDL and NO activity as relevant biomarkers in vascular ageing and age-related diseases. PMID- 25804384 TI - Conservation of pro-longevity genes among mammals. AB - Genes which confer a relative longevity advantage may be regulated at the level of transcription or translation. Alternatively, pro-longevity genes may mediate their effects at the level of protein structure-functional relationships that are beneficially optimized in long-lived species. Longevity associated genes (LAGs) may be operationally defined as genes that confer beneficial effects and are relatively more conserved among long-lived species. Global and local protein sequence alignments of over 10,000 genes across at least 30 mammalian species were examined to identify LAGs. Known LAGs, including growth hormone receptor (GHR), and breast cancer 1, early onset (BRCA1), have strong associations with maximum lifespan by our analysis. Several common categories of protein function were observed among genes ranked with the strongest associations with MLS identified by all regression models. These genes included those that function in the immune system, cell cycle regulation, and DNA damage response. We provide a ranking of genes with the strongest associations with species maximum lifespan (MLS) by several phylogenetic generalized least squares regression models, including adjustment for confounding variables such as body weight and gestation length. PMID- 25804386 TI - Cycle training induces muscle hypertrophy and strength gain: strategies and mechanisms. AB - Cycle training is widely performed as a major part of any exercise program seeking to improve aerobic capacity and cardiovascular health. However, the effect of cycle training on muscle size and strength gain still requires further insight, even though it is known that professional cyclists display larger muscle size compared to controls. Therefore, the purpose of this review is to discuss the effects of cycle training on muscle size and strength of the lower extremity and the possible mechanisms for increasing muscle size with cycle training. It is plausible that cycle training requires a longer period to significantly increase muscle size compared to typical resistance training due to a much slower hypertrophy rate. Cycle training induces muscle hypertrophy similarly between young and older age groups, while strength gain seems to favor older adults, which suggests that the probability for improving in muscle quality appears to be higher in older adults compared to young adults. For young adults, higher intensity intermittent cycling may be required to achieve strength gains. It also appears that muscle hypertrophy induced by cycle training results from the positive changes in muscle protein net balance. PMID- 25804385 TI - Microgravity activates p38 MAPK-C/EBPbeta pathway to regulate the expression of arginase and inflammatory cytokines in macrophages. AB - OBJECTIVE AND DESIGN: Molecular mechanisms of microgravity-caused immunosuppression are not fully elucidated. In the present study, we investigated the effects of simulated microgravity on macrophage functions and tried to identify the related intracellular signal pathways. MATERIAL OR SUBJECTS: Primary mouse macrophages were used in the present study. The gene expression and function of IL-4-treated mouse macrophages were detected after simulated microgravity or 1 g control. METHODS: Freshly isolated primary mouse macrophages were cultured in a standard simulated microgravity situation using a rotary cell culture system (RCCS-1) and 1 g control conditions. Real-time PCR, western blots and flow cytometry were used to investigate the related intracellular signals and molecule expression. RESULTS: The arginase mRNA and protein levels in freshly isolated primary mouse macrophages under simulated microgravity using RCCS-1 were significantly higher than those under normal gravity. Meanwhile, simulated microgravity induced over-expression of C/EBPbeta, a transcription factor of arginase promoter, and activation of p38 MAPK, which could increase C/EBPbeta expression. Furthermore, up-regulation of Interleukin-6 (IL-6) and down regulation of IL-12 p40 (IL-12B) in LPS-stimulated macrophages were also detected after simulated microgravity, which is regulated by C/EBPbeta. CONCLUSIONS: Simulated microgravity activates a p38 MAPK-C/EBPbeta pathway in macrophages to up-regulate arginase and IL-6 expression and down-regulate IL-12B expression. Both increased arginase expression and decreased IL-12B expression in macrophages during inflammation could result in immunosuppression under microgravity. PMID- 25804387 TI - Comparison of left and right ventricular adaptation in endurance-trained male athletes. AB - Characteristics of the athlete's heart have been investigated mostly in the left ventricle (LV); reports referring to the right ventricle (RV) have only appeared recently. The aim of the present study was to compare the training effects on RV and LV in elite male endurance athletes. To this end, echocardiography was conducted in 52 elite endurance athletes (A) and in 25 non-athletes (NA). Differences between A and NA in the morphology was more marked in the RV (body size-matched (rel.)) long axis diastolic diameter (RVLADd): 63.4 +/- 6.3 vs. 56.4 +/- 6.3; rel. short axis diastolic diameter (RVSADd): 27.3 +/- 3.6 vs. 23.6 +/- 2.7 mm/m, RV diastolic area 28 +/- 5.0 vs. 21.3 +/- 4.3 cm2 in all cases, p < 0.001) than in the LV (rel. LVLADd: 63.8 mm/m +/- 5.6 vs. 60.7 mm/m +/- 6.6, p < 0.05, rel.LVSADd 37.8 +/- 3.1 vs. 35.3 +/- 2.4, no difference). In the athletes ratios of peak early to late diastolic filling velocity (2.07 +/- 0.51 vs. 1.75 +/- 0.36, p < 0.01), the TDI-determined E'/A' ratio in the septal (1.89 +/- 0.55 vs. 1.62 +/- 0.55, p < 0.05) and lateral (2.62 +/- 0.72, vs. 2.18 +/- 0.87, p < 0.001) walls were significantly higher than in NA only in the LV. Results indicate that in male endurance athletes morphologic adaptation is similar or slightly stronger in the RV than in the LV, functional adaptation seems to be stronger in the LV. PMID- 25804388 TI - Noninvasive continuous arterial pressure measurements in the assessment of acute, severe central hypovolemia. AB - Acute, severe hypovolemia is a medical emergency. Traditional vital sign parameters allow no optimal triage. High predictive power of finger plethysmography-based stroke volume (SV) and pulse pressure (PP) was recently suggested. To assess the performance of the PP and SV parameters, lower body negative pressure of -40 mmHg, than -60 mmHg - corresponding to moderate and severe central hypovolemia - was applied in 22 healthy males (age 35 +/- 7 years). Slow breathing induced fluctuations in the above indices, characterized by stroke volume variability (SVV), and pulse pressure variability (PPV), were assessed. Responses in heart rate (HR) and shock index (SI) were also studied. Discriminative capacity of these parameters was characterized by the area under the ROC (receiver operating characteristic) curves (AUC). RESULTS: In comparison of baseline to severe central hypovolemia SV, PP, HR, and SI showed good discriminating capacity (AUC 99%, 88%, 87%, and 93%, respectively). The discriminating capacity of SVV and PPV was poor (77% and 70%, respectively). In comparison of moderate and severe hypovolemia, the discriminating capacity of the studied parameters was uniformly limited. CONCLUSIONS: Plethysmography-based SV and PP parameters can be used to detect acute severe volume loss. Sensitive parameters discriminating moderate and severe central hypovolemia are still lacking. PMID- 25804389 TI - Delta9-tetrahydrocannabinol treatment improved endothelium-dependent relaxation on streptozotocin/nicotinamide-induced diabetic rat aorta. AB - OBJECTIVE: In this study, we investigated the possible effect of Delta(9) tetrahydrocannabinol (THC), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on metabolic control and vascular complications of diabetes in streptozotocin/nicotinamide (STZ/NIC) induced type 2 diabetes mellitus. MATERIAL AND METHODS: Type 2 diabetes was induced with 65 mg/kg STZ, 15 minute later 85 mg/kg NIC was given intraperitoneally (i.p.) to rats. Three days after diabetes induction, THC (3 mg/kg/day, i.p.) was given for 7 days to diabetic rats. Body weight and plasma glucose levels of rats were measured in all groups before and at the end of 3 weeks after diabetes induction. Acetylcholine (Ach) and sodium nitroprusside (SNP) potency and maximum relaxant effects were calculated on aortic rings pre-contracted with noradrenaline (NA). RESULTS: At the end of 3 weeks, blood glucose levels of diabetic group significantly increased in comparison with the control group. Increased plasma glucose levels were significantly decreased by the treatment of THC. Ach induced relaxation was impaired whereas endothelium-independent relaxation to SNP was unaffected on isolated diabetic rat aorta. THC treatment enhanced Ach induced relaxation on diabetic rat aortas. DISCUSSION: These results suggested that THC improved endothelium-dependent relaxation in STZ/NIC induced diabetic rat aorta and that these effects were mediated at least in part, by control of hyperglycemia and enhanced endothelial nitric oxide bioavailability. PMID- 25804390 TI - Pre- and post-estrogen administration in global cerebral ischemia reduces blood brain barrier breakdown in ovariectomized rats. AB - The aim of present study was to determine the effect of estrogen treatment on blood-brain barrier permeability in rats with induced global cerebral ischemia. The study included six-month-old female Sprague-Dawley rats which were divided into the following groups: Control-Ischemia-Reperfusion (C + I-R); Ovariectomy Ischemia-Reperfusion (Ovx + I-R); Ovariectomy + Estrogen + Ischemia-Reperfusion (Ovx + E + I-R); Ovariectomy + Ischemia-Reperfusion + Estrogen (Ovx + I-R + E). Ischemia-reperfusion was induced by clamping two carotid arteries, then opening the clamp. Blood-brain barrier permeability was visualized by Evans Blue extravasation and quantified by spectrophotometry. Our results indicate that following ischemia-reperfusion the BBB permeability is increased in ovariectomized rats (Evans Blue extravasation) compared to the control group in the cortex, thalamus, hippocampus, cerebellum and brain stem, while in the midbrain no significant increase was detected. In contrast, BBB permeability in the groups treated with estrogen, administered either before or after ischemia reperfusion, was significantly lower than in ovariectomized animals. In conclusion, the increase in BBB permeability resulting from experimentally induced cerebral ischemia was prevented by exogenous estrogen treatment. The study results indicate that estrogen may be used for therapeutic purposes in ischemia-reperfusion. PMID- 25804391 TI - The preventive effect of beta3 adrenoceptor stimulation against experimentally induced reflux esophagitis. AB - A beta3 adrenoceptor agonist plays an important regulatory role in stimulation of thermogenesis and lipolysis and it appears to have anti-ulcer and spasmolytic effects. So the present aim was to examine the effect of BRL 37344 (a selective B3 adrenoceptor agonist) on reflux esophagitis. METHODS: Forty-eight rats were divided into twelve sham-operated with BRL 37344 and/or omeprazole with or without indomethacin. RE was induced in rats, then gastric acid output, pH, plasma nitric oxide (NO), esophageal PGE2, malondialdehyde (MDA) and reduced glutathione (GSH) were measured and the esophageal injury was assessed by macroscopic damage score. RESULTS: Pretreatment with BRL significantly increased plasma NO, GSH, decreased acid output, esophageal MDA and esophageal injury in comparison to pretreatment. In addition, there was a no significant increase in esophageal PGE2. CONCLUSION: It can be concluded that BRL 37344 has an anti oxidant protective effect in rats with RE. PMID- 25804392 TI - Autonomic adaptation after traditional and reverse swimming training periodizations. AB - The objective of the present study was to analyze the autonomic response of trained swimmers to traditional and reverse training periodization models. Seventeen swimmers were divided in two groups, performing a traditional periodization (TPG) or a reverse periodization (RPG) during a period of 10 weeks. Heart rate variability and 50 m swimming performance were analyzed before and after the training programs. After training, the TPG decreased the values of the high frequency band (HF), the number of differences between adjacent normal R-R intervals longer than 50 ms (NN50) and the percentage of differences between adjacent normal R-R intervals more than 50 ms (pNN50), and the RPG increased the values of HF and square root of the mean of the sum of the squared differences between adjacent normal R-R intervals (RMSSD). None of the groups improved significantly their performance in the 50-m test. The autonomic response of swimmers was different depending on the periodization performed, with the reverse periodization model leading to higher autonomic adaption. Complementary, the data suggests that autonomic adaptations were not critical for the 50-m swimming performance. PMID- 25804393 TI - Effect of creatine malate supplementation on physical performance, body composition and selected hormone levels in spinters and long-distance runners. AB - PURPOSE: The aim of the study was to determine whether creatine malate (CML) supplementation results in similar ergogenic effect in sprinters and long distance runners. The other goal was to compare changes in body composition, physical performance and hormone levels after six-week training in athletes, divided into subgroups supplemented with creatine malate or taking placebo. RESULTS: Six-week supplementation combined with physical training induced different effects in athletes. Significantly higher increases in relative and absolute peak power and total work (p < 0.05) were found in sprinters compared to other groups. Except for growth hormone, post-exercise venous blood serum hormone levels exhibited no statistically significant differences in athletes. After CML loading period, a significant increase in growth hormone was found in the group of sprinters. CONCLUSIONS: A significant ergogenic effect was found in sprinters, which was reflected by the increase in anaerobic exercise indices and morphological indices and elevated growth hormone level, after graded exercise testing. The significant increase in the distance covered during graded test was only observed in supplemented long-distance runners, whereas no significant changes in maximal oxygen uptake, relative peak power and relative total work were noticed. This could be caused by later anaerobic threshold appearance in exercise test to exhaustion. PMID- 25804394 TI - Simulation of dielectrophoretic assembly of carbon nanotubes using 3D finite element analysis. AB - One of the most important methods for selective and repeatable assembly of carbon nanotubes (CNTs) is alternating current dielectrophoresis (DEP). This method has been demonstrated experimentally as a viable technique for nano-scale manufacturing of novel CNT based devices. Previous numerical analyses have studied the motion of nanotubes, the volume from which they are assembled, and the rate of assembly, but have been restricted by various simplifying assumptions. In this paper we present a method for simulating the motion and behavior of CNTs subjected to dielectrophoresis using a three-dimensional electrostatic finite element analysis. By including the CNT in the finite element model, we can accurately predict the effect of the CNT on the electric field and the resulting force distribution across the CNT can be determined. We have used this information to calculate the motion of CNTs assembling onto the electrodes, and show how they tend to move towards the center of an electrode and come into contact at highly skewed angles. Our analysis suggests that the CNTs move to the electrode gap only after initially contacting the electrodes. We have also developed a model of the elastic deformation of CNTs as they approach the electrodes demonstrating how the induced forces can significantly alter the CNT shape during assembly. These results show that the CNT does not behave as a rigid body when in close proximity to the electrodes. In the future this method can be applied to a variety of real electrode geometries on a case-by-case basis and will provide more detailed insight into the specific motion and assembly parameters necessary for effective DEP assembly. PMID- 25804396 TI - Chronic sleep deprivation alters the myosin heavy chain isoforms in the masseter muscle in rats. AB - To investigate the changes in myosin heavy chain (MyHC) isoforms of rat masseter muscle fibres caused by chronic sleep deprivation and a possible link with the pathogenesis of disorders of the temporomandibular joint (TMJ). A total of 180 male rats were randomly divided into three groups (n=60 in each): cage controls, large platform controls, and chronic sleep deprivation group. Each group was further divided into three subgroups with different observation periods (7, 14, and 21 days). We investigated he expression of MyHC isoforms in masseter muscle fibres by real-time quantitative polymerase chain reaction (PCR), Western blotting, and immunohistochemical staining. In rats with chronic sleep deprivation there was increased MyHC-I expression in layers of both shallow and deep muscles at 7 and 21 days compared with the control groups, whereas sleep deprivation was associated with significantly decreased MyHC-II expression. At 21 days, there were no differences in MyHC-I or MyHC-II expression between the groups and there were no differences between the two control groups at any time point. These findings suggest that chronic sleep deprivation alters the expression of MyHC isoforms, which may contribute to the pathogenesis of disorders of the TMJ. PMID- 25804397 TI - Deciphering associations for lung cancer risk through imputation and analysis of 12,316 cases and 16,831 controls. AB - Recent genome-wide association studies have identified common variants at multiple loci influencing lung cancer risk. To decipher the genetic basis of the association signals at 3q28, 5p15.33, 6p21.33, 9p21 and 12p13.33, we performed a meta-analysis of data from five genome-wide association studies in populations of European ancestry totalling 12 316 lung cancer cases and 16 831 controls using imputation to recover untyped genotypes. For four of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant at these risk loci. PMID- 25804399 TI - The lymphatic phenotype in Turner syndrome: an evaluation of nineteen patients and literature review. AB - Turner syndrome is a complex disorder caused by an absent or abnormal sex chromosome. It affects 1/2000-1/3000 live-born females. Congenital lymphoedema of the hands, feet and neck region (present in over 60% of patients) is a common and key diagnostic indicator, although is poorly described in the literature. The aim of this study was to analyse the medical records of a cohort of 19 Turner syndrome patients attending three specialist primary lymphoedema clinics, to elucidate the key features of the lymphatic phenotype and provide vital insights into its diagnosis, natural history and management. The majority of patients presented at birth with four-limb lymphoedema, which often resolved in early childhood, but frequently recurred in later life. The swelling was confined to the legs and hands with no facial or genital swelling. There was only one case of suspected systemic involvement (intestinal lymphangiectasia). The lymphoscintigraphy results suggest that the lymphatic phenotype of Turner syndrome may be due to a failure of initial lymphatic (capillary) function. PMID- 25804398 TI - Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy. AB - Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy. PMID- 25804402 TI - Exposing participants? Population biobanks go geo. PMID- 25804400 TI - SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract. AB - Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1-q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts. PMID- 25804401 TI - Guidelines for cytogenetic investigations in tumours. PMID- 25804403 TI - Cerebral visual impairment and intellectual disability caused by PGAP1 variants. AB - Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI. PMID- 25804406 TI - Prevalence and risk factors for Leptospira exposure in New Zealand veterinarians. AB - This study assessed seroprevalence and risk factors for Leptospira (serovars Hardjo, Pomona, Ballum, Copenhageni, Tarassovi) exposure in New Zealand veterinarians. Veterinarians (n = 277) at one of two conferences were voluntarily enrolled and blood samples taken. Microscopic agglutination test (MAT) titres ?48 were considered seropositive. Fourteen veterinarians (5.1%, 95% confidence interval 2.8-8.3) were seropositive to Leptospira. Home slaughter of cattle or pigs were significant risk factors for Leptospira exposure. There were no clear relationships between the animal species handled at work and serostatus. However, veterinarians spending a 'mid to high' proportion of their time (>50% to ?75%) with pets had higher odds of being seropositive than those not working with pets. A borderline positive association (P = 0.09) was observed between seropositivity and clinical influenza-like illness (?3 days off work) in the 18 months before the study. Assuming causality, this suggests that 8.3% of these cases may be attributed to Leptospira exposure. PMID- 25804405 TI - A comparison of anatomical lateral distal femoral angles obtained with four femoral axis methods in canine femora. AB - OBJECTIVES: To report the repeatability and reproducibility of four different anatomical proximal femoral axis (a-PFA) methods for measuring anatomical lateral distal femoral angle (a-LDFA), and to compare a-LDFA values produced by each method at three different femoral elevation angles. METHODS: Digital radiographs were obtained of seven dry canine femora at 0 degrees , 12.5 degrees and 25 degrees elevations. Using image analysis software, landmarks defining four different a-PFA and the condylar axis were identified by two independent observers on two separate occasions. Corresponding a-LDFA were calculated for each femur, elevation and a-PFA. Repeatability and reproducibility parameters were calculated and compared statistically, along with the effect of technique and elevation on a-LDFA value. RESULTS: Interobserver repeatability coefficients were subjectively better for three of the a-PFA methods at 2 degrees compared to the fourth at 3.1 degrees . Median a-LDFA increased significantly (p <= 0.002) with increasing femoral elevation for all a-PFA methods, with a median increase of 3.3 degrees . The median difference in a-LDFA between a-PFA methods yielding the highest and lowest measurements was 2.6 degrees over all three elevations. CLINICAL SIGNIFICANCE: The combined effects of a-PFA choice, femoral elevation and measurement reproducibility may produce typical errors of +/- 2.6 degrees , which could have implications for the selection of candidates for corrective osteotomies. Clinicians need to be aware that values obtained with one method and femoral elevation may not be equivalent to values obtained with other methods or elevations. PMID- 25804404 TI - Partial USH2A deletions contribute to Usher syndrome in Denmark. AB - Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment, progressive visual loss owing to retinitis pigmentosa and in some cases vestibular dysfunction. Usher syndrome is divided into three subtypes, USH1, USH2 and USH3. Twelve loci and eleven genes have so far been identified. Duplications and deletions in PCDH15 and USH2A that lead to USH1 and USH2, respectively, have previously been identified in patients from United Kingdom, Spain and Italy. In this study, we investigate the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark using multiplex ligation-dependent probe amplification (MLPA). Two heterozygous deletions were identified in USH2A, but no deletions or duplications were identified in PCDH15. Next-generation mate-pair sequencing was used to identify the exact breakpoints of the two deletions identified in USH2A. Our results suggest that USH2 is caused by USH2A exon deletions in a small fraction of the patients, whereas deletions or duplications in PCDH15 might be rare in Danish Usher patients. PMID- 25804407 TI - The significance of minimal adjustments in the Muller's muscle and conjunctiva resection procedure to achieve the phenylephrine result. AB - PURPOSE: To determine if adjusting the resection amount within a small range has a significant effect in the amount of lift achieved when performing the Muller's muscle and conjunctiva resection procedure (MMCR). METHODS: A retrospective chart review was performed analyzing 102 eyelids of 68 patients with involutional blepharoptosis that had a MMCR resection amount ranging from 8.0-9.5 mm performed by a single surgeon (P.S.) RESULTS: The average lift for all resections was 2.30 mm. When comparing amongst all resection groups, there was no significant difference in the amount of lift obtained (p = 0.2454). CONCLUSION: When performing the MMCR procedure, adjusting the resection amount within a small range of 8.0-9.5 mm does not affect the amount of lift achieved. PMID- 25804409 TI - Fuel poverty as a major determinant of perceived health: the case of France. AB - OBJECTIVES: The number of households in fuel poverty is growing. Individuals increasingly struggle to heat their homes, and therefore, a growing number of individuals are exposed to low temperatures, which can affect their health. This study sought to determine the link between a subjective measure of fuel poverty (self-reported feeling cold) and self-reported health. The impact of other particular individual and environmental features on self-reported health were also analysed. STUDY DESIGN: Econometric analysis. METHODS: The study method uses self-reported perception of thermal discomfort (self-reported feeling cold) as a proxy for fuel poverty. The French database of the Healthcare and Insurance survey carried by the Institute for Research and Information on Health Economics (IRDES) was used to estimate a dichotomous probit model. RESULTS: The estimation allows us to infer a negative impact of fuel poverty on self-reported health. Thus, a person in fuel poverty is 2.36 percentage points more likely to report poor or fair health status than a person who is not in fuel poverty. CONCLUSION: It may be appropriate to reduce the impacts of fuel poverty to provide support for the most vulnerable categories of individuals with respect to the health impacts of fuel poverty and cold homes, e.g., chronic patients who experience difficulty heating their homes. PMID- 25804408 TI - Quantifying vitamin K-dependent holoprotein compaction caused by differential gamma-carboxylation using high-pressure size exclusion chromatography. AB - This study uses high-pressure size exclusion chromatography (HPSEC) to quantify divalent metal ion (X(2+))-induced compaction found in vitamin K-dependent (VKD) proteins. Multiple X(2+) binding sites formed by the presence of up to 12 gamma carboxyglutamic acid (Gla) residues are present in plasma-derived FIX (pd-FIX) and recombinant FIX (r-FIX). Analytical ultracentrifugation (AUC) was used to calibrate the Stokes radius (R) measured by HPSEC. A compaction of pd-FIX caused by the filling of Ca(2+) and Mg(2+) binding sites resulted in a 5 to 6% decrease in radius of hydration as observed by HPSEC. The filling of Ca(2+) sites resulted in greater compaction than for Mg(2+) alone where this effect was additive or greater when both ions were present at physiological levels. Less X(2+)-induced compaction was observed in r-FIX with lower Gla content populations, which enabled the separation of biologically active r-FIX species from inactive ones by HPSEC. HPSEC was sensitive to R changes of approximately 0.01nm that enabled the detection of FIX compaction that was likely cooperative in nature between lower avidity X(2+) sites of the Gla domain and higher avidity X(2+) sites of the epidermal growth factor 1 (EGF1)-like domain. PMID- 25804410 TI - Investigating a new neuromodulation treatment for brain disorders using synchronized activation of multimodal pathways. AB - Neuromodulation is an increasingly accepted treatment for neurological and psychiatric disorders but is limited by its invasiveness or its inability to target deep brain structures using noninvasive techniques. We propose a new concept called Multimodal Synchronization Therapy (mSync) for achieving targeted activation of the brain via noninvasive and precisely timed activation of auditory, visual, somatosensory, motor, cognitive, and limbic pathways. In this initial study in guinea pigs, we investigated mSync using combined activation of just the auditory and somatosensory pathways, which induced differential and timing dependent plasticity in neural firing within deep brain and cortical regions of the auditory system. Furthermore, by varying the location of somatosensory stimulation across the body, we increased or decreased spiking activity across different neurons. These encouraging results demonstrate the feasibility of systematically modulating the brain using mSync. Considering that hearing disorders such as tinnitus and hyperacusis have been linked to abnormal and hyperactive firing patterns within the auditory system, these results open up the possibility for using mSync to decrease this pathological activity by varying stimulation parameters. Incorporating multiple types of pathways beyond just auditory and somatosensory inputs and using other activation patterns may enable treatment of various brain disorders. PMID- 25804411 TI - Quantum dot-based lab-on-a-bead system for multiplexed detection of free and total prostate-specific antigens in clinical human serum samples. AB - An immunodiagnostic lab-on-a-bead suspension microarray based on microbeads encoded with quantum dots (QDs) has been developed and preclinically validated for multiplexed quantitative detection of prostate cancer markers in human serum samples. The sensitivity and specificity of the microarray are similar to those of "gold-standard" single-analyte ELISA. Moreover, the array has an improved immunoassay capacity, ensures quantitative detection of multiple cancer biomarkers and may be operational in a considerably wider dynamic range of concentrations. The array is characterized by reduced time and cost of analysis and is compatible with classical flow cytometers. Proof-of-concept preclinical tests ensured simultaneous quantitative determination of free and total prostate specific antigens in human serum, with clear discrimination between the control and clinical samples. The proposed approach is flexible and paves the way to development of a wide variety of immunodiagnostic assays for multiplexed early diagnosis of various diseases. FROM THE CLINICAL EDITOR: Early diagnosis of cancer can result in better prognosis for patients. Thus, the use of specific tumor markers is widely employed in clinical practice. Traditional screening methods only employ single markers. The authors here developed a microarray system based on microbeads encoded with quantum dots (QDs), which can be used for multiplexed quantitative detection. The validated results on patient samples should lead to the development of a wider variety of assays for other diseases. PMID- 25804412 TI - Use of asymmetric multilayer polylactide nanofiber mats in controlled release of drugs and prevention of liver cancer recurrence after surgery in mice. AB - Local tumor recurrence remains a major clinical problem following surgical treatment for most cancers such as hepatocellular carcinoma (HCC). An implantable local drug delivery system may be suitable for addressing this unmet clinical need. In this study, asymmetric multilayer polylactide nanofiber (AMPN) mats were prepared and a one-sided and prolonged release profile of hydrophilic dye or oxaliplatin was observed after they were sandwiched between two liver lobes in mice. Covering the surgery site by drug-loaded AMPN mat after tumor resection, in both subcutaneous and orthotopic HCC model in mice, the recurrence of HCC was significantly retarded and the survival time of mice was markedly prolonged. In conclusion, post-surgical therapy at tumor resection margins by drug-loaded AMPN mats may represent a suitable application of nanofiber-based local chemotherapy. FROM THE CLINICAL EDITOR: After cancer surgery, local recurrence remains a significant problem. In this study, the authors designed asymmetric multilayer PLA nanofiber (AMPN) mats and loaded them with anti-tumor drugs. Both in-vitro and in-vivo experiments showed good efficacy in preventing tumor recurrence. This novel product may point a way to the future and improve survival of cancer patients. PMID- 25804414 TI - Highly bactericidal Ag nanoparticle films obtained by cluster beam deposition. AB - The recent emergence of bacterial pathogens resistant to most or all available antibiotics is among the major global public health problems. As indirect transmission through contaminated surfaces is a main route of dissemination for most of such pathogens, the implementation of effective antimicrobial surfaces has been advocated as a promising approach for their containment, especially in the hospital settings. However, traditional wet synthesis methods of nanoparticle based antimicrobial materials leave a number of key points open for metal surfaces: such as adhesion to the surface and nanoparticle coalescence. Here we demonstrate an alternative route, i.e. supersonic cluster beam deposition, to obtain antimicrobial Ag nanoparticle films deposited directly on surfaces. The synthesized films are simple to produce with controlled density and thickness, are stable over time, and are shown to be highly bactericidal against major Gram positive and Gram negative bacterial pathogens, including extensively drug resistant strains. FROM THE CLINICAL EDITOR: The use of silver nanoparticle in health care is getting more widespread. The authors here describe the technique of cluster beam deposition for spraying silver on surfaces used in health care sectors. This may open a new avenue for future anti-bacterial coatings. PMID- 25804415 TI - Advances in drug delivery systems (DDSs) to release growth factors for wound healing and skin regeneration. AB - Current advances in novel drug delivery systems (DDSs) to release growth factors (GFs) represent a great opportunity to develop new therapies or enhance the effectiveness of available medical treatments. These advances are particularly relevant to the field of regenerative medicine, challenging healthcare issues such as wound healing and skin repair. To this end, biocompatible biomaterials have been extensively studied to improve in vivo integration of DDSs, to enhance the bioactivity of the released drugs and to deliver bioactive molecules in a localised and controlled manner. Thus, this review presents an overview of DDSs to release GFs for skin regeneration, particularly emphasising on (i) polymeric micro and nanospheres, (ii) lipid nanoparticles, (iii) nanofibrous structures, (iv) hydrogels and (v) scaffolds. In addition, this review summarises the current animal models available for studying wound healing and the clinical trials and marketed medications based on GF administration indicated for chronic wound treatment. FROM THE CLINICAL EDITOR: Chronic wounds currently pose a significant burden worldwide. With advances in science, novel drug delivery systems have been developed for growth factors delivery. In this comprehensive review, the authors highlighted current drug delivery systems for the enhancement of wound healing and their use in clinical settings. PMID- 25804413 TI - Silver nanoparticles protect human keratinocytes against UVB radiation-induced DNA damage and apoptosis: potential for prevention of skin carcinogenesis. AB - Ultraviolet (UV)-B radiation from the sun is an established etiological cause of skin cancer, which afflicts more than a million lives each year in the United States alone. Here, we tested the chemopreventive efficacy of silver nanoparticles (AgNPs) against UVB-irradiation-induced DNA damage and apoptosis in human immortalized keratinocytes (HaCaT). AgNPs were synthesized by reduction chemistry and characterized for their physicochemical properties. AgNPs were well tolerated by HaCaT cells and their pretreatment protected them from UVB irradiation-induced apoptosis along with significant reduction in cyclobutane pyrimidine-dimer formation. Moreover, AgNPs pre-treatment led to G1-phase cell cycle arrest in UVB-irradiated HaCaT cells. AgNPs were efficiently internalized in UVB-irradiated cells and localized into cytoplasmic and nuclear compartments. Furthermore, we observed an altered expression of various genes involved in cell cycle, apoptosis and nucleotide-excision repair in HaCaT cells treated with AgNPs prior to UVB-irradiation. Together, these findings provide support for potential utility of AgNPs as novel chemopreventive agents against UVB-irradiation-induced skin carcinogenesis. FROM THE CLINICAL EDITOR: Excessive exposure to the sun is known to increase the risk of skin cancer due to DNA damage. In this work, the authors tested the use of silver nanoparticles as protective agents against ultraviolet radiation. The positive results may open a door for the use of silver nanoparticle as novel agents in the future. PMID- 25804416 TI - Minimising bleeding during percutaneous coronary intervention. PMID- 25804417 TI - Management of severe acute dental infections. PMID- 25804418 TI - Crystal structure of a Xenopus laevis skin proto-type galectin, close to but distinct from galectin-1. AB - Xenopus laevis (African clawed frog) has two types of proto-type galectins that are similar to mammalian galectin-1 in amino acid sequence. One type, comprising xgalectin-Ia and -Ib, is regarded as being equivalent to galectin-1, and the other type, comprising xgalectin-Va and -Vb, is expected to be a unique galectin subgroup. The latter is considerably abundant in frog skin; however, its biological function remains unclear. We determined the crystal structures of two proto-type galectins, xgalectin-Ib and -Va. The structures showed that both galectins formed a mammalian galectin-1-like homodimer, and furthermore, xgalectin-Va formed a homotetramer. This tetramer structure has not been reported for other galectins. Gel filtration and other experiments indicated that xgalectin-Va was in a dimer-tetramer equilibrium in solution, and lactose binding enhanced the tetramer formation. The residues involved in the dimer-dimer association were conserved in xgalectin-Va and -Vb, and one of the Xenopus (Silurana) tropicalis proto-type galectins, but not in xgalectin-Ia and -Ib, and other galectin-1-equivalent proteins. Xgalectin-Va preferred Galbeta1-3GalNAc and not Galbeta1-4GlcNAc, while xgalectin-Ib preferred Galbeta1-4GlcNAc as well as human galectin-1. Xgalectin-Va/Vb would have diverged from the galectin-1 group with accompanying acquisition of the higher oligomer formation and altered ligand selectivity. PMID- 25804419 TI - TUDCA Promotes Phagocytosis by Retinal Pigment Epithelium via MerTK Activation. AB - PURPOSE: Renewal and elimination of the aged photoreceptor outer segment (POS) by RPE cells is a daily rhythmic process that is important for long-term vision. Phagocytic dysfunction results in photoreceptor cell death. Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, is known to show neuroprotective effects in stroke, neurological diseases, and retinal degeneration models. In this study, we investigated the effects of TUDCA on retinal phagocytosis. METHODS: We used pHrodo-succinimidyl ester (SE), a pH-sensitive fluorescent dye, to label the POS for monitoring phagocytosis. After ingestion, the intensity of pHrodo fluorescence increases because of the pH changes inside the liposome. An RPE cell line, ARPE-19, and primary human RPE cells were used to investigate the hydrogen peroxide (H2O2)-induced disruption of phagocytosis in the pH-sensitive fluorescence POS phagocytosis assay. Additionally, we examined whether TUDCA could promote phagocytic function. RESULTS: The intensity of pHrodo light emission increased in a time-dependent manner. Tauroursodeoxycholic acid enhanced phagocytosis of POS and protected against H2O2-induced phagocytic dysfunction. It also promoted phagocytic function via activation of Mer tyrosine kinase receptor (MerTK), which is known to have a key role in the physiological renewal of POS. CONCLUSIONS: These results suggest that TUDCA activates MerTK, which is important for phagocytosis of POS. Tauroursodeoxycholic acid may represent a new therapeutic option for the treatment of retinal diseases. PMID- 25804420 TI - 3-Methyl-methcathinone: Pharmacokinetic profile evaluation in pigs in relation to pharmacodynamics. AB - 3-Methyl-methcathinone (3-MMC) is a novel, synthetic cathinone analog, recently linked to poisoning events among recreational users. The lack of pharmacological data on 3-MMC, prompted us to explore its pharmacokinetic profile as well as its effect on feeding behavior, weight gain, and serum biochemistry. 3-MMC was administered to male pigs (n=3, three months old) as a single intravenous dose (0.3 mg/kg), followed by a multiple oral dose administration (3 mg/kg) for five days and plasma and tissue concentrations determined. Concomitantly a control group consisting of two healthy male pigs received saline solution instead of 3 MMC according to the same administration schedule. 3-MMC effects on complete blood count, biochemistry, feed intake, and body weight were examined. The pigs were sacrificed and submitted to a pathological and histopathological examination. 3-MMC displayed rapid absorption with a peak concentration achieved within 5-10 min after oral ingestion and a plasma half-life of 0.8 h. The bioavailability was about 7%. 3-MMC tissue levels were below detectable levels 24 h after the last oral dosage. No treatment-related clinical signs were observed and no histopathological findings were detected. 3-MMC caused significant change in daily feed intake and weight gain over time. The animals treated with 3-MMC displayed a lower rate of increase in mean body weight. Caution needs to be practiced in terms of extrapolating the present data to human safety, due to the low sample size, low dosage, and the relatively short study duration as well as the lack of data on abuse potential of 3-MMC. PMID- 25804421 TI - A systematic review of contemporary models of shared HIV care and HIV in primary care in high-income settings. AB - HIV shared care is uncommon in the UK although shared care could be a beneficial model of care. We review the literature on HIV shared care to determine current practice and clinical, economic and patient satisfaction outcomes. We searched MEDLINE, EMBASE, NICE Evidence, Cochrane collaboration, Google and websites of the British HIV Association, Aidsmap, Public Health England, World Health Organization and Terrence Higgins Trust using relevant search terms in August 2014. Studies published after 2000, from healthcare settings comparable to the UK that described links between primary care and specialised HIV services were included and compared using principles of the Critical Appraisal Skills Programme and Authority, Accuracy, Coverage, Objectivity, Date, Significance frameworks. Three of the nine included models reported clinical or patient satisfaction outcomes but data collection and analyses were inadequate. None reported economic outcomes although some provided financial costings. Facilitators of shared care included robust clinical protocols, training and timely communication. Few published examples of HIV shared care exist and quality of evidence is poor. There is no consistent association with improved clinical outcomes, cost effectiveness or acceptability. Models are context specific, driven by local need, although some generalisable features could inform novel service delivery. Further evaluative research is needed to determine optimal components of shared HIV care. PMID- 25804422 TI - Inertial sensors to estimate the energy expenditure of team-sport athletes. AB - OBJECTIVES: To quantify the energy expenditure of Australian Football training and matches and the total daily energy expenditure of Australian Football players using tri-axial accelerometers. DESIGN: Cross sectional observation study. METHODS: An algorithm was developed for the MiniMax 4.0 (Catapult Innovations, Scoresby Australia) using measured oxygen uptake and accelerometer data to estimate energy expenditure of 18 Australian Football players during training and matches. The algorithm was used to validate a metabolic power calculation used by Catapult Innovations (Scoresby Australia) in their proprietary GPS software. The SenseWearTM (Model MF-SW, Bodymedia, Pittsburgh, PA) armband was used to determine non-exercise activity thermogenesis and was worn for 7 days leading into a match. Training, match and non-exercise activity thermogenesis data was summed for total daily energy expenditure. RESULTS: Energy expenditure for field training was estimated to be 2719+/-666kJ and for matches to be 5745+/-1468kJ. The estimated energy expenditure in the current study showed a large correlation (r=0.57, 90% CI 0.06-0.84) with the metabolic power calculation. The mean total daily energy expenditure for an in-season main training day was approximately 18,504kJ and match day approximately 19,160kJ with non-exercise activity thermogenesis contributing approximately 85% and 69% on training and match days, respectively. CONCLUSIONS: The MiniMax 4.0 and SenseWearTM armband accelerometers provide a practical, non-invasive and an effective method to successfully measure training and match energy expenditure, and non-exercise activity thermogenesis in field sport athletes. Taking methodological limitations into consideration, measuring energy expenditure allows for individualised nutrition programming to enhance performance and achieve body composition goals. PMID- 25804423 TI - Does the recent internal load and strain on players affect match outcome in elite Australian football? AB - OBJECTIVES: To compare recent internal training load and strain of elite Australian football players for match outcome. DESIGN: Case study. METHODS: Load was quantified from session rating of perceived exertion (sRPE) for individual players from one team in 141 professional Australian football matches over six seasons, then averaged for players that competed for the team each week. Internal weekly-load and weekly-strain (load*monotony) was compared to recent-load and recent-strain (four-week rolling average) as a marker of training-stress balance for each player against the match outcome. Covariates for relative position of teams in the competition and days between matches were modelled. Differences were standardised (effect size; ES) and interpreted using magnitude based inferences. RESULTS: Weekly-load was likely higher for match wins (ES+/-90% confidence limits; 0.43+/-0.27), and when days-break was used as a covariate (0.45+/-0.27) but only possibly higher with relative ladder position covaried (RLP, 0.29+/ 0.33). There was a possibly greater positive training-stress balance for load in wins (0.31; +/-0.38) with db (0.39; +/-0.39) and RLP covaried (0.27; +/-0.48). There were no clear differences for strain for wins and losses or with either covariate. There was a likely greater positive training-stress balance for strain in wins (0.51; +/-0.41) with days-break (0.48; +/-0.41) but not RLP covaried. CONCLUSIONS: Weekly-load and a positive training-stress balance for strain were the best predictors of match success. The higher weekly-load and training-stress balance for strain highlight the conflict between maintaining the training stimulus and minimising fatigue in Australian football players between matches. PMID- 25804425 TI - Periosteal sleeve avulsion as a Tillaux variant in an adolescent male: Case report. PMID- 25804424 TI - Systems Toxicology: The Future of Risk Assessment. AB - Risk assessment, in the context of public health, is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. With increasing public health concern regarding the potential risks associated with chemical exposure, there is a need for more predictive and accurate approaches to risk assessment. Developing such an approach requires a mechanistic understanding of the process by which xenobiotic substances perturb biological systems and lead to toxicity. Supplementing the shortfalls of traditional risk assessment with mechanistic biological data has been widely discussed but not routinely implemented in the evaluation of chemical exposure. These mechanistic approaches to risk assessment have been generally referred to as systems toxicology. This Symposium Overview article summarizes 4 talks presented at the 35th Annual Meeting of the American College of Toxicology. PMID- 25804426 TI - Clinical outcomes and risk factors for posterior reversible encephalopathy syndrome in systemic lupus erythematosus: a multicentric case-control study. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a well-known but rare complication in patients (<1%) with systemic lupus erythematosus (SLE). However, current epidemiological data are quite scant. The aim of the present study was to describe potentially unrecognised risk factors. PATIENTS AND METHODS: We performed a multicentre, retrospective case-control study in Mexico between 1999 and 2014. We included a total of 168 patients who accounted for 77 episodes of PRES, as follows: SLE/PRES, 43 patients with 48 episodes; SLE without PRES, 96 patients; and PRES without SLE, 29 patients. SLE diagnosis was considered when patients fulfilled >=4 American College of Rheumatology criteria. PRES was defined by reversible neurological manifestations and MRI changes. RESULTS: Patients with SLE/PRES were younger, presented with seizures as the most common manifestation (81%) and 18% had the typical occipital MRI finding. Hypertension (OR=16.3, 95% CI 4.03 to 65.8), renal dysfunction (OR=6.65, 95% CI 1.24 to 35.6), lymphopenia (OR=5.76, 95% CI 1.36 to 24.4), Systemic Lupus Erythematosus Activity Index >= 6 points (OR=1.11, 95% CI 1.01 to 1.22) and younger age (OR=0.86, 95% CI 0.81 to 0.91, p<0.001) were independent risk factors for development of PRES in SLE. Furthermore, dyslipidemia also characterised the association between PRES and SLE (OR=10.6, 95% CI 1.17 to 96.4). CONCLUSIONS: This is the largest reported series of patients with SLE and PRES. We were able to corroborate the known risk factors for of PRES, and found two previously undescribed factors (lymphopenia and dyslipidemia), which suggests that endothelial dysfunction is a key element in PRES pathogenesis in lupus patients. PMID- 25804427 TI - Dye-free near-infrared surface-enhanced Raman scattering nanoprobes for bioimaging and high-performance photothermal cancer therapy. AB - Near-infrared surface-enhanced Raman scattering (NIR SERS) imaging is now a promising molecular imaging technology due to its narrow spectral bandwidth, low background interference and deep imaging depth. In this work, we report a novel strategy for fabrication of NIR SERS nanoprobes without using any expensive and highly toxic organic dyes. Multifunctional conducting polymer (CP) materials, serving as both biocompatible surface coatings and NIR-active reporters, are directly fabricated on the surface of gold nanorods (GNRs) via facile oxidative polymerization. The dye-free NIR SERS nanoprobes (GNR-CPs) exhibit good structural stability, good biocompatibility and intriguing NIR SERS activity. GNR CPs also show an extraordinary NIR photothermal transduction efficiency, indicating the potential for cancer therapy. The applications of GNR-CPs as new types of theranostic agents for NIR SERS imaging and high-performance photothermal therapy are accomplished in vitro and in vivo. PMID- 25804428 TI - Catalytic enhancement of the heme-based oxygen-sensing phosphodiesterase EcDOS by hydrogen sulfide is caused by changes in heme coordination structure. AB - EcDOS is a heme-based O2-sensing phosphodiesterase in which O2 binding to the heme iron complex in the N-terminal domain substantially enhances catalysis toward cyclic-di-GMP, which occurs in the C-terminal domain. Here, we found that hydrogen sulfide enhances the catalytic activity of full-length EcDOS, possibly owing to the admixture of 6-coordinated heme Fe(III)-SH(-) and Fe(II)-O2 complexes generated during the reaction. Alanine substitution at Met95, the axial ligand for the heme Fe(II) complex, converted the heme Fe(III) complex into the heme Fe(III)-SH(-) complex, but the addition of Na2S did not further reduce it to the heme Fe(II) complex of the Met95Ala mutant, and no subsequent formation of the heme Fe(II)-O2 complex was observed. In contrast, a Met95His mutant formed a stable heme Fe(II)-O2 complex in response to the same treatment. An Arg97Glu mutant, containing a glutamate substitution at the amino acid that interacts with O2 in the heme Fe(II)-O2 complex, formed a stable heme Fe(II) complex in response to Na2S, but this complex failed to bind O2. Interestingly, the addition of Na2S promoted formation of verdoheme (oxygen-incorporated, modified protoporphyrin IX) in an Arg97Ile mutant. Catalytic enhancement by Na2S was similar for Met95 mutants and the wild type, but significantly lower for the Arg97 mutants. Thus, this study shows the first isolation of spectrometrically separated, stable heme Fe(III)-SH(-), heme Fe(II) and heme Fe(II)-O2 complexes of full-length EcDOS with Na2S, and confirms that external-ligand-bound, 6-coordinated heme Fe(III)-SH(-) or heme Fe(II)-O2 complexes critically contribute to the Na2S-induced catalytic enhancement of EcDOS. PMID- 25804430 TI - Erratum to: a preliminary double-blind, placebo-controlled randomized study of baclofen effects in alcoholic smokers. PMID- 25804429 TI - [Urinary complications of pelvic exenterations for rectal cancer with urinary invasion]. AB - OBJECTIVE: Pelvic exenteration for rectal cancer is indicated in locally advanced rectal tumors or pelvic recurrence invading adjacent organs. The oncologic goal being a complete R0 resection. Our aim was to study the urinary complications resulting from pelvic exenterations with urinary reconstruction in order to obtain a complete local control of the disease. METHODS: Between April 2004 and June 2013, 42 patients who underwent pelvic exenteration for primary or recurrent rectal adenocarcinoma with urinary tract reconstruction were included. The urinary reconstruction was performed based on preoperative imaging and intraoperative findings. We studied early (within 30 postoperative days) and late urinary morbidity, as well as postoperative carcinologic control. RESULTS: Forty two exenterations were performed for primary rectal cancer (n=15) or pelvic recurrence (n=27). R0 complete resection was achieved in 64% of patients. The resection was incomplete (R1) on the urinary tract in 9.5% of patients. The urinary reconstruction methods used were: 31 transileal ureterostomies after total exenteration (bricker procedure), 6 ureteral reimplantations on psoic bladder, 2 ureteroileoplasties, 2 partial cystectomies and one ureteral resection with simple ligation. The median follow-up was 20 months. The perioperative mortality was 2.3% (n=1) and postoperative overall morbidity was 64%. Early and late urinary morbidity was 23.8% and 21.4% respectively. Six patients developed major urinary complications (>= Clavien IIIb). CONCLUSION: Pelvic exenteration with urinary resection resulted in our experience, in a local disease control of 64% (including a 90.5% for the urinary tract) at the price of an acceptable early specific morbidity and a low mortality that seems to justify an aggressive surgical approach. PMID- 25804431 TI - Computerized training system for ultrasound-guided lumbar puncture on abnormal spine models: a randomized controlled trial. AB - PURPOSE: A randomized controlled trial was carried out to determine whether Perk Tutor, a computerized training platform that displays an ultrasound image and real-time needle position in a three-dimensional (3D) anatomical model, would benefit residents learning ultrasound-guided lumbar puncture (LP) in simulation phantoms with abnormal spinal anatomy. METHODS: Twenty-four residents were randomly assigned to either the Perk Tutor (P) or the Control (C) group and asked to perform an LP with ultrasound guidance on part-task trainers with spinal pathology. Group P was trained with the 3D display along with conventional ultrasound imaging, while Group C used conventional ultrasound only. Both groups were then tested solely with conventional ultrasound guidance on an abnormal spinal model not previously seen. We measured potential tissue damage, needle path in tissue, total procedure time, and needle insertion time. Procedural success rate was a secondary outcome. RESULTS: The needle tracking measurements (expressed as median [interquartile range; IQR]) in Group P vs Group C revealed less potential tissue damage (39.7 [21.3-42.7] cm(2) vs 128.3 [50.3-208.2] cm(2), respectively; difference 88.6; 95% confidence intervals [CI] 24.8 to 193.5; P = 0.01), a shorter needle path inside the tissue (426.0 [164.9-571.6] mm vs 629.7 [306.4-2,879.1] mm, respectively; difference 223.7; 95% CI 76.3 to 1,859.9; P = 0.02), and lower needle insertion time (30.3 [14.0-51.0] sec vs 59.1 [26.0-136.2] sec, respectively; difference 28.8; 95% CI 2.2 to 134.0; P = 0.05). Total procedure time and overall success rates between groups did not differ. CONCLUSION: Residents trained with augmented reality 3D visualization had better performance metrics on ultrasound-guided LP in pathological spine models. PMID- 25804432 TI - A technique to facilitate laryngeal passage during flexible bronchoscopic intubation. PMID- 25804433 TI - Development of an LC-MS/MS assay for the quantitative determination of the intracellular 5-fluorouracil nucleotides responsible for the anticancer effect of 5-fluorouracil. AB - 5-Fluorouracil (5-FU) and its oral prodrug capecitabine are among the most widely used chemotherapeutics. For cytotoxic activity, 5-FU requires cellular uptake and intracellular metabolic activation. Three intracellular formed metabolites are responsible for the antineoplastic effect of 5-FU: 5-fluorouridine 5' triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP) and 5 fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). In this paper, we describe the development of an LC-MS/MS assay for quantification of these active 5-FU nucleotides in peripheral blood mononuclear cells (PBMCs). Because the intracellular 5-FU nucleotide concentrations were very low, maximization of the release from the cell matrix and minimization of interference were critical factors. Therefore, a series of experiments was performed to select the best method for cell lysis and nucleotide extraction. Chromatography was optimized to obtain separation from endogenous nucleotides, and the effect of different cell numbers was examined. The assay was validated for the following concentration ranges in PBMC lysate: 0.488-19.9 nM for FUTP, 1.66-67.7 nM for FdUTP and 0.748 30.7 nM for FdUMP. Accuracies were between -2.2 and 7.0% deviation for all analytes, and the coefficient of variation values were <= 4.9%. The assay was successfully applied to quantify 5-FU nucleotides in PBMC samples from patients treated with capecitabine and patients receiving 5-FU intravenously. FUTP amounts up to 3054 fmol/10(6) PBMCs and FdUMP levels up to 169 fmol/10(6) PBMCs were measured. The FdUTP concentrations were below the lower limit of quantification. To our knowledge, this is the first time that 5-FU nucleotides were quantified in cells from patients treated with 5-FU or capecitabine without using a radiolabel. PMID- 25804434 TI - Solid state compatibility study and characterization of a novel degradation product of tacrolimus in formulation. AB - Tacrolimus is macrolide drug that is widely used as a potent immunosuppressant. In the present work compatibility testing was conducted on physical mixtures of tacrolimus with excipients and on compatibility mixtures prepared by the simulation of manufacturing process used for the final drug product preparation. Increase in one major degradation product was detected in the presence of magnesium stearate based upon UHPLC analysis. The degradation product was isolated by preparative HPLC and its structure was elucidated by NMR and MS studies. Mechanism of the formation of this degradation product is proposed based on complementary degradation studies in a solution and structural elucidation data. The structure was proven to be alpha-hydroxy acid which is formed from the parent tacrolimus molecule through a benzilic acid type rearrangement reaction in the presence of divalent metallic cations. Degradation is facilitated at higher pH values. PMID- 25804436 TI - The contribution of different forms of violence exposure to internalizing and externalizing symptoms among young South African adolescents. AB - While many youth are exposed to multiple forms of co-occurring violence, the comparative impact of different forms of violence on the mental health of children and adolescents has not been clearly established. Studies from low and middle income countries in particular are lacking. The present study examined the contribution of different forms of violence to internalizing and externalizing symptoms among young adolescents in South Africa. A community-based sample of 616 high school learners completed self-report scales assessing exposure to six different forms of violence and the severity of depression, aggression and conduct disorder symptoms. In bivariate analyses, all six forms of violence were significantly associated with internalizing and externalizing difficulties. When the contribution of all forms of violence to mental health outcomes was examined simultaneously, domestic victimization emerged as the strongest predictor of both internalizing and externalizing difficulties. Cumulative exposure to other forms of violence contributed further to the prediction of aggression and conduct disorder, but not depression. Recommendations for future research, and the implications of the findings for prioritizing the development of violence prevention and intervention initiatives in the South African context, are considered. PMID- 25804435 TI - Sex and sexual orientation disparities in adverse childhood experiences and early age at sexual debut in the United States: results from a nationally representative sample. AB - Adverse childhood experiences (ACEs) have been linked to early sexual debut, which has been found to be associated with multiple adverse health outcomes. Sexual minorities and men tend to have earlier sexual debut compared to heterosexual populations and women, respectively. However, studies examining the association between ACEs and early sexual debut among men and sexual minorities are lacking. The aim of this study was to examine the sex and sexual orientation disparities in the association between ACEs and age at sexual debut. Data were obtained from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Logistic and linear regression models were used to obtain crude and adjusted estimates and 95% confidence intervals adjusting for age, race/ethnicity, income, education, insurance and marital status for the association between ACEs (neglect, physical/psychological abuse, sexual abuse, parental violence, and parental incarceration and psychopathology) and early sexual debut. Analyses were stratified by sex and sexual orientation. Larger effect estimates depicting the association between ACEs and sexual debut were seen for women compared to men, and among sexual minorities, particularly among men who have sex with men (MSM) and women who have sex with women (WSW), compared to heterosexuals. Sexual health education programs with a focus on delaying sexual debut among children and adolescents should also consider addressing ACEs, such as neglect, physical, psychological and sexual abuse, witnessing parental violence, and parental incarceration and psychopathology. Public health practitioners, researchers and sexual health education curriculum coordinators should consider these differences by sex and sexual orientation when designing these programs. PMID- 25804439 TI - A Practical Guide to Check the Consistency of Item Response Patterns in Clinical Research Through Person-Fit Statistics: Examples and a Computer Program. AB - Although there are many studies devoted to person-fit statistics to detect inconsistent item score patterns, most studies are difficult to understand for nonspecialists. The aim of this tutorial is to explain the principles of these statistics for researchers and clinicians who are interested in applying these statistics. In particular, we first explain how invalid test scores can be detected using person-fit statistics; second, we provide the reader practical examples of existing studies that used person-fit statistics to detect and to interpret inconsistent item score patterns; and third, we discuss a new R-package that can be used to identify and interpret inconsistent score patterns. PMID- 25804438 TI - Accuracy of Short Forms of the Dutch Wechsler Preschool and Primary Scale of Intelligence: Third Edition. AB - This article investigated the accuracy of six short forms of the Dutch Wechsler Preschool and Primary Scale of Intelligence-Third edition (WPPSI-III-NL) in estimating intelligent quotient (IQ) scores in healthy children aged 4 to 7 years (N = 1,037). Overall, accuracy for each short form was studied, comparing IQ equivalences based on the short forms with the original WPPSI-III-NL Full Scale IQ (FSIQ) scores. Next, our sample was divided into three groups: children performing below average, average, or above average, based on the WPPSI-III-NL FSIQ estimates of the original long form, to study the accuracy of WPPSI-III-NL short forms at the tails of the FSIQ distribution. While studying the entire sample, all IQ estimates of the WPPSI-III-NL short forms correlated highly with the FSIQ estimates of the original long form (all rs >= .83). Correlations decreased significantly while studying only the tails of the IQ distribution (rs varied between .55 and .83). Furthermore, IQ estimates of the short forms deviated significantly from the FSIQ score of the original long form, when the IQ estimates were based on short forms containing only two subtests. In contrast, unlike the short forms that contained two to four subtests, the Wechsler Abbreviated Scale of Intelligence short form (containing the subtests Vocabulary, Similarities, Block Design, and Matrix Reasoning) and the General Ability Index short form (containing the subtests Vocabulary, Similarities, Comprehension, Block Design, Matrix Reasoning, and Picture Concepts) produced less variations when compared with the original FSIQ score. PMID- 25804440 TI - Breast Reconstruction with Delayed Fat-Graft-Augmented DIEP Flap in Patients with Insufficient Donor-Site Volume. AB - BACKGROUND: Microvascular reconstruction provides natural, lasting breasts that can be integrated easily into body image but most thin patients are often not ideal candidates because of inadequate donor-site volume. The purpose of this study was to present our experience in delayed augmented DIEP flaps with large fat-volume transfer. METHODS: From 2010 to 2014, 20 consecutive patients were prospectively enrolled for delayed fat-graft-augmented DIEP flaps (active group, AG) and matched with a control group (CG) submitted to the same procedure without fat-injection. Patient's age, mastectomy and flap weight, number of take-backs to the theater for secondary procedures, total treatment period (TTP), and complications were collected and analyzed. Patient and surgeon surveys rated aesthetic outcomes. Continuous and categorical variables were analyzed using student t test and Kruskal-Wallis test, respectively. A value of p <= 0.05 was considered statistically significant. RESULTS: The groups did not differ in age and mastectomy weight (p > 0.05). The AG had a smaller BMI and flap weight (p < 0.05). Comparison of the mean number of take-backs (1.5 in AG vs. 1.4 in CG) and mean TTP (8.6 months in AG vs. 8.9 months in CG) did not show a significant difference (p > 0.05) between groups. Volume, upper/lower-pole shapes, projection, breast mound placement, IMF, symmetry, overall appearance, and general satisfaction sub-items obtained high-score evaluation without a significant difference between groups (p > 0.05). CONCLUSION: Delayed fat-graft augmented DIEP flaps can be offered to patients with insufficient donor-site volume and medium/large breasts. In comparison with the same technique without fat grafting, no additional take-backs and no prolonged TTP were required to achieve pleasing aesthetic results. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25804441 TI - Granular computing in model based abdominal organs detection. AB - Detection of region specific voxel is a true challenge in many segmentation procedures. In this study a concept of implementing granular computing in the detection of anatomical structures in abdominal computed tomography (CT) scans is introduced. After proving the usefulness of the information granules to identify voxels that mark certain organs, an automatic model-based approach has been developed. A three-parameter granule that combines the interval and density distribution of voxels has been introduced and employed to identify organ specific voxels of the liver, spleen and kidneys. The specificity of the information granules varies between 90 and 99% for the liver and spleen and over 85% for the kidneys. PMID- 25804442 TI - Memory based active contour algorithm using pixel-level classified images for colon crypt segmentation. AB - In this paper, we introduce a novel method for detection and segmentation of crypts in colon biopsies. Most of the approaches proposed in the literature try to segment the crypts using only the biopsy image without understanding the meaning of each pixel. The proposed method differs in that we segment the crypts using an automatically generated pixel-level classification image of the original biopsy image and handle the artifacts due to the sectioning process and variance in color, shape and size of the crypts. The biopsy image pixels are classified to nuclei, immune system, lumen, cytoplasm, stroma and goblet cells. The crypts are then segmented using a novel active contour approach, where the external force is determined by the semantics of each pixel and the model of the crypt. The active contour is applied for every lumen candidate detected using the pixel-level classification. Finally, a false positive crypt elimination process is performed to remove segmentation errors. This is done by measuring their adherence to the crypt model using the pixel level classification results. The method was tested on 54 biopsy images containing 4944 healthy and 2236 cancerous crypts, resulting in 87% detection of the crypts with 9% of false positive segments (segments that do not represent a crypt). The segmentation accuracy of the true positive segments is 96%. PMID- 25804437 TI - Attenuated Toxoplasma gondii Stimulates Immunity to Pancreatic Cancer by Manipulation of Myeloid Cell Populations. AB - Suppressive myeloid cells represent a significant barrier to the generation of productive antitumor immune responses to many solid tumors. Eliminating or reprogramming suppressive myeloid cells to abrogate tumor-associated immune suppression is a promising therapeutic approach. We asked whether treatment of established aggressive disseminated pancreatic cancer with the immunotherapeutic attenuated Toxoplasma gondii vaccine strain CPS would trigger tumor-associated myeloid cells to generate therapeutic antitumor immune responses. CPS treatment significantly decreased tumor-associated macrophages and markedly increased dendritic cell infiltration of the pancreatic tumor microenvironment. Tumor resident macrophages and dendritic cells, particularly cells actively invaded by CPS, increased expression of costimulatory molecules CD80 and CD86 and concomitantly boosted their production of IL12. CPS treatment increased CD4(+) and CD8(+) T-cell infiltration into the tumor microenvironment, activated tumor resident T cells, and increased IFNgamma production by T-cell populations. CPS treatment provided a significant therapeutic benefit in pancreatic tumor-bearing mice. This therapeutic benefit depended on IL12 and IFNgamma production, MyD88 signaling, and CD8(+) T-cell populations. Although CD4(+) T cells exhibited activated effector phenotypes and produced IFNgamma, CD4(+) T cells as well as natural killer cells were not required for the therapeutic benefit. In addition, CD8(+) T cells isolated from CPS-treated tumor-bearing mice produced IFNgamma after re-exposure to pancreatic tumor antigen, suggesting this immunotherapeutic treatment stimulated tumor cell antigen-specific CD8(+) T-cell responses. This work highlights the potency and immunotherapeutic efficacy of CPS treatment and demonstrates the significance of targeting tumor-associated myeloid cells as a mechanism to stimulate more effective immunity to pancreatic cancer. PMID- 25804443 TI - Prevalence and outcomes of cystic lesion of the pancreas in immunosuppressed patients with solid organ transplantation. AB - BACKGROUND: Solid organ transplant recipients have an increased risk of cancer due to immunosuppressive therapy. Pancreatic cystic lesions are increasingly being detected, some with malignant potential. We aimed to determine the prevalence of these lesions and describe their clinical course in these patients. METHODS: We identified the presence of pancreatic cystic lesions in a retrospective cohort of 3188 consecutive solid organ transplant recipients from 2000 to 2013 and compared lesion characteristics at initial and follow-up imaging, when available. RESULTS: Lesion prevalence was 11.4% (365/3188), and increased with age. Median diameter of the largest lesions was 7mm (range: 1 31mm). We noted worrisome features in two patients (0.54%) at the time of cyst diagnosis. Of 155 patients who underwent follow-up imaging, the cysts size remained stable in 80%, increased in 16%, and decreased in 4%. Two patients (1.3%) developed features concerning for cancer. One underwent pancreatic surgery, and pathology confirmed the presence of high-grade dysplasia. The other continued with conservative management due to multiple comorbidities. CONCLUSIONS: Pancreatic cystic lesions are common in solid organ transplant recipients. In lesions without high-risk features, the development of features worrisome for cancer is rare. These lesions can be managed conservatively, and their presence should not affect transplant eligibility. PMID- 25804445 TI - Probabilistic modeling of short survivability in patients with brain metastasis from lung cancer. AB - The prediction of substantially short survivability in patients is extremely risky. In this study, we proposed a probabilistic model using Bayesian network (BN) to predict the short survivability of patients with brain metastasis from lung cancer. A nationwide cancer patient database from 1996 to 2010 in Taiwan was used. The cohort consisted of 438 patients with brain metastasis from lung cancer. We utilized synthetic minority over-sampling technique (SMOTE) to solve the imbalanced property embedded in the problem. The proposed BN was compared with three competitive models, namely, naive Bayes (NB), logistic regression (LR), and support vector machine (SVM). Statistical analysis showed that performances of BN, LR, NB, and SVM were statistically the same in terms of all indices with low sensitivity when these models were applied on an imbalanced data set. Results also showed that SMOTE can improve the performance of the four models in terms of sensitivity, while keeping high accuracy and specificity. Further, the proposed BN is more effective as compared with NB, LR, and SVM from two perspectives: the transparency and ability to show the relation of factors affecting brain metastasis from lung cancer; it allows decision makers to find the probability despite incomplete evidence and information; and the sensitivity of the proposed BN is the highest among all standard machine learning methods. PMID- 25804446 TI - Distal nephron neoplasms. AB - Tumours of the distal nephron are uncommon but can create diagnostic difficulties. They may be divided into three groups-tumours of intercalated cell phenotype, those of principal cell phenotype and others with an unconfirmed distal nephron origin. Oncocytomas, chromophobe carcinoma and hybrid oncocytoma chromophobe carcinoma, all show features of intercalated cells and the distinction amongst these is one of the most common areas of diagnostic dilemma. Collecting duct carcinoma and renal medullary carcinoma are the most aggressive forms of renal cancer but recent evidence suggests they may respond to targeted therapy so their recognition becomes crucial to the management of these patients. There remains debate over the precise phenotype of both tubulocystic carcinoma and mucinous tubular and spindle cell carcinoma. PMID- 25804444 TI - Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice. AB - BACKGROUND: Ethanol can induce cytochrome P450 2E1, an active generator of reactive oxygen species, and this cytochrome is considered a risk factor for oxidative liver injury. Recently, we found that in addition to P450 2E1 also cytochrome P450 2A5, another isoform of cytochrome P450, can be induced by ethanol, and that ethanol induction of cytochrome P450 2A5 is P450 2E1-dependent. AIMS: To investigate the role of cytochrome P450 2A5 in alcohol-induced liver injury. METHODS: Cytochrome P450 2A5-knockout mice and wild type mice were fed the Lieber-Decarli ethanol liquid diet to induce liver injury. Controls were fed the Lieber-Decarli control diet. RESULTS: After 4 weeks of feeding with Lieber Decarli diet, ethanol-induced liver injury was enhanced in the knockout mice compared with wild type mice, as indicated by serum transaminases, hepatic fat accumulation (steatosis), and necroinflammation observed in liver sections with Haematoxylin & Eosin staining. Ethanol-induced oxidative stress was also higher in the knockout mice than the wild types. Ethanol feeding induced cytochrome P450 2A5 in wild type mice but not in the knockout mice, while induction of cytochrome P450 2E1 was comparable in the knockout and wild type mice. CONCLUSION: These results suggest that cytochrome P450 2A5 protects against ethanol-induced oxidative liver injury. PMID- 25804447 TI - Papillary or pseudopapillary tumors of the kidney. AB - Papillary architecture is one of the most common morphological patterns in renal cell neoplasms. Many renal cell neoplasms can also exhibit, diffusely or focally, papillary growth pattern. This article reviews all the renal cell neoplasms with papillary or pseudopapillary architecture, with an emphasis on recently described new histological types. New insights into the "old" entities, including their immunohistochemical and genetic features, will also be discussed. PMID- 25804449 TI - What type of EEG (or EEG-video) does your patient need? AB - For many years, EEG has been synonymous with 'routine' EEG, a short recording without video. With digital technology, there are now many ways to perform EEG recordings. Variable attributes of EEG recordings include: inpatient versus outpatient, prolonged versus short, with video versus without, and with provocation/activation versus without. Each method has advantages and disadvantages, and, in particular, inpatient versus outpatient studies have major cost differences. In some situations EEG-video monitoring can be performed in the ambulatory/home rather than the inpatient setting. PMID- 25804448 TI - PEComas of the kidney and of the genitourinary tract. AB - PEComas are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells that are characterized by the coexpression of muscle and melanogenetic markers. This group of lesions includes angiomyolipoma, clear cell "sugar" tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomical sites. In the genitourinary tract, PEComas have been described in the kidney, bladder, prostate, testis, and urethra. Although most PEComas behave as benign tumors, some are potentially malignant, and criteria for malignancy have been suggested for both and renal and extrarenal lesions. Recently, the expression of cathepsin K has been demonstrated in a large number of PEComas and has been proposed as a relatively specific marker to distinguish these proliferations from the majority of human cancers. In addition, a distinctive subset of PEComas harboring TFE3 gene fusions has been reported, giving rise to a possible relationship between them and MiTF/TFE family translocation renal cell carcinomas. The genetic alterations of tuberous sclerosis complex that promote activation of the mTOR pathway have been identified in PEComas. Therapy with mTORC1 inhibitors has been shown to be effective in some cases. PMID- 25804451 TI - Assessment of composite index methods for agricultural vulnerability to climate change. AB - A common way of quantifying and communicating climate vulnerability is to calculate composite indices from indicators, visualizing these as maps. Inherent methodological uncertainties in vulnerability assessments, however, require greater attention. This study examines Swedish agricultural vulnerability to climate change, the aim being to review various indicator approaches for assessing agricultural vulnerability to climate change and to evaluate differences in climate vulnerability depending on the weighting and summarizing methods. The reviewed methods are evaluated by being tested at the municipal level. Three weighting and summarizing methods, representative of climate vulnerability indices in general, are analysed. The results indicate that 34 of 36 method combinations differ significantly from each other. We argue that representing agricultural vulnerability in a single composite index might be insufficient to guide climate adaptation. We emphasize the need for further research into how to measure and visualize agricultural vulnerability and into how to communicate uncertainties in both data and methods. PMID- 25804450 TI - A DSC and FTIR spectroscopic study of the effects of the epimeric coprostan-3-ols and coprostan-3-one on the thermotropic phase behaviour and organization of dipalmitoylphosphatidylcholine bilayer membranes: Comparison with their 5 cholesten analogues. AB - We present the results of a comparative differential calorimetric and Fourier transform infrared spectroscopic study of the effect of cholesterol and five analogues on the thermotropic phase behaviour and organization of dipalmitoylphosphatidylcholine bilayer membranes. These sterols/steroids differ in both the nature and stereochemistry of the polar head group at C3 (beta-OH, alpha-OH or CO) and in the presence or absence of a double bond in ring B and in the orientation of rings A and B. The Delta(5) sterols/steroid have a trans rather than a cis ring A/B junction, and the concentration of these compounds required to abolish the DPPC pretransition, inversely related to their relative ability to disorder gel state DPPC bilayers, decreases in the order beta-OH > alpha-OH > CO. However, in the saturated ring junction-inverted (cis) series, these concentrations are much more similar, regardless of polar head group chemical structure. Similarly, the residual enthalpy of the DPPC main phase transition at 50 mol% sterol/steroid, which is inversely related to the miscibility of these compounds in fluid DPPC bilayers, also increases in the order beta-OH > alpha-OH > CO, but this effect is attenuated in the saturated series with an inverted ring A/B orientation. Moreover, replacement of the double bond at C5-C6 with a saturated linkage and inversion of the ring A/B junction reduces both sterol/steroid solubility and the ability to order the hydrocarbon chains of fluid DPPC molecules all cases. Thus, the characteristic effects of sterols/steroids on fluid lipid bilayers are generally optimal when an OH group rather than CO group is present at C3, and when this OH group is in the equatorial (beta) orientation, and when the orientation of the ring A/B fusion is trans rather than cis. Overall, these results demonstrate that variations in the saturation and stereochemistry of the steroid ring system influence the effect of variations in the nature and stereochemistry of the polar headgroup at C3 on the physical properties of phospholipid bilayers and vice versa. Moreover, the presence of a single double bond specifically at Delta(5) is required to maximize sterol solubility in fluid DPPC bilayers. PMID- 25804452 TI - An atypical manifestation of Twiddler syndrome. PMID- 25804453 TI - Transatlantic differences in assessment of risk of sudden cardiac death in patients with hypertrophic cardiomyopathy. PMID- 25804454 TI - Variation of lipoprotein(a) plasma levels after premature myocardial infarction. PMID- 25804455 TI - ECG-derived respiration: A promising tool for sleep-disordered breathing diagnosis in chronic heart failure patients. PMID- 25804456 TI - A case of pheochromocytoma with secondary dilated cardiomyopathy, ventricular fibrillation and mural thrombus of left ventricle. PMID- 25804457 TI - Novel mutations in PTPN11 gene in two girls with Noonan syndrome phenotype. PMID- 25804458 TI - Non-resectional leaflet remodeling mitral valve repair preserves leaflet mobility: A quantitative echocardiographic analysis of mitral valve configuration. PMID- 25804459 TI - Cardiogenic shock: How to overcome a clinical dilemma. Unmet needs in Emergency medicine. PMID- 25804460 TI - Aquatic exercise training and stable heart failure: A systematic review and meta analysis. AB - AIM: A meta-analysis and review of the evidence was conducted to determine the efficacy of aquatic exercise training for individuals with heart failure compared to traditional land-based programmes. METHODS: A systematic search was conducted for studies published prior to March 2014, using MEDLINE, PUBMED, Cochrane Library, CINAHL and PEDro databases. Key words and synonyms relating to aquatic exercise and heart failure comprised the search strategy. Interventions included aquatic exercise or a combination of aquatic plus land-based training, whilst comparator protocols included usual care, no exercise or land-based training alone. The primary outcome of interest was exercise performance. Studies reporting on muscle strength, quality of life and a range of haemodynamic and physiological parameters were also reviewed. RESULTS: Eight studies met criteria, accounting for 156 participants. Meta-analysis identified studies including aquatic exercise to be superior to comparator protocols for 6 minute walk test (p < 0.004) and peak power (p < 0.044). Compared to land-based training programmes, aquatic exercise training provided similar benefits for VO(2peak), muscle strength and quality of life, though was not superior. Cardiac dimensions, left ventricular ejection fraction, cardiac output and BNP were not influenced by aquatic exercise training. CONCLUSIONS: For those with stable heart failure, aquatic exercise training can improve exercise capacity, muscle strength and quality of life similar to land-based training programmes. This form of exercise may provide a safe and effective alternative for those unable to participate in traditional exercise programmes. PMID- 25804461 TI - The effectiveness of intensive medical treatment in patients initially diagnosed with refractory angina. PMID- 25804462 TI - Predictive value of NT-proBNP combined with exercise capacity variables in pulmonary artery disease: Insights from a Spanish cohort. PMID- 25804463 TI - A giant myxoma of the left atrium involving the entirety of fossa ovalis: Clinical course, diagnosis and treatment. PMID- 25804464 TI - Autophagy: A potential link between Acquired von Willebrand syndrome and congenital heart disease. PMID- 25804465 TI - A case of Pickering syndrome caused by Takayasu arteritis: Manifestation, PTRA and 6-year follow up. PMID- 25804466 TI - Successful radiofrequency ablation of a parahisian accessory pathway from the right coronary cusp. PMID- 25804467 TI - Ethnic disparities in the incidence of infective endocarditis in the Pacific. PMID- 25804468 TI - VV-ECMO and brave heart: A subtle competition? PMID- 25804469 TI - Noncompaction cardiomyopathy with apical aneurysm. PMID- 25804470 TI - c-Cbl inhibition: A novel therapeutic approach for attenuating myocardial ischemia and reperfusion injury. PMID- 25804471 TI - Carvedilol use and specific cancer risk in the population with hypertension. PMID- 25804472 TI - Accuracy of acute myocardial infarction clinical diagnosis and its implications. PMID- 25804473 TI - Small hydrophobic protein of respiratory syncytial virus as a novel vaccine antigen. PMID- 25804474 TI - Prophylactic potential of defensins and L-isoleucine in tuberculosis household contacts: an experimental model. AB - AIM: Patients with pulmonary tuberculosis (TB) are the most important source for TB infection, being the risk of infection determined by the source case infectiousness and the contact closeness. Currently, the administration of isoniazid is used to prevent the infection to some extent in household contacts. At experimental level, defensins are efficient molecules for the treatment of TB and other infectious diseases. MATERIALS & METHODS: In this work, we used a model of Mycobacterium tuberculosis transmission by long cohabitation of infected and noninfected mice, and treated the latter group with antimicrobial peptides in order to determine the potential capacity of defensins to prevent the infection. RESULTS: Our results showed that the intratracheal administration of human neutrophil peptide-1, human beta-defensin-2 alone or in combination and the use of L-isoleucine significantly prevents bacterial transmission, diminishing pulmonary lesions and bacterial loads. CONCLUSION: Data suggest the potential use of L-isoleucine as prophylactic for TB household contacts. PMID- 25804476 TI - ErbB-targeted CAR T-cell immunotherapy of cancer. AB - Chimeric antigen receptor (CAR) based immunotherapy has been under development for the last 25 years and is now a promising new treatment modality in the field of cancer immunotherapy. The approach involves genetically engineering T cells to target malignant cells through expression of a bespoke fusion receptor that couples an HLA-independent antigen recognition domain to one or more intracellular T-cell activating modules. Multiple clinical trials are now underway in several centers to investigate CAR T-cell immunotherapy of diverse hematologic and solid tumor types. The most successful results have been achieved in the treatment of patients with B-cell malignancies, in whom several complete and durable responses have been achieved. This review focuses on the preclinical and clinical development of CAR T-cell immunotherapy of solid cancers, targeted against members of the ErbB family. PMID- 25804475 TI - Adoptively transferred Tregs accumulate in a site-specific manner and ameliorate signs of less advanced collagen-induced arthritis progress in rats. AB - AIM: The aim of the study was to assess the therapeutic effect and migration of adoptively transferred Tregs in the course of collagen-induced arthritis (CIA) in rats. METHODS: Sorted CD4(+)CD25(+) cells were cultured in the presence of 17 beta-estradiol, stained with CellTracker and then administered into the articular capsule of ankle joint of animals in different stages of CIA progression. RESULTS: Tregs diminished CIA signs only in animals with less advanced disease progress. Moreover, migration of transferred cells into the LN in the near proximity of the injection site and with distal location was almost completely stopped in animals with fully developed CIA. CONCLUSION: Disease progression related differences in migratory potential of in vitro induced Tregs may be responsible for the failure of cellular therapy during the advanced stages of CIA. PMID- 25804477 TI - The inflammasome and IL-1beta: implications for the treatment of inflammatory diseases. AB - The bioactive form of IL-1beta, a key immunoregulatory and proinflammatory cytokine, is produced by the inflammasome - a caspase-1 activating molecular platform - in response to selected danger-associated molecular patterns and pathogen-associated molecular patterns. Advances in understanding the role of IL 1beta in inflammatory conditions has resulted in IL-1beta becoming a therapeutic target for a number of inflammatory diseases beyond the rare monogenic autoinflammatory diseases characterized by aberrant inflammasome function and enhanced bioactive IL-1beta production. In the monogenic autoinflammatory diseases known as cryopyrin-associated periodic syndromes, neutralization of IL 1beta results in a rapid and sustained reduction in disease severity without severe side effects, which has consequently driven off-label applications of IL 1beta-targeted therapy in other inflammatory diseases. This review summarizes inflammatory diseases for which accumulating evidence suggests a therapeutic potential for IL-1beta antagonists. PMID- 25804478 TI - Progress with the use of monoclonal antibodies for the treatment of systemic lupus erythematosus. AB - In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice. PMID- 25804479 TI - Lentiviral vectors in cancer immunotherapy. AB - Basic science advances in cancer immunotherapy have resulted in various treatments that have recently shown success in the clinic. Many of these therapies require the insertion of genes into cells to directly kill them or to redirect the host's cells to induce potent immune responses. Other analogous therapies work by modifying effector cells for improved targeting and enhanced killing of tumor cells. Initial studies done using gamma-retroviruses were promising, but safety concerns centered on the potential for insertional mutagenesis have highlighted the desire to develop other options for gene delivery. Lentiviral vectors (LVs) have been identified as potentially more effective and safer alternative delivery vehicles. LVs are now in use in clinical trials for many different types of inherited and acquired disorders, including cancer. This review will discuss current knowledge of LVs and the applications of this viral vector-based delivery vehicle to cancer immunotherapy. PMID- 25804480 TI - New immunotherapeutic strategies for the treatment of neuroblastoma. AB - The prognosis of high-risk neuroblastoma (NB) is still poor, in spite of aggressive multimodal treatment. Recently, adjuvant immunotherapy with anti-GD2 antibodies combined with IL-2 or GM-CSF has been shown to improve survival. Several other immunotherapy strategies proved efficacy in preclinical models of NB, including different types of vaccines, adoptive cell therapies and combined approaches. The remarkable differences in the immunobiology of syngeneic models and human NB may, at least in part, limit the translation of preclinical therapies to a clinical setting. Nonetheless, several preliminary evidences suggest that new antibodies, cancer vaccines and adoptive transfer of lymphocytes, genetically engineered to acquire NB specificity, may result in clinical benefit, and clinical studies are currently ongoing. PMID- 25804481 TI - Bidirectional interactions of NK cells and dendritic cells in immunotherapy: current and future perspective. AB - NK cells and dendritic cells (DC) are innate cellular components that regulate adaptive immune responses in the immune surveillance of cancer and infections. Interactions of NK and DC are bidirectional. In this mini review, we summarized how NK cells regulate immature DC editing and maturation, how DC regulate NK-cell functions reciprocally in the NK-DC crosstalk, and the importance of NK-DC crosstalk in antitumor immunity. Enhancing NK-DC crosstalk by cellular factor(s), antibodies or creating a microenvironment that promote NK activations, DC maturation and NK-DC crosstalk will provide new insights into future development of DC-based immunotherapy. PMID- 25804482 TI - Rationale for combining immunotherapy with chemotherapy. AB - Immunotherapy has usually been considered as an alternative to more traditional modalities. Moreover, it has previously been felt that chemotherapy is inherently immunosuppressive and not suitable for combining with immunotherapy. In this review, the concept of combining different modalities that result in cell death, such as radiotherapy and chemotherapy, with immunotherapy is explored. Tumors actively cause immune suppression which can be reversed by their removal but when this is not possible, enhancing the immune response with nonspecific immune stimulation can enhance the response to other modalities, such as radiotherapy and chemotherapy. Additionally, several chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells. PMID- 25804483 TI - Onset and nonlinear regimes of ternary mixture convection in a square cavity. AB - We present the results of numerical simulations of onset and nonlinear regimes of a ternary mixture convection in a square cavity subjected to the gravity field and vertical gradients of temperature and concentration. The stability problem for the non-convective state of the mixture is solved using a software package for the investigation of the stability of flows. Nonlinear regimes of convection are studied numerically by the finite difference method. The dependences of critical parameters on the net separation ratio are obtained for the cases of heating from above and below. Numerical data on the temporal evolution of the integral characteristics of flow and heat and mass transfer and of the fields of stream function, temperature and concentration are obtained for different values of the Rayleigh number and net separation ratio. PMID- 25804484 TI - Wellens syndrome caused by spasm of the proximal left anterior descending coronary artery. AB - Electrocardiographic characteristics of Wellens syndrome (WS) consist of deeply inverted T waves or biphasic T waves in anterior precordial leads. Studies have shown that patients with WS have critical stenosis or complete obstruction of the proximal left anterior descending coronary artery (LAD) and high risk for the development of extensive anterior myocardial infarction. Here, we reported a case presenting with WS and with a small plaque in the proximal LAD and slow flow in the LAD other than significant stenosis of the proximal LAD detected by coronary angiography. The mechanisms for WS of our case are discussed. PMID- 25804485 TI - Antimicrobial activity in the cuticle of the American lobster, Homarus americanus. AB - American lobster, Homarus americanus, continues to be an ecologically and socioeconomically important species despite a severe decline in catches from Southern New England and Long Island Sound (USA) and a high prevalence of epizootic shell disease in these populations. A better understanding of lobster immune defenses remains necessary. Cuticle material collected from Long Island Sound lobsters was found to be active against a broad spectrum of bacteria, including Gram-negative and -positive species. The antimicrobial activity was characterized by boiling, muffling, and size fractioning. Boiling did not significantly reduce activity, while muffling did have a significant effect, suggesting that the active component is organic and heat stable. Size fractioning with 3 and 10 kDa filters did not significantly affect activity. Fast protein liquid chromatography fractions were also tested for antimicrobial activity, and fractions exhibiting protein peaks remained active. MALDI mass spectrometry revealed peptide peaks at 1.6, 2.8, 4.6, and 5.6 kDa. The data presented suggest that one or several antimicrobial peptides contribute to antimicrobial activity present in the American lobster cuticle. PMID- 25804486 TI - Effects of replacing soybean meal with rubber seed meal on growth, antioxidant capacity, non-specific immune response, and resistance to Aeromonas hydrophila in tilapia (Oreochromis niloticus * O. aureus). AB - This study evaluated the effects of replacing soybean meal (SBM) with rubber seed meal (RSM) on growth, antioxidant capacity, non-specific immune response and resistance to Aeromonas hydrophila in tilapia (Oreochromis niloticus * Oreochromis aureus). Five experimental diets were formulated with 0 (control), 10, 20, 30, and 40% RSM replacing graded levels of SBM, respectively. Fish were fed one of the five experimental diets for eight weeks, and then challenged by A. hydrophila via intraperitoneal injection and kept for seven days. Dietary RSM inclusion level up to 30% did not affect the weight gain and daily growth coefficient, whereas these were depressed by a further inclusion. Fish fed diet with 40% RSM showed the lowest serum total antioxidant capacity, lysozyme, alternative complement pathway, respiratory burst and phagocytic activities. Dietary RSM inclusion gradually depressed the post-challenge survival rate, and that was significantly lower in fish fed diet with 40% RSM compared to fish fed the control diet. Conversely, the inclusion of RSM generally increased the serum total cholesterol level, the plasma alanine aminotransferase and aspartate aminotransferase activities, and these were significantly higher in fish fed diet with 40% RSM compared to fish fed the control diet. The results indicated that RSM can be included at level up to 30% in diet for tilapia without obvious adverse effects on the growth, antioxidant capacity, non-specific immune response and resistance to A. hydrophila infection, whereas these were depressed by a further inclusion. PMID- 25804487 TI - Vaccination with recombinant protein (r22C03), a putative attachment factor of Neoparamoeba perurans, against AGD in Atlantic salmon (Salmo salar) and implications of a co-infection with Yersinia ruckeri. AB - Amoebic gill disease (AGD) affects salmonids during the marine grow-out phase in the Tasmanian industry and in other major salmonid producing countries. During the period post-transfer to seawater, the bacterial condition yersiniosis can also cause high levels of mortality in Atlantic salmon grown in Tasmania, in addition to the hatchery outbreaks. The recombinant protein r22C03, a mannose binding protein-like (MBP-like) similar to attachment factors of other amoebae, was tested as a vaccine candidate against AGD in a large scale challenge trial. Fish were immunised with r22C03 combined with FCA via intraperitoneal (i.p.) injection, and given a booster five weeks later by either i.p. injection (RP group) or by a dip-immersion (mRP). Fish were then challenged twice with Neoparamoeba perurans: the initial challenge 16 weeks after primary immunisation was terminated due to presence of ulcerative lesions in the skin of salmon; the second challenge was carried out after five weeks of treatment with oxytetracycline. These skin lesions might have been associated with a concurrent infection with Yersinia ruckeri, which was detected by real-time qPCR in serum of a large proportion of moribund and survivor fish after the AGD challenge. Before and during the N. perurans infection, levels of antibodies against r22C03 were measured by ELISA in serum, skin mucus and supernatant from skin and gill explants. For the second challenge, the average size of AGD lesions was recorded from histology sections and survival curves were obtained. Before AGD challenge, r22C03 induced antibody responses in serum and explants with both vaccination strategies. At the end of the challenge, levels of antibodies were lower than before challenge irrespective of treatment. Both vaccinated groups presented increased serum antibody responses, while only mRP presented antibody responses in skin mucus, and no significant antibody responses were measured in the explants. Antibodies did not confer protection to N. perurans infection, as no difference was observed in the survival curves of the vaccinated and control groups, and there was no effect on the gill lesion size. The concurrent yersiniosis infection probably represented more closely infection patterns observed in commercial settings. However, it could have interfered with the survival results and with the ability of the fish to respond to the amoebae infection. PMID- 25804488 TI - The cellular protein expression of Foxp3 in lymphoid and non-lymphoid organs of Nile tilapia. AB - In the present study, an antibody highly specific to the Nile tilapia (Oreochromis niloticus) Foxp3 was produced and characterized. Immunohistochemistry analysis indicates that Foxp3 was expressed in peripheral blood mononuclear cells (PBMC) and certain packed lymphocytes in particular, what's more, the percentage of Foxp3(+) cells among PBMC was 5.7 +/- 2.0% (n = 5) in healthy adults and could be significantly up-regulated after phytohemagglutinin (50 MUg/ml) stimulation in vitro at 6, 12 and 24 h, respectively. In the lymphoid tissues, such as the thymus, spleen and head kidney, Foxp3 expression was observed mainly in lymphocyte-like cells. Surprisingly, in the non-lymphoid organ stomach, Foxp3 was detected in epithelial like cells within the mucosa. Our study demonstrates for the first time that Foxp3 protein expression occurs not only in hematopoietic cells of lymphoid organ systems but also non-hematopoietic cells of non-lymphoid organ in lower vertebrates such as the fish tilapia. The conserved expression pattern of Foxp3 at the protein and cellular levels implies that it might have conserved functions from fish to mammals. PMID- 25804489 TI - Phagocytic activities of hemocytes from the deep-sea symbiotic mussels Bathymodiolus japonicus, B. platifrons, and B. septemdierum. AB - Deep-sea mytilid mussels harbor symbiotic bacteria in their gill epithelial cells that are horizontally or environmentally transmitted to the next generation of hosts. To understand the immune defense system in deep-sea symbiotic mussels, we examined the hemocyte populations of the symbiotic Bathymodiolus mussel species Bathymodiolus japonicus, Bathymodiolus platifrons, and Bathymodiolus septemdierum, and characterized three types of hemocytes: agranulocytes (AGs), basophilic granulocytes (BGs), and eosinophilic granulocytes (EGs). Of these, the EG cells were the largest (diameter, 8.4-10.0 MUm) and had eosinophilic cytoplasm with numerous eosinophilic granules (diameter, 0.8-1.2 MUm). Meanwhile, the BGs were of medium size (diameter, 6.7-8.0 MUm) and contained small basophilic granules (diameter, 0.3-0.4 MUm) in basophilic cytoplasm, and the AGs, the smallest of the hemocytes (diameter, 4.8-6.0 MUm), had basophilic cytoplasm lacking granules. A lectin binding assay revealed that concanavalin A bound to all three hemocyte types, while wheat germ agglutinin bound exclusively to EGs and BGs. The total hemocyte population densities within the hemolymph of all three Bathymodiolus mussel species were similar (8.4-13.3 * 10(5) cells/mL), and the percentages of circulating AGs, BGs, and EGs in the hemolymph of these organisms were 44.7-48.5%, 14.3-17.6%, and 34.3-41.0%, respectively. To analyze the functional differences between these hemocytes, the phagocytic activity and post-phagocytic phagosome-lysosome fusion events were analyzed in each cell type using a fluorescent Alexa Fluor((r)) 488-conjugated Escherichia coli bioparticle and a LysoTracker((r)) lysosomal marker, respectively. While the AGs exhibited no phagocytic activity, both types of granulocytes were phagocytic. Of the three hemocyte types, the EGs exhibited the highest level of phagocytic activity as well as rapid phagosome-lysosome fusion, which occurred within 2 h of incubation. Meanwhile, the BGs showed lower phagocytic activity and lower rates of phagosome lysosome fusion than the EGs. These findings indicate that the two types of granulocyte play distinct roles in the defense system. PMID- 25804490 TI - Dual-parallel inhibition of IL-10 and TGF-beta1 controls LPS-induced inflammatory response via NF-kappaB signaling in grass carp monocytes/macrophages. AB - In fish, the knowledge on the regulation of inflammatory responses is limited. In the present study, LPS rapidly increased the mRNA levels of grass carp pro inflammatory factors, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), inducible nitric oxides synthase (iNOS) and IL-8 in monocytes/macrophages, indicating the occurrence of innate inflammatory responses in fish as seen in mammals. Intriguingly, the gene expression and protein secretion of grass carp IL-10 (gcIL-10) and TGF-beta1 (gcTGF-beta1) were induced by LPS in the same cell model, promoting us to clarify their roles in regulating inflammatory response. Results revealed that grass carp IL-10 polyclonal antibody (anti-gcIL-10 pAb) and grass carp TGF-beta1 monoclonal antibody (anti-gcTGF-beta1 mAb) could amplify the stimulation of LPS on the mRNA levels of tnfalpha, il1beta, inos and il8, suggesting the inhibitory tone of endogenous IL-10 and TGF beta1 in LPS-challenged immune responses. This notion was further supported by the fact that recombinant grass carp IL-10 (rgcIL-10) and recombinant grass carp TGF-beta1 (rgcTGF-beta1) attenuated LPS-stimulated tnfalpha, il1beta, inos and il8 gene expression in monocytes/macrophages. Further study revealed that rgcIL 10 and rgcTGF-beta1 impaired NF-kappaB activation by blocking LPS-induced grass carp IkappaBalpha (gcIkappaBalpha) protein degradation in the cells. In addition, the correlation between gcIL-10 and gcTGF-beta1 in this regulation was examined by immunoneutralization, unveiling that anti-gcTGF-beta1 mAb and anti-gcIL-10 pAb were unable to alter the inhibitory effects of rgcIL-10 and rgcTGF-beta1 on pro inflammatory factors expression in grass carp monocytes/macrophages, respectively. This dual and parallel effect of gcIL-10 and gcTGF-beta1 strengthened their importance in controlling inflammatory responses. Taken together, our findings shed a light on the functional role, regulatory mechanism and relationship of fish IL-10 and TGF-beta1 in regulating inflammatory response. PMID- 25804491 TI - Fat-associated lymphoid cluster in Cyprinus carpio: Characterisation and its relation with peritoneal haemangiosarcoma. AB - FALC cells are natural helper cells producing Th2-type cytokines, which express c kit, Sca-1, IL7R and CD45 in mouse and human. These cells are involved in allergic responses and contribute to the inflammatory reactions of adipose tissue; however, a lack of information prevails about the presence of these cells in other species. The aim of the study was to identify and characterise FALC cells in the common carp (Cyprinus carpio) using immunohistochemistry and molecular biology techniques as well as to explore their relationships with their microenvironment. Histological description of the FALC was performed using H&E and polyclonal antibodies were used against cell-surface markers such as c-kit, Sca-1 and CD45. Furthermore, gene expression of c-kit, Sca-1 and IL7R was assessed. C. carpio FALC cells express the same surface markers reported in FALC of the mouse at both the pre- and post-transcriptional level. By exposure to the soluble fraction of helminths, FALC cells produce abundant Th2 cytokines (IL-5, IL-6 and IL-13) but do not synthesise IL-1alpha. Additionally, FALC cells probably participate in vascular remodelling of the intestine vessels, inducing tumours because a malignant haemangiosarcoma in the peritoneal cavity was found. In this tumour, abundant FALC with their characteristic cell-surface markers were detected. The findings of this study suggest the involvement of some proto oncogenes such as c-kit and Sca-1, and the deregulation of Src kinases modulated by CD45 present in C. carpio FALC with the ontogeny of peritoneal haemangiosarcoma in this fish species. PMID- 25804492 TI - Cloning and characterization of three suppressors of cytokine signaling (SOCS) genes from the Pacific oyster, Crassostrea gigas. AB - Members of the suppressor of cytokine signaling (SOCS) family are crucial for the control of a variety of signal transduction pathways that are involved in the immunity, growth and development of organisms. However, in mollusks, the identity and function of SOCS proteins remain largely unclear. In the present study, three SOCS genes, CgSOCS2, CgSOCS5 and CgSOCS7, have been identified by searching and analyzing the Pacific oyster genome. Structural analysis indicated that the CgSOCS share conserved functional domains with their vertebrate counterparts. Phylogenetic analysis showed that the three SOCS genes clustered into two distinct groups, the type I and II subfamilies, indicating that these subfamilies had common ancestors. Tissue-specific expression results showed that the three genes were constitutively expressed in all examined tissues and were highly expressed in immune-related tissues, such as the hemocytes, gills and digestive gland. The expression of CgSOCS can also be induced to varying degrees in hemocytes after challenge with pathogen-associated molecular patterns (PAMPs). Moreover, dual-luciferase reporter assays showed that the over-expression of CgSOCS2 and CgSOCS7, but not CgSOC5, can activate an NF-kappaB reporter gene. Collectively, these results demonstrated that the CgSOCS might play an important role in the innate immune responses of the Pacific oyster. PMID- 25804493 TI - De novo assembly and characterization of the spleen transcriptome of common carp (Cyprinus carpio) using Illumina paired-end sequencing. AB - Common carp (Cyprinus carpio) is one of the most important aquacultured species of the family Cyprinidae, and breeding this species for disease resistance is becoming more and more important. However, at the genome or transcriptome levels, study of the immunogenetics of disease resistance in the common carp is lacking. In this study, 60,316,906 and 75,200,328 paired-end clean reads were obtained from two cDNA libraries of the common carp spleen by Illumina paired-end sequencing technology. Totally, 130,293 unique transcript fragments (unigenes) were assembled, with an average length of 1400.57 bp. Approximately 105,612 (81.06%) unigenes could be annotated according to their homology with matches in the Nr, Nt, Swiss-Prot, COG, GO, or KEGG databases, and they were found to represent 46,747 non-redundant genes. Comparative analysis showed that 59.82% of the unigenes have significant similarity to zebrafish Refseq proteins. Gene expression comparison revealed that 10,432 and 6889 annotated unigenes were, respectively, up- and down-regulated with at least twofold changes between two developmental stages of the common carp spleen. Gene ontology and KEGG analysis were performed to classify all unigenes into functional categories for understanding gene functions and regulation pathways. In addition, 46,847 simple sequence repeats (SSRs) were detected from 35,618 unigenes, and a large number of single nucleotide polymorphism (SNP) and insertion/deletion (INDEL) sites were identified in the spleen transcriptome of common carp. This study has characterized the spleen transcriptome of the common carp for the first time, providing a valuable resource for a better understanding of the common carp immune system and defense mechanisms. This knowledge will also facilitate future functional studies on common carp immunogenetics that may eventually be applied in breeding programs. PMID- 25804494 TI - Multiple biomarkers of biological effects induced by cadmium in clam Ruditapes philippinarum. AB - Cadmium (Cd) is a known heavy metal pollutant in the Bohai Sea. Manila clam Ruditapes philippinarum is an important fishery species along the Bohai coast. In this study, the biological effects induced by two concentrations (20 and 200 MUg/L) of Cd were characterized using multiple biochemical indices in the digestive glands of clam R. philippinarum. The total hemocyte counts, reactive oxygen species productions and antioxidant enzyme activities exhibited that Cd induced dose-dependent immune and oxidative stresses in clam digestive glands. Metabolic responses indicated that both Cd exposures caused immune stress marked by the elevated branched chain amino acids (valine, leucine and isoleucine), together with the disturbance in energy metabolism. The differential metabolic biomarkers related to osmotic stress, including homarine, betaine, tyrosine and phenylalanine, suggested the differential responsive mechanisms in clam digestive glands induced by Cd exposures. In addition, both Cd treatments enhanced the anaerobiosis metabolism in clam digestive glands via differential metabolic pathways. PMID- 25804496 TI - Erratum. PMID- 25804495 TI - Efficacy and safety of perindopril arginine + amlodipine in hypertension. AB - To study the efficacy and safety of a new combination of perindopril arginine and amlodipine besylate, 837 subjects were enrolled in a three-arm, prospective, 59 center, randomized clinical trial. For 42 days, subjects (average seated blood pressure [BP], 158 +/- 12/101 +/- 5 mm Hg; age, 52 +/- 10 years; 52% male; 34% black; 20% diabetic) received amlodipine/perindopril arginine (10/14 mg/d), perindopril erbumine (16 mg/d), or amlodipine (10 mg/d). Goal BP was <140/90 or <130/80 mm Hg in diabetics, per JNC 7 guidelines. The combination showed the largest change in seated BP (-23.7/-15.7 vs. -13.7/-9.5 vs. -19.3/-13.2 mm Hg, respectively; P < .0001), the highest proportion at goal BP (51% vs. 26% vs. 37%; P < .0001), and a lower incidence of pedal edema and adverse events compared with amlodipine. No deaths or significant differences across groups in early discontinuation, serum potassium, or rates of total or serious adverse events or glomerular filtration, were observed. PMID- 25804497 TI - Novel semisolid SNEDDS based on PEG-30-di-(polyhydroxystearate): Progesterone incorporation and in vitro digestion. AB - The aim of this work is to study the digestibility of PEG-30-di (polyhydroxystearate) (Cithrol((r)) DPHS) and its semisolid novel self nanoemulsifying drug delivery systems (SNEDDS). Furthermore, the SNEDDS-mediated solubility enhancement of the poorly water-soluble drug Progesterone was evaluated in different media. Additionally, the impact of digestion on Progesterone solubilization was investigated in vitro by a pancreatin digestion assay. The Progesterone-loaded semisolid self-nanoemulsifying formulation (F2) was comprehensively characterized by photon correlation spectroscopy (PCS), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). SNEDDS were able to enhance the equilibrium solubility of Progesterone at various media. Only a minor part of Cithrol((r)) DPHS was digested by pancreatin (less than 6%). Furthermore, protection of Progesterone against digestion-mediated precipitation was observed. Therefore, DPHS containing SNEDDS are attractive candidates for the development of bio robust drug delivery systems for the oral delivery of poorly soluble drugs. PMID- 25804499 TI - Spontaneous pneumomediastinum due to the Macklin effect: less is more. PMID- 25804498 TI - In-situ synchrotron wide-angle X-ray diffraction as a rapid method for cocrystal/salt screening. AB - The purpose of this work was to explore in-situ synchrotron wide-angle X-ray diffraction (WAXD) as a rapid and accurate tool to screen and monitor the formation of cocrystal/salts during heating. The active pharmaceutical ingredients (caffeine, carbamazepine and lamotrigine) were respectively mixed with the coformer (saccharin), and then heated by the hot stage. Real-time process monitoring was performed using synchrotron WAXD to assess cocrystal formation and subsequently compared to differential scanning calorimetry (DSC) measurements. The effect of heating rates and cocrystal growth behavior were investigated. Synchrotron WAXD was fast and sensitive to detect cocrystal formation with the appearance of characteristic diffraction rings, even at the heating rate of 30 degrees C/min, while DSC curves showed overlapped peaks. Unlike the indirect characterization of DSC on endo/exothermic peaks, synchrotron WAXD can directly and qualitatively determine cocrystal by diffraction peaks. The diffraction intensity-temperature curves and the corresponding first-derivative curves clearly exhibited the growth behavior of cocrystal upon heating, providing useful information to optimize the process temperature of hot melt extrusion to continuously manufacture cocrystal. The study suggests that in-situ synchrotron WAXD could provide a one-step process to screen cocrystal at high efficiency and reveal the details of cocrystal/salts growth behavior. PMID- 25804500 TI - Production, characterization, and biogas application of magnetic hydrochar from cellulose. AB - Hydrothermal carbonization (HTC) produces carbon-rich nano-micro size particles. In this study, magnetic hydrochar (MHC) was prepared from model compound cellulose by simply adding ferrites during HTC. The effects of ferrites on HTC were evaluated by characterizing solid MHC and corresponding process liquid. Additionally, magnetic stability of MHC was tested by magnetic susceptibility method. Finally, MHC was used as support media for anaerobic films in anaerobic digestion (AD). Ash-free mass yield was around 50% less in MHC than hydrochar produced without ferrites at any certain HTC reaction condition, where organic part of MHC is mainly carbon. In fact, amorphous hydrochar was growing on the surface of inorganic ferrites. MHC maintained magnetic susceptibility regardless of reaction time at reaction temperature 250 degrees C. Pronounced inhibitory effects of magnetic hydrochar occurred during start-up of AD but diminished with prolong AD times. Visible biofilms were observed on the MHC by laser scanning microscope after AD. PMID- 25804501 TI - High rate psychrophilic anaerobic digestion of high solids (35%) dairy manure in sequence batch reactor. AB - Zero liquid discharge is increasingly adopted as an objective for waste treatment process. The objective of this study was to increase the feed total solids (TS) and the organic loading rate (OLR) fed to a novel psychrophilic (20 degrees C) dry anaerobic digestion (PDAD). Duplicate laboratory-scale bioreactors were fed cow feces and wheat straw (35% TS in feed) at OLR of 6.0 g TCOD kg(-1) inoculum d(-1) during long-term operation (147 days consisting of 7 successive cycles). An overall average specific methane yield (SMY) of 151.8+/-7.9 N L CH4 kg(-1) VS fed with an averaged volatile solids removal of 42.4+/-4.3% were obtained at a volatile solids-based inoculum-to-substrate ratio (ISR) of 2.13+/-0.2. The operation was stable as indicated by biogas and VFAs profiles and the results were reproducible in successive cycles; a maximum SMY of 163.3+/-5.7 N L CH4 kg( 1) VS fed was obtained. Hydrolysis was the reaction limiting step. High rate PDAD of 35% TS dairy manure is possible in sequential batch reactor within 21 days treatment cycle length. PMID- 25804502 TI - Why Can't More Good Surgeons Learn Rhinoplasty? PMID- 25804503 TI - Correction of Sunken Upper-Eyelid Deformity in Young Asians by Minimally-Invasive Double-Eyelid Procedure and Simultaneous Orbital Fat Pad Repositioning: A One Year Follow-up Study of 250 Cases. AB - BACKGROUND: Double-eyelid procedure to construct a supratarsal fold is the most common aesthetic surgery in young Asian adults. More complex surgical procedures, such as fat grafting or filler injection, are often indicated during traditional, long-incision, double-eyelid procedures to achieve better aesthetic results for patients with hollowness of the upper eyelids. OBJECTIVES: The authors sought to determine the efficacy of minimally-invasive double-eyelid procedures with concurrent repositioning of the orbital fat pads to correct sunken upper eyelids in young Asian adults. METHODS: The study included 250 patients treated between June 2008 and July 2103. Preoperatively, all patients complained of upper-eyelid hollowness and had positive findings on a lower-eyelid compression test. All patients underwent a minimally-invasive double-eyelid procedure plus repositioning of orbital fat. RESULTS: After the minimum follow-up period of 1 year, the overall patient satisfaction rate was 76%. The relapse rate was 10% within the first year, and the complication rate was 8%. CONCLUSIONS: This minimally-invasive combination procedure may be an option for young Asian adults who have single upper eyelids and sunken eyes. The surgery resulted in a natural double eyelid and more youthful orbital appearance in the majority of patients in this study. Proper patient selection and evaluation, including lower eyelid compression testing, are essential to achieve long-term correction. PMID- 25804504 TI - Diagnosis of ruptured breast implants through high-resolution ultrasound combined with real-time elastography. AB - BACKGROUND: Implant rupture as a late complication of breast implant surgery is often a silent phenomenon that is difficult to diagnose. Sonoelastography is a new ultrasound-based technique that allows assessment of tissue elasticity. OBJECTIVES: This study was undertaken to evaluate elastographic findings in normal and ruptured breast implants. METHODS: This prospective study included 28 implants in 16 patients, all of whom underwent high-resolution ultrasound and real-time elastography. The diagnosis of implant rupture was confirmed by surgery. RESULTS: Implant rupture was diagnosed in 5 out of 28 implants (17.9%). In those patients with ruptured implants, 3 had no symptoms, 1 presented with pain, and 1 complained of ipsilateral axillary lymph node swelling. Implants with a homogenous anechoic interior were considered to be intact. Ultrasound findings indicating implant rupture included multiple parallel echogenic lines in the implant interior in 2 cases and a mix of hyperechoic and hypoechoic masses in 3 cases. The feasibility of real-time elastography of implants was demonstrated in all cases. Elastograms of intact implants revealed a typical blue-green-red pattern familiar from cystic lesions. In all 5 ruptured implants, elastography revealed yellow-green figures without typical layering. CONCLUSIONS: To the authors' knowledge this is the first series to combine high-resolution ultrasound with real-time elastography for the diagnosis of implant rupture. Since there are distinct differences between elastograms of intact and ruptured implants, addition of real-time elastography to conventional ultrasound may improve implant surveillance and obviate the need for magnetic resonance imaging. PMID- 25804505 TI - Neuroimmunology and synaptic function. PMID- 25804506 TI - It's a dirty job--A robust method for the purification and de novo genome assembly of Cryptosporidium from clinical material. AB - We have developed a novel strategy for the purification of Cryptosporidium oocysts from clinical samples using IMS and PCR amplification of target DNA to facilitate uniform coverage genome sequencing and de novo assembly. Our procedure could also be used for other microbial pathogens from clinical specimens. PMID- 25804507 TI - Integrating mobile technology with routine dietetic practice: the case of myPace for weight management. AB - The field of Mobile health (mHealth), which includes mobile phone applications (apps), is growing rapidly and has the potential to transform healthcare by increasing its quality and efficiency. The present paper focuses particularly on mobile technology for body weight management, including mobile phone apps for weight loss and the available evidence on their effectiveness. Translation of behaviour change theory into weight management strategies, including integration in mobile technology is also discussed. Moreover, the paper presents and discusses the myPace platform as a case in point. There is little clinical evidence on the effectiveness of currently available mobile phone apps in enabling behaviour change and improving health-related outcomes, including sustained body weight loss. Moreover, it is unclear to what extent these apps have been developed in collaboration with health professionals, such as dietitians, and the extent to which apps draw on and operationalise behaviour change techniques has not been explored. Furthermore, presently weight management apps are not built for use as part of dietetic practice, or indeed healthcare more widely, where face-to-face engagement is fundamental for instituting the building blocks for sustained lifestyle change. myPace is an innovative mobile technology for weight management meant to be embedded into and to enhance dietetic practice. Developed out of systematic, iterative stages of engagement with dietitians and consumers, it is uniquely designed to complement and support the trusted health practitioner-patient relationship. Future mHealth technology would benefit if engagement with health professionals and/or targeted patient groups, and behaviour change theory stood as the basis for technology development. Particularly, integrating technology into routine health care practice, rather than replacing one with the other, could be the way forward. PMID- 25804508 TI - Weak interactions as diagnostic tools for inductive effects. AB - No broadly applicable and well-defined measure for the inductive effects of substituents (outside of the context of substituted benzenes) exists. We assess the viability of two different forms of weak interactions as tools for this purpose. The responses of interatomic (I...N and Ge...N) separations in the halogen-bonded and dative covalent complexes F3CI...Y and FH3Ge...Y, where Y = NH2R, afford a direct ordering of a diverse set of substituents, R, according to their influence on the availability of the N lone pair in the base (NH2R) for bonding. Despite their structural and electronic differences, the two bonding modes that we consider show good qualitative agreement on the electron withdrawing inductive tendencies of substituents because of their sensitivity to the electronic environment at the donor site (the N center, in this case) on the base. The choice of the monosubstituted (NH2R) base minimizes steric interactions, resonance, and other electronic effects that could interfere with the bonding between N and the I or Ge centers in the complexes. We find, moreover, that the inductive tendencies for substituents in these complexes are, in general, not additive. Depending on the identity of R, the trisubstituted base (NR3) may actually reverse rather than enhance changes in the acid-base interactions that are achieved going from NH3 to NH2R. These outcomes are observed at the MP2(full) and the M06-2X levels of theory, for both halogen and dative bonding interactions. A conservative ordering of substituents according to the observed inductive tendencies is presented. PMID- 25804509 TI - Synthesis, characterization and binding interactions of amino acids coupled perylene diimides with colloidal doped and undoped TiO2. AB - Two sensitizers based on amino acids coupled with perylene moiety having absorption in the visible region have been designed and their interaction with doped and undoped TiO2 for the application of dye sensitized solar cells (DSSCs) has been studied. The synthesized compounds PDI-PA and PDI-AA were characterized using (1)H and (13)C NMR, Mass and FT-IR spectroscopic techniques. The optical properties and lifetime measurements of the sensitizers were analyzed using various solvents with different polarity. The solvatochromism effect was studied using Lippert-Mataga plot. The electrochemical studies of both dyes were investigated in DMF with various scan rate ranging from 200 to 1000 mV s(-1). Colloidal doped and undoped TiO2 was prepared and characterized by using absorption measurements. Binding ability of the sensitizers with the nanoparticles was studied through absorption, fluorescence quenching, cyclic voltammetry and FT-IR measurements. Results obtained from all the above analysis suggest the mode of quenching may be static. The binding constant values were calculated using Kamat-Fox equation indicates the binding behavior of the sensitizers with the nanoparticles. The fluorescence quenching was mainly attributed to electron transfer from the excited state of PDI's to the conduction band of colloidal semiconductors. The electron transfer mechanism was explained based on the Rehm-Weller equation as well as the energy level diagram. PMID- 25804510 TI - Isolation, spectroscopic and density functional theory studies of 7-(4 methoxyphenyl)-9H-furo[2,3-f]chromen-9-one: a new flavonoid from the bark of Millettia ovalifolia. AB - The phytochemical examination of chloroform soluble fraction (FX2) of methanolic extract of bark of Millettia ovalifolia yielded a new flavonoid; 7-(4 methoxyphenyl)-9H-furo [2,3-f]chromen-9-one (1). Compound 1 is characterized by spectroscopic analytical techniques such as UV, IR, 1D, 2D NMR spectroscopy, and mass spectrometry. A theoretical model is also developed for obtaining geometric, electronic and spectroscopic properties of 1. The geometry optimization and harmonic vibration simulations have been carried out at B3LYP/6-31G(d,p). The vibrational spectrum of compound 1 shows nice correlation with the experimental IR spectrum, through a scaling factor of 0.9613. (1)H and (13)C NMR chemical shifts are simulated using Cramer's re-parameterized function WP04 at 6-31G(d,p) basis set, and correlate nicely with the experimental chemical shifts. PMID- 25804511 TI - A new fluorescent enhanced probe based on (E)-9-(2-nitrovinyl)-anthracene for the detection of bisulfite anions and its practical application. AB - A new fluorescent enhanced probe based on (E)-9-(2-nitrovinyl)-anthracene is developed, which shows high selectivity and sensitivity for the detection of bisulfite anions at Na2HPO4 citric acid buffer solutions (pH 5.0). When addition of HSO3(-), the fluorescence intensity is significantly enhanced and the probe displays apparent fluorescence color changes from non-fluorescence to blue under a UV lamp illumination, the solution color also changes from yellow to colorless. The detection limit is determined to be as low as 6.30 MUM. This offers another specific colorimetric and fluorescent probe for bisulfite anions detection, furthermore it is applied in detecting the level of bisulfite in sugar samples. PMID- 25804512 TI - Energy transfer and luminescence properties of Sr[1-3(x+y)/2]Al2B2O7:xEu3+, yBi3+ phosphor. AB - Sr[1-3(x+y)/2]Al2B2O7:xEu(3+), yBi(3+) (x=0-5 mol% and y=0-5 mol%) phosphors are synthesized by a solid-state reaction method in air, and their crystal structure, fluorescence lifetime, and luminescence properties are investigated. The optimal composition is determined to be (Sr0.94Eu0.03Bi0.01)Al2B2O7. The PLE band peaks within the range 200-550 nm are due to O(2-)->Eu(3+) charge transfer band, (7)F0 >(5)H3, (5)D4, (5)L7, (5)L6, (5)D3, (5)D2, and (5)D1 transitions, respectively. The strongest PL band peak under excitation 394 nm light is at ~615 nm owing to (5)D0->(7)F2 transition of Eu(3+) ion. The PL intensity of Eu(3+), Bi(3+) co doped SrAl2B2O7 phosphor is 1.3 times that of Eu(3+) doped SrAl2B2O7 phosphor due to the energy transfer between Eu(3+) and Bi(3+) ions, which is explained by the energy level diagrams of Bi(3+) and Eu(3+) ions. The CIE chromaticity coordinates of Sr0.955Al2B2O7:0.03Eu(3+) and Sr0.94Al2B2O7:0.03Eu(3+), 0.01Bi(3+) phosphors under excitation 394 nm light are (x=0.6292, y=0.3702) and (x=0.6284, y=0.3711), respectively. These phosphors will be used as reddish orange emitting phosphor candidate for white LED with ~394 nm near ultraviolet LED chip. PMID- 25804513 TI - Surfactant-enhanced spectrofluorimetric determination of total aflatoxins from wheat samples after magnetic solid-phase extraction using modified Fe3O4 nanoparticles. AB - The extraction and preconcentration of total aflatoxins (including aflatoxin B1, B2, G1, and G2) using magnetic nanoparticles based solid phase extraction (MSPE) followed by surfactant-enhanced spectrofluorimetric detection was proposed. Ethylene glycol bis-mercaptoacetate modified silica coated Fe3O4 nanoparticles as an efficient antibody-free adsorbent was successfully applied to extract aflatoxins from wheat samples. High surface area and strong magnetization properties of magnetic nanoparticles were utilized to achieve high enrichment factor (97), and satisfactory recoveries (92-105%) using only 100mg of the adsorbent. Furthermore, the fast separation time (less than 10 min) avoids many time-consuming cartridge loading or column-passing procedures accompany with the conventional SPE. In determination step, signal enhancement was performed by formation of Triton X-100 micelles around the analytes in 15% (v/v) acetonitrile water which dramatically increase the sensitivity of the method. Main factors affecting the extraction efficiency and signal enhancement of the analytes including pH of sample solution, desorption conditions, extraction time, sample volume, adsorbent amount, surfactant concentration and volume and time of micelle formation were evaluated and optimized. Under the optimum conditions, wide linear range of 0.1-50 ng mL(-1) with low detection limit of 0.03 ng mL(-1) were obtained. The developed method was successfully applied to the extraction and preconcentration of aflatoxins in three commercially available wheat samples and the results were compared with the official AOAC method. PMID- 25804515 TI - Double breasting of bladder neck and posterior urethra for continence in isolated peno-pubic epispadias. AB - OBJECTIVE: The objectives of surgical repair of epispadias include the achievement of urinary continence, cosmetically acceptable genitalia with correction of curvature and normal genital function. To achieve all the aforementioned objectives, patients usually undergo two- or multiple-stage surgeries. Traditionally, the patients undergo epispadias repair in the first stage through modified Cantwell-Ransley or Mitchell-Bagli procedure. Subsequently, in the second stage, bladder neck repair is performed to achieve continence, the most common procedure being modified Young-Dees-Leadbetter. There is no reported single-stage technique of epispadias repair achieving both cosmesis and continence in isolated incontinent epispadias. The objectives of the study were to assess continence and cosmesis with partial penile disassemble and double breasting of bladder neck and posterior urethra in isolated peno-pubic epispadias. MATERIALS AND METHODS: A retrospective analysis of surgical outcome of seven cases of primary isolated incontinent peno-pubic epispadias repair from July 2008 to July 2012 was carried out. Patients' age varied from 10 months to 16 years. Penile de-gloving is done with mobilization of urethral plate from ventrum to dorsum, distally till mid-glans and proximally up to pubic symphysis with preservation of blood supply at both ends. Partial mobilization of corporal bodies from its attachment and division of peno-pubic ligament are done to lengthen the penis. A mucosal strip of 5-7 mm is excised to denude the mucosa for double breasting. Tubularization of urethral plate with double breasting from the region of bladder neck to posterior urethra is done to increase the outlet resistance and then tubularization of distal urethral plate. Approximation of mobilized pelvic floor muscles is done to complete sphincteroplasty. Spongioplasty along the entire length and corporoplasty with medial rotation of corporeal bodies is done. Glanuloplasty with meatoplasty is done to bring the meatus ventrally and then skin cover to penis is done with rotation of ventral flaps or z plasty. RESULTS: Preoperatively, three patients (42.8%) had moderate and four (58.2%) had severe chordee. Three (42.8%) of the seven patients had mild torque toward right. Six patients became fully continent and had excellent cosmesis postoperatively, while one was partially continent with a dry interval of 2 h and required anticholinergics. None of the patients developed fistula, stricture, wound dehiscence or necrosis in a follow-up period of 1-5 years; however, one patient had mild residual chordee but did not require any additional surgery. CONCLUSION: Double breasting of bladder neck and posterior urethra with sphincteroplasty and partial penile disassembly produces a reliable tubularized neourethra with complete chordee correction with emphasis on achievement of continence and near-normal-appearing penile morphology through a single-stage surgery. Mobilization of urethral plate and proximal urethra up to bladder neck helps correction of chordee as well as torsion. Partial penile disassembly keeping the urethra attached to glans maintains the dual blood supply, thus preventing stricture and fistula. This small series is a preliminary study, and more studies at different centers may authenticate it by reproducing the results. PMID- 25804516 TI - Imaging of drug loading distributions in individual microspheres of calcium silicate hydrate--an X-ray spectromicroscopy study. AB - Imaging is one of the most direct and ideal ways to track drug loading distributions in drug carriers on the molecular level, which will facilitate the optimization of drug carriers and drug loading capacities. Herein, we report the mapping of an individual mesoporous calcium silicate hydrate (CSH) microsphere before and after the loading of ibuprofen (IBU) and the interactions between drug carriers and drug molecules simultaneously by scanning transmission X-ray microscopy (STXM). Nanoscaled X-ray absorption near edge structure (XANES) spectroscopy clearly indicates that IBU is bonded to calcium and silicate sites via carboxylic acid groups. More importantly, STXM has been successfully used to determine the absolute thickness of IBU, revealing its distribution in the CSH microsphere. PMID- 25804517 TI - Source of bleeding in trauma patients with pelvic fracture and haemodynamic instability. AB - INTRODUCTION: The main cause of mortality in trauma patients with pelvic fractures is hypovolemic shock. We analyzed the association between the source of bleeding, mechanism of action and type of fracture. METHODS: Prospective descriptive study involving trauma patients older than 16 years old, admitted to the intensive care unit or dead before admission, with pelvic fractures and hemodynamic instability. Hemodynamic instability was defined as SBP <90 and/or HR> 100 beats/min. Pelvic fracture was defined by the Tile classification. RESULTS: A total of 157 of 1088 trauma patients had pelvic fracture. We included 63 patients, all hemodynamically unstable. A total of 85% of pelvic fractures after falls from great heights bled from the fracture itself, compared to only 44% of victims of impact (hit). A total of 65% of patients with stable pelvic fracture bled from associated lesions; 70% of patients with unstable fracture bled from the fracture itself. There is an interaction between the mechanism of action and type of fracture. The probability of pelvic bleeding is higher in the precipitated patient (> 80%) regardless of the type of fracture. Bleeding from associated injuries is greater in impact victims, doubling when the fracture is stable (91%). CONCLUSIONS: Mechanism of action is a key to determine the source of bleeding in patients with pelvic fracture. After falls patients bleed from the fracture itself, while patients with an impact (hit) can bleed both from the fracture and associated injuries, depending on the type of fracture. PMID- 25804518 TI - [Results of conservative treatment in patients with occult pneumothorax]. AB - INTRODUCTION: An occult pneumothorax is found in 2-15% trauma patients. Observation (without tube thoracostomy) in these patients presents still some controversies in the clinical practice. The objective of the study is to evaluate the efficacy and the adverse effects when observation is performed. METHODS: A retrospective observational study was undertaken in our center (university hospital level II). Data was obtained from a database with prospective registration. A total of 1087 trauma patients admitted in the intensive care unit from 2006 to 2013 were included. RESULTS: In this period, 126 patients with occult pneumothorax were identified, 73 patients (58%) underwent immediate tube thoracostomy and 53 patients (42%) were observed. Nine patients (12%) failed observation and required tube thoracostomy for pneumothorax progression or hemothorax. No patient developed a tension pneumothorax or experienced another adverse event related to the absence of tube thoracostomy. Of the observed patients 16 were under positive pressure ventilation, in this group 3 patients (19%) failed observation. There were no differences in mortality, hospital length of stay or intensive care length of stay between the observed and non-observed group. CONCLUSION: Observation is a safe treatment in occult pneumothorax, even in pressure positive ventilated patients. PMID- 25804519 TI - The effect of non-obstetric invasive procedures during pregnancy on perinatal outcomes. AB - PURPOSE: To evaluate the effect of non-obstetric invasive procedure during pregnancy on perinatal outcome. METHODS: The present retrospective study investigated perinatal outcome in women that underwent an invasive procedure during one of their pregnancies (n = 61); perinatal outcome was compared to other pregnancies (without an invasive procedure) of the same patients (n = 122). RESULTS: Women with a non-obstetric invasive procedure during pregnancy delivered earlier than those in the comparison group (38.5 vs. 40.0 weeks; p = 0.01) and had a significantly higher rate of cesarean sections (18 vs. 5 cases; p < 0.01). In addition, birth weight was significantly lower in patients undergoing invasive procedures during pregnancy (2908.65 vs. 3185.84 gr; p = 0.02). The absolute rate of prematurity (<37 weeks) was non-significantly higher in the study group (18.3 vs. 10.0 %; p = 0.28). CONCLUSION: Non-obstetric invasive procedures are associated with an increased rate of cesarean sections and lower birth weight. Nevertheless, no significant differences in early perinatal outcome were found in comparison to other pregnancies of the same patients. More studies are needed to evaluate the outcome following specific procedures. PMID- 25804520 TI - Comparative analysis of CsCu/ZnSOD defense role by molecular characterization: gene expression-enzyme activity-protein level. AB - Cu/ZnSOD (copper/zinc superoxide dismutase) primarily scavenges cytosolic reactive oxygen species (ROS) by converting ROS to hydrogen peroxide, which is then converted to water by the catalytic action of catalase, thus playing a pivotal role in the first line of defense mechanism against oxidative stress. In this study, we have reported a complete molecular characterization of cDNA sequence from striped murrel Channa striatus (Cs). Cellular location prediction reveals that CsCu/ZnSOD protein is cytosolic with an accuracy of 90%. Phylogenetic analysis showed that CsCu/ZnSOD belongs to SOD1 group and it shared a common clad with Asian seabass Lates calcarifer and then with other fishes. The highest CsCu/ZnSOD gene expression, SOD enzyme activity and total protein concentration were observed in the liver and its regulation was studied upon fungus (Aphanomyces invadans) and bacterial (Aeromonas hydrophila) challenges. Based on the results obtained from the above analysis, we concluded a correlation of gene expression-enzyme activity-protein concentration. Overall, the findings demonstrated that the CsCu/ZnSOD plays a critical role in the antioxidant system especially in the liver during oxidative stress caused by fungus and bacteria. PMID- 25804522 TI - High Recombinant Frequency in Extraintestinal Pathogenic Escherichia coli Strains. AB - Homologous recombination promotes genetic diversity by facilitating the integration of foreign DNA and intrachromosomal gene shuffling. It has been hypothesized that if recombination is variable among strains, selection should favor higher recombination rates among pathogens, as they face additional selection pressures from host defenses. To test this hypothesis we have developed a plasmid-based method for estimating the rate of recombination independently of other factors such as DNA transfer, selective processes, and mutational interference. Our results with 160 human commensal and extraintestinal pathogenic Escherichia coli (ExPEC) isolates show that the recombinant frequencies are extremely diverse (ranging 9 orders of magnitude) and plastic (they are profoundly affected by growth in urine, a condition commonly encountered by ExPEC). We find that the frequency of recombination is biased by strain lifestyle, as ExPEC isolates display strikingly higher recombination rates than their commensal counterparts. Furthermore, the presence of virulence factors is positively associated with higher recombination frequencies. These results suggest selection for high homologous recombination capacity, which may result in a higher evolvability for pathogens compared with commensals. PMID- 25804521 TI - No Evidence that MicroRNAs Coevolve with Genes Located in Copy Number Regions. AB - MicroRNAs (miRNAs) are a widespread class of regulatory noncoding RNAs with key roles in physiology and development, conferring robustness to noise in regulatory networks. Consistent with this buffering function, it was recently suggested that human miRNAs coevolve with genes in copy number regions (copy number variation [CNV] genes) to reduce dosage imbalance. Here, I compare miRNA regulation between CNV and non-CNV genes in four model organisms. miRNA regulation of CNV genes is elevated in human and fly but reduced in nematode and zebrafish. By analyzing 31 human CNV data sets, careful analysis of human and chimpanzee orthologs, resampling genes within species and comparing structural variant types, I show that the apparent coevolution between CNV genes and miRNAs is due to the strong dependency between 3'-untranslated region length and miRNA target prediction. Deciphering the interplay between CNVs and miRNAs will likely require a deeper understanding of how miRNAs are embedded in regulatory circuits. PMID- 25804523 TI - Scleroderma: Assessment of posture, balance and pulmonary function in a cross sectional controlled study. AB - BACKGROUND: Systemic sclerosis leads to significant physical limitations in patients, such as diffuse weakness, skin sclerosis, loss of joint function and lung damage. This study aimed to assess posture and balance in systemic sclerosis patients and secondarily to verify correlations between such measurements and lung function. METHODS: Thirty-one patients and a similar number of control subjects matched for age, gender, weight, height and body mass index underwent postural assessment using photogrammetry, balance measurement using the Berg Balance Scale and stabilometry, and pulmonary function tests. FINDINGS: When compared to healthy volunteers, the patients had postural deviations in hip angle (P=0.009 in anterior view and P=0.028 for the right side), horizontal alignment of the pelvis (P=0.002 for the right side and P=0.004 for the left side), vertical alignment of the trunk (P=0.012 for the right side) and ankle angle (P=0.019 for the right side). Postural balance was similar between the two groups as assessed by the Berg Balance Scale and stabilometry. We observed significant correlations between balance measures and posture variables involving the knee and ankle, and between postural control and lung function (ratio between forced vital capacity and diffusing capacity for carbon monoxide). INTERPRETATION: Our results suggest that posture and balance should be assessed in systemic sclerosis patients in clinical practice, as significant postural changes and compensations are needed to maintain balance. Furthermore, it is important to monitor lung function because vascular injury impacts on postural control in these patients. PMID- 25804524 TI - Repair of chronic rupture of the insertion of the gastrocnemius tendon in the dog using a polyethylene terephthalate implant. Early clinical experience and outcome. AB - OBJECTIVES: Chronic degeneration of the gastrocnemius tendon results in scar tissue formation at the insertion of the tendon, and detachment from the calcaneus. In severe cases, excision of this tissue makes repositioning of the tendon to the calcaneus extremely difficult. A polyethylene terephthalate implant, used to aide repair by bridging gaps and allowing tissue ingrowth, was evaluated. METHODS: In this retrospective study, clinical records were evaluated to assess long-term outcomes and complications. The surgical technique is also described. The implant was sutured proximally into the gastrocnemius at the myotendinous junction, and secured into the calcaneus using an interference screw. RESULTS: The implant was used in 10 patients; of which seven returned to full function. Major complications, due to infection, were identified in two of the 10 patients. Minor complications occurred in five of the 10 patients. These were associated with external coaptation in three of the patients in the immediate postoperative period. One minor infection was reported. These all resolved without further complication. Long-term outcome was available in eight patients, with six of these eight dogs returning to normal exercise. CLINICAL SIGNIFICANCE: This implant may be suitable for use in canine patients with severe gastrocnemius tendon degeneration. Ongoing evaluation is warranted. PMID- 25804525 TI - A misleading frozen section in a lacrimal gland pleomorphic adenoma of a nine year-old. AB - INTRODUCTION: Benign pleomorphic adenomas of the lacrimal gland usually present as a painless, slow growing mass in healthy adults and rarely present in childhood. This report describes a pediatric patient found to have a lacrimal gland pleomorphic adenoma that mimicked rhabdomyosarcoma on frozen section. REPORT: A nine-year-old African American male presented with two months of unilateral proptosis and was found to have a left orbital mass on computed topography. Through a lateral orbitotomy, the mass was excised, but noted to appear distinct from the lacrimal gland. An intraoperative frozen section demonstrated a myxoid matrix with scattered cells mimicking rhabdomyoblasts. Because this sample lacked additional elements, the diagnosis of rhabdomyosarcoma could not be excluded, especially considering the patient's age, short time course of symptoms, and the tumor's intraoperative appearance. Permanent sections of the whole lesion provided definitive diagnosis. CONCLUSIONS: In the rare pediatric presentations, pleomorphic adenomas of the lacrimal gland can be difficult to quickly and definitively differentiate from a rhabdomyosarcoma. The unusual age of presentation and the misleading frozen section appearance in this case demonstrate the intricacies of managing pediatric orbital tumors and highlight the importance of permanent sections for definitive diagnosis. PMID- 25804527 TI - The loss of Tm7sf gene accelerates skin papilloma formation in mice. AB - The 3beta-hydroxysterol Delta14-reductase, encoded by the Tm7sf2 gene, is an enzyme involved in cholesterol biosynthesis. Cholesterol and its derivatives control epidermal barrier integrity and are protective against environmental insults. To determine the role of the gene in skin cholesterol homeostasis, we applied 12-o-tetradecanoylphorbol-13-acetate (TPA) to the skin of Tm7sf2(+/+) and Tm7sf2(-/-) mice. TPA increased skin cholesterol levels by inducing de novo synthesis and up-take only in Tm7sf2(+/+) mouse, confirming that the gene maintains cholesterol homeostasis under stress conditions. Cholesterol sulfate, one of the major players in skin permeability, was doubled by TPA treatment in the skin of wild-type animals but this response was lost in Tm7sf2(-/-) mice. The expression of markers of epidermal differentiation concomitant with farnesoid-X receptor and p38 MAPK activation were also disrupted in Tm7sf2(-/-) mice. We then subjected Tm7sf2(+/+) and Tm7sf2(-/-) mice to a classical two-stage skin carcinogenesis protocol. We found that the loss of Tm7sf2 increased incidence and multiplicity of skin papillomas. Interestingly, the null genotype showed reduced expression of nur77, a gene associated with resistance to neoplastic transformation. In conclusion, the loss of Tm7sf2 alters the expression of proteins involved in epidermal differentiation by reducing the levels of cholesterol sulfate. PMID- 25804528 TI - Cross-Cultural Validity and Differential Item Functioning of the Orthotics and Prosthetics Users' Survey With Swedish and United States Users of Lower-Limb Prosthesis. AB - OBJECTIVES: To investigate the cross-cultural validity of the Orthotics and Prosthetics Users' Survey (OPUS), to evaluate differential item functioning (DIF) related to country, sex, age, amputation level, and amputated side (unilateral, bilateral), and to determine known-group validity of the OPUS. DESIGN: Survey. SETTING: Outpatient clinics. PARTICIPANTS: The sample (N=321) consisted of Swedish (n=195) and U.S. (n=126) adults using lower-limb prostheses. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Four OPUS modules were used: lower extremity functional status, client satisfaction with device (CSD), client satisfaction with services (CSS), and health-related quality of life. Rasch analysis was used to calculate measures for persons and items. RESULTS: The cross-cultural validity was satisfactory. Many items demonstrated DIF related to country and demographic characteristics, but the impact on mean person measures was negligible. The rating scales of CSD and CSS needed adjustments, and the unidimensionality of CSD and CSS was weak. The differences between the mean measures of known patient groups were statistically significant for 2 out of 6 comparisons. CONCLUSIONS: This study supports the validity of OPUS measure comparisons between Sweden and the United States and between subgroups with different demographic characteristics. Some of the country-related DIF may reflect the different health care financing systems. The findings demonstrate that the OPUS can discriminate between certain patient groups. The results also challenge some of our preconceptions about persons with bilateral amputation, indicating that we might know these persons less well than we think. PMID- 25804529 TI - Prevalence of low mobility and self-management self-efficacy in manual wheelchair users and the association with wheelchair skills. AB - OBJECTIVE: To estimate the prevalence of low wheelchair-mobility and self management self-efficacy and to evaluate the association with wheelchair skills. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Community-dwelling manual wheelchair users (N=123) who were >=50 years of age (mean, 59.7+/-7.5y) and from British Columbia and Quebec, Canada. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The 13-item mobility and 8-item self-management subscales from the Wheelchair Use Confidence Scale-Short Form (standardized scores range, 0-100) measured self-efficacy, and the 32-item Wheelchair Skills Test, Questionnaire Version (scores range, 0-100) measured wheelchair skills. A score of 50 was used to differentiate individuals with high and low self-efficacy, and a score of 72 differentiated between high and low wheelchair skills. RESULTS: The prevalence of low wheelchair-mobility and self-management self-efficacy was 28.5% (95% confidence interval [CI], 20.6-36.4) and 11.4% (95% CI, 5.8-17.0), respectively, and their bivariate association with wheelchair skills was r=.70 and r=.39, respectively. Of the sample, 16% reported conflicting mobility self-efficacy and skill scores; 25% reported low self-efficacy and high skills. Of the participants, 30% reported conflicting scores between self-management self efficacy and wheelchair skills, with 8.1% reporting lower self-efficacy than skill. CONCLUSIONS: Low self-efficacy was relatively high in this sample as was its discordance with wheelchair skills. Interventions to address low self efficacy and/or offset the discordant self-efficacy/skill profiles are warranted. PMID- 25804530 TI - Lipid extraction and esterification for microalgae-based biodiesel production using pyrite (FeS2). AB - In this study, pyrite (FeS2) was used for lipid extraction as well as esterification processes for microalgae-based biodiesel production. An iron mediated oxidation reaction, Fenton-like reaction, produced an expected degree of lipid extraction, but pyrite was less effective than FeCl3 commercial powder. That low efficiency was improved by using oxidized pyrite, which showed an equivalent lipid extraction efficiency to FeCl3, about 90%, when 20 mM of catalyst was used. Oxidized pyrite was also employed in the esterification step, and converted free fatty acids to fatty acid methyl esters under acidic conditions; thus, the fatal problem of saponification during esterification with alkaline catalysts was avoided, and esterification efficiency over 90% was obtained. This study clearly showed that pyrite could be utilized as a cheap catalyst in the lipid extraction and esterification steps for microalgae-based biodiesel production. PMID- 25804531 TI - A novel conditioning process for enhancing dewaterability of waste activated sludge by combination of zero-valent iron and persulfate. AB - Improvement of sludge dewaterability is crucial for reducing the costs of sludge disposal in wastewater treatment plants. This study presents a novel conditioning method for improving waste activated sludge dewaterability by combination of persulfate and zero-valent iron. The combination of zero-valent iron (0-30g/L) and persulfate (0-6g/L) under neutral pH substantially enhanced the sludge dewaterability due to the advanced oxidization reactions. The highest enhancement of sludge dewaterability was achieved at 4g persulfate/L and 15g zero-valent iron/L, with which the capillary suction time was reduced by over 50%. The release of soluble chemical oxygen demand during the conditioning process implied the decomposition of sludge structure and microorganisms, which facilitated the improvement of dewaterability due to the release of bound water that was included in sludge structure and microorganism. Economic analysis showed that the proposed conditioning process with persulfate and ZVI is more economically favorable for improving WAS dewaterability than classical Fenton reagent. PMID- 25804532 TI - Experimental investigation of ionic liquid pretreatment of sugarcane bagasse with 1,3-dimethylimadazolium dimethyl phosphate. AB - In this study, an imidazolium-based ionic liquid (IL), 1,3-dimethylimidazolium dimethyl phosphate ([Mmim][DMP]), was applied for pretreating sugarcane bagasse to produce bioethanol. The main goal of this study was to investigate the feasibility of bagasse pretreatment with this IL, and to verify the effect of different operational parameters on the pretreatment process. Results indicated that temperature and duration of IL-pretreatment have optimum values. Within the range investigated, a maximum fermentable sugar conversion of 70.38% was achieved with this IL at 120 degrees C and 120min. The corresponding value was 28.65% for the untreated biomass. The main cause for the observed enhancement in enzymatic hydrolysis was the reduction of cellulose crystallinity in the IL-pretreated biomass, as compared to the untreated sample, because it resulted in higher accessibility of the enzymes to the biomass after pretreatment. Moreover, the results indicated that aqueous [Mmim][DMP] mixtures are not as effective for pretreatment as the pure IL. PMID- 25804533 TI - Green biorefinery of fresh cattail for microalgal culture and ethanol production. AB - Green biorefinery represents an appropriate approach to utilize the fresh aquatic biomass, eliminating the drying process of conventional bioenergy-converting system. In this study, fresh cattails were homogenized and then filtered, whereby cattails were separated into a fiber-rich cake and a nutrient-rich juice. The juice was used to cultivate microalgae Chlorella spp. in different media. In addition, the solid cake was pretreated with the sonication, and used as the feedstock for ethanol production. The results showed that the cattail juice could be a highly nutritious source for microalgae that are a promising feedstock for biofuels. Sugars released from the cattail cake were efficiently fermented to ethanol using Escherichia coli KO11, with 8.6-12.3% of the theoretical yield. The ultrasonic pretreatment was not sufficient for pretreating cattails. If a dilute acid pretreatment was applied, the conversion ratio of sugars from cattails has the potential to be over 85% of the theoretical value. PMID- 25804534 TI - The enhancement of ammonium removal from ethanolamine wastewater using air cathode microbial fuel cells coupled to ferric reduction. AB - A microbial fuel cell (MFC) with biological Fe(III) reduction was implemented for simultaneous ethanolamine (ETA) degradation and electrical energy generation. In the feasibility experiment using acetate as a substrate in a single-chamber MFC with goethite and ammonium at a ratio of 3.0(mol/mol), up to 96.1% of the ammonium was removed through the novel process related to Fe(III). In addition, the highest voltage output (0.53V) and maximum power density (0.49Wm(-2)) were obtained. However, the ammonium removal and electrical performance decreased as acetate was replaced with ETA. In the long-term experiment, the electrical performance markedly decreased where the voltage loss increased due to Fe deposition on the membranes. PMID- 25804535 TI - Evolutionary engineering of Saccharomyces cerevisiae for efficient conversion of red algal biosugars to bioethanol. AB - The aim of this work was to apply the evolutionary engineering to construct a mutant Saccharomyces cerevisiae HJ7-14 resistant on 2-deoxy-D-glucose and with an enhanced ability of bioethanol production from galactose, a mono-sugar in red algae. In batch and repeated-batch fermentations, HJ7-14 metabolized 5-fold more galactose and produced ethanol 2.1-fold faster than the parental D452-2 strain. Transcriptional analysis of genes involved in the galactose metabolism revealed that moderate relief from the glucose-mediated repression of the transcription of the GAL genes might enable HJ7-14 to metabolize galactose rapidly. HJ7-14 produced 7.4 g/L ethanol from hydrolysates of the red alga Gelidium amansii within 12 h, which was 1.5-times faster than that observed with D452-2. We demonstrate conclusively that evolutionary engineering is a promising tool to manipulate the complex galactose metabolism in S. cerevisiae to produce bioethanol from red alga. PMID- 25804538 TI - Twice as NCC: Two Octotricopeptide Repeat Proteins and the Regulation of Chloroplast Gene Expression. PMID- 25804536 TI - Identification and Characterization of a Golgi-Localized UDP-Xylose Transporter Family from Arabidopsis. AB - Most glycosylation reactions require activated glycosyl donors in the form of nucleotide sugars to drive processes such as posttranslational modifications and polysaccharide biosynthesis. Most plant cell wall polysaccharides are biosynthesized in the Golgi apparatus from cytosolic-derived nucleotide sugars, which are actively transferred into the Golgi lumen by nucleotide sugar transporters (NSTs). An exception is UDP-xylose, which is biosynthesized in both the cytosol and the Golgi lumen by a family of UDP-xylose synthases. The NST based transport of UDP-xylose into the Golgi lumen would appear to be redundant. However, employing a recently developed approach, we identified three UDP-xylose transporters in the Arabidopsis thaliana NST family and designated them UDP XYLOSE TRANSPORTER1 (UXT1) to UXT3. All three transporters localize to the Golgi apparatus, and UXT1 also localizes to the endoplasmic reticulum. Mutants in UXT1 exhibit ~30% reduction in xylose in stem cell walls. These findings support the importance of the cytosolic UDP-xylose pool and UDP-xylose transporters in cell wall biosynthesis. PMID- 25804539 TI - Accuracy in Quantitative 3D Image Analysis. AB - Quantitative 3D imaging is becoming an increasingly popular and powerful approach to investigate plant growth and development. With the increased use of 3D image analysis, standards to ensure the accuracy and reproducibility of these data are required. This commentary highlights how image acquisition and postprocessing can introduce artifacts into 3D image data and proposes steps to increase both the accuracy and reproducibility of these analyses. It is intended to aid researchers entering the field of 3D image processing of plant cells and tissues and to help general readers in understanding and evaluating such data. PMID- 25804537 TI - Spontaneous dominant mutations in chlamydomonas highlight ongoing evolution by gene diversification. AB - We characterized two spontaneous and dominant nuclear mutations in the unicellular alga Chlamydomonas reinhardtii, ncc1 and ncc2 (for nuclear control of chloroplast gene expression), which affect two octotricopeptide repeat (OPR) proteins encoded in a cluster of paralogous genes on chromosome 15. Both mutations cause a single amino acid substitution in one OPR repeat. As a result, the mutated NCC1 and NCC2 proteins now recognize new targets that we identified in the coding sequences of the chloroplast atpA and petA genes, respectively. Interaction of the mutated proteins with these targets leads to transcript degradation; however, in contrast to the ncc1 mutation, the ncc2 mutation requires on-going translation to promote the decay of the petA mRNA. Thus, these mutants reveal a mechanism by which nuclear factors act on chloroplast mRNAs in Chlamydomonas. They illustrate how diversifying selection can allow cells to adapt the nuclear control of organelle gene expression to environmental changes. We discuss these data in the wider context of the evolution of regulation by helical repeat proteins. PMID- 25804542 TI - Red cell transfusions for treating anaemia in the absence of bleeding. PMID- 25804543 TI - Public anatomy classes return to UK after more than 180 years. PMID- 25804541 TI - Pea VEGETATIVE2 Is an FD Homolog That Is Essential for Flowering and Compound Inflorescence Development. AB - As knowledge of the gene networks regulating inflorescence development in Arabidopsis thaliana improves, the current challenge is to characterize this system in different groups of crop species with different inflorescence architecture. Pea (Pisum sativum) has served as a model for development of the compound raceme, characteristic of many legume species, and in this study, we characterize the pea VEGETATIVE2 (VEG2) locus, showing that it is critical for regulation of flowering and inflorescence development and identifying it as a homolog of the bZIP transcription factor FD. Through detailed phenotypic characterizations of veg2 mutants, expression analyses, and the use of protein protein interaction assays, we find that VEG2 has important roles during each stage of development of the pea compound inflorescence. Our results suggest that VEG2 acts in conjunction with multiple FLOWERING LOCUS T (FT) proteins to regulate expression of downstream target genes, including TERMINAL FLOWER1, LEAFY, and MADS box homologs, and to facilitate cross-regulation within the FT gene family. These findings further extend our understanding of the mechanisms underlying compound inflorescence development in pea and may have wider implications for future manipulation of inflorescence architecture in related legume crop species. PMID- 25804540 TI - Arabidopsis RIC1 Severs Actin Filaments at the Apex to Regulate Pollen Tube Growth. AB - Pollen tubes deliver sperms to the ovule for fertilization via tip growth. The rapid turnover of F-actin in pollen tube tips plays an important role in this process. In this study, we demonstrate that Arabidopsis thaliana RIC1, a member of the ROP-interactive CRIB motif-containing protein family, regulates pollen tube growth via its F-actin severing activity. Knockout of RIC1 enhanced pollen tube elongation, while overexpression of RIC1 dramatically reduced tube growth. Pharmacological analysis indicated that RIC1 affected F-actin dynamics in pollen tubes. In vitro biochemical assays revealed that RIC1 directly bound and severed F-actin in the presence of Ca(2+) in addition to interfering with F-actin turnover by capping F-actin at the barbed ends. In vivo, RIC1 localized primarily to the apical plasma membrane (PM) of pollen tubes. The level of RIC1 at the apical PM oscillated during pollen tube growth. The frequency of F-actin severing at the apex was notably decreased in ric1-1 pollen tubes but was increased in pollen tubes overexpressing RIC1. We propose that RIC1 regulates F-actin dynamics at the apical PM as well as the cytosol by severing F-actin and capping the barbed ends in the cytoplasm, establishing a novel mechanism that underlies the regulation of pollen tube growth. PMID- 25804544 TI - Assessment of Sentinel Node Biopsies With Full-Field Optical Coherence Tomography. AB - Current techniques for the intraoperative analysis of sentinel lymph nodes during breast cancer surgery present drawbacks such as time and tissue consumption. Full field optical coherence tomography is a novel noninvasive, high-resolution, fast imaging technique. This study investigated the use of full-field optical coherence tomography as an alternative technique for the intraoperative analysis of sentinel lymph nodes. Seventy-one axillary lymph nodes from 38 patients at Tenon Hospital were imaged minutes after excision with full-field optical coherence tomography in the pathology laboratory, before being handled for histological analysis. A pathologist performed a blind diagnosis (benign/malignant), based on the full-field optical coherence tomography images alone, which resulted in a sensitivity of 92% and a specificity of 83% (n = 65 samples). Regular feedback was given during the blind diagnosis, with thorough analysis of the images, such that features of normal and suspect nodes were identified in the images and compared with histology. A nonmedically trained imaging expert also performed a blind diagnosis aided by the reading criteria defined by the pathologist, which resulted in 85% sensitivity and 90% specificity (n = 71 samples). The number of false positives of the pathologist was reduced by 3 in a second blind reading a few months later. These results indicate that following adequate training, full-field optical coherence tomography can be an effective noninvasive diagnostic tool for extemporaneous sentinel node biopsy qualification. PMID- 25804545 TI - Emotional Lability in Preschoolers With Symptoms of ADHD. AB - OBJECTIVE: The aim of this study was to examine occurrence of emotional lability (EL) in preschoolers with ADHD symptoms versus controls. METHOD: The study was part of the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. In the present study, 495 preschoolers were clinically examined. Symptoms of ADHD, anxiety, and oppositional defiant disorder (ODD) were measured with the Preschool Age Psychiatric Assessment Interview. An EL measure was obtained from the Emotional Control subscale of the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P), which parents and teachers completed. RESULTS: EL was significantly more frequent in the ADHD group compared with controls (25% vs. 7%, p < .001). By parent report, EL correlated significantly with ADHD-, anxiety-, and ODD symptoms. By teacher report, EL was significantly correlated only with hyperactivity-impulsivity. CONCLUSION: EL appears identifiable in young preschoolers and was particularly associated with ODD in children with ADHD symptoms. PMID- 25804546 TI - Nitroxides as anti-biofilm compounds for the treatment of Pseudomonas aeruginosa and mixed-culture biofilms. AB - A series of 23 nitroxides () was tested for biofilm modulatory activity using a crystal violet staining technique. 3-(Dodecane-1-thiyl)-4-(hydroxymethyl)-2,2,5,5 tetramethyl-1-pyrrolinoxyl () was found to significantly suppress biofilm formation and elicit dispersal events in both Pseudomonas aeruginosa and mixed culture biofilms. Twitching and swarming motilities were enhanced by nitroxide , leaving the planktonic-specific swimming motility unaffected and suggesting that the mechanism of -mediated biofilm modulation is linked to the hyperactivation of surface-associated cell motilities. Preliminary structure-activity relationship studies identify the dodecanethiyl chain, hydroxymethyl substituent and the free radical moiety to be structural features pertinent to the anti-biofilm activity of . PMID- 25804547 TI - Therapeutic Strategies for Advanced Pancreatic Neuroendocrine Tumors with Segmental Portal Hypertension. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PNET) locally advanced may lead to significant local symptoms especially segmental portal hypertension (SPH) with risk of bleeding. The aim of our study was to evaluate the role of SPH on the PNET management in an expert center. METHODS: Forty-two patients treated for locally advanced PNET with SPH between January 1984 and December 2012 were retrospectively analyzed. RESULTS: The median age was 55 years (25-75). The median tumor size was 7.5 cm (3-20). Thirty four (80.9%) patients were metastatic mainly in the liver (n=33, 79%) with a frequent (n=16, 38.1%) involvement>20%. The surgery was impossible because of SPH in 7 (16.6%) cases. Pancreatic resection was performed in 28 (66.7%) cases by distal pancreatectomy. Neoadjuvant chemotherapy (n=24, 57%) had no impact on SPH with no modification of collateral circulation. Among operated on patients, complete macroscopic resection was obtained in 19 (67.8%) patients. The mortality and severe morbidity rate was respectively 3.6 and 18%. Five year overall survival (OS) was similar in operated and no operated patients. (61%; p=0.64). The 5-year OS was 77.9 or 55.4% in patients who underwent a complete or incomplete macroscopic resection of primary and metastases, respectively. CONCLUSION: PNET resection associated with SPH is feasible with a low morbimortality. SPH was not improved by chemotherapy. Prolonged survival was observed after complete macroscopic resection. PMID- 25804548 TI - Major Esophageal Dilation After Laparoscopic Adjustable Gastric Banding in Symptomatic Patients: Does It Prevent Effective Weight Loss and How Should It be Treated? AB - INTRODUCTION: Esophageal dilation (ED) has been described as a long-term complication following laparoscopic adjustable gastric banding (LAGB) with an incidence of 0.5-50%. The purpose of this study was to evaluate the effect of major ED on weight loss and find methods to diagnose ED and possible treatment strategies based on a classification. MATERIALS AND METHODS: We performed a retrospective analysis of all patients undergoing LAGB between 2004 and 2008 in three community-based hospitals. ED was classified in four stages of dilation using gastrografin swallow. We report body mass index (BMI), failure rates and reoperations among these patients, with a mean follow-up period of 6.7 years. RESULTS: Nineteen (18.4%) of 103 patients who underwent LAGB presented with esophageal dilation. Band deflation failed for all nine patients (8.7%) with major ED. The mean BMI at LAGB (BMI 1), revision (BMI 2), and 1 year after conversion (BMI 3) were 45.9+/-3.2, 42.8+/-4.9 and 30.3+/-5.5 kg/m2, respectively. No significant difference was found comparing BMI 1 and BMI 2 (p=0,065, EWL1: 14.2+/-21.7 kg/m2). In contrast, the weight loss after the revision surgery was significant (p=0.001, EWL2: 67.1+/-30 kg/m2). No significant difference was found concerning age, gender, ASA, preoperative (LAGB) weight, and mean interval between LAGB and revision comparing patients with major ED (IV) to patients with milder forms (ED I-III). CONCLUSION: ED is a serious long-term complication after LAGB and seems to prevent effective weight loss in stage IV. Furthermore, untreated dilation could cause long-term damage to the esophagus. Therefore, we suggest routine radiographic follow-up after LAGB even in asymptomatic patients and a treatment based on a classification with an early surgical revision for major ED. PMID- 25804550 TI - What Should We Tell Our Patients? Lifetime Guarantee or is it 5- to 10-year Warranty on a Parathyroidectomy for Primary Hyperparathyroidism? PMID- 25804549 TI - Visceral Fat Content Correlates with Retroperitoneal Soft Tissue Sarcoma (STS) Local Recurrence and Survival. AB - BACKGROUND: Our aim was to evaluate the association between visceral fat content with soft tissue sarcoma (STS) local recurrence and survival. METHODS: One hundred and one computed tomography imaging studies of primary STS patients who had complete macroscopic resection at our institution between 2002 and 2012 were reviewed, and retroperitoneal and circumferential fat contents were measured. Correlations between imaging findings and clinical data were analyzed. RESULTS: Fifty-seven STS tumors (56.4%) were retroperitoneal; of them, 65% were high grade, median size was 15 cm (range 3-49), and the most common histological subtype was high grade liposarcoma (31.6%). Median follow-up length for the entire cohort was 64 months (range 6-95). High visceral fat (VF) content>=15 versus <15 mm was identified as a risk factor for retroperitoneal STS local recurrence; 65.1 versus 26.7%, respectively (p=0.04); VF content did not correlate with distant metastasis. Median overall survival (OS) length of patients with VF>=15 versus <15 mm was 57 months (range 2-144) versus not reached, respectively (p=0.007). Multivariable analysis identified VF>=15 mm as an independent risk factor for decreased OS (HR: 4.2, 95% CI 1.07-16.67). In contrast, circumferential fat content did not correlate with retroperitoneal STS patient outcomes. CONCLUSION: High VF content is an independent adverse prognosticator associated with significantly higher rates of retroperitoneal STS local recurrence and decreased patients survival. Local tumor biology may be affected by the presence of adipose cells. Further clinical and molecular research is needed to establish this premise. PMID- 25804551 TI - [Surgical management of aplasia cutis congenita]. AB - INTRODUCTION: Aplasia cutis congenita (ACC) is a rare congenital malformation that commonly involves the scalp, but can affect pericranium, bone and dura mater. Complications are rare, but can be fatal, so early treatment must be achieved. The treatment remains controversial with no consensus between the conservative and surgical approach. The aim of this study is to describe our experience in the management of ACC. MATERIAL AND METHODS: Retrospective review of the medical records of all children up to 14 years diagnosed with ACC and treated between 2000 and 2013. RESULTS: There were a total of 22 cases of ACC with lesions ranging from 1cm (0.79 cm(2)) to 14cm (153.94 cm(2)). ACC of the scalp was found in 18 cases, with 3 in extremities and 1 in trunk. Conservative treatment was performed on 9 patients and 13 underwent surgical treatment (8 primary closures, 2 plasties, 2 skin grafts, and 1 skin flap). Two patients died due to complications of other diseases not related with the ACC. CONCLUSIONS: ACC is a rare disease that can be fatal. A complete initial assessment to establish early treatment is necessary to prevent this. Surgery should be considered as an initial therapeutic option in defects >4cm (>12.6 cm(2)) as it prevents the risk of fatal complications. PMID- 25804552 TI - [Spinal muscular atrophy and respiratory failure. How do primary care pediatricians act in a simulated scenario?]. AB - INTRODUCTION: Spinal muscular atrophy type 1 (SMA-1) tends to be fatal in the first year of life if there is no ventilatory support. The decision whether to start such support is an ethical conflict for healthcare professionals. MATERIAL AND METHODS: A scenario of acute respiratory failure in an infant with SMA-1 has been included in a training program using advanced simulation for Primary Care pediatricians (PCP). The performances of 34 groups of 4 pediatricians, who participated in 17 courses, were systematically analyzed. Clinical, ethical and communication aspects with parents were evaluated. RESULTS: The initial technical assistance (Administration of oxygen and immediate ventilatory support) was correctly performed by 94% of the teams. However, the PCP had problems in dealing with the ethical aspects of the case. Of the 85% of the teams that raised the ethical conflict with parents, 29% did so on their own initiative, 23% actively excluded them, and only 6% involved them and took their opinion into account in making decisions. Only 11.7% asked about the quality of life of children and 12% for their knowledge of the prognosis of the disease. None explained treatment alternatives, nor tried to contact the pediatrician responsible for the child. CONCLUSIONS: When faced with a simulated SMA-1 infant with respiratory failure, PCP have difficulties in interacting with the family, and to involve it in the decision making process. Practical training of all pediatricians should include case scenarios with an ethical clinical problem. PMID- 25804553 TI - Social cohesion and health in old age: a study in southern Taiwan. AB - BACKGROUND: Previous studies have found that social cohesion and trust (SCT) were associated with psychological well-being and physical health. In this study, we investigated the associations between SCT and mental and physical health among community-dwelling elderly in a town in southern Taiwan. METHODS: The study population consisted of 149 community-dwelling elderly aged 65 years and older (68 men, 81 women; mean age, 75.4 +/- 6.1 years) residing in the town of Dashe in southern Taiwan. Activities of daily living (ADL), SCT, depression, subjective quality of life (QOL), current medical status, past medical history, and health behaviors were assessed in face-to-face interviews. Objective neurobehavioral functions were assessed using the timed up & go (TUG) test, functional reach test, and handgrip test. RESULTS: Scores for ADL and Geriatric Depression Scale (GDS) were significantly correlated with SCT, and SCT was significantly correlated with all subjective QOL items. In addition, a strong correlation was observed between SCT and relationship with friends. Values for SCT (median >= 20) were significantly associated with both subjective sense of health (median >= 68) and subjective happiness (median >= 73) after adjusting for age, sex, and ADL. CONCLUSION: SCT is an important variable that influences self-rated health and happiness, independently of ADL, age, and sex. When assessing geriatric psychological function, SCT should be examined more carefully, given its association with subjective sense of health and happiness, depression, and physical function. PMID- 25804554 TI - Screening of athletes: An electrocardiogram is not enough. AB - Professional and amateur athletic training can cause tremendous overload of the cardiovascular system and thus become a trigger of serious and often fatal cardiac events in athletes with a previously undetected underlying cardiovascular disease. Therefore, every athlete should undergo a specialized diagnostic and qualification screening before a training program is prescribed or continued. However, it is still an unresolved issue which of the accessible diagnostic tools should be routinely applied in order to increase the safety of extreme physical training and reduce the risk of sudden cardiac death. Pre-participation athlete evaluation including a standard electrocardiogram (ECG), physical examination, and familial history of cardiovascular diseases is important, but does not always guarantee high diagnostic accuracy. Hence, the aim of this review article is to discuss the controversy over the usefulness of ECG for the detection of cardiovascular diseases in athletes as well as the views on athlete screening methods in Europe and the USA. Differential diagnostic options and screening schemes are also described in particular groups of athletes in reference to their age, cardiovascular risk factors, as well as intensity and type of sport discipline. PMID- 25804557 TI - Interfacial Engineering Importance of Bilayered ZnO Cathode Buffer on the Photovoltaic Performance of Inverted Organic Solar Cells. AB - The role of cathode buffer layer (CBL) is crucial in determining the power conversion efficiency (PCE) of inverted organic solar cells (IOSCs). The hallmarks of a promising CBL include high transparency, ideal energy levels, and tendency to offer good interfacial contact with the organic bulk-heterojunction (BHJ) layers. Zinc oxide (ZnO), with its ability to form numerous morphologies in juxtaposition to its excellent electron affinity, solution processability, and good transparency is an ideal CBL material for IOSCs. Technically, when CBL is sandwiched between the BHJ active layer and the indium-tin-oxide (ITO) cathode, it performs two functions, namely, electron collection from the photoactive layer that is effectively carried out by morphologies like nanoparticles or nanoridges obtained by ZnO sol-gel (ZnO SG) method through an accumulation of individual nanoparticles and, second, transport of collected electrons toward the cathode, which is more effectively manifested by one-dimensional (1D) nanostructures like ZnO nanorods (ZnO NRs). This work presents the use of bilayered ZnO CBL in IOSCs of poly(3-hexylthiophene) (P3HT)/[6, 6]-phenyl-C60-butyric acid methyl ester (PCBM) to overcome the limitations offered by a conventionally used single layer CBL. We found that the PCE of IOSCs with an appropriate bilayer CBL comprising of ZnO NRs/ZnO SG is ~18.21% higher than those containing ZnO SG/ZnO NRs. We believe that, in bilayer ZnO NRs/ZnO SG, ZnO SG collects electrons effectively from photoactive layer while ZnO NRs transport them further to ITO resulting significant increase in the photocurrent to achieve highest PCE of 3.70%. The enhancement in performance was obtained through improved interfacial engineering, enhanced electrical properties, and reduced surface/bulk defects in bilayer ZnO NRs/ZnO SG. This study demonstrates that the novel bilayer ZnO CBL approach of electron collection/transport would overcome crucial interfacial recombination issues and contribute in enhancing PCE of IOSCs. PMID- 25804556 TI - The Strength of Family Ties: Perceptions of Network Relationship Quality and Levels of C-Reactive Proteins in the North Texas Heart Study. AB - BACKGROUND: Although the quality of one's social relationships has been linked to important physical health outcomes, less work has been conducted examining family and friends that differ in their underlying positivity and negativity. PURPOSE: The main aim of this study was to examine the association between supportive, aversive, and ambivalent family/friends with levels of C-reactive proteins. METHODS: Three hundred participants from the North Texas Heart Study completed the social relationships index and a blood draw to assess high-sensitivity C reactive proteins (hs-CRPs). RESULTS: After standard controls, the number of supportive family members predicted lower hs-CRP levels, whereas the number of ambivalent family members predicted higher hs-CRP levels. These links were independent of depressive symptoms and perceived stress. CONCLUSIONS: These data highlight the importance of considering specific types of relationships and their underlying positive and negative aspects in research on social ties and physical health. PMID- 25804555 TI - [Prevention of cardiovascular diseases through sport and physical activity: A question of intensity?]. AB - Coronary artery disease is the leading cause of death worldwide. A sedentary lifestyle accounts for 9% of premature mortality and creates a substantial health economic burden. Measurement of physical activity in daily practice refers to metabolic equivalent tasks and assessment of cardiopulmonary fitness to measurements of peak oxygen uptake during ergometry, which can be used to classify an individual's physical activity and maximum exercise capacity. Physical activity is a multifunctional intervention tool in prevention, which exerts its effects on multiple biochemical pathways, in contrast to conventional drug therapy. These changes reduce cardiovascular morbidity and mortality. Moderate physical exercise reduces blood pressure, improves insulin sensitivity and dyslipidemia, improves body composition and enhances weight reduction. Exercise of higher intensity seems to have superior effects compared to moderate intensity training; however, the training volume also seems to be important, as negative effects of long-term intensive training have been reported, e.g. atrial fibrillation or coronary sclerosis. Overall, exercise training has a major role in primary prevention of cardiovascular disease but seems to have a maximum threshold for benefit, which may be exceeded by some individuals. PMID- 25804558 TI - CdTe and graphene co-sensitized TiO2 nanotube array photoanodes for protection of 304SS under visible light. AB - CdTe/graphene/TiO2 films that served as photoanodes for cathodic protection application were prepared by an electrochemical deposition method. The deposition of graphene and CdTe nanoparticles (NPs) on the surface of the TiO2 nanotubes was confirmed by scanning electron microscope and transmission electron microscopy. The composites exhibited high light absorption in both the UV and visible light region. The results indicated that TiO2 nanotube photoelectrodes sensitized by 20 cycle graphene and 30-cycle CdTe NPs exhibited effective photocathodic protection properties for 304 stainless steel (304SS) under the visible-light illumination, with an photopotential of -750 mV versus saturated calomel electrode and a current density of 560 MUA cm(-2). Due to the efficient photogenerated charge separation, the three-component CdTe/graphene/TiO2 showed stronger photoresponse than pure TiO2 under visible-light illumination. In summary, the CdTe/graphene could improve the photocathodic protection properties of TiO2 films. PMID- 25804559 TI - Electrochemical and catalytic properties of Ni/BaCe0.75Y0.25O3-delta anode for direct ammonia-fueled solid oxide fuel cells. AB - In this study, Ni/BaCe0.75Y0.25O3-delta (Ni/BCY25) was investigated as an anode for direct ammonia-fueled solid oxide fuel cells. The catalytic activity of Ni/BCY25 for ammonia decomposition was found to be remarkably higher than Ni/8 mol % Y2O3-ZrO2 and Ni/Ce0.90Gd0.10O1.95. The poisoning effect of water and hydrogen on ammonia decomposition reaction over Ni/BCY25 was evaluated. In addition, an electrolyte-supported SOFC employing BaCe0.90Y0.10O3-delta (BCY10) electrolyte and Ni/BCY25 anode was fabricated, and its electrochemical performance was investigated at 550-650 degrees C with supply of ammonia and hydrogen fuel gases. The effect of water content in anode gas on the cell performance was also studied. Based on these results, it was concluded that Ni/BCY25 was a promising anode for direct ammonia-fueled SOFCs. An anode supported single cell denoted as Ni/BCY25|BCY10|Sm0.5Sr0.5CoO3-delta was also fabricated, and maximum powder density of 216 and 165 mW cm(-2) was achieved at 650 and 600 degrees C, for ammonia fuel, respectively. PMID- 25804560 TI - Y-27632, a ROCK inhibitor, delays senescence of putative murine salivary gland stem cells in culture. AB - OBJECTIVE: A loss of functional salivary glands often occurs after radiotherapy for head and neck tumour, and causes many problems in oral health. Recently, the use of salispheres, which consist of salivary gland stem cells (SGSCs), has been suggested as therapy for these problems. However, an insufficient number of cells can be obtained and cultured for cell transplantation. In the present study, salispheres were propagated and passaged by suspension culture to acquire a sufficient number of SGSCs for cell therapy. DESIGN: The relationship between sphere formation and the degree of cellular senescence was investigated by analysing senescence-associated beta-galactosidase activity and the expression of senescence-related markers such as CDKN2A (p16) and p21. Because the sphere formation potential of SGSCs was decreased and the senescence of the cells was increased after passaging subculture, Y-27632, a Rho-associated kinase inhibitor, was used to treat the passaging subculture to aid the proliferation of the cells in culture. RESULTS: The number of spheres was higher in the Y-27632 treatment group than in the control group, and the expression of c-Kit, a proliferation marker, was also increased. In addition, the expression of p16 and p21 proteins tended to be lower in the Y-27632 group. CONCLUSION: Y-27632 suppresses the expression of senescence-related proteins and enhances cellular proliferation. This study points to the possibility of scaling-up the therapeutic use of SGSCs, which requires a large amount of cells. PMID- 25804561 TI - Predicting infiltration of the surface layer of natural enamel caries. AB - AIM: To test the hypothesis that the water volume more easily available for diffusion (alphad) is the best predictor among all major components of the proportion of pore volume infiltrated by a liquid in the surface layer of dry natural enamel caries (NEC). MATERIALS AND METHOD: Two aqueous solutions of mercuric and potassium iodide (Thoulet's solutions) with different refractive indexes (1.4 and 1.47) and penetration coefficients (3212 cm/s and 2297 cm/s) were tested at histological points (n = 63) of ground sections of NEC lesions. Component volumes were measured with microradiography and interpretation of birefringence. Real-time 2D mapping of capillary flow was performed with orientation-independent polarizing microscopy. RESULTS: alphad was a good predictor for both liquids (T1.40: R(2) = 0.413; T1.47: R(2) = 0.505), but was similar to the water and air volumes for Thoulet's 1.47, and to the mineral and organic volumes for Thoulet's 1.40. From real-time 2D mapping, infiltration in ground sections occurred in two propagation directions, perpendicularly to the prism paths (at the centre of the lesion bodies) and axially to the prism paths (at all parts of the lesions), with two penetration rates, the faster related to prisms sheaths and the slower related to intraprismatic pores, affecting penetration length and air displacement. CONCLUSIONS: alphad was a good predictor for both liquids, but was similar to the water and air volumes for T1.47 and to the mineral and organic volumes for T1.40. Both flow mechanics and component volumes are required to interpret infiltration of liquids into NEC. PMID- 25804562 TI - Thyroid disease as a risk factor for cerebrovascular disease. AB - BACKGROUND: Thyroid disease is the medical condition impairing function of the thyroid. Among this disorder category, hyperthyroidism is that the thyroid gland produces excessive amounts of thyroid hormones whereas hypothyroidism is that the thyroid gland does not produce enough thyroid hormone. Various studies have supported the comorbid association between thyroid disease and cardiovascular disorder. However, there is insufficient evidence to prove the relationship between cerebrovascular disease (CVD) and thyroid disease. METHODS: In this study, we tried to verify that thyroid disease increases the risk of CVD development employing a population-based database, National Health Insurance Research Database of Taiwan. A total of 16,808 hyperthyroidism cases and 5793 hypothyroidism patients with corresponding control subjects were studied, respectively. Hazard ratio (HR) by the Cox regression was used to quantify risk of CVD in different groups of subjects, that is, case patients versus matched controls. Further stratification studies for risk factors of CVD were performed to evaluate the comorbid association between CVD and hyperthyroidism/hypothyroidism. RESULTS: Evaluation results have shown that hyperthyroidism increased 38% of the hazard of developing follow-up CVD (adjusted HR, 1.38) whereas hypothyroidism increased even higher the risk (adjusted HR, 1.89). Further stratification studies for risk factors of CVD suggested that the comorbid association between hypothyroidism and CVD was comparable to those influences from cardiac risk factors, such as diabetes mellitus, hyperlipidemia, hypertension, or renal failure and so forth. CONCLUSIONS: Thyroid disease may predispose to onset of CVD. Advanced analysis is required to investigate the pathologic mechanism underlying the association between CVD and thyroid disease. PMID- 25804563 TI - A Case of Neurofibromatosis Type 1 Complicated with Repeated Intracerebral Hemorrhage due to Quasi-Moyamoya Disease. AB - Moyamoya disease (MMD) is a unique occlusive disease of the bilateral internal carotid arteries with moyamoya vessels. Inherited or acquired disorders and conditions may present in conjunction with MMD. This condition is known as quasi MMD. We report a case of quasi-MMD complicated with repeated intracerebral hemorrhage during long-term follow-up for cerebral ischemia. A 35-year-old woman who had a diagnosis of neurofibromatosis type 1 visited our hospital because of incidentally found cerebral infarction. Angiography showed occlusive changes in the distal portion of the bilateral internal carotid artery and multiple massive collateral arteries from occluded internal carotid artery. Because revascularization from external carotid artery systems developed, she was treated conservatively and followed annually with radiologic study. During follow-up, she suffered from minor intracerebral hemorrhages. At the age of 55 years, she died of massive intracerebral hemorrhages. Although the intracerebral hemorrhage is not common in quasi-MMD, it has a potential to be fatal. Long-term follow-up with radiologic study and proper surgical treatment is required. PMID- 25804564 TI - The prediction of malignant middle cerebral artery infarction: a predicting approach using random forest. AB - BACKGROUND: Malignant middle cerebral artery infarction (MMI) is always associated with high mortality rates. Early decompressive craniectomy is crucial to its treatment. The purpose of this study was to establish a reliable model for an early prediction of MMI. METHODS: Using a retrospective survey, we have collected the data of 132 patients with middle cerebral artery infarction. According to a prognosis, the patients are divided into the MMI group (n = 36) and the non-MMI group (n = 96). All the patients are represented by their clinical, biochemical, and imaging features. Then a random forest (RF) prediction model is established on the clinical data. Meanwhile, 3 traditional prediction models, including univariate linear discriminant analysis (LDA) model, multivariate LDA model, and binary logistic regression analysis (BLRA), are built to compare with the RF model. The prediction performance of different models is assessed by the area under the receiver operating characteristic curves (AUCs). RESULTS: Four parameters, Glasgow Coma Scale, midline shifting, area, and volume of focus, selected as predictors in all models. As independent predictors, their AUCs are .72-.80, and when the sensitivities are high (.91-.95), the specificities are low (.32-.53). The AUC of RF model is .96, 95% confidence interval (CI) is (.93-.99), sensitivity is 1, and specificity is .85. The AUC of the multivariate LDA model is .87 and 95% CI is (.80-.93). The AUC of the BLRA model is .86 and 95% CI is (.80-.93). CONCLUSIONS: The RF performs very well in the given clinical data set, which indicates that the RF is applicable to the early prediction of the MMI. PMID- 25804565 TI - Calcified carotid plaques show double symptomatic peaks according to agatston calcium score. AB - BACKGROUND: The precise mechanism of carotid calcification formation and its clinical significance including the difference in outcomes compared with coronary artery have not been clearly elucidated yet. We applied the calcium score for analyzing carotid plaque calcification in focus on its relationship with symptoms and discuss the difference in transitional patterns and the clinical outcome in comparison with calcified coronary plaques. METHODS: Multidetector row computed tomography angiography was performed preoperatively to determine the Agatston calcium score, volume score, and Hounsfield values for a total of 330 carotid arteries from 194 patients. Analysis focused on the relation of "the symptomatic rate" to calcium score, volume score, and Hounsfield value as well as the characteristics of calcified plaques and coexisting diseases. The symptomatic rate of carotid artery plaques in each range of the index was calculated as the percentage of the number of carotid arteries with plaques, which elicited symptoms of the contralateral limbs or the ipsilateral retina to the whole number of carotid arteries with plaques within the range. RESULTS: Calcified carotids with low symptomatic rate (<40%) tended to have calcification with significantly high calcium scores, high volume scores and mean/maximum Hounsfield values, high circularities, outer positions, positive remodeling, and carotid bulb/common carotid locations by univariate analysis, whereas high maximum Hounsfield value, high circularity, and outer position of calcification were significant independent predictors of low-symptomatic calcified carotid plaques by multivariate logistic regression analysis. When analyzed by calcium score, the rates for symptomatic carotids showed double peaks at calcium scores around 200 400 and 600-800 with a dip at 400-600. Significant independent predictors of low symptomatic carotid artery were high maximum Hounsfield value (odds ratio [OR], 5.70; P = .005), calcification encircling the carotid perimeter (OR, 7.18; P = .005), and the calcium location in the common carotid artery (OR, 6.62; P = .006) in comparing groups with low (0-400) and medium (400-600) calcium scores, whereas a high volume score (OR, .01; P = .003) alone was a significant independent determinant in the comparison between groups with high (600-1000) and medium calcium scores. CONCLUSIONS: Symptomatic rates of carotid plaque calcification were demonstrated to show double peaks with increasing calcium score and represent different features. Assessment of the 2 calcium-score parts might be helpful for appropriate comprehension of symptomatology and the complex process of carotid plaque calcification. We report a hypothesis for the mechanisms of the 2 different sections. PMID- 25804566 TI - Long-term Functional Recovery and Quality of Life after Surgical Treatment of Putaminal Hemorrhages. AB - BACKGROUND: To evaluate the long-term functional recovery and health-related quality of life (HRQOL) in patients after surgically treated putaminal hemorrhages. Surgery for putaminal hemorrhages remains a controversial issue. Although numerous reports describe conflictive results regarding short-term outcome of surgically treated patients, very little is known about their long term recovery and their HRQOL. METHODS: In this monocentric, retrospective study we analyzed mortality, long-term functional outcome, activity of daily life status, and HRQOL undergoing craniotomy for hematoma evacuation between December 2004 and January 2011. RESULTS: Forty-nine consecutive patients were identified with 8 (16.3%) patients dying during acute care. Forty-one patients surviving acute phase were transferred to neurologic rehabilitation hospitals. One patient was lost to follow-up. Median follow-up was 52.9 (17-101) months. At follow-up, 24 of 40 (60%) patients still were alive with 16 of 40 (40%) patients living with major disability (modified Rankin Scale [mRS], 4 or 5). Seven patients (17.5%) showed a mRS lesser than or equal to 3 with only 3 (7.5%) of those living functionally independent (mRS, 0-2). HRQOL in survivors was reduced with a median DEMQOL/DEMQOL (a patient/caregiver reported outcome measure designed to assess health-related quality of life of people with dementia) proxy score of 92 and 93, respectively. All patients showed severe impairment in activities of daily life. CONCLUSIONS: This is the first long-term follow-up analysis for patients with surgically treated putaminal hemorrhages. Survivors show only marginal recovery despite intensive neurologic rehabilitation; most remain dependent with a reduced HRQOL and significantly impaired activities of daily life status. PMID- 25804567 TI - Prior IV Thrombolysis Facilitates Mechanical Thrombectomy in Acute Ischemic Stroke. AB - BACKGROUND: In acute ischemic stroke (AIS), bridging therapy, including intravenous thrombolysis (IVT) and mechanical thrombectomy (MET), appears to be very promising. However, data on the impact of IVT before the endovascular procedure are limited. METHODS: To examine the impact of IVT on the MET procedure, we compared the duration of this procedure, number of passes, recanalization rate, safety issues, and outcome in consecutively recruited patients either eligible for MET alone (intravenous fibrinolysis contraindication) or receiving MET preceded by IVT for proximal middle cerebral artery (MCA) occlusion within 6 hours of stroke onset. RESULTS: From January 2011 to June 2013, 68 cases with proximal MCA occlusion were available for analysis (MET alone, 40; IVT + MET, 28). The 2 groups did not differ significantly in baseline characteristics. The median National Institutes of Health Stroke Scale score at admission was 15 (10-20) for MET and 18 (13-19) for IVT + MET groups, respectively (P = .39). The median duration of the endovascular procedure (from groin puncture to recanalization) was significantly shorter in the IVT + MET group compared with that in MET alone (35 minutes [21-60] versus 60 minutes [25 91]; P = .043). The number of passes of the thrombectomy device per patient tended to be lower in the IVT + MET group than those in the MET group (P = .080). The IVT + MET group also had a higher rate of complete recanalization and a better outcome at 3 months. CONCLUSIONS: Prior IVT may facilitate the MET procedure. Further studies on MET in AIS should assess the direct impact of IVT on the endovascular procedure. PMID- 25804569 TI - Impact of heart rate dynamics on mortality in the early phase after ischemic stroke: a prospective observational trial. AB - BACKGROUND: Growing evidence suggests that the heart rate (HR) at rest is an independent predictor of cardiovascular mortality. In ischemic stroke, continuous monitoring of HR is the standard of care, but systematic data on its dynamics and prognostic value during the acute phase are limited. METHODS: In this prospective observational study, HR was measured by continuous electrocardiographic monitoring on admission and during the first 72 hours of care among patients who were awake with ischemic stroke and survived until discharge. Functional outcome was assessed after 90 days. RESULTS: Data from 702 consecutive patients were analyzed (median age, 73 years, 54% men). The time course of HR was initially characterized by a rapid decline during the first 12 hours after admission. Among patients who survived until day 90, this was followed by a continuous downward trend in HR, whereas death after discharge was associated with a secondary increase and a reversal point 12 hours after admission. After adjustment for established risk factors, this secondary increase during the acute period was an independent predictor of death (hazard ratio, 3.73; 95% confidence interval, 1.47 9.43; P = .005). CONCLUSIONS: A secondary rise of HR during care for acute ischemic stroke is an early sign of fatality and may represent a surrogate for an unfavorable sympathetic disinhibition. Further research is warranted to clarify the role of targeted HR reduction after ischemic stroke (http://clinicaltrials.gov/, unique identifier NCT01858779). PMID- 25804568 TI - Clot characteristics on computed tomography and response to thrombolysis in acute middle cerebral artery stroke. AB - BACKGROUND: Clinical and computer tomography angiography (CTA) correlates of hyperdense middle cerebral artery sign (HMCAS) and dot sign were revisited in patients treated for acute MCA stroke. Temporal evolution of these signs over 24 hours was assessed quantitatively by density (Hounsfield unit [HU]) measurements. METHODS: Maximum pixel-sized HUs throughout proximal MCA and its insular fissure branches were determined in 131 patients with acute MCA stroke treated by intravenous thrombolysis and/or interventional thrombolysis/thrombectomy; 14 patients treated for vertebrobasilar stroke (VBS) and 42 nonstroke control subjects. Utility of visually determined HMCAS and dot sign, absolute HU of proximal and distal MCA, side-to-side HU ratio and difference, and hyperdense MCA burden score for the prediction of early dramatic recovery (EDR) and third-month favorable prognosis were evaluated. The clinical value of the changes in vessel hyperdensity over 24 hours was identified in subjects who received intravenous thrombolysis (99 MCA stoke and 11 VBS). A multivariate model with adjustment for age, baseline stroke severity (National Institutes of Health Stroke Scale [NIHSS]), and CTA-based modified clot burden score (mCBS) was used to determine independent predictors of short- and long-term clinical outcome. RESULTS: The presence of HMCAS and dot sign, their density indices (maximum HU, ipsilateral-to contralateral HU ratio, and difference), and changes in quantitative attenuation over 24 hours were not significantly associated with EDR and favorable third month outcome in the multiple regression models, whereas NIHSS and mCBS were found to be significant independent "negative predictors" of both EDR and favorable prognosis, while age was a strong "negative indicator" only for 3-month good outcome. Average HU decrease over the first day was 5.7 HU in HMCAS (+) and 2.9 HU in dot sign (+) arteries. The densities of thrombi in MCA and insular branches were not different in subjects with and without cardioembolism. CONCLUSIONS: CTA provides dependable (high sensitivity and specificity) information regarding clot size and location, whereas hyperdense artery signs have low sensitivity and just acceptable specificity levels in this regard. However, the prognostic and diagnostic information generated by the presence of hyperdense artery signs and temporal change in attenuation can be useful in acute stroke settings where CTA is not readily available. Quantitative measures, rather than qualitative evaluation have a higher yield in determination of temporal change of the hyperdensity signs and its possible clinical correlates. PMID- 25804570 TI - Limited Efficacy of a Long-term Secondary Prevention Program in Ischemic Stroke and Transient Ischemic Attack Patients. AB - BACKGROUND: Few studies have focused on the quality of care with regard to long term secondary prevention after transient ischemic attack (TIA) or ischemic stroke. The aim of this study was 2-fold: (1) to determine if ischemic stroke and TIA patients are motivated for a long-term secondary prevention program after hospital discharge and (2) to study the effect of this program on the attainment of guideline-recommended secondary prevention targets. METHODS: A single-center, cohort study of ischemic stroke and TIA patients. The number of visits to the long-term secondary prevention program and the number of patients whom achieved the composite end point of optimal medical therapy at their last visit to our outpatient clinic were assessed. RESULTS: Of the 237 included ischemic stroke and TIA patients, only 164 (69%) visited the long-term secondary prevention program at least once. Of these patients, 37% reached the primary end point of optimal medical treatment at their last visit to our outpatient clinic. We found a significant increase in secondary prevention target attainment for the primary outcome of optimal medical treatment and its individual components. CONCLUSIONS: Despite our systematic approach to care for patients after ischemic stroke or TIA, we observed that 31% of our patients did not visit our outpatient clinic for the long-term secondary prevention program at all. In addition, the long-term secondary prevention program alone, consisting of regular follow-up visits and a medication treatment algorithm, was not sufficient to reach guideline-recommended treatment targets in most of our ischemic stroke and TIA patients. PMID- 25804571 TI - Vaginal Delivery under Epidural Analgesia in Pregnant Women with a Diagnosis of Moyamoya Disease. AB - BACKGROUND: Moyamoya disease more commonly occurs in young people and women, so patients with this disease may experience pregnancy and delivery. Cesarean section (CS) is often chosen as the mode of delivery for these patients in Japan. No appropriate mode of delivery has yet been established for pregnant women with moyamoya disease in terms of stroke prevention. We have used vaginal delivery under epidural analgesia (EA) in such patients unless CS has been indicated for the maternal or fetal reasons. This study retrospectively analyzed our patients with moyamoya disease who gave birth to confirm the safety of vaginal delivery under EA. METHODS: Twelve consecutive patients diagnosed with moyamoya disease had 14 deliveries at our hospital between September 2004 and January 2013. The incidences of intrapartum stroke were compared between cases of vaginal delivery under EA and CS cases. RESULTS: Ten vaginal deliveries under EA and 4 elective CSs were performed. No intrapartum stroke was observed during either vaginal delivery under EA or CS. Among the patients who underwent vaginal delivery under EA, 1 parturient who experienced 2 deliveries suffered transient ischemic attack during both postpartum periods. All 14 infants were healthy without sequelae. CONCLUSIONS: Vaginal delivery under EA is an option for patients with moyamoya disease, provided that close cooperation with neurosurgeons, obstetricians, and anesthesiologists is assured. PMID- 25804572 TI - Compressive Cervical Radiculopathy due to Vertebral Artery Dissection. AB - Rarely, not stroke but peripheral weakness can result from cervical artery dissection. In these cases, a mural hematoma compressing the ipsilateral C5 and/or C6 root can be demonstrated. PMID- 25804573 TI - Rupture of an aneurysm of the superior cerebellar artery feeding a dural arteriovenous fistula. AB - We experienced a very rare case of bleeding from an aneurysm of a branch of the superior cerebellar artery, which feeds a dural arteriovenous fistula (DAVF) of the posterior fossa. The aneurysm was not detected on initial angiography and 2 episodes of rebleeding resulted in deterioration of the patient's condition. Although rare, aneurysms of the pial feeding arteries should be considered as a cause of bleeding in cases of DAVF. PMID- 25804574 TI - Efficacy and Safety of Cilostazol Therapy in Ischemic Stroke: A Meta-analysis. AB - BACKGROUND: Antiplatelet therapy is recommended for patients who have experienced ischemic stroke. We performed a meta-analysis to compare the efficacy and safety of cilostazol with other antiplatelet therapies in patients with ischemic stroke. METHODS: PubMed, EMBASE, MEDLINE, and the Cochrane Library were searched for randomized controlled trials published in English from May 1999 to May 2013. Clinical outcomes were compared by pooled and meta-regression analyses. RESULTS: Nine studies involving 6328 patients satisfied our inclusion criteria. Stroke recurrence (including hemorrhagic and ischemic) with cilostazol use was 5.3% (157) versus 8.3% (248) in control group (risk ratio .63 [.52-.76], 95% confidence interval [CI]). Poststroke intracranial hemorrhage was .5% (16) with cilostazol versus 1.6% (46) in control group (risk ratio .36 [.21-.63], 95% CI). Poststroke extracranial bleeding complications occurred in 2.4% (66) of the patients taking cilostazol versus 3.9% (108) in control group (risk ratio .62 [.46-.83], 95% CI). No significant difference in cerebrovascular events (nonfatal stroke, intracranial hemorrhage, and transient ischemic attack) was found between the cilostazol group (8.2%, 246) versus control group (12.0%, 360; risk ratio .71 [.50-1.01], 95% CI). In addition, the cilostazol therapy brought about a nonsignificant reduction of cardiac adverse events (heart failure, myocardial infarction, and angina pectoris) comparing with control groups, with 3.8% (99) of the cilostazol group versus 4.7% (123) of control group (risk ratio, .81 [.62 1.04], 95% CI). CONCLUSIONS: Cilostazol, alone or in combination with aspirin, significantly reduces stroke recurrence, poststroke intracranial hemorrhage, and extracranial bleeding in patients with a prior ischemic stroke as compared with other antiplatelet therapies. PMID- 25804576 TI - Objective measurement of accommodation. PMID- 25804575 TI - Extracting biomarkers of commitment to cancer development: potential role of vibrational spectroscopy in systems biology. AB - The complex processes driving cancer have so far impeded the discovery of dichotomous biomarkers associated with its initiation and progression. Reductionist approaches utilizing 'omics' technologies have met some success in identifying molecular alterations associated with carcinogenesis. Systems biology is an emerging science that combines high-throughput investigation techniques to define the dynamic interplay between regulatory biological systems in response to internal and external cues. Vibrational spectroscopy has the potential to play an integral role within systems biology research approaches. It is capable of examining global models of carcinogenesis by scrutinizing chemical bond alterations within molecules. The application of infrared or Raman spectroscopic approaches coupled with computational analysis under the systems biology umbrella can assist the transition of biomarker research from the molecular level to the system level. The comprehensive representation of carcinogenesis as a multilevel biological process will inevitably revolutionize cancer-related healthcare by personalizing risk prediction and prevention. PMID- 25804577 TI - Pinhole iris-fixated intraocular lens for dysphotopsia and photophobia. AB - We present the pinhole iris-fixated diaphragm intraocular lens (IOL), which is a 1-piece black polycarbonate IOL with rigid iris-fixated haptics, an 8.5 mm overall length, a 6.0 mm diameter optic, and a central opening, the pinhole. The IOL was implanted in a 36-year-old man who had a history of debilitating dysphotopsia (star burst, halos, glare, and ghosting) and severe light sensitivity in his right eye following several interventions for keratoconus. The diameter of the central opening of the pinhole IOL, 2.0 mm, was based on the patient's corneal aberration profile. Postoperatively, the dysphotopic symptoms and photophobia markedly improved. We recommend the use of the pinhole iris fixated IOL in patients with severe photophobia or dysphotopsia refractory to other treatment modalities. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25804578 TI - Endothelial keratoplasty combined with cataract surgery or alone using polyethylene glycol hydrogel sealant for closure of corneal incisions. AB - We present a surgical technique in which polyethylene glycol hydrogel is used to seal corneal incisions and maintain air in the anterior chamber. This technique was used in 11 eyes that had Descemet-stripping endothelial keratoplasty (DSEK). In 2 cases, DSEK was combined with cataract extraction and intraocular lens implantation. In all cases, the anterior chamber was well formed with no leakage and the donor graft remained attached following surgery. The use of polyethylene glycol hydrogel in DSEK and combined DSEK-cataract surgery may shorten surgery, decrease suture-induced corneal astigmatism, and prevent the need for suture removal. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 25804579 TI - Objective measurement of accommodative biometric changes using ultrasound biomicroscopy. AB - PURPOSE: To demonstrate that ultrasound biomicroscopy (UBM) can be used for objective quantitative measurements of anterior segment accommodative changes. SETTING: College of Optometry, University of Houston, Houston, Texas, USA. DESIGN: Prospective cross-sectional study. METHODS: Anterior segment biometric changes in response to 0 to 6.0 diopters (D) of accommodative stimuli in 1.0 D steps were measured in eyes of human subjects aged 21 to 36 years. Imaging was performed in the left eye using a 35 MHz UBM (Vumax) and an A-scan ultrasound (A 5500) while the right eye viewed the accommodative stimuli. An automated Matlab image-analysis program was developed to measure the biometry parameters from the UBM images. RESULTS: The UBM-measured accommodative changes in anterior chamber depth (ACD), lens thickness, anterior lens radius of curvature, posterior lens radius of curvature, and anterior segment length were statistically significantly linearly correlated with accommodative stimulus demands. Standard deviations of the UBM-measured parameters were independent of the accommodative stimulus demands (ACD: 0.0176 mm; lens thickness: 0.0294 mm; anterior lens radius of curvature: 0.3350 mm; posterior lens radius of curvature: 0.1580 mm; and anterior segment length: 0.0340 mm). The mean difference between the A-scan and UBM measurements was -0.070 mm for ACD and 0.166 mm for lens thickness. CONCLUSIONS: Accommodating phakic eyes imaged using UBM allowed visualization of the accommodative response, and automated image analysis of the UBM images allowed reliable, objective, quantitative measurements of the accommodative intraocular biometric changes. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 25804581 TI - Visual acuity improvement in adult amblyopic eyes with an iris-fixated phakic intraocular lens: long-term results. AB - PURPOSE: To evaluate the effect of implantation of iris-fixated phakic intraocular lenses (pIOLs) (Artisan) in adult amblyopic eyes. SETTING: Optical Express, London, United Kingdom. DESIGN: Retrospective case series. METHODS: The study analyzed data from 5 years of follow-up of amblyopic eyes that were implanted with iris-fixated pIOLs and had a preoperative corrected distance visual acuity (CDVA) of 6/15 or worse. Visual acuity, refraction, endothelial cell count, and complications were assessed. RESULTS: Data for 103 eyes were analyzed as 2 groups. Group 1 comprised 82 eyes with myopia or myopic astigmatism, and Group 2 contained 21 eyes with hyperopia or hyperopic astigmatism. The mean preoperative sphere in Group 1 was -13.42 diopters (D) +/- 5.62 (SD) with a mean cylinder of -2.35 +/- 1.75 D. In Group 2, the mean sphere and cylinder were +6.77 +/- 1.91 D and -2.63 +/- 2.43 D, respectively. The mean CDVA improved from 0.51 +/- 0.15 logMAR to 0.34 +/- 0.16 logMAR (P<.001) in Group 1 and from 0.54 +/- 0.17 logMAR to 0.46 +/- 0.14 logMAR in Group 2 (P<.005). The safety index was 1.48 in Group 1 and 1.19 in Group 2. The efficacy index was 1.21 in Group 1 and 1.00 in Group 2. The mean gain in CDVA was statistically significantly greater in Group 1 (0.17 +/- 0.14 logMAR) than in Group 2 (0.08 +/- 0.11 logMAR). Two or more lines of CDVA were gained by 48.8% of eyes in Group 1 and by 19.0% of eyes in Group 2. CONCLUSION: The iris-fixated pIOL was a safe and effective option for improving visual acuity in adult amblyopic eyes. FINANCIAL DISCLOSURE: Dr. Schallhorn is a consultant to Abbott Medical Optics, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25804582 TI - Prevention and management of collagen copolymer phakic intraocular lens exchange: causes and surgical techniques. AB - PURPOSE: To analyze causes leading to explantation and exchange of Implantable Collamer Lens phakic intraocular lenses (pIOLs) and examine the surgical techniques of pIOL exchange. SETTING: Wuhan Aier Eye Hospital, Wuhan, China. DESIGN: Retrospective analysis of prospectively collected data. METHODS: Different techniques were used to explant the pIOLs based on the amount of vaulting. Preoperative and postoperative data were collected to evaluate possible causes leading to pIOL exchange and the safety of pIOL exchange. RESULTS: Of 616 myopic eyes with previous pIOL implantation, 16 eyes of 15 patients having pIOL exchange were reviewed. Eight surgeries (50%) were performed because of low vaulting (<=100 MUm) and another 8 (50%) because of too high vaulting (>=1000 MUm). The causes leading to low vaulting included increased crystalline lens thickness (>=4.0 mm), low anterior chamber depth (ACD) (<3.1 mm), and a too-small pIOL (<12.0 mm). The high vaulting was primarily the result of oversized white-to white (WTW) measurements with Scheimpflug pachymetry (Pentacam) or the use of a digital caliper by an unskilled examiner and of ciliary body cysts. Six months after pIOL exchange, the vaulting ranged from 162 to 715 MUm. No anterior subcapsular cataracts or other complications occurred during the observation period. CONCLUSIONS: The main causes of abnormal vaulting and subsequent pIOL exchange included a thick crystalline lens, low ACD, too-small pIOL, WTW measurement error, and ciliary body cysts. Phakic IOL explantations were individually designed based on the vaulting to achieve proper safety and efficacy. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25804580 TI - Short-term comparison of accelerated and standard methods of corneal collagen crosslinking. AB - PURPOSE: To compare the 6-month results of accelerated and standard collagen crosslinking (CXL) treatment of progressive keratoconus. SETTING: Noor Eye Hospital, Tehran, Iran. DESIGN: Prospective randomized clinical trial. METHODS: Two groups of eyes (intervention and control) received corneal collagen crosslinking (CXL) treatment. The intervention group received accelerated CXL (18 mW/cm(2), 5 minutes), and the control group received standard CXL (3 mW/cm(2), 30 minutes). The eyes were evaluated for changes in the visual indices, refraction, and topography preoperatively and 1, 3, and 6 months postoperatively and regarding corneal rigidity indices and the endothelial cell count (ECC) preoperatively and at 6 months. RESULTS: The study evaluated 62 eyes (31 patient) in 2 groups. The mean changes in uncorrected (P = .733) and corrected (P = .646) distance visual acuities and manifest refraction spherical equivalent (P = .598) did not differ statistically significantly between the 2 groups. The central corneal thickness was higher in the standard group than the accelerated group (P = .025). The mean decrease in the maximum keratometry (K) (P = .865) and mean K (P = .974) and the mean changes in the asphericity (P = .272) were not statistically significantly different between the 2 groups. The mean changes in corneal hysteresis (CH) (P = .548) and the corneal resistance factor (CRF) (P = 1.000), CH-CRF (P = .282), and the area under the peak 2 (P = .260) were similar in both groups. The mean decrease in the ECC was not statistically significantly different between the 2 groups (P = .218). CONCLUSION: Based on 6-month results, accelerated and standard corneal CXL arrested the progression of keratoconus similarly. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25804583 TI - Postoperative ocular higher-order aberrations and contrast sensitivity: femtosecond lenticule extraction versus pseudo small-incision lenticule extraction. AB - PURPOSE: To evaluate and compare changes in contrast sensitivity and ocular higher-order aberrations (HOAs) after femtosecond lenticule extraction (FLEx) and pseudo small-incision lenticule extraction (SMILE). SETTING: Singapore National Eye Centre, Singapore. DESIGN: Retrospective case series. METHOD: Patients had femtosecond lenticule extraction (Group 1) or pseudo small-incision lenticule extraction (Group 2) between March 2010 and December 2011. The main outcome measures were manifest refraction, HOAs, and contrast sensitivity 1, 3, 6, and 12 months postoperatively. RESULTS: Fifty-two consecutive patients (102 eyes) were recruited, 21 patients (42 eyes) in Group 1 and the 31 patients (60 eyes) in Group 2. The uncorrected and corrected distance visual acuities were significantly better in Group 2 than in Group 1 at 12 months (P = .032). There was no significant increase in 3rd- or 4th-order aberrations at 1 year and no significant difference between the 2 groups preoperatively or postoperatively. At 1 year, there was a significant increase in mesopic contrast sensitivity in Group 2 at 1.5 cycles per degree (cpd) (P = .008) that was not found in Group 1, and photopic contrast sensitivity at 6.0 cpd was higher in Group 2 (P = .027). CONCLUSIONS: These results indicate that refractive lenticule extraction is safe and effective with no significant induction of HOAs or deterioration in contrast sensitivity at 1 year. Induction of HOAs was not significantly different between both variants of refractive lenticule extraction. However, there was significant improvement in photopic contrast sensitivity after pseudo small-incision lenticule extraction, which persisted through 1 year. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25804584 TI - Corneal light backscattering after transepithelial corneal crosslinking using iontophoresis in donor human corneal tissue. AB - PURPOSE: To analyze the spatial distribution and time course of corneal light backscattering before and after transepithelial corneal crosslinking using iontophoresis. SETTING: Fondazione G.B. Bietti-IRCCS, Rome, Italy. DESIGN: Experimental study. METHODS: Three donor human eyes with an intact corneal epithelium had transepithelial iontophoresis corneal crosslinking (using rapid ultraviolet-A [UVA] irradiation), and 3 donor eyes without corneal epithelium had standard corneal crosslinking (using standard UVA irradiation). In addition, 3 donor eyes had iontophoresis and rapid corneal crosslinking after corneal deepithelialization (epi-off iontophoresis corneal crosslinking). Scheimpflug images (Pentacam HR) of each eye globe were acquired before and immediately after administration of riboflavin 0.1% solutions and 5, 10, 30, and 120 minutes after the corneal crosslinking procedures. Corneal light backscattering was quantified across the anterior 280 MUm thickness at several points from the optical center to 3.0 mm from the center. RESULTS: Light backscattering significantly increased after iontophoresis (P < .001) in specimens with and without intact epithelium. It decreased significantly after transepithelial iontophoresis corneal crosslinking and epi-off iontophoresis corneal crosslinking (P < .001), approaching the baseline values. After standard stromal soaking with riboflavin, a large increase in corneal light backscattering was found compared with baseline measurements (P < .001) that remained unchanged up to 30 minutes after standard corneal crosslinking (P = .92). The light backscattering increase after iontophoresis in corneas with epithelium was lower than after standard soaking (P = .01). No differences were found between specimens without epithelium after iontophoresis and standard stromal soaking (P = .06). CONCLUSIONS: Scheimpflug photography provided an indirect biomarker of stromal permeation of riboflavin. Iontophoresis efficiently delivered riboflavin through the epithelium. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25804585 TI - Small-incision lenticule extraction. AB - This review looks at the benefits, limitations, complications, and future applications of the small-incision lenticule extraction procedure. Using the search terms small incision lenticule extraction and femtosecond lenticule extraction, we obtained data from 56 articles (omitting German and Chinese articles) from the PubMed database. Small-incision lenticule extraction has shown efficacy, predictability, and safety that are proportionate to those of laser in situ keratomileusis (LASIK), with the additional benefit that it eliminates flap creation and the attendant risks. The potential advantages of the procedure related to improved biomechanical stability, postoperative inflammation, and dry eye symptoms have not been fully established. Small-incision lenticule extraction treated eyes have shown a reduced degree of postoperative corneal denervation and higher-order aberrations and an accelerated rate of corneal nerve convalescence relative to LASIK. Future possibilities related to long-term cryogenic storage of extracted lenticules with eventual reimplantation or donation have been investigated with encouraging preliminary results. FINANCIAL DISCLOSURE: Drs. Reinstein and Shah are consultants to Carl Zeiss Meditec AG. No author has a financial or proprietary interest in any material or method mentioned. PMID- 25804586 TI - Cohesive versus dispersive-cohesive ophthalmic viscosurgical device in torsional intelligent phaco. PMID- 25804587 TI - Effect of cigarette smoking on intraocular pressure. PMID- 25804588 TI - March consultation #2. PMID- 25804589 TI - Refractive surgical problem: March consultation #1. PMID- 25804590 TI - March consultation #4. PMID- 25804591 TI - March consultation #2. PMID- 25804592 TI - March consultation #6. PMID- 25804593 TI - March consultation #5. PMID- 25804594 TI - March consultation #7. PMID- 25804595 TI - March consultation #8. PMID- 25804596 TI - March consultation #9. PMID- 25804597 TI - March consultation #10. PMID- 25804598 TI - Reply: To PMID 25261391. PMID- 25804599 TI - Recent awareness and consideration of intraocular pressure fluctuation during eye surgery. PMID- 25804600 TI - Two techniques for managing posterior polar cataracts: traditional phacoemulsification versus femtosecond laser-assisted cataract surgery. PMID- 25804601 TI - Training in the prevention of surgical errors in ophthalmology. PMID- 25804602 TI - Ciliary sulcus diameter, white-to-white, and the intrascleral haptic fixation technique. PMID- 25804603 TI - Reply: To PMID 25465692. PMID- 25804604 TI - Reply: To PMID 25457381. PMID- 25804605 TI - Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats. AB - Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB1) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low- or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (n=9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (n=9) or saline via i.p. injection (n=9). After 10 weeks consuming a HFD, CB1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats. PMID- 25804607 TI - Phase transitions in free water nanoparticles. Theoretical modeling of [H2O]48 and [H2O]118. AB - Classical parallel-tempering Monte Carlo simulations of [H2O]48 and [H2O]118 have been performed in the isothermal-isobaric ensemble and a two-dimensional multiple histogram method has been used to calculate the heat capacity of the two clusters. A semiempirical procedure is proposed for the inclusion of quantum effects and transformed heat capacity profiles are compared with state-of-the-art experimental data [C. Hock et al., Phys. Rev. Lett., 2009, 103, 073401]. A very good agreement is achieved. A detailed analysis of the simulation data is provided to gain an insight into the nature of the phase change which takes place in the two clusters at T ~ 100 K. PMID- 25804608 TI - Lightweight physiologic sensor performance during pre-hospital care delivered by ambulance clinicians. AB - The aim of this study was to explore the impact of motion generated by ambulance patient management on the performance of two lightweight physiologic sensors. Two physiologic sensors were applied to pre-hospital patients. The first was the Contec Medical Systems CMS50FW finger pulse oximeter, monitoring heart rate (HR) and blood oxygen saturation (SpO2). The second was the RESpeck respiratory rate (RR) sensor, which was wireless-enabled with a Bluetooth((r)) Low Energy protocol. Sensor data were recorded from 16 pre-hospital patients, who were monitored for 21.2 +/- 9.8 min, on average. Some form of error was identified on almost every HR and SpO2 trace. However, the mean proportion of each trace exhibiting error was <10 % (range <1-50 % for individual patients). There appeared to be no overt impact of the gross motion associated with road ambulance transit on the incidence of HR or SpO2 error. The RESpeck RR sensor delivered an average of 4.2 (+/-2.2) validated breaths per minute, but did not produce any validated breaths during the gross motion of ambulance transit as its pre-defined motion threshold was exceeded. However, this was many more data points than could be achieved using traditional manual assessment of RR. Error was identified on a majority of pre-hospital physiologic signals, which emphasised the need to ensure consistent sensor attachment in this unstable and unpredictable environment, and in developing intelligent methods of screening out such error. PMID- 25804609 TI - A microfluidic device based on an evaporation-driven micropump. AB - In this paper we introduce a microfluidic device ultimately to be applied as a wearable sweat sensor. We show proof-of-principle of the microfluidic functions of the device, namely fluid collection and continuous fluid flow pumping. A filter-paper based layer, that eventually will form the interface between the device and the skin, is used to collect the fluid (e.g., sweat) and enter this into the microfluidic device. A controllable evaporation driven pump is used to drive a continuous fluid flow through a microfluidic channel and over a sensing area. The key element of the pump is a micro-porous membrane mounted at the channel outlet, such that a pore array with a regular hexagonal arrangement is realized through which the fluid evaporates, which drives the flow within the channel. The system is completely fabricated on flexible polyethylene terephthalate (PET) foils, which can be the backbone material for flexible electronics applications, such that it is compatible with volume production approaches like Roll-to-Roll technology. The evaporation rate can be controlled by varying the outlet geometry and the temperature. The generated flows are analyzed experimentally using Particle Tracking Velocimetry (PTV). Typical results show that with 1 to 61 pores (diameter = 250 MUm, pitch = 500 MUm) flow rates of 7.3 * 10(-3) to 1.2 * 10(-1) MUL/min are achieved. When the surface temperature is increased by 9.4 degrees C, the flow rate is increased by 130 %. The results are theoretically analyzed using an evaporation model that includes an evaporation correction factor. The theoretical and experimental results are in good agreement. PMID- 25804606 TI - Transcriptional control and hormonal response of thermogenic fat. AB - Obesity and its associated metabolic diseases present a major public health problem around the world. The discovery that thermogenic fat is active in adult humans has sparked a renewal of interest in the study of its development and function and in the feasibility of using modulators of thermogenesis to work against obesity. In recent years, it has been shown that there are at least two distinct types of thermogenic fat cells: brown and beige fat. In this review, we discuss the transcriptional mediators of thermogenesis and the signaling molecules that regulate thermogenic cells. We also review the effects of thermogenic fat activation on whole-body metabolic parameters and evaluate the increasing evidence that activating thermogenesis in humans can be a viable method of ameliorating obesity. In these discussions, we highlight targets that can potentially be stimulated or modified in anti-obesity treatments. PMID- 25804611 TI - Effects of metformin, buformin, and phenformin on the post-initiation stage of chemically induced mammary carcinogenesis in the rat. AB - Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1 nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin. PMID- 25804610 TI - Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans. AB - The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative, and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity, and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated are lower than those that arise in their wild-type counterparts. Pharmacologic Nrf2 activation by topical biweekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacologic Nrf2 activation lowers the expression of the pro inflammatory factors IL6 and IL1beta, and COX2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate endpoint for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. PMID- 25804613 TI - Prevalence of JAK2V617F mutation in deep venous thrombosis patients and its clinical significance as a thrombophilic risk factor: Indian perspective. AB - Venous thromboembolism is known to be a complex interaction of genetic and acquired factors leading to thrombosis. JAK2V617F mutation is believed to contribute to a thrombophilic phenotype, possibly through enhanced leukocyte platelet interactions in myeloproliferative neoplasms (MPNs). Several studies have focused on the importance of screening for JAK2V617F mutation in patients with splanchnic venous thrombosis (VT) for the detection of nonovert MPNs. The role of JAK2V617F mutation in VT outside the splanchnic region is still widely unsettled. The primary aim of this study was to find out the prevalence of JAK2V617F mutation in patients with deep venous thrombosis (DVT), its clinical significance as a prothrombotic risk factor, and its possible interactions with other genetic thrombophilic risk factors. A total of 148 patients with idiopathic, symptomatic DVT were evaluated. Median age of presentation was 32 years (range 15-71 years) with a sex ratio of 1.3:1. Overall, the most common genetic prothrombotic factor was factor V Leiden mutation, found in 10.8% (16 of 148) of patients who also showed strong association with increased risk of thrombosis (odds ratio 5.94, confidence interval 1.33-26.4, P = .019). Deficiencies in protein C, protein S, and antithrombin were seen in 8 (5.4%), 10 (6.7%), and 8 (5.4%) patients, respectively. It was observed that the frequency of JAK2V617F mutation was lower in Indian patients, and it also showed weaker association with risk of thrombosis, at least in cases of venous thrombosis outside the splanchnic region. PMID- 25804612 TI - High-density lipoprotein-cholesterol, daily estradiol and progesterone, and mammographic density phenotypes in premenopausal women. AB - High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17beta-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL C, each one SD increase of salivary mid-menstrual 17beta-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies. PMID- 25804614 TI - Heparin Reexposure in Patients With a History of Heparin-Induced Thrombocytopenia. AB - OBJECTIVES: Patients with a history of heparin-induced thrombocytopenia (HIT), who require subsequent anticoagulation, have limited options. Rechallenge with unfractionated heparin (UFH) has been reported but may be associated with a risk of recurrence of HIT. The objective of this study was to determine the safety of heparin reexposure in patients with a history of HIT. METHODS: Using several search terms, all cases of heparin reexposure in patients with HIT indexed in MEDLINE (English language only) by June 2014 were reviewed. The bibliography of each relevant article was searched for additional reports. In cases of multiple reexposures, each reexposure was identified as a separate instance of reexposure during analysis. RESULTS: A total of 136 patients with a history of HIT had 141 instances of heparin reexposure. Cardiac (76%) and vascular surgeries (11%) were the most common indications. Antiplatelet factor 4/heparin antibodies were positive in 63% of evaluable cases before reexposure. Preexposure plasma exchange (11%) and postexposure nonheparin anticoagulants (63%) were frequently utilized. Complications with heparin reexposure included recurrence of HIT (2.1%, 95% confidence interval 0.73%-6.07%) and bleeding (2.1%). CONCLUSION: Intraoperative heparin reexposure in patients with a history of HIT has a small risk of developing HIT recurrence. The use of preexposure plasma exchange in patients with positive antiplatelet factor 4/heparin antibody and postexposure nonheparin anticoagulants arguably may have reduced the risk of recurrence of HIT. PMID- 25804615 TI - Effects of Paclitaxel on the Ability of Aspirin and Clopidogrel to Inhibit Platelet Aggregation. AB - The aim of this study was to investigate the effects of different paclitaxel concentrations on platelet aggregation induced by adenosine diphosphate (ADP). This experiment involved platelet suspensions that were obtained from fasting morning blood specimens from healthy adult male volunteers aged 22 to 28 years. The effect of paclitaxel on platelet aggregation induced by ADP and the inhibition rate of platelet aggregation were calculated in 6 groups with varying concentrations of paclitaxel, respectively. The optimal incubation time and concentration of ADP were 10 minutes and 10 MUmol/mL, respectively. When the concentration of paclitaxel increased, platelet aggregation induced by ADP increased accordingly. When the concentration of paclitaxel exceeded 0.1 ng/mL, the ability of ADP to induce platelet aggregation increased significantly with increasing paclitaxel concentrations. In all the 3 experimental groups, that is A, C, and AC groups, the ability to inhibit platelet aggregation was weakened as paclitaxel concentration increased. Paclitaxel can enhance platelet aggregation induced by ADP, and this ability was observed to increase as paclitaxel concentration increased. In conclusion, paclitaxel can reduce the ability of aspirin, clopidogrel, and aspirin combined with clopidogrel to inhibit platelet aggregation. Furthermore, the ability to inhibit platelet aggregation was weakened as paclitaxel concentration increased in all 3 experimental groups. PMID- 25804616 TI - Vacancy-induced initial decomposition of condensed phase NTO via bimolecular hydrogen transfer mechanisms at high pressure: a DFT-D study. AB - Density functional theory with dispersion-correction (DFT-D) was employed to study the effects of vacancy and pressure on the structure and initial decomposition of crystalline 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one (beta NTO), a high-energy insensitive explosive. A comparative analysis of the chemical behaviors of NTO in the ideal bulk crystal and vacancy-containing crystals under applied hydrostatic compression was considered. Our calculated formation energy, vacancy interaction energy, electron density difference, and frontier orbitals reveal that the stability of NTO can be effectively manipulated by changing the molecular environment. Bimolecular hydrogen transfer is suggested to be a potential initial chemical reaction in the vacancy-containing NTO solid at 50 GPa, which is prior to the C-NO2 bond dissociation as its initiation decomposition in the gas phase. The vacancy defects introduced into the ideal bulk NTO crystal can produce a localized site, where the initiation decomposition is preferentially accelerated and then promotes further decompositions. Our results may shed some light on the influence of the molecular environments on the initial pathways in molecular explosives. PMID- 25804617 TI - Congenital posterior atlas arch defects. PMID- 25804618 TI - Comment on: Chau AM, et al. Lateral extent and ventral laminar attachments of the lumbar ligamentum flavum: cadaveric study. Spine J 2014;14:2467-71. PMID- 25804619 TI - Patient and operating room personnel radiation exposure in spinal surgery. PMID- 25804620 TI - Reply to commentary on "lateral extent and ventral laminar attachments of the lumbar ligamentum flavum: cadaveric study". PMID- 25804621 TI - Intraoperative fluoroscopy, portable X-ray, and computed tomography: patient and operating room personnel radiation exposure in spinal surgery. PMID- 25804622 TI - Migraine features in migraineurs with and without anxiety-depression symptoms: a hospital-based study. AB - BACKGROUND: Migraine, anxiety and depression often coexist. A "neurolimbic" model of migraine has been recently proposed accounting for a dynamic influence of pain, mood and anxiety on the migraine disease. However, very few data exist concerning clinical migraine features in patients reporting anxiety-depression symptoms. OBJECTIVE: Aim of our study was to test differences in clinical migraine features between migraineurs with anxiety-depression symptoms and migraineurs without ones. MATERIALS AND METHODS: We recruited 200 consecutive migraineurs. Other primary headaches comorbidity and migraine prophylaxis were exclusion criteria. Each patient was interviewed following a structured questionnaire including general features about migraine, triggers, allodynia. Anxiety and depression symptoms were evaluated in each patient by two brief self reported scales: the generalized anxiety disorder 7-item scale (GAD-7) and the Patient Health Questionnaire 9-item scale (PHQ-9). A cut-off of 5 in both the GAD 7 and the PHQ-9 was considered positive for the presence of anxiety-depressive symptoms. RESULTS: One hundred and one patients (51.5%) had anxiety-depression symptoms (GAD-7 and PHQ-9 >= 5). They reported a more headaches/month (p = 0.004), higher number of triggers (p < 0.001), and were more allodynic (p = 0.005). In a binary logistic regression model triggers and allodynia made a unique statistical contribution on reporting anxiety-depression symptoms. CONCLUSION: Our results showed that the presence of anxiety-depression symptoms affects migraine clinical presentation. They are associated with enhanced migraine triggers susceptibility, more ictal allodynic symptoms as well as more headaches/month. An altered sensation in migraineurs with anxiety-depression symptoms could be a result of a lower pain threshold and an increased cortical excitability in a broader context of a neurolimbic dysfunction. PMID- 25804623 TI - SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis Associated Cancer. AB - Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression. IMPLICATIONS: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer. PMID- 25804625 TI - A post-traumatic pulsatile nodule in the right pre-auricular region. PMID- 25804624 TI - Can the Windkessel Hypothesis Explain Delayed Intraparenchymal Haemorrhage After Flow Diversion? A Case Report and Model-Based Analysis of Possible Mechanisms. AB - BACKGROUND: Delayed ipsilateral intraparenchymal haemorrhage is a recently recognised complication after endovascular flow diversion for intracranial aneurysms. Although the mechanism of this phenomenon is not understood, one proposed explanation (the windkessel hypothesis) is that removal of aneurysmal compliance increases distal pulse pressure. METHODS: We present a case of delayed haemorrhage after placement of a Pipeline stent, discuss the proposed mechanisms, and describe a novel electrical analogue model that was used to evaluate the likely haemodynamic effect of stent placement. RESULTS: Model-based analysis suggests that stenting is not likely to produce a significant change in distal pulse pressure. Moreover, basic fluid dynamics principles suggest that a local reduction in disturbed flow in the region of the aneurysm could produce only a minor increase in distal pressure (a few mmHg), which is unlikely to be the main cause of the observed haemorrhage. CONCLUSION: The windkessel hypothesis is unlikely to explain the occurrence of delayed ipsilateral intraparenchymal haemorrhage after flow diversion; however, other mechanisms involving altered haemodynamics distal to the treated aneurysm may play a role. Further studies involving the assessment of haemodynamic changes after flow diversion would be useful to understand, and eventually mitigate, this currently unpredictable risk. PMID- 25804626 TI - Where Manchester leads on control of health and social care budget London should follow. PMID- 25804627 TI - Online professionalism: A synthetic review. AB - The rise of social media has increased connectivity and blurred personal and professional boundaries, bringing new challenges for medical professionalism. Whether traditional professionalism principles apply to the online social media space remains unknown. The purpose of this synthetic literature review was to characterize the original peer-reviewed research studies published between 1 January 2000-1 November 2014 on online professionalism, to assess methodologies and approaches used, and to provide insights to guide future studies in this area. The investigators searched three databases and performed manual searches of bibliographies to identify the 32 studies included. Most studies originated in the USA. Cross-sectional surveys and analyses of publicly available online content were the most common methodologies employed. Studies covered the general areas of use and privacy, assessment of unprofessional online behaviours, consensus-gathering of what constitutes unprofessional or inappropriate online behaviours, and education and policies. Studies were of variable quality; only around half of survey studies had response rates of 50% or greater. Medical trainees were the most common population studied. Future directions for research include public perspectives of online professionalism, impact on patient trust, and how to use social media productively as medical professionals. PMID- 25804628 TI - Successful patient diabetes education in the emergency department. AB - PURPOSE: The purpose of this study was to examine the effect of diabetes self management education (DSME) provided in a large urban emergency department (ED) by a certified diabetes educator using a "learner-centered" approach to teaching survival skills. It was hypothesized that an intervention providing learner centered education in the ED would significantly improve diabetes knowledge and self-management skills. METHODS: Participants were patients who presented to the ED with uncontrolled blood glucose with type 2 diabetes mellitus (T2DM). A learner-centered DSME approach was developed. Baseline knowledge and skills were assessed in the ED with a 5-question test and a request to demonstrate meter and insulin injection technique. Education focused on identified gaps in knowledge and skills and incorporated an opportunity for the patient to exercise control in the treatment process. At outpatient follow-up, knowledge retention was assessed with the same 5-question test, and skills again were tested. RESULTS: Patients with T2DM who were provided learner-centered DSME in the ED demonstrated a significant increase in knowledge-related test scores on all questions at follow up. Significantly fewer patients required meter and insulin injection instruction postintervention, compared to the baseline. CONCLUSION: Study results provide evidence supporting the effectiveness of learner-centered DSME delivered in the ED at imparting critical knowledge and skills to patients with T2DM. PMID- 25804629 TI - Recruitment and Hiring Strategies of Private Practitioners and Implications for Practice Management Training of Veterinary Students. AB - Hiring new employees is one of the most important and difficult decisions all veterinary practice managers and owners face. In an effort to improve hiring decisions, many employers are choosing to screen potential employees more thoroughly through the use of interviews, background checks, personality assessments, and online research including social and professional networking websites. The current study reports results from an anonymous online survey created to evaluate practicing veterinarians' attitudes and practices related to the use of recruitment and hiring tools. Results suggest that, compared to those in other professions, veterinarians underutilize these evaluative tools. The profession could benefit from more opportunities for both practitioners and veterinary students to learn how to utilize a broader range of hiring and recruitment techniques. One area of particular and growing concern is the use of Internet social media for evaluation of potential employees. Despite the fairly low number of participants who indicated they currently research applicants online, a significant number plan to implement this practice in the future. Many students are unaware of how their online postings can affect their future job possibilities and career. It is therefore important to designate time within continuing education programs and professional veterinary curricula to educate these populations about hiring and recruitment tool options and about how to manage their personal Internet interactions (especially social media) to enhance and maintain their professional image (e-professionalism). PMID- 25804631 TI - Effectiveness, training and quality assurance of colonoscopy screening for colorectal cancer. AB - Screening for colorectal cancer has been proven to be effective in reducing colorectal cancer incidence and mortality. While the precise benefit of screening exclusively by colonoscopy is not yet known, unarguably, the exam is central to the success of any screening programme. The test affords the opportunity to detect and resect neoplasia across the entire large bowel and is the definitive examination when other screening tests are positive. However, colonoscopy is invasive and often requires sedation as well as extensive bowel preparation, all of which puts the patient at risk. Furthermore, the test can technically be demanding and, unarguably, there is variation in how it is performed. This variation in performance has now been definitively linked to important outcome measures. For example, interval cancers are more common in low adenoma detectors as compared with high adenoma detectors. This review outlines the most current thinking regarding the effectiveness of colonoscopy as a screening tool. It also outlines key concepts to optimise its performance through robust quality assurance programmes and high-quality training. PMID- 25804632 TI - Failure of interleukin 13 blockade in ulcerative colitis. PMID- 25804633 TI - An independent validation of the mortality score for the short-term prognostic prediction in patients with chronic HCV infection and advanced liver disease. PMID- 25804630 TI - The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis. AB - OBJECTIVE: MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. DESIGN: We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. RESULTS: MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=-0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR 224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175). CONCLUSIONS: MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC. PMID- 25804636 TI - Synthesis of a peptide that can translocate to the endoplasmic reticulum. AB - The accumulation of unfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, which has been implicated in the development of diseases. In the present study, we synthesized a peptide that entered cells and translocated to the ER. This peptide possessed fluorescein isothiocyanate (FITC), HIV-TAT, mini alphaA-crystallin, and KDEL sequences. We demonstrated that this peptide entered cells and translocated to the ER. Time course experiments revealed that this peptide existed in the ER of cos-7 cells for 16 h. Furthermore, we detected the full-length peptide in cells by fluorescent immunostaining followed by SDS-PAGE. The peptide also entered glial and neuronal cells. These results suggest that this peptide has the ability to enter cells and exert chaperone activity at the ER, and provide an insight into the development of new drugs. PMID- 25804635 TI - Female Pelvic Vein Embolization: Indications, Techniques, and Outcomes. AB - Until recently, the main indication for pelvic vein embolization (PVE) in women was to treat pelvic venous congestion syndrome (PVC) but increasingly, patients with refluxing pelvic veins associated with leg varicosities are also being treated. A more unusual reason for PVE is to treat pelvic venous malformations, although such lesions may be treated with sclerotherapy alone. Embolotherapy for treating PVC has been performed for many years with several published studies included in this review, whilst an emerging indication for PVE is to treat lower limb varicosities associated with pelvic vein reflux. Neither group, however, has been subjected to an adequate randomized, controlled trial. Consequently, some of the information presented in this review should be considered anecdotal (level III evidence) at this stage, and a satisfactory 'proof' of clinical efficacy remains deficient until higher-level evidence is presented. Furthermore, a wide range of techniques not accepted by all are used, and some standardization will be required based on future mandatory prospective studies. Large studies have also clearly shown an unacceptably high recurrence rate of leg varicose veins following venous surgery. Furthermore, minimally or non-invasive imaging is now revealing that there is a refluxing pelvic venous source in a significant percentage of women with de novo leg varicose veins, and many more with recurrent varicosities. Considering that just over half the world's population is female and a significant number of women not only have pelvic venous reflux, but also have associated leg varicosities, minimally invasive treatment of pelvic venous incompetence will become a common procedure. PMID- 25804634 TI - Liver transplantation for hepatocellular carcinoma beyond the Milan criteria. AB - OBJECTIVE: Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively. DESIGN: This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria. RESULTS: Compared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), alpha-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden <=8 cm, or tumour burden >8 cm but AFP<=100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001). CONCLUSIONS: The Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma. PMID- 25804637 TI - The effects and mechanisms of clinorotation on proliferation and differentiation in bone marrow mesenchymal stem cells. AB - Data from human and rodent studies have demonstrated that microgravity induces observed bone loss in real spaceflight or simulated experiments. The decrease of bone formation and block of maturation may play important roles in bone loss induced by microgravity. The aim of this study was to investigate the changes of proliferation and differentiation in bone marrow mesenchymal stem cells (BMSCs) induced by simulated microgravity and the mechanisms underlying it. We report here that clinorotation, a simulated model of microgravity, decreased proliferation and differentiation in BMSCs after exposure to 48 h simulated microgravity. The inhibited proliferation are related with blocking the cell cycle in G2/M and enhancing the apoptosis. While alterations of the osteoblast differentiation due to the decreased SATB2 expression induced by simulated microgravity in BMSCs. PMID- 25804638 TI - Characterization of the fusion core in zebrafish endogenous retroviral envelope protein. AB - Zebrafish endogenous retrovirus (ZFERV) is the unique endogenous retrovirus in zebrafish, as yet, containing intact open reading frames of its envelope protein gene in zebrafish genome. Similarly, several envelope proteins of endogenous retroviruses in human and other mammalian animal genomes (such as syncytin-1 and 2 in human, syncytin-A and B in mouse) were identified and shown to be functional in induction of cell-cell fusion involved in placental development. ZFERV envelope protein (Env) gene appears to be also functional in vivo because it is expressible. After sequence alignment, we found ZFERV Env shares similar structural profiles with syncytin and other type I viral envelopes, especially in the regions of N- and C-terminal heptad repeats (NHR and CHR) which were crucial for membrane fusion. We expressed the regions of N + C protein in the ZFERV Env (residues 459-567, including predicted NHR and CHR) to characterize the fusion core structure. We found N + C protein could form a stable coiled-coil trimer that consists of three helical NHR regions forming a central trimeric core, and three helical CHR regions packing into the grooves on the surface of the central core. The structural characterization of the fusion core revealed the possible mechanism of fusion mediated by ZFERV Env. These results gave comprehensive explanation of how the ancient virus infects the zebrafish and integrates into the genome million years ago, and showed a rational clue for discovery of physiological significance (e.g., medicate cell-cell fusion). PMID- 25804639 TI - Olfactory receptor Olfr544 responding to azelaic acid regulates glucagon secretion in alpha-cells of mouse pancreatic islets. AB - Olfactory receptors (ORs) are extensively expressed in olfactory as well as non olfactory tissues. Although many OR transcripts are expressed in non-olfactory tissues, only a few studies demonstrate the functional role of ORs. Here, we verified that mouse pancreatic alpha-cells express potential OR-mediated downstream effectors. Moreover, high levels of mRNA for the olfactory receptors Olfr543, Olfr544, Olfr545, and Olfr1349 were expressed in alpha-cells as assessed using RNA-sequencing, microarray, and quantitative real-time RT-PCR analyses. Treatment with dicarboxylic acids (azelaic acid and sebacic acid) increased intracellular Ca(2+) mobilization in pancreatic alpha-cells. The azelaic acid induced Ca(2+) response as well as glucagon secretion was concentration- and time dependent manner. Olfr544 was expressed in alpha-cells, and the EC50 value of azelaic acid to Olfr544 was 19.97 MUM, whereas Olfr545 did not respond to azelaic acid. Our findings demonstrate that Olfr544 responds to azelaic acid to regulate glucagon secretion through Ca(2+) mobilization in alpha-cells of the mouse pancreatic islets, suggesting that Olfr544 may be an important therapeutic target for metabolic diseases. PMID- 25804640 TI - HSF1 and NF-kappaB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy. AB - Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk old male Sprague-Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction. Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-kappaB p65 subunit, decreased the NF-kappaB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-kappaB p65 and nuclear translocation. PMID- 25804642 TI - Beamformer-based spatiotemporal imaging of linearly-related source components using electromagnetic neural signals. AB - Functional connectivity calculated using multiple channels of electromagnetic brain signals is often over- or underestimated due to volume conduction or field spread. Considering connectivity measures, coherence is suitable for the detection of rhythmic synchronization, whereas temporal correlation is appropriate for transient synchronization. This paper presents a beamformer-based imaging method, called spatiotemporal imaging of linearly-related source component (SILSC), which is capable of estimating connectivity at the cortical level by extracting the source component with the maximum temporal correlation between the activity of each targeted region and a reference signal. The spatiotemporal correlation dynamics can be obtained by applying SILSC at every brain region and with various time latencies. The results of six simulation studies demonstrated that SILSC is sensitive to detect the source activity correlated to the specified reference signal and is accurate and robust to noise in terms of source localization. In a facial expression imitation experiment, the correlation dynamics estimated by SILSC revealed the regions with mirror properties and the regions involved in motor control network when performing the imitation and execution tasks, respectively, with the left inferior frontal gyrus specified as the reference region. PMID- 25804641 TI - Using Sterol Substitution to Probe the Role of Membrane Domains in Membrane Functions. AB - Ordered membrane lipid domains rich in sphingolipids and sterols ("lipid rafts") are thought to be important in many biological processes. However, it is often difficult to distinguish domain-dependent biological functions from ones that have a specific dependence on sterol, e.g. are dependent upon a protein with a function that is dependent upon its binding to sterol. Removing cholesterol and replacing it with various sterols with varying abilities to form membrane domains or otherwise alter membrane properties has the potential to help distinguish these cases. This review describes this strategy, and how it has been applied by various investigators to understand cellular functions. PMID- 25804647 TI - Can year of the snake be an innovational period of medical education? PMID- 25804644 TI - Uncovering the clinical utility of miR-143, miR-145 and miR-224 for predicting the survival of bladder cancer patients following treatment. AB - Accurate prognosis is a key factor in establishing optimal therapeutic decisions; yet in the case of bladder cancer (BlCa) current prognostic indicators cannot ensure optimal disease management. Here, we aimed to evaluate the previously unexplored clinical potential of the urological cancer-related miR-145, miR-143 and miR-224 in BlCa. A total of 279 bladder tissue specimens were included in this study (133 BlCa, 107 adjacent normal and 39 healthy samples). Total RNA was extracted from tissues, it was polyadenylated and reverse transcribed to cDNA. The expression of target molecules was measured via quantitative real-time PCR. The expression levels of both miR-143 and miR-145 were significantly decreased, whereas those of miR-224 were increased in BlCa. Receiver operating characteristic curve analysis indicated a significant discriminatory capacity for miR-143/miR-145 levels. Important associations with disease aggressiveness were observed for all three microRNAs; elevated levels were observed in tumors of higher stage and grade, as well as in 'high-risk' TaT1 patients. More importantly, high miR-143/145 levels could effectively prognose inferior overall survival for muscle-invasive patients and could independently predict the progression of superficial tumors. Finally, the combination of miR-143/145 overexpression with the widely used prognostic markers of European Organization for Research and Treatment of Cancer-risk groups or recurrence at the first follow-up cystoscopy resulted to a superior positive prediction of non-muscle invasive bladder cancer short-term progression compared with the use of the abovementioned markers alone. The cancer-related miR-143, miR-145 and miR-224 were investigated for the first time in the clinical setting of BlCa, and miR 143/145 cluster constitutes a novel marker helpful for providing an enhanced prediction of oncologic outcome for BlCa patients. PMID- 25804645 TI - Medication overuse, healthy lifestyle behaviour and stress in chronic headache: Results from a population-based representative survey. AB - AIM: This cross-sectional study investigated associations between chronic headache (CH) with and without medication overuse, healthy lifestyle behaviour, and stress. METHODS: Questionnaires were sent to 129,150 adults. Those with headache >=15 days per month for three months were classified as having CH then further described as having medication-overuse headache (MOH) or CH without medication overuse. Associations between headache and daily smoking, physical inactivity, obesity, excessive drinking, illicit drug use, and high stress were analysed by logistic regression. RESULTS: CH with and without medication overuse (prevalence 1.8% and 1.6%, respectively) had strong, graded associations with stress. Associations with daily smoking, physical inactivity, and obesity were significant only for MOH. Odds for MOH were highest among people who had all three factors compared to those who had none (OR 2.8 in women and 5.1 in men). High stress plus any of these three factors had synergistic effects in MOH but not clearly in those who had CH without overuse. Associations between CH subtypes and excessive drinking or illicit drug use were not statistically significant. CONCLUSION: Results suggest strong links between healthy lifestyle behaviour and stress in MOH. Stress reduction and promoting healthy behaviour are highly relevant in MOH management. PMID- 25804648 TI - What kind of mentoring do we need? A review of mentoring program studies for medical students. AB - Nearly every medical school in Korea has a student advisory program, regardless of its form or method, but it is plagued by efficiency. To examine efficient means of delivering student advisory programs, we chose 'mentoring' as one solution and reviewed the concepts of a mentor and mentoring, the qualities and roles of a mentor, and examples of national and international cases of mentoring. The concept of mentoring is diverse, but it connotes and stresses aspects, such as individual guidance, tutoring, life coaching, and role modeling. We conclude that the quality of many student advisory programs can be elevated by providing holistic and systematic guidance that meets the demands of the mentees; giving individual, continuous, and intimate coaching; and guiding a balanced academic and social life and career, which will develop good doctors who can provide a holistic health care. PMID- 25804649 TI - Gender difference and specialty preference in medical career choice. AB - PURPOSE: We are entering a new era of medicine in which an equal number of men and women are becoming doctors. Many factors combine in complex and poorly understood ways to influence a medical student's career and choice of specialty. This study investigated the preferences of medical students with regard to specialty and examined differences between genders. METHODS: We administered a survey to medical students at the end of their third- or fourth-year clinical clerkships. In addition to demographic data and specialty choice, medical students selected factors that were importance to their choice of specialty. RESULTS: One hundred forty-one medical students completed the survey (81 males, 57%). For medical students who had chosen a specialty, the most common specialty was internal medicine (20.5%). Significant gender differences were observed in choosing orthopedic surgery and family medicine-17 male students chose orthopedic surgery (10.5%) versus 3.3% of female students (p=0.02), and 11 females (9.2%) were drawn toward family medicine compared with 4 male students (2.5%). More female medical students chose lower workloads (19.9%) and low-risk work (14%) than male students (p<0.05). Lifestyle and income have become more important to medical students regarding their choice of specialty. CONCLUSION: There were significant gender differences concerning the choice of medical specialty. Controllable lifestyle remains an important factor for female medical students who are choosing a specialty. We must begin to make meaningful and thoughtful changes in medical center policies that affect a balance between work and home. PMID- 25804643 TI - Gradual emergence of spontaneous correlated brain activity during fading of general anesthesia in rats: Evidences from fMRI and local field potentials. AB - Intrinsic brain activity is characterized by the presence of highly structured networks of correlated fluctuations between different regions of the brain. Such networks encompass different functions, whose properties are known to be modulated by the ongoing global brain state and are altered in several neurobiological disorders. In the present study, we induced a deep state of anesthesia in rats by means of a ketamine/medetomidine peritoneal injection, and analyzed the time course of the correlation between the brain activity in different areas while anesthesia spontaneously decreased over time. We compared results separately obtained from fMRI and local field potentials (LFPs) under the same anesthesia protocol, finding that while most profound phases of anesthesia can be described by overall sparse connectivity, stereotypical activity and poor functional integration, during lighter states different frequency-specific functional networks emerge, endowing the gradual restoration of structured large scale activity seen during rest. Noteworthy, our in vivo results show that those areas belonging to the same functional network (the default-mode) exhibited sustained correlated oscillations around 10Hz throughout the protocol, suggesting the presence of a specific functional backbone that is preserved even during deeper phases of anesthesia. Finally, the overall pattern of results obtained from both imaging and in vivo-recordings suggests that the progressive emergence from deep anesthesia is reflected by a corresponding gradual increase of organized correlated oscillations across the cortex. PMID- 25804650 TI - Group counseling for medical students with drop-out experiences. AB - PURPOSE: The purpose of this research was to describe our group counseling methods for medical students with drop-out experiences. METHODS: Group counseling was offered to 11 medical students with drop-out experiences in their previous second semester. All subjects provided written informed consent before participating and completed a 2-day group counseling program using the Gestalt approach. The self-assertiveness training group counseling program consisted of 6 sessions, each of which lasted 90 minutes. Experience reports by participants after the program and data from semi-structured qualitative interviews were qualitatively analyzed. RESULTS: Program participants reported that they were moderately satisfied with the program regarding its usefulness and helpfulness on self-awareness, understanding, and reminding them of attempts to change behavior. Most students showed heightened levels of sincerity perceptions and positive attitudes in every session. The results demonstrated significant changes in experience in self-esteem, self-recognition, and interpersonal relationships. CONCLUSION: A group counseling program using the Gestalt approach could help medical students with drop-out experiences to adjust with 1 year their juniors, enhance their self-esteem, contribute to their psychological well-being, and prevent student re-failure through effective stress management and improved interpersonal relationships. PMID- 25804651 TI - Concordance between Self and Standardized Patient Ratings of Medical Students' Communication Skills. AB - PURPOSE: The purpose of this study was to examine the concordance between self and standardized patient (SP) ratings of medical students' communication skills. METHODS: Forty-three students interviewed SPs. The students were asked to complete a communication skills questionnaire that comprised 2 measures (empathy and interpersonal communication) before the interview. After each student's interview with the SP, the latter completed the same questionnaire as the students. RESULTS: Based on Lin's concordance coefficient, there was strong disconcordance between students' self-ratings and the SPs' ratings. With regard to empathic communication, more than 50% of students who considered themselves higher than middle level were regarded by SP as low level. On interpersonal communication, 39% of students who assessed themselves as higher than middle level were scored low level by SPs. CONCLUSION: There was strong disconcordance between students' self-ratings and the SPs' ratings-students tended to overevaluate themselves regarding their communication skills. These differences might result in patient dissatisfaction and noncompliance. Further, it could become a serious hindrance to the development of a good doctor-patient relationship. Medical educators should make sincere efforts to reduce this gap by teaching medical students the importance of the patients' perception of his doctors' communication skills. PMID- 25804652 TI - Medical residents' job satisfaction and their related factors. AB - PURPOSE: This study was conducted to investigate medical residents' job satisfaction and their related factors to improve the quality of residency program. METHODS: The study subjects were 159 medical residents being trained at Chonnam National University Hospital, South Korea, in 2011. The participants were asked to complete a short form Minnesota satisfaction questionnaire (MSQ). RESULTS: The mean score for 20 items on the short form MSQ varied between 2.91 and 3.64 on a 5-point Likert scale. The assessment of related factors with job satisfaction revealed that medical residents had higher levels for job satisfaction, particularly those who were women (beta=0.200, p=0.022), and those who had mentorship experience (beta=0.219, p=0.008). CONCLUSION: This study results indicate that we should expand and support the mentorship program during medical residency to promote job satisfaction. PMID- 25804653 TI - A study on the characteristics of excellent lecturers in medical school. AB - PURPOSE: This study analyzed the characteristics of excellent lecturers, as perceived by medical students, and identified the teaching competency that lecturers should possess to enhance the quality of medical education in medical school. METHODS: To examine the characteristics of excellent lecturers and teaching competency, we administered open-ended questionnaires to a sample of 128 Year 2 medical students in May 2011. RESULTS: The students placed high value on the ability to organize and summarize the lecture as the most significant competence of lecturers, due to the massive amounts of information that is disseminated in medical college. Further, they chose lecturers who communicated to students actively and used real clinical cases properly with regard to how medical knowledge applied. They also considered generating an interest in learning by linking knowledge and its application as an important priority of excellent lecturers. CONCLUSION: We conclude that there are differences in the characteristics and competencies of excellent lecturers, as perceived by medical students and others. To increase the quality of teaching, it might be necessary to offer the opportunity to observe excellent lecturers, develop faculty development programs, and create educational culture. PMID- 25804654 TI - Facilitating class presentations. PMID- 25804655 TI - The aims of education and other essays. PMID- 25804656 TI - Radiographic and computed tomographic assessment of the development of the antebrachia and elbow joints in Labrador Retrievers with and without medial coronoid disease. AB - OBJECTIVES: To compare the development, monitored by radiography and computed tomography, of the antebrachia and elbow joints in seven Labrador Retrievers with healthy elbow joints and in seven Labrador Retrievers that developed medial coronoid disease (MCD), in order to determine whether disturbances in the development of the antebrachia and elbow joints, between the age of six and 17 weeks may lead to medial coronoid disease. METHODS: A prospective study of 14 Labrador Retrievers in their active growth stage was performed. The development of the antebrachia and elbow joints was assessed between six and 17 weeks of age using radiography and computed tomography determining the development of secondary ossification centres, radioulnar length ratio, radial angulation, and inter-relationship between the humerus, ulna and radius. RESULTS: For the parameters of ossification of secondary ossification centres, radioulnar length ratio, radial angulation, and joint congruence evaluation, there was no significant difference in the development of the antebrachia and elbow joints of seven Labrador Retrievers positive and seven Labrador Retrievers negative for MCD at the age of six to 17 weeks. CLINICAL SIGNIFICANCE: These findings demonstrate that the development of MCD in the Labrador Retrievers in our study was not related to any disturbance in the development of the antebrachia and elbow joints during the rapid growth phase. PMID- 25804657 TI - Occurrence and distribution of antibiotics in urban soil in Beijing and Shanghai, China. AB - The recycling of reclaimed wastewater for irrigation and road cleaning is an important strategy to minimize water scarcity in megacities. However, little is known regarding the potential accumulation of antibiotics contained in reclaimed wastewater in urban soil. We investigated the occurrence and distribution of eight quinolones (QNs), nine sulfonamides (SAs), and five macrolides (MLs) antibiotics in urban surface soil in Beijing and Shanghai, China. QNs, especially norfloxacin (NOR), ofloxacin (OFL), and ciprofloxacin (CIP) were the predominant antibiotics in urban surface soil, and NOR revealed the highest average concentration of 94.6 MUg kg(-1). The antibiotic concentrations in urban soil in our study were higher than those detected in agricultural soils after long-term wastewater irrigation and manure fertilization. The concentrations of antibiotics in Shanghai urban soil showed a significant negative correlation with soil pH and a positive correlation with total organic carbon (TOC), reflecting the effect of speciation and soil organic matter content on sorption and retention. In addition, antibiotic concentrations in the urban soil were positively correlated with heavy metal contents, likely due to their coexistence in reclaimed wastewater and the promoting effect of metals on the sorption of antibiotics. In several soil samples, NOR, OFL, CIP, enrofloxacin (ENR), and fleroxacin (FLE) showed higher concentrations than the trigger value of 100 MUg kg(-1) in soil, indicating a potential risk for the environment. PMID- 25804658 TI - Behaviour of estrogenic endocrine-disrupting chemicals in permeable carbonate sands. AB - The remediation of four estrogenic endocrine-disrupting compounds (EDCs), estrone (E1), estradiol (E2), ethinylestradiol (EE2) and estriol (E3), was measured in saturated and unsaturated carbonate sand-filled columns dosed with wastewater from a sewage treatment plant. The estrogen equivalency (EEQ) of inlet wastewater was 1.2 ng L(-1) and was remediated to an EEQ of 0.5 ng L(-1) through the unsaturated carbonate sand-filled columns. The high surface area of carbonate sand and associated high microbial activity may have assisted the degradation of these estrogens. The fully saturated sand columns showed an increase in total estrogenic potency with an EEQ of 2.4 ng L(-1), which was double that of the inlet wastewater. There was a significant difference (P < 0.05) in total estrogenic potency between aerobic and anaerobic columns. The breakdown of conjugated estrogens to estrogenic EDCs formed under long residence time and reducing conditions may have been responsible for the increase in the fully saturated columns. This may also be explained by the desorption of previously sorbed estrogenic EDCs. The effect of additional filter materials, such as basalt sediment and coconut fibre, on estrogenic EDC reduction was also tested. None of these amendments provided improvements in estrogen remediation relative to the unamended unsaturated carbonate sand columns. Aerobic carbonate sand filters have good potential to be used as on-site wastewater treatment systems for the reduction of estrogenic EDCs. However, the use of fully saturated sand filters, which are used to promote denitrification, and the loss of nitrogen as N2 were shown to cause an increase in EEQ. The potential for the accumulation of estrogenic EDCs under anaerobic conditions needs to be considered when designing on-site sand filtration systems required to reduce nitrogen. Furthermore, the accumulation of estrogens under anaerobic conditions such as under soil absorption systems or leachate fields has the potential to contaminate groundwater especially when the water table levels fluctuate. PMID- 25804659 TI - The reproductive cycle, condition index, and glycogen reserves of the cockles Cerastoderma glaucum from the Gulf of Gabes (Tunisia). AB - The gametogenic cycle of the Cerastoderma glaucum was analyzed using both qualitative and semi-quantitative methods. The condition index and glycogen concentrations were determined in order to provide information on energy storage. The cockles were collected monthly from a Bayyadha site located 15 km south of Sfax City (Gulf of Gabes) between January 2007 and January 2008. From histological point of view, we applied two approaches: (i) the qualitative method describing the various stages of gamete development for males and females during a cycle of 13 months, and (ii) the semi-quantitative method concerning the estimation of different tissue surfaces. The results showed that there is evidence of three periods of reproduction in this population. A comparison between the surfaces occupied by the three organs showed that the foot and the gonad surfaces are higher than the surface of the adductor muscle. This could suggest that these two organs are more involved in the process of glycogen reserve storage. The results of the glycogen concentrations in the different tissues (gonad, adductor muscle, and "remainders") show that during the second and third periods of reproduction, glycogen was stored in the adductor muscle and in the remainder during sexual rest, and in the gonad during the gametogenesis phases in order to supply the reproductive effort. On the contrary, in the first period of reproduction, the low concentrations of glycogen recorded in the gonad coincided with its high degree of development. This fact could be related to environmental conditions (low temperature and food) recorded during this period. PMID- 25804660 TI - 24-epibrassinolide mitigates the adverse effects of manganese induced toxicity through improved antioxidant system and photosynthetic attributes in Brassica juncea. AB - The objective of this study was to establish relationship between manganese induced toxicity and antioxidant system response in Brassica juncea plants and also to investigate whether brassinosteroids activate antioxidant system to confer tolerance to the plants affected with manganese induced oxidative stress. Brassica juncea plants were administered with 3, 6, or 9 mM manganese at 10-day stage for 3 days. At 31-day stage, the seedlings were sprayed with deionized water (control) or 10(-8) M of 24-epibrassinolide, and plants were harvested at 45-day stage to assess growth, leaf gas-exchange traits, and biochemical parameters. The manganese treatments diminished growth along with photosynthetic attributes and carbonic anhydrase activity in the concentration-dependent manner, whereas it enhanced lipid peroxidation, electrolyte leakage, accumulation of H2O2 as well as proline, and various antioxidant enzymes in the leaves of Brassica juncea which were more pronounced at higher concentrations of manganese. However, the follow-up application of 24-epibrassinolide to the manganese stressed plants improved growth, water relations, and photosynthesis and further enhanced the various antioxidant enzymes viz. catalase, peroxidase, and superoxide dismutase and content of proline. The elevated level of antioxidant enzymes as well as proline could have conferred tolerance to the manganese-stressed plants resulting in improved growth and photosynthetic attributes. PMID- 25804661 TI - Air and seawater pollution and air-sea gas exchange of persistent toxic substances in the Aegean Sea: spatial trends of PAHs, PCBs, OCPs and PBDEs. AB - Near-ground air (26 substances) and surface seawater (55 substances) concentrations of persistent toxic substances (PTS) were determined in July 2012 in a coordinated and coherent way around the Aegean Sea based on passive air (10 sites in 5 areas) and water (4 sites in 2 areas) sampling. The direction of air sea exchange was determined for 18 PTS. Identical samplers were deployed at all sites and were analysed at one laboratory. hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs) as well as dichlorodiphenyltrichloroethane (DDT) and its degradation products are evenly distributed in the air of the whole region. Air concentrations of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and o,p'-DDT and seawater concentrations of p,p'-DDE and p,p'-DDD were elevated in Thermaikos Gulf, northwestern Aegean Sea. The polychlorinated biphenyl (PCB) congener pattern in air is identical throughout the region, while polybrominated diphenylether (PBDE)patterns are obviously dissimilar between Greece and Turkey. Various pollutants, polycyclic aromatic hydrocarbons (PAHs), PCBs, DDE, and penta and hexachlorobenzene are found close to phase equilibrium or net volatilisational (upward flux), similarly at a remote site (on Crete) and in the more polluted Thermaikos Gulf. The results suggest that effective passive air sampling volumes may not be representative across sites when PAHs significantly partitioning to the particulate phase are included. PMID- 25804663 TI - A lagged variable model for characterizing temporally dynamic export of legacy anthropogenic nitrogen from watersheds to rivers. AB - Legacy nitrogen (N) sources originating from anthropogenic N inputs (NANI) may be a major cause of increasing riverine N exports in many regions, despite a significant decline in NANI. However, little quantitative knowledge exists concerning the lag effect of NANI on riverine N export. As a result, the N leaching lag effect is not well represented in most current watershed models. This study developed a lagged variable model (LVM) to address temporally dynamic export of watershed NANI to rivers. Employing a Koyck transformation approach used in economic analyses, the LVM expresses the indefinite number of lag terms from previous years' NANI with a lag term that incorporates the previous year's riverine N flux, enabling us to inversely calibrate model parameters from measurable variables using Bayesian statistics. Applying the LVM to the upper Jiaojiang watershed in eastern China for 1980-2010 indicated that ~97% of riverine export of annual NANI occurred in the current year and succeeding 10 years (~11 years lag time) and ~72% of annual riverine N flux was derived from previous years' NANI. Existing NANI over the 1993-2010 period would have required a 22% reduction to attain the target TN level (1.0 mg N L(-1)), guiding watershed N source controls considering the lag effect. The LVM was developed with parsimony of model structure and parameters (only four parameters in this study); thus, it is easy to develop and apply in other watersheds. The LVM provides a simple and effective tool for quantifying the lag effect of anthropogenic N input on riverine export in support of efficient development and evaluation of watershed N control strategies. PMID- 25804662 TI - A comparison of the sublethal and lethal toxicity of four pesticides in Hyalella azteca and Chironomus dilutus. AB - Laboratory toxicity testing is the primary tool used for surface water environmental risk assessment; however, there are critical information gaps regarding the sublethal effects of pesticides. In 10-day exposures, we assessed the lethal and sublethal (motility and growth) toxicities of four commonly used pesticides, bifenthrin, permethrin, cyfluthrin, and chlorpyrifos, on two freshwater invertebrates, Chironomus dilutus and Hyalella azteca. Pyrethroids were more toxic than the organophosphate chlorpyrifos in both species. Bifenthrin was most toxic to H. azteca survival and growth. Cyfluthrin was most toxic to C. dilutus. However, cyfluthrin had the greatest effect on motility on both H. azteca and C. dilutus. The evaluated concentrations of chlorpyrifos did not affect C. dilutus motility or growth, but significantly impacted H. azteca growth. Motility served as the most sensitive endpoint in assessing sublethal effects at low concentrations for both species, while growth was a good indicator of toxicity for all four pesticides for H. azteca. The integration of sublethal endpoints in ambient water monitoring and pesticide regulation efforts could improve identification of low-level pesticide concentrations that may eventually cause negative effects on food webs and community structure in aquatic environments. PMID- 25804664 TI - Brain dopaminergic system related genetic variability interacts with target/mask timing in metacontrast masking. AB - Dopaminergic system of the brain is believed to be strongly involved in normal and pathological behavioral phenotypes of attention. In metacontrast masking studies attentional effects on metacontrast are predominantly expressed when time intervals between a target stimulus and a masking stimulus are longer rather than shorter. Taken together, this predicts that variability in common genes known to be involved in dopaminergic function could interact with target/mask intervals in determining the effects of metacontrast masking. We tested this by genotyping participants of the masking experiment for the COMT Val158Met, DAT1 3'UTR 40 bp VNTR, and DRD4 exon 3 48b p VNTR variability. We found that Val homozygotes and subjects with long repeat variants of the DRD4 gene showed relatively higher level of correct target perception with a longer target/mask time interval than with a shorter time interval while DAT1 variability did not have any effects. Implications of this result for the development of psychophysical testing based methods of screening for vulnerability/resilience in relation to the pathology of the dopaminergic systems related attentional dysfunction are considered. PMID- 25804665 TI - For richer or poorer? Imageability effects in semantic dementia patients' reading aloud. AB - The degree to which a word's meaning evokes a mental image exerts an influence on performance across a variety of conceptual and linguistic tasks. In normal healthy participants, this effect takes the form of an advantage for high over low imageability words. Consideration of the influence of imageability on performance of patients with semantic dementia can provide information concerning its cognitive and neural bases. Semantic dementia patients show deficits in conceptual processing tasks, and an associated enhancement of the advantage for high over low imageability words. Semantic dementia patients also show deficits in linguistic processing tasks, including reading aloud words with inconsistent spelling-sound correspondences. This study provides the first systematic exploration of the influence of imageability on semantic dementia patients' reading aloud performance. Over 10 cases, the imageability effect seen for inconsistent words was actually reversed in reaction times, with faster performance for low than high imageability items. The same reversal was observed for inconsistent words when the frequency of legitimate alternative reading of components errors was considered, and this reversed effect grew larger with increasing semantic impairment. This result is interpreted in terms of the development of stronger connections along the direct pathway between spelling and sound for low than high imageability items that are then revealed under diminished semantic activation. This interpretation emphasises the interaction between form and meaning that occurs throughout learning in connectionist models. PMID- 25804666 TI - Institutional failure led to Ebola outbreak "spiralling out of control," says MSF. PMID- 25804667 TI - Journal editors must play their part in checking timing of clinical trial registration. PMID- 25804668 TI - Peer support groups, mobile phones and refugee women in Melbourne. AB - In this article, we discuss qualitative findings basing on the experiences of refugee women living in Melbourne, Australia, who participated in a peer support training programme and received a free mobile phone. We pay attention to social support as a health enhancing strategy and empowerment that occurred among the participants. Participation in peer support groups and access to a mobile phone were beneficial for the women. Peer support functioned as social support among group members. The programme allowed the women to be connected to their families and the wider communities and assisted them to access health care and other settlement aspects with greater ease. It also increased personal empowerment among the women. Our programme shows that by tapping on community resources to ameliorate personal or resettlement issues, the burden on service providers can be reduced. Our findings also offer a model for future research and programmes regarding refugee people elsewhere. PMID- 25804669 TI - Biomass-based palm shell activated carbon and palm shell carbon molecular sieve as gas separation adsorbents. AB - Lignocellulosic biomass has been widely recognised as a potential low-cost source for the production of high added value materials and proved to be a good precursor for the production of activated carbons. One of such valuable biomasses used for the production of activated carbons is palm shell. Palm shell (endocarp) is an abundant by-product produced from the palm oil industries throughout tropical countries. Palm shell activated carbon and palm shell carbon molecular sieve has been widely applied in various environmental pollution control technologies, mainly owing to its high adsorption performance, well-developed porosity and low cost, leading to potential applications in gas-phase separation using adsorption processes. This mini-review represents a comprehensive overview of the palm shell activated carbon and palm shell carbon molecular sieve preparation method, physicochemical properties and feasibility of palm shell activated carbon and palm shell carbon molecular sieve in gas separation processes. Some of the limitations are outlined and suggestions for future improvements are pointed out. PMID- 25804670 TI - Toxicology in the Service of Patient and Medication Safety: a Selected Glance at Past and Present Innovations. AB - Medical and medication errors remain definite threats to patients in US health care. Medical toxicologists frequently encounter patients either harmed by or at risk for harm from adverse drug events, including medication errors and inadvertent exposures. An historical perspective, as viewed through the lens of specific disciplines, can be useful to trace systemic responses to safety threats. Early efforts to address anesthesia perioperative risks and recent actions in medicine, surgery, and obstetrics to introduce checklists, communication tools, and systems approaches are reviewed. Patient safety concepts can be utilized and disseminated by toxicologists to improve medication safety and drive innovative approaches to confront patient harm. Various approaches include simulation of high-risk scenarios which might predispose to medication error, assembling multidisciplinary groups of health care providers to review events and implement mitigation strategies, and proactive patient safety rounds in clinical areas to allow frontline staff to voice concerns and introduce solutions for administration, evaluation, and implementation. We review selected lessons from the past and current innovations to achieve safe medication practice. PMID- 25804671 TI - Medications and the Culture of Safety : Conference Title: At the Precipice of Quality Health Care: The Role of the Toxicologist in Enhancing Patient and Medication Safety Venue ACMT Pre-Meeting Symposium, 2014 North American Congress of Clinical Toxicology, New Orleans, LA. AB - Medication mishaps are a common cause of morbidity and mortality both within and outside of hospitals. While the use of a variety of technologies and techniques have promised to improve these statistics, instead of eliminating errors, new ones have appeared as quickly as old ones have been improved. To truly improve safety across the entire enterprise, we must ensure that we create a culture that is willing to accept that errors occur in normal course of operation to the best of people. Focus must not be on punishment and shame, but rather building a fault tolerant system that maintains safety of both staff and patients. PMID- 25804672 TI - Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus. AB - OBJECTIVES: Autoimmune thrombocytopenia (AITP) and hemolytic anemia (AIHA) are common in childhood-onset systemic lupus erythematosus (cSLE) and may be refractory to conventional therapies. Our objectives were to: (a) examine our experience; (b) determine the rate and durability of response to rituximab; and (c) evaluate its safety in our cSLE population with refractory cytopenias. METHODS: We performed a single-center retrospective cohort study of cSLE patients with refractory AITP or AIHA treated with rituximab between 2003 and 2012. Outcomes included the time to complete clinical response, time to B-cell depletion, duration of response and time to flare. Adverse events were also analyzed. RESULTS: Twenty-four (6%) of 394 cSLE patients received rituximab for refractory cytopenia. The indication was AITP in 16 (67%), AIHA in five (21%) and both in three (13%) patients. The median (interquartile range (IQR)) time from cytopenia onset to rituximab therapy was 16 (7-27) months for AITP and 10 (2-29) months for AIHA. Complete response following the first course of rituximab occurred at a median (IQR) of 48 (14-103) days, only one patient failed to respond. Five (21%) patients had one or more flare episodes at 22 (15-27) months. Infusion reactions were rare and one infection with herpes zoster required hospitalization in the first 12 months. Three of four patients with low IgG levels prior to the first rituximab course developed persistent hypogammaglobulinemia, and three patients have required intravenous immunoglobulin replacement. CONCLUSION: Rituximab appears to be a well-tolerated, safe and long-lasting therapy for cSLE patients with refractory AITP and/or AIHA. Caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. PMID- 25804675 TI - University of Minnesota made "serious" ethical errors in trial of antipsychotics, finds report. PMID- 25804673 TI - Monocyte CD64 expression as a novel biomarker for the disease activity of systemic lupus erythematosus. AB - OBJECTIVE: Interferon alpha (IFN-alpha) is a key cytokine associated with systemic lupus erythematosus (SLE). IFN-alpha induces the expression of CD64 on monocytes (mCD64). Although enhanced mCD64 expression has been reported in patients with SLE, it has never been assessed quantitatively. The aim of this study was to investigate whether or not mCD64 expression correlates with SLE disease activity. METHODS: The mCD64 expression levels were assessed quantitatively in 40 patients with active or inactive SLE by using flow cytometry. The mCD64 expression levels were subsequently compared with the SLE disease activity index (SLEDAI) and levels of existing SLE activity biomarkers, such as anti-DNA antibody, complements, and so on. RESULTS: The mCD64 expression was significantly higher in active disease than in inactive disease SLE (median molecules/cell, interquartile range: 34,648, 8174-24,932 and 20,865, 6357-21,503, respectively; p < 0.001). The levels of mCD64 expression strongly correlated with SLEDAI (r = 0.68, p < 0.001). CONCLUSION: The mCD64 expression is a simple and useful biomarker for evaluating disease activity in patients with SLE. PMID- 25804676 TI - Problems with using numbers needed to harm. PMID- 25804674 TI - A data-driven mathematical model of multi-drug resistant Acinetobacter baumannii transmission in an intensive care unit. AB - Major challenges remain when attempting to quantify and evaluate the impacts of contaminated environments and heterogeneity in the cohorting of health care workers (HCWs) on hospital infections. Data on the detection rate of multidrug resistant Acinetobacter baumannii (MRAB) in a Chinese intensive care unit (ICU) were obtained to accurately evaluate the level of environmental contamination and also to simplify existing models. Data-driven mathematical models, including mean field and pair approximation models, were proposed to examine the comprehensive effect of integrated measures including cohorting, increasing nurse-patient ratios and improvement of environmental sanitation on MRAB infection. Our results indicate that for clean environments and with strict cohorting, increasing the nurse-patient ratio results in an initial increase and then a decline in MRAB colonization. In contrast, in contaminated environments, increasing the nurse patient ratio may lead to either a consistent increase or an initial increase followed by a decline of MRAB colonization, depending on the level of environmental contamination and the cohorting rate. For developing more effective control strategies, the findings suggest that increasing the cohorting rate and nurse-patient ratio are effective interventions for relatively clean environments, while cleaning the environment more frequently and increasing hand washing rate are suitable measures in contaminated environments. PMID- 25804677 TI - A ring to rule them all: the effect of cyclopropane Fatty acids on the fluidity of lipid bilayers. AB - Cyclopropane fatty acids are widespread in bacteria. As their concentration increases on exposure to hostile environments, they have been proposed to protect membranes. Here, the effect of cyclopropane and unsaturated fatty acids, both in cis and trans configurations, on the packing, order, and fluidity of lipid bilayers is explored using molecular dynamics simulations. It is shown that cyclopropane fatty acids disrupt lipid packing, favor the occurrence of gauche defects in the chains, and increase the lipid lateral diffusion, suggesting that they enhance fluidity. At the same time, they generally induce a greater degree of order than unsaturated fatty acids of the same configuration and limit the rotation about the bonds surrounding the cyclopropane ring. This indicates that cyclopropane fatty acids may fulfill a dual function: stabilizing membranes against adverse conditions while simultaneously promoting their fluidity. Marked differences in the effect of cis- and trans-monocyclopropanated fatty acids were also observed, suggesting that they may play alternative roles in membranes. PMID- 25804678 TI - Dose-finding study of rivaroxaban in hemodialysis patients. AB - BACKGROUND: Use of vitamin K antagonists for the prevention of stroke and systemic embolism in dialysis patients with nonvalvular atrial fibrillation is controversial. However, no good alternatives presently are available. The anti factor Xa antagonist rivaroxaban is contraindicated for lack of pharmacokinetic, pharmacodynamic, and clinical data. This study aims to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban in maintenance hemodialysis patients. STUDY DESIGN: Pharmacokinetic and pharmacodynamic study. SETTING & PARTICIPANTS: 18 maintenance hemodialysis patients without residual kidney function at 2 centers. DRUG ADMINISTRATION, OUTCOMES, & MEASUREMENTS: (1) A single dose of 10mg of rivaroxaban was administered at the end of each of 3 consecutive dialysis sessions and area under the curve (AUC) and the effect on coagulation parameters were measured for 44 hours thereafter. (2) A single dose of 10mg of rivaroxaban was given 6 to 8 hours before a dialysis session and the effect of dialysis on rivaroxaban concentrations was evaluated. (3) To assess potential accumulation, 10mg of rivaroxaban was given once daily and AUC was measured during 24 hours on days 1 and 7. RESULTS: Mean AUC0-44 of rivaroxaban plasma concentrations after a single dose of 10mg was 2,072MUg/L/h, mean maximum concentration was 172.6MUg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10mg was 20.2MUg/L. LIMITATIONS: Higher rivaroxaban doses and patients with substantial residual kidney function were not studied. CONCLUSIONS: A 10-mg dose of rivaroxaban in hemodialysis patients without residual kidney function results in drug exposure similar as published for 20mg in healthy volunteers. Rivaroxaban is not eliminated by dialysis. There is no accumulation after multiple daily dosing. The efficacy and safety of rivaroxaban in hemodialysis patients should be the subject of a large randomized trial. PMID- 25804679 TI - Serum Phosphorus and Progression of CKD and Mortality: A Meta-analysis of Cohort Studies. AB - BACKGROUND: Recent studies have indicated that phosphorus may play an independent pathogenic role in chronic kidney disease (CKD) progression, but some of those studies were underpowered and yielded inconsistent results. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Non-dialysis-dependent patients with CKD (transplant recipients were excluded). SELECTION CRITERIA FOR STUDIES: Studies assessing the risk ratio of serum phosphorus level on kidney failure and mortality for non-dialysis-dependent patients with CKD published from January 1950 to June 2014 were included following systematic searching of MEDLINE, EMBASE, and the Cochrane Library. PREDICTOR: Serum phosphorus level. OUTCOME: Kidney failure, defined as doubled serum creatinine level, 50% decline in estimated glomerular filtration rate, or end-stage kidney disease. RESULTS: In 12 cohort studies with 25,546 patients, 1,442 (8.8%) developed kidney failure and 3,089 (13.6%) died. Overall, every 1-mg/dL increase in serum phosphorus level was associated independently with increased risk of kidney failure (hazard ratio, 1.36; 95% CI, 1.20-1.55) and mortality (hazard ratio, 1.20; 95% CI, 1.05-1.37). LIMITATIONS: Existence of potential residual confounding could not be excluded. CONCLUSIONS: This meta-analysis suggests an independent association between serum phosphorus level and kidney failure and mortality among non-dialysis-dependent patients with CKD and suggests that large-scale randomized controlled trials should target disordered phosphorus homeostasis in CKD. PMID- 25804680 TI - [Non-invasive mechanical ventilation with a facial interface during sedation for a percutaneous endoscopic gastrostomy in a patient with amyotrophic lateral sclerosis]. AB - Amyotrophic lateral sclerosis is a chronic neurodegenerative disease of the central nervous system which affects the motor neurons and produces a progressive muscle weakness, leading to atrophy and muscle paralysis, and ultimately death. Performing a percutaneous endoscopic gastrostomy with sedation in patients with amyotrophic lateral sclerosis can be a challenge for the anesthesiologist. The case is presented of a 76-year-old patient who suffered from advanced stage amyotrophic lateral sclerosis, ASA III, in which a percutaneous endoscopic gastrostomy was performed with deep sedation, for which non-invasive ventilation was used as a respiratory support to prevent hypoventilation and postoperative respiratory complications. PMID- 25804681 TI - [Anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma: Description of a case and anesthetic implications]. AB - N-methyl-D-aspartate receptor encephalitis is an autoimmune encephalitis relationated or not with a neoplasm. Although its incidence is unknown, probably remains underdiagnosed. Epidemiological studies place it as the second cause of immune-mediated encephalitis and the first in patients aged less of 30 years. It shows neuropsychiatric symptoms and autonomic instability. After diagnosis, based on the detection of antibodies in serum or cerebrospinal fluid, an occult malignancy must be investigated. While increasing number of cases have been diagnosed and the important role of this receptor in general anesthesia mechanisms, the interaction of the disease with anesthetic agents and perioperative stress is unknown. We describe the case of a patient with encephalitis associated to ovarian teratoma that underwent gynaecological laparoscopy. PMID- 25804682 TI - National survey on thromboprophylaxis and anticoagulant or antiplatelet management in neurosurgical and neurocritical patients. AB - OBJECTIVES: To determine the protocols used by Spanish anaesthesiologists for thromboprophylaxis and anticoagulant or antiplatelet drugs management in neurosurgical or neurocritical care patients. MATERIAL AND METHODS: An online survey with 22 questions, with one or multiple options, launched by the Neuroscience Subcommittee of the Spanish Anaesthesia Society and available between June and October 2012. RESULTS: Of the 73 hospitals included in the National Hospitals Catalogue, a valid response to the online questionnaire was received by 41 anaesthesiologists from 37 sites (response rate 50.7%). Only one response per site was used. A specific protocol was available in 27% of these centres. Mechanical thromboprophylaxis is used, intraoperatively or postoperatively, in 80%, and pharmacological treatment is used by 75% of respondents. Enoxaparin was the most frequent heparin used in craniotomy patients (78%). Craniotomies were performed maintaining acetylsalicylic acid treatment in patients with coronary stents and double anti-platelet treatment in a half of the centres. CONCLUSIONS: Mechanical thromboprophylaxis is used more frequently than the pharmacological approach in neurosurgical or neurocritical populations in Spanish hospitals. Management of patients under previous anticoagulant treatment was highly heterogeneous among hospitals included in this survey. Previous antiplatelet treatment is modified depending on primary or secondary prescription. PMID- 25804683 TI - [The responsibility of the anesthesiologist in the patient's perioperative process]. PMID- 25804686 TI - [How to increase the clinical performance of medical students]. PMID- 25804687 TI - [A new direction for basic medical science education]. PMID- 25804684 TI - Biologic adjuvants and bone: current use in orthopedic surgery. AB - Normal bone healing is a complex process that eventually restores original structure and function to the site of trauma. However, clinical circumstances such as nonunion, critical-sized defects, systemic bone disease, and fusion procedures have stimulated a search for ways to enhance this normal healing process. Biologics are an important part of this search and many, including bone marrow aspirate concentrate, demineralized bone matrix, platelet-rich plasma, bone morphogenic proteins, and platelet-derived growth factor, are currently in clinical use. Many others, including mesenchymal stem cells, parathyroid hormone, and Nel-like molecule-1 (NELL-1) will likely be in use in the future depending on the results of preclinical and clinical trials. PMID- 25804685 TI - Inter- and Intrapopulation Variability in the Composition of Larval Defensive Secretions of Willow-Feeding Populations of the Leaf Beetle Chrysomela lapponica. AB - We explored the inter- and intrapopulation variability in the larval defensive chemistry of the leaf beetle Chrysomela lapponica with respect to the salicylic glycoside (SG) content of its host species. Secretions of larvae from three populations associated in nature with SG-poor willows contained nearly twice as many components and 40-fold higher concentrations of autogenously produced isobutyrates and 2-methylbutyrates than secretions of larvae from three populations associated with SG-rich willows, which in turn had 200-fold higher concentrations of host-derived salicylaldehyde. Reciprocal transfer experiments showed that the larvae from populations associated with SG-rich willows did not produce appreciable amounts of butyrates on either SG-rich or SG-poor willows, while populations feeding on several SG-poor willow species retained the ability for efficient sequestration of SGs, along with their ability to produce high amounts of isobutyrates and 2-methylbutyrates. Only the populations associated with SG-poor willows demonstrated among-family variation in the composition of defensive secretion and differential responses of individual families to willows with alternative SG levels, which can be seen as the prerequisites for shifting to novel hosts. These non-specialized populations show a dual defensive strategy, which corresponds to the ancestral state of this species, while populations that fully depend on host-derived toxins (feeding on SG-rich willows) or have lost the ability to produce salicylaldehyde (feeding on birches) are most deviant from the ancestral state. The results indicate that defensive strategies may differ between populations within a species, and suggest that this variation reduces extinction risks and maintains the high ecological diversity and wide distribution of C. lapponica. PMID- 25804688 TI - [Teaching medical humanities through an illness narrative]. AB - There has been growing interest regarding the 'medical humanities' in most medical schools in Korea. Medical humanities is an interdisciplinary field of humanities, social science, and the arts that aims to have a critical or supplementary role in medical education and practice. Thus, diverse educational methods should be applied to achieve the goals of medical humanities. The illness narrative is one of the most powerful tools in this context. An illness narrative is a patient's story about his illness, including the meaning of the illness in his life. The illness narrative is widely accepted as an effective educational tool in medical humanities. But, in Korea, there has been concern about the nature, theoretical background, and usefulness of the illness narrative. Medical students and doctors can obtain empathy and clinical wisdom through telling, hearing, reading, and writing illness narratives. In this article, I will examine the nature and meaning of illness narratives in teaching medical humanities and discuss several examples of narrative training programs. PMID- 25804689 TI - [Development of the scale of strategies for enhancing self-esteem among medical school students]. AB - PURPOSE: From the point of view that medical students are under the pressure of academic achievement and vulnerable to subjective distress, there is need for evaluate their strategies for enhancing self-esteem when they failed academically. This study was to develop the scale for enhancing self-esteem and to confirm the convergent, discriminant and criteria validity. METHODS: Data were collected from 279 students at a medical school in Seoul. The scale of strategies for enhancing self-esteem (SSES) comprised comparison with inferior, doubting academic failure, accepting failure, and attribution to incidental factors. Also, to confirm the validities, participants responded to items measuring self-esteem, narcissism, 5 personality factors, depression and adjustment. RESULTS: By explanatory factor analysis of SSES, composed of three factors-comparison, doubting, and acceptance-and in the confirmatory factor analysis, 3 dimensions were best fit. Notably, comparison and doubting strategies were positively associated with depression and negatively associated with adjustment. In contrast, acceptance strategies were negatively associated with depression and positively associated with adjustment. Additionally, comparison and doubting strategies were positively associated with narcissism. CONCLUSION: The SSES of medical school students after academic failure yields 3 dimensions reliably and consistently. Also, it shows satisfactory convergent and concurrent validities. PMID- 25804690 TI - [Predictors and longitudinal changes of depression and anxiety among medical college students]. AB - PURPOSE: This longitudinal study was designed to examine the change in depression and anxiety and their predictors over 1 year among premedical and medical students. We compared depression and anxiety from 2 waves and determined the predictive power of personality, narcissism, social comparison, and social reward value on them. METHODS: Two hundred twenty-six students at a medical school in Seoul were divided into 4 groups according to academic year and completed a questionnaire at the end of 2010 and 2011. The questionnaire included the Zung Depression Scale; Zung Anxiety Scale; scales for social comparison, narcissism, and social reward value; and Neuroticism-Extraversion-Openness Personality Inventory. RESULTS: Among first- and second-year medical students, depression and anxiety increased significantly over the previous year. However, irrespective of academic year, depression increased significantly after 1 year. Also, social reward value had a moderating effect. Specifically, among students with low social reward value who entered their first year of medical school, the negative impact of the tendency toward depression and anxiety was amplified compared with older students. CONCLUSION: Because the predictors of mental health differ between groups, each group must receive specific, appropriate education. Also, because social reward value is important moderating factor of mental health, education and intervention programs that focus on social reward value are needed. PMID- 25804691 TI - [Students' perceptions of team-based learning by individual characteristics in a medical school]. AB - PURPOSE: The purpose of this study was to examine medical students' perceptions of team-based learning (TBL) according to their individual characteristics: gender, team efficacy, interpersonal understanding, proactivity in problem solving, and academic ability. METHODS: Thirty-eight second-year medical students who took an integrated cardiology course participated in this study; 28 were male and 10 were female. A questionnaire on individual characteristics and a questionnaire on the perception of TBL were administered, and the scores of individual characteristics were grouped into three: high, middle, and low. The data were analyzed by t-test, analysis of variance, and multiple regression analysis. RESULTS: The TBL efficacy perception scale consisted of 3 factors: team skill, learning ability, and team learning. The group of male students and the group of students with high academic ability recognized the effect of TBL on improvements in learning ability more than females and those with low academic ability. The group of students with high team efficacy reported that TBL was effective with regard to team skill improvement. The group of students with high scores on interpersonal understanding and high proactive problem solving tended to perceive the TBL's effect on team skill improvement. Team efficacy and proactivity in problem solving had a positive effect on the perception of TBL. CONCLUSION: Medical students' perceptions of the effectiveness of TBL differ according to individual characteristics. The results of this study suggest that these individual characteristics should be considered in planning of team learning, such as TBL, to have a positive impact and stronger effects. PMID- 25804692 TI - Clinical-performance remediation program for dyscompetent medical students. AB - PURPOSE: Medical schools endeavor to ensure that students are competent with regard to clinical skills. Skills remediation is implemented in cases of poor clinical performance examination (CPX) grades, although little is known about the effectiveness of such techniques. In this study, we examined the effectiveness of a remediation program that was designed to improve the clinical performance of medical students. METHODS: A 6-week remediation program, administered jointly by Seoul National University College of Medicine's Departments of Internal Medicine (IM) and Family Medicine (FM), was initiated. The program was divided into 2 parts: 3 weeks each of IM classes that were run by specialists in various fields and FM classes that were conducted by a chief resident. Twenty-three students were required to undergo remediation after posting poor scores on 2 sessions of a CPX. On completion of the remediation program, the students' clinical performance was re-evaluated, and the changes in clinical performance scores were analyzed. RESULTS: After the remediation program, the students' total scores and scores on history taking, physical examination, physician's manner, and physician-patient interaction improved significantly. However, patient education did not improve. Most students found the remediation program to be instructive and helpful in preparation for the CPX. They were more satisfied with the chief resident's serial tutoring than with specialists' tutoring sessions. CONCLUSION: The remediation program improves clinical performance. Continued development and implementation of this program will help failing students be competent physicians. PMID- 25804693 TI - [Equating scores using bridging stations on the clinical performance examination]. AB - PURPOSE: This study examined the use of the Tucker linear equating method in producing an individual student's score in 3 groups with bridging stations over 3 consecutive days of the clinical performance examination (CPX) and compared the differences in scoring patterns by bridging number. METHODS: Data were drawn from 88 examinees from 3 different CPX groups-DAY1, DAY2, and DAY3-each of which comprised of 6 stations. Each group had 3 common stations, and each group had 2 or 3 stations that differed from other groups. DAY1 and DAY3 were equated to DAY2. Equated mean scores and standard deviations were compared with the originals. DAY1 and DAY3 were equated again, and the differences in scores (equated score-raw score) were compared between the 3 sets of equated scores. RESULTS: By equating to DAY2, DAY1 decreased in mean score from 58.188 to 56.549 and in standard deviation from 4.991 to 5.046, and DAY3 fell in mean score from 58.351 to 58.057 and in standard deviation from 5.546 to 5.856, which demonstrates that the scores of examinees in DAY1 and DAY2 were accentuated after use of the equation. The patterns in score differences between the equated sets to DAY1, DAY2, and DAY3 yielded information on the soundness of the equating results from individual and overall comparisons. CONCLUSION: To generate equated scores between 3 groups on 3 consecutive days of the CPX, we applied the Tucker linear equating method. We also present a method of equating reciprocal days to the anchoring day as much as bridging stations. PMID- 25804694 TI - [Patient-centeredness of medical students during a real patient encounter and a standardized patient encounter on the clinical performance examination]. AB - PURPOSE: Patient-centered care is one of the most important factors of high quality medical care. Medical educators have been increasingly interested in education for patient-centered care. This study was conducted to guide such education by assessing the patient-centeredness of medical students in a real patient encounter and a standardized patient encounter on the clinical performance examination (CPX). METHODS: During the first semester of 2010 and 2011, fourth-year medical students in a clinical clerkship interviewed outpatients who visited the Department of Family Medicine. The interviews were videotaped, 25 of which were selected for study. We searched the 25 students' CPX videotapes that were recorded in the same year for comparison. The patient centeredness of the students was assessed by measure of patient-centered communication (MPCC). RESULTS: The inter-rater reliability of the MPCC was 0.89 when measuring real patient encounters. MPCC scores of 25 students were very low for both real patients (mean, 28.8; range, 8.2~53.1) and for standardized patients (mean, 27.5; range, 8.2~52.7), and there was no significant difference between two groups. The component 1 MPCC scores were significantly higher for real patient encounters compared with those of CPX encounters (0.28 vs 0.18, p=0.0001). The component 2, 3 MPCC scores of two groups were not different each other. CONCLUSION: Medical educators must emphasize the importance of exploring a patient's illness and social background and involving them in making a diagnosis and treatment plan for patient-centered care. They should give students more opportunities to interview real patients and diversify scenarios for standardized patients. PMID- 25804695 TI - [Differences in attitude toward patient-centeredness in patients and physicians]. AB - PURPOSE: There have been studies on the patient-centeredness of medical students and physicians in South Korea, but no result has presented the patient-centered attitude of patients and doctors. So, this study intended to compare the attitudes of patients and doctors toward the roles that patients and physicians should play in the health care process. METHODS: One hundred and fifteen doctors and 264 patients participated in this survey using a structured questionnaire, including sociodemographic data and Patient Practitioner Orientation Scale (PPOS). The PPOS comprises sharing (sharing information, take part in decision making) and caring (respecting one's feelings, interpersonal relationships) subscales. RESULTS: The PPOS scores of the doctors and patient were 3.02 and 3.20. In detail, the doctors' sharing and caring scores were and 3.02 and 3.48, and the those of patients were 3.14 and 3.12, respectively. This results are enough to demonstrate that patients are likely to be patient-centered with regard to sharing and that doctors tend to be patient-centered in terms of caring. CONCLUSION: The patients' desire to obtain medical information and take part in decision making (sharing) are greater than those of doctors. Doctors had more patient-centered attitude than patients in terms of respects for one's feelings and interpersonal relationships (caring). PMID- 25804696 TI - [How to get students actively involved in course development: an experience in developing and implementing a mentoring program for medical students]. AB - PURPOSE: This study aims to explore development of a student-centered mentoring program and assess satisfaction about the course in order to improve system of the course on the basis of our implementation experience. METHODS: The course was designed for 58 third-year medical students in 2012. A student council acted as the core management team. We evaluate assessment about the course with a 50-item questionnaire administered on a 5-point Likert scale using SPSS version 20.0, and a short-answer form asked students, faculty, and lecturers for their opinions on the course. RESULTS: Students felt that 'Attitude on health care policies (28.6%)' was the most useful lecture. The 'Meeting with a patient' session was useful for developing students' abilities to empathize and communicate with other people (81.1%). The 50.9% of students were very satisfied with the course, as well as with the form of the course (49.2%). CONCLUSION: A bold action that medical educators can take is to get students involved from the outset of the curriculum development. Allowing students to become actively involved in developing the program is an effective means of hearing them and providing a more meaningful learning experience. PMID- 25804699 TI - Computational modelling of the scaffold-free chondrocyte regeneration: a two-way coupling between the cell growth and local fluid flow and nutrient concentration. AB - The in vitro chondrocyte cell culture process in a perfusion bioreactor provides enhanced nutrient supply as well as the flow-induced shear stress that may have a positive influence on the cell growth. Mathematical and computational modelling of such a culture process, by solving the coupled flow, mass transfer and cell growth equations simultaneously, can provide important insight into the biomechanical environment of a bioreactor and the related cell growth process. To do this, a two-way coupling between the local flow field and cell growth is required. Notably, most of the computational and mathematical models to date have not taken into account the influence of the cell growth on the local flow field and nutrient concentration. The present research aimed at developing a mathematical model and performing a numerical simulation using the lattice Boltzmann method to predict the chondrocyte cell growth without a scaffold on a flat plate placed inside a perfusion bioreactor. The model considers the two-way coupling between the cell growth and local flow field, and the simulation has been performed for 174 culture days. To incorporate the cell growth into the model, a control-volume-based surface growth modelling approach has been adopted. The simulation results show the variation of local fluid velocity, shear stress and concentration distribution during the culture period due to the growth of the cell phase and also illustrate that the shear stress can increase the cell volume fraction to a certain extent. PMID- 25804700 TI - CT virtual endoscopy for analyzing variations in the hepatic portal vein. AB - PURPOSE: To evaluate the value of CT virtual endoscopy (CTVE) for accurately distinguishing varying types of portal veins (PVs). MATERIALS AND METHODS: From 526 consecutive patients whose hepatic portal vein was well visualized, patients who were considered to have trifurcation of the main portal vein (MPV) or right portal vein (RPV) on volume rendering (VR) and maximum intensity projection (MIP) imaging were chosen for the analysis. Two radiologists evaluated the PV anatomy of these patients and re-classified the types of PV variation using the CTVE technique. The Wilcoxon rank sum test was used to calculate differences in age between males and females. RESULTS: Thirty-two patients (20 males, 12 females; age range 21-68 years; mean age 43 years) were considered to have trifurcation of the MPV (15) or RPV (17) on VR and MIP imaging. Fifteen patients in total had a trifurcation confirmed by CTVE (6 patients were proven to have an MPV trifurcation by CTVE, and 9 were confirmed to have a RPV trifurcation). CONCLUSIONS: CTVE can differentiate PV variations that cannot be identified accurately on MIP and VR. PMID- 25804701 TI - Anatomic basis of the distally based venocutaneous flap on the medial plantar artery of the hallux with medial plantar vein and nutrient vessels: a cadaveric dissection. AB - PURPOSE: This study aims to identify a repair procedure for ulcers or defect of the forefoot region. The general distribution and variation of the vascular anatomy of the distally based venocutaneous flap on the medial plantar artery of the hallux with medial plantar vein and nutrient vessels were investigated. This study especially focused on the vascularization of the medial side of the foot and the determination of the contribution of the nutrient vessels of medial plantar vein and medial dorsal cutaneous nerve to flap viability. Experiments were conducted to obtain information for operating procedures and to understand the vascular reliability of the flap. METHODS: Thirty cadavers were available for this anatomical study after arterial injection. The tuberosity of the fifth metatarsal bone was adopted as the anatomical landmark. Microdissection was conducted under a microscope, and details of the course and distribution of the medial plantar vein and the communication of the medial plantar artery of the hallux with the fascial vascular network surrounding the medial plantar vein were recorded. The flap-raising procedure was performed in a fresh cadaver specimen. RESULTS: The medial plantar vein was incorporated by the medial end of the dorsal pedal vein arch and medial dorsal vein of the hallux around the first metatarsal medial cuneiform joint. It traveled along the medial margin of the foot and drained into the great saphenous vein at the level of the medial malleolar. The outer diameter of the nerve at the intermalleolar line was 3.2 +/- 0.5 mm. These nutrifying arteries to the medial plantar vein were present segmentally and mainly came from the medial plantar artery of the hallux, which traveled forward in the fascia between the abductor hallucis tendon and the first metatarsal bone, emerged into the superficial layer 2.2 +/- 0.7 cm proximal to the first metatarsophalangeal joint, and gave off many minute branches. These branches communicated with the fascial vascular network surrounding the medial plantar vein, supplying the fascia and integument of the medial foot. CONCLUSION: Reliable venocutaneous flap with medial plantar vein and nutrient vessel flaps can be raised based solely on the perforator of the medial plantar artery of the hallux. This flap should be considered as a preferential way to reconstruct soft tissue defects of the forefoot. PMID- 25804703 TI - Electromers of the benzene dimer radical cation. AB - The well-studied benzene dimer radical cation, which is prototypical for this class of species, has been reinvestigated computationally. Thereby it turned out that both the sigma-hemibonded and the half-shifted sandwich structures of the benzene dimer cation, which had been independently proposed, represent stationary points on the B2PLYP-D potential energy surfaces. However, these structures belong to distinct electronic states, both of which are associated with potential surfaces that are very flat with regard to rotation of the two benzene rings in an opposite sense relative to each other. The surfaces of these two "electromers" of the benzene dimer cation are separated by only 3-4 kcal mol(-1) and do not intersect along the rotation coordinate, which represents a rather unique electronic structure situation. When moving on either of the two surfaces the title complex is an extremely fluxional species, in spite of its being bound by over 20 kcal mol(-1). PMID- 25804702 TI - Inhibitory effect of the branches of Hovenia dulcis Thunb. and its constituent pinosylvin on the activities of IgE-mediated mast cells and passive cutaneous anaphylaxis in mice. AB - Hovenia dulcis Thunb. (Rhamnaceae) is a hardy tree native to Europe, the Middle East, and North Africa, and it is also grown in parts of Asia and has been used in traditional medicine to treat liver toxicity, stomach disorders, and inflammation. This study investigated the anti-allergy potential of an extract of the branches of H. dulcis (HDB) using the antigen-stimulated mast cell-like cell line rat basophilic leukemia (RBL)-2H3 and a passive cutaneous anaphylaxis (PCA) mouse model. Degranulation assay, reverse transcription PCR, enzyme-lined immunosorbent assays, western blot analyses, and PCA were performed to measure allergic responses and proinflammatory mediators in antigen-stimulated rat basophilic leukemia (RBL)-2H3 mast cells and the PCA mouse model. In antigen stimulated RBL-2H3 cells, HDB inhibited the secretion of beta-hexosaminidase (indicating the inhibition of degranulation) and histamine release; decreased expression and production of the inflammatory mediators, cyclooxygenase-2 and prostaglandin E2, and cytokines interleukin-4 and tumor necrosis factor-alpha; and suppressed activation of nuclear factor kappaB, a transcription factor involved in the response to cytokines. HDB attenuated phosphorylation of the mast cell downstream effectors Lyn, Syk, phospholipase Cgamma, protein kinase CMU, extracellular signal-regulated kinase and p38. In IgE-sensitized mice, HDB inhibited mast cell-dependent PCA. Furthermore, HDB contained pinosylvin and possessed significant anti-allergic activities. These results suggest that HDB would be of value in the prevention and treatment of allergic diseases. PMID- 25804704 TI - Consciousness as a graded and an all-or-none phenomenon: A conceptual analysis. AB - The issue whether consciousness is a graded or an all-or-none phenomenon has been and continues to be a debate. Both contradictory accounts are supported by solid evidence. Starting from a level of processing framework allowing for states of partial awareness, here we further elaborate our view that visual experience, as it is most often investigated in the literature, is both graded and all-or-none. Low-level visual experience is graded, whereas high-level visual experience is all-or-none. We then present a conceptual analysis starting from the notion that consciousness is a general concept. We specify a number of different subconcepts present in the literature on consciousness, and outline how each of them may be seen as either graded, all-or-none, or both. We argue that such specifications are necessary to lead to a detailed and integrated understanding of how consciousness should be conceived of as graded and all-or-none. PMID- 25804705 TI - Placebo use in vaccine trials: Caution when using active vaccines as placebo. PMID- 25804706 TI - Bacterial phospholipases C as vaccine candidate antigens against cystic fibrosis respiratory pathogens: the Mycobacterium abscessus model. AB - BACKGROUND: Vaccine strategies represent one of the fighting answers against multiresistant bacteria in a number of clinical settings like cystic fibrosis (CF). Mycobacterium abscessus, an emerging CF pathogen, raises difficult therapeutic problems due to its intrinsic antibiotic multiresistance. METHODS: By reverse vaccinology, we identified M. abscessus phospholipase C (MA-PLC) as a potential vaccine target. We deciphered here the protective response generated by vaccination with plasmid DNA encoding the MA-PLC formulated with a tetra functional block copolymer 704, in CF (DeltaF508) mice. Protection was tested against aerosolized smooth and rough (hypervirulent) variants of M. abscessus. RESULTS: MA-PLC DNA vaccination (days 0, 21, 42) elicited a strong antibody response. A significant protective effect was obtained against aerosolized M. abscessus (S variant) in DeltaF508 mice, but not in wild-type FVB littermates; similar results were observed when: (i) challenging mice with the "hypervirulent" R variant, and; (ii) immunizing mice with purified MA-PLC protein. High IgG titers against MA-PLC protein were measured in CF patients with M. abscessus infection; interestingly, significant titers were also detected in CF patients positive for Pseudomonas aeruginosa versus P. aeruginosa-negative controls. CONCLUSIONS: MA-PLC DNA- and PLC protein-vaccinated mice cleared more rapidly M. abscessus than beta-galactosidase DNA- or PBS- vaccinated mice in the context of CF. PLCs could constitute interesting vaccine targets against common PLC producing CF pathogens like P. aeruginosa. PMID- 25804708 TI - The podiatrist as a member of the sports medicine team. AB - This article reviews the history of sports medicine highlighting the "jogging boom" of the 1970s and the advocacy of Dr George Sheehan, which boosted the position of podiatry in sports medicine. Significant events in mainstream sports medicine that promoted the rise of podiatric medicine are discussed. Reasons as to why podiatric medicine should be a member of the sports medicine team are outlined, and lastly, examples that highlight podiatric medicine as participants alongside other specialties in the evaluation and care of athletes are given. PMID- 25804707 TI - Vaccination-challenge studies with a Port Chalmers/73 (H3N2)-based swine influenza virus vaccine: Reflections on vaccine strain updates and on the vaccine potency test. AB - The human A/Port Chalmers/1/73 (H3N2) influenza virus strain, the supposed ancestor of European H3N2 swine influenza viruses (SIVs), was used in most commercial SIV vaccines in Europe until recently. If manufacturers want to update vaccine strains, they have to perform laborious intratracheal (IT) challenge experiments and demonstrate reduced virus titres in the lungs of vaccinated pigs. We aimed to examine (a) the ability of a Port Chalmers/73-based commercial vaccine to induce cross-protection against a contemporary European H3N2 SIV and serologic cross-reaction against H3N2 SIVs from Europe and North America and (b) the validity of intranasal (IN) challenge and virus titrations of nasal swabs as alternatives for IT challenge and titrations of lung tissue in vaccine potency tests. Pigs were vaccinated with Suvaxyn Flu((r)) and challenged by the IT or IN route with sw/Gent/172/08. Post-vaccination sera were examined in haemagglutination-inhibition assays against vaccine and challenge strains and additional H3N2 SIVs from Europe and North America, including an H3N2 variant virus. Tissues of the respiratory tract and nasal swabs were collected 3 days post challenge (DPCh) and from 0-7 DPCh, respectively, and examined by virus titration. Two vaccinations consistently induced cross-reactive antibodies against European H3N2 SIVs from 1998-2012, but minimal or undetectable antibody titres against North American viruses. Challenge virus titres in the lungs, trachea and nasal mucosa of the vaccinated pigs were significantly reduced after both IT and IN challenge. Yet the reduction of virus titres and nasal shedding was greater after IT challenge. The Port Chalmers/73-based vaccine still offered protection against a European H3N2 SIV isolated 35 years later and with only 86.9% amino acid homology in its HA1, but it is unlikely to protect against H3N2 SIVs that are endemic in North America. We use our data to reflect on vaccine strain updates and on the vaccine potency test. PMID- 25804709 TI - Two emerging technologies for Achilles tendinopathy and plantar fasciopathy. AB - Some common overuse injuries, such as Achilles tendinopathy and plantar fasciitis (or fasciopathy), can be refractory to treatment. When standard treatment options fail, operative intervention often becomes the treatment of last resort. Recently, newer technologies have been developed and refined, and can provide potential benefits for these conditions using noninvasive and minimally invasive approaches. Two technologies, extracorporeal shock wave therapy and ultrasound guided percutaneous tenotomy/fasciotomy are discussed. PMID- 25804710 TI - Return to play after an ankle sprain: guidelines for the podiatric physician. AB - The ankle sprain is the most common injury in sport and has a high incidence of long-term disability. This disability may be partly due to early return to sport before ligament healing has been completed. The podiatric physician can follow sound guidelines for making a return-to-play decision for athletes suffering from an ankle sprain. The decision-making process requires the podiatric physician to monitor the rehabilitation process and then administer patient self-reported questionnaires as well as functional performance tests to assess the status of ankle function after injury. PMID- 25804711 TI - Dynamic techniques for clinical assessment of the athlete. AB - Clinical diagnostic tests objectively evaluate lower extremity ailments of the athlete. The positive squeeze test is found to be reproducible for ankle syndesmotic injury but is a poor prognosticator. The anterior drawer and talar tilt tests assess lateral ankle sprains. These have limitations secondary to positioning and guarding by the athlete, so comparison with the asymptomatic extremity is recommended. The Ottawa ankle rules assess possible fractures of the ankle and midfoot. The Thompson test evaluates Achilles tendon tears, whereas the windlass technique and the modified Lachman test examine the integrity of the plantar fascia and metatarsophalangeal joint capsule. PMID- 25804712 TI - Acute forefoot and midfoot injuries. AB - Forefoot and midfoot injuries in the athlete are common. Injuries of the digits include subungual hematomas and fractures. Metatarsal fractures occur frequently in sports, and their treatments range greatly. Hyperflexion and extension injuries about the first metatarsophalangeal joint can be very debilitating. Midfoot sprains and fractures require a high index of suspicion for diagnosis. PMID- 25804713 TI - Overuse lower extremity injuries in sports. AB - When athletes train harder the risk of injury increases, and there are several common overuse injuries to the lower extremity. Three of the most common lower extremity overuse injuries in sports are discussed including the diagnosis and treatments: medial tibal stress syndrome, iliotibial band syndrome, and stress fractures. The charge of sports medicine professionals is to identify and treat the cause of the injuries and not just treat the symptoms. Symptomatology is an excellent guide to healing and often the patient leads the physician to the proper diagnosis through an investigation of the athlete's training program, past injury history, dietary habits, choice of footwear, and training surface. PMID- 25804714 TI - Considerations in treating physically active older adults and aging athletes. AB - Life spans are increasing and research is showing more and more how important exercise is to successful aging. Medical practitioners need to appreciate the physiologic and physical changes that occur with age, as well as the significant benefits of physical activity, so they not only can properly treat their older patients but also so they can promote the benefits of exercise to their sedentary older patients. PMID- 25804715 TI - Principles of rehabilitation and return to sports following injury. AB - Rehabilitation of an athlete can present its own challenges. Few protocols are available to guide physicians in proper return to sport. Rehabilitation after foot and ankle sport injury can be categorized into 3 different stages but should also be individualized. The focus of this article is to help the treating physician in creating a protocol to safely return an injured athlete back to sport based on current literature and principles. PMID- 25804716 TI - Sports related foot and ankle injuries. PMID- 25804717 TI - Sports related foot and ankle injuries. PMID- 25804718 TI - Effect of 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modification on activity of gapmer antisense oligonucleotides containing 2',4'-constrained 2'-O-ethyl nucleic acid. AB - We evaluated the effect of combining 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE), a 2'-cationic modification, with a 2',4'-constrained 2'-O-ethyl nucleic acid (cEt BNA) on the activity of an antisense oligonucleotide (ASO) using PTEN as a model target. Our results suggest that replacing one cEt BNA nucleotide with 2'-O-DMAEOE nucleotide at the 5'-end of a 2-10-2 gapmer ASO maintained the potency relative to parent ASO in liver. The cationic 2'-O-DMAEOE modification did not improve the activity of ASO in extra-hepatic tissues. Results from this study provide guidance to design improved antisense oligonucleotide drugs. PMID- 25804719 TI - Synthesis and biological evaluation of C-13' substituted 7'-homo anhydrovinblastine derivatives. AB - Recent publications highlighted that vinca derivatives either functionalized on C 12' or enlarged on cycle C' could be more cytotoxic than vinblastine or vinorelbine, both used in anti-cancer therapy. By combining these two results, nine new 7'-homo-anhydrovinblastine derivatives functionalized on C-13' were elaborated. The synthesis of key intermediates, their one-step transformation into final products in mild conditions and their biological activities are presented. PMID- 25804721 TI - Cloning, characterization and anion inhibition studies of a gamma-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune. AB - We report the cloning and catalytic activity of a gamma-carbonic anhydrase (CA, EC 4.2.1.1) isolated from the Antarctic cyanobacterium Nostoc commune, NcoCA. The enzyme has a significant catalytic activity for the physiologic reaction, CO2 hydration to bicarbonate and protons, with a k(cat) of 9.5*10(5) s(-1) and a k(cat)/K(m) of 8.3*10(7) M(-1) * s(-1), being the most catalytically efficient gamma-CA investigated so far. An anion inhibition study of NcoCA with inorganic/organic anions is also reported here. Fluoride, sulfate, perchlorate and tetrafluoroborate did not inhibit appreciably NcoCA, whereas the other halides, pseudohalides, bicarbonate, nitrate, nitrite and many complex inorganic anions showed inhibition in the millimolar range. The best NcoCA inhibitors detected so far were diethyldithiocarbamate (K(I) of 0.80 mM) as well as sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid (K(I)s in the range of 70-90 MUM). Since gamma-CAs are present in carboxysomes, being involved in photosynthesis, this study may be relevant for a better understanding of such processes in some Antarctic organisms. PMID- 25804720 TI - Identification and characterization of beta-sitosterol target proteins. AB - beta-Sitosterol is the most abundant plant sterol in the human diet. It is also the major component of several traditional medicines, including saw palmetto and devil's claw. Although beta-sitosterol is effective against enlarged prostate in human clinical trials and has anti-cancer and anti-inflammatory activities, the mechanisms of action are poorly understood. Here, we report the identification of two new binding proteins for beta-sitosterol that may underlie its beneficial effects. PMID- 25804722 TI - A multilevel approach to network meta-analysis within a frequentist framework. AB - Meta-analysis is a powerful tool to summarize knowledge. Pairwise or network meta analysis may be carried out with multivariate models that account for the dependence between treatment estimates and quantify the correlation across studies. From a different perspective, meta-analysis may be viewed as a special case of multilevel analysis having a hierarchical data structure. Hence, we introduce an alternative frequentist approach, called multilevel network meta analysis, which also allows to account for publication bias and the presence of inconsistency. We propose our approach for a three-level data structure set-up: arms within studies at the first level, studies within study designs at the second level and design configuration at the third level. This strategy differs from the traditional frequentist modeling because it works directly on an arm based data structure. An advantage of using multilevel analysis is its flexibility, since it naturally allows to add further levels to the model and to accommodate for multiple outcome variables. Moreover, multilevel modeling may be carried out with widely available statistical programs. Finally, we compare the results from our approach with those from a Bayesian network meta-analysis on a binary endpoint which examines the effect on mortality of some anesthetics at the longest follow-up available. In addition, we compare results from the Bayesian and multilevel network meta-analysis approaches on a publicly available "Thrombolytic drugs" database. We also provide the reader with a blueprint of SAS codes for fitting the proposed models, although our approach does not rely on any specific software. PMID- 25804723 TI - Prediction of a stable associated liquid of short amyloidogenic peptides. AB - Amyloid fibril formation is believed to be a nucleation-controlled process. Depending on the nature of peptide sequence, fibril nucleation can occur in one step, straight from a dilute solution, or in multiple steps via oligomers or disordered aggregates. What determines this process is poorly understood. Since the fibril formation kinetics is driven by thermodynamic forces, knowledge of the phase behavior is crucial. Here, we investigated the phase behavior of three short peptide sequences of varying side-chain hydrophobicity. Replica exchange molecular dynamics simulations of a mid-resolution model indicate that the weakly hydrophobic peptide forms fibrils directly from solution, whereas the most hydrophobic peptide forms a dense liquid phase before crystallizing into ordered fibrils at low temperatures. For the medium hydrophobic peptide we found evidence of a novel additional transition to a liquid phase consisting of clusters of aligned peptides, implying a three-step nucleation process. We tested the robustness of this prediction by applying Wertheim's theory and statistical associating fluid theory to a hard-sphere model dressed with isotropic and anisotropic attractions. We found that the ratio of interaction strengths strongly affects the phase behavior, and under certain conditions indeed gives rise to a stable polymerized liquid phase. The peptide clusters in the associated liquid tend to be slow and long-lived, which may give the oligomer droplet more time to act as a toxic oligomer, before turning into a fibril. PMID- 25804724 TI - Severe adverse reactions associated with quetiapine. PMID- 25804725 TI - Allele frequencies of 23 autosomal short tandem repeat loci in the Philippine population. AB - We characterized diversity and forensic descriptive parameters of 23 autosomal STR loci (CSF1PO, D13S317, D16S539, D5S818, D7S820, TPOX, D18S51, D21S11, D3S1358, D8S1179, FGA, TH01, vWA, D1S1656, D10S1248, D12S391, D2S441, D22S1045, D19S433, D2S1338, D6S1043, Penta D and Penta E) among 167 unrelated Filipinos. The most variable autosomal STR loci observed is Penta E (observed heterozygosity: 0.9222, match probability: 0.0167). Results reveal matching probability of 8.21*10(-28) for 23 autosomal STR loci. This dataset for the Philippine population may now be used in evaluating the weight of DNA evidence for forensic applications such as in human identification, parentage/kinship testing, and interpretation of DNA mixtures. PMID- 25804727 TI - [New AWMF S3-guidelines for volume therapy: goodbye emotions - welcome evidence]. PMID- 25804728 TI - A review of the nest protection hypothesis: does inclusion of fresh green plant material in birds' nests reduce parasite infestation? AB - The use of aromatic plants and their essential oils for ectoparasite treatment is a field of growing interest. Several species of birds regularly introduce aromatic herbs into their nests putatively to reduce parasites. The behaviour is most often seen in cavity nesting birds and after nest building has finished. The plants are included in a non-structural manner and are often strongly aromatic. Various different hypotheses have been proposed regarding the function of this behaviour; from the plants altering some non-living factor in the nest (crypsis, water loss and insulation hypotheses) to them being involved in mate selection (mate hypothesis) or even having a beneficial effect, direct or indirect, on chicks (drug or nest protection hypothesis, NPH). Many studies have been carried out over the years observing and experimentally testing these hypotheses. This review focuses on studies involving the most popular of these hypotheses, the NPH: that plants decrease nest parasites or pathogens, thereby conveying positive effects to the chicks, allowing the behaviour to evolve. Studies providing observational evidence towards this hypothesis and those experimentally testing it are discussed. PMID- 25804726 TI - [Catecholamines: pro and contra]. AB - BACKGROUND: Catecholamines with vasopressor and inotropic effects are commonly used in intensive care medicine. The aim of this review is to explain some of the physiologic actions on which a catecholamine therapy is based, but also to elucidate the risks which are associated with an uncritical and excessive use of these drugs. SIDE EFFECTS: Emphasis is placed on the myocardial damage triggered by adrenergic overstimulation. There is considerable evidence that in conditions of severe heart failure, myocardial ischemia as well as cardiogenic and septic shock especially the use of catecholamines with predominant beta-adrenergic effects (epinephrine, dobutamine, dopamine) can have a negative clinical impact. A simple cardiac risk marker might be a tachycardia. ADMINISTRATION: Vasopressor therapy with norepinephrine, based on individually applied perfusion parameters (e.g., urine output, lactate), however, seems justified in many conditions of shock and hemodynamic instability during deep analgosedation. In terms of a cardioprotective therapy, the administration of catecholamines, however, should always be reevaluated and titrated to the minimum deemed necessary. PMID- 25804730 TI - Erratum to: online determination of polycyclic aromatic hydrocarbon formation from a flame soot generator. PMID- 25804731 TI - Development of an enzyme-linked-immunosorbent-assay technique for accurate identification of poorly preserved silks unearthed in ancient tombs. AB - We report the preparation of a specific fibroin antibody and its use for the identification of unearthed ancient silk relics. Based on the 12-amino-acid repeat sequence "GAGAGSGAGAGS", which is found in fibroin of the silkworm Bombyx mori, a specific antibody against fibroin was prepared in rabbits through peptide synthesis and carrier-protein coupling. This antibody was highly specific for fibroin found in silk. Using this antibody we have successfully identified four silk samples from different time periods. Our results reveal, for the first time, a method capable of detecting silk from a few milligrams of archaeological fabric that has been buried for thousands of years, confirming that the ancient practice of wearing silk products while praying for rebirth dated back to at least 400 BCE. This method also complements current approaches in silk detection, especially for the characterization of poorly preserved silks, promoting the investigation of silk origins and of ancient clothing cultures. PMID- 25804729 TI - Bio-generation of stable isotope-labeled internal standards for absolute and relative quantitation of phase II drug metabolites in plasma samples using LC MS/MS. AB - Quantification of drug metabolites in biological samples has been of great interest in current pharmaceutical research, since metabolite concentrations and pharmacokinetics can contribute to a better understanding of the toxicity of drug candidates. Two major categories of Phase II metabolites, glucuronide conjugates and glutathione conjugates, may cause significant drug toxicity and therefore require close monitoring at early stages of drug development. In order to achieve high precision, accuracy, and robustness, stable isotope-labeled (SIL) internal standards (IS) are widely used in quantitative bioanalytical methods using liquid chromatography and tandem mass spectrometry (LC-MS/MS), due to their capability of compensating for matrix effects, extraction variations and instrument response fluctuations. However, chemical synthesis of SIL analogues of Phase II metabolites can often be very difficult and require extensive exploratory research, leading to higher cost and significant delays in drug research and development. To overcome these challenges, we have developed a generic method which can synthesize SIL analogues of Phase II metabolites from more available SIL parent drugs or SIL conjugation co-factors, using in vitro biotransformation. This methodology was successfully applied to the bio-generation of SIL glucuronide conjugates and glutathione conjugates. The method demonstrated satisfactory performance in both absolute quantitation and assessment of relative exposure coverage across species in safety tests of drug metabolites (MIST). This generic technique can be utilized as an alternative to chemical synthesis and potentially save time and cost for drug research and development. PMID- 25804733 TI - Positional information and reaction-diffusion: two big ideas in developmental biology combine. AB - One of the most fundamental questions in biology is that of biological pattern: how do the structures and shapes of organisms arise? Undoubtedly, the two most influential ideas in this area are those of Alan Turing's 'reaction-diffusion' and Lewis Wolpert's 'positional information'. Much has been written about these two concepts but some confusion still remains, in particular about the relationship between them. Here, we address this relationship and propose a scheme of three distinct ways in which these two ideas work together to shape biological form. PMID- 25804732 TI - Outcome and economic implications of proteomic test-guided second- or third-line treatment for advanced non-small cell lung cancer: extended analysis of the PROSE trial. AB - OBJECTIVES: Lung cancer accounts for a significant number of new cancer cases and deaths, with the majority of patients presenting with non-small cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors are recommended as an alternative to chemotherapy for certain patients, challenges exist for clinical utilization. The objective of this analysis was to assess the outcome and economic implications of a clinically validated serum-based proteomic test to guide treatment decisions in patients with advanced NSCLC, who are EGFR-negative or status unknown, and have progressed following at least one chemotherapy regimen. METHODS: This analysis was conducted from a US payer perspective. Clinical outcomes were evaluated over the lifetime of a patient, based on data from randomized trials and clinical studies. The clinical endpoints included treatment utilization, adverse events, survival, and a composite measure of length and quality of life, referred to as the quality adjusted life year (QALY). Costs for testing, treatment, surveillance, and management of adverse events were analyzed based on publicly available costs of the related procedures. The economic endpoints were cumulative lifetime direct medical costs and cost per QALY gained. RESULTS: In the base case, treatment recommendation for 27.3% of the patient population changed from erlotinib to chemotherapy after using the proteomic test. Overall survival increased by 0.091 year and QALYs increased by 0.050 year. The total lifetime direct medical cost per patient decreased by $135 with test-guided treatment. The findings were robust over a wide range of variation in the input parameters. CONCLUSION: The serum-based proteomic test informed treatment selection for patients with advanced NSCLC who failed previous chemotherapy regimen(s), improving QALYs and saving costs. PMID- 25804734 TI - Cellular and molecular insights into Hox protein action. AB - Hox genes encode homeodomain transcription factors that control morphogenesis and have established functions in development and evolution. Hox proteins have remained enigmatic with regard to the molecular mechanisms that endow them with specific and diverse functions, and to the cellular functions that they control. Here, we review recent examples of Hox-controlled cellular functions that highlight their versatile and highly context-dependent activity. This provides the setting to discuss how Hox proteins control morphogenesis and organogenesis. We then summarise the molecular modalities underlying Hox protein function, in particular in light of current models of transcription factor function. Finally, we discuss how functional divergence between Hox proteins might be achieved to give rise to the many facets of their action. PMID- 25804736 TI - WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals. AB - Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1. PMID- 25804735 TI - p53 Enables metabolic fitness and self-renewal of nephron progenitor cells. AB - Contrary to its classic role in restraining cell proliferation, we demonstrate here a divergent function of p53 in the maintenance of self-renewal of the nephron progenitor pool in the embryonic mouse kidney. Nephron endowment is regulated by progenitor availability and differentiation potential. Conditional deletion of p53 in nephron progenitor cells (Six2Cre(+);p53(fl/fl)) induces progressive depletion of Cited1(+)/Six2(+) self-renewing progenitors and loss of cap mesenchyme (CM) integrity. The Six2(p53-null) CM is disorganized, with interspersed stromal cells and an absence of a distinct CM-epithelia and CM stroma interface. Impaired cell adhesion and epithelialization are indicated by decreased E-cadherin and NCAM expression and by ineffective differentiation in response to Wnt induction. The Six2Cre(+);p53(fl/fl) cap has 30% fewer Six2(GFP(+)) cells. Apoptotic index is unchanged, whereas proliferation index is significantly reduced in accordance with cell cycle analysis showing disproportionately fewer Six2Cre(+);p53(fl/fl) cells in the S and G2/M phases compared with Six2Cre(+);p53(+/+) cells. Mutant kidneys are hypoplastic with fewer generations of nascent nephrons. A significant increase in mean arterial pressure is observed in early adulthood in both germline and conditional Six2(p53 null) mice, linking p53-mediated defects in kidney development to hypertension. RNA-Seq analyses of FACS-isolated wild-type and Six2(GFP(+)) CM cells revealed that the top downregulated genes in Six2Cre(+);p53(fl/fl) CM belong to glucose metabolism and adhesion and/or migration pathways. Mutant cells exhibit a ~ 50% decrease in ATP levels and a 30% decrease in levels of reactive oxygen species, indicating energy metabolism dysfunction. In summary, our data indicate a novel role for p53 in enabling the metabolic fitness and self-renewal of nephron progenitors. PMID- 25804739 TI - Lgd regulates the activity of the BMP/Dpp signalling pathway during Drosophila oogenesis. AB - The tumour suppressor gene lethal (2) giant discs (lgd) is involved in endosomal trafficking of transmembrane proteins in Drosophila. Loss of function results in the ligand-independent activation of the Notch pathway in all imaginal disc cells and follicle cells. Analysis of lgd loss of function has largely been restricted to imaginal discs and suggests that no other signalling pathway is affected. The devotion of Lgd to the Notch pathway was puzzling given that lgd loss of function also affects trafficking of components of other signalling pathways, such as the Dpp (a Drosophila BMP) pathway. Moreover, Lgd physically interacts with Shrub, a fundamental component of the ESCRT trafficking machinery, whose loss of function results in the activation of several signalling pathways. Here, we show that during oogenesis lgd loss of function causes ectopic activation of the Drosophila BMP signalling pathway. This activation occurs in somatic follicle cells as well as in germline cells. The activation in germline cells causes an extra round of division, producing egg chambers with 32 instead of 16 cells. Moreover, more germline stem cells were formed. The lgd mutant cells are defective in endosomal trafficking, causing an accumulation of the type I Dpp receptor Thickveins in maturing endosomes, which probably causes activation of the pathway. Taken together, these results show that lgd loss of function causes various effects among tissues and can lead to the activation of signalling pathways other than Notch. They further show that there is a role for the endosomal pathway during oogenesis. PMID- 25804737 TI - Duration of culture and sonic hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells. AB - Medial ganglionic eminence (MGE)-derived GABAergic cortical interneurons (cINs) consist of multiple subtypes that are involved in many cortical functions. They also have a remarkable capacity to migrate, survive and integrate into cortical circuitry after transplantation into postnatal cortex. These features have engendered considerable interest in generating distinct subgroups of interneurons from pluripotent stem cells (PSCs) for the study of interneuron fate and function, and for the development of cell-based therapies. Although advances have been made, the capacity to generate highly enriched pools of subgroup fate committed interneuron progenitors from PSCs has remained elusive. Previous studies have suggested that the two main MGE-derived interneuron subgroups--those expressing somatostatin (SST) and those expressing parvalbumin (PV)--are specified in the MGE from Nkx2.1-expressing progenitors at higher or lower levels of sonic hedgehog (Shh) signaling, respectively. To further explore the role of Shh and other factors in cIN fate determination, we generated a reporter line such that Nkx2.1-expressing progenitors express mCherry and postmitotic Lhx6 expressing MGE-derived interneurons express GFP. Manipulations of Shh exposure and time in culture influenced the subgroup fates of ESC-derived interneurons. Exposure to higher Shh levels, and collecting GFP-expressing precursors at 12 days in culture, resulted in the strongest enrichment for SST interneurons over those expressing PV, whereas the strongest enrichment for PV interneurons was produced by lower Shh and by collecting mCherry-expressing cells after 17 days in culture. These findings confirm that fate determination of cIN subgroups is crucially influenced by Shh signaling, and provide a system for the further study of interneuron fate and function. PMID- 25804738 TI - Genome-wide characterisation of Foxa1 binding sites reveals several mechanisms for regulating neuronal differentiation in midbrain dopamine cells. AB - Midbrain dopamine neuronal progenitors develop into heterogeneous subgroups of neurons, such as substantia nigra pars compacta, ventral tegmental area and retrorubal field, that regulate motor control, motivated and addictive behaviours. The development of midbrain dopamine neurons has been extensively studied, and these studies indicate that complex cross-regulatory interactions between extrinsic and intrinsic molecules regulate a precise temporal and spatial programme of neurogenesis in midbrain dopamine progenitors. To elucidate direct molecular interactions between multiple regulatory factors during neuronal differentiation in mice, we characterised genome-wide binding sites of the forkhead/winged helix transcription factor Foxa1, which functions redundantly with Foxa2 to regulate the differentiation of mDA neurons. Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, Foxa1, Foxa2 and an E-box transcription factor for its transcriptional activity. Furthermore, the chromatin remodelling factor Smarca1 was shown to function downstream of Foxa1 and Foxa2 to regulate differentiation from immature to mature midbrain dopaminergic neurons. Our genome-wide Foxa1 bound cis-regulatory sequences from ChIP-Seq and Foxa1/2 candidate target genes from RNA-Seq analyses of embryonic midbrain dopamine cells also provide an excellent resource for probing mechanistic insights into gene regulatory networks involved in the differentiation of midbrain dopamine neurons. PMID- 25804743 TI - Retraction: Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis. PMID- 25804742 TI - The melanocyte lineage in development and disease. PMID- 25804740 TI - Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory. AB - The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome--reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain. PMID- 25804744 TI - Methods for studying ER stress and UPR markers in human cells. AB - Many experimentally induced or disease-related cellular dysfunctions stress the endoplasmic reticulum, commonly resulting in an accumulation of unfolded proteins in the ER lumen which is sensed by three ER-resident transmembrane proteins, PERK, ATF6, and IRE1. Their activation by such ER stress affects the unfolded protein response, which consists of a shutoff of protein translation and at the same time the switching-on of specific transcription factors that control genes which function to reduce the burden of unfolded proteins to the ER. Here, we describe two sets of methods for monitoring the occurrence of ER stress and UPR signaling in human cells by analyzing markers of activation of all three ER stress sensor proteins. The first set of methods is based on the qualitative and quantitative analysis of UPR-induced transcripts by qPCR. The second set of methods consists of Western blot-based analysis of UPR-induced proteins or protein modifications. Their combined analysis allows assessment of activation of all three ER stress-activated signaling pathways that in combination are characteristic for the UPR. PMID- 25804745 TI - Assays for induction of the unfolded protein response and selective activation of the three major pathways. AB - The endoplasmic reticulum (ER) is responsible for the proper folding and processing of secreted and transmembrane proteins within the cell. Stimuli that disrupt ER function cause an accumulation of misfolded proteins within the ER lumen, a condition termed ER stress. The unfolded protein response (UPR) is activated in response to ER stress in an attempt to restore ER homeostasis. UPR is initiated by three transmembrane sensors that activate three signaling pathways which lead to the activation of transcription factors and production of chaperones. The coordinated action of these three pathways attempt to restore homeostasis. However, if the ER homeostasis cannot be restored, it initiates apoptosis. Deregulated or compromised functions of these pathways can therefore lead to the pathogenesis of disease. In order to understand the molecular mechanisms involved, it is important to study each pathway independently. Here, we describe a number of approaches to selectively target each arm of UPR and investigate the functional significance of the UPR pathway involved. PMID- 25804746 TI - Assays to characterize molecular chaperone function in vitro. AB - Here, we describe a set of assays, using mitochondrial citrate synthase as a model substrate, which are suitable to test for chaperone function of proteins in vitro. Additionally, these assays distinguish between the ability of suppressing the aggregation of diverse substrate proteins by stable interaction (holdase function) and the ability to assist the refolding of substrate proteins (foldase function). PMID- 25804741 TI - Activin A directs striatal projection neuron differentiation of human pluripotent stem cells. AB - The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells. PMID- 25804747 TI - Analysis of the heat shock factor complex in mammalian HSP70 promoter. AB - The heat shock response is characterized by the induction of heat shock proteins (HSPs) and is one of prominent mechanisms that regulate proteostasis capacity in the cell. In mammals, heat shock factor 1 (HSF1) regulates the expression of HSPs transcriptionally in both unstressed and stressed cells. Recent reports show that the HSF1-RPA complex constitutively gains access to nucleosomal DNA in part by recruiting a histone chaperone and a chromatin-remodeling component. Here, we describe the strategies to substitute endogenous HSF1 with ectopically expressed HSF1 or its mutant and to detect the occupancy of HSF1 transcription complex including RPA in vivo on two heat shock response elements located close together in the human or mouse HSP70 promoters by chromatin immunoprecipitation assay with high sensitivity and specificity. PMID- 25804749 TI - Visualizing the spatiotemporal dynamics of DNA damage in budding yeast. AB - Fluorescence microscopy has enabled the analysis of both the spatial distribution of DNA damage and its dynamics during the DNA damage response (DDR). Three microscopic techniques can be used to study the spatiotemporal dynamics of DNA damage. In the first part we describe how we determine the position of DNA double strand breaks (DSBs) relative to the nuclear envelope. The second part describes how to quantify the co-localization of DNA DSBs with nuclear pore clusters, or other nuclear subcompartments. The final protocols describe methods for the quantification of locus mobility over time. PMID- 25804748 TI - Immunofluorescence-based methods to monitor DNA end resection. AB - Double-strand breaks (DSBs) are the most deleterious among all types of DNA damage that can occur in the cell. These breaks arise from both endogenous (e.g., DNA replication stress) and exogenous insults (e.g., ionizing radiation). DSBs are principally repaired by one of two major pathways: nonhomologous end joining (NHEJ) or homologous recombination (HR). NHEJ is an error-prone process that can occur in all phases of the cell cycle, while HR is limited to the S and G2 phases of the cell cycle when a sister chromatid is available as a template for error free repair. The first step in HR is "DNA end resection," a process during which the broken DNA end is converted into a long stretch of 3'-ended single-stranded DNA (ssDNA). In recent years, DNA end resection has been identified as a pivotal step that controls "repair pathway choice," i.e., the appropriate choice between NHEJ and HR for DSB repair. Therefore, methods to quantitatively or semiquantitatively assess DNA end resection have gained importance in laboratories working on DNA repair. In this chapter, we describe two simple immunofluorescence-based techniques to monitor DNA end resection in mammalian cells. The first technique involves immuno-detection of replication protein A (RPA), an ssDNA-binding protein that binds to resected DNA. The second technique involves labeling of genomic DNA with 5-bromo-2'-deoxyuridine (BrdU) that can be detected by anti-BrdU antibody only after the DNA becomes single stranded due to resection. These methods are not complicated, do not involve sophisticated instrumentation or reporter constructs, and can be applied to most mammalian cell lines and, therefore, should be of broad utility as simple ways of monitoring DNA end resection in vivo. PMID- 25804750 TI - Detecting reactive oxygen species by immunohistochemistry. AB - In cultured cells, an increase in cellular levels of reactive oxygen species (ROS) can be detected using multiple techniques including colorimetric assays, immunoblotting, and immunofluorescence. These methods can also be applied for ROS measurement in tissue samples, but often require tissue homogenization, and therefore do not distinguish between the different cell types within a tissue. Here, we describe a detailed protocol for determination of altered oxidative stress levels in different cell types in tissues, by detecting ROS-caused alteration of macromolecules using immunohistochemistry (IHC). This method is demonstrated by using 4HNE as a marker for lipid peroxidation in mouse pancreas tissue that contains precancerous lesions high in cellular oxidative stress. PMID- 25804751 TI - Investigating inflammasome activation under conditions of cellular stress and injury. AB - Inflammasomes are large multiprotein complexes that assemble in response to cellular stress and infection. NOD-like receptor-related proteins (NLRPs) are essential components of these complexes and are activated by exogenous and endogenous danger signals such as crystalline substances, extracellular ATP, and pore-forming toxins. In general, inflammasome activation is accompanied by perturbations in cellular homeostasis. For example, most inflammasome activators will trigger cation efflux, reactive oxygen species (ROS) generation and caspase 1-dependent cell death, commonly referred to as pyroptosis. In this chapter, we describe protocols to examine inflammasome activation and accompanying events in vitro. PMID- 25804752 TI - Methods for studying microRNA functions during stress. AB - Constituting 5 % of the human genome, microRNAs represent a sizeable class of gene regulators that is predicted to control the expression of at least 60 % of all protein-coding RNAs. Dysregulation of microRNA function results in developmental defects and pathological diseases such as cancers and neurological disorders. Intriguingly, many phenotypes of microRNA deficiencies are subdued in normal condition but manifested apparently upon stress. Here, we outline experimental methods to monitor the level, targets, and activity of microRNAs as the first few steps to characterize how microRNA functions are altered upon stress. PMID- 25804754 TI - Detection of apoptosis using fluorescent probes. AB - Apoptosis plays a major role in both healthy and diseased cells. The analysis of apoptosis can take advantage of multiple cellular markers, enabling the process to be studied at different time points. In this chapter, several apoptosis assay protocols are provided. PMID- 25804753 TI - Measuring autophagy in stressed cells. AB - Macro-autophagy is a major catabolic process in the cell used to degrade protein aggregates, dysfunctional organelles and intracellular pathogens that would otherwise become toxic. Autophagy also generates energy and metabolites for the cell through recycling of degraded autophagosomal cargo, which can be particularly important for cell viability under stress. The significance of changes in the rates of autophagic flux for cellular function and disease is being increasingly appreciated, and interest in measuring autophagy in different experimental systems is growing accordingly. Here, we describe key methodologies used in the field to measure autophagic flux, including monitoring LC3 processing by western blot, fluorescent cell staining, and flow cytometry, in addition to changes in the levels or posttranslational modifications of other autophagy markers, such as p62/Sqstm1 and the Atg5-Atg12 conjugate. We also describe what cellular stresses may be used to induce autophagy and how to control for changes in the rates of autophagic flux as opposed to inhibition of flux. Finally, we detail available techniques to monitor autophagy in vivo. PMID- 25804755 TI - Measuring death of pancreatic beta cells in response to stress and cytotoxic T cells. AB - Apoptosis of pancreatic beta cells is a feature of type 1 and type 2 diabetes, although by different effector mechanisms. In type 1 diabetes, beta cells are the targets of cytotoxic CD8(+) T cells that kill by releasing the contents of their cytotoxic granules into the immunological synapse with the target beta cell. In type 2 diabetes, the mechanisms of beta cell apoptosis are less clear, but believed to be due to cellular stresses including endoplasmic reticulum stress and oxidative stress induced by chronic exposure to high concentrations of glucose, lipids, inflammatory cytokines, or islet amyloid polypeptide. Measuring apoptosis in primary islets can be more difficult than in a beta cell line because islets exist as a cluster of cells and it is often difficult to obtain sufficient cells for any particular type of assay. Here, we describe two different methods for measuring islet cell apoptosis. The first method is the measurement of DNA fragmentation, a hallmark of apoptosis, of islets that have been cultured with reagents that induce stress. The second method is the measurement of islet lysis by activated cytotoxic T cells. We describe methods using mouse islets, but these can easily be adapted for human islets. PMID- 25804757 TI - Studying nitrosative stress in Parkinson's disease. AB - Parkinson's disease (PD) is marked by a selective degeneration of dopaminergic neurons in the brain stem and it is the second most common neurodegenerative disorder. The pathogenic mechanism of PD is not completely known but it is believed that oxidative stress involving the imbalance of nitric oxide (NO) signaling is involved. Recent studies have suggested that NO, through the modification of protein's cysteine residues can contribute to the pathogenesis of PD. This NO modification, designated as S-nitrosylation, is emerging as an important signaling mechanism that regulates increasing number of cellular processes such as vesicle trafficking, receptor mediated signal transduction, gene transcription, and cell death. In our studies, we found that increased nitrosative stress promotes the S-nitrosylation of neuroprotective proteins and compromises their function which contributes to the development of PD. One of the obstacles in studying S-nitrosylation signaling is how to detect this modification in biological samples. Here, two simple and commonly used methods in detecting S-nitrosylated proteins are introduced for the study of this NO signaling mechanism. PMID- 25804756 TI - Adaptation of the secretory pathway in cancer through IRE1 signaling. AB - The unfolded protein response (UPR) was originally identified as a signaling network coordinating adaptive and apoptotic responses to accumulation of unfolded proteins in the endoplasmic reticulum (ER). More recent work has shown that UPR signaling can be triggered by a multitude of cellular events and that the UPR plays a critical role in the prevention of cell transformation but also in tumor development. This has been particularly well illustrated with studies on one of the three major ER stress sensors, IRE1. This ER resident type I transmembrane protein senses luminal ER stress and transduce signals through its cytosolic RNase activity. IRE1 signaling has been shown to contribute to the progression of solid tumors through pro-angiogenic mechanisms. Herein, we expose the methodologies for investigating IRE1 signaling in tumor cells and in tumors. Moreover, we show that selective pharmacological inhibition of IRE1 RNase activity sensitizes tumor cells to ER stress. PMID- 25804758 TI - Cross talk between ER stress, oxidative stress, and inflammation in health and disease. AB - In mammals, endoplasmic reticulum (ER) stress, oxidative stress, and inflammatory responses compose the major defense networks that help the cells adapt to and survive stress conditions caused by biochemical, physiological and pathological stimuli. However, chronic ER stress, oxidative stress, or inflammation have been found to be associated with the initiation and progression of a variety of human diseases in the modern world. Under many pathophysiologic conditions, ER stress response, oxidative stress, and inflammatory responses are integrated and amplified in specialized cell types to facilitate the progression of disease. In the past few decades, ER stress response, oxidative stress, and inflammation as well as their interactive relationships have been hot research topics in biomedicine. In this review, we summarize the recent advance in our understanding of the cross talk between ER stress response, oxidative stress, and inflammation in immunity and in inflammatory and metabolic diseases. PMID- 25804759 TI - Stress responses during ageing: molecular pathways regulating protein homeostasis. AB - The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases. PMID- 25804760 TI - Targeting stress responses for regenerative medicine. AB - Some internal and external stimuli elicit stress responses on the cellular level and at the level of the organism. When the stimulus is brief and its intensity mild to moderate, it triggers adaptation changes that improve the cell's or organism's survival. This adaptation is achieved through a variety of cellular mechanisms such as induction of repair mechanisms, improved removal of damaged macromolecules, upregulation of endogenous antioxidant defenses, and prevention of apoptosis triggering by moderate stressors. The key intracellular signaling pathways involved in stress adaptation are the mTORC1 and SIRT1. Manipulating these stress adaptation signaling pathways with a variety of agents, improves the cellular adaptation to stress, prolongs cell survival, and improves the transplantation outcome in animal models and in clinical trials. The challenge for the future is to fine-tune the numerous experimental techniques to suit the needs of transplantation and regenerative medicine. PMID- 25804761 TI - Catharanthus mosaic virus: A potyvirus from a gymnosperm, Welwitschia mirabilis. AB - A virus from a symptomatic plant of the gymnosperm Welwitschia mirabilis Hook. growing as an ornamental plant in a domestic garden in Western Australia was inoculated to a plant of Nicotiana benthamiana where it established a systemic infection. The complete genome sequence of 9636 nucleotides was determined using high-throughput and Sanger sequencing technologies. The genome sequence shared greatest identity (83% nucleotides and 91% amino acids) with available partial sequences of catharanthus mosaic virus, indicating that the new isolate belonged to that taxon. Analysis of the phylogeny of the complete virus sequence placed it in a monotypic group in the genus Potyvirus. This is the first record of a virus from W. mirabilis, the first complete genome sequence of catharanthus mosaic virus determined, and the first record from Australia. This finding illustrates the risk to natural and managed systems posed by the international trade in live plants and propagules, which enables viruses to establish in new regions and infect new hosts. PMID- 25804762 TI - Synthesis of methoxycarbonylpyrazolylandrostene derivatives, and their potential inhibitory effect on androgen biosynthesis and cell proliferation. AB - The Claisen condensations of 3beta-acetoxypregn-5-en-20-one (1) and 3beta acetoxypregna-5,16-diene (7) with dimethyl oxalate are known to lead to 3beta hydroxy-21-methoxalylpregn-5-en-20-one (2) and 3beta-hydroxy-21-methoxalylpregna 5,16-dien-20-one (8), respectively. The reactions of 2 with p-substituted phenylhydrazines afford pyrazol-5-yl derivatives (5) as main, and 3-yl regioisomers (4) as minor products. The corresponding reactions of 16-ene analogue 8 afford only pyrazol-5-yl regioisomer 9. Oppenauer oxidation of the pyrazolyl compounds yields the corresponding Delta(4)-3-ketosteroids. We investigated the antiandrogenic effects of new methoxycarbonylpyrazolyl compounds through determination of their in vitro inhibition of the activities of rat testicular C17,20-lyase, Delta(5)-3beta-hydroxysteroid dehydrogenase (Delta(5) 3beta-HSD) and 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3). A Delta(5)-3beta-hydroxy compound in the D-ring-saturated androst-5-ene series bearing an unsubstituted phenyl group on the pyrazolyl heterocycle (5a) proved to be a potent inhibitor of Delta(5)-3beta-HSD. The 4-methoxyphenyl derivative (5e) and the 3-oxo counterpart (6a) of 5a also displayed substantial inhibition. The other tested compounds exerted only weak inhibitory action against the enzymes investigated. The newly synthetized compounds were evaluated in vitro by means of MTT assays for antiproliferative activity against Hela (cervical carcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast adenocarcinoma) cells. In all four groups (3beta-hydroxy- and 3-ketosteroids with saturated or unsaturated ring D), the most potent analogs contain a 4-tolyl or 4-methoxyphenyl group. Compound 5d exhibited substantial antiproliferative action against the three cell lines investigated, whereas 9d inhibited the growth of Hela cells markedly. The most noteworthy inhibition was exerted by 6a against A431 cells. PMID- 25804763 TI - Concise synthesis of 12a-methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin 3(12aH)-ones as racemic 14-azaestrogen analogs. AB - A concise method for the synthesis of 14-azasteroid analogs with angular methyl group at C-13 of the steroidal nucleus has been reported in this paper. We have developed an interesting cascade reaction of arylacetylenes and N-(naphthalen-2 yl)pent-4-ynamides under gold (III)-catalysis to produce novel tetracyclic 12a methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones which may be viewed as 14-azaestrogen analogs. PMID- 25804764 TI - Evaluation of ocular movements in patients with dyslexia. AB - The aims of this study were to analyze the relationship between dyslexia and eye movements and to assess whether this method can be added to the workup of dyslexic patients. The sample was comprised of 11 children with a diagnosis of dyslexia and 11 normal between 8 and 13 years of age. All subjects underwent orthoptic evaluation, ophthalmological examinations, and eye movement analysis, specifically, stability analysis on fixating a still target, tracking saccades, analysis of fixation pauses, speed reading, saccades, and regressions through the reading of a text. Stability analysis on fixating a still target showed a significant (p < 0.001) difference between the two groups showing an increased amount of loss of fixation among dyslexic subjects (5.36 +/- 2.5 s and 0.82 +/- 2.1, respectively). Tracking saccades (left and right horizontal axis) did not show a significant difference. When reading parameters were looked into (number of saccades, number of regressions, reading time through the reading of a text), a significant (p < 0.001) difference was found between the groups. This study supports the belief that the alteration of eye movement does not depend on oculo motor dysfunction but is secondary to a defect in the visual processing of linguistic material. Inclusion of assessment of this defect might prove beneficial in determining the presence of dyslexia in young children at a younger age, and an earlier intervention could be initiated. PMID- 25804766 TI - Second cancers in chronic lymphocytic leukemia: growing importance in the era of improved treatment outcomes. PMID- 25804765 TI - Repeated dose titration versus age-based method in electroconvulsive therapy: a pilot study. AB - In electroconvulsive therapy (ECT), a dose titration method (DTM) was suggested to be more individualized and therefore more accurate than formula-based dosing methods. A repeated DTM (every sixth session and dose adjustment accordingly) was compared to an age-based method (ABM) regarding treatment characteristics, clinical outcome, and cognitive functioning after ECT. Thirty-nine unipolar depressed patients dosed using repeated DTM and 40 matched patients treated with ABM were compared. Montgomery-Asberg Depression Rating Scale (MADRS) and Mini Mental State Examination (MMSE) were assessed at baseline and at the end of the index course, as well as the total number of ECT sessions. Both groups were similar regarding age, sex, psychotic features, mean baseline MADRS, and median baseline MMSE. At the end of the index course, the two methods showed equal outcome (mean end MADRS, 11.6 +/- 8.3 in DTM and 9.5 +/- 7.6 in ABM (P = 0.26); median end MMSE, 28 (25-29) and 28 (25-29.8), respectively (P = 0.81). However, the median number of all ECT sessions differed 16 (11-22) in DTM versus 12 (10 14.8) in ABM; P = 0.02]. Using regression analysis, dosing method and age were independently associated with the total number of ECT sessions, with less sessions needed in ABM (P = 0.02) and in older patients (P = 0.001). In this comparative cohort study, ABM and DTM showed equal outcome for depression and cognition. However, the median ECT course duration in repeated DTM appeared longer. Additionally, higher age was associated with shorter ECT courses regardless of the dosing method. Further prospective studies are needed to confirm these findings. PMID- 25804767 TI - Acute myeloid leukemia cells exhibit selective down-regulation of DNMT3A isoform 2. PMID- 25804768 TI - The MEK1/2 inhibitor, MEKi-1, induces cell death in chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment and is synergistic with fludarabine. AB - The Raf-1/MEK/ERK1/2 pathway has become a focus for novel cancer therapies. This study sought to investigate whether targeting MEK1/2 may represent a therapeutic option for chronic lymphocytic leukemia (CLL). The MEK1/2 inhibitor, MEKi-1, induced apoptosis of CLL cells and was synergistic with fludarabine under conditions that mimic the tumor microenvironment, irrespective of poor-risk characteristics. MEKi-1 down-regulated the activities of AKT and ERK1/2 and was synergistic with fludarabine through a mechanism that involved potentiation of DNA damage and attenuation of the activity of ERK1/2 and expression of Mcl-1. This study highlights the significant role of the mitogen-activated protein kinase (MAPK)-ERK1/2 pathway in mediating the effects of the CLL tumor microenvironment and suggests that targeting MEK1/2 in CLL cells may impact upon the activity of both ERK1/2 and AKT. Inhibitors of MEK1/2 as single agents or in combination with DNA-damaging agents may represent a novel therapeutic strategy for CLL. PMID- 25804770 TI - Optimizing the management of relapsed chronic myeloid leukemia post-allogeneic bone marrow transplant. PMID- 25804769 TI - Allogeneic stem cell transplant may improve the outcome of adult patients with inv(16) acute myeloid leukemia in first complete remission with poor molecular responses to chemotherapy. AB - Eighty-six adult patients with inv(16) acute myeloid leukemia (AML) in first complete remission (CR1) were serially monitored for CBFB-MYH11 transcript levels during the early courses of chemotherapy. Fifty-seven and 29 of them received chemotherapy/autologous stem cell transplant (SCT) and allogeneic (allo-)SCT after second consolidation, respectively. For patients receiving chemotherapy/autologous SCT, the sole independent adverse prognostic factor for the cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) was a CBFB-MYH11 level > 0.2% after course 2 consolidation (p = 0.003, 0.003 and 0.031), which was used to define a poor molecular response (MR). Allo-SCT significantly decreased the 3-year CIR and increased the DFS and OS of patients with a poor MR (p < 0.0001, 0.0001 and 0.045) but did not improve the outcome of patients with good MR (all p > 0.05) compared with chemotherapy/autologous SCT. Therefore, allo-SCT could improve the outcome of adult patients with inv(16) AML in CR1 with a poor MR during the early courses of chemotherapy. PMID- 25804771 TI - Hedgehog inhibition as monotherapy in myelofibrosis: is there any role? PMID- 25804772 TI - [Nephrology in primary care medicine: routine management for the primary care physician or an area reserved for the specialist?]. PMID- 25804773 TI - [Hiccups]. PMID- 25804775 TI - [Hyperkalemia - what the general practitioner must know]. AB - Hyperkalemia can be a challenge for the general practitioner as it can prove to be benign as well as life-threatening. From a diagnostic point of view, four possibilities have to be differenciated: a pre-analytical cause, potassium release through cell lysis, a potassium shift, a reduced renal excretion of potassium. The first differential diagnosis can often be carried out by a thorough medical history, in particular the medication intake. Also, the first clinical and laboratory investigations can take place at the general practitioner's clinic. If the hyperkalemia proves to be a true hyperkalemia or cannot be explained by poly-medication and known diseases of the patient, not yet identified renal, endocrine or cardiac diseases should be searched for. If a serious condition is identified as the cause of hyperkalemia the patient should be referred to a specialized clinic. PMID- 25804776 TI - [Diagnosis and management of hyponatremia: review of current recommendations]. AB - Hyponatremia is defined as a serum below 135 mmol/l and is the most frequent electrolytes disorder. The treatment is essential because hyponatremia is associated with increased morbidity and mortality. There are multiple aetiologies associated with this challenging diagnosis. The correct one must be established in order to manage this disorder appropriately. Serum and urine osmolalities, serum sodium concentration and evaluation of extracellular fluid volume are necessary for the diagnosis. The rate of correction of hyponatremia should be closely monitored to avoid cerebral complications. This article reviews the recommended approaches for the diagnosis and treatment of hyponatremia. PMID- 25804777 TI - [Urinalysis in the 21st century: anything but obsolete!]. AB - Urinalysis including dipstick tests and urinary microscopy represent a non invasive, technically simple and economic screening tool. Notably, the repetitive detection and analysis of hematuria and proteinuria harbors a high sensitivity for detection of renal and systemic diseases. Due to its semiquantitative nature, urinalysis should only be interpreted after comprehensive consideration of diagnostic and technical limitations, which will be reviewed in this article. PMID- 25804778 TI - [Oxalate: a poorly soluble organic waste with consequences]. AB - Oxalate is a highly insoluble metabolic waste excreted by the kidneys. Disturbances of oxalate metabolism are encountered in enteric hyperoxaluria (secondary to malabsorption, gastric bypass or in case of insufficient Oxalobacter colonization), in hereditary hyperoxaluria and in intoxication (ethylene glycol, vitamin C). Hyperoxaluria causes a large spectrum of diseases, from isolated hyperoxaluria to kidney stones and nephrocalcinosis formation, eventually leading to kidney failure and systemic oxalosis with life-threatening deposits in vital organs. New causes of hyperoxaluria are arising recently, in particular after gastric bypass surgery, which requires regular and preemptive monitoring. The treatment of hyperoxaluria involves reduction in oxalate intake and increase in calcium intake. Optimal urine dilution and supplementation with inhibitors of kidney stone formation (citrate) are required. Some conditions may need vitamin B6 supplementation, and the addition of probiotics might be useful in the future. Primary care physicians should identify cases of recurrent calcium oxalate stones and severe hyperoxaluria. Further management of hyperoxaluria requires specialized care. PMID- 25804780 TI - [Metformin is also recommended in mild and moderate renal failure]. PMID- 25804781 TI - [Pregabalin ineffective in neurogenic claudication symptoms]. PMID- 25804779 TI - [Chronic renal failure: what is the optimal diet?]. AB - The optimal diet for chronic kidney disease (CKD) is an issue frequently brought up by patients and/or their relatives during outpatient visits. For patients without malnutrition who are motivated and supported by an experienced multidisciplinary team, the optimal protein intake of 0,6 g/kg of ideal body weight/day is recommended to halt the progression of CKD. A calorie intake of 30 to 35 kcal/kg of ideal body weight/day is necessary to reduce the risk of malnutrition from a low protein diet and to maintain a neutral nitrogen balance. A low-salt diet, namely 5 to 6 g/d, is useful to optimize the treatment of hypertension associated with CKD and to limit fluid overload. At the advanced stage of CKD, it is also necessary to restrict the intake of phosphorus and sometimes potassium. Given the complexity of optimal renal diet, coordination between general practitioners, nephrologists and dietitians is essential to foster optimal care. PMID- 25804783 TI - [CME - rheumatology 5. Antibiotic resistant pneumonia]. PMID- 25804784 TI - [Yearning for paradise]. PMID- 25804787 TI - Ferromagnetic nanocrystallines containing copper as an efficient catalyst for photoinduced water oxidation. AB - CuFe2O4 nanocrystallines with cubic jacobsite structure have been obtained by heat treatment of the coprecipitation product, which were synthesized by the reaction of Cu(2+) ions and Fe(3+) ions under alkaline conditions. Reported here is the first copper-based catalyst for photocatalytic water oxidation using [Ru(bpy)3]Cl2 as the photosensitizer and Na2S2O8 as the sacrificial electron acceptor, respectively. An apparent TOF value of 1.2 MUmol s(-1) m(-2) and an oxygen yield of 72.8% were obtained with CuFe2O4. The apparent TOF value with CuFe2O4 (1.2 MUmol s(-1) m(-2)) is the highest value among all heterogeneous photocatalytic water oxidation systems. CuFe2O4 can be easily separated from reaction solution by magnetic separation while maintaining excellent water oxidation activity in the fourth and fifth runs. The surface conditions of CuFe2O4 are slightly absent after examination by X-ray photoelectron spectroscopy (XPS) before and after the photocatalytic reaction. PMID- 25804786 TI - The experiences of the legal processes of involuntary treatment orders: tension between the legal and medical frameworks. AB - 3An involuntary treatment order (ITO) allows a person to be treated for a mental illness without consent under some circumstances. While the treatment and assessment of mental illness are essentially clinical decisions, involuntary mental health admissions are governed by a framework of legal principles, safeguards and procedures. The underlying philosophy of these laws is based on therapeutic jurisprudence. This approach focuses on the importance of the legal process as a social force and suggests that this can either protect or empower people. The legal processes can however adversely impact upon people's states of mind. This study reports on 25 qualitative interviews with involuntary inpatients of a major teaching hospital. The interviews were analysed thematically using a general inductive approach. The analysis focused on the patients' general experience of being placed under an ITO and their understanding of the ITO process. Generally, those who described the experience of an ITO in more positive terms, also experienced the ITO as a positive right. In addition to providing them with the treatment needed, they also felt that the ITO gave them protection and guidance. Conversely, those who experienced being placed under an ITO in more negative or mixed ways, described feeling powerless in the process, as they felt that the ITO took away their rights. By and large the ITO process was experienced as arbitrary when patients did not understand the reasons for their admission. In addition, these patients had limited or no information about their involuntary treatment order and they did not know what was expected of them to have the ITO revoked. Most importantly, they did not feel that there were any meaningful legal protections in place. These experiences highlight the importance of the legal processes and how these can be used as clinical tools. PMID- 25804788 TI - Competitive photoelectrochemical methanol and water oxidation with hematite electrodes. AB - Photocatalytic water and methanol oxidation were studied at thin film hematite electrodes synthesized by atomic layer deposition (ALD). Systematic photoelectrochemical characterization along with O2 evolution measurements were carried out in order to better understand the mechanisms of both water and methanol oxidation at hematite electrodes. When both water and methanol are present in the solution, they are oxidized competitively with each other, allowing the detection and assignment of distinct surface states characteristic to each process. The measurement of different surface states for methanol and water oxidation, along with the absence of measurable surface states in an inert acetonitrile electrolyte, clearly shows that the detected surface states are chemically distinct reaction intermediates of water or methanol oxidation. PMID- 25804789 TI - As(III) and As(V) removal from the aqueous phase via adsorption onto acid mine drainage sludge (AMDS) alginate beads and goethite alginate beads. AB - Acid mine drainage sludge (AMDS) is a solid waste generated following the neutralization of acid mine drainage (AMD). This material entrapped in calcium alginate was investigated for the sorption of As(III) and As(V). Three different adsorbent materials were prepared: AMDS alginate beads (AABs), goethite alginate beads (GABs), and pure alginate beads. The effects of pH and the adsorption kinetics were investigated, and the adsorption isotherms were also evaluated. The optimum pH range using the AABs was determined to be within 2-10 for As(III) and 2-9 for As(V). Adsorption equilibrium data were evaluated using the Langmuir isotherm model, and the maximum adsorption capacity qmax was 18.25 and 4.97 mg g( 1) for As(III) on AAB and GAB, respectively, and 21.79 and 10.92 mg g(-1) for As(V) on AAB and GAB, respectively. The adsorption of As(III) and As(V) was observed to follow pseudo-second order kinetics. The As K-edge X-ray absorption near-edge structure (XANES) revealed that the adsorbed As(III) on the AABs was oxidized to As(V) via manganese oxide in the AMDS. PMID- 25804790 TI - Single stage treatment of saline wastewater with marine bacterial-microalgae consortia in a fixed-bed photobioreactor. AB - Currently, the treatment of aquaculture-origin effluents is mainly performed through land-based recirculating aquaculture systems (RAS). In this study, we evaluate and introduce a novel immobilized/packed bed bioreactor which uses a synthetic textile as the support medium. A marine microbial consortium was developed on the textile by its inoculation with the microalgae Picochlorum sp. The bioreactor was tested with variable loadings of C and N and showed outstanding performance approaching removal rates up to 95% within a few hours (4 5h) of operation. Pyrosequencing analysis revealed a novel microbial consortium consisting mainly of chitrinomycetes, Pseudomonas sp. and the absence of beta proteobacteria, which is the Class encompassing autotrophic nitrifiers. Quantitative polymerase chain reaction further confirmed these findings suggesting heterotrophic nitrification and aerobic denitrification as the principal mechanisms of N-removal from the bioreactor. Overall our findings reveal the potential of the AdvanTex System for the treatment of marine aquaculture effluents-COD reduction and N-removal, in a single stage. PMID- 25804791 TI - A study on removal of elemental mercury in flue gas using fenton solution. AB - A novel technique on oxidation-separation of elemental mercury (Hg(0)) in flue gas using Fenton solution in a bubbling reactor was proposed. The effects of several process parameters (H2O2 concentration, Hg(0) inlet concentration, Fe(2+) concentration, solution temperature, solution pH, gas flow) and several flue gas components (NO, SO2, O2, CO2, inorganic ions and particulate matters on Hg(0) removal were studied. The results indicate that H2O2 concentration, Fe(2+) concentration, solution pH and gas flow have great effects on Hg(0) removal. Solution temperature, Hg(0), NO, SO2, CO3(2-) and HCO3(-) concentrations also have significant effects on Hg(0) removal. However, Cl(-), SO4(2-), NO3(-), O2 and CO2 concentrations only have slight effects on Hg(0) removal. Furthermore, reaction mechanism of Hg(0) removal and simultaneous removal process of Hg(0), NO and SO2 were also studied. Hg(0) is removed by oxidation of OH and oxidation of H2O2. The simultaneous removal efficiencies of 100% for SO2, 100% for Hg(0) and 88.3% for NO were obtained under optimal test conditions. The results demonstrated the feasibility of Hg(0) removal and simultaneous removal of Hg(0), SO2 and NO using Fenton solution in a bubbling reactor. PMID- 25804792 TI - A novel conversion of the groundwater treatment sludge to magnetic particles for the adsorption of methylene blue. AB - Iron sludge, produced from filtration and backwash of groundwater treatment plant, has long been considered as a waste for landfill. In this study, iron sludge was reused to synthesize Fe3O4 magnetic particles (MPs) by using a novel solvothermal process. Iron sludge contained abundant amounts of silicon, iron, and aluminum and did not exhibit magnetic properties. After treatment for 4h, the amorphous Fe in iron sludge was transformed into magnetite Fe3O4, which could be easily separated from aqueous solution with a magnet. The prepared particles demonstrated the intrinsic properties of soft magnetic materials and could aggregate into a size of 1 MUm. MPs treated for 10h exhibited excellent magnetic properties and a saturation magnetization value of 9 emu/g. The obtained particles presented the optimal adsorption of methylene blue under mild conditions, and the maximum adsorption capacity was 99.4 mg/g, which was higher than that of granular active carbon. The simple solvothermal method can be used to prepare Fe3O4 MPs from iron sludge, and the products could be applied to treatment of dyeing wastewater. PMID- 25804793 TI - Occurrence, distribution and ecological risk assessment of multiple classes of UV filters in marine sediments in Hong Kong and Japan. AB - Organic ultraviolet (UV) filters are used widely in various personal care products and their ubiquitous occurrence in the aquatic environment has been reported in recent years. However, data on their fate and potential impacts in marine sediments is limited. This study reports the occurrence and risk assessment of eleven widely used organic UV filters in marine sediment collected in Hong Kong and Tokyo Bay. Seven of the 11 target UV filters were detected in all sediment samples (median concentrations: G, AG, GG, and AG/GG were overrepresented in controls (P = 0.0001; odds ratio (OR) 0.22, 0.19, and 0.21 respectively). NAT2*5D 341T>C and NAT2*11A 481C>T were of comparable frequencies. For their combination, NAT2*5A, a slow acetylator, both TCTT and CCCT were overrepresented in patients (P < 0.001; OR 15.8 and 17.9 respectively). NAT2*5B (803A>G, 341T>C, 481C>T) was overrepresented in controls (P < 0.001; OR 0.12). Apparently, 803A>G ameliorated the combined effect of 341T>C and 481C>T. A similar effect was obtained with NAT2*5C (341T>A, 803A>G) (P < 0.0001; OR 0.11). For slow acetylator NAT2*7A 857G>A, GA and GA/AA were overrepresented in patients (P = 0.009 and 0.01; OR 2.74 and 2.72 respectively). NAT2*13 282C>T, NAT2*6B 590G>A, and NAT2*14A 191G>A were of comparable frequencies. NAT2 282C>A in combination with NAT2 857G>A (NAT2*7B) showed a synergistic effect in patients versus controls (P < 0.0001; OR 3.51). In conclusion, NAT2 gene polymorphism(s) with slow acetylator phenotype is generally associated with the risk of development of ALL in children. PMID- 25804799 TI - Vitamin D receptor gene polymorphisms and breast cancer risk among postmenopausal Egyptian women. AB - Many studies reported that vitamin D can protect against various types of cancers. The mechanism of vitamin D action is mediated by the vitamin D receptor (VDR). VDR may have anti-stress function because it has been identified as p53 direct target gene. This research was designed to investigate the role of VDR polymorphisms BsmI (rs 1544410), ApaI (rs 7975232), TaqI (rs 731236), and FokI (rs 10735810) in pathogenesis of breast cancer using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. The study included 130 postmenopausal breast cancer cases aged 49 to 65 years and 100 controls aged 50 to 72 years. A significantly increased risk of breast cancer among carriers of BsmI bb genotype was observed (OR = 2.5 (1.1-5.6), P = 0.025). Also, a significantly increased risk of breast cancer was detected among women carrying ApaI aa genotype (OR = 2.2 (1.02-4.5), P = 0.04), while no significant associations were observed between breast cancer risk and genotypes and allele frequencies of FokI and TaqI polymorphisms (P > 0.05). Our study showed that VDR gene polymorphisms (BsmI and ApaI) may contribute to breast cancer risk among postmenopausal women. PMID- 25804800 TI - Factors associated with treatment outcome, and long-term prognosis of patients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: a prospective multicenter study. AB - BACKGROUND: Patients with ulcerative colitis (UC) have elevated/activated myeloid lineage leucocytes and may respond favorably to adsorptive granulocyte/monocyte apheresis (GMA). However, there are patients who respond well to GMA, and patients who do not benefit. Therefore, predictive factors of GMA efficacy need to be defined. METHODS: In a prospective multicenter setting, 200 UC patients at 32 institutes received one GMA session per week over 10 weeks. Patients who achieved remission were followed for 12 months. The Clinical Activity Index (CAI) <=3 meant remission, and response meant CAI decreased by >=3. Quality of life was evaluated by the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: After final GMA, remission, response and no response rates were 67.0%, 15.0% and 18%, respectively. The remission group had a significant decrease in myeloid leucocytes and platelets. Corticosteroid dose decreased (P < 0.001); 49 of 97 patients on corticosteroids became steroid-free. Baseline CAI was lower in the remission group versus non-remission (P < 0.01), whereas IBDQ was higher in the remission group versus non-remission (P < 0.05). After 12 months, 52 of 134 patients had maintained remission. Disease duration was longer in the relapsed group versus maintained remission group (P = 0.041). Male gender, first UC episode and corticosteroid responder were significant factors for maintaining remission, whereas corticosteroid dependent UC was associating with relapse. DISCUSSION: Selective myeloid leucocyte depletion was effective for remission induction and improving patients' quality of life. Baseline demographics such as disease activity level, duration and corticosteroid dependency appear to predict response to GMA. Additionally, patients with a first UC episode who were drug naive responded well to GMA and achieved a favorable long-term disease course by avoiding pharmacologics from an early stage of their inflammatory bowel disease. These findings should help to end unnecessary use of medical resources by targeting GMA to patients who may respond well. PMID- 25804801 TI - Fibromatosis of the breast mimicking an abscess: case report of unusual sonographic features. AB - Fibromatosis of the breast, also known as a desmoid tumor, is extremely rare and most often appears as an aggressive lesion mimicking breast carcinoma. It lacks metastatic potential but can grow aggressively in a localized area. Ultrasonography often shows an irregular spiculated hypoechoic mass with posterior acoustic shadowing. We discuss a case of breast fibromatosis that presented as a painful palpable breast mass in a 32-year-old woman and mimicked an abscess in the sonogram. We found that this lesion displayed atypical sonographic features such as a heterogeneous echoic mass with an internal anechoic area. PMID- 25804802 TI - A Maitland-Japp inspired synthesis of dihydropyran-4-ones and their stereoselective conversion to functionalised tetrahydropyran-4-ones. AB - The Maitland-Japp reaction has been extended to the synthesis of highly functionalised dihydropyran-4-ones. These dihydropyran-4-ones can in turn be converted stereoselectively into tetrahydropyran-4-ones with tertiary and quaternary stereocentres via the one-pot addition of hydride or carbon nucleophiles and trapping with carbon electrophiles. The utility of this method is demonstrated by providing access to the functionalised tetrahydropyran units present in a component of the Civet fragrance and the anticancer polyketide lasonolide A. PMID- 25804803 TI - A computational mechanistic investigation of hydrogen production in water using the [Rh(III)(dmbpy)2Cl2](+)/[Ru(II)(bpy)3](2+)/ascorbic acid photocatalytic system. AB - We recently reported an efficient molecular homogeneous photocatalytic system for hydrogen (H2) production in water combining [Rh(III)(dmbpy)2Cl2](+) (dmbpy = 4,4' dimethyl-2,2'-bipyridine) as a H2 evolving catalyst, [Ru(II)(bpy)3](2+) (bpy = 2,2'-bipyridine) as a photosensitizer and ascorbic acid as a sacrificial electron donor (Chem. - Eur. J., 2013, 19, 781). Herein, the possible rhodium intermediates and mechanistic pathways for H2 production with this system were investigated at DFT/B3LYP level of theory and the most probable reaction pathways were proposed. The calculations confirmed that the initial step of the mechanism is a reductive quenching of the excited state of the Ru photosensitizer by ascorbate, affording the reduced [Ru(II)(bpy)2(bpy(-))](+) form, which is capable, in turn, of reducing the Rh(III) catalyst to the distorted square planar [Rh(I)(dmbpy)2](+) species. This two-electron reduction by [Ru(II)(bpy)2(bpy( ))](+) is sequential and occurs according to an ECEC mechanism which involves the release of one chloride after each one-electron reduction step of the Rh catalyst. The mechanism of disproportionation of the intermediate Rh(II) species, much less thermodynamically favoured, cannot be barely ruled out since it could also be favoured from a kinetic point of view. The Rh(I) catalyst reacts with H3O(+) to generate the hexa-coordinated hydride [Rh(III)(H)(dmbpy)2(X)](n+) (X = Cl(-) or H2O), as the key intermediate for H2 release. The DFT study also revealed that the real source of protons for the hydride formation as well as the subsequent step of H2 evolution is H3O(+) rather than ascorbic acid, even if the latter does govern the pH of the aqueous solution. Besides, the calculations have shown that H2 is preferentially released through an heterolytic mechanism by reaction of the Rh(III)(H) hydride and H3O(+); the homolytic pathway, involving the reaction of two Rh(III)(H) hydrides, being clearly less favoured. In parallel to this mechanism, the reduction of the Rh(III)(H) hydride into the penta coordinated species [Rh(II)(H)(dmbpy)2](+) by [Ru(II)(bpy)2(bpy(-))](+) is also possible, according to the potentials of the respective species determined experimentally and this is confirmed by the calculations. From this Rh(II)(H) species, the heterolytic and homolytic pathways are both thermodynamically favourable to produce H2 confirming that Rh(II)(H) is as reactive as Rh(III)(H) towards the production of H2. PMID- 25804804 TI - Is modulating virus virulence by induced systemic resistance realistic? AB - Induction of plant resistance, either achieved by chemicals (systemic acquired resistance, SAR) or by rhizobacteria (induced systemic resistance, ISR) is a possible and/or complementary alternative to manage virus infections in crops. SAR mechanisms operating against viruses are diverse, depending on the pathosystem, and may inhibit virus replication as well as cell-to-cell and long distance movement. Inhibition is often mediated by salicylic acid with the involvement of alternative oxidase and reactive oxygen species. However, salicylate may also stimulate a separate downstream pathway, leading to the induction of an additional mechanism, based on RNA-dependent RNA polymerase 1 mediated RNA silencing. Thus, SAR and RNA silencing would closely cooperate in the defence against virus infection. Despite tremendous recent progress in the knowledge of SAR mechanisms, only a few compounds, including benzothiadiazole and chitosan have been shown to reduce the severity of systemic virus disease in controlled environment and, more modestly, in open field. Finally, ISR induction, has proved to be a promising strategy to control virus disease, particularly by seed bacterization with a mixture of plant growth-promoting rhizobacteria. However, the use of any of these treatments should be integrated with cultivation practices that reduce vector pressure by the use of insecticides, or by Bt crops. PMID- 25804805 TI - The enhanced drought tolerance of rice plants under ammonium is related to aquaporin (AQP). AB - Previously, we demonstrated that drought resistance in rice seedlings was increased by ammonium (NH4(+)) treatment, but not by nitrate (NO3(-)) treatment, and that the change was associated with root development. To study the effects of different forms of nitrogen on water uptake and root growth under drought conditions, we subjected two rice cultivars (cv. 'Shanyou 63' hybrid indica and cv. 'Yangdao 6' indica, China) to polyethylene glycol-induced drought stress in a glasshouse using hydroponic culture. Under drought conditions, NH4(+) significantly stimulated root growth compared to NO3(-), as indicated by the root length, surface area, volume, and numbers of lateral roots and root tips. Drought stress decreased the root elongation rate in both cultivars when they were supplied with NO3(-), while the rate was unaffected in the presence of NH4(+). Drought stress significantly increased root protoplast water permeability, root hydraulic conductivity, and the expression of root aquaporin (AQP) plasma intrinsic protein (PIP) genes in rice plants supplied with NH4(+); these changes were not observed in plants supplied with NO3(-). Additionally, ethylene, which is involved in the regulation of root growth, accumulated in rice roots supplied with NO3(-) under conditions of drought stress. We conclude that the increase in AQP expression and/or activity enhanced the root water uptake ability and the drought tolerance of rice plants supplied with NH4(+). PMID- 25804806 TI - Glutathione peroxidases as redox sensor proteins in plant cells. AB - Glutathione peroxidases are thiol-based enzymes that catalyze the reduction of H2O2 and hydroperoxides to H2O or alcohols, they mitigate the toxicity of these compounds to the cell mainly using thioredoxin as an electron donor. Additionally, certain redox sensor and signaling functions are being ascribed to these enzymes in prokaryotes, fungi, and plants. We review the evolutionary history, enzymatic and biochemical evidence that make GPX proteins, in addition to being peroxiredoxins, important candidates for acting as redox sensor proteins in plants: (i) the lower peroxidase activity of Cys-GPX; (ii) the thiol catalytic center; (iii) the capacity to interact with regulatory proteins. All these characteristics suggest that at the basal level, plant GPXs have an important role in redox signal transduction in addition to their peroxidase activity. PMID- 25804807 TI - Optimising ketocarotenoid production in potato tubers: effect of genetic background, transgene combinations and environment. AB - Astaxanthin is a high value carotenoid produced by some bacteria, a few green algae, several fungi but only a limited number of plants from the genus Adonis. Astaxanthin has been industrially exploited as a feed supplement in poultry farming and aquaculture. Consumption of ketocarotenoids, most notably astaxanthin, is also increasingly associated with a wide range of health benefits, as demonstrated in numerous clinical studies. Currently astaxanthin is produced commercially by chemical synthesis or from algal production systems. Several studies have used a metabolic engineering approach to produce astaxanthin in transgenic plants. Previous attempts to produce transgenic potato tubers biofortified with astaxanthin have met with limited success. In this study we have investigated approaches to optimising tuber astaxanthin content. It is demonstrated that the selection of appropriate parental genotype for transgenic approaches and stacking carotenoid biosynthetic pathway genes with the cauliflower Or gene result in enhanced astaxanthin content, to give six-fold higher tuber astaxanthin content than has been achieved previously. Additionally we demonstrate the effects of growth environment on tuber carotenoid content in both wild type and astaxanthin-producing transgenic lines and describe the associated transcriptome and metabolome restructuring. PMID- 25804808 TI - Phylloxera (Daktulosphaira vitifoliae Fitch) alters the carbohydrate metabolism in root galls to allowing the compatible interaction with grapevine (Vitis ssp.) roots. AB - Gall forming phylloxera may compete for nutrients with meristematic tissues and develop heterotrophic structures that act as carbon sinks. In this work, we studied the underlying starch metabolism, sink-source translocation of soluble sugars towards and within root galls. We demonstrated that nodosities store carbohydrates by starch accumulation and monitored the expression of genes involved in the starch metabolic. Thereby we proved that the nodosity is symplastically connected to the source tissues through its development and that the starch metabolism is significantly affected to synthesize and degrade starch within the gall. Genes required for starch biosynthesis and degradation are up regulated. Among the carbohydrate transporters the expression of a glucose-6 phosphate translocater, one sucrose transporter and two SWEET proteins were increases, whereas hexose transporters, tonoplast monosaccharide transporter and Erd6-like sugar transporters were decreased. We found general evidence for plant response to osmotic stress in the nodosity as previously suggested for gall induction processes. We conclude that nodosities are heterogenous plant organs that accumulate starch to serve as temporary storage structure that is gradually withdrawn by phylloxera. Phylloxera transcriptionally reprograms gall tissues beyond primary metabolism and included downstream secondary processes, including response to osmotic stress. PMID- 25804810 TI - Ectopic expression of a stress-inducible glycosyltransferase from saffron enhances salt and oxidative stress tolerance in Arabidopsis while alters anchor root formation. AB - Glycosyltransferases play diverse roles in cellular metabolism by modifying the activities of regulatory metabolites. Three stress-regulated UDP glucosyltransferase-encoding genes have been isolated from the stigmas of saffron, UGT85U1, UGT85U2 and UGT85V1, which belong to the UGT85 family that includes members associated with stress responses and cell cycle regulation. Arabidopsis constitutively expressing UGT85U1 exhibited and increased anchor root development. No differences were observed in the timing of root emergence, in leaf, stem and flower morphology or flowering time. However, salt and oxidative stress tolerance was enhanced in these plants. Levels of glycosylated compounds were measured in these plants and showed changes in the composition of several indole-derivatives. Moreover, auxin levels in the roots were higher compared to wild type. The expression of several key genes related to root development and auxin homeostasis, including CDKB2.1, CDKB2.2, PIN2, 3 and 4; TIR1, SHR, and CYCD6, were differentially regulated with an increase of expression level of SHR, CYCD6, CDKB2.1 and PIN2. The obtained results showed that UGT85U1 takes part in root growth regulation via auxin signal alteration and the modified expression of cell cycle-related genes, resulting in significantly improved survival during oxidative and salt stress treatments. PMID- 25804811 TI - A ginseng PgTIP1 gene whose protein biological activity related to Ser(128) residue confers faster growth and enhanced salt stress tolerance in Arabidopsis. AB - Water movement across cellular membranes is mostly regulated by aquaporins. A tonoplast intrinsic protein PgTIP1 from Panax ginseng has been found to play an important role in plant growth and development, and also in the response of plants to abiotic stress. However, the regulation of its function and activity remains unknown. To answer this question, mutated forms of PgTIP1 were made by replacing Ser(128) with Ala (named S128A) or Asp (named S128D), and also by replacing Thr(54) with Ala (named T54A) or Asp (named T54D). Then, wild type or mutated PgTIP1 was expressed in yeast and water transport was monitored in protoplasts. The substitution of Ser(128) abolished the water channel activity of PgTIP1, while the substitution of Thr(54) did not inhibit its activity. Moreover, the overexpression of PgTIP1 but not S128A or S128D in Arabidopsis significantly increased plant growth as determined by biomass production, it also had a beneficial effect on salt stress tolerance. Importantly, the overexpression of PgTIP1 led to the altered expression of stress-related genes, which made the plants more tolerant to salt stress. Our results demonstrated that PgTIP1 conferred faster growth and enhanced tolerance to salt in Arabidopsis, and that its biological activity related to Ser(128) residue. PMID- 25804809 TI - Modification of plasma membrane NADPH oxidase activity in cucumber seedling roots in response to cadmium stress. AB - The aim of this study was to investigate the effect of cadmium on plasma membrane (PM) NADPH oxidase activity in cucumber roots. Plants were treated with cadmium for 1, 3 or 6 days. Some of the plants after 3-day exposure to cadmium were transferred to a medium without the heavy metal for the next 3 days. Treatment of plants with cadmium for 6 days stimulated the activity of NADPH oxidase. The highest stimulation of O2(*-) production by NADPH oxidase was observed in post stressed plants, which was correlated with the stimulation of activity of PM H(+) ATPase in the same conditions. In order to examine the effects of cadmium stresses on the expression level of genes encoding NADPH oxidase, putative cucumber homologs encoding RBOH proteins were selected and a real-time PCR assay was performed. NADPH is a substrate for oxidase; thus alterations in the activity of glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, NADP isocitrate dehydrogenase and NADP-malic enzyme under cadmium stress were studied. The activity of NADPH dehydrogenases was increased under cadmium stress. The results indicate that PM NADPH oxidase could be involved in plants' response to cadmium stress by affecting the activity of PM H(+)-ATPase, and NADPH-generating enzymes could play important roles in this process. PMID- 25804812 TI - Ectopic expression of EbFIE from apomictic Eulaliopsis binata in rice results in pleiotropic phenotypes likely due to interaction with OsCLF. AB - FERTILIZATION INDEPENDENT ENDOSPERM (FIE) is a core component of PcG complexes and functions in plant phase transition and seed generation. However, understanding in its function of apomictic monocot plants remains blank. Here an FIE homology EbFIE, has been isolated from apomictic Graminae species Eulaliopsis binata. EbFIE shares higher homology to OsFIE2 than OsFIE1, and has been classified into the monocot FIE2 clade. In addition, the broad expression pattern of EbFIE is also similar to OsFIE2. While, ectopic expression of EbFIE in rice resulted in pleiotropic phenotypes similar to that of OsFIE1 over-expressing plants. Meanwhile, EbFIE could bind OsCLF in vitro as OsFIE1 but different with OsFIE2. Molecular models comparison indicated that both EbFIE and OsFIE1 had a smaller E(z) protein binding groove than OsFIE2. Further site-directed mutagenesis analysis revealed that single amino acid substitution of I194F in OsFIE2 could improve its OsCLF binding capacity. Taken together, our results suggested that EbFIE was a conserved FIE homolog belonging to monocot FIE2 clade, but due to the similarity in protein conformation with FIE1, EbFIE might play a broad role in vegetative and reproductive development regulation by interaction with CLF homolog. PMID- 25804813 TI - Characterization of the heterotrimeric G-protein family and its transmembrane regulator from capsicum (Capsicum annuum L.). AB - Throughout evolution, organisms have created numerous mechanisms to sense and respond to their environment. One such highly conserved mechanism involves regulation by heterotrimeric G-protein complex comprised of alpha (Galpha), beta (Gbeta) and gamma (Ggamma) subunits. In plants, these proteins play important roles in signal transduction pathways related to growth and development including response to biotic and abiotic stresses and consequently affect yield. In this work, we have identified and characterized the complete heterotrimeric G-protein repertoire in the Capsicum annuum (Capsicum) genome which consists of one Galpha, one Gbeta and three Ggamma genes. We have also identified one RGS gene in the Capsicum genome that acts as a regulator of the G-protein signaling. Biochemical activities of the proteins were confirmed by assessing the GTP-binding and GTPase activity of the recombinant Galpha protein and its regulation by the GTPase acceleration activity of the RGS protein. Interaction between different subunits was established using yeast- and plant-based analyses. Gene and protein expression profiles of specific G-protein components revealed interesting spatial and temporal regulation patterns, especially during root development and during fruit development and maturation. This research thus details the characterization of the first heterotrimeric G-protein family from a domesticated, commercially important vegetable crop. PMID- 25804814 TI - Enhanced salt tolerance of alfalfa (Medicago sativa) by rstB gene transformation. AB - Generating salt tolerance forage plant is essential for use of the land affected by high salinity. A salt tolerance gene rstB was used as a selectable marker gene in Agrobacterium-mediated transformation of tobacco under a selective regime of 170mM NaCl. The transgenic plants showed clear improvement in salt tolerance. To improve salt tolerance of alfalfa (Medicago sativa L.), rstB gene was introduced into alfalfa genome by Agrobacterium-mediated transformation. No abnormal phenotype was observed among the transgenic plants when compared with wild type (wt) plants. Significant enhancement of resistance to salt-shock treatment was noted on the rstB transgenic (T0) plants. Transgenic second-generation (T1) seeds showed improved germination rate and seedling growth under salt-stress condition. Hindered Na(+) accumulation, but enhanced Ca(2+) accumulation was observed on the rstB T1 plants when subjected to salt-stresses. Enhanced calcium accumulation in transgenic plants was also verified by cytohistochemical localization of calcium. Under salt-stress of 50mM NaCl, about 15% of the transgenic plants finished their life-cycle but the wt plants had no flower formation. The results demonstrated that the expression of rstB gene improved salt tolerance in transgenic alfalfa. PMID- 25804815 TI - Biotechnological advances for combating Aspergillus flavus and aflatoxin contamination in crops. AB - Aflatoxins are toxic, carcinogenic, mutagenic, teratogenic and immunosuppressive byproducts of Aspergillus spp. that contaminate a wide range of crops such as maize, peanut, and cotton. Aflatoxin not only affects crop production but renders the produce unfit for consumption and harmful to human and livestock health, with stringent threshold limits of acceptability. In many crops, breeding for resistance is not a reliable option because of the limited availability of genotypes with durable resistance to Aspergillus. Understanding the fungal/crop/environment interactions involved in aflatoxin contamination is therefore essential in designing measures for its prevention and control. For a sustainable solution to aflatoxin contamination, research must be focused on identifying and improving knowledge of host-plant resistance factors to aflatoxin accumulation. Current advances in genetic transformation, proteomics, RNAi technology, and marker-assisted selection offer great potential in minimizing pre harvest aflatoxin contamination in cultivated crop species. Moreover, developing effective phenotyping strategies for transgenic as well as precision breeding of resistance genes into commercial varieties is critical. While appropriate storage practices can generally minimize post-harvest aflatoxin contamination in crops, the use of biotechnology to interrupt the probability of pre-harvest infection and contamination has the potential to provide sustainable solution. PMID- 25804816 TI - Dissecting root proteome of transgenic rice cultivars unravels metabolic alterations and accumulation of novel stress responsive proteins under drought stress. AB - Generation of drought tolerant rice plants by overexpressing Arabidopsis DREB1A is a significant development for abiotic stress research. However, the metabolic network regulated in the drought tolerant transgenic rice plants is poorly understood. In this research study, we have demonstrated the comparative proteome analysis between the roots of wild type and transgenic DREB1A overexpressing homozygous plants under drought stress condition. After 7d of dehydration stress at reproductive stage, the plants were re-watered for 24h. The roots were collected separately from wild type and transgenic plants grown under water, drought stress and re-watering conditions and total proteins were analyzed by two dimensional gel electrophoresis (2-DE) coupled with mass spectrometry (MS). Among the large number of differentially accumulated spots, 30, 27 and 20 spots were successfully identified as differentially expressed proteins in three different conditions respectively. The major class of identified proteins belongs to carbohydrate and energy metabolism category while stress and defense related proteins are especially up-accumulated under drought stress in both the plants. A novel protein, R40C1 was reported to be up-accumulated in roots of transgenic plants which may play an important role in generation of drought tolerant plants. Protein-protein interaction helps to identify the network of drought stress signaling pathways. PMID- 25804817 TI - Constitutive high-level SOS1 expression and absence of HKT1;1 expression in the salt-accumulating halophyte Salicornia dolichostachya. AB - We investigated the effects of salinity on ion accumulation and expression of candidate salt tolerance genes in the highly tolerant salt accumulating halophyte Salicornia dolichostachya and the taxonomically related glycophytic Spinacia oleracea. S. dolichostachya, in comparison with S. oleracea, constitutively expressed SOS1 at a high level, but did not detectably express HKT1;1. These findings suggest that the constitutive high level of shoot salt accumulation in S. dolichostachya is accomplished through enhancement of SOS1-mediated Na(+) xylem loading, in combination with complete suppression of HKT1;1-mediated Na(+) retrieval from the xylem. Our findings demonstrate the importance of gene expression comparisons between highly tolerant halophytes and taxonomically related glycophytes to improve the understanding of mechanisms of Na(+) movement and salt tolerance in plants. PMID- 25804818 TI - The evolution of drought escape and avoidance in natural herbaceous populations. AB - While the functional genetics and physiological mechanisms controlling drought resistance in crop plants have been intensely studied, less research has examined the genetic basis of adaptation to drought stress in natural populations. Drought resistance adaptations in nature reflect natural rather than human-mediated selection and may identify novel mechanisms for stress tolerance. Adaptations conferring drought resistance have historically been divided into alternative strategies including drought escape (rapid development to complete a life cycle before drought) and drought avoidance (reducing water loss to prevent dehydration). Recent studies in genetic model systems such as Arabidopsis, Mimulus, and Panicum have begun to elucidate the genes, expression profiles, and physiological changes responsible for ecologically important variation in drought resistance. Similar to most crop plants, variation in drought escape and avoidance is complex, underlain by many QTL of small effect, and pervasive gene by environment interactions. Recently identified major-effect alleles point to a significant role for genetic constraints in limiting the concurrent evolution of both drought escape and avoidance strategies, although these constraints are not universally found. This progress suggests that understanding the mechanistic basic and fitness consequences of gene by environment interactions will be critical for crop improvement and forecasting population persistence in unpredictable environments. PMID- 25804819 TI - Down-regulation of BdBRI1, a putative brassinosteroid receptor gene produces a dwarf phenotype with enhanced drought tolerance in Brachypodium distachyon. AB - Brassinosteroids (BRs) play important roles in plant growth, development and responses to a range of environmental cues. Although the mechanism of how BRs regulate growth and development is well-understood in Arabidopsis, the effect of BRs on stress tolerance, particularly drought tolerance remains unknown. We isolated a BRI1 (BRASSINOSTEROID INSENSITIVE 1) homologous gene, BdBRI1 from Brachypodium distachyon, a model for temperate grasses and cereals, created and characterized RNA interference (RNAi) knockdown mutants for BdBRI1 in Brachypodium. The loss-of-function BdBRI1-RNAi mutants exhibited reduced plant height, shortened internodes, narrow and short leaf, and reduced expression of BR signaling genes, BdBES1, BdBZR1, BdBLE2, and enhanced expression of BR biosynthesis genes BdD2, BdCPD and BdDWF4. More importantly, BdBRI1 RNAi mutants exhibited enhanced drought tolerance, accompanied by highly elevated expression of drought-responsive genes, BdP5CS, BdCOR47/BdRD17, together with BdERD1 and BdRD26, two putative targets of the transcription factors BES1 and BZR1 that are key components of the BR signaling pathway. Our results suggest that BR signaling and biosynthesis are largely conserved among Arabidopsis, rice and Brachypodium, and that BR signaling plays an important role in drought tolerance by directly regulating expression of key drought-responsive genes. The effect of BR biosynthesis or crosstalks between BR and other hormones or components of stress signaling pathways on drought tolerance is discussed. PMID- 25804820 TI - Dual protein trafficking to secretory and non-secretory cell compartments: clear or double vision? AB - Approximately 18% of Arabidopsis thaliana proteins encode a signal peptide for translocation to the endoplasmic reticulum (ER), the gateway of the eukaryotic secretory pathway. However, it was recently discovered that some ER proteins can undergo both co-translational import into the ER/secretory pathway and trafficking to compartments outside of the secretory pathway. This phenomenon is observed among members of the protein disulfide isomerase (PDI) family, which are traditionally regarded as ER enzymes involved in protein folding. Although classical PDIs possess an N-terminal signal peptide and a C-terminal ER retention signal, some also dual localize to secretory and non-secretory compartments, including mammalian PDI ERp57, Chlamydomonas reinhardtii PDI RB60, and A. thaliana AtPDI2. ERp57 is present in both the ER and nucleus where it influences gene transcription. RB60 localizes to the ER and chloroplast where it modulates the redox state of polyadenylate-binding protein RB47. AtPDI2, which interacts with transcription factor MEE8, localizes to the ER-secretory pathway and the nucleus. A model proposing secretory trafficking of AtPDI2 and nuclear co translocation of an AtPDI2-MEE8 complex illustrates the diversity of dual targeting mechanisms, the multifunctional roles of some PDIs, and the potential co-translocation of other proteins to multiple subcellular compartments. PMID- 25804822 TI - Reconstruction of chronic triceps tendon avulsion using synthetic mesh graft in a dog. AB - Avulsion of the triceps tendon insertion was diagnosed in a two-year-old Poodle mixed breed dog 10 weeks after traumatic injury. Diagnosis was confirmed with clinical examination and magnetic resonance imaging (MRI). The tendon was reconstructed using tension-relieving sutures augmented with a synthetic degradable porous polyurethane urea onlay mesh graft. The repair was immobilized using a transarticular external skeletal fixator with staged increases in elbow flexion. Treatment was successful, with signs of healing confirmed by MRI and normal clinical function one year after surgery. The successful outcome in this case suggests that surgical repair of a chronic triceps tendon injury using a synthetic mesh augmentation may be successful in similar cases. PMID- 25804824 TI - BioMARK as electrophysiological tool for assessing children at risk for (central) auditory processing disorders without reading deficits. AB - Biological Marker of auditory processing (BioMARK) is an electrophysiological test tool widely known as Speech-evoked ABR. Several previous investigations have shown the utility of speech-evoked ABR in the diagnosis of language based processing deficits like learning disability and specific language impairment; however missing from literature is a study that has ruled out the existence of comorbidity of such conditions and carefully delineated the efficacy of speech evoked ABR in children with children with auditory processing disorders sans reading deficits. Hence, the present study aimed at investigating Speech-evoked ABR in children with auditory processing disorders without reading problems. A total of 336 school going children in the age range of 8-12 years were screened for presence of central auditory processing deficits. Among the 51 children who were identified as at risk, 15 were randomly selected and served as experimental group. The control group comprised of fifteen age matched children. The inter group comparison was done using MANOVA, which revealed significant prolongations of latencies of waves V and A (p = 0.001) along with marginal reductions in V/A slope (p = 0.052) and amplitude of responses to first formant (p = 0.065). The responses to higher frequencies did not differ between the groups. Speech-evoked ABR are affected in children who are at risk of central auditory processing disorders sans reading deficits which probably indicates the presence of abnormal brainstem encoding of speech signal in this population. PMID- 25804823 TI - The DIEP flap breast reconstruction: Starting from scratch in a university hospital. AB - PURPOSE: The deep inferior epigastric perforator (DIEP) flap provides excellent results when performed by a trained surgical team. However, the beginning of the procedure is often complicated. To date, few authors have published their initial experiences. This study presents our team's experience using a DIEP flap in breast reconstruction. METHODS: From June 2008 until December 2013, the same leading operator performed 132 consecutive DIEP flaps. Breast reconstructions were immediate (n=18) or delayed (n=114), unilateral (n=110) or bilateral (n=11). The learning curve was assessed using the operating time, ischemic time, postoperative hospital stay, and complications. For statistical comparisons, unilateral reconstructions were divided into five chronologic groups of 22 consecutive DIEP flaps and two chronologic groups of 55 flaps. RESULTS: The average time of surgery was 291 min (range, 185-645) for unilateral breast reconstruction and 513 min (range, 400-790) for bilateral breast reconstruction. The global complication rate was 24.5%. In the unilateral series, the time of surgery decreased progressively from 415 min to 233 min (P=4.8*10(-8)). The mean postoperative hospital stay was reduced from 7.14 days to 6.32 days (P=0.042). The complications and flap failure rates had regular time distributions. Initially, the revision rate reached 50% for the first ten unilateral cases but decreased rapidly and remained steady at 6% for the following cases (P=0.0012). CONCLUSIONS: Our initial experience of DIEP flap breast reconstruction showed a significant improvement of surgical performances exceeding 50 cases, with a critical ten first case period. PMID- 25804821 TI - Destructuring plant biomass: focus on fungal and extremophilic cell wall hydrolases. AB - The use of plant biomass as feedstock for biomaterial and biofuel production is relevant in the current bio-based economy scenario of valorizing renewable resources. Fungi, which degrade complex and recalcitrant plant polymers, secrete different enzymes that hydrolyze plant cell wall polysaccharides. The present review discusses the current research trends on fungal, as well as extremophilic cell wall hydrolases that can withstand extreme physico-chemical conditions required in efficient industrial processes. Secretomes of fungi from the phyla Ascomycota, Basidiomycota, Zygomycota and Neocallimastigomycota are presented along with metabolic cues (nutrient sensing, coordination of carbon and nitrogen metabolism) affecting their composition. We conclude the review by suggesting further research avenues focused on the one hand on a comprehensive analysis of the physiology and epigenetics underlying cell wall degrading enzyme production in fungi and on the other hand on the analysis of proteins with unknown function and metagenomics of extremophilic consortia. The current advances in consolidated bioprocessing, altered secretory pathways and creation of designer plants are also examined. Furthermore, recent developments in enhancing the activity, stability and reusability of enzymes based on synergistic, proximity and entropic effects, fusion enzymes, structure-guided recombination between homologous enzymes and magnetic enzymes are considered with a view to improving saccharification. PMID- 25804825 TI - Restrictive myocardium with an unusual pattern of apical hypertrophic cardiomyopathy. AB - Loeffler endocarditis is a fibrous restrictive cardiomyopathy thought to be caused by persistent eosinophilia. It is difficult to diagnose, and the prognosis is often poor if the underlying eosinophilia is not promptly recognized and treated. We describe the case of a middle-aged woman treated for hypertrophic cardiomyopathy first detected during a routine check-up at age 35years but whose symptoms gradually progressed over the next 14years. Right ventricular biopsy showed extensive fibrosis of the endocardial tissue, and right heart catheterization revealed right heart failure and a low cardiac output state. Ultimately, she became reliant on inotropic and mechanical cardiovascular support, but we were not able to bridge her to transplant. Autopsy findings were typical of endocardial fibroelastosis, but she had not suffered from any tropical disease or traveled to high-risk areas. The presence of abnormal capillary proliferation suggested a diagnosis of Loeffler endocarditis. Nonetheless, apart from a 6-month period of eosinophilia 7years before her death, a history of well controlled asthma and several drug sensitivities, we were unable to definitively identify the disease trigger. It is critical to diagnose and treat the underlying eosinophilia of Loeffler endocarditis to avoid a poor prognosis. This case highlights the importance of considering the diagnosis of eosinophilic endomyocarditis in patients with an unusual pattern of apical hypertrophic cardiomyopathy (or myocardial fibrosis of unknown etiology), even when there is no apparent history of eosinophilia. PMID- 25804826 TI - Parents of children with physical disabilities perceive that characteristics of home exercise programs and physiotherapists' teaching styles influence adherence: a qualitative study. AB - QUESTION: What are the perceptions of parents of children with physical disabilities about the home exercise programs that physiotherapists prescribe? How do these perceptions affect adherence to home exercise programs? DESIGN: Qualitative study using focus groups and a modified grounded theory approach. PARTICIPANTS: Parents of children with physical disabilities who have been prescribed a home exercise program by physiotherapists. RESULTS: Twenty-eight parents participated in the focus groups. Two key themes that related to adherence to home exercise programs in young children with physical disabilities were identified: the characteristics of the home exercise program; and the characteristics of the physiotherapist's teaching style. In the first theme, the participants described their experiences regarding their preference for exercises, which was related to the perceived effects of the exercises, their complexity, and the number of exercises undertaken. These factors determined the amount of time spent performing the exercises, the effect of the exercises on the family's relationships, and any sense of related burden. In the second theme, participants revealed that they adhered better to prescribed exercises when their physiotherapist made an effort to build their confidence in the exercises, helped the parents to incorporate the home exercise program into their daily routine, provided incentives and increased motivation. CONCLUSION: Parents perceive that their children's adherence to home-based exercises, which are supervised by the parents, is more successful when the physiotherapist's style and the content of the exercise program are positively experienced. These findings reveal which issues should be considered when prescribing home exercise programs to children with physical disabilities. [Lillo-Navarro C, Medina-Mirapeix F, Escolar-Reina P, Montilla-Herrador J, Gomez-Arnaldos F, Oliveira-Sousa SL (2015) Parents of children with physical disabilities perceive that characteristics of home exercise programs and physiotherapists' teaching styles influence adherence: a qualitative study.Journal of Physiotherapy61: 81-86]. PMID- 25804827 TI - American Society of Hematology Annual Meeting 2014: highlights in multiple myeloma. AB - Multiple myeloma (MM) had a major presence at this meeting with 855 abstracts related to MM, 24 oral presentations and 106 posters. This, coupled with the record attendance at this year's meeting, made it a positive year for patients and clinicians alike as much of the presented data are likely to lead to major advances in the field of myeloma. Key areas of focus included: high-risk smoldering disease, minimal residual disease for monitoring response to therapy, novel therapies in clinical trials, including carfilzomib and daratumumab, and imaging modalities for MM. PMID- 25804829 TI - Reassortant highly pathogenic influenza A H5N2 virus containing gene segments related to Eurasian H5N8 in British Columbia, Canada, 2014. AB - In late November 2014 higher than normal death losses in a meat turkey and chicken broiler breeder farm in the Fraser Valley of British Columbia initiated a diagnostic investigation that led to the discovery of a novel reassortant highly pathogenic avian influenza (HPAI) H5N2 virus. This virus, composed of 5 gene segments (PB2, PA, HA, M and NS) related to Eurasian HPAI H5N8 and the remaining gene segments (PB1, NP and NA) related to North American lineage waterfowl viruses, represents the first HPAI outbreak in North American poultry due to a virus with Eurasian lineage genes. Since its first appearance in Korea in January 2014, HPAI H5N8 spread to Western Europe in November 2014. These European outbreaks happened to temporally coincide with migratory waterfowl movements. The fact that the British Columbia outbreaks also occurred at a time associated with increased migratory waterfowl activity along with reports by the USA of a wholly Eurasian H5N8 virus detected in wild birds in Washington State, strongly suggest that migratory waterfowl were responsible for bringing Eurasian H5N8 to North America where it subsequently reassorted with indigenous viruses. PMID- 25804830 TI - Predicting Positive Education Outcomes for Emerging Adults in Mental Health Systems of Care. AB - Emerging adults who receive services based on positive youth development models have shown an ability to shape their own life course to achieve positive goals. This paper reports secondary data analysis from the Longitudinal Child and Family Outcome Study including 248 culturally diverse youth ages 17 through 22 receiving mental health services in systems of care. After 12 months of services, school performance was positively related to youth ratings of school functioning and service participation and satisfaction. Regression analysis revealed ratings of young peoples' perceptions of school functioning, and their experience in services added to the significant prediction of satisfactory school performance, even controlling for sex and attendance. Finally, in addition to expected predictors, participation in planning their own services significantly predicted enrollment in higher education for those who finished high school. Findings suggest that programs and practices based on positive youth development approaches can improve educational outcomes for emerging adults. PMID- 25804828 TI - Paired TCRalphabeta analysis of virus-specific CD8(+) T cells exposes diversity in a previously defined 'narrow' repertoire. AB - T-cell receptor (TCR) usage has an important role in determining the outcome of CD8(+) cytotoxic T-lymphocyte responses to viruses and other pathogens. However, the characterization of TCR usage from which such conclusions are drawn is based on exclusive analysis of either the TCRalpha chain or, more commonly, the TCRbeta chain. Here, we have used a multiplexed reverse transcription-PCR protocol to analyse the CDR3 regions of both TCRalpha and beta chains from single naive or immune epitope-specific cells to provide a comprehensive picture of epitope specific TCR usage and selection into the immune response. Analysis of TCR repertoires specific for three influenza-derived epitopes (D(b)NP(366), D(b)PA(224) and D(b)PB1-F2(62)) showed preferential usage of particular TCRalphabeta proteins in the immune repertoire relative to the naive repertoire, in some cases, resulting in a complete shift in TRBV preference or CDR3 length, and restricted repertoire diversity. The NP(366)-specific TCRalphabeta repertoire, previously defined as clonally restricted based on TCRbeta analysis, was similarly diverse as the PA(224)- and PB1-F2(62)-specific repertoires. Intriguingly, preferred TCR characteristics (variable gene usage, CDR3 length and junctional gene usage) appeared to be able to confer specificity either independently or in concert with one another, depending on the epitope specificity. These data have implications for established correlations between the nature of the TCR repertoire and response outcomes after infection, and suggest that analysis of a subset of cells or a single TCR chain does not accurately depict the nature of the antigen-specific TCRalphabeta repertoire. PMID- 25804831 TI - Novel multiporphyrin functionalized single-walled carbon nanotubes. AB - Porphyrin monomers, 5,15-bis(4-(2,5,8,11-tetraoxatridecan-13-yloxy)phenyl)-10,20 bis(3-iodophenyl)porphyrin zinc (5a) and 5,10-bis(4-(2,5,8,11-tetraoxatridecan-13 yloxy)phenyl)-15,20-bis(3-iodophenyl)porphyrin zinc (5b), and their oligomers 6a and 6b were synthesized and characterized. The titration experiment of the monomers was carried out in THF by changing the solution percent of water. The optical properties (UV-vis and fluorescence spectra) of the monomers that possess slightly red-shifted optical spectra in water compared to the spectra obtained in THF are reported. The newly prepared porphyrin constructs were also mixed with SWCNTs to generate noncovalent hybrid materials. PMID- 25804832 TI - A Novel Cobalt-Sensitive Fluorescent Chemosensor Based on Ligand Capped CdS Quantum Dots. AB - In this work, a ligand capped CdS QDs was synthesized, characterized and its fluorescence behavior was studied. The surface of the CdS QDs was modified using N-(3-methyl-2-(thiophene-2-carboxamido) phenyl) thiophene-2-carboxamide. The immobilized ligand on the surface of the CdS QDs can interact by cationic species due to the existence of donating atoms in its structures. Thus, effect of some metal cations on the fluorescent intensity of the ligand capped CdS QDs were studied. It was found that fluorescence intensity of the modified CdS QDs quenched selectively by addition of Co(II) ion in comparison with other cations tested. The ligand capped CdS QDs can be used as a fluorescent bulk chemosensor for detection of Co(II) ions. The fluorescent quenching is linear in the range of 1.0 * 10(-5) to 1.5 * 10(-4) mol L(-1) of Co(II) ions. The limit of detection was obtained 8.3 * 10(-7) mol L(-1). The nanosensor exhibits high selectivity toward Co(II) ions in comparison with common metal ions. PMID- 25804833 TI - Trends in consumption of ultra-processed foods and obesity in Sweden between 1960 and 2010. AB - OBJECTIVE: To investigate how consumption of ultra-processed foods has changed in Sweden in relation to obesity. DESIGN: Nationwide ecological analysis of changes in processed foods along with corresponding changes in obesity. Trends in per capita food consumption during 1960-2010 were investigated using data from the Swedish Board of Agriculture. Food items were classified as group 1 (unprocessed/minimally processed), group 2 (processed culinary ingredients) or group 3 (3.1, processed food products; and 3.2, ultra-processed products). Obesity prevalence data were pooled from the peer-reviewed literature, Statistics Sweden and the WHO Global Health Observatory. SETTING: Nationwide analysis in Sweden, 1960-2010. SUBJECTS: Swedish nationals aged 18 years and older. RESULTS: During the study period consumption of group 1 foods (minimal processing) decreased by 2 %, while consumption of group 2 foods (processed ingredients) decreased by 34 %. Consumption of group 3.1 foods (processed food products) increased by 116 % and group 3.2 foods (ultra-processed products) increased by 142 %. Among ultra-processed products, there were particularly large increases in soda (315 %; 22 v. 92 litres/capita per annum) and snack foods such as crisps and candies (367 %; 7 v. 34 kg/capita per annum). In parallel to these changes in ultra-processed products, rates of adult obesity increased from 5 % in 1980 to over 11 % in 2010. CONCLUSIONS: The consumption of ultra-processed products (i.e. foods with low nutritional value but high energy density) has increased dramatically in Sweden since 1960, which mirrors the increased prevalence of obesity. Future research should clarify the potential causal role of ultra processed products in weight gain and obesity. PMID- 25804835 TI - Self-assembly of Janus particles under shear. AB - We investigate the self-assembly of colloidal Janus particles under shear flow by employing hybrid molecular dynamics simulations that explicitly take into account hydrodynamic interactions. Under quiescent conditions, the amphiphilic colloids form spherical micellar aggregates of different sizes, where the solvophobic hemispheres are directed towards the core and the solvophilic caps are exposed to the solvent. When sufficiently strong shear is applied, the micelles disaggregate with a consequent decay of the average cluster size. Nonetheless, we find an intermediate shear rate regime where the balance between rearrangement and dissociation favors the growth of the aggregates. Additionally, our simulations show that clusters composed of either 6 or 13 particles are the most stable towards the shear flow due to their high geometric symmetry. Our findings open up a new range of applications for Janus particles, ranging from biotechnology to sensor systems. PMID- 25804834 TI - Environmental heat stress modulates thyroid status and its response to repeated endotoxin challenge in steers. AB - The objective of this study was to evaluate in cattle, the effects of acute exposure to a heat stress (HS) environment on the status of the pituitary (thyrotropin, TSH)-thyroid (thyroxine, T4)-peripheral tissue T4 deiodination (type 1 5'-deiodinase [D1]; triiodothyronine [T3]; reverse-triiodothyronine [rT3]) axis, and the further response of this pituitary-thyroid-peripheral tissue axis (PTTA) to perturbation caused by the induction of the proinflammatory innate immune state provoked by the administration of gram-negative bacteria endotoxin (lipopolysaccharide [LPS]). Ten steers (318 +/- 49 kg body weight) housed in controlled environment chambers were subjected to either a thermoneutral (TN: constant 19 degrees C) or HS temperature conditions (cyclical daily temperatures: 32.2 degrees C-40.0 degrees C) for a total period of 9 d. To minimize the effects of altered plane of nutrition due to HS, steers in TN were pair-fed to animals in HS conditions. Steers received 2 LPS challenges 3 d apart (LPS1 and LPS2; 0.2 MUg/kg body weight, intravenously, Escherichia coli 055:B5) with the first challenge administered on day 4 relative to the start of the environmental conditioning. Jugular blood samples were collected at 0, 1, 2, 4, 7, and 24 h relative to the start of each LPS challenge. Plasma TSH, T4, T3, and rT3 were measured by radioimmunoassay. Liver D1 activity was measured in biopsy samples collected before the LPS1 (0 h) and 24 h after LPS2. Before the start of LPS1, HS decreased (P < 0.01 vs TN) plasma TSH (40%), T4 (45.4%), and T3 (25.9%), but did not affect rT3 concentrations. In TN steers, the LPS1 challenge decreased (P < 0.01 vs 0 h) plasma concentrations of TSH between 1 and 7 h and T4 and T3 at 7 and 24 h. In HS steers, plasma TSH concentrations were decreased at 2 h only (P < 0.05), whereas plasma T3 was decreased at 7 and 24 h (P < 0.01). Whereas plasma T4 concentrations were already depressed in HS steers at 0 h, LPS1 did not further affect the levels. Plasma rT3 concentrations were increased in all steers at 4, 7, and 24 h after LPS1 (P < 0.01). The patterns of concentration change of T4, T3, and rT3 during LPS2 mirrored those observed in LPS1; the responses in plasma TSH were of smaller magnitude than those incurred after LPS1. The LPS challenges reduced (P < 0.01) hepatic activity of D1 in all animals but no differences were observed between steers subjected to TN or HS environment. The data are consistent with the concept that acute exposure of cattle to a HS environment results in the depression of the pituitary and thyroid components of the PTTA, whereas a normal capacity to generate T3 from T4 in the liver is preserved. The data also suggest that LPS challenge further suppresses all components of the PTTA including liver T3 generation, and these PTTA perturbations are more pronounced in steers that encounter a HS exposure. PMID- 25804837 TI - Perilipin 5 mediated lipid droplet remodelling revealed by coherent Raman imaging. AB - Accumulation of fat in muscle tissue as intramyocellular lipids (IMCLs) is closely related to the development of insulin resistance and subsequent type 2 diabetes. Most IMCLs organize into lipid droplets (LDs), the fates of which are regulated by lipid droplet coat proteins. Perilipin 5 (PLIN5) is an LD coating protein, which is strongly linked to lipid storage in muscle tissue. Here we employ a tandem in vitro/ex vivo approach and use chemical imaging by label-free, hyperspectral coherent Raman microscopy to quantify compositional changes in individual LDs upon PLIN5 overexpression. Our results directly show that PLIN5 overexpression in muscle alters individual LD composition and physiology, resulting in larger LDs with higher esterified acyl chain concentration, increased methylene content, and more saturated lipid species. These results suggest that lipotoxic protection afforded by natural PLIN5 upregulation in muscle involves molecular changes in lipid composition within LDs. PMID- 25804836 TI - The M949_1556 gene plays a role on the bacterial antigenicity and pathogenicity of Riemerella anatipestifer. AB - Riemerella anatipestifer is one of the most economically important pathogens of farm ducks worldwide. However, the molecular mechanisms regarding its antigenicity and pathogenicity are poorly understood. We previously constructed a library of random Tn4351 transposon mutants using R. anatipestifer strain CH3. In this study, M949_1556 gene inactivated mutant strain CH3DeltaM949_1556 was identified by screening of the library using monoclonal antibody against R. anatipestifer serotype 1 lipopolysaccharide (LPS) (anti-LPS MAb) followed by sequence analysis. The mutant strain presented no reactivity to the anti-LPS MAb in an indirect ELISA. Animal studies showed that the median lethal dose (LD50) of CH3DeltaM949_1556 was >10(10) colony forming units (CFU), which was attenuated more than 50 times, compared with that of wild-type strain CH3 (LD50=2*10(8) CFU). The bacterial loads in the blood of CH3DeltaM949_1556 infected ducks were significantly decreased, compared with those of CH3-infected ducks. In addition, CH3DeltaM949_1556 presented significant, higher susceptibility to complement dependent killing than CH3 did in vitro. Furthermore, CH3DeltaM949_1556 showed increased bacterial adhesion and invasion capacities to Vero cells. Immunization with CH3DeltaM949_1556-inactived vaccine was effective in protecting the ducks from challenge with R. anatipestifer serotype 1 strain WJ4, serotype 2 strain Yb2 and serotype 10 strain HXb2, suggesting that the mutant strain CH3DeltaM949_1556 could provide a broad cross-protection among R. anatipestifer serotypes 1, 2 and 10 strains. Our results demonstrated that the M949_1556 gene plays a role on the bacterial antigenicity and pathogenicity of R. anatipestifer. PMID- 25804840 TI - Waiting times for x ray results in England are increasing, figures show. PMID- 25804838 TI - Evaluation of a bacteriochlorin-based photosensitizer's anti-tumor effect in vitro and in vivo. AB - PURPOSE: Bacteriochlorin derivatives are promising photosensitive agents for photodynamic therapy (PDT) of tumors. In the current study, the photodynamic activity of a novel bacteriochlorin derivative, cis-2, 3, 12, 13 tetracarboxymethyl-5, 10, 15, 20-tetraphenyl bacteriochlorin (TCTB), was evaluated both in vitro and in vivo. METHODS: Physicochemical characteristics of the novel photosensitizer were measured. The efficiency of TCTB-PDT in vitro was analyzed by MTT assay, clonogenic assay and in situ trypan blue exclusion test. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The accumulation of TCTB in human malignant tumor cells was measured by fluorescence spectrometer, and the pathway of cell death was analyzed by flow cytometry. S180 tumor model was used to evaluate the anti tumor effects of TCTB-PDT. And histopathological study was also used to confirm the anti-tumor effect. RESULTS: TCTB shows a singlet oxygen quantum yield of 0.56 and displays a characteristic long wavelength absorption peak at 732 nm. The accumulation of TCTB increased in time-dependent manner, and it was found in cytoplasm and nuclear membranes. In vitro PDT using TCTB and Nd:YAG laser showed drug concentration-, laser dose-dependent cytotoxicity to human esophageal cancer Eca-109 cells. In mice bearing osteosarcoma S180 tumors, the combined use of 10 mg/kg TCTB and 120 J/cm(2) showed superior anti-tumor activity. Histology examination of tumor tissues revealed that PDT using TCTB and the Nd:YAG laser induced tumor cells shrunken and necrotic. CONCLUSION: In in vitro and in vivo studies, we found that TCTB has excellent anti-tumor effect. It suggests that TCTB is a potential photosensitizer of PDT for cancer. PMID- 25804839 TI - Long-term follow-up of rituximab plus first-line mitoxantrone, chlorambucil, prednisolone and interferon-alpha as maintenance therapy in follicular lymphoma. AB - PURPOSE: The randomised, controlled OSHO#39 study showed promising results using first-line mitoxantrone, chlorambucil and prednisolone (MCP) chemotherapy plus rituximab in patients with advanced symptomatic follicular lymphoma (FL) in need of therapy. The aim of this long-term follow-up was to investigate whether clinical benefits are maintained after up to 9 years of observation. METHODS: Following the 4-year follow-up of OSHO#39, 77 FL patients who received rituximab plus MCP (R-MCP) and 52 patients who received MCP (129 patients alive and not previously censored in total) were followed for 5 additional years in this prospective, non-interventional, observational study. For the efficacy analysis, data were jointly analysed with OSHO#39 data (FL intention-to-treat population: 105 patients R-MCP, 96 MCP). Patients not included in the 5-year follow-up were censored. RESULTS: For surviving patients, median follow-up was 102 months (R MCP) and 87 months (MCP). Although median overall survival (OS) was not yet reached, OS was longer for patients with R-MCP compared with MCP (p = 0.0057), with 8-year-survival rates of 76.1 versus 55.9%. Further time-to-event data were substantially longer for the R-MCP group than for MCP alone: median progression free survival (PFS) was 93.4 versus 34.9 months, and median event-free survival (EFS) 89.6 versus 26.5 months. Unplanned subanalyses of patients with and without interferon maintenance showed improved PFS and EFS without an impact on OS. CONCLUSIONS: The addition of rituximab to first-line MCP chemotherapy improves clinical outcomes in advanced FL patients and translates into long-term OS benefits. R-MCP remains a promising standard option for this patient group. PMID- 25804842 TI - Computed Tomography Image Compressibility and Limitations of Compression Ratio Based Guidelines. AB - Finding optimal compression levels for diagnostic imaging is not an easy task. Significant compressibility variations exist between modalities, but little is known about compressibility variations within modalities. Moreover, compressibility is affected by acquisition parameters. In this study, we evaluate the compressibility of thousands of computed tomography (CT) slices acquired with different slice thicknesses, exposures, reconstruction filters, slice collimations, and pitches. We demonstrate that exposure, slice thickness, and reconstruction filters have a significant impact on image compressibility due to an increased high frequency content and a lower acquisition signal-to-noise ratio. We also show that compression ratio is not a good fidelity measure. Therefore, guidelines based on compression ratio should ideally be replaced with other compression measures better correlated with image fidelity. Value-of interest (VOI) transformations also affect the perception of quality. We have studied the effect of value-of-interest transformation and found significant masking of artifacts when window is widened. PMID- 25804841 TI - Cell adhesion down-regulates the expression of vacuolar protein sorting 4B (VPS4B) and contributes to drug resistance in multiple myeloma cells. AB - The expression and biologic function of the gene encoding vacuolar protein sorting 4B (VPS4B) in human multiple myeloma (MM) were investigated in this study. We determined that VPS4B expression is decreased in adherent MM cells and that knockdown of VPS4B expression induces cell adhesion-mediated drug resistance (CAM-DR) in MM. This induced CAM-DR phenotype manifested through down-regulation of cell apoptosis and requires phosphorylation of AKT and Erk. Finally, VPS4B expression was positively correlated with cell proliferation. Our findings support a role for VPS4B in MM cell proliferation, adhesion, and drug resistance, and pave the way for a novel therapeutic approach targeting this molecule. PMID- 25804843 TI - Validation of a fast and low-cost alkaline lysis method for gDNA extraction in a pharmacogenetic context. AB - PURPOSE: Translation of pharmacogenetic findings from the research laboratory to the clinical practice demands simple and efficient procedures. In this sense, we evaluated the suitability of a modified protocol for genomic DNA extraction based on alkaline lysis of cells. METHODS: Dried blood samples were obtained from 48 patients diagnosed with colorectal cancer. A total of 11 mutations in the dihydropyrimidine dehydrogenase gene and related to 5-fluorouracil toxicity were searched by amplicon sequencing and real-time PCR with fluorescent probes. RESULTS: Genomic DNA extracted with the alkaline lysis method, both from dried blood samples and buccal swabs, fulfilled the quality requirements of the two genotyping methods assayed, which yielded 100 % concordant results for 11 genetic variants with relevance to cancer chemotherapy. CONCLUSIONS: The assessed protocol has shown to be a very fast and economical approach to perform genetic analyses in the clinical laboratory for pharmacological purposes. PMID- 25804844 TI - Understanding dynamic stability from pelvis accelerometer data and the relationship to balance and mobility in transtibial amputees. AB - This study investigated whether pelvis acceleration-derived parameters can differentiate between dynamic stability states for transtibial amputees during level (LG) and uneven ground (UG) walking. Correlations between these parameters and clinical balance and mobility measures were also investigated. A convenience sample of eleven individuals with unilateral transtibial amputation walked on LG and simulated UG while pelvis acceleration data were collected at 100Hz. Descriptive statistics, Fast Fourier Transform, ratio of even to odd harmonics, and maximum Lyapunov exponent measures were derived from acceleration data. Of the 26 pelvis acceleration measures, seven had a significant difference (p<=0.05) between LG and UG walking conditions. Seven distinct, stability-relevant measures appeared in at least one of the six regression models that correlated accelerometer-derived measures to Berg Balance Scale (BBS), Community Balance and Mobility Scale (CBMS), and Prosthesis Evaluation Questionnaire (PEQ) scores, explaining up to 100% of the variability in these measures. Of these seven measures, medial-lateral acceleration range was the most frequent model variable, appearing in four models. Anterior-posterior acceleration standard deviation and stride time appeared in three models. Pelvis acceleration-derived parameters were able to differentiate between LG and UG walking for transtibial amputees. UG walking provided the most relevant data for balance and mobility assessment. These results could translate to point of patient contact assessments using a wearable system such as a smartbelt or accelerometer-equipped smartphone. PMID- 25804847 TI - [What is the best selection methods of medical freshmen and how to care the students after admission?]. PMID- 25804848 TI - [Analysis of characteristics shown in self introduction letter and professor's recommendation letter]. AB - PURPOSE: The purpose of this study was to investigate applicants' behavioral characteristics based on the evaluation of cognitive, affective and social domain shown in self introduction letter and professor's recommendation letter. METHODS: Self introduction letters and professor's recommendation letters of 109 applicants students who applied to medical school were collected. Frequency analysis and simple correlation were done in self introduction letter and professor's recommendation letter. RESULTS: Frequency analysis showed affective characteristics were most often mentioned in self introduction letter, and cognitive characteristics were most frequently described in professor's recommendation letter. There was a strong correlation between cognitive domains of self introduction letter and cognitive domain of professor's recommendation letter. There was a strong correlation between affective domain of self introduction letter and cognitive domain professor's recommendation letter. CONCLUSION: It is very important to make full use of self introduction letter and professor's recommendation letter for selecting medical students. Through the frequency analysis and simple correlation, more specific guidelines need to be suggested in order to secure fairness and objectivity in the evaluation of self introduction letter and professor's recommendation letter. PMID- 25804849 TI - [How medical students perform academically by admission types?]. AB - PURPOSE: Despite the importance of selecting students whom are capable for medical education and to become a good doctor, not enough studies have been done in the category. This study focused on analysing the medical students' academic performance (grade point average, GPA) differences, flunk and dropout rates by admission types. METHODS: From 2004 to 2010, we gathered 369 Konyang University College of Medicine's students admission data and analyzed the differences between admission method and academic achievement, differences in failure and dropout rates. Analysis of variance (ANOVA), ordinary least square, and logistic regression were used. RESULTS: The rolling students showed higher academic achievement from year 1 to 3 than regular students (p < 0.01). Using admission type variable as control variable in multiple regression model similar results were shown. But unlike the results of ANOVA, GPA differences by admission types were shown not only in lower academic years but also in year 6 (p < 0.01). From the regression analysis of flunk and dropout rate by admission types, regular admission type students showed higher drop out rate than the rolling ones which demonstrates admission types gives significant effect on flunk or dropout rates in medical students (p < 0.01). CONCLUSION: The rolling admissions type students tend to show lower flunk rate and dropout rates and perform better academically. This implies selecting students primarily by Korean College Scholastic Ability Test does not guarantee their academic success in medical education. Thus we suggest a more in-depth comprehensive method of selecting students that are appropriate to individual medical school's educational goal. PMID- 25804845 TI - Investigation of the fate of type I angiotensin receptor after biased activation. AB - Biased agonism on the type I angiotensin receptor (AT1-R) can achieve different outcomes via activation of G protein-dependent and -independent cellular responses. In this study, we investigated whether the biased activation of AT1-R can lead to different regulation and intracellular processing of the receptor. We analyzed beta-arrestin binding, endocytosis, and subsequent trafficking steps, such as early and late phases of recycling of AT1-R in human embryonic kidney 293 cells expressing wild-type or biased mutant receptors in response to different ligands. We used Renilla luciferase-tagged receptors and yellow fluorescent protein-tagged beta-arrestin2, Rab5, Rab7, and Rab11 proteins in bioluminescence resonance energy transfer measurements to follow the fate of the receptor after stimulation. We found that not only is the signaling of the receptor different upon using selective ligands, but the fate within the cells is also determined by the type of the stimulation. beta-arrestin binding and the internalization kinetics of the angiotensin II-stimulated AT1-R differed from those stimulated by the biased agonists. Similarly, angiotensin II-stimulated wild-type AT1-R showed differences compared with a biased mutant AT1-R (DRY/AAY AT1-R) with regards to beta-arrestin binding and endocytosis. We found that the differences in the internalization kinetics of the receptor in response to biased agonist stimulation are due to the differences in plasma membrane phosphatidylinositol 4,5-bisphosphate depletion. Moreover, the stability of the beta-arrestin binding is a major determinant of the later fate of the internalized AT1-R receptor. PMID- 25804850 TI - [Development of an inventory assessing medical students' attitudes towards academic misconduct]. AB - PURPOSE: Identifying medical students' perceptions of and experiences with unprofessional behavior in school can help them develop and maintain higher standards of professional ethics. The aim of this study was to develop an instrument that assesses medical students' attitudes toward academic misconduct. METHODS: A draft version of the questionnaire form was developed, based on an extensive literature review and iterative discussions. The validity of the content of this draft form was evaluated by medical students, physicians, and education specialists. A total of 803 medical students answered the questionnaire. Exploratory factor analysis was performed using principal axis factoring and Varimax rotation. A confirmatory factor analysis was also conducted by root mean square error of approximation (RMSEA) and comparative fit index (CFI). The internal consistency of the scales was calculated using the Cronbach alpha statistic. RESULTS: The exploratory factor analysis generated 6 factors with 29 items: scientific misconduct (8 items); irresponsibility in the class (6 items); disrespectful behavior in patient care (5 items); dishonesty in clerkship tasks (4 items); free-riding on group assignments (4 items); and irresponsibility during clerkship (2 items). After adding a single item that addressed cheating on examinations, a 30-item inventory was developed. A confirmatory factor analysis demonstrated a favorable RMSEA (0.082) and reasonable fit (CFI, 0.844). The coefficient alpha for each factor varied between 0.80 and 0.90. CONCLUSION: Our instrument is useful in identifying students' ethical standards with regard to academics and examining the prevalence of unprofessional behavior in medical students. PMID- 25804851 TI - [Are medical students being properly cared for? A question for the current student advisory program]. AB - PURPOSE: Medical students need close care and systematic management of their mental and emotional health during their academic tenure. This study examined the status of the current student advisory program and counseling office, the satisfaction of the current student advisory program, the core content of an advisory program, and the quality of a good advisor. METHODS: We asked 64 faculties that were in charge of the student advisory program and medical education and 774 medical students from 41 medical schools in Korea to answer a survey. Statistical analysis, chi-square test, and ordered multiple response analysis were performed. RESULTS: A significant number of faculty members (63.5%) and students (53.4%) indicated the existence of problems with the current advisory program. 'Deviations from the content (27.3%)' was the faculty's predominant complaint versus 'too formal (31.3%)' for students. A total of 55.5% of faculty members replied that the counseling program was helpful, but students were somewhat skeptical (13.9%). The core content of the advisory program was 'school life & academic counseling (28.3%)' by the faculty versus 'life as a medical doctor (22.3%)' for students. Both faculty and students replied that the quality of a good advisor is having 'concerns about students.' CONCLUSION: Current student advisory and counseling programs are not much help to students. A differentiated program for specific academic years should be considered to provide a tailored and valuable service. PMID- 25804852 TI - Premedical students' experiences in community-oriented primary care. AB - PURPOSE: Medical students must be taught community medicine to understand common community-wide health problems and develop the skills that are needed to solve them. In this study, community-oriented primary care (COPC) projects were undertaken by premedical students in a community medicine course, and their experience was assessed. METHODS: We analyzed the final reports of 570 premedical students who completed their community group projects from 2000 to 2012. RESULTS: Eighty-nine community projects were completed by the students. The average number of students per project was 6.3 (range, 3-9). The total number of project themes was 39. Sex education for high school students, guidance on learning for low socioeconomic children, and education on smoking cessation for high school students were the most frequently selected topics. The most common subjects in the projects were high school students, preschool children, elderly people, and hospice patients. With regard to methodology, the students administered questionnaires in 58 cases and held health education programs in 48 cases. In 42 cases, students used social welfare-related community resources. In their final reports, many students felt that an understanding of their identities as future physicians and of the health care and social welfare systems was meaningful. CONCLUSION: Premedical students' experiences in COPC projects varied and were positive. Teaching community medicine in a premedical course increased students' confidence with their future role as compassionate, socially responsible physicians and their understanding of community resources in a health care network. PMID- 25804853 TI - Using a medical volunteer program to motivate medical freshmen. AB - PURPOSE: A task force identified 4 core properties of motivation-related improvement and developed a medical volunteer program for 63 medical freshmen in 2012. Three overarching topics were examined: What were the contents of the program? Did students' motivation improve? Were the students satisfied with the course? Pretest and posttest motivation levels and program evaluation forms were analyzed. METHODS: We organized a series of committee meetings and identified 4 core factors of motivation. The program was conducted for 63 medical freshmen in March 2012. The program evaluation form was analyzed using SPSS 17.0. RESULTS: The core factors of motivation were interest in medical studies, volunteer mindedness, medical humanities, and self-management. The program was composed of lectures, medical volunteer hours, and program evaluation and feedback sessions. Students' motivation differed significantly with regard to interest in medical studies (t=-2.40, p=0.020) and volunteer-mindedness (t=-3.45, p=0.001). Ninety percent of students were satisfied with the program, 67.8% of students were satisfied with the medical volunteer activity, and the feedback session of the program was meaningful (66.1%). CONCLUSION: The medical volunteer program, held in the first month of the medical education year, was meaningful, but the reasons for dissatisfaction with the program should be examined. We should also develop a system that has lasting beneficial effects on academic achievement and career selection. PMID- 25804854 TI - Effective question and answer in class. PMID- 25804855 TI - Muscle and bone, two interconnected tissues. AB - As bones are levers for skeletal muscle to exert forces, both are complementary and essential for locomotion and individual autonomy. In the past decades, the idea of a bone-muscle unit has emerged. Numerous studies have confirmed this hypothesis from in utero to aging works. Space flight, bed rest as well as osteoporosis and sarcopenia experimentations have allowed to accumulate considerable evidence. Mechanical loading is a key mechanism linking both tissues with a central promoting role of physical activity. Moreover, the skeletal muscle secretome accounts various molecules that affect bone including insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (FGF-2), interleukin-6 (IL-6), IL-15, myostatin, osteoglycin (OGN), FAM5C, Tmem119 and osteoactivin. Even though studies on the potential effects of bone on muscle metabolism are sparse, few osteokines have been identified. Prostaglandin E2 (PGE2) and Wnt3a, which are secreted by osteocytes, osteocalcin (OCN) and IGF-1, which are produced by osteoblasts and sclerostin which is secreted by both cell types, might impact skeletal muscle cells. Cartilage and adipose tissue are also likely to participate to this control loop and should not be set aside. Indeed, chondrocytes are known to secrete Dickkopf-1 (DKK-1) and Indian hedgehog (Ihh) and adipocytes produce leptin, adiponectin and IL-6, which potentially modulate bone and muscle metabolisms. The understanding of this system will enable to define new levers to prevent/treat sarcopenia and osteoporosis at the same time. These strategies might include nutritional interventions and physical exercise. PMID- 25804856 TI - Design of PAMAM-COO dendron-grafted surfaces to promote Pb(II) ion adsorption. AB - An expanding area of green technology is the wastewater treatment of heavy metal ions. As the adsorption of cations onto solid surfaces has been proven to be successful, recent research has demonstrated enhanced adsorption profiles by grafting dendron brushes onto a solid support. Via the molecular dynamics technique, we examine the adsorption of Pb(II) ions onto polyamidoamine (PAMAM) with carboxylate terminal groups through a coarse-grained implicit solvent model. We identify dendron generations and grafting densities, or surface coverage levels, which demonstrate optimal adsorption of Pb(II) ions. Our results can be potentially used to design functionalized surfaces for metal ion adsorption in application entailing environmental remediation or protective surface coating. PMID- 25804858 TI - Correction. PMID- 25804857 TI - Human papillomavirus vaccination is changing the epidemiology of high-grade cervical lesions in Australia. PMID- 25804859 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Topical lignocaine patches in traumatic rib fractures. AB - A shortcut review was carried out to establish whether topical lignocaine patches (LP) are effective for rib fractures. 48 papers were found of which 2 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that there is currently no evidence to support the use of topical LP to improve pain control and reduce opiate analgesic use, in patients with traumatic rib fractures. PMID- 25804861 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Should we use an age adjusted D-dimer threshold in managing low risk patients with suspected pulmonary embolism? AB - A shortcut review was carried out to establish whether a higher age related threshold can be used when using d-dimer as a rule out test for pulmonary embolism. 29 papers were found of which 13 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that in older patients suspected of having a Pulmonary Embolus (PE), with a low pretest possibility, an age-adjusted D-dimer increases specificity with minimal change in the sensitivity, thereby increasing the number of patients who can be safely discharged without further investigations. PMID- 25804862 TI - Molecular characterization of Trichomonas gallinae isolates recovered from the Canadian Maritime provinces' wild avifauna reveals the presence of the genotype responsible for the European finch trichomonosis epidemic and additional strains. AB - Finch trichomonosis, caused by Trichomonas gallinae, emerged in the Canadian Maritime provinces in 2007 and has since caused ongoing mortality in regional purple finch (Carpodacus purpureus) and American goldfinch (Carduelis tristis) populations. Trichomonas gallinae was isolated from (1) finches and rock pigeons (Columbia livia) submitted for post-mortem or live-captured at bird feeding sites experiencing trichomonosis mortality; (2) bird seed at these same sites; and (3) rock pigeons live-captured at known roosts or humanely killed. Isolates were characterized using internal transcribed spacer (ITS) region and iron hydrogenase (Fe-hyd) gene sequences. Two distinct ITS types were found. Type A was identical to the UK finch epidemic strain and was isolated from finches and a rock pigeon with trichomonosis; apparently healthy rock pigeons and finches; and bird seed at an outbreak site. Type B was obtained from apparently healthy rock pigeons. Fe hyd sequencing revealed six distinct subtypes. The predominant subtype in both finches and the rock pigeon with trichomonosis was identical to the UK finch epidemic strain A1. Single nucleotide polymorphisms in Fe-hyd sequences suggest there is fine-scale variation amongst isolates and that finch trichomonosis emergence in this region may not have been caused by a single spill-over event. PMID- 25804863 TI - Tradeoff between manual response speed and pursuit accuracy revealed by a deadline procedure. AB - To examine the tradeoff between manual reaction times (RTs) and smooth pursuit accuracy, we manipulated manual RTs to a visual target presented during pursuit by using a deadline procedure that required different response speeds to a target (300, 400, or 500 ms). Participants attempted to pursue a moving row of circles as accurately as possible, while responding to a target within a preset time. Stimulus velocity and target position were manipulated. As the preset time became shorter, participants responded with faster manual RTs and larger pursuit velocity errors, irrespective of the stimulus velocity, indicating a tradeoff between manual RTs and pursuit accuracy. Pursuit velocity errors were also larger after target onset. These results not only suggest that attentional resources as well as spatial shifts of attention play an important role in maintaining accurate pursuit, but also support the notion that a manual RT task is useful for revealing the operation of attention during pursuit. PMID- 25804865 TI - Up to which temperature ultrasound can heat the particle? AB - Crystallographic property such as crystallite size has been used for evaluation of the temperature up to which high intensity ultrasound can heat metal particles depending on physical properties of sonication medium and particle concentration. We used >100 MUm metal particles as an in situ indicator for ultrasonically induced temperature in the particle interior. Based on powder X-ray diffraction monitoring of Al3Ni2 crystallite sizes after ultrasound treatment the average minimum temperature T particle(min) of sonicated particles in various sonication media was estimated. Additionally, it was found that crystallite size in ultrasonically treated metal particle depends on the frequency of interparticle collision. Through the adjustment of particle concentration, it is possible to either accelerate the atomic diffusion or force the melting and recrystallization processes. Overall, the energy released from collapsing cavitation bubble can be controllably transferred to the sonication matter through the appropriate choice of sonication medium and the adjustment of particle concentration. PMID- 25804864 TI - Building an internal model of a myoelectric prosthesis via closed-loop control for consistent and routine grasping. AB - Prosthesis users usually agree that myoelectric prostheses should be equipped with somatosensory feedback. However, the exact role of feedback and potential benefits are still elusive. The current study investigates the nature of human control processes within a specific context of routine grasping. Although the latter includes a fast feedforward control of the grasping force, the assumption was that the feedback would still be useful; it would communicate the outcome of the grasping trial, which the subjects could use to learn an internal model of feedforward control. Nine able-bodied subjects produced repeatedly a desired level of grasping force using different control configurations: feedback versus no-feedback, virtual versus real prosthetic hand, and joystick versus myocontrol. The outcome measures were the median and dispersion of the relative force errors. The results demonstrated that the feedback was successful in limiting the variability of the routine grasping due to uncertainties in the system and/or the command interface. The internal models of feedforward control could be employed by the subjects to control the prosthesis without the loss of performance even after the force feedback was removed. The models were, however, unstable over time, especially with myocontrol. Overall, the study demonstrates that the prosthesis system can be learned by the subjects using feedback. The feedback is also essential to maintain the model, and it could be delivered intermittently. This approach has practical advantages, but the level to which this mechanism can be truly exploited in practice depends directly on the consistency of the prosthesis control interface. PMID- 25804866 TI - [Deployment of a dermatologist in Cambodia and Somalia: Personal experience of a medical officer]. AB - BACKGROUND: Throughout history, physicians of the armed forces have gained experience in tropical medicine during deployment in tropical countries. PATIENTS AND METHODS: During deployments in Cambodia and Somalia, dermatologists treated participants of the UN missions and also local people to win their confidence. The experience acquired during these missions is reported. RESULTS: The dermatologist was mainly confronted with the diagnosis and treatment of infectious skin diseases, including genitourinary diseases. Therapy of parasitic infections rarely imported to Europe was a challenge. CONCLUSION: Training and experience in Tropical Medicine are essential for medical officers deployed on missions as well as for physicians advising travellers. PMID- 25804867 TI - Ecological and evolutionary perspectives on community assembly. AB - Ecologists often view community assembly as a process involving the dispersal of species from a static regional species pool followed by environmental filtering to establish the local community. This conceptual framework ignores the dynamic nature of species pools and fails to recognize that communities are assembled by processes operating over a vast range of temporal and spatial scales. Species pool richness and composition are influenced by metacommunity dynamics over short timescales and by speciation, extinction, and dispersal over long timescales. We suggest that a stronger focus on the geography of speciation, the formation of secondary sympatry, and the feedback between local and regional processes is needed to fully understand community assembly and the importance of dynamic species pools. PMID- 25804868 TI - How (not) to review papers on inclusive fitness. PMID- 25804869 TI - Erratum to: detection and measurement of necrosis in plants. PMID- 25804870 TI - TGF-beta3 encapsulated PLCL scaffold by a supercritical CO2-HFIP co-solvent system for cartilage tissue engineering. AB - Mimicking the native tissue microenvironment is critical for effective tissue regeneration. Mechanical cues and sustained biological cues are important factors, particularly in load-bearing tissues such as articular cartilage or bone. Carriers including hydrogels and nanoparticles have been investigated to achieve sustained release of protein drugs. However, it is difficult to apply such carriers alone as scaffolds for cartilage regeneration because of their weak mechanical properties, and they must be combined with other biomaterials that have adequate mechanical strength. In this study, we developed the multifunctional scaffold which has similar mechanical properties to those of native cartilage and encapsulates TGF-beta3 for chondrogenesis. In our previous work, we confirmed that poly(lactide-co-caprolacton) (PLCL) did not foam when exposed to supercritical CO2 below 45 degrees C. Here, we used a supercritical carbon dioxide (scCO2)-1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) co-solvent system to facilitate processing under mild conditions because high temperature causes protein denaturation and decreases bioactivity of the protein. This processing made it possible to fabricate a TGF-beta3 encapsulated elastic porous PLCL scaffold at 37 degrees C. We investigated the tissue regeneration efficiency of the TGF-beta3 encapsulated PLCL scaffold using human adipose-derived stem cells (ADSCs) in vitro and in vivo (Groups; i. PLCL scaffold+Fibrin gel+TGF-beta3, ii. TGF-beta3 encapsulated PLCL scaffold+Fibrin gel, iii. TGF-beta3 encapsulated PLCL scaffold). We evaluated the chondrogenic abilities of the scaffolds at 4, 8, and 12weeks after subcutaneous implantation of the constructs in immune-deficient mice. Based on TGF-beta3 release studies, we confirmed that TGF-beta3 molecules were released by 8weeks and remained in the PLCL matrix. Explants of TGF-beta3 encapsulated scaffolds by a co-solvent system exhibited distinct improvement in the compressive E-modulus and deposition of extracellular matrix. Furthermore, long-term delivery of TGF-beta3 formed a hyaline cartilage-specific lacunae structure and prevented the hypertrophy of differentiated chondrocytes. TGF-beta3 encapsulated PLCL scaffolds would be useful as functional scaffolds for cartilage tissue engineering. PMID- 25804871 TI - Local immunotherapy via delivery of interleukin-10 and transforming growth factor beta antagonist for treatment of chronic kidney disease. AB - Obstructive nephropathy is the leading cause of kidney disease in children. The tissue injury resulting from initial dilation precipitates a deleterious cascade of macrophage infiltration, apoptosis, and fibrosis to produce a resultant dysfunctional tissue. We propose to abate this tissue remodeling process through immunotherapy administered via the local and sustained delivery of interleukin-10 (IL-10; anti-inflammatory) and anti-transforming growth factor beta (anti TGFbeta; anti-fibrotic). Shear-thinning, injectable hyaluronic acid (HA) hydrogels were formed through supramolecular guest-host interactions and used to contain IL-10, anti-TGFbeta, or both molecules together. Degradation assays demonstrated that diffusive molecule release was associated with concurrent hydrogel erosion and was sustained for up to 3weeks in vitro. Erosion was likewise monitored in vivo by non-invasive optical imaging, where gel localization to the affected tissue was observed with near complete clearance by day 18. Hydrogels were applied to a murine model of chronic kidney disease, with subcapsular hydrogel injections acting as a delivery depot. Quantitative histological analysis (days 7, 21, and 35) was used to evaluate treatment efficacy. Notably, results demonstrated reduced macrophage infiltration beyond day 7 in treatment groups and reduced apoptosis at day 21, relative to untreated unilateral ureteral obstruction disease model. Fibrosis was reduced at the 35day timepoint in groups treated with IL-10 or anti-TGFbeta alone, but not with the combination therapy. Rather, dual delivery of IL-10 and anti-TGFbeta resulted in a paradoxical hastening of fibrosis, warranting further investigation. Localized immunotherapy is a novel approach to treat kidney disease and shows promise as a translatable therapy. PMID- 25804874 TI - Welcome R. Bryan Bell, DDS, MD, FACS, FACD. PMID- 25804873 TI - Nanoparticle-mediated growth factor delivery systems: A new way to treat Alzheimer's disease. AB - The number of people diagnosed with Alzheimer's disease (AD) is increasing steadily as the world population ages, thus creating a huge socio-economic burden. Current treatments have only transient effects and concentrate on a single aspect of AD. There is much evidence suggesting that growth factors (GFs) have a great therapeutic potential and can play on all AD hallmarks. Because GFs are prone to denaturation and clearance, a delivery system is required to ensure protection and a sustainable delivery. This review provides information about the latest advances in the development of GF delivery systems (GFDS) targeting the brain in terms of in vitro and in vivo effects in the context of AD and discusses new strategies designed to increase the availability and the specificity of GFs to the brain. This paper also discusses, on a mechanistic level, the different delivery hurdles encountered by the carrier or the GF itself from its injection site up to the brain tissue. The major mass transport phenomena influencing the delivery systems targeting the brain are addressed and insights are given about how mechanistic mathematical frameworks can be developed to use and optimize them. PMID- 25804872 TI - Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle. AB - Pancreatic ductal adenocarcinomas are characterized by the desmoplastic reaction, a dense fibrous stroma that has been shown to be supportive of tumor cell growth, invasion, and metastasis, and has been associated with resistance to chemotherapy and reduced patient survival. Here, we investigated targeted depletion of stroma for pancreatic cancer therapy via taxane nanoparticles. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethylcellulose, a construct which condenses into well-defined 120nm particles in an aqueous solution, and is suitable for intravenous injection. We examined Cellax-DTX treatment effects in highly stromal primary patient-derived pancreatic cancer xenografts and in a metastatic PAN02 mouse model of pancreatic cancer, focusing on specific cellular interactions in the stroma, pancreatic tumor growth and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts which results in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a >10 fold increase in tumor perfusion, reduced tumor weight and a reduction in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX nanoparticles interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects of which are associated with significant changes in tumor progression and metastasis. PMID- 25804875 TI - Modeling the impact of restoration efforts on phosphorus loading and transport through Everglades National Park, FL, USA. AB - Ecosystems of Florida Everglades are highly sensitive to phosphorus loading. Future restoration efforts, which focus on restoring Everglades water flows, may pose a threat to the health of these ecosystems. To determine the fate and transport of total phosphorus and evaluate proposed Everglades restoration, a water quality model has been developed using the hydrodynamic results from the M3ENP (Mike Marsh Model of Everglades National Park)--a physically-based hydrological numerical model which uses MIKE SHE/MIKE 11 software. Using advection-dispersion with reactive transport for the model, parameters were optimized and phosphorus loading in the overland water column was modeled with good accuracy (60%). The calibrated M3ENP-AD model was then modified to include future bridge construction and canal water level changes, which have shown to increase flows into ENP. These bridge additions increased total dissolved phosphorus (TP) load downstream in Shark Slough and decreased TP load in downstream Taylor Slough. However, there was a general decrease in TP concentration and TP mass per area over the entire model domain. The M3ENP-AD model has determined the mechanisms for TP transport and quantified the impacts of ENP restoration efforts on the spatial-temporal distribution of phosphorus transport. This tool can be used to guide future Everglades restoration decisions. PMID- 25804876 TI - Secondary formation of disinfection by-products by UV treatment of swimming pool water. AB - Formation of disinfection by-products (DBPs) during experimental UV treatment of pool water has previously been reported with little concurrence between laboratory studies, field studies and research groups. In the current study, changes in concentration of seven out of eleven investigated volatile DBPs were observed in experiments using medium pressure UV treatment, with and without chlorine and after post-UV chlorination. Results showed that post-UV chlorine consumption increased, dose-dependently, with UV treatment dose. A clear absence of trihalomethane formation by UV and UV with chlorine was observed, while small yet statistically significant increases in dichloroacetonitrile and dichloropropanone concentrations were detected. Results indicate that post-UV chlorination clearly induced secondary formation of several DBPs. However, the formation of total trihalomethanes was no greater than what could be replicated by performing the DBP formation assay with higher chlorine concentrations to simulate extended chlorination. Post-UV chlorination of water from a swimming pool that continuously uses UV treatment to control combined chlorine could not induce secondary formation for most DBPs. Concurrence for induction of trihalomethanes was identified between post-UV chlorination treatments and simulated extended chlorination time treatment. Trihalomethanes could not be induced by UV treatment of water from a continuously UV treated pool. This indicates that literature reports of experimentally induced trihalomethane formation by UV may be a result of kinetic increase in formation by UV. However, this does not imply that higher trihalomethane concentrations would occur in pools that apply continuous UV treatment. The bromine fraction of halogens in formed trihalomethanes increased with UV dose. This indicates that UV removes bromine atoms from larger molecules that participate in trihalomethane production during post-UV chlorination. Additionally, no significant effect on DBP formation was observed due to photo-inducible radical forming molecules NO3- (potentially present in high concentrations in pool water) and H2O2 (added as part of commercially employed DBP reducing practices). PMID- 25804877 TI - Risk of female breast cancer and serum concentrations of organochlorine pesticides and polychlorinated biphenyls: a case-control study in Tunisia. AB - The aim of this study was to investigate the association between serum concentrations of a group of organochlorine pesticides/polychlorinated biphenyls with xenoestrogenic potential and the risk of breast cancer in a female population from Tunisia. The relationship between serum levels of the pollutants and the risk of cancer was assessed using logistic regression analyses. In the unadjusted models, beta-hexachlorocyclohexane (beta-HCH), hexachlorobenzene, heptachlor, polychlorinated biphenyl congeners 138, 153, and 180, and p,p' dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with breast cancer risk. However, when the models were further adjusted for the selected covariates, only beta-HCH and p,p'-DDE remained statistically significant, and heptachlor was borderline significant. In addition, analyses using POP concentration tertiles corroborated a positive dose-response relationship that was significant for p,p'-DDE (p-trend=0.020) and borderline significant for heptachlor (p-trend=0.078). A similar trend was also confirmed for beta-HCH, in which concentrations>=limit of detection were positively associated with breast cancer risk (vs. concentrations1.3 to 7.2 ng/L) with a remote distribution site (frequently >200 h of residency) experiencing the highest concentrations found. Eight other nitrosamines (N nitrosomethylethylamine, N-nitrosodiethylamine, N-nitroso-di-n-propylamine, N nitroso-di-n-butylamine, N-nitroso-di-phenylamine, N-nitrosopyrrolidine, N nitrosopiperidine, N-nitrosomorpholine) were also monitored but none of these 8, or precursors of these 8 [as estimated with formation potential (FP) tests], were detected anywhere in raw, partially-treated or distribution samples. Throughout the year, there was evidence that seasonality may impact NDMA formation, such that lower temperatures (~5-10 degrees C) produced greater NDMA than during warmer months. The year of sampling further provided evidence that water quality and weather events may impact NDMA precursor loads. Precursor loading estimates demonstrated that NDMA precursors increased during treatment (potentially from cationic polymer coagulant aids). The precursor analysis also provided evidence that precursors may have increased further within the distribution system itself. This comprehensive study of a large-scale drinking water system provides insight into the variability of NDMA occurrence in a chloraminated system, which may be impacted by seasonality, water quality changes and/or the varied origins of NDMA precursors within a given system. PMID- 25804878 TI - Noise sensitivity and future risk of illness and mortality. AB - Aircraft and road traffic noise exposure increase the risk of cardiovascular disease (CVD). Noise annoyance is the most frequent response to environmental noise. Noise annoyance has been shown to modify the association of transport noise exposure on CVD and noise sensitivity moderates the annoyance response to noise. This study uses prospective data from phases 1, 3, 5, 7 and 9 in 3630 male and female civil servants from the UK Whitehall II Study to examine whether a single question on noise sensitivity measured by annoyance responses to noise in general predicts physical and mental ill-health and mortality. Non-fatal myocardial infarction and stroke morbidity over the follow-up were defined by MONICA criteria based on study ECGs, hospital records, hospital admission statistics or General Practitioner confirmation. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale (CES-D) and psychological distress by the General Health questionnaire (GHQ). There was no association between noise sensitivity and CVD morbidity or mortality except in people from lower employment grades where there was an association with angina. Noise sensitivity was a consistent predictor of depressive symptoms and psychological distress at phases 3, 5 and 7. High noise sensitivity scores at baseline predicted GHQ caseness at phase 3 adjusting for age, sex, employment grade, self-rated health and GHQ caseness at baseline (OR=1.56 95% CI 1.29-1.88). Noise sensitivity has been identified as a predictor of mental ill-health. More longitudinal research is needed including measures of noise exposure. PMID- 25804880 TI - Liposomal Formulation Decreases Toxicity of Amphotericin B In Vitro and In Vivo. AB - BACKGROUND: Liposomal amphotericin B is locally delivered to treat fungal orthopaedic infections but little is known about local tissue toxicity, if any, that might be associated with local delivery. QUESTIONS/PURPOSES: (1) Is liposomal amphotericin B cytotoxic in vitro? (2) Is locally delivered liposomal amphotericin B toxic to tissue in vivo? METHODS: Mouse fibroblasts (BA LB/3T3 A31) and osteoblasts (MC3T3) were exposed to two formulations of amphotericin B (liposomal and deoxycholate) at concentrations of 0, 1, 5, 10, 100, 500, and 1000 MUg/mL. Cell viability was determined by MTT assay after 1, 3, and 5 hours of exposure and a proliferation assay after 1, 4, and 7 days of exposure and then after 3 recovery days without drug. Tissue exposure occurred by local delivery of liposomal amphotericin B, 200 or 800 mg/batch antifungal-loaded bone cement (ALBC), or amphotericin B deoxycholate, 800 mg/batch ALBC in rat paraspinal muscles. White blood cell count (WBC) and serum amphotericin B levels were obtained on Days 1 and 3. Rats were euthanized at 2 and 4 weeks and semiqualitative histopathology was performed. RESULTS: Liposomal amphotericin B is cytotoxic in vitro but not toxic to tissues in vivo. All cells survived concentrations up to 1000 MUg/mL for 5 hours, 100% +/- 0%, but none survived >= 100 MUg/mL for 7 days, 0% +/- 0%. Fibrosis was seen adjacent to ALBC without inflammation or necrosis, indistinguishable from controls for both liposomal amphotericin B doses. Amphotericin B serum levels were all less than 1 ug/mL and WBC counts were all normal. CONCLUSIONS: In vitro cytotoxicity to liposomal amphotericin B occurred but no adverse tissue reaction was seen in vivo. CLINICAL RELEVANCE: Local delivery of liposomal amphotericin B in ALBC was well tolerated by mouse tissue; however, clinical studies are needed to confirm this finding in humans. PMID- 25804882 TI - Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation. AB - BACKGROUND: Short-term muscle atrophy induced by botulinum toxin A (BTxA) has been observed to impair osteogenesis in a rat closed femur fracture model. However, it is unclear whether the underlying mechanism is a direct effect of BTxA on muscle-bone interactions or an indirect effect that is driven by skeletal unloading. Because skeletal trauma in the closed fracture model also leads to disuse atrophy, we sought to mitigate this confounding variable by examining BTxA effects on muscle-bone interactions in two complementary in vivo models in which osteogenesis is induced in the absence of skeletal unloading. The overall aim of this study was to identify a potential strategy to inhibit pathological bone formation and heterotopic ossification (HO). QUESTIONS/PURPOSES: (1) Does muscle paralysis inhibit periosteal osteogenesis induced by a transcortical defect? (2) Does muscle paralysis inhibit heterotopic bone formation stimulated by intramuscular bone morphogenetic protein (BMP) injection? METHODS: Focal osteogenesis was induced in the right hindlimb of mice through surgical initiation of a small transcortical defect in the tibia (fracture callus; n = 7/group) or intramuscular injection of BMP-2 (HO lesion; n = 6/group), both in the presence/absence of adjacent calf paralysis. High-resolution micro-CT images were obtained in all experimental groups 21 days postinduction and total volume (ie, perimeter of periosteal callus or HO lesion) and bone volume (calcified tissue within the total volume) were quantified as primary outcome measures. Finally, these outcome measures were compared to determine the effect of muscle paralysis on inhibition of local osteogenesis in both studies. RESULTS: After a transcortical defect, BTxA-treated mice showed profound inhibition of osteogenesis in the periosteal fracture callus 21 days postsurgery compared with saline-treated mice (total volume: 0.08 +/- 0.06 versus 0.42 +/- 0.11 mm(3), p < 0.001; bone volume: 0.07 +/- 0.05 versus 0.32 +/- 0.07 mm(3), p < 0.001). Similarly, BMP-2-induced HO formation was inhibited by adjacent muscle paralysis at the same time point (total volume: 1.42 +/- 0.31 versus 3.42 +/- 2.11 mm(3), p = 0.034; bone volume: 0.68 +/- 0.18 versus 1.36 +/- 0.79 mm(3), p = 0.045). CONCLUSIONS: Our data indicate that BTxA-induced neuromuscular inhibition mitigated osteogenesis associated with both a transcortical defect and BMP-2 induced HO. CLINICAL RELEVANCE: Focal neuromuscular inhibition represents a promising new approach that may lead to a new clinical intervention to mitigate trauma-induced HO, a healthcare challenge that is severely debilitating for civilian and war-wounded populations, is costly to both the patient and the healthcare system, and currently lacks effective treatments. PMID- 25804884 TI - Application of insect repellents to the face. PMID- 25804883 TI - Tri-allelic patterns at the D7S820 locus detected in two generations of a Chinese family. AB - Alleles at the D7S820 STR locus have 6-14 different numbers of a four-nucleotide (GATA) repeat motif arranged in tandem. The D7S820 tri-allelic pattern is rare and has not been reported in the Chinese population. In this study we report a three-banded pattern at the D7S820 locus observed in a Chinese family, in which four family members in two generations had tri-allelic D7S820 genotype 10-11-12 and one family member had an abnormal bi-allele genotype 10-11. All of the four tri-allelic cases had the genotype 10-11-12, probably due to three copies of the D7S820 STR sequence in all cells (Type 2 tri-allelic pattern), and deduced alleles 10-11 were a linked inheritance in this family. PMID- 25804881 TI - Kaplan-Meier Survival Analysis Overestimates the Risk of Revision Arthroplasty: A Meta-analysis. AB - BACKGROUND: Although Kaplan-Meier survival analysis is commonly used to estimate the cumulative incidence of revision after joint arthroplasty, it theoretically overestimates the risk of revision in the presence of competing risks (such as death). Because the magnitude of overestimation is not well documented, the potential associated impact on clinical and policy decision-making remains unknown. QUESTIONS/PURPOSES: We performed a meta-analysis to answer the following questions: (1) To what extent does the Kaplan-Meier method overestimate the cumulative incidence of revision after joint replacement compared with alternative competing-risks methods? (2) Is the extent of overestimation influenced by followup time or rate of competing risks? METHODS: We searched Ovid MEDLINE, EMBASE, BIOSIS Previews, and Web of Science (1946, 1980, 1980, and 1899, respectively, to October 26, 2013) and included article bibliographies for studies comparing estimated cumulative incidence of revision after hip or knee arthroplasty obtained using both Kaplan-Meier and competing-risks methods. We excluded conference abstracts, unpublished studies, or studies using simulated data sets. Two reviewers independently extracted data and evaluated the quality of reporting of the included studies. Among 1160 abstracts identified, six studies were included in our meta-analysis. The principal reason for the steep attrition (1160 to six) was that the initial search was for studies in any clinical area that compared the cumulative incidence estimated using the Kaplan Meier versus competing-risks methods for any event (not just the cumulative incidence of hip or knee revision); we did this to minimize the likelihood of missing any relevant studies. We calculated risk ratios (RRs) comparing the cumulative incidence estimated using the Kaplan-Meier method with the competing risks method for each study and used DerSimonian and Laird random effects models to pool these RRs. Heterogeneity was explored using stratified meta-analyses and metaregression. RESULTS: The pooled cumulative incidence of revision after hip or knee arthroplasty obtained using the Kaplan-Meier method was 1.55 times higher (95% confidence interval, 1.43-1.68; p < 0.001) than that obtained using the competing-risks method. Longer followup times and higher proportions of competing risks were not associated with increases in the amount of overestimation of revision risk by the Kaplan-Meier method (all p > 0.10). This may be due to the small number of studies that met the inclusion criteria and conservative variance approximation. CONCLUSIONS: The Kaplan-Meier method overestimates risk of revision after hip or knee arthroplasty in populations where competing risks (such as death) might preclude the occurrence of the event of interest (revision). Competing-risks methods should be used to more accurately estimate the cumulative incidence of revision when the goal is to plan healthcare services and resource allocation for revisions. PMID- 25804885 TI - Inhibition of adherence of C. albicans to dental implants and cover screws by Cymbopogon nardus essential oil and citronellal. AB - OBJECTIVE: This study investigated the biological activity of the essential oil from Cymbopogon nardus and of the phytoconstituent citronellal on Candida strains as to the inhibition of adherence to dental implants and cover screws. MATERIAL AND METHODS: The essential oil was analyzed by gas chromatography coupled to mass spectrometry (GC-MS) and had its MIC and MFC determined against 12 strains of Candida. Then, tests of inhibition of adherence to the dental implants and cover screws were carried out using the MIC of the substances, followed by scanning electron microscopy analysis. Nystatin and chlorhexidine were used as positive controls, and experiments were performed in triplicate. RESULTS: The analysis by GC-MS of the essential oil identified citronellal as the major compound. The MICs of the essential oil, citronellal, chlorhexidine, and nystatin--able to inhibit 100 % of the strains--were found to be 64, 512, 64, and 32 MUg/ml, respectively. The essential oil significantly inhibited the adherence of Candida albicans to the dental implants and cover screws (p < 0.001). Citronellal inhibited yeast adherence only to the dental implants (p < 0.001), and no significant results were found for the cover screws (p > 0.05) compared to the growth control. CONCLUSION: The essential oil and citronellal have proven antifungal activity and are able to inhibit the in vitro adherence of C. albicans. CLINICAL RELEVANCE: There has been a search for alternative natural product-containing formulations that should be effective in inhibiting adherence of yeasts to the surfaces of materials and also able to treat oral fungal infections. Further trials could make these products an alternative to chemical removal of peri-implant biofilm. PMID- 25804886 TI - Preoperative, intraoperative, and postoperative complications in orthognathic surgery: a systematic review. AB - OBJECTIVES: The aim of this study was to determine whether orthognathic surgery is associated with any complications, and what type of complications may occur. MATERIALS AND METHODS: Data were obtained using PubMed (MEDLINE), ISI Web of Knowledge, Ovid, Cochrane Library, Embase Library, and an additional manual search. The titles and abstracts of the electronic search results were screened and evaluated by two observers for eligibility according to the inclusion and exclusion criteria. RESULTS: A total of 1924 articles were identified, and we retained 44 articles for the final analysis. The Prisma diagram flowchart demonstrates our selection scheme. For the purpose of this study, the Cochrane data extraction form was modified. One review author extracted data from the included studies, and the second author checked all of the forms. The hierarchy of evidence classification from the UK NHS Centre for Reviews and Dissemination was used to assess the level of evidence for the retrieved studies. CONCLUSIONS: An evaluation of the obtained studies revealed the existence of a large number of varied complications associated with orthognathic surgery procedures. CLINICAL RELEVANCE: Oral and maxillofacial surgeons, orthodontists, and the surgical team need to prevent such complications during preoperative, intraoperative, and postoperative periods to increase the safety of orthognathic surgery procedures. This review was registered on http://www.crd.york.ac.uk/PROSPERO as CRD42013004711. PMID- 25804887 TI - Assessing the accuracy of autofluorescence, chemiluminescence and toluidine blue as diagnostic tools for oral potentially malignant disorders--a clinicopathological evaluation. AB - OBJECTIVES: Early detection of oral cancer and their precursors is the key to reducing the high mortality rate attributable to oral cancer. A variety of new chair-side diagnostic tools are currently available that may enhance oral mucosal examination and facilitate the detection of benign and malignant disorders. The aim of this study was to investigate the accuracy of autofluorescence, chemiluminescence and toluidine blue (TBlue) when used in combination against conventional oral examination and surgical biopsy for the detection and assessing risk status of oral potentially malignant disorders. MATERIALS AND METHODS: A total of 126 patients, with white, red and mixed white and red patches were included. Following a comprehensive oral examination, all patients underwent a standard protocol of autofluorescence, chemiluminescence and TBlue examination. A surgical biopsy was performed to assess oral epithelial dysplasia. RESULTS: Seventy patients had leukoplakia/erythroplakia and 44 had epithelial dysplasia. In relation to leukoplakia/erythroplakia, autofluorescence, chemiluminescence and TBlue showed a sensitivity of 87.1, 77.1 and 52.9 % and a specificity of 21.4, 26.8 and 67.9 %, respectively. For dysplasia cases, autofluorescence, chemiluminescence and TBlue showed sensitivity and specificity of 84.1, 77.3 and 56.8 % and 15.3, 27.8 and 65.8 %, respectively. CONCLUSION: While all the three tests were useful in detecting oral mucosal changes, their accuracy in identifying oral potentially malignant disorders (OPMD) is questionable. However, in combination, the tests yielded better results, with improved specificity. CLINICAL RELEVANCE: These research tools are helpful in specialist clinics but further studies are necessary to examine their role in screening in primary care settings. PMID- 25804889 TI - N-doped crumpled graphene derived from vapor phase deposition of PPy on graphene aerogel as an efficient oxygen reduction reaction electrocatalyst. AB - Nitrogen-doped crumpled graphene (NCG) is successfully synthesized via vapor phase deposition of polypyrrole onto graphene aerogel followed by thermal treatment. The NCG was explored as an electrocatalyst for the oxygen reduction reaction, showing comparable electrocatalytic performance with the commercial Pt/C in alkaline membrane exchange fuel cells because of the well-regulated nitrogen doping and the robust micro-3D crumpled porous nanostructure. PMID- 25804890 TI - An optofluidic constriction chip for monitoring metastatic potential and drug response of cancer cells. AB - Cellular mechanical properties constitute good markers to characterize tumor cells, to study cell population heterogeneity and to highlight the effect of drug treatments. In this work, we describe the fabrication and validation of an integrated optofluidic chip capable of analyzing cellular deformability on the basis of the pressure gradient needed to push a cell through a narrow constriction. We demonstrate the ability of the chip to discriminate between tumorigenic and metastatic breast cancer cells (MCF7 and MDA-MB231) and between human melanoma cells with different metastatic potential (A375P and A375MC2). Moreover, we show that this chip allows highlighting the effect of drugs interfering with microtubule organization (paclitaxel, combretastatin A-4 and nocodazole) on cancer cells, which leads to changes in the pressure-gradient required to push cells through the constriction. Our single-cell microfluidic device for mechanical evaluation is compact and easy to use, allowing for an extensive use in different laboratory environments. PMID- 25804888 TI - Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells. AB - Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 MUM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. PMID- 25804891 TI - High Resolution Tissue Imaging Using the Single-probe Mass Spectrometry under Ambient Conditions. AB - Ambient mass spectrometry imaging (MSI) is an emerging field with great potential for the detailed spatial analysis of biological samples with minimal pretreatment. We have developed a miniaturized sampling and ionization device, the Single-probe, which uses in-situ surface micro-extraction to achieve high detection sensitivity and spatial resolution during MSI experiments. The Single probe was coupled to a Thermo LTQ Orbitrap XL mass spectrometer and was able to create high spatial and high mass resolution MS images at 8 +/- 2 and 8.5 MUm on flat polycarbonate microscope slides and mouse kidney sections, respectively, which are among the highest resolutions available for ambient MSI techniques. Our proof-of-principle experiments indicate that the Single-probe MSI technique has the potential to obtain ambient MS images with very high spatial resolutions with minimal sample preparation, which opens the possibility for subcellular ambient tissue MSI to be performed in the future. PMID- 25804892 TI - Regulated In Situ Generation of Molecular Ions or Protonated Molecules under Atmospheric-Pressure Helium-Plasma-Ionization Mass Spectrometric Conditions. AB - In an enclosed atmospheric-pressure helium-plasma ionization (HePI) source engulfed with dehumidified ambient gases, molecular cations are generated from compounds such as toluene, bromobenzene, and iodobenzene. Evidently, the ionization is effected by a direct Penning mechanism attributable to interactions of the gas-phase analyte with metastable helium atoms. It is widely known that secondary ions generated from ambient gases also play an important role in the overall ionization process. For example, when the ambient gases bear even traces of moisture, the analytes are ionized by proton transfer reactions with gaseous H3O(+). In this study, we demonstrate how a controlled variation of experimental conditions can manipulate the abundance of molecular ions and protonated molecules in a HePI source. PMID- 25804893 TI - Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration. AB - As part of an investigative nephrotoxicity study, kidney tissues from juvenile rats orally administered dabrafenib at different age intervals between postnatal day (PND) 7 to 35 were investigated by MALDI and LDI imaging mass spectrometry (IMS) to determine the chemical composition of tubular deposits. In the youngest age group (PND 7-13), MALDI IMS demonstrated that a dabrafenib carboxylic acid metabolite was diffusely localized to the regions of tubular deposits (medulla and corticomedullary junction); however, no dabrafenib-related material was detected directly from the deposits. Rather, the LDI IMS analysis determined that the deposits were composed primarily of calcium phosphate. Based on these data, the dabrafenib associated nephrotoxicity, including the formation of tubular deposits, was determined to be age dependent. Furthermore, immature renal function was hypothesized to be responsible for the susceptibility of the youngest pups. PMID- 25804894 TI - Geriatric medicine and cultural gerontology. AB - T.S. Eliot once proposed that there were two sorts of problems in life. One prompted the question, 'What are we going to do about it?' and the other provoked the questions, 'What does it mean? How does one relate to it?' Geriatric medicine, an eminently practical specialty, has concentrated with good effect on the former but with notable exceptions has yet to devote significant time to the latter. Into this breach has developed an innovative and exciting movement in gerontology to provide a deeper and more comprehensive insight into the meaning of ageing. Largely encompassed by the terms of cultural, humanistic and narrative gerontology, their intent and methodologies in many ways mirror the relationship between the medical humanities, narrative medicine and medicine. PMID- 25804895 TI - Local full-thickness skin graft of the donor arm--a novel technique for the reduction of donor site morbidity in radial forearm free flap. AB - A novel technique to reduce donor site morbidity after radial forearm free flap (RFFF) harvest, using a local full-thickness skin graft (FTSG), is described. Thirty consecutive patients undergoing RFFF for head and neck reconstruction were enrolled in a prospective study. Donor site defect closure was performed with spindle-shaped FTSGs excised from the wavelike skin incision made for the vascular pedicle. Both the removal site of the FTSG on the volar forearm and the covered RFFF donor site healed uneventfully in 29 cases, with no impairment of function related to the skin graft. No skin graft failure and no exposure, tenting, or adherence of the flexor tendons occurred. All patients expressed satisfaction with postoperative pain, the functional outcome, and cosmetic appearance. Primary donor site defect closure could be achieved in all cases with the use of a local FTSG. This graft can be gained at the access incision for the vascular pedicle, avoids expansion of the incision for a local flap technique, and does not prolong wound healing, and thus reduces both donor site and graft site morbidity of the RFFF. This technique leads to an inconspicuous aesthetic result with no apparent relevant functional deficits and avoids the need for a second donor site. PMID- 25804896 TI - Preparing for a career in biopharma research. AB - Many life sciences trainees in academia have limited exposure to how the biotechnology/pharmaceutical industry approaches drug discovery and development and what life is like in biopharma research. In this article, I will provide my perspectives on how to prepare for a successful career in biopharma research, focusing on technical background, an understanding of the drug discovery and development process, and personal and interpersonal keys to success. PMID- 25804898 TI - Longitudinal Influences of Social Network Characteristics on Subjective Well Being of Older Adults: Findings From the ELSA Study. AB - OBJECTIVE: To investigate the influence of social network characteristics on subjective well-being over 6 years in a population sample of older adults. METHOD: A total of 4,116 participants in the English Longitudinal Study of Aging provided baseline data on social network characteristics and potential confounding factors, and complete follow-up data on 2 measures of subjective well being. RESULTS: Social network size and network contact frequency were positively and independently associated with future life satisfaction and quality of life after controlling for confounding factors, including demographic characteristics, socioeconomic factors, and long-standing illness. In contrast, social network diversity was not independently related to future subjective well-being. CONCLUSION: Different aspects of people's social networks may help sustain levels of subjective well-being in older age. The role of close relationships and frequent contact in later life may be particularly important. These results highlight the need for examining different aspects of social networks for promoting well-being of older people. PMID- 25804897 TI - Type of Insurance and Use of Preventive Health Services Among Older Adults in Mexico. AB - OBJECTIVE: The main purpose of this article was to assess the differences between Seguro Popular (SP) and employer-based health insurance in the use of preventive services, including screening tests for diabetes, cholesterol, hypertension, cervical cancer, and prostate cancer among older adults at more than a decade of health care reform in Mexico. METHOD: Logistic regression models were used with data from the Mexican Health and Nutrition Survey, 2012. RESULTS: After adjusting for other factors influencing preventive service utilization, SP enrollees were more likely to use screening tests for diabetes, cholesterol, hypertension, and cervical cancer than the uninsured; however, those in employment-based and private insurances had higher odds of using preventive care for most of these services, except Pap smears. DISCUSSION: Despite all the evidence that suggests that SP has increased access to health insurance for the poor, inequalities in health care access and utilization still exist in Mexico. PMID- 25804899 TI - Characteristics Associated With Fear of Falling and Activity Restriction in South Korean Older Adults. AB - OBJECTIVES: The purpose of this study was to identify the characteristics associated with fear-induced activity restriction and determine those that distinguish older adults with fear-induced activity restriction from those with fear of falling alone. METHOD: Data taken from the survey of the Korean Longitudinal Study of Aging in 2010 were analyzed. Multiple logistic regression analysis was used to assess factors associated with fear of falling and fear induced activity restriction. RESULTS: A total of 22.5% of the participants reported no fear of falling, 48.6% reported fear of falling alone, and 28.9% reported fear-induced activity restriction. Characteristics independently associated with fear-induced activity restriction were low socioeconomic status, cognitive impairment, difficulty with activities of daily living, and a history of injurious falls. DISCUSSION: The differences between older adults with fear induced activity restriction and those with fear of falling alone may guide refinement of intervention and preventive programs. PMID- 25804901 TI - Association Between Depressive Symptoms, Multiple Dimensions of Depression, and Elder Abuse: A Cross-Sectional, Population-Based Analysis of Older Adults in Urban Chicago. AB - OBJECTIVE: Depression is conceptualized as both a risk factor for and a consequence of elder abuse; however, current research is equivocal. This study examined associations between elder abuse and dimensions of depressive symptoms in older adults. METHOD: Participants were 10,419 older adults enrolled in theChicago Health and Aging Project (CHAP), a population-based study of older adults. Regression was used to determine the relationships between depressive symptoms, depression dimensions, and abuse variables. RESULTS: Depressive symptoms were consistently associated with elder abuse. Participants in the highest tertile of depressive symptoms were twice as likely to have confirmed abuse with a perpetrator (odds ratio = 2.07, 95% confidence interval = [1.21, 3.52], p = .008). Elder abuse subtypes and depression dimensions were differentially associated. DISCUSSION: These findings highlight the importance of routine depression screening in older adults as a component of abuse prevention and intervention. They also provide profiles of depressive symptoms that may more accurately characterize risk for specific types of abuse. PMID- 25804900 TI - Association Between Lower Extremity Performance and Health-Related Quality of Life in Elderly Mexican Americans. AB - OBJECTIVE: To examine the longitudinal association between levels of lower extremity performance (LEP) and health-related quality of life (HRQoL) in older Mexican Americans aged 72 years or older participating in the Hispanic Established Population for the Epidemiological Study of the Elderly (2000-2006). METHOD: LEP was measured in 621 non-institutionalized participants with the Short Physical Performance Battery (SPPB). Participants were divided into high (SPPB score 10-12), intermediate (SPPB score 7-9), and low (SPPB score 0-6) groups based on LEP. HRQoL was assessed using the Medical Outcomes Study Short Form (SF 36), which includes a Physical Composite Scale (PCS) and a Mental Composite Scale (MCS). RESULTS: Participants in the high LEP group had slower rates of decline in the PCS, and those in the intermediate LEP group had slower rates of decline in the MCS score over time. DISCUSSION: Increased LEP was associated with slower rates of decline in physical and mental HRQoL in older Mexican Americans. PMID- 25804902 TI - Prevalence and Factors Associated to Hypertension Among Older Adults in Bogota, Colombia. AB - OBJECTIVE: To characterize older adults in Bogota with high blood pressure and identify factors associated to this condition within this population. METHOD: Using data from the Salud, Bienestar y Envejecimiento (SABE) (Health, Well-being and Aging) Bogota Study, we analyzed community-dwelling adults 60 years and older with hypertension. We estimated the prevalence and used logistic regression models to identify factors associated to hypertension. RESULTS: The overall prevalence for hypertension was 56.9%. Older age (odds ratio [OR] = 1.46, 95% confidence interval [CI] = [1.07, 1.97]), having health insurance (OR = 4.15, CI = [1.95, 8.85]), cardiovascular diseases (ORs between 1.70 and 3.65), and poor self-rated health (OR = 1.57, CI = [1.20,2.06]) significantly increased the odds of hypertension. Most individuals received pharmacologic treatment (93.5%); however, 28.4% of individuals had uncontrolled hypertension. DISCUSSION: We found a high prevalence of hypertension in our cohort and found that comorbidities and poor self-rated health increase the odds of hypertension. Future studies need to tailor interventions for hypertension management in old age. PMID- 25804903 TI - A Summary Score for the Framingham Heart Study Neuropsychological Battery. AB - OBJECTIVE: To calculate three summary scores of the Framingham Heart Study neuropsychological battery and determine which score best differentiates between subjects classified as having normal cognition, test-based impaired learning and memory, test-based multidomain impairment, and dementia. METHOD: The final sample included 2,503 participants. Three summary scores were assessed: (a) composite score that provided equal weight to each subtest, (b) composite score that provided equal weight to each cognitive domain assessed by the neuropsychological battery, and (c) abbreviated score comprised of subtests for learning and memory. Receiver operating characteristic analysis was used to determine which summary score best differentiated between the four cognitive states. RESULTS: The summary score that provided equal weight to each subtest best differentiated between the four cognitive states. DISCUSSION: A summary score that provides equal weight to each subtest is an efficient way to utilize all of the cognitive data collected by a neuropsychological battery. PMID- 25804904 TI - A novel domino cyclization for the stereoselective synthesis of indeno[2,1 c]pyran and cyclopenta[c]pyran derivatives. AB - A novel bicyclization of 2-(2-(hydroxymethyl)-1-methylene-2,3-dihydro-1H-inden-2 yl)ethanol with aldehydes in the presence of 10 mol% BF3.OEt2 in dichloromethane at 0-25 degrees C affords the biologically relevant indeno[2,1-c]pyran scaffolds in good yields with high selectivity. Similarly the bicyclization of 2-(1 (hydroxymethyl)-2-methylenecyclopentyl)ethanol with aldehydes generates the corresponding cyclopenta[c]pyran derivatives under similar conditions. This method is very useful to produce hematoxylin and brazilin like scaffolds. PMID- 25804905 TI - Helicobacter pylori dupA and smoking are associated with increased levels of interleukin-8 in gastric mucosa in Iraq-reply. PMID- 25804907 TI - Introduction: epigenetics. PMID- 25804906 TI - Loss of ADAM17 is associated with severe multiorgan dysfunction. AB - ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T cell stimulation assays showed severely diminished tumor necrosis factor-alpha and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement. PMID- 25804909 TI - The influenza viruses. PMID- 25804910 TI - Bee and wasp stings in Deniyaya; a series of 322 cases. AB - OBJECTIVES: To describe wasp and bee species that sting humans, analyse risk factors and clinical features. METHODS: A prospective observational study was conducted on patients presenting to Base Hospital Deniyaya with suspected bee and wasp stings from 2011 to 2013. Data were gathered using a questionnaire and specimens of offending insects collected for identification. When the insect specimen was unavailable, identification was made by the victim selecting (without prompting) from several dead specimens presented by the first author. RESULTS: There were 322 patients (mean age: 42.5 years, SD: 15.1, 173 [53.7%] males). Insects were brought by 55 (17%) and 267 (83%) were identified using specimens. All occurred during day-time, 142 (44.1%) during August and September, and 200 victims (62%) were tea plantation workers. Majority (78.9%) reported a localized painful self-limiting swelling without systemic features and 15 (4.6%) developed anaphylactic shock. None died. Five specimens were available from those in anaphylactic shock (four Apis dorsata, one Ropalidia marginata). Vespa tropica stinging caused a characteristic skin lesion. Of the 55 specimens, 46 (83.6%) were Apis dorsata (Giant honey-bee, ''Bambara''), 8 (14.5%) Vespa tropica (Greater banded hornet, ''Debara'') and one Ropalidia marginata (Paper wasp, ''Kaladuruwa''). CONCLUSIONS: Only three hymenoptera species stings were reported. Risk factors included day-time outdoor activities, occupation (tea plantation workers) and period of year. The latter may be due to pollen season when the insects are found in abundance. Only 4.6% of the patients developed anaphylactic shock. Vespa tropica stings led to a unique skin lesion. PMID- 25804911 TI - Secondary bacteraemia in adult patients with prolonged dengue fever. AB - INTRODUCTION: Although dengue management guidelines do not advice on use of antibiotics in dengue shock syndrome, unrecognised bactraemia is likely to contribute to morbidity and mortality. OBJECTIVES: To assess the occurance of secondary bacteraemia in adult patients with prolonged dengue fever. METHODS: A prospective study was conducted recruiting patients with confirmed acute dengue infection who had prolonged fever (>5 days). Two sets of blood cultures were taken in such patients prior to institution of antibiotic therapy. Demographic, clinical, haematological and biochemical parameters were recorded. Development of ascites and pleural effusions were detected using ultrasonography. RESULTS: Fourty patients (52.5% males) with a mean age of 29.8 years (SD 13.6) were studied. The average duration of fever was 7.9 days (SD 1.8). Ten patients (25%) had bacterial isolates in their blood cultures; Staphylococcus aureus (n=2), coliforms (n=3), pseudomonas (n=1) and 4 had mixed growths. The culture positive group had severe body aches at admission and higher fever, third space fluid accumulation, a significant drop in platelets and a higher CRP. CONCLUSIONS: A quarter of dengue patients with prolonged fever had a bacterial isolate. Culture positive patients appeared more ill with body aches and had higher degrees of fever during the latter part of the illness. Increased vascular permeability may predispose to bacterial seepage into blood. Although white cell count is not helpful in detecting bacteraemia, low platelet count and elevation of CRP seem to be helpful. PMID- 25804912 TI - Pattern of lymphoma subtypes in a cohort of Sri Lankan patients. AB - OBJECTIVES: To investigate the pattern of World Health Organization (WHO) lymphoma sub types in a sample from Sri Lanka. METHODS: Retrospective, descriptive study was carried out using biopsy specimens of patients diagnosed or suspected to have a lymphoma received by the Department of Pathology, University of Peradeniya for WHO sub typing. A sample of 227 cases diagnosed to have a lymphoma. All lymphomas were sub classified according to WHO 2007 revised classification of haematopoietic and lymphoid neoplasm using immunohistochemistry. RESULTS: There were 35 (15.4%) Hodgkin Lymphoma (HL) and 192 (84.6%) non Hodgkin Lymphoma (NHL) specimens. Of the NHL the common sub types were diffuse large B cell lymphoma 87 (38.3%), follicular lymphoma 26 (11.5%) and peripheral T cell lymphoma 25 (11%). Of the HL the common sub types were mixed cellular 20 (8.8%) and nodular sclerosis 13 (5.7%). The mean age of the patients was 48.8 +/- 19.3 years and male to female ratio was 1.4:1. The observed patterns of both HL and NHL in the study population were similar to those of other South Asian countries such as India and Pakistan. CONCLUSIONS: In the Sri Lankan sample, common sub types of lymphoma were diffuse large B cell lymphoma and follicular lymphoma. The frequency of lymphoma subtypes in the Sri Lankan sample are in accordance with the globally observed variations and similar to those observed in other South Asian countries. PMID- 25804913 TI - Prevalence of hepatitis B and hepatitis C infections and their relationship to injectable drug use in a cohort of Sri Lankan prison inmates. AB - INTRODUCTION: Prisoners are considered to be at high risk for Hepatitis B (HBV) and Hepatitis C (HCV) virus infections. This is attributed to intravenous drug use and high-risk sexual behaviour. There are no published studies on HBV and HCV among prison inmates or injecting drug users in Sri Lanka. OBJECTIVES: To determine prevalence of HBV and HCV infections, and their relationship to injectable drug use among Sri Lankan prisoners. METHODS: We investigated 393 (median age 42 years (range 16 to 93); 82% males) randomly selected inmates of Mahara and Welikada prisons. RESULTS: Though 167 (42.5%) admitted drug abuse, only 17 (4.3%) had ever used intravenous drugs. Twelve (70.6%) of them reported sharing needles. One inmate was positive for HBsAg but was negative for HBV-DNA. Twenty seven (6.9%) were positive for anti-HCV antibodies, of whom only 2 (0.5%) were positive for HCV-RNA. None of the injecting drug users were positive for HBV DNA or HCV-RNA. CONCLUSIONS: The prevalence of HBV and HCV infections as well as injecting drug use was very low among this cohort of Sri Lankan prison inmates. PMID- 25804914 TI - A low cost rapid urease test to detect Helicobacter pylori infection in resource limited settings. AB - The aim of the study was to evaluate the suitability of a modified one minute rapid urease test (one day rapid urease test) as a low cost H. pylori detection method. A sample of 205 patients clinically suspected of having H. pylori infection was tested. One day rapid urease test and histology based H. pylori tests (the gold standard) were performed on endoscopic antral biopsies. There were 6 true positives, 191 true negatives, 8 false positives and zero false negatives. The sensitivity, specificity and positive (PPV) and negative predictive values (NPV) of the test were 100%, 96%, 42.9%, and 100% respectively. The cost per patient was 0.3US$. High sensitivity, specificity and NPV, low cost and simplicity of method were the advantages of the test and the main limitation was low PPV. Hence, one day rapid urease test can be considered as a suitable low cost method to detect H. pylori infection in resource limited settings. PMID- 25804915 TI - Morphology of the tubercle of Zuckerkandl and its importance in thyroid surgery. AB - The tubercle of Zuckerkandl (ZT) is an embryological remnant of the thyroid gland. Its close relationship to the recurrent laryngeal nerve (RLN) makes it an important surgical landmark. Presence and size of the ZT was prospectively assessed during thyroidectomies done at a single surgical unit during 2013. Eighty patients were included in the study. Closest distance and relationship of the ZT to the RLN was measured. Median age was 48 years (range 20-75 years). The ZT was present in 72 (90%) patients at least on one side and 55 (69%) patients on both sides. Grade III tubercles were found in 17 (21.25%) patients. Average distance between RLN and the ZT was 1.2 mm posteriorly or posteromedially. In the majority (79%) RLN was lying at a distance of <=1 mm. Pressure symptoms were present in 19 (23.75%) patients and it was not related to the presence of grade III tubercles (p = 0.207). PMID- 25804917 TI - Does ingestion of plants from a phenetic group of Monochoria ('Diyahabarala') cause hepatotoxicity? PMID- 25804916 TI - Corrosive acid injury of the stomach. AB - Ingestion of corrosives with accidental or suicidal intent is a common problem in Sri Lanka. Management options and outcomes of corrosive injuries on stomach are not well documented in our setting. The clinical presentation, complications and management outcomes of nine patients with corrosive injury to stomach are presented. Gastric outlet obstruction seen in majority, was managed with bypass procedure (n=5) or resection (n=4). The outcomes of management were successful with both methods. PMID- 25804918 TI - Acute renal insufficiency after scorpion sting. PMID- 25804919 TI - A rare case of congenital fibre type disproportion causing delayed motor milestones. PMID- 25804920 TI - WHO suicide statistics - a cautionary tale. PMID- 25804908 TI - Sirtuins in epigenetic regulation. PMID- 25804921 TI - All-Cause Mortality up to and After Coronary Heart Disease and Stroke Events in European Middle-Aged Men: The PRIME Study. AB - BACKGROUND AND PURPOSE: The aim was to investigate prospectively the all-cause mortality risk up to and after coronary heart disease (CHD) and stroke events in European middle-aged men. METHODS: The study population comprised 10 424 men 50 to 59 years of age recruited between 1991 and 1994 in France (N=7855) and Northern Ireland (N=2747) within the Prospective Epidemiological Study of Myocardial Infarction. Incident CHD and stroke events and deaths from all causes were prospectively registered during the 10-year follow-up. In Cox's proportional hazards regression analysis, CHD and stroke events during follow-up were used as time-dependent covariates. RESULTS: A total of 769 CHD and 132 stroke events were adjudicated, and 569 deaths up to and 66 after CHD or stroke occurred during follow-up. After adjustment for study country and cardiovascular risk factors, the hazard ratios of all-cause mortality were 1.58 (95% confidence interval 1.18 2.12) after CHD and 3.13 (95% confidence interval 1.98-4.92) after stroke. CONCLUSIONS: These findings support continuous efforts to promote both primary and secondary prevention of cardiovascular disease. PMID- 25804922 TI - Acute chest pain and paraparesis. PMID- 25804923 TI - Impact of cognitive neuroscience on stroke rehabilitation. PMID- 25804924 TI - Longitudinal relationship between cerebral small-vessel disease and cerebral blood flow: the second manifestations of arterial disease-magnetic resonance study. AB - BACKGROUND AND PURPOSE: Cerebral small-vessel disease and cerebral blood flow (CBF) are interrelated. However, the direction of the relationship is unknown, and longitudinal studies are scarce. We investigated the longitudinal relationship between CBF and white matter hyperintensities (WMHs) and lacunes, as representatives of cerebral small-vessel disease, in patients with manifest arterial disease. METHODS: Within the Second Manifestations of Arterial Disease Magnetic Resonance (SMART-MR) study, 1.5T brain magnetic resonance imaging, including an MR angiography, was obtained at baseline and after on ~3.9 years of follow-up in 575 patients with manifest arterial disease (mean age, 57+/-10 years). Longitudinal associations of WMHs and lacunes with parenchymal CBF (pCBF; per 100-mL brain volume) were estimated using regression analyses, adjusted for age, sex, follow-up time, and baseline brain measures. RESULTS: Baseline pCBF was not associated with progression of WMHs and lacunes over time. However, periventricular and deep WMHs at baseline were associated with decline in pCBF; mean (95% confidence interval) decline in pCBF per % intracranial volume increase in periventricular and deep WMH volume was -0.70 (-1.40 to -0.00) and -1.01 ( 1.64 to -0.38) mL/min per 100-mL brain volume, respectively. These associations were partly explained by cardiovascular risk factors but remained significant for deep WMHs (mean decline [95% confidence interval] in pCBF per % intracranial volume increase in deep WMH volume was -0.92 [-1.56 to -0.28] mL/min per 100-mL brain volume). Lacunes were not associated with change in pCBF. CONCLUSIONS: In patients with manifest arterial disease, baseline periventricular and deep WMH volumes were associated with decline in pCBF over time, but baseline pCBF was not associated with progression of WMHs and lacunes over time. PMID- 25804925 TI - Normobaric hyperoxia slows blood-brain barrier damage and expands the therapeutic time window for tissue-type plasminogen activator treatment in cerebral ischemia. AB - BACKGROUND AND PURPOSE: Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of neurovasculature complications secondary to reperfusion. Therefore, targeting ischemic BBB damage pathogenesis is critical to reducing neurovasculature complications and expanding the therapeutic time window of tissue-type plasminogen activator (tPA) thrombolysis. This study investigates whether increasing cerebral tissue PO2 through normobaric hyperoxia (NBO) treatment will slow the progression of BBB damage and, thus, improve the outcome of delayed tPA treatment after cerebral ischemia. METHODS: Rats were exposed to NBO (100% O2) or normoxia (21% O2) during 3-, 5-, or, 7-hour middle cerebral artery occlusion. Fifteen minutes before reperfusion, tPA was continuously infused to rats for 30 minutes. Neurological score, mortality rate, and BBB permeability were determined. Matrix metalloproteinase-9 was measured by gelatin zymography and tight junction proteins (occludin and cluadin-5) by Western blot in the isolated cerebral microvessels. RESULTS: NBO slowed the progression of ischemic BBB damage pathogenesis, evidenced by reduced Evan blue leakage, smaller edema, and hemorrhagic volume in NBO-treated rats. NBO treatment reduced matrix metalloproteinase-9 induction and the loss of tight junction proteins in ischemic cerebral microvessels. NBO-afforded BBB protection was maintained during tPA reperfusion, resulting in improved neurological functions, significant reductions in brain edema, hemorrhagic volume, and mortality rate, even when tPA was given after prolonged ischemia (7 hours). CONCLUSIONS: Early NBO treatment slows ischemic BBB damage pathogenesis and significantly improves the outcome of delayed tPA treatment, providing new evidence supporting NBO as an effective adjunctive therapy to extend the time window of tPA thrombolysis for ischemic stroke. PMID- 25804926 TI - Burden of Sickness Absence Due to Chronic Disease in the Dutch Workforce from 2007 to 2011. AB - INTRODUCTION: Chronic diseases are associated with productivity loss costs due to sickness absence. It is not always clear, however, which chronic diseases in particular are involved with how many sickness days and associated costs. OBJECTIVE: To determine the prevalence, additional days of sickness absence, and associated costs of chronic diseases among the Dutch working population from 2007 to 2011. METHODS: Prevalence of chronic diseases and additional days of sickness absence were derived from the Netherlands Working Conditions Survey (NWCS) from 2007 to 2011. The cost of each sickness absence day was based on linked personal income data. We used multiple regression analysis to derive the unconfounded additional days of sickness absence due to each chronic disease. RESULTS: Annually, approximately 37 % of the Dutch working population reported some type of chronic physical or psychological disease. No clinically relevant changes in prevalence of specific chronic diseases were observed in the studied period, nor in the number of additional sickness absence days or associated costs. The national financial burden due to sickness absence associated with chronic musculoskeletal disorders amounted to ?1.3 billion annually. CONCLUSIONS: Chronic diseases result in substantial productivity loss due to sickness absence. Given the ageing population, the proposed increase in the state pension age and an increase in sedentary lifestyle and obesity, the prevalence of chronic diseases may be expected to rise. Coordinated efforts to maintain and improve the health of the working population are necessary to minimize socioeconomic consequences. PMID- 25804928 TI - Antibiotic Prophylaxis Guidelines and Infective Endocarditis: Cause for Concern? PMID- 25804927 TI - Validation of the Chinese Version of the Cognitive Symptom Checklist-Work-21 in Breast Cancer Survivors. AB - PURPOSE: The purpose of this study was to translate the Cognitive Symptom Checklist-Work-21 (CSC-W21), into Chinese, and culturally adapt and validate the Chinese version, a measure of work-related cognitive limitations in occupationally active breast cancer survivors (BCS). METHODS: The translation of the English version of the CSC-W21 followed a systematic procedure. Exploratory factor analysis was used to identify factor structures. The internal consistency of the factors was assessed by calculating the Cronbach's alpha reliability coefficients. Item- and scale-level content validity was determined. The intra class correlation coefficient (ICC) was used to analyze test-retest reliability. A total of two hundred and twenty BCS participated in the psychometric testing of the CSC-W21-C. The construct validity of the total score of the CSC-W21-C was determined through convergent validity and an analysis of its relationship with the four subscales of the Work Limitations Questionnaire (WLQ), a measure of four types of job task difficulties. RESULTS: The CSC-W21-C demonstrated item- and scale-level content validity (>.80). The factor structure of the CSC-W21-C was similar to the original English version. The internal consistency of the subscales of the CSC-W21-C ranged from .84 to .95. The ICC was between .80 and .96 indicating good test-retest reliability. The CSC-W21-C was significantly correlated with the WLQ, particularly the mental-interpersonal subscale, where it accounted for 27.3 % of the total variance. CONCLUSIONS: The findings indicate that the CSC-W21-C has sound measurement properties that strongly suggest it can be used in future assessment and intervention research to identify cognitive limitations related to specific work tasks in BCS. PMID- 25804929 TI - Genomic variation in the hybrids of white crucian carp and red crucian carp: evidence from ribosomal DNA. AB - In this study, we conducted a cross of white crucian carp (?)*red crucian carp (?) (WR), and characterized the morphology, reproduction and genetics of the progeny. Different from parents, WR with the gray color showed the hybrid morphological traits of both parents. WR possessed normal gonads producing mature eggs or sperm, and exhibited high fertilization rate (90.2%) and high hatchery rate (80.5%), which contributed to produce and enlarge the population. WR with the same DNA content as parents was a diploid fish with 100 chromosomes (2n=100). Amplified ITS of 45S rDNA, in WR the sequences consisting of 884 bp bases of the entire ITS-1 region, 5.8 S region, and entire ITS-2 region. The sequences showed high similarity between WR and its parents and leaned towards male inheritance. In WR, NTS of 5S rDNA consisted of three length types with total 654 bp bases. From sequence analysis of NTS, WR shared 94.2% and 95.1% similarities with their female and male parent, respectively. Sequence analysis of ITS and NTS revealed that there existed recombination and variation in the hybrid progeny, which was the genetic base for adaptation and speciation. In conclusion, we obtained WR from hybridization and it exhibited hybrid traits in morphology and variation in genetic composition showing essential difference with its parents. The obtainment of WR has important significance in fish genetic breeding. PMID- 25804930 TI - Associations of cord blood metabolites with early childhood obesity risk. AB - BACKGROUND/OBJECTIVE: Rapid postnatal weight gain is a potentially modifiable risk factor for obesity and metabolic syndrome. To identify markers of rapid infancy weight gain and childhood obesity, we analyzed the metabolome in cord blood from infants differing in their postnatal weight trajectories. METHODS: We performed a nested case-control study within Project Viva, a longitudinal cohort of mothers and children. We selected cases (n=26) based on top quartile of change in weight-for-age 0-6 months and body mass index (BMI) >85th percentile in mid childhood (median 7.7 years). Controls (n=26) were age and sex matched, had normal postnatal weight gain (2nd or 3rd quartile of change in weight-for-age 0-6 months) and normal mid-childhood weight (BMI 25th-75th percentile). Cord blood metabolites were measured using untargeted liquid chromatography-mass spectrometry; individual metabolites and pathways differing between cases and controls were compared in categorical analyses. We adjusted metabolites for maternal age, maternal BMI and breastfeeding duration (linear regression), and assessed whether metabolites improved the ability to predict case-control status (logistic regression). RESULTS: Of 415 detected metabolites, 16 were altered in cases versus controls (t-test, nominal P<0.05). Three metabolites were related to tryptophan: serotonin, tryptophan betaine and tryptophyl leucine (46%, 48% and 26% lower in cases, respectively, P<0.05). Mean levels of two methyl donors, dimethylglycine and N-acetylmethionine, were also lower in cases (18% and 16%, respectively, P=0.01). Moreover, the glutamine:glutamate ratio was reduced by 33% (P<0.05) in cases. Levels of serotonin, tryptophyl leucine and N-acetylmethionine remained significantly different after adjustment for maternal BMI, age and breastfeeding. Adding metabolite levels to logistic regression models including only clinical covariates improved the ability to predict case versus control status. CONCLUSIONS: Several cord blood metabolites are associated with rapid postnatal weight gain. Whether these patterns are causally linked to childhood obesity is not clear from this cross-sectional analysis, but will require further study. PMID- 25804931 TI - Congestive heart failure presence predicts delayed healing of foot ulcers in diabetes: An audit from a multidisciplinary high-risk foot clinic. AB - AIMS: This retrospective study aimed to investigate both established and less well-explored factors as potential predictive variables for failed and delayed ulcer healing. METHODS: Patients with type 1 or 2 diabetes with foot ulceration presenting consecutively to, and then subsequently managed at, a multidisciplinary, high-risk foot clinic were followed until ulcer healing, amputation or death. Data comprised prospective standardised documentation at each visit and retrospective collection from hospital records, and included patient demographics, comorbidities, laboratory variables, and ulcer infection, depth and area at each presentation. Multiple regression analysis was used to determine independent predictors of failure to heal and delayed healing. RESULTS: Of the 107 consecutive patients studied, 95 (89%) healed overall, 50 (47%) had healed in 12 weeks and the mean healing rate was a 10% decrease in ulcer area per week. Amongst all variables examined, comorbid congestive heart failure (CHF) was the only factor independently predictive of all measured outcomes of failure to heal overall, delayed healing at 12 weeks, and reduced healing rate. Ulcer infection at presentation, longer duration of antibiotic use, and liver enzyme abnormalities of raised ALT and AST:ALT<1 (each suggestive of non-alcoholic fatty liver disease), were also predictive of poor ulcer outcomes. CONCLUSIONS: Comorbid congestive cardiac failure is predictive of delayed foot ulcer healing rate as well as a lower probability of healing overall. Liver enzyme abnormalities also predicted delayed ulcer healing outcomes. The mechanisms underlying these associations with foot ulcer outcomes in diabetes are unclear. Further studies are needed to determine the role of systematic routine documentation of heart failure and its severity, and then targeting of heart failure to potentially aid the management of foot ulcers in diabetes. PMID- 25804932 TI - 18F-Fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography in mucosa-associated lymphoid tissue lymphoma: variation in 18F-FDG avidity according to site involvement. AB - The purpose of this study was to determine the 18F-FDG avidity of MALT lymphoma and the additional utility of 18F-FDG PET/CT in MALT lymphoma staging. Pretreatment 18F-FDG PET/CT scans of 222 patients with 227 MALT lymphoma lesions were retrospectively analyzed. 18F-FDG avidity of lesions was noted in 28%. The proportion was lower for gastric MALT lymphomas than for non-gastric lesions (9% vs. 60%, p<0.0001) and higher for mass-forming lesions than for superficial lesions (82% vs. 2%, p<0.0001). 18F-FDG PET/CT showed the presence of additional lesions in 23 patients: four of six true-positive lesions had 18F-FDG avid primary lesions, and 15 of 17 false-positive lesions had 18F-FDG-non avid lesions. 18F-FDG avidity differed according to the location and gross morphologic characteristics of the MALT lymphoma. Most gastric MALT lymphomas were superficial and had low 18F-FDG avidity. For staging, 18F-FDG PET/CT can be helpful mainly for 18F-FDG avid primary MALT lymphomas. PMID- 25804933 TI - Ifosfamide, carboplatin, etoposide with or without bortezomib in patients with relapsed/refractory Hodgkin lymphoma: results of a randomized phase II trial. PMID- 25804935 TI - Preparation of Janus Pd/SiO2 nanocomposite particles in inverse miniemulsions. AB - Janus Pd/SiO2 nanocomposite particles (NCPs) were successfully synthesized through a combination of the sol-gel process of tetramethoxysilane in inverse miniemulsions and in situ reduction of Pd salts via a gas diffusion process of hydrazine. The formation of Pd nanoparticles (NPs) was verified by X-ray diffraction. The Janus morphology of the Pd/SiO2 NCPs was confirmed by microscopic observation. The Pd/SiO2 NCPs displayed a mesoporous structure. The content of Pd NPs in the NCPs could be conveniently adjusted by the K2PdCl4 loading. A formation mechanism of the Janus Pd/SiO2 NCPs was proposed. The mesoporous Janus Pd/SiO2 NCPs show good catalytic activity toward the reduction of p-nitrophenol with NaBH4. PMID- 25804934 TI - A multi-locus analysis of phylogenetic relationships within grass subfamily Pooideae (Poaceae) inferred from sequences of nuclear single copy gene regions compared with plastid DNA. AB - To investigate phylogenetic relationships within the grass subfamily Pooideae we studied about 50 taxa covering all recognized tribes, using one plastid DNA (cpDNA) marker (matK gene-3'trnK exon) and for the first time four nuclear single copy gene loci. DNA sequence information from two parts of the nuclear genes topoisomerase 6 (Topo6) spanning the exons 8-13 and 17-19, the exons 9-13 encoding plastid acetyl-CoA-carboxylase (Acc1) and the partial exon 1 of phytochrome B (PhyB) were generated. Individual and nuclear combined data were evaluated using maximum parsimony, maximum likelihood and Bayesian methods. All of the phylogenetic results show Brachyelytrum and the tribe Nardeae as earliest diverging lineages within the subfamily. The 'core' Pooideae (Hordeeae and the Aveneae/Poeae tribe complex) are also strongly supported, as well as the monophyly of the tribes Brachypodieae, Meliceae and Stipeae (except PhyB). The beak grass tribe Diarrheneae and the tribe Duthieeae are not monophyletic in some of the analyses. However, the combined nuclear DNA (nDNA) tree yields the highest resolution and the best delimitation of the tribes, and provides the following evolutionary hypothesis for the tribes: Brachyelytrum, Nardeae, Duthieeae, Meliceae, Stipeae, Diarrheneae, Brachypodieae and the 'core' Pooideae. Within the individual datasets, the phylogenetic trees obtained from Topo6 exon 8-13 shows the most interesting results. The divergent positions of some clone sequences of Ampelodesmos mauritanicus and Trikeraia pappiformis, for instance, may indicate a hybrid origin of these stipoid taxa. PMID- 25804936 TI - Highlights in the treatment of chronic lymphocytic leukemia from the 2014 meeting of the American Society of Hematology. AB - The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton's tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients >=65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL. PMID- 25804937 TI - Age-related macular degeneration and the role of the complement system. AB - Age-related macular degeneration (AMD) is a leading cause of visual impairment. It is characterised by damage to a tissue complex composed of the retinal pigment epithelium, Bruch's membrane and choriocapillaris. In early AMD extracellular debris including drusen accumulates in Bruch's membrane and then in late AMD geographic atrophy and/or neovascularisation develop. Variants in genes encoding components of the alternative pathway of the complement cascade have a major influence on AMD risk, especially at the RCA locus on chromosome 1, which contains CFH and the CFHR genes. Immunohistochemical studies have demonstrated complement components in unaffected and AMD macular tissue. Whilst other factors, including oxidative stress, play important roles in AMD pathogenesis, evidence for the central role played by complement dysregulation is discussed in this review. PMID- 25804938 TI - Social intentions in Parkinson's disease patients: A kinematic study. AB - Dysfunction of the dopaminergic system leads to motor, cognitive and motivational symptoms in brain disorders such as Parkinson's disease (PD). Moreover, the dopaminergic system plays an important role in social interactions. The dopaminergic input to the basal ganglia (BG) thought to integrate social cues during the planning and execution of voluntary movements remains, however, largely unexplored. Since PD provides a model to assess this function in humans, our study aimed to investigate the effects of social intentions on actions in non demented PDpatients receiving dopamine replacement therapy (Levodopa = l-Dopa) and in neurologically healthy control participants. Patients' ability to modulate motor patterning depending on the intention motivating the action to be performed was evaluated both in "on" (with l-Dopa) and "off" (without l-Dopa) states. Participants were instructed to reach for and to grasp an object; they were then told to hand it to another person (social condition) or to place it on a concave frame (individual condition). A 'passive-observer' condition, which was similar to the 'individual' condition except for the presence of an onlooker who simply observed the scene, was also assessed to exclude the possibility that differences might be due to the presence of another person. Movement kinematics were recorded using a three-dimensional motion analysis system. Study results demonstrated that the controls and the PD patients in an 'on' state adopted different kinematic patterning for the 'social' and the 'individual' conditions; the PD patients in the 'off' state, instead, were unable to kinematically differentiate between the two conditions. These results suggest that l-Dopa treatment has positive effects on translating social intentions into specific motor patterns in PD patients. PMID- 25804939 TI - Bone Marrow Macrophages Contribute to Diabetic Stem Cell Mobilopathy by Producing Oncostatin M. AB - Diabetes affects bone marrow (BM) structure and impairs mobilization of stem cells (SCs) into peripheral blood (PB). This amplifies multiorgan complications because BMSCs promote vascular repair. Because diabetes skews macrophage phenotypes and BM macrophages (BMMPhi) prevent SC mobilization, we hypothesized that excess BMMPhi contribute to diabetic SC mobilopathy. We show that patients with diabetes have increased M1 macrophages, whereas diabetic mice have increased CD169(+) BMMPhi with SC-retaining activity. Depletion of BMMPhi restored SC mobilization in diabetic mice. We found that CD169 labels M1 macrophages and that conditioned medium (CM) from M1 macrophages, but not from M0 and M2 macrophages, induced chemokine (C-X-C motif) ligand 12 (CXCL12) expression by mesenchymal stem/stromal cells. In silico data mining and in vitro validation identified oncostatin M (OSM) as the soluble mediator contained in M1 CM that induces CXCL12 expression via a mitogen-activated protein kinase kinase-p38-signal transducer and activator of a transcription 3-dependent pathway. In diabetic mice, OSM neutralization prevented CXCL12 induction and improved granulocyte-colony stimulating factor and ischemia-induced mobilization, SC homing to ischemic muscles, and vascular recovery. In patients with diabetes, BM plasma OSM levels were higher and correlated with the BM-to-PB SC ratio. In conclusion, BMMPhi prevent SC mobilization by OSM secretion, and OSM antagonism is a strategy to restore BM function in diabetes, which can translate into protection mediated by BMSCs. PMID- 25804940 TI - Manganese-mediated MRI signals correlate with functional beta-cell mass during diabetes progression. AB - Diabetes diagnostic therapy and research would strongly benefit from noninvasive accurate imaging of the functional beta-cells in the pancreas. Here, we developed an analysis of functional beta-cell mass (BCM) by measuring manganese (Mn(2+)) uptake kinetics into glucose-stimulated beta-cells by T1-weighted in vivo Mn(2+) mediated MRI (MnMRI) in C57Bl/6J mice. Weekly MRI analysis during the diabetes progression in mice fed a high-fat/high-sucrose diet (HFD) showed increased Mn(2+)-signals in the pancreas of the HFD-fed mice during the compensation phase, when glucose tolerance and glucose-stimulated insulin secretion (GSIS) were improved and BCM was increased compared with normal diet-fed mice. The increased signal was only transient; from the 4th week on, MRI signals decreased significantly in the HFD group, and the reduced MRI signal in HFD mice persisted over the whole 12-week experimental period, which again correlated with both impaired glucose tolerance and GSIS, although BCM remained unchanged. Rapid and significantly decreased MRI signals were confirmed in diabetic mice after streptozotocin (STZ) injection. No long-term effects of Mn(2+) on glucose tolerance were observed. Our optimized MnMRI protocol fulfills the requirements of noninvasive MRI analysis and detects already small changes in the functional BCM. PMID- 25804942 TI - Hindsight: providing an easy diagnosis for a rare presentation. PMID- 25804943 TI - A giant pancreatic pseudocyst treated by cystogastrostomy. AB - We report a case of a giant pancreatic pseudocyst in a 65-year-old man presenting with abdominal pain, loss of appetite and abdominal distension. CT scans demonstrated a giant pancreatic pseudocyst measuring 25.7 cm*15.3 cm*10.9 cm anteroposteriorly, with significant compression of surrounding organs. An open cystogastrostomy was performed through a midline incision, and 3 L of fluid was drained from the giant pseudocyst. Recovery has been uneventful. PMID- 25804941 TI - Diabetes Limits Stem Cell Mobilization Following G-CSF but Not Plerixafor. AB - Previous studies suggest that diabetes impairs hematopoietic stem cell (HSC) mobilization in response to granulocyte colony-stimulating factor (G-CSF). In this study, we tested whether the CXCR4 antagonist plerixafor, differently from G CSF, is effective in mobilizing HSCs in patients with diabetes. In a prospective study, individuals with and without diabetes (n = 10/group) were administered plerixafor to compare CD34(+) HSC mobilization; plerixafor was equally able to mobilize CD34(+) HSCs in the two groups, whereas in historical data, G-CSF was less effective in patients with diabetes. In a retrospective autologous transplantation study conducted on 706 patients, diabetes was associated with poorer mobilization in patients who received G-CSF with/without chemotherapy, whereas it was not in patients who received G-CSF plus plerixafor. Similarly in an allogeneic transplantation study (n = 335), diabetes was associated with poorer mobilization in patients who received G-CSF. Patients with diabetes who received G-CSF without plerixafor had a lower probability of reaching >50/MUL CD34(+) HSCs, independent from confounding variables. In conclusion, diabetes negatively impacted HSC mobilization after G-CSF with or without chemotherapy but had no effect on mobilization induced by G-CSF with plerixafor. This finding has major implications for the care of patients with diabetes undergoing stem cell mobilization and transplantation and for the vascular regenerative potential of bone marrow stem cells. PMID- 25804944 TI - The dangers of iodine-based contrasts in an elderly patient with thyroid disease. AB - Iodine-based contrast agents are widely used in angiographic and other radiological procedures. Clinicians are familiar with many of the potential adverse events from contrast agents including allergic reactions and contrast induced nephropathy. This case describes a lesser known adverse event: 'contrast induced thyrotoxicosis' and its implications on the presentation and management of a patient with severe coronary artery disease. The management of this case was difficult and required a long inpatient admission with use of prednisolone, propylthiouracil and planned treatment with radioiodine to control the thyrotoxicosis, as well as the use of several rate-limiting agents and antianginal medications to control atrial fibrillation and prevent further episodes of angina. PMID- 25804945 TI - A tricky late occurrence of Bochdalek's hernia. PMID- 25804946 TI - Anabolic androgenic steroid-induced Takotsubo cardiomyopathy. AB - Anabolic steroid abuse, aimed at increasing muscle mass, has been growing in recent years. We describe a case of a 25-year-old bodybuilder who, after taking nandrolone and stanozolol, presented with Takotsubo syndrome. The angiography showed a normal coronary anatomy with the absence of stenosis. The left ventricular function was completely normalised after 1 week. PMID- 25804947 TI - Cat-scratch disease presenting as a solitary splenic abscess in an elderly man. AB - Patients with cat-scratch disease (CSD), which is caused by Bartonella henselae, typically present with local lymphadenopathy with a brief period of fever and general symptoms. Most cases are self-limiting and usually afflict children and young adults. Although rare, CSD can lead to serious complications, especially in immunocompromised patients. These rare complications often require intensive treatment. We describe the case of a 79-year-old man who presented with general malaise and a high fever. The physical examination findings were unremarkable. Of note, the lymph nodes were not enlarged. An abdominal CT scan with intravenous contrast revealed a solitary splenic abscess and no lymphadenopathy. The initial antibiotic treatment was ineffective and a splenectomy was indicated. A history of contact with cats raised the possibility of CSD, which was confirmed by a positive serology test result for B henselae. Antibiotic treatment with azithromycin successfully treated the splenic abscess and splenectomy was avoided. PMID- 25804948 TI - When it matters that a 'Stroke' is not a stroke. PMID- 25804949 TI - Enhancement of Oral Bioavailability of Curcumin by a Novel Solid Dispersion System. AB - The objective of this study was to improve the solubility and bioavailability of curcumin by a new curcumin dripping pills (Cur-DPs) formulation using melt mixing methods. The optimal formulation consisted of Polyethoxylated 40 hydrogenated castor oil (Cremophor RH40), Poloxamer 188, and Polyethylene glycol 4000 (PEG 4000). Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FT-IR) were used to verify the forming of Cur-DPs. All the physical characterization information proved the formation of Cur-DPs, and the results demonstrated the superiority of the dripping pills in dissolution rates. The pharmacokinetic study of Cur-DPs was performed in rats compared to the pure curcumin suspension. The oral bioavailability of poorly water-soluble curcumin was successfully improved by CUR DPs. And the stability of prepared Cur-DP was also in a good state in 3 months. These results identified the Cur-DPs was an effective new approach for pharmaceutical application. PMID- 25804950 TI - Clinical characteristics and the risk for malignancy in postmenopausal women with adnexal torsion. AB - OBJECTIVE: To compare clinical characteristics and management of adnexal torsion in postmenopausal patients as compared to premenopausal ones. METHODS: A retrospective 22 year cohort of all cases of surgically verified adnexal torsion in postmenopausal and premenopausal patients, comparing presentation, imaging, surgical procedure and histology. RESULTS: Thirty five cases of adnexal torsion among postmenopausal patients were compared to 302 cases among premenopausal ones. Complex ovarian masses and larger ovarian diameter were more common among postmenopausal patients (7.8 vs. 6.8 cm, p=0.003). The admission to surgical interval differed substantially between the groups (75.5h in postmenopausal patients vs. 24.4 in the premenopausal ones, p<0.001). The main surgical indication for postmenopausal patients was pelvic mass investigation (54.3% vs 11.6%, p<0.001), and more premenopausal patients underwent surgery with a clinical suspicion of adnexal torsion (77.1% vs. 40%, p<0.001). Extensive surgery including bilateral salpingo-oophorectomy with or without total abdominal hysterectomy was more commonly performed in postmenopausal patients, as opposed to conservative surgery, including detorsion and cystectomy/fenestration or detorsion only, in premenopausal surgeries. Cancer was diagnosed in 3% of postmenopausal patients with adnexal torsion. CONCLUSION: Adnexal torsion in postmenopausal women is rare, but presents similarly, results in more delayed and extensive surgery and involves malignancy in 3%. PMID- 25804951 TI - Effects of menopause, gender and age on lipids and high-density lipoprotein cholesterol subfractions. AB - OBJECTIVE: To distinguish the effects of menopause, gender and age on serum lipid risk markers for vascular disease, including high-density lipoprotein cholesterol (HDL-C) subfractions 2 and 3 (HDL2-C and HDL3-C). METHODS: We undertook a cross sectional database analysis of apparently healthy Caucasian pre- and postmenopausal women and men (n=515, 518 and 800, respectively) not taking drugs affecting lipid metabolism (including contraceptive or post-menopausal steroids). Measurements of serum total cholesterol (TC), low-density lipoprotein (LDL-C), triglycerides (TG), HDL-C, HDL2-C, HDL3-C and non-HDL-C concentrations and the TC/HDL-C concentration ratio were considered. RESULTS: Men had lower TC than postmenopausal women (p<0.001) and similar LDL-C. Compared with premenopausal women, postmenopausal women had a more atherogenic lipid profile with lower HDL2 C (median 0.67 vs 0.60 mmol/L, p<0.001) but no difference in HDL3-C (0.96 vs 0.96 mmol/L, p=0.8). Compared with either pre or postmenopausal women, men had a more atherogenic profile with lower HDL2-C (0.36 mmol/L) and HDL3-C (0.91 mmol/L, all p<0.001). With standardization for confounding variables, including standardization to age of menopause (50 years), differences apparent in the non standardized comparisons were generally sustained, although HDL3-C levels were lower at menopause, HDL2-C ceased to differ and LDL-C was lower in postmenopausal women than men. CONCLUSIONS: Male gender is associated with a more atherogenic profile than female gender, with appreciably lower levels of the HDL2-C subfraction. Among women, menopause is associated with a more atherogenic lipid profile, but has less effect than male gender. PMID- 25804952 TI - Biological markers, lifestyles and metabolic syndrome in workers. AB - OBJECTIVE: The association between metabolic syndrome (MetS) and biological inflammatory or anti-coagulant markers were clarified in combination with lifestyle factors. PATIENTS AND METHODS: The target subjects were 5102 working men without metabolic diseases, aged 30-60 years old. The authors measured the serum levels of high-sensitivity C-reactive protein (CRP), uric acid and plasma fibrinogen as potential key biomarkers of MetS. RESULTS: Mean values of uric acid, log-transformed serum CRP and plasma fibrinogen increased significantly as the number of components of MetS increased after adjustment for age. Multivariate analysis revealed significant associations between the presence of MetS and age, habitual exercise, not current smoking, the log-transformed value of serum CRP and serum uric acid, with odds ratios (ORs) of 1.03 (95% confidence interval (CI): 1.02-1.04; p<0.001), 0.77 (95% CI: 0.65-0.90; p<0.01), 0.82 (95% CI: 0.70 0.96; p<0.05), 3.2 (95% CI: 2.6-3.9; p<0.001) and 1.5 (95% CI: 1.4-1.6; p<0.001), respectively for the presence of MetS. CONCLUSION: Elevated serum level of CRP, uric acid, not habitual exercise and current smoking were associated with MetS in this cross-sectional study. PMID- 25804955 TI - Amend or repeal? How New Zealand tackled unpopular healthcare legislation. PMID- 25804954 TI - Lack of exacerbation of neurodegeneration in a double transgenic mouse model of mutant LRRK2 and tau. AB - LRRK2 (leucine-rich repeat kinase) mutations constitute the most common cause of familial Parkinson's disease (PD). Microtubule-associated protein tau mutations cause a group of neurodegenerative diseases termed tauopathies. Genome-wide association studies show that, after alpha-synuclein, polymorphisms in the tau gene have the second strongest genetic association with PD. In a proportion of PD patients with LRRK2 mutations, and in several transgenic animal models of LRRK2, tau hyperphosphorylation and aggregation, rather than alpha-synuclein aggregation, are the most prominent neuropathologic findings. To further examine the relationship between LRRK2 and tau, we crossed LRRK2 R1441G BAC transgenic mice (Mus musculus) with tau P301S mutant transgenic mice and characterized their behavioral, neuropathological and biochemical phenotypes. We found that the combination of the two mutations does not increase tau hyperphosphorylation or aggregation nor does it exacerbate the behavioral and pathological deficits previously described in the tau P301S mice. The double-mutant mice had no shortening of lifespan and no worsening of motor or memory deficits. There was no increase in the aggregation of tau or alpha-synuclein. Dopaminergic neuron cell counts and striatal levels of dopamine and its metabolites were unaltered. There was no exacerbation of cell loss, microgliosis or astrogliosis in multiple brain regions. These results suggest that LRRK2 and tau do not interact to exacerbate behavioral, biochemical or pathological abnormalities in neurodegeneration and that LRRK2 and tau exert their pathogenic effects through independent mechanisms. PMID- 25804957 TI - Hierarchical nature of activities of daily living in the Spanish Disability Survey. AB - Many studies have addressed the issue of dimensionality in activities of daily living (ADL) and its hierarchy, with contradictory results. This paper aims to study the unidimensional structure and the hierarchy of ADL in the Spanish Disability Survey. We analysed a sample of 8381 people aged 65 and over with at least one disability and receiving personal help with one of them. The following Rasch model properties were studied in 14 items enquiring about basic and instrumental ADL: fit to the model, reliability, unidimensionality, local independency between items and differential item functioning (DIF) by gender, age and proxy. The unidimensionality of the scale was confirmed. The final analysis of eight items showed a satisfactory fit, good reliability, local independency, unidimensionality and no DIF by age. The disability linear measure showed significant differences by gender and age. The obtained disability scale is a simple and reliable measure, and it suggests a hierarchical order of ADL and predicts a schedule of functional impairment in older adults. Rating the disability of older community-dwelling people has a predictive value that policy makers might find useful in service planning. PMID- 25804959 TI - How can medical students' rapport formation and communication skill be improved? PMID- 25804958 TI - Predictors of hospital length of stay in pediatric Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is a common, benign vasculitis in childhood which occasionally follows a protracted course and prolonged length of hospital stay. We aimed to determine clinical and laboratory characteristics that allow prediction of prolonged length of hospital stay (4 or more days) in HSP patients. We have retrospectively reviewed all HSP cases that were admitted to the Dana Duek Children's hospital between 2000 and 2013. Univariable analysis was performed to study the variables that were statistically related to length of hospital stay. These variables along with other clinically relevant variables were analyzed using stepwise backward multiple regression analysis. Variables that remained significant in the final analysis were correlated with length of stay, were each given specific weight (according to their contribution to the final R(2)) and were used to assemble an HSP presentation severity score. Out of 107 charts that were screened, 89 children were retrieved for analysis. In univariate analysis, variables that were associated with prolonged (>4 days) length of stay were: abdominal pain as initial sole presentation, C-reactive protein (CRP) 45 mg/dL (1 or 0 point) and patient's age > 6 years (0.5 or 0 points). A score of >=3 in patients diagnosed with HSP predicted a prolonged length of stay with a positive predictive value of 93 %. The HSP presentation severity score index that we describe here may serve as a practical tool to assess severity of HSP which may eventually reflected as prolonged length of hospital stay. This score should be validated in the future in an ongoing prospective study. PMID- 25804960 TI - Portfolio assessment in leadership course for premedical students. PMID- 25804961 TI - Review on the administration and effectiveness of team-based learning in medical education. AB - Team-based learning (TBL) is an active learning approach. In recent years, medical educators have been increasingly using TBL in their classes. We reviewed the concepts of TBL and discuss examples of international cases. Two types of TBL are administered: classic TBL and adapted TBL. Combining TBL and problem-based learning (PBL) might be a useful strategy for medical schools. TBL is an attainable and efficient educational approach in preparing large classes with regard to PBL. TBL improves student performance, team communication skills, leadership skills, problem solving skills, and cognitive conceptual structures and increases student engagement and satisfaction. This study suggests recommendations for administering TBL effectively in medical education. PMID- 25804962 TI - Can medical drama motivate students to have an interest in the healthcare professionalism? AB - PURPOSE: This study was planned to evaluate that a lecture employing medical drama could motivate students to have an interest in the professionalism of healthcare personnel, which has currently become a critical subject in the field of medical education. METHODS: We analyzed subject headings, learning objectives, and further plans developed by students and their responses after two drama modules, 'car crash' and 'refusal of instruction', which were selected based on the conditions made by our faculty members, were given through video or paper to our 121 second-grade medical and nursing students in year 2012. RESULTS: Meaningful subject headings and learning objectives developed by students were 58.2%~60.0% and 36.8%~38.0% and significantly more in the 'refusal of instruction' than the 'car crash' (p=0.000). According to the students' major, medical students developed significantly more than nursing students (p=0.000). In the analysis of responses, 91.7% of students reported as impressive to the educational modules and 55.3% of them described their ideas associated with healthcare professionalism. CONCLUSION: Our study results suggest a possibility that the educational module employing selected medical drama could motivate students' healthcare professionalism. PMID- 25804963 TI - Physicians' perspectives on social competency education in academic medicine. AB - PURPOSE: This study aims to explore the improvement of medical curriculums by examining the relationship between attributes of the Korean physicians and their needs for specialized departments and professionals for enhancing Korean physicians' social competence. METHODS: The uniqueness of this study is in its conduction a survey about the Korean physicians' needs of specialized departments and professionals for physicians' social competence or not, unlikely that previous studies focused on reviews. Subjects of this study are 288 physicians among the members of the Korean Society of Medical Education and The Korea Intern Resident Association. The hierarchical regression analyses are conducted. RESULTS: The authors present the results. First, the needs of specialized departments decline if physicians have ever majored on basic medical and learned professionalism ethics. Second, the older physicians are, the much more learned professionalism ethics and the needs of leadership competence physicians have, the necessities of specialized professionals are reduced. Finally, the physicians' needs of patient-oriented communication and sympathy of human in society as well as professionalism ethics increase recognitions of the importance of specialized professionals. CONCLUSION: These results show that strengthening systemic and educators' individual capacity for successful social competence curriculums is important. PMID- 25804964 TI - A study on premedical curriculum reform of one medical school. AB - PURPOSE: The aim of this study was to examine the background and improvement of the reformed premedical curriculum in Seoul National University and to analyze in which it corresponds with its intentions. It gives implications to premedical curriculum through its development model. METHODS: The background and improvement of the reformed premedical curriculum was analyzed through several reports from those of associated committees. The development model of the reformed curriculum was made in order to examine correspondence with the intentions of its reformation. RESULTS: The graduate credit increased while compulsory credit was in decrease which leads to the elimination of standardized education based on the natural sciences. The requirements in compulsory liberal arts and elective major subjects were suggested in order to develop students' perspectives in humanities. CONCLUSION: As premed is a preliminary course before studying medicine, premedical curriculum should reflect the needs of those parties concerned society, professors, students, etc.- and be based on core values and educational philosophy of the school in order to derive its competences. PMID- 25804965 TI - The characteristics of medical students' personality types and interpersonal needs. AB - PURPOSE: Medical students' personality types and interpersonal needs must be considered. The purpose of this study was to examine the characteristics of personality types and interpersonal needs. METHODS: A total of 171 students in Konyang University College of Medicine were examined using the Myers-Briggs Type Indicator (MBTI) and Fundamental Interpersonal Relations Orientation-Behavior (FIRO-B). The data were analyzed by frequency analysis, t-test, and one-sample proportion test. RESULTS: The proportion of the 4 pairs of MBTI dimensions were Extroversion (E)-Introversion (I) (53.2% vs. 46.8%), Sensing (S)-Intuition (N) (63.2% vs. 36.8%), Thinking (T)-Feeling (F) (59.7% vs. 40.4%), and Judging (J) Perceiving (P) (56.1% vs. 43.9%). The predominant personality types were ISTJ (16.4%), ESTJ (14.0%), and ESFJ (10.5%). The level of interpersonal needs were medium rage that was inclusion (mean=8.1), control (mean=8.8), affection (mean=8.1), expressed behavior (mean=12.1), wanted behavior (mean=12.9), and overall interpersonal needs (mean=25.0). Of the basic social needs, males and females differed significantly with regard to control needs (p=0.028). CONCLUSION: Educational programs that take into account personality types and characteristics of interpersonal needs are crucial in providing effective medical education. Our results suggest that the characteristics of personality types and interpersonal needs should be considered in developing an interpersonal relations improvement program for medical students. PMID- 25804953 TI - Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci. AB - Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 * 10(-30)), OSECs (P = 2.4 * 10(-23)) and HMECs (P = 6.7 * 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer. PMID- 25804966 TI - Delivering bad news to a patient: a survey of residents and fellows on attitude and awareness. AB - PURPOSE: Delivering bad news (DBN) to a patient or patient's family is one of the most difficult tasks for physicians. As a complicated task, DBN requires better than average communication skills. This study investigated trainee's attitude and awareness of DBN based on a self-assessment of their experiences and performance in practice. Survey subjects were also asked to assess their perception and the need for education in conducting DBN. METHODS: A survey was carried out on their experiences with DBN, how they currently deal such situations, how they perceive such situations and the need for education and training programs. A SPIKES protocol was used to assess how they currently deal with DBN. RESULTS: One hundred one residents and fellows being trained in a teaching hospital participated in the survey. Around 30% had bad experiences due to improperly delivered bad news to a patient. In terms of self-assessment of how to do DBN, over 80% of trainees assessed that they were doing DBN properly to patients, using a SPIKE protocol. As for how they perceived DBN, 90% of trainees felt more than the average level of stress when they do DBN. About 80% of trainees believed that education and training is much needed during their residency program for adequate skill development regarding DBN. CONCLUSION: We suggest that education and training on DBN may be needed for trainees during the residency program, so that they could avoid unnecessary conflict with patients and reduce stress from DBN. PMID- 25804967 TI - Experience of clinical skills assessment in the Busan-Gyeongnam Consortium. AB - PURPOSE: The purpose of this study is to judge the quality of clinical skills assessment in Busan-Gyeongnam Consortium. METHODS: Fourth grade medical school students (n=350 in 2012 and n=419 in 2013) in the Busan-Gyeongnam Consortium were included in the study. The examination was consisted of 6 clinical performance examination (CPX) and 6 objective structured clinical examination (OSCE) stations. The students were divided into groups to take the exam in 4 sites during 3 days. The overall reliability was estimated by Cronbach alpha coefficient across the stations and the case reliability was by alpha across checklist items. Analysis of variance and between-group variation were used to evaluate the variation of examinee performance across different days and sites. RESULTS: The mean total CPX/OSCE score was 67.0 points. The overall alpha across stations was 0.66 in 2012 and 0.61 in 2013. The alpha across-items within a station was 0.54 to 0.86 in CPX, 0.51 to 0.92 in OSCE. There was no significant increase in scores between the different days. The mean scores over sites were different in 30 out of 48 stations but between-group variances were under 30%, except 2 cases. CONCLUSION: The overall reliability was below 0.70 and standardization of exam sites was unclear. To improve the quality of exam, case development, item design, training of standardized patients and assessors, and standardization of sites are necessary. Above of all, we need to develop the well organized matrix to measure the quality of the exam. PMID- 25804968 TI - Analysis of reliability of professor recommendation letters based on concordance with self-introduction letter. AB - PURPOSE: The purpose of this study was to examine the concordance between a checklist's categories of professor recommendation letters and characteristics of the self-introduction letter. METHODS: Checklists of professor recommendation letters were analyzed and classified into cognitive, social, and affective domains. Simple correlation was performed to determine whether the characteristics of the checklists were concordant with those of the self introduction letter. The difference in ratings of the checklists by pass or fail grades was analyzed by independent sample t-test. Logistic regression analysis was performed to determine whether a pass or fail grade was influenced by ratings on the checklists. RESULTS: The Cronbach alpha value of the checklists was 0.854. Initiative, as an affective domain, in the professor's recommendation letter was highly ranked among the six checklist categories. Self-directed learning in the self-introduction letter was influenced by a pass or fail grade by logistic regression analysis (p<0.05). Successful applicants received higher ratings than those who failed in every checklist category, particularly in problem-solving ability, communication skills, initiative, and morality (p<0.05). CONCLUSION: There was a strong correlation between cognitive and affective characteristics in the professor recommendation letters and the sum of all characteristics in the self-introduction letter. PMID- 25804969 TI - Six ways to provide meaningful and effective feedback. PMID- 25804970 TI - An inferential investigation into how stride length influences temporal parameters within the baseball pitching delivery. AB - Motion analyses of lower body mechanics offer new schemas to address injury prevention strategies among baseball pitchers, where the influence of stride length remains unknown. This study examined the temporal effect of stride length at constituent pitching events and phases. Nineteen competitive pitchers (15 collegiate, 4 high school) were randomly assigned to pitch two simulated, 80 pitch games at +/-25% of their desired stride length. An integrated, three dimensional motion capture system recorded each pitch. Paired t-tests were used to determine whether differences between stride conditions at respective events and within phases were significantly different. The results demonstrate the shorter strides mediated earlier onset of stride foot contact, reduced time in single support whereas double support intervals increased (p<.001). The opposite was observed with the longer strides. However, the acceleration phase, which comprises the highest throwing arm kinematics and kinetics, remained unchanged. The interaction between stride length, stride foot contact onsets, and time in single support is inferentially evidenced. The equivalent acceleration phases suggest stride length alone influenced time in single and double support by altering the onset of stride foot contact, which perhaps affects the mechanics in preparing the throwing arm for maximal external shoulder rotation. PMID- 25804972 TI - The description of Centrorhynchus globirostris n. sp. (Acanthocephala: Centrorhynchidae) from the pheasant crow, Centropus sinensis (Stephens) in Pakistan, with gene sequence analysis and emendation of the family diagnosis. AB - A new species of Centrorhynchus (Centrorhynchidae) with receptacle insertion at the posterior third of the proboscis is described from the pheasant crow Centropus sinensis (Stephens) (Cuculidae) in Pakistan. Centrorhynchu sglobirostris n. sp. is similar to the 98 other known species of Centrorhynchus Luhe, 1911 in having long cylindrical trunk with anterior dilation and transverse anastomoses of the secondary lacunar vessels. However, specimens of C. globirostris differ from all other species of the genus by having a unique globular proboscis not divided into anterior proboscis with rooted hooks and posterior proboscis with rootless spines. Posterior hooks of C. globirostris emerge at the level of the receptacle insertion and are uniquely fully rooted. Sequencing and phylogenetic analysis of C. globirostris 18S and 28S ribosomal RNA genes reveals the genetic and evolutionary relationships between C. globirostris and other members of Centrorhynchidae which have representative orthologs in public databases. Comparison to known acanthocephalans confirms appropriate inclusion in the genus Centrorhynchus. PMID- 25804971 TI - Multilocus sequence typing of canine Giardia duodenalis from South Eastern European countries. AB - Giardia duodenalis is a worldwide occurring protozoan that can infect various mammalian hosts. While living conditions are getting closer between pet animals and owners, there is discussion whether dogs may contribute to the transmission of these pathogens to humans. The present study was conducted in order to identify the Giardia assemblages in dogs from South Eastern Europe. For this purpose, 1645 faecal samples of household and shelter dogs from Albania, Bulgaria, Hungary, Macedonia, Romania and Serbia were tested for Giardia coproantigen by enzyme-linked immunosorbent assay (ELISA). A subset of 107 faecal samples demonstrating Giardia cysts by direct immunofluorescence assay (IFA) or microscopy (15-22 per country) plus 26 IFA-positive canine faecal samples from Croatia were used for DNA extraction and multilocus sequence typing with nested PCRs targeting five different gene loci: SSU rRNA, ITS1-5.8S-ITS2, beta giardin (bg), glutamate dehydrogenase (gdh) and triosephosphate isomerase (tpi). One third (33.7%) of the samples tested positive for Giardia antigen in the coproantigen ELISA. Shelter dogs were infected more frequently than household dogs (57.2 vs. 29.7%, p < 0.01). Amplification was obtained in 82.0, 12.8, 11.3, 1.5, and 31.6%, of the investigated samples at the SSU rRNA, bg, gdh and tpi loci and the ITS1-5.8S-ITS2 region, respectively. The dog-specific assemblages C and D were identified in 50 and 68 samples, respectively. The results demonstrate that G. duodenalis should be considered as a common parasite in dogs from South Eastern Europe. However, there was no evidence for zoonotic Giardia assemblages in the investigated canine subpopulation. PMID- 25804973 TI - Comparison of genetic diversity and population structure between two Schistosoma japonicum isolates--the field and the laboratory. AB - Schistosomiasis japonicum is one of the most important human parasitic diseases, and a number of studies have recently elucidated the difference in biological characteristics of S. japonicum among different parasite isolates, for example, between the field and the laboratory isolates. Therefore, the understanding of underlying genetic mechanism is of both theoretical and practical importance. In this study, we used six microsatellite markers to assess genetic diversity, population structure, and the bottleneck effect (a sharp reduction in population size) of two parasite populations, one field and one laboratory. A total of 136 S. japonicum cercariae from the field and 86 from the laboratory, which were genetically unique within single snails, were analyzed. The results showed bigger numbers of alleles and higher allelic richness in the field parasite population than in the laboratory indicating lower genetic diversity in the laboratory parasites. A bottleneck effect was detected in the laboratory population. When the field and laboratory isolates were combined, there was a clear distinction between two parasite populations using the software Structure. These genetic differences may partially explain the previously observed contrasted biological traits. PMID- 25804974 TI - Risk factors associated with Rift Valley fever epidemics in South Africa in 2008 11. AB - Rift Valley fever (RVF) is a zoonotic and vector-borne disease, mainly present in Africa, which represents a threat to human health, animal health and production. South Africa has experienced three major RVF epidemics (1950-51, 1973-75 and 2008 11). Due to data scarcity, no previous study has quantified risk factors associated with RVF epidemics in animals in South Africa. Using the 2008-11 epidemic datasets, a retrospective longitudinal study was conducted to identify and quantify spatial and temporal environmental factors associated with RVF incidence. Cox regressions with a Besag model to account for the spatial effects were fitted to the data. Coefficients were estimated by Bayesian inference using integrated nested Laplace approximation. An increase in vegetation density was the most important risk factor until 2010. In 2010, increased temperature was the major risk factor. In 2011, after the large 2010 epidemic wave, these associations were reversed, potentially confounded by immunity in animals, probably resulting from earlier infection and vaccination. Both vegetation density and temperature should be considered together in the development of risk management strategies. However, the crucial need for improved access to data on population at risk, animal movements and vaccine use is highlighted to improve model predictions. PMID- 25804976 TI - BARLEX - the Barley Draft Genome Explorer. PMID- 25804975 TI - Rhizobium Lipo-chitooligosaccharide Signaling Triggers Accumulation of Cytokinins in Medicago truncatula Roots. AB - Legume rhizobium symbiosis is initiated upon perception of bacterial secreted lipo-chitooligosaccharides (LCOs). Perception of these signals by the plant initiates a signaling cascade that leads to nodule formation. Several studies have implicated a function for cytokinin in this process. However, whether cytokinin accumulation and subsequent signaling are an integral part of rhizobium LCO signaling remains elusive. Here, we show that cytokinin signaling is required for the majority of transcriptional changes induced by rhizobium LCOs. In addition, we demonstrate that several cytokinins accumulate in the root susceptible zone 3 h after rhizobium LCO application, including the biologically most active cytokinins, trans-zeatin and isopentenyl adenine. These responses are dependent on calcium- and calmodulin-dependent protein kinase (CCaMK), a key protein in rhizobial LCO-induced signaling. Analysis of the ethylene-insensitive Mtein2/Mtsickle mutant showed that LCO-induced cytokinin accumulation is negatively regulated by ethylene. Together with transcriptional induction of ethylene biosynthesis genes, it suggests a feedback loop negatively regulating LCO signaling and subsequent cytokinin accumulation. We argue that cytokinin accumulation is a key step in the pathway leading to nodule organogenesis and that this is tightly controlled by feedback loops. PMID- 25804977 TI - Altered mesocorticolimbic functional connectivity in psychotic disorder: an analysis of proxy genetic and environmental effects. AB - BACKGROUND: Altered dopaminergic neurotransmission in the mesocorticolimbic (MCL) system may mediate psychotic symptoms. In addition, pharmacological dopaminergic manipulation may coincide with altered functional connectivity (fc) 'in rest'. We set out to test whether MCL-fc is conditional on (familial risk for) psychotic disorder and/or interactions with environmental exposures. METHOD: Resting-state functional magnetic resonance imaging data were obtained from 63 patients with psychotic disorder, 73 non-psychotic siblings of patients with psychotic disorder and 59 healthy controls. With the nucleus accumbens (NAcc) as seed region, fc within the MCL system was estimated. Regression analyses adjusting for a priori hypothesized confounders were used to assess group differences in MCL connectivity as well as gene (group) * environmental exposure interactions (G * E) (i.e., to cannabis, developmental trauma and urbanicity). RESULTS: Compared with controls, patients and siblings had decreased fc between the right NAcc seed and the right orbitofrontal cortex (OFC) as well as the left middle cingulate cortex (MCC). Siblings showed decreased connectivity between the NAcc seed and lentiform nucleus compared with patients and controls. In addition, patients had decreased left NAcc connectivity compared with siblings in the left middle frontal gyrus. There was no evidence for a significant interaction between group and the three environmental exposures in the model of MCL-fc. CONCLUSIONS: Reduced NAcc-OFC/MCC connectivity was seen in patients and siblings, suggesting that altered OFC connectivity and MCC connectivity are vulnerability markers for psychotic disorder. Differential exposure to environmental risk factors did not make an impact on the association between familial risk and MCL connectivity. PMID- 25804978 TI - Mechanical vs. manual cleaning of hospital beds: a prospective intervention study. AB - BACKGROUND: Cleaning regimens for hospital beds were evaluated in the context of a rising prevalence of highly resistant micro-organisms and increasing financial pressure on healthcare systems. Dutch hospitals have to choose between standardized, mechanical bed-washers advised in national guidance and manual cleaning. AIM: To evaluate the quality of mechanical and manual bed-cleaning regimens. METHODS: The multi-faceted analysis of bed-cleaning regimens consisted of three steps. In Step 1, the training of the domestic service team was evaluated. In Step 2, the cleaning quality of manual and mechanical regimens was assessed. Soiled beds, obtained at random, from different departments were evaluated using microbiological analysis (N = 40) and ATP (N = 20). ATP and microbiological contamination were measured in five predetermined locations on all beds. In Step 3, manual cleaning was introduced over a two-month pilot study at the surgical short-stay unit, and beds from other departments were processed according to the 'gold standard' mechanical cleaning. ATP levels were evaluated in three locations on 300 beds after cleaning. FINDINGS: Training was found to improve the quality of cleaning significantly. Mechanical cleaning resulted in significantly lower ATP levels than manual cleaning. CONCLUSIONS: Mechanical cleaning shows less variation and results in consistently lower ATP levels than manual cleaning. PMID- 25804979 TI - In situ strain evolution during a disconnection event in a battery nanoparticle. AB - Lithium ion batteries are the dominant form of energy storage in mobile devices, increasingly employed in transportation, and likely candidates for renewable energy storage and integration into the electrical grid. To fulfil their powerful potential, electrodes with increased capacity, faster charge rates, and longer cycle life must be developed. Understanding the mechanics and chemistry of individual nanoparticles under in situ conditions is a crucial step to improving performance and mitigating damage. Here we reveal three-dimensional strain evolution within a single nanoparticle of a promising high voltage cathode material, LiNi0.5Mn1.5O4, under in situ conditions. The particle becomes disconnected during the second charging cycle. This is attributed to the formation of a cathode electrolyte interphase layer with slow ionic conduction. The three-dimensional strain pattern within the particle is independent of cell voltage after disconnection, indicating that the particle is unable to redistribute lithium within its volume or to its neighbours. Understanding the disconnection process at the single particle level and the equilibrium or non equilibrium state of nanoparticles is essential to improving performance of current and future electrochemical energy storage systems. PMID- 25804980 TI - Three-Dimensional Porous Gelapin-Simvastatin Scaffolds Promoted Bone Defect Healing in Rabbits. AB - Treatment of large bone defects (LBDs) is technically demanding. Tissue engineering is an option. A bioactive graft may be produced by combining tissue scaffolds and healing promotive factors in order to accelerate bone repair. We investigated the role of Simvastatin (Sim)-embedded porous Gelapin (Gel) scaffold on experimental bone healing. At first, the effectiveness of different concentrations of Gel and Sim powders was investigated in an experimentally induced femoral hole model in rabbits (n = 6) for 30 days. Then bone bioactive grafts were produced by combination of the effective concentrations of Gel, Sim, and Genipin. The bioimplants were subcutaneously tested in a rabbit model (n = 9) to determine their biocompatibility and biodegradability for 10-30 days. Finally, a large radial bone defect model was produced in rabbits (n = 20), and the bioimplants were inserted in the defects. The untreated and autograft-treated bone defects were served as controls. The animals were euthanized after 30 and 60 days of bone injury. The bone samples were evaluated by radiography, three dimensional CT scan, bone densitometry, histopathology, and nano-indentation. At a concentration of 5 mg/hole, Sim closed the femoral bone holes after 30 days, while in the defect, autograft, and Gel groups, the holes were open. Both the Gel and Gel-Sim scaffolds were biocompatible and biodegradable. Subcutaneously, the Gel-Sim scaffold was replaced with the newly regenerated ectopic bone after 30 days. After implantation of the Gel-Sim scaffold in the radial bone defects, the scaffold was completely replaced with new woven bone after 30 days which was then matured and remodeled into a cortical bone after 60 days. Sixty days after bone injury, the Gel-Sim-treated defects had significantly higher bone volume, matrix mineralization, elastic modulus, and contact hardness when compared to the controls. The Gel-Sim scaffold may be a suitable option in managing LBDs. PMID- 25804981 TI - Caffeic acid phenethyl ester abrogates bone resorption in a murine calvarial model of polyethylene particle-induced osteolysis. AB - Particle-induced bone loss by osteoclasts is a common cause of aseptic loosening around implants. This study investigates whether caffeic acid phenethyl ester (CAPE), a potent and specific inhibitor of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 and nuclear factor kappa B, at a low dose reduces bone resorption in a murine calvarial model of polyethylene (PE) particle induced osteolysis. The effects of particles and CAPE treatment on gastrointestinal tract (GIT) histopathology were also evaluated. Mice were scanned using in vivo animal micro-computed tomography (MUCT) as a baseline measurement. PE particles (2.82 * 10(9) particles/mL) were implanted over the calvariae on day 0. CAPE was administered subcutaneously (1 mg/kg/day) at days 0, 4, 7 and 10. Mice were killed at day 14 and serum was analysed for Type-1 carboxyterminal collagen crosslinks (CTX)-1 and osteoclast-associated receptor (OSCAR) levels. Ex vivo MUCT scans were conducted to assess bone volume (BV) change and percentage area of calvarial surface resorbed. Calvarial and GIT tissue was processed for histopathology. By day 14, PE particles significantly induced calvarial bone loss compared with control animals as evidenced by resorption areas adjacent to the implanted PE in three-dimensional MUCT images, an increase in percentage of resorbed area (p = 0.0022), reduction in BV (p = 0.0012) and increased Tartrate-resistant acid phosphatase positive cells. Serum CTX-1 (p = 0.0495) and OSCAR levels (p = 0.0006) significantly increased in the PE implant group. CAPE significantly inhibited PE particle-induced calvarial osteolysis, as evidenced by a significant reduction in surface bone resorption (p = 0.0012) and volumetric change (p = 0.0154) compared with PE only, but had no effect on systemic CTX-1. Neither particles nor CAPE had an effect on GIT histopathology. PMID- 25804984 TI - Funding Cancer Quality Improvement: Payer's Perspective. PMID- 25804983 TI - Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. AB - PURPOSE: To evaluate the impact of approval of ibrutinib and idelalisib on pharmaceutical costs in the treatment of chronic lymphocytic leukemia (CLL) at the societal level and assess individual out-of-pocket costs under Medicare Part D. METHODS: Average wholesale price of commonly used CLL treatment regimens was ascertained from national registries. Using the population of Olmsted County, Minnesota, we identified the proportion of patients with newly diagnosed CLL who experience progression to the point of requiring treatment. Using these data, total pharmaceutical cost over a 10-year period after diagnosis was estimated for a hypothetic cohort of 100 newly diagnosed patients under three scenarios: before approval of ibrutinib and idelalisib (historical scenario), after approval of ibrutinib and idelalisib as salvage therapy (current scenarios A and B), and assuming use of ibrutinib as first-line treatment (potential future scenario). RESULTS: Estimated 10-year pharmaceutical costs for 100 newly diagnosed patients were as follows: $4,565,929 (approximately $45,659 per newly diagnosed patient and $157,446 per treated patient) for the historical scenario, $7,794,843 (approximately $77,948 per newly diagnosed patient and $268,788 per treated patient) for current scenario A, $6,309,162 (approximately $63,092 per newly diagnosed patient and $217,557 per treated patient) for current scenario B, and $16,414,055 (approximately $164,141 per newly diagnosed patient and $566,002 per treated patient) for the potential future scenario. Total out-of-pocket cost for 100 patients with newly diagnosed CLL under Medicare Part D increased from $9,426 under the historical scenario (approximately $325 per treated patient) to $363,830 and $255,051 under current scenarios A and B (approximately $8,800 to $12,500 per treated patient) and to $1,031,367 (approximately $35,564 per treated patient) under the future scenario. CONCLUSION: Although ibrutinib and idelalisib are profound treatment advances, they will dramatically increase individual out of-pocket and societal costs of caring for patients with CLL. These cost considerations may undermine the potential promise of these agents by limiting access and reducing adherence. PMID- 25804985 TI - Overcoming perceived hurdles in lung cancer screening: the low risk of complications of image-guided transthoracic needle biopsy. PMID- 25804982 TI - Mechanisms in the relation between GABRA2 and adolescent externalizing problems. AB - Conduct problems, alcohol problems and hyperactive-inattentive symptoms co-occur at a high rate and are heritable in adolescence. The gamma-aminobutyric acid A receptor, alpha2 gene (GABRA2) is associated with a broad spectrum of externalizing problems and disinhibitory-related traits. The current study tested whether two important forms of disinhibition in adolescence, impulsivity and sensation seeking, mediated the effects of GABRA2 on hyperactive-inattentive symptoms, conduct problems, and alcohol problems. Participants were assessed at two waves (11-17 and 12-18 years old; N = 292). Analyses used the GABRA2 SNP, rs279858, which tags the two complementary (yin-yang) GABRA2 haplotypes. Multiple informants reported on adolescents' impulsivity and sensation seeking and adolescents self-reported their hyperactive-inattentive symptoms, conduct problems and lifetime alcohol problems. Impulsivity mediated the effect of GABRA2 on alcohol problems, hyperactive-inattentive symptoms, and conduct problems, whereas sensation seeking mediated the effect of GABRA2 on alcohol problems (AA/AG genotypes conferred risk). GABRA2 directly predicted adolescent alcohol problems, but the GG genotype conferred risk. Results suggest that there may be multiple pathways of risk from GABRA2 to adolescent externalizing problems, and suggest important avenues for future research. PMID- 25804986 TI - "Write It Down Like You Told Me": Transparent Records and My Oncology Practice. PMID- 25804987 TI - American Society of Clinical Oncology third quality care symposium. PMID- 25804988 TI - Reframing overuse in health care: time to focus on the harms. PMID- 25804990 TI - Provider Perspective on the Payer Perspective: What's in It for Me? PMID- 25804989 TI - Evaluating primary care providers' views on survivorship care plans generated by an electronic health record system. AB - PURPOSE: Survivorship care plans for cancer survivors may facilitate provider-to provider communication. Primary care provider (PCP) perspectives on care plan provision and use are limited, especially when care plans are generated by an electronic health record (EHR) system. We sought to examine PCPs' perspectives regarding EHR-generated care plans. METHODS: PCPs (N = 160) who were members of the Wisconsin Research and Education Network listserv received a sample 10-page plan (WREN cohort). PCPs (n = 81) who had or were currently seeing survivors enrolled onto one of our survivorship clinical trials received a copy of the survivor's personalized care plan (University of Wisconsin [UW] cohort). Both cohorts received a survey after reviewing the plan. All plans were generated within an EHR. RESULTS: Forty-six and 26 PCPs participated in the WREN and UW cohorts, respectively. PCPs regarded EHR-generated plans as useful in coordinating care (88%), understanding treatments (94%), understanding treatment adverse effects (89%), and supporting clinical decisions (82%). Few felt using EHR-generated plans would disrupt clinic workflow (14%) or take too much time (11%). Most (89%) preferred receiving the plan via EHR. PCPs reported consistent provision (81%) and standard location in the medical record (89%) as key factors facilitating their use of survivorship care plans. Important facilitators of care plan use included a more abbreviated plan, ideally one to three pages (32%), and/or a plan specifically tailored to PCP use (57%). CONCLUSION: Plans were viewed as useful for coordinating care and making clinical decisions. However, PCPs desired shorter, clinician-oriented plans, accessible within an EHR and delivered and located in a standardized manner. PMID- 25804991 TI - Toxic indole alkaloids avrainvillamide and stephacidin B produced by a biocide tolerant indoor mold Aspergillus westerdijkiae. AB - Toxic Aspergillus westerdijkiae were present in house dust and indoor air fall out from a residence and a kindergarten where the occupants suffered from building related ill health. The A. westerdijkiae isolates produced indole alkaloids avrainvillamide (445 Da) and its dimer stephacidin B (890 Da). It grew and sporulated in presence of high concentrations of boron or polyguanidine (PHMB, PHMG) based antimicrobial biocides used to remediate mold infested buildings. The boar sperm cells were used as sensor cells to purify toxins from HPLC fractions of the fungal biomass. Submicromolar concentrations (EC50 0.3-0.4 MUM) blocked boar spermatozoan motility and killed porcine kidney tubular epithelial cells (PK-15). Plate grown hyphal mass of the A. westerdijkiae isolates contained 300-750 ng of avrainvillamide and 30-300 ng of stephacidin B per mg (wet weight). The toxins induced rapid (30 min) loss of boar sperm motility, followed (24 h) by loss of mitochondrial membrane potential (DeltaPsim). Apoptotic cell death was observed in PK-15 cell monolayers, prior to cessation of glucose uptake or loss of DeltaPsim. Avrainvillamide and stephacidin B were 100-fold more potent towards the porcine cells than the mycotoxins stephacidin A, ochratoxin A, sterigmatocystin and citrinin. The high toxicity of stephacidin B indicates a role of nitrone group in the mechanism of toxicity. Avrainvillamide and stephacidin B represent a new class of toxins with possible a threat to human health in buildings. Furthermore, the use of biocides highly enhanced the growth of toxigenic A. westerdijkiae. PMID- 25804992 TI - Improved bioassays using a local effect, such as muscle paralysis, as an endpoint. AB - Drug potency testing consumes many animals, botulinum neurotoxin (BoNT) testing being perhaps the most notorious example. To avoid 50% lethal dose determination, the so-called digital abduction score (DAS) and other BoNT induced local paralysis assays were developed. This paper reveals that a simple mathematical expression - the Bateman's equation used in many pharmacokinetic data analyses - can describe in full detail the time dependence of the BoNT induced local paralysis; the equation hence allows robust interpolation and extrapolation, as well as integral effect (AUC), and its dose dependence, evaluation. The equation is moreover a convenient tool for experimental planning and for extracting, from experimental data, the parameters that characterise BoNT potency. Most important, one can generally reduce the number of animals needed to gain reliable results at least 20-33% (and possibly 50% or even 75%) by analysing and modelling the time course of a local effect (such as muscle paralysis) with the equation, rather than just by averaging the maximum observed effect size at one point in time. PMID- 25804993 TI - Morphology-directing synthesis of rhodamine-based fluorophore microstructures and application toward extra- and intracellular detection of Hg(2+). AB - A new, easily synthesizable rhodamine-based chemosensor with potential N2O2 donor atoms, L(3), has been characterized by single-crystal X-ray diffraction together with (1)H NMR and high-resolution mass spectrometry (HRMS) studies. L(3) was found to bind selectively and reversibly to the highly toxic Hg(2+) ion. The binding stoichiometry and formation constant of the sensor toward Hg(2+) were determined by various techniques, including UV-vis, fluorescence, and Job's studies, and substantiated by HRMS methods. None of the biologically relevant and toxic heavy metal ions interfered with the detection of Hg(2+) ion. The limit of detection of Hg(2+)calculated by the 3sigma method was 1.62 nM. The biocompatibility of L(3) with respect to its good solubility in mixed organic/aqueous media (MeCN/H2O) and cell permeability with no or negligible cytotoxicity provides good opportunities for in vitro/in vivo cell imaging studies. As the probe is poorly soluble in pure water, an attempt was made to frame nano/microstructures in the absence and in the presence of sodium dodecyl sulfate (SDS) as a soft template, which was found to be very useful in synthesizing morphologically interesting L(3) microcrystals. In pure water, micro organization of L(3) indeed occurred with block-shaped morphology very similar to that in the presence of SDS as a template. However, when we added Hg(2+) to the solution of L(3) under the above two conditions, the morphologies of the microstructures were slightly different; in the first case, a flowerlike structure was observed, and in second case, a simple well-defined spherical microstructure was obtained. Optical microscopy revealed a dotlike microstructure for L(3)-SDS assemblies, which changed to a panicle microstructure in the presence of Hg(2+). UV-vis absorption and steady-state and time-resolved fluorescence studies were also carried out in the absence and presence of Hg(2+), and also the SDS concentration was varied at fixed concentrations of the receptor and guest. The results revealed that the fluorescence intensity increased steadily with [SDS] until it became saturated at ~7 mM SDS, indicating that the extent of perturbation to the emissive species increases with the increase in [SDS] until it becomes thermodynamically stable. There was also an increase in anisotropy with increasing SDS concentration, which clearly manifests the restriction of movement of the probe in the presence of SDS. PMID- 25804994 TI - LC-MS guided isolation, quantification and antioxidant evaluation of bioactive principles from Epimedium elatum. AB - This article presents the isolation, quantification and antioxidant evaluation of bioactive principles from Epimedium elatum. LC-MS guided isolation technique was applied for the separation of target constituents. Three isolates; magnoflorine, chrysin and dibenzylideneacetone (DBA) were isolated for the first time from E. elatum using LC-MS guided isolation method. Nine natural products, viz. icariin, epimedoside A, epimedin A, epimedin B, epimedin C, ikarisoside C, baohuoside II, magnoflorine and chrysin were simultaneously quantified by reverse phase HPLC-UV DAD method. The HPLC method was validated in terms of precision and accuracy. Excellent specificity and linearity within test ranges for all standard calibration curves having regression coefficient of different linear equations in the range of 0.9966-0.9999 were observed. Relative recovery rates varied between 98.09+/-0.44 and 105.34+/-1.89% with relative standard deviation of less than 3%. This modified HPLC method is in accordance with yinyanghuo. All the 10 isolated constituents were screened for DPPH radical scavenging activity. Dibenzylideneacetone (DBA) turned out to be the most potent isolate with IC(50) of 4.32 MUM. PMID- 25804995 TI - Applicability of the ISNT and IST rules on retinal nerve fiber layer measurement on spectral-domain optical coherence tomography in normal Indian children. AB - BACKGROUND: To determine the applicability of the ISNT (inferior>superior>nasal>temporal) and IST (inferior>superior>temporal) rules on retinal nerve fiber layer (RNFL) measurement on spectral-domain optical coherence tomography (SD-OCT) in normal children. METHODS: A prospective, cross-sectional study including consecutive subjects between the ages of 5-18 years who were born at term (>=37 weeks gestational age) and with a normal birth weight (>=2500 g) presenting to the out-patient department for refractive error examination. RNFL measurement was done on Spectralis SD-OCT. Exclusion criteria were best-corrected visual acuity less than 20/20, spherical equivalent (SE) > +/- 5 diopter (D), applanation IOP >21 mmHg, cup-to-disc (C/D) ratio of >0.5, C/D ratio asymmetry of >0.2 between eyes and any retinal or optic disc anomaly as determined by mydriatic fundus examination. Subjects with amblyopia, strabismus, or family history of optic nerve or retinal disease were excluded. Poor cooperation for SDOCT imaging and lack of consent were other exclusion criteria. RESULTS: The ISNT rule on the RNFL was followed only by 30 eyes (23.8 %), while the IST rule was followed by 66 eyes (52.4 %) (p < 0.001). The superior RNFL was thicker than the inferior in 57 eyes (45.2 %) while the temporal RNFL was thicker than the nasal in 63 eyes (50 %). The age, gender, spherical equivalent, and disc size did not predict the followability of the ISNT and IST rules (p > 0.05). CONCLUSIONS: The ISNT and the IST rules for RNFL are not universally followed by all normal eyes in children. All deviations should therefore not be considered pathological. PMID- 25804996 TI - Comparing the alpha-galactosidase A biochemical properties from healthy individuals and Fabry disease patients. AB - BACKGROUND: Due to the importance and the difficulty still present in determining the biochemical diagnosis of Fabry disease (FD), the aim of this study was to establish and compare the biochemical and kinetic properties of alpha galactosidase A (GLA) in dried blood spots (DBS), plasma and leukocyte samples of FD patients and healthy subjects to evaluate the possible use of these parameters as an auxiliary tool in the diagnosis of this disease. METHODS: GLA activity in DBS, plasma and leukocyte samples from Fabry disease patients and healthy subjects was compared and characterized in terms of optimal pH, Km and Vmax and heat stability. RESULTS: A difference was observed between the Km and Vmax of FD patients and healthy controls using DBS, plasma and leukocyte samples. In leukocytes, pre-incubation at 50 degrees C for 60 min was effective to differentiate FD patients from healthy controls. CONCLUSION: These results can be used as an auxiliary method to the FD diagnosis, especially in cases of patients whose GLA activity is within normal range. PMID- 25804997 TI - Combined Alzheimer's disease and cerebrovascular staging explains advanced dementia cognition. AB - INTRODUCTION: The absence of a consensus system for full neuropathological evaluation limits clinicopathological studies and comparability between laboratories. Combined staging for Alzheimer's type and cerebral vascular pathology may allow a better classification of cases for clinical and cognitive correlation. METHODS: Cognitive and postmortem neuropathological data were obtained from 70 brains donated to the Tissue Bank of the Centro de Investigacion de Enfermedades Neurologicas (CIEN) Foundation according to recently developed staging schemes for Alzheimer's type and vascular pathology. Subjects belonged to a cohort of institutionalized patients with moderate or severe dementia and a mean follow-up period of 7 years. RESULTS: Cases were classified into three groups: Alzheimer's predominant (64.1%), vascular predominant (6.3%) and mixed pathology (29.6%). Significant differences were observed in Severe Mini-Mental State Examination and verbal fluency between the vascular predominant and the other groups of patients. DISCUSSION: The combination of scales measuring cerebral vascular and Alzheimer's type pathology allowed a classification of patients that reveals differences between groups in premortem cognitive features. PMID- 25804999 TI - Authors' reply to Williams. PMID- 25804998 TI - CSF biomarkers for the differential diagnosis of Alzheimer's disease: A large scale international multicenter study. AB - INTRODUCTION: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Abeta1-42), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia. METHODS: A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto temporal dementia (FTD), depression, or other neurological diseases. RESULTS: CSF Abeta1-42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32-62) to 77% (for FTD, 95% CI = 62-90). DISCUSSION: CSF Abeta1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies. PMID- 25805000 TI - Woven electrochemical fabric-based test sensors (WEFTS): a new class of multiplexed electrochemical sensors. AB - We present textile weaving as a new technique for the manufacture of miniature electrochemical sensors with significant advantages over current fabrication techniques. Biocompatible silk yarn is used as the material for fabrication instead of plastics and ceramics used in commercial sensors. Silk yarns are coated with conducting inks and reagents before being handloom-woven as electrodes into patches of fabric to create arrays of sensors, which are then laminated, cut and packaged into individual sensors. Unlike the conventionally used screen-printing, which results in wastage of reagents, yarn coating uses only as much reagent and ink as required. Hydrophilic and hydrophobic yarns are used for patterning so that sample flow is restricted to a small area of the sensor. This simple fluidic control is achieved with readily available materials. We have fabricated and validated individual sensors for glucose and hemoglobin and a multiplexed sensor, which can detect both analytes. Chronoamperometry and differential pulse voltammetry (DPV) were used to detect glucose and hemoglobin, respectively. Industrial quantities of these sensors can be fabricated at distributed locations in the developing world using existing skills and manufacturing facilities. We believe such sensors could find applications in the emerging area of wearable sensors for chemical testing. PMID- 25805001 TI - Which functional unit to identify sustainable foods? AB - OBJECTIVE: In life-cycle assessment, the functional unit defines the unit for calculation of environmental indicators. The objective of the present study was to assess the influence of two functional units, 100 g and 100 kcal (420 kJ), on the associations between three dimensions for identifying sustainable foods, namely environmental impact (via greenhouse gas emissions (GHGE)), nutritional quality (using two distinct nutrient profiling systems) and price. DESIGN: GHGE and price data were collected for individual foods, and were each expressed per 100 g and per 100 kcal. Two nutrient profiling models, SAIN,LIM and UK Ofcom, were used to assess foods' nutritional quality. Spearman correlations were used to assess associations between variables. Sustainable foods were identified as those having more favourable values for all three dimensions. SETTING: The French Individual and National Dietary Survey (INCA2), 2006-2007. SUBJECTS: Three hundred and seventy-three foods highly consumed in INCA2, covering 65 % of total energy intake of adult participants. RESULTS: When GHGE and price were expressed per 100 g, low-GHGE foods had a lower price and higher SAIN,LIM and Ofcom scores (r=0.59, -0.34 and -0.43, respectively), suggesting a compatibility between the three dimensions; 101 and 100 sustainable foods were identified with SAIN,LIM and Ofcom, respectively. When GHGE and price were expressed per 100 kcal, low-GHGE foods had a lower price but also lower SAIN,LIM and Ofcom scores (r=0.67, 0.51 and 0.47, respectively), suggesting that more environment-friendly foods were less expensive but also less healthy; thirty-four sustainable foods were identified with both SAIN,LIM and Ofcom. CONCLUSIONS: The choice of functional unit strongly influenced the compatibility between the sustainability dimensions and the identification of sustainable foods. PMID- 25805002 TI - Structural characterization of a novel peptide with antimicrobial activity from the venom gland of the scorpion Tityus stigmurus: Stigmurin. AB - A new antimicrobial peptide, herein named Stigmurin, was selected based on a transcriptomic analysis of the Brazilian yellow scorpion Tityus stigmurus venom gland, an underexplored source for toxic peptides with possible biotechnological applications. Stigmurin was investigated in silico, by circular dichroism (CD) spectroscopy, and in vitro. The CD spectra suggested that this peptide interacts with membranes, changing its conformation in the presence of an amphipathic environment, with predominance of random coil and beta-sheet structures. Stigmurin exhibited antibacterial and antifungal activity, with minimal inhibitory concentrations ranging from 8.7 to 69.5MUM. It was also showed that Stigmurin is toxic against SiHa and Vero E6 cell lines. The results suggest that Stigmurin can be considered a potential anti-infective drug. PMID- 25805003 TI - Peptides and the blood-brain barrier. AB - The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational molecules, informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiological changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaption goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system. PMID- 25805004 TI - Quality of life and clinical outcome after thyroid surgery in children: A 13 years single center experience. AB - BACKGROUND: Given the low mortality of pediatric patients diagnosed with thyroid disease, quality of life (QoL) after thyroid surgery is very important. To organize the best possible patient care we analyzed our experience with respect to QoL and clinical outcome. METHODS: This is a single center, retrospective cohort study. Data of patients who underwent thyroid surgery < 19 years between January 2000 and December 2012 were collected. QoL was measured using the child health questionnaire child form (CHQ-CF87, < 18 years) and the World Health Organization quality of life assessment (WHOQOL-100, >= 18 years). RESULTS: Forty patients were included (mean age 13.7 years; 29 females (72.5%)). Twenty-six patients underwent total thyroidectomy (including 7 repeat surgeries), 14 underwent hemithyroidectomy. QoL assessment in 26 patients revealed lower physical QoL in patients with a current age < 18 years (n = 11) (p < .001), but higher overall and physical QoL in patients >= 18 years (n = 15) compared with controls (p = .01 and p = .036 respectively). Patients >= 18 years, who underwent total thyroidectomy experienced lower overall and physical QoL compared with those who underwent hemithyroidectomy (p = .035 and p = .005 respectively). CONCLUSIONS: Surgery for thyroid disease during childhood significantly affects QoL. However, QoL seems to improve with increasing age, and hemi-thyroidectomy has less negative effects on QoL than total thyroidectomy. PMID- 25805005 TI - Factors impacting survival in children with renal cell carcinoma. AB - PURPOSE: Renal cell carcinoma (RCC) is an uncommon tumor in the pediatric population. We examined a large national cancer database to determine outcomes for children with RCC and to identify variables affecting long-term survival. METHODS: The National Cancer Data Base (NCDB) was queried for patients age 0 to 17 years diagnosed with RCC from 1998-2011. Patient demographics, tumor stage and characteristics, management, and outcomes were evaluated. RESULTS: A total of 304 children met inclusion criteria. Overall, 39% of children had stage I disease, 16% stage II, 33% stage III, and 12% stage IV. One-year and five-year survival for all children was 87% and 70%, respectively. Eighty-six percent of patients underwent surgical resection. In comparison to children who underwent complete nephrectomy, patients undergoing partial nephrectomy had smaller tumors and were of lower clinical stages. Survival following partial resection was 100% at one and five years. Age and gender had no significant impact on survival. Survival was negatively impacted by increasing tumor size (P<0.001), positive nodal status (P=0.001), and higher pathologic stage (P<0.001). CONCLUSION: Children with renal cell carcinoma who undergo surgical resection have excellent one-year and five year survival. Overall survival is significantly affected by pathologic stage, tumor size, and nodal status. PMID- 25805006 TI - Outcome differences between young children and adolescents undergoing kidney transplantation. AB - BACKGROUND/PURPOSE: Although graft loss remains the biggest challenge for all pediatric kidney transplant (KT) recipients, unique challenges exist within different age groups. We aim to evaluate the different characteristics and graft survival outcomes of young children and adolescents undergoing KT. METHODS: Children who underwent isolated KT between 2000 and 2013 at our institution were included in this retrospective analysis. Patient characteristics and outcomes were compared using student's t-test, chi-square test, Kaplan-Meier curve and Cox proportional hazards model. RESULTS: Of 73 children who underwent KT, 31 were <12 (young children), and 42 were >= 12 years old (adolescents). Overall patient survival was 100%. The younger group had superior 5-year (100% vs. 75.5%) and 10 year (94.4% vs. 43.8%) graft survival (p=0.008). Factors predictive of poor graft survival on multivariate analysis were older age at transplantation (HR 1.2, CI 1 1.4, p=0.047), female gender (HR 9.0, CI 1.9-43, p=0.006), and acute rejection episodes (HR 13, CI 2-90, p=0.008). The most common causes of graft loss were acute and chronic rejection episodes and immunosuppression nonadherence. CONCLUSION: Adolescents undergoing KT have inferior graft survival compared to younger children. In adjusted modeling, children with older age, female gender, and acute rejection episodes have inferior graft survival. PMID- 25805007 TI - A novel method of esophageal lengthening in a large animal model of long gap esophageal atresia. AB - PURPOSE: Long gap esophageal atresia remains a significant treatment challenge. We aimed to create the first large animal model of long gap esophageal atresia to test a degradable esophageal lengthening device. METHODS: The distal esophagus was divided 2 cm above the gastroesophageal junction in 6 minipigs. A polycaprolactone (PCL) spring device was secured inside the distal esophageal segment, and the end was oversewn. Nonexpanding PCL tubes served as controls. An esophagogastric anastomosis was created to restore continuity. After 4 weeks, the distal esophageal pouch was analyzed. RESULTS: The distal esophageal pouch of experimental animals increased in length from 1.9 to 4.5 cm. Control animals demonstrated no change. When comparing lengthened to native esophagus, there was no difference in the thickness of muscularis mucosa or muscularis propria. Mechanically lengthened esophagus showed mild to moderate superficial inflammation and fibrosis. There were no differences in the number of myenteric or submucosal ganglia. CONCLUSION: We created the first porcine model of long gap esophageal atresia and lengthened the distal esophagus with an internally placed device. This model may be used to explore novel therapies in the management of long gap esophageal atresia. PMID- 25805008 TI - A survey of the pediatric surgery program directors: optimizing resident research to make pediatric surgery training more efficient. AB - PURPOSE: Resident Research (RR) has been a presumed requirement for pediatric surgery fellowship candidates. We hypothesized that: 1) pediatric surgery leaders would no longer feel that RR was necessary for fellowship candidates, 2) the type of study performed would not impact a program's opinion of candidates, and 3) the timing of RR could be altered for those interested in a research career. METHODS: An anonymous survey was sent to pediatric surgery fellowship program directors (PDs). Sixty-three percent responded, and answers were compared via Chi square analysis with p<0.05 being significant. RESULTS: Respondents did not agree that RR was critical for pediatric surgery fellowship candidates. Seventy-five percent had no preference between one or two years of research (p=0.0005), 79% placed no heavier weight on basic or clinical research (p<0.0001), and 76% had no preference between scientific research or humanitarian efforts (p=0.0003). Sixty three percent felt that surgeon scientists would be better prepared for extramural funding if RR was performed at the end of training (p=0.04). CONCLUSION: Dedicated research time during general surgery may not be necessary. Pediatric surgery candidates who partake in RR are not penalized for their choice of study. Increasing efficiency of training is important in today's era of medical training. PMID- 25805009 TI - One hospital, one appendectomy: The cost effectiveness of a standardized doctor's preference card. AB - PURPOSE: Appendicitis in children provides a unique opportunity to explore changes that reduce variation, reduce cost, and improve value. In this study we sought to evaluate the effectiveness of standardization of surgical technique and intraoperative disposable device utilization for laparoscopic appendectomy among all surgeons at a tertiary children's hospital. METHODS: All 6 surgeons at our tertiary children's hospital agreed to standardize to a single technique of performing a laparoscopic appendectomy. We collected data on all pediatric patients who had a laparoscopic appendectomy following implementation of the uniform doctor's preference card (DPC) (March 1, 2013 to February 28, 2014) and compared them to a historical control group. RESULTS: Implementation of the uniform DPC decreased the device cost per appendectomy from $844.11 to $305.32. Operative times (skin incision to skin closure) were 34.8 minutes prior to the uniform DPC and 37.0 minutes using the uniform DPC. There were no significant differences in postappendectomy outcomes. CONCLUSION: We have demonstrated that implementation of a uniform DPC and technical standardization for laparoscopic appendectomy can significantly reduce cost. Furthermore, this can occur without dramatically increasing operative times, length of stay, or postoperative complications. PMID- 25805010 TI - Vanishing fetal lung malformations: Prenatal sonographic characteristics and postnatal outcomes. AB - BACKGROUND/PURPOSE: The purpose of this study was to examine the natural history and outcomes of prenatally diagnosed lung masses that appear to undergo complete regression before birth. METHODS: An IRB-approved retrospective review was performed on 100 consecutive fetuses with a congenital lung malformation at a single fetal center. Prenatal and postnatal imaging as well as outcomes of vanishing fetal masses was analyzed and compared to those with persistent fetal masses. RESULTS: Seventeen lesions (17%) became sonographically undetectable at 35.3 +/- 2.3 weeks gestation. Vanishing fetal masses were associated with microcystic disease (100% vs. 69%, p=0.005) and a low initial congenital pulmonary airway malformation volume ratio (CVR; 0.31 +/- 0.35 vs. 0.70 +/- 0.66, p=0.002) when compared to those with persistent fetal lesions. Based on postnatal CT imaging and pathology data, 10.3% of all fetal masses completely regressed. The positive predictive value and negative predictive value of prenatal ultrasound for detecting lung malformations in late gestation were 96% and 43%, respectively. All infants with vanishing fetal lesions were asymptomatic at birth and were more likely to be managed nonoperatively (75% vs. 22%, p<0.0001) when compared to infants with persistent fetal masses. CONCLUSIONS: Vanishing lung lesions late in gestation are relatively common and are associated with a low CVR and microcystic disease. PMID- 25805011 TI - Low eicosapentaenoic acid to arachidonic acid ratio is associated with thin-cap fibroatheroma determined by optical coherence tomography. AB - BACKGROUND: A low eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is known to be associated with cardiovascular events. However, the relationship between the EPA/AA ratio and coronary plaque vulnerability assessed by optical coherence tomography (OCT) has not been examined thoroughly. This study examined the relationship between the EPA/AA ratio and coronary plaque vulnerability assessed by OCT in patients with acute coronary syndrome (ACS). METHODS: We evaluated 59 ACS patients who had undergone percutaneous coronary intervention using OCT. We divided them into 2 groups according to OCT findings-those with and without thin-cap fibroatheroma (TCFA)-and compared the EPA/AA ratio between the groups. RESULTS: We identified 32 and 27 patients with and without TCFA, respectively. The EPA/AA ratio was significantly lower in patients with TCFA than in those without TCFA [0.35, interquartile range (0.21-0.44) vs. 0.54, interquartile range (0.42-0.70); p<0.001]. In multivariate logistic regression analysis, the EPA/AA ratio was an independent predictor of TCFA (odds ratio, 0.09; 95% confidence interval, 0.007-0.99; p=0.049). The EPA/AA ratio and fibrous cap thickness showed a significant positive correlation (Spearman rho=0.46; p<0.001). Furthermore, receiver operating characteristic curve analysis showed that an EPA/AA ratio<0.46 could predict TCFA (81.3%, sensitivity; 74.1%, specificity). CONCLUSIONS: A low serum EPA/AA ratio is significantly associated with coronary plaque vulnerability assessed by OCT in ACS patients. PMID- 25805012 TI - Hidden photoinduced reactivity of the blue fluorescent protein mKalama1. AB - Understanding the photoinduced dynamics of fluorescent proteins is essential for their applications in bioimaging. Despite numerous studies on the ultrafast dynamics, the delayed response of these proteins, which often results in population of kinetically trapped dark states of various origins, is largely unexplored. Here, by using transient absorption spectroscopy spanning the time scale from picoseconds to seconds, we reveal a hidden reactivity of the bright blue-light emitting protein mKalama1 previously thought to be inert. This protein shows no excited-state proton transfer during its nanosecond excited-state lifetime; however, its tyrosine-based chromophore undergoes deprotonation coupled to non-radiative electronic relaxation. Such deprotonation causes distinct optical absorption changes in the broad UV-to-NIR spectral range (ca. 300-800 nm); the disappearance of the transient absorption signal has a complex nature and spans the whole microsecond-to-second time scale. The mechanisms underlying the relaxation kinetics are disclosed based on the X-ray structural analysis of mKalama1 and the high-level electronic structure calculations of proposed intermediates in the photocycle. We conclude that the non-radiative excited-state decay includes two major branches: internal conversion coupled to intraprotein proton transfer, where a conserved residue E222 serves as the proton acceptor; and ionization induced by two consecutive resonant absorption events, followed by deprotonation of the chromophore radical cation to bulk solvent through a novel water-mediated proton-wire pathway. Our findings open up new perspectives on the dynamics of fluorescent proteins as tracked by its optical transient absorption in the time domain extending up to seconds. PMID- 25805014 TI - Cloning, Expression, and Biochemical Characterization of an Enantioselective Lipase, YLIP9, from Yarrowia lipolytica MSR80. AB - A novel lipase gene, ylip9, of Yarrowia lipolytica MSR80 was cloned and expressed in pEZZ18-HB101 system and was 99% identical to YLIP9 of Y. lipolytica CLIB122. It was purified using IgG-Sepharose as ZZ fused YLIP9 and had specific activity of 0.8 U/mg. ZZ-YLIP9 was most active at pH 8.0 and 70 degrees C. It was stable over a wide pH range of 3.0-11.0 and 100 % active at 70 degrees C up to 2 h and had t1/2 of 286.42 min at 80 degrees C. It showed high specificity toward p nitrophenyldecanoate with kcat and catalytic efficiency of 30.17 s(-1) and 16.67 mM(-1) s(-1), respectively. It was non-regioselective, but an S-enantioselective lipase and the percentage conversion were enhanced in presence of hexane. ZZ YLIP9 was stable in all of the organic solvents used, and its activity was enhanced by solvents having logP value less than 2. PMID- 25805013 TI - The Variations of Glycolysis and TCA Cycle Intermediate Levels Grown in Iron and Copper Mediums of Trichoderma harzianum. AB - The efficiency of optimal metabolic function by microorganism depends on various parameters, especially essential metal supplementation. In the present study, the effects of iron and copper metals on metabolism were investigated by determination of glycolysis and tricarboxylic acid (TCA) cycle metabolites' levels with respect to the metal concentrations and incubation period in Trichoderma harzianum. The pyruvate and citrate levels of T. harzianum increased up to 15 mg/L of copper via redirection of carbon flux though glycolysis by suppression of pentose phosphate pathway (PPP). However, the alpha-ketoglutarate levels decreased at concentration higher than 5 mg/L of copper to overcome damage of oxidative stress. The fumarate levels correlated with the alpha-ketoglutarate levels because of substrate limitation. Besides, in T. harzianum cells grown in various concentrations of iron-containing medium, the intracellular pyruvate, citrate, and alpha-ketoglutarate levels showed positive correlation with iron concentration due to modifying of expression of glycolysis and TCA cycle enzymes via a mechanism involving cofactor or allosteric regulation. However, as a result of consuming of prior substrates required for fumarate production, its levels rose up to 10 mg/L. PMID- 25805015 TI - Enantioselective Resolution of gamma-Lactam by a Novel Thermostable Type II (+) gamma-Lactamase from the Hyperthermophilic Archaeon Aeropyrum pernix. AB - A thermostable formamidase from the aerobic hyperthermophilic archaeon Aeropyrum pernix was revealed a novel type II (+)-gamma-lactamase. This type II (+)-gamma lactamase is only composed of 377 amino acid residues, in contrast to another thermostable (+)-gamma-lactamase from Sulfolobus solfataricus with 504 amino acid residues (type I). It is interesting that there are low identities between these two (+)-gamma-lactamases, and herein, we further proved that at least two types of (+)-gamma-lactamases exist in nature due to enzyme promiscuity. The gene of this thermostable (+)-gamma-lactamase was cloned, functionally expressed in Escherichia coli BL21, and purified by a simple yet effective heat treatment method. It showed incredible thermostability, retaining 100% of its activity after 12 h at 100 degrees C. The optimum temperature for this enzyme was supposed to be more than 100 degrees C, and the optimum pH for this enzyme was about 9.0. The lactamase maintained its activity in the presence of most metal ions, except for Cu(2+). This thermo- and alkaline-tolerant (+)-gamma-lactamase presents promising properties for the industrial application. Specifically, it could be used for the production of chirally pure (-)-gamma-lactam for the synthesis of well-known carbocyclic nucleosides like abacavir and peramivir. The optical purity of the chiral product reached over 97% enantiomeric excess. PMID- 25805016 TI - Metal Ion Coordination Essential for Specific Molecular Interactions of Butea monosperma Lectin: ITC and MD Simulation Studies. AB - Crystal structure of Butea monosperma seed lectin (BML) was analyzed and the metal ion geometry identified. In order to understand the role of metal ions for the structural stability and ligand binding, studies of demetallized protein were carried out. Binding of different ligands like GalNAc, lactose, and galactose onto native and demetallized protein was studied by isothermal titration calorimetry as well as molecular simulation methods. Molecular dynamics was applied to the structure after removing the coordinates of metal ions, to identify the effect of demetallization in silico. Docking studies of different sugar molecules as well as the fungal alpha-amylase was carried out and compared the interactions in the native and apo states. It was found that metal ions are important for the ligand binding with increased affinity. However, their absence did not make any alteration to the secondary structure. Though the metal ions were not coordinated to the loops contacting the alpha-amylase, the absence of metal ions reduced the protein-protein binding strength due to long-range changes in irregular structures of the lectin. PMID- 25805017 TI - Influence of Various Levels of Iron and Other Abiotic Factors on Siderophorogenesis in Paddy Field Cyanobacterium Anabaena oryzae. AB - Siderophore production in Anabaena oryzae was investigated under the influence of various levels of iron and other abiotic factors such as pH, temperature, light and different nitrogen sources. Optimization of culture conditions under controlled mechanisms of these abiotic factors lead to the siderophore production in significant amount. Under iron-starved condition, A. oryzae extracellularly releases 89.17% hydroxymate-type siderophore. Slightly alkaline pH and 30 degrees C temperature was found stimulatory for the cyanobacterial growth and siderophorogenesis (88.52% SU and 83.87% SU, respectively). Excess iron loading had a negative impact on siderophore production along with the alterations in the morphology and growth. Further, scanning electron microphotographs signified that higher concentrations of iron lead to complete damage of the cells and alterations in membrane proteins possibly transporters responsible for exchange of siderophore complex from environment to the cell. SDS-PAGE analysis of whole cell proteins showed overexpression of low molecular weight proteins ranges between 20.1 to 29.0 kDa up to 100-MUM iron concentrations. These polypeptides/proteins might be involved in maintaining iron homeostasis by regulating siderophore production. Results suggest that lower concentrations of iron <= 50 MUM along with other abiotic factors are stimulatory, whereas higher concentrations (>50 MUM) are toxic. Data further suggested that cyanobacterium A. oryzae can serve as a potential biofertilizer especially in iron-rich soil through sequestration by the power of natural Fe(III)-siderophore complex formation. PMID- 25805019 TI - High Production of Neuraminidase by a Vibrio cholerae Non-O1 Strain--the First Possible Alternative to Toxigenic Producers. AB - Vibrio cholerae neuraminidase (VCNA) is widely used in biochemical and medical research, in processes for preparing homogenous sialoconjugates, and in the pharmaceutical industry. Its production by non-toxigenic strains is quite desirable, in order to avoid the expensive safety measures. Here, we report the first method for highly effective production of a novel, purified V. cholerae extracellular neuraminidase from a non-toxigenic strain. The enzyme is highly active, and its properties, as well as the responsible gene nanH, are practically identical with those of the toxigenic strains. It cleaves alpha,2 -> 3 and alpha,2 -> 6 glycosidic bonds with highest affinity (K M 1.7 * 10(-5) MUM) for human transferrin. The deduced amino acid sequence of the enzyme reveals three binding sites for Ca(2+) and one for sialic acid. The sequence analysis of the nanH gene, being the first for a V. cholerae non-O1 strain, shows 99% identity with a new nanH allele of an O1 Vibrio strain. The simple laboratory technology for efficient production of the new VCNA is based on the use of common and cheap nutrient media and easily available inducer--glycomacropeptide. The rapid purification consists of salting-out and diethylaminoethanol (DEAE) and Q Sepharose chromatography steps. Purified preparation contains no aldolase and protease, which gives the production scheme a great potential for industrial application. PMID- 25805018 TI - Expression of Bioactive Callithrix jacchus Follicle-Stimulating Hormone in Pichia pastoris. AB - Callithrix jacchus (common marmoset) is a New World primate monkey, used as an animal model in biomedical research. Marmoset-specific follicle-stimulating hormone (FSH) preparation is required to improve superovulation protocols and to develop homologous FSH monitoring assays in these monkeys. In this study, we document the large-scale expression of recombinant marmoset FSH in methylotropic yeast, Pichia pastoris. The recombinant preparation was found to be immunologically active in Western blotting and radioimmunoassay. The preparation displayed receptor binding ability in radioreceptor assay. Based on the receptor binding ability, the yield of fermentation was estimated to be 7.2 mg/L. FSH induced cAMP assay and estradiol assay revealed that the recombinant hormone is able to induce signal transduction. Both immunological and in vitro biological activity of marmoset FSH was found to be comparable to purified human pituitary FSH, which served as reference hormone for these assays. Thus, the study suggests that a Pichia expression system can be used for large-scale expression of bioactive recombinant marmoset FSH. PMID- 25805020 TI - Organic and Inorganic Nitrogen Impact Chlorella variabilis Productivity and Host Quality for Viral Production and Cell Lysis. AB - Microalgae have been proposed as a potential feedstock for biofuel production; however, cell disruption is usually required for collection and utilization of cytoplasmic polysaccharides and lipids. Virus infection might be one approach to disrupt the cell wall. The concentration of yeast extract and presence of KNO3 in algae cultivation media were investigated to observe their effects on Chlorella variabilis NC64A physiology and composition and the subsequent effect on production of Chlorella virus and disruption of infected cells. Cytoplasmic starch accumulation increased from 5% to approximately 35% of the total dry weight when yeast extract decreased from 1 to 0.25 g L(-1). When cells were cultured with the lowest nitrogen levels, the total polysaccharide accounted for more than 50% of the cell wall, which was 1.7 times higher than the content in cells cultured with the highest nitrogen levels. The C/N ratio of the algal biomass decreased by a factor of approximately 2 when yeast extract increased from 0.25 to 1 g L(-1). After virus infection, cells with a low C/N ratio produced a 7.6 times higher burst size than cells with a high C/N ratio, suggesting that the nitrogen content in C. variabilis has a large influence on viral production and cell lysis. The results have implications on management of nitrogen for both the synthesis of products from algae and product recovery via viral lysis. PMID- 25805021 TI - Participation of an additional 4'-hydroxymethyl group in the cleavage and isomerization of ribonucleoside 3'-phosphodiesters. AB - 4'-(Hydroxymethyl)uridylyl-3',5'-thymidine, an RNA model bearing an extra hydroxymethyl group at the 4'-position of the 3'-linked nucleoside, has been prepared and its cleavage and isomerization reactions studied over a wide pH range (from 0 to 12). Overall, the pH-rate profiles of these reactions were very similar to those of uridylyl-3',5'-uridine (UpU) - only a very modest acceleration was observed under acidic and neutral conditions. Evidently, hydrogen bond assistance by the additional hydroxymethyl function does not play a significant role. PMID- 25805022 TI - Nuclear anomalies in exfoliated buccal cells in Pakistani cotton weavers. AB - Cotton workers in small weaving household factories (power looms) in Pakistan are typically exposed to high levels of cotton dusts. Working in the textile manufacturing industry has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer. The study set out to determine potential cytotoxic and genotoxic effects of occupational exposure to cotton dusts in exfoliated buccal cells of exposed cotton workers. Nuclear anomalies reflecting cytotoxic and genotoxic effects were evaluated in a representative sample of 51 exposed male cotton weavers and in the same number of age-matched male non-exposed subjects applying the micronucleus cytome assay. Nuclear anomalies reflecting cytotoxicity (karyolysis, karyorrhexis, condensed chromatin and pyknosis) were significantly elevated in exposed cotton workers. The frequency of micronucleated cells increased significantly with increasing years of work in power looms (odds ratio = 1.043 per year; 95% confidence interval: 1.012-1.076, P = 0.007). Results were consistent with the typical inflammatory pattern and injury in epithelia due to unprotected occupational exposure to cotton dusts and other toxic, allergic and infectious substances in the working areas of the cotton industry. Occupational exposure in power looms induces cytotoxic effects and, upon chronic exposure, DNA damage. This may eventually result in typical obstructive patterns of pulmonary symptoms and in a clinical condition called byssinosis in exposed cotton workers. Long exposure may lead to chronic inflammation and cumulative damage of DNA in buccal stem cells that may indicate an increased risk of oropharyngeal cancer. PMID- 25805023 TI - Inhibition of beta-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation. AB - Deregulation of Wnt/beta-catenin signalling plays an important role in the pathogenesis of colorectal cancer. Interestingly, this pathway has been recently implicated in transcriptional control of cytochrome P450 (CYP) family 1 enzymes, which are responsible for bioactivation of a number of dietary carcinogens. In the present study, we investigated the impact of inhibition of Wnt/beta-catenin pathway on metabolism and genotoxicity of benzo[a]pyrene (BaP), a highly mutagenic polycyclic aromatic hydrocarbon and an efficient ligand of the aryl hydrocarbon receptor, which is known as a primary regulator of CYP1 expression, in cellular models derived from colorectal tumours. We observed that a synthetic inhibitor of beta-catenin, JW74, significantly increased formation of BaP-induced DNA adducts in both colorectal adenoma and carcinoma-derived cell lines. Using the short interfering RNA (siRNA) targeting beta-catenin, we then found that beta catenin knockdown in HCT116 colon carcinoma cells significantly enhanced formation of covalent DNA adducts by BaP and histone H2AX phosphorylation, as detected by (32)P-postlabelling technique and immunocytochemistry, respectively, and it also induced expression of DNA damage response genes, such as CDKN1A or DDB2. The increased formation of DNA adducts formed by BaP upon beta-catenin knockdown corresponded with enhanced production of major BaP metabolites, as well as with an increased expression/activity of CYP1 enzymes. Finally, using siRNA mediated knockdown of CYP1A1, we confirmed that this enzyme plays a major role in formation of BaP-induced DNA adducts in HCT116 cells. Taken together, the present results indicated that the siRNA-mediated inhibition of beta-catenin signalling, which is aberrantly activated in a majority of colorectal cancers, modulated genotoxicity of dietary carcinogen BaP in colon cell model in vitro, via a mechanism involving up-regulation of CYP1 expression and activity. PMID- 25805024 TI - Mutagenicity and clastogenicity of extracts of Helicobacter pylori detected by the Ames test and in the micronucleus test using human lymphoblastoid cells. AB - Epidemiological studies have demonstrated a close association between infection with Helicobacter pylori (H.pylori) and the development of gastric carcinoma. Chronic H.pylori infection increases the frequency of mutation in gastric epithelial cells. However, the mechanism by which infection of H.pylori leads to mutation in gastric epithelial cells is unclear. We suspected that components in H.pylori may be related to the mutagenic response associated with DNA alkylation, and could be detected with the Ames test using a more sensitive strain for alkylating agents. Our investigation revealed that an extract of H.pylori was mutagenic in the Ames test with Salmonella typhimurium YG7108, which is deficient in the DNA repair of O(6)-methylguanine. The extract of H.pylori may contain methylating or alkylating agents, which might induce O (6)-alkylguanine in DNA. Mutagenicity of the alkylating agents N-methyl-N-nitrosourea (MNU) and N-methyl N'-nitro-N-nitrosoguanidine in the Ames test with S.typhimurium TA1535 was enhanced significantly in the presence of the extract of H.pylori. The tested extracts of H.pylori resulted in a significant induction of micronuclei in human derived lymphoblastoid cells. Heat instability and dialysis resistance of the extracts of H.pylori suggest that the mutagenic component in the extracts of H.pylori is a heat-unstable large molecule or a heat-labile small molecule strongly attached or adsorbed to a large molecule. Proteins in the extracts of H.pylori were subsequently fractionated using ammonium sulphate precipitation. However, all fractions expressed enhancing effects toward MNU mutagenicity. These results suggest the mutagenic component is a small molecule that is absorbed into proteins in the extract of H.pylori, which resist dialysis. Continuous and chronic exposure of gastric epithelial cells to the alkylative mutagenic component from H.pylori chronically infected in the stomach might be a causal factor in the gastric carcinogenesis associated with H.pylori. PMID- 25805026 TI - Serotonin syndrome and opioids--what's the deal? PMID- 25805025 TI - Images in emergency medicine. Woman with severe dyspnea. Tuberculous empyema. PMID- 25805027 TI - Commentary: the increasingly dangerous pastime of perambulation. PMID- 25805029 TI - Change of shift. It's the Ebola. PMID- 25805028 TI - Change of shift. Have I been lucky? PMID- 25805030 TI - Do survey results reflect the truth or a biased opinion on emergency department care?: answers to the november 2014 annals journal club questions. PMID- 25805031 TI - Images in emergency medicine. Neonate with pustular rash. Neonatal methicillin resistant staphylococcal (MRSA) pustulosis. PMID- 25805032 TI - Overdose of etizolam: the abuse and rise of a benzodiazepine analog. PMID- 25805033 TI - The Wiki: a key social media tool. PMID- 25805034 TI - The copperhead coagulopathy conundrum. PMID- 25805035 TI - In reply. PMID- 25805036 TI - In reply. PMID- 25805038 TI - Images in emergency medicine. Male with throat pain and neck swelling. Necrotizing fasciitis in association with Ludwig's angina. PMID- 25805037 TI - Point-of-care ultrasonography by pediatric emergency physicians. Policy statement. AB - Point-of-care ultrasonography is increasingly being used to facilitate accurate and timely diagnoses and to guide procedures. It is important for pediatric emergency physicians caring for patients in the emergency department to receive adequate and continued point-of-care ultrasonography training for those indications used in their practice setting. Emergency departments should have credentialing and quality assurance programs. Pediatric emergency medicine fellowships should provide appropriate training to physician trainees. Hospitals should provide privileges to physicians who demonstrate competency in point-of care ultrasonography. Ongoing research will provide the necessary measures to define the optimal training and competency assessment standards. Requirements for credentialing and hospital privileges will vary and will be specific to individual departments and hospitals. As more physicians are trained and more research is completed, there should be one national standard for credentialing and privileging in point-of-care ultrasonography for pediatric emergency physicians. PMID- 25805040 TI - Noninvasive genotyping of common marmoset (Callithrix jacchus) by fingernail PCR. AB - The common marmoset (Callithrix jacchus) is a New World primate that is a useful model for medical studies. In this study, we report a convenient, reliable, and noninvasive procedure to genotype a living common marmoset by using fingernails. This method was used to successfully genotype DNA by restriction fragment length polymorphism (RFLP) PCR without prior purification, by using the KOD FX PCR enzyme kit. Additionally, there is no sample contamination from hematopoietic chimera derived from fused placenta in utero. We compared chimeric levels between various tissues in females with male littermates using quantitative fluorescent (QF)-PCR to prepare a reliable DNA source for genetic analyses, such as genotyping, gene mapping, or genomic sequencing. The chimerism detected appeared to be restricted to lymphatic tissues, such as bone marrow, thymus, spleen, lymph nodes and blood cells. As a result, DNA from fingernails with the quick is the best DNA source for genetic research in living marmosets. PMID- 25805039 TI - Association of folate and other one-carbon related nutrients with hypermethylation status and expression of RARB, BRCA1, and RASSF1A genes in breast cancer patients. AB - Dietary methyl group donors could influence the hypermethylation status of certain putative genes. The present study explored the possible associations of dietary intake of one-carbon metabolism-related nutrients with promoter hypermethylation status and expression of retinoic acid receptor-beta (RARB), breast cancer-1 (BRCA1), and Ras association domain family-1, isoform A (RASSF1A) genes in Iranian women with breast cancer (BC). The hypermethylation status was investigated in 146 dissected BC tissue samples using methylation-specific PCR. The expression level was evaluated by real-time RT-PCR. Dietary nutrients were estimated using a validated 136-item food frequency questionnaire. Expression levels of the genes were associated with the unmethylated status of related promoters (p < 0.05). The crude dietary folate and adjusted cobalamin intakes were inversely associated with methylated RARB and BRCA1. Low intake of residual folate and cobalamin was correlated with the methylated status of RARB for subjects at <48 years of age, and folate alone was linked to BRCA1 at >48 years of age. High dietary intake of riboflavin and pyridoxine was the only determinant of the methylated promoter of RARB at odds ratios (ORs) of 4.15 (95 % confidence interval (CI) 1.28-13.50) and 2.53 (95 % CI 1.14-3.83) in multivariate models, respectively. One-carbon nutrients most often correlated inversely with the methylation-influenced expression of RARB. Although high folate intake increased the chance of unmethylation-dependent overexpression of BRCA1 3-fold, cobalamin and methionine were inversely linked to methylation-mediated expression. Nutritional epigenomics less actively influenced RASSF1A. These findings provide new insights into and a basic understanding of the selective contributions of individual B vitamins on hypermethylation and methylation-related expression of RARB and BRCA1 in BC. KEY MESSAGE: Hypermethylation at promoters of RARB, BRCA1, and RASSF1A is associated with reduced transcript levels of the respective gene in primary breast cancer tissue samples. Dietary folate and cobalamin intake is inversely associated with methylated RARB and BRCA1. High dietary intake of riboflavin and pyridoxine is associated with increased methylation in the RARB promoter. There is evidence for the age-dependent effects of nutrient intake on promoter methylation status. Bioavailability to the pool of nutrients might determine selectivity. PMID- 25805041 TI - Stable isotope paleoecology of Late Pleistocene Middle Stone Age humans from the Lake Victoria basin, Kenya. AB - Paleoanthropologists have long argued that environmental pressures played a key role in human evolution. However, our understanding of how these pressures mediated the behavioral and biological diversity of early modern humans and their migration patterns within and out of Africa is limited by a lack of archaeological evidence associated with detailed paleoenvironmental data. Here, we present the first stable isotopic data from paleosols and fauna associated with Middle Stone Age (MSA) sites in East Africa. Late Pleistocene (~100-45 ka, thousands of years ago) sediments on Rusinga and Mfangano Islands in eastern Lake Victoria (Kenya) preserve a taxonomically diverse, non-analog faunal community associated with MSA artifacts. We analyzed the stable carbon and oxygen isotope composition of paleosol carbonate and organic matter and fossil mammalian tooth enamel, including the first analyses for several extinct bovids such as Rusingoryx atopocranion, Damaliscus hypsodon, and an unnamed impala species. Both paleosol carbonate and organic matter data suggest that local habitats associated with human activities were primarily riverine woodland ecosystems. However, mammalian tooth enamel data indicate that most large-bodied mammals consumed a predominantly C4 diet, suggesting an extensive C4 grassland surrounding these riverine woodlands in the region at the time. These data are consistent with other lines of paleoenvironmental evidence that imply a substantially reduced Lake Victoria at this time, and demonstrate that C4 grasslands were significantly expanded into equatorial Africa compared with their present distribution, which could have facilitated dispersal of human populations and other biotic communities. Our results indicate that early populations of Homo sapiens from the Lake Victoria region exploited locally wooded and well-watered habitats within a larger grassland ecosystem. PMID- 25805043 TI - La Ferrassie 8 Neandertal child reloaded: New remains and re-assessment of the original collection. AB - The first evidence of the partial infant Neandertal skeleton La Ferrassie 8 (LF8) was discovered in 1970, although most of the remains were found in 1973 as part of the 1968-1973 work at the site by H. Delporte. This individual and the other Neandertal children from La Ferrassie were published in the early 1980s by J.-L. Heim, and since then LF8 has been regarded as coming from a poorly documented excavation. The recent rediscovery of the box that contained the hominin bones given by Delporte to Heim in the Museum national d'Histoire naturelle (MNHN) collection provided new fossils and helped to locate LF8 in the site: level M2 in square 1. Two visits to the Musee d'Archeologie nationale et Domaine national de Saint-Germain-en-Laye (MAN) yielded additional fossil remains from both the 1970 and 1973 excavations and resulted in the discovery of all of the notes from the excavation of H. Delporte between 1968 and 1973. Here the new fossil remains (47 after performing all possible refits), representing significant portions of the cranium, mandible, and vertebral column together with fragmentary hand and costal remains, are described. Unsurprisingly, the morphology of the bony labyrinth and of a complete stapes from the nearly complete left temporal show clear Neandertal affinities. Additionally, a complete reassessment of the original LF8 collection has resulted in the identification of several errors in the anatomical determination. Despite the significant increase in the anatomical representation of LF8, the skeletal remains are still limited to the head, thorax, pelvis, and four hand phalanges, with some very fragile elements relatively well preserved. Different hypotheses are proposed to explain this anatomical representation, which can be tested during future fieldwork. PMID- 25805042 TI - The Neanderthal in the karst: First dating, morphometric, and paleogenetic data on the fossil skeleton from Altamura (Italy). AB - In 1993, a fossil hominin skeleton was discovered in the karst caves of Lamalunga, near Altamura, in southern Italy. Despite the fact that this specimen represents one of the most extraordinary hominin specimens ever found in Europe, for the last two decades our knowledge of it has been based purely on the documented on-site observations. Recently, the retrieval from the cave of a fragment of bone (part of the right scapula) allowed the first dating of the individual, the quantitative analysis of a diagnostic morphological feature, and a preliminary paleogenetic characterization of this hominin skeleton from Altamura. Overall, the results concur in indicating that it belongs to the hypodigm of Homo neanderthalensis, with some phenetic peculiarities that appear consistent with a chronology ranging from 172 +/- 15 ka to 130.1 +/- 1.9 ka. Thus, the skeleton from Altamura represents the most ancient Neanderthal from which endogenous DNA has ever been extracted. PMID- 25805044 TI - Mobilization of pelvic musculature and its effect on continence in classical bladder exstrophy: a single-center experience of 38 exstrophy repairs. AB - Soft tissue mobilization of pelvic musculature in bladder exstrophy repair and its effect on continence. A single-center experience of 38 exstrophy repairs in children. INTRODUCTION/BACKGROUND: Bladder exstrophy is characterized by infra umbilical abdominal wall defects, evaginated bladder plate of varying size, epispadias, abnormality of genitalia and bony pelvis. The goal of repair is to provide satisfactory continence, which should preferably be done in specialized centers dedicated to exstrophy management. The concept of functional reconstruction rather than urinary diversion is the gold standard worldwide, which can be accomplished by staged or one-stage procedures. Our technique of mobilization of pelvic musculature is based on the concept that continence in bladder exstrophy can be achieved by repairing the disorganized/splayed tissues involved in normal continence (as first advocated by J.H. Kelly) without osteotomy. OBJECTIVES: A systematic review of outcomes of neonatal bladder closure followed by mobilization of pelvic musculature in bladder exstrophy repair in children. STUDY DESIGN: A retrospective chart review of all exstrophy repairs conducted over a 10-year period (between 2001 and 2011). Repairs were done in two stages: bladder closure in the neonatal period (stage 1); and mobilization of pelvic musculature and epispadias repair (stage 2), preferably done between 4 and 6 months of age. The data on complications and continence were evaluated. RESULTS: Thirty-eight patients had completed all the stages of repair. Mean follow-up was 4.5 years (range 2.5-8 years). The following complications were noted: bladder dehiscence in eight patients after stage 1 repair, penopubic fistula occurred in four patients following stage 2 repair. Vulval scarring and vulval dehiscence (2 patients) were complications seen in girls. Twenty-four of the 38 patients (63.5%) achieved complete continence. Functional continence was attained by 31 of the 38 patients (82%). Older age at bladder closure affected continence, while the number of attempts at closure did not affect outcome. The age at pelvic mobilization was not a significant factor in outcome. DISCUSSION: The pelvic floor musculature and urethral sphincters are essential for voluntary control of micturition. In bladder exstrophy, these components are splayed out and our technique is based on reorganizing these components in the second stage. The voluntary urethral sphincter is a delicate complex of musculature located dorsal to the opened urethral plate and spread over the corpora. These are identified using a muscle stimulator and repaired around the tubularized urethra. Normally the levator ani muscle, by its attachment to the pubic bone, forms a loop, by which it compresses the urethra, providing additional aid in continence. In bladder exstrophy with wide pubic diastasis, this loop configuration is lost and becomes a hammock configuration and in fact becomes a pushing force. By mobilizing the pelvic musculature and repairing it in front of the bladder neck, this loop configuration is re-established and further aids in continence. After a successful second stage, patients may have increased frequency and dribbling initially, which improves with age as bladder capacity increases. Perineal exercises aimed at strengthening the pelvic floor musculature are an integral part of our bladder exstrophy management, which begins once the child can understand the technique. The results of our technique are shown in comparison with other series employing the original Kelly's technique (see Table). None of our patients have undergone additional bladder neck repair or permanent augmentation. CONCLUSIONS: Neonatal bladder closure followed by mobilization and repair of the pelvic musculature, produce satisfactory continence in exstrophic children. Proper identification and repair of the external sphincter and levatorplasty correct the altered anatomy by relocating the bladder neck and posterior urethra deep in the pelvis, simulating normal micturition. Early neonatal bladder closure improves outcome. The results are reproducible if basic principles governing continence are followed and when done in a specialized centers. PMID- 25805045 TI - Taxonomy and Phylogeny Can Yield Comparable Results in Comparative Paleontological Analyses. AB - Many extinct taxa with extensive fossil records and mature taxonomic classifications have not yet been the subject of formal phylogenetic analysis. Here, we test whether the taxonomies available for such groups represent useful (i.e., non-misleading) substitutes for trees derived from matrix-based phylogenetic analyses. We collected data for 52 animal clades that included fossil representatives, and for which a recent cladogram and pre-cladistic taxonomy were available. We quantified the difference between the time-scaled phylogenies implied by taxonomies and cladograms using the matching cluster distance metric. We simulated phenotypic trait values and used them to estimate a series of commonly used, phylogenetically explicit measures (phylogenetic signal [Blomberg's [Formula: see text]], phylogenetic generalized least squares [PGLS], mode of evolution [Brownian vs. Ornstein-Uhlenbeck], and phylogenetic clustering of extinction [Fritz and Purvis' [Formula: see text]]) in order to determine the degree to which they co-varied on taxonomic and cladistic trees. With respect to topology taxonomies are good approximations of the underlying evolutionary relationships as recorded in inferred cladograms. Detection of phylogenetic clustering of extinction could not be properly assessed. For all other evolutionary analyses, results from taxonomy-based phylogenies (TBPs) co-varied with those from cladogram-based phylogenies (CBPs), but individual comparisons could be misleading. The relative length of terminal branches (influenced by stratigraphy and sampling rate) is a key control on the shared information between, and therefore the relative performance of, TBP and CBP. Collectively these results suggest that under particular circumstances and after careful consideration some taxonomies, or composite trees that incorporate taxonomic information, could be used in place of a formal analytical solution, but workers must be cautious. This opens certain parts of a previously inaccessible section of the fossil record to interrogation within an explicit comparative framework, which will help to test many classical macroevolutionary hypotheses formulated for groups that currently lack formal phylogenetic estimates. PMID- 25805047 TI - Cytokinin-auxin crosstalk in cell type specification. AB - Auxin and cytokinin affect cell fate specification transcriptionally and non transcriptionally, and their roles have been characterised in several founder cell specification and activation contexts. Similarly to auxin, local cytokinin synthesis and response gradients are instructive, and the roles of ARABIDOPSIS RESPONSE REGULATOR 7/15 (ARR7/15) and the negative cytokinin response regulator ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 6, as well as auxin signalling via MONOPTEROS/BODENLOS, are functionally conserved across different developmental processes. Auxin and cytokinin crosstalk is tissue- and context-specific, and may be synergistic in the shoot apical meristem (SAM) but antagonistic in the root. We review recent advances in understanding the interactions between auxin and cytokinin in pivotal developmental processes, and show that feedback complexity and the multistep nature of specification processes argue against a single morphogenetic signal. PMID- 25805046 TI - Incidence and severity of atherosclerotic cardiovascular artery disease in patients undergoing TAVI. AB - Transcatheter aortic valve implantation (TAVI) has extended the treatment options for severe, symptomatic aortic valve stenosis (AS). Risk factors for AS have been shown to be similar to atherosclerosis. Consequently, coronary artery disease (CAD), peripheral vascular and carotid artery diseases are often found concurrently with diagnostic, procedural and prognostic implications. This study sought to describe comprehensive vascular assessment in terms of prevalence, severity and correlations in TAVI candidates. A total of 323 patients (81 +/- 6 years) undergoing TAVI were enrolled. Vascular pathologies were evaluated by invasive coronary angiography, computer-tomography (abdominal aorta, renal, iliac and femoral arteries), echo-color Doppler ultrasound (carotid artery), and transoesophageal echocardiography (thoracic aorta). CAD was found in 173 (54%) patients, of which 65 (38%) had 1-vessel, 45 (26%) 2-vessel and 59 (34%) 3-vessel disease. Carotid artery disease was present in 33.6% patients, of which 23.6% unilateral and 10.0% bilateral. Iliac, femoral and renal stenosis were found in 29.2%, 22.0%, and 4.7%, respectively. Cardiovascular risk factor and gender correlated with CAD. CAD patients presented more frequently with significant stenosis (luminal narrowing >= 50%) of at least one other district. Multi districts significant stenosis stratified patients on long-term survival and the coexistence of 3-districts involvement with CAD negatively impacts on mortality. Multimodality imaging assessment shows that coronary, carotid, and peripheral artery disease are often found concurrently in patients undergoing TAVI. Several risk factors and gender correlate with the presence and severity of CAD and peripheral pathologies. Long-term mortality is increased in patients with a more compromised vascular situation. PMID- 25805050 TI - CD3 antibody and IL-2 complex combination therapy inhibits atherosclerosis by augmenting a regulatory immune response. PMID- 25805048 TI - Pulmonary epithelioid hemangioendothelioma: Nuclear medicine and 18F-FDG PET/CT findings. PMID- 25805051 TI - Interplay of cardiac and cognitive function: how much do we really understand? PMID- 25805049 TI - Identification of Proteins Possibly Involved in Glucosinolate Metabolism in L. agilis R16 and E. coli VL8. AB - This study was aimed to identify sinigrin-induced bacterial proteins potentially involved in the metabolism of glucosinolate in two glucosinolate-metabolising bacteria Lactobacillus agilis R16 and Escherichia coli VL8. Sinigrin (2 mM) was used to induce the proteins in both bacteria under anaerobic incubation for 8 h at 30 degrees C for L. agilis R16 and 37 degrees C for E. coli VL8 and the controls without sinigrin were performed. Allyl isothiocyanate and allyl nitrile as two degradation products of sinigrin were detected in sinigrin-induced cultures of L. agilis R16 (27% total products) and E. coli VL8 (38% total products) from a complete sinigrin degradation in 8 h for both bacteria. 2D gel electrophoresis was conducted to identify induced proteins with at least twofold increased abundance. Sinigrin-induced L. agilis R16 and the control produced 1561 and 1543 protein spots, respectively. For E. coli VL8, 1363 spots were detected in sinigrin-induced and 1354 spots in the control. A combination of distinct proteins and upregulated proteins of 32 and 35 spots in L. agilis R16 and E. coli VL8, respectively were detected upon sinigrin induction. Of these, 12 and 16 spots from each bacterium respectively were identified by LC-MS/MS. In both bacteria most of the identified proteins are involved in carbohydrate metabolism, oxidoreduction system and sugar transport while the minority belong to purine metabolism, hydrolysis, and proteolysis. This indicated that sinigrin induction led to the expressions of proteins with similar functions in both bacteria and these proteins may play a role in bacterial glucosinolate metabolism. PMID- 25805053 TI - Adverse events following immunization: is this time for the use of WHO causality assessment? AB - In recent years, public health authorities in industrialized countries have noted an increase in the numbers of parents choosing not to have their children vaccinated and in the activities of 'antivaccination' movements. Doubts about vaccine safety and lack of surveillance of adverse events following immunization (AEFI) are the most frequent themes proposed by antivaccination movements. This editorial aims to critically analyze the use of AEFI assessment procedures among national health authorities and public health researchers. In fact, the WHO recommended and published a systematic and standardized causality assessment process for serious AEFI, providing a method for individual causality assessment to be used by staff of national immunization programs, regulatory authorities and pharmacovigilance or surveillance departments. The last update was published in March 2013 but to date, an Internet search reveals no information or reports on AEFI surveillance that uses the WHO AEFI causality assessment. PMID- 25805054 TI - Cyclometalated iridium(III) complexes with imidazo[4,5-f][1,10]phenanthroline derivatives for mitochondrial imaging in living cells. AB - A new series of cyclometalated iridium(III) complexes with imidazo[4,5 f][1,10]phenanthroline derivatives (i.e., MitoIr1-MitoIr7) were synthesized and developed to image mitochondria in living cells. In comparison with commercially available mitochondrial trackers, these complexes exhibit a superior capacity to selectively accumulate in mitochondria with no requirement of any membrane permeabilization or replacement of the culture medium. In addition, the excellent photostability under continuous laser irradiation as well as the stable physiological pH resistance of these complexes were confirmed by photobleaching experiments and luminescence measurements. Importantly, MitoIr7, which exhibited both excellent luminescence and high ability to locate in mitochondria, was developed to track the mitochondrial morphological changes over a long period of time. PMID- 25805055 TI - Electron capture dissociation and drift tube ion mobility-mass spectrometry coupled with site directed mutations provide insights into the conformational diversity of a metamorphic protein. AB - Ion mobility mass spectrometry can be combined with data from top-down sequencing to discern adopted conformations of proteins in the absence of solvent. This multi-technique approach has particular applicability for conformationally dynamic systems. Previously, we demonstrated the use of drift tube ion mobility mass spectrometry (DT IM-MS) and electron capture dissociation (ECD) to study the metamorphic protein lymphotactin (Ltn). Ltn exists in equilibrium between distinct monomeric (Ltn10) and dimeric (Ltn40) folds, both of which can be preserved and probed in the gas-phase. Here, we further test this mass spectrometric framework, by examining two site directed mutants of Ltn, designed to stabilise either distinct fold in solution, in addition to a truncated form consisting of a minimum model of structure for Ltn10. The truncated mutant has similar collision cross sections to the wild type (WT), for low charge states, and is resistant to ECD fragmentation. The monomer mutant (CC3) presents in similar conformational families as observed previously for the WT Ltn monomer. As with the WT, the CC3 mutant is resistant to ECD fragmentation at low charge states. The dimer mutant W55D is found here to exist as both a monomer and dimer. As a monomer W55D exhibits similar behaviour to the WT, but as a dimer presents a much larger charge state and collision cross section range than the WT dimer, suggesting a smaller interaction interface. In addition, ECD on the W55D mutant yields greater fragmentation than for the WT, suggesting a less stable beta-sheet core. The results highlight the power of MS to provide insight into dynamic proteins, providing further information on each distinct fold of Ltn. In addition we observe differences in the fold stability following single or double point mutations. This approach, therefore, has potential to be a useful tool to screen for the structural effects of mutagenesis, even when sample is limited. PMID- 25805052 TI - Effects of developmental alcohol exposure vs. intubation stress on BDNF and TrkB expression in the hippocampus and frontal cortex of neonatal rats. AB - Third trimester-equivalent alcohol exposure causes significant deficits in hippocampal and cortical neuroplasticity, resulting in alterations to dendritic arborization, hippocampal adult neurogenesis, and performance on learning tasks. The current study investigated the impact of neonatal alcohol exposure (postnatal days 4-9, 5.25 g/kg/day) on expression of brain-derived neurotrophic factor (BDNF) and the tropomyosin-related kinase B (TrkB) receptor in the hippocampal and frontal cortex of infant Long-Evans rats. Levels of BDNF protein were increased in the hippocampus, but not frontal cortex, of alcohol-exposed rats 24h after the last dose, when compared with undisturbed (but not sham-intubated) control animals. BDNF protein levels showed a trend toward increase in hippocampus of sham-intubated animals as well, suggesting an effect of the intubation procedure. TrkB protein was increased in the hippocampus of alcohol exposed animals compared to sham-intubated pups, indicating an alcohol-specific effect on receptor expression. In addition, expression of bdnf total mRNA in alcohol-exposed and sham-intubated pups was enhanced in the hippocampus; however, there was a differential effect of alcohol and intubation stress on exon I- and IV-specific mRNA transcripts. Further, plasma corticosterone was found to be increased in both alcohol-exposed and sham-intubated pups compared to undisturbed animals. Upregulation of BDNF could potentially represent a neuroprotective mechanism activated following alcohol exposure or stress. The results suggest that alcohol exposure and stress have both overlapping and unique effects on BDNF, and highlight the need for the stress of intubation to be taken into consideration in studies that implement this route of drug delivery. PMID- 25805056 TI - Preformed chitosan cryogel-biphasic calcium phosphate: a potential injectable biocomposite for pathologic fracture. AB - The increasing interest in chitosan-based biomaterials stems from its desirable physicochemical properties. Although calcium phosphates have been mixed with chitosan to form injectable scaffolds, its application for bone tissue engineering has been limited and is still being explored to improve its clinical translatability. We report a biocomposite comprised of preformed chitosan cryogel with dispersed biphasic calcium phosphate that can flow under moderate pressure allowing passage through a small gauge needle, while maintaining sufficient integrity and strength during injection for gel recovery. The formed samples were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction analysis and protein adsorption measurements. Composite with 1% w/v biphasic calcium phosphate (CSG1) resulted in a homogeneous and rigid final structure. Injectable composite cryogel CSG1 (2.5 +/- 0.2 N, 23G needle) exhibited good protein adsorption and biocompatibility. Results of subcutaneous implantation in rats reveal relatively high presence of polymorphonuclear cells but with no fibrous encapsulation with the composites, allowing further infiltration of cells within the sample implants. The biocomposite system presents a less-invasive delivery of bone filling material for stabilizing pathologic fractures. PMID- 25805057 TI - Mechanical and physicochemical characterization along with biological interactions of a new Ti25Nb21Hf alloy for bone tissue engineering. AB - Nowadays, one of the main challenges in metal implants for bone substitution is the achievement of an elastic modulus close to that of human cortical bone as well as to provide an adequate interaction with the surrounding tissue avoiding in vivo foreign body reaction. From this perspective, a new Ti-based alloy has been developed with Nb and Hf as alloying elements which are known as non-toxic and with good corrosion properties. The microstructure, mechanical behaviour and the physicochemical properties of this novel titanium alloy have been studied. Relationship of surface chemistry and surface electric charge with protein adsorption and cell adhesion has been evaluated due to its role for understanding the mechanism of biological interactions with tissues. The Ti25Nb21Hf alloy presented a lower elastic modulus than commercial alloys with a superior ultimate strength and yield strength than CP-Ti and very close to Ti6Al4V. It also exhibited good corrosion resistance. Furthermore, the results revealed that it had no cytotoxic effect on rat mesenchymal stem cells and allowed protein adsorption and cell adhesion. The experimental results make this alloy a promising material for bone substitution or for biomedical devices. PMID- 25805058 TI - To Model Chemical Reactivity in Heterogeneous Emulsions, Think Homogeneous Microemulsions. AB - Two important and unsolved problems in the food industry and also fundamental questions in colloid chemistry are how to measure molecular distributions, especially antioxidants (AOs), and how to model chemical reactivity, including AO efficiency in opaque emulsions. The key to understanding reactivity in organized surfactant media is that reaction mechanisms are consistent with a discrete structures-separate continuous regions duality. Aggregate structures in emulsions are determined by highly cooperative but weak organizing forces that allow reactants to diffuse at rates approaching their diffusion-controlled limit. Reactant distributions for slow thermal bimolecular reactions are in dynamic equilibrium, and their distributions are proportional to their relative solubilities in the oil, interfacial, and aqueous regions. Our chemical kinetic method is grounded in thermodynamics and combines a pseudophase model with methods for monitoring the reactions of AOs with a hydrophobic arenediazonium ion probe in opaque emulsions. We introduce (a) the logic and basic assumptions of the pseudophase model used to define the distributions of AOs among the oil, interfacial, and aqueous regions in microemulsions and emulsions and (b) the dye derivatization and linear sweep voltammetry methods for monitoring the rates of reaction in opaque emulsions. Our results show that this approach provides a unique, versatile, and robust method for obtaining quantitative estimates of AO partition coefficients or partition constants and distributions and interfacial rate constants in emulsions. The examples provided illustrate the effects of various emulsion properties on AO distributions such as oil hydrophobicity, emulsifier structure and HLB, temperature, droplet size, surfactant charge, and acidity on reactant distributions. Finally, we show that the chemical kinetic method provides a natural explanation for the cut-off effect, a maximum followed by a sharp reduction in AO efficiency with increasing alkyl chain length of a particular AO. We conclude with perspectives and prospects. PMID- 25805059 TI - WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 1: basic principles and terminology. AB - Conventional diagnostic ultrasound images of the anatomy (as opposed to blood flow) reveal differences in the acoustic properties of soft tissues (mainly echogenicity but also, to some extent, attenuation), whereas ultrasound-based elasticity images are able to reveal the differences in the elastic properties of soft tissues (e.g., elasticity and viscosity). The benefit of elasticity imaging lies in the fact that many soft tissues can share similar ultrasonic echogenicities but may have different mechanical properties that can be used to clearly visualize normal anatomy and delineate pathologic lesions. Typically, all elasticity measurement and imaging methods introduce a mechanical excitation and monitor the resulting tissue response. Some of the most widely available commercial elasticity imaging methods are 'quasi-static' and use external tissue compression to generate images of the resulting tissue strain (or deformation). In addition, many manufacturers now provide shear wave imaging and measurement methods, which deliver stiffness images based upon the shear wave propagation speed. The goal of this review is to describe the fundamental physics and the associated terminology underlying these technologies. We have included a questions and answers section, an extensive appendix, and a glossary of terms in this manuscript. We have also endeavored to ensure that the terminology and descriptions, although not identical, are broadly compatible across the WFUMB and EFSUMB sets of guidelines on elastography (Bamber et al. 2013; Cosgrove et al. 2013). PMID- 25805060 TI - Non-speech oral motor treatment for children with developmental speech sound disorders. AB - BACKGROUND: Children with developmental speech sound disorders have difficulties in producing the speech sounds of their native language. These speech difficulties could be due to structural, sensory or neurophysiological causes (e.g. hearing impairment), but more often the cause of the problem is unknown. One treatment approach used by speech-language therapists/pathologists is non speech oral motor treatment (NSOMT). NSOMTs are non-speech activities that aim to stimulate or improve speech production and treat specific speech errors. For example, using exercises such as smiling, pursing, blowing into horns, blowing bubbles, and lip massage to target lip mobility for the production of speech sounds involving the lips, such as /p/, /b/, and /m/. The efficacy of this treatment approach is controversial, and evidence regarding the efficacy of NSOMTs needs to be examined. OBJECTIVES: To assess the efficacy of non-speech oral motor treatment (NSOMT) in treating children with developmental speech sound disorders who have speech errors. SEARCH METHODS: In April 2014 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (R) and Ovid MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Education Resources Information Center (ERIC), PsycINFO and 11 other databases. We also searched five trial and research registers, checked the reference lists of relevant titles identified by the search and contacted researchers to identify other possible published and unpublished studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared (1) NSOMT versus placebo or control; and (2) NSOMT as adjunctive treatment or speech intervention versus speech intervention alone, for children aged three to 16 years with developmental speech sound disorders, as judged by a speech and language therapist. Individuals with an intellectual disability (e.g. Down syndrome) or a physical disability were not excluded. DATA COLLECTION AND ANALYSIS: The Trials Search Co-ordinator of the Cochrane Developmental, Psychosocial and Learning Problems Group and one review author ran the searches. Two review authors independently screened titles and abstracts to eliminate irrelevant studies, extracted data from the included studies and assessed risk of bias in each of these studies. In cases of ambiguity or information missing from the paper, we contacted trial authors. MAIN RESULTS: This review identified three studies (from four reports) involving a total of 22 children that investigated the efficacy of NSOMT as adjunctive treatment to conventional speech intervention versus conventional speech intervention for children with speech sound disorders. One study, a randomised controlled trial (RCT), included four boys aged seven years one month to nine years six months - all had speech sound disorders, and two had additional conditions (one was diagnosed as "communication impaired" and the other as "multiply disabled"). Of the two quasi-randomised controlled trials, one included 10 children (six boys and four girls), aged five years eight months to six years nine months, with speech sound disorders as a result of tongue thrust, and the other study included eight children (four boys and four girls), aged three to six years, with moderate to severe articulation disorder only. Two studies did not find NSOMT as adjunctive treatment to be more effective than conventional speech intervention alone, as both intervention and control groups made similar improvements in articulation after receiving treatments. One study reported a change in postintervention articulation test results but used an inappropriate statistical test and did not report the results clearly. None of the included studies examined the effects of NSOMTs on any other primary outcomes, such as speech intelligibility, speech physiology and adverse effects, or on any of the secondary outcomes such as listener acceptability.The RCT was judged at low risk for selection bias. The two quasi-randomised trials used randomisation but did not report the method for generating the random sequence and were judged as having unclear risk of selection bias. The three included studies were deemed to have high risk of performance bias as, given the nature of the intervention, blinding of participants was not possible. Only one study implemented blinding of outcome assessment and was at low risk for detection bias. One study showed high risk of other bias as the baseline characteristics of participants seemed to be unequal. The sample size of each of the included studies was very small, which means it is highly likely that participants in these studies were not representative of its target population. In the light of these serious limitations in methodology, the overall quality of the evidence provided by the included trials is judged to be low. Therefore, further research is very likely to have an important impact on our confidence in the estimate of treatment effect and is likely to change the estimate. AUTHORS' CONCLUSIONS: The three included studies were small in scale and had a number of serious methodological limitations. In addition, they covered limited types of NSOMTs for treating children with speech sound disorders of unknown origin with the sounds /s/ and /z/. Hence, we judged the overall applicability of the evidence as limited and incomplete. Results of this review are consistent with those of previous reviews: Currently no strong evidence suggests that NSOMTs are an effective treatment or an effective adjunctive treatment for children with developmental speech sound disorders. Lack of strong evidence regarding the treatment efficacy of NSOMTs has implications for clinicians when they make decisions in relation to treatment plans. Well-designed research is needed to carefully investigate NSOMT as a type of treatment for children with speech sound disorders. PMID- 25805062 TI - Flow-induced 2D protein crystallization: characterization of the coupled interfacial and bulk flows. AB - Two-dimensional crystallization of the protein streptavidin, crystallizing below a biotinylated lipid film spread on a quiescent air-water interface is a well studied phenomenon. More recently, 2D crystallization induced by a shearing interfacial flow has been observed at film surface pressures significantly lower than those required in a quiescent system. Here, we quantify the interfacial and bulk flow associated with 2D protein crystallization through numerical modeling of the flow along with a Newtonian surface model. Experiments were conducted over a wide range of conditions resulting in a state diagram delineating the flow strength required to induce crystals for various surface pressures. Through measurements of the velocity profile at the air-water interface, we found that even in the cases where crystals are formed, the macroscopic flow at the interface is well described by the Newtonian model. However, the results show that even in the absence of any protein in the system, the viscous response of the biotinylated lipid film is complicated and strongly dependent on the strength of the flow. This observation suggests that the insoluble lipid film plays a key role in flow-induced 2D protein crystallization. PMID- 25805061 TI - Preliminary cognitive scale of basic and instrumental activities of daily living for dementia and mild cognitive impairment. AB - In the present study we explored cognitive and functional deficits in patients with multidomain mild cognitive impairment (MCI), patients with dementia, and healthy age-matched control participants using the Cognitive Scale for Basic and Instrumental Activities of Daily Living, a new preliminary informant-based assessment tool. This tool allowed us to evaluate four key cognitive abilities task memory schema, error detection, problem solving, and task self-initiation-in a range of basic and instrumental activities of daily living (BADL and IADL, respectively). The first part of the present study was devoted to testing the psychometric adequateness of this new informant-based tool and its convergent validity with other global functioning and neuropsychological measures. The second part of the study was aimed at finding the patterns of everyday cognitive factors that best discriminate between the three groups. We found that patients with dementia exhibited impairment in all cognitive abilities in both basic and instrumental activities. By contrast, patients with MCI were found to have preserved task memory schema in both types of ADL; however, such patients exhibited deficits in error detection and task self-initiation but only in IADL. Finally, patients with MCI also showed a generalized problem solving deficit that affected even BADL. Studying various cognitive processes instantiated in specific ADL differing in complexity seems a promising strategy to further understand the specific relationships between cognition and function in these and other cognitively impaired populations. PMID- 25805063 TI - Magnesium amino-bis(phenolato) complexes for the ring-opening polymerization of rac-lactide. AB - Magnesium compounds of tetradentate amino-bis(phenolato) ligands, Mg[L1] (1) and Mg[L2] (2) (where [L1] = 2-pyridyl-N,N-bis(2-methylene-4-methoxy-6-tert butylphenolato), and [L2] = dimethylaminoethylamino-N,N-bis(2-methylene-4-methyl 6-tert-butylphenolato)) were prepared. The proligands, H2[L1] and H2[L2] were reacted with di(n-butyl)magnesium in toluene to give the desired compounds in high yields. Compounds 1 and 2 exhibit dimeric structures in solutions of non coordinating solvents as observed by NMR spectroscopy and in the solid state as shown by the single crystal X-ray structure of 2. These compounds exhibit good activity for rac-lactide polymerization in solution and in molten lactide. PMID- 25805064 TI - Muscle-related differences in mechanomyography frequency-force relationships are model dependent. AB - The purpose of this study was to examine the surface mechanomyographic mean power frequency (MMG MPF)-force relationships with linear regression models applied to the absolute and log-transformed values for the first dorsal interosseous (FDI), vastus lateralis (VL) and rectus femoris (RF) muscles. Thirteen healthy males performed isometric ramp contractions of the leg extensors and index finger from 10 to 80% of their maximal voluntary contraction with MMG sensors positioned on the VL, RF, and FDI. Simple linear regression models were fit to the absolute and log-transformed MMG MPF-force relationships. Skinfold thickness measurements were taken at each sensor site. There were significant differences for the slopes from the log-transformed MMG MPF-force relationships between the FDI and the leg extensors (P < 0.001) but not the absolute model (P = 0.168). The Y-intercepts were greater for the FDI than the leg extensors for the absolute (P < 0.001) and log-transformed models (P < 0.001), which reflected similar muscle-related differences (P < 0.001) for skinfold thickness. However, there were no significant correlations between Y-intercepts and skinfold thicknesses. Differences in the patterns of response between the FDI and leg extensors were only quantified with the log-transformed model. PMID- 25805065 TI - Addition of angiotensin-converting enzyme inhibitors to beta-blockers has a distinct effect on hispanics compared with african americans and whites with heart failure and reduced ejection fraction: a propensity score-matching study. AB - BACKGROUND: There are currently no data on the efficacy of angiotensin-converting enzyme inhibitors (ACEis) in Hispanic patients with heart failure (HF) and reduced ejection fraction (HFrEF). We aimed to investigate the effect of adding ACEis to beta-blockers on mortality and hospitalization for HF exacerbation in patients with HFrEF stratified by race/ethnicity. METHODS AND RESULTS: From Montefiore Medical Center's 3 large hospitals, 618 consecutive patients with HFrEF (left ventricular ejection fraction [LVEF] <35%) who were on a beta-blocker were retrospectively identified. Patients were divided into 2 groups based on whether or not they were on an ACEi for 24 consecutive months. Propensity score matching including all baseline characteristics was performed and patients were then categorized into 3 groups: African Americans, Hispanics, and Whites/Caucasians. We evaluated 2-year all-cause mortality and 2-year hospitalization for HF exacerbation. Of 618 patients, 66% were categorized as ACEi and 34% as no-ACEi. Four hundred twenty-seven patients were matched 2:1 between the ACEi and no-ACEi groups. After matching, overall 2-year mortality and hospitalization rates were similar between ACEi and no-ACEi (12.4% vs 17.8%, hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.38-1.16; P = .14; and 8.1% vs 9.5%, HR 0.84, 95% CI 0.44-1.60; P = .6; respectively). After stratifying patients based on race/ethnicity, ACEi demonstrated a lower 2-year mortality compared with no-ACEi in Hispanics (9.8% vs 28.4%, HR 0.33, 95% CI 0.13-0.87; P = .018) but not in African Americans (17.0% vs 11.8%, HR 0.94, 95% CI 0.34-2.65; P = .91) or Whites (9.2% vs 10.3%, HR 0.89, 95% CI 0.29-2.74; P = .83). Two-year hospitalization was not different between ACEi and no-ACEi in Hispanics, African Americans, or Whites (all P = NS). In multivariate analysis, ACEi therapy was an independent predictor of lower 2-year mortality (HR 0.33, 95% CI 0.12-0.89; P = .028) in Hispanics only. CONCLUSIONS: In this retrospective propensity-matched study of patients with HFrEF who were on a beta-blocker, ACEi therapy was associated with greater mortality reduction in Hispanic patients compared with African Americans and Whites. These findings need to be confirmed in large national studies that include a significant fraction of Hispanic patients. PMID- 25805066 TI - Nasopharyngeal hyalinizing clear cell carcinoma with EWSR1 rearrangements diagnosed by fluorescence in situ hybridization. AB - Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade salivary gland neoplasm with a predilection for the palate and tongue. A 63-year-old woman presented a 14*14*17-mm mass at the roof of the nasopharynx. Endoscopic resection was performed via a transnasal approach. Histopathological findings of the salivary gland tumor indicated hyalinization of the stroma and neoplastic cells with clear cytoplasm without mucin. Fluorescence in situ hybridization analysis revealed that the tumor cells were positive for EWSR1 rearrangement. We finally diagnosed this case as HCCC of the nasopharynx. EWSR1 rearrangements are non existent in other salivary gland tumors with clear cell change; thus, the identification of this rearrangement was very useful in accurately diagnosing HCCC. PMID- 25805067 TI - Atypical post-adenoidectomy Grisel's syndrome in Crouzon child with kyphotic skull base. AB - Crouzon syndrome is characterized by abnormal craniofacial growth due to craniosynostosis. Skull base may also be involved in the pattern of malformations. Grisel's syndrome, an inflammation-mediated atlanto-axial instability occurs rarely in children after adenoidectomy. We report a 9-year-old female Crouzon patient, without vertebral anomalies, who developed severe torticollis few days after adenoid curettage. A deformity of the skull base alone might have induced an irregular arrangement of the craniocervical junction elements, thus increasing the susceptibility to cervical spine complications. PMID- 25805069 TI - In vitro activity of fosfomycin in combination with colistin against clinical isolates of carbapenem-resistant Pseudomas aeruginosa. AB - The shortage of effective antibiotics against carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a public health threat. Combination treatment may represent a good choice for treating infections caused by CRPA. The aim of this study was to evaluate the in vitro efficacy of fosfomycin in combination with colistin against clinical CRPA isolates. Eighty-seven isolates were collected from three hospitals in China. The checkerboard method and time-kill assay were used to assess the interactions between fosfomycin and colistin. The fosfomycin/colistin combination displayed synergistic and partial synergistic activity against 21.84% and 27.59% of the isolates, respectively. Antagonism was not observed. In combination, the colistin MIC values were ?0.5 MUg ml(-1) for 91.95% of the isolates. This result differed significantly from those obtained using a single agent treatment (The colistin MIC values were ?0.5 MUg ml(-1) for only 25.29% of the isolates). In addition, the time-kill assay demonstrated that the fosfomycin/colistin combination treatment exerted bactericidal effects against five isolates and that the regrowth observed after colistin monotherapy was prevented. In summary, the combination of fosfomycin and colistin demonstrated synergistic activity against the CRPA isolates tested in this study. Furthermore, fosfomycin may potentially widen the therapeutic window of colistin, suggesting that this combination could be applied clinically to control infections caused by CRPA. PMID- 25805070 TI - Induced production of BE-31405 by co-culturing of Talaromyces siamensis FKA-61 with a variety of fungal strains. AB - While isolating fungal strains from soil samples, two strains, Talaromyces siamensis FKA-61 and Phomopsis sp. FKA-62, were found to produce a black pigment near the boundary with an adjoining colony on agar plates. Moreover, strain FKA 61 inhibited the growth of strain FKA-62. Co-culture of T. siamensis FKA-61 with Phomopsis sp. FKA-62 resulted in the production of an antifungal agent, BE-31405, which proved active against Phomopsis sp. FKA-62. We screened for fungal genera that have the ability to induce production of antifungal BE-31405. Surprisingly, production of BE-31405 was induced only by co-culturing T. siamensis FKA-61 with a variety of BE-31405-sensitive fungal strains but never with BE-31405 insensitive strains. This is the first report of the induced production of a specific antibiotic active against antibiotic-sensitive fungal strains by co culturing with them. PMID- 25805071 TI - Characterization of an infectious pancreatic necrosis virus from rainbow trout fry (Onhorhynchus mykiss) in West Ukraine. PMID- 25805072 TI - Surface specific heats of metal nanocrystals at low temperatures. AB - In order to quantitatively explain the enhanced specific heat of metal nanocrystals measured from 4.2 K to 80 K, an analytical expression has been deduced to determine the surface specific heat in nanocrystals, which is proportional to T(2.5) at low temperatures. The consequently calculated specific heat and surface Debye temperature of copper nanocrystals are in good agreement with the experimental data. This explains why the experimental specific heat of copper nanocrystals is enhanced with respect to the bulk and why it exhibits a different feature as a function of temperature from that of the bulk at low temperatures. The first experimental evidence is presented that the spatial dimension of surfaces should be neither pure 2D nor 3D, but between 2D and 3D, due to the effect of atoms in the core of the nanocrystals. PMID- 25805068 TI - Adolescent and Early Adulthood Dietary Carbohydrate Quantity and Quality in Relation to Breast Cancer Risk. AB - BACKGROUND: We investigated quantity and quality of dietary carbohydrate as well as insulin load and insulin index during adolescence and also early adulthood in relation to risk of breast cancer in the Nurses' Health Study II. METHODS: During 20 years of follow-up of 90,534 premenopausal women who completed a diet questionnaire in 1991, 2,833 invasive breast cancer cases were documented. In 1998, 44,263 of these women also completed a questionnaire about their diet during high school; among these women, we documented 1,118 cases of breast cancer. Multivariable-adjusted Cox proportional hazards regression was used to model relative risks (RR) and 95% confidence intervals (95% CI) for breast cancer across categories of dietary carbohydrate, glycemic index (GI), glycemic load (GL), as well as insulin load and insulin index scores. RESULTS: Adolescent or early adult intakes of GI or GL were not associated with risk of breast cancer. Comparing women in the highest versus lowest quintile, the multivariable-adjusted RRs were 1.14 (0.95-1.38) for adolescent GI scores and 1.03 (0.91-1.16) for early adulthood GI scores. We also did not observe associations with insulin index and insulin load scores in adolescence or early adulthood and breast cancer risk. CONCLUSIONS: We found that diets high in GI, GL, insulin index, and insulin load during adolescence or early adulthood were not associated with an increased risk of breast cancer in this cohort study. IMPACT: Diets with a high glucose or insulin response in adolescence or early adulthood were not significant predictors of breast cancer incidence. PMID- 25805073 TI - Educating medical students in a more optimized way. PMID- 25805074 TI - Using the SPICES model to develop innovative teaching opportunities in ambulatory care venues. AB - It is possible to begin new teaching opportunities in a variety of ambulatory care venues and design these teaching and learning programmes using the SPICES approach to curriculum reform. In an ambulatory care teaching programme it is possible to stimulate more student-centred learning and to move away from clinician-focused teaching. Opportunities for integrated learning and problem solving can be provided and an inter-professional approach fostered. Learning in the clinical context can be structured to meet both students' needs and curriculum requirements. Finally, opportunities for elective studies can be taken by students with a particular interest in a topic encountered. Developing a new teaching programme in an ambulatory care venue provides an opportunity to introduce elements of the SPICES approach to learning. The new programme created can be a model of innovative teaching in a medical school wishing to develop a revised undergraduate curriculum. PMID- 25805075 TI - An ideal model of informed consent communication. AB - Informed consent (IC) should be a form of communication between a physician and patient in which information regarding all options of a medical procedure and the patient's preference is shared. The aim of this study was to create a standard for communication by IC for physicians. The IC standard was developed based on an analysis of a dialogue in our previous experience with a medical communication program and a review of the literature. The dialogue pattern of the IC standard had the following six elements: opening; orientation; disclosure of information; conforming and complementing; shared decision making; and closing. Factors that influenced effective IC-based communication included preparation, attitude, empathy, listening, a psychosocial factor, nonverbal communication, explanation, and understanding. The IC communication standard will be useful in improving the quality of communication between a physician and patient in obtaining IC. It will also be used as a guideline for communication educators and medical students. Innovative strategies and rigorous studies are needed to improve IC counseling to establish effective patient-centered interviews. PMID- 25805076 TI - The correlation between achievement goals, learning strategies, and motivation in medical students. AB - PURPOSE: The purpose of this study is to investigate the pursuit of achievement goals in medical students and to assess the relationship between achievement goals, learning strategy, and motivation. METHODS: Two hundred seventy freshman and sophomore premedical students and sophomore medical school students participated in this study, which used the Achievement Goals Scale and the Self Regulated Learning Strategy Questionnaire. RESULTS: The achievement goals of medical students were oriented toward moderate performance approach levels, slightly high performance avoidance levels, and high mastery goals. About 40% of the students were high or low in all three achievement goals. The most successful adaptive learners in the areas of learning strategies, motivation, and school achievement were students from group 6, who scored high in both performance approach and mastery goals but low in performance avoidance goals. And goal achievement are related to the academic self-efficacy, learning strategies, and motivation in medical students. CONCLUSION: In the context of academic achievement, mastery goals and performance approach goals are adaptive goals. PMID- 25805077 TI - Is remediation program using team-based learning effective for at-risk medical students? AB - PURPOSE: Although remediation and reassessment of at-risk students are essential functions of medical education, there are no guidelines on how best to remediate such students. In this study, we described and examined the effectiveness of a remediation program that was delivered as team-based learning (TBL) sessions. METHODS: After a written examination, 15 of 145 fourth-year students were found to require remediation, and assigned to teams of four to five students. Clinical topics related to items of the Korean Medical License Examination were taught in the remediation period of 3 weeks, and all students took reexamination. Changes in test scores were analyzed, and student feedback was documented. RESULTS: Students who participated in the remediation program had significantly better total scores on re-examination (remediation group 225.8 to 263.0 vs. control group 290.8 to 304.0, p<0.05). Most students found that the remediation program was instructive and helped them prepare for the examination. Moreover, students gained confidence, and all of them passed the graduation examination. CONCLUSION: TBL is an effective method of remediating at-risk students. Further research with regard to the successful design and implementation of a remediation program for at-risk students is needed. PMID- 25805078 TI - Peer assessment of small-group presentations by medical students and its implications. AB - PURPOSE: The purpose of this study was to explore the relationships among medical students' assessments on peers' group presentations, instructors' assessments of those presentations, and students' educational achievements in other assignments and tests. METHODS: A total of 101 first-year students from a medical school participated in the study. The students' educational achievements in a 4-week long integrated curriculum were analyzed. Student's final grades were comprised of the following education criteria: two written tests (60%), 15 group reports (25%), one individual report (7%), and four group presentations (15%). We compared scores of the group presentation assessed by the peers and the two instructors. Furthermore, we compared peers' assessment scores with each component of the evaluation criteria. RESULTS: Pearson correlation analysis showed significant correlaton for the assessments between peers and instructors (r=0.775, p<0.001). Peer assessment scores also correlated significantly with scores for the group assignments (r=0.777, p<0.001), final grades on the curriculum (r=0.345, p<0.001), and scores for individual assignments (r=0.334, p<0.001); however, no significant correlation was observed between the peer assessed group presentation scores and the two written test scores. CONCLUSION: Peer assessments may be a reliable and valid method for evaluating medical students' performances in an integrated curriculum, especially if the assessments are used to academic processes, such as presentations, with explicit evaluation and judgment criteria. Peer assessments on group presentations might assess different learning domains compared to written tests that primarily evaluate limited medical knowledge and clinical reasoning. PMID- 25805079 TI - Evaluation of first year outcomes of Lee Jong-Wook Seoul Project using Kirkpatrick's four-level evaluation approach. AB - PURPOSE: The Lee Jong-Wook Seoul Project, which began in 2011, is a training program that aims to educate faculty members of Lao University of Health Sciences in medical knowledge and skills. The project has tremendous significance, attempting to apply the Korean health care developmental model to developing countries. Precise evaluation of the project outcome must be performed to enhance the effectiveness, improve the shortcomings, and adjust the future direction of the program. METHODS: Trainers and exchange professors were asked to fill out questionnaires in the middle and at the end of the program. Eight months after its completion, an evaluation team visited Lao and interviewed each exchange professor individually. Also, 360-degree feedback was obtained from their colleagues. We analyzed the answers to the questionnaires, based on Kirkpatrick's 4-level model. RESULTS: The trainers and exchange professors had positive reactions to the program. All participants felt that their knowledge and skills improved (in their respective fields), although the actual improvement was not extensive, according to their trainers' assessments. The 360-degree feedback demonstrated that the participants actively passed on their experience, knowledge, and skills to their colleagues on returning to work. CONCLUSION: Although a 4-level evaluation was not conducted and despite the limitations in examining academic achievement, interviewing Lao professors, and acquiring quantitative data at Lao University of Health Sciences, this project has demonstrated its value in the development of individual professors and their colleagues. PMID- 25805080 TI - Depressive symptoms in medical students: prevalence and related factors. AB - PURPOSE: This study was designed to estimate the prevalence of depression and the factors that influence it in Korean medical students. METHODS: We evaluated depression in 122 first- and second-year medical students in December 2011 using the Korean Beck Depression Inventory (K-BDI). Sixteen potential factors were considered: gender, class year, grade point average, breakfast habits, residence type, leisure activity, sleep satisfaction, relationship status, a close friend or a significant other, finances, present health status, history of mood disorders, family history of mood disorders, religion, and self-esteem. RESULTS: The average BDI score was 8.9. There were 80 (65.6%), 16 (13.1%), 15 (12.3%), and 11 (9.0%) students with minimal, mild, moderate, and severe depression, respectively. The group with depressive symptoms comprised males with a total BDI score > or =24 and females with total BDI > or =25 and constituted 9.0% of students. Students in the depressive symptom group had lower self-esteem and lower grade point averages and were more frequently ill, less likely to be in a relationship, and more likely to have a history of mood disorders (p<0.05 for all). In particular, low self-esteem score was an independent factor. CONCLUSION: The BDI scores in our study were similar to those that have been reported in other countries but slightly higher than in other Korean medical and university students. Self-esteem, grade point average, health status, history of mood disorders, family history of mood disorders, and presence of a significant other correlated significantly with depression in medical students. PMID- 25805081 TI - The relationship between ego-state and communication skills in medical students. AB - PURPOSE: The purpose of this study was to examine the relationship between ego states and communication skills in medical students. METHODS: A total of 109 medical school students participated in this study, which used the communication skills self-test papers and the Egogram checklist. The data were analyzed by frequency analysis, and Pearson correlation analysis. RESULTS: Ego-state was related to communication skills. In particular, adapted child ego-state was negatively associated with each sphere of communication skills. CONCLUSION: Our results suggested that ego-state types should be considered in developing a communication skills education program for medical students. PMID- 25805083 TI - India plans to improve public health by strengthening primary care. PMID- 25805084 TI - Lower limb alignment control: is it more challenging in lateral compared to medial unicondylar knee arthroplasty? AB - INTRODUCTION: Limb alignment after unicondylar knee arthroplasty (UKA) has a significant impact on outcomes. The literature lacks lateral UKA alignment studies, making our understanding of this issue based on medial UKA. METHODS: We evaluated limb alignment in 241 patients who underwent medial (229 knees) or lateral (37 knees) UKA. Alignment was measured pre and postoperatively in radiographs and intra-operatively using a navigation system. We compared the percentage of over-correction and the difference between post-operative alignment and navigation measurement. RESULTS: Percentage of overcorrection was significantly higher in the lateral UKAs (11%) compared to the medial UKAs (4%). In medial UKAs, the mean difference between the intraoperative alignment and the post-operative was 1.33 degrees . This was significantly lower than the mean 1.86 degrees difference in the lateral UKAs. CONCLUSIONS: Our data demonstrated an increased risk of "overcorrection," and greater difficulty in predicting postoperative alignment using computer navigation, when performing lateral UKAs compared to medial UKAs. PMID- 25805086 TI - Assessing participation in the ACL injured population: Selecting a patient reported outcome measure on the basis of measurement properties. AB - BACKGROUND/AIM: A return to pre injury activity participation remains a common but often elusive goal following ACL injury. Investigations to improve our understanding of participation restrictions are limited by inconsistent use of insufficiently investigated measurement tools. The aim of this study was to follow the consensus based standards for the selection of health measurement instruments (COSMIN) guideline to provide a comparative evaluation of four patient reported outcomes (PROMs) on the basis of measurement properties. This will inform recommendations for measuring participation of ACL injured subjects, particularly in the United Kingdom (UK) National Health Service (NHS). METHODS: Thirteen criteria were compiled from the COSMIN guideline. These included reliability, measurement error, content validity, construct validity, responsiveness and interpretability. Data from 51 subjects collected as part of a longitudinal observational study of recovery over the first year following ACLR was used in the analysis. RESULTS: Of the thirteen criteria, the required standard was met in 11 for Tegner, 11 for International Knee Documentation Committee (IKDC), 6 for Cincinnati Sports Activity Scale (CSAS) and 6 for Marx. The two weaknesses identified for the Tegner are more easily compensated for during interpretation than those in the IKDC; for this reason the Tegner is the recommended PROM. CONCLUSIONS: The Tegner activity rating scale performed consistently well in respect of all measurement properties in this sample, with clear benefits over the other PROMs. The measurement properties presented should be used to inform implementation and interpretation of this outcome measure in clinical practice and research. LEVEL OF EVIDENCE: Level II prospective study. PMID- 25805085 TI - Prospective multi-centre study on a composite ceramic femoral component in total knee arthroplasty: Five-year clinical and radiological outcomes. AB - BACKGROUND: Enhanced wear resistance of ceramics in general and improved mechanical characteristics of composite ceramics in terms of strength and resistance meet the demands for application in TKA. The aim of this prospective international multi-centre study was to evaluate the 5-year clinical and radiological outcomes of an unconstrained TKA with a composite ceramic femoral component. METHODS: A total of 107 patients (109 knees) underwent TKA with the MULTIGEN-PLUS Ceramic Knee at seven centres in three European countries. Clinical and radiological assessments were performed preoperatively and postoperatively at 3, 12, 24 and 60 months, using HSS, WOMAC, SF-36 and standardised radiographs. RESULTS: Mean HSS and WOMAC increased significantly from 55.1+/-11.5 (21-83) and 48.1+/-16.6 (3-90) preoperatively to 85.6+/-9.6 (49-98) and 73.3+/-20.4 (17-100) at 60 months. Mean SF-36 showed significant improvements in patients' quality of life (49.1+/-17.6 (12-96) preoperatively versus 67.7+/-23.1 (12-100) at 60 months). Non-progressive radiolucent lines (<1 mm) were observed around the femoral component in four cases. Neither implant migration nor loosening were registered. Kaplan-Meier survivorship was 96.0% at 60 months (92.1-100%, CI 95%). CONCLUSIONS: Five-year implant survival rate of the ceramic knee is comparable to other metallic and ceramic unconstrained TKA systems. Although the assessment of long-term implant survivorship is still pending, the ceramic implants represent a promising solution for patients with allergies against metallic components and furthermore for the general osteoarthritis population due to enhanced wear resistance. PMID- 25805087 TI - [The PATENT-1 and CHEST-1 studies]. PMID- 25805088 TI - [The HEAT-PPCI study]. PMID- 25805089 TI - [Bypass surgery versus percutaneous coronary intervention: evidence, indications and patient preference according to the latest European guidelines on myocardial revascularization]. PMID- 25805090 TI - [Clinical competence certification for advanced heart failure: an emerging need also in Italy?]. AB - Advanced heart failure (HF) is a deadly condition. Fortunately, an increasing array of effective (but often expensive) therapies has become available. The management of patients with advanced HF is complex and requires a high level of expertise. The American Board of Internal Medicine was the first regulatory board to recognize the need for a subspecialty in Advanced HF and Transplant Cardiology. More recently, the HF Association of the European Society of Cardiology has proposed a curriculum for HF specialists that includes the optional module of advanced HF therapy. However, the successful completion of such a curriculum does not result in a European Certification in Heart Failure, because no European Board of Medicine does exist. While in some European countries the secondary specialty of HF has been implemented, no country has a subspecialty in advanced HF. The ANMCO HF Area has proposed a survey to 25 Italian centers with accredited programs for heart transplant or ventricular assist device implant as destination therapy with the aim to assess the actual need of a certification of clinical competence in advanced HF and a certification of institutional competence for the centers with the highest expertise in advanced HF management. The survey indicated that there is a perceived need. A first step towards education of advanced HF specialists could be the implementation of CME courses by Scientific Societies. As regards certification of institutional competence for the centers with the highest expertise in advanced HF management, the government appears to be the only entity that can grant it. PMID- 25805091 TI - [The Italian pathway to the acknowledgment of clinical competence for the management of patients with advanced heart failure and cardiac transplantation]. PMID- 25805092 TI - [Eligibility to competitive and non-competitive sports activity in Cardiology]. AB - Subjects with heart diseases at risk of sudden death may be free from symptoms and be able to perform high-level sports activities. Preparticipation screening helps to detect these diseases, reducing the risk of sudden death in athletes. Fortunately, sudden death in athletes is a rare event (1-2/100 000 in subjects aged <35 years). As a consequence, it is not clear whether extensive preparticipation screening is cost-effective. In Italy pre-participation screening is mandatory for both agonistic and nonagonistic sports, whereas in the United States it is not requested. In addition, many US authors suggest that compulsory medicine visits are in conflict with the freedom of any people to self determine its own destiny. In the presence of heart disease, international guidelines exist that provide recommendations for sports eligibility. Although all of them are similar, US guidelines are more permissive. Guidelines are not laws. However, in case of legal disputes, they are taken into account and, hence, it is a good rule to know and follow them. PMID- 25805093 TI - [Transposition of the great arteries]. AB - Dextro-transposition of the great arteries with intact ventricular septum (d-TGA) is the most frequent cyanotic congenital heart disease in neonates. In newborns affected by d-TGA, the pulmonary and systemic circulations are in parallel instead of being in series. The survival of babies affected by d-TGA is related to the level of mixing at the patent foramen ovale. The diagnosis of d-TGA is an indication for treatment due to scarce survival beyond the neonatal period if not corrected. The current surgical approach is the anatomical correction with the arterial switch operation, which has excellent early and medium-term results. In this review, we discuss treatment of d-TGA and the arterial switch operation, the medium- and long-term results following surgery, and the reasons that have led the arterial switch operation to its popularity compared to the former physiological correction of d-TGA, i.e. the Senning and Mustard procedures. PMID- 25805094 TI - [New Technologies in coronary interventional cardiology: results from the first inter-regional survey promoted by SICI-GISE in four regions of northern Italy ("the GISE TOLOVE" area: Tuscany, Lombardy, Veneto, Emilia-Romagna)]. AB - BACKGROUND: The implementation of the latest medical innovations can vary widely within the same geographic area. This study aimed to describe the current status of recent innovations in the field of coronary interventional cardiology in 4 regions of Northern Italy. METHODS: From April to May 2014, 4 regional delegations of the Italian Society of Invasive Cardiology (SICI-GISE) have promoted a multicenter survey. By means of a web-based methodology, a focused questionnaire was administered to head physicians of 97 cath-labs in 4 Italian regions within the "GISE TOLOVE" area (Lombardy, Veneto, Tuscany, Emilia Romagna). RESULTS: Pharmacological and technological innovations in coronary interventional cardiology appear to be widely used in the area covered by this survey, with uniformity in application and availability of therapeutic devices and drugs within the 4 regions involved. The main limiting factors to the adoption of new technologies and drugs were economic factors or lack of scientific evidence for some specific devices or drugs. CONCLUSIONS: This survey showed widespread and consistent application of the main latest innovations in coronary interventional cardiology across 4 Italian regions of Northern Italy. PMID- 25805095 TI - [Successful double retrograde approach for recanalization of double total chronic occlusions]. AB - Chronic total occlusions (CTO) still remain one of the most technically challenging scenarios in which interventions are performed. Although the antegrade approach is the most common method of CTO recanalization, management of CTOs has recently been refined through the development of a retrograde approach that offers an additional possibility of success after antegrade failure. Knowledge of the different devices and techniques along with awareness of the possible complications could result in the practical implementation of these techniques with high procedural success and low complication rates. We present a case of successful percutaneous coronary intervention of double CTOs in the left anterior descending artery, which were successfully recanalized step by step using two different retrograde approaches. PMID- 25805096 TI - [Two catheters for one coronary perforation]. AB - Coronary perforation is a severe complication of percutaneous coronary intervention (PCI) with high mortality and morbidity. The incidence of coronary perforation in patients undergoing PCI ranges from 0.1% to 0.5%. The use of long balloon inflation and reversal anticoagulation is associated with high mortality, periprocedural myocardial infarction and emergency coronary bypass surgery. We present a case of severe coronary perforation treated with the dual catheter technique through the radial and femoral approach. The dual catheter technique enabled rapid delivery of a covered stent without losing control of the perforation site. Our patient did not show pericardial effusion, hemodynamic instability or need for emergency bypass surgery. About 1h after PCI, he developed acute stent thrombosis treated with thromboaspiration and biolimus eluting stent implantation. At 2 years of follow-up, he was asymptomatic without evidence of exercise-induced ischemia. We conclude that the dual catheter technique is a safe and effective approach to treat PCI-induced severe coronary perforation, and may significantly improve patient outcome compared to historical series. PMID- 25805097 TI - [Position paper on the theoretical basis, practical application and health economic evaluation of the functional assessment of coronary lesions endorsed by the Italian Society of Invasive Cardiology (SICI-GISE)]. AB - Functional assessment of coronary lesions has become an integral part of routine practice in most cath labs. Such evaluation is performed using a pressure wire that allows measurement of fractional flow reserve (FFR). The latter has received a class I indication with level of evidence A according to the most recent European guidelines on myocardial revascularization for the assessment of angiographically moderate coronary lesions. The present document has the following objectives: 1) to summarize the theoretical basis of FFR; 2) to provide a guideline for vasodilator therapy; 3) to summarize scientific evidence supporting FFR; 4) to provide a model of health economy evaluation focusing on resource sparing associated with the use of FFR. PMID- 25805099 TI - Intralesional 5-fluorouracil in keloid treatment: a systematic review. AB - In the 1990s, 5-flourouracil (5-FU) was introduced as a treatment for keloids; however, there is still no consensus on its use. In order to guide clinical practice, a systematic review of the clinical evidence on the effectiveness of 5 FU in keloid treatment was carried out. Eight databases were searched on 10 September 2014 using the terms "keloid" and "5-FU", together with all synonyms of these terms. Two reviewers selected original research reports using 5-FU alone or combined with a maximum of 2 other therapies. Eighteen papers were found that reported either on intralesional 5-FU alone, or on 5-FU combined with triamcinolone acetonide (TAC:5-FU) or excision, including 482 patients. 5-FU treatment was effective in 45-96% of patients, but only TAC:5-FU may perform better than TAC alone. Due to a poor level of evidence, further research should establish the superiority of repeated intralesional TAC:5-FU injections over TAC alone with several doses and injection schedules. PMID- 25805100 TI - Ambulance use in acute coronary syndrome in Ireland: A cross-sectional study. AB - BACKGROUND: As myocardial salvage is time dependent, prompt emergency department attendance is imperative in the presence of unresolved acute coronary syndrome symptoms. Although ambulance use is the recommended mode of transport during an acute coronary syndrome event, people regularly have misperceptions about its role. Consequently, many fail to use this service when warranted. AIM: To evaluate factors associated with ambulance usage among patients admitted to emergency departments with acute coronary syndrome symptoms in Ireland. METHODS: Patients (N=1947) diagnosed with acute coronary syndrome were recruited across five hospitals. The ACS Response Index was used to identify mode of transport to access the emergency department, symptom context and experience and the rationale for non-ambulance use. Using logistic regression, predictors of ambulance use were identified. RESULTS: Only 40.1% of the sample used an ambulance. The primary reason for non-ambulance use was the perception that it was unwarranted (31%). A further 23.8% thought another mode of transportation would be faster. Independent predictors of ambulance usage differed among the three sub-diagnoses of acute coronary syndrome. For each group, visiting the general practitioner with symptoms was associated with a greater likelihood of not using an ambulance. CONCLUSION: The use of ambulance services is not positively embraced by the public. Furthermore, it appears that general practitioners may not always promote its use, particularly in the early stages of acute coronary syndrome symptom onset. The findings from our study suggest that a public education drive is necessary to promote ambulance usage during an acute coronary syndrome event. PMID- 25805101 TI - Structural social capital and health in Italy. AB - This paper presents the first empirical assessment of the causal relationship between social capital and health in Italy. The analysis draws on the 2000 wave of the Multipurpose Survey on Household conducted by the Italian Institute of Statistics on a representative sample of the population (n=46,868). Our measure of social capital is the frequency of meetings with friends. Based on IV and bivariate probit estimates, we find that individuals who meet friends every day or more time times a week are approximately 11-16% more likely to report good health. PMID- 25805102 TI - Raman micro-spectroscopy for rapid screening of oral squamous cell carcinoma. AB - Raman spectroscopy can provide a molecular-level fingerprint of the biochemical composition and structure of cells with excellent spatial resolution and could be useful to monitor changes in composition for dysplasia and early, non-invasive cancer diagnosis (carcinoma in situ), both ex-vivo and in vivo. In this study, we demonstrate this potential by collecting Raman spectra of the nucleoli, nuclei and cytoplasm from oral epithelial cancer (SCC-4) and dysplastic (pre-cancerous, DOK) cell lines and from normal oral epithelial primary cell cultures, in vitro, which were then analysed by principal component analysis (PCA) as a multivariate statistical method to discriminate the spectra. Results show significant discrimination between cancer and normal cell lines. Furthermore, the dysplastic and cancer cell lines could be discriminated based on the spectral profiles of the cytoplasmic regions. The principal component loading plot, which elucidates the biochemical features responsible for the discrimination, showed significant contributions of nucleic acid and proteins for nucleolar and nuclear sites and variation in features of lipids for the cytoplasmic area. This technique may provide a rapid screening method and have potential use in the diagnosis of dysplasia and early, non-invasive oral cancer, the treatment of which involves much less extensive and complex surgery and a reduction in associated co morbidity for the patient. PMID- 25805103 TI - Identification of dysfunctional biological pathways and their synergistic mechanism in hepatocellular carcinoma process. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a lethal and prevalent cancer worldwide. This study was conducted to investigate dysfunctional pathways and their synergistic mechanism in the HCC process. METHODS: We downloaded transcriptome profiling data (GSE25097) from the Gene Expression Omnibus (GEO) database, including 6 healthy liver samples, 40 cirrhosis samples, 243 adjacent non-tumor samples, and 268 HCC samples. Robust Multi-Array (RMA) in R software was employed to preprocess the downloaded dataset, and Student's t-test (FDR less than 0.001) was performed to identify the differentially expressed genes (DEGs) between 4 sample groups. Then, pathway enrichment analysis (FDR less than 0.05) based on iSubpathwayMiner was performed. Furthermore, we performed collaborative analysis on these pathways through calculating the Jaccard index, and crosstalk networks were constructed and visualized by Cytoscape. RESULTS: Totally, 4617, 9517, and 12,479 DEGs were identified between healthy liver and cirrhosis samples, cirrhosis and adjacent non-tumor samples, and adjacent non-tumor and HCC samples, respectively. Furthermore, a total of 26 crosstalks involving 13 pathways, 78 crosstalks involving 54 pathways, and 86 crosstalks involving 52 pathways were identified through the DEGs between healthy liver and cirrhosis samples, cirrhosis and adjacent non-tumor samples, and adjacent non-tumor and HCC samples, respectively. Moreover, 5 dysfunctional pathways were found to co-exist in the three processes of HCC. Among them, 3 dysfunctional pathways have collaborative relationship, including Staphylococcus aureus infection, leishmaniasis, and Chagas disease. CONCLUSIONS: In this study, dysfunctional pathways in the HCC process and crosstalks between these pathways were investigated for the first time, providing new insight into the potential mechanisms of HCC. PMID- 25805104 TI - Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. AB - Genes associated with protein folding have been found to have certain prognostic significance in a subset of cancers. The aim of this study is to evaluate the clinical impact of DNAJC12 expression in patients with rectal cancers receiving neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Through data mining from a public transcriptomic dataset of rectal cancer focusing on genes associated with protein folding, we found that DNAJC12, a member of the HSP40/DNAJ family, was the most significant such gene correlated with the CCRT response. We further evaluated the expression of DNAJC12 by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancers. From this set, we statistically analyzed the association of DNAJC12 expression with various clinicopathological factors, tumor regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of DNAJC12 was significantly associated with advanced pre- and post treatment tumor status (P<0.001), advanced pre- and post-treatment nodal status (P<0.001), increased vascular invasion (P=0.015), increased perineural invasion (P=0.023) and lower tumor regression grade (P=0.009). More importantly, high expression of DNAJC12 was found to be correlated with poor prognosis for OS (P=0.0012), DFS (P<0.0001) and LRFS (P=0.0001). In multivariate analysis, DNAJC12 overexpression still emerged as an independent prognosticator for shorter OS (P=0.040), DFS (P<0.001) and LRFS (P=0.016). The data indicate that DNAJC12 overexpression acts as a negative predictive factor for the response to neoadjuvant CCRT and was significantly associated with shorter survival in patients with rectal cancers receiving neoadjuvant CCRT followed by surgery. PMID- 25805105 TI - Urinary stone composition in Oman: with high incidence of cystinuria. AB - Urinary stones are a common problem in Oman and their composition is unknown. The aim of this study is to analyze the components of urinary stones of Omani patients and use the obtained data for future studies of etiology, treatment, and prevention. Urinary stones of 255 consecutive patients were collected at the Sultan Qaboos University Hospital. Stones were analyzed by Fourier transform infrared spectrophotometer. The biochemical, metabolic, and radiological data relating to the patients and stones were collected. The mean age was 41 years, with M:F ratio of 3.7:1. The common comorbidities associated with stone formation were hypertension; diabetes, benign prostate hyperplasia; urinary tract infection; obesity; and atrophic kidney. The common presentation was renal colic and flank pain (96%). Stones were surgically retrieved in 70% of patients. Mean stone size was 9 +/- 0.5 mm (range 1.3-80). Stone formers had a BMI >= 25 in 56% (P = 0.006) and positive family history of stones in 3.8%. The most common stones in Oman were as follows: Calcium Oxalates 45% (114/255); Mixed calcium phosphates & calcium oxalates 22% (55/255); Uric Acid 16% (40/255); and Cystine 4% (10/255). The most common urinary stones in Oman are Calcium Oxalates. Overweight is an important risk factor associated with stone formation. The hereditary Cystine stones are three times more common in Oman than what is reported in the literature that needs further genetic studies. PMID- 25805106 TI - Synthetic bone mimetic matrix-mediated in situ bone tissue formation through host cell recruitment. AB - Advances in tissue engineering have offered new opportunities to restore anatomically and functionally compromised tissues. Although traditional tissue engineering approaches that utilize biomaterials and cells to create tissue constructs for implantation or biomaterials as a scaffold to deliver cells are promising, strategies that can activate endogenous cells to promote tissue repair are more clinically attractive. Here, we demonstrate that an engineered injectable matrix mimicking a calcium phosphate (CaP)-rich bone-specific microenvironment can recruit endogenous cells to form bone tissues in vivo. Comparison of matrix alone with that of bone marrow-soaked or bFGF-soaked matrix demonstrates similar extent of neo-bone formation and bridging of decorticated transverse processes in a posterolateral lumbar fusion rat model. Synthetic biomaterials that stimulate endogenous cells without the need for biologics to assist tissue repair could circumvent limitations associated with conventional tissue engineering approaches, including ex vivo cell processing and laborious efforts, thereby accelerating the translational aspects of regenerative medicine. PMID- 25805108 TI - Mesenchymal stromal cell implantation for stimulation of long bone healing aggravates Staphylococcus aureus induced osteomyelitis. AB - Large bone defects requiring long-term osteosynthetic stabilization or repeated surgeries show a considerable rate of infection. Mesenchymal stromal cells (MSCs) have been successfully used to enhance bone regeneration, but their powerful immunomodulatory effects may impose an enhanced risk for osteomyelitis development. In order to unravel whether implantation of MSCs aggravates a simultaneous bone infection, a hydrogel-supported osteomyelitis ostectomy model was developed in which rats received a femoral bone defect with rigid plate fixation. After fibrin-assisted transfer of Staphylococcus aureus (SA), effects of MSC implantation on osteomyelitis development were quantified over 3-4 weeks. All SA-infected animals developed an acute local osteomyelitis with significantly increased blood neutrophil count, abscess formation and bone destruction. MSC treatment of infected defects aggravated osteomyelitis according to a significantly elevated osteomyelitis score and enhanced distal bone loss with spongy alteration of cortical bone architecture. Increased attraction of macrophages, osteoclasts and regulation of pro- and anti-inflammatory mediators were potential MSC actions. Overall trophic actions of MSCs implanted into non sterile bone defects may enhance an infection and/or exacerbate osteomyelitis. Studies on antibiotic carrier augmentation or antibiotic treatment are warranted to decide whether MSC implantation is a safe and promising therapy for orthopedic implant-stabilized bone defects at high risk for development of infection. PMID- 25805109 TI - Combinational effect of matrix elasticity and alendronate density on differentiation of rat mesenchymal stem cells. AB - Differentiation of mesenchymal stem cells (MSCs) is regulated by multivariate physical and chemical signals in a complicated microenvironment. In this study, polymerizable double bonds (GelMA) and osteo-inductive alendronate (Aln) (Aln GelMA) were sequentially grafted onto gelatin molecules. The biocompatible hydrogels with defined stiffness in the range of 4-40 kPa were prepared by using polyethylene glycol diacrylate (PEGDA) as additional crosslinker. The Aln density was adjusted from 0 to 4 MUM by controlling the ratio between the GelMA and Aln GelMA. The combinational effects of stiffness and Aln density on osteogenic differentiation of MSCs were then studied in terms of ALP activity, collagen type I and osteocalcin expression, and calcium deposition. The results indicated that the stiffness and Aln density could synergistically improve the expression of all these osteogenesis markers. Their osteo-inductive effects are comparable to some extent, and high Aln density could be more effective than the stiffness. PMID- 25805107 TI - The role of organic proteins on the crack growth resistance of human enamel. AB - With only 1% protein by weight, tooth enamel is the most highly mineralized tissue in mammals. The focus of this study was to evaluate contributions of the proteins on the fracture resistance of this unique structural material. Sections of enamel were obtained from the cusps of human molars and the crack growth resistance was quantified using a conventional fracture mechanics approach with complementary finite element analysis. In selected specimens the proteins were extracted using a potassium hydroxide treatment. Removal of the proteins resulted in approximately 40% decrease in the fracture toughness with respect to the fully proteinized control. The loss of organic content was most detrimental to the extrinsic toughening mechanisms, causing over 80% reduction in their contribution to the total energy to fracture. This degradation occurred by embrittlement of the unbroken bridging ligaments and consequent reduction in the crack closure stress. Although the organic content of tooth enamel is very small, it is essential to crack growth toughening by facilitating the formation of unbroken ligaments and in fortifying their potency. Replicating functions of the organic content will be critical to the successful development of bio-inspired materials that are designed for fracture resistance. PMID- 25805110 TI - A Novel Cause of Free Intraperitoneal Air in the Emergency Department. AB - Although all emergency physicians are familiar with catastrophic causes of free intraperitoneal air, we describe the case of a healthy 26-year-old woman who presented to our emergency department (ED) with a nonsurgical and previously unreported cause of pneumoperitoneum. The patient presented to our ED with complaints of shoulder and neck pain several hours after having undergone FemVue ultrasonography (Femasys, Suwanee, GA) for infertility evaluation. The technique uses an air and saline solution mixture injected into the uterine cavity to assess for tubal patency and uterine cavity morphology. Although the cause of her free air and pain was determined to be iatrogenic and ultimately benign, this complication is previously unreported and, without complaints of abdominal pain, presented a diagnostic challenge. PMID- 25805111 TI - A Systematic Review and Meta-analysis of D-dimer as a Rule-out Test for Suspected Acute Aortic Dissection. AB - STUDY OBJECTIVE: The aim of this systematic review and meta-analysis is to determine the diagnostic accuracy of D-dimer as a rule-out test for acute aortic dissection. Previous meta-analyses have had methodological problems with conflicting conclusions, and new diagnostic accuracy studies have been published since. METHODS: All prospective cross-sectional analytic studies of D-dimer as a diagnostic test for acute aortic dissection were included where diagnosis was confirmed by an accepted reference standard. Studies were identified with MEDLINE, EMBASE, Medion, Google Scholar, Web of Science, and bibliographies of relevant articles and previous systematic reviews. Two reviewers independently screened articles for inclusion, assessed study quality, and extracted data. RESULTS: Abstracts from 800 articles were reviewed, yielding 30 potentially relevant studies that were reviewed in full text. Five studies met all eligibility criteria. Data from 4 studies (1,557 participants) that used a D dimer cutoff of 0.50 MUg/mL were pooled to estimate sensitivity, specificity, and positive and negative likelihood ratios. Overall, sensitivity and negative likelihood ratio were 98.0% (95% confidence interval [CI] 96.3% to 99.1%) and 0.05 (95% CI 0.03 to 0.09), respectively. These measurements had little statistical heterogeneity. Specificity (41.9%; 95% CI 39.0% to 44.9%) and positive likelihood ratio (2.11; 95% CI 1.46 to 3.05) showed significant statistical heterogeneity. When applied to a low-risk population as defined by the American Heart Association (prevalence 6%), the posttest probability for acute aortic dissection was 0.3%. CONCLUSION: This meta-analysis suggests that a negative D-dimer result may be useful to help rule out acute aortic dissection in low-risk patients. PMID- 25805112 TI - Are Balanced Crystalloids the Preferred Resuscitation Fluid for Severe Sepsis and Septic Shock? PMID- 25805113 TI - Does Clopidogrel Plus Aspirin Dual Therapy Reduce Risk of Stroke in Patients at High Risk for Stroke? PMID- 25805114 TI - Treating Gastritis, Peptic Ulcer Disease, and Dyspepsia in the Emergency Department: The Feasibility and Patient-Reported Outcomes of Testing and Treating for Helicobacter pylori Infection. AB - STUDY OBJECTIVE: Helicobacter pylori infection is a known cause of gastritis, dyspepsia, and peptic ulcer disease. Testing for infection is indicated in high prevalence outpatient settings. The objective of this prospective cohort study is to examine the feasibility of a test-and-treat strategy in the emergency department (ED) setting. METHODS: During a 13-month period at an academic ED, symptomatic patients underwent a point-of-care urea breath test (BreathID; Exalenz Bioscience Inc., Modiin, Israel) during the ED visit. Research assistants abstracted treatment information from the electronic medical record. Patients who tested positive were prescribed triple-therapy medication. All enrollees were telephoned 2 weeks after the index ED visit to ascertain symptom resolution and treatment compliance. H pylori-positive subjects were asked to return to the ED for retest. Risk differences in patient and clinical characteristics were compared by H pylori infection status, and a paired t test was used to estimate differences in pain resolution at the ED visit and follow-up. RESULTS: Of the 465 symptomatic patients, 271 were eligible and 212 enrolled and were tested for H pylori. Forty-nine patients (23%) (95% confidence interval [CI] 18% to 30%) had a positive result, 33 of 49 (67%) (95% CI 53% to 79%) self-reported receiving the medication as prescribed at follow-up, 23 of 49 (47%) (95% CI 34% to 61%) were retested, and 20 of 49 (41%) (95% CI 28% to 55%) had a negative result. There was a significant reduction in pain severity, regardless of H pylori infection status. CONCLUSION: A test-and-treat strategy is feasible in the ED setting and could benefit symptomatic patients. PMID- 25805115 TI - Can Transtracheal Ultrasonography Be Used to Verify Endotracheal Tube Placement? PMID- 25805116 TI - Communication of Vital Signs at Emergency Department Handoff: Opportunities for Improvement. AB - STUDY OBJECTIVE: We describe the prevalence of vital sign communication errors during emergency department (ED) handoffs. Our secondary objective is to evaluate the association between handoff behaviors and ED crowding on vital sign handoff errors. METHODS: This was a prospective observational study of ED handoffs conducted at an urban academic hospital. We observed a prespecified convenience sample of ED shift rounds and included all patients whose care was subject to a handoff during ED shift change. The primary outcome was vital sign communication errors, defined as the failure to communicate an episode of medical-record documented hypotension or hypoxia during ED shift rounds. Trained research assistants used a standardized data collection tool to collect data through direct observation and electronic health record abstraction. We report descriptive statistics and results of a logistic regression model constructed with generalized estimating equations to describe the association between handoff and rounds-level characteristics and handoff errors. RESULTS: We observed 1,163 patient handoffs during 130 ED shift rounds. Of 117 patients with episodes of hypotension and 156 patients with hypoxia, 66 (42%) and 116 (74%) were not communicated at rounds, respectively. One hundred sixty-six handoffs (14%) included a vital sign communication error of omission. In multivariate analysis, no handoff or rounds characteristic, including the ED occupancy rate, was associated with omission errors of vital sign communication. CONCLUSION: Providers omitted communication of patient hypotension or hypoxia in nearly 1 in 7 ED handoffs. These communication errors do not appear to be related to ED crowding or care interruptions. PMID- 25805117 TI - Vibrational models for a crystal with 36 water molecules in the unit cell: IR spectra from experiment and calculation. AB - We present experimental and calculated IR spectra of the water molecules in crystalline aluminium nitrate nonahydrate and a method to generate a realistic and well resolved isotope-isolated spectrum from periodic DFT calculations. Our sample crystal contains 18 structurally different OH groups and is a perfect benchmark compound to validate vibrational models and the structure-property relationship of bound water molecules. FTIR spectra (ATR technique) were recorded for the Al(NO3)3.9H2O crystal at 138 and 298 K, and due to a multitude of OH contributions and couplings, they are naturally poorly resolved and yield a broad OH band in the range 3500 to 2700 cm(-1) at both temperatures. Isotope-isolated IR spectra have the clear advantage over non-deuterated spectra that they are better resolved and easier to interpret - here we have extended the experimental study by simulating the isotope-isolated IR spectrum, using PBE-D2 and auxiliary B3LYP calculations and an anharmonic OH vibrational model. We find excellent agreement between the shapes and frequency ranges of the experimental and calculated OH spectral bands. We make use of four different vibrational models: (i) a harmonic lattice-dynamical model for the isotope-isolated crystal with 1 H among 71 D, (ii) a harmonic lattice-dynamical model for the normal undeuterated crystal involving all the vibrational couplings, (iii) a harmonic 1-dimensional uncoupled OH vibrational model, and (iv) the anharmonic variant of the previous model, which yields the final spectrum. We also use the individual frequencies, resolved by the calculations, to quantify new or extended relationships involving OH frequencies versus local electric fields and H-bond distances. We explore the correlation between OH frequency and molecular dipole moment for bound water molecules. PMID- 25805119 TI - Influence of electric potentials on friction of sliding contacts lubricated by an ionic liquid. AB - Tribological investigations on the macroscopic scale revealed that friction can be influenced in situ by applying electric potentials, if electrically conductive fluid such as an ionic liquid is used as a lubricant. Enrichment of charged ions at a steel interface occurs by applying electric surface potentials in a three electrode setup. As a consequence, the lubrication conditions change. It is supposed that electrically influenced surface adsorption and electrokinetic effects are the main mechanisms by which friction is varied. PMID- 25805118 TI - Psychological treatments for early psychosis can be beneficial or harmful, depending on the therapeutic alliance: an instrumental variable analysis. AB - BACKGROUND: The quality of the therapeutic alliance (TA) has been invoked to explain the equal effectiveness of different psychotherapies, but prior research is correlational, and does not address the possibility that individuals who form good alliances may have good outcomes without therapy. METHOD: We evaluated the causal effect of TA using instrumental variable (structural equation) modelling on data from a three-arm, randomized controlled trial of 308 people in an acute first or second episode of a non-affective psychosis. The trial compared cognitive behavioural therapy (CBT) over 6 weeks plus routine care (RC) v. supportive counselling (SC) plus RC v. RC alone. We examined the effect of TA, as measured by the client-rated CALPAS, on the primary trial 18-month outcome of symptom severity (PANSS), which was assessed blind to treatment allocation. RESULTS: Both adjunctive CBT and SC improved 18-month outcomes, compared to RC. We showed that, for both psychological treatments, improving TA improves symptomatic outcome. With a good TA, attending more sessions causes a significantly better outcome on PANSS total score [effect size -2.91, 95% confidence interval (CI) -0.90 to -4.91]. With a poor TA, attending more sessions is detrimental (effect size +7.74, 95% CI +1.03 to +14.45). CONCLUSIONS: This is the first ever demonstration that TA has a causal effect on symptomatic outcome of a psychological treatment, and that poor TA is actively detrimental. These effects may extend to other therapeutic modalities and disorders. PMID- 25805120 TI - Polymer composite electrolytes having core-shell silica fillers with anion trapping boron moiety in the shell layer for all-solid-state lithium-ion batteries. AB - Core-shell silica particles with ion-conducting poly(ethylene glycol) and anion trapping boron moiety in the shell layer were prepared to be used as fillers for polymer composite electrolytes based on organic/inorganic hybrid branched copolymer as polymer matrix for all-solid-state lithium-ion battery applications. The core-shell silica particles were found to improve mechanical strength and thermal stability of the polymer matrix and poly(ethylene glycol) and boron moiety in the shell layer increase compatibility between filler and polymer matrix. Furthermore, boron moiety in the shell layer increases both ionic conductivity and lithium transference number of the polymer matrix because lithium salt can be more easily dissociated by the anion-trapping boron. Interfacial compatibility with lithium metal anode is also improved because well dispersed silica particles serve as protective layer against interfacial side reactions. As a result, all-solid-state battery performance was found to be enhanced when the copolymer having core-shell silica particles with the boron moiety was used as solid polymer electrolyte. PMID- 25805121 TI - Comparative biology of the pentraxin protein family: evolutionarily conserved component of innate immune system. AB - The immune system is based on the actions of the collection of specialized immune defense cells and their secreted proteins and peptides that defend the host against infection by parasites. Parasites are organisms that live part or all of their lives in close physical association with the host and extract nutrients from the host and, by releasing toxins and virulence factors, cause disease with the potential for injury and premature death of that host. Parasites of the metazoa can be viruses, eubacteria, fungi, protozoans, and other metazoans. The immune system operates to kill or eliminate parasites and eliminate or detoxify their toxins and virulence factors. Although some of the elements of immune systems are specific to a particular phylum of metazoans, others show extensive evolutionary conservation, being present in several or all major phyla of the metazoa. The pentraxins display this latter character in their roles in immune defense. Pentraxins have been documented in vertebrates, nonvertebrate chordates, arthropods, and mollusks and may be present in other taxa of metazoans. Presumably the pentraxins appeared early in the evolution of metazoa, prior to their evolutionary divergence in the Precambrian epoch into many phyla present today, and have been preserved for the 542 million years since that explosive evolutionary radiation. The fidelity with which these phyla have preserved the pentraxins suggests that the functions of these proteins are important for survival of the members of these diverse taxa of animals. PMID- 25805122 TI - New insights into the role of ficolins in the lectin pathway of innate immunity. AB - In the innate immune system, a variety of recognition molecules provide the first line host defense to prevent infection and maintain endogenous homeostasis. Ficolin is a soluble recognition molecule, which senses pathogen-associated molecular patterns on microbes and aberrant sugar structures on self-cells. It consists of a collagen-like stalk and a globular fibrinogen-like domain, the latter binding to carbohydrates such as N-acetylglucosamine. Ficolins have been widely identified in animals from higher invertebrates to mammals. In mammals, ficolins form complexes with mannose-binding lectin-associated serine proteases (MASPs), and ficolin-MASP complexes trigger complement activation via the lectin pathway. Once activated, complement mediates many immune responses including opsonization, phagocytosis, and cytokine production. Although the precise function of each ficolin is still under investigation, accumulating information suggests that ficolins have a crucial role in host defense by recognizing a variety of microorganisms and interacting with effector proteins. PMID- 25805123 TI - Leguminous plants: inventors of root nodules to accommodate symbiotic bacteria. AB - Legumes and a few other plant species can establish a symbiotic relationship with nitrogen-fixing rhizobia, which enables them to survive in a nitrogen-deficient environment. During the course of nodulation, infection with rhizobia induces the dedifferentiation of host cells to form primordia of a symbiotic organ, the nodule, which prepares plants to accommodate rhizobia in host cells. While these nodulation processes are known to be genetically controlled by both plants and rhizobia, recent advances in studies on two model legumes, Lotus japonicus and Medicago truncatula, have provided great insight into the underlying plant-side molecular mechanism. In this chapter, we review such knowledge, with particular emphasis on two key processes of nodulation, nodule development and rhizobial invasion. PMID- 25805124 TI - New insights into the mechanisms of mammalian erythroid chromatin condensation and enucleation. AB - A unique feature in mammalian erythropoiesis is the dramatic chromatin condensation followed by enucleation. This step-by-step process starts at the beginning of terminal erythropoiesis after the hematopoietic stem cells are committed to erythroid lineage. Although this phenomenon is known for decades, the mechanisms of chromatin condensation and enucleation remain elusive. Recent advances in cell and molecular biology have started to reveal the molecular pathways in the regulation of chromatin condensation, the establishment of nuclear polarity prior enucleation, and the rearrangement of actin cytoskeleton in enucleation. However, many challenging questions, especially whether and how the apoptotic mechanisms are involved in chromatin condensation and how to dissect the functions of many actin cytoskeleton proteins in cytokinesis and enucleation, remain to be answered. Here I review our current understanding of mammalian erythroid chromatin condensation and enucleation during terminal differentiation with a focus on more recent studies. I conclude with my perspective of future works in this rising topic in developmental and cell biology. PMID- 25805125 TI - Store-operated calcium entry: unveiling the calcium handling signalplex. AB - Store-operated Ca(2+) entry (SOCE) is an important mechanism for Ca(2+) influx in non-excitable cells, also present in excitable cells. The activation of store operated channels (SOCs) is finely regulated by the filling state of the intracellular agonist-sensitive Ca(2+) compartments, and both, the mechanism of sensing the Ca(2+) stores and the nature and functional properties of the SOCs, have been a matter of intense investigation and debate. The identification of STIM1 as the endoplasmic reticulum Ca(2+) sensor and both Orai1, as the pore forming subunit of the channels mediating the Ca(2+)-selective store-operated current, and the members of the TRPC subfamily of proteins, as the channels mediating the cation-permeable SOCs, has shed new light on the underlying events. This review summarizes the initial hypothesis and the current advances on the mechanism of activation of SOCE. PMID- 25805127 TI - Molecular, cellular, and physiological significance of N-terminal acetylation. AB - Protein N-terminal acetylation is catalyzed by N-terminal acetyltransferases and represents one of the most common protein modifications in eukaryotes. An increasing number of studies report on the importance of N-terminal acetylation for protein degradation, complex formation, subcellular targeting, and protein folding. N-terminal acetyltransferases are recognized to play important roles in a diversity of cellular processes like apoptosis, cell proliferation, sister chromatid cohesion, and chromatin silencing and are even linked to the development of rare genetic disorders and cancer. This article summarizes our current knowledge on the implications of N-terminal acetylation at the protein, cellular, and physiological levels. PMID- 25805128 TI - The role of early pharmacotherapy in the development of posttraumatic stress disorder symptoms after traumatic injury: an observational cohort study in consecutive patients. AB - OBJECTIVE: Pharmacological intervention during traumatic memory consolidation has been suggested to prevent posttraumatic stress disorder (PTSD). The aim of this study was to examine the association between prescription of early pharmacotherapy and the risk of developing PTSD symptoms following traumatic injury. METHOD: The use of opiate analgesics, beta-adrenergic blockers, corticosteroids and benzodiazepines within 48 h postinjury was documented based on hospital charts for 629 Level 1 trauma center patients. PTSD symptoms were assessed using structured clinical interviews. Primary outcome was 6-week PTSD symptoms. Secondary outcomes were PTSD diagnoses at 6 weeks and during 1 year posttrauma. RESULTS: Linear regression analyses showed that opiate administration within 48 h was negatively associated with PTSD symptoms at 6 weeks (beta=-0.14, P=.009) after controlling for demographic and injury-related characteristics and concurrent pharmacotherapy. Fewer patients with opiates had a PTSD diagnosis at 6 weeks (P=.047) and during 1 year posttrauma (P=.013) than patients with none of the specified pharmacotherapies. Low prescription frequency of beta-blockers (3.8%), corticosteroids (2.2%) and benzodiazepines (7.8%) precluded further examination of their role in the development of PTSD symptoms because of limited statistical power. CONCLUSIONS: This study suggests a possible beneficial influence of opiate administration within 48 h posttrauma on the development of PTSD symptoms. Future studies may evaluate the effectiveness of inhospital opiate analgesics compared to placebo in preventing PTSD and may focus on the mechanisms underlying the effect of opiates in preventing PTSD. PMID- 25805129 TI - Fatty acid metabolism meets organelle dynamics. AB - Upon nutrient deprivation, cells metabolize fatty acids (FAs) in mitochondria to supply energy, but how FAs, stored as triacylglycerols in lipid droplets, reach mitochondria has been mysterious. Rambold et al. (2015) now show that FA mobilization depends on triacylglycerol lipolysis, whereas autophagy feeds the lipid droplet pool for continued fueling of mitochondria. PMID- 25805130 TI - Proteostatic hotspots in amyloid fibrils protect us from neurodegeneration. AB - Alzheimer's disease remains a formidable challenge for therapeutic management. In a recent report in Nature Structural and Molecular Biology, Cohen et al. (2015) present intriguing results showing that "designer" molecular chaperones may hold the key to an evolutionarily conserved program for management of toxic oligomer species contributing to brain pathobiology. PMID- 25805131 TI - Dynamic networking for epidermal differentiation. AB - In this issue of Developmental Cell, Lopez-Pajares et al. (2015) identify regulatory networks that are controlled by the transcriptional regulators MAF:MAFB. These networks play a crucial and previously unrecognized role in epidermal differentiation, functioning both to repress progenitor genes and to activate early and late differentiation genes. PMID- 25805132 TI - Meiosis: early DNA double-strand breaks pave the way for inter-homolog repair. AB - During meiotic prophase, the repair of induced DNA double-strand breaks (DSBs) promotes interactions between homologous chromosomes (homologs). A study by Joshi et al. (2015) now highlights how the global DSB activity in a nucleus influences the choice between the homolog and the sister chromatid for DSB repair. PMID- 25805133 TI - Ciliary vesicle formation: a prelude to ciliogenesis. AB - Reporting recently in Nature Cell Biology, Lu et al. (2015) identify two Eps15 homology-domain-containing proteins as critical effectors of ciliary vesicle formation, an early event in ciliogenesis. Functional dissection reveals that one of them works to convert small vesicles associated with mother centriole distal appendages into a larger ciliary vesicle. PMID- 25805126 TI - Endoplasmic reticulum stress signaling in mammalian oocytes and embryos: life in balance. AB - Mammalian oocytes and embryos are exquisitely sensitive to a wide range of insults related to physical stress, chemical exposure, and exposures to adverse maternal nutrition or health status. Although cells manifest specific responses to various stressors, many of these stressors intersect at the endoplasmic reticulum (ER), where disruptions in protein folding and production of reactive oxygen species initiate downstream signaling events. These signals modulate mRNA translation and gene transcription, leading to recovery, activation of autophagy, or with severe and prolonged stress, apoptosis. ER stress signaling has recently come to the fore as a major contributor to embryo demise. Accordingly, agents that modulate or inhibit ER stress signaling have yielded beneficial effects on embryo survival and long-term developmental potential. We review here the mechanisms of ER stress signaling, their connections to mammalian oocytes and embryos, and the promising indications that interventions in this pathway may provide new opportunities for improving mammalian reproduction and health. PMID- 25805134 TI - Submandibular parasympathetic gangliogenesis requires sprouty-dependent Wnt signals from epithelial progenitors. AB - Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found that deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation, and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons, and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus, K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance. PMID- 25805136 TI - FOXKs promote Wnt/beta-catenin signaling by translocating DVL into the nucleus. AB - Dishevelled (DVL) proteins serve as crucial regulators that transduce canonical Wnt signals to the GSK3beta-destruction complex, resulting in the stabilization of beta-catenin. Emerging evidence underscores the nuclear functions of DVLs, which are critical for Wnt/beta-catenin signaling. However, the mechanism underlying DVL nuclear localization remains poorly understood. Here we discovered two Forkhead box (FOX) transcription factors, FOXK1 and FOXK2, as bona fide DVL interacting proteins. FOXK1 and FOXK2 positively regulate Wnt/beta-catenin signaling by translocating DVL into the nucleus. Moreover, FOXK1 and FOXK2 protein levels are elevated in human colorectal cancers and correlate with DVL nuclear localization. Conditional expression of Foxk2 in mice induced intestinal hyper-proliferation that featured enhanced DVL nuclear localization and upregulated Wnt/beta-catenin signaling. Together, our results not only reveal a mechanism by which DVL is translocated into the nucleus but also suggest unexpected roles of FOXK1 and FOXK2 in regulating Wnt/beta-catenin signaling. PMID- 25805135 TI - A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation. AB - Progenitor differentiation requires remodeling of genomic expression; however, in many tissues, such as epidermis, the spectrum of remodeled genes and the transcription factors (TFs) that control them are not fully defined. We performed kinetic transcriptome analysis during regeneration of differentiated epidermis and identified gene sets enriched in progenitors (594 genes), in early (159 genes), and in late differentiation (387 genes). Module mapping of 1,046 TFs identified MAF and MAFB as necessary and sufficient for progenitor differentiation. MAF:MAFB regulated 393 genes altered in this setting. Integrative analysis identified ANCR and TINCR lncRNAs as essential upstream MAF:MAFB regulators. ChIP-seq analysis demonstrated MAF:MAFB binding to known epidermal differentiation TF genes whose expression they controlled, including GRHL3, ZNF750, KLF4, and PRDM1. Each of these TFs rescued expression of specific MAF:MAFB target gene subsets in the setting of MAF:MAFB loss, indicating they act downstream of MAF:MAFB. A lncRNA-TF network is thus essential for epidermal differentiation. PMID- 25805137 TI - Light regulates the ciliary protein transport and outer segment disc renewal of mammalian photoreceptors. AB - The outer segment (OS) of the rod photoreceptor is a light-sensing cilium containing ~1,000 membrane-bound discs. Each day, discs constituting the distal tenth of the OS are shed, whereas nascent discs are formed at the base of the OS through the incorporation of molecules transported from the inner segment. The mechanisms regulating these processes remain elusive. Here, we show that rhodopsin preferentially enters the OS in the dark. Photoexcitation of post-Golgi rhodopsins retains them in the inner segment. Disc-rim protein peripherin2/rds enters the OS following a rhythm complementary to that of rhodopsin. Light-dark cycle-regulated protein trafficking serves as a mechanism to segregate rhodopsin rich and peripherin2/rds-rich discs into alternating stacks, which are flanked by characteristic cytoplasmic pockets. This periodic cytostructure divides the OS into approximately ten fractions, each containing discs synthesized in a single day. This mechanism may explain how the rod photoreceptor balances the quantity of discs added and removed daily. PMID- 25805140 TI - Isolated neutral peptides. AB - This chapter examines the structural characterisation of isolated neutral amino acids and peptides. After a presentation of the experimental and theoretical state-of-the-art in the field, a review of the major structures and shaping interactions is presented. Special focus is made on conformationally-resolved studies which enable one to go beyond simple structural characterisation; probing flexibility and excited-state photophysics are given as examples of promising future directions. PMID- 25805141 TI - Halogen bonding in solution. AB - Because of its expected applicability for modulation of molecular recognition phenomena in chemistry and biology, halogen bonding has lately attracted rapidly increasing interest. As most of these processes proceed in solution, the understanding of the influence of solvents on the interaction is of utmost importance. In addition, solution studies provide fundamental insights into the nature of halogen bonding, including, for example, the relative importance of charge transfer, dispersion, and electrostatics forces. Herein, a selection of halogen bonding literature is reviewed with the discussion focusing on the solvent effect and the electronic characteristics of halogen bonded complexes. Hence, charged and neutral systems together with two- and three-center bonds are presented in separate sub-sections. Solvent polarity is shown to have a slight stabilizing effect on neutral, two-center halogen bonds while strongly destabilizes charged, two-center complexes. It does not greatly influence the geometry of three-center halogen bonds, even though polar solvents facilitate dissociation of the counter-ion of charged three-center bonds. The charged three center bonds are strengthened by increased environment polarity. Solvents possessing hydrogen bond donor functionalities efficiently destabilize all types of halogen bonds, primarily because of halogen vs hydrogen bond competition. A purely electrostatic model is insufficient for the description of halogen bonds in polar systems whereas it may give reasonable correlation to experimental data obtained in noninteracting, apolar solvents. Whereas dispersion plays a significant role for neutral, two-center halogen bonds, charged halogen bond complexes possess a significant charge transfer characteristic. PMID- 25805138 TI - Pitfalls of mapping high-throughput sequencing data to repetitive sequences: Piwi's genomic targets still not identified. AB - Huang et al. (2013) recently reported that chromatin immunoprecipitation sequencing (ChIP-seq) reveals the genome-wide sites of occupancy by Piwi, a piRNA guided Argonaute protein central to transposon silencing in Drosophila. Their study also reported that loss of Piwi causes widespread rewiring of transcriptional patterns, as evidenced by changes in RNA polymerase II occupancy across the genome. Here we reanalyze their data and report that the underlying deep-sequencing dataset does not support the authors' genome-wide conclusions. PMID- 25805142 TI - Applications of Chemical Ligation in Peptide Synthesis via Acyl Transfer. AB - The utility of native chemical ligation (NCL) in the solution or solid phase synthesis of peptides, cyclic peptides, glycopeptides, and neoglycoconjugates is reviewed. In addition, the mechanistic details of inter- or intra-molecular NCLs are discussed from experimental and computational points of view. PMID- 25805143 TI - Excitons in Time-Dependent Density-Functional Theory. AB - This chapter gives an overview of the description of the optical and dielectric properties of bulk insulators and semiconductors in time-dependent density functional theory (TDDFT), with an emphasis on excitons. We review the linear response formalism for periodic solids, discuss excitonic exchange-correlation kernels, calculate exciton binding energies for various materials, and compare the treatment of excitons with TDDFT and with the Bethe-Salpeter equation. PMID- 25805139 TI - Reassessment of Piwi binding to the genome and Piwi impact on RNA polymerase II distribution. AB - Drosophila Piwi was reported by Huang et al. (2013) to be guided by piRNAs to piRNA-complementary sites in the genome, which then recruits heterochromatin protein 1a and histone methyltransferase Su(Var)3-9 to the sites. Among additional findings, Huang et al. (2013) also reported Piwi binding sites in the genome and the reduction of RNA polymerase II in euchromatin but its increase in pericentric regions in piwi mutants. Marinov et al. (2015) disputed the validity of the Huang et al. bioinformatic pipeline that led to the last two claims. Here we report our independent reanalysis of the data using current bioinformatic methods. Our reanalysis agrees with Marinov et al. (2015) that Piwi's genomic targets still remain to be identified but confirms the Huang et al. claim that Piwi influences RNA polymerase II distribution in the genome. This Matters Arising Response addresses the Marinov et al. (2015) Matters Arising, published concurrently in this issue of Developmental Cell. PMID- 25805145 TI - Molecular Mechanochemistry: Engineering and Implications of Inherently Strained Architectures. AB - Mechanical activation of chemical bonds is usually achieved by applying external forces. However, nearly all molecules exhibit inherent strain of their chemical bonds and angles as a result of constraints imposed by covalent bonding and interactions with the surrounding environment. Particularly strong deformation of bonds and angles is observed in hyperbranched macromolecules caused by steric repulsion of densely grafted polymer branches. In addition to the tension amplification, macromolecular architecture allows for accurate control of strain distribution, which enables focusing of the internal mechanical tension to specific chemical bonds and angles. As such, chemically identical bonds in self strained macromolecules become physically distinct because the difference in bond tension leads to the corresponding difference in the electronic structure and chemical reactivity of individual bonds within the same macromolecule. In this review, we outline different approaches to the design of strained macromolecules along with physical principles of tension management, including generation, amplification, and focusing of mechanical tension at specific chemical bonds. PMID- 25805147 TI - Dynamic formation of a microchannel array enabling kinesin-driven microtubule transport between separate compartments on a chip. AB - Microtubules driven by kinesin motors have been utilised as "molecular shuttles" in microfluidic environments with potential applications in autonomous nanoscale manipulations such as capturing, separating, and/or concentrating biomolecules. However, the conventional flow cell-based assay has difficulty in separating bound target molecules from free ones even with buffer flushing because molecular manipulations by molecular shuttles take place on a glass surface and molecular binding occurs stochastically; this makes it difficult to determine whether molecules are carried by molecular shuttles or by diffusion. To address this issue, we developed a microtubule-based transport system between two compartments connected by a single-micrometre-scale channel array that forms dynamically via pneumatic actuation of a polydimethylsiloxane membrane. The device comprises three layers-a control channel layer (top), a microfluidic channel layer (middle), and a channel array layer (bottom)-that enable selective injection of assay solutions into a target compartment and dynamic formation of the microchannel array. The pneumatic channel also serves as a nitrogen supply path to the assay area, which reduces photobleaching of fluorescently labelled microtubules and deactivation of kinesin by oxygen radicals. The channel array suppresses cross-contamination of molecules caused by diffusion or pressure driven flow between compartments, facilitating unidirectional transport of molecular shuttles from one compartment to another. The method demonstrates, for the first time, efficient and unidirectional microtubule transport by eliminating diffusion of target molecules on a chip and thus may constitute one of the key aspects of motor-driven nanosystems. PMID- 25805146 TI - Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and breast cancer risk in the Cancer de Mama (CAMA) study. AB - OBJECTIVE: We investigated the association between adherence to the recommendations of the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and breast cancer (BC) risk in the Cancer de Mama (CAMA) study in a Mexican population. DESIGN: Population-based case-control study. SUBJECTS: Incident BC cases (n 1000) and controls (n 1074) matched on age, region and health-care system were recruited. SETTING: In-person interviews were conducted to assess BC risk factors and habitual diet was assessed with an FFQ. Conformity to the WCRF/AICR recommendations was evaluated through a score incorporating seven WCRF/AICR components (body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods, alcoholic drinks and breast-feeding), with high scores indicating adherence to the WCRF/AICR recommendations. RESULTS: No statistically significant associations between WCRF/AICR score and risk of BC were observed. After excluding BMI from the WCRF/AICR score, the top quartile was associated with a decreased BC risk overall, with ORQ4-Q1=0.68 (95% CI 0.49, 0.92, P trend=0.03), and among postmenopausal women, with ORQ4-Q1=0.60 (95% CI 0.39, 0.94, P trend=0.03). Inverse associations were observed between BMI and risk of BC overall and among premenopausal women, with OR=0.57 (95% CI 0.42, 0.76, P trend <0.01) and 0.48 (95% CI 0.31, 0.73, P trend<0.01), respectively. Physical activity level was inversely associated with BC risk. CONCLUSIONS: The WCRF/AICR index was not related with BC risk in the CAMA study. A combination of six components excluding BMI showed strong protective associations, particularly in postmenopausal women. Further prospective studies are required to clarify the role of adherence to WCRF/AICR recommendations, particularly with respect to BMI, in the Mexican population. PMID- 25805144 TI - Total synthesis of glycosylated proteins. AB - Glycoproteins are an important class of naturally occurring biomolecules which play a pivotal role in many biological processes. They are biosynthesized as complex mixtures of glycoforms through post-translational protein glycosylation. This fact, together with the challenges associated with producing them in homogeneous form, has hampered detailed structure-function studies of glycoproteins as well as their full exploitation as potential therapeutic agents. By contrast, chemical synthesis offers the unique opportunity to gain access to homogeneous glycoprotein samples for rigorous biological evaluation. Herein, we review recent methods for the assembly of complex glycopeptides and glycoproteins and present several examples from our laboratory towards the total chemical synthesis of clinically relevant glycosylated proteins that have enabled synthetic access to full-length homogeneous glycoproteins. PMID- 25805148 TI - Effects of contextual information and stimulus ambiguity on overt visual sampling behavior. AB - The sampling of our visual environment through saccadic eye movements is an essential function of the brain, allowing us to overcome the limits of peripheral vision. Understanding which parts of a scene attract overt visual attention is subject to intense research, and considerable progress has been made in unraveling the underlying cortical mechanisms. In contrast to spatial aspects, however, relatively little is understood about temporal aspects of overt visual sampling. At every fixation, the oculomotor system faces the decision whether to keep exploring different aspects of an object or scene or whether to remain fixated to allow for in-depth cortical processing - a situation that can be understood in terms of an exploration-exploitation dilemma. To improve our understanding of the factors involved in these decisions, we here investigate how the level of visual information, experimentally manipulated by scene context and stimulus ambiguity, changes the sampling behavior preceding the recognition of centrally presented ambiguous and disambiguated objects. Behaviorally, we find that context, although only presented until the first voluntary saccade, biases the perceptual outcome and significantly reduces reaction times. Importantly, we find that increased information about an object significantly alters its visual exploration, as evident through increased fixation durations and reduced saccade amplitudes. These results demonstrate that the initial sampling of an object, preceding its recognition, is subject to change based on the amount of information available in the system: increased evidence for its identity biases the exploration-exploitation strategy towards in-depth analyses. PMID- 25805149 TI - Human urine and plasma concentrations of bisphenol A extrapolated from pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and semi-physiological pharmacokinetic modeling. AB - The aim of this study was to extrapolate to humans the pharmacokinetics of estrogen analog bisphenol A determined in chimeric mice transplanted with human hepatocytes. Higher plasma concentrations and urinary excretions of bisphenol A glucuronide (a primary metabolite of bisphenol A) were observed in chimeric mice than in control mice after oral administrations, presumably because of enterohepatic circulation of bisphenol A glucuronide in control mice. Bisphenol A glucuronidation was faster in mouse liver microsomes than in human liver microsomes. These findings suggest a predominantly urinary excretion route of bisphenol A glucuronide in chimeric mice with humanized liver. Reported human plasma and urine data for bisphenol A glucuronide after single oral administration of 0.1mg/kg bisphenol A were reasonably estimated using the current semi-physiological pharmacokinetic model extrapolated from humanized mice data using algometric scaling. The reported geometric mean urinary bisphenol A concentration in the U.S. population of 2.64MUg/L underwent reverse dosimetry modeling with the current human semi-physiological pharmacokinetic model. This yielded an estimated exposure of 0.024MUg/kg/day, which was less than the daily tolerable intake of bisphenol A (50MUg/kg/day), implying little risk to humans. Semi-physiological pharmacokinetic modeling will likely prove useful for determining the species-dependent toxicological risk of bisphenol A. PMID- 25805151 TI - Bacterial cell surface properties: role of loosely bound extracellular polymeric substances (LB-EPS). AB - This study investigated the effect of loosely bound extracellular polymeric substances (LB-EPS) on the comprehensive surface properties of four bacteria (Bacillus subtilis, Streptococcus suis, Escherichia coli and Pseudomonas putida). The removal of LB-EPS from bacterial surfaces by high-speed centrifugation (12,000*g) was confirmed by SEM images. Viability tests showed that the percentages of viable cells ranged from 95.9% to 98.0%, and no significant difference was found after treatment (P>0.05). FTIR spectra revealed the presence of phosphodiester, carboxylic, phosphate, and amino functional groups on bacteria surfaces, and the removal of LB-EPS did not alter the types of cell surface functional groups. Potentiometric titration results suggested the total site concentrations on the intact bacteria were higher than those on LB-EPS free bacteria. Most of the acidity constants (pKa) were almost identical, except the increased pKa values of phosphodiester groups on LB-EPS free S. suis and E. coli surfaces. The electrophoretic mobilities and hydrodynamic diameters of the intact and LB-EPS free bacteria were statistically unchanged (P>0.05), indicating LB-EPS had no influence on the net surface charges and size distribution of bacteria. However, LB-ESP could enhance cell aggregation processes. The four LB-EPS free bacteria all exhibited fewer hydrophobicity values (26.1-65.0%) as compared to the intact cells (47.4-69.3%), suggesting the removal of uncharged nonpolar compounds (e.g., carbohydrates) in LB-EPS. These findings improve our understanding of the changes in cell surface characterizations induced by LB-EPS, and have important implications for assessing the role of LB-EPS in bacterial adhesion and transport behaviors. PMID- 25805150 TI - Improved DNA microarray detection sensitivity through immobilization of preformed in solution streptavidin/biotinylated oligonucleotide conjugates. AB - A novel immobilization approach involving binding of preformed streptavidin/biotinylated oligonucleotide conjugates onto surfaces coated with biotinylated bovine serum albumin is presented. Microarrays prepared according to the proposed method were compared, in terms of detection sensitivity and specificity, with other immobilization schemes employing coupling of biotinylated oligonucleotides onto directly adsorbed surface streptavidin, or sequential coupling of streptavidin and biotinylated oligonucleotides onto a layer of adsorbed biotinylated bovine serum albumin. A comparison was performed employing biotinylated oligonucleotides corresponding to wild- and mutant-type sequences of seven single point mutations of the BRCA1 gene. With respect to the other immobilization protocols, the proposed oligonucleotide immobilization approach offered the highest hybridization signals (at least 5 times higher) and permitted more elaborative washings, thus providing considerably higher discrimination between complimentary and non-complementary DNA sequences for all mutations tested. In addition, the hybridization kinetics were significantly enhanced compared to two other immobilization protocols, permitting PCR sample analysis in less than 40 min. Thus, the proposed oligonucleotide immobilization approach offered improved detection sensitivity and discrimination ability along with considerably reduced analysis time, and it is expected to find wide application in DNA mutation detection. PMID- 25805153 TI - Study on the interaction between bovine serum albumin and starch nanoparticles prepared by isoamylolysis and recrystallization. AB - The current study primarily investigated the interaction of bovine serum albumin (BSA) with starch nanoparticles (SNPs) prepared by isoamylolysis and recrystallization using UV-vis, fluorescence, transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and circular dichroism (CD). The enhanced absorbance observed by UV-vis spectroscopy and decreased intensity of fluorescence spectroscopy suggested that BSA could bind to SNPs and form a BSA SNP complex. The synchronous fluorescence spectra revealed that the emission maximum of Tyr residue (at Deltalambda=15nm) was red-shifted at the investigated concentrations range, indicating that the conformation of BSA was changed. Quenching parameters showed that the quenching effect of SNPs was static quenching. TEM images showed that the SNPs were surrounded by protein coronae, indicating that nanoparticle-protein complexes had formed. The FTIR and CD characterization indicated that the SNPs induced structural changes in the secondary structure of BSA. PMID- 25805152 TI - Grazing incidence diffraction studies of the interactions between ursane-type antimicrobial triterpenes and bacterial anionic phospholipids. AB - alpha-Amyrin (AMalf) and ursolic acid (Urs) are ursane-type pentacyclic triterpenes which exhibit wide spectrum of antibacterial activity. These surface active compounds can be incorporated into bacterial membranes and alter their structure and function; however, the exact mechanism of their action still needs to be elucidated. Thus, we decided to study the interactions of these terpenes with specific anionic phospholipids:cardiolipins and phosphatidylglycerols extracted from Escherichia coli in the model environment of Langmuir monolayers. To characterize the ordering of the terpene molecules in one-component films as well as to study their interactions with the bacterial phospholipids in binary monolayers we applied grazing incidence X-ray diffraction (GIXD). It turned out that amyrins and ursolic acid molecules form crystalline hexagonal phases in Langmuir monolayers, in which the molecules are oriented uprightly. Regarding the mixtures, it was found that in the monolayers with Urs crystalline domains are present till moderate or even low Urs proportion. In contrast, in the mixtures with AMalf crystalline domains were observed only at the highest terpene concentration. In the interpretation of our results we underlined the significance of the interactions between the cyclopropane ring present in the hydrophobic part of the bacterial phospholipids and the terminal ring of the terpene structure. We proposed that the significant differences between the systems with AMalf and Urs are connected with the formation of hydrogen bonds between the Urs hydrophobic moieties. It can be inferred from the results that Urs is a more membrane-active agent than AMalf. PMID- 25805154 TI - Adiposity and early adolescent emotional/behavioral problems. AB - OBJECTIVE: To examine whether life course adiposity is associated with emotional/behavioral problems in a non-Western developed setting with little social patterning of adiposity. STUDY DESIGN: In a prospective, population representative Chinese birth cohort, "Children of 1997," multivariable partial least squares regression was used to assess the adjusted associations of birth weight z-score, body mass index (BMI) z-scores at ages 3 months, 9 months, 3 years, 7 years, 9 years, and BMI z-score changes with emotional/behavioral problems at ~ 11 years of age, assessed from the Chinese version of the Revised Parent's Rutter Scales. RESULTS: Rutter score was available for 4976 (62.8% follow-up). Birth weight z-score, BMI z-scores at ages 3 months, 9 months, 3 years, 7 years, 9 years, and successive BMI z-scores changes had little association with Rutter score or subscores at ~ 11 years of age, adjusted for socioeconomic position, although birth weight was negatively associated with specifically hyperactivity. CONCLUSIONS: In a developed, non-Western setting, we did not find adiposity be a factor in the development of emotional/behavioral problems in early adolescence. Although, we cannot rule out the possibility of residual confounding by genetic or familial factors, our results suggest that the reported associations may be contextually specific rather than biologically based. Whether lower birth weight is associated with hyperactivity in early adolescence needs to be confirmed or refuted in other suitable settings. PMID- 25805155 TI - The BASES expert statement on exercise therapy for people with chronic kidney disease. AB - Chronic kidney disease (CKD) is becoming a serious health problem throughout the world and is one of the most potent known risk factors for cardiovascular disease, which is the leading cause of morbidity and mortality in this patient population. Physical inactivity has emerged as a significant and independent risk factor for accelerated deterioration of kidney function, physical function, cardiovascular function and quality of life in people in all stages of CKD. CKD specific research evidence, combined with the strong evidence on the multiple health benefits of regular and adequate amounts of PA in other cardiometabolic conditions, has resulted in physical inactivity being identified by national and international CKD clinical practice guidelines as one of the multiple risk factors that require simultaneous and early intervention for optimum prevention/management of CKD. Despite this realisation, physical inactivity is not systematically addressed by renal care teams. The purpose of this expert statement is therefore to inform exercise and renal care specialists about the clinical value of exercise therapy in CKD, as well as to provide some practical recommendations on how to more effectively translate the existing evidence into effective clinical practice. PMID- 25805156 TI - Automatic QRS Selvester scoring system in patients with left bundle branch block. AB - AIMS: The Selvester QRS scoring system uses quantitative criteria from the standard 12-lead electrocardiogram (ECG) to estimate the myocardial scar size of patients, including those with left bundle branch block (LBBB). Automation of the scoring system could facilitate the clinical use of this technique which requires a set of multiple QRS patterns to be identified and measured. METHODS AND RESULTS: We developed a series of algorithms to automatically detect and measure the QRS parameters required for Selvester scoring. The 'QUantitative and Automatic REport of Selvester Score' was designed specifically for the analysis of ECGs from patients meeting new strict criteria for complete LBBB. The algorithms were designed using a training (n = 36) and a validation (n = 180) set of ECGs, consisting of signal-averaged 12-lead ECGs (1000 Hz sampling) recorded from 216 LBBB patients from the MADIT-CRT. We assessed the performance of the methods using expert manually adjudicated ECGs. The average of absolute differences between automatic and adjudicated Selvester scoring was 1.2 +/- 1.5 points. The range of average differences for continuous measurements of wave locations and interval durations varied between 0 and 6 ms. Erroneous detection of Q, R, S, R', and S' waves (oversensed or missed) were 3, 1, 1, 16, and 6%, respectively. Seven percent of notches detected in the first 40 ms were misdetected. CONCLUSION: We propose an efficient computerized method for the automatic measurement of the Selvester score in patients with the strict LBBB. PMID- 25805157 TI - Remote monitoring of cardiac implantable electrical devices in Europe: quo vadis? PMID- 25805159 TI - [Primary renal angiosarcoma. Uncommon manifestation of a rare malignancy]. AB - This article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved. PMID- 25805158 TI - Precision medicine to improve use of bleeding avoidance strategies and reduce bleeding in patients undergoing percutaneous coronary intervention: prospective cohort study before and after implementation of personalized bleeding risks. AB - OBJECTIVE: To examine whether prospective bleeding risk estimates for patients undergoing percutaneous coronary intervention could improve the use of bleeding avoidance strategies and reduce bleeding. DESIGN: Prospective cohort study comparing the use of bleeding avoidance strategies and bleeding rates before and after implementation of prospective risk stratification for peri-procedural bleeding. SETTING: Nine hospitals in the United States. PARTICIPANTS: All patients undergoing percutaneous coronary intervention for indications other than primary reperfusion for ST elevation myocardial infarction. MAIN OUTCOME MEASURES: Use of bleeding avoidance strategies, including bivalirudin, radial approach, and vascular closure devices, and peri-procedural bleeding rates, stratified by bleeding risk. Observed changes were adjusted for changes observed in a pool of 1135 hospitals without access to pre-procedural risk stratification. Hospital level and physician level variability in use of bleeding avoidance strategies was examined. RESULTS: In a comparison of 7408 pre-intervention procedures with 3529 post-intervention procedures, use of bleeding avoidance strategies within intervention sites increased with pre-procedural risk stratification (odds ratio 1.81, 95% confidence interval 1.44 to 2.27), particularly among higher risk patients (2.03, 1.58 to 2.61; 1.41, 1.09 to 1.83 in low risk patients, after adjustment for control sites; P for interaction = 0.05). Bleeding rates within intervention sites were significantly lower after implementation of risk stratification (1.0% v 1.7%; odds ratio 0.56, 0.40 to 0.78; 0.62, 0.44 to 0.87, after adjustment); the reduction in bleeding was greatest in high risk patients. Marked variability in use of bleeding avoidance strategies was observed across sites and physicians, both before and after implementation. CONCLUSIONS: Prospective provision of individualized bleeding risk estimates was associated with increased use of bleeding avoidance strategies and lower bleeding rates. Marked variability between providers highlights an important opportunity to improve the consistency, safety, and quality of care. Study registration Clinicaltrials.gov NCT01383382. PMID- 25805160 TI - Caesarean delivery before 39 weeks associated with selecting an auspicious time for birth in Taiwan. AB - BACKGROUND: Caesarean delivery before 39 weeks of gestation increases the risk of morbidity among infants. Taiwan has one of the highest caesarean rates in the world, but little attention has been paid to this issue. This study aimed to describe the rate of caesarean delivery before 39 weeks gestation among women who did not have labour signs and had a non-emergency caesarean delivery in Taiwan and to examine whether the phenomenon was associated with the Chinese cultural practice of selecting an auspicious time for birth. METHODS: We recruited women at 15-28 weeks of pregnancy at 5 hospitals in northern Taiwan and followed them at 4 or 5 weeks after delivery using structured questionnaires. This analysis included 150 primiparous mothers with a singleton pregnancy who had a non emergency caesarean delivery without the presence of labour signs. RESULTS: Ninety-three of these women (62.0%) had caesarean deliveries before 39 weeks of gestation. Logistic regression analysis showed that women who had selected an auspicious time for delivery (OR=2.82, 95% CI: 1.15-6.95) and delivered in medical centres (OR=5.26, 95% CI: 2.25-12.26) were more likely to deliver before 39 weeks of gestation. CONCLUSION: Non-emergency caesarean delivery before 39 weeks of gestation was common among the study women, and was related to the Chinese cultural practice of selecting an auspicious time for birth. Further studies are needed to examine the risks and benefits associated with timing of caesarean delivery in Taiwan in order to generate a consensus among obstetricians and give pregnant women appropriate information. PMID- 25805161 TI - Fire and Parasites: An Under-Recognized Form of Anthropogenic Land Use Change and Mechanism of Disease Exposure. AB - Anthropogenic land use changes have altered ecosystems and exacerbated the spread of infectious diseases. Recent reviews, however, have revealed that fire suppression in fire-prone natural areas has not been recognized as a form of anthropogenic land use change. Furthermore, fire suppression has been an under recognized mechanism altering the risk and transmission of infectious disease pathogens and host-parasite dynamics. However, as settlement patterns changed, especially due to colonial expansion in North America, Africa, and Australia, fire suppression became a major form of land use change which has led to broad scale ecosystem changes. Because parasites of humans and animals can vector viral, bacterial, prion, fungal, or protozoan pathogens, concomitant changes associated with anthropogenic-induced changes to fire frequencies and intensities are of concern. I provide reference to 24 studies that indicate that restoring fire in natural areas has the potential to reduce ectoparasites without wings such as ticks, chiggers, fleas, and lice; ectoparasites with wings such as mosquitos, horn flies, face flies, and stable flies; and endoparasites affecting livestock and wildlife. This suggests that fire ecology and parasitology be considered as a priority area for future research that has implications for both humans and animals. PMID- 25805162 TI - Point-of-care testing in anticoagulation reversal. PMID- 25805163 TI - Ex vivo neutralization of unfractionated heparin for assessing overall haemostatic potential in patient plasma. PMID- 25805164 TI - Probiotics for the prevention of antibiotic-associated diarrhoea in older patients: a systematic review. AB - OBJECTIVE: Here, we evaluated the efficacy of probiotic interventions in prevention of antibiotic-associated diarrhoea (AAD) and Clostridium difficile diarrhoea (CDD) in older patients. METHODS: PubMed, Embase, CENTRAL, CINAHL, and Web of Science were comprehensively searched from their dates of inception to May 2014. Only randomised controlled trials reporting data on probiotics including Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus-alone or in combination-versus placebo or absence of treatment in older patients (age >=65 years) were included. Risk ratios (RRs) for AAD and CDD relative to placebo or absence of treatment were estimated. RESULTS: Six trials with a total of 3562 patients were included. Only one trial showed that Bacillus licheniformis was effective for preventing AAD in older patients. However, there was no preventive effect for AAD and CDD with Lactobacillus acidophilus (Florajen), Lactobacillus casei Shirota, Saccharomyces cerevisiae (boulardii) lyo, mixture of Lactobacillus acidophilus and Bifidobacterium bifidum (Cultech strains), and mixture of Lactobacillus acidophilus CUL60, CUL21, Bifidobacterium bifidum CUL20 and B. lactis CUL34. CONCLUSIONS: Our findings indicate that probiotics may not reduce the risk of AAD and CDD in older patients. However, with current published data, it is difficult to draw concrete conclusions. To confirm these findings, sample sizes, multi-centre, double-blind studies that consider factors such as probiotic strains and types of antibiotics are required. PMID- 25805167 TI - Human genetics special issue on computational molecular medicine. PMID- 25805165 TI - Lipid, Oxidative and Inflammatory Profile and Alterations in the Enzymes Paraoxonase and Butyrylcholinesterase in Plasma of Patients with Homocystinuria Due CBS Deficiency: The Vitamin B12 and Folic Acid Importance. AB - Cystathionine-beta-synthase (CBS) deficiency is the main cause of homocystinuria. Homocysteine (Hcy), methionine, and other metabolites of Hcy accumulate in the body of affected patients. Despite the fact that thromboembolism represents the major cause of morbidity in CBS-deficient patients, the mechanisms of cardiovascular alterations found in homocystinuria remain unclear. In this work, we evaluated the lipid and inflammatory profile, oxidative protein damage, and the activities of the enzymes paraoxonase (PON1) and butyrylcholinesterase (BuChE) in plasma of CBS-deficient patients at diagnosis and during the treatment (protein-restricted diet supplemented with pyridoxine, folic acid, betaine, and vitamin B12). We also investigated the effect of folic acid and vitamin B12 on these parameters. We found a significant decrease in HDL cholesterol and apolipoprotein A1 (ApoA-1) levels, as well as in PON1 activity in both untreated and treated CBS-deficient patients when compared to controls. BuChE activity and IL-6 levels were significantly increased in not treated patients. Furthermore, significant positive correlations between PON1 activity and sulphydryl groups and between IL-6 levels and carbonyl content were verified. Moreover, vitamin B12 was positively correlated with PON1 and ApoA-1 levels, while folic acid was inversely correlated with total Hcy concentration, demonstrating the importance of this treatment. Our results also demonstrated that CBS-deficient patients presented important alterations in biochemical parameters, possibly caused by the metabolites of Hcy, as well as by oxidative stress, and that the adequate adherence to the treatment is essential to revert or prevent these alterations. PMID- 25805168 TI - p/n-Polarity of thiophene oligomers in photovoltaic cells: role of molecular vs. supramolecular properties. AB - Molecular and supramolecular properties play key roles in the optoelectronic properties and photovoltaic performances of organic materials. In the present work, we show how small changes in the molecular structure affect such properties, which in turn control the intrinsic and fundamental properties such as the p/n-polarity of organic semiconductors in bulk-heterojunction solar cells. Herein, we designed and synthesized two acceptor-donor-acceptor type semiconducting thiophene oligomers end-functionalized with oxazolone/isoxazolone derivatives (OT1 and OT2 respectively). The HOMO-LUMO energy levels of both derivatives were found to be positioned in such a way that they can act as electron acceptors to P3HT and electron donors to PCBM. However, OT1 functions as a donor (with PCBM) and OT2 as an acceptor (with P3HT) in BHJ photovoltaic cells, and their reverse roles results in either no or poor performance of the cells. Detailed studies using UV-vis absorption and fluorescence spectroscopy, time correlated single photon counting, UV-photoelectron spectroscopy, density functional theory calculations, X-ray diffraction, and thermal gravimetric analysis proved that both molecular and supramolecular properties contributed equally but in a contrasting manner to the abovementioned observation. The obtained results were further validated by flash-photolysis time-resolved microwave conductivity studies which showed an excellent correlation between the structure, property, and device performances of the materials. PMID- 25805169 TI - Modelling elderly cardiac patients decision making using Cognitive Work Analysis: identifying requirements for patient decision aids. AB - BACKGROUND: Patients make various healthcare decisions on a daily basis. Such day to-day decision making can have significant consequences on their own health, treatment, care, and costs. While decision aids (DAs) provide effective support in enhancing patient's decision making, to date there have been few studies examining patient's decision making process or exploring how the understanding of such decision processes can aid in extracting requirements for the design of DAs. OBJECTIVE: This paper applies Cognitive Work Analysis (CWA) to analyse patient's decision making in order to inform requirements for supporting self-care decision making. METHOD: This study uses focus groups to elicit information from elderly cardiovascular disease (CVD) patients concerning a range of decision situations they face on a daily basis. Specifically, the focus groups addressed issues related to the decision making of CVD in terms of medication compliance, pain, diet and exercise. RESULTS: The results of these focus groups are used to develop high level views using CWA. CWA framework decomposes the complex decision making problem to inform three approaches to DA design: one design based on high level requirements; one based on a normative model of decision-making for patients; and the third based on a range of heuristics that patients seem to use. CONCLUSION: CWA helps in extracting and synthesising decision making from different perspectives: decision processes, work organisation, patient competencies and strategies used in decision making. As decision making can be influenced by human behaviour like skills, rules and knowledge, it is argued that patients require support to different types of decision making. This paper also provides insights for designers in using CWA framework for the design of effective DAs to support patients in self-management. PMID- 25805166 TI - Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire. AB - Rubinstein-Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55% of cases) and EP300 (~8%) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30-50 %) and deletions (~10%). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23% of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype. PMID- 25805170 TI - Ribosome A and P sites revealed by length analysis of ribosome profiling data. AB - The high-throughput sequencing of nuclease-protected mRNA fragments bound to ribosomes, a technique known as ribosome profiling, quantifies the relative frequencies with which different regions of transcripts are translated. This technique has revealed novel translation initiation sites with unprecedented scope and has furthered investigations into the connections between codon biases and translation rates. Yet the location of the codon being decoded in ribosome footprints is still unknown, and has been complicated by the recent observation of footprints with non-canonical lengths. Here we show how taking into account the variations in ribosome footprint lengths can reveal the ribosome aminoacyl (A) and peptidyl (P) site locations. These location assignments are in agreement with the proposed mechanisms for various ribosome pauses and further enhance the resolution of the profiling data. We also show that GC-rich motifs at the 5' ends of footprints are found in yeast, calling into question the anti-Shine-Dalgarno effect's role in ribosome pausing. PMID- 25805171 TI - "What Program Directors Think" II: Results of the 2013 and 2014 Annual Surveys of the Association of Program Directors in Radiology. AB - RATIONALE AND OBJECTIVES: The Association of Program Directors in Radiology (APDR) surveys residents' educational experiences, work responsibilities, and benefits to support radiology residency programs and their directors. MATERIALS AND METHODS: This is an observational cross-sectional study using three Web-based surveys posed to the APDR membership in the spring of 2013 (March 7-29, 2013; 44 items), the fall of 2013 (October 24 to November 15, 2013; 36 items), and the spring of 2014 (March 3-21, 2014; 49 items) on the American Board of Radiology (ABR) Core examination, organization of Clinical Competency Committees (CCCs), fellowship match, and interventional radiology (IR)-diagnostic radiology (DR) training programs. RESULTS: Responses were collected electronically, results were tallied using SurveyMonkey software, and qualitative responses were tabulated or summarized as comments. Findings were reported during the 60th and 61st annual meetings of the Association of University Radiologists, respectively. The maximal response rate was 35% in the spring 2013, 39% in the fall 2013, and 39% in the spring 2014. CONCLUSIONS: With the ABR Core examination, radiology educators increasingly included multiple choice questions in teaching conferences. "Boards frenzy" was alive and well. The number of programs with a CCC was growing, chaired primarily by the Program Director (PD), with the most commonly used tool being the rotation evaluation. In view of "fellowship frenzy" in the third year of residency, only a minority of PDs were against a fellowship match in the National Resident Matching Program (NRMP). The majority of respondents replied that the new IR/DR pathway would negatively affect the DR residency. PMID- 25805172 TI - The Power of Physiology in Changing Landscapes: Considerations for the Continued Integration of Conservation and Physiology. AB - The growing field of conservation physiology applies a diversity of physiological traits (e.g., immunological, metabolic, endocrine, and nutritional traits) to understand and predict organismal, population, and ecosystem responses to environmental change and stressors. Although the discipline of conservation physiology is gaining momentum, there is still a pressing need to better translate knowledge from physiology into real-world tools. The goal of this symposium, ''Physiology in Changing Landscapes: An Integrative Perspective for Conservation Biology'', was to highlight that many current investigations in ecological, evolutionary, and comparative physiology are necessary for understanding the applicability of physiological measures for conservation goals, particularly in the context of monitoring and predicting the health, condition, persistence, and distribution of populations in the face of environmental change. Here, we outline five major investigations common to environmental and ecological physiology that can contribute directly to the progression of the field of conservation physiology: (1) combining multiple measures of physiology and behavior; (2) employing studies of dose-responses and gradients; (3) combining a within-individual and population-level approach; (4) taking into account the context-dependency of physiological traits; and (5) linking physiological variables with fitness metrics. Overall, integrative physiologists have detailed knowledge of the physiological systems that they study; however, communicating theoretical and empirical knowledge to conservation biologists and practitioners in an approachable and applicable way is paramount to the practical development of physiological tools that will have a tangible impact for conservation. PMID- 25805175 TI - Priming of object detection under continuous flash suppression depends on attention but not on part-whole configuration. AB - Previous research has shown that the identification of visual objects can rely on both view-dependent, holistic as well as view-independent, analytic representation, depending on visual attention. Here, we asked whether the initial conscious detection of objects reveals similar dependencies and may therefore share similar perceptual mechanisms. We used continuous flash suppression to render objects presented in familiar views invisible at the beginning of a trial and recorded the time these target objects needed to break into awareness. Target objects were preceded by spatially attended or unattended primes that were either shown in the same familiar view as the targets or horizontally split (i.e., with their halves swapping positions) in order to disrupt holistic processing. Relative to an unprimed baseline, suppression times were shorter for all priming conditions. Although spatial attention enhanced this priming effect on access to awareness, even unattended primes facilitated awareness of a related target, indicating that object detection does not fully concur with the idea of attention demanding analytic object representations. Moreover, priming effects were of similar strength for primes shown in the same familiar view as the targets and for horizontally split primes, indicating that holistic (template-like) representations do not play an integral role in object detection. These results suggest that the initial detection of an object relies on representations of object features rather than holistic representations used for recognition. The perceptual mechanisms mediating conscious object detection are therefore markedly different from those underlying object identification. PMID- 25805176 TI - Optical angular constancy is maintained as a navigational control strategy when pursuing robots moving along complex pathways. AB - The optical navigational control strategy used to intercept moving targets was explored using a real-world object that travels along complex, evasive pathways. Fielders ran across a gymnasium attempting to catch a moving robot that varied in speed and direction, while ongoing position was measured using an infrared motion capture system. Fielder running paths were compared with the predictions of three lateral control models, each based on maintaining a particular optical angle relative to the robotic target: (a) constant alignment angle (CAA), (b) constant eccentricity angle (CEA), and (c) linear optical trajectory (LOT). Findings reveal that running pathways were most consistent with maintenance of LOT and least consistent with CEA. This supports that fielders use the same optical control strategy of maintaining angular constancy using a LOT when navigating toward targets moving along complex pathways as when intercepting simple ballistic trajectories. In those cases in which a target dramatically deviates from its optical path, fielders appear to simply reset LOT parameters using a new constant angle value. Maintenance of such optical angular constancy has now been shown to work well with ballistic, complex, and evasive moving targets, confirming the LOT strategy as a robust, general-purpose optical control mechanism for navigating to intercept catchable targets, both airborne and ground based. PMID- 25805177 TI - Modulated textures with shape structures implied by a closed flow are processed globally. AB - Radial frequency (RF) patterns, shapes deformed from circular by a sinusoidal modulation of radius, have been used to demonstrate global integration of shape information around a closed path by showing that the modulation depth required to detect shape deformation decreases rapidly as larger segments of the contour are modulated. In this psychophysical study we use a field of Gabor patches to examine integration of shape information in sampled RF patterns either alone or placed within an orientation-noise background and show that orientation-noise can be disregarded during the integration of modulation information. We also examine integration in modulated textures with local orientations that flow parallel or perpendicular to an underlying RF shape-structure. In using modulated textures comprising of elements with a random radial position but with orientation modulated such that it conforms to the local orientation of an RF pattern (RF texture) we demonstrate integration around texture patterns that imply shape. Texture patterns with element orientations locally orthogonal (RFO textures) to those of RF textures, however, exhibit a rate of decrease in modulation threshold, which is substantially reduced. When the textures are scrambled by permuting the polar positions of the patches the rate of decrease in threshold with increasing number of patches modulated in orientation is reduced for RF textures but not RFO textures. Detection of modulation in both scrambled textures is shown to be consistent with the detection of local cues. We conclude that implied closure in a modulated flow appears to be critical for global integration of textures. PMID- 25805178 TI - Dopamine release in the lateral hypothalamus is stimulated by alpha-MSH in both the anticipatory and consummatory phases of feeding. AB - alpha-Melanocyte-stimulating hormone (alpha-MSH), is a hypothalamic neuropeptide signaling satiation, but it is not known if alpha-MSH may stimulate dopamine release in a feeding control brain region of the lateral hypothalamic area (LHA), during the anticipatory and consummatory phases of feeding behavior. To address these questions, dynamics of dopamine release were measured in 15 min microdialysis samples simultaneously from the LHA and the nucleus accumbens (NAc) during consecutive exposure and provision of food and 1% sucrose in Wistar rats after overnight food deprivation. alpha-MSH was infused via the microdialysis probe either into the LHA or NAc starting before food exposure. Food, sucrose and water intakes were automatically monitored and analyzed concomitantly with microdialysis samples. We found that LHA-alpha-MSH-infused rats stopped eating earlier and consumed less food and sucrose as compared to control and NAc-alpha MSH-infused rats. Exposure to food produced a peak of LHA dopamine in both LHA alpha-MSH and NAc-alpha-MSH-infused rats but not in the controls. During food provision, LHA dopamine levels were strongly elevated in LHA-alpha-MSH infused rats, while delivery of alpha-MSH into the NAc induced a less intense increase of dopamine in both NAc and LHA. In all rats, LHA dopamine levels correlated inversely with sucrose intake. In conclusion, our study showed that alpha-MSH stimulates dopamine release in the LHA during both the anticipatory and consummatory phases of feeding, decreases food intake and inhibits sucrose intake. These data suggest that LHA dopamine release can be involved in alpha-MSH anorexigenic effects. PMID- 25805179 TI - Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis. AB - B23/NPM is a multifunctional nucleolar protein frequently overexpressed, mutated, or rearranged in neoplastic tissues. B23/NPM is involved in diverse biological processes and is mainly regulated by heteroligomer association and posttranslational modification, phosphorylation being a major posttranslational event. While the role of B23/NPM in supporting and/or driving malignant transformation is widely recognized, the particular relevance of its CK2-mediated phosphorylation remains unsolved. Interestingly, the pharmacologic inhibition of such phosphorylation event by CIGB-300, a clinical-grade peptide drug, was previously associated to apoptosis induction in tumor cell lines. In this work, we sought to identify the biological processes modulated by CIGB-300 in a lung cancer cell line using subtractive suppression hybridization and subsequent functional annotation clustering. Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis (ES = 8.4, p < 0.001), mitochondrial ATP metabolism (ES = 2.5, p < 0.001), and ribosomal biogenesis (ES = 1.5, p < 0.05). The impairment of these cellular processes by CIGB-300 was corroborated at the molecular and cellular levels by Western blot (P-S6/P-4EBP1, translation), confocal microscopy (JC-1, mitochondrial potential), qPCR (45SrRNA/p21, ribosome biogenesis), and electron microscopy (nucleolar structure, ribosome biogenesis). Altogether, our findings provide new insights on the potential relevance of the CK2-mediated phosphorylation of B23/NPM in cancer cells, revealing at the same time the potentialities of its pharmacological manipulation for cancer therapy. Finally, this work also suggests several candidate gene biomarkers to be evaluated during the clinical development of the anti-CK2 peptide CIGB-300. PMID- 25805182 TI - Synthesis of planar chiral [2.2]paracyclophane-based bisoxazoline ligands bearing no central chirality and application to Cu-catalyzed asymmetric O-H insertion reaction. AB - C2-symmetric planar chiral [2.2]paracyclophane-based bisoxazoline ligands, characterized by the inserted benzene spacer, which has a sterically demanding substituent, were synthesized and it was shown that up to 80% ee was obtained for the Cu-catalyzed O-H insertion reaction of alpha-diazo esters without the aid of the central chirality. PMID- 25805181 TI - Impact of handgrip exercise intensity on brachial artery flow-mediated dilation. AB - PURPOSE: Previous studies that have examined the impact of exercise intensity on conduit artery endothelial function have involved large muscle group exercise which induces local and systemic effects. The aim of this study was to examine flow-mediated dilation (FMD) before and after incremental intensities of handgrip exercise (HE), to assess the role of local factors such as blood flow and shear rate on post-exercise brachial artery function. METHODS: Eleven healthy men attended the laboratory on three occasions. Subjects undertook 30 min of handgrip exercise at three intensities (5, 10 or 15 % MVC). Brachial artery FMD, shear and blood flow patterns were examined before, immediately after and 60 min post exercise. RESULTS: Handgrip exercise increased mean and antegrade shear rate (SR) and blood flow (BF) and reduced retrograde SR and BF (all P < 0.01). Exercise intensity was associated with a dose-dependent increase in both mean and antegrade BF and SR (interaction, P < 0.01). Post-hoc tests revealed that, whilst handgrip exercise did not immediately induce post-exercise changes, FMD was significantly higher 60 min post-exercise following the highest exercise intensity (5.9 +/- 2.8-10.4 +/- 5.8 %, P = 0.01). CONCLUSIONS: Handgrip exercise leads to intensity-and time-dependent changes in conduit artery function, possibly mediated by local increases in shear, with improvement in function evident at 1 h post-exercise when performed at a higher intensity. PMID- 25805184 TI - The Italian consensus to virtual colonoscopy. AB - OBJECTIVES: To produce an informed consent for CT colonography (CTC), to be diffused by the Italian Society of Radiology, aimed to make patients and referring physicians aware of CTC examination protocol, advantages and disadvantages, limits and potential related risks. MATERIALS AND METHODS: Delphi method was used to create a consensus among experts on an informed consent for CTC. The overall agreement among different consulted specialists was evaluated and ranked using the Cronbach's correlation coefficient (alpha) at two time points: after the first and the second 'round' of consultation. RESULTS: The Cronbach index was 0.84 at the end of the first round and 0.93 at the end of the second round. The number of disagreements dropped from an overall of 11-5, from the first to the second round. CONCLUSIONS: The experts were able to produce an informed consent for CTC, hoping that this may be the beginning of a process focused on implementation of quality standards in CTC. PMID- 25805180 TI - Flow Cytometry: Impact on Early Drug Discovery. AB - Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens of thousands of cells per second and more than five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, "sip-and-spit" sampling technology has restricted it to low-sample throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens of thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multiparameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage, and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536 well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry, and parallel sample processing promise dramatically expanded single-cell profiling capabilities to bolster systems-level approaches to drug discovery. PMID- 25805185 TI - [Lipoma arborescens of the knee in a patient with ankylosing spondylitis: case report and literature review]. AB - Lipoma arborescens (LA) is defined as a villous lipomatous proliferation of the synovial membrane with diffuse substitution of the synovial tissue by mature fat cells. The injury is very rare, involving the knee joint (suprapatellar region) and is associated with degenerative joint disease. We describe the case of a male patient, suffering from ankylosing spondylitis with monoarthritis of the right knee and swelling in suprapatellar region important. The diagnosis of lipoma arborescens was confirmed from the MRI of the right knee. PMID- 25805183 TI - Contrast-enhanced ultrasound to predict the risk of microembolization during carotid artery stenting. AB - OBJECTIVES: Cerebral microembolization, one of the most frequent complications of carotid artery stenting, is associated with an increased risk of peri- and post procedural stroke and transient ischemic attack and a mid-term risk of neurocognitive decline. A valuable tool to evaluate carotid plaque instability and risk of embolization is contrast-enhanced ultrasound. With this prospective study we sought to determine the correlation between contrast enhancement of the plaque and cerebral microembolization after carotid stent deployment and to evaluate the clinical impact of the neurological injury. MATERIALS AND METHODS: Thirty-five consecutive patients with carotid artery stenosis and indications for endovascular stenting were enrolled. Before the procedure, patients were evaluated with contrast-enhanced ultrasound to define plaque enhancement (signal intensity). All endovascular procedures were performed under cerebral filter protection. Diffusion-weighted magnetic resonance imaging scans to detect microemboli were obtained before and 48 h after the stent deployment. The Ray auditory verbal learning test to assess neurocognitive function was administered before and 1 month after the procedure. RESULTS: Nineteen patients (54 %) developed new cerebral ischemic lesions after carotid artery stenting. Contrast enhancement of the plaque was greater in the patients with post-procedural microembolization than in those without it [maximum signal intensity 26 +/- 7.7 vs. 21 +/- 5.2, respectively, (p = 0.039), mean signal intensity, 20.7 +/- 6.1 vs. 16.5 +/- 5.3, respectively (p = 0.048)]. No correlation was found between neurocognitive test scores and microembolization or plaque enhancement. CONCLUSION: Contrast enhancement of the carotid plaque is strongly associated with post-procedural microembolization and for this reason it can be considered a reliable tool for an accurate selection of patients undergoing this endovascular treatment. However, the neurocognitive test scores performed in this study are not enough sensible to appreciate the impact of the neurological injury on the day life activities. PMID- 25805186 TI - Penetration of Streptococcus sobrinus and Streptococcus sanguinis into dental enamel. AB - The aim of this pilot study was to assess the difference in virulence of acidogenic and aciduric oral streptococci in an in vitro caries model using their penetration depths into dental enamel. 30 caries-free extracted molars from 11- to 16-year-olds were cleaned ultrasonically for 1 min with de-ionized water and, after air-drying, embedded in epoxy resin. After 8-h of setting at room temperature, the specimens were ground on the buccal side with SiC-paper 1200 (particle size 13-16 MUm). Enamel was removed in circular areas sized 3 mm in diameter; the mean depth of removed enamel was 230 +/- 60 MUm. 15 specimens each were incubated anaerobically under standardized conditions with 24 h-cultures of Streptococcus sanguinis 9S or Streptococcus sobrinus OMZ 176 in Balmelli broth at 37 +/- 2 degrees C; the pH-values of the broths were measured at the beginning and end of each incubation cycle. After 2, 4, 6, 8, and 10 weeks 3 teeth each were fixed in 2.5% glutaraldehyde in cacodylate buffer for 24 h, washed 3* and dehydrated 30-60min by sequential washes through a series of 30-100% graded ethanol. The teeth were cut in half longitudinally; afterward, two slits were made to obtain fracture surfaces in the infected area. After critical-point drying the fragments were gold-sputtered and viewed in a scanning electron microscope at magnifications of *20-20,000. After 10 weeks of incubation, penetration of S. sanguinis of 11.13 +/- 24.04 MUm below the break edges into the enamel was observed. The invasion of S. sobrinus reached depths of 87.53 +/- 76.34 MUm. The difference was statistically significant (paired t test: p = 0.033). The experimental penetration depths emphasize the importance of S. sanguinis versus S. sobrinus in the context of the extended ecological plaque hypothesis. PMID- 25805188 TI - Designed synthesis of MOF-derived magnetic nanoporous carbon materials for selective enrichment of glycans for glycomics analysis. AB - In this work, magnetic nanoporous carbon (NPC) materials were synthesized by choosing a MOF as a sacrificial template and a carbon precursor. The obtained Co ZIF-67 materials showed strong magnetic response, high surface area, a uniform size of mesopores and high carbon content. The Co-ZIF-67 materials were successfully applied to glycomics analysis by enriching N-linked glycans in bio samples with high selectivity and efficiency. PMID- 25805187 TI - Efficacy and safety of linagliptin co-administered with low-dose metformin once daily versus high-dose metformin twice daily in treatment-naive patients with type 2 diabetes: a double-blind randomized trial. AB - INTRODUCTION: The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose (LD) metformin once daily versus high-dose (HD) metformin twice daily in treatment-naive patients with type 2 diabetes. METHODS: Patients (n = 689) were randomized (1:1) to double-blind treatment with linagliptin 5 mg + LD metformin (1000 mg) or HD metformin (2000 mg) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to Week 14 in patients who tolerated a daily metformin dose of >=1000 mg after 2 weeks. RESULTS: At Week 14, HbA1c changed from a mean baseline of 8.0% (64 mmol/mol) by -0.99% (-11 mmol/mol) for linagliptin + LD metformin, and -0.98% (-11 mmol/mol) for HD metformin [treatment difference -0.01% (95% confidence interval -0.13, 0.12) (0 mmol/mol), P = 0.8924]. The proportion of patients who achieved HbA1c <7.0% (53 mmol/mol) without occurrence of moderate or severe gastrointestinal (GI) events (including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite) was the same in both groups (51.3% for both). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events (18.5% versus 24.3%). The incidence of hypoglycemia was low in both groups. CONCLUSION: Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses >1000 mg/day. FUNDING: Boehringer Ingelheim. PMID- 25805189 TI - Cancer control of partial nephrectomy for high-risk localized renal cell carcinoma: population-based and single-institutional analysis. AB - PURPOSE: Cancer control of partial nephrectomy for high-risk localized renal cell carcinoma is unclear. To assess whether PN provides adequate cancer control in high-risk disease (HRD), survival outcomes were compared in both a population based cohort and an institutional cohort. METHODS: Surveillance, Epidemiology, and End Results database and a prospectively maintained institutional database were queried for patients with RCC who underwent PN or RN for a localized tumor <=7 cm and were found to have high-grade and/or high-stage disease (HRD). Cancer specific (CSS) or recurrence-free survival (RFS) and overall survival (OS) were primary outcomes measured and were compared between those who underwent PN and RN using multivariable Cox proportional hazards and propensity analysis. RESULTS: The population cohort consisted of 12,757 (24.9 %) patients with HRD, 85.2 and 14.8 % of which underwent RN and PN, respectively. RN was not associated with CSS (HR 1.23, p = 0.08) but was independently associated with poor OS (HR 1.16, p = 0.031). Propensity analysis showed that RN resulted in a 20 % increased risk of death from all causes (p = 0.008). In the institutional cohort, of 317 patients, 35.9 % had HRD, 56 and 52 of which underwent RN and PN, respectively. Adjusting for age-adjusted Charlson index, RN was a predictor of poor OS (OR 6.20, p = 0.041). Propensity analysis showed that RFS and OS were not related to nephrectomy type (RN HR 0.65, p = 0.627 and RN HR 1.70, p = 0.484). CONCLUSIONS: In patients with pathologic high-risk RCC, partial excision is associated with similar cancer control as compared to radical excision. PMID- 25805190 TI - Formate metabolism in fetal and neonatal sheep. AB - By virtue of its role in nucleotide synthesis, as well as the provision of methyl groups for vital methylation reactions, one-carbon metabolism plays a crucial role in growth and development. Formate, a critical albeit neglected component of one-carbon metabolism, occurs extracellularly and may provide insights into cellular events. We examined formate metabolism in chronically cannulated fetal sheep (gestation days 119-121, equivalent to mid-third trimester in humans) and in their mothers as well as in normal full-term lambs. Plasma formate levels were much higher in fetal lamb plasma and in amniotic fluid (191 +/- 62 and 296 +/- 154 MUM, respectively) than in maternal plasma (33 +/- 13 MUM). Measurements of folate, vitamin B12, and homocysteine showed that these high formate levels could not be due to vitamin deficiencies. Elevated formate levels were also found in newborn lambs and persisted to about 8 wk of age. Formate was also found in sheep milk. Potential precursors of one-carbon groups were also measured in fetal and maternal plasma and in amniotic fluid. There were very high concentrations of serine in the fetus (~1.6 mM in plasma and 3.5 mM in the amniotic fluid) compared with maternal plasma (0.19 mM), suggesting increased production of formate; however, we cannot rule out decreased formate utilization. Dimethylglycine, a choline metabolite, was also 30 times higher in the fetus than in the mother. PMID- 25805192 TI - Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-alpha. AB - Progesterone exerts beneficial effects on the human cardiovascular system by inducing rapid increases in nitric oxide (NO) production in vascular endothelial cells, but the receptors mediating these nongenomic progesterone actions remain unclear. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that progesterone binds to plasma membranes of HUVECs with the characteristics of membrane progesterone receptors (mPRs). The selective mPR agonist Org OD 02-0 had high binding affinity for the progesterone receptor on HUVEC membranes, whereas nuclear PR (nPR) agonists R5020 and medroxyprogesterone acetate displayed low binding affinities. Immunocytochemical and Western blot analyses confirmed that mPRs are expressed in HUVECs and are localized on their plasma membranes. NO levels increased rapidly after treatment with 20 nM progesterone, Org OD 02-0, and a progesterone-BSA conjugate but not with R5020, suggesting that this progesterone action is at the cell surface and initiated through mPRs. Progesterone and Org OD 02-0 (20 nM) also significantly increased endothelial nitric oxide synthase (eNOS) activity and eNOS phosphorylation. Knockdown of mPRalpha expression by treatment with small-interfering RNA (siRNA) blocked the stimulatory effects of 20 nM progesterone on NO production and eNOS phosphorylation, whereas knockdown of nPR was ineffective. Treatment with PI3K/Akt and MAP kinase inhibitors blocked the stimulatory effects of progesterone, Org OD 02-0, and progesterone-BSA on NO production and eNOS phosphorylation and also prevented progesterone- and Org OD 02-0-induced increases in Akt and ERK phosphorylation. The results suggest that progesterone stimulation of NO production in HUVECs is mediated by mPRalpha and involves signaling through PI3K/Akt and MAP kinase pathways. PMID- 25805191 TI - Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice. AB - The adaptive response of skeletal muscle to exercise training is tightly controlled and therefore requires transcriptional regulation. DNA methylation is an epigenetic mechanism known to modulate gene expression, but its contribution to exercise-induced adaptations in skeletal muscle is not well studied. Here, we describe a genome-wide analysis of DNA methylation in muscle of trained mice (n = 3). Compared with sedentary controls, 2,762 genes exhibited differentially methylated CpGs (P < 0.05, meth diff >5%, coverage >10) in their putative promoter regions. Alignment with gene expression data (n = 6) revealed 200 genes with a negative correlation between methylation and expression changes in response to exercise training. The majority of these genes were related to muscle growth and differentiation, and a minor fraction involved in metabolic regulation. Among the candidates were genes that regulate the expression of myogenic regulatory factors (Plexin A2) as well as genes that participate in muscle hypertrophy (Igfbp4) and motor neuron innervation (Dok7). Interestingly, a transcription factor binding site enrichment study discovered significantly enriched occurrence of CpG methylation in the binding sites of the myogenic regulatory factors MyoD and myogenin. These findings suggest that DNA methylation is involved in the regulation of muscle adaptation to regular exercise training. PMID- 25805194 TI - How to apply small group teaching method. PMID- 25805193 TI - Restoring force of medical school. PMID- 25805195 TI - How different are premedical freshmen who enter after introducing a multiple mini interview in a medical school? AB - PURPOSE: Seoul National University College of Medicine (SNUMC) introduced a multiple mini-interview (MMI) to assess the noncognitive ability of applicants in 2013. This study aims to examine whether students differ with regard to their personal career values and academic achievements by admission type. METHODS: We administered a survey about career values and self-perception of competencies. We then compared the survey results and academic achievements by admission type. Finally, the correlation coefficient between MMI score and academic achievement was calculated in the MMI group. The data were analyzed by t-test and correlation analysis. RESULTS: There was no statistically significant difference in career values between groups. For self-perception of competency, only the 'interact in heterogeneous groups' domain was higher for those who entered through the MMI. The MMI group had a higher and broader level of academic achievement. Within the MMI group, there was a significant correlation between grade point average and MMI station scores. CONCLUSION: The characteristics of students who entered through the MMI were more in accordance with the goals of SNUMC and the competency of future doctors. Considering the unique feature of premedical academic achievement, this result implies that such students have superior noncognitive abilities, such as self-development and internal motivation. How these differences change subsequently remains to be seen. PMID- 25805196 TI - Changes in medical students' patient-centeredness attitudes by implementation of clinical performance examination. AB - PURPOSE: From 2009, the Korean Medical Licensure Exam implemented a clinical performance examination (CPX) that highlighted the importance of good patient physician relationships in medical education. This study aimed to examine changes in medical students' attitudes before and after implementation of the CPX in their medical education curriculum. METHODS: In 2006 and 2009, 236 fourth-year medial students of C College of Medicine took the Patient Practitioner Orientation Scale (PPOS) by Krupet et al. (2000), which measures patient-centered attitudes in patient-physician relationships. The data were analyzed by independent t-test and two-way analysis of variance using SPSS 21.0. RESULTS: The PPOS scores of year 2006 students were 3.88+/-0.25 for males and 3.98+/-0.38 for females. For year 2009 students, males scored 3.81+/-0.42 and females scored 4.01+/-0.48. All students had higher Care scores than Share scores (2006: Share, 3.67+/-0.47 vs. Care, 4.19+/-0.51; 2009: Share, 3.56+/-0.34 vs. Care, 4.18+/ 0.53). There were significant differences in PPOS and Share scores by gender before and after the CPX. With regard to Care scores, female students' scores tended to rise and males' scores declined over time. CONCLUSION: An educational program is needed for students to foster patient-centered attitudes, but gender differences should be taken into account. PMID- 25805197 TI - Necessity of introducing postencounter note describing history and physical examination at clinical performance examination in Korea. AB - PURPOSE: Information gathering ability had been evaluated mainly via checklists in clinical performance examinations (CPX). But, it is not proved yet if students write the information correctly in postencounter note (PN), although they asked questions or performed physical examinations (PE) about the information when they interacted with standardized patients in CPX. This study addressed the necessity of introducing PN to evaluate the ability in CPX. METHODS: After patient encounters, students were instructed to write the findings of history taking and physical examination that they considered as important information in approaching the patient's problems in PN. PNs were scored using answer keys selected from checklist items, which were considered to be recorded in PN by CPX experts. RESULTS: PNs of six CPX cases from 54 students were analyzed. Correlation coefficients between the key-checklist scores and PN scores of six cases were moderate to high (0.52 to 0.79). However, students frequently neglected some cardinal features of chief complains, pertinent findings of past/social history and PE, and pertinent negative findings of associated symptoms in PNs, which were checked as 'done' in the keys of checklists. CONCLUSION: It is necessary to introduce PN in CPX to evaluate the students' ability of synthesis and integration of patient information. PMID- 25805198 TI - Educational effect of intraosseous access for medical students. AB - PURPOSE: The purpose of this study was to determine the educational effects of intraosseous (IO) vascular access for medical students and analyze the possibility of including IO access in medical education. METHODS: A before-and after study was conducted in a course with 50 participating medical students. The course comprised a 1-hour didactic lecture and a 1-hour hands-on session with a battery-operated EZ-IO device (Vidacare Corp.) and artificial tibia. After the course, the participant skills were tested (final success rate, mean procedural time, and detailed skills) with regard to IO access. Before and after the course, the knowledge, possibility of clinical use, and adequacy of medical education on IO access were examined in a structured questionnaire. RESULTS: The final success rate of insertion was 88% (n=44), and the mean procedural time for the first trial was 78.1+/-20.6 seconds. "Combination needle with drill" and "proper angle during insertion" were the procedures that were performed the best, and "dressing on insertion site" was the worst-performed procedure. "Proper location of landmarks" was the only significant skill factor that was related to the success of IO access between those who succeeded and failed (p<0.05). In the analysis of the structured questionnaire, median knowledge score, possibility for clinical use, and adequacy of IO access in medical education increased significantly after the course (p<0.01). CONCLUSION: The educational effect of IO access for medical students was tremendous, and the knowledge of and attitude toward IO access improved significantly after the training course. We consider IO access to be adequate for medical education in Korea. PMID- 25805199 TI - The perceptual differences in learning outcomes between education and achievement levels between faculty and students in medical schools. AB - PURPOSE: The purpose of this study was to compare the perception of learning outcomes between faculty and students in medical schools. METHODS: A total of 1,766 medical students and 436 faculty members participated in the survey. They responded to the perception of four learning outcomes: medical knowledge and problem solving, clinical skills, medical ethics, and clinical communication. The participants responded to the education and achievement levels of the learning outcomes. RESULTS: In all four learning outcomes, the student's perception of education level differed by educational system, and the students in mixed systems had the highest scores. Students differed significantly in achievement level of medical ethics between genders, wherein male students perceived their achievement level to be higher than females. Students perceived their achievement level to be lower than the education level. The students' clinical skills were the highest in the education and achievement levels. The faculty perceived the education level to be higher than the student's achievement level. In particular, the faculty's perception of education level of medical knowledge and problem solving was the highest, whereas the students' achievement level of it was lower. The faculty assessed the education level to be higher than students. The students showed higher perception of achievement level than faculty. CONCLUSION: There were perceptual differences in learning outcomes between students and faculty. The results of this study are expected to be used to design outcome-based learning methods. PMID- 25805200 TI - What do faculties need most in a faculty development program? AB - PURPOSE: This study examined two overarching topics: to what extent do faculties acknowledge class readiness, execution of lessons, and evaluation of the session; and what core content should be strengthened in a medical school faculty development program? METHODS: In November 2012, 37 faculties completed a detailed survey on the needs of medical school faculty development programs. The 14-item survey assessed the importance, operational frequency, difficulty in accomplishment, class readiness, execution of teaching, and evaluation of the session. RESULTS: Faculties were aware of the importance of class readiness, execution of teaching, and evaluation of the session but had a low level of accomplishment with regard to execution of the instruction and evaluation of the session. Four subitems of session evaluation were considered very important but showed low operational frequency, high difficulty in accomplishment, and low accomplishment ability. The successful discussion class item had the lowest operational frequency and accomplishment ability. The core contents that should be strengthened in medical school faculty development programs are diagnose students' class readiness (prior knowledge) (35.5%) and providing class session with suitable level/content (32.3%). CONCLUSION: Before designing faculty development programs, a needs assessment is useful in providing more tailored content for the faculty. PMID- 25805201 TI - The mentoring pocketbook. PMID- 25805202 TI - Exposing the cuing task: the case of gaze and arrow cues. AB - The prevailing theoretical accounts of social cognitive processes propose that attention is preferentially engaged by social information. However, empirical investigations report virtually indistinguishable attention effects for social (e.g., gaze) and nonsocial (e.g., arrow) stimuli when a cuing task is used. Here, we show that this discrepancy between theory and data reflects a difference in how the extraneous processes induced by the cuing task's parameters (i.e., tonic alertness and voluntary temporal preparation) modulate cue-specific attentional effects. Overall, we found that tonic alertness and voluntary temporal preparation interacted within the cuing task, resulting in underadditive magnitudes of spatial orienting and superadditive magnitudes of the foreperiod effect. However, those interactions differentially affected social and nonsocial attention. While typical rapid social orienting was resilient to changing task parameters, sustained social orienting was eliminated only when the contribution of both extraneous processes was reduced. In contrast, orienting elicited by nonsocial arrows grew in magnitude with the reduction of voluntary temporal preparation and was delayed by the joint reduction of tonic alertness and voluntary temporal preparation. Together, these data indicate that cue-specific attention effects are masked by task dynamics of the cuing paradigm and highlight a pivotal role of the cuing task parameters in both the measurement and the theoretical attribution of spatial attention effects. PMID- 25805203 TI - Surrendering control, or nothing to lose: Parents' preferences about participation in a randomised trial of childhood strabismus surgery. AB - BACKGROUND: Intermittent exotropia is the most common form of divergent strabismus (squint) in children. Evidence regarding its optimum management is limited. A pilot randomised controlled trial has recently been completed (Surgery versus Active Monitoring in Intermittent Exotropia trial) to determine the feasibility of a full randomised controlled trial. PURPOSE: To identify drivers for and barriers against parents' participation in Surgery versus Active Monitoring in Intermittent Exotropia and to seek their views on information received, the need for randomisation, and enhancing acceptability. METHODS: Multiple method qualitative study using semi-structured telephone interviews to explore parents' motivations and trial screening logs to provide an indication of common barriers. Exploratory thematic analysis identified key themes. RESULTS: A total of 48 interviews were conducted (14 participants; 34 non-participants). Barriers included no desire for surgery/preference to 'wait and see', wanting surgery immediately, feeling uncomfortable about 'surrendering control' over decision-making/being managed 'at random', lack of confidence in the effectiveness of surgery, believing the risks outweighed the benefits, and lack of trust. Drivers included desiring surgery, 'nothing to lose', benefits offsetting the risks, and being in a trial would result in better care. Some also mentioned 'doing their bit' for research. Suggestions for enhancing acceptability included allowing choice of treatment group, giving more time for decision making, expanding on information given, and improving communication. Many felt the necessity of randomisation was adequately explained, but there was some indication that it was misunderstood. Information extracted from the screening logs of 80/89 eligible non-participants indicated the most prevalent barrier was not wanting surgery/preferring to observe (56%), followed by desiring surgery straightaway (15%). Opposition to randomisation/wanting to retain control was recorded in 9% of cases as was the belief that the child's squint was not severe enough to warrant surgery. LIMITATIONS: Interviews were not audio-recorded. Not all who consented to interview could be contacted, although the response/contact rate was good (48/62). A few parents did not provide reasons for refusing the trial. CONCLUSION: Opposition to surgery and concerns about surrendering control were common obstacles to participation, whereas parents keen for their child to undergo the operation but happy to defer tended to embrace a 'nothing to lose' attitude. Many non-participants would have consented if allowed to choose group, although most of these would have chosen observation. While most parents felt happy with information given and that randomisation was adequately explained, it is of concern that there may be some misunderstanding, which should be addressed in any trial. These findings will inform future trials in childhood exotropia, for example, consideration of preference arms and improving communication. Lessons learnt from the Surgery versus Active Monitoring in Intermittent Exotropia trial could prove valuable to paediatric and surgical trials generally. PMID- 25805206 TI - Response to: 'Conventional bronchoscopic techniques in sarcoidosis: not too far behind' by Dhooria et al. PMID- 25805204 TI - Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. AB - OBJECTIVE: To compare the benefit and harm of restrictive versus liberal transfusion strategies to guide red blood cell transfusions. DESIGN: Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. DATA SOURCES: Cochrane central register of controlled trials, SilverPlatter Medline (1950 to date), SilverPlatter Embase (1980 to date), and Science Citation Index Expanded (1900 to present). Reference lists of identified trials and other systematic reviews were assessed, and authors and experts in transfusion were contacted to identify additional trials. TRIAL SELECTION: Published and unpublished randomised clinical trials that evaluated a restrictive compared with a liberal transfusion strategy in adults or children, irrespective of language, blinding procedure, publication status, or sample size. DATA EXTRACTION: Two authors independently screened titles and abstracts of trials identified, and relevant trials were evaluated in full text for eligibility. Two reviewers then independently extracted data on methods, interventions, outcomes, and risk of bias from included trials. random effects models were used to estimate risk ratios and mean differences with 95% confidence intervals. RESULTS: 31 trials totalling 9813 randomised patients were included. The proportion of patients receiving red blood cells (relative risk 0.54, 95% confidence interval 0.47 to 0.63, 8923 patients, 24 trials) and the number of red blood cell units transfused (mean difference -1.43, 95% confidence interval -2.01 to -0.86) were lower with the restrictive compared with liberal transfusion strategies. Restrictive compared with liberal transfusion strategies were not associated with risk of death (0.86, 0.74 to 1.01, 5707 patients, nine lower risk of bias trials), overall morbidity (0.98, 0.85 to 1.12, 4517 patients, six lower risk of bias trials), or fatal or non-fatal myocardial infarction (1.28, 0.66 to 2.49, 4730 patients, seven lower risk of bias trials). Results were not affected by the inclusion of trials with unclear or high risk of bias. Using trial sequential analyses on mortality and myocardial infarction, the required information size was not reached, but a 15% relative risk reduction or increase in overall morbidity with restrictive transfusion strategies could be excluded. CONCLUSIONS: Compared with liberal strategies, restrictive transfusion strategies were associated with a reduction in the number of red blood cell units transfused and number of patients being transfused, but mortality, overall morbidity, and myocardial infarction seemed to be unaltered. Restrictive transfusion strategies are safe in most clinical settings. Liberal transfusion strategies have not been shown to convey any benefit to patients. TRIAL REGISTRATION: PROSPERO CRD42013004272. PMID- 25805205 TI - The Study Team for Early Life Asthma Research (STELAR) consortium 'Asthma e-lab': team science bringing data, methods and investigators together. AB - We created Asthma e-Lab, a secure web-based research environment to support consistent recording, description and sharing of data, computational/statistical methods and emerging findings across the five UK birth cohorts. The e-Lab serves as a data repository for our unified dataset and provides the computational resources and a scientific social network to support collaborative research. All activities are transparent, and emerging findings are shared via the e-Lab, linked to explanations of analytical methods, thus enabling knowledge transfer. eLab facilitates the iterative interdisciplinary dialogue between clinicians, statisticians, computer scientists, mathematicians, geneticists and basic scientists, capturing collective thought behind the interpretations of findings. PMID- 25805207 TI - Sarcopenia in COPD. PMID- 25805208 TI - The Harlequin sign. PMID- 25805210 TI - Multidrug-resistant Escherichia coli in Asia: epidemiology and management. AB - Escherichia coli has become multiresistant by way of production of a variety of beta-lactamases. The prevalence of CTX-M-producing E. coli has reached 60-79% in certain parts of Asia. The acquisition of CTX-M plasmids by E. coli sequence type 131, a successful clone of E. coli, has caused further dissemination of CTX-M producing E. coli. The prevalence of carbapenemase-producing E. coli, especially Klebsiella pneumoniae carbapenemase, and New Delhi metallo-beta-lactamase (NDM) producing E. coli has been increasing in Asia. K. pneumoniae carbapenemase and NDM have now been found in E. coli sequence type 131. The occurrence of NDM producing E. coli is a major concern particularly in the Indian subcontinent, but now elsewhere in Asia as well. There are multiple reasons why antibiotic resistance in E. coli in Asia has reached such extreme levels. Approaches beyond antibiotic therapy, such as prevention of antibiotic resistance by antibiotic stewardship and protecting natural microbiome, are strategies to avoid further spread of antibiotic resistance. PMID- 25805209 TI - Impact of TB on the survival of people living with HIV infection in England, Wales and Northern Ireland. AB - INTRODUCTION: The impact of TB disease on survival in people living with HIV in high resource settings is not well documented in the antiretroviral treatment (ART) era. We calculated TB incidence rates and compared the mortality of persons with and without HIV-TB in a UK HIV cohort in the post-ART era, to determine the impact of HIV-TB on survival in the UK. METHODS: We linked the national cohort of persons (aged >=15 years) diagnosed with HIV between 2000 and 2008 in England, Wales and Northern Ireland with the national TB register and deaths from the Office of National Statistics. We compared all-cause and AIDS-specific mortality in patients with and without TB by estimating HRs using Cox regression modelling allowing for potential predictors. RESULTS: Overall, 3188 (7.2%) individuals developed TB infection among a cohort of 44 050 HIV-diagnosed persons and 149 663 person-years. The cumulative TB incidence rate was 2.13 per 100 person-years with a spike within the first 6 months after HIV diagnosis. TB coinfected patients comprised 18% of the 1880 deaths during follow-up and 79% of deaths (n=967) in the year following HIV diagnosis. TB coinfection (HR 4.77, 95% CI 4.11 to 5.54) was significantly associated with increased all-cause mortality. Analysis of AIDS related survival showed similar results. DISCUSSION: The unexpected high mortality in patients with HIV-TB in a population with good healthcare access and ART availability highlights the importance of improving active and latent TB case finding among patients with HIV, and HIV-testing among patients with TB, to ensure appropriate and prompt treatment initiation for both diseases. PMID- 25805211 TI - Azide-alkyne cycloaddition-mediated cyclization of phosphonopeptides and their evaluation as PTP1B binders and enrichment tools. AB - Protein tyrosine phosphatases (PTPs) are important enzymes in health and disease, and chemical tools are crucial to understand and modulate their biological roles. PTP1B is involved in diabetes, obesity and cancer. One of the main challenges for the design of chemical tools for PTP1B is the homology to TCPTP, making tool selectivity a highly challenging task. Here, we aimed to study if azide-alkyne cycloaddition-mediated cyclization of a peptide inhibitor could increase its selectivity toward PTP1B over TCPTP, and if cyclic and linear peptide binders can be applied as enrichment tools of endogenous PTP1B. While the cyclization of the peptide binders did not improve the selectivity toward PTP1B over TCPTP, it enhanced strongly the efficiency to co-precipitate endogenous PTP1B out of cell lysates. Our results show that fine-tuning the molecular structure of peptidic pull-down baits can greatly enhance their efficiency compared to the parental peptide sequences. PMID- 25805212 TI - Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. AB - Direct vagus nerve stimulation (dVNS) is known to improve mood, epilepsy, and memory. Memory improvements have been observed in Alzheimer's disease patients after long-term stimulation. The potential of transcutaneous vagus nerve stimulation (tVNS), a noninvasive alternative to dVNS, to alter memory performance remains unknown. We aimed to investigate the effect of a single session tVNS on associative memory performance in healthy older individuals. To investigate this, we performed a single-blind sham-controlled randomized crossover pilot study in healthy older individuals (n = 30, 50% female). During the stimulation or sham condition, participants performed an associative face name memory task. tVNS enhanced the number of hits of the memory task, compared with the sham condition. This effect was specific to the experimental task. Participants reported few side effects. We conclude that tVNS is a promising neuromodulatory technique to improve associative memory performance in older individuals, even after a single session. More research is necessary to investigate its underlying neural mechanisms, the impact of varying stimulation parameters, and its applicability in patients with cognitive decline. PMID- 25805213 TI - Top-Down Control of Diesel-Degrading Prokaryotic Communities. AB - Biostimulation through the addition of inorganic nutrients has been the most widely practiced bioremediation strategy in oil-polluted marine waters. However, little attention has so far been paid to the microbial food web and the impact of top-down control that directly or indirectly influences the success of the bioremediation. We designed a mesocosm experiment using pre-filtered (<50 MUm) surface seawater from the Bay of Banyuls-sur-Mer (North-Western Mediterranean Sea) and examined the top-down effect exerted by heterotrophic nanoflagellates (HNF) and virus-like particles (VLP) on prokaryotic abundance, activity and diversity in the presence or absence of diesel fuel. Prokaryotes, HNF and VLP abundances showed a predator-prey succession, with a co-development of HNF and VLP. In the polluted system, we observed a stronger impact of viral lysis on prokaryotic abundances than in the control. Analysis of the diversity revealed that a bloom of Vibrio sp. occurred in the polluted mesocosm. That bloom was rapidly followed by a less abundant and more even community of predation resistant bacteria, including known hydrocarbon degraders such as Oleispira spp. and Methylophaga spp. and opportunistic bacteria such as Percisivirga spp., Roseobacter spp. and Phaeobacter spp. The shift in prokaryotic dominance in response to viral lysis provided clear evidence of the 'killing the winner' model. Nevertheless, despite clear effects on prokaryotic abundance, activity and diversity, the diesel degradation was not impacted by top-down control. The present study investigates for the first time the functioning of a complex microbial network (including VLP) using a nutrient-based biostimulation strategy and highlights some key processes useful for tailoring bioremediation. PMID- 25805214 TI - Biogeography of Planktonic and Benthic Archaeal Communities in a Subtropical Eutrophic Estuary of China. AB - Mounting evidence suggests that Archaea are widespread and abundant in aquatic and terrestrial habitats and play fundamental roles in global biogeochemical cycles, yet the pattern and its ecological drivers of biogeographic distribution of archaeal community in estuarine ecosystem are still not well understood. Here, we investigated planktonic and benthic archaeal communities in the human-impacted Jiulong River estuary (JRE), southern China by using real-time PCR (RT-PCR) and Illumina 16S ribosomal RNA (rRNA) amplicon sequencing. RT-PCR analysis indicated that Archaea accounted for an average of 0.79 and 5.31 % of prokaryotic biomass in water and sediment samples of the JRE, respectively. The diversity of planktonic archaeal community decreased gradually from the river runoff to seawater, whereas that of benthic community did not show the similar pattern. The results of taxonomic assignments indicated that Thaumarchaeota (Nitrosopumilus and Cenarchaeum), Methanocorpusculum, and Methanospirillum were significantly more abundant in planktonic than benthic communities, whereas the relative abundances of Miscellaneous Crenarchaeotic Group, Marine Benthic Group-B/-D, anaerobic methane-oxidizing Archaea -1/-2D, and South Africa Gold Mine Euryarchaeotic Group 1 were higher in sediments than in surface waters. Moreover, planktonic archaeal community composition varied significantly at broad and finer scale taxonomic levels along the salinity gradient. Multivariate statistical analyses revealed that salinity is the main factor structuring the JRE planktonic but not benthic archaeal community at both total community and population level. SourceTrakcer analysis indicated that river might be a major source of archaea in the freshwater zone of the JRE. Overall, this study advances our understanding of the biogeographic patterns and its ecological drivers of estuarine archaeal communities. PMID- 25805215 TI - Population-based dose-response curve of glomerular filtration rate to dietary protein intake. AB - BACKGROUND: Kidney function measured as estimated glomerular filtration rate (eGFR) is a risk factor for mortality and severe diseases. Protein intake up regulates kidney function. The dose-response curve of eGFR over protein intake is unknown. Urinary urea nitrogen is an objective index of protein intake. METHODS: The study cross-sectionally analysed the relation between overnight urinary urea nitrogen ((on)U-ureaN) and eGFR with and without control for other variables in 4106 adults of the Gubbio population. Analyses were done for serum creatinine (S cr) also to investigate the independency of results from eGFR calculation. RESULTS: Higher (on)U-ureaN associated with higher eGFR, and lower S-cr independently of sex and age (simple and partial correlation coefficients >0.100, P < 0.001). Analyses by (on)U-ureaN decile indicated sigmoid curves of eGFR and S cr over (on)U-ureaN with trend to flatness in the lowest 20% and the highest 20% of (on)U-ureaN (<5.19 and >10.12 mg/h, respectively). Multi-variable spline regression indicated that the relation of eGFR over (on)U-ureaN was non significant for (on)U-ureaN <5.19 mg/h (coefficient = +0.27, 95% CI = 0.31/+0.84, P = 0.364), positive for (on)U-ureaN in the range 5.19-10.12 mg/h (coefficients = 1.35-1.64, lower 95% CI >= +0.48, P <= 0.002), and non significant for (on)U-ureaN >10.12 mg/h (coefficient = +0.05, 95% CI = -0.06/ +0.16, P = 0.394). eGFR differed by ~8 mL/min * 1.73 m(2) between the lowest and highest 20% of (on)U-ureaN distribution. CONCLUSIONS: Higher protein intake relates to higher eGFR. The relation is sigmoid with eGFR up-regulation for (on)U ureaN >5.19 mg/h, a threshold approximately corresponding to the recommended daily allowance for protein intake (0.8 g/day per kg of ideal weight). PMID- 25805220 TI - [Variations in health care]. AB - The issue of Regional variability of health interventions is financially relevant, since an increasing rate of unjustified performances could be a source of waste. But the problem is also related to the evaluation of the healthcare appropriateness. An excess of medical interventions could damage the patient, being useless and therefore harmful; but an insufficient availability of interventions or facilities could favor inequalities in the access to the health services. This topic requires more attention by the National and Regional health institutions, and a better performance monitoring is needed. PMID- 25805216 TI - Functional characterization of a novel lytic phage EcSw isolated from Sus scrofa domesticus and its potential for phage therapy. AB - In this study, multi-drug resistant Escherichia coli Sw1 (E. coli Sw1) and active lytic phage EcSw was isolated from feces samples of Sus scrofa domesticus (piglet) suffering from diarrhea. Transmission electron microscopy (TEM) indicated that isolated EcSw belongs to the Myoviridae family with an icosahedral head (80 +/- 4) and a long tail (180 +/- 5 nm). The EcSw phage genome size was estimated to be approximately 75 Kb of double-stranded DNA (dsDNA). Phage dynamic studies show that the latent period and burst size of EcSw were approximately 20 min and 28 PFU per cell, respectively. Interestingly, the EcSw phage can tolerate a wide range of environmental conditions, such as temperature, pH and ions (Ca(2+) and Mg(2+)). Furthermore, genome sequence analysis revealed that the lytic genes of the EcSw phage are notably similar to those of enterobacteria phages. In addition, phage-antibiotic synergy has notable effects compared with the effects of phages or antibiotics alone. Inhibition of E. coli Sw1 and 0157:H7 strains showed that the limitations of host specificity and infectivity of EcSw. Even though, it has considerable potential for phage therapy for handling the problem of the emergence of multidrug resistant pathogens. PMID- 25805217 TI - Dissemination of evidence-based body image interventions: A pilot study into the effectiveness of using undergraduate students as interventionists in secondary schools. AB - Dissonance-based body image interventions are among the most effective interventions for adolescent girls. However, dissemination of these interventions remains challenging. In addition, the emerging field of positive body image suggests that interventions should promote body appreciation as well as reduce pathology. The current study examines whether undergraduate students can effectively deliver a dissonance-based intervention to secondary school girls. In addition, it examines whether this intervention can increase body appreciation. Sixty-two adolescent girls were randomly allocated to the intervention or control condition. In the intervention group, body dissatisfaction was significantly reduced and body appreciation was significantly improved from pre- to post intervention. There were no changes in body dissatisfaction or body appreciation in the control group. There was a reduction in thin-ideal internalization for all participants. These preliminary findings suggest that undergraduate students can be effective interventionists for dissonance-based programs in schools and dissonance-based interventions can promote body appreciation. PMID- 25805221 TI - [Patients facing with the decision to undergo percutaneous coronary intervention]. AB - Percutaneous coronary intervention (PCI) is a common procedure to treat coronary artery stenoses. Several studies had demonstrated that PCI does not reduce the risk of death or myocardial infarction when performed to patients with stable angina. However it has been observed that most patients believe that PCI will reduce their risk for death and myocardial infarction. On the other hand, cardiologists generally acknowledge the limitation of PCI according to the current literature.Cardiologists' decision to refer a patient to PCI is based on factors other then perceived benefits such as fear of missing a needed procedure, defensive medicine, desire of demonstrating their professional competence, vested professional and economic interests, accomplish patient expectation, the so called oculo-stenotic reflex, when a lesion is dilated regardless the clinical indication. Patients' misleading perception of harm and benefits of a procedure is mainly related to the cognitive dissonance, when individuals tend to reduce the conflict of an uncomfortable decision adopting information, which are likely to reduce their discomfort. Furthermore, patients believe that doing more means doing better, that technologic intervention are better than pharmacological treatment that in turn are better than doing nothing. Finally, they assume that a procedure is really effective since their physician suggested it.It should be emphasized that physicians and patients do not communicate successfully about key decision and how little we know about patient understanding of the factors that influence important medical care decisions. Although considerable attention is given to facilitating informed consent, patients' perceived benefits of elective PCI do not match existing evidence, as they overestimated both the benefits and urgency of their procedures. These findings suggest that an even greater effort at patient education is needed prior to elective PCI to facilitate fully informed decision-making. PMID- 25805222 TI - [Multidisciplinary care pathway to manage osteoarticular chronic pain. ASON proposal]. AB - As recognized by law no. 38 of March 15, 2010 patients with chronic pain should have access to an appropriate diagnostic and therapeutic path with continuity of care. In addition to clinical guidelines it is necessary to implement a multidisciplinary care to manage patients with osteoarticular chronic pain to start an early analgesic treatment and to optimize the health system resources. Through a triage territorial of patients with pain we identify the most complex cases to be sent to the network of pain (Spoke and Hub), and we differentiate those that must be managed in a territorial path. The proposal by National Association Osteoarticular Specialists (ASON) suggests a multidisciplinary personalized path, coordinated by general practitioners and specialists, aims to improve patient-health system relationship. PMID- 25805223 TI - [The mosquito-borne viruses in Europe]. AB - Epidemiologic changes of vector-borne diseases in recent years have multiple causes, including climate change. There are about 3500 species of mosquitoes worldwide, three-quarters of which live in tropical and subtropical wetlands. Main viruses transmitted by mosquitoes in Europe belong to the genus Flavivirus; some of them have been recently reported in Italy (Usutu and Japanese encephalitis virus), while others have been circulating for years and autochthonous transmission has been documented (West Nile virus). Mosquito-borne viruses can be classified according to the vector (Aedes or Culex), which, in turn, is associated with different vertebrate host and pathology. The Flavivirus transmitted by Culex have birds as a reservoir and can cause meningoencephalitis, while viruses transmitted by Aedes have primates as reservoir, do not have neurotropism and mainly cause hemorrhagic diseases. Other arbovirus, potentially responsible of epidemics, are the Chikungunya virus (Alphavirus family), introduced for the first time in Europe in 2007, and the virus of Rift Valley fever (Phlebovirus family). The spread in non-endemic areas of vector-born diseases have highlighted the importance of surveillance systems and vector control strategies. PMID- 25805224 TI - [Bio-molecular evaluation of human transcriptomic profile in whole blood sample: a potential clinical approach?]. AB - At present, the analysis of transcriptional profile of blood samples is the more efficient and promising approach to study diagnostic and prognostic biomarkers, complementing the quantitative information obtained by a simple plasma assay, with the qualitative one of mRNA expression. More novel and available blood collection techniques are being developed reducing problems linked to the invasive bioptic approach. To this purpose, in the last years, methods able to isolate leukocytes from minimal quantity of whole blood have been developed, among these the PAXgene methods offer undeniable advantages. This latter method allows to study the transcriptomic profile of many biomarkers and related pathways involved in different pathologies, until now analyzed only with molecular biology techniques at tissue level, identifying new and more specific therapeutic targets. PMID- 25805225 TI - [Short-term effects of stimulation in the right ventricular outflow tract]. AB - INTRODUCTION: Stimulation in the right ventricular outflow tract (RVOT) showed better clinical and hemodynamic results at short, medium and long term than apical pacing. METHODS: We enrolled 30 patients undergoing pacemaker implantation with positioning of electrocatheters in the high or low RVOT. All patients underwent clinical, echocardiographic and electrocardiographic evaluation after implantation and at 6-month follow-up. RESULTS: After 6 months of pacing, no significant changes in echocardiographic parameters were observed, whereas differences were found between the duration of spontaneous QRS and the duration of QRS stimulated at the time of implantation. Electrocatheter implantation in the high RVOT showed a particular benefit. CONCLUSIONS: Chronic stimulation in RVOT, preferably in the high tract, can be considered a viable alternative to apical pacing in patients with likely high rates of stimulation, especially of young age. PMID- 25805226 TI - [Not Available]. PMID- 25805229 TI - Authors' reply to Rivers. PMID- 25805232 TI - Well-organized meso-macroporous TiO2/SiO2 film derived from amphiphilic rubbery comb copolymer. AB - We report the facile synthesis of a well-organized meso-macroporous TiO2/SiO2 thin film with high porosity and good interconnectivity from a binary mixture (i.e., titania precursor and polymer template). Our process is based on self assembly of the amphiphilic rubbery comb copolymer, poly(dimethylsiloxane)-g poly(oxyethylene methacrylate) (PDMS-g-POEM) with titanium tetraisopropoxide (TTIP). SiO2 is self-provided by thermal oxidation of PDMS chains during calcination under air. The selective, preferential interaction between TTIP and the hydrophilic POEM chains was responsible for the formation of well-organized TiO2/SiO2 films, as supported by transmission electron microscopy, scanning electron microscopy, X-ray photospectroscopy, and X-ray diffraction analyses. We investigated in detail the effect of precursor content, solvent type, and polymer concentration on thin film morphology. Photodegradation of methyl orange by the well-organized meso-macroporous TiO2/SiO2 film was greater than that of a dense TiO2 film prepared without PDMS-g-POEM as well as a SiO2-etched TiO2 film. These results indicate that the well-organized structure and SiO2 doping of the TiO2 film play a pivotal role in enhancing its photocatalytic properties. PMID- 25805230 TI - The acquired radioresistance in HeLa cells under conditions mimicking hypoxia was attenuated by a decreased expression of HIF subunit genes induced by RNA interference. AB - The cancer cells residing in the hypoxic layer are resistant to radiation and these are ones responsible for cancer recurrence after radiation therapy. One of the reasons why hypoxic cancer cells acquire radioresistance may be attributable to changes in the gene expression profile by the activation of hypoxia inducible factors (HIFs). However, the details underlying this process remain unknown. In this study, we investigated the effects of knockdown of HIF subunit genes to elucidate how HIF subunit genes may be involved in the radioresistance acquired by HeLa cells following exposure to a hypoxia mimic. Interestingly, HIF-1alpha and HIF-2alpha seemed mutually complementary for each other when either of them was suppressed. We thus suppressed the expression of both genes simultaneously. To do this, we developed a short hairpin RNA (shRNA) targeting a high homology region between HIF-1alpha and HIF-2alpha. It was shown that the expression of the shRNA effectively suppressed the acquisition of radioresistance following the hypoxia mimic. Moreover, it was confirmed that suppression of both subunits resulted in the downregulation of stem cell markers and the suppression of spheroid formation during the hypoxia mimicking-conditions. This shRNA-mediated knockdown method targeting a common region shared by a family of genes may offer a new candidate cancer treatment. PMID- 25805233 TI - Characteristics of Multifocal and Multicentric Breast Cancers. AB - BACKGROUND: Multifocality and multicentricity are increasingly recognized in breast cancer. However, little is known about the characteristics and biology of these cancers and the clinical implications are controversial. METHODS: A retrospective, institutional database was used to compare characteristics of multifocal (MF) and multicentric (MC) breast cancers with unifocal (UF) cancers to study concordance of histology and receptor status among primary and secondary foci and to evaluate predictors of lymph node positivity using multivariate logistic regression. RESULTS: Of 1495 invasive cancers, 1231 (82.3 %) were UF, 169 (11.3 %) were MF, and 95 (6.4 %) were MC cancers. When MF and MC cancers were compared with UF cancers, MC but not MF cancers were associated with young age at diagnosis, larger tumor size, lymphovascular invasion, and node positivity. MF but not MC tumors were more likely to be ER/PR+Her2+ tumors and less likely to be triple-negative cancers compared with UF tumors. MF tumors were more likely to be infiltrating ductal carcinomas with an extensive intraductal component, and MC tumors were more likely to be infiltrating lobular carcinomas. Concordance of histology and receptor status between primary and secondary foci was high and was similar for both MF and MC cancers. Multicentricity remained an independent predictor of lymph node positivity on multivariate analysis. CONCLUSION: MF and MC tumors seem to be biologically different diseases. MC is clinicopathologically more aggressive than MF disease and is more frequently associated with younger age and larger tumor size and also is an independent predictor of node positivity. PMID- 25805234 TI - Feasibility of Gastrectomy with Standard Lymphadenectomy for Patients Over 85 Years Old with Gastric Cancer. AB - BACKGROUND: The feasibility of gastrectomy with standard lymphadenectomy for patients over 85 years of age is not known. This study investigated short- and long-term outcomes and the tolerability of gastrectomy with standard lymphadenectomy for patients over 85 years with gastric cancer. METHODS: Altogether, 77 patients aged over 85 years underwent gastrectomy with lymphadenectomy for gastric cancer at the Cancer Institute Hospital, Japan from May 2000 to February 2012. Postoperative short-term outcomes and survivals were analyzed retrospectively. Standard lymphadenectomy was defined according to the Japanese Gastric Cancer Association guidelines. Lymphadenectomy without splenectomy during total gastrectomy was called "reduced" lymphadenectomy. RESULTS: Distal gastrectomy was performed in 51 patients, total gastrectomy in 20, remnant total gastrectomy in 5, and proximal gastrectomy in 1 patient. Gastrectomy with standard lymphadenectomy was initially planned for 50 (64.9 %) patients and completed in 42 (54.5 %) patients. The other 8 patients underwent reduced lymphadenectomy because they required R1 or R2 resection. There were no deaths. The morbidity rate was 55.8 % overall and 54.8 % with standard lymphadenectomy. The most frequent complication was intestinal hypoperistalsis (29.9 %). The mean postoperative hospital stay was 19 days (range 10-70 days). The median overall survival time was 46.8 months. CONCLUSION: Coupled with comprehensive postoperative medical care due to the relative high morbidity risk, gastrectomy with standard lymphadenectomy for gastric cancer may be acceptable for relatively healthy patients over 85 years of age. Decisions to reduce the extent of lymphadenectomy during gastrectomy should not be based on advanced age alone. PMID- 25805235 TI - The Platelet-to-Lymphocyte Ratio Versus Neutrophil-to-Lymphocyte Ratio: Which is Better as a Prognostic Factor in Gastric Cancer? AB - BACKGROUND: As indicators of the systemic inflammatory response, the neutrophil to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been proposed to predict the clinical outcome in some cancers. The purpose of this study was to investigate the impact of NLR and PLR on the prognosis of gastric cancer. METHODS: From 2000 to 2009, 1986 consecutive patients who underwent curative surgery for gastric cancer were enrolled. The optimal cutoff value of PLR and NLR was determined according to receiver operating characteristic analysis. We categorized the patients into the high or low PLR and NLR group based on the cutoff value, and the clinical features of these two groups were comparatively analyzed. RESULTS: The high NLR and PLR groups were significantly associated with poor prognosis. The NLR was an independent prognostic factor for overall survival [hazard ratio (HR) = 1.403; p = 0.023]; however, the PLR was not (p = 0.788). CONCLUSIONS: Although both the PLR and NLR can reflect the prognosis, the NLR is more predictive of overall survival than the PLR. PMID- 25805236 TI - Suppression of SAMSN1 Expression is Associated with the Malignant Phenotype of Hepatocellular Carcinoma. AB - BACKGROUND: Identification of molecular markers for sensitive detection of hepatocellular carcinoma (HCC) is required to achieve efficacious personalized therapy. METHODS: We focused here on SAM domain, SH3 domain, and nuclear localization signals 1 (SAMSN1) and investigated expression and methylation status of SAMSN1 in HCC cell lines and 144 pairs of surgical specimens. RESULTS: SAMSN1 was expressed at significantly lower levels in tumor tissue compared with the corresponding noncancerous tissues of patients with HCC. Analysis of HCC cell lines revealed that hypermethylation of the SAMSN1 promoter correlated with decreased expression of SAMSN1 mRNA. Furthermore, treating cells with a DNA demethylating drug increased SAMSN1 transcription. The levels of SAMSN1 mRNA in noncancerous liver were not affected by background liver inflammation or fibrosis. Moreover, the levels of SAMSN1 mRNA in HCC tissues inversely correlated with tumor size and preoperative levels of proteins induced by vitamin K absence. The clinical significance of SAMSN1 was further indicated by the correlation between its decreased expression in patients with HCC and their shorter overall and recurrence-free survival as well as recurrence following initial resection. Moreover, multivariate analysis identified SAMSN1 as an independent prognostic factor of HCC progression. The expression pattern of SAMSN1 correlated significantly with that of SAMSN1 mRNA, making it possible to use PCR techniques to readily quantitate SAMSN1 expression in tumors. CONCLUSIONS: Our findings indicate that inhibition of SAMSN1 transcription through DNA hypermethylation may influence the progression of HCC and thus represent a novel biomarker of the phenotype of HCC cells. PMID- 25805237 TI - Correlation Between F-18 Fluorodeoxyglucose Positron Emission Tomography Metabolic Parameters and Dynamic Contrast-Enhanced MRI-Derived Perfusion Data in Patients with Invasive Ductal Breast Carcinoma. AB - PURPOSE: The aim of this study was to establish possible relationships among the metabolic and vascular characteristics of breast cancer using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. METHODS: Sixty seven female patients with invasive ductal breast carcinoma (age 32-79 years) who underwent FDG PET/CT and DCE-MRI prior to cancer treatment were included in the study. The maximum standardized uptake value (SUVmax), metabolic tumor volume, total lesion glycolysis (TLG), and heterogeneity factor (HF) were derived from FDG PET/CT. The DCE-MRI parameters K trans, K ep, and V e were obtained for all tumors, and relationships between the metabolic and perfusion parameters were sought via Spearman's rank correlation analysis. The prognostic significance of clinicopathological and imaging parameters in terms of recurrence-free survival (RFS) was also evaluated. RESULTS: No significant correlation between perfusion and metabolic parameters (p > 0.05) was found, except between SUVmax and V e (p = 0.001, rho = -0.391). Recurrence developed in 12 of the 67 patients (17.9 %, follow-up period 8-41 months). Age (p = 0.016) and HF (p = 0.027) were significant independent predictors of recurrence-free survival (RFS) upon multivariate analysis. The RFS of patients under 40 years of age was significantly poorer than that of older patients (p < 0.001). Survival of patients with more heterogeneous tumors (HF less than -0.12) was poorer than those with relatively homogenous tumors (p = 0.033). CONCLUSIONS: Tumors with higher levels of glucose metabolism (SUVmax values) exhibited higher tumor cellularities (V e values). Also, of the various metabolic and perfusion parameters available, tumor heterogeneity measured via FDG PET/CT (HF) may be useful in predicting RFS in breast cancer patients. PMID- 25805238 TI - Designing a ticket to ride with the Cognitive Work Analysis Design Toolkit. AB - Cognitive work analysis has been applied in the design of numerous sociotechnical systems. The process used to translate analysis outputs into design concepts, however, is not always clear. Moreover, structured processes for translating the outputs of ergonomics methods into concrete designs are lacking. This paper introduces the Cognitive Work Analysis Design Toolkit (CWA-DT), a design approach which has been developed specifically to provide a structured means of incorporating cognitive work analysis outputs in design using design principles and values derived from sociotechnical systems theory. This paper outlines the CWA-DT and describes its application in a public transport ticketing design case study. Qualitative and quantitative evaluations of the process provide promising early evidence that the toolkit fulfils the evaluation criteria identified for its success, with opportunities for improvement also highlighted. PRACTITIONER SUMMARY: The Cognitive Work Analysis Design Toolkit has been developed to provide ergonomics practitioners with a structured approach for translating the outputs of cognitive work analysis into design solutions. This paper demonstrates an application of the toolkit and provides evaluation findings. PMID- 25805239 TI - TEP versus TAPP: comparison of the perioperative outcome in 17,587 patients with a primary unilateral inguinal hernia. AB - INTRODUCTION: More than 20 years since the introduction of TAPP and TEP into clinical routine, there is a lack of clarity due to conflicting comparative data. Therefore, more results from registries are needed. PATIENTS AND METHODS: A total of 17,587 patients were enrolled prospectively between September 1, 2009, and April 15, 2013, in the Herniamed registry. Of these patients, 10,887 (61.9%) had a TAPP and 6700 (38.1%) a TEP repair. The dependent variables were intra- and postoperative complication rates, number of reoperations as well as absolute and relative frequencies. The results of unadjusted analyses were verified via multivariable analyses. RESULTS: Multivariable analysis verified the results of unadjusted analysis, indicating that the surgical technique did not have any significant impact, also while taking account of other factors, on occurrence of intraoperative [p = 0.1648; OR = 1.214 (0.923; 1.596)] and general postoperative complications [p = 0.0738; OR = 1.315 (0.974; 1.775)]. Postoperative surgical complications [OR = 2.323 (1.882; 2.866); p < 0.0001] were noted more often after TAPP. Furthermore, the hernia defect size [p < 0.0001; I vs III: OR = 0.439 (0.313; 0.615), II vs III: OR = 0.712 (0.582; 0.872)] or scrotal [p < 0.0001; OR = 2.170 (1.501; 3.137)] hernia and age [p = 0.0002; 10-year OR = 1.135 (1.062; 1.213)] had a significant impact on the occurrence of postoperative complications. Complications were observed more commonly for larger hernia defects and a scrotal hernia. However, the difference in the postoperative complication rate between TEP and TAPP did not result in any difference in the reoperation rate (TEP 0.82% vs TAPP 0.90%; p = 0.6165). CONCLUSION: The intraoperative and general postoperative complication rates as well as the reoperation rate for complications show no significant difference between TEP and TAPP. The higher postoperative complication rate for TAPP, which could be managed conservatively, is partly explained by larger defect sizes, more scrotal hernias and older age. PMID- 25805240 TI - Endoscopic foreign body removal in the upper gastrointestinal tract: risk factors predicting conversion to surgery. AB - BACKGROUND/AIMS: Most foreign bodies of the upper gastrointestinal tract (UGIT) are successfully removed by endoscopic techniques without complications. However, some require conversion to surgery due to failure of endoscopic removal. The aim of this study was to analyze the risk factors predicting the need to convert to surgery after inability to endoscopically remove the foreign body. PATIENTS AND METHODS: The medical records of 885 patients treated between January 2006 and March 2014 for suspected foreign bodies in the UGIT were retrospectively reviewed. Patient characteristics, the type of foreign bodies, clinical outcomes, and risk factors predicting the conversion to surgery were analyzed. RESULTS: While endoscopic removal was successful in 94.7% (665/702) of the patients, the remaining 5.3% (37/702) needed conversion to surgery. There were no procedure related deaths. According to the multivariate logistic regression analyses, older age (>70 years, p = 0.004), location (upper esophagus, p = 0.001), larger size (maximal diameter > 30 mm, p = 0.005), and longer impaction time (>40 h, p < 0.001) were significant risk factors predicting conversion to surgery due to inability to remove the foreign body endoscopically. CONCLUSIONS: Most of the foreign bodies in the UGIT were successfully removed by endoscopic techniques. However, surgical removal might need to be considered in patients with age >70 years, and those with foreign bodies in the upper esophagus, maximal diameter >30 mm, and impaction time >40 h, due to the possible high failure rate of endoscopic removal. PMID- 25805242 TI - Importance of diaphragm thickness in amyotrophic lateral sclerosis patients with diaphragm pacing system implantation. AB - INTRODUCTION: Severe respiratory failure develops as a result of the involvement of the respiratory muscles in patients with amyotrophic lateral sclerosis (ALS). Implantation of diaphragm pacing system (DPS) has been carried out on ALS patients since 2005 to avoid these situations, but the importance of diaphragm thickness has not yet been established clearly. MATERIAL AND METHOD: We retrospectively evaluated 34 ALS patients who had previously implanted DPS to detect the importance of diaphragm thickness. We investigated the effect of diaphragm thickness, which was measured by preoperative thorax computerized tomography on preoperative respiratory function tests (RFT), arterial blood gas (ABG) analysis, postoperative 3- and 6-month oxygen saturations and mortality. RESULTS: The right diaphragm thickness was calculated as 4.60 (2.95-6.00) mm, while the left diaphragm thickness was 4.10 (2.77-6.00) mm. Six patients died during the follow-up period. We did not detect a significant relationship between ABG parameters, RFT and diaphragm thickness. However, according to our observations, the diaphragm thickness was significantly related to mortality. The right diaphragm was significantly thinner in cases that required preoperative respiratory support and had percutaneous endoscopic gastrostomy. When the cut-off values for the diaphragm thickness were accepted as 3.50 mm, significantly higher mortality among patients below this was observed. CONCLUSION: Diaphragm thickness is an important criterion in cases for which DPS implantation is planned. We consider that avoidance of DPS implantation is more suitable for cases with a diaphragm thickness below 3.50 mm because of mortality. PMID- 25805244 TI - Role of synergistic pi-pi stacking and X-H...Cl (X = C, N, O) H-bonding interactions in gelation and gel phase crystallization. AB - The self-assembly of p-pyridyl-ended oligo-p-phenylenevinylenes (OPVs) in ethanol leads to the formation of either hollow or solid microrods. The corresponding protonated OPVs with n-butyl chains induce transparent gelation and also gel phase crystallization owing to various synergistic noncovalent interactions. The chloride ion-selective gelation, AIEE and stimuli responsiveness of the gel are also observed. PMID- 25805241 TI - 3D visualization reduces operating time when compared to high-definition 2D in laparoscopic liver resection: a case-matched study. AB - OBJECTIVE: To evaluate the effect of three-dimensional (3D) visualization on operative performance during elective laparoscopic liver resection (LLR). BACKGROUND: Major limitations of conventional laparoscopy are lack of depth perception and tactile feedback. Introduction of robotic technology, which employs 3D imaging, has removed only one of these technical obstacles. Despite the significant advantages claimed, 3D systems have not been widely accepted. METHODS: In this single institutional study, 20 patients undergoing LLR by high definition 3D laparoscope between April 2014 and August 2014 were matched to a retrospective control group of patients who underwent LLR by two-dimensional (2D) laparoscope. RESULTS: The number of patients who underwent major liver resection was 5 (25%) in the 3D group and 10 (25%) in the 2D group. There was no significant difference in contralateral wedge resection or combined resections between the 3D and 2D groups. There was no difference in the proportion of patients undergoing previous abdominal surgery (70 vs. 77%, p = 0.523) or previous hepatectomy (20 vs. 27.5%, p = 0.75). The operative time was significantly shorter in the 3D group when compared to 2D (225 +/- 109 vs. 284 +/ 71 min, p = 0.03). There was no significant difference in blood loss in the 3D group when compared to 2D group (204 +/- 226 in 3D vs. 252 +/- 349 ml in 2D group, p = 0.291). The major complication rates were similar, 5% (1/20) and 7.5% (3/40), respectively, (p >= 0.99). CONCLUSION: 3D visualization may reduce the operating time compared to high-definition 2D. Further large studies, preferably prospective randomized control trials are required to confirm this. PMID- 25805243 TI - Superior vena cava cannulation in aortic valve surgery: an alternative strategy for a hemisternotomy approach. AB - Minimally invasive aortic surgery is increasingly being utilized, in particular, through ministernotomy. The choice of the cannulation site is problematic. Venous cannulation may result in wound complications if the femoral vein is used, or may be bulky if the right atrial appendage is used. Our technique of superior vena cava cannulation not only avoids the risk of complications related to the groin but also provides good visualization of the aortic valve making valve implantation easier, especially when using sutureless bioprosthetic valves. PMID- 25805245 TI - Nitration of plant apoplastic proteins from cell suspension cultures. AB - Nitric oxide causes numerous protein modifications including nitration of tyrosine residues. This modification, though one of the greatest biological importance, is poorly recognized in plants and is usually associated with stress conditions. In this study we analyzed nitrotyrosines from suspension cultures of Arabidopsis thaliana and Nicotiana tabacum, treated with NO modulators and exposed to osmotic stress, as well as of BY2 cells long-term adapted to osmotic stress conditions. Using confocal microscopy, we showed that the cell wall area is one of the compartments most enriched in nitrotyrosines within a plant cell. Subsequently, we analyzed nitration of ionically-bound cell-wall proteins and identified selected proteins with MALDI-TOF spectrometry. Proteomic analysis indicated that there was no significant increase in the amount of nitrated proteins under the influence of NO modulators, among them 3-morpholinosydnonimine (SIN-1), considered a donor of nitrating agent, peroxynitrite. Moreover, osmotic stress conditions did not increase the level of nitration in cell wall proteins isolated from suspension cells, and in cultures long-term adapted to stress conditions; that level was even reduced in comparison with control samples. Among identified nitrotyrosine-containing proteins dominated the ones associated with carbon circulation as well as the numerous proteins responding to stress conditions, mainly peroxidases. BIOLOGICAL SIGNIFICANCE: High concentrations of nitric oxide found in the cell wall and the ability to produce large amounts of ROS make the apoplast a site highly enriched in nitrotyrosines, as presented in this paper. Analysis of ionically bound fraction of the cell wall proteins indicating generally unchanged amounts of nitrotyrosines under influence of NO modulators and osmotic stress, is noticeably different from literature data concerning, however, the total plant proteins analysis. This observation is supplemented by further nitroproteome analysis, for cells long-term adapted to stressful conditions, and results showing that such conditions did not always cause an increase in nitrotyrosine content. These findings may be interpreted as characteristic features of apoplastic protein nitration. PMID- 25805247 TI - Role of the nanocrystallinity on the chemical ordering of Co(x)Pt(100-x) nanocrystals synthesized by wet chemistry. AB - Co(x)Pt(100-x) nanoalloys have been synthesized by two different chemical processes either at high or at low temperature. Their physical properties and the order/disorder phase transition induced by annealing have been investigated depending on the route of synthesis. It is demonstrated that the chemical synthesis at high temperature allows stabilization of the fcc structure of the native nanoalloys while the soft chemical approach yields mainly poly or non crystalline structure. As a result the approach of the order/disorder phase transition is strongly modified as observed by high-resolution transmission electron microscopy (HR-TEM) studies performed during in situ annealing of the different nanoalloys. The control of the nanocrystallinity leads to significant decrease in the chemical ordering temperature as the ordered structure is observed at temperatures as low as 420 degrees C. This in turn preserves the individual nanocrystals and prevents their coalescence usually observed during the annealing necessary for the transition to an ordered phase. PMID- 25805248 TI - 3D-printed system optimizing dissolution of hyperpolarized gaseous species for micro-sized NMR. AB - Dissolution of hyperpolarized species in liquids of interest for NMR is often hampered by the presence of bubbles that degrade the field homogeneity. Here a device composed of a bubble pump and a miniaturized NMR cell both fitted inside the narrow bore of an NMR magnet is built by 3D printing. (129)Xe NMR experiments performed with hyperpolarized xenon reveal high and homogeneous dissolution of the gas in water. PMID- 25805246 TI - The role of childhood maltreatment in the altered trait and global expression of personality in cocaine addiction. AB - BACKGROUND AND AIMS: Drug addictions are debilitating disorders that are highly associated with personality abnormalities. Early life stress (ELS) is a common risk factor for addiction and personality disturbances, but the relationships between ELS, addiction, and personality are poorly understood. METHODS: Ninety five research participants were assessed for and grouped by ELS history and cocaine dependence. NEO-FFI personality measures were compared between the groups to define ELS- and addiction-related differences in personality traits. ELS and cocaine dependence were then examined as predictors of personality trait scores. Finally, k-means clustering was used to uncover clusters of personality trait configurations within the sample. Odds of cluster membership across subject groups was then determined. RESULTS: Trait expression differed significantly across subject groups. Cocaine-dependent subjects with a history of ELS (cocaine+/ELS+) displayed the greatest deviations in normative personality. Cocaine dependence significantly predicted four traits, while ELS predicted neuroticism and agreeableness; there was no interaction effect between ELS and cocaine dependence. The cluster analysis identified four distinct personality profiles: Open, Gregarious, Dysphoric, and Closed. Distribution of these profiles across subject groups differed significantly. Inclusion in cocaine+/ELS+, cocaine /ELS+, and cocaine-/ELS- groups significantly increased the odds of expressing the Dysphoric, Open and Gregarious profiles, respectively. CONCLUSIONS: Cocaine dependence and early life stress were significantly and differentially associated with altered expression of individual personality traits and their aggregation as personality profiles, suggesting that individuals who are at-risk for developing addictions due to ELS exposure may benefit from personality centered approaches as an early intervention and prevention. PMID- 25805249 TI - Unexpected diagnosis of basal cell carcinoma. PMID- 25805250 TI - A study of Internet searches for medical information in dermatology patients: The patient-physician relationship. AB - BACKGROUND: The use of the Internet to search for medical information is considered by some physicians as an invasion of their medical domain and a reflection of a lack of trust in their advice and recommendations. OBJECTIVE: The main objective of this study was to estimate the amount of medical information gathered from the Internet and to establish whether these online searches reflect a lower degree of patient satisfaction. PATIENTS AND METHODS: A survey was conducted among 175 patients seen at the melanoma and psoriasis units of San Cecilio University Hospital in Granada, Spain between May 2010 and December 2011. RESULTS: Online searches for medical information were performed by 44.4% of patients who returned correctly completed questionnaires. The main reasons given for these searches were to complement appropriate information provided by the physician (67.3%) and to gather information before consultation with the physician (36.5%). Variables associated with the search for medical information on the Internet in the multivariate analysis were a higher educational level, a higher score on two items in the Need for Cognition Scale, and consultation of mass media other than the Internet. LIMITATIONS: Studies with larger numbers of patients and other diseases, however, are required to confirm these results. CONCLUSIONS: The search for medical information is a widespread reality among patients with psoriasis and melanoma and it is not associated with a poor relationship with the physician. Dermatologists can play a beneficial role by recommending trustworthy Internet sites during the patient's visit and by promoting the development of pages by scientific societies to provide high quality information. PMID- 25805251 TI - Placental arsenic concentrations in relation to both maternal and infant biomarkers of exposure in a US cohort. AB - Arsenic crosses the placenta and may have adverse consequences in utero and later in life. At present, little is known about arsenic concentrations in placenta and their relation to maternal and infant exposures particularly at common levels of exposure. We measured placenta arsenic in a US cohort potentially exposed via drinking water from private wells, and evaluated the relationships between placenta and maternal and infant biomarker arsenic concentrations. We measured total arsenic concentrations in placental samples from women enrolled in the New Hampshire Birth Cohort Study (N=766). We compared these data to maternal urinary arsenic (total arsenic and individual species) collected at approximately 24-28 week gestation, along with maternal post-partum toenails and infant toenails using non-parametric multivariate analysis of log10-transformed data. We also examined the association between placental arsenic and household drinking water arsenic. Placenta arsenic concentrations were related to arsenic concentrations in maternal urine (beta 0.55, P value <0.0001), maternal (beta 0.30, P value 0.0196) and infant toenails (beta 0.40, P value 0.0293) and household drinking water (beta 0.09, P value <0.0001). Thus, our data suggest that placenta arsenic concentrations reflect both maternal and infant exposures. PMID- 25805252 TI - Chlorine isotopic composition of perchlorate in human urine as a means of distinguishing among exposure sources. AB - Perchlorate (ClO4(-)) is a ubiquitous environmental contaminant with high human exposure potential. Natural perchlorate forms in the atmosphere from where it deposits onto the surface of Earth, whereas synthetic perchlorate is manufactured as an oxidant for industrial, aerospace, and military applications. Perchlorate exposure can potentially cause adverse health effects in humans by interfering with the production of thyroid hormones through competitively blocking iodide uptake. To control and reduce perchlorate exposure, the contributions of different sources of perchlorate exposure need to be quantified. Thus, we demonstrate a novel approach for determining the contribution of different perchlorate exposure sources by quantifying stable and radioactive chlorine isotopes of perchlorate extracted from composite urine samples from two distinct populations: one in Atlanta, USA and one in Taltal, Chile (Atacama region). Urinary perchlorate from the Atlanta region resembles indigenous natural perchlorate from the western USA (delta(37)Cl=+4.1+/-1.00/00; (36)Cl/Cl=1 811 (+/ 136) * 10(-15)), and urinary perchlorate from the Taltal, Chile region is similar to natural perchlorate in nitrate salt deposits from the Atacama Desert of northern Chile (delta(37)Cl=-11.0+/-1.00/00; (36)Cl/Cl=254 (+/-40) * 10(-15)). Neither urinary perchlorate resembled the isotopic pattern found in synthetic perchlorate. These results indicate that natural perchlorate of regional provenance is the dominant exposure source for the two sample populations, and that chlorine isotope ratios provide a robust tool for elucidating perchlorate exposure pathways. PMID- 25805253 TI - Assessment of exposures and potential risks to the US adult population from wear (attrition and abrasion) of gold and ceramic dental restorations. AB - Little has been published on the chemical exposures and risks of dental restorative materials other than from dental amalgam and composite resins. Here we provide the first exposure and risk assessment for gold (Au) alloy and ceramic restorative materials. Based on the 2001-2004 US National Health and Nutrition Examination Survey (NHANES), we assessed the exposure of US adults to the components of Au alloy and ceramic dental restorations owing to dental material wear. Silver (Ag) is the most problematic component of Au alloy restorations, owing to a combination of toxicity and proportional composition. It was estimated that adults could possess an average of four tooth surfaces restored with Au alloy before exceeding, on average, the reference exposure level (REL) for Ag. Lithium (Li) is the most problematic component of dental ceramics. It was estimated that adults could possess an average of 15 tooth surfaces restored with ceramics before exceeding the REL for Li. Relative risks of chemical exposures from dental materials decrease in the following order: Amalgam>Au alloys>ceramics>composite resins. PMID- 25805257 TI - [Journal's step to leap to the international level and communication skill]. PMID- 25805255 TI - A geospatial approach to the prediction of indoor radon vulnerability in British Columbia, Canada. AB - Radon is a carcinogenic radioactive gas produced by the decay of uranium. Accumulation of radon in residential structures contributes to lung cancer mortality. The goal of this research is to predict residential radon vulnerability classes for the province of British Columbia (BC) at aggregated spatial units. Spatially referenced indoor radon concentration data were partitioned into low, medium, and high classes of radon vulnerability. Radon vulnerability classes were then linked to environmental and housing data derived from existing geospatial datasets. A Balanced Random Forests algorithm was used to model environmental predictors of indoor radon vulnerability and values at un sampled locations across BC. A model was generated and evaluated using accuracy, precision, and kappa statistics. The influence of predictor variables was investigated through variable importance and partial dependence plots. The model performed 34% better than a random classifier. Increased probabilities of high vulnerability were associated with cold and dry winters, close proximity to major river systems, and fluvioglacial and colluvial soil parent materials. The Kootenays and Columbia-Shuswap regions were most at risk. Here, we present a novel method for predictive radon mapping that is broadly applicable to regions throughout the world. PMID- 25805258 TI - [Long for wonderful leadership in a new era of the Korean Association of Medical Colleges]. PMID- 25805259 TI - Five suggestions for future medical education in Korea. AB - This study is to investigate the historical characteristics of medical education and healthcare environment in Korea and to suggest the desirable direction for future medical education. We draw a consensus through the literature analysis and several debates from the eight experts of medical education. There are several historical characteristics of medical education: medical education as vocational education and training, as a higher education, rapid growth of new medical schools, change to the medical education system, curriculum development, reinforcement of medical humanities, improvement of teaching and evaluation methods, validation of the national health personnel licensing examination, accreditation system for quality assurance, and establishment of specialized medical education division. The changes of health care environment in medical education are development of medical technologies, changes in the structures of the population and diseases, growth of information and communication technology, consumer-centered society, and increased intervention by the third party stakeholder. We propose five suggestions to be made to improve future medical education. They are plan for outcome and competency-based medical education, connection between the undergraduate and graduate medical education, reinforcement of continuous quality improvement of medical education, reorganization of the medical education system and construction of leadership of "academic medicine." PMID- 25805256 TI - Donepezil reverses intermittent stress-induced generalized chronic pain syndrome in mice. AB - Treatment of fibromyalgia is an unmet medical need. To develop novel therapies for the treatment of fibromyalgia, we explored pain therapeutic actions of existing pharmaceuticals, which inhibit the somatic symptoms frequently observed in fibromyalgia patients. This study first examined the therapeutic actions of pilocarpine, which inhibits dry-eye and dry-mouth symptoms, using an experimental fibromyalgia-like chronic pain model produced by intermittent cold stress (ICS) in mice. A single intraperitoneal and intracerebroventricular, but not intrathecal, pilocarpine administration attenuated ICS-induced thermal hyperalgesia and mechanical allodynia, and this action was abolished by muscarinic antagonist pirenzepine (i.c.v.). Treatment with 1-10 MUg/kg donepezil (i.p.), which can easily penetrate into the brain, also showed similar therapeutic effects. Importantly, we found that both pilocarpine and donepezil produced antihyperalgesic effects via supraspinal action. Furthermore, repeated donepezil treatments completely cured the ICS-induced hyperalgesia and allodynia even after the cessation of drug treatments. Acute and chronic treatments of these cholinomimetics had no effects on the nociceptive threshold in control animals. By contrast, the lack of morphine (i.c.v.) analgesia initially observed in the ICS model remained in ICS model mice treated with long-term donepezil. Collectively, these findings suggest that stimulation of the muscarinic cholinergic system effectively inhibits some mechanisms underlying chronic pain in the ICS model, but does not inhibit the lack of descending pain-inhibitory mechanisms, which are driven by central morphine. PMID- 25805260 TI - Evaluating the short-term effects of a communication skills program for preclinical medical students. AB - PURPOSE: Regardless of the growing importance of communication skills as a core clinical competence, few studies have determined the effects of communication skills courses in undergraduate medical curricula in Asian medical schools. The purpose of this study was to examine the effectiveness of a communication skills program for preclinical medical students. METHODS: A communication skills course was provided to 111 second-year medical students in a medical college in Korea. Students' self-assessed competency of communication skills was evaluated by a questionnaire survey. To examine the improvement in observed communication skills, the students' encounters with standardized patients (SPs) were assessed at the first session and at the final course assessment. A structured checklist, consisting of 25 communication skills items, was used for the assessment. RESULTS: Students' self-assessed competency of communication skills increased significantly after completion of the course (p<0.001). The observed communication skills scores also improved significantly at the end of the course; the mean scores of the first SPs encounters was 49.6 (standard deviation [SD], 11.1), and those of cases A and B at the final assessment were 61.5 (SD, 8.4) and 69.6 (SD, 7.8), respectively (F61=269.54, p<0.001). CONCLUSION: Even a short period of medical communication skills course was beneficial in developing and improving communication skills competency in preclinical medical students. Further studies should be followed to examine whether the acquisition of communication skills during preclinical studies can be sustained into clerkship and actual practice. PMID- 25805261 TI - The development and effects of a medical communication skills program for medical school students. AB - PURPOSE: The purpose of the study is to develop education programs for improving medical school students' medical communication ability, and to provide basic information to help develop and operate medical communication education programs by analyzing the education programs and students satisfaction from the education effects. METHODS: The method was to survey 116 sophomores in C medical school in 2014 in order to research students' demands for the medical communication education, level differences of communication between before and after of the education, and students' satisfaction from the education program. Analysis of frequency, paired samples t-test, descriptive statistic analysis were used for the research. RESULTS: There were not only many students who did not get general communication educations before admission, but also many students who said they need medical communication education. On the whole, students' abilities of communication were improved. Building relationship, information gathering, sharing information, understanding one's perspectives factors was improved meaningfully in the statistics. However opening relationship, reach agreement, and providing closure were not improved meaningfully in the statistics. On the whole, the students were satisfied from the education programs. CONCLUSION: To develop education programs for medical communication ability, we need to construct the objectives of education and contents by researching students' demands and level of learning in communication area. Moreover we have to design curriculum to maintain the education effects consistently. PMID- 25805262 TI - Development and validation of the medical student stress scale in Korea. AB - PURPOSE: Medical students experience various stresses that arise in a special environment. However, there is no specific stress scale for medical students with regard to their environment in Korea. Therefore, in this study, we developed and confirmed the validity of a stress scale for medical students in Korea. METHODS: A draft version of the scale was developed on the basis of open-ended questionnaires from 97 medical students. The validity of the content of this scale was evaluated by three medical educationists. The scale was administered to 435 third and fourth grade medical students as the main survey. For our data, we performed an exploratory factor analysis and confirmatory factor analysis. We used Cronbach alpha index to determine internal consistency. RESULTS: Six factors with 40 items were extracted through the exploratory factor analysis: academic stress (9 items); clerkship stress (11 items); interpersonal stress (7 items); career stress (8 items); health-related stress (3 items); and financial stress (2 items). These factors showed a statistically significant correlation. The confirmatory factor analysis demonstrated a favorable RMSEA (0.053) and reasonable fit (CFI=0.847, TLI=0.833). Cronbach alpha values of the six factors ranged from 0.63 to 0.85. CONCLUSION: The medical student stress scale had a good model fit. It is a valid and reliable instrument in identifying stress in medical students and can be used in future studies. Also, the scale is expected to provide individual stress profiles for students to help them manage stress more effectively. PMID- 25805263 TI - Analysis of medical students' needs for development of a career guidance program. AB - PURPOSE: The purpose of this study is to provide basic data for the development of a career guidance program through a demand survey. For this purpose, three study topics were examined: Is there a difference between the satisfaction and importance of a career program? Is there a difference between the satisfaction and importance of a career program by gender, grade level? and What type of mentor and the mentoring way of medical students demanded? METHODS: The subjects were 380 students at Seoul National University College of Medicine. The data were analyzed by frequency analysis, paired t-test, and Borich's formula. RESULTS: By t-test with matched samples for satisfaction-importance, We noted statistically significant differences in all domains. In particular, the difference was greater in the second year. According to the needs analysis, the most urgent program is meeting with seniors in various career areas. Also, medical students hope for mentor from clinical professors of the university and successful medical practitioners, and personal counseling. CONCLUSION: These results show that medical students need a career guidance program. The findings of the study can be used to guide the development of career education programs and curriculum for medicine students. PMID- 25805254 TI - The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: assessment of environmental exposures. AB - The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3-4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set. PMID- 25805264 TI - How well do medical students express empathy? AB - PURPOSE: Empathy is an important trait of a physician and a key element in the physician-patient relationship. This study evaluated the ability to express empathy in medical students. METHODS: Medical student empathy was measured by the modified Pencil-and-Paper Empathy Rating Test of Winefield and Chur-Hansen. The subjects comprised 110 medical students. The data were analyzed by descriptive analysis and t-test using SPSS version 21.0 (IBM Corp.). RESULTS: Empathy rating test scores were low-level in medical students (mean, 12.59). There were no differences in the level of ability to express empathy between genders (t=-1.714, p=0.089). CONCLUSION: Our results suggest that practical training in expressing empathy should be included in medical education and that an empathy training program must be focused on changes in behavior. PMID- 25805265 TI - Can the multiple mini-interview predict academic achievement in medical school? AB - PURPOSE: The purpose of this study was to determine whether the multiple mini interview (MMI) predicts academic achievement for subjects in a medical school curriculum. METHODS: Of 49 students who were admitted in 2008, 46 students finished the entire medical education curriculum within 4 years. We calculated the Pearson correlation coefficients between the total MMI score of the 46 graduates and their academic achievements in all subjects of the curriculum. RESULTS: The correlation coefficients between total MMI score and academic achievement in Medical Interview and History Taking, Problem-Based Learning, Doctoring I, and Clinical Practice of Surgery ranged from 0.4 to 0.7, indicating that they were moderately related. The values between total MMI score and achievement in Research Overview, Technical and Procedural Skills, Clinical Performance Examinations 1 and 3, Clinical Practice of Laboratory Medicine and Psychiatry, Neurology, and Orthopedics ranged from 0.2 to 0.4, which meant that they were weakly related. CONCLUSION: MMI score can predict medical student' academic achievement in subjects in the medical humanities and clinical practice. PMID- 25805266 TI - What kind of feedback do medical students want? AB - PURPOSE: Feedback in medical education is as important as developing the curriculum and choosing the right method of instruction. This study measured three overarching areas: student satisfaction rates with academic feedback, the type and helpfulness of the feedback, and the types of feedback that students want. METHODS: In December 2013, 166 students answered a student survey that consisted of 26 items. The survey asked questions on their experiences with the overall feedback that was given the previous semester, the satisfaction rate, the type of feedback that was received, the helpfulness of the feedback, and the types of feedback that were desired after examinations and learning tasks. RESULTS: Overall, 35% of the students were satisfied with the feedback that they received in the previous semester. Students wanted more systematic (61.4%) and timely feedback (30.1%). The types of feedback that were most desired were "written comment feedback from the teacher" (51.8%) for learning tasks and "item difficulty, percentile ranks feedback" for examinations (62.0%). CONCLUSION: Students found the current feedback to be helpful, but the lack of feedback that students desired indicates that we must provide more systematic feedback in a more timely manner. PMID- 25805267 TI - Biological characteristics of muscle-derived satellite cells isolated from rats at different postnatal days. AB - This study investigated the in vitro growth characteristics and differential potential of muscle-derived satellite cells (MDSCs) derived from rats at different postnatal (P) stages, in order to expand the range of source material for tissue engineering. Rat MDSCs were isolated from P5, P10, P15, P21 and P42 rat skeletal muscles using double enzyme digestion and differential adherent culture. Neurogenic, osteogenic and myogenic induction media were used to induce directed differentiation. Differentiated nerve cells, osteoblasts and myotubes were identified by their morphology and immunohistochemical staining. Most cells transformed into spindle-shaped mononuclear cells after 48 h and proliferated rapidly. MDSCs were difficult to isolate from P42 rats. After neurogenesis, four groups MDSCs formed neuron-specific enolase positive polygonal-shaped dendritic cells. After osteogenesis, P5, P10, P15 and P21 MDSCs formed Alizarin red- and osteocalcin-positive bone nodules. After myogenesis, myotubes were formed and were fast muscle myosin-positive. MDSCs derived from P5, P10, P15 and P21 rat skeletal muscle are easy to isolate, culture and amplify in vitro, which increases the range of source material available for tissue engineering. PMID- 25805268 TI - Revisiting Verhulst and Monod models: analysis of batch and fed-batch cultures. AB - The paper re-evaluates Verhulst and Monod models. It has been claimed that standard logistic equation cannot describe the decline phase of mammalian cells in batch and fed-batch cultures and in some cases it fails to fit somatic growth data. In the present work Verhulst, population-based mechanistic growth model was revisited to describe successfully viable cell density (VCD) in exponential and decline phases of batch and fed-batch cultures of three different CHO cell lines. Verhulst model constants, K, carrying capacity (VCD/ml or MUg/ml) and r, intrinsic growth factor (h(-1)) have physical meaning and they are of biological significance. These two parameters together define the course of growth and productivity and therefore, they are valuable in optimisation of culture media, developing feeding strategies and selection of cell lines for productivity. The Verhulst growth model approach was extended to develop productivity models for batch and fed-batch cultures. All Verhulst models were validated against blind data (R(2) > 0.95). Critical examination of theoretical approaches concluded that Monod parameters have no physical meaning. Monod-hybrid (pseudo-mechanistic) batch models were validated against specific growth rates of respective bolus and continuous fed-batch cultures (R(2) ~ 0.90). The reduced form of Monod-hybrid model CL/(KL + CL) describes specific growth rate during metabolic shift (R(2) ~ 0.95). Verhulst substrate-based growth models compared favourably with Monod hybrid models. Thus, experimental evidence implies that the constants in the Monod-hybrid model may not have physical meaning but they behave similarly to the biological constants in Michaelis-Menten enzyme kinetics, the basis of the Monod growth model. PMID- 25805269 TI - Effect of Trace and Toxic Elements of Different Brands of Cigarettes on the Essential Elemental Status of Irish Referent and Diabetic Mellitus Consumers. AB - Cigarette smoking interferes with the metal homeostasis of the human body, which plays a crucial role for maintaining the health. A significant flux of heavy metals, among other toxins, reaches the lungs through smoking. In the present study, the relationship between toxic element (TE) exposure via cigarette smoking and diabetic mellitus incidence in population living in Dublin, Ireland is investigated. The trace [zinc (Zn) and selenium (Se)] and toxic elements arsenic (As), aluminum (Al), cadmium (Cd), nickel (Ni), mercury (Hg), and lead (Pb) were determined in biological (scalp hair and blood) samples of patients diagnosed with diabetic mellitus, who are smokers living in Dublin, Ireland. These results were compared with age- and sex-matched healthy, nonsmokers controls. The different brands of cigarette (filler tobacco, filter, and ash) consumed by the studied population were also analyzed for As, Al, Cd, Ni, Hg, and Pb. The concentrations of TEs in biological samples and different components of cigarette were measured by inductively coupled plasma atomic emission spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked using certified reference materials (CRM). The recovery of all the studied elements was found to be in the range of 96.4-99.7% in certified reference materials. The filler tobacco of different branded cigarettes contains Hg, As, Al, Cd, Ni, and Pb concentrations in the ranges of 9.55-12.4 ng/cigarette, 0.432-0.727 MUg/cigarette, 360-496 MUg/cigarette, 1.70-2.12 MUg/cigarette, 0.715-1.52 MUg/cigarette, and 0.378-1.16 MUg/cigarette, respectively. The results of this study showed that the mean values of Al, As, Cd, Hg, Ni, and Pb were significantly higher in scalp hair and blood samples of diabetic mellitus patients in relation to healthy controls, while the difference was significant in the case of smoker patients (p < 0.001). The levels of all six toxic elements were twofolds to threefolds higher in scalp hair and blood samples of nondiabetic mellitus smoker subjects as compared to nonsmoker controls. The high exposure of toxic metals as a result of cigarette smoking may be synergistic with risk factors associated with diabetic mellitus. PMID- 25805270 TI - Chromium Is Elevated in Fin Whale (Balaenoptera physalus) Skin Tissue and Is Genotoxic to Fin Whale Skin Cells. AB - Hexavalent chromium (Cr(VI)) is present in the marine environment and is a known carcinogen and reproductive toxicant. Cr(VI) is the form of chromium that is well absorbed through the cell membrane. It is also the most prevalent form in seawater. We measured the total Cr levels in skin biopsies obtained from healthy free-ranging fin whales from the Gulf of Maine and found elevated levels relative to marine mammals in other parts of the world. The levels in fin whale biopsies ranged from 1.71 to 19.6 MUg/g with an average level of 10.07 MUg/g. We also measured the cytotoxicity and genotoxicity of Cr(VI) in fin whale skin cells. We found that particulate and soluble Cr(VI) are both cytotoxic and genotoxic to fin whale skin cells in a concentration-dependent manner. The concentration range used in our cell culture studies used environmentally relevant concentrations based on the biopsy measurements. These data suggest that Cr(VI) may be a concern for whales in the Gulf of Maine. PMID- 25805271 TI - Ameliorative Effects of Selenium on Cadmium-Induced Oxidative Stress and Endoplasmic Reticulum Stress in the Chicken Kidney. AB - The harmful influences of dietary cadmium (Cd) on the chicken kidney and the protective role of selenium (Se) against Cd-induced nephrotoxicity in the chicken are relatively unexplored subjects. The aim of this study was to investigate the ameliorative role of Se on the effects of Cd-induced oxidative stress, endoplasmic reticulum stress, and apoptosis in chicken kidneys. For this study, 100-day-old chickens received Se (as 10 mg Na2SeO3/kg dry weight of diet), Cd (as 150 mg CdCl2/kg dry weight of diet), or Cd + Se in their diets for 60 days. Then, the histopathological changes, Cd and Se contents, levels of oxidative stress, inducible nitric oxide synthase-nitric oxide (iNOS-NO) system activity, levels of endoplasmic reticulum (ER) stress, results of the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay of apoptosis, and expression levels of Bcl-2 and caspase 3 in the kidney were examined. The results showed that Cd exposure caused histopathological and ultrastructural damage and apoptosis of the kidneys. Cd administration significantly increased the accumulation of Cd, the malondialdehyde (MDA) content, NO production, iNOS activity, iNOS expression levels, expression levels of ER stress-related genes (GRP78, GRP94, ATF4, ATF6, and IRE) and the pro-apoptosis gene caspase 3, and the rate of apoptosis. Cd administration markedly decreased the Se content, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, and anti apoptosis gene Bcl-2 expression levels. Co-treatment with Se and Cd obviously reduced the accumulation of Cd, Cd-induced histopathological and ultrastructural changes, oxidative stress, iNOS-NO system activity, ER stress, caspase 3 expression levels, and the rate of apoptosis in the kidneys. These results suggested that Cd exposure caused renal injury and that Se ameliorated Cd-induced nephrotoxicity in chickens. PMID- 25805272 TI - Human Skin Cells Are More Sensitive than Human Lung Cells to the Cytotoxic and Cell Cycle Arresting Impacts of Particulate and Soluble Hexavalent Chromium. AB - Hexavalent chromium Cr(VI) is a known human lung carcinogen, with solubility playing an important role in its carcinogenic potency. Dermal exposure to Cr(VI) is common and has been associated with skin damage; however, no link between chromate exposure and skin cancer has been found. In this study, we compared the cytotoxic and clastogenic effects of Cr(VI) and its impacts on cell cycle progression in human lung and skin fibroblasts. We found human skin cells arrested earlier in their cell cycle and exhibit more cytotoxicity than human lung cells, despite taking up similar amounts of Cr. These outcomes are consistent with a hypothesis that different cellular and molecular responses underlie the differences in carcinogenic outcome in these two tissues. PMID- 25805273 TI - Comparison of weight-for-height and mid-upper arm circumference (MUAC) in a therapeutic feeding programme in South Sudan: is MUAC alone a sufficient criterion for admission of children at high risk of mortality? AB - OBJECTIVE: The present study was performed to describe the operational implications of using mid-upper arm circumference (MUAC) as a single admission criterion for treatment of severe acute malnutrition in South Sudan. DESIGN: We performed a retrospective analysis of routine programme data of children with severe acute malnutrition aged 6-59 months admitted to a therapeutic feeding programme using weight-for-height Z-score (WHZ) and/or MUAC. To understand the implications of using MUAC as a single admission criterion, we compared patient characteristics and treatment outcomes for children admitted with MUAC<115 mm (irrespective of WHZ) v. children admitted with WHZ<-3 and MUAC>=115 mm. RESULTS: Of 2205 children included for analysis, 719 (32.6 %) were admitted to the programme with MUAC<115 mm and 1486 (67.4 %) with WHZ<-3 and MUAC>=115 mm. Children who would have been admitted using a single MUAC<115 mm criterion were more severely malnourished and more likely to be female and younger. Compared with children admitted with WHZ<-3 and MUAC>=115 mm, children who would have been admitted using MUAC<115 mm were less likely to recover (54 % v. 69 %) and had higher risk of death (4 % v. 1 %), but responded to treatment with greater weight and MUAC gains. MUAC<115 mm would have failed to identify 33 % of deaths, while 98 % were identified by WHZ<-3 alone and 100 % by MUAC<130 mm. CONCLUSIONS: The study shows that MUAC<115 mm identified more severely malnourished children with a higher risk of mortality but failed to identify a third of the children who died. Admission criteria for therapeutic feeding should be adapted to the programmatic context with consideration for both operational and public health implications. PMID- 25805274 TI - A systematic examination of the effect of tissue glues on rhytidectomy complications. AB - BACKGROUND: Fibrin glue has widespread use in multiple fields of surgery. There have been numerous studies on the use of fibrin glue in facelifts, with no consensus regarding differences in outcomes. OBJECTIVES: This study compared the risk of hematoma, seroma, and the 24-hour drainage volume in all published prospective controlled trials. METHODS: A MEDLINE search of English-language articles on fibrin glue and rhytidectomy published up to July 2013 yielded 49 citations. After screening, we examined 7 relevant controlled trials. The DerSimonian and Laird random-effects model was used to perform the meta-analysis. RESULTS: Seven controlled trials measuring the outcomes of fibrin glue in facelifts were used to estimate the pooled relative risk of complications and confidence intervals. Hematoma formation was four times less likely with the use of fibrin glue (relative risk 0.25, P = .002). There was no significant reduction in seroma formation (relative risk 0.56, P = .19). There was not enough data to properly measure 24-hour drainage and ecchymoses. CONCLUSIONS: This analysis suggests that fibrin glue reduces the rates of hematoma formation, but does not significantly reduce the rates of seroma development. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 25805275 TI - Environmental factors that contribute to upper eyelid ptosis: a study of identical twins. AB - BACKGROUND: Current literature provides little information about the impact of environmental exposures on the severity of acquired blepharoptosis. OBJECTIVE: The authors assessed environmental factors that may contribute to eyelid ptosis in a population of identical twins. METHODS: Photographs of 286 sets of twins from a prospectively collected database from 2008 to 2010 were reviewed. The authors identified 96 sets of identical twins (192 individual persons) who had differing severity of ptosis. Digital photographs were analyzed, and the degree of ptosis was measured in each eye of every subject. The external factors that could potentially contribute to blepharoptosis were taken into consideration. The authors then assessed the correlations of 9 different environmental risk factors with ptosis. Generalized linear mixed model were constructed to determine the associations of ptosis measurements with environmental risk factors obtained from the subject survey database. RESULTS: The mean level of upper eyelid ptosis in the study population was 1.1 mm. The mean difference in ptosis between twins was 0.5 mm. Wearing contact lenses, either hard or soft, was significantly associated with ptosis. The mean ptosis measurement among twins who did not wear contact lenses was 1.0 mm; for those who wore soft contact lenses, the mean was 1.41 mm, and for those who wore hard contact lenses, the mean was 1.84 mm. CONCLUSIONS: Acquired ptosis is not linked to body mass index, smoking behavior, sun exposure, alcohol use, work stress, or sleep. Wearing either hard or soft lenses was associated with an increased risk of ptosis. These influences are independent of genetic predisposition. LEVEL OF EVIDENCE: 3 Diagnostic. PMID- 25805277 TI - Commentary on: The Osseocartilaginous Vault of the Nose: Anatomy and Surgical Observations. PMID- 25805276 TI - The osseocartilaginous vault of the nose: anatomy and surgical observations. AB - BACKGROUND: The dorsal hump and dorsal aesthetic lines have been considered bony and cartilaginous structures. Knowledge of the anatomy of the osseocartilaginous vault is essential for obtaining aesthetically pleasing results of rhinoplasty. OBJECTIVES: The authors described the morphology, embryology, and clinical relevance of the nasal vault and the changes that occur in this area during rhinoplasty. METHODS: Dissections were performed on 15 fresh adult cadavers to examine the anatomy of the osseocartilaginous vault. Intraoperative endoscopic examination of the vault also was performed in 9 rhinoplasty patients before and after dorsal hump reduction. RESULTS: In the cadaver study, the average length of the dorsal keystone area, measured along the dorsal septum, was 8.9 mm, and the average width was 4.9 mm. No significant difference in length was observed between cadaver subgroups with straight or humped nasal profiles. The extent of lateral overlap of the nasal bones with the cephalic portion of the upper lateral cartilages varied. In rhinoplasty patients, the average length of the cartilaginous vault exposed during dorsal reduction was 7.6 mm. CONCLUSIONS: The aesthetic lines and profile of the nose before dorsal reduction are dictated by the cartilaginous vault. After reduction, the dorsal lines are determined by the bony vault edges. In routine rhinoplasty, reduction of dorsal height generally corresponds to removal of the dorsal cartilaginous septum. PMID- 25805278 TI - Rhinoplasty: the nasal bones - anatomy and analysis. AB - BACKGROUND: The analysis of nasal anatomy, and especially the nasal bones including the osseocartilaginous vault, is significant for functional and aesthetic reasons. OBJECTIVES: The objective was to understand the anatomy of the nasal bones by establishing new descriptions, terms, and definitions because the existing parameters were insufficient. Adequate terminology was employed to harmonize the anthropometric and clinical measurements. METHODS: A two-part harvest technique consisting of resecting the specimen and then creating a replica of the skull was performed on 44 cadavers to obtain specific measurements. RESULTS: The nasal bones have an irregular, variable shape, and three distinct angles can be found along the dorsal profile line beginning with the nasion angle (NA), the dorsal profile angulation (DPA) and the kyphion angulation (KA). In 12% of cases, the caudal portion of the nasal bones was straight and without angulation resulting in a "V-shape" configuration. In 88% of cases, the caudal portion of the bone was angulated, which resulted in an "S shape" nasal bone configuration. The intervening cephalic bone, nasion to sellion (N-S), represents the radix while the caudal bone, sellion to r (S-R), represents the bony dorsum. CONCLUSIONS: By standardizing and measuring existing nasal landmarks and understanding the different anatomic configurations of the nasal bones, rhinoplasty surgeons can better plan their operations within the radix and bony and osseocartilaginous vaults. PMID- 25805279 TI - Commentary on: Rhinoplasty: The Nasal Bones - Anatomy and Analysis. PMID- 25805280 TI - Utility of video-assisted endoscopy in transaxillary breast augmentation. AB - BACKGROUND: Breast augmentation through incisions in the axillae is an option for patients who wish to avoid scars on the breasts. The axillary approach also preserves the mammary parenchyma and lactiferous ducts. The utility of video assisted endoscopy during this procedure as a means to improve safety and aesthetic outcomes remains debatable. OBJECTIVES: The authors compared outcomes of transaxillary breast augmentation with and without video-assisted endoscopy. METHODS: Thirty-four women who underwent transaxillary breast augmentation with or without video-assisted endoscopy were evaluated in a prospective, randomized study. Patients received high-profile silicone implants in the subglandular plane and were monitored for an average of 25 months. Operating time, complication rates, postoperative pain, patient satisfaction, and aesthetic parameters were evaluated. RESULTS: Operative time were significantly longer for patients who underwent transaxillary breast augmentation with video-assisted endoscopy compared with patients who underwent nonendoscopic surgery. CONCLUSIONS: Video assisted endoscopy increased operating time but did not improve the safety of transaxillary breast augmentation or yield better aesthetic outcomes. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 25805281 TI - Assessing the augmented breast: a blinded study comparing round and anatomical form-stable implants. AB - BACKGROUND: Controversy persists as to whether round or anatomical form-stable breast implants provide the most aesthetically pleasing results, and there is a paucity of evidence comparing cosmetic outcomes of these two implants. A blinded study comparing aesthetic outcomes was conducted in an attempt to address this issue. OBJECTIVES: The authors compare aesthetic outcomes between round and anatomical form-stable breast implants. METHODS: Pre- and postoperative photographs of 60 consecutive patients undergoing breast augmentation (33 round, 27 anatomical) by a single surgeon were reviewed by 22 plastic surgeons. Photographs were graded on a modified Likert scale (1, poor; 4, excellent) for overall aesthetic result, upper pole contour, and natural appearance. The panel was asked to determine implant shape. RESULTS: Anatomical implants scored higher for upper pole contour: anatomical 2.80 (+/-0.44 - standard deviation) vs round 2.60 (+/-0.38). With regard to natural appearance and overall aesthetic results, anatomical implants scored higher: 2.89 (+/-0.42) vs 2.56 (+/-0.36) and 2.86 (+/ 0.41) vs 2.72 (+/-0.37), respectively. None of these differences achieved statistical significance, and 62.7% of round and 49% of anatomical implants were correctly identified. There was no significant difference in the body mass index (BMI) between the 2 groups (P = .21). CONCLUSIONS: No significant difference (P > .05) in the general and specific cosmetic points between round and anatomical implants was demonstrated; many on the panel were unable to identify implant shape correctly. Both techniques seem to yield good cosmetic results. Clearly the decision on which implant to use must be made on an individual patient basis because many factors influence overall aesthetic outcome. Anatomical implants should not be assumed to produce a more natural result. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 25805283 TI - Methodological guide to adopting new aesthetic surgical innovations. AB - Aesthetic surgery is known for its prolific introduction of new techniques, devices, and products. The implementation of any aesthetic innovation, however, may inadvertently expose patients to potential complications and adverse events. How do we decide whether a new technique or technology is superior-in both safety and effectiveness-compared with prevailing interventions? In this paper, we present some basic steps anchored in evidence-based surgery that aesthetic surgeons need to pursue in the adoption of a new technique, technology, or product. These steps include: (1) gaining familiarity with and understanding the levels of evidence; (2) performing an effective literature search; (3) formulating a critical appraisal of an article; (4) making the decision to adopt or reject; (5) recognizing the need for continued assessment; (6) acknowledging the need for education and credentialing; and (7) translation of the gathered knowledge. We hope that this paper will foster critical thinking and reduce the reliance on "photographic evidence" in aesthetic surgery literature. PMID- 25805282 TI - Development and validation of a photographic scale for assessment of lip fullness. AB - BACKGROUND: As lip augmentation becomes more popular, validated measures of lip fullness for quantification of outcomes are needed. OBJECTIVE: Develop a scale for rating lip fullness and establish its reliability and sensitivity for assessing clinically meaningful differences. METHODS: The initial Allergan Lip Fullness Scale (iLFS; a four-point photographic scale with verbal descriptions) was validated by eight physicians rating 55 live subjects during two rounds, conducted on one day. In addition, subjects performed self-evaluations. The revised Allergan Lip Fullness Scale (LFS), a five-point scale with a broader range of lip presentations, was validated by 21 clinicians in two online image rating sessions, >=14 days apart, in which they used the LFS to rate overall, upper, and lower lip fullness of 144 3-dimensional (3D) images. Physician inter- and intra-rater agreement, subject intra-rater agreement (iLFS), and subject physician agreement (iLFS) were evaluated. Additionally, during online rating session 1, raters ranked 38 pairs of 3D images, taken before and after lip augmentation, as "clinically different" or "not clinically different." The median LFS score difference for clinically different pairs was calculated to determine the clinically meaningful difference. RESULTS: Clinician inter- and intra-rater agreement for the iLFS and LFS was substantial to almost perfect. Subject self assessments (iLFS) had substantial intra-rater reliability and a high level of agreement with physician assessments. Median LFS score differences for overall, upper, and lower lip fullness were 1 (mean: 0.63-0.69) for "clinically different" and 0 (mean: 0.28-0.36) for "not clinically different" image pairs; thus, clinical significance of a 1-point difference in LFS score was established. CONCLUSIONS: The LFS is a reliable instrument for physician classification of lip fullness. A 1-point score difference can detect clinically meaningful differences in lip fullness. PMID- 25805284 TI - Improved fat graft survival by different volume fractions of platelet-rich plasma and adipose-derived stem cells. AB - BACKGROUND: The success of soft-tissue augmentation is offset by the low survival rates of grafted fat tissue. Research shows that adipose-derived stem cells (ASCs) and platelet-rich plasma (PRP) are beneficial to tissue healing. OBJECTIVES: To evaluate the long-term effects of different volume fractions of PRP combined with ASCs on fat graft. METHODS: ASCs were isolated from human fat tissue, and PRP was obtained from human blood. Cell count kit-8 and real-time polymerase chain reaction (PCR) were used to evaluate the influence of PRP (0%, 10%, 20%, and 30%; volume/volume [v/v]) in medium on ASC proliferation and adipogenic differentiation, respectively. A novel lipoinjection consisting of granular fat, PRP, and ASCs was subcutaneously transplanted into nude mice. The grafts were volumetrically and histologically evaluated 10, 30, 60, and 90 days after transplantation. RESULTS: The addition of PRP improved ASC proliferation. Expression of adipogenic-related genes, peroxisome proliferator-activated receptor-gamma, lipoprotein lipase, and adipophilin were up-regulated in PRP induced ASCs. Compared with other groups, granular fat grafts formed with 20% (v/v) and 30% (v/v) PRP significantly improved residual volumes. More intact adipocytes and capillary formation, but less vacuolization, were observed in the 20% (v/v) and 30% (v/v) PRP groups at 30, 60, and 90 days. However, no significant difference was observed between the 20% (v/v) and 30% (v/v) PRP groups in retaining fat grafts and improving histology. CONCLUSIONS: Fat grafting with 20% (v/v) PRP and ASCs constitutes an appropriate transplantation strategy for improving graft survival and provides a potential approach for soft-tissue restoration in plastic and reconstructive surgery. PMID- 25805285 TI - Influence of negative pressure on the viability of adipocytes and mesenchymal stem cell, considering the device method used to harvest fat tissue. AB - BACKGROUND: Transplanted adipose tissue has many applications in regenerative medicine. However, fat grafting yields unpredictable results because the fat that is transferred can suffer variable degrees of fat reabsorption. It is necessary to identify methods and maneuvers to minimize reabsorption rates and provide predictable long-term results. OBJECTIVES: Our study aimed to identify the optimal method of harvesting, as well as the optimal pressure regime for fat aspiration. The primary objective was to assess the degree of adipocyte and mesenchymal stem cell death that occurred with the various devices and pressure levels used to harvest fat. METHODS: This study was a prospective, randomized, comparative study in 15 healthy male and female subjects aged 25 to 60 who were undergoing abdominal cosmetic surgery. Various apparatuses and pressure regimens were used to harvest 8 samples of fat tissue. These samples (R1 = R8) underwent histological analysis in order to verify the integrity and functionality of the adipocytes and mesenchymal stem cells that had been harvested. RESULTS: A total of 14 females and 1 male underwent abdominal cosmetic surgery. Quantitative analysis revealed that the adipocytes in all 8 samples had homogeneous quantitative profiles. The adipose mesenchymal stem cell (AMSC) analysis, according to Friedman ANOVA, revealed no significant variation in the percentage of mesenchymal stem cells (P = .045) between the various samples. CONCLUSIONS: The type of device, nozzle diameter tip, and pressure regimen used in this study for harvesting fat tissue did not significantly affect the number of the adipocytes or viable AMSC harvested. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 25805287 TI - Aesthetic innovations: is the tail wagging the dog? PMID- 25805286 TI - Spreader flap correction of dorsal septal deviations. PMID- 25805288 TI - Pneumosinus dilatans: rare cause of slowly changing frontal contours. AB - Frontal pneumosinus dilatans is a rare entity that is documented only by a few reports. It is an abnormal expansion of the aerated frontal sinus, with sinus walls of normal thickness. The expansion of the bone may be generalized or focal. It is not only an aesthetic problem but may also have functional consequences. We herein present the case of a 23-year-old woman who had been referred to the maxillofacial and plastic unit in Sousse (Tunisia) complaining of a prominence on her right supraorbital region and forehead. The cause was unknown and there were no functional problems. Computed tomography showed a large pneumatized frontal sinus and confirmed the resulting bony prominence. The patient was taken to the operating room, where the frontal and supraorbital regions were exposed through a bicoronal incision. The anterior wall of the right frontal sinus was removed, and was divided into segments that were then fixed in the desired position using a titanium mesh plate. Excellent results were obtained, and the patient had no complaints and was satisfied with her appearance. She remained well two years postoperatively. Pneumosinus dilatans is an entity every plastic surgeon should be aware of because its treatment falls within the realm of craniofacial surgery. The etiology remains unclear, and surgical management is directed toward surgical exploration of the sinus to ensure recontouring of the anterior table of the frontal sinus to correct any cosmetic deformity. Several authors have published different surgical techniques. LEVEL OF EVIDENCE: 5 Therapeutic. PMID- 25805289 TI - Autologous fat injection into the pectoralis major as an adjunct to surgical correction of gynecomastia. AB - BACKGROUND: Correction of gynecomastia in males is a frequently performed aesthetic procedure. Various surgical options involving the removal of excess skin, fat, or glandular tissue have been described. However, poor aesthetic outcomes, including a flat or depressed pectoral area, limit the success of these techniques. OBJECTIVES: The authors sought to determine patient satisfaction with the results of upper chest augmentation by direct intrapectoral fat injection in conjunction with surgical correction of gynecomastia. METHODS: In this prospective study, 26 patients underwent liposuction and glandular excision, glandular excision alone, or Benelli-type skin excision. All patients received intramuscular fat injections in predetermined zones of the pectoralis major (PM). The mean volume of fat injected was 160 mL (range, 80-220 mL per breast) bilaterally. Patients were monitored for an average of 16 months (range, 8-24 months). RESULTS: Hematoma formation and consequent infraareolar depression was noted in 1 patient and was corrected by secondary lipografting. Mean patient satisfaction was rated as 8.4 on a scale of 1 (unsatisfactory) to 10 (highly satisfactory). CONCLUSIONS: Autologous intrapectoral fat injection performed simultaneously with gynecomastia correction can produce a masculine appearance. The long-term viability of fat cells injected into the PM needs to be determined. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 25805290 TI - The limitations of three-dimensional simulations in breast augmentation. PMID- 25805291 TI - Response to "the limitations of three-dimensional simulations in breast augmentation". PMID- 25805292 TI - Comments on "Three-Dimensional Imaging for Breast Augmentation: Is this Technology Providing Accurate Simulations?". PMID- 25805293 TI - Response to "Comments on: Three-Dimensional Imaging for Breast Augmentation: Is This Technology Providing Accurate Simulations?". PMID- 25805294 TI - Response to "comments on 'breast implant-associated anaplastic large cell lymphoma: report of 2 cases and review of the literature'". PMID- 25805295 TI - Comments on "abdominoplasty-derived dermal-fat graft augmentation gluteoplasty". PMID- 25805296 TI - Response to "comments on 'abdominoplasty-derived dermal-fat graft augmentation gluteoplasty'". PMID- 25805298 TI - Response to "comments on 'evaluation of a microfocused ultrasound system for improving skin laxity and tightening in the lower face'". PMID- 25805297 TI - Comments on "evaluation of a microfocused ultrasound system for improving skin laxity and tightening in the lower face". PMID- 25805299 TI - Fullerene recognition with molecular tweezers made up of efficient buckybowls: a dispersion-corrected DFT study. AB - In 2007, Sygula and co-workers introduced a novel type of molecular tweezers with buckybowl pincers that have attracted the substantial interest of researchers due to their ideal architecture for recognizing fullerenes by concave-convex pi???pi interactions (A. Sygula et al., J. Am. Chem. Soc., 2007, 129, 3842). Although in recent years some modifications have been performed on these original molecular tweezers to improve their ability for catching fullerenes, very few improvements were achieved to date. For that reason, in the present work a series of molecular tweezers have been devised and their supramolecular complexes with C60 studied at the B97-D2/TZVP//SCC-DFTB-D and B97-D2/TZVP levels. Three different strategies have been tested: (1) changing the corannulene pincers to other buckybowls, (2) replacing the tetrabenzocyclooctatetraene tether by a buckybowl, and (3) adding methyl groups on the molecular tweezers. According to the results, all the three approaches are effective, in such a way that a combination of the three strategies results in buckycatchers with complexation energies (with C60) up to 2.6 times larger than that of the original buckycatcher, reaching almost -100 kcal mol(-1). The B97-D2/TZVP//SCC-DFTB-D approach can be a rapid screening tool for testing new molecular tweezers. However, since this approach does not reproduce correctly the deformation energy and this energy represents an important contribution to the total complexation energy of complexes, subsequent higher-level re-optimization is compulsory to achieve reliable results (the full B97-D2/TZVP level is used herein). This re-optimization could be superfluous when quite rigid buckycatchers are studied. PMID- 25805301 TI - 2014 Rossi Award lecture:* beyond internal validity. AB - BACKGROUND: For much of the last 40 years, the evaluation profession has been consumed in a battle over internal validity. Today, that battle has been decided. Random assignment, while still far from universal in practice, is almost universally acknowledged as the preferred method for impact evaluation. It is time for the profession to shift its attention to the remaining major flaws in the "standard model" of evaluation: (i) external validity and (ii) the high cost and low hit rate of experimental evaluations as currently practiced. RECOMMENDATIONS: To raise the profession's attention to external validity, the author recommends some simple, easy steps to be taken in every evaluation. The author makes two recommendations to increase the number of interventions found to be effective within existing resources: First, a two-stage evaluation strategy in which a cheap, streamlined Stage 1 evaluation is followed by a more intensive Stage 2 evaluation only for those interventions found to be effective in a Stage 1 trial and, second, use of random assignment to guide the myriad program management decisions that must be made in the course of routine program operations. This article is not intended as a solution to these issues: It is intended to stimulate the evaluation community to take these issues more seriously and to develop innovative solutions. PMID- 25805300 TI - Ofatumumab in combination with glucocorticoids for primary therapy of chronic graft-versus-host disease: phase I trial results. AB - Standard primary therapy for chronic graft-versus-host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I trial examining the combination of standard (1 mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti CD20 monoclonal antibody, for primary chronic GVHD therapy. Patients ages >= 18 with National Institutes of Health Consensus moderate-to-severe chronic GVHD newly requiring 1 mg/kg/day prednisone were treated at 3 escalating dose levels (300 mg, 700 mg, and 1000 mg) of i.v. ofatumumab on days 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade >= 3 organ toxicities, or grade 4 neutropenia lasting > 14 days. A total of 12 patients (median age 54; range, 25 to 72) were treated (dose level 1: n = 3; level 2: n = 3; level 3: n = 6). At enrollment, overall chronic GVHD was moderate (n = 7) or severe (n = 5), with diverse organ involvement (skin: n = 8; mouth: n = 8; eye: n = 8; lung: n = 4; gastrointestinal: n = 3; liver: n = 5; genital: n = 2; joint/fascia: n = 5). Infusion of ofatumumab was well tolerated, and no DLT was observed. From the total number of adverse events (n = 29), possibly related adverse events (n = 4) included grade 1 fatigue, grade 1 transaminitis, and 2 infusion reactions (grades 2 and 3). Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy. Ofatumumab in combination with prednisone is safe and a phase II examination of efficacy is ongoing. PMID- 25805302 TI - High frequency of adverse reactions and discontinuation with benznidazole treatment for chronic Chagas disease in Milan, Italy. PMID- 25805303 TI - Fatal Aspiration Pneumonia as a Complication of Fecal Microbiota Transplant. PMID- 25805304 TI - Reply to Antinori et al. PMID- 25805305 TI - Instagram and Clinical Infectious Diseases. PMID- 25805306 TI - Operator experience determines performance in a simulated computer-based brain tumor resection task. AB - PURPOSE: Develop measures to differentiate between experienced and inexperienced neurosurgeons in a virtual reality brain surgery simulator environment. METHODS: Medical students (n = 71) and neurosurgery residents (n = 12) completed four simulated Glioblastoma multiforme resections. Simulated surgeries took place over four days with intermittent spacing in between (average time between surgeries of 4.77 +/- 0.73 days). The volume of tumor removed (cc), volume of healthy brain removed (cc), and instrument path length (mm) were recorded. Additionally, surgical effectiveness (% tumor removed divided by % healthy brain removed) and efficiency (% tumor removed divided by instrument movement in mm) were calculated. Performance was compared (1) between groups, and (2) for each participant over time to assess the learning curve. In addition, the effect of real-time instruction ("coaching") was assessed with a randomly selected group of medical students. RESULTS: Neurosurgery residents removed less healthy brain, were more effective in removing tumor and sparing healthy brain tissue, required less instrument movement, and were more efficient in removing tumor tissue than medical students. Medical students approached the resident level of performance over serial sessions. Coached medical students showed more conservative surgical behavior, removing both less tumor and less healthy brain. In sum, neurosurgery residents removed more tumor, removed less healthy brain, and required less instrument movement than medical students. Coaching modified medical student performance. CONCLUSIONS: Virtual Reality brain surgery can differentiate operators based on both recent and long-term experience and may be useful in the acquisition and assessment of neurosurgical skills. Coaching alters the learning curve of naive inexperienced individuals. PMID- 25805308 TI - Thymoquinone inhibits lipopolysaccharide-induced inflammatory mediators in BV2 microglial cells. AB - Thymoquinone, the major active compound isolated from the medicinal Nigella sativa, has been demonstrated to have anti-inflammatory activity. The aim of this study was to investigate the anti-inflammatory effects and mechanisms of thymoquinone on LPS-stimulated BV2 microglial cells. The effects of thymoquinone on inflammatory mediators TNF-alpha, IL-1beta, NO and PGE2 production were detected by ELISA. The effects of thymoquinone on PI3K, Akt phosphorylation, and NF-kappaB activation were detected by western blot analysis. Our results showed that thymoquinone dose-dependently inhibited LPS-induced TNF-alpha, IL-1beta, NO and PGE2 production. Thymoquinone also inhibited LPS-induced NF-kappaB activation. Furthermore, thymoquinone was found to inhibit LPS-induced PI3K and Akt phosphorylation, which were upstream molecules of NF-kappaB. In conclusion, our data demonstrated that thymoquinone might inhibit LPS-induced PI3K and Akt phosphorylation, which leading to the inhibition of NF-kappaB activation and inflammatory mediator production in BV2 microglia cells. PMID- 25805310 TI - Interventions to increase the reporting of occupational diseases by physicians. AB - BACKGROUND: Under-reporting of occupational diseases is an important issue worldwide. The collection of reliable data is essential for public health officials to plan intervention programmes to prevent occupational diseases. Little is known about the effects of interventions for increasing the reporting of occupational diseases. OBJECTIVES: To evaluate the effects of interventions aimed at increasing the reporting of occupational diseases by physicians. SEARCH METHODS: We searched the Cochrane Occupational Safety and Health Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), EMBASE, OSH UPDATE, Database of Abstracts of Reviews of Effects (DARE), OpenSIGLE, and Health Evidence until January 2015.We also checked reference lists of relevant articles and contacted study authors to identify additional published, unpublished, and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs (cRCTs), controlled before-after (CBA) studies, and interrupted time series (ITS) of the effects of increasing the reporting of occupational diseases by physicians. The primary outcome was the reporting of occupational diseases measured as the number of physicians reporting or as the rate of reporting occupational diseases. DATA COLLECTION AND ANALYSIS: Pairs of authors independently assessed study eligibility and risk of bias and extracted data. We expressed intervention effects as risk ratios or rate ratios. We combined the results of similar studies in a meta-analysis. We assessed the overall quality of evidence for each combination of intervention and outcome using the GRADE approach. MAIN RESULTS: We included seven RCTs and five CBA studies. Six studies evaluated the effectiveness of educational materials alone, one study evaluated educational meetings, four studies evaluated a combination of the two, and one study evaluated a multifaceted educational campaign for increasing the reporting of occupational diseases by physicians. We judged all the included studies to have a high risk of bias.We did not find any studies evaluating the effectiveness of Internet-based interventions or interventions on procedures or techniques of reporting, or the use of financial incentives. Moreover, we did not find any studies evaluating large-scale interventions like the introduction of new laws, existing or new specific disease registries, newly established occupational health services, or surveillance systems. Educational materialsWe found moderate quality evidence that the use of educational materials did not considerably increase the number of physicians reporting occupational diseases compared to no intervention (risk ratio of 1.11, 95% confidence interval (CI) 0.74 to 1.67). We also found moderate-quality evidence showing that sending a reminder message of a legal obligation to report increased the number of physicians reporting occupational diseases (risk ratio of 1.32, 95% CI 1.05 to 1.66) when compared to a reminder message about the benefits of reporting.We found low-quality evidence that the use of educational materials did not considerably increase the rate of reporting when compared to no intervention. Educational materials plus meetingsWe found moderate-quality evidence that the use of educational materials combined with meetings did not considerably increase the number of physicians reporting when compared to no intervention (risk ratio of 1.22, 95% CI 0.83 to 1.81).We found low-quality evidence that educational materials plus meetings did not considerably increase the rate of reporting when compared to no intervention (rate ratio of 0.77, 95% CI 0.42 to 1.41). Educational meetingsWe found very low quality evidence showing that educational meetings increased the number of physicians reporting occupational diseases (risk ratio at baseline: 0.82, 95% CI 0.47 to 1.41 and at follow-up: 1.74, 95% CI 1.11 to 2.74) when compared to no intervention.We found very low-quality evidence that educational meetings did not considerably increase the rate of reporting occupational diseases when compared to no intervention (rate ratio at baseline: 1.57, 95% CI 1.22 to 2.02 and at follow-up: 1.92, 95% CI 1.48 to 2.47). Educational campaignWe found very low quality evidence showing that the use of an educational campaign increased the number of physicians reporting occupational diseases when compared to no intervention (risk ratio at baseline: 0.53, 95% CI 0.19 to 1.50 and at follow-up: 11.59, 95% CI 5.97 to 22.49). AUTHORS' CONCLUSIONS: We found 12 studies to include in this review. They provide evidence ranging from very low to moderate quality showing that educational materials, educational meetings, or a combination of the two do not considerably increase the reporting of occupational diseases. The use of a reminder message on the legal obligation to report might provide some positive results. We need high-quality RCTs to corroborate these findings.Future studies should investigate the effects of large-scale interventions like legislation, existing or new disease-specific registries, newly established occupational health services, or surveillance systems. When randomisation or the identification of a control group is impractical, these large-scale interventions should be evaluated using an interrupted time-series design.We also need studies assessing online reporting and interventions aimed at simplifying procedures or techniques of reporting and the use of financial incentives. PMID- 25805307 TI - The protective effect of vitamin E against prenatal and early postnatal ethanol treatment-induced heart abnormality in rats: a 3-month follow-up study. AB - Ethanol consumption during pregnancy is associated with fetal heart malformation. However, the underlying mechanism of prenatal ethanol exposure causing heart malfunction is not well known. The current study examined the effect of prenatal and early postnatal ethanol consumption on heart abnormality resulting from oxidative and inflammatory stress. It was also intended to find out whether vitamin E inhibits the abnormality induced by ethanol in rats' heart tissue. Pregnant Wistar rats received ethanol with/without vitamin E from the seventh day of gestation (GD7) throughout lactation. The proliferation in heart muscle cells and coronary smooth muscle cells, protein carbonyl, IL-6, TNF-alpha, homocysteine levels, also lipid profile in heart and plasma of male pups were measured at the end of lactation (PN 21) and 90 days after birth (PN 90). The results indicated proliferation of heart muscle and coronary smooth muscle cells along with heart structural alteration, protein oxidation, lipid peroxidation, inflammatory reaction, and hyperhomocysteinemia in offspring after 21 and 90 days of birth compared with the controls. Vitamin E treatment significantly decreased cell proliferation and heart structural alteration, compared with the group treated by ethanol alone. Furthermore, it reduced the elevation of protein carbonyl, lipid peroxidation, and increased inflammatory proteins to levels as those of the controls. These findings strongly support the idea that ethanol intake by dams during pregnancy and early postnatal days induces heart abnormality mediated by oxidative stress and inflammatory reactions, and that these effects can be alleviated by using vitamin E as an antioxidant and anti-inflammatory molecule. PMID- 25805311 TI - Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics. AB - Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex(r) as a rational, non invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells. PMID- 25805313 TI - Production and separation of (186g)Re from proton bombardment of (186)WC. AB - A proof of concept study was undertaken where non-carrier added (186 g)Re was produced from the cyclotron bombardment of (186)WC. (186)WC was carbo-thermally generated from a novel precursor synthesized from (186)WO3, aqueous ammonia and hexamethyltetramine. The inherent high electrical and thermal conductivity of this material, coupled with its high melting point, made it an ideal candidate for proton bombardment for production of (186)Re. An18 MUA irradiation for 3h and processing via thermo-chromatography, (186)WC yielded 0.93 mCi of (186 g)Re which corresponds to 89% of the calculated theoretical yields. The radiochemical purity of the desired (186 g)Re species was found to be between 95 and 97% with small contaminants of (186)ReO2. The radiochemistry utility of the product was investigated using S-benzoyl-MAG3, and 100% complexation was achieved with stability being maintained for 96 h. The re-oxidation of (186)WC back to(186)WO3 by oxygen in the thermo-chromatography method of processing ensured that the starting material was regenerated and recovered from the process in 94-98% yield. PMID- 25805312 TI - The Effect of Dose and Quality Assurance in Early Prostate Cancer Treated with Low Dose Rate Brachytherapy as Monotherapy. AB - AIMS: To examine the relationship between post-implant computed tomography dosimetry and long-term prostate-specific antigen relapse-free survival in patients treated with iodine 125 (I-125) low dose rate prostate brachytherapy as monotherapy and, second, to audit recent practice against Royal College of Radiologists' (RCR) guidelines after the re-introduction of post-implant dosimetry for all patients in our centre. MATERIALS AND METHODS: Between March 1995 and September 2007, 2157 consecutive patients with localised prostate cancer underwent I-125 permanent prostate brachytherapy as monotherapy in a single UK centre. All patients were transrectal ultrasound planned delivering a 145 Gy (TG 43) minimum peripheral dose. None received supplemental external beam radiotherapy. Post-implant computed tomography-based dosimetry was undertaken between 4 and 6 weeks after treatment and was available for 711 (33%). Outcomes were analysed in terms of the relationship of D90 to prostate-specific antigen relapse-free survival (nadir 2+ definition) and all patients had a minimum follow up of 5 years. For contemporary patients from 2011, quality metrics from post implant computed tomography as defined by RCR guidelines are presented. RESULTS: A mean D90 of 138.7 Gy (standard deviation 24.7) was achieved for the historic cohort. Biochemical control at 10 years was 76% in patients with D90 > 140 Gy and 68% in those with D90 < 140 Gy (P < 0.01). In current practice, over the last 3 years the mean (standard deviation) D90 has increased from 154 (15.3) Gy in 2011 to 164 (13.5) Gy in 2013. Similarly, an increase in the mean (standard deviation) V100 from 92 (4.4) to 95 (3.2) % is noted over time. No difference between clinicians was noted. CONCLUSION: D90 values of less than 140 Gy continue to be predictive of increased risk of recurrence of prostate cancer across risk groups with longer follow-up. Quality assurance can be used to ensure improved and consistent implant quality in a team with multiple clinicians. PMID- 25805315 TI - Quantitative trait locus analysis of agronomic and quality-related traits in cultivated peanut (Arachis hypogaea L.). AB - KEY MESSAGE: SSR-based QTL mapping provides useful information for map-based cloning of major QTLs and can be used to improve the agronomic and quality traits in cultivated peanut by marker-assisted selection. Cultivated peanut (Arachis hypogaea L.) is an allotetraploid species (AABB, 2n = 4* = 40), valued for its edible oil and digestible protein. Linkage mapping has been successfully conducted for most crops, and it has been applied to detect the quantitative trait loci (QTLs) of biotic and abiotic traits in peanut. However, the genetic basis of agronomic and quality-related traits remains unclear. In this study, high levels of phenotypic variation, broad-sense heritability and significant correlations were observed for agronomic and quality-related traits in an F 2:3 population. A genetic linkage map was constructed for cultivated peanut containing 470 simple sequence repeat (SSR) loci, with a total length of 1877.3 cM and average distance of 4.0 cM between flanking markers. For 10 agronomic traits, 24 QTLs were identified and each QTL explained 1.69-18.70 % of the phenotypic variance. For 8 quality-related traits, 12 QTLs were identified that explained 1.72-20.20 % of the phenotypic variance. Several QTLs for multiple traits were overlapped, reflecting the phenotypic correlation between these traits. The majority of QTLs exhibited obvious dominance or over-dominance effects on agronomic and quality traits, highlighting the importance of heterosis for breeding. A comparative analysis revealed genomic duplication and arrangement of peanut genome, which aids the assembly of scaffolds in genomic sequencing of Arachis hypogaea. Our QTL analysis results enabled us to clearly understand the genetic base of agronomic and quality traits in cultivated peanut, further accelerating the progress of map-based cloning of major QTLs and marker-assisted selection in future breeding. PMID- 25805314 TI - Diversity and evolution of Rp1 rust resistance genes in four maize lines. AB - KEY MESSAGE: This manuscript provides genome-level analysis of disease resistance genes in four maize lines, including studies of haplotype and resistance gene number as well as selection and recombination. The Rp1 locus of maize is a complex resistance gene (R-gene) cluster that confers race-specific resistance to Puccinia sorghi, the causal agent of common leaf rust. Rp1 NB-LRR disease resistance genes were isolated from two Rp1 haplotypes (HRp1-B and HRp1-M) and two maize inbred lines (B73 and H95). Sixty-one Rp1 genes were isolated from Rp1 B, Rp1-M, B73 and H95 with a PCR-based approach. The four maize lines carried from 12 to 19 Rp1 genes. From 4 to 9 of the identified Rp1 genes were transcribed in the four maize lines. The Rp1 gene nucleotide diversity was higher in HRp1-B and HRp1-M than in B73 and H95. Phylogenic analysis of 69 Rp1 genes revealed that the Rp1 genes maintained in HRp1-B, HRp1-M and H95 are evolving independently of each other, while Rp1 genes in B73 and HRp1-D appear more like each other than they do genes in the other lines. The results also revealed that the analysed Rp1 R-genes were under positive selection in HRp1-M and B73. Intragenic recombination was detected in Rp1 genes maintained in the four maize lines. This demonstrates that a genetic process that has the potential to generate new resistance genes with new specificities is active at the Rp1 locus in the four analysed maize lines and that the new resistance genes may act against newly arising pathogen races that become prevalent in the pathogen population. PMID- 25805317 TI - Quantitative trait loci mapping of partial resistance to Diamondback moth in cabbage (Brassica oleracea L). AB - KEY MESSAGE: The resistance to Diamondback moth insect in cabbage is governed by many minor loci in quantitative nature, and at least four genetic loci should be incorporated in marker-assisted breeding program for developing partially resistant DBM cabbage cultivars. The Diamondback moth (DBM), Plutella xylostella (L.), is the most destructive insect infesting cruciferous plants worldwide. Earlier studies have reported that the glossy leaves of cabbage are associated with resistance to this insect. However, until now, genetics of DBM resistance has not been studied in detail, and no QTL/gene mapping for this trait has been reported. In this paper, we report quantitative trait loci (QTL) mapping of DBM resistant trait using 188 randomly selected segregating F 3 population derived from crossing a partially DBM-resistant glossy leaf cabbage (748) with a susceptible smooth cabbage line (747). Quantitative trait loci mapping using phenotypic data of four consecutive years (2008, 2009, 2010, and 2011) on DBM insect infestation detected a total of eight QTL on five linkage groups suggesting that DBM resistance is a quantitative in nature. Of these QTL, four QTL, i.e., qDbm 1 on LG1, qDbm5 and qDbm6 on LG7, and qDbm8 on LG9, were detected in different tests and years. The QTL, qDbm6 on LG7, was consecutively detected over 3 years. Tightly linked molecular markers have been developed for qDbm8 QTL on LG9 which could be used in marker-assisted breeding program. Our research demonstrated that for desired DBM resistance cultivar breeding, those four genetic loci have to be taken into consideration. Furthermore, the comparative study revealed that DBM resistance QTL is conserved between close relative model plant Arabidopsis thaliana and Brassica oleracea genome. PMID- 25805316 TI - The Co-4 locus on chromosome Pv08 contains a unique cluster of 18 COK-4 genes and is regulated by immune response in common bean. AB - KEY MESSAGE: The common bean locus Co - 4, traditionally referred to as an anthracnose-resistant gene, contains a cluster of predicted receptor-like kinases (COK-4 and CrRLK1-like), and at least two of these kinases are co-regulated with the plant's basal immunity. Genetic resistance to anthracnose, caused by the fungus Colletotrichum lindemuthianum (Sacc. and Magnus) Briosi and Cavara, is conferred by major loci throughout the Phaseolus vulgaris genome, named Co. The complex Co-4 locus was previously reported to have several copies of the COK-4 gene that is predicted to code for a receptor-like kinase (RLK). In general, plant RLKs are involved in pathogen perception and signal transduction; however, the molecular function of COK-4 remains elusive. Using newly identified molecular markers (PvTA25 and PvSNPCOK-4), the SAS13 marker, COK-4 sequences and phylogeny, and the recently released bean genome sequence, we determined the most probable boundaries of the Co-4 locus: a 325-Kbp region on chromosome Pv08. Out of the 49 predicted transcripts in that region, 24 encode for putative RLKs (including 18 COK-4 copies) with high similarity to members of the Catharanthus roseus RLK1 like (CrRLK1L) protein family from different plant species, including the well described FERONIA (FER) and ANXUR. We also determined that two RLK-coding genes in the Co-4 locus (COK-4-3 and FER-like) are transcriptionally regulated when bean plants are challenged with the flg22 peptide, a commonly used elicitor of plant immunity, or the bacterium Pseudomonas syringae pv. phaseolicola, the causal agent of halo blight. While COK-4-3 is activated during immune response, FER-like is downregulated suggesting that these genes could play a role in plant responses to biotic stress. These results highlight the importance of dissecting the regulation and molecular function of individual genes within each locus, traditionally referred to as resistance gene based on genetic segregation analysis. PMID- 25805318 TI - Cochliobolus hawaiiensis Sinusitis, a Tropical Disease? A Case Report and Review of the Literature. AB - A sinusitis caused by Cochliobolus hawaiiensis (anamorph: Bipolaris hawaiiensis) was diagnosed in metropolitan France in a patient originating from New Caledonia. The patient completely recovered after surgical treatment consisting in marsupialization of the mucoceles and removal of the fungus balls located in the left nasal cavity and the left maxilla and ethmoid sinuses. One year after, both endoscopic examination and CT scan of the sinuses were normal. Various clinical presentations of diseases associated with C. hawaiiensis have been reported. A review of the literature indicates that although C. hawaiiensis is very rarely reported in Europe, it is one of the major rhinosinusitis agents in areas with a relatively warmer climate, such as India or Southwestern USA. This is the first report of a sinusitis caused by C. hawaiiensis diagnosed in France, with a total recovery outcome. PMID- 25805319 TI - The unexpected conundrum of endometrioid carcinoma in deep rectal endometriosis arising 11 years after total hysterectomy bilateral salpingo-oophorectomy. PMID- 25805320 TI - Risk factors for infection with Foot-and-Mouth Disease virus in a cattle population vaccinated with a non-purified vaccine in Iran. AB - In this study, we estimated the level of Foot-and-Mouth (FMD) virus infection in a cattle-dense north-western province of Islamic Republic of Iran and analyzed putative risk factors for FMD infection. Calves (6-24 months of age) from all 17 districts of West Azerbaijan were tested for antibodies against non-structural proteins (NSP-Ab) of FMD virus. A proportional stratification with a minimum of 30 epi-units was applied for 3 different husbandry systems: villages, dairy and mixed farms. Within an epi-unit, 30 calves were sampled. For the interpretation of ELISA test results, we used the 50% inhibition (50PI) cut-off as per producer's instructions and created one at 75% inhibition (75PI) based on the lowest point of the histogram of PI results. This approach resulted in three categories of outcomes; negative (N), low-positive (LP) and high-positive (HP). A generalized mixed-effect model for binary outcomes was used for analysing putative risk factors and was run for both cut-off values. A total of 8378 calves from 202 villages, 51 dairy farms and 28 mixed farms were eligible for analysis. The percentage of calves testing positive (LP+HP) was 53.7% (95% Confidence interval (CI): 52.6%-54.8%), with 39.6% (95% CI: 38.6-40.7%) testing HP (n=3309) while 14.1% (95% CI: 13.5-15.0%) of calves tested LP (n=1188). Of 281 epi-units sampled, all calves sampled tested negative in only 2 epi-units (0.7% (95% CI: 0.1-2.5%)) and more than 25 calves tested positive in 29 epi-units (10.3% (95% CI: 7.0-14.5%)). Outcomes of regression modelling using the 50 PI cut-off indicated that, for each month increase in age, the odds of testing positive increased 1.01 times (95% CI: 1.00-1.03). The odds of calves testing NSP-positive increased 1.46 times (95% CI: 1.22-1.77) for calves residing in epi-units that had experienced clinical FMD in the 12 months preceding this study. The odds of calves owned by livestock owners who traded livestock testing positive were 1.4 1.6 times higher than those owned by persons not engaged in trading while the odds for calves testing positive in dairy herds was 1.62 (95% CI: 1.10-2.35) times higher compared with calves in villages. The results of the model using the 75 PI cut-off value resulted in comparable estimates, with the age-effect becoming more evident. These results have confirmed widespread FMD infection and were used in developing a risk-based control strategy on FMD, in line with Stage 1 of the Progressive Control Pathway for FMD (PCP-FMD). PMID- 25805321 TI - Pre-slaughter rectal temperature as an indicator of pork meat quality. AB - This study investigates whether rectal temperature of pigs, prior to slaughter, can give an indication of the risk of developing pork with PSE characteristics. A total of 1203 pigs were examined, measuring the rectal temperature just before stunning, of which 794 rectal temperatures were measured immediately after stunning. pH30LT (M. Longissimus thoracis) and temperature of the ham (Temp30Ham) were collected from about 530 carcasses, 30 min after sticking. The results present a significant positive linear correlation between rectal temperature just before and after slaughter, and Temp30Ham. Moreover, pH30LT is negatively correlated with rectal temperature and Temp30Ham. Finally, a linear mixed model for pH30LT was established with the rectal temperature of the pigs just before stunning and the lairage time. This model defines that measuring rectal temperature of pigs just before slaughter allows discovery of pork with PSE traits, taking into account pre-slaughter conditions. PMID- 25805322 TI - Proinflammatory status in the aqueous humor of high myopic cataract eyes. AB - High myopia has long been recognized as an inflammation-related disease, and high myopic eyes are thought to have a proinflammatory internal microenvironment, which might predispose to the occurrence of certain inflammation-related complications such as fibrotic capsular contraction syndrome after cataract surgery. Therefore, the purpose of this study was to detect inflammatory cytokines expressed in the aqueous humor (AH) of high myopic cataract (HMC) patients. The cytokines were screened using a RayBio Human Cytokine Antibody Array in AH samples from 15 age-related cataract (ARC) patients and 15 HMC patients. Those detected by the screening assays were verified using a Bio-Plex Suspension Array System in AH samples from 35 ARC patients and 45 HMC patients. The cytokine antibody array showed that the expression level of interleukin-1 receptor antagonist (IL-1ra) in the AH was higher in ARC than in HMC, whereas opposite trends were found for monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and presumably secreted (RANTES), IL-8, platelet-derived growth factor-BB, and IL-6 (all P < 0.05). In the verification assay using the suspension cytokine array, only the expression levels of IL-1ra and MCP-1 were significantly different between the ARC and HMC groups (P = 0.014 and 0.038, respectively); these results were confirmed by western blot assays. Our results demonstrated that the expression of IL-1ra was significantly lower and the expression of MCP-1 was significantly higher in the AH of HMC than in ARC, suggestive of a proinflammatory status in the anterior chamber of HMC eyes. PMID- 25805324 TI - FAMACHA(c) system assessment by previously trained sheep and goat farmers in Brazil. AB - The aim of this study was to evaluate the degree of adoption and the correct use of the FAMACHA(c) system amongst sheep and goat farmers trained in a previous hands-on course. A survey was carried out with 1375 people who received FAMACHA(c) training from July 2009 to May 2011 in Parana State, Brazil. The survey was conducted from March 2012 to May 2013. Firstly, a questionnaire was applied with specific questions for farmers about their anthelmintic (AH) treatment practices before and after the FAMACHA(c) training. In a second step, eight of the questionnaire respondents classified as sheep or goat farmers were contacted for an in loco visit during which the application of the FAMACHA(c) system was evaluated in the respective farms and blood samples were collected from 20 animals to calculate sensitivity and specificity. A total of 124 farmers responded the questionnaire (9% of project participants). Farmers accounted for 48.4% of total responses. Half of these farmers (51.6%) reported losses related to parasites in their property before the training. Antiparasitic treatments, at fixed intervals, were responsible for 93.1% of deworming practices before the training project. FAMACHA(c) was unknown for 51.7% of the respondents, and 31% knew the chart, but did not use it. After the project, 69% had adopted the system and 83% assessed the animals at regular intervals. However, 18.9% did not evaluate all animals. During the in loco visits, problems reported included the incorrect exposure of the ocular mucosa (50% of farmers) and not using the chart (87.5%). Also, 62.5% did not keep records of the FAMACHA(c) assessment history of the flock. However, sensitivity was 100%, with 0% false negatives. We conclude that, amongst farmers who adopted the system, despite some methodological errors regarding its use, the objectives were met in terms of reducing the number of anthelmintic treatments and providing anemic animals with AH treatment. Trained farmers seemed to require technical guidance post-training to promote effective use of the FAMACHA(c) system. PMID- 25805323 TI - End effects and cross-dimensional interference in identification of time and length: Evidence for a common memory mechanism. AB - Memory plays a critical role in time estimation, yet detailed mechanisms underlying temporal memory have not been fully understood. The current functional magnetic resonance imaging (fMRI) study investigated memory phenomena in absolute identification of time durations and line lengths. In both time and length identification, participants responded faster to end-of-range stimuli (e.g., the shortest or longest items of the stimulus set) than to middle stimuli. Participants performed worse in the incongruent condition (mismatch between time and length in the stimulus position) than in the congruent condition, indicating cross-dimensional interference between time and length. Both phenomena reflect increased difficulty of retrieving information relevant to the current context in the presence of context-irrelevant information. A region in the lateral inferior prefrontal cortex showed a greater response to the middle stimuli and in the incongruent condition suggesting greater demands for controlled memory retrieval. A cognitive model based on the ACT-R (Adaptive Control of Thought - Rational) declarative memory mechanisms accounted for the major behavioral and imaging results. The results suggest that contextual effects in temporal memory can be understood in terms of domain-general memory principles established outside the time estimation domain. PMID- 25805325 TI - Optimizing care for Canadians with diabetic nephropathy in 2015. AB - Diabetic chronic kidney disease (CKD) is the cause of kidney failure in approximately 35% of Canadian patients requiring dialysis. Traditionally, only a minority of patients with type 2 diabetes and CKD progress to kidney failure because they die of a cardiovascular event first. However, with contemporary therapies for diabetes and cardiovascular disease, this may no longer be true. The classic description of diabetic CKD is the development of albuminuria followed by progressive kidney dysfunction in a patient with longstanding diabetes. Many exciting candidate agents are under study to halt the progression of diabetic CKD; current therapies center on optimizing glycemic control, renin angiotensin system inhibition, blood pressure control and lipid management. Lifestyle modifications, such as salt and protein restriction as well as smoking cessation, may also be of benefit. Unfortunately, these accepted therapies do not entirely halt the progression of diabetic CKD. Also unfortunately, the presence of CKD in general is under-recognized by primary care providers, which can lead to late referral, missed opportunities for preventive care and inadvertent administration of potentially harmful interventions. Not all patients require referral to nephrology for diagnosis and management, but modern risk-prediction algorithms, such as the kidney failure risk equation, may help to guide referral appropriateness and dialysis modality planning in subspecialty nephrology multidisciplinary care clinics. PMID- 25805326 TI - White matter tracts critical for recognition of sarcasm. AB - Failure to recognize sarcasm can lead to important miscommunications. Few previous studies have identified brain lesions associated with impaired recognition of sarcasm. We tested the hypothesis that percent damage to specific white matter tracts, age, and education together predict accuracy in sarcasm recognition. Using multivariable linear regression, with age, education, and percent damage to each of eight white matter tracts as independent variables, and percent accuracy on sarcasm recognition as the dependent variable, we developed a model for predicting sarcasm recognition. Percent damage to the sagittal stratum had the greatest weight and was the only independent predictor of sarcasm recognition. PMID- 25805327 TI - Endovascular management of rupture in acute type B aortic dissections. AB - OBJECTIVE: Reports of thoracic endovascular aortic repair (TEVAR) for complicated acute type B aortic dissection (ABAD) bring together a large range of clinical presentations. With a 30 day mortality of 50% when managed with open surgery, rupture is the most devastating complication of ABAD. This study investigated the outcome of TEVAR for ABAD complicated by rupture (r-ABAD) to assess the results of this particularly critical subgroup. METHODS: A review of consecutive TEVAR for r-ABAD in two tertiary referral centers was performed using a prospectively maintained database. RESULTS: Between 2000 and 2013, 24 patients (mean age 71 years; 14 males) underwent TEVAR for r-ABAD. Sixteen (67%) were in shock (Systolic blood pressure <80 mmHg) before surgery. Seven patients had coverage of the left subclavian artery, of whom four had partial arch debranching procedures via cervical access concomitant with TEVAR. Median length of aortic coverage was 150 mm, median proximal oversizing was 13.3% (range 6.2-33.3%). Technical success was achieved in 100%. There were four in hospital deaths (16%). Two patients (8%) had paraplegia, but neither stroke nor renal insufficiency requiring dialysis occurred. During a mean follow up of 28 months, there was one aortic dissection related death and eight patients (40% of the surviving patients) required re intervention. All re-interventions were managed endovascularly. At last follow up CT scan, eight patients (40%) had complete remodeling of the aortic wall. CONCLUSION: With 16% in hospital mortality and 8% early major complications, this study confirms the feasibility of TEVAR for r-ABAD with a lower peri-operative morbidity and mortality rate compared with open surgery. Given the high rate of re-intervention, close follow up is required in surviving patients. PMID- 25805328 TI - Necrotizing soft tissue infections in intravenous drug users: a vascular surgical emergency. AB - OBJECTIVE: To assess the short and long-term outcomes of necrotizing soft tissue infection (NSTI) in intravenous drug users (IVDU) in a regional vascular centre. METHODS: This was a retrospective analysis of all IVDUs with NSTI admitted to the regional vascular surgical unit between January 2009 and July 2014. Clinical outcome measures were interval between admission and surgery, length of ITU/HDU and hospital stays, post-operative complications, in hospital and one year mortality. RESULTS: 25 patients were admitted. The median age was 39 years (range 30-53 years) with a female to male ratio of 1:3.3. The median interval between admission and surgery was 23 hours (range 2-195 hours), however, this was significantly less when the admitting specialty was directly to vascular surgery (median 4 hours, range 2-7) compared with other specialties (median 38 hours, range 7-195 hours). Ten patients required HDU/ITU care with a median duration of 4 days (range 1-12 days). Five patients (20%) required amputation, of whom two (40%) had a prosthetic limb fitted. There was one in hospital death (4%). Another patient died while awaiting limb fitting 4 months post discharge, giving a 1 year mortality of 8%. CONCLUSIONS: NSTI in IVDUs carries high risk of amputation with a very low rate of limb fitting. Intervention is significantly delayed when the admitting specialty is not vascular surgery, and half of these patients require HDU/ITU care, with significant morbidity and mortality. Early diagnosis and referral to vascular surgery is crucial in management of these patients. PMID- 25805329 TI - Molecular dynamics of the asymmetric dimers of EGFR: simulations on the active and inactive conformations of the kinase domain. AB - Abnormal activation of EGFR is associated with human cancer, and thus it is a key target for inhibition in cancer therapy. There is evidence suggesting that the activation mechanism of EGFR is based upon the formation of the asymmetric dimer of the kinase domains. Here, we performed MD simulations on the asymmetric dimer for both active and inactive conformations of EGFR kinase domain to investigate flexibility and intrinsic motions of the proteins. Simulations of the active conformation showed that the formation of the asymmetric dimer changes the dynamics of EGFR kinase domain by suppressing fluctuation of the protein and altering the direction of motion of the protein. In contrast, the asymmetric dimerization of the inactive conformation does not alter the overall fluctuation of the kinase domain and does not initiate destabilizing of the inactive structure. We also investigated the intermolecular interactions in the EGFR asymmetric dimers and found that in the active conformation the interactions are dominated by loop-loop contacts rather than those from the helix-helix interactions. In contrast, helix-helix interaction seemed to be more significant for the inactive kinase structure. This work helps us to better understand the conformational flexibility and dynamics of the EGFR kinase domain, as well as provides information that may be useful to develop newer classes of inhibitors that can block allosteric sites rather than the more traditional catalytic site. PMID- 25805330 TI - India may not meet millennium development goal on infant mortality. PMID- 25805331 TI - Differentiation of benign and malignant skeletal lesions with quantitative diffusion weighted MRI at 3T. AB - OBJECTIVES: To investigate the accuracy of quantitative diffusion-weighted imaging with apparent diffusion coefficient (ADC) mapping for characterizing bone lesions as benign or malignant. METHODS: At 3T, 31 subjects with intramedullary lesions imaged by DWI (b-values 50, 400, 800s/mm(2)) were included. ADC values (minimum, mean, maximum) were recorded by three observers independently. Interobserver variability and differences between ADC values in benign and malignant lesions were assessed (unpaired t-test, receiver operating characteristic (ROC) analysis). RESULTS: Of 31 lesions, 18 were benign (osteoblastic (n=1), chondroid (n=6), cysts (n=4), hemangiomatosis (n=1), fibrous (n=3), eosinophilic granuloma (n=1), giant cell tumor (n=1), osteomyelitis (n=1)) and 13 were malignant (primary (n=5), metastases (n=8)). Overall, there were higher minimum (1.27 * 10(-3)mm(2)/s vs 0.68 * 10(-3)mm(2)/s, p<0.001), mean (1.68 * 10(-3)mm(2)/s vs 1.13 * 10(-3)mm(2)/s, p<0.001), and maximum (2.09 * 10( 3)mm(2)/s vs 1. 7 * 10(-3)mm(2)/s, p=0.03). ADC values in benign lesions compared with those in malignancies. ROC analysis revealed areas under the curve for minimum, mean, and maximum ADC values of 0.91, 0.85, and 0.71, respectively. ADC measurements were made with high inter-observer concordance (rho=0.83-0.96). CONCLUSION: Quantitative ADC maps may have predictive value for the characterization of bone lesions. Benign lesions generally have higher minimum, mean, and maximum ADC values than malignancies, with the minimum value offering the highest accuracy for characterization. PMID- 25805332 TI - Regional bronchodilator response assessed by computed tomography in chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: The reliability of CT assessment of regional bronchodilation is not universally accepted. In this study, using our proprietary 3D-CT software, we first examined airway inner luminal area (Ai) before and after inhalation of SFC in a group of COPD patients and then evaluated the same parameters for two sets of CT data obtained from clinically stable subjects with no intervention. METHODS: We conducted CT at deep inspiration and pulmonary function tests before and one week after inhalation of SFC in 23 COPD patients. As a non-intervention group, we used two sets of CT data obtained with one-year interval in another group of subjects who demonstrated stable pulmonary function (n=8). We measured Ai at the mid-portions of 3rd to 6th generation in 8 bronchi of the right lung, a total of 32 identical sites before and after intervention. RESULTS: The average bronchodilation at all sites (DeltaAi%: 28.2 +/- 4.1 (SE)%) (r=0.65, p<0.001) and that of each generation significantly correlated with % improvement of FEV1 (DeltaFEV1%), which increased from 1.40 +/- 0.10 L to 1.58 +/ 0.10 L. When subjects were classified into two groups in terms of mean DeltaFEV1%, even the poor responders (DeltaFEV1% <14% above baseline, n=13) displayed significantly larger DeltaAi% compared with the non-intervention group (19.1 +/- 4.6% versus 2.1 +/- 3.9%). Inter-observer variability for overall DeltaAi% was within acceptable levels. CONCLUSIONS: CT can reliably detect the regional bronchodilation in 3rd to 6th generation airways when DeltaFEV1 is as small as 180 ml on average. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) system (http://www.umin.ac.jp/. No. UMIN 000002668). PMID- 25805333 TI - Cannabinoids to treat spinal cord injury. AB - Spinal cord injury (SCI) is a devastating condition for which there is no standard treatment beyond rehabilitation strategies. In this review, we discuss the current knowledge on the use of cannabinoids to treat this condition. The endocannabinoid system is expressed in the intact spinal cord, and it is dramatically upregulated after lesion. Endogenous activation of this system counteracts secondary damage following SCI, and treatments with endocannabinoids or synthetic cannabinoid receptor agonists promote a better functional outcome in experimental models. The use of cannabinoids in SCI is a new research field and many questions remain open. Here, we discuss caveats and suggest some future directions that may help to understand the role of cannabinoids in SCI and how to take advantage of this system to regain functions after spinal cord damage. PMID- 25805335 TI - Electronic band structure and low-temperature transport properties of the type-I clathrate Ba8Ni(x)Ge(46-x-y?y). AB - We present the evolution of the low-temperature thermodynamic, galvanomagnetic and thermoelectric properties of the type-I clathrate Ba8Ni(x)Ge(46-x-y?y) with the Ni concentration studied on polycrystalline samples with 0.0 <= x <= 6.0 by means of specific heat, Hall effect, electrical resistivity, thermopower and thermal conductivity measurements in the 2-350 K temperature range and supported by first-principles calculations. The experimental results evidence a 2a * 2a * 2a supercell described in the space group Ia3d for x <= 1.0 and a primitive unit cell a * a * a (space group Pm3n) above this Ni content. This concentration also marks the limit between a regime where both electrons and holes contribute to the electrical conduction (x <= 1.0) and a conventional, single-carrier regime (x > 1.0). This evolution is traced by the variations in the thermopower and Hall effect with x. In agreement with band structure calculations, increasing the Ni content drives the system from a nearly-compensated semimetallic state (x = 0.0) towards a narrow-band-gap semiconducting state (x = 4.0). A crossover from an n type to a p-type conduction occurs when crossing the x = 4.0 concentration i.e. for x = 4.1. The solid solution Ba8Ni(x)Ge(46-x-y?y) therefore provides an excellent experimental platform to probe the evolution of the peculiar properties of the parent type-I clathrate Ba8Ge43?3 upon Ge/Ni substitution and filling up of the vacancies, which might be universal among the ternary systems at low substitution levels. PMID- 25805334 TI - Discrepancy between perceived pain and cortical processing: A voxel-based morphometry and contact heat evoked potential study. AB - OBJECTIVES: The purpose of this study was to determine if local gray and white matter volume variations between subjects could account for variability in responses to CHEP stimulation. METHODS: Structural magnetic resonance imaging was used to perform voxel-based morphometry (VBM) of gray and white matter in 30 neurologically healthy subjects. Contact heat stimulation was performed on the dorsum of the right hand at the base of the thumb. Evoked potentials were acquired from a vertex-recording electrode referenced to linked ears. RESULTS: Controlling for age, total intracranial volume, and skull/scalp thickness, CHEP amplitude and pain rating were not significantly correlated between subjects. A VBM region of interest approach demonstrated a significant interaction between pain rating and N2 amplitude in the right insular cortex (p<0.05, family-wise error corrected, FWE). In white matter, a significant interaction was localized in the right inferior frontal occipital fasciculus (IFOF, p<0.05 FWE). CONCLUSIONS: Accounting for gray matter volume in the right insular cortex, resulted in a significant relationship between CHEP amplitude and pain rating. SIGNIFICANCE: This finding suggests that the discrepancy between pain ratings and the amplitude of evoked potentials is not solely related to measurement artifact, but rather attributable, in part, to anatomical differences between subjects. PMID- 25805336 TI - MAP kinase phosphatase-1 expression is regulated by 15-deoxy-Delta12,14 prostaglandin J2 via a HuR-dependent post-transcriptional mechanism. AB - In the present study, we demonstrate a mechanism through which 15-deoxy Delta(12,14)-prostaglandin J2 (15d-PGJ2) induces MKP-1 expression in rat primary astrocytes, leading to the regulation of inflammatory responses. We show that 15d PGJ2 enhances the efficiency of MKP-1 pre-mRNA processing (constitutive splicing and 3'-end processing) and increases the stability of the mature mRNA. We further report that this occurs via the RNA-binding protein, Hu antigen R (HuR). Our experiments show that HuR knockdown abrogates the 15d-PGJ2-induced increases in the pre-mRNA processing and mature mRNA stability of MKP-1, whereas HuR overexpression further enhances the 15d-PGJ2-induced increases in these parameters. Using cysteine (Cys)-mutated HuR proteins, we show that the Cys-245 residue of HuR (but not Cys-13 or Cys-284) is critical for the direct binding of HuR with 15d-PGJ2 and the effects downstream of this interaction. Collectively, our data show that HuR is a novel target of 15d-PGJ2 and reveal HuR-mediated pre mRNA processing and mature mRNA stabilization as important regulatory steps in the 15d-PGJ2-induced expression of MKP-1. The potential to use a small molecule such as 15d-PGJ2 to regulate the induction of MKP-1 at multiple levels of gene expression could be exploited as a novel therapeutic strategy aimed at combating a diverse range of MKP-1-associated pathologies. PMID- 25805337 TI - Inhibitory activities of caffeoylquinic acid derivatives from Ilex kudingcha C.J. Tseng on alpha-glucosidase from Saccharomyces cerevisiae. AB - Polyphenols and caffeoylquinic acid (CQA) derivatives (3-CQA, 4-CQA, 5-CQA, 3,4 diCQA, 3,5-diCQA, and 4,5-diCQA) were prepared from Ilex kudingcha C.J. Tseng, and their effects and mechanisms on the activities of alpha-glucosidase from Saccharomyces cerevisiae were investigated in the present study. As results, the IC50 values for CQA derivatives were 0.16-0.39 mg/mL, and the inhibition mode of CQA derivatives was noncompetitive. On the basis of fluorescence spectroscopy and circular dichroism spectroscopy data, the binding constants and number of binding sites were calculated to be 10(6)-10(8) M(-1) and 1.42-1.87, respectively. CQA derivatives could bind to the enzyme mainly through hydrophobic interaction, altering the microenvironment and molecular conformation of the enzyme, thus decreasing the catalytic activity. To the authors' knowledge, this is the first report on alpha-glucosidase inhibitory mechanism by CQA derivatives from I. kudingcha, and the findings suggest a potential use of kudingcha as functional foods for the prevention and treatment of diabetes and related symptoms. PMID- 25805338 TI - Early seedling vigour, an imperative trait for direct-seeded rice: an overview on physio-morphological parameters and molecular markers. AB - MAIN CONCLUSION: Rapid uniform germination and accumulation of biomass during initial phase of seedling establishment is an essential phenotypic trait considered as early seedling vigour for direct seeded situation in rice irrespective of environment. Enhanced role of carbohydrate, amylase, growth hormones, antioxidant enzymes and ascorbic acid brings changes in vigour and phenotype of seedling. Early establishment and demanding life form dominate the surroundings. Crop plant that has better growth overdrives the weed plant and suppresses its growth. Seedling early vigour is the characteristic of seed quality and describes the rapid, uniform germination and the establishment of strong seedlings in any environmental condition. The phenotype of modern rice varieties has been changed into adaptable for transplanted rice with thirst toward water and selection pressure for semi-dwarf architecture resulting in reduced early vigour. Decreasing freshwater availability and rising labour cost drives the search for a suitable alternative management system to enhance grain yield productivity for the burgeoning world population. In view of these issues, much attention has been focused on dry direct-seeded rice, because it demands low input. A rice cultivar with a strong seedling vigour trait is desirable in case of direct seeding. However, seedling vigour has not been selected in crop improvement programmes in conventional breeding due to its complex nature and quantitative inheritance. Molecular markers have been proven effective in increasing selection efficiency, particularly for quantitative traits that are simply inherited. Marker-assisted selection approach has facilitated efficient and precise transfer of genes/QTL(s) into many crop species and suggests a speedy and efficient technique over conventional breeding and selection methods. In this review, we present the findings and investigations in the field of seedling vigour in rice that includes the nature of inheritance of physio-morphological and biochemical traits and QTLs to assist plant breeders who work for direct seeded rice. PMID- 25805340 TI - Production of pinoresinol diglucoside, pinoresinol monoglucoside, and pinoresinol by Phomopsis sp. XP-8 using mung bean and its major components. AB - Phomopsis sp. XP-8 is an endophytic fungus that has the ability to produce pinoresinol diglucoside (PDG) in vitro and thus has potential application for the biosynthesis of PDG independent of plants. When cultivated in mung bean medium, PDG production was significantly improved and pinoresinol monoglucoside (PMG) and pinoresinol (Pin) were also found in the culture medium. In this experiment, starch, protein, and polysaccharides were isolated from mung beans and separately used as the sole substrate in order to explore the mechanism of fermentation and identify the major substrates that attributed to the biotransformation of PDG, PMG, and Pin. The production of PDG, PMG, and Pin was monitored using high performance liquid chromatography (HPLC) and confirmed using HPLC-MS. Activities of related enzymes, including phenylalanine ammonia-lyase (PAL), trans-cinnamate 4-hydroxylase (C4H), and 4-coumarate-CoA ligase (4CL) were analyzed and tracked during the cultivation. The reaction system contained the compounds isolated from mung bean in the designed amount. Accumulation of phenylalanine, cinnamic acid, p coumaric acid, PDG, PMG, and Pin and the activities of PAL, C4H, and 4CL were measured during the bioconversion. PMG was found only when mung bean polysaccharide was analyzed, while production of PDG and Pin were found when both polysaccharide and starch were analyzed. After examining the monosaccharide composition of the mung bean polysaccharide and the effect of the different monosaccharides had on the production of PMG, PDG, and Pin, galactose in mung bean polysaccharide proved to be the major factor that stimulates the production of PMG. PMID- 25805339 TI - Iron- and manganese-assisted cadmium tolerance in Oryza sativa L.: lowering of rhizotoxicity next to functional photosynthesis. AB - MAIN CONCLUSION: Cadmium toxicity is alleviated by iron and manganese supplements because of reduction in cadmium accumulation and upholding of redox regulation that prevent cadmium-inducible damage to root growth and photosynthesis. Cadmium toxicity in Oryza sativa L. MTU 7029 was investigated in the presence of different concentrations of the micronutrients Fe and Mn. It had been observed that these micronutrients reduce Cd uptake and minimize Cd-inducible rhizotoxicity. The photosynthetic electron transport chain, which is the hub of Fe containing metalloproteins, was severely affected by Cd and resulted in reduced bioproductivity under Cd stress. However, exogenous Fe restored the photosynthetic electron transport. Thus, due to the maintenance of the photosynthetic electron transport, the Cd tolerance was improved during Fe supplement. Both antioxidant enzymes and non-enzymatic antioxidant metabolites were found to play important roles in the alleviation of Cd stress under Fe or Mn supplement. It is concluded that the presence of excess Fe and Mn protects rice plants from Cd stress. PMID- 25805341 TI - Nicotine-degrading microorganisms and their potential applications. AB - Nicotine-degrading microorganisms (NDMs) are a special microbial group which can use nicotine as the sole carbon and nitrogen source for growth. Since the 1950s, the bioconversion of nicotine by microbes has received increasing attention, and several NDMs have been identified, such as Arthrobacter nicotinovorans, Microsporum gypseum, Pellicularia filamentosa JTS-208, and Pseudomonas sp. 41. In recent years, increasing numbers of NDMs have been isolated and identified from tobacco plantation soil, leaf, and tobacco waste. Meanwhile, the metabolic pathway and degradation mechanism of nicotine have been elucidated in several NDMs, such as A. nicotinovorans, Agrobacterium tumefaciens S33, Aspergillus oryzae, and Pseudomonas putida S16. Moreover, several NDMs have been used in improving the quality of cigarettes, treating tobacco waste, and producing valuable intermediates of nicotine. Here, we summarize the diversity, phylogenetic analysis, and potential applications of NDMs. PMID- 25805342 TI - Effect of pH and dilution rate on specific production rate of extra cellular metabolites by Lactobacillus salivarius UCO_979C in continuous culture. AB - The effect of pH and dilution rate on the production of extracellular metabolites of Lactobacillus salivarius UCO_979 was studied. The experiments were carried out in continuous mode, with chemically defined culture medium at a temperature of 37 degrees C, 200 rpm agitation and synthetic air flow of 100 ml/min. Ethanol, acetic acid, formic acid, lactic acid and glucose were quantified through HPLC, while exopolysaccharide (EPS) was extracted with ethanol and quantified through the Dubois method. The results showed no linear trends for the specific production of lactic acid, EPS, acetic acid and ethanol, while the specific glucose consumption and ATP production rates showed linear trends. There was a metabolic change of the strain for dilution rates below 0.3 h(-1). The pH had a significant effect on the metabolism of the strain, which was evidenced by a higher specific glucose consumption and increased production of ATP at pH 6 compared with that obtained at pH 7. This work shows not only the metabolic capabilities of L. salivarius UCO_979C, but also shows that it is possible to quantify some molecules associated with its current use as gastrointestinal probiotic, especially regarding the production of organic acids and EPS. PMID- 25805343 TI - An efficient high-throughput screening assay for rapid directed evolution of halohydrin dehalogenase for preparation of beta-substituted alcohols. AB - Halohydrin dehalogenases (HHDHs) are an important class of enzymes for preparing optically active haloalcohols, epoxides, and beta-substituted alcohols. However, natural HHDHs rarely meet the requirements of industrial applications. Here, a novel high-throughput screening (HTS) methodology for directed evolution of HHDH was developed based on the colorimetric determination of azide. In this method, azide was involved in the HHDH-catalyzed ring-opening process and the decrease of azide was used to quantitatively evaluate HHDH activity. The HTS methodology was simple and sensitive (epsilon460 = 1.2173 * 10(4) L mol(-1) cm(-1)) and could be performed in a microplate format using whole cells. To verify the efficiency of the HTS methodology, it was adopted to engineer a HHDH (HHDH-PL) from Parvibaculum lavamentivorans DS-1, which was applied in the process for ethyl (R) 4-cyano-3-hydroxybutanoate (HN) by the conversion of ethyl (S)-4-chloro-3 hydroxybutanoate ((S)-CHBE)). A random mutant library containing 2500 colonies was screened using the HTS methodology, and three beneficial mutants F176M, A187R, and A187S were obtained. By combining the beneficial mutated residues, the variant F176M/A187R was identified with 2.8-fold higher catalytic efficiency for preparation of HN. The high-throughput colorimetric assay would be very useful for directed evolution of HHDH for preparing beta-substituted alcohols. PMID- 25805344 TI - Efficient production of reuterin from glycerol by magnetically immobilized Lactobacillus reuteri. AB - Reuterin is a compound that contains the monomeric, hydrated monomeric, and cyclic dimeric forms of 3-hydroxypropionaldehyde (3-HPA). It is widely used as a food preservative due to its antimicrobial properties, and 3-HPA is also an important precursor for several industrial chemicals. In this study, we first developed an efficient immobilization process involving magnetic cell entrapment for production of reuterin from glycerol by Lactobacillus reuteri. The cell growth condition was optimized by statistical approaches. High conversion efficiency was achieved using k-carrageenan as the immobilization support and Fe3O4 as magnetic nanoparticles. Furthermore, addition of 0.02 g/L vitamin B12, 10 mmol/L Mg(2+), and glucose in a molar ratio of 0.15 to glycerol significantly increased the conversion rate. Under optimal conditions, 235.9 mmol/L 3-HPA was produced from 250 mmol/L initial glycerol in 1.5 h, with a molar yield of 94.4 % and a productivity of 15.4 mmol/(g dry cell weight?L?h), which were the highest values to date. Thus, this study demonstrated a promising process for the improvement of biocatalyst efficiency in biotransformation. PMID- 25805345 TI - Production and transcriptional regulation of proanthocyanidin biosynthesis in forage legumes. AB - Proanthocyanidins (PA), also known as condensed tannins, contribute to important forage legumes traits including disease resistance and forage quality. PA in forage plants has both positive and negative effects on feed digestibility and animal performance. The analytical methods and their applicability in measuring the contents of PA in forage plants are essential to studies on their nutritional effects. In spite of important breakthroughs in our understanding of the PA biosynthesis, important questions still remain to be answered such as the PA polymerization and transport. Recent advances in the understanding of transcription factor-mediated gene regulation mechanisms in anthocyanin and PA biosynthetic pathway in model plants suggest new approaches for the metabolic engineering of PA in forage plants. The present review will attempt to present the state-of-the-art of research in these areas and provide an update on the production and metabolic engineering of PA in forage plants. We hope that this will contribute to a better understanding of the ways in which PA production to manipulate the content of PA for beneficial effects in forage plants. PMID- 25805347 TI - [Omosexual parents: does a need exist for a reflection by mental health experts?]. AB - The upbringing of children by couples of omosexual parents, both male and female, is a rapidly growing phenomenon in many countries, despite some differences due to variable national laws. In front of the numerical increase of new family typologies, their acceptance by the public opinion is very often a critical and this attitude is prevailingly shared also by the experts of mental health, such as psychologists and psychiatrists. Nevertheless, absolutely without any a priori prejudice, the absence of not yet available statistical data in large populations emphasizes the need to explore in depth the possible existence of specific psychological late consequences in young and adult age, in studies devoid of any cultural bias. Considering the children not as objects of the right of a couple to have sons, but as subjects of their own right to receive a well regulated and balanced affective and relational education should be a critical ethical issue. PMID- 25805346 TI - Preparation of pellets with controlled release of glucose as prevention of hypoglycaemia in paediatric patients. AB - Hypoglycaemic episodes represent serious and frequent complications of type 1 and 2 diabetes. Theoretically, the risk of hypoglycaemic states can be affected by a dosage form based on a food supplement containing a delayed release formulation of glucose. The release of glucose should compensate for balance the peak effect of an antidiabetic treatment. In clinical practice, a diet with fibre and grains is recommended and patients are broadly educated in the topic of low and high glycaemic indexes to achieve the same effect. However, a precisely-timed release of carbohydrates can favourably target expected hypoglycaemia and concurrently decrease carbohydrate content. To study the possibility of preparing the dosage form with controlled-release carbohydrates, a dosage form of pellets containing four osmotically active substances coated by a membrane created of ethylcellulose was prepared. These pellets can be administered in a mixture with liquid or semisolid food. The resulting dissolution profiles for selected compositions showed that delayed release can be achieved for 120, 240 and 360min in vitro, representing an ideal delay for clinical purposes. PMID- 25805348 TI - [Shall psychiatry change its target? Reflections on the evolving role of psychiatry]. AB - In this paper we will describe cultural, social and scientific changes occurred in psychiatry in the last years, identifying the new target for mental health professionals. Groups of young psychiatrists from the Italian Psychiatric Association, the European Psychiatric Association and the World Psychiatric Association have established an international network that launched a debate on the future role of psychiatry. In a rapidly changing world, there is the need to: 1) adapt training in psychiatry to the modern world; 2) identify the new target of mental health professionals; 3) enhance the image of psychiatry in the society; 4) overcome stigma towards people with mental disorders. In recent years, socio-cultural and scientific changes have had a significant impact on the psychiatrists' clinical practice. Mental health professionals should deal with these changes appropriately in order to overcome the current "crisis" of psychiatry, which should be considered as a developmental phase rather than a conceptual one. From time to time psychiatry is criticized both from inside and outside the profession. The current crisis was unavoidable due to the recent socio-cultural changes, but it should be considered an opportunity to adapt the profession to modern times. PMID- 25805349 TI - [Aripiprazole in pregnancy: a review of literature]. AB - AIM: Data on tolerability and safety of aripiprazolo during pregnancy and in childbirth are so far limited. Aim of the present study is to provide a review of the literature on the safety profile of aripiprazole during pregnancy and on maternal and neonatal outcomes, including two cases coming from our database (www.degradatabase.it). METHODS: Medline database was searched for English language articles by using the following keywords: "aripiprazole", "atypical antipsychotic", "major malformations", "perinatal complications", "pregnancy". We reported 2 cases of women treated with aripiprazole during their pregnancy at the Clinic of Affective Disorders in Pregnancy and Postpartum of the United Hospital of Ancona (DEGRA Center - www.depressionegravidanza.it). RESULTS: The data available in the literature did not provide clear evidence about the safety and potential risks related to this drug during pregnancy. Data coming from our database did not detected any malformations and perinatal complications after exposure to aripiprazole in 2 newborns beyond the first trimester of pregnancy. DISCUSSION AND CONCLUSION: From the evidence available, aripiprazole seems to be an antipsychotic effective and well tolerated in the treatment of women with psychotic disorders in pregnancy. However, further studies are needed to better establish the safety of aripiprazole during pregnancy, particularly as the risk of major malformtions and perinatal complications is concerned. PMID- 25805350 TI - Stalking: a neurobiological perspective. AB - Nowadays stalking is becoming a real social emergency, as it may often fuel severe aggressive behaviours. No exhaustive aetiological hypothesis is still available regarding this complex phenomenon. However, the detailed descriptions of some of its peculiar features allow to draw with cautions some general suggestions. Probably stalking may arise from the derangement of those neural networks subserving the so-called social brain and the pair bonding formation, in particular the processes of attachment/separation, attraction/romantic love/reward. In addition, it seems to be modulated by excessive functioning of the dopamine system coupled with decreased serotonin tone. It is believed that the investigation and deepening of its possible neurobiological substrates may be helpful in the prevention of the severe consequences of stalking. PMID- 25805351 TI - [Neurobiology of alcohol and pharmacological aspects of nalmefene]. AB - The brain imaging together with the images obtained using the supermicroscopy has recently demonstrated the chronic elevated intake of ethanol induces both functional and structural changes of neurons, a phenomenon associated to altered mental function. The most recent experimental and clinical studies have indicated the treatment with nalmefene as a specific therapy able to significantly reduce ethanol intake in ethanol-dependent patients. Thanks to its peculiar action (partial agonist for kappa oppioid receptors and pure antagonist of delta and u receptors) nalmenfene, in contrast to naltrexone (a pure antagonist at kappa, delta, u receptors) is able to rimodulate the content of dopamine in the nucleus accumbens of ethanol dependent patients. This mechanism markedly reduces the negative emotional state, disphoria, depression and anhedonia following the disregulation of the mesolimbic dopaminergic system elicited by long-term intake of high amount of ethanol. PMID- 25805353 TI - [SCQ as a tool for screening ASD comorbidities with ADHD]. AB - The aim of the study is to evaluate the effectiveness of the Social Communication Questionnaire (SCQ) to early recognize autistic spectrum disorder (ASD) patients with a comorbidity of attention deficit hyperactivity disorder (ADHD). The SCQ is a 40 items questionnaire developed as a screening tool for ASD in children, with yes/no questions (presence of symptoms with a score of 1/ absence of symptoms with a score of 0) and a risk cutoff. We have analyzed 75 questionnaires completed by both parents of the 75 children referred to the Child Neuropsychiatry Unit of the "Aldo Moro" University of Bari for a psychopathological assessment. These patients received a diagnosis of ASD with a comorbidity of ADHD (24) or without a comorbidity with ADHD (51). Results indicate a higher score of SCQ in patients with overlap diagnosis rather than patients with pure ASD. In particular, the items with a higher frequency are deficit in sociability, empathy and impulse control. Furthermore, patients with intellectual disabilities have a higher score. Findings highlight the use of the SCQ in the assessment of ASD population to early detect potential comorbidity with ADHD. PMID- 25805352 TI - [Predictive factors for further suicide attempts in individuals presenting to an emergency service for an attempted suicide. A one-year longitudinal study]. AB - Suicide attempts (SA) have been recognized among the most important predictors of suicide. AIM: The aim of this study was to assess suicidal ideation, socio demographic and clinical characteristics in patients admitted to the emergency room for a SA and to identify factors associated with clinical outcome. Admission to a Psychiatric Intensive Care Unit and further SA within one year were considered. MATERIALS AND METHODS: Patients that agreed to participate in the study were evaluated in the emergency room with a clinical interview and they were administered the Intent Score Scale. Patients were then contacted and interviewed by telephone 1, 6, and 12 months after the SA. Clinical outcomes and the occurrence of new SA were investigated. RESULTS: Seventy-four patients were enrolled and 49, 24, and 20 patients were reassessed at the 1, 6, and 12 month follow-up respectively. Eight patients reported at least one new SA within one year. Six SA occurred within the first month. Unemployment and underemployment were significantly associated with further SA. The time interval before a new SA was longer for patients admitted at the Psychiatric Intensive Care Unit and shorter for those with high suicidal intent at the first SA. CONCLUSIONS: Although with limitations, our study might suggest that future research should focus on the role of hospitalization in the management of SA. PMID- 25805354 TI - [Psychological variables and alcohol consumption in a sample of students of medicine: gender differences]. AB - AIM: To evaluate in a sample of college students alcohol consumption in relation with socio-demographic and psychopathological variables. METHODS: The psychopathological variables have been investigated through the Self-Report Symptom Inventory-Revised (SCL-90-R), the levels of alcohol consumption through the Alcohol Use Disorders Identification Test (AUDIT). The total score, as well as the scores of the subscales and of the indices of the SCL-90-R, General Symptomatic Index (GSI) in particular, have been analysed also considering gender differences. A multivariate analysis have been performed adjusting for age and variables resulted to be statistically significant at the univariate analysis when comparing males vs. females. The correlations between AUDIT and psychopathological variables have been investigated. RESULTS: The sample was composed by 200 subjects (105 women, 95 men), average age of 21.85 +/- 3.09. The 27% and 13% had values worthy of clinical attention (above the cut-off) of GSI and AUDIT. Women had higher values of total SCL-90-R and of the subscales somatization, obsessive-compulsive, depression and anxiety. In addition, they presented significantly higher scores of GSI. Conversely, men had higher scores at the AUDIT. With the increase of the age the alcohol consumption increased; the latter was positively correlated with the variables sensitivity, anxiety and obsessive-compulsive. The consumption of alcohol negatively correlated with somatization and phobic anxiety. CONCLUSIONS: The psychopathological variables seem to have a great impact on the consumption of alcohol. The abuser of alcohol often tends to minimize his problem, so it is important to pay attention to the "alarm bells". It would therefore be desirable to adopt strategies of counseling and prevention dedicated to the university students. PMID- 25805355 TI - [A case of shared psychotic disorder (folie a deux) with original aspects associated with cross-cultural elements]. AB - Shared psychotic disorder (folie a deux) is a rare condition characterized by the transmission of delusional aspects from a patient (the "dominant partner") to another (the "submissive partner") linked to the first by a close relationship. We report the case of two Moroccan sisters who have experienced a combined delusional episode diagnosed as shared psychotic disorder. In these circumstances, assessment of symptoms from a cross-cultural perspective is a key factor for proper diagnostic evaluation. PMID- 25805356 TI - [In Process Citation]. PMID- 25805357 TI - Layer-dependent dopant stability and magnetic exchange coupling of iron-doped MoS2 nanosheets. AB - Using density-functional theory calculations including a Hubbard U term we explore structural stability, electronic and magnetic properties of Fe-doped MoS2 nanosheets. Unlike previous reports, the geometry and the stability of Fe dopant atoms in MoS2 nanosheets strongly depend on the chemical potential and the layer number of sheets. The substitution Fe dopant atoms at the Mo sites are energetically favorable in monolayer MoS2 and the formation of intercalated and substitutional Fe complexes are preferred in bilayer and multilayer ones under the S-rich regime that is a popular condition for the synthesis of MoS2 nanosheets. We find that the Fe dopants prefer to the ferromagnetic coupling in monolayer MoS2 and the antiferromagnetic coupling in bilayer and multilayer ones, suggesting the layer dependence of magnetic exchange coupling (MEC). The transition of MEC in Fe-doped MoS2 sheets induced by the change of layer number arises from the competition mechanism between the double-exchange and superexchange couplings. The findings provide a route to facilitate the design of MoS2-based diluted magnetic semiconductors and spintronic devices. PMID- 25805359 TI - Fabrication of flexible, transparent and conductive films from single-walled carbon nanotubes with high aspect ratio using poly((furfuryl methacrylate)-co-(2 (dimethylamino)ethyl methacrylate)) as a new polymeric dispersant. AB - We synthesized poly((furfuryl methacrylate)-co-(2-(dimethylamino)ethyl methacrylate)) (p(FMA-co-DMAEMA)) for the dispersion of single-walled carbon nanotubes (SWCNTs) while maintaining their high aspect ratios. The nanotubes' length and height were 2.0 MUm and 2 nm, as determined by transmission electron microscopy and atomic force microscopy, respectively. Transparent conductive films (TCFs) were fabricated by individually dispersed long SWCNTs onto a flexible polyethylene terephthalate substrate. The sheet resistance (Rs) was 210 Omega ?(-1) with 81% transmittance at a wavelength of 550 nm. To reduce their Rs, the TCFs were treated with HNO3 and SOCl2. After treatment, the TCFs had an Rs of 85.75 Omega ?(-1) at a transmittance of 85%. The TCFs exhibited no appreciable change over 200 repeated bending cycles. Dispersing SWCNTs with this newly synthesized polymer is an effective way to fabricate a transparent, highly conductive and flexible film. PMID- 25805358 TI - The development of vaccination perspectives among chiropractic, naturopathic and medical students: a case study of professional enculturation. AB - An important influence on parents' decisions about pediatric vaccination (children under 6 years of age) is the attitude of their health care providers, including complementary and alternative medicine (CAM) providers. Very limited qualitative research exists, however, on how attitudes towards vaccination develop among healthcare professionals in-training. We explored perspective development among three groups of students: medical, chiropractic, and naturopathic. We conducted focus group sessions with participants from each year of study at three different healthcare training programs in Ontario, Canada. Semi structured and open-ended questions were used to elicit dynamic interaction among participants and explore how they constructed their attitudes toward vaccination at the beginning and part way through their professional training. Analyses of verbatim transcripts of audiotaped interviews were conducted both inductively and deductively using questions structured by existing literature on learning, professional socialization and interprofessional relations. We found five major themes and each theme was illustrated with representative quotes. Numerous unexpected insights emerged within these themes, including students' general open mindedness towards pediatric vaccination at the beginning of their training; the powerful influence of both formal education and informal socialization; uncritical acceptance of the vaccination views of senior or respected professionals; students' preference for multiple perspectives rather than one sided, didactic instruction; the absence of explicit socio-cultural tensions among professions; and how divergences among professional students' perspectives result from differing emphases with respect to lifestyle, individual choice, public health and epidemiological factors-rather than disagreement concerning the biomedical evidence. This last finding implies that their different perspectives on pediatric vaccination may be complementary rather than irreconcilable. Our findings should be considered by developers of professional and interprofessional educational curricula and public health officials formulating policy on pediatric vaccination. PMID- 25805360 TI - Effect of B vitamin (folate, B6, and B12) supplementation on osteoporotic fracture and bone turnover markers: a meta-analysis. AB - BACKGROUND: B vitamins (including folate, B6, and B12) supplementation can effectively and easily modify high plasma homocysteine (Hcy). However, the role of Hcy in the pathogenesis of osteoporotic fracture and bone turnover is still controversial. This meta-analysis aimed to assess the impact of B vitamin supplementation on occurrence of any osteoporotic fracture and bone turnover by pooling the results of previous studies. MATERIAL AND METHODS: Relevant randomized controlled trials (RCTs) were searched in databases. Data integration and analysis were done by using Review Manager 5.3 (the Cochrane Collaboration). The risk ratio (RR) and corresponding 95% confidence intervals (CI) of fracture (intervention vs. control) were estimated. Changes in bone turnover indicators (continuous data), weighted mean difference (WMD), and corresponding 95% (CI) were pooled for estimation. RESULTS: Based on the results of 4 RCTs, this meta analysis failed to identify a risk-reducing effect of daily supplementation of B vitamins on osteoporotic fracture in patients with vascular disease and with relatively normal plasma Hcy. In addition, we also did not find any positive effects of B vitamin supplementation on bone turnover. CONCLUSIONS: B vitamin supplementation might not be effective in preventing fracture and improving bone turnover. However, the possible benefits in selective populations, such as populations with very high plasma Hcy and from regions without B vitamin fortification should be explored in the future. PMID- 25805361 TI - Endothelial dysfunction and oxidative stress in children with sleep disordered breathing: role of NADPH oxidase. AB - OBJECTIVE: Oxidative stress plays a crucial role in impairing endothelial function in sleep disordered breathing (SDB) but the underlying mechanism is still undefined. The objective of this study was to evaluate the interplay between oxidative stress, assessed by serum isoprostanes (8-iso-PGF2alpha) and soluble NOX2-dp (sNOX2-dp), and endothelial function, assessed by flow-mediated dilation (FMD), in children with SDB and healthy controls (HC). METHODS: One hundred forty-four children including 45 with primary snoring (PS), 22 with obstructive sleep apnea (OSA) and 67 HC were recruited in this study; in 15 out of 22 OSA children FMD, serum 8-iso-PGF2alpha and sNOX2-dp were assessed before and after one month post adeno-tonsillectomy (AT). RESULTS: Compared with HC, OSA and PS children had significantly higher sNOX2-dp and serum 8-iso-PGF2alpha levels and lower FMD; compared with PS, FMD was significantly lower in OSA children. No significant difference for sNOX2-dp and serum 8-iso-PGF2alpha was observed between OSA and PS children. FMD was inversely correlated with sNOX2-dp levels (p<0.001) and with serum 8-iso-PGF2alpha (p<0.001). In multiple linear regression analysis, sNOX2-dp (p<0.001) and serum 8-iso-PGF2alpha (p<0.001) were the only independent predictive variables associated with FMD. AT significantly decreased sNOX2-dp and serum 8-iso-PGF2alpha levels (from 38.2+/-8.8 to 22.4+/ 11.1 pg/ml, p<0.001, and from 281.4+/-69.7 to 226.0+/-66.4 pg/ml, p<0.001, respectively); conversely, FMD significantly increased after AT in OSA children (from 3.0+/-1.5 to 8.0+/-2.8%, p<0.001). CONCLUSION: This study suggests that NOX2-derived oxidative stress is involved in artery dysfunction in SDB children. Such hypothesis is reinforced by FMD improvement after AT coincidentally with oxidative stress lowering. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02247167. PMID- 25805363 TI - Dissolution-precipitation processes in tank experiments for testing numerical models for reactive transport calculations: Experiments and modelling. AB - In the context of testing reactive transport codes and their underlying conceptual models, a simple 2D reactive transport experiment was developed. The aim was to use simple chemistry and design a reproducible and fast to conduct experiment, which is flexible enough to include several process couplings: advective-diffusive transport of solutes, effect of liquid phase density on advective transport, and kinetically controlled dissolution/precipitation reactions causing porosity changes. A small tank was filled with a reactive layer of strontium sulfate (SrSO4) of two different grain sizes, sandwiched between two layers of essentially non-reacting quartz sand (SiO2). A highly concentrated solution of barium chloride was injected to create an asymmetric flow field. Once the barium chloride reached the reactive layer, it forced the transformation of strontium sulfate into barium sulfate (BaSO4). Due to the higher molar volume of barium sulfate, its precipitation caused a decrease of porosity and lowered the permeability. Changes in the flow field were observed with help of dye tracer tests. The experiments were modelled using the reactive transport code OpenGeosys GEM. Tests with non-reactive tracers performed prior to barium chloride injection, as well as the density-driven flow (due to the high concentration of barium chloride solution), could be well reproduced by the numerical model. To reproduce the mineral bulk transformation with time, two populations of strontium sulfate grains with different kinetic rates of dissolution were applied. However, a default porosity permeability relationship was unable to account for measured pressure changes. Post mortem analysis of the strontium sulfate reactive medium provided useful information on the chemical and structural changes occurring at the pore scale at the interface that were considered in our model to reproduce the pressure evolution with time. PMID- 25805362 TI - PTX3, Anti-PTX3, and Anti-C1q Autoantibodies in Lupus Glomerulonephritis. AB - Pentraxin 3 (PTX3) is an acute-phase protein involved in C1q clearance. The presence of anti-C1q and the absence of anti-PTX3 antibodies were associated with lupus glomerulonephritis (LGLN). Our aim was to assess soluble and kidney expressed PTX3 and their relationships with anti-C1q and anti-PTX3 antibodies in LGLN. Serum PTX3, anti-C1q, anti-dsDNA, and anti-PTX3 antibodies were tested in 130 systemic lupus erythematosus (SLE) patients, 130 healthy and 127 disease controls. Twenty-nine renal biopsies from SLE patients were analyzed and PTX3 immunostaining was quantified by morphometric analysis. Parametric and nonparametric statistics were performed. PTX3 serum levels were lower in SLE versus controls, but they were correlated with proteinuria in LGLN patients (p = 0.001). LGLN patients had higher anti-C1q and lower anti-PTX3 antibody levels than those without (p < 0.0001). LGLN was more prevalent in anti-C1q(+)/anti PTX3(-) than in anti-C1q(+)/anti-PTX3(+) patients (p < 0.001). No LGLN was observed in anti-C1q(-)/anti-PTX3(+) patients. PTX3 was expressed in glomeruli and renal interstitium. Renal PTX3 was correlated with proteinuria (p = 0.024) and interstitial fibrosis (p = 0.023). PTX3 staining and fibrosis were higher in anti-PTX3(-) than anti-PTX3(+) patients. In conclusion, PTX3 is expressed in glomeruli of LGLN patients, primarily in anti-PTX3(-) patients, where it is correlated with renal fibrosis. Anti-C1q/anti-PTX3 antibody profile seems to be useful in LGLN assessment. PMID- 25805365 TI - An enzyme-activatable probe with a self-immolative linker for rapid and sensitive alkaline phosphatase detection and cell imaging through a cascade reaction. AB - We report the design and synthesis of a novel probe (1) for ALP assay by incorporating a self-immolative linker between a phosphate moiety and resorufin. Because of its good biocompatibility and rapid cell internalization, this probe also exhibited great potential for real-time monitoring of endogenous phosphatase activity in living cells. PMID- 25805364 TI - Cotransport of bismerthiazol and montmorillonite colloids in saturated porous media. AB - While bismerthiazol [N,N'-methylene-bis-(2-amino-5-mercapto-1,3,4-thiadiazole)] is one of the most widely used bactericides, the transport of bismerthiazol in subsurface environments is unclear to date. Moreover, natural colloids are ubiquitous in the subsurface environments. The cotransport of bismerthiazol and natural colloids has not been investigated. This study conducted laboratory column experiments to examine the transport of bismerthiazol in saturated sand porous media both in the absence and presence of montmorillonite colloids. Results show that a fraction of bismerthiazol was retained in sand and the retention was higher at pH7 than at pH 4 and 10. The retention did not change with ionic strength. The retention was attributed to the complex of bismerthiazol with metals/metal oxides on sand surfaces through ligand exchange. The transport of bismerthiazol was enhanced with montmorillonite colloids copresent in the solutions and, concurrently, the transport of montmorillonite colloids was facilitated by the bismerthiazol. The transport of montmorillonite colloids was enhanced likely because the bismerthiazol and the colloids competed for the attachment/adsorption sites on collector surfaces and the presence of bismerthiazol changed the Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction energies between colloids and collectors. The transport of bismerthiazol was inhibited if montmorillonite colloids were pre-deposited in sand because bismerthiazol could adsorb onto the colloid surfaces. The adsorbed bismerthiazol could be co-remobilized with the colloids from primary minima by decreasing ionic strength. Whereas colloid-facilitated transport of pesticides has been emphasized, our study implies that transport of colloids could also be facilitated by the presence of pesticides. PMID- 25805366 TI - Multi-frame image super resolution based on sparse coding. AB - An image super-resolution method from multiple observation of low-resolution images is proposed. The method is based on sub-pixel accuracy block matching for estimating relative displacements of observed images, and sparse signal representation for estimating the corresponding high-resolution image, where correspondence between high- and low-resolution images are modeled by a certain degradation process. Relative displacements of small patches of observed low resolution images are accurately estimated by a computationally efficient block matching method. The matching scores of the block matching are used to select a subset of low-resolution patches for reconstructing a high-resolution patch, that is, an adaptive selection of informative low-resolution images is realized. The proposed method is shown to perform comparable or superior to conventional super resolution methods through experiments using various images. PMID- 25805367 TI - Emergency general surgery outcomes at safety net hospitals. AB - BACKGROUND: The United States hospital safety net is defined by the Agency for Healthcare Research and Quality as the top decile of hospitals, which see the greatest proportion of uninsured patients. These hospitals provide important access to health care for uninsured patients but are commonly believed to have worse outcomes. The aim of this study was to compare the outcomes of emergency general surgery procedures performed at safety net and nonsafety net hospitals. MATERIAL AND METHODS: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 2008-2010 was used to create a cohort of inpatients who underwent emergency appendectomy, cholecystectomy, or herniorrhaphy. Outcomes measured included length of stay, charge, cost, death in hospital, complications, and failure to rescue (FTR). Univariate and logistic regression analysis was performed to associate variables with outcomes. RESULTS: A total of 187,913 emergency general surgery cases were identified, 11.5% of which were performed at safety net hospitals. The safety net cohort had increased length of stay but lower mean charge and cost. Age, comorbidity score, black race, male gender, and Medicaid and Medicare insurance were associated with mortality, complication, and FTR. Lower socioeconomic status was associated with mortality and complication. Safety net status was positively associated with complication but not mortality or FTR. CONCLUSIONS: Safety net hospitals had higher complication rates but no difference in FTR or mortality. This may mean that the hospitals are able to effectively recognize and treat patient complications and do so without increased cost. PMID- 25805368 TI - In vitro characterization of a novel C,N-cyclometalated benzimidazole Ru(II) arene complex: stability, intracellular distribution and binding, effects on organic osmolyte homeostasis and induction of apoptosis. AB - In the present work a novel C,N-cyclometalated benzimidazole Ru(ii) arene complex (GY34) was characterized by applying an alternative, diverse approach considering both chemical and biological aspects. RP-HPLC-ICP-MS and RP-HPLC-ESI-MS analysis proved that GY34 in both RPMI-1640 cell medium and ammonium acetate buffer was transformed into several subspecies and the importance of evaluating and controlling analyte stability throughout experiments was demonstrated. Applying a novel cell fractionation protocol GY34 was found to target cell nuclei and mitochondria in Ehrlich Lettre Ascites (ELA) cells, with the intracellular distribution depending on GY34 concentration in the cell medium during incubation. In ELA cells 96 +/- 0.2% of cytosolic GY34 was bound to high molecular species. Furthermore, using the tracer technique GY34 was found to reduce uptake and increase release of the organic osmolyte taurine in ELA cells, with innate resistance to Cisplatin and in A2780 human ovarian cancer cells, with acquired resistance to Cisplatin. Importantly, FACS analysis revealed that GY34 induced apoptosis in ELA cells. The present data suggest the potential of GY34 in overcoming Cisplatin resistance. The methodology applied can be used as a general protocol and an additional tool in the initial evaluation of novel metal-based drugs. PMID- 25805369 TI - Factors controlling the long-term temporal and spatial patterns of nitrate nitrogen export in a dairy farming watershed. AB - It is difficult to investigate the factors that control the riverine nitrate nitrogen (NO3--N) export in a watershed which gains or losses groundwater. To control the NO3--N contamination in these watersheds, it is necessary to investigate the factors that are related to the export of NO3--N that is only produced by the watershed itself. This study was conducted in the Shibetsu watershed located in eastern Hokkaido, Japan, which gains external groundwater contribution (EXT) and 34% of the annual NO3--N loading occurs through EXT. The riverine NO3--N exports from 1980 to 2009 were simulated by the SWAT model, and the factors controlling the temporal and spatial patterns of NO3--N exports were investigated without considering the EXT. The results show that hydrological events control NO3--N export at the seasonal scale, while the hydrological and biogeochemical processes are likely to control NO3--N export at the annual scale. There was an integrated effect among the land use, topography, and soil type related to denitrification process, that regulated the spatial patterns of NO3--N export. The spatial distribution of NO3--N export from hydrologic response units (HRUs) identified the agricultural areas with surplus N that are vulnerable to nitrate contamination. A new standard for the N fertilizer application rate including manure application should be given to control riverine NO3--N export. This study demonstrates that applying the SWAT model is an appropriate method to determine the temporal and spatial patterns of NO3--N export from the watershed which includes EXT and to identify the crucial pollution areas within a watershed in which the management practices can be improved to more effectively control NO3 -N export to water bodies. PMID- 25805370 TI - Suitability of enzymatic markers to assess the environmental condition of natural populations of Gambusia affinis and Daphnia magna--a case study. AB - In recent years, the use of biochemical markers, especially in the assessment of toxic effects and modes of action, under controlled laboratory conditions has increased. However, transposing their use to in situ monitoring or risk assessment evaluations has encountered barriers, mainly related to the difficulty in interpreting the meaning of biochemical variation. In this work, we aimed at understanding if biochemical marker activities (cholinesterase, glutathione S transferase and lactate dehydrogenase) can be used to monitor the health status of natural populations of fish (Gambusia affinis) and daphnids (Daphnia magna). For that, two ponds with different water properties were chosen as study sites, and organisms collected at four sampling periods along the year. The pattern of biochemical marker responses was not the same in the two species, showing higher integrated biochemical marker response values in the winter for G. affinis and in the autumn for D. magna, suggesting specificities that must be taken into account in biomonitoring programmes by including representative species of several trophic levels. In the case of G. affinis, the differences in key physicochemical parameters between the two ponds (especially dissolved oxygen levels) did not seem to affect biochemical marker levels as if organisms were already perfectly adapted to their environment. In general, seasonal variation of water quality seems to have an important role on biochemical marker responses. Several parameters above Environmental Quality Standards were identified such as dissolved oxygen (DO), ammonia, nitrites, sulphides and metals, but eventual responses to these stressors could not be discriminated from natural variation except for particular cases. PMID- 25805372 TI - Forms of phosphorus transfer in runoff under no-tillage in a soil treated with successive swine effluents applications. AB - Successive swine effluent applications can substantially increase the transfer of phosphorus (P) forms in runoff. The aim of this study was to evaluate P accumulation in the soil and transfer of P forms in surface runoff from a Hapludalf soil under no-tillage subjected to successive swine effluent applications. This research was carried out in the Agricultural Engineering Department of the Federal University of Santa Maria, Brazil, from 2004 to 2007, on a Typic Hapludalf soil. Swine effluent rates of 0, 20, 40, and 80 m3 ha(-1) were broadcast over the soil surface prior to sowing of different species in a crop rotation. Soil samples were collected in stratified layers, and the levels of available P were determined. Samples of water runoff from the soil surface were collected throughout the period, and the available, soluble, particulate, and total P were measured. Successive swine effluent applications led to increases in P availability, especially in the soil surface, and P migration through the soil profile. Transfer of P forms was closely associated with runoff, which is directly related to rainfall volume. Swine effluent applications also reduced surface runoff. These results show that in areas with successive swine effluent applications, practices that promote higher water infiltration into the soil are required, e.g., crop rotation and no-tillage system. PMID- 25805371 TI - Ecotoxicological risk of polycyclic aromatic hydrocarbons (PAHs) in urban soil of Isfahan metropolis, Iran. AB - Concentration, distribution, probable sources, and health risks of 16 polycyclic aromatic hydrocarbons (PAHs) were investigated in 52 soil samples collected within a radius 50 km from Isfahan metropolis center. Total concentration of PAHs ranged from 57.70 to 11,730.08 MUg/kg averaging 2,000.56 MUg/kg. Spatial PAH profiles were site-specific and higher concentration of PAHs was observed in the vicinity of industrial zones within Isfahan metropolis. The molecular indices, ring classes, and principal component analysis indicated that the sources of PAHs were both geogenic and pyrogenic. The incremental lifetime cancer risks of exposure to soil PAHs for adults and children living in the study area were 2.3*10(-2) and 2.2*10(-3), respectively. The results suggest that current PAHs levels in Isfahan metropolis soil are highly carcinogenic and may hold a serious health risk for local resident. PMID- 25805373 TI - A message for 2015. PMID- 25805374 TI - Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome. PMID- 25805375 TI - American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. PMID- 25805376 TI - American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. PMID- 25805377 TI - Nursing science or is it the science of nursing? PMID- 25805378 TI - Listening: important to the stuff of a life. AB - The author presents ideas from Parse's humanbecoming paradigm, including living quality as the stuff of a life. The following question is explored: In what way could listening be important to living the core knowings of living quality? Three ways of viewing listening as connected to living quality are presented: listening as silence, listening as dialogue, and listening as ethics. PMID- 25805379 TI - The conundrum: whether or not to let a golden nugget slip away. AB - The conundrum of using data pertinent to a study that were gathered after an official interview ceased is considered in this column. First, details of a proposed study on losing a partner will be provided followed by a snippet of a dialogue with one participant. Then the conundrum of whether or not to use the data is explored and a conclusion reached through consideration of standards for qualitative research. PMID- 25805380 TI - Ethics and the politics of advancing nursing knowledge. AB - The politics of academia involve intricate human relationships that are political in nature as nurse leaders and scholars struggle to advance nursing science with complex leading-following situations. This article begins a dialogue of considering potential meanings for what it means to be political within competing interest groups in academia, and within the discipline of nursing. What is most important in the struggle for identity and what possibilities surface when potential competing interests in academia collide? The ethical tenets of humanbecoming and the leading-following model are used to illustrate issues surrounding academic integrity and possibilities for the advancement of nursing scholarship in future generations. PMID- 25805381 TI - Politically charged issues in nursing's teaching-learning environments. AB - Many people, depending on different times of the year, become exhausted hearing about politics. Yet, politics can no more be avoided than traffic on a freeway. It always exists. Nursing education then is also infused with politically-driven ideas and trends which can influence program success and quality. The author focuses on and explores some of the ever-present politically charged issues involving degree requirements for nurses, general political issues for nursing programs, and promotion and tenure. The author concludes with a discussion on Parse's teaching-learning model as a means for nurse educators to transcend political turmoil. PMID- 25805382 TI - Expanding humanbecoming theory. PMID- 25805383 TI - Living the art of humanbecoming with the Smith family. AB - The author presents the humanbecoming family model with family living with dementia. A brief overview of the humanbecoming paradigm is presented followed by a discussion about the humanbecoming family model, true presence, and living the art of humanbecoming. A description of the Smith family living with dementia illustrates living the art of humanbecoming. PMID- 25805384 TI - Meta-theory in nursing: necessary for practice? AB - The author argues that the ever-growing body of nursing science should be the basis for both research and practice. Understanding the philosophical and scientific base of the discipline would ideally be required for both advanced practice and research. PMID- 25805385 TI - Psychological factors associated with weight loss maintenance: theory-driven practice for nurse practitioners. AB - The authors discuss the psychological factors associated with weight loss maintenance and the use of Pender's health promotion model as a guide for the construction of clinical interventions to address these factors. The psychological factors include internal drive for weight maintenance, ongoing self monitoring, long-term flexibility, positive mood and emotions, appropriate goals, and management of external stimuli. Nurse practitioners can help combat obesity trends through caring for patients in a holistic manner. Periodic psychological needs-assessments for patients who desire to maintain weight loss may further promote long-term success in weight management. PMID- 25805386 TI - Management of bulimia nervosa: a case study with the Roy adaptation model. AB - Bulimia nervosa is a crippling and chronic disorder, with individuals experiencing repeated binge-purge episodes. It is not widely understood by society. The use of the Roy adaptation model for the management of bulimia nervosa is examined in this article. Nursing models are utilized to provide a structure for planning and implementation of patient management. The Roy adaptation model focuses on the importance of individuals as able to adapt well to their changing surrounding environments. This model can be useful in managing patients with bulimia nervosa. PMID- 25805387 TI - The orientation period: essential for new registered nurses' adaptation. AB - The purpose of this research study was to explore adaptation in new registered nurses using the Roy adaptation model as the guiding conceptual framework. This quantitative study employed a random sampling of new nurses in the state of North Carolina. Personal attributes of the new registered nurses and characteristics of their work setting were modeled with four measures considered suitable proxies for adaptation. Being in a formal orientation period significantly supported the new nurses' overall adaptation. This may represent the benefit of social support, including education, which seems to facilitate adaptation. PMID- 25805388 TI - King's theory of goal attainment: exploring functional status. AB - Imogene King's Theory of Goal Attainment provides a schema for nurses interested in functional status. However, the lack of a uniform definition for functional status has hindered development of a concise understanding of this phenomenon. Functional status is particularly important to nurses who are concerned with the safety and wellbeing of clients. With healthcare's increased focus on client family-centered care it is important to develop innovative approaches for evaluating functional status that incorporate the client-family perspective. King's focus on mutual decision-making is an underutilized resource that can provide great insight into the study and understanding of functional status. PMID- 25805389 TI - A study of graduate nursing students' reflections on the art of Tibetan medicine. AB - This global perspective column focuses on a humanbecoming hermeneutic study of first semester graduate nursing students' reflections on an art museum exhibit titled; Bodies in Balance: The Art of Tibetan Medicine. The research question that guided the study was "what is the emerging meaning of living balance as depicted in the exhibit? The students' essays were interpreted in light of the humanbecoming perspective. The essays were summarized and yielded four themes; surprising and amazing, interconnectedness of all things, unexpected elements and commonalities, and attention to daily living. Parse's three core knowings of living quality (fortifying wisdom, discerning witness and penetrating silence) were considered with the emergent meanings from the students' essays on living balance as depicted in The Art of Tibetan Medicine exhibit. This study showed the use of art in the teaching about global health in graduate nursing education. PMID- 25805390 TI - Nursing science leaders. AB - This introduces the guest author's column on perspectives on the development of leaders in science. The need for leadership in science is discussed and a model for the development of science leaders in nursing is outlined. PMID- 25805391 TI - Leadership in science. AB - In this article, there is a leadership discussion related to the development of leaders in nursing science-a topic rarely discussed. Given the recent dramatic shifts in funding as well as changes in methods of inquiry and data models, there is a clear need for individuals in nursing science who can not only negotiate the turbulent waters of funding but can also lead teams of others, and the discipline, to generate and translate knowledge that will truly be useful to providers, patients, and families. This requires leaders in science who can challenge the prevailing views and traditional paths to excellence held sacred by some. PMID- 25805392 TI - Invisible nursing research: thoughts about mixed methods research and nursing practice. AB - In this this essay, the author addresses the close connection between mixed methods research and nursing practice. If the assertion that research and practice are parallel processes is accepted, then nursing practice may be considered "invisible mixed methods research," in that almost every encounter between a nurse and a patient involves collection and integration of qualitative (word) and quantitative (number) information that actually is single-case mixed methods research. PMID- 25805396 TI - Letter to the editor: the heart of a leader. PMID- 25805397 TI - Cooking with soyabean oil increases whole-blood alpha-linolenic acid in school aged children: results from a randomized trial. AB - OBJECTIVE: Supply of essential n-3 PUFA is limited worldwide. While fish-oil supplementation effectively improves n-3 PUFA status, it may not be a sustainable intervention. The use of alpha-linolenic acid (ALA)-rich cooking oils in the household may be a suitable alternative but its effect on PUFA status is unclear. We aimed to compare the effect of providing families with soyabean oil, an ALA rich cooking oil, v. sunflower oil on whole-blood PUFA levels of children aged 11 18 years. DESIGN: In a randomized, masked, parallel trial, we assigned families to receive a one-month supply of either soyabean or sunflower oil. Fatty acid concentrations were quantified in whole-blood samples obtained from the children before and at the end of the intervention. Changes in fatty acids were compared between treatment arms with use of linear regression for repeated measures. SUBJECTS: Sixty low- and middle-income families. SETTING: Bogota, Colombia. RESULTS: Soyabean oil significantly increased ALA concentrations by 0.05 percentage points of total serum fatty acids whereas sunflower oil decreased them by 0.12 percentage points (soyabean v. sunflower oil effect=0.17; 95% CI 0.11, 0.24). Concentrations of both n-3 and n-6 very-long-chain PUFA, including docosapentaenoic acid, DHA, dihomo-gamma-linolenic acid and arachidonic acid, increased significantly in both intervention arms. Levels of oleic acid and palmitic acid decreased, irrespective of oil assignment. Total energy or energy intake from saturated fat did not change. CONCLUSIONS: Replacing cooking oils at the household level is an effective intervention to improve essential PUFA status of children. PMID- 25805398 TI - Uterine carcinosarcoma: A review of the literature. AB - OBJECTIVE: Uterine carcinosarcomas (UCSs) are aggressive tumors previously considered to be sarcomas, but now recognized as malignancies composed of metaplastic transformation of epithelial elements. Much of the management for UCS has been extrapolated from studies of endometrial carcinomas and sarcomas. This article critically reviews the literature pertinent to the pathology, pathogenesis, diagnosis and management of women with UCS. METHODS: MEDLINE was searched for English language literature on UCS with a focus on the past 20years. Given the rarity of this tumor, studies were not limited by design or number of reported patients. RESULTS: UCS is biologically a de-differentiated endometrial carcinoma with its own pathogenesis and molecular profile. It commonly presents with extrauterine disease which can be identified by comprehensive surgical staging. Most UCS patients are candidates for adjuvant chemotherapy. The role of radiation is less clear. Combination therapy, while commonly used, has not been studied in depth. The high recurrence rate and poor overall survival for UCS suggest an ongoing need for clinical trials for UCS specifically. CONCLUSIONS: UCS represents a distinct subtype of uterine malignancy, and should be studied as such via focused clinical trials. PMID- 25805399 TI - Clinicopathological characteristics and lymph node metastasis pathway of non small-cell lung cancer located in the left lingular division. AB - OBJECTIVES: The purpose of this study is to assess the clinicopathological characteristics of non-small-cell lung cancer (NSCLC) occurring in the left lingular division (LLD) in association with a proposal of the LLD-specific regional lymph node stations. METHODS: Medical records of patients, who underwent complete tumour resection with mediastinal lymph node dissection (MLND) for LLD NSCLC from 2000 to 2009 in multiple institutions, were retrospectively examined. We analysed patient clinicopathological characteristics and obtained the LLD specific regional lymph node stations, and then the validity of intraoperative navigation in lymphadenectomy for LLD-NSCLC was investigated. RESULTS: One hundred and eighty-four LLD-NSCLC patients (97 males and 87 females, and 128 adenocarcinomas and 56 non-adenocarcinomas) were studied. The 5-year overall survival (OS) and disease-free survival (DFS) rates for all LLD-NSCLC patients were 72.9 and 58.3%, respectively. We examined the lymph node metastasis patterns in 42 node-positive tumours. The frequent metastatic lymph node stations were #12u lobar node (n = 22), #5 subaortic node (n = 15) and #11 interlobar node (n = 13) in order. These three node stations were also single metastatic sites in some patients. Metastases to sub-carinal (#7) or inferior mediastinal nodes (#8) were rare. Thus, we assigned the three stations (#5, #11, #12u) as the regional lymph node stations for LLD-NSCLC. If these regional lymph node stations had been examined pathologically during surgery for a total of 160 LLD-NSCLC patients with c-T2N1M0 or lower stage disease, 125 p-N0 and 5 p-N1 patients diagnosed with no metastasis would have been subjected to selective MLND, while 14 p-N1 and all 16 p-N2 patients diagnosed with metastasis would have had complete MLND carried out. As a result, these regional lymph node stations could accurately predict the existence of p-N2 metastasis, and appropriately lead to a selective or complete MLND. CONCLUSIONS: An intraoperative pathological examination using our proposed LLD-specific regional lymph node stations may accurately diagnose the status of node metastasis, and appropriately lead to selective or complete MLND in LLD NSCLC patients with c-T2N1M0 or lower stage disease. PMID- 25805400 TI - Gastrointestinal autonomic nerve tumors: a clinical review. AB - PURPOSE: Gastrointestinal autonomic nerve tumors (GANTs) are believed to be rare accounting for 1 % of all malignant gastrointestinal tumors. Many gastrointestinal surgeons and gastroenterologists are unaware of this entity. This review aims to highlight the salient clinical features and prognosis of GANTs. METHODS: Using the common search engines and manual cross-referencing, a search of the English literature was conducted for "gastrointestinal autonomic nerve tumor." RESULTS: All of the published literature on GANTs is either case reports or small case series. From 49 retrieved articles, a total of 107 GANT cases were collected with a mean age of 54 years and equal male to female preponderance. The most commonly affected site was small bowel followed by stomach. Esophageal and colorectal GANTs were less frequent. Clinical presentation was variable ranging from non-specific symptoms, abdominal pain, weight loss, iron-deficiency anemia, to obstruction and gastrointestinal bleeding. Acute presentation due to free rupture or perforation with subsequent peritonitis was extremely rare. Endoscopic and radiological investigations were valuable in tumor localization and determination of distant spread. Thirteen patients were lost to or had no follow-up, leaving 94 patients for long-term outcome analysis. All patients were treated by radical surgical resection of the involved organ as this offered the only hope of cure. Local recurrence, metastases, or both developed in 40 % of cases despite radical surgical resection. Resection for local recurrences and hepatic metastases was feasible in some selected cases. Response to adjuvant chemoradiation was poor and imatinib mesilate was effective in cases of metastatic or inoperable CD117-positive GANTs. CONCLUSION: Radical surgical resection of GANTs is the mainstay of treatment. The aggressive behavior after radical resection coined with the poor response to adjuvant chemotherapy call for the urgent need to develop new adjuvant therapies. PMID- 25805402 TI - Nature's lessons in design: nanomachines to scaffold, remodel and shape membrane compartments. AB - Compartmentalisation of cellular processes is fundamental to regulation of metabolism in Eukaryotic organisms and is primarily provided by membrane-bound organelles. These organelles are dynamic structures whose membrane barriers are continually shaped, remodelled and scaffolded by a rich variety of highly sophisticated protein complexes. Towards the goal of bottom-up assembly of compartmentalised protocells in synthetic biology, we believe it will be important to harness and reconstitute the membrane shaping and sculpting characteristics of natural cells. We review different in vitro membrane models and how biophysical investigations of minimal systems combined with appropriate theoretical modelling have been used to gain new insights into the intricate mechanisms of these membrane nanomachines, paying particular attention to proteins involved in membrane fusion, fission and cytoskeletal scaffolding processes. We argue that minimal machineries need to be developed and optimised for employment in artificial protocell systems rather than the complex environs of a living organism. Thus, well-characterised minimal components might be predictably combined into functional, compartmentalised protocellular materials that can be engineered for wide-ranging applications. PMID- 25805401 TI - Interkingdom networking within the oral microbiome. AB - Different sites within the oropharynx harbour unique microbial communities. Co evolution of microbes and host has resulted in complex interkingdom circuitries. Metabolic signalling is crucial to these processes, and novel microbial communication factors are progressively being discovered. Resolving interkingdom networks will lead to better understanding of oral health or disease aetiology. PMID- 25805403 TI - Factor structure and reliability of the Italian adaptation of the Hypomania Check List-32, second revision (HCL-32-R2). AB - OBJECTIVE: To assess the psychometric properties of the Italian adaptation of the Hypomania-Check-List 32-item, second revision (HCL-32-R2) for the detection of bipolarity in major depressive disorder (MDD) treatment-seeking outpatients. METHODS: A back-to-back Italian adaption of the "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" English module of the HCL-32-R2 was administered between March 2013 and October 2014 across twelve collaborating sites in Italy. Diagnostic and Statistical Manual Fourth edition (DSM-IV) diagnoses were made adopting the mini-international neuropsychiatric interview, using bipolar disorder (BD) patients as controls. RESULTS: In our sample (n=441, of whom, BD-I=68; BD-II=117; MDD=256), using a cut-off of 14 allowed the HCL-32 R2 to discriminate DSM-IV-defined MDD patients between "true unipolar" (HCL-32 R2(-)) and "sub-threshold bipolar depression" (HCL-32-R2(+)) with sensitivity=89% and specificity=79%. Area under the curve was .888; positive and negative predictive values were 75.34% and 90.99% respectively. Owing to clinical interpretability considerations and consistency with previous adaptations of the HCL-32, a two-factor solution (F1="hyperactive/elated" vs. F2="irritable/distractible/impulsive") was preferred using exploratory and confirmatory factor analyses, whereas items n.33 ("I gamble more") and n.34 ("I eat more") introduced in the R2 version of the scale slightly loaded onto F2 and F1 respectively. Cronbach's alpha=.88 for F1 and .71 for F2. LIMITATIONS: No cross-validation with any additional validated screening tool; treatment-seeking outpatient sample; recall bias; no systematic evaluation of eventual medical/psychiatric comorbidities, current/lifetime pharmacological history, neither record of severity of current MDE. CONCLUSIONS: Our results seem to indicate fair accuracy of HCL-32 as a screening instrument for BD, though replication studies are warranted. PMID- 25805404 TI - Long-term work disability and absenteeism in anxiety and depressive disorders. AB - BACKGROUND: This longitudinal study aims to compare long-term work disability and absenteeism between anxiety and depressive disorders focusing on the effects of different course trajectories (remission, recurrence and chronic course) and specific symptom dimensions (anxiety arousal, avoidance behaviour and depressive mood). METHODS: We included healthy controls, subjects with a history of - and current anxiety and/or depressive disorders with a paid job (n=1632). The Composite International Diagnostic Interview was used to diagnose anxiety and depressive disorders and to assess course trajectories at baseline, over 2 and 4 years. The World Health Organization Disability Assessment Schedule II and the Health and Labour Questionnaire Short Form were used to measure work disability and absenteeism. Symptom dimensions were measured using the Beck Anxiety Inventory, the Fear Questionnaire and the Inventory for Depressive Symptomatology. RESULTS: A history of - and current anxiety and/or depressive disorders were associated with increasing work disability and absenteeism over 4 years, compared to healthy controls. Long-term work disability and absenteeism were most prominent in comorbid anxiety-depressive disorder, followed by depressive disorders, and lowest in anxiety disorders. A chronic course, anxiety arousal and depressive mood were strong predictors for long-term work disability while baseline psychiatric status, a chronic course and depressive mood were strong predictors for long-term work absenteeism. LIMITATIONS: Results cannot be generalized to other anxiety disorders, such as obsessive compulsive disorder, posttraumatic stress disorder and specific phobias. Self-reported measures of work disability and absenteeism were used. CONCLUSIONS: Our results demonstrate that depressive syndromes and symptoms have more impact on future work disability and absenteeism than anxiety, implying that prevention of depression is of major importance. PMID- 25805405 TI - Positive imagery cognitive bias modification (CBM) and internet-based cognitive behavioral therapy (iCBT): a randomized controlled trial. AB - BACKGROUND: Accruing evidence suggests that positive imagery-based cognitive bias modification (CBM) could have potential as a standalone targeted intervention for depressive symptoms or as an adjunct to existing treatments. We sought to establish the benefit of this form of CBM when delivered prior to Internet cognitive behavioral therapy (iCBT) for depression METHODS: A randomized controlled trial (RCT) of a 1-week Internet-delivered positive CBM vs. an active control condition for participants (N=75, 69% female, mean age=42) meeting diagnostic criteria for major depression; followed by a 10-week iCBT program for both groups. RESULTS: Modified intent-to-treat marginal and mixed effect models demonstrated no significant difference between conditions following the CBM intervention or the iCBT program. In both conditions there were significant reductions (Cohen's d .57-1.58, 95% CI=.12-2.07) in primary measures of depression and interpretation bias (PHQ9, BDI-II, AST-D). Large effect size reductions (Cohen's d .81-1.32, 95% CI=.31-1.79) were observed for secondary measures of distress, disability, anxiety and repetitive negative thinking (K10, WHODAS, STAI, RTQ). Per protocol analyses conducted in the sample of participants who completed all seven sessions of CBM indicated between-group superiority of the positive over control group on depression symptoms (PHQ9, BDI-II) and psychological distress (K10) following CBM (Hedges g .55-.88, 95% CI=-.03-1.46) and following iCBT (PHQ9, K10). The majority (>70%) no longer met diagnostic criteria for depression at 3-month follow-up. LIMITATIONS: The control condition contained many active components and therefore may have represented a smaller 'dose' of the positive condition. CONCLUSIONS: Results provide preliminary support for the successful integration of imagery-based CBM into an existing Internet-based treatment for depression. PMID- 25805407 TI - Low-dose energetic protons induce adaptive and bystander effects that protect human cells against DNA damage caused by a subsequent exposure to energetic iron ions. AB - During interplanetary missions, astronauts are exposed to mixed types of ionizing radiation. The low 'flux' of the high atomic number and high energy (HZE) radiations relative to the higher 'flux' of low linear energy transfer (LET) protons makes it highly probable that for any given cell in the body, proton events will precede any HZE event. Whereas progress has been made in our understanding of the biological effects of low-LET protons and high-LET HZE particles, the interplay between the biochemical processes modulated by these radiations is unclear. Here we show that exposure of normal human fibroblasts to a low mean absorbed dose of 20 cGy of 0.05 or 1-GeV protons (LET ~ 1.25 or 0.2 keV/MUm, respectively) protects the irradiated cells (P < 0.0001) against chromosomal damage induced by a subsequent exposure to a mean absorbed dose of 50 cGy from 1 GeV/u iron ions (LET ~ 151 keV/MUm). Surprisingly, unirradiated (i.e. bystander) cells with which the proton-irradiated cells were co-cultured were also significantly protected from the DNA-damaging effects of the challenge dose. The mitigating effect persisted for at least 24 h. These results highlight the interactions of biological effects due to direct cellular traversal by radiation with those due to bystander effects in cell populations exposed to mixed radiation fields. They show that protective adaptive responses can spread from cells targeted by low-LET space radiation to bystander cells in their vicinity. The findings are relevant to understanding the health hazards of space travel. PMID- 25805410 TI - A novel dromedary camel enterovirus in the family Picornaviridae from dromedaries in the Middle East. AB - The recent emergence of Middle East respiratory syndrome coronavirus from the Middle East and the discovery of the virus from dromedary camels have boosted interest in the search for novel viruses in dromedaries. Whilst picornaviruses are known to infect various animals, their existence in dromedaries was unknown. We describe the discovery of a novel picornavirus, dromedary camel enterovirus (DcEV), from dromedaries in Dubai. Among 215 dromedaries, DcEV was detected in faecal samples of four (1.9 %) dromedaries [one (0.5 %) adult dromedary and three (25 %) dromedary calves] by reverse transcription PCR. Analysis of two DcEV genomes showed that DcEV was clustered with other species of the genus Enterovirus and was most closely related to and possessed highest amino acid identities to the species Enterovirus E and Enterovirus F found in cattle. The G+C content of DcEV was 45 mol%, which differed from that of Enterovirus E and Enterovirus F (49-50 mol%) by 4-5 %. Similar to other members of the genus Enterovirus, the 5' UTR of DcEV possessed a putative type I internal ribosome entry site. The low ratios of the number of nonsynonymous substitutions per non synonymous site to the number of synonymous substitutions per synonymous site (Ka/Ks) of various coding regions suggested that dromedaries are the natural reservoir in which DcEV has been stably evolving. These results suggest that DcEV is a novel species of the genus Enterovirus in the family Picornaviridae. Western blot analysis using recombinant DcEV VP1 polypeptide showed a high seroprevalence of 52 % among serum samples from 172 dromedaries for IgG, concurring with its much higher infection rates in dromedary calves than in adults. Further studies are important to understand the pathogenicity, epidemiology and genetic evolution of DcEV in this unique group of animals. PMID- 25805409 TI - A comparison of the impact of Shimen and C strains of classical swine fever virus on Toll-like receptor expression. AB - Classical swine fever is one of the most important swine diseases worldwide and has tremendous socioeconomic impact. In this study, we focused on the signalling pathways of Toll-like receptors (TLRs) because of their roles in the detection and response to viral infections. To this end, two classical swine fever virus (CSFV) strains, namely the highly virulent CSFV Shimen strain and the avirulent C strain (a vaccine strain), were employed, and the expression of 19 immune effector genes was analysed by real-time PCR, Western blot analyses, ELISA and flow cytometry analyses. In vitro experiments were conducted with porcine monocyte-derived macrophages (pMDMs). The results showed that the mRNA and protein levels of TLR2, TLR4 and TLR7 were upregulated in response to CSFV infection, but TLR3 remained unchanged, and was downregulated after infection with the C strain and the Shimen virus, respectively. Furthermore, TLR3-mediated innate immune responses were inhibited in Shimen-strain-infected pMDMs by stimulation with poly(I : C). Accordingly, comprehensive analyses were performed to detect TLR-dependent cytokine responses and the activation of TLR signalling elements. CSFV infection induced mitogen-activated protein kinase activation, but did not elicit NFkappaB activation, thereby affecting the production of pro inflammatory cytokines. The Shimen strain infection resulted in a significant activation of IFN regulatory factor IRF7 and suppression of IRF3. These data provided clues for understanding the effect of CSFV infection on the TLR-mediated innate immune response and associated pathological changes. PMID- 25805411 TI - Detection of exosomal prions in blood by immunochemistry techniques. AB - In most forms of prion diseases, blood is infectious, but detection by immunochemistry techniques of the only available marker of infection (the misfolded prion protein, PrPTSE) in blood remains elusive. We developed a novel method for the detection of PrPTSE in blood of prion-infected rodents based on the finding that PrPTSE is associated with plasma exosomes. However, further purification of the exosomes on a sucrose gradient was necessary to remove plasma immunoglobulins, which interfere with PrPTSE, masking its detection by immunochemistry. Finally, we report that about 20% of plasma infectivity is associated with exosomes. PMID- 25805408 TI - Notch signaling as a novel regulator of metabolism. AB - Evolutionarily unprepared for modern high-calorie diets and sedentary lifestyles, humans are now unprecedentedly susceptible to metabolic disorders such as obesity, type 2 diabetes (T2D), nonalcoholic fatty liver, and cardiovascular disease. These metabolic conditions are intertwined, together known as metabolic syndrome, and compromise human life quality as well as lives. Notch signaling, a fundamental signal transduction pathway critical for cell-cell communication and development, has recently been recognized as a key player in metabolism. This review summarizes the emerging roles of Notch signaling in regulating the metabolism of various cell and tissue types, with emphasis on the underlying molecular mechanisms and the potential of targeting this signal axis to treat metabolic diseases. PMID- 25805413 TI - Towards protein-based viral mimetics for cancer therapies. AB - High resistance and recurrence rates, together with elevated drug clearance, compel the use of maximum-tolerated drug doses in cancer therapy, resulting in high-grade toxicities and limited clinical applicability. Promoting active drug accumulation in tumor tissues would minimize such issues and improve therapeutic outcomes. A new class of therapeutic drugs suitable for the task has emerged based on the concept of virus-mimetic nanocarriers, or 'artificial viruses'. Among the spectrum of materials under exploration in nanocarrier research, proteins offer unparalleled structural and functional versatility for designing virus-like molecular vehicles. By exhibiting 'smart' functions and biomimetic traits, protein-based nanocarriers will be a step ahead of the conventional drug protein conjugates already in the clinic in ensuring efficient delivery of passenger antitumor drugs. PMID- 25805412 TI - Use and impact of thrombectomy in primary percutaneous coronary intervention for acute myocardial infarction with persistent ST-segment elevation: results of the prospective ALKK PCI-registry. AB - BACKGROUND: Data about the impact of thrombectomy in primary percutaneous coronary intervention (PCI) are inconsistent. The aim of our study was an evaluation of both the real-world use of thrombectomy and the impact of thrombectomy on outcome in unselected patients treated with primary PCI for ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: We used the data of the prospective ALKK PCI-registry of 35 hospitals from January 2010 to December 2013. A total of 10,755 patients receiving single-vessel primary PCI for acute STEMI were included. In 2176 patients (20.2 %) thrombectomy was performed. There was a wide range of use of thrombectomy in the different ALKK hospitals from 1.1 to 61.7 % (median 18.6 %, quartiles 6.0 and 40.3 %) with a general increase of use over the first years of the study period. In patients with and without thrombectomy there was TIMI 0 flow present before PCI in 6010 patients, TIMI 1 in 1338, TIMI 2 in 2002, and TIMI 3 in 1405. Patients with acute heart failure or cardiogenic shock received significantly more often thrombectomy. Fluoroscopy time (8.1 vs. 7.3 min, p < 0.0001) and dose area product (5373 cGy * cm(2) vs. 4802 cGy * cm(2), p < 0.0001) were significantly higher in patients treated with thrombectomy. The subgroup of patients with TIMI 0 flow before PCI had significantly higher rates of TIMI 3 flow after PCI when treated with thrombectomy (87.1 vs. 84.1 %, p < 0.01), while there was no difference in post PCI TIMI 3 flow in patients with TIMI 1, 2 or 3 flow before PCI. Rates of major adverse cardiac and cerebrovascular events were similar in both groups in general and in all subgroups of TIMI flow. CONCLUSIONS: The use of thrombectomy in patients with STEMI is heterogenous between hospitals. Overall, there was no impact of thrombectomy on TIMI 3 patency or mortality after PCI. In the subgroup of STEMI patients with TIMI 0 flow before PCI individualized thrombectomy had a positive impact on restoration of normal blood flow. PMID- 25805415 TI - Combination of keratins and alpha-smooth muscle actin distinguishes secretory coils from ducts of eccrine sweat glands. AB - Eccrine sweat glands are comprised of secretory coils and ducts, which are distinct in morphology and function. To better understand the roles of the two parts in development, homeostasis, wound repair and regeneration of eccrine sweat glands, we must distinguish between them. In this study, the localization of keratins and alpha-SMA in human eccrine sweat glands was examined by immunofluorescence staining. Based on the differential localization of keratins and alpha-SMA in different cell types, four pairs of antibodies (K5/K7, K5/alpha SMA, K14/K7 and K14/alpha-SMA) were used to differentiate secretory coils from ducts by double-immunofluorescence staining. Immunofluorescence staining showed that myoepithelial cells of secretory coils expressed K5, K14 and alpha-SMA, whereas secretory cells of secretory coils expressed K7, K8, K15, K18 and K19. Ductal cells expressed K5, K8, K14 and K19. Double-staining showed that the secretory coils were K5(+)/K7(+), K5(+)/alpha-SMA(+), K14(+)/K7(+) and K14(+)/alpha-SMA(+), whereas ducts were K5(+)/K7(-), K5(+)/alpha-SMA(-), K14(+)/K7(-) and K14(+)/alpha-SMA(-). In conclusion, by combining use of keratins and alpha-SMA antibodies, secretory coils can be easily differentiated from ducts in morphology. PMID- 25805417 TI - Importance of serotonin (5-HT) and its precursor l-tryptophan for homeostasis and function of skeletal muscle in rats. A morphological and endocrinological study. AB - Serotonin (5-HT) is a neurotransmitter, synthesized in serotonergic neurons of the central nervous system and in enterochromaffin cells of the gastrointestinal tract, which is involved in the regulation of several body functions, including muscle tissue development and growth and its contractile response. l-Tryptophan (l-Trp) is an essential amino acid and precursor of 5-HT. The aim of the present study was to better understand the mechanisms that govern neuroendocrine homeostasis of muscle tissue and emphasize the importance of a diet, complete in all its elements, referring specifically to the essential amino acids such as l Trp, crucial in several neuroendocrine functions.We analyzed the possible consequences of l-Trp-free diet on 5-HT production and on skeletal muscle morphology and function in young female rats. We also evaluated the eventual alterations of hormone production such as growth hormone (GH), thyroid stimulating hormone (TSH) and thyroid hormones (T3 and T4) that control and regulate growth, metabolism and efficiency of the skeletal muscle. Our results showed a strong decrease of 5-HT, GH, TSH, T3 and T4 levels associated to a clear difference in body weight between experimental and control rats. Moreover, the muscle samples of experimental rats showed histological and ultrastructural alterations. These findings thus supported a strong link between l-Trp, serotonergic system, hormone secretion and morphology of skeletal muscle tissue and thus, the importance of a balanced daily diet. PMID- 25805414 TI - Association of a 62 Variants Type 2 Diabetes Genetic Risk Score With Markers of Subclinical Atherosclerosis: A Transethnic, Multicenter Study. AB - BACKGROUND: Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. METHODS AND RESULTS: In a cross-sectional analysis, including <=9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors-adjusted model (significance, P<0.01=0.05/5, number of traits analyzed). An inverse association with coronary artery calcium score in Multi-Ethnic Study of Atherosclerosis Europeans (fully-adjusted P=0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study (P=0.009) was not confirmed in other study cohorts, either separately or in meta analysis. Secondary analyses showed no consistent associations with beta-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. CONCLUSIONS: SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci. PMID- 25805418 TI - Genetic Distinctions in Patients With Primary Sclerosing Cholangitis: Immunoglobulin G4 Elevations and HLA Risk. PMID- 25805416 TI - Chicken trunk neural crest migration visualized with HNK1. AB - The development of the nervous system involves cells remaining within the neural tube (CNS) and a group of cells that delaminate from the dorsal neural tube and migrate extensively throughout the developing embryo called neural crest cells (NCC). These cells are a mesenchymal highly migratory group of cells that give rise to a wide variety of cell derivatives: melanocytes, sensory neurons, bone, Schwann cells, etc. But not all NCC can give rise to all derivatives, they have fate restrictions based on their axial level of origin: cranial, vagal, trunk and sacral. Our aim was to provide a thorough presentation on how does trunk neural crest cell migration looks in the chicken embryo, in wholemount and in sections using the unique chicken marker HNK1. The description presented here makes a good guideline for those interested in viewing trunk NCC migration patterns. We show how before HH14 there are few trunk NCC delaminating and migrating, but between HH15 through HH19 trunk NCC delaminate in large numbers. Melanocytes precursors begin to enter the dorsolateral pathway by HH17. We found that by HH20 HNK1 is not a valid good marker for NCC and that HNK1 is a better marker than Sox10 when looking at neural crest cells morphology and migration details. PMID- 25805419 TI - On stress and the liver: a chicken and egg conundrum. PMID- 25805420 TI - Colonoscopy versus capsule: sharing the spotlight. PMID- 25805421 TI - Decreasing mortality in patients hospitalized with cirrhosis. PMID- 25805422 TI - Advanced training in neurogastroenterology and gastrointestinal motility. PMID- 25805423 TI - Serial fecal calprotectin measurements to detect endoscopic recurrence in postoperative Crohn's disease: is colonoscopic surveillance no longer needed? PMID- 25805424 TI - The Toronto consensus guidelines for nonhospitalized ulcerative colitis: a welcome update but not the end of the story. PMID- 25805425 TI - Structure-dependent water transport across nanopores of carbon nanotubes: toward selective gating upon temperature regulation. AB - Determining water structure in nanopores and its influence on water transport behaviour is of great importance for understanding and regulating the transport across nanopores. Here we report an ultrafast-slow flow transition phenomenon for water transport across nanopores of carbon nanotubes owing to the change in water structure in nanopores induced by temperature. By performing extensive molecular dynamics simulations, we show the dependence of water transport behaviours on water structures. Our results indicate that owing to the change in water structure in nanopores, water flux across nanopores with certain pore sizes decreases sharply (nearly 3 orders of magnitude) with the decreasing temperature. This phenomenon is very sensitive to the pore size. The threshold temperatures for the occurrence of the ultrafast-slow flow transition for water transport are also determined for various pore sizes. These findings suggest a novel protocol for selective gating of water and proton conduction across nanopores and temperature-controlled drug release. PMID- 25805426 TI - Real-Time Motion Capture Toolbox (RTMocap): an open-source code for recording 3-D motion kinematics to study action-effect anticipations during motor and social interactions. AB - We present here a toolbox for the real-time motion capture of biological movements that runs in the cross-platform MATLAB environment (The MathWorks, Inc., Natick, MA). It provides instantaneous processing of the 3-D movement coordinates of up to 20 markers at a single instant. Available functions include (1) the setting of reference positions, areas, and trajectories of interest; (2) recording of the 3-D coordinates for each marker over the trial duration; and (3) the detection of events to use as triggers for external reinforcers (e.g., lights, sounds, or odors). Through fast online communication between the hardware controller and RTMocap, automatic trial selection is possible by means of either a preset or an adaptive criterion. Rapid preprocessing of signals is also provided, which includes artifact rejection, filtering, spline interpolation, and averaging. A key example is detailed, and three typical variations are developed (1) to provide a clear understanding of the importance of real-time control for 3 D motion in cognitive sciences and (2) to present users with simple lines of code that can be used as starting points for customizing experiments using the simple MATLAB syntax. RTMocap is freely available (http://sites.google.com/site/RTMocap/) under the GNU public license for noncommercial use and open-source development, together with sample data and extensive documentation. PMID- 25805427 TI - Prediction of pathological complete response to neoadjuvant chemotherapy by magnetic resonance imaging in breast cancer patients. AB - The purpose of this study was to evaluate whether the baseline breast MRI findings would be useful for the prediction for pathological complete response (pCR) by breast cancer patients to neoadjuvant chemotherapy. Primary breast cancer patients (stage II-III) preoperatively treated with sequential paclitaxel (12 cycles) and fluorouracil, epirubicin, and cyclophosphamide (4 cycles), followed by surgery were retrospectively enrolled, and 229 patients were eligible. Before chemotherapy, breast MRI studies were performed. Breast tumors were dichotomized into round + oval and irregular types based on MRI morphology. The round + oval tumors showed a significantly higher pCR rate than the irregular tumors (42.0% vs 17.3%; P < 0.001). In addition, PAM50 analysis revealed that basal and HER2-enriched tumors were significantly more prevalent among round + oval than irregular type tumors (P = 0.015). Baseline MRI morphology appears to be a significant predictor for pCR. The higher rate of the basal and HER2 enriched tumors among the round + oval tumors may explain their better chemo sensitivity. PMID- 25805428 TI - Practice of first aid in burn related injuries in a developing country. AB - INTRODUCTION: First aid with cool running water reduces the severity of burn. Low level of knowledge of first aid in burns was shown in previous studies with few patients receiving first aid by water lavage. A study investigating the use of water lavage as first aid in patients presenting to hospital with burn in Lagos, Nigeria was carried out. METHODS: Patients admitted to a University Teaching Hospital for treatment of burns were recruited for this prospective study. Data detailing demographics, scene and aetiology of burns, material used for first aid, who administered first aid, level of education and relationship of first aider with patients, length of hospital stay, complications and outcome of treatment were collected and statistical analysis performed. RESULTS: 168 patients; 73 (43.4%) children and 95 (56.6%) adults were seen. Burns were sustained at home in 95 (74.2%) cases and outside in 33 (25.8%). Water lavage was used in 49 (29.2%) cases, raw eggs in 21 (12.5%), pap in 16 (9.5%) and other materials in 48.8%. 40 (23.8%) patients had not received any form of first aid at presentation. Patients that received no water first aid had higher complication rate (35.3% versus 18.4%) compared with those that had water first aid. CONCLUSION AND RECOMMENDATIONS: The use of water first aid in burns was shown to reduce complication rate in this study. People should be educated on the efficacy of water first aid in pre-hospital care of burns. PMID- 25805431 TI - [News from Denmark]. PMID- 25805429 TI - Determinants of coronary artery calcification in maintenance hemodialysis patients. AB - In addition to the well-known traditional risk factors, uremia-related so-called novel risk factors and medications appear to affect coronary artery calcification in hemodialysis patients. This study was performed to evaluate coronary artery calcification score (CACS) in maintenance hemodialysis (MHD) patients, and to identify significantly related factors. We assessed CACS using Agatston Score by MDCT, sex, age, dialysis vintage, presence of diabetes mellitus, smoking history, presence of >=100 ml urine volume/day, normalized protein catabolic rate, geriatric nutritional risk index, administration of active vitamin D3, cinacalcet, phosphate binders or antihypertensive agents, and circulation parameters including creatinine, albumin, corrected calcium and phosphate in 207 MHD patients. Coronary artery calcifications were observed in 192 patients (92.8%). In multivariate analysis, CACS showed direct associations with age (p < 0.001), dialysis vintage (p < 0.001) and presence of diabetes mellitus (p < 0.01), and an inverse association only with active vitamin D3 administration (p < 0.001) in MHD patients. Patients with active vitamin D3 showed significantly lower CACS than in those without it (1349.6 +/- 1635.0 vs. 2475.6 +/- 2646.6 H, p < 0.05). Older age, longer duration of dialysis and diabetes mellitus are risk factors and administration of active vitamin D3 is protective factor for coronary artery calcification in MHD patients. PMID- 25805432 TI - Cross-sectional study assessing HIV-related knowledge, attitudes and behavior in the Namibian truck transport sector: Readjusting HIV prevention programs in the workplace. AB - The objectives of this study were to assess the current status of HIV-related knowledge, attitudes, and behavior (KAB) of employees in the private transport sector in Namibia and to compare companies with established HIV workplace program (WPPs) with those that have recently initiated the implementation of such programs. The study was designed as a cross-sectional questionnaire-based survey. Between January and March 2011, the survey was conducted in the Namibian truck transport sector in six companies of different sizes. The participants were selected randomly from the workforce. Data collection was based on a KAB questionnaire. The range of correct answers to the survey concerning the knowledge of HIV transmission was 67-95%. Twenty percent of the employees had never been tested for HIV. Additionally, risky sexual behaviors were quite prevalent and included having multiple concurrent partners and the use of sex for incentives. This study revealed that drivers and laborers were especially at risk for such behaviors. The employees of companies with established WPPs were tested for HIV more often than those of companies with new WPPs; however, aside from this difference, only minor differences were observed between the two groups. The findings of this study highlight the need for on-going HIV information and prevention campaigns that focus on the special needs of mobile and low-income workers. WPPs should be tailored accordingly and shift their focus to more practical approaches, such as voluntary counseling and testing (VCT), to increase their effectiveness. PMID- 25805433 TI - Adaptive rhythm sequencing: A method for dynamic rhythm classification during CPR. AB - OBJECTIVE: The accuracy of methods that classify the cardiac rhythm despite CPR artifact could potentially be improved by utilizing continuous ECG data. Our objective is to compare three approaches which use identical ECG features and differ only in their degree of temporal integration: (1) static classification, which analyzes 4-s ECG frames in isolation; (2) "best-of-three averaging," which takes the average of three consecutive static classifications successively; and (3) "adaptive rhythm sequencing," which uses hidden Markov models to model ECG segments as rhythm sequences. METHODS: Defibrillator recordings from 95 out-of hospital cardiac arrests were divided into training and test sets. Each method classified the rhythm as asystole, organized rhythm or shockable rhythm throughout the recordings. Classifications were compared to the gold standard of physician review. The primary outcome was accuracy during CPR, which was estimated using a generalized linear mixed-effects model. RESULTS: In the training set, accuracies during CPR were 0.89 (95% CI 0.85, 0.92), 0.92 (95% CI 0.89, 0.94) and 0.97 (95% CI 0.95, 0.98) for the static, best-of-three averaging and adaptive rhythm sequencing methods, respectively. The corresponding results in the test set were 0.92 (95% CI 0.86, 0.96), 0.94 (95% CI 0.89, 0.97), and 0.97 (95% CI 0.94, 0.99). Of the dynamic methods, only adaptive rhythm sequencing was significantly more accurate than static classification in the training (p < 0.001) and test (p = 0.03) sets. CONCLUSION: In a continuous monitoring setting, adaptive rhythm sequencing was significantly more accurate than static rhythm classification during CPR. PMID- 25805434 TI - Regulation of 3-hydroxyhexanoate composition in PHBH synthesized by recombinant Cupriavidus necator H16 from plant oil by using butyrate as a co-substrate. AB - A (R)-3-hydroxyhexanoate (3HH) composition-regulating technology for poly (3 hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH) production was developed using recombinant Cupriavidus necator H16 with butyrate as a co-substrate. A new (R)-3 hydroxyhexanoyl-CoA ((R)-3HH-CoA) synthesis pathway was designed and enhanced by replacing the PHA synthase gene (phaC1) of C. necator by the phaCAcNSDG (encoding the N149S and D171G mutant of PHA synthase from Aeromonas caviae) and deactivation of the phaA gene (encoding (beta-ketothiolase) from C. necator H16 chromosome). The effect of butyrate as co-substrate was assessed in high-cell density fed-batch cultures of several C. necator mutants, and the 3HH fraction was successfully increased by adding butyrate to the culture. Moreover, overexpression of BktB (encoding the second beta-ketothiolase with broad substrate specificity) enhanced the (R)-3HH-CoA synthesis pathway in the phaA deactivated mutant of C. necator by promoting the condensation of acetyl-CoA and butyryl-CoA into 3-ketohexanoyl-CoA. Consequently, PHBH containing 4.2-13.0 mol% 3HH was produced from butyrate and palm kernel oil by the genetically modified C. necator H16 strains. PMID- 25805436 TI - Usefulness of metal artifact reduction with WARP technique at 1.5 and 3T MRI in imaging metal-on-metal hip resurfacings. AB - OBJECTIVE: To evaluate the usefulness of the metal artifact reduction technique "WARP" in the assessment of metal-on-metal hip resurfacings at 1.5 and 3T in the context of image quality and imaging speed. MATERIALS AND METHODS: Nineteen patients (25 hip resurfacings) were randomized for 1.5 and 3T MRI, both including T1 and T2 turbo spin-echo as well as turbo inversion recovery magnitude sequences with and without view angle tilting and high bandwidth. Additional 3T sequences were acquired with a reduced number of averages and using the parallel acquisition technique for accelerating imaging speed. Artifact size (diameter, area), image quality (5-point scale) and delineation of anatomical structures were compared among the techniques, sequences and field strengths using the Wilcoxon sign-rank and paired t-test with Bonferroni correction. RESULTS: At both field strengths, WARP showed significant superiority over standard sequences regarding image quality, artifact size and delineation of anatomical structures. At 3T, artifacts were larger compared to 1.5T without affecting diagnostic quality, and scanning time could be reduced by up to 64 % without quality degradation. CONCLUSION: WARP proved useful in imaging metal-on-metal hip resurfacings at 1.5T as well as 3T with better image quality surrounding the implants. At 3T imaging could be considerably accelerated without losing diagnostic quality. PMID- 25805435 TI - Development of egocentric and allocentric spatial representations from childhood to elderly age. AB - Spatial reference frames are fundamental to represent the position of objects or places. Although research has reported changes in spatial memory abilities during childhood and elderly age, no study has assessed reference frames processing during the entire lifespan using the same task. Here, we aimed at providing some preliminary data on the capacity to process reference frames in 283 healthy participants from 6 to 89 years of age. A spatial memory task requiring egocentric/allocentric verbal judgments about objects in peri-/extrapersonal space was used. The main goals were: (1) tracing a baseline of the normal process of development of these spatial components; (2) clarifying if reference frames are differently vulnerable to age-related effects. Results showed a symmetry between children of 6-7 years and older people of 80-89 years who were slower and less accurate than all other age groups. As regards processing time, age had a strong effect on the allocentric component, especially in extrapersonal space, with a longer time in 6- to 7-year-old children and 80- to 89-year-old adults. The egocentric component looked less affected by aging. Regarding the level of spatial ability (accuracy), the allocentric ability appeared less sensitive to age-related variations, whereas the egocentric ability progressively improved from 8 years and declined from 60 years. The symmetry in processing time and level of spatial ability is discussed in relation to the development of executive functions and to the structural and functional changes due to incomplete maturation (in youngest children) and deterioration (in oldest adults) of underlying cerebral areas. PMID- 25805439 TI - Ankle Impingement Caused by an Intra-articular Plica: A Report of 2 Cases. AB - Entrapment of soft tissues in the anterolateral gutter of the ankle can cause impingement. When symptomatic, patients complain of chronic ankle pain exacerbated with dorsiflexion. Symptoms of instability and a history of recurring ankle sprains are common findings. Plain radiographs and magnetic resonance imaging may assist clinicians in identifying associated pathology. We present 2 cases of ankle impingement occurring in the setting of equivocal examination and imaging findings. In both cases, arthroscopy revealed a likely congenital, intra articular plica. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case Study. PMID- 25805438 TI - Hallux Varus: An Underreported Presentation of Rheumatoid Arthritis. AB - The prevalence of hallux varus deformity in rheumatoid arthritis (RA) has been reported to be extremely rare. However, in South Asian Countries, where open-toed shoes are habitual footwear for the majority of people, we have found that hallux varus is a common deformity in patients with RA. This rate of occurrence is much more common than that in published hallux deformities in RA and reinforces the impact of footwear on the development of hallux deformities. In this report, we present 3 illustrative cases of hallux varus developed in patients with RA and review the etiology of hallux varus deformity. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case Study. PMID- 25805440 TI - Obesity and pelvic floor dysfunction. AB - Obesity is associated with a high prevalence of pelvic floor disorders. Patients with obesity present with a range of urinary, bowel and sexual dysfunction problems as well as uterovaginal prolapse. Urinary incontinence, faecal incontinence and sexual dysfunction are more prevalent in patients with obesity. Uterovaginal prolapse is also more common than in the non-obese population. Weight loss by surgical and non-surgical methods plays a major role in the improvement of these symptoms in such patients. The treatment of symptoms leads to an improvement in their quality of life. However, surgical treatment of these symptoms may be accompanied by an increased risk of complications in obese patients. A better understanding of the mechanism of obesity-associated pelvic floor dysfunction is essential. PMID- 25805442 TI - Raman study of laser-induced heating effects in free-standing silicon nanocrystals. AB - This paper demonstrates that free-standing silicon nanocrystals (Si NCs) have significantly different thermal conductivity properties compared to Si NCs embedded in a host matrix. The temperatures of Si NCs under laser illumination have been determined by measuring the ratio of the Anti-Stokes to Stokes intensities of the first order Si-Si transverse optical (TO) phonon mode. It is found that large free-standing Si NCs are easily heated up to ~953 K by the laser light. The laser heating effects are reversible to a large extent, however the nature of the free-standing Si NCs is slightly modified after intensive illumination. The free-standing Si NCs can even be easily melted when exposed to a well-focused laser beam. Under these conditions, the blackbody radiation of the heated Si NCs starts to compete with the detected Raman signals. A simplified model of the heating effects is proposed to study the size dependence of the heated free-standing Si NCs with increasing laser power. It is concluded that the huge red-shift of the Si-Si TO mode observed under intensive laser illumination originates from laser-induced heating effects. In contrast, under similar illumination conditions Si NCs embedded in matrixes are hardly heated due to better thermal conductivity. PMID- 25805441 TI - EEG-guided meditation: A personalized approach. AB - The therapeutic potential of meditation for physical and mental well-being is well documented, however the possibility of adverse effects warrants further discussion of the suitability of any particular meditation practice for every given participant. This concern highlights the need for a personalized approach in the meditation practice adjusted for a concrete individual. This can be done by using an objective screening procedure that detects the weak and strong cognitive skills in brain function, thus helping design a tailored meditation training protocol. Quantitative electroencephalogram (qEEG) is a suitable tool that allows identification of individual neurophysiological types. Using qEEG screening can aid developing a meditation training program that maximizes results and minimizes risk of potential negative effects. This brief theoretical conceptual review provides a discussion of the problem and presents some illustrative results on the usage of qEEG screening for the guidance of mediation personalization. PMID- 25805444 TI - Two Synchronous Colonic Adenocarcinomas, a Gastric Schwannoma and a Mucinous Neoplasm of the Appendix: a Case Report. PMID- 25805443 TI - An updated protocol to detect invalid entries in an online survey of men who have sex with men (MSM): how do valid and invalid submissions compare? AB - Researchers use protocols to screen for suspicious survey submissions in online studies. We evaluated how well a de-duplication and cross-validation process detected invalid entries. Data were from the Sexually Explicit Media Study, an Internet-based HIV prevention survey of men who have sex with men. Using our protocol, 146 (11.6 %) of 1254 entries were identified as invalid. Most indicated changes to the screening questionnaire to gain entry (n = 109, 74.7 %), matched other submissions' payment profiles (n = 56, 41.8 %), or featured an IP address that was recorded previously (n = 43, 29.5 %). We found few demographic or behavioral differences between valid and invalid samples, however. Invalid submissions had lower odds of reporting HIV testing in the past year (OR 0.63), and higher odds of requesting no payment compared to check payments (OR 2.75). Thus, rates of HIV testing would have been underestimated if invalid submissions had not been removed, and payment may not be the only incentive for invalid participation. PMID- 25805445 TI - Layer-by-layer deposition of tannic acid and Fe3+ cations is of electrostatic nature but almost ionic strength independent at pH 5. AB - The step-by-step assembly of tannic acid (TA) and of Fe(3+) cations allows to produce films of controlled thickness using exclusively small multivalent ions. In the present investigation, it is shown that even if electrostatic interactions are dominant over ligand to metal charge transfer interactions in stabilizing such films, those electrostatic interactions display a small sensitivity to concentration in NaCl used as a supporting electrolyte as well as to the concentration in sodium acetate in the absence of NaCl. This finding highlights the strong stability of the films obtained through the step-by-step deposition of TA and Fe(3+) cations. Complementarily, the films made from 6 deposition cycles of TA and Fe(3+) cations do not form Prussian Blue when put in contact with hexacyanoferrate anions. This shows that Fe(3+) is so tightly bound to the film that it is not able to form a coordination polymer with Fe(CN)6(4-) anions. PMID- 25805446 TI - Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors. AB - A new class of colchicine derivatives were designed and synthesized as tubulin HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2 105 nM). PMID- 25805448 TI - Probing extracellular acidity of live cells in real time for cancer detection and monitoring anti-cancer drug activity. AB - We report a novel electrochemical strategy to probe the microenvironment of live cells in real time in terms of its extracellular pH. This approach allowed highly sensitive detection of cancer cells down to five cells. Utility of the sensor for evaluating the efficacy of glycolysis inhibiting anti-cancer drugs is also demonstrated. PMID- 25805447 TI - New mimetic peptides inhibitors of Alphabeta aggregation. Molecular guidance for rational drug design. AB - A new series of mimetic peptides possessing a significant Abeta aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Abeta aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Abeta42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Abeta aggregation. Thus, significant alterations in the structure of our Abeta42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the beta1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands. PMID- 25805449 TI - GPU accelerated dynamic functional connectivity analysis for functional MRI data. AB - Recent advances in multi-core processors and graphics card based computational technologies have paved the way for an improved and dynamic utilization of parallel computing techniques. Numerous applications have been implemented for the acceleration of computationally-intensive problems in various computational science fields including bioinformatics, in which big data problems are prevalent. In neuroimaging, dynamic functional connectivity (DFC) analysis is a computationally demanding method used to investigate dynamic functional interactions among different brain regions or networks identified with functional magnetic resonance imaging (fMRI) data. In this study, we implemented and analyzed a parallel DFC algorithm based on thread-based and block-based approaches. The thread-based approach was designed to parallelize DFC computations and was implemented in both Open Multi-Processing (OpenMP) and Compute Unified Device Architecture (CUDA) programming platforms. Another approach developed in this study to better utilize CUDA architecture is the block based approach, where parallelization involves smaller parts of fMRI time-courses obtained by sliding-windows. Experimental results showed that the proposed parallel design solutions enabled by the GPUs significantly reduce the computation time for DFC analysis. Multicore implementation using OpenMP on 8 core processor provides up to 7.7* speed-up. GPU implementation using CUDA yielded substantial accelerations ranging from 18.5* to 157* speed-up once thread based and block-based approaches were combined in the analysis. Proposed parallel programming solutions showed that multi-core processor and CUDA-supported GPU implementations accelerated the DFC analyses significantly. Developed algorithms make the DFC analyses more practical for multi-subject studies with more dynamic analyses. PMID- 25805450 TI - Palliative care in patients with ovarian cancer and bowel obstruction. AB - OBJECTIVE: Malignant bowel obstruction (MBO) is usually a pre-terminal event in patients with ovarian cancer. However, because of the lack of data in literature, decisions around surgical intervention, non-resectional procedures, or medical treatment of MBO in patients with ovarian cancer cannot be lightly undertaken. We analyzed medical and surgical procedures, performance status, nutritional status, cachexia, and their prognostic value in this group of patients. METHODS: We retrospectively selected all consecutive patients with recurrent ovarian cancer who received medical or surgical treatment for MBO between October 2008 and January 2014 at the Academic Department of Gynecological Oncology of Mauriziano Hospital of Turin (Italy). RESULTS: We found 40 patients: 18 of them underwent medical treatment and 22 of them were submitted to surgery. In the group of surgery, the hospitalization was shorter (p 0.02), the pain reduction was more effective (p 0.001), the number of chemotherapy lines was higher (p 0.03), and re obstruction was more rare (p 0.02). Between the two groups, we did not find any differences in post-palliation episodes of vomit (p 0.83), type of diet (p 0.34), ability to return home (p 0.72), and death setting (p 0.28). Median survival after palliation was longer in the group of surgery (p 0.025). Cachexia, low performance status, and poor nutritional status were significant predictors of worse survival after MBO, independently by the treatment. CONCLUSIONS: Surgery has to be considered in patients without serious contraindications; otherwise, a medical protocol, including antisecretory drugs, is the standard of care in frail patients. PMID- 25805452 TI - Appendicular ataxia without position sense loss in a patient with parietal lobe infarct. PMID- 25805451 TI - Chemotherapy interruptions in relation to symptom severity in advanced breast cancer. AB - PURPOSE: Interruptions in medical treatment such as dose delays, reductions, or stoppages can lead to suboptimal treatment of cancer. Knowing how and for whom symptom severity and symptom interference with activities of daily living (ADL) are associated with treatment interruptions can guide behavioral interventions for supportive care. The purpose of this analysis is to inform research and clinical practice by bringing attention to specific patient symptoms that may hinder dose completion. METHODS: A secondary analysis of data collected in a randomized clinical trial (RCT) of reflexology for symptom management was performed. The trial enrolled women with advanced breast cancer undergoing treatment (N = 385). Outcome data were collected at baseline, weeks 5 and 11 using valid and reliable measures. Medical records provided data on treatment interruptions and metastasis. The association between alterations in medical treatment during the study period with symptom severity, symptom interference with ADLs, and metastatic status were tested using generalized estimating equation (GEE) models. RESULTS: The relationship between dose delays and dose reductions and symptom severity was differential according to metastatic status, with the higher strength of association among women with distant metastasis compared to those with loco-regional disease (p = 0.02). The interaction of symptom interference and metastatic status was also significantly related to dose delays and reductions (p = 0.04). Severity of pain was a stronger predictor of dose delays or reductions among patients with distant metastasis compared to those with loco-regional disease (p < 0.01). CONCLUSION: The analysis highlights the importance of understanding symptom outcomes that impact research, practice, and treatment decisions. PMID- 25805453 TI - Orienting network dysfunction in progressive multiple sclerosis. PMID- 25805454 TI - Tic-reducing effects of music in patients with Tourette's syndrome: Self-reported and objective analysis. AB - BACKGROUND: Self-reports by musicians affected with Tourette's syndrome and other sources of anecdotal evidence suggest that tics stop when subjects are involved in musical activity. For the first time, we studied this effect systematically using a questionnaire design to investigate the subjectively assessed impact of musical activity on tic frequency (study 1) and an experimental design to confirm these results (study 2). METHODS: A questionnaire was sent to 29 patients assessing whether listening to music and musical performance would lead to a tic frequency reduction or increase. Then, a within-subject repeated measures design was conducted with eight patients. Five experimental conditions were tested: baseline, musical performance, short time period after musical performance, listening to music and music imagery. Tics were counted based on videotapes. RESULTS: Analysis of the self-reports (study 1) yielded in a significant tic reduction both by listening to music and musical performance. In study 2, musical performance, listening to music and mental imagery of musical performance reduced tic frequency significantly. We found the largest reduction in the condition of musical performance, when tics almost completely stopped. Furthermore, we could find a short-term tic decreasing effect after musical performance. CONCLUSIONS: Self-report assessment revealed that active and passive participation in musical activity can significantly reduce tic frequency. Experimental testing confirmed patients' perception. Active and passive participation in musical activity reduces tic frequency including a short-term lasting tic decreasing effect. Fine motor control, focused attention and goal directed behavior are believed to be relevant factors for this observation. PMID- 25805455 TI - Malignancy does not dictate the hypercoagulable state following liver resection. AB - BACKGROUND: A hypercoagulable state following intra-abdominal malignant resections has been reported. Whether this is because of the operation or the malignancy, a known cause of hypercoagulability, remains unclear. We determined if malignancy status affected the coagulation profile following liver resection by assessing perioperative thromboelastogram (TEG) values. METHODS: Retrospective review of prospectively collected TEG values in patients who received a liver resection was conducted. Values among patients with benign or malignant disease were compared. RESULTS: Fourteen and 63 patients were resected for benign and malignant disease, respectively. No significant differences in TEG values existed between the groups. Combining the groups, patients developed a relative hypercoagulable state postoperatively with decreased R-times (P < .05), although median values remained within the normal range. CONCLUSION: Following liver resection, no differences in TEG values existed between patients with benign and malignant disease; the relative hypercoagulable state is more likely driven by postoperative coagulopathy rather than the malignancy status of the patient. PMID- 25805457 TI - Hemispheric dorsolateral prefrontal cortex lateralization in the regulation of empathy for pain. AB - The dorsolateral prefrontal cortex (DLPFC) is involved in the cognitive appraisal and modulation of the pain experience. In this sham-controlled study, with healthy volunteers, we used bi-hemispheric transcranial direct current stimulation (tDCS) over the DLPFC to assess emotional reactions elicited by pain observation. Left-cathodal/right-anodal tDCS decreased valence and arousal evaluations compared to other tDCS conditions. Compared to sham condition, both left-cathodal/right-anodal and left-anodal/right-cathodal tDCS decreased hostility, sadness and self-pain perception. These decreased sensations after both active tDCS suggest a common role for left and right DLPFC in personal distress modulation. However, the differences in arousal and valence evaluations point to distinct roles of lateralized DLPFC in cognitive empathy, probably through distinct emotion regulation mechanisms. PMID- 25805458 TI - Neurogenic potential of spinal cord organotypic culture. AB - There are several neurogenic niches in the adult mammalian central nervous system. In the central nervous system, neural stem cells (NSC) localize not only to the periventricular area, but are also diffusely distributed in the parenchyma. Here, we assessed neurogenic potential of organotypic cultures prepared from adult mouse spinal cord. Slices were placed on Millipore inserts for organotypic culture and incubated in neurobasal media supplemented with B27 and N2 for up to 9 weeks. After 3-4 weeks, the cell's aggregates formed in the slices. The aggregate's cells were BrdU-uptake, nestin and alkaline phosphatase positive. At the later stage of incubation, we observed Oct3/4 in the inner mass of the neurospheres as well as expression of Dppa1, which is an Oct-4 downstream target gene and a marker for pluripotency. To check differentiation, the formed neurospheres were isolated and cultured for several days in differentiation media. The obtained data demonstrated the cells from isolated neurospheres differentiate into astrocytes and MAP2-positive neurons. Immunostaining for HB9 and Lim2 revealed subsequent differentiation of MAP2-positive cells into motor neurons and interneurons, respectively. We hypothesized neuronal loss and/or long term culturing of spinal cord slices may trigger a reset of the internal cell program and promote proliferation and further differentiation of NSC. PMID- 25805456 TI - An abdominal computed tomography may be safe in selected hypotensive trauma patients with positive Focused Assessment with Sonography in Trauma examination. AB - BACKGROUND: Positive Focused Assessment with Sonography in Trauma examination and hypotension often indicate urgent surgery. An abdomen/pelvis computed tomography (apCT) may allow less invasive management but the delay may be associated with adverse outcomes. METHODS: Patients in the Prospective Observational Multicenter Major Trauma Transfusion study with hypotension and a positive Focused Assessment with Sonography in Trauma (HF+) examination who underwent a CT (apCT+) were compared with those who did not. RESULTS: Of the 92 HF+ identified, 32 (35%) underwent apCT during initial evaluation and apCT was associated with decreased odds of an emergency operation (odds ratio .11, 95% confidence interval .001 to .116) and increased odds of angiographic intervention (odds ratio 14.3, 95% confidence interval 1.5 to 135). There was no significant difference in 30-day mortality or need for dialysis. CONCLUSIONS: An apCT in HF+ patients is associated with reduced odds of emergency surgery, but not mortality. Select HF+ patients can safely undergo apCT to obtain clinically useful information. PMID- 25805460 TI - The endoscopic management of pancreatic pseudocysts (with videos). PMID- 25805461 TI - Colonic polypectomy (with videos). PMID- 25805459 TI - Effects of postprandial starvation on mRNA expression of endocrine-, amino acid and peptide transporter-, and metabolic enzyme-related genes in zebrafish (Danio rerio). AB - The goal of this study was to systematically evaluate the molecular activities of endocrine-, amino acid and peptide transporters-, and metabolic enzyme-related genes in 35-day-old mixed-sex zebrafish (Danio rerio) after feeding . Zebrafish with initial body weights ranging from 9 to 11 mg were fasted for 384 h in a controlled indoor environment. Fish were sampled at 0, 3, 6, 12, 24, 48, 96, 192, and 384 h after fed. Overall, the present study results show that the regulatory mechanism that insulin-like growth factor I negative feedback regulated growth hormone is conserved in zebrafish, as it is in mammals, but that regulation of growth hormone receptors is highly intricate. Leptin and cholecystokinin are time dependent negative feedback signals, and neuropeptide Y may be an important positive neuropeptide for food intake in zebrafish. The amino acid/carnitine transporters B(0,+) (ATB(0,+)) and broad neutral (0) amino acid transporter 1(B(0)AT1) mRNA levels measured in our study suggest that protein may be utilized during 24-96 h of fasting in zebrafish. Glutamine synthetase mRNA levels were downregulated, and glutamate dehydrogenase, alanine aminotransferase, aspartate transaminase, and trypsin mRNA levels were upregulated after longtime fasting in this study. The mRNA expression levels of fatty acid synthetase decreased significantly (P < 0.05), whereas those of lipoprotein lipase rapidly increased after 96 h of fasting. Fasting activated the expression of glucose synthesis genes when fasting for short periods of time; when fasting is prolonged, the mRNA levels of glucose breakdown enzymes and pentose phosphate shunt genes decreased. PMID- 25805462 TI - Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis. AB - BACKGROUND: Current guidelines recommend CT scan or magnetic resonance imaging as the initial imaging modalities for the work-up of suspected pancreatic neuroendocrine tumors (PNETs). OBJECTIVE: To determine the incremental benefit of preoperative EUS (IBEUS) for the detection of suspected PNETs after other investigative modalities have been attempted. DESIGN: This systematic review searched MEDLINE, EMBASE, bibliographies of included articles, and conference proceedings for studies reporting original data regarding the preoperative detection of PNETs. Pooled IBEUS was calculated by using random effects models. Heterogeneity was explored by using stratified meta-analysis and meta-regression. Evidence of small-study effects was assessed by using funnel plots and the Begg test. PATIENTS: Patients with suspected PNETs. INTERVENTIONS: EUS evaluation. MAIN OUTCOME MEASUREMENTS: The pooled IBEUS for the detection of PNETs after CT scan, with or without additional investigative modalities. RESULTS: Among 4505 citations identified, we included 17 cohort studies (612 patients). EUS identified PNETs in 97% of cases. Improved PNET identification with EUS was observed in all of the studies. After adjusting for small-study effects, meta analysis showed that EUS alone could identify PNETs in approximately 1 in 4 patients (adjusted IBEUS 26%; 95% confidence interval, 17%-37%). The pooled IBEUS varied based on the study design, study size, type of CT scan used, and the number of modalities used prior to EUS. LIMITATIONS: The majority of included studies were retrospective. Small-study effects were observed. CONCLUSION: Preoperative EUS is associated with an increase in PNET detection after other modalities are attempted. PMID- 25805463 TI - Emergency video capsule endoscopy: a game-changing strategy? Toward a better use of endoscopic resources. PMID- 25805464 TI - Simulator training in colonoscopy: when less is better. PMID- 25805465 TI - Human epidermal growth factor receptor 2 testing in gastric and gastroesophageal junction adenocarcinomas: role of the gastroenterologist. AB - Endoscopic biopsy sampling of a gastric or GEJ mass is no longer just for histologic diagnosis. The biopsy material may be used for ancillary IHC and/or DNA testing. When possible, multiple biopsy specimens for sampling different areas of the tumor should be obtained to provide the best opportunity to identify overexpression of HER2 and abnormalities in other genes/proteins that may be expressed in different areas of the tumor. Thorough sampling at the time of initial diagnosis may prevent the need for future endoscopic procedures for the sole purpose of obtaining additional tissue for biomarker studies. Communication and coordination with oncologists and pathologists is essential to ensure an appropriate HER2 evaluation is performed. In the coming age of targeted therapeutics, endoscopy may not only be used to obtain tissue for histology and biomarker evaluation but may also be used for the direct in vivo evaluation of biomarkers that guide therapy. PMID- 25805466 TI - Successful decompression of a massively dilated bile duct by use of a through-the scope esophageal stent. PMID- 25805468 TI - Telescoping caps with over-the-scope clip for full-thickness resection of GI lesions (Xtender technique). PMID- 25805467 TI - Endoscopic rescue of a dislodged transabdominal decompressive esophagostomy tube. PMID- 25805469 TI - Percutaneous passage of an extraction balloon to assist recanalization of the common bile duct after surgical transection. PMID- 25805470 TI - Electrohydraulic lithotripsy and removal of a gallstone obstructing the duodenum: Bouveret syndrome. PMID- 25805471 TI - Submucosal tumor in the small bowel resected by EMR at double-balloon endoscopy. PMID- 25805472 TI - Abdominal necrotic abscess from colonic fistula treated endoscopically. PMID- 25805473 TI - Doppler US-guided endoscopic needle-knife septectomy for ileal pouch outlet obstruction. PMID- 25805474 TI - Endoscopic submucosal dissection for an early ileal cancer. PMID- 25805475 TI - Endoscopic incision with esophageal stent placement for the treatment of refractory benign esophageal strictures. PMID- 25805476 TI - Successful hemostasis of arterial bleeding in chronic pseudocyst by direct endoscopic injection of N-butyl-2-cyanoacrylate in the pseudoaneurysm. PMID- 25805478 TI - Response. PMID- 25805477 TI - Lubiprostone in small-bowel capsule endoscopy: meta-analyzing the data. PMID- 25805479 TI - Severe radiation esophagitis successfully treated with Ankaferd hemostat. PMID- 25805480 TI - Ring around the ROSE: pancreatic acinar cell carcinoma diagnosed on site by EUS FNA. PMID- 25805481 TI - An unusual presentation of anisakiasis in the colon (with video). PMID- 25805482 TI - Chasing zebras: large hyperplastic gastric polyp with inflammatory fibroid changes. PMID- 25805483 TI - Endoscopic palliation of advanced cholangiocarcinoma: a need for a real trial! PMID- 25805484 TI - Response. PMID- 25805485 TI - Impact of "regression to the mean" on colonoscopy performance data. PMID- 25805486 TI - Response. PMID- 25805487 TI - Use of radiofrequency ablation probe for eradication of residual adenoma after ampullectomy. PMID- 25805488 TI - The endoscopic morphology of major papillae influences the selected precut technique for biliary access. PMID- 25805489 TI - Response. PMID- 25805490 TI - Is laparoscopic Heller's myotomy superior to pneumatic dilation? PMID- 25805491 TI - Response. PMID- 25805492 TI - Endoscopic treatment of esophageal varices in hemophiliac patients with liver cirrhosis. PMID- 25805493 TI - Using Functional Needs and Personal Care Assistance Rather Than Disability Status During Chronic Care Triage in Community Mass Care. AB - OBJECTIVE: To evaluate Medical Reserve Corps volunteers and public health workers in conducting chronic care triage by use of a rubric prior to sheltering to connect survivors with services. METHODS: Participants were randomly assigned to 1 of 3 algorithms or a control group during a simulated disaster scenario and were asked to rate 20 survivors arriving at a chronic care triage station with situation-appropriate transport services. Survivors were simulated on the basis of the expected disability distributions of mobility, sensory-visual, cognition, medical devices, capacity to perform activities of daily living (ADLs), age (18 to 90 years), weight, and gender expected in the general population but expanded to 90% of those presenting. Mean percentage correct scores were assessed by using one-way analysis of variance. RESULTS: Accounting for personal care assistance and service methodology during chronic care triage increased efficiency by up to 8% in meeting chronic care health service needs during disaster community mass care management. CONCLUSIONS: A chronic care triage process as part of community mass care management that considers the availability of personal care assistance and service methodology will enhance the allocation of functional needs support services and increase compliance with Americans with Disabilities Act requirements regarding not segregating persons because of disability. (Disaster Med Public Health Preparedness. 2015;9:265-274). PMID- 25805494 TI - Effect of carboxymethylation on physicochemical and release characteristics of Indian Palo starch. AB - Limited application of native starch has created the interest in the modification of starch to extend its asset for pharmaceutical application. An effort has been made to study the influence of carboxymethylation on morphological, physicochemical and drug release properties of wild Indian Palo (Curcuma angustifolia) starch. Carboxymethyl starches of different degree of substitution (0.046-0.256) were prepared using varying amount of monochloroacetic acid. The characteristic peaks at around 1600cm(-1) confirmed the carboxymethylation of starch. Morphological studies showed that porous structure formed on the surface of the starch granules and degree of deformity was found to be increased with the increment in the degree of substitution. Amylose content was decreased with the increase in degree of substitution. The TGA data showed that the carboxymethyl starches were thermally stable. Swelling and solubility power was found to be improved with the increase in the temperature. Micromeritic properties of carboxymethyl starches proved its usefulness as excipients in tablet manufacturing. Release profile of paracetamol was found to be decreased with the increase in the degree of substitution, and this proves the suitability of carboxymethyl Indian Palo starch in sustained-release tablets. PMID- 25805495 TI - Significant predictors of patients' uncertainty in primary brain tumors. AB - Patients with primary brain tumors (PBT) face uncertainty related to prognosis, symptoms and treatment response and toxicity. Uncertainty is correlated to negative mood states and symptom severity and interference. This study identified predictors of uncertainty during different treatment stages (newly-diagnosed, on treatment, followed-up without active treatment). One hundred eighty six patients with PBT were accrued at various points in the illness trajectory. Data collection tools included: a clinical checklist/a demographic data sheet/the Mishel Uncertainty in Illness Scale-Brain Tumor Form. The structured additive regression model was used to identify significant demographic and clinical predictors of illness-related uncertainty. Participants were primarily white (80 %) males (53 %). They ranged in age from 19-80 (mean = 44.2 +/- 12.6). Thirty-two of the 186 patients were newly-diagnosed, 64 were on treatment at the time of clinical visit with MRI evaluation, 21 were without MRI, and 69 were not on active treatment. Three subscales (ambiguity/inconsistency; unpredictability disease prognoses; unpredictability-symptoms and other triggers) were different amongst the treatment groups (P < .01). However, patients' uncertainty during active treatment was as high as in newly-diagnosed period. Other than treatment stages, change of employment status due to the illness was the most significant predictor of illness-related uncertainty. The illness trajectory of PBT remains ambiguous, complex, and unpredictable, leading to a high incidence of uncertainty. There was variation in the subscales of uncertainty depending on treatment status. Although patients who are newly diagnosed reported the highest scores on most of the subscales, patients on treatment felt more uncertain about unpredictability of symptoms than other groups. Due to the complexity and impact of the disease, associated symptoms, and interference with functional status, comprehensive assessment of patients is necessary throughout the illness trajectory. PMID- 25805496 TI - The wrapping loop and Rap1 C-terminal (RCT) domain of yeast Rap1 modulate access to different DNA binding modes. AB - Budding yeast Rap1 is a specific double-stranded DNA-binding protein involved in repression and activation of gene transcription and in the establishment of the nucleoprotein complex formed at telomeres. The DNA-binding domain (DBD) of Rap1 forms a high affinity complex with DNA where both Myb-like domains bind to the recognition site. However, we recently showed that the DBD can also access an alternative, lower affinity DNA-binding mode where a single Myb-like domain binds. This results in Rap1-DNA complexes with stoichiometry higher than previously anticipated. In this work, we show that the ability of the DBD to form higher stoichiometry complexes on DNA is maintained also in larger Rap1 constructs. This indicates that transition between at least two DNA-binding modes is a general property of the protein and not a specific feature of the DBD in isolation. The transition between binding modes is modulated by the C-terminal wrapping loop within the DBD, consistent with the proposed model in which the transient opening of this region allows a switch between binding modes. Finally, we provide evidence that the Rap1 C terminus interacts with the DNA-binding domain, suggesting a complex network of interactions that couples changes in conformation of the protein to the binding of its DNA recognition sequence. PMID- 25805497 TI - STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization. AB - Tumor cells use broad spectrum proteolytic activity of plasmin to invade tissue and form metastatic foci. Cell surface-associated enolase-1 (ENO-1) enhances plasmin formation and thus participates in the regulation of pericellular proteolysis. Although increased levels of cell surface bound ENO-1 have been described in different types of cancer, the molecular mechanism responsible for ENO-1 exteriorization remains elusive. In the present study, increased ENO-1 protein levels were found in ductal breast carcinoma and on the cell surface of highly metastatic breast cancer cell line MDA-MB-231. Elevated cell surface associated ENO-1 expression correlated with augmented MDA-MB-231 cell migratory and invasive properties. Exposure of MDA-MB-231 cells to LPS potentiated translocation of ENO-1 to the cell surface and its release into the extracellular space in the form of exosomes. These effects were independent of de novo protein synthesis and did not require the classical endoplasmic reticulum/Golgi pathway. LPS-triggered ENO-1 exteriorization was suppressed by pretreatment of MDA-MB-231 cells with the Ca(2+) chelator BAPTA or an inhibitor of endoplasmic reticulum Ca(2+)-ATPase pump, cyclopiazonic acid. In line with these observations, the stromal interaction molecule (STIM) 1 and the calcium release-activated calcium modulator (ORAI) 1-mediated store-operated Ca(2+) entry were found to regulate LPS-induced ENO-1 exteriorization. Pharmacological blockage or knockdown of STIM1 or ORAI1 reduced ENO-1-dependent migration of MDA-MB-231 cells. Collectively, our results demonstrate the pivotal role of store-operated Ca(2+) channel-mediated Ca(2+) influx in the regulation of ENO-1 exteriorization and thus in the modulation of cancer cell migratory and invasive properties. PMID- 25805498 TI - Microtubule severing by katanin p60 AAA+ ATPase requires the C-terminal acidic tails of both alpha- and beta-tubulins and basic amino acid residues in the AAA+ ring pore. AB - The microtubule (MT) network is highly dynamic and undergoes dramatic reorganizations during the cell cycle. Dimers of alpha- and beta-tubulins rapidly polymerize to and depolymerize from the end of MT fibrils in an intrinsic GTP dependent manner. MT severing by ATP-driven enzymes such as katanin and spastin contributes significantly to microtubule dynamics, and it has been shown that katanin p60, a AAA+ family protein, has ATPase and MT-severing activities. The mechanism of MT severing by katanin p60 is poorly understood, and the residues in katanin p60 and tubulins important for severing activity were therefore explored in this study. MT-severing activity, but not ATPase activity, was inhibited by mutations of the conserved aromatic residue and the flanking basic residues in the pore region of the katanin p60 hexameric ring. When the acidic residue-rich C terminal unstructured segment of either alpha- or beta-tubulin was removed, polymerized MTs were resistant to katanin p60 treatment. Interactions between katanin p60 and the mutant MTs, on the other hand, were unaffected. Taken together, these findings led us to propose that the interactions between the positively charged residues of katanin p60 and the acidic tails of both tubulins are essential for efficient severing of MTs. PMID- 25805499 TI - Estrogen-related Receptor beta Reduces the Subnuclear Mobility of Estrogen Receptor alpha and Suppresses Estrogen-dependent Cellular Function. AB - Estrogen-related receptor (ERR) is a member of the nuclear receptor superfamily that has strong homology with estrogen receptor (ER) alpha. ERR has three subtypes (alpha, beta, and gamma) expressed in estrogen-sensitive organs, including ovary, breast, and brain. No endogenous ligands of ERRs have been identified, but these receptors share a common DNA element with ERalpha and control estrogen-mediated gene transcription. Recent evidence suggests a role of ERRs in estrogen-related pathophysiology, but the detailed mechanisms of ERR functions in estrogen-related tissues are unclear. Using live-cell imaging with fluorescent protein labeling, we found that only ERRbeta among the ERRs exhibits a punctate intranuclear pattern overlapping with ERalpha following 17beta estradiol (E2)-stimulation. Fluorescence recovery after photobleaching showed significant reduction of the mobility of ligand-activated ERalpha with co expression of ERRbeta. Fluorescence resonance energy transfer revealed that ERRbeta directly interacts with ERalpha. The N-terminal domain of ERRbeta was identified as the region that interacts with ERalpha. We also found a correlation between punctate cluster formation of ERalpha and interaction between the receptors. Expression of ERRbeta significantly repressed ERalpha-mediated transactivity, whereas that of other ERR subtypes had no effect on the transactivity of ERalpha. Consistent with this finding, E2-stimulated proliferation of MCF-7 breast carcinoma cells and bcl-2 expression was significantly inhibited by expression of ERRbeta. These results provide strong evidence for a suppressive effect of ERRbeta on estrogen signaling through reduction of the intranuclear mobility of ERalpha. The findings further suggest a unique inhibitory role for ERRbeta in estrogen-dependent cellular function such as cancer cell proliferation. PMID- 25805500 TI - Identification of Novel Crk-associated Substrate (p130Cas) Variants with Functionally Distinct Focal Adhesion Kinase Binding Activities. AB - Elevated levels of p130(Cas) (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1 gene) are associated with aggressiveness of breast tumors. Following phosphorylation of its substrate domain, p130(Cas) promotes the integration of protein complexes involved in multiple signaling pathways and mediates cell proliferation, adhesion, and migration. In addition to the known BCAR1-1A (wild-type) and 1C variants, we identified four novel BCAR1 mRNA variants, generated by alternative first exon usage (1B, 1B1, 1D, and 1E). Exons 1A and 1C encode for four amino acids (aa), whereas 1D and 1E encode for 22 aa and 1B1 encodes for 50 aa. Exon 1B is non-coding, resulting in a truncated p130(Cas) protein (Cas1B). BCAR1-1A, 1B1, and variant 1C mRNAs were ubiquitously expressed in cell lines and a survey of human tissues, whereas 1B, 1D, and 1E expression was more restricted. Reconstitution of all isoforms except for 1B in p130(Cas)-deficient murine fibroblasts induced lamellipodia formation and membrane ruffling, which was unrelated to the substrate domain phosphorylation status. The longer isoforms exhibited increased binding to focal adhesion kinase (FAK), a molecule important for migration and adhesion. The shorter 1B isoform exhibited diminished FAK binding activity and significantly reduced migration and invasion. In contrast, the longest variant 1B1 established the most efficient FAK binding and greatly enhanced migration. Our results indicate that the p130(Cas) exon 1 variants display altered functional properties. The truncated variant 1B and the longer isoform 1B1 may contribute to the diverse effects of p130(Cas) on cell biology and therefore will be the target of future studies. PMID- 25805502 TI - Insulin resistance induces posttranslational hepatic sortilin 1 degradation in mice. AB - Insulin promotes hepatic apolipoprotein B100 (apoB100) degradation, whereas insulin resistance is a major cause of hepatic apoB100/triglyceride overproduction in type 2 diabetes. The cellular trafficking receptor sortilin 1 (Sort1) was recently identified to transport apoB100 to the lysosome for degradation in the liver and thus regulate plasma cholesterol and triglyceride levels. Genetic variation of SORT1 was strongly associated with cardiovascular disease risk in humans. The major goal of this study is to investigate the effect and molecular mechanism of insulin regulation of Sort1. Results showed that insulin induced Sort1 protein, but not mRNA, in AML12 cells. Treatment of PI3K or AKT inhibitors decreased Sort1 protein, whereas expression of constitutively active AKT induced Sort1 protein in AML12 cells. Consistently, hepatic Sort1 was down-regulated in diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome dependent Sort1 degradation. Administration of a PI3K inhibitor to mice decreased hepatic Sort1 protein and increased plasma cholesterol and triglyceride levels. Adenovirus-mediated overexpression of Sort1 in the liver prevented PI3K inhibitor induced Sort1 down-regulation and decreased plasma triglyceride but had no effect on plasma cholesterol in mice. This study identified Sort1 as a novel target of insulin signaling and suggests that Sort1 may play a role in altered hepatic apoB100 metabolism in insulin-resistant conditions. PMID- 25805504 TI - Capsule Commentary on Shelton et al., Reducing PSA-Based Prostate Cancer Screening in Men >= 75 Years Old with Highly Specific Computerized Clinical Decision Support. PMID- 25805501 TI - Bipartite Topology of Treponema pallidum Repeat Proteins C/D and I: OUTER MEMBRANE INSERTION, TRIMERIZATION, AND PORIN FUNCTION REQUIRE A C-TERMINAL beta BARREL DOMAIN. AB - We previously identified Treponema pallidum repeat proteins TprC/D, TprF, and TprI as candidate outer membrane proteins (OMPs) and subsequently demonstrated that TprC is not only a rare OMP but also forms trimers and has porin activity. We also reported that TprC contains N- and C-terminal domains (TprC(N) and TprC(C)) orthologous to regions in the major outer sheath protein (MOSP(N) and MOSP(C)) of Treponema denticola and that TprC(C) is solely responsible for beta barrel formation, trimerization, and porin function by the full-length protein. Herein, we show that TprI also possesses bipartite architecture, trimeric structure, and porin function and that the MOSP(C)-like domains of native TprC and TprI are surface-exposed in T. pallidum, whereas their MOSP(N)-like domains are tethered within the periplasm. TprF, which does not contain a MOSP(C)-like domain, lacks amphiphilicity and porin activity, adopts an extended inflexible structure, and, in T. pallidum, is tightly bound to the protoplasmic cylinder. By thermal denaturation, the MOSP(N) and MOSP(C)-like domains of TprC and TprI are highly thermostable, endowing the full-length proteins with impressive conformational stability. When expressed in Escherichia coli with PelB signal sequences, TprC and TprI localize to the outer membrane, adopting bipartite topologies, whereas TprF is periplasmic. We propose that the MOSP(N)-like domains enhance the structural integrity of the cell envelope by anchoring the beta barrels within the periplasm. In addition to being bona fide T. pallidum rare outer membrane proteins, TprC/D and TprI represent a new class of dual function, bipartite bacterial OMP. PMID- 25805503 TI - Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States (US) Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases. OBJECTIVES: Using a US military cohort who receives equal and open access to healthcare, we sought to examine demographic, clinical features and outcomes with NSCLC. DESIGN AND PARTICIPANTS: We conducted a retrospective cohort analysis of 4,751 patients, aged >= 18 years and diagnosed with a first primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD) cancer registry. MAIN MEASURES: Differences by patient and disease characteristics were compared using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed overall survival. RESULTS: The mean age at diagnosis was 66 years, 64 % were male, 72 % were Caucasian, 41 % were diagnosed at early stage, 77 % received treatment and 82 % had a history of tobacco use. Mean age at diagnosis was highest among Caucasians (67 years) and lowest among African Americans (AA; 62 years). Asian/Pacific Islanders (PI) were more likely to be female (p < 0.0001), have adenocarcinoma histology (p = 0.0003) and less likely to have a history of tobacco use (p < 0.0001) compared to other racial/ethnic groups. In multivariable survival analysis, older age, male gender, increasing stage, not receiving treatment, and tobacco history were associated with higher mortality risk. Untreated patients exhibited a 39 % higher mortality risk compared to treated patients (HR = 1.39; 95%CI = 1.23-1.57). Compared to Caucasian patients, Asian/PIs demonstrated a 20 % lower risk of death (HR = 0.80; 95%CI = 0.66-0.96). There was no difference in mortality risk between AAs and Hispanics compared to Caucasians. CONCLUSION: The lack of significant outcome disparity between AAs and Caucasians and the earlier stage at diagnosis than usually seen in civilian populations suggest that equal access to healthcare may play a role in early detection and survival. PMID- 25805508 TI - ISG15 uncut: Dissecting enzymatic and non-enzymatic functions of USP18 in vivo. AB - Posttranslational protein modification by ISG15 plays an important role in antiviral defense. We selectively inactivated the ISG15 isopeptidase activity of USP18 in mice. Increased ISGylation was accompanied by enhanced viral resistance without causing detrimental side effects suggesting that USP18 protease inhibition might be a suitable antiviral strategy. PMID- 25805507 TI - Isolation and characterization of multifunctional Streptomyces species with antimicrobial, nematicidal and phytohormone activities from marine environments in Egypt. AB - Different strategies have been employed for selective isolation of Streptomycetes from 20 marine samples varied in their biological nature. The recovery of Streptomycetes isolates (112) was influenced preferentially by different strategies; sediment samples were the best source of potential candidate Streptomycetes. All isolates exhibited antimicrobial activities with variable spectrum; the most promising isolates (31) were phenotypically characterized and identified as Streptomyces sp.; these isolates exhibited variable capacity for secretion of numerous hydrolytic enzymes such as catalase, protease, amylase, lipase, lecithinase, asparaginase, chitinase and pectinase. All the strains resisted both penicillin and streptomycin, 29 were sensitive to neomycin; the majority of strains (25) showed multiple antibiotic resistance index greater than 0.2; 23, 22 and 13 degraded the shrimp shell, chicken feather and corn cob, respectively, producing bioactive substance(s) which indicates their diversity and their ecological role in the marine ecosystem. At least 28 strains exhibited nematicidal activity in vitro and in vivo against root-knot nematode and supported plant growth. In vitro, the assessed Streptomyces species exhibited the ability to produce gibberellic acid, indole acetic acid, abscisic acid, kinetin and benzyladenine. Except for indole acetic acid, this is the first report concerning the ability of marine Streptomyces to produce such phytohormones and the use of shrimp shell waste as a mono component medium for production of phytohormones. The study is efficacious in selecting effective biodiverse strains of marine Streptomyces that may work under diverse agro-ecological conditions as a useful element in plant nutrition and as biocontrol agents involved in integrated management programs. PMID- 25805505 TI - Number and brightness analysis of sFRP4 domains in live cells demonstrates vesicle association signal of the NLD domain and dynamic intracellular responses to Wnt3a. AB - The Wnts are secreted, lipidated glycoproteins that play a role in cellular processes of differentiation, proliferation, migration, survival, polarity and stem cell self-renewal. The majority of Wnts biological effects are through binding to specific frizzled (Fzd) receptor complexes leading to activation of downstream pathways. Secreted frizzled-related proteins (sFRPs) were first identified as antagonists of Wnt signalling by binding directly to Wnts. They comprise two domains, a Fzd-like cysteine rich domain (CRD) and a netrin-like domain (NLD). Subsequently sFRPs have been shown to also interact with Fzd receptors and more diverse functions have been identified, including potentiation of Wnt signalling. Many aspects of the biology of this family remain to be elucidated. We used the number and brightness (N&B) method, a technique based on fluorescence fluctuation analysis, to characterise the intracellular aggregation and trafficking of sFRP4 domains. We expressed sFRP4 and its' domains as EGFP fusions and then characterised the effect of endogenous Wnt3a by fluorescence confocal imaging. We observed vesicular trafficking of sFRP4 and that the NLD domain has a vesicular association signal. We found that sFRP4 and the CRD formed oligomeric aggregates in the perinuclear region while the NLD was distributed evenly throughout the cell with a larger proportion of aggregates. Most significantly we observed intracellular redistribution of sFRP4 in response to Wnt3a suggesting that Wnt3a can modulate intracellular localisation and secretion of sFRP4. Our results reveal a number of novel findings regarding sFRP4 which are likely to have relevance to this wider family. PMID- 25805510 TI - [Common German language nomenclature for systemic sclerosis]. AB - Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine. PMID- 25805509 TI - Angiogenesis stimulated by novel nanoscale bioactive glasses. AB - The ability of biomaterials to induce rapid vascular formation is critical in tissue regeneration. Combining recombinant angiogenic growth factors with bioengineered constructs have proven to be difficult due to several issues, including the instability of recombinant proteins, the need for sustained delivery and the dosage of factors. New formulations of bioactive glass, 58S nanosized bioactive glass (58S-NBG), have been reported to enhance wound healing in animal models better than the first generation of 45S5 Bioglass. Therefore, we investigated the effects of extracts of 58S-NBG and 80S-NBG on cultures of human umbilical vein endothelial cells (HUVECs). Cell viability was assessed by MTS assay. In vitro angiogenesis was measured using an ECM gel tube formation assay, and levels of mRNAs for five angiogenic related genes were measured by qRT-PCR. Extracts of 58S-NBG and 80S-NBG stimulated the proliferation of HUVECs, accelerated cell migration, up-regulated expression of the vascular endothelial growth factor, basic fibroblast growth factor, their receptors, and endothelial nitric oxide synthase, resulting in enhanced tube formation in vitro. The enhanced angiogenic response correlated with increased levels of Ca and Si in the extracts of 58S-NBG and 80S-NBG. The ability of 58S-NBG and 80S-NBG to stimulate angiogenesis in vitro provides alternative approaches for stimulating neovascularization of tissue-engineered constructs. PMID- 25805511 TI - [From uncertainty to evidence : modern statistics in rheumatology]. PMID- 25805513 TI - New analysis tools for observational studies. AB - Observational studies, which are very common in rheumatology, usually follow a selected group of patients for a predetermined period of time, or infinitely, with regard to a certain outcome. Such an outcome could be a "score" reflecting an important aspect of the disease (e.g., a disease activity score), or an "event" (e.g., myocardial infarction). Rather than investigating the efficacy of a particular treatment, observational studies serve to investigate clinical associations between different (outcome) variables. Confounding, which may spuriously inflate or reduce the magnitude of a particular association, is an inherent risk in observational studies. The modern analytical approach of an observational study depends on the study question, the study design, and on how the outcome of interest has been assessed. The current article discusses several aspects of the analytical approach and requirements of the database. The focus is on longitudinal analysis, subgroup analysis, and adjustment for confounding. It is concluded that the appropriate analysis of an observational study should be a close collaboration between the clinical researcher with sufficient epidemiological knowledge and the expert statistician with sufficient interest in clinical questions. PMID- 25805512 TI - [Modern study designs and analysis methods in clinical research]. AB - BACKGROUND: Progress in the field of medical research requires further development of clinical trial methodology to overcome the challenges resulting from small patient populations and restricted resources. METHODS: Classical single-stage designs with fixed sample sizes do not allow for interim analyses or design modifications. In contrast, adaptive designs adhere to established quality criteria while providing flexibility when conducting a clinical trial. In the face of new discoveries or information collected in the course of a trial, sample size adjustment, the selection of the target population and further design modifications can be performed. This enhances the chance of success of a clinical trial. Besides adaptive designs, classical approaches may be replaced or complemented by Bayesian methods. In a Bayesian approach prior knowledge can be efficiently included and hence the amount of information utilized in statistical analyses is increased. Furthermore, Bayes procedures allow the results of a statistical evaluation to be displayed very clearly. CONCLUSION: Modern approaches, such as adaptive designs and Bayesian designs overcome the challenges in clinical research due to enhanced flexibility and efficiency. In addition, both approaches can be combined. PMID- 25805514 TI - [How do register data support clinical decision-making?]. AB - BACKGROUND: Patients in daily rheumatological care differ in their individual risk profiles from participants in randomized controlled trials (RCT), e.g. due to comorbidities and age. Transferring results from RCTs into routine daily practice is therefore limited. OBJECTIVE: The aim of this study was to evaluate the contribution of observational studies for decision-making in routine rheumatology practice. MATERIAL AND METHODS: We used data from the German biologics register RABBIT which includes patients with rheumatoid arthritis (RA) when starting synthetic (s) or biologic (b) disease-modifying antirheumatic drugs (DMARD). They are observed for at least 5 years. Comorbidities and clinically relevant aspects (e.g. history of malignancies) are reported at baseline and adverse events at regular follow-up. RESULTS: Only one out of three patients treated with bDMARDs in RABBIT would have fulfilled the inclusion criteria of the respective pivotal study. Register data enabled developing a risk scoring model which evaluates the individual risk of a patient for serious infections depending on different risk factors and the respective DMARD treatment. Open online access to the score provides the possibility of risk estimation for all rheumatologists. Further results identified long-standing high disease activity as a dominant risk factor for a worsening of prevalent comorbidities. In patients with heart failure it was shown that effective treatment and control of disease activity with tumor necrosis factor (TNF) inhibitors was more likely to be protective than harmful. CONCLUSION: Observational studies contribute essentially to the assessment of individual risks of patients. The results provide valuable information to support clinical decision-making and therefore strengthen the evidence when treating patients of higher age or with existing comorbidities. PMID- 25805515 TI - [Lessons learnt from 15 years of investigator-initiated trials on axial spondyloarthritis]. AB - BACKGROUND: Clinical research is receiving an increasing amount of attention and is essential for improving treatment of patients with rheumatic diseases. AIMS: This article reports on 15 years of experience with conducting investigator initiated studies on axial spondyloarthritis including ankylosing spondylitis. RESULTS: We have organized and successfully conducted a series of open-labelled and placebo-controlled double-blind treatment studies and also non-interventional studies on this topic. The installation of a qualified and motivated trial unit and intensive collaboration with a statistician were crucial requirements for success. These results have increased our knowledge about the disease and changed and improved the diagnostic possibilities and the therapeutic options. CONCLUSION: Investigator-initiated trials are an important link between basic and clinical research and can substantially contribute to improvement of patient care. This kind of research should be more systematically funded in the future. PMID- 25805516 TI - [Role of statisticians in epidemiological research]. AB - The relevance of statistical methods for epidemiological research in rheumatology is under discussion. Different from randomized clinical studies in observational studies, the danger of a systematic bias always exists due to prognostic differences between the groups that are to be compared. A special professional competence in statistics is indispensable in order to handle this adequately, to apply suitable methods and to develop methods anew to achieve clinically relevant results. This is made clear with the help of various studies from a statistician's field of work. PMID- 25805517 TI - Cervical cancer outcome prediction to high-dose rate brachytherapy using quantitative magnetic resonance imaging analysis of tumor response to external beam radiotherapy. AB - BACKGROUND AND PURPOSE: In order to assess tumor regression and outcomes, a volumetric analysis was conducted for cervical cancer patients treated with magnetic resonance imaging (MRI)-based image-guided brachytherapy (IGBT). MATERIALS AND METHODS: Consecutive patients with FIGO stage IB1-IVA cervical cancer receiving chemoradiation from 2007 to 2013 were identified, excluding patients with perineal template-based interstitial brachytherapy or without undergoing MRI. A ring and tandem applicator+/-interstitial needles was used. T2 weighted imaging was completed following applicator insertion. Gross tumor volumes (GTVs) were retrospectively contoured: initial GTV (GTV(Pre-EBRT)), GTV at first brachytherapy (GTV(IGBT)) and percent residual GTV at first brachytherapy (% GTV(Residual)). RESULTS: Eighty-four patients were identified. With 20.8-month median follow-up, two-year estimates of local control (LC), disease-free survival (DFS) and overall survival (OS) were 91.3, 79.8, and 85.0%, respectively. Multivariate Cox regression revealed adenocarcinoma (HR 5.88, p=0.03) and GTV(IGBT) (HR 1.17, p<0.01) as predictors for local failure. GTV(IGBT)>7.5 cc was associated with inferior 2-year LC (75.0 vs. 96.6%, p<0.01), DFS (42.6 vs. 91.6%, p<0.01) and OS (65.2 vs. 91.5%, p<0.01). No difference in mean HRCTV D(90) EQD(2) was seen between the groups (p=0.61). CONCLUSION: Aside from known benefits of IGBT, MRI-based planning allows for assessment of tumor regression and prognosticates patients. PMID- 25805518 TI - Characterization of gut bacteria at different developmental stages of Asian honey bees, Apis cerana. AB - Previous surveys have shown that adult workers of the Asian honey bee Apis cerana harbor four major gut microbes (Bifidobacterium, Snodgrassella alvi, Gilliamella apicola, and Lactobacillus). Using quantitative PCR we characterized gut bacterial communities across the life cycle of A. cerana from larvae to workers. Our results indicate that the presence and quantity of these four bacteria were low on day 1, increased rapidly after day 5, and then peaked during days 10-20. They stabilized from days 20-25 or days 25-30, then dropped to a low level at day 30. In addition, the larvae infected by Sacbrood virus or European foulbrood had significantly lower copies of 16S rRNA genes than healthy individuals. PMID- 25805519 TI - Unveiling chemical defense in the rice stalk stink bug against the entomopathogenic fungus Metarhizium anisopliae. AB - Eggs, nymphs (1st-5th instar) and adults of Tibraca limbativentris were challenged by conidial suspensions of its major fungal pathogen Metarhizium anisopliae in order to assess their susceptibility. The role of chemical defensive compounds from exocrine secretions produced by both nymphs and adults were examined for their participation on M. anisopliae infection. Although insect susceptibility to M. anisopliae followed a dose-dependent manner, adults followed by older nymphs displayed the highest resistance. Eggs were highly susceptible showing >96% fungal infection. Crude extracts isolated from metathoracic scent gland and dorsal abdominal glands of adults and nymphs, respectively, showed fungistatic effects by impairing spore germination, vegetative growth and sporulation. Gas chromatography-mass spectrometry analysis of these extracts revealed that the major components were short-chain hydrocarbons (C10-13) and unsaturated aldehydes. In vitro tests with the corresponding synthetic standards indicated compounds with greater antifungal activity including (E)-2-hexenal, (E) 2-octenal, and (E)-2-decenal, with the latter being the most deleterious to fungal fitness. We demonstrated that differential susceptibility of the rice stalk stink bug to M. anisopliae infection is age-specific and partly mediated by fungistatic properties of aldehydes, which are produced by scent glands of both nymphs and adults. PMID- 25805520 TI - Protein recognition using synthetic small-molecular binders toward optical protein sensing in vitro and in live cells. AB - Chemical sensing of amino acids, peptides, and proteins provides fruitful information to understand their biological functions, as well as to develop the medical and technological applications. To detect amino acids, peptides, and proteins in vitro and in vivo, vast kinds of chemical sensors including small synthetic binders/sensors, genetically-encoded fluorescent proteins and protein based semisynthetic biosensors have been intensely investigated. This review deals with concepts, strategies, and applications of protein recognition and sensing using small synthetic binders/sensors, which are now actively studied but still in the early stage of investigation. The recognition strategies for peptides and proteins can be divided into three categories: (i) recognition of protein substructures, (ii) protein surface recognition, and (iii) protein sensing through protein-ligand interaction. Here, we overview representative examples of protein recognition and sensing, and discuss biological or diagnostic applications such as potent inhibitors/modulators of protein-protein interactions. PMID- 25805521 TI - Meta-analysis of Androgen Insensitivity in Preoperative Hormone Therapy in Hypospadias. AB - OBJECTIVE: To define androgen insensitivity prevalence in hypospadias patients treated with preoperative hormone therapy. MATERIALS AND METHODS: We searched databases that were published in English and Chinese up to September 10, 2014 for our studies. Eligibility criteria were pre-established. Title, abstract, and full text screenings were conducted by 2 authors independently. Discrepancies were resolved by consensus. Quality assessment of included studies was completed. Meta analysis was done when appropriate using R, version 3.1.1 for Windows. Heterogeneity among individual studies was tested using the Cochran chi-square Q test and quantified by calculating the I(2) index. RESULTS: Thirteen of 1278 publications met inclusion criteria and were incorporated into this study. Of 306 patients with preoperative hormone therapy, 25 displayed androgen resistance. Meta-analysis demonstrated that the random-effects model generates a pooled estimate of 7.14% (95% confidence interval [CI], 3.16%-15.31%), whereas the fixed effect model provides an estimate of 14.61% (95% CI, 10.00%-20.85%). Heterogeneity among included studies was found above medium (I(2) = 67.1% [95% CI, 41.2%-81.6%]; P = .0003]. After exclusion of the heterogeneity, both random effects and fixed-effect models produce a consistent pooled estimate of 6.95% (95% CI, 0%-47.8%). CONCLUSION: We have defined that the prevalence of androgen resistance in hypospadias is 7.14% (95% CI, 3.16%-15.31%). To distinguish isolated hypospadias from patients with androgen insensitivity syndrome, we recommend that androgen-resistant patients should be specifically targeted by molecularly focused diagnosis. Management strategies should include identification of mutations in the androgen receptor gene, timely surgery to repair hypospadias, and long-term follow-up of sexual function and fertility later in life. PMID- 25805522 TI - Long-term Satisfaction After Open Radical Prostatectomy. AB - OBJECTIVE: To determine the association between baseline factors, post-treatment factors, and long-term satisfaction after radical prostatectomy (RP). METHODS: Between January 2000 and March 2009, 1425 men who underwent RP by a single surgeon were enrolled in an institutional review board-approved, prospective, longitudinal outcomes study. Baseline characteristics and post-treatment functional and oncologic outcomes were captured through 2013. Patient survey responses from 875 (61.4%) of these men were used to evaluate satisfaction with treatment outcome and treatment decision. RESULTS: Overall, 88.2% and 91.0% men were satisfied to very satisfied with treatment outcome and treatment decision, respectively. Baseline sexual function was associated with satisfaction with both treatment outcome (adjusted odds ratio [aOR] = 1.40; 95% confidence interval [CI], 1.01-1.93) and treatment decision (aOR = 1.47; 95% CI, 1.08-2.01). Among post-treatment factors, higher University of California, Los Angeles Prostate Cancer Sexual Function (aOR = 2.95; 95% CI, 2.06-4.22), University of California, Los Angeles Prostate Cancer Urinary Function (aOR = 2.38; 95% CI, 1.66-3.40), and lower urinary tract symptom scores (aOR = 1.91; 95% CI, 1.19-3.06) were predictors of satisfaction with outcome. Bother due to incontinence and sexual dysfunction, and perception of cure were independent predictors of both satisfaction with treatment outcome and treatment decision. CONCLUSION: Nearly 90% of men are satisfied with both their treatment outcome and treatment decision after open RP. Improving long-term satisfaction after RP requires efforts to provide realistic expectations and improve functional outcomes. PMID- 25805523 TI - Revascularization of a giant right renal artery aneurysm near the hilum. AB - This article describes a case of a giant right renal artery aneurysm near the hilum treated with surgical excision, ex vivo renal artery reconstruction, and orthotopic autotransplantation with successful outcome. The giant right renal artery aneurysm is rare, and the successful outcome in our case report proved the safety and effectiveness of the ex vivo reconstruction in treatment of complex renal artery lesions. A 57-year-old male smoker with a history of recurrent abdominal pain was diagnosed with a 5.1-cm right renal artery aneurysm near the hilum. We chose surgical excision, ex vivo reconstruction, and orthotopic renal autotransplantation to treat this patient according to the preoperative computed tomography angiography and glomerular filtration rate. The operation was successful and the patient recovered uneventfully. PMID- 25805525 TI - [Thoughts on the hypersensitivity to prune aroma as an excipient]. PMID- 25805524 TI - Daptomycin non-susceptible, vancomycin-intermediate Staphylococcus aureus endocarditis treated with ceftaroline and daptomycin: case report and brief review of the literature. AB - We report a case of clearance of persistent bacteremia due to daptomycin non susceptible, vancomycin-intermediate Staphylococcus aureus native mitral valve endocarditis with a combination of ceftaroline and daptomycin, in an 81-year-old medically complex patient who was not an operative candidate. PMID- 25805527 TI - Laparoscopic assistance for primary transanal pull-through in Hirschsprung's disease: a systematic review and meta-analysis. AB - OBJECTIVE: To compare outcomes following totally transanal endorectal pull through (TTERPT) versus pull-through with any form of laparoscopic assistance (LAPT) for infants with uncomplicated Hirschsprung's disease. DESIGN: Systematic review and meta-analysis. SETTING: Five hospitals with a paediatric surgical service. PARTICIPANTS: 405 infants with uncomplicated Hirschsprung's disease. INTERVENTIONS: TTERPT versus LAPT. PRIMARY AND SECONDARY OUTCOME MEASURES: PRIMARY OUTCOMES: mortality, postoperative enterocolitis, faecal incontinence, constipation, unplanned laparotomy or stoma formation, and injury to abdominal viscera. SECONDARY OUTCOMES: Haemorrhage requiring transfusion of blood products, abscess formation, intestinal obstruction, intestinal ischaemia, enteric fistula formation, urinary incontinence or retention, impotency and duration of procedure. RESULTS: Five eligible studies comprising 405 patients were identified from 2107 studies. All studies were retrospective case series, with variability in outcome assessment quality and length of follow-up. Operative duration was 50.29 min shorter with TTERPT (95% CI 39.83 to 60.74, p<0.00001). There were no significant differences identified between TTERPT and LAPT for incidence of postoperative enterocolitis (OR=0.78, 95% CI 0.44 to 1.38, p=0.39), faecal incontinence (OR=0.44, 95% CI 0.09 to 2.20, p=0.32) or constipation (OR=0.84, 95% CI 0.32 to 2.17, p=0.71). CONCLUSIONS: This meta-analysis did not find any evidence to suggest a higher rate of enterocolitis, incontinence or constipation following TTERPT compared with LAPT. Further long-term comparative studies and multicentre data pooling are needed to determine whether a purely transanal approach offers any advantages over a laparoscopically assisted approach to rectosigmoid Hirschsprung's disease. TRIAL REGISTRATION NUMBER: PROSPERO registry CRD42013005698. PMID- 25805526 TI - The labour market, psychosocial outcomes and health conditions in cancer survivors: protocol for a nationwide longitudinal survey 2 and 5 years after cancer diagnosis (the VICAN survey). AB - INTRODUCTION: Today, a growing need exists for greater research into cancer survivorship, focusing on different spheres of the day-to-day life of diagnosed patients. This article describes the design and implementation of VICAN (VIe apres le CANcer), a national survey on French cancer survivors. METHOD AND ANALYSIS: The target population included patients aged 18-82, diagnosed with cancer between January and June 2010, and registered in one of the three main French Health Insurance Schemes. It was restricted to 12 tumour sites. Sampling was stratified using a non-proportional allocation, based on age at diagnosis (18 52 and 53-82) and tumour site. Data were collected from telephone interviews with patients 2 and 5 years after diagnosis, a medical survey completed by the physician who initiated cancer treatment, and information from the national medicoadministrative database on reimbursement data and hospital discharge records. First data collection, 2 years after diagnosis, occurred between March and December 2012. Second data collection, 5 years after diagnosis, will be conducted in 2015. Analyses will be conducted on various outcomes: quality of life, health status and psychosocial conditions, with a particular focus on the impact of cancer diagnosis on the labour market. The variety of measurements included in the survey will enable us to control a wide range of factors. ETHICS AND DISSEMINATION: The methodology of the VICAN survey was approved by three national ethics commissions. Results of the study will be disseminated through national and international research conferences, and in articles published in international peer-reviewed journals. PMID- 25805528 TI - Why do patients with multimorbidity in England report worse experiences in primary care? Evidence from the General Practice Patient Survey. AB - OBJECTIVES: To describe and explain the primary care experiences of people with multiple long-term conditions in England. DESIGN AND METHODS: Using questionnaire data from 906,578 responders to the English 2012 General Practice Patient Survey, we describe the primary care experiences of patients with long-term conditions, including 583,143 patients who reported one or more long-term conditions. We employed mixed effect logistic regressions to analyse data on six items covering three care domains (access, continuity and communication) and a single item on overall primary care experience. We controlled for sociodemographic characteristics, and for general practice using a random effect, and further, controlled for, and explored the importance of, health-related quality of life measured using the EuroQoL (EQ-5D) scale. RESULTS: Most patients with long-term conditions report a positive experience of care at their general practice (after adjusting for sociodemographic characteristics and general practice, range 74.0 93.1% reporting positive experience of care across seven questions) with only modest variation by type of condition. For all three domains of patient experience, an increasing number of comorbid conditions is associated with a reducing percentage of patients reporting a positive experience of care. For example, compared with respondents with no long-term condition, the OR for reporting a positive experience is 0.83 (95% CI 0.80 to 0.87) for respondents with four or more long-term conditions. However, this relationship is no longer observed after adjusting for health-related quality of life (OR (95% CI) single condition=1.23 (1.21 to 1.26); four or more conditions=1.31 (1.25 to 1.37)), with pain making the greatest difference among five quality of life variables included in the analysis. CONCLUSIONS: Patients with multiple long-term conditions more frequently report worse experiences in primary care. However, patient-centred measures of health-related quality of life, especially pain, are more important than the number of conditions in explaining why patients with multiple long-term conditions report worse experiences of care. PMID- 25805529 TI - Weekly variations of stroke occurrence: an observational cohort study based on the Kyoto Stroke Registry, Japan. AB - OBJECTIVES: Understanding the temporal pattern of stroke onset and exploring the possible triggers are important strategies to reducing the incidence of stroke. If stroke occurs frequently on a specific day of the week, it is assumed that other factors, that is, 'triggering factors', induce stroke. The aim of the study is to investigate differences in the incidences of stroke among days of the week. DESIGN: Hospital-based registry stroke over an 11-year period. SETTING: Kyoto Prefecture, Japan. PARTICIPANTS: A total of 13,788 patients with stroke identified from January 1999 to December 2009 inclusive in the entire Kyoto Prefecture and registered in the Kyoto Stroke Registry (KSR). MAIN OUTCOME MEASURES: Patients with stroke were classified into seven groups based on the day of the week on which stroke developed. We confirmed the differences in the incidence among days using the chi(2) test and then performed multinomial logistic analysis referring to the stroke incidence on Sunday to calculate the OR and 95% CI of the stroke occurrence on each day of the week. RESULTS: The OR (95% CI) for stroke occurring on Monday, Tuesday, Wednesday, Thursday, Friday and Saturday was 1.157 (1.030 to 1.293), 1.101 (0.981 to 1.236), 1.059 (0.943 to 1.188), 1.091 (0.972 to 1.225), 1.053 (0.938 to 1.205) and 1.074 (0.956 to 1.205), respectively. After stratification by stroke subtypes, cerebral infarction occurred more frequently on Monday than on Sunday (OR and 95% CI were 1.189 and 1.034 to 1.366, p=0.014) independent of age and gender. There was no significant day of the week variation in cerebral haemorrhage or subarachnoid haemorrhage. CONCLUSIONS: Some factors that arise periodically appear to affect the incidence of cerebral infarction, which gradually develops over years, and this suggests an aetiological mechanism different from the conventional cumulative effect of risk factors due to long-term exposure. We propose a hypothesis that there is a 'triggering factor' for the development of cerebral infarction. PMID- 25805531 TI - Acupuncture for erectile dysfunction: a systematic review protocol. AB - INTRODUCTION: This systematic review protocol aims to provide a protocol for assessing the safety and effectiveness of acupuncture for the treatment of erectile dysfunction(ED). Previous systematic reviews did not draw convincing conclusions owing to high heterogeneity and few included randomised controlled trials, so it is necessary to reassess the efficacy and safety of acupuncture for ED. METHODS AND ANALYSIS: Eight electronic databases will be searched: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, EMBASE, PsycInfo, the Chinese Biomedical Literature Database (CBM), the Chinese Medical Current Content (CMCC) and the China National Knowledge Infrastructure (CNKI). Related Chinese literature will be searched in other Chinese databases. All relevant randomised controlled trials in English or Chinese without any restrictions of publication type will be included. The main outcome measure will be improvements in sexual activity assessed by validated questionnaires. Assessment of risk of bias, data synthesis and subgroup analysis will be carried out using Review Manager 5.3. ETHICS AND DISSEMINATION: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. The data we will use do not include individual patient data, so ethical approval is not required. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014013575. PMID- 25805532 TI - Fecal microbiota transplant protocol for clostridium difficile infection. AB - Fecal microbiota transplant has become more acceptable as a therapeutic for recurrent Clostridium difficile infection. The FDA has an enforcement discretion policy for practitioner's performing this therapy, which includes informed consent for this experimental treatment. This manuscript describes a typical procedure that can be followed that includes the important aspects of this preparation and treatment. PMID- 25805533 TI - Langerhans cell sarcoma: a systematic review. AB - Langerhans cell sarcoma (LCS) is a rare malignant tumour of Langerhans cells with a poor outcome. Given its rarity, there is a lack of evidence regarding the most appropriate treatment for this condition. Therefore the aim of this work was to review, compile, analyse and present clinical details and to determine the optimal treatment regimen. A search of PubMed, CINAHL, EMBASE, Cochrane, CENTRAL, clinicaltrials.gov and Google Scholar was supplemented by hand searching. Data extracted included demographics, treatment, type of LCS and clinical outcome. Of 510 citations identified by a systematic literature search, 46 case series including 66 subjects with LCS met criteria for analysis. The most common treatment modality was chemotherapy, used alone or in combination in 47 cases (71%) followed by surgery in 31 cases (47%). Overall mean (S.E.) disease specific survival and disease free survival were 27.2 (3.9) and 18.3 (3.8) months respectively. There was a significant difference in both disease specific and disease free survival between the local, loco-regional and disseminated disease cohorts (DSS p=0.014; DFS p<0.001). More localised disease confers a survival advantage. Multi-modality therapy appears to be most effective, with the addition of radiotherapy to chemotherapy appearing beneficial. Complete surgical excision with clear margins being most effective for local disease control. Any adjuvant therapy should not be delayed. Bone marrow transplant appears to be the most reliable treatment in terms of outcome especially in disseminated disease however has well known patient selection and toxicity/tolerance issues. The role of cell surface markers for prognostication remains unclear. PMID- 25805530 TI - The CORE study protocol: a stepped wedge cluster randomised controlled trial to test a co-design technique to optimise psychosocial recovery outcomes for people affected by mental illness in the community mental health setting. AB - INTRODUCTION: User engagement in mental health service design is heralded as integral to health systems quality and performance, but does engagement improve health outcomes? This article describes the CORE study protocol, a novel stepped wedge cluster randomised controlled trial (SWCRCT) to improve psychosocial recovery outcomes for people with severe mental illness. METHODS: An SWCRCT with a nested process evaluation will be conducted over nearly 4 years in Victoria, Australia. 11 teams from four mental health service providers will be randomly allocated to one of three dates 9 months apart to start the intervention. The intervention, a modified version of Mental Health Experience Co-Design (MH ECO), will be delivered to 30 service users, 30 carers and 10 staff in each cluster. Outcome data will be collected at baseline (6 months) and at completion of each intervention wave. The primary outcome is improvement in recovery score using the 24-item Revised Recovery Assessment Scale for service users. Secondary outcomes are improvements to user and carer mental health and well-being using the shortened 8-item version of the WHOQOL Quality of Life scale (EUROHIS), changes to staff attitudes using the 19-item Staff Attitudes to Recovery Scale and recovery orientation of services using the 36-item Recovery Self Assessment Scale (provider version). Intervention and usual care periods will be compared using a linear mixed effects model for continuous outcomes and a generalised linear mixed effects model for binary outcomes. Participants will be analysed in the group that the cluster was assigned to at each time point. ETHICS AND DISSEMINATION: The University of Melbourne, Human Research Ethics Committee (1340299.3) and the Federal and State Departments of Health Committees (Project 20/2014) granted ethics approval. Baseline data results will be reported in 2015 and outcomes data in 2017. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry ACTRN12614000457640. PMID- 25805534 TI - Outcomes and Experience with Lumbopleural Shunts in the Management of Idiopathic Intracranial Hypertension. AB - OBJECTIVE: To report five patients who underwent lumbopleural (LPl) shunting for the treatment of idiopathic intracranial hypertension (IIH) and to describe the considerations, complications, and outcomes related to this rarely described procedure. METHODS: The clinical data of five patients treated with LPl shunting over a 23-year period were retrospectively analyzed. Factors including the age at diagnosis of IIH, age at time of LPl shunting, body mass index (BMI), reason for LPl shunt placement, number of revisions before LPl shunt placement, valve type, time to first revision, presence of overdrainage and its management, complications and their management, survival time of LPl shunt, and clinical course at last follow-up were analyzed. RESULTS: All patients were morbidly obese females with an average of 4.6 shunt revisions before an LPl shunt. The average overall survival time of the LPl shunt was 48 months. Two patients experienced failure of their LPl shunts with subsequent replacement within the first year. Four patients experienced complications related to shunt overdrainage, requiring placement of an antisiphon device (ASD) or additional valve. One patient developed a symptomatic pleural effusion, and one patient developed a small pneumothorax, which was managed conservatively. CONCLUSIONS: LPl shunting, though rarely used, is a viable option in the treatment of IIH refractory to standard peritoneal shunting. When pursuing this treatment, a valve and ASD are recommended to mitigate the risks of overdrainage and pleural effusion. Chest imaging should be obtained if the patient becomes symptomatic but can be deferred if the patient remains asymptomatic and is doing well. PMID- 25805535 TI - Histological Analysis of Aneurysm Wall Occluded with Clip Blades. A Case Report. AB - Reports on histological changes of vascular wall following clipping surgery have been scarce. The authors experienced a case of unruptured cerebral aneurysm in which the tissue occluded by clip blades for 6 years was obtained and histologically examined. The aneurysmal wall following clipping showed granulomatous inflammation with necrosis, and occluded aneurysmal walls were found with collagenous fibrous tissue. Mild infiltration by lymphocytes and fibrous thickened intima occurred. PMID- 25805536 TI - Power of national economy, disease control and employment status in patients with RA-an analytical multi-site ecological study. AB - In rheumatology, sufficient disease control is a central part of the treatment concept. However, modern treatment strategies are associated with a substantial economic burden for health care systems. Ecological studies offer the unique opportunity to analyse differences between groups as well as group level effects. In the present analytical multi-site ecological study, we investigated whether more powerful national economies as measured by the gross domestic product per capita (GDPpc) are associated with better disease control in RA patients as measured by the disease activity score 28 (DAS28). We used aggregated data on RA patients from the recently published COMORA study as well as the World Health Organization database. There was a strong negative correlation between DAS28 and GDPpc (r = -0.815; p = 0.0002). Adjustment for sex, smoking status, disease duration or current employment status did not significantly change this association. There was a strong, negative correlation between DAS28 and age (r = 0.870; p < 0.001) and a strong, positive correlation between GDPpc and age (r = 0.737; p = 0.002). Adjustment for age reduced the regression coefficient (DAS28/GDPpc) to -0.000018 (p = 0.054). There was a negative correlation between DAS28 and current employment status (r = -0.642; p = 0.008) and a positive correlation between GDPpc and employment status (r = 0.722; p = 0.002). In conclusion, there is evidence of an association between disease control and GDPpc. This association is alleviated after adjustment for age. Of note, in countries with higher GDPpc, a higher proportion of RA patients are currently employed. This is true despite the fact that RA patients in countries with higher GDPpc are also older. PMID- 25805537 TI - Percutaneous creation of an arteriovenous fistula for hemodialysis access. AB - PURPOSE: Arteriovenous fistulae (AVFs) created by conventional surgical techniques are associated with suboptimal short- and long-term patency. This study investigated the feasibility of creating fistulae with a percutaneous system and evaluated the utility of percutaneous AVFs (pAVFs) in providing hemodialysis access. MATERIALS AND METHODS: From August 2012 to September 2013, a percutaneous system was used to attempt pAVF creation between the proximal ulnar artery and a closely associated ulnar vein in 33 patients. Technical success, adverse events, and time to pAVF maturity were recorded, as was clinical effectiveness at 6 months. RESULTS: A pAVF was successfully created in 32 of 33 patients (97%). Four patients died during the follow-up period from causes unrelated to the procedure; one patient was lost to follow-up. Of the remaining 27 patients, 24 were undergoing successful dialysis via their pAVF at 6 months. Two additional patients had usable access but did not initiate dialysis during the study. One spontaneous pAVF thrombosis occurred in a patient with preexisting central vein stenosis. Cumulative pAVF patency at 6 months was 96.2% (26 of 27; standard error, 3.8%). Mean time to pAVF maturation was 58 days (range, 37-168 d). There was one serious procedure-related adverse event and five minor procedure-related adverse events. CONCLUSIONS: Although larger studies are required to validate efficacy in a wide range of patients, this study demonstrates hemodialysis access successfully created with an endovascular catheter-based system. Patency of pAVFs and time to maturation were superior to published results of surgical techniques. PMID- 25805538 TI - Embolization of metastatic neuroendocrine tumor resulting in clinical manifestations of syndrome of inappropriate secretion of antidiuretic hormone. AB - Complications after hepatic artery embolization are usually minor and transient. This report describes a patient with a pancreatic neuroendocrine tumor with hepatic metastases who repeatedly developed clinical findings of syndrome of inappropriate secretion of antidiuretic hormone with hyponatremia (sodium < 130 mEq/L), low plasma osmolarity (< 275 mOsm/kg), and high urine osmolarity (> 500 mOsm/kg) after every session of hepatic artery embolization. PMID- 25805540 TI - Transcatheter CT hepatic arteriography-guided percutaneous ablation to treat ablation site recurrences of colorectal liver metastases: the incomplete ring sign. AB - Transcatheter computed tomography (CT) arterial portography-guided percutaneous liver tumor ablation has been proved to be feasible and accurate in treating liver metastases from colorectal origin that are obscure on ultrasound and unenhanced CT. However, distinguishing local recurrence from scars after ablation can still be difficult. This report describes nine patients with recurrences after ablation in whom transcatheter CT hepatic arteriography allowed differentiation of recurring and residual tumor tissue (incomplete ring enhancing lesion) from tumor-free nonenhancing scars. Using CT hepatic arteriography, it is possible to plan and guide percutaneous retreatment and confirm technical success without performing oversized repeat ablations or jeopardizing patients renal function. PMID- 25805541 TI - Balloon-assisted osteoplasty of periacetabular tumors following percutaneous cryoablation. AB - PURPOSE: To describe the feasibility, safety, and effectiveness of a technique using vertebral augmentation balloons to promote delivery of cement into periacetabular tumors after cryoablation for fracture prevention. MATERIALS AND METHODS: A retrospective review was performed of seven consecutive patients (six men and one woman; mean age, 64 y +/- 8) with unilateral periacetabular tumors (mean size, 4.2 cm +/- 1.4) treated with cryoablation and balloon-assisted osteoplasty for fracture prevention. Cortical defects were seen in six (86%) tumors, and additional pathologic fractures occurred in five (71%) tumors before treatment. The cohort included six (86%) Harrington class I defects and one (14%) class II defect. Procedures were performed with computed tomography fluoroscopic guidance and general anesthesia. Vertebral augmentation balloons (mean, 2; range, 1-4) were inflated within the ablation cavity immediately before or during cement injection. RESULTS: All procedures were technically successful. Median percentage tumor fill was 63% (range, 17%-96%). Minor cement leakage occurred in two (29%) patients with no symptomatic or intraarticular extravasation. A new nondisplaced fracture occurred in one patient and was conservatively managed. No major complications occurred. Local tumor progression occurred in one (20%) of five patients with imaging follow-up. CONCLUSIONS: Balloon-assisted osteoplasty after cryoablation of periacetabular tumors appears feasible, safe, and effective for fracture prevention. This technique directs cement instillation into ablation defects with a high degree of filling and minimal leakage. PMID- 25805543 TI - Ultrasound-guided phrenic nerve block for CT-guided percutaneous pulmonary fine needle aspiration biopsy. PMID- 25805542 TI - Percutaneous augmented osteoplasty of the humeral bone using a combination of microneedles mesh and cement. PMID- 25805544 TI - Hemothorax resulting from injury to the right inferior phrenic artery following transhepatic procedures. PMID- 25805546 TI - The Chiari Network: a rare cause of intracardiac guide wire entrapment. PMID- 25805545 TI - Combined transhepatic portal venous and transarterial treatment of superior mesenteric arteriovenous fistula in a patient with cirrhosis. PMID- 25805547 TI - Treatment of a ruptured abdominal aortic aneurysm with an adverse anatomy using the nellix endovascular aneurysm sealing system. PMID- 25805548 TI - Successful endovascular retrieval of an ALN inferior vena cava filter causing asymptomatic aortic dissection, perforation of the cava wall and duodenum. PMID- 25805549 TI - Ti-Sb-Te alloy: a candidate for fast and long-life phase-change memory. AB - Phase-change memory (PCM) has great potential for numerous attractive applications on the premise of its high-device performances, which still need to be improved by employing a material with good overall phase-change properties. In respect to fast speed and high endurance, the Ti-Sb-Te alloy seems to be a promising candidate. Here, Ti-doped Sb2Te3 (TST) materials with different Ti concentrations have been systematically studied with the goal of finding the most suitable composition for PCM applications. The thermal stability of TST is improved dramatically with increasing Ti content. The small density change of T0.32Sb2Te3 (2.24%), further reduced to 1.37% for T0.56Sb2Te3, would greatly avoid the voids generated at phase-change layer/electrode interface in a PCM device. Meanwhile, the exponentially diminished grain size (from ~200 nm to ~12 nm), resulting from doping more and more Ti, enhances the adhesion between phase change film and substrate. Tests of TST-based PCM cells have demonstrated a fast switching rate of ~10 ns. Furthermore, because of the lower thermal conductivities of TST materials, compared with Sb2Te3-based PCM cells, T0.32Sb2Te3-based ones exhibit lower required pulse voltages for Reset operation, which largely decreases by ~50% for T0.43Sb2Te3-based ones. Nevertheless, the operation voltages for T0.56Sb2Te3-based cells dramatically increase, which may be due to the phase separation after doping excessive Ti. Finally, considering the decreased resistance ratio, TixSb2Te3 alloy with x around 0.43 is proved to be a highly promising candidate for fast and long-life PCM applications. PMID- 25805550 TI - Systematic Review of Clinical Practice Guidelines for the Improvement of Medication Adherence. AB - BACKGROUND: Poor adherence to medications is a significant problem that leads to increased morbidity, mortality, and health care costs. Recommended approaches to address medication adherence vary, and existing practice guidelines are unclear. PURPOSE: This review evaluated clinical practice guidelines designed to help health care providers address patients' medication adherence. METHOD: Multiple search methods were used to identify national or international guidelines addressing medication adherence. We included guidelines published in English, as well as guidelines with an English-language summary or translation. RESULTS: We identified 23 guidelines of varying detail and quality. Recommendations were categorized as assessment strategies (n = 20 guidelines); educational strategies (n = 18); behavioral strategies (n = 17); therapeutic relationship, communication, and provider factors (n = 19); and addressing outside influences/co-morbidities (n = 10). CONCLUSION: Future guidelines should be more clearly guided by research findings and comparative effectiveness methods. When implemented, guidelines will facilitate health care providers and health systems in supporting optimal adherence and improved health outcomes. PMID- 25805551 TI - Inferring lung cancer risk factor patterns through joint Bayesian spatio-temporal analysis. AB - BACKGROUND: Preventing risk factor exposure is vital to reduce the high burden from lung cancer. The leading risk factor for developing lung cancer is tobacco smoking. In Australia, despite apparent success in reducing smoking prevalence, there is limited information on small area patterns and small area temporal trends. We sought to estimate spatio-temporal patterns for lung cancer risk factors using routinely collected population-based cancer data. METHODS: The analysis used a Bayesian shared component spatio-temporal model, with male and female lung cancer included separately. The shared component reflected lung cancer risk factors, and was modelled over 477 statistical local areas (SLAs) and 15 years in Queensland, Australia. Analyses were also run adjusting for area level socioeconomic disadvantage, Indigenous population composition, or remoteness. RESULTS: Strong spatial patterns were observed in the underlying risk factor estimates for both males (median Relative Risk (RR) across SLAs compared to the Queensland average ranged from 0.48 to 2.00) and females (median RR range across SLAs 0.53-1.80), with high risks observed in many remote areas. Strong temporal trends were also observed. Males showed a decrease in the underlying risk across time, while females showed an increase followed by a decrease in the final 2 years. These patterns were largely consistent across each SLA. The high underlying risk estimates observed among disadvantaged, remote and indigenous areas decreased after adjustment, particularly among females. CONCLUSION: The modelled underlying risks appeared to reflect previous smoking prevalence, with a lag period of around 30 years, consistent with the time taken to develop lung cancer. The consistent temporal trends in lung cancer risk factors across small areas support the hypothesis that past interventions have been equally effective across the state. However, this also means that spatial inequalities have remained unaddressed, highlighting the potential for future interventions, particularly among remote areas. PMID- 25805554 TI - Exploring a novel preparation method of 1D metal organic frameworks based on supercritical CO2. AB - The preparation of copper(II) one-dimensional MOFs using an eco-efficient method is reported here. This method is based exclusively on using supercritical CO2 as a solvent, without the addition of any other additive or co-solvent. Neutral acetylacetonate copper complexes and two linear linkers, namely, the bidentate 4,4'-bipyridine and 4,4'-trimethylenedipyridine molecules, were reacted under compressed CO2 at 60 degrees C and 20 MPa for periods of 4 or 24 h. The success achieved in the synthesis of the different studied 1D-MOFs was related to the solubility of the reagents in supercritical CO2. The reaction yield of the synthesized coordination polymers via the supercritical route was close to 100% because both the reactants were almost completely depleted in the performed experiments. PMID- 25805552 TI - Delaying urinary catheter insertion in the reception and resuscitation of blunt multitrauma and using a full bladder to tamponade pelvic bleeding. AB - This article proposes a counter-argument to standard Advanced Trauma Life Support (ATLS) training--which advocates bladder catheterisation to be performed as an adjunct to the primary survey and resuscitation for early decompression of the bladder and urine output monitoring. We argue the case for delaying bladder catheterisation until after definitive truncal Computed Tomography (CT) imaging. To reduce pelvic volume and associated bleeding, our trauma team delay catheter insertion until after the initial CT scan. The benefits of a full bladder also include improved views on initial Focussed Assessment with Sonography in Trauma (FAST) scan and improved interpretation of injuries on CT. Our urinary catheter related infection rates anecdotally decreased when insertion was delayed and consequently performed in a more controlled, non-resuscitation setting following CT. Adult blunt multitrauma patients with pelvic ring fractures are at risk of significant haemorrhage. Venous, arterial and medullary injuries with associated bleeding may be potentiated by an increased pelvic volume with ring disruption, as well as a reduced pressure effect from retroperitoneal and intra-pelvic organs on bleeding sites. Various techniques are used to reduce intra-pelvic bleeding. For shocked patients who have sustained major pelvic injuries with no other signs of urinary tract trauma and minimal urine in the bladder on initial FAST scan, we advocate careful, aseptic Foley catheter insertion followed by bladder insufflation with 500-600 mL of Normal Saline (NS) and subsequent catheter clamping to tamponade pelvic bleeding. PMID- 25805553 TI - Identifying patients at risk for high-grade intra-abdominal hypertension following trauma laparotomy. AB - BACKGROUND: Abdominal Compartment Syndrome (ACS) is an uncommon but deleterious complication after trauma laparotomy. Early recognition of patients at risk of developing ACS is crucial for their outcome. The aim of this study was to compare the characteristics of patients who developed high-grade intra-abdominal hypertension (IAH) (i.e., grade III or IV; intra-abdominal pressure, IAP >20 mm Hg) following an injury-related laparotomy versus those who did not (i.e., IAP <=20 mm Hg). METHODS: A retrospective analysis of consecutive trauma patients admitted to a level 1 trauma centre in Australia between January 1, 1995 and January 31, 2010 was performed. A comparison was made between characteristics of patients who developed high-grade IAH following trauma laparotomy versus those who did not. RESULTS: A total of 567 patients (median age 31 years) were included in this study. Of these patients 10.2% (58/567) developed high-grade IAH of which 51.7% (30/58) developed ACS. Patients with high-grade IAH were older (p<0.001), had a higher Injury Severity Score (p<0.001), larger base deficit (p<0.001) and lower temperature at admission (p=0.011). In the first 24h of admission, patients with high-grade IAH received larger volumes of crystalloids (p<0.001), larger volumes of colloids (p<0.001) and more units of packed red blood cells (p<0.001). Following surgery prolonged prothrombin (p<0.001) and partial thromboplastin times (p<0.001) were seen. The patients with high-grade IAH suffered higher mortality rates (25.9% (15/58) vs. 12.2% (62/509); p=0.012). CONCLUSION: Of all patients who underwent a trauma laparotomy, 10.2% developed high-grade IAH, which increases the risk of mortality. Patients with acidosis, coagulopathy, and hypothermia were especially at risk. In these patients, the abdomen should be left open until adequate resuscitation has been achieved, allowing for definitive surgery. LEVEL OF EVIDENCE: This is a level III retrospective study. PMID- 25805555 TI - Erythrocyte: A systems model of the control of aggregation and deformability. AB - Human erythrocytes are highly specialized enucleate cells that are involved in providing efficient gas transport. Erythrocytes have been extensively studied both experimentally and by mathematical modeling in recent years. However, understanding of how aggregation and deformability are regulated is limited. These properties of the erythrocyte are essential for the physiological functioning of the cell. In this work, we propose a novel mathematical model of the molecular system that controls the aggregation and deformability of the erythrocyte. This model is based on the experimental results of previously published studies. Our model suggests fundamentally new mechanisms that regulate aggregation and deformability in a latch-like manner. The results of this work could be used as a general explanation of how the erythrocytes regulate their aggregation and deformability, and are essential in understanding erythrocyte disorders and aging. PMID- 25805556 TI - [Pneumoperitoneum after cardiac surgery. A complete anamnesis is the clue]. AB - Herein we present the case of an 82 year-old patient undergoing cardiac surgery for mitral valve replacement. Fifteen years earlier, the patient had undergone surgery to replace his aortic valve, so that it was now a cardiac reoperation. Through sternotomy, and release of pericardial adherences, there was an accidental opening of a small portion of the peritoneum, proceeding to repair with simple suture. Postoperatively, the presence of pneumoperitoneum alarmed about the possibility of an intra-abdominal complication but it was subsequently discarded with recent surgical process. Through this article we review what the pneumoperitoneum consist, its causes and management, as well as highlighting possible etiologies sometimes not considered as a recent cardiac surgery, simply because the patient in found in different contexts and we do not think about those possibilities. PMID- 25805557 TI - PET/MRI for the body imager: abdominal and pelvic oncologic applications. AB - The purpose of this pictorial review is to describe emerging clinical applications of positron emission tomography (PET)/magnetic resonance imaging (MRI), the newest clinical hybrid imaging modality, with a specific focus on abdominal and pelvic malignancies. Important issues regarding the clinical implementation of PET/MRI systems, including workflow considerations and protocol development, are examined. The unique technical challenges of simultaneous PET/MRI acquisition and MRI-based attenuation correction are also briefly discussed. This article is intended to provide the body imager with an overview of the potential diagnostic advantages of PET/MRI, as compared to PET/CT or MRI alone. PMID- 25805558 TI - Short-term reproducibility of apparent diffusion coefficient estimated from diffusion-weighted MRI of the prostate. AB - PURPOSE: The purpose of the study is to determine short-term reproducibility of apparent diffusion coefficient (ADC) estimated from diffusion-weighted magnetic resonance (DW-MR) imaging of the prostate. METHODS: Fourteen patients with biopsy proven prostate cancer were studied under an Institutional Review Board-approved protocol. Each patient underwent two, consecutive and identical DW-MR scans on a 3T system. ADC values were calculated from each scan and a deformable registration was performed to align corresponding images. The prostate and cancerous regions of interest (ROIs) were independently analyzed by two radiologists. The prostate volume was analyzed by sextant. Per-voxel absolute and relative percentage variations in ADC were compared between sextants. Per-voxel and per-ROI variations in ADC were calculated for cancerous ROIs. RESULTS: Per voxel absolute difference in ADC in the prostate ranged from 0 to 1.60 * 10(-3) mm(2)/s (per-voxel relative difference 0% to 200%, mean 10.5%). Variation in ADC was largest in the posterior apex (0% to 200%, mean 11.6%). Difference in ADC variation between sextants was not statistically significant. Cancer ROIs' per voxel variation in ADC ranged from 0.001 * 10(-3) to 0.841 * 10(-3) mm(2)/s (0% to 67.4%, mean 11.2%) and per-ROI variation ranged from 0 to 0.463 * 10(-3) mm(2)/s (mean 0.122 * 10(-3) mm(2)/s). CONCLUSIONS: Variation in ADC within the human prostate is reasonably small, and is on the order of 10%. PMID- 25805559 TI - Comparison of a pocket-size ultrasound device with a premium ultrasound machine: diagnostic value and time required in bedside ultrasound examination. AB - PURPOSE: Time savings and clinical accuracy of a new miniature ultrasound device was investigated utilizing comparison with conventional high-end ultrasound instruments. Our objective was to determine appropriate usage and limitations of this diagnostic tool in internal medicine. METHODS: We investigated 28 patients from the internal-medicine department. Patients were examined with the Acuson P10 portable device and a Sonoline Antares instrument in a cross-over design. All investigations were carried out at the bedside; the results were entered on a standardized report form. The time for the ultrasound examination (transfer time, setting up and disassembly, switching on and off, and complete investigation time) was recorded separately. RESULTS: Mean time for overall examination per patient with the portable ultrasound device was shorter (25.0 +/- 4.5 min) than with the high-end machine (29.4 +/- 4.4 min; p < 0.001). When measuring the size of liver, spleen, and kidneys, the values obtained differed significantly between portable device and the high-end instrument. In our study, we identified 113 pathological ultrasound findings with the high-end ultrasound machine, while 82 pathological findings (73%) were concordantly detected with the portable ultrasound device. The main diagnostic strengths of the portable device were in the detection of ascites (sensitivity 80%), diagnosis of fatty liver, and identification of severe parenchymal liver damage. CONCLUSIONS: The clinical utility of portable ultrasound machines is limited. There will be clinical roles for distinct clinical questions such as detection of ascites or pleural effusion when used by experienced examiners. However, sensitivity in detecting multiple pathologies is not comparable to high-end ultrasound machines. PMID- 25805561 TI - Response to drs. Hollo and clemens. PMID- 25805563 TI - J-aggregation, its impact on excited state dynamics and unique solvent effects on macroscopic assembly of a core-substituted naphthalenediimide. AB - Herein we reveal a straightforward supramolecular design for the H-bonding driven J-aggregation of an amine-substituted cNDI in aliphatic hydrocarbons. Transient absorption spectroscopy reveals sub-ps intramolecular electron transfer in isolated NDI molecules in a THF solution followed by a fast recombination process, while a remarkable extension of the excited state lifetime by more than one order of magnitude occurred in methylcyclohexane likely owing to an increased charge-separation as a result of better delocalization of the charge-separated states in J-aggregates. We also describe unique solvent-effects on the macroscopic structure and morphology. While J-aggregation with similar photophysical characteristics was noticed in all the tested aliphatic hydrocarbons, the morphology strongly depends on the "structure" of the solvents. In linear hydrocarbons (n-hexane, n-octane, n-decane or n-dodecane), formation of an entangled fibrillar network leads to macroscopic gelation while in cyclic hydrocarbons (methylcyclohexane or cyclohexane) although having a similar polarity, the cNDI exhibits nanoscale spherical particles. These unprecedented solvent effects were rationalized by establishing structure-dependent specific interactions of the solvent molecules with the cNDI which may serve as a general guideline for solvent-induced morphology-control of structurally related self assembled materials. PMID- 25805562 TI - Comparative biodistribution in mice of cyanine dyes loaded in lipid nanoparticles. AB - Two near infrared cyanine dyes, DiD (1,1'-dioctadecyl-3,3,3',3' tetramethylindotricarbocyanine perchlorate) and ICG (Indocyanine Green) were loaded in lipid nanoparticles (LNP). DiD-LNP and ICG-LNP presented similar physicochemical characteristics (hydrodynamic diameter, polydispersity, zeta potential), encapsulation efficiency, and colloidal stability when stored in PBS buffer. However, whereas DiD had similar biodistribution than cholesteryl-1-(14)C oleate ([(14)C]CHO, a constituent of the nanoparticle used as a reference radiotracer), ICG displayed a different biodistribution pattern, similar to that of the free dye, indicative of its immediate leakage from the nanovector after blood injection. NMR spectroscopy using Proton NOE (Nuclear Overhauser Effect) measurements showed that the localization of the dye in the lipid nanoparticles was slightly different: ICG, more amphiphilic than DiD, was found both inside the lipid core and at particle interface, whereas DiD, more hydrophobic, appeared exclusively located inside the particle core. The ICG release rate from the particles was 7% per 1 month under storage conditions (4 degrees C, dark, 10% of lipids), whereas no leakage could be detected for DiD. ICG leakage increased considerably in the presence of BSA 40 g/L (45% leakage in 24h at 100 mg/mL of lipids), because of the high affinity of the fluorophore for plasma proteins. On the contrary, no DiD leakage was observed, until high dilution of the nanoparticles which triggered their dissociation (45% leakage in 24h at 1 mg/mL of lipids). Altogether, the subtle difference in dye localization into the nanoparticles, the partial dissociation of the LNP in diluted media, and more importantly the high ICG affinity for plasma proteins, accounted for the differences observed in the fluorescence biodistribution after tail vein injection of the dye-loaded nanoparticles. PMID- 25805560 TI - Eating high fat chow decreases dopamine clearance in adolescent and adult male rats but selectively enhances the locomotor stimulating effects of cocaine in adolescents. AB - BACKGROUND: Feeding conditions can influence dopamine neurotransmission and impact behavioral and neurochemical effects of drugs acting on dopamine systems. This study examined whether eating high fat chow alters the locomotor effects of cocaine and dopamine transporter activity in adolescent (postnatal day 25) and adult (postnatal day 75) male Sprague-Dawley rats. METHODS: Dose-response curves for cocaine-induced locomotor activity were generated in rats with free access to either standard or high fat chow or restricted access to high fat chow (body weight matched to rats eating standard chow). RESULTS: Compared with eating standard chow, eating high fat chow increased the sensitivity of adolescent, but not adult, rats to the acute effects of cocaine. When tested once per week, sensitization to the locomotor effects of cocaine was enhanced in adolescent rats eating high fat chow compared with adolescent rats eating standard chow. Sensitization to cocaine was not different among feeding conditions in adults. When adolescent rats that previously ate high fat chow ate standard chow, sensitivity to cocaine returned to normal. As measured by chronoamperometry, dopamine clearance rate in striatum was decreased in both adolescent and adult rats eating high fat chow compared with age-matched rats eating standard chow. CONCLUSIONS: These results suggest that high fat diet-induced reductions in dopamine clearance rate do not always correspond to increased sensitivity to the locomotor effects of cocaine, suggesting that mechanisms other than dopamine transporter might play a role. Moreover, in adolescent but not adult rats, eating high fat chow increases sensitivity to cocaine and enhances the sensitization that develops to cocaine. PMID- 25805564 TI - Identification of an atypical CD8 T cell epitope encoded by murine cytomegalovirus ORF-M54 gaining dominance after deletion of the immunodominant antiviral CD8 T cell specificities. AB - Control of murine cytomegalovirus (mCMV) infection is mediated primarily by CD8 T cells, with four specificities dominating in BALB/c mice. Functional deletion of the respective immunodominant epitopes (IDEs) in mutant virus Delta4IDE revealed a still efficient control of infection. In a murine model of hematopoietic cell transplantation and infection with Delta4IDE, an mCMV-specific open reading frame (ORF) library screening assay indicated a strong CD8 T cell reactivity against the ORF-M54 product, the highly conserved and essential mCMV homolog of human CMV DNA polymerase UL54, which is a known inducer of in vivo protection against mCMV by DNA immunization. Applying bioinformatic algorithms for CD8 T cell epitope prediction, the top-scoring peptides were used to stimulate ex vivo-isolated CD8 T cells and to generate cytolytic T cell lines; yet, this approach failed to identify M54 epitope(s). As an alternative, a peptide library consisting of 549 10-mers with an offset of two amino acids (aa), covering the complete aa-sequence of the M54 protein, was synthesized and used for the stimulation. A region of 12 aa proved to encompass an epitope. An 'alanine walk' over this antigenic 12-mer and all possible 11-, 10- and 9-mers derived thereof revealed aa-residues critical for antigenicity, and terminal truncations identified the H-2D(d) presented 8-mer M5483-90 as the optimal epitope. An increased frequency of the corresponding CD8 T cells in the absence of the 4 IDEs indicated immunodomination by the IDE-specific CD8 T cells as a mechanism by which the generation of M54 specific CD8 T cells is inhibited after infection with wild-type mCMV. PMID- 25805565 TI - Mechanism of tumor remission by cytomegalovirus in a murine lymphoma model: evidence for involvement of virally induced cellular interleukin-15. AB - A murine model of B and T cell lymphomas in recipients after hematoablative conditioning for hematopoietic cell transplantation (HCT) has previously revealed a tumor-repressive, metastasis-inhibiting function of murine cytomegalovirus (mCMV). More recently, this prediction from the experimental model was put on trial in several clinical studies that indeed gave evidence for a lower incidence of tumor relapse associated with early reactivation of latent human cytomegalovirus (hCMV) after allogeneic HCT in patients treated against different types of hematopoietic malignancies, including lymphoma and acute as well as chronic leukemias. Due to the limitations inherent to clinical studies, the tumor repressive role of hCMV remained observational with no approach to clarify mechanisms. Although the tumor-repressive mechanisms of mCMV and hCMV may differ and depend on the type of tumor, experimental approaches in the murine model might give valuable hints for concepts to follow in clinical research. We have previously shown for the liver-adapted A20-derived B cell lymphoma E12E that mCMV does not infect the lymphoma cells for causing cell death by viral cytopathogenicity but triggers tumor-selective apoptosis at a tissue site of tumor metastasis distant from a local site of infection. This finding suggested involvement of a cytokine that triggers apoptosis, directly or indirectly. Here we used a series of differential high-density microarray analyses to identify cellular genes whose expression is specifically upregulated at the site of virus entry only by viruses capable of triggering lymphoma cell apoptosis. This strategy identified interleukin-15 (IL-15) as most promising candidate, eventually confirmed by lymphoma repression with recombinant IL-15. PMID- 25805566 TI - Cell signaling events differentiate ER-negative subtypes from ER-positive breast cancer. AB - Currently available markers routinely used in clinical practice are of limited value to patients with estrogen receptor-negative (ER(-)) breast cancer [basal like and HER2neu-positive (HER(+))], an aggressive subtype. Our aim was to uncover molecular pathways and signaling networks exposed by differentially methylated genes informative of the biology of ER(-) breast cancer (BC) subtypes versus ER-positive (ER(+)). Whole-genome methylation array analysis was carried out using the Illumina Infinium HumanMethylation27 BeadChip on 14 primary BC: five ER(+), four triple-negative (TNBC), and five ER(-)HER2(+). Degree of methylation was calculated as a beta-value (ranging from 0 to 1), and M-values [log (beta/(1 - beta)] were used for significance tests. To identify methylated genes associated with ER(-) subtypes (TNBC and ER(-)HER2(+)) and distinct from ER(+), a weighted algorithm, developed to increase statistical rigor, called out genes in which methylation changed dramatically between ER(+) and ER(-) subtypes. Differentially methylated gene lists examined using Ingenuity Pathway Analysis called out canonical pathways and networks with clues to biological distinctiveness as well as relatedness between ER(-) subtypes as compared to ER(+) BC. The study highlights the interplay of ER(-) subtype-specific genes and their signaling pathways as potential putative fingerprints in refining classification of BC subtypes and as potential biological markers designed to hit multiple targets. PMID- 25805567 TI - The role of CD29-ILK-Akt signaling-mediated epithelial-mesenchymal transition of liver epithelial cells and chemoresistance and radioresistance in hepatocellular carcinoma cells. AB - Hepatocellular carcinomas (HCC) are aggressive cancers, and the prognosis of HCC patients is poor. This study investigated the roles of CD29 in epithelial mesenchymal transition (EMT) and chemoresistance and radioresistance in HCC tumors. CD29 expression in HCC and peritumoral tissues was measured by immunohistochemistry. CD29 overexpression was established by an adenovirus carrying CD29 gene expression cassette, while silencing of CD29 expression was established by an adenovirus-carrying shRNA. Western blot was used to measure protein expression, and MTT was used to analyze cell viability. Xenograft HCC mouse model was established by inoculating isolated CD29(+) and CD29(-) HCC tumor cells. Significantly higher percentage of positive CD29 expression was observed in HCC tissues compared to peritumoral tissues. Xenograft CD29(+) tumors grew more quickly than CD29(-) tumors. CD29(+) tumors were more resistant to radiotherapy and cisplatin therapy than CD29(-) tumors. Overexpression of CD29 significantly increased the resistance of CD29(-) tumors to radiation and cisplatin treatment. In contrast, silencing of CD29 expression significantly sensitized CD29(+) tumors to irradiation and cisplatin treatment. Overexpression of CD29 decreased E-cadherin, but increased fibronectin, vimentin, ILK activity, Akt Ser(473) phosphorylation, and mTORC1 protein expression in Hep G2 and THLE-3 cells. Moreover, overexpression of CD29 significantly increased the resistance of Hep G2 and THLE-3 cells to starvation, radiation, and cisplatin treatments. This study suggests that CD29 plays a crucial role in the resistance of HCC to chemo/radiotherapy and EMT of liver epithelial cells. PMID- 25805569 TI - Oxidation with air by ascorbate-driven quinone redox cycling. AB - Transition metal-free oxidation with air at room temperature has been achieved by simply using ascorbate (vitamin C) and catalytic amounts of menadione (vitamin K3). A combination of the mentioned vitamins transforms atmospheric oxygen into hydrogen peroxide, which is able to oxidize arylboronic acids and other chemical moieties. PMID- 25805568 TI - Medication type modifies inflammatory response to traffic exposure in a population with type 2 diabetes. AB - The association between residential traffic exposure and change in C-reactive protein over 2-years was evaluated using multivariate linear regression including interaction models for traffic and diabetes medication use/type (insulin vs. oral hypoglycemic agents (OHAs)). The study population was Puerto Rican adults (n = 356) residing in greater Boston with type 2 diabetes. Traffic was characterized as proximity to roads with >20,000 weekday traffic volumes, and multi-directional traffic density. Increases in CRP concentration were significantly associated with residence <=100 m of a roadway (p = 0.009) or near multiple roadways (p < 0.001), vs. further away, for individuals using insulin in stratified models, with consistent results in interaction models (p = 0.071 and p = 0.002). CRP was significantly lower with highest traffic density exposure in stratified (p = 0.03) and interaction models (p = 0.024) for individuals using OHAs. Individuals on insulin experienced increased CRP concentrations with traffic exposure over a 2-year study period, while those using OHAs did not experience increases. PMID- 25805570 TI - Collateral donor artery physiology and the influence of a chronic total occlusion on fractional flow reserve. AB - BACKGROUND: The presence of a concomitant chronic total coronary occlusion (CTO) and a large collateral contribution might alter the fractional flow reserve (FFR) of an interrogated vessel, rendering the FFR unreliable at predicting ischemia should the CTO vessel be revascularized and potentially affecting the decision on optimal revascularization strategy. We tested the hypothesis that donor vessel FFR would significantly change after percutaneous coronary intervention of a concomitant CTO. METHODS AND RESULTS: In consecutive patients undergoing percutaneous coronary intervention of a CTO, coronary pressure and flow velocity were measured at baseline and hyperemia in proximal and distal segments of both nontarget vessels, before and after percutaneous coronary intervention. Hemodynamics including FFR, absolute coronary flow, and the coronary flow velocity-pressure gradient relation were calculated. After successful percutaneous coronary intervention in 34 of 46 patients, FFR in the predominant donor vessel increased from 0.782 to 0.810 (difference, 0.028 [0.012 to 0.044]; P=0.001). Mean decrease in baseline donor vessel absolute flow adjusted for rate pressure product: 177.5 to 139.9 mL/min (difference -37.6 [-62.6 to -12.6]; P=0.005), mean decrease in hyperemic flow: 306.5 to 272.9 mL/min (difference, 33.5 [-58.7 to -8.3]; P=0.011). Change in predominant donor vessel FFR correlated with angiographic (%) diameter stenosis severity (r=0.44; P=0.009) and was strongly related to stenosis severity measured by the coronary flow velocity pressure gradient relation (r=0.69; P<0.001). CONCLUSIONS: Recanalization of a CTO results in a modest increase in the FFR of the predominant collateral donor vessel associated with a reduction in coronary flow. A larger increase in FFR is associated with greater coronary stenosis severity. PMID- 25805571 TI - Letter by De Rosa and Indolfi regarding article, "Clinical presentation and outcomes of coronary in-stent restenosis across 3-stent generations". PMID- 25805572 TI - Response to letter regarding article, "Clinical presentation and outcomes of coronary in-stent restenosis across 3-stent generations". PMID- 25805573 TI - Fate of right ventricle to pulmonary artery conduits after complete repair of pulmonary atresia and major aortopulmonary collaterals. AB - BACKGROUND: Surgical repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals (PA/VSD/MAPCAs) requires insertion of a conduit from the right ventricle to the reconstructed pulmonary arteries. Although there is extensive literature on conduit longevity for many forms of congenital heart defects, there is currently limited information for PA/VSD/MAPCAs. It is likely that conduits will have a different longevity in PA/VSD/MAPCAs because pulmonary artery pressures are higher after unifocalization than in other congenital heart defects. The purpose of this study was to evaluate the fate of right ventricle to pulmonary artery conduits after complete repair of PA/VSD/MAPCAs. METHODS: This was a retrospective review of 103 infants who underwent complete repair of PA/VSD/MAPCAs with insertion of an aortic homograft conduit. The average age at complete repair was 5.1 +/- 2.8 months, average conduit size was 13 +/- 2 mm, and average conduit z score was a positive 1.6 +/- 0.9. RESULTS: Conduit z scores were linearly correlated with increasing homograft conduit size. The average longevity of small homografts (8 to 11 mm) was 15 +/- 4 months, medium homografts (12 to 14 mm) was 39 +/- 7 months, and large homografts (15 to 17 mm) was 50 +/- 14 months. There was a negative correlation between increasing pulmonary artery pressure and conduit longevity. CONCLUSIONS: Conduit z scores and conduit size worked synergistically to predict the longevity of right ventricle to pulmonary artery conduits after complete repair of PA/VSD/MAPCAs. Pulmonary artery pressure was an additional modifier of longevity. These data provide a framework for expectations of aortic homograft conduits used in the repair of PA/VSD/MAPCAs. PMID- 25805574 TI - CD1d-dependent endogenous and exogenous lipid antigen presentation. AB - Invariant natural killer T (iNKT) cells recognize endogenous and exogenous lipids in the context of CD1d molecules, and through the activation and maturation of dendritic cells and B cells, can significantly enhance priming of antigen specific T and B cell responses. Recent findings have provided important insights into the recognition of several novel endogenous lipids by iNKT cells, and into the mechanisms controlling their generation and loading onto CD1d molecules. In this review we discuss these latest findings and describe the role of autophagy in iNKT cell development and activation. PMID- 25805575 TI - Analysis of cervical and global spine alignment under Roussouly sagittal classification in Chinese cervical spondylotic patients and asymptomatic subjects. AB - PURPOSE: To explore the relationship between cervical spine and the global spine alignment and to postulate the hypotheses that a lordotic alignment of cervical spine is not the only standard to identify asymptomatic subjects, and the degenerative modification of cervical curves depends primarily on their spinal pelvic alignment. METHODS: A cohort of 120 cases of Chinese asymptomatic subjects and a cohort of 121 cases of Chinese cervical spondylotic patients were recruited prospectively from 2011 to 2012. Roussouly Classification was utilized to categorize all subjects and patients according to their thoracic spine, lumbar spine and pelvic alignment. The cervical alignments were evaluated as lordosis, straight, sigmoid or kyphosis. Through the lateral X-ray images of neutral cervical and global spine, a number of parameters were measured and analyzed, including pelvic incidence, pelvic tilt, sacral slope, thoracic kyphosis (TK), lumbar lordosis, global cervical angles (angles between two lines parallel with posterior walls of C2 and C7), practical cervical angles (the addition of different cervical end plate angles from C3 to C7, and inter-vertebral angles from C23 to C67), T1 slope, spinal sacral angles (SSA), Hip to C7/Hip to Sacrum and C0-C2 angle. RESULTS: The percentages of cervical lordosis were 28.3% and 36.4% in asymptomatic and spondylotic group, respectively. The cervical spine alignments correlated with Roussouly types of global spine alignment in both asymptomatic and cervical spondylotic group (P < 0.001). And there were significant differences between Roussouly Type 2 and 4, Type 3 and 4, Type 1 and 3 in cervical angles in spondylotic group (P < 0.05). In the comparison of the two cohorts, significant differences were found in both general and practical cervical angles in Roussouly Type 4 (P = 0.00 and 0.01, respectively), and there were significant differences in inter-vertebral angle in Roussouly Type 2 at C4-5 and C5-6 levels (P = 0.04 and 0.04, respectively), and in Roussouly Type 3 at C6 7 level (P = 0.01). The SSA showed significant difference between Roussouly Type 2 and 4 in asymptomatic subjects (P = 0.00), and between Type 1 and 3, 1 and 4, 2 and 3, 2 and 4 in cervical spondylotic patients (P = 0.01, 0.02, 0.00 and 0.01, respectively). The T1 slope was significantly different among Roussouly types (P = 0.04) with its largest value in Type 1 in cervical spondylotic group. There are significant differences in C0-C2 angles in all Roussouly types (P = 0.01, 0.02, 0.00 and 0.01, respectively), as well as in the ratio of Hip to C7/hip to sacrum in Type 2 (P = 0.01), and Type 3 (P = 0.00) in the comparison of the two cohorts. The multiple linear regression of all parameters showed both general and practical cervical angles were significantly related to TK, C0-C2 and T1 slope (P = 0.01, 0.00 and 0.00, respectively). CONCLUSION: The cervical alignment correlates with their global spine and pelvic curves. And lordosis is not the only presentation in asymptomatic subjects. The degenerative modification of cervical disc angles was the compensation of global spine degeneration for horizontal gaze. Cervical angles are influenced by their TK angles, occipital-C2 joint and the tilt of T1 vertebral body. The occipital-C2 joint has a compensating mechanism in all Roussouly types in cervical spondylosis. PMID- 25805576 TI - Two level pedicle substraction osteotomies for the treatment of severe fixed sagittal plane deformity: computer software-assisted preoperative planning and assessing. AB - PURPOSE: To evaluate the efficacy of two level pedicle substraction osteotomies (PSOs) planned preoperatively with a computer software, in the patients with severe fixed sagittal plane deformities. METHODS: In the literature, there are studies indicating that two level PSOs may be required in severe cases. However, the results of two level PSOs preoperatively planned with computer software assistance have not yet been reported in the English literature. Severe fixed sagittal plane deformities of 11 patients are described. Preoperative surgical planning was done with the aid of a computer software. Two level PSOs were indicated after the process. After the application of the indicated surgical technique, clinical and radiological results were evaluated in the preoperative, the early postoperative periods and during the last follow-up. RESULTS: The mean sagittal vertical axis was found as 190.5 (range 161-220) mm in the preoperative period, 23.5 (range -27 to 61) mm in the early postoperative period (P < 0.001) (87.7 % correction) and 34.5 (range -3 to 55) mm during the last follow-up (P < 0.001). The mean pelvic tilt (PT) significantly decreased from 38.3 degrees (range 21 degrees -63 degrees ) preoperatively to 23.8 degrees (range 18 degrees -42 degrees ) postoperatively (P = 0.008) and to 27.5 degrees (range 17 degrees 42 degrees ) during the last follow-up (P = 0.042). The mean lumbar lordosis (LL) was 2.8 degrees (range -29 degrees to 20 degrees ) preoperatively, -35.6 degrees (range -54 degrees to 23 degrees ) early postoperatively (P < 0.001) and -33.6 degrees (range -52 degrees to 20 degrees ) during the last follow-up (P < 0.001). The average amount of bleeding was 5345 (range 2600-7415) ml. CONCLUSION: Although a statistically significant correction was obtained, the mean PT and PI-LL value could not be restored in physiological limits during the last follow-up. Thus, two level PSOs performed after computer software (surgimap) assisted preoperative planning failed to correct severe fixed sagittal plane deformities. Besides, this procedure is of possible risks for major complications such as a result of excessive bleeding. We recommend that two level PSOs should be rarely indicated, but preferred as an alternative technique only in the most severe cases. PMID- 25805579 TI - Nontraumatic posterior atlantooccipital dislocation associated with atlantoaxial instability. AB - INTRODUCTION: Nontraumatic posterior atlantooccipital dislocation has only been rarely reported. In the current study, the authors reported an extremely rare case of nontraumatic posterior atlantooccipital dislocation associated with atlantoaxial instability. MATERIALS AND METHODS: A 47-year-old female was referred with a history of neck pain for 5 years. The patient had no history of trauma. The axial rotation of range of motion of the cervical spine was severely restricted. Posterior atlantooccipital dislocation with atlantoaxial instability was confirmed through conventional radiography, computed tomography and magnetic resonance imaging. We performed realignment of the dislocation and posterior occipitocervical (C0-C2) fusion. After the surgery, the patient's symptoms improved significantly and she manifested neurological improvement. CONCLUSION: To our knowledge, this lesion has not been reported previously. Anomalies of upper cervical spine may have induced this instability. PMID- 25805580 TI - Neutrophils: new sensor of bacterial DNA. PMID- 25805577 TI - A meta-analysis of the fusion rate from surgical treatment for odontoid factures: anterior odontoid screw versus posterior C1-C2 arthrodesis. AB - PURPOSE: Surgical treatment for odontoid fractures is widely performed in practice. However, the choice of different surgical procedures remains controversial. Regardless of the surgical technique, the fusion situation is one of the important factors that affect the clinical efficacy. A discrepancy in fusion rate between the anterior odontoid screw fixation approach and the posterior C1-C2 arthrodesis approach has been suggested in clinical research, yet no consensus has been reached. This meta-analysis aims to synthesize the currently available evidence on the topic. METHODS: Most published comparative studies have limited statistical power to reach a solid conclusion due to the sample size constraint. In this condensed meta-analysis, we focused on the analysis of the reported fusion rates among selected comparative studies. The targeted comparative study design was chosen to control for potential confounding factors. However, the inclusion criteria of comparative studies limited our sample size and we were not able to obtain statistically meaningful sample size for other endpoints. On the other hand, fusion rate serves as an important clinical outcome and is the most commonly reported one from odontoid fracture studies. RESULTS: Results show that the overall fusion rate is lower in anterior group than in posterior group in both fixed effect model (RR = 0.90, 95 % CI 0.82 0.99) and random effect model (RR = 0.90, 95 % CI 0.83-0.97). There was no significant heterogeneity between these studies (p value = 0.5718), and no evident publication bias was detected by the Egger's test (t = -0.3541, df = 6, p value = 0.7354) and funnel plots. In general, age is not statistically associated with the choice of surgical approach (chi(2) = 0.29, df = 1, p value = 0.59) but appears to affect the clinical efficacy. The protective effect of posterior C1-C2 arthrodesis treatment on fusion remains significant in the elderly (>=60 years), but loses its significance in the younger age population (<60 years). CONCLUSIONS: In light of these findings, we concluded that significant higher fusion rates were observed in patients who underwent posterior C1-C2 arthrodesis surgeries compared to those treated with anterior odontoid screw fixation. PMID- 25805578 TI - Restoration of lumbopelvic sagittal alignment and its maintenance following transforaminal lumbar interbody fusion (TLIF): comparison between straight type versus curvilinear type cage. AB - PURPOSE: To evaluate a radiological and clinical difference between the curvilinear type cages compared to the straight type cages for the restoration of lumbopelvic sagittal alignment and its maintenance after transforaminal lumbar interbody fusion (TLIF) procedure. METHODS: 68 patients who underwent single level TLIF using either the straight type or curvilinear type cage were retrospectively reviewed. Assessment of the lumbopelvic parameters and the height of disc space was performed before surgery as well as 2 days, 6 and 12 months after surgery. Clinical outcome was assessed using VAS and ODI. RESULTS: The curvilinear type cages were positioned more anteriorly than the straight type. Restoration of the segmental lordosis (SL) in the curvilinear group was significantly greater than the straight group and at 12 months of follow-up, the straight group showed greater decrease in the disc height than the curvilinear group. The straight group failed to show improvement of lumbar lordosis (LL), while the curvilinear group showed significant restoration of LL and could maintain it to the 6 months of follow-up. In both groups, pelvic tilt was significantly decreased and it lasted to 6 months in the straight group; whereas in the curvilinear group, it was maintained to the last follow-up of 12 months. There were no significant differences between the two groups in mean VAS and ODI score over the follow-up period. CONCLUSIONS: This study demonstrates that the curvilinear type cage is superior to the straight type cage in improving the SL and maintaining both the restored lumbopelvic parameters and elevated disc height. These results could be attributable to the anterior position of the curvilinear cage which permits easy restoration of segmental lordosis and less sinking of cages. PMID- 25805583 TI - Assessment of micronuclei induction in peripheral blood and gill cells of some fish species from Aliaga Bay Turkey. AB - The aim of this paper was to assess the biological damages in fish caused by various mutagenic agents present in polluted waters of Aliaga Bay. For this purpose, micronuclei (MN) test was performed using peripheral erythrocytes and gill cells of different fish specimens caught from both polluted and relatively clean sites from Aliaga Bay (Turkey). Micronuclei tests is a system of mutagenicity testing used for determining changes in DNA fragments such as micronuclei in the cytoplasm of interphase cells caused by the pollution and chemicals in the environment. Thus, it was attempted to determine whether pollution affected the erythrocytes and gills of fish living in Aliaga Bay at the level of DNA by the means of micronuclei (MN) test. According to the results of present study, frequency of MN was found at high level in polluted site. In conclusion, this study indicates that the micronuclei test gives sensitive results in monitoring the pollution, especially the pollution of harbor, and thus it might be used as standard method in regularly monitoring pollution of coastal ecosystem. PMID- 25805584 TI - Cracking the diverse biologic code of diffuse large B-cell lymphoma. PMID- 25805585 TI - The histological classification of diffuse large B-cell lymphomas. AB - Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic, and pathologic diversity, in part reflecting the functional diversity of the B-cell system and multiple pathways of transformation. In recent years, the advent of new high-throughput genomic technologies has provided new insights into the biology of DLBCL, leading to the identification of distinct molecular identities and novel pathogenetic pathways. This increasing complexity had led to an expanding number of entities in the World Health Organization classification. Using a multi-modality approach, the updated 2008 classification delineated some new subgroups, including DLBCLs associated with particular age groups or specific anatomic sites, as well as two borderline categories (tumors at the interface between classical Hodgkin lymphoma and DLBCL as well as between Burkitt lymphoma and DLBCL). This article reviews the histopathologic features of the various aggressive B-cell lymphoma subtypes included in the 2008 classification, with emphasis on some of the new entities as well as areas of diagnostic challenge. PMID- 25805586 TI - The genetic landscape of diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in the western world, is an aggressive disease that remains incurable in approximately 30% of patients. Over the past decade, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic and transcriptional changes has revolutionized our understanding of the genetic basis of DLBCL by providing a comprehensive and unbiased view of the genes/pathways that are disrupted by genetic alterations in this disease, and may contribute to tumor initiation and expansion. These studies uncovered the existence of several previously unappreciated alterations in key cellular pathways that may also influence treatment outcome. Indeed, a number of newly identified genetic lesions are currently being explored as markers for improved diagnosis and risk stratification, or are entering clinical trials as promising therapeutic targets. This review focuses on recent advances in the genomic characterization of DLBCL and discusses how information gained from these efforts has provided new insights into its biology, uncovering potential targets of prognostic and therapeutic relevance. PMID- 25805589 TI - MYC alterations in diffuse large B-cell lymphomas. AB - MYC is a transcription factor associated with numerous physiological functions, including apoptosis, and strong oncogenic potential. MYC expression is tightly regulated in normal lymphoid cells with high levels in the initial steps of the secondary lymphoid follicle formation and in a subset of centrocytes of the germinal center light zone. BCL6 and BLIMP1 repress MYC expression in normal germinal center B and plasma cells, respectively. Paradoxically, most lymphomas with MYC genetic alterations originate from cells that usually do not express MYC, suggesting that these tumors need to develop additional oncogenic events to overcome the MYC regulatory mechanisms and also its proapoptotic function. MYC rearrangements, and to a lesser extent gene amplifications, have been detected in approximately 5% to 14% of diffuse large B-cell lymphoma (DLBCL) and these alterations are frequently associated with BCL2 or BCL6 rearrangements. The concurrent presence of these alterations confers a more aggressive behavior to the tumors with poor outcome of the patients. BCL2 and MYC protein may also be coexpressed in DLBCL independently of gene alterations and this double expression also confers poor prognosis, although not as dismal as that of double genetic hits. Additional factors may modulate the biological effect of the double hit lesions because tumors in which MYC is translocated to non-IGH partner or MYC and BCL2 protein that are expressed at lower levels may have a less aggressive behavior. Further studies are needed to define the clinical implications of MYC aberrations in DLBCL and determine the most appropriate diagnostic strategy to identify these tumors. PMID- 25805587 TI - B-cell receptor signaling in diffuse large B-cell lymphoma. AB - The importance of understanding the genetic and biochemical basis of B-cell receptor (BCR) survival signaling in diffuse large B-cell lymphoma (DLBCL) is underscored by the recent clinical success of agents that target the BCR pathway. DLBCL is composed of multiple distinct molecular subtypes with divergent clinical outcomes. The activated B-cell-like (ABC) subtype is the most aggressive form of DLBCL and is often resistant to standard chemotherapies. ABC DLBCL expresses numerous genes found in antigen-activated B cells, and genetic and pharmacologic studies have demonstrated that ABC DLBCL tumors are addicted to NF-kappaB activity. The origins of this NF-kappaB activity remained obscure until RNA interference screens established that the majority of ABC DLBCL cell lines rely on expression of BCR components and downstream signaling effectors for NF-kappaB activation. Pharmacological inhibition with ibrutinib of Bruton's tyrosine kinase, a kinase that is required for BCR signaling to engage NF-kappaB, is selectively toxic for ABC DLBCL tumors; a finding that has now been translated to the clinic. These novel targets not only offer a promising new therapy option for ABC DLBCL, but also demonstrate the value of a deep molecular understanding of oncogenic signaling pathways. PMID- 25805590 TI - Treatment approach to newly diagnosed diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma in western countries. High prognostic heterogeneity is observed among patients with DLBCL with long-term survival ranging from 30% to more than 90% according to clinic-biological prognostics such as the International Prognostic Index (IPI) and its subsequent revised variants. Recent advances in the understanding of DLBCL biology as cell-of-origin (COO) determination has led to significant improvement of prognostic tools but also shed light on new potential targeted compounds for specific DLBCL subtypes. First DLBCL subset has been designed germinal center B-cell like DLBCL (GCB) because it expresses genes characteristic of germinal center B cells. Second DLBCL subset has been designed activated B-cell like DLBCL (ABC) because it expresses genes upregulated in response to in vitro activation. In this review, we will present state-of-the-art treatment of DLBCL in young and elderly patients, recent results in dose-dense regimen as well as potential interest for high-dose therapy followed by autologous stem cell transplant. A special emphasis will be given to new treatment developments according to COO in DLBCL. In particular, we will focus on new drugs that might alleviate the worse prognosis associated to DLBCL ABC subtype in the near future. PMID- 25805588 TI - The epigenetic basis of diffuse large B-cell lymphoma. AB - The pathogenesis of diffuse large B-cell lymphoma (DLBCL) is strongly linked to perturbation of epigenetic mechanisms. The germinal center (GC) B cells from which DLBCLs arise are prone to instability in their cytosine methylation patterns. DLBCLs inherit this epigenetic instability and display variable degrees of epigenetic heterogeneity. Greater epigenetic heterogeneity is linked with poor clinical outcome. Somatic mutations of histone-modifying proteins have also emerged as a hallmark of DLBCL. The effect of these somatic mutations may be to disrupt epigenetic switches that control the GC phenotype and "lock in" certain oncogenic features of GC B cells, resulting in malignant transformation. DNA methyltransferase and histone methyltransferase inhibitors are emerging as viable therapeutic approaches to erase aberrant epigenetic programming, suppress DLBCL growth, and overcome chemotherapy resistance. This review will discuss these recent advances and their therapeutic implications. PMID- 25805591 TI - Emerging biological insights and novel treatment strategies in primary mediastinal large B-cell lymphoma. AB - While primary mediastinal large B-cell lymphoma (PMBCL) is considered to be a subtype of diffuse large B-cell lymphoma, it is a distinct clinicopathologic entity, with clinical and biological features closely resembling nodular sclerosing Hodgkin lymphoma. Recent studies have highlighted the shared biology of these two entities and identified novel critical pathways of lymphomagenesis, including the presence of distinct mutations. Mediastinal grey zone lymphomas with features in between PMBCL and nodular sclerosing Hodgkin lymphoma have been described as the missing link between the two parent entities. While the standard therapeutic approach to PMBCL has been immunochemotherapy followed by mediastinal radiation, strategies that obviate the need for radiation and thus eliminate its long-term toxicities have recently been developed. The identification of novel targets in PMBCL and mediastinal grey zone lymphomas have paved the way for testing of agents such as small molecule inhibitors of Janus kinase pathways and immune checkpoint inhibitors. Future directions in these diseases should focus on combining effective novel agents with immunochemotherapy platforms. PMID- 25805592 TI - Novel targeted therapies in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin's lymphoma. Next-generation sequencing techniques have improved our understanding of the molecular pathways that may drive oncogenesis. Many novel classes of drugs are in development that may improve the treatment of DLBCL, either as single agents or in combination, that exploit their synergy to overcome resistance. We review the key novel targets and therapeutics in the treatment of DLBCL, including immunomodulatory agents and immunotherapy. PMID- 25805593 TI - Current status of the role of PET imaging in diffuse large B-cell lymphoma. AB - PET-CT (positron emission tomography-computed tomography) has emerged as an indispensable tool in the management of patients with diffuse large B-cell lymphoma (DLBCL). It is the standard imaging test for initial staging and is superior to CT in determining remission status and has replaced CT in this regard. The focus of this seminar will highlight controversial aspects on the role of PET-CT in the treatment of patients with DLBCL and will address the following questions: 1) Is a contrasted enhanced CT scan necessary for initial staging in the PET era? 2) Is a bone marrow biopsy required for initial staging of DLBCL in the era of PET imaging? 3) What is the role of interim PET in management? 4) Should PET scans be used for surveillance in patients in remission? 5) What is the role of semiquantitative PET and CT metrics in prognostication and response assessment? PMID- 25805594 TI - Summary and future directions. AB - Our understanding of disease biology and treatment paradigms in diffuse large B cell lymphoma (DLBCL) is now sufficiently mature that we are poised to enter a new phase of hematological oncology. To achieve the goal of precision medicine and begin to logically deploy the vast array of currently available, novel targeted therapies we must develop a roadmap for clinical research. We urgently need robust biomarkers to inform the results of current and planned randomized, controlled phase III clinical trials. These biomarkers should capitalize on our current understanding of the genetic landscape of DLBCL and will help to define those patients destined to fail R-CHOP. But more importantly, they will inform the molecular correlates of treatment failure for planned clinical trials testing novel agents and combinations. If successful, we can move the field past the vast array of prognostic markers and develop predictive biomarkers that direct future therapy. PMID- 25805596 TI - Light-induced deformation of polymer networks containing azobenzene chromophores and liquid crystalline mesogens. AB - Two-component polymer networks containing liquid crystalline (LC) mesogens and azobenzene chromophores belong to a class of smart materials which combine uniquely the orientation order of liquid crystals and light-induced deformation of photosensitive polymers. In the present study we develop a theory of light induced deformation of azobenzene-containing LC networks. It is shown that preferential reorientation of chromophores perpendicular to the polarization direction of the light E leads to the reorientation of the mesogens due to LC interactions between the components. Reorientation of the chromophores and mesogens results in the light-induced deformation of the polymer network. The sign of deformation (expansion/contraction with respect to the vector E) depends on the orientation distribution of the mesogens and chromophores inside the network strands. The magnitude of deformation increases with increase of the volume fraction of chromophores and the strength of LC interactions between the components. The influence of the dilution of azobenzene-containing networks by the bent cis-isomers of the chromophores on the light-induced deformation is discussed. PMID- 25805595 TI - Effect of testosterone therapy on the urinary bladder in experimental hypogonadism of rats. AB - Testosterone (T) deficiency is prevalent particularly in elderly men and lead to physical and sexual morbidities. Although low levels of T are associated with low urinary tract symptoms, the correlation between T deficiency and bladder dysfunction is not clearly identified. The aim of this study was to investigate the effect of high dose testosterone replacement therapy (TRT) on the histological structure of the UB in castrated rats. Twenty-five adult male rats were divided into three groups: control, castrated and castrated + TRT. T was administrated in high dose (100 mg/kg) two intramuscular injections/week for 60 days. UB sections were prepared and stained with H&E, Masson's trichrome and immunohistochemical detection of Cytokeratin 20 (Ck20). All data were morphometrically and statistically analyzed. In castrated group, significant atrophy of the urothelium (P < 0.001) accompanied with widening of the corium were observed. The smooth muscle appeared thin with marked increase in the collagen fibers. On treating the castrated group with TRT, atypical Ck20 expression as well as significant increase in urothelial thickness (P < 0.05) and smooth muscle/collagen ratio (P < 0.001) were detected. In castrated rat model, high dose TRT has a positive effect on the UB smooth muscle rather than the urothelium which acquired atypical patterns. PMID- 25805597 TI - Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability. AB - There are numerous factors in individual variability that make the development and implementation of precision medicine a challenge in the clinic. One of the main goals of precision medicine is to identify the correct dose for each individual in order to maximize therapeutic effect and minimize the occurrence of adverse drug reactions. Many promising advances have been made in identifying and understanding how factors such as genetic polymorphisms can influence drug pharmacokinetics (PK) and contribute to variable drug response (VDR), but it is clear that there remain many unidentified variables. Underlying liver diseases such as nonalcoholic steatohepatitis (NASH) alter absorption, distribution, metabolism, and excretion (ADME) processes and must be considered in the implementation of precision medicine. There is still a profound need for clinical investigation into how NASH-associated changes in ADME mediators, such as metabolism enzymes and transporters, affect the pharmacokinetics of individual drugs known to rely on these pathways for elimination. This review summarizes the key PK factors in individual variability and VDR and highlights NASH as an essential underlying factor that must be considered as the development of precision medicine advances. A multifactorial approach to precision medicine that considers the combination of two or more risk factors (e.g. genetics and NASH) will be required in our effort to provide a new era of benefit for patients. PMID- 25805598 TI - Preparation and Evaluation of Multiple Nanoemulsions Containing Gadolinium (III) Chelate as a Potential Magnetic Resonance Imaging (MRI) Contrast Agent. AB - PURPOSE: The objective was to develop, characterize and assess the potentiality of W1/O/W2 self-emulsifying multiple nanoemulsions to enhance signal/noise ratio for Magnetic Resonance Imaging (MRI). METHODS: For this purpose, a new formulation, was designed for encapsulation efficiency and stability. Various methods were used to characterize encapsulation efficiency ,in particular calorimetric methods (Differential Scanning Calorimetry (DSC), thermogravimetry analysis) and ultrafiltration. MRI in vitro relaxivities were assessed on loaded DTPA-Gd multiple nanoemulsions. RESULTS: Characterization of the formulation, in particular of encapsulation efficiency was a challenge due to interactions found with ultrafiltration method. Thanks to the specifically developed DSC protocol, we were able to confirm the formation of multiple nanoemulsions, differentiate loaded from unloaded nanoemulsions and measure the encapsulation efficiency which was found to be quite high with a 68% of drug loaded. Relaxivity studies showed that the self-emulsifying W/O/W nanoemulsions were positive contrast agents, exhibiting higher relaxivities than those of the DTPA-Gd solution taken as a reference. CONCLUSION: New self-emulsifying multiple nanoemulsions that were able to load satisfactory amounts of contrasting agent were successfully developed as potential MRI contrasting agents. A specific DSC protocol was needed to be developed to characterize these complex systems as it would be useful to develop these self-formation formulations. PMID- 25805599 TI - Religiousness and suicide in a nationally representative sample of Trinidad and Tobago adolescents and young adults. AB - PURPOSE: The present study examines religiousness and its connection to suicidal thoughts, plans, and attempts among Trinidad and Tobago adolescents and young adults. METHOD: Data are from Trend Research Empowering National Development on adolescents and young adults in Trinidad and Tobago (N = 4448). Religious affiliation, self-perceived religiousness, attendance at religious services, prayer frequency, socio-demographic variables, and suicidal thoughts, plans, and attempts were assessed. RESULTS: Compared to nonreligious, Catholics (OR 0.63, p < 0.05) and Seventh-day Adventists (OR 0.47, p < 0.01) were less likely to think about suicide, and hindus (OR 5.81, p < 0.05) and other affiliates (OR 7.28, p < 0.01) were more likely to be treated for suicide. Higher self-rated religiosity was related to lower likelihood of thinking about suicide (OR 0.86, p < 0.01) and lower likelihood of planning suicide (OR 0.78, p < 0.001). Attendance at religious services was related to lower likelihood of thinking about suicide (OR 0.94, p < 05) and fewer suicide attempts (beta = -0.11, p < 0.01). More frequent prayer was related to lower likelihood of thinking about suicide (OR 0.92, p < 0.01) and lower likelihood of planning suicide (OR 0.90, p < 0.001). CONCLUSIONS: Religiousness may offer benefits for adolescents and young adults in Trinidad and Tobago by reducing the likelihood that they engage in suicide thoughts and behaviors. Results may hold implications for counselors, clergy, teachers, and others working with adolescents and young adults in Trinidad and Tobago. PMID- 25805600 TI - Chlorobenzylidene malononitrile tear gas exposure: Rinsing with amphoteric, hypertonic, and chelating solution. AB - OBJECTIVE: Chlorobenzylidene malononitrile (CS) is the tear gas used by the police. The aim was to evaluate an amphoteric, hypertonic, and chelating rinsing solution in CS exposure. METHODS: The first (CS) group of six police officers was exposed to CS only. The second (preexposure) group of eight sprayed their faces with an aqueous, hypertonic, amphoteric, and chelating solution before CS exposure. The third (postexposure) group of eight sprayed their faces with an aqueous, hypertonic, amphoteric, and chelating solution after CS exposure. The time between exiting the CS cloud and arriving at the "ready for action" checkpoint was measured. Their facial pain both inside the CS cloud and at the checkpoint was assessed (0-10 points). RESULTS: The pain level inside the CS cloud was significantly lower in the preexposed group (5.6 +/- 1.1; p = 0.01) than in the CS group (9.7 +/- 0.5) and in the postexposure group (9.1 +/- 0.4) where it was similar. The time interval between CS exposure and arrival at the checkpoint in the preexposure group (1:26 +/- 0:44 min) was significantly shorter than both in the CS group (2:28 +/- 0:25 min; p = 0.04) and postexposure group (2:30 +/- 0:48 min; p = 0.02) where it was not different. The residual pain at the checkpoint in the preexposure (1.1 +/- 0.4) and postexposure (1.4 +/- 0.7) groups was similar with a significant lower pain level than in the CS group (2.3 +/- 0.5; p = 0.02). CONCLUSION: CS decontamination with an aqueous, hypertonic, amphoteric, and chelating solution reduces facial pain, whereas prevention with it reduces pain and recovery time. PMID- 25805601 TI - Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice. AB - Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties. PMID- 25805602 TI - A microtubule organizing centre (MTOC) is responsible for the production of the sperm flagellum in Matsucoccus feytaudi (Hemiptera: Coccoidea). AB - A microtubule organizing centre (MTOC) has been described in the spermatid of the hemipteran Matsucoccus feytaudi (Coccoidea). This structure, revealed as a fluorescent ring by treatment with gamma-tubulin antibody, gives rise to a bundle of microtubules which surrounds the elongated cylindrical nucleus. This microtubule bundle has been considered an atypical sperm flagellum provided with sperm motility. A comparison of the M. feytaudi MTOC with the material associated with the centriole of Drosophila melanogaster spermatids confirms the great similarity between the two structures, both involved in the nucleation of microtubules. Like the D. melanogaster material associated with the centriole, the M. feytaudi MTOC is a transient structure which disappears or degenerates at the end of spermiogenesis and is no longer visible in the mature sperm. PMID- 25805603 TI - Web search activity data accurately predict population chronic disease risk in the USA. AB - BACKGROUND: The WHO framework for non-communicable disease (NCD) describes risks and outcomes comprising the majority of the global burden of disease. These factors are complex and interact at biological, behavioural, environmental and policy levels presenting challenges for population monitoring and intervention evaluation. This paper explores the utility of machine learning methods applied to population-level web search activity behaviour as a proxy for chronic disease risk factors. METHODS: Web activity output for each element of the WHO's Causes of NCD framework was used as a basis for identifying relevant web search activity from 2004 to 2013 for the USA. Multiple linear regression models with regularisation were used to generate predictive algorithms, mapping web search activity to Centers for Disease Control and Prevention (CDC) measured risk factor/disease prevalence. Predictions for subsequent target years not included in the model derivation were tested against CDC data from population surveys using Pearson correlation and Spearman's r. RESULTS: For 2011 and 2012, predicted prevalence was very strongly correlated with measured risk data ranging from fruits and vegetables consumed (r=0.81; 95% CI 0.68 to 0.89) to alcohol consumption (r=0.96; 95% CI 0.93 to 0.98). Mean difference between predicted and measured differences by State ranged from 0.03 to 2.16. Spearman's r for state wise predicted versus measured prevalence varied from 0.82 to 0.93. CONCLUSIONS: The high predictive validity of web search activity for NCD risk has potential to provide real-time information on population risk during policy implementation and other population-level NCD prevention efforts. PMID- 25805604 TI - Spatial distributions of lipids in atherosclerosis of human coronary arteries studied by time-of-flight secondary ion mass spectrometry. AB - The accurate spatial distribution of various lipid species during atherogenesis has remained unexplored. Herein, we used time-of-flight secondary ion mass spectrometry (TOF-SIMS) to analyze the lipid distribution in human coronary artery cryosections. The images from the TOF-SIMS allowed visualization of ions derived from individual species of cholesterol esters, phospholipids, and triacylglycerols in the context of lesion characteristics and severity. In addition, cholesterol-containing crystal-like structures were seen in high resolution images of advanced lesions. The ratio of cholesterol fragment ions (m/z 385:m/z 369) was found to differentiate unesterified cholesterol from cholesterol esters. This ratio changed during atherogenesis and in different areas of the lesions, reflecting differences in the accumulation of the two forms of cholesterol. Thus, atheromas were characterized by accumulation of cholesterol esters with apolipoprotein B near the intima-media border, whereas in the complicated lesions, unesterified cholesterol dominated in neovessel-containing areas enriched in glycophorin A. Interestingly, triacylglycerols were found in areas surrounding neovessels and lacking either form of cholesterol. The lipid composition of the tunica media reflected the alterations observed in the intimal lipids, yet being more subtle. The detailed molecular information obtained by TOF SIMS revealed unanticipated differences in the type and composition of the accumulating lipids in different stages of atherogenesis, notably the spatial segregation of cholesterol and triglycerides in the advancing lesions. PMID- 25805605 TI - Effect of microstructure characteristics on tetracalcium phosphate-nanomonetite cement in vitro cytotoxicity. AB - MC3T3E1 murine pre-osteoblastic cells were used to evaluate the cytotoxicity of tetracalcium phosphate (TTCP)-nanomonetite (DCPA) cement. The starting cement powder mixture was prepared by the in situ reaction between TTCP and a diluted solution of orthophosphoric acid in a planetary ball mill. The cements in the form of pressed cement powder mixture discs differ from each other by the method of pre-treatment and degree of the transformation of cement components in phosphate-buffered saline (PBS). For the evaluation of TTCP-DCPA cement to be non cytotoxic, it was sufficient to apply the short-time soaking in PBS solution, regardless of whether the cement components were completely transformed or not. If the texture motif and hydroxyapatite particle morphology were properly developed during the initial stage of hardening, the cement cytotoxicity or osteoblast proliferation were insignificantly influenced by the soaking time or the texture stability during cell cultivation, but the lattice ordering enhanced cell proliferation. Results showed that the surface texture and the hydroxyapatite particle morphology are crucial for in vitro cement cytotoxicity evaluation. PMID- 25805607 TI - JBS special issue on therapeutic antibody discovery and development: biologics come of age. AB - In this special issue of the Journal of biomolecular screening, we have assembled a series of articles that exemplify and discuss various aspects and challenges associated with the discovery, development, and manufacture of biologics with an emphasis on those topics that we feel will appeal to readers of this journal. We hope you enjoy them! PMID- 25805609 TI - A rare para-anastomotic femoral artery aneurysm in a patient with history of femoro-popliteal bypass graft occlusion. AB - INTRODUCTION: Para-anastomotic aneurysms may develop as a late complication of arterial reconstructions. They are mostly seen after abdominal aortic procedures and also are mostly encountered as pseudoaneurysms. PRESENTATION OF CASE: We report a true para-anastomotic aneurysm in the common femoral artery of a 57 year old man with an occluded femoro-popliteal bypass graft. We discuss the surgical management and possible causation of this extremely rare condition DISCUSSION: Para-anastomotic aneurysms can have some life-threatening consequences, such as erosion of adjacent tissues, distal embolization from mural thrombus and rupture of the aneurysmal sac. CONCLUSION: Endovascular treatment using stent grafts is highly effective, but it has some handicaps such as occlusion of major arterial orifices. For this reason, surgical reconstruction is the preferable choice for the management of para-anastomotic aneurysms. PMID- 25805608 TI - Comparison of the Pharmacokinetics of Salmeterol and Fluticasone Propionate 50/100 ug Delivered in Combination as a Dry Powder Via a Capsule-Based Inhaler and a Multi-Dose Inhaler. AB - BACKGROUND AND OBJECTIVES: The Rotacaps((r))/Rotahaler((r)) system is a single unit dose inhaler being developed to deliver inhaled salmeterol/fluticasone propionate combination (SFC) as an alternative treatment option to the metered dose inhaler and the multi-dose dry powder inhaler, Diskus((r)). The aim of this study was to compare the systemic exposure of SFC 50/100 ug following delivery via the Rotacaps((r))/Rotahaler((r)) and the Diskus((r)). METHODS: This was an open-label, randomized, cross-over, repeat-dose (3.5 days of twice-daily dosing) study comparing salmeterol and fluticasone propionate systemic exposure following inhaled SFC 50/100 ug delivered via the Rotacaps((r))/Rotahaler((r)) and Diskus((r)), in healthy subjects. Pharmacokinetic sampling was conducted over 12 h post-dose on the last day of each treatment. Pharmacokinetic samples were analysed using solid phase extraction followed by high performance liquid chromatography/tandem mass spectrometry. Co-primary endpoints were fluticasone propionate area under the concentration-time curve over the dosing interval (AUC0 tau ) and salmeterol maximum plasma concentration (C max) on the last day of treatment. RESULTS: Following SFC 50/100 ug Rotacaps((r))/Rotahaler((r)), fluticasone propionate and salmeterol systemic exposures were comparable with Diskus((r)) in terms of both AUC0-tau [geometric mean ratio (GMR) with 90 % confidence interval (CI) of Rotahaler((r))/Diskus((r)) for fluticasone propionate: 0.98 (0.91, 1.06) and salmeterol: 1.04 (0.99, 1.10)] and C max [GMR (90 % CI) for fluticasone propionate: 1.04 (0.94, 1.15) and salmeterol: 0.97 (0.87, 1.08)], meeting the pre-defined criteria for comparability (upper limit of the 90 % CI for the GMRs (Rotahaler((r))/Diskus((r))) <=1.25]. SFC delivered from both inhalers was well tolerated. CONCLUSIONS: SFC 50/100 ug Rotacaps((r))/Rotahaler((r)) showed comparable fluticasone propionate and salmeterol systemic exposure to Diskus((r)) for all pharmacokinetic endpoints with GMR and both upper and lower limits of 90 % CIs within conventional acceptance criteria for bioequivalence (0.8, 1.25), sufficient for considering progression of the Rotacaps((r))/Rotahaler((r)) product for further clinical development. PMID- 25805610 TI - A rare combination of hepatic and pericardial hydatid cyst and review of literature. AB - Hydatid disease in human beings, as in all intermediate hosts, manifest as hydatid cyst (HC). It is an important cyclozoonotic disease, endemic in various sheep and cattle raising areas of the world, including India. The tapeworm commonly involved is Echinococcus granulosus. HC can occur almost anywhere in the body, most common organs being liver and lungs, and are usually solitary. In 25% of cases combination of liver HC with HC in other extra pulmonary locations are found. Cardiac HCs comprise of 0.5-2% of all HC cases. Within the heart, HCs are usually situated in the left or right ventricle and rarely found in the peri cardium. Pericardial HC does not produce symptoms and is often painless and silent, until the cysts grow to a large size over the years, when the usual complications develop, such as cyst rupture, cardiac compression, atrial fibrillation, and even sudden death. We describe the case of a 39 year old house wife, of rural origin, with proximity to livestock, who had an asymptomatic pericardial HC along with a symptomatic hepatic HC. She clinically presented with an abdominal lump for one year with recent onset of abdominal pain for 1 month, when radiological imaging confirmed the diagnosis of an unruptured hepatic HC and a pericardial HC. The patient recovered after pericardiectomy along with excision of the HC over the left ventricle and enucleation of hepatic HC, by thoracoabdominal approach. She is doing well after 5 years of followup without recurrence. PMID- 25805611 TI - Hepatic venous outflow obstruction after living donor liver transplantation managed with ectopic placement of a foley catheter: A case report. AB - INTRODUCTION: The early hepatic venous outflow obstruction (HVOO) is a rare but serious complication after liver transplantation, which may result in graft loss. We report a case of early HVOO after living donor liver transplantation, which was managed by ectopic placement of foley catheter. PRESENTATION: A 51 years old male patient with end stage liver disease received a right hemi-liver graft. On the first postoperative day the patient developed impairment of the liver functions. Doppler ultrasound (US) showed absence of blood flow in the right hepatic vein without thrombosis. The decision was to re-explore the patient, which showed torsion of the graft upward and to the right side causing HVOO. This was managed by ectopic placement of a foley catheter between the graft and the diaphragm and the chest wall. Gradual deflation of the catheter was gradually done guided by Doppler US and the patient was discharged without complications. DISCUSSION: Mechanical HVOO results from kinking or twisting of the venous anastomosis due to anatomical mismatch between the graft and the recipient abdomen. It should be managed surgically by repositioning of the graft or redo of venous anastomosis. Several ideas had been suggested for repositioning and fixation of the graft by the use of Sengstaken-Blakemore tubes, tissue expanders, and surgical glove expander. CONCLUSION: We report the use of foley catheter to temporary fix the graft and correct the HVOO. It is a simple and safe way, and could be easily monitored and removed under Doppler US without any complications. PMID- 25805612 TI - Calvarial ectopic meningothelial meningioma. AB - BACKGROUND: Meningiomas are the most common benign neoplasm of the brain whereas ectopic presentation, although reported, is rare. Among these ectopic tumors, there are a group of purely intraosseous meningiomas, which usually are diagnosed differentially from common primary osseous tumor such as fibrous dysplasia and osteoid osteoma. CASE DESCRIPTION: We report a 62-year-old female with a history of headaches and 6 months of progressive right parietal bulging, with no neurological signs. Parietal craniotomy was performed with immediate titanium cranioplasty of the parietal convexity. Histopathology exams revealed an ectopic intradiploic meningioma without invasion of cortical layers, with positive staining for progesterone receptors and epithelial membrane antigen. CONCLUSIONS: Ectopic intraosseous meningiomas remain a rare neoplasm with only a few cases reported. The main theories to justify the unusual topography appear to be embryological remains of neuroectodermal tissue or cellular dedifferentiation. Surgical treatment seems the best curative option. PMID- 25805613 TI - Considerations and management of a patient with three metachronous cancers in association with Lynch syndrome and ileal Crohn's disease: A case report. AB - INTRODUCTION: Lynch syndrome and Crohn's disease are two entirely separate conditions but each have major gastrointestinal characteristics and carry a substantial increase in the risk of intestinal malignancy. Their co-existence in the patient who is the subject of this report dictated the need for an individualised treatment plan to deal with both conditions adequately. PRESENTATION OF CASE: We report a case of a 51 year old female with a past medical history that includes Lynch syndrome and small bowel Crohn's disease. Over a period of fifteen months, she developed three separate primary metachronous tumors in her endometrium, colon and duodenum. DISCUSSION: A patient with a combination of Lynch syndrome and ileal Crohn's disease presents significant therapeutic implications that are not usually present when these conditions are treated in isolation. CONCLUSION: The surgical treatment of patients with Lynch syndrome requires a sound knowledge of the possible neoplastic conditions that can arise in the syndrome. Early detection is paramount, either by implementation of evidence based surveillance programs or at least by a heightened clinical awareness of the features of this disease. Ideally this will result in both reduced surgical morbidity and improved oncologic outcome. Furthermore, the medical treatment of Crohn's disease in a patient with tumors arising from Lynch syndrome must be undertaken with at least a consideration of the possibility that the use of immunosuppressive medication might increase the risk of cancer recurrence. PMID- 25805615 TI - A rare presentation of tuberculous prostatic abscess in young patient. AB - INTRODUCTION: Genitourinary tuberculosis contributes 15-20% of extra pulmonary tuberculosis. Prostatic tuberculosis is much less common than renal, vesico seminal and epididymal TB. Predisposing factor include prior tubercular infection, immunocompromised status, previous BCG therapy. Nevertheless, isolated tuberculous prostatic abscess are uncommon especially in immunocompetent patient. PRESENTATION OF CASE: We report a case of tuberculous prostatic abscess in young, healthy immunocompetent patient, from India, who has initial presentation of pyrexia of unknown origin. All his investigation and treatment were done in India. He was diagnosed with prostatic abscess, treated with TRUS guided aspiration and antituberculous drugs. But he did not respond to the treatment and later on presented as extraprostatic extension of abscess and rectal sinus, a rare complication. MRI revealed this finding. Sigmoidoscopy was done and in same sitting we drained the abscess through perineal route. ATT was continued and he responded to treatment. DISCUSSION: Urogenital tuberculosis most frequently affects the kidneys. Ureter and bladder tuberculosis is secondary to descending infection. Prostate tuberculosis is usually asymptomatic and as an incidental prostatectomy finding. Prostatic abscess is rare but occur in AIDS patients with urogenital TB. Prostatic tuberculous cavities or abscesses may discharge into the surrounding tissues, forming sinuses or fistulae to the perineum or rectum and are demonstrated best on MRI scans. CONCLUSION: Tuberculous prostatic abscess although very uncommon in immunocompetent patient, we should have high index of suspicion in patients of PUO. Once diagnosed it should be treated with complete drainage of abscess and ATT with close follow up. PMID- 25805614 TI - Aortic dissection associated with blunt chest trauma diagnosed by elevated D dimer. AB - INTRODUCTION: Similar to spontaneous aortic dissection, traumatic aortic dissection is diagnosed with a careful history and physical exam, chest radiograph, and ultimately, dedicated aortic imaging. The diagnosis of spontaneous aortic dissection may be aided by using the serum D-dimer test. The use of D-dimer for diagnosing aortic injury in the setting of blunt trauma has not previously been reported. PRESENTATION OF CASE: We present a case of aortic dissection in a 61-year-old male diagnosed when the patient presented with chest pain after blunt chest trauma. DISCUSSION: The patient had no known history or risk factors for aortic disease. None of the classic findings were present by history, physical examination or chest radiograph and the diagnosis was made as the result of an elevated D-dimer. We discuss how the D-dimer test fortuitously led to the diagnosis in this case, and the implications. CONCLUSION: D-dimer could be helpful in diagnosing aortic injuries in low-risk chest trauma patients. PMID- 25805616 TI - Process-driven bacterial community dynamics are key to cured meat colour formation by coagulase-negative staphylococci via nitrate reductase or nitric oxide synthase activities. AB - The cured colour of European raw fermented meats is usually achieved by nitrate into-nitrite reduction by coagulase-negative staphylococci (CNS), subsequently generating nitric oxide to form the relatively stable nitrosomyoglobin pigment. The present study aimed at comparing this classical curing procedure, based on nitrate reductase activity, with a potential alternative colour formation mechanism, based on nitric oxide synthase (NOS) activity, under different acidification profiles. To this end, meat models with and without added nitrate were fermented with cultures of an acidifying strain (Lactobacillus sakei CTC 494) and either a nitrate-reducing Staphylococcus carnosus strain or a rare NOS positive CNS strain (Staphylococcus haemolyticus G110), or by relying on the background microbiota. Satisfactory colour was obtained in the models prepared with added nitrate and S. carnosus. In the presence of nitrate but absence of added CNS, however, cured colour was only obtained when L. sakei CTC 494 was also omitted. This was ascribed to the pH dependency of the emerging CNS background microbiota, selecting for nitrate-reducing Staphylococcus equorum strains at mild acidification conditions but for Staphylococcus saprophyticus strains with poor colour formation capability when the pH decrease was more rapid. This reliance of colour formation on the composition of the background microbiota was further explored by a side experiment, demonstrating the heterogeneity in nitrate reduction of a set of 88 CNS strains from different species. Finally, in all batches prepared with S. haemolyticus G110, colour generation failed as the strain was systematically outcompeted by the background microbiota, even when imposing milder acidification profiles. Thus, when aiming at colour formation through CNS metabolism, technological processing can severely interfere with the composition and functionality of the meat-associated CNS communities, for both nitrate reductase and NOS activities. Several major bottlenecks, among which the rareness of phenotypic NOS activity in meat-compatible CNS, need to be considered, which is seriously questioning the relevance of this pathway in fermented meats. PMID- 25805617 TI - Modulation of Cervical Facet Joint Nociception and Pain Attenuates Physical and Psychological Features of Chronic Whiplash: A Prospective Study. AB - OBJECTIVE: To investigate changes in clinical (physical and psychological) features of individuals with chronic whiplash-associated disorder who had previously undergone cervical radiofrequency neurotomy at the time point when the effects of radiofrequency neurotomy had dissipated and pain returned. DESIGN: Prospective cohort observational trial of consecutive patients. SETTING: Tertiary spinal intervention centre in Calgary, Alberta, Canada. PATIENTS: A total of 53 consecutive individuals with chronic whiplash-associated disorder. METHODS: Individuals underwent radiofrequency neurotomy and were assessed before radiofrequency neurotomy, at 1 and 3 months postprocedure, and then after the return of pain (approximately 10 months postprocedure). MAIN OUTCOME MEASUREMENTS: Quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test), nociceptive flexion reflex, and motor function (cervical range of movement; craniocervical flexion test) were measured. Self reported disability, psychological distress, pain catastrophization, and posttraumatic stress disorder symptoms also were measured. RESULTS: Upon the return of pain after radiofrequency neurotomy, levels of disability increased (P < .0001), and were no different to those before radiofrequency neurotomy (P = .99). There also was a significant deterioration in quantitative sensory testing measures and reduced cervical range of motion after the return of pain (all P < .05); all approaching values were recorded before radiofrequency neurotomy (P > .22). There were no significant changes in pressure hyperalgesia (P > .054) or craniocervical flexion test performance (P > .07) after the return of pain. Psychological distress and pain catastrophizing increased significantly after the return of pain (P < .01), and again were no different than measures taken prior to radiofrequency neurotomy (P > .13). However, there was no difference in number or severity of posttraumatic stress symptoms after the return of pain (P > .30). CONCLUSIONS: Physical and psychological features of chronic whiplash-associated disorder are modulated dynamically with cervical radiofrequency neurotomy. These findings indicate that peripheral nociception is involved in the manifestations of chronic whiplash-associated disorder in this cohort of individuals. PMID- 25805618 TI - Lymphocutaneous fistula. PMID- 25805619 TI - Non-invasive detection of liver fibrosis: MR imaging features vs. MR elastography. AB - PURPOSE: To compare accuracy of morphological features of liver on MRI and liver stiffness with MR elastography (MRE) for detection of significant liver fibrosis and cirrhosis. MATERIALS AND METHODS: In this retrospective study, we evaluated 62 patients who underwent liver MRI with MRE and histological confirmation of liver fibrosis within 6 months. Two radiologists, blinded to histology results, independently evaluated liver parenchyma texture, surface nodularity, signs of volumetric changes, and portal hypertension for presence of significant fibrosis and cirrhosis. Two more readers independently calculated mean liver stiffness values with MRE. Interobserver agreement was evaluated with kappa and intra-class correlation coefficient (ICC) analysis. Diagnostic accuracy was assessed with area under receiver operating characteristic (AUROC) analysis. Comparison of AUROCs of MRI and MRE was performed. RESULTS: Liver fibrosis was present in 37 patients. The interobserver agreement was poor to good (kappa = 0.12-0.74) for MRI features and excellent for MRE (ICC 0.97, 95% CI 0.95-0.98). MRI features had 48.5%-87.9% sensitivity, 55.2%-100% specificity, and 71.5%-81.6% accuracy/for detection of significant fibrosis. MRE performed better with 100% sensitivity, 96.5% specificity, and 98.9% accuracy. For the detection of cirrhosis, MRE performed better than MRI features with 88.2% sensitivity (vs. 41.2%-82.3%), 91.1% specificity (vs. 64.4%-95.6%), and 93.5% accuracy (vs. 60.6%-80.5%). Among the MRI features, surface nodularity and overall impression had the best accuracies of 80.3% and 81.6% for detection of significant fibrosis, respectively. For cirrhosis, parenchyma texture and overall impression had the best accuracies of 80.5% and 79.7%, respectively. Overall, MRE had significantly greater AUROC than MRI features for detection of both significant fibrosis (0.98.9 vs 0.71-0.82, P < 0.001) and cirrhosis (0.93.5 vs. 0.61-0.80.5, P < 0.01). CONCLUSION: MRE is superior to MRI for the non-invasive diagnosis of significant liver fibrosis and cirrhosis. PMID- 25805621 TI - The role of TIMPs in regulation of extracellular matrix proteolysis. AB - Tissue inhibitors of metalloproteinases (TIMPs), which inhibit matrix metalloproteinases (MMPs) as well as the closely related, a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs), were traditionally thought to control extracellular matrix (ECM) proteolysis through direct inhibition of MMP-dependent ECM proteolysis. This classical role for TIMPs suggests that increased TIMP levels results in ECM accumulation (or fibrosis), whereas loss of TIMPs leads to enhanced matrix proteolysis. Mice lacking TIMP family members have provided support for such a role; however, studies with these TIMP deficient mice have also demonstrated that loss of TIMPs can often be associated with an accumulation of ECM. Collectively, these studies suggest that the divergent roles of TIMPs in matrix accumulation and proteolysis, which together can be referred to as ECM turnover, are dependent on the TIMP, specific tissue, and local tissue environment (i.e. health vs. injury/disease). Ultimately, these combined factors dictate the specific metalloproteinases being regulated by a given TIMP, and it is likely the diversity of metalloproteinases and their physiological substrates that determines whether TIMPs inhibit matrix proteolysis or accumulation. In this review, we discuss the evidence for the dichotomous roles of TIMPs in ECM turnover highlighting some of the common findings between different TIMP family members. Importantly, while we now have a better understanding of the role of TIMPs in regulating ECM turnover, much remains to be determined. Data on the specific metalloproteinases inhibited by different TIMPs in vivo remains limited and must be the focus of future studies. PMID- 25805620 TI - Abrogation of both short and long forms of latent transforming growth factor-beta binding protein-1 causes defective cardiovascular development and is perinatally lethal. AB - Latent transforming growth factor-beta binding protein-1 (LTBP-1) is an extracellular protein that is structurally similar to fibrillin and has an important role in controlling transforming growth factor-beta (TGF-beta) signaling by storing the cytokine in the extracellular matrix and by being involved in the conversion of the latent growth factor to its active form. LTBP-1 is found as both short (LTBP-1S) and long (LTBP-1L) forms, which are derived through the use of separate promoters. There is controversy regarding the importance of LTBP-1L, as Ltbp1L knockout mice showed multiple cardiovascular defects but the complete null mice did not. Here, we describe a third line of Ltbp1 knockout mice generated utilizing a conditional knockout strategy that ablated expression of both L and S forms of LTBP-1. These mice show severe developmental cardiovascular abnormalities and die perinatally; thus these animals display a phenotype similar to previously reported Ltbp1L knockout mice. We reinvestigated the other "complete" knockout line and found that these mice express a splice variant of LTBP-1L and, therefore, are not complete Ltbp1 knockouts. Our results clarify the phenotypes of Ltbp1 null mice and re-emphasize the importance of LTBP-1 in vivo. PMID- 25805622 TI - Time matters and so does communication - prioritising time with patients. PMID- 25805623 TI - Infection of Siberian chipmunks (Tamias sibiricus barberi) with Borrelia sp. reveals a low reservoir competence under experimental conditions. AB - Reservoir competence is a key parameter in understanding the role of host species in the epidemiology of multi-host-especially vector-borne-pathogens. With this aim in view, we studied the reservoir competence of the Siberian chipmunk (Tamias sibiricus barberi) recently introduced into Europe, for the multi-host tick-borne bacteria, Borrelia burgdorferi sl, the agent of Lyme borreliosis. T. sibiricus were experimentally exposed to bites from Ixodes ricinus ticks infected with Borrelia burgdorferi sensu stricto and Borrelia afzelii, with subsequent assessment of bacteremia and antibody responses. Borrelia was detected in chipmunk blood samples, ear biopsies and organ necropsies, and in nymphs used for xenodiagnosis (at one and six months after the initial chipmunk infection) via both serological and molecular methods. In total, eight out of twelve chipmunks showed evidence of infection by Borrelia sp., either by ELISA or PCR. Five chipmunks developed an immune response against the bacteria one month after infection. Borrelia infection in at least one organ was observed in seven animals at 14, 38, 93 or 178 days post-infection. Xenodiagnosis was positive for one chipmunk at 38 days, but no longer at 178 days post-infection. Four chipmunks remained uninfected, despite similar infection pressures to those observed in the field. Taken together, these results suggest that chipmunks can be infected through Borrelia-infected tick bites, and can transmit Borrelia to nymphs, but do not remain persistently infected. PMID- 25805624 TI - Kilogram-scale synthesis of Pd-loaded quintuple-shelled Co3O4 microreactors and their application to ultrasensitive and ultraselective detection of methylbenzenes. AB - We report the kilogram-scale, simple, and cost-effective synthesis of Pd-loaded quintuple-shelled Co3O4 microreactors by spray drying of aqueous droplets containing cobalt nitrate, palladium nitrate, citric acid, and ethylene glycol and subsequent heat treatment. Highly viscous gel spheres containing Co and Pd salts were successfully converted into multi thin-shelled Co3O4 reactors uniformly loaded with Pd catalysts by the sequential combustion of carbon and decomposition of the metal salts from the outer to the inner regions during one step heat treatment. The responses (resistance ratio) of the Pd-loaded quintuple shelled Co3O4 microreactors to 5 ppm toluene and p-xylene were 30.8 and 64.2, respectively, and the selectivity values to toluene and p-xylene against ethanol interference (response ratio) were 14.5 and 30.1, respectively. The unprecedented high response and selectivity were attributed to the effective dissociation of less reactive methylbenzenes into more active smaller species assisted both by catalytic Co3O4 and Pd during the prolonged retention within the microreactors. Kilogram-scale preparation of noble metal-loaded multishelled microreactors and their unique gas-sensing characteristics based on a novel microreactor concept can pave a new way to design of high-performance gas sensors for practical applications. PMID- 25805626 TI - Carbon nanomaterial-based electrochemical biosensors: an overview. AB - Carbon materials on the nanoscale exhibit diverse outstanding properties, rendering them extremely suitable for the fabrication of electrochemical biosensors. Over the past two decades, advances in this area have continuously emerged. In this review, we attempt to survey the recent developments of electrochemical biosensors based on six types of carbon nanomaterials (CNs), i.e., graphene, carbon nanotubes, carbon dots, carbon nanofibers, nanodiamonds and buckminsterfullerene. For each material, representative samples are introduced to expound the different roles of the CNs in electrochemical bioanalytical strategies. In addition, remaining challenges and perspectives for future developments are also briefly discussed. PMID- 25805625 TI - Dying in a nursing home: treatable symptom burden and its link to modifiable features of work context. AB - IMPORTANCE: High-quality care at the end of life supports freedom from pain and other potentially burdensome symptoms. Lowering symptom burden at the end of life is an urgent and achievable goal in delivering services in nursing home settings. Few published reports describe symptom burden among older adults in nursing homes; none examine links between symptom burden and modifiable features of nursing home organizational context (work environment). OBJECTIVES: To examine the influence of organizational context on symptom burden and to compare symptom burden in the last year of life between nursing home residents with and without dementia. DESIGN: Retrospective analysis of longitudinal survey data. SETTING: A stratified random sample of 36 nursing homes in the Canadian provinces of Alberta, Manitoba, and Saskatchewan. PARTICIPANTS: A total of 2635 residents with dementia and 1012 without dementia; 1381 front-line care staff. MEASUREMENTS: (1) Trajectories of 6 symptoms (dyspnea, pain, pressure ulcers, urinary tract infections, challenging behavior, delirium), assessed with the Resident Assessment Instrument-Minimum Data Set, version 2.0, between 2008 and 2012. All residents received assessments in each quarter of the year before death. (2) Modifiable organizational context, assessed with the Alberta Context Tool. Hierarchical mixed model, repeated measures regression, to simultaneously evaluate effects of time, dementia, and context on symptom trajectories. RESULTS: For all residents, prevalence of symptoms increased over time. In the last quarter before death, challenging behavior was the most frequent symptom in the dementia group (40.2%), delirium the most frequent symptom in the nondementia group (31.0%), and urinary tract infections least frequent (9.0% to 10.0%). Facilities with more favorable context had significantly higher prevalence of challenging behavior and delirium and significantly lower use of antipsychotics without diagnosis of psychosis. CONCLUSION: Symptom burden increases as the end of life approaches but differs between high- and low-context facilities and between residents with and without dementia. Trajectories of treatable, burdensome symptoms at the end of life in nursing homes should be a priority focus for quality improvement. Modifiable features of organizational context that are linked to symptom burden offer new potential strategies and interventions for quality improvement. PMID- 25805628 TI - Imagery Rescripting for Obsessive Compulsive Disorder: A single case experimental design in 12 cases. AB - BACKGROUND AND OBJECTIVES: Some individuals with Obsessive Compulsive Disorder (OCD) may experience recurrent intrusive distressing images, which may be emotionally linked to past aversive memories. Our aim was to investigate whether Imagery Rescripting was an effective intervention for such individuals with OCD. METHOD: Twelve cases who experienced intrusive distressing images are presented in a A1BA2CA3 single case experimental design. After a baseline of symptom monitoring (A1), participants had a control intervention of talking about the memory related image (B), followed by symptom monitoring (A2), a single session of Imagery Rescripting (C) and further monitoring for up to 3 months (A3). RESULTS: Minimal change was seen following the control intervention. However, at 3 months following ImRs, there was a drop in the Yale-Brown Obsessive Compulsive Scale, with a decrease from a mean of 24.1 to 10.7. Reliable improvement was achieved in 9 out of the 12 cases and clinically significant change in 7 out of 12 at 3-month follow up. The limitations are that all cases were selected on the basis that they had an aversive memory linked to their imagery. CONCLUSIONS: Imagery Rescripting is a promising therapeutic technique for OCD as an adjunct to CBT where intrusive images are linked to aversive memories. PMID- 25805627 TI - The inflammasome accelerates radiation-induced lung inflammation and fibrosis in mice. AB - Although lung inflammation and fibrosis are well-documented dose-limiting side effects of lung irradiation, the mechanisms underlying these pathologies are unknown. An improved mechanistic understanding of radiation-induced pneumonitis is a prerequisite for the development of more effective radiotherapy; this was the rationale for the current study. Mouse lungs were focally irradiated with 75 Gy. The numbers of neutrophils, lymphocytes, macrophages, and total cells in the bronchoalveolar lavage fluid were counted, and pro-inflammatory cytokine levels were measured. Histological analysis and immunohistochemical staining for Tgf beta1 and Cd68 (a macrophage-specific protein) was also performed. After irradiation, mice developed pneumonitis, and exhibited higher numbers of neutrophils, lymphocytes, eosinophils, macrophages, and total cells compared to controls. In addition, inflammasome (Nlrp3, and caspase 1, Il1a, and Il1beta), adhesion molecule (Vcam1), and cytokine (Il6) genes were significantly upregulated in the IR group. Cd68 and Tgfb1 proteins were significantly increased after irradiation. Upregulation of Cd68 and Tgfb1 correlates with the onset of radiation-induced pneumonitis and fibrosis. In addition, radiation-induced pneumonitis and fibrosis are accompanied by upregulation of phenotypic markers of inflammasome activity. Our findings have implications for the onset and exacerbation of damage in normal lung tissue. PMID- 25805630 TI - Actinomadura syzygii sp. nov., an endophytic actinomycete isolated from the roots of a jambolan plum tree (Syzygium cumini L. Skeels). AB - The taxonomic position of an endophytic actinomycete, strain GKU 157T, isolated from the roots of a jambolan plum tree (Syzygium cumini L. Skeels) collected at Khao Khitchakut National Park, Chantaburi province, Thailand, was determined using a polyphasic taxonomic approach. 16S rRNA gene sequence analysis revealed that strain GKU 157T belongs to the genus Actinomadura and formed a distinct phyletic line with Actinomadura chibensis NBRC 106107T (98.6 % similarity). Strain GKU 157T formed an extensively branched, non-fragmenting substrate mycelium and aerial hyphae that differentiated into hooked to short spiral chains of about 20 non-motile spores with a warty surface. The cell wall contained meso diaminopimelic acid and the whole-cell sugars were galactose, glucose, madurose, mannose and ribose. The N-acyl type of muramic acid was acetyl. Mycolic acids were absent. The phospholipids included phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylinositol (PI), phosphatidylinositolmannoside (PIM) and two unknown phospholipids (PLs). The major menaquinone was MK-9(H6) and the predominant fatty acids were C16:0, iso C16:0, C18:1omega9c, C18:0 and 10-methyl C18:0 (tuberculostearic acid). The genomic DNA G+C content was 73.1 mol%. A combination of DNA-DNA hybridization results and significant differences from related species in cultural, physiological and chemical characteristics indicated that strain GKU 157T represents a novel species of the genus Actinomadura, for which the name Actinomadura syzygii sp. nov. is proposed. The type strain is GKU 157T ( = BCC 70456T = NBRC 110399T). PMID- 25805632 TI - A needle with sand-blasted steel at the tip of the bevel is valid for ultrasound guided deep nerve block. PMID- 25805629 TI - Cytosine derivatized bis(2,2'-bithienyl)methane molecularly imprinted polymer for selective recognition of 6-thioguanine, an antitumor drug. AB - A molecularly imprinted polymer (MIP) was designed and synthesized to serve as a functional material for selective recognition of 6-thioguanine (6TG), an antitumor drug. For that, the newly synthesized functional monomer, cytosine bis(2,2'-bithienyl)-(4-carboxyphenyl)methane ester (Cyt-S4), revealed Watson Crick type nucleobase pairing of 6TG. Formation of the Cyt-S4 and 6TG complex of the 2:1 stoichiometry was postulated based on the DFT calculations at the B3LYP/3 21G((*)) level and experimentally confirmed by fluorescence titration. The molecularly imprinted polymer (MIP) film was deposited by potentiodynamic electropolymerization on a Pt disk electrode as well as on an Au-coated glass slide and on an Au-quartz crystal resonator. The statistical model of formation of this film was successfully simulated by molecular dynamics. Completeness of the subsequent 6TG template extraction from MIP was confirmed by the UV-visible spectroscopy. An imprinting factor of 2.9 for the MIP film was determined by piezoelectric microgravimetry using ECQM. The double-layer capacity and alternating current measurements under flow-injection analysis (FIA) conditions were selected to transduce the 6TG recognition signal into the change of the double-layer capacity dependence on the 6TG concentration in solution for different supporting electrolyte concentrations. Detectability of the resulting chemosensor was 10 uM 6TG for the 0.5 M KF carrier solution in FIA. Selectivity of the chemosensor with respect to common interferences was high, e.g., it exceeded 130 to 2-amino-6-methylmercaptopurine, a 6TG metabolite. PMID- 25805633 TI - Illustration of O2 and CO2 recirculation to interpret respiratory and circulatory physiology. PMID- 25805634 TI - Successful use of size 0.5 air-Q in a low birth weight neonate. PMID- 25805631 TI - Nocardioides echinoideorum sp. nov., isolated from sea urchins (Tripneustes gratilla). AB - A Gram-stain-positive, aerobic, non-motile, rod-shaped, yellow-pigment-producing bacterium, (designated strain CC-CZW004T), was isolated from seafood samples (sea urchins) at Penghu Island in Taiwan. Strain CC-CZW004T grew optimally at pH 7.0 and 30 degrees C in the presence of 3 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA genes revealed a distinct taxonomic position attained by strain CC CZW004T with respect to other members of the genus Nocardioides. The novel strain shared highest 16S rRNA gene sequence similarities to Nocardioides daejeonensis JCM 16922T (96.4 %), Nocardioides pacificus JCM 19260T (96.3 %), and Marmoricola scoriae JCM 17444T (96.2 %). The major fatty acids of strain CC-CZW004T consisted of C17:0, C16:1omega5c, C17:1omega8c', iso-C16:0 and C19:1omega11c/C19:1omega9c (summed feature 6). The diagnostic diamino acid in the cell wall was ll-2,6 diaminopimelic acid. The polar lipid profile was composed of major amounts of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and aminophospholipid. The DNA G+C content was 73.3 mol%. The predominant quinone system was menaquinone (MK-8). On the basis of polyphasic taxonomic evidences presented here, strain CC-CZW004T represents a novel species of the genus Nocardioides, for which the name Nocardioides echinoideorum sp. nov. is proposed. The type strain is CC-CZW004T ( = BCRC 16974T = JCM 30276T). PMID- 25805635 TI - A patient-controlled analgesia device equipped with 2 flow controllers is effective for bilateral trunk nerve blocks. PMID- 25805636 TI - Is There a Need for Performance Measures for Cochlear Implant Centers? AB - Performance measures (PMs), or quality indicators, are metrics based on objective data that allow one to assess whether a system achieves a prespecified goal. Given the relatively high level of resource utilization and potential morbidity associated with cochlear implantation (CI), PMs could be used to evaluate quality of care provided by implant centers and, ultimately, optimize care delivery. This article discusses PMs currently in use, how PMs are developed, potential downsides of using PMs, and various examples of PMs that could be used in CI centers. PMID- 25805637 TI - Quality in otolaryngology: where we have been and where we are going. AB - The patient safety and quality improvement era began in 1999, and it has exploded in otolaryngology in the last decade. Although there have been some successes, it is not clear that, overall, otolaryngology is much safer than 15 years ago. We discuss why a prolonged lag between improvement efforts and improvements is not surprising and how the safety and quality movement is likely to evolve in the upcoming years. PMID- 25805638 TI - Multimodality management of high-risk head and neck basal cell carcinoma requiring free-flap reconstruction. AB - OBJECTIVES: (1) Investigate overall survival (OS) and disease-free survival (DFS) for high-risk head and neck basal cell carcinoma (HNBCC) requiring large extirpation with free-flap reconstruction. (2) Determine impact of prognostic features-tumor size, subsite, number of high-risk features, perineural invasion, and bony invasion-on high-risk HNBCC survival. (3) Determine survival benefit of adjuvant radiation for high-risk HNBCC. STUDY DESIGN: Case series with chart review (2002-2013). SETTING: Academic tertiary care center. SUBJECTS AND METHODS: Consecutive head and neck patients (N = 431) required free-flap reconstruction following tumor extirpation, 38 for aggressive HNBCC. All cases were high risk. DFS and OS were examined using Kaplan-Meier analysis. Prognostic variables and adjuvant radiation were analyzed utilizing Student's t test for continuous variables and Fisher's exact testing for categorical dependent variables. Complications were reported. RESULTS: Mean tumor diameter was 5.17 cm (range, 1.2 15.0 cm). Mean follow-up was 19.9 months. Overall 2-year survival was 80%, falling to 66% at 5 years. Two-year disease-free survival was 72%. Six patients recurred (n = 5 local, 1 distant). Adjuvant radiotherapy improved DFS (P < .01) but not OS (P = .66). Tumors >2.5 cm did not affect OS (P = .61), regardless of subsite. Bone involvement (44.7% cases) did not affect DFS (P = .39) or OS (P = .18). CONCLUSIONS: Larger HNBCC warranting free tissue transfer do not confer worse outcomes, independent of subsite. Adjuvant radiotherapy does not improve OS but significantly affected DFS, allowing for 13.7 additional months of DFS. Bone involvement does not influence DFS or OS and should not preclude surgery, even in advanced cases requiring free-flap reconstruction. PMID- 25805639 TI - Anterior-commissure laryngoscope extraction of esophageal coins in children using an apnea technique. AB - This is a case series with chart review of 59 consecutive pediatric patients with a diagnosis of cervical esophageal coin who underwent anterior-commissure laryngoscope (ACLA) extraction during apnea. The purpose of this study was (1) to evaluate the efficacy and safety of coin extraction and (2) to analyze foreign body features and intraoperative physiological parameters (apnea time, O2 saturation and end-tidal CO2 (ETCO2) of apnea, minimum O2 during procedure, and heart rate). The technique was completed in 94.9% of the sample. The mean of the length of apnea was 57.7 +/- 25.2 seconds. The median minimum O2 saturation was 99.5% (minimum = 93, maximum = 100), and the median of the ETCO2 at the end of the procedure was 35.7 +/- 4.8 mm Hg. Heart rates remained at baseline values during the procedure (P < .001). This technique represents an efficient and secure modality for treatment. If successful, the patient can be safely discharged after clearance from anesthesia and a swallowing trial. PMID- 25805640 TI - Metabolic Syndrome Increases the Risk of Sudden Sensorineural Hearing Loss in Taiwan: A Case-Control Study. AB - OBJECTIVE: Sudden sensorineural hearing loss has been reported to be associated with diabetes mellitus, hypertension, and hyperlipidemia in previous studies. The aim of this study was to examine whether metabolic syndrome increases the risk of sudden sensorineural hearing loss in Taiwan. STUDY DESIGN: A case-control study. SETTING: Tertiary university hospital. SUBJECTS AND METHODS: We retrospectively investigated 181 cases of sudden sensorineural hearing loss and 181 controls from the Department of Otorhinolaryngology, Kaohsiung Medical University Hospital, in southern Taiwan from 2010 to 2012, comparing their clinical variables. We analyzed the relationship between metabolic syndrome and sudden sensorineural hearing loss. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III with Asian modifications. The demographic and clinical characteristics, audiometry results, and outcome were reviewed. RESULTS: Subjects with metabolic syndrome had a 3.54-fold increased risk (95% confidence interval [CI] = 2.00-6.43, P < .01) of having sudden sensorineural hearing loss compared with those without metabolic syndrome, after adjusting for age, sex, smoking, diabetes mellitus, hypertension, and hyperlipidemia. With increases in the number of metabolic syndrome components, the risk of sudden sensorineural hearing loss increased (P for trend <.01). Vertigo was associated with a poor outcome (P = .02; 95% CI = 1.13~5.13, adjusted odds ratio = 2.39). The hearing loss pattern may influence the outcome of sudden sensorineural hearing loss (P < .01). CONCLUSION: These results suggest that metabolic syndrome is an independent risk factor for sudden sensorineural hearing loss in Taiwan. Vertigo and total hearing loss were indicators of a poor outcome in sudden sensorineural hearing loss. PMID- 25805641 TI - Safety and postoperative adverse events in pediatric otologic surgery: analysis of American College of Surgeons NSQIP-P 30-Day outcomes. AB - OBJECTIVES: Describe safety and postoperative sequelae of pediatric otologic surgery and identify predictive factors for postoperative events. STUDY DESIGN: Retrospective cohort study of the American College of Surgeons National Surgery Quality Improvement Program-Pediatric (NSQIP-P) database. SETTING: Data pooled from the 2012 NSQIP-P public use file (50 institutions). SUBJECTS AND METHODS: Current procedural terminology codes were used to identify children who underwent otologic surgery. Variables of interest included demographics and 30-day postoperative events grouped as reoperation, readmission, and complication. Event rates were determined and prevalence of events compared by procedure type and within patient subgroups according to chi-square analysis. Multivariate logistic regression evaluated predictive factors for postoperative events. RESULTS: Of 37,319 pediatric operations, 2556 (6.8%) were otologic procedures. The most common procedure was tympanoplasty (n = 893, 34.9%), followed by myringoplasty (n = 741, 30.0%), cochlear implantation (n = 464, 18.2%), and tympanomastoidectomy (n = 458, 17.9%). There were 9 reoperations (0.4%), 32 readmissions (1.3%), and 18 complications (0.7%). Children undergoing tympanomastoidectomy or cochlear implantation were more likely to be readmitted irrespective of other factors (odds ratio = 5.5, P = .010; odds ratio = 3.5, P = .083). Children <3 years old were 4 times more likely to be readmitted than older children (odds ratio = 4.4, P < .001). CONCLUSION: Pediatric otologic procedures are common and have low rates of global 30-day postoperative events. Tympanomastoidectomy and cochlear implantation have the highest risk of 30-day readmission. Young children (<3 years) are more likely to be readmitted following these procedures. Further optimization of the NSQIP-P to include specialty and procedure-specific variables is necessary to assess complete, actionable outcomes of pediatric otologic surgery, however the present study provides a foundation to build upon for safety and quality improvement initiatives in pediatric otology. PMID- 25805642 TI - Management of First Branchial Cleft Anomalies via a Cartilage-Splitting Technique. AB - First branchial cleft anomalies are uncommon lesions that often present as periauricular infections. They have high recurrence rates, due in part to scarring secondary to prior infections and their management. These lesions have a close relationship with the facial nerve, and most authors recommend its identification and dissection because of this relationship. Nonetheless, facial nerve palsy has been reported in up to 15% of cases. We describe a novel technique for the management of first branchial cleft anomalies. Such lesions that presented in an infra- or postauricular location were approached via an incision through the cartilage of the pinna, between the tragus and antitragus. This technique affords direct access to the lesion without the need for facial nerve dissection. Six patients were treated. Five had prior surgery, including 3 with previous attempts at excision. There were no complications. The median follow-up was 35 months. One patient developed a recurrence. PMID- 25805643 TI - Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. AB - Thal amyloid phase, which describes the pattern of progressive amyloid-beta plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-epsilon4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-epsilon4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2. PMID- 25805646 TI - Policies allowing family presence during resuscitation and patterns of care during in-hospital cardiac arrest. AB - BACKGROUND: A growing number of hospitals have begun to implement policies allowing for family presence during resuscitation (FPDR). However, the overall safety of these policies and their effect on resuscitation care is unknown. METHODS AND RESULTS: We conducted an observational cohort study of 252 hospitals in the United States with 41,568 adults with cardiac arrest. Multivariable hierarchical regression models were used to evaluate patterns of care at hospitals with and without an FPDR policy. Primary outcomes included return of spontaneous circulation and survival to discharge. Secondary outcomes included resuscitation quality, interventions, and facility-reported potential resuscitation systems errors. There were no significant differences in facility characteristics between hospitals with and without an FPDR policy, nor were there significant differences in return of spontaneous circulation (adjusted risk ratio, 1.02; 95% confidence interval, 0.95-1.06) or survival to discharge (adjusted risk ratio, 1.05; 95% confidence interval, 0.95-1.15). There was a small, borderline significant decrease in the mean time to defibrillation at hospitals with an FPDR policy compared with hospitals without the policy (mean difference, 0.32 minutes; 95% confidence interval, -0.01 to 0.64). Resuscitation quality, interventions, and facility-reported potential resuscitation systems errors did not meaningfully differ between hospitals with and without an FPDR policy. CONCLUSIONS: Hospitals with an FPDR policy generally have no statistically significant differences in outcomes and processes of care as hospitals without this policy, suggesting such policies may not negatively affect resuscitation care. Further study is warranted about the direct effect of FPDR attempts on adult patients with an in-hospital cardiac arrest and their families. PMID- 25805645 TI - Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease. AB - After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders. PMID- 25805648 TI - miR-146a-5p Antagonized AGEs- and P.g-LPS-Induced ABCA1 and ABCG1 Dysregulation in Macrophages via IRAK-1 Downregulation. AB - The miR-146-mediated IL-1 receptor-associated kinase 1 (IRAK-1) feedback circuit has been shown to inhibit inflammatory response in macrophages against lipopolysaccharide (LPS). The aim of this study is to compare the antagonized effects of miR-146a-5p on Porphyromonas gingivalis (P.g) lipolysaccharide (LPS)- and advanced glycation end products (AGEs)-triggered ABCA1 and ABCG1 dysregulation and explore the underlying mechanism. THP-1-derived macrophages transfected with miRNA mimics or not were treated with P.g LPS or AGE-BSA, respectively. The mechanism of endotoxin tolerance was mimicked. miR-146a-5p levels and protein levels of IRAK-1, LXRalpha/beta, ABCA1, and ABCG1 were detected by stem-loop reverse transcription followed by TaqMan PCR analysis and Western blotting. Our results showed that miR-146a-5p levels were significantly increased in macrophages after 24 h of stimulation with high dose of P.g LPS or AGE-BSA. Macrophages transfected with miR-146a-5p mimics attenuated the dysregulation of ABCA1/G1 induced by P.g LPS and AGEs through IRAK-1 downregulation. In low-dose LPS-tolerized cells, elevated miR-146a-5p antagonized the increase of ABCA1, ABCG1, and IRAK-1. However, low-dose AGE-BSA did not increase miR-146a-5p levels. In conclusion, the model of endotoxin tolerance is suitable for the antagonistic effects on the dysregulation of ABCA1/G1 induced by high dose of P.g LPS. Conversely, low-dose AGEs did not induce the model of P.g LPS-mediated tolerance. PMID- 25805644 TI - Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. AB - In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFkappaB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown. PMID- 25805649 TI - Identification of predictors of response to basal insulin and DPP4 inhibitors in patients with type 2 diabetes failing to other therapies. AB - AIM: Basal insulin and DPP4 inhibitors are both possible options in patients with type 2 diabetes failing to oral drugs. The identification of clinical predictors of success with either one of the two approaches could be of help in personalizing therapy. METHODS: The retrospective study was performed on a consecutive series of patients with type 2 diabetes (n = 1,002) failing to at least one oral agent, who had been prescribed either basal insulin or DPP4 inhibitors in the previous 2 years, with a duration of follow-up of at least 6 months. Clinical predictors of success after 6 months from the beginning of second-line treatment were identified in the cohort. RESULTS: Among patients receiving a prescription of basal insulin, the proportion of therapeutic success at 6 months was 26.5 %. At multivariate analysis, a higher age and BMI, and a lower duration of diabetes were associated with success, as well as treatment with acarbose; conversely, a history of ischemic heart disease was associated with failure. Prescription of DPP4 inhibitors produced a therapeutic success in 24.8 % of cases. At multivariate analysis, success was associated with a lower baseline HbA1c and duration of diabetes, and a higher BMI and comorbidity; in addition, a lower success rate was found in women after adjusting for other confounders. CONCLUSIONS: The present data support the view that insulin treatment is preferable in patients with severe hyperglycemia, failing to one or more drugs, whereas DPP4 inhibitors appear to be more useful in those with comorbid conditions. PMID- 25805650 TI - Nest and food search behaviour in desert ants, Cataglyphis: a critical comparison. AB - North African desert ants, Cataglyphis, use path integration to calculate a home vector during their foraging trips, constantly informing them about their position relative to the nest. This home vector is also used to find the way back to a productive feeding site the ant has encountered and thus memorized. When the animal fails to arrive at its goal after having run off the home or food vector, a systematic search is initiated. The basic search strategies are identical for nest and food searches, consisting of a search spiral superimposed by a random walk. While nest searches have been investigated in much detail, food site searches have received comparatively little attention. Here, we quantify and compare nest and food site searches recorded under similar conditions, particularly constant nest-feeder distance, and we observe notable differences in nest and food search performances. The parameters of nest searches are relatively constant and improve little with experience, although those small improvements had not been recognized previously. Food searches, by contrast, are more flexible and cover smaller or larger areas, mainly depending on the reliability of food encounter over several visits. Intriguingly, food site searches may be significantly more focussed than nest searches, although the nest should be the most important goal in an ant's life. These results demonstrate both adaptability and high accuracy of the ants' search programme. PMID- 25805651 TI - Does target animacy influence manual laterality of monkeys? First answer from northern pig-tailed macaques (Macaca leonina). AB - The evolutionary origin of human right-handedness remains unclear. Many factors such as emotion and tool use have been implicated in primate handedness evolution. With regard to emotional lateralization, most related research focuses on facial asymmetry and behavioral laterality under the non-social context, whereas few studies investigate social laterality. This study, for the first time, investigates the effect of target animacy on hand preference in Old World monkeys, compares our findings with previous related studies in great apes and humans, and aids in filling the knowledge gap on primate handedness evolution. Nine captive northern pig-tailed macaques (Macaca leonina) were chosen as focal subjects in this study. There was no group-level handedness for both animate and inanimate targets. No significant interaction was found between lateral hand use and target animacy. Left-hand use was more frequent than right-hand use for animate targets, whereas right-hand use was more frequent than left-hand use for inanimate targets, both of which demonstrate no significant level. On the whole, northern pig-tailed macaques showed a similar tendency as that in great apes and humans. Regarding handedness linked with emotive stimuli, it is likely that Old World monkeys, great apes and humans evolved from a common ancestor. PMID- 25805647 TI - Cluster-randomized trial of a physician/pharmacist collaborative model to improve blood pressure control. AB - BACKGROUND: The purpose of this study was to evaluate if a physician/pharmacist collaborative model would be implemented as determined by improved blood pressure (BP) control in primary care medical offices with diverse geographic and patient characteristics and whether long-term BP control could be sustained. METHODS AND RESULTS: Prospective, cluster-randomized trial of 32 primary care offices stratified and randomized to control, 9-month intervention (brief), and 24-month intervention (sustained). We enrolled 625 subjects with uncontrolled hypertension; 54% from racial/ethnic minority groups and 50% with diabetes mellitus or chronic kidney disease. The primary outcome of BP control at 9 months was 43% in intervention offices (n=401) compared with 34% in the control group (n=224; adjusted odds ratio, 1.57 [95% confidence interval, 0.99-2.50]; P=0.059). The adjusted difference in mean systolic/diastolic BP between the intervention and control groups for all subjects at 9 months was -6.1/-2.9 mm Hg (P=0.002 and P=0.005, respectively), and it was -6.4/-2.9 mm Hg (P=0.009 and P=0.044, respectively) in subjects from racial or ethnic minorities. BP control and mean BP were significantly improved in subjects from racial minorities in intervention offices at 18 and 24 months (P=0.048 to P<0.001) compared with the control group. CONCLUSIONS: Although the results of the primary outcome (BP control) were negative, the key secondary end point (mean BP) was significantly improved in the intervention group. Thus, the findings for secondary end points suggest that team based care using clinical pharmacists was implemented in diverse primary care offices and BP was reduced in subjects from racial minority groups. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00935077. PMID- 25805652 TI - Predicting student nurse success: A behavioural science approach. PMID- 25805653 TI - Ten recent advances that could not have come about without applying physiology. PMID- 25805654 TI - Bioengineering mini functional thymic units with EAK16-II/EAKIIH6 self-assembling hydrogel. AB - Herein, we highlight the technical feasibility of generating a functional mini thymus with a novel hydrogel system, based on a peptide-based self-assembly platform that can induce the formation of 3-D thymic epithelial cell (TEC) clusters. Amphiphilic peptide EAK16-II co-assembled with its histidinylated analogue EAKIIH6 into beta-sheet fibrils. When adaptor complexes (recombinant protein A/G molecules loaded with both anti-His and anti-EpCAM IgGs) were added to the mix, TECs were tethered to the hydrogel and formed 3-D mini clusters. TECs bound to the hydrogel composites retained their molecular properties; and when transplanted into athymic nude mice, they supported the development of functional T-cells. These mini thymic units of TECs can be useful in clinical applications to reconstitute T-cell adaptive immunity. PMID- 25805655 TI - Silent brain infarcts in two patients with zeta chain-associated protein 70 kDa (ZAP70) deficiency. AB - Zeta-chain associated protein 70 kDa deficiency (ZAP70) is a form of severe combined immunodeficiency (SCID). It is caused by defects in the signaling pathways associated with T-lymphocyte activation. ZAP70 deficiency is characterized by a marked reduction in peripheral CD8+ T-cells. In this report, we described two patients with ZAP70 deficiency who presented with recurrent infections, lung tuberculosis (TBC), congenital nephrotic syndrome (CNS), and silent brain infarcts (SBIs) as a common feature. The first patient initially presented with recurrent infections and TBC as in a classic SCID patient. At the age of 4, he was interned with febrile seizure. Cranial magnetic resonance imaging (MRI) showed SBIs. The second patient, an 8-month-old boy, presented with congenital nephrotic syndrome caused by cytomegalovirus (CMV) and he had also SBIs. PMID- 25805656 TI - Similar percentages in most abundant chronic granulomatous disease autosomal recessive forms in a Spanish cohort. PMID- 25805657 TI - Risk factors for multiple sclerosis and associations with anti-EBV antibody titers. AB - Multiple sclerosis (MS) is an inflammatory demyelination of the central nervous system. We investigated the prevalence of EBV seropositivity and other known risk factors for MS (age, smoking, low vitamin D) and their effect on anti-EBV antibody titers. We retrospectively studied 249 MS patients receiving care at the American University of Beirut Medical Center and 230 controls, during 2010-2014. EBV seropositivity was higher in MS patients compared to controls for both anti VCA (99.5%; 97.2%) and anti-EBNA-1 (96.3%; 89.4%), and the titers were significantly higher in MS patients. MS patients had a significantly lower vitamin D level (15.5 +/- 8.3 ng/ml) compared to controls (20.4 +/- 11.3 ng/ml). The proportion of heavy smokers and overweight individuals was significantly higher in MS patients. Lebanese MS patients have risk factors similar to those in western countries. Older age and female gender were associated with a higher anti VCA titer and male gender with a higher anti-EBNA-1. PMID- 25805658 TI - Gastrointestinal immunity against tryptophan hydroxylase-1, aromatic L-amino-acid decarboxylase, AIE-75, villin and Paneth cells in APECED. AB - Gastrointestinal dysfunction is a disabling manifestation of APECED possibly related to an autoimmune intestinal aggression. We evaluated its features in a cohort of 31 Finnish patients. The most frequent manifestations were constipation (48%), diarrhea, dysphagia and retrosternal pain (45%). AADC and TPH-1 autoantibodies were detected in 51% and 45% of the patients, respectively. Forty three percent displayed a T-cell response to AADC. One third of the patients also had AIE-75 (33%) and villin (29%)-specific autoantibodies while antibodies against brush borders and Paneth cells were detected in 29% and 20%, respectively. Intestinal IL-17 expression was absent/decreased in 77% of the cases. Duodenal CgA and serotonin expression was absent/decreased in 50% and 66% of the patients, respectively. Constipation correlated with lacking serotonin expression and AADC antibodies (p < 0.05). PMID- 25805660 TI - Predictors of adherence in a prevention program for patients with metabolic syndrome. AB - The study objectives were (1) comparison of baseline characteristics between individuals with metabolic syndrome, adhering/not adhering to a primary prevention program modificacao do estilo de vida e risco cardiovascular; and (2) determination of risk factors for program adherence. The sample included 127 participants with mean age (+/-standard deviation) of 49.58 (+/-7.77) years, participating in the modificacao do estilo de vida e risco cardiovascular between 2010 and 2012. Results show that program adherence predictors were age (odds ratio: 1.134, 95% confidence interval: 1.106-1.833); practicing physical exercise (odds ratio: 1.322, 95% confidence interval: 1.115-7.589); self-efficacy for regular eating habits (odds ratio: 2.044, 95% confidence interval: 1.184-3.377); low binge eating scores (odds ratio: 1.922, 95% confidence interval: 1.118 3.974); and low isolation and depression scores (odds ratio: 0.721, 95% confidence interval: 0.322-0.917). PMID- 25805665 TI - Hierarchically biomimetic scaffold of a collagen-mesoporous bioactive glass nanofiber composite for bone tissue engineering. AB - Mesoporous bioactive glass nanofibers (MBGNFs) were prepared by a sol gel/electrospinning technique. Subsequently, a collagen-MBGNF (CM) composite scaffold that simultaneously possessed a macroporous structure and collagen nanofibers was fabricated by a gelation and freeze-drying process. Additionally, immersing the CM scaffold in a simulated body fluid resulted in the formation of bone-like apatite minerals on the surface. The CM scaffold provided a suitable environment for attachment to the cytoskeleton. Based on the measured alkaline phosphatase activity and protein expression levels of osteocalcin and bone sialoprotein, the CM scaffold promoted the differentiation and mineralization of MG63 osteoblast-like cells. In addition, the bone regeneration ability of the CM scaffold was examined using a rat calvarial defect model in vivo. The results revealed that CM is biodegradable and could promote bone regeneration. Therefore, a CM composite scaffold is a potential bone graft for bone tissue engineering applications. PMID- 25805667 TI - Comparative difficulty and the strategic regulation of accuracy: the impact of test-list context on monitoring and meta-metacognition. AB - A growing body of research has shown that context manipulations can have little or no impact on accuracy performance, yet still significantly influence metacognitive performance. For example, participants in a test-list context paradigm study one list of words with a medium levels-of-processing task and a second word list with either a shallow or deep task: Recognition for medium words does not differ across conditions, however medium words are significantly more likely to be labeled as "remembered" (vs. merely familiar) if they had been studied with a shallow word list (Bodner & Lindsay, 2003). The goal of the current studies was to extend the test-list context paradigm to strategic regulation (report/withhold recognition test), and broaden it to incorporate different types of stimuli (i.e., face stimuli in place of a medium word list). The paradigm also was modified to include separate answer (studied/new) confidence and decision (report/withhold) confidence ratings at test. Results showed that context did not impact recognition accuracy for faces across the context conditions, however participants were more likely to report (i.e., volunteer) their face responses if they had studied the shallow word list. The results also demonstrated a difference between answer confidence and decision confidence, and the pattern of this difference depended on whether responses were reported or withheld (Experiment 1). Overall, the data are presented as support for the functional account of memory, which views memory states as inferential and attributional rather than static categories. PMID- 25805666 TI - Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease. AB - Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results in animal models. PMID- 25805659 TI - Cellular and molecular targeting for nanotherapeutics in transplantation tolerance. AB - The induction of donor-specific tolerance to transplanted cells and organs, while preserving immune function as a whole, remains a highly sought after and elusive strategy for overcoming transplant rejection. Tolerance necessitates modulating a diverse array of cell types that recognize and respond to alloantigens, including antigen presenting cells and T lymphocytes. Nanotherapeutic strategies that employ cellular and biomaterial engineering represent an emerging technology geared towards the goal of inducing transplant tolerance. Nanocarriers offer a platform for delivering antigens of interest to specific cell types in order to achieve tolerogenic antigen presentation. Furthermore, the technologies also provide an opportunity for local immunomodulation at the graft site. Nanocarriers delivering a combination of antigens and immunomodulating agents, such as rapamycin, provide a unique technology platform with the potential to enhance outcomes for the induction of transplant tolerance. PMID- 25805669 TI - Iron-refractory iron deficiency anemia. AB - Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the "atypical" microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field. PMID- 25805668 TI - Contingent vouchers and motivational interviewing for cigarette smokers in residential substance abuse treatment. AB - Residential drug treatment provides an opportunity to intervene with smokers with substance use disorders (SUD). A randomized controlled clinical trial compared: (1) contingent vouchers (CV) for smoking abstinence to noncontingent vouchers (NCV), crossed with (2) motivational interviewing (MI) or brief advice (BA), for 184 smokers in SUD treatment. During the voucher period, 36% of carbon monoxide readings indicated smoking abstinence for those receiving CV versus 13% with NCV (p < .001). Post-treatment (3-9 months) point-prevalence abstinence rates were low (3-4% at each follow up), with more abstinence when CV was combined with MI (6.6% on average) than with BA (0% on average). No differential effects on drug use or motivation to quit smoking occurred. Thus, CV had limited effects on long term smoking abstinence in this population but effects were improved when CV was combined with MI. More effective methods are needed to increase motivation to quit smoking and quit rates in this high-risk population. PMID- 25805671 TI - Are the high serum interleukin-6 and vascular endothelial growth factor levels useful prognostic markers in aggressive non-hodgkin lymphoma patients? AB - OBJECTIVE: Pro-inflammatory and pro-angiogenic cytokines play an important role in the pathogenesis of lymphoma, and recent studies have shown that cytokines can be used as prognostic markers. Non-Hodgkin lymphoma (NHL) patients with high levels of serum interleukin-6 (s-IL6) and serum vascular endothelial growth factor (s-VEGF) have poor prognosis and shorter survival time. We aimed to determine pre-treatment levels of s-IL6 and s-VEGF and their relation with known prognostic markers, especially International Prognostic Index (IPI) scores, and to examine their effects on overall survival in newly diagnosed, untreated aggressive NHL patients. MATERIALS AND METHODS: The study included 51 newly diagnosed NHL patients and 17 healthy controls. Blood samples were obtained to study s-IL6 and s-VEGF cytokine levels. RESULTS: Patients with aggressive NHL diagnosis had higher s-VEGF and s-IL6 levels than the healthy population. If the s-IL6 levels of patients were above the cut-off levels, the overall survival time was shorter. There was no relation between s-VEGF and overall survival time. CONCLUSION: s-IL6 is an independent prognostic factor that may be included in IPI risk classification. In addition to the s-IL6 level, age, erythrocyte sedimentation rate, beta-2 microglobulin, WHO performance status, and IPI score are independent prognostic factors that are effective, especially for overall survival, in the clinical follow-up of NHL patients. PMID- 25805670 TI - Prognostic significance of lymphoid enhancer-binding factor-1 expression in egyptian adult B-acute lymphocytic leukemia patients. AB - OBJECTIVE: Lymphoid enhancer-binding factor-1 (LEF-1) is a key transcription factor of wingless-type (Wnt) signaling in various tumors and it is associated with a number of malignant diseases such as leukemia. We explored the expression profile of LEF-1 in acute lymphoblastic leukemia (ALL) and determined its specific prognostic significance in this disease. MATERIALS AND METHODS: We studied LEF-1 expression in 56 newly diagnosed B-acute ALL adult patients using real-time quantitative polymerase chain reaction to investigate whether LEF-1 expression was associated with clinical patient characteristics and treatment outcomes. RESULTS: High LEF-1 expression was associated with significantly poorer disease-free survival (p=0.03) and overall survival (p=0.005). Patients with high LEF-1 expression had a significantly higher relapse rate compared with low LEF-1 expression (p=0.01). CONCLUSION: We provide evidence that high LEF-1 expression is a prognostic marker in adult B-acute ALL patients. PMID- 25805672 TI - Prevalence of monoclonal B lymphocytosis in first-degree relatives of chronic lymphocytic leukemia patients in Turkey. AB - OBJECTIVE: Monoclonal B lymphocytosis (MBL) is considered to be a precursor state for chronic lymphocytic leukemia (CLL). This study was planned to evaluate the MBL prevalence in first-degree relatives of CLL patients in Turkey, which is considered to be an ethnic and geographic bridge between the Eastern and Western worlds. MATERIALS AND METHODS: A total of 136 volunteers [median age: 40 (17-77) years; male/female: 60/76] from 61 families were included. Flow cytometry analysis by 4-colour staining was used for MBL diagnosis. RESULTS: MBL was demonstrated in 17 cases (12.5%). A total of 14 cases (10.3%) were classified as CLL-like MBL, while 3 (2.2%) exhibited a non-CLL-like phenotype. The prevalence of MBL was 12.72% in subjects aged less than 40 years, 12.28% in subjects between 40 and 60 years, and 40% in subjects over 60 years, without statistical significance (p>0.05). A total of 115 cases were evaluated for intermarriage, which was observed in 19 cases (16.5%). The prevalence of MBL did not differ based on intermarriage status (p>0.05). CONCLUSION: The current report is the first MBL prevalence study in a Eurasian population that demonstrates a similar distribution pattern of MBL in Anatolian CLL kindreds. Further efforts should be made to refine our understanding of the natural history and clinical outcomes of MBL. PMID- 25805673 TI - Myeloid sarcomas: a clinicopathologic study of 20 cases. AB - OBJECTIVE: Myeloid sarcoma is a tumoral mass of mature or immature myeloid blasts in extramedullary anatomic locations. It can be seen de novo or in association with acute myeloid leukemia, myeloproliferative neoplasias, or myelodysplastic syndrome. Isolated myeloid sarcoma can be seen as a relapse in cases with allogenic bone marrow transplantation. Although it may involve any tissue in the body, the most common locations are skin, soft tissues, lymph nodes, and the gastrointestinal tract. Immunohistochemically, most cases show myelomonocytic or pure monoblastic differentiation. We reviewed the clinicopathological features of 20 cases of myeloid sarcoma diagnosed in our institute in view of the literature. MATERIALS AND METHODS: The cases diagnosed between 2005 and 2012 at the Ankara University Faculty of Medicine, Department of Pathology, were selected. Clinicopathological findings including the age and sex of the patients; symptoms; anatomic location; accompanying hematological disease; and the morphological, immunohistochemical, and cytogenetic features of the cases were noted. RESULTS: Sixteen of the patients were male and 4 were female. The median age at diagnosis was 47 years. The most commonly involved locations were the lymph nodes and skin. Immunohistochemically, eleven cases were of the myelomonocytic and 7 cases were of the myeloid phenotype, whereas 2 cases showed pure monoblastic differentiation. The median follow-up period for the 18 cases with known clinical data was 33 weeks. Five patients died of the disease in an average of 36 weeks. CONCLUSION: Myeloid sarcoma is a rare presentation of leukemias, myeloproliferative neoplasias, or myelodysplastic syndrome, composed of immature myelomonocytic cells in extramedullary tissues. It may present with variable morphological and phenotypic features, always creating a challenge in pathological diagnosis. PMID- 25805674 TI - Osteoporosis and osteopathy markers in patients with mastocytosis. AB - OBJECTIVE: Osteoporosis, osteosclerosis, and lytic bone lesions have been observed in patients with systemic mastocytosis (SM). We examined bone mineral density (BMD) biochemical turnover markers and serum tryptase levels in SM, which is considered a rare disease. MATERIALS AND METHODS: Seventeen adult patients (5 females, 12 males; median age: 33 years, range: 20-64) with mastocytosis were included in this study. We investigated the value of quantitative ultrasound (QUS) of the calcaneus in the assessment of BMD in SM patients, as well as BMD of the lumbar spine (L1-L4), femoral neck, and distal radius using dual energy x-ray absorptiometry (DXA) and plasma tryptase levels, biochemical markers of bone turnover. RESULTS: At lumbar spine L1-L4, the femoral neck, and the distal radius or as calcaneus stiffness, 12 of 17 patients had T-scores of less than -1 at least at 1 site, reflecting osteopenia. Three of 17 patients had T-scores showing osteoporosis (T-score <-2.5). There was no relationship between DXA and bone lesion severity. We also found a significant positive correlation between tryptase levels and disease severity, as well as between disease severity and pyridinoline (p<0.01 by Spearman's test). CONCLUSION: DXA and calcaneal QUS may not be appropriate techniques to assess bone involvement in SM patients because of the effects of osteosclerosis. This study further shows that the osteoclastic marker pyridinoline is helpful in patients with severe disease activity and sclerotic bone lesions to show bone demineralization. PMID- 25805675 TI - Tunnelled central venous catheter-related problems in the early phase of haematopoietic stem cell transplantation and effects on transplant outcome. AB - OBJECTIVE: Haematopoietic stem cell recipients need central venous catheters (CVCs) for easy administration of intravenous fluid, medications, apheresis, or dialysis procedures. However, CVCs may lead to infectious or non-infectious complications such as thrombosis. The effect of these complications on transplantation outcome is not clear. This manuscript presents the complication rates of double-lumen tunnelled CVCs and their effect on transplantation outcome. MATERIALS AND METHODS: Data from 111 consecutive patients, of whom 75 received autologous and 36 received allogeneic peripheral blood stem cell transplantations, were collected retrospectively. The data were validated by the Record Inspection Group of the related JACIE-accredited transplantation centre. RESULTS: Thrombosis developed in 2.7% of recipients (0.9 per 1000 catheter days). Catheter-related infection was identified in 14 (12.6%) patients (3.6 per 1000 catheter days). Coagulase-negative Staphylococcus was the most common causative agent. Engraftment time, rate of 100-day mortality, and development of grade II IV graft-versus-host disease were not found to be associated with catheter related complications. CONCLUSION: These results indicate that adverse events related with tunnelled CVCs are manageable and have no negative effects on transplant outcome. PMID- 25805676 TI - Growth Arrest-Specific 6 (Gas6) and TAM Receptors in Mouse Platelets. AB - OBJECTIVE: Growth arrest-specific 6 (Gas6) is a newly discovered vitamin K dependent protein, which is a ligand for TAM receptors [Tyro3 (Sky), Axl, and Mer] from the tyrosine kinase family. Gas6 knockout mice were resistant to venous and arterial thrombosis. There are contradictory reports on the presence of Gas6 and its receptors in mouse platelets. The objective of this study was to investigate whether Gas6 and its receptors were present in mouse platelets or not. MATERIALS AND METHODS: Specific pathogen-free BALB/c male and female mice of 8-10 weeks old and 25-30 g in weight were anesthetized under light ether anesthesia and blood samples were taken from their hearts. RNAs were isolated from isolated platelets, and then mRNAs encoding Gas6 and TAM receptors were detected by reverse transcription-polymerase chain reaction (RT-PCR). Protein concentrations of Gas6 and TAM receptors in platelets were measured by ELISA, but not those of Mer, because of the absence of any commercial ELISA kit for mouse specimens. RESULTS: RT-PCR results indicated the presence of mRNAs encoding Gas6 and Mer in mouse platelets. However, although RT-PCR reactions were performed at various temperatures and cycles, we could not detect the presence of mRNAs encoding Axl and Tyro3 (Sky). Receptor protein levels of Axl and Tyro3 were below the detection limits of the ELISA method. CONCLUSION: We found the presence of mRNAs encoding Gas6 and the receptor Mer in mouse platelets, but not Axl and Tyro3. Gas6, Axl, and Tyro3 protein levels were below the detection limits of the ELISA. The presence of mRNA is not obvious evidence of protein expression in platelets that have no nucleus or DNA. Further studies are required to clarify the presence of Gas6/TAM receptors in platelets using real-time PCR and more sensitive immunological methods, and future studies on mechanisms will indicate whether the Gas6/TAM pathway is a strategy for treatment of disorders. PMID- 25805677 TI - Acute Megakaryoblastic Leukemia with t(1;22) Mimicking Neuroblastoma in an Infant. AB - Acute megakaryoblastic leukemia (AMKL) with t(1;22) (p13;q13) is an extremely rare subtype of acute myeloid leukemia that is almost always described in infants. t(1;22) (p13;q13)-positive AMKL with extramedullary infiltration has been previously reported only once in the literature. Herein, we report a 3-month old infant presenting with a pelvic mass and pancytopenia suggesting neuroblastoma. Bone marrow evaluation revealed t(1;22)-positive AMKL that responded well to a regimen containing high-dose cytarabine. PMID- 25805678 TI - Dasatinib-related chylothorax. AB - Dasatinib is a potent second-generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia. The most common adverse event associated with dasatinib therapy is fluid retention, including pleural effusion. Dasatinib related chylothorax has rarely been reported. The clinical manifestations, pathophysiology, management, and prognosis are not fully understood. Here we report a 40-year-old woman presenting with chylothorax following dasatinib use. We propose the hypothesis of its mechanism as well as offering a review of the relevant literature. PMID- 25805679 TI - Successful Off-Label Use of Recombinant Factor VIIa and Coil Embolization in an Adolescent with Massive Hemoptysis Due to Invasive Pulmonary Aspergillosis. AB - Invasive fungal infections have turned out to be a significant cause of morbidity and mortality in pediatric patients with malignant disorders. Massive hemoptysis, a rare complication of invasive pulmonary aspergillosis, may threaten the lives of patients, usually during the resolution of neutropenia. In this report, we describe a patient with massive hemoptysis due to invasive pulmonary aspergillosis whose bleeding was controlled successfully with off-label use of recombinant factor VIIa and subsequent coil embolization of the right pulmonary artery. PMID- 25805680 TI - Trisomy chromosome 6 as a sole cytogenetic abnormality in acute myeloid leukemia. AB - Identification of cytogenetic abnormalities plays an important role in the diagnosis and prognosis of leukemias. Isolated trisomy 6 is a rare abnormality, the prognostic significance of which is not well established. We report one case of acute myeloid leukemia (AML-M5 variant) with trisomy 6 as the sole cytogenetic abnormality. Previously, trisomy 6 has been reported in aplastic anemia, myelodysplastic syndrome, and AML, usually associated with hypocellular marrow. However, our patient had a very short history and hypercellular marrow infiltrated with blasts. We report this case due to the rarity of the condition. More studies are required to ascertain the role of trisomy 6 in the development of leukemia as well as in prognosis. PMID- 25805681 TI - Post-partum ovarian vein thrombosis: combined effect of infection and factor v leiden mutation. PMID- 25805682 TI - Recurrent Monosomies Confirmed by Interphase FISH in Three Chronic Myeloid Leukemia Cases. PMID- 25805683 TI - An unusual presentation of metastatic breast carcinoma as cold autoimmune hemolytic anemia. PMID- 25805684 TI - A child with psoriasis, hypogammaglobulinemia, and monosomy 7-positive myelodysplastic syndrome. PMID- 25805685 TI - Clinical picture in hematology. PMID- 25805686 TI - About chediak-higashi, hemoglobin lansing, and hemoglobin jabalpur. PMID- 25805687 TI - About microangiopathic hemolytic anemia. PMID- 25805688 TI - Oral lesions and hematology. PMID- 25805689 TI - Follicular lymphoma. PMID- 25805690 TI - Rhinocerebral mucormycosis in a patient with acute promyelocytic leukemia. PMID- 25805691 TI - Rapid Progression of Blastic Plasmacytoid Dendritic Cell Neoplasm without Extracutaneous Manifestation. PMID- 25805692 TI - Sustained delivery of exogenous melatonin influences biomarkers of oxidative stress and total antioxidant capacity in summer-stressed anestrous water buffalo (Bubalus bubalis). AB - High ambient temperature during summer in tropical and subtropical countries predisposes water buffaloes (Bubalus bubalis) to develop oxidative stress having antigonadotropic and antisteroidogenic actions. Melatonin is a regulator of seasonal reproduction in photoperiodic species and highly effective antioxidant and free radical scavenger. Therefore, a study was designed to evaluate the effect of sustained-release melatonin on biomarkers of oxidative stress i.e., the serum malondialdehyde (MDA) and nitric oxide (NO), and the total antioxidant capacity (TAC). For the study, postpartum buffaloes diagnosed as summer anestrus (absence of overt signs of estrus, concurrent rectal examination, and RIA for serum progesterone) were grouped as treated (single subcutaneous injection of melatonin at 18 mg/50 kg body weight dissolved in sterilized corn oil as vehicle, n = 20) and untreated (subcutaneous sterilized corn oil, n = 8). Blood sampling for estimation of serum TAC and MDA (mmol/L) and NO (MUmol/L) was carried out at 4 days of interval from 8 days before treatment till 28 days after treatment or for the ensuing entire cycle length. Results showed serum TAC concentration was higher in the treatment group with a significant (P < 0.05) increasing trend, whereas MDA and NO revealed a significant (P < 0.05) decline. Serum MDA and NO were higher in control compared with those of treatment group. Moreover, buffaloes in the treatment group showed 90% estrus induction with 18.06 +/- 1.57 days mean interval from treatment to the onset of estrus. These results report that melatonin has a protective effect by elevating antioxidant status and reducing oxidative stress resulting in the induction of cyclicity in summer stressed anestrous buffaloes. PMID- 25805693 TI - Fixed-time insemination with frozen semen in mares: is it suitable for poorly fertile stallions? AB - The purpose of the present study was to compare two protocols for equine frozen semen programs using either postovulation insemination or fixed-time insemination (FT), evaluating both pregnancy rates and intrauterine fluid (IUF) accumulation after artificial insemination with semen obtained from either highly or poorly fertile stallions. Six ejaculates from two stallions (n = 12) were processed. After thawing, semen samples were evaluated by computerized semen analysis. Fifteen mares (30 cycles) were inseminated with frozen semen from highly fertile stallion A, and 14 mares (28 cycles) were inseminated with frozen semen from poorly fertile stallion B. Ovulations were induced with 1 mg (intramuscular) of deslorelin acetate after the observation of a greater than 35 mm follicle and uterine edema. In postovulation insemination group, mares were inseminated once with 800 * 10(6) total sperm in a maximum 6-hour interval after ovulation. In FT group, mares were inseminated twice with 400 * 10(6) total sperm, 24 and 40 hours after induction. Mares were ultrasonographically examined for IUF accumulation 24 hours and for pregnancy diagnosis 14 days after the last insemination. Although IUF accumulation was more evident in mares inseminated once postovulation, pregnancy rates were similar for both protocols, regardless of the stallion, although a significant effect of the stallion was observed. These results indicated that FTs may be used for both highly and poorly fertile stallions as a practical tool to help spreading the use of frozen semen in equine reproduction programs. PMID- 25805694 TI - Cryopreservation of in vitro-produced sheep embryos: Effects of different protocols of lipid reduction. AB - The low survival of sheep in vitro-produced (IVP) embryos after cryopreservation is a key limiting step to the widespread of this technology. In the present work, different approaches for enhancing cryosurvival of these embryos were compared: embryo delipidation by centrifugation in the absence or presence of cytochalasin D, a cytoskeleton stabilizer or by embryo culture in the presence of different doses of the trans-10 cis-12-conjugated linoleic acid isomer (CLA). Three experiments were conducted. In experiment 1, IVP blastocysts before vitrification were randomly distributed into four groups: control; centrifuged (cent), cytochalasin D (cyto-D), centrifuged + cytochalasin D (cent + cyto-D). In experiment 2, different doses of CLA (25, 50, and 100 MUM) were supplemented during embryo culture before vitrification of blastocysts. A control group ran simultaneously. A third experiment was performed to compare both approaches from the previous ones but without the groups with the worst results (groups: control, cyto-D, cent + cyto-D, CLA25, CLA50). In all experiments, embryos integrity and reexpansion were assessed after warming and after 3 hours of culture. In experiment 1, the postwarming integrity rate was the lowest (P < 0.05) in embryos from the cent group (cent: 50.6 +/- 10.3% vs. CONTROL: 74.6 +/- 9.2%, cyto-D: 92.3 +/- 9.7%, and cent + cyto-D: 90.5 +/- 11.2%), whereas the best (P < 0.05) reexpansion scores were obtained in cent + cyto-D embryos (cent + cyto-D: 2.6 +/- 0.28 vs. CONTROL: 1.8 +/- 0.08, cent: 1.9 +/- 0.2, and cyto-D: 1.8 +/- 0.31). In experiments 2 and 3, higher (P < 0.05) cleavage rates were observed in CLA25 (50.9 +/- 6.2% and 49.2 +/- 5.6%, respectively) and CLA50 (48.9 +/- 6.2% and 47.6 +/- 5.6%, respectively) than those in the control (41.8 +/- 6.1% and 40.4 +/- 5.4%, respectively) group. In experiment 2, CLA100 presented the lowest (P < 0.002) Day-6 and -7 embryo production rate and quality. After warming, superior (P < 0.02) expansion scores were achieved in CLA25 (3.1 +/- 0.29) and CLA50 (3.8 +/- 0.17) than in the control (1.9 +/- 0.10) group. Similar results were attained in experiment 3. However, although cent + cyto-D embryos showed higher (P = 0.008) postwarming expansion scores than the control (2.8 +/- 0.29 vs. 1.9 +/- 0.07) group, this score was lower (P = 0.0009) than that in CLA50 embryos (3.8 +/ 0.17). In conclusion, our results showed that different protocols of lipid reduction can be successfully applied to improve the cryotolerance of IVP sheep embryos. PMID- 25805695 TI - The neural bases of the pseudohomophone effect: Phonological constraints on lexico-semantic access in reading. AB - We investigated phonological processing in normal readers to answer the question to what extent phonological recoding is active during silent reading and if or how it guides lexico-semantic access. We addressed this issue by looking at pseudohomophone and baseword frequency effects in lexical decisions with event related functional magnetic resonance imaging (fMRI). The results revealed greater activation in response to pseudohomophones than for well-controlled pseudowords in the left inferior/superior frontal and middle temporal cortex, left insula, and left superior parietal lobule. Furthermore, we observed a baseword frequency effect for pseudohomophones (e.g., FEAL) but not for pseudowords (e.g., FEEP). This baseword frequency effect was qualified by activation differences in bilateral angular and left supramarginal, and bilateral middle temporal gyri for pseudohomophones with low- compared to high-frequency basewords. We propose that lexical decisions to pseudohomophones involves phonology-driven lexico-semantic activation of their basewords and that this is converging neuroimaging evidence for automatically activated phonological representations during silent reading in experienced readers. PMID- 25805697 TI - A strategy to synergistically increase the number of active edge sites and the conductivity of MoS2 nanosheets for hydrogen evolution. AB - Nanostructured MoS2 is very promising as an electrocatalyst for hydrogen evolution due to a greater number of active edge sites. However, a very large resistance between basal planes decreases the overall efficiency of hydrogen evolution, and greatly limits its application in industry. Herein we develop a facile strategy to synergistically increase the number of active edge sites and the conductivity of MoS2. MoS2 nanosheet arrays can be grown vertically on a carbon fiber cloth (CFC) substrates by a facile strategy. On the one hand, ammonium fluoride in the reaction system could effectively etch the inert basal plane of the MoS2 nanosheets, leading to the formation of pits in the inert basal plane of the MoS2 nanosheets. Thereby the number of active edge sites is significantly increased. On the other hand, the vertical growth of MoS2 nanosheet arrays on CFCs can significantly decrease the resistance of MoS2-based electrocatalysts. As a result, the MoS2-based electrocatalysts exhibit excellent catalytic activity for hydrogen evolution reactions, with a small Tafel slope and a large cathodic current density. Moreover, the CFC can be repeatedly utilized as a template to grow ultrathin MoS2 nanosheet arrays for HERs. The excellent activity and recyclable utilization, as well as mass production, indicate that the composite has promising applications in industry. PMID- 25805696 TI - Ecto-5'-nucleotidase (CD73) is involved in chronic cerebral hypoperfusion-induced white matter lesions and cognitive impairment by regulating glial cell activation and pro-inflammatory cytokines. AB - Recent studies have demonstrated that inflammatory and immune mechanisms play important roles in the progression of chronic cerebral hypoperfusion (CCH) induced white matter lesions (WMLs). As an endogenous neuromodulator in the brain, the extracellular levels of adenosine represent a critical endogenous mechanism for the regulation of immune and inflammatory responses. Ecto-5' nucleotidase (CD73), which dephosphorylates AMP to adenosine, is considered to catalyze the rate-limiting step in the generation of extracellular adenosine. However, the role of CD73 in the development of CCH-induced WMLs remains unclear. In the present study, we investigated the expression and activity of CD73 using immunohistochemistry, Western blot analysis and measurements of the rate of AMP hydrolysis in a mouse model of CCH via bilateral common carotid artery stenosis (BCAS) surgery. Moreover, C57BL/6-CD73 knockout (KO) and their wild-type littermates were subjected to BCAS surgery to further investigate the functional roles of CD73 in the WMLs. White matter (WM) changes, astrocyte and microglia proliferation, proinflammatory cytokine levels in the corpus callosum and cognitive function were assessed on the 30th day after BCAS. The results indicated that CD73 expression and activities significantly increased in the corpus callosum on the 30th day after BCAS. Moreover, CD73 deficiency exacerbated CCH-induced WMLs and cognitive impairment. More reactive astrocytes and microglia were observed in the corpus callosum in CD73-KO mice. CD73 deficiency significantly increased the levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) in the BCAS model of CCH. These findings suggest that CD73 plays a protective role in the development of CCH-induced WMLs and cognitive impairment via the regulation of glial cell activation and proinflammatory cytokine expression. PMID- 25805698 TI - Deformation mechanisms of human amnion: Quantitative studies based on second harmonic generation microscopy. AB - Multiphoton microscopy has proven to be a versatile tool to analyze the three dimensional microstructure of the fetal membrane and the mechanisms of deformation on the length scale of cells and the collagen network. In the present contribution, dedicated microscopic tools for in situ mechanical characterization of tissue under applied mechanical loads and the related methods for data interpretation are presented with emphasis on new stepwise monotonic uniaxial experiments. The resulting microscopic parameters are consistent with previous ones quantified for cyclic and relaxation tests, underlining the reliability of these techniques. The thickness reduction and the substantial alignment of collagen fiber bundles in the compact and fibroblast layer starting at very small loads are highlighted, which challenges the definition of a reference configuration in terms of a force threshold. The findings presented in this paper intend to inform the development of models towards a better understanding of fetal membrane deformation and failure, and thus of related problems in obstetrics and other clinical conditions. PMID- 25805699 TI - Water-soluble thin film transistors and circuits based on amorphous indium gallium-zinc oxide. AB - This paper presents device designs, circuit demonstrations, and dissolution kinetics for amorphous indium-gallium-zinc oxide (a-IGZO) thin film transistors (TFTs) comprised completely of water-soluble materials, including SiNx, SiOx, molybdenum, and poly(vinyl alcohol) (PVA). Collections of these types of physically transient a-IGZO TFTs and 5-stage ring oscillators (ROs), constructed with them, show field effect mobilities (~10 cm2/Vs), on/off ratios (~2*10(6)), subthreshold slopes (~220 mV/dec), Ohmic contact properties, and oscillation frequency of 5.67 kHz at supply voltages of 19 V, all comparable to otherwise similar devices constructed in conventional ways with standard, nontransient materials. Studies of dissolution kinetics for a-IGZO films in deionized water, bovine serum, and phosphate buffer saline solution provide data of relevance for the potential use of these materials and this technology in temporary biomedical implants. PMID- 25805700 TI - Diversity and evolution of sound production in the social behavior of Chaetodon butterflyfishes. AB - Fish produce context-specific sounds during social communication, but it is not known how acoustic behaviors have evolved in relation to specializations of the auditory system. Butterflyfishes (family Chaetodontidae) have a well-defined phylogeny and produce pulsed communication sounds during social interactions on coral reefs. Recent work indicates that two sound production mechanisms exist in the bannerfish clade and that other mechanisms are used in the Chaetodon clade, which is distinguished by an auditory specialization, the laterophysic connection (LC). Here, we determine the kinematic action patterns associated with sound production during social interactions in four Chaetodon subgenera and the non laterophysic fish Forcipiger flavissimus. Some Chaetodon species share the head bob acoustic behavior with F. flavissimus, which along with other sounds in the 100-1000 Hz spectrum, are probably adequate to stimulate the ear, swim bladder or LC of a receiver fish. In contrast, only Chaetodon species produced the tail slap sound, which involves a 1-30 Hz hydrodynamic pulse that is likely to stimulate the receiver's ear and lateral line at close distances, but not the swim bladder or LC. Reconstructions of ancestral character states appear equivocal for the head bob and divergent for the tail slap acoustic behaviors. Independent contrast analysis shows a correlation between sound duration and stimulus intensity characters. The intensities of the tail slap and body pulse sounds in Chaeotodon species are correlated with body size and can provide honest communication signals. Future studies on fish acoustic communication should investigate low frequency and infrasound acoustic fields to understand the integrated function of the ear and lateral line, and their evolutionary patterns. PMID- 25805701 TI - Transcranial light affects plasma monoamine levels and expression of brain encephalopsin in the mouse. AB - Encephalopsin (OPN3) belongs to the light-sensitive transmembrane receptor family mainly expressed in the brain and retina. It is believed that light affects mammalian circadian rhythmicity only through the retinohypothalamic tract, which transmits light information to the suprachiasmatic nucleus in the hypothalamus. However, it has been shown that light penetrates the skull. Here, we present the effect of transcranial light treatment on OPN3 expression and monoamine concentrations in mouse brain and other tissues. Mice were randomly assigned to control group, morning-light group and evening-light group, and animals were illuminated transcranially five times a week for 8 min for a total of 4 weeks. The concentrations of OPN3 and monoamines were analysed using western blotting and HPLC, respectively. We report that transcranial light treatment affects OPN3 expression in different brain areas and plasma/adrenal gland monoamine concentrations. In addition, when light was administered at a different time of the day, the response varied in different tissues. These results provide new information on the effects of light on transmitters mediating mammalian rhythmicity. PMID- 25805702 TI - Copper-catalyzed oxygen atom transfer of N-oxides leading to a facile deoxygenation procedure applicable to both heterocyclic and amine N-oxides. AB - Deoxygenation of various types of N-oxides including both heterocyclic and alkyl(aryl)amine derivatives has successfully been developed by the copper catalyzed oxygen atom transfer using diazo compounds as the oxygen acceptor. The reaction proceeds smoothly over a broad range of substrates with excellent functional group tolerance under mild conditions. PMID- 25805703 TI - Reproductive and transgenerational toxicities of phenanthrene on female marine medaka (Oryzias melastigma). AB - Phenanthrene (PHE) is one of the most abundant polycyclic aromatic hydrocarbons in the aquatic environment and often results from oil spills. To assess the effects of PHE on fish, marine medaka (Oryzias melastigma) was exposed to PHE at 0.06, 0.6, 6 and 60 MUg/L. The reproductive functions and transgenerational effects were investigated. After 80 days exposure, the percentage of previtellogenic and vitellogenic oocytes in the ovary showed a significant decrease in the 0.06 and 60 MUg/L groups. The mRNA levels of salmon-type gonadotropin releasing hormone, the follicle-stimulating hormone FSHbeta, and the luteinizing hormone LHbeta in the brain; the cytochrome P450 aromatase gene CYP19A and the estrogen receptor alpha (ERalpha) in the ovary; and ERalpha and vitellogenin VTG1 and 2 in the liver all exhibited significant down-regulation in the 0.06 and 60 MUg/L groups, but did not significantly change in the 6 MUg/L group compared to the control, which was quite consistent with development of the oocytes. A significant elevation of PHE accumulation in the brain in the 0.06 and 60 MUg/L groups gave a reasonable explanation for the nonmonotonic dose-response and also elucidated the action pathway via the brain-pituitary-gonadal axis. The reduction of the time to hatch and the increased cardiac rhythm of embryos were in accord with the PHE accumulative levels in the eggs. The results demonstrated that exposure to PHE at both low and high concentrations can inhibit ovary development. In addition, PHE can be maternally transferred to embryos and influence the health and sustainability of the next generation. PMID- 25805704 TI - Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia. AB - Evidence indicates that the adenosine A2A receptor subtype is of critical importance in stroke. In previous studies, in the model of permanent middle cerebral artery occlusion (pMCAo), the adenosine A2A receptor antagonist, SCH58261, administered soon after ischemia, proved protective against excessive glutamate outflow in the first 4 h after ischemia and against neurological deficit and tissue damage evaluated 24 h after pMCAo. In the present work, we investigated if neuroprotective effect of SCH58261 was maintained 7 days after transient MCAo (tMCAo). SCH58261 (0.01 mg/kg, i.p.), administered twice/day for 7 days, protected from neurological deficit 1 day after tMCAo, but no more after 5 and 7 days. Two days after tMCAo, SCH58261 did not reduce blood cell infiltration, evaluated as HIS-48 positive cells, into ischemic striatal and cortical tissue. Moreover, 7 days after tMCAo, SCH58261 has not protected ischemic areas from damage and has not ameliorated myelin organization into the ischemic striatum. Protection by the A2A receptor antagonist 24 h after ischemia is attributable to reduced excitotoxicity. Seven days after ischemia the early protective effect of the A2A receptor antagonist likely has been overwhelmed by a secondary damage due to blood cell infiltration and neuroinflammation. PMID- 25805705 TI - Radiosurgery reirradiation for high-grade glioma recurrence: a retrospective analysis. AB - Despite various treatment strategies being available, recurrent high-grade gliomas (r-HGG) are difficult to manage. To obtain local control, radiosurgery (SRS) reirradiation has been considered as potential treatment. In the present study, a retrospective analysis was performed on r-HGG patients treated with salvage single- (s-SRS) or multi-fraction SRS (m-SRS). The aim of this study was to evaluate the effectiveness of salvage SRS in terms of overall survival (OS); toxicity was analyzed as well. Between 2004 May and 2011 December, 128 r-HGG patients (161 lesions) treated with CyberKnife((r)) SRS reirradiation were retrospectively analyzed. Toxicity was graded according to Radiation Therapy Oncology Group and by Common Terminology Criteria for Adverse Events v.3 criteria. OS from the diagnosis date and OS from reirradiation were estimated using the Kaplan-Meier method. Median follow-up was 9 months (range 15 days-82 months). All patients completed SRS without high-grade toxicity. Radiation necrosis was observed in seven patients (6 %) with large volume lesions. The median survival from initial diagnosis was 32 months. The 1-, 2-, and 3-years survival rates from diagnosis were 95, 62, and 45 % respectively. Median survival following SRS was 11.5 months. The 1-, 2-, and 3-years survival rate following SRS was 48, 20, and 17 % respectively. On multivariate analysis, age <40 years, salvage surgery before SRS, and other post-SRS therapies (second-line chemotherapy and/or surgery) were found to significantly improve survival (p = 0.03). SRS represents a safe and feasible option to treat r-HGG patients with low complication rates and potential survival benefit. PMID- 25805706 TI - Cerebral cortex, hippocampus, striatum and cerebellum show differential susceptibility to quinolinic acid-induced oxidative stress. AB - Quinolinic acid (QA) is a NMDA receptor agonist implicated in pathological conditions, such as neurodegenerative diseases and epilepsy. Time-course responses of different brain regions after QA i.c.v. infusion are not known. We aimed to investigate the time-course effects of QA infusion on oxidative stress related parameters on different brain regions. In cerebral cortex, QA infusion promoted an early (1 h) decrease of NPSH levels and GR activity followed by a later increase in ROS production (8 h) and TBARS detection (24-72 h). In the hippocampus, QA promoted an increase in ROS production that lasted 8 h. Striatal tissue presented a later increase in ROS generation (8-72 h) after QA infusion. In the cerebellum, an increase in the GPx activity after 8 h was the only effect observed. These results show that oxidative stress induced by QA i.c.v. infusion is region and time dependent. PMID- 25805707 TI - Auditory startle response is normal in juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) is hypothesized to originate from the dysfunction of thalamo-cortical circuit. We aimed to analyze any changes in auditory startle response in JME patients to determine the role of brainstem in JME. The responses of 18 JME patients to auditory simulation were recorded over the unilateral orbicularis oculi, masseter, sternocleidomastoid, and extremity muscles. Results were compared with those of 18 age and gender matched healthy volunteers. Total auditory startle response frequencies were similar between the two groups (31.1 +/- 11.1 % vs. 33.7 +/- 8.7 %, p = 0.400). Other parameters over each muscle were also similar. There were no impacts of antiepileptic drug use or disease duration. We may conclude that our findings may provide sufficient evidence for the lack of functional changes of the auditory startle response circuit even in longstanding cases of JME. PMID- 25805708 TI - Midbrain-to-pons ratio in autopsy-confirmed progressive supranuclear palsy: replication in an independent cohort. AB - Recent neuropathologically confirmed clinical data suggest that the midbrain-to pons ratio, as calculated from conventional brain MRI, has high specificity and sensitivity for the diagnosis of progressive supranuclear palsy (PSP). Here, we aimed to replicate these findings in an independent autopsy-confirmed cohort of 6 PSP patients and 23 non-PSP patients. Patients with confirmed PSP had clearly lower midbrain-to-pons ratios compared to non-PSP patients (p < 0.0001). All non PSP patients had midbrain-to-pons ratios higher than 0.50, whereas all but one PSP patient had a ratio lower than 0.50. The positive predictive value (PPV) of the ratio (<0.50) was 100% and the negative predictive value (NPV) was 95.8 %. The results of this second autopsy-confirmed sample confirm that midbrain-to brain ratios constitute reliable and clinically useful estimates of diagnostic midbrain atrophy in relation to PSP pathology. PMID- 25805709 TI - Blumensaat's line is not always straight: morphological variations of the lateral wall of the femoral intercondylar notch. AB - PURPOSE: The purpose of this study was to evaluate the morphological variations of the lateral wall of the femoral intercondylar notch. METHODS: Fifty-two non paired human cadaver knees were used. All soft tissues around the knee were resected except the ACL. The ACL was cut in the middle, and the femoral bone was cut at the most proximal point of the femoral notch parallel to the plane of the femoral bone shaft. The ACL was carefully dissected, and the periphery of the ACL insertion site was outlined on the femoral side. An accurate lateral view of the femoral condyle was photographed with a digital camera, and the images were downloaded to a personal computer. The morphological variations of Blumensaat's line, the height and area of the lateral wall of the femoral intercondylar notch and the size of the femoral ACL footprints were measured with Image J software. RESULTS: Blumensaat's line exhibited three types of morphological variations. A straight line was observed in 19 knees (37 %) (straight type). A protrusion spanning less than half of the line was observed at the proximal part of Blumensaat's line in 10 knees (19 %) (small hill type). A protrusion spanning more than half of the line was observed at the proximal part of the line in 23 knees (44 %) (large hill type). In some knees with this large hill type variation, the appearance was similar to that of anterior spur. No significant differences between these three types were observed in either the height and area of the lateral wall of the femoral intercondylar notch or the area of the femoral ACL footprint. CONCLUSION: In conclusion, Blumensaat's line has three types of morphological variations (straight, small hill and large hill types). For the clinical relevance, when ACL surgery is performed in knees with small or large hill type variations, surgeons should pay close attention to femoral tunnel evaluation and placement, especially for the use of Quadrant method. The grid placement of Quadrant method would be changed in the knees of these type variations. PMID- 25805710 TI - A case-matched comparison of single-incision versus multiport laparoscopic right colectomy for colon cancer. AB - PURPOSE: To minimize the parietal trauma associated with multiple surgical access sites, single-incision laparoscopic surgery for colectomy has been emerging with the improvements in instrumentation and surgical techniques. The purpose of this study was to compare the clinicopathological outcomes between single-incision laparoscopic right colectomy (SILC) and multiport laparoscopic right colectomy (MLC) for right colon cancer. METHODS: Thirty-five consecutive patients undergoing SILC from a prospective single-institution database were case matched according to demographic data to an equivalent number of patients who underwent MLC. RESULTS: The SILC patients had decreased scores for maximal pain assessed by a visual analog scale on postoperative days 1 and 3, and used fewer postoperative systemic narcotics. The median length of the hospital stay for the SILC patients was significantly shorter compared with the MLC patients. The postoperative morbidity rates were similar between the groups. The oncological findings were not significantly different between the groups. CONCLUSION: SILC is a feasible and safe alternative to conventional MLC for patients with right colon cancer. PMID- 25805712 TI - Diagnostic Accuracy of Various Imaging Modalities for Suspected Lower Extremity Stress Fractures: A Systematic Review With Evidence-Based Recommendations for Clinical Practice. AB - BACKGROUND: The literature is filled with conflicting findings regarding diagnostic accuracy and protocols for imaging suspected lower extremity stress fractures. The absence of systematic reviews on this topic has limited the development of evidence-based recommendations for appropriate imaging protocols in cases of suspected lower extremity stress fractures. PURPOSE: To determine the diagnostic accuracy statistics of imaging modalities used to diagnose lower extremity stress fractures and to synthesize evidence-based recommendations for clinical practice. STUDY DESIGN: Systematic review. METHODS: A generic search strategy for published studies was performed using multiple databases. A study was eligible for inclusion if it met all of the following criteria: (1) at least 1 diagnostic imaging modality was studied, (2) at least 1 radiological reference standard was used, (3) the study reported or allowed computation of diagnostic accuracy statistics (sensitivity, specificity, positive likelihood ratio, negative likelihood ratio), (4) a full-text version was available, (5) the article was written in English, and (6) the study included lower extremity stress fractures. Studies that examined asymptomatic individuals or patients with fractures due to disease or pharmacologic intervention were excluded. RESULTS: Reported sensitivity and specificity (95% CI) were as follows: For conventional radiography, sensitivity ranged from 12% (0%-29%) to 56% (39%-72%) and specificity ranged from 88% (55%-100%) to 96% (87%-100%). For nuclear scintigraphy (NS), sensitivity ranged from 50% (23%-77%) to 97% (90%-100%) and specificity from 33% (12%-53%) to 98% (93%-100%). For magnetic resonance imaging (MRI), sensitivity ranged from 68% (45%-90%) to 99% (95%-100%) and specificity from 4% (0%-11%) to 97% (88%-100%). For computed tomography, sensitivity ranged from 32% (8%-57%) to 38% (16%-59%) and specificity from 88% (55%-100%) to 98% (91%-100%). For ultrasound, sensitivity ranged from 43% (26%-61%) to 99% (95% 100%) and specificity from 13% (0%-45%) to 79% (61%-96%). CONCLUSION: MRI was identified as the most sensitive and specific imaging test for diagnosing stress fractures of the lower extremity. When MRI is available, NS is not recommended because of its low specificity, high dosage of ionizing radiation, and other limitations. Conventional radiographs are likely to result in false negatives upon initial presentation, particularly in the early stages of stress fracture, and in some cases may not reveal an existing stress fracture at any time. A diagnostic imaging algorithm was developed with specific recommendations for cost efficient imaging of low-risk and high-risk suspected stress fractures. PMID- 25805711 TI - Cardiometabolic correlates of low type 2 diabetes incidence in western Alaska Native people - The WATCH study. AB - AIMS: Previously rare among Alaska Native (AN) people, type 2 diabetes (DM2) prevalence as indicated by registry data has increased by as much as 300% in some western Alaska regions. We sought to determine prevalence and incidence of DM2 and analyze associated cardiometabolic risk factors in western AN people. METHODS: DM2 and prediabetes prevalence and incidence were determined by the Western Alaska Tribal Collaborative for Health using consolidated data from cohort studies conducted during 2000-2010. Crude and age-adjusted incidence for DM2 and prediabetes were calculated using 2010 American Diabetes Association criteria. Effects of covariates on DM2 and prediabetes were determined using univariate and multivariate Cox proportional hazards analyses, adjusted for age and sex. RESULTS: Excluding baseline diabetes (n=124, 4.5%), 53 cases of new DM2 were identified among 2630 participants. Age- and sex-adjusted DM2 incidence was 4.3/1000 (95% CI 2.9, 5.0) person-years over an average 5.9-year follow up. After excluding baseline prediabetes, 387 new cases of prediabetes were identified among 1841 participants; adjusted prediabetes incidence was 44.5/1000 (95% CI 39.5, 49.5) person years. Independent predictors for DM2 included age, impaired fasting glucose, and metabolic syndrome; family history of diabetes and obesity were additional independent predictors for prediabetes. CONCLUSIONS: DM2 incidence in western AN people is substantially lower than that for U.S. whites; however, incidence of prediabetes is more than 10-fold higher than western AN DM2 incidence and more closely aligned with U.S. rates. Interventions aimed at achieving healthy lifestyles are needed to minimize risk factors and maximize protective factors for DM2 in this population. PMID- 25805713 TI - The Subjective Experiences of Firesetting by Men With Mild Intellectual Disabilities Detained in a Secure Hospital. AB - This article explores the lived experiences of men with mild intellectual disabilities who have deliberately set a fire and are detained in a secure hospital. Semi-structured interviews were used to explore the subjective experiential claims of seven male firesetters with mild intellectual disabilities residing in a forensic intellectual disability hospital. Interpretative Phenomenological Analysis was used to interpret participants' meaning making of their firesetting. Five super-ordinate themes emerged from the analysis: (a) "the importance of the first fire," (b) "firesetting to escape distress," (c) "firesetting to enable positive emotional experiences," (d) "firesetting to communicate with services," and (e) "Fire Setters Treatment Programme." The analysis provides an understanding of why some firesetting behaviours emerge and highlights factors that contribute to the maintenance and desistence of repeat firesetting acts. The findings are considered in relation to evolving risk assessment measures and risk reduction strategies for facilitating rehabilitation into community settings. PMID- 25805714 TI - Correlation of Hope and Self-Efficacy With Job Satisfaction, Job Stress, and Organizational Commitment for Correctional Officers in the Taiwan Prison System. AB - The aim of this study was to explore the correlation of hope and self-efficacy with job satisfaction, job stress, and organizational commitment for correctional officers in the Taiwan prison system while controlling for the shared effects of the nature of the institution (i.e., for male or female inmates) and personal characteristics of the officers (i.e., gender, age, and years of work experience). Hope in the context of this study refers to a cognitive set and motivational state that involves reciprocal interaction between goal-directed energy (agency) and planned pathways to meet the goals (pathway). It is a personality trait of hopefulness, rather than having hope for the prisoners restructuring their future. Self-efficacy refers to the belief that individuals have regarding their ability to perform necessary tasks to achieve goals. Although they share similar constructs, hope theory places emphasis on cross situational goal-directed thought, whereas the concept of self-efficacy focuses on situation-specific goals. The participants were 133 correctional personnel from two correctional institutions, one with male inmates and the other with female inmates, in central Taiwan. The results of ordinary least squares regression analysis indicated that hope had a significant positive association with job satisfaction and a significant negative association with job stress. Self-efficacy had a significant positive association with job satisfaction and organizational commitment. Finally, job satisfaction had a significant positive association with organizational commitment. PMID- 25805715 TI - A Strengths-Based Approach to Prisoner Reentry: The Fresh Start Prisoner Reentry Program. AB - Scholars have called for a strengths-based approach to prisoner reentry, yet there are few available program models that outline how to integrate this approach into the current reentry program landscape. The present article highlights a strengths-based prisoner reentry program that provided services to men both pre- and post-release from prison to the community in the United States. Qualitative findings from focus groups provide preliminary support for the strengths-based approach and highlight men's strengths and needs as well as challenges related to the program's implementation. The reentry program then drew from participants' reports to inform program development activities. Implications and recommendations for integrating strengths-based approaches into prisoner reentry interventions are discussed. PMID- 25805716 TI - Down-regulation of the cotton endo-1,4-beta-glucanase gene KOR1 disrupts endosperm cellularization, delays embryo development, and reduces early seedling vigour. AB - Towards the aim of examining the potential function of KORRIGAN (KOR), a highly conserved membrane-bound endoglucanase, in reproductive development, here transgenic evidence is provided that a cotton (Gossypium hirsutum) endoglucanase, GhKOR1, plays significant roles in endosperm and embryo development. RNA interference (RNAi)- and co-suppression-mediated down-regulation of GhKOR1 resulted in smaller filial tissue and reduced seed weight, which were characterized by disrupted endosperm cellularization and delayed embryo development, leading to a delayed germination and a weak growth of seedlings early in development. The transgenic seeds exhibited fewer and smaller endosperm cells with irregular and brittle cell walls, and their embryos developed only to the globular stage at 10 days post-anthesis (DPA) when the wild-type endosperm has become highly cellularized and the embryo has progressed to the heart stage. The transgenic seed also displayed a significant reduction of callose in the seed coat transfer cells and reduced cellulose content both in the seed coat and in mature fibres. These findings demonstrate that GhKOR1 is required for the developmental of both seed filial and maternal tissues and the establishment of seedling vigour. PMID- 25805718 TI - Lifestyle exercises for bone health and health-related quality of life among premenopausal women: a randomised controlled trial. AB - PURPOSE: Growing evidence supports engagement in physical exercise throughout life for optimal bone health. However, promotion of physical exercise among premenopausal women presents significant challenges, which are yet to be addressed in the design of many bone-health exercise regimes. As a deviation from traditional, facility-based, supervised, long-duration and intense exercise regimes, the efficacy of short-duration, practical, lifestyle physical exercises for improving bone health and quality of life was examined. METHODS: Premenopausal women (N = 96, mean age 22.25 +/- 3.5 years; mean BMI 23.43 +/- 3.5 kg/m(2)) participated in a 6-month randomised trial of lifestyle physical exercises for the intervention group and sham exercises for the control group. The participants' scores on the outcome measure SF-36 was accessed pre- and post intervention and compared with general population norms according to the SF-36 scoring manual. Paired t-tests were used to examine changes within trial arms from baseline to post-intervention, while analysis of covariance was performed to examine the effect of the lifestyle exercise programme on quality of life of premenopausal women. RESULTS: Compared to 51% at baseline, 63% of the participants were either at or above the general population norm for general health, and the percentage of participants who were below the population health norm for mental health was reduced from 46% at baseline to 38% post-exercise intervention. Comparable improvements in quality of life were found in both trial arms post-participation in the bone-health promotion programme. CONCLUSIONS: Bone health exercises, when implemented as easily adoptable, lifestyle physical activity, may also enhance the quality of life of premenopausal women. Hence, a practical lifestyle approach to exercise may offer a much-needed public health strategy for bone-health promotion among women. PMID- 25805717 TI - Identification and characterization of a novel group of legume-specific, Golgi apparatus-localized WRKY and Exo70 proteins from soybean. AB - Many plant genes belong to families that arise from extensive proliferation and diversification allowing the evolution of functionally new proteins. Here we report the characterization of a group of proteins evolved from WRKY and exocyst complex subunit Exo70 proteins through fusion with a novel transmembrane (TM) domain in soybean (Glycine max). From the soybean genome, we identified a novel WRKY-related protein (GmWRP1) that contains a WRKY domain with no binding activity for W-box sequences. GFP fusion revealed that GmWRP1 was targeted to the Golgi apparatus through its N-terminal TM domain. Similar Golgi-targeting TM domains were also identified in members of a new subfamily of Exo70J proteins involved in vesicle trafficking. The novel TM domains are structurally most similar to the endosomal cytochrome b561 from birds and close homologues of GmWRP1 and GmEx070J proteins with the novel TM domain have only been identified in legumes. Transient expression of some GmExo70J proteins or the Golgi-targeting TM domain in tobacco altered the subcellular structures labelled by a fluorescent Golgi marker. GmWRP1 transcripts were detected at high levels in roots, flowers, pods, and seeds, and the expression levels of GmWRP1 and GmExo70J genes were elevated with increased age in leaves. The legume-specific, Golgi apparatus localized GmWRP1 and GmExo70J proteins are probably involved in Golgi-mediated vesicle trafficking of biological molecules that are uniquely important to legumes. PMID- 25805719 TI - Design of a coil satellite centrifuge and its performance on counter-current chromatographic separation of 4-methylumbelliferyl sugar derivatives with polar organic-aqueous two-phase solvent systems. AB - A new high-speed counter-current chromatograph, named coil satellite centrifuge (CSC), was designed and fabricated in our laboratory. The CSC apparatus produces the satellite motion such that the coiled column simultaneously rotates around the sun axis (the angular velocity, omega1), the planet axis (omega2) and the satellite axis (the central axis of the column) (omega3). In order to achieve this triplicate rotary motion without twisting of the flow tube, the rotation of each axis was determined by the following formula: omega1=omega2+omega3. This relation enabled to lay out the flow tube without twisting by the simultaneous rotation of three axes. The flow tube was introduced from the bottom side of the apparatus into the sun axis of the first rotary frame reaching the upper side of the planet axis and connected to the column in the satellite axis. The performance of the apparatus was examined on separation of 4-methylumbelliferyl (MU) sugar derivatives as test samples with organic-aqueous two-phase solvent systems composed of ethyl acetate/1-butanol/water (3:2:5, v/v) for lower phase mobile and (1:4:5, v/v) for upper phase mobile. With lower phase mobile, five 4 MU sugar derivatives including beta-D-cellobioside (Cel), beta-D-glucopyranoside, alpha-D-mannopyranoside, beta-D-fucopyranoside and alpha-L-fucopyranoside (alpha L-Fuc) were separated with the combined rotation around each axis at counterclockwise (CCW) (omega1) - CCW (omega2) - CCW (omega3) by the flow tube distribution. With upper phase mobile, three 4-MU sugar derivatives including alpha-L-Fuc, beta-D-galactopyranoside and Cel were separated with the combined rotation around each axis at clockwise (CW) (omega1) - CW (omega2) - CW (omega3) by the flow tube distribution. A series of experiments on peak resolution and stationary phase retention revealed that better partition efficiencies were obtained at the flow rate of 0.5 mL/min (column 1) and 0.8 mL/min (column 2) for lower phase mobile and 0.2 mL/min (column 1) and 0.4 mL/min (column 2) for upper phase mobile when using the left-handed multilayer coil (total capacity: 57.0 mL for column 1 and 75.0 mL for column 2) under the rotation speeds of approximately omega1=300 rpm, omega2=150 rpm and omega3=150 rpm. PMID- 25805720 TI - Purification process of recombinant monoclonal antibodies with mixed mode chromatography. AB - An innovative process to purify mAb from CHO cell culture supernatant was developed. This three-step process involved two mixed mode resins and an anion exchange membrane. We used a human IgG mixture to determine the optimal conditions for each purification step. Thereafter, the whole process was evaluated and improved for the purification of a recombinant mAb produced in the supernatant of CHO cells. Once optimized, yield and purity of 88% and 99.9%, respectively were comparable to those obtained in a conventional process based on a capture step using protein A. In addition, aggregates, HCPs and DNA levels in the purified fraction were below regulatory specifications. Then we used mass spectrometry to identify contaminating proteins in the antibody fraction in order to highlight the behavior of HCPs. PMID- 25805721 TI - Design of shortest double-stranded DNA sequences covering all k-mers with applications to protein-binding microarrays and synthetic enhancers. PMID- 25805722 TI - Identification of cell types from single-cell transcriptomes using a novel clustering method. AB - MOTIVATION: The recent advance of single-cell technologies has brought new insights into complex biological phenomena. In particular, genome-wide single cell measurements such as transcriptome sequencing enable the characterization of cellular composition as well as functional variation in homogenic cell populations. An important step in the single-cell transcriptome analysis is to group cells that belong to the same cell types based on gene expression patterns. The corresponding computational problem is to cluster a noisy high dimensional dataset with substantially fewer objects (cells) than the number of variables (genes). RESULTS: In this article, we describe a novel algorithm named shared nearest neighbor (SNN)-Cliq that clusters single-cell transcriptomes. SNN-Cliq utilizes the concept of shared nearest neighbor that shows advantages in handling high-dimensional data. When evaluated on a variety of synthetic and real experimental datasets, SNN-Cliq outperformed the state-of-the-art methods tested. More importantly, the clustering results of SNN-Cliq reflect the cell types or origins with high accuracy. AVAILABILITY AND IMPLEMENTATION: The algorithm is implemented in MATLAB and Python. The source code can be downloaded at http://bioinfo.uncc.edu/SNNCliq. PMID- 25805723 TI - EW_dmGWAS: edge-weighted dense module search for genome-wide association studies and gene expression profiles. AB - We previously developed dmGWAS to search for dense modules in a human protein protein interaction (PPI) network; it has since become a popular tool for network assisted analysis of genome-wide association studies (GWAS). dmGWAS weights nodes by using GWAS signals. Here, we introduce an upgraded algorithm, EW_dmGWAS, to boost GWAS signals in a node- and edge-weighted PPI network. In EW_dmGWAS, we utilize condition-specific gene expression profiles for edge weights. Specifically, differential gene co-expression is used to infer the edge weights. We applied EW_dmGWAS to two diseases and compared it with other relevant methods. The results suggest that EW_dmGWAS is more powerful in detecting disease associated signals. PMID- 25805724 TI - Sublethal exposure to commercial formulations of the herbicides dicamba, 2,4 dichlorophenoxyacetic acid, and glyphosate cause changes in antibiotic susceptibility in Escherichia coli and Salmonella enterica serovar Typhimurium. AB - Biocides, such as herbicides, are routinely tested for toxicity but not for sublethal effects on microbes. Many biocides are known to induce an adaptive multiple-antibiotic resistance phenotype. This can be due to either an increase in the expression of efflux pumps, a reduced synthesis of outer membrane porins, or both. Exposures of Escherichia coli and Salmonella enterica serovar Typhimurium to commercial formulations of three herbicides-dicamba (Kamba), 2,4 dichlorophenoxyacetic acid (2,4-D), and glyphosate (Roundup)-were found to induce a changed response to antibiotics. Killing curves in the presence and absence of sublethal herbicide concentrations showed that the directions and the magnitudes of responses varied by herbicide, antibiotic, and species. When induced, MICs of antibiotics of five different classes changed up to 6-fold. In some cases the MIC increased, and in others it decreased. Herbicide concentrations needed to invoke the maximal response were above current food maximum residue levels but within application levels for all herbicides. Compounds that could cause induction had additive effects in combination. The role of soxS, an inducer of the AcrAB efflux pump, was tested in beta-galactosidase assays with soxS-lacZ fusion strains of E. coli. Dicamba was a moderate inducer of the sox regulon. Growth assays with Phe Arg beta-naphtylamide (PAbetaN), an efflux pump inhibitor, confirmed a significant role of efflux in the increased tolerance of E. coli to chloramphenicol in the presence of dicamba and to kanamycin in the presence of glyphosate. Pathways of exposure with relevance to the health of humans, domestic animals, and critical insects are discussed. IMPORTANCE: Increasingly common chemicals used in agriculture, domestic gardens, and public places can induce a multiple-antibiotic resistance phenotype in potential pathogens. The effect occurs upon simultaneous exposure to antibiotics and is faster than the lethal effect of antibiotics. The magnitude of the induced response may undermine antibiotic therapy and substantially increase the probability of spontaneous mutation to higher levels of resistance. The combination of high use of both herbicides and antibiotics in proximity to farm animals and important insects, such as honeybees, might also compromise their therapeutic effects and drive greater use of antibiotics. To address the crisis of antibiotic resistance requires broadening our view of environmental contributors to the evolution of resistance. PMID- 25805725 TI - The intracellular Scots pine shoot symbiont Methylobacterium extorquens DSM13060 aggregates around the host nucleus and encodes eukaryote-like proteins. AB - Endophytes are microbes that inhabit plant tissues without any apparent signs of infection, often fundamentally altering plant phenotypes. While endophytes are typically studied in plant roots, where they colonize the apoplast or dead cells, Methylobacterium extorquens strain DSM13060 is a facultatively intracellular symbiont of the meristematic cells of Scots pine (Pinus sylvestris L.) shoot tips. The bacterium promotes host growth and development without the production of known plant growth-stimulating factors. Our objective was to examine intracellular colonization by M. extorquens DSM13060 of Scots pine and sequence its genome to identify novel molecular mechanisms potentially involved in intracellular colonization and plant growth promotion. Reporter construct analysis of known growth promotion genes demonstrated that these were only weakly active inside the plant or not expressed at all. We found that bacterial cells accumulate near the nucleus in intact, living pine cells, pointing to host nuclear processes as the target of the symbiont's activity. Genome analysis identified a set of eukaryote-like functions that are common as effectors in intracellular bacterial pathogens, supporting the notion of intracellular bacterial activity. These include ankyrin repeats, transcription factors, and host-defense silencing functions and may be secreted by a recently imported type IV secretion system. Potential factors involved in host growth include three copies of phospholipase A2, an enzyme that is rare in bacteria but implicated in a range of plant cellular processes, and proteins putatively involved in gibberellin biosynthesis. Our results describe a novel endophytic niche and create a foundation for postgenomic studies of a symbiosis with potential applications in forestry and agriculture. IMPORTANCE: All multicellular eukaryotes host communities of essential microbes, but most of these interactions are still poorly understood. In plants, bacterial endophytes are found inside all tissues. M. extorquens DSM13060 occupies an unusual niche inside cells of the dividing shoot tissues of a pine and stimulates seedling growth without producing cytokinin, auxin, or other plant hormones commonly synthesized by plant associated bacteria. Here, we tracked the bacteria using a fluorescent tag and confocal laser scanning microscopy and found that they localize near the nucleus of the plant cell. This prompted us to sequence the genome and identify proteins that may affect host growth by targeting processes in the host cytoplasm and nucleus. We found many novel genes whose products may modulate plant processes from within the plant cell. Our results open up new avenues to better understand how bacteria assist in plant growth, with broad implications for plant science, forestry, and agriculture. PMID- 25805726 TI - Vaginal microbiota of adolescent girls prior to the onset of menarche resemble those of reproductive-age women. AB - Puberty is an important developmental stage wherein hormonal shifts mediate the physical and physiological changes that lead to menarche, but until now, the bacterial composition of vaginal microbiota during this period has been poorly characterized. We performed a prospective longitudinal study of perimenarcheal girls to gain insight into the timing and sequence of changes that occur in the vaginal and vulvar microbiota during puberty. The study enrolled 31 healthy, premenarcheal girls between the ages of 10 and 12 years and collected vaginal and vulvar swabs quarterly for up to 3 years. Bacterial composition was characterized by Roche 454 pyrosequencing and classification of regions V1 to V3 of 16S rRNA genes. Contrary to expectations, lactic acid bacteria, primarily Lactobacillus spp., were dominant in the microbiota of most girls well before the onset of menarche in the early to middle stages of puberty. Gardnerella vaginalis was detected at appreciable levels in approximately one-third of subjects, a notable finding considering that this organism is commonly associated with bacterial vaginosis in adults. Vulvar microbiota closely resembled vaginal microbiota but often exhibited additional taxa typically associated with skin microbiota. Our findings suggest that the vaginal microbiota of girls begin to resemble those of adults well before the onset of menarche. IMPORTANCE: This study addresses longitudinal changes in vaginal and vulvar microbial communities prior to and immediately following menarche. The research is significant because microbial ecology of the vagina is an integral aspect of health, including resistance to infections. The physiologic changes of puberty and initiation of cyclic menstruation are likely to have profound effects on vaginal microbiota, but almost nothing is known about changes that normally occur during this time. Our understanding has been especially hampered by the lack of thorough characterization of microbial communities using techniques that do not rely on the cultivation of fastidious bacteria, as well as a dearth of studies on girls in the early to middle stages of puberty. This study improves our understanding of the normal development of vaginal microbiota during puberty and onset of menarche and may better inform clinical approaches to vulvovaginal care of adolescent girls. PMID- 25805727 TI - Malaria parasites produce volatile mosquito attractants. AB - The malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid organelle that possesses plant-like metabolic pathways. Plants use the plastidial isoprenoid biosynthesis pathway to produce volatile odorants, known as terpenes. In this work, we describe the volatile chemical profile of cultured malaria parasites. Among the identified compounds are several plant-like terpenes and terpene derivatives, including known mosquito attractants. We establish the molecular identity of the odorant receptors of the malaria mosquito vector Anopheles gambiae, which responds to these compounds. The malaria parasite produces volatile signals that are recognized by mosquitoes and may thereby mediate host attraction and facilitate transmission. IMPORTANCE: Malaria is a key global health concern. Mosquitoes that transmit malaria are more attracted to malaria parasite-infected mammalian hosts. These studies aimed to understand the chemical signals produced by malaria parasites; such an understanding may lead to new transmission-blocking strategies or noninvasive malaria diagnostics. PMID- 25805728 TI - The number of alphaherpesvirus particles infecting axons and the axonal protein repertoire determines the outcome of neuronal infection. AB - Infection by alphaherpesviruses invariably results in invasion of the peripheral nervous system (PNS) and establishment of either a latent or productive infection. Infection begins with long-distance retrograde transport of viral capsids and tegument proteins in axons toward the neuronal nuclei. Initial steps of axonal entry, retrograde transport, and replication in neuronal nuclei are poorly understood. To better understand how the mode of infection in the PNS is determined, we utilized a compartmented neuron culturing system where distal axons of PNS neurons are physically separated from cell bodies. We infected isolated axons with fluorescent-protein-tagged pseudorabies virus (PRV) particles and monitored viral entry and transport in axons and replication in cell bodies during low and high multiplicities of infection (MOIs of 0.01 to 100). We found a threshold for efficient retrograde transport in axons between MOIs of 1 and 10 and a threshold for productive infection in the neuronal cell bodies between MOIs of 1 and 0.1. Below an MOI of 0.1, the viral genomes that moved to neuronal nuclei were silenced. These genomes can be reactivated after superinfection by a nonreplicating virus, but not by a replicating virus. We further showed that viral particles at high-MOI infections compete for axonal proteins and that this competition determines the number of viral particles reaching the nuclei. Using mass spectrometry, we identified axonal proteins that are differentially regulated by PRV infection. Our results demonstrate the impact of the multiplicity of infection and the axonal milieu on the establishment of neuronal infection initiated from axons. IMPORTANCE: Alphaherpesvirus genomes may remain silent in peripheral nervous system (PNS) neurons for the lives of their hosts. These genomes occasionally reactivate to produce infectious virus that can reinfect peripheral tissues and spread to other hosts. Here, we use a neuronal culture system to investigate the outcome of axonal infection using different numbers of viral particles and coinfection assays. We found that the dynamics of viral entry, transport, and replication change dramatically depending on the number of virus particles that infect axons. We demonstrate that viral genomes are silenced when the infecting particle number is low and that these genomes can be reactivated by superinfection with UV-inactivated virus, but not with replicating virus. We further show that viral invasion rapidly changes the profiles of axonal proteins and that some of these axonal proteins are rate limiting for efficient infection. Our study provides new insights into the establishment of silent versus productive alphaherpesvirus infections in the PNS. PMID- 25805729 TI - Manganese homeostasis in group A Streptococcus is critical for resistance to oxidative stress and virulence. AB - Streptococcus pyogenes (group A Streptococcus [GAS]) is an obligate human pathogen responsible for a spectrum of human disease states. Metallobiology of human pathogens is revealing the fundamental role of metals in both nutritional immunity leading to pathogen starvation and metal poisoning of pathogens by innate immune cells. Spy0980 (MntE) is a paralog of the GAS zinc efflux pump CzcD. Through use of an isogenic mntE deletion mutant in the GAS serotype M1T1 strain 5448, we have elucidated that MntE is a manganese-specific efflux pump required for GAS virulence. The 5448DeltamntE mutant had significantly lower survival following infection of human neutrophils than did the 5448 wild type and the complemented mutant (5448DeltamntE::mntE). Manganese homeostasis may provide protection against oxidative stress, explaining the observed ex vivo reduction in virulence. In the presence of manganese and hydrogen peroxide, 5448DeltamntE mutant exhibits significantly lower survival than wild-type 5448 and the complemented mutant. We hypothesize that MntE, by maintaining homeostatic control of cytoplasmic manganese, ensures that the peroxide response repressor PerR is optimally poised to respond to hydrogen peroxide stress. Creation of a 5448DeltamntE-DeltaperR double mutant rescued the oxidative stress resistance of the double mutant to wild-type levels in the presence of manganese and hydrogen peroxide. This work elucidates the mechanism for manganese toxicity within GAS and the crucial role of manganese homeostasis in maintaining GAS virulence. IMPORTANCE: Manganese is traditionally viewed as a beneficial metal ion to bacteria, and it is also established that most bacteria can tolerate high concentrations of this transition metal. In this work, we show that in group A Streptococcus, mutation of the mntE locus, which encodes a transport protein of the cation diffusion facilitator (CDF) family, results in accumulation of manganese and sensitivity to this transition metal ion. The toxicity of manganese is indirect and is the result of a failure of the PerR regulator to respond to oxidative stress in the presence of high intracellular manganese concentrations. These results highlight the importance of MntE in manganese homeostasis and maintenance of an optimal manganese/iron ratio in GAS and the impact of manganese on resistance to oxidative stress and virulence. PMID- 25805730 TI - Contribution of resistance-nodulation-cell division efflux systems to antibiotic resistance and biofilm formation in Acinetobacter baumannii. AB - Acinetobacter baumannii is a nosocomial pathogen of increasing importance due to its multiple resistance to antibiotics and ability to survive in the hospital environment linked to its capacity to form biofilms. To fully characterize the contribution of AdeABC, AdeFGH, and AdeIJK resistance-nodulation-cell division (RND)-type efflux systems to acquired and intrinsic resistance, we constructed, from an entirely sequenced susceptible A. baumannii strain, a set of isogenic mutants overexpressing each system following introduction of a point mutation in their cognate regulator or a deletion for the pump by allelic replacement. Pairwise comparison of every derivative with the parental strain indicated that AdeABC and AdeFGH are tightly regulated and contribute to acquisition of antibiotic resistance when overproduced. AdeABC had a broad substrate range, including beta-lactams, fluoroquinolones, tetracyclines-tigecycline, macrolides lincosamides, and chloramphenicol, and conferred clinical resistance to aminoglycosides. Importantly, when combined with enzymatic resistance to carbapenems and aminoglycosides, this pump contributed in a synergistic fashion to the level of resistance of the host. In contrast, AdeIJK was expressed constitutively and was responsible for intrinsic resistance to the same major drug classes as AdeABC as well as antifolates and fusidic acid. Surprisingly, overproduction of AdeABC and AdeIJK altered bacterial membrane composition, resulting in decreased biofilm formation but not motility. Natural transformation and plasmid transfer were diminished in recipients overproducing AdeABC. It thus appears that alteration in the expression of efflux systems leads to multiple changes in the relationship between the host and its environment, in addition to antibiotic resistance. IMPORTANCE: Increased expression of chromosomal genes for RND-type efflux systems plays a major role in bacterial multidrug resistance. Acinetobacter baumannii has recently emerged as an important human pathogen responsible for epidemics of hospital-acquired infections. Besides its remarkable ability to horizontally acquire resistance determinants, it has a broad intrinsic resistance due to low membrane permeability, endogenous resistance genes, and antibiotic efflux. The study of isogenic mutants from a susceptible A. baumannii clinical isolate overproducing or deleted for each of the three major RND-type pumps demonstrated their major contribution to intrinsic resistance and to the synergism between overproduction of an efflux system and acquisition of a resistance gene. We have also shown that modulation of expression of the structural genes for the efflux systems results in numerous alterations in membrane-associated cellular functions, in particular, in a decrease in biofilm formation and resistance gene acquisition. PMID- 25805732 TI - (Per)chlorate-reducing bacteria can utilize aerobic and anaerobic pathways of aromatic degradation with (per)chlorate as an electron acceptor. AB - The pathways involved in aromatic compound oxidation under perchlorate and chlorate [collectively known as (per)chlorate]-reducing conditions are poorly understood. Previous studies suggest that these are oxygenase-dependent pathways involving O2 biogenically produced during (per)chlorate respiration. Recently, we described Sedimenticola selenatireducens CUZ and Dechloromarinus chlorophilus NSS, which oxidized phenylacetate and benzoate, two key intermediates in aromatic compound catabolism, coupled to the reduction of perchlorate or chlorate, respectively, and nitrate. While strain CUZ also oxidized benzoate and phenylacetate with oxygen as an electron acceptor, strain NSS oxidized only the latter, even at a very low oxygen concentration (1%, vol/vol). Strains CUZ and NSS contain similar genes for both the anaerobic and aerobic-hybrid pathways of benzoate and phenylacetate degradation; however, the key genes (paaABCD) encoding the epoxidase of the aerobic-hybrid phenylacetate pathway were not found in either genome. By using transcriptomics and proteomics, as well as by monitoring metabolic intermediates, we investigated the utilization of the anaerobic and aerobic-hybrid pathways on different electron acceptors. For strain CUZ, the results indicated utilization of the anaerobic pathways with perchlorate and nitrate as electron acceptors and of the aerobic-hybrid pathways in the presence of oxygen. In contrast, proteomic results suggest that strain NSS may use a combination of the anaerobic and aerobic-hybrid pathways when growing on phenylacetate with chlorate. Though microbial (per)chlorate reduction produces molecular oxygen through the dismutation of chlorite (ClO2(-)), this study demonstrates that anaerobic pathways for the degradation of aromatics can still be utilized by these novel organisms. IMPORTANCE: S. selenatireducens CUZ and D. chlorophilus NSS are (per)chlorate- and chlorate-reducing bacteria, respectively, whose genomes encode both anaerobic and aerobic-hybrid pathways for the degradation of phenylacetate and benzoate. Previous studies have shown that (per)chlorate-reducing bacteria and chlorate-reducing bacteria (CRB) can use aerobic pathways to oxidize aromatic compounds in otherwise anoxic environments by capturing the oxygen produced from chlorite dismutation. In contrast, we demonstrate that S. selenatireducens CUZ is the first perchlorate reducer known to utilize anaerobic aromatic degradation pathways with perchlorate as an electron acceptor and that it does so in preference over the aerobic-hybrid pathways, regardless of any oxygen produced from chlorite dismutation. D. chlorophilus NSS, on the other hand, may be carrying out anaerobic and aerobic hybrid processes simultaneously. Concurrent use of anaerobic and aerobic pathways has not been previously reported for other CRB or any microorganisms that encode similar pathways of phenylacetate or benzoate degradation and may be advantageous in low-oxygen environments. PMID- 25805731 TI - Type IV pilus secretins have extracellular C termini. AB - Type IV pili (T4Ps) are surface appendages used by Gram-negative and Gram positive pathogens for motility and attachment to epithelial surfaces. In Gram negative bacteria, such as the important pediatric pathogen enteropathogenic Escherichia coli (EPEC), during extension and retraction, the pilus passes through an outer membrane (OM) pore formed by the multimeric secretin complex. The secretin is common to Gram-negative assemblies, including the related type 2 secretion (T2S) system and the type 3 secretion (T3S) system. The N termini of the secretin monomers are periplasmic and in some systems have been shown to mediate substrate specificity. In this study, we mapped the topology of BfpB, the T4P secretin from EPEC, using a combination of biochemical and biophysical techniques that allowed selective identification of periplasmic and extracellular residues. We applied rules based on solved atomic structures of outer membrane proteins (OMPs) to generate our topology model, combining the experimental results with secondary structure prediction algorithms and direct inspection of the primary sequence. Surprisingly, the C terminus of BfpB is extracellular, a result confirmed by flow cytometry for BfpB and a distantly related T4P secretin, PilQ, from Pseudomonas aeruginosa. Keeping with prior evidence, the C termini of two T2S secretins and one T3S secretin were not detected on the extracellular surface. On the basis of our data and structural constraints, we propose that BfpB forms a beta barrel with 16 transmembrane beta strands. We propose that the T4P secretins have a C-terminal segment that passes through the center of each monomer. IMPORTANCE: Secretins are multimeric proteins that allow the passage of secreted toxins and surface structures through the outer membranes (OMs) of Gram negative bacteria. To date, there have been no atomic structures of the C terminal region of a secretin, although electron microscopy (EM) structures of the complex are available. This work provides a detailed topology prediction of the membrane-spanning domain of a type IV pilus (T4P) secretin. Our study used innovative techniques to provide new and comprehensive information on secretin topology, highlighting similarities and differences among secretin subfamilies. Additionally, the techniques used in this study may prove useful for the study of other OM proteins. PMID- 25805733 TI - A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity. AB - Clostridium difficile is a leading cause of nosocomial infections worldwide and has become an urgent public health threat requiring immediate attention. Epidemic lineages of the BI/NAP1/027 strain type have emerged and spread through health care systems across the globe over the past decade. Limiting person-to-person transmission and eradicating C. difficile, especially the BI/NAP1/027 strain type, from health care facilities are difficult due to the abundant shedding of spores that are impervious to most interventions. Effective prophylaxis for C. difficile infection (CDI) is lacking. We have genetically modified a contractile R-type bacteriocin ("diffocin") from C. difficile strain CD4 to kill BI/NAP1/027 type strains for this purpose. The natural receptor binding protein (RBP) responsible for diffocin targeting was replaced with a newly discovered RBP identified within a prophage of a BI/NAP1/027-type target strain by genome mining. The resulting modified diffocins (a.k.a. Avidocin-CDs), Av-CD291.1 and Av CD291.2, were stable and killed all 16 tested BI/NAP1/027-type strains. Av CD291.2 administered in drinking water survived passage through the mouse gastrointestinal (GI) tract, did not detectably alter the mouse gut microbiota or disrupt natural colonization resistance to C. difficile or the vancomycin resistant Enterococcus faecium (VREF), and prevented antibiotic-induced colonization of mice inoculated with BI/NAP1/027-type spores. Given the high incidence and virulence of the pathogen, preventing colonization by BI/NAP1/027 type strains and limiting their transmission could significantly reduce the occurrence of the most severe CDIs. This modified diffocin represents a prototype of an Avidocin-CD platform capable of producing targetable, precision anti-C. difficile agents that can prevent and potentially treat CDIs without disrupting protective indigenous microbiota. IMPORTANCE: Treatment and prevention strategies for bacterial diseases rely heavily on traditional antibiotics, which impose strong selection for resistance and disrupt protective microbiota. One consequence has been an upsurge of opportunistic pathogens, such as Clostridium difficile, that exploit antibiotic-induced disruptions in gut microbiota to proliferate and cause life-threatening diseases. We have developed alternative agents that utilize contractile bactericidal protein complexes (R-type bacteriocins) to kill specific C. difficile pathogens. Efficacy in a preclinical animal study indicates these molecules warrant further development as potential prophylactic agents to prevent C. difficile infections in humans. Since these agents do not detectably alter the indigenous gut microbiota or colonization resistance in mice, we believe they will be safe to administer as a prophylactic to block transmission in high-risk environments without rendering patients susceptible to enteric infection after cessation of treatment. PMID- 25805736 TI - Genetic contribution of DKK-1 polymorphisms to RA structural severity and DKK-1 level of expression. PMID- 25805737 TI - Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis. Results of the INMUNOREMAR study. PMID- 25805734 TI - Upregulation of microRNA-146a by hepatitis B virus X protein contributes to hepatitis development by downregulating complement factor H. AB - Hepatic injuries in hepatitis B virus (HBV) patients are caused by immune responses of the host. In our previous study, microRNA-146a (miR-146a), an innate immunity-related miRNA, and complement factor H (CFH), an important negative regulator of the alternative pathway of complement activation, were differentially expressed in HBV-expressing and HBV-free hepatocytes. Here, the roles of these factors in HBV-related liver inflammation were analyzed in detail. The expression levels of miR-146a and CFH in HBV-expressing hepatocytes were assessed via analyses of hepatocyte cell lines, transgenic mice, adenovirus infected mice, and HBV-positive human liver samples. The expression level of miR 146a was upregulated in HBV-expressing Huh-7 hepatocytes, HBV-expressing mice, and patients with HBV infection. Further results demonstrated that the HBV X protein (HBx) was responsible for its effects on miR-146a expression through NF kappaB-mediated enhancement of miR-146a promoter activity. HBV/HBx also downregulated the expression of CFH mRNA in hepatocyte cell lines and the livers of humans and transgenic mice. Furthermore, overexpression and inhibition of miR 146a in Huh-7 cells downregulated and upregulated CFH mRNA levels, respectively. Luciferase reporter assays demonstrated that miR-146a downregulated CFH mRNA expression in hepatocytes via 3'-untranslated-region (UTR) pairing. The overall effect of this process in vivo is to promote liver inflammation. These results demonstrate that the HBx-miR-146a-CFH-complement activation regulation pathway might play an important role in the immunopathogenesis of chronic HBV infection. These findings have important implications for understanding the immunopathogenesis of chronic hepatitis B and developing effective therapeutic interventions. IMPORTANCE: Hepatitis B virus (HBV) remains an important pathogen and can cause severe liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma. Although HBV was found in 1966, the molecular mechanisms of pathogenesis are still poorly understood. In the present study, we found that the HBV X protein (HBx) promoted the expression of miR-146a, an innate immunity-related miRNA, through the NF-kappaB signal pathway and that increasingly expressed miR-146a downregulated its target complement factor H (CFH), an important negative regulator of the complement alternative pathway, leading to the promotion of liver inflammation. We demonstrated that the HBx-miR 146a-CFH-complement activation regulation pathway is potentially an important mechanism of immunopathogenesis caused by chronic HBV infection. Our data provide a novel molecular mechanism of HBV pathogenesis and thus help to understand the correlations between the complement system, an important part of innate immunity, and HBV-associated disease. These findings will also be important to identify potential therapeutic targets for HBV infection. PMID- 25805738 TI - A scoping review of bereavement risk assessment measures: Implications for palliative care. AB - BACKGROUND: Palliative care standards and policies recommend that bereavement support be provided to family caregivers, yet uncertainty surrounds whether support currently offered by palliative care services throughout developed countries meets caregiver needs. The public health model of bereavement support, which aligns bereavement support needs with intervention, may address this gap between policy and practice. AIM: The aim was to review the literature to identify bereavement risk assessment measures appropriate for different points in the caring and bereavement trajectories, evaluate their psychometric properties and assess feasibility for use in palliative care. DESIGN: A scoping review was systematically undertaken following Arksey and O'Malley's methodological framework. DATA SOURCES: PsycINFO, CINAHL, PubMed and Cochrane Reviews databases, as well as grey literature including Internet searches of Google, World Health Organization, CareSearch, the Grey Literature Report and OAIster were searched. Bereavement organisations and palliative care websites, reference lists in obtained articles and grief and bereavement handbooks were also scrutinised. RESULTS: Of 3142 records screened, 356 records yielded 70 grief measures. In all, 19 measures published between 1982 and 2014 were identified for inclusion in this review, and categorised for use with family caregivers at three points in time - before the patient's death (n = 5), in the period following the death (n = 10) and for screening of prolonged or complex grief (n = 4). The majority had acceptable psychometric properties; feasibility for use in palliative care varied substantially. CONCLUSION: This review is an important preliminary step in improving the assessment of bereavement risk and, consequently, better bereavement outcomes for palliative care family caregivers. PMID- 25805739 TI - The meaning of home at the end of life: A video-reflexive ethnography study. AB - BACKGROUND: While 'home' is cited most frequently as being the preferred place of death, most people will die in institutions. Yet, the meaning and significance of home for people nearing the end of life has not been fully explored. AIM: The aim of this article is to critically examine the meaning of home for dying patients and their families. DESIGN: The qualitative study used video-reflexive ethnography methods. Data were collected and analysed over an 18-month period. SETTING/PARTICIPANTS: Participants were recruited from two Australian sites: a palliative care day hospital and an acute hospital. Participants included patients with a prognosis of 6 months or less (n = 29), their nominated family member(s) (n = 5) and clinicians (n = 36) caring for them. Patients and families were 'followed' through care settings including the palliative care unit and into their own homes. RESULTS: Whether or not participants deemed space(s) safe or unsafe was closely related to the notion of home. Six themes emerged concerning this relationship: 'No place like home'; 'Safety, home and the hospital'; 'Hospital "becomes" home'; 'Home "becomes" hospital'; 'Hospital and "connections with home"'; and 'The built environment'. CONCLUSION: Home is a dynamic concept for people nearing the end of life and is concerned with expression of social and cultural identity including symbolic and affective connections, as opposed to being merely a physical dwelling place or street address. Clinicians caring for people nearing the end of life can foster linkages with home by facilitating connections with loved ones and meaningful artefacts. PMID- 25805735 TI - The soil microbiome influences grapevine-associated microbiota. AB - Grapevine is a well-studied, economically relevant crop, whose associated bacteria could influence its organoleptic properties. In this study, the spatial and temporal dynamics of the bacterial communities associated with grapevine organs (leaves, flowers, grapes, and roots) and soils were characterized over two growing seasons to determine the influence of vine cultivar, edaphic parameters, vine developmental stage (dormancy, flowering, preharvest), and vineyard. Belowground bacterial communities differed significantly from those aboveground, and yet the communities associated with leaves, flowers, and grapes shared a greater proportion of taxa with soil communities than with each other, suggesting that soil may serve as a bacterial reservoir. A subset of soil microorganisms, including root colonizers significantly enriched in plant growth-promoting bacteria and related functional genes, were selected by the grapevine. In addition to plant selective pressure, the structure of soil and root microbiota was significantly influenced by soil pH and C:N ratio, and changes in leaf- and grape-associated microbiota were correlated with soil carbon and showed interannual variation even at small spatial scales. Diazotrophic bacteria, e.g., Rhizobiaceae and Bradyrhizobium spp., were significantly more abundant in soil samples and root samples of specific vineyards. Vine-associated microbial assemblages were influenced by myriad factors that shape their composition and structure, but the majority of organ-associated taxa originated in the soil, and their distribution reflected the influence of highly localized biogeographic factors and vineyard management. IMPORTANCE: Vine-associated bacterial communities may play specific roles in the productivity and disease resistance of their host plant. Also, the bacterial communities on grapes have the potential to influence the organoleptic properties of the wine, contributing to a regional terroir. Understanding that factors that influence these bacteria may provide insights into management practices to shape and craft individual wine properties. We show that soil serves as a key source of vine-associated bacteria and that edaphic factors and vineyard-specific properties can influence the native grapevine microbiome preharvest. PMID- 25805741 TI - Interventions for bereaved parents following a child's death: A systematic review. AB - BACKGROUND: A child's death is one of the most stressful events that parents and siblings may experience. Interventions for bereaved families following a child's death have been examined over the last several decades. However, there is little high-quality evidence to support any rationale for determining optimal interventions for bereaved parents and siblings. AIM: This study objectives were to evaluate the efficacy of interventions for bereaved parents and siblings following a child's death, to collect empirical evidence of the quality of these intervention studies, and to identify methodological challenges. DESIGN: A systematic review of data from randomized controlled trials of interventions for parents or siblings bereaved after a child loss. DATA SOURCES: We searched MEDLINE (from 1949), PsycINFO (from 1806), and CINAHL (from 1806) databases for key terms and checked the reference lists of potentially relevant articles. RESULTS: We identified nine articles describing eight eligible trials from which we extracted data. The four types of intervention included support groups, counseling, psychotherapy, and crisis intervention. Most intervention trials showed some effect on participants in at least one outcome measure. However, we identified many severe methodological issues and outcome sets in these trials. CONCLUSION: Very little evidence of sufficient quality is available to confirm the effects of intervention measures on bereaved parents and siblings following a child's death. Well-designed randomized controlled trials are needed to improve our understanding of the efficacy and implementation of interventions targeting bereaved parents and siblings. PMID- 25805740 TI - Comparison of preferences for end-of-life care among patients with advanced cancer and their caregivers: A discrete choice experiment. AB - BACKGROUND: Patients with advanced cancer often have to make difficult decisions, such as how much to spend on moderately life-extending treatments. This and other end-of-life decisions are also influenced by their informal caregivers. Understanding the relative value that patients and their caregivers place on various aspects of end-of-life care can help clinicians tailor treatments to best meet the preferences of their patients. AIM: To quantify willingness to pay of patients with advanced cancer and their caregivers to extend the patients' life by 1 year and to compare this result to their willingness to pay for other end-of life improvements. DESIGN: Cross-sectional survey using a discrete choice experiment. PARTICIPANTS: A total of 211 patients with stage IV cancer and their informal caregivers. RESULTS: The willingness to pay of patients to extend their life by 1 year (S$18,570; 95% confidence interval: S$6687-S$30,542) was not statistically different from their willingness to pay to avoid severe pain (S$22,199; S$11,648-S$32,450), to die at home (S$31,256; S$21,249-S$41,391), not be a burden on family and friends (S$4051; -S$3543 to S$11,568), or to receive a high-quality health-care experience (S$16,191; S$9266-S$23,037). Consistent with our hypothesis, caregivers had a greater willingness to pay than patients to extend life (S$61,368; S$37,030-S$86,210) and for most other end-of-life improvements. CONCLUSION: Results highlight the importance of pain management, supporting home deaths, and addressing other end-of-life concerns, in addition to efforts to extend life. Differences in willingness to pay of patients and caregivers suggest the need for eliciting patient preferences during treatment decision making as opposed to relying on caregiver input. PMID- 25805742 TI - Twenty-five years of European Union collaboration in ANCA-associated vasculitis research. AB - This special edition reviews the progress in understanding of systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). European research groups have contributed to this research including the original observations of the association between ANCA and vasculitis. Areas of interest include classification and epidemiology, genetics and pathogenesis, disease assessment, histology and long-term outcomes. Clinical trials conducted by the European Vasculitis Study group have helped to define the current standard of care for the treatment of patients with vasculitis and provided a platform for the investigation of newer therapies. The prognosis of patients with ANCA associated vasculitis has improved over this period as a result of facilitated diagnosis and development of consensus, evidence-based, treatment recommendations. The ANCA story represents an example of the power of a biomarker in influencing a disease area, inspiring research and providing physicians with better tools to treat patients with these disorders. PMID- 25805743 TI - Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody associated vasculitis. AB - BACKGROUND: Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) since 2003. Our objective was to describe outcomes and adverse events following rituximab since that time in an inception cohort. METHODS: Patients with AAV (diagnosed 1991-2012) who received rituximab (n = 120) were evaluated and incidence per person-year (PPY) with 95% confidence interval was calculated for relapse and infections. Time to remission and relapse by number of rituximab infusions given per treatment course (<=2 versus >2) and by ever having been exposed to cyclophosphamide were compared using Kaplan-Meier curves. Rituximab-treated patients were characterized in comparison with AAV patients treated with cyclophosphamide but not exposed to rituximab (n = 351) using Fisher's exact or rank tests. RESULTS: Rituximab resulted in 86% achieving remission and 41% having a subsequent relapse in a median of 19 months (range 9 29). Time to remission and relapse were similar between rituximab infusion courses (<=2 versus >2; remission P = 0.86 and relapse P = 0.78, respectively). Incidence of relapse was 0.22 PPY (0.14, 0.31) and of severe infection was 0.12 PPY (0.08, 0.24). Time to relapse was shorter in those never exposed to cyclophosphamide (n = 20): 50% by 8 months versus 50% by 24 and 30 months for those with prior or concurrent exposure to cyclophosphamide (n = 100). Compared with those who never received rituximab, rituximab-treated patients were younger (P < 0.001), more likely to have granulomatosis with polyangiitis (P = 0.001) and had more upper airway (P = 0.01) and less kidney involvement (P = 0.007). CONCLUSIONS: Rituximab is beneficial when prescribed outside of a trial setting. Response to treatment and relapse is similar regardless of infusion number. Rituximab without cyclophosphamide may result in a shorter time to relapse supporting combination of these therapies. PMID- 25805744 TI - Use of mycophenolate in ANCA-associated renal vasculitis: 13 years of experience at a university hospital. AB - INTRODUCTION: Standard therapy with corticosteroids (CS) and cyclophosphamide (CYC) followed by azathioprine has been shown to improve renal and patient survival in ANCA-associated renal vasculitis (rAAV). Mycophenolate mofetil (MF) has been progressively introduced for the treatment of rAAV in the last years because of its immunosuppressive efficacy combined with a lower toxicity profile. In this study, we retrospectively analyse the results of the introduction of MF for maintenance and induction therapy in rAAV in our institution from 2001 to 2013. RESULTS: We reported 67 patients treated with MF as a maintenance treatment, divided by baseline serum creatinine (>500 umol/L: Group 1 and <500 umol/L: Group 2) and treatment schedule. Twenty-nine of the 67 patients were also treated with MF as induction treatment, mostly in Group 2. During the follow-up (2 years after the diagnosis) creatinine levels for serum glomerular filtration rate, ANCA titres, C-reactive protein and percentage of haematuria decreased in all groups. In Group 2, parameters and also relapse rates were similar at 24 months in patients treated with CYC or MF as an induction treatment (Subgroups 2a and 2b, respectively). Median dose of MF in maintenance treatment was 1000 mg daily and prednisone dose was tapered to 10 mg daily from Month 3. After 24 months, 82% of patients remained on MF therapy, 18% had discontinued the treatment, seven of them due to medical indication and two because of gastrointestinal intolerance. The percentage of patients that started renal replacement therapy was irregular in Group 1 depending on the subgroup (25-100%), and 10% in Group 2. Adverse effects, such as neutropenia, infections and neoplasia, were more prevalent in groups treated with CYC. CONCLUSION: In conclusion, in our patients with rAAV, MF demonstrated to be an effective and well-tolerated option for maintenance treatment. As an induction treatment, MF seems to be similar to CYC for patients with moderate renal failure in the diagnosis. PMID- 25805745 TI - High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis. AB - BACKGROUND: Mycophenolic acid (MPA) is used in the maintenance therapy of antineutrophil cytoplasm antibody-associated systemic vasculitis (AASV). MPA exerts its immunosuppression by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), depleting activated lymphocytes of guanine nucleotides and retarding their proliferation. The purpose of our study was to examine the correlation between clinical outcome and pharmacokinetic-pharmacodynamic (PD) relationships of MPA in patients with AASV. METHODS: We studied 358 Caucasian control patients without any MPA therapy to examine basal IMPDH activity. Thirty Caucasian patients with AASV under maintenance therapy with mycophenolate mofetil (MMF) underwent therapeutic drug monitoring. RESULTS: We observed a high interindividual variability with regard to basal IMPDH activity in patients without any MPA treatment (0.8-35 nmol/mg protein/h). Patients were followed for a mean (+/-SD) period of 22 +/- 8 months. During the observation period, seven patients had a relapse with an elevated Birmingham Vasculitis Activity Score of 9.2 +/- 6. The basal IMPDH activity (Abasal) in patients who subsequently relapsed was raised at baseline, before receiving their first dose of MMF, and further increased at the time of relapse, when compared with stable patients. Patients with a relapse during the maintenance therapy had significantly higher levels of IMPDH activity [IMPDH enzyme activity curve (AEC) (0-12)] than stable patients (P = 0.001), indicating inadequate IMPDH suppression. MPA-AUC (0-12) was significantly decreased in relapse patients, in contrast to stable patients (P < 0.05). CONCLUSIONS: Due to the highly variable response to maintenance therapy with MPA, PD drug monitoring is a new tool for detecting inadequate immunosuppression in AASV patients. PMID- 25805746 TI - Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. AB - It is now 25 years since the first European studies on vasculitis--the anti neutrophil cytoplasmic antibody (ANCA) standardization project. Over that period of time, there have been major developments in the classification of the vasculitides, which has permitted the conduct of high-quality epidemiology studies. Studying the epidemiology of rare diseases such as the ANCA-associated vasculitides (AAV) poses considerable challenges to epidemiologists. The first is the need for a clear definition of a case with good differentiation from similar disorders. The second is case capture. The vasculitides are rare, and therefore, a large population is required to determine the incidence and prevalence, and this poses questions of feasibility. A large population increases the risk of incomplete case detection but permits a reasonable number of cases to be collected in a practicable time frame, whereas a smaller population requires a much longer time frame to collect the necessary cases, which may also not be feasible. Statistical methods of capture-recapture analysis enable estimates to be made of the number of missing cases. The third is case ascertainment. The AAV are virtually always managed in secondary care, and therefore, hospital-based case ascertainment may be appropriate. Fourthly, the rarity of the conditions makes prospective case-control studies investigating risk factors difficult to conduct because the population size required to achieve statistical confidence is in excess of that which is readily available. Thus, much of the data on risk factors are derived from retrospective studies with inherent potential bias. PMID- 25805748 TI - Twenty-five years of RENHIS: a history of histopathological studies within EUVAS. AB - In the early 1990s, an international working group of experienced renal pathologists, the Renal Histology group, set up a scoring system for biopsies with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. This scoring system subdivided glomerular, interstitial and vascular lesions and served as a tool for the evaluation of all renal biopsies from studies of the European Vasculitis Study Group (EUVAS). Histopathological studies gave new insights into the prediction of renal outcome in patients with ANCA-associated glomerulonephritis. Percentage of normal glomeruli and a selected number of interstitial parameters were reliable predictors of long-term follow-up glomerular filtration rate in all studies. Out of these results, a histopathological classification distinguishing focal, crescentic, mixed and sclerotic classes of ANCA-associated glomerulonephritis was developed. Until today, 13 studies have validated this classification system. Future studies will try to determine if and how renal histology could be helpful in guiding treatment of ANCA-associated glomerulonephritis. PMID- 25805747 TI - Adverse events and infectious burden, microbes and temporal outline from immunosuppressive therapy in antineutrophil cytoplasmic antibody-associated vasculitis with native renal function. AB - BACKGROUND: Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV. METHODS: Biopsy-proven AAV patients (diagnosed 1/1991-6/2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or >=3. Cox regression was used to estimate hazard ratios with 95% confidence intervals. RESULTS: A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Staphylococcus aureus was most frequently seen among positive cultures (41%, 78 S. aureus/192 total positive cultures), and only one Pneumocystis jiroveci pneumonia (6 weeks into treatment). All-cause death in 12 months was associated with infections (% deaths: 0 infections 3%; 1-2 infections 10%, >=3 infections 13%, P = 0.002). Controlling for age, sex and kidney function, patients with severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0 8.7; P = 0.001). CONCLUSIONS: More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity. PMID- 25805749 TI - A historical essay on detection of anti-neutrophil cytoplasmic antibodies. AB - In this essay we describe a number of the known and not so known experiences of the early anti-neutrophil cytoplasmic antibodies (ANCAs) days, explaining why and how we reached consensus on the standard indirect immunofluorescence (IIF) techniques, the naming of the two principal C- and P-ANCA patterns, why we chose to use IIF as the standard technique, how the solid phase assays have developed and where we stand today, the use of ANCA for diagnosis and the importance of using several techniques for that purpose, how ANCA titres are related to disease activity and the clinical impact of this, and finally the implications of ANCA being a natural, polyclonal antibody response against various epitopes in relation to diagnostics and disease patterns. PMID- 25805750 TI - Impaired Endothelial Regeneration Through Human Parvovirus B19-Infected Circulating Angiogenic Cells in Patients With Cardiomyopathy. AB - Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage. PMID- 25805751 TI - Proton-Pump Inhibitor Exposure Aggravates Clostridium difficile-Associated Colitis: Evidence From a Mouse Model. AB - BACKGROUND: Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients. In addition to the infection due to toxigenic C. difficile in the gastrointestinal tract of susceptible hosts, other predisposing factors for C. difficile infection (CDI) are identified, including advanced age, a prolonged hospital stay, and use of acid-suppressive drugs. Of note, exposure to gastric acid-reducing agents, such as H2 blockers and proton pump inhibitors (PPIs), remains a controversial risk factor, and has been associated with CDI in some studies but not in others. A mouse model of antibiotic-associated clostridial colitis was established to examine the role of PPIs for CDI. MATERIALS AND METHODS: A mouse model of antibiotic-associated clostridial colitis was set up. NF-kappaB reporter mice were used to address the in vivo spatial and temporal inflammatory patterns of C. difficile-associated colitis. Serum levels of lipopolysaccharide and dextran-FITC were measured to reflect the barrier permeability of affected intestines. RESULTS: Mice with CDI that were exposed to PPI exhibited greater losses of stool consistency and body and cecal weights than those that were not exposed to PPI. Further, more neutrophilic infiltrations, epithelial damage, and inflammatory cytokine expression were noted in colon specimens of the mice with PPI exposure. More evident inflammatory responses were detected by in vivo imaging of NF-kappaB reporter mice with CDI that were exposed to PPI. Gut barrier permeability was increased to a greater extent, as reflected by higher serum levels of lipopolysaccharide and dextran-FITC in mice with CDI that were exposed to PPI. CONCLUSIONS: Our mouse model demonstrates that PPI exposure increases the severity of intestinal inflammation in mice with C. difficile-associated colitis. PMID- 25805752 TI - USP38, FREM3, SDC1, DDC, and LOC727982 Gene Polymorphisms and Differential Susceptibility to Severe Malaria in Tanzania. AB - Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Within a case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified in recent genome wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism, 6.3%; alpha-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions. PMID- 25805753 TI - Lack of Galectin-3 Prevents Cardiac Fibrosis and Effective Immune Responses in a Murine Model of Trypanosoma cruzi Infection. AB - BACKGROUND: Chagas disease is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. One of the major causes of mortality in the disease is the cardiomyopathy observed in chronic patients, despite the low number of parasites detected in cardiac tissue. Galectin-3, a carbohydrate binding protein with affinity for beta-galactoside-containing glycoconjugates, is upregulated upon infection, and it has been recently involved in the pathophysiology of heart failure. METHODS: We investigated the role of galectin-3 in systemic and local responses in a murine model of T. cruzi infection, using knockout animals. Molecular mechanisms underlying galectin-3-dependent inflammatory responses were further assessed in cultured dendritic cells in vitro. RESULTS: Mice deficient for galectin-3 have elevated blood parasitemia levels and impaired cytokine production during infection. Remarkably, galectin-3 promotes cellular infiltration in the heart of infected mice and subsequent collagen deposition and cardiac fibrosis. Furthermore, we show that an unbalanced Toll-like receptor expression on antigen-presenting cells may be the cause of the impaired immune response observed in galectin-3-deficient mice in vivo. CONCLUSIONS: These results suggest that galectin-3 is strongly involved in Chagas disease, not only in the immune response against T. cruzi, but also in mediating cardiac tissue damage. PMID- 25805754 TI - Can a knee brace reduce the strain in the anterior cruciate ligament? A study using combined in vivo/in vitro method. AB - BACKGROUND AND AIM: It is unknown whether prophylactic knee braces can reduce the strain in the anterior cruciate ligament during dynamic activities. TECHNIQUE: An athlete, who had characteristics of high anterior cruciate ligament injury risk, was chosen. A motion capture system (Optotrak Certus; Northern Digital, Waterloo, ON, Canada) was used to record dynamic trials during drop-landing activity of this subject with and without the knee brace being worn. A musculoskeletal model was used to estimate the muscle forces during this activity. A dynamic knee simulator then applied kinematics and muscle forces on a cadaver knee with and without the brace mounted on it. The anterior cruciate ligament strain was measured. DISCUSSION: The peak strain in the anterior cruciate ligament was substantially lower for the braced (7%) versus unbraced (20%) conditions. Functional knee braces could decrease the strain in the anterior cruciate ligament during dynamic activities in a high-risk subject. However, the reduction seems to be a result of altered muscle firing pattern due to the brace. CLINICAL RELEVANCE: Prophylactic knee brace could reduce the strain in the anterior cruciate ligament of high-risk subjects during drop-landing through altered muscle firing pattern associated with brace wear. This could help reduce the anterior cruciate ligament injury risk. PMID- 25805755 TI - Stagnation of treatment times over a decade: results of a pooled analysis from the MERCI registry, MERCI, TREVO, and TREVO 2 trials. AB - BACKGROUND: There has been a growing interest in improving systems of care for the endovascular treatment of acute ischemic stroke. We analyzed data from previous registries and studies to determine if there has been an improvement in times to reperfusion with increasing experience. METHODS: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), MERCI Registry and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), and TREVO 2 trials and assessed times from last known normal to puncture, from hospital arrival to puncture, and procedure duration by year to determine if there has been a reduction in times. Demographic, radiographic, and clinical information were also assessed in a multivariate regression analysis to determine the predictors of good outcomes defined as a modified Rankin Scale score of 0-2 at 3 months. RESULTS: 1248 patients of mean age 68+/-14 years and median NIH Stroke Scale score 18 were analyzed from 2001 to 2011. Procedure times showed a significant improvement while last known normal to puncture times remained static. In multivariate logistic regression analysis, longer last known normal to puncture time and longer procedure duration were associated with a decreased chance of a good outcome (OR 0.84, 95% CI 0.76 to 0.92, p=0.0004 and OR 0.75, 95% CI 0.61 to 0.91, p=0.0040, respectively). CONCLUSIONS: Despite a reduction in procedure times, there has not been a corresponding improvement in overall last known normal to puncture times over a 10-year period. The current study shows that there are many opportunities to create more efficient endovascular stroke systems of care in trials. PMID- 25805756 TI - Combined association of occupational and leisure-time physical activity with all cause and coronary heart disease mortality among a cohort of men followed-up for 22 years. AB - OBJECTIVES: Leisure-time physical activity (LTPA) is a well-established protective factor for all-cause mortality and cardiovascular mortality while occupational physical activity (OPA) has shown contradictory results. We examined the association between OPA and all-cause and coronary heart disease (CHD) mortality, and tested its combined effect with LTPA. METHODS: The CORDIS Study (Cardiovascular Occupational Risk Factor Determination in Israel Study) is a prospective cohort study of industrial workers examined during 1985-1989 and followed-up for 22 years. Data on self-reported OPA and LTPA among 4819 males (20 70 years old) were merged with data on all-cause and CHD mortality obtained from the National Death Registry. RESULTS: A higher incidence rate of all-cause mortality and CHD mortality was observed among men who performed moderate-hard OPA compared with those who performed none-mild OPA. Multiple regression analysis based on the Cox proportional hazards model showed that moderate-hard OPA was associated with increased risk of all-cause mortality (HR=1.42, 95% CI 1.16 to 1.74, p<0.001), while LTPA (30 min at least twice a week vs less or none) was associated with reduced risk for all-cause mortality (HR=0.61, 95% CI 0.48 to 0.79, p<0.001), after adjusting for potential confounders, including sociodemographic variables, body mass index, comorbidity and lifestyle habits. Employees who performed moderate-hard OPA and no LTPA had the greatest risk for all-cause mortality and employees who performed none-light OPA and LTPA had the lowest risk. Similar but non-significant trends were observed for the association with CHD mortality. CONCLUSIONS: Moderate-hard OPA among industrial male workers may be deleterious to health and should not be a substitute to LTPA. PMID- 25805757 TI - Determinants of shortened, disrupted, and mistimed sleep and associated metabolic health consequences in healthy humans. AB - Recent increases in the prevalence of obesity and type 2 diabetes mellitus (T2DM) in modern societies have been paralleled by reductions in the time their denizens spend asleep. Epidemiological studies have shown that disturbed sleep-comprising short, low-quality, and mistimed sleep-increases the risk of metabolic diseases, especially obesity and T2DM. Supporting a causal role of disturbed sleep, experimental animal and human studies have found that sleep loss can impair metabolic control and body weight regulation. Possible mechanisms for the observed changes comprise sleep loss-induced changes in appetite-signaling hormones (e.g., higher levels of the hunger-promoting hormone ghrelin) or hedonic brain responses, altered responses of peripheral tissues to metabolic signals, and changes in energy intake and expenditure. Even though the overall consensus is that sleep loss leads to metabolic perturbations promoting the development of obesity and T2DM, experimental evidence supporting the validity of this view has been inconsistent. This Perspective aims at discussing molecular to behavioral factors through which short, low-quality, and mistimed sleep may threaten metabolic public health. In this context, possible factors that may determine the extent to which poor sleep patterns increase the risk of metabolic pathologies within and across generations will be discussed (e.g., timing and genetics). PMID- 25805759 TI - Dietary iron, circadian clock, and hepatic gluconeogenesis. PMID- 25805758 TI - The streetlight effect in type 1 diabetes. AB - In the nearly 100 years since the discovery of therapeutic insulin, significant research efforts have been directed at finding the underlying cause of type 1 diabetes (T1D) and developing a "cure" for the disease. While progress has clearly been made toward each of these goals, neither vision has been fulfilled. With increasing pressure from both public and private funders of diabetes research, growing impatience of those with T1D at the lack of practical discoveries, increased competition for research funds, uncertainties on the reproducibility of published scientific data, and questions regarding the value of animal models, the current research environment has become extraordinarily difficult to traverse from the perspective of investigators. As a result, there is an increasing pressure toward performance of what might be considered "safe" research, where the aim is to affirm existing dogmas rather than to pioneer efforts involving unconventional thought. Psychologists refer to this practice as "observational bias" while cartoonists label the process the "streetlight effect." In this Perspective, we consider notions in T1D research that should be subject to bold question and provide additional concepts, many somewhat orphan to research efforts, whose investigation could lead to a means for truly identifying the cause of and a cure for T1D. PMID- 25805760 TI - New insights into the mechanisms of islet inflammation in type 2 diabetes. PMID- 25805761 TI - Unacylated ghrelin: a gut-limb connection. PMID- 25805762 TI - beta-Hydroxypyruvate: a new diabetogenic factor? PMID- 25805763 TI - Allelic expression imbalance: tipping the scales to elucidate the function of type 2 diabetes-associated loci. PMID- 25805764 TI - The streetlight effect--is there light at the end of the tunnel? PMID- 25805765 TI - Deletion of both Rab-GTPase-activating proteins TBC14KO and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport. Diabetes 2015;64:746 759. PMID- 25805767 TI - Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling. AB - The hypothalamus is important for regulation of energy intake. Mutations in genes involved in the function of the hypothalamus can lead to early-onset severe obesity. To look further into this, we have followed a strategy that allowed us to identify rare and common gene variants as candidates for the background of extreme obesity from a relatively small cohort. For that we focused on subjects with a well-selected phenotype and on a defined gene set and used a rich source of genetic data with stringent cut-off values. A list of 166 genes functionally related to the hypothalamus was generated. In those genes complete exome sequence data from 30 extreme obese subjects (60 genomes) were screened for novel rare indel, nonsense, and missense variants with a predicted negative impact on protein function. In addition, (moderately) common variants in those genes were analyzed for allelic association using the general population as reference (false discovery rate<0.05). Six novel rare deleterious missense variants were found in the genes for BAIAP3, NBEA, PRRC2A, RYR1, SIM1, and TRH, and a novel indel variant in LEPR. Common variants in the six genes for MBOAT4, NPC1, NPW, NUCB2, PER1, and PRRC2A showed significant allelic association with extreme obesity. Our findings underscore the complexity of the genetic background of extreme obesity involving rare and common variants of genes from defined metabolic and physiologic processes, in particular regulation of the circadian rhythm of food intake and hypothalamic signaling. PMID- 25805768 TI - A critical test of the assumption that men prefer conformist women and women prefer nonconformist men. AB - Five studies tested the common assumption that women prefer nonconformist men as romantic partners, whereas men prefer conformist women. Studies 1 and 2 showed that both men and women preferred nonconformist romantic partners, but women overestimated the extent to which men prefer conformist partners. In Study 3, participants ostensibly in a small-group interaction showed preferences for nonconformist opposite-sex targets, a pattern that was particularly evident when men evaluated women. Dating success was greater the more nonconformist the sample was (Study 4), and perceptions of nonconformity in an ex-partner were associated with greater love and attraction toward that partner (Study 5). On the minority of occasions in which effects were moderated by gender, it was in the reverse direction to the traditional wisdom: Conformity was more associated with dating success among men. The studies contradict the notion that men disproportionately prefer conformist women. PMID- 25805769 TI - Corrigendum. AB - Craig, M. A., & Richeson, J. A. (2014). More diverse yet less tolerant? How the increasingly diverse racial landscape affects White Americans' racial attitudes. Personality and Social Psychology Bulletin, 40(6), 750-761. doi:10.1177/0146167214524993. PMID- 25805770 TI - Using the Haddon matrix: introducing the third dimension. PMID- 25805771 TI - Scared safe? Abandoning the use of fear in urban violence prevention programmes. PMID- 25805772 TI - MENTOR-VIP and broader capacity building for injury and violence prevention. PMID- 25805773 TI - An evaluation of the impact of the key information summary on GPs and out-of hours clinicians in NHS Scotland. AB - BACKGROUND AND AIMS: Key information summary is one of the first national shared electronic patient records enabling GPs to share clinical information with unscheduled care providers, including out-of-hours. Implemented during 2013, over 90,000 patient records have been created. This evaluation identified the impact of key information summary on healthcare services. METHODS: Evidence was collected using online questionnaires and structured telephone interviews. Opinions providing a numerical estimate of value were analysed using statistical methods, while qualitative responses were synthesised using thematic analysis. RESULTS: The vast majority of respondents from 441 GP practices and 33 out-of hours clinicians show that key information summary enhances patient safety, improves clinical management, reduces hospital admissions, empowers clinicians, aids communication across services and enables decisions to be responsive to patients' wishes. CONCLUSIONS: Patients willingly consent to share data with unscheduled care clinicians. Patients benefitting include those with palliative, complex or multiple conditions, at high risk of using emergency services. Out-of hours clinicians would welcome more key information summaries, all well-completed and including social care information. Improvements include software enhancements and wider sharing of information with all unscheduled care services. PMID- 25805774 TI - Erratum for Lamichhane et al., lack of tRNA modification isopentenyl-A37 alters mRNA decoding and causes metabolic deficiencies in fission yeast. PMID- 25805776 TI - Monitoring adolescent health behaviours and social determinants cross-nationally over more than a decade: introducing the Health Behaviour in School-aged Children (HBSC) study supplement on trends. PMID- 25805777 TI - Building knowledge on adolescent health: reflections on the contribution of the Health Behaviour in School-aged Children (HBSC) study. PMID- 25805778 TI - Trend analyses in the health behaviour in school-aged children study: methodological considerations and recommendations. AB - BACKGROUND: This article presents the scope and development of the Health Behaviour in School-aged Children (HBSC) study, reviews trend papers published on international HBSC data up to 2012 and discusses the efforts made to produce reliable trend analyses. METHODS: The major goal of this article is to present the statistical procedures and analytical strategies for upholding high data quality, as well as reflections from the authors of this article on how to produce reliable trends based on an international study of the magnitude of the HBSC study. HBSC is an international cross-sectional study collecting data from adolescents aged 11-15 years, on a broad variety of health determinants and health behaviours. RESULTS: A number of methodological challenges have stemmed from the growth of the HBSC-study, in particular given that the study has a focus on monitoring trends. Some of those challenges are considered. When analysing trends, researchers must be able to assess whether a change in prevalence is an expression of an actual change in the observed outcome, whether it is a result of methodological artefacts, or whether it is due to changes in the conceptualization of the outcome by the respondents. CONCLUSION: The article present recommendations to take a number of the considerations into account. The considerations imply methodological challenges, which are core issues in undertaking trend analyses. PMID- 25805779 TI - Trends in self-rated health in European and North-American adolescents from 2002 to 2010 in 32 countries. AB - BACKGROUND: Self-rated health (SRH) in adolescence is known to be associated with health outcomes in later life. We carried out a trend analysis on data coming from three waves of data collected in 32 countries (mostly European) from 2002 to 2010 coming from the Health Behaviour in School-Aged Children surveys. METHODS: SRH in adolescents was assessed using a Likert scale (excellent, good, fair and poor). Responses were dichotomized into 'excellent' vs. 'rest'. Country, age and gender groups were compared based on the odds ratio of declaring excellent SRH in 2010 with respect to 2002 and 2006. RESULTS: The trend for European adolescents indicates an improvement over the last decade, although, in the majority of countries, a higher proportion of adolescents rate their health as excellent during the period 2002-06 with respect to the second half of the decade (2006 10).Girls were found to constantly rate their health as poorer, compared to their male peers, in all countries. Age has also a very stable trend towards a decreasing rating of health with increasing age. CONCLUSION: Decreased rating of health in the period 2006-10 may be a signal of the socio-economic difficulties of Europe in the last part of this decade. PMID- 25805781 TI - Trends in toothbrushing in 20 countries/regions from 1994 to 2010. AB - BACKGROUND: For maintaining good oral health, twice-a-day toothbrushing routine is recommended world-wide. As an association between oral diseases and the main non-communicable diseases is confirmed, the importance of brushing is rising. The aim of this article is to describe trends in more-than-once-a-day toothbrushing frequency in 20 countries/regions participating in five consecutive HBSC Surveys between 1994 and 2010. METHODS: Eleven-, 13-, and 15-year-old children, who replied to the questionnaire in any of the five surveys, were included (N = 474 760). Trends were analysed by logistic regression and multilevel logistic regression modelling. RESULTS: Prevalence of recommended toothbrushing behaviour increased in all countries except in Scandinavia, which had already attained a very high level in 1994. The highest increase (more than + 16%) was observed in Estonia, Russia, Latvia, Finland and in Flemish Belgium. Girls had higher prevalence of toothbrushing than boys (OR = 2.06, 99% CI 2.03-2.10). However, the increasing trend was stronger among boys (OR(2010 vs. 1994) for boys 1.60; for girls 1.48), and among the younger adolescents (OR(2010 vs. 1994) for 11-year olds 1.64; for 15-year-olds 1.45). CONCLUSION: Recommended toothbrushing frequency increased in most of the studied countries/regions and differences between the countries diminished during 2004-2010. PMID- 25805780 TI - Fruit and vegetable consumption trends among adolescents from 2002 to 2010 in 33 countries. AB - BACKGROUND: Fruit and vegetable consumption is linked to many positive health outcomes, nevertheless many adolescents do not consume fruit and vegetables on a daily basis. METHODS: Data of 488,951 adolescents, aged 11-, 13- and 15- years, from 33 mainly European and North American countries/regions participating in the cross-sectional Health Behaviour in School-aged Children surveys in 2002, 2006 and 2010, were used to investigate trends in daily fruit and vegetable consumption between 2002 and 2010. RESULTS: Multilevel logistic regression analyses showed an increase in daily fruit and vegetable consumption between 2002 and 2010 in the majority of countries for both genders and all three age groups. A decrease in consumption was noticed in five countries for fruit and five countries for vegetables. CONCLUSION: Overall, a positive trend was noticed, however increases in daily fruit and vegetable consumption are still indicated. PMID- 25805782 TI - Trends in multiple recurrent health complaints in 15-year-olds in 35 countries in Europe, North America and Israel from 1994 to 2010. AB - BACKGROUND: Health complaints are a good indicator of an individual's psychosocial health and well-being. Studies have shown that children and adolescents report health complaints which can cause significant individual burden. METHODS: Using data from the international Health Behaviour in School aged Children study, this article describes trends in multiple recurrent health complaints (MHC) in 35 countries among N = 237 136 fifteen-year-olds from 1994 to 2010. MHC was defined as the presence of two or more health complaints at least once a week. Logistic regression analysis was performed to evaluate trends across the five survey cycles for each country. RESULTS: Lowest prevalence throughout the period 1994-2010 was 16.9% in 1998 in Austria and highest in 2006 in Israel (54.7%). Overall, six different trend patterns could be identified: No linear or quadratic trend (9 countries), linear decrease (7 countries), linear increase (5 countries), U-shape (4 countries), inverted U-shape (6 countries) and unstable (4 countries). CONCLUSION: Trend analyses are valuable in providing hints about developments in populations as well as for benchmarking and evaluation purposes. The high variation in health complaints between the countries requires further investigation, but may also reflect the subjective nature of health complaints. PMID- 25805783 TI - Trends in overweight prevalence among 11-, 13- and 15-year-olds in 25 countries in Europe, Canada and USA from 2002 to 2010. AB - BACKGROUND: The purpose of this study was to assess recent changes in the prevalence of overweight (including obesity) among 11-, 13- and 15-year-olds in 33 countries from 2002 to 2010. METHODS: Data from 25 countries from three consecutive survey cycles (2002, 2006 and 2010) that had at least 80% response rate for self-reported height, weight and age were analysed using logistic regression analysis. RESULTS: Overweight prevalence increased among boys in 13 countries and among girls in 12 countries; in 10 countries, predominantly in Eastern Europe, an increase was observed for both boys and girls. Stabilization in overweight rates was noted in the remaining countries; none of the countries exhibited a decrease over the 8-year period examined. In the majority of countries (20/25) there were no age differences in trends in overweight prevalence. CONCLUSION: In over half of the countries examined overweight prevalence did not change during 2002-2010. However, increasing overweight prevalence was noted in many Eastern European countries over this time period. Overweight prevalence remained high in several countries in Europe and North America. These patterns call for continued research in youth overweight and highlight the need to understand cross-national differences by examining macro level indicators. Such research should feed into developing sound translations and practices to prevent and reduce overweight in youth. PMID- 25805784 TI - Trend in injury-related mortality and morbidity among adolescents across 30 countries from 2002 to 2010. AB - BACKGROUND: The aim was to examine temporal trends in injury mortality and morbidity across 30 countries in Europe and North America, and the impact of regional geography and adolescent risk behaviours (including substance use and physical fighting) on such trends. METHOD: s: Data were obtained for 30 countries in 2002, 2006 and 2010. Mortality data were obtained from the World Health Organization's (WHO) Health for all database. Trends over time were described by WHO Regions using standardized rates comparisons and Poisson regression analyses. RESULTS: Injury-related mortality, but not morbidity, declined over time across all countries (from 10 to 8 deaths per 100 000 between 2001 and 2010), with notable differences observed by Regions (e.g. from 48 to 39 deaths in Russia). Risk behaviours included in the models were consistently and significantly associated with injury morbidity, with substance increasing the risk for injury by 1.15 to 1.36 among girls, and physical fighting increasing the risk by 1.21 to 1.31 among boys across WHO Regions. Risk behaviours did not explain the observed temporal trends. CONCLUSIONS: Injury mortality and morbidity represent different health phenomena. Efforts that have been made to make societies safer for children have seemed to be successful in reducing injury morbidity. PMID- 25805785 TI - Secular trends in moderate-to-vigorous physical activity in 32 countries from 2002 to 2010: a cross-national perspective. AB - BACKGROUND: Sufficient levels of moderate to vigorous physical activity (MVPA) give substantial health benefits to adolescents. This article examines trends in physical activity (PA) from 2002 to 2010 across 32 countries from Europe and North America. METHODS: Representative samples included 479 674 pupils (49% boys) aged 11 years (n = 156 383), 13 years (n = 163 729) and 15 years (n = 159 562). The trends in meeting the recommendations for PA (at least 60 min daily) were evaluated using logistic regression. RESULTS: There was a slight overall increase between 2002 and 2010 (17.0% and 18.6%, respectively). MVPA increased significantly (P <= 0.05) among boys in 16 countries. Conversely, nine countries showed a significant decrease. Among girls, 10 countries showed a significant increase (P <= 0.05). Eight countries showed a significant decrease. For all countries combined, girls were slightly less likely to show an increase in PA over time. CONCLUSIONS: The majority of adolescents do not meet current recommendations of PA. Further investment at national and international levels is therefore necessary to increase PA participation among children and adolescents and reduce the future health burden associated with inactivity. PMID- 25805786 TI - International trends in electronic media communication among 11- to 15-year-olds in 30 countries from 2002 to 2010: association with ease of communication with friends of the opposite sex. AB - BACKGROUND: Electronic media has become a central part of the lives of adolescents. Therefore, this study examines trends in adolescent electronic media communication (EMC) and its relationship with ease of communication with friends of the opposite sex, from 2002 to 10 in 30 European and North American regions. METHODS: Data from the HBSC study were collected using self-report questionnaires from 11-, 13- and 15-year-old participants (N = 404 523). RESULTS: EMC use has grown over the years in most of these regions and increases with age. Even though Internet usage is often blamed for its negative effects on teenagers' social interactions in the physical world, in this study EMC was found to predict ease of communication with friends. Especially, the more they use EMC, the easier they find it to talk with friends of the opposite sex. Although these findings suggest that EMC reinforces communication, the interaction between year (2002-2006-2010) and EMC usage was not significant. CONCLUSION: This finding contradicts research that suggests that EMC contributes to loneliness and isolation, and supports other studies that present electronic media as a powerful tool for helping to connect people. PMID- 25805787 TI - Trends in adolescents' perceived parental communication across 32 countries in Europe and North America from 2002 to 2010. AB - BACKGROUND: The quality of communication with parents is a determinant of health and well-being during adolescence, being predictive of self-esteem, self-rated health and the ability to navigate health risk behaviours. METHODS: This article describes trends in adolescent's (aged 11, 13 and 15 years) perception of communication with mothers and fathers by gender across 32 European and North American countries from 2002 to 2010. Analyses were performed on 425 699 records employing a General Linear Model (MANOVA). RESULTS: In most countries, significant increases in the prevalence of ease of communication with both mothers and fathers were observed, with the greatest positive changes over time in Estonia, Denmark and Wales. In some countries, the opposite trend was found with the greatest negative changes occurring in France, Slovenia and Poland. Across the pooled dataset, a significant positive trend was observed for ease of communication with father, for both boys and girls and for ease of communication with mother for boys only. CONCLUSION: The temporal trends demonstrated an increase in a positive health asset for many young people, that of family communication. Positive trends may be a feature of the economic boom over the past decade coupled with cultural changes in attitudes to parenting, especially fathering. PMID- 25805788 TI - Cross-national trends in perceived school pressure by gender and age from 1994 to 2010. AB - BACKGROUND: Pressure within school can be a critical component in understanding how the school experience influences young people's intellectual development, physical and mental health and future educational decisions. METHODS: Data from five survey rounds (1993/1994, 1997/1998, 2001/2002, 2005/2006 and 2009/2010) were used to examine time-, age- and gender-related trends in the amounts of reported school pressure among 11-, 13- and 15-year-olds, in five different regions (North America, Great Britain, Eastern Europe, Nordic and Germanic countries). RESULTS: Across the regions the reported perceptions of school pressure did not change between 1994 and 2010, despite a temporary increase in 2002 and 2006. With the exception of children at 11 years of age, girls reported higher levels of school pressure than boys (Cohen's d from 0.12 to 0.58) and school pressure was higher in older age groups. These findings were consistent across countries. Regionally, children in North America reported the highest levels of school pressure, and students in the Germanic countries the lowest. CONCLUSION: Factors associated with child development and differences in societal expectations and structures, along with the possible, albeit, differential impact of the Programme for International Student Assessment (PISA), may partially explain the differences and trends found in school pressure. School pressure increases alongside the onset of adolescence and the shift from elementary school to the higher demanding expectations of secondary education. Time-related increases in school pressure occurred in the years following the release of the PISA results, and were larger in those regions in which results were less positive. PMID- 25805789 TI - Trends in social inequalities in adolescent health complaints from 1994 to 2010 in Europe, North America and Israel: The HBSC study. AB - BACKGROUND: Studies have shown constant or increasing health inequalities in adulthood in the last decades, but less is known about trends in health inequalities among adolescents. The aim is to analyse changes in socioeconomic differences in subjective health complaints from 1994 to 2010 among 11- to 15 year-olds in Europe, North America and Israel. METHODS: Data were obtained from the international 'Health Behaviour in School-aged Children' (HBSC) survey. Analyses were based on the HBSC surveys conducted in 1994 (19 countries), 1998 (25 countries), 2002 (32 countries), 2006 (37 countries) and 2010 (36 countries) covering a time period of up to 16 years. Log binomial regression models were used to assess inequalities in multiple health complaints. Socioeconomic position was measured using perceived family wealth. RESULTS: Inequalities in multiple health complaints emerged in almost all countries, in particular since 2002 (RR 1.1-1.7). Trend analyses showed stable (29 countries), increased (5 countries), decreased (one country) and no social inequalities (2 countries) in adolescent health complaints. CONCLUSION: In almost all countries, social inequalities in health complaints remained constant over a period of up to 16 years. Our findings suggest a need to intensify efforts in social and health policy to tackle existing inequalities. PMID- 25805790 TI - Cross-national time trends in bullying victimization in 33 countries among children aged 11, 13 and 15 from 2002 to 2010. AB - BACKGROUND: Bullying among children and adolescents is a public health concern; victimization is associated with psychological and physical health problems. The purpose of this study is to examine temporal trends in bullying victimization among school-aged children in Europe and North America. METHODS: Data were obtained from cross-sectional self-report surveys collected as part of the Health Behaviour in School-aged Children (HBSC) study from nationally representative samples of 11-, 13- and 15-year-olds, from 33 countries and regions which participated in the 2001-02, 2005-06 and 2009-10 surveys. Responses from 581 838 children were included in the analyses. Binary logistic regression was used for the data analyses. RESULTS: The binary logistic regression models showed significant decreasing trends in occasional and chronic victimization between 2001-02 and 2009-10 across both genders in a third of participating countries. One country reported significant increasing trends for both occasional and chronic victimization. Gender differences in trends were evident across many countries. CONCLUSION: Overall, while still common in many countries, bullying victimization is decreasing. The differences between countries highlight the need to further investigate measures undertaken in countries demonstrating a downward trend. PMID- 25805791 TI - Gendered trends in early and very early sex and condom use in 20 European countries from 2002 to 2010. AB - BACKGROUND: Sexual activity is often initiated during the adolescent period, and previous research suggests that the age of first sexual intercourse and condom use are crucial determinants of later sexual health. This study examined trends in adolescent sexual behaviours from 2002 to 2010 in 20 countries across four geographical regions of Europe. METHODS: Data were collected by self-report questionnaires from 15-year-olds in classrooms during 2002, 2006 and 2010. Linear time trends were determined through logistic regression models, stratified for gender. RESULTS: No linear trend over time was documented for most countries for sexual intercourse at the age of 13 or younger. Increased initiation among girls in Eastern Europe and decreased very early initiation among girls in Northern Europe emerged, along with a general increase in condom use in boys and most notably in girls. CONCLUSION: Overall prevalence of early and very early sexual intercourse initiation was quite stable in Europe between 2002 and 2010, while condom use increased. More detailed research and policy attention to the antecedents of non-condom use among young people is warranted; and further study of the relationships between age of sexual initiation and condom or pill use would be particularly valuable. PMID- 25805792 TI - Decreases in adolescent weekly alcohol use in Europe and North America: evidence from 28 countries from 2002 to 2010. AB - BACKGROUND: This study examined trends in adolescent weekly alcohol use between 2002 and 2010 in 28 European and North American countries. METHODS: Analyses were based on data from 11-, 13- and 15-year-old adolescents who participated in the Health Behaviour in School-Aged Children (HBSC) study in 2002, 2006 and 2010. RESULTS: Weekly alcohol use declined in 20 of 28 countries and in all geographic regions, from 12.1 to 6.1% in Anglo-Saxon countries, 11.4 to 7.8% in Western Europe, 9.3 to 4.1% in Northern Europe and 16.3 to 9.9% in Southern Europe. Even in Eastern Europe, where a stable trend was observed between 2002 and 2006, weekly alcohol use declined between 2006 and 2010 from 12.3 to 10.1%. The decline was evident in all gender and age subgroups. CONCLUSIONS: These consistent trends may be attributable to increased awareness of the harmful effects of alcohol for adolescent development and the implementation of associated prevention efforts, or changes in social norms and conditions. Although the declining trend was remarkably similar across countries, prevalence rates still differed considerably across countries. PMID- 25805793 TI - Trends in the co-occurrence of tobacco and cannabis use in 15-year-olds from 2002 to 2010 in 28 countries of Europe and North America. AB - BACKGROUND: Cannabis and tobacco use frequently co-occur. Adolescents who consume both substances experience more respiratory distress and psychosocial problems and are less likely to stop compared with those who use either tobacco or cannabis alone. This study examined time trends in tobacco and cannabis use among 15-year-olds in Europe and North America between 2002 and 2010. METHODS: Twenty eight countries were included and merged into six regions based on their welfare systems. Adolescents (n = 142 796) were divided in four 'user groups': 'no users', 'tobacco and cannabis users', 'tobacco-only users' and 'cannabis-only users'. Prevalence rates are reported by study-wave and region. Logistic regressions with study wave as independent variable were used to study trends in the user groups and regions. Interaction effects between time and gender were considered. RESULTS: Overall, tobacco use, and concurrent tobacco and cannabis use decreased by 3 and 3.7%, respectively, but prevalence rates varied by region. Only in North America, an interaction effect between time and gender was found in tobacco and cannabis users. CONCLUSIONS: Although this study demonstrates a decrease in tobacco and cannabis use in most regions, it also shows that the use of both substances is related. Therefore, studying the co-occurring use of tobacco and cannabis is necessary. PMID- 25805795 TI - Trends in life satisfaction in European and North-American adolescents from 2002 to 2010 in over 30 countries. AB - BACKGROUND: Life satisfaction (LS) is an indicator which is widely used for assessing the perception of a child's feeling about his life. METHODS: LS is assessed in Health Behaviour in School-aged Children via the Cantril ladder with 10 steps indicating the worst and best possible life. This range of values (0-10) was dichotomized into 'low' (0-5) vs. 'high' (6-10). Countries, age groups and genders were compared based on the odds ratio (OR) of declaring a higher LS in 2010 with respect to 2002. RESULTS: Analyzing the difference between 2002 and 2010, six countries from Western Europe show decreasing LS: Austria, Canada, Switzerland, Denmark, Finland and Greenland. In contrast, a group of Eastern European Countries, that is, Estonia, Croatia, Lithuania, Latvia, Russia and Ukraine, show a significant increase in LS. Data on gender and age differences confirm the lower rating of LS in girls and a decreasing rating with age. CONCLUSION: The LS scale appears to be a tool capable of discriminating the level of wellbeing of adolescent population among countries. PMID- 25805794 TI - Adolescents' medicine use for headache: secular trends in 20 countries from 1986 to 2010. AB - BACKGROUND: This study reports secular trends in medicine use for headache among adolescents in 20 countries from 1986 to 2010. METHODS: The international Health Behaviour in School-aged Children (HBSC) survey includes self-reported data about medicine use for headaches among nationally representative samples of 11-, 13- and 15-year-olds. We included 20 countries with data from at least three data collection waves, with a total of 380 129 participants. RESULTS: The prevalence of medicine use for headaches varied from 16.5% among Hungarian boys in 1994 to 62.9% among girls in Wales in 1998. The prevalence was higher among girls than boys in every country and data collection year. The prevalence of medicine use for headaches increased in 12 of 20 countries, most notably in the Czech Republic, Poland, Russia, Sweden and Wales. CONCLUSION: The prevalence of medicine use for headaches among adolescents is high and increasing in many countries. As some medicines are toxic this may constitute a public health problem. PMID- 25805796 TI - Trends in health complaints from 2002 to 2010 in 34 countries and their association with health behaviours and social context factors at individual and macro-level. AB - BACKGROUND: This article describes trends and stability over time in health complaints in adolescents from 2002 to 2010 and investigates associations between health complaints, behavioural and social contextual factors at individual level and economic factors at macro-level. METHODS: Comprising N = 510 876 11-, 13- and 15-year-old children and adolescents in Europe, North America and Israel, data came from three survey cycles of the international Health Behaviour in School aged Children (HBSC) study. Age- and gender-adjusted trends in health complaints were examined in each country by means of linear regression. By using the country as the random effects variable, we tested to what extent individual and contextual variables were associated with health complaints. RESULTS: Significant associations are stronger for individual level determinants (e.g. being bullied, smoking) than for determinants at macro-level (e.g. GDP, Gini), as can be seen by the small effect sizes (less than 5% for different trends). Health complaints are fairly stable over time in most countries, and no clear international trend in health complaints can be observed between 2002 and 2010. The most prominent stable determinants were being female, being bullied, school pressure and smoking. CONCLUSION: Factors associated with health complaints are more related to the proximal environment than to distal macro-level factors. This points towards intensifying targeted interventions, (e.g. for bullying) and also targeting specific risk groups. The comparably small effect size at country-level indicates that country-level factors have an impact on health and should not be ignored. PMID- 25805797 TI - EpiProfile Quantifies Histone Peptides With Modifications by Extracting Retention Time and Intensity in High-resolution Mass Spectra. AB - Histone post-translational modifications contribute to chromatin function through their chemical properties which influence chromatin structure and their ability to recruit chromatin interacting proteins. Nanoflow liquid chromatography coupled with high resolution tandem mass spectrometry (nanoLC-MS/MS) has emerged as the most suitable technology for global histone modification analysis because of the high sensitivity and the high mass accuracy of this approach that provides confident identification. However, analysis of histones with this method is even more challenging because of the large number and variety of isobaric histone peptides and the high dynamic range of histone peptide abundances. Here, we introduce EpiProfile, a software tool that discriminates isobaric histone peptides using the distinguishing fragment ions in their tandem mass spectra and extracts the chromatographic area under the curve using previous knowledge about peptide retention time. The accuracy of EpiProfile was evaluated by analysis of mixtures containing different ratios of synthetic histone peptides. In addition to label-free quantification of histone peptides, EpiProfile is flexible and can quantify different types of isotopically labeled histone peptides. EpiProfile is unique in generating layouts (i.e. relative retention time) of histone peptides when compared with manual quantification of the data and other programs (such as Skyline), filling the need of an automatic and freely available tool to quantify labeled and non-labeled modified histone peptides. In summary, EpiProfile is a valuable nanoflow liquid chromatography coupled with high resolution tandem mass spectrometry-based quantification tool for histone peptides, which can also be adapted to analyze nonhistone protein samples. PMID- 25805799 TI - First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. AB - PURPOSE: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models. EXPERIMENTAL DESIGN: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry. RESULTS: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUC SS: 6686 ng.h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively. CONCLUSIONS: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses. PMID- 25805800 TI - TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging. AB - PURPOSE: Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models. The effect of oxygen modification on the combination treatment was evaluated and the effect of TH-302 on the hypoxic fraction (HF) was monitored using [(18)F]HX4-PET imaging and pimonidazole IHC stainings. EXPERIMENTAL DESIGN: Rhabdomyosarcoma R1 and H460 NSCLC tumor-bearing animals were treated with TH-302 and radiotherapy (8 Gy, single dose). The tumor oxygenation status was altered by exposing animals to carbogen (95% oxygen) and nicotinamide, 21% or 7% oxygen breathing during the course of the treatment. Tumor growth and treatment toxicity were monitored until the tumor reached four times its start volume (T4*SV). RESULTS: Both tumor models showed a growth delay after TH-302 treatment, which further increased when combined with radiotherapy (enhancement ratio rhabdomyosarcoma 1.23; H460 1.49). TH-302 decreases the HF in both models, consistent with its hypoxia-targeting mechanism of action. Treatment efficacy was dependent on tumor oxygenation; increasing the tumor oxygen status abolished the effect of TH-302, whereas enhancing the HF enlarged TH-302's therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by [(18)F]HX4-PET imaging and the T4*SV. CONCLUSIONS: The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [(18)F]HX4 hypoxia PET imaging for patient selection. PMID- 25805798 TI - Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines. AB - PURPOSE: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). EXPERIMENTAL DESIGN: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. RESULTS: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8(+) T cells in association with PD ligand-1 (PD-L1) expressing sarcoma cells. No tumor regressions were observed. CONCLUSIONS: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction. PMID- 25805802 TI - The role and quality of hb a1c: a continuing evolution. PMID- 25805801 TI - Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment. AB - PURPOSE: Activating ALK mutations are present in almost 10% of primary neuroblastomas and mark patients for treatment with small-molecule ALK inhibitors in clinical trials. However, recent studies have shown that multiple mechanisms drive resistance to these molecular therapies. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can aid to identify potential fragile nodes as additional targets for combination therapies. EXPERIMENTAL DESIGN: To achieve this goal, transcriptome profiling was performed in neuroblastoma cell lines with the ALK(F1174L) or ALK(R1275Q) hotspot mutations, ALK amplification, or wild-type ALK following pharmacologic inhibition of ALK using four different compounds. Next, we performed cross-species genomic analyses to identify commonly transcriptionally perturbed genes in MYCN/ALK(F1174L) double transgenic versus MYCN transgenic mouse tumors as compared with the mutant ALK-driven transcriptome in human neuroblastomas. RESULTS: A 77-gene ALK signature was established and successfully validated in primary neuroblastoma samples, in a neuroblastoma cell line with ALK(F1174L) and ALK(R1275Q) regulable overexpression constructs and in other ALKomas. In addition to the previously established PI3K/AKT/mTOR, MAPK/ERK, and MYC/MYCN signaling branches, we identified that mutant ALK drives a strong upregulation of MAPK negative feedback regulators and upregulates RET and RET-driven sympathetic neuronal markers of the cholinergic lineage. CONCLUSIONS: We provide important novel insights into the transcriptional consequences and the complexity of mutant ALK signaling in this aggressive pediatric tumor. The negative feedback loop of MAPK pathway inhibitors may affect novel ALK inhibition therapies, whereas mutant ALK induced RET signaling can offer novel opportunities for testing ALK-RET oriented molecular combination therapies. PMID- 25805803 TI - Response to correspondence on "lissencephaly with brainstem and cerebellar hypoplasia and congenital cataracts". PMID- 25805804 TI - Opinion: Lay summaries needed to enhance science communication. PMID- 25805807 TI - A successful nationwide implementation of the 'FIFA 11 for Health' programme in Brazilian elementary schools. AB - OBJECTIVES: To deliver a nationwide implementation of the 'FIFA 11 for Health' programme in Brazil and to compare the outcomes with results obtained previously in Sub-Saharan Africa. METHOD: A cohort study among 3694 Brazilian children aged 9-12 years within 128 elementary schools situated in 12 cities in the five Regions of Brazil. The 'FIFA 11 for Health' programme contains 11 90 min sessions: the first 45 min serve to encourage physical activity through the development of football skills (Play Football) and the second 45 min provide a vehicle for delivering 10 health messages (Play Fair). We measured preintervention and postintervention health knowledge (29-item questionnaire) and the children's evaluation of the programme (6-item questionnaire). RESULTS: Mean age of the children across the five Regions was 10.6 years (range 9.2-11.6). The mean preintervention health knowledge score for the five Regions was 60.2% (range 53.8-65.3%); the mean postintervention score was 78.6% (range 70.7-86.8%); thus the mean increase in health knowledge was 18.4% (range 13.6-29.1%). 91% of the children gave a positive evaluation for the programme (range across five Regions: 82.3-96.7%). SUMMARY: The study showed that the 'FIFA 11 for Health' programme, which was originally developed in English and translated into another language, was delivered successfully with results equivalent to those previously obtained in Sub-Saharan Africa. The programme was effective across the five Regions of Brazil. PMID- 25805809 TI - The triumph of medicine: how overdiagnosis is turning healthy people into patients. PMID- 25805808 TI - Loss-of-function de novo mutations play an important role in severe human neural tube defects. AB - BACKGROUND: Neural tube defects (NTDs) are very common and severe birth defects that are caused by failure of neural tube closure and that have a complex aetiology. Anencephaly and spina bifida are severe NTDs that affect reproductive fitness and suggest a role for de novo mutations (DNMs) in their aetiology. METHODS: We used whole-exome sequencing in 43 sporadic cases affected with myelomeningocele or anencephaly and their unaffected parents to identify DNMs in their exomes. RESULTS: We identified 42 coding DNMs in 25 cases, of which 6 were loss of function (LoF) showing a higher rate of LoF DNM in our cohort compared with control cohorts. Notably, we identified two protein-truncating DNMs in two independent cases in SHROOM3, previously associated with NTDs only in animal models. We have demonstrated a significant enrichment of LoF DNMs in this gene in NTDs compared with the gene specific DNM rate and to the DNM rate estimated from control cohorts. We also identified one nonsense DNM in PAX3 and two potentially causative missense DNMs in GRHL3 and PTPRS. CONCLUSIONS: Our study demonstrates an important role of LoF DNMs in the development of NTDs and strongly implicates SHROOM3 in its aetiology. PMID- 25805806 TI - A new era of secreted phospholipase A2. AB - Among more than 30 members of the phospholipase A2 (PLA2) superfamily, secreted PLA2 (sPLA2) enzymes represent the largest family, being Ca(2+)-dependent low molecular-weight enzymes with a His-Asp catalytic dyad. Individual sPLA2s exhibit unique tissue and cellular distributions and enzymatic properties, suggesting their distinct biological roles. Recent studies using transgenic and knockout mice for nearly a full set of sPLA2 subtypes, in combination with sophisticated lipidomics as well as biochemical and cell biological studies, have revealed distinct contributions of individual sPLA2s to various pathophysiological events, including production of pro- and anti-inflammatory lipid mediators, regulation of membrane remodeling, degradation of foreign phospholipids in microbes or food, or modification of extracellular noncellular lipid components. In this review, we highlight the current understanding of the in vivo functions of sPLA2s and the underlying lipid pathways as revealed by a series of studies over the last decade. PMID- 25805810 TI - How I treat acute lymphoblastic leukemia in older adolescents and young adults. AB - At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients. PMID- 25805811 TI - Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. AB - The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara C). To evaluate vosaroxin, we performed 2 randomized comparisons within the "Pick a Winner" program. A total of 104 patients were randomized to vosaroxin vs low dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely. PMID- 25805813 TI - Falls in older women are not reduced by exercise or vitamin D, study finds. PMID- 25805814 TI - Reply to Proenca et al.: Sown biodiverse pastures are not a universal solution to invasion risk. PMID- 25805815 TI - Highly productive sown biodiverse pastures with low invasion risk. PMID- 25805812 TI - Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia. AB - The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome. PMID- 25805816 TI - Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK). AB - With-no-lysine kinase 4 (WNK4) inhibits the activity of the potassium channel KCNJ1 (ROMK) in the distal nephron, thereby contributing to the maintenance of potassium homeostasis. This effect is inhibited via phosphorylation at Ser1196 by serum/glucocorticoid-induced kinase 1 (SGK1), and this inhibition is attenuated by the Src-family protein tyrosine kinase (SFK). Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. Mutation of Tyr(1092) or Tyr(1143) to phenylalanine decreased the association of c-Src or PTP 1D with WNK4, respectively. Moreover, the Tyr1092Phe mutation markedly reduced ROMK inhibition by WNK4; this inhibition was completely absent in the double mutant WNK4(Y1092/1094F). Similarly, c-Src prevented SGK1-induced phosphorylation of WNK4 at Ser(1196), an effect that was abrogated in the double mutant. WNK4(Y1143F) inhibited ROMK activity as potently as wild-type (WT) WNK4, but unlike WT, the inhibitory effect of WNK4(Y1143F) could not be reversed by SGK1. The failure to reverse WNK4(Y1143F)-induced inhibition of ROMK by SGK1 was possibly due to enhancing endogenous SFK effect on WNK4 by decreasing the WNK4 PTP-1D association because inhibition of SFK enabled SGK1 to reverse WNK4(Y1143F) induced inhibition of ROMK. We conclude that WNK4 is a substrate of SFKs and that the association of c-Src and PTP-1D with WNK4 at Tyr(1092) and Tyr(1143) plays an important role in modulating the inhibitory effect of WNK4 on ROMK. PMID- 25805817 TI - Constraints, independence, and evolution of thermal plasticity: probing genetic architecture of long- and short-term thermal acclimation. AB - Seasonal and daily thermal variation can limit species distributions because of physiological tolerances. Low temperatures are particularly challenging for ectotherms, which use both basal thermotolerance and acclimation, an adaptive plastic response, to mitigate thermal stress. Both basal thermotolerance and acclimation are thought to be important for local adaptation and persistence in the face of climate change. However, the evolutionary independence of basal and plastic tolerances remains unclear. Acclimation can occur over longer (seasonal) or shorter (hours to days) time scales, and the degree of mechanistic overlap is unresolved. Using a midlatitude population of Drosophila melanogaster, we show substantial heritable variation in both short- and long-term acclimation. Rapid cold hardening (short-term plasticity) and developmental acclimation (long-term plasticity) are positively correlated, suggesting shared mechanisms. However, there are independent components of these traits, because developmentally acclimated flies respond positively to short-term acclimation. A strong negative correlation between basal cold tolerance and developmental acclimation suggests that basal cold tolerance may constrain developmental acclimation, whereas a weaker negative correlation between basal cold tolerance and short-term acclimation suggests less constraint. Using genome-wide association mapping, we show the genetic architecture of rapid cold hardening and developmental acclimation responses are nonoverlapping at the SNP and corresponding gene level. However, genes associated with each trait share functional similarities, including genes involved in apoptosis and autophagy, cytoskeletal and membrane structural components, and ion binding and transport. These results indicate substantial opportunity for short-term and long-term acclimation responses to evolve separately from each other and for short-term acclimation to evolve separately from basal thermotolerance. PMID- 25805818 TI - Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. AB - The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer. PMID- 25805819 TI - Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development. AB - Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-Cre(ERT2)/Myocd(F/F) conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes. PMID- 25805820 TI - The entropic contributions in vitamin B12 enzymes still reflect the electrostatic paradigm. AB - The catalytic power of enzymes containing coenzyme B12 has been, in some respects, the "last bastion" for the strain hypothesis. Our previous study of this system established by a careful sampling that the major part of the catalytic effect is due to the electrostatic interaction between the ribose of the ado group and the protein and that the strain contribution is very small. This finding has not been sufficiently appreciated due to misunderstandings of the power of the empirical valence bond (EVB) calculations and the need of sufficient sampling. Furthermore, some interesting new experiments point toward entropic effects as the source of the catalytic power, casting doubt on the validity of the electrostatic idea, at least, in the case of B12 enzymes. Here, we focus on the observation of the entropic effects and on analyzing their origin. We clarify that our EVB approach evaluates free energies rather than enthalpies and demonstrate by using the restraint release (RR) approach that the observed entropic contribution to the activation barrier is of electrostatic origin. Our study illustrates the power of the RR approach by evaluating the entropic contributions to catalysis and provides further support to our paradigm for the origin of the catalytic power of B12 enzymes. Overall, our study provides major support to our electrostatic preorganization idea and also highlights the basic requirements from ab initio quantum mechanics/molecular mechanics calculations of activation free energies of enzymatic reactions. PMID- 25805822 TI - Route to thermalization in the alpha-Fermi-Pasta-Ulam system. AB - We study the original alpha-Fermi-Pasta-Ulam (FPU) system with N = 16, 32, and 64 masses connected by a nonlinear quadratic spring. Our approach is based on resonant wave-wave interaction theory; i.e., we assume that, in the weakly nonlinear regime (the one in which Fermi was originally interested), the large time dynamics is ruled by exact resonances. After a detailed analysis of the alpha-FPU equation of motion, we find that the first nontrivial resonances correspond to six-wave interactions. Those are precisely the interactions responsible for the thermalization of the energy in the spectrum. We predict that, for small-amplitude random waves, the timescale of such interactions is extremely large and it is of the order of 1/epsilon(8), where epsilon is the small parameter in the system. The wave-wave interaction theory is not based on any threshold: Equipartition is predicted for arbitrary small nonlinearity. Our results are supported by extensive numerical simulations. A key role in our finding is played by the Umklapp (flip-over) resonant interactions, typical of discrete systems. The thermodynamic limit is also briefly discussed. PMID- 25805821 TI - N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes. AB - The epidermal growth factor receptor (EGFR) regulates several critical cellular processes and is an important target for cancer therapy. In lieu of a crystallographic structure of the complete receptor, atomistic molecular dynamics (MD) simulations have recently shown that they can excel in studies of the full length receptor. Here we present atomistic MD simulations of the monomeric N glycosylated human EGFR in biomimetic lipid bilayers that are, in parallel, also used for the reconstitution of full-length receptors. This combination enabled us to experimentally validate our simulations, using ligand binding assays and antibodies to monitor the conformational properties of the receptor reconstituted into membranes. We find that N-glycosylation is a critical determinant of EGFR conformation, and specifically the orientation of the EGFR ectodomain relative to the membrane. In the absence of a structure for full-length, posttranslationally modified membrane receptors, our approach offers new means to structurally define and experimentally validate functional properties of cell surface receptors in biomimetic membrane environments. PMID- 25805823 TI - Reply to Jefferys: Declining HIV virulence. PMID- 25805825 TI - Genetic changes likely to predict response to immunotherapy in bowel cancer are identified. PMID- 25805824 TI - Evidence for HIV weakening over time. PMID- 25805826 TI - Safety 2014: global highlights in injury prevention. PMID- 25805827 TI - Next steps to advance injury and violence prevention. PMID- 25805828 TI - Tuberculosis in India. PMID- 25805829 TI - omega-3 Supplementation increases amyloid-beta phagocytosis and resolvin D1 in patients with minor cognitive impairment. AB - We investigated the effects of 4-17 month supplementation with omega-3 fatty acids and antioxidants (Smartfish drink; Smartfish AS, Oslo, Norway) in 12 patients with minor cognitive impairment (MCI) [minimental state examination (MMSE) >=19], 2 patients with pre-MCI (normal MMSE), and 7 patients with Alzheimer disease (AD) (MMSE <19). We measured the phagocytosis of amyloid-beta 1 42 (Abeta) by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 (RvD1) by enzyme immunoassay, and the cognitive status by MMSE. In patients with MCI and pre-MCI, phagocytosis of Abeta by monocytes increased from 530 to 1306 mean fluorescence intensity units (P = 0.016). The increase in patients with AD was not significant (N.S.). The lipidic mediator RvD1, which stimulates Abeta phagocytosis in vitro, increased in macrophages in 80% of patients with MCI and pre-MCI (mean increase 9.95 pg/ml) (N.S.). Transcription of inflammatory genes' mRNAs was increased in a subgroup of patients with low transcription at baseline, whereas it was not significantly changed in patients with high transcription at baseline. The mean MMSE score of patients with MCI and pre-MCI was 25.9 at baseline and 25.7 after 4-17 months (N.S.). Our study is the first to show significant immune and biochemical effects of omega-3 fatty acids with antioxidants in patients with MCI. Cognitive benefits of omega-3 supplementation in patients with MCI should be tested in a clinical trial. PMID- 25805831 TI - Ca2+ channel subunit alpha 1D promotes proliferation and migration of endometrial cancer cells mediated by 17beta-estradiol via the G protein-coupled estrogen receptor. AB - Calcium and calcium channels are closely related to the estrogen-induced nongenomic effect of endometrial carcinoma, but the specific role of calcium channels is unknown. This study aimed to explore the expression and the biologic effect of the L-type calcium channel in endometrial carcinoma cells and to clarify the molecular mechanism of the relationship between L-type calcium channels and estrogen. The immunohistochemical results showed that Ca(2+) channel subunit alpha 1D (Cav1.3) expression was high in atypical hyperplasia (1.90 +/- 0.35) and endometrial carcinoma tissues (2.05 +/- 0.82) but weak (0.80 +/- 0.15) in benign endometrial tissues (P < 0.05). Treatment with 17beta-estradiol rapidly increased Cav1.3 expression in a dose- and time-dependent manner, and 100 nM cell impermeable beta-estradiol-6-(O-carboxymethyl)oxime:bovine serum albumin also promoted Cav1.3 expression. Transfection with small interfering RNA against G protein-coupled estrogen receptor (GPER) suppressed estrogen-induced up regulation of Cav1.3 compared with control cells and markedly reduced the estrogen-induced phosphorylation of ERK1/2 and CREB. Knocking down the Cav1.3 significantly suppressed estrogen-stimulated Ca(2+) influx, cell proliferation, and migration in endometrial cancer cells. Taken together, Cav1.3 was overexpressed in atypical hyperplasia and endometrial carcinoma, and the estrogen induced phosphorylation of downstream molecular ERK1/2 and CREB is the result of activation of the GPER pathway. L-type channel Cav1.3 is required for estrogen stimulated Ca(2+) influx and contributes broadly to the development of endometrial cancer. The Cav1.3 channel may be a new target for endometrial carcinoma treatment. PMID- 25805833 TI - Isolation of chicken astrovirus from specific pathogen-free chicken embryonated eggs. AB - Astroviruses have been associated with enteric disorders in many animal species, including chickens. Here, we describe the isolation, propagation, and pathological characteristics of chicken astrovirus (CAstV) in specific pathogen free (SPF) chicken embryonated eggs (CEE) from chickens with diarrhea and runting stunting syndrome. The CEE were inoculated via the yolk sac route. Viral confirmation was carried out using PCR techniques and transmission electron microscopy negative staining with ammonium molybdate. The intestinal contents were screened for CAstV, and differential diagnostic testing was performed for avian nephritis virus, avian rotavirus, avian reovirus, chicken parvovirus, infectious bronchitis virus, and fowl adenovirus Group I to detect co-infection with other infectious agents. Seven- or 14-day-old CEEs presented with hemorrhages, edema, a gelatinous aspect, deformities, and dwarfism. The supporting membranes did not show any alterations. Here, we have described the isolation of CAstV and its pathological characteristics in SPF CEE. PMID- 25805830 TI - Activated Kupffer cells inhibit insulin sensitivity in obese mice. AB - Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-kappaB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF kappaB complex caused loss of NF-kappaB p65 expression in KCs without disrupting NF-kappaB in hepatocytes or macrophages in other tissues. Silencing of NF-kappaB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease. PMID- 25805834 TI - Antioxidative activity of the polyphenols from the involucres of Castanea mollissima Blume and their mitigating effects on heat stress. AB - Polyphenols extracted from plants have multiple functions in animal production. To explore new sources of tannin-rich extracts, which have potential benefits for animal health, this study focused on the effects of polyphenolic extracts from involucres of Castanea mollissima Blume (PICB) on heat-stressed broilers. In vitro experiments were first performed using intestinal cryptlike epithelial cell line-6 (IEC-6) cells to evaluate the effects of PICB on cell proliferation and antioxidative parameters under normal and heat-stress conditions. Then in vivo experiments were carried out with 2 trials: in trial 1, 400 one-d-old male Arbor Acres (AA) broilers were randomly assigned to 5 groups (4 replicates/group, 20 chicks/replicate): group 1 was a normal control group fed the basic ration; groups 2 to 5 were fed the basic ration supplemented with 0.2% vitamin C and 0.2%, 0.3%, and 0.4% PICB, respectively. Trial 1 lasted 42 d, and growth performance was monitored every week. At the end of the trial, the chicks were sacrificed and sampled. In trial 2, 400 twenty-eight-d-old chicks were randomly assigned to 5 groups as described in trial 1. After 1 week of adaptation, heat stress was applied for 7 consecutive days. On days 3 and 7 of heat stress, the chicks were sacrificed and sampled. The results showed that PICB could stimulate IEC-6 cell proliferation and had strong in vitro antioxidant activity. PICB had no effect on the growth performance and carcass parameters of AA broilers in trial 1, whereas in trial 2, group 4 saw improved growth performance and antioxidant activity compared to the first three groups (P < 0.05). In conclusion, PICB had no effects on the growth performance of IEC-6 cells and AA broilers under normal conditions, whereas it could mitigate heat-stress effects on the growth performance and antioxidant activity of IEC-6 cells and AA broilers, implying that PICB could be used as a suitable additive to improve animal production under heat-stress conditions. PMID- 25805835 TI - India should screen all tuberculosis patients for drug resistant disease at diagnosis. PMID- 25805832 TI - A novel role of sphingosine kinase-1 in the invasion and angiogenesis of VHL mutant clear cell renal cell carcinoma. AB - Sphingosine kinase 1 (SK1), the enzyme responsible for sphingosine 1-phosphate (S1P) production, is overexpressed in many human solid tumors. However, its role in clear cell renal cell carcinoma (ccRCC) has not been described previously. ccRCC cases are usually associated with mutations in von Hippel-Lindau (VHL) and subsequent normoxic stabilization of hypoxia-inducible factor (HIF). We previously showed that HIF-2alpha up-regulates SK1 expression during hypoxia in glioma cells. Therefore, we hypothesized that the stabilized HIF in ccRCC cells will be associated with increased SK1 expression. Here, we demonstrate that SK1 is overexpressed in 786-0 renal carcinoma cells lacking functional VHL, with concomitant high S1P levels that appear to be HIF-2alpha mediated. Moreover, examining the TCGA RNA seq database shows that SK1 expression was ~2.7-fold higher in solid tumor tissue from ccRCC patients, and this was associated with less survival. Knockdown of SK1 in 786-0 ccRCC cells had no effect on cell proliferation. On the other hand, this knockdown resulted in an ~3.5-fold decrease in invasion, less phosphorylation of focal adhesion kinase (FAK), and an ~2-fold decrease in angiogenesis. Moreover, S1P treatment of SK1 knockdown cells resulted in phosphorylation of FAK and invasion, and this was mediated by S1P receptor 2. These results suggest that higher SK1 and S1P levels in VHL-defective ccRCC could induce invasion in an autocrine manner and angiogenesis in a paracrine manner. Accordingly, targeting SK1 could reduce both the invasion and angiogenesis of ccRCC and therefore improve the survival rate of patients. PMID- 25805838 TI - End stigmatizing language in tuberculosis research and practice. PMID- 25805836 TI - Overexpression of glyceraldehyde 3-phosphate dehydrogenase prevents neurovascular degeneration after retinal injury. AB - Ischemia and reperfusion (I/R) injury is a common cause of many vascular and neuronal diseases. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been found down-regulated or dysfunctional in several tissues upon I/R injury. To investigate the role of GAPDH in retinal I/R injury-induced neurovascular degeneration, the injured retinas of GAPDH transgenic (Tg) mice and wild-type (WT) littermates were analyzed. I/R injury induced neurovascular degeneration, energy failure, DNA damage, and necroptosis in the retinas of WT mice. In contrast, the GAPDH Tg mice showed resistance to all of these injury-induced abnormalities. In addition, I/R-induced effects were further examined in a neuroblastoma cell line and an endothelial cell line, which were transfected with a vector encoding human GAPDH or a control vector. After I/R challenge, energy failure, DNA damage, and elevation of receptor-interacting serine/threonine protein kinase (RIP) 1/3 were observed in the cells transfected with the control vector. However, overexpression of GAPDH in these cells prevented the injury induced RIP3 up-regulation by restoring energy production and preventing DNA damage. Together, the protective role of GAPDH in retinal neurovascular degeneration after I/R injury provides a better understanding of the underlying mechanism of I/R injury and a potential therapeutic target to attenuate I/R injury-related diseases. PMID- 25805837 TI - Use of a Flexible Cryoprobe for Removal of Tracheobronchial Blood Clots. PMID- 25805840 TI - Expression of Matrix Metalloproteinase (MMP)-20 and Potential Interaction with Dentin Sialophosphoprotein (DSPP) in Human Major Salivary Glands. AB - Matrix metalloproteinase-20 (MMP-20) expression is widely regarded as tooth specific, with expression limited to dental hard tissues. Necessary for sound enamel formation, MMP-20 and MMP-2 proteolytically process dentin sialophosphoprotein (DSPP) into dentin sialoprotein, dentin phosphoprotein, and dentin glycoprotein during tooth formation. In the mid-2000s, three members of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) were reported to bind specifically with high affinity (nM) to, and activate, three MMPs in vitro: bone sialoprotein with MMP-2; osteopontin with MMP-3; and dentin matrix protein1 with MMP-9. The SIBLING-MMP interaction was confirmed in biological systems such as the ducts of salivary glands, where all five members of the SIBLINGs are expressed. Recently, we documented MMP-20 expression and interaction with DSPP (another member of the SIBLING family) in human oral squamous cell carcinoma. Here we report the expression of MMP-20, and confirm its co-expression and potential interaction with DSPP in human major salivary gland tissues and cell line using immunohistochemistry, immunofluorescence, western blot, quantitative RT-PCR, and proximity ligation assay. This report reinforces our earlier suggestion that the SIBLING-MMP complexes may be involved in the turnover of extracellular proteins damaged by oxidation byproducts in metabolically active duct epithelial systems. PMID- 25805839 TI - Correlation between Fibrillin-1 Degradation and mRNA Downregulation and Myofibroblast Differentiation in Cultured Human Dental Pulp Tissue. AB - Myofibroblasts and extracellular matrix are important components in wound healing. Alpha-smooth muscle actin (alpha-SMA) is a marker of myofibroblasts. Fibrillin-1 is a major constituent of microfibrils and an extracellular-regulator of TGF-beta1, an important cytokine in the transdifferentiation of resident fibroblasts into myofibroblasts. To study the correlation between changes in fibrillin-1 expression and myofibroblast differentiation, we examined alterations in fibrillin-1 and alpha-SMA expression in organotypic cultures of dental pulp in vitro. Extracted healthy human teeth were cut to 1-mm-thick slices and cultured for 7 days. In intact dental pulp, fibrillin-1 was broadly distributed, and alpha SMA was observed in pericytes and vascular smooth muscle cells. After 7 days of culture, immunostaining for fibrillin-1 became faint concomitant with a downregulation in its mRNA levels. Furthermore, fibroblasts, odontoblasts and Schwann cells were immunoreactive for alpha-SMA with a significant increase in alpha-SMA mRNA expression. Double immunofluorescence staining was positive for pSmad2/3, central mediators of TGF-beta signaling, and alpha-SMA. The administration of inhibitors for extracellular matrix proteases recovered fibrillin-1 immunostaining; moreover, fibroblasts lost their immunoreactivity for alpha-SMA along with a downregulation in alpha-SMA mRNA. These findings suggest that the expression of alpha-SMA is TGF-beta1 dependent, and fibrillin-1 degradation and downregulation might be implicated in the differentiation of myofibroblasts in dental pulp wound healing. PMID- 25805842 TI - A repressor activator protein1 homologue from an oleaginous strain of Candida tropicalis increases storage lipid production in Saccharomyces cerevisiae. AB - The repressor activator protein1 (Rap1) has been studied over the years as a multifunctional regulator in Saccharomyces cerevisiae. However, its role in storage lipid accumulation has not been investigated. This report documents the identification and isolation of a putative transcription factor CtRap1 gene from an oleaginous strain of Candida tropicalis, and establishes the direct effect of its expression on the storage lipid accumulation in S. cerevisiae, usually a non oleaginous yeast. In silico analysis revealed that the CtRap1 polypeptide binds relatively more strongly to the promoter of fatty acid synthase1 (FAS1) gene of S. cerevisiae than ScRap1. The expression level of CtRap1 transcript in vivo was found to correlate directly with the amount of lipid produced in oleaginous native host C. tropicalis. Heterologous expression of the CtRap1 gene resulted in ~ 4-fold enhancement of storage lipid content (57.3%) in S. cerevisiae. We also showed that the functionally active CtRap1 upregulates the endogenous ScFAS1 and ScDGAT genes of S. cerevisiae, and this, in turn, might be responsible for the increased lipid production in the transformed yeast. Our findings pave the way for the possible utility of the CtRap1 gene in suitable microorganisms to increase their storage lipid content through transcription factor engineering. PMID- 25805841 TI - Alcohol dehydrogenases and an alcohol oxidase involved in the assimilation of exogenous fatty alcohols in Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica can assimilate hydrophobic substrates, including n alkanes and fatty alcohols. Here, eight alcohol dehydrogenase genes, ADH1-ADH7 and FADH, and a fatty alcohol oxidase gene, FAO1, were analyzed to determine their roles in the metabolism of hydrophobic substrates. A mutant deleted for all of these genes (ALCY02 strain) showed severely defective growth on fatty alcohols, and enhanced sensitivity to fatty alcohols in glucose-containing media. The ALCY02 strain grew normally on n-tetradecane or n-hexadecane, but exhibited slightly defective growth on n-decane or n-dodecane. It accumulated more 1 dodecanol and less dodecanoic acid than the wild-type strain when n-dodecane was fed. Expression of ADH1, ADH3 or FAO1, but not that of other ADH genes or FADH, in the ALCY02 strain restored its growth on fatty alcohols. In addition, a triple deletion mutant of ADH1, ADH3 and FAO1 showed similarly defective growth on fatty alcohols and on n-dodecane to the ALCY02 strain. Microscopic observation suggests that Adh1p and Adh3p are localized in the cytosol and Fao1p is in the peroxisome. These results suggest that Adh1p, Adh3p and Fao1p are responsible for the oxidation of exogenous fatty alcohols but play less prominent roles in the oxidation of fatty alcohols derived from n-alkanes. PMID- 25805844 TI - Are College Students' Assessments of Threat Shaped by the Dangers of Their Childhood Environment? AB - Humans internalize environmental cues of mortality risk at an early age, which influences subsequent risk perceptions and behavior. In this respect, an individual's current risk assessment may be viewed as an adaptive response to the dangers present within his or her early local environment. Here we examine the relationship between several variables indicating threat within an individual's early environment (e.g., prevalence of violent and property crimes, registered sex offenders) and their perception of crime risk within both the childhood and current adult environments. We recruited a group of 657 students who hail from diverse geographic backgrounds to provide the zip code location of their childhood residence along with subjective ratings of danger of that and their current location, which enabled us to compare their ratings of risk/danger with the federally reported crime statistics of each setting. Our results indicate that the early prevalence of registered sex offenders indeed influences an individual's risk perception in adulthood, and that these factors have a differential effect on males and females. Our findings provide support for the theory that early environmental factors signaling danger affect how individuals assess risk within their adult environment. PMID- 25805843 TI - Whole-genome sequencing of six Mauritian Cynomolgus macaques (Macaca fascicularis) reveals a genome-wide pattern of polymorphisms under extreme population bottleneck. AB - Cynomolgus macaques (Macaca fascicularis) were introduced to the island of Mauritius by humans around the 16th century. The unique demographic history of the Mauritian cynomolgus macaques provides the opportunity to not only examine the genetic background of well-established nonhuman primates for biomedical research but also understand the effect of an extreme population bottleneck on the pattern of polymorphisms in genomes. We sequenced the whole genomes of six Mauritian cynomolgus macaques and obtained an average of 20-fold coverage of the genome sequences for each individual. The overall level of nucleotide diversity was 23% smaller than that of the Malaysian cynomolgus macaques, and a reduction of low-frequency polymorphisms was observed. In addition, we also confirmed that the Mauritian cynomolgus macaques were genetically closer to a representative of the Malaysian population than to a representative of the Indochinese population. Excess of nonsynonymous polymorphisms in low frequency, which has been observed in many other species, was not very strong in the Mauritian samples, and the proportion of heterozygous nonsynonymous polymorphisms relative to synonymous polymorphisms is higher within individuals in Mauritian than Malaysian cynomolgus macaques. Those patterns indicate that the extreme population bottleneck made purifying selection overwhelmed by the power of genetic drift in the population. Finally, we estimated the number of founding individuals by using the genome-wide site frequency spectrum of the six samples. Assuming a simple demographic scenario with a single bottleneck followed by exponential growth, the estimated number of founders (~20 individuals) is largely consistent with previous estimates. PMID- 25805846 TI - Childhood Family Income and Violent Victimization During Youth and Young Adulthood: Trends in Hospital Care During 1988-2007 in Finland. AB - The purpose of the current study was to examine whether the relationship between childhood family income and risk of violent victimization has changed between 1988 and 2007 in Finland, as prior studies have suggested that socioeconomic differences in exposure to violence have increased during the recent decades. Existing studies have mostly relied on survey data, while such trends in hospital discharge data-a data source that covers the total population well and is not compromised by attrition or self-report bias-have not been thoroughly investigated before. The current study used register-based individual-level data from 1988-2007 (n = 283,505) to study changes in the relationship between childhood family income and victimization risk among 15- to 30-year-old Finnish men and women. We found a persisting difference in violent victimization between the top and bottom income quintiles for both men and women. While the estimates suggest that this difference has increased rather than decreased during the observation period particularly among women, this change was not statistically significant. These conclusions remain after controlling for the composition of income quintiles. Research could benefit from more extensive use of administrative hospital records in analyzing of the trends and causes of serious violence. PMID- 25805845 TI - Mechanisms of Partner Violence Reduction in a Group HIV-Risk Intervention for Hispanic Women. AB - The objective of this study was to test whether partner communication about HIV and/or alcohol intoxication mediated reductions in intimate partner violence (IPV) in SEPA (Salud [health], Educacion [education], Promocion [promotion], y [and] Autocuidado [self-care]), a culturally specific, theoretically based group HIV-risk reduction intervention for Hispanic women. SEPA had five sessions covering sexually transmitted infection (STI)/HIV prevention, partner communication, condom negotiation and use, and IPV. SEPA reduced IPV and alcohol intoxication, and improved partner communication compared with controls in a randomized trial with adult U.S. Hispanic women (SEPA, n = 274; delayed intervention control, n = 274) who completed structured interviews at baseline and 3, 6, and 12 months post-baseline. Parallel process latent growth curve models indicated that partner communication about HIV mediated the reduction in male-to-female IPV in SEPA, B = -0.78, SE = 0.14, p< .001, but alcohol intoxication did not, B = -0.15, SE = 0.19, p = .431. Male-to-female IPV mediated the intervention effect on female-to-male IPV, B = -1.21, SE = 0.24, p< .001. Skills building strategies originally designed to enhance women's communication with their partners about sexual risk behaviors also worked to reduce male-to female IPV, which in turn reduced female-to-male IPV. These strategies could be integrated into other types of health promotion interventions. PMID- 25805848 TI - Phenotypic evolution through variation in splicing of the noncoding RNA COOLAIR. AB - The extent to which natural polymorphisms in noncoding sequences have functional consequences is still unknown. A large proportion of the natural variation in flowering in Arabidopsis thaliana accessions is due to noncoding cis polymorphisms that define distinct haplotypes of FLOWERING LOCUS C (FLC). Here, we show that a single natural intronic polymorphism in one haplotype affects FLC expression and thus flowering by specifically changing splicing of the FLC antisense transcript COOLAIR. Altered antisense splicing increases FLC expression via a cotranscriptional mechanism involving capping of the FLC nascent transcript. Single noncoding polymorphisms can therefore be a major contributor to phenotypic evolution through modulation of noncoding transcripts. PMID- 25805847 TI - Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. AB - Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin-SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs. PMID- 25805850 TI - Mechanically Induced Trapping of Molecular Interactions and Its Applications. AB - Measuring binding affinities and association/dissociation rates of molecular interactions is important for a quantitative understanding of cellular mechanisms. Many low-throughput methods have been developed throughout the years to obtain these parameters. Acquiring data with higher accuracy and throughput is, however, necessary to characterize complex biological networks. Here, we provide an overview of a high-throughput microfluidic method based on mechanically induced trapping of molecular interactions (MITOMI). MITOMI can be used to obtain affinity constants and kinetic rates of hundreds of protein-ligand interactions in parallel. It has been used in dozens of studies to measure binding affinities of transcription factors, map protein interaction networks, identify pharmacological inhibitors, and perform high-throughput, low-cost molecular diagnostics. This article covers the technological aspects of MITOMI and its applications. PMID- 25805849 TI - A novel approach for studying histone H1 function in vivo. AB - In this report, we investigate the mechanisms that regulate Drosophila histone H1 expression and its association with chromatin in vivo. We show that histone H1 is subject to negative autoregulation and exploit this result to examine the effects of mutations of the main phosphorylation site of histone H1. PMID- 25805851 TI - Propagation of Intracellular Ca2+ Signals in Aged Exocrine Cells. AB - There is little information on the effects of aging in the propagation of calcium signals and its underlying mechanisms. We studied the effects of aging on propagation of Ca(2+) signals in pancreatic acinar cells. Fura-2 loaded cells isolated from young (3-4 months old) and aged (24 months old) mouse responded to acetylcholine (ACh) and cholecystokinin (CCK) with a polarized Ca(2+) response initiated at the secretory pole before spreading to the basal one. Aging slowed down the propagation of the response to ACh but enhanced the velocity of the CCK response. This pattern can be explained by the age-induced depolarization of mitochondria, because it can be reproduced in young cells by mitochondrial inhibitors. Aging also increased the role of acidic stores in the CCK signal, as judged by the folimycin-induced suppression of the polarization in aged but not in young cells. The involvement of ryanodine receptors in the ACh response was also enhanced, as indicated by the loss of polarization after the treatment with 8Br-cyclic ADP ribose. Therefore, we conclude that aging modifies differentially the propagation of ACh and CCK-evoked Ca(2+) signals through mitochondrial depolarization and changes in the role of the acidic Ca(2+) stores and ryanodine receptors in the initiation of the signals. PMID- 25805853 TI - Splicing predictions reliably classify different types of alternative splicing. AB - Alternative splicing is a key player in the creation of complex mammalian transcriptomes and its misregulation is associated with many human diseases. Multiple mRNA isoforms are generated from most human genes, a process mediated by the interplay of various RNA signature elements and trans-acting factors that guide spliceosomal assembly and intron removal. Here, we introduce a splicing predictor that evaluates hundreds of RNA features simultaneously to successfully differentiate between exons that are constitutively spliced, exons that undergo alternative 5' or 3' splice-site selection, and alternative cassette-type exons. Surprisingly, the splicing predictor did not feature strong discriminatory contributions from binding sites for known splicing regulators. Rather, the ability of an exon to be involved in one or multiple types of alternative splicing is dictated by its immediate sequence context, mainly driven by the identity of the exon's splice sites, the conservation around them, and its exon/intron architecture. Thus, the splicing behavior of human exons can be reliably predicted based on basic RNA sequence elements. PMID- 25805852 TI - Genome-wide profiling of the C. elegans dsRNAome. AB - Recent studies hint that endogenous dsRNA plays an unexpected role in cellular signaling. However, a complete understanding of endogenous dsRNA signaling is hindered by an incomplete annotation of dsRNA-producing genes. To identify dsRNAs expressed in Caenorhabditis elegans, we developed a bioinformatics pipeline that identifies dsRNA by detecting clustered RNA editing sites, which are strictly limited to long dsRNA substrates of Adenosine Deaminases that act on RNA (ADAR). We compared two alignment algorithms for mapping both unique and repetitive reads and detected as many as 664 editing-enriched regions (EERs) indicative of dsRNA loci. EERs are visually enriched on the distal arms of autosomes and are predicted to possess strong internal secondary structures as well as sequence complementarity with other EERs, indicative of both intramolecular and intermolecular duplexes. Most EERs were associated with protein-coding genes, with ~1.7% of all C. elegans mRNAs containing an EER, located primarily in very long introns and in annotated, as well as unannotated, 3' UTRs. In addition to numerous EERs associated with coding genes, we identified a population of prospective noncoding EERs that were distant from protein-coding genes and that had little or no coding potential. Finally, subsets of EERs are differentially expressed during development as well as during starvation and infection with bacterial or fungal pathogens. By combining RNA-seq with freely available bioinformatics tools, our workflow provides an easily accessible approach for the identification of dsRNAs, and more importantly, a catalog of the C. elegans dsRNAome. PMID- 25805855 TI - Identification of elements in human long 3' UTRs that inhibit nonsense-mediated decay. AB - The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3' UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3' UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3' UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3' UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMD-inhibiting cis elements in the first 200 nt. A smaller subset of long 3' UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3' UTRs. PMID- 25805856 TI - Determination of the secondary structure of group II bulge loops using the fluorescent probe 2-aminopurine. AB - Eleven RNA hairpins containing 2-aminopurine (2-AP) in either base-paired or single nucleotide bulge loop positions were optically melted in 1 M NaCl; and, the thermodynamic parameters DeltaH degrees , DeltaS degrees , DeltaG degrees 37, and TM for each hairpin were determined. Substitution of 2-AP for an A (adenosine) at a bulge position (where either the 2-AP or A is the bulge) in the stem of a hairpin, does not affect the stability of the hairpin. For group II bulge loops such as AA/U, where there is ambiguity as to which of the A residues is paired with the U, hairpins with 2-AP substituted for either the 5' or 3' position in the hairpin stem have similar stability. Fluorescent melts were performed to monitor the environment of the 2-AP. When the 2-AP was located distal to the hairpin loop on either the 5' or 3' side of the hairpin stem, the change in fluorescent intensity upon heating was indicative of an unpaired nucleotide. A database of phylogenetically determined RNA secondary structures was examined to explore the presence of naturally occurring bulge loops embedded within a hairpin stem. The distribution of bulge loops is discussed and related to the stability of hairpin structures. PMID- 25805854 TI - Diversity and functional convergence of small noncoding RNAs in male germ cell differentiation and fertilization. AB - The small noncoding RNAs (sncRNAs) are considered as post-transcriptional key regulators of male germ cell development. In addition to microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), other sncRNAs generated from small nucleolar RNAs (snoRNAs), tRNAs, or rRNAs processing may also play important regulatory roles in spermatogenesis. By next-generation sequencing (NGS), we characterized the sncRNA populations detected at three milestone stages in male germ differentiation: primordial germ cells (PGCs), pubertal spermatogonia cells, and mature spermatozoa. To assess their potential transmission through the spermatozoa during fertilization, the sncRNAs of mouse oocytes and zygotes were also analyzed. Both, microRNAs and snoRNA-derived small RNAs are abundantly expressed in PGCs but transiently replaced by piRNAs in spermatozoa and endo-siRNAs in oocytes and zygotes. Exhaustive analysis of miRNA sequence variants also shows an increment of noncanonical microRNA forms along male germ cell differentiation. RNAs-derived from tRNAs and rRNAs interacting with PIWI proteins are not generated by the ping-pong pathway and could be a source of primary piRNAs. Moreover, our results strongly suggest that the small RNAs-derived from tRNAs and rRNAs are interacting with PIWI proteins, and specifically with MILI. Finally, computational analysis revealed their potential involvement in post transcriptional regulation of mRNA transcripts suggesting functional convergence among different small RNA classes in germ cells and zygotes. PMID- 25805857 TI - The low information content of Neurospora splicing signals: implications for RNA splicing and intron origin. AB - When we expressed a small (0.9 kb) nonprotein-coding transcript derived from the mitochondrial VS plasmid in the nucleus of Neurospora we found that it was efficiently spliced at one or more of eight 5' splice sites and ten 3' splice sites, which are present apparently by chance in the sequence. Further experimental and bioinformatic analyses of other mitochondrial plasmids, random sequences, and natural nuclear genes in Neurospora and other fungi indicate that fungal spliceosomes recognize a wide range of 5' splice site and branchpoint sequences and predict introns to be present at high frequency in random sequence. In contrast, analysis of intronless fungal nuclear genes indicates that branchpoint, 5' splice site and 3' splice site consensus sequences are underrepresented compared with random sequences. This underrepresentation of splicing signals is sufficient to deplete the nuclear genome of splice sites at locations that do not comprise biologically relevant introns. Thus, the splicing machinery can recognize a wide range of splicing signal sequences, but splicing still occurs with great accuracy, not because the splicing machinery distinguishes correct from incorrect introns, but because incorrect introns are substantially depleted from the genome. PMID- 25805858 TI - Structural fidelity and NMR relaxation analysis in a prototype RNA hairpin. AB - RNA hairpins are widespread and very stable motifs that contribute decisively to RNA folding and biological function. The GTP1G2C3A4C5U6U7C8G9G10U11G12C13C14 construct (with a central UUCG tetraloop) has been extensively studied by solution NMR, and offers and excellent opportunity to evaluate the structure and dynamical description afforded by molecular dynamics (MD) simulations. Here, we compare average structural parameters and NMR relaxation rates estimated from a series of multiple independent explicit solvent MD simulations using the two most recent RNA AMBER force fields (ff99 and ff10). Predicted overall tumbling times are ~20% faster than those inferred from analysis of NMR data and follow the same trend when temperature and ionic strength is varied. The Watson-Crick stem and the "canonical" UUCG loop structure are maintained in most simulations including the characteristic syn conformation along the glycosidic bond of G9, although some key hydrogen bonds in the loop are partially disrupted. Our analysis pinpoints G9-G10 backbone conformations as a locus of discrepancies between experiment and simulation. In general the results for the more recent force-field parameters (ff10) are closer to experiment than those for the older ones (ff99). This work provides a comprehensive and detailed comparison of state of the art MD simulations against a wide variety of solution NMR measurements. PMID- 25805859 TI - A novel mechanism of LIN-28 regulation of let-7 microRNA expression revealed by in vivo HITS-CLIP in C. elegans. AB - The evolutionarily conserved gene lin-28 encodes an RNA-binding protein and is an important regulator of the proper temporal succession of several developmental events in both invertebrates and vertebrates. At the cellular level, LIN-28 promotes stemness and proliferation, and inhibits differentiation, a feature best illustrated by its ability to induce pluripotency when ectopically expressed in human fibroblasts in combination with NANOG, OCT4, and SOX2. Mammalian LIN28 functions in part by regulating processing of the let-7 microRNA through a GGAG binding site in the pre-let-7's distal loop region. However, many human and animal let-7 precursors lack the GGAG binding motif. In order to dissect the molecular mechanisms underlying its biological functions in a living animal, we identified a map of LIN-28 interactions with the transcriptome by in vivo HITS CLIP in Caenorhabditis elegans. LIN-28 binds a large pool of messenger RNAs, and a substantial fraction of the bona fide LIN-28 targets are involved in aspects of animal development. Furthermore, our data show that LIN-28 regulates the expression of the let-7 microRNA by binding its primary transcript in a previously unknown region, revealing a novel regulatory mechanism. PMID- 25805860 TI - SHAPE Selection (SHAPES) enrich for RNA structure signal in SHAPE sequencing based probing data. AB - Selective 2' Hydroxyl Acylation analyzed by Primer Extension (SHAPE) is an accurate method for probing of RNA secondary structure. In existing SHAPE methods, the SHAPE probing signal is normalized to a no-reagent control to correct for the background caused by premature termination of the reverse transcriptase. Here, we introduce a SHAPE Selection (SHAPES) reagent, N-propanone isatoic anhydride (NPIA), which retains the ability of SHAPE reagents to accurately probe RNA structure, but also allows covalent coupling between the SHAPES reagent and a biotin molecule. We demonstrate that SHAPES-based selection of cDNA-RNA hybrids on streptavidin beads effectively removes the large majority of background signal present in SHAPE probing data and that sequencing-based SHAPES data contain the same amount of RNA structure data as regular sequencing based SHAPE data obtained through normalization to a no-reagent control. Moreover, the selection efficiently enriches for probed RNAs, suggesting that the SHAPES strategy will be useful for applications with high-background and low probing signal such as in vivo RNA structure probing. PMID- 25805863 TI - New long-acting insulin analogs: from clamp studies to clinical practice. PMID- 25805861 TI - SRD: a Staphylococcus regulatory RNA database. AB - An overflow of regulatory RNAs (sRNAs) was identified in a wide range of bacteria. We designed and implemented a new resource for the hundreds of sRNAs identified in Staphylococci, with primary focus on the human pathogen Staphylococcus aureus. The "Staphylococcal Regulatory RNA Database" (SRD, http://srd.genouest.org/) compiled all published data in a single interface including genetic locations, sequences and other features. SRD proposes novel and simplified identifiers for Staphylococcal regulatory RNAs (srn) based on the sRNA's genetic location in S. aureus strain N315 which served as a reference. From a set of 894 sequences and after an in-depth cleaning, SRD provides a list of 575 srn exempt of redundant sequences. For each sRNA, their experimental support(s) is provided, allowing the user to individually assess their validity and significance. RNA-seq analysis performed on strains N315, NCTC8325, and Newman allowed us to provide further details, upgrade the initial annotation, and identified 159 RNA-seq independent transcribed sRNAs. The lists of 575 and 159 sRNAs sequences were used to predict the number and location of srns in 18 S. aureus strains and 10 other Staphylococci. A comparison of the srn contents within 32 Staphylococcal genomes revealed a poor conservation between species. In addition, sRNA structure predictions obtained with MFold are accessible. A BLAST server and the intaRNA program, which is dedicated to target prediction, were implemented. SRD is the first sRNA database centered on a genus; it is a user friendly and scalable device with the possibility to submit new sequences that should spread in the literature. PMID- 25805865 TI - Mortality trends among people with type 1 and type 2 diabetes in Australia: 1997 2010. Diabetes Care 2014;37:2579-2586. PMID- 25805864 TI - The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and meta-analysis of intervention studies. AB - OBJECTIVE: Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. This reduced risk might be explained by improved insulin sensitivity or improved glycemic status, but results of intervention studies on this relation are inconsistent. The purpose of this study was to conduct a systematic review and meta-analysis of intervention studies investigating the effect of alcohol consumption on insulin sensitivity and glycemic status. RESEARCH DESIGN AND METHODS: PubMed and Embase were searched up to August 2014. Intervention studies on the effect of alcohol consumption on biological markers of insulin sensitivity or glycemic status of at least 2 weeks' duration were included. Investigators extracted data on study characteristics, outcome measures, and methodological quality. RESULTS: Fourteen intervention studies were included in a meta-analysis of six glycemic end points. Alcohol consumption did not influence estimated insulin sensitivity (standardized mean difference [SMD] 0.08 [-0.09 to 0.24]) or fasting glucose (SMD 0.07 [-0.11 to 0.24]) but reduced HbA1c (SMD -0.62 [-1.01 to -0.23]) and fasting insulin concentrations (SMD -0.19 [-0.35 to -0.02]) compared with the control condition. Alcohol consumption among women reduced fasting insulin (SMD -0.23 [-0.41 to -0.04]) and tended to improve insulin sensitivity (SMD 0.16 [-0.04 to 0.37]) but not among men. Results were similar after excluding studies with high alcohol dosages (>40 g/day) and were not influenced by dosage and duration of the intervention. CONCLUSIONS: Although the studies had small sample sizes and were of short duration, the current evidence suggests that moderate alcohol consumption may decrease fasting insulin and HbA1c concentrations among nondiabetic subjects. Alcohol consumption might improve insulin sensitivity among women but did not do so overall. PMID- 25805866 TI - Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care 2015;38:264 270. PMID- 25805862 TI - Rapid isolation and single-molecule analysis of ribonucleoproteins from cell lysate by SNAP-SiMPull. AB - Large macromolecular complexes such as the spliceosomal small nuclear ribonucleoproteins (snRNPs) play a variety of roles within the cell. Despite their biological importance, biochemical studies of snRNPs and other machines are often thwarted by practical difficulties in the isolation of sufficient amounts of material. Studies of the snRNPs as well as other macromolecular machines would be greatly facilitated by new approaches that enable their isolation and biochemical characterization. One such approach is single-molecule pull-down (SiMPull) that combines in situ immunopurification of complexes from cell lysates with subsequent single-molecule fluorescence microscopy experiments. We report the development of a new method, called SNAP-SiMPull, that can readily be applied to studies of splicing factors and snRNPs isolated from whole-cell lysates. SNAP SiMPull overcomes many of the limitations imposed by conventional SiMPull strategies that rely on fluorescent proteins. We have used SNAP-SiMPull to study the yeast branchpoint bridging protein (BBP) as well as the U1 and U6 snRNPs. SNAP-SiMPull will likely find broad use for rapidly isolating complex cellular machines for single-molecule fluorescence colocalization experiments. PMID- 25805867 TI - Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study. Diabetes Care 2015;38:302-307. PMID- 25805869 TI - Social media and diabetes: can Facebook and Skype improve glucose control in patients with type 1 diabetes on pump therapy? One-year experience. PMID- 25805870 TI - Low toe-brachial pressure index predicts increased risk of recurrent cardiovascular disease in type 2 diabetes. PMID- 25805872 TI - Comment on Palmas et al. Results of the Northern Manhattan Diabetes Community Outreach Project: a randomized trial studying a community health worker intervention to improve diabetes care in Hispanic adults. Diabetes Care 2014;37:963-969. PMID- 25805871 TI - Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. PMID- 25805873 TI - Response to comment on Palmas et al. Results of the Northern Manhattan Diabetes Community Outreach Project: a randomized trial studying a community health worker intervention to improve diabetes care in Hispanic adults. Diabetes Care 2014;37:963-969. PMID- 25805874 TI - Comment on Wong et al. Real-time continuous glucose monitoring among participants in the T1D exchange clinic registry. Diabetes Care 2014;37:2702-2709. PMID- 25805875 TI - Response to comment on Wong et al. Real-time continuous glucose monitoring among participants in the T1D exchange clinic registry. Diabetes Care 2014;37:2702 2709. PMID- 25805876 TI - Comment on Venskutonyte et al. Longitudinal development of left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 2014;37:3092-3097. PMID- 25805877 TI - Comment on Tay et al. A very low-carbohydrate, low-saturated fat diet for type 2 diabetes management: a randomized trial. Diabetes Care 2014;37:2909-2918. PMID- 25805878 TI - Response to comment on Tay et al. A very low-carbohydrate, low-saturated fat diet for type 2 diabetes management: a randomized trial. Diabetes Care 2014;37:2909 2918. PMID- 25805879 TI - Comment on Duran et al. Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos Gestational Diabetes Study. Diabetes Care 2014;37:2442-2450. PMID- 25805880 TI - Response to comment on Duran et al. Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos Gestational Diabetes Study. Diabetes Care 2014;37:2442-2450. PMID- 25805882 TI - Justification of CT scans using referral guidelines for imaging. AB - This study analyses the efficiency of the justification of individual computed tomography (CT) procedures using the good practice guide. The conformity of the CT scans with guide's recommendations was retrospectively analysed in a paediatric emergency hospital in Romania. The involved patient doses were estimated. The results show that around one-third of the examinations were not prescribed in conformity with the guide's recommendations, but these results are affected by unclear guide provisions, discussed here. The implications of the provisions of the revised International Atomic Energy Agency's Basic Safety Standards and of the Council Directive 2013/59/EURATOM were analysed. The education and training courses for medical doctors disseminating the provisions of the good practice guide should be considered as the main support for the justification of the CT scans at the individual level. PMID- 25805881 TI - Mechanistic investigation of the preclinical pharmacokinetics and interspecies scaling of PF-05231023, a fibroblast growth factor 21-antibody protein conjugate. AB - PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG1 kappa scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5 fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2 fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics. PMID- 25805883 TI - Justification of the hybrid nuclear medicine examinations. AB - The annual frequency of nuclear medicine examinations is increasing worldwide. This is partly a consequence of the recently introduced single photon emission tomography, combined with computed tomography, and positron emission tomography, combined with computed tomography, techniques, which combine functional, metabolic and morphological information important for the diagnosis of many diseases. However, since the effective radiation dose is the sum of the dose of two components, the hybrid examinations result in increased patient exposure. Accordingly, their justification becomes mandatory. It starts with their clinical importance-the opportunity to resolve a clinical problem decisive for patients' management. Knowledge of the indications, contraindications and the examinations' limitations is the responsibility of the nuclear medicine physician, as well as the choice of the most adequate examination and protocol. In conclusion, the cost and the accessibility of the examinations should not be the principal consideration as opposed to the diagnostic value and the exposure. Flexible protocols and algorithms should be used for hybrid nuclear medicine examinations. PMID- 25805884 TI - Cone beam CT for dental and maxillofacial imaging: dose matters. AB - The widespread use of cone-beam CT (CBCT) in dentistry has led to increasing concern regarding justification and optimisation of CBCT exposures. When used as a substitute to multidetector CT (MDCT), CBCT can lead to significant dose reduction; however, low-dose protocols of current-generation MDCTs show that there is an overlap between CBCT and MDCT doses. More importantly, although the 3D information provided by CBCT can often lead to improved diagnosis and treatment compared with 2D radiographs, a routine or excessive use of CBCT would lead to a substantial increase of the collective patient dose. The potential use of CBCT for paediatric patients (e.g. developmental disorders, trauma and orthodontic treatment planning) further increases concern regarding its proper application. This paper provides an overview of justification and optimisation issues in dental and maxillofacial CBCT. The radiation dose in CBCT will be briefly reviewed. The European Commission's Evidence Based Guidelines prepared by the SEDENTEXCT Project Consortium will be summarised, and (in)appropriate use of CBCT will be illustrated for various dental applications. PMID- 25805885 TI - Entrance surface air kerma in X-ray systems for paediatric interventional cardiology: a national survey. AB - The aims of this work were to report the results of a national survey on entrance surface air kerma (ESAK) values for different phantom thicknesses and operation modes in paediatric interventional cardiology (IC) systems and to compare them with previous values. The national survey also offers suggested investigation levels (ILs) for ESAK in paediatric cardiac procedures. ESAK was measured on phantoms of 4-16 cm thickness of polymethyl methacrylate slabs. For low fluoroscopy mode (FM), ESAK rates ranged from 0.11 to 33.1 mGy min(-1) and for high FM from 0.34 to 61.0 mGy min(-1). For cine mode, values of ESAK per frame were from 1.9 to 78.2 uGy fr(-1). The ILs were suggested as the third quartile of the values measured. This research showed lower ESAK values than in previous research, particularly for ESAK values in cine modes. This work represents a first step towards launching a national programme in paediatric dosimetry for IC procedures. PMID- 25805888 TI - Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response. AB - Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal transactivation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD. PMID- 25805887 TI - Survey of genome sequences in a wild sweet potato, Ipomoea trifida (H. B. K.) G. Don. AB - Ipomoea trifida (H. B. K.) G. Don. is the most likely diploid ancestor of the hexaploid sweet potato, I. batatas (L.) Lam. To assist in analysis of the sweet potato genome, de novo whole-genome sequencing was performed with two lines of I. trifida, namely the selfed line Mx23Hm and the highly heterozygous line 0431-1, using the Illumina HiSeq platform. We classified the sequences thus obtained as either 'core candidates' (common to the two lines) or 'line specific'. The total lengths of the assembled sequences of Mx23Hm (ITR_r1.0) was 513 Mb, while that of 0431-1 (ITRk_r1.0) was 712 Mb. Of the assembled sequences, 240 Mb (Mx23Hm) and 353 Mb (0431-1) were classified into core candidate sequences. A total of 62,407 (62.4 Mb) and 109,449 (87.2 Mb) putative genes were identified, respectively, in the genomes of Mx23Hm and 0431-1, of which 11,823 were derived from core sequences of Mx23Hm, while 28,831 were from the core candidate sequence of 0431 1. There were a total of 1,464,173 single-nucleotide polymorphisms and 16,682 copy number variations (CNVs) in the two assembled genomic sequences (under the condition of log2 ratio of >1 and CNV size >1,000 bases). The results presented here are expected to contribute to the progress of genomic and genetic studies of I. trifida, as well as studies of the sweet potato and the genus Ipomoea in general. PMID- 25805886 TI - The Impact of Aerobic Exercise on Brain-Derived Neurotrophic Factor and Neurocognition in Individuals With Schizophrenia: A Single-Blind, Randomized Clinical Trial. AB - Individuals with schizophrenia display substantial neurocognitive deficits for which available treatments offer only limited benefits. Yet, findings from studies of animals, clinical and nonclinical populations have linked neurocognitive improvements to increases in aerobic fitness (AF) via aerobic exercise training (AE). Such improvements have been attributed to up-regulation of brain-derived neurotrophic factor (BDNF). However, the impact of AE on neurocognition, and the putative role of BDNF, have not been investigated in schizophrenia. Employing a proof-of-concept, single-blind, randomized clinical trial design, 33 individuals with schizophrenia were randomized to receive standard psychiatric treatment (n = 17; "treatment as usual"; TAU) or attend a 12 week AE program (n = 16) utilizing active-play video games (Xbox 360 Kinect) and traditional AE equipment. Participants completed assessments of AF (indexed by VO2 peak ml/kg/min), neurocognition (MATRICS Consensus Cognitive Battery), and serum-BDNF before and after and 12-week period. Twenty-six participants (79%) completed the study. At follow-up, the AE participants improved their AF by 18.0% vs a -0.5% decline in the TAU group (P = .002) and improved their neurocognition by 15.1% vs -2.0% decline in the TAU group (P = .031). Hierarchical multiple regression analyses indicated that enhancement in AF and increases in BDNF predicted 25.4% and 14.6% of the neurocognitive improvement variance, respectively. The results indicate AE is effective in enhancing neurocognitive functioning in people with schizophrenia and provide preliminary support for the impact of AE-related BDNF up-regulation on neurocognition in this population. Poor AF represents a modifiable risk factor for neurocognitive dysfunction in schizophrenia for which AE training offer a safe, nonstigmatizing, and side effect-free intervention. PMID- 25805889 TI - DDR2 (discoidin domain receptor 2) suppresses osteoclastogenesis and is a potential therapeutic target in osteoporosis. AB - Osteoporosis is a disease characterized by abnormal skeletal fragility due to an imbalance in bone homeostasis. Finding therapeutic targets that promote bone formation is valuable for treating osteoporosis. Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that promotes the differentiation of bone depositing cells, osteoblasts, and bone formation. We investigated the role of DDR2 in osteoclastogenesis, the formation of cells responsible for bone resorption. We found that, although differentiated osteoclasts had catalytically active DDR2, its abundance was decreased. Overexpression of DDR2 inhibited the expression of osteoclastic markers, osteoclast maturation, and osteoclast mediated bone resorption in a culture model of bone matrix. Conversely, knocking down Ddr2 through RNA interference accelerated osteoclast differentiation and bone resorption in mice. Further, we identified the co-receptor Neuropilin-1 (Nrp1) as a DDR2-interacting protein. DDR2 facilitated the binding of Nrp1 and the co-receptor PlexinA1 by forming a DDR2-Nrp1-PlexinA1 complex, which blocked PlexinA1-mediated stimulation of osteoclastogenesis. DDR2 prevented PlexinA1 from interacting with the receptor TREM2 and the adaptor DAP12. Moreover, knocking down Nrp1 rescued the expression of osteoclastic markers observed in DDR2 overexpressing cells, whereas ectopic expression of Nrp1 in DDR2-silenced cells inhibited the induction of osteoclastogenesis. Nrp1 enhanced the function of DDR2 in promoting osteoblast differentiation and bone formation in mice. In an ovariectomized mouse model of osteoporosis, adenovirus-mediated delivery of DDR2 to the femur bone alleviated osteopenic phenotypes. Our results revealed that DDR2 functions as an inhibitor of osteoclastogenesis, as well as a promoter of osteoblastogenesis, suggesting that enhancing DDR2 may be therapeutic for patients with osteoporosis. PMID- 25805891 TI - The Effect of a Personalized Dementia Care Intervention for Caregivers From Australian Minority Groups. AB - Most caregiver interventions in a multicultural society are designed to target caregivers from the mainstream culture and exclude those who are unable to speak English. This study addressed the gap by testing the hypothesis that personalized caregiver support provided by a team led by a care coordinator of the person with dementia would improve competence for caregivers from minority groups in managing dementia. A randomised controlled trial was utilised to test the hypothesis. Sixty-one family caregivers from 10 minority groups completed the trial. Outcome variables were measured prior to the intervention, at 6 and 12 months after the commencement of trial. A linear mixed effect model was used to estimate the effectiveness of the intervention. The intervention group showed a significant increase in the caregivers' sense of competence and mental components of quality of life. There were no significant differences in the caregivers' physical components of quality of life. PMID- 25805892 TI - Associated aortic coarctation and thoraco-abdominal aneurysm in a 17-year old woman with moderate mitral regurgitation. PMID- 25805890 TI - Monocyte-derived macrophages from Crohn's disease patients are impaired in the ability to control intracellular adherent-invasive Escherichia coli and exhibit disordered cytokine secretion profile. AB - BACKGROUND: Ileal lesions of Crohn's disease [CD] patients are colonised by adherent-invasive Escherichia coli [AIEC] able to survive in macrophage cell lines. We analysed the ability of monocyte-derived macrophages [MDM] from CD patients to control AIEC intracellular replication and the pro-inflammatory cytokine response of the infected-MDM. METHODS: Peripheral blood MDM were obtained from 24 CD genotyped for NOD2 and ATG16L1 mutations, 5 ulcerative colitis [UC] patients and 12 healthy controls [HC]. The numbers of intracellular bacteria were determined using gentamicin assay. Cytokine secretion was quantified by ELISA assay. RESULTS: We observed that higher levels of bacteria were internalised within MDM from CD patients than MDM from HC or UC patients. MDM from CD patients were unable to restrict AIEC intracellular replication. Infection of MDM from CD patients with AIEC resulted in significantly increased secretion of IL-6 and tumour necrosis factor alpha [TNF alpha] than did infection with non-pathogenic E. coli. AIEC-infected MDM from CD patients exhibited a disordered cytokines secretion compared with MDM from UC patients and HC. AIEC infected MDM from patients with quiescent CD released significantly higher amounts of IL-6 and TNF-alpha than those with active disease or those from HC. The level of secreted TNF-alpha was correlated to the number of intracellular AIEC in MDM from CD patients. Treatment of MDM with infliximab did not change the MDM behaviour. CONCLUSIONS: MDM from CD patients are unable to restrict intracellular AIEC replication, leading to disordered inflammatory response influenced by disease activity. PMID- 25805894 TI - MECHANISMS IN ENDOCRINOLOGY: Medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions. AB - Anabolic androgenic steroids (AASs) are appearance and performance-enhancing drugs (APEDs) used in competitive athletics, in recreational sports, and by body builders. The global lifetime prevalence of AASs abuse is 6.4% for males and 1.6% for women. Many AASs, often obtained from the internet and dubious sources, have not undergone proper testing and are consumed at extremely high doses and in irrational combinations, also along with other drugs. Controlled clinical trials investigating undesired side effects are lacking because ethical restrictions prevent exposing volunteers to potentially toxic regimens, obscuring a causal relationship between AASs abuse and possible sequelae. Because of the negative feedback in the regulation of the hypothalamic-pituitary-gonadal axis, in men AASs cause reversible suppression of spermatogenesis, testicular atrophy, infertility, and erectile dysfunction (anabolic steroid-induced hypogonadism). Should spermatogenesis not recover after AASs abuse, a pre-existing fertility disorder may have resurfaced. AASs frequently cause gynecomastia and acne. In women, AASs may disrupt ovarian function. Chronic strenuous physical activity leads to menstrual irregularities and, in severe cases, to the female athlete triad (low energy intake, menstrual disorders and low bone mass), making it difficult to disentangle the effects of sports and AASs. Acne, hirsutism and (irreversible) deepening of the voice are further consequences of AASs misuse. There is no evidence that AASs cause breast carcinoma. Detecting AASs misuse through the control network of the World Anti-Doping Agency (WADA) not only aims to guarantee fair conditions for athletes, but also to protect them from medical sequelae of AASs abuse. PMID- 25805895 TI - Thoracic periaortic adipose tissue is increased in patients with subclinical hypothyroidism. AB - OBJECTIVE: To evaluate thoracic periaortic adipose tissue (TAT) volume in patients with subclinical hypothyroidism (SH) in comparison with controls and in relation to cardiovascular risk factors. METHODS: The study population consisted of 28 newly diagnosed SH patients (mean (s.d.) age: 37.3 (+/-11.4) years, 85.7% were females) and 37 healthy volunteers (mean (s.d.) age: 35.3 (+/-10.7) years, 81.5% were females). Comparisons between patient and control groups used demographic characteristics, anthropometrics, and laboratory findings. All participants underwent thoracic radiographic assessment in the supine position, using an eight-slice multidetector computed tomography scanner and TAT volume was measured. RESULTS: The TAT volume was determined to be 27.2 (+/-12.7) cm(3) in the SH group and 16.3 (+/-8.1) cm(3) in the control group, and the difference was statistically significant (P<0.001). In addition, TSH levels were significantly higher in the patient group compared with the control group (P<0.001). A significant correlation was also found between TSH levels and TAT volume (r=0.572; P<0.001). In SH patients, no significant difference was noted in TAT levels with respect to sex (P=0.383) or concomitant smoking status (P=0.426). CONCLUSIONS: Our findings indicate that SH patients have significantly higher TAT values than controls and that increased TAT levels correlate with increased TSH levels. PMID- 25805893 TI - The effect of past antibiotic exposure on diabetes risk. AB - OBJECTIVE: Gut microbiota influence metabolic pathways related to the pathogenesis of obesity, insulin-resistance and diabetes. Antibiotic therapy can alter the microbiota, and is commonly used in western countries. We sought to evaluate whether past antibiotic exposure increases diabetes risk. RESEARCH DESIGN AND METHODS: We conducted a nested case-control study using a large population-based database from the UK. The cases were defined as those with incident diagnosis of diabetes. For every case, four eligible controls matched on age, sex, practice-site, and duration of follow-up before index-date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy >1 year before index-date. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression. The risk was adjusted for BMI, smoking, last glucose level, and number of infections before index-date, as well as past medical history of coronary artery disease and hyperlipidaemia. RESULTS: The study included 208 002 diabetic cases and 815 576 matched controls. Exposure to a single antibiotic prescription was not associated with higher adjusted diabetes risk. Treatment with two to five antibiotic courses was associated with increase in diabetic risk for penicillin, cephalosporins, macrolides and quinolones with adjusted OR ranging from 1.08 (95% CI 1.05-1.11) for penicillin to 1.15 (95% CI 1.08-1.23) for quinolones. The risk increased with the number of antibiotic courses and reached 1.37 (95% CI 1.19-1.58) for more than 5 courses of quinolones. There was no association between exposure to anti-virals and anti fungals and diabetes risk. CONCLUSIONS: Exposure to certain antibiotic groups increases diabetes risk. PMID- 25805896 TI - Endocrinology in pregnancy: management of the pregnant patient with a prolactinoma. AB - A woman with a prolactinoma is usually infertile. Dopamine agonists usually restore ovulation and fertility and such treatment generally is preferred over transsphenoidal surgery because of higher efficacy and safety. Cabergoline is usually preferred over bromocriptine because of its better efficacy with fewer adverse effects. Either drug increases the rates of spontaneous abortions, preterm deliveries, multiple births, or congenital malformations over what may be expected. However, the number of pregnancies reporting such experience is about sevenfold greater for bromocriptine. Tumor growth causing significant symptoms and requiring intervention has been reported to occur in 2.4% of those with microadenomas, 21% in those with macroadenomas without prior surgery or irradiation, and 4.7% of those with macroadenomas with prior surgery or irradiation. Visual fields should be assessed periodically during gestation in women with macroadenomas. If significant tumor growth occurs, most patients respond well to reinstitution of the dopamine agonist. Delivery of the baby and placenta can also be considered if the pregnancy is sufficiently advanced. Transsphenoidal debulking of the tumor is rarely necessary. PMID- 25805897 TI - The prevalence, risk factors and short-term outcomes of delirium in Thai elderly emergency department patients. AB - BACKGROUND: We sought to determine the prevalence of delirium in a Thai emergency department (ED). The secondary objective was to identify risk factors and short term outcomes in delirious elderly ED patients. METHODS: This was a prospective cross-sectional study in the ED of an urban tertiary care hospital. Patients aged >=65 years who presented to the ED were included. We excluded patients who had severe dementia, were not responsive to verbal stimuli, had severe trauma and were blind, deaf, aphasic or unable to speak Thai. Delirium was determined using the Confusion Assessment Method for the Intensive Care Unit. We collected 30-day mortality rate, hospital length of stay and revisit rate as short-term outcomes. RESULTS: We had a final sample size of 232 patients; 27 (12%) were delirious in the ED, of which 16 (59%) were not recognised to be delirious by the emergency physician. Multivariable logistic regression analysis showed dementia (adjusted OR (AOR) 13.1; 95% CI 2.9 to 59.6), auditory impairment (AOR 4.8; 95% CI 1.6 to 13.8) and ED diagnosis of metabolic derangement (AOR 6.5; 95% CI 1.6 to 26.8) were associated with delirium in the ED. Delirium was associated with a higher mortality rate than those without delirium (15% vs 2%, p=0.004). CONCLUSIONS: In one middle-income country, elderly ED patients were delirious >10% of the time. Delirium was underdiagnosed and was associated with an increased 30-day mortality rate. Delirium screening needs to be improved, potentially focusing on high-risk patients. PMID- 25805899 TI - Contemplating 3-Hydroxypropionic Acid Biosynthesis in Klebsiella pneumoniae. AB - 3-Hydroxypropionic acid (3-HP) is a commercially valuable platform chemical from which an array of C3 compounds can be generated. Klebsiella pneumoniae has been considered a promising species for biological production of 3-HP. Despite a wealth of reports related to 3-HP biosynthesis in K. pneumoniae, its commercialization is still in infancy. The major hurdle hindering 3-HP overproduction lies in the poor understanding of glycerol dissimilation in K. pneumoniae. To surmount this problem, this review aims to portray a picture of 3 HP biosynthesis, involving 3-HP-synthesizing strains, biochemical attributes, metabolic pathways and key enzymes. Inspired by the state-of-the-art advances in metabolic engineering and synthetic biology, here we advocate protocols for overproducing 3-HP in K. pneumoniae. These protocols range from cofactor regeneration, alleviation of metabolite toxicity, genome editing, remodeling of transport system, to carbon flux partition via logic gate. The feasibility for these protocols was also discussed. PMID- 25805898 TI - Meddling Vibrio cholerae Murmurs: A Neoteric Advancement in Cholera Research. AB - Cholera, a known diarrheal disease is associated with various risk factors like hypovolemic shock, rice watery stools, and death in developing countries. The overuse of antibiotics to treat cholera imposed a selective pressure for the emergence and spread of multi-drug resistant Vibrio cholerae strains. The failure of conventional antimicrobial therapy urged the researchers to find an alternative therapy that could meddle the cholera murmurs (Quorum Sensing). It seems to effectively overcome the conventional cholera therapies in parallel to decrease the morbidity and mortality rate in the developing countries. The paramount objective of this review essentially focuses on the different Quorum Sensing (QS) regulatory switches governing virulence and pathogenicity of Vibrio cholerae. This review also provides an insight into the plausible QS targets that could be exploited to bring about a breakthrough to the prevailing cholera therapy. PMID- 25805900 TI - Insights into the Origin of Clostridium botulinum Strains: Evolution of Distinct Restriction Endonuclease Sites in rrs (16S rRNA gene). AB - Diversity analysis of Clostridium botulinum strains is complicated by high microheterogeneity caused by the presence of 9-22 copies of rrs (16S rRNA gene). The need is to mine genetic markers to identify very closely related strains. Multiple alignments of the nucleotide sequences of the 212 rrs of 13 C. botulinum strains revealed intra- and inter-genomic heterogeneity. Low intragenomic heterogeneity in rrs was evident in strains 230613, Alaska E43, Okra, Eklund 17B, Langeland, 657, Kyoto, BKT015925, and Loch Maree. The most heterogenous rrs sequences were those of C. botulinum strains ATCC 19397, Hall, H04402065, and ATCC 3502. In silico restriction mapping of these rrs sequences was observable with 137 type II Restriction endonucleases (REs). Nucleotide changes (NC) at these RE sites resulted in appearance of distinct and additional sites, and loss in certain others. De novo appearances of RE sites due to NC were recorded at different positions in rrs gene. A nucleotide transition A>G in rrs of C. botulinum Loch Maree and 657 resulted in the generation of 4 and 10 distinct RE sites, respectively. Transitions A>G, G>A, and T>C led to the loss of RE sites. A perusal of the entire NC and in silico RE mapping of rrs of C. botulinum strains provided insights into their evolution. Segregation of strains on the basis of RE digestion patterns of rrs was validated by the cladistic analysis involving six house keeping genes: dnaN, gyrB, metG, prfA, pyrG, and Rho. PMID- 25805901 TI - Phylogenetic study of methanol oxidizers from chilika-lake sediments using genomic and metagenomic approaches. AB - Group-wise diversity of sediment methylotrophs of Chilika lake (Lat. 19 degrees 28'-19 degrees 54'N; Long. 85 degrees 06'-85 degrees 35'E) Odisha, India at various identified sites was studied. Both the culturable and unculturable (metagenome) methylotrophs were investigated in the lake sediments employing both mxaF and 16S rRNA genes as markers. ARDRA profiling, 16S rRNA gene sequencing, PAGE profiling of HaeIII, EcoRI restricted mxaF gene and the mxaF gene sequences using culture-dependent approach revealed the relatedness of alpha-proteobacteria and Methylobacterium, Hyphomicrobium and Ancyclobacter sp. The total viable counts of the culturable aerobic methylotrophs were relatively higher in sediments near the sea mouth (S3; Panaspada), also demonstrated relatively high salinity (0.1 M NaCl) tolerance. Metagenomic DNA from the sediments, amplified using GC clamp mxaF primers and resolved through DGGE, revealed the diversity within the unculturable methylotrophic bacterium Methylobacterium organophilum, Ancyclobacter aquaticus, Burkholderiales and Hyphomicrobium sp. Culture independent analyses revealed that up to 90 % of the methylotrophs were unculturable. The study enhances the general understandings of the metagenomic methylotrophs from such a special ecological niche. PMID- 25805902 TI - Antibacterial Activity of Green Synthesized Silver Nanoparticles Using Vasaka (Justicia adhatoda L.) Leaf Extract. AB - There is an increasing demand for silver nanoparticles due to its wide applicability in various area of biological science such as in field of antimicrobial and therapeutics, biosensing, drug delivery etc. To use in bioprocess the silver nanoparticles should be biocompatible and free from toxic chemicals. In the present study we report a cost effective and environment friendly route for green synthesis of silver nanoparticles using Vasaka (Justicia adhatoda L.) leaf extract as reducing as well as capping agent. This plant has been opted for the present study for its known medicinal properties and it is easily available. The biosynthesized silver nanoparticles are characterized by UV Vis spectroscopy and TEM analysis. It is observed the nanoparticles are well shaped and the average particle size is 20 nm in the range of 5-50 nm. The antibacterial activity of these nanoparticles against Pseudomonas aeruginosa MTCC 741 has been measured by disc diffusion method, agar cup assay and serial dilution turbidity measurement assay. The results show green synthesized silver nanoparticles, using Vasaka leaf extract, have a potential to inhibit the growth of bacteria. PMID- 25805903 TI - Antimicrobial Activities of Silver Nanoparticles Synthesized by Using Water Extract of Arnicae anthodium. AB - Green synthesis of nanoparticles has gained significant importance in recent years and has become the one of the most preferred methods. Also, green synthesis of nanoparticles is valuable branch of nanotechnology. Plant extracts are eco friendly and can be an economic option for synthesis of nanoparticles. This study presents method the synthesis of silver nanoparticles using water extract of Arnicae anthodium. Formation of silver nanoparticles was confirmed by UV-visble spectroscopy, Fourier transform infrared spectroscopy and total reflection X-ray fluorescence analysis. The morphology of the synthesized silver nanoparticles was verified by SEM-EDS. The obtained silver nanoparticles were used to study their antimicrobial activity. PMID- 25805905 TI - Molecular, Physiological and Phenotypic Characterization of Paracoccus denitrificans ATCC 19367 Mutant Strain P-87 Producing Improved Coenzyme Q10. AB - Coenzyme Q10 (CoQ10) is a blockbuster nutraceutical molecule which is often used as an oral supplement in the supportive therapy for cardiovascular diseases, cancer and neurodegenerative diseases. It is commercially produced by fermentation process, hence constructing the high yielding CoQ10 producing strains is a pre-requisite for cost effective production. Paracoccus denitrificans ATCC 19367, a biochemically versatile organism was selected to carry out the studies on CoQ10 yield improvement. The wild type strain was subjected to iterative rounds of mutagenesis using gamma rays and NTG, followed by selection on various inhibitors like CoQ10 structural analogues and antibiotics. The screening of mutants were carried out using cane molasses based optimized medium with feeding strategies at shake flask level. In the course of study, the mutant P-87 having marked resistance to gentamicin showed 1.25-fold improvements in specific CoQ10 content which was highest among all tested mutant strains. P-87 was phenotypically differentiated from the wild type strain on the basis of carbohydrate assimilation and FAME profile. Molecular differentiation technique based on AFLP profile showed intra specific polymorphism between wild type strain and P-87. This study demonstrated the beneficial outcome of induced mutations leading to gentamicin resistance for improvement of CoQ10 production in P. denitrificans mutant strain P-87. To investigate the cause of gentamicin resistance, rpIF gene from P-87 and wild type was sequenced. No mutations were detected on the rpIF partial sequence of P-87; hence gentamicin resistance in P 87 could not be conferred with rpIF gene. However, detecting the mutations responsible for gentamicin resistance in P-87 and correlating its role in CoQ10 overproduction is essential. Although only 1.25-fold improvement in specific CoQ10 content was achieved through mutant P-87, this mutant showed very interesting characteristic, differentiating it from its wild type parent strain P. denitrificans ATCC 19367, which are presented in this paper. PMID- 25805904 TI - Essential Oils, Silver Nanoparticles and Propolis as Alternative Agents Against Fluconazole Resistant Candida albicans, Candida glabrata and Candida krusei Clinical Isolates. AB - Development of effective and safe therapeutic treatment of fungal infections remains one of the major challenge for modern medicine. The aim of presented investigation was to analyze the in vitro antifungal activity of selected essential oils, ethanolic extracts of propolis and silver nanoparticles dropped on TiO2 against azole-resistant C. albicans (n = 20), C. glabrata (n = 14) and C. krusei (n = 10) clinical isolates. Among tested essential oils, the highest activity has definitely been found in the case of the oil isolated from the bark of Cinnamomum cassia, with MIC and MFC values for all tested strains in the range of 0.0006-0.0097 % (v/v) and 0.0012-0.019 % (v/v), respectively. High activity was also observed for the Lemon, Basil, Thyme, Geranium and Clove (from buds) essential oils. Significant differences in fungicidal activity have been observed in the case of four tested propolis samples. Only one of them revealed high activity, with MFC values in the range from 0.156 to 1.25 % (v/v). Satisfactory fungicidal activity, against C. albicans and C. glabrata isolates, was also observed in the case of silver nanoparticles, however C. krusei isolates were mostly resistant. We also revealed that constituents of most of essential oils and propolis as well as silver nanoparticles are not substrates for drug transporters, which belong to the most important factors affecting resistance of Candida spp. clinical isolates to many of conventional antimycotics. To conclude, the results of our investigation revealed that essential oils, propolis and silver nanoparticles represent high potential for controlling and prevention candidiasis. PMID- 25805906 TI - Heterologous Expression and Efficient Secretion of Chitosanase from Microbacterium sp. in Escherichia coli. AB - A recombinant expression vector, pCT7-CHISP6H, was constructed for the secretory expression of mature peptide of chitosanase (mMschito) from Microbacterium sp. OU01. The vector contains several elements, including T7 promoter, signal peptide sequence of mschito, 6 * His-tag sequence and PmaCI restriction enzyme cloning site. In pCT7-CHISP6H, mMschito was fused into signal peptide sequence of mschito gene to construct recombinant plasmid pCT7-CHISP6H-mMschito. The recombinant plasmid was transformed into Escherichia coli BL21(DE3) and then expressed. The recombinant protein was secreted into the Luria-Bertani broth and the chitosanase activity in supernatant of the culture could reach up to 67.56 U/mL. The rmMschito in the broth supernatant was purified using HisTrapTM FF Crude column and the purified rmMschito was shown to be apparent homogeneity by 12 % SDS-PAGE analysis. Detected by 4700 MALDI-TOF-TOF-MS, the molecular weight of the purified rmMschito was 26,758.1875 and it was consistent with the predicted molecular weight. Chitosan (degree of deacetylation of 99 %) was mostly hydrolyzed into chitopentaose, chitotriose, and chitobiose by the purified rmMschito. PMID- 25805908 TI - IAA Producing Enterobacter sp. I-3 as a Potent Bio-herbicide Candidate for Weed Control: A Special Reference with Lettuce Growth Inhibition. AB - Development of bio-herbicides is an emerging method to weed management in agricultural field. Very few studies were conducted on identification of microbial bio-herbicides to weed control. The present study was aimed to isolate and identify the effective bio-herbicide potential bacterium from soil and assess their role on plant growth inhibition. Three-hundred and one rhizobacteria were isolated from agriculture field soil samples collected from various parts of Republic of Korea. Two bacterial strains, I-4-5 and I-3 were significantly reduced the seedling growth of radish when compared to their controls. The highest rate of seedling growth inhibition was observed in I-3 bacterial isolate treatment in lettuce and radish. The mechanism of an effective bio-herbicide I-3 to plant growth inhibition was determined by analyzing IAA in their culture medium. IAA biosynthesis pathway of Enterobacter sp. I-3 was identified as tryptophan-dependent pathway and its production was increased due to addition of tryptophan in culture medium as quantified by using GC-MS SIM. In an in vitro study revealed that I-3 bacterial culture exudate combined with tryptophan significantly decreased leaf length, leaf width, root length and increased the number of lateral roots of lettuce. Indeed, the genomic DNA of I-3 bacterium was isolated and 16S rDNA was sequenced to find out the name of the bacterium. Based on phylogenetic analysis, I-3 isolate was identified and named into Enterobacter sp. I-3. The results of this study suggest that the utilization of Enterobacter sp. I-3 to crop field can be act as a potential bio-herbicide against weed growth. PMID- 25805907 TI - Direct Biotransformation of Dioscin into Diosgenin in Rhizome of Dioscorea zingiberensis by Penicillium dioscin. AB - Diosgenin is an important precursor for synthesis of more than 200 steroidal hormone medicines. Rhizome of Dioscorea zingiberensis C. H. Wright (RDZ) contained the highest content of diosgenin in Dioscorea plant species. Diosgenin is traditionally extracted by acid hydrolysis from RDZ. However, the acid hydrolysis process produces massive wastewater which caused serious environment pollution. In this study, diosgenin extraction by direct biotransformation with Penicillium dioscin was investigated. The spawn cultivation conditions were optimized as: Czapeks liquid culture medium without sugar and agar (1,000 ml) + 6.0 g dioscin/6.0 g DL, 30 degrees C, 36 h; solid fermentation of RDZ: mycelia/RDZ of 0.05 g/kg, 30 degrees C, 50 h; the yield of diosgenin was over 90 %. Spawn cultivation was crucial for the direct biotransformation. In the spawn cultivation, amount and ratio of dioscin/DL were the key factors to promote biotransformation activity of P. dioscin. This biotransformation method was environment-friendly, simple and energy saving, and might be a potential substitute for acid hydrolysis in diosgenin extraction industry. PMID- 25805909 TI - Rapid diagnosis and simultaneous identification of tuberculous and bacterial meningitis by a newly developed duplex polymerase chain reaction. AB - The present study describes the development and evaluation of a duplex polymerase chain reaction (D-PCR) for diagnosis and simultaneous identification of tuberculous meningitis (TBM) and bacterial meningitis (BM) in a single reaction. A D-PCR with primers amplifying portions of the Mycobacterium tuberculosis IS6110 and the eubacteria 16SrDNA sequence in a same reaction mix was developed and tested on DNA extracted from 150 clinical CSF samples from different categories (TBM = 39, BM = 26, control infectious and non-infectious category = 85). The results indicate a clear differentiation between bands for eubacteria and M. tuberculosis with an analytical sensitivity of 10(3) cfu/ml for eubacteria and 10(2) cfu/ml for M. tuberculosis. When evaluated in clinical samples, D-PCR overall diagnosed 100 % confirmed TBM and 100 % confirmed BM cases with overall specificity of 96.5 %. D-PCR can be an effective tool for diagnosis and simultaneous identification of TBM or BM in a single PCR reaction. It saves time, cost, labour and sample amount and help in administration of appropriate antimicrobial therapy. The proposed diagnostic assay would be helpful in correct and rapid management of TBM and BM patients. PMID- 25805911 TI - Development of PCR diagnostic system for detection of the seed-transmitted tobacco ringspot virus in quarantine. AB - Tobacco ringspot virus (TRSV) is a plant quarantine virus in Korea. As such, a TRSV examination is conducted when importing various crops. In this study, RT-PCR and nested PCR systems for TRSV detection in quarantine sites, and the modified positive control plasmid for proving laboratory contamination and false positive reactions were developed. The developed diagnostic system was used to detect TRSV in the quarantine site. It revealed that from 2012 to August 2014, a total of 12 cases were detected in imported various crops. The system is expected to continue contributing to TRSV detection in plant quarantine. PMID- 25805912 TI - Emission Reduction of Fuel-Staged Aircraft Engine Combustor Using an Additional Premixed Fuel Nozzle. AB - The Japan Aerospace Exploration Agency (JAXA) is conducting research and development on aircraft engine technologies to reduce environmental impact for the Technology Development Project for Clean Engines (TechCLEAN). As a part of the project, combustion technologies have been developed with an aggressive target that is an 80% reduction over the NOx threshold of the International Civil Aviation Organization (ICAO) Committee on Aviation Environmental Protection (CAEP)/4 standard. A staged fuel nozzle with a pilot mixer and a main mixer was developed and tested using a single-sector combustor under the target engine's landing and takeoff (LTO) cycle conditions with a rated output of 40 kN and an overall pressure ratio of 25.8. The test results showed a 77% reduction over the CAEP/4 NOx standard. However, the reduction in smoke at thrust conditions higher than the 30% MTO condition and of CO emission at thrust conditions lower than the 85% MTO condition are necessary. In the present study, an additional fuel burner was designed and tested with the staged fuel nozzle in a single-sector combustor to control emissions. The test results show that the combustor enables an 82% reduction in NOx emissions relative to the ICAO CAEP/4 standard and a drastic reduction in smoke and CO emissions. PMID- 25805910 TI - Using a Label Free Quantitative Proteomics Approach to Identify Changes in Protein Abundance in Multidrug-Resistant Mycobacterium tuberculosis. AB - Reports in recent years indicate that the increasing emergence of resistance to drugs be using to TB treatment. The resistance to them severely affects to options for effective treatment. The emergence of multidrug-resistant tuberculosis has increased interest in understanding the mechanism of drug resistance in M. tuberculosis and the development of new therapeutics, diagnostics and vaccines. In this study, a label-free quantitative proteomics approach has been used to analyze proteome of multidrug-resistant and susceptible clinical isolates of M. tuberculosis and identify differences in protein abundance between the two groups. With this approach, we were able to identify a total of 1,583 proteins. The majority of identified proteins have predicted roles in lipid metabolism, intermediary metabolism, cell wall and cell processes. Comparative analysis revealed that 68 proteins identified by at least two peptides showed significant differences of at least twofolds in relative abundance between two groups. In all protein differences, the increase of some considering proteins such as NADH dehydrogenase, probable aldehyde dehydrogenase, cyclopropane mycolic acid synthase 3, probable arabinosyltransferase A, putative lipoprotein, uncharacterized oxidoreductase and six membrane proteins in resistant isolates might be involved in the drug resistance and to be potential diagnostic protein targets. The decrease in abundance of proteins related to secretion system and immunogenicity (ESAT-6-like proteins, ESX-1 secretion system associated proteins, O-antigen export system and MPT63) in the multidrug resistant strains can be a defensive mechanism undertaken by the resistant cell. PMID- 25805913 TI - Evaluation of Computational Fluid Dynamics and Coupled Fluid-Solid Modeling for a Direct Transfer Preswirl System. AB - The prediction of the preswirl cooling air delivery and disk metal temperature are important for the cooling system performance and the rotor disk thermal stresses and life assessment. In this paper, standalone 3D steady and unsteady computation fluid dynamics (CFD), and coupled FE-CFD calculations are presented for prediction of these temperatures. CFD results are compared with previous measurements from a direct transfer preswirl test rig. The predicted cooling air temperatures agree well with the measurement, but the nozzle discharge coefficients are under predicted. Results from the coupled FE-CFD analyses are compared directly with thermocouple temperature measurements and with heat transfer coefficients on the rotor disk previously obtained from a rotor disk heat conduction solution. Considering the modeling limitations, the coupled approach predicted the solid metal temperatures well. Heat transfer coefficients on the rotor disk from CFD show some effect of the temperature variations on the heat transfer coefficients. Reasonable agreement is obtained with values deduced from the previous heat conduction solution. PMID- 25805914 TI - Conceptual Mean-Line Design of Single and Twin-Shaft Oxy-Fuel Gas Turbine in a Semiclosed Oxy-Fuel Combustion Combined Cycle. AB - The aim of this study was to compare single- and twin-shaft oxy-fuel gas turbines in a semiclosed oxy-fuel combustion combined cycle (SCOC-CC). This paper discussed the turbomachinery preliminary mean-line design of oxy-fuel compressor and turbine. The conceptual turbine design was performed using the axial through flow code luax-t, developed at Lund University. A tool for conceptual design of axial compressors developed at Chalmers University was used for the design of the compressor. The modeled SCOC-CC gave a net electrical efficiency of 46% and a net power of 106 MW. The production of 95% pure oxygen and the compression of CO2 reduced the gross efficiency of the SCOC-CC by 10 and 2 percentage points, respectively. The designed oxy-fuel gas turbine had a power of 86 MW. The rotational speed of the single-shaft gas turbine was set to 5200 rpm. The designed turbine had four stages, while the compressor had 18 stages. The turbine exit Mach number was calculated to be 0.6 and the calculated value of AN2 was 40 . 106 rpm2m2. The total calculated cooling mass flow was 25% of the compressor mass flow, or 47 kg/s. The relative tip Mach number of the compressor at the first rotor stage was 1.15. The rotational speed of the twin-shaft gas generator was set to 7200 rpm, while that of the power turbine was set to 4800 rpm. A twin shaft turbine was designed with five turbine stages to maintain the exit Mach number around 0.5. The twin-shaft turbine required a lower exit Mach number to maintain reasonable diffuser performance. The compressor turbine was designed with two stages while the power turbine had three stages. The study showed that a four-stage twin-shaft turbine produced a high exit Mach number. The calculated value of AN2 was 38 . 106 rpm2m2. The total calculated cooling mass flow was 23% of the compressor mass flow, or 44 kg/s. The compressor was designed with 14 stages. The preliminary design parameters of the turbine and compressor were within established industrial ranges. From the results of this study, it was concluded that both single- and twin-shaft oxy-fuel gas turbines have advantages. The choice of a twin-shaft gas turbine can be motivated by the smaller compressor size and the advantage of greater flexibility in operation, mainly in the off design mode. However, the advantages of a twin-shaft design must be weighed against the inherent simplicity and low cost of the simple single-shaft design. PMID- 25805915 TI - Design and Experimental Study of an Over-Under TBCC Exhaust System. AB - Turbine-based combined-cycle (TBCC) propulsion systems have been a topic of research as a means for more efficient flight at supersonic and hypersonic speeds. The present study focuses on the fundamental physics of the complex flow in the TBCC exhaust system during the transition mode as the turbine exhaust is shut off and the ramjet exhaust is increased. A TBCC exhaust system was designed using methods of characteristics (MOC) and subjected to experimental and computational study. The main objectives of the study were: (1) to identify the interactions between the two exhaust jet streams during the transition mode phase and their effects on the whole flow-field structure; (2) to determine and verify the aerodynamic performance of the over-under TBCC exhaust nozzle; and (3) to validate the simulation ability of the computational fluid dynamics (CFD) software according to the experimental conditions. Static pressure taps and Schlieren apparatus were employed to obtain the wall pressure distributions and flow-field structures. Steady-state tests were performed with the ramjet nozzle cowl at six different positions at which the turbine flow path were half closed and fully opened, respectively. Methods of CFD were used to simulate the exhaust flow and they complemented the experimental study by providing greater insight into the details of the flow field and a means of verifying the experimental results. Results indicated that the flow structure was complicated because the two exhaust jet streams interacted with each other during the exhaust system mode transition. The exhaust system thrust coefficient varied from 0.9288 to 0.9657 during the process. The CFD simulation results agree well with the experimental data, which demonstrated that the CFD methods were effective in evaluating the aerodynamic performance of the TBCC exhaust system during the mode transition. PMID- 25805916 TI - Effects of Cavity on the Performance of Dual Throat Nozzle During the Thrust Vectoring Starting Transient Process. AB - The dual throat nozzle (DTN) technique is capable to achieve higher thrust vectoring efficiencies than other fluidic techniques, without compromising thrust efficiency significantly during vectoring operation. The excellent performance of the DTN is mainly due to the concaved cavity. In this paper, two DTNs of different scales have been investigated by unsteady numerical simulations to compare the parameter variations and study the effects of cavity during the vector starting process. The results remind us that during the vector starting process, dynamic loads may be generated, which is a potentially challenging problem for the aircraft trim and control. PMID- 25805917 TI - Numerical Investigation on Aerodynamic and Combustion Performance of Chevron Mixer Inside an Afterburner. AB - To improve the performance of the afterburner for the turbofan engine, an innovative type of mixer, namely, the chevron mixer, was considered to enhance the mixture between the core flow and the bypass flow. Computational fluid dynamics (CFD) simulations investigated the aerodynamic performances and combustion characteristics of the chevron mixer inside a typical afterburner. Three types of mixer, namely, CC (chevrons tilted into core flow), CB (chevrons tilted into bypass flow), and CA (chevrons tilted into core flow and bypass flow alternately), respectively, were studied on the aerodynamic performances of mixing process. The chevrons arrangement has significant effect on the mixing characteristics and the CA mode seems to be advantageous for the generation of the stronger streamwise vortices with lower aerodynamic loss. Further investigations on combustion characteristics for CA mode were performed. Calculation results reveal that the local temperature distribution at the leading edge section of flame holder is improved under the action of streamwise vortices shedding from chevron mixers. Consequently, the combustion efficiency increased by 3.5% compared with confluent mixer under the same fuel supply scheme. PMID- 25805918 TI - The Influence of Inlet Asymmetry on Steam Turbine Exhaust Hood Flows. AB - It has been widely recognized for some decades that it is essential to accurately represent the strong coupling between the last stage blades (LSB) and the diffuser inlet, in order to correctly capture the flow through the exhaust hoods of steam turbine low pressure cylinders. This applies to any form of simulation of the flow, i.e., numerical or experimental. The exhaust hood flow structure is highly three-dimensional and appropriate coupling will enable the important influence of this asymmetry to be transferred to the rotor. This, however, presents challenges as the calculation size grows rapidly when the full annulus is calculated. The size of the simulation means researchers are constantly searching for methods to reduce the computational effort without compromising solution accuracy. However, this can result in excessive computational demands in numerical simulations. Unsteady full-annulus CFD calculation will remain infeasible for routine design calculations for the foreseeable future. More computationally efficient methods for coupling the unsteady rotor flow to the hood flow are required that bring computational expense within realizable limits while still maintaining sufficient accuracy for meaningful design calculations. Research activity in this area is focused on developing new methods and techniques to improve accuracy and reduce computational expense. A novel approach for coupling the turbine last stage to the exhaust hood employing the nonlinear harmonic (NLH) method is presented in this paper. The generic, IP free, exhaust hood and last stage blade geometries from Burton et al. (2012. "A Generic Low Pressure Exhaust Diffuser for Steam Turbine Research,"Proceedings of the ASME Turbo Expo, Copenhagen, Denmark, Paper No. GT2012-68485) that are representative of modern designs, are used to demonstrate the effectiveness of the method. This is achieved by comparing results obtained with the NLH to those obtained with a more conventional mixing-plane approach. The results show that the circumferential asymmetry can be successfully transferred in both directions between the exhaust hood flow and that through the LSB, by using the NLH. This paper also suggests that for exhaust hoods of generous axial length, little change in Cp is observed when the circumferential asymmetry is captured. However, the predicted flow structure is significantly different, which will influence the design and placement of the exhaust hood internal "furniture." PMID- 25805919 TI - Windage Heating in a Shrouded Rotor-Stator System. AB - This paper has experimentally and numerically studied the windage heating in a shrouded rotor-stator disk system with superimposed flow. Temperature rise in the radius direction on the rotating disk is linked to the viscous heating process when cooling air flows through the rotating component. A test rig has been developed to investigate the effect of flow parameters and the gap ratio on the windage heating, respectively. Experimental results were obtained from a 0.45 m diameter disk rotating at up to 12,000 rpm with gap ratio varying from 0.02 to 0.18 and a stator of the same diameter. Infrared temperature measurement technology has been proposed to measure the temperature rise on the rotor surface directly. The PIV technique was adapted to allow for tangential velocity measurements. The tangential velocity data along the radial direction in the cavity was compared with the results obtained by CFD simulation. The comparison between the free disk temperature rise data and an associated theoretical analysis for the windage heating indicates that the adiabatic disk temperature can be measured by infrared method accurately. For the small value of turbulence parameter, the gap ratio has limited influence on the temperature rise distribution along the radius. As turbulence parameter increases, the temperature rise difference is independent of the gap ratio, leaving that as a function of rotational Reynolds number and throughflow Reynolds number only. The PIV results show that the swirl ratio of the rotating core between the rotor and the stator has a key influence on the windage heating. PMID- 25805921 TI - Perioperative management of distal pancreatectomy. AB - Recent advances in surgical techniques and perioperative management have markedly reduced operative morbidity after distal pancreatectomy (DP). However, some questions remain regarding the protocol for the perioperative management of DP, in particular, with regard to the development of pancreatic fistula (PF). A review of DP was therefore conducted in order to standardize the management of patients for a favorable outcome. Overall, operative technique and perioperative management emerged as two critical factors contributing to favorable outcome in DP patients. As for the operative method, surgical and closure techniques exhibited differences in outcome. Laparoscopic DP generally yields more favorable perioperative outcomes compared to open DP, and is applicable for benign tumors and some ductal carcinomas of the pancreas. Robotic DP is also available for safe pancreatic surgery. En bloc celiac axis resection offers a high R0 resection rate and potentially allows for some local control in the case of advanced pancreatic cancer. Following resection, staple closure was not found to reduce the rate of PF when compared to hand-sewn closure. In addition, ultrasonic dissection devices, fibrin glue sealing, and staple closure with mesh reinforcement were shown to significantly reduce PF, although there was some bias in these studies. In perioperative management, both preoperative and postoperative treatment affected outcome. First, preoperative endoscopic pancreatic stenting may be an effective prophylactic measure against fistula development following DP in selected patients. Second, in postoperative management, a multifactorial approach including prophylactic antibiotics improved high surgical site infection rates following complex hepato-pancreato-biliary surgery. Furthermore, although conflicting results have been reported, somatostatin analogues should be administered selectively to patients considered to have a high risk for PF. Finally, careful drain management also facilitates a favorable outcome in patients with PF after DP. The results of the review indicate that laparoscopic DP coupled with perioperative management influences outcome in DP patients. PMID- 25805920 TI - Update on the management of pancreatic cancer: surgery is not enough. AB - Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of death in cancer and has a 5-year survival of < 5%. Only about 15% of the patients present with a resectable PDAC with potential to undergo "curative" surgery. After surgery, local and systemic recurrence, is though very common. The median survival of resected patients with adjuvant chemotherapy after surgery is only 20 23 mo. This underscores the significant need to improve PDAC management strategies. Increased survival rate is dependent on new breakthroughs in our understanding of not at least tumor biology. The aim of this review is to update and comment on recent knowledge concerning PDAC biology and new diagnostics and treatment modalities. One fundamental approach to improve survival rates is by earlier and improved diagnosis of the disease. In recent years, novel blood-based biomarkers have emerged based on genetic, epigenetic and protein changes in PDAC with very promising results. For biomarkers to enter clinical practice they need to have been developed using adequate control groups and provide high sensitivity and specificity and by this identify patients at risk already in a pre symptomatic stage. Another way to improve outcomes, is by employing neoadjuvant treatments thereby increasing the number of resectable cases. Novel systemic treatment regimes like FOLFIRINOX and nab-paclitaxel have demonstrated improvements in prolonging survival in advanced cases, but long-term survival is still scarce. The future improved understanding of PDAC biology will inevitably render new treatment options directed against both the cancer cells and the surrounding microenvironment. PMID- 25805922 TI - Contra-lateral liver lobe hypertrophy after unilobar Y90 radioembolization: an alternative to portal vein embolization? AB - Liver resection (LR) with negative margins confers survival advantage in many patients with hepatic malignancies. However, an adequate future liver remnant (FLR) is imperative for safe LR. Presently, in patients with an inadequate FLR; the 2 most established clinical techniques performed to induce liver hypertrophy are portal vein embolization (PVE) and portal vein ligation. More recently, it has been observed that patients who undergo treatment via Y90 radioembolization experience hypertrophy of the contra-lateral untreated liver lobe. Based on these observations, several investigators have proposed the potential use of this modality as an alternative technique for increasing the FLR prior to liver resection. Y90 radioembolization induces hypertrophy at a slower rate than PVE but has the added advantage of concomitant local disease control and tumour down staging. PMID- 25805923 TI - Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. AB - Nuclear factor kappa B (NF-kappaB) has an established role in the regulation of innate immunity and inflammation. NF-kappaB is also involved in critical mechanisms connecting inflammation and cancer development. Recent investigations suggest that the NF-kappaB signaling cascade may be the central mediator of gastrointestinal malignancies including esophageal, gastric and colorectal cancers. This review will explore NF-kappaB's function in inflammation-associated gastrointestinal malignancies, highlighting its oncogenic contribution to each step of carcinogenesis. NF-kappaB's role in the inflammation-to-carcinoma sequence in gastrointestinal malignancies warrants stronger emphasis upon targeting this pathway in achieving greater therapeutic efficacy. PMID- 25805924 TI - Updates in vaccination: recommendations for adult inflammatory bowel disease patients. AB - Treatment regimens for inflammatory bowel disease (IBD) incorporate the use of a variety of immunosuppressive agents that increase the risk of infections. Prevention of many of these infections can be achieved by the timely and judicious use of vaccinations. IBD patients tend to be under-immunized. Some of the contributing factors are lack of awareness regarding the significance of vaccinating IBD patients, misperception about safety of vaccinations in immunocompromised patients, ambiguity about the perceived role of the gastroenterologist in contrast to the primary care physician and unavailability of vaccination guidelines focused on IBD population. In general, immunocompetent IBD patients can be vaccinated using standard vaccination recommendations. However there are special considerations for IBD patients receiving immunosuppressive therapy, IBD travelers and pregnant women with IBD. This review discusses current vaccination recommendations with updates for adult IBD patients. Centers for Disease Control and Prevention 2013 vaccination guidelines with 2014 updates and the Advisory Committee on Immunization Practices recommendations have been highlighted as a primary source of recommendations. PMID- 25805925 TI - Hyponatremia in cirrhosis: pathophysiology and management. AB - Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. The development of ascites in patients with cirrhosis is multi-factorial. Portal hypertension and the associated systemic vasodilation lead to activation of the sodium-retaining neurohumoral mechanisms which include the renin-angiotensin-aldosterone system, sympathetic nervous system and antidiuretic hormone (ADH). The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume resulting in the development of ascites. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and ascites leads to impairment of the kidneys to eliminate solute- free water. This leads to additional compensatory mechanisms including non-osmotic secretion of ADH, also known as arginine vasopressin, further worsening excess water retention and thereby hyponatremia. Hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic marker both before and after liver transplant. The management of hyponatremia in this setting is a challenge as conventional therapy for hyponatremia including fluid restriction and loop diuretics are frequently inefficacious. In this review, we discuss the pathophysiology and various treatment modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with cirrhosis. PMID- 25805926 TI - Novel CD9-targeted therapies in gastric cancer. AB - There are 33 human tetraspanin proteins, emerging as key players in malignancy, the immune system, fertilization, cellular signaling, adhesion, morphology, motility, proliferation, and tumor invasion. CD9, a member of the tetraspanin family, associates with and influences a variety of cell-surface molecules. Through these interactions, CD9 modifies multiple cellular events, including adhesion, migration, proliferation, and survival. CD9 is therefore considered to play a role in several stages during cancer development. Reduced CD9 expression is generally related to venous vessel invasion and metastasis as well as poor prognosis. We found that treatment of mice bearing human gastric cancer cells with anti-CD9 antibody successfully inhibited tumor progression via antiproliferative, proapoptotic, and antiangiogenic effects, strongly indicating that CD9 is a possible therapeutic target in patients with gastric cancer. Here, we describe the possibility of CD9 manipulation as a novel therapeutic strategy in gastric cancer, which still shows poor prognosis. PMID- 25805928 TI - Biomarkers in nonalcoholic fatty liver disease-the emperor has no clothes? AB - Fatty liver is present in over ten percentage of the world population and it is a growing public health problem. Nonalcoholic fatty liver disease (NAFLD) is not a single disease, but encompasses a spectrum of diseases of different etiologies. It is difficult to find highly specific and sensitive diagnostic biomarkers when a disease is very complex. Therefore, we should aim to find relevant prognostic markers rather than accurate diagnostic markers which will help to minimize the frequency of liver biopsies to evaluate disease progression. There are several biomarker panels commercially available, however, there is no clear evidence that more sophisticated panels are better compared to simple criteria such as, presence of diabetes over five years, metabolic syndrome, obesity, obstructive sleep apnea, aspartate transaminase/alanine transaminase (ALT) ratio > 0.8 or ferritin levels > 1.5 times normal in patients with over six month history of raised ALT and/or ultrasonological evidence of fat in the liver. Currently the biomarker panels are not a replacement for a liver biopsy. However the need and benefit of liver biopsy in NAFLD is questionable because there is no convincing evidence that biopsy and detailed staging of NAFLD improves the management of NAFLD and benefits the patient. After all there is no evidence based treatment for NAFLD other than management of lifestyle and components of "metabolic syndrome". PMID- 25805927 TI - Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is currently considered as the most common liver disease in Western countries, and is rapidly becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. The ghrelin-ghrelin O acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. Ghrelin, the natural ligand of the growth hormone secretagogue receptor, is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT. The ghrelin-GOAT system is involved in insulin resistance, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD. A better understanding of ghrelin GOAT system biology led to the identification of its potential roles in NAFLD. Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied, which provide a new insight into the pathogenesis of NAFLD. This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD. PMID- 25805929 TI - Mitochondrial uncoupling protein 2 and pancreatic cancer: a new potential target therapy. AB - Overall 5-years survival of pancreatic cancer patients is nearly 5%, making this cancer type one of the most lethal neoplasia. Furthermore, the incidence rate of pancreatic cancer has a growing trend that determines a constant increase in the number of deceases caused by this pathology. The poor prognosis of pancreatic cancer is mainly caused by delayed diagnosis, early metastasis of tumor, and resistance to almost all tested cytotoxic drugs. In this respect, the identification of novel potential targets for new and efficient therapies should be strongly encouraged in order to improve the clinical management of pancreatic cancer. Some studies have shown that the mitochondrial uncoupling protein 2 (UCP2) is over-expressed in pancreatic cancer as compared to adjacent normal tissues. In addition, recent discoveries established a key role of UCP2 in protecting cancer cells from an excessive production of mitochondrial superoxide ions and in the promotion of cancer cell metabolic reprogramming, including aerobic glycolysis stimulation, promotion of cancer progression. These observations together with the demonstration that UCP2 repression can synergize with standard chemotherapy to inhibit pancreatic cancer cell growth provide the molecular rationale to consider UCP2 as a potential therapeutic target for pancreatic cancer. In this editorial, recent advances describing the relationship between cancer development and mitochondrial UCP2 activity are critically provided. PMID- 25805931 TI - MicroRNA-1290 promotes esophageal squamous cell carcinoma cell proliferation and metastasis. AB - AIM: To investigate the biological role of miR-1290 in esophageal squamous cell carcinoma (ESCC) progression and invasion and the underlying mechanism. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate miR-1290 expression in ESCC tissue samples. The roles of miR-1290 in cell proliferation, migration and invasion were identified using miR-1290 mimic transfected cells. In addition, the regulatory effect of miR-1290 on suppressor of cancer cell invasion (SCAI) was evaluated using qRT-PCR, Western blot analysis and a dual luciferase reporter assay. RESULTS: miR-1290 was significantly upregulated in ESCC tissue samples compared with normal adjacent tissues (9.213 +/- 1.150 vs 1.000 +/- 0.0), (P < 0.01). Upregulation of miR-1290 was associated with tumor differentiation (P = 0.021), N classification (P = 0.006) and tumor node-metastasis stage (P = 0.021) in ESCC patients. Moreover, ectopic miR-1290 expression potently promoted ESCC cell growth (P < 0.01), migration (P < 0.01) and invasion (P < 0.01) in vitro. miR-1290 overexpression in ESCC cell lines decreased SCAI expression at the translational level and reduced SCAI-driven luciferase-reporter activity (P < 0.01). CONCLUSION: Our findings suggested that miR-1290 may play an oncogenic role in cellular processes of ESCC. PMID- 25805930 TI - Effects of urotensin-II on cytokines in early acute liver failure in mice. AB - AIM: To investigate urotensin-II (UII) and its effects on tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in early acute liver failure (ALF). METHODS: We investigated the time-dependent alteration in UII levels and its effects on TNF-alpha and IL-1beta in liver and blood in the early stage of lipopolysaccharide/D-galactosamine-induced ALF. RESULTS: After lipopolysaccharide/D-galactosamine challenge, UII rose very rapidly and reached a maximal level 0.5 h, and the level remained significantly elevated after 2 h (P < 0.05). Six hours after challenge, UII began to degrade, but remained higher than at 0 h (P < 0.05). Pretreatment with urantide, an inhibitor of the UII receptor, suppressed the degree of UII increase in liver and blood at 6 h after challenge (P < 0.05 vs paired controls). In addition, liver and blood TNF-alpha increased from 1 to 6 h, and reached a peak at 1 and 2 h, respectively; however, IL-1beta did not rise until 6 h after challenge. Urantide pretreatment inhibited the degree of TNF-alpha and IL-1beta increase following downregulation of UII post challenge (all P < 0.05). CONCLUSION: UII plays a role in the pathogenesis and priming of ALF by triggering an inflammatory cascade and driving the early release of cytokines in mice. PMID- 25805932 TI - High-mobility group box 1 expression and lymph node metastasis in intrahepatic cholangiocarcinoma. AB - AIM: To evaluate the prognostic value of high-mobility group box 1 (HMGB1) expression in intrahepatic cholangiocarcinoma (IHCC) and the possible underlying mechanism. METHODS: Tissue microarray was constructed from 65 IHCC patients. Immunohistochemistry was performed to validate expression of HMGB1 and Vascular endothelial growth factor C (VEGF-C). Real-time PCR and Western blot analyses were used to study transcript and protein levels. The interaction between HMGB1 and VEGF-C was evaluated by siRNA, real-time PCR, and enzyme-linked immuno assays. The correlation between HMGB1 expression and other clinicopathologic parameters was analyzed by chi (2) test, and the univariate as well as multivariate analyses were accomplished by Kaplan-Meier method and Cox-regression model, respectively. RESULTS: Overall, overexpression of HMGB1 was found in 38/65 (58.8%) IHCCs, whereas VEGF-C overexpression was present in 30/65 (46.2%) cases. Overexpression of HMGB1 was significantly correlated with lymphatic microvessel density (P = 0.031, r = 0.268) and VEGF-C expression (P = 0.041, r = 0.254). With univariate analysis, both HMGB1 (P = 0.001) and VEGF-C (P = 0.004) were identified to be significantly associated with overall survival rate. Multivariate analysis indicated that HMGB1 could be served as an unfavorable independent prognostic factor in IHCCs (P = 0.005). siRNA knockdown of HMGB1 inhibited transforming growth factor-beta-induced epithelial-mesenchymal transition (EMT) by elevating E-Cadherin expression and reducing expression of N Cadherin, Vimentin and Snail in RBE cells. Further in vitro study revealed that HMGB1 silencing significantly decreased the level of VEGF-C, whereas the recombinant HMGB1 increased the VEGF-C level in RBE cells (both P < 0.05), which suggested that HMGB1 could promote lymphatic microvessel density, and subsequently lymphatic invasion, via promoting VEGF-C expression. CONCLUSION: Our results define an important role of HMGB1 in the progression of cholangiocarcinoma, and HMGB1 may serve as a prognostic marker for IHCC patients. PMID- 25805933 TI - Hepatitis E in hemodialysis and kidney transplant patients in south-east Italy. AB - AIM: To investigate the serovirological prevalence and clinical features of hepatitis E virus (HEV) infection in end-stage renal failure patients and in the healthy population. METHODS: HEV infection is a viral disease that can cause sporadic and epidemic hepatitis. Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects, including hemodialysis (HD) patients and patients who had undergone kidney transplant. A cohort/case control study was carried out from January 2012 to August 2013 in two hospitals in southern Italy (Foggia and S. Giovanni Rotondo, Apulia). The seroprevalence of HEV was determined in 801 subjects; 231 HD patients, 120 renal transplant recipients, and 450 health individuals. All HD patients and the recipients of renal transplants were attending the Departments of Nephrology and Dialysis at two hospitals located in Southern Italy, and were included progressively in this study. Serum samples were tested for HEV antibodies (IgG/IgM); in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA, and the HEV genotypes were determined. RESULTS: A total of 30/801 (3.7%) patients were positive for anti-HEV Ig (IgG and/or IgM) and by Western blot. The healthy population presented with a prevalence of 2.7%, HD patients had a prevalence of 6.0%, and transplant recipients had a prevalence of 3.3%. The overall combined HEV-positive prevalence in the two groups with chronic renal failure was 5.1%. The rates of exposure to HEV (positivity of HEV-IgG/M in the early samples) were lower in the healthy controls, but the difference among the three groups was not statistically significant (P > 0.05). Positivity for anti HEV/IgM was detected in 4/30 (13.33%) anti-HEV Ig positive individuals, in 2/14 HD patients, in 1/4 transplant individuals, and in 1/12 of the healthy population. The relative risk of being HEV-IgM-positive was significantly higher among transplant recipients compared to the other two groups (OR = 65.4, 95%CI: 7.2-592.7, P < 0.001), but the subjects with HEV-IgM positivity were numerically too few to calculate a significant difference. No patient presented with chronic hepatitis from HEV infection alone. CONCLUSION: This study indicated a higher, but not significant, circulation of HEV in hemodialysis patients vs the healthy population. Chronic hepatitis due to the HEV virus was not observed. PMID- 25805934 TI - Ratio of metastatic lymph nodes is more important for rectal cancer patients treated with preoperative chemoradiotherapy. AB - AIM: To evaluate the predictive value of the lymph node (LN) ratio (LNR, number of metastatic LNs/ examined LNs) for recurrence in patients with rectal cancer and to compare its applicability according to preoperative chemoradiotherapy (PCRT). METHODS: From 2000 to 2009, 967 patients with metastatic LNs after curative resection for locally advanced rectal cancer were identified. Patients were categorized according to PCRT (PCRT vs No PCRT). The cut-off LNR was determined based on the pN1 vs pN2 when the recommended number of LNs was harvested. The 5-year recurrence-free survival (RFS) rates using the Kaplan-Meier method were compared according to p/yp N stage and the LNR in each group. RESULTS: Among patients with the same p/ypN stage, the 5-year RFS rate differed according to the LNR. In addition, the 5-year RFS rate was significantly different between pN and LNR groups in patients with No PCRT. In PCRT group, however, only LNR was associated with prognosis. On multivariate analysis, both pN and LNR were significant independent prognostic factors for 5-year RFS in the No PCRT group. In the PCRT group, only LNR category was found to be associated with RFS (HR = 2.36, 95%CI: 1.31-3.84, and P = 0.001). CONCLUSION: The LNR is an important prognostic predictor of RFS in rectal cancer patients especially treated with PCRT. Current pN categories could not discriminate between prognostic groups of RFS after PCRT. PMID- 25805935 TI - Real-life outcome of anti-tumor necrosis factor alpha in the ambulatory treatment of ulcerative colitis. AB - AIM: To evaluate the outcome of anti-tumor necrosis factor alpha (anti-TNFalpha) therapy in outpatients with ulcerative colitis at a tertiary referral center. METHODS: All patients with a confirmed diagnosis of ulcerative colitis undergoing therapy with infliximab and/or adalimumab at the outpatient clinic for inflammatory bowel diseases at the University Hospital Heidelberg between January 2011 and February 2014 were retrospectively enrolled. Patients with a follow-up period of less than 6 mo from start of anti-TNFalpha therapy were excluded. Medical records of all eligible individuals were carefully reviewed. Steroid-free clinical remission of a duration of at least 3 mo, colectomy rate, duration of anti-TNFalpha therapy, need for anti-TNFalpha dose escalation, and the occurrence of adverse events were evaluated as the main outcome parameters. RESULTS: Seventy two patients were included (35 treated with infliximab, 17 with adalimumab, 20 with both consecutively). Median follow-up was 27 mo (range: 6-87 mo). Steroid free clinical remission was achieved by 22.2% of the patients (median duration: 21 mo until end of follow-up; range: 3-66 mo). Patients attaining steroid-free clinical remission displayed lower hemoglobin and albumin blood levels at the start of treatment than those who did not achieve remission. The overall colectomy rate was 20.8%. Nearly 50% of the patients underwent anti-TNFalpha dose escalation during the follow-up period. For both the infliximab and the adalimumab treated patients, non-response to anti-TNFalpha therapy was the major reason for treatment discontinuation. 18.2% of the infliximab-treated patients and 13.5% of the adalimumab-treated patients had to discontinue their therapy due to adverse events. CONCLUSION: Real-life remission rates of ulcerative colitis under anti-TNFalpha are overall low, but some patients have a clear long-term benefit. PMID- 25805939 TI - High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation. AB - AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF). METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes. RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR >= 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT. CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF. PMID- 25805937 TI - Hepatectomy vs radiofrequency ablation for colorectal liver metastasis: a propensity score analysis. AB - AIM: To compare outcomes from radiofrequency ablation (RFA) and hepatectomy for treatment of colorectal liver metastasis (CRLM). METHODS: From January 2000 to December 2009, 408 patients underwent curative intent treatment for CRLM. We excluded patients using the criteria: size of CRLM > 3 cm, number of CRLM >= 5, percutaneous RFA, follow-up period < 12 mo, double primary cancer, or treatment with both RFA and hepatectomy. We matched 51 patients who underwent RFA with 102 patients who underwent hepatectomy by propensity scores. RESULTS: The median follow-up period was 45 mo (range, 12 mo to 158 mo). Hepatic recurrence was more frequent in the RFA than the hepatectomy group (P = 0.021) although extrahepatic recurrence curves were similar (P = 0.716). Survival curves of hepatectomy group were better than that of RFA for multiple, large (> 2 cm) CRLM (P = 0.034). However, survival curves were similar for single or small (<= 2 cm) CRLM (P = 0.714, P = 0.740). CONCLUSION: Hepatectomy is better than RFA for the treatment of CRLM. However, RFA might be suitable for selected patients with single, small (<= 2 cm) CRLM. PMID- 25805936 TI - Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver. AB - AIM: To investigate the relationship between the iron-metabolism-related gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients. METHODS: The hepatic expression profile of iron-metabolism-related genes was analyzed and its association with virological response to pegylated interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolism-related genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry. RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes. CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment. PMID- 25805938 TI - Significant risk and associated factors of active tuberculosis infection in Korean patients with inflammatory bowel disease using anti-TNF agents. AB - AIM: To evaluate the incidence and risk factors of Korean tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) undergoing anti-TNF treatment. METHODS: The data of IBD patients treated with anti-TNFs in 13 tertiary referral hospitals located in the southeastern region of Korea were collected retrospectively. They failed to show response or were intolerant to conventional treatments, including steroids or immunomodulators. Screening measures for latent TB infection (LTBI) and the incidence and risk factors of active TB infection after treatment with anti-TNFs were identified. RESULTS: Overall, 376 IBD patients treated with anti-TNF agents were recruited (male 255, mean age of anti-TNF therapy 32.5 +/- 13.0 years); 277 had Crohn's disease, 99 had ulcerative colitis, 294 used infliximab, and 82 used adalimumab. Before anti TNF treatment, screening tests for LTBI including an interferon gamma release assay or a tuberculin skin test were performed in 82.2% of patients. Thirty patients (8%) had LTBI. Sixteen cases of active TB infection including one TB related mortality occurred during 801 person-years (PY) follow-up (1997.4 cases per 100000 PY) after anti-TNF treatment. LTBI (OR = 5.76, 95%CI: 1.57-21.20, P = 0.008) and WBC count < 5000 mm(3) (OR = 4.5, 95%CI: 1.51-13.44, P = 0.007) during follow-up were identified as independently associated risk factors. CONCLUSION: Anti-TNFs significantly increase the risk of TB infection in Korean patients with IBD. The considerable burden of TB and marked immunosuppression might be attributed to this risk. PMID- 25805941 TI - Recurrent anal fistulae: limited surgery supported by stem cells. AB - AIM: To study the results of stem-cell therapy under a Compassionate-use Program for patients with recurrent anal fistulae. METHODS: Under controlled circumstances, and approved by European and Spanish laws, a Compassionate-use Program allows the use of stem-cell therapy for patients with very complex anal fistulae. Candidates had previously undergone multiple surgical interventions that had failed to resolve the fistulae, and presented symptomatic recurrence. The intervention consisted of limited surgery (with closure of the internal opening), followed by local implant of stem cells in the fistula-tract wall. Autologous expanded adipose-derived stem cells were the main cell type selected for implant. The first evaluation was performed on the 8(th) postoperative week; outcome was classified as response or partial response. Evaluation one year after the intervention confirmed if complete healing of the fistula was achieved. RESULTS: Ten patients (8 male) with highly recurrent and complex fistulae were treated (mean age: 49 years, range: 28-76 years). Seven cases were non-Crohn's fistulae, and three were Crohn's-associated fistulae. Previous surgical attempts ranged from 3 to 12. Two patients presented with preoperative incontinence (Wexner scores of 12 and 13 points). After the intervention, six patients showed clinical response on the 8(th) postoperative week, with a complete cessation of suppuration from the fistula. Three patients presented a partial response, with an evident decrease in suppuration. A year later, six patients (60%) remained healed, with complete reepithelization of the external opening. Postoperative Wexner Scores were 0 in six cases. The two patients with previous incontinence improved their scores from 12 to 8 points and from 13 to 5 points. No adverse reactions or complications related to stem-cell therapy were reported during the study period. CONCLUSION: Stem cells are safe and useful for treating anal fistulae. Healing can be achieved in severe cases, sparing fecal incontinence risk, and improving previous scoring. PMID- 25805940 TI - Lack of correlation between Treg quantification assays in inflammatory bowel disease patients. AB - AIM: To compare the number of regulatory T-cells (Tregs) measured by flow cytometry with those obtained using a real-time quantitative PCR (qPCR) method in patients suffering from inflammatory bowel disease (IBD). METHODS: Tregs percentages obtained by both flow cytometry and qPCR methods in 35 adult IBD patients, 18 out of them with Crohn's disease (CD) and 17 with ulcerative colitis (UC) were compared to each other as well as to scores on two IBD activity questionnaires using the Harvey Bradshaw Index (HBI) for CD patients and the Simple Colitis Clinical Activity Index (SCCAI) for UC patients. The Treg percentages by flow cytometry were defined as CD4(+)CD25(high)CD127(low)FOXP3(+) cells in peripheral blood mononuclear cells, whereas the Treg percentages by qPCR method were determined as FOXP3 promoter demethylation in genomic DNA. RESULTS: We found an average of 1.56% +/- 0.78% Tregs by using flow cytometry, compared to 1.07% +/- 0.53% Tregs by using qPCR in adult IBD patients. There were no significant correlations between either the percentages of Tregs measured by flow cytometry or qPCR and the HBI or SCCAI questionnaire scores in CD or UC patients, respectively. In addition, there was no correlation between Treg percentages measured by qPCR and those measured by flow cytometry (r = -0.06, P = 0.73; Spearman Rho). These data suggest that, either Treg-related immune function or the clinical scores in these IBD patients did not accurately reflect actual disease activity. Until the cause(s) for these differences are more clearly defined, the results suggest caution in interpreting studies of Tregs in various inflammatory disorders. CONCLUSION: The two methods did not produce equivalent measures of the percentage of total Tregs in the IBD patients studied which is consistent with the conclusion that Tregs subtypes are not equally detected by these two assays. PMID- 25805942 TI - Economic and medical benefits of ultrasound screenings for gallstone disease. AB - AIM: To investigate whether screening for gallstone disease was economically feasible and clinically effective. METHODS: This clinical study was initially conducted in 2002 in Taipei, Taiwan. The study cohort total included 2386 healthy adults who were voluntarily admitted to a regional teaching hospital for a physical check-up. Annual follow-up screening with ultrasound sonography for gallstone disease continued until December 31, 2007. A decision analysis using the Markov Decision Model was constructed to compare different screening regimes for gallstone disease. The economic evaluation included estimates of both the cost-effectiveness and cost-utility of screening for gallstone disease. RESULTS: Direct costs included the cost of screening, regular clinical fees, laparoscopic cholecystectomy, and hospitalization. Indirect costs represent the loss of productivity attributable to the patient's disease state, and were estimated using the gross domestic product for 2011 in Taiwan. Longer time intervals in screening for gallstone disease were associated with the reduced efficacy and utility of screening and with increased cost. The cost per life-year gained (average cost-effectiveness ratio) for annual screening, biennial screening, 3 year screening, 4-year screening, 5-year screening, and no-screening was new Taiwan dollars (NTD) 39076, NTD 58059, NTD 72168, NTD 104488, NTD 126941, and NTD 197473, respectively (P < 0.05). The cost per quality-adjusted life-year gained by annual screening was NTD 40725; biennial screening, NTD 64868; 3-year screening, NTD 84532; 4-year screening, NTD 110962; 5-year screening, NTD 142053; and for the control group, NTD 202979 (P < 0.05). The threshold values indicated that the ultrasound sonography screening programs were highly sensitive to screening costs in a plausible range. CONCLUSION: Routine screening regime for gallstone disease is both medically and economically valuable. Annual screening for gallstone disease should be recommended. PMID- 25805943 TI - Weekly pattern of emergency room admissions for peptic ulcers: a population-based study. AB - AIM: To investigate variations in the incidence of peptic ulcers (PUs) in Taiwan by day of the week within age subgroups. METHODS: Ambulatory care data were retrieved from the Longitudinal Health Insurance Database 2000. There were 7204 subjects >= 18 years-old with an emergency room admission claim for the treatment of PUs, resulting in a total of 9234 emergency room visits for PUs between 2009 and 2011. Data was divided into the seven days of the week and an additional variable for holidays. One-way analysis of variance was used to examine associations among the daily mean number of PU emergency room admissions and holidays/weekends/weekdays. RESULTS: One-way analysis of variance showed that there was a significant difference in emergency room admissions for PUs by the day of the week (P < 0.001), with admission more likely to occur on Sundays or holidays than weekdays within the total and working populations. The weekday patterns of admission were similar for the patients aged 18-64 years and >= 65 years of age. Holidays, followed by Sundays, had higher PU admissions than the mean daily PU emergency room admissions. Furthermore, inclusion of only those treated for PUs with hemorrhage or perforation, Sundays and holidays had higher mean emergency room admissions than other days. Inclusion of patients who diagnosed with Helicobacter pylori infection, only holidays had higher mean emergency room admissions than other days. Inclusion of patients who had been prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for over 30 d, Sundays and holidays had higher mean PU ER admissions than other non-holiday weekdays. CONCLUSION: There is a higher incidence of emergency room admission for PUs on weekends than on weekdays for the total and working populations. PMID- 25805944 TI - Diagnostic value of magnetic resonance cholangiopancreatography in choledocholithiasis. AB - AIM: To evaluate the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) in patients with choledocholithiasis. METHODS: We systematically searched MEDLINE, EMBASE, Web of Science, and Cochrane databases for studies reporting on the sensitivity, specificity and other accuracy measures of diagnostic effectiveness of MRCP for detection of common bile duct (CBD) stones. Pooled analysis was performed using random effects models, and receiver operating characteristic curves were generated to summarize overall test performance. Two reviewers independently assessed the methodological quality of studies using standards for reporting diagnostic accuracy and quality assessment for studies of diagnostic accuracy tools. RESULTS: A total of 25 studies involving 2310 patients with suspected choledocholithiasis and 738 patients with CBD stones met the inclusion criteria. The average inter-rater agreement on the methodological quality checklists was 0.96. Pooled analysis of the ability of MRCP to detect CBD stones showed the following effect estimates: sensitivity, 0.90 (95%CI: 0.88-0.92, chi (2) = 65.80; P < 0.001); specificity, 0.95 (95%CI: 0.93-1.0, chi (2) = 110.51; P < 0.001); positive likelihood ratio, 13.28 (95%CI: 8.85-19.94, chi (2) = 78.95; P < 0.001); negative likelihood ratio, 0.13 (95%CI: 0.09-0.18, chi (2) = 6.27; P < 0.001); and diagnostic odds ratio, 143.82 (95%CI: 82.42-250.95, chi (2) = 44.19; P < 0.001). The area under the receiver operating characteristic curve was 0.97. Significant publication bias was not detected (P = 0.266). CONCLUSION: MRCP has high diagnostic accuracy for the detection of choledocholithiasis. MRCP should be the method of choice for suspected cases of CBD stones. PMID- 25805945 TI - New therapeutic option for irritable bowel syndrome: serum-derived bovine immunoglobulin. AB - Oral prescription medical foods have long been used in hospital settings but are also appropriate therapies for gastrointestinal disorders in outpatient medical practice. Oral serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown in clinical studies to reduce loose stools and improve stool consistency as well as other symptoms (i.e., abdominal pain, bloating, and urgency) in patients with irritable bowel syndrome with diarrhea (IBS-D) and human immunodeficiency virus-associated enteropathy. This case series reports the outcomes of 14 IBS patients who received SBI as an addition to standard of care at an individual physician's clinical practice. The patients: 2 IBS with constipation (IBS-C), 7 IBS-D, 2 mixed diarrhea and constipation IBS (IBS-M) and 3 undefined IBS (IBS-U; also described by some physicians as IBS-Bloating), ranged in age from 22-87 years. SBI (5 g or 10 g daily dose) was added to the patient's current standard care and followed for several weeks to determine if symptoms were improved with the addition of SBI. Overall, 12 of the 14 patients indicated some level of improvement through direct questioning of the patients regarding changes from the prior visit. One IBS-Bloating patient had a resolution of symptoms and two patients (1 IBS-Bloating and 1 IBS-C) discontinued therapy because of insufficient relief. The 12 patients who continued on therapy reported an overall improvement in symptoms with better stool consistency, decreased frequency as well as reductions in abdominal pain, bloating, distention, and incontinence. In most cases, therapeutic effects of SBI were seen within the first four weeks of therapy with continued improvements at subsequent visits. SBI has a multifaceted mechanism of action and may help to manage IBS by providing a distinct protein source required to normalize bowel function, gastrointestinal microbiota, and nutritionally enhance tight junction protein expression between intestinal epithelial cells. SBI as a medical food provides a safe option for patients with IBS-D but may have application in other forms of IBS. PMID- 25805946 TI - Strongyloidiasis: a case with acute pancreatitis and a literature review. AB - Strongyloides stercoralis, a soil transmitted helminth infection, affects millions with varying prevalence worldwide. A large number of affected hosts are asymptomatic. Symptoms pertaining to pulmonary and gastrointestinal involvement may be present. Manifestations of involvement beyond lung and intestine can be seen with dissemination of infection and lethal hyperinfection. Immunosuppression secondary to use of steroids or other immunosuppressants and coexistence of human T-lymphotropic virus type-1 are the known risk factors for dissemination and hyperinfection. Diagnostic modalities comprise stool examination, serology and molecular testing. Stool tests are inexpensive but are limited by low sensitivity, whereas serologic and molecular tests are more precise but at the expense of higher cost. Treatment with Ivermectin or Albendazole as an alternative is safe and efficacious. We present a rare case of acute pancreatitis secondary to Strongyloides. High index of suspicion in patients specifically from endemic countries of origin and lack of other common etiologies of acute pancreatitis may help in early diagnosis and prompt treatment of this potentially fatal infection. PMID- 25805947 TI - Proposed case of mesalazine-induced cardiomyopathy in severe ulcerative colitis. AB - Five-amino salicylic acids are recommended for use in the management of inflammatory bowel disease, cardiac complications are a rare although recognised phenomenon. This report aims to highlight this serious but rare adverse reaction. We report here a case of a young man presenting with cardiogenic shock in the context of recent mesalazine treatment in severe ulcerative colitis. PMID- 25805948 TI - Colonic sarcoidosis: unusual onset of a systemic disease. AB - Sarcoidosis is a multisystem chronic inflammatory condition of unknown etiology that has the potential to involve every tissue in the body. Sarcoidosis in the gastrointestinal system, and particularly the colon, is very rare. Here, we report the case of a 57-year-old man with no previous diagnosis of sarcoidosis who presented with new onset of abdominal pain and constipation. A colonoscopy revealed that the abdominal pain was caused by an obstructing lesion in the cecum ascending colon and lacked a clear histologic diagnosis. Radiologic investigation revealed concentric wall thickening of the cecum-ascending colon with multiple satellite lymphadenopathies, highly suggestive of a malignancy. The patient underwent a laparotomy and a right hemicolectomy was performed. A diagnosis of colonic sarcoidosis was made after the resected specimen was examined. Additionally, a chest computed tomography scan revealed lung involvement with atypical radiologic features in the absence of respiratory symptoms. Only histologic examination of the surgical specimen can yield a diagnosis of gastrointestinal sarcoidosis due to the non-specificity of endoscopic and radiologic findings. PMID- 25805949 TI - Giant gastrointestinal stromal tumour of rare sarcomatoid epithelioid subtype: case study and literature review. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, but they represent less than 3% of all gastrointestinal tract malignancies. This is a detailed case study of a 52-year old male patient treated for very uncommon histological subtype of gastric GIST with atypical clinical presentation, asymptomatic progress and late diagnosis. The resected tumour, giant in diameters, was confirmed to represent the most rare histopathologic subtype of GISTs - sarcomatoid epithelioid GIST. We report this case and review the literature with a special focus on pathomorphological evaluation, biological aggressiveness and prognostic factors. To our knowledge this is the first report of giant GIST of very uncommon sarcomatoid epithelioid subtype. It is concluded that clinicians should pay attention to the fact that initial diagnosis may be delayed due to mildly asymptomatic and non-specific clinical presentation. Asymptomatic tumours diagnosed at a late stage, which is often the case, can be large on presentation. Prognosis for patients diagnosed with GIST depend on tumour size, mitotic rate, histopathologic subtype and tumour location. That is why early diagnosis and R0 resection, which is usually feasible and safe even in giant gastric sarcomatoid epithelioid subtype of GISTs, are the key factors for further treatment and good prognosis. PMID- 25805950 TI - Bronchial bleeding caused by recurrent pneumonia after radical esophagectomy for esophageal cancer. AB - We herein report a case of bronchial bleeding after radical esophagectomy that was treated with lobectomy. A 65-year-old male who underwent subtotal esophagectomy with three-field lymph node dissection for esophageal carcinoma was referred to our hospital because of sudden hemoptysis. After the esophagectomy, bilateral vocal cord paralysis was observed, and the patient suffered from repeated episodes of aspiration pneumonia. Bronchoscopy revealed hemosputum in the right middle lobe bronchus, and contrast-enhanced computed tomography showed tortuous arteries arising from the right inferior phrenic artery and left subclavian artery toward the right middle lobe bronchus. Although bronchial arterial embolization was performed twice to control the recurrent hemoptysis, the procedures were unsuccessful. Right middle lobectomy was therefore performed via video-assisted thoracic surgery. Engorged bronchial arterys with medial hypertrophy and overgrowth of the small branches were noted near the bronchus in the resected specimen. The patient recovered uneventfully and was discharged on postoperative day 14. PMID- 25805951 TI - Endoscopic ultrasound-guided drainage of postoperative intra-abdominal abscesses. AB - Although endoscopic ultrasound (EUS)-guided drainage has become the standard procedure for pancreatic pseudocysts in recent years and is generally regarded as a safe and effective method, there have been few reports of EUS-guided drainage of postoperative intra-abdominal abscesses. Here we report our experience with 4 cases of postoperative intra-abdominal abscesses for which EUS-guided drainage was performed between May 2011 and May 2014. Distal pancreatectomy had been performed in 3 cases, whereas low anterior resection for rectal cancer was performed in the remaining case. All patients underwent transgastric naso-cystic drainage, which resulted in clinical improvement without complications, even when performed within 4 wk after surgery. On average, the naso-cystic drain was removed 10 d after placement, with no abscess recurrence. Based on these findings, we believe that EUS-guided drainage of postoperative intra-abdominal abscesses is a safe and effective method, although further large-scale investigations are required to confirm our findings. PMID- 25805952 TI - Pediatric gastric cancer presenting with massive ascites. AB - Gastric adenocarcinoma is quite rare in children and as a result very little experience has been reported on with regards to clinical presentation, treatment and outcome. We describe the case of a 16-year-old boy presenting with abdominal fullness and poor appetite for 7 d. Sonography showed massive ascites and computed tomography imaging revealed the presence of gastric mucosa thickness with omentum caking. The diagnosis of gastric adenocarcinoma was biopsy-proven endoscopically. Despite gastric adenocarcinoma being quite rare in the pediatric patient population, we should not overlook the possibility of gastric adenocarcinoma when a child presents with distended abdomen and massive ascites. PMID- 25805953 TI - Hepatocellular carcinoma with concomitant hepatic angiomyolipoma and cavernous hemangioma in one patient. AB - The risk of developing hepatocellular carcinoma (HCC) is strongly associated with hepatitis B virus infection. Hepatic angiomyolipoma (AML), a rare benign tumor, is composed of a heterogeneous mixture of adipose cells, smooth muscle cells and blood vessels. Here, we report the case of a 44-year-old man who developed HCC with a concomitant hepatic AML and a cavernous hemangioma, in the absence of cirrhosis. To our knowledge, based on an extensive literature search using the www.pubmed.gov website, this is the first report of an HCC case with both concomitant AML and cavernous hemangioma at the same position in the liver. The presence of the hepatitis B surface antigen was detected, but the liver function was normal. Clinical and pathological data were collected before and during the treatment. Hepatic AML was diagnosed based on the typical histological characteristics and immunohistochemical staining, which revealed, a positive staining with a melanocytic cell-specific monoclonal antibody. There was no evidence of tuberous sclerosis complex in this patient. Although the HCC was poor to moderately-differentiated, the characteristics of the AML and the cavernous hemangioma in this patient did not match any criteria for malignancy. Hepatectomy followed by transarterial chemoembolization treatment were effective therapeutic methods for the adjacent lesions in this patient. This case is an interesting coincidence. PMID- 25805954 TI - Partial splenectomy using a laparoscopic bipolar radiofrequency device: a case report. AB - We report a 51-year-old female patient with a solitary lymphangioma located in the upper splenic pole which was managed successfully with laparoscopic partial splenectomy. Surgery lasted 170 min and did not require blood transfusions. The patient recovered well post-operatively and was asymptomatic at the 3-mo follow up. She had a normal platelet count and no recurrence on ultrasonography or computed tomography. Laparoscopic partial splenectomy is a safe, minimally invasive technique for the treatment of solitary splenic lymphangiomas in the splenic pole. We performed the procedure using the Habib(TM) 4X device. This laparoscopic bipolar radiofrequency device ensured a "bloodless" splenic parenchymal resection. PMID- 25805955 TI - Congenital left intrahepatic bile duct draining into gastric wall mimicking biliary reflux gastritis. AB - Abnormalities and variations of the biliary ducts are not rare. Most aberrant bile ducts eventually drain into the descending part of duodenum through the papilla of vater. However, drainage of the left hepatic bile duct into the stomach is extremely rare. A 29-year old man was admitted to the hospital with the diagnosis of biliary reflux gastritis. Comprehensive imaging modalities were performed including electronic endoscopy, endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography and magnetic resonance cholangio pancreatography. Finally, congenital ectopic left intrahepatic bile duct draining into the stomach was found, which caused biliary reflux gastritis. The patient did not receive any surgery. Good recovery was achieved by medical treatment. PMID- 25805956 TI - Rare case of Helicobacter pylori-positive multiorgan IgG4-related disease and gastric cancer. AB - A 61-year-old male from Northeast China presented with a 2-mo history of abdominal distension, pruritus and jaundice. Laboratory testing revealed an elevated serum IgG4 level. A computed tomography scan showed a typical feature of autoimmune pancreatitis (AIP) and cholecystocholangitis. Early gastric cancer was incidentally discovered when endoscopic untrasound-guided fine needle aspiration (EUS-FNA) of the pancreas was carried out. The patient underwent radical subtotal gastrectomy for gastric cancer combined with cholecystectomy. Helicobacter pylori (H. pylori) and IgG4-positive plasmacytes were detected in gastric cancer tissue, pancreatic EUS-FNA sample and resected gallbladder specimen by immunohistochemistry. The patient was diagnosed with H. pylori-positive IgG4 related AIP and sclerosing cholecystocholangitis as well as H. pylori-positive gastric cancer. He responded well to steroid therapy and remains healthy with no signs of recurrence at one year follow-up. We speculate that H. pylori might act as a trigger via direct or indirect action in the initiation of onset of gastric cancer and multiorgan IgG4-related disease. PMID- 25805957 TI - Gastrointestinal hemorrhage due to ileal metastasis from primary lung cancer. AB - We report a patient with small intestinal metastasis from lung squamous cell carcinoma. A 66-year-old man who underwent radical lung cancer surgery was admitted to our hospital. Before starting his fifth cycle of chemotherapy, he was found to have a positive fecal occult blood test. Abdominal computed tomography scan revealed an ileal tumor with mesenteric lymph node enlargement. He underwent laparoscopic resection of the involved small intestine and mesentery. Histopathological analysis confirmed metastasis from lung cancer. We conducted a review of the literature and 64 documented cases of small intestinal metastasis from lung cancer were found. The pathologic diagnosis, clinical presentation, site of metastasis, and survival time in these cases were reviewed. PMID- 25805959 TI - Cobalamin deficiency as an extra intestinal manifestation of Helicobacter pylori infection. AB - We read with great interest the excellent review by Wong et al on extra intestinal manifestations of Helicobacter pylori (H. pylori) infection published in the journal. This is a well-documented and structured review. However, I believe that Wong et al failed to report the relationship between H. pylori infection and cobalamin. PMID- 25805958 TI - Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report. AB - A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative. PMID- 25805960 TI - Reduced pulmonary blood flow in regions of injury 2 hours after acid aspiration in rats. AB - BACKGROUND: Aspiration-induced lung injury can decrease gas exchange and increase mortality. Acute lung injury following acid aspiration is characterized by elevated pulmonary blood flow (PBF) in damaged lung areas in the early inflammation stage. Knowledge of PBF patterns after acid aspiration is important for targeting intravenous treatments. We examined PBF in an experimental model at a later stage (2 hours after injury). METHODS: Anesthetized Wistar-Unilever rats (n = 5) underwent unilateral endobronchial instillation of hydrochloric acid. The PBF distribution was compared between injured and uninjured sides and with that of untreated control animals (n = 6). Changes in lung density after injury were measured using computed tomography (CT). Regional PBF distribution was determined quantitatively in vivo 2 hours after acid instillation by measuring the concentration of [(68)Ga]-radiolabeled microspheres using positron emission tomography. RESULTS: CT scans revealed increased lung density in areas of acid aspiration. Lung injury was accompanied by impaired gas exchange. Acid aspiration decreased the arterial pressure of oxygen from 157 mmHg [139;165] to 74 mmHg [67;86] at 20 minutes and tended toward restoration to 109 mmHg [69;114] at 110 minutes (P < 0.001). The PBF ratio of the middle region of the injured versus uninjured lungs of the aspiration group (0.86 [0.7;0.9], median [25%;75%]) was significantly lower than the PBF ratio in the left versus right lung of the control group (1.02 [1.0;1.05]; P = 0.016). CONCLUSIONS: The PBF pattern 2 hours after aspiration-induced lung injury showed a redistribution of PBF away from injured regions that was likely responsible for the partial recovery from hypoxemia over time. Treatments given intravenously 2 hours after acid-induced lung injury may not preferentially reach the injured lung regions, contrary to what occurs during the first hour of inflammation. Please see related article: http://dx.doi.org/10.1186/s12871-015-0014-z. PMID- 25805961 TI - The effects of topical and intravenous JM-1232(-) on cerebral pial microvessels of rabbits. AB - BACKGROUND: JM-1232(-) is a novel anesthetic agent which acts through gamma aminobutyric acid receptors. Cerebral pial vascular effects of JM-1232(-) are unknown. We thus evaluated topical and intravenous effects of JM-1232(-) on cerebral pial microvessels in rabbits, and the extent to which carbon dioxide (CO2) reactivity is preserved. METHODS: Closed cranial windows were used to visualize cerebral pial circulation in 29 Japanese white rabbits. In the first experiment, the cranial window was superfused with increasing concentrations of JM-1232(-): 10(-11), 10(-9), 10(-7), 10(-5) mol/L, n = 8 per concentration. In the second experiment, we examined the effects of an intravenous bolus of 1 mg/kg bolus of JM-1232(-), followed by the continuous infusion at 0.3 mg/kg/minute on cerebral pial vascular alteration (n = 9). In the third, we examined CO2 reactivity of cerebral pial vessels under JM-1232(-) (n = 6) or sevoflurane anesthesia (n = 6). RESULTS: Topical application of JM-1232(-) did not change pial venular diameter, and constricted arterials only at the highest concentration. Intravenous administration of JM-1232(-) produced cerebral pial constriction which gradually diminished over time. Under intravenous administration of JM-1232(-) and inhaled sevoflurane, diameters of vessels increased in parallel with CO2 partial pressure. Slopes of linear regression and correlation coefficients in arterioles and venules were comparable for JM-1232(-) anesthesia and sevoflurane anesthesia. CONCLUSIONS: Topical application of JM 1232(-) had little effect on cerebral pial vessels. Intravenous administration produced vasoconstriction of cerebral pial arterioles and venules, however those changes were clinically unimportant. In addition, JM-1232(-) did not impair CO2 responsiveness. At least from the perspective of vascular reactivity, JM-1232(-) thus appears safe for neurosurgical patients. PMID- 25805962 TI - Granulocyte colony-stimulating factor potentiates all-trans retinoic acid-induced granulocytic differentiation in acute promyelocytic leukemia cell line HT93A. AB - BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) promotes proliferation, survival, and differentiation of myeloid-linage leukemic cells, as well as normal hematopoietic cells. Terminal granulocytic differentiation can be induced in acute promyelocytic (APL) cell line HT93A by G-CSF and all-trans retinoic acid (ATRA). Because the detailed mechanism has never been shown, we investigated the signal transduction pathway in granulocytic differentiation by G-CSF, alone or in combination with ATRA. METHODS: HT93A cell viability and growth were investigated by trypan blue exclusion assay. Cell differentiation was assessed by CD11b and CD34 expressions. Intracellular protein expressions were also evaluated by flow cytometry after fixation and permeabilization. RESULTS: ATRA (100 nM) induced granulocytic differentiation (upregulation of CD11b and downregulation of CD34) and the effect was potentiated by addition of G-CSF, while G-CSF alone had no effect on HT93A cells. The addition of G-CSF to ATRA had little or no effect on NB4 and THP-1 cells in comparison to ATRA alone. G-CSF receptor expression was reduced by ATRA treatment in a time-dependent manner. After 5 days' incubation with ATRA, the expression levels of signal transducer and activator of transcription (STAT) 3, and phosphorylated STAT3 and STAT5, were significantly reduced. STAT5 was strongly activated by G-CSF stimulation in ATRA-pretreated cells in comparison to untreated cells. In contrast, STAT3 showed no response to G-CSF. Janus kinase (JAK) inhibitor ruxolitinib (320 nM) had little or no effect on ATRA-induced differentiation, but eliminated the enhancing effect of G-CSF, as evidenced by the levels of CD11b and CD34 expression. These results suggest G-CSF activates STAT5 through the JAK pathway in combination with ATRA, resulting in myeloid differentiation in HT93A cells. CONCLUSIONS: In conclusion, activation of the JAK-STAT pathway is likely essential for inducting differentiation in the APL cell line HT93A; thus, monitoring its expression and activation is important for predicting clinical efficacy and understanding the mechanisms of cytokine dependent myelopoiesis, proliferation, and differentiation of acute myeloid leukemia. PMID- 25805963 TI - Electrode replacement does not affect classification accuracy in dual-session use of a passive brain-computer interface for assessing cognitive workload. AB - The passive brain-computer interface (pBCI) framework has been shown to be a very promising construct for assessing cognitive and affective state in both individuals and teams. There is a growing body of work that focuses on solving the challenges of transitioning pBCI systems from the research laboratory environment to practical, everyday use. An interesting issue is what impact methodological variability may have on the ability to reliably identify (neuro)physiological patterns that are useful for state assessment. This work aimed at quantifying the effects of methodological variability in a pBCI design for detecting changes in cognitive workload. Specific focus was directed toward the effects of replacing electrodes over dual sessions (thus inducing changes in placement, electromechanical properties, and/or impedance between the electrode and skin surface) on the accuracy of several machine learning approaches in a binary classification problem. In investigating these methodological variables, it was determined that the removal and replacement of the electrode suite between sessions does not impact the accuracy of a number of learning approaches when trained on one session and tested on a second. This finding was confirmed by comparing to a control group for which the electrode suite was not replaced between sessions. This result suggests that sensors (both neurological and peripheral) may be removed and replaced over the course of many interactions with a pBCI system without affecting its performance. Future work on multi-session and multi-day pBCI system use should seek to replicate this (lack of) effect between sessions in other tasks, temporal time courses, and data analytic approaches while also focusing on non-stationarity and variable classification performance due to intrinsic factors. PMID- 25805964 TI - Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease. AB - Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson's disease (PD) which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of alpha-synuclein allows it to adopt different conformations, i.e., bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of alpha-synuclein, transmission and toxicity, that could help to understand the pathological characteristics of PD. One important feature of alpha-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of alpha-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation that lead to apoptosis pathway activation and consequent cell death. The complexity of alpha-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease. PMID- 25805965 TI - Recruitment of hypothalamic orexin neurons after formalin injections in adult male rats exposed to a neonatal immune challenge. AB - Exposure to early life physiological stressors, such as infection, is thought to contribute to the onset of psychopathology in adulthood. In animal models, injections of the bacterial immune challenge, lipopolysaccharide (LPS), during the neonatal period has been shown to alter both neuroendocrine function and behavioral pain responses in adulthood. Interestingly, recent evidence suggests a role for the lateral hypothalamic peptide orexin in stress and nociceptive processing. However, whether neonatal LPS exposure affects the reactivity of the orexin system to formalin-induced inflammatory pain in later life remains to be determined. Male Wistar rats (n = 13) were exposed to either LPS or saline (0.05 mg/kg, i.p) on postnatal days (PND) 3 and 5. On PND 80-97, all rats were exposed to a subcutaneous hindpaw injection of 2.25% formalin. Following behavioral testing, animals were perfused and brains processed for Fos-protein and orexin immunohistochemistry. Rats treated with LPS during the neonatal period exhibited decreased licking behaviors during the interphase of the formalin test, the period typically associated with the active inhibition of pain, and increased grooming responses to formalin in adulthood. Interestingly, these behavioral changes were accompanied by an increase in the percentage of Fos-positive orexin cells in the dorsomedial and perifornical hypothalamus in LPS-exposed animals. Similar increases in Fos-protein were also observed in stress and pain sensitive brain regions that receive orexinergic inputs. These findings highlight a potential role for orexin in the behavioral responses to pain and provide further evidence that early life stress can prime the circuitry responsible for these responses in adulthood. PMID- 25805967 TI - The undermining effect of facial attractiveness on brain responses to fairness in the Ultimatum Game: an ERP study. AB - To investigate the time course of the neural processing of facial attractiveness and its influence on fairness consideration during social interactions, event related potentials (ERP) were recorded from 21 male subjects performing a two person Ultimatum Game (UG). During this bargaining game, the male subjects played responders who decided whether to accept offers from female proposers, whose facial images (grouped as "attractive" and "unattractive") were presented prior to the offer presentation. The behavioral data demonstrated that the acceptance ratio increased with the fairness level of the offers and, more importantly, the subjects were more likely to accept unfair offers when presented with the attractive-face condition compared with the unattractive-face condition. The reaction times (RTs) for five offers (1:9, 2:8, 3:7, 4:6, and 5:5) in the unattractive-face condition were not significantly different. In contrast, the subjects reacted slower to the attractive proposers' unfair offers and quicker to fair offers. The ERP analysis of the face presentation demonstrated a decreased early negativity (N2) and enhanced late positive potentials (LPPs) elicited by the attractive faces compared with the unattractive faces. In addition, the feedback-related negativity (FRN) in response to an offer presentation was not significantly different for the unfair (1:9 and 2:8) and fair (4:6 and 5:5) offers in the attractive-face condition. However, the unfair offers generated larger FRNs compared with the fair offers in the unattractive-face condition (consistent with prior studies). A similar effect was identified for P300. The present study demonstrated an undermining effect of proposer facial attractiveness on responder consideration of offer fairness during the UG. PMID- 25805966 TI - Neuronal migration abnormalities and its possible implications for schizophrenia. AB - Schizophrenia is a complex mental disorder that displays behavioral deficits such as decreased sensory gating, reduced social interaction and working memory deficits. The neurodevelopmental model is one of the widely accepted hypotheses of the etiology of schizophrenia. Subtle developmental abnormalities of the brain which stated long before the onset of clinical symptoms are thought to lead to the emergence of illness. Schizophrenia has strong genetic components but its underlying molecular pathogenesis is still poorly understood. Genetic linkage and association studies have identified several genes involved in neuronal migrations as candidate susceptibility genes for schizophrenia, although their effect size is small. Recent progress in copy number variation studies also has identified much higher risk loci such as 22q11. Based on these genetic findings, we are now able to utilize genetically-defined animal models. Here we summarize the results of neurodevelopmental and behavioral analysis of genetically-defined animal models. Furthermore, animal model experiments have demonstrated that embryonic and perinatal neurodevelopmental insults in neurogenesis and neuronal migrations cause neuronal functional and behavioral deficits in affected adult animals, which are similar to those of schizophrenic patients. However, these findings do not establish causative relationship. Genetically-defined animal models are a critical approach to explore the relationship between neuronal migration abnormalities and behavioral abnormalities relevant to schizophrenia. PMID- 25805968 TI - Dysfunctional HCN ion channels in neurological diseases. AB - Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed as four different isoforms (HCN1-4) in the heart and in the central and peripheral nervous systems. HCN channels are activated by membrane hyperpolarization at voltages close to resting membrane potentials and carry the hyperpolarization-activated current, dubbed If (funny current) in heart and Ih in neurons. HCN channels contribute in several ways to neuronal activity and are responsible for many important cellular functions, including cellular excitability, generation, and modulation of rhythmic activity, dendritic integration, transmission of synaptic potentials, and plasticity phenomena. Because of their role, defective HCN channels are natural candidates in the search for potential causes of neurological disorders in humans. Several data, including growing evidence that some forms of epilepsy are associated with HCN mutations, support the notion of an involvement of dysfunctional HCN channels in different experimental models of the disease. Additionally, some anti-epileptic drugs are known to modify the activity of the Ih current. HCN channels are widely expressed in the peripheral nervous system and recent evidence has highlighted the importance of the HCN2 isoform in the transmission of pain. HCN channels are also present in the midbrain system, where they finely regulate the activity of dopaminergic neurons, and a potential role of these channels in the pathogenesis of Parkinson's disease has recently emerged. The function of HCN channels is regulated by specific accessory proteins, which control the correct expression and modulation of the neuronal Ih current. Alteration of these proteins can severely interfere with the physiological channel function, potentially predisposing to pathological conditions. In this review we address the present knowledge of the association between HCN dysfunctions and neurological diseases, including clinical, genetic, and physiopathological aspects. PMID- 25805969 TI - Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca(2+) signaling. AB - Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca(2+) signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca(2+) signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca(2+) waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca(2+) entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S nitrosylation and the Ca(2+)-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca(2+) signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca(2+) influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca(2+) signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process. PMID- 25805970 TI - SIRT1 in the brain-connections with aging-associated disorders and lifespan. AB - The silent mating type information regulation 2 proteins (sirtuins) 1 of class III histone deacetylases (HDACs) have been associated with health span and longevity. SIRT1, the best studied member of the mammalian sirtuins, has a myriad of roles in multiple tissues and organs. However, a significant part of SIRT1's role that impinges on aging and lifespan may lie in its activities in the central nervous system (CNS) neurons. Systemically, SIRT1 influences energy metabolism and circadian rhythm through its activity in the hypothalamic nuclei. From a cell biological perspective, SIRT1 is a crucial component of multiple interconnected regulatory networks that modulate dendritic and axonal growth, as well as survival against stress. This neuronal cell autonomous activity of SIRT1 is also important for neuronal plasticity, cognitive functions, as well as protection against aging-associated neuronal degeneration and cognitive decline. We discuss recent findings that have shed light on the various activities of SIRT1 in the brain, which collectively impinge on aging-associated disorders and lifespan. PMID- 25805972 TI - Physiological consequences of doublet discharges on motoneuronal firing and motor unit force. AB - The double discharges are observed at the onset of contractions of mammalian motor units (MUs), especially during their recruitment to strong or fast movements. Doublets lead to MU force increase and improve ability of muscles to maintain high force during prolonged contractions. In this review we discuss an ability to produce doublets by fast and slow motoneurons (MNs), their influence on the course of action potential afterhyperpolarization (AHP) as well as its role in modulation of the initial stage of the firing pattern of MNs. In conclusion, a generation of doublets is an important strategy of motor control, responsible for fitting the motoneuronal firing rate to the optimal for MUs at the start of their contraction, necessary for increment of muscle force. PMID- 25805973 TI - Insulin signaling is acutely required for long-term memory in Drosophila. AB - Memory formation has been shown recently to be dependent on energy status in Drosophila. A well-established energy sensor is the insulin signaling (InS) pathway. Previous studies in various animal models including human have revealed the role of insulin levels in short-term memory but its role in long-term memory remains less clear. We therefore investigated genetically the spatial and temporal role of InS using the olfactory learning and long-term memory model in Drosophila. We found that InS is involved in both learning and memory. InS in the mushroom body is required for learning and long-term memory whereas long-term memory specifically is impaired after InS signaling disruption in the ellipsoid body, where it regulates the level of p70s6k, a downstream target of InS and a marker of protein synthesis. Finally, we show also that InS is acutely required for long-term memory formation in adult flies. PMID- 25805971 TI - Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor. AB - Understanding brain development remains a major challenge at the heart of understanding what makes us human. The neocortex, in evolutionary terms the newest part of the cerebral cortex, is the seat of higher cognitive functions. Its normal development requires the production, positioning, and appropriate interconnection of very large numbers of both excitatory and inhibitory neurons. Pax6 is one of a relatively small group of transcription factors that exert high level control of cortical development, and whose mutation or deletion from developing embryos causes major brain defects and a wide range of neurodevelopmental disorders. Pax6 is very highly conserved between primate and non-primate species, is expressed in a gradient throughout the developing cortex and is essential for normal corticogenesis. Our understanding of Pax6's functions and the cellular processes that it regulates during mammalian cortical development has significantly advanced in the last decade, owing to the combined application of genetic and biochemical analyses. Here, we review the functional importance of Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of cortical layers and highlight important differences between rodents and primates. We also review the pathological effects of PAX6 mutations in human neurodevelopmental disorders. We discuss some aspects of Pax6's molecular actions including its own complex transcriptional regulation, the distinct molecular functions of its splice variants and some of Pax6's known direct targets which mediate its actions during cortical development. PMID- 25805975 TI - Neural correlates of high-risk behavior tendencies and impulsivity in an emotional Go/NoGo fMRI task. AB - Improved neuroscientific understanding of high-risk behaviors such as alcohol binging, drug use, and unsafe sex will lead to therapeutic advances for high-risk groups. High-risk behavior often occurs in an emotionally-charged context, and behavioral inhibition and emotion regulation play important roles in risk-related decision making. High impulsivity is an important potential contributor to high risk behavior tendencies. We explored the relationships between high-risk behavior tendencies, impulsivity, and fMRI brain activations in an emotional Go/NoGo task. This task presented emotional distractor pictures (aversive vs. neutral) simultaneously with Go/NoGo stimuli (square vs. circle) that required a button press or withholding of the press, respectively. Participants' risk behavior tendencies were assessed with the Cognitive Appraisal of Risky Events (CARE) scale. The Barratt Impulsivity Scale 11 (BIS) was used to assess participant impulsivity. Individuals with higher CARE risk scores exhibited reduced activation related to response inhibition (NoGo-Go) in right orbital frontal cortex (OFC) and ventromedial prefrontal cortex. These regions did not show a significant relationship with impulsivity scores. Conversely, more impulsive individuals showed reduced emotion-related activity (aversive-neutral distractors) in dorsomedial prefrontal cortex, perigenual anterior cingulate cortex, and right posterior OFC. There were distinct neural correlates of high risk behavior tendency and impulsivity in terms of brain activity in the emotional Go/NoGo task. This dissociation supports the conception of high-risk behavior tendency as a distinct construct from that of impulsivity. Our results suggest that treatment for high-risk behavior may be more effective with a nuanced approach that does not conflate high impulsivity necessarily with high risk behavior tendencies. PMID- 25805974 TI - The cortical modulation of stimulus-specific adaptation in the auditory midbrain and thalamus: a potential neuronal correlate for predictive coding. AB - To follow an ever-changing auditory scene, the auditory brain is continuously creating a representation of the past to form expectations about the future. Unexpected events will produce an error in the predictions that should "trigger" the network's response. Indeed, neurons in the auditory midbrain, thalamus and cortex, respond to rarely occurring sounds while adapting to frequently repeated ones, i.e., they exhibit stimulus specific adaptation (SSA). SSA cannot be explained solely by intrinsic membrane properties, but likely involves the participation of the network. Thus, SSA is envisaged as a high order form of adaptation that requires the influence of cortical areas. However, present research supports the hypothesis that SSA, at least in its simplest form (i.e., to frequency deviants), can be transmitted in a bottom-up manner through the auditory pathway. Here, we briefly review the underlying neuroanatomy of the corticofugal projections before discussing state of the art studies which demonstrate that SSA present in the medial geniculate body (MGB) and inferior colliculus (IC) is not inherited from the cortex but can be modulated by the cortex via the corticofugal pathways. By modulating the gain of neurons in the thalamus and midbrain, the auditory cortex (AC) would refine SSA subcortically, preventing irrelevant information from reaching the cortex. PMID- 25805976 TI - Wearable functional near infrared spectroscopy (fNIRS) and transcranial direct current stimulation (tDCS): expanding vistas for neurocognitive augmentation. AB - Contemporary studies with transcranial direct current stimulation (tDCS) provide a growing base of evidence for enhancing cognition through the non-invasive delivery of weak electric currents to the brain. The main effect of tDCS is to modulate cortical excitability depending on the polarity of the applied current. However, the underlying mechanism of neuromodulation is not well understood. A new generation of functional near infrared spectroscopy (fNIRS) systems is described that are miniaturized, portable, and include wearable sensors. These developments provide an opportunity to couple fNIRS with tDCS, consistent with a neuroergonomics approach for joint neuroimaging and neurostimulation investigations of cognition in complex tasks and in naturalistic conditions. The effects of tDCS on complex task performance and the use of fNIRS for monitoring cognitive workload during task performance are described. Also explained is how fNIRS + tDCS can be used simultaneously for assessing spatial working memory. Mobile optical brain imaging is a promising neuroimaging tool that has the potential to complement tDCS for realistic applications in natural settings. PMID- 25805977 TI - Role of the thalamic nucleus reuniens in mediating interactions between the hippocampus and medial prefrontal cortex during spatial working memory. AB - Despite decades of research, the neural mechanisms of spatial working memory remain poorly understood. Although the dorsal hippocampus is known to be critical for memory-guided behavior, experimental evidence suggests that spatial working memory depends not only on the hippocampus itself, but also on the circuit comprised of the hippocampus and the medial prefrontal cortex (mPFC). Disruption of hippocampal-mPFC interactions may result in failed transfer of spatial and contextual information processed by the hippocampus to the circuitry in mPFC responsible for decision making and goal-directed behavior. Oscillatory synchrony between the hippocampus and mPFC has been shown to increase in tasks with high spatial working memory demand. However, the mechanisms and circuitry supporting hippocampal-mPFC interactions during these tasks is unknown. The midline thalamic nucleus reuniens (RE) is reciprocally connected to both the hippocampus and the mPFC and has been shown to be critical for a variety of working memory tasks. Therefore, it is likely that hippocampal-mPFC oscillatory synchrony is modulated by RE activity. This article will review the anatomical connections between the hippocampus, mPFC and RE along with the behavioral studies that have investigated the effects of RE disruption on working memory task performance. The article will conclude with suggestions for future directions aimed at identifying the specific role of the RE in regulating functional interactions between the hippocampus and the PFC and investigating the degree to which these interactions contribute to spatial working memory. PMID- 25805979 TI - Anatomical constitution of sense organs as a marker of mental disorders. PMID- 25805978 TI - Adaptive effort investment in cognitive and physical tasks: a neurocomputational model. AB - Despite its importance in everyday life, the computational nature of effort investment remains poorly understood. We propose an effort model obtained from optimality considerations, and a neurocomputational approximation to the optimal model. Both are couched in the framework of reinforcement learning. It is shown that choosing when or when not to exert effort can be adaptively learned, depending on rewards, costs, and task difficulty. In the neurocomputational model, the limbic loop comprising anterior cingulate cortex (ACC) and ventral striatum in the basal ganglia allocates effort to cortical stimulus-action pathways whenever this is valuable. We demonstrate that the model approximates optimality. Next, we consider two hallmark effects from the cognitive control literature, namely proportion congruency and sequential congruency effects. It is shown that the model exerts both proactive and reactive cognitive control. Then, we simulate two physical effort tasks. In line with empirical work, impairing the model's dopaminergic pathway leads to apathetic behavior. Thus, we conceptually unify the exertion of cognitive and physical effort, studied across a variety of literatures (e.g., motivation and cognitive control) and animal species. PMID- 25805980 TI - Stronger pharmacological cortisol suppression and anticipatory cortisol stress response in transient global amnesia. AB - Transient global amnesia (TGA) is a disorder characterized by a sudden attack of severe anterograde memory disturbance that is frequently preceded by emotional or physical stress and resolves within 24 h. By using MRI following the acute episode in TGA patients, small lesions in the hippocampus have been observed. Hence, it has been hypothesized that the disorder is caused by a stress-related transient inhibition of memory formation in the hippocampus. To study the factors that may link stress and TGA, we measured the cortisol day-profile, the dexamethasone feedback inhibition and the effect of experimental exposure to stress on cortisol levels (using the socially evaluated cold pressor test and a control procedure) in 20 patients with a recent history of TGA and in 20 healthy controls. We used self-report scales of depression, anxiety and stress, and a detailed neuropsychological assessment to characterize our collective. We did not observe differences in mean cortisol levels in the cortisol day-profile between the two groups. After administration of low-dose dexamethasone, TGA patients showed significantly stronger cortisol suppression in the daytime profile compared to the control group (p = 0.027). The mean salivary cortisol level was significantly higher in the TGA group prior to and after the experimental stress exposure (p = 0.008 and 0.010 respectively), as well as prior to and after the control condition (p = 0.022 and 0.024, respectively). The TGA group had higher scores of depressive symptomatology (p = 0.021) and anxiety (p = 0.007), but the groups did not differ in the neuropsychological assessment. Our findings of a stronger pharmacological suppression and higher cortisol levels in anticipation of experimental stress in participants with a previous TGA indicate a hypersensitivity of the HPA axis. This suggests that an individual stress sensitivity might play a role in the pathophysiology of TGA. PMID- 25805981 TI - Higher integrity of the motor and visual pathways in long-term video game players. AB - Long term video game players (VGPs) exhibit superior visual and motor skills compared with non-video game control subjects (NVGCs). However, the neural basis underlying the enhanced behavioral performance remains largely unknown. To clarify this issue, the present study compared the whiter matter integrity within the corticospinal tracts (CST), the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the inferior fronto-occipital fasciculus (IFOF) between the VGPs and the NVGCs using diffusion tensor imaging. Compared with the NVGCs, voxel-wise comparisons revealed significantly higher fractional anisotropy (FA) values in some regions within the left CST, left SLF, bilateral ILF, and IFOF in VGPs. Furthermore, higher FA values in the left CST at the level of cerebral peduncle predicted a faster response in visual attention tasks. These results suggest that higher white matter integrity in the motor and higher-tier visual pathways is associated with long-term video game playing, which may contribute to the understanding on how video game play influences motor and visual performance. PMID- 25805982 TI - Across the consciousness continuum-from unresponsive wakefulness to sleep. AB - Advances in the development of new paradigms as well as in neuroimaging techniques nowadays enable us to make inferences about the level of consciousness patients with disorders of consciousness (DOC) retain. They, moreover, allow to predict their probable development. Today, we know that certain brain responses (e.g., event-related potentials or oscillatory changes) to stimulation, circadian rhythmicity, the presence or absence of sleep patterns as well as measures of resting state brain activity can serve the diagnostic and prognostic evaluation process. Still, the paradigms we are using nowadays do not allow to disentangle VS/UWS and minimally conscious state (MCS) patients with the desired reliability and validity. Furthermore, even rather well-established methods have, unfortunately, not found their way into clinical routine yet. We here review current literature as well as recent findings from our group and discuss how neuroimaging methods (fMRI, PET) and particularly electroencephalography (EEG) can be used to investigate cognition in DOC or even to assess the degree of residual awareness. We, moreover, propose that circadian rhythmicity and sleep in brain-injured patients are promising fields of research in this context. PMID- 25805983 TI - EEVEE: the Empathy-Enhancing Virtual Evolving Environment. AB - Empathy is a multifaceted emotional and mental faculty that is often found to be affected in a great number of psychopathologies, such as schizophrenia, yet it remains very difficult to measure in an ecological context. The challenge stems partly from the complexity and fluidity of this social process, but also from its covert nature. One powerful tool to enhance experimental control over such dynamic social interactions has been the use of avatars in virtual reality (VR); information about an individual in such an interaction can be collected through the analysis of his or her neurophysiological and behavioral responses. We have developed a unique platform, the Empathy-Enhancing Virtual Evolving Environment (EEVEE), which is built around three main components: (1) different avatars capable of expressing feelings and emotions at various levels based on the Facial Action Coding System (FACS); (2) systems for measuring the physiological responses of the observer (heart and respiration rate, skin conductance, gaze and eye movements, facial expression); and (3) a multimodal interface linking the avatar's behavior to the observer's neurophysiological response. In this article, we provide a detailed description of the components of this innovative platform and validation data from the first phases of development. Our data show that healthy adults can discriminate different negative emotions, including pain, expressed by avatars at varying intensities. We also provide evidence that masking part of an avatar's face (top or bottom half) does not prevent the detection of different levels of pain. This innovative and flexible platform provides a unique tool to study and even modulate empathy in a comprehensive and ecological manner in various populations, notably individuals suffering from neurological or psychiatric disorders. PMID- 25805984 TI - A preliminary fMRI study of a novel self-paced written fluency task: observation of left-hemispheric activation, and increased frontal activation in late vs. early task phases. AB - Neuropsychological tests of verbal fluency are very widely used to characterize impaired cognitive function. For clinical neuroscience studies and potential medical applications, measuring the brain activity that underlies such tests with functional magnetic resonance imaging (fMRI) is of significant interest-but a challenging proposition because overt speech can cause signal artifacts, which tend to worsen as the duration of speech tasks becomes longer. In a novel approach, we present the group brain activity of 12 subjects who performed a self paced written version of phonemic fluency using fMRI-compatible tablet technology that recorded responses and provided task-related feedback on a projection screen display, over long-duration task blocks (60 s). As predicted, we observed robust activation in the left anterior inferior and medial frontal gyri, consistent with previously reported results of verbal fluency tasks which established the role of these areas in strategic word retrieval. In addition, the number of words produced in the late phase (last 30 s) of written phonemic fluency was significantly less (p < 0.05) than the number produced in the early phase (first 30 s). Activation during the late phase vs. the early phase was also assessed from the first 20 s and last 20 s of task performance, which eliminated the possibility that the sluggish hemodynamic response from the early phase would affect the activation estimates of the late phase. The last 20 s produced greater activation maps covering extended areas in bilateral precuneus, cuneus, middle temporal gyrus, insula, middle frontal gyrus and cingulate gyrus. Among these areas, greater activation was observed in the bilateral middle frontal gyrus (Brodmann area BA 9) and cingulate gyrus (BA 24, 32) likely as part of the initiation, maintenance, and shifting of attentional resources. Consistent with previous pertinent fMRI literature involving overt and covert verbal responses, these findings highlight the promise and practicality of fMRI of written phonemic fluency. PMID- 25805985 TI - Collinear facilitation and contour integration in autism: evidence for atypical visual integration. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, atypical communication and a restricted repertoire of interests and activities. Altered sensory and perceptual experiences are also common, and a notable perceptual difference between individuals with ASD and controls is their superior performance in visual tasks where it may be beneficial to ignore global context. This superiority may be the result of atypical integrative processing. To explore this claim we investigated visual integration in adults with ASD (diagnosed with Asperger's Syndrome) using two psychophysical tasks thought to rely on integrative processing-collinear facilitation and contour integration. We measured collinear facilitation at different flanker orientation offsets and contour integration for both open and closed contours. Our results indicate that compared to matched controls, ASD participants show (i) reduced collinear facilitation, despite equivalent performance without flankers; and (ii) less benefit from closed contours in contour integration. These results indicate weaker visuospatial integration in adults with ASD and suggest that further studies using these types of paradigms would provide knowledge on how contextual processing is altered in ASD. PMID- 25805986 TI - Alterations in interhemispheric functional and anatomical connectivity are associated with tobacco smoking in humans. AB - Abnormal interhemispheric functional connectivity correlates with several neurologic and psychiatric conditions, including depression, obsessive-compulsive disorder, schizophrenia, and stroke. Abnormal interhemispheric functional connectivity also correlates with abuse of cannabis and cocaine. In the current report, we evaluated whether tobacco abuse (i.e., cigarette smoking) is associated with altered interhemispheric connectivity. To that end, we examined resting state functional connectivity (RSFC) using magnetic resonance imaging (MRI) in short term tobacco deprived and smoking as usual tobacco smokers, and in non-smoker controls. Additionally, we compared diffusion tensor imaging (DTI) in the same subjects to study differences in white matter. The data reveal a significant increase in interhemispheric functional connectivity in sated tobacco smokers when compared to controls. This difference was larger in frontal regions, and was positively correlated with the average number of cigarettes smoked per day. In addition, we found a negative correlation between the number of DTI streamlines in the genual corpus callosum and the number of cigarettes smoked per day. Taken together, our results implicate changes in interhemispheric functional and anatomical connectivity in current cigarette smokers. PMID- 25805988 TI - Commentary on Structured chaos shapes spike-response noise entropy in balanced neural networks, by Lajoie, Thivierge, and Shea-Brown. PMID- 25805987 TI - Modeling violations of the race model inequality in bimodal paradigms: co activation from decision and non-decision components. AB - The redundant-signals paradigm (RSP) is designed to investigate response behavior in perceptual tasks in which response-relevant targets are defined by either one or two features, or modalities. The common finding is that responses are speeded for redundantly compared to singly defined targets. This redundant-signals effect (RSE) can be accounted for by race models if the response times do not violate the race model inequality (RMI). When there are violations of the RMI, race models are effectively excluded as a viable account of the RSE. The common alternative is provided by co-activation accounts, which assume that redundant target signals are integrated at some processing stage. However, "co-activation" has mostly been only indirectly inferred and the accounts have only rarely been explicitly modeled; if they were modeled, the RSE has typically been assumed to have a decisional locus. Yet, there are also indications in the literature that the RSE might originate, at least in part, at a non-decisional or motor stage. In the present study, using a distribution analysis of sequential-sampling models (ex-Wald and Ratcliff Diffusion model), the locus of the RSE was investigated for two bimodal (audio-visual) detection tasks that strongly violated the RMI, indicative of substantial co-activation. Three model variants assuming different loci of the RSE were fitted to the quantile reaction time proportions: a decision, a non-decision, and a combined variant both to vincentized group as well as individual data. The results suggest that for the two bimodal detection tasks, co-activation has a shared decisional and non-decisional locus. These findings point to the possibility that the mechanisms underlying the RSE depend on the specifics (task, stimulus, conditions, etc.) of the experimental paradigm. PMID- 25805989 TI - Cognitive training-induced short-term functional and long-term structural plastic change is related to gains in global cognition in healthy older adults: a pilot study. AB - Computerized cognitive training (CCT) is a safe and inexpensive intervention to enhance cognitive performance in the elderly. However, the neural underpinning of CCT-induced effects and the timecourse by which such neural changes occur are unknown. Here, we report on results from a pilot study of healthy older adults who underwent three 1-h weekly sessions of either multidomain CCT program (n = 7) or an active control intervention (n = 5) over 12 weeks. Multimodal magnetic resonance imaging (MRI) scans and cognitive assessments were performed at baseline and after 9 and 36 h of training. Voxel-based structural analysis revealed a significant Group * Time interaction in the right post-central gyrus indicating increased gray matter density in the CCT group compared to active control at both follow-ups. Across the entire sample, there were significant positive correlations between changes in the post-central gyrus and change in global cognition after 36 h of training. A post-hoc vertex-based analysis found a significant between-group difference in rate of thickness change between baseline and post-training in the left fusiform gyrus, as well as a large cluster in the right parietal lobe covering the supramarginal and post-central gyri. Resting state functional connectivity between the posterior cingulate and the superior frontal gyrus, and between the right hippocampus and the superior temporal gyrus significantly differed between the two groups after 9 h of training and correlated with cognitive change post-training. No significant interactions were found for any of the spectroscopy and diffusion tensor imaging data. Though preliminary, our results suggest that functional change may precede structural and cognitive change, and that about one-half of the structural change occurs within the first 9 h of training. Future studies are required to determine the role of these brain changes in the mechanisms underlying CCT-induced cognitive effects. PMID- 25805990 TI - Clearance of amyloid beta-protein and its role in the spreading of Alzheimer's disease pathology. PMID- 25805992 TI - Corrigendum: Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions. AB - [This corrects the article on p. 162 in vol. 5, PMID: 25071580.]. PMID- 25805991 TI - Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins. AB - Cysteine is susceptible to a variety of modifications by reactive oxygen and nitrogen oxide species, including glutathionylation; and when two cysteines are involved, disulfide formation. Glutathione-cysteine adducts may be removed from proteins by glutaredoxin, whereas disulfides may be reduced by thioredoxin. Glutaredoxin is homologous to the disulfide-reducing thioredoxin and shares similar binding modes of the protein substrate. The evolution of these systems is not well characterized. When a single Cys is present in a protein, conjugation of the redox buffer glutathione may induce conformational changes, resulting in a simple redox switch that effects a signaling cascade. If a second cysteine is introduced into the sequence, the potential for disulfide formation exists. In favorable protein contexts, a bistable redox switch may be formed. Because of glutaredoxin's similarities to thioredoxin, the mutated protein may be immediately exapted into the thioredoxin-dependent redox cycle upon addition of the second cysteine. Here we searched for examples of protein substrates where the number of redox-active cysteine residues has changed throughout evolution. We focused on cross-strand disulfides (CSDs), the most common type of forbidden disulfide. We searched for proteins where the CSD is present, absent and also found as a single cysteine in protein orthologs. Three different proteins were selected for detailed study-CD4, ERO1, and AKT. We created phylogenetic trees, examining when the CSD residues were mutated during protein evolution. We posit that the primordial cysteine is likely to be the cysteine of the CSD which undergoes nucleophilic attack by thioredoxin. Thus, a redox-active disulfide may be introduced into a protein structure by stepwise mutation of two residues in the native sequence to Cys. By extension, evolutionary acquisition of structural disulfides in proteins can potentially occur via transition through a redox active disulfide state. PMID- 25805994 TI - G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease. AB - G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target. PMID- 25805995 TI - Utilizing GCaMP transgenic mice to monitor endogenous Gq/11-coupled receptors. AB - The family of GCaMPs are engineered proteins that contain Ca(2+) binding motifs within a circularly permutated variant of the Aequorea Victoria green fluorescent protein (cp-GFP). The rapidly advancing field of utilizing GCaMP reporter constructs represents a major step forward in our ability to monitor intracellular Ca(2+) dynamics. With the use of these genetically encoded Ca(2+) sensors, investigators have studied activation of endogenous Gq types of G protein-coupled receptors (GPCRs) and subsequent rises in intracellular calcium. Escalations in intracellular Ca(2+) from GPCR activation can be faithfully monitored in space and time as an increase in fluorescent emission from these proteins. Further, transgenic mice are now commercially available that express GCaMPs in a Cre recombinase dependent fashion. These GCaMP reporter mice can be bred to distinct Cre recombinase driver mice to direct expression of this sensor in unique populations of cells. Concerning the central nervous system (CNS), sources of calcium influx, including those arising from Gq activation can be observed in targeted cell types like neurons or astrocytes. This powerful genetic method allows simultaneous monitoring of the activity of dozens of cells upon activation of endogenous Gq-coupled GPCRs. Therefore, in combination with pharmacological tools, this strategy of monitoring GPCR activation is amenable to analysis of orthosteric and allosteric ligands of Gq-coupled receptors in their endogenous environments. PMID- 25805996 TI - Ceftriaxone and cefazolin attenuate the cue-primed reinstatement of alcohol seeking. AB - Alcohol consumption and the reinstatement of alcohol-seeking rely on glutamate and GABA transmission. Modulating these neurotransmitters may be a viable treatment strategy to prevent alcohol relapse. N-acetylcysteine (NAC) and the antibiotic ceftriaxone (CEF) alter the glial reuptake and release of glutamate while the antibiotic cefazolin (CEFAZ) modulates GABA signaling without affecting glutamate. Here, we used the extinction-reinstatement model of relapse to test the ability of these compounds to attenuate the reinstatement of alcohol-seeking. Male Sprague-Dawley rats were trained to self-administer 20% (v/v) alcohol in the home cage using an intermittent schedule (24 h on, 24 h off) for 12 sessions. Subsequently, animals self-administered alcohol during daily 45-min operant sessions for 26 sessions, followed by extinction training. We tested whether chronic administration of NAC, CEF, or CEFAZ attenuated the cue-primed reinstatement of alcohol-seeking. CEF and CEFAZ attenuated cue-primed reinstatement of alcohol-seeking while NAC had no effect. We subsequently investigated whether CEF and CEFAZ alter the self-administration of sucrose and chow pellets and if CEFAZ attenuates the reinstatement of cocaine-seeking. The operant self-administration of regular chow and sucrose was not altered by either CEF or CEFAZ. CEFAZ had no effect on cocaine reinstatement, a behavior that has been strongly tied to altered glutamate homeostasis in the nucleus accumbens. Thus the ability of CEFAZ to attenuate alcohol reinstatement likely does not involve the glial modulation of glutamate levels. The dampening of GABA transmission may be a common mechanism of action of cefazolin and ceftriaxone. PMID- 25805997 TI - Physiological implications of biased signaling at histamine H2 receptors. AB - Histamine mediates numerous functions acting through its four receptor subtypes all belonging to the large family of seven transmembrane G-protein coupled receptors. In particular, histamine H2 receptor (H2R) is mainly involved in gastric acid production, becoming a classic pharmacological target to treat Zollinger-Ellison disease and gastric and duodenal ulcers. H2 ligands rank among the most widely prescribed and over the counter-sold drugs in the world. Recent evidence indicate that some H2R ligands display biased agonism, selecting and triggering some, but not all, of the signaling pathways associated to the H2R. The aim of the present work is to study whether famotidine, clinically widespread used ligand acting at H2R, exerts biased signaling. Our findings indicate that while famotidine acts as inverse agonist diminishing cAMP basal levels, it mimics the effects of histamine and the agonist amthamine concerning receptor desensitization and internalization. Moreover, the treatment of HEK293T transfected cells with any of the three ligands lead to a concentration dependent pERK increment. Similarly in AGS gastric epithelial cells, famotidine treatment led to both, the reduction in cAMP levels as well as the increment in ERK phosphorylation, suggesting that this behavior could have pharmacological relevant implications. Based on that, histidine decarboxylase expression was studied by quantitative PCR in AGS cells and its levels were increased by famotidine as well as by histamine and amthamine. In all cases, the positive regulation was impeded by the MEK inhibitor PD98059, indicating that biased signaling toward ERK1/2 pathway is the responsible of such enzyme regulation. These results support that ligand bias is not only a pharmacological curiosity but has physiological and pharmacological implications on cell metabolism. PMID- 25805998 TI - Differential effects of buffer pH on Ca(2+)-induced ROS emission with inhibited mitochondrial complexes I and III. AB - Excessive mitochondrial reactive oxygen species (ROS) emission is a critical component in the etiology of ischemic injury. Complex I and complex III of the electron transport chain are considered the primary sources of ROS emission during cardiac ischemia and reperfusion (IR) injury. Several factors modulate ischemic ROS emission, such as an increase in extra-matrix Ca(2+), a decrease in extra-matrix pH, and a change in substrate utilization. Here we examined the combined effects of these factors on ROS emission from respiratory complexes I and III under conditions of simulated IR injury. Guinea pig heart mitochondria were suspended in experimental buffer at a given pH and incubated with or without CaCl2. Mitochondria were then treated with either pyruvate, a complex I substrate, followed by rotenone, a complex I inhibitor, or succinate, a complex II substrate, followed by antimycin A, a complex III inhibitor. H2O2 release rate and matrix volume were compared with and without adding CaCl2 and at pH 7.15, 6.9, or 6.5 with pyruvate + rotenone or succinate + antimycin A to simulate conditions that may occur during in vivo cardiac IR injury. We found a large increase in H2O2 release with high [CaCl2] and pyruvate + rotenone at pH 6.9, but not at pHs 7.15 or 6.5. Large increases in H2O2 release rate also occurred at each pH with high [CaCl2] and succinate + antimycin A, with the highest levels observed at pH 7.15. The increases in H2O2 release were associated with significant mitochondrial swelling, and both H2O2 release and swelling were abolished by cyclosporine A, a desensitizer of the mitochondrial permeability transition pore (mPTP). These results indicate that ROS production by complex I and by complex III is differently affected by buffer pH and Ca(2+) loading with mPTP opening. The study suggests that changes in the levels of cytosolic Ca(2+) and pH during IR alter the relative amounts of ROS produced at mitochondrial respiratory complex I and complex III. PMID- 25805999 TI - Role of E2-Ub-conjugating enzymes during skeletal muscle atrophy. AB - The Ubiquitin Proteasome System (UPS) is a major actor of muscle wasting during various physio-pathological situations. In the past 15 years, increasing amounts of data have depicted a picture, although incomplete, of the mechanisms implicated in myofibrillar protein degradation, from the discovery of muscle specific E3 ligases to the identification of the signaling pathways involved. The targeting specificity of the UPS relies on the capacity of the system to first recognize and then label the proteins to be degraded with a poly-ubiquitin (Ub) chain. It is fairly assumed that the recognition of the substrate is accomplished by the numerous E3 ligases present in mammalian cells. However, most E3s do not possess any catalytic activity and E2 enzymes may be more than simple Ub providers for E3s since they are probably important actors in the ubiquitination machinery. Surprisingly, most authors have tried to characterize E3 substrates, but the exact role of E2s in muscle protein degradation is largely unknown. A very limited number of the 35 E2s described in humans have been studied in muscle protein breakdown experiments and the vast majority of studies were only descriptive. We review here the role of E2 enzymes in skeletal muscle and the difficulties linked to their study and provide future directions for the identification of muscle E2s responsible for the ubiquitination of contractile proteins. PMID- 25806001 TI - Warburg revisited: lessons for innate immunity and sepsis. PMID- 25806000 TI - Store-operated calcium entry and the localization of STIM1 and Orai1 proteins in isolated mouse sinoatrial node cells. AB - In many non-excitable and excitable cells, store-operated calcium entry (SOCE) represents an additional pathway for calcium entry upon Ca(2+) store depletion. In a previous study, we demonstrated SOCE activity in intact mouse cardiac pacemaker tissue, specifically from sinoatrial node (SAN) tissue. However, store content as a key determinant of SOCE activity is difficult to measure in intact SAN tissue. Therefore, to investigate the interaction between SOCE and store content and its role in cardiac pacemaking, it is necessary to investigate SOCE activity in single cardiac pacemaker cells. Furthermore, recent studies in other tissues have identified two new proteins involved in SOCE, stromal interacting molecule (STIM), which is an ER Ca(2+) sensor, and the surface membrane channel Orai, a prototypic gene encoding for SOCE. However, whether STIM and Orai are expressed in native pacemaker cells is still unknown. In this current study, we examined SOCE activity in single firing pacemaker cells isolated from mouse sinoatrial node tissue. We found a significant rise in Ca(2+) entry in response to Ca(2+) store depletion. SOCE blockers reduced the amplitude and frequency of spontaneous Ca(2+) transients and reduced Ca(2+) store content. We demonstrated for the first time that STIM and Orai are expressed in pacemaker cells. After store depletion, STIM1 redistributed to the cell periphery and showed increased co-localization with surface membrane located Orai1, indicating a possible involvement of these proteins in SOCE activity in native cardiac pacemaker cells. These results suggest the novel concept that SOCE plays a functional role in regulating intracellular Ca(2+) of cardiac pacemaker cells. PMID- 25805993 TI - Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors. AB - Human herpesviruses (HHVs) are widespread infectious pathogens that have been associated with proliferative and inflammatory diseases. During viral evolution, HHVs have pirated genes encoding viral G protein-coupled receptors (vGPCRs), which are expressed on infected host cells. These vGPCRs show highest homology to human chemokine receptors, which play a key role in the immune system. Importantly, vGPCRs have acquired unique properties such as constitutive activity and the ability to bind a broad range of human chemokines. This allows vGPCRs to hijack human proteins and modulate cellular signaling for the benefit of the virus, ultimately resulting in immune evasion and viral dissemination to establish a widespread and lifelong infection. Knowledge on the mechanisms by which herpesviruses reprogram cellular signaling might provide insight in the contribution of vGPCRs to viral survival and herpesvirus-associated pathologies. PMID- 25806003 TI - Thinking Back about a Positive Event: The Impact of Processing Style on Positive Affect. AB - The manner in which individuals recall an autobiographical positive life event has affective consequences. Two studies addressed the processing styles during positive memory recall in a non-clinical sample. Participants retrieved a positive memory, which was self-generated (Study 1, n = 70) or experimenter chosen (i.e., academic achievement, Study 2, n = 159), followed by the induction of one of three processing styles (between-subjects): in Study 1, a "concrete/imagery" vs. "abstract/verbal" processing style was compared. In Study 2, a "concrete/imagery," "abstract/verbal," and "comparative/verbal" processing style were compared. The processing of a personal memory in a concrete/imagery based way led to a larger increase in positive affect compared to abstract/verbal processing in Study 1, as well as compared to comparative/verbal thinking in Study 2. Results of Study 2 further suggest that it is making unfavorable verbal comparisons that may hinder affective benefits to positive memories (rather than general abstract/verbal processing per se). The comparative/verbal thinking style failed to lead to improvements in positive affect, and with increasing levels of depressive symptoms it had a more negative impact on change in positive affect. We found no evidence that participant's tendency to have dampening thoughts in response to positive affect in daily life contributed to the affective impact of positive memory recall. The results support the potential for current trainings in boosting positive memories and mental imagery, and underline the search for parameters that determine at times deleterious outcomes of abstract/verbal memory processing in the face of positive information. PMID- 25806002 TI - Complexity analyses show two distinct types of nonlinear dynamics in short heart period variability recordings. AB - Two diverse complexity metrics quantifying time irreversibility and local prediction, in connection with a surrogate data approach, were utilized to detect nonlinear dynamics in short heart period (HP) variability series recorded in fetuses, as a function of the gestational period, and in healthy humans, as a function of the magnitude of the orthostatic challenge. The metrics indicated the presence of two distinct types of nonlinear HP dynamics characterized by diverse ranges of time scales. These findings stress the need to render more specific the analysis of nonlinear components of HP dynamics by accounting for different temporal scales. PMID- 25806004 TI - VSNL1 Co-Expression Networks in Aging Include Calcium Signaling, Synaptic Plasticity, and Alzheimer's Disease Pathways. AB - The visinin-like 1 (VSNL1) gene encodes visinin-like protein 1, a peripheral biomarker for Alzheimer disease (AD). Little is known, however, about normal VSNL1 expression in brain and the biologic networks in which it participates. Frontal cortex gray matter obtained from 209 subjects without neurodegenerative or psychiatric illness, ranging in age from 16 to 91, was processed on Affymetrix GeneChip 1.1 ST and Human SNP Array 6.0. VSNL1 expression was unaffected by age and sex, and not significantly associated with SNPs in cis or trans. VSNL1 was significantly co-expressed with genes in pathways for calcium signaling, AD, long term potentiation, long-term depression, and trafficking of AMPA receptors. The association with AD was driven, in part, by correlation with amyloid precursor protein (APP) expression. These findings provide an unbiased link between VSNL1 and molecular mechanisms of AD, including pathways implicated in synaptic pathology in AD. Whether APP may drive increased VSNL1 expression, VSNL1 drives increased APP expression, or both are downstream of common pathogenic regulators will need to be evaluated in model systems. PMID- 25806007 TI - Causal inferences about others' behavior among the Wampar, Papua New Guinea - and why they are hard to elicit. AB - As social beings, people need to be able to interact intelligently with others in their social environment. Accordingly, people spend much time conversing with one another in order to understand the broad and fine aspects of the relations that link them. They are especially interested in the interactive behaviors that constitute social relations, such as mutual aid, gift giving and exchange, sharing, informal socializing, or deception. The evaluations of these behaviors are embedded in social relationships and charged with values and emotions. We developed tasks to probe how people in an unfamiliar socio-cultural setting understand and account for the behavior of others conditional upon their category membership - by trying to elicit the basic categories, stereotypes, and models that inform the causal perceptions, inferences and reasoning people use in understanding others' interactive behaviors - and we tested these tasks among the Wampar in Papua New Guinea. The results show changes in the relevance of social categories among the Wampar but also, and perhaps more important, limitations in the translation and applicability of cognitive tasks. PMID- 25806006 TI - The functional anatomy of psychomotor disturbances in major depressive disorder. AB - Psychomotor disturbances (PMD) are a classic feature of depressive disorder that provides rich clinical information. The aim our narrative review was to characterize the functional anatomy of PMD by summarizing findings from neuroimaging studies. We found evidence across several neuroimaging modalities that suggest involvement of fronto-striatal neurocircuitry, and monoaminergic pathways and metabolism. We suggest that PMD in major depressive disorder emerge from an alteration of limbic signals, which influence emotion, volition, higher order cognitive functions, and movement. PMID- 25806008 TI - How absent negativity relates to affect and motivation: an integrative relief model. AB - The present paper concerns the motivational underpinnings and behavioral correlates of the prevention or stopping of negative stimulation - a situation referred to as relief. Relief is of great theoretical and applied interest. Theoretically, it is tied to theories linking affect, emotion, and motivational systems. Importantly, these theories make different predictions regarding the association between relief and motivational systems. Moreover, relief is a prototypical antecedent of counterfactual emotions, which involve specific cognitive processes compared to factual or mere anticipatory emotions. Practically, relief may be an important motivator of addictive and phobic behaviors, self destructive behaviors, and social influence. In the present paper, we will first provide a review of conflicting conceptualizations of relief. We will then present an integrative relief model (IRMO) that aims at resolving existing theoretical conflicts. We then review evidence relevant to distinctive predictions regarding the moderating role of various procedural features of relief situations. We conclude that our integrated model results in a better understanding of existing evidence on the affective and motivational underpinnings of relief, but that further evidence is needed to come to a more comprehensive evaluation of the viability of IRMO. PMID- 25806009 TI - A meta-analysis of functional reading systems in typically developing and struggling readers across different alphabetic languages. AB - Functional neuroimaging research has identified multiple brain regions supporting reading-related activity in typical and atypical readers across different alphabetic languages. Previous meta-analyses performed on these functional magnetic resonance imaging findings typically report significant between-group contrasts comparing typical readers and readers with reading difficulty or a clinical diagnosis of developmental dyslexia. In order to advance our understanding of cross-linguistic convergence of reading-related brain activations for these reader groups, analyses using activation likelihood estimation were carried out separately for typical and atypical readers who ranged from children to adults. Contrasts were analyzed for tasks involving rhyming or reading of letter or word stimuli presented visually in English, Dutch, Italian, German, French, or Norwegian. Typical readers showed reliable activation in only left lateralized regions, including the inferior frontal area, precentral area and middle temporal gyrus. Atypical readers also showed activation in the left inferior frontal area and precentral region, in addition to significant activations in the right hemisphere, including the superior, medial and inferior frontal regions, lingual gyrus and the inferior occipital area. These results distinguish between typical and atypical reader group activations, showing common and distinct regions of activation when engaged in reading-related activities, extending previous meta-analyses on identifying brain regions relevant to reading to include cross-linguistic analyses for alphabetic scripts. Results support the universality of a signature pattern of brain activation in developmental dyslexia across alphabetic languages. PMID- 25806010 TI - The activity view of inner speech. AB - We distinguish two general approaches to inner speech (IS)-the "format" and the "activity" views-and defend the activity view. The format view grounds the utility of IS on features of the representational format of language, and is related to the thesis that the proper function of IS is to make conscious thinking possible. IS appears typically as a product constituted by representations of phonological features. The view also has implications for the idea that passivity phenomena in cognition may be misattributed IS. The activity view sees IS as a speaking activity that does not have a proper function in cognition. It simply inherits the array of functions of outer speech. We argue that it is methodologically advisable to start from this variety of uses, which suggests commonalities between internal and external activities. The format view has several problems; it has to deny "unsymbolized thinking"; it cannot easily explain how IS makes thoughts available to consciousness, and it cannot explain those uses of IS where its format features apparently play no role. The activity view not only lacks these problems but also has explanatory advantages: construing IS as an activity allows it to be integrally constituted by its content; the view is able to construe unsymbolized thinking as part of a continuum of phenomena that exploit the same mechanisms, and it offers a simple explanation for the variety of uses of IS. PMID- 25806011 TI - Instructed illiteracy reveals expertise-effects on unconscious processing. AB - We used a new methodological approach to investigate whether top-down influences like expertise determine the extent of unconscious processing. This approach does not rely on preexisting differences between experts and novices, but instructs essentially the same task in a way that either addresses a domain of expertise or not. Participants either were instructed to perform a lexical decision task (expert task) or to respond to a combination of single features of word and non word stimuli (novel task). The stimuli and importantly also the mapping of responses to those stimuli, however, were exactly the same in both groups. We analyzed congruency effects of masked primes depending on the instructed task. Participants performing the expert task responded faster and less error prone when the prime was response congruent rather than incongruent. This effect was significantly reduced in the novel task, and even reversed when excluding identical prime-target pairs. This indicates that the primes in the novel task had an effect on a perceptual level, but were not able to impact on response activation. Overall, these results demonstrate an expertise-based top-down modulation of unconscious processing that cannot be explained by confounds that are otherwise inherent in comparisons between novices and experts. PMID- 25806012 TI - Working memory and referential communication-multimodal aspects of interaction between children with sensorineural hearing impairment and normal hearing peers. AB - Whereas the language development of children with sensorineural hearing impairment (SNHI) has repeatedly been shown to differ from that of peers with normal hearing (NH), few studies have used an experimental approach to investigate the consequences on everyday communicative interaction. This mini review gives an overview of a range of studies on children with SNHI and NH exploring intra- and inter-individual cognitive and linguistic systems during communication. Over the last decade, our research group has studied the conversational strategies of Swedish speaking children and adolescents with SNHI and NH using referential communication, an experimental analog to problem-solving in the classroom. We have established verbal and non-verbal control and validation mechanisms, related to working memory capacity and phonological short term memory. We present main findings and future directions relevant for the field of cognitive hearing science and for the clinical and school-based management of children and adolescents with SNHI. PMID- 25806013 TI - Corrigendum: A question of scent: lavender aroma promotes interpersonal trust. AB - [This corrects the article on p. 1486 in vol. 5, PMID: 25628577.]. PMID- 25806014 TI - Expanded transition spaces: the case of Garrwa. AB - Accounts of turn-taking in much of the CA literature have largely focused on talk which progresses with minimal gaps between turns at talk, longer gaps being found to be symptomatic of, for example, engagement in non-talk activities, or as indicators of some kind of trouble in the interaction. In this paper we present an account of turn-taking in conversations between Indigenous Australians where longer gaps are frequent and regular. We show that in sequences of such slow paced conversation, gaps are not always treated as problematic, nor are they associated with non-talk activities that might inhibit talk. In such contexts we argue that there is less orientation to gap minimization, reflecting a lack of pressure for continuous talk. We also discuss qualitative differences in the nature of the gaps between turns in which there is a selection of next speaker, and those where no next speaker has been selected. Finally we consider whether such talk is a feature of Indigenous Australian conversation, or a more widespread practice. PMID- 25806015 TI - Fear and anger have opposite effects on risk seeking in the gain frame. AB - Emotions strongly influence our decisions, particularly those made under risk. A classic example of the effect of emotion on decision making under risk is the "framing effect," which involves predictable shifts in preferences when the same problem is formulated in different ways. According to dual process theories, this bias could stem from an affective heuristic belonging to an intuitive type of reasoning. In this study, we examined whether specific incidental negative emotions (i.e., fear and anger) influence framing susceptibility and risk-taking identically. In each trial, participants received an initial amount of money, and pictures of angry or fearful faces were presented to them. Finally, participants chose between a sure option and a gamble option of equally expected value in a gain or loss frame. Risk-taking was modulated by emotional context: fear and anger influenced risk-taking specifically in the gain frame and had opposite effects. Fear increased risk-averse choices, whereas anger decreased risk-averse choices, leading to a suppression of the framing effect. These results confirm that emotions play a key role in framing susceptibility. PMID- 25806016 TI - Psychological perspectives on expertise. PMID- 25806017 TI - Resting heart rate variability predicts self-reported difficulties in emotion regulation: a focus on different facets of emotion regulation. AB - The Model of Neurovisceral Integration suggests that vagally mediated heart rate variability (vmHRV) represents a psychophysiological index of inhibitory control and thus, is associated with emotion regulation capacity. Over the past decade, growing empirical evidence supports this notion, showing that those with higher resting vmHRV can regulate negative emotions more adequately. However, to our knowledge, no study has previously examined how resting vmHRV may relate to everyday perceived difficulties in emotion regulation. The present study attempts to examine such relationship in 183 undergraduate students (98 female, 60 minority, mean Age = 19.34). Resting vmHRV was collected during a 5-min resting baseline period, and everyday difficulties in emotion regulation were assessed using the Difficulties in Emotion Regulation Scale (DERS). Controlling for potential covariates (including both trait anxiety and rumination), results revealed a negative relationship between resting vmHRV and DERS such that lower resting vmHRV was associated with greater difficulties in emotional regulation, especially a lack of emotional clarity and impulse control, as indicated by the respective subscales of the DERS. These findings provide further evidence for the Neurovisceral Integration Model, suggesting that emotion regulation and autonomic regulation share neural networks within the brain. Moreover, the present study extends prior research by highlighting two distinct facets of emotion regulation (impulse control and emotional clarity) that should be of particular interest when investigating the link between emotion regulation, resting vmHRV, and related health outcomes including morbidity and mortality. PMID- 25806018 TI - PET Imaging of Tau Pathology in Alzheimer's Disease and Tauopathies. PMID- 25806019 TI - Long Non-Coding RNA Expression during Aging in the Human Subependymal Zone. AB - The human subependymal zone (SEZ) is debatably a source of newly born neurons throughout life and neurogenesis is a multi-step process requiring distinct transcripts during cell proliferation and early neuronal maturation, along with orchestrated changes in gene expression during cell state/fate transitions. Furthermore, it is becoming increasingly clear that the majority of our genome that results in production of non-protein-coding RNAs plays vital roles in the evolution, development, adaptation, and region-specific function of the human brain. We predicted that some transcripts expressed in the SEZ may be unique to this specialized brain region, and that a comprehensive transcriptomic analysis of this region would aid in defining expression changes during neuronal birth and growth in adult humans. Here, we used deep RNA sequencing of human SEZ tissue during adulthood and aging to characterize the transcriptional landscape with a particular emphasis on long non-coding RNAs (lncRNAs). The data show predicted age-related changes in mRNAs encoding proliferation, progenitor, and inflammatory proteins as well as a unique subset of lncRNAs that are highly expressed in the human SEZ, many of which have unknown functions. Our results suggest the existence of robust proliferative and neuronal differentiation potential in the adult human SEZ and lay the foundation for understanding the involvement of lncRNAs in postnatal neurogenesis and potentially associated neurodevelopmental diseases that emerge after birth. PMID- 25806005 TI - Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases? AB - There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer's, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies. PMID- 25806020 TI - Transcriptional Response of Polycomb Group Genes to Status Epilepticus in Mice is Modified by Prior Exposure to Epileptic Preconditioning. AB - Exposure of the brain to brief, non-harmful seizures can activate protective mechanisms that temporarily generate a damage-refractory state. This process, termed epileptic tolerance, is associated with large-scale down-regulation of gene expression. Polycomb group (PcG) proteins are master controllers of gene silencing during development that are re-activated by injury to the brain. Here, we explored the transcriptional response of genes associated with polycomb repressive complex (PRC) 1 (Ring1A, Ring1B, and Bmi1) and PRC2 (Ezh1, Ezh2, and Suz12), as well as additional transcriptional regulators Sirt1, Yy1, and Yy2, in a mouse model of status epilepticus (SE). Findings were contrasted to changes after SE in mice previously given brief seizures to evoke tolerance. Real-time quantitative PCR showed SE prompted an early (1 h) increase in expression of several genes in PRC1 and PRC2 in the hippocampus, followed by down-regulation of many of the same genes at later times points (4, 8, and 24 h). Spatio-temporal differences were found among PRC2 genes in epileptic tolerance, including increased expression of Ezh2, Suz12, and Yy2 relative to the normal injury response to SE. In contrast, PRC1 complex genes including Ring 1B and Bmi1 displayed differential down-regulation in epileptic tolerance. The present study characterizes PcG gene expression following SE and shows prior seizure exposure produces select changes to PRC1 and PRC2 composition that may influence differential gene expression in epileptic tolerance. PMID- 25806022 TI - Evolution of parathyroid hormone receptor family and their ligands in vertebrate. AB - The presence of the parathyroid hormones in vertebrates, including PTH, PTH related peptide (PTHrP), and tuberoinfundibular peptide of 39 residues (TIP39), has been proposed to be the result of two rounds of whole genome duplication in the beginning of vertebrate diversification. Bioinformatics analyses, in particular chromosomal synteny study and the characterization of the PTH ligands and their receptors from various vertebrate species, provide evidence that strongly supports this hypothesis. In this mini-review, we summarize recent advances in studies regarding the molecular evolution and physiology of the PTH ligands and their receptors, with particular focus on non-mammalian vertebrates. In summary, the PTH family of peptides probably predates early vertebrate evolution, indicating a more ancient existence as well as a function of these peptides in invertebrates. PMID- 25806023 TI - Anaerobic degradation of cyclohexane by sulfate-reducing bacteria from hydrocarbon-contaminated marine sediments. AB - The fate of cyclohexane, often used as a model compound for the biodegradation of cyclic alkanes due to its abundance in crude oils, in anoxic marine sediments has been poorly investigated. In the present study, we obtained an enrichment culture of cyclohexane-degrading sulfate-reducing bacteria from hydrocarbon-contaminated intertidal marine sediments. Microscopic analyses showed an apparent dominance by oval cells of 1.5 * 0.8 MUm. Analysis of a 16S rRNA gene library, followed by whole-cell hybridization with group- and sequence-specific oligonucleotide probes showed that these cells belonged to a single phylotype, and were accounting for more than 80% of the total cell number. The dominant phylotype, affiliated with the Desulfosarcina-Desulfococcus cluster of the Deltaproteobacteria, is proposed to be responsible for the degradation of cyclohexane. Quantitative growth experiments showed that cyclohexane degradation was coupled with the stoichiometric reduction of sulfate to sulfide. Substrate response tests corroborated with hybridization with a sequence-specific oligonucleotide probe suggested that the dominant phylotype apparently was able to degrade other cyclic and n-alkanes, including the gaseous alkane n-butane. Based on GC-MS analyses of culture extracts cyclohexylsuccinate was identified as a metabolite, indicating an activation of cyclohexane by addition to fumarate. Other metabolites detected were 3-cyclohexylpropionate and cyclohexanecarboxylate providing evidence that the overall degradation pathway of cyclohexane under anoxic conditions is analogous to that of n-alkanes. PMID- 25806021 TI - Modulating central gain in tinnitus: changes in nitric oxide synthase in the ventral cochlear nucleus. AB - A significant challenge in tinnitus research lies in explaining how acoustic insult leads to tinnitus in some individuals, but not others. One possibility is genetic variability in the expression and function of neuromodulators - components of neural signaling that alter the balance of excitation and inhibition in neural circuits. An example is nitric oxide (NO) - a free radical and potent neuromodulator in the mammalian brain - that regulates plasticity via both pre-synaptic and postsynaptic mechanisms. Changes in NO have previously been implicated in tinnitus generation, specifically in the ventral cochlear nucleus (VCN). Here, we examined nitric oxide synthase (NOS) - the enzyme responsible for NO production - in the guinea pig VCN following acoustic trauma. NOS was present in most cell types - including spherical and globular bushy cells, small, medium, and large multipolar cells, and octopus cells - spanning the entire extent of the VCN. The staining pattern was symmetrical in control animals. Unilateral acoustic over-exposure (AOE) resulted in marked asymmetries between ipsilateral and contralateral sides of the VCN in terms of the distribution of NOS across the cochlear nuclei in animals with behavioral evidence of tinnitus: fewer NOS positive cells and a reduced level of NOS staining was present across the whole extent of the contralateral VCN, relative to the ipsilateral VCN. The asymmetric pattern of NOS-containing cells was observed as early as 1 day after AOE and was also present in some animals at 3, 7, and 21 days after AOE. However, it was not until 8 weeks after AOE, when tinnitus had developed, that asymmetries were significant overall, compared with control animals. Asymmetrical NOS expression was not correlated with shifts in the threshold hearing levels. Variability in NOS expression between animals may represent one underlying difference that can be linked to whether or not tinnitus develops after noise exposure. PMID- 25806024 TI - The novel transcriptional regulator SA1804 Is involved in mediating the invasion and cytotoxicity of Staphylococcus aureus. AB - The two-component regulatory system, SaeRS, controls expression of important virulence factors, including toxins and invasins, which contribute to the pathogenicity of Staphylococcus aureus. Previously, we conducted a transcriptomics study for identification of SaeRS regulon and found that inactivation of SaeRS dramatically enhances the transcription of a novel transcriptional regulator (SA1804). This led us to question whether SA1804 is involved in bacterial pathogenicity by regulating the expression of virulence factors. To address this question, we created sa1804, saeRS, and sa1804/saeRS double deletion mutants in a USA300 community-acquired MRSA strain, 923, and determined their impact on the pathogenicity. The deletion of sa1804 dramatically increased the cytotoxicity and enhanced the capacity of bacteria to invade into the epithelial cells (A549), whereas the deletion of saeRS eliminated the cytotoxicity and abolished the bacterial ability to invade into the epithelial cells. Moreover, the double deletions of sa1804 and saeRS appeared a similar phenotype with the saeRS null mutation. Furthermore, we determined the regulatory mechanism of SA1804 using qPCR and gel-shift approaches. Our data indicate that the novel virulence repressor SA1804 is dependent on the regulation of SaeRS. This study sheds light on the regulatory mechanism of virulence factors and allows for us further elucidate the molecular pathogenesis of S. aureus. PMID- 25806026 TI - Detection of inhibitors of Candida albicans Cdr transporters using a diS-C3(3) fluorescence. AB - Candida albicans is a major cause of opportunistic and life-threatening, systemic fungal infections. Hence new antifungal agents, as well as new methods to treat fungal infections, are still needed. The application of inhibitors of drug-efflux pumps may increase the susceptibility of C. albicans to drugs. We developed a new fluorescence method that allows the in vivo activity evaluation of compounds inhibiting of C. albicans transporters. We show that the potentiometric dye 3,3' dipropylthiacarbocyanine iodide diS-C3(3) is pumped out by both Cdr1 and Cdr2 transporters. The fluorescence labeling with diS-C3(3) enables a real-time observation of the activity of C. albicans Cdr1 and Cdr2 transporters. We demonstrate that enniatin A and beauvericin show different specificities toward these transporters. Enniatin A inhibits diS-C3(3) efflux by Cdr1 while beauvericin inhibits both Cdr1p and Cdr2p. PMID- 25806025 TI - The use of evolutionary approaches to understand single cell genomes. AB - The vast majority of environmental bacteria and archaea remain uncultivated, yet their genome sequences are rapidly becoming available through single cell sequencing technologies. Reconstructing metabolism is one common way to make use of genome sequences of ecologically important bacteria, but molecular evolutionary analysis is another approach that, while currently underused, can reveal important insights into the function of these uncultivated microbes in nature. Because genome sequences from single cells are often incomplete, metabolic reconstruction based on genome content can be compromised. However, this problem does not necessarily impede the use of phylogenomic and population genomic approaches that are based on patterns of polymorphisms and substitutions at nucleotide and amino acid sites. These approaches explore how various evolutionary forces act to assemble genetic diversity within and between lineages. In this mini-review, I present examples illustrating the benefits of analyzing single cell genomes using evolutionary approaches. PMID- 25806028 TI - Calomys callosus chronically infected by Toxoplasma gondii clonal type II strain and reinfected by Brazilian strains is not able to prevent vertical transmission. AB - Considering that Toxoplasma gondii has shown high genetic diversity in Brazil, the aim of this study was to determine whether Calomys callosus chronically infected by the ME-49 strain might be susceptible to reinfection by these Brazilian strains, including vertical transmission of the parasite. Survival curves were analyzed in non-pregnant females chronically infected with ME-49 and reinfected with the TgChBrUD1 or TgChBrUD2 strain, and vertical transmission was analyzed after reinfection of pregnant females with these same strains. On the 19th day of pregnancy (dop), placentas, uteri, fetuses, liver, spleen, and lung were processed for detection of the parasite. Blood samples were collected for humoral and cellular immune response analyses. All non-pregnant females survived after reinfection and no changes were observed in body weight and morbidity scores. In pregnant females, parasites were detected in the placentas of ME-49 chronically infected females and reinfected females, but were only detected in the fetuses of reinfected females. TgChBrUD2 reinfected females showed more impaired pregnancy outcomes, presenting higher numbers of animals with fetal loss and a higher resorption rate, in parallel with higher levels of pro-inflammatory cytokines and IgG2a subclass antibodies. Vertical transmission resulting from chronic infection of immunocompetent C. callosus is considered a rare event, being attributed instead to either reactivation or reinfection. That is, the pregnancy may be responsible for reactivation of the latent infection or the reinfection may promote T. gondii vertical transmission. Our results clearly demonstrate that, during pregnancy, protection against T. gondii can be breached after reinfection with parasites belonging to different genotypes, particularly when non-clonal strains are involved in this process and in this case the reinfection promoted vertical transmission of both type II and Brazilian T. gondii strains. PMID- 25806027 TI - A novel pro-inflammatory protein of Streptococcus suis 2 induces the Toll-like receptor 2-dependent expression of pro-inflammatory cytokines in RAW 264.7 macrophages via activation of ERK1/2 pathway. AB - Streptococcus suis 2 is an important swine pathogen and an emergent zoonotic pathogen. Excessive inflammation caused by S. suis is responsible for the high levels of early mortality observed in septic shock-like syndrome cases. However, the mechanisms through which S. suis 2 (SS2) causes excessive inflammation remain unclear. Thus, this study aimed to identify novel pro-inflammatory mediators that play important roles in the development of therapies against SS2 infection. In this study, the novel pro-inflammatory protein HP0459, which was encoded by the SSUSC84_0459 gene, was discovered. The stimulation of RAW 264.7 macrophages with recombinant HP0459 protein induced the expression of pro-inflammatory cytokines (IL-1beta, MCP-1 and TNF-alpha). Compared with the wild-type (WT) strain, the isogenic knockout of HP0459 in SS2 led to reduced production of pro-inflammatory cytokines in RAW264.7 macrophages and in vivo. The pro-inflammatory activity of HP0459 was significantly reduced by an antibody against Toll-like receptor 2 (TLR2) in RAW264.7 macrophages and was lower in TLR2-deficient (TLR2-/-) macrophages than in WT macrophages. Furthermore, specific inhibitors of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways significantly decreased the HP0459-induced pro-inflammatory cytokine production, and a western blot assay showed that HP0459 stimulation induced the activation of the ERK1/2 pathway. Taken together, our data indicate that HP0459 is a novel pro inflammatory mediator of SS2 and induces TLR2-dependent pro-inflammatory activity in RAW264.7 macrophages through the ERK1/2 pathway. PMID- 25806029 TI - Construction of a self-luminescent cyanobacterial bioreporter that detects a broad range of bioavailable heavy metals in aquatic environments. AB - A self-luminescent bioreporter strain of the unicellular cyanobacterium Synechococcus sp. PCC 7942 was constructed by fusing the promoter region of the smt locus (encoding the transcriptional repressor SmtB and the metallothionein SmtA) to luxCDABE from Photorhabdus luminescens; the sensor smtB gene controlling the expression of smtA was cloned in the same vector. The bioreporter performance was tested with a range of heavy metals and was shown to respond linearly to divalent Zn, Cd, Cu, Co, Hg, and monovalent Ag. Chemical modeling was used to link bioreporter response with metal speciation and bioavailability. Limits of Detection (LODs), Maximum Permissive Concentrations (MPCs) and dynamic ranges for each metal were calculated in terms of free ion concentrations. The ranges of detection varied from 11 to 72 pM for Hg(2+) (the ion to which the bioreporter was most sensitive) to 1.54-5.35 MUM for Cd(2+) with an order of decreasing sensitivity as follows: Hg(2+) >> Cu(2+) >> Ag(+) > Co(2+) >= Zn(2+) > Cd(2+). However, the maximum induction factor reached 75-fold in the case of Zn(2+) and 56-fold in the case of Cd(2+), implying that Zn(2+) is the preferred metal in vivo for the SmtB sensor, followed by Cd(2+), Ag(+) and Cu(2+) (around 45-50-fold induction), Hg(2+) (30-fold) and finally Co(2+) (20-fold). The bioreporter performance was tested in real environmental samples with different water matrix complexity artificially contaminated with increasing concentrations of Zn, Cd, Ag, and Cu, confirming its validity as a sensor of free heavy metal cations bioavailability in aquatic environments. PMID- 25806030 TI - Engineering nanoparticles to silence bacterial communication. AB - The alarming spread of bacterial resistance to traditional antibiotics has warranted the study of alternative antimicrobial agents. Quorum sensing (QS) is a chemical cell-to-cell communication mechanism utilized by bacteria to coordinate group behaviors and establish infections. QS is integral to bacterial survival, and therefore provides a unique target for antimicrobial therapy. In this study, silicon dioxide nanoparticles (Si-NP) were engineered to target the signaling molecules [i.e., acylhomoserine lactones (HSLs)] used for QS in order to halt bacterial communication. Specifically, when Si-NP were surface functionalized with beta-cyclodextrin (beta-CD), then added to cultures of bacteria (Vibrio fischeri), whose luminous output depends upon HSL-mediated QS, the cell-to-cell communication was dramatically reduced. Reductions in luminescence were further verified by quantitative polymerase chain reaction (qPCR) analyses of luminescence genes. Binding of HSLs to Si-NPs was examined using nuclear magnetic resonance (NMR) spectroscopy. The results indicated that by delivering high concentrations of engineered NPs with associated quenching compounds, the chemical signals were removed from the immediate bacterial environment. In actively-metabolizing cultures, this treatment blocked the ability of bacteria to communicate and regulate QS, effectively silencing and isolating the cells. Si NPs provide a scaffold and critical stepping-stone for more pointed developments in antimicrobial therapy, especially with regard to QS-a target that will reduce resistance pressures imposed by traditional antibiotics. PMID- 25806031 TI - The Consequences of Multiple Simultaneous C-Type Lectin-Ligand Interactions: DCIR Alters the Endo-Lysosomal Routing of DC-SIGN. AB - Antigen-presenting cells (APCs) are equipped with multiple receptors to allow proper pathogen recognition and capture. C-type lectin receptors (CLRs) recognize glycan structures on pathogens and endogenous glycoproteins for internalization and antigen processing and presentation. Often, the glycan specificity of these receptors is overlapping and/or pathogens are decorated with ligands for multiple CLRs, posing the question whether interference or cooperativity within the CLR family exists. Here, we used imaging flow cytometry to investigate the internalization properties of four different CLRs [mannose receptor, DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), macrophage galactose-type lectin, and dendritic cell immunoreceptor (DCIR)] on different APCs, as well as their intracellular routing. Although the internalization score of the investigated CLRs was similar on monocytes, macrophages, and dendritic cells (DCs), DCIR internalization rates were lower compared to the other CLRs. Upon triggering, DCIR routed to intracellular compartments outside of the classical endo-lysosomal pathway, resulting in poor CD4(+) T-cell stimulation. Although DC maturation reduced CLR expression levels, it did not affect their internalization rates. Although CLR internalization appeared to be independently regulated, DC-SIGN routing was affected when DCIR was triggered simultaneously. In conclusion, our results provide new insights for the design of DC-based immunotherapeutic strategies and suggest that DCIR is an inferior target in this respect. PMID- 25806032 TI - Effects of maternal inflammation and exposure to cigarette smoke on birth weight and delivery of preterm babies in a cohort of indigenous Australian women. AB - Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among Indigenous Australians. This study aimed to determine the effects of inflammatory responses and exposure to cigarette smoke, two important factors associated with sudden death in infancy, on preterm birth, and birth weight in a cohort of Indigenous mothers. Indigenous Australian women (n = 131) were recruited as part of a longitudinal study while attending antenatal care clinics during pregnancy; blood samples were collected up to three times in pregnancy. Serum cotinine, indicating exposure to cigarette smoke, was detected in 50.4% of mothers. Compared with non-Indigenous women, the cohort had 10 times the prevalence of antibodies to Helicobacter pylori (33 vs. 3%). Levels of immunoglobulin G, antibodies to H. pylori, and C-reactive protein (CRP) were all inversely correlated with gestational age (P < 0.05). CRP levels were positively associated with maternal body mass index (BMI; rho = 0.449, P = 0.001). The effects of cigarette smoke (cotinine) and inflammation (CRP) were assessed in relation to risk factors for SIDS: gestational age at delivery and birth weight. Serum cotinine levels were negatively associated with birth weight (rho = -0.37, P < 0.001), this correlation held true for both male (rho = -0.39, P = 0.002) and female (rho = -0.30, P = 0.017) infants. Cotinine was negatively associated with gestational age at delivery (rho = -0.199, P = 0.023). When assessed by fetal sex, this was significant only for males (rho = -0.327, P = 0.011). CRP was negatively associated with gestational age at delivery for female infants (rho = 0.46, P < 0.001). In contrast, maternal BMI was significantly correlated with birth weight. These data highlight the importance of putting programs in place to reduce cigarette smoke exposure in pregnancy and to treat women with chronic infections such as H. pylori to improve pregnancy outcomes and decrease risk factors for sudden death in infancy. PMID- 25806034 TI - Probiotic Treatment Decreases the Number of CD14-Expressing Cells in Porcine Milk Which Correlates with Several Intestinal Immune Parameters in the Piglets. AB - Modulating the mucosal immune system of neonates by probiotic treatment of their mothers is a promising approach which can only be investigated through the use of animal models. Here, we used sows and their piglets to investigate the impact of a bacterial treatment on the sow's milk and on the neonate piglet intestinal immune system. In previous experiments, feed supplementation of sows with the probiotic Enterococcus faecium NCIMB 10415 during pregnancy and lactation had been shown to affect intestinal microbiota and cytokine expression of the offspring during the suckling and weaning periods. We therefore investigated the composition of the milk from treated sows in comparison to samples from a control group. In treated sows, the amount of lactose increased, and the somatic cell numbers were reduced. In all milk samples, the percentage of cells expressing membranous CD14 (mCD14) was greater than the fractions of immune cells, indicating expression of mCD14 on mammary epithelial cells. However, in the milk of E. faecium-treated sows, mCD14(+) cells were reduced. Furthermore, the number of CD14(+) milk cells was positively correlated with the percentages of B cells and activated T cells in the ileal MLN of the piglets. This study provides evidence for the expression of mCD14 by the porcine mammary epithelium, and suggests an immunological effect of mCD14(+) milk cells on the piglets' intestinal immune system. Our study further suggests that mCD14(+) mammary epithelial cell populations can be modulated by probiotic feed supplementation of the sow. PMID- 25806036 TI - Successional changes of phytodiversity on a short rotation coppice plantation in Oberschwaben, Germany. AB - To allow for information on successional changes in phytodiversity over time and space, as well as information on differences between clones and treatments, phytodiversity was monitored on a poplar short rotation coppice plantation in Oberschwaben, Southwest Germany, in four consecutive years. The investigated plantation was divided into two core areas, one planted with poplar clone Max4, the other with Monviso; each core area was divided into two blocks with alternating treatments: (i) irrigation and fertilization; (ii) irrigation; and (iii) no treatment. All vascular plant species of the ground vegetation were recorded in 72 permanent sampling plots of 25 m(2) each during vegetation periods using the Braun-Blanquet scale. Results showed that total number of species increased in first 2 years and declined after harvest of the SRC-trees. Total vegetation cover decreased during the 4 years of study. Especially for the two clones there was an opposed trend: grass layer had a high cover on Monviso plots, but low cover on Max4 plots; herb layer the very reverse. However, there was no significant difference between the three treatments compared within each year. Perennial species were dominating over all years, as well as light-demanding species, but their proportion decreased steadily. Our results confirm the conclusion of previous studies which indicate that plant community succession takes place in ground vegetation of SRC and imply that species composition is age dependent. The selection of clones for SRC can influence ground vegetation; some floristic changes for example caused by different treatments may be visible only when monitored over a longer period of time. PMID- 25806033 TI - Eliminating Schistosomes through Vaccination: What are the Best Immune Weapons? AB - The successful development of vaccines depends on the knowledge of the immunological mechanisms associated with the elimination of the pathogen. In the case of schistosomes, its complex life cycle and the mechanisms developed to evade host immune system, turns the development of a vaccine against the disease into a very difficult task. Identifying the immunological effector mechanisms involved in parasite attrition and the major targets for its response is a key step to formulate an effective vaccine. Recent studies have described some promising antigens to compose a subunit vaccine and have pointed to some immune factors that play a role in parasite elimination. Here, we review the immune components and effector mechanisms associated with the protective immunity induced by those vaccine candidates and the lessons we have learned from the studies of the acquired resistance to infection in humans. We will also discuss the immune factors that correlate with protection and therefore could help to evaluate those vaccine formulations in clinical trials. PMID- 25806035 TI - Introducing a sensor to measure budburst and its environmental drivers. AB - Budburst is a key adaptive trait that can help us understand how plants respond to a changing climate from the molecular to landscape scale. Despite this, acquisition of budburst data is constrained by a lack of information at the plant scale on the environmental stimuli associated with the release of bud dormancy. Additionally, to date, little effort has been devoted to phenotyping plants in natural populations due to the challenge of accounting for the effect of environmental variation. Nonetheless, natural selection operates on natural populations, and investigation of adaptive phenotypes in situ is warranted and can validate results from controlled laboratory experiments. To identify genomic effects on individual plant phenotypes in nature, environmental drivers must be concurrently measured, and characterized. Here, we designed and evaluated a sensor to meet these requirements for temperate woody plants. It was designed for use on a tree branch to measure the timing of budburst together with its key environmental drivers; temperature, and photoperiod. Specifically, we evaluated the sensor through independent corroboration with time-lapse photography and a suite of environmental sampling instruments. We also tested whether the presence of the device on a branch influenced the timing of budburst. Our results indicated the following: the temperatures measured by the budburst sensor's digital thermometer closely approximated the temperatures measured using a thermocouple touching plant tissue; the photoperiod detector measured ambient light with the same accuracy as did time lapse photography; the budburst sensor accurately detected the timing of budburst; and the sensor itself did not influence the budburst timing of Populus clones. Among other potential applications, future use of the sensor may provide plant phenotyping at the landscape level for integration with landscape genomics. PMID- 25806037 TI - Deciphering the link between salicylic acid signaling and sphingolipid metabolism. AB - The field of plant sphingolipid biology has evolved in recent years. Sphingolipids are abundant in cell membranes, and genetic analyses revealed essential roles for these lipids in plant growth, development, and responses to abiotic and biotic stress. Salicylic acid (SA) is a key signaling molecule that is required for induction of defense-related genes and rapid and localized cell death at the site of pathogen infection (hypersensitive response) during incompatible host-pathogen interactions. Conceivably, while levels of SA rapidly increase upon pathogen infection for defense activation, they must be tightly regulated during plant growth and development in the absence of pathogens. Genetic and biochemical evidence suggest that the sphingolipid intermediates, long-chain sphingoid bases, and ceramides, play a role in regulating SA accumulation in plant cells. However, how signals generated from the perturbation of these key sphingolipid intermediates are transduced into the activation of the SA pathway has long remained to be an interesting open question. At least four types of molecules - MAP kinase 6, reactive oxygen species, free calcium, and nitric oxide - could constitute a mechanistic link between sphingolipid metabolism and SA accumulation and signaling. PMID- 25806038 TI - Evolution and function of epigenetic processes in the endosperm. AB - The endosperm is an ephemeral tissue surrounding the embryo that is essential for its development. Aside from the embryo nourishing function, the endosperm serves as a battlefield for epigenetic processes that have been hypothesized to reinforce transposable element silencing in the embryo. Specifically, global DNA demethylation in the central cell may serve to produce small RNAs that migrate to egg cell and embryo to induce de novo DNA methylation. The Polycomb Repressive Complex 2 (PRC2) is particularly targeted to DNA hypomethylated regions, possibly alleviating the negative effects associated with loss of DNA methylation in the endosperm. The functional requirement of the PRC2 in the endosperm can be bypassed by increasing the maternal genome dosage in the endosperm, suggesting a main functional role of the endosperm PRC2 in reducing sexual conflict. We therefore propose that the functional requirement of an endosperm PRC2 was coupled to the evolution of a sexual endosperm and mechanisms enforcing transposon silencing in the embryo. The evolutionary consequences of this scenario for genome expansion will be discussed. PMID- 25806040 TI - Common reed accumulates starch in its stem by metabolic adaptation under Cd stress conditions. AB - In a previous study, we reported that the common reed accumulates water-soluble Cd complexed with an alpha-glucan-like molecule, and that the synthesis of this molecule is induced in the stem of the common reed under Cd stress. We studied the metabolic background to ensure alpha-glucan accumulation under the Cd stress conditions that generally inhibit photosynthesis. We found that the common reed maintained an adequate CO2 assimilation rate, tended to allocate more assimilated (11)C to the stem, and accumulated starch granules in its stem under Cd stress conditions. AGPase activity, which is the rate-limiting enzyme for starch synthesis, increased in the stem of common reed grown in the presence of Cd. Starch accumulation in the stem of common reed was not obvious under other excess metal conditions. Common reed may preferentially allocate assimilated carbon as the carbon source for the formation of Cd and alpha-glucan complexes in its stem followed by prevention of Cd transfer to leaves acting as the photosynthetic organ. These responses may allow the common reed to grow even under severe Cd stress conditions. PMID- 25806039 TI - Citrus PH5-like H(+)-ATPase genes: identification and transcript analysis to investigate their possible relationship with citrate accumulation in fruits. AB - PH5 is a petunia gene that encodes a plasma membrane H(+)-ATPase and determines the vacuolar pH. The citrate content of fruit cell vacuoles influences citrus organoleptic qualities. Although citrus could have PH5-like homologs that are involved in citrate accumulation, the details are still unknown. In this study, extensive data-mining with the PH5 sequence and PCR amplification confirmed that there are at least eight PH5-like genes (CsPH1-8) in the citrus genome. CsPHs have a molecular mass of approximately 100 kDa, and they have high similarity to PhPH5, AtAHA10 or AtAHA2 (from 64.6 to 80.9%). They contain 13-21 exons and 12-20 introns and were evenly distributed into four subgroups of the P3A-subfamily (CsPH1, CsPH2, and CsPH3 in Group I, CsPH4 and CsPH5 in Group II, CsPH6 in Group IV, and CsPH7 and CsPH8 in Group III together with PhPH5). A transcript analysis showed that CsPH1, 3, and 4 were predominantly expressed in mature leaves, whereas CsPH2 and 7 were predominantly expressed in roots, CsPH5 and 6 were predominantly expressed in flowers, and CsPH8 was predominantly expressed in fruit juice sacs (JS). Moreover, the CsPH transcript profiles differed between orange and pummelo, as well as between high-acid and low-acid cultivars. The low acid orange "Honganliu" exhibits low transcript levels of CsPH3, CsPH4, CsPH5, and CsPH8, whereas the acid-free pummelo (AFP) has only a low transcript level of CsPH8. In addition, ABA injection increased the citrate content significantly, which was accompanied by the obvious induction of CsPH2, 6, 7, and 8 transcript levels. Taken together, we suggest that CsPH8 seems likely to regulate citrate accumulation in the citrus fruit vacuole. PMID- 25806041 TI - Improved evidence-based genome-scale metabolic models for maize leaf, embryo, and endosperm. AB - There is a growing demand for genome-scale metabolic reconstructions for plants, fueled by the need to understand the metabolic basis of crop yield and by progress in genome and transcriptome sequencing. Methods are also required to enable the interpretation of plant transcriptome data to study how cellular metabolic activity varies under different growth conditions or even within different organs, tissues, and developmental stages. Such methods depend extensively on the accuracy with which genes have been mapped to the biochemical reactions in the plant metabolic pathways. Errors in these mappings lead to metabolic reconstructions with an inflated number of reactions and possible generation of unreliable metabolic phenotype predictions. Here we introduce a new evidence-based genome-scale metabolic reconstruction of maize, with significant improvements in the quality of the gene-reaction associations included within our model. We also present a new approach for applying our model to predict active metabolic genes based on transcriptome data. This method includes a minimal set of reactions associated with low expression genes to enable activity of a maximum number of reactions associated with high expression genes. We apply this method to construct an organ-specific model for the maize leaf, and tissue specific models for maize embryo and endosperm cells. We validate our models using fluxomics data for the endosperm and embryo, demonstrating an improved capacity of our models to fit the available fluxomics data. All models are publicly available via the DOE Systems Biology Knowledgebase and PlantSEED, and our new method is generally applicable for analysis transcript profiles from any plant, paving the way for further in silico studies with a wide variety of plant genomes. PMID- 25806042 TI - Starch phosphorylation in potato tubers is influenced by allelic variation in the genes encoding glucan water dikinase, starch branching enzymes I and II, and starch synthase III. AB - Starch phosphorylation is an important aspect of plant metabolism due to its role in starch degradation. Moreover, the degree of phosphorylation of starch determines its physicochemical properties and is therefore relevant for industrial uses of starch. Currently, starch is chemically phosphorylated to increase viscosity and paste stability. Potato cultivars with elevated starch phosphorylation would make this process unnecessary, thereby bestowing economic and environmental benefits. Starch phosphorylation is a complex trait which has been previously shown by antisense gene repression to be influenced by a number of genes including those involved in starch synthesis and degradation. We have used an association mapping approach to discover genetic markers associated with the degree of starch phosphorylation. A diverse collection of 193 potato lines was grown in replicated field trials, and the levels of starch phosphorylation at the C6 and C3 positions of the glucosyl residues were determined by mass spectrometry of hydrolyzed starch from tubers. In addition, the potato lines were genotyped by amplicon sequencing and microsatellite analysis, focusing on candidate genes known to be involved in starch synthesis. As potato is an autotetraploid, genotyping included determination of allele dosage. Significant associations (p < 0.001) were found with SNPs in the glucan water dikinase (GWD), starch branching enzyme I (SBEI) and the starch synthase III (SSIII) genes, and with a SSR allele in the SBEII gene. SNPs in the GWD gene were associated with C6 phosphorylation, whereas polymorphisms in the SBEI and SBEII genes were associated with both C6 and C3 phosphorylation and the SNP in the SSIII gene was associated with C3 phosphorylation. These allelic variants have potential as genetic markers for starch phosphorylation in potato. PMID- 25806044 TI - Aging alters circadian regulation of redox in Drosophila. AB - Circadian coordination of metabolism, physiology, and neural functions contributes to healthy aging and disease prevention. Clock genes govern the daily rhythmic expression of target genes whose activities underlie such broad physiological parameters as maintenance of redox homeostasis. Previously, we reported that glutathione (GSH) biosynthesis is controlled by the circadian system via effects of the clock genes on expression of the catalytic (Gclc) and modulatory (Gclm) subunits comprising the glutamate cysteine ligase (GCL) holoenzyme. The objective of this study was to determine whether and how aging, which leads to weakened circadian oscillations, affects the daily profiles of redox-active biomolecules. We found that fly aging is associated with altered profiles of Gclc and Gclm expression at both the mRNA and protein levels. Analysis of free aminothiols and GCL activity revealed that aging abolishes daily oscillations in GSH levels and alters the activity of glutathione biosynthetic pathways. Unlike GSH, its precursors and products of catabolism, methionine, cysteine and cysteinyl-glycine, were not rhythmic in young or old flies, while rhythms of the glutathione oxidation product, GSSG, were detectable. We conclude that the temporal regulation of GSH biosynthesis is altered in the aging organism and that age-related loss of circadian modulation of pathways involved in glutathione production is likely to impair temporal redox homeostasis. PMID- 25806043 TI - Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. AB - The human mitochondrial genome (mtDNA) encodes 22 tRNAs (mt-tRNAs) that are necessary for the intraorganellar translation of the 13 mtDNA-encoded subunits of the mitochondrial respiratory chain complexes. Maturation of mt-tRNAs involves 5' and 3' nucleolytic excision from precursor RNAs, as well as extensive post transcriptional modifications. Recent data suggest that over 7% of all mt-tRNA residues in mammals undergo post-transcriptional modification, with over 30 different modified mt-tRNA positions so far described. These processing and modification steps are necessary for proper mt-tRNA function, and are performed by dedicated, nuclear-encoded enzymes. Recent growing evidence suggests that mutations in these nuclear genes (nDNA), leading to incorrect maturation of mt tRNAs, are a cause of human mitochondrial disease. Furthermore, mtDNA mutations in mt-tRNA genes, which may also affect mt-tRNA function, processing, and modification, are also frequently associated with human disease. In theory, all pathogenic mt-tRNA variants should be expected to affect only a single process, which is mitochondrial translation, albeit to various extents. However, the clinical manifestations of mitochondrial disorders linked to mutations in mt tRNAs are extremely heterogeneous, ranging from defects of a single tissue to complex multisystem disorders. This review focuses on the current knowledge of nDNA coding for proteins involved in mt-tRNA maturation that have been linked to human mitochondrial pathologies. We further discuss the possibility that tissue specific regulation of mt-tRNA modifying enzymes could play an important role in the clinical heterogeneity observed for mitochondrial diseases caused by mutations in mt-tRNA genes. PMID- 25806047 TI - Drosophila nervous system as a target of aging and anti-aging interventions. PMID- 25806045 TI - Reduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero: a South African Fetal Alcohol Syndrome cohort study. AB - Fetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from alcohol exposure during fetal development. It is a considerable public health problem worldwide and is characterized by central nervous system abnormalities, dysmorphic facial features, and growth retardation. Imprinted genes are known to play an important role in growth and development and therefore four imprinting control regions (ICRs), H19 ICR, IG-DMR, KvDMR1 and PEG3 DMR were examined. It is proposed that DNA methylation changes may contribute to developmental abnormalities seen in FAS and which persist into adulthood. The participants included FAS children and controls from the Western and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive a quantitative estimate of methylation at selected CpG dinucleotides: H19 ICR (six CpG sites; 50 controls and 73 cases); KvDMR1 (7, 55, and 86); IG-DMR (10, 56, and 84); and PEG3 DMR (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal development. In this study we report on epigenetic effects observed in blood which may not directly reflect tissue-specific alterations in the developing brain. After adjusting for age and sex (known confounders for DNA methylation), there was a significant difference at KvDMR1 and PEG3 DMR, but not the H19 ICR, with only a small effect (0.84% lower in cases; p = 0.035) at IG DMR. The two maternally imprinted loci, KvDMR1 and PEG3 DMR, showed lower average locus-wide methylation in the FAS cases (1.49%; p < 0.001 and 7.09%; p < 0.001, respectively). The largest effect was at the PEG3 DMR though the functional impact is uncertain. This study supports the role of epigenetic modulation as a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of imprinted loci in a locus-specific manner. PMID- 25806048 TI - Between-array normalization for 450K data. AB - The Illumina Infinium HumanMethylation450 BeadChip is frequently used in epigenetic research. Besides quantile normalization there is currently no standard method to normalize the data between arrays. We describe some properties of the data generated by this platform and present a normalization method based on local regression. We compare the performance of this method with other commonly used approaches in three benchmarks (correlation between 21 pairs of technical replicates, detection of differential methylation and correlation of methylation levels for smoking-associated CpG sites with smoking behavior of 655 participants of an epidemiological study). Results indicate that the proposed method improves reproducibility, whereas some commonly used methods can have adverse effects. PMID- 25806050 TI - Letter from Editors-in-Chief. PMID- 25806046 TI - Non-coding RNA in neural function, disease, and aging. AB - Declining brain and neurobiological function is arguably one of the most common features of human aging. The study of conserved aging processes as well as the characterization of various neurodegenerative diseases using different genetic models such as yeast, fly, mouse, and human systems is uncovering links to non coding RNAs. These links implicate a variety of RNA-regulatory processes, including microRNA function, paraspeckle formation, RNA-DNA hybrid regulation, nucleolar RNAs and toxic RNA clearance, amongst others. Here we highlight these connections and reveal over-arching themes or questions related to recently appreciated roles of non-coding RNA in neural function and dysfunction across lifespan. PMID- 25806051 TI - Functional proteomics of adenosine triphosphatase system in the rat striatum during aging. AB - The maximum rates of adenosine triphosphatase (ATPase) systems related to energy consumption were systematically evaluated in synaptic plasma membranes isolated from the striata of male Wistar rats aged 2, 6, 12, 18, and 24 months, because of their key role in presynaptic nerve ending homeostasis. The following enzyme activities were evaluated: sodium-potassium-magnesium adenosine triphosphatase (Na(+), K(+), Mg(2+)-ATPase); ouabain-insensitive magnesium adenosine triphosphatase (Mg(2+)-ATPase); sodium-potassium adenosine triphosphatase (Na(+), K(+)-ATPase); direct magnesium adenosine triphosphatase (Mg(2+)-ATPase); calcium magnesium adenosine triphosphatase (Ca(2+), Mg(2+)-ATPase); and acetylcholinesterase. The results showed that Na(+), K(+)-ATPase decreased at 18 and 24 months, Ca(2+), Mg(2+)-ATPase and acetylcholinesterase decreased from 6 months, while Mg(2+)-ATPase was unmodified. Therefore, ATPases vary independently during aging, suggesting that the ATPase enzyme systems are of neuropathological and pharmacological importance. This could be considered as an experimental model to study regeneration processes, because of the age-dependent modifications of specific synaptic plasma membranes. ATPases cause selective changes in some cerebral functions, especially bioenergetic systems. This could be of physiopathological significance, particularly in many central nervous system diseases, where, during regenerative processes, energy availability is essential. PMID- 25806052 TI - Experience-dependent expression of Nogo-A and Nogo receptor in the developing rat visual cortex. AB - Nogo-A and Nogo receptor (NgR) expression in the visual cortex following a critical developmental period (postnatal days 20-60) has been previously shown. However, little is known regarding Nogo-A and NgR expression between postnatal day 0 and initiation of the critical period. The present study analyzed Nogo-A and NgR expression at four different time points: postnatal day 0 (P0), before critical period (P14), during critical period (P28), and after critical period (P60). Results showed significantly increased Nogo-A mRNA and protein expression levels in the visual cortex following birth, and expression levels remained steady between P28 and P60. NgR mRNA or protein expression was dramatically upregulated with age and peaked at P14 or P28, respectively, and maintained high expression to P60. In addition, Nogo-A and NgR expression was analyzed in each visual cortex layer in normal developing rats and rats with monocular deprivation. Monocular deprivation decreased Nogo-A and NgR mRNA and protein expression in the rat visual cortex, in particular in layers II-III and IV in the visual cortex contralateral to the deprived eye. These findings suggested that Nogo-A and NgR regulated termination of the critical period in experience- dependent visual cortical plasticity. PMID- 25806055 TI - Morphological and migratory alterations in retinal Muller cells during early stages of hypoxia and oxidative stress. AB - In the present study, retinal Muller cells were cultured in vitro and treated with hydrogen peroxide (oxidative stressor) and cobalt chloride (hypoxic injury). Following 24 hours of culture, compensatory hypertrophy was observed and cellular apoptosis increased. Hypoxia enhanced the migration ability of retinal Muller cells and induced the expression of alpha-smooth muscle actin. Oxidative stress altered the morphology of Muller cells when compared with hypoxia treatment. PMID- 25806054 TI - 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6 tetrahydro-1- methylpyridine oxalate, a novel xanomeline derivative, improves neural cells proliferation and survival in adult mice. AB - The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-1 ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-1-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M1/M4 receptor agonist, on hippocampal neurogenesis in adult C57BL6 mice. Results showed that 15-day EUK1001 treatment via intraperitoneal injection promoted neural cell proliferation in the dentate gyrus, although cell differentiation did not change. The majority of bromodeoxyuridine-positive cells co-expressed the immature neuronal marker doublecortin. In addition, the level of neurogenesis in the subventricular zone was not altered. Brain-derived neurotrophic factor mRNA expression was up regulated following EUK1001 treatment, but no change was observed in expression of camp-responsive element binding protein 1, paired box gene 6, vascular endothelial growth factor alpha, neurogenic differentiation factor 1, and wingless-related mouse mammary tumor virus integration site 3A mRNA. These experimental findings indicated that EUK1001 enhanced proliferation and survival of hippocampal cells, possibly by increasing brain-derived neurotrophic factor expression. PMID- 25806053 TI - Dark rearing maintains tyrosine hydroxylase expression in retinal amacrine cells following optic nerve transection. AB - The present study examined changes in retinal tyrosine hydroxylase (TH) expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigate the effects of amacrine cells on axonal regeneration in retinal ganglion cells and on the synapses that transmit visual signals. The results revealed that retinal TH expression gradually decreased following optic nerve transection in rats housed under a normal day/night cycle, reaching a minimum at 5 days. In contrast, retinal TH expression decreased to a minimum at 1 day following optic nerve transection in dark reared rats, gradually increasing afterward and reaching a normal level at 5-7 days. The number of TH-positive synaptic particles correlated with the TH levels, indicating that dark rearing can help maintain TH expression during the synaptic degeneration stage (5-7 days after optic nerve injury) in retinal amacrine cells. PMID- 25806056 TI - Morphology cluster and prediction of growth of human brain pyramidal neurons. AB - Predicting neuron growth is valuable to understand the morphology of neurons, thus it is helpful in the research of neuron classification. This study sought to propose a new method of predicting the growth of human neurons using 1 907 sets of data in human brain pyramidal neurons obtained from the website of NeuroMorpho.Org. First, we analyzed neurons in a morphology field and used an expectation-maximization algorithm to specify the neurons into six clusters. Second, naive Bayes classifier was used to verify the accuracy of the expectation maximization algorithm. Experiment results proved that the cluster groups here were efficient and feasible. Finally, a new method to rank the six expectation maximization algorithm clustered classes was used in predicting the growth of human pyramidal neurons. PMID- 25806057 TI - Human amniotic epithelial cells express specific markers of nerve cells and migrate along the nerve fibers in the corpus callosum. AB - Human amniotic epithelial cells were isolated from a piece of fresh amnion. Using immunocytochemical methods, we investigated the expression of neuronal phenotypes (microtubule-associated protein-2, glial fibrillary acidic protein and nestin) in human amniotic epithelial cells. The conditioned medium of human amniotic epithelial cells promoted the growth and proliferation of rat glial cells cultured in vitro, and this effect was dose-dependent. Human amniotic epithelial cells were further transplanted into the corpus striatum of healthy adult rats and the grafted cells could integrate with the host and migrate 1-2 mm along the nerve fibers in corpus callosum. Our experimental findings indicate that human amniotic epithelial cells may be a new kind of seed cells for use in neurograft. PMID- 25806049 TI - Regulation of the DNA damage response by ubiquitin conjugation. AB - In response to DNA damage, cells activate a highly conserved and complex kinase based signaling network, commonly referred to as the DNA damage response (DDR), to safeguard genomic integrity. The DDR consists of a set of tightly regulated events, including detection of DNA damage, accumulation of DNA repair factors at the site of damage, and finally physical repair of the lesion. Upon overwhelming damage the DDR provokes detrimental cellular actions by involving the apoptotic machinery and inducing a coordinated demise of the damaged cells (DNA damage induced apoptosis, DDIA). These diverse actions involve transcriptional activation of several genes that govern the DDR. Moreover, recent observations highlighted the role of ubiquitylation in orchestrating the DDR, providing a dynamic cellular regulatory circuit helping to guarantee genomic stability and cellular homeostasis (Popovic et al., 2014). One of the hallmarks of human cancer is genomic instability (Hanahan and Weinberg, 2011). Not surprisingly, deregulation of the DDR can lead to human diseases, including cancer, and can induce resistance to genotoxic anti-cancer therapy (Lord and Ashworth, 2012). Here, we summarize the role of ubiquitin-signaling in the DDR with special emphasis on its role in cancer and highlight the therapeutic value of the ubiquitin-conjugation machinery as a target in anti-cancer treatment strategy. PMID- 25806059 TI - Ultrasound microbubbles combined with liposome-mediated pNogo-R shRNA delivery into neural stem cells. AB - In the present study, ultrasound-mediated microbubble destruction (UMMD) alone and combined with liposome technology was used as a novel nonviral technique to transfect a Nogo receptor (Nogo-R) shRNA plasmid (pNogo-R shRNA) into neural stem cells (NSCs). Using green fluorescent protein as a reporter gene, transfection efficiency of NSCs was significantly higher in the group transfected with UMMD combined with liposomes compared with that of the group transfected with UMMD or liposomes alone, and did not affect cell vitality. In addition, Nogo-R mRNA and protein expression was dramatically decreased in the UMMD combined with liposome mediated group compared with that of other groups after 24 hours of transfection. The UMMD technique combined with liposomes is a noninvasive gene transfer method, which showed minimal effects on cell viability and effectively increased transfer of Nogo-R shRNA into NSCs. PMID- 25806058 TI - Transplantation of autologous bone marrow-derived mesenchymal stem cells for traumatic brain injury. AB - Results from the present study demonstrated that transplantation of autologous bone marrow-derived mesenchymal stem cells into the lesion site in rat brain significantly ameliorated brain tissue pathological changes and brain edema, attenuated glial cell proliferation, and increased brain-derived neurotrophic factor expression. In addition, the number of cells double-labeled for 5 bromodeoxyuridine/glial fibrillary acidic protein and cells expressing nestin increased. Finally, blood vessels were newly generated, and the rats exhibited improved motor and cognitive functions. These results suggested that transplantation of autologous bone marrow-derived mesenchymal stem cells promoted brain remodeling and improved neurological functions following traumatic brain injury. PMID- 25806060 TI - Chondroitinase ABC improves recovery of long sciatic nerve defects. AB - Sciatic nerves from allogeneic Sprague-Dawley rats were pretreated with chondroitinase ABC and were used to bridge damaged sciatic nerves in Wistar rats. Chondroitin sulfate proteoglycans were removed from the chemically extracted acellular nerves. At 3 months after grafting, the footplate pinch test result was positive in the Wistar rats. Autotomy scores decreased, and increased muscular contraction tension appeared when triceps surae muscles were stimulated. In addition, the recovery rate of wet triceps surae muscle weight increased, and the distal segment of the chondroitinase ABC-treated graft exhibited Schwann cells next to the nerve fibers. These results suggested that chondroitinase ABC pretreatment enhanced repair of long nerve defects via acellular nerve grafting. PMID- 25806061 TI - How close is the stem cell cure to the Alzheimer's disease: Future and beyond? AB - Alzheimer's disease, a progressive neurodegenerative illness, is the most common form of dementia. So far, there is neither an effective prevention nor a cure for Alzheimer's disease. In recent decades, stem cell therapy has been one of the most promising treatments for Alzheimer's disease patients. This article aims to summarize the current progress in the stem cell treatments for Alzheimer's disease from an experiment to a clinical research. PMID- 25806062 TI - Scientific literature on monosialoganglioside in the Science Citation Index Expanded: A bibliometric analysis of articles from 1942 to 2011 by each decade. AB - BACKGROUND: The monosialoganglioside (GM1) is a popular topic of research but the bibliometric analysis of GM1 over the decades in Science Citation Index-Expanded (SCI-E) remains poorly understood. OBJECTIVE: To identify the global research and to improve the understanding of research trends in the GM1 field from 1942 to 2011. DESIGN: A bibliometric study. DATA RETRIEVAL: We performed a bibliometric analysis based on the SCI-E published by the Institute of Scientific Information. INCLUSIVE CRITERIA: Articles closely related to GM1 were included. Exclusive criteria: (1) Articles related to gangliosidosis, disialo-ganglioside, trisialo ganglioside or ganglioside GQIb. (2) Document types such as meeting abstracts, reviews, proceedings papers, notes, and letters. MAIN OUTCOME MEASURES: (1) Type of publication output; (2) number of author outputs; (3) distribution of output in subject categories; (4) publication distribution of countries; (5) distribution of output in journals, and (6) distribution of citations in each decade. RESULTS: During 1942 to 2011, there were 10 126 papers on GM1 that were added to the SCI. Articles (8 004) were the most frequently used document type comprising 79.0%, followed by meeting abstracts, reviews and proceedings papers. Research on GM1 could be found in the SCI from 1942, it was developed in the 1970s, greatly increased in the 1980s, and reached a peak in the 1990s, and it was slightly decreased in 2000. The distribution of subject categories showed that GM1 research covered both clinical and basic science research. The USA, Japan, and Germany were the three most productive countries, and the publication numbers in the USA were highest in all decades. The Journal of Biological Chemistry, Journal of Neurochemistry and Biochemistry were core subject journals in GM1 studies in each decade. CONCLUSION: This study highlights the topics in GM1 research that are being published around the world. PMID- 25806064 TI - Reconstruction of the adenosine system by bone marrow-derived mesenchymal stem cell transplantation. AB - In the present study, we transplanted bone marrow-derived mesenchymal stem cells into the CA3 area of the hippocampus of chronic epilepsy rats kindled by lithium chloride-pilocarpine. Immunofluorescence and western blotting revealed an increase in adenosine A1 receptor expression and a decrease in adenosine A2a receptor expression in the brain tissues of epileptic rats 3 months after transplantation. Moreover, the imbalance in the A1 adenosine receptor/A2a adenosine receptor ratio was improved. Electroencephalograms showed that frequency and amplitude of spikes in the hippocampus and frontal lobe were reduced. These results suggested that mesenchymal stem cell transplantation can reconstruct the normal function of the adenosine system in the brain and greatly improve epileptiform discharges. PMID- 25806063 TI - Effects of lateral ventricular transplantation of bone marrow-derived mesenchymal stem cells modified with brain-derived neurotrophic factor gene on cognition in a rat model of Alzheimer's disease. AB - In the present study, transplantation of bone marrow-derived mesenchymal stem cells modified with brain-derived neurotrophic factor gene into the lateral ventricle of a rat model of Alzheimer's disease, resulted in significant attenuation of nerve cell damage in the hippocampal CA1 region. Furthermore, brain-derived neurotrophic factor and tyrosine kinase B mRNA and protein levels were significantly increased, and learning and memory were significantly improved. Results indicate that transplantation of bone marrow-derived mesenchymal stem cells modified with brain-derived neurotrophic factor gene can significantly improve cognitive function in a rat model of Alzheimer's disease, possibly by increasing the levels of brain-derived neurotrophic factor and tyrosine kinase B in the hippocampus. PMID- 25806065 TI - Dispase rapidly and effectively purifies Schwann cells from newborn mice and adult rats. AB - In the present study, Schwann cells were isolated from the sciatic nerve of neonatal mice and purified using dispase and collagenase. Results showed that after the first round of purification with dispase, most of the Schwann cells appeared round in shape and floated in culture solution after 15 minutes. In addition, cell yield and cell purity were higher when compared to the collagenase group. After the second round of purification, the final cell yield for the dispase group was higher than that for the collagenase group, but no significant difference was found in cell purity. Moreover, similar results in cell quantity and purity were observed in adult Sprague-Dawley rats. These findings indicate that purification with dispase can result in the rapid isolation of Schwann cells with a high yield and purity. PMID- 25806066 TI - The active principle region of Buyang Huanwu decoction induced differentiation of bone marrow-derived mesenchymal stem cells into neural-like cells: Superior effects over original formula of Buyang Huanwu decoction. AB - The present study induced in vitro-cultured passage 4 bone marrow-derived mesenchymal stem cells to differentiate into neural-like cells with a mixture of alkaloid, polysaccharide, aglycone, glycoside, essential oils, and effective components of Buyang Huanwu decoction (active principle region of decoction for invigorating yang for recuperation). After 28 days, nestin and neuron-specific enolase were expressed in the cytoplasm. Reverse transcription-PCR and western blot analyses showed that nestin and neuron-specific enolase mRNA and protein expression was greater in the active principle region group compared with the original formula group. Results demonstrated that the active principle region of Buyang Huanwu decoction induced greater differentiation of rat bone marrow derived mesenchymal stem cells into neural-like cells in vitro than the original Buyang Huanwu decoction formula. PMID- 25806067 TI - A quantitative study on changes of the myelinated fibers in the cerebral cortex of cortical dysplasia rats. AB - An animal model of cortical dysplasia was established through X-ray irradiation induced subcortical heterotopic nodules in rats. Transmission electron microscopy detection of the ultrastructure and the stereology examination showed that there was a significant decrease in cerebral white matter and hippocampal volume, the total volume, volume density, length density and total length of the myelinated fibers in the white matter of cortical dysplasia rats. Subcortical heterotopic nodules of the hippocampal CA1 region and synaptic number density in the CA3 region were reduced compared with normal rats. Our experimental findings indicate that erosed subcortical heterotopic nodules, decreased total length of myelinated nerve fibers and demyelination directly lead to a reduction of white matter volume. PMID- 25806069 TI - Increased CD133(+) cell infiltration in the rat brain following fluid percussion injury. AB - The prominin-1/CD133 epitope is expressed in undifferentiated cells. Studies have reported that craniocerebral trauma in animal models of fluid percussion injury induces production of a specific stem cell subgroup. It has been hypothesized that fluid percussion injury induces CD133(+) cell infiltration in the brain tissue. The present study established a traumatic brain injury model through fluid percussion injury. Immunohistochemical staining showed significantly increased CD133 antigen expression in the rat brain following injury. CD133(+) cells were mainly distributed in hippocampal CA1-3 regions, as well as the dentate gyrus and hilus, of the lesioned hemisphere. Occasional cells were also detected in the cortex. In addition, reverse transcription-PCR revealed that no change in CD133 mRNA expression in injured brain tissue. These results suggested that fluid percussion injury induced CD133 antigen expression in the brain tissues as a result of conformational epitope changes, but not transcriptional expression. PMID- 25806068 TI - N-methyl-D-aspartate receptor subtype 3A promotes apoptosis in developing mouse brain exposed to hyperoxia. AB - In the present study, 7 day postnatal C57/BL6 wild-type mice (hyperoxia group) and 7 day postnatal N-methyl-D-aspartate receptor subtype 3A knockout mice (NR3A KO group) were exposed to 75% oxygen and 15% nitrogen in a closed container for 5 days. Wild-type mice raised in normoxia served as controls. TdT-mediated dUTP nick end labeling (TUNEL)/neuron-specific nuclear protein (NeuN) and 5-bromo-2' deoxyuridine (BrdU)/NeuN immunofluorescence staining showed that the number of apoptotic cells and the number of proliferative cells in the dentate subgranular zone significantly increased in the hyperoxia group compared with the control group. However, in the same hyperoxia environment, the number of apoptotic cells and the number of proliferative cells significantly decreased in the NR3A KO group compared with hyperoxia group. TUNEL(+)/NeuN(+) and BrdU(+)/NeuN(+) cells were observed in the NR3A KO and the hyperoxia groups. These results demonstrated that the NR3A gene can promote cell apoptosis and mediate the potential damage in the developing brain induced by exposure to non-physiologically high concentrations of oxygen. PMID- 25806070 TI - Effects of fulvestrant on biological activity and Wnt expression in rat GH3 cells. AB - The present study investigated the influence of anti-estrogen treatment (fulvestrant) on pituitary adenoma cell line GH3 biological activity, the estrogen receptor alpha pathway, the WnT pathway, and mechanisms of decreased Wnt inhibitory factor-1 expression in GH3 cells. Results showed that fulvestrant suppressed GH3 cell proliferation and reduced hormone secretion in a dose dependent manner. Estrogen receptor alpha and Wnt4 expression decreased, but Wnt inhibitory factor-1 expression increased in a dose-dependent manner following fulvestrant treatment, and beta-catenin expression remained unchanged. Inhibitors of DNA methylation and histone modification upregulated Wnt inhibitory factor-1 expression. Results suggested that fulvestrant suppressed biological activity of GH3 cells via the estrogen receptor alpha and Wnt pathways. These results suggested that decreased Wnt inhibitory factor-1 expression in GH3 cells played a role in epigenetic mechanisms. Anti-estrogen therapies could provide novel treatments for growth hormone adenomas. PMID- 25806071 TI - DNA degradation within mouse brain and dental pulp cells 72 hours postmortem. AB - In this study, we sought to elucidate the process of DNA degradation in brain and dental pulp cells of mice, within postmortem 0-72 hours, by using the single cell gel electrophoresis assay and professional comet image analysis and processing techniques. The frequency of comet-like cells, the percentage of tail DNA, tail length, tail moment, Olive moment and tail area increased in tandem with increasing postmortem interval. In contrast, the head radius, the percentage of head DNA and head area showed a decreasing trend. Linear regression analysis revealed a high correlation between these parameters and the postmortem interval. The findings suggest that the single cell gel electrophoresis assay is a quick and sensitive method to detect DNA degradation in brain and dental pulp cells, providing an objective and accurate new way to estimate postmortem interval. PMID- 25806072 TI - Erythropoietin upregulates growth associated protein-43 expression and promotes retinal ganglion cell axonal regeneration in vivo after optic nerve crush. AB - In this study, we established a rat model of optic nerve crush to explore the effects of erythropoietin on retinal ganglion cell axonal regeneration. At 15 days after injury in erythropoietin treated rats, retinal ganglion cell densities in regions corresponding to the 1/6, 3/6 and 5/6 ratios of the retinal radius were significantly increased. In addition, the number of growth associated protein-43 positive axons was significantly increased at different distances (50, 250 and 500 MUm) from the crush site after erythropoietin treatment. Erythropoietin significantly increased growth associated protein-43 protein levels in the retina after crush injury, as determined by western blot and immunofluorescence analysis. These results demonstrate that erythropoietin protects injured retinal ganglion cells and promotes axonal regeneration. PMID- 25806074 TI - Skin electrodes transduced signals to the bladder resulting in ameliorated hypomotility in a rabbit model of diabetes. AB - Electric signals from a chest skin electrode can be conducted to the heart and activate contraction. In the present study, normal and diabetic rabbits were stimulated by skin electrode on the abnormal bladder projection area using three levels of exporting voltage (5.84 V, 8.00 V, and 11.00 V). Results demonstrated significantly attenuated electric signals from both groups, in particular the diabetes group. The skin electrode signals were conducted to the bladders, and all vesical signals increased according to strength of stimulating signals from the skin electrode. However, vesical signals from diabetic rabbits were less than those from normal rabbits at the same stimulating strength of exporting voltage. Vesical pressures from the two groups increased along with increased vesical signals, but vesical pressure was less those from diabetic rabbits than in normal rabbits (basic status and different stimulating levels). Linear correlation analysis showed a significantly positive correlation between vesical pressure and signal. These results demonstrated that electric signals from skin electrodes resulted in increased vesical pressure, and vesical pressure increased along with stimulation strength. PMID- 25806073 TI - Nerve growth factor and inducible nitric oxide synthase expression in the mesencephalon and diencephalon, as well as visual- and auditory-related nervous tissues, in a macaque model of type 2 diabetes. AB - The present study detected distribution and expression of nerve growth factor and inducible nitric oxide synthase in the mesencephalon and diencephalon, as well as visual- and auditory-related nervous tissues, in a macaque model of type 2 diabetes using immunohistochemistry. Results showed that nerve growth factor expression decreased, but inducible nitric oxide synthase expression increased, in the mesencephalon and diencephalon, as well as visual- and auditory- related nervous tissues. These results suggested that nerve growth factor and inducible nitric oxide synthase play an important role in regulating the development of diabetic visual- and auditory-related diseases. PMID- 25806076 TI - Mycobacterium marinum infection: a case report. AB - The infection by Mycobacterium marinum in humans is relatively uncommon. When it occurs, it mainly affects the skin, usually with a chronic, indolent and benign evolution. The diagnosis requires a high index of suspicion, and a significant delay may be observed between the first symptoms to the final diagnosis. This present case reports a M. marinum infection in an immunocompetent patient that had a chronic undiagnosed injury on the dominant hand for at least five years. The patient had several medical consultations, without proper suspicion, hampering adequate diagnostic investigation. Histopathology detected tuberculoid granulomas, but showed no acid-fast bacilli. The culture in appropriate medium and the polymerase chain reaction-restriction enzyme analysis (PRA)-hsp65 confirmed the diagnosis. Treatment with clarithromycin (1 g/day) for three months was effective. Although uncommon, this infection is a contact zoonosis. Therefore, it is important for clinicians to be aware of this diagnosis and properly guide preventable measures to professionals that are in risk group. PMID- 25806075 TI - Rationale for the use of multifunctional drugs as neuroprotective agents for glaucoma. AB - Glaucoma, the leading cause globally of irreversible blindness, is a neurodegenerative disease characterized by progressive retinal ganglion cell death. To date, no drug has been shown to prevent the retinal ganglion cell loss associated with glaucoma. Multiple mechanisms lead to ganglion cell death in glaucoma, suggesting that a neuroprotectant that has a single mode of action, like memantine, would have a limited positive effect at slowing down ganglion cell death. Conversely, simultaneously targeting several factors may be the best therapeutic approach to improve outcomes. Multifunctional drugs are fast gaining acceptance as a strategy for the treatment of complex disorders of the central nervous system, such as Parkinson's disease, Alzheimer's disease and other progressive neurodegenerative diseases. In this paper, we review the current literature on multifunctional drugs and propose a rationale for the use of multifunctional drugs in glaucomatous optic neuropathy. PMID- 25806077 TI - An age-dependent alteration of the respiratory exchange ratio in the db/db mouse. AB - The leptin receptor-deficient db/db mouse is a rodent model of type 2 diabetes and obesity. Diabetes in db/db mice shows an age-dependent progression, with early insulin resistance followed by an insulin secretory defect resulting in profound hyperglycemia. However, there is insufficient data on agedependent changes of energy metabolism in db/db mice. We demonstrated an age-dependent decrease in the respiratory exchange ratio (RER), calculated by a ratio of VO2/VCO2, in db/db mice. The RER determined by indirect calorimetry, was 1.03 in db/db mice under 6 weeks of age, which were similar to those in heterozygote (db/+) and wild-type (+/+) mice. However, RER decreased from approximately 0.9 to 0.8 by 10 weeks of age and subsequently returned to approximately 0.9 at 22 weeks of age. The changes in RER were concurrent with the alterations in body weight and blood glucose level. However, other metabolic indicators such as glucose tolerance, changes in body fat mass, and urinary glucose levels, did not change with age. The results suggested that the energy source utilized in db/db mice changed with the age-related progression of diabetes. PMID- 25806078 TI - Comparative analysis of anti-Helicobacter pylori activities of FEMY-R7 composed of Laminaria japonica and Oenothera biennis extracts in mice and humans. AB - Helicobacter pylori-eliminating effects of FEMY-R7, composed of Laminaria japonica and Oenothera biennis extracts, were investigated in mice and humans. Male C57BL/6 mice were infected with the bacteria by intragastric inoculation (1*10(9) CFU/mouse) 3 times at 2-day intervals, and simultaneously, orally treated twice a day with total 20, 64 or 200 mg/kg/day FEMY-R7 for 2 weeks. In Campylobcter-like organism (CLO)-detection tests on gastric mucosa and feces, FEMY-R7 reduced the urease-positive reactivity in a dose-dependent manner; i.e., the positivity ratios were decreased to 70, 20, and 10% for gastric mocosa and to 80, 50, and 20% for feces. In a clinical sudy, human subjects, confirmed to be infected with Helicobacter pylori, were orally administered twice a day with capsules containing total 100, 320 or 1,000 mg/man/day FEMY-R7 (matching doses for 20, 64 or 200 mg/kg/day, respectively, in mice from a body surface area-based dose translation) for 8 weeks. FEMY-R7 decreased the positivity ratios in feces to 70, 40, and 30%, respectively. In bacterial culture, H. pylori was identified from the CLO-positive stools of mice and humans. The bacterial identification ratios exhibited a good correlation between the matching doses in mice and humans. It is suggested that FEMY-R7 could be a promising functional food without tolerance as an adjunct to reduce the dosage of antibiotics for the treatment of recurrent H. pylori infection. PMID- 25806079 TI - Beneficial effects of ethanol extracts of Red Liriope platyphylla on vascular dysfunction in the aorta of spontaneously hypertensive rats. AB - Some biological effects of Red Liriope platyphylla (RLP) on various chronic diseases including Alzheimer's disease, diabetes and obesity were suggested after a report of the production from Liriope platyphylla (L. platyphylla, LP) roots using a steaming process. To examine the beneficial effects of ethanol extracts RLP (EEtRLP) on the vascular dysfunction of hypertension, alterations in key factors related to vascular regulation and antioxidant conditions were investigated in spontaneously hypertensive rats (SHR) after EEtRLP treatment for 2 weeks. High levels of 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity were detected in 500 or 1,000 mg/mL EEtRLP. Although no significant improvement of systolic blood pressure or aortic wall thickness were observed in the EEtRLP treated group, the expression level of angiotensin converting enzyme (ACE) and ACE2 increased significantly after EEtRLP treatment. Moreover, the concentration of aldosterone and K ion in serum rapidly recovered in the EEtRLP treated group relative to the vehicle treated group. Furthermore, the endothelial nitric oxide synthase (eNOS) expression and superoxide dismutase (SOD) activity were significantly increased in the EEtRLP treated group relative to the vehicle treated group, while the level of malondialdehyde (MDA) and NOx in the serum of the same group were recovered to the level of Wistar Kyoto (WKY) rats. Overall, the results presented herein provide novel evidence that EEtRLP treatment may improve vascular dysfunction in the aorta of the SHR through up regulation of the antioxidant state and down regulation of aldosterone and K ion concentration. These results also suggest that EEtRLP may be a potential candidate for treatment of various chronic diseases showing vascular dysfunction. PMID- 25806080 TI - Effectiveness of the combinational treatment of Laminaria japonica and Cistanche tubulosa extracts in hair growth. AB - Since scalp hair loss has increased recently even in young people, seriously affecting individual's quality of life, the hair growth-stimulating effects of Laminaria japonica extract (LJE) and Cistanche tubulosa extract (CTE) were investigated. After confirming anagen phase of follicles under shaving, male C57BL/6 mice were dermally applied with 3% Minoxidil or orally administered with the combinations of LJE and CTE for 21 days. Minoxidil promoted the hair regrowth and increased gamma-glutamyl transpeptidase (gamma-GTP) and alkaline phosphatase (ALP) activities. In addition, Minoxidil up-regulated epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) levels. Co-administration of LJE and CTE at 54 mg/kg LJE plus 162 mg/kg CTE exerted synergistic promoting effects on the hair regrowth, comparable to 3% Minoxidil. LJE preferentially enhanced ALP activity, while CTE increased both gamma-GTP and ALP activities as well as EGF and VEGF expressions. In vivo air pouch inflammation model, carrageenan-induced vascular exudation and increased nitric oxide and prostaglandin E2 concentrations in the exudates were synergistically suppressed by co-administration of LJE and CTE. In addition, inflammatory cell infiltration was substantially inhibited by the combinational treatment. The results suggest that combinational oral treatment with LJE and CTE in appropriate doses and ratios prevent hair loss and improve alopecia, which might be in part mediated by their anti-inflammatory activities. PMID- 25806081 TI - The relaxing effect of Poncirus fructus and its flavonoid content on porcine coronary artery. AB - Coronary artery disease is a common occurrence in human, and causes enormous social cost. Poncirus fructus (PF), the dried immature fruits of Poncirus trifoliata Rafinesquem, is used in the treatment of womb contraction and dyspepsia, as a prokinetic, and in improving blood circulation. This study was performed to investigate the effects of PF and some of its flavonoids components on the coronary from the pig. The arterial ring was suspended by a pair of stainless steel stirrups in an organ bath. The end of the upper stirrup was connected to an isometric force transducer. A dose-dependent induction of relaxation was observed by both water and 70% ethanol extracts of PF in the porcine coronary artery precontracted with U46619 (100 nM), a stable analogue of the potent vasoconstrictor thromboxane A2. The 70% ethanol extract showed more efficacy than the water extract. Pretreatment of the artery with L-NAME (100 uM), a nitric oxide synthase inhibitor, resulted in a significant reduction in the relaxation induced by PF extract. In addition, ODQ (10 uM), a soluble guanylate cyclase inhibitor, also significantly reduced the effects of PF extracts. Hesperidin, a flavonoid present in PF, induced very weak relaxation of the porcine coronary artery at a high concentration (100 uM), while its aglycone, hesperetin, demonstrated a dose-dependent relaxation. In conclusion, PF extracts induced relaxation in the porcine coronary artery, partially through the nitric oxide-cGMP pathway, and the aglycones of flavonoids might be also involved in the relaxation of the same artery. PMID- 25806082 TI - Estradiol attenuates down-regulation of PEA-15 and its two phosphorylated forms in ischemic brain injury. AB - Estradiol exerts a neuroprotective effect against focal cerebral ischemic injury through the inhibition of apoptotic signals. Phosphoprotein enriched in astrocytes 15 (PEA-15) is mainly expressed in brain that perform anti-apoptotic functions. This study investigated whether estradiol modulates the expression of PEA-15 and two phosphorylated forms of PEA-15 (Ser 104 and Ser 116) in middle cerebral artery occlusion (MCAO)-induced injury and glutamate exposure-induced neuronal cell death. Adult female rats were ovariectomized to remove endogenous estradiol and treated with vehicle or estradiol prior to MCAO. Focal cerebral ischemia was induced by MCAO and cerebral cortices were collected 24 h after MCAO. Western blot analysis indicated that estradiol prevents the MCAO-induced decrease in PEA-15, phospho-PEA-15 (Ser 104), phospho-PEA-15 (Ser 116). Glutamate exposure induced a reduction in PEA-15, phospho-PEA-15 (Ser 104), phospho-PEA-15 (Ser 116) in cultured neurons, whereas estradiol treatment attenuated the glutamate toxicity-induced decrease in the expression of these proteins. It has been known that phosphorylation of PEA-15 is an important step in carrying out its anti-apoptotic function. Thus, these findings suggest that the regulation of PEA-15 phosphorylation by estradiol contributes to the neuroprotective function of estradiol in ischemic brain injury. PMID- 25806083 TI - An optical imaging chamber for viewing living plant cells and tissues at high resolution for extended periods. AB - BACKGROUND: Recent developments in both microscopy and fluorescent protein technologies have made live imaging a powerful tool for the study of plant cells. However, the complications of keeping plant material alive during a long duration experiment while maintaining maximum resolution has limited the use of these methods. RESULTS: Here, we describe an imaging chamber designed to overcome these limitations, which is flexible enough to support a range of sizes of plant materials. We were able use confocal microscopy to follow growth and development of plant cells and tissues over several days. The chamber design is based on a perfusion system, so that the addition of drugs and other experimental treatments are also possible. CONCLUSIONS: In this article we present a design of imaging chamber that makes it possible to image plant material with high resolution for extended periods of time. PMID- 25806084 TI - Bufothionine induced the mitochondria-mediated apoptosis in H22 liver tumor and acute liver injury. AB - BACKGROUND: Bufothionine is an alkaloid in Cinobufacini (Huachansu). This study aims to investigate the effects of bufothionine on liver tumors and acute liver injury. METHODS: In the hepatoprotective experiment, fifty rats were randomly divided into five groups (n = 10): normal saline group, model group, compound glycyrrhizin injection (9.14 mL/kg); cinobufacini injection (3.42 mL/kg) (InjA) and bufothionine (9.77 mL/kg) (BufoA) group. Liver weight indices were recorded to judge the degree of liver swelling, hematoxylin and eosin (H&E) staining of liver tissues was carried out to observe liver histological morphology injury and biochemical indicators including aspartate aminotransferase (AST); alanine aminotransferase (ALT); alkaline phosphatase (ALP); and total bilirubin (TBIL) were determined by modular auto-analyzer. In anti-tumor experiment, H22-tumor bearing mice were randomly divided into five groups (n = 10): normal saline group, model group, cinobufacini injection (InjB) (5.14 mL/kg), bufothionine (8.02 mL/kg) (BufoB) and 5-fluorouracil (5-Fu) (3.42 mL/kg). Tumors were picked out and determined with vernier calipers. Histological morphology of tumors was observed by H&E staining. In SMMC-7721 cells, expressions of proteins related to mitochondria-mediated apoptosis pathway including Bcl-2, Bax, caspase-3, caspase 9, cyto-c, Bid, and p53 were analyzed by western blotting at low, medium, high concentrations of bufothione (3.62 MUg/mL, 18.12 MUg/mL,90.62 MUg/mL). RESULTS: Butothionine relieved CCl4-induced liver morphology, decreased the level of ALT (P =2.46 * 10(-2)) and expressed tendency to decrease other biochemical markers including AST, ALP and TBIL. Butothionine could also promote necrosis of tumor tissue in H22-tumor-bearing mice and restrained tumor growth with 65.16% inhibition rate. Its mechanism might relate to up-regulation of p53 (at low, mediate and high concentration, corresponding P values were 0.142, 0.0257, 0.0162), caspase-3 (P = 0.246, 0.0267 and 0.0236), cyto-c (P = 0.276, 0.0343 and 0.0429), Bid (P = 0.0125, 0.0395 and 0.0132) and Bax (P = 0.563, 0.0492 and 0.0357) in a dose-dependent manner, down-regulation of Bcl-2 expression (P = 0.0232, 0.0178 and 0.0464), but had no significant effects on caspase-9 (P = 0.253, 0.147 and 0.287). CONCLUSION: Bufothionine induced the proteins for the mitochondria-mediated apoptosis that inhibits liver tumors and protects the liver against acute injury. PMID- 25806085 TI - Health system governance to support integrated mental health care in South Africa: challenges and opportunities. AB - BACKGROUND: While South Africa has a new policy framework supporting the integration of mental health care into primary health care, this is not sufficient to ensure transformation of the health care system towards integrated primary mental health care. Health systems strengthening is needed, incorporating, inter alia, capacity building and resource inputs, as well as good governance for ensuring that the relevant policy imperatives are implemented. OBJECTIVES: To identify systemic factors within institutional and policy contexts that are likely to facilitate or impede the implementation of integrated mental health care in South Africa. METHODS: Semi-structured qualitative interviews were conducted with 17 key stakeholders in the Department of Health and Department of Social Development at national level, at provincial level in the North West Province, and at district level in the Dr Kenneth Kaunda district. Participants were purposively identified based on their positions and job responsibilities. Interview questions were guided by a hybrid of Siddiqi et al.'s governance framework principles and Mikkelsen-Lopez et al.'s health system governance approach. Data were analysed using framework analysis in NVivo. RESULTS: Facilitative factors included the recent mental health care policy framework and national action plan that embraces integrated care using a task sharing model and provides policy imperatives for the establishment of district mental health teams to facilitate the development and implementation of district mental health care plans; the roll out of the integrated chronic disease service delivery platform that can be leveraged to increase access and resources as well as decrease stigma; and the presence of NGOs that can assist with service delivery. Challenges included the low prioritisation and stigmatisation of mental illness; weak managerial and planning capacity to develop and implement mental health care plans at provincial and district level; poor pre-service training of generalists in mental health care; weak orientation to integrated care; high staff turnover; weak intersectoral coordination; infrastructural constraints; and no dedicated mental health budget. CONCLUSION: This study identifies strategies to support and improve integrated mental health care in primary health care services. PMID- 25806086 TI - DNA demethylation by 5-aza-2'-deoxycytidine is imprinted, targeted to euchromatin, and has limited transcriptional consequences. AB - BACKGROUND: DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2' deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. RESULTS: We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic 'imprint' of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci-encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. CONCLUSIONS: Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation. PMID- 25806087 TI - Deciphering chicken gut microbial dynamics based on high-throughput 16S rRNA metagenomics analyses. AB - BACKGROUND: Chicken gut microbiota has paramount roles in host performance, health and immunity. Understanding the topological difference in gut microbial community composition is crucial to provide knowledge on the functions of each members of microbiota to the physiological maintenance of the host. The gut microbiota profiling of the chicken was commonly performed previously using culture-dependent and early culture-independent methods which had limited coverage and accuracy. Advances in technology based on next-generation sequencing (NGS), offers unparalleled coverage and depth in determining microbial gut dynamics. Thus, the aim of this study was to investigate the ileal and caecal microbiota development as chicken aged, which is important for future effective gut modulation. MATERIAL AND METHODS: Ileal and caecal contents of broiler chicken were extracted from 7, 14, 21 and 42-day old chicken. Genomic DNA was then extracted and amplified based on V3 hyper-variable region of 16S rRNA. Bioinformatics, ecological and statistical analyses such as Principal Coordinate Analysis (PCoA) was performed in mothur software and plotted using PRIMER 6. Additional analyses for predicted metagenomes were performed through PICRUSt and STAMP software package based on Greengenes databases. RESULTS: A distinctive difference in bacterial communities was observed between ilea and caeca as the chicken aged (P < 0.001). The microbial communities in the caeca were more diverse in comparison to the ilea communities. The potentially pathogenic bacteria such as Clostridium were elevated as the chicken aged and the population of beneficial microbe such as Lactobacillus was low at all intervals. On the other hand, based on predicted metagenomes analysed, clear distinction in functions and roles of gut microbiota such as gene pathways related to nutrient absorption (e.g. sugar and amino acid metabolism), and bacterial proliferation and colonization (e.g. bacterial motility proteins, two-component system and bacterial secretion system) were observed between ilea and caeca, respectively (P < 0.05). CONCLUSIONS: The caeca microbial communities were more diverse in comparison to ilea. The main functional differences between the two sites were found to be related to nutrient absorption and bacterial colonization. Based on the composition of the microbial community, future gut modulation with beneficial bacteria such as probiotics may benefit the host. PMID- 25806088 TI - Obesity phenotypes in urban and rural Cameroonians: a cross-sectional study. AB - BACKGROUND: Despite the increasing prevalence of diabetes and other health consequences of obesity, little is known on the metabolic profile across categories of body mass index (BMI) among African populations. We therefore assessed the prevalence and distribution of body size phenotypes among urban and rural Cameroonians. METHODS: Adults (n = 1628; 41% rural dwellers) aged 24-74 years in 1994 provided data on BMI and metabolic health, defined on the basis of elevated levels of blood pressure (BP); triglycerides, fasting plasma glucose (FPG), and insulin resistance as assessed with homeostasis model assessment (HOMA). Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Metabolic measures include elevated blood pressure; elevated triglycerides (>=150 mg/dL or 1.69mmo/L), elevated fasting plasma glucose (>=100 mg/dl or 5.6 mmol/L or documented use of antidiabetic medications), and elevated homeostasis model assessment of insulin resistance value (HOMA-IR > 90(th) percentile). RESULTS: A total of 25.2% of participants were overweight yet metabolically healthy (<1 abnormality) and 10.1% were obese yet metabolically healthy, whereas 1.4% were normal weight but metabolically abnormal (>=2 abnormalities). Proportion of rural dwellers with abnormal metabolic phenotype across normal-weight, overweight, obese categories were 2.9%, 0.8% and 0.3%, respectively; and 0 .3%, 2.2% and 2.6% among urban dwellers. Metabolically abnormal participants increased linearly across BMI categories (p < 0.001). BMI categories and metabolic status interacted to affect age, gender, BMI, FPG, triglycerides, and BP status distributions (all p < 0.04). Metabolic status and residence (rural vs. urban) interacted to influence the distribution across BMI categories of diastolic BP, BMI, waist circumference, fasting and 2 hour glucose, triglycerides, HOMA-IR, and prevalent diabetes (all p < 0.005), with differential occurrence of BMI categories and metabolic status among urban and rural participants. CONCLUSIONS: Metabolic healthy obesity and obesity with a favorable cardiometabolic profile are not uncommon among Cameroonians, including among rural dwellers; but the latter group tended to have a better profile. PMID- 25806089 TI - An epigenetic map of age-associated autosomal loci in northern European families at high risk for the metabolic syndrome. AB - BACKGROUND: The prevalence of chronic diseases such as cancer, type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease increases with age in all populations. Epigenetic features are hypothesized to play important roles in the pathophysiology of age-associated diseases, but a map of these markers is lacking. We searched for genome-wide age-associated methylation signatures in peripheral blood of individuals at high risks for MetS by profiling 485,000 CpG sites in 192 individuals of Northern European ancestry using the Illumina HM450 array. Subjects (ages 6-85 years) were part of seven extended families, and 73% of adults and 32% of children were overweight or obese. RESULTS: We found 22,122 genome-wide significant age-associated CpG sites (P alpha=0.05 = 3.65 * 10(-7) after correction for multiple testing) of which 14,155 are positively associated with age while 7,967 are negatively associated. By applying a positional density based clustering algorithm, we generated a map of epigenetic 'hot-spots' of age associated genomic segments, which include 290 age-associated differentially methylated CpG clusters (aDMCs), of which 207 are positively associated with age. Gene/pathway enrichment analyses were performed on these clusters using FatiGO. Genes localized to both the positively (n = 241) and negatively (n = 16) age associated clusters are significantly enriched in specific KEGG pathways and GO terms. The most significantly enriched pathways are the hedgehog signaling pathway (adjusted P = 3.96 * 10(-3)) and maturity-onset diabetes of the young (MODY) (adjusted P = 6.26 * 10(-3)) in the positive aDMCs and type I diabetes mellitus (adjusted P = 3.69 * 10(-7)) in the negative aDMCs. We also identified several epigenetic loci whose age-associated change rates differ between subjects diagnosed with MetS and those without. CONCLUSION: We conclude that in a family cohort at high risk for MetS, age-associated epigenetic features enrich in biological pathways important for determining the fate of fat cells and for insulin production. We also observe that several genes known to be related to MetS show differential epigenetic response to age in individuals with and without MetS. PMID- 25806090 TI - Genome-scale hypomethylation in the cord blood DNAs associated with early onset preeclampsia. AB - BACKGROUND: Preeclampsia is one of the leading causes of fetal and maternal morbidity and mortality worldwide. Preterm babies of mothers with early onset preeclampsia (EOPE) are at higher risks for various diseases later on in life, including cardiovascular diseases. We hypothesized that genome-wide epigenetic alterations occur in cord blood DNAs in association with EOPE and conducted a case control study to compare the genome-scale methylome differences in cord blood DNAs between 12 EOPE-associated and 8 normal births. RESULTS: Bioinformatics analysis of methylation data from the Infinium HumanMethylation450 BeadChip shows a genome-scale hypomethylation pattern in EOPE, with 51,486 hypomethylated CpG sites and 12,563 hypermethylated sites (adjusted P <0.05). A similar trend also exists in the proximal promoters (TSS200) associated with protein-coding genes. Using summary statistics on the CpG sites in TSS200 regions, promoters of 643 and 389 genes are hypomethylated and hypermethylated, respectively. Promoter-based differential methylation (DM) analysis reveals that genes in the farnesoid X receptor and liver X receptor (FXR/LXR) pathway are enriched, indicating dysfunction of lipid metabolism in cord blood cells. Additional biological functional alterations involve inflammation, cell growth, and hematological system development. A two-way ANOVA analysis among coupled cord blood and amniotic membrane samples shows that a group of genes involved in inflammation, lipid metabolism, and proliferation are persistently differentially methylated in both tissues, including IL12B, FAS, PIK31, and IGF1. CONCLUSIONS: These findings provide, for the first time, evidence of prominent genome-scale DNA methylation modifications in cord blood DNAs associated with EOPE. They may suggest a connection between inflammation and lipid dysregulation in EOPE associated newborns and a higher risk of cardiovascular diseases later in adulthood. PMID- 25806091 TI - Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy. AB - BACKGROUND: Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m(2)/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m(2)/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed. RESULTS: Thirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 MUg/g tumor. The platinum concentration increased 3- to 18 fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival. CONCLUSIONS: Oxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration. PMID- 25806092 TI - Methylation analysis of histone H4K12ac-associated promoters in sperm of healthy donors and subfertile patients. AB - BACKGROUND: Histone to protamine exchange and the hyperacetylation of the remaining histones are hallmarks of spermiogenesis. Acetylation of histone H4 at lysine 12 (H4K12ac) was observed prior to full decondensation of sperm chromatin after fertilization suggesting an important role for the regulation of gene expression in early embryogenesis. Similarly, DNA methylation may contribute to gene silencing of several developmentally important genes. Following the identification of H4K12ac-binding promoters in sperm of fertile and subfertile patients, we aimed to investigate whether the depletion of histone-binding is associated with aberrant DNA methylation in sperm of subfertile men. Furthermore, we monitored the transmission of H4K12ac, 5-methylcytosine (5mC) and 5 hydroxymethylcytosine (5hmC) from the paternal chromatin to the embryo applying mouse in vitro fertilization and immunofluorescence. RESULTS: Chromatin immunoprecipitation (ChIP) with anti-H4K12ac antibody was performed with chromatin isolated from spermatozoa of subfertile patients with impaired sperm chromatin condensation assessed by aniline blue staining. Fertile donors were used as control. DNA methylation analysis of selected H4K12ac-interacting promoters in spermatozoa was performed by pyrosequencing. Depletion of binding sites for H4K12ac was observed within the following developmentally important promoters: AFF4, EP300, LRP5, RUVBL1, USP9X, NCOA6, NSD1, and POU2F1. We found 5% to 10% hypomethylation within CpG islands of selected promoters in the sperm of fertile donors, and it was not significantly altered in the subfertile group. Our results demonstrate that the H4K12ac depletion in selected developmentally important promoters of subfertile patients was not accompanied by a change of DNA methylation. Using a murine model, immunofluorescence revealed that H4K12ac co localize with 5mC in the sperm nucleus. During fertilization, when the pronuclei are formed, the paternal pronucleus exhibits a strong acetylation signal on H4K12, while in the maternal pronucleus, there is a permanent increase of H4K12ac until pronuclei fusion. Simultaneously, there is an increase of the 5hmC signal and a decrease of the 5mC signal. CONCLUSIONS: We suggest that aberrant histone acetylation within developmentally important gene promoters in subfertile men, but not DNA methylation, may reflect insufficient sperm chromatin compaction affecting the transfer of epigenetic marks to the oocyte. PMID- 25806093 TI - RARbeta2 hypermethylation is associated with poor recurrence-free survival in never-smokers with adenocarcinoma of the lung. AB - BACKGROUND: This study was aimed at investigating if the effect of RARbeta2 hypermethylation on recurrence-free survival (RFS) in non-small cell lung cancer (NSCLC) depends on one's smoking status and specific interacting proteins. RESULTS: We retrospectively analyzed the expressions of five proteins using immunohistochemistry in archival formalin-fixed and paraffin-embedded tissues from 578 NSCLC patients who had undergone surgical resection from 1994 through 2004. Promoter methylation of RARbeta2 was assessed by bisulfite pyrosequencing. Recurrence was found in 268 (46%) of 578 NSCLCs with a median follow-up period of 4.8 years. Overexpression of beta-catenin, c-MET, cyclin D1, and EGFR occurred in 55%, 72%, 51%, and 41% of the patients, respectively. E-cadherin expression was negative in 62% of the patients, and RARbeta2 hypermethylation was found in 37%. The abnormal expression of c-MET (P = 0.002) and EGFR (P = 0.001) was found to be highly prevalent in never-smokers. RARbeta2 hypermethylation was significantly associated with poor recurrence-free survival (RFS) in 128 never-smokers with adenocarcinoma (P = 0.01) For parsimonious model building, the five proteins were clustered into three groups (beta-catenin and E-cadherin; c-MET; cyclin D1 and EGFR) by an unsupervised hierarchical clustering and were included in a multivariate analysis. Cox proportional hazard analysis showed that RARbeta2 hypermethylation was significantly associated with poor RFS in 128 never-smokers with adenocarcinoma (adjusted hazard ratio [HR] = 2.19, 95% confidence interval [CI] = 1.28 to 3.47; P = 0.009), after adjusting for interacting proteins. CONCLUSIONS: The present study suggests that RARbeta2 hypermethylation may be an independent prognostic factor of RFS in never-smokers with adenocarcinoma of the lung. PMID- 25806094 TI - Energy coding in neural network with inhibitory neurons. AB - This paper aimed at assessing and comparing the effects of the inhibitory neurons in the neural network on the neural energy distribution, and the network activities in the absence of the inhibitory neurons to understand the nature of neural energy distribution and neural energy coding. Stimulus, synchronous oscillation has significant difference between neural networks with and without inhibitory neurons, and this difference can be quantitatively evaluated by the characteristic energy distribution. In addition, the synchronous oscillation difference of the neural activity can be quantitatively described by change of the energy distribution if the network parameters are gradually adjusted. Compared with traditional method of correlation coefficient analysis, the quantitative indicators based on nervous energy distribution characteristics are more effective in reflecting the dynamic features of the neural network activities. Meanwhile, this neural coding method from a global perspective of neural activity effectively avoids the current defects of neural encoding and decoding theory and enormous difficulties encountered. Our studies have shown that neural energy coding is a new coding theory with high efficiency and great potential. PMID- 25806095 TI - Decisions about prophylactic gynecologic surgery: a qualitative study of the experience of female Lynch syndrome mutation carriers. AB - BACKGROUND: Women who carry a mutation for Lynch syndrome face complex decisions regarding strategies for managing their increased cancer risks. At present, there is limited understanding of the factors influencing women's prophylactic surgery decisions. METHODS: As part of an exploratory pilot project, semi-structured interviews were conducted with 10 women who were Lynch syndrome mutation carriers and had made prophylactic surgery decisions. Nine of 10 women had chosen to undergo prophylactic hysterectomy and/or oophorectomy as a means of managing their increased gynecological cancer risks. RESULTS: Study findings revealed that surgery decisions were influenced by multiple factors, including demographic variables such as age and parity, as well as psychosocial factors such as cancer worry, in addition to personal and social knowledge of gynecological cancer. While all women were satisfied with their surgery decision, some reported they were not fully informed about the negative impact on their quality of life post surgery (e.g., complications of surgically-induced menopause), nor about the potential for, or risks and benefits of, hormone replacement therapy. CONCLUSIONS: Study findings highlight some of the factors associated with prophylactic surgery decisions and women's perceptions about pre-surgical information provision and needs. Suggestions are made for improving the information and support provided to female carriers of a Lynch syndrome mutation. PMID- 25806096 TI - The value of high-resolution MRI technique in patients with rectal carcinoma: pre operative assessment of mesorectal fascia involvement, circumferential resection margin and local staging. AB - BACKGROUND: The purpose of the study was to identify the accuracy of high resolution MRI in the pre-operative assessment of mesorectal fascia involvement, circumfrential resection margin (CRM) and local staging in patients with rectal carcinoma. MATERIAL/METHODS: The study included 56 patients: 32 male and 24 female. All patients underwent high-resolution MRI and had confirmed histopathological diagnosis of rectal cancer located within 15 cm from the anal verge, followed by surgery. MRI findings were compared with pathological and surgical results. RESULTS: The overall accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI-based T-staging were 92.8, 88.8%, 96.5%, 96%, and 90.3%, respectively. The accuracy, sensitivity, specificity, PPV, and NPV of MRI-based assessment of CRM were 94.6%, 84.6%, 97.6%, 91.4, and 94.6%, respectively. The accuracy, sensitivity, specificity, PPV, and NPV of MRI-based N-staging were 82.1%, 75%, 67.3%, 60%, and 86.1%, respectively. CONCLUSIONS: Preoperative high-resolution rectal MRI is accurate in predicting tumor stage and CRM involvement. MRI is a precise diagnostic tool to select patients who may benefit from neo-adjuvant therapy and to avoid overtreatment in those patients who can proceed directly to surgery. PMID- 25806097 TI - Sclerosing adenosis of the breast: report of two cases and review of the literature. AB - BACKGROUND: Sclerosing adenosis is a benign, usually asymptomatic lobulocentric proliferative process that involves both the epithelial and the mesenchymal component of the breast. It is commonly an incidental finding in perimenopausal women undergoing screening mammography. CASE REPORT: We reported on two patients with sclerosing adenosis assessed with mammography, ultrasound, and contrast enhanced magnetic resonance imaging. Case 1 was a 21-year-old woman with a palpable lesion in her right breast that was depicted as an irregular mass on contrast-enhanced magnetic resonance imaging. Case 2 was an asymptomatic 42-year old woman with suspicious ultrasound findings in her left breast; contrast enhanced magnetic resonance imaging showed regional non-mass-like enhancement associated with increased vascularity. Both patients underwent ultrasound-guided vacuum-assisted biopsy. Sclerosing adenosis does not have distinctive radiological features and can mimic a malignant growth process, thus requiring a diagnostic biopsy. CONCLUSIONS: SA is a common, benign, generally asymptomatic proliferative lesion of the breast. It is associated with a doubling of the risk of developing breast carcinoma, even though its role in carcinogenesis remains to be elucidated. It does not exhibit distinctive MG, US or even MRI features. Since it may mimic a carcinoma it requires further investigation with a diagnostic biopsy. PMID- 25806098 TI - Coexistence of left internal carotid agenesis, klippel-feil syndrome and postaxial polydactyly. AB - BACKGROUND: Internal carotid artery agenesis is a rare anomaly that can be clinically asymptomatic. Klippel-Feil syndrome is a skeletal malformation characterized by vertebral fusion. Presence of postaxial polydactyly is suggestive of an underlying syndrome. CASE REPORT: We report a rare case of a 44 year-old patient with non-specific symptoms and an association between these three rare abnormalities. Vascular anomalies were found using intracranial MR angiography and multi-detector CT angiography of the supraaortic arteries. CONCLUSIONS: Presence of a single aforementioned anomaly requires cautious imaging assessment in order to detect possible associated anomalies and avoid diagnostic pitfalls. A possible common genetic background could explain the coexistence of these three anomalies. PMID- 25806100 TI - Imaging spectrum of cerebellar pathologies: a pictorial essay. AB - The cerebellum is a crucial structure of hindbrain which helps in maintaining motor tone, posture, gait and also coordinates skilled voluntary movements including eye movements. Cerebellar abnormalities have different spectrum, presenting symptoms and prognosis as compared to supratentorial structures and brainstem. This article intends to review the various pathological processes involving the cerebellum along with their imaging features on MR, which are must to know for all radiologists, neurologists and neurosurgeons for their prompt diagnosis and management. PMID- 25806101 TI - HELLP Syndrome at 17 Weeks Gestation: A Rare and Catastrophic Phenomenon. AB - HELLP syndrome is a collection of symptoms described as hemolysis, elevated liver enzymes and low platelets. HELLP syndrome complicates 0.01-0.6% of pregnancies and can be considered a severe variant of preeclampsia. The occurrence of HELLP syndrome diagnosed before the 20th week of gestation has been most commonly reported in association with antiphospholipid antibody syndrome (APS) or triploid chromosomal anomalies. A 41-year-old primigravida was admitted at 17 weeks and 6 days gestation with hypertension, proteinuria, hemolytic anemia and acute renal injury. She was diagnosed with HELLP syndrome, and subsequently suffered from an intrauterine fetal demise. After delivery, the clinical manifestations of HELLP syndrome resolved within 7 days with the exception of her acute renal failure. Interdisciplinary teams of physicians were able to exclude other imitators of preeclampsia, such as hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), APS, lupus and acute fatty liver of pregnancy. This case is difficult to diagnose, given the similar presentation of several microangiopathic hemolytic anemias. The clinical manifestations and laboratory findings of HELLP and its mimicking conditions seem as if they are mirror images of each other. However, the discrete differences in our patient presentation, clinical findings, laboratory results and overall postpartum course leave HELLP syndrome as the most consistent diagnosis. It is imperative to investigate for all possible etiologies as HELLP syndrome at 17 weeks gestation is extremely rare and mimicking conditions may require alternative management strategies. PMID- 25806099 TI - High-Intensity Focused Ultrasound (HIFU) in Localized Prostate Cancer Treatment. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) applies high-intensity focused ultrasound energy to locally heat and destroy diseased or damaged tissue through ablation. This study intended to review HIFU to explain the fundamentals of HIFU, evaluate the evidence concerning the role of HIFU in the treatment of prostate cancer (PC), review the technologies used to perform HIFU and the published clinical literature regarding the procedure as a primary treatment for PC. MATERIAL/METHODS: Studies addressing HIFU in localized PC were identified in a search of internet scientific databases. The analysis of outcomes was limited to journal articles written in English and published between 2000 and 2013. RESULTS: HIFU is a non-invasive approach that uses a precisely delivered ultrasound energy to achieve tumor cell necrosis without radiation or surgical excision. In current urological oncology, HIFU is used clinically in the treatment of PC. Clinical research on HIFU therapy for localized PC began in the 1990s, and the majority of PC patients were treated with the Ablatherm device. CONCLUSIONS: HIFU treatment for localized PC can be considered as an alternative minimally invasive therapeutic modality for patients who are not candidates for radical prostatectomy. Patients with lower pre-HIFU PSA level and favourable pathologic Gleason score seem to present better oncologic outcomes. Future advances in technology and safety will undoubtedly expand the HIFU role in this indication as more of patient series are published, with a longer follow-up period. PMID- 25806102 TI - Metabolomics and partial least square discriminant analysis to predict history of myocardial infarction of self-claimed healthy subjects: validity and feasibility for clinical practice. AB - BACKGROUND: The dynamics of metabolomics in establishing a prediction model using partial least square discriminant analysis have enabled better disease diagnosis; with emphasis on early detection of diseases. We attempted to translate the metabolomics model to predict the health status of the Orang Asli community whom we have little information. The metabolite expressions of the healthy vs. diseased patients (cardiovascular) were compared. A metabotype model was developed and validated using partial least square discriminant analysis (PLSDA). Cardiovascular risks of the Orang Asli were predicted and confirmed by biochemistry profiles conducted concurrently. RESULTS: Fourteen (14) metabolites were determined as potential biomarkers for cardiovascular risks with receiver operating characteristic of more than 0.7. They include 15S-HETE (AUC = 0.997) and phosphorylcholine (AUC = 0.995). Seven Orang Asli were clustered with the patients' group and may have ongoing cardiovascular risks and problems. This is supported by biochemistry tests results that showed abnormalities in cholesterol, triglyceride, HDL and LDL levels. CONCLUSIONS: The disease prediction model based on metabolites is a useful diagnostic alternative as compared to the current single biomarker assays. The former is believed to be more cost effective since a single sample run is able to provide a more comprehensive disease profile, whilst the latter require different types of sampling tubes and blood volumes. PMID- 25806103 TI - Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. AB - BACKGROUND: Based on the hypothesis that cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary or alternative therapy for treatment of malignant gliomas. CASE PRESENTATION: We report here our experience in treating two glioma patients with an IRB-approved energy-restricted ketogenic diet (ERKD) protocol as monotherapy and review the literature on KD therapy for human glioma patients. An ERKD protocol was used in this pilot clinical study. In addition to the two patients who enrolled in this study, we also reviewed findings from 30 other patients, including 5 patients from case reports, 19 patients from a clinical trial reported by Rieger and 6 patients described by Champ. A total of 32 glioma patients have been treated using several different KD protocols as adjunctive/complementary therapy. The two patients who enrolled in our ERKD pilot study were monitored with twice daily measurements of blood glucose and ketones and daily weights. However, both patients showed tumor progression while on the ERKD therapy. Immunohistochemistry reactions showed that their tumors had tissue expression of at least one of the two critical mitochondrial ketolytic enzymes (succinyl CoA: 3-oxoacid CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1). The other 30 glioma patients in the literature were treated with several different KD protocols with varying responses. Prolonged remissions ranging from more than 5 years to 4 months were reported in the case reports. Only one of these patients was treated using KD as monotherapy. The best responses reported in the more recent patient series were stable disease for approximately 6 weeks. No major side effects due to KD have been reported in any of these patients. CONCLUSIONS: We conclude that 1. KD is safe and without major side effects; 2. ketosis can be induced using customary foods; 3. treatment with KD may be effective in controlling the progression of some gliomas; and 4. further studies are needed to determine factors that influence the effectiveness of KD, whether as a monotherapy, or as adjunctive or supplemental therapy in treating glioma patients. TRIAL REGISTRATION: ClinicalTrials.gov# NCT01535911. PMID- 25806104 TI - Factors associated with primary transmission of multidrug-resistant tuberculosis compared with healthy controls in Henan Province, China. AB - BACKGROUND: It is estimated that there are about 74,000 primary multidrug resistant tuberculosis (MDR-TB) patients per year according to the prevalence of MDR-TB of 5.7% among new TB patients in China. Thus, the risks of primary transmission of MDR-TB require further attention. This study aimed to identify the factors associated with primary transmission of MDR-TB in Henan province, where the number of new TB patients is ranked second highest in China. METHODS: A 1:1 matched case-control study was conducted in Henan, China. Cases were primary MDR-TB patients who were individually matched with a healthy control without TB from the same neighborhood. The study was conducted from July 2013 to June 2014. Both case and control were matched by age (+/-5 years) and sex. Conditional logistic regression was used to compute adjusted odds ratios (AORs) with corresponding 95% confidence intervals (CIs) for risk factors associated with primary MDR-TB. RESULTS: For the study, 146 pairs of participants were recruited. The final multivariable logistic regression model disclosed that after adjusting for age and sex, primary MDR-TB cases were more likely to be single (AOR, 5.4; 95% CI, 1.4-20.7), earn an annual income of <= 12,000 yuan (RMB) (AOR, 9.9; 95% CI, 2.0-48.1), experience more life pressure/stress (AOR, 10.8; 95% CI, 2.8 41.5), not be medically insured (AOR, 50.1; 95% CI, 8.2-306.8), and suffer from diabetes, cardiovascular disease or other respiratory diseases, or cancer (AOR, 57.1; 95% CI, 8.6-424.2). CONCLUSIONS: In order to control primary transmission of MDR-TB in China, we recommend that improving the social support, living standards and medical security of the lower social class become a priority. PMID- 25806105 TI - Combination of IFNalpha and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction. AB - BACKGROUND: BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8(+) T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs. METHODS: Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data. RESULTS: Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNalpha and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNalpha or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNalpha + poly-I:C regimen did not show additional advantage. CONCLUSIONS: The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNalpha and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases. PMID- 25806107 TI - Preamble to the 2015 SITC immunotherapy biomarkers taskforce. AB - The Society for Immunotherapy of Cancer (SITC) has regularly hosted workshops and working groups focused on immunologic monitoring and immune biomarkers. Due to advances in cancer immunotherapy, including positive results from clinical trials testing new agents and combinations, emerging new technologies for measuring aspects of immunity, and novel candidate biomarkers from early phase trials, the SITC Immune Biomarkers Taskforce has reconvened to review the state of the art, identify current hurdles to further success and to make recommendations to the field. Topics being addressed by individual working groups include: (1) validation of candidate biomarkers, (2) identification of the most promising technologies, (3) testing of high throughput immune signatures and (4) investigation of the pre-treatment tumor microenvironment. Resultant recommendations will be published in JITC. PMID- 25806106 TI - Immunotherapeutic approaches to ovarian cancer treatment. AB - Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for ovarian cancer patients are inadequate. Immunotherapy offers a novel and promising therapeutic strategy for treating ovarian tumors. Following the demonstration of the immunogenicity of ovarian tumors, multiple immunotherapeutic modalities have been developed. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery. PMID- 25806109 TI - Immune therapy of metastatic melanoma developing after allogeneic bone marrow transplant. AB - Metastatic melanoma is frequently treated with immune activating therapy, which poses a theoretical risk of inducing graft versus host disease (GVHD) in those who have received allogeneic stem cell transplantation. The literature reporting the safety of immunotherapy in post transplant patients is limited. We report two patients with metastatic melanoma who received treatment with immunotherapy after allogeneic stem cell transplantation that did not result in GVHD. PMID- 25806110 TI - Highly cadmium tolerant fungi: their tolerance and removal potential. AB - BACKGROUND: Soil and effluent of lead and zinc industries contain high concentration of cadmium. The present study was conducted to isolate tolerant fungal strains from cadmium -polluted sites in Zanjan province, Iran. METHODS: Cadmium tolerance and bioremediation capacity of seven isolates including Aspergilus versicolor, Aspergillus fumigatus, Paecilomyces sp.9, Paecilomyces sp.G, Terichoderma sp, Microsporum sp,Cladosporium sp were determined. RESULTS: Minimum inhibitory concentration values among 1,000-4,000 mg l-(1)proved great ability of isolated strains to survive in cadmium polluted environments. The most tolerant fungi, Aspergilus versicolor, showed tolerance index of 0.8 in 100 mg l (1) cadmium agar media. Fungal resistance against cadmium is depended directly on strain's biological function. A. versicolor was found to bioaccumulate over7 mg of cadmium per 1 g of mycelium, followed by 5.878, 5.243, and 5.075, 4.557 by Paecilomyces sp, Aspergilus fumigatus, Microsporum sp and Terichoderma sp, respectively. CONCLUSION: It can be noted that tolerance of the strains appears to be independent from bioaccumulation capacity. Finally, the results indicated that A. versicolor could be a prospective candidate for bioremediation processes. PMID- 25806111 TI - Modelling and evaluation of light railway system's noise using neural predictors. AB - BACKGROUND: Noise is defined as a sound or series of sounds that are considered to be invasive, irritating, objectionable and disruptive to the quality of daily life. Noise is one of the environmental pollutants, and in cities it is usually originated from road traffic, railway traffic, airports, industry etc. The tram is generally considered as environmentally friendly, namely non-polluting and silent. However complaints from residents living along the tramway lines prove that it may sometimes cause annoyance. In this study, a Global Pointing System (GPS) receiver for determining the sampling locations and a frequency based noise measurement system for collecting the noise data are used to analyse the noise level in the city centre. Both environmental (background) and tram noises are measured. RESULTS: Three types of neural networks are used to predict the noises of the tram and environment. The results of three approaches indicate that the proposed neural network with Radial Basis Function (RBF) has superior performance to predict the noises of the tram and environment. CONCLUSIONS: For making a decision about transportation planning, this network model can help urban planners for evaluating and/or isolating the tram noise in terms of human health. PMID- 25806112 TI - Biosorption of Hg(II) and Cu(II) by biomass of dried Sargassum fusiforme in aquatic solution. AB - The biosorption of heavy metals Hg(II) and Cu(II) from aquatic solution by biomass of dried Sargassum fusiforme was studied in the paper. The Sargassum fusiforme was able to absorb appreciable amount of mercury and copper from the aquatic solutions within 60 min of contact time with the metal solution and exhibited high removal of mercury and copper at low equilibrium concentrations. The specific adsorption of both Hg(II) and Cu(II) increased at low concentration of biomass and decreased when biomass concentration exceeded 2.0 g/L. The binding of mercury followed Freundlich model while copper supported Langmuir isotherm for adsorption with their r(2) values of 0.971 and 0.923, respectively. The maximum adsorption per unit masses of Sargassum fusiforme (mg/L) at equilibrium (qmax) for Hg(II) and Cu(II) were calculated to be 30.86 and 7.69 mg/g, respectively. The biosorption by Sargassum fusiforme was best described using a pseudo-second order kinetic model for copper and mercury ions in solution in the study. The adsorption was pH dependent as the maximum mercury biosorption and copper adsorption was happened at solution pH of 8-10. PMID- 25806113 TI - Mindfulness-based stress reduction in patients with interstitial lung diseases: a pilot, single-centre observational study on safety and efficacy. AB - BACKGROUND: Chronic, progressive respiratory symptoms are associated with great psychological and emotional impact in patients suffering from interstitial lung disease (ILD). This single-centre pilot study evaluated for the first time the safety, feasibility and efficacy of a Mindfulness Based Stress Reduction Program (MBSR) in a group of patients with ILD. METHODS: Prospective observational study set in a university hospital ILD outpatient clinic. Nineteen patients with different ILDs were recruited 2 months prior to the start of the 8-week MBSR program and followed up for 12 months. Primary outcomes were program safety and feasibility, while secondary outcomes were changes in moods and stress (assessed by Profile Of Mood State (POMS) and Perceived Stress Scale (PSS) questionnaires), symptoms (Shortness Of Breath (SOB) and Cough And Sputum Assessment (CASA-Q) questionnaires), lung function and exercise tolerance at 12 months. RESULTS: Two patients (10.5%) dropped out in the observational period before the start of the MBSR intervention because of non-respiratory causes. All 17 patients who entered the 8-week MBSR program managed to complete it with an adherence average of eight sessions of nine. No adverse events related to the mindfulness training were reported. Statistically significant improvements in the POMS total score and in several individual items of POMS and PSS were observed throughout the study. However, respiratory questionnaire scores, lung function and exercise tolerance did not show a significant difference over time. CONCLUSIONS: An MBSR program appears to be safe and feasible in patients with ILD, and might affect perceived moods and stress producing a positive and lasting improvement in several stress related negative domains. These findings pave the way to larger (possibly multicentre), randomised, controlled confirmatory trials. PMID- 25806114 TI - Patients' practices and experiences of using nebuliser therapy in the management of COPD at home. AB - BACKGROUND AND AIM: How patients use their nebulisers at home is vital to ensure effective treatment and optimal health outcomes for patients with chronic obstructive pulmonary disease (COPD). The aim of the study was to identify the practicalities and problems associated with nebuliser use by patients with COPD at home, which may impact on the safety and effectiveness of therapy. DESIGN AND SETTING: A cross-sectional descriptive study in which participants were recruited from two levels of care: primary care, involving 38 GP practices in North West London, and intermediate care with a major acute hospital. METHOD: In-depth interviews were conducted with a representative sample of 50 patients with COPD using nebulisers in their home, recruited from general practice populations and at hospital discharge. A checklist was used to record activities and patients demonstrated use of their nebuliser. Qualitative procedures were employed to identify the range of problems experienced with nebuliser use. RESULTS: A wide range of practical issues was identified at all stages: problems prior to nebulisation: setting up equipment, lack of instructions, manual dexterity and time required. Problems during medication administration: inhalation technique, duration of nebulisation and understanding how to achieve optimal efficacy. Problems post-administration: inadequate cleaning of nebuliser components, access to accessories and use of damaged parts or self-repairs. Other problems included noise, weight and non-portability of equipment. CONCLUSIONS: Patients with COPD using nebulisers at home experienced problems with all aspects, many of which may be anticipated to compromise clinical outcomes. Healthcare providers should be aware of these problems to effectively support patients with COPD with the use of their nebulisers at home. PMID- 25806108 TI - New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy. AB - About 50% of human cancers harbor somatic mutations of the tumor suppressor p53 (p53 or Trp53) gene. Many of those mutations result in the inactivation of the p53 pathway and are often associated with the stabilization and accumulation of mutant p53 proteins. Therefore, increased p53 expression in tumors is frequently used as a surrogate marker for p53 mutation and inactivation. Moreover, this elevated p53 expression also makes it an ideal tumor associated antigen (TAA) for cancer vaccines. Recent advances in our understanding of p53 as a crucial transcription factor reveal that p53 is an important sensor of cellular stress under genotoxic, chemotoxic, pathological, and even normal physiological conditions. Experimental and clinical observations by our laboratory and others have demonstrated that p53 also participates in immune regulation as p53 dysfunction skews host immune responses towards pro-inflammation, which further promotes tumor progression. Furthermore, recent studies using a genetic approach revealed that p53-restoration or re-activation led to tumor regression and clearance, which were at least partially caused by the activation of innate antitumor immunity. Since many of the currently used cancer therapeutics, including radiotherapy and chemotherapy, disrupt tumor growth by inducing DNA damage via genotoxic or chemotoxic stress, which activates the p53 pathway in the tumor microenvironment, we postulate that some of those observed therapeutic benefits might also be partially mediated through their immune stimulatory effects. Here, we briefly review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and, subsequently, extend our discussion to the immunostimulatory potential of existing and new approaches of targeting the p53-pathway to alter the immunological landscape of tumors for maximizing immunotherapy outcome. PMID- 25806115 TI - Impact of increased visceral adiposity with normal weight on the progression of arterial stiffness in Japanese patients with type 2 diabetes. AB - OBJECTIVE: Normal-weight abdominal obesity has been reported to be associated with poor mortality. We aimed to investigate the impact of increased visceral adiposity with normal weight (OB(-)VA(+)) on the progression of arterial stiffness in patients with type 2 diabetes. METHODS: This was a cross-sectional study of 414 patients with type 2 diabetes (mean age 64+/-12 years; 40.3% female). Visceral fat area (VFA, cm(2)) was measured by a dual bioelectrical impedance analyzer. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV, cm/s). Patients were divided into four groups by VFA and body mass index (BMI, kg/m(2)) as the following: BMI<25 kg/m(2) and VFA<100 cm(2) (obesity (OB)(-)visceral adiposity (VA)(-)), BMI>=25 kg/m(2) and VFA<100 cm(2) (OB(+)VA(-)), BMI<25 kg/m(2) and VFA>=100 cm(2) (OB(-)VA(+)), and BMI>=25 kg/m(2) and VFA>=100 cm(2) (OB(+)VA(+)). Multivariate linear regression analysis was done to determine the impact of OB(-)VA(+) on arterial stiffness. RESULTS: Among the patients, 7.2% were OB(-)VA(+) with higher baPWV levels (1956+/-444 cm/s) than those with OB(+)VA(-) (1671+/-416 cm/s, p=0.014), those with OB(+)VA(+) (1744+/ 317 cm/s, p=0.048), and those with OB(-)VA(-) (1620+/-397 cm/s, p=0.024). In multivariate linear regression analysis, OB(-)VA(+) remained independently associated with baPWV (standardized beta 0.184, p=0.001). CONCLUSIONS: This study provides evidence for the burden of arterial stiffness in OB(-)VA(+) patients with type 2 diabetes; therefore, evaluation of visceral adiposity is of clinical relevance for the better management of non-obese individuals as well as obese populations. PMID- 25806116 TI - When morphogenetic proteins encounter special extracellular matrix and cell-cell connections at the interface of the renal stem/progenitor cell niche. AB - Reciprocal exchange of morphogenetic proteins between epithelial and mesenchymal cells in a stem/progenitor cell niche results in formation of a nephron. To maintain diffusion of morphogenetic proteins, it is assumed that a close contact exists between involved cells. However, recent publications underline that both types of stem/progenitor cells are separated by a striking interface. To explore this microarchitecture in detail, neonatal rabbit kidneys were fixed in traditional glutaraldehyde (GA) solution for transmission electron microscopy. For contrast enhancing specimens were fixed in GA solution including cupromeronic blue, ruthenium red or tannic acid. To record same perspectives, embedded blocks of parenchyma were cut in exactly orientated vertical and transverse planes to lining collecting ducts. Electron microscopy of specimens fixed by traditional GA solution illustrates a spatial separation of stem/progenitor cells and an unobstrusively looking interface. In contrast, advanced fixation of specimens in GA solution including cupromeronic blue, ruthenium red and tannic acid unmasks earlier not visible extracellular matrix. In addition, projections of mesenchymal cells covered by matrix cross the interface to contact epithelial cells. Surprisingly, the end of a mesenchymal cell projection does not dangle but is enclosed in a fitting sleeve and connected via tunneling nanotubes with the plasma membrane of an epithelial cell. Regarding this complex ensemble the question is to what extent illustrated cell-cell connections and extracellular matrix are involved in communication and transmission of morphogenetic proteins during induction of a nephron. PMID- 25806117 TI - The role of soluble common gamma chain in autoimmune disease. AB - The common gamma chain (gammac) is the central signaling unit for a number of cytokine receptors collectively known as the gammac cytokine receptor family. gammac is critical for ligand binding and signaling by gammac cytokines. gammac cytokine signaling had been thought to be mainly regulated by cytokine-specific receptor alpha chain expression levels with little or no effect by gammac surface levels because gammac expression was presumed to remain unchanged during T-cell activation and development. The extent of gammac cytokine responses is thought to be regulated by cytokine specific receptor subunits and not by the gammac receptor. In contrast to this prevailing view, we have recently reported that gammac itself actively regulates gammac cytokine responses. Interestingly, gammac exerted its regulatory effects not only as a conventional membrane receptor protein but also as a secreted protein whose expression was upregulated upon T cell stimulation. Here we will review how a soluble form of gammac, which is generated by alternative splicing, regulates gammac cytokine signaling and plays a role in controlling immune activation related to autoimmune disease. PMID- 25806118 TI - Mechanistic insights into pancreatic beta-cell mass regulation by glucose and free fatty acids. AB - Pancreatic islets are responsible for blood glucose homeostasis. Reduced numbers of functional (insulin-secreting) beta-cells in pancreatic islets underlies diabetes. Restoration of the secretion of the proper amount of insulin is a goal. Beta-cell mass is increased by neogenesis, proliferation and cell hypertrophy, and is decreased by beta-cell death primarily through apoptosis. Many hormones and nutrients affect beta-cell mass, and glucose and free fatty acid are thought to be the most important determinants of beta-cell equilibrium. A number of molecular pathways have been implicated in beta-cell mass regulation and have been studied. This review will focus on the role of the principle metabolites, glucose and free fatty acid, and the downstream signaling pathways regulating beta-cell mass by these metabolites. PMID- 25806120 TI - Innervation of submandibular and sublingual glands in elderly donated cadavers: a preliminary histological study of differences in nerve morphology between mucous and serous acini. AB - We examined morphological differences between the sublingual and submandibular glands with special reference to their innervation. The sublingual gland contained abundant periodic acid Schiff-positive mucous acini: some lobules were composed of purely mucous acini, while others were purely serous or mixed. However, in the submandibular gland, the area of mucous acini was very limited. Notably, in the sublingual gland, immunohistochemistry for neuron-specific enolase demonstrated that the serous acini carried a higher density of nerve elements than the mucous acini. However, no such difference was evident in the submandibular gland, possibly due to the small areas of the mucous acini. In both types of gland, neuronal nitric oxide synthase-positive parasympathetic nerves as well as tyrosine hydroxylase-positive sympathetic nerves were observed in the interlobular tissue, but we were unable to trace these thin fibers to the acini. Myoepithelial cells expressed smooth muscle actin, but were negative for S100B protein, glial fibrillary acidic protein and neuron-specific enolase. However, antibody against S100A stained some of the myoepithelial cells and ductal cells in the sublingual gland. Cells positive for peripheral myelin protein 22 were seen in some of the ductal cells in the submandibular gland, but not in the sublingual gland. Therefore, with regard to the neurogenic features of the gland cells, S100B reactivity might disappear first in postnatal life, whereas S100A reactivity is likely to remain as aging progresses. The sublingual gland in elderly individuals seems to provide a good model for comparison of the nerve supply between mucous and serous acini. PMID- 25806121 TI - Glioblastoma specific antigens, GD2 and CD90, are not involved in cancer stemness. AB - Glioblastoma multiforme (GBM) is the most malignant World Health Organization grade IV brain tumor. GBM patients have a poor prognosis because of its resistance to standard therapies, such as chemotherapy and radiation. Since stem like cells have been associated with the treatment resistance of GBM, novel therapies targeting the cancer stem cell (CSC) population is critically required. However, GBM CSCs share molecular and functional characteristics with normal neural stem cells (NSCs). To elucidate differential therapeutic targets of GBM CSCs, we compared surface markers of GBM CSCs with adult human NSCs and found that GD2 and CD90 were specifically overexpressed in GBM CSCs. We further tested whether the GBM CSC specific markers are associated with the cancer stemness using primarily cultured patient-derived GBM cells. However, results consistently indicated that GBM cells with or without GD2 and CD90 had similar in vitro sphere formation capacity, a functional characteristics of CSCs. Therefore, GD2 and CD90, GBM specific surface markers, might not be used as specific therapeutic targets for GBM CSCs, although they could have other clinical utilities. PMID- 25806119 TI - Neurosphere and adherent culture conditions are equivalent for malignant glioma stem cell lines. AB - Certain limitations of the neurosphere assay (NSA) have resulted in a search for alternative culture techniques for brain tumor-initiating cells (TICs). Recently, reports have described growing glioblastoma (GBM) TICs as a monolayer using laminin. We performed a side-by-side analysis of the NSA and laminin (adherent) culture conditions to compare the growth and expansion of GBM TICs. GBM cells were grown using the NSA and adherent culture conditions. Comparisons were made using growth in culture, apoptosis assays, protein expression, limiting dilution clonal frequency assay, genetic affymetrix analysis, and tumorigenicity in vivo. In vitro expansion curves for the NSA and adherent culture conditions were virtually identical (P=0.24) and the clonogenic frequencies (5.2% for NSA vs. 5.0% for laminin, P=0.9) were similar as well. Likewise, markers of differentiation (glial fibrillary acidic protein and beta tubulin III) and proliferation (Ki67 and MCM2) revealed no statistical difference between the sphere and attachment methods. Several different methods were used to determine the numbers of dead or dying cells (trypan blue, DiIC, caspase-3, and annexin V) with none of the assays noting a meaningful variance between the two methods. In addition, genetic expression analysis with microarrays revealed no significant differences between the two groups. Finally, glioma cells derived from both methods of expansion formed large invasive tumors exhibiting GBM features when implanted in immune-compromised animals. A detailed functional, protein and genetic characterization of human GBM cells cultured in serum-free defined conditions demonstrated no statistically meaningful differences when grown using sphere (NSA) or adherent conditions. Hence, both methods are functionally equivalent and remain suitable options for expanding primary high-grade gliomas in tissue culture. PMID- 25806122 TI - Expression of SIRT1 and SIRT3 varies according to age in mice. AB - Sirtuins (SIRTs) are involved in multiple cellular processes including those related to aging, cancer, and a variety of cellular functions including cell cycle progression, DNA repair, and cellular proliferation. SIRTs have been shown to extend the yeast life span, although there is presently little known about SIRT expression in the organs of mice. In the present study, we were especially interested in identifying differences in SIRT expression between young mice and aged mice. Specifically, we investigated the expression of SIRT1 and SIRT3 in the kidney, lung, skin, adipose tissue, and spleens of 6-month-old and 24-month-old mice using immunohistochemical staining. Compared with that in younger mice, the expression of SIRT1 in 24-month-old rats was increased in kidney, lung, and spleen tissue, while that of SIRT3 was decreased in adipose, kidney, and lung tissue. The results of our study suggest that aging is associated with altered patterns of expression of SIRT1 and SIRT3. In addition, we noted that the expression patterns of SIRT1 and SIRT3 varied by organ. Taken together, the results of this study suggest the possibility that SIRTs may be involved in diseases associated with aging. PMID- 25806123 TI - Variations of the cubital superficial vein investigated by using the intravenous illuminator. AB - The purpose of this study was to report variations of the cubital superficial vein patterns in the Korean subjects, which was investigated by using venous illuminator, AccuVein. The 200 Korean subjects were randomly chosen from the patients and staff of the Keimyung University Dongsan Medical Center in Daegu, Korea. After excluding the inappropriate cases for detecting venous pattern, we collected 174 cases of right upper limbs and 179 cases of left upper limbs. The superficial veins of the cubital fossa were detected and classified into four types according to the presence of the median cubital vein (MCV) or median antebrachial vein. The type II, presenting the both cephalic and basilic vein connected by the MCV, was most common (177 upper limbs, 50.1%). Although the most common type in male and female was different as type I (108 upper limbs, 49.3%) and type II (75 upper limbs, 56.0%), respectively, statistical significance was not detected (P=0.241). The frequency of the each types between right and left upper limbs was also not different (P=0.973). Among 154 subjects who were observed the venous pattern in the both upper limbs, 76 subjects (49.3%) had the same venous pattern. Using AccuVein to investigate the venous pattern has an advantage of lager scale examination compared to the cadaver study. Our results might be helpful for medical practitioner to be aware of the variation of the superficial cubital superficial vein. PMID- 25806124 TI - Cisplatin induces primary necrosis through poly(ADP-ribose) polymerase 1 activation in kidney proximal tubular cells. AB - Treatment with cisplatin for cancer therapy has a major side effect such as nephrotoxicity; however, the role of poly (ADP-ribose) polymerase 1 (PARP1) in necrosis in response to cisplatin nephrotoxicity remains to be defined. Here we report that cisplatin induces primary necrosis through PARP1 activation in kidney proximal tubular cells derived from human, pig and mouse. Treatment with high dose of cisplatin for 4 and 8 hours induced primary necrosis, as represented by the percentage of propidium iodide-positive cells and lactate dehydrogenase release. The primary necrosis was correlated with PARP1 activation during cisplatin injury. Treatment with PJ34, a potent PARP1 inhibitor, at 2 hours after injury attenuated primary necrosis after 8 hours of cisplatin injury as well as PARP1 activation. PARP1 inhibition also reduced the release of lactate dehydrogenase and high mobility group box protein 1 from kidney proximal tubular cells at 8 hours after cisplatin injury. Oxidative stress was increased by treatment with cisplatin for 8 hours as shown by 8-hydroxy-2'-deoxyguanosine and lipid hydroperoxide assays, but PARP1 inhibition at 2 hours after injury reduced the oxidative damage. These data demonstrate that cisplatin-induced PARP1 activation contributes to primary necrosis through oxidative stress in kidney proximal tubular cells, resulting in the induction of cisplatin nephrotoxicity and inflammation. PMID- 25806125 TI - Morphological assessment of the anterior loop of the mandibular canal in Koreans. AB - The mandibular canal divides into the mental and incisive canals at the premolar region, forms the anterior loop which crosses anterior to the mental foramen, and turns back to reach the mental foramen. The aim of this study was to elucidate the general anatomical structure of the anterior loop of the mandibular canal using morphometry. Twenty-six hemimandibles from 19 cadavers (16 males, 3 females; mean age at death, 54.4 years) were studied by meticulous dissection with the aid of a surgical microscope. The location of the anterior loop, the diameters of the mandibular, mental, and incisive canals, and their distances from bony landmarks were measured using digital calipers. The anterior loop of the mandibular canal was located 3.05+/-1.15 mm (mean+/-SD) anterior to the anterior margin of the mental foramen and 2.72+/-1.41 mm inferior to the superior margin of the mental foramen, and was 4.34+/-1.46 mm long. The diameters of the mandibular, mental, and incisive canals were 2.8+/-0.49, 2.63+/-0.64, and 2.22+/ 0.59 mm, respectively. The distances between the inferior border of the mandible and each of these canals were 7.82+/-1.52, 10.11+/-1.27, and 9.08+/-1.66 mm, respectively. The anterior loop of the mandibular canal was located a mean of 3.1 mm anterior and 2.7 mm inferior to the mental foramen, and continued upward and backward into the mental canal, and forward into the incisive canal. These detailed morphological features of the anterior loop of the mandibular canal represent useful practical anatomical knowledge regarding the interforaminal region. PMID- 25806126 TI - Unduly extensive uncinate process of pancreas in conjunction with pancreatico duodenal fold. AB - Anatomical variations of pancreatic head and uncinate process are rarely encountered in clinical practice. These variations are primarily attributed to the complex development of the pancreas. An unduly enlarged uncinate process of the pancreas overlapping the third part of duodenum was discovered during dissection. This malformation of the pancreatic uncinate process was considered to be due to excessive fusion between the ventral and dorsal buds during embryonic development. On further dissection, an avascular pancreatico-duodenal fold guarding the pancreatico-duodenal recess was observed. The enlarged uncinate process can cause compression of neurovascular structures and also cause compression of adjoining viscera. The pancreatico-duodenal recess becomes a potential site for internal herniation. This case is of particular interest to the gastroenterologists and surgeons performing surgical resections. Precise knowledge of embryogenesis of such pancreatic anomalies is necessary for understanding and thus treating many diseases of the pancreas. PMID- 25806127 TI - Transient Rotation of a Non-ptotic Kidney Secondary to Acute Pulmonary Thromboembolism. AB - We present a case of an acquired, transient, rotated right kidney in a 43-year old woman with an enterocutaneous fistula who presented with acute pulmonary embolism. This non-ptotic rotated kidney returned to its normal orientation within 10 days. We postulate that this transient kidney rotation is due to transient hepatomegaly and passive renal congestion secondary to pulmonary embolism. While in this patient there were no untoward sequelae, it has been reported that ureteral obstruction or vascular occlusion can occur in patients with ptotic and malrotated kidneys, and radiologists, therefore, should be aware of this unusual occurrence and the potential complications. PMID- 25806128 TI - HRCT Correlation with Round Window Identification during Cochlear Implantation in Children. AB - OBJECTIVE: To determine the accuracy of High Resolution Computer Tomography (HRCT) temporal bone measurements in predicting the actual visualization of round window niche as viewed through posterior tympanotomy (i.e. facial recess). MATERIALS AND METHODS: This is a prospective study of 37 cochlear implant candidates, aged between 1and 6 years, who were referred for HRCT temporal bone during the period December 2013 to July 2014. Cochlear implantation was done in 37 children (25 in the right ear and 12 in the left ear). The distance between the short process of incus and the round window niche and the distance between the oval window and the round window niche were measured preoperatively on sub millimeter (0.7 mm) HRCT images. We classified the visibility of round window niche based on the surgical view (i.e. through posterior tympanotomy) during surgery into three types: 1) Type 1- fully visible, 2) Type 2- partially visible, and 3) Type 3- difficult to visualize. The preoperative HRCT measurements were used to predict the type of visualization of round window niche before surgery and correlated with the findings during surgery. RESULTS: The mean and standard deviation for the distance between the short process of incus and the round window niche and for the distance between the oval window and the round window niche for Types 1, 2, and 3 were 8.5 +/- 0.2 mm and 3.2 +/- 0.2 mm, 8.0 +/- 0.4 mm and 3.8 +/- 0.2 mm, 7.5 +/- 0.2 mm and 4.4 +/- 0.2 mm respectively, and showed statistically significant difference (P < 0.01) between them. The preoperative HRCT measurements had a sensitivity and specificity of 92.3% and 96.2%, respectively, in determining the actual visualization of round window niche. CONCLUSION: This study shows preoperative HRCT temporal bone measurements are useful in predicting the actual visualization of round window niche as viewed through posterior tympanotomy. PMID- 25806129 TI - MRI of uncommon lesions of the large bowel: a pictorial essay. AB - This pictorial essay briefly discusses methods for optimizing bowel imaging with magnetic resonance imaging (MRI) and illustrates the MRI appearance of a variety of unusual lesions involving or related specifically to the large bowel. PMID- 25806130 TI - Primary follicular lymphoma of the common bile duct mimicking cholangiocarcinoma. AB - Primary non-Hodgkin's lymphoma of the common bile duct is extremely rare. We present a case with history of inflammatory bowel disease and clinical manifestations of obstructive jaundice. Abdominal magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRCP) was done and demonstrated tight stricture at the middle part of common bile duct, and radiological findings were supportive of extra-hepatic cholangiocarcinoma. Whipple's procedure was performed and the case was histopathologically proven to be non-Hodgkin's lymphoma of follicular subtype involving the common bile duct. Lymphoma of the hepatobiliary system is usually present as secondary manifestation of systemic malignant lymphoma. However, primary malignant lymphomas arising from the hepatobiliary tree are extremely rare. The radiological appearance of common bile duct lymphoma is very similar to cholangiocarcinoma, making preoperative diagnosis very difficult, as in our present case. We also compare the imaging findings of our case to those seen in reported cases of follicular lymphoma of the common bile duct. PMID- 25806131 TI - Superior mesenteric artery-related aortic pseudomass as a form of reverberation artifact in a 10-year-old boy. AB - Artifacts are encountered routinely in clinical ultrasonography practice. The ability to recognize and eliminate potentially correctable ultrasound artifacts is of great importance to image quality improvement and optimal patient care. We describe an example of a superior mesenteric artery-related pseudomass as a form of reverberation artifact that could lead to misinterpretation of sonographic findings. We present the ultrasonographic and computed tomography angiography findings and give an explanation for the appearance of the artifact. PMID- 25806132 TI - Radiography of cardiac conduction devices: a pictorial review of pacemakers and implantable cardioverter defibrillators. AB - Cardiac conduction devices (CCDs) depend on correct anatomic positioning to function properly. Chest radiography is the preferred imaging modality to evaluate CCD's anatomic location, lead wire integrity, and help in identifying several complications. In this pictorial review, our goal is to familiarize radiologists with CCD implantation techniques, appropriate positioning of the device, common causes of malfunction, methods to improve report accuracy, and assure maximal therapeutic benefit. PMID- 25806133 TI - Biliary Anastomotic Leakage following Orthotopic Liver Transplant: The Use of Primovist (Gadoxetate Disodium) as an Intravenous MR Cholangiography Contrast Agent for Biliary Leakage. AB - We present a case of postoperative biliary anastomotic leakage demonstrated on intravenous contrast-enhanced MRI performed with Primovist (Gadoxetate Disodium). Primovist has been widely used for its combined extracellular and hepatocyte specific properties in the characterization of liver lesions. Another recognized, but less widely utilized property of Primovist is its ability to provide morphologic and functional assessment of the biliary system. In our case, Primovist-enhanced MR imaging demonstrated the presence and location of an active biliary leakage which was associated with free spillage into the peritoneum. PMID- 25806134 TI - Unusual Larva in the CSF and Unique MRI Findings in a Case of Eosinophilic Meningitis. AB - Eosinophilic meningitis may be caused by non-infectious and infectious agents. Angiostrongylus cantonensis is the commonest causative agent of eosinophilic meningitis. Rats are the primary hosts of this parasite. Humans get infected by ingestion of raw or inadequately cooked hosts (snails or monitor lizard) or food contaminated with the infective third-stage larvae. A 16-year-old boy was admitted to our hospital with history of fever, headache, and altered sensorium. Magnetic resonance imaging of the brain showed unique findings. Cerebrospinal fluid (CSF) examination showed eosinophilia and the CSF wet mount identified a larva. Patient history revealed ingestion of monitor lizard 2 weeks prior to onset of symptoms. Hence, a diagnosis of eosinophilic meningitis caused by A. cantonensis was made. He was treated with oral albendazole and steroids, resulting in gradual improvement. A. cantonensis as a cause of eosinophilic meningitis is a possibility in patients who present with headache and vomiting after eating raw meat (monitor lizard). To the best of our knowledge, this is a very rare case being reported from India where the larva was identified during the microscopic examination of the CSF. PMID- 25806135 TI - Accuracy of computerized vertical measurements on digital orthopantomographs: posterior mandibular region. AB - OBJECTIVES: Orthopantomographs are commonly used for diagnosis in clinical dentistry. Although the manufacturers claim a constant magnification effect, the reliability of measuring dimensions on the panoramic radiographs is not clear. The aim of this study was to evaluate the accuracy of measuring vertical dimensions in the posterior mandibular area on digital orthopantomographs. MATERIALS AND METHODS: A retrospective survey of 20 orthopantomographs with unrestored implants (only with cover screw) in the mandibular posterior region (molars and premolars) was conducted. All radiographs were taken using the same machine by skilled technicians. Two examiners were asked to measure the vertical dimension of the implants seen on the radiographs viewed using two differently sized display screens. Inter-examiner and intra-examiner reliability tests were performed. Differences between the measured length and the actual length using each screen type were compared. RESULTS: High coefficients of reliability were observed on intra- and inter-examiner correlation. The overall reliability of measuring the vertical dimensions of implants between both examiners for the large screen and the small screen were 97.4% (Cronbach's alpha 0.993) and 94.0% (Cronbach's alpha 0.984), respectively. There were no significant differences between the errors seen with either the large screen or the small screen, when each of them was compared to the original length (P = 0.146). CONCLUSION: This study shows that vertical dimensions in the posterior mandibular region (molar and premolars) can be reliably measured on an orthopantomograph using a calibrated machine and special software. PMID- 25806136 TI - In vivo quantification of cerebral r2*-response to graded hyperoxia at 3 tesla. AB - OBJECTIVES: This study aims to quantify the response of the transverse relaxation rate of the magnetic resonance (MR) signal of the cerebral tissue in healthy volunteers to the administration of air with step-wise increasing percentage of oxygen. MATERIALS AND METHODS: The transverse relaxation rate (R2*) of the MR signal was quantified in seven volunteers under respiratory intake of normobaric gas mixtures containing 21, 50, 75, and 100% oxygen, respectively. End-tidal breath composition, arterial blood saturation (SaO2), and heart pulse rate were monitored during the challenge. R2* maps were computed from multi-echo, gradient echo magnetic resonance imaging (MRI) data, acquired at 3.0T. The average values in the segmented white matter (WM) and gray matter (GM) were tested by the analysis of variance (ANOVA), with Bonferroni post-hoc correction. The GM R2* reactivity to hyperoxia was modeled using the Hill's equation. RESULTS: Graded hyperoxia resulted in a progressive and significant (P < 0.05) decrease of the R2* in GM. Under normoxia the GM-R2* was 17.2 +/- 1.1 s(-1). At 75% O2 supply, the R2* had reached a saturation level, with 16.4 +/- 0.7 s(-1) (P = 0.02), without a significant further decrease for 100% O2. The R2*-response of GM correlated positively with CO2 partial pressure (R = 0.69 +/- 0.19) and negatively with SaO2 (R = -0.74 +/- 0.17). The WM showed a similar progressive, but non-significant, decrease in the relaxation rates, with an increase in oxygen intake (P = 0.055). The Hill's model predicted a maximum R2* response of the GM, of 3.5%, with half the maximum at 68% oxygen concentration. CONCLUSIONS: The GM R2* responds to hyperoxia in a concentration-dependent manner, suggesting that monitoring and modeling of the R2*-response may provide new oxygenation biomarkers for tumor therapy or assessment of cerebrovascular reactivity in patients. PMID- 25806137 TI - Energy Limits in Second Generation High-pitch Dual Source CT - Comparison in an Upper Abdominal Phantom. AB - OBJECTIVES: The aim of our study was to find out how much energy is applicable in second-generation dual source high-pitch computed tomography (CT) in imaging of the abdomen. MATERIALS AND METHODS: We examined an upper abdominal phantom using a Somatom Definition Flash CT-Scanner (Siemens, Forchheim, Germany). The study protocol consisted of a scan-series at 100 kV and 120 kV. In each scan series we started with a pitch of 3.2 and reduced it in steps of 0.2, until a pitch of 1.6 was reached. The current was adjusted to the maximum the scanner could achieve. Energy values, image noise, image quality, and radiation exposure were evaluated. RESULTS: For a pitch of 3.2 the maximum applicable current was 142 mAs at 120 kV and in 100 kV the maximum applicable current was 114 mAs. For conventional abdominal imaging, current levels of 200 to 260 mAs are generally used. To achieve similar current levels, we had to decrease the pitch to 1.8 at 100 kV - at this pitch we could perform our imaging at 204 mAs. At a pitch of 2.2 in 120 kV we could apply a current of 206 mAs. CONCLUSION: We conclude our study by stating that if there is a need for a higher current, we have to reduce the pitch. In a high-pitch dual source CT, we always have to remember where our main focus is, so we can adjust the pitch to the energy we need in the area of the body that has to be imaged, to find answers to the clinical question being raised. PMID- 25806138 TI - Noninvasive Fractional Flow Reserve for the Diagnosis of Lesion-specific Ischemia: A Case Example. AB - A physically active 52-year-old male with atypical chest pain was referred to our department. A coronary computed tomography angiography (CCTA) showed a stenotic plaque in the mid left anterior descending coronary artery (LAD). A rest-stress Rubidium-82 myocardial perfusion was normal. One year later the patient sustained a cardiac arrest and percutaneous coronary intervention of the mid-LAD was successfully performed. The original CCTA data were submitted for noninvasive determination of fractional flow reserve (FFRCT) revealing an ischemia-producing lesion in the mid-LAD. This case demonstrates the inherent limitations of assessing lesion-specific ischemia. FFRCT shows promise as a new method for future selection of patients for coronary angiography. PMID- 25806139 TI - Role of Imaging and Cytogenetics in Evaluation of DiGeorge Syndrome - A Rare Entity in Clinical Practice. AB - DiGeorge syndrome is a congenital genetic disorder that affects the endocrine system, mainly the thymus and parathyroid glands. The syndrome produces different symptoms, which vary in severity and character between patients. It manifests with craniofacial dysmorphism and defects in the heart, parathyroid, and thymus. Patients can present with a palatal deformity and nasal speech. This rare entity is caused mainly due to deletion of chromosome 22q11.2. Radiographic evaluation of DiGeorge syndrome is necessary to define aberrant anatomy, evaluate central nervous system, craniofacial abnormalities, musculoskeletal system, and cardiothoracic contents. It also helps in planning surgical procedures and surgical reconstructions. We report a case of DiGeorge syndrome in a 4-month-old neonate and discuss the clinical, imaging, and cytogenetic findings that helped in the diagnosis of this rare entity. PMID- 25806141 TI - Bilateral renal lymphangiectasia: radiological findings by ultrasound, computed tomography, and magnetic resonance imaging. AB - Renal lymphangiectasia is a rare benign condition of the kidney without specific clinical presentations. Classic imaging findings are described in literature. Here, we present a case of renal lymphangiectasia with history of bilateral flank pain and abnormal renal function tests. The radiological appearance on ultrasound (US) and computed tomography (CT) showed features of bilateral renal lymphangiectasia but the patient refused invasive procedure for aspiration of the cysts. So, follow-up of the patient was done by magnetic resonance imaging (MRI). Imaging findings of our case on US, CT, and MRI are discussed along with details of the additional finding of dilated retroperitoneal lymphatic channels, cisterna chyli, as well as the thoracic duct. PMID- 25806140 TI - Transcatheter renal interventions: a review of established and emerging procedures. AB - Catheter-based interventions play an important role in the multidisciplinary management of renal pathology. The array of procedures available to interventional radiologists (IRs) includes established techniques such as angioplasty, stenting, embolization, thrombolysis, and thrombectomy for treatment of renovascular disease, as well as embolization of renal neoplasms and emerging therapies such as transcatheter renal artery sympathectomy for treatment of resistant hypertension. Here, we present an overview of these minimally invasive therapies, with an emphasis on interventional technique and clinical outcomes of the procedure. PMID- 25806142 TI - Unilateral agenesis of internal carotid artery with intercavernous anastomosis: a rare case report. AB - Unilateral agenesis of internal carotid artery (ICA) with intercavernous anastomosis is a rare congenital anomaly. We present a case of a 25-year-old female with 2-month history of holocranial headache. Neurological examination was unremarkable. Magnetic resonance imaging (MRI) with magnetic resonance angiography (MRA) showed absence of left ICA with an abnormal intercavernous vessel in the sella. Computed tomography (CT) showed absence of the left carotid canal. Doppler ultrasonography (USG) showed high resistance flow in the left common carotid artery (CCA). Since no hemorrhage or aneurysm was seen, patient was managed conservatively and is on regular follow-up. Based on our knowledge, this is the first case to demonstrate the features of unilateral agenesis of ICA with intercavernous anastomosis in X-ray, Doppler USG, CT, and MRI scans of the brain. PMID- 25806143 TI - Hypertrophic olivary degeneration - a report of two cases. AB - Hypertrophic olivary degeneration (HOD) is seen following lesions in the Guillain Mollaret triangle. This is unique because the inferior olivary nucleus hypertrophies following degeneration unlike the typical atrophy seen in other structures. We report two cases of HOD in two different clinical scenarios. PMID- 25806144 TI - Automatic Segmentation of Polypoidal Choroidal Vasculopathy from Indocyanine Green Angiography Using Spatial and Temporal Patterns. AB - PURPOSE: To develop a computer-aided diagnostic tool for automated detection and quantification of polypoidal regions in indocyanine green angiography (ICGA) images. METHODS: The ICGA sequences of 59 polypoidal choroidal vasculopathy (PCV) treatment-naive patients from five Asian countries (Hong Kong, Singapore, South Korea, Taiwan, and Thailand) were provided by the EVEREST study. The ground truth was provided by the reading center for the presence of polypoidal regions. The proposed detection algorithm used both temporal and spatial features to characterize the severity of polypoidal lesions in ICGA sequences. Leave-one-out cross validation was carried out so that each patient was used once as the validation sample. For each patient, a fixed detection threshold of 0.5 on the severity was applied to obtain sensitivity, specificity, and balanced accuracy with respect to the ground truth. RESULTS: Our system achieved an average accuracy of 0.9126 (sensitivity = 0.9125, specificity = 0.9127) for detection of polyps in the 59 ICGA sequences. Among the total of 222 features extracted from ICGA sequence, the spatial variances exhibited best discriminative power in distinguishing between polyp and nonpolyp regions. The results also indicated the importance of combining spatial and temporal features to further improve detection accuracy. CONCLUSIONS: The developed software provided a means of detecting and quantifying polypoidal regions in ICGA images for the first time. TRANSLATIONAL RELEVANCE: This preliminary study demonstrated a computer-aided diagnostic tool, which enables objective evaluation of PCV and its progression. Ophthalmologists can easily visualize the polypoidal regions and obtain quantitative information about polyps by using the proposed system. PMID- 25806145 TI - Definitive Response to Denniss and Artes: The Paired Eyes and Brain in One Person Are One Unit. PMID- 25806148 TI - Something in need is something indeed. PMID- 25806147 TI - Tumor grade of clear cell renal cell carcinoma assessed by contrast-enhanced computed tomography. AB - The purpose of this study was to clarify the association between CT findings and Fuhrman grade of clear cell renal cell carcinoma (ccRCC). The study group consisted of 214 surgically proven ccRCC in 214 patients. Contrast-enhanced CT studies were retrospectively assessed for tumor size, cystic versus solid, calcification, heterogeneity of lesions, percentage of non-enhancing (necrotic) areas, and growth pattern. CT findings and Fuhrman grade were compared. Nineteen of 22 (86.4%) cystic ccRCC were low grade (Fuhrman grades 1-2). There was no significant correlation between tumor size and grade in cystic ccRCC (P = 0.43). In predominantly solid ccRCC, there was significant correlation between tumor size and grade (P < 0.0001). Thirty-eight of 43 (88.4%) infiltrative ccRCC were high grade (Fuhrman grades 3-4). Logistic regression showed tumor size and infiltrative growth were significantly associated with grades 3-4 (P = 0.00083 and P = 0.0059). Cystic ccRCC tends to be low grade. Infiltrative growth and larger tumor size may increase the likelihood of high grade ccRCC. PMID- 25806146 TI - 4 weeks of high-intensity interval training does not alter the exercise-induced growth hormone response in sedentary men. AB - This study determined the effects of high-intensity interval training on the exercise-induced growth hormone (GH) responses, whole body and regional fat content. Twenty-four sedentary males were randomized to either a high-intensity interval training (HIT) group or a low-intensity continuous training (LT) group. The HIT group performed intermittent exercises at 85% of [Formula: see text], whereas the LT group performed continuous exercise for 22 min at 45% of [Formula: see text]. Before and after 4 weeks of training, hormonal and metabolic responses to acute exercise were determined. Acute exercise significantly increased GH concentrations in both groups (p < 0.05). However, the responses did not change after training period in either group. Furthermore, the training did not significantly affect intramyocellular or intrahepatic lipid content in either group. The present study indicates that 4 weeks of high-intensity interval training does not alter the exercise-induced GH responses, whole body fat mass or intramyocellular and intrahepatic lipid content in sedentary males. PMID- 25806149 TI - EGFR-TKIs in EGFR-mutated lung cancer: Setting the new standard for 1(st) line therapy. PMID- 25806150 TI - Advances on EGFR mutation for lung cancer. AB - Patients with advanced non-small-cell lung cancer (NSCLC) and somatic activating mutations of the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene represent a biologically distinct disease entity that shows exquisite sensitivity to the reversible EGFR-TK inhibitors (-TKIs) gefitinib or erlotinib. Phase III randomized studies have clearly demonstrated that a reversible EGFR-TKI is significantly superior in terms of response rate, progression-free survival and quality of life to platinum-based chemotherapy in advanced NSCLC patients who carry an activating EGFR mutation, thus resulting into a new standard of care for this biologically selected group of patients. Unfortunately, approximately one third of EGFR-mutated patients show primary resistance to gefitinib or erlotinib, whereas virtually all patients who initially benefit from treatment will eventually develop acquired resistance. Importantly, revealing the molecular mechanisms that underlie resistance to reversible EGFR-TKIs is key to the development of EGFR-targeting strategies with the potential to prevent, delay or overcome such resistance. Early results of clinical trials with irreversible EGFR-TKIs or dual combination strategies aiming to block EGFR-mediated signaling at different levels have shown encouraging results in EGFR-mutated patients pretreated or not with a reversible EGFR-TKI. Therefore, in the near future it is reasonable to hypothesize that EGFR-mutated NSCLCs could be treated with multiple lines of EGFR-targeting therapies beyond disease progression, limiting chemotherapy to selected cases of resistant disease. This evolving treatment scenario highlights once again how important is the identification of a single oncogenic "addiction" that functions as unique determinant of progression and survival of NSCLC. PMID- 25806152 TI - Statistical considerations and endpoints for clinical lung cancer studies: Can progression free survival (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials for advanced non-small-cell lung cancer? AB - In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become more evident. The identification of novel tumor targets with different pathways has stimulated the search for anti-tumor agents with a specific target directed mode of action, stipulating the need of testing these agents in clinical trials with an appropriate choice of the study endpoint. Gold standard as an endpoint has been so far overall survival (OS). By definition there are 3 categories of classical endpoints applied generally in clinical lung cancer studies: survival time endpoints, symptom endpoints, and endpoints relying on patients' reporting. Beside classical endpoints like OS which are tending to show the direct clinical effect of treatment, efforts have been taken to substitute these classical endpoints by surrogates. As a surrogate candidate for OS progression-free survival (PFS) should have the inherent considerable advantage, that it can detect subpopulations with longer PFS intervals early. Based on the (sub-) population treated and having in mind the risk-benefit profile of the drug under consideration, PFS can be considered for regulatory decision making. If accompanied by some independent measures like quality of life or treatment toxicity, PFS should be able to cover the clinical benefit achieved by treatment. Selecting PFS as primary endpoint in Phase III trials of advanced NSCLC may be based on a number of questions such as: Does the definition of PFS fit into the setting used by other trials? Are there accepted consensus standards? Are there consistent surveillance intervals? Is validation for each agent group planned? Is the incremental improvement of PFS big enough (>=30%)? And are there some additional measures to confine clinical benefit? OS is still accepted as the gold standard in trials investigating advanced NSCLC. OS is easy to measure and precise but it may be difficult to interpret if treatment action takes place only in a small subinterval of overall survival. PFS with some additional measures has become attractive when it seems advisable to make study results available earlier. Candidates for supporting PFS as "additional measures" may be treatment toxicity and quality of life measures. PFS allows a more precise detection and attribution to effects of the investigational treatment without being compromised by subsequent treatments. Therefore "enriched PFS" can be considered as an alternative primary endpoint replacing OS in studies investigating advanced NSCLC. The endpoint selection process should always be performed carefully considering all true and surrogate endpoint options in respect to the hypotheses to be proven. PMID- 25806153 TI - Circulating soluble intercellular adhesion molecule-1 in lung cancer: a systematic review. AB - Soluble intercellular adhesion molecule-1(sICAM-1) has been implicated in tumor progression and metastasis. However the expression of circulating sICAM-1 as well as its diagnostic and prognostic value in patients with lung cancer remains controversial. We performed an electronic database (including PubMed, Web of Science, and Medline) search with the terms "ICAM", "intercellular adhesion molecule" and "lung cancer", and summarized the results of eligible studies in order to review the expression of sICAM-1 as well as its clinical significance in lung cancer. According to our literature search, we conducted a final analysis of 1258 patients from 16 studies. And we revealed that the circulating concentration of sICAM-1 in lung cancer patients was significantly higher than that in healthy controls. Additionally, baseline sICAM-1 levels apparently were associated with ECOG performance status, gender, histology type and disease stages. Furthermore, there seems to be a significantly inverse association between sICAM-1 levels, prognosis and response rate in NSCLC patients. In conclusion, sICAM-1 appeared to be a potential diagnostic and prognostic biomarker in lung cancer patients. Additional prospective studies are required to confirm this issue. PMID- 25806154 TI - Are three doses of stereotactic ablative radiotherapy (SABR) more effective than 30 doses of conventional radiotherapy? AB - In early stage non-small cell lung cancer (NSCLC) definitive radiation therapy is an appropriate alternative to surgery. Recent studies show, that in such patients hypofractionation schedules (for example 3 times 18 Gy or 5 times 12 Gy), can be safely applied, without causing severe toxicities and achieving high local control rates of up to 90% and more. In the last couple of years a lot of knowledge about the cancer biology, technical aspects, clinical outcomes and toxicities has been accumulated from different clinical trials. The purpose of this review is to summarize recent outcomes and developments in stereotactic radiation therapy for patients with early stage NSCLC. PMID- 25806155 TI - Cetuximab in non-small-cell lung cancer. AB - Cetuximab is a chimeric monoclonal antibody that is directed towards the epidermal growth factor receptor (EGFR). It has been evaluated in combination with first-line chemotherapy in several phase II and two phase III trials in patients with advanced NSCLC. The phase III FLEX trial demonstrated improved survival for cetuximab combined with cisplatin plus vinorelbine compared to chemotherapy alone. The BMS099 trial failed to show a significant improvement in progression-free survival but resulted in a hazard ratio for death similar to the one seen in the FLEX trial. A meta-analysis of four randomized trials confirmed the efficacy of cetuximab when added to chemotherapy. EGFR expression levels based on an immunohistochemistry score have recently been shown to predict benefit from cetuximab in the FLEX trial. In patients with high EGFR expression, patients had prolonged survival when treated with chemotherapy plus cetuximab compared to chemotherapy alone. In patients with low EGFR expression, outcome was not different between the two treatment arms. Thus platinum-based chemotherapy combined with cetuximab represents a new treatment option for patients with advanced NSCLC and high EGFR expression in their tumors. Cetuximab is also evaluated in combination with chemoradiotherapy in patients with stage III NSCLC. PMID- 25806151 TI - Angiogenesis in cancer: Anti-VEGF escape mechanisms. AB - It is now widely accepted that tumor-angiogenesis plays a crucial role in tumor growth, tumor propagation and metastasis formation. Among several angiogenic activators, the vascular endothelial growth factor (VEGF) and its receptors represent one of the major inducers of tumor angiogenesis. Thus, this system has become the focus of therapeutic interventions, which led to the approval of the anti-VEGF blocking antibody bevacizumab and the VEGFR-2 pathway inhibitors pazopanib, sorafenib and sunitinib. However, not every cancer patient benefits from such treatment or finally becomes resistant to anti-VEGF approaches; others are suffering from adverse effects. Thus, there is an urgent need for a better understanding of VEGF-independent mechanisms leading to angiogenesis in cancer. This review focuses on anti-VEGF escape mechanisms of tumor cells and its microenvironment. PMID- 25806157 TI - Multi-targeted tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: an era of individualized therapy. AB - Multi-targeted tyrosine kinase inhibitors (TKIs) have played an increasingly important role in the treatment of non-small cell lung cancer (NSCLC). Many recently published phase III trials have shown bittersweet efficacies of these drugs. How to optimize the efficacies of TKIs has been a hot topic in the era of individualized therapy. In this article, we review the up-to-dated advances in research on the application of TKIs for NSCLC treatment. PMID- 25806156 TI - Chemotherapy of lung cancer: A global perspective of the role of ifosfamide. AB - The oxazaphosphorine cytostatic ifosfamide (IFO) has been successfully integrated in the treatment of various hematological and solid tumors. The purpose of this review is to summarize the evidence for its use in lung cancer starting from basic data of preclinical studies followed by a global summary of the phase III and seminal phase II clinical studies. Global in double respect: first covering both the small cell as well as the non-small cell indications, and, second tracing those studies performed in Europe and the United States as well as those from Asian countries. PMID- 25806160 TI - Conflict-Management within clinical and administrative stakeholders in medical structures. PMID- 25806159 TI - Updating advances on recombinant human endostatin combined with radiotherapy for non-small cell lung cancer with brain metastasis. AB - Brain metastases (BM) heavily affects the prognosis of advanced non-small cell lung cancer (NSCLC). Although whole-brain radiotherapy remains the mainstream therapy for BM caused by NSCLC, the effectiveness is unsatisfactory. Endostar, a recombinant human endostatin (RHES), has shown certain therapeutic effect on advanced NSCLC. This article reviews the feasibility of Endostar combined with radiotherapy in the treatment of BM caused by NSCLC. PMID- 25806158 TI - Functional CT imaging techniques for the assessment of angiogenesis in lung cancer. PMID- 25806161 TI - Status quo and prospects of the translational research on lung cancer in China. PMID- 25806162 TI - Gefitinib NSCLC maintenance therapy. PMID- 25806163 TI - Biomarkers in the selection of maintenance therapy in non-small cell lung cancer. PMID- 25806164 TI - A strong step forward in maintenance therapy for non-small cell lung cancer treatment. PMID- 25806165 TI - INFORM; C-TONG 0805: A multicenter, double blind randomized phase III trial of maintenance gefitinib compared to placebo in advanced non-small cell lung cancer. PMID- 25806166 TI - Maintenance therapy in non-small-cell lung cancer. AB - With standard doublet chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we have reached an outcome plateau of about 10 months median overall survival over the last decades. Several studies have now demonstrated some survival benefits for patients treated beyond induction chemotherapy. In the current discussion about treatment duration, the terms "switch" and "continuation" maintenance therapy are now most commonly used by the scientific community. Switch maintenance is the treatment with an agent with a different mode of action after completion of induction chemotherapy in patients who's tumors have not progressed, whereas continuation maintenance is the continuation of one compound of the induction regimen. Chemotherapeutic compounds successfully investigated in the maintenance setting are Gemcitabine, Docetaxel and Pemetrexed. Targeted agents, recently investigated as maintenance therapy are Bevacizumab, Cetuximab and Erlotinib. New peer-reviewed publications of phase III randomized clinical trials on maintenance chemotherapy have led to a change in current practice guidelines and the use of maintenance therapy represents a new treatment option in advanced NSCLC. The pivotal trials are described and summarized in this review article. PMID- 25806167 TI - From tissue to molecular phenotyping: pre-analytical requirements heidelberg experience. AB - Lung cancer is a leading cause of tumor-related death worldwide through years. Efforts to individualize lung cancer therapy to improve prognosis nowadays employ molecular analyses besides routine histopathological examination of tissue samples. In general, tissues are provided by bronchoscopy, CT-guided procedures or surgery. The sequence of tissue removal, storage, and processing has a considerable impact on the success and reliability of subsequent molecular biological analyses and will supposedly also influence therapeutic decisions. There is still an ongoing need for updated statements about the minimal requirements of tissue sampling for molecular diagnosis at international level and for certified/accredited quality control programs of the sampling procedures. Several of these issues may have to be adjusted to the individual local conditions. We will present several aspects of experiences gained in Thoraxklinik at the University Hospital of Heidelberg (TK-HD) with pre-analytical tissue requirements. PMID- 25806168 TI - Targeting angiogenesis in lung cancer - Pitfalls in drug development. AB - In non-small-cell lung cancer, anti-angiogenic strategies like bevacizumab have developed into standard treatment options. New anti-angiogenic drugs like tyrosine kinase inhibitors generated optimistic results in phase II trials, but failed to translate into positive results in phase III trials. In this overview some critical aspects of the biology of tumor angiogenesis and potential pitfalls of anti-angiogenic drug development are discussed. These include the design of clinical trials, dosage of investigational drugs or the choice of combinational drugs, the lack of validated biomarkers and the complexity of the patho-biology of tumor angiogenesis. Future trials should also direct attention to the role of cigarette smoke and the stage of the disease, which is investigated. PMID- 25806170 TI - EGFR IHC score for selection of cetuximab treatment: Ready for clinical practice? PMID- 25806169 TI - Erlotinib in patients with advanced non-small-cell lung cancer: A meta-analysis. AB - Erlotinib is a potent reversible HER1/epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with single-agent activity in patients with non-small cell lung cancer (NSCLC). In this article, we updated the evidence of erlotinib in treating advanced NSCLC by adding new results of RCTs published between January 2011 and May 2012 into a pooled analysis which had been published in 2011. Outcomes analyzed were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events. Twenty trials including 9,005 patients were identified, and six of them were recently published. As first line therapy compared to placebo or chemotherapy, there was a similar ORR (P=0.29 and 0.42), PFS (P=0.09 and 0.25) and OS (P=0.73 and 0.49). However, for the patients with EGFR mutations, erlotinib based regimens could significantly improve ORR (P<0.01), prolong PFS (P<0.0), but did not prolong OS (P=0.22). As maintenance therapy compared with placebo, erlotinib based regimens significantly increased ORR (P<0.01), prolonged PFS (P<0.01), but did not improve OS (P=0.22). As second/third-line therapy comparing with placebo, erlotinib based regimens also significantly increased ORR (P<0.01), prolonged PFS (P<0.01), and improved OS (P<0.01). As second/third-line therapy compared with chemotherapy, gefitinib, or vandetanib, the outcomes were similar between two arms. However, compared with PF299804, there was a decreased ORR (P=0.02), and shorten PFS (P=0.02). Meanwhile, The patients treated with erlotinib based regimens suffered from more diarrhea, rash, and less fatigue, neutropenia, and thrombocytopenia than other agent based regimens. Our meta analysis showed that erlotinib based regimens could significantly increase ORR, improve PFS as first-line maintenance therapy or second/third-line therapy comparing with placebo or PF299804. PMID- 25806171 TI - TKIs in NSCLC: the down of a new era? PMID- 25806172 TI - Treating acquired resistance to EGFR-tyrosine kinase inhibitors:still a work in progress. AB - While most patients with metastatic non-small cell lung cancer (NSCLC) containing sensitizing mutations in the epidermal growth factor receptor (EGFR) gene will achieve an objective response to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, patients inevitably develop resistance to these agents. One of the strategies being tested to overcome acquired resistance to EGFR TKIs is the use of irreversible EGFR inhibitors such as afatinib. In the randomized phase 2b/3 LUX-Lung 1 trial in advanced NSCLC patients who progressed after at least 12 weeks of benefit from EGFR TKIs, afatinib failed to improve overall survival compared to placebo. Although the liberal entry criteria likely allowed the inclusion of some patients without true acquired resistance, the failure of this study calls into question the viability of irreversible EGFR inhibitors in this patient population. PMID- 25806173 TI - Is there a third line option after chemotherapy and TKI failure in advanced non small cell lung cancer? PMID- 25806174 TI - TRAIL apoptotic pathway-targeted therapies for NSCLC. PMID- 25806175 TI - Dulanermin in cancer therapy: still much to do. PMID- 25806176 TI - EGFR TKIs as maintenance therapy in NSCLC: Finding the old in the new INFORMation. PMID- 25806177 TI - Establishment of a malignant pleural effusion mouse model: pathogenesis pathways. PMID- 25806178 TI - Malignant pleural effusion: further translational research is crucial. PMID- 25806179 TI - Establishment of a malignant pleural effusion mouse model with lewis lung carcinoma cell lines expressing enhanced green fluorescent protein. AB - BACKGROUND AND OBJECTIVE: Malignant pleural effusion (MPE) is a poor prognostic factor in patients with advanced lung cancer. The aim of this study is to establish a mouse model of MPE using Lewis lung carcinoma (LLC) cell lines expressing enhanced green fluorescent protein (EGFP). METHODS: The mouse model was created by injecting LLC-EGFP cells directly into the pleural cavity of nude mice under the guidance of stereomicroscope and then mice were sacrificed periodically. The dynamic growth and metastasis of tumor cells were screened using in vivo fluorescence imaging. The remaining mice were subjected to transverse computed tomography (CT) periodically to analyze the rate of MPE formation. The survival rate and tumor metastasis were also observed after modeling. Pleural fluid was gently aspirated using a 1 mL syringe and its volume was measured. When two or more mice bore MPE at the same time, we calculated the average volume. The correlation of MPE with the integrated optical density (IOD) were analyzed. RESULTS: Four days after the inoculation of LLC-EGFP cells, green fluorescence was observed by opening the chest wall. The tumor formation rate was 100%, and the IOD gradually increased after inoculation. The metastatic foci were mediastinal, contralateral pleural and pericardial. The metastasis rates were 87%, 73%, and 20%, respectively. CT imagings revealed that the rates of MPE formation on days 7, 14 and 21 were 13%, 46%, and 53%. The mean survival time of nude mice was 28.8 days. The average MPE volume increased obviously on day 10 and peaked on day 16 with a value of 0.5 mL. The MPE volume and IOD were significantly correlated (r=0.91, P<0.0001). CONCLUSIONS: This study was the first to establish a mouse model of MPE by injecting LLC-EGFP into the pleural cavity under the guidance of a stereomicroscope. The model can enable dynamic observations of the biological behavior of tumor cells in the pleural cavity. It might be helpful for basic research on advanced lung cancer as well as anti-tumor drug development. PMID- 25806184 TI - First line erlotinib for NSCLC patients not selected by EGFR mutation: keep carrying the TORCH or time to let the flame die? PMID- 25806185 TI - Turn on the TORCH before treat your patients: a lesson from a first line study in advanced NSCLC. PMID- 25806182 TI - Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a concise review. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) offers a minimally invasive alternative to mediastinoscopy with additional access to the hilar nodes, a better safety profile, and it removes the costs and hazards of theatre time and general anesthesia with comparable sensitivity, although the negative predictive value of mediastinoscopy (and sample size) is greater. EBUS- TBNA also obtains larger samples than conventional TBNA, has superior performance and theoretically is safer, allowing real-time sampling under direct vision. It can also have predictive value both in sonographic appearance of the nodes and histological characteristics. EBUS-TBNA is therefore indicated for NSCLC staging, diagnosis of lung cancer when there is no endobronchial lesion, and diagnosis of both benign (especially tuberculosis and sarcoidosis) and malignant mediastinal lesions. The procedure is different than for flexible bronchoscopy, takes longer, and requires more training. EBUS-TBNA is more expensive than conventional TBNA but can save costs by reducing the number of more costly mediastinoscopies. In the future, endobronchial ultrasound may have applications in airways disease and pulmonary vascular disease. PMID- 25806183 TI - Combined treatment with MET inhibitors and other therapies in lung cancer. PMID- 25806181 TI - MET genetic lesions in non-small-cell lung cancer: pharmacological and clinical implications. AB - Lung cancer is the leading cause of death for solid tumors worldwide with an annual mortality of over one million. Lung carcinoma includes a series of different diseases which are roughly divided into two groups based on clinical and histo-pathological features: non-small cell lung cancer (NSCLC), accounting for almost 80% of lung cancer diagnosis and small cell lung cancer (SCLC) responsible for the remaining 20%. The NSCLC molecular profile has been deeply investigated; alterations in several oncogenes, tumor suppressor genes and transcription factors have been detected, mainly in adenocarcinomas. Dissection of such a complex scenario represents a still open challenge for both researchers and clinicians. MET, the receptor for Hepatocyte Growth Factor (HGF), has been recently identified as a novel promising target in several human malignancies, including NSCLC. Deregulation of the HGF/MET signaling pathway can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. While the role of MET mutations in NSCLC is not yet fully understood, MET amplification emerged as a critical event in driving cell survival, with preclinical data suggesting that MET-amplified cell lines are exquisitely sensitive to MET inhibition. True MET amplification, which has been associated with poor prognosis in different retrospective series, is a relatively uncommon event in NSCLC, occurring in 1-7% of unselected cases. Nevertheless, in highly selected cohorts of patients, such as those harboring somatic mutations of EGFR with acquired resistance to EGFR tyrosine kinase inhibitors, MET amplification can be observed in up to 20% of cases. Preclinical data suggested that a treatment approach including a combination of EGFR and MET tyrosine kinases could be an effective strategy in this setting and led to the clinical investigation of multiple MET inhibitors in combination with anti-EGFR agents. Results from ongoing and future trials will clarify the role of anti-MET molecules for the treatment of NSCLC and will provide insights into the most appropriate timing for their use. The present review recapitulates the current knowledge on the role of MET signaling in NSCLC mainly focusing on its implications in molecular diagnostic approach and on the novel targeted inhibitors. PMID- 25806180 TI - Role of HGF/MET axis in resistance of lung cancer to contemporary management. AB - Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes. The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this MET/HGF axis interacts with other oncogenic signaling pathways such as the epidermal growth factor receptor (EGFR) pathway and the vascular endothelial growth factor receptor (VEGFR) pathway. This functional cross-talk forms the basis for the role of MET/HGF axis in resistance against anti-EGFR and anti-VEGF targeted therapies. MET and/or HGF overexpression from gene amplification and activation are mechanisms of resistance to cetuximab and EGFR-TKIs. VEGF inhibition promotes hypoxia induced transcriptional activation of MET proto-oncogene that promotes angiogenesis and confers resistance to anti-angiogenic therapy. An extensive understanding of these resistance mechanisms is essential to design combinations with enhanced cytotoxic effects. Lung cancer treatment is challenging. Current therapies have limited efficacy due to primary and acquired resistance. The MET/HGF axis plays a key role in development of this resistance. Combining MET/HGF inhibitors with chemotherapy, radiotherapy and targeted therapy holds promise for improving outcomes. PMID- 25806186 TI - Front-line erlotinib in unselected patient with advanced NSCLC followed by standard chemotherapy with gemcitabine and cisplatin - TORCH study. PMID- 25806187 TI - Intrapulmonary lymph node retrieval: unclear benefit for aggressive pathologic dissection. PMID- 25806188 TI - Gene therapy for lung cancer malignant pleural effusion: current and future nano biotechnology. PMID- 25806189 TI - MET inhibitors in combination with other therapies in non-small cell lung cancer. AB - MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF 02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer. PMID- 25806191 TI - Innovative technologies in thoracic radiation therapy for lung cancer. AB - Radiation therapy plays a major role in the cure of patients affected with lung cancer, both in early and locally advanced disease. Local control and survival rates are still poor, even with the best combination with chemotherapy and/or targeted agents. The recent technical advances in radiotherapy changed the planning and delivery processes, enabling radiation oncologists to modify treatment schedules towards further dose intensification, while opening a new scenario for future clinical studies. In this paper we briefly review the major technical changes in the field of thoracic radiotherapy for primary lung tumors and their potential in improving clinical outcomes. PMID- 25806193 TI - Pulmonary adenocarcinoma histology. PMID- 25806190 TI - Potential toxicities of prophylactic cranial irradiation. AB - Prophylactic cranial irradiation (PCI) with total doses of 20-30 Gy reduces the incidence of brain metastasis (BM) and increases survival of patients with limited and extensive-disease small-cell lung cancer (SCLC) that showed any response to chemotherapy. PCI is currently not applied in non-small-cell lung cancer (NSCLC) since it has not proven to significantly improve OS rates in stage IIIA/B, although novel data suggest that subgroups that could benefit may exist. Here we briefly review potential toxicities of PCI which have to be considered before prescribing PCI. They are mostly difficult to delineate from pre-existing risk factors which include preceding chemotherapy, patient age, paraneoplasia, as well as smoking or atherosclerosis. On the long run, this will force radiation oncologists to evaluate each patient separately and to estimate the individual risk. Where PCI is then considered to be of benefit, novel concepts, such as intensity-modulated radiotherapy and/or neuroprotective drugs with potential to lower the rates of side effects will eventually be superior to conventional therapy. This in turn will lead to a re-evaluation whether benefits might then outweigh the (lowered) risks. PMID- 25806192 TI - EGFR-directed monoclonal antibodies in non-small cell lung cancer: how to predict efficacy? AB - Cetuximab improved survival when added to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer. In order to determine those patients who will derive the greatest benefit from the addition of cetuximab, the associations of clinical and tumor features with clinical outcome were determined. High EGFR expression of tumor cells based on an immunohistochemistry score was shown to predict benefit of cetuximab. Among patients with high EGFR expression, the hazard ratio for death was 0.73 in favor of chemotherapy plus cetuximab compared to chemotherapy alone. Among patients with low EGFR expression, no difference in survival was observed between patients treated with chemotherapy plus cetuximab compared to those treated with chemotherapy alone. The treatment interaction test was significant. KRAS mutation status and EGFR copy numbers were without predictive value. Patients with EGFR-activating mutations in their tumors had longer survival independent of the use of cetuximab. In conclusion, EGFR expression levels lend themselves as predictive biomarkers for the selection of those patients who will benefit from the addition of cetuximab to first-line chemotherapy with platinum-based doublets. PMID- 25806194 TI - Neoadjuvant EGFR TKIs: toward personalized management in non-small-cell lung cancer. PMID- 25806195 TI - The TORCH trial. PMID- 25806196 TI - Expanding options for EGFR targeting in lung cancer. PMID- 25806197 TI - Spontaneous bilateral pneumothorax in a patient with metastatic synovial sarcoma while under chemotherapy. AB - We report a case of synovial sarcoma of the lower limbs with pulmonary metastasis in a 24-year-old male patient who developed progressive spontaneous bilateral pneumothorax while he was on chemotherapy. Chest tubes inserted and achieved recovery in the left side whereas the right side became worse. Right lung decortication was carried out and the biopsy confirmed the diagnosis of synovial sarcoma metastasis. Thereafter, the patient was kept on chemotherapy of IV ifosfamide + etoposide D1-5, and after 2 cycles he traveled back to his country to continue treatment there. PMID- 25806198 TI - Incomplete intrapulmonary lymph node retrieval after routine pathologic examination of resected lung cancer. PMID- 25806199 TI - New insights into the functional consequences of ephrin A3 mutations in non-small cell lung cancer. PMID- 25806200 TI - Is overall survival still the primary endpoint in maintenance non-small cell lung cancer studies? An analysis of phase III randomised trials. AB - BACKGROUND: In advanced non-small cell lung cancer (NSCLC), the increasing number of active compounds available in second line settings makes overall survival (OS) with maintenance treatment a not frequently observed endpoint. A literature review was conducted to examine whether post-progression survival (PPS) correlates with OS in maintenance trials. MATERIALS AND METHODS: PPS was defined as median OS - median PFS. The authors used the coefficient of correlation (r) to assess the correlation between them. They also evaluated the surrogacy of PFS and OS. RESULTS: Ten trials with 11 arms were identified. Overall, a stronger correlation was observed between OS and PPS [Spearman rank correlation coefficient (r) =0.75] than OS and PFS time (r=0.37). The correlation of differences in median PFS (DeltaPFS) and median OS (DeltaOS) is 0.64 (P=0.0326). The slope of the regression line is 0.76, indicating that a maintenance therapy producing a one-month gain in PFS will yield an estimated three weeks prolongation in OS. CONCLUSIONS: PPS is strongly associated with OS because of intensive post-study further lines of treatment. However, improvements in PFS are moderately associated with improvements in OS. Hence, in this setting, PFS is a possible surrogate for OS. PMID- 25806201 TI - Inhibition of insulin-like growth factor receptor: end of a targeted therapy? AB - The Insulin-like Growth Factor 1 (IGF-1) signaling pathway activates several downstream signals important to lung cancer development and survival. IGF-1R activation has been linked to cancer risk in epidemiological studies and tumorigenesis in preclinical models. Several inhibitors of the insulin-like growth factor 1 receptor (IGF-1R) have been tested in clinical trials. Despite promising data in early phase studies, most studies of IGF-1R antagonists in combination with chemotherapy or with epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) yielded disappointing results. Biomarker studies of clinical trials have identified IGF-1 levels as a potential marker of sensitivity to IGF-1R inhibition. Further study will need to focus on selection of NSCLC patients most likely to benefit from the addition of IGF-1R antagonists to standard therapy and the development of rational strategies for combination therapy in NSCLC. PMID- 25806204 TI - Does the order of factors affect the product? Lessons learned from the TORCH trial. PMID- 25806203 TI - Irreversible EGFR-TKIs: dreaming perfection. AB - In the last few years, the treatment of Non-Small-Cell Lung Cancer (NSCLC) has dramatically changed. Presence of activating mutations in the Epidermal Growth Factor Receptor (EGFR) identified a particular group of NSCLC patients with different clinical characteristics and outcome. For EGFR mutant patients first generation EGFR tyrosine-kinase inhibitors (TKIs), such as gefitinib and erlotinib, represent the best therapeutic option in first, second and maintenance setting. Unfortunately, all patients develop acquired resistance and despite an initial benefit, virtually all patients progress due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance and the two prominent are the up-regulation of the downstream signal by mesenchymal-epidermal transition (MET) amplification and the emergence of T790M EGFR gatekeeper mutation. Preclinical and early clinical trials suggested a potential efficacy of a new class of panHER inhibitor, also called irreversible or covalent inhibitor, in overcome acquired resistance related to T790M. Afatinib, dacomitinib and neratinib, are currently in development in different setting and results from these trials are awaited in order to establish the role of these new compounds in the treatment of NSCLC. PMID- 25806205 TI - Keeping our fingers crossed on 2(nd) generation EGFR TKIs: is better good enough? PMID- 25806202 TI - MET inhibition in lung cancer. AB - Targeted agents have completely changed cancer treatment strategy, leading it from a "one size fits all" approach to a customized therapy. In this scenario Met, a heterodimere receptor tyrosine kinase deeply involved into embryogenesis and organogenesis, has been introduced many years ago as a potential target for biological agents, becoming "druggable" only in this last period of time. Met can be altered through receptor overexpression, genomic amplification, mutations or alternative splicing, autocrine or paracrine secretion of hepatic growth factor (HGF): these dysregulations stimulate tumorigenesis (in terms of cell-cell detachment, proliferation, invasion, angiogenesis and survival) and metastatization. Met is overexpressed in lung cancer and Met gene amplification can drive the dependency of cell survival and proliferation upon the Met signaling. Both Met overexpression and amplification seem to correlate with poor prognosis. Met amplification is also described to be linked to EGFR acquired resistance. Several Met inhibitors have been tested both in preclinical and human trials, demonstrating activity in lung cancer treatment. This paper aims to summarize data on Met biological function, on its interaction with cell signaling and other pathways and to present data on those Met inhibitors currently under evaluation. PMID- 25806207 TI - The TOPICAL study should be more topical! PMID- 25806206 TI - Front-line erlotinib in unselected patients with advanced NSCLC and poor performance status - the TOPICAL study. PMID- 25806208 TI - ZEPHYR illustrates the perils of testing targeted treatments in unselected non small-cell lung cancer patients. PMID- 25806209 TI - Antiangiogenic tyrosine kinase inhibitors in non-small-cell-lung cancer: lights and shadows. PMID- 25806210 TI - Angiogenesis, multitarget kinase inhibitors and non-small cell lung cancer: a lesson from MONET1 trial. PMID- 25806212 TI - Dr Haiquan Chen: clinical significance of RET fusion gene for patients with NSCLC. PMID- 25806211 TI - Targeted versus chrono-targeted chemotherapy for inhaled chemotherapy in non small cell lung cancer. AB - Lung cancer long term survival still remains poor and early detection is still the best methodology to treatment. Therefore several novel approaches have been investigated for anticancer drug administration. Inhaled therapies for lung diseases are used since the ancient times. Inhaled anticancer treatment administration was firstly investigated almost 30 years ago. Since then the inclusion and exclusion criteria have been investigated in correlation with the safety and efficacy of cisplatin, 5-fluoracil, carboplatin, paclitaxel, docetaxel, 9-nitro camptothecine, gemcitabine, cetuximab, granulocyte-colony stimulating factor, interleukins and recently with bevasizumab. Along with the anticancer drug formulations administered, other aspects of this local treatment have been also investigated to improve the efficiency and safety, such as; proper nebulization system, drug formulation delivery system, setting of administration, aerosol protection measures, inhalation techniques and safety issues follow up. During the last years with the use of actigraphy wrist watches, an extended investigation of the circadian rhythm of animals and humans has been performed and new insights are included in lung cancer chemotherapy administration. The "personalized" therapy administration should not be considered only as a molecular pathway inhibition, but also as a chrono-targeted anticancer treatment. PMID- 25806214 TI - Endobronchial carcinoid tumor in a Crohn disease patient treated with a TNFalpha inhibitor. AB - A young patient with Crohn's disease is presented in whom pulmonary carcinoid tumor was incidentally found. Bronchoscopy showed an endobronchial lesion and biopsy pathology was consistent with atypical carcinoid. Octeotride scan suggested primary origin of the tumor. Although patients with Crohn's disease have been reported to have increased incidence of intestinal carcinoid, we believe this to be the second case of primary carcinoid pulmonary located in this population. PMID- 25806213 TI - Recurrent left chest mass: a case report. AB - Empyema necessitans is a rare complication of untreated pleural space infections. Untreated empyema that spontaneously burrows through the parietal pleura can present with a subcutaneous abscess. In the following case report, we present a 55 year old male who presented with an intermittent left chest mass later to be diagnosed as empyema necessitans. The patient suffered from a hemothorax treated by tube thoracostomy three years prior. The patient had been seen several times and no mass could be appreciated. The patient was diagnosed with empyema necessitans on computed tomography and treated with a left thoracotomy. Empyema necessitans can develop if pleural infections are left untreated. We present an unusual presentation of this rare complication. Empyema necessitans should be kept in the differential diagnosis of patients with left chest masses or abscesses. PMID- 25806215 TI - ZEPHYR: failure of a "spring wind" in lung cancer. PMID- 25806216 TI - Vandetanib in advanced non small cell lung cancer: a promise unfulfilled. PMID- 25806217 TI - CK-coated magnetic-based beads as a tool to isolate circulating tumor cells (CTCs) in human tumors. AB - Circulating tumor cells (CTCs) can be detected in the blood of many cancer patients and play a key role in metastasis. In addition, after the development of technologies with the necessary sensitivity and reproducibility, the diagnostic potential of these cells is being actively explored. Recently, the U.S. Food and Drug Administration has approved the CellSearch((r)) System, based on magnetic beads coated with epithelial cell-adhesion molecule (EpCAM) antibody. Despite its usefulness, this system can miss CTCs that lose epithelial antigens due to the epithelial-mesenchymal transition and, in the case of advanced NSCLC, CTCs positivity can be demonstrated only in 30-50% of patients. In an effort to overcome these drawbacks, new methods are being developed. In this study, we have evaluated CK-coated beads as a system to isolate CTCs from lung cancer patients in the clinical setting, and have evaluated if they can be a useful source of material for genetic testing. We were able to identify CTCs in 17 of the 30 patients included in the study (57%), with a range of 1 to 7 cells. In two of them, we found only CTCs with an EMT pattern. CTC positivity seemed to correlate with the clinical history of the malignancy. CTCs could be detected in more than 80% of stage III-IV lung cancer patients at presentation or in blood samples taken immediately after surgery. The percentage dropped to 13% in patients responding to chemotherapy or TKIs, raising again to 57% after tumor progression. Finally, we tested the CTCs isolated from 8 patients for EGFR and k-ras mutations, but gene amplification was successful only in the 3 patients with 4 or more CTCs. PMID- 25806219 TI - Comprehensive molecular screening: from the RT-PCR to the RNA-seq. AB - Up to now, the analysis of the mRNA expression in tumoral and non-tumoral has been conducted via RT-PCR. It is considered to be the gold standard for measuring the number of copies of specific cDNA targets. The application of RT-PCR has demonstrated that levels of RNA transcripts stratify patients and predict outcomes in a variety of diseases, providing the basis for several important clinical tests. However, the inherent variability in the quality of any quantitative PCR data makes it difficult to replicate and the analysis is time consuming in the laboratory for the analysis of one gene. Moreover, comparing expression levels across different experiments is often difficult and can require complicated normalization methods. Many techniques have been developed over the years but without good clinical applications. A new, simple and effective way to measure transcriptome composition and to discover new exons or genes is by the RNA-seq. Some advantages of this technique are high reproducibility, the large dynamic range, requirement of less sample RNA, and the ability to detect novel transcripts, alternative splicing, even in the absence of a sequenced genome. However, this RNA-Seq technique will not likely replace current RT-PCR methods, but will be complementary depending on the needs and the resources of the clinic and the laboratory as the results of the RNA-Seq will identify those genes that need to then be examined using RT-PCR methods. The application of the two complementary technologies in the routine analysis of cancer laboratories would be useful in characterizing patients and would assist oncologists in making clinical decisions, as it allows us to identify all molecular characteristics of the tumor. PMID- 25806218 TI - ALK and ROS1 as a joint target for the treatment of lung cancer: a review. AB - Rearrangements of the anaplastic lymphoma kinase (ALK) have been described in multiple malignancies, including non-small cell lung cancer (NSCLC). ALK fusions have gain of function properties while activating mutations in wild-type ALK can also occur within the tyrosine kinase domain. ALK rearrangements define a new molecular subtype of NSCLC that is exquisitely sensitive to ALK inhibition. Crizotinib, an orally available small molecule ATP-mimetic compound which was originally designed as a MET inhibitor, was recognized to have "off-target" anti ALK activity and has been approved in the USA for the treatment of patients with ALK-positive NSCLC. Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase have also been recently described in NSCLC, while crizotinib is currently under clinical trial in this molecular subset of NSCLC patients. The basic approaches of any computer aided drug design work in terms of structure and ligand based drug design. Details of each of these approaches should be covered with an emphasis on utilizing both in order to develop multi-targeted small molecule kinase inhibitors. Such multi-targeted tyrosine kinase inhibitors can have antiproliferative activity against both ROS1and ALK rearranged NSCLC. Herein, we highlight the importance of targeting these proteins and the advances in optimizing more potent and selective ALK and ROS1 kinase inhibitors. PMID- 25806220 TI - FGFR1 amplifications in squamous cell carcinomas of the lung: diagnostic and therapeutic implications. AB - Fibroblast growth factor receptor 1 (FGFR1) is a type 4 receptor tyrosine kinase. The receptor and its ligands play an important role in development and physiology. However, constitutive activation of FGFR1 by gene amplification, translocation or mutation is associated with various malignancies as, for example, breast cancer or myeloproliferative diseases. We have recently reported that FGFR1 amplification occurs in 20% of pulmonary squamous cell carcinomas, and preclinical tests have shown that these alterations are therapeutically tractable. These findings make FGFR1 amplification a potential biomarker for lung cancer treatment. Squamous cell carcinomas of the lung are characterized by an uneven FGFR1 gene copy number distribution. Therefore, fluorescence in situ hybridization assays need to address focality and heterogeneity of FGFR1 in these tumors. Here, we review our proposal for a reading and evaluation strategy. Furthermore, we highlight the emerging landscape of clinical trials with selective and unselective FGFR inhibitors and provide first response data from early clinical trials. PMID- 25806221 TI - Copy number gains of FGFR1 and 3q chromosome in squamous cell carcinoma of the lung. AB - Squamous cell carcinoma of the lung (SQCCL) remains a leading cause of cancer related death. Unlike non-smoker adenocarcinoma of the lung, where highly efficient tyrosine kinase inhibitors are available for treating mutant EGFR or ALK-rearranged, no targetable biomarkers are available for SQCCL. The frequent and focal amplification of FGFR1 has generated great expectations in offering new therapeutical options in case of 16-22% of SQCCL patients. Broad 3q chromosome amplification is widely recognized as the most common chromosomal aberration found in SQCCL, where PIK3CA, SOX2, ACK1, PRKCI, TP63, PLD1, ECT2, and others genes are located. Although SOX2 has been postulated as a key regulator of basal stem cells transformation and tumor progression, it seems to confer a good prognosis in SQCCL. It is known that each patient might carry a different length of 3q chromosome amplicon. Thus, we suggest that the number and the biological importance of the genes spanned along each patient's 3q amplicon might help to explain inter-individual outcome variations of the disease and its potential predictive value, especially when relevant oncogenes such as those mentioned above are implicated. Currently, there is no clinical predictive data available from clinical trials. In this review, we have focused on the potential role of FGFR1 in SQCCL prognosis. Additionally, we have explored recently available public data on the comprehensive genomic characterization of SQCCL, in relation to the protein-coding genes that have a strong gene copy number - mRNA correlation in 3q chromosome, that were previously described as potential driver oncogenes or its modifiers in SQCCL. PMID- 25806223 TI - HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches. AB - Oncogenic driver mutations identified in non-small cell lung cancer (NSCLC) have triggered the development of drugs capable of interfering in intracellular signaling pathways involved in tumorigenesis. Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced NSCLC that harbor EGFR mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerization or heterodimerization with other ERBB receptors. Deregulation of HER2 gene, by overexpression and/or gene amplification has been proved important in breast and gastric cancer, in which overexpression of HER2 confers greater response to specific anti-HER2 treatment, including trastuzumab. In lung carcinogenesis, HER2 mutations are thought to be more clinically relevant than overexpression or gene amplification. HER2 mutations in NSCLC, described exclusively in adenocarcinoma histology, are present in approximately 4% of this subset of lung cancer patients, suggesting that thousands of patients per year may possibly benefit from targeted therapy. Therefore, we conclude that systematic genotypic testing in this subgroup of NSCLC patients should include detection of HER2 mutations. In addition, clinical trials with standard antiHER2 agents and new investigational therapies are ongoing, with promising preliminary results, as illustrated in this review, although further research is warranted in this field. PMID- 25806222 TI - Activated RET and ROS: two new driver mutations in lung adenocarcinoma. AB - Rearrangements of ROS1 and RET have been recently described as new driver mutations in lung adenocarcinoma with a frequency of about 1% each. RET and ROS1 rearrangements both represent unique molecular subsets of lung adenocarcinoma with virtually no overlap with other known driver mutations described so far in lung adenocarcinoma. Specific clinicopathologic characteristics have been described and several multitargeted receptor kinase inhibitors have shown in vitro activity against NSCLC cells harbouring these genetic alterations. In addition, the MET/ALK/ROS inhibitor crizotinib has already shown impressive clinical activity in patients with advanced ROS1-positive lung cancer. Currently, several early proof of concept clinical trials are testing various kinase inhibitors in both molecular subsets of lung adenocarcinoma patients. Most probably, personalized treatment of these genetically defined new subsets of lung adenocarcinoma will be implemented in routine clinical care of lung cancer patients in the near future. PMID- 25806226 TI - Response to editorial titled 'Intrapulmonary lymph node retrieval: unclear benefit for aggressive pathologic dissection'. PMID- 25806227 TI - Response to: intrapulmonary lymph node retrieval. PMID- 25806225 TI - KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach. AB - K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific "synthetic lethal" interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID- 25806224 TI - Targeting EML4-ALK driven non-small cell lung cancer (NSCLC). PMID- 25806228 TI - Adaptive resistance to targeted therapies in cancer. AB - It is widely acknowledged that there is a need for molecular profiling in non small-cell lung cancer. For example, treatment based on EGFR mutation status has attained successful results. However, in spite of excellent initial response to oral EGFR tyrosine kinase inhibitors (TKIs), progression-free survival is still limited. Current research has focused mostly on acquired resistance mechanisms, such as overexpression of AXL and loss of the Mediator MED12. In this review, in contrast, we discuss adaptive, rather than acquired, resistance. Adaptive resistance can occur almost immediately after starting targeted therapy through a rapid rewiring of cancer cell signaling. By losing ERK negative feedback on receptor tyrosine kinase (RTK) expression, cancer cells are exposed to the stimuli of several ligands, and the ensuing activation of several RTKs reprograms all the canonical signaling pathways. The overexpression of several RTKs was observed in breast cancer cell lines treated with a MEK inhibitor and in BRAF(V600E) melanoma cell lines treated with BRAF inhibitors. This rebound effect of overexpression of several RTKs, including ERBB3, also occurs in lung cancers driven by Kras or EGFR mutations when treated with MEK, PI3K or dual PI3K/mTOR inhibitors. Synthetic lethality can be effectively induced by co-targeting these overexpressed RTKs. We speculate that in patients with EGFR mutations, adaptive resistance occurs in a significant proportion of patients. Rebiopsies performed hours after starting treatment with EGFR TKIs can identify which RTKs are overexpressed after treatment. Efficient co-targeting of these RTKs can induce synthetic lethality and help overcome the limited effect of EGFR TKI monotherapy. PMID- 25806229 TI - Predictive models for customizing chemotherapy in advanced non-small cell lung cancer (NSCLC). AB - The backbone of first-line treatment for Epidermal Growth Factor (EGFR) wild-type (wt) advanced Non-small cell lung cancer (NSCLC) patients is the use of a platinum-based chemotherapy combination. The treatment is characterized by great inter-individual variability in outcome. Molecular predictive markers are extremely needed in order to identify patients most likely to benefit from platinum-based treatment and resistant ones, thus optimizing chemotherapy approach in NSCLC. Several components of DNA repair response (DRR) have been investigated as potential predictive markers. Among them, high levels of expression of ERCC1, both at protein and mRNA levels, have been associated with resistance to cisplatin in NSCLC. In addition, low levels of expression of RRM1, a target for gemcitabine, have been associated with improved OS in advanced NSCLC patients treated with cisplatin and gemcitabine. Preclinical data and retrospective analyses showed that BRCA1 is able to induce resistance to cisplatin and sensitivity to antimicrotubule agents. In addition, the mRNA levels of expression of RAP80, encoding for a protein cooperating with BRCA1 in homologous recombination (HR), have demonstrated to further sub-classify low BRCA1 NSCLC tumors, improving the predictive model. On the basis of biological knowledge on DNA repair pathway and recent controversial results from clinical validation of potential molecular markers, integrated analysis of multiple DNA repair components could improve predictive information and pave the way to a new approach to customized chemotherapy clinical trials. PMID- 25806230 TI - The role of SOX2 in small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung. AB - SOX2 is a stem cell transcription factor that plays a crucial role in the regulation of embryonic development. It is one of the genes in a set of factors (Oct4, SOX2, Nanog) that are able to reprogram human somatic cells to pluripotent stem cells. Overexpression of SOX2 has been described in all types of lung cancer tissues, including small cell and squamous cell carcinoma but also adenocarcinoma. An in-depth view of the spectrum of genomic alterations in small cell lung cancer (SCLC) has identified SOX2 as a potential target for therapeutic intervention. Amplification of 3q, the most common genomic aberration in squamous lung cancer, has been demonstrated in the evolution of preinvasive squamous lung cancer and implicates SOX2 as a key target of this dynamic process, making SOX2 and its downstream effector components potential targets for biological therapeutics of squamous carcinomas. SOX2 is expressed in nearly 20% of lung adenocarcinoma and is associated with poor prognosis. SOX2 activity was found to promote squamous identity instead of a loss of cellular differentiation consistent with the role of SOX2 as a "lineage-survival oncogene." Interestingly, SOX2 transcription factor is the predominant downstream target of EGFR signaling and plays a major role in self-renewal growth and expansion of side population cells. In light of the complex actions of SOX2 in regulating normal and tumor development, the elucidation of SOX2-dependent pathways may identify new therapeutic vulnerabilities in lung cancer and uncover additional common pathways between cancer, normal development, and the maintenance of pluripotency. PMID- 25806232 TI - State of the art of radiotherapy. AB - Locally advanced or stage III disease accounts for ~30% of patients with non small-cell lung cancer (NSCLC), which means only in the United States, more than 50,000 new patients each year. Stage III is a very heterogeneous disease, the management of patients is complex and several conditions (performance status, weight loss, comorbidities, characteristics of nodal involvement or resectability) must be considered before selecting the best treatment, which in most cases is chemotherapy (CT) and radiotherapy (RT). In this article, we will review key changes in the management of unresectable stage III during the last decades. Also we will highlight some challenges and areas of active research. PMID- 25806231 TI - Customized chemotherapy in metastatic non-small cell lung cancer (NSCLC). AB - Metastatic non-small cell lung cancer (NSCLC) unfortunately remains a lethal disease, despite recent genetic characterization of subclasses of NSCLC, mainly adenocarcinoma, which has led to the development of targeted therapies that improve progression-free survival (PFS). Ultimately, however, patients fatally relapse. In this review we will focus on the search to improve survival for NSCLC patients deemed to be pan-negative for the common driver alterations susceptible to targeted therapy, above all those with EGFR mutations or ALK, ROS or RET translocations. Other uncommon driver mutations such as HER2 and BRAF mutations should be tested in order to rule out targeted treatment before assigning patients to chemotherapy. Chemotherapy yields short lived response with median survival still less than one year. Customized chemotherapy represents one way to attempt to prolong survival, although to date no prospective randomized customized studies have reported sufficient evidence to support this. In one attempt to demonstrate the role of tailoring chemotherapy, the Spanish Lung Cancer Group (SLCG) phase II customized chemotherapy trial (NCT00883480) showed that RAP80, a component of the BRCA1-A complex, influenced outcome in patients with low BRCA1 expression treated with cisplatin/gemcitabine, and in patients with intermediate/high BRCA1 levels receiving cisplatin/docetaxel or docetaxel alone. We are currently performing a prospective, randomized phase III trial comparing non-customized cisplatin/docetaxel with customized therapy in metastatic NSCLC patients (NCT00617656/GECP-BREC) and a parallel phase II study (ChiCTR-TRC-12001860) is being carried out in China (BREC-China) under the auspices of the SLCG. PMID- 25806233 TI - Management of elderly patients. AB - SUMMARY: Elderly patients are often excluded from clinical trials, yet more than two-thirds of patients diagnosed with lung cancer are over 65 years old. It is therefore important to develop specific tools and trials for this specific patient population. METHODS: This chapter first examines the management specificities of elderly patients. Randomized trials specifically involving elderly patients are then described, and likely future developments are considered. RESULTS: Older people have several specificities. In addition to traditional criteria such as age and performance status, other important factors include the number of comorbidities and age-related changes such as cognitive deficits and depression. Specific indices taking these factors into account have been published and validated. Single-agent therapy has been widely used to treat metastatic lung cancer in the elderly, following publication of negative results from randomized phase III trials of combination chemotherapy. Recently, however, a trial of doublet therapy gave positive results, in a subgroup of independent older patients. The benefit of patient selection based on a combination of these indices has been demonstrated in open-label and randomized trials. These results must now be confirmed in phase III trials including the use of tyrosine kinase inhibitors combined with chemotherapy. CONCLUSIONS: Indices based on a combination of age-related factors, together with judicious use of biological markers, will further improve the prognosis of elderly lung cancer patients. PMID- 25806235 TI - International trial of adjuvant therapy in high risk stage I non-squamous cell carcinoma identified by a 14-gene prognostic signature. AB - There is widespread agreement amongst clinical oncologists that more refined risk stratification in early-stage lung cancer patients beyond conventional TNM staging is needed. Over the past decade, a number of molecular prognostic signatures have been designed to meet this need by correlating patterns in the differences in gene expression or modification to patient prognosis. Unfortunately, the majority of proposed signatures are not amenable to practical widespread implementation or have not yet undergone large-scale, rigorous clinical validation. A practical 14-gene prognostic signature that has undergone large-scale blinded independent validation is now ready for widespread clinical use. An international clinical trial is underway that has been designed to document the precise degree of benefit derived from adjuvant therapy in high-risk stage I patients identified by the 14-gene prognostic assay. PMID- 25806234 TI - Are we ready to use biomarkers for staging, prognosis and treatment selection in early-stage non-small-cell lung cancer? AB - Lung cancer accounts for the majority of cancer-related deaths worldwide. At present, platinum-based therapy represents the standard of care in fit stage II and IIIA non-small cell lung cancer (NSCLC) patients following surgical resection. In advanced disease, personalized chemotherapy and targeted biologic therapy based on histological and molecular tumor profiling have already shown promise in terms of optimizing treatment efficacy. While disease stage is associated with outcome and is commonly used to determine adjuvant treatment eligibility, it is known that a subset of patients with early stage disease experience shorter survival than others with the same clinicopathological characteristics. Improved methods for identifying these individuals, at or near the time of initial diagnosis, may inform the decision to pursue adjuvant therapy options. Among the numerous candidate molecular biomarkers, only few gene expression profiling signatures provide clinically relevant information, while real-time quantitative polymerase-chain reaction (RT-qPCR) strategy involving relatively small numbers of genes offers a practical alternative with high cross platform performance. mRNA and/or protein expression levels of excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M subunit 1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) are among the most promising potential biomarkers for early disease and their clinical utility is currently being evaluated in randomized phase II and III clinical trials. This review describes the most promising clinicopathological and molecular biomarkers with predictive and prognostic significance in lung cancer that have been identified through advanced research and which could influence adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine clinical practice. PMID- 25806236 TI - Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients. AB - NSCLC patients with mutations in epidermal growth factor receptor (EGFR) gene have dramatic responses with the EGFR tyrosine kinase inhibitors (TKI) in the majority of patients. However, all patients will eventually present progression of disease because of both primary and acquired resistance to EGFR TKI. In the recent years several studies have identified mechanisms involved in primary and secondary resistance to EGFR TKI treatment that can also be potential therapeutic strategies, although up to 30% of cases of acquired resistance to EGFR TKI are still unexplained. In this review we describe the mechanisms of resistance to EGFR TKIs in NSCLC patients that have been discovered and potential therapeutic strategies to overcome EGFR TKI resistance. Additionally we highlight the importance of performing additional biopsies not only at time of acquired resistance to EGFR TKI but also immediately after initiation of therapy to discover the remaining unknown mechanisms of acquired resistance to EGFR TKI as well as the underlying molecular basis of the heterogeneity in response to EGFR TKI. PMID- 25806238 TI - BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors. AB - Inhibitors targeting active protein kinases, such as EGFR or ALK, have demonstrated significant efficacy in the treatment of lung cancer. Activating mutations in the MAPK pathway, which includes the enzymes RAS, RAF, MEK, and ERK, result in constitutive signalling, leading to oncogenic cell proliferation and escape from apoptosis; therefore this pathway is a focus of crucial interest for the development of cancer drugs. In melanoma, the most commonly mutated gene is BRAF, with mutations usually occurring in about 50% of all tumours. The BRAF Val600Glu (V600E) mutation constitutes more than 90% of mutations in melanoma. V600E BRAF mutation shows a great dependency on MEK activity, and offers a rational therapeutic strategy for this genetically defined tumour subtype. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. The frequency of V600E BRAF mutation in lung adenocarcinoma is 1.5% to 2.8%. Treatment of V600E BRAF-mutant lung adenocarcinomas with dabrafenib is under evaluation in a phase 2 trial, and could represent another milestone in individualized therapy for lung cancer patients. The next step will be a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. PMID- 25806237 TI - Apoptotic agents. PMID- 25806239 TI - EGFR molecular testing in African-American non-small cell lung cancer patients - a review of discrepant data. AB - Substantial discrepancy in the literature has recently emerged regarding epidermal growth factor receptor (EGFR) mutational frequency in African American (AA) NSCLC. The first wave of tissue profiling studies, including by our group in 2009, consistently observed a significantly lower frequency of EGFR mutation in AA vs. White NSCLC, whereas three recent reports appear to directly contradict these findings. Reasons for this discrepancy are unclear, but one plausible explanation arises from Simpson's paradox, the consequence of aggregating heterogeneous study cohorts (in this case, the proportion of never-smokers in the study cohort). Our review of all prior studies (combined total 386 AA NSCLC cases) underscores the wide variation in the proportion of AA never-smokers among various studies (13-57%), calling inter-study comparisons into question. In parallel, we assessed objective response by RECIST to EGFR targeted therapy for AA NSCLC in the community setting, prior to the advent of routine EGFR testing. We observed a trend toward reduced response for community-based treatment of unselected AA NSCLC (5%; 3/57) as compared to overall response rates of 10% reported by large North American trials of primarily White NSCLC patients, but this was not significant (P=0.223). PMID- 25806240 TI - Following the crumbs: from tissue samples, to pharmacogenomics, to NSCLC therapy. PMID- 25806241 TI - Association of the metformin with the risk of lung cancer: a meta-analysis. AB - OBJECTIVE: To assess the correlation between metformin and risk of developing lung cancer by meta-analysis. METHODS: Papers on the correlation between metformin and risk of lung cancer were searched from PubMed, MEDLINE, EMBASE, ISI Web of Science, and Cochrane Library. RESULTS: Six papers on case-control study were included in this study, involving 39,787 metformin users and 177,752 controls. Meta-analysis showed that the risk of developing lung cancer was lower in metformin users than in those without metformin (OR=0.55, 95% CI: 0.35-0.85, P<0.001). CONCLUSIONS: The risk of developing lung cancer is lower in metformin users than in those without metformin. PMID- 25806242 TI - New TNM classification: achievements and hurdles. AB - The 7th edition of TNM for Lung Cancer represented a major advance from previous editions, in the process of revision, the size and breadth of the data base used, its international character, the intensity of the analysis and the critical nature of the internal and external validation undertaken before its launch in January 2010. This all came about by the involvement of the International Association for the Study of Lung Cancer (IASLC), which assumed the role previously performed by Dr. Mountain, of developing data-driven revisions for the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC). In taking on this task the IASLC made the global lung cancer community aware of the limitations of previous revisions and now stand accountable and subject to the same scrutiny. In this article we describe the achievements of the IASLC TNM and Prognostic Factors Committee, but also the short-comings of the 7th edition, as an essential step towards rectifying deficiencies and further improving the classification in future revisions. PMID- 25806244 TI - Non-neuronal cholinergic system in airways and lung cancer susceptibility. AB - In the airway tract acetylcholine (ACh) is known to be the mediator of the parasympathetic nervous system. However ACh is also synthesized by a large variety of non-neuronal cells. Strongest expression is documented in neuroendocrine and in epithelial cells (ciliated, basal and secretory elements). Growing evidence suggests that a cell-type specific Ach expression and release do exist and act with local autoparacrine loop in the non-neuronal airway compartment. Here we review the molecular mechanism by which Ach is involved in regulating various aspects of innate mucosal defense, including mucociliary clearance, regulation of macrophage activation as well as in promoting epithelial cells proliferation and conferring susceptibility to lung carcinoma onset. Importantly this non-neuronal cholinergic machinery is differently regulated than the neuronal one and could be specifically therapeutically targeted. PMID- 25806245 TI - Post-therapeutic positron emission tomography/computed tomography for early detection of non-small cell lung cancer recurrence. AB - Patients after curative treatment of non-small cell lung cancer (NSCLC) have a high risk of loco-regional and/or distant tumor recurrence, especially within the first two years. Timely and accurate detection of recurrence is crucial in order to start salvage or palliative therapies with the overall goal of increasing patients' survival and quality of life. However, with the emerging use of non surgical curative-intended therapies, follow-up of patients becomes even more challenging, as local recurrence has to be distinguished from various post therapeutic changes at the site of the primary cancer. Integrated positron emission tomography/computed tomography (PET/CT), which is already an established imaging modality in the staging of NSCLC, is increasingly used in recurrence surveillance algorithms. By detailed morphological information being combined with additional information about the metabolic activity of suspicious sites, determination of suspicious lesions as benign or malignant can be improved. This article reviews the value of integrated PET/CT in assessing recurrence in NSCLC patients after potentially curative surgery and after curative-intended non surgical therapies and raises as well the issue of cost-effectiveness of PET/CT for follow-up. PMID- 25806243 TI - Molecular determinants of lung cancer metastasis to the central nervous system. AB - Lung cancer remains the leading cause of cancer-related mortality worldwide. The propensity for metastasis to the central nervous system (CNS) is a major clinical hurdle contributing to the low five-year survival rate of advanced disease. CNS metastases significantly outnumber primary brain tumors and carry a dismal prognosis in part due to the inability of therapeutic agents to cross the blood brain barrier. Standard treatment using radiation has been largely ineffective in improving mortality, suggesting the need for new agents targeting the critical metastatic drivers. The genetic and molecular events governing CNS metastasis from the lung are poorly understood at this time. This review highlights genetic events associated with CNS dissemination from the lung and molecular mechanisms associated with CNS metastasis. In vivo model systems that faithfully recapitulate escape from the lung and colonization of the CNS are described as tools for understanding the metastatic phenotype and for testing new therapeutic agents. A deeper understanding of the mechanisms of lung cancer metastasis to the CNS is needed to elucidate novel therapeutic avenues towards the improvement of the mortality associated with advanced stage lung cancer. PMID- 25806246 TI - Resistance to anti-angiogenic agents: a brief review of mechanisms and consequences. PMID- 25806248 TI - Highlights in management of early stage non-small cell lung cancer. PMID- 25806249 TI - Highlights in lung cancer: explore treatment and care for lung cancer with world experts. PMID- 25806247 TI - LigaSure meets endobronchial valve in a case of lung cancer with pneumoconiosis. AB - Resection of lung cancer associated with pneumoconiosis may be difficult since fibrosis limits the exposure of hilum, and the use of stapler; yet, surgery may be complicated by persistent air leaks due to the underlying disease. In this setting, LigaSure was used to perform the tumor resection, and the postoperative treatment of air leaks in the same patient was treated with placement of endobronchial valves. PMID- 25806250 TI - Management of early stage non-small cell lung cancer. PMID- 25806252 TI - Alternatives to surgery in early stage disease-stereotactic body radiotherapy. AB - The management of early stage non-small cell lung carcinoma (NSCLC) has been revolutionized by the introduction of stereotactic body radiotherapy (SBRT). SBRT is now the standard of care for medically inoperable patients with early stage NSCLC. However, the role of SBRT in medically operable patients remains controversial. This article will review the indications, the technical considerations, image guidance principles, potential toxicities and special circumstances in lung SBRT. PMID- 25806251 TI - Interventional pulmonology approaches in the diagnosis and treatment of early stage non small cell lung cancer. AB - Lung cancer management is complex and requires a multi-disciplinary approach to provide comprehensive care. Interventional pulmonology (IP) is an evolving field that utilizes minimally invasive modalities for the initial diagnosis and staging of suspected lung cancers. Endobronchial ultrasound guided sampling of mediastinal lymph nodes for staging and detection of driver mutations is instrumental for prognosis and treatment of early and later stage lung cancers. Advances in navigational bronchoscopy allow for histological sampling of suspicious peripheral lesions with minimal complication rates, as well as assisting with fiducial marker placements for stereotactic radiation therapy. Furthermore, IP can also offer palliation for inoperable cancers and those with late stage diseases. As the trend towards early lung cancer detection with low dose computed tomography is developing, it is paramount for the pulmonary physician with expertise in lung nodule management, minimally invasive sampling and staging to integrate into the paradigm of multi-specialty care. PMID- 25806254 TI - Management of ground-glass opacities: should all pulmonary lesions with ground glass opacity be surgically resected? AB - Pulmonary nodules with ground-glass opacity (GGO) are frequently observed and will be increasingly detected. GGO can be observed in both benign and malignant conditions, including lung cancer and its preinvasive lesions. Atypical adenomatous hyperplasia and adenocarcinoma in situ are typically manifested as pure GGOs, whereas more advanced adenocarcinomas may include a larger solid component within the GGO region. The natural history of GGOs has been gradually clarified. Approximately 20% of pure GGOs and 40% of part-solid GGOs gradually grow or increase their solid component, whereas others remain unchanged for years. Therefore, it remains unclear whether all pulmonary lesions with GGO should be surgically resected or whether lesions without changes may not require resection. To distinguish GGOs with growth from those without growth, a 3-year follow-up observation period is a reasonable benchmark based on the data that the volume-doubling time (VDT) of pure GGOs ranges from approximately 600 to 900 days and that of part-solid GGOs ranges from 300 to 450 days. Future studies on the genetic differences between GGOs with growth and those without growth will help establish an appropriate management algorithm. PMID- 25806253 TI - Alternative to surgery in early stage NSCLC-interventional radiologic approaches. AB - Interventional radiologists have a variety of techniques in their armamentarium to treat pulmonary tumors. While most therapies are targeted to metastasis or palliation, percutaneous thermal ablation represents a potential therapy for not only palliation, but to treat inoperable early stage disease. Although radiofrequency ablation (RFA) is the most studied of these ablative techniques, newer technologies of thermal ablation, such as microwave and cryoablation have emerged as additional options. In this article, we will review the three different thermal ablative modalities, including patient selection, technique, outcomes, complications, and imaging follow-up. A brief discussion of state of the art techniques such as irreversible electroporation (IRE) and catheter directed therapies will also be included. PMID- 25806255 TI - Towards optimal pathologic staging of resectable non-small cell lung cancer. AB - Pathologic nodal staging is the most accurate means of determining prognosis of patients with resectable non-small cell lung cancer (NSCLC), but confusion prevails about the optimal pre-operative and surgical lymph node examination procedures for candidates of curative-intent resection. The landmark American College of Surgeons Oncology Group Z0030 trial revealed no difference in the survival of patients with clinical T1 or T2, N0 or N1 (hilar node-negative), M0 NSCLC who either had a fastidious, pre-defined systematic hilar and mediastinal lymph node sampling procedure, or who received a complete mediastinal lymph node dissection. We place the results of this major trial into a contemporary clinical practice context, and discuss problems associated with apparent misunderstanding of the lessons from this trial, especially in light of evidence of prevailing sub optimal nodal examination practices. We also discuss evolving knowledge about the origin of the quality gap in pathologic nodal staging and the emerging literature on corrective interventions. PMID- 25806258 TI - Neoadjuvant chemotherapy in early-stage non-small cell lung cancer. AB - Surgical resection followed by adjuvant chemotherapy is the standard of care for completely resected stages II and III non-small cell lung cancer (NSCLC) patients. In order to improve survival in patients with early-stage NSCLC, efforts have been focused on the use of chemotherapy and radiotherapy before surgery with the aim of reducing the risk of relapse. Neoadjuvant chemotherapy is an attractive treatment option which is employed in different tumors and may well be associated with certain advantages in NSCLC patients such as being effective in treating occult microscopic systemic disease, downstaging mediastinal lymph node and improving the success of surgery by tumor reduction. Furthermore, chemotherapy compliance prior to surgery is generally better than after surgery. The potential disadvantages are treatment-related toxicities and the delay of surgery. At present, neoadjuvant chemotherapy is still considered an experimental treatment modality in early-stage disease and its role should be more clearly defined. PMID- 25806256 TI - Prognostic and predictive biomarkers in early stage non-small cell lung cancer: tumor based approaches including gene signatures. AB - In early stage non-small cell lung cancer (NSCLC) large randomized trials have demonstrated that in patients with radically resected disease adjuvant chemotherapy improves 5-year survival rates. However, a customization of systemic treatment is needed to avoid treatments in patients cured by surgery alone or to justify the use of adjuvant chemotherapy in high risk patients, including those in stage IA. Recently, the possibility of identifying prognostic and predictive factors related to the genetic signatures of the tumor that could affect adjuvant and neo-adjuvant treatment choices for resectable non-small cell lung cancer (NSCLC) has been of interest. This review summarizes the current status and future opportunities for clinical application of genotyping and genomic tests in early NSCLC. PMID- 25806260 TI - Adjuvant molecularly targeted therapy-epidermal growth factor tyrosine kinase inhibition and beyond. PMID- 25806257 TI - Prognostic and predictive biomarkers in early stage NSCLC: CTCs and serum/plasma markers. AB - Resection of early stage non-small cell lung cancer (NSCLC) offers patients the best hope of cure, however recurrence rates post-resection remain high suggesting the presence of micro-metastatic disease at the time of surgery undetected by standard staging methods. A critical step in the metastatic cascade is the entry of tumor cells into the circulation enabling their distribution to and seeding of distant organs. This review explores the evidence for predictive and prognostic circulating biomarkers in the early stage NSCLC population. We summarize studies that have explored a variety of targets including circulating proteins, nucleic acids and more recently circulating tumor cells (CTCs) as potentially clinically relevant biomarkers in the early stage setting. Circulating biomarkers may add clinically relevant information about the biological behavior of tumors over and above that provided by pathological staging. Improvement in the stratification of patients according to the likelihood of metastatic relapse after radical treatments such as surgical resection could allow more effective targeting of systemic therapies such as adjuvant chemotherapy. PMID- 25806259 TI - Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC). AB - Surgery is regarded as the primary treatment modality for early stage non-small cell lung cancer (NSCLC), but even after complete resection, a substantial percentage of these patients eventually develop local recurrence or distant metastases. Therefore more effective treatment strategies to reduce lung cancer mortality and recurrence rate are needed. Only recently has the use of adjuvant chemotherapy become standard in early stage NSCLC, at least for stage II and resected IIIA NSCLC. Controversies remain about the benefit for stage I patients. Five-year survival improvements of 5% to 10% have been reported with cisplatin based adjuvant chemotherapy from multiple large randomized phase III clinical trials and meta-analyses. Questions remain as to which patients benefit and which regimens are best. In this paper, important clinical research in the field of adjuvant chemotherapy of NSCLC is reviewed. PMID- 25806261 TI - Anti-tumor immune response in early stage non small cell lung cancer (NSCLC): implications for adjuvant therapy. AB - The demonstration that systemic chemotherapy improves survival in patients who have had resection of early stage non-small cell lung cancer (NSCLC) represents a significant advance. The absolute benefit of adjuvant chemotherapy in this setting is small with an overall survival improvement of 5%. In addition, there are many patients who have contraindications to cisplatin-based adjuvant therapy. Adjuvant chemotherapy is intended to target systemic micrometastases that remain after primary resection. The observation that cancers can relapse months or years after initial surgery implies that the residual micrometastases exist in a latent or dormant state. The concept of tumor dormancy offers therapeutic potential through induction or maintenance of the dormant state in disseminated tumor cells or through eradication of these dormant cells. Cancer dormancy is a complex process with multiple potential mechanisms. This review will focus on some of the evidence for immune related tumor dormancy and the potential for immune therapies to improve outcomes in the adjuvant setting in NSCLC. PMID- 25806263 TI - TLCR is endorsed by the Spanish Lung Cancer Group (SLCG): new horizons for strong academic collaboration in lung cancer. PMID- 25806264 TI - Gefitinib in non-small-cell lung cancer-an old lesson new re-visited. AB - Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer, and it is the most common cause of death in men and second only to breast cancer in women. Combination chemotherapy, usually platinum-based, is currently the first-line therapy of choice, however, the prognosis for patients with advanced NSCLC remains poor with a median survival time of 8-11 months and a 1-year survival rate of 30%. Maintenance therapy is a treatment strategy that has been investigated extensively in NSCLC and has been the subject of considerable recent debate. The outstanding results of the JMEN study proved that maintenance of pemetrexed significantly improved the overall survival (OS) in advanced NSCLC patients was a proof of principle. Subsequently, the results of the SATURN study also showed a significant prolongation of progression-free survival (PFS) and OS with maintenance erlotinib compared with placebo. Despite considerable controversy, it has become an acceptable treatment paradigm and both drugs are approved for maintenance therapy of advanced NSCLC patients in Europe and the USA. In addition, several large phase III clinical trials (e.g., INFORM trial) provided evidence that maintenance therapy with gefitinib also significantly improved PFS in NSCLC patients, with greatest PFS benefit in patients harboring EGF-R mutations. However, OS was unchanged. The question still remains whether the benefit of maintenance therapy for NSCLC is best defined by PFS. Truely, PFS is the best predictor for improved OS (and is independent of subsequent treatment), but OS is acknowledged as the key clinical outcome in the treatment of advanced NSCLC. The approval of pemetrexed and erlotinib by the FDA and the EMEA and the promising data with gefitinib have certainly shifted the pendulum towards maintenance therapy, however, the precise role for the treatment strategy of NSCLC in terms of a maintenance approach is far from being clear and additional studies are warranted to further clarify this option. PMID- 25806262 TI - Post-operative radiation therapy. AB - In completely resected non-small-cell lung cancer (NSCLC) patients with pathologically involved mediastinal lymph nodes (N2), administration of adjuvant platinum-based chemotherapy is now considered the standard of care, based on level 1 evidence. The role of post-operative radiotherapy (PORT) in this group of patients remains controversial. In the PORT meta-analysis published in 1998, the conclusions were that if adjuvant radiotherapy was detrimental to patients with early-stage completely resected NSCLC, the role of PORT in the treatment of tumours with N2 involvement was unclear and further research was warranted. Recent retrospective and non-randomized studies as well as subgroup analyses of recent randomized trials evaluating adjuvant chemotherapy, provide evidence of the possible benefit of PORT in patients with mediastinal nodal involvement. The question of PORT indication is also valid for those patients with proven N2 disease who undergo neo-adjuvant chemotherapy followed by surgery. The risk of local recurrence for N2 patients varies between 20% and 60%. Based on currently available data, PORT should be discussed for fit patients with completely resected NSCLC with N2 nodal involvement, within a multidisciplinary setting, preferably after completion of adjuvant chemotherapy or after surgery if patients have had neo-adjuvant chemotherapy. There is need for new randomized evidence to reassess PORT using modern three-dimensional conformal radiation technique, with attention to normal organ sparing, particularly lung and heart, to reduce the possible additional toxicity. Randomized evidence is needed. A new large international multi-institutional randomized trial Lung ART evaluating PORT in this patient population is now underway, as well as a Chinese study comparing postoperative sequential chemotherapy followed by radiotherapy versus adjuvant chemotherapy alone. PMID- 25806265 TI - Endothelial Dll4-Notch signaling in tumor microenvironment: is there any hidden therapeutic opportunity? AB - Tumor microenvironmental cross-talk between endothelial and cancer cells plays an essential role in growth, progression and therapeutic outcome of cancer. In response to tumor cell-derived vascular endothelial growth factor (VEGF), the endothelial delta-like ligand 4 (Dll4) regulates angiogenesis and tumor growth via Notch signaling. However, in view of intriguing effects of emerging Dll4 Notch signaling in various tumor types, the missing links need to be elucidated for development of this signaling as a possible therapeutic target for cancer therapy. PMID- 25806266 TI - Influence of chemotherapy on EGFR mutation status. AB - Lung cancer is the leading cause of cancer death in the world. The frequency of epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) has ranged from 5-30%, depending on the population studied. Lung cancer patients with tumor EGFR activating mutations have a more favorable prognosis than those without. With regard to second-line tyrosine kinase inhibitors (TKIs) following platinum-based chemotherapy, its tumor response rate was less than first-line TKIs in patients with EGFR mutations. The change of EGFR mutation status during disease course may partially explain the difference in the predictive value of EGFR mutation between first- and second-line TKIs treatment. First-line chemotherapy may have influence on status of EGFR mutations, and thus, EGFR mutation status collected from the initial specimens for diagnosis might be inadequate for predicting efficacy of EGFR-TKI treatment after first-line chemotherapy. Intratumoral heterogeneity in the initial single tumor biopsy specimen could also lead to misinterpretation of the tumor EGFR mutation status and difficulty in making precise treatment decision. Many investigators used plasma EGFR mutation obtained from peripheral blood samples to represent the post chemotherapy EGFR mutation status. However, many studies revealed that plasma EGFR mutation could not completely represent EGFR mutation status in the tumor tissue. There could be many reasons for the change of EGFR mutation status after chemotherapy. Influence of chemotherapy on EGFR mutation status may be one of the explanations for this phenomenon. Intratumoral heterogeneity also plays an important role in diversity of tumor EGFR mutation status. Further studies will be necessary to explain the mechanisms of chemotherapy-induced EGFR mutation change. PMID- 25806267 TI - EGFR mutation heterogeneity and mixed response to EGFR tyrosine kinase inhibitors of non small cell lung cancer: a clue to overcoming resistance. AB - The presence of an EGFR activating mutation is predictive of benefit from reversible and irreversible EGFR tyrosine kinase inhibitor (EGFR-TKI) allowing personalized medicine in lung cancer. However, intratumoral heterogeneity in EGFR mutation status has recently been described and ranged from 13.9% to 27% in some studies. Intratumor heterogeneity may have important consequences for personalized-medicine approaches that commonly rely on a single tumor-biopsy to portray tumor mutational landscape. EGFR mutation heterogeneity could also explain the mixed responses phenomenon and act as a mechanism of acquired resistance to EGFR-TKI. In order to a better tailored treatment in advanced non small cell lung cancer (NSCLC), it is extremely important to elucidate the relevance and degree of heterogeneous distribution of the targeted biomarker regarding the metastasis localisation, previous systemic treatments and interval between primary tumor and metastasis. Additionally, these findings would also help us to design new strategies for patients with lung cancer harboring heterogeneous EGFR mutations. PMID- 25806268 TI - Notch signaling: a hero or villain in the war against cancer? AB - The Notch signal transduction pathway regulates cell fate decisions throughout embryonic development. The mechanisms through which Notch signaling maintains cellular integrity are well understood. However, Notch signaling is more complex than previously thought as Notch is also involved in cancer where it functions as both an oncogene and tumor suppressor depending on the cellular context. Aberrant activation of oncogenic Notch is found in various cancers prompting the search for therapeutic agents to attenuate constitutively active Notch. However, there is also substantial evidence that Notch signaling suppresses tumor growth and progression, suggesting that Notch activators might be of therapeutic benefit in other cancers. This editorial describes the dual role of Notch signaling observed within and across multiple cancers. We highlight a study in non-small cell lung cancer cells (NSCLC) revealing a tumor suppressive role for endothelial cell Dll4 activated Notch1 and the underlying molecular mechanism involving suppression of PI3K signaling. PMID- 25806269 TI - Personalized maintenance therapy in advanced non-small cell lung cancer. AB - Maintenance therapy is a treatment strategy that can prolong survival in patients with advanced non-small cell lung cancer (NSCLC). The increased survival achieved with maintenance therapy has led to new treatment options that should be chosen in accordance with the preferences of patients and physicians. Personalized maintenance therapy involves identification of histological subtypes and molecular features of tumors, thereby improving treatment outcomes. Many clinical trials have been conducted to establish new treatment strategies for patients with advanced NSCLC with non-squamous cell histology. The discovery of epidermal growth factor receptor (EGFR) mutations was the most significant innovation for personalized therapy in NSCLC patients. First generation EGFR-tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have significantly contributed to greatly increased survival in specific patients harboring activating EGFR mutations such as exon 19 deletion and L858R point mutation. Based on clinical trials of different maintenance therapy strategies, we identified the regimen is the most promising and highlighted for patients whom should be given specific kinds of therapy now and in future studies. PMID- 25806270 TI - The use of quantitative proteomics towards biomarker discovery in lung squamous cell carcinoma. AB - The high mortality rate in advanced lung cancer, due to a preponderance of tumors discovered at advanced stage, demands the discovery and clinical validation of biomarkers for diagnosing early stage disease. Quantitative proteomics technologies are capable of identifying protein biomarkers with diagnostic, prognostic, and predictive value. Recent works have demonstrated the utility in using quantitative proteomics across normal, pre-cancerous, and cancerous lesions towards the discovery of biomarkers for early stage lung cancer, as well as discovering novel mechanisms of lung carcinogenesis. PMID- 25806271 TI - Gene alterations, smoking and histology: when the deeper means the rarer. PMID- 25806272 TI - RET-targeting molecular stratified non-small-cell lung cancers. AB - Recent advances in lung cancer genomics have successfully characterized therapeutic targets of lung cancer. RET fusion gene products are among the newest target molecules for lung adenocarcinoma. Preclinical findings and preliminary reports regarding potential tumor control by RET-targeting multi-kinase inhibitors encourage further clinical trials. The infrequent prevalence of RET fusion gene-positive cases may be a major obstacle hindering the development of RET-targeted therapy. Thus, it is necessary to recruit appropriate participants for trials to develop an efficient RET fusion gene detection system to achieve targeted therapy for lung adenocarcinomas stratified by this molecular target. PMID- 25806274 TI - Professor Solange Peters: cooperation is important for managing lung cancer. PMID- 25806273 TI - Dll4/Notch1 signaling from tip/stalk endothelial cell specification to stroma dependent lung tumor inhibition: a flavor of Dll4/Notch1 pleiotropy in tumor cell biology. AB - Non-small cell lung cancer (NSCLC) still represents the leading cause of cancer death. Treating this disease with systemic chemotherapy has reached a plateau in effectiveness and is rather toxic to the patients, while molecularly targeted therapies against Epidermal Growth Factor Receptor can lead to resistance. On the other hand, therapies based on tumor angiogenesis inhibition have been recently proposed. Here we will discuss on the pleiotropy of the Dll4/Notch1 cell-to-cell signaling in NSCLC, as alternative target for future therapeutic approaches. PMID- 25806275 TI - New wave of immunotherapy against lung cancer rolls in to clinic. PMID- 25806276 TI - Immunotherapy in lung cancer. AB - Immunotherapy has emerged in recent years as a promising therapeutic approach in lung cancer. Two approaches are of particular interest: immune checkpoint inhibition, which aims to counteract the physiologic mechanisms of immune tolerance co-opted by some tumors, and vaccine therapy, which enables enhanced exposure to tumor antigen. Immune checkpoint therapies include the monoclonal antibody blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) with ipilimumab, as well as antibody blockade of the programmed cell death-1 (PD-1) receptor and the PD-1 ligand. These immune checkpoint therapies have been evaluated in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with early evidence of activity. Vaccines include antigen specific therapies which induce specific antitumor immunity against relevant tumor associated antigens. In lung cancer, these include the melanoma-associated antigen-A3 (MAGE-A3), membrane-associated glycoprotein (MUC-1), and the epidermal growth factor receptor (EGFR). Whole tumor vaccines have also been evaluated in lung cancer and influence the patient's immune system to allow recognition of the tumor as foreign creating de novo immunity. This review summarizes the evidence to date for the efficacy and safety of immunotherapies in lung cancer. PMID- 25806278 TI - gammadelta T cell therapy for the treatment of non-small cell lung cancer. AB - gammadelta T cells are attractive effector cells for cancer immunotherapy as they can secrete cytokines abundantly and exert potent cytotoxicity against a wide range of cancer cells. They comprise 1-5% of peripheral blood T cells, the majority expressing the Vgamma9Vdelta2 T cell receptor that recognizes phosphoantigens. Direct in vivo activation of Vgamma9Vdelta2 T cells in cancer patients as well as adoptive transfer of ex vivo expanded Vgamma9Vdelta2 T cells has been investigated in several clinical trials. We previously established a large-scale in vitro expansion method for Vgamma9Vdelta2 T cells using zoledronate and interleukin-2 (IL-2). We found that Vgamma9Vdelta2 T cells from patients with advanced cancer as well as from healthy donors underwent extensive proliferation under these conditions. Such cultured Vgamma9Vdelta2 T cells retained cytokine secretion capacity and mediated cytotoxicity against a variety of cancer cell lines. Recently, we conducted a phase I clinical study to evaluate safety and potential anti-tumor effects of re-infusing ex vivo expanded gammadelta T cells in patients with advanced or recurrent non-small-cell lung cancer (NSCLC) refractory to or intolerant of current conventional treatments. There were no severe adverse events related to the therapy. All patients remained alive during the study period with a median survival of 589 days and median progression-free survival of 126 days. Six patients had stable disease (SD), whereas the remaining six evaluable patients experienced progressive disease (PD) four weeks after the sixth transfer. We conclude that adoptive transfer of zoledronate-expanded gammadelta T cells is safe and feasible in patients with NSCLC, refractory to other treatments. PMID- 25806277 TI - Mechanisms of immune response regulation in lung cancer. AB - Lung cancer is a leading cause of cancer deaths. As a solid tumor with low antigenicity and heterogenic phenotype lung cancer evades host immune defense. The cytotoxic anticancer effect is suppressed by a complex mechanism in tumor microenvironment. The population of regulatory T cells (Tregs) plays a crucial role in this inhibition of immune response. Tregs are defined by presence of forkhead box P3 (Foxp3) molecule. The high expression of Foxp3 was found in lung cancer cells and in tumor infiltrating lymphocytes (TIL). Cytotoxic T-lymphocyte antigen 4 (CTLA4) is constitutively expressed on Tregs and suppresses T cell activation. The elevated CTLA4 expression in lymphocytes in patients with lung cancer was found. Recently the antibodies blocking CTLA4 showed some clinical efficacy in patients with lung cancer. Cancer cells and immune cells release many cytokines capable to show suppressive immune effect in cancer microenvironment. The most active are transforming growth factorbeta (TGFbeta) and IL-10. The pleiotropic function of Th17 population is TGFbeta related. The myeloid lineage of suppressor cells in lung cancer is represented by tumor associated macrophages (TAM) with phenotype of M2 macrophages and some regulatory properties with releasing amounts of IL-10 and TGFbeta. The myeloid derived suppressor cells (MDSCs) control cytotoxic T cell activity in mechanisms which are highly dependent on the context of tumor environment. The mechanisms of anticancer immune response regulation need further investigation as an important target to new way of treatment. PMID- 25806280 TI - Lung cancer vaccines: current status and future prospects. AB - Designing a cancer treatment that very specifically targets and kills tumor cells with little to no side effects is the "holy grail" of oncology. Cancer vaccines have this potential. Vaccines utilize the immune system to specifically target and eliminate tumor cells. Historically, vaccination approaches against lung cancer have been disappointing. However, over the past decade, a greater understanding of the immune system and of the antigens expressed by tumors, coupled with advances in immunoadjuvants and improved delivery systems, has led to advances in the use of immunotherapy including vaccines to target lung cancer. Proof of principle phase I/II clinical trials targeting the MAGE-A3 and MUC1 tumor antigens, as well as cell-based vaccines such as belagenpumatucel-L have suggested improved survival, leading to larger scale phase III clinical trials. This review will discuss cancer vaccines in relation to lung cancer and present clinical data supporting their use. PMID- 25806282 TI - 10(th) Congress on Lung Cancer-updates on clinical trials: goal. AB - Lung cancer is a leading cause of cancer death and probably one of the most challenging cancers to treat. Platinum-based chemotherapy remains as the standard of treatment for most of advanced non-small cell lung cancer (NSCLC) patients, and although therapeutic improvements have been achieved in the last years, the benefits are quite modest. One of the most important advances in NSCLC care has been the identification of oncogenic mutations that contribute to the pathogenesis of lung cancer, suggesting that some tumors can rely on a specific gene for their survival and proliferation, and the subsequent development of drugs targeted to these specific alterations. Activating mutations of the epidermal growth factor receptor (EGFR) have been the first molecular event that can be targeted with specific drugs in NSCLC. The discovery of the first reversible EGFR small-molecule inhibitors (TKIs) in the past decade, has changed the history of lung cancer treatment. EGFR inhibition has emerged to be an important strategy in the treatment of NSCLC. However, all patients will eventually present progression of disease because of both primary and acquired resistance to EGFR TKIs. In the future, a better understanding of the tumor heterogeneity as well as tumor resistance mechanisms will evolve more rational therapies and potential combinations of different targeted therapies. PMID- 25806279 TI - Immunotherapy prospects in the treatment of lung cancer and mesothelioma. AB - A very recent finding is the role of immune activation in cancer. The assumption that stimulating the patient's immune system to attack tumors is a valuable treatment option in malignant diseases has gained more acceptance. However the high immunosuppressive effects caused by the tumor limits this beneficial effect. There is a delicate balance between immunoactivation and immunosuppression in a patient. Especially in non small cell lung cancer (NSCLC), the role of immunosuppressive cells hampering immune activation is high. But also in small cell lung cancer (SCLC) and mesothelioma immunosuppressive activity is high. This is suggested to be related to the type of tumor, advanced stage of the disease, and the tumor load. In this review, we provide an overview of the progress and challenges in the immunotherapeutic approaches in lung cancer. We conclude with the concept that immunotherapy in thoracic malignancies must be tailored made to the balance of the immune system. PMID- 25806281 TI - Immunotherapy in lung cancer. AB - Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC. PMID- 25806283 TI - Concordance of IHC, FISH and RT-PCR for EML4-ALK rearrangements. AB - The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) has emerged as the second most important driver oncogene in lung cancer and the first targetable fusion oncokinase to be identified in 4-6% of lung adenocarcinomas. Crizotinib, along with a diagnostic test-the Vysis ALK Break Apart fluorescence in situ hybridization (FISH) Probe Kit-is approved for the treatment of ALK positive advanced non-small cell lung cancer (NSCLC). However, the success of a targeted drug is critically dependent on a sensitive and specific screening assay to detect the molecular drug target. In our experience, reverse transcription polymerase chain reaction (RT-PCR)-based detection of EML4-ALK is a more sensitive and reliable approach compared to FISH and immunohistochemistry (IHC). Although ALK FISH is clinically validated, the assay can be technically challenging and other diagnostic modalities, including IHC and RT-PCR should be further explored. PMID- 25806285 TI - Targeted therapy in NSCLC driven by HER2 insertions. AB - HER2 mutations, largely exon 20 in-frame insertions, have been described as an oncogenic driver alteration in 1% to 4% of NSCLC, exclusively in adenocarcinoma histology. The prognostic implication of these alterations is not known. Phase I and II trial data suggest that afatinib, neratinib and dacomitinib have some activity in this molecular subgroup. No comparative data, or any data regarding the activity of pertuzumab or trastuzumab-emtansine is available. HER2 deregulation either by protein overexpression or gene amplification, has little clinical relevance to date, as trials investigating trastuzumab activity merely suggest a benefit in the very small minority of patients whose tumor highly overexpresses HER2, a subpopulation that amounts to 2% to 6% of mostly adenocarcinomas. PMID- 25806284 TI - Hippo/YAP pathway for targeted therapy. AB - Malignant pleural mesothelioma (MPM) is molecularly characterized by loss of function or mutations in the neurofibromin 2 (NF2) and the cyclin-dependent kinase inhibitor 2 genes. NF2 activates a cascade of kinases, called Hippo pathway, which downregulates Yes associated protein (YAP) function as transcription co-activator for TEA domain transcription factors (TEAD). In the absence of functional NF2, the expression of genes essential for cell cycling such as survivin is increased. New therapeutic strategies aimed at interfering with YAP activity include inhibition of hedgehog pathway, which downregulates the YAP protein, verteporfin, which inhibits the assembly of a functional YAP-TEAD transcription factor, and interference with thrombin and lysophosphatidic acid (LPA) receptors downstream signalling, since upon agonist binding they activate YAP. PMID- 25806286 TI - Therapeutic integration of new molecule-targeted therapies with radiotherapy in lung cancer. AB - Lung cancer is the most common form of the disease and the leading cause of cancer deaths worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancers. Forty percent of all cases present with stage III, and many of them are considered inoperable (staged IIIA with mediastinal lymph node involvement) or stage IIIB disease. Concurrent platinum based chemotherapy and thoracic radiation has demonstrated survival benefits in these patients. We review the role of new target agents in combination with radiotherapy in stage III NSCLC. Antiangiogenics improve tumor oxygenation thereby improving the therapeutic efficacy of irradiation in models. Bevacizumab in combination with thoracic radiation has shown high toxicity. However, other antiangiogenic agents are more promising. Radiation activates epidermal growth factor receptor (EGFR) pathways, inducing radioresistance, cell proliferation and enhanced DNA repair. After promising data from preclinical models and early clinical trials, cetuximab did not show any benefit in a recent phase III trial. Panitumumab and nimotuzumab are under evaluation. Gefitinib has been investigated in combination with radiotherapy for unresectable stage III NSCLC, but results in maintenance treatment after chemoradiotherapy were not encouraging. Erlotinib has also been tested in a phase II trial with chemoradiotherapy. Other new pathways and agents are being studied, such as m-TOR pathway, bortezomib, heat shock protein 90 (Hsp90) inhibition, histone deacetylase inhibitors (HDACS), aurora kinases, mitogen activated protein kinases (MARK) and PARP inhibitors. PMID- 25806287 TI - State of the art in surgery for early stage NSCLC-does the number of resected lymph nodes matter? AB - Surgery is the treatment of choice in patients with early stage NSCLC. However, the results remain poor in these patients. Lymph node involvement is the main prognostic factor in patients with NSCLC, but there is still no clear definition of the number of nodes required to consider a lymphadenectomy as complete. Although there is no defined minimum number of lymph nodes required for a complete lymphadenectomy, there are some recommendations to perform this procedure, published by different scientific societies. Current practice in thoracic surgery regarding lymphadenectomy, differs on some points from the guidelines recommendations, with data regarding patients with no mediastinal assessment between 30-45% according to some of the published data. Different studies have probed the fact that the probability of finding a positive node increases with the number of lymph nodes analyzed. Therefore, a complete lymphadenectomy provides proper staging, which helps to identify the patient's real prognosis. Several nonrandomized studies and retrospective series have shown that survival increases in the group of patients with a higher number of lymph nodes removed. There is no contraindication to performing a complete lymphadenectomy. The increase in survival in patients with a complete lymphadenectomy may be due to more accurate staging. Therefore, complete lymphadenectomy should be mandatory even in early stage patients. PMID- 25806288 TI - Individual profiling of circulating tumor cell composition in patients with non small cell lung cancer receiving platinum based treatment. AB - BACKGROUND: Circulating tumor cells (CTC) could serve as a "liquid biopsy" for individualizing and monitoring treatment in patients with solid tumors as recently shown by our group. We assessed which non-hematopoietic cell types are identifiable in the peripheral blood of patients with non-small cell lung cancer (NSCLC) and correlated those to clinical characteristics. METHODS: Blood from NSCLC patients (n=43) was processed as previously described. For subtype analyses CTC were negatively enriched by hematopoietic cell depletion. The remaining cell suspension included pre-enriched tumor cells and was spun onto glass slides and further characterized by multi-immunofluorescence staining against epithelial markers pan-cytokeratin (CK) and epithelial cell adhesion molecule (EpCAM), mesenchymal marker N-cadherin, stem cell marker CD133, hematopoietic marker CD45 and nuclear counterstain DAPI. Individual cell type profiles were analyzed and correlated to therapeutic outcome. RESULTS: Among other associations of CTC subtypes with clinical parameters Kaplan-Meier test revealed that an increased CD133-positive to pan-CK-positive cell type ratio (stem cell like to epithelial ratio) and the presence of mesenchymal N-cadherin+ cells, both were significantly associated to shortened PFS (2 vs. 8 months, P=0.003, HR =4.43; 5 vs. 8 months, P=0.03, HR =2.63). CONCLUSIONS: Our data suggest that different CTC populations are identifiable in peripheral blood and that these individual cell type profiles might be used to predict outcome to platinum based systemic therapies in lung cancer patients. PMID- 25806289 TI - Predicting resistance by selection of signaling pathways. AB - Epidermal growth factor receptor (EGFR) mutations occur in 17% of non-small-cell lung cancer (NSCLC) patients with notable response to single agent therapy but with low complete remission rate and, eventually, disease progression. Priming BIM, a pro-apoptotic signaling BH3-only protein, induces sensitivity to erlotinib in EGFR-mutant cell lines. Synthetic lethal approaches and preemptive therapies based on the initial expression of BIM may significantly improve the treatment outcome. EGFR mutations result in transient pro-death imbalance of survival and apoptotic signaling in response to EGFR inhibition. SHP2 is essential to the balance between ERK and the phosphoinositide-3-kinase (PI3K)/AKT and signal transducer activator of transcription (STAT) activity, while mTOR can be an additional marker for patients with high BIM expression. Furthermore, stromal hepatocyte growth factor (HGF) confers EGFR tyrosine kinase inhibitor (TKI) resistance and induces interreceptor crosstalk with integrin-b4, Eph2, CUB domain containing protein-1 (CDCP1), AXL and JAK1. Only by understanding better, and in more depth, complex cancer molecular biology will we have the information that will help us to design strategies to augment efficacy of EGFR TKIs and offer our patients the best, most correct therapeutic option. PMID- 25806290 TI - How old is "too old" for translational research? AB - BACKGROUND: Targeted therapies are now widely used for lung cancer management. Numerous biomarkers are performed in these patients in the diagnosis phase and have consequences on patient's management. There are some changes during elderly which can influence the biology of cancer; particularly mitochondrial dysfunction and deregulation of nutrient sensing. Elderly patients are candidate to these biological assessments, like younger ones. METHODS: We review all the published papers based on Mesh carries with "elderly", "lung cancer", "targeted therapy". RESULTS: After description of biological modification during elderly, the use of targeted therapies in non-small cell lung cancer (NSCLC) is presented and discussed. Tyrosine kinase inhibitors (TKIs) and antiangiogenic molecules were depicted in selected or unselected population. CONCLUSIONS: Targeted therapies can be used in older patients with lung cancer and are sometimes an optimal choice in this particular population. PMID- 25806291 TI - ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation. AB - BACKGROUND: Activation of bypass signaling pathways, impairment of apoptosis and mutation of epidermal growth factor receptor (EGFR) to a drug-resistant state are well known mechanisms of resistance to single-agent erlotinib therapy in non small-cell lung cancer (NSCLC) driven by EGFR mutations. Orphan receptor 1 (ROR1) knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated. METHODS: We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome. RESULTS: Progression-free survival (PFS) was 11.8 months for erlotinib-treated patients with low/intermediate and 5.8 months for those with high ROR1 levels. PFS for chemotherapy-treated patients was 5.6 and 9 months, respectively (P=0.0165). A total of 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was 10.8 months for those with low/intermediate compared to 2.7 months for those with high ROR1 levels. In contrast, among 12 chemotherapy-treated patients with concomitant T790M mutations, PFS was 5.8 months for those with low/intermediate, compared to 14.2 months for those with high ROR1 levels (P=0.0138). CONCLUSIONS: ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation. PMID- 25806293 TI - Potential biomarkers for lung cancer screening. AB - Notwithstanding the encouraging results of the National Lung Screening Trial (NLST) the scientific community still debates on the cost-benefit profile of low dose computed tomography (LDCT) lung cancer screening. Several major concerns regard how to identify subjects at high risk of developing lung cancer, the optimal diagnostic algorithm, the management of lung nodules and the high false positive rates. The use of complementary biomarkers would be a useful strategy for dealing with most of these issues. This short review will focus on candidates' biomarkers circulating in serum or plasma that already reached an advanced validation phase also in LDCT lung cancer screening series. The biomarkers presented below are examples of the value of searching candidates by looking not only to the tumor itself but also to the interplay between the tumor and the host in order to identify early changes related to the biological reactivity of the host to a developing cancer. PMID- 25806292 TI - Lung cancer screening guidelines: common ground and differences. AB - Lung cancer accounts for almost one-third of all cancer related deaths. Lung cancer risk persists even after smoking cessation and so many lung cancers now are diagnosed in former smokers. Five-year survival of lung cancer has marginally improved over decades and significantly lags behind that of colon, breast and prostate cancer. Over the past one decade, lung cancer screening trials have shown promising results. Results from National Lung Cancer Screening Trial (NLST), have shown a significant 20% reduction in mortality with annual low dose computed tomography (LDCT) screening. Based on these results, annual LDCT testing has been recommended for lung cancer screening in high risk population. However, development and acceptance of lung cancer screening as a public health policy is still in the nascent stages. Major concerns relate to risk of radiation, overdiagnosis bias, proportion of false positives and cost benefit analysis. This article reviews the literature pertaining to lung cancer screening guidelines and above mentioned concerns. PMID- 25806295 TI - Is surgery still the best management option for early stage NSCLC? AB - Under the formidable thrust of alternative management options for early stage lung cancer, the role of surgery in this disease subset has been questioned. Stereotactic body radiotherapy (SBRT) has been advocated as an ideal substitute for surgery not only in high risk patients or for the ones who refuse surgery but also in lieu of sublobar resection in otherwise fit patients. The therapeutic modalities for early stage NSCLC were compared as to warranting local control, enabling adequate tissue sampling for biomolecular studies, and effecting optimal pathologic staging while saving lung parenchyma. As a result, surgery still remains the best management option for early stage lung cancer in 2014. PMID- 25806294 TI - Prognostic markers in lung cancer: is it ready for prime time? AB - Non-small cell lung cancer (NSCLC) is a heterogeneity disease and to date, specific clinical factors and tumor stage are established as prognostic markers. Nevertheless, prognosis within stage may vary significantly. During the last 3 decades, genes/proteins that drive tumor initiation and progression, such as oncogenes and tumor suppressor genes have been studied as additional potential prognostic markers. The protein markers as evaluated by immunohistochemistry (IHC) have previously dominated these studies. However, with the development of high-throughput techniques to interrogate genome wide genetic or gene expression changes, DNA (copy number and mutation) and RNA (mRNA and microRNA) based markers have more recently been studied as prognostic markers. Largely due to the heterogeneity and complexity of NSCLC, single gene markers including KRAS mutation has not been validated as strong prognostic markers. In contrast, several gene expression signatures representing mRNA levels of multiple genes have been developed and validated in multiple microarray datasets of independent patient cohorts. The salient features of these gene signatures and their potential value to predict benefit from adjuvant chemotherapy is discussed. PMID- 25806297 TI - Italian multicenter survey to evaluate the opinion of patients and their reference clinicians on the "tolerance" to targeted therapies already available for non-small cell lung cancer treatment in daily clinical practice. AB - INTRODUCTION: The introduction of targeted therapies in non-small cell lung cancer (NSCLC) treatment has led to emerging toxicities, whose management and impact on quality-of-life (QoL) is not clearly defined. Aim of this Italian multicenter survey was to highlight any discrepancy between patients' and clinicians' perception of such toxicities in order to improve their management. METHODS: From October 2013 to April 2014, 133 NSCLC advanced patients, treated with targeted therapies, were consecutively enrolled to assess toxicities and QoL with dedicated questionnaires. One hundred and sixteen patients were included in the final analysis, having attended three consecutive evaluations (T0, T1, T2), starting at least 15 days after the biological treatment. The survey required monthly compilation of both physicians and patients' questionnaires, basing adverse event evaluation on CTCAE version 4.0. RESULTS: Most of the patients received either an EGFR-TKI or an anaplastic lymphoma kinase (ALK) inhibitor as targeted therapy (84.5% and 13.8%, respectively). At every checkpoint (T0, T1, T2) a significant difference in terms of perception of targeted therapies-related toxicities of any type and grade was described (P value =0.0001 in all cases). This difference was more pronounced for skin toxicity, fatigue and diarrhea. Furthermore, also the assessment of QoL revealed contrasting data between patients and clinicians, mainly QoL reported as good by the majority of patients and daily activities considered as slightly influenced by targeted therapies. CONCLUSIONS: In our knowledge, this is the first prospective survey in patients and doctors specifically designed for targeted therapies in advanced NSCLC. The results show an underestimation of toxicities by clinicians when compared with patients, the difference being greater for adverse events more strongly associated with daily life and QoL. Further studies are needed to confirm our first results. The discrepancy in perception of targeted therapies-related toxicities should be a result from which to start thinking about a new approach in their management. PMID- 25806298 TI - Focus on treatment complications and optimal management surgery. AB - Thoracic surgery comprises major procedures which may be challenging, not only from a technical point of view but also regarding anesthetic and postoperative management. Complications are common occurrences which are also related to the comorbidity of the patients. After major lung resections pulmonary and pleural complications are often encountered. In this overview more surgically related complications are discussed, focusing on postpneumonectomy pulmonary edema, thromboembolic disease including pulmonary embolism, prolonged air leak, lobar torsion, persistent pleural space, empyema and bronchopleural fistula. Prevention, timely recognition, and early adequate treatment are key points as complications initially considered to be minor, may suddenly turn into life threatening events. To this end multidisciplinary cooperation is necessary. Preoperative smoking cessation, adequate pain control, attention to nutritional status, incentive spirometry and early mobilization are important factors to reduce the incidence of postoperative complications. PMID- 25806296 TI - Sublobar resection for early-stage lung cancer. AB - Since the 1995 report of the prospective randomized trial of lobectomy versus sublobar resection for stage I non-small cell lung cancer (NSCLC) performed by the the Lung Cancer Study Group, lobectomy remains the standard of care for the surgical management of stage I NSCLC. Sublobar resection has been typically used for high-risk patients who are operative candidates but for whom a lobectomy is contraindicated. Recent advances in imaging and staging modalities and improved spatial resolution of computed tomography (CT) scan have refined the presentation and diagnosis of early-stage NSCLC. The detection of small tumors and ground glass opacity (GGO) appearance associated with a favorable histology have led to the increased use of sublobar resection in many institutes to include good-risk patients. There is an increasing body of evidence that sublobar resection may achieve oncological outcomes similar to those with lobectomy in early-stage NSCLC, especially that 2 cm or less in size. However, whether or not sublobar resection constitutes adequate treatment for small-sized lung cancer or for the radiographic "early" lung cancer such as a GGO-dominant lesion is still being prospectively investigated. Sublobar resection will be expected to play an important role as a primary treatment option for patients with small stage IA NSCLC, based on an anatomical functional advantage over lobectomy as well as comparable prognostic outcomes between sublobar resection and lobectomy. PMID- 25806300 TI - Oligometastatic NSCLC: the changing role of surgery. AB - There is a very limited role for pulmonary resection in the management of NSCLC that has already metastasized systemically. Well selected individuals who present with limited metastatic disease (oligometastases) to a single organ may be considered for resection or an alternative local therapy to both the lung and the extrapulmonary site in rare instances where a thorough metastatic evaluation fails to reveal other foci of disease. This evaluation must include a negative mediastinoscopy. PMID- 25806299 TI - Focus on treatment complications and optimal management: radiation oncology. AB - BACKGROUND: Esophagitis and pneumonitis are the most important treatment complications and dose-limiting toxicities in non-small cell lung cancer (NSCLC) patients treated with radiotherapy (RT) alone or combined modality therapy. METHODS: A literature research was performed to identify published articles relating clinical and dosimetric parameters associated with significant radiation pneumonitis (RP) and esophagitis in NSCLC patients treated with three-dimensional conformal RT. RESULTS: Possible clinical parameters associated with acute and or late esophagitis are concurrent chemoradiation, hyperfractionated and accelerated radiation regimens, dysphagia and neutropenia during treatment. Mean dose <34 Gy is currently used as standard dosimetric recommendation. Addition of chemotherapy and hyperfractionation are also associated with the risk of pneumonitis. Both the V20 and the mean lung dose are used as dosimetric parameter to correlate with the risk of high-grade radiation pneumonitis. CONCLUSIONS: A variety of clinical and dosimetric parameters have been associated with acute and late toxicity. Treatment consist mainly in symptomatic relieve. Further research is necessary, as many studies led to different and sometimes even contradictory results. PMID- 25806302 TI - Molecular epidemiology of lung cancer and geographic variations with special reference to EGFR mutations. AB - Lung cancer is a leading cause of cancer-related mortality in many countries. Although recent advances in targeted therapy against driver oncogenes have significantly improved patient outcome, cure of this disease is still exceptional. Although tobacco is a known cause of lung cancer, not all smokers develop lung cancer, and conversely many patients, especially Asian female patients with lung cancer, are lifetime never-smokers. Therefore, efforts to understand the basis for different susceptibilities to lung cancer among individuals with different genetic, biologic, ethnic, and social backgrounds are important to help develop effective preventive measures. Lung cancer in never smokers has many different characteristics to lung cancer in smokers, such as adenocarcinoma predominance and high frequency of epidermal growth factor receptor (EGFR) mutation yet low number of genetic changes. Epidemiologic studies suggest that East Asians are more susceptible to smoking-unrelated lung cancer but less susceptible to smoking-related lung cancer compared with Caucasians. Mutations in the EGFR gene are more common in Asian females and never-smokers. Our case-control study suggests that EGFR mutation occurs independent of smoking, and that the apparent low frequency of EGFR mutations in smokers may be the result of dilution by smoking-related lung cancer. The frequencies of three EGFR gene polymorphisms associated with increased protein expression are significantly different between East Asians and Caucasians, favoring lower protein expression in East Asians. Although these may be associated with preferred expression of the EGFR mutant allele, it is difficult to explain the frequent EGFR mutation in Asian patients. Genome wide association studies (GWAS) revealed several loci related to lung cancer susceptibility. In the future, GWAS may identify loci that are specifically related to EGFR-targeted carcinogenesis, leading to identification of carcinogens that induce EGFR mutations and effective prevention measures. PMID- 25806301 TI - Challenges in the treatment of early non-small cell lung cancer: what is the standard, what are the challenges and what is the future for radiotherapy? AB - In the last 15 years, the use of Stereotactic Ablative Radiation Therapy (SABRT) in the management of small peripheral lung tumours has developed considerably, so that it currently represents a standard of care for inoperable stage I non-small cell lung cancer (NSCLC), offering a survival advantage over traditional radiotherapy, local control rates at 3 years around 90%, with a low risk of toxicity. Indications have extended to larger tumours up to 5 cm and centrally located tumours. In this review we will explore the role of SABRT in early stage NSCLC, the state of the art, the challenges and the future for this technique. There are ongoing studies to optimize such approaches within a multicentric setting. Trials comparing surgery to SABRT in operable or marginally operable have failed because of poor accrual. Several questions remain that need to be addressed in prospective studies. PMID- 25806305 TI - Radiotherapy for single station N2 NSCLC. AB - Clinical 'single station N2' is a prognostic factor, which is only moderately identifiable preoperatively, even after adequate mediastinal staging. There is little evidence that 'single station N2' predicts for the outcome of any radical treatment strategy, or for a benefit of postoperative radiotherapy. In adequately staged patients with clinical 'single station N2' involvement, modern definitive chemoradiation therapy results in equivalent outcome as induction therapy followed by resection. PMID- 25806306 TI - An alternative way to initiate Notch1 signaling in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) cells activate Notch1 signaling to promote cell proliferation and facilitate their survival. It now emerges that endothelial Delta-like ligand 4 (Dll4) may mediate Notch1 activation and inhibit tumor cell growth. PMID- 25806304 TI - Preoperative mediastinal lymph node staging for non-small cell lung cancer: 2014 update of the 2007 ESTS guidelines. AB - Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. Over the last years more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of CT-enlarged or PET positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography (EBUS/EUS) with fine needle aspiration is the first choice (when available) since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred over mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumors <=3 cm located in the outer third of the lung. In central tumors or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and fine needle aspiration or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumors larger than 3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high SUV uptake. PMID- 25806303 TI - SBRT in operable early stage lung cancer patients. AB - Since decades the gold standard for treatment of early stage non-small cell lung cancer (NSCLC) is surgical lobectomy plus mediastinal lymph node dissection. Patients in worse health status are treated with sublobar resection or radiation treatment. With development of stereotactic-body-radiotherapy (SBRT), outcome of patients treated with radiation was substantially improved. Comparison of SBRT and surgical techniques is difficult due to the lack of randomized trials. However, all available evidence in form of case control studies of population based studies show equivalence between sublobar resection and SBRT indicating that SBRT-when performed by a trained and experienced team-should be offered to all high-risk surgical patients. For patients not willing to take the risk of lobectomy and therefore refusing surgery, SBRT is an excellent treatment option. PMID- 25806307 TI - Recurrence after surgery in patients with NSCLC. AB - Surgery remains the only potentially curative modality for early-stage non-small cell lung cancer (NSCLC) patients and tissue availability is made possible. However, a proportion of lung cancer patients develop recurrence, even after curative resection. This review discusses the superiority of surgery, the reasons for recurrence, the timing and pattern of recurrence, the identification of factors related to recurrence, current provisions for treatment and perspectives about surgery for patients with NSCLC. PMID- 25806309 TI - Coexistent pulmonary granular cell tumor and adenocarcinoma of the lung. AB - We report a case of granular cell tumor (GCT) of the lung with coexistent invasive adenocarcinoma. GCTs are rare tumors and often benign and amenable to local bronchoscopic excision. However, occasionally they are more aggressive and locally infiltrative requiring definitive surgical resection. Our patient had a central and infiltrative GCT, in addition a very small (6 mm) peripheral nodule in the same lobe as the GCT, which after careful examination of the surgical specimen during grossing was found to be an invasive adenocarcinoma. There are a few reports in the literature of GCTs with coexistent bronchogenic cancer. Our case highlights the importance of careful evaluation and exploration of the surgical specimens during grossing of patients with GCTs. In GCT patients presenting with additional pulmonary nodules, a more definitive surgical approach should be considered. PMID- 25806310 TI - Gavin M. Wright: current treatments for NSCLC. PMID- 25806308 TI - ALK and crizotinib: after the honeymoon...what else? Resistance mechanisms and new therapies to overcome it. AB - The last few decades have witnessed a silent revolution in the war against NSCLC, thanks to the discovery of "oncogenic drivers" and the subsequent development of targeted therapies. The discovery of the EML4-ALK fusion gene in a subgroup of patients with NSCLC and the subsequent clinical development of crizotinib has been an amazing success story in lung cancer translational-research, and its accelerated approval [only 4 years from the discovery of ALK rearrangement in NSCLC to the approval by the Food and Drug Administration (FDA)] marked the beginning of the new decade of targeted therapy. However, common to all targeted therapies, despite an initial benefit, patients inevitably experience tumor progression, due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance, such as secondary mutations of ALK kinase domain or amplification of ALK fusion gene, or the activation of other oncogenic drivers, which may cause resistance independently of ALK genetic alterations. Pre-clinical data and early clinical trials showed the promising efficacy of a new class of ALK-inhibitors in overcoming acquired resistance. The inhibition of the molecular chaperone, HSP90, represents another promising strategy to overcome crizotinib resistance in ALK-rearranged NSCLC. Several molecules are currently under investigation in order to establish their specific role in the treatment of ALK-rearranged NSCLC. PMID- 25806312 TI - Tobacco control in Poland-successes and challenges. AB - For many years, tobacco smoking was the major single avoidable cause of premature mortality in Poland. In the 1970s and 1980s, Poland was a country with an extremely high prevalence of smoking and lung cancer mortality among men in the world. By 1990, over 40% of Polish men died prematurely from smoking-attributed diseases. However, the enforcement of comprehensive tobacco-control measures and programs based on the World Health Organization recommendations and the best practices from other countries, contributed to a spectacular decrease of smoking incidence, particularly in men. This led to dramatic decrease in lung cancer incidence and mortality, and to a substantial improvement in public health in Poland. This article reviews the achievements of tobacco-control in Poland over the past decades and points out current challenges in this field. PMID- 25806313 TI - Implementation of lung cancer screening: promises and hurdles. AB - Lung cancer screening is a subject of considerable interest in the medical community and the general population. Since the publication of the data from the national lung screening trial (NLST) in 2011, the interest in lung cancer screening has increased even more. Data from many sources provide evidence that low-dose computed tomography (LD-CT) lung cancer screening can be performed with even greater efficacy if inclusion criteria as well as nodule management are optimized. There are, however, also a number of potential hurdles for the implementation of lung cancer screening. Among these are, in particular, the high prevalence of screen-detected pulmonary nodules, the unknown extent of over diagnosis, the potential harms of the cumulative radiation dose and the insufficient data on cost-efficiency of lung cancer screening. In this article, the most recent insights into some of the most imminent questions are reviewed to provide an understanding of the challenges we still face in lung cancer screening. PMID- 25806311 TI - Lung cancer molecular epidemiology in China: recent trends. AB - Lung cancer is both the most common diagnosed cancer and the leading cause of cancer related deaths in China. During the past three decades, the incidence and mortality of lung cancer in China are increasing rapidly. According to data from National Central Cancer Registry (NCCR) in 2010, the crude incidence of lung cancer in China was 46.08 per 100,000 population (61.86 per 100,000 men and 29.54 per 100,000 women), with an estimated over 600,000 new diagnosed lung cancer patients (416,333 males and 189,613 females). Meanwhile, the crude mortality of lung cancer in China was 37.00 per 100,000 population (50.04 per 100,000 men and 23.33 per 100,000 women). Consistent with the change in developed countries, adenocarcinoma has become the most predominant histological subtype of lung cancer in China. For the majority advanced non-small-cell lung cancer (NSCLC) patients, especially patients with adenocarcinoma, targeted therapy became increasing important in the treatment. Chinese researcher have done a lot work in terms of lung cancer molecular epidemiology, therefore, in this review, we further summarized the epidemiology of driver genes in NSCLC, hoping to help clinicians to better screen certain driver genes in China for treatment decisions. PMID- 25806314 TI - Molecular testing in lung cancer in the era of precision medicine. AB - The clinical expectations how pathologists should submit lung cancer diagnosis have changed dramatically. Until mid 90-ties a clear separation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) was mostly sufficient. With the invention of antiangiogenic treatment a differentiation between squamous and non-squamous NSCLC was requested. When epidermal growth factor receptor (EGFR) mutation was detected in patients with pulmonary adenocarcinomas and subsequent specific treatment with tyrosine kinase inhibitors (TKIs) was invented, sub-classification of NSCLC and molecular analysis of the tumor tissue for mutations was asked for. Pathologists no longer submit just a diagnosis, but instead are involved in a multidisciplinary team for lung cancer patient management. After EGFR several other driver genes such as echinoderm microtubule associated protein like 4-AL-Kinase 1 (EML4-ALK1), c-ros oncogene 1, receptor tyrosine kinase (ROS1), discoidin domain receptor tyrosine kinase 2 (DDR2), fibroblast growth factor receptor 1 (FGFR1) were discovered, and more to come. Due to new developments in bronchology (EUS, EBUS) the amount of tissue submitted for diagnosis and molecular analysis is decreasing, however, the genes to be analyzed are increasing. Many of these driver gene aberrations are inversions or translocations and thus require FISH analysis. Each of these analyses requires a certain amount of tumor cells or one to two tissue sections from an already limited amount of tissues or cells. In this respect new genetic test systems have been introduced such as next generation sequencing, which enables not only to detect multiple mutations in different genes, but also amplifications and fusion genes. As soon as these methods have been validated for routine molecular analysis this will enable the analysis of multiple genetic changes simultaneously. In this review we will focus on genetic aberrations in NSCLC, resistance to new target therapies, and also to methodological requirements for a meaningful evaluation of lung cancer tissue and cells. PMID- 25806317 TI - Clinical trials for lung cancer in China. AB - Lots of international multi-center clinical trials have been conducted in China over the past 10 years. We also have more and more clinical trials designed and launched by qualified Chinese investigators in recent years, especially after the establishment of the Chinese Thoracic Oncology Group (CTONG) in 2007. These trials are mainly about targeted drugs. The finished ones provided more evidence for the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the first-line/maintenance/second-line settings in Chinese patients. The ongoing ones will diversify the use of EGFR-TKIs in 1(st)/2(nd)/3(rd) line settings and help to answer the questions whether patients will benefit from (neo)adjuvant EGFR-TKIs and chemotherapy intercalating and maintenance use of EGFR-TKIs. Here, we introduce far-reaching clinical trials conducted, ongoing and will be launched soon in China. PMID- 25806315 TI - Minimal requirements for the molecular testing of lung cancer. AB - From the aspect of the contemporary pathologic diagnostics of lung cancer, it is a key issue of the tissue obtained since small biopsies and cytology still play a major role. In the non-small cell lung cancer era, cytology considered equal to biopsy. However, in recent years it is unable to provide quality diagnosis and must be replaced by biopsy. Various molecular techniques can handle various different tissue samples which must be considered during molecular pathology diagnosis. Besides, tumor cell-normal cell ratio in the obtained tissue as well as the absolute tumor cell number have great significance whose information must be provided in the primary lung cancer diagnosis. Last but not least, for continuous sustainable molecular diagnostics of lung cancer rational algorythms, affordable technology and appropriate reimbursement are equally necessary. PMID- 25806316 TI - Adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. AB - Adjuvant chemotherapy has been established as a standard for patients with completely resected non-small cell lung cancer (NSCLC). Adjuvant chemotherapy increased the 5-year survival rates by 4% to 15% within randomized trials and, based on a meta-analysis of five cisplatin-based trials, by 5.4%. Adjuvant chemotherapy consists of a cisplatin-based doublet, preferentially cisplatin plus vinorelbine. Future improvements in outcome of adjuvant therapy are expected by customized chemotherapy and the integration of targeted therapies or immunotherapy. PMID- 25806318 TI - Special issue on personalized therapy in lung cancer. PMID- 25806319 TI - Update on third-generation EGFR tyrosine kinase inhibitors. PMID- 25806320 TI - Is the third generation EGFR TKIs the solution for making EGFR mutant NSCLC a curable disease? PMID- 25806321 TI - EGFR, EGFR TKI, and EMSI: a never-ending story. PMID- 25806322 TI - Recent advances in the development of mutant-selective EGFR inhibitors for non small cell lung cancer patients with EGFR-TKI resistance. PMID- 25806323 TI - Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer. AB - The first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Unfortunately, disease progression generally occurs after 9 to 14 months of targeted therapy. The substitution of threonine with methionine at amino acid position 790 (T790M), as the second mutation in EGFR, is the most common resistance mechanism and is detected in tumor cells from more than 50-60% of patients after disease progression. However, current targeted therapeutic strategies for patients with acquired resistance are limited. This has led to the development of "third generation" EGFR-TKIs that are designed to target T790M and EGFR-TKI sensitizing mutations more selectively than wild-type. AZD9291, as a mono-anilino-pyrimidine compound, is a novel, irreversible EGFR-TKI, has proved to be more effective against both EGFR-TKI sensitizing and resistance T790M mutations in preclinical models. This phase I clinical study showed that AZD9291 has robust efficacy and is well tolerated in EGFR mutant NSCLC patients with acquired resistance to EGFR-TKIs. PMID- 25806324 TI - Clinical development and approval of second generation ALK inhibitors for ALK rearranged lung cancer. PMID- 25806326 TI - Ceritinib-a second-generation ALK inhibitor overcoming resistance in ALK rearranged non-small cell lung cancer. PMID- 25806325 TI - Ceritinib as a promising therapy for ALK related diseases. AB - Ceritinib, also known as LDK-378 or Zykadia (Novartis), is a second generation inhibitor able to specifically target the anaplastic lymphoma kinase (ALK). In the last five years the interest for ALK small inhibitors grew rapidly, mainly because it was discovered that a small but significant percentage of non-small cell lung cancer (NSCLC) patients carries the oncogenic fusion protein EML4-ALK, in addition to about half percent of anaplastic large cell lymphoma (ALCL) patients, an aggressive but definitely rarer non Hodgkin's T cell lymphoma, and other malignancies. Moreover the first ALK inhibitor, crizotinib (Xalkori or PF02341066) was successfully approved for the treatment of late stages or metastatic ALK+ NSCLC, giving a new, safer therapeutic option for those patients. As predicted from previous clinical experience with other kinase inhibitors, crizotinib resistance inevitably occurred, so the clinical availability of new compounds able to overcome crizotinib resistance became a priority. Recently the first clinical data from the phase I trial on ceritinib were published (N Engl J Med 2014;370:1189-97): 59 patients were enrolled in the dose-escalation phase while additional 71 patients were treated in the following expansion phase. For 19 patients relapsed upon crizotinib treatment, ceritinib was used as second line therapy. Collectively, ORR was 58%, 56% for patients who received crizotinib before. Maximum tolerated dose (MTD) was established at 750 mg daily, but more than half patients had to reduce the drug dose because of adverse events. Finally PFS was 7.0 months. Here we discuss the clinical data presented in this article, comparing ceritinib with the first line inhibitor crizotinib and another second generation ALK inhibitor, alectinib (Chugai-Roche). PMID- 25806327 TI - Necitumumab: a new therapeutic option for squamous cell lung cancer? PMID- 25806328 TI - A critical question for cancer therapy: what new targets exist? AB - Designing molecular targeted therapy with high specificity based on novel tumor biomarkers is a high priority in lung cancer research. Several molecular aberrations have been already identified in non-small cell lung cancer (NSCLC), with subsequent development of drugs targeted to these aberrations. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase which frequently interacts with other key oncogenic tyrosine kinases including epidermal growth factor receptor (EGFR) and ERBB3 leading to resistance to anti EGFR therapies. However a phase III trial enrolling only patients with MET positive tumors was stopped in early March due to futility since there was no evidence that the addition of onartuzumab to erlotinib has any positive effect. From the results of the MET lung phase III trial, we provide new pieces of information that can contribute to further preclinical validation and also be part of the armamentarium for clinical translational research. PMID- 25806329 TI - Targeting MET in NSCLC: looking for a needle in a haystack. PMID- 25806330 TI - Negative results of METLung study: an opportunity to better understand the role of MET pathway in advanced NSCLC. PMID- 25806331 TI - Targeting MET and EGFR in NSCLC-what can we learn from the recently reported phase III trial of onartuzumab in combination with erlotinib in advanced non small cell lung cancer? PMID- 25806333 TI - Nivolumab as first line monotherapy for advanced non-small cell lung cancer: could we replace first line chemotherapy with immunotherapy? PMID- 25806332 TI - Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC. AB - In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time. PMID- 25806334 TI - Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced non-small cell lung cancer. PMID- 25806335 TI - A phase I study of MEDI4736, NNT-PD-L1 antibody in patients with advanced solid tumors. AB - A review and critical consideration of immunotherapeutical concepts in non-small cell lung cancer (NSCLC) is given. Nivolumab represents a promising option in various malignancies with more results exceeding treatment of metastatic malignant melanoma eagerly awaited. PMID- 25806336 TI - A new addition to the PD-1 checkpoint inhibitors for non-small cell lung cancer the anti-PDL1 antibody-MEDI4736. PMID- 25806337 TI - Reflections on immune checkpoint inhibition in non-small cell lung cancer. PMID- 25806338 TI - Highlights in the 14(th) Central European Lung Cancer Conference (CELCC). PMID- 25806339 TI - Translational Lung Cancer Research is indexed by PubMed. PMID- 25806340 TI - Expanding the portfolio of anti-ALK weapons. AB - The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the onset of several malignancies. In particular, ALK is the driving oncogenic lesion in a small but significant fraction of non-small cell lung cancer (NSCLC) patients. ALK+ NSCLCs can be treated with the dual ALK/MET inhibitor crizotinib, with better outcome compared to standard chemotherapy. However, relapses frequently occur, due to various mechanisms, limiting overall efficacy of the treatment. Point mutations within the ALK catalytic domain or ALK gene amplification account for approximately 30-40% of crizotinib-resistant cases, suggesting that the diseases still relies on ALK activity and that more potent inhibitors could be useful in this setting. Ceritinib is a novel selective ALK inhibitor with preclinical activity against crizotinib-resistant ALK mutants. A recent article in the New England Journal of Medicine reports on clinical evaluation of ceritinib. Response rate and progression-free survival (PFS) were comparable to crizotinib, but most importantly, crizotinib-resistant patients were successfully treated, with efficacy similar to crizotinib-naive patients. The study extends the array of available anti-ALK drugs. Based on these data, ceritinib was approved by FDA in April 2014. PMID- 25806341 TI - Pre-operative chemotherapy for non-small cell lung carcinoma. AB - The roll by the cytotoxic chemotherapy and its efficacy in the treatment of non small cell carcinoma (NSCLC) was not clearly identified until the 1980s when studies showed that cisplatin was beneficial in the treatment of NSCLC. The first randomized controlled trial (RCT) to evaluate the efficacy of post-operative (adjuvant) chemotherapy using the cisplatin regimen for resectable NSCLC was reported in 1988. Since then, an increasing number of RCTs have been carried out to evaluate post-operative chemotherapy. Pre-operative (neo-adjuvant) chemotherapy is a relatively new treatment strategy, as its name indicates. Compared with post-operative chemotherapy, fewer RCTs have been carried out to evaluate pre-operative chemotherapy. Given the inconsistency of the results from the RCTs, at least 12 meta-analyses have been published. Most of these meta analyses reported overall survival (OS) benefit with hazard ratios (HRs) in the range of 0.81 to 0.89 in favor of pre-operative chemotherapy. An individual patient data meta-analysis by Burdett in 2014 indicates that the option of pre operative chemotherapy + surgery is associated with better OS (HR 0.87, 95% CI, 0.78-0.96, P=0.007) and recurrence-free survival (RFS) (HR 0.85, 95% CI, 0.76 0.94, P=0.002) survival for operable NSCLC when compared with treatment with surgery alone. Although the current consensus recommends the use of post operative chemotherapy, pre-operative chemotherapy has equivalent efficacy. Both strategies should be regarded as the first choice treatment options. Despite Burdett's comment, indication of pre-operative chemotherapy for stage IA disease should be judged carefully. PMID- 25806342 TI - The lesson learned from figitumumab clinical program and the hope for better results in squamous lung cancer. PMID- 25806343 TI - Ratio of maximum standardized uptake value to primary tumor size is a prognostic factor in patients with advanced non-small cell lung cancer. AB - PURPOSE: Ratio of maximum standardized uptake value to primary tumor size (SUVmax/tumor size) was previously demonstrated to be a more important indicator of prognosis than primary tumor SUVmax alone in surgically resected non-small cell lung cancer (NSCLC). The aim of this study was to investigate whether SUVmax/tumor size was associated with response to first-line therapy and prognosis in patients with advanced NSCLC. PATIENTS AND METHODS: A retrospective review of patients who had a pretreatment (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) before receiving first line therapy for advanced (III & IV) NSCLC was performed. Survival curves were stratified by median SUVmax and SUVmax/tumor size by the Kaplan-Meier method and statistical differences were assessed using the log-rank test. Multivariate proportional hazards (Cox) regression analyses were applied to test the SUVmax's and SUVmax/tumor size's independency of other prognostic factors for the prediction of survival. RESULTS: In total 181 patients were enrolled into the current study. Median overall survival (OS) was 15.4 months (range, 3.1-64.0 months), progression-free survival (PFS) was 5.6 months (range, 0.8-29.1 months), and post-progression survival (PPS) was 8.2 months (range, 0-51.3 months). The statistical analysis data indicated that only clinical response to first-line therapy (P=0.000, OR =6.555) was independent prognostic factors for PFS, stage (P=0.028, OR =1.673) was associated with PPS independently, and for OS, SUVmax/tumor size (P=0.050, OR =1.656) and clinical response (P=0.002, OR =2.803) were all independent prognostic factors. CONCLUSIONS: SUVmax/tumor size may be an important indicator of prognosis in patients with advanced NSCLC. PMID- 25806344 TI - Itraconazole can inhibit malignant pleural effusion by suppressing lymphangiogenesis in mice. AB - BACKGROUND: The presence of malignant pleural effusion (MPE) indicates a poor prognosis in patients with non-small cell lung cancer (NSCLC). Itraconazole has been identified as a potent inhibitor of endothelial cell proliferation that suppresses angiogenesis; however, its role in the suppression of lymphangiogenesis is still unclear. The aim of this study was to investigate the efficacy of itraconazole for MPE and the mechanism of lymphangiogenesis suppression. METHODS: Lewis lung carcinoma (LLC) cells were injected into the mouse pleural cavity to establish the MPE mouse model, followed by randomization of the mice into three groups. Each mice was injected with either a high dose of itraconazole (25 mg/kg, H-ITCZ), a low dose of itraconazole (8 mg/kg, L-ITCZ), or 50 MUL of hydroxypropyl-beta-cyclodextrin (130 mg/mL, H-beta-C) into the pleural cavity four times every 3 days. The MPE of the mice was collected and measured with a 1 mL syringe. The vascular endothelial growth factor-C (VEGF-C) expression level in the MPE was detected by enzyme-linked immunosorbent assay (ELISA), while the VEGF-C expression and lymphatic micro vessel density (LMVD) in the tumor tissue was observed by immunohistochemistry (IHC) staining. RESULTS: The number of pleural tumor foci, the volume of pleural effusion, the LMVD and the VEGF-C expression levels in the tumor tissue were significantly reduced in the H-ITCZ treated group. CONCLUSIONS: Our results revealed that itraconazole may play an important role in the MPE mice by suppressing lymphangiogenesis, which demonstrated the usefulness of itraconazole in the treatment of MPE. PMID- 25806346 TI - The role of interleukin-6 in malignant mesothelioma. AB - Malignant mesothelioma (MM) still remains a dismal disease with a median overall survival between 9-12 months. During the past decade since the introduction of the multi-folate antagonist, pemetrexed, there have been no significant advances in its systemic treatment, particularly with novel therapeutics that have exhibited varying degrees of success in other solid tumours. In recent years, the pleiotropic proinflammatory cytokine, interleukin-6 (IL-6) has emerged as a mediator of pivotal processes such as cell proliferation and chemoresistance within the mesothelioma tumour microenvironment in addition to clinical symptoms commonly witnessed in this disease. This manuscript provides a brief summary on the pathophysiology and clinical management of MM, followed by the role of IL-6 in its tumourigenesis and the rationale for utilising anti-IL-6 therapeutics alongside standard chemotherapy and targeted agents in an attempt to prolong survival. PMID- 25806348 TI - Neoadjuvant and adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer. AB - The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or lymph node biopsy). On the other hand, case reports and several phase II clinical trials with small sample size tried to elbow their way on respect of preoperative TKI treatment and advised that TKI tended to improve response rate. However, no data on survival rate was present. The first phase II study of biomarker-guided neoadjuvant therapy for stage IIIA-N2 NSCLC patients stratified by EGFR mutation status, sponsored by CSLC0702, showed erlotinib tended to improve response rate, but failed to show benefits of disease free survival (DFS) or OS. Subsequently, CTONG1103 was designed to investigate efficacy of erlotinib vs. combination of gemcitabine/cisplatin (GC) as neoadjuvant treatment in stage IIIA-N2 NSCLC with sensitizing EGFR mutation in exon 19 or 21. All these ongoing trials should be worthy of our expect to provide convincing evidences for customized therapy for patients with resectable NSCLC. PMID- 25806350 TI - Professor Suresh Senan: controversies on radiotherapy in lung cancer. PMID- 25806349 TI - A 61-year-old man with cough and white sputum. AB - A 61-year-old man with cough and white sputum had an abnormal pulmonary mass in the left lower lobe in the computed tomography (CT) imaging. According to the lung cancer multidisciplinary team (MDT) discussion, the patient took the left lower lobe resection and lymphadenectomy and finally diagnosed as left lung adenocarcinoma with TNM stage IIIA (pT3N2M0). After four cycles of postoperative chemotherapy with pemetrexed and nedaplatin and 10-month release, a solitary pulmonary nodule (SPN) appeared in the middle lobe of right lung in CT scanning. The patient took a second operation "the right middle lobe resection" and was diagnosed as left lung adenocarcinoma at TNM stage IV (pT3N2M1a, two lungs) with neither EGFR mutation nor ALK-EML4 fusion gene. After operation, the patient took another four cycles of postoperative chemotherapy with Docetaxel and Nedaplatin. During the follow-up, another PET/CT scanning reported that several enlarged mediastinal lymph nodes, a SPN in left upper lobe and lesion in cerebellum and the brain metastasis was also proved in MRI. The patient was now diagnosed as left lung adenocarcinoma at TNM stage IV (pT3N2M1b, brain). In the third-line therapy, the patient took the stereotactic radiotherapy for metastatic mediastinal lymph nodes and took erlotinib once a day after the radiotherapy. However, the number of small lesions on lungs was increased and the brain metastasis was enlarged. The stereotactic radiotherapy for the single brain metastasis and single agent chemotherapy of abraxane were taken. The whole body examination suggested that there was progression-free after two cycles of chemo. The patient is now took five cycles of single agent chemotherapy of abraxane. The latest whole body examination showed disease was stable with no new lesions and metastasis, performance status (PS) score is 0 and the overall survival (OS) time is 34 months. PMID- 25806351 TI - Professor Paul Van Schil: close interaction, discussion and cooperation with younger and older colleagues make our profession beautiful and worthwhile. PMID- 25806347 TI - Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. AB - Lung cancer is the leading cause of cancer related deaths in Canada with non small cell lung cancer (NSCLC) being the predominant form of the disease. Tumor characterization can identify cancer-driving mutations as treatment targets. One of the most successful examples of cancer targeted therapy is inhibition of mutated epidermal growth factor receptor (EGFR), which occurs in ~10-30% of NSCLC patients. While this treatment has benefited many patients with activating EGFR mutations, almost all who initially benefited will eventually acquire resistance. Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, many of the remaining mechanisms of resistance are still unknown. Much work has been done to elucidate the remaining mechanisms of resistance. This review aims to highlight both the mechanisms of resistance that have already been identified in patients and potential novel mechanisms identified in preclinical models which have yet to be validated in the patient settings. PMID- 25806345 TI - Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. AB - In recent years, there has been a major paradigm shift in the management of non small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future. PMID- 25806352 TI - CHRNA3 rs1051730 polymorphism and lung cancer susceptibility in Asian population: a meta-analysis. AB - Many studies have examined the association between the CHRNA3 rs1051730 polymorphism gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. The PubMed was searched for case-control studies published up to Jan 01, 2015. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. In this meta-analysis, we assessed four published studies involving comprising 2,890 lung cancer cases and 2,521 controls of the association between CHRNA3 rs1051730 polymorphism and lung cancer risk. For the T allele carriers (C/T + T/T) and the homozygote T/T, the pooled ORs for all studies combined 2,890 cases and 2,521 controls were 1.93 (95% CI =1.48-2.53, P=0.34 for heterogeneity) and 1.63 (95% CI =1.27-1.99, P=0.46 for heterogeneity), when compared with the homozygous wild-type genotype (C/C). There was no observable publication bias for both polymorphisms. These results from the meta-analysis suggest that CHRNA3 rs1051730 polymorphism contributes to risk of lung cancer among Asian population. PMID- 25806354 TI - p53 Calls upon CIA (Calcium Induced Apoptosis) to Counter Stress. PMID- 25806353 TI - Single cell transcriptomics: methods and applications. AB - Traditionally, gene expression measurements were performed on "bulk" samples containing populations of thousands of cells. Recent advances in genomic technology have made it possible to measure gene expression in hundreds of individual cells at a time. As a result, cellular properties that were previously masked in "bulk" measurements can now be observed directly. In this review, we will survey emerging technologies for single cell transcriptomics, and describe how they are used to study complex disease such as cancer, as well as other biological phenomena such as tissue regeneration, embryonic development, and immune response. PMID- 25806355 TI - A meta-analysis of cognitive impairment and decline associated with adjuvant chemotherapy in women with breast cancer. AB - A meta-analysis was performed to quantify the magnitude and nature of the association between adjuvant chemotherapy and performance on a range of cognitive domains among breast cancer patients. A total of 27 studies (14 cross-sectional, 8 both cross-sectional and prospective, and 5 prospective) were included in the analyses, involving 1562 breast cancer patients who had undergone adjuvant chemotherapy and 2799 controls that included breast cancer patients who did not receive adjuvant chemotherapy. A total of 737 effect sizes (Cohen's d) were calculated for cross-sectional and prospective longitudinal studies separately and classified into eight cognitive domains. The mean effect sizes varied across cross-sectional and prospective longitudinal studies (ranging from -1.12 to 0.62 and -0.29 to 1.12, respectively). Each cognitive domain produced small effect sizes for cross-sectional and prospective longitudinal studies (ranging from 0.25 to 0.41). Results from cross-sectional studies indicated a significant association between adjuvant chemotherapy and cognitive impairment that held across studies with varied methodological approaches. For prospective studies, results generally indicated that cognitive functioning improved over time after receiving adjuvant chemotherapy. Greater cognitive impairment was reported in cross-sectional studies comparing chemotherapy groups with healthy control groups. Results suggested that cognitive impairment is present among breast cancer patients irrespective of a history of chemotherapy. Prospective longitudinal research is warranted to examine the degree and persisting nature of cognitive impairment present both before and after chemotherapy, with comparisons made to participants' cognitive function prior to diagnosis. Accurate understanding of the effects of chemotherapy is essential to enable informed decisions regarding treatment and to improve quality of life among breast cancer patients. PMID- 25806356 TI - Identification of potential genetic components involved in the deviant quorum sensing signaling pathways of Burkholderia glumae through a functional genomics approach. AB - Burkholderia glumae is the chief causal agent for bacterial panicle blight of rice. The acyl-homoserine lactone (AHL)-mediated quorum-sensing (QS) system dependent on a pair of luxI and luxR homologs, tofI and tofR, is the primary cell to-cell signaling mechanism determining the virulence of this bacterium. Production of toxoflavin, a major virulence factor of B. glumae, is known to be dependent on the tofI/tofR QS system. In our previous study, however, it was observed that B. glumae mutants defective in tofI or tofR produced toxoflavin if they grew on the surface of a solid medium, suggesting that alternative signaling pathways independent of tofI or tofR are activated in that growth condition for the production of toxoflavin. In this study, potential genetic components involved in the tofI- and tofR-independent signaling pathways for toxoflavin production were sought through screening random mini-Tn5 mutants of B. glumae to better understand the intercellular signaling pathways of this pathogen. Fifteen and three genes were initially identified as the potential genetic elements of the tofI- and tofR-independent pathways, respectively. Especially, the ORF (bglu_2g06320) divergently transcribed from toxJ, which encodes an orphan LuxR protein and controls toxoflavin biosynthesis, was newly identified in this study as a gene required for the tofR-independent toxoflavin production and named as toxK. Among those genes, flhD, dgcB, and wzyB were further studied to validate their functions in the tofI-independent toxoflavin production, and similar studies were also conducted with qsmR and toxK for their functions in the tofR independent toxoflavin production. This work provides a foundation for future comprehensive studies of the intercellular signaling systems of B. glumae and other related pathogenic bacteria. PMID- 25806357 TI - Socioeconomic inequalities and diabetes: A systematic review from Iran. AB - Socioeconomic factor is a determinant of health may contribute to diabetes. We conducted a systematic review to summarizing evidences on associations between socioeconomic factors and diabetes in Iranian population. We systematically searched international databeses; ISI, PubMed/Medline, Scopus, and national databases Iranmedex, Irandoc, and Scientific Information Database (SID) to retrieve relevant articles to socioeconomic factors and diabetes without limitation on time. All identified articles were screened, quality assessed and data extracted by two authors independently. From 74 retrieved articles, 15 cases were relevant. We found increased diabetes prevalence among female sex, over 50 years' old age, illiterate population, retired status, unemployed, urban residents, and low economic status. There was a negative association between social capital and diabetes control. Diabetes complications were more frequent in upper age group, higher education levels and low income populations. Socioeconomic factors were associated with diabetes that leads to inequality. Improving modifiable factors through priority based interventions helps to diabetes prevention and control. PMID- 25806359 TI - Recurrent hypoglycaemia in type 2 diabetic patient due to hypothyroidism. AB - OBJECTIVE: To present a case report of recurrent hypoglycaemia in type 2 diabetic patient due to hypothyroidism. METHODS: We describe a case with type 2 diabetes who complained of episodes of recurrent hypoglycaemia in last few weeks. We also discuss the results of the diagnostic workup done to find out the cause of recurrent hypoglycaemia. RESULT: After ruling out common causes like overdosing of oral hypoglycaemic agents or insulin, renal or hepatic impairment we found overt hypothyroidism as a cause of recurrent hypoglycaemia. Levothyroxine therapy was started in this patient. Upon normalization of thyroid function, patient did not further experience any episodes of hypoglycaemia. We did not find any report on hypothyroidism as a cause of recurrent hypoglycaemia in type 2 diabetic patients. CONCLUSION: We conclude that during workup, clinicians should take hypothyroidism into consideration as a potential cause of hypoglycaemia in type 2 diabetic patients. PMID- 25806358 TI - Role of breast cancer inhibitors on diabetes mellitus- an in silico approach. AB - BACKGROUND: Breast cancer and diabetes mellitus type-2 are two of the major diseases, which cause death to the women worldwide. Around 16% of the breast cancer patients also suffer from diabetes mellitus. It has been noted that the risk of occurrence of the breast cancer is more in patients suffering from diabetes mellitus. METHODS: Owing to this, the present article deals with an objective of using the breast cancer inhibitors for the diabetes drug target- 1ADS. Ten breast cancer inhibitors were drawn using Marvin Sketch. The docking was performed using Molegro software (Molegro Virtual Docker, MVD). RESULTS: The docking wizard generated 50 poses with the highest Mol Dock score -131.649. CONCLUSION: This investigation successfully evaluated the effect of breast cancer inhibitors on diabetes mellitus, providing a new dimension in endocrine research. PMID- 25806360 TI - Effect of calcitriol supplementation and tail suspension on serum biomarkers of bone formation in rats. AB - BACKGROUND: Calcitriol is documented to cause significant increase in bone mass densitometry counteracting osteoporosis. Promising results of calcitriol supplementation in studies aiming space flight induced osteoporosis is little and the effect of this hormone on biomarkers of bone metabolism is not examined yet in space flight models of osteoporosis in rats. METHODS: This was an interventional animal study being performed in a 1-month period. We included 21 Sprague Dawley strain rats (>200 gr, >6 week) who were randomly assigned to receive daily supplementation of oral 0.03MUgr calcitriol and to be submitted to tail suspension model. Rats were followed for 1 month and were tested for serum osteocalcin (OC), alkaline phosphatase (ALP) and serum calcium at the beginning and the end of the study period. The results were analyzed and compared between groups. RESULTS: Although serum levels of osteocalcin and alkaline phosphatase biomarkers and total serum calcium were not significantly different within and between study groups, their levels were increased in tail suspension model compared to control group. The levels of these biomarkers were lower in those who were submitted to tail suspension model and received calcitriol supplementation compared to those who were only submitted to tail suspension (60.14 +/- 11.73 ng/mL vs. 58.29 +/- 2.69 ng/mL; p = 0.696 for osteocalcin and 381.86 +/- 99.16 mU/mL vs. 362.57 +/- 27.41 ng/mL; p = 0.635 for alkaline phosphatase). CONCLUSION: Supplementation of daily diet with calcitriol in rats under weightlessness conditions may results in lower values for bone metabolic biomarkers of alkaline phosphatase and osteocalcin and serum calcium. This pattern of change in biomarkers of bone formation, may point to the capacity of calcitriol supplementation in preventing cellular process of osteoporosis. Thus calcitriol supplementation could be an available, economic and effective strategy for preventing bone metabolic changes related to weightlessness commonly encountered in space flight. The outcome of this study needs to be further studied in future trying to find more definite results. PMID- 25806361 TI - Reported sildenafil side effects in pediatric pulmonary hypertension patients. AB - BACKGROUND: Sildenafil, a phosphodiestase type 5 inhibitor, was approved in 2005 for the treatment of pulmonary arterial hypertension (PAH) in adults and is commonly used off-label for pediatric patients. Little is known, however, about sildenafil's side effects in this population. METHODS: Single institution, longitudinal survey-based study performed in an outpatient pediatric cardiology clinic. Pediatric patients on sildenafil [alone or in combination with other pulmonary hypertension (PH) therapies] completed questionnaires regarding frequency of vascular, gastrointestinal, neurologic, and hematologic side effects. RESULTS: Between January 2011 and May 2014, 66 pediatric patients with PH on sildenafil filled out 214 surveys, 32 patients (96 surveys) on monotherapy, and 43 patients (118 surveys) on sildenafil plus an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) and/or a prostacyclin (epoprostenol or treprostinil). Overall, 30% of respondents identified at least one side effect. For all patients on sildenafil, incidence of side effects by system was 37% gastrointestinal, 35% vascular, and 22% neurologic. For patients on sildenafil monotherapy, incidence of side effects by system was 24% gastrointestinal, 21% vascular, and 18% neurologic compared to patients on combination therapy who reported an incidence of 48% gastrointestinal, 45% vascular, and 25% neurologic. CONCLUSION: Incidence of vascular, gastrointestinal, and neurologic side effect in pediatric patients on sildenafil therapy for PAH was 30%. Side effects were more common in patients on combination therapy with an ERA and/or prostacyclin than in patients on sildenafil monotherapy. PMID- 25806362 TI - Collective Impact through Public Health and Academic Partnerships: A Kentucky Public Health Accreditation Readiness Example. AB - In the ever-changing, resource-limited public health environment, the use of partners found in the faculty and students of Colleges of Public Health can provide training, consultation, and technical assistance needed to increase local health department (LHD) workforce capacity to meet new public health demands including national public heath accreditation. This manuscript describes the provision of the backbone support activities of facilitation, data management, and project management by University of Kentucky's College of Public Health to Kentucky's LHDs seeking national public health accreditation. PMID- 25806364 TI - A plea for good global governance. PMID- 25806363 TI - Circulating Strains of Brucella abortus in Cattle in Santo Domingo De Los Tsachilas Province - Ecuador. AB - The Province of Santo Domingo de los Tsachilas in Ecuador represents the largest informal cattle market. Because of its strategic position, cattle movement is very high and therefore we selected this region, to determine the strain variation of Brucella sp. Part of the study aimed at the isolation, biotyping, and genotyping of Brucella species from milk and supra-mammary lymph nodes of sero-positive bovines, using selective Farrell medium, biochemical assays, and IS711-PCR, AMOS-PCR, and HOOF-Prints techniques. In total, 656 animals from 12 sero-positive dairy herds and from the provincial slaughterhouse were diagnosed by Rose Bengal and Wright's Slow Agglutination test with EDTA. Amongst these animals, 50 animals were sero-positive for brucellosis. Twenty-five lymph nodes and 25 milk samples from each group of positive reactors were transferred to culture medium. Isolation was possible from 4 (16%) lymph nodes and 9 (36%) milk samples; out of these, 10 isolates were diagnosed as Brucella sp. All four isolates of lymphatic tissue corresponded to Brucella abortus biotype 1, confirmed as field strains by molecular analysis. Milk isolations, showed biochemically a more dispersed pattern in which B. abortus biotypes 1 and 4 were found; yet four samples gave a pattern similar to B. abortus biotype 2; however, only biotypes 1 and 4 were confirmed by molecular analysis. The concordance between biochemical and molecular diagnostic tests reached 76.9%. PMID- 25806365 TI - A validated model of the pro- and anti-inflammatory cytokine balancing act in articular cartilage lesion formation. AB - Traumatic injuries of articular cartilage result in the formation of a cartilage lesion and contribute to cartilage degeneration and the risk of osteoarthritis (OA). A better understanding of the framework for the formation of a cartilage lesion formation would be helpful in therapy development. Toward this end, we present an age and space-structured model of articular cartilage lesion formation after a single blunt impact. This model modifies the reaction-diffusion-delay models in Graham et al. (2012) (single impact) and Wang et al. (2014) (cyclic loading), focusing on the "balancing act" between pro- and anti-inflammatory cytokines. Age structure is introduced to replace the delay terms for cell transitions used in these earlier models; we find age structured models to be more flexible in representing the underlying biological system and more tractable computationally. Numerical results show a successful capture of chondrocyte behavior and chemical activities associated with the cartilage lesion after the initial injury; experimental validation of our computational results is presented. We anticipate that our in silico model of cartilage damage from a single blunt impact can be used to provide information that may not be easily obtained through in in vivo or in vitro studies. PMID- 25806366 TI - Enhanced acylcarnitine annotation in high-resolution mass spectrometry data: fragmentation analysis for the classification and annotation of acylcarnitines. AB - Metabolite annotation and identification are primary challenges in untargeted metabolomics experiments. Rigorous workflows for reliable annotation of mass features with chemical structures or compound classes are needed to enhance the power of untargeted mass spectrometry. High-resolution mass spectrometry considerably improves the confidence in assigning elemental formulas to mass features in comparison to nominal mass spectrometry, and embedding of fragmentation methods enables more reliable metabolite annotations and facilitates metabolite classification. However, the analysis of mass fragmentation spectra can be a time-consuming step and requires expert knowledge. This study demonstrates how characteristic fragmentations, specific to compound classes, can be used to systematically analyze their presence in complex biological extracts like urine that have undergone untargeted mass spectrometry combined with data dependent or targeted fragmentation. Human urine extracts were analyzed using normal phase liquid chromatography (hydrophilic interaction chromatography) coupled to an Ion Trap-Orbitrap hybrid instrument. Subsequently, mass chromatograms and collision-induced dissociation and higher-energy collisional dissociation (HCD) fragments were annotated using the freely available MAGMa software. Acylcarnitines play a central role in energy metabolism by transporting fatty acids into the mitochondrial matrix. By filtering on a combination of a mass fragment and neutral loss designed based on the MAGMa fragment annotations, we were able to classify and annotate 50 acylcarnitines in human urine extracts, based on high-resolution mass spectrometry HCD fragmentation spectra at different energies for all of them. Of these annotated acylcarnitines, 31 are not described in HMDB yet and for only 4 annotated acylcarnitines the fragmentation spectra could be matched to reference spectra. Therefore, we conclude that the use of mass fragmentation filters within the context of untargeted metabolomics experiments is a valuable tool to enhance the annotation of small metabolites. PMID- 25806368 TI - Can the natural diversity of quorum-sensing advance synthetic biology? AB - Quorum-sensing networks enable bacteria to sense and respond to chemical signals produced by neighboring bacteria. They are widespread: over 100 morphologically and genetically distinct species of eubacteria are known to use quorum sensing to control gene expression. This diversity suggests the potential to use natural protein variants to engineer parallel, input-specific, cell-cell communication pathways. However, only three distinct signaling pathways, Lux, Las, and Rhl, have been adapted for and broadly used in engineered systems. The paucity of unique quorum-sensing systems and their propensity for crosstalk limits the usefulness of our current quorum-sensing toolkit. This review discusses the need for more signaling pathways, roadblocks to using multiple pathways in parallel, and strategies for expanding the quorum-sensing toolbox for synthetic biology. PMID- 25806367 TI - G-CNV: A GPU-Based Tool for Preparing Data to Detect CNVs with Read-Depth Methods. AB - Copy number variations (CNVs) are the most prevalent types of structural variations (SVs) in the human genome and are involved in a wide range of common human diseases. Different computational methods have been devised to detect this type of SVs and to study how they are implicated in human diseases. Recently, computational methods based on high-throughput sequencing (HTS) are increasingly used. The majority of these methods focus on mapping short-read sequences generated from a donor against a reference genome to detect signatures distinctive of CNVs. In particular, read-depth based methods detect CNVs by analyzing genomic regions with significantly different read-depth from the other ones. The pipeline analysis of these methods consists of four main stages: (i) data preparation, (ii) data normalization, (iii) CNV regions identification, and (iv) copy number estimation. However, available tools do not support most of the operations required at the first two stages of this pipeline. Typically, they start the analysis by building the read-depth signal from pre-processed alignments. Therefore, third-party tools must be used to perform most of the preliminary operations required to build the read-depth signal. These data intensive operations can be efficiently parallelized on graphics processing units (GPUs). In this article, we present G-CNV, a GPU-based tool devised to perform the common operations required at the first two stages of the analysis pipeline. G-CNV is able to filter low-quality read sequences, to mask low-quality nucleotides, to remove adapter sequences, to remove duplicated read sequences, to map the short-reads, to resolve multiple mapping ambiguities, to build the read depth signal, and to normalize it. G-CNV can be efficiently used as a third-party tool able to prepare data for the subsequent read-depth signal generation and analysis. Moreover, it can also be integrated in CNV detection tools to generate read-depth signals. PMID- 25806370 TI - Effect of benfotiamine in podocyte damage induced by peritoneal dialysis fluid. AB - BACKGROUND: In peritoneal dialysis (PD), residual renal function (RRF) fundamentally contributes to improved quality of life and patient survival. High glucose and advanced glycation end-products (AGE) contribute locally to peritoneal and systemically to renal damage. Integrity of podocyte structure and function is of special importance to preserve RRF. Benfotiamine could counteract the glucose and AGE-mediated toxicity by blocking hyperglycemia-associated podocyte damage via the pentose-phosphate pathway. METHODS: A human differentiated podocyte cell line was incubated with control solution (control), 2.5% glucose solution (glucose), and 2.5% peritoneal dialysis fluid (PDF) for 48 h either +/-50 MUM benfotiamine. Podocyte damage and potential benefit of benfotiamine were analyzed using immunofluorescence, western blot analysis, and a functional migration assay. For quantitation, a semiquantitative score was used. RESULTS: When incubating podocytes with benfotiamine, glucose, and PDF-mediated damage was reduced, resulting in lower expression of AGE and intact podocin and ZO-1 localization. The reorganization of the actin cytoskeleton was restored in the presence of benfotiamine as functional podocyte motility reached control level. Decreased level of inflammation could be shown as well as reduced podocyte apoptosis. CONCLUSION: These data suggest that benfotiamine protects podocytes from glucose and PDF-mediated dysfunction and damage, in particular, with regard to cytoskeletal reorganization, motility, inflammation, and podocyte survival. PMID- 25806369 TI - Epigenetic reprogramming and re-differentiation of a Ewing sarcoma cell line. AB - Developmental reprogramming techniques have been used to generate induced pluripotent stem (iPS) cells from both normal and malignant cells. The derivation of iPS cells from cancer has the potential to provide a unique scientific tool to overcome challenges associated with the establishment of cell lines from primary patient samples and a readily expandable source of cells that may be used to model the initial disease. In the current study we developmentally reprogrammed a metastatic Ewing sarcoma (EWS) cell line to a meta-stable embryonic stem (ES) like state sharing molecular and phenotypic features with previously established ES and iPS cell lines. EWS-iPS cells exhibited a pronounced drug resistant phenotype despite persistent expression of the oncogenic EWS-FLI1 fusion transcript. This included resistance to compounds that specifically target downstream effector pathways of EWS-FLI1, such as MAPK/ERK and PI3K/AKT, which play an important role in EWS pathogenesis. EWS-iPS cells displayed tumor initiation abilities in vivo and formed tumors exhibiting characteristic Ewing histopathology. In parallel, EWS-iPS cells re-differentiated in vitro recovered sensitivity to molecularly targeted chemotherapeutic agents, which reiterated pathophysiological features of the cells from which they were derived. These data suggest that EWS-iPS cells may provide an expandable disease model that could be used to investigate processes modulating oncogenesis, metastasis, and chemotherapeutic resistance in EWS. PMID- 25806373 TI - Formation of 5- and 6-methyl-1H-indene (C10H10) via the reactions of the para tolyl radical (C6H4CH3) with allene (H2CCCH2) and methylacetylene (HCCCH3) under single collision conditions. AB - The reactions of the p-tolyl radical with allene-d4 and methylacetylene-d4 as well as of the p-tolyl-d7 radical with methylacetylene-d1 and methylacetylene-d3 were carried out under single collision conditions at collision energies of 44-48 kJ mol(-1) and combined with electronic structure and statistical (RRKM) calculations. Our experimental results indicated that the reactions of p-tolyl with allene-d4 and methylacetylene-d4 proceeded via indirect reaction dynamics with laboratory angular distributions spanning about 20 degrees in the scattering plane. As a result, the center-of-mass translational energy distribution determined a reaction exoergicity of 149 +/- 28 kJ mol(-1) and exhibited a pronounced maximum at around 20 to 30 kJ mol(-1). In addition, the center-of-mass angular flux distribution T(theta) depicted a forward-backward symmetry and indicated geometric constraints upon the decomposing complex(es). Combining with calculations, these results propose that the bicyclic polycyclic aromatic hydrocarbons, 6-methyl-1H-indene (p1) and 5-methyl-1H-indene (p2), are formed under single collision conditions at fractions of at least 85% in both reaction systems. For the p-tolyl-methylacetylene system, experiments with partially deuterated reactants also reveal the formation of a third isomer p5 (1 methyl-4-(1-propynyl)benzene) at levels of 5-10%, highlighting the importance in conducting reactions with partially deuterated reactants to elucidate the underlying reaction pathways comprehensively. PMID- 25806372 TI - Acute Kidney Injury in Critically Ill Vascular Surgery Patients is Common and Associated with Increased Mortality. AB - INTRODUCTION: Vascular surgery patients have multiple risk factors for renal dysfunction, but acute kidney injury (AKI) is poorly studied in this group. The purpose of this study was to define the incidence, risk factors, and outcomes of AKI in high-risk vascular patients. METHODS: Critically ill vascular surgery patients admitted during January-December 2012 were retrospectively analyzed with 1-year follow-up. The endpoint was AKI by established RIFLE creatinine criteria. The primary analysis was between patients with or without AKI, with secondary analysis of post-operative AKI. Outcomes were inpatient and 1-year mortality, inpatient lengths of stay, and discharge renal function. RESULTS: One-hundred and thirty six vascular surgery patients were included, representing 27% of all vascular surgery admissions during the study period. Sixty-five (48%) developed AKI. Independent global risk factors for AKI were diabetes, increasing critical illness severity, and sepsis. While intraoperative blood loss and hypotension were associated with subsequent renal dysfunction, post-operative AKI rates were similar for patients undergoing aortic, carotid, endovascular, or peripheral vascular procedures. All RIFLE grades of AKI were associated with worse outcomes. Overall, patients with AKI had significantly increased short- and long-term mortality, longer inpatient lengths of stay, and worse discharge renal function. CONCLUSION: AKI is common among critically ill vascular surgery patients. Importantly, the type of surgical procedure appears to be less important than intra- and perioperative management in determining renal dysfunction. Regardless of its severity, AKI is a clinically significant complication that is associated with substantially worse patient outcomes. PMID- 25806371 TI - Molecular and pathogenetic aspects of tumor budding in colorectal cancer. AB - In recent years, tumor budding in colorectal cancer has gained much attention as an indicator of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival, and as an independent prognostic factor. Tumor buds, defined as the presence of single tumor cells or small clusters of up to five tumor cells at the peritumoral invasive front (peritumoral buds) or within the main tumor body (intratumoral buds), are thought to represent the morphological correlate of cancer cells having undergone epithelial-mesenchymal transition (EMT), an important mechanism for the progression of epithelial cancers. In contrast to their undisputed prognostic power and potential to influence clinical management, our current understanding of the biological background of tumor buds is less established. Most studies examining tumor buds have attempted to recapitulate findings of mechanistic EMT studies using immunohistochemical markers. The aim of this review is to provide a comprehensive summary of studies examining protein expression profiles of tumor buds and to illustrate the molecular pathways and crosstalk involved in their formation and maintenance. PMID- 25806374 TI - Professor Marco Metra discusses his aspirations for the European Journal of Heart Failure as he takes over as editor. PMID- 25806375 TI - Reply to comments on: "Efficacy of low-level laser therapy in the management of orthodontic pain: a systematic review and meta-analysis". PMID- 25806376 TI - Bettina Heidecker,MD. PMID- 25806377 TI - People's corner: Mouaz Al-Mallah MD. PMID- 25806378 TI - Trans-Atlantic debate: does endovascular repair offers a survival advantage over open repair for ruptured abdominal aortic aneurysms? PMID- 25806379 TI - International Chamber of Shipping to support Ballast Water Management Convention. PMID- 25806381 TI - Mechanisms of zooxanthella expulsion from coral. PMID- 25806380 TI - Methane leaking from permafrost offshore Siberia. PMID- 25806382 TI - Alaska fish adjust to climate change by following the food. PMID- 25806383 TI - Trade winds ventilate the tropical oceans...... PMID- 25806384 TI - ......and link with global climate change. PMID- 25806385 TI - Distribution of fish on the northeast US shelf. PMID- 25806386 TI - 'Tipping points' for sea level rise related flooding established. PMID- 25806387 TI - EU warns four more states in fight to end illegal fishing. PMID- 25806388 TI - Nereid Under Ice vehicle. PMID- 25806389 TI - China to support civil litigation against environmental offenders. PMID- 25806390 TI - Mercury from gold mines accumulates far downstream. PMID- 25806392 TI - [In Process Citation]. PMID- 25806391 TI - Modern genetics confirm ancient relationship between fins and hands. PMID- 25806393 TI - Expand your leadership to the board room. PMID- 25806395 TI - NICHE solutions--twelfth in a series: focus on pain and palliative care. PMID- 25806394 TI - Depression in assisted living. PMID- 25806396 TI - New guidance on the prevention and treatment of postoperative delirium in older adults. PMID- 25806397 TI - COPD exacerbation. What are the keys to treating it in the prehospital setting?. PMID- 25806398 TI - A Multimodal Intervention Improves Postanesthesia Care Unit Handovers. AB - BACKGROUND: Failures of communication are a major contributor to perioperative adverse events. Transitions of care may be particularly vulnerable. We sought to improve postoperative handovers. METHODS: We introduced a multimodal intervention in an adult and a pediatric postanesthesia care unit (PACU) to improve postoperative handovers between anesthesia providers (APs) and PACU registered nurses (RNs). The intervention included a standardized electronic handover report form, a didactic webinar, mandatory simulation training focused on improving interprofessional communication, and post-training performance feedback. Trained, blinded nurse observers scored PACU handovers during 17 months using a structured tool consisting of 8 subscales and a global score (1-5 scale). Multivariate logistic regression assessed the effect of the intervention on the proportion of observed handovers receiving a global effectiveness rating of >=3. RESULTS: Four hundred fifty-two clinicians received the simulation-based training, and 981 handovers were observed and rated. In the adult PACU, the estimated percentages of acceptable handovers (global ratings >=3) among AP-RN pairs, where neither received simulation-based training (untrained dyads), was 3% (95% confidence interval, 1%-11%) at day 0, 10% (5%-19%) at training initiation (day 40), and 57% (33%-78%) at 1-year post-training initiation (day 405). For AP-RN pairs where at least one received the simulation-based training (trained dyads), these percentages were estimated to be 18% (11%-28%) and 68% (57%-76%) on days 40 and 405, respectively. The percentage of acceptable handovers was significantly greater on day 405 than it was on day 40 for both untrained (P < 0.001) and trained dyads (P < 0.001). Similar patterns were observed in the pediatric PACU. Three years later, the unadjusted estimate of the probability of an acceptable handover was 87% (72%-95%) in the adult PACU and 56% (40%-72%) in the pediatric PACU. CONCLUSIONS: A multimodal intervention substantially improved interprofessional PACU handovers, including those by clinicians who had not undergone formal simulation training. An effect appeared to be present >3 years later. PMID- 25806399 TI - An Anesthesia Preinduction Checklist to Improve Information Exchange, Knowledge of Critical Information, Perception of Safety, and Possibly Perception of Teamwork in Anesthesia Teams. AB - BACKGROUND: An anesthesia preinduction checklist (APIC) to be performed before anesthesia induction was introduced and evaluated with respect to 5 team-level outcomes, each being a surrogate end point for patient safety: information exchange (the percentage of checklist items exchanged by a team, out of 12 total items); knowledge of critical information (the percentage of critical information items out of 5 total items such as allergies, reported as known by the members of a team); team members' perceptions of safety (the median scores given by the members of a team on a continuous rating scale); their perception of teamwork (the median scores given by the members of a team on a continuous rating scale); and clinical performance (the percentage of completed items out of 14 required tasks, e.g., suction device checked). METHODS: A prospective interventional study comparing anesthesia teams using the APIC with a control group not using the APIC was performed using a multimethod design. Trained observers rated information exchange and clinical performance during on-site observations of anesthesia inductions. After the observations, each team member indicated the critical information items they knew and their perceptions of safety and teamwork. RESULTS: One hundred five teams using the APIC were compared with 100 teams not doing so. The medians of the team-level outcome scores in the APIC group versus the control group were as follows: information exchange: 100% vs 33% (P < 0.001), knowledge of critical information: 100% vs 90% (P < 0.001), perception of safety: 91% vs 84% (P < 0.001), perception of teamwork: 90% vs 86% (P = 0.028), and clinical performance: 93% vs 93% (P = 0.60). CONCLUSIONS: This study provides empirical evidence that the use of a preinduction checklist significantly improves information exchange, knowledge of critical information, and perception of safety in anesthesia teams-all parameters contributing to patient safety. There was a trend indicating improved perception of teamwork. PMID- 25806400 TI - A Randomized Controlled Trial Comparing Two Multimodal Analgesic Techniques in Patients Predicted to Have Severe Pain After Cesarean Delivery. AB - BACKGROUND: Improved pain control after cesarean delivery remains a challenging objective. Poorly treated acute pain following delivery is associated with an increased risk of chronic pain and depression. This study was conducted to determine whether the addition of systemic acetaminophen and an increased dose of intrathecal morphine would further reduce acute pain. The primary outcome was pain intensity with movement at 24 hours postoperatively. Secondary measures included persistent pain and depression at 8 weeks. METHODS: Seventy-four parturients scheduled for elective cesarean delivery under spinal anesthesia that were predicted to be above the 80th percentile for evoked pain intensity based on a 3-item preoperative screening questionnaire were enrolled. Patients in the intervention group received 300 mcg spinal morphine and 1 gram acetaminophen every 6 hours for 24 hours postoperatively. Patients in the control group received 150 mcg spinal morphine and placebo tablets. All patients received scheduled ibuprofen by mouth and IV morphine patient-controlled analgesia. At 24 hours, patients rated their pain intensity with movement, at rest, on average, and worst score using a visual analog scale for pain (100-mm unmarked line). The presence of persistent pain and depression was assessed at 8 weeks using the Edinburgh postpartum depression survey. RESULTS: Providing a higher dose of spinal morphine combined with systemic acetaminophen to patients predicted to be at high risk for severe post-cesarean delivery pain significantly reduced evoked pain scores with movement at 24 hours (mean +/- SD: 46 +/- 25 mm in control group versus 31 +/-17 mm in intervention group, P = 0.009; 95% confidence interval for the difference between means: 4 mm, 26 mm). There was no difference in the incidence of persistent pain (13% (4/30) in control group versus 10% (3/30) in intervention group, P > 0.99), or depression at 8 weeks postoperatively (10% (3/30) in control group versus 13% (4/30) in intervention group, P > 0.99). CONCLUSIONS: Adding a higher dose of intrathecal morphine and oral acetaminophen to a multimodal pain regimen in patients predicted to be at risk for high acute postpartum pain after cesarean delivery results in a significant reduction of acute postoperative pain scores at 24 hours. PMID- 25806401 TI - Elective endovascular treatment of unruptured intracranial aneurysms: a management case series of patient outcomes after institutional change to admit patients principally to postanesthesia care unit rather than to intensive care. AB - BACKGROUND: Our intention in this case series was to review the postoperative care and neurologic outcomes of patients who had undergone elective endovascular treatment of unruptured intracranial aneurysms. The case series is unique managerially in that a progressively increasing percentage of patients were admitted to the postanesthesia care unit (PACU; 1:2 nurse-to-patient ratio) and subsequently to the neurosurgical ward (1:3 nurse-to-patient ratio) instead of directly to the intensive care unit (ICU; 1:1 nurse-to-patient ratio). METHODS: A retrospective review was performed of 170 consecutive elective endovascular procedures to treat unruptured intracranial aneurysms between July 2009 and September 2012. Data included patient, aneurysm, procedural characteristics, and adverse events within 96 hours after the procedure. Rates of ICU admission and perioperative neurologic adverse events were compared over time. RESULTS: Although direct ICU admission rates decreased over time (P < 0.0001) from 100% to 15%, perioperative neurologic event rates did not change (P = 0.79). Sixteen of 170 patients experienced perioperative neurologic events. The percentages of patients with neurologic events who died or had deficits that did not resolve before discharge were 38% (3 of 8) among patients directly admitted to the ICU versus 38% (3 of 8) among those first admitted to the PACU. Although the duration of anesthesia was greater among patients admitted to the ICU, duration was not useful in predicting decisions on the day of surgery for individual patients. The duration of anesthesia also was not meaningfully associated with information available preoperatively (i.e., for use when scheduling the case). CONCLUSIONS: In centers in which PACU and ward care are comparable to those in this case series, in the absence of intraoperative events with the potential for ongoing cerebral ischemia, most patients undergoing elective endovascular treatment of unruptured cerebral aneurysms can be managed without direct ICU admission. Scheduling all these procedures by using the mean historical anesthesia duration is reasonable. PMID- 25806403 TI - The Influence of a Night-Float Call System on the Incidence of Unintentional Dural Puncture: A Retrospective Impact Study. AB - BACKGROUND: Resident night-float systems have been associated with adverse outcomes. We hypothesized that an obstetric anesthesia night float would increase the incidence of unintentional dural punctures. METHODS: The July to December incidence of unintentional dural puncture before (control group) and with night float (night-float group) was compared retrospectively. The incidence of unintentional dural puncture by day of week and trainee level was evaluated. RESULTS: The unintentional dural puncture rate of control group was 0.73% (20 of 2758) vs 1.49% (39 of 2612) in the night-float group (P = 0.008; relative risk = 2.06; 95% confidence interval = 1.23-3.74). The proportion of unintentional dural punctures attributed to clinical anesthesia-1 residents in the night-float and control groups was 28.2% (11 of 39) and 5.0% (1 of 20), respectively (relative risk = 5.64; 95% confidence interval = 1.07-152; P = 0.044). CONCLUSIONS: Implementation of night float increased the incidence of unintentional dural puncture. PMID- 25806404 TI - Quadrupedal galloping control for a wide range of speed via vertical impulse scaling. AB - This paper presents a bio-inspired quadruped controller that allows variable speed galloping. The controller design is inspired by observations from biological runners. Quadrupedal animals increase the vertical impulse that is generated by ground reaction forces at each stride as running speed increases and the duration of each stance phase reduces, whereas the swing phase stays relatively constant. Inspired by this observation, the presented controller estimates the required vertical impulse at each stride by applying the linear momentum conservation principle in the vertical direction and prescribes the ground reaction forces at each stride. The design process begins with deriving a planar model from the MIT Cheetah 2 robot. A baseline periodic limit cycle is obtained by optimizing ground reaction force profiles and the temporal gait pattern (timing and duration of gait phases). To stabilize the optimized limit cycle, the obtained limit cycle is converted to a state feedback controller by representing the obtained ground reaction force profiles as functions of the state variable, which is monotonically increasing throughout the gait, adding impedance control around the height and pitch trajectories of the obtained limit cycle and introducing a finite state machine and a pattern stabilizer to enforce the optimized gait pattern. The controller that achieves a stable 3 m s(-1) gallop successfully adapts the speed change by scaling the vertical ground reaction force to match the momentum lost by gravity and adding a simple speed controller that controls horizontal speed. Without requiring additional gait optimization processes, the controller achieves galloping at speeds ranging from 3 m s(-1) to 14.9 m s(-1) while respecting the torque limit of the motor used in the MIT Cheetah 2 robot. The robustness of the controller is verified by demonstrating stable running during various disturbances, including 1.49 m step down and 0.18 m step up, as well as random ground height and model parameter variations. PMID- 25806402 TI - The Effect of Progestins on Tumor Necrosis Factor alpha-Induced Matrix Metalloproteinase-9 Activity and Gene Expression in Human Primary Amnion and Chorion Cells In Vitro. AB - BACKGROUND: Current treatment modalities for preventing preterm premature rupture of membranes are limited, but progestins may play a role. Tumor necrosis factor alpha (TNFalpha) enhances matrix metalloproteinase-9 (MMP-9) gene expression and activity in fetal membranes, contributing to membrane weakening and rupture. We previously demonstrated that progestins attenuate TNFalpha-induced MMP-9 activity in a cytotrophoblast cell line. However, whether they have a similar effect in primary amnion and chorion cells of fetal membranes is unknown. In this study, we evaluated the effect of progestins on basal and TNFalpha-induced MMP-9 activity and gene expression in primary chorion and amnion cells harvested from the fetal membranes of term nonlaboring patients. METHODS: Primary amnion and chorion cells were isolated from fetal membranes obtained from term uncomplicated nonlaboring patients following elective cesarean delivery (n = 11). Confluent primary amnion and chorion cell cultures were both pretreated with vehicle (control), progesterone (P4), 17alpha-hydroxyprogesterone caproate (17P), or medroxyprogesterone acetate (MPA) at 10 M concentration for 6 hours followed by stimulation with TNFalpha at 10 ng/mL for an additional 24 hours. Cell cultures pretreated with the vehicle only served as the unstimulated control and the vehicle stimulated with TNFalpha served as the stimulated control. Both controls were assigned a value of 100 units. Cell culture medium was harvested for MMP-9 enzymatic activity quantification using gelatin zymography. Total RNA was extracted for quantifying MMP-9 gene expression using real-time quantitative PCR. Basal MMP-9 activity and gene expression data were normalized to the unstimulated control. TNFalpha-stimulated MMP-9 activity and gene expression were normalized to the stimulated control. The primary outcome was the effect of progestins on TNFalpha-induced MMP-9 enzymatic activity in term human primary amnion and chorion cells in vitro. Secondary outcomes included the effect of progestin therapy on TNFalpha-induced MMP-9 gene expression and on basal MMP-9 activity and gene expression in primary amnion and chorion cells in vitro. RESULTS: Primary cells were harvested from 11 patients. Compared with the unstimulated control, TNFalpha increased MMP-9 activity (P = 0.005 versus control in primary amnion cells and P < 0.001 versus control in primary chorion cells) and MMP-9 gene expression (P = 0.030 versus control in primary amnion cells, P < 0.001 versus control in primary chorion cells). Compared with the unstimulated controls, MPA, but not P4 or 17P, reduced basal MMP-9 activity [mean difference (95% CI) -49.6 ( 81.9, -17.3) units, P = 0.001] and gene expression [mean difference (95% CI) 53.4 (-105.9, -0.9) units, P = 0.045] in primary amnion cells. Compared with the stimulated control, MPA also reduced TNFalpha-induced MMP-9 activity [mean difference (95% CI) -69.0 (-91.8, -46.3) units, P < 0.001] and gene expression [mean difference (95% CI) -86.0 (-120.7, -51.3) units, P < 0.001] in primary amnion cells. Progestin pretreatment had no significant effect on basal or TNFalpha-induced MMP-9 activity and gene expression in primary chorion cells. CONCLUSIONS: The inhibitory effect of MPA on both basal and TNFalpha-induced MMP 9 activity and gene expression in primary amnion cells demonstrate a possible mechanism by which progestins may prevent fetal membrane weakening leading to preterm premature rupture of membranes. PMID- 25806405 TI - Sense overlapping transcripts in IS1341-type transposase genes are functional non coding RNAs in archaea. AB - The existence of sense overlapping transcripts that share regulatory and coding information in the same genomic sequence shows an additional level of prokaryotic gene expression complexity. Here we report the discovery of ncRNAs associated with IS1341-type transposase (tnpB) genes, at the 3'-end of such elements, with examples in archaea and bacteria. Focusing on the model haloarchaeon Halobacterium salinarum NRC-1, we show the existence of sense overlapping transcripts (sotRNAs) for all its IS1341-type transposases. Publicly available transcriptome compendium show condition-dependent differential regulation between sotRNAs and their cognate genes. These sotRNAs allowed us to find a UUCA tetraloop motif that is present in other archaea (ncRNA family HgcC) and in a H. salinarum intergenic ncRNA derived from a palindrome associated transposable elements (PATE). Overexpression of one sotRNA and the PATE-derived RNA harboring the tetraloop motif improved H. salinarum growth, indicating that these ncRNAs are functional. PMID- 25806406 TI - Cryptococcosis in Patients With Cirrhosis of the Liver and Posttransplant Outcomes. AB - BACKGROUND: The outcomes and optimal management of cirrhotic patients who develop cryptococcosis before transplantation are not fully known. METHODS: We conducted a multicenter study involving consecutive patients with cirrhosis and cryptococcosis between January 2000 and March 2014. Data collected were generated as standard of care. RESULTS: In all, 112 patients were followed until death or up to 9 years. Disseminated disease and fungemia were present in 76.8% (86/112) and 90-day mortality was 57.1% (64/112). Of the 39 patients listed for transplant, 20.5% (8) underwent liver transplantation, including 2 with active but unrecognized disease before transplantation. Median duration of pretransplant antifungal therapy and posttransplant therapy was 43 days (interquartile range, 8 130 days) and 272 days (interquartile range, 180-630 days), respectively. Transplantation was associated with lower mortality (P = 0.002). None of the transplant recipients developed disease progression during the median follow-up of 3.5 years with a survival rate of 87.5%. CONCLUSIONS: Cryptococcosis in patients with cirrhosis has grave prognosis. Our findings suggest that transplantation after recent cryptococcal disease may not be a categorical exclusion and may be cautiously undertaken in liver transplant candidates who are otherwise deemed clinically stable. PMID- 25806408 TI - Nerve Growth Factor Improves Survival and Function of Transplanted Islets Via TrkA-mediated beta Cell Proliferation and Revascularization. AB - BACKGROUND: Nerve growth factor (NGF), which plays important roles in promoting growth and differentiation of nerve cells, has recently been reported as a regulator in pancreatic beta cells in terms of insulin releasing function. In this study, we examined whether NGF stimulation would promote islet graft survival and function in islet transplantation. METHODS: We found that supplementation of cultured islets with NGF improved the viability of islet cells and induced the production of insulin, vascular endothelial growth factor, and cellular proliferative markers. Because a specific inhibitor of TrkA, K252a, blocked all these effects, we propose that the TrkA receptor is the mediator of NGF stimulation. RESULTS: After transplantation to the kidney subcapsule and liver of syngenic diabetic mice, a higher rate of normoglycemic achievement, increased serum insulin, and improved glucose tolerance were observed in the mice transplanted with NGF-pretreated islet grafts. Histological analysis revealed higher expression of insulin and vascular endothelial growth factor, an increase in proliferative beta cells, and revascularization in NGF-pretreated islet grafts without activation of any inflammatory cells. CONCLUSIONS: The NGF treatment can therefore serve as a new and promising therapeutic tool for improving islet graft viability and function in islet transplantation. PMID- 25806407 TI - Monitoring of Allogeneic Islet Grafts in Nonhuman Primates Using MRI. AB - BACKGROUND: Information regarding the longevity of transplanted pancreatic islet grafts could provide valuable information for treatment options. In our previous studies, we showed that isolated autologous pancreatic islets could be labeled with iron oxide nanoparticles and monitored after transplantation using MRI. Here, we report on in vivo monitoring of a secondary damage that occurs at the later stages because of allogeneic immune rejection. METHODS: In the proof-of principle studies, iron oxide-labeled autologous pancreatic islets were transplanted under the renal capsules of nonhuman primates. To demonstrate acute graft loss, the animals were injected with streptozotocin. Graft monitoring was performed by in vivo MRI. Next, iron oxide-labeled allogeneic islets were transplanted into the liver and monitored by MRI after withdrawal of immunosuppression. RESULTS: In autologous model, we observed a pronounced drop in graft volume after streptozotocin challenge as assessed by MRI. In allogeneic model of islet transplantation, there was an initial islet loss after the procedure followed by relative stabilization of the graft volume. After immunosuppression was discontinued, there was a noticeable drop in graft volume that gradually continued during the course of the study. Importantly, the loss of graft volume observed on MR preceded the raise in blood glucose. CONCLUSIONS: This study demonstrated that in vivo MRI was able to reveal graft volume loss before any changes in blood glucose that can be measured by standard methods. We believe that these results could provide means for clinicians to follow islet fate noninvasively and longitudinally using clinically relevant scanners. PMID- 25806410 TI - What are the most loving moments of your life? PMID- 25806409 TI - Active site and remote contributions to catalysis in methylthioadenosine nucleosidases. AB - 5'-Methylthioadenosine/S-adenosyl-l-homocysteine nucleosidases (MTANs) catalyze the hydrolysis of 5'-methylthioadenosine to adenine and 5-methylthioribose. The amino acid sequences of the MTANs from Vibrio cholerae (VcMTAN) and Escherichia coli (EcMTAN) are 60% identical and 75% similar. Protein structure folds and kinetic properties are similar. However, binding of transition-state analogues is dominated by favorable entropy in VcMTAN and by enthalpy in EcMTAN. Catalytic sites of VcMTAN and EcMTAN in contact with reactants differ by two residues; Ala113 and Val153 in VcMTAN are Pro113 and Ile152, respectively, in EcMTAN. We mutated the VcMTAN catalytic site residues to match those of EcMTAN in anticipation of altering its properties toward EcMTAN. Inhibition of VcMTAN by transition-state analogues required filling both active sites of the homodimer. However, in the Val153Ile mutant or double mutants, transition-state analogue binding at one site caused complete inhibition. Therefore, a single amino acid, Val153, alters the catalytic site cooperativity in VcMTAN. The transition-state analogue affinity and thermodynamics in mutant VcMTAN became even more unlike those of EcMTAN, the opposite of expectations from catalytic site similarity; thus, catalytic site contacts in VcMTAN are unable to recapitulate the properties of EcMTAN. X-ray crystal structures of EcMTAN, VcMTAN, and a multiple-site mutant of VcMTAN most closely resembling EcMTAN in catalytic site contacts show no major protein conformational differences. The overall protein architectures of these closely related proteins are implicated in contributing to the catalytic site differences. PMID- 25806411 TI - Effects of Ultraviolet Germicidal Irradiation (UVGI) on N95 Respirator Filtration Performance and Structural Integrity. AB - The ability to disinfect and reuse disposable N95 filtering facepiece respirators (FFRs) may be needed during a pandemic of an infectious respiratory disease such as influenza. Ultraviolet germicidal irradiation (UVGI) is one possible method for respirator disinfection. However, UV radiation degrades polymers, which presents the possibility that UVGI exposure could degrade the ability of a disposable respirator to protect the worker. To study this, we exposed both sides of material coupons and respirator straps from four models of N95 FFRs to UVGI doses from 120-950 J/cm(2). We then tested the particle penetration, flow resistance, and bursting strengths of the individual respirator coupon layers, and the breaking strength of the respirator straps. We found that UVGI exposure led to a small increase in particle penetration (up to 1.25%) and had little effect on the flow resistance. UVGI exposure had a more pronounced effect on the strengths of the respirator materials. At the higher UVGI doses, the strength of the layers of respirator material was substantially reduced (in some cases, by >90%). The changes in the strengths of the respirator materials varied considerably among the different models of respirators. UVGI had less of an effect on the respirator straps; a dose of 2360 J/cm(2) reduced the breaking strength of the straps by 20-51%. Our results suggest that UVGI could be used to effectively disinfect disposable respirators for reuse, but the maximum number of disinfection cycles will be limited by the respirator model and the UVGI dose required to inactivate the pathogen. PMID- 25806412 TI - Strain wave elastography for evaluation of renal parenchyma in chronic kidney disease. AB - OBJECTIVE: Chronic kidney disease (CKD) is an important and costly health problem in developed countries and has a tendency to progress to end-stage renal disease regardless of the aetiology. This progress ends in interstitial fibrosis, which decreases the elasticity of tissue. Elastography is a developing technique to assess tissue elasticity. The aim of this study was to determine the difference of strain index (SI) value of renal parenchyma between patients with CKD and healthy individuals. In addition, SI differences of inter-stages were studied. METHODS: Toshiba (Toshiba Medical Systems Corporation, Otawara, Japan) AplioTM 500 ultrasound device and 3.5- to 5.0-MHz convex probe were used for the elastography examinations. RESULTS: A total of 58 patients with CKD from nephrology and endocrinology clinics (30 males and 28 females; mean age, 56.14 +/ 11.60 years) and 40 normal healthy individuals (19 males and 21 females; mean age, 51.70 +/- 11.71 years) were included in this prospective study. The mean SI of normal healthy individuals and patients with CKD (regardless of stages) was 0.42 +/- 0.30 and 1.81 +/- 0.88, respectively (p < 0.001). SI values were not statistically significant among the CKD stages (except CKD Stages 1 and 3). The area under the receiver operating characteristic curve was 0.956 for SI. The optimal cut-off value for the prediction of CKD was 0.935 (sensitivity, 88% and specificity, 95%). CONCLUSION: SI value of sonoelastography can be used to differentiate patients with CKD and healthy individuals. Sonoelastography is an acceptable technique to approach patients with CKD, but we have not shown that it can reliably differentiate different stages. ADVANCES IN KNOWLEDGE: Determining a cut-off SI value between normal and diseased renal parenchyma can help in the diagnosis of CKD. PMID- 25806413 TI - Effects of test stress during an objective structured clinical examination. AB - OBJECTIVE: The existence of test stress has been widely reported among professional students. To our knowledge, no studies exist that explore student stress response to objective structured clinical examinations. The aim of this study was to evaluate possible correlations between stress and objective structured clinical examination performance in a sample of chiropractic students. METHODS: A total of 116 students completed a 2-part questionnaire to assess test stress and the physiological symptoms and signs of stress. Heart rate, systolic blood pressure, and diastolic were measured during the physical examination laboratory class within the first 3 weeks and then again just prior to their objective structured clinical examination in week 5. Statistical tests were then performed for questionnaire data, heart rate and blood pressure differences, and correlation between the objective structured clinical examination grade and symptoms and signs. RESULTS: Questionnaire results showed that 5.1%-22.4% of students sometimes or often felt a certain degree of stress. More than 50% had 1 or more physiological symptoms and signs of stress. The objective structured clinical examination heart rate (75.23 +/- 11.20 vs 68.16 +/- 8.82, p < .001), systolic blood pressure (120.43 +/- 9.59 vs 114.97 +/- 11.83, p < .001), and diastolic blood pressure (73.00 +/- 7.93 vs 69.32 +/- 7.76, p < .001) were significantly higher than baseline. There were also negative linear correlations between objective structured clinical examination grades and physiological symptoms and signs and between objective structured clinical examination grades and feeling statement score. CONCLUSION: The results support our hypothesis that chiropractic students experience stress when performing the objective structured clinical examination and that high levels of stress had a negative impact on performance. PMID- 25806414 TI - An efficient solid-phase strategy for total synthesis of naturally occurring amphiphilic marine siderophores: amphibactin-T and moanachelin ala-B. AB - Microorganisms such as bacteria, fungi and some plants secrete an abundance of suites of low molecular weight, high-affinity iron(iii)-chelating acylated siderophores. The peptide composition of a suite of amphiphilic siderophores generated by a Vibrio species, isolated from oligotrophic open ocean water, contained the same iron(iii)-scavenging polar head group and is attached to a fatty acid. In the present study, we report the first total synthesis of the naturally obtainable marine siderophores amphibactin-T and moanachelin ala-B on solid-phase using standard Fmoc-chemistry. Furthermore, we discuss the preparation of orthogonal protected Orn amino acid 'N(alpha)-Fmoc-N(delta) (acetyl)-N(delta)-(benzoyloxy)-ornithine' [Fmoc-Orn(Ac,OBz)-OH], which is the most important constructive building block for amphibactin and moanachelin siderophores syntheses. The applications of this Orn unit on solid-phase have also been discussed. PMID- 25806415 TI - Corporate America and community health: exploring the business case for investment. AB - OBJECTIVES: The principal aim of this project was to learn from corporate executives about the most important components of a business case for employer leadership in improving community health. METHODS: We used dialogue sessions to gain insight into this issue. RESULTS: The strongest elements included metrics and measurement, return on investment, communications, shared values, shared vision, shared definitions, and leadership. Important barriers included lack of understanding, lack of clear strategy, complexity of the problem, trust, lack of resources and leadership, policies and regulations, and leadership philosophy. Substantial variability was observed in the degree of understanding of the relationship between corporate health and community health. CONCLUSIONS: The business case for intentional and strategic corporate investment in community health occurs along a continuum has a set of clearly defined elements that address why investment may make sense, but also asks questions about the "what-to do" and the "how-to-do-it." PMID- 25806416 TI - Comparison of Mortality Disparities in Central Appalachian Coal- and Non-Coal Mining Counties. AB - OBJECTIVE: Determine whether select cause of death mortality disparities in four Appalachian regions is associated with coal mining or other factors. METHODS: We calculated direct age-adjusted mortality rates and associated 95% confidence intervals by sex and study group for each cause of death over 5-year time periods from 1960 to 2009 and compared mean demographic and socioeconomic values between study groups via two-sample t tests. RESULTS: Compared with non-coal-mining areas, we found higher rates of poverty in West Virginia and Virginia (VA) coal counties. All-cause mortality rates for males and females were higher in coal counties across all time periods. Virginia coal counties had statistically significant excesses for many causes of death. CONCLUSIONS: We found elevated mortality and poverty rates in coal-mining compared with non-coal-mining areas of West Virginia and VA. Future research should examine these findings in more detail at the individual level. PMID- 25806417 TI - A Comparative Study of Workplace Bullying Among Public and Private Employees in Europe. AB - OBJECTIVES: Workplace bullying emerges from a set of individual, organizational, and contextual factors. The purpose of this article is hence to identify the influence of these factors among public and private employees. METHODS: The study is carried out as a statistical-empirical cross-sectional study. The database used was obtained from the 5th European Working Conditions Survey 2010. RESULTS: The results reveal a common core with respect to the factors that determine workplace bullying. Despite this common base that integrates both models, the distinctive features of the harassed employee within the public sector deal with age, full-time work, the greater nighttime associated with certain public service professions, and a lower level of motivation. CONCLUSIONS: The present work summarizes a set of implications and proposes that, under normal conditions, workplace bullying could be reduced if job demands are limited and job resources are increased. PMID- 25806418 TI - Engineering a Highly Hydrophilic PVDF Membrane via Binding TiO2Nanoparticles and a PVA Layer onto a Membrane Surface. AB - A highly hydrophilic PVDF membrane was fabricated through chemically binding TiO2 nanoparticles and a poly(vinyl alcohol) (PVA) layer onto a membrane surface simultaneously. The chemical composition of the modified membrane surface was determined by X-ray photoelectron spectroscopy, and the binding performance of TiO2 nanoparticles and the PVA layer was investigated by a rinsing test. The results indicated that the TiO2 nanoparticles were uniformly and strongly tailored onto the membrane surface, while the PVA layer was firmly attached onto the surface of TiO2 nanoparticles and the membrane by adsorption-cross-linking. The possible mechanisms during the modification process and filtration performance, i.e., water permeability and bovine serum albumin (BSA) rejection, were investigated as well. Furthermore, antifouling property was discussed through multicycles of BSA solution filtration tests, where the flux recovery ratio was significantly increased from 20.0% for pristine PVDF membrane to 80.5% for PVDF/TiO2/PVA-modified membrane. This remarkable promotion is mainly ascribed to the improvement of surface hydrophilicity, where the water contact angle of the membrane surface was decreased from 84 degrees for pristine membrane to 24 degrees for PVDF/TiO2/PVA membrane. This study presents a novel and varied strategy for immobilization of nanoparticles and PVA layer on substrate surface, which could be easily adapted for a variety of materials for surface modification. PMID- 25806420 TI - Genetic Modifiers of Sickle Cell Disease: A Genotype-Phenotype Relationship Study in a Cohort of 82 Children on Mayotte Island. AB - Sickle cell disease presents a great clinical variability that remains largely misunderstood. New disease protective genetic modifiers acting mainly through an increased Hb F level have recently been described. We studied relations between clinical and hematological phenotypes and known sickle cell disease genetic modifiers in patients from Mayotte Island, a remote French territory located in the Indian Ocean. Eighty-two children with sickle cell disease were enrolled; their median age was 5.9 years (range 1-18). Clinical and hematological features of sickle cell disease were retrospectively collected. Genetic studies included determination of beta-globin genotypes [Hb SS, Hb S-beta(0)-thalassemia (Hb S beta(0)-thal), Hb S-beta(+)-thal], beta(S)-globin locus haplotype, alpha thalassemia (alpha-thal), and single nucleotide polymorphisms (SNPs) located in quantitative trait loci for Hb F expression (XmnI polymorphism, BCL11A rs4671393 and rs11886868, intergenic region of HBS1L-MYB rs28384513, rs4895441 and rs9399137). Univariate and multivariate analyses were conducted. Twenty-eight percent of the patients had Hb S-beta-thal (eight different mutations in 21 patients), 55.0% had the -alpha(3.7) (rightward) deletion and 88.0% of the homozygous Hb SS patients were carrying a homozygous Bantu haplotype. In the multivariate model, the prognosis role of the SNP BCL11A rs4671393 was confirmed in the studied population showing a significant association with an elevated Hb F level and with a low hospitalization rate. The -alpha(3.7) deletion, XmnI polymorphism and intergenic region HBS1L-MYB SNPs were not significantly linked to any clinical criteria of severity. This report, the first to describe the main features of children with sickle cell disease on Mayotte Island, highlights the protective effect of the BCL11A polymorphism in this population. PMID- 25806419 TI - Screening for thalassemia carriers in populations with a high rate of iron deficiency: revisiting the applicability of the Mentzer Index and the effect of iron deficiency on Hb A2 levels. AB - Differentiating between beta-thalassemia (beta-thal) minor and iron deficiency has important implications in thalassemia carrier screening. Several complete blood count (CBC)-based equations have been proposed for differentiating these two conditions. The applicability of these equations in populations with high rates of iron deficiency and beta-thal minor, where patients can have both conditions, is limited. In addition, there have been conflicting reports on the possible effect of iron deficiency on Hb A2 level with possible consequences for thalassemia screening programs. Here, we demonstrate that in our population the Mentzer Index separates individuals with beta-thal minor from those without beta thal minor, regardless of their iron status. Iron deficiency also does not reduce Hb A2 levels in beta-thal minor patients. Correction of iron deficiency is not required for diagnosis of beta-thal minor using high performance liquid chromatography (HPLC). PMID- 25806421 TI - Is the medical home for adult patients with sickle cell disease a reality or an illusion? AB - Recently, the patient-centered medical home (PCMH) emerged as a viable method to improve delivery of medical care. Due to all the promotion about the effectiveness of the PCMH, patients with sickle cell disease, their families and the community hoped that this could be a possible solution to the problems that arise in the treatment of adult patients with sickle cell disease. Review of the literature and review of the criteria for the establishment of a PCMH show that the PCMH is not an ideal model for patients with sickle cell disease because finding a personal physician, which is the first criteria of a functional PCMH, is a major problem in the process of transitioning the care of patients with sickle cell disease from pediatrics to adult care. Moreover, garnering hospital support to defray the initial costs to establish a PCMH for adults with sickle cell disease is unlikely given the already high costs of care for patients with sickle cell disease. Moreover, recent studies have shown insufficient evidence to determine the presumed beneficial effects of the PCMH, especially in patients with chronic disease. PMID- 25806422 TI - A simple method for GFP- and RFP-based dual color single-molecule localization microscopy. AB - The recent development of single-molecule localization-based super-resolution techniques has afforded a resolution in the nanometer range in light microscopy. The ability to resolve biological structures on this scale by multicolor techniques faces significant challenges which have prevented their widespread use. Here, we provide a generic approach for high-quality simultaneous two-color single-molecule localization microscopy imaging of any combination of GFP- and RFP-tagged proteins with the use of nanobodies. Our method addresses a number of common issues related to two-color experiments, including accuracy and density of labeling as well as chromatic aberration and color-crosstalk with only minimal technical requirements. We demonstrate two-color imaging of various nanoscopic structures and show a compound resolution down to the limit routinely achieved only in a single color. PMID- 25806423 TI - Insights in the pathogenesis and resistance of Arcobacter: A review. AB - Arcobacter genus currently comprises 18 recognized species, among which Arcobacter butzleri, Arcobacter cryaerophilus and Arcobacter skirrowii have been associated with human and animal disease. Although these organisms, with special emphasis A. butzleri, are emerging as clinical pathogens, several aspects of their epidemiology and virulence are only starting to be clarified. In vitro human and animal cell culture assays have been used to show that several Arcobacter species can adhere to and invade eukaryotic cells, induce an immune response and produce toxins that damage host cells. In addition, data from genome sequencing highlighted several potential markers that may be helpful candidates for the study and understanding of these mechanisms; however, more work is necessary to clarify the molecular mechanisms involved in Arcobacter virulence. Arcobacter can be considered a relatively robust organism showing to be able to survive in adverse conditions, as the ones imposed by food processing and storage. Moreover, these bacteria have shown increased antibiotic resistance, along with high multidrug resistance. In this review, we seek to update the state of-the-art concerning Arcobacter distribution, its interaction with the host, the trends of antibiotic resistance, its ability to survive, and finally the use of natural antimicrobials for control of Arcobacter. PMID- 25806424 TI - Highly efficient detection of hydrogen peroxide in solution and in the vapor phase via fluorescence quenching. AB - Herein we report the highly efficient and sensitive detection of hydrogen peroxide in both aqueous solution and in the vapor phase via fluorescence quenching (turn-off mechanism) of the amplified fluorescent conjugated polymer titanium complex induced by hydrogen peroxide. Inter- and intra-polymer energy migration leads to extremely high sensitivity. PMID- 25806425 TI - The future of immunization policies in Italy and in the European Union: The Declaration of Erice. AB - On December 2014 the Employment, Social Policy, Health and Consumer Affairs Council (EPSCO) of the European Union adopted the Council Conclusions on "Vaccinations as an effective tool in public health," a crucial step to strengthen EU action supporting Member States (MS) to implement effective immunization policies and programs. As a contribution to the ongoing pan-European discussion and to the Italian commitment to stay at the forefront of promoting vaccination policies, the Erice Declaration was drafted by Italy's best experts in the field of immunization to transpose to the national level the goals set by the EPSCO Conclusions. The aim of the current letter is to present to the broader international audience the Italian perspective as a case study to assess different immunization policy models, challenges and priorities. PMID- 25806426 TI - Platelets microparticles as a link between micro- and macro-angiopathy in young patients with type 1 diabetes. AB - The development of vasculopathies in diabetes involves multifactorial processes. Increased levels of platelets-derived microparticles (PMPs) have been reported in diseases associated with thrombotic risk, but few data are available in diabetes. We explored the level of PMPs in young patients with type 1 diabetes in relation to inflammation, glycemic control, micro-vascular complications and carotid intima media thickness (CIMT). Eighty children and adolescents with type 1 diabetes were divided into two groups according to the presence of micro-vascular complications and compared with 40 healthy controls. Patients were subjected to medical history, clinical examination and assessment of high-sensitivity C reactive protein (hs-CRP), HbA1c, urinary albumin creatinine ratio (UACR), flow cytometric analysis for PMPs using anti-CD41b and CIMT. PMP levels were significantly increased in all patients with type 1 diabetes (2.92 +/- 1.3%) whether with micro-vascular complications (3.46 +/- 1.11%) or those without complications (2.37 +/- 1.28%) compared with healthy controls (1.28 +/- 0.64%; p < 0.001). CIMT was significantly elevated in all patients, and the highest levels were among those with micro-vascular complications (p < 0.001). Significant positive correlations were found between PMPs and body mass index, HbA1c, serum creatinine, total cholesterol, UACR, hs-CRP and CIMT (p < 0.05). Multiple linear regression analysis showed that HbA1c, UACR, hs-CRP and CIMT were independently related to PMPs levels in type 1 diabetes. According to Receiver operating characteristic curve analysis, the cutoff value of PMPs at 2.48% could differentiate patients with and without micro-vascular complications with a sensitivity of 80% and specificity of 73.3%. PMPs are elevated in patients with type 1 diabetes and can be considered as an early marker of micro-vascular complications and subclinical atherosclerosis. PMID- 25806428 TI - All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T. AB - Ligand-stabilized human telomeric G-quadruplex DNA is believed to be an anticancer agent, as it can impede the continuous elongation of telomeres by telomerase in cancer cells. In this study, five well-established human telomeric G-quadruplex DNA models were probed on their binding behaviors with thioflavin T (ThT) via both conventional molecular dynamics (MD) and well-tempered metadynamics (WT-MetaD) simulations. Novel dynamics and characteristic binding patterns were disclosed by the MD simulations. It was observed that the K(+) promoted parallel and hybridized human telomeric G-quadruplex conformations pose higher binding affinities to ThT than the Na(+) and K(+) promoted basket conformations. It is the end, sandwich, and base stacking driven by pi-pi interactions that are identified as the major binding mechanisms. As the most energy favorable binding mode, the sandwich stacking observed in (3 + 1) hybridized form 1 G-quadruplex conformation is triggered by reversible conformational change of the G-quadruplex. To further examine the free energy landscapes, WT-MetaD simulations were utilized on G-quadruplex-ThT systems. It is found that all of the major binding modes predicted by the MD simulations are confirmed by the WT-MetaD simulations. The results in this work not only accord with existing experimental findings, but also reinforce our understanding on the dynamics of G-quadruplexes and aid future drug developments for G-quadruplex stabilization ligands. PMID- 25806427 TI - Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) have opened new opportunities for understanding human development, modelling disease processes and developing new therapeutics. However, these applications are hindered by the low efficiency and heterogeneity of cell types, such as motorneurons (MNs), differentiated from hPSCs as well as our inability to maintain the potency of lineage-committed progenitors. Here by using a combination of small molecules that regulate multiple signalling pathways, we develop a method to guide human embryonic stem cells to a near-pure population (>95%) of motor neuron progenitors (MNPs) in 12 days, and an enriched population (>90%) of functionally mature MNs in an additional 16 days. More importantly, the MNPs can be expanded for at least five passages so that a single MNP can be amplified to 1 * 10(4). This method is reproducible in human-induced pluripotent stem cells and is applied to model MN degenerative diseases and in proof-of-principle drug-screening assays. PMID- 25806431 TI - The reverse galeal hinge flap: another valuable technique in the repair of scalp defects extending to the calvarium. PMID- 25806430 TI - Interleukin-10-1082A/G polymorphism and diabetic nephropathy: a meta-analysis. AB - BACKGROUND: Studies have assessed the association between Interleukin-10 (IL-10) 1082A/G polymorphism and diabetic nephropathy (DN) risk, but the results were inconclusive and contradictory. Therefore, we performed a meta-analysis to investigate the association between IL10-1082A/G polymorphism and DN risk. MATERIAL AND METHODS: All relevant studies were searched by using PubMed and EMBASE. Data were extracted by 2 authors independently. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Nine case control studies with 4165 subjects were included in this meta-analysis. We found that IL10-1082A/G polymorphism was significantly associated with an increased DN risk (OR=1.21; 95% CI 1.07-1.37; P=0.002). In the subgroup analysis by race, both Caucasians and Asians with IL10-1082A/G polymorphism showed increased DN risk (OR=1.25; 95% CI 1.03-1.52; P=0.03 and OR=1.25; 95% CI 1.04-1.49; P=0.02), respectively. When we deleted the study without diabetes type, the result was not altered (OR=1.21; 95% CI 1.02-1.44; P=0.03). In the subgroup analysis by sample size, both studies with large sample size and studies with small sample size showed increased DN risk (OR=1.16; 95% CI 1.02-1.31; P=0.02 and OR=1.50; 95% CI 1.14-1.98; P=0.004), respectively. CONCLUSIONS: This meta-analysis confirmed that IL10-1082A/G polymorphism might contribute to the susceptibility for DN. PMID- 25806429 TI - The effect of music performance on the transcriptome of professional musicians. AB - Music performance by professional musicians involves a wide-spectrum of cognitive and multi-sensory motor skills, whose biological basis is unknown. Several neuroscientific studies have demonstrated that the brains of professional musicians and non-musicians differ structurally and functionally and that musical training enhances cognition. However, the molecules and molecular mechanisms involved in music performance remain largely unexplored. Here, we investigated the effect of music performance on the genome-wide peripheral blood transcriptome of professional musicians by analyzing the transcriptional responses after a 2-hr concert performance and after a 'music-free' control session. The up-regulated genes were found to affect dopaminergic neurotransmission, motor behavior, neuronal plasticity, and neurocognitive functions including learning and memory. Particularly, candidate genes such as SNCA, FOS and DUSP1 that are involved in song perception and production in songbirds, were identified, suggesting an evolutionary conservation in biological processes related to sound perception/production. Additionally, modulation of genes related to calcium ion homeostasis, iron ion homeostasis, glutathione metabolism, and several neuropsychiatric and neurodegenerative diseases implied that music performance may affect the biological pathways that are otherwise essential for the proper maintenance of neuronal function and survival. For the first time, this study provides evidence for the candidate genes and molecular mechanisms underlying music performance. PMID- 25806432 TI - Full-thickness skin grafts for lower leg defects: an effective repair option. AB - BACKGROUND: Repair of lower leg defects after excision of skin lesions that are not amenable to primary closure can be challenging. OBJECTIVE: To evaluate the outcome of full-thickness skin grafts (FTSG) to repair lower leg defects after excision of cutaneous lesions. To assess graft take at Days 7 and 30 and the number of visits to secondary care after procedure. MATERIALS AND METHODS: Retrospective review of 50 consecutive patients who underwent FTSG to cover defects below the knee between January 2009 and February 2014. Graft take was defined as good (90% healing and pink/purple), moderate (50% healing and pink/purple and >50% graft take), or poor (>50% graft failure). RESULTS: Mean age was 75 years (range, 49-96 years). The mean area of the defect was 52.4 cm. The mean maximum and minimum diameters of the defect were 2.8 and 2.3 cm. Graft take was good in 44 patients (88%), moderate in 5 patients (10%), and poor in 1 patient (2%) at Day 30. Complications were infrequent and included infection and ulceration. There was no significant association between the graft size and graft take. CONCLUSION: Full-thickness skin graft is an effective method of repairing defects on the lower leg after removal of cutaneous lesions. The aftercare of FTSG was acceptable with 86% of patients requiring 5 or fewer visits to secondary care. PMID- 25806433 TI - Altered cytokine levels in pediatric ITP. AB - Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children, the disease resolves, but in some, it becomes chronic. Cytokines are important mediators of the immune response and are known to be dysregulated in autoimmune diseases. Therefore, our aim was to investigate differences in plasma levels of cytokines between children with ITP and healthy controls. We had two cohorts of children: one Swedish with 18 children with ITP and seven healthy children and a second Chinese one with 58 children with ITP and 30 healthy children. Plasma levels of chemokine (C-X3-C motif) ligand 1 (CX3CL1), transforming growth factor beta1 (TGF-beta1), and interleukin 22 (IL-22) were analyzed in both cohorts using enzyme-linked immunosorbent assays (ELISAs). We found lower plasma levels of TGF-beta1 and elevated levels of CX3CL1 and IL-22 in children with ITP compared with controls in both the Swedish and the Chinese cohort. In conclusion, all three cytokines differ between pediatric ITP and healthy controls and may, therefore, be potential biomarkers for the disease. PMID- 25806434 TI - Introduction of the 4,4,4-trifluorobut-2-ene chain exploiting a regioselective Tsuji-Trost reaction catalyzed by palladium nanoparticles. AB - A palladium-nanoparticle-catalyzed Tsuji-Trost reaction of 4,4,4-trifluorobut-2 en-1-yl acetate and ethyl(4,4,4-trifluorobut-2-en-1-yl)carbonate was accomplished with various nucleophiles including phenols, amines, and malonates. In the case of the phenols, isomerization of the double bond in the product (up to 20%) was observed as a side reaction. Further synthetic transformations including hydrogenation, the Diels-Alder reaction, and asymmetric dihydroxylation of a product were also examined. PMID- 25806435 TI - Enhanced biofilm production by a toluene-degrading Rhodococcus observed after exposure to perfluoroalkyl acids. AB - This study focuses on interactions between aerobic soil-derived hydrocarbon degrading bacteria and a suite of perfluorocarboxylic acids and perfluoroalkylsulfonates that are found in aqueous film-forming foams used for fire suppression. No effect on toluene degradation rate or induction time was observed when active cells of Rhodococcus jostii strain RHA1 were exposed to toluene and a mixture of perfluoroalkyl acids (PFAAs) including perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) at concentrations near the upper bounds of groundwater relevance (11 PFAAs at 10 mg/L each). However, exposure to aqueous PFAA concentrations above 2 mg/L (each) was associated with enhanced aggregation of bacterial cells and significant increases in extracellular polymeric substance production. Flocculation was only observed during exponential growth and not elicited when PFAAs were added to resting incubations; analogous flocculation was also observed in soil enrichments. Aggregation was accompanied by 2- to 3-fold upregulation of stress-associated genes, sigF3 and prmA, during growth of this Rhodococcus in the presence of PFAAs. These results suggest that biological responses, such as microbial stress and biofilm formation, could be more prominent than suppression of co-contaminant biodegradation in subsurface locations where poly- and perfluoroalkyl substances occur with hydrocarbon fuels. PMID- 25806438 TI - Let's take a fresh look at learning. PMID- 25806437 TI - Ligand-promoted intramolecular dehydrogenative cross-coupling using a Cu catalyst: direct access to polycyclic heteroarenes. AB - A copper(II)-promoted intramolecular C-H coupling reaction between indole-2 and imidazole-2 moieties has been developed for polycyclic heteroarene synthesis. The method provides direct access to biheteroaryl incorporated polycyclic frameworks, which are of huge interest in the area of functional materials and drug discovery. PMID- 25806436 TI - Toward breeding new land-sea plant hybrid species irrigable with seawater for dry regions. AB - A plant species growing in sea or coastal saltmarsh is greatly tolerant to high concentrations of salts, and a plant species growing in desert or dry regions is highly tolerant to drought. Breeding a new plant hybrid species from both species by means of cellular grafting, genome fusion or nuclear transfer would generate, at least in theory, a hybrid plant species that should be strongly tolerant to harsh aridity and salinity and would be potentially irrigable with seawater. Such prospective species can be used for example as a fodder, biofuel crop or stabilizer species to protect soil from wind erosion and sandy storms in dry regions. Breeding such species would change the surface of the world and help to solve major challenges of starvation, malnutrition and poverty. Here, I propose potential approaches that would be worthy of investigation toward this purpose. PMID- 25806440 TI - Many NHS trusts take a relaxed approach to ward visiting times. PMID- 25806441 TI - Washing uniforms below 60 degrees C may increase risk of bacterial infection. PMID- 25806442 TI - Stress experienced at work is affecting staff health, survey finds. PMID- 25806443 TI - Call for training to continue for a year after graduation. PMID- 25806444 TI - Proposals to introduce staff ratios in Wales dismissed as too rigid. PMID- 25806445 TI - Risk reduction plans needed for long shifts. PMID- 25806446 TI - Voters position health service at top of the election agenda. PMID- 25806447 TI - Savile review urges NHS to tighten its patient safety procedures. PMID- 25806448 TI - Report calls for leaders to help staff blow the whistle. PMID- 25806449 TI - A place on the team. PMID- 25806450 TI - Decisions, decisions. PMID- 25806452 TI - Vantage point--Should research focus on now or the future? PMID- 25806455 TI - Commit to safety first. PMID- 25806462 TI - Sign up to Safety: developing a safety improvement plan. AB - The Sign up to Safety (SutS) programme was launched in June 2014 by health secretary Jeremy Hunt. It focuses on listening to patients, carers and staff, learning from what they say when things go wrong, and then taking action to improve patient safety. The programme aims to make the NHS the safest healthcare system in the world by creating a culture devoted to continuous learning and improvement (NHS England 2014). Musgrove Park Hospital, part of Taunton and Somerset NHS Foundation Trust, was one of 12 NHS organisations that signed up to the SutS programme, making public its commitment to the national pledges to be 'open and transparent' and to develop a safety improvement plan. This paper describes the development of the strategy. PMID- 25806463 TI - Early warning scores: a sign of deterioration in patients and systems. AB - The early warning score system is a decision-making tool that has a simple design, yet its implementation in healthcare organisations is proving complex. This article reports the results of a survey that evaluated nurses' experiences of using the National Early Warning Score (NEWS) in an acute hospital in Ireland. Staff reported that the NEWS was easy to use, did not increase workload and enhanced their ability to identify deteriorating patients. However, they also identified problems related to doctors' delayed response times, doctors' lack of training in the use of the tool, and a failure by doctors to modify trigger parameters for patients with chronic conditions. NEWS enhances nurses' roles in early detection of patient deterioration, but delays in response times by doctors expose systematic flaws in health care. This suggests that it is not only an indicator of patient deterioration, but also of deteriorating healthcare systems. PMID- 25806464 TI - Specific standards of care for adults with intellectual disabilities. AB - Individuals with intellectual and developmental disabilities (ID) represent a small but important group of patients who have high levels of hospitalisation, and who are likelier to have more complications and spend more days in intensive care than those without ID admitted to hospital for similar problems. However, nursing and medical staff lack training in the care of people with ID. To address the needs of this patient group, an academic medical centre in the mid-western United States has developed specific standards of nursing care. This article describes the standards, which cover nursing interventions to enhance communication, the provision of safe and accessible environments, and collaboration with and support for caregivers; it also outlines the online educational programme that was developed for nurses to support their implementation and use of the standards. PMID- 25806465 TI - Privileged to lead. PMID- 25806466 TI - In situ characterization of nanowire dimensions and growth dynamics by optical reflectance. AB - Optical reflectometry is commonly used as an accurate and noninvasive characterization tool when growing planar semiconductor layers. However, thin film analysis schemes cannot be directly applied to nanowire systems due to their complex optical response. Here, we report on reliable in situ characterization of nanowire growth with high accuracy using optical reflectance spectra for analysis. The method makes it possible to determine the nanowire length, diameter, and growth rate in situ in real time with high resolution. We demonstrate the method's versatility by using the optical reflectance data for determining nanowire dimensions on both particle-assisted and selective-area grown nanowires. To indicate the full potential of in situ characterization of nanowire synthesis we evaluate the growth dynamics of InP nanowires in the presence of the p-type dopant precursor diethylzinc. We observe that the growth rate is strongly affected by the diethylzinc. At low diethylzinc flows, the growth rate decreases monotonously while higher flows lead to an initially increasing growth rate. From these in situ characterization data, we conclude that the surface migration length of adatom species is affected strongly by the addition of diethylzinc. We believe that this characterization method will become a standard tool for in situ growth monitoring and aid in elucidating the complex growth dynamics often exhibited during nanowire growth. PMID- 25806467 TI - The marine metabolite SZ-685C induces apoptosis in primary human nonfunctioning pituitary adenoma cells by inhibition of the Akt pathway in vitro. AB - Nonfunctioning pituitary adenoma (NFPA) is one of the most common types of pituitary adenoma. The marine anthraquinone derivative SZ-685C has been isolated from the secondary metabolites of the mangrove endophytic fungus Halorosellinia sp. (No. 1403) which is found in the South China Sea. Recent research has shown that SZ-685C possesses anticancer and tumor suppressive effects. The tetrazolium based colorimetric assay (MTT assay) to investigate the different effect of the marine compound SZ-685C on the proliferation of primary human NFPA cells, rat normal pituitary cells (RPCs) and rat prolactinoma MMQ cell lines. Hoechst 33342 dye/propidium iodide (PI) double staining and fluorescein isothiocyanate conjugated Annexin V/PI (Annexin V-FITC/PI) apoptosis assays detected an enhanced rate of apoptosis in cells treated with SZ-685C. Enhanced expression levels of caspase 3 and phosphate and tensin homolog (PTEN) were determined by Western blotting. Notably, the protein expression levels of Akt were decreased when the primary human NFPA cells were treated with SZ-685C. Here, we show that SZ-685C induces apoptosis of human NFPA cells through inhibition of the Akt pathway in vitro. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. PMID- 25806469 TI - Long-term prognostic role of uric acid in patients with ST-elevation myocardial infarction and renal dysfunction. AB - Patients with renal impairment have decreased excretion of uric acid, thus being particularly prone to having elevated serum uric acid concentrations. No data are available on the long-term prognostic role of uric acid in patients with ST elevation myocardial infarction (STEMI) and renal dysfunction, submitted to percutaneous coronary intervention (PCI). We therefore prospectively assessed, in 329 patients with STEMI and renal dysfunction (admission estimated glomerular filtration rate <60 ml/min/1.73 m), all submitted to PCI, whether uric acid levels are associated with increased mortality at 1-year postdischarge follow up.Patients in the third tertile of uric acid showed a higher BMI (P = 0.014), a higher incidence of hypertension (P = 0.029), and two or more comorbidities (P = 0.034). The highest incidence of bleeding and of acute kidney injury was detectable in patients in the third tertile (P = 0.011 and P < 0.001, respectively) who showed the highest mortality rate at 1-year postdischarge follow-up (P = 0.008). At Cox regression analysis, uric acid was an independent predictor of 1-year postdischarge mortality (hazard ratio 1.26, 95% confidence interval 1.06-1.51, P = 0.011).In STEMI patients with estimated glomerular filtration rate below 60 ml/min/1.73 m treated with PCI, uric acid helps in identifying a subset of patients at a higher risk of bleeding and acute kidney injury. Increased uric acid is an independent prognostic risk factor for 1-year mortality. Further studies performed in larger cohorts of patients are needed to confirm our findings and to evaluate whether lowering uric acid in these patients is beneficial. PMID- 25806470 TI - Atrial fibrillation and female sex. AB - Atrial fibrillation is the most common supraventricular arrhythmia. Its prevalence increases with age and preferentially affects male patients. Over 75 years of age, however, female patients being more prevalent, the absolute number of patients affected is similar between sexes. Despite this, few data are available in the literature concerning sex-related differences in atrial fibrillation patients. The present systematic review therefore considers comorbidities, referring symptoms, quality of life, pharmacological approaches and trans-catheter ablation in female rather than in male atrial fibrillation patients in search of parameters that may have an impact on the treatment outcome. In brief, female atrial fibrillation patients more commonly present comorbidities, leading to a higher prevalence of persistent atrial fibrillation; moreover, they refer to hospital care later and with a longer disease history. Atrial fibrillation symptoms relate to low quality of life in female patients; in fact, atrial fibrillation paroxysm usually presents higher heart rate, leading to preferentially adopt a rate rather than a rhythm-control strategy. Female atrial fibrillation patients present an increased risk of stroke, worsened by the lower oral anticoagulant prescription rate related to the concomitant higher haemorrhagic risk profile. Trans-catheter ablation is under-used in female patients and, on the contrary, they are more commonly affected by anti-arrhythmic drug side effects. PMID- 25806468 TI - Recent advances in the synthesis of 2-pyrones. AB - The present review summarizes the recent progresses in the synthesis of 2-pyrones and the application to the synthesis of marine natural products. Especially, much attention was placed on the transition metal catalyzed synthetic methodologies in this review. PMID- 25806471 TI - Coronary stenting approaches in the treatment of chronic total occlusion: contemporary registry-based experience. AB - AIMS: This 'real-world' investigation attempted to determine the long-term prognoses of patients who have undergone successful revascularization of chronic total occlusion (CTO) lesions. METHODS: All consecutive unselected patients from January 2006 to June 2011, undergoing stenting for CTO (n = 272), were retrospectively identified through an institutional registry. Procedural failure was defined as final diameter stenosis greater than 30% or postdilatation thrombolysis in myocardial infarction flow less than 3. Outcomes were assessed based on stenting type [bare metal stent (BMS), drug-eluting stent (DES), or mixed] in the successful procedural cohort. Multiple logistic regression analyses were used to account for known baseline cardiovascular risk imbalances. The primary endpoint was 2-year target vessel revascularization. RESULTS: Overall procedural failure occurred in 55 (20.2%) patients presenting with CTO lesions. Failed revascularization was independently associated with multivessel disease, lesion lengths greater than 15 mm, tortuous segments, and presence of calcifications. Major complications included coronary dissection (10%) and perforation (2%). Of the successful procedures, 141 (64%) underwent pure DES, 46 (21%) pure BMS, and 34 (15%) mixed stenting. At 2-year follow-up, fewer patients in the DES group required repeat revascularization compared to the mixed stenting group (6 vs. 26%; P = 0.002). Mixed stenting was an independent predictor of long term target vessel revascularization (adjusted odds ratio 2.1, 95% confidence interval 1.1-4.1, P = 0.02) compared to DES. CONCLUSIONS: Failed revascularization of CTO lesions occurs in a fifth of patients and appears to be associated with complex vessel anatomy. Our data suggest that DES use in this setting are associated with improved 2-year clinical endpoints compared with pure BMS or mixed stenting approaches. PMID- 25806472 TI - Differential susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes. AB - OBJECTIVE: Circadian disturbances common to modern lifestyles have been associated with mood disorders. Animal models that mimic such rhythm disturbances are useful in translational research to explore factors contributing to depressive disorders. This study aimed to verify the susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes. METHODS: Thermochron iButtons implanted in the mouse abdomen were used to characterize temperature rhythms. Mice were maintained under a 12:12 h light-dark (LD) cycle for 15 days, followed by a 10:10 h LD cycle for 10 days. Cosinor analysis, Rayleigh z test, periodograms, and Fourier analysis were used to analyze rhythm parameters. Paired Student's t test was used to compare temperature amplitude, period, and power of the first harmonic between normal and shortened cycles. RESULTS: The shortened LD cycle significantly changed temperature acrophases and rhythm amplitude in all mouse strains, but only BALB/c showed altered period. CONCLUSION: These findings suggest that BALB/c, the preferred strain for stress-induced models of depression, should also be favored for exploring the relationship between circadian rhythms and mood. Temperature rhythm proved to be a useful parameter for characterizing rhythm disruption in mice. Although disruption of temperature rhythm has been successfully documented in untethered mice, an evaluation of desynchronization of other rhythms is warranted. PMID- 25806473 TI - Neuropsychological dysfunction in adults with early-onset obsessive-compulsive disorder: the search for a cognitive endophenotype. AB - OBJECTIVE: Evidence suggests that early-onset obsessive-compulsive disorder (OCD) is an etiologically distinct subtype of OCD. The objective of the present work was to search for neurocognitive endophenotypes of early-onset OCD based on assessments of attention, memory, and executive function in patients with the disorder and their unaffected siblings. METHODS: We compared the performance of 40 adult patients with early-onset OCD, 40 of their unaffected siblings, and 40 unrelated healthy controls on a neuropsychological battery designed for this study. We searched for associations among test performance, demographic variables (age, sex and years of education) and clinical symptoms of early-onset OCD. RESULTS: Patients performed significantly worse than healthy controls on the Tower of Hanoi, and the Stroop and Wisconsin tests, indicating impairments in planning, mental flexibility and inhibitory control. The performance of the unaffected first-degree siblings of patients with early-onset OCD on the Stroop and Wisconsin tests also differed from that of healthy controls. Symptom severity in early-onset OCD was strongly correlated with performance on the Tower of Hanoi. CONCLUSIONS: Our findings support the existence of specific executive function deficits in patients with early-onset OCD. Relatives presented an intermediate phenotype between patients and controls, suggesting that executive functions such as mental flexibility and response inhibition may be considered candidate endophenotypes of early-onset OCD. PMID- 25806474 TI - Mechanically driven branching of bacterial colonies. AB - A continuum mathematical model with sharp interface is proposed for describing the occurrence of patterns in initially circular and homogeneous bacterial colonies. The mathematical model encapsulates the evolution of the chemical field characterized by a Monod-like uptake term, the chemotactic response of bacteria, the viscous interaction between the colony and the underlying culture medium and the effects of the surface tension at the boundary. The analytical analysis demonstrates that the front of the colony is linearly unstable for a proper choice of the parameters. The simulation of the model in the nonlinear regime confirms the development of fingers with typical wavelength controlled by the size parameters of the problem, whilst the emergence of branches is favored if the diffusion is dominant on the chemotaxis or for high values of the friction parameter. Such results provide new insights on pattern selection in bacterial colonies and may be applied for designing engineered patterns. PMID- 25806476 TI - Effect of laparoscopic surgery on health care utilization and costs in patients who undergo colectomy. AB - IMPORTANCE: Laparoscopic colectomy is safe and effective in the treatment of many colorectal diseases. However, the effect of increasing use of laparoscopy on overall health care utilization and costs, especially in the long term, has not been thoroughly investigated. OBJECTIVE: To evaluate the effect of laparoscopic vs open colectomy on short- and long-term health care utilization and costs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective multivariate regression analysis of national health insurance claims data was used to evaluate health care utilization and costs up to 1 year following elective colectomy. Data were obtained from the Truven Health Analytics MarketScan Commercial Claims and Encounters database. Patients aged 18 to 64 years who underwent elective laparoscopic or open colectomy from January 1, 2010, through December 31, 2010, were included. Patients with complex diagnoses that require increased non-surgery related health care utilization, including malignant neoplasm, inflammatory bowel disease, human immunodeficiency virus, transplantation, and pregnancy, were excluded. Of 25 481 patients who underwent colectomy, 4160 were included in the study. MAIN OUTCOMES AND MEASURES: Healthcare utilization, including office, hospital outpatient, and emergency department visits and inpatient services 90 and 365 days after the index procedure; total health care costs; and estimated days off from work owing to health care utilization. RESULTS: Of 25 481 patients who underwent colectomy, 4160 were included in the study (laparoscopic, 45.6%; open, 54.4%). The mean (SD) net and total payments were lower for laparoscopy ($23 064 [$14 558] and $24 196 [$14 507] vs $29 753 [$21 421] and $31 606 [$23 586]). In the first 90 days after surgery, an open approach was significantly associated with a 1.26-fold increase in health care costs (estimated, $1715; 95% CI, $338-$2853), increased use of heath care services, and more estimated days off from work (2.78 days; 95% CI, 1.93-3.59). Similar trends were found in the full postoperative year, with an estimated 1.18-fold increase (95% CI, 1.04-1.35) in health care expenditures and an increase of 1.15 times (95% CI, 1.08-1.23) the number of health care utilization days compared with laparoscopy. CONCLUSIONS AND RELEVANCE: Laparoscopic colectomy results in a significant reduction in health care costs and utilization in the short- and long-term postoperative periods. PMID- 25806477 TI - [Effect of partial and generalised epileptic seizures on sleep architecture in rats]. AB - INTRODUCTION: It is a well-known fact that epileptic seizures disrupt sleep, yet little information is available about sleep disorders according to the type of epileptic seizures. MATERIALS AND METHODS: The sleep architecture of rats was evaluated in polysomnography recordings 36 hours after inducing partial and generalised epileptic seizures in them. The epileptic seizures were induced by applying 50-100 IU of sodium G penicillin in the amygdala of the temporal lobe. RESULTS: Partial and generalised seizures triggered an increase in the latency of slow wave sleep (SWS) and rapid eye movement (REM) sleep. The number of episodes of the phases of wakefulness, SWS and REM sleep was reduced and the mean duration of the episodes of wakefulness and SWS increased, while that of REM sleep diminished. The total percentage of REM sleep diminished significantly. During the first period of light the partial and generalised seizures triggered an increase in wakefulness and a reduction in the phases of SWS and REM sleep. In the period of darkness, the SWS increased and wakefulness decreased, while there were no changes in REM sleep. In the second period of light, the percentages of the phases of wakefulness and SWS returned to control values and the percentage of REM sleep continued to be reduced. CONCLUSIONS: Changes in the structuring of sleep depend on the type of epileptic seizure that presents. Generalised epileptic seizures caused greater deterioration in REM sleep. PMID- 25806478 TI - [Analysis of the stay and morbidity and mortality rates in a unit for neurocritical patients following surgery for a brain tumour]. AB - AIM: To evaluate the association between the pre- and post-operative variables with stays in hospital lasting more than one day and the morbidity and mortality rates of patients undergoing surgery for a brain tumour during their stay in a neurocritical intensive care unit (NCU). PATIENTS AND METHODS: The retrospective study, over a period of three years (2010-2012), involving a cohort of 317 patients who consecutively underwent surgical interventions due to brain tumours performed by different neurosurgeons and were hospitalised in the NCU. RESULTS: A total of 21.5% (n = 68) of the patients were hospitalised for more than one day (group L), and 78.5% (n = 249) stayed for one day or less (group S). The univariable association of the pre- and post-operative risks with the length of stay was evaluated. There were no significant differences between groups L and S in terms of the demographic data, the physical status according to the classification of the American Society of Anesthesiologists (ASA), the pathological features or the radiological tumour severity index. Tracheal intubation was required in 42.6% (n = 29) of the patients in group L at some time during the post-operative period. Of the patients in group L, 19.1% (n = 13) had systemic and regional complications simultaneously. CONCLUSIONS: An important fraction of patients remain in an NCU for more than one day. The need for both tracheal intubation and respiratory assistance, together with the appearance of systemic and regional complications, can require stays in an NCU for more than one day. PMID- 25806475 TI - Oxidative Transformation of Demethoxy- and Bisdemethoxycurcumin: Products, Mechanism of Formation, and Poisoning of Human Topoisomerase IIalpha. AB - Extracts from the rhizome of the turmeric plant are widely consumed as anti inflammatory dietary supplements. Turmeric extract contains the three curcuminoids, curcumin (~80% relative abundance), demethoxycurcumin (DMC; ~15%), and bisdemethoxycurcumin (BDMC; ~5%). A distinct feature of pure curcumin is its instability at physiological pH, resulting in rapid autoxidation to a bicyclopentadione within 10-15 min. Here, we describe oxidative transformation of turmeric extract, DMC, and BDMC and the identification of their oxidation products using LC-MS and NMR analyses. DMC autoxidized over the course of 24 h to the expected bicyclopentadione diastereomers. BDMC was resistant to autoxidation, and oxidative transformation required catalysis by horseradish peroxidase and H2O2 or potassium ferricyanide. The product of BDMC oxidation was a stable spiroepoxide that was equivalent to a reaction intermediate in the autoxidation of curcumin. The ability of DMC and BDMC to poison recombinant human topoisomerase IIalpha was significantly increased in the presence of potassium ferricyanide, indicating that oxidative transformation was required to achieve full DNA cleavage activity. DMC and BDMC are less prone to autoxidation than curcumin and contribute to the enhanced stability of turmeric extract at physiological pH. Their oxidative metabolites may contribute to the biological effects of turmeric extract. PMID- 25806479 TI - [Assessment of therapeutic passive hypothermia in newborns with hypoxic-ischemic encephalopathy that need interhospital transport]. AB - INTRODUCTION: Induced hypothermia for the first hours of life in a newborn is an effective treatment to reduce mortality and serious effects in neonates that had suffered a hypoxia episode. This method needs an universal attendance independently of the place of birth being usually necessary a transfer to the reference hospital. AIM: To analyze the efficacy of the newborn with hypoxic ischemic encephalopathy transfer in passive hypothermia. PATIENTS AND METHODS: Descriptive study of series of cases with retrospective character of newborn from Cadiz's province that need induced hypothermia. 46 newborn were included in the study: 33 of them (71.74%) needed being transfer by the Critical Patients Transport service (CPT group), the rest (28.26%) were born into the reference hospital. RESULTS: Both groups are similar in age gestational at birth, sex, weight and hypoxic-ischemic encephalopathy degree. It analyzed variables related to hypothermia therapy and in addition in CPT group transfer specific variables. At discharge, it does not exist significant differences between groups in the efficiency-consequence of neuroprotection therapy with hypothermia (p = 0.159). It does not find complications derived from the interhospital move. CONCLUSIONS: Neonatal inter-hospital transfer in passive therapeutic hypothermia is effective, safe and necessary for the therapy compliance. It is required reach an agreement between the attendance and the reference service, setting up guides for the support and suitable range of temperature. PMID- 25806480 TI - [Hirayama disease in paediatrics: a clinical case report and review of the literature]. AB - INTRODUCTION: Hirayama disease is a rare children's muscular atrophy that affects young Asian males, with muscular atrophy usually in one of the upper limbs that progresses slowly and later stabilises. It is diagnosed by means of electromyographic/electroneurographic with conduction speed studies (EMG/ENG-CS) and by magnetic resonance imaging (MRI) of the spinal cord in a neutral position and with cervical flexion. Treatment is based on the cervical collar and surgery (severe cases). Very few studies have been conducted on patients at the paediatric age. CASE REPORT: We report the case of a 7-year-old girl with atrophy of the muscles of the left hand and forearm, and a disease history of two years. The EMG/ENG-CS scans presented signs of very severe chronic denervation in the myotomes of C7, C8 and T1 on the left side, with conservation of the amplitudes of sensory evoked potentials, consistent with cervical myelopathy. Results of an MRI scan of the cervical spinal cord in a neutral position were normal at that level. Later, owing to suspicions pointing towards Hirayama disease, a new MRI scan of the cervical spinal cord was performed in a neutral position and in flexion. This second scan showed asymmetry in the size and morphology of the anterior funiculi of the spinal cord at C6/C7, hypersignal in the homolateral anterior horn and ingurgitation of the posterior epidural venous plexus. With a diagnosis of Hirayama disease, treatment is started with a cervical collar in order to prevent the damage from getting worse. CONCLUSIONS: This case of Hirayama disease is peculiar due to its epidemiological characteristics and is presented here with the aim of making this entity more widely known in our milieu. If diagnosed at an early stage, treatment is effective, and the studies conducted on children at the paediatric age are reviewed. PMID- 25806481 TI - [The role of experience in the neurology of facial expression of emotions]. AB - INTRODUCTION: Facial expression of emotion has an important social function that facilitates interaction between people. This process has a neurological basis, which is not isolated from the context, or the experience of the interaction between people in that context. Yet, to date, the impact that experience has on the perception of emotions is not completely understood. AIMS: To discuss the role of experience in the recognition of facial expression of emotions and to analyze the biases towards emotional perception. DEVELOPMENT: The maturation of the structures that support the ability to recognize emotion goes through a sensitive period during adolescence, where experience may have greater impact on emotional recognition. Experiences of abuse, neglect, war, and stress generate a bias towards expressions of anger and sadness. Similarly, positive experiences generate a bias towards the expression of happiness. CONCLUSIONS: Only when people are able to use the facial expression of emotions as a channel for understanding an expression, will they be able to interact appropriately with their environment. This environment, in turn, will lead to experiences that modulate this capacity. Therefore, it is a self-regulatory process that can be directed through the implementation of intervention programs on emotional aspects. PMID- 25806482 TI - [Guidelines for monitoring late-onset Pompe disease.Sociedad Espanola de Medicina Interna (SEMI), Sociedad Espanola de Neurologia (SEN) y Sociedad Espanola de Neumologia y CirugiaToracica (SEPAR)]. AB - Although treatment with alglucosidase alfa has helped improve the prognosis of patients with late-onset Pompe disease, both the development of the disease and the effectiveness of the treatment need to be monitored on a regular basis. This is the reason that has led a committee of Spanish experts to draw up a series of guidelines on how to follow up these patients. The committee proposes a model of follow-up tests for late-onset Pompe disease. First of all, the nutritional status and swallowing function must be evaluated. Second, and due to the variability of the clinical features, the committee recommends the simultaneous use of several scales to measure different functions and parameters. Thus, muscular force is assessed with the Medical Research Council scale; motor functioning, with the six-minute walk test and timed tests; disability, with the Rasch-built Pompe-specific Activity scale; respiratory functioning, with measurement of the forced vital capacity and oxygen saturation; and fatigue, with the fatigue intensity scale. Lastly, the safety and tolerability of enzyme replacement therapy are controlled by registering and treating the potential side effects and measurement of the anti-alglucosidase alfa antibodies. A number of different general recommendations are also included. PMID- 25806483 TI - [Cystic schwannoma of the spine]. PMID- 25806485 TI - [Carotid dissection as the cause of perinatal strokes]. PMID- 25806486 TI - An experimental and theoretical mechanistic study of biexciton quantum yield enhancement in single quantum dots near gold nanoparticles. AB - In this work, we systematically investigated the plasmonic effect on blinking, photon antibunching behavior and biexciton emission of single CdSe/CdS core/shell quantum dots (QDs) near gold nanoparticles (NPs) with a silica shell (Au@SiO2). In order to obtain a strong interaction between the plasmons and excitons, the Au@SiO2 NPs and CdSe/CdS QDs of appropriate sizes were chosen so that the plasmon resonance overlaps with the absorption and emission of the QDs. We observed that in the regime of a low excitation power, the photon antibunching and blinking properties of single QDs were modified significantly when the QDs were on the Au@SiO2 substrates compared to those on glass. Most significantly, second-order photon intensity correlation data show that the presence of plasmons increases the ratio of the biexciton quantum yield over the exciton quantum yield (QYBX/QYX). An electrodynamics model was developed to quantify the effect of plasmons on the lifetime, quantum yield, and emission intensity of the biexcitons for the QDs. Good agreement was obtained between the experimentally measured and calculated changes in QYBX/QYX due to Au@SiO2 NPs, showing the validity of the developed model. The theoretical studies also indicated that the relative position of the QDs to the Au NPs and the orientation of the electric field are important factors that regulate the emission properties of the excitons and biexcitons of QDs. The study suggests that the multiexciton emission efficiency in QD systems can be manipulated by employing properly designed plasmonic structures. PMID- 25806487 TI - A firmly hybridizable, DNA-like architecture with DAD/ADA- and ADD/DAA-type nonnatural base pairs as an extracellular genetic candidate. AB - We describe artificial DNA molecules exclusively consisting of four types of alkynyl C-nucleotides with nonnatural bases. The artificial DNA exhibited almost the same characteristics as natural DNA, such as in regard to the stepwise duplex and triplex formation and the right-handed higher-order structure with an antiparallel alignment fashion. PMID- 25806488 TI - Bifunctional alkyl chain barriers for efficient perovskite solar cells. AB - Perovskite solar cells as a hot research topic show the necessity of controlling the interface. In this work, an insulating alkyl chain layer is self-assembled at the perovskite/hole transport material interface, which successfully exhibits a dual function: blocking electron recombination and resisting moisture at the same time. Improved solar energy conversion efficiency and stability of the device are both achieved. PMID- 25806489 TI - Biomaterials. PMID- 25806490 TI - Textiles: Fabrics of life. PMID- 25806491 TI - Polymers: Secrets from the deep sea. PMID- 25806492 TI - Structure: Artificial armour. PMID- 25806493 TI - Artificial organs: Honey, I shrunk the lungs. PMID- 25806494 TI - Perspective: Special delivery for the gut. PMID- 25806495 TI - Learning from nature's best. PMID- 25806496 TI - Spiders: Web of intrigue. PMID- 25806497 TI - Synthetic coatings: Super surfaces. PMID- 25806499 TI - Sample quality criteria. AB - The concept of Sample Quality Criteria (SQC) is the initial step in the scientific approach to representative sampling. It includes the establishment of sampling objectives, Decision Unit (DU), and confidence. Once fully defined, these criteria serve as input, in addition to material properties, to the Theory of Sampling for developing a representative sampling protocol. The first component of the SQC establishes these questions: What is the analyte(s) of concern? What is the concentration level of interest of the analyte(s)? How will inference(s) be made from the analytical data to the DU? The second component of the SQC establishes the DU, i.e., the scale at which decisions are to be made. On a large scale, a DU could be a ship or rail car; examples for small-scale DUs are individual beans, seeds, or kernels. A well-defined DU is critical because it defines the spatial and temporal boundaries of sample collection. SQC are not limited to a single DU; they can also include multiple DUs. The third SQC component, the confidence, establishes the desired probability that a correct inference (decision) can be made. The confidence level should typically correlate to the potential consequences of an incorrect decision (e.g., health or economic). The magnitude of combined errors in the sampling, sample processing and analytical protocols determines the likelihood of an incorrect decision. Thus, controlling error to a greater extent increases the probability of a correct decision. The required confidence level directly affects the sampling effort and QC measures. PMID- 25806498 TI - Association of maternal report of infant and toddler gastrointestinal symptoms with autism: evidence from a prospective birth cohort. AB - IMPORTANCE: Gastrointestinal (GI) comorbidities are frequently described in association with autism spectrum disorder (ASD). However, the prevalence of GI disturbances and the age at which such problems first appear are unclear, and their specificity for ASD compared with other neurodevelopmental disorders is uncertain. OBJECTIVE: To compare maternal report of GI symptoms during the first 3 years of life in children with ASD, developmental delay (DD), and typical development (TD). DESIGN, SETTING, AND PARTICIPANTS: This large prospective cohort study consists of participants in the Norwegian Mother and Child Cohort Study. During a 10-year period (January 1, 1999, through December 31, 2008), women throughout Norway were recruited at the first prenatal ultrasonographic visit (approximately 18 weeks' gestation). The study enrolled 95,278 mothers, 75,248 fathers, and 114,516 children. Our analyses are based on MoBa data released through October 1, 2013, and NPR diagnoses registered through December 31, 2012, and include children born from January 1, 2002, through December 31, 2008, with completed age 18- and 36-month questionnaires. EXPOSURES: We defined 3 groups of children: children with ASD (n = 195), children with DD and delayed language and/or motor development (n = 4636), and children with TD (n = 40 ,95). MAIN OUTCOMES AND MEASURES: The GI symptoms were based on maternal report of constipation, diarrhea, and food allergy/intolerance. RESULTS: Children with ASD were at significantly increased odds of maternally reported constipation (adjusted odds ratio [aOR], 2.7; 95% CI, 1.9-3.8; P < .001) and food allergy/intolerance (aOR, 1.7; 95% CI, 1.1-2.6; P = .01) in the 6- to 18-month old age period and diarrhea (aOR, 2.3; 95% CI, 1.5-3.6; P < .001), constipation (aOR, 1.6; 95% CI, 1.2-2.3; P < .01), and food allergy/intolerance (aOR, 2.0; 95% CI, 1.3-3.1; P < .01) in the 18- to 36-month-old age period compared with children with TD. Similar results for these symptom categories were observed in comparisons with children with DD, but ORs were slightly lower. Mothers of children with ASD were significantly more likely to report 1 or more GI symptom in either the 6- to 18-month or the 18- to 36-month-old age period and more than twice as likely to report at least 1 GI symptom in both age periods compared with mothers of children with TD or DD. CONCLUSIONS AND RELEVANCE: In this large prospective cohort, maternally reported GI symptoms are more common and more often persistent during the first 3 years of life in children with ASD than in children with TD or DD. PMID- 25806501 TI - [Investigating work, age, health and work participation in the ageing work force in Germany]. AB - Working life in Germany is changing. The work force is ageing and the number of people available to the labour market will - from now on - shrink considerably. Prospectively, people will have to work longer; but still today, most people leave employment long before reaching official retirement age. What are the reasons for this? In this report, a conceptual framework and the German lidA Cohort Study are presented. The "lidA conceptual framework on work, age, health and work participation" visualises determinants of employment (11 "domains") in higher working age, e. g., "work", "health", "social status" and "life style". The framework reveals 4 key characteristics of withdrawal from work: leaving working life is the result of an interplay of different domains (complexity); (early) retirement is a process with in part early determinants in the life course (processual character); retirement has a strong individual component (individuality); retirement is embedded in a strong structural frame (structure). On the basis of this framework, the "lidA Cohort Study on work, age, health and work participation" (www.lida-studie.de) investigates long-term effects of work on health and work participation in the ageing work force in Germany. It is the only large study in Germany operationalising the concept of employability in a broad interdisciplinary approach. Employees subject to social security and born in 1959 or in 1965 will be interviewed (CAPI) every 3 years (N[wave 1]=6 585, N[wave 2]=4 244) and their data will be linked (where consented) with social security data covering employment history and with health insurance data. The study design ("Schaie's most efficient design") allows for a tri-factor model that isolates the impact of age, cohort and time. In 2014, the second wave was completed. In the coming years lidA will analyse the association of work, health and work participation, and identify age as well as generation differences. lidA will investigate the complexity of work participation and assess the benefit of broader conceptual and methodological research approaches in the field. PMID- 25806500 TI - Representative sampling for food and feed materials: a critical need for food/feed safety. PMID- 25806502 TI - [Effects of atypical employment on difficulties in falling asleep and maintaining sleep - gender differences in the lidA study]. AB - BACKGROUND AND AIM: Due to the increasing flexibilisation of the European labour market, new forms of atypical work organisation have been arising. Atypical employment may cause negative health effects similar to unemployment. Considering the health-promoting relevance of sleep for work productivity, we investigate if different forms of atypical employment are associated with difficulties falling and maintaining asleep among middle-aged male and female employees. METHODS: Data were retrieved from the 1(st) wave of the lidA study, a nation-wide survey among employees in Germany in 2011. According to the Integrated Employment Biography (IEB) of the Institute of Employment Research (IAB), participants were born in 1959 or 1965 and subject to mandatory social insurance contributions on 31.12.11. Our analysis is based on 4 544 participants. Using logistic regression models separately for men and women, difficulties falling and maintaining asleep were modelled to depend on years mostly spent in full-time, part-time, in marginal employment or in unemployment during the period from 1999-2010 as well as on years in the current position, fixed-term employment contract, organisational restructuring and dismissals at time of the survey in 2011. RESULTS: Women (9%) were more affected by difficulties falling and maintaining asleep than men (5%). Among women, past years mostly spent in full-time, part-time, marginal employment or in unemployment were not associated with sleep disturbances. Men who had mostly worked part-time or unemployment were more likely to report difficulties falling and maintaining asleep. Likewise, in men a fixed-term contract was linked with a higher risk of sleep disturbances. In women, witnessed dismissal in the working environment was a significant influencing factor. CONCLUSION: Atypical employment can be related to difficulties falling and maintaining asleep. In future research gender-specific reasons for atypical employment as well as adverse working conditions should be taken into account. Changes between different forms of atypical employment as well as cumulative measures of these employment exposures in employees' biographies should be included in future studies. PMID- 25806503 TI - [Psychometric Testing of a New Scale Assessing the Reasons for Non-Utilisation of Health Care Services by People with Migration Backgrounds]. AB - BACKGROUND: In Germany live a lot of migrants. Cultural and migration specific aspects seem to have an effect on utilisation of health care. There are no instruments that measure such factors of influence. METHODS: A systematic literature research or article that identify the difficulties of the migrants in using the health care system, was made. The relevant aspects were explored during a health related opinion survey of migrants from former USSR, Turkey, Italy and Spain. The psychometric qualities of this questionnaire were investigated with factor and reliability analyses. RESULTS: There were 24 reasons identified for non-utilisation health care. They were combined in a questionnaire. The factor analysis showed 2-factor structure ("janguage und information related Reasons" Chronbach's alpha=0.928 and "experience with/attitude toward health care system", Chronbach's alpha=0.879). Furthermore, there was a total scale with Chronbach's alpha=0.945. The acceptance was between 80.0 and 96.3%. CONCLUSIONS: The results confirm the psychometric quality of this measuring instrument. For further generalisability more verification will be necessary. PMID- 25806504 TI - [Vaccine Preventable Diseases: Knowledge, Attitudes and Vaccination Status of Medical Students]. AB - Study Objective: Health-care workers (HCW) have an increased risk of acquiring infectious diseases and constitute a risk of transmission to their patients. Medical students working as HCW should therefore have the same immunity against vaccine preventable diseases as HCW. The aim of the study was to assess medical students' knowledge and attitudes towards occupationally indicated vaccinations as well as their vaccination status. Methods: Questionnaires were anonymously answered by medical students of the fourth preclinical semester at the Goethe University Frankfurt. Results and Conclusion: Despite a high acceptance among medical students concerning vaccinations in general, the knowledge and vaccination status of the students should be improved. For instance, only 46.4% of the medical students knew that there is a general recommendation for HCW to receive the influenza vaccination and only 76.8% of the students stated to have received 2 measles vaccinations. Overall, 2/3 of the students were "very much in favour of vaccinations" or "completely in favour of vaccinations" and estimated the probability for unvaccinated HCW to acquire an occupationally associated infectious disease to be "quite high" or "very high". Having observed a positive attitude among medical students towards vaccinations, it should be possible to reach high vaccination coverage amongst students by offering them occupationally indicated vaccinations. Further knowledge concerning vaccine preventable diseases and the occupation-related increased risk for infectious diseases should be offered, as well. PMID- 25806505 TI - [Text Comprehensibility of Hospital Report Cards]. AB - Objectives: Recently, the number of hospital report cards that compare quality of hospitals and present information from German quality reports has greatly increased. Objectives of this study were to a) identify suitable methods for measuring the readability and comprehensibility of hospital report cards, b) to obtain reliable information on the comprehensibility of texts for laymen, c) to give recommendations for improvements and d) to recommend public health actions. Methods: The readability and comprehensibility of the texts were tested with a) a computer-aided evaluation of formal text characteristics (readability indices Flesch (German formula) and 1. Wiener Sachtextformel formula), b) an expert-based heuristic analysis of readability and comprehensibility of texts (counting technical terms and analysis of text simplicity as well as brevity and conciseness using the Hamburg intelligibility model) and c) a survey of subjects about the comprehensibility of individual technical terms, the assessment of the comprehensibility of the presentations and the subjects' decisions in favour of one of the 5 presented clinics due to the better quality of data. In addition, the correlation between the results of the text analysis with the results from the survey of subjects was tested. Results: The assessment of texts with the computer-aided evaluations showed poor comprehensibility values. The assessment of text simplicity using the Hamburg intelligibility model showed poor comprehensibility values (-0.3). On average, 6.8% of the words used were technical terms. A review of 10 technical terms revealed that in all cases only a minority of respondents (from 4.4% to 39.1%) exactly knew what was meant by each of them. Most subjects (62.4%) also believed that unclear terms worsened their understanding of the information offered. The correlation analysis showed that presentations with a lower frequency of technical terms and better values for the text simplicity were better understood. Conclusion: The determination of the frequency of technical terms and the assessment of text simplicity using the Hamburg intelligibility model were suitable methods to determine the readability and comprehensibility of presentations of quality indicators. The analysis showed predominantly poor comprehensibility values and indicated the need to improve the texts of report cards. PMID- 25806506 TI - [Effectiveness of School-based Interventions to Prevent and/or Reduce Substance Use among Primary and Secondary School Pupils: A Review of Reviews]. AB - OBJECTIVE: The aim of this study is to provide a current overview of the effectiveness of school-based interventions on prevention and/or reduction of substance use among children and adolescents aged 5-19 years. METHODS: A systematic literature search was conducted in PubMed, Cochrane Library, Campbell Collaboration, NICE and ERIC. Systematic reviews and meta-analyses published between 2007 and 2013 were included in the analysis. 2 reviewers assessed the quality of the identified review articles and extracted the data. RESULTS: 14 review articles of moderate to good quality fulfilled the a-priori defined inclusion criteria. Capacity-promoting interventions, e. g., those focusing on strengthening self-confidence and peer resistance, show promising evidence of effectiveness. Multi-component and multi-level interventions are more suitable for the prevention of alcohol and cannabis consumption. Findings on the prevention of tobacco consumption are inconsistent. The effectiveness of knowledge-based interventions is limited. The long-term effectiveness of smoke free competitions cannot be conclusively evaluated as the findings are discrepant. CONCLUSIONS: School-based interventions should include capacity promoting components and should address further levels beyond the individual, for example, organisational changes of the school setting. Further research is needed, in particular on the effectiveness of multi-component and multi-level interventions for the prevention of tobacco consumption. PMID- 25806507 TI - Correction: interrogation of the Burkholderia pseudomallei genome to address differential virulence among isolates. AB - [This corrects the article DOI: 10.1371/journal.pone.0115951.]. PMID- 25806508 TI - Longitudinal changes in plasma Caspase-1 and Caspase-3 during the first 2 years of HIV-1 infection in CD4Low and CD4High patient groups. AB - Over 95% of CD4 cell death occurs by Caspase-1-mediated pyroptosis during HIV infection. Caspase-3-mediated apoptosis accounts for the death in a small proportion of infected CD4 cells. To date, there have been no reports on the dynamics of Caspase-1 and Caspase-3 and their relationship with disease progression in acute HIV-1 infection. In this study, two distinct HIV-1 patient groups were enrolled. The CD4High group maintained a CD4 level above 450 cells/MUl while CD4 levels in the CD4Low group dropped below 250 cells/MUl within 2 years after infection. Blood samples were collected at 1, 2, 3, 4, 6, 12 and 24 months after HIV infection. Plasma Caspase-1 and Caspase-3 levels in the two patients groups were determined by a single-step ELISA using commercially available monoclonal antibodies. The results showed that Caspase-1 and Caspase-3 levels in the CD4High group increased rapidly and then decreased within a short time during early HIV-1 infection. In contrast, Caspase-1 and Caspase-3 levels in the CD4Low group were obviously increased after 1 year of HIV-1 infection. PMID- 25806510 TI - Efficient inference of parsimonious phenomenological models of cellular dynamics using S-systems and alternating regression. AB - The nonlinearity of dynamics in systems biology makes it hard to infer them from experimental data. Simple linear models are computationally efficient, but cannot incorporate these important nonlinearities. An adaptive method based on the S system formalism, which is a sensible representation of nonlinear mass-action kinetics typically found in cellular dynamics, maintains the efficiency of linear regression. We combine this approach with adaptive model selection to obtain efficient and parsimonious representations of cellular dynamics. The approach is tested by inferring the dynamics of yeast glycolysis from simulated data. With little computing time, it produces dynamical models with high predictive power and with structural complexity adapted to the difficulty of the inference problem. PMID- 25806509 TI - Differences in muscle strength in parkinsonian patients affected on the right and left side. AB - BACKGROUND: Muscular weakness is a frequent cause of instability that contributes to falls in Parkinson's disease (PD). Isokinetic dynamometry is a method of muscle assessment useful to measure the muscular strength giving a quantification of the weakness, but only few studies about isokinetic assessment were performed in PD. The aims of the study were to evaluate the muscle strength in PD and to investigate the differences in patients affected on the right and left side. METHODS: Knee flexor and extensor muscles strength was assessed using an isokinetic dynamometer in 25 patients in stage 3 H&Y and in 15 healthy controls. Subjects were tested in both legs at three fixed angular velocities: 90 degrees /s, 120 degrees /s, 180 degrees /s. RESULTS: Considering the whole population of Parkinsonians, no difference in strength was observed with respect to controls. Considering the side, patients affected on the right side showed a clear tendency to be weaker than patients affected on the left side and controls. CONCLUSIONS: PD patients affected on the right side, but not those affected on the left side, had a reduction in muscle strength as compared to controls. We postulate a central origin deficit in muscle strength in PD. It is known that dopamine transporter binding is more severely reduced in the left posterior putamen and our results suggest that the control of the muscle strength in PD is linked to the right-left hemispheric asymmetry of the functional organization of basal ganglia and with their connections to cortical motor and pre-motor areas. PMID- 25806511 TI - Division of labor in hand usage is associated with higher hand performance in free-ranging bonnet macaques, Macaca radiate [corrected]. AB - A practical approach to understanding lateral asymmetries in body, brain, and cognition would be to examine the performance advantages/disadvantages associated with the corresponding functions and behavior. In the present study, we examined whether the division of labor in hand usage, marked by the preferential usage of the two hands across manual operations requiring maneuvering in three-dimensional space (e.g., reaching for food, grooming, and hitting an opponent) and those requiring physical strength (e.g., climbing), is associated with higher hand performance in free-ranging bonnet macaques, Macaca radiate [corrected]. We determined the extent to which the macaques exhibit laterality in hand usage in an experimental unimanual and a bimanual food-reaching task, and the extent to which manual laterality is associated with hand performance in an experimental hand-performance-differentiation task. We observed negative relationships between (a) the latency in food extraction by the preferred hand in the hand-performance differentiation task (wherein, lower latency implies higher performance), the preferred hand determined using the bimanual food-reaching task, and the normalized difference between the performance of the two hands, and (b) the normalized difference between the performance of the two hands and the absolute difference between the laterality in hand usage in the unimanual and the bimanual food-reaching tasks (wherein, lesser difference implies higher manual specialization). Collectively, these observations demonstrate that the division of labor between the two hands is associated with higher hand performance. PMID- 25806512 TI - Multiplicity of steady states in glycolysis and shift of metabolic state in cultured mammalian cells. AB - Cultured mammalian cells exhibit elevated glycolysis flux and high lactate production. In the industrial bioprocesses for biotherapeutic protein production, glucose is supplemented to the culture medium to sustain continued cell growth resulting in the accumulation of lactate to high levels. In such fed-batch cultures, sometimes a metabolic shift from a state of high glycolysis flux and high lactate production to a state of low glycolysis flux and low lactate production or even lactate consumption is observed. While in other cases with very similar culture conditions, the same cell line and medium, cells continue to produce lactate. A metabolic shift to lactate consumption has been correlated to the productivity of the process. Cultures that exhibited the metabolic shift to lactate consumption had higher titers than those which didn't. However, the cues that trigger the metabolic shift to lactate consumption state (or low lactate production state) are yet to be identified. Metabolic control of cells is tightly linked to growth control through signaling pathways such as the AKT pathway. We have previously shown that the glycolysis of proliferating cells can exhibit bistability with well-segregated high flux and low flux states. Low lactate production (or lactate consumption) is possible only at a low glycolysis flux state. In this study, we use mathematical modeling to demonstrate that lactate inhibition together with AKT regulation on glycolysis enzymes can profoundly influence the bistable behavior, resulting in a complex steady-state topology. The transition from the high flux state to the low flux state can only occur in certain regions of the steady state topology, and therefore the metabolic fate of the cells depends on their metabolic trajectory encountering the region that allows such a metabolic state switch. Insights from such switch behavior present us with new means to control the metabolism of mammalian cells in fed-batch cultures. PMID- 25806514 TI - Correction: Derivation of iPSCs after culture of human dental pulp cells under defined conditions. PMID- 25806515 TI - Severe Interferon/Ribavirin-Induced Hyperuricemia and Urate Nephropathy Requiring Rasburicase and Hemodialysis in a Liver Transplant Recipient. AB - INTRODUCTION: Hyperuricemia caused by pegylated-interferon-alpha2a and ribavirin therapy has been rarely reported. We report a case of severe hyperuricemia and urate nephropathy in a liver transplant recipient with recurrent hepatitis C, which required discontinuation of therapy, rasburicase, and hemo-dialysis. CASE REPORT: A 64-year-old female liver transplant recipient was begun on treatment of fibrosis cholestatic hepatitis with pegylated-interferon-alpha2a and ribavirin therapy. She received a one-time dose of pegylated-interferon-alpha2a 135 mcg subcutaneously, and ribavirin was initiated. Within 24 hours of treatment initiation, she developed an acute kidney injury with serum creatinine increased from a baseline 132.6 MUmol/L (1.5 mg/dL) to 459.7 MUmol/L (5.2 mg/dL) within 72 hours. Ultrasound and computed tomography of the kidneys were normal with no stones and urinalysis showed no crystals. Her ribavirin dosage was adjusted based on her changing renal function. Within 72 hours after treatment initiation, her serum uric acid level was 1392 MUmol/L (23.4 mg/dL), for which she received rasburicase 3 mg intravenously. Ribavirin was discontinued at this time. The next day, her serum uric acid level and remained elevated at 1166 MUmol/L (19.6 mg/dL) and she received a second dose of rasburicase 7.5 mg and hemodialysis. Her serum uric acid level decreased to 131 MUmol/L (2.2 mg/dL) and remained within normal limits; however, she continued to require intermittent hemodialysis until she died from complications of sepsis 38 days after admission. After discontinuation, she was not rechallenged with pegylated-interferon-alpha2a /and ribavirin. CONCLUSIONS: A liver transplant recipient with recurrent hepatitis C developed severe hyperuricemia and urate nephropathy shortly after receiving pegylated interferon-alpha2a and ribavirin therapy. The patient's hyperuricemia was managed with rasbu-ricase and hemodialysis. This rare but potentially serious adverse reaction can limit the use of these agents in patients with recurrence of life threatening hepatitis C after liver transplant. PMID- 25806513 TI - Immune antibodies and helminth products drive CXCR2-dependent macrophage myofibroblast crosstalk to promote intestinal repair. AB - Helminth parasites can cause considerable damage when migrating through host tissues, thus making rapid tissue repair imperative to prevent bleeding and bacterial dissemination particularly during enteric infection. However, how protective type 2 responses targeted against these tissue-disruptive multicellular parasites might contribute to homeostatic wound healing in the intestine has remained unclear. Here, we observed that mice lacking antibodies (Aid-/-) or activating Fc receptors (Fcrg-/-) displayed impaired intestinal repair following infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb), whilst transfer of immune serum could partially restore chemokine production and rescue wound healing in Aid-/- mice. Impaired healing was associated with a reduced expression of CXCR2 ligands (CXCL2/3) by macrophages (MPhi) and myofibroblasts (MF) within intestinal lesions. Whilst antibodies and helminths together triggered CXCL2 production by MPhi in vitro via surface FcR engagement, chemokine secretion by intestinal MF was elicited by helminths directly via Fcrg-chain/dectin2 signaling. Blockade of CXCR2 during Hpb challenge infection reproduced the delayed wound repair observed in helminth infected Aid-/ and Fcrg-/- mice. Finally, conditioned media from human MPhi stimulated with infective larvae of the helminth Ascaris suum together with immune serum, promoted CXCR2-dependent scratch wound closure by human MF in vitro. Collectively our findings suggest that helminths and antibodies instruct a chemokine driven MPhi-MF crosstalk to promote intestinal repair, a capacity that may be harnessed in clinical settings of impaired wound healing. PMID- 25806516 TI - Building a comprehensive mill-level database for the Industrial Sectors Integrated Solutions (ISIS) model of the U.S. pulp and paper sector. AB - Air emissions from the U.S. pulp and paper sector have been federally regulated since 1978; however, regulations are periodically reviewed and revised to improve efficiency and effectiveness of existing emission standards. The Industrial Sectors Integrated Solutions (ISIS) model for the pulp and paper sector is currently under development at the U.S. Environmental Protection Agency (EPA), and can be utilized to facilitate multi-pollutant, sector-based analyses that are performed in conjunction with regulatory development. The model utilizes a multi sector, multi-product dynamic linear modeling framework that evaluates the economic impact of emission reduction strategies for multiple air pollutants. The ISIS model considers facility-level economic, environmental, and technical parameters, as well as sector-level market data, to estimate the impacts of environmental regulations on the pulp and paper industry. Specifically, the model can be used to estimate U.S. and global market impacts of new or more stringent air regulations, such as impacts on product price, exports and imports, market demands, capital investment, and mill closures. One major challenge to developing a representative model is the need for an extensive amount of data. This article discusses the collection and processing of data for use in the model, as well as the methods used for building the ISIS pulp and paper database that facilitates the required analyses to support the air quality management of the pulp and paper sector. PMID- 25806517 TI - Postanesthetic effects of isoflurane on behavioral phenotypes of adult male C57BL/6J mice. AB - Isoflurane was previously the major clinical anesthetic agent but is now mainly used for veterinary anesthesia. Studies have reported widespread sites of action of isoflurane, suggesting a wide array of side effects besides sedation. In the present study, we phenotyped isoflurane-treated mice to investigate the postanesthetic behavioral effects of isoflurane. We applied comprehensive behavioral test batteries comprising sensory test battery, motor test battery, anxiety test battery, depression test battery, sociability test battery, attention test battery, and learning test battery, which were started 7 days after anesthesia with 1.8% isoflurane. In addition to the control group, we included a yoked control group that was exposed to the same stress of handling as the isoflurane-treated animals before being anesthetized. Our comprehensive behavioral test batteries revealed impaired latent inhibition in the isoflurane treated group, but the concentration of residual isoflurane in the brain was presumably negligible. The yoked control group and isoflurane-treated group exhibited higher anxiety in the elevated plus-maze test and impaired learning function in the cued fear conditioning test. No influences were observed in sensory functions, motor functions, antidepressant behaviors, and social behaviors. A number of papers have reported an effect of isoflurane on animal behaviors, but no systematic investigation has been performed. To the best of our knowledge, this study is the first to systematically investigate the general health, neurological reflexes, sensory functions, motor functions, and higher behavioral functions of mice exposed to isoflurane as adults. Our results suggest that the postanesthetic effect of isoflurane causes attention deficit in mice. Therefore, isoflurane must be used with great care in the clinical setting and veterinary anesthesia. PMID- 25806520 TI - Conspicuous female ornamentation and tests of male mate preference in threespine sticklebacks (Gasterosteus aculeatus). AB - Sexual selection drives the evolution of exaggerated male ornaments in many animal species. Female ornamentation is now acknowledged also to be common but is generally less well understood. One example is the recently documented red female throat coloration in some threespine stickleback (Gasterosteus aculeatus) populations. Although female sticklebacks often exhibit a preference for red male throat coloration, the possibility of sexual selection on female coloration has been little studied. Using sequential and simultaneous mate choice trials, we examined male mate preferences for female throat color, as well as pelvic spine color and standard length, using wild-captured threespine sticklebacks from the Little Campbell River, British Columbia. In a multivariate analysis, we found no evidence for a population-level mate preference in males, suggesting the absence of directional sexual selection on these traits arising from male mate choice. Significant variation was detected among males in their preference functions, but this appeared to arise from differences in their mean responsiveness across mating trials and not from variation in the strength (i.e., slope) of their preference, suggesting the absence of individual-level preferences as well. When presented with conspecific intruder males, male response decreased as intruder red throat coloration increased, suggesting that males can discriminate color and other aspects of phenotype in our experiment and that males may use these traits in intrasexual interactions. The results presented here are the first to explicitly address male preference for female throat color in threespine sticklebacks. PMID- 25806519 TI - Role of the deubiquitylating enzyme DmUsp5 in coupling ubiquitin equilibrium to development and apoptosis in Drosophila melanogaster. AB - Protein ubiquitylation is a dynamic process that affects the function and stability of proteins and controls essential cellular processes ranging from cell proliferation to cell death. This process is regulated through the balanced action of E3 ubiquitin ligases and deubiquitylating enzymes (DUB) which conjugate ubiquitins to, and remove them from target proteins, respectively. Our genetic analysis has revealed that the deubiquitylating enzyme DmUsp5 is required for maintenance of the ubiquitin equilibrium, cell survival and normal development in Drosophila. Loss of the DmUsp5 function leads to late larval lethality accompanied by the induction of apoptosis. Detailed analyses at a cellular level demonstrated that DmUsp5 mutants carry multiple abnormalities, including a drop in the free monoubiquitin level, the excessive accumulation of free polyubiquitins, polyubiquitylated proteins and subunits of the 26S proteasome. A shortage in free ubiquitins results in the induction of a ubiquitin stress response previously described only in the unicellular budding yeast. It is characterized by the induction of the proteasome-associated deubiquitylase DmUsp14 and sensitivity to cycloheximide. Removal of DmUsp5 also activates the pro-apoptotic machinery thereby resulting in widespread apoptosis, indicative of an anti-apoptotic role of DmUsp5. Collectively, the pleiotropic effects of a loss of DmUsp5 function can be explained in terms of the existence of a limited pool of free monoubiquitins which makes the ubiquitin-dependent processes mutually interdependent. PMID- 25806518 TI - Genetic and molecular characterization of submergence response identifies Subtol6 as a major submergence tolerance locus in maize. AB - Maize is highly sensitive to short term flooding and submergence. Early season flooding reduces germination, survival and growth rate of maize seedlings. We aimed to discover genetic variation for submergence tolerance in maize and elucidate the genetic basis of submergence tolerance through transcriptional profiling and linkage analysis of contrasting genotypes. A diverse set of maize nested association mapping (NAM) founder lines were screened, and two highly tolerant (Mo18W and M162W) and sensitive (B97 and B73) genotypes were identified. Tolerant lines exhibited delayed senescence and lower oxidative stress levels compared to sensitive lines. Transcriptome analysis was performed on these inbreds to provide genome level insights into the molecular responses to submergence. Tolerant lines had higher transcript abundance of several fermentation-related genes and an unannotated Pyrophosphate-Dependent Fructose-6 Phosphate 1-Phosphotransferase gene during submergence. A coexpression network enriched for CBF (C-REPEAT/DRE BINDING FACTOR: C-REPEAT/DRE BINDING FACTOR) genes, was induced by submergence in all four inbreds, but was more activated in the tolerant Mo18W. A recombinant inbred line (RIL) population derived from Mo18W and B73 was screened for submergence tolerance. A major QTL named Subtol6 was mapped to chromosome 6 that explains 22% of the phenotypic variation within the RIL population. We identified two candidate genes (HEMOGLOBIN2 and RAV1) underlying Subtol6 based on contrasting expression patterns observed in B73 and Mo18W. Sources of tolerance identified in this study (Subtol6) can be useful to increase survival rate during flooding events that are predicted to increase in frequency with climate change. PMID- 25806521 TI - A cross-cultural perspective on the preference for potential effect: an individual participant data (IPD) meta-analysis approach. AB - A recent paper [Tormala ZL, Jia JS, Norton MI (2012). The preference for potential. Journal of personality and social psychology, 103: 567-583] demonstrated that persons often prefer potential rather than achievement when evaluating others, because information regarding potential evokes greater interest and processing, resulting in more favorable evaluations. This research aimed to expand on this finding by asking two questions: (a) Is the preference for potential effect replicable in other cultures? (b) Is there any other mechanism that accounts for this preference for potential? To answer these two questions, we replicated Tormala et al.'s study in multiple cities (17 studies with 1,128 participants) in China using an individual participant data (IPD) meta analysis approach to test our hypothesis. Our results showed that the preference for potential effect found in the US is also robust in China. Moreover, we also found a pro-youth bias behind the preference for potential effect. To be specific, persons prefer a potential-oriented applicant rather than an achievement-oriented applicant, partially because they believe that the former is younger than the latter. PMID- 25806522 TI - Frequency of maternal and newborn birth outcomes, Lima, Peru, 2013. AB - OBJECTIVE: This study describes the pregnancy and birth outcomes at two hospitals in Lima, Peru. The data collection and analysis is intended to inform patients, providers, and policy makers on Peru's progress toward achieving the Millennium Development Goals and to help set priorities for action and further research. METHODS: Data were collected retrospectively from a sample of 237 women who delivered between December 2012 and September 2013 at the Instituto Nacional Materno Perinatal or the Hospital Nacional Arzobispo Loayza. The outcomes were recorded by a trained mid-wife through telephone interviews with patients and by review of hospital records. Associations between participant demographic characteristics and pregnancy outcomes were tested with Chi-squared, Fisher's exact, or Student's t-test. RESULTS: Over 37% of women experienced at least one maternal or perinatal complication, and the most frequent were hypertension/preeclampsia and macrosomia. The women in our sample had a cesarean section rate of 50.2%. CONCLUSION: Maternal and perinatal complications are not uncommon among women in the lower socioeconomic strata of Lima. Also, the high cesarean rate underpins the need for a more comprehensive understanding of the indications for cesarean section deliveries, which could help reduce the number of unnecessary procedures and preventable complications. PMID- 25806523 TI - Measurement of individual doses of radiation by personal dosimeter is important for the return of residents from evacuation order areas after nuclear disaster. AB - To confirm the availability of individual dose evaluation for the return of residents after the accident at the Fukushima Dai-ichi Nuclear Power Plant (FNPP), we evaluated individual doses of radiation as measured by personal dosimeters in residents who temporarily stayed in Evacuation Order Areas in Kawauchi village, which is partially located within a 20 km radius of the FNPP. We also compared individual doses with the external radiation doses estimated from the ambient dose rates and with doses estimated from the concentrations of radionuclides in the soil around each individual's house. Individual doses were significantly correlated with the ambient doses in front of the entrances to the houses (r = 0.90, p<0.01), in the backyards (r = 0.41, p<0.01) and in the nearby fields (r = 0.80, p<0.01). The maximum cumulative ambient doses in the backyards and fields around the houses were 6.38 and 9.27 mSv/y, respectively. The maximum cumulative individual dose was 3.28 mSv/y, and the median and minimum doses were 1.35 and 0.71 mSv/y. The estimated external effective doses from concentrations of artificial radionuclides in soil samples ranged from 0.03 to 23.42 mSv/y. The individual doses were moderately correlated with external effective doses in the backyards (r = 0.38, p<0.01) and in the fields (r = 0.36, p<0.01); however, the individual doses were not significantly correlated with the external effective doses in front of the entrances (r = 0.01, p = 0.92). Our study confirmed that individual doses are low levels even in the evacuation order area in Kawauchi village, and external effective dose levels are certainly decreasing due to the decay of artificial radionuclides and the decontamination of contaminated soil. Long-term follow-up of individual doses as well as internal-exposure doses, environmental monitoring and reconstruction of infrastructure are needed so that residents may return to their hometowns after a nuclear disaster. PMID- 25806524 TI - Digital PCR modeling for maximal sensitivity, dynamic range and measurement precision. AB - The great promise of digital PCR is the potential for unparalleled precision enabling accurate measurements for genetic quantification. A challenge associated with digital PCR experiments, when testing unknown samples, is to perform experiments at dilutions allowing the detection of one or more targets of interest at a desired level of precision. While theory states that optimal precision (Po) is achieved by targeting ~1.59 mean copies per partition (lambda), and that dynamic range (R) includes the space spanning one positive (lambdaL) to one negative (lambdaU) result from the total number of partitions (n), these results are tempered for the practitioner seeking to construct digital PCR experiments in the laboratory. A mathematical framework is presented elucidating the relationships between precision, dynamic range, number of partitions, interrogated volume, and sensitivity in digital PCR. The impact that false reaction calls and volumetric variation have on sensitivity and precision is next considered. The resultant effects on sensitivity and precision are established via Monte Carlo simulations reflecting the real-world likelihood of encountering such scenarios in the laboratory. The simulations provide insight to the practitioner on how to adapt experimental loading concentrations to counteract any one of these conditions. The framework is augmented with a method of extending the dynamic range of digital PCR, with and without increasing n, via the use of dilutions. An example experiment demonstrating the capabilities of the framework is presented enabling detection across 3.33 logs of starting copy concentration. PMID- 25806525 TI - Sustainable development under population pressure: lessons from developed land consumption in the conterminous U.S. AB - Population growth will result in a significant anthropogenic environmental change worldwide through increases in developed land (DL) consumption. DL consumption is an important environmental and socioeconomic process affecting humans and ecosystems. Attention has been given to DL modeling inside highly populated cities. However, modeling DL consumption should expand to non-metropolitan areas where arguably the environmental consequences are more significant. Here, we study all counties within the conterminous U.S. and based on satellite-derived product (National Land Cover Dataset 2001) we calculate the associated DL for each county. By using county population data from the 2000 census we present a comparative study on DL consumption and we propose a model linking population with expected DL consumption. Results indicate distinct geographic patterns of comparatively low and high consuming counties moving from east to west. We also demonstrate that the relationship of DL consumption with population is mostly linear, altering the notion that expected population growth will have lower DL consumption if added in counties with larger population. Added DL consumption is independent of a county's starting population and only dependent on whether the county belongs to a Metropolitan Statistical Area (MSA). In the overlapping MSA and non-MSA population range there is also a constant DL efficiency gain of approximately 20 km2 for a given population for MSA counties which suggests that transitioning from rural to urban counties has significantly higher benefits in lower populations. In addition, we analyze the socioeconomic composition of counties with extremely high or low DL consumption. High DL consumption counties have statistically lower Black/African American population, higher poverty rate and lower income per capita than average in both NMSA and MSA counties. Our analysis offers a baseline to investigate further land consumption strategies in anticipation of growing population pressures. PMID- 25806528 TI - Correction: the inhibitory effects of anacardic Acid on hepatitis C virus life cycle. AB - [This corrects the article DOI: 10.1371/journal.pone.0117514.]. PMID- 25806526 TI - Transcriptome sequencing and positive selected genes analysis of Bombyx mandarina. AB - The wild silkworm Bombyx mandarina is widely believed to be an ancestor of the domesticated silkworm, Bombyx mori. Silkworms are often used as a model for studying the mechanism of species domestication. Here, we performed transcriptome sequencing of the wild silkworm using an Illumina HiSeq2000 platform. We produced 100,004,078 high-quality reads and assembled them into 50,773 contigs with an N50 length of 1764 bp and a mean length of 941.62 bp. A total of 33,759 unigenes were identified, with 12,805 annotated in the Nr database, 8273 in the Pfam database, and 9093 in the Swiss-Prot database. Expression profile analysis found significant differential expression of 1308 unigenes between the middle silk gland (MSG) and posterior silk gland (PSG). Three sericin genes (sericin 1, sericin 2, and sericin 3) were expressed specifically in the MSG and three fibroin genes (fibroin-H, fibroin-L, and fibroin/P25) were expressed specifically in the PSG. In addition, 32,297 Single-nucleotide polymorphisms (SNPs) and 361 insertion-deletions (INDELs) were detected. Comparison with the domesticated silkworm p50/Dazao identified 5,295 orthologous genes, among which 400 might have experienced or to be experiencing positive selection by Ka/Ks analysis. These data and analyses presented here provide insights into silkworm domestication and an invaluable resource for wild silkworm genomics research. PMID- 25806527 TI - Understanding Thiel embalming in pig kidneys to develop a new circulation model. AB - The quality of tissue preservation in Thiel embalmed bodies varies. Research on the administered embalming volume and its vascular distribution may elucidate one of the mechanisms of tissue preservation and allow for new applications of Thiel embalming. Vascular embalming with (group 1, n = 15) or without (group 2, n = 20) contrast agent was initiated in pig kidneys. The distribution of Thiel embalming solution in group 1 was visualized using computed tomography. The kidneys in both groups were then immersed in concentrated salt solutions to reduce their weight and volume. Afterwards, to mimic a lifelike circulation in the vessels, group 2 underwent pump-driven reperfusion for 120 minutes with either paraffinum perliquidum or diluted polyethylene glycol. The circulation was imaged with computed tomography. All of the kidneys were adequately preserved. The embalming solution spread diffusely in the kidney, but fluid accumulation was present. Subsequent immersion in concentrated salt solutions reduced weight (P < 0.01) and volume (P < 0.01). Reperfusion for 120 minutes was established in group 2. Paraffinum perliquidum filled both major vessels and renal tissue, whereas diluted polyethylene glycol spread widely in the kidney. There were no increases in weight (P = 0.26) and volume (P = 0.79); and pressure further decreased (P = 0.032) after more than 60 minutes of reperfusion with paraffinum perliquidum, whereas there were increases in weight (P = 0.005), volume (P = 0.032) and pressure (P < 0.0001) after reperfusion with diluted polyethylene glycol. Arterial embalming of kidneys results in successful preservation due to complete parenchymatous spreading. More research is needed to determine whether other factors affect embalming quality. Dehydration is an effective method to regain the organs' initial status. Prolonged vascular reperfusion with paraffinum perliquidum can be established in this model without increases in weight, volume and pressure. PMID- 25806529 TI - Post-migration adaptation and age at menarche in the second generation of migrants. AB - Age at menarche is one of the most important measures of sexual maturation in girls. Since it has a high level of ecosensitivity, early environmental stress may trigger early puberty. One of these stress factors may be parental stress caused by the change of living conditions related to migration and adaptation to the new environment. Therefore, the aim of this study was to investigate the relationship between parental migration status and the timing of sexual maturity in second generation, i.e. migrants' daughters. Data were collected during the 2(nd) Polish Anthropological Survey carried out in 1966 - 1969. The information on age at menarche as well as demographic and social characteristics were collected by the use of a questionnaire. The results show that the age at menarche has been accelerated in girls from low socioeconomic status (low-SES) migrant families in comparison to low-SES non-migrant families. This study provides new biosocial evidence on the impact of the parental long-lasting post migration adaptation on the timing of maturation in the second generation of migrants. PMID- 25806531 TI - Mitigating reptile road mortality: fence failures compromise ecopassage effectiveness. AB - Roadways pose serious threats to animal populations. The installation of roadway mitigation measures is becoming increasingly common, yet studies that rigorously evaluate the effectiveness of these conservation tools remain rare. A highway expansion project in Ontario, Canada included exclusion fencing and ecopassages as mitigation measures designed to offset detrimental effects to one of the most imperial groups of vertebrates, reptiles. Taking a multispecies approach, we used a Before-After-Control-Impact study design to compare reptile abundance on the highway before and after mitigation at an Impact site and a Control site from 1 May to 31 August in 2012 and 2013. During this time, radio telemetry, wildlife cameras, and an automated PIT-tag reading system were used to monitor reptile movements and use of ecopassages. Additionally, a willingness to utilize experiment was conducted to quantify turtle behavioral responses to ecopassages. We found no difference in abundance of turtles on the road between the un mitigated and mitigated highways, and an increase in the percentage of both snakes and turtles detected dead on the road post-mitigation, suggesting that the fencing was not effective. Although ecopassages were used by reptiles, the number of crossings through ecopassages was lower than road-surface crossings. Furthermore, turtle willingness to use ecopassages was lower than that reported in previous arena studies, suggesting that effectiveness of ecopassages may be compromised when alternative crossing options are available (e.g., through holes in exclusion structures). Our rigorous evaluation of reptile roadway mitigation demonstrated that when exclusion structures fail, the effectiveness of population connectivity structures is compromised. Our project emphasizes the need to design mitigation measures with the biology and behavior of the target species in mind, to implement mitigation designs in a rigorous fashion, and quantitatively evaluate road mitigation to ensure allow for adaptive management and optimization of these increasingly important conservation tools. PMID- 25806533 TI - Correction: A bovine cell line that can be infected by natural sheep scrapie prions. PMID- 25806532 TI - Transducin duplicates in the zebrafish retina and pineal complex: differential specialisation after the teleost tetraploidisation. AB - Gene duplications provide raw materials that can be selected for functional adaptations by evolutionary mechanisms. We describe here the results of 350 million years of evolution of three functionally related gene families: the alpha, beta and gamma subunits of transducins, the G protein involved in vision. Early vertebrate tetraploidisations resulted in separate transducin heterotrimers: gnat1/gnb1/gngt1 for rods, and gnat2/gnb3/gngt2 for cones. The teleost-specific tetraploidisation generated additional duplicates for gnb1, gnb3 and gngt2. We report here that the duplicates have undergone several types of subfunctionalisation or neofunctionalisation in the zebrafish. We have found that gnb1a and gnb1b are co-expressed at different levels in rods; gnb3a and gnb3b have undergone compartmentalisation restricting gnb3b to the dorsal and medial retina, however, gnb3a expression was detected only at very low levels in both larvae and adult retina; gngt2b expression is restricted to the dorsal and medial retina, whereas gngt2a is expressed ventrally. This dorsoventral distinction could be an adaptation to protect the lower part of the retina from intense light damage. The ontogenetic analysis shows earlier onset of expression in the pineal complex than in the retina, in accordance with its earlier maturation. Additionally, gnb1a but not gnb1b is expressed in the pineal complex, and gnb3b and gngt2b are transiently expressed in the pineal during ontogeny, thus showing partial temporal subfunctionalisation. These retina-pineal distinctions presumably reflect their distinct functional roles in vision and circadian rhythmicity. In summary, this study describes several functional differences between transducin gene duplicates resulting from the teleost-specific tetraploidisation. PMID- 25806530 TI - Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER stress-induced apoptosis. AB - By suppressing neuronal apoptosis, Icariin is a potential therapeutic drug for neuronal degenerative diseases. The molecular mechanisms of Icariin anti apoptotic functions are still largely unclear. In this report, we found that Icariin induces the expression of Synoviolin, an endoplasmic reticulum (ER) anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis. The nuclear factor erythroid 2-related factor 1 (NFE2L1) is responsible for Icariin-mediated Synoviolin gene expression. Mutation of the NFE2L1-binding sites in a distal region of the Synoviolin promoter abolished Icariin-induced Synoviolin promoter activity, and knockdown of NFE2L1 expression prevented Icariin-stimulated Synoviolin expression. More importantly, Icariin protected ER stress-induced apoptosis of PC12 cells in a Synoviolin-dependent manner. Therefore, our study reveals Icariin-induced Synoviolin expression through NFE2L1 as a previously unappreciated molecular mechanism underlying the neuronal protective function of Icariin. PMID- 25806535 TI - Correction: crystal structure of the fibre head domain of the atadenovirus snake adenovirus 1. PMID- 25806536 TI - Correction: Thymoquinone inhibits murine leukemia WEHI-3 cells in vivo and in vitro. PMID- 25806534 TI - AIDS-related stigma and mental disorders among people living with HIV: a cross sectional study in Cambodia. AB - BACKGROUND: AIDS-related stigma and mental disorders are the most common conditions in people living with HIV (PLHIV). We therefore conducted this study to examine the association of AIDS-related stigma and discrimination with mental disorders among PLHIV in Cambodia. METHODS: A two-stage cluster sampling method was used to select 1,003 adult PLHIV from six provinces. The People Living with HIV Stigma Index was used to measure stigma and discrimination, and a short version of general health questionnaire (GHQ-12) was used to measure mental disorders. Multivariate logistic regression analysis was conducted. RESULTS: The reported experiences of discrimination in communities in the past 12 months ranged from 0.8% for reports of being denied health services to 42.3% for being aware of being gossiped about. Internal stigma was also common ranging from 2.8% for avoiding going to a local clinic and/or hospital to 59.6% for deciding not to have (more) children. The proportions of PLHIV who reported fear of stigma and discrimination ranged from 13.9% for fear of being physically assaulted to 34.5% for fear of being gossiped about. The mean score of GHQ-12 was 3.2 (SD = 2.4). After controlling for several potential confounders, higher levels of mental disorders (GHQ-12>= 4) remained significantly associated with higher levels of experiences of stigma and discrimination in family and communities (AOR = 1.9, 95% CI = 1.4-2.6), higher levels of internal stigma (AOR = 1.7, 95% CI = 1.2 2.3), and higher levels of fear of stigma and discrimination in family and communities (AOR = 1.5, 95% CI = 1.1-2.2). CONCLUSIONS: AIDS-related stigma and discrimination among PLHIV in Cambodia are common and may have potential impacts on their mental health conditions. These findings indicate a need for community based interventions to reduce stigma and discrimination in the general public and to help PLHIV to cope with this situation. PMID- 25806538 TI - A hyper-realistic method for facial approximation: the case of the Italian humanist Angelo Poliziano. AB - Frequently, identification of individuals is problematical due to the level of associated decomposition and even more when the skeletal remains are incomplete or fragmented. The identikit, which includes a sketch or a facial reconstruction, could assist investigators with determining the identity of the decedent. Similarly, in archeology and physical anthropology it gives a realistic appearance to a historical character known only through iconography. We examined the skull of Angelo Poliziano, an Italian humanist of the 15(th) century. Previously, his facial approximation was completed in clay according to the Manchester protocol and then a duplication was prepared in ultra-realistic materials. This technique returns a long lasting 3D model of the individual and provides the perception to be in front of a real person and, although expensive, applied in forensic context could it improve the recognition of the individual. PMID- 25806537 TI - Enterovirus-infected beta-cells induce distinct response patterns in BDCA1+ and BDCA3+ human dendritic cells. AB - Enteroviruses often cause mild disease, yet are also linked to development of autoimmune diabetes. Dendritic cells (DCs) shape both innate and adaptive immune responses, including anti-viral responses. How different human DC subsets shape anti-viral responses, whether they have complementary or overlapping functions and how this relates to autoimmune responses is largely unknown. We used enterovirus-infected beta-cells and freshly isolated human myeloid DC (mDC) subsets as a model for autoimmune type 1 diabetes. Our data show that both the BDCA1+ and BDCA3+ mDC subsets engulf mock- as well as virus-infected beta-cells, albeit BDCA1+ mDCs are more efficient. Uptake of enterovirus-infected, but not mock-infected cells, activated both DC subsets as indicated by the induction of co-stimulatory molecules and secretion of type I and type III interferons. Both subsets produced similar amounts of interferon-alpha, yet the BDCA3+ DC were superior in IFN-lambda production. The BDCA1+ mDCs more strongly upregulated PD L1, and were superior in IL-12 and IL-10 production as compared to the BDCA3+ DC. Despite lack of IL-12 production by the BDCA3+ DC, both BDCA1+ and BDCA3+ DCs activated T cells in allogeneic mixed lymphocyte reaction towards a Th1-type reactivity while suppressing Th2-associated cytokines. PMID- 25806539 TI - A cascade of iron-containing proteins governs the genetic iron starvation response to promote iron uptake and inhibit iron storage in fission yeast. AB - Iron is an essential cofactor, but it is also toxic at high levels. In Schizosaccharomyces pombe, the sensor glutaredoxin Grx4 guides the activity of the repressors Php4 and Fep1 to mediate a complex transcriptional response to iron deprivation: activation of Php4 and inactivation of Fep1 leads to inhibition of iron usage/storage, and to promotion of iron import, respectively. However, the molecular events ruling the activity of this double-branched pathway remained elusive. We show here that Grx4 incorporates a glutathione-containing iron-sulfur cluster, alone or forming a heterodimer with the BolA-like protein Fra2. Our genetic study demonstrates that Grx4-Fra2, but not Fep1 nor Php4, participates not only in iron starvation signaling but also in iron-related aerobic metabolism. Iron-containing Grx4 binds and inactivates the Php4 repressor; upon iron deprivation, the cluster in Grx4 is probably disassembled, the proteins dissociate, and Php4 accumulates at the nucleus and represses iron consumption genes. Fep1 is also an iron-containing protein, and the tightly bound iron is required for transcriptional repression. Our data suggest that the cluster containing Grx4-Fra2 heterodimer constitutively binds to Fep1, and upon iron deprivation the disassembly of the iron cluster between Grx4 and Fra2 promotes reverse metal transfer from Fep1 to Grx4-Fra2, and de-repression of iron-import genes. Our genetic and biochemical study demonstrates that the glutaredoxin Grx4 independently governs the Php4 and Fep1 repressors through metal transfer. Whereas iron loss from Grx4 seems to be sufficient to release Php4 and allow its nuclear accumulation, total or partial disassembly of the Grx4-Fra2 cluster actively participates in iron-containing Fep1 activation by sequestering its iron and decreasing its interaction with promoters. PMID- 25806540 TI - Reverse correlating love: highly passionate women idealize their partner's facial appearance. AB - A defining feature of passionate love is idealization--evaluating romantic partners in an overly favorable light. Although passionate love can be expected to color how favorably individuals represent their partner in their mind, little is known about how passionate love is linked with visual representations of the partner. Using reverse correlation techniques for the first time to study partner representations, the present study investigated whether women who are passionately in love represent their partner's facial appearance more favorably than individuals who are less passionately in love. In a within-participants design, heterosexual women completed two forced-choice classification tasks, one for their romantic partner and one for a male acquaintance, and a measure of passionate love. In each classification task, participants saw two faces superimposed with noise and selected the face that most resembled their partner (or an acquaintance). Classification images for each of high passion and low passion groups were calculated by averaging across noise patterns selected as resembling the partner or the acquaintance and superimposing the averaged noise on an average male face. A separate group of women evaluated the classification images on attractiveness, trustworthiness, and competence. Results showed that women who feel high (vs. low) passionate love toward their partner tend to represent his face as more attractive and trustworthy, even when controlling for familiarity effects using the acquaintance representation. Using an innovative method to study partner representations, these findings extend our understanding of cognitive processes in romantic relationships. PMID- 25806541 TI - Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells. AB - Zinc has an important role in normal pancreatic beta cell physiology as it regulates gene transcription, insulin crystallization and secretion, and cell survival. Nevertheless, little is known about how zinc is transported through the plasma membrane of beta cells and which of the class of zinc influx transporters (Zip) is involved. Zip4 was previously shown to be expressed in human and mouse beta cells; however, its function there is still unknown. Therefore, the aim of this study was to define the zinc transport role of Zip4 in beta cells. To investigate this, Zip4 was over-expressed in MIN6 beta cells using a pCMV6 Zip4GFP plasmid. Organelle staining combined with confocal microscopy showed that Zip4 exhibits a widespread localization in MIN6 cells. Time-lapse zinc imaging experiments showed that Zip4 increases cytoplasmic zinc levels. This resulted in increased granular zinc content and glucose-stimulated insulin secretion. Interestingly, it is unlikely that the increased glucose stimulated insulin secretion was triggered by a modulation of mitochondrial function, as mitochondrial membrane potential remained unchanged. To define the role of Zip4 in-vivo, we generated a beta cell-specific knockout mouse model (Zip4BKO). Deletion of the Zip4 gene was confirmed in Zip4BKO islets by PCR, RT-PCR, and immuno-histochemistry. Zip4BKO mice showed slightly improved glucose homeostasis but no change in insulin secretion during an oral glucose tolerance test. While Zip4 was not found to be essential for proper glucose homeostasis and insulin secretion in vivo in mice, this study also found that Zip4 mediates increases in cytoplasmic and granular zinc pools and stimulates glucose dependant insulin secretion in-vitro. PMID- 25806542 TI - Conservatism and novelty in the genetic architecture of adaptation in Heliconius butterflies. AB - Understanding the genetic architecture of adaptive traits has been at the centre of modern evolutionary biology since Fisher; however, evaluating how the genetic architecture of ecologically important traits influences their diversification has been hampered by the scarcity of empirical data. Now, high-throughput genomics facilitates the detailed exploration of variation in the genome-to phenotype map among closely related taxa. Here, we investigate the evolution of wing pattern diversity in Heliconius, a clade of neotropical butterflies that have undergone an adaptive radiation for wing-pattern mimicry and are influenced by distinct selection regimes. Using crosses between natural wing-pattern variants, we used genome-wide restriction site-associated DNA (RAD) genotyping, traditional linkage mapping and multivariate image analysis to study the evolution of the architecture of adaptive variation in two closely related species: Heliconius hecale and H. ismenius. We implemented a new morphometric procedure for the analysis of whole-wing pattern variation, which allows visualising spatial heatmaps of genotype-to-phenotype association for each quantitative trait locus separately. We used the H. melpomene reference genome to fine-map variation for each major wing-patterning region uncovered, evaluated the role of candidate genes and compared genetic architectures across the genus. Our results show that, although the loci responding to mimicry selection are highly conserved between species, their effect size and phenotypic action vary throughout the clade. Multilocus architecture is ancestral and maintained across species under directional selection, whereas the single-locus (supergene) inheritance controlling polymorphism in H. numata appears to have evolved only once. Nevertheless, the conservatism in the wing-patterning toolkit found throughout the genus does not appear to constrain phenotypic evolution towards local adaptive optima. PMID- 25806543 TI - 'Satellite DNA transcripts have diverse biological roles in Drosophila'. PMID- 25806544 TI - Effects of dispersal plasticity on population divergence and speciation. AB - Phenotypic plasticity is thought to have a role in driving population establishment, local adaptation and speciation. However, dispersal plasticity has been underappreciated in this literature. Plasticity in the decision to disperse is taxonomically widespread and I provide examples for insects, molluscs, polychaetes, vertebrates and flowering plants. Theoretical work is limited but indicates an interaction between dispersal distance and plasticity in the decision to disperse. When dispersal is confined to adjacent patches, dispersal plasticity may enhance local adaptation over unconditional (non-plastic) dispersal. However, when dispersal distances are greater, plasticity in dispersal decisions strongly reduces the potential for local adaptation and population divergence. Upon dispersal, settlement may be random, biased but genetically determined, or biased but plastically determined. Theory shows that biased settlement of either type increases population divergence over random settlement. One model suggests that plasticity further enhances chances of speciation. However, there are many strategies for deciding on where to settle such as a best of-N strategy, sequential sampling with a threshold for acceptance or matching with natal habitat. To date, these strategies do not seem to have been compared within a single model. Although we are just beginning to explore evolutionary effects of dispersal plasticity, it clearly has the potential to enhance as well as inhibit population divergence. Additional work should pay particular attention to dispersal distance and the strategy used to decide on where to settle. PMID- 25806545 TI - Genetic architecture and genomic patterns of gene flow between hybridizing species of Picea. AB - Hybrid zones provide an opportunity to study the effects of selection and gene flow in natural settings. We employed nuclear microsatellites (single sequence repeat (SSR)) and candidate gene single-nucleotide polymorphism markers (SNPs) to characterize the genetic architecture and patterns of interspecific gene flow in the Picea glauca * P. engelmannii hybrid zone across a broad latitudinal (40-60 degrees) and elevational (350-3500 m) range in western North America. Our results revealed a wide and complex hybrid zone with broad ancestry levels and low interspecific heterozygosity, shaped by asymmetric advanced-generation introgression, and low reproductive barriers between parental species. The clinal variation based on geographic variables, lack of concordance in clines among loci and the width of the hybrid zone points towards the maintenance of species integrity through environmental selection. Congruency between geographic and genomic clines suggests that loci with narrow clines are under strong selection, favoring either one parental species (directional selection) or their hybrids (overdominance) as a result of strong associations with climatic variables such as precipitation as snow and mean annual temperature. Cline movement due to past demographic events (evidenced by allelic richness and heterozygosity shifts from the average cline center) may explain the asymmetry in introgression and predominance of P. engelmannii found in this study. These results provide insights into the genetic architecture and fine-scale patterns of admixture, and identify loci that may be involved in reproductive barriers between the species. PMID- 25806547 TI - Iso-petromyroxols: novel dihydroxylated tetrahydrofuran enantiomers from sea lamprey (Petromyzon marinus). AB - An enantiomeric pair of new fatty acid-derived hydroxylated tetrahydrofurans, here named iso-petromyroxols, were isolated from sea lamprey larvae-conditioned water. The relative configuration of iso-petromyroxol was elucidated with 1D and 2D NMR spectroscopic analyses. The ratio of enantiomers (er) in the natural sample was measured by chiral-HPLC-MS/MS to be ca. 3:1 of (-)- to (+)-antipodes. PMID- 25806546 TI - Selective C-arylation of 2,5-dibromo-3-hexylthiophene via Suzuki cross coupling reaction and their pharmacological aspects. AB - The present study reports the synthesis of various new derivatives based on 5 aryl-2-bromo-3-hexylthiophene with moderate-to-good yields via a palladium catalyzed Suzuki cross-coupling reaction. This coupling method involved the reaction of 2,5-dibromo-3-hexylthiophene with several arylboronic acids in order to synthesize corresponding thiophene derivatives under controlled and optimal reaction conditions. The different substituents (CH3, OCH3, Cl, F etc.) present on arylboronic acids are found to have significant electronic effects on the overall properties of new products. The synthesized thiophene molecules were studied for their haemolytic, biofilm inhibition and anti-thrombolytic activities, and almost all products showed potentially good properties. The compound 2-bromo-5-(3-chloro-4-fluorophenyl)-3-hexylthiophenein particular exhibited the highest values for haemolytic and bio-film inhibition activities among all newly synthesized derivatives. In addition, the compound 2-bromo-3 hexyl-5-(4-iodophenyl)thiophene also showed high anti-thrombolytic activity, suggesting the potential medicinal applications of these newly synthesized compounds. PMID- 25806548 TI - Effect of pulsed electric fields on the flavour profile of red-fleshed sweet cherries (Prunus avium var. Stella). AB - The aim of this research was to study the effect of pulsed electric fields (PEF) on the flavour profile of red-fleshed sweet cherries (Prunus avium variety Stella). The cherry samples were treated at a constant pulse frequency of 100 Hz, a constant pulse width of 20 MUs, different electric field strengths between 0.3 and 2.5 kV/cm and specific energy ranging from 31 to 55 kJ/kg. Volatile compounds of samples were analysed using an automated headspace solid phase microextraction (HS-SPME) method coupled with gas chromatography-mass spectrometry (GC-MS). A total of 33 volatile compounds were identified with benzaldehyde, hexanal, (E)-2 hexenal, (Z)-2-hexen-1-ol, and benzyl alcohol being the predominant volatiles in different PEF-treated samples. Aldehydes namely butanal, octanal, 2-octenal, and nonanal, and (Z)-2-hexen-1-ol increased significantly 24 h after PEF treatment at electric field strengths of more than 1.0 kV/cm. Samples incubated for 24 h after PEF treatment (S3) generated higher concentrations of volatiles than samples immediately after PEF treatments (S2). Quantitative results revealed that more flavour volatiles were released and associated with S3 samples after 24 h storage and S2 samples immediately after PEF both with the highest electric field intensities. Interestingly, this study found that the PEF treatments at the applied electric field strength and energy did not result in releasing/producing undesirable flavour compounds. PMID- 25806549 TI - Bacillus toyonensis strain AEMREG6, a bacterium isolated from South African marine environment sediment samples produces a glycoprotein bioflocculant. AB - A bioflocculant-producing bacteria, isolated from sediment samples of a marine environment in the Eastern Cape Province of South Africa demonstrated a flocculating activity above 60% for kaolin clay suspension. Analysis of the 16S ribosomal deoxyribonucleic acid (rDNA) nucleotide sequence of the isolate in the GenBank database showed 99% similarity to Bacillus toyonensis strain BCT-7112 and it was deposited in the GenBank as Bacillus toyonensis strain AEMREG6 with accession number KP406731. The bacteria produced a bioflocculant (REG-6) optimally in the presence of glucose and NH4NO3 as the sole carbon and nitrogen source, respectively, initial medium pH of 5 and Ca2+ as the cation of choice. Chemical analysis showed that purified REG-6 was a glycoprotein mainly composed of polysaccharide (77.8%) and protein (11.5%). It was thermally stable and had strong flocculating activity against kaolin suspension over a wide range of pH values (3-11) with a relatively low dosage requirement of 0.1 mg/mL in the presence of Mn2+. Fourier transform infrared spectroscopy (FTIR) revealed the presence of hydroxyl, carboxyl and amide groups preferred for flocculation. Scanning electron microscopy (SEM) revealed that bridging was the main flocculation mechanism of REG-6. The outstanding flocculating performance of REG 6 holds great potential to replace the hazardous chemical flocculants currently used in water treatment. PMID- 25806550 TI - Omics-based depression and inflammation research. PMID- 25806551 TI - Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. AB - OBJECTIVES: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. METHODS: Open-label trial conducted in an inpatient psychiatric unit. RESULTS: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. CONCLUSIONS: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder. PMID- 25806552 TI - Depression rather than liver impairment reduces quality of life in patients with hepatitis C. AB - OBJECTIVE: Patients with chronic hepatitis C (CHC) have a poorer quality of life than those with other chronic liver diseases. However, some of the factors that determine health-related quality of life (HRQOL) in these patients, such as the degree of liver fibrosis, are still controversial. Therefore, the aim of the present study was to investigate the impact of CHC on HRQOL by conducting clinical, psychiatric, and sociodemographic evaluations. METHODS: One hundred and twenty-four consecutive patients attending a referral center for hepatitis were evaluated using the Mini-International Neuropsychiatry Interview, the Hamilton Depression Rating Scale, the Hospital Anxiety and Depression Scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey. Multiple linear regression analyses were used to quantify independent associations between HRQOL and the clinical, psychiatric, and sociodemographic variables of interest. RESULTS: Reduced HRQOL was independently associated with major depressive disorder (MDD) and with elevated levels of alanine aminotransferase, but was not associated with hepatic cirrhosis. CONCLUSIONS: MDD rather than the grade of liver fibrosis was strongly associated with HRQOL impairment in patients with CHC. These findings highlight that, in patients with CHC, the psychological effects of the disease deserve more attention and the implementation of integrated medical, psychiatric, and psychological care may be helpful. PMID- 25806554 TI - Structural and functional neuroimaging findings associated with the use of clozapine in schizophrenia: a systematic review. AB - OBJECTIVE: Schizophrenia is one of the most severe psychiatric disorders, and its current treatment relies on antipsychotic medications with only partial effectiveness. Clozapine is an atypical antipsychotic with a specific profile of action indicated for treatment-resistant schizophrenia. Neuroimaging studies assessing the effects of clozapine could help shed light on the neural underpinnings of the effects of this drug in the brain. The objective of this study was to review the available literature on the structural and functional neuroimaging findings associated with use of clozapine. METHOD: We conducted a systematic review of the indexed literature using the PubMed, BIREME, and ISI Web of Knowledge search engines and the following keywords: clozapine, neuroimaging, computed tomography, MRI, functional magnetic resonance, PET, SPECT, and DTI. RESULTS: A total of 23 articles were included in the review. In structural studies, the use of clozapine was associated with volume reductions in the basal ganglia, especially the caudate nucleus, where functional neuroimaging studies also found decreased perfusion. In the frontal lobe, clozapine treatment was associated with increased gray matter volume and reduced perfusion. CONCLUSION: The results of the studies reviewed suggest that the use of clozapine is associated with distinctive structural and functional neuroimaging findings that are not shared with other antipsychotics. PMID- 25806555 TI - Injection of crack cocaine: a case report. PMID- 25806553 TI - The Brazilian policy of withholding treatment for ADHD is probably increasing health and social costs. AB - OBJECTIVE: To estimate the economic consequences of the current Brazilian government policy for attention-deficit/hyperactivity disorder (ADHD) treatment and how much the country would save if treatment with immediate-release methylphenidate (MPH-IR), as suggested by the World Health Organization (WHO), was offered to patients with ADHD. METHOD: Based on conservative previous analyses, we assumed that 257,662 patients aged 5 to 19 years are not receiving ADHD treatment in Brazil. We estimated the direct costs and savings of treating and not treating ADHD on the basis of the following data: a) spending on ADHD patients directly attributable to grade retention and emergency department visits; and b) savings due to impact of ADHD treatment on these outcomes. RESULTS: Considering outcomes for which data on the impact of MPH-IR treatment are available, Brazil is probably wasting approximately R$ 1.841 billion/year on the direct consequences of not treating ADHD in this age range alone. On the other hand, treating ADHD in accordance with WHO recommendations would save approximately R$ 1.163 billion/year. CONCLUSIONS: By increasing investments on MPH-IR treatment for ADHD to around R$ 377 million/year, the country would save approximately 3.1 times more than is currently spent on the consequences of not treating ADHD in patients aged 5 to 19 years. PMID- 25806556 TI - Subarachnoid hemorrhage misdiagnosed as adjustment disorder. PMID- 25806557 TI - Marchiafava-Bignami disease as a cause of visual hallucinations. PMID- 25806558 TI - Spirituality or religiosity: is there any difference? PMID- 25806559 TI - Edgar Allan Poe's psychic daguerreotype. PMID- 25806560 TI - Corrigendum. PMID- 25806561 TI - Corrigendum. PMID- 25806562 TI - Prophylactic milrinone for the prevention of low cardiac output syndrome and mortality in children undergoing surgery for congenital heart disease. AB - BACKGROUND: Children with congenital heart disease often undergo heart surgery at a young age. They are at risk for postoperative low cardiac output syndrome (LCOS) or death. Milrinone may be used to provide inotropic and vasodilatory support during the immediate postoperative period. OBJECTIVES: This review examines the effectiveness of prophylactic postoperative use of milrinone to prevent LCOS or death in children having undergone surgery for congenital heart disease. SEARCH METHODS: Electronic and manual literature searches were performed to identify randomised controlled trials. We searched CENTRAL, MEDLINE, EMBASE and Web of Science in February 2014 and conducted a top-up search in September 2014 as well as clinical trial registries and reference lists of published studies. We did not apply any language restrictions. SELECTION CRITERIA: Only randomised controlled trials were selected for analysis. We considered studies with newborn infants, infants, toddlers, and children up to 12 years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data according to a pre-defined protocol. We obtained additional information from all study authors. MAIN RESULTS: Three of the five included studies compared milrinone versus levosimendan, one study compared milrinone with placebo, and one compared milrinone verus dobutamine, with 101, 242, and 50 participants, respectively. Three trials were at low risk of bias while two were at higher risk of bias. The number and definitions of outcomes were non-uniform as well. In one study comparing two doses of milrinone and placebo, there was some evidence in an overall comparison of milrinone versus placebo that milrinone lowered risk for LCOS (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.28 to 0.96; 227 participants). The results from two small studies do not provide enough information to determine whether milrinone increases the risk of LCOS when compared to levosimendan (RR 1.22, 95% CI 0.32 to 4.65; 59 participants). Mortality rates in the studies were low, and there was insufficient evidence to draw conclusions on the effect of milrinone compared to placebo or levosimendan or dobutamine regarding mortality, the duration of intensive care stay, hospital stay, mechanical ventilation, or maximum inotrope score (where available). Numbers of patients requiring mechanical cardiac support were also low and did not allow a comparison between studies, and none of the participants of any study received a heart transplantation up to the end of the respective follow-up period. Time to death within three months was not reported in any of the included studies. A number of adverse events was examined, but differences between the treatment groups could not be proven for hypotension, intraventricular haemorrhage, hypokalaemia, bronchospasm, elevated serum levels of liver enzymes, or a reduced left ventricular ejection fraction < 50% or reduced left ventricular fraction of shortening < 28%. Our analysis did not prove an increased risk of arrhythmias in patients treated prophylactically with milrinone compared with placebo (RR 3.59, 95% CI 0.83 to 15.42; 238 participants), a decreased risk of pleural effusions (RR 1.78, 95% CI 0.92 to 3.42; 231 participants), or a difference in risk of thrombocytopenia on milrinone compared with placebo (RR 0.86, 95% CI 0.39 to 1.88; 238 participants). Comparisons of milrinone with levosimendan or with dobutamine, respectively, did not clarify the risk of arrhythmia and were not possible for pleural effusions or thrombocytopenia. AUTHORS' CONCLUSIONS: There is insufficient evidence of the effectiveness of prophylactic milrinone in preventing death or low cardiac output syndrome in children undergoing surgery for congenital heart disease, compared to placebo. So far, no differences have been shown between milrinone and other inodilators, such as levosimendan or dobutamine, in the immediate postoperative period, in reducing the risk of LCOS or death. The existing data on the prophylactic use of milrinone has to be viewed cautiously due to the small number of small trials and their risk of bias. PMID- 25806563 TI - Cost savings associated with expanded hospice use in Medicare. PMID- 25806566 TI - Small Convenience Stores and the Local Food Environment: An Analysis of Resident Shopping Behavior Using Multilevel Modeling. AB - PURPOSE: Local food environments can influence the diet and health of individuals through food availability, proximity to retail stores, pricing, and promotion. This study focused on how small convenience stores, known in New York City as bodegas, influence resident shopping behavior and the food environment. DESIGN: Using a cross-sectional design, 171 bodegas and 2118 shoppers were sampled. SETTING: Small convenience stores in New York City. SUBJECTS: Any bodega shopper aged 18+ who purchased food or beverage from a participating store. MEASURES: Data collection consisted of a store assessment, a health and behavior survey given to exiting customers, and a bag check that recorded product information for all customer purchases. ANALYSIS: Descriptive statistics were generated for bodega store characteristics, shopper demographics, and purchase behavior. Multilevel models were used to assess the influence of product availability, placement, and advertising on consumer purchases of sugar-sweetened beverages (SSBs), water, and fruits and vegetables. RESULTS: Seventy-one percent of participants reported shopping at bodegas five or more times per week, and 35% reported purchasing all or most of their monthly food allotment at bodegas. Model results indicated that lower amounts of available fresh produce were significantly and independently associated with a higher likelihood of SSB purchases. A second, stratified multilevel model showed that the likelihood of purchasing an SSB increased with decreasing varieties of produce when produce was located at the front of the store. No significant effects were found for water placement and beverage advertising. CONCLUSIONS: Small convenience stores in New York City are an easily accessible source of foods and beverages. Bodegas may be suitable for interventions designed to improve food choice and diet. PMID- 25806564 TI - Flow-cytometric visualization of C>U mRNA editing reveals the dynamics of the process in live cells. AB - APOBEC1 is the catalytic subunit of the complex that edits ApolipoproteinB (ApoB) mRNA, which specifically deaminates cytidine 6666 to uracil in the human transcript. The editing leads to the generation of a stop codon, resulting in the synthesis of a truncated form of ApoB. We have developed a method to quantitatively assay ApoB RNA editing in live cells by using a double fluorescent mCherry-EGFP chimera containing a ~ 300 bp fragment encompassing the region of ApoB subject to RNA editing. Coexpression of APOBEC1 together with this chimera causes specific RNA editing of the ApoB fragment. The insertion of a stop codon between the mCherry and EGFP thus induces the loss of EGFP fluorescence. Using this method we analyze the dynamics of APOBEC1-dependent RNA editing under various conditions. Namely we show the interplay of APOBEC1 with known interactors (ACF, hnRNP-C1, GRY-RBP) in cells that are RNA editing-proficient (HuH-7) or -deficient (HEK-293T), and the effects of restricted cellular localization of APOBEC1 on the efficiency of the editing. Furthermore, our approach is effective in assaying the induction of RNA editing in Caco-2, a cellular model physiologically capable of ApoB RNA editing. PMID- 25806565 TI - Usage and Understanding of Serving Size Information on Food Labels in the United States. AB - PURPOSE: To investigate consumer understanding and usage of serving size (SS) information on Nutrition Facts (NF) labels. DESIGN: We analyzed three data sources: (1) U.S. Food and Drug Administration (FDA) Health and Diet Survey (HDS) 1994 (n = 1945), 1995 (n = 1001), and 2008 (n = 2584); (2) National Health and Nutrition Examination Survey (NHANES) 2005-2006 and 2007-2008 (n = 10,750); and (3) 2011 FDA Nutrition Facts Label Experimental Study (NFLES) (n = 9493). Data from FDA are cross-sectional and we focused on usage and meaning of SS. SETTING: United States. SUBJECTS: Adults (18+ years). MEASURES: Both HDS and NHANES addressed how often participants used SS information and HDS also asked how SS is determined. Both NHANES and NFLES contained similar questions on the meaning of SS but NFLES also included an open-ended response option. ANALYSIS: We included both quantitative and qualitative measures. Questions were analyzed by demographic variables and body mass index with frequencies, cross-tabulations, and chi(2) statistics reported. RESULTS: HDS showed that the percentage of consumers who used SS information often or sometimes increased from 54% in 1994 to 64% in 2008. NHANES and NFLES data indicated that a majority of respondents had misinterpreted the meaning of SS. Women and obese individuals were more likely to use SS often or sometimes, but were also more likely to misinterpret the meaning of SS. A small subsample of NFLES participants expressed a distrust of the SS information. CONCLUSION: There is a widespread misunderstanding about SS, suggesting the need for clearer NF labels or enhanced education efforts. PMID- 25806567 TI - Motivation for HPV Vaccination Among Young Adult Men: Validation of TTM Decisional Balance and Self-Efficacy Constructs. AB - PURPOSE: In the United States, 36% of human papillomavirus (HPV)-related cancers occur among men. HPV vaccination can substantially reduce the risk of HPV infection; however, the vast majority of men are unvaccinated. This study developed and validated transtheoretical model-based measures for HPV vaccination in young adult men. DESIGN: Cross-sectional measurement development. SETTING: Online survey of young adult men. SUBJECTS: Three hundred twenty-nine mostly college-attending men, ages 18 to 26. MEASURES: Stage of change, decisional balance (pros/cons), and self-efficacy. ANALYSIS: The sample was randomly split into halves for exploratory principal components analysis (PCA), followed by confirmatory factor analyses (CFA) to test measurement models. Multivariate analyses examined relationships between scales. RESULTS: For decisional balance, PCA revealed two uncorrelated five-item factors (pros alpha = .78; cons alpha = .83). For the self-efficacy scale, PCA revealed a single-factor solution (alpha = .83). CFA confirmed that the two-factor uncorrelated model for decisional balance and a single-factor model for self-efficacy. Follow-up analyses of variance supported the theoretically predicted relationships between stage of change, pros, and self-efficacy. CONCLUSION: This study resulted in reliable and valid measures of pros and self-efficacy for HPV vaccination that can be used in future clinical research. PMID- 25806568 TI - Associations Between Physical Activity and Metabolic Syndrome: Comparison Between Self-Report and Accelerometry. AB - PURPOSE: To assess the relationship between self-reported and objectively measured physical activity (PA) and metabolic syndrome and its risk factors in U.S. adults. DESIGN: A cross-sectional design was used for this study. SETTING: The study was set among a nationally representative sample of U.S. adults. SUBJECTS: Adults, ages 20 years and older, from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 (n = 5580) participated in the study. MEASURES: PA measures included minutes per week of moderate plus vigorous PA estimated by self-report (MVPAsr), total 7-day accelerometry (MVPAa), and accelerometer-based MVPA performed in 10-minute bouts (MVPAb). Risk factors for metabolic syndrome included blood pressure, high-density lipoprotein cholesterol, triglycerides, glucose, and waist circumference. ANALYSIS: Odds ratios (ORs) for having metabolic syndrome were calculated for men and women who met the Physical Activity Guidelines for Americans compared to those who did not. RESULTS: Women who did not meet the PA guidelines had significantly greater odds of having metabolic syndrome according to MVPAsr (OR = 2.20; 95% confidence interval [CI] = 1.65-2.94), MVPAa (OR = 4.40; 95% CI = 2.65-7.31), and MVPAb (OR = 2.91; 95% CI = 1.42-5.96). Men had significantly higher odds of having metabolic syndrome according to MVPAa (OR = 2.57; 95% CI = 1.91-3.45) and MVPAb (OR = 2.83; 95% CI = 1.55-5.17), but not MVPAsr. These ORs remained significant after adjusting for all potential confounders except body mass index, after which only MVPAsr in women and MVPAb in men remained significant. CONCLUSION: Individuals who do not meet the PA guidelines exhibited greater odds of having metabolic syndrome. This relationship tended to be stronger for objective PA measures than for self report. PMID- 25806571 TI - Understanding small business engagement in workplace violence prevention programs. AB - PURPOSE: Worksite wellness, safety, and violence prevention programs have low penetration among small, independent businesses. This study examined barriers and strategies influencing small business participation in workplace violence prevention programs (WVPPs). APPROACH: A semistructured interview guide was used in 32 telephone interviews. SETTING: The study took place at the University of North Carolina Injury Prevention Research Center. PARTICIPANTS: Participating were a purposive sample of 32 representatives of small business-serving organizations (e.g., business membership organizations, regulatory agencies, and economic development organizations) selected for their experience with small businesses. INTERVENTION: This study was designed to inform improved dissemination of Crime Free Business (CFB), a WVPP for small, independent retail businesses. METHODS: Thematic qualitative data analysis was used to identify key barriers and strategies for promoting programs and services to small businesses. RESULTS: Three key factors that influence small business engagement emerged from the analysis: (1) small businesses' limited time and resources, (2) low salience of workplace violence, (3) influence of informal networks and source credibility. Identified strategies include designing low-cost and convenient programs, crafting effective messages, partnering with influential organizations and individuals, and conducting outreach through informal networks. CONCLUSION: Workplace violence prevention and public health practitioners may increase small business participation in programs by reducing time and resource demands, addressing small business concerns, enlisting support from influential individuals and groups, and emphasizing business benefits of participating in the program. PMID- 25806572 TI - Microshear Bond Strength of Adhesives to Enamel Remineralized Using Casein Phosphopeptide Agents. AB - OBJECTIVE: This study was carried out to evaluate the difference between bonding to demineralized enamel and remineralized enamel using casein phosphopeptide amorphous calcium phosphate with fluoride (CPP-ACFP) or without fluoride (CPP ACP) compared to normal enamel. Another aim was to test if the newly introduced Single Bond Universal adhesive system would show better bonding to any enamel condition in comparison to the other tested adhesive systems. METHODS: The lingual enamel surfaces of 40 non carious human third molars were divided into four main groups according to the enamel condition (ground normal enamel [negative control]; demineralized enamel [positive control]; and remineralized enamel with CPP-ACP or with CPP-ACFP, respectively). Within each main group, the lingual enamel surface of each tooth was sectioned into three slabs, resulting in 30 slabs that were distributed into three subgroups according to the adhesive system utilized (Clearfil S(3) Bond Plus, Single Bond Universal, or G-aenial Bond). Two resin composite microcylinder buildups were made on each enamel slab using Filtek Z350 XT. The MUSBS was evaluated at a crosshead speed of 0.5 mm/min. Modes of failure were detected using an environmental scanning electron microscope at 300* magnification. RESULTS: The two-way analysis of variance with repeated measures revealed a significant effect for the enamel condition. However, there was no significant effect for the type of adhesive system. The interaction between the enamel condition and the type of adhesive system was also not significant. Modes of failure were mainly adhesive except for the demineralized enamel. It showed a mixed type of failure, in which cohesive failure in enamel was recorded. CONCLUSIONS: All single-step self-etch adhesives revealed comparable MUSBS values to ground enamel and enamel remineralized with CPP-ACP or CPP-ACFP. Bonding to demineralized enamel was ineffective. With any enamel condition, no tested single-step self-etch adhesive was superior in its bonding. PMID- 25806573 TI - Polarity in the early floral meristem of Arabidopsis. AB - The diversity of angiosperm flowers depends on organ meristy and position. However, the signaling pathways that establish polarity and positional information remain largely unelucidated. Use of the founder-cell marker DORNROSCHEN-LIKE (DRNL) in Arabidopsis has recently highlighted the importance of the abaxial-adaxial axis for early floral development. We have extended the use of DRNL::GFP to further characterize floral organogenesis in genotypes that are altered in floral organ meristy or position, including ettin (ett-3) and blade-on petiole (bop)1-11 bop2-4 double mutants. The creation of supernumery sepals by the splitting of sepal founder-cell populations along an ab-/adaxial axis strengthens the importance of the ab-/adaxial developmental axis in early floral meristem development. Furthermore, we confirm the dependency of the wildtype sequence of sepal initiation on bract suppression and demonstrate that supernumery stamens derive from the imprecise resolution of a ring of DRNL expression. Expression of DRNL in apetala1 (ap1-1) and ap2-8 mutants reflect the altered whorl structure and show that these homeotic genes function upstream of DRNL. Analyzing the dynamism of early floral meristem ontogeny at a fine temporal and spatial resolution in Arabidopsis can reveal mechanisms of organogenesis and is applicable to other species with differing floral body plans in a comparative evolutionary context. PMID- 25806574 TI - 'Not Until I'm Absolutely Half-Dead and Have To:' Accounting for Non-Use of Antiretroviral Therapy in Semi-Structured Interviews with People Living with HIV in Australia. AB - Current debates regarding the use of antiretroviral therapy (ART) to promote both individual- and population-level health benefits underscore the importance of understanding why a subpopulation of people with diagnosed HIV and access to treatment choose not to use it. Semi-structured interviews were conducted between 2012 and 2014 with 27 people living with HIV in Australia who were not using ART at the time of interview. Analytic triangulation permitted an appreciation of not only the varied personal reasons for non-use of treatment, but also underlying views on HIV treatment, and the ideal conditions imagined necessary for treatment initiation. Policy goals to increase the number of people with HIV using ART must recognize the diverse explanations for non-use of ART, which include concerns about the various impacts of committing to lifelong pharmaceutical treatment use. Our research identified distinctive subgroups among people who are not using antiretroviral therapy, with a range of individual and social needs that may affect treatment decisions. These findings challenge assumptions about treatment non-use in resource-rich settings, revealing persistent consumer fears about the potent and unknown effects of HIV medications that deserve greater recognition in policy debate on treatment uptake. PMID- 25806575 TI - Megakaryocytic emperipolesis and platelet function abnormalities in five patients with gray platelet syndrome. AB - The gray platelet syndrome (GPS) is a rare congenital platelet disorder characterized by mild to moderate bleeding diathesis, macrothrombocytopenia and lack of azurophilic alpha-granules in platelets. Some platelet and megakaryocyte (MK) abnormalities have been described, but confirmative studies of the defects in larger patient cohorts have not been undertaken. We studied platelet function and bone marrow (BM) features in five GPS patients with NBEAL2 autosomal recessive mutations from four unrelated families. In 3/3 patients, we observed a defect in platelet responses to protease-activated receptor (PAR)1-activating peptide as the most consistent finding, either isolated or combined to defective responses to other agonists. A reduction of PAR1 receptors with normal expression of major glycoproteins on the platelet surface was also found. Thrombin-induced fibrinogen binding to platelets was severely impaired in 2/2 patients. In 4/4 patients, the BM biopsy showed fibrosis (grade 2-3) and extensive emperipolesis, with many (36-65%) MKs containing 2-4 leukocytes engulfed within the cytoplasm. Reduced immunolabeling for platelet factor 4 together with normal immunolabeling for CD63 in MKs of two patients demonstrated that GPS MKs display an alpha granule-specific defect. Increased immunolabeling for P-selectin and decreased immunolabeling for PAR1, PAR4 and c-MPL were also observed in MKs of two patients. Marked emperipolesis, specific defect of MK alpha-granule content and defect of PAR1-mediated platelet responses are present in all GPS patients that we could study in detail. These results help to further characterize the disease. PMID- 25806577 TI - Complete mitogenome of the semi-aquatic grasshopper Oxya intricate (Stal.) (Insecta: Orthoptera: Catantopidae). AB - The complete mitogenome of Oxya intricate (Stal.) has been reconstructed from whole-genome Illumina sequencing data with an average coverage of 294*. The circular genome is 15,466 bp in length, and consists of 22 transfer RNAs (tRNAs), 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs) and 1 D-loop region. All PCGs are initiated with ATN codons, and are terminated with TAR codons except for ND5 with the incomplete stop codon T. The nucleotide composition is asymmetric (42.5%A, 14.6%C, 10.6%G, 32.3%T) with an overall GC content of 25.2%. These data would contribute to the design of novel molecular markers for population and evolutionary studies of this and related orthopteran species. PMID- 25806576 TI - The polymorphisms of tumor necrosis factor-induced protein 3 gene may contribute to the susceptibility of chronic primary immune thrombocytopenia in Chinese population. AB - Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by decrease of the platelet count and increased risk of mucocutaneous bleeding. Multiple factors have been demonstrated in ITP pathogenesis, including the genetic variants. Tumor necrosis factor-induced protein 3 (TNFAIP3) gene encodes the ubiquitin-modifying enzyme A20 which limits inflammation by terminating NF-kappaB activation through several signaling pathways including TNF and Toll-like receptors and regulates immunostimulatory effects of dendritic cells and attenuates antigen presentation. Single nucleotide polymorphisms (SNPs) of TNFAIP3 have been associated with susceptibilities to several autoimmune diseases. Therefore, we speculated that TNFAIP3 polymorphisms might be associated with the susceptibility of chronic ITP in Chinese population. We investigated the distribution of TNFAIP3 (rs2230926 and rs5029939) polymorphisms in 222 patients with chronic ITP and 153 controls by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. We observed significant difference in the allelic and genotypic distributions of rs2230926 and rs5029939 between the ITP and control groups (p < 0.05). Stratified analysis by gender revealed the association of rs2230926 polymorphism with chronic ITP in male groups. However, none of the two polymorphisms contributed to the onset age of chronic ITP. These data suggest an association of TNFAIP3 SNPs with susceptibility to chronic ITP. Together with previous reports, our finding provides further evidence for TNFAIP3 being a general autoimmunity gene. PMID- 25806579 TI - The complete mitochondrial genome of Gobiobotia filifer (Teleostei, Cypriniformes: Cyprinidae). AB - The Gobiobotia filifer is a small economic fish which distributes in the upstream of Yangtze River and its distributaries. For the environmental pollution and overfishing, its population declined drastically in recent decades, so it is essential to protect its resource. In this study, the complete mitochondrial genome sequence of G. filifer was determined with PCR technology, which contains 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a non-coding control region with the total length of 16,613 bp. The order and composition of genes were similar to most of the other teleost fish. Most of the genes were encoded on heavy strand, except for ND6 genes and eight tRNAs. Just like most other vertebrates, the bias of G and C has been found in different genes/regions. The complete mitochondrial genome sequence of G. filifer would contribute to better understand evolution of this lineage, population genetics, and will help administrative department to make rules and laws to protect this lineage. PMID- 25806578 TI - Sequencing and analysis of the complete mitochondrial genome of Elaphe davidi (Squamata: Colubridae). AB - The mitochondrial genome sequence of Elaphe davidi is analyzed and presented for the first time in this work. The genome was 17,117 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 2 control region. The overall base composition is A (35.4%), C (25.2%), T (27.0%), and G (12.4%). The base compositions present clearly the A-T skew, which was most obviously in the control region and protein-coding genes. Mitochondrial genomes analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the 12 Colubridae species. Two major phyletic lineages were present in Colubridae. A clade included the six species (Dinodon semicarinatus, E. poryphyracea, Oocatochus rufodorsatus, Orthriophis taeniurus, E. bimaculata and E. davidi) of subfamily Colubrinae except for Oligodon ningshaanensis. Another clade (Hypsiglena chlorophaea, H. unaocularus, H. torquata and Imantodes cenchoa) included Thermophis zhaoermii and O. ningshaanensis as the sister taxon to Colubrinae. The genus Elaphe, Dinodon, Oocatochus and Orthriophis formed a monophyletic group with the high bootstrap value (100 %) in all examinations. PMID- 25806580 TI - The complete mitochondrial genome of Diploprion bifasciatum (Perciformes, Serranidae). AB - The complete mitochondrial genome (mitogenome) of Diploprion bifasciatum was first determined. The mitogenome was 16,805 bp in length and contained 13 protein coding genes, 24 tRNAs, 2 rRNA, and 2 non-coding regions. The overall base composition of the mitogenome was estimated to be T 25.72%, G 17.10%, A 28.24%, and C 28.94%, with a slight A + T bias of 53.96%, indicating an obvious anti-G bias commonly observed invertebrates. It shared 78.9%, 78.7%, 76.8%, and 72.5% identities with that of Grammistes sexlineatus, Epinephelus moara, Plectropomus areolatus, and Hypoplectrus gemma, respectively. PMID- 25806581 TI - Sequencing and analysis of the complete mitochondrial genome of Gloydius saxatilis (Squamata: Viperidae: Crotalinae). AB - The mitochondrial genome sequence of Gloydius saxatilis is analyzed and presented for the public for the first time. The genome was 17,218 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 2 control regions. The overall base composition was A (32.3%), C (28.9%), T (25.8%), and G (13.0%). The base compositions presented clearly the A-C skew, which was most obviously in the protein-coding genes. The extended termination associated sequence domain, the central conserved domain and the conserved sequence block domain are defined in the mitochondrial genome control region of G. saxatilis. Mitochondrial genomes analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees, indicating a close phylogenetic affinity of the thirteen Crotalinae species. It appeared that no less than two major phyletic lineages were present in Crotalinae. The main clades within the Crotalinae supported are: A clade including the Protobothrops. A clade (G. brevicaudus, G. ussuriensis, G. intermedius, G. saxatilis) with the Ovophis as the sister taxon to Protobothrops and was supported by bootstrap values of 88%. The four Gloydius species formed a paraphyletic group with the high bootstrap value (100%) in all examinations. PMID- 25806582 TI - The complete mitochondrial genome of the common lizard Zootoca vivipara (Squamata: Lacertidae). AB - The mitochondrial genome of Zootoca vivipara (Squamata: Lacertidae) is a circular molecule of 17,046 bp in size and consists of 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs and a control region. The A + T content of the overall base composition of H-strand is 63.43% (T: 30.95%, C: 24.03%, A: 32.48%, G: 12.54%). Protein-coding genes begin with ATG as start codon except COII with GTG. ND1, ATP8, ATP6, ND4L, ND5 and Cyt b genes are terminated with TAA as stop codon, ND2 ends with TAG, COI and ND6 end with AGG, and the other four protein coding genes end with an incomplete stop codon (a single stop nucleotide T). PMID- 25806583 TI - Phylogenetic relationships among four new complete mitogenome sequences of Pelophylax (Amphibia: Anura) from the Balkans and Cyprus. AB - We present the full-length mitogenome sequences of four European water frog species: Pelophylax cypriensis, P. epeiroticus, P. kurtmuelleri and P. shqipericus. The mtDNA size varied from 17,363 to 17,895 bp, and its organization with the LPTF tRNA gene cluster preceding the 12 S rRNA gene displayed the typical Neobatrachian arrangement. Maximum likelihood and Bayesian inference revealed a well-resolved mtDNA phylogeny of seven European Pelophylax species. The uncorrected p-distance for among Pelophylax mitogenomes was 9.6 (range 0.01 0.13). Most divergent was the P. shqipericus mitogenome, clustering with the "P. lessonae" group, in contrast to the other three new Pelophylax mitogenomes related to the "P. bedriagae/ridibundus" lineage. The new mitogenomes resolve ambiguities of the phylogenetic placement of P. cretensis and P. epeiroticus. PMID- 25806584 TI - Reply letter regarding terminology in 'Maternal Immunization: Clinical experiences, challenges and opportunities in vaccine acceptance'. PMID- 25806585 TI - Improvement of the agronomic traits of a wheat-barley centric fusion by introgressing the 3HS.3BL translocation into a modern wheat cultivar. AB - The 3HS.3BL spontaneous Robertsonian translocation obtained from the progenies of wheat-barley (Chinese Spring * Betzes) hybrids backcrossed with wheat line Mv9kr1 was transferred into the modern Martonvasar wheat cultivar Mv Bodri. The translocation was identified with molecular cytogenetic methods. The inheritance of the translocation was traced using genomic in situ hybridization. Fluorescence in situ hybridization using barley subtelomeric (HvT01) and centromere-specific [(AGGGAG)4] repetitive DNA probes confirmed that the complete barley chromosome arm was involved in the Robertsonian translocation. The wheat-specific repetitive DNA probes identified the presence of the whole wheat genome, except the short arm of the 3B chromosome. Genotypes homozygous for the centric fusion were selected, after which morphological analysis was performed on the plants and the yield components were measured in the field during two consecutive vegetative seasons. The introgression of the 3HS.3BL translocation into the modern wheat cultivar Mv Bodri significantly reduced the plant height due to the incorporation of the dwarfing allele RhtD1b. The presence of the 3HS.3BL translocation in the Mv9kr1 and Mv Bodri wheat background improved tillering and seeds per plant productivity in field experiments carried out in Martonvasar and Keszthely, Hungary. PMID- 25806586 TI - Influences of Patellofemoral Pain and Fatigue in Female Dancers during Ballet Jump-Landing. AB - This study investigated the influence of patellofemoral pain (PFP) and fatigue on lower-extremity joint biomechanics in female dancers during consecutive simple ground echappe. 3-dimensional joint mechanics were analyzed from the no-fatigue to fatigue conditions. 2-way mixed ANOVAs were used to compare the differences of the kinematic and kinetic variables between groups and conditions. Group main effects were seen in increased jump height (p=0.03), peak vertical ground reaction force (p=0.01), knee joint power absorption (p=0.04), and patellofemoral joint stress (PFJS, p=0.04) for PFP group. Fatigue main effects were found for decreased jump height (p<0.01), decreased ankle plantarflexion at initial foot ground contact (p=0.01), and decreased ankle displacement (p<0.01). Hip external rotation impulse and hip joint stiffness increased (both p<0.01) while knee extension and external rotation moment, and ankle joint power absorption decreased (p<0.01, p=0.02, p<0.01, respectively) after fatigue. The peak PFJS also decreased after fatigue (p<0.01). Female ballet dancers with PFP sustained great ground impact and loads on the knee probably due to higher jump height compared to the controls. All dancers presented diminished knee joint loading for the protective mechanism and endurance of ankle joint musculature required for the dissipation of loads and displayed a distal-to-proximal dissipation strategy after fatigue. PMID- 25806587 TI - The Impact of Partial Vascular Occlusion on Oxidative Stress Markers during Resistance Exercise. AB - This study sought to examine the effects of partial vascular occlusion (PVO) on oxidative stress markers in response to resistance exercise and at rest in young resistance-trained males. 12 resistance-trained males performed 6 conditions in random counterbalanced order: rest (R), low-intensity (LIRE: 30% 1RM) and moderate-intensity (MIRE: 70% 1RM) resistance exercise with or without PVO. Blood samples were obtained before and immediately after each condition and plasma protein carbonyls (PC), glutathione ratio, oxygen radical absorbance capacity (ORAC), and xanthine oxidase (XO) were evaluated. The addition of PVO resulted in significantly greater plasma PC and glutathione ratio in the rest condition. During LIRE the addition of PVO significantly attenuated plasma PC. The MIRE condition, independent of PVO, resulted in significantly higher PC concentration and glutathione ratio compared to the rest and LIRE conditions. The addition of PVO during MIRE resulted in a significant increase in PC. Thus, this study revealed that PVO increased oxidative stress at rest and enhanced the oxidative stress response to MIRE, but when combined with LIRE oxidative stress was attenuated. These findings suggest that the utilization of PVO during LIRE may alter ROS-induced accumulation in the blood which may influence cellular signaling. PMID- 25806588 TI - Force-velocity Relationship of Muscles Performing Multi-joint Maximum Performance Tasks. AB - Manipulation of external loads typically provides a range of force, velocity, and power data that allows for modeling muscle mechanical characteristics. While a typical force-velocity relationship obtained from either in vitro muscles or isolated muscle groups can be described by a hyperbolic equation, the present review paper reveals the evidence that the same relationship obtained from maximum-performance multi-joint movements could be approximately linear. As a consequence, this pattern also results in a relatively simple shape of the power velocity relationship. The parameters of the linear force-velocity relationship reveal the maximum force, velocity and power. Recent studies conducted on various functional movement tasks reveal that these parameters could be reliable, on average moderately valid, and typically sensitive enough to detect differences among populations of different physical abilities. Therefore, the linear force velocity relationship together with the associated parabolic power-velocity relationship could provide both a new and simplified approach to studies of the design and function of human muscular system and its modeling. Regarding the practical applications, the reviewed findings also suggest that the loaded multi joint movements could be developed into relatively simple routine tests of the force-, velocity- and power-generating capacity of the neuromuscular system. PMID- 25806589 TI - Frequency and Duration Modulate Anticarcinogenic Effects of a Physical Training in the Colon. AB - Physical exercise has proven protective against colon carcinogenesis. We sought to clarify whether the frequency and duration of physical training were key factors for its anticarcinogenic effects on the colon. Either sedentary or physically trained male Wistar rats (n=82) were either exposed or not to the carcinogen dimethylhidrazine (DMH). The first protocol investigated whether swimming for 60 min in different frequencies modulates antipreneoplastic effects of physical training. Another protocol then explored whether the duration for training 5 times a week impacts on the development of colon preneoplastic lesions. After 8 weeks, serum and colon samples were collected and analyzed afterwards. Swimming once a week for 60 min did not promote those anticarcinogenic effects found in rats trained 5 times weekly. Such weekly sustained physical training not only decreased the development of colon preneoplastic, but also epithelial proliferation, and subepithelial cyclooxygenase 2 (COX-2) expression. Interestingly, a 5 time per week training for less than 60 min was not as protective against colon carcinogenesis as swimming for 90 min. This 90 min training indeed reduced serum cholesterol and triglycerides levels, as well as colonic lipid peroxidation in carcinogen-exposed rats. Our collective data suggest anticarcinogenic effects of physical exercises are potentially promoted when training 5 times a week for at least 60 min. PMID- 25806590 TI - Replicate Measurements of Haemoglobin Mass during a Single Day are Feasible and Precise. AB - Duplicate haemoglobin mass (Hbmass) measurements are recommended before and after altitude training sojourns to identify individual adaptations in athletes with a high level of certainty. Duplicate measurements reduce typical error (TE) and disclose measurement outliers, but are usually made on separate days, which is not a practical protocol for routine services in elite sport settings. The aim of this study was therefore to investigate whether it is safe (carboxyhaemoglobin<10%) to measure Hbmass twice on the same day and to compare TE with measurements made on separate days. 18 healthy men completed 3 different procedures to measure Hbmass twice a day with the carbon monoxide rebreathing method: A (Hbmass measured twice within 6 h), B (dito A, combined with 1 h of hyperoxic training between the tests), C (dito B, within 2 h). First Hbmass measurements of the 3 test days served as procedure D. Carboxyhaemoglobin did not exceed 10% in any procedure. TE and confidence limits for procedures A, B, C and D were 1.4% (1.0-2.1%), 1.1% (0.8-1.7%), 1.3% (1.0-2.0%) and 1.5% (1.2-2.1%), respectively. Duplicate measurements of Hbmass on the same day are feasible and show TE similar to triplicate measurements on separate days. PMID- 25806591 TI - Validation of a Trunk-mounted Accelerometer to Measure Peak Impacts during Team Sport Movements. AB - This study assessed the validity of an accelerometer to measure impacts in team sports. 76 participants completed a team sport circuit. Accelerations were collected concurrently at 100 Hz using an accelerometer and a 36-camera motion analysis system. The largest peak accelerations per movement were compared in 2 ways: i) pooled together and filtered at 13 different cut-off frequencies (range 6-25 Hz) to identify the optimal filtering frequency, and ii) the optimal cut-off frequency split into the 7 movements performed (n=532). Raw and 25-16 Hz filtering frequencies significantly overestimated and 6 Hz underestimated motion analysis peak accelerations (P <0.007). The 12 Hz filtered accelerometer data revealed the strongest relationship with motion analysis data (accuracy - 0.01+/ 0.27 g, effect size - 0.01, agreement - 0.55 to 0.53 g, precision 0.27 g, and relative error 5.5%; P=1.00). The accelerometer underestimated peak accelerations during tackling and jumping, and overestimated during walking, jogging, sprinting and change of direction. Lower agreement and reduced precision were associated with sprinting, jumping and tackling. The accelerometer demonstrated an acceptable level of concurrent validity compared to a motion analysis system when filtered at a cut-off frequency of 12 Hz. The results advocate the use of accelerometers to measure movements in team sport. PMID- 25806592 TI - beta-ketophosphonate formation via aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonates. AB - A synergistic Cu/Fe-catalyzed aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonate is disclosed. The useful beta-ketophosphonate products were obtained in good yields under oxygen atmosphere in a novel way. This reaction exhibits a wide substrate scope, and the mechanistic experiments indicate that a radical mechanism forms both C-P and C?O bonds simultaneously. This mechanism contrasts existing aerobic difunctionalization of alkynes. PMID- 25806593 TI - Magnetite/Ceria-Codecorated Titanoniobate Nanosheet: A 2D Catalytic Nanoprobe for Efficient Enrichment and Programmed Dephosphorylation of Phosphopeptides. AB - Global characterization and in-depth understanding of phosphoproteome based on mass spectrometry (MS) desperately needs a highly efficient affinity probe during sample preparation. In this work, a ternary nanocomposite of magnetite/ceria codecorated titanoniobate nanosheet (MC-TiNbNS) was synthesized by the electrostatic assembly of Fe3O4 nanospheres and in situ growth of CeO 2 nanoparticles on pre-exfoliated titanoniobate and eventually utilized as the probe and catalyst for the enrichment and dephosphorylation of phosphopeptides. The two-dimensional (2D) structured titanoniobate nanosheet not only promoted the efficacy of capturing phosphopeptides with enlarged surface area, but also functioned as a substrate for embracing the magnetic anchor Fe3O4 to enable magnetic separation and mimic phosphatase CeO2 to produce identifying signatures of phosphopeptides. Compared to single-component TiNbNS or CeO2 nanoparticles, the ternary nanocomposite provided direct evidence of the number of phosphorylation sites while maintaining the enrichment efficiency. Moreover, by altering the on-sheet CeO2 coverage, the dephosphorylation activity could be fine tuned, generating continuously adjustable signal intensities of both phosphopeptides and their dephosphorylated tags. Exhaustive detection of both mono- and multiphosphorylated peptides with precise counting of their phosphorylation sites was achieved in the primary mass spectra in the cases of digests of standard phosphoprotein and skim milk, as well as a more complex biological sample, human serum. With the resulting highly informative mass spectra, this multifunctional probe can be used as a promising tool for the fast and comprehensive characterization of phosphopeptides in MS-based phosphoproteomics. PMID- 25806594 TI - Sulfinato iron(III) complex for electrocatalytic proton reduction. AB - We report the first example of a sulfinato Fe(III) complex acting as a highly active electrocatalyst for proton reduction. The sulfinate binds to the metal through oxygen, resulting in a seven-membered chelate ring that is likely hemilabile during catalysis. Proton reduction occurs at -1.57 V versus Fc/Fc(+) in CH3CN with an ic/ip = 13 in CH3CN (kobs = 3300 s(-1)) and an overpotential of 800 mV. The catalysis is first order with respect to [catalyst] and second order with respect to [trifluoracetic acid]. An 11% increase in catalytic activity is observed in the presence of water, suggesting that sulfinate moieties are viable functional groups for aqueous proton reduction catalysts. PMID- 25806596 TI - Hydantoin-based molecular photoswitches. AB - A new family of molecular photoswitches based on arylidenehydantoins is described together with their synthesis and photochemical and photophysical studies. A series of hydantoin derivatives have been prepared as single isomers using simple and versatile chemistry in good yields. Our studies show that the photostationary states of these compounds can be easily controlled by means of external factors, such as the light source or filters. Moreover, the detailed investigations proved that these switches are efficient (i.e., they make efficient use of the light energy, are high fatigue resistant, and are very photostable). In some cases, the switches can be completely turned on/off, a desirable feature for specific applications. A series of theoretical calculations have also been carried out to understand the photoisomerization mechanism at the molecular level. PMID- 25806597 TI - Linkage Isomerization via Geminate Cage or Bimolecular Mechanisms: Time-Resolved Investigations of an Organometallic Photochrome. AB - The extent of the photoinitiated linkage isomerization of dicarbonyl(3 cyanomethylpyridine-kappaN)(eta(5)-methylcyclopentadienyl)manganese (4) to dicarbonyl(3-cyano-kappaN-methylpyridine)(eta(5)-methylcyclopentadienyl)manganese (5) was examined by time-resolved infrared spectroscopy on picosecond to microsecond time scales in room temperature isooctane to determine the extent the isomerization occurs as a geminate cage rearrangement. We previously reported that a substantial part of the conversion between 4 and 5 must be a bimolecular reaction between a solvent coordinated dicarbonyl(eta(5) methylcyclopentadienyl)manganese (3) and uncoordinated 3-cyanomethylpyridine. For the purpose of designing a molecular device, it would be desirable for the photoisomerization to occur in a geminate cage reaction, because the faster the isomerization, the less opportunity for side reactions to occur. In this study, assignments of transients are identified by comparison with transients observed for model reactions. Within 100 MUs after photolysis of 4 in isooctane, no 5 is observed. Instead, the solvent coordinated 3 is observed within 25 ps after irradiation. The formation of 5 is observed only in the presence of 9 mM 3 cyanomethylpyridine but not until 10-50 MUs after irradiation of 4. Within the limits of detection, these results indicate the conversion of 4 to 5 occurs exclusively via a bimolecular reaction of 3-cyanomethylpyridine with solvent coordinated 3 and not a geminate cage reaction between 3-cyanomethylpyridine and the dicarbonyl(eta(5)-methylcyclopentadienyl)manganese fragment. PMID- 25806598 TI - Enzyme Kinetics in Liquid Crystalline Mesophases: Size Matters, But Also Topology. AB - Lyotropic liquid crystalline systems (LLCs) are excellent immobilizing carriers for enzymes, due to their biocompatibility and well-defined pore nanostructure. Here we show that the liquid crystalline mesophase topology can greatly influence the enzymatic activity in a typical peroxidase (Horseradish peroxidase, HRP) enzymatic reaction. Enzyme kinetics was investigated in different LLC mesophases based on monolinolein, with varying symmetries and dimensions such as the 1D cylindrical inverse hexagonal phase (HII), the 2D planar lamellar phase (Lalpha), and two 3D bicontinuous cubic phases of double diamond (Pn3m) and gyroid (Ia3d) space groups. As expected, the mesophase with largest water channel size shows highest activity, regardless of the topology. Interestingly, however, when mesophases with different topologies have the same water channel size, then the topology plays the dominant role, and the enzyme showed the highest activity in the 3D tetra-fold connected Pn3m, followed by the Ia3d with trifold connectivity, and finally the 1D HII phase. This study demonstrates that the enzymatic activity in LLC mesophases depends on both the water channel size and the topology of the mesophase. PMID- 25806595 TI - Enzymatic oxidation of methane. AB - Methane monooxygenases (MMOs) are enzymes that catalyze the oxidation of methane to methanol in methanotrophic bacteria. As potential targets for new gas-to liquid methane bioconversion processes, MMOs have attracted intense attention in recent years. There are two distinct types of MMO, a soluble, cytoplasmic MMO (sMMO) and a membrane-bound, particulate MMO (pMMO). Both oxidize methane at metal centers within a complex, multisubunit scaffold, but the structures, active sites, and chemical mechanisms are completely different. This Current Topic review article focuses on the overall architectures, active site structures, substrate reactivities, protein-protein interactions, and chemical mechanisms of both MMOs, with an emphasis on fundamental aspects. In addition, recent advances, including new details of interactions between the sMMO components, characterization of sMMO intermediates, and progress toward understanding the pMMO metal centers are highlighted. The work summarized here provides a guide for those interested in exploiting MMOs for biotechnological applications. PMID- 25806599 TI - Engineering nanoparticle-coated bacteria as oral DNA vaccines for cancer immunotherapy. AB - Live attenuated bacteria are of increasing importance in biotechnology and medicine in the emerging field of cancer immunotherapy. Oral DNA vaccination mediated by live attenuated bacteria often suffers from low infection efficiency due to various biological barriers during the infection process. To this end, we herein report, for the first time, a new strategy to engineer cationic nanoparticle-coated bacterial vectors that can efficiently deliver oral DNA vaccine for efficacious cancer immunotherapy. By coating live attenuated bacteria with synthetic nanoparticles self-assembled from cationic polymers and plasmid DNA, the protective nanoparticle coating layer is able to facilitate bacteria to effectively escape phagosomes, significantly enhance the acid tolerance of bacteria in stomach and intestines, and greatly promote dissemination of bacteria into blood circulation after oral administration. Most importantly, oral delivery of DNA vaccines encoding autologous vascular endothelial growth factor receptor 2 (VEGFR2) by this hybrid vector showed remarkable T cell activation and cytokine production. Successful inhibition of tumor growth was also achieved by efficient oral delivery of VEGFR2 with nanoparticle-coated bacterial vectors due to angiogenesis suppression in the tumor vasculature and tumor necrosis. This proof of-concept work demonstrates that coating live bacterial cells with synthetic nanoparticles represents a promising strategy to engineer efficient and versatile DNA vaccines for the era of immunotherapy. PMID- 25806601 TI - Distributional assumptions in food and feed commodities- development of fit-for purpose sampling protocols. AB - Material heterogeneity influences the effectiveness of sampling procedures. Most sampling guidelines used for assessment of food and/or feed commodities are based on classical statistical distribution requirements, the normal, binomial, and Poisson distributions-and almost universally rely on the assumption of randomness. However, this is unrealistic. The scientific food and feed community recognizes a strong preponderance of non random distribution within commodity lots, which should be a more realistic prerequisite for definition of effective sampling protocols. Nevertheless, these heterogeneity issues are overlooked as the prime focus is often placed only on financial, time, equipment, and personnel constraints instead of mandating acquisition of documented representative samples under realistic heterogeneity conditions. This study shows how the principles promulgated in the Theory of Sampling (TOS) and practically tested over 60 years provide an effective framework for dealing with the complete set of adverse aspects of both compositional and distributional heterogeneity (material sampling errors), as well as with the errors incurred by the sampling process itself. The results of an empirical European Union study on genetically modified soybean heterogeneity, Kernel Lot Distribution Assessment are summarized, as they have a strong bearing on the issue of proper sampling protocol development. TOS principles apply universally in the food and feed realm and must therefore be considered the only basis for development of valid sampling protocols free from distributional constraints. PMID- 25806600 TI - The impact of specialty practice nursing care on health-related quality of life in persons with ostomies. AB - PURPOSE: Ostomy patients suffer significant physiological challenges that can affect psychological variables and health-related quality of life (HRQOL). The purpose of this study was to compare HRQOL in a group of patients cared for in hospitals that employed nurses specializing in ostomy care versus patients who were cared for at hospitals that did not employ nurses specializing in ostomy care. DESIGN: Multicenter, quasi-experimental, prospective, longitudinal study. SUBJECTS AND SETTING: This is a national study set in Spain. We collected data from 402 ostomy patients in health centers among 16 Spanish regions from March 2012 to June 2013. The average age of the patients was 61.3 +/- 13.71 years (mean +/- SD). METHODS: Questionnaires were administered by the investigators prior to and 3 months after the ostomy surgery. Two groups of patients were compared: patients in group 1 were treated by nurses specializing in ostomies; patients in group 2 were not treated by an ostomy nurse specialist. Two validated scales were used to determine HRQOL: EQ-5 D (Spanish version) and the Montreux questionnaire. RESULTS: Patients in group 1 adapted better to their ostomies than group 2. They exhibited less concern with appearance; increased comfort with cleaning, changing, and throwing away ostomy bags; and decreased pain and pain frequency. They reported less fearfulness; improvements in sleep, weight concerns, and strength; and better overall health, leading to a greater percentage of patients able to lead a normal life (P < .05). Sexual activity was the only variable that worsened in both groups, but it was more satisfactory at postoperation stage in group 1 (P = .015). CONCLUSIONS: Patients who received specialized ostomy care experienced significant improvements in HRQOL compared to patients who were not cared for by specialist nurses. Our findings strongly suggest that patients undergoing ostomy surgery should be provided access to a nurse specialist in ostomy care since our results highlight the potential benefit promoting the HRQOL of patients. PMID- 25806602 TI - Significance of radiologic location and extent of portal venous involvement on prognosis after resection for pancreatic adenocarcinoma. AB - OBJECTIVES: The aim of this study was to determine the prognosis of pancreatic adenocarcinoma patients with portal venous involvement according to its location and extent on radiologic findings. METHODS: From January 2003 to December 2011, the medical records of 543 patients who had undergone pancreaticoduodenectomy (PD) for pancreas head cancer in Asan Medical Center were retrospectively reviewed. The portal vein (PV) resection (PVR) patients (n = 147) were classified according to the location (NPVC group, without PV confluence invasion; PVC group, with PV confluence invasion) and extent (group A, the tumor surrounded less than two thirds of the vessel perimeter; group B, the tumor extended over two thirds) of venous involvement on radiologic findings. RESULTS: The survival rate of the patients who underwent PD with PVR was significantly lower than that of the patients who underwent PD without PVR (P = 0.009). The NPVC group and group A had significantly better prognoses than the PVC group and group B (P = 0.033 and P = 0.005, respectively). CONCLUSIONS: Pancreatic cancer with venous involvement had different prognoses according to the location and extent of venous involvement. The patients with PV confluence or extensive vein invasion are recommended the neoadjuvant treatments. PMID- 25806603 TI - Improving uptake of screening for colorectal cancer: a study on invitation strategies and different test kit use. AB - OBJECTIVE: The aim of this study was to compare the uptake of mail-delivered tests for colorectal cancer screening. We assessed the effect of an advance notification letter and a reminder letter, and analysed the proportion of inappropriately handled tests. MATERIALS AND METHODS: Fifteen thousand randomly selected residents of Latvia aged 50-74 years were allocated to receive one of three different test systems: either a guaiac faecal occult blood test (gFOBT) or one of two laboratory-based immunochemical tests (FIT) - FOB Gold or OC-Sensor. Half of the target population received an advance notification letter; all nonresponders were sent a reminder letter. RESULTS: The uptake of screening was 31.2% for the gFOBT, 44.7% for FOB Gold and 47.4% for the OC-Sensor (odds ratio 0.55; 95% confidence interval 0.51-0.60 for gFOBT vs. FOB Gold; odds ratio 0.90; 95% confidence interval 0.83-0.98 for FOB Gold vs. OC-Sensor). The uptake in the gFOBT group was improved by the advance notification letter (7.7%, P<0.0001). 30.9% returned tests were received after the reminder letter. The proportion of tests that could not be analysed because of inadequate handling was 0.9% for gFOBT, 4.4% for FOB Gold and 0.2% for the OC-Sensor (P=0.002 for gFOBT vs. OC Sensor; P<0.001 for all comparisons vs. FOB Gold). CONCLUSION: The use of FIT resulted in higher uptake. Receipt of a reminder letter was critical to participation, but the use of an advance notification letter was important mainly for gFOBT. The proportion of inappropriately handled tests was markedly higher for FOB Gold. PMID- 25806604 TI - Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low dose morphine thermal hyperalgesia. AB - Accumulating evidence suggests that opioid analgesics can lead to paradoxical sensitization to pain when delivered in different administration patterns. Although opioid tolerance-induced hyperalgesia is largely studied, little is known about the mechanisms underlying acute ultra-low-dose morphine hyperalgesia. Activation of spinal glial cells is reported to regulate pain hypersensitivity. To elucidate the mechanism involved in acute ultra-low-dose morphine hyperalgesia, we tested whether an opioid agonist promoted the activation of spinal astrocytes and microglia and investigated the cellular pathways involved. Ultra-low-dose morphine activated spinal astrocytes with no effect on microglia. The astrocyte activation was selectively prevented by the opioid antagonist naloxone, the MU-opioid receptor (MOR) silencing and the JNK inhibitor SP600125. Morphine elevated spinal JNK1, JNK2, and c-Jun phosphorylation. Conversely, phosphorylation of cAMP response element-binding protein (CREB) and signal transducer and activator of transcription-1 (STAT-1) was not elevated, and nuclear factor kappa B (NF-kappaB) levels remained unmodified. Administration of SP600125 and the N-methyl-D-aspartate (NMDA) antagonist MK801 prevented morphine hyperalgesia. Ultra-low-dose morphine increased protein kinase C (PKC) gamma phosphorylation. Pretreatment with a PKC inhibitor prevented morphine hyperalgesia and JNK and c-Jun overphosphorylation, indicating PKC is a JNK upstream modulator and illustrating the presence of a pathway involving PKC, NMDA, and JNK activated by morphine. Immunofluorescence experiments indicated the neuronal localization of spinal MOR. However, JNK was not detected in MOR expressing cells, showing the presence of a neuron-astrocyte signaling pathway. These results illustrate the selective activation of an astrocyte JNK pathway after the stimulation of neuronal MOR, which contributes to ultra-low-dose morphine hyperalgesia. PMID- 25806606 TI - What can the medical record reveal about problem opioid use? PMID- 25806605 TI - Neuromodulation of conditioned placebo/nocebo in heat pain: anodal vs cathodal transcranial direct current stimulation to the right dorsolateral prefrontal cortex. AB - Placebo and nocebo play an important role in clinical practice and medical research. Modulating placebo/nocebo responses using noninvasive brain stimulation methods, such as transcranial direct current stimulation (tDCS), has the potential to harness these effects to therapeutic benefit in a clinical setting. In this study, we assessed the effect of anodal and cathodal tDCS over the right dorsolateral prefrontal cortex (rDLPFC) on conditioned placebo/nocebo cue response to heat pain. Two matched groups of healthy volunteers were subjected to an identical session of conditioning, during which low and high cues (abstract images) were associated with low and high pain levels, respectively. Twenty minute 2-mA tDCS (either anodal or cathodal) over the rDLPFC was applied. The influence of tDCS current polarity (anodal vs cathodal) on placebo and nocebo was assessed, using subjects' pain ratings in response to identical pain preceded by the conditioned high or low cues. The duration of cue presentation varied to allow either fully conscious or subliminal processing. Significant placebo and nocebo effects in the anodal but not the cathodal group were elicited with the conditioning paradigm. This study provides evidence of a possibility to modulate the conditioned placebo and nocebo effect by changing the excitability of the rDLPFC using tDCS. PMID- 25806613 TI - Human Fitting Studies of Cleveland Clinic Continuous-Flow Total Artificial Heart. AB - Implantation of mechanical circulatory support devices is challenging, especially in patients with a small chest cavity. We evaluated how well the Cleveland Clinic continuous-flow total artificial heart (CFTAH) fit the anatomy of patients about to receive a heart transplant. A mock pump model of the CFTAH was rapid prototyped using biocompatible materials. The model was brought to the operative table, and the direction, length, and angulation of the inflow/outflow ports and outflow conduits were evaluated after the recipient's ventricles had been resected. Thoracic cavity measurements were based on preoperative computed tomographic data. The CFTAH fit well in all five patients (height, 170 +/- 9 cm; weight, 75 +/- 24 kg). Body surface area was 1.9 +/- 0.3 m (range, 1.6-2.1 m). The required inflow and outflow port orientation of both the left and right housings appeared consistent with the current version of the CFTAH implanted in calves. The left outflow conduit remained straight, but the right outflow direction necessitated a 73 +/- 22 degree angulation to prevent potential kinking when crossing over the connected left outflow. These data support the fact that our design achieves the proper anatomical relationship of the CFTAH to a patient's native vessels. PMID- 25806614 TI - Readmissions After Continuous Flow Left Ventricular Assist Device Implantation: Differences Observed Between Two Contemporary Device Types. AB - Readmissions after continuous flow left ventricular assist devices implantation are common. We compared the frequency and etiology of readmissions between two continuous flow left ventricular assist devices 6 months after implant. We retrospectively assessed readmissions in 81 patients who received a bridge to transplant HeartMate-II (HM-II) n = 35, 43% or HeartWare (HW) n = 46, 57%, from 2009 to 2014. Readmissions were divided into cardiac, infection, gastrointestinal bleeding, stroke, pump thrombosis, and miscellaneous profiles. Age, gender, creatinine, INTERMACS profiles were comparable between groups (p > 0.05). Sixty one patients accounted for 141 readmissions. At 6 months, the overall readmission rate was higher among HM-II versus HW recipients (2.3 +/- 1.7 vs. 1.4 +/- 1.3; p = 0.024). Multiple readmissions (>=2) occurred more frequently in HM-II recipients (HM-II 23, 66% vs. HW 20, 44%; p = 0.047) which accounted for 87% of overall readmission frequency. Cardiac profile was the most common reason for readmission (HM-II = 15, HW = 17; p = 0.95). Readmission for arrhythmia (HM-II = 10, HW = 3; p = 0.021) and overall infection rate (0.49 +/- 0.70 vs. 0.17 +/- 0.68; p = 0.001) were more common among HM-II recipients; however, other readmission profiles were comparable between devices (p > 0.05). Readmission frequency, multiple readmissions, and clinical profile characteristics were different between HM-II and HW recipients. PMID- 25806612 TI - Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension. AB - This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID- 25806615 TI - Estimation of Residual Peritoneal Volume Using Technetium-99m Sulfur Colloid Scintigraphy. AB - Residual peritoneal volume (RPV) may contribute in the development of ultrafiltration failure in patients with normal transcapillary ultrafiltration. The aim of this study was to estimate the RPV using intraperitoneal technetium 99m Sulfur Colloid (Tc). Twenty patients on peritoneal dialysis were studied. RPV was estimated by: 1) intraperitoneal instillation of Tc (RPV-Tc) and 2) classic Twardowski calculations using endogenous solutes, such as urea (RPV-u), creatinine (RPV-cr), and albumin (RPV-alb). Each method's reproducibility was assessed in a subgroup of patients in two consecutive measurements 48 h apart. Both methods displayed reproducibility (r = 0.93, p = 0.001 for RPVTc and r = 0.90, p = 0.001 for RPV-alb) between days 1 and 2, respectively. We found a statistically significant difference between RPV-Tc and RPV-cr measurements (347.3 +/- 116.7 vs. 450.0 +/- 67.8 ml; p =0.001) and RPV-u (515.5 +/- 49.4 ml; p < 0.001), but not with RPV-alb (400.1 +/- 88.2 ml; p = 0.308). A good correlation was observed only between RPV-Tc and RPV-alb (p < 0.001). The Tc method can estimate the RPV as efficiently as the high molecular weight endogenous solute measurement method. It can also provide an imaging estimate of the intraperitoneal distribution of RPV. PMID- 25806617 TI - Large-scale, low-cost synthesis of monodispersed gold nanorods using a gemini surfactant. AB - In this work, we demonstrate that monodispersed gold nanorods (AuNRs) can be obtained in a large-scale and cost-effective way. By using an industrial grade gemini surfactant (P16-8-16), the cost of the synthesis of high-quality AuNRs can be significantly reduced by 90%. The synthesis can be scaled up to over 4 L. The aspect ratio of AuNRs can be well tuned from ~2.4 to ~6.3, resulting in a wide tunability of the SPR properties. Systematic studies reveal that P16-8-16 could have a dual function: it can not only act as a capping ligand to stabilize AuNRs but also it can pre-reduce Au(3+) to Au(+) by the unsaturated C[double bond, length as m-dash]C bond. Furthermore, the shape of AuNRs can be tailored from straight nanorods to "dog-bones" by simply varying the concentration of the surfactant. A mechanistic study shows that the shape change can be attributed to the presence of excess bromide ions because of the complex effect between bromide ions and gold ions. This work will not only help to achieve the industrial production of AuNRs, but also promote research into practical applications of various nanomaterials. PMID- 25806616 TI - Successful interventional thrombectomy of a basilar artery thrombus in a long term LVAD patient. AB - Cerebral thromboembolism builds the Achilles heel for patients on left ventricular support (LVAD). Thrombolytic therapy is usually contraindicated considering the increased risk of intracranial hemorrhage in patients with LVAD under therapeutic oral anticoagulation with concomitant platelet inhibition. We report on an alternative approach to this dilemma. On day 1,091 of LVAD support (INCOR Berlin Heart), a 69 year-old male patient was admitted to a rural hospital unconscious with a left-sided hemiplegia. Cerebral computed tomography (CT) with CT angiography revealed a thromboembolic distal basilar artery occlusion. The patient was immediately transported to our medical center, where an interventional thrombectomy restored full patency of the vessel. The patient recovered without neurologic sequelae within days. This case highlights the fact that patients on LVAD support with a neurologic event should be immediately transferred to a neurovascular center for appropriate treatment including a neurointervention. PMID- 25806618 TI - Organocatalytic enantioselective Michael addition of cyclic hemiacetals to nitroolefins: a facile access to chiral substituted 5- and 6-membered cyclic ethers. AB - An efficient aminocatalytic enantioselective Michael addition of readily available cyclic hemiacetals to nitroolefins has been developed. The strategy serves as a powerful approach to synthetically valuable chiral 3-substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs). The synthetic utilities of the versatile Michael adducts also have been demonstrated in the synthesis of 2,3 disubstituted cyclic ethers, alpha-substituted lactones and venlafaxine analogues. PMID- 25806619 TI - From slow to fast--the user controls the rate of the release of molecules from masked forms using a photoswitch and different types of light. AB - Exposure to UV light generates a ring-closed isomer of a diarylethene, which undergoes very slow bond breaking and release even after the light is turned off. The rate of release is increased by exposing the isomer to UV and/or visible light. PMID- 25806620 TI - Elucidating the conformational energetics of glucose and cellobiose in ionic liquids. AB - A major challenge for the utilization of lignocellulosic feedstocks for liquid fuels and other value added chemicals has been the recalcitrant nature of crystalline cellulose to various hydrolysis techniques. Ionic liquids (ILs) are considered to be a promising solvent for the dissolution and conversion of cellulose to simple sugars, which has the potential to facilitate the unlocking of biomass as a supplement and/or replacement for petroleum as a feedstock. Recent studies have revealed that the orientation of the hydroxymethyl group, described via the omega dihedral, and the glycosidic bond, described via the phi psi dihedrals, are significantly modified in the presence of ILs. In this study, we explore the energetics driving the orientational preference of the omega dihedral and the phi-psi dihedrals for glucose and cellobiose in water and three imidazolium based ILs. It is found that interactions between the cation and the ring oxygen in glucose directly impact the conformational preference of the omega dihedral shifting the distribution towards the gauche-trans (GT) conformation and creating an increasingly unfavorable gauche-gauche (GG) conformation with increasing tail length. This discovery modifies the current hypothesis that intramolecular hydrogen bonding is responsible for the shift in the omega dihedral distribution and illuminates the importance of the cation's character. In addition, it is found that the IL's interaction with the glycosidic bond results in the modification of the observed phi-psi dihedrals, which may have implications for hydrolysis in the presence of ILs. The molecular level information gained from this study identifies the favorable IL-sugar interactions that need to be exploited in order to enhance the utilization of lignocellulosic biomass as a ubiquitous feedstock. PMID- 25806621 TI - Learning curves in health professions education. AB - Learning curves, which graphically show the relationship between learning effort and achievement, are common in published education research but are not often used in day-to-day educational activities. The purpose of this article is to describe the generation and analysis of learning curves and their applicability to health professions education. The authors argue that the time is right for a closer look at using learning curves-given their desirable properties-to inform both self-directed instruction by individuals and education management by instructors.A typical learning curve is made up of a measure of learning (y axis), a measure of effort (x-axis), and a mathematical linking function. At the individual level, learning curves make manifest a single person's progress towards competence including his/her rate of learning, the inflection point where learning becomes more effortful, and the remaining distance to mastery attainment. At the group level, overlaid learning curves show the full variation of a group of learners' paths through a given learning domain. Specifically, they make overt the difference between time-based and competency-based approaches to instruction. Additionally, instructors can use learning curve information to more accurately target educational resources to those who most require them.The learning curve approach requires a fine-grained collection of data that will not be possible in all educational settings; however, the increased use of an assessment paradigm that explicitly includes effort and its link to individual achievement could result in increased learner engagement and more effective instructional design. PMID- 25806624 TI - The nurse in the context of chronic disease. PMID- 25806625 TI - Changes and events over life course: a comparative study between groups of older adults. AB - OBJECTIVE: to identify the changes which had occurred over the last year in the life of older adults, as well as the values attributed to these changes. METHOD: this is a multicentric, cross-sectional study, of the inquiry type, undertaken in three cities of the Brazilian Northeast, investigating two distinct groups of older adults. RESULTS: among the 236 older adults interviewed, it was observed that 30.0% reported health as the main change in their life course in the last year, this category being the most significant response among the older adults aged between 80 and 84 years old (37.7%). Changes in the family were mentioned by 11.5% of the older adults; death (9.6%) and alterations in routine activities (9.6%). In relation to the value attributed to these changes, it was ascertained that for 64.7% of the older adults aged between 65 and 69 years old, these changes were positive. In the older group, 49.4% of the older adults believe that their changes were related to losses. CONCLUSION: the knowledge of the changes mentioned, the value attributed to these changes, and the self-evaluation of health provide information which assists in formulating actions which are more specific to the real needs of these age groups. They also provide the health professionals with a better understanding of how some experiences are experienced in the life trajectories of these older adults. PMID- 25806623 TI - Phytogenic compounds as alternatives to in-feed antibiotics: potentials and challenges in application. AB - This article summarizes current experimental knowledge on the efficacy, possible mechanisms and feasibility in the application of phytogenic products as feed additives for food-producing animals. Phytogenic compounds comprise a wide range of plant-derived natural bioactive compounds and essential oils are a major group. Numerous studies have demonstrated that phytogenic compounds have a variety of functions, including antimicrobial/antiviral, antioxidative and anti inflammation effects and improvement in the palatability of feed and gut development/health. However, the mechanisms underlying their functions are still largely unclear. In the past, there has been a lack of consistency in the results from both laboratory and field studies, largely due to the varied composition of products, dosages, purities and growing conditions of animals used. The minimal inhibitory concentration (MIC) of phytogenic compounds required for controlling enteric pathogens may not guarantee the best feed intake, balanced immunity of animals and cost-effectiveness in animal production. The lipophilic nature of photogenic compounds also presents a challenge in effective delivery to the animal gut and this can partially be resolved by microencapsulation and combination with other compounds (synergistic effect). Interestingly, the effects of photogenic compounds on anti-inflammation, gut chemosensing and possible disruption of bacterial quorum sensing could explain a certain number of studies with different animal species for the better production performance of animals that have received phytogenic feed additives. It is obvious that phytogenic compounds have good potential as an alternative to antibiotics in feed for food animal production and the combination of different phytogenic compounds appears to be an approach to improve the efficacy and safety of phytogenic compounds in the application. It is our expectation that the recent development of high throughput and "omics" technologies can significantly advance the studies on the mechanisms underlying phytogenic compounds' functions and, therefore, guide the effective use of the compounds. PMID- 25806622 TI - Biofilms in infections of the eye. AB - The ability to form biofilms in a variety of environments is a common trait of bacteria, and may represent one of the earliest defenses against predation. Biofilms are multicellular communities usually held together by a polymeric matrix, ranging from capsular material to cell lysate. In a structure that imposes diffusion limits, environmental microgradients arise to which individual bacteria adapt their physiologies, resulting in the gamut of physiological diversity. Additionally, the proximity of cells within the biofilm creates the opportunity for coordinated behaviors through cell-cell communication using diffusible signals, the most well documented being quorum sensing. Biofilms form on abiotic or biotic surfaces, and because of that are associated with a large proportion of human infections. Biofilm formation imposes a limitation on the uses and design of ocular devices, such as intraocular lenses, posterior contact lenses, scleral buckles, conjunctival plugs, lacrimal intubation devices and orbital implants. In the absence of abiotic materials, biofilms have been observed on the capsule, and in the corneal stroma. As the evidence for the involvement of microbial biofilms in many ocular infections has become compelling, developing new strategies to prevent their formation or to eradicate them at the site of infection, has become a priority. PMID- 25806628 TI - Evaluation of the pressure ulcers risk scales with critically ill patients: a prospective cohort study. AB - AIMS: to evaluate the accuracy of the Braden and Waterlow risk assessment scales in critically ill inpatients. METHOD: this prospective cohort study, with 55 patients in intensive care units, was performed through evaluation of sociodemographic and clinical variables, through the application of the scales (Braden and Waterlow) upon admission and every 48 hours; and through the evaluation and classification of the ulcers into categories. RESULTS: the pressure ulcer incidence was 30.9%, with the Braden and Waterlow scales presenting high sensitivity (41% and 71%) and low specificity (21% and 47%) respectively in the three evaluations. The cut off scores found in the first, second and third evaluations were 12, 12 and 11 in the Braden scale, and 16, 15 and 14 in the Waterlow scale. CONCLUSION: the Braden scale was shown to be a good screening instrument, and the Waterlow scale proved to have better predictive power. PMID- 25806626 TI - Quality of life of coronary artery disease patients after the implementation of planning strategies for medication adherence. AB - OBJECTIVE: to compare the general and specific health-related quality of life (HRQoL) between the Intervention (IG) and Control (CG) groups of coronary artery disease patients after the implementation of Action Planning and Coping Planning strategies for medication adherence and to verify the relationship between adherence and HRQoL. METHOD: this was a controlled and randomized study. RESULTS: the sample (n=115) was randomized into two groups, IG (n=59) and CG (n=56). Measures of medication adherence and general and specific HRQoL were obtained in the baseline and after two months of monitoring. CONCLUSION: the findings showed that the combination of intervention strategies - Action Planning and Coping Planning for medication adherence did not affect the HRQoL of coronary artery disease patients in outpatient monitoring. PMID- 25806627 TI - Comparative analysis of non-adherence to medication treatment for systemic arterial hypertension in urban and rural populations. AB - OBJECTIVE: to evaluate the indexes and the main factors associated with non adherence to medication treatment for systemic arterial hypertension between urban and rural areas. METHOD: analytical study based on an epidemiological survey with a sample of 247 hypertensive residents of rural and urban areas, with application of a socio-demographic and economic questionnaire, and treatment adherence assessment. The Pearson's Chi-square test was used and the odds ratio (OD) was calculated to analyze the factors related to non-adherence. RESULTS: the prevalence of non-adherence was 61.9% and it was higher in urban areas (63.4%). Factors significantly associated with non-adherence were: male gender (OR=1.95; 95% CI 1.08-3.50), age 20-59 years old (OR=2.51; 95% CI 1.44-4.39), low economic status (OR=1.95; 95% CI 1.09-3.47), alcohol consumption (OR=5.92, 95% CI 1.73 20.21), short time of hypertension diagnosis (OR=3.07; 95% CI 1.35-6.96) and not attending the health service for routine consultations (OR=2.45; 1.35-4.42). CONCLUSION: the socio-demographic/economic characteristics, lifestyle habits and how to relate to health services were the factors that presented association with non-adherence regardless of the place of residence. PMID- 25806629 TI - Use of identification wristbands among patients receiving inpatient treatment in a teaching hospital. AB - OBJECTIVE: to evaluate the use of identification wristbands among patients hospitalized in inpatient units. METHOD: quantitative, descriptive and transversal research, with a sample of 385 patients. Data collection occurred through the observational method through the filling out of a structured questionnaire which aimed to check the presence of the identification wristband and the identifiers used. Descriptive statistics with absolute and relative frequencies was used for analysis. RESULTS: it was obtained that 83.9% of the patients were found to have the correctly identified wristband, 11.9% had a wristband with errors, and 4.2% of the patients were without a wristband. The main nonconformities found on the identification wristbands were incomplete name, different registration numbers, illegibility of the data and problems with the physical integrity of the wristbands. CONCLUSION: the study demonstrated the professionals' engagement in the process of patient identification, evidencing a high rate of conformity of the wristbands. Furthermore, it contributed to identify elements in the use of wristbands which may be improved for a safe identification process. PMID- 25806630 TI - Home-based nursing interventions improve knowledge of disease and management in patients with heart failure. AB - OBJECTIVE: to assess patient knowledge of heart failure by home-based measurement of two NOC Nursing Outcomes over a six-month period and correlate mean outcome indicator scores with mean scores of a heart failure Knowledge Questionnaire. METHODS: in this before-and-after study, patients with heart failure received four home visits over a six-month period after hospital discharge. At each home visit, nursing interventions were implemented, NOC outcomes were assessed, and the Knowledge Questionnaire was administered. RESULTS: overall, 23 patients received home visits. Mean indicator scores for the outcome Knowledge: Medication were 2.27+/-0.14 at home visit 1 and 3.55+/-0.16 at home visit 4 (P<0.001); and, for the outcome Knowledge: Treatment Regimen, 2.33+/-0.13 at home visit 1 and 3.59+/-0.14 at home visit 4 (P<0.001). The correlation between the Knowledge Questionnaire and the Nursing Outcomes Classification scores was strong at home visit 1 (r=0.7, P<0.01), but weak and non significant at visit 4. CONCLUSION: the results show improved patient knowledge of heart failure and a strong correlation between Nursing Outcomes Classification indicator scores and Knowledge Questionnaire scores. The NOC Nursing Outcomes proved effective as knowledge assessment measures when compared with the validated instrument. PMID- 25806631 TI - Clinical applicability of nursing outcomes in the evolution of orthopedic patients with Impaired Physical Mobility. AB - AIM: to evaluate the clinical applicability of outcomes, according to the Nursing Outcomes Classification (NOC) in the evolution of orthopedic patients with Impaired Physical Mobility METHOD: longitudinal study conducted in 2012 in a university hospital, with 21 patients undergoing Total Hip Arthroplasty, evaluated daily by pairs of trained data collectors. Data were collected using an instrument containing five Nursing Outcomes, 16 clinical indicators and a five point Likert scale, and statistically analyzed. RESULTS: The outcomes Body Positioning: self-initiated, Mobility, Knowledge: prescribed activity, and Fall Prevention Behavior presented significant increases in mean scores when comparing the first and final evaluations (p<0.001) and (p=0.035). CONCLUSION: the use of the NOC outcomes makes it possible to demonstrate the clinical progression of orthopedic patients with Impaired Physical Mobility, as well as its applicability in this context. PMID- 25806632 TI - Systematization of Nursing Care in undergraduate training: the perspective of Complex Thinking. AB - AIM: to evaluate the clinical applicability of outcomes, according to the Nursing Outcomes Classification (NOC) in the evolution of orthopedic patients with Impaired Physical Mobility METHOD: longitudinal study conducted in 2012 in a university hospital, with 21 patients undergoing Total Hip Arthroplasty, evaluated daily by pairs of trained data collectors. Data were collected using an instrument containing five Nursing Outcomes, 16 clinical indicators and a five point Likert scale, and statistically analyzed. RESULTS: The outcomes Body Positioning: self-initiated, Mobility, Knowledge: prescribed activity, and Fall Prevention Behavior presented significant increases in mean scores when comparing the first and final evaluations (p<0.001) and (p=0.035). CONCLUSION: the use of the NOC outcomes makes it possible to demonstrate the clinical progression of orthopedic patients with Impaired Physical Mobility, as well as its applicability in this context. PMID- 25806633 TI - Survival and mortality among users and non-users of hydroxyurea with sickle cell disease. AB - OBJECTIVE: to estimate survival, mortality and cause of death among users or not of hydroxyurea with sickle cell disease. METHOD: cohort study with retrospective data collection, from 1980 to 2010 of patients receiving inpatient treatment in two Brazilian public hospitals. The survival probability was determined using the Kaplan-Meier estimator, survival calculations (SPSS version 10.0), comparison between survival curves, using the log rank method. The level of significance was p=0.05. RESULTS: of 63 patients, 87% had sickle cell anemia, with 39 using hydroxyurea, with a mean time of use of the drug of 20.0+/-10.0 years and a mean dose of 17.37+/-5.4 to 20.94+/-7.2 mg/kg/day, raising the fetal hemoglobin. In the comparison between those using hydroxyurea and those not, the survival curve was greater among the users (p=0.014). A total of 10 deaths occurred, with a mean age of 28.1 years old, and with Acute Respiratory Failure as the main cause. CONCLUSION: the survival curve is greater among the users of hydroxyurea. The results indicate the importance of the nurse incorporating therapeutic advances of hydroxyurea in her care actions. PMID- 25806634 TI - Sociodemographic and clinical factors of women with HPV and their association with HIV. AB - OBJECTIVE: to identify the association between HIV-seropositive or HIV seronegative status and the sociodemographic and clinical variables of women with genital HPV infection. METHOD: cross-sectional, retrospective study in a reference service in Ribeirao Preto. A total of 824 women undergoing HIV testing who had high or low grade cervical intraepithelial lesions or condylomatous genital lesions caused by HPV were studied. The chi-square test and logistic regression analysis with the calculation of the odds ratio and a confidence interval of 95% were conducted to verify the association. RESULTS: a higher probability of seropositivity was identified for non-white women; with low education; widowed; who consumed alcohol, tobacco or illicit drugs; with hepatitis C; who had multiple partners; and that worked as prostitutes. CONCLUSION: the increasing impairment of women due to sexually transmitted infections, considering the influence of the socioeconomic and behavioral context on the course of these infections, highlights the importance of public policies that establish intervention strategies involving the prevention, early diagnosis and timely treatment of these diseases, so that there is the promotion of quality of life in this population. PMID- 25806635 TI - Barriers for the inclusion of sexuality in nursing care for women with gynecological and breast cancer: perspective of professionals. AB - AIM: qualitative study, which aimed to identify the barriers that influence nursing care practices related to the sexuality of women with gynecological and breast cancer. METHODS: the study was conducted with 16 professionals of the nursing area (nurses, nursing technicians and nursing assistants) from two sectors of a university hospital situated in the state of Sao Paulo, Brazil. The data was collected using semi-structured, in-depth individual interviews. All the interviews were recorded and the participants' responses were identified and categorized using Content Analysis. RESULTS: three major themes were identified. These are as follows: 1) barriers related to the biomedical model; 2) barriers related to institutional dynamics and 3) barriers related to the social interpretations of sexuality. CONCLUSIONS: the results of this study showed that the systematized inclusion of this issue in nursing care routines requires changes in the health paradigm and in the work dynamic, as well as reflection on the personal values and social interpretations related to the topic. A major challenge is to divest sexuality of the taboos and prejudices which accompany it, as well as to contribute to the nursing team being more aware of the difficulties faced by women with gynaecological and breast cancer. PMID- 25806636 TI - Knowledge about breast cancer and hereditary breast cancer among nurses in a public hospital. AB - OBJECTIVE: To assess the knowledge of nurses involved in the care of oncology patients in a public university hospital, regarding breast cancer and hereditary breast cancer, and to verify the use of such knowledge in their daily practice. METHODS: This is a descriptive cross-sectional study. Data were obtained through a structured, self-administered questionnaire. Out of 154 nurses, 137 (88.9%) agreed to participate in the study. Two questionnaires were excluded such that 135 questionnaires were analyzed. RESULTS: The global percentage of correct answers was not associated with age (p=0.173) or degree/specialization (p=0.815). Questions were classified into categories. In categories involving knowledge of established breast cancer risk factors and indicators of hereditary breast cancer, the rate of correct answers was 65.8% and 66.4%, respectively. On the practice of genetic counseling, 40.7% of those interviewed were not sure about the definition of genetic counseling and 78.5% reported never having identified or referred a patient at genetic risk for specialized risk assessment. Practice of educational actions regarding this subject was reported by 48.5% of those interviewed. CONCLUSION: This study reinforces the need to develop qualifying actions for nurses, so that strategies to control breast cancer become effective in their health care practice. PMID- 25806637 TI - Evaluation of Nosocomial Infection Control Programs in health services. AB - OBJECTIVES: to evaluate the Nosocomial Infection Control Programs in hospital institutions regarding structure and process indicators. METHOD: this is a descriptive, exploratory and quantitative study conducted in 2013. The study population comprised 13 Nosocomial Infection Control Programs of health services in a Brazilian city of the state of Sao Paulo. Public domain instruments available in the Manual of Evaluation Indicators of Nosocomial Infection Control Practices were used. RESULTS: The indicators with the highest average compliance were "Evaluation of the Structure of the Nosocomial Infection Control Programs" (75%) and "Evaluation of the Epidemiological Surveillance System of Nosocomial Infection" (82%) and those with the lowest mean compliance scores were "Evaluation of Operational Guidelines" (58.97%) and "Evaluation of Activities of Control and Prevention of Nosocomial Infection" (60.29%). CONCLUSION: The use of indicators identified that, despite having produced knowledge about prevention and control of nosocomial infections, there is still a large gap between the practice and the recommendations. PMID- 25806639 TI - Napping during the night shift and recovery after work among hospital nurses. AB - OBJECTIVE: To analyze the association between the length of napping during the night shift and the recovery after work among nurses. METHOD: Cross-sectional epidemiological study involving 1940 nurses from 18 public hospitals in the City of Rio de Janeiro. A multidimensional and self-applied questionnaire was used with information about health, sociodemographic and occupational characteristics, health-related behaviors and housework. Multiple logistic regression was applied to identify the association, adjusted for confounding variables. RESULTS: The gross analyses showed 44%, 127% and 66% higher chances of a high level of recovery after work for nurses who sleep up to two hours, between 2.1 and 3 hours and 3.1 hours or more, respectively, when compared to the nurses who do not sleep. After adjusting for confounding variables, the association only continues significant for the group that sleeps 2.1 to 3 hours during the night shift (OR=1.79; 95%CI=1.33-2.41). CONCLUSION: The association between the length of napping and the high level of recovery after work, confirmed in the present results, can be included in the studies that aim to support more appropriate policies aimed at improving the workers' work, life and health conditions, not only in nursing, but night-shift workers in general. PMID- 25806638 TI - Nursing leadership in intensive care units and its relationship to the work environment. AB - AIM: To establish whether there is any relationship between the work environment and nursing leadership at intensive care units (ICUs). METHOD: Correlational study conducted at four ICUs in southern Sao Paulo (SP), Brazil. The study population was comprised of 66 pairs (nurses and nursing technicians) established by lottery. The nurses responded to three instruments: 1) characterization; 2) a validated Portuguese version of the Nursing Work Index Revised (B-NWI-R); and 3) Grid & Leadership in Nursing: ideal behavior. The nursing technicians responded to 1) characterization and to 2) Grid and Leadership in Nursing: actual behavior, relative to the corresponding randomly-assigned nurse. The data were analyzed by means of analysis of variance (ANOVA) at p <= 0.05. RESULTS: The work environment was not associated with actual nursing leadership (p = 0.852). The public or private nature of the institutions where the investigated ICUs were located had no significant effect on leadership (p = 0.437). Only the nurse-physician relationship domain stood out (p = 0.001). CONCLUSION: The choice of leadership styles by nurses should match the ICU characteristics. Leadership skills could be developed, and the work environment did not exert any influence on the investigated population. PMID- 25806640 TI - The contribution of distance learning to the knowledge of nursing lecturers regarding assessment of chronic wounds. AB - OBJECTIVE: to identify the contribution made by a refresher course on the assessment of chronic wounds, offered through the Moodle virtual learning environment (VLE), to the knowledge relating to this issue of nursing lecturers and nurses linked to higher education. METHOD: a prospective, quasi-experimental study, with data collection before and after the educational intervention. The study was undertaken in three stages using the Moodle VLE. The sample was made up of 28 participants who answered the pre-test on the knowledge, devised in accordance with international guidelines on chronic wounds. Afterwards, the refresher course was offered (intervention) and was accessed in accordance with individuals' schedules, during the established time period. At the end of the course, 26 participants answered the post-test. Those who did not participate in the post-tests were excluded from the study, as it is pairwise analysis of the sample. RESULT: the participants obtained, on average, 55.5% of correct answers in the pre-test on their knowledge, and 73.4% in the post-test, this difference being statistically significant. There was a negative correlation between the time of experience in lecturing and the performance in the test on their knowledge. CONCLUSION: the participation in the online refresher course contributed to improving the lecturers' performance in the test on their knowledge, in relation to the recommendations for assessing chronic wounds, based in scientific evidence. PMID- 25806641 TI - Adaptation and validation of the Caregiver Burden Inventory for use with caregivers of elderly individuals. AB - OBJECTIVE: to adapt and validate the Caregiver Burden Inventory for use with caregivers of older adults in Brazil. METHOD: methodological study involving initial translation, synthesis of translations, back translation, expert committee review, pre-testing, submission of the final version to the original authors, and assessment of the inventory's psychometric properties. The inventory assesses five dimensions of caregiver burden: time-dependence, developmental, physical, social and emotional dimensions. RESULTS: a total of 120 family caregivers took part in the study. All care-receivers were older adults dependent on assistance to perform activities of daily living, and lived in the central region of the city of Porto Alegre, RS, Brasil. Cronbach's alpha value for the inventory was 0.936, and the Pearson correlation coefficient for the relationship between the scores obtained on the Caregiver Burden Inventory and the Burden Interview was 0.814. The intraclass correlation coefficient was 0.941, and the value of Student's T-test comparing test and retest scores was 0.792. CONCLUSION: the instrument presented adequate reliability and the suitability of its items and factors was confirmed in this study. PMID- 25806643 TI - Adaptation and validation of indicators concerning the sterilization process of supplies in Primary Health Care services. AB - OBJECTIVES: to adapt and validate, by expert consensus, a set of indicators used to assess the sterilization process of dental, medical and hospital supplies to be used in PHC services. METHOD: qualitative methodological study performed in two stages. The first stage included a focal group composed of experts to adapt the indicators to be used in PHC. In the second stage, the indicators were validated using a 4-point Likert scale, which was completed by judges. A Content Validity Index of >= 0.75 was considered to show approval of the indicators. RESULTS: the adaptations implemented by the focal group mainly referred to the physical structure, inclusion of dental care professionals, inclusion of chemical disinfection, and replacement of the hot air and moist heat sterilization methods. The validation stage resulted in an index of 0.96, which ranged from 0.90 to 1.00, for the components of the indicators. CONCLUSION: the judges considered the indicators after adaptation to be validated. Even though there may be differences among items processed around the world, there certainly are common characteristics, especially in countries with economic and cultural environments similar to Brazil. The inclusion of these indicators to assess the safety of healthcare supplies used in PHC services should be considered. PMID- 25806644 TI - Cultural adaptation, content validity and inter-rater reliability of the "STAR Skin Tear Classification System". AB - AIMS: to perform the cultural adaptation of the STAR Skin Tear Classification System into the Portuguese language and to test the content validity and inter rater reliability of the adapted version. METHODS: methodological study with a quantitative approach. The cultural adaptation was developed in three phases: translation, evaluation by a committee of judges and back-translation. The instrument was tested regarding content validity and inter-rater reliability. RESULTS: the adapted version obtained a regular level of concordance when it was applied by nurses using photographs of friction injuries. Regarding its application in clinical practice, the adapted version obtained a moderate and statistically significant level of concordance. CONCLUSION: the study tested the content validity and inter-rater reliability of the version adapted into the Portuguese language. Its inclusion in clinical practice will enable the correct identification of this type of injury, as well as the implementation of protocols for the prevention and treatment of friction injuries. PMID- 25806642 TI - A validation of the construct and reliability of an emotional intelligence scale applied to nursing students. AB - OBJECTIVE: The current study aimed to validate the construct and reliability of an emotional intelligence scale. METHOD: The Trait Meta-Mood Scale-24 was applied to 349 nursing students. The process included content validation, which involved expert reviews, pilot testing, measurements of reliability using Cronbach's alpha, and factor analysis to corroborate the validity of the theoretical model's construct. RESULTS: Adequate Cronbach coefficients were obtained for all three dimensions, and factor analysis confirmed the scale's dimensions (perception, comprehension, and regulation). CONCLUSION: The Trait Meta-Mood Scale is a reliable and valid tool to measure the emotional intelligence of nursing students. Its use allows for accurate determinations of individuals' abilities to interpret and manage emotions. At the same time, this new construct is of potential importance for measurements in nursing leadership; educational, organizational, and personal improvements; and the establishment of effective relationships with patients. PMID- 25806645 TI - Episiotomy healing assessment: Redness, Oedema, Ecchymosis, Discharge, Approximation (REEDA) scale reliability. AB - OBJECTIVE: to analyse the Redness, Oedema, Ecchymosis, Discharge, Approximation (REEDA) scale reliability when evaluating perineal healing after a normal delivery with a right mediolateral episiotomy. METHOD: observational study based on data from a clinical trial conducted with 54 randomly selected women, who had their perineal healing assessed at four time points, from 6 hours to 10 days after delivery, by nurses trained in the use of this scale. The kappa coefficient was used in the reliability analysis of the REEDA scale. RESULTS: the results indicate good agreement in the evaluation of the discharge item (0.75< Kappa >=0.88), marginal and good agreement in the first three assessments of oedema (0.16< Kappa >=0.46), marginal agreement in the evaluation of ecchymosis (0.25< Kappa >=0.42) and good agreement regarding redness (0.46< Kappa >=0.66). For the item coaptation, the agreement decreased from excellent in the first assessment to good in the last assessment. In the fourth evaluation, the assessment of all items displayed excellent or good agreement among the evaluators. CONCLUSION: the difference in the scores among the evaluators when applying the scale indicates that this tool must be improved to allow an accurate assessment of the episiotomy healing process. PMID- 25806646 TI - Interruptions of nurses' activities and patient safety: an integrative literature review. AB - OBJECTIVES: to identify characteristics related to the interruption of nurses in professional practice, as well as to assess the implications of interruptions for patient safety. METHOD: integrative literature review. The following databases were searched: Pubmed/Medline, LILACS, SciELO and Cochrane Library, using the descriptors interruptions and patient safety. An initial date was not established, but the final date was December 31, 2013. A total of 29 papers met the inclusion criteria. RESULTS: all the papers included describe interruptions as a harmful factor for patient safety. Data analysis revealed three relevant categories: characteristics of interruptions, implications for patient safety, and interventions to minimize interruptions. CONCLUSION: interruptions favor the occurrence of errors in the health field. Therefore, there is a need for further studies to understand such a phenomenon and its effects on clinical practice. PMID- 25806647 TI - Oxycodone frequently induced nausea and vomiting in oxycodone-naive patients with hepatic dysfunction. PMID- 25806648 TI - Persistence with opioid treatment in Germany in patients suffering from chronic non-malignant or cancer pain. AB - BACKGROUND: The aim of the present study was to assess factors influencing opioid persistence in a large patient cohort of 32,158 patients receiving opioid treatment for either chronic non-malignant or cancer pain. METHODS: Data from 32,158 patients with first-time prescription of an opioid in the timeframe from January 2009 until December 2013 treated in 115 orthopedic, 104 neurological and 1129 general practitioner practices were retrospectively analyzed (Disease Analyzer database Germany). A Cox proportional hazards regression model was used to estimate the relationship between non-persistence and the demographic and clinical variables described previously for a maximum follow-up period of 1 year. RESULTS: After 1 year of follow-up, 69% of patients treated with opioids had stopped medication intake (refill gap of 90 days). There was a significantly increased risk of treatment discontinuation for younger patients (<40 years HR: 1.45; 41-50 years HR: 1.37; 51-60 years HR: 1.23; 61-70 years HR: 1.22) as compared with patients aged >70. Cancer pain was associated with a significantly lower risk of therapy discontinuation (HR: 0.69), whereas persistence was considerably less probable for diagnoses such as various kinds of back pain (HR: 1.26), osteoarthritis (HR: 1.14) and spondylarthritis (HR: 1.09). Chronic comorbidities such as diabetes, hypertension, heart insufficiency, and dementia were associated with a decreased risk of treatment discontinuation. CONCLUSION: Our study showed that persistence with opioid treatment is associated with cancer pain, chronic comorbidities and depression, while younger age and chronic non malignant pain (especially due to back pain) increase the possibility of opioid discontinuation. It will be the task of future studies to assess reasons for opioid discontinuation in more detail, which is an important step towards improving patient care and health outcomes. PMID- 25806650 TI - Preparing normal tissue cells for space flight experiments. AB - Deterioration of health is a problem in modern space flight business. In order to develop countermeasures, research has been done on human bodies and also on single cells. Relevant experiments on human cells in vitro are feasible when microgravity is simulated by devices such as the Random Positioning Machine or generated for a short time during parabolic flights. However, they become difficult in regard to performance and interpretation when long-term experiments are designed that need a prolonged stay on the International Space Station (ISS). One huge problem is the transport of living cells from a laboratory on Earth to the ISS. For this reason, mainly rapidly growing, rather robust human cells such as cancer cells, embryonic cells, or progenitor cells have been investigated on the ISS up to now. Moreover, better knowledge on the behavior of normal mature cells, which mimic the in vivo situation, is strongly desirable. One solution to the problem could be the use of redifferentiable cells, which grow rapidly and behave like cancer cells in plain medium, but are reprogrammed to normal cells when substances like retinoic acid are added. A list of cells capable of redifferentiation is provided, together with names of suitable drugs, in this review. PMID- 25806649 TI - A virtual reconstruction and comparative analysis of the KNM-ER 42700 cranium. AB - The taxonomic attribution of the 1.55 million year old young adult fossil calvaria KNM-ER 42700 from Ileret, Kenya, is subject to ongoing controversy. It has been attributed to H. erectus based on comparative description and linear measurements. However, 3-D geometric morphometric analysis found that this specimen fell outside the range of variation of H. erectus in its cranial shape, which was intermediate between H. erectus and modern humans. One problem is that analyses so far were conducted on the original specimen, which shows slight post mortem distortion. Here we use a surface scan of a high resolution cast of KNM-ER 42700 to virtually reconstruct the calvaria and conduct a new 3D geometric morphometric analysis of both its original and its reconstructed shape. Our comparative sample included several specimens of H. erectus (s.l., including the subadult KNM-WT 15000), H. habilis, H. heidelbergenis (s.l.) and H. neanderthalensis, as well as early and Upper Paleolithic H. sapiens. Our principal component analysis results showed that, like the original specimen, our virtual reconstruction of KNM-ER 42700 is also intermediate in shape between fossil Homo and modern humans. Taphonomic distortion, therefore, appears to not have been a major factor affecting previous 3-D geometric morphometric analyses. The intermediate shape of KNM-ER 42700 might instead be related to the young developmental age of the specimen. Further work on reconstructing the original specimen or based on computed tomorgraphic scans is needed to confirm these results. PMID- 25806651 TI - Newborn APOE genotype influences maternal lipid profile and the severity of high risk pregnancy - preeclampsia: Interaction with maternal genotypes as a modulating risk factor in preeclampsia. AB - AIM: To establish the role of the interaction between maternal and newborn apolipoprotein E (APOE) genotypes on the risk, lipid profile and prognosis of preeclampsia (PE). MATERIALS AND METHODS: Forty-seven preeclamptic women and 94 normotensive pregnant women and their newborns were genotyped for APOE using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Maternal APOE-epsilon4 allele was associated with an about eight times higher risk of PE (adjusted OR = 8.4, 95% CI: 2.51-28.17, p = 0.001). The multivariate logistic regression model showed that the newborn APOE-epsilon4 allele was associated with an about six times higher risk of PE (adjusted OR = 5.6, 95% CI: 2.09-15.21, p = 0.001) for the given gestational age levels. Pregnant women with severe PE whose newborns carried the APOE-epsilon4 allele delivered at earlier gestational ages neonates with a lower birth weight compared to pregnant women with newborns negative for this allele. Higher TG and LDL-C levels and lower HDL-C levels were found in pregnant women with severe PE whose newborns were carriers of the APOE-epsilon4 allele compared to preeclamptic women whose newborns were carriers of the epsilon3/epsilon3 genotype. If we checked the combined effect of the mother/newborn genotypes on the risk of PE, we found that the risk to develop PE was 15.4-fold (p < 0.001) increased if mothers or newborns were carriers of the APOE-epsilon4 allele. The risk increased to 20.02 (p < 0.001) if both the mother and newborn were carriers of the APOE-epsilon4 allele. CONCLUSIONS: Our study confirms the maternal/newborn APOE genotype interaction influences the risk for PE, as well as prognosis and lipid profile. PMID- 25806652 TI - Health messaging to individuals who perceive ambiguity in health communications: the promise of self-affirmation. AB - The perception that extant health messages about risk factors for a disease are ambiguous can be associated with greater anxiety and reduced interest in taking precautionary action. In this experiment, 247 female alcohol consumers who perceived varying degrees of ambiguity in current cancer prevention messages read an unambiguous article about the documented link between alcohol consumption and breast cancer. Before reading the article, half were given the opportunity to self-affirm by reflecting on an important value-a technique previously shown to enhance receptivity to threatening messages. The authors found that self affirmation increased message acceptance among those who perceived relatively higher levels of ambiguity in cancer communications. Also, the relation between perceived ambiguity and risk perception became positive among self-affirmed participants, suggesting they had become less defensive. Self-affirmation may be an effective technique to use when delivering health communications to audiences who perceive a lack of consistency in prevention messages. PMID- 25806653 TI - Historical view and future demand for knee arthroplasty in Sweden. AB - BACKGROUND AND PURPOSE: The incidence of knee osteoarthritis will most likely increase. We analyzed historical trends in the incidence of knee arthroplasty in Sweden between 1975 and 2013, in order to be able to provide projections of future demand. PATIENTS AND METHODS: We obtained information on all knee arthroplasties in Sweden in the period 1975-2013 from the Swedish Knee Arthroplasty Register, and used public domain data from Statistics Sweden on the evolution of and forecasts for the Swedish population. We forecast the incidence, presuming the existence of a maximum incidence. RESULTS: We found that the incidence of knee arthroplasty will continue to increase until a projected upper incidence level of about 469 total knee replacements per 10(5) Swedish residents aged 40 years and older is reached around the year 2130. In 2020, the estimated incidence of total knee arthroplasties per 10(5) Swedish residents aged 40 years and older will be 334 (95% prediction interval (PI): 281-374) and in 2030 it will be 382 (PI: 308-441). Using officially forecast population growth data, around 17,500 operations would be expected to be performed in 2020 and around 21,700 would be expected to be performed in 2030. INTERPRETATION: Today's levels of knee arthroplasty are well below the expected maximum incidence, and we expect a continued annual increase in the total number of knee arthroplasties performed. PMID- 25806654 TI - Non-dioxin-like PCB and PBDE deposition on Zea mays L. leaves: modelled contamination in milk from dairy animals fed on silage. AB - Maize (Zea mays L.) can intercept airborne pollutants before their deposition on soil. Selected non-dioxin-like polychlorinated biphenyls (Sigma6NDL-PCBs) and polybrominated diphenyl ethers (Sigma8PBDEs) with feed and food safety relevance were measured on maize leaves harvested for silage in dairy animals from 28 fields in Italy. Analyses were carried out by gas chromatography coupled to high- and low-resolution mass spectrometry. Contamination ranged from 0.65 to 5.3 ng g( 1) with 12% moisture for Sigma6NDL-PCBs, and from 2.7 to 6.2 for Sigma8 PBDEs. Modelled contamination in cow's milk was estimated to fall within the range 0.27 16 ng g(-1) for PCBs, 0.17-1.9 for PBDE number 47, and 0.22-2.1 for PBDE number 99 on a lipid basis. The results indicate that maize silage alone may raise Sigma6NDL-PCB contamination in dairy milk up to the 95th percentile in the European Union. Results are discussed in terms of air quality standards able to support food safety. PMID- 25806657 TI - Mean platelet volume in children with Reye-like syndrome. AB - Reye-like syndrome (RLS) is considered to be a systemic disorder in which the cytokine storm plays a major role. Mean platelet volume (MPV), which is commonly used as a measure of platelet size, indicates the rate of platelet production and platelet activation. We aimed to study MPV in children with RLS. The study population consisted of 30 children with RLS and 30 healthy control subjects. White blood cell (WBC) count, aspartate transaminase (AST) and alanine transaminase (ALT) values were significantly higher and MPV values were significantly lower in patients with RLS at an early stage of illness when compared to controls. Erythrocyte sedimentation rate (ESR), C-reactive protein, AST and ALT values were significantly decreased in patients with RLS after the treatment when compared to baseline whereas MPV values were increased. MPV values were negatively correlated with ESR and WBC. In conclusion, at an early stage of RLS MPV values were lower when compared to controls. PMID- 25806656 TI - Integrin GPIIIa49-57 is the pivotal switch controlling platelet fragmentation. AB - Unique autologous antibodies (Abs) against platelet integrin GPIIIa49-66 (CAPESIEFPVSEARVLED) have been detected in patients with HIV-1 immune-related thrombocytopenia (HIV-1-ITP), which is capable of inducing complement-independent platelet fragmentation through reactive oxygen species (ROS) release. However, the efficiency of inducing platelet fragmentation is inconsistent among the different patient Abs or similar rabbit polyclonal Abs against the region and the reason remains unclear. In this study, we developed a batch of murine monoclonal antibodies (mAbs) against different locus of GPIIIa49-66 region by hybridoma technology. All these mAbs are capable of binding to human platelets. Among these mAbs, clones 1E7 and 5A10 were identified to target the epitope of GPIIIa49-57 (CAPESIEFP, named P1); clones 1C1 and 1E5 target GPIIIa57-64 (PVSEARVL, named P2), and clones 4D5 and 5F8 target GPIIIa59-66 (SEARVLED, named P3). By incubation of human platelets with these mAbs, the platelet fragmentation induced by mAbs against P1 was 5-6 folds higher than that by the control mAb (6-fold for 5A10 and 5.6-fold for 1E7). However, platelet fragmentation induced by mAbs against P2 (1C1) and P3 (5F8) was only 1.9- and 1.1-fold higher than that by the control mAb, respectively. Thus, our data demonstrate that platelet integrin GPIIIa49-57 is the pivotal switch controlling platelet fragmentation. PMID- 25806655 TI - Socio-economic position and subjective health and well-being among older people in Europe: a systematic narrative review. AB - OBJECTIVES: Previous studies of older European populations have established that disability and morbidity vary with indicators of socio-economic position (SEP). We undertook a systematic narrative review of the literature to ascertain to what extent there is evidence of similar inequalities in the subjective health and well-being of older people in Europe. METHOD: Relevant original research articles were searched for using Medline, Global Health, Embase, Social Policy and Practice, Cinahl, Web of Science and International Bibliography of the Social Sciences (IBSS). We included studies of SEP and indicators of subjective health and well-being (self-rated health; life satisfaction; quality of life) conducted since 1991 using population-based samples of older people in Europe and published 1995-2013. RESULTS: A total of 71 studies were identified. Poorer SEP was associated with poorer subjective health and well-being. Associations varied somewhat depending on the SEP measure and subjective health and well-being outcome used. Associations were weaker when social support and health-related behaviours were adjusted for suggesting that these factors mediate the relationship between SEP and subjective health and well-being. Associations tended to be weaker in the oldest age groups. The patterns of associations by gender were not consistent and tended to diminish after adjusting for indicators of health and life circumstances. CONCLUSION: The results of this systematic narrative review of the literature demonstrate the importance of social influences on later life subjective health and well-being and indicate areas which need further investigation, such as more studies from Eastern Europe, more longitudinal studies and more research on the role of mediating factors. PMID- 25806658 TI - Genetic stability of vaccine strains by multilocus sequence typing and pulsed field gel electrophoresis analysis: Implications for quality control of the leptospiral vaccine. AB - Quality control of vaccine strains is directly associated with the safety and efficacy of inactivated whole bacterial vaccines. The assessment of genetic stability is one of the essential elements to guarantee the quality of vaccine strains. The multiple-valence inactivated leptospiral vaccine, comprising the main circulating serogroups, has played an important role in the control of Leptospira infection in China. In the present study, to assess the genetic stability of vaccine strains and develop novel quality control tests that enhance and extend the existing procedures, 7 Chinese leptospiral vaccine strains were characterized during in vivo and in vitro passages by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) analysis. The seven vaccine strains were found to have distinct sequence types (STs) and PFGE profiles. Further analysis showed that the ST and PFGE pattern of each vaccine strain, after in vivo or serial in vitro passages (up to 20 passages), were identical to those of the initial strain, demonstrating that these strains were genetically stable and homogeneous. Taken together, PFGE and MLST provide a reproducible and reliable means for confirming the identity and genetic stability of vaccine seeds, suggesting that these approaches can be used to evaluate the quality of leptospiral vaccine strains. PMID- 25806659 TI - Magical Empiricism and 'Exposed Being' in Medicine and Traditional Healing. AB - Southern African traditional healers often generalize too broadly from discrete ('accidental') instances of success, partly to recruit a clientele, while biomedicine frequently reasons incorrectly from the general to the specific. Both logics are based on empirical observations, but are inversions of each other; these I characterize as 'magical empiricism.' 'Magic' functions as a metapragmatic discourse to recruit a clientele from a skeptical public that doubts the efficacy of any therapeutic interventions, and it acts in parallel with other practical (and efficacious) healing acts. I introduce the concept of 'exposed beings' to describe locally specific constructions of the person as patient and healer. This helps to explain the existence and enduring appeal of many different medical practices and beliefs in South Africa, but I suggest that 'medical parallelism' rather than 'pluralism' might be more accurate. PMID- 25806660 TI - Risk of discharge to postacute care: a patient-centered outcome for the american college of surgeons national surgical quality improvement program surgical risk calculator. AB - IMPORTANCE: Individualized risk prediction tools have an important role as decision aids for use by patients and surgeons before surgery. Patient-centered outcomes should be incorporated into such tools to widen their appeal and improve their usability. OBJECTIVE: To develop a patient-centered outcome for the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator, a web-based, individualized risk prediction tool. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using data from the ACS NSQIP, a national clinical data registry. A total of 973 211 patients from July 2010 to June 2012, encompassing 392 hospitals, were used in this analysis. MAIN OUTCOMES AND MEASURES: Risk of discharge to a postacute care setting. RESULTS: The overall rate of discharge to postacute care was 8.8%. Significant predictors of discharge to postacute care included being 85 years or older (odds ratio [OR] = 9.17; 95% CI, 8.84-9.50), the presence of septic shock (OR = 2.43; 95% CI, 2.20-2.69) or ventilator dependence (OR = 2.81; 95% CI, 2.56 3.09) preoperatively, American Society of Anesthesiologists class of 4 or 5 (OR = 3.59; 95% CI, 3.46-3.71), and totally dependent functional status (OR = 2.27; 95% CI, 2.11-2.44). The final model predicted risk of discharge to postacute care with excellent accuracy (C statistic = 0.924) and calibration (Brier score = 0.05). CONCLUSIONS AND RELEVANCE: Individualized risk of discharge to postacute care can be predicted with excellent accuracy. This outcome will be incorporated into the ACS NSQIP Surgical Risk Calculator. PMID- 25806662 TI - Cerebral autoregulation in the preterm newborn using near-infrared spectroscopy: a comparison of time-domain and frequency-domain analyses. AB - The aim was to compare two conventional methods used to describe cerebral autoregulation (CA): frequency-domain analysis and time-domain analysis. We measured cerebral oxygenation (as a surrogate for cerebral blood flow) and mean arterial blood pressure (MAP) in 60 preterm infants. In the frequency domain, outcome variables were coherence and gain, whereas the cerebral oximetry index (COx) and the regression coefficient were the outcome variables in the time domain. Correlation between coherence and COx was poor. The disagreement between the two methods was due to the MAP and cerebral oxygenation signals being in counterphase in three cases. High gain and high coherence may arise spuriously when cerebral oxygenation decreases as MAP increases; hence, time-domain analysis appears to be a more robust-and simpler-method to describe CA. PMID- 25806661 TI - Dialectical behavior therapy for high suicide risk in individuals with borderline personality disorder: a randomized clinical trial and component analysis. AB - IMPORTANCE: Dialectical behavior therapy (DBT) is an empirically supported treatment for suicidal individuals. However, DBT consists of multiple components, including individual therapy, skills training, telephone coaching, and a therapist consultation team, and little is known about which components are needed to achieve positive outcomes. OBJECTIVE: To evaluate the importance of the skills training component of DBT by comparing skills training plus case management (DBT-S), DBT individual therapy plus activities group (DBT-I), and standard DBT which includes skills training and individual therapy. DESIGN, SETTING, AND PARTICIPANTS: We performed a single-blind randomized clinical trial from April 24, 2004, through January 26, 2010, involving 1 year of treatment and 1 year of follow-up. Participants included 99 women (mean age, 30.3 years; 69 [71%] white) with borderline personality disorder who had at least 2 suicide attempts and/or nonsuicidal self-injury (NSSI) acts in the last 5 years, an NSSI act or suicide attempt in the 8 weeks before screening, and a suicide attempt in the past year. We used an adaptive randomization procedure to assign participants to each condition. Treatment was delivered from June 3, 2004, through September 29, 2008, in a university-affiliated clinic and community settings by therapists or case managers. Outcomes were evaluated quarterly by blinded assessors. We hypothesized that standard DBT would outperform DBT-S and DBT-I. INTERVENTIONS: The study compared standard DBT, DBT-S, and DBT-I. Treatment dose was controlled across conditions, and all treatment providers used the DBT suicide risk assessment and management protocol. MAIN OUTCOMES AND MEASURES: Frequency and severity of suicide attempts and NSSI episodes. RESULTS: All treatment conditions resulted in similar improvements in the frequency and severity of suicide attempts, suicide ideation, use of crisis services due to suicidality, and reasons for living. Compared with the DBT-I group, interventions that included skills training resulted in greater improvements in the frequency of NSSI acts (F1,85 = 59.1 [P < .001] for standard DBT and F1,85 = 56.3 [P < .001] for DBT-S) and depression (t399 = 1.8 [P = .03] for standard DBT and t399 = 2.9 [P = .004] for DBT-S) during the treatment year. In addition, anxiety significantly improved during the treatment year in standard DBT (t94 = -3.5 [P < .001]) and DBT-S (t94 = -2.6 [P = .01]), but not in DBT-I. Compared with the DBT-I group, the standard DBT group had lower dropout rates from treatment (8 patients [24%] vs 16 patients [48%] [P = .04]), and patients were less likely to use crisis services in follow up (ED visits, 1 [3%] vs 3 [13%] [P = .02]; psychiatric hospitalizations, 1 [3%] vs 3 [13%] [P = .03]). CONCLUSIONS AND RELEVANCE: A variety of DBT interventions with therapists trained in the DBT suicide risk assessment and management protocol are effective for reducing suicide attempts and NSSI episodes. Interventions that include DBT skills training are more effective than DBT without skills training, and standard DBT may be superior in some areas. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00183651. PMID- 25806663 TI - Robotic-assisted thymectomy: surgical procedure and results. AB - BACKGROUND: Thymectomy is an essential component in the treatment of myasthenia gravis (MG) and the best treatment for localized thymoma. Minimally invasive thymectomy has advanced to include robotic-assisted techniques. The acceptance of this approach is growing rapidly, while the debate on the adequate technique for thymectomy remains open. METHODS: We describe the technique of robotic-assisted thymectomy and its modifications. The worldwide registries and the literature are reviewed. The experience from the largest single-center database is analyzed. RESULTS: The unilateral three-trocar approach for robotic thymectomy from either left or right side has been standardized. More than 100 centers worldwide perform robotic thymectomy. The annual number of this procedure increased steadily and reached 1,000 in 2012, while the largest single-center experiences comprise almost 500 cases. The end points improvement of MG and recurrence of thymoma are comparable to open procedures. There are special advantages of robotic assistance for complete mediastinal dissection. The perioperative complication rate is below 2%. CONCLUSION: Robotic thymectomy combines minimal incisional discomfort with extensive mediastinal dissection. As its use expands, robotic thymectomy may become the standard for all indications of thymectomy. PMID- 25806664 TI - Highly Efficient Red-Light Emission in An Organic-Inorganic Hybrid Ferroelectric: (Pyrrolidinium)MnCl3. AB - Luminescence of ferroelectric materials is one important property for technological applications, such as low-energy electron excitation. However, the vast majority of doped inorganic ferroelectric materials have low luminescent efficiency. The past decade has envisaged much progress in the design of both ferroelectric and luminescent organic-inorganic hybrid complexes for optoelectronic applications. The combination of ferroelectricity and luminescence within organic-inorganic hybrids would lead to a new type of luminescent ferroelectric multifunctional materials. We herein report a hybrid molecular ferroelectric, (pyrrolidinium)MnCl3, which exhibits excellent ferroelectricity with a saturation polarization of 5.5 MUC/cm(2) as well as intense red luminescence with high quantum yield of 56% under a UV excitation. This finding may extend the application of organic-inorganic hybrid compounds to the field of ferroelectric luminescence and/or multifunctional devices. PMID- 25806665 TI - Copper-mediated radical 1,2-bis(trifluoromethylation) of alkenes with sodium trifluoromethanesulfinate. AB - An efficient chemoselective 1,2-bis(trifluoromethylation) of alkenes with CF3SO2Na promoted by t-BuOOH/CuCl was developed. This protocol provided the first convenient preparation of 1,2-bis(trifluoromethylated) compounds by the vicinal difunctionalization of alkenes. The chemoselectivity of this reaction was accomplished by increasing the concentration of the CF3 radical. PMID- 25806666 TI - NiO hierarchical nanorings on SiC: enhancing relaxation to tune microwave absorption at elevated temperature. AB - We fabricated NiO nanorings on SiC, a novel hierarchical architecture, by a facile two-step method. The dielectric properties depend on temperature and frequency in the range from 373 to 773 K and X band. The imaginary part and loss tangent increase more than four times and three times with increasing temperature, respectively. The architecture demonstrates multirelaxation and possesses high-efficient absorption. The reflection loss exceeds -40 dB and the bandwidth covers 85% of X band (approximately -20 dB). The synergistic effect between multirelaxation and conductance is beneficial to the microwave absorption. Our findings provide a novel and feasible strategy to tune microwave absorption. PMID- 25806668 TI - H-adamantylphosphinates as universal precursors of P-stereogenic compounds. AB - A new family of H-adamantylphosphinates as universal precursors of P-stereogenic ligands was obtained in one step from commercial chlorophosphines. Both enantiomers of these air- and moisture-stable intermediates can easily be separated by semipreparative chiral HPLC on a gram scale and individually undergo stereoselective transformations to afford each enantiomer of a set of P stereogenic compounds such as secondary phosphine oxides and boron-protected monophosphines. PMID- 25806667 TI - Target-responsive DNA hydrogel mediated "stop-flow" microfluidic paper-based analytic device for rapid, portable and visual detection of multiple targets. AB - A versatile point-of-care assay platform was developed for simultaneous detection of multiple targets based on a microfluidic paper-based analytic device (MUPAD) using a target-responsive hydrogel to mediate fluidic flow and signal readout. An aptamer-cross-linked hydrogel was used as a target-responsive flow regulator in the MUPAD. In the absence of a target, the hydrogel is formed in the flow channel, stopping the flow in the MUPAD and preventing the colored indicator from traveling to the final observation spot, thus yielding a "signal off" readout. In contrast, in the presence of a target, no hydrogel is formed because of the preferential interaction of target and aptamer. This allows free fluidic flow in the MUPAD, carrying the indicator to the observation spot and producing a "signal on" readout. The device is inexpensive to fabricate, easy to use, and disposable after detection. Testing results can be obtained within 6 min by the naked eye via a simple loading operation without the need for any auxiliary equipment. Multiple targets, including cocaine, adenosine, and Pb(2+), can be detected simultaneously, even in complex biological matrices such as urine. The reported method offers simple, low cost, rapid, user-friendly, point-of-care testing, which will be useful in many applications. PMID- 25806669 TI - Molecular Structure and Equilibrium Forces of Bovine Submaxillary Mucin Adsorbed at a Solid-Liquid Interface. AB - By combining dynamic light scattering, circular dichroism spectroscopy, atomic force microscopy, and surface force apparatus, the conformation of bovine submaxillary mucin in dilute solution and nanomechanical properties of mucin layers adsorbed on mica have been investigated. The samples were prepared by additional chromatographic purification of commercially available products. The mucin molecule was found to have a z-average hydrodynamic diameter of ca. 35 nm in phosphate buffered solution, without any particular secondary or tertiary structure. The contour length of the mucin is larger than, yet of the same order of magnitude as the diameter, indicating that the molecule can be modeled as a relatively rigid polymeric chain due to the large persistence length of the central glycosylated domain. Mucin molecules adsorbed abundantly onto mica from saline buffer, generating polymer-like, long-ranged, repulsive, and nonhysteretic forces upon compression of the adsorbed layers. Detailed analysis of such forces suggests that adsorbed mucins had an elongated conformation favored by the stiffness of the central domain. Acidification of aqueous media was chosen as means to reduce mucin-mucin and mucin-substrate electrostatic interactions. The hydrodynamic diameter in solution did not significantly change when the pH was lowered, showing that the large persistence length of the mucin molecule is due to steric hindrance between sugar chains, rather than electrostatic interactions. Remarkably, the force generated by an adsorbed layer with a fixed surface coverage also remained unaltered upon acidification. This observation can be linked to the surface-protective, pH-resistant role of bovine submaxillary mucin in the variable environmental conditions of the oral cavity. PMID- 25806670 TI - Further efforts toward a molecular dynamics force field for simulations of peptides in 40% trifluoroethanol-water. AB - A set of force field parameters for trifluoroethanol (TFE) was shown in earlier work from this lab to give a good accounting of system density, translational diffusion coefficients, and the solvent fluorine-solute hydrogen NMR cross relaxation parameter (?HF) for acetate dissolved in 40% TFE-water. It has since been found that this parameter set performs poorly when used to predict ?HF for interactions of TFE with the hydrogens of an octapeptide, [val(5)]angiotensin. In the present work, adjustment of nonbonded force field parameters for interactions of fluorine with hydrogen was explored with the goal of improving these predictions. Six sets of TFE parameters were examined. When used in conjunction with the TIP5PE water model, all gave values for system density, translational diffusion coefficients, and ?HF for acetate-TFE interactions that were similar to experimental results. Increasing the Lennard-Jones sigmaHF for fluorine-hydrogen interactions by 10% led to calculated solvent-solute cross-relaxation parameters that are in better agreement with experiment for many of the peptide hydrogens. Changing the Lennard-Jones epsilonHF parameters for the same interactions had little effect on calculated ?HF values. There was no discernible influence of the TFE model used on the radius of gyration of the peptide or on the backbone conformational angles of the peptide, implying that the conformational properties of the peptide are not strongly influenced by changes in the force field description of TFE in 40% TFE-water. A recent parameter set for TFE proposed by Vymetal and Vondrasek (2014), which reproduces well various physical properties of neat TFE and TFE-water mixtures, was shown to predict cross-relaxation terms for this system poorly. PMID- 25806672 TI - Local environmental grassroots activism: contributions from environmental psychology, sociology and politics. AB - Local environmental grassroots activism is robust and globally ubiquitous despite the ebbs and flows of the general environmental movement. In this review we synthesize social movement, environmental politics, and environmental psychology literatures to answer the following questions: How does the environment emerge as a topic for community action and how a particular environmental discourse (preservation, conservation, public health, Deep Ecology, justice, localism and other responses to modernization and development) becomes dominant? How does a community coalesce around the environmental issue and its particular framing? What is the relationship between local and supralocal (regional, national, global) activism? We contrast "Not in My Back Yard" (NIMBY) activism and environmental liberation and discuss the significance of local knowledge and scale, nature as an issue for activism, place attachment and its disruption, and place-based power inequalities. Environmental psychology contributions to established scholarship on environmental activism are proposed: the components of place attachment are conceptualized in novel ways and a continuous dweller and activist place attachment is elaborated. PMID- 25806671 TI - Liposome-based engineering of cells to package hydrophobic compounds in membrane vesicles for tumor penetration. AB - Natural membrane vesicles (MVs) derived from various types of cells play an essential role in transporting biological materials between cells. Here, we show that exogenous compounds are packaged in the MVs by engineering the parental cells via liposomes, and the MVs mediate autonomous intercellular migration of the compounds through multiple cancer cell layers. Hydrophobic compounds delivered selectively to the plasma membrane of cancer cells using synthetic membrane fusogenic liposomes were efficiently incorporated into the membrane of MVs secreted from the cells and then transferred to neighboring cells via the MVs. This liposome-mediated MV engineering strategy allowed hydrophobic photosensitizers to significantly penetrate both spheroids and in vivo tumors, thereby enhancing the therapeutic efficacy. These results suggest that innate biological transport systems can be in situ engineered via synthetic liposomes to guide the penetration of chemotherapeutics across challenging tissue barriers in solid tumors. PMID- 25806674 TI - Improved Presbyopic Vision With Miotics. AB - OBJECTIVE: To evaluate the efficacy of using a parasympathomimetic drug (carbachol) with an alpha agonist (brimonidine) to create optically beneficial miosis to reduce the effect of presbyopia. METHODS: In this prospective, double masked, randomized, placebo-controlled clinical trial, 48 naturally emmetropic and presbyopic subjects aged between 43 and 56 years with an uncorrected distance visual acuity of at least 20/20 in both eyes without additional ocular pathology were eligible for inclusion. Subjects were divided into 2 groups. The treatment group (n=30 eyes) received single dose of 2.25% carbachol plus 0.2% brimonidine eye drops. The control group (n=18 eyes) received placebo drops. Drops were given to all subjects in a masked fashion, in their nondominant eye. The minimum posttreatment follow-up was 3 months. The subjects' pupil size and both near and distance visual acuities were evaluated before and after treatment at 1, 2, 4, 8, and 10 hr, by a masked examiner at the same room illumination. RESULTS: Statistically significant improvement in near visual acuity was achieved in all subjects who received carbachol plus brimonidine drops (P<0.0001). In this masked study, all subjects liked and would use this therapy if it was available. None would use the placebo. There was no evidence of tolerance or tachyphylaxis during the study period. CONCLUSIONS: Improving the depth of focus by making the pupil smaller caused statistically significant improvement in near visual acuity in emmetropic presbyopic subjects. Carbachol plus brimonidine seem to be an acceptable and safe alternative to corrective lenses and surgical procedures. PMID- 25806673 TI - Diffusion of Antimicrobials Across Silicone Hydrogel Contact Lenses. AB - OBJECTIVES: To measure the diffusion of topical preparations of moxifloxacin, amphotericin B (AmB), and polyhexamethylene biguanide (PHMB) through silicone hydrogel (SH) contact lenses (CLs) in vitro. METHODS: Using an in vitro model, the diffusion of three antimicrobials through SH CLs was measured. Diffused compounds were measured using a spectrophotometer at set time points over a period of 4 hr. The amount of each diffused antimicrobial was determined by comparing the experimental value with a standard curve. A biological assay was performed to validate the CL diffusion assay by testing antimicrobial activity of diffused material against lawns of susceptible bacteria (Staphylococcus epidermidis) and yeast (Saccharomyces cerevisiae). Experiments were repeated at least two times with a total of at least four independent replicates. RESULTS: Our data show detectable moxifloxacin and PHMB diffusion through SH CLs at 30 min, whereas AmB diffusion remained below the limit of detection within the 4-hr experimental period. In the biological assay, diffused moxifloxacin demonstrated microbial killing starting at 20 min on bacterial lawns, whereas PHMB and AmB failed to demonstrate killing on microbial lawns over the course of the 60-min experiment. CONCLUSIONS: In vitro diffusion assays demonstrate limited penetration of certain anti-infective agents through SH CLs. Further studies regarding the clinical benefit of using these agents along with bandage CL for corneal pathologic condition are warranted. PMID- 25806676 TI - Intestinal Anastomotic Ulcers in Children With Short Bowel Syndrome and Anemia Detected by Capsule Endoscopy. AB - OBJECTIVES: Anastomotic ulcers are a known cause of anemia in children with a history of intestinal resection. Upper endoscopy and colonoscopy can be used to diagnose these ulcers; however, the area of involvement may be difficult to visualize with standard endoscopic techniques. Capsule endoscopy (CE) offers an alternative method for visualizing the small bowel in these patients. We describe a cohort of patients with short bowel syndrome (SBS) and anemia who had anastomotic ulcers detected by CE. METHODS: Retrospective chart review of patients with SBS at our institution who underwent CE for chronic gastrointestinal (GI) blood loss. RESULTS: Four patients who underwent a total of 6 CE procedures were identified. The underlying diagnoses included necrotizing enterocolitis (n = 2), gastroschisis (n = 1), and jejunal atresia (n = 1). All of the patients had their ileocecal valves resected during previous surgeries and had received blood transfusions within the previous several months. The median age at the time of CE was 5.5 years (range 4-14 years). Enterocolonic anastomotic ulcers were noted in the studies as wide, flat circumferential lesions with a white base. The CE results guided a change in medical management in all of the 4 patients, including surgical revision of their anastomosis. CONCLUSIONS: CE may be a helpful adjunctive tool for detecting anastomotic ulcers in patients with SBS and chronic GI blood loss. PMID- 25806677 TI - Celiac Disease Alone and Associated With Type 1 Diabetes Mellitus. AB - OBJECTIVES: The aim of the study was to evaluate complication screening and follow-up patterns in a population with type 1 diabetes mellitus and celiac disease (T1D/CD) in relation to a matched cohort with celiac disease (CD) alone at our center. METHODS: We retrospectively reviewed the health charts of 41 children with T1D and biopsy-proven CD and compared anthropometrics and complication of screening within 2 years from CD diagnosis. Follow-up patterns were determined 3 years postdiagnosis. This population was then compared with a population with both symptomatic and asymptomatic CD matched for age and sex. RESULTS: In comparison with T1D/CD, patients with CD alone had a significantly lower height, weight and body mass index (BMI z score 0.01 vs 0.81, P = 0.001) and higher rates of screening for anemia (95% vs 71%, P = 0.003) and bone health (49% vs 29%, P = 0.05). Minimal rates of laboratory abnormalities were observed in either group, irrespective of symptoms at presentation, but CD alone more often presented with anemia than T1D/CD. Repeat serology testing was significantly more frequently performed in the T1D/CD group. Follow-up was equally variable with a median of 3 (range 0-4) visits with a gastroenterologist during the first 3 years postdiagnosis. CONCLUSIONS: These results suggest that patients with T1D/CD represent a distinct and possibly milder phenotype from CD alone. Complication screening was variable and negative for the majority of the patients. Guidelines for follow-up may need to be tailored to specific groups to standardize evaluation and complication screening, especially with regard to bone health. PMID- 25806675 TI - Use and Safety of Erythromycin and Metoclopramide in Hospitalized Infants. AB - OBJECTIVE: Prokinetic medications are used in premature infants to promote motility and decrease time to full enteral feeding. Erythromycin and metoclopramide are the most commonly used prokinetic medications in the neonatal intensive care unit (NICU), but their safety profile is not well defined. METHODS: We conducted a large retrospective cohort study using data from 348 NICUs managed by the Pediatrix Medical Group. All of the infants exposed to >=1 dose of erythromycin, metoclopramide, or both, from a cohort of 8,87,910 infants discharged between 1997 and 2012 were included. We collected laboratory and clinical information while infants were exposed to erythromycin or metoclopramide and described the frequency of laboratory abnormalities and clinical adverse events (AEs). RESULTS: Metoclopramide use increased from 1997 to 2005 and decreased from 2005 to 2012, whereas erythromycin use remained stable. Erythromycin use was most often associated with a diagnosis of feeding problem (40%), whereas metoclopramide was most often associated with a diagnosis of gastroesophageal reflux (59%). The most common laboratory AE during exposure to erythromycin or metoclopramide was hyperkalemia (8.6/1000 infant days on erythromycin and 11.0/1000 infant days on metoclopramide). Incidence of pyloric stenosis was greater with erythromycin than with metoclopramide (10/1095, 0.9% vs 76/19,001, 0.4%; P = 0.01), but odds were not significantly increased after adjusting for covariates (odds ratio 0.52, 95% confidence interval [CI] 0.26 1.02, P = 0.06). More infants experienced an AE while treated with metoclopramide than with erythromycin (odds ratio 1.21, 95% CI 1.03-1.43). CONCLUSIONS: Metoclopramide was associated with increased risk of AEs compared with erythromycin. Studies are needed to confirm safety and effectiveness of both the drugs in infants. PMID- 25806678 TI - Exposure to Gastric Acid-Suppression Therapy Is Associated With Health Care- and Community-Associated Clostridium difficile Infection in Children. AB - OBJECTIVE: The aim of the study was to determine whether gastric acid-suppression therapy is associated with Clostridium difficile infection (CDI) in both inpatient and outpatient pediatric populations. METHODS: We conducted a retrospective case-control study at a 200-bed academic pediatric hospital and associated outpatient clinics during 2005-2010. We defined cases as children 1 to 18 years of age with a first positive test for C difficile toxin A/B, and matched each case to 2 controls without C difficile. We conducted chart review to elicit selected comorbidities and exposure to gastric acid-suppression therapy and antibiotics in the preceding 3 months of the infection or encounter date. We used bivariate and multivariable logistic regression to evaluate the association between antacid use and CDI, controlling for potential confounders. RESULTS: We identified 138 children with health care- or community-associated CDIs and 276 controls. The use of any acid suppression therapy was more common in cases compared with controls (34% vs 20%, P = 0.002). When adjusted for demographic variables and comorbidities, gastric acid-suppression therapy remained significantly associated with CDI (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.0-3.1). Antibiotic use (aOR 1.7, 95% CI 1.1-2.7) and immunosuppressed state were also associated with CDI in our adjusted model (aOR 2.5, 95% CI 1.2-5.2). CONCLUSIONS: Gastric acid-suppression therapy was associated with both health care- and community-associated CDIs in children. Larger pediatric studies are necessary to determine the role of proton pump inhibitors specifically in causing CDI in children. PMID- 25806679 TI - Acute Abducens Nerve Paralysis in the Pediatric Emergency Department: Analysis of 14 Patients. AB - OBJECTIVES: Sixth cranial nerve (SCN) palsy is an uncommon but important neurological problem in patients admitted to pediatric emergency department. The underlying etiology of SCN palsy has a wide range from viral infections to intracranial tumors; therefore, a careful and systematic approach is necessary while examining these patients. METHODS: Fourteen patients who presented with acute SCN paralysis to pediatric emergency department during the last 10 years were examined. RESULTS: The age at the time of admission ranged between 14 months and 16 years (median, 9.5 years). Of the 14 patients, 5 were girls and 9 were boys. A total of 3 of the 14 patients had bilateral cranial nerve VI paralysis, and 9 patients had additional abnormal findings on neurological examination. Neuroimaging studies included cranial tomography (n = 3) and brain magnetic resonance imaging in all patients. The underlying etiology was malignancy (n = 3); glioma, medulloblastoma, acute lymphoblastic leukemia, and dural sinus thrombosis (n = 2); as well as Guillain-Barre syndrome (n = 2), multiple sclerosis (n = 1), pseudotumor cerebri (n = 1), and meningitis (n = 1). The remaining 4 patients had miscellaneous benign etiologies. CONCLUSIONS: Other lesions of primary brain tumors causing increased intracranial pressure constitute 50% of the underlying etiology, followed by Guillain-Barre syndrome (14.2%). However, these patients had neurological symptoms signs, in addition to diplopia or SCN paralysis. Patients admitted to pediatric emergency department with acute SCN paralysis should be examined in detail to disclose the underlying etiology especially if they present with additional clinical signs or symptoms. PMID- 25806680 TI - Paracrine effects of mesenchymal stem cells induce senescence and differentiation of glioblastoma stem-like cells. AB - Glioblastoma multiforme (GBM) displays high resistance to radiation and chemotherapy, due to the presence of a fraction of GBM stem-like cells (GSLCs), which are thus representing the target for GBM elimination. Since mesenchymal stem cells (MSCs) display high tumor tropism, we examined possible antitumor effects of the secreted factors from human MSCs on four GSLC lines (NCH421k, NCH644, NIB26, and NIB50). We found that conditioned media from bone marrow and umbilical cord-derived MSCs (MSC-CM) mediated cell cycle arrest of GSLCs by downregulating cyclin D1. PCR arrays revealed significantly deregulated expression of 13 genes associated with senescence in NCH421k cells exposed to MSC CM. Among these, ATM, CD44, COL1A1, MORC3, NOX4, CDKN1A, IGFBP5, and SERPINE1 genes were upregulated, whereas IGFBP3, CDKN2A, CITED2, FN1, and PRKCD genes were found to be downregulated. Pathway analyses in GO and KEGG revealed their association with p53 signaling, which can trigger senescence via cell cycle inhibitors p21 or p16. For both, upregulated expression was proven in all four GSLC lines exhibiting senescence after MSC-CM exposure. Moreover, MSC paracrine signals were shown to increase the sensitivity of NCH421k and NCH644 cells toward temozolomide, possibly by altering them toward more differentiated cell types, as evidenced by vimentin and GFAP upregulation, and Sox-2 and Notch-1 downregulation. Our findings support the notion that MSCs posses an intrinsic ability to inhibit cell cycle and induce senescence and differentiation of GSLCs. PMID- 25806681 TI - Considerations in sampling of water. AB - Sampling water is no different than sampling any other media. It starts with the development of Sample Quality Criteria, understanding of material properties, then application of the Theory of Sampling. The main difference with sampling water as opposed to solids is the material properties. This paper addresses some of the material properties and consequences of those properties for the development of the sampling protocols. Two properties that must be addressed for water are the temporal nature and the inclusion of suspended solids. Examples are provided for three specific water sampling scenarios which may have application to other water sampling scenarios. PMID- 25806682 TI - RNA chaperones buffer deleterious mutations in E. coli. AB - Both proteins and RNAs can misfold into non-functional conformations. Protein chaperones promote native folding of nascent polypeptides and refolding of misfolded species, thereby buffering mutations that compromise protein structure and function. Here, we show that RNA chaperones can also act as mutation buffers that enhance organismal fitness. Using competition assays, we demonstrate that overexpression of select RNA chaperones, including three DEAD box RNA helicases (DBRHs) (CsdA, SrmB, RhlB) and the cold shock protein CspA, improves fitness of two independently evolved Escherichia coli mutator strains that have accumulated deleterious mutations during short- and long-term laboratory evolution. We identify strain-specific mutations that are deleterious and subject to buffering when introduced individually into the ancestral genotype. For DBRHs, we show that buffering requires helicase activity, implicating RNA structural remodelling in the buffering process. Our results suggest that RNA chaperones might play a fundamental role in RNA evolution and evolvability. PMID- 25806683 TI - Recombination occurs within minutes of replication blockage by RTS1 producing restarted forks that are prone to collapse. AB - The completion of genome duplication during the cell cycle is threatened by the presence of replication fork barriers (RFBs). Following collision with a RFB, replication proteins can dissociate from the stalled fork (fork collapse) rendering it incapable of further DNA synthesis unless recombination intervenes to restart replication. We use time-lapse microscopy and genetic assays to show that recombination is initiated within ~ 10 min of replication fork blockage at a site-specific barrier in fission yeast, leading to a restarted fork within ~ 60 min, which is only prevented/curtailed by the arrival of the opposing replication fork. The restarted fork is susceptible to further collapse causing hyper recombination downstream of the barrier. Surprisingly, in our system fork restart is unnecessary for maintaining cell viability. Seemingly, the risk of failing to complete replication prior to mitosis is sufficient to warrant the induction of recombination even though it can cause deleterious genetic change. PMID- 25806684 TI - Experimental evolution reveals hidden diversity in evolutionary pathways. AB - Replicate populations of natural and experimental organisms often show evidence of parallel genetic evolution, but the causes are unclear. The wrinkly spreader morph of Pseudomonas fluorescens arises repeatedly during experimental evolution. The mutational causes reside exclusively within three pathways. By eliminating these, 13 new mutational pathways were discovered with the newly arising WS types having fitnesses similar to those arising from the commonly passaged routes. Our findings show that parallel genetic evolution is strongly biased by constraints and we reveal the genetic bases. From such knowledge, and in instances where new phenotypes arise via gene activation, we suggest a set of principles: evolution proceeds firstly via pathways subject to negative regulation, then via promoter mutations and gene fusions, and finally via activation by intragenic gain-of function mutations. These principles inform evolutionary forecasting and have relevance to interpreting the diverse array of mutations associated with clinically identical instances of disease in humans. PMID- 25806685 TI - Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion. AB - The role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo. Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma TGs. Mice lacking Lpcat3 in the liver show reduced plasma TGs, hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles. These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways. PMID- 25806686 TI - Three ancient hormonal cues co-ordinate shoot branching in a moss. AB - Shoot branching is a primary contributor to plant architecture, evolving independently in flowering plant sporophytes and moss gametophytes. Mechanistic understanding of branching is largely limited to flowering plants such as Arabidopsis, which have a recent evolutionary origin. We show that in gametophytic shoots of Physcomitrella, lateral branches arise by re-specification of epidermal cells into branch initials. A simple model co-ordinating the activity of leafy shoot tips can account for branching patterns, and three known and ancient hormonal regulators of sporophytic branching interact to generate the branching pattern- auxin, cytokinin and strigolactone. The mode of auxin transport required in branch patterning is a key divergence point from known sporophytic pathways. Although PIN-mediated basipetal auxin transport regulates branching patterns in flowering plants, this is not so in Physcomitrella, where bi-directional transport is required to generate realistic branching patterns. Experiments with callose synthesis inhibitors suggest plasmodesmal connectivity as a potential mechanism for transport. PMID- 25806687 TI - Non-crossover gene conversions show strong GC bias and unexpected clustering in humans. AB - Although the past decade has seen tremendous progress in our understanding of fine-scale recombination, little is known about non-crossover (NCO) gene conversion. We report the first genome-wide study of NCO events in humans. Using SNP array data from 98 meioses, we identified 103 sites affected by NCO, of which 50/52 were confirmed in sequence data. Overlap with double strand break (DSB) hotspots indicates that most of the events are likely of meiotic origin. We estimate that a site is involved in a NCO at a rate of 5.9 * 10( 6)/bp/generation, consistent with sperm-typing studies, and infer that tract lengths span at least an order of magnitude. Observed NCO events show strong allelic bias at heterozygous AT/GC SNPs, with 68% (58-78%) transmitting GC alleles (p = 5 * 10(-4)). Strikingly, in 4 of 15 regions with resequencing data, multiple disjoint NCO tracts cluster in close proximity (~20-30 kb), a phenomenon not previously seen in mammals. PMID- 25806689 TI - MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells. AB - Osteoblast differentiation of valve interstitial cells (VICs) is a key step in valve calcification, but the molecular mechanisms involved are not fully understood. In this study, we aimed to investigate whether microRNA (miR)-204 regulated VICs differentiation through modulation of runt-related transcription factor 2 (Runx2), a key transcription factor for osteogenesis. Our data demonstrated that miR-204 was markedly downregulated in both human calcified aortic valves and bone morphogenetic protein (BMP)-2-stimulated aortic VICs. In vitro experiments showed that miR-204 acted as a negative regulator of osteogenic differentiation by repressing Runx2 and thereby inhibiting expression of osteoblast-related genes, including alkaline phosphatase and osteocalcin, which were all induced by BMP-2. Luciferase reporter assays validated Runx2 as the direct target of miR-204. Furthermore, increased alkaline phosphatase activity and osteocalcin expression after miR-204 inhibition were abolished by small interfering RNA-mediated silencing of Runx2. Overall, these data suggested miR 204 as a possible molecular switch inhibiting osteoblastic transdifferentiation of human aortic VICs and targeting miR-204 may have therapeutic potential for human aortic valve calcification. PMID- 25806691 TI - Hyper-expanded interlayer separations in superconducting barium intercalates of FeSe. AB - Intercalation of Ba in beta-FeSe by ammonothermal synthesis results in the formation of different superconducting phases with interlayer distance ranging between 8.4 and 13.1 A. The values of Tc are primarily dependent on Ba content, and are further modulated by the interlayer spacing through facile intercalation and deintercalation of ammonia. PMID- 25806690 TI - Resolvin D1 Reduces Infarct Size Through a Phosphoinositide 3-Kinase/Protein Kinase B Mechanism. AB - This study was designed to determine if Resolvin D1 (RvD1), a pro-resolution metabolite of the omega-3 polyunsaturated fatty acid docosahexaenoic acid, could decrease myocardial infarct size with delivered at the onset of ischemia. Male Sprague Dawley rats underwent 40 minutes of myocardial ischemia followed by reperfusion. These animals received 1 intraventricular injection of RvD1 (0.01, 0.1, or 0.3 MUg RvD1) or vehicle (saline) before coronary occlusion. Infarct size and neutrophil accumulation were evaluated 24 hours after the onset of reperfusion. Caspase-3, caspase-8, protein kinase B (Akt) activities were evaluated 30 minutes after the reperfusion. Rats receiving 0.1 or 0.3 MUg RvD1 showed a significant decrease of infarct size and caspase-3 and caspase-8 activities compared with the vehicle controls. Neutrophil accumulations were reduced in rats administered RvD1 compared with vehicle, independently of dose level. Akt activation was increased only in animals receiving 0.1 or 0.3 MUg, whereas no change was observed in the 0.01 MUg group. When they were treated with LY-294002, a phosphoinositide 3-kinase (PI3K)/Akt inhibitor, cardioprotection by RvD1 was abrogated. RvD1 treatment at the onset of ischemia decreases infarct size by a mechanism involving the PI3K/Akt pathway. PMID- 25806692 TI - Nature index 2015 Asia-Pacific. PMID- 25806693 TI - The Asia-Pacific impact. PMID- 25806694 TI - China. PMID- 25806695 TI - Japan. PMID- 25806688 TI - Combination Treatment With Antihypertensive Agents Enhances the Effect of Qiliqiangxin on Chronic Pressure Overload-induced Cardiac Hypertrophy and Remodeling in Male Mice. AB - We previously showed that Qiliqiangxin (QL) capsules could ameliorate cardiac hypertrophy and remodeling in a mouse model of pressure overload. Here, we compared the effects of QL alone with those of QL combined with the following 3 types of antihypertensive drugs on cardiac remodeling and dysfunction induced by pressure overload for 4 weeks in mice: an angiotensin II type 1 receptor (AT1-R) blocker (ARB), an angiotensin-converting enzyme inhibitor (ACEI), and a beta adrenergic receptor (beta-AR) blocker (BB). Adult male mice (C57B/L6) were subjected to either transverse aortic constriction or sham operation for 4 weeks, and the drugs (or saline) were orally administered through gastric tubes. Cardiac function and remodeling were evaluated through echocardiography, catheterization, histology, and analysis of hypertrophic gene expression. Cardiomyocyte apoptosis and autophagy, AT1-R and beta1-AR expression, and cell proliferation-related molecules were also examined. Although pressure overload-induced cardiac remodeling and dysfunction, hypertrophic gene reprogramming, AT1-R and beta1-AR expression, and ERK phosphorylation were significantly attenuated by QL alone, QL + ARB, QL + ACEI, and QL + BB, the attenuation was stronger in the combination treatment groups. Moreover, apoptosis was reduced to a larger extent by each combination treatment than by QL alone, whereas autophagy was more strongly attenuated by either QL + ARB or QL + ACEI. None of the treatments significantly upregulated ErbB2 or ErbB4 phosphorylation, and none significantly downregulated C/EBPbeta expression. Therefore, the effects of QL on chronic pressure overload induced cardiac remodeling may be significantly increased when QL is combined with an ARB, an ACEI, or a BB. PMID- 25806696 TI - South Korea. PMID- 25806697 TI - Australia. PMID- 25806698 TI - India. PMID- 25806699 TI - Asian Tigers, Pacific Panthers. PMID- 25806700 TI - A guide to the Nature Index. PMID- 25806702 TI - Imaging in vivo glutamate fluctuations with [(11)C]ABP688: a GLT-1 challenge with ceftriaxone. AB - Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [(11)C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [(11)C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP(ND)) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [(11)C]ABP688 BP(ND) in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions. PMID- 25806704 TI - Cerebrovascular reactivity is increased with acclimatization to 3,454 m altitude. AB - Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO2 reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAv mean) CVR was assessed during hyperventilation (hypocapnia) and CO2 administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26 +/- 4 years (mean +/- s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAv mean was not altered. Hypercapnic CVR was decreased at HA0 (1.16% +/- 0.16%/mm Hg, mean +/- s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13% +/- 0.18% and 2.96% +/- 0.10%/mm Hg) and HA22 (3.32% +/- 0.12% and 3.24% +/- 0.14%/mm Hg) compared with SL (1.98% +/- 0.22% and 2.38% +/- 0.10%/mm Hg; P < 0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAv mean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude. PMID- 25806707 TI - Correction: Pure and Zn-doped Pt clusters go flat and upright on MgO(100). PMID- 25806705 TI - Synthesis, structural characterization and biological activity of two diastereomeric JA-Ile macrolactones. AB - Jasmonates are phytohormones involved in a wide range of plant processes, including growth, development, senescence, and defense. Jasmonoyl-L-isoleucine (JA-Ile, 2), an amino acid conjugate of jasmonic acid (JA, 1), has been identified as a bioactive endogenous jasmonate. However, JA-Ile (2) analogues trigger different responses in the plant. omega-Hydroxylation of the pentenyl side chain leads to the inactive 12-OH-JA-Ile (3) acting as a "stop" signal. On the other hand, a lactone derivative of 12-OH-JA (5) (jasmine ketolactone, JKL) occurs in nature, although with no known biological function. Inspired by the chemical structure of JKL (6) and in order to further explore the potential biological activities of 12-modified JA-Ile derivatives, we synthesized two macrolactones (JA-Ile-lactones (4a) and (4b)) derived from 12-OH-JA-Ile (3). The biological activity of (4a) and (4b) was tested for their ability to elicit nicotine production, a well-known jasmonate dependent secondary metabolite. Both macrolactones showed strong biological activity, inducing nicotine accumulation to a similar extent as methyl jasmonate does in Nicotiana attenuata leaves. Surprisingly, the highest nicotine contents were found in plants treated with the JA-Ile-lactone (4b), which has (3S,7S) configuration at the cyclopentanone not known from natural jasmonates. Macrolactone (4a) is a valuable standard to explore for its occurrence in nature. PMID- 25806708 TI - Multi-modular, tris(triphenylamine) zinc porphyrin-zinc phthalocyanine-fullerene conjugate as a broadband capturing, charge stabilizing, photosynthetic 'antenna reaction center' mimic. AB - A broadband capturing, charge stabilizing, photosynthetic antenna-reaction center model compound has been newly synthesized and characterized. The model compound is comprised of a zinc porphyrin covalently linked to three units of triphenylamine entities and a zinc phthalocyanine entity. The absorption and fluorescence spectra of zinc porphyrin complemented that of zinc phthalocyanine offering broadband coverage. Stepwise energy transfer from singlet excited triphenylamine to zinc porphyrin, and singlet excited zinc porphyrin to zinc phthalocyanine (kENT ~ 10(11) s(-1)) was established from spectroscopic and time resolved transient absorption techniques. Next, an electron acceptor, fullerene was introduced via metal-ligand axial coordination to both zinc porphyrin and zinc phthalocyanine centers, and they were characterized by spectroscopic and electrochemical techniques. An association constant of 4.9 * 10(4) M(-1) for phenylimidazole functionalized fullerene binding to zinc porphyrin, and 5.1 * 10(4) M(-1) for it binding to zinc phthalocyanine was obtained. An energy level diagram for the occurrence of different photochemical events within the multi modular donor-acceptor conjugate was established from spectral and electrochemical data. Unlike the previous zinc porphyrin-zinc phthalocyanine fullerene conjugates, the newly assembled donor-acceptor conjugate has been shown to undergo the much anticipated initial charge separation from singlet excited zinc porphyrin to the coordinated fullerene followed by a hole shift process to zinc phthalocyanine resulting in a long-lived charge separated state as revealed by femto- and nanosecond transient absorption spectroscopic techniques. The lifetime of the final charge separated state was about 100 ns. PMID- 25806709 TI - Manganese catalyzed C-H functionalization of indoles with alkynes to synthesize bis/trisubstituted indolylalkenes and carbazoles: the acid is the key to control selectivity. AB - The Mn-catalyzed C-H alkenylation reactions of indole with terminal- and internal alkynes have been developed. In the presence of a catalytic amount of acid, the procedure efficiently affords bis/trisubstituted indolyl-alkenes in a highly regio- and stereo-selective manner. Without the addition of acid, the reaction undergoes a [2+2+2] cyclization process to give carbazoles with release of hydrogen gas. Notably, the directing pyrimidyl group can be readily removed. Experimental studies reveal that the reaction is initiated by a C-H activation step and the acid is the selectivity controller via a hydrogen transfer process. PMID- 25806706 TI - A family of transposable elements co-opted into developmental enhancers in the mouse neocortex. AB - The neocortex is a mammalian-specific structure that is responsible for higher functions such as cognition, emotion and perception. To gain insight into its evolution and the gene regulatory codes that pattern it, we studied the overlap of its active developmental enhancers with transposable element (TE) families and compared this overlap to uniformly shuffled enhancers. Here we show a striking enrichment of the MER130 repeat family among active enhancers in the mouse dorsal cerebral wall, which gives rise to the neocortex, at embryonic day 14.5. We show that MER130 instances preserve a common code of transcriptional regulatory logic, function as enhancers and are adjacent to critical neocortical genes. MER130, a nonautonomous interspersed TE, originates in the tetrapod or possibly Sarcopterygii ancestor, which far predates the appearance of the neocortex. Our results show that MER130 elements were recruited, likely through their common regulatory logic, as neocortical enhancers. PMID- 25806710 TI - Thermal evolution of the crystal structure of proton conducting BaCe0.8Y0.2O3 delta from high-resolution neutron diffraction in dry and humid atmosphere. AB - The crystal structure of the proton conducting perovskite BaCe(0.8)Y(0.2)O(3 delta) (BCY20) has been studied via high-resolution in situ neutron diffraction performed in controlled dry and humid (heavy water) oxygen flow. Two phase transitions, cubic Pm3[combining macron]m->R3[combining macron]c (775 degrees C) >Imma (250 degrees C) were observed on cooling from 1000 degrees C in dry O(2). A significant shift of the phase stability fields was observed on cooling in wet oxygen (pD(2)O ~ 0.2 atm) with the R3[combining macron]c structure stabilised at 900 degrees C, and the R3[combining macron]c->Imma transition occurring at 675 degrees C. On cooling below 400 degrees C a monoclinic, I2/m, phase started to appear. The structural dependence on hydration level is primarily due to the de stabilisation of the correlated, octahedra tilts as a consequence of structural relaxation around the oxygen vacancies present in the non-hydrated phase. The tendency of hydrated BaCe(0.8)Y(0.2)O(3-delta) to show octahedral tilting is also found to be enhanced, indicating that the deuteronic (protonic) defects influence the crystal structure, possibly via hydrogen bonding. Stabilisation of the monoclinic I2/m phase is attributed to the structural effect of deuterons that is inferred to increase on cooling as deuterons localise to a greater extent. Changing from wet oxidising (O(2) + D2O(g)) to wet reducing (5% H2 in Ar + D2O(g)) atmosphere did not influence the structure or the phase stability, indicating that Ce(4+) was not reduced under the present conditions. Based on the observed cell volume expansion protonic defects are present in the material at 900 degrees C at a D(2)O partial pressure of ~0.2 atm. The origin of the chemical expansion is explained by the effective size of the oxygen vacancy being significantly smaller than the [OD] defect. Rietveld analysis has been used to locate possible sites for the deuterons in the high temperature, R3[combining macron]c and Imma, phases that are most relevant for proton transport. PMID- 25806703 TI - Targeting neutrophils in ischemic stroke: translational insights from experimental studies. AB - Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood-brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions. PMID- 25806712 TI - Squamous non-small cell lung cancer as a distinct clinical entity. AB - Traditionally, the treatment of lung cancer has been based on histologic type [non-small cell lung cancer (NSCLC) or small cell lung cancer], performance status, and stage of disease. However, more recently, treatment decisions are being made based on molecular and histologic characteristics of the tumor. Specifically, the subclassification of NSCLC as squamous or nonsquamous is important in the context of newer treatments because clinical data have demonstrated differences in the tolerability and activity of these agents. Although progress continues to be made in the treatment of nonsquamous NSCLC, a significant unmet need exists for patients with squamous NSCLC. For both targeted and chemotherapeutic agents, the majority of regulatory approvals and updates to clinical practice guidelines for advanced NSCLC have focused on nonsquamous disease. In addition, because of safety concerns, patients with squamous NSCLC have been excluded from a number of clinical trials of investigational agents, particularly those targeting angiogenesis. This review discusses the importance of histology for treatment selection in NSCLC and summarizes recently completed and ongoing trials of investigational agents in squamous NSCLC. In addition, exciting developments in next-generation sequencing of squamous NSCLC have highlighted differences between squamous and nonsquamous disease and revealed potential new therapeutic targets. Advances in the molecular genetics of squamous NSCLC and implications for therapy will also be reviewed. Although progress in squamous NSCLC has faced limitations, momentum is building toward the identification of more effective treatments for this patient population. PMID- 25806711 TI - MYC and human telomerase gene (TERC) copy number gain in early-stage non-small cell lung cancer. AB - OBJECTIVES: We investigated the frequency of MYC and TERC increased gene copy number (GCN) in early-stage non-small cell lung cancer (NSCLC) and evaluated the correlation of these genomic imbalances with clinicopathologic parameters and outcome. MATERIALS AND METHODS: Tumor tissues were obtained from 113 resected NSCLCs. MYC and TERC GCNs were tested by fluorescence in situ hybridization (FISH) according to the University of Colorado Cancer Center (UCCC) criteria and based on the receiver operating characteristic (ROC) classification. RESULTS: When UCCC criteria were applied, 41 (36%) cases for MYC and 41 (36%) cases for TERC were considered FISH-positive. MYC and TERC concurrent FISH-positive was observed in 12 cases (11%): 2 (17%) cases with gene amplification and 10 (83%) with high polysomy. By using the ROC analysis, high MYC (mean >= 2.83 copies/cell) and TERC (mean >= 2.65 copies/cell) GCNs were observed in 60 (53.1%) cases and 58 (51.3%) cases, respectively. High TERC GCN was associated with squamous cell carcinoma (SCC) histology (P=0.001). In univariate analysis, increased MYC GCN was associated with shorter overall survival (P=0.032 [UCCC criteria] or P=0.02 [ROC classification]), whereas high TERC GCN showed no association. In multivariate analysis including stage and age, high MYC GCN remained significantly associated with worse overall survival using both the UCCC criteria (P=0.02) and the ROC classification (P=0.008). CONCLUSIONS: Our results confirm MYC as frequently amplified in early-stage NSCLC and increased MYC GCN as a strong predictor of worse survival. Increased TERC GCN does not have prognostic impact but has strong association with squamous histology. PMID- 25806714 TI - Multiple lentigines confined to psoriatic plaques induced by biologic agents in psoriasis therapy: a case and review of the literature. AB - Multiple lentigines confined to psoriatic plaques is a rare entity, which is more frequently recognized after the use of systemic biologic agents for psoriasis therapy. Although this phenomenon was previously accepted as a postinflammatory reaction, recent observations suggest psoriasis-related cytokines and their efficient supression by biologic agents strongly associate with melanogenesis and melanocytic proliferation. Hereby, we report a patient who developed multiple lentigines arising in resolved psoriatic plaques induced by infliximab and review similar cases reported in the literature induced after biologic treatments of psoriasis. PMID- 25806713 TI - Efficacy of oxaliplatin-based chemotherapy + bevacizumab as first-line treatment for advanced colorectal cancer: a systematic review and pooled analysis of published trials. AB - OBJECTIVES: Oxaliplatin and either capecitabine or infusional/bolus 5 fluorouracil (5FU)-based chemotherapy + bevacizumab (XELOX + B and FOLFOX + B) represent 2 of the approved first-line treatments for advanced colorectal cancer (CRC). However, the addition of B did not offer a survival benefit compared with FOLFOX/XELOX alone in the phase III, NO16966 trial. The aim of this review was to aggregate all published data on the efficacy of XELOX and FOLFOX-B in prospective and retrospective studies as first-line therapy for stage IV CRC. METHODS: We performed a systematic review, through PubMed and EMBASE, of all published studies exploring the efficacy of fluoropyrimidines + oxaliplatin + B-based chemotherapy as first-line chemotherapy in advanced CRC patients. Pooled estimates of the response rates, weighted medians of progression-free survival, and overall survival from all FOLFOX + B and XELOX + B arms were calculated. RESULTS: A total of 25 studies were retrieved, with a total of 7878 patients. Overall, the pooled response rates (n=20 publications) was 49.1%. The median progression-free survival and overall survival (n=21 and 22 publications, respectively) were 10.3 and 23.7 months, respectively. The pooled median rate of surgical resection of metastases (n=13 publications) was 14%. CONCLUSIONS: XELOX + B and FOLFOX + B are active combinations as first-line treatment of advanced CRC. The efficacy is confirmed for the first time from this pooled analysis of 25 trials. Both the XELOX + B and the FOLFOX + B arms represent 2 of the cornerstone combinations when B is used as first-line therapy. PMID- 25806715 TI - Caffeine impairs gastrointestinal function in newborn rats. AB - BACKGROUND: Feeding intolerance is commonly documented in premature infants. Caffeine is routinely utilized for apnea of prematurity treatment and known to reduce the lower esophageal sphincter (LES) muscle tone, but the caffeine effect on the newborn gastrointestinal function is unknown. We hypothesized that caffeine impairs esophageal and gastrointestinal motor function. As such, we investigated the drug effect on the tissue's mechanical properties and the newborn rat's in vivo gastric emptying rate. METHODS: The effects of caffeine on LES, gastric fundal and antrum, as well as ileal and colonic muscle force potential and relaxation response, were measured in newborn and adult rats. The caffeine-induced (10 mg/kg i.p.) newborn gastric emptying rate changes were evaluated following 3 h of fasting. RESULTS: Caffeine relaxed the precontracted LES and fundal muscle (P < 0.01), reduced the gastric and intestinal muscle contraction (P < 0.01), and delayed the pups' gastric emptying time (P < 0.01). The caffeine-induced muscle relaxant effect was independent of age and mediated via ryanodine receptors. CONCLUSION: Caffeine administration to newborn rats at a dose comparable to the one therapeutically used for preterm neonates impairs LES and gastrointestinal motor function. Further clinical investigation on the possible contribution of caffeine to neonatal feeding intolerance is warranted. PMID- 25806716 TI - Urinary neutrophil gelatinase-associated lipocalin: potential biomarker for late onset sepsis. AB - BACKGROUND: To assess the ability of urinary neutrophil gelatinase-associated lipocalin (UNGAL) to discriminate between culture-positive vs. culture-negative late-onset sepsis evaluations. METHODS: This is a prospective observational study of 136 neonates who underwent >=1 sepsis evaluation at >72 h of age. Urine was obtained at the time of sepsis evaluation to measure UNGAL concentration. Using generalized estimating equations controlling for gender, gestational and postnatal age, acute kidney injury, and within-patient correlations, pair-wise contrasts between mean log UNGAL concentrations of infants with negative sepsis evaluations vs. culture-positive sepsis and presumed sepsis were assessed. Discrimination characteristics at several UNGAL cutoff concentrations were assessed using receiver-operating characteristic curves. RESULTS: The predicted mean log UNGAL values of culture-positive sepsis and presumed sepsis vs. negative sepsis evaluations differed significantly (P < 0.001 and P = 0.02, respectively). At a cutoff >= 50 ng/ml, UNGAL discriminated between culture-positive sepsis and culture-negative sepsis evaluations with sensitivity = 86%, specificity = 56%, positive predictive value = 41%, negative predictive value = 92%, and number needed to treat = 3. CONCLUSION: UNGAL is a noninvasive biomarker with high negative predictive value at the time of late-onset sepsis evaluation in neonates and could be a useful adjunct to traditional components of sepsis evaluations. PMID- 25806718 TI - Optimization of polyphenol extraction from red grape pomace using aqueous glycerol/tartaric acid mixtures and response surface methodology. AB - Grape pomace is a food industry waste containing a high burden of antioxidant polyphenols and several methodologies have been developed for their efficient extraction. However, a sustainable and environmentally friendly process should involve recovery means composed of benign, non-toxic solvents, such as tartaric acid and glycerol, which are natural food constituents. In this line, this study examined the extraction of polyphenols using aqueous tartaric acid/glycerol solutions. The aim was to assess the role of acid and glycerol concentration in the extraction yield, employing a Box-Behnken experimental design and response surface methodology. The results showed that solutions containing only glycerol (20%, w/v) are more suitable for retrieving polyphenols, flavonoids, and pigments from grape pomace, while tartaric acid exerted a negative effect in this regard, when tested at concentrations up to 2% (w/v). PMID- 25806717 TI - Heparin-binding EGF-like growth factor and enteric neural stem cell transplantation in the prevention of experimental necrotizing enterocolitis in mice. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is associated with loss of neurons and glial cells in the enteric nervous system (ENS). Our goal was to determine whether enteric neural stem cell (NSC) transplantation, in conjunction with heparin-binding epidermal growth factor-like growth factor (HB-EGF), could protect against experimental NEC. METHODS: In vitro, HB-EGF on NSC proliferation and migration, and the effects of receptors utilized by HB-EGF to exert these effects, were determined. In vivo, mouse pups were exposed to experimental NEC and treated with NSC alone, HB-EGF alone, NSC+HB-EGF, or HB-EGF overexpressing NSC. NSC engraftment and differentiation into neurons in the ENS, intestinal injury, intestinal permeability, and intestinal motility were determined. RESULTS: HB-EGF promoted NSC proliferation via ErbB-1 receptors and enhanced NSC migration via ErbB-1, ErbB-4, and Nardilysin receptors. HB-EGF significantly enhanced the engraftment of transplanted NSC into the ENS during NEC. NSC transplantation significantly reduced NEC incidence and improved gut barrier function and intestinal motility, and these effects were augmented by simultaneous administration of HB-EGF or by transplantation of HB-EGF overexpressing NSC. CONCLUSION: HB-EGF promotes NSC proliferation and migration. HB-EGF and NSC reduce intestinal injury and improve gut barrier function and intestinal motility in experimental NEC. Combined HB-EGF and NSC transplantation may represent a potential future therapy to prevent NEC. PMID- 25806719 TI - Initial constructs for patient-centered outcome measures to evaluate brain computer interfaces. AB - PURPOSE: The authors describe preliminary work toward the creation of patient centered outcome (PCO) measures to evaluate brain-computer interface (BCI) as an assistive technology (AT) for individuals with severe speech and physical impairments (SSPI). METHOD: In Phase 1, 591 items from 15 existing measures were mapped to the International Classification of Functioning, Disability and Health (ICF). In Phase 2, qualitative interviews were conducted with eight people with SSPI and seven caregivers. Resulting text data were coded in an iterative analysis. RESULTS: Most items (79%) were mapped to the ICF environmental domain; over half (53%) were mapped to more than one domain. The ICF framework was well suited for mapping items related to body functions and structures, but less so for items in other areas, including personal factors. Two constructs emerged from qualitative data: quality of life (QOL) and AT. Component domains and themes were identified for each. CONCLUSIONS: Preliminary constructs, domains and themes were generated for future PCO measures relevant to BCI. Existing instruments are sufficient for initial items but do not adequately match the values of people with SSPI and their caregivers. Field methods for interviewing people with SSPI were successful, and support the inclusion of these individuals in PCO research. Implications for Rehabilitation Adapted interview methods allow people with severe speech and physical impairments to participate in patient-centered outcomes research. Patient-centered outcome measures are needed to evaluate the clinical implementation of brain-computer interface as an assistive technology. PMID- 25806721 TI - "Smart guns" and bed net update. PMID- 25806723 TI - A 15-year-old girl with weakness, fatigue, chest pain, and headaches. PMID- 25806722 TI - Helping families around military deployments. PMID- 25806724 TI - A pediatric practice's journey to provide care to "healthy babies and children". AB - In 1923, Dr. Alfred Traisman literally hung out his shingle on the corner of Clark Street and Arthur Avenue in the East Rogers Park neighborhood of Chicago, IL, and thus began over 90 years of our practice-providing care to pediatric patients in the Chicagoland area. We have witnessed many changes since those early days but what has stayed consistent is the continuity of care, the focus on the patient, and our office as the medical home. The practice has 3 generations of Traisman pediatricians and some families can actually be traced back 5 generations. PMID- 25806725 TI - A 10-year-old girl with gastrointestinal hemorrhage. PMID- 25806726 TI - A 7-year-old girl with periodic flank discomfort. PMID- 25806728 TI - Assessment and treatment of attention-deficit/hyperactivity disorder: part 1. AB - Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Affecting up to 10% of children in the United States, it is one of the most frequently encountered conditions in primary care. ADHD is a chronic condition, and a significant number of youth continue to show impairment into adulthood. Given the national shortage of specialty mental health providers, primary care providers need to feel comfortable and competent in screening, assessing, and managing ADHD. Successful assessment for this disorder involves regular screening for symptoms of inattention, impulsivity, and hyperactivity during office visits. If ADHD is suspected, a more comprehensive evaluation utilizing standardized rating scales and multiple informants (eg, parents and teachers) is recommended to confirm the diagnosis and guide initial treatment interventions. PMID- 25806727 TI - Common signs and symptoms and unusual diagnoses: part 2. PMID- 25806729 TI - A 15-year-old girl with fever and abdominal pain. AB - We present a case of a previously healthy 15-year-old girl with fever, right lower quadrant pain, and hip pain. Her history was notable for a recent laparoscopic appendectomy that was complicated by the development of intraabdominal abscesses. She reported normal bowel movements and good appetite on a regular diet, although she did endorse a recent 5-kg weight loss. Further investigation and examination revealed a diagnosis of Crohn's disease with recurrent psoas muscle abscess as the etiology of her pain and fevers. Psoas abscess is a rare complication of Crohn's disease, and vague presenting symptoms may complicate its diagnosis. This case demonstrates the importance of maintaining a broad differential diagnosis when treating a child presenting with abdominal pain and fever. PMID- 25806720 TI - Antimicrobial peptides in 2014. AB - This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human alpha-defensin HD-6 is only antimicrobial under reduced conditions. The pH dependent oligomerization of human cathelicidin LL-37 is linked to double stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms. PMID- 25806730 TI - A 9-month-old boy with right-hand preference. AB - We present a case of a 9-month-old boy with a history of unequal hand movements, right-hand preference on physical examination, and cortical dysplasia on brain magnetic resonance imaging who was eventually diagnosed with cerebral palsy (CP). Although spasticity involving one or more limbs is the most common neurologic sign of CP, there can be a variety of other presenting symptoms including early hand preference, hypotonia, and oral motor dysfunction. In addition, traditional risk factors of premature birth and intrapartum complications are not always present. Given the wide clinical spectrum of CP, it is important for primary care providers to maintain a high index of suspicion to ensure appropriate diagnosis and early access to interventions. PMID- 25806731 TI - An athletic adolescent girl with proteinuria and hypertension. AB - An 18-year-old athletic adolescent presents with hypertension found during a routine screening. Her prior history includes familial hyperlipidemia. Hypertension in the adolescent is classified based on percentiles for age, sex, and height. The most common secondary cause of hypertension in the pediatric and adolescent patient is renal disease. This patient was found to have nephrotic syndrome and because of her age, a renal biopsy was required to make the diagnosis and to direct subsequent treatment plans. She was diagnosed with C3 glomerulopathy, which is the result of dysregulation and uncontrolled activation of the alternative complement pathway; new therapies are emerging for this disease. In this case, we review the diagnosis and initial assessment of hypertension in the pediatric patient, and the causes of nephrotic syndrome with a focus on C3 glomerulopathy. PMID- 25806732 TI - A rare cause of vomiting in a 5-year-old girl. AB - A 5-year-old previously healthy girl presented to the emergency department (ED) with vomiting for 6 days. Her activity level was normal but her parents described progressive exercise intolerance with frequent recreational breaks approximately 2 days prior to presentation. In addition, the child complained of mild abdominal discomfort that began 24 hours prior to her presentation. She had no diarrhea or changes in her diet or oral intake; she had no dysuria or changes in urination. She had no cough, shortness of breath, dizziness, vision changes, falls, or decreased coordination. PMID- 25806733 TI - A 15-year-old boy with abdominal pain, growth retardation, and anemia secondary to Helicobacter pylori-associated peptic ulcer. AB - A 15-year-old boy with abdominal pain, growth retardation, and symptomatic anemia requiring blood transfusion was seen by a gastroenterologist and found to have a large ulcerated, fungating, and actively bleeding mass in his stomach. Initially, the patient was screened for Helicobacter pylori and found to be negative, so there was concern for malignancy after multiple endoscopic procedures. The patient did not respond to initial ulcer treatment and immediately prior to scheduled partial gastrectomy, additional tissue sections from the initial biopsy were stained for H. pylori and rare positive staining organisms were found. The test was positive, and the patient was started empirically on treatment to which he responded and ultimately recovered fully. Gastrectomy was not performed, and following treatment, the ulcer, anemia, and poor growth resolved. PMID- 25806734 TI - The elephant in the room. PMID- 25806735 TI - The problematical prostate cancer. PMID- 25806736 TI - [People practising complementary therapy's responsibility]. PMID- 25806737 TI - [Re: An inside look from a hospital admission unit]. PMID- 25806738 TI - [Re: An inside look from a hospital admission unit]. PMID- 25806739 TI - [Re: An inside look from a hospital admission unit]. PMID- 25806741 TI - [Re: Hearing loss in children in Ostfold county 2000-09]. PMID- 25806742 TI - [S-H. Anderssen and colleagues reply]. PMID- 25806744 TI - [Re: Advance care planning discussions with geriatric patients]. PMID- 25806745 TI - [P. Friis replies]. PMID- 25806746 TI - [Re: An integrated understanding of subjective disorders in clinical practice]. PMID- 25806748 TI - [Re: Medicinal cannabis]. PMID- 25806749 TI - [Re: Medicinal cannabis]. PMID- 25806750 TI - [Re: Medicinal cannabis]. PMID- 25806751 TI - [Re: Occupational lung cancer in Sor-Trondelag county]. PMID- 25806752 TI - [Re: Amphetamine-induced psychosis or schizophrenia?]. PMID- 25806753 TI - [Correction. The incidence of melanoma is increasing again]. PMID- 25806754 TI - [A world free of nuclear weapons]. PMID- 25806755 TI - [More could benefit from bariatric surgery]. PMID- 25806757 TI - [Why orthogeriatrics?]. PMID- 25806760 TI - Preparedness for severe malaria. AB - BACKGROUND: About 60 patients with malaria are admitted to Norwegian hospitals every year. The prescription figures for malaria medication may suggest that Norwegians are increasingly exposed to malaria infection. MATERIAL AND METHOD: All Norwegian hospitals with a department of internal medicine were sent an electronic questionnaire for reporting the available methods for diagnosing and treating malaria. RESULTS: There was a 100% response (48/48). Microscopy for malaria diagnosis was available at 92% (44/48) and a rapid test for detecting malaria antigen at 67% (32/48), while 6% (3/48) had no malaria detection test available. Artesunate and quinine for intravenous treatment were both available at 6% (3/48), only artesunate at 27% (13/48) and only quinine at 27% (13/48) of the hospitals. Drugs for intravenous treatment of severe malaria were not available at 40% (19/48) of the hospitals. INTERPRETATION: More than a third of Norwegian hospitals lack preparedness for treating severe malaria, and some hospitals lack diagnostic procedures. Severe malaria is a condition that may rapidly become life-threatening and is treated with artesunate or quinine intravenously. All Norwegian hospitals should have procedures for emergency treatment of the disease. PMID- 25806761 TI - [Patient reporting of adverse drug reactions in Norway 2010-13]. AB - BACKGROUND: Since 1 March 2010, patients in Norway have had the opportunity to report adverse reactions to The Norwegian Medicines Agency. The purpose of this study was to review these reports. MATERIAL AND METHOD: The content of adverse reaction reports received from patients in the period from 1 March 2010 to 31 December 2013 was classified based on age, gender, suspected drug and suspected adverse reactions. The patient reports were compared to the adverse reaction reports received from health care professionals in the same period. RESULTS: A total of 755 reports from patients and 9629 reports from health care professionals were received during the period in question. The 20-39-year age group was most frequently represented in the patient reports. In the reports from health care professionals, the main age group was 0-9 years, followed by the 60 69-year age group. The drug group most often mentioned in the patient reports was drugs acting on the nervous system, and above all psychotropic drugs and analgesics, while vaccines dominated in the reports from health care professionals. Adverse mental and neurological reactions were most frequently reported by patients, while general symptoms and local reactions were most common in the reports from health care professionals. A total of 74 different adverse reactions were reported only by patients and not by the health care professionals. INTERPRETATION: Adverse drug reaction reports from patients are different from reports by health care professionals. Our findings indicate that the system with patient reporting functions as a supplement to reporting from health care professionals. PMID- 25806762 TI - [Cardiovascular safety of non-steroidal anti-inflammatory drugs]. AB - BACKGROUND: The selective cyclooxygenase (COX)-2 inhibitor rofecoxib was withdrawn from the market in 2004 due to cardiovascular toxicity. We have evaluated data on adverse cardiovascular effects caused by COX-2 inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDs) since 2004. MATERIAL AND METHOD: Searches in PubMed (2004-2014) identified 243 relevant articles. Following a selection process, 63 articles were reviewed and evaluated in light of Norwegian practice. RESULTS: The results from the studies reviewed are heterogenous. A majority of data indicate that all the selective COX-2 inhibitors, diclofenac and high-dose ibuprofen cause adverse cardiovascular effects to a problematic extent, whereas naproxen consistently exhibits low or no risk. For most NSAIDs high dosage is related to increased risk, and the increase in risk appears to be present from the start of treatment. The effects of length of treatment and predisposition for cardiovascular disease are less clear. INTERPRETATION: Adverse cardiovascular effects is as a group effect that applies to all the NSAIDs studied, except for naproxen and low-dose ibuprofen. The traditional classification of NSAIDs as COX-2 selective and non-selective drugs is unsuited for risk stratification. The current pattern of consumption of NSAIDs in the population does not correspond to our knowledge of the increased risk to which patients are exposed. PMID- 25806763 TI - Low-dose-rate brachytherapy for low-grade prostate cancer. AB - BACKGROUND: Prostate cancer is a radiosensitive type of cancer for which radiotherapy is used for both curative and palliative purposes. Low-dose-rate brachytherapy is an internal radiotherapy technique which allows high doses of radiation to be delivered to a tumour at short range and with a high degree of precision. We have conducted a systematic review of the evidence base for this treatment. The method is not established in Norway. METHOD: This review is based on systematic review articles and publications on treatment, outcomes, adverse effects and health economics considerations found by searching the databases Cochrane Library, Current Controlled Trials, Medline, Embase and NICE (National Institute of Clinical Excellence). RESULTS: Subsequent to long-term observations of the efficacy, adverse effects and costs presented in 43 selected studies, including one randomised, controlled trial, there is still uncertainty as to which of the three methods low-dose brachytherapy, external radiotherapy and radical prostatectomy is optimal. The reason for this is the methodological differences in patient selection and in endpoints such as biochemical disease free interval and cause-specific survival. The evidence base appears to suggest that low-dose-rate brachytherapy causes more frequent grade 2 and 3 doctor reported urogenital adverse effects than prostatectomy, but better patient reported sexual functions and fewer patients with urinary incontinence than after surgery. Low-dose-rate brachytherapy appears to be socioeconomically cost effective. INTERPRETATION: The evidence base with respect to therapeutic effect and toxicity in men with low-risk prostate cancer treated with low-dose brachytherapy is regarded as solidly documented. However, there are no good prospective randomised multi-centre trials with overall survival as an endpoint. PMID- 25806764 TI - [High voltage injury to the head]. PMID- 25806765 TI - A young woman with slender hands. PMID- 25806766 TI - Who has misled Trond Mohn? PMID- 25806767 TI - My Nepalese eye. PMID- 25806768 TI - [Staring death in the eye]. PMID- 25806769 TI - [The aged are the oldest--or just older?]. PMID- 25806770 TI - [Transfusion--not blood transfusion]. PMID- 25806774 TI - [Better patient safety?]. PMID- 25806775 TI - [Working when you are sick]. PMID- 25806781 TI - Unwarranted optimism in media portrayals of genetic research on addiction overshadows critical ethical and social concerns. AB - The cost of addiction in the United States, in combination with a host of new tools and techniques, has fueled an explosion of genetic research on addiction. Because the media has the capacity to reflect and influence public perception, there is a need to examine how treatments and preventive approaches projected to emerge from addiction genetic research are presented to the public. The authors conducted a textual analysis of 145 news articles reporting on genetic research on addiction from popular print media in the United States and from popular news and medical internet sites. In articles that report on prevention, the media emphasize vaccine development and identifying individuals at genetic risk through population screening. Articles that emphasize treatment often promote current pharmaceutical solutions and highlight the possibility of tailoring treatments to specific genetic variants. The authors raise concerns about the tendency of this coverage to focus on the benefits of pharmaceutical treatments and genetic-based approaches to prevention while neglecting or downplaying potential risks and ethical issues. This analysis suggests a need for more balanced, evidence-based media reporting on the potential outcomes of genetic research. PMID- 25806780 TI - Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy. AB - We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9 12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment. PMID- 25806782 TI - Memory of pain induced by physical exercise. AB - The aim of this study was to assess the memory of pain induced by running a marathon and the factors that influence it. Sixty-two marathon runners participated in the study, which comprised two phases. Immediately after a participant had reached the finishing line of the marathon, they were asked to rate the intensity and the unpleasantness of their pain and the emotions they felt at that time. Either three or six months later they were asked again to rate the intensity and the unpleasantness of the same pain experience. Regardless of the length of recall delay, participants underestimated both recalled pain intensity and unpleasantness. The pain and negative affect reported at the time of the pain experience accounted for 24% of the total variance in predicting recalled pain intensity and 22% of the total variance in predicting recalled pain unpleasantness. Positive affect at the time of pain experience was not a significant predictor of both the recalled pain intensity and pain unpleasantness. It is concluded that pain induced by physical exercise is not remembered accurately and the pain and negative affect experienced influence recall. Further research is needed on the influence of positive affect on the memory of pain. PMID- 25806783 TI - Narrowband UV-B Phototherapy for Steroid-Refractory Sclerotic Chronic Cutaneous Graft-vs-Host Disease. AB - IMPORTANCE: Chronic graft-vs-host disease (GVHD) affects 50% to 70% of patients who receive allogeneic hematopoietic cell transplants (HCTs), and the skin is the most common site of involvement. Chronic cutaneous GVHD can present with sclerotic or nonsclerotic changes of the skin and often requires treatment with systemic immunosuppressants, extracorporeal photopheresis, or phototherapy. We describe the first reported case, to our knowledge, of the effective treatment of sclerotic chronic cutaneous GVHD with narrowband UV-B (NB UV-B) phototherapy. OBSERVATIONS: A woman in her 40s presented with sclerotic chronic GVHD of the skin 6 years after HCT for treatment of chronic myelogenous leukemia. The patient's cutaneous disease progressed despite treatment with prednisone and oral tacrolimus. The patient was initiated on NB UV-B phototherapy 3 times per week, resulting in clinically significant improvement of cutaneous lesions over the first 2 months. The NB UV-B regimen allowed for a reduction of prednisone dose and continued control of cutaneous GVHD over 6 months of therapy. CONCLUSIONS AND RELEVANCE: Our case report describes the successful use of NB UV-B phototherapy for the treatment of sclerotic chronic cutaneous GVHD. Further study should be performed to evaluate the effectiveness of this therapeutic modality for patients with sclerotic chronic cutaneous GVHD. PMID- 25806784 TI - Towards anatomic scale agent-based modeling with a massively parallel spatially explicit general-purpose model of enteric tissue (SEGMEnT_HPC). AB - Perhaps the greatest challenge currently facing the biomedical research community is the ability to integrate highly detailed cellular and molecular mechanisms to represent clinical disease states as a pathway to engineer effective therapeutics. This is particularly evident in the representation of organ-level pathophysiology in terms of abnormal tissue structure, which, through histology, remains a mainstay in disease diagnosis and staging. As such, being able to generate anatomic scale simulations is a highly desirable goal. While computational limitations have previously constrained the size and scope of multi scale computational models, advances in the capacity and availability of high performance computing (HPC) resources have greatly expanded the ability of computational models of biological systems to achieve anatomic, clinically relevant scale. Diseases of the intestinal tract are exemplary examples of pathophysiological processes that manifest at multiple scales of spatial resolution, with structural abnormalities present at the microscopic, macroscopic and organ-levels. In this paper, we describe a novel, massively parallel computational model of the gut, the Spatially Explicitly General-purpose Model of Enteric Tissue_HPC (SEGMEnT_HPC), which extends an existing model of the gut epithelium, SEGMEnT, in order to create cell-for-cell anatomic scale simulations. We present an example implementation of SEGMEnT_HPC that simulates the pathogenesis of ileal pouchitis, and important clinical entity that affects patients following remedial surgery for ulcerative colitis. PMID- 25806786 TI - Platelets in inflammation and infection. AB - Although platelets are traditionally recognized for their central role in hemostasis, many lines of research clearly demonstrate these rather ubiquitous blood components are potent immune modulators and effectors. Platelets have been shown to directly recognize, sequester and kill pathogens, to activated and recruit leukocytes to sites of infection and inflammation, and to modulate leukocyte behavior, enhancing their ability to phagocytose and kill pathogens and inducing unique effector functions, such as the production of Neutrophil Extracellular Traps (NETs). This multifaceted response to infection and inflammation is due, in part, to the huge array of soluble mediators and cell surface molecules expressed by platelets. From their earliest origins as primordial hemocytes in invertebrates to their current form as megakaryocyte derived cytoplasts, platelets have evolved to be one of the key regulators of host intravascular immunity and inflammation. In this review, we present the diverse roles platelets play in immunity and inflammation associated with autoimmune diseases and infection. Additionally, we highlight recent advances in our understanding of platelet behavior made possible through the use of advanced imaging techniques that allow us to visualize platelets and their interactions, in real-time, within the intact blood vessels of a living host. PMID- 25806787 TI - Perspectives on global prevention and control of mycotoxins. Foreword. PMID- 25806785 TI - Genetic interaction between G2/M phase-specific transcription factor MYB3R4 and MAPKKK ANP3 for execution of cytokinesis in Arabidopsis thaliana. AB - Plant cells are surrounded by rigid cell walls, and hence, their division is associated with a plant-specific mode of cytokinesis in which the cell plate, a new cell wall, is generated and separates 2 daughter nuclei. The successful execution of cytokinesis requires the timely activation of multiple regulatory pathways, which include the AtNACK1/HINKEL kinesin-induced MAPK cascade and MYB3R1/4-mediated transcriptional activation of G2/M-specific genes. However, it remains unclear whether and how these pathways are functionally interconnected to each other. By analyzing enhancer mutations of myb3r4, here we found a close genetic interaction between the 2 pathways; a mutation in ANP3, which encodes MAPKKK (acting downstream of AtNACK1/HINKEL), strongly enhanced the defective cytokinesis observed in the myb3r4 mutant. This interaction may not be due to the direct activation of MYB3R1/4 by the MAPK cascade; rather, possibly to the downstream targets of these 2 signaling pathways, acting in close proximity. Our results showed that MYB3R1/4 may positively affect cytokinesis via multiple pathways, one of which may act independently from the KNOLLE-dependent pathway defined previously, and affect the downstream events that may also be under the control of the AtNACK1/HINKEL-mediated MAPK cascade. PMID- 25806789 TI - Correction: The Wobbler mouse model of amyotrophic lateral sclerosis (ALS) displays hippocampal hyperexcitability, and reduced number of interneurons, but no presynaptic vesicle release impairments. PMID- 25806788 TI - Paternal age and offspring congenital heart defects: a national cohort study. AB - Paternal age has been associated with offspring congenital heart defects (CHDs), which might be caused by increased mutations in the germ cell line because of cumulated cell replications. Empirical evidences, however, remain inconclusive. Furthermore, it is unknown whether all subtypes of CHDs are affected by paternal age. We aimed to explore the relationship between paternal age and the risk of offspring CHDs and its five common subtypes using national register data in Denmark. A total of 1,893,899 singletons born in Denmark from 1977 to 2008 were included in this national-based cohort study. Cox's proportion hazards model with robust sandwich estimate option was used to estimate the hazards ratio (95% confidence interval) for the associations between paternal age and all CHDs, as well as subtypes of CHDs (patent ductus arteriosus (PDA), ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of fallot (TOF) and coarctation of the aorta (CoA)). We did not observe an overall association between paternal age and offspring CHDs. However, compared to the paternal age of 25-29 years, paternal age of older than 45 years was associated with a 69% increased risk of PDA (HR45+ = 1.69, 95%CI:1.17-2.43). We observed similar results when subanalyses were restricted to children born to mothers of 27-30 years old. After taking into consideration of maternal age, our data suggested that advanced paternal age was associated with an increased prevalence of one subtype of offspring congenital heart defects (CHDs), namely patent ductus arteriosus (PDA). PMID- 25806790 TI - Accelerated senescence and enhanced disease resistance in hybrid chlorosis lines derived from interspecific crosses between tetraploid wheat and Aegilops tauschii. AB - Hybrid chlorosis, a type of hybrid incompatibility, has frequently been reported in inter- and intraspecific crosses of allopolyploid wheat. In a previous study, we reported some types of growth abnormalities such as hybrid necrosis and observed hybrid chlorosis with mild or severe abnormalities in wheat triploids obtained in crosses between tetraploid wheat cultivar Langdon and four Ae. tauschii accessions and in their derived synthetic hexaploids. However, the molecular mechanisms underlying hybrid chlorosis are not well understood. Here, we compared cytology and gene expression in leaves to characterize the abnormal growth in wheat synthetics showing mild and severe chlorosis. In addition, we compared disease resistance to wheat blast fungus. In total 55 and 105 genes related to carbohydrate metabolism and 53 and 89 genes for defense responses were markedly up-regulated in the mild and severe chlorosis lines, respectively. Abnormal chloroplasts formed in the mesophyll cells before the leaves yellowed in the hybrid chlorosis lines. The plants with mild chlorosis showed increased resistance to wheat blast and powdery mildew fungi, although significant differences only in two, third internode length and maturation time, out of the examined agricultural traits were found between the wild type and plants showing mild chlorosis. These observations suggest that senescence might be accelerated in hybrid chlorosis lines of wheat synthetics. Moreover, in wheat synthetics showing mild chlorosis, the negative effects on biomass can be minimized, and they may show substantial fitness under pathogen-polluted conditions. PMID- 25806793 TI - Social distancing and the unvaccinated. PMID- 25806792 TI - Novel analysis of maturation of murine bone-marrow-derived dendritic cells induced by Ginkgo Seed Polysaccharides. AB - Our understanding of the mechanisms of effect of Ginkgo Seed Polysaccharides (GSPs) on the immune system remains unclear. The aim of this work was to investigate the effect of GSPs on the maturation and function of bone-marrow derived dendritic cells (BMDCs). The results demonstrate that GSP could exert positive immune modulation on the maturation and functions of BMDCs. This effect was evidenced by decreased changes of phagosome number inside BMDCs, decreased activity of acidic phosphatase (ACP), decreased phagocytosis of BMDCs, and increased changes of key membrane molecules on BMDCs. Upregulated production of cytokines IL-12 and TNF-alpha also was confirmed. Therefore, it can be concluded that GSPs can efficiently induce the maturation of BMDCs. Our exploration provides direct data and a rationale for potential application of GSPs as an immune enhancer in improving immunity and as a potent adjuvant in the design of DC-based vaccines. PMID- 25806791 TI - Activation of HIFa pathway in mature osteoblasts disrupts the integrity of the osteocyte/canalicular network. AB - The hypoxia-inducible factors (HIFs), HIF-1alpha and HIF-2alpha, are the central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Previous studies indicated that disruption of the von Hippel-Lindau gene (Vhl) coincides with the activation of HIFalpha signaling. Here we show that inactivation of Vhl in mature osteoblasts/osteocytes induces their apoptosis and disrupts the cell/canalicular network. VHL-deficient (DeltaVHL) mice exhibited a significantly increased cortical bone area resulting from enhanced proliferation and osteogenic differentiation of the bone marrow stromal cells (BMSCs) by inducing the expression of beta-catenin in the BMSC. Our data suggest that the VHL/HIFalpha pathway in mature osteoblasts/osteocytes plays a critical role in the bone cell/canalicular network and that the changes of osteocyte morphology/function and cell/canalicular network may unleash the bone formation, The underlying mechanism of which was the accumulation of beta-catenin in the osteoblasts/osteoprogenitors of the bone marrow. PMID- 25806794 TI - Is loneliness in later life a self-fulfilling prophecy? AB - OBJECTIVES: There are many stereotypes about ageing and later life. We looked at the association between expectations and stereotyping of loneliness in old age and actual self-reported loneliness status 8 years later in English Longitudinal Study of Ageing (ELSA). METHOD: Data from 4465 ELSA core members aged over 50 who responded to Waves 2 (2004) did not report loneliness in Wave 2, and responded to loneliness questions at least once between Waves 3 and 6 (2006-2012) were used in multivariable repeated measures logit regression analysis to estimate relationship between perceived stereotypes and expectation of loneliness in older age and actual loneliness reported within 8 years of follow-up. RESULTS: Twenty four per cent of respondents from the analytical sample agreed at Wave 2 that old age is time of loneliness and 33% expected to be lonely in old age. Loneliness was reported by 11.5% of respondents at Waves 3-6. Both stereotypes and expectation were significantly associated with later reported loneliness (OR 2.65 (95% CI 2.05-3.42) for stereotypes and 2.98 (95% CI 2.33-3.75) for expectations in age-sex adjusted analysis). Both variables significantly predicted future loneliness even when socio-demographic circumstances were taken into account and both variables were mutually adjusted although the effect was reduced (OR's 1.53 (95% CI 1.16-2.01) for stereotypes and 2.38 (95% CI 1.84-3.07) for expectations). CONCLUSIONS: Stereotypes and expectations related to loneliness in the old age were significantly associated with reported loneliness 8 years later. Interventions aimed at changing age-related stereotypes in population may have more impact on reducing loneliness than individually based services. PMID- 25806797 TI - Risks for nonaffective psychotic disorder and bipolar disorder in young people with autism spectrum disorder: a population-based study. AB - IMPORTANCE: Whether individuals with autism spectrum disorder (ASD) are at increased risk for nonaffective psychotic disorder (NAPD) or bipolar disorder (BD) is unknown. OBJECTIVE: To test whether the risks for NAPD and BD in individuals with ASD are increased and whether these risks are higher than those of their siblings not diagnosed as having ASD. DESIGN, SETTING, AND PARTICIPANTS: We performed a nested case-control study of all individuals 17 years or younger who ever resided in Stockholm County, Sweden, from January 1, 2001, through December 31, 2011 (Stockholm Youth Cohort). We included cohort members ever diagnosed as having ASD (n = 9062) and their full siblings never diagnosed as having ASD. Each case was matched with 10 control individuals of the same sex born during the same month and year. Using Swedish registers, cases, siblings, and controls were followed up until December 31, 2011. By then, the oldest individuals had reached the age of 27 years. EXPOSURES: Autism spectrum disorder, registered before age 16 or 28 years. We distinguished between ASD with and without intellectual disability (ID). MAIN OUTCOMES AND MEASURES: We calculated odds ratios (ORs) for NAPD and BD adjusted for age, sex, population density of place of birth, personal or parental history of migration, hearing impairment, parental age, parental income, parental educational level, and parental history of psychiatric disorder. RESULTS: The adjusted ORs for NAPD and BD for cases with non-ID ASD registered before age 16 years were 5.6 (95% CI, 3.3-8.5) and 5.8 (95% CI, 3.9-8.7), respectively; the adjusted ORs for cases with ID ASD were 3.5 (95% CI, 2.0-6.0) and 1.8 (95% CI, 0.8-4.1). The adjusted ORs for NAPD and BD in cases with non-ID ASD registered before age 28 years were 12.3 (95% CI, 9.5-15.9) and 8.5 (95% CI, 6.5-11.2), respectively; for cases with ID ASD, these ORs were 6.4 (95% CI, 4.2-9.8) and 2.0 (95% CI, 1.0-3.9), respectively. The ORs for NAPD and BD for the nonautistic full siblings of cases for whom ASD was registered before age 16 years, adjusted for hearing loss, were 1.8 (95% CI, 1.1-2.7) and 1.7 (95% CI, 1.1-2.6), respectively. CONCLUSIONS AND RELEVANCE: A diagnosis of ASD is associated with a substantially increased risk for NAPD and BD. This finding contributes to our understanding of these disorders and has implications for the management of ASD. PMID- 25806795 TI - Mechanism of interaction of Al3+ with the proteins composition of photosystem II. AB - The inhibitory effect of Al3+on photosystem II (PSII) electron transport was investigated using several biophysical and biochemical techniques such as oxygen evolution, chlorophyll fluorescence induction and emission, SDS-polyacrylamide and native green gel electrophoresis, and FTIR spectroscopy. In order to understand the mechanism of its inhibitory action, we have analyzed the interaction of this toxic cation with proteins subunits of PSII submembrane fractions isolated from spinach. Our results show that Al 3+, especially above 3 mM, strongly inhibits oxygen evolution and affects the advancement of the S states of the Mn4O5Ca cluster. This inhibition was due to the release of the extrinsic polypeptides and the disorganization of the Mn4O5Ca cluster associated with the oxygen evolving complex (OEC) of PSII. This fact was accompanied by a significant decline of maximum quantum yield of PSII (Fv/Fm) together with a strong damping of the chlorophyll a fluorescence induction. The energy transfer from light harvesting antenna to reaction centers of PSII was impaired following the alteration of the light harvesting complex of photosystem II (LHCII). The latter result was revealed by the drop of chlorophyll fluorescence emission spectra at low temperature (77 K), increase of F0 and confirmed by the native green gel electrophoresis. FTIR measurements indicated that the interaction of Al 3+ with the intrinsic and extrinsic polypeptides of PSII induces major alterations of the protein secondary structure leading to conformational changes. This was reflected by a major reduction of alpha-helix with an increase of beta sheet and random coil structures in Al 3+-PSII complexes. These structural changes are closely related with the functional alteration of PSII activity revealed by the inhibition of the electron transport chain of PSII. PMID- 25806799 TI - Correction: The Irish potato famine pathogen Phytophthora infestans translocates the CRN8 kinase into host plant cells. PMID- 25806796 TI - Obesity alters gene expression for GH/IGF-I axis in mouse mammary fat pads: differential role of cortistatin and somatostatin. AB - Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology. PMID- 25806798 TI - Depth as an organizing force in Pocillopora damicornis: intra-reef genetic architecture. AB - Relative to terrestrial plants, and despite similarities in life history characteristics, the potential for corals to exhibit intra-reef local adaptation in the form of genetic differentiation along an environmental gradient has received little attention. The potential for natural selection to act on such small scales is likely increased by the ability of coral larval dispersal and settlement to be influenced by environmental cues. Here, we combine genetic, spatial, and environmental data for a single patch reef in Kane'ohe Bay, O'ahu, Hawai'i, USA in a landscape genetics framework to uncover environmental drivers of intra-reef genetic structuring. The genetic dataset consists of near exhaustive sampling (n = 2352) of the coral, Pocillopora damicornis at our study site and six microsatellite genotypes. In addition, three environmental parameters - depth and two depth-independent temperature indices - were collected on a 4 m grid across 85 locations throughout the reef. We use ordinary kriging to spatially interpolate our environmental data and estimate the three environmental parameters for each colony. Partial Mantel tests indicate a significant correlation between genetic relatedness and depth while controlling for space. These results are also supported by multi-model inference. Furthermore, spatial Principle Component Analysis indicates a statistically significant genetic cline along a depth gradient. Binning the genetic dataset based on size-class revealed that the correlation between genetic relatedness and depth was significant for new recruits and increased for larger size classes, suggesting a possible role of larval habitat selection as well as selective mortality in structuring intra-reef genetic diversity. That both pre- and post-recruitment processes may be involved points to the adaptive role of larval habitat selection in increasing adult survival. The conservation importance of uncovering intra-reef patterns of genetic diversity is discussed. PMID- 25806801 TI - Correction: melatonin inhibits endoplasmic reticulum stress and epithelial mesenchymal transition during bleomycin-induced pulmonary fibrosis in mice. PMID- 25806800 TI - Demedicalizing Health: The Kitchen as a Site of Care. AB - Attention to culinary care can enrich the framing of health within medical anthropology. We focus on care practices in six Latin American kitchens to illuminate forms of health not located within a singular human subject. In these kitchens, women cared not for individuals but for meals, targeting the health of families and landscapes. Many medical anthropologists have critiqued health for its associations with biomedicine/biocapitalism, some even taking a stance 'against health.' Although sympathetic to this critique, our focus on women's practices of caring for health through food highlights dissonances between clinical and nonclinical forms of health. We call for the development of an expanded vocabulary of health that recognizes health care treatment strategies that do not target solely the human body but also social, political, and environmental afflictions. PMID- 25806802 TI - Low expression of lncRNA-GAS5 is implicated in human primary varicose great saphenous veins. AB - The cellular mechanisms of primary varicose great saphenous veins (GSVs) involve inflammation, apoptosis, and proliferation of local cells and extracellular matrix degradation. Long non-coding RNAs (lncRNAs) play important roles in these cellular processes; however, which and how lncRNAs related to these mechanisms take effect on GSVs remain unclear. By screening lncRNAs that might experience changes in GSV varicosities, we selected the lower expressed lncRNA-GAS5 (growth arrest specific transcript 5) for functional assessments. Silencing of lncRNA GAS5 promoted cell proliferation and migration, and cell cycle of the human saphenous vein smooth muscle cells (HSVSMCs), whereas overexpressing it inhibited these cellular behaviors and reduced apoptosis of HSVSMCs. RNA pull-down experiment revealed a direct bind of lncRNA-GAS5 to a Ca2+-dependent RNA-binding protein, Annexin A2. Further experiments showed that silencing of Annexin A2 reduced the HSVSMCs proliferation and vice versa. In the context of lncRNA-GAS5 knockdown, silencing of Annexin A2 reduced the proliferation of HSVSMCs while overexpression of Annexin A2 increased the proliferation. Thus, the low expression of lncRNA-GAS5 may facilitate HSVSMCs proliferation and migration through Annexin A2 and thereby the pathogenesis of GSV varicosities. PMID- 25806804 TI - A new species of Microhyla (Anura: Microhylidae) from Nilphamari, Bangladesh. AB - A new species of Microhyla frog from the Nilphamari district of Bangladesh is described and compared with its morphologically similar and geographically proximate congeners. Molecular phylogeny derived from mitochondrial DNA sequences revealed that although the new species--designated here as Microhyla nilphamariensis sp. nov.--forms a clade with M. ornate, it is highly divergent from M. ornata and all of its congeners, with 5.7-13.2% sequence divergence at the 16S rRNA gene. The new species can be identified phenotypically on the basis of a set of diagnostic (both qualitative and quantitative) characters as follows: head length is 77% of head width, distance from front of eyes to the nostril is roughly six times greater than nostril-snout length, internarial distance is roughly five times greater than nostril-snout length, interorbital distance is two times greater than internarial distance, and distance from back of mandible to back of the eye is 15% of head length. Furthermore, inner metacarpal tubercle is small and ovoid-shaped, whereas outer metacarpal tubercle is very small and rounded. Toes have rudimentary webbing, digital discs are absent, inner metatarsal tubercle is small and round, outer metatarsal tubercle is ovoid shaped, minute, and indistinct. PMID- 25806803 TI - NOX1 supports the metabolic remodeling of HepG2 cells. AB - NADPH oxidases are important sources of reactive oxygen species (ROS) which act as signaling molecules in the regulation of protein expression, cell proliferation, differentiation, migration and cell death. The NOX1 subunit is over-expressed in several cancers and NOX1 derived ROS have been repeatedly linked with tumorigenesis and tumor progression although underlying pathways are ill defined. We engineered NOX1-depleted HepG2 hepatoblastoma cells and employed differential display 2DE experiments in order to investigate changes in NOX1 dependent protein expression profiles. A total of 17 protein functions were identified to be dysregulated in NOX1-depleted cells. The proteomic results support a connection between NOX1 and the Warburg effect and a role for NOX in the regulation of glucose and glutamine metabolism as well as of lipid, protein and nucleotide synthesis in hepatic tumor cells. Metabolic remodeling is a common feature of tumor cells and understanding the underlying mechanisms is essential for the development of new cancer treatments. Our results reveal a manifold involvement of NOX1 in the metabolic remodeling of hepatoblastoma cells towards a sustained production of building blocks required to maintain a high proliferative rate, thus rendering NOX1 a potential target for cancer therapy. PMID- 25806805 TI - Postoperative changes in in vivo measured friction in total hip joint prosthesis during walking. AB - Loosening of the artificial cup and inlay is the most common reasons for total hip replacement failures. Polyethylene wear and aseptic loosening are frequent reasons. Furthermore, over the past few decades, the population of patients receiving total hip replacements has become younger and more active. Hence, a higher level of activity may include an increased risk of implant loosening as a result of friction-induced wear. In this study, an instrumented hip implant was used to measure the contact forces and friction moments in vivo during walking. Subsequently, the three-dimensional coefficient of friction in vivo was calculated over the whole gait cycle. Measurements were collected from ten subjects at several time points between three and twelve months postoperative. No significant change in the average resultant contact force was observed between three and twelve months postoperative. In contrast, a significant decrease of up to 47% was observed in the friction moment. The coefficient of friction also decreased over postoperative time on average. These changes may be caused by 'running-in' effects of the gliding components or by the improved lubricating properties of the synovia. Because the walking velocity and contact forces were found to be nearly constant during the observed period, the decrease in friction moment suggests an increase in fluid viscosity. The peak values of the contact force individually varied by 32%-44%. The friction moment individually differed much more, by 110%-129% at three and up to 451% at twelve months postoperative. The maximum coefficient of friction showed the highest individual variability, about 100% at three and up to 914% at twelve months after surgery. These individual variations in the friction parameters were most likely due to different 'running-in' effects that were influenced by the individual activity levels and synovia properties. PMID- 25806806 TI - Abnormal pregnancy outcomes in mice using an induced periodontitis model and the haematogenous migration of Fusobacterium nucleatum sub-species to the murine placenta. AB - OBJECTIVES: To investigate if there is subspecies specific migration to the placenta by Fusobacterium nucleatum (Fn) and to determine whether experimentally induced periodontitis results in adverse pregnancy outcomes (APO) in mice. METHODS: Periodontitis was induced in pregnant mice using an inoculum of Fn and Porphyromonas gingivalis. In parallel, four sub-species of Fn were individually injected into the circulatory system. At day 18 of gestation, the placenta, liver, spleen and blood were harvested and litter size, number of viable fetuses and resorptions, maternal, fetal and placenta weights were recorded. For the direct inoculation group, some mice were allowed to deliver for assessment of length of gestation, litter size, maternal, placental and pup weight. The presence of Fn was assessed by PCR and inflammatory mediators were measured by ELISA or multiplex analysis. RESULTS: Mice with alveolar bone loss, a marker of periodontitis, demonstrated significantly higher fetal weights (p = 0.015) and fetal/placental weight ratios (p = 0.030). PCR analysis of maternal organs did not identify Fn in any extracted tissues. In mice that received direct injection of Fn subspecies, varying degrees of APO were observed including preterm birth, intrauterine growth restriction, and fetal loss. Haematogenous spread of only Fn subsp. nucleatum to the placenta was confirmed. Litter size was significantly smaller (p = 0.023) and the number of resorptions was higher in inoculated versus control groups. Mice injected with subsp. nucleatum had significantly increased circulating CRP levels (p = 0.020) compared to controls while the mice with induced periodontitis had increased levels of IL-6 (p = 0.047) and IL-8 (p = 0.105). CONCLUSIONS: Periodontitis in mice elevated fetal weight and the fetal weight/placental weight ratio. This study found that subsp. nucleatum migrated haematogenously to the placenta, leading to APO in mice. The study supports the potential role of Fn in the association between periodontitis and APO. PMID- 25806807 TI - Transcriptome profiling of khat (Catha edulis) and Ephedra sinica reveals gene candidates potentially involved in amphetamine-type alkaloid biosynthesis. AB - Amphetamine analogues are produced by plants in the genus Ephedra and by khat (Catha edulis), and include the widely used decongestants and appetite suppressants (1S,2S)-pseudoephedrine and (1R,2S)-ephedrine. The production of these metabolites, which derive from L-phenylalanine, involves a multi-step pathway partially mapped out at the biochemical level using knowledge of benzoic acid metabolism established in other plants, and direct evidence using khat and Ephedra species as model systems. Despite the commercial importance of amphetamine-type alkaloids, only a single step in their biosynthesis has been elucidated at the molecular level. We have employed Illumina next-generation sequencing technology, paired with Trinity and Velvet-Oases assembly platforms, to establish data-mining frameworks for Ephedra sinica and khat plants. Sequence libraries representing a combined 200,000 unigenes were subjected to an annotation pipeline involving direct searches against public databases. Annotations included the assignment of Gene Ontology (GO) terms used to allocate unigenes to functional categories. As part of our functional genomics program aimed at novel gene discovery, the databases were mined for enzyme candidates putatively involved in alkaloid biosynthesis. Queries used for mining included enzymes with established roles in benzoic acid metabolism, as well as enzymes catalyzing reactions similar to those predicted for amphetamine alkaloid metabolism. Gene candidates were evaluated based on phylogenetic relationships, FPKM-based expression data, and mechanistic considerations. Establishment of expansive sequence resources is a critical step toward pathway characterization, a goal with both academic and industrial implications. PMID- 25806810 TI - Temporal effects in trend prediction: identifying the most popular nodes in the future. AB - Prediction is an important problem in different science domains. In this paper, we focus on trend prediction in complex networks, i.e. to identify the most popular nodes in the future. Due to the preferential attachment mechanism in real systems, nodes' recent degree and cumulative degree have been successfully applied to design trend prediction methods. Here we took into account more detailed information about the network evolution and proposed a temporal-based predictor (TBP). The TBP predicts the future trend by the node strength in the weighted network with the link weight equal to its exponential aging. Three data sets with time information are used to test the performance of the new method. We find that TBP have high general accuracy in predicting the future most popular nodes. More importantly, it can identify many potential objects with low popularity in the past but high popularity in the future. The effect of the decay speed in the exponential aging on the results is discussed in detail. PMID- 25806808 TI - Is objectively measured sitting time associated with low back pain? A cross sectional investigation in the NOMAD study. AB - BACKGROUND: Studies on the association between sitting time and low back pain (LBP) have found contrasting results. This may be due to the lack of objectively measured sitting time or because socioeconomic confounders were not considered in the analysis. OBJECTIVES: To investigate the association between objectively measured sitting time (daily total, and occupational and leisure-time periods) and LBP among blue-collar workers. METHODS: Two-hundred-and-one blue-collar workers wore two accelerometers (GT3X+ Actigraph) for up to four consecutive working days to obtain objective measures of sitting time, estimated via Acti4 software. Workers reported their LBP intensity the past month on a scale from 0 (no pain) to 9 (worst imaginable pain) and were categorized into either low (<= 5) or high (> 5) LBP intensity groups. In the multivariate-adjusted binary logistic regression analysis, total sitting time, and occupational and leisure time sitting were both modeled as continuous (hours/day) and categorical variables (i.e. low, moderate and high sitting time). RESULTS: The multivariate logistic regression analysis showed a significant positive association between total sitting time (per hour) and high LBP intensity (odds ratio; OR = 1.43, 95%CI = 1.15-1.77, P = 0.01). Similar results were obtained for leisure-time sitting (OR = 1.45, 95%CI = 1.10-1.91, P = 0.01), and a similar but non significant trend was obtained for occupational sitting time (OR = 1.34, 95%CI 0.99-1.82, P = 0.06). In the analysis on categorized sitting time, high sitting time was positively associated with high LBP for total (OR = 3.31, 95%CI = 1.18 9.28, P = 0.03), leisure (OR = 5.31, 95%CI = 1.57-17.90, P = 0.01), and occupational (OR = 3.26, 95%CI = 0.89-11.98, P = 0.08) periods, referencing those with low sitting time. CONCLUSION: Sitting time is positively associated with LBP intensity among blue-collar workers. Future studies using a prospective design with objective measures of sitting time are recommended. PMID- 25806809 TI - Interactions between environmental factors and melatonin receptor type 1A polymorphism in relation to oral cancer susceptibility and clinicopathologic development. AB - BACKGROUND: The purpose of this study was to explore the combined effect of melatonin receptor type 1A (MTNR1A) gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of oral cancer. METHODOLOGY AND PRINCIPAL FINDINGS: Three polymorphisms of the MTNR1A gene from 618 patients with oral cancer and 560 non cancer controls were analyzed by real-time polymerase chain reaction (PCR). The CTA haplotype of the studied MTNR1A polymorphisms (rs2119882, rs13140012, rs6553010) was related to a higher risk of oral cancer. Moreover, MTNR1A gene polymorphisms exhibited synergistic effects of environmental factors (betel quid and tobacco use) on the susceptibility of oral cancer. Finally, oral-cancer patients with betel quid-chewing habit who had T/T allele of MTNR1A rs13140012 were at higher risk for developing an advanced clinical stage and lymph node metastasis. CONCLUSION: These results support gene-environment interactions of MTNR1A polymorphisms with smoking and betel quid-chewing habits possibly altering oral-cancer susceptibility and metastasis. PMID- 25806811 TI - Drug combinations against Borrelia burgdorferi persisters in vitro: eradication achieved by using daptomycin, cefoperazone and doxycycline. AB - Although most Lyme disease patients can be cured with antibiotics doxycycline or amoxicillin using 2-4 week treatment durations, some patients suffer from persistent arthritis or post-treatment Lyme disease syndrome. Why these phenomena occur is unclear, but possibilities include host responses, antigenic debris, or B. burgdorferi organisms remaining despite antibiotic therapy. In vitro, B. burgdorferi developed increasing antibiotic tolerance as morphology changed from typical spirochetal form in log phase growth to variant round body and microcolony forms in stationary phase. B. burgdorferi appeared to have higher persister frequencies than E. coli as a control as measured by SYBR Green I/propidium iodide (PI) viability stain and microscope counting. To more effectively eradicate the different persister forms tolerant to doxycycline or amoxicillin, drug combinations were studied using previously identified drugs from an FDA-approved drug library with high activity against such persisters. Using a SYBR Green/PI viability assay, daptomycin-containing drug combinations were the most effective. Of studied drugs, daptomycin was the common element in the most active regimens when combined with doxycycline plus either beta-lactams (cefoperazone or carbenicillin) or an energy inhibitor (clofazimine). Daptomycin plus doxycycline and cefoperazone eradicated the most resistant microcolony form of B. burgdorferi persisters and did not yield viable spirochetes upon subculturing, suggesting durable killing that was not achieved by any other two or three drug combinations. These findings may have implications for improved treatment of Lyme disease, if persistent organisms or detritus are responsible for symptoms that do not resolve with conventional therapy. Further studies are needed to validate whether such combination antimicrobial approaches are useful in animal models and human infection. PMID- 25806812 TI - Phylogenetic reconstruction by cross-species chromosome painting and G-banding in four species of Phyllostomini tribe (Chiroptera, Phyllostomidae) in the Brazilian Amazon: an independent evidence for monophyly. AB - The subfamily Phyllostominae comprises taxa with a variety of feeding strategies. From the cytogenetic point of view, Phyllostominae shows different rates of chromosomal evolution between genera, with Phyllostomus hastatus probably retaining the ancestral karyotype for the subfamily. Since chromosomal rearrangements occur rarely in the genome and have great value as phylogenetic markers and in taxonomic characterization, we analyzed three species: Lophostoma silvicola (LSI), Phyllostomus discolor (PDI) and Tonatia saurophila (TSA), representing the tribe Phyllostomini, collected in the Amazon region, by classic and molecular cytogenetic techniques in order to reconstruct the phylogenetic relationships within this tribe. LSA has a karyotype of 2n=34 and FN=60, PDI has 2n=32 and FN=60 and TSA has 2n=16 and FN=20. Comparative analysis using G-banding and chromosome painting show that the karyotypic complement of TSA is highly rearranged relative to LSI and PHA, while LSI, PHA and PDI have similar karyotypes, differing by only three chromosome pairs. Nearly all chromosomes of PDI and PHA were conserved in toto, except for chromosome 15 that was changed by a pericentric inversion. A strongly supported phylogeny (bootstrap=100 and Bremer=10 steps), confirms the monophyly of Phyllostomini. In agreement with molecular topologies, TSA was in the basal position, while PHA and LSI formed sister taxa. A few ancestral syntenies are conserved without rearrangements and most associations are autapomorphic traits for Tonatia or plesiomorphic for the three genera analyzed here. The karyotype of TSA is highly derived in relation to that of other phyllostomid bats, differing from the supposed ancestral karyotype of Phyllostomidae by multiple rearrangements. Phylogenies based on chromosomal data are independent evidence for the monophyly of tribe Phyllostomini as determined by molecular topologies and provide additional support for the paraphyly of the genus Tonatia by the exclusion of the genus Lophostoma. PMID- 25806813 TI - Motor activity improves temporal expectancy. AB - Certain brain areas involved in interval timing are also important in motor activity. This raises the possibility that motor activity might influence interval timing. To test this hypothesis, we assessed interval timing in healthy adults following different types of training. The pre- and post-training tasks consisted of a button press in response to the presentation of a rhythmic visual stimulus. Alterations in temporal expectancy were evaluated by measuring response times. Training consisted of responding to the visual presentation of regularly appearing stimuli by either: (1) pointing with a whole-body movement, (2) pointing only with the arm, (3) imagining pointing with a whole-body movement, (4) simply watching the stimulus presentation, (5) pointing with a whole-body movement in response to a target that appeared at irregular intervals (6) reading a newspaper. Participants performing a motor activity in response to the regular target showed significant improvements in judgment times compared to individuals with no associated motor activity. Individuals who only imagined pointing with a whole-body movement also showed significant improvements. No improvements were observed in the group that trained with a motor response to an irregular stimulus, hence eliminating the explanation that the improved temporal expectations of the other motor training groups was purely due to an improved motor capacity to press the response button. All groups performed a secondary task equally well, hence indicating that our results could not simply be attributed to differences in attention between the groups. Our results show that motor activity, even when it does not play a causal or corrective role, can lead to improved interval timing judgments. PMID- 25806815 TI - Overtreatment of young adults with colon cancer: more intense treatments with unmatched survival gains. AB - IMPORTANCE: Colon cancer is increasing among adults younger than 50 years. However, the prognosis of young-onset colon cancer remains poorly defined given significant age-related demographic, disease, and treatment differences. OBJECTIVE: To define stage-specific treatments and prognosis of colon cancer diagnosed in young adults (ages 18-49 years) vs older adults (ages 65-75 years) outside of the clinical trial setting while accounting for real-world age-related variations in patient, tumor, and treatment factors. DESIGN, SETTING, AND PARTICIPANTS: A nationwide cohort study was conducted among US hospitals accredited by the American College of Surgeons Commission on Cancer. Participants were 13 102 patients diagnosed as having young-onset colon adenocarcinoma aged 18 to 49 years and 37 007 patients diagnosed as having later-onset colon adenocarcinoma aged 65 to 75 years treated between January 1, 2003, and December 31, 2005, and reported to the National Cancer Data Base. EXPOSURES: Patients who underwent surgical resection and postoperative systemic chemotherapy of curative intent. MAIN OUTCOMES AND MEASURES: The primary end point was stage-specific relative survival, an objective measure of survival among patients with cancer, adjusting for baseline mortality rates and independent of the data on cause of death. The secondary end point was stage-specific likelihood of receiving postoperative systemic chemotherapy. RESULTS: Most young-onset colon cancer was initially seen at advanced stages (61.8% had stage III or IV). After adjusting for patient-related and tumor-related factors, young patients were more likely to receive systemic chemotherapy, particularly multiagent regimens, at all stages relative to those with later-onset disease. These odds ratios were 2.88 (95% CI, 2.21-3.77) for stage I, 3.93 (95% CI, 3.58-4.31) for stage II, 2.42 (95% CI, 2.18 2.68) for stage III, and 2.74 (95% CI, 2.44-3.07) for stage IV. The significantly more intense treatments received by younger patients were unmatched by any survival gain, which was nil for stage II (relative risk, 0.90; 95% CI, 0.69 1.17) and marginal for stage III (relative risk, 0.89; 95% CI, 0.81-0.97) and stage IV (relative risk, 0.84; 95% CI, 0.79-0.90). CONCLUSIONS AND RELEVANCE: Young adults with colon cancer received significantly more postoperative systemic chemotherapy at all stages, but they experienced only minimal gain in adjusted survival compared with their older counterparts who received less treatment. This mismatch suggests that attention should be given to long-term cancer survivorship in young adults with colon cancer because they likely face survivorship needs that are distinct from those of their older counterparts. PMID- 25806816 TI - Enantioselective Lewis Acid Catalysis in Intramolecular [2 + 2] Photocycloaddition Reactions: A Mechanistic Comparison between Representative Coumarin and Enone Substrates. AB - The intramolecular [2 + 2] photocycloaddition of three 4-(alk-4-enyl)coumarins and three 1-(alk-4-enoyl)-2,3-dihydropyridones was studied in the absence and in the presence of Lewis acids (irradiation wavelength lambda = 366 nm). Spectral and kinetic data were collected for the respective parent compounds with a pent-4 enyl and a pent-4-enoyl chain. For the substrates with a methyl group in cis- or trans-position of the terminal alkene carbon atom (hex-4-enyl and hex-4-enoyl substitution), the stereochemical outcome of the [2 + 2] photocycloaddition was investigated. The mechanistic course of the uncatalyzed coumarin reactions was found to be a singlet pathway, whereas Lewis acid-catalyzed reactions proceeded with higher reaction rates in the triplet manifold. Contrary to that, the dihydropyridones underwent a fast triplet reaction in the absence of the Lewis acid. In the presence of a chiral Lewis acid the reactions slowed down but, due to the high extinction coefficient of the Lewis acid/dihydropyridone complexes at lambda = 366 nm, still resulted in high enantioselectivity. PMID- 25806814 TI - Functions of Fun30 chromatin remodeler in regulating cellular resistance to genotoxic stress. AB - The Saccharomyces cerevisiae Fun30 chromatin remodeler has recently been shown to facilitate long-range resection of DNA double strand break (DSB) ends, which proceeds homologous recombination (HR). This is believed to underlie the role of Fun30 in promoting cellular resistance to DSB inducing agent camptothecin. We show here that Fun30 also contributes to cellular resistance to genotoxins methyl methanesulfonate (MMS) and hydroxyurea (HU) that can stall the progression of DNA replication. We present evidence implicating DNA end resection in Fun30-dependent MMS-resistance. On the other hand, we show that Fun30 deletion suppresses the MMS and HU-sensitivity of cells lacking the Rad5/Mms2/Ubc13-dependent error-free DNA damage tolerance mechanism. This suppression is not the result of a reduction in DNA end resection, and is dependent on the key HR component Rad51. We further show that Fun30 negatively regulates the recovery of rad5Delta mutant from MMS induced G2/M arrest. Therefore, Fun30 has two functions in DNA damage repair: one is the promotion of cellular resistance to genotoxic stress by aiding in DNA end resection, and the other is the negative regulation of a Rad51-dependent, DNA end resection-independent mechanism for countering replicative stress. The latter becomes manifest when Rad5 dependent DNA damage tolerance is impaired. In addition, we find that the putative ubiquitin-binding CUE domain of Fun30 serves to restrict the ability of Fun30 to hinder MMS- and HU-tolerance in the absence of Rad5. PMID- 25806817 TI - Using bioconductor package BiGGR for metabolic flux estimation based on gene expression changes in brain. AB - Predicting the distribution of metabolic fluxes in biochemical networks is of major interest in systems biology. Several databases provide metabolic reconstructions for different organisms. Software to analyze flux distributions exists, among others for the proprietary MATLAB environment. Given the large user community for the R computing environment, a simple implementation of flux analysis in R appears desirable and will facilitate easy interaction with computational tools to handle gene expression data. We extended the R software package BiGGR, an implementation of metabolic flux analysis in R. BiGGR makes use of public metabolic reconstruction databases, and contains the BiGG database and the reconstruction of human metabolism Recon2 as Systems Biology Markup Language (SBML) objects. Models can be assembled by querying the databases for pathways, genes or reactions of interest. Fluxes can then be estimated by maximization or minimization of an objective function using linear inverse modeling algorithms. Furthermore, BiGGR provides functionality to quantify the uncertainty in flux estimates by sampling the constrained multidimensional flux space. As a result, ensembles of possible flux configurations are constructed that agree with measured data within precision limits. BiGGR also features automatic visualization of selected parts of metabolic networks using hypergraphs, with hyperedge widths proportional to estimated flux values. BiGGR supports import and export of models encoded in SBML and is therefore interoperable with different modeling and analysis tools. As an application example, we calculated the flux distribution in healthy human brain using a model of central carbon metabolism. We introduce a new algorithm termed Least-squares with equalities and inequalities Flux Balance Analysis (Lsei-FBA) to predict flux changes from gene expression changes, for instance during disease. Our estimates of brain metabolic flux pattern with Lsei-FBA for Alzheimer's disease agree with independent measurements of cerebral metabolism in patients. This second version of BiGGR is available from Bioconductor. PMID- 25806818 TI - Design and evaluation of a cochlear implant strategy based on a "Phantom" channel. AB - Unbalanced bipolar stimulation, delivered using charge balanced pulses, was used to produce "Phantom stimulation", stimulation beyond the most apical contact of a cochlear implant's electrode array. The Phantom channel was allocated audio frequencies below 300 Hz in a speech coding strategy, conveying energy some two octaves lower than the clinical strategy and hence delivering the fundamental frequency of speech and of many musical tones. A group of 12 Advanced Bionics cochlear implant recipients took part in a chronic study investigating the fitting of the Phantom strategy and speech and music perception when using Phantom. The evaluation of speech in noise was performed immediately after fitting Phantom for the first time (Session 1) and after one month of take-home experience (Session 2). A repeated measures of analysis of variance (ANOVA) within factors strategy (Clinical, Phantom) and interaction time (Session 1, Session 2) revealed a significant effect for the interaction time and strategy. Phantom obtained a significant improvement in speech intelligibility after one month of use. Furthermore, a trend towards a better performance with Phantom (48%) with respect to F120 (37%) after 1 month of use failed to reach significance after type 1 error correction. Questionnaire results show a preference for Phantom when listening to music, likely driven by an improved balance between high and low frequencies. PMID- 25806820 TI - Evaluation of arch form between Vietnamese and North American Caucasians using 3 dimensional virtual models. AB - The purpose of this study was to investigate the three-dimensional (3D) morphologic differences in the mandibular arch of Vietnamese and North American White subjects. The sample included 113 Vietnamese subjects (41 Class I, 37 Class II and 35 Class III) and 96 White subjects (29 Class I, 30 Class II and 37 Class III). The samples were regrouped according to arch form types (tapered, ovoid, and square) to compare the frequency distribution of the three arch forms between ethnic groups in each angle classification. The facial axis point of each tooth was digitized on 3D virtual models. Four linear and two ratio variables were measured. In comparing arch dimensions, the intercanine and intermolar widths were wider in Vietnamese than in Whites (p < 0.001, p = 0.042, respectively). In the White group, there was even frequency distribution of the three arch forms. However, in the Vietnamese group, the square arch form was the most frequent followed by tapered and ovoid arch forms. The arch forms of Whites were narrower than Vietnamese. In North American Whites, the distribution of the arch form types showed similar frequency. In Vietnamese, the square arch form was more frequent. PMID- 25806819 TI - Seasonality and paleoecology of the late Cretaceous multi-taxa vertebrate assemblage of "Lo Hueco" (central eastern Spain). AB - Isotopic studies of multi-taxa terrestrial vertebrate assemblages allow determination of paleoclimatic and paleoecological aspects on account of the different information supplied by each taxon. The late Campanian-early Maastrichtian "Lo Hueco" Fossil-Lagerstatte (central eastern Spain), located at a subtropical paleolatitude of ~31 degrees N, constitutes an ideal setting to carry out this task due to its abundant and diverse vertebrate assemblage. Local delta18OPO4 values estimated from delta18OPO4 values of theropods, sauropods, crocodyliforms, and turtles are close to delta18OH2O values observed at modern subtropical latitudes. Theropod delta18OH2O values are lower than those shown by crocodyliforms and turtles, indicating that terrestrial endothermic taxa record delta18OH2O values throughout the year, whereas semiaquatic ectothermic taxa delta18OH2O values represent local meteoric waters over a shorter time period when conditions are favorable for bioapatite synthesis (warm season). Temperatures calculated by combining theropod, crocodyliform, and turtle delta18OH2O values and gar delta18OPO4 have enabled us to estimate seasonal variability as the difference between mean annual temperature (MAT, yielded by theropods) and temperature of the warmest months (TWMs, provided by crocodyliforms and turtles). DeltaTWMs-MAT value does not point to a significantly different seasonal thermal variability when compared to modern coastal subtropical meteorological stations and Late Cretaceous rudists from eastern Tethys. Bioapatite and bulk organic matter delta13C values point to a C3 environment in the "Lo Hueco" area. The estimated fractionation between sauropod enamel and diet is ~150/00. While waiting for paleoecological information yielded by the ongoing morphological study of the "Lo Hueco" crocodyliforms, delta13C and delta18OCO3 results point to incorporation of food items with brackish influence, but preferential ingestion of freshwater. "Lo Hueco" turtles showed the lowest delta13C and delta18OCO3 values of the vertebrate assemblage, likely indicating a diet based on a mixture of aquatic and terrestrial C3 vegetation and/or invertebrates and ingestion of freshwater. PMID- 25806821 TI - Rare earth element transfer from soil to navel orange pulp (Citrus sinensis Osbeck cv. Newhall) and the effects on internal fruit quality. AB - The effects of soil rare earth element (REE) on navel orange quality and safety in rare earth ore areas have gained great attention. This study investigated the transfer characteristics of REE from soil to navel orange pulp (Citrus sinensis Osbeck cv. Newhall) and examined the effects of soil REE on internal fruit quality in Xinfeng County, Jiangxi province, China. Path analysis showed that soil REE, pH, cation exchange capacity (CEC), and Fe oxide (Feox) significantly affected pulp REE concentrations. A Freundlich-type prediction model for pulp REE was established: log[REEpulp] = -1.036 + 0.272 log[REEsoil] - 0.056 pH - 0.360 log[CEC] + 0.370 log[Feox] (n = 114, R2 = 0.60). From the prediction model, it was inferred that even when soil REE and Feox were as high as 1038 mg kg-1 and 96.4 g kg-1, respectively, and pH and CEC were as low as 3.75 and 5.08 cmol kg-1, respectively, pulp REE concentrations were much lower than the food limit standard. Additionally, soil REE levels were significantly correlated with selected fruit quality indicators, including titratable acidity (r = 0.52, P < 0.01), total soluble solids (r = 0.48, P < 0.01) and vitamin C (r = 0.56, P < 0.01). Generally, under routine methods of water and fertilization management, the cultivation of navel oranges in rare earth ore areas of south China with soil REE ranging from 38.6 to 546 mg kg-1 had improved in internal fruit quality. PMID- 25806822 TI - Selective Endothelin-B Receptor Stimulation Increases Vascular Endothelial Growth Factor in the Rat Brain during Postnatal Development. AB - Endothelin, vascular endothelial growth factor and nerve growth factor play important roles in development of the central nervous system. ET(B) receptors have been shown to promote neurovascular remodeling in the adult ischemic brain through an increase in VEGF and NGF. It is possible that ET(B) receptors may be involved in postnatal development of the brain through VEGF and NGF. In the present study, the brains of male rat pups on postnatal days 1, 7, 14 and 28 were analyzed for expression of ET(B) receptors, VEGF and NGF. In order to determine the effect of ET(B) receptor stimulation, a separate group of pups were administered saline or ET(B) receptor agonist, IRL-1620, on day 21, and their brains were analyzed on day 28. The intensity of ET(B) receptor and VEGF staining in the vasculature as well as the number of blood vessels of normal pups increased with age and was significantly higher on postnatal day 14 compared to day 1 and day 7. In contrast, both ET(B) and NGF staining intensity in the cortex and subventricular zones decreased (P<0.01) at postnatal day 14 compared to earlier time points. Stimulation of ET(B) receptors resulted in a significant increase in VEGF and ET(B) intensity both in the vasculature and the brain (P<0.05), however, IRL-1620 did not produce any change in NGF expression. Results indicate that ET(B) receptors appear to play a role in the development of the CNS and selective stimulation of ET(B) receptors enhances VEGF but not NGF in the postnatal rat brain. PMID- 25806823 TI - Correction: Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. PMID- 25806824 TI - Aerobic fitness, micronutrient status, and academic achievement in Indian school aged children. AB - Aerobic fitness has been shown to have several beneficial effects on child health. However, research on its relationship with academic performance has been limited, particularly in developing countries and among undernourished populations. This study examined the association between aerobic fitness and academic achievement in clinically healthy but nutritionally compromised Indian school-aged children and assessed whether micronutrient status affects this association. 273 participants, aged 7 to 10.5 years, were enrolled from three primary schools in Bangalore, India. Data on participants' aerobic fitness (20-m shuttle test), demographics, anthropometry, diet, physical activity, and micronutrient status were abstracted. School-wide exam scores in mathematics and Kannada language served as indicators of academic performance and were standardized by grade level. The strength of the fitness/achievement association was analyzed using Spearman's rank correlation, multiple variable logistic regression, and multi-level models. Significant positive correlations between aerobic capacity (VO2 peak) and academic scores in math and Kannada were observed (P < 0.05). After standardizing scores across grade levels and adjusting for school, gender, socioeconomic status, and weight status (BMI Z-score), children with greater aerobic capacities (mL * kg(-1) * min(-1)) had greater odds of scoring above average on math and Kannada exams (OR=1.08, 95% CI: 1.02 to 1.15 and OR=1.11, 95% CI: 1.04 to 1.18, respectively). This association remained significant after adjusting for micronutrient deficiencies. These findings provide preliminary evidence of a fitness/achievement association in Indian children. While the mechanisms by which aerobic fitness may be linked to academic achievement require further investigation, the results suggest that educators and policymakers should consider the adequacy of opportunities for physical activity and fitness in schools for both their physical and potential academic benefits. PMID- 25806825 TI - Predominant leptospiral serogroups circulating among humans, livestock and wildlife in Katavi-Rukwa ecosystem, Tanzania. AB - BACKGROUND: Leptospirosis is a worldwide zoonotic disease and a serious, under reported public health problem, particularly in rural areas of Tanzania. In the Katavi-Rukwa ecosystem, humans, livestock and wildlife live in close proximity, which exposes them to the risk of a number of zoonotic infectious diseases, including leptospirosis. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional epidemiological study was carried out in the Katavi region, South-west Tanzania, to determine the seroprevalence of Leptospira spp in humans, domestic ruminants and wildlife. Blood samples were collected from humans (n = 267), cattle (n = 1,103), goats (n = 248), buffaloes (n = 38), zebra (n = 2), lions (n = 2), rodents (n = 207) and shrews (n = 11). Decanted sera were tested using the Microscopic Agglutination Test (MAT) for antibodies against six live serogroups belonging to the Leptospira spp, with a cutoff point of >= 1:160. The prevalence of leptospiral antibodies was 29.96% in humans, 30.37% in cattle, 8.47% in goats, 28.95% in buffaloes, 20.29% in rodents and 9.09% in shrews. Additionally, one of the two samples in lions was seropositive. A significant difference in the prevalence P<0.05 was observed between cattle and goats. No significant difference in prevalence was observed with respect to age and sex in humans or any of the sampled animal species. The most prevalent serogroups with antibodies of Leptospira spp were Sejroe, Hebdomadis, Grippotyphosa, Icterohaemorrhagie and Australis, which were detected in humans, cattle, goats and buffaloes; Sejroe and Grippotyphosa, which were detected in a lion; Australis, Icterohaemorrhagie and Grippotyphosa, which were detected in rodents; and Australis, which was detected in shrews. Antibodies to serogroup Ballum were detected only in humans. CONCLUSIONS: The results of this study demonstrate that leptospiral antibodies are widely prevalent in humans, livestock and wildlife from the Katavi-Rukwa ecosystem. The disease poses a serious economic and public health threat in the study area. This epidemiological study provides information on circulating serogroups, which will be essential in designing intervention measures to reduce the risk of disease transmission. PMID- 25806827 TI - Behavior of nanoparticles in extended nanospace measured by evanescent wave-based particle velocimetry. AB - The transport and behavior of nanoparticles, viruses, and biomacromolecules in 10 1000 nm confined spaces (hereafter "extended nanospaces") are important for novel analytical devices based on nanofluidics. This study investigated the concentration and diffusion of 64 nm nanoparticles in a fused-silica nanochannel of 410 nm depth, using evanescent wave-based particle velocimetry. We found that the injection of nanoparticles into the nanochannel by pressure-driven flow was significantly inhibited and that the nanoparticle diffusion was hindered anisotropically. A 0.2-pN repulsive force induced by the interaction between the nanoparticles and the channel wall is proposed as the dominant factor governing the behavior of nanoparticles in the nanochannel, on the basis of both experimental measurements and theoretical estimations. The results of this study will greatly further our understanding of mass transfer in extended nanospaces. PMID- 25806828 TI - Cooperative effect of pH-dependent ion transport within two symmetric-structured nanochannels. AB - A novel and simple design is introduced to construct bichannel nanofluid diodes by combining two poly(ethylene terephthalate) (PET) films with columnar nanochannel arrays varying in size or in surface charge. This type of bichannel device performs obvious ion current rectification, and the pH-dependent tunability and degree of rectification can be improved by histidine modification. The origin of the ion current rectification and its pH-dependent tunability are attributed to the cooperative effect of the two columnar half-channels and the applied bias on the mobile ions. As a result of surface groups on the bichannel being charged with different polarities or degrees at different pH values, the function of the bichannel device can be converted from a nanofluid diode to a normal nanochannel or to a reverse diode. PMID- 25806826 TI - The PAX3-FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-beta pathway. AB - PAX3-FOXO1 (PAX3-FKHR) is the fusion protein produced by the genomic translocation that characterizes the alveolar subtype of Rhabdomyosarcoma, a pediatric sarcoma with myogenic phenotype. PAX3-FOXO1 is an aberrant but functional transcription factor. It retains PAX3-DNA-binding activity and functionally overlaps PAX3 function while also disturbing it, in particular its role in myogenic differentiation. We herein show that PAX3-FOXO1 interferes with normal FOXO function. PAX3-FOXO1 affects FOXO-family member trans-activation capability and the FOXO-dependent TGF-beta response. PAX3-FOXO1 may contribute to tumor formation by inhibiting the tumor suppressor activities which are characteristic of both FOXO family members and TGF-beta pathways. The recognition of this mechanism raises new questions about how FOXO family members function. PMID- 25806829 TI - In naming the dead: Autosomal and Y-chromosomal STR typing on human skeletal remains from an 18th/19th century aristocratic crypt in Gallspach, Upper Austria. AB - Ancient DNA analyses have shown to be a powerful tool in the joint transdisciplinary assessment of archaeological records involving human remains. In this study we set out to identify single inhumations by synoptically evaluating the historical, archaeological, anthropological and molecular records on human remains from the crypt of the aristocratic family of Hoheneck (or: Hohenegg) dating to the 18(th) and 19(th) century AD. A total of 11 individuals were under investigation, yielding complete autosomal and Y-chromosomal STR profiles for 5 persons clearly showing a family group. DNA results, anthropological data and archaeological records taken together resulted in (almost) unambiguous correlation to historical records on the persons entombed in the crypt. PMID- 25806830 TI - Effects of levosimendan on heart failure in normotensive patients: does loading dose matter? AB - BACKGROUND: Levosimendan is a calcium sensitizer and K(+)-ATP channel opener with inotropic and vasodilatatory effects irrespective of myocardial oxygen consumption, used for treatment of heart failure (HF). A loading dose is usually given by infusion for 12 h; however, profound lowering of blood pressure often disrupts or prolongs the infusion. The aim of this study was to assess clinical, biochemical and myocardial differences between different regimes of levosimendan therapy, with or without loading dose, and compared to standard therapy in heart failure. METHODS: Fifty-seven patients (mean age +/- SD: 60.9 +/- 9.3 years, 45 males) with HF, New York Heart Association (NYHA) III-IV, reduced left ventricular ejection fraction (LVEF) were included. Twenty patients (NB group) were given levosimendan without loading dose, 14 patients (B group) were given levosimendan with loading dose, and 23 patients (C group) were given standard therapy. Clinical, biochemical and echocardiographic characteristics at baseline and one week after treatment were evaluated. RESULTS: Groups were similar at baseline. After one week NHYA class (P < 0.001), NT pro-BNP (P < 0.001), LVEF (P = 0.045), E/A (P = 0.048) E/e' (P < 0.001), and PAPs (P < 0.001) decreased. DT (P = 0.011) and TAPSE (P = 0.035) increased in all groups. CONCLUSIONS: Levosimendan, as well as standard therapy, improves myocardial function and symptoms of HF, irrespective of the loading dose administration. Treatment options for patients with end-stage heart failure refractory to conventional medical therapy are limited. Inotropic drugs play an important role in heart failure (HF). PMID- 25806831 TI - Structural origin of fragility in Ge-As-S glasses investigated by calorimetry and Raman spectroscopy. AB - The fragility index (m) of a series of Ge-As-S glasses covering a wide range of mean coordination (?r?) and stoichiometry is measured by differential scanning calorimetry. The evolution of the fragility index appears to be better predicted by the stoichiometry than the mean coordination, and m shows a well-defined dependence on the departure from stoichiometry quantified as the at. % excess or deficiency in sulfur. The effect of stoichiometry on the fragility of Ge-As-S glasses is very similar to that observed in the Ge-As-Se system. A systematic Raman spectroscopy investigation also indicates the presence of large fractions of molecular species such as S8, As4S4, and As4S3 in the structure of some glasses. The presence of molecular species is shown to increase the fragility and decrease the glass transition temperature (Tg). These results emphasize that short-range order rather than long-range characteristics such as structural rigidity appears to control the fragility of chalcogenide glasses. PMID- 25806833 TI - Effects of cholesterol and saturated sphingolipids on acyl chain order in 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers--a comparative study with phase-selective fluorophores. AB - Saturated sphingolipids have high acyl chain order. Our aim was to study how palmitoylated sphingomyelin (PSM), ceramide (PCer), glucosyl (GlcPCer)-, and galactosylceramide (GalPCer) were able to order the bulk acyl chains of 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), in comparison with cholesterol. For this reason, we used lipid probes which had preferred phases that were either the disordered phase (1-oleoyl-2-propionyl[DPH-sn-glycero-3 phosphcholine (18:1-DPH-PC) or the ordered phase (trans parinaric acid (tPA). DPH was also used, although it has no clear phase preference. We measured steady state anisotropy (all probes) and performed fluorescence lifetime analysis (tPA) as a function of composition and temperature. At concentrations where the saturated sphingolipids were not aggregated into ordered domains (and 23 degrees C), they did not increase POPC acyl chain order as determined from 18:1-DPH-PC anisotropy. As expected, cholesterol increased the POPC acyl chain order linearly as a function of concentration (0-28 mol %). Since PCer already forms ordered domains below 5 mol % (at 23 degrees C), we measured the acyl chain ordering effect of PCer at 50 degrees C (0-13 mol %) and observed that PCer ordered POPC acyl chains as efficiently as cholesterol. We conclude that the bulk acyl chain order of POPC was not markedly affected in bilayers where disordered and ordered domains coexist. PMID- 25806832 TI - Influence of alkoxy groups on rates of acetal hydrolysis and tosylate solvolysis: electrostatic stabilization of developing oxocarbenium ion intermediates and neighboring-group participation to form oxonium ions. AB - The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 10(6)-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom. PMID- 25806836 TI - Glass-Like Slow Dynamics in a Colloidal Solid with Multiple Ground States. AB - We study the phase-ordering dynamics of a 2D model colloidal solid using molecular dynamics simulations. The colloid particles interact with each other with a Hamaker potential modified by the presence of equatorial "patches" of attractive and repulsive regions. The total interaction potential between two such colloids is, therefore, strongly directional and has a 3-fold symmetry. Working in the canonical ensemble, we determine the phase diagram in the density temperature plane. We obtain three distinct crystalline ground states, viz., a low density honeycomb solid, a rectangular solid at intermediate density, and finally a high-density triangular structure. We show that when cooled rapidly from the liquid phase along iso-chores, the system undergoes a transition to a "strong glass", while slow cooling gives rise to crystalline phases. We claim that geometrical frustration arising from the presence of many competing crystalline ground states causes glassy ordering and dynamics in this solid. Our results may be easily confirmed by suitable experiments on patchy colloids. PMID- 25806835 TI - Whispering gallery mode resonators for rapid label-free biosensing in small volume droplets. AB - Rapid biosensing requires fast mass transport of the analyte to the surface of the sensing element. To optimize analysis times, both mass transport in solution and the geometry and size of the sensing element need to be considered. Small dielectric spheres, tens of microns in diameter, can act as label-free biosensors using whispering gallery mode (WGM) resonances. WGM resonances are sensitive to the effective refractive index, which changes upon analyte binding to recognition sites on functionalized resonators. The spherical geometry and tens of microns diameter of these resonators provides an efficient target for sensing while their compact size enables detection in limited volumes. Here, we explore conditions leading to rapid analyte detection using WGM resonators as label-free sensors in 10 MUL sample droplets. Droplet evaporation leads to potentially useful convective mixing, but also limits the time over which analysis can be completed. We show that active droplet mixing combined with initial binding rate measurements is required for accurate nanomolar protein quantification within the first minute following injection. PMID- 25806834 TI - Label-free detection of rare cell in human blood using gold nano slit surface plasmon resonance. AB - Label-free detection of rare cells in biological samples is an important and highly demanded task for clinical applications and various fields of research, such as detection of circulating tumor cells for cancer therapy and stem cells studies. Surface Plasmon Resonance (SPR) as a label-free method is a promising technology for detection of rare cells for diagnosis or research applications. Short detection depth of SPR (400 nm) provides a sensitive method with minimum interference of non-targets in the biological samples. In this work, we developed a novel microfluidic chip integrated with gold nanoslit SPR platform for highly efficient immunomagnetic capturing and detection of rare cells in human blood. Our method offers simple yet efficient detection of target cells with high purity. The approach for detection consists of two steps. Target cells are firs captured on functionalized magnetic nanoparticles (MNPs) with specific antibody I. The suspension containing the captured cells (MNPs-cells) is then introduced into a microfluidic chip integrated with a gold nanoslit film. MNPs-cells bind with the second specific antibody immobilized on the surface of the gold nanoslit and are therefore captured on the sensor active area. The cell binding on the gold nanoslit was monitored by the wavelength shift of the SPR spectrum generated by the gold nanoslits. PMID- 25806837 TI - Measuring emissions from oil and natural gas well pads using the mobile flux plane technique. AB - We present a study of methane emissions from oil and gas producing well pad facilities in the Barnett Shale region of Texas, measured using an innovative ground-based mobile flux plane (MFP) measurement system, as part of the Barnett Coordinated Campaign.1 Using only public roads, we measured the emissions from nearly 200 well pads over 2 weeks in October 2013. The population of measured well pads is split into well pads with detectable emissions (N = 115) and those with emissions below the detection limit of the MFP instrument (N = 67). For those well pads with nonzero emissions, the distribution was highly skewed, with a geometric mean of 0.63 kg/h, a geometric standard deviation of 4.2, and an arithmetic mean of 1.72 kg/h. Including the population of nonemitting well pads, we find that the arithmetic mean of the well pads sampled in this study is 1.1 kg/h. This distribution implies that 50% of the emissions is due to the 6.6% highest emitting well pads, and 80% of the emissions is from the 22% highest emitting well pads. PMID- 25806838 TI - All silicon electrode photocapacitor for integrated energy storage and conversion. AB - We demonstrate a simple wafer-scale process by which an individual silicon wafer can be processed into a multifunctional platform where one side is adapted to replace platinum and enable triiodide reduction in a dye-sensitized solar cell and the other side provides on-board charge storage as an electrochemical supercapacitor. This builds upon electrochemical fabrication of dual-sided porous silicon and subsequent carbon surface passivation for silicon electrochemical stability. The utilization of this silicon multifunctional platform as a combined energy storage and conversion system yields a total device efficiency of 2.1%, where the high frequency discharge capability of the integrated supercapacitor gives promise for dynamic load-leveling operations to overcome current and voltage fluctuations during solar energy harvesting. PMID- 25806839 TI - National trends in the incidence, outcomes and charges of pediatric osteoarticular infections, 1997-2012. AB - In the United States, the incidence of osteoarticular infections among hospitalized children increased 15% from 2.07 to 2.38 cases per 1000 admissions from 1997 through 2012. The incidence of methicillin-resistant Staphylococcus aureus-coded infections increased from 0.02 to 0.36 cases per 1000 admissions. Methicillin-resistant S. aureus-coded cases had a larger number of therapeutic procedures, longer hospital stays and higher hospital charges. PMID- 25806840 TI - Red chromonychia in Kawasaki disease. PMID- 25806841 TI - Plasmodium vivax malaria: challenges in diagnosis, treatment and elimination. PMID- 25806842 TI - Renal aspergillosis in a 6-year-old male with Burkitt's lymphoma. PMID- 25806843 TI - Empiric treatment of neonatal sepsis in developing countries. AB - Infections are among the leading causes of neonatal mortality, and about 75% of the burden occurs in developing countries. Diagnosis of neonatal sepsis in these countries is dependent on the recognition of a set of nonspecific clinical signs that maximize sensitivity because staff making initial assessments may not have specialist pediatric training. Accurate diagnosis is usually limited by the unavailability of reliable microbiological investigation. The World Health Organization recommends ampicillin (or penicillin; cloxacillin if staphylococcal infection is suspected) plus gentamicin for empiric treatment of neonates with suspected clinical sepsis or meningitis. However, there is a lack of comprehensive data on the causes of infection and antimicrobial susceptibility in developing countries to support these recommendations, especially in rural settings. Bacterial pathogens (predominantly Gram negative) with reduced susceptibility to empiric medication have been reported, with variations both between and within regions. Nosocomial infections with resistant organisms and high case fatality challenge the first-line use of cephalosporins. Improving local surveillance data using standardized antimicrobial susceptibility testing methods and validation of diagnostic algorithms against microbial findings are essential. Standardized reporting of treatment outcomes is required to evaluate practice, provide guidance on second-line regimes and for studies of new approaches, such as simplified community-based regimens, and to determine the appropriate duration of empiric treatment for apparently low-risk neonates with early resolution of clinical signs, or where available, negative blood cultures. Thus, a multifaceted approach, with attention to microbiological quality assurance, is needed to better guide antimicrobial use and reduce mortality and long-term impairments. PMID- 25806844 TI - Cryptococcal osteomyelitis in an adolescent survivor of T-cell acute lymphoblastic leukemia. AB - Cryptococcosis is infrequent in children, and isolated cryptococcal osteomyelitis is rarely encountered. Here, we describe a 14-year-old patient in remission from T-cell acute lymphoblastic leukemia with osteomyelitis because of Cryptococcus neoformans var. grubii. The patient was effectively treated with antifungal therapy. PMID- 25806846 TI - Photodynamic therapy relieves colitis and prevents colitis-associated carcinogenesis in mice. AB - BACKGROUND: Inflammatory bowel diseases are incurable illnesses of the gastrointestinal tract, which substantially enhance the risk of developing colorectal carcinogenesis. Conventional photodynamic therapy is a clinically approved therapeutic modality used in the treatment of neoplastic diseases. Recent preclinical and clinical studies have shown that photodynamic therapy with low doses of photosensitizer and/or light improves inflammatory conditions, including colitis. This study aims therefore at investigating the therapeutic potential of low-dose photodynamic therapy (LDPDT) with a liposomal formulation of meta-tetra(hydroxyphenyl)chlorin (namely Foslip) in the prevention of colitis associated cancer in mice. METHODS: LDPDT efficacy was evaluated by endoscopic, macroscopic, and histological analysis. Myeloperoxidase levels were quantified by enzyme linked immunosorbent assay and cytokines expression by quantitative RT-PCR analysis. The integrity of the intestinal barrier was evaluated by immunostaining, and bacterial composition of the fecal microbiota was determined by 454 pyrosequencing of V3-V4 region of bacterial 16S rRNA genes. RESULTS: LDPDT reduced intestinal tumor growth by decreasing the expression of a wide range of inflammatory mediators and by lowering neutrophil influx. LDPDT treatment prevents onset of a dysbiotic microbiota in the colitis-associated cancer model. CONCLUSIONS: LDPDT with Foslip could be considered as a novel treatment modality to prevent colorectal carcinogenesis in patients with inflammatory bowel disease. PMID- 25806845 TI - Prevalence and Risk Factors for Therapy Escalation in Ulcerative Colitis in the Swiss IBD Cohort Study. AB - BACKGROUND: Physicians traditionally treat ulcerative colitis (UC) using a step up approach. Given the paucity of data, we aimed to assess the cumulative probability of UC-related need for step-up therapy and to identify escalation associated risk factors. METHODS: Patients with UC enrolled into the Swiss IBD Cohort Study were analyzed. The following steps from the bottom to the top of the therapeutic pyramid were examined: (1) 5-aminosalicylic acid and/or rectal corticosteroids, (2) systemic corticosteroids, (3) immunomodulators (IM) (azathioprine, 6-mercaptopurine, methotrexate), (4) TNF antagonists, (5) calcineurin inhibitors, and (6) colectomy. RESULTS: Data on 996 patients with UC with a median disease duration of 9 years were examined. The point estimates of cumulative use of different treatments at years 1, 5, 10, and 20 after UC diagnosis were 91%, 96%, 96%, and 97%, respectively, for 5-ASA and/or rectal corticosteroids, 63%, 69%, 72%, and 79%, respectively, for systemic corticosteroids, 43%, 57%, 59%, and 64%, respectively, for IM, 15%, 28%, and 35% (up to year 10 only), respectively, for TNF antagonists, 5%, 9%, 11%, and 12%, respectively, for calcineurin inhibitors, 1%, 5%, 9%, and 18%, respectively, for colectomy. The presence of extraintestinal manifestations and extended disease location (at least left-sided colitis) were identified as risk factors for step up in therapy with systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and surgery. Cigarette smoking at diagnosis was protective against surgery. CONCLUSIONS: The presence of extraintestinal manifestations, left-sided colitis, and extensive colitis/pancolitis at the time of diagnosis were associated with use of systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and colectomy during the disease course. PMID- 25806848 TI - Immunization information systems. PMID- 25806849 TI - Strengthening negotiation skills, part II: moving beyond sheer knowledge with 4 additional key strategies to create influence for public health leaders. PMID- 25806850 TI - Shared technology infrastructure for the public health enterprise: the time is now. PMID- 25806847 TI - Endoscopic evaluation of surgically altered bowel in patients with inflammatory bowel diseases. AB - Patients with inflammatory bowel diseases often undergo surgical procedures for medically refractory disease or colitis associated dysplasia. Endoscopic evaluation of the surgically altered bowel is often needed to assess for disease recurrence, its severity, and for therapy. It is important to obtain and review the operative report and abdominal imaging before performing the endoscopy. Diagnostic and therapeutic endoscopy can be safely performed in most patients with inflammatory bowel disease with altered bowel anatomy under conscious sedation without fluoroscopy. Carefully planned stricture therapy with balloon dilation or needle knife stricturotomy can be performed for simple, short, and fibrotic strictures. A multidisciplinary approach involving a team of endoscopist, endoscopy nurse, colorectal surgeon, gastrointestinal pathologist, and gastrointestinal radiologist is important for a safe and effective endoscopy. We attempt to review the aspects that need consideration before the endoscopy, the technique of endoscopy, and briefly the therapies that can be performed during endoscopy of the bowel through an ileostomy, a colostomy, in the diverted large bowel or ileal pouch, and small bowel after stricturoplasty and bowel bypass surgery in patients with inflammatory bowel diseases. PMID- 25806851 TI - Public health transformation: helping local health departments navigate change through adaptive leadership. PMID- 25806852 TI - Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome. AB - The Sezary Syndrome (SS) is an aggressive CD4+ leukemic variant of cutaneous T cell lymphoma. Epigenetic modification of cancer cell genome is often linked to the expression of important cancer-related genes. Here we addressed the hypothesis that, in SS, DNA hypomethylation is involved in upregulation of PLS3, GATA6, and TWIST1, genes that are undetected in normal lymphocytes. Pyrosequencing analysis of CpG rich regions, and CpG dinucleotides within the 5' regulatory regions, confirmed hypomethylation of all three genes in SS, compared with controls. We then studied how methylation regulates PLS3 transcription in vitro using PLS3-negative (Jurkat) and PLS3-positive (HT-1080) cell lines. Treatment with the hypomethylating agent 5-azacytidine induced PLS3 expression in Jurkat cells and in vitro methylation of the cloned PLS3 promoter suppressed luciferase expression in HT-1080 cells. In conclusion, we show that promoter hypomethylation is associated with PLS3, GATA6, and TWIST1 overexpression in SS CD4+ T cells and that methylation can regulate PLS3 expression in vitro. The mechanisms of DNA hypomethylation in vivo and the functional role of PLS3, TWIST1, and GATA6 in SS are being investigated. PMID- 25806853 TI - UV Radiation Induces the Epidermal Recruitment of Dendritic Cells that Compensate for the Depletion of Langerhans Cells in Human Skin. AB - UVR causes skin injury and inflammation, resulting in impaired immune function and increased skin cancer risk. Langerhans cells (LCs), the immune sentinels of the epidermis, are depleted for several days following a single UVR exposure and can be reconstituted from circulating monocytes. However, the differentiation pathways leading to the recovery of a normal pool of LCs is still unclear. To study the dynamic changes in human skin with UV injury, we exposed a cohort of 29 healthy human volunteers to a clinically relevant dose of UVR and analyzed sequential epidermal biopsies for changes in leukocyte and dendritic cell (DC) subsets. UV-induced depletion of CD1a(high) LC was compensated by sequential appearance of various epidermal leukocytes. CD14(+) monocytes were recruited as early as D1 post exposure, followed by recruitment of two inflammatory DC subsets that may represent precursors of LCs. These CD1a(low) CD207(-) and the heretofore unknown CD1a(low) CD207(+) DCs appeared at day 1 and day 4 post UVR, respectively, and were endowed with T-cell-activating properties similar to those of LCs. We conclude that recruitment of monocytes and inflammatory DCs appear as a physiological response of the epidermis in order to repair UVR-induced LC depletion associated with immune suppression. PMID- 25806854 TI - Capsiate Inhibits DNFB-Induced Atopic Dermatitis in NC/Nga Mice through Mast Cell and CD4+ T-Cell Inactivation. AB - Capsaicin has many biological effects, such as antioxidant, anticancer, and antiangiogenic effects, but it is rarely used because of its high pungency. Capsiate, a nonpungent capsaicin analog, also has multiple biological effects, similar to those of capsaicin, but does not cause irritation. However, the effect of capsiate on allergic responses and immune cells has not been well studied. In this study, we investigated the effect of capsiate on atopic dermatitis, mouse CD4+ T cells, and mast cell activation. Capsiate inhibited DNFB-induced atopic dermatitis in NC/Nga mice. Topical treatment with capsiate suppressed serum IgE levels and cytokine and chemokine expression in the skin of DNFB-treated NC/Nga mice. In addition, it suppressed the activation of CD4+ T cells and mast cells, which are implicated in allergic diseases. Capsiate inhibited the differentiation of naive CD4+ T cells into T helper type 1 (Th1), Th2, and Th17 cells. Treatment with capsiate inhibited the expression of pro-inflammatory cytokines and degranulation from activated bone marrow-derived mast cells through the inhibition of extracellular signal-regulated kinase signal pathways. Consistent with these results, treatment with capsiate inhibited passive cutaneous anaphylaxis. Taken together, our results suggest that capsiate might be a good candidate molecule for the treatment of allergic diseases such as atopic dermatitis. PMID- 25806855 TI - Pd-catalyzed enantioselective intramolecular alpha-arylation of alpha-substituted cyclic ketones: facile synthesis of functionalized chiral spirobicycles. AB - Catalytic synthesis of chiral spirocyclic ketones was accomplished via the Pd catalyzed intramolecular alpha-arylation of alpha-substituted cyclic ketones. The obtained spirocyclic ketone could be converted into a bifunctional organocatalyst. PMID- 25806856 TI - Dynamic control of chirality in phosphine ligands for enantioselective catalysis. AB - Chirality plays a fundamental role in biology and chemistry and the precise control of chirality in a catalytic conversion is a key to modern synthesis most prominently seen in the production of pharmaceuticals. In enantioselective metal based catalysis, access to each product enantiomer is commonly achieved through ligand design with chiral bisphosphines being widely applied as privileged ligands. Switchable phosphine ligands, in which chirality is modulated through an external trigger signal, might offer attractive possibilities to change enantioselectivity in a catalytic process in a non-invasive manner avoiding renewed ligand synthesis. Here we demonstrate that a photoswitchable chiral bisphosphine based on a unidirectional light-driven molecular motor, can be used to invert the stereoselectivity of a palladium-catalysed asymmetric transformation. It is shown that light-induced changes in geometry and helicity of the switchable ligand enable excellent selectivity towards the racemic or individual enantiomers of the product in a Pd-catalysed desymmetrization reaction. PMID- 25806857 TI - Ultrasonic welding for fast bonding of self-aligned structures in lab-on-a-chip systems. AB - Ultrasonic welding is a rapid, promising bonding method for the bonding of polymer chips; yet its use is still limited. We present two lab-on-a-chip applications where ultrasonic welding can be preferably applied: (1) self-aligned gapless bonding of a two-part chip with a tolerance of 50 MUm; (2) bonding of a large area shallow chamber (1.8 cm(2) * 150 MUm). Using injection moulding combined with ultrasonic welding we achieved a total production and bonding time of 60 s per chip, and a batch of chips could be produced within a day going from design to finished chips. We believe that the technical solutions offered here can significantly help bridge the gap between academia and industry, where the differences in production methods and materials pose a challenge when transferring technology. PMID- 25806858 TI - No pain, no gain: lack of exercise obstructs neurogenesis. AB - Bedridden patients develop atrophied muscles, their daily activities greatly reduced, and some display a depressive mood. Patients who are able to receive physical rehabilitation sometimes show surprising clinical improvements, including reduced depression and attenuation of other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for CNS disorders, namely, transplantation of exogenous stem cells and amplification of endogenous neurogenesis. The latter strategy embraces a natural way of reinnervating the damaged brain and correcting the neurological impairments. In this study, we discussed how immobilization-induced disuse atrophy, using the hindlimb suspension model, affects neurogenesis in rats. The overarching hypothesis is that immobilization suppresses neurogenesis by reducing the circulating growth or trophic factors, such as vascular endothelial growth factor or brain-derived neurotrophic factor. That immobilization alters neurogenesis and stem cell differentiation in the CNS requires characterization of the stem cell microenvironment by examining the trophic and growth factors, as well as stress related proteins that have been implicated in exercise-induced neurogenesis. Although accumulating evidence has revealed the contribution of "increased" exercise on neurogenesis, the reverse paradigm involving "lack of exercise," which mimics pathological states (e.g., stroke patients are often immobile), remains underexplored. This novel paradigm will enable us to examine the effects on neurogenesis by a nonpermissive stem cell microenvironment likely produced by lack of exercise. BrdU labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid and brain levels of trophic factors, growth factors, and stress-related proteins are proposed as indices of neurogenesis, while quantitative measurements of spontaneous movements will reveal psychomotor components of immobilization. Studies designed to reveal how in vivo stimulation, or lack thereof, alters the stem cell microenvironment are needed to begin to develop treatment strategies for enhancing neurogenesis in bedridden patients. PMID- 25806859 TI - Considerations for sampling contaminants in agricultural soils. AB - Sampling agricultural soils for contaminants is relatively new. Existing standard sampling protocols used for the evaluation of soil nutrients are likely insufficient for contaminants. The main reasons are the very low analyte levels and differences in heterogeneity between nutrients and contaminants. To evaluate the adequacy of existing sampling protocols or to develop new protocols, a systematic scientific approach is needed. This approach begins with the development of the Sample Quality Criteria followed by a realistic understanding of the properties of the material to be sampled, most notably its heterogeneity. The Sample Quality Criteria and material properties are inputs into the Theory of Sampling. With these inputs, the Theory of Sampling can be used to determine the specifics of the sampling protocol (e.g., mass, number of increments, tool selection) that must be implemented to control error to reliably estimate the concentration of the analyte(s) of interest. Development of sampling protocols in this manner will ensure sample representativeness and therefore improve data equivalency among various parties involved. This is the only way to provide a sound technical basis for defensible decision making to ensure increased safety of food and feed, specifically with respect to contaminants in agricultural soils. PMID- 25806860 TI - Europium-engineered iron oxide nanocubes with high T1 and T2 contrast abilities for MRI in living subjects. AB - Magnetic resonance imaging (MRI) contrast agents with both positive (T1) and negative (T2) contrast abilities are needed in clinical diagnosis for fault-free accurate detection of lesions. We report a facile synthesis of europium engineered iron oxide (EuIO) nanocubes as T1 and T2 contrast agents for MRI in living subjects. The Eu(iii) oxide-embedded iron oxide nanoparticles significantly increase the T1 relaxivity with an enhanced positive contrast effect. EuIO nanocubes with 14 nm in diameter showed a high r1 value of 36.8 mM( 1) s(-1) with respect to total metal ions (Fe + Eu), which is about 3 times higher than that of Fe3O4 nanoparticles with similar size. Moreover, both r1 and r2 values of EuIO nanocubes can be tuned by varying their sizes and Eu doping ratios. After citrate coating, EuIO nanocubes can provide enhanced T1 and T2 contrast effects in small animals, particularly in the cardiac and liver regions. This work may provide an insightful strategy to design MRI contrast agents with both positive and negative contrast abilities for biomedical applications. PMID- 25806861 TI - High temperature sublimation of alpha-amino acids: a realistic prebiotic process leading to large enantiomeric excess. AB - The reiterative high temperature co-sublimation of an enantiopure or an enantioenriched alpha-amino acid mixed with racemic alpha-amino acids leads to deracemization of the latter. A synergistic effect is observed for complex mixtures, and the sense of the handedness is, for all compounds, identical to that of the enantioenriched starting material. PMID- 25806862 TI - Effects of serum creatinine calibration on estimated renal function in african americans: the Jackson heart study. AB - BACKGROUND: The calibration to isotope dilution mass spectrometry-traceable creatinine is essential for valid use of the new Chronic Kidney Disease Epidemiology Collaboration equation to estimate the glomerular filtration rate. METHODS: For 5,210 participants in the Jackson Heart Study (JHS), serum creatinine was measured with a multipoint enzymatic spectrophotometric assay at the baseline visit (2000-2004) and remeasured using the Roche enzymatic method, traceable to isotope dilution mass spectrometry in a subset of 206 subjects. The 200 eligible samples (6 were excluded, 1 for failure of the remeasurement and 5 for outliers) were divided into 3 disjoint sets-training, validation and test-to select a calibration model, estimate true errors and assess performance of the final calibration equation. The calibration equation was applied to serum creatinine measurements of 5,210 participants to estimate glomerular filtration rate and the prevalence of chronic kidney disease (CKD). RESULTS: The selected Deming regression model provided a slope of 0.968 (95% confidence interval [CI], 0.904-1.053) and intercept of -0.0248 (95% CI, -0.0862 to 0.0366) with R value of 0.9527. Calibrated serum creatinine showed high agreement with actual measurements when applying to the unused test set (concordance correlation coefficient 0.934, 95% CI, 0.894-0.960). The baseline prevalence of CKD in the JHS (2000-2004) was 6.30% using calibrated values compared with 8.29% using noncalibrated serum creatinine with the Chronic Kidney Disease Epidemiology Collaboration equation (P < 0.001). CONCLUSIONS: A Deming regression model was chosen to optimally calibrate baseline serum creatinine measurements in the JHS, and the calibrated values provide a lower CKD prevalence estimate. PMID- 25806863 TI - Proposal of new upper airway margins in children assessed by CBCT. AB - OBJECTIVES: Recently, studies have performed three-dimensional analyses of upper airways in children. However, there was a lack of airway delineation according to anatomical boundaries and/or easily mobile soft-tissue landmarks were used. The aim of the present study was to define new upper airway margins in children on CBCT according to anatomical bony landmarks and to validate the method. METHODS: 25 scans were randomly selected from a larger database containing CBCT scans of children prior to orthodontic treatment (14 girls and 11 boys; mean age, 10.9 +/- 2.5 years). Scans were evaluated by two observers. Specific head positioning and virtual orientation protocols were adopted and greyscale thresholding was established for each patient. Volume and minimum cross-sectional area of the oropharynx were calculated. Intra- and interobserver reliability were assessed by reassessment of the CBCTs 2 weeks later. RESULTS: The new airway margins were defined superiorly by a line passing through the palatal plane (anterior nasal spine to posterior nasal spine) extending to the posterior wall of the pharynx, inferiorly by a line passing from the anterosuperior edge of C4 to menton, anteriorly by a line passing from the soft palate to menton, posteriorly and laterally by the respective pharyngeal walls. Method error for airway volume and minimal cross-sectional area was <=2.00%, and intra- and interobserver reliability ranged from 0.99 to 1.00. CONCLUSIONS: The proposed protocol utilizes easily identifiable bony landmarks to delineate the upper airway on cone beam scans of children and was found to be reliable and reproducible. PMID- 25806864 TI - To see bruxism: a functional MRI study. AB - OBJECTIVE: Since the pathophysiology of bruxism is not clearly understood, there exists no possible treatment. The aim of this study is to investigate the cerebral activation differences between healthy subjects and patients with bruxism on behalf of possible aetiological factors. METHODS: 12 healthy subjects and 12 patients with bruxism, a total of 24 right-handed female subjects (aged 20 27 years) were examined using functional MRI during tooth-clenching and resting tasks. Imaging was performed with 3.0-T MRI scanner with a 32-channel head coil. Differences in regional brain activity between patients with bruxism and healthy subjects (control group) were observed with BrainVoyager QX 2.8 (Brain Innovation, Maastricht, Netherlands) statistical data analysis program. Activation maps were created using the general linear model: single study and multistudy multisubject for statistical group analysis. This protocol was approved by the ethics committee of medical faculty of Kirikkale University, Turkey (02/04), based on the guidelines set forth in the Declaration of Helsinki. RESULTS: The group analysis revealed a statistically significant increase in blood oxygenation level-dependent signal of three clusters in the control group (p<0.005), which may indicate brain regions related with somatognosis, repetitive passive motion, proprioception and tactile perception. These areas coincide with Brodmann areas 7, 31, 39 and 40. It is conceivable that there are differences between healthy subjects and patients with bruxism. CONCLUSIONS: Our findings indicate that there was a decrease of cortical activation pattern in patients with bruxism in clenching tasks. This indicates decreased blood flow and activation in regional neuronal activity. Bruxism, as an oral motor disorder concerns dentistry, neurology and psychiatry. These results might improve the understanding and physiological handling of sleep bruxism. PMID- 25806865 TI - Correlation between temporomandibular joint morphology and disc displacement by MRI. AB - OBJECTIVES: The aim was to evaluate the morphology of the temporomandibular joint's (TMJs) disc and condyle as well as its correlation with disc displacement, using MRI. METHODS: 190 TMJs were retrospectively analysed. The condyle morphology of each TMJ was evaluated by two observers using both axial and coronal views, as were their disc morphology and displacement, using sagittal view. Condyle morphology was classified as flat, convex, angled or rounded in the coronal sections and as anterior side flat/posterior side convex, biconvex, anterior side concave/posterior side convex, flat or biconcave in the axial view. Disc morphology was determined as biconcave, biplanar, biconvex, hemiconvex or folded. chi2, Fisher exact and Bonferroni correction tests were used to evaluate the data. ANOVA followed by post hoc Tukey's test was used to evaluate the interaction between age and disc displacement. RESULTS: Anterior disc displacement with reduction; convex condyle morphology in the coronal view; anterior side concave/posterior side convex morphology in the axial view; and biconcave discs were found to be the most prevalent findings. An association was observed between disc morphology and disc displacement (p<0.001). No correlation between condyle morphology and TMJ disc displacement was found (p=0.291 for axial and p=0.14 for coronal views). CONCLUSIONS: The results of this study suggest that TMJ disc morphology is associated with disc displacement. PMID- 25806866 TI - Flexible membranes of MoS2/C nanofibers by electrospinning as binder-free anodes for high-performance sodium-ion batteries. AB - A flexible membrane consisting of MoS2/carbon nanofibers has been fabricated by a simple electrospinning method. MoS2 nanosheets are uniformly encapsulated in the inter-connected carbon nanofibers with diameters of ~150 nm. When evaluated as a binder-free electrode for sodium-ion batteries, the as-obtained electrode demonstrates high performances, including high reversible capacity of 381.7 mA h g(-1) at 100 mA g(-1) and superior rate capability (283.3, 246.5 and 186.3 mA h g(-1) at 0.5, 1 and 2 A g(-1), respectively). Most importantly, the binder-free electrode made of MoS2 and carbon nanofibers can still deliver a charge capacity of 283.9 mA h g(-1) after 600 cycles at a current density of 100 m A g(-1), indicating a very promising anode for long-life SIBs. PMID- 25806867 TI - Comparison between solid-state and powder-state alkali pretreatment on saccharification and fermentation for bioethanol production from rice straw. AB - The efficacy of different concentrations of NaOH (0.25%, 0.50%, 0.75%, and 1.00%) for the pretreatment of rice straw in solid and powder state in enzymatic saccharification and fermentation for the production of bioethanol was evaluated. A greater amount of biomass was recovered through solid-state pretreatment (3.74 g) from 5 g of rice straw. The highest increase in the volume of rice straw powder as a result of swelling was observed with 1.00% NaOH pretreatment (48.07%), which was statistically identical to 0.75% NaOH pretreatment (32.31%). The surface of rice straw was disrupted by the 0.75% NaOH and 1.00% NaOH pretreated samples as observed using field-emission scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM). In Fourier-transform infrared (FT-IR) spectra, absorbance of hydroxyl groups at 1,050 cm(-1) due to the OH group of lignin was gradually decreased with the increase of NaOH concentration. The greatest amounts of glucose and ethanol were obtained in 1.00% NaOH solid-state pretreated and powder-state hydrolyzed samples (0.804 g g(-1) and 0.379 g g(-1), respectively), which was statistically similar to the use of 0.75% NaOH (0.763 g g(-1) and 0.358 g g(-1), respectively). Thus, solid-state pretreatment with 0.75% NaOH and powder-state hydrolysis appear to be suitable for fermentation and bioethanol production from rice straw. PMID- 25806868 TI - A CMOS pressure sensor tag chip for passive wireless applications. AB - This paper presents a novel monolithic pressure sensor tag for passive wireless applications. The proposed pressure sensor tag is based on an ultra-high frequency RFID system. The pressure sensor element is implemented in the 0.18 um CMOS process and the membrane gap is formed by sacrificial layer release, resulting in a sensitivity of 1.2 fF/kPa within the range from 0 to 600 kPa. A three-stage rectifier adopts a chain of auxiliary floating rectifier cells to boost the gate voltage of the switching transistors, resulting in a power conversion efficiency of 53% at the low input power of -20 dBm. The capacitive sensor interface, using phase-locked loop archietcture, employs fully-digital blocks, which results in a 7.4 bits resolution and 0.8 uW power dissipation at 0.8 V supply voltage. The proposed passive wireless pressure sensor tag costs a total 3.2 uW power dissipation. PMID- 25806869 TI - A novel abandoned object detection system based on three-dimensional image information. AB - A new idea of an abandoned object detection system for road traffic surveillance systems based on three-dimensional image information is proposed in this paper to prevent traffic accidents. A novel Binocular Information Reconstruction and Recognition (BIRR) algorithm is presented to implement the new idea. As initial detection, suspected abandoned objects are detected by the proposed static foreground region segmentation algorithm based on surveillance video from a monocular camera. After detection of suspected abandoned objects, three dimensional (3D) information of the suspected abandoned object is reconstructed by the proposed theory about 3D object information reconstruction with images from a binocular camera. To determine whether the detected object is hazardous to normal road traffic, road plane equation and height of suspected-abandoned object are calculated based on the three-dimensional information. Experimental results show that this system implements fast detection of abandoned objects and this abandoned object system can be used for road traffic monitoring and public area surveillance. PMID- 25806870 TI - Radar imaging of non-uniformly rotating targets via a novel approach for multi component AM-FM signal parameter estimation. AB - A novel radar imaging approach for non-uniformly rotating targets is proposed in this study. It is assumed that the maneuverability of the non-cooperative target is severe, and the received signal in a range cell can be modeled as multi component amplitude-modulated and frequency-modulated (AM-FM) signals after motion compensation. Then, the modified version of Chirplet decomposition (MCD) based on the integrated high order ambiguity function (IHAF) is presented for the parameter estimation of AM-FM signals, and the corresponding high quality instantaneous ISAR images can be obtained from the estimated parameters. Compared with the MCD algorithm based on the generalized cubic phase function (GCPF) in the authors' previous paper, the novel algorithm presented in this paper is more accurate and efficient, and the results with simulated and real data demonstrate the superiority of the proposed method. PMID- 25806871 TI - Bayesian deconvolution for angular super-resolution in forward-looking scanning radar. AB - Scanning radar is of notable importance for ground surveillance, terrain mapping and disaster rescue. However, the angular resolution of a scanning radar image is poor compared to the achievable range resolution. This paper presents a deconvolution algorithm for angular super-resolution in scanning radar based on Bayesian theory, which states that the angular super-resolution can be realized by solving the corresponding deconvolution problem with the maximum a posteriori (MAP) criterion. The algorithm considers that the noise is composed of two mutually independent parts, i.e., a Gaussian signal-independent component and a Poisson signal-dependent component. In addition, the Laplace distribution is used to represent the prior information about the targets under the assumption that the radar image of interest can be represented by the dominant scatters in the scene. Experimental results demonstrate that the proposed deconvolution algorithm has higher precision for angular super-resolution compared with the conventional algorithms, such as the Tikhonov regularization algorithm, the Wiener filter and the Richardson-Lucy algorithm. PMID- 25806873 TI - Degradation prediction model based on a neural network with dynamic windows. AB - Tracking degradation of mechanical components is very critical for effective maintenance decision making. Remaining useful life (RUL) estimation is a widely used form of degradation prediction. RUL prediction methods when enough run-to failure condition monitoring data can be used have been fully researched, but for some high reliability components, it is very difficult to collect run-to-failure condition monitoring data, i.e., from normal to failure. Only a certain number of condition indicators in certain period can be used to estimate RUL. In addition, some existing prediction methods have problems which block RUL estimation due to poor extrapolability. The predicted value converges to a certain constant or fluctuates in certain range. Moreover, the fluctuant condition features also have bad effects on prediction. In order to solve these dilemmas, this paper proposes a RUL prediction model based on neural network with dynamic windows. This model mainly consists of three steps: window size determination by increasing rate, change point detection and rolling prediction. The proposed method has two dominant strengths. One is that the proposed approach does not need to assume the degradation trajectory is subject to a certain distribution. The other is it can adapt to variation of degradation indicators which greatly benefits RUL prediction. Finally, the performance of the proposed RUL prediction model is validated by real field data and simulation data. PMID- 25806874 TI - Improving the precision and speed of Euler angles computation from low-cost rotation sensor data. AB - This article compares three different algorithms used to compute Euler angles from data obtained by the angular rate sensor (e.g., MEMS gyroscope)-the algorithms based on a rotational matrix, on transforming angular velocity to time derivations of the Euler angles and on unit quaternion expressing rotation. Algorithms are compared by their computational efficiency and accuracy of Euler angles estimation. If attitude of the object is computed only from data obtained by the gyroscope, the quaternion-based algorithm seems to be most suitable (having similar accuracy as the matrix-based algorithm, but taking approx. 30% less clock cycles on the 8-bit microcomputer). Integration of the Euler angles' time derivations has a singularity, therefore is not accurate at full range of object's attitude. Since the error in every real gyroscope system tends to increase with time due to its offset and thermal drift, we also propose some measures based on compensation by additional sensors (a magnetic compass and accelerometer). Vector data of mentioned secondary sensors has to be transformed into the inertial frame of reference. While transformation of the vector by the matrix is slightly faster than doing the same by quaternion, the compensated sensor system utilizing a matrix-based algorithm can be approximately 10% faster than the system utilizing quaternions (depending on implementation and hardware). PMID- 25806875 TI - A robust trust establishment scheme for wireless sensor networks. AB - Security techniques like cryptography and authentication can fail to protect a network once a node is compromised. Hence, trust establishment continuously monitors and evaluates node behavior to detect malicious and compromised nodes. However, just like other security schemes, trust establishment is also vulnerable to attack. Moreover, malicious nodes might misbehave intelligently to trick trust establishment schemes. Unfortunately, attack-resistance and robustness issues with trust establishment schemes have not received much attention from the research community. Considering the vulnerability of trust establishment to different attacks and the unique features of sensor nodes in wireless sensor networks, we propose a lightweight and robust trust establishment scheme. The proposed trust scheme is lightweight thanks to a simple trust estimation method. The comprehensiveness and flexibility of the proposed trust estimation scheme make it robust against different types of attack and misbehavior. Performance evaluation under different types of misbehavior and on-off attacks shows that the detection rate of the proposed trust mechanism is higher and more stable compared to other trust mechanisms. PMID- 25806872 TI - The application of biomedical engineering techniques to the diagnosis and management of tropical diseases: a review. AB - This paper reviews a number of biomedical engineering approaches to help aid in the detection and treatment of tropical diseases such as dengue, malaria, cholera, schistosomiasis, lymphatic filariasis, ebola, leprosy, leishmaniasis, and American trypanosomiasis (Chagas). Many different forms of non-invasive approaches such as ultrasound, echocardiography and electrocardiography, bioelectrical impedance, optical detection, simplified and rapid serological tests such as lab-on-chip and micro-/nano-fluidic platforms and medical support systems such as artificial intelligence clinical support systems are discussed. The paper also reviewed the novel clinical diagnosis and management systems using artificial intelligence and bioelectrical impedance techniques for dengue clinical applications. PMID- 25806876 TI - A hybrid PCA-CART-MARS-based prognostic approach of the remaining useful life for aircraft engines. AB - Prognostics is an engineering discipline that predicts the future health of a system. In this research work, a data-driven approach for prognostics is proposed. Indeed, the present paper describes a data-driven hybrid model for the successful prediction of the remaining useful life of aircraft engines. The approach combines the multivariate adaptive regression splines (MARS) technique with the principal component analysis (PCA), dendrograms and classification and regression trees (CARTs). Elements extracted from sensor signals are used to train this hybrid model, representing different levels of health for aircraft engines. In this way, this hybrid algorithm is used to predict the trends of these elements. Based on this fitting, one can determine the future health state of a system and estimate its remaining useful life (RUL) with accuracy. To evaluate the proposed approach, a test was carried out using aircraft engine signals collected from physical sensors (temperature, pressure, speed, fuel flow, etc.). Simulation results show that the PCA-CART-MARS-based approach can forecast faults long before they occur and can predict the RUL. The proposed hybrid model presents as its main advantage the fact that it does not require information about the previous operation states of the input variables of the engine. The performance of this model was compared with those obtained by other benchmark models (multivariate linear regression and artificial neural networks) also applied in recent years for the modeling of remaining useful life. Therefore, the PCA-CART-MARS-based approach is very promising in the field of prognostics of the RUL for aircraft engines. PMID- 25806878 TI - The costs of hope. PMID- 25806877 TI - Clinico-pathological correlation of serial measurement of circulating tumor cells in 24 metastatic colorectal cancer patients receiving chemotherapy reveals interpatient heterogeneity correlated with CEA levels but independent of KRAS and BRAF mutation. AB - BACKGROUND: The Veridex CellSearch is an FDA-approved technology for enumerating circulating tumor cells in blood samples of metastatic colorectal cancer mCRC) patients and has prognostic value. It is important to understand how counts of circulating tumor cells (CTCs), which are advocated to be tools for "liquid biopsy" of tumors, correlate with clinical and pathologic variables of significance in these patients. In this study, we have attempted to make such correlations along with evaluating how CTC counts change during the course of chemotherapy. PATIENTS AND METHODS: Following an IRB-approved protocol, blood samples were collected from 24 patients with mCRC along with relevant clinico pathological data. Blood was collected at defined time-points both prior to as well as during the course of treatment with combination chemotherapy, and CTC counts were enumerated from 7.5 ml of blood. RESULTS: Seventeen out of 24 patients with mCRC showed a CTC count of 2 or less cells in 7.5 ml of blood at base-line assessment before chemotherapy while 7 patients showed 3 or more cells in 7.5 ml of blood at that point. A correlation was found between high carcino embryonic antigen (CEA) levels and high CTC counts (P = 0.018) although it was also found that some patients had elevated CTCs without an elevated CEA. No correlation with the time interval between detection of primary tumor and appearance of secondary (metastatic) tumor(s) was found. CTC counts did not correlate with the presence of lung or liver metastases, i.e. a number of mCRC patients with lung or liver metastases had a count of zero CTCs at baseline. We also noted no correlation between CTC number and the status of KRAS or BRAF mutation. CTC counts dropped immediately after the start of chemotherapy in 11 out of 21 patients, and also reduced from the baseline at the end of chemotherapy in 5 out of 10 patients. Six of 7 patients who started with 3 or more CTCs in 7.5 ml at baseline also showed a final CTC reduction at the end of the therapy assessment. CONCLUSIONS: Analysis of circulating tumor cells may be of use in monitoring response to therapy in mCRC, either in combination with CEA monitoring or alone when CTCs are elevated but CEA level is not. PMID- 25806879 TI - Prevalence and correlates of strength exercise among breast, prostate, and colorectal cancer survivors. AB - PURPOSE/OBJECTIVES: To identify and compare the prevalence and correlates of strength exercise among breast, prostate, and colorectal cancer survivors.? DESIGN: Cross-sectional, descriptive survey.? SETTING: Nova Scotia, Canada.? SAMPLE: 741 breast, prostate, and colorectal cancer survivors.?. METHODS: A stratified sample of 2,063 breast, prostate, and colorectal cancer survivors diagnosed from 2003-2011 were identified and mailed a questionnaire. Descriptive, chi-square, and logistic regression analyses were used to determine any correlations among the main research variables. ? MAIN RESEARCH VARIABLES: Strength exercise behavior; medical, demographic, and motivational correlates using the Theory of Planned Behavior.? FINDINGS: Of 741 respondents, 23% were meeting the strength exercise guidelines of two or more days per week. Cancer survivors were more likely to meet guidelines if they were younger, more educated, had a higher income, better perceived general health, fewer than two comorbidities, and a healthy body weight. In addition, those meeting guidelines had significantly more favorable affective attitude, instrumental attitude, injunctive norm, perceived behavioral control, planning, and intention. The correlates of strength exercise did not differ by cancer site.? CONCLUSIONS: The prevalence of strength exercise is low among breast, prostate, and colorectal cancer survivors in Nova Scotia and the correlates are consistent across those survivor groups. ?. IMPLICATIONS FOR NURSING: Nurses should take an active role in promoting strength exercise among cancer survivors using the Theory of Planned Behavior, particularly among those survivors at higher risk of not performing strength exercise. ? PMID- 25806880 TI - Transitions of male partners of women with breast cancer: hope, guilt, and quality of life. AB - PURPOSE/OBJECTIVES: To (a) describe the types of transitions experienced by male spousal caregivers of women with breast cancer and the strategies used by male spouses to deal with these transitions and (b) examine factors related to their quality of life, including demographic variables, self-efficacy, caregiver guilt, hope, the quality of life of their partner with breast cancer, and transitions. DESIGN: Cross-sectional, transformational, mixed-methods approach. SETTING: Participants' homes. SAMPLE: 105 dyads of male spouses and their female partners diagnosed with stages I-III breast cancer. METHODS: 600 surveys were mailed to women with breast cancer and their male partners. Significant variables were entered into a multivariate model. MAIN RESEARCH VARIABLE: Male caregiver quality of life. FINDINGS: The quality of life of male spouse participants was positively influenced by hope (p < 0.01). It was negatively influenced by caregiver guilt scores (p < 0.01) and the method of dealing with their transitions by "doing what needs to be done" (p = 0.04). CONCLUSIONS: The male caregivers with higher quality-of-life scores reported higher hope and lower caregiver guilt scores. They reported lower quality-of-life scores if they dealt with transitions by "doing what needs to be done."? IMPLICATIONS FOR NURSING: Strategies to support male spouses of women with breast cancer should involve ways to foster hope, reduce feelings of guilt, and encourage male caregivers to engage more in supporting their spouses. PMID- 25806882 TI - Using Web-based interventions to support caregivers of patients with cancer: a systematic review. AB - PURPOSE/OBJECTIVES: To explore the literature to examine the physical, social, psychological, financial, usability, and feasibility outcomes of Web-based interventions on caregivers of people with cancer and to identify potential trends in this body of evidence. DATA SOURCES: PubMed, CINAHL(r), PsycINFO(r), and Inspec. DATA SYNTHESIS: Six articles met inclusion criteria. Across studies, most caregivers were middle-aged female spouses with some college attendance who felt "somewhat comfortable" using the Internet. Caregiver interventions used single- and multicomponent services and reduced negative mood. CONCLUSIONS: Web based caregiver interventions can be beneficial in offering information and support and may positively influence the social and psychological outcomes in this population. IMPLICATIONS FOR NURSING: Many studies described caregiver Internet usage and interventional perceptions and needs, but few have examined the impact of web-based interventions on caregivers. More research is needed to produce high-quality evidence in this population. PMID- 25806881 TI - Consistency of breast and arm symptoms during the first two years after breast cancer surgery. AB - PURPOSE/OBJECTIVES: To examine the severity and development of breast and arm symptoms separately during the two years following breast cancer surgery, and to examine whether previously defined predictors of arm symptoms are associated with breast symptoms. DESIGN: Prospective cohort study with two-year follow-up. SETTING: Three institutions in the Stockholm, Sweden, region. SAMPLE: 645 women, aged 20-63 years, enrolled within 12 weeks of surgery for primary breast cancer. METHODS: Baseline register and questionnaire data with five follow-ups were submitted to descriptive, inferential, and logistic regression analysis. MAIN RESEARCH VARIABLES: Severity of breast and arm symptoms measured by the European Organisation for Research and Treatment of Cancer breast cancer-specific quality of-life questionnaire. FINDINGS: Most participants had undergone breast conserving ?surgery and sentinel lymph node dissection, and were scheduled for postoperative radiation therapy. Overall mean levels of breast and arm symptoms were low, but with large individual variations. At all six time points, the mean levels of breast symptoms were significantly higher than those of arm symptoms. Overall, the mean level of both types of symptoms decreased during follow-up. A body mass index (BMI) of 25 or greater and breast symptoms at eight months were associated with having breast symptoms at two years. Arm symptoms at baseline and at eight months, and radiation therapy and a BMI of 25 or greater were associated with having arm symptoms at two years. CONCLUSIONS: Breast symptoms show different patterns of change and are not associated with the same factors as arm symptoms. IMPLICATIONS FOR NURSING: For nurses monitoring women treated for breast cancer, the results of this study provide knowledge regarding the importance of early symptom identification and long-term symptoms after treatment. PMID- 25806884 TI - Training oncology nurses to use remote symptom support protocols: a retrospective pre-/post study. AB - PURPOSE/OBJECTIVES: To evaluate the impact of training on nurses' satisfaction and perceived confidence using symptom protocols for remotely supporting patients undergoing cancer treatment. DESIGN: Retrospective pre-/post-study guided by the Knowledge-to-Action Framework. SETTING: Interactive workshops at three ambulatory oncology programs in Canada. SAMPLE: 107 RNs who provide remote support to patients with cancer. METHODS: Workshops included didactic presentation, role play with protocols, and group discussion. Post-training, a survey measured satisfaction with training and retrospective pre-/post-perceived confidence in the ability to provide symptom support using protocols. One-tailed, paired t tests measured change. MAIN RESEARCH VARIABLES: Satisfaction with the workshop and perceived confidence in the ability to provide symptom support and use protocols. FINDINGS: Twenty-two workshops, 30-60 minutes each, were conducted with 107 participants. Ninety completed the survey. Compared to preworkshop, postworkshop nurses had improved self-confidence to assess, triage, and guide patients in self-care for cancer treatment-related symptoms, and use protocols to facilitate symptom assessment, triage, and care. Workshops were rated as easy to understand, comprehensive, and provided new information on remote symptom management. Some specified that the workshop did not provide enough time for role play, but most said they would recommend it to others. CONCLUSIONS: The workshop increased nurses' perceived confidence with providing remote symptom support and was well received. IMPLICATIONS FOR NURSING: Subsequent workshops should ensure adequate time for role play to enhance nurses' skills in using protocols and documenting symptom support. PMID- 25806883 TI - Evidence-based practice beliefs and behaviors of nurses providing cancer pain management: a mixed-methods approach. AB - PURPOSE/OBJECTIVES: To describe evidence-based practice (EBP) beliefs and behaviors of nurses who provide cancer pain management. DESIGN: Descriptive, cross-sectional with a mixed-methods approach. SETTING: Two inpatient oncology units in the Pacific Northwest. SAMPLE: 40 RNs.? METHODS: Data collected by interviews and web-based surveys. MAIN RESEARCH VARIABLES: EBP beliefs, EBP implementation, evidence-based pain management. FINDINGS: Nurses agreed with the positive aspects of EBP and their implementation ability, although implementation level was low. They were satisfied with their pain management practices. Oncology nursing certification was associated with innovativeness, and innovativeness was associated with EBP beliefs. Themes identified were (a) limited definition of EBP, (b) varied evidence-based pain management decision making, (c) limited identification of evidence-based pain management practices, and (d) integration of nonpharmacologic interventions into patient care. CONCLUSIONS: Nurses' low level of EBP implementation in the context of pain management was explained by their trust that standards of care and medical orders were evidence-based. IMPLICATIONS FOR NURSING: Nurses' EBP beliefs and behaviors should be considered when developing strategies for sustaining evidence-based pain management practices. Implementation of the EBP process by nurses may not be realistic in the inpatient setting; therefore, hospital pain management policies need to be evidence-based and reinforced with nurses. PMID- 25806885 TI - Improving couples' quality of life through a Web-based prostate cancer education intervention. AB - PURPOSE/OBJECTIVES: To evaluate the feasibility and acceptability of a newly developed web-based, couple-oriented intervention called Prostate Cancer Education and Resources for Couples (PERC). DESIGN: Quantitative, qualitative, mixed-methods approach. SETTING: Oncology outpatient clinics at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center at UNC-Chapel Hill. SAMPLE: 26 patients with localized prostate cancer (PCa) and their partners. METHODS: Pre- and postpilot quantitative assessments and a postpilot qualitative interview were conducted. MAIN RESEARCH VARIABLES: General and PCa-specific symptoms, quality of life, psychosocial factors, PERC's ease of use, and web activities. FINDINGS: Improvement was shown in some PCa-specific and general symptoms (small effect sizes for patients and small-to-medium effect sizes for partners), overall quality of life, and physical and social domains of quality of life for patients (small effect sizes). Web activity data indicated high PERC use. Qualitative and quantitative analyses indicated that participants found PERC easy to use and understand,as well as engaging, of high quality, and relevant. Overall, participants were satisfied with PERC and reported that PERC improved their knowledge about symptom management and communication as a couple. CONCLUSIONS: PERC was a feasible, acceptable method of reducing the side effects of PCa treatment-related symptoms and improving quality of life. IMPLICATIONS FOR NURSING: PERC has the potential to reduce the negative impacts of symptoms and enhance quality of life for patients with localized PCa and their partners, particularly for those who live in rural areas and have limited access to post treatment supportive care. PMID- 25806886 TI - Conducting pilot and feasibility studies. AB - Planning a well-designed research study can be tedious and laborious work. However, this process is critical and ultimately can produce valid, reliable study findings. Designing a large-scale randomized, controlled trial (RCT)-the gold standard in quantitative research-can be even more challenging. Even the most well-planned study potentially can result in issues with research procedures and design, such as recruitment, retention, or methodology. One strategy that may facilitate sound study design is the completion of a pilot or feasibility study prior to the initiation of a larger-scale trial. This article will discuss pilot and feasibility studies, their advantages and disadvantages, and implications for oncology nursing research. ?. PMID- 25806887 TI - The role of resilience and mindful leadership in oncology nursing. AB - When oncology nurses think of the word resilient, they often describe the term in the context of the patients and families they care for each day. When patients face a diagnosis of cancer, their lives have suddenly been altered in a frightening manner. Everything changes, and they must find a way to navigate the troubled waters ahead. ?. PMID- 25806889 TI - Resources to increase genetics and genomics capacity of oncology nurses. AB - Since the completion of the Human Genome Project (HGP) in 2003, the understanding of genetics and its influence on disease, particularly cancer, has increased dramatically. The initial focus after the completion of HGP was on identifying single-gene disorders, such as many hereditary cancer syndromes (e.g., BRCA1, BRCA2, HNPCC). As research continues, the major impact that genetics and genomics have across the healthcare continuum is only beginning to become clear. PMID- 25806890 TI - A review of "Family caregivers of women with breast cancer in Iran report high psychological impact six months after diagnosis". PMID- 25806888 TI - Richter syndrome: an aggressive transformation. AB - A 71-year-old male patient named M.R. was diagnosed with chronic lymphocytic leukemia (CLL). At the time of diagnosis, M.R. had generalized lymphadenopathy and splenomegaly, which caused him to experience significant abdominal discomfort. M.R. was treated with six cycles of fludarabine, cyclophosphamide, and rituximab (FCR), which is standard first-line chemotherapy, and tolerated this fairly well. His lymphadenopathy quickly resolved and, aside from mild nausea, had no complications from treatment. ?. PMID- 25806892 TI - Walking improves sleep in individuals with cancer: a meta-analysis of randomized, controlled trials. AB - PURPOSE/OBJECTIVES: To evaluate the effectiveness of walking exercise on sleep in people with cancer.? DATA SOURCES: Databases searched included China Knowledge Resource Integrated Database, CINAHL(r), Cochrane Central Register of Controlled Trials, EMBASE, PsycINFO(r), PubMed, Wanfang Data, and Web of Science. ? DATA SYNTHESIS: Nine randomized, controlled trials involving 599 patients were included. Most of the studies used moderate-intensity walking exercise. Overall, walking exercise significantly improved sleep in people with cancer (Hedges' g = 0.52). Moderator analyses showed that walking exercise alone and walking exercise combined with other forms of interventions yielded comparable effects on sleep improvement, and that the effect size did not differ among participants who were at different stages of cancer. The effect sizes for studies involving individuals with breast cancer and for studies including individuals with other types of cancer were similar.? CONCLUSIONS: Moderate-intensity walking exercise is effective in improving sleep in individuals with cancer. ? IMPLICATIONS FOR NURSING: The authors' findings support the inclusion of walking exercise into the multimodal approaches to managing sleep in people with cancer. Healthcare providers must convey the benefits of walking exercise to individuals with cancer who are suffering from sleep problems. ? PMID- 25806891 TI - Novel intervention with acupuncture for anorexia and cachexia in patients with gastrointestinal tract cancers: a feasibility study. AB - PURPOSE/OBJECTIVES: To investigate the feasibility of using acupuncture as a complementary intervention to existing treatments and to evaluate the efficacy of acupuncture in improving appetite and slowing weight loss with patients with gastrointestinal (GI) tract cancers. ? DESIGN: One-group pre- and postintervention feasibility study. ? SETTING: Outpatient clinic for patients with cancer and a community setting, both in Florida. ? SAMPLE: A convenience sample of seven adults with GI cancer.? METHODS: Eight acupuncture sessions were provided during eight weeks. Data were collected using the visual analog scale (VAS) for appetite, Simplified Nutritional Appetite Questionnaire (SNAQ), Karnofsky Performance Status, and bioelectrical impedance analysis. ? MAIN RESEARCH VARIABLES: Appetite, weight, attrition rate.? FINDINGS: Seven patients with a mean age of 61 years completed the intervention. Acupuncture was well accepted, feasible, and safe without any reported side effects. Appetite showed improvement, with an average score of 3.04 on the VAS and 4.14 on SNAQ compared to the preintervention scores. The average weight loss was 1.32% compared to the baseline during an eight-week period. ? CONCLUSIONS: The acupuncture intervention was feasible and indicated positive outcomes. Because of the small sample size and lack of a control group, statistical significance of effectiveness was not determined. Acupuncture seemed to improve appetite and slow weight loss in patients with GI cancers, so additional studies with a larger sample size and a variety of cancers are warranted. ? IMPLICATIONS FOR NURSING: Oncology nurses are uniquely able to equip patients with information about complementary therapy modalities, such as acupuncture, which is a promising way to improve appetite and slow weight loss in patients with GI cancers.? PMID- 25806893 TI - A pilot randomized, controlled trial of the effectiveness of a psychoeducational intervention on family caregivers of patients with advanced cancer. AB - PURPOSE/OBJECTIVES: To evaluate the effectiveness of a psychoeducational intervention, the Caring for the Caregiver Programme (CCP).? DESIGN: A pilot randomized, controlled trial, two-group pretest, and repeated post-tests.? SETTING: Four home hospice organizations and an outpatient clinic in Singapore.? SAMPLE: 80 caregivers were randomized into experimental and standard care groups.? METHODS: Outcomes were measured at baseline, week 4, and week 8 after the intervention. The standard care group received routine home hospice care, and the intervention group received the CCP in addition to routine care.? MAIN RESEARCH VARIABLES: Quality of life (QOL), social support, stress and depression, self-efficacy in self-care, closeness with the patient, rewards, and knowledge.? FINDINGS: Compared to the standard care group, the intervention group reported significantly higher QOL, social support satisfaction and number of supported people, closeness with the patient, self-efficacy in self-care, rewards of caregiving, and knowledge, and lower stress and depression. ? CONCLUSIONS: The CCP had positive effects on family caregivers of patients with advanced cancer. ? IMPLICATIONS FOR NURSING: A psychoeducational intervention potentially could help caregivers cope with the demands of caregiving. ? PMID- 25806894 TI - Symptom assessment in hospitalized older palliative patients with cancer: agreement among patients, nurses, and proxies. AB - PURPOSE/OBJECTIVES: To evaluate the level of agreement of symptom assessment among older adult palliative patients with cancer, nurses, and patients' proxies.? DESIGN: A cross-sectional study.? SETTING: Two general hospitals in Flanders, Belgium.? SAMPLE: 120 palliative patients with cancer, aged 65 years and older.? METHODS: A validated 36-item instrument developed to assess physical, psychological, functional, social, and existential symptoms in older palliative patients with cancer was independently completed by patients, the nurses, and proxies.? MAIN RESEARCH VARIABLES: Frequency and intensity of 36 symptoms.? FINDINGS: The study indicates that nurses and proxies tend to underestimate physical and social symptoms and overestimate psychological, functional, and existential symptoms. Agreement scores between patients and nurses and patients and proxies were only significantly different in 39% and 20% of the cases, respectively. Higher intraclass correlation coefficients were measured between patients and proxies compared to patients and nurses. Agreement was associated with demographic and clinical factors, such as gender and prognosis.? CONCLUSIONS: This study indicates discrepancies among patient, nurse, and proxy in the assessment of symptoms. ? IMPLICATIONS FOR NURSING: Patients should be encouraged to report their true experiences. Nurses and proxies should be taught to recognize and assess symptoms and to communicate about them with patients. PMID- 25806896 TI - Emotional tone of ontario newspaper articles on the health effects of industrial wind turbines before and after policy change. AB - Newspapers are often a primary source of health information for the public about emerging technologies. Information in newspapers can amplify or attenuate readers' perceptions of health risk depending on how it is presented. Five geographically distinct wind energy installations in Ontario, Canada were identified, and newspapers published in their surrounding communities were systematically searched for articles on health effects from industrial wind turbines from May 2007 to April 2011. The authors retrieved 421 articles from 13 community, 2 provincial, and 2 national newspapers. To measure the emotional tone of the articles, the authors used a list of negative and positive words, informed from previous studies as well as from a random sample of newspaper articles included in this study. The majority of newspaper articles (64.6%, n = 272) emphasized negative rather than positive/neutral tone, with community newspapers publishing a higher proportion of negative articles than provincial or national newspapers, chi(2)(2) = 15.1, p < .001. Articles were more likely to be negative when published 2 years after compared with 2 years before provincial legislation to reduce dependence on fossil fuels (the Green Energy Act), chi(2)(3) = 9.7, p < .05. Repeated public exposure to negative newspaper content may heighten readers' health risk perceptions about wind energy. PMID- 25806897 TI - Biopsy Use in Skin Cancer Diagnosis: Comparing Dermatology Physicians and Advanced Practice Professionals. PMID- 25806895 TI - Patient-reported symptoms and quality of life ?in adults with acute leukemia: a systematic review. AB - PURPOSE/OBJECTIVES: Systematically summarize findings from research conducted on adult acute leukemia survivors as they relate to symptoms and quality of life (QOL). ? DATA SOURCES: Systematic review of the literature from 1990-2013 found in the PubMed, PsycINFO(r), EMBASE, and CINAHL(r) databases, as well as manual searches. ? DATA SYNTHESIS: The review identified 16 quantitative studies and 1 qualitative study published from 1990-2013 that used a self-reported QOL or symptom questionnaire. Fatigue was the most commonly assessed and reported symptom, followed by depression. ? CONCLUSIONS: Acute leukemia and its treatment have a significant impact in all QOL domains. Future studies should include longitudinal research, more than one recruitment site, increased minority representation, and home-based exercise interventions as ways to improve all domains of QOL. ? IMPLICATIONS FOR NURSING: This review increases awareness of commonly reported symptoms faced by adults with acute leukemia. Oncology nurses are central in monitoring and reporting symptoms to the interdisciplinary team that may contribute to changes in function, with the overall goal of optimizing QOL over time. ? PMID- 25806898 TI - The price of pain: the economics of chronic adolescent pain. PMID- 25806899 TI - Persistent pain following groin hernia repair: what is the best practice in pain management? PMID- 25806900 TI - The global burden of neuropathic pain: IASP's educational and advocacy efforts to enhance the management of neuropathic pain sufferers. PMID- 25806901 TI - Adenosine A3 receptor agonists: do recent findings offer new hope in chronic pain treatment? PMID- 25806902 TI - Sex differences in N-palmitoylethanolamide effectiveness in neuropathic pain associated with lumbosciatalgia. AB - BACKGROUND: Response to N-palmitoylethanolamide (PEA) appear to be influenced by hormonal changes. OBJECTIVE: To evaluate sex differences in the effectiveness of PEA. METHOD: Patients with neuropathic pain resulting from lumbosciatalgia were assigned to conventional treatment plus PEA or conventional treatment. The pain variables were measured using a visual analog scale and quality of life was assessed. RESULTS: One hundred and twelve patients were included. Significant differences were seen in men for all the variables. In women the differences were only significant for pain. A multivariate linear regression analysis showed a positive interaction between men and PEA treatment for the SF-12 mental component. CONCLUSION: Men treated with PEA are more likely to improve their quality of life regarding mental health, compared with women. PMID- 25806904 TI - Ensuring safe prescribing of controlled substances for pain following surgery by developing a transitional pain service. AB - Chronic postsurgical pain is a significant complication following major surgery, which impairs patient's quality of life. Opioid medications are the mainstay of most postoperative analgesic regimens. Growing evidence suggests inherent risks associated with opioids used for postoperative pain. Beyond common opioid-related side effects, increased mortality in the community and developing persistent opioid problems have been reported. There is a paucity of literature regarding the safe and effective management of postoperative pain as patients transition from the hospital to home/community. The introduction of a transitional pain service, whose aim is to optimize pain control, monitor and appropriately wean patients off opioid medications, prevent unnecessary readmissions post-discharge, and reduce disability associated with the development of chronic post surgical pain, will be of benefit to patients and the healthcare system. PMID- 25806905 TI - Risk factors for chronic postsurgical abdominal and pelvic pain. AB - Chronic postsurgical pain (CPSP) may develop after any surgical procedure, and is a common feature after abdominal and pelvic surgery with a prevalence varying between 10 and 40%. The pathological mechanisms leading to chronic CPSP are probably inflammation, tissue and nerve damage and alterations in central pain processing. The mechanisms in chronic postsurgical abdominal and pelvic pain are poorly studied and research has largely focused on reporting of prevalence and describing risk factors, including patient characteristics, psychological factors, surgical procedure and pre- and acute postoperative pain. In this review, the most important risk factors are discussed, and aiming for preventive, personalized health care, possible methods for prediction of susceptibility and potential strategies for diminishing chronic postsurgical abdominal and pelvic pain are provided. PMID- 25806903 TI - Placebo analgesia: understanding the mechanisms. AB - Expectations of pain relief drive placebo analgesia. Understanding how expectations of improvement trigger distinct biological systems to shape therapeutic analgesic outcomes has been the focus of recent pharmacologic and neuroimaging studies in the field of pain. Recent findings indicate that placebo effects can imitate the actions of real painkillers and promote the endogenous release of opioids and nonopioids in humans. Social support and observational learning also contribute to placebo analgesic effects. Distinct psychological traits can modulate expectations of analgesia, which facilitate brain pain control mechanisms involved in pain reduction. Many studies have highlighted the importance and clinical relevance of these responses. Gaining deeper understanding of these pain modulatory mechanisms has important implications for personalizing patient pain management. PMID- 25806906 TI - Additives to local anesthetics for peripheral nerve blocks or local anesthesia: a review of the literature. AB - A multitude of studies have focused on individual additives to local anesthetics and their effect on quality, onset, duration, spread and selectivity, as well as the potential toxic effects of their use. This review aims to give a broad overview of the current evidence in this developing field, based on beneficial and adverse effects of these drugs. We discuss the limitations of the available data and hope to convey implications and future perspectives for clinicians and researchers alike. PMID- 25806907 TI - Epidural steroid injections: an updated review on recent trends in safety and complications. AB - Epidural steroid injections (ESIs), which can provide significant but temporary pain relief in well-selected patients, are the most commonly performed procedure in pain management. The anatomy of the epidural space provides a framework for understanding risks associated with ESIs, a topic relevant to both patients and physicians in interventional pain, surgery and primary care. Safety considerations of epidural steroids include drug preparation and myriad physiological effects stemming from steroid exposure. Although major complications associated with ESI occur rarely, potentially catastrophic events resulting from infectious, hematologic and neurologic morbidity may lead to permanent injury. The safety profile of ESIs may improve with development and dissemination of sound injection technique, safer compounds manufactured in a sterile manner and deficient of thromboembolic potential and the application of existing technology. PMID- 25806909 TI - Value of combination of the neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in primary percutaneous coronary intervention. PMID- 25806908 TI - Magnesium stress signaling in plant: just a beginning. AB - Magnesium (Mg) is one of the most important nutrients, involves mainly in plant growth and development. However, the signaling pathways response to magnesium stresses (MgSs) is known little, but several studies lately may improve the research development. Several phytohormones such as abscisic acid (ABA), ethylene, auxins, and their factors were found responding to MgSs, and there may be some signal pathways linking these hormones and downstream reactions together, e.g., carbon fixation and transfer, starch and sugar metabolism, ion uptaking and reactive oxygen species (ROS) increasing. Consequently, Arabidopsis morphogenesis is remodeled. In this review, we mainly discussed recent literatures involving in plant response to MgSs (Mg deficiency (MgD) and Mg toxicity (MgT)), including plant morphogenesis remodeling, magnesium transporters and signaling transductions. Moreover, the future study challenges related to the responding signalings to MgSs in plants are also presented. Regardless, the iceberg of signal transduction of MgSs in plants is appeared. PMID- 25806912 TI - Health care for immigrants--implications of Obama's executive action. PMID- 25806911 TI - Herpes zoster vaccine effectiveness and manifestations of herpes zoster and associated pain by vaccination status. AB - Options for managing herpes zoster (HZ)-related pain and complications have limited effectiveness, making HZ prevention through vaccination an important strategy. Limited data are available on HZ vaccine effectiveness against confirmed HZ and manifestations of HZ among vaccinated persons. We conducted a matched case-control study to assess HZ vaccine effectiveness for prevention of HZ and other HZ-related outcomes and a cohort study of persons with HZ to compare HZ-related outcomes by vaccination status. Cases were identified through active surveillance among persons age >= 60 years with HZ onset and health-care encounters during 2010-2011 in Southeastern Minnesota. Controls were age- and sex matched to cases. Data were collected by medical record review and from participants via interviews and daily pain diaries. 266 HZ case-patients and 362 matched controls were enrolled in the vaccine effectiveness studies and 303 case patients in the cohort study of HZ characteristics by vaccination status. Vaccination was associated with 54% (95% CI:32%-69%) reduction in HZ incidence, 58% (95% CI:31%-75%) reduction in HZ prodromal symptoms, and 70% (95% CI:33%-87%) reduction in medically-attended prodrome. HZ vaccine was statistically significant effective at preventing postherpetic neuralgia (PHN) measured at 30 d after rash onset, 61% (95% CI: 22%-80%). Among persons who developed HZ, no differences were found by vaccination status in severity or duration of HZ pain after rash onset. In this population-based study, HZ vaccination was associated with >50% reduction in HZ, HZ prodrome, and medically-attended prodrome. PMID- 25806913 TI - Forced vital capacity in idiopathic pulmonary fibrosis--FDA review of pirfenidone and nintedanib. PMID- 25806910 TI - The empirical evidence for the telemedicine intervention in diabetes management. AB - OBJECTIVE: The research presented here assesses the scientific evidence for the telemedicine intervention in the management of diabetes (telediabetes), gestational diabetes, and diabetic retinopathy. The impetus derives from the confluence of high prevalence of these diseases, increasing incidence, and rising costs, while telemedicine promises to ameliorate, if not prevent, type 2 diabetes and its complications. MATERIALS AND METHODS: A purposeful review of the literature identified relevant publications from January 2005 to December 2013. These were culled to retain only credible research articles for detailed review and analysis. The search yielded approximately 17,000 articles with no date constraints. Of these, 770 appeared to be research articles within our time frame. A review of the abstracts yielded 73 articles that met the criteria for inclusion in the final analysis. Evidence is organized by research findings regarding feasibility/acceptance, intermediate outcomes (e.g., use of service, and screening compliance), and health outcomes (control of glycemic level, lipids, body weight, and physical activity.) RESULTS: Definitions of telediabetes varied from study to study vis-a-vis diabetes subtype, setting, technology, staffing, duration, frequency, and target population. Outcome measures also varied. Despite these vagaries, sufficient evidence was obtained from a wide variety of research studies, consistently pointing to positive effects of telemonitoring and telescreening in terms of glycemic control, reduced body weight, and increased physical exercise. The major contributions point to telemedicine's potential for changing behaviors important to diabetes control and prevention, especially type 2 and gestational diabetes. Similarly, screening and monitoring for retinopathy can detect symptoms early that may be controlled or treated. CONCLUSIONS: Overall, there is strong and consistent evidence of improved glycemic control among persons with type 2 and gestational diabetes as well as effective screening and monitoring of diabetic retinopathy. PMID- 25806915 TI - Chikungunya virus and the global spread of a mosquito-borne disease. PMID- 25806916 TI - Sciatica. PMID- 25806914 TI - Human infection with a zoonotic orthopoxvirus in the country of Georgia. AB - During 2013, cutaneous lesions developed in two men in the country of Georgia after they were exposed to ill cows. The men had never received vaccination against smallpox. Tests of lesion material with the use of a quantitative real time polymerase-chain-reaction assay for non-variola virus orthopoxviruses were positive, and DNA sequence analysis implicated a novel orthopoxvirus species. During the ensuing epidemiologic investigation, no additional human cases were identified. However, serologic evidence of exposure to an orthopoxvirus was detected in cows in the patients' herd and in captured rodents and shrews. A third case of human infection that occurred in 2010 was diagnosed retrospectively during testing of archived specimens that were originally submitted for tests to detect anthrax. Orthopoxvirus infection should be considered in persons in whom cutaneous lesions develop after contact with animals. PMID- 25806917 TI - Images in clinical medicine. Becker's nevus. PMID- 25806918 TI - Case records of the Massachusetts General Hospital. Case 10-2015. A 15-year-old girl with Graves' disease and psychotic symptoms. PMID- 25806919 TI - Gigantism, acromegaly, and GPR101 mutations. PMID- 25806920 TI - Gigantism, acromegaly, and GPR101 mutations. PMID- 25806921 TI - Gigantism, acromegaly, and GPR101 mutations. PMID- 25806922 TI - Biologically inactive leptin and early-onset extreme obesity. PMID- 25806923 TI - Biologically inactive leptin and early-onset extreme obesity. PMID- 25806925 TI - Disorders of plasma sodium. PMID- 25806924 TI - Disorders of plasma sodium. PMID- 25806926 TI - Disorders of plasma sodium. PMID- 25806927 TI - Disorders of plasma sodium. PMID- 25806928 TI - Disorders of plasma sodium. PMID- 25806929 TI - Atypical hyperplasia of the breast. PMID- 25806930 TI - Atypical hyperplasia of the breast. PMID- 25806931 TI - Atypical hyperplasia of the breast. PMID- 25806932 TI - Case 39-2014: a girl with Crohn's disease and pulmonary nodules. PMID- 25806933 TI - Case 39-2014: A girl with Crohn's disease and pulmonary nodules. PMID- 25806934 TI - More on remission of recalcitrant dermatomyositis treated with ruxolitinib. PMID- 25806935 TI - More on remission of recalcitrant dermatomyositis treated with ruxolitinib. PMID- 25806937 TI - Images in clinical medicine. Spina ventosa. PMID- 25806936 TI - Ebola virus disease among children in West Africa. PMID- 25806940 TI - Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta analyses. AB - IMPORTANCE: Studies have shown that the scientific literature has overestimated the efficacy of antidepressants for depression, but other indications for these drugs have not been considered. OBJECTIVE: To examine reporting biases in double blind, placebo-controlled trials on the pharmacologic treatment of anxiety disorders and quantify the extent to which these biases inflate estimates of drug efficacy. DATA SOURCES AND STUDY SELECTION: We included reviews obtained from the US Food and Drug Administration (FDA) for premarketing trials of 9 second generation antidepressants in the treatment of anxiety disorders. A systematic search for matching publications (until December 19, 2012) was performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. DATA EXTRACTION AND SYNTHESIS: Double data extraction was performed for the FDA reviews and the journal articles. The Hedges g value was calculated as the measure of effect size. MAIN OUTCOMES AND MEASURES: Reporting bias was examined and classified as study publication bias, outcome reporting bias, or spin (abstract conclusion not consistent with published results on primary end point). Separate meta-analyses were conducted for the 2 sources, and the effect of publication status on the effect estimates was examined using meta-regression. RESULTS: The findings of 41 of the 57 trials (72%) were positive according to the FDA, but 43 of the 45 published article conclusions (96%) were positive (P < .001). Trials that the FDA determined as positive were 5 times more likely to be published in agreement with that determination compared with trials determined as not positive (risk ratio, 5.20; 95% CI, 1.87 to 14.45; P < .001). We found evidence for study publication bias (P < .001), outcome reporting bias (P = .02), and spin (P = .02). The pooled effect size based on the published literature (Hedges g, 0.38; 95% CI, 0.33 to 0.42; P < .001) was 15% higher than the effect size based on the FDA data (Hedges g, 0.33; 95% CI, 0.29 to 0.38; P < .001), but this difference was not statistically significant (beta = 0.04; 95% CI, -0.02 to 0.10; P = .18). CONCLUSIONS AND RELEVANCE: Various reporting biases were present for trials on the efficacy of FDA-approved second-generation antidepressants for anxiety disorders. Although these biases did not significantly inflate estimates of drug efficacy, reporting biases led to significant increases in the number of positive findings in the literature. PMID- 25806941 TI - Correction: Crowdsourcing the unknown: the satellite search for Genghis Khan. PMID- 25806939 TI - Endogenously generated plasmin at the vascular wall injury site amplifies lysine binding site-dependent plasminogen accumulation in microthrombi. AB - The fibrinolytic system plays a pivotal role in the regulation of hemostasis; however, it remains unclear how and when the system is triggered to induce thrombolysis. Using intra-vital confocal fluorescence microscopy, we investigated the process of plasminogen binding to laser-induced platelet-rich microthrombi generated in the mesenteric vein of transgenic mice expressing green fluorescent protein (GFP). The accumulation of GFP-expressing platelets as well as exogenously infused Alexa Fluor 568-labeled Glu-plasminogen (Glu-plg) on the injured vessel wall was assessed by measuring the increase in the corresponding fluorescence intensities. Glu-plg accumulated in a time-dependent manner in the center of the microthrombus, where phosphatidylserine is exposed on platelet surfaces and fibrin formation takes place. The rates of binding of Glu-plg in the presence of epsilon-aminocaproic acid and carboxypeptidase B, as well as the rates of binding of mini-plasminogen lacking kringle domains 1-4 and lysine binding sites, were significantly lower than that of Glu-plg alone, suggesting that the binding was dependent on lysine binding sites. Furthermore, aprotinin significantly suppressed the accumulation of Glu-plg, suggesting that endogenously generated plasmin activity is a prerequisite for the accumulation. In spite of the endogenous generation of plasmin and accumulation of Glu-plg in the center of microthrombi, the microthrombi did not change in size during the 2 hour observation period. When human tissue plasminogen activator was administered intravenously, Glu-plg further accumulated and the microthrombi were lysed. Glu plg appeared to accumulate in the center of microthrombi in the early phase of microthrombus formation, and plasmin activity and lysine binding sites were required for this accumulation. PMID- 25806938 TI - Social support and cognitive functioning as resources for elderly persons with chronic arthritis pain. AB - OBJECTIVE: Arthritis pain and depression are prevalent physical and psychological disorders in late life and co-occur frequently. We explored the stability and covariation of arthritis pain and depressive symptoms. We also addressed the influence of cognitive functioning and social support on the relationship between pain and depressive symptoms among community-dwelling older individuals. METHOD: This longitudinal study utilized a sample of 299 residents of Florida retirement communities who participated in a long-term panel study using yearly assessments across 4 years. Using multilevel modeling, we modeled the individual differences as well as stability in arthritis pain and depressive symptoms simultaneously. Further, we tested the role of cognitive functioning and social support in the association between arthritis pain and depressive symptoms. RESULTS: We found substantial within-person variation in both pain and depressive symptoms (between 58% and 65%) across 4 years even after controlling for a time effect. After controlling for arthritis pain, persons with higher social support and higher cognitive functioning reported lower levels of depressive symptoms. DISCUSSION: Findings suggest that fluctuations in pain and depressive symptoms are common for older adults. Furthermore, social support and intact cognitive functioning may serve as useful resources, as they buffer the negative impact of arthritis pain on depressive symptoms. PMID- 25806942 TI - Social communication in mice--are there optimal cage conditions? AB - Social communication is heavily affected in patients with neuropsychiatric disorders. Accordingly, mouse models designed to study the mechanisms leading to these disorders are tested for this phenotypic trait. Test conditions vary between different models, and the effect of these test conditions on the quantity and quality of social interactions and ultrasonic communication is unknown. The present study examines to which extent the habituation time to the test cage as well as the shape/size of the cage influence social communication in freely interacting mice. We tested 8 pairs of male mice in free dyadic social interactions, with two habituation times (20 min and 30 min) and three cage formats (rectangle, round, square). We tested the effect of these conditions on the different types of social contacts, approach-escape sequences, follow behavior, and the time each animal spent in the vision field of the other one, as well as on the emission of ultrasonic vocalizations and their contexts of emission. We provide for the first time an integrated analysis of the social interaction behavior and ultrasonic vocalizations. Surprisingly, we did not highlight any significant effect of habituation time and cage shape/size on the behavioral events examined. There was only a slight increase of social interactions with the longer habituation time in the round cage. Remarkably, we also showed that vocalizations were emitted during specific behavioral sequences especially during close contact or approach behaviors. The present study provides a protocol reliably eliciting social contacts and ultrasonic vocalizations in adult male mice. This protocol is therefore well adapted for standardized investigation of social interactions in mouse models of neuropsychiatric disorders. PMID- 25806944 TI - Climate adaptation and policy-induced inflation of coastal property value. AB - Human population density in the coastal zone and potential impacts of climate change underscore a growing conflict between coastal development and an encroaching shoreline. Rising sea-levels and increased storminess threaten to accelerate coastal erosion, while growing demand for coastal real estate encourages more spending to hold back the sea in spite of the shrinking federal budget for beach nourishment. As climatic drivers and federal policies for beach nourishment change, the evolution of coastline mitigation and property values is uncertain. We develop an empirically grounded, stochastic dynamic model coupling coastal property markets and shoreline evolution, including beach nourishment, and show that a large share of coastal property value reflects capitalized erosion control. The model is parameterized for coastal properties and physical forcing in North Carolina, U.S.A. and we conduct sensitivity analyses using property values spanning a wide range of sandy coastlines along the U.S. East Coast. The model shows that a sudden removal of federal nourishment subsidies, as has been proposed, could trigger a dramatic downward adjustment in coastal real estate, analogous to the bursting of a bubble. We find that the policy-induced inflation of property value grows with increased erosion from sea level rise or increased storminess, but the effect of background erosion is larger due to human behavioral feedbacks. Our results suggest that if nourishment is not a long-run strategy to manage eroding coastlines, a gradual removal is more likely to smooth the transition to more climate-resilient coastal communities. PMID- 25806943 TI - Antiviral effect of methylated flavonol isorhamnetin against influenza. AB - Influenza is an infectious respiratory disease with frequent seasonal epidemics that causes a high rate of mortality and morbidity in humans, poultry, and animals. Influenza is a serious economic concern due to the costly countermeasures it necessitates. In this study, we compared the antiviral activities of several flavonols and other flavonoids with similar, but distinct, hydroxyl or methyl substitution patterns at the 3, 3', and 4' positions of the 15 carbon flavonoid skeleton, and found that the strongest antiviral effect was induced by isorhamnetin. Similar to quercetin and kaempferol, isorhamnetin possesses a hydroxyl group on the C ring, but it has a 3'-methyl group on the B ring that is absent in quercetin and kaempferol. Co-treatment and pre-treatment with isorhamnetin produced a strong antiviral effect against the influenza virus A/PR/08/34(H1N1). However, isorhamnetin showed the most potent antiviral potency when administered after viral exposure (post-treatment method) in vitro. Isorhamnetin treatment reduced virus-induced ROS generation and blocked cytoplasmic lysosome acidification and the lipidation of microtubule associated protein1 light chain 3-B (LC3B). Oral administration of isorhamnetin in mice infected with the influenza A virus significantly decreased lung virus titer by 2 folds, increased the survival rate which ranged from 70-80%, and decreased body weight loss by 25%. In addition, isorhamnetin decreased the virus titer in ovo using embryonated chicken eggs. The structure-activity relationship (SAR) of isorhamnetin could explain its strong anti-influenza virus potency; the methyl group located on the B ring of isorhamnetin may contribute to its strong antiviral potency against influenza virus in comparison with other flavonoids. PMID- 25806945 TI - Defining a conformational consensus motif in cotransin-sensitive signal sequences: a proteomic and site-directed mutagenesis study. AB - The cyclodepsipeptide cotransin was described to inhibit the biosynthesis of a small subset of proteins by a signal sequence-discriminatory mechanism at the Sec61 protein-conducting channel. However, it was not clear how selective cotransin is, i.e. how many proteins are sensitive. Moreover, a consensus motif in signal sequences mediating cotransin sensitivity has yet not been described. To address these questions, we performed a proteomic study using cotransin treated human hepatocellular carcinoma cells and the stable isotope labelling by amino acids in cell culture technique in combination with quantitative mass spectrometry. We used a saturating concentration of cotransin (30 micromolar) to identify also less-sensitive proteins and to discriminate the latter from completely resistant proteins. We found that the biosynthesis of almost all secreted proteins was cotransin-sensitive under these conditions. In contrast, biosynthesis of the majority of the integral membrane proteins was cotransin resistant. Cotransin sensitivity of signal sequences was neither related to their length nor to their hydrophobicity. Instead, in the case of signal anchor sequences, we identified for the first time a conformational consensus motif mediating cotransin sensitivity. PMID- 25806947 TI - Correction: Steroid receptor RNA activator (SRA) modification by the human pseudouridine synthase 1 (hPus1p): RNA binding, activity, and atomic model. PMID- 25806946 TI - Long tree-ring chronologies provide evidence of recent tree growth decrease in a Central African tropical forest. AB - It is still unclear whether the exponential rise of atmospheric CO2 concentration has produced a fertilization effect on tropical forests, thus incrementing their growth rate, in the last two centuries. As many factors affect tree growth patterns, short -term studies might be influenced by the confounding effect of several interacting environmental variables on plant growth. Long-term analyses of tree growth can elucidate long-term trends of plant growth response to dominant drivers. The study of annual rings, applied to long tree-ring chronologies in tropical forest trees enables such analysis. Long-term tree-ring chronologies of three widespread African species were measured in Central Africa to analyze the growth of trees over the last two centuries. Growth trends were correlated to changes in global atmospheric CO2 concentration and local variations in the main climatic drivers, temperature and rainfall. Our results provided no evidence for a fertilization effect of CO2 on tree growth. On the contrary, an overall growth decline was observed for all three species in the last century, which appears to be significantly correlated to the increase in local temperature. These findings provide additional support to the global observations of a slowing down of C sequestration in the trunks of forest trees in recent decades. Data indicate that the CO2 increase alone has not been sufficient to obtain a tree growth increase in tropical trees. The effect of other changing environmental factors, like temperature, may have overridden the fertilization effect of CO2. PMID- 25806949 TI - Large impact of Eurasian lynx predation on roe deer population dynamics. AB - The effects of predation on ungulate populations depend on several factors. One of the most important factors is the proportion of predation that is additive or compensatory respectively to other mortality in the prey, i.e., the relative effect of top-down and bottom-up processes. We estimated Eurasian lynx (Lynx lynx) kill rate on roe deer (Capreolus capreolus) using radio-collared lynx. Kill rate was strongly affected by lynx social status. For males it was 4.85 +/- 1.30 S.E. roe deer per 30 days, for females with kittens 6.23 +/- 0.83 S.E. and for solitary females 2.71 +/- 0.47 S.E. We found very weak support for effects of prey density (both for Type I (linear) and Type II (non-linear) functional responses) and of season (winter, summer) on lynx kill rate. Additionally, we analysed the growth rate in a roe deer population from 1985 to 2005 in an area, which lynx naturally re-colonized in 1996. The annual roe deer growth rate was lower after lynx re-colonized the study area, but it was also negatively influenced by roe deer density. Before lynx colonized the area roe deer growth rate was lambda = 1.079 (+/- 0.061 S.E.), while after lynx re-colonization it was lambda = 0.94 (+/- 0.051 S.E.). Thus, the growth rate in the roe deer population decreased by Deltalambda = 0.14 (+/- 0.080 S.E.) after lynx re-colonized the study area, which corresponded to the estimated lynx predation rate on roe deer (0.11 +/- 0.042 S.E.), suggesting that lynx predation was mainly additive to other mortality in roe deer. To conclude, this study suggests that lynx predation together with density dependent factors both influence the roe deer population dynamics. Thus, both top-down and bottom-up processes operated at the same time in this predator-prey system. PMID- 25806948 TI - Roles and programming of Arabidopsis ARGONAUTE proteins during Turnip mosaic virus infection. AB - In eukaryotes, ARGONAUTE proteins (AGOs) associate with microRNAs (miRNAs), short interfering RNAs (siRNAs), and other classes of small RNAs to regulate target RNA or target loci. Viral infection in plants induces a potent and highly specific antiviral RNA silencing response characterized by the formation of virus-derived siRNAs. Arabidopsis thaliana has ten AGO genes of which AGO1, AGO2, and AGO7 have been shown to play roles in antiviral defense. A genetic analysis was used to identify and characterize the roles of AGO proteins in antiviral defense against Turnip mosaic virus (TuMV) in Arabidopsis. AGO1, AGO2 and AGO10 promoted anti TuMV defense in a modular way in various organs, with AGO2 providing a prominent antiviral role in leaves. AGO5, AGO7 and AGO10 had minor effects in leaves. AGO1 and AGO10 had overlapping antiviral functions in inflorescence tissues after systemic movement of the virus, although the roles of AGO1 and AGO10 accounted for only a minor amount of the overall antiviral activity. By combining AGO protein immunoprecipitation with high-throughput sequencing of associated small RNAs, AGO2, AGO10, and to a lesser extent AGO1 were shown to associate with siRNAs derived from silencing suppressor (HC-Pro)-deficient TuMV-AS9, but not with siRNAs derived from wild-type TuMV. Co-immunoprecipitation and small RNA sequencing revealed that viral siRNAs broadly associated with wild-type HC-Pro during TuMV infection. These results support the hypothesis that suppression of antiviral silencing during TuMV infection, at least in part, occurs through sequestration of virus-derived siRNAs away from antiviral AGO proteins by HC-Pro. These findings indicate that distinct AGO proteins function as antiviral modules, and provide a molecular explanation for the silencing suppressor activity of HC Pro. PMID- 25806950 TI - Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population. AB - Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients. PMID- 25806951 TI - Sustainability and long-term effectiveness of the WHO surgical safety checklist combined with pulse oximetry in a resource-limited setting: two-year update from Moldova. AB - IMPORTANCE: Little is known about the sustainability and long-term effect of surgical safety checklists when implemented in resource-limited settings. A previous study demonstrated the marked, short-term effect of a structured hospital-wide implementation of a surgical safety checklist in Moldova, a lower middle-income country, as have studies in other low-resource settings. OBJECTIVES: To assess the long-term reduction in perioperative harm following the introduction of a checklist-based surgical quality improvement program in a resource-limited setting and to understand the long-term effects of such programs. DESIGN, SETTING, AND PARTICIPANTS: Twenty months after the initial implementation of a surgical safety checklist and the provision of pulse oximetry at a referral hospital in Moldova, a lower-middle-income, resource-limited country in Eastern Europe, we conducted a prospective study of perioperative care and outcomes of 637 consecutive patients undergoing noncardiac surgery (the long term follow-up group), and we compared the findings with those from 2106 patients who underwent surgery shortly after implementation (the short-term follow-up group). Preintervention data were collected from March to July 2010. Data collection during the short-term follow-up period was performed from October 2010 to January 2011, beginning 1 month after the implementation of the launch period. Data collection during the long-term follow-up period took place from May 25 to July 6, 2012, beginning 20 months after the initial intervention. MAIN OUTCOMES AND MEASURES: The primary end points of interest were surgical morbidity (ie, the complication rate), adherence to safety process measures, and frequency of hypoxemia. RESULTS: Between the short- and long-term follow-up groups, the complication rate decreased 30.7% (P = .03). Surgical site infections decreased 40.4% (P = .05). The mean (SD) rate of completion of the checklist items increased from 88% (14%) in the short-term follow-up group to 92% (11%) in the long-term follow-up group (P < .001). The rate of hypoxemic events continued to decrease (from 8.1 events per 100 hours of oximetry for the short-term follow-up group to 6.8 events per 100 hours of oximetry for the long-term follow-up group; P = .10). CONCLUSIONS AND RELEVANCE: Sustained use of the checklist was observed with continued improvements in process measures and reductions in 30-day surgical complications almost 2 years after a structured implementation effort that demonstrated marked, short-term reductions in harm. The sustained effect occurred despite the absence of continued oversight by the research team, indicating the important role that local leadership and local champions play in the success of quality improvement initiatives, especially in resource-limited settings. PMID- 25806952 TI - Carbohydrate-mediated purification of petrochemicals. AB - Metal-organic frameworks (MOFs) are known to facilitate energy-efficient separations of important industrial chemical feedstocks. Here, we report how a class of green MOFs-namely CD-MOFs-exhibits high shape selectivity toward aromatic hydrocarbons. CD-MOFs, which consist of an extended porous network of gamma-cyclodextrins (gamma-CDs) and alkali metal cations, can separate a wide range of benzenoid compounds as a result of their relative orientation and packing within the transverse channels formed from linking (gamma-CD)6 body centered cuboids in three dimensions. Adsorption isotherms and liquid-phase chromatographic measurements indicate a retention order of ortho- > meta- > para xylene. The persistence of this regioselectivity is also observed during the liquid-phase chromatography of the ethyltoluene and cymene regioisomers. In addition, molecular shape-sorting within CD-MOFs facilitates the separation of the industrially relevant BTEX (benzene, toluene, ethylbenzene, and xylene isomers) mixture. The high resolution and large separation factors exhibited by CD-MOFs for benzene and these alkylaromatics provide an efficient, reliable, and green alternative to current isolation protocols. Furthermore, the isolation of the regioisomers of (i) ethyltoluene and (ii) cymene, together with the purification of (iii) cumene from its major impurities (benzene, n-propylbenzene, and diisopropylbenzene) highlight the specificity of the shape selectivity exhibited by CD-MOFs. Grand canonical Monte Carlo simulations and single component static vapor adsorption isotherms and kinetics reveal the origin of the shape selectivity and provide insight into the capability of CD-MOFs to serve as versatile separation platforms derived from renewable sources. PMID- 25806953 TI - Nascent SecM chain outside the ribosome reinforces translation arrest. AB - SecM, a bacterial secretion monitor protein, contains a specific amino acid sequence at its C-terminus, called arrest sequence, which interacts with the ribosomal tunnel and arrests its own translation. The arrest sequence is sufficient and necessary for stable translation arrest. However, some previous studies have suggested that the nascent chain outside the ribosome affects the stability of translation arrest. To clarify this issue, we performed in vitro translation assays with HaloTag proteins fused to the C-terminal fragment of E. coli SecM containing the arrest sequence or the full-length SecM. We showed that the translation of HaloTag proteins, which are fused to the fragment, is not effectively arrested, whereas the translation of HaloTag protein fused to full length SecM is arrested efficiently. In addition, we observed that the nascent SecM chain outside the ribosome markedly stabilizes the translation arrest. These results indicate that changes in the nascent polypeptide chain outside the ribosome can affect the stability of translation arrest; the nascent SecM chain outside the ribosome stabilizes the translation arrest. PMID- 25806954 TI - Spatiotemporal detection of unusual human population behavior using mobile phone data. AB - With the aim to contribute to humanitarian response to disasters and violent events, scientists have proposed the development of analytical tools that could identify emergency events in real-time, using mobile phone data. The assumption is that dramatic and discrete changes in behavior, measured with mobile phone data, will indicate extreme events. In this study, we propose an efficient system for spatiotemporal detection of behavioral anomalies from mobile phone data and compare sites with behavioral anomalies to an extensive database of emergency and non-emergency events in Rwanda. Our methodology successfully captures anomalous behavioral patterns associated with a broad range of events, from religious and official holidays to earthquakes, floods, violence against civilians and protests. Our results suggest that human behavioral responses to extreme events are complex and multi-dimensional, including extreme increases and decreases in both calling and movement behaviors. We also find significant temporal and spatial variance in responses to extreme events. Our behavioral anomaly detection system and extensive discussion of results are a significant contribution to the long-term project of creating an effective real-time event detection system with mobile phone data and we discuss the implications of our findings for future research to this end. PMID- 25806956 TI - Correction: olmesartan decreased levels of IL-1beta and TNF-alpha, down-regulated MMP-2, MMP-9, COX-2, RANK/RANKL and up-regulated SOCs-1 in an intestinal mucositis model. PMID- 25806955 TI - Assessing the consequences of stigma for tuberculosis patients in urban Zambia. AB - BACKGROUND: Stigma is one of the many factors hindering tuberculosis (TB) control by negatively affecting hospital delay and treatment compliance. In Zambia, the morbidity and mortality due to TB remains high, despite extended public health attempts to control the epidemic and to diminish stigma. STUDY AIM: To enhance understanding of TB-related stigmatizing perceptions and to describe TB patients' experiences of stigma in order to point out recommendations to improve TB policy. METHODS: We conducted a mixed method study at Kanyama clinic and surrounding areas, in Lusaka, Zambia; structured interviews with 300 TB patients, multiple in depth interviews with 30 TB patients and 10 biomedical health workers, 3 focus group discussions with TB patients and treatment supporters, complemented by participant observation and policy analysis of the TB control program. Predictors of stigma were identified by use of multivariate regression analyses; qualitative analysis of the in-depth interviews, focus group discussions and participant observation was used for triangulation of the study findings. RESULTS: We focused on the 138/300 patients that described TB-related perceptions and attitudes, of whom 113 (82%) reported stigma. Stigma provoking TB conceptions were associated with human immunodeficiency virus (HIV)-infection, alleged immoral behaviour, (perceived) incurability, and (traditional) myths about TB aetiology. Consequences of stigma prevailed both among children and adults and included low self-esteem, insults, ridicule, discrimination, social exclusion, and isolation leading to a decreased quality of life and social status, non-disclosure, and/or difficulties with treatment compliance and adherence. Women had significantly more stigma-related problems than men. CONCLUSIONS: The findings illustrate that many TB patients faced stigma-related issues, often hindering effective TB control and suggesting that current efforts to reduce stigma are not yet optimal. The content and implementation of sensitization programs should be improved and more emphasis needs to be placed on women and children. PMID- 25806958 TI - Reactive Oxygen Species Response to Exercise Training and Weight Loss in Sedentary Overweight and Obese Female Adults. AB - PURPOSE: Reactive oxygen species (ROS) are implicated in cardiovascular disease and in the pathogenesis of type 2 diabetes and its complications, and it has been shown to increase insulin resistance. The purpose of this study was to examine the effect of aerobic exercise training and weight loss on ROS in overweight and obese patients as applied in a community clinical setting. METHODS: Fifty healthy female clinic patients (M +/- SEM: age, 41.0 +/- 1.8 years; body mass index, 28.2 +/- 0.8 kg/m2), free of cardiovascular events and not on drug therapy were evaluated before and after 3 months of dietary restriction (~150 to 300 kcal/day deficit) and aerobic training (3 days/week for 1 hour at ~75% VO2max). Measures included ROS, maximal power (kg/min) on cycle ergometry, postexercise heart rate recovery responses at 1 and 2 minutes, and selected anthropometric and hematologic variables. RESULTS: Significant (P < .01) improvements were observed after aerobic training and weight loss in body weight in kilograms (-7.1%); maximal power in kg/min (+32.6%), ROS in U.CARR (Carratelli units) (-25.7%); and heart rate recovery 1 minute in beats per minute (-37.6%) following the program. Significant improvements were also noted in other anthropometric, cardiovascular, and hematologic measures. CONCLUSIONS: A 12-week program of nutritional and exercise intervention in overweight/obese sedentary women improves levels of oxidative stress when accompanied by weight loss and improved fitness. More than restricted caloric intake, physical activity at a relatively high intensity was effective in improving cardiovascular risk markers. The reduction in ROS may be an additional mechanism by which physical activity may contribute to preventing metabolic syndrome and subsequent atherosclerotic disease. PMID- 25806957 TI - Oxidative damage markers are significantly associated with the carotid artery intima-media thickness after controlling for conventional risk factors of atherosclerosis in men. AB - BACKGROUND: This study aimed to assess the association between oxidative damage markers and carotid artery intima-media thickness (CIMT) after controlling for conventional risk factors of atherosclerosis in multiple logistic regression models. METHODS AND FINDINGS: Fifty-one case male participants (CIMT >= 0.9 mm) were enrolled during their visits to Korean Genomic Rural Cohort Study of Wonju centers between May 1 and August 31, 2011, along with 51 control participants (CIMT < 0.9 mm) selected using frequency matching by age group. The levels of oxidative damage markers, 8-hydroxy-2'-deoxyquuanosine (8-OHdG), malondialdehyde (MDA), and 8-iso-prostaglandin F2alpha (Isoprostane), were measured. Conditional logistic regression models were used to evaluate relative relationships between the oxidative damage markers and the risk of high CIMT. RESULTS: The markers of oxidative lipid (Isoprostane and MDA) and DNA (8-OHdG) damage were associated with CIMT after controlling for the conventional risk factors, including age, low density lipoprotein, body mass index, smoking history, alcohol consumption, and metabolic syndrome (ORs [95% CI] for Isoprostane: 3rd tertile, 8.47 [2.59-27.67]; for MDA: 3rd tertile, 8.47 [2.59-27.67]; for 8-OHdG: 3rd tertile, 5.58 [1.79 17.33]). When all the oxidative damage markers were incorporated in the same logistic regression model, only Isoprostane was significantly related to CIMT (OR [95% CI]: 4.22 [1.31-13.53] in 2nd tertile and 14.21 [3.34-60.56] in 3rd tertile). CONCLUSIONS: In this nested case-control study, the oxidative damage markers of lipid and DNA were associated with CIMT even after controlling for the conventional risk factors of cardiovascular diseases. PMID- 25806960 TI - Experimental model of hyperfibrinolysis designed for rotational thromboelastometry in children with congenital heart disease. AB - We assessed an in-vitro model of hyperfibrinolysis using rotational thromboelastometry (ROTEM) by the addition of increasing concentrations of tissue type plasminogen activator (t-PA) on whole blood obtained from children undergoing cardiac surgery. We assessed the relevance of this model by repeating the tests in the same population after tranexamic acid (TXA) infusion. In addition, we determined the sensitivity and specificity of ROTEM parameters to detect the different degrees of fibrinolysis. Blood samples obtained from 20 children were analyzed at two predefined timepoints: after induction of anesthesia, before TXA (baseline), and at the end of surgery during TXA infusion (end surgery). At baseline, an extrinsic activation with tissue factor (EXTEM) test was performed without and with increasing concentration of t-PA (102, 255, 512, 1024, 1535, and 2539 units t-PA/ml). At the end of surgery, a second EXTEM test was performed without and with two different t-PA concentrations (1535 and 2539 units t-PA/ml). At baseline, increasing t-PA concentrations in the EXTEM test induced a gradual increase of hyperfibrinolysis characterized by a reduction in clot firmness and stability parameters. In the presence of TXA, t-PA-induced hyperfibrinolysis was completely abolished. Lysis-onset time (LOT) and degree of fibrinolysis measured at 30 min (LI30) best assessed the degree of fibrinolysis. This in-vitro model of t-PA-induced hyperfibrinolysis using the EXTEM test of ROTEM may represent a promising tool to assess hyperfibrinolysis in the pediatric population. In addition, we observed that LOT and LI30 should be considered as the best parameters to detect different degrees of fibrinolysis. PMID- 25806959 TI - New opportunities at the wild frontier. AB - A better understanding of the natural history of model organisms will increase their value as model systems and also keep them at the forefront of research. PMID- 25806961 TI - The level of red cell distribution width cannot identify deep vein thrombosis in patients undergoing total joint arthroplasty. AB - Recently, studies have reported that increased level of red cell distribution width (RDW) is associated with deep vein thrombosis (DVT). We are aiming to evaluate the validity of RDW in DVT in patients undergoing total joint arthroplasty (TJA). A total of 110 patients (55 patients with DVT and 55 control individuals undergoing TJA) were included in this retrospective cross-sectional study. Age, sex, RDW, red blood cell count, D-dimer, hematocrit and hemoglobin levels of patients were matched. The relationship between RDW and DVT has been estimated. There is no statistical difference of RDW levels between the DVT group and the control group (13.12 +/- 0.12 vs. 13.08 +/- 0.13; P = 0.84). Pearson's correlation analysis showed that there were no significant associations between RDW and other referral groups. Logistic regression analysis indicated that RDW, red blood cell count, hemoglobin and hematocrit were not associated with DVT. Meanwhile, age, sex and D-dimer were independently associated with DVT. The receiver-operating characteristic curve and area under the curve demonstrated low accuracy of RDW in predicting DVT. Although D-dimer may identify the risk of venous thrombosis, the specificity and sensitivity were low. Preoperative level of RDW does not show predictive value for diagnosis of DVT in patients undergoing TJA. PMID- 25806962 TI - Abnormal cytoplasmic extensions associated with active alphaIIbbeta3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome. AB - Mutations in the ITGA2B or ITGB3 genes that encode for the alphaIIbbeta3 platelet integrin usually cause Glanzmann thrombasthenia, a severe autosomal recessive bleeding disorder characterized by absence of platelet aggregation, but normal platelet number and size. Several rare mutations cause a Glanzmann-like syndrome which manifests macrothrombocytopenia and usually displays autosomal dominant inheritance. The exact mechanism causing Glanzmann-like syndrome is unknown. One typical example of Glanzmann-like mutations causes deletion of 40 amino acids (p.647-686) in the beta3 beta-tail domain (betaTD_del) that was found in the heterozygous state in Italian and Japanese families. A second example is a missense mutation, C560R, located in the epidermal growth factor-like domain, found in the homozygous state in a French patient. Both mutations cause constitutive activation of alphaIIbbeta3, but differ in their surface expression. In the current study, we generated cultured cells expressing beta3-betaTD_del or beta3-C560R mutations along with wild-type alphaIIb, and examined the cells' ability to create tubulin-dependent protrusions compared to cells expressing wild type alphaIIbbeta3. Unlike cells expressing wild-type alphaIIbbeta3, cells harboring each of the mutations exhibited abnormal cytoplasmic extensions on immobilized fibrinogen or Von Willebrand factor, which resembled extensions formed in megakaryocyte leading to proplatelets. Moreover, we showed that formation of abnormal extensions occurred also in wild-type alphaIIbbeta3 cells when activated by activating antibody. These results suggest that the active conformation of alphaIIbbeta3 can induce cytoskeletal rearrangements that lead to impaired proplatelet formation. PMID- 25806964 TI - Fe3O4NPs mediated nonenzymatic electrochemical immunosensor for the total protein of Nosema bombycis detection without addition of substrate. AB - In this work, we proposed a novel electrochemical immunosensor for sensitive detection of the total protein of Nosema bombycis based on Fe3O4 nanoparticles (Fe3O4NPs) as catalyst to electrocatalyze the reduction of methylene blue (MB) with the aid of Fe3O4NPs-DNA dendrimers for the signal amplification. PMID- 25806963 TI - Force dependent biotinylation of myosin IIA by alpha-catenin tagged with a promiscuous biotin ligase. AB - Tissues and organs undergo constant physical perturbations and individual cells must respond to mechanical forces to maintain tissue integrity. However, molecular interactions underlying mechano-transduction are not fully defined at cell-cell junctions. This is in part due to weak and transient interactions that are likely prevalent in force-induced protein complexes. Using in situ proximal biotinylation by the promiscuous biotin ligase BirA tagged to alpha-catenin and a substrate stretch cell chamber, we sought to identify force-dependent molecular interactions surrounding alpha-catenin, an actin regulator at the sites of cadherin mediated cell-cell adhesion. While E-cadherin, beta-catenin, vinculin and actin localize with alpha-catenin at cell-cell contacts in immuno-fluorescent staining, only beta-catenin and plakoglobin were biotinylated, suggesting that this proximal biotinylation is limited to the molecules that are in the immediate vicinity of alpha-catenin. In mechanically stretched samples, increased biotinylation of non-muscle myosin IIA, but not myosin IIB, suggests close spatial proximity between alpha-catenin and myosin IIA during substrate stretching. This force-induced biotinylation diminished as myosin II activity was inhibited by blebbistatin. Taken together, this promising technique enables us to identify force sensitive complexes that may be essential for mechano-responses in force bearing cell adhesion. PMID- 25806965 TI - Ti-substituted tunnel-type Na0.44MnO2 oxide as a negative electrode for aqueous sodium-ion batteries. AB - The aqueous sodium-ion battery system is a safe and low-cost solution for large scale energy storage, because of the abundance of sodium and inexpensive aqueous electrolytes. Although several positive electrode materials, for example, Na0.44MnO2, were proposed, few negative electrode materials, for example, activated carbon and NaTi2(PO4)3, are available. Here we show that Ti-substituted Na0.44MnO2 (Na0.44[Mn1-xTix]O2) with tunnel structure can be used as a negative electrode material for aqueous sodium-ion batteries. This material exhibits superior cyclability even without the special treatment of oxygen removal from the aqueous solution. Atomic-scale characterizations based on spherical aberration-corrected electron microscopy and ab initio calculations are utilized to accurately identify the Ti substitution sites and sodium storage mechanism. Ti substitution tunes the charge ordering property and reaction pathway, significantly smoothing the discharge/charge profiles and lowering the storage voltage. Both the fundamental understanding and practical demonstrations suggest that Na0.44[Mn1-xTix]O2 is a promising negative electrode material for aqueous sodium-ion batteries. PMID- 25806967 TI - Searching for the oldest baobab of Madagascar: radiocarbon investigation of large Adansonia rubrostipa trees. AB - We extended our research on the architecture, growth and age of trees belonging to the genus Adansonia, by starting to investigate large individuals of the most widespread Malagasy species. Our research also intends to identify the oldest baobabs of Madagascar. Here we present results of the radiocarbon investigation of the two most representative Adansonia rubrostipa (fony baobab) specimens, which are located in south-western Madagascar, in the Tsimanampetsotse National Park. We found that the fony baobab called "Grandmother" consists of 3 perfectly fused stems of different ages. The radiocarbon date of the oldest sample was found to be 1136 +/- 16 BP. We estimated that the oldest part of this tree, which is mainly hollow, has an age close to 1,600 yr. This value is comparable to the age of the oldest Adansonia digitata (African baobab) specimens. By its age, the Grandmother is a major candidate for the oldest baobab of Madagascar. The second investigated specimen, called the "polygamous baobab", consists of 6 partially fused stems of different ages. According to dating results, this fony baobab is 1,000 yr old. This research is the first investigation of the structure and age of Malagasy baobabs. PMID- 25806966 TI - Kidney function, endothelial activation and atherosclerosis in black and white Africans with rheumatoid arthritis. AB - OBJECTIVE: To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA). METHODS: We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. RESULTS: The CKD-EPI eGFR was <90 ml/min/1.73m2 in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval) = 2.19 (1.28-3.75), p = 0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p = 0.3), whereas the respective relationship was significant or borderline significant (p = 0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. CONCLUSION: Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients. PMID- 25806968 TI - Hybridization of two major termite invaders as a consequence of human activity. AB - While hybridization of an invasive species with a native species is a common occurrence, hybridization between two invasive species is rare. Formosan subterranean termites (Coptotermes formosanus) and Asian subterranean termites (C. gestroi) are both ecologically successful and are the two most economically important termite pests in the world. Both species have spread throughout many areas of the world due to human activity; however, their distributions overlap in only three narrow areas because of distinct ecological requirements. In south Florida, where C. formosanus and C. gestroi are both invasive, the dispersal flight seasons of both species overlapped for the first time on record in 2013 and 2014. Pairings of heterospecific individuals were readily observed in the field and C. gestroi males preferentially engaged in mating behavior with C. formosanus females rather than females from their own species. In the laboratory, heterospecific and conspecific pairings had an equal colony establishment rate, but heterospecific incipient colonies had twice the growth rate of conspecific incipient colonies, suggesting a potential case of hybrid vigor. As all pre zygotic barriers were lifted between the two species in the field, the apparent absence of post-zygotic barriers in the laboratory raises the possibility for introgressive hybridization in south Florida. While laboratory observations remain to be confirmed in the field, and the alate hybrid fertility is currently unknown, our results raise a tangible concern about the hybridization of two major destructive pest species. Such hybridization would likely be associated with a new economic impact. PMID- 25806971 TI - Flexible Polymer-on-Polymer Architecture for Piezo/Pyroelectric Energy Harvesting. AB - An all polymer piezo/pyroelectric device was fabricated using beta phase poly(vinylidene fluoride) (PVDF) as the active material and vapor phase polymerized (VPP) poly(3,4-ethylenedioxythiphene) (PEDOT) as the flexible electrode overlay material. Inherent problems usually associated with coating polymeric electrodes onto the low surface energy PVDF were overcome by air plasma treating the film in conjunction with utilizing the VPP technique to simultaneously synthesize and in situ deposit the PEDOT electrode. Strain measurements up to the breaking-strain of PVDF (approximately 35%) indicated that the change in R/Ro was significantly smaller for the PEDOT based electrodes compared to the platinum electrode. Plasma treatment of the PVDF film increased the level of surface oxygenated carbon species that contributed to increased surface energy, as confirmed by confirmed by contact angle measurement. The enhanced adhesion between the two polymers layers contributed to a significant increase in the measured piezoelectric output voltage from 0.2 to 0.5 V for the same strain conditions. Pyroelectric voltage outputs were obtained by placing the film onto and off of a hotplate, for temperatures up to 50 degrees C above ambient. Finally, as a proof of concept, a simple energy harvesting device (plastic tube with slots for mounting multiple piezo/pyro films) was fabricated. The device was able to generate a usable level of peak output current (>3.5 MUA) from human inhalation and exhalation "waste energy". PMID- 25806969 TI - Indirect acquisition of pain-related fear: an experimental study of observational learning using coloured cold metal bars. AB - BACKGROUND: Previous research has demonstrated that pain-related fear can be acquired through observation of another's pain behaviour during an encounter with a painful stimulus. The results of two experimental studies were presented, each with a different pain stimulus, of which the aim was to investigate the effect of observational learning on pain expectancies, avoidance behaviour, and physiological responding. Additionally, the study investigated whether certain individuals are at heightened risk to develop pain-related fear through observation. Finally, changes in pain-related fear and pain intensity after exposure to the feared stimulus were examined. METHODS: During observational acquisition, healthy female participants watched a video showing coloured cold metal bars being placed against the neck of several models. In a differential fear conditioning paradigm, one colour was paired with painful facial expressions, and another colour was paired with neutral facial expressions of the video models. During exposure, both metal bars with equal temperatures (-25 degrees or +8 degrees Celsius) were placed repeatedly against participants' own neck. RESULTS: Results showed that pain-related beliefs can be acquired by observing pain in others, but do not necessarily cause behavioural changes. Additionally, dispositional empathy might play a role in the acquisition of these beliefs. Furthermore, skin conductance responses were higher when exposed to the pain-associated bar, but only in one of two experiments. Differential pain related beliefs rapidly disappeared after first-hand exposure to the stimuli. CONCLUSIONS: This study enhances our understanding of pain-related fear acquisition and subsequent exposure to the feared stimulus, providing leads for pain prevention and management strategies. PMID- 25806970 TI - CRISPR-Cas9 Based Engineering of Actinomycetal Genomes. AB - Bacteria of the order Actinomycetales are one of the most important sources of pharmacologically active and industrially relevant secondary metabolites. Unfortunately, many of them are still recalcitrant to genetic manipulation, which is a bottleneck for systematic metabolic engineering. To facilitate the genetic manipulation of actinomycetes, we developed a highly efficient CRISPR-Cas9 system to delete gene(s) or gene cluster(s), implement precise gene replacements, and reversibly control gene expression in actinomycetes. We demonstrate our system by targeting two genes, actIORF1 (SCO5087) and actVB (SCO5092), from the actinorhodin biosynthetic gene cluster in Streptomyces coelicolor A3(2). Our CRISPR-Cas9 system successfully inactivated the targeted genes. When no templates for homology-directed repair (HDR) were present, the site-specific DNA double strand breaks (DSBs) introduced by Cas9 were repaired through the error-prone nonhomologous end joining (NHEJ) pathway, resulting in a library of deletions with variable sizes around the targeted sequence. If templates for HDR were provided at the same time, precise deletions of the targeted gene were observed with near 100% frequency. Moreover, we developed a system to efficiently and reversibly control expression of target genes, deemed CRISPRi, based on a catalytically dead variant of Cas9 (dCas9). The CRISPR-Cas9 based system described here comprises a powerful and broadly applicable set of tools to manipulate actinomycetal genomes. PMID- 25806973 TI - Correction: Period2 deficiency blunts hypoxia-induced mobilization and function of endothelial progenitor cells. PMID- 25806975 TI - Ethnic ancestry and smoking, farming of wine grapes in semiarid regions, and the potentials of Manihot multifida in medicine use. PMID- 25806974 TI - Differences in undergoing cardiac procedures within three months after first myocardial infarction by country of birth in women and men: a Swedish national cohort study. AB - OBJECTIVE: To examine the relationship between country of birth and the utilization of coronary angiography, percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) after a first-time myocardial infarction (MI). DESIGN, SETTING AND PATIENTS: 117,494 MI patients of all ages who were admitted to coronary care units between 2001 and 2009 in Sweden were followed-up for three months after admission. MAIN OUTCOME MEASURES: Undergoing coronary angiography, PCI or CABG after first-time MI. RESULTS: proportion of patients undergoing angiography and PCI increased whereas proportion of patients undergoing CABG also delay time for all three procedures decreased over the study period. The proportion of women undergoing any of the three procedures was markedly lower and delay time longer than those of men regardless of study period and migration background. Overall foreign-born first MI patients had higher rate of angiography (HR = 1.30, 95% CI: 1.27-1.33), PCI (HR = 1.27, 95% CI: 1.24-1.30) and CABG (HR = 1.21, 95% CI: 1.15-1.28) compared with Sweden born first MI patients. After controlling for potential confounding factors in multivariable models, the overall differences vanished for angiography and reduced markedly for PCI and CABG. However, multivariable stratified analysis by specific country of birth yielded higher rate of angiography among men born in Uganda (HR = 2.11, 95% CI: 1.00-4.43) and Peru (HR = 1.98, 95% CI: 1.07-3.68) and lower rate among men born in Croatia (HR = 0.71, 95% CI: 0.52-0.99) and women born in Thailand (HR = 0.49, 95% CI: 0.35-0.94). PCI adjusted rates were higher among women born in Palestine state (HR = 2.44, 95% CI: 1.15-5.16), Iraq (HR = 1.34, 95% CI: 1.04 1.74) and Poland (HR = 1.21, 95% CI: 1.02-1.44) and rate of CABG was higher among immigrants from some parts of Asia, including men born in Sri Lanka (HR = 3.19, 95% CI: 1.43-7.12), India (HR = 1.95, 95% CI: 1.21-3.14), Vietnam (HR = 2.65, 95% CI: 1.32-5.33), Palestine State (HR = 2.11, 95% CI: 1.06-4.24), and women born in Syria (HR = 2.36, 95% CI: 1.25-4.45), Iraq (HR = 1.74, 95% CI: 1.02-2.94), and Turkey (HR = 1.70, 95% CI: 1.03-2.79). CONCLUSIONS: The observed high rate of CABG for immigrants and particularly those born in some Asian countries was not explained by the potential confounding factors. A more severe coronary disease in this population might explain this high rate but needs further research. Awareness and subsequent intervention at earlier stage of coronary disease among immigrants could prolong their life and reduce the healthcare costs. PMID- 25806972 TI - ARID5B, IKZF1 and non-genetic factors in the etiology of childhood acute lymphoblastic leukemia: the ESCALE study. AB - Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms. PMID- 25806976 TI - Use of Doehlert and constrained mixture designs in the development of a photo oxidation procedure using UV radiation/H2O2 for decomposition of landfill leachate samples and determination of metals by flame atomic absorption spectrometry. AB - This work proposes the use of photo-oxidation degradation with UV radiation/H2O2 as sample treatment for the determination of Fe, Zn, Mn, Ni and Co in municipal solid waste landfill leachate by flame atomic absorption spectrometry (FAAS). Three variables (pH, irradiation time and buffer concentration) were optimized using Doehlert design and the proportions of mixture components submitted to UV radiation (leachate sample, buffer solution and H2O2 30%, v/v) were optimized using a constrained mixture design. Using the experimental conditions established, this procedure allows limits of detection of 0.075, 0.025, 0.010, 0.075 and 0.041 ug mL-1, and the precision levels expressed as relative standard (%RSD, 0.5 ug mL-1) were 3.6, 1.8, 1.3, 3.3 and 1.7%, for Fe, Mn, Zn, Ni and Co respectively. Recovery tests were carried out for evaluation of the procedure accuracy and recoveries were between 92 and 106% for the studied metals. This procedure has been applied for the analysis of the landfill leachate collected in Jequie, a city of the southwestern region of the State of Bahia, Brazil. The results were compared with those obtained by acid digestion. There was no significant difference between the results obtained by the two methods based on paired t-test at 95% confidence level. PMID- 25806977 TI - On the fossil remains of Panochthus Burmeister, 1866 (Xenarthra, Cingulata, Glyptodontidae) from the Pleistocene of southern Brazil. AB - The genus Panochthus represents the last lineage of "Panochthini" recorded in the Pleistocene. This genus has a wide latitudinal distribution in South America, and in Brazil it occurs in the southern and northeastern regions. In this paper we describe new material (isolated osteoderms and caudal tube fragments) assigned to Panochthus from the state of Rio Grande do Sul (southern Brazil) and discuss some taxonomic issues related to Panochthus tuberculatus and Panochthus greslebini based on this material . The occurrence of P. greslebini is the first for outside the Brazilian Intertropical Region. In addition, we describe new diagnostic features to differentiate the osteoderms of P. greslebini and P. tuberculatus. Unfortunately, it was not possible to identify some osteoderms at the species level. Interestingly, they showed four distinct morphotypes characterized by their external morphology, and thus were attributed to Panochthus sp. Lastly, we conclude that in addition to P.tuberculatus registered to southern Brazil, there is another species of the genus, assignable to P. cf. P. greslebini. Our analysis reinforce the reliability of caudal tube characters for the classification of species of Panochthus. PMID- 25806978 TI - Late quaternary dynamics in the Madeira River basin, southern Amazonia (Brazil), as revealed by paleomorphological analysis. AB - Ancient drainage systems are being increasingly documented in the Amazon basin and their characterization is crucial for reconstructing fluvial evolution in this area. Fluvial morphologies, including elongate belts, are well preserved along the Madeira River. Digital Elevation Model from the Shuttle Radar Topography Mission favored the detection of these features even where they are covered by dense rainforest. These paleomorphologies are attributed to the shifting position of past tributaries of the Madeira River through avulsions. These radial paleodrainage networks produced fan-shaped morphologies that resemble distributary megafans. Distinguishing avulsive tributary systems from distributary megafans in the sedimentary record is challenging. Madeira's paleodrainage reveals the superposition of tributary channels formed by multiple avulsions within a given time period, rather than downstream bifurcation of coexisting channels. Channel avulsion in this Amazonian area during the late Quaternary is related to tectonics due to features as: (i) straight lineaments coincident with fault directions; (ii) northeastward tilting of the terrain with Quaternary strata; and (iii) several drainage anomalies, including frequent orthogonal drainage inflections. These characteristics altogether lead to propose that the radial paleodrainage present at the Madeira River margin results from successive avulsions of tributary channels over time due to tectonics. PMID- 25806979 TI - Detection of proteases from Sporosarcina aquimarina and Algoriphagus antarcticus isolated from Antarctic soil. AB - Two psychrophilic bacterial samples were isolated from King George Island soil, in Antarctica. The phylogenetic analysis based on the 16S rRNA (rrs) gene led to the correlation with the closest related isolates as Sporosarcina aquimarina (99%) and Algoriphagus antarcticus (99%), with query coverage of 99% and 98%, respectively. The spent culture media from both isolates displayed proteolytic activities detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis containing gelatin as protein substrate. Under the employed conditions, S. aquimarina showed a 55 kDa protease with the best activity detected at pH 7.0 and at 27 degrees C. A. antarcticus also showed a single extracellular protease, however its molecular mass was around 90kDa and its best activity was detected at pH 9.0 and at 37 degrees C. The proteases from both isolates were inhibited by 1,10-phenanthroline and EDTA, two metalloprotease inhibitors. This is the first record of protease detection in both species, and our results may contribute to broaden the basic knowledge of proteases from the Antarctica environment and may help prospecting future biotechnological applications of these enzymes. PMID- 25806980 TI - Wide-range genetic connectivity of Coney, Cephalopholis fulva (Epinephelidae), through oceanic islands and continental Brazilian coast. AB - The Epinephelidae form a group of species of high biological and economical interests. It's phylogeographic patterns are not well known especially the distributed populations in the western region of the Atlantic Ocean. Among the representatives is a small species called Cephalopholis fulva, Coney, which presents a wide geographical distribution, polychromia, hermaphroditism and is quickly becoming a large target for the exploration of commercial fishing. The genetic and historical demography were obtained through the partial sequence analysis of Control Region from six locations on the coastline of Brazil from the northeast coast to the southwest coast, including the oceanic islands of Rocas Atoll and Fernando de Noronha Archipelago. The analyzed samples revealed a high genetic variability and a strong gene flow among the sampled locations. Additionally, the genetic data revealed that population expansions probably occurred due to the changes in the sea levels that occurred during the Pleistocene. The large population connectivity found in Coney constitutes relevant conditions for their biological conservation. PMID- 25806981 TI - Plant-pollinator interactions in Crambe abyssinica Hochst. (Brassicaceae) associated with environmental variables. AB - Despite the economic importance of Crambe abyssinica, the present study is the first report on bees that occur with this species, and could aid in developing alternative methods for controlling insect pests without seriously impacting pollinators. The present study examined the following questions: (1) Which species are potential pollinators of C. abyssinica? (2) How do environmental conditions influence pollinator visitation fluctuations? Insects were sampled on a weekly basis between 08:00 and 16:00 during five weeks of flowering. When the results of analyses of variance were significant, the data was adjusted using regression equations at a 5% level of probability; the environmental variables were examined using Pearson's correlation coefficient. Apis mellifera, Geotrigona mombuca, Exomalopsis (Exomalopsis) fulvofasciata, Plebeia sp. and Dialictus sp. were observed visiting C. abyssinica flowers. A. mellifera and G. mombuca were observed to be potential pollinators, with the former demonstrating visitation peaks during flowering weeks II and IV at 12:00 and 08:00, respectively and the latter visiting during weeks III and IV at 12:00 and 10:00, respectively. Environmental factors such as temperature, relative humidity, and wind speed have different effect on the activity of bees. PMID- 25806982 TI - Antimicrobial activity of apitoxin, melittin and phospholipase A2 of honey bee (Apis mellifera) venom against oral pathogens. AB - In this work, we used the Minimum Inhibitory Concentration (MIC) technique to evaluate the antibacterial potential of the apitoxin produced by Apis mellifera bees against the causative agents of tooth decay. Apitoxin was assayed in natura and in the commercially available form. The antibacterial actions of the main components of this apitoxin, phospholipase A2, and melittin were also assessed, alone and in combination. The following bacteria were tested: Streptococcus salivarius, S. sobrinus, S. mutans, S. mitis, S. sanguinis, Lactobacillus casei, and Enterococcus faecalis. The MIC results obtained for the commercially available apitoxin and for the apitoxin in natura were close and lay between 20 and 40 ug / mL, which indicated good antibacterial activity. Melittin was the most active component in apitoxin; it displayed very promising MIC values, from 4 to 40 ug / mL. Phospholipase A2 presented MIC values higher than 400 ug / mL. Association of mellitin with phospholipase A2 yielded MIC values ranging between 6 and 80 ug / mL. Considering that tooth decay affects people's health, apitoxin and its component melittin have potential application against oral pathogens. PMID- 25806983 TI - Leaf and inflorescence axis anatomy of Brazilian species of Rapateoideae (Rapateaceae, Poales). AB - The anatomy of leaves and inflorescence axes of Spathanthus (2 spp.), Rapatea (2 spp.), Cephalostemon (1 sp.), and Duckea (1 sp.) (Rapateoideae, Rapateaceae) was studied to identify useful characters for taxonomy. The cross-section shape of inflorescence axis differentiates the genera, while the cross-section shape and structure of leaf midrib has a specific value. The following characteristics are exclusive of Spathanthus: silica cells randomly distributed in the leaf epidermis; plicate chlorenchyma in the leaf blade; presence of fiber bundles in the mesophyll and in the inflorescence axis parenchyma. Spathanthus is also distinguished by the number, type and distribution of vascular bundles in the inflorescence axis. The genus Rapatea is characterized by the presence of stomata and silica cells only on the abaxial epidermis of the leaves and chlorenchyma composed of arm cells in the leaf blade. Characteristics with diagnostic value for Cephalostemon riedelianus are: leaf epidermal cells with straight to slightly sinuous walls in frontal view, inflorescence axes presenting a defined cortex, fiber bundles facing the larger vascular bundles and a fistulous pith. The anatomical characteristics of the leaves and inflorescence axes thus proved to be of taxonomic value in generic and specific levels. They are also useful to differentiate Rapateoideae from other subfamilies of Rapateaceae. PMID- 25806985 TI - Didelphidae marsupials (Mammalia, Didelphimorphia) from the late Pleistocene deposit of the Gruta dos Moura Cave, northern Brazil. AB - The present study acknowledges the diversity of fossil marsupials from the Gruta dos Moura cave, as well as environmental and climatic aspects during the Quaternary. The results show that this is the largest diversity of Pleistocene marsupials recorded in a single cave: Didelphis albiventris, D. aurita, Gracilinanus agilis, G. microtarsus, Marmosa murina, Monodelphis brevicaudata, M. domestica and Sairadelphys tocantinensis. Furthermore, the described specimens are also part of the only fossil assemblage unequivocally referable to the late Pleistocene. Paleontological studies suggest an intimate association with dry and open environments with high abundance of water sources. Since most of the identified taxa are characteristic of open forests and gallery forests, this could represent the actual environment around the Gruta dos Moura cave. Recent studies identified sympatric occurrences between species from open and dry environments and species from humid forests that were identified among our material and are characteristic of humid regions. Therefore, these species could inhabit gallery forests and capons, or even ecotones, inside a dry and open environment. Moreover, the extinction of Sairadelphys could also indicate that the climatic and environmental conditions changed or that the past environment was more heterogeneous than the current environment of the region. PMID- 25806984 TI - Nicotine-enhanced oxidation of low-density lipoprotein and its components by myeloperoxidase/H2O2/Cl- system. AB - In this study, the effect of nicotine on the LDL oxidation by the MPO/H2O2/Cl- system and the effect of HOCl on LDL and some of its components, such as methyl linoleate, vitamin E and the amino acid tryptophan were explored. Nicotine, in micromolar concentrations, enhanced the tryptophan oxidation, either present in LDL or free, in solution. Nicotine also decreased the formation of conjugated dienes and oxygen consumption in a methyl linoleate / HOCl system, and there was evidence to suggest an increase in chlorohydrin formation. Acceleration of the vitamin E oxidation by HOCl was also observed in the presence of nicotine. These data show that the interaction of nicotine and HOCl can promote significant biochemical modifications in LDL particle and some of its components involved in the pathogenesis of cardiovascular and other diseases. PMID- 25806986 TI - Setting boundaries: environmental and spatial effects on Odonata larvae distribution (Insecta). AB - Environmental characteristics and spatial distances between sites have been used to explain species distribution in the environment, through Neutral (space) and Niche theory (environment) predictions. We evaluated the effects of spatial and environmental factors on Odonata larvae distribution along the Suia-Missu River Basin, state of Mato Grosso. We tested the hypotheses that (1) the environment is the main factor structuring the community due to its ecophysiological requirements; and (2) the pattern, if present, is clearer for Zygoptera. Samples were made in 12 sites on the Suia-Missu River Basin in three seasons (2007/2008), with a total of 1.382 Odonata larvae, comprising 10 families, 51 genera and 100 morphospecies. The Anisoptera were more abundant than Zygoptera, comprising 81% of all specimens. The environment affected Zygoptera (R=0.291; p=0.007) and was the main factor structuring the assembly. Thus, Niche theory was confirmed. The absence of this effect on Anisoptera may be due to the ecophysiological adaptations that enable it to occupy different habitats. Zygoptera larvae are indicators of changes in habitat structure. The effects of environmental variables on larvae ecology emphasize the strong relationship between these organisms and environmental integrity. PMID- 25806987 TI - A study of the dry forest communities in the Dominican Republic. AB - This paper is a floristic and phytosociological study of the dry forest communities of the Dominican Republic. A total of 69 releves in dry forest biotopes were carried out. The samples were subsequently subjected to Detrended Correspondence Analysis for the determination and study of possible groupings. The study does not cover tree formations growing on serpentines, nor the so called semideciduous forests, peculiar to areas with higher rainfall. A total of nine phytocoenoses were identified. The most significant results led to the description of six new phytosociological associations: Simaroubetum berteroani (thorny dry forest on coastal dunes), Phyllostylo rhamnoidis-Prosopidetum juliflorae (southern Dominican disturbed dry forest), Consoleo moniliformis Camerarietum linearifoliae (dry forest on hard limestones), Lemaireocereo hystricis-Prosopidetum juliflorae (northern Dominican disturbed dry forest), Lycio americani-Prosopidetum juliflorae (disturbed dry forest on saline soils) and Guettardo ellipticae-Guapiretum discoloris (dry forest on flat-topped hillocks in Montecristi). This is an important step forward in the phytosociological and floristic studies of the Caribbean territories. PMID- 25806988 TI - Chemosystematic aspects of polyisoprenylated benzophenones from the genus Clusia. AB - Benzophenone derivatives are special metabolites that arouse great scientific interest. The Clusiaceae family is known for producing large amounts of benzophenone derivatives with several isoprene residues on their structures, which are responsible for the observed complexity and structural variety in this class of substances, and also contribute to their biological activities. Clusia is an important genus belonging to Clusiaceae, with 55 different polyisoprenylated benzophenones identified so far. These substances were analyzed from biosynthetic and chemosystematic points of view, allowing the determination of characteristics regarding their production, accumulation and distribution within this genus. Polyisoprenylated benzophenones found in Clusia showed a high prenylation degree, with 2 to 5 isoprene units and a greater occurrence in flowers and fruits. Section Cordylandra showed a very similar occurrence of 2,4,6 trihydroxybenzophenone derivatives and bicyclo[3.3.1]nonane-2,4,9-trione derivatives, the majority of them with 4 isoprene units. In section Anandrogyne there is a predominance of simple 2,4,6-trihydroxy-benzophenone derivatives, with 2 isoprene units, and in Chlamydoclusia predominates bicyclo[3.3.1]nonane-2,4,9 trione derivatives with 4 isoprene units. Although highly prenylated, these substances showed low oxidation indexes, which from an evolutionary perspective corroborates the fact that Clusiaceae is a family in transition, with some common aspects with both basal and derived botanical families. PMID- 25806989 TI - The effects of cyclosporin A and Heteropterys tomentosa on the rat liver. AB - Cyclosporin A (CsA) is a widely employed immunosuppressive drug that is associated with several side effects, among then hepatotoxicity. Heteropterys tomentosa is a Brazilian plant efficient in reducing damage caused by CsA on the rat testis and prostate. The aim of this study was to evaluate the effect of CsA and H. tomentosa (administered isolated or simultaneously) on the liver of Wistar rats. The animals were treated daily with water (control), CsA (15 mg/kg/day), H. tomentosa infusion or CsA+H. tomentosa, for 21 or 56 days. The treatments did not alter liver morphology or cause fibrosis. H. tomentosa administered for 21 days increased the number of hepatocyte nuclei and Kupffer cell volumetric proportion. After 56 days of treatment, H. tomentosa administration did not alter the parameters analyzed. Biochemical plasma dosages and liver stereology showed impairment caused by CsA-treatment after 21 days; these results were not observed after 56 days of treatment. The simultaneous treatment with CsA and H. tomentosa for 21 or 56 days did not alleviate nor accentuate CsA hepatic effects. The present study showed that the 21 days treatment with CsA caused more alteration to the liver than the 56 days treatment; this could be related to hepatic recovery after the long term treatment. PMID- 25806990 TI - Effect of essential oil from Citrus aurantium in maternal reproductive outcome and fetal anomaly frequency in rats. AB - Citrus aurantium L., commonly known as bitter orange, is widely used in folk medicine, but there is little data in the literature about the effects on pregnancy. The aim of the present study was to evaluate the influence of essential oil obtained from fruits of Citrus aurantium on the maternal reproductive outcome and fetal anomaly incidence in rats. Pregnant Wistar rats were randomized into four groups (n minimum = 12 animals/group): G1 = control, G2 to G4 = treated with essential oil from C. aurantium at dose 125, 250 and 500 mg/kg, respectively. Rats were orally treated, by gavage, with plant essential oil or vehicle during pre-implantation and organogenic period (gestational day 0 14). On gestational day 20 the rats were anaesthetized and the gravid uterus was weighed with its contents and the fetuses were analyzed. Results showed that the treated group with 500 mg/kg presented decreased placental weights and placental index, although the treatment with bitter orange essential oil did not show any alteration in maternal reproductive performance, toxicological effect, changes in ossification sites, and malformation index. In conclusion, the treatment of Citrus aurantium essential oil was not teratogenic and did not alter the maternal reproductive outcome. PMID- 25806991 TI - Effect of thermal treatments on technological properties of wood from two Eucalyptus species. AB - The effect of thermal treatments on physical and mechanical properties of rose gum and Sydney blue gum wood was evaluated. Wood samples were thermally modified in a combination: pre-treatment in an autoclave (127 degrees C - 1h) and treatment in an oven (180-240 degrees C - 4h); and only treatment in an oven at 180-240 degrees C for 4h. Chemical changes in the structure of woods were evaluated through infrared spectroscopy. Evaluation of physical properties was performed through mass loss, specific gravity, equilibrium moisture content and dimensional stability tests. Surface changes were analyzed through apparent contact angle technique and static bending tests were carried out to evaluate the mechanical behavior. Use of pre-treatment in autoclave affected the properties analyzed, however oven, resulted in the highest changes on wood from both species. Chemical changes were related to the degradation of hemicelluloses. Moreover, a significant decrease of hygroscopicity and mechanical strength of thermally modified woods was observed, while specific gravity did not significantly change for either of the species studied. The best results of decrease of wettability were found in low temperatures, while dimensional stability increased as a function of temperature of exposure in oven. The highest loss of mechanical strength was observed at 240 degrees C for both species. PMID- 25806993 TI - Economic aspects of production of Caiman crocodilus yacare. AB - The breeding of crocodilians is still a recent activity in Brazil. Its peak was in the 1990's, but it has gaps in its production, as there are no norms for the commercial breeding of these animals in captivity. However, its economic potential is great, and the search for ecological balance and viability of commercial production has become a challenge among farmers of this activity. Therefor, the objective of the study was to economically analyze the production of Caiman crocodilus yacare on a farm located in Caceres, state of Mato Grosso, identifying relevant items of costs in the activity, as well as the parameters related to the profitability and viability of the activity. The economic results for the breeding of this animal were positive, with profitability ratios higher than 70%. PMID- 25806992 TI - Physical attributes of Ultisol of Brazil's northeastern semiarid under organic farming of wine grapes. AB - The purpose of this study was to evaluate the effects of organic farming of wine grapes under physical and chemical characteristics of Ultisol Brazil's northeastern semiarid region. The samples of soil were collected from the row and interrow of the farming and from the fallow area, at the depths of 0.0-0.10, 0.10 0.20, 0.20-0.30 and 0.30-0.60 m. The samples were collected at six and twelve months after the culture implementation to evaluate the state of aggregation, bulk density and total soil porosity, flocculation index and organic matter contents, calcium, magnesium, and sodium. The results were submitted to statistical analysis. The adoption of organic farming contributed to the soil aggregation process. The bulk density and total soil porosity did not differ significantly between the evaluations, but were within the critical limits for sandy soils. The index flocculation did not have a great influence on the aggregates formation, being this process influenced by organic matter. The period of one year was considered short to obtain conclusive results in improving the soil quality by organic farming, since there are difficulties in tropical soils in promoting significant increases in organic matter content in short time. PMID- 25806994 TI - Fitting mathematical models to lactation curves from Holstein cows in the southwestern region of the state of Parana, Brazil. AB - The objective of this study was to evaluate four mathematical models with regards to their fit to lactation curves of Holstein cows from herds raised in the southwestern region of the state of Parana, Brazil. Initially, 42,281 milk production records from 2005 to 2011 were obtained from "Associacao Paranaense de Criadores de Bovinos da Raca Holandesa (APCBRH)". Data lacking dates of drying and total milk production at 305 days of lactation were excluded, resulting in a remaining 15,142 records corresponding to 2,441 Holstein cows. Data were sorted according to the parity order (ranging from one to six), and within each parity order the animals were divided into quartiles (Q25%, Q50%, Q75% and Q100%) corresponding to 305-day lactation yield. Within each parity order, for each quartile, four mathematical models were adjusted, two of which were predominantly empirical (Brody and Wood) whereas the other two presented more mechanistic characteristics (models Dijkstra and Pollott). The quality of fit was evaluated by the corrected Akaike information criterion. The Wood model showed the best fit in almost all evaluated situations and, therefore, may be considered as the most suitable model to describe, at least empirically, the lactation curves of Holstein cows raised in Southwestern Parana. PMID- 25806995 TI - Efficiency of eugenol as anesthetic for the early life stages of Nile tilapia (Oreochromis niloticus). AB - In aquaculture, activities with anesthetic compounds are usually used in order to ensure the welfare of farmed fish, allowing handling out of water with decreased trauma by stress. Presently, there is no information about anesthetic action of eugenol in early life stages of Nile tilapia (Oreochromis niloticus). The objective of this study was to evaluate different concentrations of eugenol for larvae and juveniles of Nile tilapia. Sixty animals were used for each group of weight, group I = 0.02 g; group II = 0.08 g; group III = 0.22 g; group IV = 2.62 g; and group V = 11.64 g. The eugenol concentrations tested were 50, 75, 100, 125, 150 and 175 mg L-1. No mortality was reported during the tests with eugenol. Tilapia larvae with 0.02 g and juveniles around 11.64 g can be anesthetized with eugenol concentrations between 150 and 175 mg L-1, since they determine the shortest sedation time (23 and 72 seconds, for the group of lowest and highest weights, respectively). PMID- 25806996 TI - 3D Bioprinting Human Chondrocytes with Nanocellulose-Alginate Bioink for Cartilage Tissue Engineering Applications. AB - The introduction of 3D bioprinting is expected to revolutionize the field of tissue engineering and regenerative medicine. The 3D bioprinter is able to dispense materials while moving in X, Y, and Z directions, which enables the engineering of complex structures from the bottom up. In this study, a bioink that combines the outstanding shear thinning properties of nanofibrillated cellulose (NFC) with the fast cross-linking ability of alginate was formulated for the 3D bioprinting of living soft tissue with cells. Printability was evaluated with concern to printer parameters and shape fidelity. The shear thinning behavior of the tested bioinks enabled printing of both 2D gridlike structures as well as 3D constructs. Furthermore, anatomically shaped cartilage structures, such as a human ear and sheep meniscus, were 3D printed using MRI and CT images as blueprints. Human chondrocytes bioprinted in the noncytotoxic, nanocellulose-based bioink exhibited a cell viability of 73% and 86% after 1 and 7 days of 3D culture, respectively. On the basis of these results, we can conclude that the nanocellulose-based bioink is a suitable hydrogel for 3D bioprinting with living cells. This study demonstrates the potential use of nanocellulose for 3D bioprinting of living tissues and organs. PMID- 25806997 TI - Multi-Step Protocol for Automatic Evaluation of Docking Results Based on Machine Learning Methods--A Case Study of Serotonin Receptors 5-HT(6) and 5-HT(7). AB - Molecular docking, despite its undeniable usefulness in computer-aided drug design protocols and the increasing sophistication of tools used in the prediction of ligand-protein interaction energies, is still connected with a problem of effective results analysis. In this study, a novel protocol for the automatic evaluation of numerous docking results is presented, being a combination of Structural Interaction Fingerprints and Spectrophores descriptors, machine-learning techniques, and multi-step results analysis. Such an approach takes into consideration the performance of a particular learning algorithm (five machine learning methods were applied), the performance of the docking algorithm itself, the variety of conformations returned from the docking experiment, and the receptor structure (homology models were constructed on five different templates). Evaluation using compounds active toward 5-HT6 and 5-HT7 receptors, as well as additional analysis carried out for beta-2 adrenergic receptor ligands, proved that the methodology is a viable tool for supporting virtual screening protocols, enabling proper discrimination between active and inactive compounds. PMID- 25806998 TI - Correction: Glucose biosensor based on a glassy carbon electrode modified with polythionine and multiwalled carbon nanotubes. PMID- 25806999 TI - Involvement of Reactive Oxygen Species and Mitochondrial Proteins in Biophoton Emission in Roots of Soybean Plants under Flooding Stress. AB - To understand the mechanism of biophoton emission, ROS and mitochondrial proteins were analyzed in soybean plants under flooding stress. Enzyme activity and biophoton emission were increased in the flooding stress samples when assayed in reaction mixes specific for antioxidant enzymes and reactive oxygen species; although the level of the hydroxyl radicals was increased at day 4 (2 days of flooding) compared to nonflooding at day 4, the emission of biophotons did not change. Mitochondria were isolated and purified from the roots of soybean plants grown under flooding stress by using a Percoll gradient, and proteins were analyzed by a gel-free proteomic technique. Out of the 98 mitochondrial proteins that significantly changed abundance under flooding stress, 47 increased and 51 decreased at day 4. The mitochondrial enzymes fumarase, glutathione-S transferase, and aldehyde dehydrogenase increased at day 4 in protein abundance and enzyme activity. Enzyme activity and biophoton emission decreased at day 4 by the assay of lipoxygenase under stress. Aconitase, acyl CoA oxidase, succinate dehydrogenase, and NADH ubiquinone dehydrogenase were up-regulated at the transcription level. These results indicate that oxidation and peroxide scavenging might lead to biophoton emission and oxidative damage in the roots of soybean plants under flooding stress. PMID- 25807000 TI - An enantioselective formal synthesis of montelukast sodium. AB - A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the C-C bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki-Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)propan-2-ol secured direct access to the 3-(2-(2 hydroxypropan-2-yl)phenyl)-1-phenylpropan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the Mizoroki Heck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-Xyl BINAP)((R,R)-DPEN)RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1. PMID- 25807002 TI - Improved reliability for fractal dimension calculation of the vascular imprints on the cranial vault mapped with topographical correction. AB - We presented a novel approach to studies of the vascular grooves located on the inner surface of the cranial vault. A three-dimensional vision system that acquired the endocranial surface topography was used for this purpose. The acquired data were used to generate images showing the branching pattern of the middle meningeal artery. Fractal dimension was used to characterize and analyze branching pattern complexity. We discussed the usefulness of the latter method and indicated difficulties and potential errors connected to the fractal dimension application. The technique introduced for recording traits of the object surface appears to be helpful in anatomical study of morphological variation of dural vascularization. It may also be applicable in paleoneurological research based on analysis of the cranial remnants. Fractal dimension should be used carefully as a method sensitive to many aspects of data acquisition and processing. PMID- 25807001 TI - Early life-history consequences of growth-hormone transgenesis in rainbow trout reared in stream ecosystem mesocosms. AB - There is persistent commercial interest in the use of growth modified fishes for shortening production cycles and increasing overall food production, but there is concern over the potential impact that transgenic fishes might have if ever released into nature. To explore the ecological consequences of transgenic fish, we performed two experiments in which the early growth and survival of growth hormone transgenic rainbow trout (Oncorhynchus mykiss) were assessed in naturalized stream mesocosms that either contained predators or were predator free. We paid special attention to the survival bottleneck that occurs during the early life-history of salmonids, and conducted experiments at two age classes (first-feeding fry and 60 days post-first-feeding) that lie on either side of the bottleneck. In the late summer, the first-feeding transgenic trout could not match the growth potential of their wild-type siblings when reared in a hydrodynamically complex and oligotrophic environment, irrespective of predation pressure. Furthermore, overall survival of transgenic fry was lower than in wild type (transgenic = 30% without predators, 8% with predators; wild-type = 81% without predators, 31% with predators). In the experiment with 60-day old fry, we explored the effects of the transgene in different genetic backgrounds (wild versus domesticated). We found no difference in overwinter survival but significantly higher growth by transgenic trout, irrespective of genetic background. We conclude that the high mortality of GH-transgenic trout during first-feeding reflects an inability to sustain the basic metabolic requirements necessary for life in complex, stream environments. However, when older, GH transgenic fish display a competitive advantage over wild-type fry, and show greater growth and equal survival as wild-type. These results demonstrate how developmental age and time of year can influence the response of genotypes to environmental conditions. We therefore urge caution when extrapolating the results of GH-transgenesis risk assessment studies across multiple life-history or developmental stages. PMID- 25807004 TI - Inverted Leidenfrost-like Effect during Condensation. AB - Water droplets condensing on solidified phase change materials such as benzene and cyclohexane near their melting point show in-plane jumping and continuous "crawling" motion. The jumping drop motion has been tentatively explained as an outcome of melting and refreezing of the materials surface beneath the droplets and can be thus considered as an inverted Leidenfrost-like effect (in the classical case vapor is generated from a droplet on a hot substrate). We present here a detailed investigation of jumping movements using high-speed imaging and static cross-sectional cryogenic focused ion beam scanning electron microscope imaging. Our results show that drop motion is induced by a thermocapillary (Marangoni) effect. The in-plane jumping motion can be delineated to occur in two stages. The first stage occurs on a millisecond time scale and comprises melting the substrate due to drop condensation. This results in droplet depinning, partial spreading, and thermocapillary movement until freezing of the cyclohexane film. The second stage occurs on a second time scale and comprises relaxation motion of the drop contact line (change in drop contact radius and contact angle) after substrate freezing. When the cyclohexane film cannot freeze, the droplet continuously glides on the surface, resulting in the crawling motion. PMID- 25807003 TI - Chronic stress induces a hyporeactivity of the autonomic nervous system in response to acute mental stressor and impairs cognitive performance in business executives. AB - The present study examined the incidence of chronic stress in business executives (109 subjects: 75 male and 34 female) and its relationship with cortisol levels, cognitive performance, and autonomic nervous system (ANS) reactivity after an acute mental stressor. Blood samples were collected from the subjects to measure cortisol concentration. After the sample collection, the subjects completed the Lipp Inventory of Stress Symptoms for Adults and the Stroop Color-Word Test to evaluate stress and cognitive performance levels, respectively. Saliva samples were collected prior to, immediately after, and five minutes after the test. The results revealed that 90.1% of the stressed subjects experienced stress phases that are considered chronic stress. At rest, the subjects with chronic stress showed higher cortisol levels, and no gender differences were observed. No differences were found between the stressed and non-stressed subjects regarding salivary amylase activity prior to test. Chronic stress also impaired performance on the Stroop test, which revealed higher rates of error and longer reaction times in the incongruent stimulus task independently of gender. For the congruent stimulus task of the Stroop test, the stressed males presented a higher rate of errors than the non-stressed males and a longer reaction time than the stressed females. After the acute mental stressor, the non-stressed male group showed an increase in salivary alpha-amylase activity, which returned to the initial values five minutes after the test; this ANS reactivity was not observed in the chronically stressed male subjects. The ANS responses of the non-stressed vs stressed female groups were not different prior to or after the Stroop test. This study is the first to demonstrate a blunted reactivity of the ANS when male subjects with chronic psychological stress were subjected to an acute mental stressor, and this change could contribute to impairments in cognitive performance. PMID- 25807007 TI - Glass transitions of poly(methyl methacrylate) confined in nanopores: conversion of three- and two-layer models. AB - The glass transitions of poly(methyl methacrylate) (PMMA) oligomer confined in alumina nanopores with diameters much larger than the polymer chain dimension were investigated. Compared with the case of 80 nm nanopores, PMMA oligomer confined in 300 nm nanopores shows three glass transition temperatures (from from low to high, denoted as Tg,lo, Tg,inter, and Tg,hi). Such phenomenon can be interpreted by a three-layer model: there exists an interphase between the adsorbed layer and core volume called the interlayer, which has an intermediate Tg. The behavior of multi-Tg parameters is ascribed to the propagation of the interfacial interaction during vitrifaction process. Besides, because of the nonequilibrium effect in the adsorbed layer, the cooling rate plays an important role in the glass transitions: the fast cooling rate generates a single Tg; the intermediate cooling rate induces three Tg values, while the ultraslow cooling rate results in two Tg values. With decreasing the cooling rate, the thickness of interlayer would continually decrease, while those of the adsorbed layer and core volume gradually increase; meanwhile, the Tg,lo gradually increases, Tg,inter almost stays constant, and the Tg,hi value keeps decreasing. In such a process, the dynamic exchanges between the interlayer and adsorbed layer, core volume should be dominant. PMID- 25807005 TI - A combined approach to heat stress effect on male fertility in Nasonia vitripennis: from the physiological consequences on spermatogenesis to the reproductive adjustment of females mated with stressed males. AB - In recent years, several studies have shown a decline in reproductive success in males in both humans and wildlife. Research on male fertility has largely focused on vertebrates, although invertebrates constitute the vast majority of terrestrial biodiversity. The reduction of their reproductive capacities due to environmental stresses can have strong negative ecological impacts, and also dramatic consequences on world food production if it affects the reproductive success of biological control agents, such as parasitic wasps used to control crop pests. Here Nasonia vitripennis, a parasitic wasp of various fly species, was studied to test the effects of 24h-heat stress applied during the first pupal stage on male fertility. Results showed that only primary spermatocytes were present at the first pupal stage in all cysts of the testes. Heat stress caused a delay in spermatogenesis during development and a significant decrease in sperm stock at emergence. Females mated with these heat-stressed males showed a reduce sperm count stored in their spermatheca. Females did not appear to distinguish heat-stressed from control males and did not remate more frequently to compensate for the lack of sperm transferred. As a result, females mated with heat-stressed males produced a suboptimal lifetime offspring sex ratio compared to those mated with control males. This could further impact the population dynamics of this species. N. vitripennis appears to be an interesting biological model to study the mechanisms of subfertility and its consequence on female reproductive strategies and provides new research perspectives in both invertebrates and vertebrates. PMID- 25807008 TI - Correction: CD73 is dispensable for the regulation of inflationary CD8+ T-cells after murine cytomegalovirus infection and adenovirus immunisation. PMID- 25807010 TI - Correction: novel anti-nicotine vaccine using a trimeric coiled-coil hapten carrier. AB - [This corrects the article DOI: 10.1371/journal.pone.0114366.]. PMID- 25807009 TI - Validation of a microsphere immunoassay for serological leptospirosis diagnosis in human serum by comparison to the current gold standard. AB - A microsphere immunoassay (MIA) utilising Luminex xMap technology that is capable of determining leptospirosis IgG and IgM independently was developed. The MIA was validated using 200 human samples submitted for routine leptospirosis serology testing. The traditional microscopic agglutination (MAT) method (now 100 years old) suffers from a significant range of technical problems including a dependence on antisera which is difficult to source and produce, false positive reactions due to auto-agglutination and an inability to differentiate between IgG and IgM antibodies. A comparative validation method of the MIA against the MAT was performed and used to determine the ability of the MIA to detect leptospiral antibodies when compared with the MAT. The assay was able to determine samples in the reactive, equivocal and non-reactive ranges when compared to the MAT and was able to differentiate leptospiral IgG antibodies from leptospiral IgM antibodies. The MIA is more sensitive than the MAT and in true infections was able to detect low levels of antibody in the later stages of the acute phase as well as detect higher levels of IgM antibody earlier in the immune phase of the infection. The relatively low cost, high throughput platform and significantly reduced dependency on large volumes of rabbit antisera make this assay worthy of consideration for any microbiological assay that currently uses agglutination assays. PMID- 25807011 TI - Impacts of organic ligands on forsterite reactivity in supercritical CO2 fluids. AB - Subsurface injection of CO2 for enhanced hydrocarbon recovery, hydraulic fracturing of unconventional reservoirs, and geologic carbon sequestration produces a complex geochemical setting in which CO2-dominated fluids containing dissolved water and organic compounds interact with rocks and minerals. The details of these reactions are relatively unknown and benefit from additional experimentally derived data. In this study, we utilized an in situ X-ray diffraction technique to examine the carbonation reactions of forsterite (Mg2SiO4) during exposure to supercritical CO2 (scCO2) that had been equilibrated with aqueous solutions of acetate, oxalate, malonate, or citrate at 50 degrees C and 90 bar. The organics affected the relative abundances of the crystalline reaction products, nesquehonite (MgCO3 . 3H2O) and magnesite (MgCO3), likely due to enhanced dehydration of the Mg(2+) cations by the organic ligands. These results also indicate that the scCO2 solvated and transported the organic ligands to the forsterite surface. This phenomenon has profound implications for mineral transformations and mass transfer in the upper crust. PMID- 25807006 TI - Neuroplasticity beyond Sounds: Neural Adaptations Following Long-Term Musical Aesthetic Experiences. AB - Capitalizing from neuroscience knowledge on how individuals are affected by the sound environment, we propose to adopt a cybernetic and ecological point of view on the musical aesthetic experience, which includes subprocesses, such as feature extraction and integration, early affective reactions and motor actions, style mastering and conceptualization, emotion and proprioception, evaluation and preference. In this perspective, the role of the listener/composer/performer is seen as that of an active "agent" coping in highly individual ways with the sounds. The findings concerning the neural adaptations in musicians, following long-term exposure to music, are then reviewed by keeping in mind the distinct subprocesses of a musical aesthetic experience. We conclude that these neural adaptations can be conceived of as the immediate and lifelong interactions with multisensorial stimuli (having a predominant auditory component), which result in lasting changes of the internal state of the "agent". In a continuous loop, these changes affect, in turn, the subprocesses involved in a musical aesthetic experience, towards the final goal of achieving better perceptual, motor and proprioceptive responses to the immediate demands of the sounding environment. The resulting neural adaptations in musicians closely depend on the duration of the interactions, the starting age, the involvement of attention, the amount of motor practice and the musical genre played. PMID- 25807012 TI - Investigation of band-offsets at monolayer-multilayer MoS2 junctions by scanning photocurrent microscopy. AB - The thickness-dependent band structure of MoS2 implies that discontinuities in energy bands exist at the interface of monolayer (1L) and multilayer (ML) thin films. The characteristics of such heterojunctions are analyzed here using current versus voltage measurements, scanning photocurrent microscopy, and finite element simulations of charge carrier transport. Rectifying I-V curves are consistently observed between contacts on opposite sides of 1L/ML junctions, and a strong bias-dependent photocurrent is observed at the junction. Finite element device simulations with varying carrier concentrations and electron affinities show that a type II band alignment at single layer/multilayer junctions reproduces both the rectifying electrical characteristics and the photocurrent response under bias. However, the zero-bias junction photocurrent and its energy dependence are not explained by conventional photovoltaic and photothermoelectric mechanisms, indicating the contributions of hot carriers. PMID- 25807014 TI - Sedation: definitions and regulations. PMID- 25807015 TI - The pharmacology of total intravenous anesthesia. PMID- 25807013 TI - Crystal structures of the kinase domain of the sulfate-activating complex in Mycobacterium tuberculosis. AB - In Mycobacterium tuberculosis the sulfate activating complex provides a key branching point in sulfate assimilation. The complex consists of two polypeptide chains, CysD and CysN. CysD is an ATP sulfurylase that, with the energy provided by the GTPase activity of CysN, forms adenosine-5'-phosphosulfate (APS) which can then enter the reductive branch of sulfate assimilation leading to the biosynthesis of cysteine. The CysN polypeptide chain also contains an APS kinase domain (CysC) that phosphorylates APS leading to 3'-phosphoadenosine-5' phosphosulfate, the sulfate donor in the synthesis of sulfolipids. We have determined the crystal structures of CysC from M. tuberculosis as a binary complex with ADP, and as ternary complexes with ADP and APS and the ATP mimic AMP PNP and APS, respectively, to resolutions of 1.5 A, 2.1 A and 1.7 A, respectively. CysC shows the typical APS kinase fold, and the structures provide comprehensive views of the catalytic machinery, conserved in this enzyme family. Comparison to the structure of the human homolog show highly conserved APS and ATP binding sites, questioning the feasibility of the design of specific inhibitors of mycobacterial CysC. Residue Cys556 is part of the flexible lid region that closes off the active site upon substrate binding. Mutational analysis revealed this residue as one of the determinants controlling lid closure and hence binding of the nucleotide substrate. PMID- 25807017 TI - Xenon. PMID- 25807018 TI - Soft drug strategies in anesthesiology. PMID- 25807016 TI - The molecular pharmacology of volatile anesthetics. PMID- 25807020 TI - Fospropofol and remimazolam. PMID- 25807019 TI - The pharmacology of etomidate and etomidate derivatives. PMID- 25807021 TI - Closed-loop pharmacology in anesthesia and critical care: benefits and limitations. PMID- 25807023 TI - Preface: new advances in pharmacology. PMID- 25807024 TI - Influence of Load Intensity on Postexercise Hypotension and Heart Rate Variability after a Strength Training Session. AB - The purpose of this study was to compare blood pressure and heart rate variability (HRV) responses in trained men after strength training (ST) sessions with loads of 60, 70, and 80% of a 1 repetition maximum (1RM). Eleven men (age: 26.1 +/- 3.6 years; body mass: 74.1 +/- 8.1 kg; height: 172.0 +/- 4.0 cm; body mass index: 25.0 +/- 1.96 kg.m(-2); %G: 18.3 +/- 6.4) with at least 6-month ST experience participated in this study. After assessment of 1RM loads for the bench press (BP), lat pull-down (LPD), shoulder press (SP), biceps curl (BC), triceps extension (TE), leg press (LP), leg extension (LE), and leg curl (LC), subjects performed 3 experimental sessions in random order. During each experimental session, subjects performed 3 sets of 8-10 repetitions at 60, 70, or 80% of 1RM loads, with 2-minute rest intervals between sets and exercises. All experimental sessions were performed in the following exercise order: BP, LPD, SP, BC, TE, LP, LE, and LC. Before and for 1 hour after each experimental session, blood pressure and HRV were tracked. The results demonstrated a greater duration of postexercise hypotension (PEH) after the 70% of 1RM session vs. the 60 or 80% of 1RM session. These results indicate that the load/volume associated with completion of 8-10 repetitions at 70% of 1RM load may provide the best stimulus for the PEH response when compared with training with a 60 or 80% of 1RM loads. In conclusion, strength and conditioning professionals may prescribe exercises with 60, 70, and 80% of 1RM loads if the intent is to elicit an acute decrease in blood pressure after an ST session; however, 70% of 1RM provides a longer PEH. PMID- 25807025 TI - Dissociated Time Course of Muscle Damage Recovery Between Single- and Multi-Joint Exercises in Highly Resistance-Trained Men. AB - This study compared the time course of elbow flexor muscle recovery after multi- and single-joint exercises in highly resistance-trained men. Sixteen men (24.5 +/ 5.5 years) performed, in a counterbalanced order, 8 sets of 10 repetition maximum (RM) unilateral seated row exercise and 8 sets of 10RM unilateral biceps preacher curl exercise using the contralateral arm. Maximum isometric peak torque (PT) and delayed onset muscle soreness (DOMS) were recorded at baseline (pre), 10 minutes, 24, 48, 72, and 96 hours after each exercise protocol. There was a significant decrease (p <= 0.05) in elbow flexor PT 10 minutes after both the multi- and single-joint exercise sessions. However, PT decrease was greater after single-joint (26.8%) when compared with multi-joint (15.1%) exercise (p <= 0.05). In addition, elbow flexor PT was lower (8.4%) than baseline 24 hours after the single-joint exercise (p < 0.01), whereas PT returned to baseline 24 hours after the multi-joint exercise. Compared with baseline, DOMS increased at 24, 48, and 72 hours after single-joint exercise (p <= 0.05). However, DOMS returned to baseline levels after 72 hours after multi-joint exercise. In addition, DOMS after single-joint exercise was greater (p <= 0.05) than after multi-joint exercise at 24, 48, and 72 hours after exercise. Our data suggest that after a resistance training session, highly resistance-trained men experience dissimilar elbow flexor strength recovery between single-joint and multi-joint exercises. Likewise, elbow flexor DOMS is greater and takes longer to recover after single joint exercise. PMID- 25807027 TI - Assessing the Energy Expenditure of Elite Female Soccer Players: A Preliminary Study. AB - The aim of this study was to assess the total and exercise energy expenditure of elite female soccer players during a training week. Eight elite female soccer players wore SenseWear Mini Armbands (SWAs) for 7 consecutive days during the preseason phase of a national league competition. In addition, players wore 15-Hz GPSports tracking devices during 4 training sessions and a friendly game. Total energy expenditure, exercise energy expenditure, and training and game demands were collected from the SWA and GPSports devices. Mean daily energy expenditure for the game day, training days, and rest days were 12,242 kJ (SD = 603 kJ), 11,692 (SD = 274 kJ), and 9,516 (SD = 369 kJ), respectively, with significant differences shown between activities (p < 0.001, partial eta2 = 0.357), as well as between individual days (p < 0.001, partial eta2 = 0.517). Mean values for energy expenditure during the friendly game (mean = 2,695 kJ, SD = 301 kJ) and training sessions (mean = 2,538 kJ, SD = 316 kJ) were similar (p = 0.278, Cohen's d = 0.5). However, there were significant differences found between individual training sessions (p = 0.001-0.035). Total and exercise energy expenditure differs throughout the week in female soccer players. Nutritional intake should be adjusted accordingly to avoid energy imbalances for optimal performance and recovery. PMID- 25807028 TI - Training for Power and Speed: Effects of Increasing or Decreasing Jump Squat Velocity in Elite Young Soccer Players. AB - The aim of this study was to test the effects of 2 different velocity-oriented power training regimens by either increasing or decreasing the jump squat velocity during jump training sessions applied 3 times a week for 6 weeks in soccer players. Twenty-four elite under-20 soccer players were randomly assigned to an increased bar velocity group (IVG) or a reduced bar velocity group (RVG). Athletes had their countermovement jump heights, mean propulsive velocities (MPVs) in jump squat, leg press maximum dynamic strength (1 repetition maximum [RM]), 20-m sprint times, and zig-zag change of direction (COD) abilities assessed before and after the intervention. Performance in all tests improved after training in both groups. However, greater gains in 1RM and MPV using 50-90% of body mass (BM) were noted for the RVG. The IVG demonstrated greater improvements in speed at 5, 10, and 20 m and MPV with no additional external load and with 40% BM. Both groups improved similarly in countermovement jumps and COD. To conclude, both velocity-oriented power training regimens were effective in eliciting neuromechanical adaptations, leading to better strength/power/speed performances, and the choice as to the most suitable method should be tailored according to players' needs/deficiencies. PMID- 25807029 TI - Effects of Different Magnitudes of Whole-Body Vibration on Dynamic Squatting Performance. AB - The purpose of this study was to examine the effects (a) of different whole-body vibration (WBV) accelerations when applied simultaneously during a set of squats on performance and perceived exertion and (b) of different linear increases and decreases of vibrations during the squats. It is a randomized, crossover experimental design. Undergraduate students (3 female; 16 male) participated. Each participant completed 5 laboratory sessions in this study (4 familiarization and 1 test session). The test session then had each participant complete one 20 second set of dynamics quarter-squats for 5 separate conditions followed by 5 minutes of rest. Squatting was performed at maximum speed from full extension knee with plantar-flexion ankle to a knee angle of 70 degrees (0 degrees = anatomic position) with dorsiflexion ankle. All sets were performed on the WBV platform in random order, where the 5 different conditions were (a) no WBV-sham, (b) 30 Hz (30 Hz low amplitude), (c) 50 Hz (50 Hz high amplitude), (d) 30-50 Hz (increasing frequency from 30 to 50 Hz; 1 Hz per second with high amplitude), and (e) 50-30 Hz (decreasing frequency from 50 to 30 Hz; 1 Hz per second). There was a significant decrease in the mean velocity of squatting performed during the 30- to 50-Hz condition compared with all other conditions (p <= 0.05). There were a significantly lower amount of repetitions performed during the 30- to 50-Hz exposure compared with the no-WBV and 30-Hz conditions. There was a significantly lower Rating of Perceived Exertion (RPE) during the 30-Hz condition compared with the no-WBV, 50-Hz, 30-50-Hz, and 50-30-Hz conditions. PMID- 25807030 TI - Block vs. Weekly Undulating Periodized Resistance Training Programs in Women. AB - The aim of this study was to compare the effects of resistance training using block periodization (BP) and weekly undulating (WUD) model on maximal strength and hypertrophy in recreationally strength trained women. Seventeen recreationally trained women were randomly assigned to either a BP group (n = 9; age = 24.7 +/- 4.2 years; body mass = 62.1 +/- 5.3 kg; height = 166.4 +/- 6.0 cm) or a WUD group (n = 8; age = 23.2 +/- 2.2 years; body mass = 59.8 +/- 11.9 kg; height = 160.1 +/- 4.1 cm). Participants of both groups trained 3 days a week for 10 weeks. The BP and WUD programs used the same exercises, and the difference between the 2 programs was in the distribution of the training volume within each training phase. Anthropometric measures and strength testing were performed before (PRE) and after 10 weeks (POST) of training. The results revealed that both BP and WUD groups made significant increases in strength and power, but improvements in lower-body strength were significantly (p = 0.039) greater in the WUD group (+27.7%) compared with the BP group (+15.2%). Both groups significantly increased arm muscle hypertrophy (p < 0.001), whereas improvements in thigh muscle size were significant in the WUD group only (+5.8%, p = 0.001). Results of this study indicate that the WUD model is more effective than the BP model for increasing maximal strength and muscle size in the lower body in women. PMID- 25807031 TI - Elastic Bands in Combination With Free Weights in Strength Training: Neuromuscular Effects. AB - This study compared the effects of a variable vs. a constant lower limb resistance training program on muscle strength, muscle activation, and ballistic muscle performance at different knee angles. Thirty-two females were randomized to a constant resistance training free-weight group (FWG) or a variable resistance training group using free weights in combination with elastic bands (EBG). Two variations of the squat exercise (back squat and split) were performed 2 days per week for 10 weeks. Knee extensor maximal voluntary isometric contraction (MVC) and countermovement jump were assessed at knee angles of 60, 90, and 120 degrees before and after the intervention. During the MVCs, muscle activation of the superficial knee extensor muscles was measured using surface electromyography. The FWG increased their MVCs at 60 and 90 degrees (24 and 15%, respectively), whereas the EBG only increased significantly at 60 degrees (15%). The FWG increased their jump height significantly at all angles (12-16%), whereas the EBG only improved significantly at 60 and 90 degrees (15 and 10%, respectively). Both groups improved their 6-repetition maximum free-weight squat performance (EBG: 25% and FWG: 23%). There were no significant changes in muscle activation. In conclusion, constant and variable resistance training provided similar increases in dynamic and isometric strength, and ballistic muscle performance, albeit most consistently for the group training only with free weights. PMID- 25807032 TI - Inhibition of a multiproduct terpene synthase from Medicago truncatula by 3 bromoprenyl diphosphates. AB - The multiproduct sesquiterpene synthase MtTPS5 from Medicago truncatula catalyzes the conversion of farnesyl diphosphate (FDP) into a complex mixture of 27 terpenoids. 3-Bromo substrate analogues of geranyl diphosphate (3-BrGDP) and farnesyl diphosphate (3-BrFDP) were evaluated as substrates of MTPS5 enzyme. Kinetic studies demonstrated that these compounds were highly potent competitive inhibitors of the MtTPS5 enzyme with fast binding and slow reversibility. Since there is a lack of knowledge about the crystal structure of multiproduct terpene synthases, these molecules might be ideal candidates for obtaining a co-crystal structure with multiproduct terpene synthases. Due to the structural and mechanistic similarity between various terpene synthases we expect these 3-bromo isoprenoids to be ideal probes for crystal structure studies. PMID- 25807033 TI - Pharyngeal sense organs drive robust sugar consumption in Drosophila. AB - The fly pharyngeal sense organs lie at the transition between external and internal nutrient-sensing mechanisms. Here we investigate the function of pharyngeal sweet gustatory receptor neurons, demonstrating that they express a subset of the nine previously identified sweet receptors and respond to stimulation with a panel of sweet compounds. We show that pox-neuro (poxn) mutants lacking taste function in the legs and labial palps have intact pharyngeal sweet taste, which is both necessary and sufficient to drive preferred consumption of sweet compounds by prolonging ingestion. Moreover, flies putatively lacking all sweet taste show little preference for nutritive or non nutritive sugars in a short-term feeding assay. Together, our data demonstrate that pharyngeal sense organs play an important role in directing sustained consumption of sweet compounds, and suggest that post-ingestive sugar sensing does not effectively drive food choice in a simple short-term feeding paradigm. PMID- 25807034 TI - What is nephrocalcinosis? AB - The available publications on nephrocalcinosis are wide-ranging and have documented multiple causes and associations of macroscopic or radiological nephrocalcinosis, most often located in the renal medulla, with various metabolic and genetic disorders; in fact, so many and various are these that it is difficult to define a common underlying mechanism. We have reviewed nephrocalcinosis in relation to its definition, genetic associations, animal models, and putative mechanisms. We have concluded, and hypothesized, that nephrocalcinosis is primarily a renal interstitial process, resembling metastatic calcification, and that it may have some features in common with, and pathogenic links to, vascular calcification. PMID- 25807035 TI - Superior outcomes in HIV-positive kidney transplant patients compared with HCV infected or HIV/HCV-coinfected recipients. AB - The prerequisite for an 'undetectable' HIV viral load has restricted access to transplantation for HIV-infected kidney recipients. However, HCV-infected recipients, owing to the historic limitations of HCV therapy in patients with renal disease, are commonly viremic at transplant and have universal access. To compare the effect of HIV, HCV, and HIV/HCV coinfection on kidney transplant patient and allograft outcomes, we performed a retrospective study of kidney recipients transplanted from January 1996 through December 2013. In multivariable analysis, patient (hazard ratio 0.90, 95% confidence interval 0.66-1.24) and allograft survival (0.60, 40-0.88) in 492 HIV patients did not differ significantly from the 117,791 patient-uninfected reference group. This was superior to outcomes in both the 5605 patient HCV group for death (1.44, 1.33 1.56) and graft loss (1.43, 1.31-1.56), as well as the 147 patient HIV/HCV coinfected group for death (2.26, 1.45-3.52) and graft loss (2.59, 1.60-4.19). HIV infection did not adversely affect recipient or allograft survival and was associated with superior outcomes compared with both HCV infection and HIV/HCV coinfection in this population. Thus, pretransplant viral eradication and/or immediate posttransplant eradication should be studied as potential strategies to improve posttransplant outcomes in HCV-infected kidney recipients. PMID- 25807039 TI - Positively-charged reduced graphene oxide as an adhesion promoter for preparing a highly-stable silver nanowire film. AB - An ultrathin conductive adhesion promoter using positively charged reduced graphene oxide (rGO-NH3(+)) has been demonstrated for preparing highly stable silver nanowire transparent conductive electrodes (AgNW TCEs). The adhesion promoter rGO-NH3(+), spray coated between the substrate and AgNWs, significantly enhances the chemical and mechanical stabilities of the AgNW TCEs. Besides, the ultrathin thickness of the rGO-NH3(+) ensures excellent optical transparency and mechanical flexibility for TCEs. The AgNW films prepared using the adhesion promoter are extremely stable under harsh conditions, including ultrasonication in a variety of solvents, 3M Scotch tape detachment test, mechanical bending up to 0.3% strain, or fatigue over 1000 cycles. The greatly enhanced adhesion force is attributed to the ionic interactions between the positively charged protonated amine groups in rGO-NH3(+) and the negatively charged hydroxo- and oxo-groups on the AgNWs. The positively charged GO-NH3(+) and commercial polycationic polymer (poly allylamine hydrochloride) are also prepared as adhesion promoters for comparison with rGO-NH3(+). Notably, the closely packed hexagonal atomic structure of rGO offers better barrier properties to water permeation and demonstrates promising utility in durable waterproof electronics. This work offers a simple method to prepare high-quality TCEs and is believed to have great potential application in flexible waterproof electronics. PMID- 25807036 TI - Gluten exacerbates IgA nephropathy in humanized mice through gliadin-CD89 interaction. AB - IgA1 complexes containing deglycosylated IgA1, IgG autoantibodies, and a soluble form of the IgA receptor (sCD89), are hallmarks of IgA nephropathy (IgAN). Food antigens, notably gluten, are associated with increased mucosal response and IgAN onset, but their implication in the pathology remains unknown. Here, an IgAN mouse model expressing human IgA1 and CD89 was used to examine the role of gluten in IgAN. Mice were given a gluten-free diet for three generations to produce gluten sensitivity, and then challenged for 30 days with a gluten diet. A gluten free diet resulted in a decrease of mesangial IgA1 deposits, transferrin 1 receptor, and transglutaminase 2 expression, as well as hematuria. Mice on a gluten-free diet lacked IgA1-sCD89 complexes in serum and kidney eluates. Disease severity depended on gluten and CD89, as shown by reappearance of IgAN features in mice on a gluten diet and by direct binding of the gluten-subcomponent gliadin to sCD89. A gluten diet exacerbated intestinal IgA1 secretion, inflammation, and villous atrophy, and increased serum IgA1 anti-gliadin antibodies, which correlated with proteinuria in mice and patients. Moreover, early treatment of humanized mice with a gluten-free diet prevented mesangial IgA1 deposits and hematuria. Thus, gliadin-CD89 interaction may aggravate IgAN development through induction of IgA1-sCD89 complex formation and a mucosal immune response. Hence, early-stage treatment with a gluten-free diet could be beneficial to prevent disease. PMID- 25807040 TI - Alternating polystannanes: syntheses and properties. AB - A new condensation polymerization route leading to alternating polystannanes is presented. The stoichiometric reaction of tin dihydrides and tin diamides in diethyl ether or toluene under mild reaction conditions afforded three new moderate molecular weight alternating polystannanes, -[Ph2Sn-alt-Sn(n-Bu)2]n-, [Ph2Sn-alt-SnMe2]n-, -[Me2Sn-alt-Sn(n-Bu)2]n-, in addition to a known homopolymer, -[(n-Bu)2]n-. PMID- 25807037 TI - Primary prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with end-stage renal disease undergoing dialysis. AB - Current evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce the incidence of new atrial fibrillation (AF) in a variety of clinical conditions, including the treatment of left ventricular dysfunction or hypertension. Here we assessed whether ACEIs and ARBs could decrease incidence of new-onset AF in patients with end-stage renal disease (ESRD). We identified patients from the Registry for Catastrophic Illness, a nation-wide database encompassing almost all of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios for new-onset AF. Among 113,186 patients, 13% received ACEIs, 14% received ARBs therapy, and 9% received ACEIs or ARBs alternatively. After a median follow-up of 1524 days, the incidence of new-onset AF significantly decreased in patients treated with ACEIs (hazard ratio 0.587, 95% confidence interval 0.519-0.663), ARBs (0.542, 0.461-0.637), or ACEIs/ARBs (0.793, 0.657-0.958). The prevention of new-onset AF was significantly better in patients taking longer duration of ACEI or ARB therapy. The effect remained robust in subgroup analyses. Thus both ACEIs and ARBs appear to be effective in the primary prevention of AF in patients with ESRD. Hence, renin-angiotensin system inhibition may be an emerging treatment target for the primary prevention of AF. PMID- 25807038 TI - Amino-functionalized green fluorescent carbon dots as surface energy transfer biosensors for hyaluronidase. AB - Amino-functionalized fluorescent carbon dots have been prepared by hydrothermal treatment of glucosamine with excess pyrophosphate. The produced carbon dots showed stabilized green emission fluorescence at various excitation wavelengths and pH environments. Herein, we demonstrate the surface energy transfer between the amino-functionalized carbon dots and negatively charged hyaluronate stabilized gold nanoparticles. Hyaluronidase can degrade hyaluronate and break down the hyaluronate stabilized gold nanoparticles to inhibit the surface energy transfer. The developed fluorescent carbon dot/gold nanoparticle system can be utilized as a biosensor for sensitive and selective detection of hyaluronidase by two modes which include fluorescence measurements and colorimetric analysis. PMID- 25807041 TI - Materials properties: heterogeneity and appropriate sampling modes. AB - The target audience for this Special Section comprises parties related to the food and feed sectors, e.g., field samplers, academic and industrial scientists, laboratory personnel, companies, organizations, regulatory bodies, and agencies who are responsible for sampling, as well as project leaders, project managers, quality managers, supervisors, and directors. All these entities face heterogeneous materials, and the characteristics of heterogeneous materials needs to be competently understood by all of them. Before delivering analytical results for decision-making, one form or other of primary sampling is always necessary, which must counteract the effects of the sampling target heterogeneity. Up to five types of sampling error may arise as a specific sampling process interacts with a heterogeneous material; two sampling errors arise because of the heterogeneity of the sampling target, and three additional sampling errors are produced by the sampling process itself-if not properly understood, reduced, and/or eliminated, which is the role of Theory of Sampling. This paper discusses the phenomenon and concepts involved in understanding, describing, and managing the adverse effects of heterogeneity in sampling. PMID- 25807044 TI - QC of sampling processes- a first overview: from field to test portion. AB - Quality control (QC) is a systematic approach for estimating and minimizing significant error contributions to the measurement uncertainty from the full sampling and analysis process. Many types of QC measures can be implemented; the three dealt with here are primary sampling reproducibility, sample processing reproducibility, and contamination. Sampling processes can be subject to QC by applying a replication experiment, used either from the top by replication of the entire sampling/ preparation/analysis process, or in a hierarchical fashion successively at each subsequent sampling stage. The analytical repeatability is necessarily always included in either alternative. The replication experiment results in a quality index, the Relative Sampling Variability, which is used to assess the total error associated with the full field-to-analysis pathway. Contamination can occur at essentially all locations in the sampling regimen in the food/feed realm, affecting sample containers, sampling tools, sample processing equipment, environmental conditions, and sampling personnel. QC events to determine contamination should always be included where appropriate, but is of most concern for low concentration and/or volatile analytes. It is also of key importance in the development of new sampling protocols or carried-over protocols intended for use on new types of materials/lots than the ones for which they were originally developed. We here establish a first practical framework for QC as applied to the sampling context. PMID- 25807042 TI - Estrogens prevent metabolic dysfunctions induced by circadian disruptions in female mice. AB - Circadian disruption has become a significant factor contributing to the epidemics of obesity and insulin resistance. However, interventions to treat metabolic dysfunctions induced by circadian disruptions are limited. The ovarian hormone, estrogen, produces important antiobesity and antidiabetic effects in female animals and has profound effects on daily behavioral rhythms. Here, we show that in female mice depleted with endogenous estrogens, a jet-lag paradigm induced visceral fat accumulation and systemic insulin resistance, which were associated with altered expression of multiple circadian genes in the visceral fat depot. Interestingly, all these jet-lag-induced deficits were completely rescued in female mice supplemented with exogenous estrogens. We further examined 24-hour oscillations of circadian genes in adipose tissues in female mice with estrogen depletion or replacement and showed that expression levels of the circadian gene, period circadian protein homolog 2, oscillate in visceral adipose tissue in an estrogen-dependent manner. Together, our results indicate that estrogens interact with the intrinsic circadian clock in adipose tissue and prevent abnormal lipid accumulation caused by circadian disruptions. PMID- 25807045 TI - Intravenous Lignocaine to Blunt Extubation Responses: A Double-Edged Sword. AB - Extubation after general anesthetic procedures is often accompanied by transient undesirable responses such as hypertension, tachycardia, coughing, bucking, and raised intracranial and intraocular pressures. In neurosurgical procedures, they need to be stringently controlled to prevent the rise in cerebral blood flow, increase in intracranial pressure, and intracranial bleeding. Intravenous (IV) lignocaine (1-1.5 mg/kg) administration is one such method to blunt extubation responses. We describe a case where IV lignocaine was administered within the recommended doses to inhibit the extubation response, but the same resulted in generalized convulsions because of the clinical and physiological status of the patient at that point of time. Intravenous lignocaine administered to obtund extubation responses can itself manifest in toxic reactions depending on the preexisting clinical and physiological state of the patients. Thus, extreme caution and vigilance is to be maintained whenever IV local anesthetics are used for such purposes. PMID- 25807043 TI - Bisphenol a exposure disrupts metabolic health across multiple generations in the mouse. AB - Accumulating evidence has suggested that a suboptimal early life environment produces multigenerational developmental defects. A proposed mechanism is stable inheritance of DNA methylation. Here we show that maternal bisphenol A (BPA) exposure in C57BL/6 mice produces multigenerational metabolic phenotypes in their offspring. Using various methods including dual-energy X-ray absorptiometry analyses, glucose tolerance tests, and perifusion islet studies, we showed that exposure to 10 MUg/kg/d and 10 mg/kg/d BPA in pregnant F0 mice was associated with higher body fat and perturbed glucose homeostasis in F1 and F2 male offspring but not female offspring. To provide insight into the mechanism of the multigenerational metabolic abnormalities, we investigated the maternal metabolic milieu and inheritance of DNA methylation across generations. We showed that maternal glucose homeostasis during pregnancy was altered in the F0 but not F1 female mice. The results suggested that a compromised maternal metabolic milieu may play a role in the health of the F1 offspring but cannot account for all of the observed multigenerational phenotypes. We further demonstrated that the metabolic phenotypes in the F1 and F2 BPA male offspring were linked to fetal overexpression of the imprinted Igf2 gene and increased DNA methylation at the Igf2 differentially methylated region 1. Studies in H19(Delta3.8/+) mouse mutants supported the role of fetal Igf2 overexpression in altered adult glucose homeostasis. We conclude that early life BPA exposure at representative human exposure levels can perturb metabolic health across multiple generations in the mouse through stable inheritance of DNA methylation changes at the Igf2 locus. PMID- 25807047 TI - Alternative dosing schedules for ustekinumab therapy. PMID- 25807046 TI - Directed natural product biosynthesis gene cluster capture and expression in the model bacterium Bacillus subtilis. AB - Bacilli are ubiquitous low G+C environmental Gram-positive bacteria that produce a wide assortment of specialized small molecules. Although their natural product biosynthetic potential is high, robust molecular tools to support the heterologous expression of large biosynthetic gene clusters in Bacillus hosts are rare. Herein we adapt transformation-associated recombination (TAR) in yeast to design a single genomic capture and expression vector for antibiotic production in Bacillus subtilis. After validating this direct cloning "plug-and-play" approach with surfactin, we genetically interrogated amicoumacin biosynthetic gene cluster from the marine isolate Bacillus subtilis 1779. Its heterologous expression allowed us to explore an unusual maturation process involving the N acyl-asparagine pro-drug intermediates preamicoumacins, which are hydrolyzed by the asparagine-specific peptidase into the active component amicoumacin A. This work represents the first direct cloning based heterologous expression of natural products in the model organism B. subtilis and paves the way to the development of future genome mining efforts in this genus. PMID- 25807048 TI - Investigation of mixotrophic, heterotrophic, and autotrophic growth of Chlorella vulgaris under agricultural waste medium. AB - Growth of Chlorella vulgaris and its lipid production were investigated under autotrophic, heterotrophic, and mixotrophic conditions. Cheap agricultural waste molasses and corn steep liquor from industries were used as carbon and nitrogen sources, respectively. Chlorella vulgaris grew remarkably under this agricultural waste medium, which resulted in a reduction in the final cost of the biodiesel production. Maximum dry weight of 2.62 g L(-1) was obtained in mixotrophic growth with the highest lipid concentration of 0.86 g L(-1). These biomass and lipid concentrations were, respectively, 140% and 170% higher than autotrophic growth and 300% and 1200% higher than heterotrophic growth. In mixotrophic growth, independent or simultaneous occurrence of autotrophic and heterotrophic metabolisms was investigated. The growth of the microalgae was observed to take place first heterotrophically to a minimum substrate concentration with a little fraction in growth under autotrophic metabolism, and then the cells grew more autotrophically. It was found that mixotrophic growth was not a simple combination of heterotrophic and autotrophic growth. PMID- 25807050 TI - Anti-CMV-IgG positivity of donors is beneficial for alloHSCT recipients with respect to the better short-term immunological recovery and high level of CD4+CD25high lymphocytes. AB - Hematopoietic stem cell transplantation from anti-cytomegalovirus immunoglobulin G (anti-CMV-IgG) positive donors facilitated immunological recovery post transplant, which may indicate that chronic CMV infection has an effect on the immune system. This can be seen in the recipients after reconstitution with donor lymphocytes. We evaluated the composition of lymphocytes at hematologic recovery in 99 patients with hematologic malignancies post hematopoietic stem cell transplantation (HSCT). Anti-CMV-IgG seropositivity of the donor was associated with higher proportions of CD4+ (227.963 +/- 304.858 * 106 vs. 102.050 +/- 17.247 * 106 cells/L, p = 0.009) and CD4+CD25high (3.456 +/- 0.436 * 106 vs. 1.589 +/- 0.218 * 106 cells/L, p = 0.003) lymphocytes in the blood at hematologic recovery. The latter parameter exerted a diverse influence on the risk of acute graft versus-host disease (GvHD) if low (1.483 +/- 0.360 * 106 vs. 3.778 +/- 0.484 * 106 cells/L, p < 0.001) and de novo chronic GvHD (cGvHD) if high (3.778 +/- 0.780 * 106 vs. 2.042 +/- 0.261 * 106 cells/L, p = 0.041). Higher values of CD4+ lymphocytes in patients who received transplants from anti-CMV-IgG-positive donors translated into a reduced demand for IgG support (23/63 vs. 19/33, p = 0.048), and these patients also exhibited reduced susceptibility to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and/or human herpes 6 virus (HHV6) infection/reactivation (12/50 vs. 21/47, p = 0.032). Finally, high levels (30.4%) of CD4+CD25high lymphocytes were significantly associated with better post-transplant survival (56% vs. 38%, four-year survival, p = 0.040). Donors who experience CMV infection/reactivation provide the recipients with lymphocytes, which readily reinforce the recovery of the transplanted patients' immune system. PMID- 25807051 TI - Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters. AB - Adenovirus infections of immunocompromised pediatric hematopoietic stem cell transplant patients can develop into serious and often deadly multi-organ disease. There are no drugs approved for adenovirus infections. Cidofovir (an analog of 2-deoxycytidine monophosphate) is used at times but it can be nephrotoxic and its efficacy has not been proven in clinical trials. Brincidofovir, a promising lipid-linked derivative of cidofovir, is in clinical trials. Ganciclovir, an analog of 2-deoxyguanosine, has been employed occasionally but with unknown efficacy in the clinic. In this study, we evaluated valganciclovir against disseminated adenovirus type 5 (Ad5) infection in our permissive immunosuppressed Syrian hamster model. We administered valganciclovir prophylactically, beginning 12 h pre-infection or therapeutically starting at Day 1, 2, 3, or 4 post-infection. Valganciclovir significantly increased survival, reduced viral replication in the liver, and mitigated the pathology associated with Ad5 infection. In cultured cells, valganciclovir inhibited Ad5 DNA replication and blocked the transition from early to late stage of infection. Valganciclovir directly inhibited Ad5 DNA polymerase in vitro, which may explain, at least in part, its mechanism of action. Ganciclovir and valganciclovir are approved to treat infections by certain herpesviruses. Our results support the use of valganciclovir to treat disseminated adenovirus infections in immunosuppressed patients. PMID- 25807049 TI - Impacts of humanized mouse models on the investigation of HIV-1 infection: illuminating the roles of viral accessory proteins in vivo. AB - Human immunodeficiency virus type 1 (HIV-1) encodes four accessory genes: vif, vpu, vpr, and nef. Recent investigations using in vitro cell culture systems have shed light on the roles of these HIV-1 accessory proteins, Vif, Vpr, Vpu, and Nef, in counteracting, modulating, and evading various cellular factors that are responsible for anti-HIV-1 intrinsic immunity. However, since humans are the exclusive target for HIV-1 infection, conventional animal models are incapable of mimicking the dynamics of HIV-1 infection in vivo. Moreover, the effects of HIV-1 accessory proteins on viral infection in vivo remain unclear. To elucidate the roles of HIV-1 accessory proteins in the dynamics of viral infection in vivo, humanized mouse models, in which the mice are xenotransplanted with human hematopoietic stem cells, has been utilized. This review describes the current knowledge of the roles of HIV-1 accessory proteins in viral infection, replication, and pathogenicity in vivo, which are revealed by the studies using humanized mouse models. PMID- 25807053 TI - Interaction research on the antiviral molecule dufulin targeting on southern rice black streaked dwarf virus p9-1 nonstructural protein. AB - Southern rice black streaked dwarf virus (SRBSDV) causes severe harm to rice production. Unfortunately, studies on effective antiviral drugs against SRBSDV and interaction mechanism of antiviral molecule targeting on SRBSDV have not been reported. This study found dufulin (DFL), an ideal anti-SRBSDV molecule, and investigated the interactions of DFL targeting on the nonstructural protein P9-1. The biological sequence information and bonding characterization of DFL to four kinds of P9-1 protein were described with fluorescence titration (FT) and microscale thermophoresis (MST) assays. The sequence analysis indicated that P9-1 had highly-conserved C- and N-terminal amino acid residues and a hypervariable region that differed from 131 aa to 160 aa. Consequently, wild-type (WT-His-P9 1), 23 C-terminal residues truncated (TR-DeltaC23-His-P9-1), 6 N-terminal residues truncated (TR-DeltaN6-His-P9-1), and Ser138 site-directed (MU-138-His-P9 1) mutant proteins were expressed. The FT and MST assay results indicated that DFL bounded to WT-His-P9-1 with micromole affinity and the 23 C-terminal amino acids were the potential targeting site. This system, which combines a complete sequence analysis, mutant protein expression, and binding action evaluating system, could further advance the understanding of the interaction abilities between antiviral drugs and their targets. PMID- 25807052 TI - Modulation of SIV and HIV DNA vaccine immunity by Fas-FasL signaling. AB - Signaling through the Fas/Apo-1/CD95 death receptor is known to affect virus specific cell-mediated immune (CMI) responses. We tested whether modulating the Fas-apoptotic pathway can enhance immune responses to DNA vaccination or lymphocytic choriomeningitis virus (LCMV) infection. Mice were electroporated with plasmids expressing a variety of pro- or anti-apoptotic molecules related to Fas signaling and then either LCMV-infected or injected with plasmid DNA expressing SIV or HIV antigens. Whereas Fas or FasL knockout mice had improved CMI, down-regulation of Fas or FasL by shRNA or antibody failed to improve CMI and was accompanied by increases in regulatory T cells (Treg). Two "adjuvant" plasmids were discovered that significantly enhanced plasmid immunizations. The adjuvant effects of Fas-associated death domain (FADD) and of cellular FLICE inhibitory protein (cFLIP) were consistently accompanied by increased effector memory T lymphocytes and increased T cell proliferation. This adjuvant effect was also observed when comparing murine infections with LCMV-Armstrong and its persisting variant LCMV-Clone 13. LCMV-Armstrong was cleared in 100% of mice nine days after infection, while LCMV-Clone 13 persisted in all mice. However, half of the mice pre-electroporated with FADD or cFLIP plasmids were able to clear LCMV Clone 13 by day nine, and, in the case of cFLIP, increased viral clearance was accompanied by higher CMI. Our studies imply that molecules in the Fas pathway are likely to affect a number of events in addition to the apoptosis of cells involved in immunity. PMID- 25807054 TI - Chondroitin sulfate N-acetylgalactosaminyltransferase-2 contributes to the replication of infectious bursal disease virus via interaction with the capsid protein VP2. AB - Infectious bursal disease virus (IBDV) is a birnavirus that causes a highly contagious immunosuppressive disease in young chickens. The capsid protein VP2 of IBDV plays multiple roles in its life cycle. To more comprehensively understand the functions of VP2 involved in the communication between virus and host, we used yeast two-hybrid screening to identify the cellular factors that interact with this protein. We found that chondroitin sulfate N acetylgalactosaminyltransferase-2 (CSGalNAcT2), a typical type II transmembrane protein located in Golgi apparatus, could interact with VP2, and we confirmed this interaction by co-immunoprecipitation and confocal laser scanning microscopy assays. Additionally, up-regulation of CSGalNAcT2 during IBDV infection was observed. Overexpression and siRNA-mediated knockdown of CSGalNAcT2 assays suggested that CSGalNAcT2 promoted IBDV replication. Moreover, this enhancing effect of CSGalNAcT2 could be inhibited by Brefeldin A, which is a Golgi disturbing agent. This indicated that the integrity of Golgi apparatus structure was involved in the function of CSGalNAcT2. Taken together, we concluded that CSGalNAcT2, located in the Golgi apparatus, contributed to the replication of IBDV via interaction with VP2. PMID- 25807055 TI - Facilitation of rice stripe virus accumulation in the insect vector by Himetobi P virus VP1. AB - The small brown planthopper (SBPH) is the main vector for rice stripe virus (RSV), which causes serious rice stripe disease in East Asia. To characterize the virus-vector interactions, the SBPH cDNA library was screened with RSV ribonucleoprotein (RNP) as bait using a GAL4-based yeast two-hybrid system. The interaction between RSV-RNP and the Himetobi P virus (HiPV, an insect picorna like virus) VP1 protein was identified. The relationships between HiPV and RSV in SBPH were further investigated, and the results showed that the titer of RSV was commonly higher in single insect that exhibited more VP1 expression. After the VP1 gene was repressed by RNA silencing, the accumulation of RSV decreased significantly in the insect, whereas the virus acquisition ability of SBPH was unaffected, which suggests that HiPV VP1 potentially facilitates the accumulation of RSV in SBPH. PMID- 25807058 TI - When are signal transduction targeted therapies acting as immunotherapy? PMID- 25807059 TI - Endogenous Life Cycle of Eimeria marmosopos (Apicomplexa: Eimeriidae) from the Opossum, Didelphis marsupialis (Didelphimorphia: Didelphidae) in Costa Rica. AB - The endogenous life cycle of Eimeria marmosopos was studied in experimentally infected young opossums, Didelphis marsupialis . All the endogenous stages were located in the epithelial cells of villi in the small intestine. Giemsa-stained mucosal scrapings and histological sections were studied for the diagnosis of all the life cycle stages. Eimeria marmosopos has 3 generations of meronts (M) that differ by size, shape, and number of merozoites (m), which also differ in their size, shape, and location of their nuclei within the cytoplasm of the meronts. The 3 meront types, M(1)-M(3), respectively, had 8-15 (m(1)), 4-9 (m(2)), and 22 30 (m(3)) merozoites. Macrogametocytes and microgametocytes, as well as macrogametes and microgametes, completed the sexual cycle, finishing with the formation of unsporulated oocysts. This parasite's endogenous development produced severe intestinal lesions in experimentally infected opossums. There are 56 Eimeria species known from all marsupials worldwide, but this is the first complete life cycle in which both the asexual and sexual stages have been documented. PMID- 25807060 TI - Topical Drug Innovation From 2000 Through 2014. PMID- 25807057 TI - Viral interference with functions of the cellular receptor tyrosine phosphatase CD45. AB - The receptor tyrosine phosphatase CD45 is expressed on the surface of almost all cells of hematopoietic origin. CD45 functions are central to the development of T cells and determine the threshold at which T and B lymphocytes can become activated. Given this pivotal role of CD45 in the immune system, it is probably not surprising that viruses interfere with the activity of CD45 in lymphocytes to dampen the immune response and that they also utilize this molecule to accomplish their replication cycle. Here we report what is known about the interaction of viral proteins with CD45. Moreover, we debate putative interactions of viruses with CD45 in myeloid cells and the resulting consequences-subjects that remain to be investigated. Finally, we summarize the evidence that pathogens were the driving force for the evolution of CD45. PMID- 25807061 TI - Comparison of brief health literacy screens in the emergency department. AB - Measuring health literacy efficiently yet accurately is of interest both clinically and in research. The authors examined 6 brief health literacy measures and compared their categorization of patient health literacy levels and their comparative associations with patients' health status. The authors assessed 400 emergency department patients with the Short Test of Functional Health Literacy in Adults, the Newest Vital Sign, Single Item Literacy Screen, brief screening questions, Rapid Estimate of Adult Literacy in Medicine-Revised, and the Medical Term Recognition Test. The authors analyzed data using Spearman's correlation coefficients and ran separate logistic regressions for each instrument for patient self-reported health status. Tests differed in the proportion of patients' skills classified as adequate, but all instruments were significantly correlated; instruments targeting similar skills were more strongly correlated. Scoring poorly on any instrument was significantly associated with worse health status after adjusting for age, sex and race, with a score in the combined inadequate/marginal category on the Short Test of Functional Health Literacy in Adults carrying the largest risk (OR = 2.94, 95% CI [1.23, 7.05]). Future research will need to further elaborate instrument differences in predicting different outcomes. PMID- 25807056 TI - Molecular genetic analysis of orf virus: a poxvirus that has adapted to skin. AB - Orf virus is the type species of the Parapoxvirus genus of the family Poxviridae. It induces acute pustular skin lesions in sheep and goats and is transmissible to humans. The genome is G+C rich, 138 kbp and encodes 132 genes. It shares many essential genes with vaccinia virus that are required for survival but encodes a number of unique factors that allow it to replicate in the highly specific immune environment of skin. Phylogenetic analysis suggests that both viral interleukin 10 and vascular endothelial growth factor genes have been "captured" from their host during the evolution of the parapoxviruses. Genes such as a chemokine binding protein and a protein that binds granulocyte-macrophage colony stimulating factor and interleukin-2 appear to have evolved from a common poxvirus ancestral gene while three parapoxvirus nuclear factor (NF)-kappaB signalling pathway inhibitors have no homology to other known NF-kappaB inhibitors. A homologue of an anaphase-promoting complex subunit that is believed to manipulate the cell cycle and enhance viral DNA synthesis appears to be a specific adaptation for viral-replication in keratinocytes. The review focuses on the unique genes of orf virus, discusses their evolutionary origins and their role in allowing viral-replication in the skin epidermis. PMID- 25807064 TI - Bacteria-induced intracellular signalling in platelets. AB - Multiple studies have now shown that various species of bacteria can stimulate platelets; many in a strain and donor-dependent manner. The signalling pathways underlying this platelet activation has been the subject of scrutiny for the last decade. The best-delineated pathway is that in response to Streptococcal species, such as Streptococcus sanguinis (S. sanguinis), Streptococcus gordonii (S. gordonii) and Streptococcus oralis (S. oralis), where a pathway is initiated by the engagement of the low affinity IgG receptor, FcgammaRIIA. This leads to and involves the tyrosine kinase Syk, the adaptor protein Linker of Activated T Cells (LAT) and subsequently both phospholipase Cgamma2 (PLCgamma2) and phosphatidylinositol-3-kinase (PI-3-K). Finally, this leads to the expression of the alphaIIbbeta3 integrin, the synthesis and release of thromboxane A2 (T * A2) and the exocytosis of PF4, each of which plays a crucial role in secondary signalling and full platelet activation. Roles for other signalling pathways in Streptococcal-induced platelet activation are less clear, although an ADP mediated inhibition of adenylyl cyclase, a glycoprotein Ib/IX/V-mediated pathway and perhaps a complement-induced pathway have each been proposed. Platelet activation by Porphyromonas gingivalis (P. gingivalis) at least partially shares the FcgammaRIIA/Syk/PLCgamma2/PI-3-K mechanism utilised by Streptococcal species. However, it has also been suggested that P. gingivalis activates platelets by two additional methods; stimulation of the protease-activated receptors leading to activation of phospholipase Cbeta (PLCbeta), and the engagement of Toll-like receptors 2 and 4 by released lipopolysaccharide leading to an ill-defined pathway which may involve PI-3-K. Consequently, it appears that bacteria can stimulate platelets by eliciting multiple signalling pathways some of which are common, and some unique, to individual species. PMID- 25807063 TI - Exotic Dance in Baltimore: From Entry to STI/HIV Risk. AB - Research has documented health risks associated with sex work, but few U.S. studies have focused on the exotic dance industry. We undertook this study to describe the factors that influenced women's entry into exotic dance and explored the relation of these forces to their subsequent sexually transmitted infection (STI)/HIV risk trajectory. Qualitative interviews (N = 25) were conducted with female exotic dancers from June through August 2009. Data were analyzed through Atlas-ti using an inductive approach. Economic vulnerability was the primary force behind women's initiation into the profession. Drug use, physical abuse, and enjoyment of dancing were often concurrent with economic need and provided a further push toward exotic dance. Social networks facilitated entry by normalizing the profession and presenting it as a solution to financial hardship. Characteristics of exotic dance clubs, such as immediate hire and daily pay, attracted women in a state of financial vulnerability. Women's motivations for dancing, including economic vulnerability and drug use practices, shaped their STI/HIV risk once immersed in the club environment, with social networks often facilitating sexual risk behavior. Understanding the factors that drive women to exotic dance and influence risk behavior in the club may assist in the development of targeted harm reduction interventions for exotic dancers. PMID- 25807062 TI - The polarity protein Scribble regulates myelination and remyelination in the central nervous system. AB - The development and regeneration of myelin by oligodendrocytes, the myelin forming cells of the central nervous system (CNS), requires profound changes in cell shape that lead to myelin sheath initiation and formation. Here, we demonstrate a requirement for the basal polarity complex protein Scribble in CNS myelination and remyelination. Scribble is expressed throughout oligodendroglial development and is up-regulated in mature oligodendrocytes where it is localised to both developing and mature CNS myelin sheaths. Knockdown of Scribble expression in cultured oligodendroglia results in disrupted morphology and myelination initiation. When Scribble expression is conditionally eliminated in the myelinating glia of transgenic mice, myelin initiation in CNS is disrupted, both during development and following focal demyelination, and longitudinal extension of the myelin sheath is disrupted. At later stages of myelination, Scribble acts to negatively regulate myelin thickness whilst suppressing the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAP) kinase pathway, and localises to non-compact myelin flanking the node of Ranvier where it is required for paranodal axo-glial adhesion. These findings demonstrate an essential role for the evolutionarily-conserved regulators of intracellular polarity in myelination and remyelination. PMID- 25807065 TI - Repression of AS2 by WOX family transcription factors is required for leaf development in Medicago and Arabidopsis. AB - WOX transcription factors are key regulators of meristematic activity in plants. The Medicago WOX gene, STF, functions in maintenance of leaf marginal meristem, analogous to the function of WUS in the shoot apical meristem. Both STF and WUS directly repress AS2 expression in their respective domains. Ectopic expression of AS2 with WUS promoter leads to a narrow leaf phenotype and other phenotypes similar to the wus mutant. We also found that a wox1 prs wus triple mutant produces much narrower leaf blades than the wox1 prs double mutant, indicating that WUS genetically interacts with WOX1 and PRS in Arabidopsis leaf blade development. Our data points to a general requirement for AS2 repression in meristematic regions to allow cell proliferation. PMID- 25807067 TI - Reliability of ultra-short-term analysis as a surrogate of standard 5-min analysis of heart rate variability. AB - BACKGROUND: Despite the increasing demands of ultra-short-term heart rate (HR) variability (HRV) for practical ambulatory applications, there have been few studies that have investigated R-R interval recording for less than 5 min for HRV analysis. It has not been extensively validated, and, currently, no normative data for ultra-short-term HRV exist. The aim of this study was to investigate the relationship between standard 5-min and ultra-short-term HRV by collecting data from a large population consisting of a wide range of age groups. MATERIALS AND METHODS: The 5-min R-R interval series were obtained from 467 healthy volunteers ranging from 8 to 69 years of age. The original R-R interval was segmented into 270, 240, 210, 180, 150, 120, 90, 60, 30, 20, and 10 s, and those HRV features most commonly reported within the literature were calculated and compared with those using the original 5-min R-R interval series. The Pearson correlation r, the p value by the Kruskal-Wallis test, and the Bland-Altman plot analysis computations were performed for each HRV variable calculated using different lengths of R-R interval series. RESULTS: For each HRV variable, the minimum length of the R-R interval required to reliably estimate the 5-min HRV was identified. The results were different for each age group: 10 s for HR, 20 s for high-frequency, 30 s for root mean square difference, 60 s for proportion of the number of interval differences of successive NN intervals greater than 50 ms divided by total number of NNs, 90 s for low-frequency, normalized low-frequency, normalized high-frequency, and low-frequency/high-frequency, 240 s for standard deviation of successive NN interval differences and time-frequency, and 270 s for very low-frequency. In addition, the reference value for short-term HRV from normal healthy subjects was also presented. CONCLUSIONS: Some HRV variables calculated from R-R interval series shorter than 5 min were well matched with those calculated from the 5-min R-R interval. Thus, ultra-short-term HRV is likely to be a good surrogate method to assess trends in HRV. PMID- 25807066 TI - Effects of prenatal exposure to air pollutants (polycyclic aromatic hydrocarbons) on the development of brain white matter, cognition, and behavior in later childhood. AB - IMPORTANCE: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and neurotoxic environmental contaminants. Prenatal PAH exposure is associated with subsequent cognitive and behavioral disturbances in childhood. OBJECTIVES: To identify the effects of prenatal PAH exposure on brain structure and to assess the cognitive and behavioral correlates of those abnormalities in school-age children. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional imaging study in a representative community-based cohort followed up prospectively from the fetal period to ages 7 to 9 years. The setting was urban community residences and an academic imaging center. Participants included a sample of 40 minority urban youth born to Latina (Dominican) or African American women. They were recruited between February 2, 1998, and March 17, 2006. MAIN OUTCOMES AND MEASURES: Morphological measures that index local volumes of the surface of the brain and of the white matter surface after cortical gray matter was removed. RESULTS: We detected a dose-response relationship between increased prenatal PAH exposure (measured in the third trimester but thought to index exposure for all of gestation) and reductions of the white matter surface in later childhood that were confined almost exclusively to the left hemisphere of the brain and that involved almost its entire surface. Reduced left hemisphere white matter was associated with slower information processing speed during intelligence testing and with more severe externalizing behavioral problems, including attention-deficit/hyperactivity disorder symptoms and conduct disorder problems. The magnitude of left hemisphere white matter disturbances mediated the significant association of PAH exposure with slower processing speed. In addition, measures of postnatal PAH exposure correlated with white matter surface measures in dorsal prefrontal regions bilaterally when controlling for prenatal PAH. CONCLUSIONS AND RELEVANCE: Our findings suggest that prenatal exposure to PAH air pollutants contributes to slower processing speed, attention-deficit/hyperactivity disorder symptoms, and externalizing problems in urban youth by disrupting the development of left hemisphere white matter, whereas postnatal PAH exposure contributes to additional disturbances in the development of white matter in dorsal prefrontal regions. PMID- 25807069 TI - Myb via TGFbeta is required for collagen type 1 production and skin integrity. AB - Skin integrity requires an ongoing replacement and repair orchestrated by several cell types. We previously investigated the architecture of the skin of avian myeloblastosis viral oncogene homolog (Myb) knock-out (KO) embryos and wound repair in Myb(+/)(-) mice revealing a need for Myb in the skin, attributed to fibroblast-dependent production of collagen type 1. Here, using targeted Myb deletion in keratin-14 (K14) positive cells we reveal further Myb-specific defects in epidermal cell proliferation, thickness and ultrastructural morphology. This was associated with a severe deficit in collagen type 1 production, reminiscent of that observed in patients with ichthyosis vulgaris and Ehlers-Danlos syndrome. Since collagen type 1 is a product of fibroblasts, the collagen defect observed was unexpected and appears to be directed by the loss of Myb with significantly reduced tumor growth factor beta 1 (Tgfbeta-1) expression by primary keratinocytes. Our findings support a specific role for Myb in K14+ epithelial cells in the preservation of adult skin integrity and function. PMID- 25807068 TI - The tail domain of lamin B1 is more strongly modulated by divalent cations than lamin A. AB - The nucleoskeleton contains mainly nuclear intermediate filaments made of lamin proteins. Lamins provide nuclear structure and also play a role in various nuclear processes including signal transduction, transcription regulation and chromatin organization. The disparate functions of lamins may be related to the intrinsic disorder of the tail domains, which allows for altered and promiscuous binding. Here, we show modulation of lamin tail domain structures in the presence of divalent cations. We utilize changes in fluorescence of tryptophan residues within the Ig-fold flanked by disordered regions to experimentally measure protein thermodynamics. Using spectroscopy experiments and molecular dynamics simulations, we show that the tail domain of lamin B1 shows enhanced association with both Ca(2+) and Mg(2+) compared to the tail domain of lamin A. Binding curves show a similar KD between protein and ion (250-300 MUM) for both proteins with both ions. However, we observe a maximum binding of ions to lamin B1 tail domain which is 2-3 times greater than that for lamin A tail domain by both experiment and simulation. Using simulations, we show that divalent ion association alters the Ig-fold by pinning flanking regions. With cells in culture, we observe altered lamin B1 organization in the presence of excess Mg(2+) more so than for lamin A. We suggest that the differential sensitivity to divalent cations contributes to the vastly different functionalities and binding of the 2 proteins. PMID- 25807070 TI - Simultaneous imaging of the topography and electrochemical activity of a 2D carbon nanotube network using a dual functional L-shaped nanoprobe. AB - The application of nanomaterials for biosensors and fuel cells is becoming more common, but it requires an understanding of the relationship between the structure and electrochemical characteristics of the materials at the nanoscale. Herein, we report the development of scanning electrochemical microscopy-atomic force microscopy (SECM-AFM) nanoprobes for collecting spatially resolved data regarding the electrochemical activity of nanomaterials such as carbon nanotube (CNT) networks. The fabrication of the nanoprobe begins with the integration of a CNT-bundle wire into a conventional AFM probe followed by the deposition of an insulating layer and cutting of the probe end. In addition, a protrusive insulating tip is integrated at the end of the insulated CNT-bundle wire to maintain a constant distance between the nanoelectrode and the substrate; this yields an L-shaped nanoprobe. The resulting nanoprobes produced well-fitted maps of faradaic current data with less than 300 nm spatial resolution and topographical images of CNT networks owing to the small effective distance (of the order of tens of nanometers) between the electrode and the substrate. Electrochemical imaging using the L-shaped nanoprobe revealed that the electrochemical activity of the CNT network is not homogeneous and provided further understanding of the relationship between the topography and electrochemical characteristics of CNT networks. PMID- 25807072 TI - Chronic idiopathic urticaria: treatment with omalizumab. AB - Chronic idiopathic urticaria (CIU) is a common autoimmune skin condition characterized by spontaneously recurring hives for 6 weeks or longer. The new terminology used for CIU in most countries including Canada is chronic spontaneous urticaria (CSU). CSU is associated with significant psychosocial morbidity with a markedly negative impact on overall quality of life. Conventional approaches with antihistamines, even at high doses, is effective in about 50% of patients suffering from CSU. A new treatment option, omalizumab, a humanized monoclonal antibody against the Fc domain of IgE, has undergone the scrutiny of randomized research studies evaluating the efficacy in CSU. This editorial reviews mechanisms of action of omalizumab, efficacy, cost and potential side effect profile. Omalizumab has emerged as a very promising treatment option for patients with CSU. Future research is necessary to establish standardized protocols related to dosing as well as monitoring possible adverse effects of long-term treatment. PMID- 25807071 TI - A modular analysis of the auxin signalling network. AB - Auxin is essential for plant development from embryogenesis onwards. Auxin acts in large part through regulation of transcription. The proteins acting in the signalling pathway regulating transcription downstream of auxin have been identified as well as the interactions between these proteins, thus identifying the topology of this network implicating 54 Auxin Response Factor (ARF) and Aux/IAA (IAA) transcriptional regulators. Here, we study the auxin signalling pathway by means of mathematical modeling at the single cell level. We proceed analytically, by considering the role played by five functional modules into which the auxin pathway can be decomposed: the sequestration of ARF by IAA, the transcriptional repression by IAA, the dimer formation amongst ARFs and IAAs, the feedback loop on IAA and the auxin induced degradation of IAA proteins. Focusing on these modules allows assessing their function within the dynamics of auxin signalling. One key outcome of this analysis is that there are both specific and overlapping functions between all the major modules of the signaling pathway. This suggests a combinatorial function of the modules in optimizing the speed and amplitude of auxin-induced transcription. Our work allows identifying potential functions for homo- and hetero-dimerization of transcriptional regulators, with ARF:IAA, IAA:IAA and ARF:ARF dimerization respectively controlling the amplitude, speed and sensitivity of the response and a synergistic effect of the interaction of IAA with transcriptional repressors on these characteristics of the signaling pathway. Finally, we also suggest experiments which might allow disentangling the structure of the auxin signaling pathway and analysing further its function in plants. PMID- 25807073 TI - 5% Minoxidil: treatment for female pattern hair loss. AB - Minoxidil is a Health Canada and US FDA-approved medication for hair loss in men and women. While 5% minoxidil foam has been approved for men since 2006, Health Canada and the FDA only approved 5% minoxidil foam for female pattern hair loss (FPHL) in 2014. Recent Phase III clinical trials demonstrated the efficacy of once daily 5% minoxidil foam for treatment of FPHL, where a significant change from baseline in the target area hair count was observed compared to placebo. Similar changes in hair count for 5% foam and twice daily 2% minoxidil solution established noninferiority of the 5% foam formulation. Five percent minoxidil foam provides an additional option for women with FPHL and will soon be available in Canada. PMID- 25807075 TI - Incidental findings in the pancreas (and elsewhere): putting our patients (and ourselves) in a difficult situation. PMID- 25807074 TI - Photoresponsive DNA monolayer prepared by primer extension reaction on the electrode. AB - We describe a simple and convenient method for the preparation of photoresponsive DNA-modified electrodes using primer extension (PEX) reactions. A naphthalimide derivative was used as the photosensitizer that was attached to the C5-position of 2'-deoxyuridine-5'-triphosphate (dUTP(NI)). It has been found that dUTP(NI) is a good substrate for the PEX reactions using KOD Dash and Vent (exo-) enzymes in solutions to incorporate naphthalimide (NI) moieties into the DNA sequences. On the electrode surface immobilized with the primer/template DNA, the PEX reactions to incorporate dUTP(NI) molecules into the DNA sequence were found to efficiently proceed. With this solid-phase method, the DNA monolayers capable of generating photocurrent due to the photoresponsive NI molecule can be constructed. It was shown that the photocurrent generation was significantly suppressed by a single nucleotide mismatch included in the primer/template DNA, which is applicable for the design of photoelectrochemical sensors to discriminate single-nucleotide sequences. PMID- 25807076 TI - Energetic multifunctionalized nitraminopyrazoles and their ionic derivatives: ternary hydrogen-bond induced high energy density materials. AB - Diverse functionalization was introduced into the pyrazole framework giving rise to a new family of ternary hydrogen-bond induced high energy density materials. By incorporating extended cationic interactions, nitramine-based ionic derivatives exhibit good energetic performance and enhanced molecular stability. Performance parameters including heats of formation and detonation properties were calculated by using Gaussian 03 and EXPLO5 v6.01 programs, respectively. It is noteworthy to find that 5-nitramino-3,4-dinitropyrazole, 4, has a remarkable measured density of 1.97 g cm(-3) at 298 K, which is consistent with its crystal density (2.032 g cm(-3), 150 K), and ranks highest among azole-based CHNO compounds. Energetic evaluation indicates that, in addition to the molecular compound 4, some ionic derivatives, 9, 11, 12, 17, 19, and 22, also have high densities (1.83-1.97 g cm(-3)), excellent detonation pressures and velocities (P, 35.6-41.6 GPa; vD, 8880-9430 m s(-1)), as well as acceptable impact and friction sensitivities (IS, 4-30 J; FS, 40-240 N). These attractive features highlight the application potential of nitramino hydrogen-bonded interactions in the design of advanced energetic materials. PMID- 25807077 TI - Tumor cells switch to mitochondrial oxidative phosphorylation under radiation via mTOR-mediated hexokinase II inhibition--a Warburg-reversing effect. AB - A unique feature of cancer cells is to convert glucose into lactate to produce cellular energy, even under the presence of oxygen. Called aerobic glycolysis [The Warburg Effect] it has been extensively studied and the concept of aerobic glycolysis in tumor cells is generally accepted. However, it is not clear if aerobic glycolysis in tumor cells is fixed, or can be reversed, especially under therapeutic stress conditions. Here, we report that mTOR, a critical regulator in cell proliferation, can be relocated to mitochondria, and as a result, enhances oxidative phosphorylation and reduces glycolysis. Three tumor cell lines (breast cancer MCF-7, colon cancer HCT116 and glioblastoma U87) showed a quick relocation of mTOR to mitochondria after irradiation with a single dose 5 Gy, which was companied with decreased lactate production, increased mitochondrial ATP generation and oxygen consumption. Inhibition of mTOR by rapamycin blocked radiation-induced mTOR mitochondrial relocation and the shift of glycolysis to mitochondrial respiration, and reduced the clonogenic survival. In irradiated cells, mTOR formed a complex with Hexokinase II [HK II], a key mitochondrial protein in regulation of glycolysis, causing reduced HK II enzymatic activity. These results support a novel mechanism by which tumor cells can quickly adapt to genotoxic conditions via mTOR-mediated reprogramming of bioenergetics from predominantly aerobic glycolysis to mitochondrial oxidative phosphorylation. Such a "waking-up" pathway for mitochondrial bioenergetics demonstrates a flexible feature in the energy metabolism of cancer cells, and may be required for additional cellular energy consumption for damage repair and survival. Thus, the reversible cellular energy metabolisms should be considered in blocking tumor metabolism and may be targeted to sensitize them in anti-cancer therapy. PMID- 25807078 TI - The Pitch Imagery Arrow Task: effects of musical training, vividness, and mental control. AB - Musical imagery is a relatively unexplored area, partly because of deficiencies in existing experimental paradigms, which are often difficult, unreliable, or do not provide objective measures of performance. Here we describe a novel protocol, the Pitch Imagery Arrow Task (PIAT), which induces and trains pitch imagery in both musicians and non-musicians. Given a tonal context and an initial pitch sequence, arrows are displayed to elicit a scale-step sequence of imagined pitches, and participants indicate whether the final imagined tone matches an audible probe. It is a staircase design that accommodates individual differences in musical experience and imagery ability. This new protocol was used to investigate the roles that musical expertise, self-reported auditory vividness and mental control play in imagery performance. Performance on the task was significantly better for participants who employed a musical imagery strategy compared to participants who used an alternative cognitive strategy and positively correlated with scores on the Control subscale from the Bucknell Auditory Imagery Scale (BAIS). Multiple regression analysis revealed that Imagery performance accuracy was best predicted by a combination of strategy use and scores on the Vividness subscale of BAIS. These results confirm that competent performance on the PIAT requires active musical imagery and is very difficult to achieve using alternative cognitive strategies. Auditory vividness and mental control were more important than musical experience in the ability to perform manipulation of pitch imagery. PMID- 25807079 TI - Ionizing radiation-induced adaptive response in fibroblasts under both monolayer and 3-dimensional conditions. AB - To observe the adaptive response (AR) induced by ionizing radiation in human fibroblasts under monolayer and 3-dimensional (3-D) condition. Three kinds of fibroblasts were cultured under both monolayer and 3-D condition. Immunofluorescent staining was used to detect the gamma-H2AX foci and the morphological texture. Trypan blue staining was used to detect the cell death. Western blot was used to detect the expressions of gamma-H2AX, p53 and CDKN1A/p21 (p21). We found that DNA damage increased in a dose-dependent and time-dependent manner after high doses of radiation. When cells were pretreated with a priming low dose of radiation followed by high dose radiation, DNA damage was attenuated under both monolayer and 3-D condition, and the adaptive response (AR) was induced. Additionally, the morphology of cells under monolayer and 3-D conditions were different, and radiation also induced AR according to morphological texture analysis. Priming low dose radiation induced AR both under monolayer and 3-D condition. Interestingly, 3-D microenvironment made cells more sensitive to radiation. The expression of p53 and p21 was changed and indicated that they might participate in the regulation of AR. PMID- 25807080 TI - Characterization of MATE-type multidrug efflux pumps from Klebsiella pneumoniae MGH78578. AB - We previously described the cloning of genes related to drug resistance from Klebsiella pneumoniae MGH78578. Of these, we identified a putative gene encoding a MATE-type multidrug efflux pump, and named it ketM. Escherichia coli KAM32 possessing ketM on a plasmid showed increased minimum inhibitory concentrations for norfloxacin, ciprofloxacin, cefotaxime, acriflavine, Hoechst 33342, and 4',6 diamidino-2-phenyl indole (DAPI). The active efflux of DAPI was observed in E. coli KAM32 possessing ketM on a plasmid. The expression of mRNA for ketM was observed in K. pneumoniae cells, and we subsequently disrupted ketM in K. pneumoniae ATCC10031. However, no significant changes were observed in drug resistance levels between the parental strain ATCC10031 and ketM disruptant, SKYM. Therefore, we concluded that KetM was a multidrug efflux pump, that did not significantly contribute to intrinsic resistance to antimicrobial chemicals in K. pneumoniae. MATE-type transporters are considered to be secondary transporters; therefore, we investigated the coupling cations of KetM. DAPI efflux by KetM was observed when lactate was added to produce a proton motive force, indicating that KetM effluxed substrates using a proton motive force. However, the weak efflux of DAPI by KetM was also noted when NaCl was added to the assay mixture without lactate. This result suggests that KetM may utilize proton and sodium motive forces. PMID- 25807082 TI - Return customers: foraging site fidelity and the effect of environmental variability in wide-ranging antarctic fur seals. AB - Strategies employed by wide-ranging foraging animals involve consideration of habitat quality and predictability and should maximise net energy gain. Fidelity to foraging sites is common in areas of high resource availability or where predictable changes in resource availability occur. However, if resource availability is heterogeneous or unpredictable, as it often is in marine environments, then habitat familiarity may also present ecological benefits to individuals. We examined the winter foraging distribution of female Antarctic fur seals, Arctocephalus gazelle, over four years to assess the degree of foraging site fidelity at two scales; within and between years. On average, between-year fidelity was strong, with most individuals utilising more than half of their annual foraging home range over multiple years. However, fidelity was a bimodal strategy among individuals, with five out of eight animals recording between-year overlap values of greater than 50%, while three animals recorded values of less than 5%. High long-term variance in sea surface temperature, a potential proxy for elevated long-term productivity and prey availability, typified areas of overlap. Within-year foraging site fidelity was weak, indicating that successive trips over the winter target different geographic areas. We suggest that over a season, changes in prey availability are predictable enough for individuals to shift foraging area in response, with limited associated energetic costs. Conversely, over multiple years, the availability of prey resources is less spatially and temporally predictable, increasing the potential costs of shifting foraging area and favouring long-term site fidelity. In a dynamic and patchy environment, multi-year foraging site fidelity may confer a long-term energetic advantage to the individual. Such behaviours that operate at the individual level have evolutionary and ecological implications and are potential drivers of niche specialization and modifiers of intra-specific competition. PMID- 25807081 TI - Long-term dietary supplementation of pomegranates, figs and dates alleviate neuroinflammation in a transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease with no specific treatment at present. The APPsw/Tg2576 mice exhibit age-related deterioration in memory and learning as well as amyloid-beta (Abeta) accumulation, and this mouse strain is considered an effective model for studying the mechanism of accelerated brain aging and senescence. The present study was aimed to investigate the beneficial effects of dietary supplements pomegranate, figs, or the dates on suppressing inflammatory cytokines in APPsw/Tg2576 mice. Changes in the plasma cytokines and Abeta, ATP, and inflammatory cytokines were investigated in the brain of transgenic mice. Significantly enhanced levels of inflammatory cytokines IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, TNF alpha and Eotaxin activity were decreased by administration of the diet supplements containing pomegranates, figs, or dates. In addition, putative delays in the formation of senile plaques, as indicated by a decreasing tendency of brain Abeta1-40 and Abeta1-42 contents, were observed. Thus, novel results mediated by reducing inflammatory cytokines during aging may represent one mechanism by which these supplements exert their beneficial effects against neurodegenerative diseases such as AD. PMID- 25807084 TI - Planting molecular functions in an ecological context with Arabidopsis thaliana. AB - The vascular plant Arabidopsis thaliana is a central genetic model and universal reference organism in plant and crop science. The successful integration of different fields of research in the study of A. thaliana has made a large contribution to our molecular understanding of key concepts in biology. The availability and active development of experimental tools and resources, in combination with the accessibility of a wealth of cumulatively acquired knowledge about this plant, support the most advanced systems biology approaches among all land plants. Research in molecular ecology and evolution has also brought the natural history of A. thaliana into the limelight. This article showcases our current knowledge of the natural history of A. thaliana from the perspective of the most closely related plant species, providing an evolutionary framework for interpreting novel findings and for developing new hypotheses based on our knowledge of this plant. PMID- 25807086 TI - The fascinating and secret wild life of the budding yeast S. cerevisiae. AB - The budding yeast Saccharomyces cerevisiae has been used in laboratory experiments for over a century and has been instrumental in understanding virtually every aspect of molecular biology and genetics. However, it wasn't until a decade ago that the scientific community started to realise how little was known about this yeast's ecology and natural history, and how this information was vitally important for interpreting its biology. Recent large scale population genomics studies coupled with intensive field surveys have revealed a previously unappreciated wild lifestyle of S. cerevisiae outside the restrictions of human environments and laboratories. The recent discovery that Chinese isolates harbour almost twice as much genetic variation as isolates from the rest of the world combined suggests that Asia is the likely origin of the modern budding yeast. PMID- 25807087 TI - Advancing biology through a deeper understanding of zebrafish ecology and evolution. AB - Over the last two decades, the zebrafish has joined the ranks of premier model organisms for biomedical research, with a full suite of tools and genomic resources. Yet we still know comparatively little about its natural history. Here I review what is known about the natural history of the zebrafish, where significant gaps in our knowledge remain, and how a fuller appreciation of this organism's ecology and behavior, population genetics, and phylogeny can inform a variety of research endeavors. PMID- 25807083 TI - The unexhausted potential of E. coli. AB - E. coli's hardiness, versatility, broad palate and ease of handling have made it the most intensively studied and best understood organism on the planet. However, research on E.coli has primarily examined it as a model organism, one that is abstracted from any natural history. But E. coli is far more than just a microbial lab rat. Rather, it is a highly diverse organism with a complex, multi faceted niche in the wild. Recent studies of 'wild' E. coli have, for example, revealed a great deal about its presence in the environment, its diversity and genomic evolution, as well as its role in the human microbiome and disease. These findings have shed light on aspects of its biology and ecology that pose far reaching questions and illustrate how an appreciation of E. coli's natural history can expand its value as a model organism. PMID- 25807085 TI - Genetic, evolutionary and plant breeding insights from the domestication of maize. AB - The natural history of maize began nine thousand years ago when Mexican farmers started to collect the seeds of the wild grass, teosinte. Invaluable as a food source, maize permeated Mexican culture and religion. Its domestication eventually led to its adoption as a model organism, aided in large part by its large chromosomes, ease of pollination and growing agricultural importance. Genome comparisons between varieties of maize, teosinte and other grasses are beginning to identify the genes responsible for the domestication of modern maize and are also providing ideas for the breeding of more hardy varieties. PMID- 25807088 TI - An organismal perspective on C. intestinalis development, origins and diversification. AB - The ascidian Ciona intestinalis, commonly known as a 'sea squirt', has become an important model for embryological studies, offering a simple blueprint for chordate development. As a model organism, it offers the following: a small, compact genome; a free swimming larva with only about 2600 cells; and an embryogenesis that unfolds according to a predictable program of cell division. Moreover, recent phylogenies reveal that C. intestinalis occupies a privileged branch in the tree of life: it is our nearest invertebrate relative. Here, we provide an organismal perspective of C. intestinalis, highlighting aspects of its life history and habitat-from its brief journey as a larva to its radical metamorphosis into adult form-and relate these features to its utility as a laboratory model. PMID- 25807090 TI - Does starting allopurinol prolong acute treated gout? A randomized clinical trial. AB - BACKGROUND: Traditionally, allopurinol is not initiated during an acute gout attack to avoid prolonging the painful arthritis. The 2012 American College of Rheumatology Guidelines for the Management of Gout suggest that urate-lowering therapy can be started during an acute attack, based on "consensus opinion of experts, case studies, or standard of care." OBJECTIVE: The aim of this study was to determine whether initiating allopurinol will adversely affect the resolution of acute, treated gout. METHODS: We conducted a 28-day, placebo-controlled, double-blind study of allopurinol initiation in patients with acute gout. Patients with crystal-proven gout by arthrocentesis were enrolled if they presented to the rheumatology clinic with an acute gout attack within 72 hours from initial therapy. The patients were also required to meet at least 1 additional criterion for urate-lowering therapy including (1) the presence of gouty tophi, (2) more than 1 acute gout attack per year, (3) a history of nephrolithiasis, or (4) urate overproduction (>1000 mg in 24-hour urine collection). Patients were excluded from the study if they had a glomerular filtration rate of less than 50 or liver function test of greater than 1.25 times the upper limit of normal. The treating physician determined therapy for the acute gout attack. Standard prophylaxis, with colchicine or nonsteroidal anti inflammatory drugs, was prescribed. Allopurinol or placebo was initiated at 100 mg daily for the first 14 days and then increased to 200 mg daily for the next 14 days. The primary end point was protocol defined days to resolution of acute gout, incorporating patient-rated joint pain and physician examination. Secondary measures included Physician Global Assessment, patient-rated pain, adverse effects of therapy, and serum uric acid. RESULTS: Thirty-one patients (17 on placebo, 14 on allopurinol) completed the study. Both intent-to-treat and completer analyses showed only a statistically insignificant difference in days to resolution (15.4 days in the allopurinol group completers vs 13.4 days in the placebo group; P = 0.5). The secondary measures revealed that the acute phase of pain rapidly improved in both groups. CONCLUSIONS: We initiated allopurinol at low doses during an acute gout attack in patients who met criteria for starting urate-lowering therapy and did not have abnormal kidney or liver function. In this cohort, allopurinol did not prolong the acute, treated attack. PMID- 25807089 TI - An examination of the mechanisms involved in secondary clinical failure to adalimumab or etanercept in inflammatory arthropathies. AB - BACKGROUND: Biological therapies against tumor necrosis factor alpha have revolutionized the treatment of several inflammatory rheumatic diseases. However, 30% of responders will present a clinical failure after having controlled the disease for at least 6 months (secondary clinical failure). Biological therapies may induce an unwanted immune response, which may alter the bioavailability of the drug causing a loss of clinical response. OBJECTIVE: The objective of this study was to assess the correlation between secondary clinical failure (based on Disease Activity Score in 28 Joints or Bath Ankylosing Spondylitis Disease Activity Index) and the type of mechanism involved in failure (based on drug levels) in patients with inflammatory arthropathies treated with anti-tumor necrosis factor alpha. METHODS: Drug and antidrug antibodies (ADAs) serum levels were determined by enzyme-linked immunosorbent assay immediately before drug administration in patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis who presented secondary clinical failure after at least 6 months of treatment with adalimumab (ADL) or etanercept (ETN). RESULTS: Thirty six patients with secondary clinical failure were recruited: 63.88% had rheumatoid arthritis, 22.22% had psoriatic arthritis, and 13.88% had ankylosing spondylitis; 58.33% did not respond to ADL, whereas 41.66% did not to ETN. None of the patients treated with ETN showed either subtherapeutic drugs levels or ADAs (failure due to a primary mechanism) whereas it was found that 23.80% of the patients treated with ADL had subtherapeutic drug levels for reasons attributable to immunogenicity (failure due to a secondary mechanism; P = 0.000048). CONCLUSIONS: We suggest the utility of measuring drug and ADA levels in patients with secondary clinical failure to ADL for a better optimization and rational use, but not in patients who fail to ETN. PMID- 25807091 TI - Vitamin D status and its association with quality of life, physical activity, and disease activity in rheumatoid arthritis patients. AB - BACKGROUND: Vitamin D deficiency is common in rheumatoid arthritis (RA) and may be related to disease activity. Population-based studies have shown the influence of vitamin D deficiency on quality of life (QoL), but it was not investigated in RA patients. OBJECTIVES: The aim of the study was to determine possible relationship between vitamin D deficiency, QoL, physical activity (PA), and disease activity in RA. METHODS: In 97 consecutive RA patients without vitamin D supplementation (86 women and 11 men, aged 59.4 +/- 12 years), serum 25 hydroxycholecalciferol (25(OH)D), calcium, phosphorus, and parathyroid hormone were measured. The patients completed Short Form 36 (SF-36), Beck Depression Inventory, and Health Assessment Questionnaire, assessed the intensity of pain, fatigue, and PA. Disease Activity Score in 28 Joints was used to assess disease activity. A comparison control group consisted of 28 osteoarthritis patients (25 women and 3 men aged 56.2 +/- 15 years). RESULTS: Vitamin D deficiency was detected in 76.3% of RA and in 78.6% of osteoarthritis patients (P = 0.75). There was a negative correlation between 25(OH)D serum concentration and Disease Activity Score in 28 Joints in patients with active arthritis. There was a positive correlation between serum 25(OH)D and the level of PA and most aspects of SF-36, and negative correlation between serum 25(OH)D and Health Assessment Questionnaire and Beck Depression Inventory in patients with disease duration of 1 year or longer. After inclusion of PA into multivariable analysis, only the correlations between 25(OH)D and SF-36 mental subscale (MCS) and pain remained significant. CONCLUSIONS: Vitamin D deficiency is highly prevalent in RA patients and is associated with higher disease activity and worse QoL indices. Regular PA correlates with higher vitamin D titers and better QoL in RA. Further studies are needed to explain possible influence of vitamin D on RA activity. PMID- 25807092 TI - Clinical practice extenders in rheumatology. PMID- 25807093 TI - General applications of ultrasound in rheumatology: why we need it in our daily practice. AB - Ultrasound (US) is a noninvasive imaging technique that continues to gain interest among rheumatologists because of its undoubted utility for the assessment of a wide range of abnormalities in rheumatic diseases. It also has a great potential to be used at the time of consultation as an extension of the clinical examination.Current data demonstrate that the standard clinical approach could result in an insensitive assessment of some the different aspects of the various rheumatic diseases for which US has become a feasible and effective imaging modality that allows early detection of anatomical changes, careful guidance for the aspiration and/or local treatment, and short- and long-term therapy monitoring at the joint, tendon, enthesis, nail, and skin levels. The spectrum of pathological conditions for which US plays a crucial role continues to increase over time and includes rheumatoid arthritis, spondyloarthropathies, osteoarthritis, crystal-related arthropathies, connective tissue disorders, and vasculitis.It is expected that the inclusion of more longitudinal studies with a larger number of patients and more rigorous methodological approach will undoubtedly provide a better understanding of the significance of the abnormal US findings detected in order to provide the proper diagnostic and/or therapeutic approaches. In this article, we analyze the current potential applications of US in rheumatology and discuss the evidence supporting its use in the daily rheumatologic practice. PMID- 25807094 TI - Atypical presentation of CLIPPERS syndrome: a new entity in the differential diagnosis of central nervous system rheumatologic diseases. AB - Numerous autoimmune diseases can affect the central nervous system (CNS), and variable clinical presentations confound the differential diagnosis. The challenging task of properly characterizing various CNS autoimmune diseases enables patients to be rapidly triaged and appropriately treated. In this review article, we aim to explore different CNS manifestations of rheumatologic diseases with emphasis on the utility of imaging and cerebrospinal fluid findings. We review the classic physical examination findings, characteristic imaging features, cerebrospinal fluid results, and serum biomarkers. In addition, we also present a unique case of newly described autoimmune entity CLIPPERS syndrome. Our case is unique in that this is the first case which demonstrates involvement of the supratentorial perivascular spaces in addition to the classic infratentorial involvement as initially described by Pittock et al (Brain. 2010;133:2626-2634). PMID- 25807096 TI - Atlantoaxial subluxation and nasopharyngeal necrosis complicating suspected granulomatosis with polyangiitis. AB - Granulomatosis polyangiitis (GPA, formerly Wegener granulomatosis) is a vasculitis that typically involves the upper respiratory tract, lungs, and kidneys. The 2 established methods to confirm a suspicion of GPA are the antineutrophil cytoplasmic antibody (ANCA) test and biopsy. However, ANCA negative cases have been known to occur, and it can be difficult to find biopsy evidence of granulomatous disease.We report a case of suspected granulomatosis with polyangiitis limited to the nasopharynx. With a negative ANCA and no histological evidence, our diagnosis was founded on the exclusion of other diagnoses and the response to cyclophosphamide therapy. This case is unique because the patient's lesion resulted in atlantoaxial instability, which required a posterior spinal fusion at C1-C2. This is the first reported case of suspected GPA producing damage to the cervical spine and threatening the spinal cord. PMID- 25807095 TI - Systemic sclerosis: commonly asked questions by rheumatologists. PMID- 25807097 TI - Arthroscopic findings in melorheostosis. AB - Melorheostosis is a rare dysplastic bone formation disease that can also affect the joints. We present a case of a patient with knee pain that was radiographically diagnosed as melorheostosis because of "dripping wax" image. An exploratory arthroscopy was made. In the joint, we found hyperplasic synovial tissue and an increased retropatellar Hoffa pad, which was surrounding an intra articular ossification resulting from the disease. This was removed and led to a clinical and functional improvement. PMID- 25807098 TI - Palmar Gottron papules and Gottron sign. PMID- 25807099 TI - A clinical picture of ectrodactyly hand. PMID- 25807101 TI - Ultrasound-guided dry-needle synovial tissue aspiration for diagnostic microscopy in gout patients presenting without synovial effusion or clinically detectable tophi. PMID- 25807102 TI - Osteonecrosis of multiple joints in a patient with limited scleroderma/CREST syndrome. PMID- 25807103 TI - Severe dilated cardiomyopathy induced by adalimumab and ustekinumab. PMID- 25807106 TI - Approaches to Improving Adherence to Secondary Prophylaxis for Rheumatic Fever and Rheumatic Heart Disease: A Literature Review with a Global Perspective. AB - Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune conditions resulting from infection with group A streptococcus. Current management of these conditions includes secondary antibiotic prevention. This comprises regular 3 to 4 weekly long-acting intramuscular benzathine penicillin injections. Secondary antibiotic prevention aims to protect individuals against reinfection with group A streptococcus, thereby preventing recurrent ARF and the risk of further damage to the heart valves. However, utilization of benzathine penicillin can be poor leaving patients at risk of avoidable and progressive heart damage. This review utilizes the Chronic Care Model as a framework to discuss initiatives to enhance the delivery of secondary antibiotic prophylaxis for ARF and RHD. Results from the search strategy utilized revealed that there is limited pertinent published evidence. The evidence that is available suggests that register/recall systems, dedicated health teams for delivery of secondary antibiotic prophylaxis, education about ARF and RHD, linkages with the community (particularly between health services and schools), and strong staff-patient relationships may be important. However, it is difficult to generalize findings from individual studies to other settings and high quality studies are lacking. Although secondary antibiotic prophylaxis is an effective treatment for those with ARF or RHD, the difficulties in implementing effective programs that reduce the burden of ARF and RHD demonstrates the importance of ongoing work in developing and evaluating research translation initiatives. PMID- 25807104 TI - Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues. AB - Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1) were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot). Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues. PMID- 25807107 TI - Cardiac Transplantation in the New Era. AB - The prevalence of heart failure continues to rise due to the aging population and longer survival of people with conditions that lead to heart failure, eg, hypertension, diabetes, and coronary artery disease. Although medical therapy has had an important impact on survival of patients and improving quality of life, heart transplantation remains the definitive therapy for patients that eventually deteriorate. Since the first successful heart transplantation in 1967, significant improvements have been made regarding donor and recipient selection, surgical techniques, and postoperative care. However, the number of potential organ donors has not changed and the growing number of patients in need for transplantation has resulted an increase in waiting list time, and the need for mechanical support. To overcome this issue, the United Network for Organ Sharing implemented an allocation system to prioritize the sickest patients on the list to receive organs. Despite the careful selection of patients, pretransplant immunological screening, and multidrug immunosuppressive regimens, acute and chronic rejections occur and potentially limit graft and patient survival. Treatment for rejection largely depends on the type of rejection, the presence of hemodynamic compromise, and time after transplantation. The limiting factor for long-term graft survival is allograft vasculopathy, an immune-mediated process causing diffuse narrowing of the coronary arteries. Percutaneous coronary intervention and coronary artery bypass surgery are often not an option for this vasculopathy due to the lack of focal lesions, and retransplantation is the only option in appropriate patients. PMID- 25807105 TI - A Novel Class of Human Cardiac Stem Cells. AB - Following the recognition that hematopoietic stem cells improve the outcome of myocardial infarction in animal models, bone marrow mononuclear cells, CD34 positive cells, and mesenchymal stromal cells have been introduced clinically. The intracoronary or intramyocardial injection of these cell classes has been shown to be safe and to produce a modest but significant enhancement in systolic function. However, the identification of resident cardiac stem cells in the human heart (hCSCs) has created great expectation concerning the potential implementation of this category of autologous cells for the management of the human disease. Although phase 1 clinical trials have been conducted with encouraging results, the search for the most powerful hCSC for myocardial regeneration is in its infancy. This manuscript discusses the efforts performed in our laboratory to characterize the critical biological variables that define the growth reserve of hCSCs. Based on the theory of the immortal DNA template, we propose that stem cells retaining the old DNA represent 1 of the most powerful cells for myocardial regeneration. Similarly, the expression of insulin-like growth factor-1 receptors in hCSCs recognizes a cell phenotype with superior replicating reserve. However, the impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this hCSC class for the treatment of human heart failure. PMID- 25807108 TI - HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. AB - Hepatitis C virus (HCV) induces autophagy to enhance its replication. However, how HCV regulates the autophagic pathway remains largely unclear. In this report, we demonstrated that HCV infection could induce the expression of Rubicon and UVRAG, which inhibited and stimulated the maturation of autophagosomes, respectively. The induction of Rubicon by HCV was prompt whereas the induction of UVRAG was delayed, resulting in the accumulation of autophagosomes in the early time points of viral infection. The role of Rubicon in inhibiting the maturation of autophagosomes in HCV-infected cells was confirmed by siRNA knockdown and the over-expression of Rubicon, which enhanced and suppressed the maturation of autophagosomes, respectively. Rubicon played a positive role in HCV replication, as the suppression of its expression reduced HCV replication and its over expression enhanced HCV replication. In contrast, the over-expression of UVRAG facilitated the maturation of autophagosomes and suppressed HCV replication. The HCV subgenomic RNA replicon, which expressed only the nonstructural proteins, could also induce the expression of Rubicon and the accumulation of autophagosomes. Further analysis indicated that the HCV NS4B protein was sufficient to induce Rubicon and autophagosomes. Our results thus indicated that HCV, by differentially inducing the expression of Rubicon and UVRAG, temporally regulated the autophagic flux to enhance its replication. PMID- 25807111 TI - Cyano- and chloro-substituted coronene diimides as solution-processable electron transporting semiconductors. AB - 3,4,9,10-Tetracyano- and tetrachlorocoronene-1,6,7,12-tetracarboxy diimides with low LUMO levels at -3.9 to -4.2 eV are developed. These molecules manifest potent n-type semiconductive capability in solution-processed field-effect transistors, with electron mobilities of up to 0.16 cm(2) V(-1) s(-1) measured in air. The device performances of analogous molecules elucidate the importance of side chain structures in the semiconductive properties. PMID- 25807109 TI - Tobacco-related mortality among persons with mental health and substance abuse problems. AB - The rate of cigarette smoking is greater among persons with mental health and/or substance abuse problems. There are few population-based datasets with which to study tobacco mortality in these vulnerable groups. The Oregon Health Authority identified persons who received publicly-funded mental health or substance abuse services from January 1996 through December 2005. These cases were then matched to Oregon Vital Statistics records for all deaths (N= 148,761) in the period 1999 2005. The rate of tobacco-related death rates was higher among persons with substance abuse problems only (53.6%) and those with both substance abuse and mental health problems (46.8%), as compared to the general population (30.7%). The rate of tobacco-related deaths among persons with mental health problems (30%) was similar to that in the general population. Persons receiving substance abuse treatment alone, or receiving both substance abuse and mental health treatment, were more likely to die and more likely to die prematurely of tobacco related causes as compared to the general population. Persons receiving mental health services alone were not more likely to die of tobacco-related causes, but tobacco-related deaths occurred earlier in this population. PMID- 25807113 TI - Excited-state ring-opening mechanism of cyclic ketones: a MS-CASPT2//CASSCF study. AB - We have employed complete active space self-consistent field (CASSCF) and its second-order perturbation (MS-CASPT2) methods to study the S1 and T1 excited state ring-opening mechanisms and S1 excited-state deactivation channels of cyclopropanone, cyclobutanone, cyclopentanone, and cyclohexanone. On the basis of optimized minima, transition states, conical intersections, refined energies, and relaxed two-dimensional S1 and T1 potential energy surfaces, we find that, with the ring-strain decrease from cyclopropanone to cyclohexanone, (1) the ring opening S1 and T1 barrier increases from 0.0 and 0.0 to 19.7 and 10.4 kcal/mol, respectively; (2) the electronic state responsible for the dominant ring-opening reaction varies from the S1 state of cyclopropanone to the T1 state of cyclopentanone and cyclohexanone; and (3) the S1 ring opening gradually becomes inefficient even blocked in cyclopentanone and cyclohexanone. This work shows that these dissimilar excited-state dynamics could originate from different ring strain of small cyclic ketones. PMID- 25807110 TI - Subsistence strategies in traditional societies distinguish gut microbiomes. AB - Recent studies suggest that gut microbiomes of urban-industrialized societies are different from those of traditional peoples. Here we examine the relationship between lifeways and gut microbiota through taxonomic and functional potential characterization of faecal samples from hunter-gatherer and traditional agriculturalist communities in Peru and an urban-industrialized community from the US. We find that in addition to taxonomic and metabolic differences between urban and traditional lifestyles, hunter-gatherers form a distinct sub-group among traditional peoples. As observed in previous studies, we find that Treponema are characteristic of traditional gut microbiomes. Moreover, through genome reconstruction (2.2-2.5 MB, coverage depth * 26-513) and functional potential characterization, we discover these Treponema are diverse, fall outside of pathogenic clades and are similar to Treponema succinifaciens, a known carbohydrate metabolizer in swine. Gut Treponema are found in non-human primates and all traditional peoples studied to date, suggesting they are symbionts lost in urban-industrialized societies. PMID- 25807112 TI - StaRProtein, a web server for prediction of the stability of repeat proteins. AB - Repeat proteins have become increasingly important due to their capability to bind to almost any proteins and the potential as alternative therapy to monoclonal antibodies. In the past decade repeat proteins have been designed to mediate specific protein-protein interactions. The tetratricopeptide and ankyrin repeat proteins are two classes of helical repeat proteins that form different binding pockets to accommodate various partners. It is important to understand the factors that define folding and stability of repeat proteins in order to prioritize the most stable designed repeat proteins to further explore their potential binding affinities. Here we developed distance-dependant statistical potentials using two classes of alpha-helical repeat proteins, tetratricopeptide and ankyrin repeat proteins respectively, and evaluated their efficiency in predicting the stability of repeat proteins. We demonstrated that the repeat specific statistical potentials based on these two classes of repeat proteins showed paramount accuracy compared with non-specific statistical potentials in: 1) discriminate correct vs. incorrect models 2) rank the stability of designed repeat proteins. In particular, the statistical scores correlate closely with the equilibrium unfolding free energies of repeat proteins and therefore would serve as a novel tool in quickly prioritizing the designed repeat proteins with high stability. StaRProtein web server was developed for predicting the stability of repeat proteins. PMID- 25807114 TI - Pharmacokinetics and immunogenicity of broadly neutralizing HIV monoclonal antibodies in macaques. AB - The identification of highly potent broadly neutralizing antibodies (bnAbs) against HIV-1, and success in preventing SHIV infection following their passive administration, have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV-1 infection. However, while broad and potent neutralizing activity is an essential prerequisite, in vivo properties such as good circulatory stability and non-immunogenicity are equally critical for developing a human treatment. In the present study, glycoforms of the bnAbs 10-1074, NIH45-46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, PG9, PG16, VRC01 and b12 were produced by Agrobacterium-mediated transient transfection of Nicotiana benthamiana and assessed following administration in rhesus macaques. The results indicate that (i) N-glycans within the VL domain impair plasma stability of plant derived bnAbs and (ii) while PGT121 and b12 exhibit no immunogenicity in rhesus macaques after multiple injections, VRC01, 10-1074 and NIH45-46G54W elicit high titer anti-idiotypic antibodies following a second injection. These anti idiotypic antibodies specifically bind the administered bnAb or a close family member, and inhibit the bnAb in neutralization assays. These findings suggest that specific mutations in certain bnAbs contribute to their immunogenicity and call attention to the prospect that these mutated bnAbs will be immunogenic in humans, potentially compromising their value for prophylaxis and therapy of HIV 1. PMID- 25807116 TI - Synthesis of amorphous platinum nanofibers directly on an ITO substrate and its heterogeneous catalytic hydrogenation characterization. AB - This paper reports a facile, solution-phase approach to synthesizing a one dimensional amorphous face-centered-cubic (fcc) platinum (a-Pt) nanostructure (nanofibers) directly on an indium-tin oxide (ITO) substrate. The electron microscopy analysis result shows that the a-Pt nanofiber has a diameter and length of approximately 50 nm and 1 MUm, respectively, and is grown in high density on the entire surface of the ITO substrate. The X-ray photoelectron spectroscopy analysis result further reveals that the a-Pt nanofibers feature metallic properties with highly reactive surface chemistry, promising novel performance in electrochemistry, catalysis, and sensors. A synergetic interplay between the formic acid reducing agent and the hexamethylenetetramine surfactant in the reduction of Pt ions is assumed as the driving force for the formation of the amorphous phase in the Pt nanostructure. The catalytic properties of a-Pt were examined in the acetone hydrogenation reaction under microwave irradiation. a-Pt shows excellent heterogeneous catalytic properties for converting acetone to isopropyl alcohol with turnover number and frequency as high as 400 and 140 min( 1), respectively. The preparation and formation mechanism of the a-Pt nanofibers will be discussed in detail in this paper. PMID- 25807117 TI - Correction: Dynamics of actin waves on patterned substrates: a quantitative analysis of circular dorsal ruffles. PMID- 25807115 TI - Association between antibiotic prescribing in pregnancy and cerebral palsy or epilepsy in children born at term: a cohort study using the health improvement network. AB - BACKGROUND: Between 19%-44% pregnant women are prescribed antibiotics during pregnancy. A single, large randomised-controlled-trial (ORACLE Childhood Study II) found an increased risk of childhood cerebral palsy and possibly epilepsy following prophylactic antibiotic use in pregnant women with spontaneous preterm labour. We ascertained whether this outcome could be reproduced across the population of babies delivered at term and prospectively followed in primary-care using data from The Health Improvement Network. METHODS: We determined the risk of cerebral palsy or epilepsy in children whose mothers were prescribed antibiotics during pregnancy using a cohort of 195,909 women linked to their live, term-born, singleton children. We compared the effect of antibiotic class, number of courses and timing of prescribing in pregnancy. Analyses were adjusted for maternal risk factors (e.g. recorded infection, age, chronic conditions, social deprivation, smoking status). Children were followed until age seven years or cessation of registration with the primary-care practitioner. RESULTS: In total, 64,623 (33.0%) women were prescribed antibiotics in pregnancy and 1,170 (0.60%) children had records indicating cerebral palsy or epilepsy. Adjusted analyses showed no association between prescribing of any antibiotic and cerebral palsy or epilepsy (adj.HR 1.04, 95%CI 0.91-1.19). However, compared with penicillins, macrolides were associated with an increased risk of cerebral palsy or epilepsy (adj.HR 1.78, 95%CI 1.18-2.69; number needed to harm 153, 95%CI 71 671). CONCLUSIONS: We found no overall association between antibiotic prescribing in pregnancy and cerebral palsy and/or epilepsy in childhood. However, our finding of an increased risk of cerebral palsy or epilepsy associated with macrolide prescribing in pregnancy adds to evidence that macrolide use is associated with serious harm. PMID- 25807119 TI - Correction: computational identification and systematic classification of novel cytochrome P450 genes in Salvia miltiorrhiza. PMID- 25807118 TI - How effective are biodiversity conservation payments in Mexico? AB - We assess the additional forest cover protected by 13 rural communities located in the southern state of Chiapas, Mexico, as a result of the economic incentives received through the country's national program of payments for biodiversity conservation. We use spatially explicit data at the intra-community level to define a credible counterfactual of conservation outcomes. We use covariate matching specifications associated with spatially explicit variables and difference-in-difference estimators to determine the treatment effect. We estimate that the additional conservation represents between 12 and 14.7 percent of forest area enrolled in the program in comparison to control areas. Despite this high degree of additionality, we also observe lack of compliance in some plots participating in the PES program. This lack of compliance casts doubt on the ability of payments alone to guarantee long-term additionality in context of high deforestation rates, even with an augmented program budget or extension of participation to communities not yet enrolled. PMID- 25807120 TI - Twin-twin transfusion syndrome: what really matters concerning developmental outcome of survivals? PMID- 25807121 TI - Timed Up and Go test: a simple test gives important information in elderly. PMID- 25807122 TI - Age and education influence the performance of elderly women on the dual-task Timed Up and Go test. AB - Gait variability is related to functional decline in the elderly. The dual-task Timed Up and Go Test (TUG-DT) reflects the performance in daily activities. Objective To evaluate the differences in time to perform the TUG with and without DT in elderly women with different ages and levels of education and physical activity. Method Ninety-two elderly women perfomed the TUG at usual and fast speeds, with and without motor and cognitive DT. Results Increases in the time to perform the TUG-DT were observed at older ages and lower educational levels, but not at different levels of physical activity. More educated women performed the test faster with and without DT at both speeds. When age was considered, significant differences were found only for the TUG-DT at both speeds. Conclusion Younger women with higher education levels demonstrated better performances on the TUG-DT. PMID- 25807123 TI - Twin-twin transfusion syndrome: neurodevelopmental screening test. AB - OBJECTIVE: To assess the neurodevelopmental functions (cognition, language and motor function) of survivors of twin-twin transfusion syndrome (TTTS). METHOD: Observational cross-sectional study of a total of 67 monochorionic diamniotic twins who underwent fetoscopic laser coagulation (FLC) for treatment of TTTS. The study was conducted at the Center for Investigation in Pediatrics (CIPED), Universidade Estadual de Campinas. Ages ranged from one month and four days to two years four months. Bayley Scales of Infant and Toddler Development Screening Test-III, were used for evaluation. RESULTS: Most children reached the competent category and were classified as having appropriate performance. The preterm children scored worse than term infants for gross motor subtest (p = 0.036). CONCLUSION: The majority of children reached the expected development according to their age. Despite the good neurodevelopment, children classified at risk should be monitored for development throughout childhood. PMID- 25807124 TI - Personality factors in recently diagnosed multiple sclerosis patients: a preliminary investigation with the NEO-FFI scale. AB - This article describes some prevalent personality dimensions of recently diagnosed multiple sclerosis patients. A sample of 33 female recently diagnosed with relapsing-remitting multiple sclerosis (RRMS) was assessed with the NEO-FFI personality scale. Beck depression (BDI) and anxiety (BAI) scales were also used. No significant levels of anxiety or depression were identified in this group. As for personality factors, conscientiousness was the most common factor found, whereas openness to experience was the least observed. Literature on the relationship between personality and MS is scarce and there are no Brazilian studies on this subject. Some personality traits might complicate or facilitate the experience of living with a chronic, disabling and uncertain neurological condition such as MS. PMID- 25807125 TI - In adolescents with epilepsy, high scores of anxiety and depression are associated with occurrence of seizures in public places. AB - OBJECTIVE: To assess depression and anxiety symptoms of adolescents with epilepsy compared with adolescents without epilepsy. METHOD: The study sample consisted of: case participants (50 subjects) attending the pediatric epilepsy clinic of a tertiary hospital and control participants (51 subjects) from public schools. The instruments utilized were: identification card with demographic and epilepsy data, Beck Depression Inventory and State-Trait Anxiety Inventory. RESULTS: No significant differences were founded between the groups regarding scores for depression and anxiety symptoms but both groups presented moderate scores of anxiety. A correlation was found between low scores anxiety and not frequent seizures, low scores anxiety and perception of seizure control, high scores of anxiety and depression and occurrence of seizures in public places. CONCLUSION: Low scores of anxiety are associated with not frequent seizures; high scores of anxiety and depression are associated with occurrence of seizures in public places. PMID- 25807126 TI - Shorter epilepsy duration is associated with better seizure outcome in temporal lobe epilepsy surgery. AB - OBJECTIVE: To investigate the influence of patient's age and seizure onset on surgical outcome of temporal lobe epilepsy (TLE). METHOD: A retrospective observational investigation performed from a cohort of patients from 2000 to 2012. RESULTS: A total of 229 patients were included. One-hundred and eleven of 179 patients (62%) were classified as Engel I in the group with < 50 years old, whereas 33 of 50 (66%) in the group with >= 50 years old group (p = 0.82). From those Engel I, 88 (61%) reported epilepsy duration inferior to 10 years and 56 (39%) superior to 10 years (p < 0.01). From the total of patients not seizure free, 36 (42%) reported epilepsy duration inferior to 10 years and 49 (58%) superior to 10 years (p < 0.01). CONCLUSION: Patients with shorter duration of epilepsy before surgery had better postoperative seizure control than patients with longer duration of seizures. PMID- 25807127 TI - The use of neurovascular ultrasound versus digital subtraction angiography in acute ischemic stroke. AB - Cervical and intracranial arterial evaluation is an important issue for acute ischemic stroke (IS). OBJECTIVE: Compare the use of the neurovascular ultrasound examination (NVUE) to digital subtraction angiography (DSA) in acute IS patients for diagnosing significant extracranial and intracranial arteriopathy. METHOD: Nonconsecutive patients with IS or transient ischemic attack admitted within 12 hours of the onset of symptoms were evaluated retrospectively. Standardized NVUE and DSA were done in all patients within the first 120 hours of hospital admission. RESULTS: Twenty-four patients were included in the study. Compared to DSA, the NVUE demonstrated 94.7% sensitivity and 100% specificity for identifying symptomatic extracranial and/or intracranial arteriopathy. CONCLUSION: The standardized NVUE technique demonstrated high sensitivity and specificity compared to DSA for diagnosing arterial abnormalities in acute IS patients. PMID- 25807128 TI - Error related negativity and multi-source interference task in children with attention deficit hyperactivity disorder-combined type. AB - OBJECTIVE: To compare performance of children with attention deficit hyperactivity disorders-combined (ADHD-C) type with control children in multi source interference task (MSIT) evaluated by means of error related negativity (ERN). METHOD: We studied 12 children with ADHD-C type with a median age of 7 years, control children were age- and gender-matched. Children performed MSIT and simultaneous recording of ERN. RESULTS: We found no differences in MSIT parameters among groups. We found no differences in ERN variables between groups. We found a significant association of ERN amplitude with MSIT in children with ADHD-C type. Some correlation went in positive direction (frequency of hits and MSIT amplitude), and others in negative direction (frequency of errors and RT in MSIT). CONCLUSION: Children with ADHD-C type exhibited a significant association between ERN amplitude with MSIT. These results underline participation of a cingulo-fronto-parietal network and could help in the comprehension of pathophysiological mechanisms of ADHD. PMID- 25807129 TI - Intervention for executive functions in attention deficit and hyperactivity disorder. AB - This study aimed to investigate if an executive functions (EF) intervention could promote these skills in individuals with attention deficit and hyperactivity disorder (ADHD). Eighteen children and adolescents, 7-13 years old, divided into experimental (EG, N = 8) and control (CG, N = 10) groups, were assessed in the Block Design and Vocabulary subtests of the WISC III and seven tests of EF. Parents answered two scales, measuring EF and inattention and hyperactivity signs. EG children participated in a program to promote EF in twice-weekly group sessions of one hour each. After 8 months of intervention, groups were assessed again. ANCOVA, controlling for age, intelligence quotient and pretest performance, revealed gains in attention/inhibition and auditory working memory measures for the EG. No effect was found for scales or measures of more complex EF. Results are not conclusive, but they illustrate some promising data about EF interventions in children and adolescents with ADHD. PMID- 25807130 TI - Liposomal topical capsaicin in post-herpetic neuralgia: a safety pilot study. AB - Topical treatments have gained popularity for general use as an adjunct to systemic drugs in neuropathic pain, but their use produces variable clinical results and local adverse events. OBJECTIVE: To evaluate the safety and analgesic effect of a formulation of liposomal capsaicin (LC) (0.025%) in patients with post herpetic neuralgia (PHN). METHOD: Patients who remained symptomatic after first-and second-line treatment were randomized to receive LC for six weeks in a placebo-controlled, crossover design study. Clinical assessment was performed at baseline, in the second, fourth and sixth week of treatment. RESULTS: Thirteen patients completed both treatment periods. Visual Analog Scale (VAS) was significantly decreased after the end of the study (p = 0.008), however the effect of treatment was not significant (p = 0.076). There was no difference on global impression of change and other pain characteristics. LC was safe and well tolerated. However, at the concentration used, its analgesic effects were marginal and not significant. PMID- 25807131 TI - Prevalence and correlates of sleep disorders in Parkinson's disease: a polysomnographic study. AB - OBJECTIVE: Sleep disorders in Parkinson's disease are very common. Polysomnography (PSG) is considered the gold standard for diagnosis. The aim of the present study is to assess the prevalence of nocturnal sleep disorders diagnosed by polysomnography and to determine the associated clinical factors. METHOD: A total of 120 patients with Parkinson's disease were included. All patients underwent a standardized overnight, single night polysomnography. RESULTS: Ninety-four (78.3%) patients had an abnormal PSG. Half of the patients fulfilled criteria for sleep apnea-hypopnea syndrome (SAHS); rapid eye movement behavior disorder (RBD) was present in 37.5%. Characteristics associated with SAHS were age (p = 0.049) and body mass index (p = 0.016). Regarding RBD, age (p < 0.001), left motor onset (p = 0.047) and levodopa equivalent dose (p = 0.002) were the main predictors. CONCLUSION: SAHS and RBD were the most frequent sleep disorders. Higher levodopa equivalent dose and body mass index appear to be risk factors for RBD and SAHS, respectively. PMID- 25807132 TI - C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases. AB - Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC) of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant. PMID- 25807134 TI - Subarachnoid hemorrhage due to neurognathostomiasis: a summary on reported Thai cases. PMID- 25807133 TI - Acute demyelination with leukoencephalopathy and cerebellar involvement in vitamin B12 deficiency. PMID- 25807136 TI - Brazilian consensus on guidelines for diagnosis and treatment for restless legs syndrome. AB - The Consensus on restless legs syndrome is an effort of neurologists from several Brazilian states, which tirelessly reviewed the literature of recent years in search of evidence, both in regard to diagnosis and treatment, according to the Oxford Centre for Evidence-based Medicine. PMID- 25807137 TI - Poly(2-oxazoline)-Based Microgel Particles for Neuronal Cell Culture. AB - An increasing number of in vivo and in vitro neuro-engineering applications are making use of colloidal particles as neuronal cell carriers. Recent studies highlight the shortcomings of commercial glass particles and stress the benefit of using soft microgel particles (MGPs) instead. This study describes first the fabrication of MGPs from telechelic poly(2-methyl-2-oxazoline)s (PMeOx) cross linkers and hydrophilic neutral (hydroxyethyl)methacrylate (HEMA) or charged 2 methacryloxyethyltrimethylammonium (METAC) monomers by emulsion polymerization, and it discusses their ability to support cell growth. It establishes that uncharged copolymers lead to MGPs with nonfouling properties inappropriate for cell culture, and it provides a protocol to amend their surface properties to enable cell adhesion. Finally, it demonstrates that the introduction of positive charges by METAC is necessary to obtain surface properties suitable for neuronal cell development. Through the optimization of the PMeOx30 MGP properties, this work provides general guidelines to evaluate and tune MGP chemistry to obtain microcarriers for neuro-engineering applications. PMID- 25807138 TI - Correction: ecological niche modeling and land cover risk areas for rift valley fever vector, Culex tritaeniorhynchus giles in Jazan, Saudi Arabia. AB - [This corrects the article DOI: 10.1371/journal.pone.0065786.]. PMID- 25807139 TI - Proteomic Signature of Endothelial Dysfunction Identified in the Serum of Acute Ischemic Stroke Patients by the iTRAQ-Based LC-MS Approach. AB - Acute ischemic stroke (AIS) is a devastating cerebrovascular disorder that leads to permanent physical and neurological disabilities in adults worldwide. Proteins associated with stroke pathogenesis may appear in the serum of AIS patients due to blood-brain barrier dysfunction, thus permitting the development of blood based biomarkers for early diagnosis of stroke. These biomarkers could perhaps be an adjunct to the existing imaging modalities and aid in better management and therapeutic intervention during the course of the disease. For this exploratory study, a combination of multiplexed isobaric tagging using iTRAQ reagents and high resolution tandem mass spectrometry was used to identify differentially expressed proteins in serum samples from AIS patients. The quantitative proteomic analysis of serum from both AIS and control subjects revealed 389 high confidence protein identifications and their relative levels. Among them, 60 proteins showed a >=1.5-fold change in the AIS subjects. We verified the altered serum levels of candidate proteins such as vWF, ADAMTS13, S100A7, and DLG4 through ELISA, and the results also corroborate with the experimental findings. vWF and ADAMTS13 are key players that regulate blood hemostasis, and their altered concentration may contribute to endothelial dysfunction. S100A7 is a novel candidate protein identified in this study that is also known to mediate inflammation, endothelial proliferation, and angiogenesis. The current study provided a potential and novel biomarker panel that may in turn provide diagnostic aid to the existing imaging modalities for the rapid diagnosis of ischemic stroke. PMID- 25807140 TI - Itinerant magnetism in metallic CuFe2Ge2. AB - Theoretical calculations are performed to understand the electronic structure and magnetic properties of CuFe2Ge2. The band structure reveals large electron density N(EF) at the Fermi level suggesting a strong itinerant character of magnetism. The Fermi surface is dominated by two dimensional sheet like structures, with potentially strong nesting between them. The magnetic ground state appears to be ferromagnetic along a and antiferromagnetic in other directions. These results show that CuFe2Ge2 is an antiferromagnetic metal, with similarities to the Fe-based superconductors; such as magnetism with substantial itinerant character and coupling between magnetic order and electrons at the Fermi energy. PMID- 25807142 TI - Glycosylation with 2-Acetamido-2-deoxyglycosyl Donors at a Low Temperature: Scope of the Non-Oxazoline Method. AB - A direct construction of 1,2-trans-beta-linked 2-acetamido-2-deoxyglycosides was investigated. The 3,4,6-tri-O-benzyl- and 3,4,6-tri-O-acetyl-protected glycosyl diethyl phosphites and 4,6-O-benzylidene-protected galactosyl diethyl phosphite each reacted with a variety of acceptor alcohols in the presence of a stoichiometric amount of Tf2NH in CH2Cl2 at -78 degrees C to afford the corresponding beta-glycosides in good to high yields with complete stereoselectivity. Some experiments provided strong evidence that the corresponding oxazolinium ions are not responsible for the reaction. We demonstrated that glycosylations with the corresponding glycosyl imidate and thioglycoside also proceeded at a low temperature, indicating the possibility of these donors being attractive alternatives to the phosphite. A plausible reaction mechanism, which features glycosyl triflimide and contact ion pair as reactive intermediates, is proposed on the basis of the results obtained with 2-acetamido 2-deoxymannosyl donors. PMID- 25807141 TI - MicroRNA profiling in intraocular medulloepitheliomas. AB - PURPOSE: To study the differential expression of microRNA (miRNA) profiles between intraocular medulloepithelioma (ME) and normal control tissue (CT). MATERIAL AND METHODS: Total RNA was extracted from formalin fixed paraffin embedded (FFPE) intraocular ME (n=7) and from age matched ciliary body controls (n=8). The clinical history and phenotype was recorded. MiRNA profiles were determined using the Affymetrix GeneChip miRNA Arrays analyzed using expression console 1.3 software. Validation of significantly dysregulated miRNA was confirmed by quantitative real-time PCR. The web-based DNA Intelligent Analysis (DIANA)-miRPath v2.0 was used to perform enrichment analysis of differentially expressed (DE) miRNA gene targets in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. RESULTS: The pathologic evaluation revealed one benign (benign non-teratoid, n=1) and six malignant tumors (malignant teratoid, n=2; malignant non-teratoid, n = 4). A total of 88 miRNAs were upregulated and 43 miRNAs were downregulated significantly (P<0.05) in the tumor specimens. Many of these significantly dysregulated miRNAs were known to play various roles in carcinogenesis and tumor behavior. RT-PCR validated three significantly upregulated miRNAs and three significantly downregulated miRNAs namely miR-217, miR-216a, miR-216b, miR-146a, miR-509-3p and miR-211. Many DE miRNAs that were significant in ME tumors showed dysregulation in retinoblastoma, glioblastoma, and precursor, normal and reactive human cartilage. Enriched pathway analysis suggested a significant association of upregulated miRNAs with 15 pathways involved in prion disease and several types of cancer. The pathways involving significantly downregulated miRNAs included the toll-like receptor (TLR) (p<4.36E 16) and Nuclear Factor kappa B (NF-kappaB) signaling pathways (p<9.00E-06). CONCLUSIONS: We report significantly dysregulated miRNAs in intraocular ME tumors, which exhibited abnormal profiles in other cancers as well such as retinoblastoma and glioblastoma. Pathway analysis of all dysregulated miRNAs shared commonalities with other cancer pathways. PMID- 25807143 TI - Factors that influence the way communities respond to proposals for major changes to local emergency services: a qualitative study. AB - OBJECTIVE: According to policy commentators, decisions about how best to organise care involve trade-offs between factors relating to care quality, workforce, cost, and patient access. In England, proposed changes such as Emergency Department closures often face public opposition. This study examined the way communities respond to plans aimed at reorganising emergency services, including the trade-offs inherent in such decisions. DESIGN: Cross-sectional study involving in-depth interviews. Participants selected their priorities for emergency care, including aspects they might be prepared to have 'less' of (e.g. rapid access) if it meant having 'more' of another (e.g. consultant-delivered care). A thematic analysis was carried out, combining inductive and deductive approaches, drawing on theories about risk perception. SETTING: Two urban areas of England; one where changes to emergency services were under consideration ('Greenville'), and one where they were not ('Hilltown'). PARTICIPANTS: 28 participants in total. Greenville interviewees included more common emergency service users - parents of young children (n=5) and older people (n=6) - plus patient representatives and individuals campaigning against service closures (n=9). Hilltown interviewees (n=8) received outpatient care for Chronic Obstructive Pulmonary Disease, an important cause of emergency admission. RESULTS: Most participants, in both areas, were not willing to accommodate the trade-offs involved in consolidating emergency services, principally because of the belief that timely access is associated with better outcomes. Participants did not consider the proposed improvements as gains worth having; interviewees believed care quality would be adversely impact, partly because increased patient numbers would place staff under greater pressure and result in longer waiting times. CONCLUSIONS: Visible clinical leadership and detailed explanation of the case for change were insufficient to overcome opposition to the reconfiguration in Greenville, challenging the assumption that communities can be persuaded by evidence. Commissioners should make explicit credible plans to accommodate changes in patient flows, as well as clarifying the roles played by key staff groups. PMID- 25807144 TI - Cell-penetrating peptide derived from human eosinophil cationic protein inhibits mite allergen Der p 2 induced inflammasome activation. AB - Newly discovered cell penetration peptides derived from human eosinophil cationic proteins (CPPecp) have the characteristic of cell internalization, but the effect of CPPecp on immunomodulation has not been clarified. House dust mite (HDM) major allergen, Der p 2, can induce proinflammatory cytokine production which contributes to airway inflammation and allergic asthma. However, the mechanism of Der p 2 on NLRP3 inflammasome activation remains unclear. The aim of this study was to investigate the immunomodulatory effect of CPPecp on inhibition of Der p 2 induced inflammasome activation. We showed that proinflammatory cytokines IL 1beta, IL-6 and IL-8 were significantly upregulated in peripheral blood mononuclear cells (PBMCs) derived from HDM allergic patients after Der p 2 stimulation. Expression of NLRP3, ASC, Caspase-1, IL-1beta and Caspase-1 activity was upregulated in THP-1 cells after Der p 2 stimulation. Proinflammatory cytokine production, NLRP3 inflammasome activation and caspase-1 activity were downregulated in THP-1 cells and CD14+ cells co-cultured with Der p 2 and CPPecp. The immunomodulatory effect of CPPecp was through upregulation of IFN-alpha production but not induction of autophagy. These results suggested Der p 2 plays an important role in NLRP3 inflammasome activation and CPPecp has the potential to be a novel anti-inflammatory agent for allergic inflammation treatment in the future. PMID- 25807147 TI - The combination of phylogenetic analysis with epidemiological and serological data to track HIV-1 transmission in a sexual transmission case. AB - OBJECTIVE: To investigate the linkage of HIV transmission from a man to a woman through unprotected sexual contact without disclosing his HIV-positive status. METHODS: Combined with epidemiological information and serological tests, phylogenetic analysis was used to test the a priori hypothesis of HIV transmission from the man to the woman. Control subjects, infected with HIV through heterosexual intercourse, from the same location were also sampled. Phylogenetic analyses were performed using the consensus gag, pol and env sequences obtained from blood samples of the man, the woman and the local control subjects. The env quasispecies of the man, the woman, and two controls were also obtained using single genome amplification and sequencing (SGA/S) to explore the paraphyletic relationship by phylogenetic analysis. RESULTS: Epidemiological information and serological tests indicated that the man was infected with HIV-1 earlier than the woman. Phylogenetic analyses of the consensus sequences showed a monophyletic cluster for the man and woman in all three genomic regions. Furthermore, gag sequences of the man and woman shared a unique recombination pattern from subtype B and C, which was different from those of CRF07_BC or CRF08_BC observed in the local samples. These indicated that the viral sequences from the two subjects display a high level of similarity. Further, viral quasispecies from the man exhibited a paraphyletic relationship with those from the woman in the Bayesian and maximum-likelihood (ML) phylogenetic trees of the env region, which supported the transmission direction from the man to the woman. CONCLUSIONS: In the context of epidemiological and serological evidence, the results of phylogenetic analyses support the transmission from the man to the woman. PMID- 25807146 TI - Acceleration of age-associated methylation patterns in HIV-1-infected adults. AB - Patients with treated HIV-1-infection experience earlier occurrence of aging associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x 10(-200) and 0.47, p<1 x 10(-200). Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: betaage=0.007088, p=2.08 x 10(-9); betaHIV=0.099574, p=0.0011; Data set 2: betaage=0.008762, p=1.27 x 10(-5); betaHIV=0.128649, p=0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher exact p=5.6 x 10(-6), odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging. PMID- 25807148 TI - The mediating effect of body mass index on the relationship between cigarette smoking and atopic sensitization in Chinese adults. AB - BACKGROUND: It is unclear whether the relationship between cigarette smoking and atopy is mediated by body fat mass, such as the Body Mass Index (BMI). We assessed the mediating role of BMI on the relationship between smoking and atopy in Chinese adults. METHODS: A hospital-based case-control study of 786 atopic cases and 2771 controls was conducted in adults aged 18 years or older from March 2010 to September 2014 in Harbin, China. Mediation models were used to estimate the indirect effects of smoking on atopic sensitization through BMI. RESULTS: Compared to non-smokers, light smokers and moderate smokers had a lower risk of inhalant allergen sensitization. The indirect effect of smoking and sensitization to aeroallergens were only observed in light smokers (point estimate, -0.026; 95% CI, -0.062 to -0.004). The mediating roles of BMI on the relationships between smoking and other types of allergic sensitization were not statistically significant. CONCLUSION: BMI appeared to partially mediate the effect of light smoking on sensitization to aeroallergens. However, considering the other harmful health effects of cigarette smoking, the effective method to lower the incidence of atopy would be to decrease body fat mass by physical exercise and employing other more healthy ways of living rather than smoking. PMID- 25807150 TI - Accurate calculation of conformational free energy differences in explicit water: the confinement-solvation free energy approach. AB - The calculation of the free energy of conformation is key to understanding the function of biomolecules and has attracted significant interest in recent years. Here, we present an improvement of the confinement method that was designed for use in the context of explicit solvent MD simulations. The development involves an additional step in which the solvation free energy of the harmonically restrained conformers is accurately determined by multistage free energy perturbation simulations. As a test-case application, the newly introduced confinement/solvation free energy (CSF) approach was used to compute differences in free energy between conformers of the alanine dipeptide in explicit water. The results are in excellent agreement with reference calculations based on both converged molecular dynamics and umbrella sampling. To illustrate the general applicability of the method, conformational equilibria of met-enkephalin (5 aa) and deca-alanine (10 aa) in solution were also analyzed. In both cases, smoothly converged free-energy results were obtained in agreement with equilibrium sampling or literature calculations. These results demonstrate that the CSF method may provide conformational free-energy differences of biomolecules with small statistical errors (below 0.5 kcal/mol) and at a moderate computational cost even with a full representation of the solvent. PMID- 25807151 TI - van der Waals epitaxial growth of atomically thin Bi2Se3 and thickness-dependent topological phase transition. AB - Two-dimensional (2D) atomic-layered heterostructures stacked by van der Waals interactions recently introduced new research fields, which revealed novel phenomena and provided promising applications for electronic, optical, and optoelectronic devices. In this study, we report the van der Waals epitaxial growth of high-quality atomically thin Bi2Se3 on single crystalline hexagonal boron nitride (h-BN) by chemical vapor deposition. Although the in-plane lattice mismatch between Bi2Se3 and h-BN is approximately 65%, our transmission electron microscopy analysis revealed that Bi2Se3 single crystals epitaxially grew on h-BN with two commensurate states; that is, the (1210) plane of Bi2Se3 was preferably parallel to the (1100) or (1210) plane of h-BN. In the case of the Bi2Se3 (2110) ? h-BN (1100) state, the Moire pattern wavelength in the Bi2Se3/h-BN superlattice can reach 5.47 nm. These naturally formed thin crystals facilitated the direct assembly of h-BN/Bi2Se3/h-BN sandwiched heterostructures without introducing any impurity at the interfaces for electronic property characterization. Our quantum capacitance (QC) measurements showed a compelling phenomenon of thickness dependent topological phase transition, which was attributed to the coupling effects of two surface states from Dirac Fermions at/or above six quintuple layers (QLs) to gapped Dirac Fermions below six QLs. Moreover, in ultrathin Bi2Se3 (e.g., 3 QLs), we observed the midgap states induced by intrinsic defects at cryogenic temperatures. Our results demonstrated that QC measurements based on h-BN/Bi2Se3/h-BN sandwiched structures provided rich information regarding the density of states of Bi2Se3, such as quantum well states and Landau quantization. Our approach in fabricating h-BN/Bi2Se3/h-BN sandwiched device structures through the combination of bottom-up growth and top-down dry transferring techniques can be extended to other two-dimensional layered heterostructures. PMID- 25807149 TI - Associations of baroreflex sensitivity, heart rate variability, and initial orthostatic hypotension with prenatal and recent postnatal methylmercury exposure in the Seychelles Child Development Study at age 19 years. AB - BACKGROUND: A few studies have suggested an association between prenatal exposure to methylmercury and decreased heart rate variability (HRV) related to autonomic heart function, but no study has examined this association using baroreflex sensitivity (BRS). In this study we assessed the distribution of BRS and immediate orthostatic hypotension (IOH) in young Seychellois adults and their associations with exposure to prenatal and recent postnatal methylmercury. METHODS: Subjects in the Seychelles Child Development Study (SCDS) main cohort were evaluated at age 19 years. Non-invasive beat-to-beat blood pressure (BP) monitoring (Finapres, Ohmeda) was performed at rest and during active standing in 95 consecutive subjects. Recent postnatal mercury exposure was measured in subjects' hair at the age of 19 years and prenatal exposure in maternal hair grown during pregnancy. BRS was estimated by sequence analysis to identify spontaneous ascending and descending BP ramps. HRV was estimated by the following markers: PNN50 (relative numbers of normal-to-normal intervals which are shorter by more than 50 ms than the immediately following normal-to-normal intervals); rMSSD (root mean of the squared sum of successive interval differences); LF/HF (low frequency/high frequency component ratio); ratio of the mean expiratory/inspiratory RR intervals (EI ratio); and the ratio between the longest RR interval 30 s after active standing and the shortest RR interval at 15 s (Max30/Min15). IOH was estimated by the deepest BP fall within the first 15 s after active standing up. RESULTS: Prenatal MeHg exposures were similar in boys and girls (6.7+/-4.3, 6.7+/-3.8 ng/g) but recent postnatal mercury levels were higher in males than females (11.2+/-5.8 vs 7.9+/-4.3 ng/g, p=0.003). Markers of autonomic heart rate control were within the normal range (BRS: 24.8+/-7 ms/mm Hg, PNN50: 24.9+/-6.8%, rMSSD: 68+/-22, LF/HF: 0.61+/-0.28) in both sexes. After standing, 51.4% of subjects had a transient systolic BP drop>40 mm Hg, but only 5.3% reported dizziness or had syncope. Prenatal and recent postnatal MeHg levels, overall, were not associated with BRS, E/I ratio, PNN50, rMSSD, LF/HF ratio, Max30/Min15 ratio, and IOH. CONCLUSIONS: This study provides no support for the hypothesis that prenatal or recent postnatal MeHg exposure from fish consumption is associated with impaired autonomic heart rate control. PMID- 25807153 TI - Physical activity interventions: an essential component in recovery from mental illness. PMID- 25807155 TI - Patient Reported Outcome Measures (PROMs) have arrived in sports and exercise medicine: Why do they matter? PMID- 25807154 TI - BJSM education to improve your ECG reading skills. PMID- 25807156 TI - Fifty shades of grey: concussion complexities and constructive conclusions. PMID- 25807157 TI - Road to recovery graph. PMID- 25807158 TI - Success story: how exercise physiologists improve the health of Australians. PMID- 25807145 TI - Discovery of molecular markers to discriminate corneal endothelial cells in the human body. AB - The corneal endothelium is a monolayer of hexagonal corneal endothelial cells (CECs) on the inner surface of the cornea. CECs are critical in maintaining corneal transparency through their barrier and pump functions. CECs in vivo have a limited capacity in proliferation, and loss of a significant number of CECs results in corneal edema called bullous keratopathy which can lead to severe visual loss. Corneal transplantation is the most effective method to treat corneal endothelial dysfunction, where it suffers from donor shortage. Therefore, regeneration of CECs from other cell types attracts increasing interests, and specific markers of CECs are crucial to identify actual CECs. However, the currently used markers are far from satisfactory because of their non-specific expression in other cell types. Here, we explored molecular markers to discriminate CECs from other cell types in the human body by integrating the published RNA-seq data of CECs and the FANTOM5 atlas representing diverse range of cell types based on expression patterns. We identified five genes, CLRN1, MRGPRX3, HTR1D, GRIP1 and ZP4 as novel markers of CECs, and the specificities of these genes were successfully confirmed by independent experiments at both the RNA and protein levels. Notably none of them have been documented in the context of CEC function. These markers could be useful for the purification of actual CECs, and also available for the evaluation of the products derived from other cell types. Our results demonstrate an effective approach to identify molecular markers for CECs and open the door for the regeneration of CECs in vitro. PMID- 25807159 TI - Why registries analysing cruciate ligament surgery are important. PMID- 25807160 TI - Regulation of energy balance by brown adipose tissue: at least three potential roles for physical activity. PMID- 25807161 TI - Common misconceptions about back pain in sport: Tiger Woods' case brings five fundamental questions into sharp focus. PMID- 25807162 TI - 'Load me up, Scotty': mechanotherapy for plantar fasciopathy (formerly known as plantar fasciitis). PMID- 25807163 TI - The sexy scalpel: unnecessary shoulder surgery on the rise. PMID- 25807164 TI - Energy balance: a crucial issue for exercise and sports medicine. PMID- 25807165 TI - The importance of listening: engaging and incorporating the athlete's voice in theory and practice. PMID- 25807166 TI - Death by effectiveness: exercise as medicine caught in the efficacy trap! PMID- 25807167 TI - Comprehending concussion: evolving and expanding our clinical insight. PMID- 25807169 TI - Biological affinities and regional microevolution among pre-Hispanic communities of Colombia's Northern Andes. AB - Dental non-metric data were used to examine the biological continuity of pre Hispanic peoples of Colombia's Northern Andes, including highland, lowland and coastal peoples. This report contributes to studies regarding the peopling of South America by establishing a benchmark comparison that includes pre-Hispanic populations of the Northern Andes. The sample consisted of a total of 583 individuals from 56 cemeteries ranging in time from the Early Holocene (10,000 BP) to the Final Late Holocene (500 BP). Permanent dentitions from individuals between 5 and 40 years of age were scored for 87 dental traits based on the ASUDAS. A divergence matrix was programmed using the Smith's Mean Measure of Divergence equation (MMD). Bartlett's adjustment and Ascombe transformation were considered into MMD calculations. Principal Coordenate analysis was applied based on MMD matrix scores. A clear group was found that associated Initial Late Holocene samples with Final Late Holocene samples. Early Holocene samples are very different to that, and Middle Holocene samples show as morphologically intermediate series. A comparison of the frequencies by time and period showed that a limited biological continuity existed. Interbreeding among initial populations of the same regions is expressed in similar frequencies of dental traits within Early Holocene and Middle Holocene samples. Early Holocene samples did not match with Sinodont pattern according to discriminant function analysis. These findings help us to better understand the settlement process of human groups in the Northern Andes and its relationship with migratory movements in South America. PMID- 25807168 TI - Nucleotide diversity analysis of three major bacterial blight resistance genes in rice. AB - Nucleotide sequence polymorphisms among R gene alleles influence the process of co-evolutionary interaction between host and pathogen by shaping the response of host plants towards invading pathogens. Here, we present the DNA sequence polymorphisms and diversities present among natural alleles of three rice bacterial blight resistance genes, Xa21, Xa26 and xa5. The diversity was examined across different wild relatives and cultivars of Oryza species. Functional significance of selected alleles was evaluated through semi-quantitative reverse transcription polymerase chain reaction and real time PCR. The greatest nucleotide diversity and singleton variable sites (SVS) were present in Xa26 (pi = 0.01958; SVS = 182) followed by xa5 and Xa21 alleles. The highest frequency of single nucleotide polymorphisms were observed in Xa21 alleles and least in xa5. Transition bias was observed in all the genes and 'G' to 'A' transitions were more favored than other form of transitions. Neutrality tests failed to show the presence of selection at these loci, though negative Tajima's D values indicate the presence of a rare form of polymorphisms. At the interspecies level, O. nivara exhibited more diversity than O. sativa. We have also identified two nearly identical resistant alleles of xa5 and two sequentially identical alleles of Xa21. The alleles of xa5 showed basal levels of expression while Xa21 alleles were functionally not expressed. PMID- 25807170 TI - Long-term patency of endoscopically harvested radial arteries: from a randomized controlled trial. AB - OBJECTIVE: From 2005 to 2007, 119 patients were enrolled in a prospective randomized controlled trial comparing open and endoscopically harvested radial arteries for coronary artery bypass grafting. The objective of the current study was to compare graft patency between intervention groups at more than 5 years from the initial trial. We hypothesized that endoscopically harvested radial arteries would show equivalent patency to those conventionally harvested. METHODS: At 5 years or greater from their operation, all consenting patients underwent a single-day anatomic and functional cardiac assessment with coronary computed tomography angiography and sestamibi myocardial perfusion scanning. Medical Outcomes Study 36-Item Short-Form Health Surveys and Seattle Angina Questionnaires were completed to assess the overall quality of life. All patients had received calcium channel blocker therapy for at least 6 months postoperatively. RESULTS: The mean (SD) duration of follow-up was 79.2 (8.6) months for all patients. One death occurred within 30 days of coronary artery bypass grafting in each treatment group, and eight additional noncardiac deaths occurred during the study time frame. Of 119 patients, 66 consented to follow-up. Thirty-two had open radial artery harvest, and 34 had endoscopic radial artery harvest. At more than 5 years, there were 28 patent conventionally harvested radial arteries (87.5%) and 31 patent endoscopically harvested radial arteries (91.2%) (P = 0.705). Measured quality of life was comparable between groups. CONCLUSIONS: Endoscopic radial artery harvest is safe and effective when compared with open radial artery harvest, with excellent graft patency demonstrated at more than 5 years. Patency results are noninferior in endoscopic radial artery harvest. PMID- 25807171 TI - Implantation of the eSVS Mesh: modification of recommended technique. AB - The eSVS Mesh is a knitted wire lattice manufactured in cylindrical sheaths of various diameters, designed to be placed around the outer surface of a saphenous vein graft before use in coronary surgery. The goal is to improve long-term vein graft patency by preventing expansive endothelial injury obviating neointimal hyperplasia and subsequent graft atherosclerosis. Since the First-In-Man feasibility trial of the eSVS Mesh, postmarket studies in Europe and a feasibility trial in the United States are ongoing. Consensus from the principal investigators indicated the trials had confounding variables that may impact results other than evaluation of the eSVS Mesh alone. With input from these investigators, the recommended operative technique has been modified for future trials by removing the mesh from proximal and distal anastomoses and eliminating the use of fibrin sealant. These changes allow for use of an implant technique closer to standard vein bypass grafting and a more focused evaluation of the eSVS Mesh. PMID- 25807174 TI - Interface-enforced complexation between copolymer blocks. AB - Binary diblock copolymers and corresponding ternary miktoarm stars are studied at oil-water interfaces. All polymers contain oil-soluble poly(propylene oxide) PPO, water-soluble poly(dimethylaminoethyl methacrylate) PDMAEMA and/or poly(ethylene oxide) PEO. The features of their Langmuir compression isotherms are well related to the ones of the corresponding homopolymers. Within the Langmuir-trough, PEO-b PPO acts as the most effective amphiphile compared to the other PPO-containing copolymers. In contrast, the compression isotherms show a complexation of PPO and PDMAEMA for PPO-b-PDMAEMA and the star, reducing their overall amphiphilicity. Such complex formation between the blocks of PPO-b-PDMAEMA is prevented in bulk water but facilitated at the interface. The weakly-interacting blocks of PPO-b PDMAEMA form a complex due to their enhanced proximity in such confined environments. Scanning force microscopy and Monte Carlo simulations with varying confinement support our results, which are regarded as compliant with the mathematical random walk theorem by Polya. Finally, the results are expected to be of relevance for e.g. emulsion formulation and macromolecular engineering. PMID- 25807172 TI - Attachment, symptom severity, and depression in medically unexplained musculoskeletal pain and osteoarthritis: a cross-sectional study. AB - BACKGROUND: Attachment insecurity relates to the onset and course of chronic pain via dysfunctional reactions to pain. However, few studies have investigated the proportion of insecure attachment styles in different pain conditions, and results regarding associations between attachment, pain severity, and disability in chronic pain are inconsistent. This study aims to clarify the relationships between insecure attachment and occurrence or severity of chronic pain with and without clearly defined organic cause. To detect potential differences in the importance of global and romantic attachment representations, we included both concepts in our study. METHODS: 85 patients with medically unexplained musculoskeletal pain (UMP) and 89 patients with joint pain from osteoarthritis (OA) completed self-report measures of global and romantic attachment, pain intensity, physical functioning, and depression. RESULTS: Patients reporting global insecure attachment representations were more likely to suffer from medically unexplained musculoskeletal pain (OR 3.4), compared to securely attached patients. Romantic attachment did not differ between pain conditions. Pain intensity was associated with romantic attachment anxiety, and this relationship was more pronounced in the OA group compared to the UMP group. Both global and romantic attachment anxiety predicted depression, accounting for 15% and 17% of the variance, respectively. Disability was independent from attachment patterns. CONCLUSIONS: Our results indicate that global insecure attachment is associated with the experience of medically unexplained musculoskeletal pain, but not with osteoarthritis. In contrast, insecure attachment patterns seem to be linked to pain intensity and pain-related depression in unexplained musculoskeletal pain and in osteoarthritis. These findings suggest that relationship-informed focused treatment strategies may alleviate pain severity and psychological distress in chronic pain independent of underlying pathology. PMID- 25807175 TI - Methyl 3,4-dihydroxybenzoate promote rat cortical neurons survival and neurite outgrowth through the adenosine A2a receptor/PI3K/Akt signaling pathway. AB - Methyl 3,4-dihydroxybenzoate (MDHB), a kind of phenolic acid compounds, has been reported to have antioxidant effects. Moreover, our previous study found that it could promote neurite outgrowth and brain-derived neurotrophic factor expression in cortical neurons of neonatal rats. In the present study, we focused on the mechanism of its neurotrophic effect; the results showed that MDHB-induced upregulation of neuronal survival and neurite outgrowth in cultured primary cortical neurons could be blocked by the adenosine A2a receptor inhibitor (ZM241385) and the phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Subsequently, we found that the upregulation of Akt phosphorylation by MDHB could be suppressed by A2a-R and PI3K-specific inhibitor, but not the Trk-R inhibitor. Furthermore, MDHB could activate Akt in a concentration-dependent manner. These results suggested that activation of the PI3K/Akt signaling pathway may be involved in the MDHB-induced neurotrophic effects and MDHB could be a candidate compound to develop drugs for neurodegenerative disease. PMID- 25807173 TI - Bacterial communities associated with host-adapted populations of pea aphids revealed by deep sequencing of 16S ribosomal DNA. AB - Associations between microbes and animals are ubiquitous and hosts may benefit from harbouring microbial communities through improved resource exploitation or resistance to environmental stress. The pea aphid, Acyrthosiphon pisum, is the host of heritable bacterial symbionts, including the obligate endosymbiont Buchnera aphidicola and several facultative symbionts. While obligate symbionts supply aphids with key nutrients, facultative symbionts influence their hosts in many ways such as protection against natural enemies, heat tolerance, color change and reproduction alteration. The pea aphid also encompasses multiple plant specialized biotypes, each adapted to one or a few legume species. Facultative symbiont communities differ strongly between biotypes, although bacterial involvement in plant specialization is uncertain. Here, we analyse the diversity of bacterial communities associated with nine biotypes of the pea aphid complex using amplicon pyrosequencing of 16S rRNA genes. Combined clustering and phylogenetic analyses of 16S sequences allowed identifying 21 bacterial OTUs (Operational Taxonomic Unit). More than 98% of the sequencing reads were assigned to known pea aphid symbionts. The presence of Wolbachia was confirmed in A. pisum while Erwinia and Pantoea, two gut associates, were detected in multiple samples. The diversity of bacterial communities harboured by pea aphid biotypes was very low, ranging from 3 to 11 OTUs across samples. Bacterial communities differed more between than within biotypes but this difference did not correlate with the genetic divergence between biotypes. Altogether, these results confirm that the aphid microbiota is dominated by a few heritable symbionts and that plant specialization is an important structuring factor of bacterial communities associated with the pea aphid complex. However, since we examined the microbiota of aphid samples kept a few generations in controlled conditions, it may be that bacterial diversity was underestimated due to the possible loss of environmental or transient taxa. PMID- 25807176 TI - Auditory short-term memory trace formation for nonspeech and speech in SLI and dyslexia as indexed by the N100 and mismatch negativity electrophysiological responses. AB - This study investigates nonspeech and speech processing in specific language impairment (SLI) and dyslexia. We used a passive mismatch negativity (MMN) task to tap automatic brain responses and an active behavioural task to tap attended discrimination of nonspeech and speech sounds. Using the roving standard MMN paradigm, we varied the number of standards ('few' vs. 'many') to investigate the effect of sound repetition on N100 and MMN responses. The results revealed that the SLI group needed more repetitions than dyslexics and controls to create a strong enough sensory trace to elicit MMN. In contrast, in the behavioural task, we observed good discrimination of speech and nonspeech in all groups. The findings indicate that auditory processing deficits in SLI and dyslexia are dissociable and that memory trace formation may be implicated in SLI. PMID- 25807177 TI - Hypoxia-inducible factor-1alpha upregulates tyrosine hydroxylase and dopamine transporter by nuclear receptor ERRgamma in SH-SY5Y cells. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor relevant to the development of many mammalian organs including the brain. However, the molecular mechanisms by which signaling events mediate neuronal differentiation have not been fully elucidated. In the present study, we show for the first time that the orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is upregulated by HIF-1alpha and plays essential roles in HIF-1alpha-induced upregulation of dopaminergic marker molecules such as tyrosine hydroxylase and dopamine transporter. We found that deferoxamine upregulated HIF-1alpha and enhanced the dopaminergic phenotype and neurite outgrowth of SH-SY5Y cells. Deferoxamine activated transcription and protein expression of ERRgamma, and deferoxamine-induced upregulation of tyrosine hydroxylase and dopamine transporter was attenuated by using the ERRgamma inverse agonist or silencing ERRgamma. Altogether, these results suggest that HIF-1alpha can positively regulate the dopaminergic phenotype through ERRgamma. This study could provide new perspectives for understanding the mechanisms underlying the promotion of dopaminergic neuronal differentiation by hypoxia. PMID- 25807178 TI - Correspondence. PMID- 25807179 TI - Reply: To PMID 23881226. PMID- 25807180 TI - Ferromagnetism induced by entangled charge and orbital orderings in ferroelectric titanate perovskites. AB - In magnetic materials, the Pauli exclusion principle typically drives anti alignment between electron spins on neighbouring species resulting in antiferromagnetic behaviour. Ferromagnetism exhibiting spontaneous spin alignment is a fairly rare behaviour, but once materialized is often associated with itinerant electrons in metals. Here we predict and rationalize robust ferromagnetism in an insulating oxide perovskite structure based on the popular titanate series. In half-doped layered titanates, the combination of Jahn-Teller and oxygen breathing motions opens a band gap and creates an unusual charge and orbital ordering of the Ti d electrons. It is argued that this intriguingly intricate electronic network favours the elusive inter-site ferromagnetic (FM) ordering, on the basis of intra-site Hund's rules. Finally, we find that the layered oxides are also ferroelectric with a spontaneous polarization approaching that of BaTiO3. The concepts are general and design principles of the technologically desirable FM ferroelectric multiferroics are presented. PMID- 25807182 TI - Carbon nanotube-bonded graphene hybrid aerogels and their application to water purification. AB - We present carbon nanotube (CNT)-bonded graphene hybrid aerogels that are prepared by growing CNTs on a graphene aerogel surface with nickel catalyst. The presence of bonded CNTs in the graphene aerogel results in vastly improved mechanical and electrical properties. A significant increase in specific surface area is also realized. The presence of the CNTs transforms the hybrid aerogels into a mesoporous material. The viscoelasticity of the hybrid aerogels is found to be invariant with respect to temperature over a range of between -150 degrees C and 450 degrees C. These characteristics along with the improved properties make the hybrid aerogels an entirely different class of material with applications in the fields of biotechnology and electrochemistry. The mesoporous nature of the material along with its high specific surface area also makes the hybrid aerogel attractive for application in water treatment. Both anionic and cationic dyes can be effectively removed from water by the hybrid aerogel. A number of organics and oils can be selectively separated from water by the hybrid aerogel. The hybrid aerogel is easy to handle and separate from water due to its magnetic nature, and can readily be recycled and reused. PMID- 25807181 TI - Transformation of truncated gold octahedrons into triangular nanoprisms through the heterogeneous nucleation of silver. AB - Described is a straightforward procedure for forming organized substrate immobilized nanoprisms which are single crystalline, surfactant-free and which form a heteroepitaxial relationship with the underlying substrate. The devised route utilizes truncated Au octahedrons formed through solid state dewetting techniques as high temperature heterogeneous nucleation sites for Ag adatoms which are arriving to the substrate surface in the vapour phase. Observed is a morphological and compositional transformation of the Au structures to triangular nanoprisms comprised of a homogeneous AuAg alloy. During this transformation, the localized surface plasmon resonance red-shifts, broadens and increases in strength. The shape transformation, which cannot be rationalized using thermodynamic arguments dependent on the surface energy minimization, is described in terms of a kinetically driven growth mode, previously predicted by molecular dynamic simulations. The so-formed structures, when coated with a thin layer of Pd, are demonstrated as plasmonic sensing elements for hydrogen detection. PMID- 25807183 TI - The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6. AB - The matricellular protein CCN1 (CYR61) is known to function in wound healing and is upregulated in colons of patients with Crohn's disease and ulcerative colitis, yet its specific role in colitis is unknown. Here we have used Ccn1(dm/dm) knockin mice expressing a CCN1 mutant unable to bind integrins alpha6beta1 and alphaMbeta2 as a model to probe CCN1 function in dextran sodium sulfate (DSS) induced colitis. Ccn1(dm/dm) mice exhibited high mortality, impaired mucosal healing, and diminished interleukin-6 (IL-6) expression during the repair phase of DSS-induced colitis compared with wild-type mice, despite having comparable severity of initial inflammation and tissue injury. CCN1-induced IL-6 expression in macrophages through integrin alphaMbeta2 and in fibroblasts through alpha6beta1, and IL-6 promoted intestinal epithelial cell (IEC) proliferation. Administration of purified CCN1 protein fully rescued Ccn1(dm/dm) mice from DSS induced mortality, restored IEC proliferation and enhanced mucosal healing, whereas delivery of IL-6 partially rectified these defects. CCN1 therapy accelerated mucosal healing and recovery from DSS-induced colitis even in wild type mice. These findings reveal a critical role for CCN1 in restoring mucosal homeostasis after intestinal injury in part through integrin-mediated induction of IL-6 expression, and suggest a therapeutic potential for activating the CCN1/IL-6 axis for treating inflammatory bowel disease. PMID- 25807186 TI - 2,14-Dithiacalix[4]arene and its homooxa analogues: synthesis and dynamic NMR study of conformational behaviour. AB - A simple and scalable synthesis of 2,14-dithiacalix[4]arene with alternating bridges (-CH2- and -S-) is reported. Proper selection of the bisphenol-based starting building blocks can provide not only the title compound (58%) but also yet unreported homooxa analogues possessing three different bridging units (-CH2 , -S- and -CH2-O-CH2-) in the molecule. These systems exhibit interesting conformational behaviour allowing for the study of flip-flop motion of the circular hydrogen bond arrays using dynamic NMR techniques. PMID- 25807187 TI - Assembly of a tile-based multilayered DNA nanostructure. AB - The Watson-Crick complementarity of DNA is exploited to construct periodically patterned nanostructures, and we herein demonstrate tile-based three dimensional (3D) multilayered DNA nanostructures that incorporate two design strategies: vertical growth and horizontal layer stacking with substrate-assisted growth. To this end, we have designed a periodically holed double-double crossover (DDX) template that can be used to examine the growth of the multilayer structures in both the vertical and horizontal directions. For vertical growth, the traditional 2D double crossover (DX) DNA lattice is seeded and grown vertically from periodic holes in the DDX template. For horizontal stacking, the DDX layers are stacked by binding the connector tiles between each layer. Although both types of multilayers exhibited successful formation, the observations with an atomic force microscope indicated that the DDX layer growth achieved with the horizontal stacking approach could be considered to be slightly better relative to the vertical growth of the DX layers in terms of uniformity, layer size, and discreteness. In particular, the newly designed DDX template layer provided a parallel arrangement between each domain with substrate-assisted growth. This kind of layer arrangement suggests a possibility of using our design scheme in the construction of other periodic structures. PMID- 25807185 TI - T regulatory cells and B cells cooperate to form a regulatory loop that maintains gut homeostasis and suppresses dextran sulfate sodium-induced colitis. AB - Regulatory T cells (Tregs) and B cells present in gut-associated lymphoid tissues (GALT) are both implicated in the resolution of colitis. However, how the functions of these cells are coordinated remains elusive. We used the dextran sulfate sodium (DSS)-induced colitis model combined with gene-modified mice to monitor the progression of colitis, and simultaneously examine the number of Tregs and B cells, and the production of IgA antibodies. We found that DSS treated mice exhibited more severe colitis in the absence of B cells, and that the adoptive transfer of B cells attenuated the disease. Moreover, the transfer of IL-10(-/-) B cells also attenuated colitis, suggesting that B cells inhibited colitis through an interleukin-10 (IL-10)-independent pathway. Furthermore, antibody depletion of Tregs resulted in exacerbated colitis. Intriguingly, the number of GALT Tregs in B cell-deficient mice was significantly decreased during colitis and the adoptive transfer of B cells into these mice restored the Treg numbers, indicating that B cells contribute to Treg homeostasis. We also found that B cells induced the proliferation of Tregs that in turn promoted B-cell differentiation into IgA-producing plasma cells. These results demonstrate that B cells and Tregs interact and cooperate to prevent excessive immune responses that can lead to colitis. PMID- 25807184 TI - Eosinophils in mucosal immune responses. AB - Eosinophils, multifunctional cells that contribute to both innate and adaptive immunity, are involved in the initiation, propagation, and resolution of immune responses, including tissue repair. They achieve this multifunctionality by expression of a diverse set of activation receptors, including those that directly recognize pathogens and opsonized targets, and by their ability to store and release preformed cytotoxic mediators that participate in host defense, to produce a variety of de novo pleotropic mediators and cytokines, and to interact directly and indirectly with diverse cell types, including adaptive and innate immunocytes and structural cells. Herein, we review the basic biology of eosinophils and then focus on new emerging concepts about their role in mucosal immune homeostasis, particularly maintenance of intestinal IgA. We review emerging data about their development and regulation and describe new concepts concerning mucosal eosinophilic diseases. We describe recently developed therapeutic strategies to modify eosinophil levels and function and provide collective insight about the beneficial and detrimental functions of these enigmatic cells. PMID- 25807189 TI - Correction: Emotion attribution to a non-humanoid robot in different social situations. PMID- 25807188 TI - Gut instincts: knowledge, attitudes, and practices regarding soil-transmitted helminths in rural China. AB - BACKGROUND: Soil-transmitted helminth (STH) infections affect more than two out of every five schoolchildren in the poorest regions of rural China, an alarmingly high prevalence rate given the low cost and wide availability of safe and effective deworming treatment. Understanding of local knowledge, attitudes, and practices regarding STH infection in rural China has until now, been sparse, although such information is critical for prevention and control initiatives. METHODOLOGY/PRINCIPAL FINDINGS: This study aims to elucidate the structural and sociocultural factors that underlie high STH infection rates as well as explain why deworming treatment is rarely sought for children. In-depth, qualitative interviews were conducted in six rural villages in Guizhou Province; participants included schoolchildren, children's parents and grandparents, and village doctors. Data analysis exposed three predominant reasons for high STH prevalence: (1) lack of awareness and skepticism about the high prevalence of STH infection, (2) local myths about STH infection and deworming treatment, and (3) poor quality of village health care. CONCLUSIONS/SIGNIFICANCE: The findings from this study reveal reasons for why deworming treatment is not sought, and inform specific recommendations for a deworming intervention that can more effectively address underlying barriers to deworming in areas of persistently high STH infection rates. The main barrier to seeking STH treatment is not availability or cost of the drugs, but rather the lack of impetus to seek the drugs. A comprehensive nationwide deworming program in China should involve annual provision of free deworming treatment in village clinics or schools, distribution of culturally appropriate educational materials to inform children and families about STH infection, and improvement of the quality of health care delivered by village clinicians. PMID- 25807190 TI - Correction: correlation of the apparent diffusion coefficient (ADC) with the Standardized Uptake Value (SUV) in lymph node metastases of non-small cell lung cancer (NSCLC) patients using hybrid 18F-FDG PET/MRI. AB - [This corrects the article DOI: 10.1371/journal.pone.0116277.]. PMID- 25807191 TI - Discordant Type I Preaxial Polydactyly in Monozygotic Twins on the Same Hand: A Case Report. AB - There are 4 types of preaxial polydactyly (PPD), and type I (PPD-I), also known as thumb duplication, is the most common. This frequently encountered condition has since been further described and classified by Wassel based on the level of duplication of skeletal anatomy. Genetic studies have localized possible candidate gene(s) for PPD types II to IV to the chromosomal region 7q36 but the current literature attributes PPD-I to isolated, spontaneous mutations typically with unilateral involvement only. Recent epidemiological studies have also suggested nongenetic causes for PPD-I including social and environmental factors. Herein, we would like to present a case of discordant PPD-I expression affecting the same hand in a pair of monozygotic twins and suggest possible reasons for this presentation because previous similar reports only had involvement of 1 child. PMID- 25807193 TI - Gallic Acid Decreases Inflammatory Cytokine Secretion Through Histone Acetyltransferase/Histone Deacetylase Regulation in High Glucose-Induced Human Monocytes. AB - Hyperglycemia contributes to diabetes and several diabetes-related complications. Gallic acid is a polyhydroxy phenolic compound found in various natural products. In this study, we investigated the effects and mechanism of gallic acid on proinflammatory cytokine secretion in high glucose-induced human monocytes (THP-1 cells). THP-1 cells were cultured under normoglycemic or hyperglycemic conditions, in the absence or presence of gallic acid. Hyperglycemic conditions significantly induced histone acetylation, nuclear factor-kappaB (NF-kappaB) activation, and proinflammatory cytokine release from THP-1 cells, whereas gallic acid suppressed NF-kappaB activity and cytokine release. It also significantly reduced CREB-binding protein/p300 (CBP/p300, a NF-kappaB coactivator) gene expression, acetylation levels, and CBP/p300 histone acetyltransferase (HAT) activity. In addition, histone deacetylase 2 (HDAC2) expression was significantly induced. These results suggest that gallic acid inhibits hyperglycemic-induced cytokine production in monocytes through epigenetic changes involving NF-kappaB. Therefore, gallic acid may have potential for the treatment and prevention of diabetes and its complications. PMID- 25807194 TI - Critical practicalities in sampling for mycotoxins in feed. AB - The presence of mycotoxins, in particular aflatoxin B1 , can cause significant health problems as well as severe economic loss, and are therefore regulated with respect to maximum acceptable concentration for various feed- and foodstuffs. International regulatory authorities have recognized the importance of representative sampling, and sampling guidelines that only partly comply with the Theory of Sampling have been formulated. Practical guidance regarding sampling, including correct design and operation of sampling devices and explanations on how to develop sufficient sampling protocols are lacking in current guidelines. These are critical practicalities of main importance, especially when dealing with trace concentrations and/or concentrations that are irregularly distributed, as for mycotoxins. Heterogeneity characterization, which is necessary to be able develop valid sampling protocols or validation assessments of existing sampling operations, is currently not mentioned in the existing guidelines. This paper explains all critical practicalities with respect to sampling of mycotoxins for 1 D and 3-0 feed decision units. Correct design and use of sampling and mass reduction devices, as well as structural guidelines for correctly designing experimental heterogeneity characterizations are presented, allowing evaluation of sampling representativeness and determination of optimal number of increments per composite sample. Practical examples are given on how to extract information from variographic analysis and replication experiments, based on an extensive field trials performed to determine aflatoxin levels in various feed components. PMID- 25807192 TI - Hydrophobic mismatch demonstrated for membranolytic peptides, and their use as molecular rulers to measure bilayer thickness in native cells. AB - Hydrophobic mismatch is a well-recognized principle in the interaction of transmembrane proteins with lipid bilayers. This concept was extended here to amphipathic membranolytic alpha-helices. Nine peptides with lengths between 14 and 28 amino acids were designed from repeated KIAGKIA motifs, and their helical nature was confirmed by circular dichroism spectroscopy. Biological assays for antimicrobial activity and hemolysis, as well as fluorescence vesicle leakage and solid-state NMR spectroscopy, were used to correlate peptide length with membranolytic activity. These data show that the formation of transmembrane pores is only possible under the condition of hydrophobic matching: the peptides have to be long enough to span the hydrophobic bilayer core to be able to induce vesicle leakage, kill bacteria, and cause hemolysis. By correlating the threshold lengths for biological activity with the biophysical results on model vesicles, the peptides could be utilized as molecular rulers to measure the membrane thickness in different cells. PMID- 25807196 TI - Evaluation of mono or mixed cultures of lactic acid bacteria in type II sourdough system. AB - The aim of this study was to evaluate the use of mono and mixed lactic acid bacteria (LAB) cultures to determine suitable LAB combinations for a type II sourdough system. In this context, previously isolated sourdough LAB strains with antimicrobial activity, which included Lactobacillus plantarum PFC22, Lactobacillus brevis PFC31, Pediococcus acidilactici PFC38, and Lactobacillus sanfranciscensis PFC80, were used as mono or mixed culture combinations in a fermentation system to produce type II sourdough, and subsequently in bread dough production. Compared to the monoculture fermentation of dough, the use of mixed cultures shortened the adaptation period by half. In addition, the use of mixed cultures ensured higher microbial viability, and enhanced the fruity flavor during bread dough production. It was determined that the combination of L. plantarum PFC22 + P. acidilactici PFC38 + L. sanfranciscensis PFC80 is a promising culture mixture that can be used in the production of type II sourdough systems, and that may also contribute to an increase in metabolic activity during bread production process. PMID- 25807195 TI - Enhanced D1 and D2 inhibitions induced by low-frequency trains of conditioning stimuli: differential effects on H- and T-reflexes and possible mechanisms. AB - Mechanically evoked reflexes have been postulated to be less sensitive to presynaptic inhibition (PSI) than the H-reflex. This has implications on investigations of spinal cord neurophysiology that are based on the T-reflex. Preceding studies have shown an enhanced effect of PSI on the H-reflex when a train of ~10 conditioning stimuli at 1 Hz was applied to the nerve of the antagonist muscle. The main questions to be addressed in the present study are if indeed T-reflexes are less sensitive to PSI and whether (and to what extent and by what possible mechanisms) the effect of low frequency conditioning, found previously for the H-reflex, can be reproduced on T-reflexes from the soleus muscle. We explored two different conditioning-to-test (C-T) intervals: 15 and 100 ms (corresponding to D1 and D2 inhibitions, respectively). Test stimuli consisted of either electrical pulses applied to the posterior tibial nerve to elicit H-reflexes or mechanical percussion to the Achilles tendon to elicit T reflexes. The 1 Hz train of conditioning electrical stimuli delivered to the common peroneal nerve induced a stronger effect of PSI as compared to a single conditioning pulse, for both reflexes (T and H), regardless of C-T-intervals. Moreover, the conditioning train of pulses (with respect to a single conditioning pulse) was proportionally more effective for T-reflexes as compared to H-reflexes (irrespective of the C-T interval), which might be associated with the differential contingent of Ia afferents activated by mechanical and electrical test stimuli. A conceivable explanation for the enhanced PSI effect in response to a train of stimuli is the occurrence of homosynaptic depression at synapses on inhibitory interneurons interposed within the PSI pathway. The present results add to the discussion of the sensitivity of the stretch reflex pathway to PSI and its functional role. PMID- 25807197 TI - Towards a unified sampling terminology: clarifying misperceptions. AB - International acceptance of data is a much-desired wish in many sectors to ensure equal standards for valid information and data exchange, facilitate trade, support food safety regulation, and promote reliable communication among all parties involved. However, this cannot be accomplished without a harmonized approach to sampling and a joint approach to assess the practical sampling protocols used. Harmonization based on a nonrepresentative protocol, or on a restricted terminology tradition forced upon other sectors would negate any constructive outcome. An international discussion on a harmonized approach to sampling is severely hampered by a plethora of divergent sampling definitions and terms. Different meanings for the same term are frequently used by the different sectors, and even within one specific sector. In other cases, different terms are used for the same concept. Before efforts to harmonize can be attempted, it is essential that all stakeholders can at least communicate effectively in this context. Therefore, a clear understanding of the main vocabularies becomes an essential prerequisite. As a first step, commonalities and dichotomies in terminology are here brought to attention by providing a comparative summary of the. terminology as defined by the Theory of Sampling {TOS) and those in current use by the International Organization for Standardization, the World Health Organization, the Food and Agriculture Organization Codex Alimentarius, and the U.S. Food and Drug Administration. Terms having contradictory meaning to the TOS are emphasized. To the degree possible, we present a successful resolution of some of the most important issues outlined, sufficient to support the objectives of the present Special Section. PMID- 25807198 TI - Multi-organ failure secondary to a Clostridium perfringens gaseous liver abscess following a self-limited episode of acute gastroenteritis. AB - BACKGROUND: Clostridium perfringens is an unusual pathogen responsible for the development of a gas-forming pyogenic liver abscess. Progression to septicemia with this infection has amplified case fatality rates. CASE REPORT: We report a case of an 81-year-old lady with pyogenic liver abscess with gas formation that was preceded by an acute gastroenteritis. The most common precipitating factors are invasive procedures and immunosuppression. Clostridium perfringens was unexpectedly isolated in the drained abscess, as well as blood. It is a normal inhabitant of the human bowel and a common cause of food poisoning, notoriously leading to tissue necrosis and gas gangrene. CONCLUSIONS: We report a case of gas forming pyogenic liver abscess and bacteremia progressing to fatal septic shock, caused by an uncommon Clostridium perfringens isolate. PMID- 25807200 TI - Acanthocephalan Cystacanths from Flatfish (Order Pleuronectiformes) in Tropical Australian Waters. AB - Cystacanths of 4 species of Acanthocephala are reported for the first time from various species of fish belonging to the Order Pleuronectiformes from waters of the western Gulf of Carpentaria and the central coast of Queensland, Australia: Corynosoma cetaceum Johnston and Best, 1942 (Family Polymorphidae), Serrasentis cf. sagittifer (Linton, 1889) and Rhadinorhynchus sp. (Family Rhadinorhynchidae), and Gorgorhynchoides sp. (Family Isthmosacanthidae). Approximately 32% of the 515 individual fish belonging to 24 species were infected with at least 1 cystacanth. Serrasentis cf. sagittifer was the most-commonly encountered, infecting a total of 18 species of fish across both regions. Gorgorhynchoides sp. infected 7 fish species in the Gulf of Carpentaria only while Rhadinorhynchus sp. (1 fish species) and C. cetaceum (7 fish species) were only found on the central coast of Queensland. Most fish were infected with a single cystacanth of any species. There was no relationship between total length of fish and intensity of infection for any species. This paper provides information on parasite infections in fish hosts commonly caught as by-catch and outlines the need for further studies on these fish to be able to determine sustainability of such fish stocks. PMID- 25807201 TI - Painful Erythema and Edema of the Ears. PMID- 25807202 TI - Evaluation of the Dustiness of Different Kaolin Samples. AB - Several samples of kaolin with different mean particle size were prepared and tested using the continuous drop method, one of the reference test methods according to standard EN 15051:2006 "Workplace atmospheres - Measurement of the dustiness of bulk materials - Requirements and reference test methods." On the other hand, with a view to relating the dustiness of the materials to their properties, particle size distribution, specific surface area, and Hausner ratio of these samples were determined. This article presents a characterization of these samples and an assessment of the influence of some material parameters on dustiness. The results show that dustiness may significantly be affected by mean particle size, specific surface area, and Hausner ratio. Moreover, it is highlighted that a detailed study of the influence of fine particles content on the dustiness was carried out. This information is deemed essential for establishing the most efficient preventive and/or corrective measures to reduce the generation of fugitive emissions of particulate matter during kaolin processing, both into the outside atmosphere (air pollution) and inside the facilities (occupational health). PMID- 25807199 TI - Circulating tumor cell isolation during resection of colorectal cancer lung and liver metastases: a prospective trial with different detection techniques. AB - BACKGROUND: Colorectal cancer (CRC) metastasectomy improves survival, however most patient develop recurrences. Circulating tumor cells (CTCs) are an independent prognostic marker in stage IV CRC. We hypothesized that CTCs can be enriched during metastasectomy applying different isolation techniques. METHODS: 25 CRC patients undergoing liver (16 (64%)) or lung (9 (36%)) metastasectomy were prospectively enrolled (clinicaltrial.gov identifier: NCT01722903). Central venous (liver) or radial artery (lung) tumor outflow blood (7.5 ml) was collected at incision, during resection, 30 min after resection, and on postoperative day (POD) 1. CTCs were quantified with 1. EpCAM-based CellSearch(r) system and 2. size-based isolation with a novel filter device (FMSA). CTCs were immunohistochemically identified using CellSearch(r)'s criteria (cytokeratin 8/18/19+, CD45- cells containing a nucleus (DAPI+)). CTCs were also enriched with a centrifugation technique (OncoQuick(r)). RESULTS: CTC numbers peaked during the resection with the FMSA in contrast to CellSearch(r) (mean CTC number during resection: FMSA: 22.56 (SEM 7.48) (p = 0.0281), CellSearch(r): 0.87 (SEM +/- 0.44) (p = 0.3018)). Comparing the 2 techniques, CTC quantity was significantly higher with the FMSA device (range 0-101) than CellSearch(r) (range 0-9) at each of the 4 time points examined (P < 0.05). Immunofluorescence staining of cultured CTCs revealed that CTCs have a combined epithelial (CK8/18/19) and macrophage (CD45/CD14) phenotype. CONCLUSIONS: Blood sampling during CRC metastasis resection is an opportunity to increase CTC capture efficiency. CTC isolation with the FMSA yields more CTCs than the CellSearch(r) system. Future studies should focus on characterization of single CTCs to identify targets for molecular therapy and immune escape mechanisms of cancer cells. PMID- 25807203 TI - Unemotional on all counts: Evidence of reduced affective responses in individuals with high callous-unemotional traits across emotion systems and valences. AB - The current study aimed to identify atypical neurophysiological activity associated with deficient affective processing in individuals with high callous unemotional traits (CU). Fifty-six participants (M age = 20.52; 46% male) divided in two groups, differentiated on levels of CU traits, were invited to participate in the experimental phase of the study. Medial prefrontal cortex activity, measured with functional Near-Infrared Spectroscopy, and facial electro-myography activity were recorded during videos depicting violent, comedy and neutral scenes. Individuals high on CU traits showed similar medial prefrontal cortex oxygenated hemoglobin (HbO(2)) activity to positive and negative films, while the pre-frontal cortical responses of low CU individuals were more pronounced to positive than negative materials. High CU participants also showed reduced facial electromyography at the corrugator muscle in response to violent films, which was not differentiated from their responses to comedy films. These findings suggest that individuals high on CU traits show reduced but not absent (i.e., flat) affect to emotional material. Deficits in processing positive and negative valent material, measured with different neuro-physiological modalities, might be essential to understand CU traits. PMID- 25807204 TI - Animal Personality Relates to Thermal Preference in Wild-Type Zebrafish, Danio rerio. AB - It has been widely supported that individual animals express different strategies to cope with environmental challenge. In ectothermic species such as fish, individuals must use behavioral thermoregulation mechanisms to optimize physiological performance. In the present study, thermal preference was tested in groups of wild-type zebrafish, Danio rerio, screened for proactive and reactive animal personalities. Three replicate groups of proactive, reactive, and naive randomly sampled non-screened controls were used for the experiments. The frequency distribution of the animals was recorded in a custom-built multichamber tank under both constant temperature (temperature restricted conditions: TR) and a continuous thermal gradient profile (temperature choice: TCh ranging from 21 degrees C to 35 degrees C). Proactive and reactive animal personalities expressed significantly different thermal preferences and general activity within the temperature gradient. Our results show that proactive fish, generally characterized as being more aggressive, bold risk takers, and prone to routine formation, have a preference for higher temperature environments. Reactive fish, which are shy, less risk-prone, and more flexible, favor medium colder temperatures. This is the first report of thermopreferendum in zebrafish where individual animal personality coupled to freedom of thermal choice has been applied to understand variation in individual preferences within a population. PMID- 25807205 TI - Platelet interaction with bacterial toxins and secreted products. AB - Bacteria that enter the bloodstream will encounter components of the cellular and soluble immune response. Platelets contribute to this response and have emerged as an important target for bacterial pathogens. Bacteria produce diverse extracellular proteins and toxins that have been reported to modulate platelet function. These interactions can result in complete or incomplete platelet activation or inhibition of platelet activation, depending on the bacteria and bacterial product. The nature of the platelet response may be highly relevant to disease pathogenesis. PMID- 25807206 TI - Escherichia coli O157:H7 in wild boars (Sus scrofa) and Iberian ibex (Capra pyrenaica) sharing pastures with free-ranging livestock in a natural environment in Spain. AB - BACKGROUND: Wild ungulates have greatly increased in abundance and range throughout Europe. This new situation presents a concern for public health because many wild ungulates are known reservoirs of zoonotic pathogens. OBJECTIVES: In this work, we tested for the presence of the zoonotic pathogen Escherichia coli O157:H7 in free-ranging livestock and sympatric wild boars (Sus scrofa) and Iberian ibex (Capra pyrenaica) in NE Spain from 2009 to 2011. In addition, antimicrobial resistance and virulence factors were assessed. ANIMALS AND METHODS: In total, individual fecal samples were obtained from 117 hunter harvested wild boars and 160 Iberian ibexes. Fifty-five samples were obtained from cattle (5 herds, 380 animals in total) and four from the only horse herd in the Natural Park 'Ports de Tortosa i Beseit' (32 animals). Fecal samples were processed according to the ISO 16.654:2001 protocol to obtain E. coli O157 based on immunomagnetic separation. In addition, a multiplex polymerase chain reaction (PCR) targeting nine virulence factors characteristic of human pathotypes was performed. The prevalence was compared between host species with Fisher's exact test. RESULTS: Four wild boars (3.41%, 95% CI = 0.94-8.52) and two Iberian ibexes (1.25%, 95% CI = 0.15-4.4) carried E. coli O157:H7, which was not found in livestock feces (n = 59, 95% CI = 0-8.94). All E. coli O157:H7 isolates were susceptible to all antimicrobial agents tested. CONCLUSIONS: These results indicate that when prevalence in co-habiting livestock is low, wild ungulates do not seem to play an important role as reservoirs of E. coli O157:H7. PMID- 25807207 TI - Hospital cost implications of increased use of minimally invasive surgery. PMID- 25807208 TI - Prevalence and Mean Intensity of Anisakidae Parasite in Seafood Caught in the Mediterranean Sea Focusing on Fish Species at Risk of Being Raw-consumed. A Meta Analysis and Systematic Review. AB - OBJECTIVE: To assess the prevalence and mean intensity of anisakids in seafood caught in the Mediterranean Sea, focusing on fish species at risk of being raw consumed. DESIGN: Systematic review and meta-analysis of studies published from 1960-2012. STUDY SELECTION: Main criteria for the inclusion of studies were as follows: Findings of anisakid larvae, in both muscles and viscera; fish species for human consumption caught in the Mediterranean Sea; prevalence and mean intensity data for each species; and sample size equal to or more than 40 fishes. RESULTS: Twelve studies were identified. Among these, four studies considered the following three fish species that are often consumed raw or preserved lightly, or not cooked thoroughly: anchovy, pilchard, and Atlantic mackerel. DATA SYNTHESIS: All pooled analyses were based on the random-effect model. Anisakids prevalence in fish muscle was 0.64% (P < 0.0001), in viscera it was 1.34% (P < 0.0001), and overall prevalence was 0.95% (P < 0.0001). Mean intensity in muscle was 2.31 (P = 0.0083), in viscera it was 1.55 (P = 0.0174), and overall it was 1.81 (P < 0.0005). Heterogeneity indices (I(2)) were significantly high with the exception of viscera mean intensity. CONCLUSIONS: Anchovy, pilchard, and Atlantic mackerel have a low prevalence and mean intensity of anisakidae larvae in both viscera and muscles. Mean Intensity was also low. PMID- 25807210 TI - Association of Angiotensin-Converting Enzyme ACE Gene Polymorphism with ACE Activity and Susceptibility to Vitiligo in Egyptian Population. AB - AIM: The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with vitiligo in the Indians and Koreans, but not in those of English or Turkish background. We investigated the ACE (I/D) polymorphism in vitiligo patients for the first time in Egypt and compared serum ACE levels between vitiligo patients and controls. The present study was carried out in 100 vitiligo patients (40 males and 60 females) and in 100 healthy controls of an Egyptian population using the polymerase chain reaction genotyping method. RESULTS: The ACE genotype and allele frequency was significantly different between vitiligo patients and controls. Our results revealed a significant increase in the frequency of the ACE I allele (p=0.002; odds ratio: 1.99; 95% confidence intervals: 1.207-3.284) with an overrepresentation of I/D genotype in the vitiligo patient group. Furthermore, there was a significant difference between the segmental, nonsegmental, and focal vitiligo in ACE gene genotype distribution. Serum ACE levels were significantly increased in vitiligo patients compared to controls (p=0.034). CONCLUSION: This study suggests that, for the first time, ACE gene polymorphism confers susceptibility to vitiligo in the Egyptian population. PMID- 25807211 TI - Corrigendum. PMID- 25807209 TI - Rice ubiquitin ligase EL5 prevents root meristematic cell death under high nitrogen conditions and interacts with a cytosolic GAPDH. AB - Root formation in rice transformants overexpressing mutated EL5 (mEL5) was severely inhibited because of meristematic cell death. Cell death was caused by nitrogen sources, particularly nitrate forms, in the culture medium. Nitrite treatment increased the cytokinin contents in roots, but mEL5 contained more cytokinins than non-transformants. Transcriptome profiling showed overlaps between nitrite-responsive genes in non-transformants and genes with altered expression in untreated mEL5. These results indicate that impairment of EL5 function activates nitrogen signaling despite the absence of a nitrogen source. Physical interaction between the EL5 C-terminal region and a cytosolic glyceraldehyde-3-phosphate dehydrogenase, OsGapC2, was demonstrated in vitro and in vivo. Elucidation of the role of glyceraldehyde-3-phosphate dehydrogenase in oxidative cell death in plants is expected in future. PMID- 25807212 TI - A biotic game design project for integrated life science and engineering education. AB - Engaging, hands-on design experiences are key for formal and informal Science, Technology, Engineering, and Mathematics (STEM) education. Robotic and video game design challenges have been particularly effective in stimulating student interest, but equivalent experiences for the life sciences are not as developed. Here we present the concept of a "biotic game design project" to motivate student learning at the interface of life sciences and device engineering (as part of a cornerstone bioengineering devices course). We provide all course material and also present efforts in adapting the project's complexity to serve other time frames, age groups, learning focuses, and budgets. Students self-reported that they found the biotic game project fun and motivating, resulting in increased effort. Hence this type of design project could generate excitement and educational impact similar to robotics and video games. PMID- 25807213 TI - Crosstalk of homocysteinylation, methylation and acetylation on histone H3. AB - Homocysteine (hcy) is an intermediate metabolite in the metabolic pathway of cysteine and methionine. As a non-coded amino acid, hcy is not normally incorporated into protein. However, homocysteine can be recognized and activated by methionyl-tRNA synthetase (MetRs) to produce Hcy-thiolactone (HTL), which can react with the epsilon-amino group of a protein lysine residue. The N-hcy-linked protein carrying a free thiol group can influence protein structure and function, thus leading to severe diseases. Histone has multiple specific dynamic post translational modifications (PTMs), especially on the N-terminal tail of histones enriched with lysine and arginine residues. In this study, we confirmed that histone H3 can be modified by HTL on lysine residue. Relative and absolute quantification methods based on mass spectrometry demonstrated the crosstalk between methylation and acetylation of H3 in response to excess HTL. Overall, our data provide novel insights into histone modifications and the regulatory mechanisms of diseases related to homocysteinylation. PMID- 25807214 TI - Interleukin-17 (IL-17) inhibitors in the treatment of plaque psoriasis: a review. AB - Acting on keratinocytes to produce antimicrobial peptides and chemokines, which in turn attract neutrophils and other inflammatory cells, interleukin-17 (IL-17) is believed to be a potent driver of plaque psoriasis. Its proinflammatory characteristics make IL-17 an attractive therapeutic target for addressing immune dysregulation. This review examines the role of IL-17 in the pathogenesis of plaque psoriasis and the potential implications of its inhibition. The efficacy and safety results from Phase 2 and 3 trials with monoclonal antibodies targeting IL-17RA (brodalumab), and IL-17A (ixekizumab and secukinumab) validate IL-17 as an effective therapeutic target for the treatment of plaque psoriasis. PMID- 25807215 TI - Sinecatechins 10% ointment: a green tea extract for the treatment of external genital warts. AB - External genital warts (EGWs) resulting from the human papilloma virus (HPV) are a common sexually transmitted infection and cause significant impairments in patient quality of life and sexual well-being. Therapeutic options for EGWs can be provider-assisted, but many patients opt for treatment that can be applied at home. Sinecatechins 10% ointment is a new botanically based patient-administered therapy for EGWs. It is comprised of >85% catechins, green tea polyphenols that have been shown to possess antioxidant, antiproliferative, antiviral, and antitumor properties. Phase III trials of sinecatechins 10% ointment have demonstrated higher efficacy and lower recurrence rates compared to currently available patient-applied treatments. Therefore, sinecatechins 10% ointment presents an alternative self-administered topical treatment for EGWs. PMID- 25807216 TI - Computational investigation of drug action on human-induced stem cell-derived cardiomyocytes. AB - We compare experimental and computational results for the actions of the cardioactive drugs Lidocaine, Verapamil, Veratridine, and Bay K 8644 on a tissue monolayer consisting of mainly fibroblasts and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSc-CM). The choice of the computational models is justified and literature data is collected to model drug action as accurately as possible. The focus of this work is to evaluate the validity and capability of existing models for native human cells with respect to the simulation of pharmaceutical treatment of monolayers and hiPSc-CM. From the comparison of experimental and computational results, we derive suggestions for model improvements which are intended to computationally support the interpretation of experimental results obtained for hiPSc-CM. PMID- 25807217 TI - Structure, stability, and properties of the intergrowth compounds ([SnSe]1+delta)m(NbSe2)n, where m = n = 1-20. AB - Intergrowth compounds of ([SnSe]1+delta)m(NbSe2)n, where 1 <= m = n <= 20, with the same atomic composition but different c-axis lattice parameters and number of interfaces per volume were synthesized using the modulated elemental reactant technique. A c-axis lattice parameter change of 1.217(6) nm as a function of one unit of m = n was observed. In-plane X-ray diffraction shows an increase in distortion of the rock salt layer as a function of m and a broadening of the NbSe2 reflections as n increases, indicating the presence of different coordination environments for Nb (trigonal prismatic and octahedral) and smaller crystallite size, which were confirmed via scanning transmission electron microscopy investigations. The electrical resistivities of all 12 compounds exhibit metallic temperature dependence and are similar in magnitude as would be expected for isocompositional compounds. Carrier concentration and mobility of the compounds vary within a narrow range of 2-6 * 10(21) cm(-3) and 2-6 cm(2) V( 1) s(-1), respectively. Even at a thickness of 12 nm for the SnSe and NbSe2 blocks, the properties of the intergrowth compounds cannot be explained as composite behavior, due to significant charge transfer between them. Upon being annealed at 500 degrees C, the higher order m = n compounds were found to convert to the thermodynamically stable phase, the (1,1) compound. This suggests that the capacitive energy of the interfaces stabilizes these intergrowth compounds. PMID- 25807218 TI - Assessing cutoff values for increased exercise blood pressure to predict incident hypertension in a general population. AB - OBJECTIVE: Cutoff values for increased exercise blood pressure (BP) are not established in hypertension guidelines. The aim of the study was to assess optimal cutoff values for increased exercise BP to predict incident hypertension. METHODS: Data of 661 normotensive participants (386 women) aged 25-77 years from the Study of Health in Pomerania (SHIP-1) with a 5-year follow-up were used. Exercise BP was measured at a submaximal level of 100 W and at maximum level of a symptom-limited cycle ergometry test. Cutoff values for increased exercise BP were defined at the maximum sum of sensitivity and specificity for the prediction of incident hypertension. The area under the receiver-operating characteristic curve (AUC) and net reclassification index (NRI) were calculated to investigate whether increased exercise BP adds predictive value for incident hypertension beyond established cardiovascular risk factors. RESULTS: In men, values of 160 mmHg (100 W level; AUC = 0.7837; NRI = 0.534, P < 0.001) and 210 mmHg (maximum level; AUC = 0.7677; NRI = 0.340, P = 0.003) were detected as optimal cutoff values for the definition of increased exercise SBP. A value of 190 mmHg (AUC = 0.8347; NRI = 0.519, P < 0.001) showed relevance for the definition of increased exercise SBP in women at the maximum level. CONCLUSION: According to our analyses, 190 and 210 mmHg are clinically relevant cutoff values for increased exercise SBP at the maximum exercise level of cycle ergometry test for women and men, respectively. In addition, for men, our analyses provided a cutoff value of 160 mmHg for increased exercise SBP at the 100 W level. PMID- 25807220 TI - From dietary factors to drug adherence: approaches to improve understanding and treatment of hypertension. PMID- 25807219 TI - Protective effects of Brassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP: role of AMPK/PPARalpha/UCP2 axis. AB - OBJECTIVES: Renal damage precedes occurrence of stroke in high-sodium/low potassium-fed stroke-prone spontaneously hypertensive rat (SHRSP). We previously reported a marked suppression of uncoupling protein-2 (UCP2) upon high-salt Japanese-style diet in SHRSP kidneys. Vegetable compounds are known to exert protective effects in cardiovascular diseases. We aimed at evaluating the impact of Brassica oleracea sprouts juice toward renal damage in Japanese diet-fed SHRSP and exploring the role of 5'-adenosine monophosphate-activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1 (SIRT1)/peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC1alpha)/peroxisome proliferator activated receptor-alpha (PPARalpha)/UCP2 axis. METHODS: SHRSP received Japanese diet for 4 weeks. A group of SHRSP received Japanese diet and B. oleracea. A third group received Japanese diet, B. oleracea, and PPARalpha inhibitor (GW6471). A group of SHRSP fed with regular diet served as control. RESULTS: Japanese diet induced marked increases of oxidative stress, inflammation, and proteinuria, along with glomerular and tubular damage, as compared with regular diet. A significant suppression of AMPK/UCP2 pathway was observed. Despite Japanese diet feeding, concomitant administration of B. oleracea prevented oxidative stress accumulation, inflammation, renal damage, and proteinuria. All components of the UCP2 regulatory pathway were significantly increased by B. oleracea. Superoxide dismutase 2 and phosphoendothelial nitric oxide synthase were also stimulated. Addition of PPARalpha inhibitor to B. oleracea and Japanese diet significantly reduced the B. oleracea beneficial effects. SBP levels were comparable among the different groups of rats.In vitro, UCP2 inhibition by genipin offset the antioxidant effect of B. oleracea in renal mesangial and proximal tubular cells. CONCLUSION: B. oleracea administration prevented renal damage in salt-loaded SHRSP, independently from SBP, with parallel stimulation of AMPK/SIRT1/PGC1alpha/PPARalpha/UCP2 axis. Stimulation of the latter mechanism may provide relevant renal protective effect and play a therapeutic role in target organ damage progression in hypertension. PMID- 25807221 TI - New pharmacologic interventions to increase cardiac contractility: challenges and opportunities. AB - PURPOSE OF REVIEW: The most extensively studied inotropic agents in patients with heart failure are phosphodiesterase (PDE) 3 inhibitors, which increase contractility by raising intracellular cyclic adenosine monophosphate content. In clinical trials, the inotropic benefits of these agents have been outweighed by an increase in sudden cardiac death. Here, I review recent findings that help explain what are likely to be distinct mechanisms involved in the beneficial and adverse effects of PDE3 inhibition. RECENT FINDINGS: The proapoptotic consequences of PDE3 inhibition are becoming more apparent. Moreover, it has also become clear that individual PDE3 isoforms in cardiac myocytes are selectively regulated to interact with different proteins in different intracellular compartments. The beneficial and adverse effects of PDE3 inhibition may thus be attributable to the inhibition of different isoforms in different intracellular domains. In particular, PDE3A1 has been shown to interact directly with sarcoplasmic/endoplasmic reticulum Ca ATPase (SERCA2) in the sarcoplasmic reticulum through a phosphorylation of a site in its unique N-terminal domain, making it possible that this isoform can be selectively targeted to increase intracellular Ca cycling. SUMMARY: Conventional PDE3 inhibitors target several functionally distinct isoforms of these enzymes. Isoform-selective and/or compartment-selective targeting of PDE3, through its protein-protein interactions, may produce the inotropic benefits of PDE3 inhibition without the adverse consequences. PMID- 25807222 TI - Hormone replacement therapy in heart failure. AB - PURPOSE OF REVIEW: Despite major advances in medical treatments, survival rates of chronic heart failure (CHF) have not significantly changed in the past 50 years, making it imperative to search for novel pathophysiological mechanisms and therapeutic targets. In this article, we summarize the current knowledge regarding the possibility to treat such anabolic deficiencies with hormone replacement therapy (HRT). RECENT FINDINGS: Mounting evidence supports the concept that CHF is a disease characterized not only by excessive neurohormonal activation but also by a reduced anabolic drive that carries functional and prognostic significance. The recent demonstration of overall beneficial effects of HRT in CHF may pave the way to slow the disease progression in patients with coexisting CHF and hormone deficiencies. The hypothesis is to identify a considerable subset of CHF patients also affected with hormone deficiency and to treat them with HRT. SUMMARY: Single or multiple HRT may in theory be performed in CHF. Such a novel approach may improve left ventricular architecture, function, and physical capacity as well as quality of life. Larger randomized, controlled trials are needed to confirm this working hypothesis. PMID- 25807223 TI - Atrial fibrillation ablation and left appendage closure in heart failure patients. AB - PURPOSE OF REVIEW: Patients with atrial fibrillation and heart failure experience an increased morbidity and mortality from the hemodynamic consequences of atrial fibrillation and an increased stroke risk. Consequently, there has been increased attention to procedural alternatives to pharmacologic rhythm control and anticoagulation for stroke prevention. This review aims to evaluate the evidence for atrial fibrillation ablation and left atrial appendage closure in heart failure patients. RECENT FINDINGS: Several randomized control trials and systematic reviews demonstrate the safety and efficacy of atrial fibrillation ablation in patients with heart failure and left ventricular systolic dysfunction. In multiple trials, these patients have shown clinical benefit from atrial fibrillation ablation including improved left ventricular systolic function, quality of life, and clinical heart failure symptoms. The evidence of clinical benefit of atrial fibrillation ablation in heart failure patients with preserved ejection fraction remains limited. Only a handful of randomized controlled trials have been performed evaluating left atrial appendage closure, and there is insufficient data regarding the safety and efficacy of these procedures in heart failure patients. SUMMARY: Atrial fibrillation ablation in heart failure patients remains well tolerated with an overall efficacy comparable to atrial fibrillation ablation in patients without heart failure. There is consistent evidence for the clinical benefit of atrial fibrillation ablation in heart failure patients with left ventricular systolic dysfunction and limited evidence for atrial fibrillation ablation in heart failure patients with preserved ejection fraction. Currently, there is insufficient data regarding the safety and efficacy of left atrial appendage closure devices in heart failure patients. PMID- 25807225 TI - Innovative devices for advanced heart failure: exploring the current state and future direction of device therapies. AB - PURPOSE OF REVIEW: Despite improvements in medical and device therapies for the treatment of heart failure, the incidence and prevalence of heart failure continue to increase. Given the relative stagnation in new pharmacologic therapies, considerable attention has been given in recent years to device therapies to supplement care in patients with advanced heart failure. Recent successful clinical trial results with an angiotensin-neprilysin inhibitor are not expected to change this situation significantly; the drug has been shown to delay, not eliminate, the progression of heart failure. This review focuses on the technologies that are currently in development for the treatment of advanced heart failure. RECENT FINDINGS: Novel devices that involve electrical, neurohormonal or structural remodeling of the heart that can be inserted either percutaneously or with a minimally invasive surgery are currently at various stages of clinical development. All, however, have shown promising clinical results in preclinical and early clinical studies. SUMMARY: Novel device therapies for advanced heart failure continue to show promising clinical results. Randomized controlled trials are still needed to better evaluate their efficacy. Nevertheless, it can be anticipated that at least several of these devices will be among the armamentarium of treatment options for advanced heart failure in the future. PMID- 25807226 TI - Inflammation in cardiac injury, repair and regeneration. AB - PURPOSE OF REVIEW: Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. This manuscript discusses new findings that advanced our understanding of the role of inflammation in cardiac injury and repair. RECENT FINDINGS: Recently published studies have identified interleukin-1alpha and RNA released by necrotic cardiomyocytes as key danger signals that trigger the inflammatory response following infarction. Interleukin-1 promotes activation of a proinflammatory phenotype in leukocytes and fibroblasts, and delays myofibroblast transdifferentiation. Inhibitory lymphocytes play a crucial role in negative regulation of the postinfarction inflammatory response by modulating macrophage and fibroblast phenotype. Cardiac macrophages exhibit significant heterogeneity and phenotypic plasticity and may orchestrate the reparative response following infarction. In neonatal mice, resident embryonic macrophage subpopulations may promote a regenerative response. In contrast, in adult animals replacement of resident macrophage populations with monocyte-derived macrophages may induce inflammation while inhibiting cardiac regeneration. These exciting observations highlight the crucial role of macrophages in cardiac injury and repair, but should be interpreted with caution considering the limitations of murine models of neonatal myocardial injury. SUMMARY: Design of novel strategies to reduce cardiac injury, improve repair and promote regeneration is dependent on understanding of the cell biology of the inflammatory response. PMID- 25807224 TI - Diagnosing and treating the failing right heart. AB - PURPOSE OF REVIEW: Right ventricular failure (RVF) is associated with significant morbidity and mortality. There is an increasing interest in proper assessment of right ventricle (RV) function as well as understanding mechanisms behind RVF. RECENT FINDINGS: Within this article, we discuss the metabolic changes that occur in the RV in response to RVF, in particular, a shift toward glycolysis and increased glutaminolysis. We will detail the advances made in noninvasive imaging in assessing the function of the RV and review the methods to assess right ventricle-pulmonary artery coupling. We lastly investigate the role of new treatment options in the failing RV, such as beta-blocker therapy. SUMMARY: RVF is a complicated entity. Although some inferences on RV function and treatment can be made from our understanding of the left ventricle, the RV has unique features, anatomically, metabolically and embryologically, that require dedicated RV-directed research. PMID- 25807227 TI - Advances in the pathophysiology and treatment of heart failure with preserved ejection fraction. AB - PURPOSE OF REVIEW: With the failure of multiple trials to identify a successful therapy for heart failure with preserved ejection fraction (HFpEF), attention has shifted to defining specific phenotypes within the HFpEF spectrum in an effort to develop a targeted approach to treatment. Here we summarize the most recent studies investigating the pathophysiology and clinical features of HFpEF, and discuss recent clinical trials in the context of developing treatments that look toward the underlying cause of this disorder. RECENT FINDINGS: Advances in basic science and clinical research have further characterized HFpEF, identifying multiple pathophysiological mechanisms that ultimately lead to exercise intolerance and volume overload. The success of small studies focused on specific subsets of the HFpEF population has promoted the concept that there may not be one treatment strategy that can universally be applied to HFpEF. SUMMARY: HFpEF is associated with significant morbidity and mortality and accounts for approximately half of patients with chronic heart failure. HFpEF is a complex disease, encompassing a diverse cohort of patients and marked by the presence of multiple etiological mechanisms. The failure to develop successful therapies for the management of HFpEF may be because of inadequate standardization of the HFpEF diagnosis, overly broad inclusion criteria and inadequate differentiation of disease subtypes. Given the heterogeneity among patients with HFpEF, much of the current research is focused on understanding of pathophysiology and identifying disease phenotypes that may respond to a targeted treatment approach. Several newer approaches, including neprilysin inhibition and device therapy, offer promise for a new era of HFpEF treatment. PMID- 25807230 TI - A single cis-2 regioisomer of ethylene-tethered indene dimer-fullerene adduct as an electron-acceptor in polymer solar cells. AB - A pure cis-2 isomer of indene dimer-based fullerene bis-adduct has been synthesized, isolated and applied to bulk heterojunction solar cells for the first time. The device based on the cis-2 isomer and poly(3-hexylthiophene) exhibited a power conversion efficiency of 2.8%, which is higher than those of the reference devices. PMID- 25807229 TI - A novel pathway producing dimethylsulphide in bacteria is widespread in soil environments. AB - The volatile compound dimethylsulphide (DMS) is important in climate regulation, the sulphur cycle and signalling to higher organisms. Microbial catabolism of the marine osmolyte dimethylsulphoniopropionate (DMSP) is thought to be the major biological process generating DMS. Here we report the discovery and characterization of the first gene for DMSP-independent DMS production in any bacterium. This gene, mddA, encodes a methyltransferase that methylates methanethiol and generates DMS. MddA functions in many taxonomically diverse bacteria including sediment-dwelling pseudomonads, nitrogen-fixing bradyrhizobia and cyanobacteria, and mycobacteria including the pathogen Mycobacterium tuberculosis. The mddA gene is present in metagenomes from varied environments, being particularly abundant in soil environments, where it is predicted to occur in up to 76% of bacteria. This novel pathway may significantly contribute to global DMS emissions, especially in terrestrial environments and could represent a shift from the notion that DMSP is the only significant precursor of DMS. PMID- 25807231 TI - Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury. AB - Interruption of spinal cord (SC) continuity leads to functional loss below the lesion level. The purpose of this study was to evaluate the safety and efficacy of bone marrow nucleated cell (BMNC) and multiple mesenchymal stem cell (MSC) transplantations in spinal cord injury (SCI). A patient with total SC interruption at the Th2-3 level underwent experimental therapy with BMNC and MSC transplantations followed with intensive neurorehabilitation treatment. At admission, 6 h after SCI, the patient was scored ASIA A, had a Th1 sensation level, paraplegia with sphincter palsy, and was without the ability to control trunk movement. Neurophysiology examination showed bilateral axonal damage to the motor and sensory neural fibers with no motor unit potentials or peripheral motor nerve conduction in the lower extremities. The standard therapy had been applied and had not produced any positive results. The patient was treated with autologous BMNCs injected intravenously (3.2*10(9)) and intrathecally (0.5*10(9)) 10 weeks after the SCI and with five rounds of MSCs every 3-4 months (1.3 3.65*10(7)) administered via lumbar puncture. Total number of transplanted MSC cells during the course of treatment was 1.54*10(8). There were no complications related to transplantations and no side effects related to the therapy during 2 years of treatment. The ASIA score improved from A to C/D (from 112 to 231 points). The sensation level expanded from Th1 to L3-4, and the patient's ability to control the body trunk was fully restored. Bladder filling sensation, bladder control, and anal sensation were also restored. Muscle strength in the left lower extremities improved from plegia to deep paresis (1 on the Lovett scale). The patient's ability to move lower extremities against gravity supported by the movements in quadriceps was restored. The patient gained the ability to stand in a standing frame and was able to walk with the support of hip and knee ortheses. Magnetic resonance imaging (MRI) revealed that at the Th2/Th3 level, where the hemorrhagic necrosis was initially observed, small tissue structures appeared. Our results suggest that repeated intrathecal infusions of MSCs might have the potential to produce clinically meaningful improvements for SCI patients. PMID- 25807228 TI - Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy? AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM) have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10 tetraazacyclododecane-NN',N",N'"-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A) which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM. METHODS: 15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68), proliferative activity (Ki67) as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET) imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry. RESULTS: The amount of microglia/macrophages ranged from <10% to >50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns. CONCLUSION: SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM. PMID- 25807233 TI - Theoretical study on the microhydration of atmospherically important carbonyl sulfide in its neutral and anionic forms: bridging the gap between the bulk and finite size microhydrated cluster. AB - Carbonyl sulfide (OCS) is the most abundant and stable sulfur-containing triatomic gas present in the atmosphere that plays an important role in aerosol formation. Structure, energetics, and photoelectron spectral properties of the microhydrated OCS in its neutral and anionic forms have been studied by using the BP86, B3LYP, and MP2 methods. OCS is linear in the neutral state but bent in the anionic state. Water binds with the OCS through a single hydrogen bond (O-H...O) in the OCS-(H2O)n [n = 1-6], whereas binding of OCS(-) with water takes place through single as well as double hydrogen bonds (O-H...S and O-H...O). Energy decomposition analysis shows that electrostatic and exchange energies are the main contributors to the stabilization energy of the microhydrated OCS and OCS(-) clusters. Detachment as well as solvation energies are calculated with different levels of theory and compared with the existing experimental values. Finally, an analytical expression has been used to obtain the bulk value of the detachment and solvation energies from the existing information on the finite size clusters. The present study reveals that hydration increases the detachment energy of the OCS(-) by 3.2 eV. In the absence of experimental bulk values of the detachment and solvation energies for this system, the values obtained by the solvent-number dependent theoretical expression will definitely reduce this gap and may be used for the modeling of the OCS in the atmosphere. PMID- 25807232 TI - Using femtosecond laser to create customized corneal flaps for patients with low and moderate refractive error differing in corneal thickness. AB - This study is designed to evaluate the visual outcomes, accuracy, and predictability of corneal flaps with different thicknesses created by 60-kHz femtosecond laser according to different corneal thicknesses in the patients with low and moderate refractive error. A total of 182 eyes were divided according to the central corneal thickness (470 MUm-499 MUm in Group A, 500 MUm-549 MUm in Group B, and 550 MUm-599 MUm in Group C) and underwent femtosecond laser-assisted LASIK for a target corneal flap thickness (100 MUm for Group A, 110 MUm for Group B, and 120 MUm for Group C). Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and refractive status were examined. The flap thickness of each eye was measured by anterior segment optical coherence tomography (AS-OCT) on 30 points at 1-month follow-up to assess the accuracy and predictability. Postoperatively, at least 75% of eyes had a UDVA of 20/16 or better, less than 2% of eyes lost one line, over 30% of eyes gained one or more lines in CDVA, at least 95% of eyes had astigmatism of less than 0.25 D, all eyes achieved a correction within +/- 1.00 D from the target spherical equivalent refraction. The visual and refractive outcomes did not differ significantly in all groups (P >0.05). The mean flap thickness was 100.36 +/- 4.32 MUm (range: 95 113 MUm) in Group A, 111.64 +/- 3.62 MUm (range: 108-125 MUm) in Group B, and 122.32 +/- 2.88 MUm (range: 112-128 MUm) in Group C. The difference at each measured point among the three groups was significant (P < 0.05). The accuracy and predictability were satisfactory in all three groups. In conclusion, this customized treatment yielded satisfactory clinical outcomes with accurate and predictable flap thickness for patients with low and moderate refractive error. PMID- 25807234 TI - Sex-specific effects of cardiovascular risk factors on endothelium-dependent dilation and endothelin activity in middle-aged women and men. AB - BACKGROUND: Healthy middle-aged postmenopausal women have higher endothelium dependent dilation and lower vasoconstrictor activity of endothelin-1 than men. Whether these sex-specific differences extend to patients with cardiovascular risk factors has not been investigated. The current study aimed to determine whether, in patients with cardiovascular risk factors, sex-specific differences exist in endothelium-dependent dilation and endothelin-1 activity. METHODS: Forearm blood flow responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine, sodium nitroprusside, and the selective endothelin type A receptor blocker BQ-123 in 50 women and 64 men with cardiovascular risk factors. RESULTS: Acetylcholine and sodium nitroprusside induced a significant vasodilation in women and men alike (p < 0.01 for both). Also BQ-123 caused a significant vasodilation (p < 0.001) in both groups. The vasodilator response to acetylcholine was greater in women compared to men; however there were no differences in the response to sodium nitroprusside and BQ 123 (p = NS for both) between the two sex groups. CONCLUSIONS: Middle-aged women with cardiovascular risk factors have significantly higher endothelium-dependent dilation than middle-aged men; however, vascular endothelin 1 activity is similar in the two groups. These findings suggest that the presence of cardiovascular risk factors is associated with sex-specific effects on endothelium-dependent dilation but not on endothelin 1 activity. Further study is needed to confirm our findings and to characterize the mechanisms underlying this sex-specific regulation of endothelial function. PMID- 25807235 TI - Effects of malaria parasite density on blood cell parameters. AB - Changes in blood cell parameters are already a well-known feature of malarial infections. To add to this information, the objective of this study was to investigate the varying effects that different levels of parasite density have on blood cell parameters. Patients diagnosed with malaria at Phobphra Hospital, Tak Province, Thailand between January 1st 2009 and January 1st 2012 were recruited as subjects for data collection. Blood cell parameters of 2,024 malaria-infected patients were evaluated and statistically analyzed. Neutrophil and platelet counts were significantly higher, however, RBC count was significantly lower in patients with P. falciparum infection compared to those with P. vivax infection (p<0.0001). Leukocyte counts were also significantly higher in patients with high parasitemia compared to those with low and moderate parasitemia. In terms of differential leukocyte count, neutrophil count was significantly higher in patients with high parasitemia compared to those with low and moderate parasitemia (p<0.0001). On the other hand, both lymphocyte and monocyte counts were significantly lower in patients with high parasitemia (p<0.0001). RBC count and Hb concentration, as well as platelet count were also significantly reduced (p<0.05) and (p<0.0001), respectively. To summarize, patients infected with different malaria parasites exhibited important distinctive hematological parameters, with neutrophil and eosinophil counts being the two hematological parameters most affected. In addition, patients infected with different malarial densities also exhibited important changes in leukocyte count, platelet count and hemoglobin concentration during the infection. These findings offer the opportunity to recognize and diagnose malaria related anemia, help support the treatment thereof, as well as relieve symptoms of severe malaria in endemic regions. PMID- 25807238 TI - Preparation of fluorescent conjugated polymer fibrous membranes for rapid recognition of aromatic solvents. AB - Fluorescent poly(phenylenevinylene) (PPV)/poly(vinyl alcohol) (PVA) fibrous membrane was prepared via electrospinning of PPV precursor and PVA aqueous solution followed by thermal elimination. Further cross-linking produced the cross-linked membrane PPV/CPVA. Both PPV/PVA and PPV/CPVA membranes were found to have similar morphology and photophysics. These membranes showed a great fluorescence quenching response to aromatic solvents and a much smaller response to other organic solvents. Water also effectively quenched the fluorescence of PPV/PVA but not that of PPV/CPVA. This was attributed to un-cross-linked PVA being able to dissolve in water and the cross-linking improving the resistance of the membrane toward water. The sensing behavior was found to have good reversibility. The contact angle study showed that addition of only about 1% of PPV into the matrix reduced the hydrophilicity of the membrane significantly, suggesting that the PPV chains would be located at the surface of the fibers. X ray photoelectron spectroscopy (XPS) investigation further confirmed such surface enrichment of PPV in the binary polymer blends. The PPV chain on the surface facilitated the pi-pi interaction between the polymer backbones and the aromatic molecules, thus leading to good selectivity and fast response of the two fibrous membranes toward aromatic solvents. PMID- 25807236 TI - Interactions of the gasotransmitters contribute to microvascular tone (dys)regulation in the preterm neonate. AB - BACKGROUND & AIMS: Hydrogen sulphide (H2S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow. METHODS: 90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co oximetry. NO was measured as nitrate and nitrite in urine. H2S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions. RESULTS: No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H2S (p = 0.008, r = 0.28) and an inverse relationship between CO and H2S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented. CONCLUSIONS: The relationships between NO and H2S, and CO and H2S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H2S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based. PMID- 25807237 TI - Chronic lead exposure decreases the vascular reactivity of rat aortas: the role of hydrogen peroxide. AB - We investigated whether exposure to small concentrations of lead alters blood pressure and vascular reactivity. Male Wistar rats were sorted randomly into the following two groups: control (Ct) and treatment with 100 ppm of lead (Pb), which was added to drinking water, for 30 days. Systolic blood pressure (BP) was measured weekly. Following treatment, aortic ring vascular reactivity was assessed. Tissue samples were properly stored for further biochemical investigation. The lead concentration in the blood reached approximately 8 MUg/dL. Treatment increased blood pressure and decreased the contractile responses of the aortic rings to phenylephrine (1 nM-100 mM). Following N-nitro-L arginine methyl ester (L-NAME) administration, contractile responses increased in both groups but did not differ significantly between them. Lead effects on Rmax were decreased compared to control subjects following superoxide dismutase (SOD) administration. Catalase, diethyldithiocarbamic acid (DETCA), and apocynin increased the vasoconstrictor response induced by phenylephrine in the aortas of lead-treated rats but did not increase the vasoconstrictor response in the aortas of untreated rats. Tetraethylammonium (TEA) potentiated the vasoconstrictor response induced by phenylephrine in aortic segments in both groups, but these effects were greater in lead-treated rats. The co-incubation of TEA and catalase abolished the vasodilatory effect noted in the lead group. The present study is the first to demonstrate that blood lead concentrations well below the values established by international legislation increased blood pressure and decreased phenylephrine-induced vascular reactivity. The latter effect was associated with oxidative stress, specifically oxidative stress induced via increases in hydrogen peroxide levels and the subsequent effects of hydrogen peroxide on potassium channels. PMID- 25807239 TI - The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia. AB - RATIONALE: There are conflicting reports describing the effect of macrolide resistance on the presentation and outcomes of patients with Streptococcus pneumoniae pneumonia. OBJECTIVES: We aimed to determine the effect of macrolide resistance on the presentation and outcomes of patients with pneumococcal pneumonia. METHODS: We conducted a retrospective, observational study in the Hospital Clinic of Barcelona of all adult patients hospitalized with pneumonia who had positive cultures for S. pneumoniae from January 1, 2000 to December 31, 2013. Outcomes examined included bacteremia, pulmonary complications, acute renal failure, shock, intensive care unit admission, need for mechanical ventilation, length of hospital stay, and 30-day mortality. MEASUREMENTS AND MAIN RESULTS: Of 643 patients hospitalized for S. pneumoniae pneumonia, 139 (22%) were macrolide resistant. Patients with macrolide-resistant organisms were less likely to have bacteremia, pulmonary complications, and shock, and were less likely to require noninvasive mechanical ventilation. We found no increase in the incidence of acute renal failure, the frequency of intensive care unit admission, the need for invasive ventilatory support, the length of hospital stay, or the 30-day mortality in patients with (invasive or noninvasive) macrolide-resistant S. pneumoniae pneumonia, and no effect on outcomes as a function of whether treatment regimens did or did not comply with current guidelines. CONCLUSIONS: We found no evidence suggesting that patients hospitalized for macrolide-resistant S. pneumoniae pneumonia were more severely ill on presentation or had worse clinical outcomes if they were treated with guideline-compliant versus noncompliant regimens. PMID- 25807240 TI - Differential effects of epidural analgesia on modes of delivery and perinatal outcomes between nulliparous and multiparous women: a retrospective cohort study. AB - BACKGROUND: Epidural analgesia is considered one of the most effective methods for pain relief during labor. However, it is not clear whether similar effects of epidural analgesia on the progression of labor, modes of delivery, and perinatal outcomes exist between nulliparous and multiparous women. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort study was conducted to analyze all deliveries after 37 weeks of gestation, with the exclusion of pregnancies complicated by multiple gestations and fetal anomalies and deliveries without trials of labor; these criteria produced a study population of n=16,852. A multivariable logistic regression model was constructed to control for confounders. In total, 7260 of 10,175 (71.4%) nulliparous and 2987 of 6677 (44.7%) multiparous parturients were administered epidural analgesia. The independent factors for intrapartum epidural analgesia included a low prepregnancy body mass index, genetic amniocentesis, group B streptococcal colonization of the genito-rectal tract, and augmentation and induction of labor. In the nulliparous women, epidural analgesia was a significant risk factor for operative vaginal delivery (adjusted odds ratio [OR] 2.14, 95% confidence interval [CI] 1.80-2.54); however, it was a protective factor against Caesarean delivery (adjusted OR 0.62, 95% CI 0.55-0.69). Epidural analgesia remained a significant risk factor for operative vaginal delivery (adjusted OR 2.17, 95% CI 1.58-2.97) but not for Caesarean delivery (adjusted OR 1.09, 95% CI 0.77-1.55) in the multiparous women. Furthermore, the women who were administered epidural analgesia during the trials of labor had similar rates of adverse perinatal outcomes compared with the women who were not administered epidural analgesia, except that a higher rate of 1-minute Apgar scores less than 7 was noted in the nulliparous women who were administered epidural analgesia. CONCLUSIONS/SIGNIFICANCE: Intrapartum epidural analgesia has differential effects on the modes of delivery between nulliparous and multiparous women, and it is not associated with adverse perinatal outcomes. PMID- 25807241 TI - Compass: clinical evaluation of a new instrument for the diagnosis of glaucoma. AB - AIMS: To evaluate Compass, a new instrument for glaucoma screening and diagnosis that combines scanning ophthalmoscopy, automated perimetry, and eye tracking. MATERIALS AND METHODS: A total of 320 human subjects (200 normal, 120 with glaucoma) underwent full ophthalmological evaluation and perimetric evaluation using the Humphrey SITA standard 24 degrees test (HFA), and the Compass test that consisted of a full-threshold program on the central 24 degrees with a photograph of the central 30 degrees of the retina. A subgroup of normal subjects and glaucoma patients underwent a second Compass test during the same day in order to study test-retest variability. After exclusion of 30 patients due to protocol rules, a database was created to compare the Compass to the HFA, and to evaluate retinal image quality and fixation stability. RESULTS: The difference in mean sensitivity between Compass and HFA was -1.02 +/- 1.55 dB in normal subjects (p<0.001) and -1.01 +/- 2.81 dB in glaucoma (p<0.001). Repeatability SD for the average sensitivity was 1.53 for normal subjects and 1.84 for glaucoma. Test time with the Compass was 634+/-96 s (607+/-78 for normals, 678+/-108 for glaucoma). Compass analysis showed the percentage of fixation within the central 1 degrees was 86.6% in normal subjects, and 79.3% in glaucoma patients. Color image quality was sufficient for diagnostic use in >65% of cases; Image-based diagnosis was in accordance with the initial diagnosis in 85% of the subjects. CONCLUSIONS: Based on preliminary results, Compass showed useful diagnostic characteristics for the study of glaucoma, and combined morphological information with functional data. PMID- 25807242 TI - Antiproliferative Constituents of the Roots of Ethiopian Podocarpus falcatus and Structure Revision of 2alpha-Hydroxynagilactone F and Nagilactone I. AB - Bioassay-guided fractionation using the human colorectal adenocarcinoma (HT-29) cell line of the methanol extract of dried roots of Podocarpus falcatus led to the isolation of two new type C nagilactones, 16-hydroxynagilactone F (1) and 2beta,16-dihydroxynagilactone F (2), and the new totarane-type bisditerpenoid 7beta-hydroxymacrophyllic acid (4), along with the seven known compounds 2beta hydroxynagilactone F (3), macrophyllic acid (5), nagilactone D (6), 15 hydroxynagilactone D (7), nagilactone I (8), inumakiol D (9), and ponasterone A (10). The structures of the new compounds were determined by 1D and 2D NMR, HRESIMS, UV, and IR and by comparison with the reported spectroscopic data of their congeners. The orientation of the C-2 hydroxy group of 3 and 8 was revised to be beta based on evidence from detailed analysis of 1D and 2D NMR data and single-crystal X-ray diffraction studies. Among the isolated compounds, the nagilactones, including the new dilactones 16-hydroxynagilactone F (1) and 2beta,16-dihydroxynagilactone F (2), were the most active (IC50 0.3-5.1 MUM range) against the HT-29 cell line, whereas the bisditerpenoids (4 and 5) and the other known compounds 9 and 10 were inactive. The presence of the bioactive nagilactones in P. falcatus supports its traditional use. PMID- 25807244 TI - Association between increased serum thyrotropin concentration and the oldest old: what do we know? AB - To assess studies that evaluate the relation between serum thyrotropin concentration, very old subjects, and their events. We searched the PubMed, SciELO, and LILACS databases for articles published between 2004 and 2012. Our search was restricted to studies involving humans aged 65 years or older, and written in English, Spanish, or Portuguese. Studies that evaluated the association between elevated serum thyrotropin concentration among elderly subjects with subclinical hypothyroidism were chosen since at least in part they included a subpopulation of individuals aged 80 years and above. Thirteen studies were selected. No significant increase in risk of cardiovascular events, coronary heart disease, or total mortality was observed. Elevated thyrotropin concentration was associated with longevity. More randomized controlled trials are required to better define the potential benefits of elevated thyrotropin concentration in this oldest old population, hormone replacement, and longevity. PMID- 25807243 TI - MHC structure and function - antigen presentation. Part 2. AB - The second part of this review deals with the molecules and processes involved in the processing and presentation of the antigenic fragments to the T-cell receptor. Though the nature of the antigens presented varies, the most significant class of antigens is proteins, processed within the cell to be then recognized in the form of peptides, a mechanism that confers an extraordinary degree of precision to this mode of immune response. The efficiency and accuracy of this system is also the result of the myriad of mechanisms involved in the processing of proteins and production of peptides, in addition to the capture and recycling of alternative sources aiming to generate further diversity in the presentation to T-cells. PMID- 25807245 TI - MHC structure and function - antigen presentation. Part 1. AB - The setting for the occurrence of an immune response is that of the need to cope with a vast array of different antigens from both pathogenic and non-pathogenic sources. When the first barriers against infection and innate defense fail, adaptive immune response enters the stage for recognition of the antigens by means of extremely variable molecules, namely immunoglobulins and T-cell receptors. The latter recognize the antigen exposed on cell surfaces, in the form of peptides presented by the HLA molecule. The first part of this review details the central role played by these molecules, establishing the close connection existing between their structure and their antigen presenting function. PMID- 25807246 TI - Hypodermoclysis: a literature review to assist in clinical practice. AB - The aim of this study was to analyze the information available in the literature about the drugs that can be administered through hypodermoclysis and the resulting impact that this information may have on the routine of the pharmacist working at a hospital. The study was based on a review of the literature. The results showed positive points of the procedure, but little specific information about medications such as routes of administration, standard dilutions, optimal doses, etc. Thus, it was possible to verify that there is no definite information as to the correct way to administer the drugs in this route, even though this is an effective and safe option, according to the literature. The lack of information has a negative impact on the support provided by the pharmacist to the nursing staff to ensure that the drug actually reaches its therapeutic goals safely. PMID- 25807247 TI - Association between participation and compliance with Continuing Medical Education and care production by physicians: a cross-sectional study. AB - OBJECTIVE: Physician participation in Continuing Medical Education programs may be influenced by a number of factors. To evaluate the factors associated with compliance with the Continuing Medical Education requirements at a private hospital, we investigated whether physicians' activity, measured by volumes of admissions and procedures, was associated with obtaining 40 Continuing Medical Education credits (40 hours of activities) in a 12-month cycle. METHODS: In an exclusive and non-mandatory Continuing Medical Education program, we collected physicians' numbers of hospital admissions and numbers of surgical procedures performed. We also analyzed data on physicians' time since graduation, age, and gender. RESULTS: A total of 3,809 credentialed, free-standing, private practice physicians were evaluated. Univariate analysis showed that the Continuing Medical Education requirements were more likely to be achieved by male physicians (odds ratio 1.251; p=0.009) and who had a higher number of hospital admissions (odds ratio 1.022; p<0.001). Multivariate analysis showed that age and number of hospital admissions were associated with achievement of the Continuing Medical Education requirements. Each hospital admission increased the chance of achieving the requirements by 0.4%. Among physicians who performed surgical procedures, multivariate analysis showed that male physicians were 1.3 time more likely to achieve the Continuing Medical Education requirements than female physicians. Each surgical procedure performed increased the chance of achieving the requirements by 1.4%. CONCLUSION: The numbers of admissions and number of surgical procedures performed by physicians at our hospital were associated with the likelihood of meeting the Continuing Medical Education requirements. These findings help to shed new light on our Continuing Medical Education program. PMID- 25807248 TI - Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer. AB - The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP.664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb based therapies and vaccines intended to induce bNAbs. PMID- 25807251 TI - Face averages enhance user recognition for smartphone security. AB - Our recognition of familiar faces is excellent, and generalises across viewing conditions. However, unfamiliar face recognition is much poorer. For this reason, automatic face recognition systems might benefit from incorporating the advantages of familiarity. Here we put this to the test using the face verification system available on a popular smartphone (the Samsung Galaxy). In two experiments we tested the recognition performance of the smartphone when it was encoded with an individual's 'face-average'--a representation derived from theories of human face perception. This technique significantly improved performance for both unconstrained celebrity images (Experiment 1) and for real faces (Experiment 2): users could unlock their phones more reliably when the device stored an average of the user's face than when they stored a single image. This advantage was consistent across a wide variety of everyday viewing conditions. Furthermore, the benefit did not reduce the rejection of imposter faces. This benefit is brought about solely by consideration of suitable representations for automatic face recognition, and we argue that this is just as important as development of matching algorithms themselves. We propose that this representation could significantly improve recognition rates in everyday settings. PMID- 25807249 TI - Attenuation of choroidal neovascularization by histone deacetylase inhibitor. AB - Choroidal neovascularization (CNV) is a blinding complication of age-related macular degeneration that manifests as the growth of immature choroidal blood vessels through Bruch's membrane, where they can leak fluid or hemorrhage under the retina. Here, we demonstrate that the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) can down-regulate the pro-angiogenic hypoxia-inducible factor-1alpha and vascular endothelial growth factor (VEGF), and up-regulate the anti-angiogenic and neuro-protective pigment epithelium derived factor in human retinal pigment epithelial (RPE) cells. Most strikingly, TSA markedly down regulates the expression of VEGF receptor-2 in human vascular endothelial cells and, thus, can knock down pro-angiogenic cell signaling. Additionally, TSA suppresses CNV-associated wound healing response and RPE epithelial-mesenchymal transdifferentiation. In the laser-induced model of CNV using C57Bl/6 mice, systemic administration of TSA significantly reduces fluorescein leakage and the size of CNV lesions at post-laser days 7 and 14 as well as the immunohistochemical expression of VEGF, VEGFR2, and smooth muscle actin in CNV lesions at post-laser day 7. This report suggests that TSA, and possibly HDACi's in general, should be further evaluated for their therapeutic potential for the treatment of CNV. PMID- 25807250 TI - Random mutagenesis identifies a C-terminal region of YopD important for Yersinia type III secretion function. AB - A common virulence mechanism among bacterial pathogens is the use of specialized secretion systems that deliver virulence proteins through a translocation channel inserted in the host cell membrane. During Yersinia infection, the host recognizes the type III secretion system mounting a pro-inflammatory response. However, soon after they are translocated, the effectors efficiently counteract that response. In this study we sought to identify YopD residues responsible for type III secretion system function. Through random mutagenesis, we identified eight Y. pseudotuberculosis yopD mutants with single amino acid changes affecting various type III secretion functions. Three severely defective mutants had substitutions in residues encompassing a 35 amino acid region (residues 168-203) located between the transmembrane domain and the C-terminal putative coiled-coil region of YopD. These mutations did not affect regulation of the low calcium response or YopB-YopD interaction but markedly inhibited MAPK and NFkappaB. [corrected] activation. When some of these mutations were introduced into the native yopD gene, defects in effector translocation and pore formation were also observed. We conclude that this newly identified region is important for YopD translocon function. The role of this domain in vivo remains elusive, as amino acid substitutions in that region did not significantly affect virulence of Y. pseudotuberculosis in orogastrically-infected mice. PMID- 25807253 TI - Low-dose ionizing radiation rapidly affects mitochondrial and synaptic signaling pathways in murine hippocampus and cortex. AB - The increased use of radiation-based medical imaging methods such as computer tomography is a matter of concern due to potential radiation-induced adverse effects. Efficient protection against such detrimental effects has not been possible due to inadequate understanding of radiation-induced alterations in signaling pathways. The aim of this study was to elucidate the molecular mechanisms behind learning and memory deficits after acute low and moderate doses of ionizing radiation. Female C57BL/6J mice were irradiated on postnatal day 10 (PND10) with gamma doses of 0.1 or 0.5 Gy. This was followed by evaluation of the cellular proteome, pathway-focused transcriptome, and neurological development/disease-focused miRNAome of hippocampus and cortex 24 h postirradiation. Our analysis showed that signaling pathways related to mitochondrial and synaptic functions were changed by acute irradiation. This may lead to reduced mitochondrial function paralleled by enhanced number of dendritic spines and neurite outgrowth due to elevated long-term potentiation, triggered by increased phosphorylated CREB. This was predominately observed in the cortex at 0.1 and 0.5 Gy and in the hippocampus only at 0.5 Gy. Moreover, a radiation induced increase in the expression of several neural miRNAs associated with synaptic plasticity was found. The early changes in signaling pathways related to memory formation may be associated with the acute neurocognitive side effects in patients after brain radiotherapy but might also contribute to late radiation induced cognitive injury. PMID- 25807254 TI - Synthesis of the Tetrasaccharide Repeating Unit from Acinetobacter baumannii Serogroup O18 Capitalizing on Phosphorus-Containing Leaving Groups. AB - The first convergent synthesis of the tetrasaccharide repeating unit of the polymeric O antigen isolated from Acinetobacter baumannii serogroup O18 has been achieved. The ManNAcbeta1->4Gal and GalNAcbeta1->3Gal units were successfully obtained through beta-selective glycosylation with 2-azido-4,6-O-benzylidene-2 deoxymannosyl diphenyl phosphate and Tf2NH-promoted glycosylation with 2 acetamido-2-deoxygalactosyl diethyl phosphite, respectively. The disaccharide units could be coupled with the aid of TMSClO4 as an activator of the diphenyl phosphate leaving group, and global deprotection completed the synthesis of the tetrasaccharide. PMID- 25807255 TI - Correction: Adeno-associated viral vector serotype 5 poorly transduces liver in rat models. PMID- 25807252 TI - The type 3 adenylyl cyclase is required for the survival and maturation of newly generated granule cells in the olfactory bulb. AB - The type 3 adenylyl cyclase (AC3) is localized to olfactory cilia in the main olfactory epithelium (MOE) and primary cilia in the adult mouse brain. Although AC3 has been strongly implicated in odor perception and olfactory sensory neuron (OSN) targeting, its role in granule cells (GCs), the most abundant interneurons in the main olfactory bulb (MOB), remains largely unknown. Here, we report that the deletion of AC3 leads to a significant reduction in the size of the MOB as well as the level of adult neurogenesis. The cell proliferation and cell cycle in the subventricular zone (SVZ), however, are not suppressed in AC3-/- mice. Furthermore, AC3 deletion elevates the apoptosis of GCs and disrupts the maturation of newly formed GCs. Collectively, our results identify a fundamental role for AC3 in the development of adult-born GCs in the MOB. PMID- 25807256 TI - Correction: Profiling cellular protein complexes by proximity ligation with dual tag microarray readout. PMID- 25807257 TI - Cathelicidin-BF, a Novel Antimicrobial Peptide from Bungarus fasciatus, Attenuates Disease in a Dextran Sulfate Sodium Model of Colitis. AB - Antimicrobial peptides are molecules of innate immunity. Cathelicidin-BF is the first cathelicidin peptide found in reptiles. However, the immunoregulatory and epithelial barrier protective properties of C-BF have not been reported. Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, can lead to colon cancer, the third most common malignant tumor. The objective is to develop the new found cathelicidin-BF as a therapeutic to patients of ulcerative colitis. The morphology of the colon epithelium was observed by H&E staining; apoptosis index and infiltration of inflammatory cells in colonic epithelium were measured by TUNEL and immunohistochemistry; the expression level of endogenous mCRAMP was analyzed by immunofluorescence; and phosphorylation of the transcription factors c-jun and NF-kappaB in colon were analyzed by Western blot. Our results showed that the morphology of the colon epithelium in the C BF+DSS group was improved compared with the DSS group. Apoptosis and infiltration of inflammatory cells in colonic epithelium were also significantly attenuated in the C-BF+DSS group compared with the DSS group, and the expression level of endogenous mCRAMP in the DSS group was significantly higher than other groups. DSS-induced phosphorylation level of c-jun and NF-kappaB while C-BF effectively inhibited phosphorylation of NF-kappaB (p65). The barrier protective effect of C BF was still excellent. In conclusion, C-BF effectively attenuated inflammation and improved disrupted barrier function. Notably, this is the first report to demonstrate that C-BF attenuates DSS-induced UC both through the regulation of intestinal immune and retention of barrier function, and the exact pathway was through NF-kappaB. PMID- 25807258 TI - Hospital mental health admissions in women after unsuccessful infertility treatment and in vitro fertilization: an Australian population-based cohort study. AB - OBJECTIVE: To examine the association between in vitro fertilization (IVF) and later admission to hospital with a mental health diagnosis in women who remained childless after infertility treatment. METHODS: This was a population-based cohort study using linked administrative hospital and registry data. The study population included all women commencing hospital treatment for infertility in Western Australia between the years 1982 and 2002 aged 20-44 years at treatment commencement who did not have a recorded birth by the end of follow-up (15 August 2010) and did not have a hospital mental health admission prior to the first infertility admission (n=6,567). Of these, 2,623 women had IVF and 3,944 did not. We used multivariate Cox regression modeling of mental health admissions and compared women undergoing IVF treatment with women having infertility treatment but not IVF. RESULTS: Over an average of 17 years of follow-up, 411 women in the cohort were admitted to hospital with a mental health diagnosis; 93 who had IVF and 318 who did not. The unadjusted hazard ratio (HR) for a hospital mental health admission comparing women who had IVF with those receiving other infertility treatment was 0.50 (95% confidence interval [CI] 0.40-0.63). After adjustment for age, calendar year and socio-economic status the HR was 0.56 (95% CI 0.44-0.71). CONCLUSIONS: IVF treatment is associated with a reduced risk of hospital mental health admissions in women after unsuccessful infertility treatment. This may be explained by the healthy cohort effect. PMID- 25807260 TI - Correction: Staphylococcus aureus manganese transport protein C (MntC) is an extracellular matrix- and plasminogen-binding protein. PMID- 25807259 TI - Sex differences in peripheral mu-opioid receptor mediated analgesia in rat orofacial persistent pain model. AB - Unilateral ligation of the tendon of anterior superficial part of rat masseter muscle (TASM) leads to long-lasting allodynia. Sex differences in peripheral mu opioid receptor (MOR)-mediated analgesia under persistent myogenic pain are not well understood. In this study, we examined (1) whether locally applied MOR agonists attenuate persistent pain following TASM ligation in a sex dependent manner, (2) whether there are sex differences of MOR expression changes in rat trigeminal ganglia (TG). The effects of MOR agonist, D-Ala2, N-Me-Phe4, Gly5-ol] Enkephalin acetate salt (DAMGO), were assessed 14 days after TASM ligation in male, female and orchidectomized (GDX) male rats. MOR mRNA and protein levels in TG 14 days following tendon ligation were also determined. The mechanical thresholds of the injured side were significantly decreased in both male and female rats, from 3 days to 28 days after TASM ligation. A10 MUg DAMGO significantly attenuated allodynia in male rats. A 10-fold higher dose of DAMGO was required in female and GDX male rats to produce the level of anti- allodynia achieved in male rats. The level of MOR mRNA in TG from male rats was significantly greater 14 days after TASM ligation compared with the sham-operated male rats, but not from female and GDX male rats. After TASM ligation, males had significantly more MOR immunoreactivity in TG compared to sham-operated males. The MOR levels increased to 181.8% of the sham level in male rats receiving tendon injury. But there was no significant change in female rats receiving tendon injury compared to the sham female rats. Taken together, our data suggest that there were sex differences in the effects of peripheral MOR agonists between male and female rats under TASM ligation developing long-lasting pain condition, which is partly mediated by sex differences in the changes of MOR expressions and testosterone is an important factor in the regulation of MOR. PMID- 25807261 TI - Discovery of benzo[f]indole-4,9-dione derivatives as new types of anti inflammatory agents. AB - Certain benzo[f]indole-4,9-dione derivatives were synthesized and evaluated for their inhibitory effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. Results indicated that (Z)-1-benzyl-4-(hydroxyimino)-1H benzo[f]indol-9(4H)-one (10) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 value of 2.78 and 2.74 MUM respectively. The action mechanisms of 10 in human neutrophils were further investigated. Our results showed that compound 10 did not alter fMLF-induced phosphorylation of Src (Src family Y416). Notably, phosphorylation of Akt (S473) and mobilization of [Ca2+]i caused by fMLF was inhibited by compound 10. Further structural optimization of 10 is ongoing. PMID- 25807262 TI - The potential of the combination of CRISPR/Cas9 and pluripotent stem cells to provide human organs from chimaeric pigs. AB - Clinical organ allotransplantation is limited by the availability of deceased human donors. However, the transplantation of human organs produced in other species would provide an unlimited number of organs. The pig has been identified as the most suitable source of organs for humans as organs of any size would be available. Genome editing by RNA-guided endonucleases, also known as clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), in combination with induced pluripotent stem cells (iPSC), may have the potential to enable the creation of human organs from genetically-modified chimaeric pigs. These could potentially provide an unlimited supply of organs that would not be rejected by the recipient's immune system. However, substantial research is needed to prove that this approach will work. Genetic modification of chimaeric pigs could also provide useful models for developing therapies for various human diseases, especially in relation to drug development. PMID- 25807263 TI - Amniotic fluid embolism pathophysiology suggests the new diagnostic armamentarium: beta-tryptase and complement fractions C3-C4 are the indispensable working tools. AB - Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word "AFE" was searched singularly and associated individually to each of the other keywords. Of the 146 sources found, only 19 were considered appropriate for the purpose of this paper. The clinical course is characterized by a rapid onset of symptoms, which include: acute hypotension and/or cardiac arrest, acute hypoxia (with dyspnoea, cyanosis and/or respiratory arrest), coagulopathies (disseminated intravascular coagulation and/or severe hemorrhage), coma and seizures. The pathology still determines a significant morbidity and mortality and potential permanent neurological sequelae for surviving patients. At this moment, numerous aspects involving the pathophysiology and clinical development are still not understood and several hypotheses have been formulated, in particular the possible role of anaphylaxis and complement. Moreover, the detection of serum tryptase and complement components and the evaluation of fetal antigens can explain several aspects of immune response. PMID- 25807265 TI - Activity analysis and preliminary inducer screening of the chicken DAZL gene promoter. AB - This study was aimed at identifying the active control area of chicken DAZL gene core promoter, to screen optimum inducers of the DAZL gene, thus to enhance the differentiation of embryonic stem cells into spermatogonial stem cells. Fragments of chicken DAZL gene promoter were cloned into fluorescent reporter plasmids and transfected into DF-1 cells. Then Dual-Luciferase(r) Reporter Assay System was used to identify the activity of the DAZL gene under different inducers. Our studies showed that the DAZL core promoter region for the Suqin yellow chicken was -383 to -39 bp. The dual-luciferase(r) reporter showed that all-trans retinoic acid (ATRA), a retinoic acid receptor alpha agonist (tamibarotene/Am80), or estradiol (E2) could significantly enhance DAZL transcription. The in vitro inductive culture of chicken ESCs demonstrated that, with ATRA treatment, DAZL transcription peaked at 6 days and then decreased slowly; whereas, DAZL transcription was continuous and peaked at 10 days with Am80 treatment. E2 treatment significantly increased DAZL expression after 8 days. All three treatments were associated with the appearance of male germ cell (MGC)-like cells on day 10. These results provide the optimum inducer screening of the DAZL gene and lay the foundation for further screening of compounds that can induce the differentiation of ESCs into MGCs in vitro. PMID- 25807266 TI - Coronary artery calcium screening: does it perform better than other cardiovascular risk stratification tools? AB - Coronary artery calcium (CAC) has been advocated as one of the strongest cardiovascular risk prediction markers. It performs better across a wide range of Framingham risk categories (6%-10% and 10%-20% 10-year risk categories) and also helps in reclassifying the risk of these subjects into either higher or lower risk categories based on CAC scores. It also performs better among population subgroups where Framingham risk score does not perform well, especially young subjects, women, family history of premature coronary artery disease and ethnic differences in coronary risk. The absence of CAC is also associated with excellent prognosis, with 10-year event rate of 1%. Studies have also compared with other commonly used markers of cardiovascular disease risk such as Carotid intima-media thickness and highly sensitive C-reactive protein. CAC also performs better compared with carotid intima-media thickness and highly sensitive C reactive protein in prediction of coronary heart disease and cardiovascular disease events. CAC scans are associated with relatively low radiation exposure (0.9-1.1 mSv) and provide information that can be used not only for risk stratification but also can be used to track the progression of atherosclerosis and the effects of statins. PMID- 25807264 TI - Aminoacyl-tRNA synthetase complexes in evolution. AB - Aminoacyl-tRNA synthetases are essential enzymes for interpreting the genetic code. They are responsible for the proper pairing of codons on mRNA with amino acids. In addition to this canonical, translational function, they are also involved in the control of many cellular pathways essential for the maintenance of cellular homeostasis. Association of several of these enzymes within supramolecular assemblies is a key feature of organization of the translation apparatus in eukaryotes. It could be a means to control their oscillation between translational functions, when associated within a multi-aminoacyl-tRNA synthetase complex (MARS), and nontranslational functions, after dissociation from the MARS and association with other partners. In this review, we summarize the composition of the different MARS described from archaea to mammals, the mode of assembly of these complexes, and their roles in maintenance of cellular homeostasis. PMID- 25807268 TI - Higher PBDE serum concentrations may be associated with feline hyperthyroidism in Swedish cats. AB - Serum from 82 individual cats was analyzed for decabromobiphenyl (BB-209), polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and 2,4,6 TBP in order to study differences in body burden between healthy and sick cats diagnosed with Feline Hyperthyroidism (FH). Within the study group, 60 of these cats had a euthyroid (n = 23) or hyperthyroid (n = 37) status, all of which were used in the comparison. This study shows that hyperthyroid compared to euthyroid cats have higher serum concentrations for some of the investigated PBDEs (BDE-99, BDE-153, and BDE-183) and CB-153 on a fat weight basis. Further, it is intriguing, and beyond explanation, why the flame retardant BB-209 (discontinued in 2000) is present in all of the cat serum samples in concentrations similar to BDE-209. Median BDE-47/-99 ratios are 0.47 and 0.32 for healthy and euthyroid cats, respectively, which differs significantly from Swedes, where the ratio is 3.5. Another important finding is the occurrence of very low levels or the absence of hydroxylated PBDE metabolites in the cats. In addition, the major OH PBDE, 6-OH-BDE47, is likely of natural origin, probably ingested via cat food. The statistics indicate an association between elevated PBDE concentrations in the cats and FH. PMID- 25807267 TI - Structural dynamics and thermostabilization of neurotensin receptor 1. AB - The neurotensin receptor NTSR1 binds the peptide agonist neurotensin (NTS) and signals preferentially via the Gq protein. Recently, Grisshammer and co-workers reported the crystal structure of a thermostable mutant NTSR1-GW5 with NTS bound. Understanding how the mutations thermostabilize the structure would allow efficient design of thermostable mutant GPCRs for protein purification, and subsequent biophysical studies. Using microsecond scale molecular dynamics simulations (4 MUs) of the thermostable mutant NTSR1-GW5 and wild type NTSR1, we have elucidated the structural and energetic factors that affect the thermostability and dynamics of NTSR1. The thermostable mutant NTSR1-GW5 is found to be less flexible and less dynamic than the wild type NTSR1. The point mutations confer thermostability by improving the interhelical hydrogen bonds, hydrophobic packing, and receptor interactions with the lipid bilayer, especially in the intracellular regions. During MD, NTSR1-GW5 becomes more hydrated compared to wild type NTSR1, with tight hydrogen bonded water clusters within the transmembrane core of the receptor, thus providing evidence that water plays an important role in improving helical packing in the thermostable mutant. Our studies provide valuable insights into the stability and functioning of NTSR1 that will be useful in future design of thermostable mutants of other peptide GPCRs. PMID- 25807269 TI - Gaining insights into the codon usage patterns of TP53 gene across eight mammalian species. AB - TP53 gene is known as the "guardian of the genome" as it plays a vital role in regulating cell cycle, cell proliferation, DNA damage repair, initiation of programmed cell death and suppressing tumor growth. Non uniform usage of synonymous codons for a specific amino acid during translation of protein known as codon usage bias (CUB) is a unique property of the genome and shows species specific deviation. Analysis of codon usage bias with compositional dynamics of coding sequences has contributed to the better understanding of the molecular mechanism and the evolution of a particular gene. In this study, the complete nucleotide coding sequences of TP53 gene from eight different mammalian species were used for CUB analysis. Our results showed that the codon usage patterns in TP53 gene across different mammalian species has been influenced by GC bias particularly GC3 and a moderate bias exists in the codon usage of TP53 gene. Moreover, we observed that nature has highly favored the most over represented codon CTG for leucine amino acid but selected against the ATA codon for isoleucine in TP53 gene across all mammalian species during the course of evolution. PMID- 25807270 TI - The mechanism of slow hot-hole cooling in lead-iodide perovskite: first principles calculation on carrier lifetime from electron-phonon interaction. AB - We report on an analysis of hot-carrier lifetimes from electron-phonon interaction in lead iodide perovskites using first-principles calculations. Our calculations show that the holes in CsPbI3 have very long lifetimes in the valence band region situated 0.6 eV below the top of the valence band. On the other hand, no long lifetime is predicted in PbI3(-). These different results reflect the different electronic density of states (DOSs) in the valence bands, that is, a small DOS for the former structure while a sharp DOS peak for the latter structure. We propose a reduction of the relaxation paths in the small valence DOS as being the origin of the slow hot-hole cooling. Analyzing the generalized Eliashberg functions, we predict that different perovskite A-site cations do not have an impact on the carrier decay mechanism. The similarity between the DOS structures of CsPbI3 and CH3NH3PbI3 enables us to extend the description of the decay mechanism of fully inorganic CsPbI3 to its organic inorganic counterpart, CH3NH3PbI3. PMID- 25807271 TI - An in vivo study on brain microstructure in biological and chronological ageing. AB - This study aimed to investigate whether magnetization transfer imaging (MTI) parameters of cortical gray and white matter and subcortical gray matter structures differ between subjects enriched for human familial longevity and control subjects to provide a thorough description of the brain phenotype of familial longevity. Moreover, we aimed to describe cerebral ageing effects on MTI parameters in an elderly cohort. All subjects were included from the Leiden Longevity Study and underwent 3 Tesla MTI of the brain. In total, 183 offspring of nonagenarian siblings, who are enriched for familial factors of longevity, were contrasted with 163 environmentally and age-matched controls. No differences in cortical and subcortical gray matter and white matter MTI parameters were found between offspring and control subjects using histogram-based and voxel-wise analyses. Cortical gray matter and white matter MTI parameters decreased with increasing chronological age (all p < 0.001). Decrease of white matter magnetization transfer ratio (MTR) was homogeneous throughout the whole mean white matter skeleton except for parts of the callosal splenium and partly the posterior limb of the internal capsule and superior region of the corona radiata (p < 0.05). Mean MTR of subcortical gray matter structures decreased with increasing age (p amygdala, caudate nucleus and putamen < 0.001; p pallidum = 0.001, p thalamus = 0.002). In conclusion, the brain phenotype of human familial longevity is - at a mean age of 66 years - not characterized by preserved macromolecular brain tissue integrity. PMID- 25807274 TI - A new lattice Monte Carlo simulation for dielectric saturation in ion-containing liquids. AB - We develop a new, rapid method for the lattice Monte Carlo simulation of ion containing liquids that accounts for the effects of the reorganization of solvent dipoles under external electrostatic fields. Our results are in reasonable agreement with the analytical solutions to the dielectric continuum theory of Booth for single ions, ion pairs, and ionic cross-links. We also illustrate the substantial disparity between the dielectric functions for like and unlike charges on the nanometer scale. Our simulation rationalizes the experimental data for the dependence of the bulk dielectric value of water on ion concentrations in terms of saturated dipoles near ions. PMID- 25807273 TI - Juxtaposition of system dynamics and agent-based simulation for a case study in immunosenescence. AB - Advances in healthcare and in the quality of life significantly increase human life expectancy. With the aging of populations, new un-faced challenges are brought to science. The human body is naturally selected to be well-functioning until the age of reproduction to keep the species alive. However, as the lifespan extends, unseen problems due to the body deterioration emerge. There are several age-related diseases with no appropriate treatment; therefore, the complex aging phenomena needs further understanding. It is known that immunosenescence is highly correlated to the negative effects of aging. In this work we advocate the use of simulation as a tool to assist the understanding of immune aging phenomena. In particular, we are comparing system dynamics modelling and simulation (SDMS) and agent-based modelling and simulation (ABMS) for the case of age-related depletion of naive T cells in the organism. We address the following research questions: Which simulation approach is more suitable for this problem? Can these approaches be employed interchangeably? Is there any benefit of using one approach compared to the other? Results show that both simulation outcomes closely fit the observed data and existing mathematical model; and the likely contribution of each of the naive T cell repertoire maintenance method can therefore be estimated. The differences observed in the outcomes of both approaches are due to the probabilistic character of ABMS contrasted to SDMS. However, they do not interfere in the overall expected dynamics of the populations. In this case, therefore, they can be employed interchangeably, with SDMS being simpler to implement and taking less computational resources. PMID- 25807272 TI - Neutral and adaptive drivers of microgeographic genetic divergence within continuous populations: the case of the neotropical tree Eperua falcata (Aubl.). AB - BACKGROUND: In wild plant populations, genetic divergence within continuous stands is common, sometimes at very short geographical scales. While restrictions to gene flow combined with local inbreeding and genetic drift may cause neutral differentiation among subpopulations, microgeographical variations in environmental conditions can drive adaptive divergence through natural selection at some targeted loci. Such phenomena have recurrently been observed in plant populations occurring across sharp environmental boundaries, but the interplay between selective processes and neutral genetic divergence has seldom been studied. METHODS: We assessed the extent of within-stand neutral and environmentally-driven divergence in the Neotropical tree Eperua falcate Aubl. (Fabaceae) through a genome-scan approach. Populations of this species grow in dense stands that cross the boundaries between starkly contrasting habitats. Within-stand phenotypic and candidate-gene divergence have already been proven, making this species a suitable model for the study of genome-wide microgeographic divergence. Thirty trees from each of two habitats (seasonally flooded swamps and well-drained plateaus) in two separate populations were genotyped using thousands of AFLPs markers. To avoid genotyping errors and increase marker reliability, each sample was genotyped twice and submitted to a rigorous procedure for data cleaning, which resulted in 1196 reliable and reproducible markers. RESULTS: Despite the short spatial distances, we detected within-populations genetic divergence, probably caused by neutral processes, such as restrictions in gene flow. Moreover, habitat-structured subpopulations belonging to otherwise continuous stands also diverge in relation to environmental variability and habitat patchiness: we detected convincing evidence of divergent selection at the genome-wide level and for a fraction of the analyzed loci (comprised between 0.25% and 1.6%). Simulations showed that the levels of differentiation for these outliers are compatible with scenarios of strong divergent selection. PMID- 25807275 TI - Home range use and movement patterns of non-native feral goats in a tropical island montane dry landscape. AB - Advances in wildlife telemetry and remote sensing technology facilitate studies of broad-scale movements of ungulates in relation to phenological shifts in vegetation. In tropical island dry landscapes, home range use and movements of non-native feral goats (Capra hircus) are largely unknown, yet this information is important to help guide the conservation and restoration of some of the world's most critically endangered ecosystems. We hypothesized that feral goats would respond to resource pulses in vegetation by traveling to areas of recent green-up. To address this hypothesis, we fitted six male and seven female feral goats with Global Positioning System (GPS) collars equipped with an Argos satellite upload link to examine goat movements in relation to the plant phenology using the Normalized Difference Vegetation Index (NDVI). Movement patterns of 50% of males and 40% of females suggested conditional movement between non-overlapping home ranges throughout the year. A shift in NDVI values corresponded with movement between primary and secondary ranges of goats that exhibited long-distance movement, suggesting that vegetation phenology as captured by NDVI is a good indicator of the habitat and movement patterns of feral goats in tropical island dry landscapes. In the context of conservation and restoration of tropical island landscapes, the results of our study identify how non-native feral goats use resources across a broad landscape to sustain their populations and facilitate invasion of native plant communities. PMID- 25807276 TI - Analysis of pharmacogenomic variants associated with population differentiation. AB - In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding. PMID- 25807278 TI - Artificial nacre-like papers based on noncovalent functionalized boron nitride nanosheets with excellent mechanical and thermally conductive properties. AB - Inspired by the nano/microscale hierarchical structure and the precise inorganic/organic interface of natural nacre, we fabricated artificial nacre-like papers based on noncovalent functionalized boron nitride nanosheets (NF-BNNSs) and poly(vinyl alcohol) (PVA) via a vacuum-assisted self-assembly technique. The artificial nacre-like papers exhibit excellent tensile strength (125.2 MPa), on a par with that of the natural nacre, and moreover display a 30% higher toughness (2.37 MJ m(-3)) than that of the natural nacre. These excellent mechanical properties result from an ordered 'brick-and-mortar' arrangement of NF-BNNSs and PVA, in which the long-chain PVA molecules act as the bridge to link NF-BNNSs via hydrogen bonds. The resulting papers also render high thermal conductivity (6.9 W m(-1) K(-1)), and reveal their superiority as flexible substrates to support light-emitting-diode chips. The combined mechanical and thermal properties make the materials highly desirable as flexible substrates for next-generation commercial portable electronics. PMID- 25807277 TI - Laparoscopic manipulation of a probe-based confocal laser endomicroscope using a steerable intravascular catheter. AB - Probe-based confocal laser endomicroscopy is an emerging imaging modality that enables visualization of histologic details during endoscopy and surgery. A method of guiding the probe with millimeter accuracy is required to enable imaging in all regions of the abdomen accessed during laparoscopy. On the basis of a porcine model of laparoscopic liver resection, we report our experience of using a steerable intravascular catheter to guide a probe-based confocal laser endomicroscope. PMID- 25807279 TI - Nanostructured pseudocapacitive materials decorated 3D graphene foam electrodes for next generation supercapacitors. AB - Nowadays, advancement in performance of proficient multifarious electrode materials lies conclusively at the core of research concerning energy storage devices. To accomplish superior capacitance performance the requirements of high capacity, better cyclic stability and good rate capability can be expected from integration of electrochemical double layer capacitor based carbonaceous materials (high power density) and pseudocapacitive based metal hydroxides/oxides or conducting polymers (high energy density). The envisioned three dimensional (3D) graphene foams are predominantly advantageous to extend potential applicability by offering a large active surface area and a highly conductive continuous porous network for fast charge transfer with decoration of nanosized pseudocapacitive materials. In this article, we review the latest methodologies and performance evaluation for several 3D graphene based metal oxides/hydroxides and conducting polymer electrodes with improved electrochemical properties for next-generation supercapacitors. The most recent research advancements of our and other groups in the field of 3D graphene based electrode materials for supercapacitors are discussed. To assess the studied materials fully, a careful interpretation and rigorous scrutiny of their electrochemical characteristics is essential. Auspiciously, both nano-structuration as well as confinement of metal hydroxides/oxides and conducting polymers onto a conducting porous 3D graphene matrix play a great role in improving the performance of electrodes mainly due to: (i) active material access over large surface area with fast charge transportation; (ii) synergetic effect of electric double layer and pseudocapacitive based charge storing. PMID- 25807281 TI - Letters from Iceland. AB - The largest-ever set of human genomes from a single population and the consequent insights into mutation, evolution, gene function and disease predisposition are reported in four linked papers. These results provide a strategy for the analysis of the full spectrum of genetic variation in any population and raise questions about how society should implement the knowledge gained. PMID- 25807280 TI - Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. AB - The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown, and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), which are transient embryonic structures, are the source of the diaphragm's muscle connective tissue and regulate muscle development, and we show that the striking migration of PPF cells controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant, leading to CDH. Thus, the PPFs and muscle connective tissue are critical for diaphragm development, and mutations in PPF-derived fibroblasts are a source of CDH. PMID- 25807282 TI - Identification of a large set of rare complete human knockouts. AB - Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261). PMID- 25807283 TI - Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. AB - We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 * 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 * 10(-15)). PMID- 25807285 TI - The Y-chromosome point mutation rate in humans. AB - Mutations are the fundamental source of biological variation, and their rate is a crucial parameter for evolutionary and medical studies. Here we used whole-genome sequence data from 753 Icelandic males, grouped into 274 patrilines, to estimate the point mutation rate for 21.3 Mb of male-specific Y chromosome (MSY) sequence, on the basis of 1,365 meioses (47,123 years). The combined mutation rate for 15.2 Mb of X-degenerate (XDG), X-transposed (XTR) and ampliconic excluding palindromes (rAMP) sequence was 8.71 * 10(-10) mutations per position per year (PPPY). We observed a lower rate (P = 0.04) of 7.37 * 10(-10) PPPY for 6.1 Mb of sequence from palindromes (PAL), which was not statistically different from the rate of 7.2 * 10(-10) PPPY for paternally transmitted autosomes. We postulate that the difference between PAL and the other MSY regions may provide an indication of the rate at which nascent autosomal and PAL de novo mutations are repaired as a result of gene conversion. PMID- 25807284 TI - Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. AB - Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition. PMID- 25807287 TI - Fluorescence responsive conjugated poly(tetraphenylethene) and its morphological transition from micelle to vesicle. AB - A crown ether-functionalized poly(tetraphenylethene) (AP-TPE) is synthesized and the rotation of the TPE group is successfully restricted via the complexation of crown ether and organic ammonium salts, leading to a stepwise enhanced fluorescence accompanied by a morphological transition from micellar to vesicular. PMID- 25807286 TI - Large-scale whole-genome sequencing of the Icelandic population. AB - Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20*. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity. PMID- 25807288 TI - Intraspinal Delivery of Polyethylene Glycol-coated Gold Nanoparticles Promotes Functional Recovery After Spinal Cord Injury. AB - Failure of the mammalian central nervous system (CNS) to regenerate effectively after injury leads to mostly irreversible functional impairment. Gold nanoparticles (AuNPs) are promising candidates for drug delivery in combination with tissue-compatible reagents, such as polyethylene glycol (PEG). PEG administration in CNS injury models has received interest for potential therapy, but toxicity and low bioavailability prevents clinical application. Here we show that intraspinal delivery of PEG-functionalized 40-nm-AuNPs at early stages after mouse spinal cord injury is beneficial for recovery. Positive outcome of hind limb motor function was accompanied by attenuated inflammatory response, enhanced motor neuron survival, and increased myelination of spared or regrown/sprouted axons. No adverse effects, such as body weight loss, ill health, or increased mortality were observed. We propose that PEG-AuNPs represent a favorable drug delivery platform with therapeutic potential that could be further enhanced if PEG-AuNPs are used as carriers of regeneration-promoting molecules. PMID- 25807291 TI - Room temperature infrared imaging sensors based on highly purified semiconducting carbon nanotubes. AB - High performance infrared (IR) imaging systems usually require expensive cooling systems, which are highly undesirable. Here we report the fabrication and performance characteristics of room temperature carbon nanotube (CNT) IR imaging sensors. The CNT IR imaging sensor is based on aligned semiconducting CNT films with 99% purity, and each pixel or device of the imaging sensor consists of aligned strips of CNT asymmetrically contacted by Sc and Pd. We found that the performance of the device is dependent on the CNT channel length. While short channel devices provide a large photocurrent and a rapid response of about 110 MUs, long channel length devices exhibit a low dark current and a high signal-to noise ratio which are critical for obtaining high detectivity. In total, 36 CNT IR imagers are constructed on a single chip, each consists of 3 * 3 pixel arrays. The demonstrated advantages of constructing a high performance IR system using purified semiconducting CNT aligned films include, among other things, fast response, excellent stability and uniformity, ideal linear photocurrent response, high imaging polarization sensitivity and low power consumption. PMID- 25807289 TI - Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques. AB - Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts. PMID- 25807293 TI - Craniofacial plasticity in ancient Peru. AB - Numerous studies have utilized craniometric data to explore the roles of genetic diversity and environment in human cranial shape variation. Peru is a particularly interesting region to examine cranial variation due to the wide variety of high and low altitude ecological zones, which in combination with rugged terrain have created isolated populations with vastly different physiological adaptations. This study examines seven samples from throughout Peru in an effort to understand the contributions of environmental adaptation and genetic relatedness to craniofacial variation at a regional scale. Morphological variation was investigated using a canonical discriminant analysis and Mahalanobis D(2) analysis. Results indicate that all groups are significantly different from one another with the closest relationship between Yauyos and Jahuay, two sites that are located geographically close in central Peru but in very different ecozones. The relationship between latitude/longitude and face shape was also examined with a spatial autocorrelation analysis (Moran's I) using ArcMap and show that there is significant spatial patterning for facial measures and geographic location suggesting that there is an association between biological variation and geographic location. PMID- 25807290 TI - [(18)F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility. AB - Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent gamma-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity purified CD34-TK75(+)-selected donor T cells (1.0-13 * 10(5))/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-((18)F)fluoro-3-hydroxymethyl-butyl]guanine ([(18)F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [(18)F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [(18)F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. PMID- 25807294 TI - Correction: The odorant receptor co-receptor from the bed bug, Cimex lectularius L. PMID- 25807292 TI - Dead shrimp blues: a global assessment of extinction risk in freshwater shrimps (Crustacea: Decapoda: Caridea). AB - We present the first global assessment of extinction risk for a major group of freshwater invertebrates, caridean shrimps. The risk of extinction for all 763 species was assessed using the IUCN Red List criteria that include geographic ranges, habitats, ecology and past and present threats. The Indo-Malayan region holds over half of global species diversity, with a peak in Indo-China and southern China. Shrimps primarily inhabit flowing water; however, a significant subterranean component is present, which is more threatened than the surface fauna. Two species are extinct with a further 10 possibly extinct, and almost one third of species are either threatened or Near Threatened (NT). Threats to freshwater shrimps include agricultural and urban pollution impact over two thirds of threatened and NT species. Invasive species and climate change have the greatest overall impact of all threats (based on combined timing, scope and severity of threats). PMID- 25807296 TI - (7-Chloroquinolin-4-yl)arylhydrazones: Candida albicans enzymatic repression and cytotoxicity evaluation, Part 2. AB - OBJECTIVE: This work describes the anti-enzymatic activity of (7-chloroquinolin-4 yl)arylhydrazones against Candida albicans and examines their cytotoxicity. MATERIAL AND METHODS: Ten C. albicans strains [nine isolates and one azole resistant standard strain (ATCC 62342)] were used to assess the anti-enzymatic activity. Fifteen compounds at sub-antifungal concentrations ranging from 12.5 to 100 ug/ml were assessed after a 30-min exposure. The strains were seeded onto petri dishes with selective agar media for aspartyl proteases (Saps) and phospholipases (PLs). Enzymatic inhibition was measured by the reduction of the precipitation zone (Pz) against untreated strains (positive control). A colorimetric MTT assay was used with 3T3/NIH mouse fibroblasts to evaluate cytotoxicity. Cells were exposed to 15 compounds in concentrations from 6.25 to 100 ug/ml for 24 and 48 h. RESULTS: Four hydrazones showed enzymatic repression values over 40% to Pl and three over 20% to Saps. The cell viability was over 50% at hydrazone concentrations of 25-100 ug/ml. CONCLUSION: These results revealed that select (7-chloroquinolin-4-yl)arylhydrazones may be potential antifungal agents for the control of C. albicans infections. PMID- 25807295 TI - Overexpression of poplar xylem sucrose synthase in tobacco leads to a thickened cell wall and increased height. AB - Sucrose synthase (SuSy) is considered the first key enzyme for secondary growth because it is a highly regulated cytosolic enzyme that catalyzes the reversible conversion of sucrose and UDP into UDP-glucose and fructose. Although SuSy enzymes preferentially functions in the direction of sucrose cleavage at most cellular condition, they also catalyze the synthetic reaction. We isolated a gene that encodes a SuSy from Populus simonii*Populus nigra and named it PsnSuSy2 because it shares high similarity to SuSy2 in Populus trichocarpa. RT-PCR revealed that PsnSuSy2 was highly expressed in xylem, but lowly expressed in young leaves. To characterize its functions in secondary growth, multiple tobacco overexpression transgenic lines of PnsSuSy2 were generated via Agrobacterium mediated transformation. The PsnSuSy2 expression levels and altered wood properties in stem segments from the different transgenic lines were carefully characterized. The results demonstrated that the levels of PsnSuSy2 enzyme activity, chlorophyll content, total soluble sugars, fructose and glucose increased significantly, while the sucrose level decreased significantly. Consequently, the cellulose content and fiber length increased, whereas the lignin content decreased, suggesting that PsnSuSy2 plays a significant role in cleaving sucrose into UDP-glucose and fructose to facilitate cellulose biosynthesis and that promotion of cellulose biosynthesis suppresses lignin biosynthesis. Additionally, the noticeable increase in the lodging resistance in transgenic tobacco stem suggested that the cell wall characteristics were altered by PsnSuSy2 overexpression. Scanning electron microscopy was performed to study the cell wall morphology of stem, and surprisingly, we found that the secondary cell wall was significantly thicker in transgenic tobacco. However, the thickened secondary cell wall did not negatively affect the height of the plants because the PsnSuSy2- overexpressing lines grew taller than the wildtype plants. This systematic analysis demonstrated that PsnSuSy2 plays an important role in cleaving sucrose coupled with cellulose biosynthesis in wood tissue. PMID- 25807297 TI - Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives. AB - The interest towards coumarin-based structures stems from their polypharmacological profile. Herein, we present a series of Mannich bases and 7 azomethine-linked coumarin derivatives exhibiting antiplatelet and antithrombotic activities, in addition to the already known anti-inflammatory and antioxidant activities. Among others, compounds 15 and 16 were found to be the most potent and selective inhibitors of platelet aggregation whereas compound 3 also proved to be the most potent in the clot retraction assay. Structure-activity relationship studies were conducted to elucidate the molecular determinants responsible for the herein observed activities. The chance of inhibiting cyclooxygenase-1 was also investigated for evaluating the platelet aggregation induced by arachidonic acid. Taken together, these results suggest that the investigation of other targets connected to the antiplatelet activity, such as phosphodiesterase-3 (PDE3), could be a viable strategy to shed light on the polypharmacological profile of coumarin-based compounds. Docking simulations towards PDE3 were also carried out. PMID- 25807298 TI - Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies. AB - Herein, we report compound KST9046, a new agent possessing quinazoline-urea scaffold. Preliminary biological evaluation done by the National Cancer Institute (NCI), USA, showed a great inhibitory effect of KST9046 over the 60 cell-line tumor panel. Accordingly, it was selected for a dose-response assay; a broad spectrum antiproliferative activity with GI(50) ranging from 1.3 to 3.9 uM was exerted. To explore a potential kinase inhibitory effect, KST9046 was applied at a single dose of 10 uM against a kinase panel of 347 different enzymes representing >50% of the predicted human protein kinome. Interestingly, selective inhibition of 76% was observed on DDR1 kinase. Further, KST9046 showed an IC(50) value of 4.38 uM for DDR1. A molecular docking model presented KST9046 as a potential type III inhibitor for DDR1 kinase with an allosteric mode of interaction, which may offer an explanation for its selectivity. As further investigation, CYP450 assay was carried out for KST9046, it showed a promising toxicity profile against four different isoforms. Based on these findings, KST9046 can be further evaluated as a promising safe new hit for the development of broad spectrum anticancer agents with a selectivity for DDR1 kinase. PMID- 25807299 TI - Bicyclic gamma-amino acids as inhibitors of gamma-aminobutyrate aminotransferase. AB - The gamma-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally. PMID- 25807300 TI - (Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies. AB - Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi targeted role in the discovery of new drugs against the neurodegenerative diseases. PMID- 25807301 TI - The slow dissociation rate of K-1602 contributes to the enhanced inhibitory activity of this novel alkyl-aryl-bearing fluoroketolide. AB - Ketolides belong to the latest generation of macrolides and are not only effective against macrolide susceptible bacterial strains but also against some macrolide resistant strains. Here we present data providing insights into the mechanism of action of K-1602, a novel alkyl-aryl-bearing fluoroketolide. According to our data, the K-1602 interacts with the ribosome as a one-step slow binding inhibitor, displaying an association rate constant equal to 0.28 * 10(4) M(-1) s(-1) and a dissociation rate constant equal to 0.0025 min(-1). Both constants contribute to produce an overall inhibition constant Ki equal to 1.49 * 10(-8) M, which correlates very well with the superior activity of this compound when compared with many other ketolides or fluoroketolides. PMID- 25807304 TI - Statistical optimization of lovastatin production by Omphalotus olearius (DC.) singer in submerged fermentation. AB - In this study, culture conditions were optimized to improve lovastatin production by Omphalotus olearius, isolate OBCC 2002, using statistical experimental designs. The Plackett-Burman design was used to select important variables affecting lovastatin production. Accordingly, glucose, peptone, and agitation speed were determined as the variables that have influence on lovastatin production. In a further experiment, these variables were optimized with a Box Behnken design and applied in a submerged process; this resulted in 12.51 mg/L lovastatin production on a medium containing glucose (10 g/L), peptone (5 g/L), thiamine (1 mg/L), and NaCl (0.4 g/L) under static conditions. This level of lovastatin production is eight times higher than that produced under unoptimized media and growth conditions by Omphalotus olearius. To the best of our knowledge, this is the first attempt to optimize submerged fermentation process for lovastatin production by Omphalotus olearius. PMID- 25807302 TI - Annexin V-induced rat Leydig cell proliferation involves Ect2 via RhoA/ROCK signaling pathway. AB - This study investigated the effect of annexin V on the proliferation of primary rat Leydig cells and the potential mechanism. Our results showed that annexin V promoted rat Leydig cell proliferation and cell cycle progression in a dose- and time-dependent manner. Increased level of annexin V also enhanced Ect2 protein expression. However, siRNA knockdown of Ect2 attenuated annexin V-induced proliferation of rat Leydig cells. Taken together, these data suggest that increased level of annexin V induced rat Leydig cell proliferation and cell cycle progression via Ect2. Since RhoA activity was increased following Ect2 activation, we further investigated whether Ect2 was involved in annexin V induced proliferation via the RhoA/ROCK pathway, and the results showed that annexin V increased RhoA activity too, and this effect was abolished by the knockdown of Ect2. Moreover, inhibition of the RhoA/ROCK pathway by a ROCK inhibitor, Y27632, also attenuated annexin V-induced proliferation and cell cycle progression. We thus conclude that Ect2 is involved in annexin V-induced rat Leydig cell proliferation through the RhoA/ROCK pathway. PMID- 25807306 TI - Theory of sampling: four critical success factors before analysis. AB - Food and feed materials characterization, risk assessment, and safety evaluations can only be ensured if QC measures are based on valid analytical data, stemming from representative samples. The Theory of Sampling (TOS) is the only comprehensive theoretical framework that fully defines all requirements to ensure sampling correctness and representativity, and to provide the guiding principles for sampling in practice. TOS also defines the concept of material heterogeneity and its impact on the sampling process, including the effects from all potential sampling errors. TOS's primary task is to eliminate bias-generating errors and to minimize sampling variability. Quantitative measures are provided to characterize material heterogeneity, on which an optimal sampling strategy should be based. Four critical success factors preceding analysis to ensure a representative sampling process are presented here. PMID- 25807305 TI - The prognostic role of Ki-67/MIB-1 in cervical cancer: a systematic review with meta-analysis. AB - BACKGROUND: A significant relationship has been reported in which Ki-67/MIB-1 expression is correlated with survival in cervical cancer patients. However, the prognostic value of Ki-67/MIB-1 in cervical cancer is still not well understood. MATERIAL AND METHOD: A meta-analysis was carried out to explore the prognostic value of Ki-67/MIB-1 on overall survival (OS) and/or disease-free survival (DFS) in cervical cancer. The databases of PubMed, ISI Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, ScienceDirect, and Wiley Online Library were used to identify relevant literature. RESULTS: We included 18 studies covering 1344 patients in the meta-analysis. The effect of Ki-67/MIB-1 on OS for pooled random effects HR estimate was 1.63 (95% confidence intervals (CI) 1.09 2.45; P<0.05). Subgroup analysis by ethnicity suggested that high expression of Ki-67/MIB-1 had association with Asians (1.84, 95% CI 1.04-3.23), but not with Africans (HR=1.53, 95% CI 0.34-6.86) or Europeans (HR=1.29, 95% CI 0.74-2.23). Furthermore, subgroup analysis of diverse treatments revealed no difference in surgery (HR=1.97, 95% CI 0.78-4.99) and radiation therapy (RT) (HR=1.56, 95% CI 0.93-2.63). The pooled HR for DFS was 1.26 (95% CI 0.58-2.73; P>0.05) and the subgroup analysis indicated Ki-67/MIB1 was associated with DFS (HR=3.67, 95% CI 2.65-5.09) in Asians. In the treatment subgroup analysis, no direct value was found among surgery (HR=1.13, 95% CI 0.10-13.53) and RT (HR=1.26, 95% CI 0.71 2.24). CONCLUSIONS: Our meta-analysis concludes that Ki-67/MIB-1 had a prognostic value for OS in cervical cancer patients. To further evaluate the prognostic role of Ki-67/MIB-1 on DFS, studies with larger numbers of patients are needed to validate our findings. PMID- 25807307 TI - Impact of tumor angiogenic profile on the outcome of patients with metastatic breast carcinoma treated with weekly docetaxel. A Hellenic Cooperative Oncology Group (HeCOG) study. AB - BACKGROUND: Metronomic taxane administration has putative antiangiogenic properties. Herein, we examined the baseline tumor angiogenic profile of patients with metastatic breast carcinoma (MBC) in a prospective-retrospective translational research study. The interplay between the angiogenic factors expressed in the tumors and their prognostic value in MBC were investigated. PATIENTS AND METHODS: Tumor tissues from patients with MBC treated with weekly docetaxel (n=159) were examined by immunohistochemistry for VEGF-A, VEGF-C, VEGFR 1, VEGFR-2, VEGFR-3 and osteopontin (OPN) and by mRNA analysis for expression of VEGF-A, VEGFxxxa, VEGFxxxb, VEGF-C, thrombospondin-1 (THBS-1), hypoxia-inducible factor-1alpha (HIF-1alpha) and von Hippel-Lindau (VHL) genes. Associations between these parameters and outcome were statistically analyzed. RESULTS: Statistically significant correlations were identified between almost all biomarkers examined in continuous form, particularly at the mRNA level: VEGF-A with VEGFxxxa (rho=0.70); VEGF-C with VEGFxxxa, VEGFxxxb and VHL (rho=0.51, 0.60 and 0.44 respectively); HIF-1alpha with VEGF-C and THBS1 (rho= 0.48 and 0.45). High VEGF-A mRNA was associated with worse survival (p=0.0279) and marginally with progression free survival (PFS). Intratumoral co-expression of VEGFR-1 and VEGFR-2 proteins was associated with more favorable survival (p=0.0337). In multivariate analysis, only high VEGF-A mRNA levels retained their prognostic role for worse PFS and survival (PFS: HR=2.34, 95% CI=1.25-4.40, p=0.0080; survival: HR=3.15, 95% CI=1.48-6.72, p=0.0029). CONCLUSIONS: In MBC, this study confirms the adverse prognostic effect of high intratumoral VEGF-A mRNA and reveals the combined VEGFR-1/VEGFR-2 protein expression as a potentially favorable prognosticator, which merits further evaluation in larger studies. PMID- 25807308 TI - Fucci2a mouse upgrades live cell cycle imaging. PMID- 25807309 TI - Population Structure of Xylella fastidiosa Associated with Almond Leaf Scorch Disease in the San Joaquin Valley of California. AB - Xylella fastidiosa causes disease in many commercial crops, including almond leaf scorch (ALS) disease in susceptible almond (Prunus dulcis). In this study, genetic diversity and population structure of X. fastidiosa associated with ALS disease were evaluated. Isolates obtained from two almond orchards in Fresno and Kern County in the San Joaquin Valley of California were analyzed for two successive years. Multilocus simple-sequence repeat (SSR) analysis revealed two major genetic clusters that were associated with two host cultivars, 'Sonora' and 'Nonpareil', respectively, regardless of the year of study or location of the orchard. These relationships suggest that host cultivar selection and adaptation are major driving forces shaping ALS X. fastidiosa population structure in the San Joaquin Valley. This finding will provide insight into understanding pathogen adaptation and host selection in the context of ALS disease dynamics. PMID- 25807310 TI - Lectin complement protein Collectin 11 (CL-K1) and susceptibility to urinary schistosomiasis. AB - BACKGROUND: Urinary Schistosomiasis is a neglected tropical disease endemic in many sub Saharan -African countries. Collectin Kidney 1 (CL-K1, encoded by COLEC11 on chromosome 2p25.3), a member of the vertebrate C-type lectin super family, has recently been identified as pattern-recognition molecule (PRR) of the lectin complement pathway. CL-K1 is preferentially expressed in the kidneys, but also in other organs and it is considered to play a role in host defense to some infectious agents. Schistosome teguments are fucosylated and CL-K1 has, through its collagen-like domain, a high binding affinity to fucose. METHODOLOGY/PRINCIPAL FINDINGS: We utilized a Nigerian study group consisting of 167 Schistosoma haematobium infected individuals and 186 matched healthy subjects, and investigated the contribution of CL-K1 deficiency and of COLEC11 polymorphisms to infection phenotype. Higher CL-K1 serum levels were associated with decreased risk of schistosome infection (P corr = 0.0004). CL-K1 serum levels were differentially distributed between the COLEC11 genotypes and haplotypes observed. The non-synonymous variant p.R216H was associated with the occurrence of schistosomiasis (OR = 0.44, 95%CI = 0.22-0.72, P corr = 0.0004). The reconstructed COLEC11*TCCA haplotypes were associated with higher CL-K1 serum levels (P = 0.002) and with decreased schistosomiasis (OR = 0.38, 95%CI = 0.23 0.63, P corr = 0.0001). CONCLUSIONS: In agreement with findings from our earlier published study, our findings support the observation that CL-K1 and their functional variants may be host factors associated with protection in schistosomiasis and may be a useful marker for further investigations. PMID- 25807313 TI - Considerations for inference to Decision Units. AB - The goal of sampling is to take a small portion of a target material for analysis instead of collecting all the material. If sampling is done following certain principles, then inference can be made from analytical results of the portion taken back to the entire target material (Decision Unit). There are different sampling strategies that are dependent on the properties of the material being sampled as well as different methods for making inferences from analytical results to the Decision Unit (DU). A thorough understanding of material properties and methods for inference is therefore critical for the development of proper sampling protocols. This paper addresses inferences from analytical test results to DUs and the implications to the development of a sampling protocol. PMID- 25807311 TI - Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment. AB - IMPORTANCE: Adalimumab has proven to be effective in suppressing psoriasis disease activity and is administered in a standard dose. OBJECTIVE: To establish a therapeutic range for adalimumab trough levels in the treatment of plaque-type psoriasis, leading to a more personalized treatment. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, prospective, observational, daily practice cohort study conducted at an academic hospital with affiliated secondary care hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2). Both cohorts included adult patients treated with adalimumab for plaque-type psoriasis. Cohort 1 comprised 73 patients who were being treated with adalimumab for more than 24 weeks until 401 weeks. In cohort 2 (n = 62), serum samples were obtained between weeks 24 and 52 of treatment. INTERVENTIONS: Before the start of adalimumab therapy and at time of serum sampling, Psoriasis Area and Severity Index (PASI) scores were determined. MAIN OUTCOMES AND MEASURES: Adalimumab trough level and PASI score at the time of serum sampling to determine the receiver-operator characteristics analyses and concentration effect curve. RESULTS: By means of receiver-operator characteristics analyses with an area under the curve of 0.756 (SD, 0.046; 95% CI, 0.666-0.847) and a sensitivity of 78% and a specificity of 70%, 3.51 mg/L was established as the lower margin for the therapeutic range. By means of a concentration effect curve, 7 mg/L was established as the upper margin. One-third of patients had an adalimumab trough concentration exceeding 7 mg/L. CONCLUSIONS AND RELEVANCE: A therapeutic range of adalimumab trough levels of 3.51 mg/L to 7.00 mg/L, which corresponds to an optimal clinical effect, was identified. In one-third of patients, it was observed that trough concentrations exceeded the therapeutic window. Based on the established range, a therapeutic algorithm for adalimumab treatment for patients with psoriasis can be developed and validated in a prospective patient cohort. By identifying this range, a step has been taken toward a more rational use of biological therapy in psoriasis. Developing a therapeutic algorithm may lead to less overtreatment of patients and cost savings. PMID- 25807312 TI - Airborne Exposures to Polycyclic Aromatic Compounds Among Workers in Asphalt Roofing Manufacturing Facilities. AB - We studied exposure of 151 workers to polycyclic aromatic compounds and asphalt emissions during the manufacturing of asphalt roofing products-including 64 workers from 10 asphalt plants producing oxidized, straight-run, cutback, and wax or polymer-modified asphalts, and 87 workers from 11 roofing plants producing asphalt shingles and granulated roll roofing. The facilities were located throughout the United States and used asphalt from many refiners and crude oils. This article helps fill a gap in exposure data for asphalt roofing manufacturing workers by using a fluorescence technique that targets biologically active 4-6 ring polycyclic aromatic compounds and is strongly correlated with carcinogenic activity in animal studies. Worker exposures to polycyclic aromatic compounds were compared between manufacturing plants, at different temperatures and using different raw materials, and to important external benchmarks. High levels of fine limestone particulate in the plant air during roofing manufacturing increased polycyclic aromatic compound exposure, resulting in the hypothesis that the particulate brought adsorbed polycyclic aromatic compounds to the worker breathing zone. Elevated asphalt temperatures increased exposures during the pouring of asphalt. Co-exposures in these workplaces which act as confounders for both the measurement of total organic matter and fluorescence were detected and their influence discussed. Exposures to polycyclic aromatic compounds in asphalt roofing manufacturing facilities were lower than or similar to those reported in hot-mix paving application studies, and much below those reported in studies of hot application of built-up roofing asphalt. These relatively low exposures in manufacturing are primarily attributed to air emission controls in the facilities, and the relatively moderate temperatures, compared to built-up roofing, used in these facilities for oxidized asphalt. The exposure to polycyclic aromatic compounds was a very small part of the overall worker exposure to asphalt fume, on average less than 0.07% of the benzene-soluble fraction. Measurements of benzene-soluble fraction were uniformly below the American Conference of Governmental Industrial Hygienists' Threshold Limit Value for asphalt fume. PMID- 25807314 TI - Antiviral treatment among older adults hospitalized with influenza, 2006-2012. AB - OBJECTIVE: To describe antiviral use among older, hospitalized adults during six influenza seasons (2006-2012) in Davidson County, Tennessee, USA. METHODS: Among adults >=50 years old hospitalized with symptoms of respiratory illness or non localizing fever, we collected information on provider-initiated influenza testing and nasal/throat swabs for influenza by RT-PCR in a research laboratory, and calculated the proportion treated with antivirals. RESULTS: We enrolled 1753 adults hospitalized with acute respiratory illness. Only 26% (457/1753) of enrolled patients had provider-initiated influenza testing. Thirty-eight patients had a positive clinical laboratory test, representing 2.2% of total patients and 8.3% of tested patients. Among the 38 subjects with clinical laboratory-confirmed influenza, 26.3% received antivirals compared to only 4.5% of those with negative clinical influenza tests and 0.7% of those not tested (p<0.001). There were 125 (7.1%) patients who tested positive for influenza in the research laboratory. Of those with research laboratory-confirmed influenza, 0.9%, 2.7%, and 2.8% received antivirals (p=.046) during pre-pandemic, pandemic, and post-pandemic influenza seasons, respectively. Both research laboratory-confirmed influenza (adjusted odds ratio [AOR] 3.04 95%CI 1.26-7.35) and clinical laboratory-confirmed influenza (AOR 3.05, 95%CI 1.07-8.71) were independently associated with antiviral treatment. Severity of disease, presence of a high-risk condition, and symptom duration were not associated with antiviral use. CONCLUSIONS: In urban Tennessee, antiviral use was low in patients recognized to have influenza by the provider as well as those unrecognized to have influenza. The use of antivirals remained low despite recommendations to treat all hospitalized patients with confirmed or suspected influenza. PMID- 25807316 TI - Mortality from Circulatory System Diseases among French Uranium Miners: A Nested Case-Control Study. AB - A significant association has been observed between radon exposure and cerebrovascular disease (CeVD) mortality among French uranium miners, but risk factors for circulatory system diseases (CSD) have not been previously considered. We conducted new analyses in the recently updated (through 2007) French cohort of uranium miners (n = 5,086), which included 442 deaths from CSD, 167 of them from ischemic heart disease (IHD) and 105 from CeVD. A nested case control study was then set up to collect and investigate the influence of these risk factors on the relationships between mortality from CSD and occupational external gamma ray and internal ionizing radiation exposure (radon and long-lived radionuclides) in this updated cohort. The nested case-control study included miners first employed after 1955, still employed in 1976 and followed up through 2007. Individual information about CSD risk factors was collected from medical files for the 76 deaths from CSD (including 26 from IHD and 16 from CeVD) and 237 miners who had not died of CSD by the end of follow-up. The exposure-risk relationships were assessed with a Cox proportional hazard model weighted by the inverse sampling probability. A significant increase in all CSD and CeVD mortality risks associated with radon exposure was observed in the total cohort [hazard ratios: HRCSD/100 working level months (WLM) = 1.11, 95% confidence interval (1.01; 1.22) and HRCeVD/100 WLM = 1.25 (1.09; 1.43), respectively]. A nonsignificant exposure-risk relationship was observed for every type of cumulative ionizing radiation exposure and every end point [e.g., HRCSD/100WLM = 1.43 (0.71; 2.87)]. The adjustment for each CSD risk factor did not substantially change the exposure-risk relationships. When the model was adjusted for overweight, hypertension, diabetes, hypercholesterolemia and smoking status, the HR/100WLM for CSD, for example, was equal to 1.21 (0.54; 2.75); and when it was adjusted for risk factors selected with the Akaike information criterion, it was equal to 1.44 (0.66; 3.14). To our knowledge, this is the first study to use a uranium miner cohort to consider the major standard CSD risk factors in assessing the relationships between ionizing radiation exposure and the risk of death from these diseases. These results suggest that the significant relationship between CeVD risk and radon exposure observed in the total French cohort is probably not affected by the CSD risk factors. Extending the collection of information about CSD risk factors to a larger subsample would be useful to confirm this result. PMID- 25807315 TI - Interleukin-6 and asymmetric dimethylarginine are associated with platelet activation after percutaneous angioplasty with stent implantation. AB - Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are scarce. Moreover, the interrelation between endothelial dysfunction as early marker of atherosclerosis and platelet activation has not been studied, so far. We therefore sought to investigate the associations of inflammation, endothelial dysfunction and cardiovascular risk factors with platelet activation and monocyte-platelet aggregate (MPA) formation in 330 patients undergoing angioplasty with stent implantation for atherosclerotic cardiovascular disease. P-selectin expression, activation of glycoprotein IIb/IIIa and MPA formation were determined by flow cytometry. Interleukin (IL)-6, high sensitivity C-reactive protein and asymmetric dimethylarginine (ADMA) were measured by commercially available assays. IL-6 was the only parameter which was independently associated with platelet P-selectin expression and activated GPIIb/IIIa as well as with leukocyte-platelet interaction in multivariate regression analysis (all p<0.05). ADMA was independently associated with GPIIb/IIIa activation (p<0.05). Patients with high IL-6 exhibited a significantly higher expression of P-selectin than patients with low IL-6 (p=0.001), whereas patients with high ADMA levels showed a more pronounced activation of GPIIb/IIIa than patients with low ADMA (p=0.003). In conclusion, IL-6 and ADMA are associated with platelet activation after percutaneous angioplasty with stent implantation. It remains to be established whether they act prothrombotic and atherogenic themselves or are just surrogate markers for atherosclerosis with concomitant platelet activation. PMID- 25807317 TI - Response to Comments on "Estimating Risks of Low Radiation Doses-A Critical Review of the BEIR VII Report and Its Use of the Linear No-Threshold (LNT) Hypothesis". PMID- 25807319 TI - Comments on Estimating Risks of Low Radiation Doses-A Critical Review of the BEIR VII Report and Its Use of the Linear No-Threshold (LNT) Hypothesis by Edward J. Calabrese and Michael K. O'Connor. PMID- 25807320 TI - Ionizing radiation-induced cell death is partly caused by increase of mitochondrial reactive oxygen species in normal human fibroblast cells. AB - Radiation-induced cell death is thought to be caused by nuclear DNA damage that cannot be repaired. However, in this study we found that a delayed increase of mitochondrial reactive oxygen species (ROS) is responsible for some of the radiation-induced cell death in normal human fibroblast cells. We have previously reported that there is a delayed increase of mitochondrial (.)O2(-), measured using MitoSOXTM Red reagent, due to gamma irradiation. This is dependent on Drp1 localization to mitochondria. Here, we show that knockdown of Drp1 expression reduces the level of DNA double-strand breaks (DSBs) remaining 3 days after 6 Gy irradiation. Furthermore, cells with knockdown of Drp1 expression are more resistant to gamma radiation. We then tested whether the delayed increase of ROS causes DNA damage. The antioxidant, 2-glucopyranoside ascorbic acid (AA-2G), was applied before or after irradiation to inhibit ROS production during irradiation or to inhibit delayed ROS production from mitochondria. Interestingly, 1 h after exposure, the AA-2G treatment reduced the level of DSBs remaining 3 days after 6 Gy irradiation. In addition, irradiated AA-2G-treated cells were more resistant to radiation than the untreated cells. These results indicate that delayed mitochondrial ROS production may cause some of the cell death after irradiation. PMID- 25807321 TI - Chronic Gamma-Irradiation Induces a Dose-Rate-Dependent Pro-inflammatory Response and Associated Loss of Function in Human Umbilical Vein Endothelial Cells. AB - A central question in radiation protection research is dose and dose-rate relationship for radiation-induced cardiovascular diseases. The response of endothelial cells to different low dose rates may contribute to help estimate risks for cardiovascular diseases by providing mechanistic understanding. In this study we investigated whether chronic low-dose-rate radiation exposure had an effect on the inflammatory response of endothelial cells and their function. Human umbilical vein endothelial cells (HUVECs) were chronically exposed to radiation at a dose of 1.4 mGy/h or 4.1 mGy/h for 1, 3, 6 or 10 weeks. We determined the pro-inflammatory profile of HUVECs before and during radiation exposure, and investigated the functional consequences of this radiation exposure by measuring their capacity to form vascular networks in matrigel. Expression levels of adhesion molecules such as E-selectin, ICAM-1 and VCAM-1, and the release of pro-inflammatory cytokines such as MCP-1, IL-6 and TNF-alpha were analyzed. When a total dose of 2 Gy was given at a rate of 4.1 mGy/h, we observed an increase in IL-6 and MCP-1 release into the cell culture media, but this was not observed at 1.4 mGy/h. The increase in the inflammatory profile induced at the dose rate of 4.1 mGy/h was also correlated with a decrease in the capacity of the HUVECs to form a vascular network in matrigel. Our results suggest that dose rate is an important parameter in the alteration of HUVEC inflammatory profile and function. PMID- 25807318 TI - Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid. AB - We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy gamma radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from -24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from -12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by >=34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4-8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome. PMID- 25807323 TI - Platelet to lymphocyte ratio as a prognostic marker in primary percutaneous coronary intervention. PMID- 25807322 TI - Tonsillectomy versus tonsillotomy for sleep-disordered breathing in children: a meta analysis. AB - OBJECTIVES: Tonsillotomy has gained popular acceptance as an alternative to the traditional tonsillectomy in the management of sleep-disordered breathing in children. Many studies have evaluated the outcomes of the two techniques, but uncertainty remains with regard to the efficacy and complications of tonsillotomy versus a traditional tonsillectomy. This study was designed to investigate the efficacy and complications of tonsillotomy versus tonsillectomy, in terms of the short- and long-term results. METHODS: We collected data from electronic databases including MEDLINE, EMBASE, and the Cochrane Library. The following inclusion criteria were applied: English language, children, and prospective studies that directly compared tonsillotomy and tonsillectomy in the management of sleep disordered breathing. Subgroup analysis was then performed. RESULTS: In total, 10 eligible studies with 1029 participants were included. Tonsillotomy was shown to be advantageous over tonsillectomy in short-term measures, such as a lower hemorrhage rate, shorter operation time, and faster pain relief. In long term follow-up, there was no significant difference in resolution of upper-airway obstructive symptoms, the quality of life, or postoperative immune function between the tonsillotomy and tonsillectomy groups. The risk ratio of SDB recurrence was 3.33 (95% confidence interval = 1.62 6.82, P = 0.001), favoring tonsillectomy at an average follow-up of 31 months. CONCLUSIONS: Tonsillotomy may be advantageous over tonsillectomy in the short term measures and there are no significant difference of resolving obstructive symptoms, quality of life and postoperative immune function. For the long run, the dominance of tonsillotomy may be less than tonsillectomy with regard to the rate of sleep-disordered breathing recurrence. PMID- 25807325 TI - Companion rabbit and companion bird management practices among a representative sample of guardians in Victoria, Australia. AB - Although companion animal management practices used by caregivers can influence the welfare of the companion animals, there is little existing information about the ways in which people attempt to meet their companion animals' needs. A representative sample of rabbit guardians (n = 93, representing 63,000 people) and bird guardians (n = 203, representing 157,000 people) in Victoria, Australia, completed an online survey. Items were related to the environmental, diet/exercise, behavioral, social, and health management practices used by guardians. Guardians sometimes meet their companion animals' welfare needs, but they do not always engage in best practices. Most (79%) bird guardians reported that they interacted with their birds daily, but only 68% of rabbit guardians did the same. Likewise, 32% of rabbit guardians and 55% of bird guardians never had their companion animals vaccinated. These results may be used for educational campaigns for improving companion animal welfare. PMID- 25807326 TI - Letter to the editor: MRI is essential for triage of the "? CES" patient. PMID- 25807327 TI - Effect of perioperative inefficiency on neurosurgical theatre efficacy: A 15-year analysis. AB - INTRODUCTION: Effective utilisation of operating theatre time is an important issue in neurosurgery. There is a commonly held belief amongst surgeons that throughput of theatre is decreasing secondary to worsening perioperative delays. The aim of this paper is to explore some of the factors that lead to delays in the perioperative period by determining whether there has been a trend in the increasing length of case time over a fifteen-year period. MATERIALS AND METHODS: Case notes of all elective patients who consented for surgery between January 1998 and the end of 2012 were reviewed. Only patients who underwent elective surgery were included. Variables recorded included transit time from the ward to theatre, anaesthetic time, surgical time and time spent in recovery. These were compared over the 15-year period to look for apparent trends. RESULTS: The total number of patients who consented for elective surgery at our institution between January 1998 and December 2012 was 6760. The mean anaesthetic time considering all operations performed was 43 mins each over the 15-year period. Anaesthetic time was deemed to be trending upwards from 1998 where the mean time was 27 -60 mins in December 2012, thus reflecting an increase of 33 mins. The mean surgical times over the 15-year period were 131 mins. However in 1998, mean surgical time was 127 mins compared with 133 mins in 2012. DISCUSSION AND CONCLUSION: For the operations analysed, anaesthetic time seems to be increasing and has effectively doubled over a 15-year period. Surgical time and non-clinical time are shown to be virtually constant. This delays the overall theatre list and increases the cancellation rate. For compensating this, changes need to be made when allocating resources to both elective and emergency theatres. Staff recruitment needs to be assessed and internal audits need to be conducted within institutions to analyse ways to optimise the throughput of an operation theatre. If these principles are not adhered to, it will have a negative impact as our populations, and hence our case loads increase to instrumental levels. This will in turn have a negative impact on health workers and patients alike. PMID- 25807328 TI - Factors influencing feasibility of direct posterior reduction in irreducible traumatic atlantoaxial dislocation secondary to isolated odontoid fracture. AB - INTRODUCTION: Direct posterior reduction by intraoperative manipulation of joints for irreducible traumatic atlantoaxial dislocation (IrTAAD) has gained acceptance in the recent past. However, factors determining its feasibility have not been elucidated. Our study aims to examine the clinico-radiological factors predicting feasibility of direct posterior reduction in IrTAAD secondary to isolated odontoid fracture, in an attempt to differentiate the "truly irreducible" from those "deemed irreducible." MATERIALS AND METHODS: The onset and progression of neck pain and myelopathy was studied in 6 patients of IrTAAD with fracture odontoid, which failed to reduce despite traction. The dynamic X-rays and computed tomography (CT) scans of craniovertebral junction, along with the vertebral artery angiogram were studied to look for the slightest mobility, interface of fractured fragments, malunion, callous, and relationship of the C1-2 facets and vertebral artery. RESULTS: All 6 patients had progressive worsening of neck pain. Three patients had progressive myelopathy. Three patients presented 6 months after trauma. Radiology showed type-II fracture with IrTAAD (anterolisthesis in 5 and retrolisthesis with lateral dislocation in 1) and locked facets in all. X-rays showed doubtful callous formation in 3 patients and CT confirmed non-union. Three patients showed angular movement on dynamic X-rays despite irreducibility and locked facets. Angiogram showed thrombosis of vertebral artery in one patient. Intraoperative reduction could be achieved in all 6 patients with good clinico-radiological outcome. CONCLUSION: Worsening pain, progression of myelopathy, some movement on dynamic X-rays, a malunion ruled out on CT scan, and the presence of locked facets make direct posterior reduction feasible in patients with IrTAAD. The difficulty increases in remote fractures due to fibrosis around the dislocated joints. The role of the CT angiogram, in defining the relationship of Vertebral artery (VA) to the dislocated facets, and in determining the extent of VA injury, is vital. Preoperative detection of VA injury reduces the chance of intraoperative reduction, especially if only unilateral joint approach is planned. PMID- 25807329 TI - CSF hydrothorax: An unusual cause of pleural effusion. AB - A 20-year-old male with hydrocephalus managed with a ventriculoperitoneal shunt (VP) was diagnosed with a cerebrospinal fluid (CSF) pleural effusion. Imaging studies revealed an intrathoracic course of a disconnected VP shunt. Physicians should consider CSF effusion in their differential diagnosis in patients with a VP shunt and an unexplained pleural effusion. PMID- 25807330 TI - Neuronavigation-assisted percutaneous balloon compression for the treatment of trigeminal neuralgia: The technique and short-term clinical results. AB - BACKGROUND: Percutaneous balloon compression (PBC) has been widely used in the treatment of trigeminal neuralgia. However, this technique has a steep learning curve and significant complications were reported that were related to foramen ovale puncturing. The aim of this study was to evaluate the clinical results of a small patient group who underwent neuronavigation-assisted PBC. METHODS: An intraoperative computed tomography (CT) device (CereTom, Neurologica, Danvers, MA/USA) was used to obtain CT scans with 2-mm slice thicknesses. The data were transferred to a neuronavigation system planning station (BrainLab, Feldkirchen, Germany). A soft touch registration system was used for image registration. With the image guidance, a trajectory was defined and the foramen ovale was cannulated using neuronavigation and Hartel's landmarks. RESULTS: Sixteen procedures were performed on 13 patients (4 female and 9 male) without complications. The total length of the procedure was not more than 57 min in all instances. CONCLUSIONS: We believe that image-guided neuronavigation is useful for neurosurgeons who are at the beginning of their PBC learning curve. It may also be an alternative for particular patients with significant anatomic variations that result in an unsuccessful foramen ovale puncture. PMID- 25807331 TI - Benign sacral schwannomas - A case and short review of the literature. AB - Schwannomas are primarily benign. Sacral schwannomas in the retroperitoneum are rare and symptoms are uncharacteristic, often hampering diagnosis. Treatment of choice in symptomatic cases is complete excision while observing asymptomatic patients. We present a case of a 68-year-old male with a large intrasacral tumor extending into the pelvis. PMID- 25807332 TI - Intradural lipoma at the foramen magnum presenting with classical Chiari symptoms: A case report. AB - Intradural lipomas are rare lesions, usually associated with spinal dysraphism, affecting the spinal cord. Intracranial lipomas make up less than 1% of intracranial tumours; only 13 cases of these lesions being located at the craniocervical junction are reported in the literature. These lesions tend to present with neurological deficits such as quadraparesis and incontinence. We present the first case of a successfully treated intradural lipoma at the foramen magnum in a 15-year-old girl who presented with classical Chiari symptoms and no neurological deficits. PMID- 25807333 TI - Effect of breast cancer after ovarian cancer on mortality for BRCA mutation carriers. PMID- 25807335 TI - Interleukin-23 in the pathogenesis and treatment of psoriasis. AB - In the past three decades, major advances have been made in understanding the pathogenesis of psoriasis. The currently accepted theory is that T-cell mediated immune dysregulation triggers keratinocyte hyperproliferation in psoriasis. Recent research indicates that the Th17/interleukin (IL)-23 pathway plays a prominent role in the amplification phase of psoriasis. The discovery of the Th17/ IL-23 pathway provides targets for new drug development. This review focuses on the role of IL-23 in psoriasis pathogenesis and the current therapies targeting IL-23 that are in clinical trials. PMID- 25807334 TI - Comprehensive analysis of regulatory elements of the promoters of rice sulfate transporter gene family and functional characterization of OsSul1;1 promoter under different metal stress. AB - Adverse environmental conditions including heavy metal stress impose severe effects on the plant growth and development limiting productivity and yield. Studies demonstrated that changes in genome-wide expression modulate various biochemical processes and molecular components in response to heavy metal stress in plants. Some of the key components involved in such a regulation are the transcription initiation machinery, nucleotide sequence of promoters and presence of cis-acting elements. Therefore, identification of the putative cis-acting DNA sequences involved in gene regulation and functional characterization of promoters are important steps in understanding response of plants to heavy metal stress. In this study, comprehensive analysis of the proximal promoters of members of rice sulfate transporter gene family which is an essential component of stress response has been carried out. Analysis suggests presence of various common stress related cis-acting elements in the promoters of members of this gene family. In addition, transcriptional regulation of the arsenic-responsive high affinity sulfate transporter, OsSul1;1, has been studied through development of Arabidopsis transgenic lines expressing reporter gene encoding beta glucuronidase under the control of OsSul1;1 promoter. Analysis of the transgenic lines suggests differential response of the OsSul1;1 promoter to various heavy metals as well as other abiotic stresses. PMID- 25807336 TI - Male aesthetics. AB - Men are a fast growing segment of the aesthetic industry. A review was performed for publications on gender differences in facial anatomy, behavior, and the use of minimally invasive aesthetic procedures in men. There are substantial facial anatomical differences between genders with men having a larger but unique cranial shape, increased skeletal muscle mass, unique subcutaneous fat distribution, and more severe facial rhytides. Men also exhibit poor behavior that can accelerate aging including poor utilization of preventive health care services, higher rates of smoking, and increased ultraviolet light exposure. Despite gender differences in facial anatomy and behavior, few studies have examined the role of gender in cosmetic procedures. Men require a unique injection technique with botulinum toxin and dermal fillers due to differences in facial anatomy. PMID- 25807338 TI - Three-dimensional local measurements of bone strain and displacement: comparison of three digital volume correlation approaches. AB - Different digital volume correlation (DVC) approaches are currently available or under development for bone tissue micromechanics. The aim of this study was to compare accuracy and precision errors of three DVC approaches for a particular three-dimensional (3D) zero-strain condition. Trabecular and cortical bone specimens were repeatedly scanned with a micro-computed tomography (CT). The errors affecting computed displacements and strains were extracted for a known virtual translation, as well as for repeated scans. Three DVC strategies were tested: two local approaches, based on fast-Fourier-transform (DaVis-FFT) or direct-correlation (DaVis-DC), and a global approach based on elastic registration and a finite element (FE) solver (ShIRT-FE). Different computation subvolume sizes were tested. Much larger errors were found for the repeated scans than for the virtual translation test. For each algorithm, errors decreased asymptotically for larger subvolume sizes in the range explored. Considering this particular set of images, ShIRT-FE showed an overall better accuracy and precision (a few hundreds microstrain for a subvolume of 50 voxels). When the largest subvolume (50-52 voxels) was applied to cortical bone, the accuracy error obtained for repeated scans with ShIRT-FE was approximately half of that for the best local approach (DaVis-DC). The difference was lower (250 microstrain) in the case of trabecular bone. In terms of precision, the errors shown by DaVis-DC were closer to the ones computed by ShIRT-FE (differences of 131 microstrain and 157 microstrain for cortical and trabecular bone, respectively). The multipass computation available for DaVis software improved the accuracy and precision only for the DaVis-FFT in the virtual translation, particularly for trabecular bone. The better accuracy and precision of ShIRT-FE, followed by DaVis-DC, were obtained with a higher computational cost when compared to DaVis-FFT. The results underline the importance of performing a quantitative comparison of DVC methods on the same set of samples by using also repeated scans, other than virtual translation tests only. ShIRT-FE provides the most accurate and precise results for this set of images. However, both DaVis approaches show reasonable results for large nodal spacing, particularly for trabecular bone. Finally, this study highlights the importance of using sufficiently large subvolumes, in order to achieve better accuracy and precision. PMID- 25807339 TI - The Safe Use of Electroconvulsive Therapy in a Patient With a Repaired Arteriovenous Malformation: Images Showing Surgical Clips. AB - We present images showing surgical clips from a remotely repaired cerebral arteriovenous malformation in a patient treated safely with electroconvulsive therapy. PMID- 25807337 TI - Cervical Carcinoma in a Renal Transplant Recipient: A Case Report. AB - A range of cancer types, at increased rates, is described in renal transplant recipients receiving immunosuppression. Aside from immunodeficiency, heightened medical surveillance for cancer, lifestyle, and other risk factors all play a role. Although the relation between cancer risk and degree of immunodeficiency might not be linear, and might be different for a wide range of cancer subtypes, human papillomavirus-related cancers in long-term transplant recipients may suggest the role of even modest immunosuppression, when present long enough. High risk human papillomavirus types are recognized as the cause of cancer of the cervix. We report a 49-year-old female renal transplant recipient diagnosed with cervical squamous cell carcinoma, 5 years after the transplant. Based on this patient, we highlight difficulties in surgical approach and the importance of close clinical follow-up including regular gynecologic screening for cervical premalignant and malignant lesions. PMID- 25807340 TI - Defining the Unique Scope of Psychiatric Practice in 2015. PMID- 25807341 TI - Clinical Pilot Study and Computational Modeling of Bitemporal Transcranial Direct Current Stimulation, and Safety of Repeated Courses of Treatment, in Major Depression. AB - OBJECTIVES: This study aimed to examine a bitemporal (BT) transcranial direct current stimulation (tDCS) electrode montage for the treatment of depression through a clinical pilot study and computational modeling. The safety of repeated courses of stimulation was also examined. METHODS: Four participants with depression who had previously received multiple courses of tDCS received a 4-week course of BT tDCS. Mood and neuropsychological function were assessed. The results were compared with previous courses of tDCS given to the same participants using different electrode montages. Computational modeling examined the electric field maps produced by the different montages. RESULTS: Three participants showed clinical improvement with BT tDCS (mean [SD] improvement, 49.6% [33.7%]). There were no adverse neuropsychological effects. Computational modeling showed that the BT montage activates the anterior cingulate cortices and brainstem, which are deep brain regions that are important for depression. However, a fronto-extracephalic montage stimulated these areas more effectively. No adverse effects were found in participants receiving up to 6 courses of tDCS. CONCLUSIONS: Bitemporal tDCS was safe and led to clinically meaningful efficacy in 3 of 4 participants. However, computational modeling suggests that the BT montage may not activate key brain regions in depression more effectively than another novel montage--fronto-extracephalic tDCS. There is also preliminary evidence to support the safety of up to 6 repeated courses of tDCS. PMID- 25807342 TI - Microarray Analysis of Human Blood During Electroconvulsive Therapy. AB - INTRODUCTION: Electroconvulsive therapy (ECT) is currently regarded as a significant treatment option for intractable psychiatric disorders, such as catatonic schizophrenia or treatment-resistant depression; however, the underlying molecular mechanism for its therapeutic effect remains obscure. METHODS: Employing microarray analysis (Human Genome U133 Plus 2.0 Array; Affymetrix, United States) of cDNA derived from the peripheral blood of patients with catatonic schizophrenia (n = 5), we detected a significant change in 145 genes (0.68%) before and after modified ECT (mECT). Moreover, we performed quantitative polymerase chain reaction validation of genes that had previously been suggested to be functionally related to schizophrenia. RESULTS: Of 4 genes examined (AKT3, TCF7, PPP3R1, and GADD45B), only TCF7 was increased during the mECT procedure (P = 0.0025). DISCUSSION: This study describes the first attempt to uncover the molecular mechanism of mECT using a microarray assay of mRNA derived from peripheral blood, and our results suggest that the TCF family may play a role in the functional mechanism of mECT. PMID- 25807343 TI - Cathodal Transcranial Direct Current Stimulation Over Left Temporoparietal Area for Treatment-Refractory Delusions and Auditory Hallucinations in Schizophrenia: A Case Study. PMID- 25807345 TI - Nitric oxide releasing plasma polymer coating with bacteriostatic properties and no cytotoxic side effects. AB - We report a stable plasma polymer coating, using isopentyl nitrite as a volatile precursor, which releases nitric oxide at bacteriostatic concentrations when contacted with water, inhibiting bacterial growth without cytotoxic side effects to human mesenchymal stem/stromal cells. PMID- 25807344 TI - Trained immunity in newborn infants of HBV-infected mothers. AB - The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns' immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-alpha2. Our data uncover a potentially symbiotic relationship between HBV and its natural host, and highlight the plasticity of the fetal immune system following viral exposure in utero. PMID- 25807347 TI - Bone and morphogenetic protein signalling and muscle mass. AB - PURPOSE OF REVIEW: The purpose of this study is to discuss the involvement of bone and morphogenetic proteins (BMPs) in the control of muscle mass. RECENT FINDINGS: The transforming growth factor-beta (TGFbeta) superfamily comprises a large number of secreted proteins that regulate a variety of fundamental biological processes. Sequence similarities define two ligand subfamilies: the TGFbeta/Activin subfamily and the BMP subfamily. Within the members of TGFbeta subfamily, myostatin emerged as the most critical ligand that affects muscle size and function. Indeed, mutations that inactivate Myostatin lead to important muscle growth in animals and humans. However, recent findings have increased the complexity of the TGFbeta superfamily. Indeed, two independent groups have shown that BMP pathway, acting through Smad1/5/8, is the fundamental hypertrophic signal and dominates Myostatin signalling. Moreover, BMP-Smad1/5/8 negatively regulates a novel ubiquitin ligase, named MUSA1 that is required for muscle loss. This article reviews the rapid progress made in the last year regarding the signalling downstream TGFbeta superfamily and its involvement in the homeostasis of adult muscle fibres. SUMMARY: The recent insights gained into the interplay of TGFbeta and BMP signalling in muscle have challenged our pre-existing ideas of how the adult skeletal muscle phenotype is regulated in health and disease. PMID- 25807348 TI - Transition of maternal and child nutrition in Asia: implications for public health. AB - PURPOSE OF REVIEW: This article reviews the maternal and child nutrition situation in Asia in transition and its public health implications. RECENT FINDINGS: Countries in Asia are facing a double burden of malnutrition. Accessibility to high energy, less nutrient-dense foods or processed foods affects current dietary patterns, whereas industrialization is leading to more sedentary lifestyles both in rural and urban areas. Stunting and wasting among young children persist but have declined in severity, whereas overweight and obesity have risen rapidly. Growth faltering in height during the first 2 years of life has affected muscle mass accretion, but rapid weight gain after 2 years of age has led to more fat accretion, imposing risks of childhood obesity and consequent metabolic disorders. The number of women entering pregnancy with low BMI has decreased, but increasing BMI is noticeable. Prepregnancy BMI and gestational weight gain are important determinants of maternal nutrition during pregnancy, the risk of gestational diabetes and postpartum weight retention, as well as obesity and diet-related noncommunicable diseases in later adulthood. SUMMARY: Asia in transition is faced with persistent undernutrition and increasing trends of obesity and metabolic disorders among children and women. The first 1000 days from conception is a critical period, but it is also a window of opportunity for preventing double burden of malnutrition in Asian countries characterized by a nutrition transition. PMID- 25807346 TI - Protein intake and muscle function in older adults. AB - PURPOSE OF REVIEW: We provide an update on the recent advances in nutrition research regarding the role of protein intake in the development and treatment of sarcopenia of aging. RECENT FINDINGS: Specific muscle mass, strength and function cut-points for the diagnosis of sarcopenia have been identified. There is mounting evidence, as highlighted by multiple consensus statements, that the Recommended Dietary Allowance (0.8 g/kg body weight) may be inadequate to promote optimal health in older adults. Recent research indicates that in addition to total daily protein intake the timing of protein intake is also important to best stimulate muscle protein synthesis, and maintain muscle mass and function in older adults. SUMMARY: Recent evidence suggests that the Recommended Dietary Allowance for protein is inadequate, and that the timing and distribution of protein consumption throughout daily meals may be as important as the total quantity. Research has continued to advance our understanding of protein's effects on muscle metabolism; however, there remains a need for large, long-term, randomized clinical trials examining whether the positive effects of dietary protein on muscle metabolism seen in acute studies will translate over the long term into gains of muscle mass, function, and the overall health of older adults. PMID- 25807350 TI - Modifying diet and physical activity to support pregnant women who are overweight or obese. AB - PURPOSE OF REVIEW: Overweight and obesity represent a significant health burden during pregnancy, placing women and their infants at increased risk of adverse health outcomes. Although there is considerable observational literature describing the effect of gestational weight gain in pregnancy, research efforts have focused on limiting gestational weight gain among pregnant women who are overweight or obese, with limited reporting of clinical outcomes. RECENT FINDINGS: The LIMIT randomized trial recruited 2212 pregnant women with a BMI at least 25 kg/m2. Providing an antenatal dietary and lifestyle intervention was associated with significant improvements in maternal diet and physical activity patterns, and a significant reduction in the risk of infants being born with high birth weight. SUMMARY: The findings of the LIMIT randomized trial provide the first evidence that changes in maternal diet and physical activity during pregnancy can reduce the risk of high infant birth weight among women who are overweight or obese, and from a public health perspective, may represent a significant strategy to tackle the increasing problem of childhood and adulthood obesity. PMID- 25807351 TI - Iron interventions in children from low-income and middle-income populations: benefits and risks. AB - PURPOSE OF REVIEW: Children from low- and middle-income countries are particularly vulnerable to develop iron deficiency and iron deficiency anaemia (IDA), which can be prevented or controlled with different iron intervention strategies. However, there is a debate on the efficacy and safety of iron interventions, especially in children from areas with a high infectious disease burden. This review provides an overview of recent trials that investigated the benefits and potential risks of iron interventions in children from low and middle-income countries. RECENT FINDINGS: Recent studies showed that intermittent iron supplementation is a promising strategy in reducing iron deficiency and IDA. Only a few studies investigated the effect of iron interventions on developmental outcomes, such as growth and cognition, and provided mixed results. An increasing number of studies reported that iron intervention increases morbidity and causes unfavourable shifts in the gut microbial composition along with increases in intestinal inflammation, particularly in children with a high infectious disease burden. SUMMARY: More studies in children from low and middle-income populations are needed that provide evidence for the beneficial effects of iron interventions on functional outcomes beyond alleviating iron deficiency and IDA, and that explore potential mechanisms underlying the negative effects of iron reported in recent trials. PMID- 25807349 TI - Preterm infant nutrition, gut bacteria, and necrotizing enterocolitis. AB - PURPOSE OF REVIEW: Provide research that relates the developing intestinal microbiome, nutrition, and the subsequent host response to the development of necrotizing enterocolitis (NEC), one of the most common and deadliest diseases seen in newborn infants. After nearly 50 years of little to no progress in this area, we are finally beginning to obtain evidence that is likely to lead to better understanding of both pathophysiology and prevention of the disease. RECENT FINDINGS: We will discuss new discoveries related to the development of the microbiome from prenatal to postnatal life, as well as new findings of microbes and human milk oligosaccharides in human milk as they relate to pathogenesis of NEC. The effect of antibiotics and acid blocking agents, as they may increase the odds of development of NEC, will also be discussed. SUMMARY: The implications of these findings are that improved understanding of the developing microbiome, the factors that affect the microbiome including nutrition such as donor milk versus baby's own mother's milk, and certain drugs, will help clinicians to adjust their current feeding and drug utilization to potentially prevent this disease. PMID- 25807352 TI - B-vitamin interventions for women and children in low-income populations. AB - PURPOSE OF REVIEW: This review examines the effect of B vitamins on women and child health from recent evidence available. RECENT FINDINGS: Findings were related to functional outcomes. In terms of foetal growth, although supplementation with B12 increased B12 status of nonpregnant and pregnant women and infants, maternal plasma homocysteine, which is related to multiple deficiencies of vitamin B12, B6, riboflavin or folate, has been shown to be associated with lower birth size rather than solely plasma B12. However, an experimental study with thiamine supplementation showed improvement in status in thiamine-deficient mothers and breast milk concentration, but not in infant status. Given the multiple aetiology of anaemia, the use of multiple micronutrient fortification has expectedly shown a reduction in anaemia prevalence in women. Furthermore, these micronutrients can interact with each other: high maternal folate intakes coupled with low B12 intakes were associated with a higher risk of delivering a small-for-gestational age infant. A high maternal plasma folate was also associated with insulin resistance in children aged 9.5 and 13.5 years. SUMMARY: Interventions with B vitamins were found to be efficacious in improving the status in women and children. In multiple micronutrient supplementation programmes, the optimum composition of the supplement needs to be determined. The deleterious effect of high folate intakes with low B12 intakes needs to be explored further. PMID- 25807353 TI - Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy. AB - PURPOSE OF REVIEW: Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. RECENT FINDINGS: Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. SUMMARY: Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function. PMID- 25807355 TI - Challenges in breast milk fortification for preterm infants. AB - PURPOSE OF REVIEW: To outline new evidence published from 2013 to 2014 about breast milk fortification in preterm infants. RECENT FINDINGS: Breast milk is the feeding choice for preterm infants because of its immunoprotective properties. However, breast milk's nutrient content is not sufficient for preterm infants, and interindividual variation is high. The variation challenges standard fortification, which assumes a standard breast milk composition. Two new fortification strategies (adjustable fortification and target fortification) optimize macronutrient intake and improve growth. Adjustable fortification uses blood urea nitrogen levels to adjust fortifier strength. Target fortification analyzes breast milk and fortifies macronutrients individually to achieve targeted intake. Its feasibility is shown in clinical routine. Current breast milk analyzers used for target fortification achieve acceptable precision for protein and fat but not for lactose and energy. Evidence of benefits for postdischarge breast milk fortification is lacking. Eliminating cow's milk products and feeding exclusively breast milk may decrease the occurrence of feeding intolerance and necrotizing enterocolitis. To facilitate exclusively breast milk diets, a collaboration of prenatal, nutrition and lactation stakeholders is key. Fortification increases osmolality; however, safety cutoffs to prevent necrotizing enterocolitis are unclear. There is also new evidence that composition and structure of various macronutrients and micronutrients affect growth and development, and might play a role in future fortification concepts. SUMMARY: Recent research focuses on the variability of breast milk composition, its impact on postnatal growth patterns and the usefulness of target fortification. As well, diets exclusively composed of human milk are a promising approach to improve feeding tolerance. For safe fortification, osmolality cutoff levels are needed. PMID- 25807357 TI - Correction: Highly dynamic and sex-specific expression of microRNAs during early ES cell differentiation. AB - [This corrects the article DOI: 10.1371/journal.pgen.1000620.]. PMID- 25807354 TI - Latest consensus and update on protein-energy wasting in chronic kidney disease. AB - PURPOSE OF REVIEW: Protein-energy wasting (PEW) is a state of metabolic and nutritional derangements in chronic disease states including chronic kidney disease (CKD). Cumulative evidence suggests that PEW, muscle wasting and cachexia are common and strongly associated with mortality in CKD, which is reviewed here. RECENT FINDINGS: The malnutrition-inflammation score (KALANTAR Score) is among the comprehensive and outcome-predicting nutritional scoring tools. The association of obesity with poor outcomes is attenuated across more advanced CKD stages and eventually reverses in the form of obesity paradox. Frailty is closely associated with PEW, muscle wasting and cachexia. Muscle loss shows stronger associations with unfavorable outcomes than fat loss. Adequate energy supplementation combined with low-protein diet for the management of CKD may prevent the development of PEW and can improve adherence to low-protein diet, but dietary protein requirement may increase with aging and is higher under dialysis therapy. Phosphorus burden may lead to poor outcomes. The target serum bicarbonate concentration is normal range and at least 23 mEq/l for nondialysis dependent and dialysis-dependent CKD patients, respectively. A benefit of exercise is suggested but not yet conclusively proven. SUMMARY: Prevention and treatment of PEW should involve individualized and integrated approaches to modulate identified risk factors and contributing comorbidities. PMID- 25807356 TI - Muscle wasting: is mitochondrial dysfunction a key target? PMID- 25807358 TI - Gas-phase reactions of molecular oxygen with uranyl(V) anionic complexes synthesis and characterization of new superoxides of uranyl(VI). AB - Gas-phase complexes of uranyl(V) ligated to anions X(-) (X = F, Cl, Br, I, OH, NO3, ClO4, HCO2, CH3CO2, CF3CO2, CH3COS, NCS, N3), [UO2X2](-), were produced by electrospray ionization and reacted with O2 in a quadrupole ion trap mass spectrometer to form uranyl(VI) anionic complexes, [UO2X2(O2)](-), comprising a superoxo ligand. The comparative rates for the oxidation reactions were measured, ranging from relatively fast [UO2(OH)2](-) to slow [UO2I2](-). The reaction rates of [UO2X2](-) ions containing polyatomic ligands were significantly faster than those containing the monatomic halogens, which can be attributed to the greater number of vibrational degrees of freedom in the polyatomic ligands to dissipate the energy of the initial O2-association complexes. The effect of the basicity of the X(-) ligands was also apparent in the relative rates for O2 addition, with a general correlation between increasing ligand basicity and O2-addition efficiency for polyatomic ligands. Collision-induced dissociation of the superoxo complexes showed in all cases loss of O2 to form the [UO2X2](-) anions, indicating weaker binding of the O2(-) ligand compared to the X(-) ligands. Density functional theory computations of the structures and energetics of selected species are in accord with the experimental observations. PMID- 25807361 TI - [Life as regulatory activity and self-realization: debate surrounding the concept of biological regulation in Goldstein and Canguilhem]. AB - The influence of Kurt Goldstein on the thinking of Georges Canguilhem extended throughout his entire work. This paper seeks to examine this relationship in order to conduct a study of the norm as a nexus or connection between the concept and life. Consequently, this work will be a reflection on the approach to life as a regulatory activity and self-realization. For this, it will be necessary to redefine the concepts of health and disease, and make a crossover between the two. At the end of this trajectory, it will be found that these concepts can explain the identity between the concept and life, which leads to the unexpected conclusion that the cure is ultimately self-healing. PMID- 25807362 TI - [The "return of the repressed": the role of sexuality in the reception of psychoanalysis in Chilean medical circles, 1910-1940]. AB - This article discusses the reception of psychoanalysis in Chilean medical circles from the decade of 1910 onwards. The findings make it possible to reconstruct how Freudianism was initially rejected by the incipient local psychiatric milieu, accusing it of being pansexualist. In the 1930s, this situation changed, and a reassessment of psychoanalysis was made at a local level, describing it precisely as a branch of knowledge specialized in sexuality. The highlighting of the "sublimation" mechanism, esteemed for its ability to transmute the danger of the "id" into culturally accepted products, is a milestone that marked this "return of the repressed" of the sexual factor of psychoanalysis in Chile. The possible social, political and economic variables that influenced this phenomenon are duly discussed. PMID- 25807360 TI - Establishment and characterization of a new cell line of canine inflammatory mammary cancer: IPC-366. AB - Canine inflammatory mammary cancer (IMC) shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as a natural model for human inflammatory breast cancer (IBC). The aim of this study was to characterize a new cell line from IMC (IPC-366) for the comparative study of both IMC and IBC. Tumors cells from a female dog with clinical IMC were collected. The cells were grown under adherent conditions. The growth, cytological, ultrastructural and immunohistochemical (IHC) characteristics of IPC 366 were evaluated. Ten female Balb/SCID mice were inoculated with IPC-366 cells to assess their tumorigenicity and metastatic potential. Chromosome aberration test and Karyotype revealed the presence of structural aberration, numerical and neutral rearrangements, demonstrating a chromosomal instability. Microscopic examination of tumor revealed an epithelial morphology with marked anysocytosis. Cytological and histological examination of smears and ultrathin sections by electron microscopy revealed that IPC-366 is formed by highly malignant large round or polygonal cells characterized by marked atypia and prominent nucleoli and frequent multinucleated cells. Some cells had cytoplasmic empty spaces covered by cytoplasmic membrane resembling capillary endothelial cells, a phenomenon that has been related to s vasculogenic mimicry. IHC characterization of IPC-366 was basal-like: epithelial cells (AE1/AE3+, CK14+, vimentin+, actin-, p63-, ER-, PR-, HER-2, E-cadherin, overexpressed COX-2 and high Ki-67 proliferation index (87.15 %). At 2 weeks after inoculating the IPC-366 cells, a tumor mass was found in 100 % of mice. At 4 weeks metastases in lung and lymph nodes were found. Xenograph tumors maintained the original IHC characteristics of the female dog tumor. In summary, the cell line IPC-366 is a fast growing malignant triple negative cell line model of inflammatory mammary carcinoma that can be used for the comparative study of both IMC and IBC. PMID- 25807359 TI - Role of signal transducer and activator of transcription 1 in murine allergen induced airway remodeling and exacerbation by carbon nanotubes. AB - Asthma is characterized by a T helper type 2 phenotype and by chronic allergen induced airway inflammation (AAI). Environmental exposure to air pollution ultrafine particles (i.e., nanoparticles) exacerbates AAI, and a concern is possible exacerbation posed by engineered nanoparticles generated by emerging nanotechnologies. Signal transducer and activator of transcription (STAT) 1 is a transcription factor that maintains T helper type 1 cell development. However, the role of STAT1 in regulating AAI or exacerbation by nanoparticles has not been explored. In this study, mice with whole-body knockout of the Stat1 gene (Stat1( /-)) or wild-type (WT) mice were sensitized to ovalbumin (OVA) allergen and then exposed to multiwalled carbon nanotubes (MWCNTs) by oropharygneal aspiration. In Stat1(-/-) and WT mice, OVA increased eosinophils in bronchoalveolar lavage fluid, whereas MWCNTs increased neutrophils. Interestingly, OVA sensitization prevented MWCNT-induced neutrophilia and caused only eosinophilic inflammation. Stat1(-/-) mice displayed increased IL-13 in bronchoalveolar lavage fluid at 1 day compared with WT mice after treatment with OVA or OVA and MWCNTs. At 21 days, the lungs of OVA-sensitized Stat1(-/-) mice displayed increased eosinophilia, goblet cell hyperplasia, airway fibrosis, and subepithelial apoptosis. MWCNTs further increased OVA-induced goblet cell hyperplasia, airway fibrosis, and apoptosis in Stat1(-/-) mice at 21 days. These changes corresponded to increased levels of profibrogenic mediators (transforming growth factor-beta1, TNF-alpha, osteopontin) but decreased IL-10 in Stat1(-/-) mice. Finally, fibroblasts isolated from the lungs of Stat1(-/-) mice produced significantly more collagen mRNA and protein in response to transforming growth factor-beta1 compared with WT lung fibroblasts. Our results support a protective role for STAT1 in chronic AAI and exacerbation of remodeling caused by MWCNTs. PMID- 25807366 TI - Urinary proteins, vitamin D and genetic polymorphisms as risk factors for febrile urinary tract infection and relation with bacteremia: a case control study. AB - OBJECTIVE/PURPOSE: Febrile urinary tract infection (UTI) is a common bacterial disease that may lead to substantial morbidity and mortality especially among the elderly. Little is known about biomarkers that predict a complicated course. Our aim was to determine the role of certain urinary cytokines or antimicrobial proteins, plasma vitamin D level, and genetic variation in host defense of febrile UTI and its relation with bacteremia. METHODS: A case-control study. Out of a cohort of consecutive adults with febrile UTI (n = 787) included in a multi center observational cohort study, 46 cases with bacteremic E.coli UTI and 45 cases with non-bacteremic E.coli UTI were randomly selected and compared to 46 controls. Urinary IL-6, IL-8, LL37, beta-defensin 2 and uromodulin as well as plasma 25-hydroxyvitamin D were measured. In 440 controls and 707 UTI patients polymorphisms were genotyped in the genes CXCR1, DEFA4, DEFB1, IL6, IL8, MYD88, UMOD, TIRAP, TLR1, TLR2, TLR5 and TNF. RESULTS: IL-6, IL-8, and LL37 are different between controls and UTI patients, although these proteins do not distinguish between patients with and without bacteremia. While uromodulin did not differ between groups, inability to produce uromodulin is more common in patients with bacteremia. Most participants in the study, including the controls, had insufficient vitamin D and, at least in winter, UTI patients have lower vitamin D than controls. Associations were found between the CC genotype of IL6 SNP rs1800795 and occurrence of bacteremia and between TLR5 SNP rs5744168 and protection from UTI. The rare GG genotype of IL6 SNP rs1800795 was associated with higher beta-defensin 2 production. CONCLUSION: Although no biomarker was able to distinguish between UTI with or without bacteremia, two risk factors for bacteremia were identified. These were inability to produce uromodulin and an IL6 rs1800795 genotype. PMID- 25807367 TI - Anti-inflammatory activity of Choisya ternata Kunth essential oil, ternanthranin, and its two synthetic analogs (methyl and propyl N-methylanthranilates). AB - Choisya ternata Kunth (Rutaceae) is native to North America where it is popularly known as "Mexican orange". In this study, the anti-inflammatory effects of the essential oil (EO) obtained from the leaves of C. ternata, one of its minor components (ternanthranin-ISOAN) and its two synthetic analogues (methyl and propyl N-methylanthranilate--MAN and PAN) were evaluated. Mice pretreated with the EO (EO) obtained from C. ternata leaves (3-100 mg/kg, p.o.), ISOAN, MAN or PAN (1-30 mg/kg, p.o.) and the reference drugs, morphine (1 mg/kg, p.o.) and acetylsalicylic acid (ASA, 100 mg/kg, p.o.), were evaluated in inflammation models such as formalin and subcutaneous air pouch models, with measurement of cell migration, exudate volume, protein extravasation, nitric oxide and pro inflammatory cytokines. The EO from C. ternata significantly inhibited the time that the animals spent licking the formalin-injected paw in the second phase of the model at their higher doses (30 and 100 mg/kg, respectively). An inhibition of the inflammatory reaction induced after subcutaneous carrageenan injection into air pouch was also observed. In this model, the EO significantly reduced cell migration, exudate volume, protein extravased, and the increase in levels of inflammatory mediators (nitric oxide, TNF-alpha and IL-1beta). ISOAN, MAN and PAN behaved in the same fashion at much smaller doses. Also, these molecules were able to show significant effects in the reduction of paw edema (at all tested doses) when the phlogistic agent was carrageenan, bradykinin, 5-HT, PGE2, C48/80 or 12-O-tetradecanoylphorbol-acetate (TPA). None of the tested doses had any effect in reducing histamine-induced edema. Our results indicate that the EO from C. ternata and anthranilate derivatives demonstrates an anti-inflammatory effect. PMID- 25807368 TI - A maize jasmonate Zim-domain protein, ZmJAZ14, associates with the JA, ABA, and GA signaling pathways in transgenic Arabidopsis. AB - Jasmonate (JA) is an important signaling molecule involved in the regulation of many physiological and stress-related processes in plants. Jasmonate ZIM-domain (JAZ) proteins have been implicated in regulating JA signaling pathways and the cross talk between various phytohormones. Maize is not only an important cereal crop, but also a model plant for monocotyledon studies. Although many JAZ proteins have been characterized in Arabidopsis and rice, few reports have examined the function of JAZ proteins in maize. In this report, we examined the phylogenetic relationship and expression pattern of JAZ family genes in maize. In addition, a tassel and endosperm-specific JAZ gene, ZmJAZ14, was identified using microarray data analysis and real-time RT-PCR, and its expression was induced by polyethylene glycol (PEG), jasmonate (JA), abscisic acid (ABA), and gibberellins (GAs). ZmJAZ14 was shown to be localized in the nucleus and possessed no transcriptional activating activity, suggesting that it functions as a transcriptional regulator. We found that overexpression of ZmJAZ14 in Arabidopsis enhanced plant tolerance to JA and ABA treatment, as well as PEG stress, while it promoted growth under GA stimulus. Moreover, ZmJAZ14 interacted with a subset of transcription factors in Arabidopsis, and the accumulation of several marker genes involved in JA, ABA, and GA signaling pathways were altered in the overexpression lines. These results suggest that ZmJAZ14 may serve as a hub for the cross talk among the JA, ABA, and GA signaling pathways. Our results can be used to further characterize the function of JAZ family proteins in maize, and the gene cloned in this study may serve as a candidate for drought tolerance and growth promotion regulation in maize. PMID- 25807369 TI - Genetic control of the leaf angle and leaf orientation value as revealed by ultra high density maps in three connected maize populations. AB - Plant architecture is a key factor for high productivity maize because ideal plant architecture with an erect leaf angle and optimum leaf orientation value allow for more efficient light capture during photosynthesis and better wind circulation under dense planting conditions. To extend our understanding of the genetic mechanisms involved in leaf-related traits, three connected recombination inbred line (RIL) populations including 538 RILs were genotyped by genotyping-by sequencing (GBS) method and phenotyped for the leaf angle and related traits in six environments. We conducted single population quantitative trait locus (QTL) mapping and joint linkage analysis based on high-density recombination bin maps constructed from GBS genotype data. A total of 45 QTLs with phenotypic effects ranging from 1.2% to 29.2% were detected for four leaf architecture traits by using joint linkage mapping across the three populations. All the QTLs identified for each trait could explain approximately 60% of the phenotypic variance. Four QTLs were located on small genomic regions where candidate genes were found. Genomic predictions from a genomic best linear unbiased prediction (GBLUP) model explained 45+/-9% to 68+/-8% of the variation in the remaining RILs for the four traits. These results extend our understanding of the genetics of leaf traits and can be used in genomic prediction to accelerate plant architecture improvement. PMID- 25807370 TI - Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2 Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress. AB - Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4 thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol (1,2-NQH2-SH) and a generator of reactive oxygen species (ROS), we demonstrate that protein thiols can be modified by a reactive sulfenic acid to form disulfide adducts that undergo rapid cleavage in the presence of glutathione (GSH). As expected, 1,2-NQH2-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2 NQ-SH, resulting in a redox cycling reaction that produces ROS through a chemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SH and 1,2-NQH2-SH were detected by derivatization experiments with dimedone. 1,2-NQH2-SOH modified Keap1 at Cys171 to produce a Keap1-S-S-1,2-NQH2 adduct. Subsequent exposure of A431 cells to 1,2-NQ or 1,2-NQH2-SAc caused an extensive chemical modification of cellular proteins in both cases. Protein adduction by 1,2-NQ through a thio ether (C-S-C) bond slowly declined through a GSH-dependent S-transarylation reaction, whereas that originating from 1,2-NQH2-SAc through a disulfide (C-S-S-C) bond was rapidly restored to the free protein thiol in the cells. Under these conditions, 1,2-NQH2-SAc activated Nrf2 and upregulated its target genes, which were enhanced by pretreatment with buthionine sulfoximine (BSO), to deplete cellular GSH. Pretreatment of catalase conjugated with poly(ethylene glycol) suppressed Nrf2 activation by 1,2-NQH2-SAc. These results suggest that RSS-mediated reversible electrophilic signaling takes place through sulfenic acids formation under oxidative stress. PMID- 25807371 TI - Analysis of disease-associated protein expression using quantitative proteomics fibulin-5 is expressed in association with hepatic fibrosis. AB - Hepatic fibrosis and cirrhosis are major health problems worldwide. Until now, highly invasive biopsy remains the diagnostic gold standard despite many disadvantages. To develop noninvasive diagnostic assays for the assessment of liver fibrosis, it is urgently necessary to identify molecules that are robustly expressed in association with the disease. We analyzed biopsied tissue samples from 95 patients with HBV/HCV-associated hepatic fibrosis using three different quantification methods. We performed a label-free proteomics discovery study to identify novel disease-associated proteins using a subset of the cohort (n = 27). Subsequently, gene expression data from all available clinical samples were analyzed (n = 77). Finally, we performed a targeted proteomics approach, multiple reaction monitoring (MRM), to verify the disease-associated expression in samples independent from the discovery approach (n = 68). We identified fibulin-5 (FBLN5) as a novel protein expressed in relation to hepatic fibrosis. Furthermore, we confirmed the altered expression of microfibril-associated glycoprotein 4 (MFAP4), lumican (LUM), and collagen alpha-1(XIV) chain (COL14A1) in association to hepatic fibrosis. To our knowledge, no tissue-based quantitative proteomics study for hepatic fibrosis has been performed using a cohort of comparable size. By this means, we add substantial evidence for the disease-related expression of the proteins examined in this study. PMID- 25807373 TI - [2.2]Paracyclophane-derived monodentate phosphoramidite ligands for copper catalyzed asymmetric conjugate addition of diethylzinc to substituted chalcones. AB - Copper-catalyzed asymmetric conjugate addition of diethylzinc to chalcones could be realized by using [2.2]paracyclophane-derived monodentate phosphoramidite ligands. The excellent yield and enantioselectivity (up to 98% yield and 95% enantiomeric excess) could be realized with low catalyst loading of 1.0 mol % and low ligand loading of 1.2%. PMID- 25807372 TI - Significance of oxygen supply in jarosite biosynthesis promoted by Acidithiobacillus ferrooxidans. AB - Jarosite [(Na+, K+, NH4+, H3O+)Fe3(SO4)2(OH)6] is an efficient scavenger for trace metals in Fe- and SO42--rich acidic water. During the biosynthesis of jarosite promoted by Acidithiobacillus ferrooxidans, the continuous supply of high oxygen levels is a common practice that results in high costs. To evaluate the function of oxygen in jarosite production by A. ferrooxidans, three groups of batch experiments with different oxygen supply levels (i.e., loading volume percentages of FeSO4 solution of 20%, 40%, and 70% v/v in the flasks), as well as three groups of sealed flask experiments with different limiting oxygen supply conditions (i.e., the solutions were not sealed at the initial stage of the ferrous oxidation reaction by paraffin but were rather sealed at the end of the ferrous oxidation reaction at 48 h), were tested. The formed Fe-precipitates were characterized via X-ray powder diffraction and scanning electron microscope energy dispersive spectral analysis. The results showed that the biosynthesis of jarosite by A. ferrooxidans LX5 could be achieved at a wide range of solution loading volume percentages. The rate and efficiency of the jarosite biosynthesis were poorly correlated with the concentration of dissolved oxygen in the reaction solution. Similar jarosite precipitates, expressed as KFe3 (SO4) 2(OH)6 with Fe/S molar ratios between 1.61 and 1.68, were uniformly formed in unsealed and 48 h sealed flasks. These experimental results suggested that the supply of O2 was only essential in the period of the oxidation of ferrous iron to ferric but was not required in the period of ferric precipitation. PMID- 25807375 TI - Correction: Reprogramming of Yersinia from virulent to persistent mode revealed by complex in vivo RNA-seq analysis. PMID- 25807374 TI - Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways. AB - Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through _3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts. PMID- 25807377 TI - n-Type semiconducting naphthalene diimide-perylene diimide copolymers: controlling crystallinity, blend morphology, and compatibility toward high performance all-polymer solar cells. AB - Knowledge of the critical factors that determine compatibility, blend morphology, and performance of bulk heterojunction (BHJ) solar cells composed of an electron accepting polymer and an electron-donating polymer remains limited. To test the idea that bulk crystallinity is such a critical factor, we have designed a series of new semiconducting naphthalene diimide (NDI)-selenophene/perylene diimide (PDI)-selenophene random copolymers, xPDI (10PDI, 30PDI, 50PDI), whose crystallinity varies with composition, and investigated them as electron acceptors in BHJ solar cells. Pairing of the reference crystalline (crystalline domain size Lc = 10.22 nm) NDI-selenophene copolymer (PNDIS-HD) with crystalline (Lc = 9.15 nm) benzodithiophene-thieno[3,4-b]thiophene copolymer (PBDTTT-CT) donor yields incompatible blends, whose BHJ solar cells have a power conversion efficiency (PCE) of 1.4%. However, pairing of the new 30PDI with optimal crystallinity (Lc = 5.11 nm) as acceptor with the same PBDTTT-CT donor yields compatible blends and all-polymer solar cells with enhanced performance (PCE = 6.3%, Jsc = 18.6 mA/cm(2), external quantum efficiency = 91%). These photovoltaic parameters observed in 30PDI:PBDTTT-CT devices are the best so far for all polymer solar cells, while the short-circuit current (Jsc) and external quantum efficiency are even higher than reported values for [70]-fullerene:PBDTTT-CT solar cells. The morphology and bulk carrier mobilities of the polymer/polymer blends varied substantially with crystallinity of the acceptor polymer component and thus with the NDI/PDI copolymer composition. These results demonstrate that the crystallinity of a polymer component and thus compatibility, blend morphology, and efficiency of polymer/polymer blend solar cells can be controlled by molecular design. PMID- 25807376 TI - Words analysis of online Chinese news headlines about trending events: a complex network perspective. AB - Because the volume of information available online is growing at breakneck speed, keeping up with meaning and information communicated by the media and netizens is a new challenge both for scholars and for companies who must address public relations crises. Most current theories and tools are directed at identifying one website or one piece of online news and do not attempt to develop a rapid understanding of all websites and all news covering one topic. This paper represents an effort to integrate statistics, word segmentation, complex networks and visualization to analyze headlines' keywords and words relationships in online Chinese news using two samples: the 2011 Bohai Bay oil spill and the 2010 Gulf of Mexico oil spill. We gathered all the news headlines concerning the two trending events in the search results from Baidu, the most popular Chinese search engine. We used Simple Chinese Word Segmentation to segment all the headlines into words and then took words as nodes and considered adjacent relations as edges to construct word networks both using the whole sample and at the monthly level. Finally, we develop an integrated mechanism to analyze the features of words' networks based on news headlines that can account for all the keywords in the news about a particular event and therefore track the evolution of news deeply and rapidly. PMID- 25807380 TI - A game theoretic framework for analyzing re-identification risk. AB - Given the potential wealth of insights in personal data the big databases can provide, many organizations aim to share data while protecting privacy by sharing de-identified data, but are concerned because various demonstrations show such data can be re-identified. Yet these investigations focus on how attacks can be perpetrated, not the likelihood they will be realized. This paper introduces a game theoretic framework that enables a publisher to balance re-identification risk with the value of sharing data, leveraging a natural assumption that a recipient only attempts re-identification if its potential gains outweigh the costs. We apply the framework to a real case study, where the value of the data to the publisher is the actual grant funding dollar amounts from a national sponsor and the re-identification gain of the recipient is the fine paid to a regulator for violation of federal privacy rules. There are three notable findings: 1) it is possible to achieve zero risk, in that the recipient never gains from re-identification, while sharing almost as much data as the optimal solution that allows for a small amount of risk; 2) the zero-risk solution enables sharing much more data than a commonly invoked de-identification policy of the U.S. Health Insurance Portability and Accountability Act (HIPAA); and 3) a sensitivity analysis demonstrates these findings are robust to order-of-magnitude changes in player losses and gains. In combination, these findings provide support that such a framework can enable pragmatic policy decisions about de identified data sharing. PMID- 25807378 TI - Differential effect of amylin on endothelial-dependent vasodilation in mesenteric arteries from control and insulin resistant rats. AB - Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, amylin has long been related to IR. However the role of amylin in the vascular dysfunction associated to IR is not well addressed. Therefore, the aim of the study was to assess the effect of acute treatment with amylin on endothelium-dependent vasodilation of isolated mesenteric arteries from control (CR) and insulin resistant (IRR) rats and to evaluate the possible mechanisms involved. Five week-old male Wistar rats received 20% D-fructose dissolved in drinking water for 8 weeks and were compared with age-matched CR. Plasmatic levels of glucose, insulin and amylin were measured. Mesenteric microvessels were dissected and mounted in wire myographs to evaluate endothelium-dependent vasodilation to acetylcholine. IRR displayed a significant increase in plasmatic levels of glucose, insulin and amylin and reduced endothelium-dependent relaxation when compared to CR. Acute treatment of mesenteric arteries with r amylin (40 pM) deteriorated endothelium-dependent responses in CR. Amylin-induced reduction of endothelial responses was unaffected by the H2O2 scavenger, catalase, but was prevented by the extracellular superoxide scavenger, superoxide dismutase (SOD) or the NADPH oxidase inhibitor (VAS2870). By opposite, amylin failed to further inhibit the impaired relaxation in mesenteric arteries of IRR. SOD, or VAS2870, but not catalase, ameliorated the impairment of endothelium dependent relaxation in IRR. At concentrations present in insulin resistance conditions, amylin impairs endothelium-dependent vasodilation in mircrovessels from rats with preserved vascular function and low levels of endogenous amylin. In IRR with established endothelial dysfunction and elevated levels of amylin, additional exposure to this peptide has no effect on endothelial vasodilation. Increased superoxide generation through NADPH oxidase activity may be a common link involved in the endothelial dysfunction associated to insulin resistance and to amylin exposure in CR. PMID- 25807379 TI - Improving transformation of Staphylococcus aureus belonging to the CC1, CC5 and CC8 clonal complexes. AB - Methicillin resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen found in hospital and community environments that can cause serious infections. A major barrier to genetic manipulations of clinical isolates has been the considerable difficulty in transforming these strains with foreign plasmids, such as those from E. coli, in part due to the type I and IV Restriction Modification (R-M) barriers. Here we combine a Plasmid Artificial Modification (PAM) system with DC10B E. coli cells (dcm mutants) to bypass the barriers of both type I and IV R-M of S. aureus, thus allowing E. coli plasmid DNA to be transformed directly into clinical MRSA strains MW2, N315 and LAC, representing three of the most common clonal complexes. Successful transformation of clinical S. aureus isolates with E. coli-derived plasmids should greatly increase the ability to genetically modify relevant S. aureus strains and advance our understanding of S. aureus pathogenesis. PMID- 25807383 TI - Correction: Pulmonary hypertension: epidemiology in different CKD stages and its association with cardiovascular morbidity. PMID- 25807382 TI - Phosphorylation of Mycobacterium tuberculosis ParB participates in regulating the ParABS chromosome segregation system. AB - Here, we present for the first time that Mycobacterium tuberculosis ParB is phosphorylated by several mycobacterial Ser/Thr protein kinases in vitro. ParB and ParA are the key components of bacterial chromosome segregation apparatus. ParB is a cytosolic conserved protein that binds specifically to centromere-like DNA parS sequences and interacts with ParA, a weak ATPase required for its proper localization. Mass spectrometry identified the presence of ten phosphate groups, thus indicating that ParB is phosphorylated on eight threonines, Thr32, Thr41, Thr53, Thr110, Thr195, and Thr254, Thr300, Thr303 as well as on two serines, Ser5 and Ser239. The phosphorylation sites were further substituted either by alanine to prevent phosphorylation or aspartate to mimic constitutive phosphorylation. Electrophoretic mobility shift assays revealed a drastic inhibition of DNA binding by ParB phosphomimetic mutant compared to wild type. In addition, bacterial two-hybrid experiments showed a loss of ParA-ParB interaction with the phosphomimetic mutant, indicating that phosphorylation is regulating the recruitment of the partitioning complex. Moreover, fluorescence microscopy experiments performed in the surrogate Mycobacterium smegmatis DeltaparB strain revealed that in contrast to wild type Mtb ParB, which formed subpolar foci similar to M. smegmatis ParB, phoshomimetic Mtb ParB was delocalized. Thus, our findings highlight a novel regulatory role of the different isoforms of ParB representing a molecular switch in localization and functioning of partitioning protein in Mycobacterium tuberculosis. PMID- 25807384 TI - A framework for understanding and generating integrated solutions for residential peak energy demand. AB - Supplying peak energy demand in a cost effective, reliable manner is a critical focus for utilities internationally. Successfully addressing peak energy concerns requires understanding of all the factors that affect electricity demand especially at peak times. This paper is based on past attempts of proposing models designed to aid our understanding of the influences on residential peak energy demand in a systematic and comprehensive way. Our model has been developed through a group model building process as a systems framework of the problem situation to model the complexity within and between systems and indicate how changes in one element might flow on to others. It is comprised of themes (social, technical and change management options) networked together in a way that captures their influence and association with each other and also their influence, association and impact on appliance usage and residential peak energy demand. The real value of the model is in creating awareness, understanding and insight into the complexity of residential peak energy demand and in working with this complexity to identify and integrate the social, technical and change management option themes and their impact on appliance usage and residential energy demand at peak times. PMID- 25807381 TI - Changes in membrane plasmalogens of Clostridium pasteurianum during butanol fermentation as determined by lipidomic analysis. AB - Changes in membrane lipid composition of Clostridium pasteurianum NRRL B-598 were studied during butanol fermentation by lipidomic analysis, performed by high resolution electrospray ionization tandem mass spectrometry. The highest content of plasmalogen phospholipids correlated with the highest butanol productivity, which indicated a probable role of these compounds in the complex responses of cells toward butanol stress. A difference in the ratio of saturated to unsaturated fatty acids was found between the effect of butanol produced by the cells and butanol added to the medium. A decrease in the proportion of saturated fatty acids during conventional butanol production was observed while a rise in the content of these acids appeared when butanol was added to the culture. The largest change in total plasmalogen content was observed one hour after butanol addition i.e. at the 7th hour of cultivation. When butanol is produced by bacterial cells, then the cells are not subjected to severe stress and responded to it by relatively slowly changing the content of fatty acids and plasmalogens, while after a pulse addition of external butanol (to a final non-lethal concentration of 0.5 % v/v) the cells reacted relatively quickly (within a time span of tens of minutes) by increasing the total plasmalogen content. PMID- 25807388 TI - A panorama of tooth wear during the medieval period. AB - Tooth wear is a natural phenomenon and a universal occurrence that has existed from the origin of humankind and depends on the way of life, especially diet. Tooth wear was very serious in ancient populations up to the medieval period. The aim of this paper is to present a global view of tooth wear in medieval times in Europe through different parameters: scoring systems, quantity and direction of wear, gender, differences between maxilla and mandible, relations with diet, caries, tooth malpositions and age. PMID- 25807387 TI - Total 25-hydroxyvitamin D concentration as a predictor for all-cause death and cardiovascular event risk among ethnic Chinese adults: a cohort study in a Taiwan community. AB - BACKGROUND: Evidence of an inverse association between serum 25-hydoroxyvitamin D [25(OH)D] and the risk of all-cause death and cardiovascular disease from prospective studies is inconsistent. We tested the relationship between 25(OH)D and the risk among adult ethnic Chinese in Taiwan. METHODS: We conducted a community-based cohort study of 1816 participants (age 60.2+/-10.2 yrs, 45.0% women) in the Chin-Shan Community Cardiovascular Cohort Study who were free of cardiovascular diseases at baseline and provided 25(OH)D measurements. RESULTS: During a median 9.6 (interquartile range, 8.8- 10.5) years' follow-up period, totally 263 cases developed cardiovascular death events and 559 participants were documented to death from any cause. As 25(OH)D concentration increased, the incidence rates of cardiovascular events and all-cause death decreased progressively. 25(OH)D was inversely associated with all-cause death: the adjusted hazard ratio was 0.49 (95% confidence interval [CI], 0.25-0.97) for the third quartile and a significant J-shape relationship was found. The performance measures by integrated discriminative improvement showed significant improvement after adding 25(OH)D information (0.14%, 95% CI, 0.03-0.31, P=0.050, for all cause death and 0.32%, 95% CI, 0.02-0.62, P=0.018 for cardiovascular events). CONCLUSION: These findings suggested a modest inverse association between 25(OH)D and the risk of all-cause death among diabetic participants and a good predictive factor in the community. Further studies to investigate the mechanism of vitamin D role on health effect are warranted. PMID- 25807390 TI - Differentiating self-projection from simulation during mentalizing: evidence from fMRI. AB - We asked participants to predict which of two colors a similar other (student) and a dissimilar other (retiree) likes better. We manipulated if color-pairs were two hues from the same color-category (e.g. green) or two conceptually different colors (e.g. green versus blue). In the former case, the mental state that has to be represented (i.e., the percept of two different hues of green) is predominantly non-conceptual or phenomenal in nature, which should promote mental simulation as a strategy for mentalizing. In the latter case, the mental state (i.e. the percept of green versus blue) can be captured in thought by concepts, which facilitates the use of theories for mentalizing. In line with the self projection hypothesis, we found that cortical midline areas including vmPFC / orbitofrontal cortex and precuneus were preferentially activated for mentalizing about a similar other. However, activation was not affected by the nature of the color-difference, suggesting that self-projection subsumes simulation-like processes but is not limited to them. This indicates that self-projection is a universal strategy applied in different contexts--irrespective of the availability of theories for mentalizing. Along with midline activations linked to self-projection, we also observed activation in right lateral frontal and dorsal parietal areas showing a theory-like pattern. Taken together, this shows that mentalizing does not operate based on simulation or theory, but that both strategies are used concurrently to predict the choices of others. PMID- 25807391 TI - Japanese lifestyle during childhood prevents the future development of obesity among Japanese-Americans. AB - OBJECTIVE: To evaluate whether a Japanese lifestyle during childhood could protect against the future development of obesity-associated metabolic diseases by comparing native Japanese with Japanese-Americans in whom genetic factors are the same. METHODS: Study subjects were 516 native Japanese and 781 Japanese Americans who underwent medical examinations between 2007 and 2010. Japanese Americans were divided into 444 first-generation immigrants (JA-1), who were born in Japan, and 337 second- or later-generation descendants (JA-2), who were born in the United States. The JA-2 group was then divided into the kibei subgroup (N = 79), who had moved to Japan before the age of 18 years and later returned to the United States, and the non-kibei subgroup (N = 258), who had never lived in Japan. RESULTS: The JA-2 group had the highest percentages of obesity, metabolic syndrome, and type 2 diabetes compared with native Japanese and JA-1. Furthermore, among JA-2, the prevalence of obesity and metabolic syndrome in the kibei subgroup was significantly lower than that in the non-kibei subgroup. The prevalence of diabetes in the kibei subgroup also tended to be lower than in the non-kibei subgroup. CONCLUSIONS: The prevalence of obesity and metabolic diseases differed with residence in Japan during childhood among Japanese-Americans. These findings indicate the possibility that Japanese lifestyle during childhood could reduce the future risks for obesity-associated metabolic diseases. PMID- 25807389 TI - Inferring synaptic structure in presence of neural interaction time scales. AB - Biological networks display a variety of activity patterns reflecting a web of interactions that is complex both in space and time. Yet inference methods have mainly focused on reconstructing, from the network's activity, the spatial structure, by assuming equilibrium conditions or, more recently, a probabilistic dynamics with a single arbitrary time-step. Here we show that, under this latter assumption, the inference procedure fails to reconstruct the synaptic matrix of a network of integrate-and-fire neurons when the chosen time scale of interaction does not closely match the synaptic delay or when no single time scale for the interaction can be identified; such failure, moreover, exposes a distinctive bias of the inference method that can lead to infer as inhibitory the excitatory synapses with interaction time scales longer than the model's time-step. We therefore introduce a new two-step method, that first infers through cross correlation profiles the delay-structure of the network and then reconstructs the synaptic matrix, and successfully test it on networks with different topologies and in different activity regimes. Although step one is able to accurately recover the delay-structure of the network, thus getting rid of any a priori guess about the time scales of the interaction, the inference method introduces nonetheless an arbitrary time scale, the time-bin dt used to binarize the spike trains. We therefore analytically and numerically study how the choice of dt affects the inference in our network model, finding that the relationship between the inferred couplings and the real synaptic efficacies, albeit being quadratic in both cases, depends critically on dt for the excitatory synapses only, whilst being basically independent of it for the inhibitory ones. PMID- 25807395 TI - Hole selective NiO contact for efficient perovskite solar cells with carbon electrode. AB - In this study, we communicate an investigation on efficient CH3NH3PbI3-based solar cells with carbon electrode using mesoporous TiO2 and NiO layers as electron and hole selective contacts. The device possesses an appreciated power conversion efficiency of 14.9% under AM 1.5G illumination. The detailed information can be disclosed with impedance spectroscopy via tuning the interfaces between CH3NH3PbI3 and different charge selective contacts. The results clearly show charge accumulation at the interface of CH3NH3PbI3. The NiO is believed to efficiently accelerate charge extraction to the external circuit. The extracted charge could improve photovoltaic performance by shifting hole Fermi level down, achieving a high device photovoltage. A fast interfacial recombination at the interface of CH3NH3PbI3/electron selective contact layer (mesoporous TiO2), occurring in millisecond domains, is the critical issue for charge carrier recombination loss. PMID- 25807385 TI - Factors associated with patient and provider delays for tuberculosis diagnosis and treatment in Asia: a systematic review and meta-analysis. AB - BACKGROUND: Delays in tuberculosis (TB) diagnosis and treatment is a major barrier to effective management of the disease. Determining the factors associated with patient and provider delay of TB diagnosis and treatment in Asia may contribute to TB prevention and control. METHODS: We searched the PubMed, EMBASE and Web of Science for studies that assessed factors associated with delays in care-seeking, diagnosis, or at the beginning of treatment, which were published from January 1992 to September 2014. Two reviewers independently identified studies that were related to our meta-analysis and extracted data from each study. Independent variables were categorized in separate tables for patient and provider delays. RESULTS: Among 45 eligible studies, 40 studies assessed patient delay whereas 30 assessed provider delay. Cross-sectional surveys were used in all but two articles, which included 17 countries and regions. Socio demographic characteristics, TB-related symptoms and medical examination, and conditions of seeking medical care in TB patients were frequently reported. Male patients and long travel time/distance to the first healthcare provider led to both shorter patient delays [odds ratio (OR) (95% confidence intervals, CI) = 0.85 (0.78, 0.92); 1.39 (1.08, 1.78)] and shorter provider delays [OR (95%CI) = 0.96 (0.93, 1.00); 1.68 (1.12, 2.51)]. Unemployment, low income, hemoptysis, and positive sputum smears were consistently associated with patient delay [ORs (95%CI) = 1.18 (1.07, 1.30), 1.23 (1.02, 1.49), 0.64 (0.40, 1.00), 1.77 (1.07, 2.94), respectively]. Additionally, consultation at a public hospital was associated with provider delay [OR (95%CI) = 0.43 (0.20, 0.91)]. CONCLUSIONS: We propose that the major opportunities to reduce delays involve enabling socio demographic factors and medical conditions. Male, unemployed, rural residence, low income, hemoptysis, positive sputum smear, and long travel time/distance significantly correlated with patient delay. Male, long travel time/distance and consultation at a public hospital were related to provider delay. PMID- 25807386 TI - Angiotensin II-induced arterial thickening, fibrosis and stiffening involves elevated arginase function. AB - BACKGROUND: Arterial stiffness (AS) is an independent risk factor for cardiovascular morbidity/mortality. Smooth muscle cell (SMC) proliferation and increased collagen synthesis are key features in development of AS. Arginase (ARG), an enzyme implicated in many cardiovascular diseases, can compete with nitric oxide (NO) synthase for their common substrate, L-arginine. Increased arginase can also provide ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT), leading to vascular cell proliferation and collagen formation, respectively. We hypothesized that elevated arginase activity is involved in Ang II-induced arterial thickening, fibrosis, and stiffness and that limiting its activity can prevent these changes. METHODS AND RESULTS: We tested this by studies in mice lacking one copy of the ARG1 gene that were treated with angiotensin II (Ang II, 4 weeks). Studies were also performed in rat aortic Ang II-treated SMC. In WT mice treated with Ang II, we observed aortic stiffening (pulse wave velocity) and aortic and coronary fibrosis and thickening that were associated with increases in ARG1 and ODC expression/activity, proliferating cell nuclear antigen, hydroxyproline levels, and collagen 1 protein expression. ARG1 deletion prevented each of these alterations. Furthermore, exposure of SMC to Ang II (1 MUM, 48 hrs) increased ARG1 expression, ARG activity, ODC mRNA and activity, cell proliferation, collagen 1 protein expression and hydroxyproline content. Treatment with ABH prevented these changes. CONCLUSION: Arginase 1 is crucially involved in Ang II-induced SMC proliferation and arterial fibrosis and stiffness and represents a promising therapeutic target. PMID- 25807396 TI - Correction: New clothes for the jasmonic acid receptor COI1: delayed abscission, meristem arrest and apical dominance. PMID- 25807394 TI - Frequent video game players resist perceptual interference. AB - Playing certain types of video games for a long time can improve a wide range of mental processes, from visual acuity to cognitive control. Frequent gamers have also displayed generalized improvements in perceptual learning. In the Texture Discrimination Task (TDT), a widely used perceptual learning paradigm, participants report the orientation of a target embedded in a field of lines and demonstrate robust over-night improvement. However, changing the orientation of the background lines midway through TDT training interferes with overnight improvements in overall performance on TDT. Interestingly, prior research has suggested that this effect will not occur if a one-hour break is allowed in between the changes. These results have suggested that after training is over, it may take some time for learning to become stabilized and resilient against interference. Here, we tested whether frequent gamers have faster stabilization of perceptual learning compared to non-gamers and examined the effect of daily video game playing on interference of training of TDT with one background orientation on perceptual learning of TDT with a different background orientation. As a result, we found that non-gamers showed overnight performance improvement only on one background orientation, replicating previous results with the interference in TDT. In contrast, frequent gamers demonstrated overnight improvements in performance with both background orientations, suggesting that they are better able to overcome interference in perceptual learning. This resistance to interference suggests that video game playing not only enhances the amplitude and speed of perceptual learning but also leads to faster and/or more robust stabilization of perceptual learning. PMID- 25807393 TI - A unique HMG-box domain of mouse Maelstrom binds structured RNA but not double stranded DNA. AB - Piwi-interacting piRNAs are a major and essential class of small RNAs in the animal germ cells with a prominent role in transposon control. Efficient piRNA biogenesis and function require a cohort of proteins conserved throughout the animal kingdom. Here we studied Maelstrom (MAEL), which is essential for piRNA biogenesis and germ cell differentiation in flies and mice. MAEL contains a high mobility group (HMG)-box domain and a Maelstrom-specific domain with a presumptive RNase H-fold. We employed a combination of sequence analyses, structural and biochemical approaches to evaluate and compare nucleic acid binding of mouse MAEL HMG-box to that of canonical HMG-box domain proteins (SRY and HMGB1a). MAEL HMG-box failed to bind double-stranded (ds)DNA but bound to structured RNA. We also identified important roles of a novel cluster of arginine residues in MAEL HMG-box in these interactions. Cumulatively, our results suggest that the MAEL HMG-box domain may contribute to MAEL function in selective processing of retrotransposon RNA into piRNAs. In this regard, a cellular role of MAEL HMG-box domain is reminiscent of that of HMGB1 as a sentinel of immunogenic nucleic acids in the innate immune response. PMID- 25807392 TI - A new asynchronous parallel algorithm for inferring large-scale gene regulatory networks. AB - The reconstruction of gene regulatory networks (GRNs) from high-throughput experimental data has been considered one of the most important issues in systems biology research. With the development of high-throughput technology and the complexity of biological problems, we need to reconstruct GRNs that contain thousands of genes. However, when many existing algorithms are used to handle these large-scale problems, they will encounter two important issues: low accuracy and high computational cost. To overcome these difficulties, the main goal of this study is to design an effective parallel algorithm to infer large scale GRNs based on high-performance parallel computing environments. In this study, we proposed a novel asynchronous parallel framework to improve the accuracy and lower the time complexity of large-scale GRN inference by combining splitting technology and ordinary differential equation (ODE)-based optimization. The presented algorithm uses the sparsity and modularity of GRNs to split whole large-scale GRNs into many small-scale modular subnetworks. Through the ODE-based optimization of all subnetworks in parallel and their asynchronous communications, we can easily obtain the parameters of the whole network. To test the performance of the proposed approach, we used well-known benchmark datasets from Dialogue for Reverse Engineering Assessments and Methods challenge (DREAM), experimentally determined GRN of Escherichia coli and one published dataset that contains more than 10 thousand genes to compare the proposed approach with several popular algorithms on the same high-performance computing environments in terms of both accuracy and time complexity. The numerical results demonstrate that our parallel algorithm exhibits obvious superiority in inferring large-scale GRNs. PMID- 25807397 TI - Modeling the citation network by network cosmology. AB - Citation between papers can be treated as a causal relationship. In addition, some citation networks have a number of similarities to the causal networks in network cosmology, e.g., the similar in-and out-degree distributions. Hence, it is possible to model the citation network using network cosmology. The casual network models built on homogenous spacetimes have some restrictions when describing some phenomena in citation networks, e.g., the hot papers receive more citations than other simultaneously published papers. We propose an inhomogenous causal network model to model the citation network, the connection mechanism of which well expresses some features of citation. The node growth trend and degree distributions of the generated networks also fit those of some citation networks well. PMID- 25807398 TI - Probable prostate cancer in a pre-Incaic individual from Pukara de la Cueva, northwestern Argentina. AB - Prostate carcinoma is a common malignant neoplasia that mostly metastasizes to bone in males. Nonetheless, the number of paleopathological cases reported is very small. Most of them were identified in Europe, and only two came from South American individuals. The purpose of this paper is to document the lesions identified in a pre-Columbian (around 1400 AD) individual that corresponds to a middle adult male from Pukara de la Cueva, Jujuy province, in the Northwest region of Argentina. The skeleton was found disarticulated but it is nearly complete and well preserved. The general character of the lesions observed is predominantly proliferative in nature, but osteolytic and mixed patterns were also detected in both axial and appendicular skeleton. Macroscopically, this overall pattern and the distribution of the lesions are compatible with a secondary cancer. Radiological examination showed multiple dense and irregular areas in several bones. The lesions visible by external inspection and by radiographs are in concordance with changes which are documented to occur in the course of prostatic carcinoma. The exuberance and dissemination of the lesions all over the skeleton led infer individual cachexy implying that he would have been assisted by his family and/or social group during the chronic process. Different carcinogenic risk factors associated to this kind of disease are discussed. This analysis adds new evidence of pre-Columbian carcinoma in South American native populations, as knowledge from clinical cases is considered to delineate a differential diagnosis. PMID- 25807400 TI - An analysis of the effectiveness of a state trauma system: treatment at designated trauma centers is associated with an increased probability of survival. AB - BACKGROUND: States struggle to continue support for recruitment, funding and development of designated trauma centers (DTCs). The purpose of this study was to evaluate the probability of survival for injured patients treated at DTCs versus nontrauma centers. METHODS: We reviewed 188,348 patients from the state's hospital discharge database and identified 13,953 severely injured patients admitted to either a DTC or a nontrauma center between 2008 and 2012. DRG International Classification of Diseases-9th Rev. Injury Severity Scores (ICISS), an accepted indicator of injury severity, was assigned to each patient. Severe injury was defined as an ICISS less than 0.85 (indicating >=15% probability of mortality). Three subgroups of the severely injured patients were defined as most critical, intermediate critical, and least critical. A full information maximum likelihood bivariate probit model was used to determine the differences in the probability of survival for matched cohorts. RESULTS: After controlling for injury severity, injury type, patient demographics, the presence of comorbidities, as well as insurance type and status, severely injured patients treated at a DTC have a 10% increased probability of survival. The largest improvement was seen in the intermediate subgroup. CONCLUSION: Treatment of severely injured patients at a DTC is associated with an improved probability of survival. This argues for continued resources in support of DTCs within a defined statewide network. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25807401 TI - Decreased mortality in traumatic brain injury following regionalization across hospital systems. AB - BACKGROUND: The Northern Ohio Trauma System (NOTS) was established to improve outcomes of trauma patients across the region. We hypothesized that mortality in patients with traumatic brain injury (TBI) would improve after regionalization. METHODS: All patients older than 14 years with a TBI were identified from NOTS, a regional trauma system consisting of two large health care systems and regional emergency medical services providers. Data from 2008 through 2012 were analyzed before and after NOTS formation in 2010. Multivariate logistic regression analysis was performed to evaluate independent predictors of survival. RESULTS: A total of 11,220 patients were identified with TBI in the NOTS database, 4,507 (40%) before NOTS and 6,713 (60%) after NOTS formation. Admissions to the regional Level 1 center post-NOTS formation increased from 36% to 46% (p < 0.0001). Injury Severity Scores (ISSs) and Abbreviated Injury Scale (AIS) scores were similar between periods. The mortality rate decreased from 6.2% to 4.9% (p = 0.005) among all TBIs and from 19% to 14% (p < 0.0001) in TBIs with a head AIS score of 3 or greater (n = 3,538). Craniotomy procedures increased from 1.8% to 2.7% (p = 0.003) overall and from 5.9% to 8.1% (p = 0.02) in TBIs with head AIS score of 3 or greater. Logistic regression analysis demonstrated an independent effect on survival for post-NOTS period in all patients (odds ratio, 0.76; 95% confidence interval, 0.62-0.94; C statistic = 0.96) and in TBIs with head AIS score of 3 or greater (odds ratio, 0.72; 95% confidence interval, 0.58-0.89; C statistic = 0.86). CONCLUSION: Regionalization of trauma care across hospital systems is associated with a reduced mortality rate for patients with TBI, particularly for patients with a head AIS score of 3 or greater. Mortality decreased by 24% for all TBIs and by 28% for severe TBIs. These findings support regionalization of trauma care with collaboration and consolidation of care across health care systems. LEVEL OF EVIDENCE: Therapeutic/care management, level IV; epidemiologic study, level III. PMID- 25807402 TI - Early autologous fresh whole blood transfusion leads to less allogeneic transfusions and is safe. AB - BACKGROUND: The practice of transfusing ones' own shed whole blood has obvious benefits such as reducing the need for allogeneic transfusions and decreasing the need for other fluids that are typically used for resuscitation in trauma. It is not widely adopted in the trauma setting because of the concern of worsening coagulopathy and the inflammatory process. The aim of this study was to assess outcomes in trauma patients receiving whole blood autotransfusion (AT) from hemothorax. METHODS: This is a multi-institutional retrospective study of all trauma patients who received autologous whole blood transfusion from hemothorax from two Level I trauma centers. Patients who received AT were matched to patients who did not receive AT (No-AT) using propensity score matching in a 1:1 ratio for admission age, sex, mechanism, type of injury, Injury Severity Score (ISS), Glasgow Coma Scale (GCS) score, systolic blood pressure, heart rate, hemoglobin, international normalized ratio (INR), prothrombin time, partial prothrombin time, and lactate. AT was defined as transfusion of autologous blood from patient's hemothorax, which was collected from the chest tubes and anticoagulated with citrate phosphorous dextrose. Outcome measures were in hospital complications, 24-hour INR, and mortality. In-hospital complications were defined as adult respiratory distress syndrome, sepsis, disseminated intravascular coagulation, renal insufficiency, and transfusion-related acute lung injury. RESULTS: A total of 272 patients (AT, 136; No-AT, 136) were included. There was no difference in admission age (p = 0.6), ISS (p = 0.56), head Abbreviated Injury Scale (AIS) score (p = 0.42), systolic blood pressure (p = 0.88), and INR (p = 0.62) between the two groups. There was no significant difference in in-hospital complications (p = 0.61), mortality (p = 0.51), and 24 hour postadmission INR (0.31) between the AT and No-AT groups. Patients who received AT had significantly lower packed red blood cell (p = 0.01) and platelet requirements (p = 0.01). Cost of transfusions (p = 0.01) was significantly lower in the AT group compared with the No-AT group. CONCLUSION: The autologous transfusion of the patient's shed blood collected through chest tubes for hemothorax was found to be safe without complications in this study. It also reduced the need for allogeneic transfusions and decreased hospital costs. This study demonstrates safety data that would help in designing larger prospective multicenter studies to determine whether this practice is truly safe and effective. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. PMID- 25807404 TI - Is limited prehospital resuscitation with plasma more beneficial than using a synthetic colloid? An experimental study in rabbits with parenchymal bleeding. AB - BACKGROUND: Reports of survival benefits of early transfusion of plasma with red blood cells (1:1 ratio) in trauma patients suggest that plasma may be a better fluid to replace Hextend for battlefield resuscitation. We studied possible advantages of prehospital resuscitation with plasma compared with Hextend or albumin in a model of uncontrolled hemorrhage. METHODS: Male New Zealand white rabbits (3.3 +/- 0.1 kg) were anesthetized, instrumented, and subjected to a splenic injury with uncontrolled bleeding. Ten minutes after injury (mean arterial pressure [MAP] < 40 mm Hg), the rabbits received small and equal volumes (15 mL/kg) of rabbit plasma (n = 10), Hextend (n = 10), or 5% human albumin (n = 9) or no fluid. Fluids were administered in two bolus injections (20 minutes apart) and targeted to a MAP of 65 mm Hg. Animals were monitored for 2.5 hours or until death, and their blood losses were measured. Arterial blood samples were collected at different times and analyzed for ABG, CBC, and coagulation tests. RESULTS: There were no differences in baseline measures among groups. Splenic injury caused similar hemorrhages (9.1 +/- 0.4 mL/kg at 10 minutes) and decreased MAP in all subjects. Subsequent resuscitation initiated additional bleeding. At 60 minutes after injury (20 minutes after resuscitation), longer activated partial thromboplastin time and lower fibrinogen concentrations were apparent compared with baseline values with differences among groups. Thrombelastography analysis indicated faster and stronger clot formation with plasma and albumin resuscitation than with Hextend use. Shock indices were increased in all groups, but smaller changes were measured in the albumin group. Total blood loss did not differ among resuscitated rabbits but was higher (p < 0.05) than among nonresuscitated animals. Survival rates were 11% (untreated), 40% (Hextend and plasma), and 89% (albumin, p < 0.05). CONCLUSION: Resuscitation with plasma or albumin better preserved coagulation function than did Hextend. However, despite these improvements, plasma resuscitation did not reduce blood loss or improve survival, while albumin administration seemed beneficial. PMID- 25807399 TI - A controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized pilot trial. AB - BACKGROUND: Optimal resuscitation of hypotensive trauma patients has not been defined. This trial was performed to assess the feasibility and safety of controlled resuscitation (CR) versus standard resuscitation (SR) in hypotensive trauma patients. METHODS: Patients were enrolled and randomized in the out-of hospital setting. Nineteen emergency medical services (EMS) systems in the Resuscitation Outcome Consortium participated. Eligible patients had an out-of hospital systolic blood pressure (SBP) of 90 mm Hg or lower. CR patients received 250 mL of fluid if they had no radial pulse or an SBP lower than 70 mm Hg and additional 250-mL boluses to maintain a radial pulse or an SBP of 70 mm Hg or greater. The SR group patients received 2 L initially and additional fluid as needed to maintain an SBP of 110 mm Hg or greater. The crystalloid protocol was maintained until hemorrhage control or 2 hours after hospital arrival. RESULTS: A total of 192 patients were randomized (97 CR and 95 SR). The CR and SR groups were similar at baseline. The mean (SD) crystalloid volume administered during the study period was 1.0 L (1.5) in the CR group and 2.0 L (1.4) in the SR group, a difference of 1.0 L (95% confidence interval [CI], 0.6-1.4). Intensive care unit-free days, ventilator-free days, renal injury, and renal failure did not differ between the groups. At 24 hours after admission, there were 5 deaths (5%) in the CR group and 14 (15%) in the SR group (adjusted odds ratio, 0.39; 95% CI, 0.12-1.26). Among patients with blunt trauma, 24-hour mortality was 3% (CR) and 18% (SR) with an adjusted odds ratio of 0.17 (0.03-0.92). There was no difference among patients with penetrating trauma (9% vs. 9%; adjusted odds ratio, 1.93; 95% CI, 0.19-19.17). CONCLUSION: CR is achievable in out-of-hospital and hospital settings and may offer an early survival advantage in blunt trauma. A large scale, Phase III trial to examine its effects on survival and other clinical outcomes is warranted. LEVEL OF EVIDENCE: Therapeutic study, level I. PMID- 25807405 TI - Can mesenchymal stem cells reverse chronic stress-induced impairment of lung healing following traumatic injury? AB - BACKGROUND: One week following unilateral lung contusion (LC), rat lungs demonstrate full histologic recovery. When animals undergo LC plus the addition of chronic restraint stress (CS), wound healing is significantly delayed. Mesenchymal stem cells (MSCs) are pluripotent cells capable of immunomodulation, which have been the focus of much research in wound healing and tissue regeneration. We hypothesize that the addition of MSCs will improve wound healing in the setting of CS. METHODS: Male Sprague-Dawley rats (n = 6-7 per group) were subjected to LC/CS with or without the injection of MSCs. MSCs were given as a single intravenous dose of 5 * 10 cells in 1 mL Iscove's Modified Dulbecco's Medium at the time of LC. Rats were subjected to 2 hours of restraint stress on Days 1 to 6 following LC. Seven days following injury, rats were sacrificed, and the lungs were examined for histologic evidence of wound healing using a well established histologic lung injury score (LIS) to grade injury. LIS examines inflammatory cells/high-power field (HPF) averaged over 30 fields, interstitial edema, pulmonary edema, and alveolar integrity, with scores ranging from 0 (normal) to 11 (highly damaged). Peripheral blood was analyzed by flow cytometry for the presence of T-regulatory (C4CD25FoxP3) cells. Data were analyzed by analysis of variance followed by Tukey's multiple comparison test, expressed as mean (SD). RESULTS: As previously shown, 7 days following isolated LC, LIS has returned to 0.83 (0.41), with a subscore of zero for inflammatory cells/HPF. The addition of CS results in an LIS of 4.4 (2.2), with a subscore of 1.9 (0.7) for inflammatory cells/HPF. Addition of MSC to LC/CS decreased LIS to 1.7 (0.8), with a subscore of zero for inflammatory cells/HPF. Furthermore, treatment of animals undergoing LC/CS with MSCs increased the %T-regulatory cells by 70% in animals undergoing LC/CS alone (12.9% [2.4]% vs. 6.2% [1.3%]). CONCLUSION: Stress-induced impairment of wound healing is reversed by the addition of MSCs given at the time of injury in this rat LC model. This improvement in lung healing is associated with a decrease in the number of inflammatory cells and an increase in the number of T-regulatory cells. Further study into the mechanisms by which MSCs hasten wound healing is warranted. PMID- 25807403 TI - Pathologic metabolism: an exploratory study of the plasma metabolome of critical injury. AB - BACKGROUND: Severe trauma is associated with massive alterations in metabolism. Thus far, investigations have relied on traditional bioanalytic approaches including calorimetry or nuclear magnetic resonance. However, recent strides in mass spectrometry (MS)-based metabolomics present enhanced analytic opportunities to characterize a wide range of metabolites in the critical care setting. METHODS: MS-based metabolomics analyses were performed on plasma samples from severely injured patients' trauma activation field blood and plasma samples obtained during emergency department thoracotomy. These were compared against the metabolic profiles of healthy controls. RESULTS: Few significant alterations were observed between trauma activation field blood and emergency department thoracotomy patients. In contrast, we identified trauma-dependent metabolic signatures, which support a state of hypercatabolism, driven by sugar consumption, lipolysis and fatty acid use, accumulation of ketone bodies, proteolysis and nucleoside breakdown, which provides carbon and nitrogen sources to compensate for trauma-induced energy consumption and negative nitrogen balance. Unexpectedly, metabolites of bacterial origin (including tricarballylate and citramalate) were detected in plasma from trauma patients. CONCLUSION: In the future, the correlation between metabolomics adaptation and recovery outcomes could be studied by MS-based approaches, and this work can provide a method for assessing the efficacy of alternative resuscitation strategies. PMID- 25807406 TI - Correction of acute traumatic coagulopathy with small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ occurs within 5 minutes: a ROTEM analysis. AB - BACKGROUND: Acute traumatic coagulopathy is a major contributor to mortality and morbidity following hemorrhagic shock. Our aim was to examine the effect of small volume 7.5% NaCl with adenosine, lidocaine, and Mg (ALM) resuscitation on the timing of correction of coagulopathy in the rat model of severe hemorrhagic shock using ROTEM. METHODS: Male rats (300-450 g, n = 64) were randomly assigned to (1) baseline, (2) sham, (3) bleed, (4) shock, (5) 7.5% NaCl for 5 minutes, (6) 7.5% NaCl with ALM for 5 minutes, (7) 7.5% NaCl for 60 minutes, or (8) 7.5% NaCl with ALM for 60 minutes (all n = 8). For resuscitation, 0.3-mL intravenous bolus of 7.5% NaCl was administered with and without ALM (n = 8 each group). Hemodynamics and coagulopathy were assessed. RESULTS: After hemorrhage, prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased approximately four to six times, and ROTEM indicated hypocoagulopathy. After 60-minute shock, no sustainable clots could form. 7.5% NaCl increased mean arterial pressure (MAP) to 46 +/- 2 mm Hg at 5 minutes and generated a weak clot in EXTEM with hyperfibrinolysis in all tests. At 60 minutes, 7.5% NaCl failed to sustain MAP (43 +/- 5 mm Hg) and generate a viable clot. In direct contrast, 7.5% NaCl with ALM at 5 minutes resuscitated MAP to 64 +/- 3 mm Hg, corrected PT and aPTT, and generated fully formed EXTEM and FIBTEM clots. At 60 minutes, MAP was 69 +/- 5 mm Hg, PT and aPTT were fully corrected, and alpha angle, clot amplitudes (A10, A30), as well as clot firmness and elasticity were not significantly different from baseline. ALM clot lysis at 60 minutes was significantly less than bleed, shock, or 7.5% NaCl, indicating protection against hyperfibrinolysis. CONCLUSION: Small-volume 7.5% NaCl failed to resuscitate and correct coagulopathy. In contrast, 7.5% NaCl with ALM resuscitated MAP and corrected coagulopathy at 5 minutes, with further improvements at 60 minutes in clot kinetics, propagation, and firmness. ALM fully reversed hyperfibrinolysis to baseline. The possible mechanisms are discussed. PMID- 25807407 TI - Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF kappaB suppression. AB - BACKGROUND: Ketamine, as an anesthetic agent, has an anti-inflammatory effect. In the present study, we investigated whether ketamine inhibits release of high mobility group box 1 (HMGB1), a late-phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated macrophages through heme oxygenase-1 (HO-1) induction. METHODS: Macrophages were preincubated with various concentrations of ketamine and then treated with LPS (1 MUg/mL). The cell culture supernatants were collected to measure inflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor-alpha, and interleukin 1beta) by enzyme-linked immunosorbent assay. Moreover, HO-1 protein expression, the phosphorylation and degradation of IkappaB alpha, and the nuclear translocation of nuclear factor E2-related factor 2 and nuclear factor kappaB (NF-kappaB) p65 were tested by Western blot analysis. In addition, to further identify the role of HO-1 in this process, tin protoporphyrin (SnPP), an HO-1 inhibitor, was used. RESULTS: Ketamine treatment dose-dependently attenuated the increased levels of proinflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor alpha, and interleukin 1beta) and increased the HO-1 protein expression in LPS-activated macrophages. Furthermore, ketamine suppressed the phosphorylation and degradation of IkappaB-alpha as well as the LPS-stimulated nuclear translocation of NF-kappaB p65 in macrophages. In addition, the present study also demonstrated that ketamine induced HO-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 in macrophages. The effects of ketamine on LPS-induced proinflammatory cytokines production were partially reversed by the HO inhibitor tin protoporphyrin (SnPP). CONCLUSION: Ketamine inhibits the release of HMGB1 in LPS stimulated macrophages, and this effect is at least partly mediated by the activation of the Nrf2/HO-1 pathway and NF-kappaB suppression. PMID- 25807408 TI - Predictors of muscle protein synthesis after severe pediatric burns. AB - BACKGROUND: Following a major burn, skeletal muscle protein synthesis rate increases but is often insufficient to compensate for massively elevated muscle protein breakdown rates. Given the long-term nature of the pathophysiologic response to burn injury, we hypothesized that muscle protein synthesis rate would be chronically elevated in severely burned children. The objectives of this study were to characterize muscle protein synthesis rate of burned children over a period of 24 months after injury and to identify predictors that influence this response. METHODS: A total of 87 children with 40% or greater total body surface area (TBSA) burned were included. Patients participated in stable isotope infusion studies at 1, 2, and approximately 4 weeks after burn and at 6, 12, and 24 months after injury to determine skeletal muscle protein fractional synthesis rate. Generalized estimating equations with log link normal distribution were applied to account for clustering of patients and control for patient characteristics. RESULTS: Patients (8 +/- 6 years) had large (62, 51-72% TBSA) and deep (47% +/- 21% TBSA third degree) burns. Muscle protein fractional synthesis rate was elevated throughout the first 12 months after burn compared with established values from healthy young adults. Muscle protein fractional synthesis rate was lower in boys, in children older than 3 years, and when burns were greater than 80% TBSA. CONCLUSION: Muscle protein synthesis is elevated for at least 1 year after injury, suggesting that greater muscle protein turnover is a component of the long-term pathophysiologic response to burn trauma. Muscle protein synthesis is highly affected by sex, age, and burn size in severely burned children. These findings may explain the divergence in net protein balance and lean body mass in different populations of burn patients. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 25807409 TI - Pseudomonas aeruginosa wound infection involves activation of its iron acquisition system in response to fascial contact. AB - BACKGROUND: Wound infections are traditionally thought to occur when microbial burden exceeds the innate clearance capacity of host immune system. Here, we introduce the idea that the wound environment itself plays a significant contributory role to wound infection. METHODS: We developed a clinically relevant murine model of soft tissue infection to explore the role of activation of microbial virulence in response to tissue factors as a mechanism by which pathogenic bacteria cause wound infections. Mice underwent abdominal skin incision and light muscle injury with a crushing forceps versus skin incision alone followed by topical inoculation of Pseudomonas aeruginosa. Mice were sacrificed on postoperative Day 6, and abdominal tissues were analyzed for clinical signs of wound infection. To determine if specific wound tissue components induce bacterial virulence, P. aeruginosa was exposed to the skin, fascia, and muscle. RESULTS: Gross wound infection caused by P. aeruginosa was observed to be significantly increased in injured tissues versus noninjured (80% vs.10%) tissues (n = 20 per group, p < 0.0001). Exposure of P. aeruginosa to individual tissue components demonstrated that fascia significantly induced bacterial virulence as judged by the production of pyocyanin, a redox-active phenazine compound known to kill immune cells. Whole-genome transcriptional profiling of P. aeruginosa exposed to the fascia demonstrated activation of multiple genes responsible for the synthesis of the iron scavenging molecule pyochelin. CONCLUSION: We conclude that wound elements, in particular fascia, may play a significant role in enhancing the virulence of P. aeruginosa and may contribute to the pathogenesis of clinical wound infection. PMID- 25807411 TI - The obesity factor in critical illness: Between consensus and controversy. PMID- 25807410 TI - Close to home: an analysis of the relationship between location of residence and location of injury. AB - BACKGROUND: Injury surveillance is critical in identifying the need for targeted prevention initiatives. Understanding the geographic distribution of injuries facilitates matching prevention programs with the population most likely to benefit. At the population level, however, the geographic site of injury is rarely known, leading to the use of location of residence as a surrogate. To determine the accuracy of this approach, we evaluated the relationship between the site of injury and of residence over a large geographic area. METHODS: Data were derived from a population-based, prehospital registry of persons meeting triage criteria for major trauma. Patients dying at the scene or transported to the hospital were included. Distance between locations of residence and of injury was calculated using geographic information system network analysis. RESULTS: Among 3,280 patients (2005-2010), 88% were injured within 10 miles of home (median, 0.2 miles). There were significant differences in distance between residence and location of injury based on mechanism of injury, age, and hospital disposition. The large majority of injuries involving children, the elderly, pedestrians, cyclists, falls, and assaults occurred less than 10 miles from the patient's residence. Only 77% of motor vehicle collision occurred within 10 miles of the patient's residence. CONCLUSION: Although the majority of patients are injured less than 10 miles from their residence, the probability of injury occurring "close to home" depends on patient and injury characteristics. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25807412 TI - Spinal cord injury without radiologic abnormality in children: a systematic review and meta-analysis. AB - BACKGROUND: Spinal cord injury in children is associated with severe morbidity and immense socioeconomic burden. In spinal cord injury without radiologic abnormalities (SCIWORA), magnetic resonance imaging (MRI) can detect intramedullary or extramedullary pathologies or show absence of neuroimaging abnormalities. However, the prognostic and therapeutic consequences of specific MRI patterns are unclear. A comprehensive systematic literature search was performed to examine patient characteristics and imaging patterns of pediatric SCIWORA and to evaluate the prognostic value of a MRI-based classification system. METHODS: MEDLINE, Cochrane Central Register of Controlled Trials, and Google Scholar were searched for studies on SCIWORA in children. Inclusion criteria were (1) traumatic spinal cord injury with acute neurologic deficit, (2) absence of fractures and/or dislocations of the spine, and (3) an immature skeleton or age of less than 18 years. MRI patterns and clinical course were correlated. RESULTS: Forty articles reporting 114 patients were identified. At admission, neurologic deficit assessed by the American Spinal Injury Association impairment scale was A in 28%, B in 17%, C in 31%, and D in 25%. At final follow up, these were 19%, 6%, 10%, and 16%, respectively. In 43%, no MRI abnormalities (Type I) were detected, and 57% exhibited abnormal scan results (Type II): 6% revealed extraneural (Type IIa), 38% intraneural (Type IIb), and 13% combined abnormalities (Type IIc). At admission and follow-up, American Spinal Injury Association impairment scale differed significantly between the imaging types. CONCLUSION: This systematic review emphasizes the prognostic value of spinal MRI for children with SCIWORA. It highlights the role of the MRI classification system in improving the comparability and interpretability. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 25807415 TI - Correction: Leishmania-HIV co-infection: clinical presentation and outcomes in an urban area in Brazil. PMID- 25807416 TI - The current graphene safety landscape--a literature mining exercise. AB - As for any novel nanomaterial, the development of applications and industrial adoption of graphene-based materials will be subject to the confirmation of their safety profile and risk assessment. The analysis performed here maps the current knowledge of the safety of graphene-based materials as extracted by a literature mapping exercise of studies investigating these materials in preclinical animal models. We attempt to identify gaps for future studies and elucidate the critically important structure-function correlations between reported biological effects and graphene-based material physicochemical characteristics. PMID- 25807418 TI - Surgical treatment of tuberculous spondylodiscitis. PMID- 25807417 TI - Effects of orange juice formulation on prebiotic functionality using an in vitro colonic model system. AB - A three-stage continuous fermentative colonic model system was used to monitor in vitro the effect of different orange juice formulations on prebiotic activity. Three different juices with and without Bimuno, a GOS mixture containing galactooligosaccharides (B-GOS) were assessed in terms of their ability to induce a bifidogenic microbiota. The recipe development was based on incorporating 2.75g B-GOS into a 250 ml serving of juice (65 degrees Brix of concentrate juice). Alongside the production of B-GOS juice, a control juice--orange juice without any additional Bimuno and a positive control juice, containing all the components of Bimuno (glucose, galactose and lactose) in the same relative proportions with the exception of B-GOS were developed. Ion Exchange Chromotography analysis was used to test the maintenance of bimuno components after the production process. Data showed that sterilisation had no significant effect on concentration of B GOS and simple sugars. The three juice formulations were digested under conditions resembling the gastric and small intestinal environments. Main bacterial groups of the faecal microbiota were evaluated throughout the colonic model study using 16S rRNA-based fluorescence in situ hybridization (FISH). Potential effects of supplementation of the juices on microbial metabolism were studied measuring short chain fatty acids (SCFAs) using gas chromatography. Furthermore, B-GOS juices showed positive modulations of the microbiota composition and metabolic activity. In particular, numbers of faecal bifidobacteria and lactobacilli were significantly higher when B-GOS juice was fermented compared to controls. Furthermore, fermentation of B-GOS juice resulted in an increase in Roseburia subcluster and concomitantly increased butyrate production, which is of potential benefit to the host. In conclusion, this study has shown B-GOS within orange juice can have a beneficial effect on the fecal microbiota. PMID- 25807419 TI - Mitral annular tissue velocity in the diagnosis of coronary artery disease. PMID- 25807420 TI - Coronal approach to zygomaticomaxillary complex fractures. AB - OBJECTIVE: Trauma of the zygomaticomaxillary complex constitutes 45% of all midface fractures. In the author's medical unit, the proportion is 40% of all fractures of the facial skeleton. Most zygomaticomaxillary complex fractures can be treated via local incisions, however; multiple, comminuted and late fractures require wide exposure of the fragments in order to adequately reposition them and to apply rigid fixation. PATIENTS AND METHODS: Thirty-one cases of comminuted or multiple fractures of the zygomaticomaxillary complex were treated with open reduction and rigid fixation by a coronal approach and analyzed for indications and postoperative complications. Twenty three patients had a hemi coronal approach and eight had a bicoronal approach. RESULTS: Among the early complications noted were one case of hemorrhage, no infections, and two patients experienced paresthesia/ anesthesia in the supra orbital region, two patients in the temporal/parietal region, six patients experienced facial nerve weakness related to nerve retraction and moderate surgical edema was observed in three patients. Late complications included two cases of alopecia/baldness along the incision, one case of persistent paresthesia in the operative area. As far as the esthetics in relation to the incision was concerned, all patients were extremely satisfied. CONCLUSIONS: The results of this study suggest that a coronal approach will facilitate accurate reduction and fixation of fragments and will allow good cosmetic result with minimal or no complications. The coronal incisions should be the first choice in case of comminuted, multiple and late zygomaticomaxillary complex fractures. However, indications for the use of coronal incisions must be strictly applied. PMID- 25807421 TI - Comparative evaluation of 2.3 mm locking plate system vs conventional 2.0 mm non locking plate system for mandibular condyle fracture fixation: a seven year retrospective study. AB - OBJECTIVE: This retrospective study evaluated the efficacy of a 2.3 mm locking plate/screw system compared with a 2.0-mm non-locking plate/screw system in fixation of isolated non comminuted mandibular condyle fractures. PATIENTS AND METHODS: Surgical records of 101 patients who received either a 2.3 mm locking plate (group A, n = 51) or 2.0 mm non locking plate (group B, n = 50) were analyzed. All patients were followed up to a minimum of 6 months postoperatively and evaluated for hardware related complications, occlusal stability, need for and duration of MMF and mandibular functional results. RESULTS: Four complications occurred in the locking group and eighteen in the non locking group with complication rates equalling 8% and 36% respectively. When comparing the overall results according to plates used, the chi2 test showed a statistically significant difference between the locking and non locking plates (p < 0.001). Fewer patients required postoperative MMF in group A. CONCLUSIONS: Mandibular condyle fractures treated with a 2.3 mm locking plate exhibited stable osteosynthesis, were associated with minimal complications and resulted in acceptable mandibular range of motion compared with a 2.0 mm non locking plate. PMID- 25807423 TI - Unilateral perirenal fibrosis without aorta involvement. AB - Retroperitoneal fibrosis (RPF) located unilateral perirenal without aorta involvement is very rare. We report a case of unilateral perirenal fibrosis which was misdiagnosed as malignancy even after biopsy. RPF should be in mind in dealing with perirenal mass. PMID- 25807422 TI - Flavoxate: present and future. AB - OBJECTIVE: This non-systematic review discusses the available evidence on the use of flavoxate in the treatment of overactive bladder (OAB). METHODS: Medline was searched for inclusion of relevant studies. No limitations in time were considered. RESULTS: Flavoxate hydrochloride is an antispasmodic agent which exerts an inhibition of the phosphodiesterases, a moderate calcium antagonistic activity, and a local anesthetic effect. Results from preclinical and clinical studies show that flavoxate significantly increases bladder volume capacity (BVC), with greater results if compared to other drugs such as emepronium bromide and propantheline. Moreover in clinical trials, both versus placebo or versus active comparators, flavoxate treatment was associated with a significant improvement in different low urinary tract symptoms, such as diurnal and night frequency, urgency and urinary incontinence, suprapubic pain, dysuria, hesitancy and burning. In addition flavoxate was associated with an overall more favourable safety profile than competitors. CONCLUSIONS: Several researches and a number of years of clinical practice have proven the efficacy and tolerability of flavoxate administration in the treatment of OAB and associated symptoms. However, new studies are necessary to collect more evidence on the role of this molecule in the treatment of OAB and to further explore its use in other indications such as symptomatic treatment of lower urinary tract infections. PMID- 25807424 TI - Identification of genes and pathways associated with osteoarthritis by bioinformatics analyses. AB - OBJECTIVE: This study aimed to explore the molecular mechanism of osteoarthritis (OA) development and discover underlying genes associated with OA. DATA AND METHODS: Gene expression profile GSE48556 including 106 peripheral blood mononuclear cells (PBMCs) of osteoarthritis patients and 33 PBMCs of healthy controls was downloaded from the Gene Expression Omnibus database. The limma package was used to identify the differentially expressed genes (DEGs) by paired t-test. The functional enrichment analyses of DEGs was performed, followed by the construction of protein-protein interaction (PPI) network. RESULTS: Total 432 DEGs including 178 up-regulated DEGs and 254 down-regulated DEGs were identified. Pathways of cytokine-cytokine receptor interaction and T cell receptor signaling pathway were significantly up-regulated in OA. Biological processes of negative regulation of transcription from RNA polymerase II promoter and negative regulation of transcription, DNA-dependent were significantly down-regulated in OA. The platelet-derived growth factor receptor, beta polypeptide (PDGFRB), interferon, gamma (IFNG), early growth response 1 (EGR1), Fas ligand (TNF superfamily, member 6) (FASLG), H3 histone, family 3B (H3.3B) (H3F3B) and so on had higher connectivity degree in the PPI networks. CONCLUSIONS: DEGs of OA were mainly enriched in the pathways associated with cytokine-cytokine receptor interaction and T cell receptor signaling pathway. The DEGs such as PDGFRB, IFNG, EGR1, FASLG and H3F3B may be the potential targets for OA diagnosis and treatment. PMID- 25807425 TI - Polymyalgia rheumatica: inflammation suppression with low dose of methylprednisolone or modified-release prednisone. AB - OBJECTIVE: Polymyalgia rheumatica (PMR) is an inflammatory disease that affects people aged > 50 years, and is characterised by pain and morning stiffness in the shoulder and pelvic girdle with synovitis of the proximal joints and extra articular synovial structures. It is currently mainly treated with glucocorticoids (GCs). The aim of the study was to evaluate changes in inflammatory markers and their correlations with cortisol levels after treatment with 6-methylprednisolone (6-MP) or modified-release prednisone (MR-P) in patients with "early" PMR. PATIENTS AND METHODS: The study involved 81 GC-naive with "early" PMR diagnosed on the basis of the 2012 EULAR/ACR criteria: 38 treated with 6-MP at a starting dose of 12 mg at 8.00 a.m, gradually tapered to 8, 4 and 2 mg/day, and 43 treated with MR-P at a starting dose of 10 mg at 10 p.m, tapered to 7, 5, 3, 2 and 1 mg. The markers of inflammation (ESR mm/h, CRP mg/dL and fibrinogen mg/dL), the circulating serum levels of cytokines (TNFa and IL-6), and morning serum cortisol levels were evaluated at baseline and during GC treatment. RESULTS: There were significant differences between baseline and the end of treatment in the serum levels of IL-6 (5.3 +/- 9.3 vs 2.8 +/- 3.3 pg/mL; p < 0.05) and CRP (2.1 +/- 3.3 vs 0.9 +/- 1.7 mg/dL; p < 0.01) in the patients treated with MR-P, and in serum cortisol levels (15.8+/-6.4 vs 13.6+5.6 ug/dL; p < 0.01) in the patients treated with 6-MP. After the first month of treatment, 76.7% of the patients treated with MR-P had IL6 levels at or below the upper normal limit, whereas 52.6% of those treated with 6-MP had normal IL6 levels (p < 0.05). There was also a significant difference in the percentage of patients in whom the daily GC dose was tapered within eight months (6.7% in the MR-P group vs 25% in the 6-MP group; p < 0.001) and, by the end of the study, respectively 59.5% vs 35.1% patients were receiving a low GC dose or had discontinued treatment altogether (OR 2.7, 95% CI 1.0-6.77; p < 0.001). After six and 12 months, respectively 10.3% and 14.3% of the patients had discontinued MR-P, as against none of the patients treated with 6-MP (p < 0.05). CONCLUSIONS: In this prospective observational study of PMR patients receiving low-dose GCs, the changes in inflammatory markers were similar in those treated with 6-MP or MR-P, whereas morning cortisol levels remained unchanged only in the MR-P group. During the first month of treatment, MR-P chronotherapy given at bedtime significantly decreased IL-6 levels. The percentage of patients stopping GC treatment was higher in the MR-P group than in the 6-MP group. PMID- 25807426 TI - miR-28 promotes cardiac ischemia by targeting mitochondrial aldehyde dehydrogenase 2 (ALDH2) in mus musculus cardiac myocytes. AB - OBJECTIVE: Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in protecting the heart from ischemic. MicroRNAs (miRNAs) are involved in gene down regulation. However, this mechanism is unclear. The aim of this study was to investigate the role of miR-28 in the regulation of ALDH2 and to explore the mechanism of miR-28 in musculus of myocardial ischemia. MATERIALS AND METHODS: To evaluate the role of miR-28, we assessed cellular apoptosis. In addition, the regulation of ALDH2 by miR-199b was evaluated by Western blotting and luciferase assay. RESULTS: MiR-28 was up-regulated, while ALDH2 expression decreased in a time-dependent manner under normoxic conditions. The miR-28-transfected cells showed a significant decrease in the cellular apoptosis. Compared with the negative control 1 precursor molecules, miR-28 over-expression caused about 55% increase in myocardial apoptosis under hypoxic conditions, and miR-28 silencing by anti-miR-28 attenuated a 41% decreasing in apoptosis. MiR-28 and pGL3-ALDH2 vector-transfected cells showed that ALDH2 protein expression was suppressed and luciferase activity was reduced. CONCLUSIONS: These findings suggest that miR-28 promotes myocardial ischemia through the inhibition of ALDH2 expression in mus. miRNAs is as a probable index in identification of myocardial ischemia after acute myocardial infarction. PMID- 25807427 TI - Protective effects of valsartan and benazepril combined with atorvastatin on cardiorenal syndrome in rats. AB - OBJECTIVE: To study the protective effects of valsartan (Val) and benazepril, (Ben) combined with atorvastatin (Ato), on cardiorenal syndrome (CRS) in rats. MATERIALS AND METHODS: After establishing cardiorenal syndrome model, the rats were randomly divided into control, Ato, Ben+Ato and Val+Ato groups, which were treated with corresponding drugs. Before and 4 weeks after treatment, the serum creatinine (Scr), blood urea nitrogen (BUN), type-B natriuretic peptide (BNP), aldosterone (ALD), angiotensin (Ang) II, C-reactive protein (CRP), blood lipid and urine protein were determined. The left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP) as well as maximum rising and falling rates of left ventricular pressure (+/-dp/dtmax) were detected. The heart weight index was also determined. RESULTS: 6, 3, 1 and 2 rats control, Ato, Ben+Ato and Val+Ato groups died, respectively. Compared with control group, the serum Cr, BUN, BNP, ALD, CRP and urinary protein levels in treatment groups significantly decreased, and the blood lipid level, LVDP, LVEDP and heart weight index significantly decreased, with increased LVSP. No statistically significant difference was observed among treatment groups. CONCLUSIONS: Valsartan and benazepril, combined with atorvastatin, can have significant protective effects on cardiorenal functions of rats with CRS, with no significant difference between these two drugs. PMID- 25807428 TI - Relationship between left atrial functions, P-terminal force and interatrial block in chronic haemodialysis patients. AB - OBJECTIVE: Interatrial block (IAB) connotes a P wave duration >= 110 msec on electrocardiography (ECG). P-terminal force corresponds to a biphasic P wave with its terminal negative phase >= 40 msec x mm in V1 derivation on ECG. IAB and P terminal force are closely related parameters and they are accepted as predictors for left atrial dysfunction, left atrial dilatation, atrial fibrillation and strokes. Left atrial functions in chronic haemodialysis patients becomes worse in the course of time because of long standing pressure and volume overload. The aim of this study is to evaluate the relationship between IAB, P-terminal force and left atrial functions. PATIENTS AND METHODS: 68 chronic haemodialysis patients and 60 control subjects were included in the study. Conventional echocardiography and left atrial dynamic functions were measured in all cases. The subjects with IAB and P-terminal force on ECG were identified. RESULTS: Left ventricular size, wall thickness and left atrial diameters were significantly greater in haemodialysis patients than the control group (p < 0.001). 42 (62%) patients had IAB (>= 110 msec) and 45 (66%) patients had P-terminal force ( >= 40 msec x mm) in the haemodialysis group. Left atrial reservoir, conduit and pump functions were significantly lower in the haemodialysis group than the control group (p < 0.001). There was a statistically significant correlation between left atrial functions, IAB (>= 110 msec) and P-terminal force (>= 40msec x mm) in all parameters (p < 0.001). CONCLUSIONS: This study showed that decreased left atrial functions in chronic haemodialysis patients are closely correlated with IAB and P terminal force. PMID- 25807429 TI - Chronic blockade of class I PI3-kinase attenuates Ang II-induced cardiac hypertrophy and autophagic alteration. AB - OBJECTIVE: Chronic Ang II stimulation is linked to cardiac remodeling characterized by fibrosis and cardiac hypertrophy. However, the underlying cellular mechanisms involved are not yet fully known. Here, we studied the molecular mechanisms underlying the chronic effect of Ang II on cardiac hypertrophy, fibrosis, and autophagy. MATERIALS AND METHODS: The role of class I PI3-kinase in these actions of Ang II was studied using lentiviral vector mediated expression of a dominant negative form of PI3-kinase subunit p85alpha (Lv-DNp85) in the heart. Ang II was infused subcutaneously for 4 weeks on rats using osmotic pumps. Cardiac hypertrophy, fibrosis, reactive oxygen species (ROS), and autophagy were examined in four groups of rats (Ang II+Lv-DNp85, Ang II+Lv-GFP, Saline+Lv-DNp85, Saline+Lv-GFP). RESULTS: Chronic infusion of Ang II induced severe cardiac hypertrophy and perivascular fibrosis in the heart. These effects were associated with a significant reduction in LC3 II and elevation in ROS levels, suggesting marked impairment of cardiac autophagy and increased generation of ROS. Cardiac transduction of Lv-DNp85 significantly attenuated Ang II-induced impairment of autophagy and elevation of ROS, as well as Ang II induced cardiac hypertrophy and perivascular fibrosis. To study the cellular mechanisms underlying those actions of Ang II, phosphorylated Akt and mTOR were measured in hearts from these rats. Ang II increased phosphorylation of Akt and mTOR; and cardiac transduction of Lv-DNp85 significantly abolished Ang II-induced phosphorylation of Akt and mTOR, a signaling pathway inhibiting autophagy. CONCLUSIONS: These results demonstrate that class I PI3-kinase, via activation of the Akt-mTOR pathway, is involved in Ang II-induced impairment of autophagy, elevation of ROS, cardiac hypertrophy, and fibrosis, suggesting a novel target for cardiac protection. PMID- 25807430 TI - Serum uric acid level predicts new-onset atrial fibrillation after coronary artery bypass graft operation. AB - OBJECTIVE: To investigate the association between serum uric acid levels and the risk of incident atrial fibrillation in patients after coronary artery bypass graft (cABG) operation. PATIENTS AND METHODS: A total of 174 patients undergoing nonemergency coronary artery bypass graft operation were included in the study. Patients with previous atrial arrhythmia or requiring concomitant valve surgery were excluded. We prospectively analyzed 174 patients (mean age: 59.8 years; 109 male and 65 female). The serum uric acid level was determined preoperatively. RESULTS: After a coronary artery bypass graft operation operation, 35 (20%) patients developed atrial fibrillation. Preoperative uric acid levels were significantly higher in patients who developed atrial fibrillation than in those who did not (7.8 +/- 1.1 vs 5 +/- 0.9). Using a cutpoint of 6.55, the preoperative level correlated with the appearance of atrial fibrillation with a sensitivity of 91.4% and specificity of 84.2%. CONCLUSIONS: Serum uric acid level can increase the sensitivity and specificity in predicting atrial fibrillation in patients after CABG operation. PMID- 25807431 TI - The correlation between the mouth diameter of left atrial appendage and stroke risk score in patients with atrial fibrillation. AB - OBJECTIVE: Our objective is to explore the correlation between the mouth diameter of left atrial appendage (LAA) and stroke risk score in patients with atrial fibrillation (AF), to find the effective ways to improve diagnosis and treatment level. PATIENTS AND METHODS: 112 patients with AF during January 2011-April 2013 were retrospectively analyzed, including 79 cases with paroxysmal AF and 32 cases with persistent AF or long-standing persistent AF (LS-AF). Radiofrequency catheter ablation (RFCA) and transesophageal echocardiography were used to detect the maximum mouth diameter of LAA, the correlation of which with stroke risk score was analyzed. RESULTS: In the patients with paroxysmal AF, the mouth diameter of LAA was 18.63 +/- 4.14 mm, CHADS2 score was 0.91 +/- 0.90 points and CHA2DS2-VASc score was 1.89 +/- 1.36 points while in the patients with persistent AF or LS-AF, the mouth diameter of LAA was 20.68 +/- 5.49 mm, CHADS2 score was 0.85 +/- 0.84 points and CHA2DS2-VASc score was 1.67 +/- 1.41 points. The mouth diameters of LAA, CHADS2 score and CHA2DS2-VASc score were statistically different between these two types of AF (p < 0.05). Moreover, the mouth diameter of LAA, CHADS2 score and CHA2DS2-VASc were not statistically correlated with paroxysmal AF or persistent AF (p > 0.05). CONCLUSIONS: Different types of AF are correlated with the mouth diameter of LAA, however, the mouth diameter of LAA is not correlated with stroke risk score. PMID- 25807432 TI - Effects of platelet infusion, anticoagulant and other risk factors on the rehaemorrhagia after surgery of hypertensive cerebral hemorrhage. AB - OBJECTIVE: Our objective is to explore the effect of platelet infusion, anticoagulant and other risk factors on the rehaemorrhagia after surgery of hypertensive cerebral hemorrhage (HCH), and to provide a reference for the prevention and treatment of rehaemorrhagia in patients with HCH. PATIENTS AND METHODS: The patients with HCH admitted during April, 2007-June, 2012 in our hospital were selected. The general data such as age and gender, disease course, past pathogenic characters, past and present medical history such as treatment, personal history, family history and son on, were collected. The data were analyzed by t test, ANOVA, Chi-squared test and logistic regression analysis. RESULTS: The application of aspirin and platelets has significant effect on rehaemorrhagia after surgery of HCH: 72 patients received aspirin, of which 14 cases had rehaemorrhagia while 197 patients did not receive aspirin, of which 20 cases had rehaemorrhagia. The difference between these two groups was statistically significant (p < 0.05). 186 patients received platelet infusions, of which 18 cases had rehaemorrhagia whereas among other 83 patients not receiving platelet infusions, 16 cases had rehaemorrhagia. Statistical analysis showed a significant difference between these two groups (p < 0.05). In the univariate logistic regression analysis of related data in patients with rehaemorrhagia after surgery of HCH, diastolic or systolic blood pressure at admission, the time from onset to surgery, coagulation disorder, surgical method, hematoma volume, cerebral hemia, effect of hematoma clearance and GCS at admission were the potential risk factors for rehaemorrhagia after surgery of HCH (p < 0.05). In the multivariate logistic regression analysis of related data in the same patients, diastolic blood pressure at admission (> 120 mmHg), systolic blood pressure at admission (> 200 mmHg), the time from onset to surgery and coagulation disorder were screened out (p < 0.05) to be associated with rehaemorrhagia. CONCLUSIONS: Aspirin increased the risk of rehaemorrhagia after surgery of HCH. On the contrary, infusion of platelets decreased the risk of rehaemorrhagia and improved the prognosis of patients. High diastolic and/or high systolic blood pressure at admission, ultra-early surgery after onset of HCH and coagulation disorder were related with rehaemorrhagia after operation of HCH. Our results indicate that rehaemorrhagia rate can be decreased by controlling related risk factors. PMID- 25807433 TI - E-recruitment based clinical research: notes for Research Ethics Committees/Institutional Review Boards. AB - Patient recruitment is a critical point of today's clinical research. Several proposals have been made for improving it, but the effectiveness of these measures is actually uncertain. The use of Internet (e-recruitment) could represent a great chance to improve patient enrolment, even though the effectiveness of this implementation is not so evident. E-recruitment could bring some advantages, such as better interaction between clinical research demand and clinical research supply, time and resources optimization, and reduction of data entry errors. It raises some issues too, such as sampling errors, validity of informed consent, and protection of privacy. Research Ethics Committees/Institutional Review Boards should consider these critical points. The paper deals with Internet recruitment for clinical research. It also attempts to provide Research Ethics Committees/Institutional Review Boards with notes for assessing e-recruitment based clinical protocols. PMID- 25807434 TI - Epidemiology of prostate cancer: current status. AB - Prostate cancer is one of the most common cancers affecting men with > 1,100,000 new cases and 300,000 deaths worldwide each year. The disease is more common among older men, with a median age at diagnosis around age above 60 years. Prostate cancer is a major medical problem that needs immediate attention as the disease is indolent, shows prolonged latency in association with high morbidity and mortality. Administration of diagnostic tests including PSA test and biopsies and the advances in other diagnostic procedures have led to early detection of the disease with therapeutic steps being taken early on, there has been a steady decline in the disease-specific mortality. Global incidence and mortality rates show that the disease is more prevalent among black people, even though the differences cannot be attributed entirely to race, as the influence of socioeconomic situation and the resultant limited access to medical technologies and treatment could not be ruled out completely. Several genes have been identified that when mutated confer high risk for the disease. Besides the genetic factors, family history and nutritional factors such as lack of enough vitamin D, high intake of calcium, obesity and high fat diets have been implicated as risk factors for prostate cancer. Therapeutic measures for prostate cancer involve mostly radical prostatectomy followed by radiotherapy in combination with hormonal treatment as needed. PMID- 25807435 TI - Expression of RASSF1A in epithelial ovarian cancers. AB - OBJECTIVE: Ovarian cancer is the third most common cancer in female reproductive system. But ovarian cancer is hard to detect at early phase. It is very urgent to develop effective early diagnosis method for ovarian cancer. RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor, which modulates multiple apoptotic and cell cycle checkpoint pathways. We amed to find out the relationship between RASSF1A and ovarian cancer. METHODS: We compared the expressions of RASSF1A gene in different ovarian cancer cell lines, and also in epithelial ovarian cancer tissues and normal ovarian tissues through RT-PCR (reverse transcription polymerase chain reaction) technique. RESULTS: RASSF1A was expressed in HO8910 and HO8910PM cells, while RASSF1A mRNA was absent in SKOV-3 and OVCAR-3 cells. RASSF1A was expressed in 10 normal ovarian tissue samples (10/10, 100%), while RASSF1A was only expressed in 2 ovarian cancers tissue samples (2/47, 4.3%). The difference in the frequency was significant in tissue samples (100% vs. 4.3%, p < 0.05). CONCLUSIONS: RASSF1A could be served as a potential molecular marker for diagnosing ovarian cancer at early phase. PMID- 25807436 TI - The histone deacetylase SIRT6 inhibits ovarian cancer cell proliferation via down regulation of Notch 3 expression. AB - OBJECTIVE: SIRT6 belongs to the NAD+-dependent class III deacetylase sirtuin family. Accumulating evidences have supported the critical role of SIRT6 in the proliferation, differentiation, cell cycle progression and apoptosis of cancer cells. The present study aims to determine the expression of SIRT6 in human ovarian cancer tissues and further investigate its the biological effect in ovarian cancer. MATERIALS AND METHODS: Real time PCR and western blot were performed to examine the mRNA and protein levels SIRT6 in human ovarian cancer tissues and normal tissues. The proliferation of ovarian cancer cells was determined using MTT methods. Small interfering RNA (siRNA) technology was used to down-regulate the expression of SIRT6 and Notch 3. RESULTS: We found that the SIRT6 expression was significantly reduced in human ovarian cancer tissues compared to the normal tissues. Furthermore, our data showed that overexpression of SIRT6 inhibited the proliferation of ovarian cancer cells SKOV3 and OVCAR3. By contrast, down-regulation of SIRT6 enhanced ovarian cancer cells growth. In addition, our study showed that SIRT6 suppressed the expression of Notch 3 both at the mRNA and protein levels in ovarian cancer cells. CONCLUSIONS: Our findings indicated that SIRT6 inhibited the proliferation of ovarian cancer cells through down-regulation of Notch 3 expression, and might provide novel therapeutic targets for ovarian cancer therapy. PMID- 25807437 TI - Identification of miRNA-mRNA crosstalk in pancreatic cancer by integrating transcriptome analysis. AB - OBJECTIVE: Pancreatic cancer is one of the most lethal diseases, and the pathogenesis remains largely unknown. To this end, we performed an integrated analysis of miRNA and mRNA expression data to explore the deregulation of miRNA and mRNA and regulatory processes underlying pancreatic cancer. MATERIALS AND METHODS: We combined mRNA and miRNA expression data with miRNA target predictions to infer new miRNA regulation activities in pancreatic cancer. We first integrated miRNA and mRNA expression profiling separately to identify differently expressed miRNA and mRNA in pancreatic cancer. Then we adopted miRWalk databases prediction to obtain potential target genes of differently expressed miRNA, and compared these target genes to the gene list of integrated mRNA expression profiling to select differentially expressed miRNA-target gene whose expression was reversely correlated with that of corresponding miRNAs. Gene Ontology (GO) classification analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were employed to understand the functions and pathways of miRNA target genes. Finally we construct a miRNA-target gene regulatory network. RESULTS: 42 differentially expressed miRNAs, 1376 differentially expressed mRNAs were identified by combining three expression profiles of miRNA and mRNA separately in pancreatic cancer, 146 miRNA target genes were found in the gene list of integrated mRNA expression profiling based on bioinformatics prediction. Functional annotation was performed to understand the functions and pathways of miRNA target genes. Finally, we constructed a miRNA-target gene regulatory network including 206 miRNA-target gene pairs. Five miRNAs (hsa-miR-130b, hsa-miR 106b, hsa-miR-181c, hsa-miR-153 and hsa-miR-125a-5p) demonstrated the highest connectivities, whereas three miRNAs (MYC, E2F1 and IL6) were the mRNAs with the highest connectivities. CONCLUSIONS: Our findings may provide new insights into the knowledge of molecular mechanisms of pancreatic cancer and development of novel targeting therapies. PMID- 25807438 TI - Radioactive iodine labeling of monoclonal antibody against Hsp90alpha and its use in diagnostic imaging in prostate cancer xenograft model. AB - OBJECTIVE: Heat shock protein (Hsp90) resides exclusively in the cytosol in normal cells, but is activated and then removes to the cell surface in tumor cells. The detecting upregulation or activation of Hsp90 is an early indicator of malignant behavior of cancer cells. Hsp90 has emerged as an important target for diagnosis or therapy of prostate cancer. In this study, we labeled Hsp90alpha specific monoclonal antibody (Hsp90alpha-mAb) with radioiodine Na131I and investigated its potential usage in diagnostic imaging of prostate tumor in xenograft mice model. METHODS: Hsp90alpha-mAb was radioiodinated by using chloramine-T. The radiolabeling efficiency and radiochemical purity were assessed in vitro. 131I-Hsp90alpha-mAb was then injected into the nude mice bearing human prostate carcinoma. The planar gamma Imaging was performed at 3, 6, 9 and 12 h after injection. RESULTS: The radiochemical purity of 131I-Hsp90alpha-mAb exceeded 95% after purification. This radiolabeled mAb was stable in human blood serum. In planar gamma imaging study, the prostate tumors in mice model were imaged clearly at 3h after injection of 131I-Hsp90alpha-mAb. CONCLUSIONS: The results suggest that 131I-HSP90alpha-mAb could be a new promising molecular probe for diagnostic imaging of prostate tumors. PMID- 25807439 TI - Epigenetic mechanisms in chronic obstructive pulmonary disease. AB - Epigenetic modification may affect the expression of multiple inflammatory genes in lungs of patients with chronic obstructive pulmonary disease (COPD). Major epigenetic events include DNA methylation and various post-translational modifications of histones, such as histone methylation, acetylation, phosphorylation, ubiquitination, and sumoylation. Enzymes which regulate these epigenetic modifications can be activated by smoking. Both environmental and genetic factors play significant effect in development of COPD which have been reported by most references; however, little is known about the epigenetic pathways involved in the disease. Understanding the epigenetic mechanisms can help us clarify the pathogenesis of COPD and identify novel targets for developing new therapies for patients with COPD. PMID- 25807441 TI - General issues on microbial translocation in HIV-infected patients. AB - The lumen of the gastrointestinal tract is home to an enormous quantity of different bacterial species that thrive in an often symbiotic relationship with the host. It is the principal source of microbial products because of its massive bacterial load. Injury to the immune component of the gastrointestinal mucosal surface, along with damage to the intestinal epithelial microenvironment with its antimicrobial functions, may affect systemic immune activation during the chronic phase of HIV infection through the increased translocation of luminal microbial products. Moreover, microbial translocation, which is defined as "the passage of both viable and nonviable microbes and microbial products such as endotoxin across anatomically intact intestinal barrier", may be a fundamental mechanism through which HIV accelerates progression of chronic viral hepatitis. Improvements in the tools available to microbiota research, and especially advancement of our knowledge in this area may help us in controlling the evolution of HIV disease, although population complexity and diversity between individuals make this challenging. PMID- 25807440 TI - Mesenchymal stem cell-based FGF2 gene therapy for acute lung injury induced by lipopolysaccharide in mice. AB - OBJECTIVE: Bone marrow-derived mesenchymal stem cells (MSCs) can serve as a vehicle for gene therapy. FGF2 (basic fibroblast growth factor) is a multifunctional growth factor and exhibits diverse function in different cell types, it also has pleiotropic effects in different tissues and organs, including potent angiogenic effects and an important role in the differentiation and function of the central nervous system. We hypothesized that MSC-based FGF2 gene therapy might be a potential therapeutic approach for lipopolysaccharide (LPS) induced lung injury. MATERIALS AND METHODS: MSCs were isolated from 6 week-old inbred male mice and transduced with the FGF2 gene, using a lentivirus vector. RESULTS: In the in vivo mouse model, the LPS-induced lung injury was markedly alleviated in the group treated with MSCs carrying FGF2 (MSCs-FGF2), compared with groups treated with MSCs alone. The histopathological index of LPS-induced lung injury was improved after MSCs-based FGF2 gene treatment. The MSCs-FGF2 administration also reduced the level of inflammatory cytokines. CONCLUSIONS: These results suggest that MSCs and FGF2 have a synergistic role in the treatment of LPS-induced lung injury. PMID- 25807442 TI - Antioxidant potential of Aesculus hippocastanum extract and escin against reactive oxygen and nitrogen species. AB - OBJECTIVE: Antioxidant, anti-inflammatory and venoconstrictor properties have been attributed to extracts from Aesculus hippocastanum. These unusual and diverse properties may be possibly basically linked with ability to scavenge free radicals. MATERIALS AND METHODS: The scavenging capacity of dry horse chestnut extract of and escin have been investigated in vitro against superoxide anion radicals, hydroxyl radicals, nitrites and peroxynitrite. RESULTS: In general, the activity of the whole extract against superoxide radicals did not exceed 15% at pH 7.4, but the highest inhibition (46.11%) was recorded against hydroxyl radicals at a concentration of 100 ug.ml-1; however, the activity against other radicals was lower. Escin demonstrated a better ability to counteract nitric oxide oxidation products, nitrites. However, the efficiency of the whole extract completely disappeared as the concentration increased. Both extracts showed very low activity towards peroxynitrite. Escin was even able to induce peroxynitrite formation at the lower concentrations used. CONCLUSIONS: Whole extract showed better antiradical properties compared to its main active ingredient, escin, probably due to potential synergistic interaction with a mixture of compounds present in the plant extract. These findings can be the basis of both the presentation of side-effects and the persistence of disease in spite of ongoing treatment. PMID- 25807443 TI - Effects of kefir on ischemia-reperfusion injury. AB - OBJECTIVE: We aimed to investigate the effect of kefir on Ischemia-Reperfusion (I/R) injury on rats. MATERIALS AND METHODS: 24 male Sprague-Dawley rats between 250-350 g were selected. Rats were divided into three groups, and there were eight rats in each group. Rats were fed for 60 days. All of the rats were fed with the same diet for the first 30 days. In the second thirty days, kefir [10 cc/kg/day body weight (2 x 109 cfu/kg/day)] was added to the diet of the study group by gavage method. In all groups, lung and kidney tissues were removed after the procedure and rats were sacrificed. The biochemical and histopathological changes were observed in the lung and kidney within the samples. Serum urea, creatinine and tumor necrosis factor (TNF-alpha) were determined. RESULTS: Kefir + I/R groups was compared with I/R groups, a significant decrease (p < 0.05) was seen in Lipid peroxidation (MDA) levels of lung and renal tissues. Superoxide dismutase (SOD), Catalase (CAT) and Glutathione peroxidase (GSH-Px) activities of lung and kidney tissues decreased in I/R groups (p < 0.05). The enzyme activities in Kefir + I/R groups of renal tissues were significantly (p < 0.05) higher than I/R, not significantly different in lung tissues (p < 0.05). Kefir reduced the levels of serum urea, creatinine and TNF-alpha significantly. CONCLUSIONS: This would be useful in this model against ischemia/reperfusion, and shows the protective effect of kefir in tissue and serum functions. PMID- 25807444 TI - Dabigatran etexilate and LMWH for the prevention of venous thromboembolism in 532 patients undergoing hip surgery. AB - OBJECTIVE: Patients undergoing total hip replacement (THR) are at high risk of venous thromboembolism (VTE) and according to guidelines they should receive pharmacological prophylaxis. We would like to compare the efficacy, adherence and safety of dabigatran and low molecular weight heparins (LMWH) for the prevention of VTE in patients who underwent THR. PATIENTS AND METHODS: This study enrolled patients undergoing THR treated with dabigatran (110 mg loading dose then 220 mg/day for 34 days) or the LMWH dalteparin (2500 IU, 6-8 hours before surgery then 5000 IU/day for 35 days). The primary endpoint was adherence to treatment. RESULTS: Of the 532 patients screened and enrolled in the study, 407 (mean age 57.7 +/- 12.3 years) completed the study (211 dabigatran, 196 LMWH). Over the 35 days of treatment, adherence was comparable between dabigatran and LMWH: 10.9% and 14.3% of patients receiving dabigatran and LMWH treatment missed > 1 dose of the drug, respectively. There was a lower need for external support in patients who received dabigatran (8.5% vs 58.2%; p < 0.0001) and a lower number of patients receiving dabigatran required support by a professional nurse (1.4% vs 17.3% of patients with LMWH; p < 0.0001). Dabigatran and LMWH were similarly well tolerated; however, fewer patients receiving dabigatran reported bleeding events. CONCLUSIONS: This study demonstrates that dabigatran is associated with high adherence. A lower need for external support in patients who received dabigatran may provide an added benefit compared with other oral treatments for VTE prophylaxis. PMID- 25807445 TI - Stribild: a review of component characteristics and combination drug efficacy. AB - BACKGROUND: Numerous methods have been devised to combat human immunodeficiency virus (HIV) replication and disease progression. Composed of an integrase strand transfer inhibitor, a pharmacoenhancer, and two reverse transcriptase inhibitors, Stribild is a relatively new combination HIV drug formulated for once-a-day dosing. METHODS: Relevant information, original research articles and reviews, were gathered primarily through the use of the PubMed database. The search was conducted without date restrictions in order to collect both historical and recent information concerning HIV, individual drugs, and combinations for a thorough overview. RESULTS: Stribild, when taken with food, provides therapeutic drug concentrations as seen through comparison with the respective individual or boosted individual drugs. Stribild non-inferiority has been shown when compared to other HIV drug combinations, ritonavir-boosted atazanavir or efavirenz each with a tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) backbone. The co-formulation also retained high viral suppression in patients switching from other regimens, such as efavirenz/TDF/FTC, raltegravir/TDF/FTC, or various ritonavir-boosted protease inhibitors with TDF/FTC. The elvitegravir and cobicistat combination was unaffected by moderate hepatic impairment; however, hepatic and renal function along with changes in bone mineral density should be monitored closely. Stribild presented with relatively few side effect occurrences, but drug interactions may pose a larger problem for continuous therapy. CONCLUSIONS: Stribild provides viral suppression, comparable to other combination HIV drugs through review of non-inferiority and regimen simplification studies, with minimal adverse effects. Although the breadth of Stribild effectiveness has begun to unfold, studies are lacking in older patients as well as adolescents. PMID- 25807447 TI - Photocatalytic Performances of Ag3PO4 Polypods for Degradation of Dye Pollutant under Natural Indoor Weak Light Irradiation. AB - It is still a big challenge for Ag3PO4 to be applied in practice mainly because of its low stability resistant to photo corrosion, although it is an efficient photocatalyst. Herein, we have mainly investigated its activity and stability under indoor weak light for the degradation of dye pollutants. It is amazing that under indoor weak light irradiation, rhodamine B (RhB) can be completely degraded by Ag3PO4 polypods after 36 h, but only 18% of RhB by N-doped TiO2 after 120 h. It is found that under indoor weak light irradiation, the degradation rate (0.08099 h(-1)) of RhB over Ag3PO4 polypods are 46 times higher than that (0.00173 h(-1)) of N-doped TiO2. The high activity of Ag3PO4 polypods are mainly attributed to the three-dimensional branched nanostructure and high-energy {110} facets exposed. After three cycles, surprisingly, Ag3PO4 polypods show a high stability under indoor weak light irradiation, whereas Ag3PO4 have been decomposed into Ag under visible light irradiation with an artificial Xe light source. This natural weak light irradiation strategy could be a promising method for the other unstable photocatalysts in the degradation of environmental pollutants. PMID- 25807449 TI - Code blue: do you know what to do? PMID- 25807450 TI - Patient discharge information: tools for success. PMID- 25807446 TI - Pioglitazone treatment increases survival and prevents body weight loss in tumor bearing animals: possible anti-cachectic effect. AB - Cachexia is a multifactorial syndrome characterized by profound involuntary weight loss, fat depletion, skeletal muscle wasting, and asthenia; all symptoms are not entirely attributable to inadequate nutritional intake. Adipose tissue and skeletal muscle loss during cancer cachexia development has been described systematically. The former was proposed to precede and be more rapid than the latter, which presents a means for the early detection of cachexia in cancer patients. Recently, pioglitazone (PGZ) was proposed to exhibit anti-cancer properties, including a reduction in insulin resistance and adipose tissue loss; nevertheless, few studies have evaluated its effect on survival. For greater insight into a potential anti-cachectic effect due to PGZ, 8-week-old male Wistar rats were subcutaneously inoculated with 1 mL (2*107) of Walker 256 tumor cells. The animals were randomly assigned to two experimental groups: TC (tumor + saline control) and TP5 (tumor + PGZ/5 mg). Body weight, food ingestion and tumor growth were measured at baseline and after removal of tumor on days 7, 14 and 26. Samples from different visceral adipose tissue (AT) depots were collected on days 7 and 14 and stored at -80o C (5 to 7 animals per day/group). The PGZ treatment showed an increase in the survival average of 27.3% (P< 0.01) when compared to TC. It was also associated with enhanced body mass preservation (40.7 and 56.3%, p< 0.01) on day 14 and 26 compared with the TC group. The treatment also reduced the final tumor mass (53.4%, p<0.05) and anorexia compared with the TC group during late-stage cachexia. The retroperitoneal AT (RPAT) mass was preserved on day 7 compared with the TC group during the same experimental period. Such effect also demonstrates inverse relationship with tumor growth, on day 14. Gene expression of PPAR-gamma, adiponectin, LPL and C/EBP-alpha from cachectic rats was upregulated after PGZ. Glucose uptake from adipocyte cells (RPAT) was entirely re-established due to PGZ treatment. Taken together, the results demonstrate beneficial effects of PGZ treatment at both the early and final stages of cachexia. PMID- 25807448 TI - A multiparametric computational algorithm for comprehensive assessment of genetic mutations in mucopolysaccharidosis type IIIA (Sanfilippo syndrome). AB - Mucopolysaccharidosis type IIIA (MPS-IIIA, Sanfilippo syndrome) is a Lysosomal Storage Disease caused by cellular deficiency of N-sulfoglucosamine sulfohydrolase (SGSH). Given the large heterogeneity of genetic mutations responsible for the disease, a comprehensive understanding of the mechanisms by which these mutations affect enzyme function is needed to guide effective therapies. We developed a multiparametric computational algorithm to assess how patient genetic mutations in SGSH affect overall enzyme biogenesis, stability, and function. 107 patient mutations for the SGSH gene were obtained from the Human Gene Mutation Database representing all of the clinical mutations documented for Sanfilippo syndrome. We assessed each mutation individually using ten distinct parameters to give a comprehensive predictive score of the stability and misfolding capacity of the SGSH enzyme resulting from each of these mutations. The predictive score generated by our multiparametric algorithm yielded a standardized quantitative assessment of the severity of a given SGSH genetic mutation toward overall enzyme activity. Application of our algorithm has identified SGSH mutations in which enzymatic malfunction of the gene product is specifically due to impairments in protein folding. These scores provide an assessment of the degree to which a particular mutation could be treated using approaches such as chaperone therapies. Our multiparametric protein biogenesis algorithm advances a key understanding in the overall biochemical mechanism underlying Sanfilippo syndrome. Importantly, the design of our multiparametric algorithm can be tailored to many other diseases of genetic heterogeneity for which protein misfolding phenotypes may constitute a major component of disease manifestation. PMID- 25807452 TI - Graphene based energy devices. PMID- 25807451 TI - Complexation between Sodium Poly(styrenesulfonate) and Alkyltrimethylammonium Bromides in the Presence of Dodecyl Maltoside. AB - In the present paper, the impact of dodecyl maltoside (C12G2) on the association of sodium poly(styrenesulfonate) (PSS) with dodecyl- and hexadecyltrimethylammonium bromides (DTAB and CTAB) was studied. A low amount of nonionic surfactant enhances the binding of the investigated cationic amphiphiles on PSS, reducing the cationic surfactant-to-polyanion ratio needed for charge neutralization and precipitation. This effect is more pronounced for DTAB than for CTAB due to the considerably higher free surfactant concentration of the former cationic amphiphile. The synergistic surfactant binding also affects the nonequilibrium features of PSS/CTAB association via enhancing the kinetically stable concentration range of overcharged polyion/surfactant nanoparticle dispersions. With increasing C12G2 concentration, however, an opposite effect of the uncharged additive dominates. Namely, the CTAB molecules are solubilized excessively into mixed surfactant micelles, which reduces the surface charge of the PSS/CTAB/C12G2 nanoparticles and thus destabilizes their dispersion. At appropriately large nonionic surfactant concentrations, the binding of CTAB is largely reduced, resulting in the redissolution of the precipitate. In contrast, neither the destabilization nor the resolubilization effects of the added dodecyl maltoside were observed for the PSS/DTAB system due to the much lower driving force of DTAB binding compared to CTAB. Our results clearly demonstrate that the alkyl chain length of the ionic amphiphile has a pronounced effect on both the equilibrium and nonequilibrium aspects of polyion/mixed surfactant complexation which might be further exploited in various next generation applications. PMID- 25807453 TI - The impacts of media messaging and age and sex variance on adolescent smoking habits in Croatia. AB - OBJECTIVES: To analyze the effects of age, sex, and media messages that encourage or discourage smoking, in conjunction with having 1 or more parents, close friends, teachers, or family members who smoke, on differences in patterns of adolescent smoking. METHODS: This research is based on Croatian responses to the 2011 Global Youth Tobacco Survey. A total of 4245 Croatian youths responded to the Global Youth Tobacco Survey, of which individuals 3551 were aged 13 to 15 years. Of this cross section, 1644 individuals were male; 1856 were female; and 51 were of unknown sex. RESULTS: There were significant differences among responses in terms of age. Older adolescents were more likely to smoke (P < 0.001) and more likely to experience the following: (1) outdoor exposure to other smokers, including teachers (P < 0.001) and fellow students (P < 0.001); (2) smoking in the presence of parents or guardians (P < 0.001) and best friends (P < 0.001). The most prominent predictor of smoking among male adolescents was the existence of a best friend who smokes, with an odds ratio of 6.38 and a corresponding 95% confidence interval of 3.69 to 11.01. Likewise, the most prominent predictor among female adolescents was also the existence of a best friend who smokes, with an odds ratio of 10.21 and a corresponding 95% confidence interval of 4.94 to 21.13. The majority of nonsmokers, 65.5% (n = 1640), and smokers, 58.8% (n = 506), have never seen advertisements for cigarettes broadcast during televised concerts, and 58.5% of nonsmokers (n = 1469) and 58.6% of smokers (n = 505) have never seen advertisements for cigarettes while attending concerts. CONCLUSIONS: Our study shows that there is no sex difference between the number of nonsmokers and smokers. Older adolescents tend to smoke more, and students who smoke outside reported seeing other adolescents and their teachers smoking almost daily. A majority of youths who reported that they smoke have parents who smoke at home and have close friends who smoke; having a close or best friend who smokes is the highest prediction factor that both male and female youths will begin smoking. The majority of nonsmokers and smokers have never seen pro-smoking messages when going to concerts or during other community and social events. This lack of exposure to smoking-related advertising is the result of new legal restrictions imposed in 2008 on tobacco-product producers. There is no statistical significance among smokers' and nonsmokers' perceptions of antismoking media messaging. Peer pressure has been shown to be the second-most influential factor, after having a best friend who smokes, for the likelihood that an individual will become a smoker, among both male and female adolescents. PMID- 25807455 TI - "Crack lung": a pulmonary complication of crack cocaine case. PMID- 25807457 TI - A novel CO2- and SO2-tolerant dual phase composite membrane for oxygen separation. AB - A novel dual phase composite oxygen transport membrane (Al0.02Ga0.02Zn0.96O1.02 Gd0.1Ce0.9O1.95-delta) was successfully prepared and tested. This membrane shows chemical stability against CO2 and SO2, and stable oxygen permeation over 300 hours in CO2 was demonstrated. ZnO is cheap and non-toxic and is therefore highly advantageous compared to other common materials used for this purpose. PMID- 25807454 TI - The stepped treatment engagement protocol for homeless, needle exchange heroin dependent patients. PMID- 25807458 TI - An intuitional hierarchical assembly of cluster-organic frameworks with a thickness of 1.97 nm from a discrete Co14 cluster. AB - An intuitional hierarchical assembly, metaphorically referred to as a "blossom and yield fruit" process, from a discrete cluster {[Co14(CH3O)4(dpbt)6Cl12].14CH3OH, ()} to 2D cluster organic frameworks {[Co14(CH3O)10(dpbt)6 Cl6].12CH3OH, ()}, has been established. The magnetic ordering of was obviously improved compared with . PMID- 25807459 TI - Glycosyl phosphatidylinositol anchor biosynthesis is essential for maintaining epithelial integrity during Caenorhabditis elegans embryogenesis. AB - Glycosylphosphatidylinositol (GPI) is a post-translational modification resulting in the attachment of modified proteins to the outer leaflet of the plasma membrane. Tissue culture experiments have shown GPI-anchored proteins (GPI-APs) to be targeted to the apical membrane of epithelial cells. However, the in vivo importance of this targeting has not been investigated since null mutations in GPI biosynthesis enzymes in mice result in very early embryonic lethality. Missense mutations in the human GPI biosynthesis enzyme pigv are associated with a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease and renal anomalies. However, it is currently unknown how these phenotypes are linked to PIGV function. Here, we identify a temperature-sensitive hypomorphic allele of PIGV in Caenorhabditis elegans, pigv-1(qm34), enabling us to study the role of GPI-APs in development. At the restrictive temperature we found a 75% reduction in GPI-APs at the surface of embryonic cells. Consequently, ~80% of pigv-1(qm34) embryos arrested development during the elongation phase of morphogenesis, exhibiting internal cysts and/or surface ruptures. Closer examination of the defects revealed them all to be the result of breaches in epithelial tissues: cysts formed in the intestine and excretory canal, and ruptures occurred through epidermal cells, suggesting weakening of the epithelial membrane or membrane-cortex connection. Knockdown of piga-1, another GPI biosynthesis enzymes resulted in similar phenotypes. Importantly, fortifying the link between the apical membrane and actin cortex by overexpression of the ezrin/radixin/moesin ortholog ERM-1, significantly rescued cyst formation and ruptures in the pigv-1(qm34) mutant. In conclusion, we discovered GPI-APs play a critical role in maintaining the integrity of the epithelial tissues, allowing them to withstand the pressure and stresses of morphogenesis. Our findings may help to explain some of the phenotypes observed in human syndromes associated with pigv mutations. PMID- 25807460 TI - OsKinesin-13A is an active microtubule depolymerase involved in glume length regulation via affecting cell elongation. AB - Grain size is an important trait influencing both the yield and quality of rice and its major determinant is glume size. However, how glume size is regulated remains largely unknown. Here, we report the characterization of OsKinesin-13A, which regulates cell elongation and glume length in rice. The mutant of OsKinesin 13A, sar1, displayed length reduction in grains and other organs including internodes, leaves and roots. The grain phenotype in sar1 was directly caused by reduction in glume length, which in turn restricted caryopsis size. Histological results revealed that length decrease in sar1 organs resulted from abnormalities in cell elongation. The orientation of cellulose microfibrils was defective in sar1. Consistently, sar1 showed reduced transverse orientation of cortical microtubules. Further observations demonstrated that microtubule turnover was decreased in sar1. OsKinesin-13A was shown to be an active microtubule depolymerase and mainly distributed on vesicles derived from the Golgi apparatus and destined for the cell surface. Thus, our results suggest that OsKinesin-13A utilizes its microtubule depolymerization activity to promote microtubule turnover, which may not only influence transverse orientation of cortical microtubules but also facilitate vesicle transport from the Golgi apparatus to the cell surface, and thus affects cellulose microfibril orientation and cell elongation. PMID- 25807461 TI - Loss of PLZF expression in prostate cancer by immunohistochemistry correlates with tumor aggressiveness and metastasis. AB - PLZF is a transcription repressor, which plays a critical role in development, spermatogenesis and oncogenesis. Down-regulation of PLZF has been found in various tumor cell lines. There has been virtually no tissue study on the expression of PLZF in prostate cancer (PCa). PCa is a heterogeneous disease, most of which are indolent and non-lethal. Currently there are no biomarkers that distinguish indolent from aggressive PCa; therefore there is an urgent need for such markers to provide clinical decision support. This study aimed to investigate the expression of PLZF by immunohistochemistry in different grade as well as metastatic PCa and to correlate the alteration of PLZF expression with PCa aggressiveness. We studied a total of 83 primary PCa from biopsies, 43 metastatic PCa and 8 paired primary and metastatic PCa from radical prostatectomies with lymph node dissection. Our results demonstrated that PLZF was strongly expressed in almost all (~100%) benign luminal cells (n=77) and low grade (Gleason pattern 3) PCa (n=70) and weak or absent (100%) in basal cells (n=70). Decreased or lost expression of PLZF was evidenced in 26% of high-grade (Gleason 4 and 5) primary PCa (n=70) and 84% metastatic PCa (n=43). The primary high grade PCa in the prostatectomies shared similar PLZF loss/decrease and histomorphology to that of paired parallel lymph node metastases. These data demonstrated that down-regulation of PLZF is an important molecular process for tumor progression and loss of PLZF expression detected by routine immunohistochemistry is a promising and valuable biomarker for PCa aggressiveness and metastasis in the personalized care of PCa. PMID- 25807462 TI - Transition diseases in grazing dairy cows are related to serum cholesterol and other analytes. AB - The objectives of this study were to describe the incidence of postpartum disease and to evaluate the association with serum cholesterol concentrations during the first 3 weeks after calving in grazing dairy cows. The association between non esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), calcium and postpartum diseases was also evaluated. A total of 307 Holstein dairy cows from 6 commercial grazing herds in Osorno, Chile, were monitored from calving until 21 days in milk. Cases of retained placenta, clinical hypocalcemia and clinical mastitis were recorded by the farmer using established definitions. Twice weekly, cows were evaluated for metritis by the same veterinarian based on vaginal discharge and body temperature. Postpartum blood samples were collected weekly and analyzed for serum concentrations of cholesterol, NEFA, BHBA and calcium. Cows were considered as having subclinical ketosis if BHBA >1.2 mmol/L, and subclinical hypocalcemia if calcium <2.0 mmol/L in any of the 3 weekly samples. Overall, 56% of the cows studied developed at least one clinical or subclinical disease after calving. Incidence of individual diseases was 8.8% for retained placenta, 4.2% for clinical hypocalcemia, 11.7% for clinical mastitis, 41.1% for metritis, 19.9% for subclinical hypocalcemia and 16.6% for subclinical ketosis. Lower postpartum cholesterol in cows was associated with developing severe metritis or having more than one clinical disease after calving. For every 0.4 mmol/L decrease in serum cholesterol cows were nearly twice as likely to be diagnosed with multiple clinical diseases after calving. Higher BHBA concentrations and lower calcium concentrations during week 1 were associated with severe cases of metritis. Low serum calcium concentration during week 1 was also associated with developing more than one clinical disorder after calving. In conclusion, the incidence of postpartum diseases can be high even in grazing herds and lower serum cholesterol concentrations were associated with occurrence of clinical postpatum disorders. PMID- 25807463 TI - Sixty hertz neurostimulation amplifies subthalamic neural synchrony in Parkinson's disease. AB - High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson's disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony. Here we demonstrate for the first time that during intra-operative 60 Hz STN DBS, one or more bands of resting state neural synchrony were amplified in the STN in PD. We recorded intra operative STN resting state local field potentials (LFPs) from twenty-eight STNs in seventeen PD subjects after placement of the DBS lead (model 3389, Medtronic, Inc.) before and during three randomized neurostimulation sets (130 Hz/1.35V, 130 Hz/2V, 60 Hz/2V). During 130 Hz/2V DBS, baseline (no DBS) STN alpha (8-12 Hz) and beta (13-35 Hz) band power decreased (N=14, P < 0.001 for both), whereas during 60 Hz/2V DBS, alpha band and peak frequency power increased (P = 0.012, P = 0.007, respectively). The effect of 60 Hz/2V DBS opposed that of power-equivalent (130 Hz/1.35V) DBS (alpha: P < 0.001, beta: P = 0.006). These results show that intra-operative 60 Hz STN DBS amplified whereas 130 Hz STN DBS attenuated resting state neural synchrony in PD; the effects were frequency-specific. We demonstrate that neurostimulation may be useful as a tool to selectively modulate resting state resonant bands of neural synchrony and to investigate its influence on motor and non-motor behaviors in PD and other neuropsychiatric diseases. PMID- 25807465 TI - A Bayesian modelling framework for tornado occurrences in North America. AB - Tornadoes represent one of nature's most hazardous phenomena that have been responsible for significant destruction and devastating fatalities. Here we present a Bayesian modelling approach for elucidating the spatiotemporal patterns of tornado activity in North America. Our analysis shows a significant increase in the Canadian Prairies and the Northern Great Plains during the summer, indicating a clear transition of tornado activity from the United States to Canada. The linkage between monthly-averaged atmospheric variables and likelihood of tornado events is characterized by distinct seasonality; the convective available potential energy is the predominant factor in the summer; vertical wind shear appears to have a strong signature primarily in the winter and secondarily in the summer; and storm relative environmental helicity is most influential in the spring. The present probabilistic mapping can be used to draw inference on the likelihood of tornado occurrence in any location in North America within a selected time period of the year. PMID- 25807464 TI - Helicobacter pylori cag pathogenicity island's role in B7-H1 induction and immune evasion. AB - During Helicobacter pylori (H. pylori) infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. We have previously shown that H. pylori upregulates B7 H1 expression on GEC, which, in turn, suppress T cell proliferation, effector function, and induce Treg cells in vitro. In this study, we investigated the underlying mechanisms and the functional relevance of B7-H1 induction by H. pylori infection to chronic infection. Using H. pylori wild type (WT), cag pathogenicity island (cag PAI-) and cagA- isogenic mutant strains we demonstrated that H. pylori requires its type 4 secretion system (T4SS) as well as its effector protein CagA and peptidoglycan (PG) fragments for B7-H1 upregulation on GEC. Our study also showed that H. pylori uses the p38 MAPK pathway to upregulate B7-H1 expression in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, which has a functional T4SS delivery system, but not with H. pylori SS1 strain lacking a functional T4SS, led to a strong upregulation of B7-H1 expression in the gastric mucosa, increased bacterial load, induction of Treg cells in the stomach, increased IL-10 in the serum. Interestingly, B7-H1-/- mice showed less Treg cells and reduced bacterial loads after infection. These studies demonstrate how H. pylori T4SS components activate the p38 MAPK pathway, upregulate B7-H1 expression by GEC, and cause Treg cell induction; thus, contribute to establishing a persistent infection characteristic of H. pylori. PMID- 25807466 TI - Network intrusion detection based on a general regression neural network optimized by an improved artificial immune algorithm. AB - To effectively and accurately detect and classify network intrusion data, this paper introduces a general regression neural network (GRNN) based on the artificial immune algorithm with elitist strategies (AIAE). The elitist archive and elitist crossover were combined with the artificial immune algorithm (AIA) to produce the AIAE-GRNN algorithm, with the aim of improving its adaptivity and accuracy. In this paper, the mean square errors (MSEs) were considered the affinity function. The AIAE was used to optimize the smooth factors of the GRNN; then, the optimal smooth factor was solved and substituted into the trained GRNN. Thus, the intrusive data were classified. The paper selected a GRNN that was separately optimized using a genetic algorithm (GA), particle swarm optimization (PSO), and fuzzy C-mean clustering (FCM) to enable a comparison of these approaches. As shown in the results, the AIAE-GRNN achieves a higher classification accuracy than PSO-GRNN, but the running time of AIAE-GRNN is long, which was proved first. FCM and GA-GRNN were eliminated because of their deficiencies in terms of accuracy and convergence. To improve the running speed, the paper adopted principal component analysis (PCA) to reduce the dimensions of the intrusive data. With the reduction in dimensionality, the PCA-AIAE-GRNN decreases in accuracy less and has better convergence than the PCA-PSO-GRNN, and the running speed of the PCA-AIAE-GRNN was relatively improved. The experimental results show that the AIAE-GRNN has a higher robustness and accuracy than the other algorithms considered and can thus be used to classify the intrusive data. PMID- 25807468 TI - Positive deviance study to inform a Chagas disease control program in southern Ecuador. AB - Chagas disease is caused by Trypanosoma cruzi, which is mainly transmitted by the faeces of triatomine insects that find favourable environments in poorly constructed houses. Previous studies have documented persistent triatomine infestation in houses in the province of Loja in southern Ecuador despite repeated insecticide and educational interventions. We aim to develop a sustainable strategy for the interruption of Chagas disease transmission by promoting living environments that are designed to prevent colonisation of rural houses by triatomines. This study used positive deviance to inform the design of an anti-triatomine prototype house by identifying knowledge, attitudes and practices used by families that have remained triatomine-free (2010-2012). Positive deviants reported practices that included maintenance of structural elements of the house, fumigation of dwellings and animal shelters, sweeping with "insect repellent" plants and relocation of domestic animals away from the house, among others. Participants favoured construction materials that do not drastically differ from those currently used (adobe walls and tile roofs). They also expressed their belief in a clear connection between a clean house and health. The family's economic dynamics affect space use and must be considered in the prototype's design. Overall, the results indicate a positive climate for the introduction of housing improvements as a protective measure against Chagas disease in this region. PMID- 25807469 TI - Evolution of Trypanosoma cruzi: clarifying hybridisations, mitochondrial introgressions and phylogenetic relationships between major lineages. AB - Several different models of Trypanosoma cruzi evolution have been proposed. These models suggest that scarce events of genetic exchange occurred during the evolutionary history of this parasite. In addition, the debate has focused on the existence of one or two hybridisation events during the evolution of T. cruzi lineages. Here, we reviewed the literature and analysed available sequence data to clarify the phylogenetic relationships among these different lineages. We observed that TcI, TcIII and TcIV form a monophyletic group and that TcIII and TcIV are not, as previously suggested, TcI-TcII hybrids. Particularly, TcI and TcIII are sister groups that diverged around the same time that a widely distributed TcIV split into two clades (TcIVS and TcIVN). In addition, we collected evidence that TcIII received TcIVS kDNA by introgression on several occasions. Different demographic hypotheses (surfing and asymmetrical introgression) may explain the origin and expansion of the TcIII group. Considering these hypotheses, genetic exchange should have been relatively frequent between TcIII and TcIVS in the geographic area in which their distributions overlapped. In addition, our results support the hypothesis that two independent hybridisation events gave rise to TcV and TcVI. Consequently, TcIVS kDNA was first transferred to TcIII and later to TcV and TcVI in TcII/TcIII hybridisation events. PMID- 25807471 TI - The rising importance of Triatoma rubrofasciata. AB - The migration of invasive vector species has contributed to the worldwide extension of infectious diseases such as dengue (Aedes aegypti) and chikungunya (Aedes albopictus). It is probably a similar behaviour for certain vectors of Chagas disease which allowed it to become a continental burden in Latin America. One of them, Triatoma rubrofasciata has also been spreading throughout the tropical and subtropical world. Here, the recent and massive peridomestic presence of T. rubrofasciata in Vietnam cities is reported, and tentatively explained, highlighting the need for improved entomological surveillance. PMID- 25807472 TI - A quantitative interpretation of the response of articular cartilage to atomic force microscopy-based dynamic nanoindentation tests. AB - In this paper, a quantitative interpretation for atomic force microscopy-based dynamic nanoindentation (AFM-DN) tests on the superficial layers of bovine articular cartilage (AC) is provided. The relevant constitutive parameters of the tissue are estimated by fitting experimental results with a finite element model in the frequency domain. Such model comprises a poroelastic stress-strain relationship for a fibril reinforced tissue constitution, assuming a continuous distribution of the collagen network orientations. The identification procedure was first validated using a simplified transversely isotropic constitutive relationship; then, the experimental data were manually fitted by using the continuous distribution fibril model. Tissue permeability is derived from the maximum value of the phase shift between the input harmonic loading and the harmonic tissue response. Tissue parameters related to the stiffness are obtained from the frequency response of the experimental storage modulus and phase shift. With this procedure, an axial to transverse stiffness ratio (anisotropy ratio) of about 0.15 is estimated. PMID- 25807474 TI - [Treatment of chronic heart failure: what's not (yet) in the guidelines]. PMID- 25807476 TI - Effect of breast cancer after ovarian cancer on mortality for BRCA mutation carriers--reply. PMID- 25807475 TI - The effect of daily co-trimoxazole prophylaxis on natural development of antibody mediated immunity against P. falciparum malaria infection in HIV-exposed uninfected Malawian children. AB - BACKGROUND AND OBJECTIVES: Co-trimoxazole prophylaxis, currently recommended in HIV-exposed, uninfected (HEU) children as protection against opportunistic infections, also has some anti-malarial efficacy. We determined whether daily co trimoxazole prophylaxis affects the natural development of antibody-mediated immunity to blood-stage Plasmodium falciparum malaria infection. METHODS: Using an enzyme-linked immunosorbent assay, we measured antibodies to 8 Plasmodium falciparum antigens (AMA-1, MSP-119, MSP-3, PfSE, EBA-175RII, GLURP R0, GLURP R2 and CSP) in serum samples from 33 HEU children and 31 HIV-unexposed, uninfected (HUU) children, collected at 6, 12 and 18 months of age. RESULTS: Compared to HIV uninfected children, HEU children had significantly lower levels of specific IgG against AMA-1 at 6 months (p = 0.001), MSP-119 at 12 months (p = 0.041) and PfSE at 6 months (p = 0.038), 12 months (p = 0.0012) and 18 months (p = 0.0097). No differences in the IgG antibody responses against the rest of the antigens were observed between the two groups at all time points. The breadth of specificity of IgG response was reduced in HEU children compared to HUU children during the follow up period. CONCLUSIONS: Co-trimoxazole prophylaxis seems to reduce IgG antibody responses to P. falciparum blood stage antigens, which could be as a result of a reduction in exposure of those children under this regime. Although antibody responses were regarded as markers of exposure in this study, further studies are required to establish whether these responses are correlated in any way to clinical immunity to malaria. PMID- 25807477 TI - Correlation Between Structural and Functional Retinal Changes in Parkinson Disease. AB - BACKGROUND: To evaluate structural changes in the retina and correlate those with visual function measurements in patients with Parkinson disease (PD). METHODS: A cross-sectional comparative study of 20 patients with PD and 20 age-matched healthy controls was conducted. Visual acuity, color vision, contrast sensitivity, visual fields, pattern visual-evoked response (VER), and multifocal electroretinogram were recorded to determine functional change, whereas structural changes were evaluated with retinal nerve fiber layer (RNFL) thickness, macular thickness, macular volume, and ganglion cell-inner plexiform layer complex (GCL-IPL) thickness using spectral domain ocular coherence tomography (SD-OCT). RESULTS: PD patients ranged from Stage 1-3, with median Stage 2 (Hoehn and Yahr Classification) with mean Unified Parkinson Disease Rating Scale III score of 19 +/- 10.42, and average disease duration of 5.8 +/- 2.78 years. Visual acuity, color vision, and visual fields were unaffected but contrast sensitivity was significantly worse than controls (P < 0.001). Multifocal electroretinogram values in the central 2 degrees field revealed decreased foveal electrical activity, with increased pattern VER amplitude and latency. Significant RNFL thinning was observed in the average RNFL (P = 0.033), superior (P = 0.018), and temporal (P = 0.036) quadrants. Significant ganglion cell layer loss was captured on SD-OCT with average, minimum GCL-IPL, and all 6 sectors showing thinning (P <= 0.003). The functional changes correlated significantly with structural changes, disease duration, and severity. There was no correlation between structural changes in the retina and disease duration or severity. CONCLUSIONS: Subclinical visual dysfunction was observed in patients with PD with good structural-functional correlation. GCL-IPL thinning may be a more reliable parameter than RNFL thickness for structural alterations of the retina in patients with PD. PMID- 25807478 TI - Neuro-Ophthalmology in Brazil. PMID- 25807479 TI - Food and Feed Safety Assessment: The Importance of Proper Sampling. AB - The general principles for safety and nutritional evaluation of foods and feed and the potential health risks associated with hazardous compounds are described as developed by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) and further elaborated in the European Union-funded project Safe Foods. We underline the crucial role of sampling in foods/feed safety assessment. High quality sampling should always be applied to ensure the use of adequate and representative samples as test materials for hazard identification, toxicological and nutritional characterization of identified hazards, as well as for estimating quantitative and reliable exposure levels of foods/feed or related compounds of concern for humans and animals. The importance of representative sampling is emphasized through examples of risk analyses in different areas of foods/feed production. The Theory of Sampling (TOS) is recognized as the only framework within which to ensure accuracy and precision of all sampling steps involved in the field-to-fork continuum, which is crucial to monitor foods and feed safety. Therefore, TOS must be integrated in the well-established FAO/WHO risk assessment approach in order to guarantee a transparent and correct frame for the risk assessment and decision making process. PMID- 25807480 TI - Correction: direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients. PMID- 25807482 TI - Molecular biology: RNA interference hangs by a thread. PMID- 25807481 TI - The Paf1 complex represses small-RNA-mediated epigenetic gene silencing. AB - RNA interference (RNAi) refers to the ability of exogenously introduced double stranded RNA to silence expression of homologous sequences. Silencing is initiated when the enzyme Dicer processes the double-stranded RNA into small interfering RNAs (siRNAs). Small RNA molecules are incorporated into Argonaute protein-containing effector complexes, which they guide to complementary targets to mediate different types of gene silencing, specifically post-transcriptional gene silencing and chromatin-dependent gene silencing. Although endogenous small RNAs have crucial roles in chromatin-mediated processes across kingdoms, efforts to initiate chromatin modifications in trans by using siRNAs have been inherently difficult to achieve in all eukaryotic cells. Using fission yeast, here we show that RNAi-directed heterochromatin formation is negatively controlled by the highly conserved RNA polymerase-associated factor 1 complex (Paf1C). Temporary expression of a synthetic hairpin RNA in Paf1C mutants triggers stable heterochromatin formation at homologous loci, effectively silencing genes in trans. This repressed state is propagated across generations by the continual production of secondary siRNAs, independently of the synthetic hairpin RNA. Our data support a model in which Paf1C prevents targeting of nascent transcripts by the siRNA-containing RNA-induced transcriptional silencing complex and thereby epigenetic gene silencing, by promoting efficient transcription termination and rapid release of the RNA from the site of transcription. We show that although compromised transcription termination is sufficient to initiate the formation of bi-stable heterochromatin by trans-acting siRNAs, impairment of both transcription termination and nascent transcript release is imperative to confer stability to the repressed state. Our work uncovers a novel mechanism for small RNA-mediated epigenome regulation and highlights fundamental roles for Paf1C and the RNAi machinery in building epigenetic memory. PMID- 25807483 TI - Global genetic analysis in mice unveils central role for cilia in congenital heart disease. AB - Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling. PMID- 25807487 TI - Saturn's fast spin determined from its gravitational field and oblateness. AB - The alignment of Saturn's magnetic pole with its rotation axis precludes the use of magnetic field measurements to determine its rotation period. The period was previously determined from radio measurements by the Voyager spacecraft to be 10 h 39 min 22.4 s (ref. 2). When the Cassini spacecraft measured a period of 10 h 47 min 6 s, which was additionally found to change between sequential measurements, it became clear that the radio period could not be used to determine the bulk planetary rotation period. Estimates based upon Saturn's measured wind fields have increased the uncertainty even more, giving numbers smaller than the Voyager rotation period, and at present Saturn's rotation period is thought to be between 10 h 32 min and 10 h 47 min, which is unsatisfactory for such a fundamental property. Here we report a period of 10 h 32 min 45 s +/- 46 s, based upon an optimization approach using Saturn's measured gravitational field and limits on the observed shape and possible internal density profiles. Moreover, even when solely using the constraints from its gravitational field, the rotation period can be inferred with a precision of several minutes. To validate our method, we applied the same procedure to Jupiter and correctly recovered its well-known rotation period. PMID- 25807485 TI - Therapy-induced tumour secretomes promote resistance and tumour progression. AB - Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy. PMID- 25807484 TI - Loss of delta-catenin function in severe autism. AB - Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders. PMID- 25807486 TI - Primary transcripts of microRNAs encode regulatory peptides. AB - MicroRNAs (miRNAs) are small regulatory RNA molecules that inhibit the expression of specific target genes by binding to and cleaving their messenger RNAs or otherwise inhibiting their translation into proteins. miRNAs are transcribed as much larger primary transcripts (pri-miRNAs), the function of which is not fully understood. Here we show that plant pri-miRNAs contain short open reading frame sequences that encode regulatory peptides. The pri-miR171b of Medicago truncatula and the pri-miR165a of Arabidopsis thaliana produce peptides, which we term miPEP171b and miPEP165a, respectively, that enhance the accumulation of their corresponding mature miRNAs, resulting in downregulation of target genes involved in root development. The mechanism of miRNA-encoded peptide (miPEP) action involves increasing transcription of the pri-miRNA. Five other pri-miRNAs of A. thaliana and M. truncatula encode active miPEPs, suggesting that miPEPs are widespread throughout the plant kingdom. Synthetic miPEP171b and miPEP165a peptides applied to plants specifically trigger the accumulation of miR171b and miR165a, leading to reduction of lateral root development and stimulation of main root growth, respectively, suggesting that miPEPs might have agronomical applications. PMID- 25807489 TI - Ultra-sensitive ROS-responsive tellurium-containing polymers. AB - A novel tellurium-containing polymer micelle system is reported to be responsive to 100 MUM H2O2 and can undergo a series of morphological changes. The polymer micelles also respond to 2 Gy gamma radiation, which is the exact dosage a patient receives per day for clinical radiation therapy. PMID- 25807488 TI - Plant biology: Coding in non-coding RNAs. PMID- 25807491 TI - Pathologic potential of astrocytic vesicle traffic: new targets to treat neurologic diseases? AB - Vesicles are small intracellular organelles that are fundamental for constitutive housekeeping of the plasmalemma, intercellular transport, and cell-to-cell communications. In astroglial cells, traffic of vesicles is associated with cell morphology, which determines the signaling potential and metabolic support for neighboring cells, including when these cells are considered to be used for cell transplantations or for regulating neurogenesis. Moreover, vesicles are used in astrocytes for the release of vesicle-laden chemical messengers. Here we review the properties of membrane-bound vesicles that store gliotransmitters, endolysosomes that are involved in the traffic of plasma membrane receptors, and membrane transporters. These vesicles are all linked to pathological states, including amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, trauma, edema, and states in which astrocytes contribute to developmental disorders. In multiple sclerosis, for example, fingolimod, a recently introduced drug, apparently affects vesicle traffic and gliotransmitter release from astrocytes, indicating that this process may well be used as a new pathophysiologic target for the development of new therapies. PMID- 25807492 TI - A systematic approach to representative sampling- sampling quality criteria, material properties, theory of sampling. PMID- 25807490 TI - Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation. AB - Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production. PMID- 25807493 TI - Tocotrienol-rich fraction (TRF) suppresses the growth of human colon cancer xenografts in Balb/C nude mice by the Wnt pathway. AB - Tocotrienols have been shown many biologic functions such as antioxidant, anti cancer, maintaining fertility and regulating the immune system and so on. In this study, after feeding with tocotrienol-rich fraction from palm oil (TRF) for 2 weeks, Balb/c nude mice were inoculated human colon SW620 cancer cell and then continued to feed TRF for 4 weeks. At termination of experiments, xenografts were removed and determined the expression of Wnt-pathways related protein by immunohistochemistry or western blotting. Liver tissues were homogenated for determining the levels of antioxidative enzymes activity or malondialdehyde (MDA). The results showed that TRF significantly inhibited the growth of xenografts in nude mice. TRF also affected the activity of antioxidative enzymes in the liver tissue of mice. These changes were partly contributed to activation of wnt pathways or affecting their related protein. Thus, these finding suggested that the potent anticancer effect of TRF is associated with the regulation of Wnt signal pathways. PMID- 25807496 TI - Historical isolation of the Galapagos carpenter bee (Xylocopa darwini) despite strong flight capability and ecological amplitude. AB - Colonization across the Galapagos Islands by the carpenter bee (Xylocopa darwini) was reconstructed based on distribution of mitochondrial haplotypes (cytochrome oxidase II (COII) sequences) and haplotype lineages. A total of 12 haplotypes were found in 118 individuals of X. darwini. Distributional, phylogenetic and phylogeographic analyses suggest early colonization of most islands followed by historical isolation in two main groups: eastern and central-western islands. Evidence of recurrent inter-island colonization of haplotypes is largely lacking, despite strong flight capability and ecological amplitude of the species. Recent palaeogeographic data suggest that several of the current islands were connected in the past and thus the isolation pattern may have been even more pronounced. A contrast analysis was also carried out on 10 animal groups of the Galapagos Islands, and on haplotype colonization of seven animal and plant species from several oceanic archipelagos (the Galapagos, Azores, Canary Islands). New colonization metrics on the number of potential vs. inferred colonization events revealed that the Galapagos carpenter bee shows one of the most significant examples of geographic isolation. PMID- 25807495 TI - Schip1 is a novel podocyte foot process protein that mediates actin cytoskeleton rearrangements and forms a complex with Nherf2 and ezrin. AB - BACKGROUND: Podocyte foot process effacement accompanied by actin cytoskeleton rearrangements is a cardinal feature of many progressive human proteinuric diseases. RESULTS: By microarray profiling of mouse glomerulus, SCHIP1 emerged as one of the most highly enriched transcripts. We detected Schip1 protein in the kidney glomerulus, specifically in podocytes foot processes. Functionally, Schip1 inactivation in zebrafish by morpholino knock-down results in foot process disorganization and podocyte loss leading to proteinuria. In cultured podocytes Schip1 localizes to cortical actin-rich regions of lamellipodia, where it forms a complex with Nherf2 and ezrin, proteins known to participate in actin remodeling stimulated by PDGFbeta signaling. Mechanistically, overexpression of Schip1 in vitro causes accumulation of cortical F-actin with dissolution of transversal stress fibers and promotes cell migration in response to PDGF-BB stimulation. Upon actin disassembly by latrunculin A treatment, Schip1 remains associated with the residual F-actin-containing structures, suggesting a functional connection with actin cytoskeleton possibly via its interaction partners. A similar assay with cytochalasin D points to stabilization of cortical actin cytoskeleton in Schip1 overexpressing cells by attenuation of actin depolymerisation. CONCLUSIONS: Schip1 is a novel glomerular protein predominantly expressed in podocytes, necessary for the zebrafish pronephros development and function. Schip1 associates with the cortical actin cytoskeleton network and modulates its dynamics in response to PDGF signaling via interaction with the Nherf2/ezrin complex. Its implication in proteinuric diseases remains to be further investigated. PMID- 25807497 TI - Genome based phylogeny and comparative genomic analysis of intra-mammary pathogenic Escherichia coli. AB - Escherichia coli is an important cause of bovine mastitis and can cause both severe inflammation with a short-term transient infection, as well as less severe, but more chronic inflammation and infection persistence. E. coli is a highly diverse organism that has been classified into a number of different pathotypes or pathovars, and mammary pathogenic E. coli (MPEC) has been proposed as a new such pathotype. The purpose of this study was to use genome sequence data derived from both transient and persistent MPEC isolates (two isolates of each phenotype) to construct a genome-based phylogeny that places MPEC in its phylogenetic context with other E. coli pathovars. A subsidiary goal was to conduct comparative genomic analyses of these MPEC isolates with other E. coli pathovars to provide a preliminary perspective on loci that might be correlated with the MPEC phenotype. Both concatenated and consensus tree phylogenies did not support MPEC monophyly or the monophyly of either transient or persistent phenotypes. Three of the MPEC isolates (ECA-727, ECC-Z, and ECA-O157) originated from within the predominately commensal clade of E. coli, referred to as phylogroup A. The fourth MPEC isolate, of the persistent phenotype (ECC-1470), was sister group to an isolate of ETEC, falling within the E. coli B1 clade. This suggests that the MPEC phenotype has arisen on numerous independent occasions and that this has often, although not invariably, occurred from commensal ancestry. Examination of the genes present in the MPEC strains relative to the commensal strains identified a consistent presence of the type VI secretion system (T6SS) in the MPEC strains, with only occasional representation in commensal strains, suggesting that T6SS may be associated with MPEC pathogenesis and/or as an inter bacterial competitive attribute and therefore could represent a useful target to explore for the development of MPEC specific inhibitors. PMID- 25807498 TI - Trypanosoma cruzi-infected pregnant women without vector exposure have higher parasitemia levels: implications for congenital transmission risk. AB - BACKGROUND: Congenital transmission is a major source of new Trypanosoma cruzi infections, and as vector and blood bank control continue to improve, the proportion due to congenital infection will grow. A major unanswered question is why reported transmission rates from T. cruzi-infected mothers vary so widely among study populations. Women with high parasite loads during pregnancy are more likely to transmit to their infants, but the factors that govern maternal parasite load are largely unknown. Better understanding of these factors could enable prioritization of screening programs to target women most at risk of transmission to their infants. METHODOLOGY/PRINCIPAL FINDINGS: We screened pregnant women presenting for delivery in a large urban hospital in Bolivia and followed infants of infected women for congenital Chagas disease. Of 596 women screened, 128 (21.5%) had confirmed T. cruzi infection; transmission occurred from 15 (11.7%) infected women to their infants. Parasite loads were significantly higher among women who transmitted compared to those who did not. Congenital transmission occurred from 31.3% (9/29), 15.4% (4/26) and 0% (0/62) of women with high, moderate and low parasite load, respectively (chix2 for trend 18.2; p<0.0001). Twin births were associated with higher transmission risk and higher maternal parasite loads. Infected women without reported vector exposure had significantly higher parasite loads than those who had lived in an infested house (median 26.4 vs 0 parasites/mL; p<0.001) with an inverse relationship between years of living in an infested house and parasite load. CONCLUSIONS/SIGNIFICANCE: We hypothesize that sustained vector-borne parasite exposure and repeated superinfection by T. cruzi may act as an immune booster, allowing women to maintain effective control of the parasite despite the down regulation of late pregnancy. PMID- 25807494 TI - Antigenic properties of the human immunodeficiency virus envelope glycoprotein gp120 on virions bound to target cells. AB - The HIV-1 envelope glycoprotein, gp120, undergoes multiple molecular interactions and structural rearrangements during the course of host cell attachment and viral entry, which are being increasingly defined at the atomic level using isolated proteins. In comparison, antigenic markers of these dynamic changes are essentially unknown for single HIV-1 particles bound to target cells. Such markers should indicate how neutralizing and/or non-neutralizing antibodies might interdict infection by either blocking infection or sensitizing host cells for elimination by Fc-mediated effector function. Here we address this deficit by imaging fluorescently labeled CCR5-tropic HIV-1 pseudoviruses using confocal and superresolution microscopy to track the exposure of neutralizing and non neutralizing epitopes as they appear on single HIV-1 particles bound to target cells. Epitope exposure was followed under conditions permissive or non permissive for viral entry to delimit changes associated with virion binding from those associated with post-attachment events. We find that a previously unexpected array of gp120 epitopes is exposed rapidly upon target cell binding. This array comprises both neutralizing and non-neutralizing epitopes, the latter being hidden on free virions yet capable of serving as potent targets for Fc mediated effector function. Under non-permissive conditions for viral entry, both neutralizing and non-neutralizing epitope exposures were relatively static over time for the majority of bound virions. Under entry-permissive conditions, epitope exposure patterns changed over time on subsets of virions that exhibited concurrent variations in virion contents. These studies reveal that bound virions are distinguished by a broad array of both neutralizing and non-neutralizing gp120 epitopes that potentially sensitize a freshly engaged target cell for destruction by Fc-mediated effector function and/or for direct neutralization at a post-binding step. The elucidation of these epitope exposure patterns during viral entry will help clarify antibody-mediated inhibition of HIV-1 as it is measured in vitro and in vivo. PMID- 25807499 TI - Perceptual strategies of pigeons to detect a rotational centre--a hint for star compass learning? AB - Birds can rely on a variety of cues for orientation during migration and homing. Celestial rotation provides the key information for the development of a functioning star and/or sun compass. This celestial compass seems to be the primary reference for calibrating the other orientation systems including the magnetic compass. Thus, detection of the celestial rotational axis is crucial for bird orientation. Here, we use operant conditioning to demonstrate that homing pigeons can principally learn to detect a rotational centre in a rotating dot pattern and we examine their behavioural response strategies in a series of experiments. Initially, most pigeons applied a strategy based on local stimulus information such as movement characteristics of single dots. One pigeon seemed to immediately ignore eccentric stationary dots. After special training, all pigeons could shift their attention to more global cues, which implies that pigeons can learn the concept of a rotational axis. In our experiments, the ability to precisely locate the rotational centre was strongly dependent on the rotational velocity of the dot pattern and it crashed at velocities that were still much faster than natural celestial rotation. We therefore suggest that the axis of the very slow, natural, celestial rotation could be perceived by birds through the movement itself, but that a time-delayed pattern comparison should also be considered as a very likely alternative strategy. PMID- 25807500 TI - Where do the poorest go to seek outpatient care in Bangladesh: hospitals run by government or microfinance institutions? AB - INTRODUCTION: Health programs implemented by microfinance institutions (MFIs) aim to benefit the poor, but whether these services reach the poorest remains uncertain. This study intended to investigate the socioeconomic distribution of patients in hospitals operated by microfinance institutions (i.e. MFI hospitals) in Bangladesh and compare the differences with public hospitals to determine if the programs were consistent with their pro-poor mandate. METHODS: In this cross sectional study, we used the convenience sampling method to conduct an interviewer-assisted questionnaire survey among 347 female outpatients, with 170 in public hospitals and 177 in MFI hospitals. Independent variables were patient characteristics categorized into predisposing factors (age, education, marital status, family size), enabling factors (microcredit membership, household income) and need factors (self-rated health, perceived needs for care). We employed Generalized Estimating Equations (GEE) to evaluate how these factors contributed to MFI hospital use. RESULTS: Use of MFI hospitals was associated with microcredit membership over 5 years (OR=2.9, p<.01), moderately poor household (OR=4.09, p<.001), non-poor household (OR=7.34, p<.01) and need for preventive care (OR=3.4, p<.01), compared with public hospitals. Combining membership and income, we found microcredit members had a higher tendency towards utilization but membership effect pertained to the non- and moderately-poor. Compared with the group who were non-members and the poorest, microcredit members who were non poor had the highest likelihood (OR=7.46, p<.001) to visit MFI hospitals, followed by members with moderate income (OR=6.91, p<.001) and then non-members in non-poor households (OR=4.48, p<.01). Those who were members but the poorest had a negative association (OR=0.42), though not significant. Despite a higher utilization of preventive services in MFI hospitals, expenditure there was significantly higher. CONCLUSION: Inequity was more pronounced in MFI hospitals than public ones. MFI hospitals appeared to miss their target population. We suggest that MFIs reorganize health programs toward primary health care to make care equitable and universally accessible. This study holds practical implications for governments, development agencies and microfinance practitioners working at the grassroots level. PMID- 25807503 TI - Increasing scientific data insights about exascale class simulations under power and storage constraints. PMID- 25807504 TI - Tapestry: a different kind of conference on storytelling with data. PMID- 25807501 TI - Histone deacetylase inhibition enhances tissue plasminogen activator release capacity in atherosclerotic man. AB - The expression of the tissue plasminogen activator (t-PA) gene appears to be under epigenetic control and can be affected by histone deacetylation inhibition. The study aimed to test if histone deacetalyase inhibitor treatment lead to increased t-PA release or reduced exhaustion in t-PA release in response to stimulation, as well as change in plasminogen activator inhibitor-1 (PAI-1) in subjects with coronary disease. In this clinical study, 16 post-myocardial infarction subjects, the perfused forearm model was used with isoprenaline provocation during 20 minutes, to stimulate local t-PA release. Each subject was measured twice on the same day (repeated stimuli sequences) as well as on two different occasions, without treatment and after four weeks of treatment with valproic acid (500 mg, twice daily). Net forearm release for t-PA in response to isoprenaline at minutes 1.5, 3, 6, 9, 12, 15 and 18 was measured, allowing assessment of cumulative t-PA release. There was a reduction in the exhaustion of cumulative t-PA release during repeated and prolonged stimulation with valproic acid treatment compared to non-treatment. Plasma PAI-1 antigen was decreased following treatment compared to non-treatment (18.4 +/- 10.0 vs. 11.0 +/- 7.1 nanograms/ml respectively, mean with 95% confidence interval). These findings demonstrate that histone deacetylation inhibition increases the capacity for endogenous t-PA release in subjects with vascular disease. Furthermore, the fibrinolytic balance is favored with suppressed PAI-1 levels. More studies are needed to establish the clinical relevance of these findings. TRIAL REGISTRATION: EU Clinical Trials Register 2012-004950-27. PMID- 25807505 TI - Preparing undergraduates for visual analytics. PMID- 25807506 TI - Visual computing as a key enabling technology for Industrie 4.0 and Industrial Internet. PMID- 25807507 TI - Legibility in industrial AR: text style, color coding, and illuminance. PMID- 25807502 TI - APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts. AB - Classic deamination mRNA changes, including cytidine to uridine (C-to-U) and adenosine to inosine (A-to-I), are important exceptions to the central dogma and lead to significant alterations in gene transcripts and products. Although there are a few reports of non-classic mRNA alterations, as yet there is no molecular explanation for these alternative changes. Wilms Tumor 1 (WT1) mutations and variants are implicated in several diseases, including Wilms tumor and acute myeloid leukemia (AML). We observed two alternative G-to-A changes, namely c.1303G>A and c.1586G>A in cDNA clones and found them to be recurrent in a series of 21 umbilical cord blood mononuclear cell (CBMC) samples studied. Two less conserved U-to-C changes were also observed. These alternative changes were found to be significantly higher in non-progenitor as compared to progenitor CBMCs, while they were found to be absent in a series of AML samples studied, indicating they are targeted, cell type-specific mRNA editing modifications. Since APOBEC/ADAR family members are implicated in RNA/DNA editing, we screened them by RNA-interference (RNAi) for WT1-mRNA changes and observed near complete reversal of WT1 c.1303G>A alteration upon APOBEC3A (A3A) knockdown. The role of A3A in mediating this change was confirmed by A3A overexpression in Fujioka cells, which led to a significant increase in WT1 c.1303G>A mRNA editing. Non-progenitor CBMCs showed correspondingly higher levels of A3A-mRNA and protein as compared to the progenitor ones. To our knowledge, this is the first report of mRNA modifying activity for an APOBEC3 protein and implicates A3A in a novel G-to-A form of editing. These findings open the way to further investigations into the mechanisms of other potential mRNA changes, which will help to redefine the RNA editing paradigm in both health and disease. PMID- 25807509 TI - Gestalt principles in multimodal data representation. PMID- 25807508 TI - Maximizing smart factory systems by incrementally updating point clouds. PMID- 25807510 TI - Demystifying quadrilateral remeshing. PMID- 25807512 TI - The wearable revolution. PMID- 25807511 TI - Midair user interfaces employing particle screens. PMID- 25807514 TI - Unbalanced 2 x 2 factorial designs and the interaction effect: a troublesome combination. AB - In this power study, ANOVAs of unbalanced and balanced 2 x 2 datasets are compared (N = 120). Datasets are created under the assumption that H1 of the effects is true. The effects are constructed in two ways, assuming: 1. contributions to the effects solely in the treatment groups; 2. contrasting contributions in treatment and control groups. The main question is whether the two ANOVA correction methods for imbalance (applying Sums of Squares Type II or III; SS II or SS III) offer satisfactory power in the presence of an interaction. Overall, SS II showed higher power, but results varied strongly. When compared to a balanced dataset, for some unbalanced datasets the rejection rate of H0 of main effects was undesirably higher. SS III showed consistently somewhat lower power. When the effects were constructed with equal contributions from control and treatment groups, the interaction could be re-estimated satisfactorily. When an interaction was present, SS III led consistently to somewhat lower rejection rates of H0 of main effects, compared to the rejection rates found in equivalent balanced datasets, while SS II produced strongly varying results. In data constructed with only effects in the treatment groups and no effects in the control groups, the H0 of moderate and strong interaction effects was often not rejected and SS II seemed applicable. Even then, SS III provided slightly better results when a true interaction was present. ANOVA allowed not always for a satisfactory re-estimation of the unique interaction effect. Yet, SS II worked better only when an interaction effect could be excluded, whereas SS III results were just marginally worse in that case. Overall, SS III provided consistently 1 to 5% lower rejection rates of H0 in comparison with analyses of balanced datasets, while results of SS II varied too widely for general application. PMID- 25807513 TI - Novel pedicle screw and plate system provides superior stability in unilateral fixation for minimally invasive transforaminal lumbar interbody fusion: an in vitro biomechanical study. AB - PURPOSE: This study aims to compare the biomechanical properties of the novel pedicle screw and plate system with the traditional rod system in asymmetrical posterior stabilization for minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). We compared the immediate stabilizing effects of fusion segment and the strain distribution on the vertebral body. METHODS: Seven fresh calf lumbar spines (L3-L6) were tested. Flexion/extension, lateral bending, and axial rotation were induced by pure moments of +/- 5.0 Nm and the range of motion (ROM) was recorded. Strain gauges were instrumented at L4 and L5 vertebral body to record the strain distribution under flexion and lateral bending (LB). After intact kinematic analysis, a right sided TLIF was performed at L4-L5. Then each specimen was tested for the following constructs: unilateral pedicle screw and rod (UR); unilateral pedicle screw and plate (UP); UR and transfacet pedicle screw (TFS); UP and TFS; UP and UR. RESULTS: All instrumented constructs significantly reduced ROM in all motion compared with the intact specimen, except the UR construct in axial rotation. Unilateral fixation (UR or UP) reduced ROM less compared with the bilateral fixation (UP/UR+TFS, UP+UR). The plate system resulted in more reduction in ROM compared with the rod system, especially in axial rotation. UP construct provided more stability in axial rotation compared with UR construct. The strain distribution on the left and right side of L4 vertebral body was significantly different from UR and UR+TFS construct under flexion motion. The strain distribution on L4 vertebral body was significantly influenced by different fixation constructs. CONCLUSIONS: The novel plate could provide sufficient segmental stability in axial rotation. The UR construct exhibits weak stability and asymmetrical strain distribution in fusion segment, while the UP construct is a good alternative choice for unilateral posterior fixation of MI-TLIF. PMID- 25807516 TI - Management of local stressors can improve the resilience of marine canopy algae to global stressors. AB - Coastal systems are increasingly threatened by multiple local anthropogenic and global climatic stressors. With the difficulties in remediating global stressors, management requires alternative approaches that focus on local scales. We used manipulative experiments to test whether reducing local stressors (sediment load and nutrient concentrations) can improve the resilience of foundation species (canopy algae along temperate rocky coastlines) to future projected global climate stressors (high wave exposure, increasing sea surface temperature), which are less amenable to management actions. We focused on Fucoids (Cystoseira barbata) along the north-western Adriatic coast in the Mediterranean Sea because of their ecological relevance, sensitivity to a variety of human impacts, and declared conservation priority. At current levels of sediment and nutrients, C. barbata showed negative responses to the simulated future scenarios of high wave exposure and increased sea surface temperature. However, reducing the sediment load increased the survival of C. barbata recruits by 90.24% at high wave exposure while reducing nutrient concentrations resulted in a 20.14% increase in the survival and enhanced the growth of recruited juveniles at high temperature. We conclude that improving water quality by reducing nutrient concentrations, and particularly the sediment load, would significantly increase the resilience of C. barbata populations to projected increases in climate stressors. Developing and applying appropriate targets for specific local anthropogenic stressors could be an effective management action to halt the severe and ongoing loss of key marine habitats. PMID- 25807515 TI - Phosphoenolpyruvate carboxykinase 1 gene (Pck1) displays parallel evolution between Old World and New World fruit bats. AB - Bats are an ideal mammalian group for exploring adaptations to fasting due to their large variety of diets and because fasting is a regular part of their life cycle. Mammals fed on a carbohydrate-rich diet experience a rapid decrease in blood glucose levels during a fast, thus, the development of mechanisms to resist the consequences of regular fasts, experienced on a daily basis, must have been crucial in the evolution of frugivorous bats. Phosphoenolpyruvate carboxykinase 1 (PEPCK1, encoded by the Pck1 gene) is the rate-limiting enzyme in gluconeogenesis and is largely responsible for the maintenance of glucose homeostasis during fasting in fruit-eating bats. To test whether Pck1 has experienced adaptive evolution in frugivorous bats, we obtained Pck1 coding sequence from 20 species of bats, including five Old World fruit bats (OWFBs) (Pteropodidae) and two New World fruit bats (NWFBs) (Phyllostomidae). Our molecular evolutionary analyses of these sequences revealed that Pck1 was under purifying selection in both Old World and New World fruit bats with no evidence of positive selection detected in either ancestral branch leading to fruit bats. Interestingly, however, six specific amino acid substitutions were detected on the ancestral lineage of OWFBs. In addition, we found considerable evidence for parallel evolution, at the amino acid level, between the PEPCK1 sequences of Old World fruit bats and New World fruit bats. Test for parallel evolution showed that four parallel substitutions (Q276R, R503H, I558V and Q593R) were driven by natural selection. Our study provides evidence that Pck1 underwent parallel evolution between Old World and New World fruit bats, two lineages of mammals that feed on a carbohydrate-rich diet and experience regular periods of fasting as part of their life cycle. PMID- 25807518 TI - Elevated levels of mercapturic acids of acrolein and crotonaldehyde in the urine of Chinese women in Singapore who regularly cook at home. AB - Lung cancer is unusually common among non-smoking women in Southeastern Asia but the causes of this frequently fatal disease are not well understood. Several epidemiology studies indicate that inhalation of fumes from high temperature Chinese style cooking with a wok may be a cause. Only one previous study investigated uptake of potential toxicants and carcinogens by women who cook with a wok. We enrolled three-hundred twenty-eight non-smoking women from Singapore for this study. Each provided a spot urine sample and answered a questionnaire concerning their cooking habits and other factors. The urine samples were analyzed by liquid chromatography-tandem mass spectrometry for mercapturic acid metabolites of acrolein (3-hydroxypropylmercapturic acid), crotonaldehyde (3 hydroxy-1-methylpropylmercapturic acid), and benzene (S-phenylmercapturic acid), accepted biomarkers of uptake of these toxic and carcinogenic compounds. We observed statistically significant effects of wok cooking frequency on levels of 3-hydroxypropylmercapturic acid and 3-hydroxy-1-methylpropylmercapturic acid, but not S-phenylmercapturic acid. Women who cooked greater than 7 times per week had a geometric mean of 2600 (95% CI, 2189-3090) pmol/mg creatinine 3 hydroxypropylmercapturic acid compared to 1901 (95% CI, 1510-2395) pmol/mg creatinine when cooking less than once per week (P for trend 0.018). The corresponding values for 3-hydroxy-1-methylpropylmercapturic acid were 1167 (95% CI, 1022-1332) and 894 (95% CI, 749-1067) pmol/mg creatinine (P for trend 0.008). We conclude that frequent wok cooking leads to elevated exposure to the toxicants acrolein and crotonaldehyde, but not benzene. Kitchens should be properly ventilated to decrease exposure to potentially toxic and carcinogenic fumes produced during Chinese style wok cooking. PMID- 25807520 TI - Distribution of the CCR5-delta32 deletion in Southwest Germany. AB - A 32 base pair deletion in the c-c chemokine receptor gene 5 (CCR5) leads to an inactive protein. Carriers of this deletion must have had a selective advantage because the allelic frequency of the CCR5-delat32 mutation is much higher than expected. Furthermore, there is a decline from North to South Europe. For Germany there are just very few cross-sectional surveys available. Here we investigated a large number of healthy blood donors from Northern Baden-Wuerttemberg. We observed an allelic frequency of 9.21 % of the CCR5-delta32 deletion. The distribution did not follow the Hardy-Weinberg equilibrium suggesting that homozygous carriers of the deletion were overrepresented in this random sample. PMID- 25807517 TI - Muscle oxygen changes following Sprint Interval Cycling training in elite field hockey players. AB - This study examined the effects of Sprint Interval Cycling (SIT) on muscle oxygenation kinetics and performance during the 30-15 intermittent fitness test (IFT). Twenty-five women hockey players of Olympic standard were randomly selected into an experimental group (EXP) and a control group (CON). The EXP group performed six additional SIT sessions over six weeks in addition to their normal training program. To explore the potential training-induced change, EXP subjects additionally completed 5 x 30s maximal intensity cycle testing before and after training. During these tests near-infrared spectroscopy (NIRS) measured parameters; oxyhaemoglobin + oxymyoglobin (HbO2+ MbO2), tissue deoxyhaemoglobin + deoxymyoglobin (HHb+HMb), total tissue haemoglobin (tHb) and tissue oxygenation (TSI %) were taken. In the EXP group (5.34 +/- 0.14 to 5.50 +/- 0.14 m.s(-1)) but not the CON group (pre = 5.37 +/- 0.27 to 5.39 +/- 0.30 m.s(-1)) significant changes were seen in the 30-15 IFT performance. EXP group also displayed significant post-training increases during the sprint cycling: DeltaTSI (-7.59 +/ 0.91 to -12.16 +/- 2.70%); DeltaHHb+HMb (35.68 +/- 6.67 to 69.44 +/- 26.48 MUM.cm); and DeltaHbO2+ MbO2 (-74.29 +/- 13.82 to -109.36 +/- 22.61 MUM.cm). No significant differences were seen in DeltatHb (-45.81 +/- 15.23 to -42.93 +/- 16.24). NIRS is able to detect positive peripheral muscle oxygenation changes when used during a SIT protocol which has been shown to be an effective training modality within elite athletes. PMID- 25807519 TI - Competition between serum IgG, IgM, and IgA anti-glycan antibodies. AB - Anti-glycan antibodies are an abundant subpopulation of serum antibodies with critical functions in many immune processes. Changes in the levels of these antibodies can occur with the onset of disease, exposure to pathogens, or vaccination. As a result, there has been significant interest in exploiting anti glycan antibodies as biomarkers for many diseases. Serum contains a mixture of anti-glycan antibodies that can recognize the same antigen, and competition for binding can potentially influence the detection of antibody subpopulations that are more relevant to disease processes. The most abundant antibody isotypes in serum are IgG, IgM, and IgA, but little is known regarding how these different isotypes compete for the same glycan antigen. In this study, we developed a multiplexed glycan microarray assay and applied it to evaluate how different isotypes of anti-glycan antibodies (IgA, IgG, and IgM) compete for printed glycan antigens. While IgG and IgA antibodies typically outcompete IgM for peptide or protein antigens, we found that IgM outcompete IgG and IgA for many glycan antigens. To illustrate the importance of this effect, we provide evidence that IgM competition can account for the unexpected observation that IgG of certain antigen specificities appear to be preferentially transported from mothers to fetuses. We demonstrate that IgM in maternal sera compete with IgG resulting in lower than expected IgG signals. Since cord blood contains very low levels of IgM, competition only affects maternal IgG signals, making it appear as though certain IgG antibodies are higher in cord blood than matched maternal blood. Taken together, the results highlight the importance of competition for studies involving anti-glycan antibodies. PMID- 25807521 TI - Wnt3a protein reduces growth factor-driven expansion of human hematopoietic stem and progenitor cells in serum-free cultures. AB - Ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) is a promising approach to improve insufficient engraftment after umbilical cord blood stem cell transplantation (UCB-SCT). Although culturing HSPC with hematopoietic cytokines results in robust proliferation, it is accompanied with extensive differentiation and loss of self-renewal capacity. Wnt signaling has been implicated in regulating HSPC fate decisions in vivo and in promoting HSPC self renewal by inhibition of differentiation, but the effects of Wnt on the ex vivo expansion of HSPC are controversial. Here, we demonstrate that exogenous Wnt3a protein suppresses rather than promotes the expansion of UCB-derived CD34+ cells in serum free expansion cultures. The reduced expansion was also observed in cultures initiated with Lin-CD34+CD38lowCD45RA-CD90+ cells which are highly enriched in HSC and was also observed in response to activation of beta-catenin signaling by GSK3 inhibition. The presence of Wnt3a protein during the culture reduced the frequency of multilineage CFU-GEMM and the long-term repopulation ability of the expanded HSPC. These data suggest that Wnt signaling reduces expansion of human HSPC in growth factor-driven expansion cultures by promoting differentiation of HSPC. PMID- 25807522 TI - "On-off" thermoresponsive coating agent containing salicylic acid applied to maize seeds for chilling tolerance. AB - Chilling stress is an important constraint for maize seed establishment in the field. In this study, a type of "on-off" thermoresponsive coating agent containing poly (N-isopropylacrylamide-co-butylmethacrylate) (Abbr. P(NIPAm-co BMA)) hydrogel was developed to improve the chilling tolerance of coated maize seed. The P(NIPAm-co-BMA) hydrogel was synthesized by free-radical polymerization of N-isopropylacrylamide (NIPAm) and butylmethacrylate (BMA). Salicylic acid (SA) was loaded in the hydrogel as the chilling resistance agent. SA-loaded P(NIPAm-co BMA) was used for seed film-coating of two maize varieties, Huang C (HC, chilling tolerant) and Mo17 (chilling-sensitive), to investigate the coated seed germination and seedling growth status under chilling stress. The results showed that the hydrogel obtained a phase transition temperature near 12 degrees C with a NIPAM to MBA weight ratio of 1: 0.1988 (w/w). The temperature of 12 degrees C was considered the "on-off" temperature for chilling-resistant agent release; the SA was released from the hydrogel more rapidly at external temperatures below 12 degrees C than above 12 degrees C. In addition, when seedlings of both maize varieties suffered a short chilling stress (5 degrees C), higher concentrations of SA-loaded hydrogel resulted in increased germination energy, germination percentage, germination index, root length, shoot height, dry weight of roots and shoots and protective enzyme activities and a decreased malondialdehyde content in coated maize seeds compared to single SA treatments. The majority of these physiological and biochemical parameters achieved significant levels compared with the control. Therefore, SA-loaded P(NIPAm-co-BMA), a nontoxic thermoresponsive hydrogel, can be used as an effective material for chilling tolerance in film-coated maize seeds. PMID- 25807523 TI - Functional characterization of bacteria isolated from ancient arctic soil exposes diverse resistance mechanisms to modern antibiotics. AB - Using functional metagenomics to study the resistomes of bacterial communities isolated from different layers of the Canadian high Arctic permafrost, we show that microbial communities harbored diverse resistance mechanisms at least 5,000 years ago. Among bacteria sampled from the ancient layers of a permafrost core, we isolated eight genes conferring clinical levels of resistance against aminoglycoside, beta-lactam and tetracycline antibiotics that are naturally produced by microorganisms. Among these resistance genes, four also conferred resistance against amikacin, a modern semi-synthetic antibiotic that does not naturally occur in microorganisms. In bacteria sampled from the overlaying active layer, we isolated ten different genes conferring resistance to all six antibiotics tested in this study, including aminoglycoside, beta-lactam and tetracycline variants that are naturally produced by microorganisms as well as semi-synthetic variants produced in the laboratory. On average, we found that resistance genes found in permafrost bacteria conferred lower levels of resistance against clinically relevant antibiotics than resistance genes sampled from the active layer. Our results demonstrate that antibiotic resistance genes were functionally diverse prior to the anthropogenic use of antibiotics, contributing to the evolution of natural reservoirs of resistance genes. PMID- 25807525 TI - Neural signals evoked by stimuli of increasing social scene complexity are detectable at the single-trial level and right lateralized. AB - Classification of neural signals at the single-trial level and the study of their relevance in affective and cognitive neuroscience are still in their infancy. Here we investigated the neurophysiological correlates of conditions of increasing social scene complexity using 3D human models as targets of attention, which may also be important in autism research. Challenging single-trial statistical classification of EEG neural signals was attempted for detection of oddball stimuli with increasing social scene complexity. Stimuli had an oddball structure and were as follows: 1) flashed schematic eyes, 2) simple 3D faces flashed between averted and non-averted gaze (only eye position changing), 3) simple 3D faces flashed between averted and non-averted gaze (head and eye position changing), 4) animated avatar alternated its gaze direction to the left and to the right (head and eye position), 5) environment with 4 animated avatars all of which change gaze and one of which is the target of attention. We found a late (> 300 ms) neurophysiological oddball correlate for all conditions irrespective of their complexity as assessed by repeated measures ANOVA. We attempted single-trial detection of this signal with automatic classifiers and obtained a significant balanced accuracy classification of around 79%, which is noteworthy given the amount of scene complexity. Lateralization analysis showed a specific right lateralization only for more complex realistic social scenes. In sum, complex ecological animations with social content elicit neurophysiological events which can be characterized even at the single-trial level. These signals are right lateralized. These finding paves the way for neuroscientific studies in affective neuroscience based on complex social scenes, and given the detectability at the single trial level this suggests the feasibility of brain computer interfaces that can be applied to social cognition disorders such as autism. PMID- 25807526 TI - Recovery of aging-related size increase of skin epithelial cells: in vivo mouse and in vitro human study. AB - The size increase of skin epithelial cells during aging is well-known. Here we demonstrate that treatment of aging cells with cytochalasin B substantially decreases cell size. This decrease was demonstrated on a mouse model and on human skin cells in vitro. Six nude mice were treated by topical application of cytochalasin B on skin of the dorsal left midsection for 140 days (the right side served as control for placebo treatment). An average decrease in cell size of 56+/-16% resulted. A reduction of cell size was also observed on primary human skin epithelial cells of different in vitro age (passages from 1 to 8). A cell strain obtained from a pool of 6 human subjects was treated with cytochalasin B in vitro for 12 hours. We observed a decrease in cell size that became statistically significant and reached 20-40% for cells of older passage (6-8 passages) whereas no substantial change was observed for younger cells. These results may be important for understanding the aging processes, and for cosmetic treatment of aging skin. PMID- 25807527 TI - Multi-spectral fluorescent reporter influenza viruses (Color-flu) as powerful tools for in vivo studies. AB - Seasonal influenza A viruses cause annual epidemics of respiratory disease; highly pathogenic avian H5N1 and the recently emerged H7N9 viruses cause severe infections in humans, often with fatal outcomes. Although numerous studies have addressed the pathogenicity of influenza viruses, influenza pathogenesis remains incompletely understood. Here we generate influenza viruses expressing fluorescent proteins of different colours ('Color-flu' viruses) to facilitate the study of viral infection in in vivo models. On adaptation to mice, stable expression of the fluorescent proteins in infected animals allows their detection by different types of microscopy and by flow cytometry. We use this system to analyse the progression of viral spread in mouse lungs, for live imaging of virus infected cells, and for differential gene expression studies in virus antigen positive and virus antigen-negative live cells in the lungs of Color-flu-infected mice. Collectively, Color-flu viruses are powerful tools to analyse virus infections at the cellular level in vivo to better understand influenza pathogenesis. PMID- 25807524 TI - GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. AB - JQ1 and I-BET151 are selective inhibitors of BET bromodomain proteins that have efficacy against a number of different cancers. Since the effectiveness of targeted therapies is often limited by development of resistance, we examined whether it was possible for cancer cells to develop resistance to the BET inhibitor JQ1. Here we show that pancreatic cancer cells developing resistance to JQ1 demonstrate cross-resistance to I-BET151 and insensitivity to BRD4 downregulation. The resistant cells maintain expression of c-MYC, increase expression of JQ1-target genes FOSL1 and HMGA2, and demonstrate evidence of epithelial-mesenchymal transition (EMT). However, reverting EMT fails to sensitize the resistant cells to JQ1 treatment. Importantly, the JQ1-resistant cells remain dependent on c-MYC that now becomes co-regulated by high levels of GLI2. Furthermore, downregulating GLI2 re-sensitizes the resistant cells to JQ1. Overall, these results identify a mechanism by which cancer cells develop resistance to BET inhibitors. PMID- 25807528 TI - Deregulated expression of Aurora kinases is not a prognostic biomarker in papillary thyroid cancer patients. AB - A number of reports indicated that Aurora-A or Aurora-B overexpression represented a negative prognostic factor in several human malignancies. In thyroid cancer tissues a deregulated expression of Aurora kinases has been also demonstrated, but no information regarding its possible prognostic role in differentiated thyroid cancer is available. Here, we evaluated Aurora-A and Aurora-B mRNA expression and its prognostic relevance in a series of 87 papillary thyroid cancers (PTC), with a median follow-up of 63 months. The analysis of Aurora-A and Aurora-B mRNA levels in PTC tissues, compared to normal matched tissues, revealed that their expression was either up- or down-regulated in the majority of cancer tissues. In particular, Aurora-A and Aurora-B mRNA levels were altered, respectively, in 55 (63.2%) and 79 (90.8%) out of the 87 PTC analyzed.A significant positive correlation between Aurora-A and Aurora-B mRNAs was observed (p=0.001). The expression of both Aurora genes was not affected by the BRAFV600E mutation. Univariate, multivariate and Kaplan-Mayer analyses documented the lack of association between Aurora-A or Aurora-B expression and clinicopathological parameters such as gender, age, tumor size, histology, TNM stage, lymph node metastasis and BRAF status as well as disease recurrences or disease-free interval. Only Aurora-B mRNA was significantly higher in T(3-4) tissues, with respect to T(1-2) PTC tissues. The data reported here demonstrate that the expression of Aurora kinases is deregulated in the majority of PTC tissues, likely contributing to PTC progression. However, differently from other human solid cancers, detection of Aurora-A or Aurora-B mRNAs is not a prognostic biomarker in PTC patients. PMID- 25807531 TI - Innate immunity drives the initiation of a murine model of primary biliary cirrhosis. AB - Invariant natural killer T (iNKT) cells play complex roles in bridging innate and adaptive immunity by engaging with glycolipid antigens presented by CD1d. Our earlier work suggested that iNKT cells were involved in the initiation of the original loss of tolerance in primary biliary cirrhosis (PBC). To address this issue in more detail and, in particular, to focus on whether iNKT cells activated by a Th2-biasing agonist (2s,3s,4r)-1-O-(alpha-D-galactopyranosyl)-N tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), can influence the development of PBC in a xenobiotic-induced PBC murine model. Groups of mice were treated with either OCH or, as a control, alpha-galactosylceramide (alpha-GalCer) and thence serially followed for cytokine production, markers of T cell activation, liver histopathology and anti-mitochondrial antibody responses. Further, additional groups of CD1d deleted mice were similarly studied. Our data indicate that administration of OCH has a dramatic influence with exacerbation of portal inflammation and hepatic fibrosis similar to mice treated with alpha-GalCer. Further, iNKT cell deficient CD1d knockout mice have decreased inflammatory portal cell infiltrates and reduced anti-mitochondrial antibody responses. We submit that activation of iNKT cells can occur via overlapping and/or promiscuous pathways and highlight the critical role of innate immunity in the natural history of autoimmune cholangitis. These data have implications for humans with PBC and emphasize that therapeutic strategies must focus not only on suppressing adaptive responses, but also innate immunity. PMID- 25807529 TI - Opposing Oxytocin Effects on Intergroup Cooperative Behavior in Intuitive and Reflective Minds. AB - People often favor ingroup over outgroup members when choosing to cooperate. Such ingroup-favored cooperation is promoted by oxytocin-a neuropeptide shown to facilitate social cognition and that has emerged as a pharmacological target for treatments of social functioning deficits. The current study applied a dual process model to investigate whether and how intuitive and reflective cognitive styles affect the oxytocin-motivated ingroup favoritism in cooperation. We examined oxytocin effects on ingroup favoritism in a double-blind, placebo controlled between-subjects design where cognitive processing (intuition vs reflection) was experimentally manipulated in healthy Chinese males (n=150). We also supplemented this experimental manipulation with an individual difference analysis by assessing participants' inclination toward intuition or reflection in daily life. Intranasal administration of oxytocin (vs placebo) increased ingroup favoritism among participants primed to be intuitive or those who preferred intuition in daily life. In contrast, oxytocin decreased ingroup favoritism in participants primed to rely on reflective thinking or those who preferred reflective decision-making in daily life. Our results demonstrate that oxytocin has distinct functional roles when different cognitive styles (ie, intuition vs reflection) are promoted during social cooperation in a group situation. Our findings have implications for oxytocin pharmacotherapy of social dysfunction in that whether the effects of oxytocin on social functioning are facilitative, debilitative, or null, depends on an individual's cognitive style. PMID- 25807530 TI - Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. AB - Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome. PMID- 25807533 TI - Altered Nrf2 signaling mediates hypoglycemia-induced blood-brain barrier endothelial dysfunction in vitro. AB - Hypoglycemia impairs blood-brain barrier (BBB) endothelial function; a major hallmark in the pathogenesis of various CNS disorders. Previously, we have demonstrated that prolonged hypoglycemic exposure down-regulated BBB endothelial NF-E2 related factor-2 (Nrf2) expression; a redox-sensitive transcriptional factor that regulates endothelial function. Here, we sought to determine the functional role of Nrf2 in preserving BBB integrity and molecular mechanisms underlying hypoglycemia-induced Nrf2 down-regulation in vitro using human cerebral microvascular endothelial cell line (hCMEC/D3). Cell monolayers were exposed to normal or hypoglycemic (5.5 or 2.2mM D-glucose) media for 3-24h. Pharmacological or gene manipulation (by silencing RNA) approaches were used to investigate specific molecular pathways implicated in hypoglycemia-induced Nrf2 degradation. BBB integrity was assessed by paracellular permeability to labeled dextrans of increasing molecular sizes (4-70kDa). Silencing Nrf2 expression in hCMEC/D3 cells abrogated the expression of claudin-5 and VE-cadherin, while ZO-1 was up-regulated. These effects were paralleled by a decrease in electrical resistance of hCMEC/D3 monolayers and potential increase in permeability to all labeled dextrans. Hypoglycemic exposure (3-24h) led to progressive and sustained down-regulation of Nrf2 (without affecting mRNA) and its target, NQO-1, with a concomitant increase in the cytosolic pool of E3 ubiquitin ligase, Siah2 (but not Keap1). Pretreatment with protease inhibitor MG132, or selective knock-down of Siah2 (but not Keap1) significantly attenuated hypoglycemia-induced Nrf2 destabilization. While hypoglycemic exposure triggered a significant increase in BBB permeability to dextrans, silencing Siah2 gene abrogated the effects of hypoglycemia and restored BBB integrity. In summary, our data indicate a potential role for Nrf2 signaling in regulating tight junction integrity and maintaining BBB function. Nrf2 suppression by increased Siah2-driven proteasomal degradation mediates hypoglycemia-evoked endothelial dysfunction and loss of BBB integrity. Overall, this study suggests that sustained activation of endothelial Nrf2 signaling could have therapeutic potential to prevent hypoglycemia-induced cerebrovascular dysfunction. PMID- 25807534 TI - H-index is important for postural control for people with impaired foot sole sensation. AB - INTRODUCTION: People with Peripheral Neuropathy (PN), especially those with impaired sensory inputs through the small-afferent fiber (type II afferent fibers) reflex loop (SAF), might depend more on the large-afferent fiber (type I afferent fibers) reflex loop (LAF) for postural control. PURPOSE: To examine whether the function of the LAF reflex loop, reflected by the H-reflex and ankle joint proprioception, influences postural control when the SAF reflex loop is impaired, as indicated by reduced foot sole cutaneous sensation. METHODS: Thirteen participants (8 women, 5 men) diagnosed with PN and 12 age-matched controls (7 women, 5 men) completed the testing protocol. Measures of interest included the H-index, active (AAP) and passive (PAP) ankle proprioception, plantar pressure sensitivity (PPS), average sway velocity (VAVG) and area (A95) during 30 seconds eyes-closed standing, 6-minute walk distance (6MWD) and timed up-and-go duration (TUG). RESULTS: Statistically significant group-dependent regression was observed between VAVG and H-index. Compared to the control group, the PN group demonstrated reduced PPS (2.0 +/- 1.9 vs. 4.2 +/- 1.2, P < .05) and H-index (63.6 +/- 10.9 vs. 76.4 +/- 16.0, P < .05), greater VAVG (3.5 +/- 2.1 vs. 1.6 +/- 0.6 cm/s, P < .05) and A95 (10.0 +/- 10.1 vs. 2.5 +/- 1.5 cm2, P < .05), shorter 6MWD (442.2 +/- 93.0 vs. 525.3 +/- 68.2 m, P < .05), and longer TUG (9.4 +/- 1.6 vs. 6.5 +/- 1.3 s, P < .05). Within the PN group, but not the control group, the H-index was correlated with VAVG (r = -.56, P < .05). Moreover, within the PN group only, PAP scores were correlated with 6MWD (r = -.68, P < .05) and TUG (r = -.59, P < .05) performance. No other statistically significant group difference, correlation or group-dependent regression was observed. CONCLUSION: VAVG, 6MWD, and TUG correlated with LAF reflex loop function observed among those with impaired functioning of the SAF reflex loop. This observation suggests that the LAF reflex loop may be critical to the control of balance in those individuals suffering from small-fiber PN. PMID- 25807535 TI - Establishment of lal-/- myeloid lineage cell line that resembles myeloid-derived suppressive cells. AB - Myeloid-derived suppressor cells (MDSCs) in mouse are inflammatory cells that play critical roles in promoting cancer growth and metastasis by directly stimulating cancer cell proliferation and suppressing immune surveillance. In order to facilitate characterization of biochemical and cellular mechanisms of MDSCs, it is urgent to establish an "MDSC-like" cell line. By cross breeding of immortomouse (simian virus 40 large T antigen transgenic mice) with wild type and lysosomal acid lipase (LAL) knock-out (lal-/-) mice, we have established a wild type (HD1A) and a lal-/- (HD1B) myeloid cell lines. Compared with HD1A cells, HD1B cells demonstrated many characteristics similar to lal-/- MDSCs. HD1B cells exhibited increased lysosomes around perinuclear areas, dysfunction of mitochondria skewing toward fission structure, damaged membrane potential, and increased ROS production. HD1B cells showed increased glycolytic metabolism during blockage of fatty acid metabolism to fuel the energy need. Similar to lal /- MDSCs, the mTOR signal pathway in HD1B cells is overly activated. Rapamycin treatment of HD1B cells reduced ROS production and restored the mitochondrial membrane potential. HD1B cells showed much stronger immunosuppression on CD4+ T cell proliferation and function in vitro, and enhanced cancer cells proliferation. Knockdown of mTOR with siRNA reduced the HD1B cell ability to immunosuppress T cells and stimulate cancer cell proliferation. Therefore, the HD1B myeloid cell line is an "MDSC-like" cell line that can be used as an alternative in vitro system to study how LAL controls various myeloid cell functions. PMID- 25807532 TI - Non-invasive technology that improves cardiac function after experimental myocardial infarction: Whole Body Periodic Acceleration (pGz). AB - Myocardial infarction (MI) may produce significant inflammatory changes and adverse ventricular remodeling leading to heart failure and premature death. Pharmacologic, stem cell transplantation, and exercise have not halted the inexorable rise in the prevalence and great economic costs of heart failure despite extensive investigations of such treatments. New therapeutic modalities are needed. Whole Body Periodic Acceleration (pGz) is a non-invasive technology that increases pulsatile shear stress to the endothelium thereby producing several beneficial cardiovascular effects as demonstrated in animal models, normal humans and patients with heart disease. pGz upregulates endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS) to improve myocardial function in models of myocardial stunning and preconditioning. Here we test whether pGz applied chronically after focal myocardial infarction in rats improves functional outcomes from MI. Focal MI was produced by left coronary artery ligation. One day after ligation animals were randomized to receive daily treatments of pGz for four weeks (MI-pGz) or serve as controls (MI-CONT), with an additional group as non-infarction controls (Sham). Echocardiograms and invasive pressure volume loop analysis were carried out. Infarct transmurality, myocardial fibrosis, and markers of inflammatory and anti-inflammatory cytokines were determined along with protein analysis of eNOS, p-eNOS and inducible nitric oxide synthase (iNOS).At four weeks, survival was 80% in MI-pGz vs 50% in MI-CONT (p< 0.01). Ejection fraction and fractional shortening and invasive pressure volume relation indices of afterload and contractility were significantly better in MI pGz. The latter where associated with decreased infarct transmurality and decreased fibrosis along with increased eNOS, p-eNOS. Additionally, MI-pGz had significantly lower levels of iNOS, inflammatory cytokines (IL-6, TNF-alpha), and higher level of anti-inflammatory cytokine (IL-10). pGz improved survival and contractile performance, associated with improved myocardial remodeling. pGz may serve as a simple, safe, non-invasive therapeutic modality to improve myocardial function after MI. PMID- 25807537 TI - Pathology of the calcified zone of articular cartilage in post-traumatic osteoarthritis in rat knees. AB - OBJECTIVES: This study aimed to investigate the pathology occurring at the calcified zone of articular cartilage (CZC) in the joints afflicted with post traumatic osteoarthritis (PTOA). METHODS: Rats underwent bilateral anterior cruciate ligament (ACL) transection and medial meniscectomy to induce PTOA. Sham surgery was performed on another five rats to serve as controls. The rats were euthanized after four weeks of surgery and tibial plateaus were dissected for histology. The pathology of PTOA, CZC area and the tidemark roughness at six pre defined locations on the tibial plateaus were quantified by histomorphometry. RESULTS: PTOA developed in the knees, generally more severe at the medial plateau than the lateral plateau, of rats in the experimental group. The CZC area was unchanged in the PTOA joints, but the topographic variations of CZC areas that presented in the control knees were reduced in the PTOA joints. The tidemark roughness decreased in areas of the medial plateau of PTOA joints and that was inversely correlated with the Mankin's score of PTOA pathology. CONCLUSION: Reduced tidemark roughness and unchanged CZC area differentiate PTOA from primary osteoarthritis, which is generally believed to have the opposite pathology at CZC, and may contribute to the distinct disease progression of the two entities of arthropathy. PMID- 25807536 TI - Population genomic analysis of 962 whole genome sequences of humans reveals natural selection in non-coding regions. AB - Whole genome analysis in large samples from a single population is needed to provide adequate power to assess relative strengths of natural selection across different functional components of the genome. In this study, we analyzed next generation sequencing data from 962 European Americans, and found that as expected approximately 60% of the top 1% of positive selection signals lie in intergenic regions, 33% in intronic regions, and slightly over 1% in coding regions. Several detailed functional annotation categories in intergenic regions showed statistically significant enrichment in positively selected loci when compared to the null distribution of the genomic span of ENCODE categories. There was a significant enrichment of purifying selection signals detected in enhancers, transcription factor binding sites, microRNAs and target sites, but not on lincRNA or piRNAs, suggesting different evolutionary constraints for these domains. Loci in "repressed or low activity regions" and loci near or overlapping the transcription start site were the most significantly over-represented annotations among the top 1% of signals for positive selection. PMID- 25807540 TI - Correction: SslE elicits functional antibodies that impair in vitro mucinase activity and in vivo colonization by both intestinal and extraintestinal Escherichia coli strains. PMID- 25807539 TI - The highly conserved codon following the slippery sequence supports -1 frameshift efficiency at the HIV-1 frameshift site. AB - HIV-1 utilises -1 programmed ribosomal frameshifting to translate structural and enzymatic domains in a defined proportion required for replication. A slippery sequence, U UUU UUA, and a stem-loop are well-defined RNA features modulating -1 frameshifting in HIV-1. The GGG glycine codon immediately following the slippery sequence (the 'intercodon') contributes structurally to the start of the stem loop but has no defined role in current models of the frameshift mechanism, as slippage is inferred to occur before the intercodon has reached the ribosomal decoding site. This GGG codon is highly conserved in natural isolates of HIV. When the natural intercodon was replaced with a stop codon two different decoding molecules-eRF1 protein or a cognate suppressor tRNA-were able to access and decode the intercodon prior to -1 frameshifting. This implies significant slippage occurs when the intercodon is in the (perhaps distorted) ribosomal A site. We accommodate the influence of the intercodon in a model of frame maintenance versus frameshifting in HIV-1. PMID- 25807541 TI - Decoding diffusivity in multiple sclerosis: analysis of optic radiation lesional and non-lesional white matter. AB - OBJECTIVES: Diffusion tensor imaging (DTI) has been suggested as a new promising tool in MS that may provide greater pathological specificity than conventional MRI, helping, therefore, to elucidate disease pathogenesis and monitor therapeutic efficacy. However, the pathological substrates that underpin alterations in brain tissue diffusivity are not yet fully delineated. Tract specific DTI analysis has previously been proposed in an attempt to alleviate this problem. Here, we extended this approach by segmenting a single tract into areas bound by seemingly similar pathological processes, which may better delineate the potential association between DTI metrics and underlying tissue damage. METHOD: Several compartments were segmented in optic radiation (OR) of 50 relapsing-remitting MS patients including T2 lesions, proximal and distal parts of fibers transected by lesion and fibers with no discernable pathology throughout the entire length of the OR. RESULTS: Asymmetry analysis between lesional and non-lesional fibers demonstrated a marked increase in Radial Diffusivity (RD), which was topographically limited to focal T2 lesions and potentially relates to the lesional myelin loss. A relative elevation of Axial Diffusivity (AD) in the distal part of the lesional fibers was observed in a distribution consistent with Wallerian degeneration, while diffusivity in the proximal portion of transected axons remained normal. A moderate, but significant elevation of RD in OR non-lesional fibers was strongly associated with the global (but not local) T2 lesion burden and is probably related to microscopic demyelination undetected by conventional MRI. CONCLUSION: This study highlights the utility of the compartmentalization approach in elucidating the pathological substrates of diffusivity and demonstrates the presence of tissue-specific patterns of altered diffusivity in MS, providing further evidence that DTI is a sensitive marker of tissue damage in both lesions and NAWM. Our results suggest that, at least within the OR, parallel and perpendicular diffusivities are affected by tissue restructuring related to distinct pathological processes. PMID- 25807538 TI - PACAP enhances axon outgrowth in cultured hippocampal neurons to a comparable extent as BDNF. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities including modulation of synaptic plasticity and memory, hippocampal neurogenesis, and neuroprotection, most of which are shared with brain-derived neurotrophic factor (BDNF). Therefore, the aim of this study was to compare morphological effects of PACAP and BDNF on primary cultured hippocampal neurons. At days in vitro (DIV) 3, PACAP increased neurite length and number to similar levels by BDNF, but vasoactive intestinal polypeptide showed much lower effects. In addition, PACAP increased axon, but not dendrite, length, and soma size at DIV 3 similarly to BDNF. The PACAP antagonist PACAP6-38 completely blocked the PACAP induced increase in axon, but not dendrite, length. Interestingly, the BDNF induced increase in axon length was also inhibited by PACAP6-38, suggesting a mechanism involving PACAP signaling. K252a, a TrkB receptor inhibitor, inhibited axon outgrowth induced by PACAP and BDNF without affecting dendrite length. These results indicate that in primary cultured hippocampal neurons, PACAP shows morphological actions via its cognate receptor PAC1, stimulating neurite length and number, and soma size to a comparable extent as BDNF, and that the increase in total neurite length is ascribed to axon outgrowth. PMID- 25807543 TI - Do reef fish habituate to diver presence? Evidence from two reef sites with contrasting historical levels of SCUBA intensity in the Bay Islands, Honduras. AB - Contact between humans and the marine environment is increasing, but the capacity of communities to adapt to human presence remains largely unknown. The popularization of SCUBA diving has added a new dimension to human impacts in aquatic systems and, although individual-level impacts have been identified, cumulative effects on ecosystem function and community-wide responses are unclear. In principle, habituation may mitigate the consequences of human presence on the biology of an individual and allow the quick resumption of its ecological roles, but this has not been documented in aquatic systems. Here, we investigate the short-term impact of human presence and the long-term habituation potential of reef-fish communities to recreational SCUBA divers by studying symbiotic cleaning interactions on coral reefs with differing levels of historical contact with divers. We show that incidences of human contact result in a smaller decline in ecosystem function and more rapid resumption of baseline services on a reef in Utila, Honduras that has heavy historical levels of SCUBA diver presence, compared to an un-dived reef site in the Cayos Cochinos Marine Protected Area (CCMPA). Nonetheless, despite the generally smaller change in ecosystem function and decades of regular contact with divers, cleaning behavior is suppressed by >50% at Utila when divers are present. We hypothesize that community-wide habituation of reef fish is not fully achievable and may be biologically restricted to only partial habituation. Differential responses to human presence impacts the interpretation and execution of behavioral research where SCUBA is the predominant means of data collection, and provides an important rationale for future research investigating the interplay between human presence, ecosystem function, and community structure on coral reefs. PMID- 25807542 TI - The unique chemistry of Eastern Mediterranean water masses selects for distinct microbial communities by depth. AB - The waters of the Eastern Mediterranean are characterized by unique physical and chemical properties within separate water masses occupying different depths. Distinct water masses are present throughout the oceans, which drive thermohaline circulation. These water masses may contain specific microbial assemblages. The goal of this study was to examine the effect of physical and geological phenomena on the microbial community of the Eastern Mediterranean water column. Chemical measurements were combined with phospholipid fatty acid (PLFA) analysis and high throughput 16S rRNA sequencing to characterize the microbial community in the water column at five sites. We demonstrate that the chemistry and microbial community of the water column were stratified into three distinct water masses. The salinity and nutrient concentrations vary between these water masses. Nutrient concentrations increased with depth, and salinity was highest in the intermediate water mass. Our PLFA analysis indicated different lipid classes were abundant in each water mass, suggesting that distinct groups of microbes inhabit these water masses. 16S rRNA gene sequencing confirmed the presence of distinct microbial communities in each water mass. Taxa involved in autotrophic nitrogen cycling were enriched in the intermediate water mass suggesting that microbes in this water mass may be important to the nitrogen cycle of the Eastern Mediterranean. The Eastern Mediterranean also contains numerous active hydrocarbon seeps. We sampled above the North Alex Mud Volcano, in order to test the effect of these geological features on the microbial community in the adjacent water column. The community in the waters overlaying the mud volcano was distinct from other communities collected at similar depths and was enriched in known hydrocarbon degrading taxa. Our results demonstrate that physical phenomena such stratification as well as geological phenomena such as mud volcanoes strongly affect microbial community structure in the Eastern Mediterranean water column. PMID- 25807544 TI - Dosimetric verification by using the ArcCHECK system and 3DVH software for various target sizes. AB - OBJECTIVE: To investigate the usefulness of the 3DVH software with an ArcCHECK 3D diode array detector in newly designed plans with various target sizes. METHODS: The isocenter dose was measured with an ion-chamber and was compared with the planned and 3DVH predicted doses. The 2D gamma passing rates were evaluated at the diode level by using the ArcCHECK detector. The 3D gamma passing rates for specific regions of interest (ROIs) were also evaluated by using the 3DVH software. Several dose-volume histograms (DVH)-based predicted metrics for all structures were also obtained by using the 3DVH software. RESULTS: The isocenter dose deviation was <1% in all plans except in the case of a 1 cm target. Besides the gamma passing rate at the diode level, the 3D gamma passing rate for specific ROIs tended to decrease with increasing target size; this was more noticeable when a more stringent gamma criterion was applied. No correlation was found with the gamma passing rates and the DVH-based metrics especially in the ROI with high dose gradients. CONCLUSIONS: Delivery quality assurance by using 3DVH and ArcCHECK can provide substantial information through a simple and easy approach, although the accuracy of this system should be judged cautiously. PMID- 25807545 TI - Revised timeline and distribution of the earliest diverged human maternal lineages in southern Africa. AB - The oldest extant human maternal lineages include mitochondrial haplogroups L0d and L0k found in the southern African click-speaking forager peoples broadly classified as Khoesan. Profiling these early mitochondrial lineages allows for better understanding of modern human evolution. In this study, we profile 77 new early-diverged complete mitochondrial genomes and sub-classify another 105 L0d/L0k individuals from southern Africa. We use this data to refine basal phylogenetic divergence, coalescence times and Khoesan prehistory. Our results confirm L0d as the earliest diverged lineage (~172 kya, 95%CI: 149-199 kya), followed by L0k (~159 kya, 95%CI: 136-183 kya) and a new lineage we name L0g (~94 kya, 95%CI: 72-116 kya). We identify two new L0d1 subclades we name L0d1d and L0d1c4/L0d1e, and estimate L0d2 and L0d1 divergence at ~93 kya (95%CI:76-112 kya). We concur the earliest emerging L0d1'2 sublineage L0d1b (~49 kya, 95%CI:37 58 kya) is widely distributed across southern Africa. Concomitantly, we find the most recent sublineage L0d2a (~17 kya, 95%CI:10-27 kya) to be equally common. While we agree that lineages L0d1c and L0k1a are restricted to contemporary inland Khoesan populations, our observed predominance of L0d2a and L0d1a in non Khoesan populations suggests a once independent coastal Khoesan prehistory. The distribution of early-diverged human maternal lineages within contemporary southern Africans suggests a rich history of human existence prior to any archaeological evidence of migration into the region. For the first time, we provide a genetic-based evidence for significant modern human evolution in southern Africa at the time of the Last Glacial Maximum at between ~21-17 kya, coinciding with the emergence of major lineages L0d1a, L0d2b, L0d2d and L0d2a. PMID- 25807546 TI - Stability of the octameric structure affects plasminogen-binding capacity of streptococcal enolase. AB - Group A Streptococcus (GAS) is a human pathogen that has the potential to cause invasive disease by binding and activating human plasmin(ogen). Streptococcal surface enolase (SEN) is an octameric alpha-enolase that is localized at the GAS cell surface. In addition to its glycolytic role inside the cell, SEN functions as a receptor for plasmin(ogen) on the bacterial surface, but the understanding of the molecular basis of plasmin(ogen) binding is limited. In this study, we determined the crystal and solution structures of GAS SEN and characterized the increased plasminogen binding by two SEN mutants. The plasminogen binding ability of SENK312A and SENK362A is ~2- and ~3.4-fold greater than for the wild-type protein. A combination of thermal stability assays, native mass spectrometry and X-ray crystallography approaches shows that increased plasminogen binding ability correlates with decreased stability of the octamer. We propose that decreased stability of the octameric structure facilitates the access of plasmin(ogen) to its binding sites, leading to more efficient plasmin(ogen) binding and activation. PMID- 25807547 TI - Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif) receptor 2 with implications for chronic kidney disease. AB - Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1) and Chemokine (C-C motif) Receptor 2 (CCR2). However the molecular mechanisms are not understood. We investigated AT1-CCR2 functional interaction in vitro using bioluminescence resonance energy transfer in HEK293 cells and in vivo using subtotal-nephrectomized rats as a well-established model for chronic kidney disease. Our data revealed functional heteromers of these receptors resulting in CCR2-Galphai1 coupling being sensitive to AT1 activation, as well as apparent enhanced beta-arrestin2 recruitment with agonist co-stimulation that is synergistically reversed by combined antagonist treatment. Moreover, we present in vivo findings where combined treatment with AT1- and CCR2-selective inhibitors was synergistically beneficial in terms of decreasing proteinuria, reducing podocyte loss and preventing renal injury independent of blood pressure in the subtotal-nephrectomized rat model. Our findings further support a role for G protein-coupled receptor functional heteromerization in pathophysiology and provide insights into previous observations indicating the importance of AT1-CCR2 functional interaction in inflammation, renal and hypertensive disorders. PMID- 25807548 TI - Timp3 deficient mice show resistance to developing breast cancer. AB - Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3-/- mice have delayed tumor onset and 36% of MMTV-Neu Timp3-/- mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1. PMID- 25807549 TI - A novel approach for the detection and genetic analysis of live melanoma circulating tumor cells. AB - BACKGROUND: Circulating tumor cell (CTC) detection and genetic analysis may complement currently available disease assessments in patients with melanoma to improve risk stratification and monitoring. We therefore sought to establish the feasibility of a telomerase-based assay for detecting and isolating live melanoma CTCs. METHODS: The telomerase-based CTC assay utilizes an adenoviral vector that, in the presence of elevated human telomerase activity, drives the amplification of green fluorescent protein. Tumor cells are then identified via an image processing system. The protocol was tested on melanoma cells in culture or spiked into control blood, and on samples from patients with metastatic melanoma. Genetic analysis of the isolated melanoma CTCs was then performed for BRAF mutation status. RESULTS: The adenoviral vector was effective for all melanoma cell lines tested with sensitivity of 88.7% (95%CI 85.6-90.4%) and specificity of 99.9% (95%CI 99.8-99.9%). In a pilot trial of patients with metastatic disease, CTCs were identified in 9 of 10 patients, with a mean of 6.0 CTCs/mL. At a cutoff of 1.1 CTCs/mL, the telomerase-based assay exhibits test performance of 90.0% sensitivity and 91.7% specificity. BRAF mutation analysis of melanoma cells isolated from culture or spiked control blood, or from pilot patient samples was found to match the known BRAF mutation status of the cell lines and primary tumors. CONCLUSIONS: To our knowledge, this is the first report of a telomerase based assay effective for detecting and isolating live melanoma CTCs. These promising findings support further studies, including towards integrating into the management of patients with melanoma receiving multimodality therapy. PMID- 25807550 TI - High prevalence of the EBER variant EB-8m in endemic nasopharyngeal carcinomas. AB - Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are the most highly expressed transcripts in all EBV-associated tumors and are involved in both lymphoid and epithelioid carcinogenesis. Our previous study on Chinese isolates from non endemic area of nasopharyngeal carcinoma (NPC) identified new EBER variants (EB 8m and EB-10m) which were less common but relatively more frequent in NPC cases than healthy donors. In the present study, we determined the EBER variants in NPC cases and healthy donors from endemic and non-endemic areas of NPC within China and compared the EBER variants, in relation to the genotypes at BamHI F region (prototype F and f variant), between population groups and between two areas. According to the phylogenetic tree, four EBER variants (EB-6m, EB-8m, EB-10m and B95-8) were identified. EB-6m was dominant in all population groups except for endemic NPC group, in which EB-8m was dominant. EB-8m was more common in endemic NPC cases (82.0%, 41/50) than non-endemic NPC cases (33.7%, 32/95) (p<0.0001), and it was also more frequent in healthy donors from endemic area (32.4%, 24/74) than healthy donors from non-endemic area (1.1%, 1/92) (p<0.0001). More importantly, the EB-8m was more prevalent in NPC cases than healthy donors in both areas (p<0.0001). The f variant, which has been suggested to associate with endemic NPC, demonstrated preferential linkage with EB-8m in endemic isolates, however, the EB-8m variant seemed to be more specific to NPC isolates than f variant. These results reveal high prevalence of EBER EB-8m variant in endemic NPC cases, suggesting an association between NPC development and EBV isolates carrying EB-8m variant. Our finding identified a small healthy population group that shares the same viral strain which predominates in NPC cases. It could be interesting to carry extensive cohort studies following these individuals to evaluate the risk to develop NPC. PMID- 25807552 TI - Accelerometers identify new behaviors and show little difference in the activity budgets of lactating northern fur seals (Callorhinus ursinus) between breeding islands and foraging habitats in the eastern Bering Sea. AB - We tagged 82 lactating northern fur seals (Callorhinus ursinus) with tri-axial accelerometers and magnetometers on two eastern Bering Sea islands (Bogoslof and St. Paul) with contrasting population trajectories. Using depth data, accelerometer data and spectral analysis we classified time spent diving (30%), resting (~7%), shaking and grooming their pelage (9%), swimming in the prone position (~10%) and two types of previously undocumented rolling behavior (29%), with the remaining time (~15%) unspecified. The reason for the extensive rolling behavior is not known. We ground-truthed the accelerometry signals for shaking and grooming and rolling behaviors--and identified the acceleration signal for porpoising--by filming tagged northern fur seals in captivity. Speeds from GPS interpolated data indicated that animals traveled fastest while in the prone position, suggesting that this behavior is indicative of destination-based swimming. Very little difference was found in the percentages of time spent in the categorical behaviors with respect to breeding islands (Bogoslof or St. Paul Island), forager type (cathemeral or nocturnal), and the region where the animals foraged (primarily on-shelf <200 m, or off-shelf > 200 m). The lack of significant differences between islands, regions and forager type may indicate that behaviors summarized over a trip are somewhat hardwired even though foraging trip length and when and where animals dive are known to vary with island, forager type and region. PMID- 25807553 TI - Uptake of WHO recommendations for first-line antiretroviral therapy in Kenya, Uganda, and Zambia. AB - INTRODUCTION: Antiretroviral therapy (ART) guidelines were significantly changed by the World Health Organization in 2010. It is largely unknown to what extent these guidelines were adopted into clinical practice. METHODS: This was a retrospective observational analysis of first-line ART regimens in a sample of health facilities providing ART in Kenya, Uganda, and Zambia between 2007-2008 and 2011-2012. Data were analyzed for changes in regimen over time and assessed for key patient- and facility-level determinants of tenofovir (TDF) utilization in Kenya and Uganda using a mixed effects model. RESULTS: Data were obtained from 29,507 patients from 146 facilities. The overall percentage of patients initiated on TDF-based therapy increased between 2007-2008 and 2011-2012 from 3% to 37% in Kenya, 2% to 34% in Uganda, and 64% to 87% in Zambia. A simultaneous decrease in stavudine (d4T) utilization was also noted, but its use was not eliminated, and there remained significant variation in facility prescribing patterns. For patients initiating ART in 2011-2012, we found increased odds of TDF use with more advanced disease at initiation in both Kenya (odds ratio [OR]: 2.78; 95% confidence interval [CI]: 1.73-4.48) and Uganda (OR: 2.15; 95% CI: 1.46-3.17). Having a CD4 test performed at initiation was also a significant predictor in Uganda (OR: 1.43; 95% CI: 1.16-1.76). No facility-level determinants of TDF utilization were seen in Kenya, but private facilities (OR: 2.86; 95% CI: 1.45 5.66) and those employing a doctor (OR: 2.86; 95% CI: 1.48-5.51) were more likely to initiate patients on TDF in Uganda. DISCUSSION: d4T-based ART has largely been phased out over the study period. However, significant in-country and cross country variation exists. Among the most recently initiated patients, those with more advanced disease at initiation were most likely to start TDF-based treatment. No facility-level determinants were consistent across countries to explain the observed facility-level variation. PMID- 25807551 TI - Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors. AB - Binding of alpha5beta1 and alphavbeta3/beta5 integrin receptors on the endothelium to their fibronectin substrate in the extracellular matrix has been targeted as a possible means of blocking tumor angiogenesis and tumor growth. However, clinical trials of blocking antibodies and peptides have been disappointing despite promising preclinical results, leading to questions about the mechanism of the inhibitors and the reasons for their failure. Here, using tissue-specific and inducible genetics to delete the alpha5 and alphav receptors in the endothelium or their fibronectin substrate, either in the endothelium or globally, we show that both are dispensable for tumor growth, in transplanted tumors as well as spontaneous and angiogenesis-dependent RIP-Tag-driven pancreatic adenocarcinomas. In the nearly complete absence of fibronectin, no differences in vascular density or the deposition of basement membrane laminins, ColIV, Nid1, Nid2, or the TGFbeta binding matrix proteins, fibrillin-1 and -2, could be observed. Our results reveal that fibronectin and the endothelial fibronectin receptor subunits, alpha5 and alphav, are dispensable for tumor angiogenesis, suggesting that the inhibition of angiogenesis induced by antibodies or small molecules may occur through a dominant negative effect, rather than a simple functional block. PMID- 25807554 TI - Chloroquine enhances gefitinib cytotoxicity in gefitinib-resistant nonsmall cell lung cancer cells. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib resistant cells (PC-9/gef) from PC-9 cells (containing exon 19 deletion EGFR) after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3) were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor) and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation), indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3 nM). Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose) polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC 9/gefB4 cells, oral administration of gefitinib (50 mg/kg) completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p.) and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients. PMID- 25807555 TI - Distribution, persistence and interchange of Epstein-Barr virus strains among PBMC, plasma and saliva of primary infection subjects. AB - Our study aimed at investigating the distribution, persistence and interchange of viral strains among peripheral blood mononuclear cells (PBMC), plasma and saliva of primary Epstein-Barr virus (EBV) infection subjects. Twelve infectious mononucleosis (IM) patients and eight asymptomatic individuals (AS) with primary EBV infection were followed longitudinally at several time points for one year from the time of diagnosis, when blood and saliva samples were collected and separated into PBMC, plasma and saliva, representing circulating B cell, plasma and epithelial cell compartments, respectively. To survey the viral strains, genotyping assays for the natural polymorphisms in two latent EBV genes, EBNA2 and LMP1, were performed and consisted of real-time PCR on EBNA2 to distinguish type 1 and 2 viruses, fluorescent-based 30-bp typing assay on LMP1 to distinguish deletion and wild type LMP1, and fluorescent-based heteroduplex tracking assays on both EBNA2 and LMP1 to distinguish defined polymorphic variants. No discernible differences were observed between IM patients and AS. Multiple viral strains were acquired early at the start of infection. Stable persistence of dominant EBV strains in the same tissue compartment was observed throughout the longitudinal samples. LMP1-defined strains, China 1, China 2 and Mediterranean+, were the most common strains observed. EBNA2-defined groups 1 and 3e predominated the PBMC and saliva compartments. Concordance of EBNA2 and LMP1 strains between PBMC and saliva suggested ready interchange of viruses between circulating B cell and epithelial cell pools, whilst discordance of viral strains observed between plasma and PBMC/saliva indicated presence of viral pools in other undetermined tissue compartments. Taken together, the results indicated that the distribution, persistence and interchange of viral strains among the tissue compartments are more complex than those proposed by the current model of EBV life cycle. PMID- 25807556 TI - Mechanisms involved in the anti-inflammatory action of a polysulfated fraction from Gracilaria cornea in rats. AB - The anti-inflammatory mechanisms of the sulfated polysaccharidic fraction obtained from red marine alga Gracilaria cornea (Gc-FI) were investigated using a paw edema model induced in rats by different inflammatory agents (carrageenan, dextran, serotonin, bradykinin, compound 48/80 or L-arginine). Gc-FI at the doses of 3, 9 or 27 mg/kg, subcutaneously--s.c., significantly inhibited rat paw edema induced by carrageenan and dextran, as confirmed by myeloperoxidase and Evans' blue assessments, respectively. Gc-FI (9 mg/kg, s.c.) inhibited rat paw edema induced by histamine, compound 48/80 and L-arginine. Additionally, Gc-FI (9 mg/kg, s.c.) inhibited Cg-induced edema in animals with intact mast cells but did not inhibit that with degranulated mast cells by compound 48/80, revealing a protective role on mast cell membranes. Gc-FI down-regulated the IL-1beta, TNF alpha and COX-2 mRNA and protein levels compared with those of the carrageenan group, based on qRT-PCR and immunohistochemistry analyses. After inhibition with ZnPP IX, a specific heme oxygenase-1 (HO-1) inhibitor, the anti-inflammatory effect of Gc-FI was not observed in Cg-induced paw edema, suggesting that the anti-inflammatory effect of Gc-FI is, in part, dependent on the integrity of the HO-1 pathway. Gc-FI can target a combination of multiple points involved in inflammatory phenomena. PMID- 25807558 TI - Classifying measures of biological variation. AB - Biological variation is commonly measured at two basic levels: variation within individual communities, and the distribution of variation over communities or within a metacommunity. We develop a classification for the measurement of biological variation on both levels: Within communities into the categories of dispersion and diversity, and within metacommunities into the categories of compositional differentiation and partitioning of variation. There are essentially two approaches to characterizing the distribution of trait variation over communities in that individuals with the same trait state or type tend to occur in the same community (describes differentiation tendencies), and individuals with different types tend to occur in different communities (describes apportionment tendencies). Both approaches can be viewed from the dual perspectives of trait variation distributed over communities (CT perspective) and community membership distributed over trait states (TC perspective). This classification covers most of the relevant descriptors (qualified measures) of biological variation, as is demonstrated with the help of major families of descriptors. Moreover, the classification is shown to open ways to develop new descriptors that meet current needs. Yet the classification also reveals the misclassification of some prominent and widely applied descriptors: Dispersion is often misclassified as diversity, particularly in cases where dispersion descriptor allow for the computation of effective numbers; the descriptor GST of population genetics is commonly misclassified as compositional differentiation and confused with partitioning-oriented differentiation, whereas it actually measures partitioning-oriented apportionment; descriptors of beta-diversity are ambiguous about the differentiation effects they are supposed to represent and therefore require conceptual reconsideration. PMID- 25807557 TI - Higher Alu methylation levels in catch-up growth in twenty-year-old offsprings. AB - Alu elements and long interspersed element-1 (LINE-1 or L1) are two major human intersperse repetitive sequences. Lower Alu methylation, but not LINE-1, has been observed in blood cells of people in old age, and in menopausal women having lower bone mass and osteoporosis. Nevertheless, Alu methylation levels also vary among young individuals. Here, we explored phenotypes at birth that are associated with Alu methylation levels in young people. In 2010, 249 twenty-years old volunteers whose mothers had participated in a study association between birth weight (BW) and nutrition during pregnancy in 1990, were invited to take part in our present study. In this study, the LINE-1 and Alu methylation levels and patterns were measured in peripheral mononuclear cells and correlated with various nutritional parameters during intrauterine and postnatal period of offspring. This included the amount of maternal intake during pregnancy, the mother's weight gain during pregnancy, birth weight, birth length, and the rate of weight gain in the first year of life. Catch-up growth (CUG) was defined when weight during the first year was >0.67 of the standard score, according to WHO data. No association with LINE-1 methylation was identified. The mean level of Alu methylation in the CUG group was significantly higher than those non-CUG (39.61% and 33.66 % respectively, P < 0.0001). The positive correlation between the history of CUG in the first year and higher Alu methylation indicates the role of Alu methylation, not only in aging cells, but also in the human growth process. Moreover, here is the first study that demonstrated the association between a phenotype during the newborn period and intersperse repetitive sequences methylation during young adulthood. PMID- 25807560 TI - Physiological plasticity to water flow habitat in the damselfish, Acanthochromis polyacanthus: linking phenotype to performance. AB - The relationships among animal form, function and performance are complex, and vary across environments. Therefore, it can be difficult to identify morphological and/or physiological traits responsible for enhancing performance in a given habitat. In fishes, differences in swimming performance across water flow gradients are related to morphological variation among and within species. However, physiological traits related to performance have been less well studied. We experimentally reared juvenile damselfish, Acanthochromis polyacanthus, under different water flow regimes to test 1) whether aspects of swimming physiology and morphology show plastic responses to water flow, 2) whether trait divergence correlates with swimming performance and 3) whether flow environment relates to performance differences observed in wild fish. We found that maximum metabolic rate, aerobic scope and blood haematocrit were higher in wave-reared fish compared to fish reared in low water flow. However, pectoral fin shape, which tends to correlate with sustained swimming performance, did not differ between rearing treatments or collection sites. Maximum metabolic rate was the best overall predictor of individual swimming performance; fin shape and fish total length were 3.3 and 3.7 times less likely than maximum metabolic rate to explain differences in critical swimming speed. Performance differences induced in fish reared in different flow environments were less pronounced than in wild fish but similar in direction. Our results suggest that exposure to water motion induces plastic physiological changes which enhance swimming performance in A. polyacanthus. Thus, functional relationships between fish morphology and performance across flow habitats should also consider differences in physiology. PMID- 25807559 TI - Correlation between infectivity and disease associated prion protein in the nervous system and selected edible tissues of naturally affected scrapie sheep. AB - The transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of a pathological form of a host protein known as prion protein (PrP). The validation of abnormal PrP detection techniques is fundamental to allow the use of high throughput laboratory based tests, avoiding the limitations of bioassays. We used scrapie, a prototype TSE, to examine the relationship between infectivity and laboratory based diagnostic tools. The data may help to optimise strategies to prevent exposure of humans to small ruminant TSE material via the food chain. Abnormal PrP distribution/accumulation was assessed by immunohistochemistry (IHC), Western blot (WB) and ELISA in samples from four animals. In addition, infectivity was detected using a sensitive bank vole bioassay with selected samples from two of the four sheep and protein misfolding cyclic amplification using bank vole brain as substrate (vPMCA) was also carried out in selected samples from one animal. Lymph nodes, oculomotor muscles, sciatic nerve and kidney were positive by IHC, WB and ELISA, although at levels 100-1000 fold lower than the brain, and contained detectable infectivity by bioassay. Tissues not infectious by bioassay were also negative by all laboratory tests including PMCA. Although discrepancies were observed in tissues with very low levels of abnormal PrP, there was an overall good correlation between IHC, WB, ELISA and bioassay results. Most importantly, there was a good correlation between the detection of abnormal PrP in tissues using laboratory tests and the levels of infectivity even when the titre was low. These findings provide useful information for risk modellers and represent a first step toward the validation of laboratory tests used to quantify prion infectivity, which would greatly aid TSE risk assessment policies. PMID- 25807562 TI - Quantitative Analysis of Deformable Model-Based 3-D Reconstruction of Coronary Artery From Multiple Angiograms. AB - Three-dimensional (3-D) reconstruction of the coronary artery is important for the diagnosis and interventional treatment of cardiovascular diseases. In this paper, a novel mean composited external force back-projective composition model is proposed and integrated into the deformable model framework for the 3-D reconstruction of coronary arteries from multiple angiograms. The parametric snake evolves toward the real vascular centerline in 3-D space based on the integrated internal energy and composited external energy. In addition, a polynomial function is constructed to determine the diameter of the cross section of the vascular segments, which fully utilizes the back-projection information of multiple angiograms. The deformable and proposed methods are comparatively validated using phantom datasets and routine angiographic images with respect to space and reprojection Euclidean distance errors. The experimental results demonstrate the effectiveness and robustness of the proposed model, which can achieve a mean space error of 0.570 mm and a mean reprojection error of 0.351 mm. In addition, the influence of the angle difference to the reconstruction accuracy is discussed and validated on phantom datasets, which demonstrate that an angle difference of for any two angiograms is suitable for the 3-D reconstruction process. PMID- 25807563 TI - Assessment of Stroke Volume From Brachial Blood Pressure Using Arterial Characteristics. AB - GOAL: The goal of this study is to present a modified pulse contour method to estimate the stroke volume (SV) based on an oscillometric sphygmomanometer. METHODS: The pulse contour was extracted from the pulse signal of the cuff pressure. The characteristics of the brachial artery, as well as the compliance ( C(artery)) and time constant tau of the Windkessel model, could be determined and used to estimate the SV once the apparatus finished the blood pressure measurement. RESULTS: Assessments of the SV by echocardiography and our method were carried out in 55 subjects. The change in the brachial arterial volume obtained by our method was significantly correlated with that of the two dimensional ultrasound method (r(v) = 0.871). The estimated SV values by our method for male and female groups, SV(estimate), were also significantly correlated with the echocardiography results, SV(ref) (r(male) = 0.680, r(female) = 0.706 ). The Bland-Altman plot showed agreement between SV(ref) and SV(estimate), with all data points contained within the limits of agreement (+/- 2 SD). The mean difference and standard deviation (mean +/- SD) were 0.101 +/- 14.880 ml and 0.650 +/- 11.990 ml for the male and female groups, respectively. CONCLUSION: The blood pressure, SV, and cardiac output were measured simultaneously, making our method well suited for home use. SIGNIFICANCE: Our method was embedded in an oscillometric sphygmomanometer. PMID- 25807564 TI - Hierarchical Spectral Consensus Clustering for Group Analysis of Functional Brain Networks. AB - A central question in cognitive neuroscience is how cognitive functions depend on the integration of specialized widely distributed brain regions. In recent years, graph theoretical methods have been used to characterize the structure of the brain functional connectivity. In order to understand the organization of functional connectivity networks, it is important to determine the community structure underlying these complex networks. Moreover, the study of brain functional networks is confounded by the fact that most neurophysiological studies consists of data collected from multiple subjects; thus, it is important to identify communities representative of all subjects. Typically, this problem is addressed by averaging the data across subjects which omits the variability across subjects or using voting methods, which requires a priori knowledge of cluster labels. In this paper, we propose a hierarchical consensus spectral clustering approach to address these problems. Furthermore, new information theoretic criteria are introduced for selecting the optimal community structure. The proposed framework is applied to electroencephalogram data collected during a study of error-related negativity to better understand the community structure of functional networks involved in the cognitive control. PMID- 25807561 TI - Chicory (Cichorium intybus L.) root extract regulates the oxidative status and antioxidant gene transcripts in CCl4-induced hepatotoxicity. AB - The ability of Cichorium intybus root extract (chicory extract) to protect against carbon tetrachloride (CCl4)-induced oxidative stress and hepatotoxicity was evaluated in male rats. The rats were divided into four groups according to treatment: saline (control); chicory extract (100 mg/kg body weight daily, given orally for 2 weeks); CCl4 (1 ml/kg body weight by intraperitoneal injection for 2 consecutive days only); or chicory extract (100 mg/kg body weight daily for 2 weeks) + CCl4 injection on days 16 and 17. The levels of hepatic lipid peroxidation, antioxidants, and molecular biomarkers were estimated twenty-four hours after the last CCl4 injection. Pretreatment with chicory extract significantly reduced CCl4-induced elevation of malondialdehyde levels and nearly normalized levels of glutathione and activity of glutathione S-transferase, glutathione peroxidase (GPx), glutathione reductase, catalase (CAT), paraoxonase 1 (PON1), and arylesterase in the liver. Chicory extract also attenuated CCl4 induced downregulation of hepatic mRNA expression levels of GPx1, CAT and PON1 genes. Results of DNA fragmentation support the ability of chicory extract to ameliorate CCl4-induced liver toxicity. Taken together, our results demonstrate that chicory extract is rich in natural antioxidants and able to attenuate CCl4 induced hepatocellular injury, likely by scavenging reactive free radicals, boosting the endogenous antioxidant defense system, and overexpressing genes encoding antioxidant enzymes. PMID- 25807565 TI - Fast Volume Reconstruction From Motion Corrupted Stacks of 2D Slices. AB - Capturing an enclosing volume of moving subjects and organs using fast individual image slice acquisition has shown promise in dealing with motion artefacts. Motion between slice acquisitions results in spatial inconsistencies that can be resolved by slice-to-volume reconstruction (SVR) methods to provide high quality 3D image data. Existing algorithms are, however, typically very slow, specialised to specific applications and rely on approximations, which impedes their potential clinical use. In this paper, we present a fast multi-GPU accelerated framework for slice-to-volume reconstruction. It is based on optimised 2D/3D registration, super-resolution with automatic outlier rejection and an additional (optional) intensity bias correction. We introduce a novel and fully automatic procedure for selecting the image stack with least motion to serve as an initial registration target. We evaluate the proposed method using artificial motion corrupted phantom data as well as clinical data, including tracked freehand ultrasound of the liver and fetal Magnetic Resonance Imaging. We achieve speed-up factors greater than 30 compared to a single CPU system and greater than 10 compared to currently available state-of-the-art multi-core CPU methods. We ensure high reconstruction accuracy by exact computation of the point-spread function for every input data point, which has not previously been possible due to computational limitations. Our framework and its implementation is scalable for available computational infrastructures and tests show a speed-up factor of 1.70 for each additional GPU. This paves the way for the online application of image based reconstruction methods during clinical examinations. The source code for the proposed approach is publicly available. PMID- 25807566 TI - Adaptive image denoising by targeted databases. AB - We propose a data-dependent denoising procedure to restore noisy images. Different from existing denoising algorithms which search for patches from either the noisy image or a generic database, the new algorithm finds patches from a database that contains relevant patches. We formulate the denoising problem as an optimal filter design problem and make two contributions. First, we determine the basis function of the denoising filter by solving a group sparsity minimization problem. The optimization formulation generalizes existing denoising algorithms and offers systematic analysis of the performance. Improvement methods are proposed to enhance the patch search process. Second, we determine the spectral coefficients of the denoising filter by considering a localized Bayesian prior. The localized prior leverages the similarity of the targeted database, alleviates the intensive Bayesian computation, and links the new method to the classical linear minimum mean squared error estimation. We demonstrate applications of the proposed method in a variety of scenarios, including text images, multiview images, and face images. Experimental results show the superiority of the new algorithm over existing methods. PMID- 25807567 TI - Single image superresolution based on gradient profile sharpness. AB - Single image superresolution is a classic and active image processing problem, which aims to generate a high-resolution (HR) image from a low-resolution input image. Due to the severely under-determined nature of this problem, an effective image prior is necessary to make the problem solvable, and to improve the quality of generated images. In this paper, a novel image superresolution algorithm is proposed based on gradient profile sharpness (GPS). GPS is an edge sharpness metric, which is extracted from two gradient description models, i.e., a triangle model and a Gaussian mixture model for the description of different kinds of gradient profiles. Then, the transformation relationship of GPSs in different image resolutions is studied statistically, and the parameter of the relationship is estimated automatically. Based on the estimated GPS transformation relationship, two gradient profile transformation models are proposed for two profile description models, which can keep profile shape and profile gradient magnitude sum consistent during profile transformation. Finally, the target gradient field of HR image is generated from the transformed gradient profiles, which is added as the image prior in HR image reconstruction model. Extensive experiments are conducted to evaluate the proposed algorithm in subjective visual effect, objective quality, and computation time. The experimental results demonstrate that the proposed approach can generate superior HR images with better visual quality, lower reconstruction error, and acceptable computation efficiency as compared with state-of-the-art works. PMID- 25807568 TI - A source-channel coding approach to digital image protection and self-recovery. AB - Watermarking algorithms have been widely applied to the field of image forensics recently. One of these very forensic applications is the protection of images against tampering. For this purpose, we need to design a watermarking algorithm fulfilling two purposes in case of image tampering: 1) detecting the tampered area of the received image and 2) recovering the lost information in the tampered zones. State-of-the-art techniques accomplish these tasks using watermarks consisting of check bits and reference bits. Check bits are used for tampering detection, whereas reference bits carry information about the whole image. The problem of recovering the lost reference bits still stands. This paper is aimed at showing that having the tampering location known, image tampering can be modeled and dealt with as an erasure error. Therefore, an appropriate design of channel code can protect the reference bits against tampering. In the present proposed method, the total watermark bit-budget is dedicated to three groups: 1) source encoder output bits; 2) channel code parity bits; and 3) check bits. In watermark embedding phase, the original image is source coded and the output bit stream is protected using appropriate channel encoder. For image recovery, erasure locations detected by check bits help channel erasure decoder to retrieve the original source encoded image. Experimental results show that our proposed scheme significantly outperforms recent techniques in terms of image quality for both watermarked and recovered image. The watermarked image quality gain is achieved through spending less bit-budget on watermark, while image recovery quality is considerably improved as a consequence of consistent performance of designed source and channel codes. PMID- 25807570 TI - Data-Mining-Based Intelligent Differential Relaying for Transmission Lines Including UPFC and Wind Farms. AB - This paper presents a data-mining-based intelligent differential relaying scheme for transmission lines, including flexible ac transmission system device, such as unified power flow controller (UPFC) and wind farms. Initially, the current and voltage signals are processed through extended Kalman filter phasor measurement unit for phasor estimation, and 21 potential features are computed at both ends of the line. Once the features are extracted at both ends, the corresponding differential features are derived. These differential features are fed to a data mining model known as decision tree (DT) to provide the final relaying decision. The proposed technique has been extensively tested for single-circuit transmission line, including UPFC and wind farms with in-feed, double-circuit line with UPFC on one line and wind farm as one of the substations with wide variations in operating parameters. The test results obtained from simulation as well as in real-time digital simulator testing indicate that the DT-based intelligent differential relaying scheme is highly reliable and accurate with a response time of 2.25 cycles from the fault inception. PMID- 25807569 TI - Identification of Vibrotactile Patterns Encoding Obstacle Distance Information. AB - Delivering distance information of nearby obstacles from sensors embedded in a white cane-in addition to the intrinsic mechanical feedback from the cane-can aid the visually impaired in ambulating independently. Haptics is a common modality for conveying such information to cane users, typically in the form of vibrotactile signals. In this context, we investigated the effect of tactile rendering methods, tactile feedback configurations and directions of tactile flow on the identification of obstacle distance. Three tactile rendering methods with temporal variation only, spatio-temporal variation and spatial/temporal/intensity variation were investigated for two vibration feedback configurations. Results showed a significant interaction between tactile rendering method and feedback configuration. Spatio-temporal variation generally resulted in high correct identification rates for both feedback configurations. In the case of the four finger vibration, tactile rendering with spatial/temporal/intensity variation also resulted in high distance identification rate. Further, participants expressed their preference for the four-finger vibration over the single-finger vibration in a survey. Both preferred rendering methods with spatio-temporal variation and spatial/temporal/intensity variation for the four-finger vibration could convey obstacle distance information with low workload. Overall, the presented findings provide valuable insights and guidance for the design of haptic displays for electronic travel aids for the visually impaired. PMID- 25807572 TI - A Bias and Variance Analysis for Multistep-Ahead Time Series Forecasting. AB - Multistep-ahead forecasts can either be produced recursively by iterating a one step-ahead time series model or directly by estimating a separate model for each forecast horizon. In addition, there are other strategies; some of them combine aspects of both aforementioned concepts. In this paper, we present a comprehensive investigation into the bias and variance behavior of multistep ahead forecasting strategies. We provide a detailed review of the different multistep-ahead strategies. Subsequently, we perform a theoretical study that derives the bias and variance for a number of forecasting strategies. Finally, we conduct a Monte Carlo experimental study that compares and evaluates the bias and variance performance of the different strategies. From the theoretical and the simulation studies, we analyze the effect of different factors, such as the forecast horizon and the time series length, on the bias and variance components, and on the different multistep-ahead strategies. Several lessons are learned, and recommendations are given concerning the advantages, disadvantages, and best conditions of use of each strategy. PMID- 25807571 TI - Machine Learning Methods for Attack Detection in the Smart Grid. AB - Attack detection problems in the smart grid are posed as statistical learning problems for different attack scenarios in which the measurements are observed in batch or online settings. In this approach, machine learning algorithms are used to classify measurements as being either secure or attacked. An attack detection framework is provided to exploit any available prior knowledge about the system and surmount constraints arising from the sparse structure of the problem in the proposed approach. Well-known batch and online learning algorithms (supervised and semisupervised) are employed with decision- and feature-level fusion to model the attack detection problem. The relationships between statistical and geometric properties of attack vectors employed in the attack scenarios and learning algorithms are analyzed to detect unobservable attacks using statistical learning methods. The proposed algorithms are examined on various IEEE test systems. Experimental analyses show that machine learning algorithms can detect attacks with performances higher than attack detection algorithms that employ state vector estimation methods in the proposed attack detection framework. PMID- 25807573 TI - A 0.33 nJ/bit IEEE802.15.6/Proprietary MICS/ISM Wireless Transceiver With Scalable Data Rate for Medical Implantable Applications. AB - This paper presents an ultra-low power wireless transceiver specialized for but not limited to medical implantable applications. It operates at the 402-405-MHz medical implant communication service band, and also supports the 420-450-MHz industrial, scientific, and medical band. Being IEEE 802.15.6 standard compliant with additional proprietary modes, this highly configurable transceiver achieves date rates from 11 kb/s to 4.5 Mb/s, which covers the requirements of conventional implantable applications. The phase-locked loop-based transmitter architecture is adopted to support various modulation schemes with limited power budget. The zero-IF receiver has programmable gain and bandwidth to accommodate different operation modes. Fabricated in 40-nm CMOS technology with 1-V supply, this transceiver only consumes 1.78 mW for transmission and 1.49 mW for reception. The ultra-low power consumption together with the 15.6-compliant performance in term of modulation accuracy, sensitivity, and interference robustness make this transceiver competent for various implantable applications. PMID- 25807574 TI - Hierarchical classification of large-scale patient records for automatic treatment stratification. AB - In this paper, a hierarchical learning algorithm is developed for classifying large-scale patient records, e.g., categorizing large-scale patient records into large numbers of known patient categories (i.e., thousands of known patient categories) for automatic treatment stratification. Our hierarchical learning algorithm can leverage tree structure to train more discriminative max-margin classifiers for high-level nodes and control interlevel error propagation effectively. By ruling out unlikely groups of patient categories (i.e., irrelevant high-level nodes) at an early stage, our hierarchical approach can achieve log-linear computational complexity, which is very attractive for big data applications. Our experiments on one specific medical domain have demonstrated that our hierarchical approach can achieve very competitive results on both classification accuracy and computational efficiency as compared with other state-of-the-art techniques. PMID- 25807575 TI - Using Contextual Learning to Improve Diagnostic Accuracy: Application in Breast Cancer Screening. AB - Clinicians need to routinely make management decisions about patients who are at risk for a disease such as breast cancer. This paper presents a novel clinical decision support tool that is capable of helping physicians make diagnostic decisions. We apply this support system to improve the specificity of breast cancer screening and diagnosis. The system utilizes clinical context (e.g., demographics, medical history) to minimize the false positive rates while avoiding false negatives. An online contextual learning algorithm is used to update the diagnostic strategy presented to the physicians over time. We analytically evaluate the diagnostic performance loss of the proposed algorithm, in which the true patient distribution is not known and needs to be learned, as compared with the optimal strategy where all information is assumed known, and prove that the false positive rate of the proposed learning algorithm asymptotically converges to the optimum. In addition, our algorithm also has the important merit that it can provide individualized confidence estimates about the accuracy of the diagnosis recommendation. Moreover, the relevancy of contextual features is assessed, enabling the approach to identify specific contextual features that provide the most value of information in reducing diagnostic errors. Experiments were conducted using patient data collected at a large academic medical center. Our proposed approach outperforms the current clinical practice by 36% in terms of false positive rate given a 2% false negative rate. PMID- 25807576 TI - Reconstruction of Precordial Lead Electrocardiogram From Limb Leads Using the State-Space Model. AB - A new electrocardiogram (ECG) reconstruction method based on a state-space model is presented. This method was applied to reconstruct precordial leads from limb leads (lead I, II, III) for its validity verification. The system matrices of the state-space model were estimated at the model estimation stage by considering the limb lead signals as the input of the system and precordial lead signals as the output. To evaluate the performance of the proposed method, all of the 549 records of the Physikalisch Technische Bundesanstalt diagnostic ECG database were used, and the correlation coefficients (CC) and root-mean-square errors between reconstructed ECG and measured ECG were calculated. For a more objective evaluation, the results were compared with those of linear regression model that has been typically used for ECG reconstruction. The mean and median values of CCs were higher than 0.988 and 0.995, respectively, for healthy subject data, and also higher than 0.981 and 0.993, respectively, for cardiac patient data and comparable to those by linear regression model. In addition, it was found that the reconstruction performance depended on the type of disease rather than lead type. Among cardiac patient data, hypertrophy, myocarditis, valvular heart disease, and stable heart angina showed higher CC (>0.990), while unstable angina and heart failure showed lower CC of 0.932 and 0.914, respectively. Moreover, when ECG contaminated with the noise was used for reconstruction, the proposed method demonstrated better performance than linear regression model in general. PMID- 25807577 TI - Multiobjective Optimization of Linear Cooperative Spectrum Sensing: Pareto Solutions and Refinement. AB - In linear cooperative spectrum sensing, the weights of secondary users and detection threshold should be optimally chosen to minimize missed detection probability and to maximize secondary network throughput. Since these two objectives are not completely compatible, we study this problem from the viewpoint of multiple-objective optimization. We aim to obtain a set of evenly distributed Pareto solutions. To this end, here, we introduce the normal constraint (NC) method to transform the problem into a set of single-objective optimization (SOO) problems. Each SOO problem usually results in a Pareto solution. However, NC does not provide any solution method to these SOO problems, nor any indication on the optimal number of Pareto solutions. Furthermore, NC has no preference over all Pareto solutions, while a designer may be only interested in some of them. In this paper, we employ a stochastic global optimization algorithm to solve the SOO problems, and then propose a simple method to determine the optimal number of Pareto solutions under a computational complexity constraint. In addition, we extend NC to refine the Pareto solutions and select the ones of interest. Finally, we verify the effectiveness and efficiency of the proposed methods through computer simulations. PMID- 25807579 TI - Nonimmune fetal ascites: identification of ultrasound findings predictive of perinatal death. AB - AIM: To determine the ultrasonographic findings that predict death in fetal ascites. METHODS: This was a retrospective cohort study involving pregnancies with ultrasonographic findings related to fetal ascites. The inclusion criteria were as follows: single pregnancy with a live fetus; ultrasound findings of ascites; ascites unrelated to maternal fetal alloimmunization; and pregnancy follow-up at our institution. The chi2-test was used to evaluate the association of ultrasound findings and death. Multiple logistic regression analysis was performed to determine the ultrasound findings that are predictive of death prior to hospital discharge. RESULTS: A total of 154 pregnancies were included in the study. In 8 (5.19%) cases, ascites was an isolated finding, and in 146 cases, other alterations were observed during the ultrasound evaluation. Death before hospital discharge occurred in 117 cases (76.00%). The following ultrasonographic findings were significantly associated with death: gestational age at diagnosis <24 weeks (P<0.0001); stable/progressive ascites evolution (P=0.004); the presence of hydrops (P<0.0001); and the presence of cystic hygroma (P<0.0001). The presence of hydrops, the presence of respiratory tract malformations, and stable/progressive ascites evolution were significantly associated with the prediction of death. CONCLUSIONS: Based on ultrasound examination, the presence of hydrops, malformation of the respiratory tract, and stable/progressive evolution of ascites increase the chances of death in cases of fetal ascites. PMID- 25807582 TI - Perspectives on biologically inspired hybrid and multi-modal locomotion. PMID- 25807580 TI - Can a healthy youth development clinic serving latino families be youth friendly and family oriented? A mixed-methods evaluation. AB - BACKGROUND: Parenting adolescents poses challenges that are exacerbated by immigration. Aqui Para Ti [Here for You] (APT) is a clinic-based, healthy youth development program that provides family-centered care for Latino youth and their families who are mostly immigrants from Mexico and Latin America. OBJECTIVES: To present the APT model of care and report the experiences of youth and their parents. SUBJECTS: APT patients between 11 and 24 years (n=30) and parents (n=15). Most youth patients were female, between 11 and 17 years, and from Mexico. Most parents were female, 40 years or younger, and from Mexico. METHODS: Youth participants completed a survey and participated in an individual semi structured interview, and parent participants attended focus groups. Descriptive statistics summarized survey data. Interviews and focus groups were transcribed and analyzed in Spanish using content analysis by two independent coders. Quantitative and qualitative findings were integrated using side-by-side comparisons. Researchers not involved in the coding process contributed with the interpretation of the findings. RESULTS: Youth and parents were satisfied with the services received at APT. Youth felt listened to by their providers (100%), felt they could trust them (100%) and valued comprehensive care. Eighty-seven percent reported that their experiences at APT were better than at other clinics. Parents valued the family parallel care, confidentiality, family-centeredness, and the cultural inclusivity of the APT services. CONCLUSION: Patients and parents were satisfied with the services offered at APT. Family parallel care could be a positive alternative to deliver confidential and family-centered services to immigrant families. PMID- 25807581 TI - Protective effect of some selected fruit blends on testicular toxicity in alloxan induced diabetic rats. AB - BACKGROUND: The protective effect of a developed drink from blends of selected fruits on the sperm quality of alloxan-induced diabetic rats was investigated. METHODS: Diabetes was intraperitoneally induced with alloxan; the formulated drink blend was orally administered 2.5 or 5 mL/day. Treatment lasted for 14 days and the rats were humanely sacrificed by cervical dislocation. The antioxidant status via assessment of reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and lipid peroxidation (LPO) was carried out on the testis, while sperm cells were analyzed for sperm motility, counts and abnormality. RESULTS: Induction of diabetes led to a significant (p < 0.05) decrease in GSH level, elevated SOD and CAT activities, significant (p < 0.05) decrease in the sperm quality parameters studied. However, treatment with the formulated drink led to a significant (p < 0.05) reduction of LPO, SOD and CAT activities as well as increase in GSH level. CONCLUSIONS: This study shows an improvement in testicular antioxidant activities and sperm qualities by single and double doses of the formulation, suggesting its protective potential against testicular toxicity in diabetic rats. PMID- 25807578 TI - Association of Roadway Proximity with Fasting Plasma Glucose and Metabolic Risk Factors for Cardiovascular Disease in a Cross-Sectional Study of Cardiac Catheterization Patients. AB - BACKGROUND: The relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollution on human health. OBJECTIVE: We examined associations between roadway proximity and traffic exposure zones, as markers of TRAP exposure, and metabolic biomarkers for cardiovascular disease risk in a cohort of patients undergoing cardiac catheterization. METHODS: We performed a cross-sectional study of 2,124 individuals residing in North Carolina (USA). Roadway proximity was assessed via distance to primary and secondary roadways, and we used residence in traffic exposure zones (TEZs) as a proxy for TRAP. Two categories of metabolic outcomes were studied: measures associated with glucose control, and measures associated with lipid metabolism. Statistical models were adjusted for race, sex, smoking, body mass index, and socioeconomic status (SES). RESULTS: An interquartile-range (990 m) decrease in distance to roadways was associated with higher fasting plasma glucose (beta = 2.17 mg/dL; 95% CI: -0.24, 4.59), and the association appeared to be limited to women (beta = 5.16 mg/dL; 95% CI: 1.48, 8.84 compared with beta = 0.14 mg/dL; 95% CI: -3.04, 3.33 in men). Residence in TEZ 5 (high-speed traffic) and TEZ 6 (stop-and-go traffic), the two traffic zones assumed to have the highest levels of TRAP, was positively associated with high-density lipoprotein cholesterol (HDL-C; beta = 8.36; 95% CI: -0.15, 16.9 and beta = 5.98; 95% CI: -3.96, 15.9, for TEZ 5 and 6, respectively). CONCLUSION: Proxy measures of TRAP exposure were associated with intermediate metabolic traits associated with cardiovascular disease, including fasting plasma glucose and possibly HDL-C. PMID- 25807583 TI - Folding in and out: passive morphing in flapping wings. AB - We present a new mechanism for passive wing morphing of flapping wings inspired by bat and bird wing morphology. The mechanism consists of an unactuated hand wing connected to the arm wing with a wrist joint. Flapping motion generates centrifugal accelerations in the hand wing, forcing it to unfold passively. Using a robotic model in hover, we made kinematic measurements of unfolding kinematics as functions of the non-dimensional wingspan fold ratio (2-2.5) and flapping frequency (5-17 Hz) using stereo high-speed cameras. We find that the wings unfold passively within one to two flaps and remain unfolded with only small amplitude oscillations. To better understand the passive dynamics, we constructed a computer model of the unfolding process based on rigid body dynamics, contact models, and aerodynamic correlations. This model predicts the measured passive unfolding within about one flap and shows that unfolding is driven by centrifugal acceleration induced by flapping. The simulations also predict that relative unfolding time only weakly depends on flapping frequency and can be reduced to less than half a wingbeat by increasing flapping amplitude. Subsequent dimensional analysis shows that the time required to unfold passively is of the same order of magnitude as the flapping period. This suggests that centrifugal acceleration can drive passive unfolding within approximately one wingbeat in small and large wings. Finally, we show experimentally that passive unfolding wings can withstand impact with a branch, by first folding and then unfolding passively. This mechanism enables flapping robots to squeeze through clutter without sophisticated control. Passive unfolding also provides a new avenue in morphing wing design that makes future flapping morphing wings possibly more energy efficient and light-weight. Simultaneously these results point to possible inertia driven, and therefore metabolically efficient, control strategies in bats and birds to morph or recover within a beat. PMID- 25807584 TI - Distributed flow estimation and closed-loop control of an underwater vehicle with a multi-modal artificial lateral line. AB - Bio-inspired sensing modalities enhance the ability of autonomous vehicles to characterize and respond to their environment. This paper concerns the lateral line of cartilaginous and bony fish, which is sensitive to fluid motion and allows fish to sense oncoming flow and the presence of walls or obstacles. The lateral line consists of two types of sensing modalities: canal neuromasts measure approximate pressure gradients, whereas superficial neuromasts measure local flow velocities. By employing an artificial lateral line, the performance of underwater sensing and navigation strategies is improved in dark, cluttered, or murky environments where traditional sensing modalities may be hindered. This paper presents estimation and control strategies enabling an airfoil-shaped unmanned underwater vehicle to assimilate measurements from a bio-inspired, multi modal artificial lateral line and estimate flow properties for feedback control. We utilize potential flow theory to model the fluid flow past a foil in a uniform flow and in the presence of an upstream obstacle. We derive theoretically justified nonlinear estimation strategies to estimate the free stream flowspeed, angle of attack, and the relative position of an upstream obstacle. The feedback control strategy uses the estimated flow properties to execute bio-inspired behaviors including rheotaxis (the tendency of fish to orient upstream) and station-holding (the tendency of fish to position behind an upstream obstacle). A robotic prototype outfitted with a multi-modal artificial lateral line composed of ionic polymer metal composite and embedded pressure sensors experimentally demonstrates the distributed flow sensing and closed-loop control strategies. PMID- 25807585 TI - Vaporized: with cigarette sales down and e-cigarettes hot, lawmakers find themselves in a bit of a revenue quagmire. PMID- 25807586 TI - Filling the gap: after years of spending cuts to mental health programs, lawmakers have begun to boost funding for the most effective approaches. PMID- 25807587 TI - What's hot for 2015: lawmakers have a slew of hot issues to juggle as sessions rev up around the country this month. PMID- 25807588 TI - Helping the helpers: new state laws support the millions of Americans who minister to aging relatives and form the backbone of the nation's long-term care system. PMID- 25807589 TI - Hitting the open road: the debate over requiring motorcyclists to wear helmets revs up once again. PMID- 25807590 TI - Calling the shots. PMID- 25807591 TI - What's behind health insurance rate increases? an examination of what insurers reported to the federal government in 2013-2014. AB - The Affordable Care Act requires health insurers to justify rate increases that are 10 percent or more for nongrandfathered plans in the individual and small group markets. Analyzing these filings for renewals taking effect from mid-2013 through mid-2014, this brief finds that the average rate increase submitted for review was 13 percent. Insurers attributed the great bulk of these larger rate increases to routine factors such as trends in medical costs. Most insurers did not attribute any portion of these medical cost trends to factors related to the Affordable Care Act. The ACA-related factors mentioned most often were nonmedical: the new federal taxes on insurers, and the fee for the transitional reinsurance program. On average, insurers that quantified any ACA impact attributed about a third of their larger rate increases to these new ACA assessments. PMID- 25807592 TI - The rise in health care coverage and affordability since health reform took effect: findings from the Commonwealth Fund Biennial Health Insurance Survey, 2014. AB - New results from the Commonwealth Fund Biennial Health Insurance Survey, 2014, indicate that the Affordable Care Act's subsidized insurance options and consumer protections reduced the number of uninsured working-age adults from an estimated 37 million people, or 20 percent of the population, in 2010 to 29 million, or 16 percent, by the second half of 2014. Conducted from July to December 2014, for the first time since it began in 2001, the survey finds declines in the number of people who report cost-related access problems and medical-related financial difficulties. The number of adults who did not get needed health care because of cost declined from 80 million people, or 43 percent, in 2012 to 66 million, or 36 percent, in 2014. The number of adults who reported problems paying their medical bills declined from an estimated 75 million people in 2012 to 64 million people in 2014. PMID- 25807593 TI - Obamacare "red meat" as campaign battles heat up leading toward mid-term elections. PMID- 25807594 TI - Develop a data and device destruction policy in five easy steps. AB - Destroying and disposing of data or devices that contain protected health information is an essential part of a practice's privacy and security procedures. It also is critical to managing financial risk and risk to your practice's reputation. Many practices, however, have not developed a policy or process for safely discarding the data, or the devices on which the data resides. This article covers five key action steps a practice can take to mitigate the risks involved in destroying and disposing of clinical and financial data. PMID- 25807595 TI - Variation reduction: what's old is new again. AB - The essence of variation reduction is to give physicians transparent data on theirr clinical practice and stimulate a discussion on what should be the standard of care. Physicians choose topics that they are willing to pursue. Top down decision-making is avoided. Variation reduction is a valuable tool in the development of successful Accountable Care Organizations. PMID- 25807596 TI - Business associates gone bad: five tales of woe and ways to prevent them from happening to you. AB - Liability for confidentiality of protected health information extends beyond the walls of a medical practice. Studies show a significant number of breaches occur via the actions or inactions of third-party entities/business associates. These business associates are trusted with patient information to assist a medical practice and can include collection agencies, third-party billing firms, transcription services, etc. Medical practices can be legally liable for the breaches of their business associates. This article provides an overview as to proper methods of retaining and monitoring business associates in an effort to minimize exposure from these firms. PMID- 25807597 TI - Cloud computing and patient engagement: leveraging available technology. AB - Cloud computing technology has the potential to transform medical practices and improve patient engagement and quality of care. However, issues such as privacy and security and "fit" can make incorporation of the cloud an intimidating decision for many physicians. This article summarizes the four most common types of clouds and discusses their ideal uses, how they engage patients, and how they improve the quality of care offered. This technology also can be used to meet Meaningful Use requirements 1 and 2; and, if speculation is correct, the cloud will provide the necessary support needed for Meaningful Use 3 as well. PMID- 25807598 TI - Defining the culture of your practice. AB - Your practice should want patients to understand and appreciate its uniqueness and beliefs. Simply stated, the culture of your practice is the excellent care you provide and how your practice is able to achieve that excellence. Defining and sharing your culture will encourage patients to choose your practice for their healthcare. Monitoring and continually updating your definition of "culture" will help your practice thrive and maintain high standards. PMID- 25807599 TI - An innovative strategy to improve provider engagement through social networking. AB - In this article, we describe a model for secure, intra-practice social networking using Web-based technology to facilitate continuous provider engagement. The focus is to create and share practice improvement strategies and other professional content in IPC The Hospitalist Company's community. We also summarize lessons learned from seven years of experience with this model including successes, challenges, next steps, and recommendations for how other healthcare organizations can apply our experience to improve their practices. Overall, this model for social networking represents an untapped opportunity for leadership to increase provider engagement. PMID- 25807600 TI - Long-term continuity care: unanticipated consequences, viable solutions. AB - To many researchers, long-term continuity care seems a given. Behind their confidence, however, lie issues of concern. This article addresses the unanticipated consequences of long-term continuity care. It identifies issues such as the liabilities of long-term therapeutic relationships, continuity care diagnostic fatigue, intellectual curiosity fatigue, and the adverse economics of long-term continuity care and the practice setting that fosters "routinized," protocol-driven care, among others. It discusses these issues and suggests ways to mitigate their impact. The authors elicit debate by portraying long-term continuity care as both a problem and a solution, and conclude by making the case for a more perfect long-term continuity care process: one that is safe, efficient, and economically advantageous for all stakeholders. PMID- 25807601 TI - Losing a valued member of the medical practice team. AB - Losing a valued member of your staff can be disruptive, painful, and costly to your medical practice. And despite your best intentions and impeccable employee management policies and skills, things will happen beyond your control, and people move on. Being prepared for that possibility will help you minimize and contain the damage and move your practice forward. This article suggests 15 strategies that you can use to mitigate the effects of losing a valued employee. These include strategies to protect your practice's interests and several that will smooth the transition for your remaining staff. This article also describes 10 ways that losing a valued employee can impact a practice. It offers 10 additional strategies to help you cope with the death of an employee, one of the most difficult challenges a practice manager may ever face. This article further suggests several easy-to-implement practice management techniques that will help you soften the blow of employee turnover. It offers a sample farewell letter to announce an employee's departure from your practice and suggests six knowledge transfer questions to ask before the employee leaves. Finally, this article provides a comprehensive list of more than 30 thoughtful, eye-opening, and revealing questions that you can ask in an employee exit interview or exit survey. PMID- 25807602 TI - Multiple employer plans: helping you tackle tomorrow today. AB - With the day-to-day issues that you face, planning for retirement probably isn't at the top of your list. Tomorrow will be here before you know it, and saving for retirement should be a priority for us all. But where to start? Multiple employer plans are a great way to save time and money. This article details how you can gain efficiency in your retirement plan administration. PMID- 25807603 TI - HIPAA investigation risks are increasing: make sure you avoid the "wall of shame". PMID- 25807604 TI - Outsourcing your medical practice call center: how to choose a vendor to ensure regulatory compliance. AB - Medical practices receive hundreds if not thousands of calls every week from patients, payers, pharmacies, and others. Outsourcing call centers can be a smart move to improve efficiency, lower costs, improve customer care, ensure proper payer management, and ensure regulatory compliance. This article discusses how to know when it's time to move to an outsourced call center, the benefits of making the move, how to choose the right call center, and how to make the transition. It also provides tips on how to manage the call center to ensure the objectives are being met. PMID- 25807606 TI - Traumatized by practice: PTSD in physicians. AB - Posttraumatic stress disorder (PTSD) is underrecognized in physicians, even though it may be more prevalent in physicians than in the general population in the United States. Five types of physicians appear to be particularly prone to developing PTSD: (1) emergency physicians; (2) physicians practicing in underserved and remote areas; (3) physicians in training (i.e., medical residents); (4) physicians involved in malpractice litigation; and (5) physicians who are "second victims" in the sense that they are indirectly exposed to trauma. In addition to experiencing trauma, the cumulative stress of practice may cause PTSD. The road to recovery for physicians with PTSD entails proper diagnosis and treatment, which includes maintaining a high index of suspicion for the occurrence of PTSD in predisposed physicians, and individual or group therapy. Physicians in leadership positions should advocate for effective support programs for their colleagues with PTSD. PMID- 25807605 TI - Identifying healthcare activities using a real-time location system. AB - This article discusses human resource allocation in a Veterans Health Administration audiology clinic as a model for clinics facing similar challenges in maximizing quality, safety, and effectiveness of care. A framework is proposed combining automatic identification technology with simulation and visualization software, asserting a relationship between location of staff within the facility and clinical activity, focusing healthcare staff on high-value activities to deliver safe, quality care. This enables "what-if" analyses of potential resource allocation scenarios, correlating location information from radiofrequency identification tags worn by clinicians and technicians in the clinic as part of a real-time location system, then inferring probable activity from the data. Once the baseline "as-is" can be established, the model will be refined to supply predictive analyses of resource allocation and management. Simulations of activities in specialized spaces saves time managing resources, which means more time can be spent on patient safety and increased satisfaction. PMID- 25807607 TI - Managing the chronically late patient. AB - Every practice has patients who are chronically late. This wrecks havoc with your schedule and makes you less productive. Patients can be trained to respect your time and arrive in the office on time. This article discusses several approaches to managing the chronically late patient. PMID- 25807608 TI - (Annual) conference call: will you answer? PMID- 25807609 TI - The primary role: how the availability of primary care physicians affects diabetes care management. AB - This article discusses how the primary care physician shortage impacts health outcomes, specifically diabetes. The effect of the availability of primary care physicians on diabetes care management is examined by assessing primary care physician-to-population ratios and comparing those ratios against evidence-based medicine preventive practices for diabetes care. A discussion is included as to how the Patient-Centered Medical Home model can greatly contribute to primary care success through better care delivery implementation methods. PMID- 25807610 TI - Doctors going mobile. AB - Having a Web page and a blog site are the minimum requirements for an Internet presence in the new millennium. However, a Web page that loads on a personal computer or a laptop will be ineffective on a mobile or cellular phone. Today, with more existing and potential patients having access to cellular technology, it is necessary to reconfigure the appearance of your Web site that appears on a mobile phone. This article discusses mobile computing and suggestions for improving the appearance of your Web site on a mobile or cellular phone. PMID- 25807611 TI - Computer briefs. But it's only about wellness. PMID- 25807612 TI - Midterm elections to have an impact on healthcare policy future. PMID- 25807613 TI - Great patient experiences can earn big payer bonuses. AB - Although many healthcare providers have been railing against the stringent new requirements of the Affordable Care Act and the burdensome mandates from the Centers for Medicare & Medicaid Services, making simple improvements in patient satisfaction can require little to no expense and can result in increased dollars, as well as more satisfied patients. By following six simple steps, successful organizations have been able to transform their patients' experiences and raise satisfaction scores through a series of practical activities designed to assess the current environment, improve patient and employee/provider experience, and maintain the improvement gains. It doesn't always take money to make money. It's a matter of telling employees what the organization expects of them and holding them accountable. When the patient has a positive experience, everyone profits! PMID- 25807615 TI - December financial checkup for physicians. AB - December is a busy month for holiday fun, but don't neglect your financial health! Physicians should review their business and personal finances at year end to ensure they are on target both for income generated and taxes paid. Preparing for the April 15 tax filing is aided by a thorough review in December. Payroll items such as W2s, 1099s, and employee benefits need to be reviewed. Retirement savings should be analyzed. Make sure to look at your business profit/loss statement and balance sheet. Personal contributions and other tax planning strategies need to be completed by the end of the year. Your CPA can help! PMID- 25807614 TI - The chaotic physician work world. AB - Physicians are immersed in a work environment where daily challenges seem to represent a condition or place of increasing disorder and confusion. The degree of "entropy" in the physician workplace is increasing exponentially. Healthcare systems are in a state of chaos and are dynamic--meaning the behavior at one time influences its behavior in the future. The initial changes have future exponential fluctuations that have created a state of healthcare crisis. These systems are nonlinear; the metaphor to describe the unruly nature of the physician work world is that in which the flap of a butterfly wing in Brazil can set off a tornado in Texas. The tornado affecting physician work life must be understood to be rectified. Physicians must slow down and pay attention. PMID- 25807616 TI - Titles are terrific: creating titles that will attract attention. AB - There are millions of blogs posted every day. However, the majority of them don't get read. Often this is because the title is not engaging and does not motivate the reader to read the content of the blog. Your blog content has to be informative and engaging, but first the blog must have a title that makes the reader want to take the time to read the blog. This article will discuss techniques and methods to use to create engaging titles that will get your blog read and, more importantly, move the reader from the blog to your Web site, and then to go online and make an appointment with your practice. PMID- 25807617 TI - Is your practice at risk for medical identity theft? AB - Medical identity theft has become increasingly prevalent. Medical practices need to take action and have policies and procedures in place to prevent data breaches. This will protect both the patient and the practice from medical identity theft. PMID- 25807618 TI - Increasing physician engagement: start with what's important to physicians. AB - Physician engagement has never been more important in this environment of healthcare reform--yet few healthcare organizations can define it or identify the elements of engagement that make increasing it possible. This may explain why a recent survey of physicians on the specifics regarding engagement from their perspective found, among other things, that levels of engagement over the past three years have increased at a lukewarm pace, at best. The survey confirmed that feeling engaged was very important to physicians' job satisfaction. It delved into what was important to them--and where there are gaps between what they want and what they are currently experiencing in their organizations--at a granular level, as well as measuring their current levels of engagement with their organizations and their work. It also explored the impact that feelings of engagement have on physicians' decisions around accepting or leaving a job or practice. A companion survey with administrators pointed out areas where there were gaps between their perceptions and those of physicians. The results point to actions that healthcare organizations can take to increase engagement--and, by extension, participation and buy-in--among their physician populations to reach critical goals and achieve greater success with key initiatives at a time of increasing physician shortages and competition between health systems for top physician talent. PMID- 25807619 TI - Concierge Medicine: is it becoming mainstream? Part II. Steps to developing a concierge practice. AB - Review your current practice, patient load and demographics, revenue, and insurance processing procedures. Work with an expert to develop a business plan of a direct-pay practice, and compare the expected patient load and demographics and revenue to that of your current practice. Will a direct-pay/concierge practice: Increase your revenue/decrease your expenses? Offer your patients better healthcare by taking decisions out of the hands of the insurance company? Provide your patients easier access to you and your staff? Maintain or attract a sufficient number of patients? Offer you more career satisfaction? Any change can be daunting, but many times, the results are well worth the challenges. PMID- 25807620 TI - Health management education: current alternatives. AB - The past several decades have witnessed a significant increase in the number of graduate programs in health management, either on campus or online. The alternative for a health professional to attending a graduate program on campus is to receive an MBA or MHA degree online. The current cost ranges from $13,600 to $78,000, with the more expensive online programs tied to graduate programs that are accredited by the Commission on the Accreditation of Healthcare Management Education and provide the names and qualifications of their faculty. The for-profit online programs have not been forthcoming to this author concerning their health management faculty or their curriculum. For the individual desiring more health management education who is unable to enroll, for family or financial reasons, in an on-campus program, the top-tier online programs seem like a worthwhile but is a relatively expensive option. PMID- 25807621 TI - Hiring the right employees. AB - Current employees provide the best examples of the type of aptitude, attitude, motivation, and fit we are looking for, or not looking for, in new employees. All four of these attributes are present in star employees. Using what we know about our best and worst employees can assist us in developing questions and scoring templates that will help us categorize current applicants. Hiring managers should formulate questions in a way that elicits informative responses from candidates about past performance in situations similar to those they will face on the job. Nonverbal clues can help provide insight beyond the simple verbal answer given by candidates. Practice, critique, and critical review of the outcomes of our hiring decisions improve our ability to become good hiring managers. PMID- 25807622 TI - Overhead and operations: cutting where it counts. AB - To remain a profitable entity, whether a retail operation, manufacturing plant, or a medical practice, the common denominator is the same: where can you cut your costs, increase your revenue, and maintain additional profitability? Learning where to cut your operational expenses is as important to your business's profit ability as bringing in additional dollars. PMID- 25807623 TI - Medical assistants' roles in electronic health record processes in primary care practices: the untold story. AB - The role of the medical assistant has been undervalued in the past. Many publications have detailed the integral role of the nursing staff and physicians, but the medical assistant role has come last in formal recognition. As healthcare settings move toward a more Patient-Centered Medical Home (PCMH) model, the attitudes of this model will need to be adopted, two of which are team-based care and adoption of the electronic health record (EHR). As the EHR continues to gain more traction in healthcare, a thorough understanding of it, by everyone, will be vital for its success. In this article, the medical assistant's relationship with the EHR is outlined through qualitative interviews and observations with medical assistants in PCMH programs. The data describe diverse EHR experiences and how these experiences are influenced by and reflected in workflow issues, training, patient care, and an expanding role of the medical assistant. PMID- 25807625 TI - Fighting the "golden rule". PMID- 25807624 TI - Working well with the informal leaders in your practice. AB - Anyone with an up-to-date organizational chart can determine the formal leadership roles in a medical practice. What many practice administrators fail to realize, however, is that there is another, complementary leadership model that exists between the lines in an org chart: informal leadership. This article defines the term informal leadership and describes informal leaders' three bases of power. It suggests seven characteristics of informal leaders and the specific techniques a practice administrator can use to identify the real informal leaders in the practice. This article also offers practice administrators practical tips for dealing effectively with informal leaders who oppose them. It suggests strategies for counseling a reluctant informal leader and for developing the informal leaders in a medical practice. Finally, this article argues that informal leaders can be a source of great help for medical practices that have been downsized or restructured. PMID- 25807627 TI - Captive insurance companies. AB - The landscape of the business world is changing; and now, more than ever, business owners are recognizing that life is filled with risks: known risk, calculated risk, and unexpected risk. Every day, businesses thrive or fail based on understanding the risk of owning and operating their business, and business owners are recognizing that there are alternative risk financing mechanisms other than simply taking out a basket of standard coverage as recommended by your friendly neighborhood agent. A captive insurance company is an insurance company established to provide a broad range of risk management capabilities to affiliated companies. The captive is owned by the business owner and can provide insurance to the business for potential future losses, whether or not the losses are already covered by a commercial carrier or are "self-insured." The premiums paid by your business are tax deductible. Meanwhile, the premiums that your captive collects are tax-free up to $1.2 million annually. PMID- 25807628 TI - Developing clinical research incentives for academic oncologists. AB - Incentive plans can be developed to promote clinical research activities for academic oncologists. Such plans encourage faculty to devote the necessary time and effort to enroll patients in clinical trials. It is crucial to decide what types of activities will be incentivized and to define expectations at the outset. An incentive program requires resources that should remain stable over time. A resource allocation ideally would be indexed to a level of clinical research activity so that, as activity increases, more funding is available for distribution as incentives. Most academic oncologists are familiar with incentive based reimbursement for clinical activities; a similar structure for academic pursuits such as clinical research can be incorporated into, or used in conjunction with, a clinical incentive plan. PMID- 25807626 TI - Effect of an electronic alert on treatment of skin and soft tissue infections. AB - This is a prospective intervention study conducted between 2007 and 2011 to evaluate whether an electronic alert can influence provider practice in treatment of skin and soft tissue infections (SSTIs). A best-practice alert (BPA) was programmed to appear for intervention ICD-9 SSTI diagnoses. Controls were patients who had other SSTI ICD-9 codes where the BPA was not programmed to fire. Rate of culture taken in patients was compared between patients in the intervention and control groups. We found that cultures were taken among 13.5% of the intervention group and 5.4% of the control group (p <.0001). A logistic regression analysis controlling for covariates showed the odds of the intervention group having a culture taken was 2.6 times that of the control group. The results of this study support the use of BPAs for improving the management of SSTIs. PMID- 25807629 TI - Controlling public speaking jitters: making the butterflies fly in formation. AB - Nearly every person who has been asked to give a speech or who has volunteered to make a presentation to a group of strangers develops fear and anxiety prior to the presentation. Most of us, the authors included, start hyperventilating, our pulse quickens, and we feel a little weak in the knees. We grab the lectern and our knuckles turn white as we hold on for dear life. This is a normal response that everyone experiences. However, this stress can be controlled and made manageable by understanding the stress response cycle and practicing a few techniques that calm those butterflies flying around in the pit of your stomach. PMID- 25807630 TI - Affordable Care Act compliance, new type of annuity contract, and taxation of employer-provided parking. PMID- 25807631 TI - 40 years external quality assessment--what have we achieved? A personal view. AB - The present report deals with a personal interaction with different external quality assessment (EQA) programmes over the past four decades for different groups of analytes. The effects of national and international legislation and standardization, as well as certification and accreditation standards have also been taken into account. The effects and limitations of reference method procedures and reference materials are also discussed as are the trends in accuracy and precision, the latter especially in terms of automation and decentralization of laboratory analyses. The effects seen are not only positive and, often, legislation and commercial interests are in conflict with the primary aims of EQA and standardization. PMID- 25807632 TI - Applications of photonic crystals in medicine. AB - Photonic crystals are periodic optical nanostructures that affect the motion of photons in much the same way that ionic lattices affect electrons in solids. Even though porous silicon (pSi) was first obtained as early as 1956, it was long used only as electrical insulator. Unique optical and photophysical properties of this material have been studied in detail in the past decade and, in particular, the porosity has been found to affect the pSi refraction index. Until now, they have been used in many areas, but recent trends in the applications of pSi are related to biomedicine, such as drug delivery, biosensing, and photodynamic therapy. This paper concerns the medical applications in these fields and prospective analysis of photonic crystals. PMID- 25807633 TI - Role of Smac in apoptosis of lung cancer cells A549 induced by Taxol. AB - BACKGROUND: A series of structurally unique second mitochondria-derived activators of caspase (Smac) that act as antagonists of inhibitor of apoptosis proteins (IAPs) directly have been discovered and have been shown to promote chemotherapy-induced apoptosis. In this study, we investigate the role of Smac in Taxol-induced apoptosis of lung cancer cell in vitro. METHODS: PcDNA3.1/Smac recombinants were transfected into the non-small cell lung cancer cell line A549. Smac expression was detected by RT-PCR and Western blot. The invasive ability of cells was examined. Flow cytometry was used to analyze apoptosis of cells induced by Taxol with Annexin V/PI double staining technique. RESULTS: Smac expression was significantly higher in the PcDNA3.1/Smac recombinant group than in the untransfected group at mRNA and protein level (p < 0.05) and lower invasion through a basal membrane was apparent after transfection (p < 0.05). A small number of cells were promoted to apoptosis in the PcDNA3.1/Smac group. There were significant differences compared to the empty vector group and control group. The apoptosis rate was significantly higher in PcDNA3.1/Smac + Taxol group than in other groups (p < 0.05). CONCLUSIONS: Transfected Smac can enhance the chemosensitivity of the non-small cell lung cancer cell line A549 to Taxol. PMID- 25807634 TI - Imbalance of interleukin-18 and interleukin-18 binding protein in patients with IgA nephropathy implicating renal vasculopathy. AB - BACKGROUND: Interleukin-18 (IL-18) is a proinflammatory cytokine which induces interferon-gamma production and plays a crucial role in immune systems. IL-18 binding protein (IL-18BP) is a naturally occurring inhibitor of IL-18. The aim was to investigate the involvement of IL-18 and IL-18BP in IgA nephropathy (IgAN). METHODS: Serum samples from 21 IgAN patients and 16 idiopathic membranous nephropathy (MN) patients and 32 healthy controls were assayed by an enzyme linked immunosorbent method. RESULTS: Compared to the controls, IgAN patients showed significantly higher levels of IL-18 and the increased IL-18/IL-18BP ratio. Despite IL-18 elevation, the levels of IL-18BP did not parallel the increase of IL-18, which resulted in an increased IL-18/IL-18BP ratio. Furthermore, the ratio in patients with renal vasculopathy was significantly increased compared to those without arteriolar lesions. CONCLUSIONS: These findings provide the first evidence that there is an imbalance of IL-18/IL-18BP ratio in IgAN patients, which may be associated with the pathophysiology of renal vasculopathy. PMID- 25807635 TI - Monitoring of omalizumab therapy by measuring free IgE using a bedside immunoassay. AB - BACKGROUND: The monoclonal anti-IgE antibody omalizumab is used as add-on therapy for improved asthma control in patients with severe persistent allergic bronchial asthma. The aim of the study was to examine the effectiveness of omalizumab and to demonstrate the hitherto unavailable possibilities for treatment monitoring by means of a bedside immunoassay. METHODS: In the prospective longitudinal study, 9 patients aged 8 to 15 years with severe persistent allergic asthma received add on treatment with omalizumab. Besides the parameters of general physical examination, recordings of exacerbation rate, asthma control and lung function (FEV1), and total IgE concentrations in serum were determined after 6 and 12 months; free IgE was measured using the Milenia QuickLine immunoassay. RESULTS: The mean duration of treatment was 56 +/- 7.5 months. After 12 months, omalizumab showed good tolerability and effectiveness with a reduced exacerbation rate, a significant improvement of asthma control (ACT; p < 0.001) and FEV1 (p < 0.01). Already after six months of therapy, a significant reduction in total IgE from 1253 +/- 407 IU/mL to 466 +/- 120 IU/mL (p < 0.01) was observed. Free IgE levels were below the detection limit in all patients during treatment with omalizumab, even following dose reduction; they increased only after cessation of the treatment. CONCLUSIONS: Our data 1) confirmed good therapeutic effectiveness of omalizumab in patients with severe persistent asthma and 2) indicated that a quick and easy-to-use immunoassay to measure free IgE together with thorough clinical assessment may be a potential instrument for monitoring omalizumab treatment. PMID- 25807636 TI - Markers of endothelial activation in preeclampsia. AB - BACKGROUND: The study aimed at finding a laboratory approach to detect endothelial damage in normal pregnancy as well as in pregnancy complicated by preeclampsia using selected markers of endothelial activation. MATERIALS: A total of 403 healthy pregnant women without a history of deep vein thrombosis and/or hypertension were prospectively studied. From all women, venous blood was collected before the end of the 1st trimester, between weeks 24 and 28 of gestation, and in the 3rd trimester (weeks 34-36). Assays of tissue plasminogen activator, plasminogen activator inhibitor-1, von Willebrand factor activity and antigen, thrombomodulin, endothelial protein C receptor, and endothelial microparticles activated by TF were performed. RESULTS: When comparing women who developed preeclampsia during pregnancy (the average levels were 23.41 MUg/L, 34.33 MUg/L, and 53.56 MUg/L in the 1st, 2nd, and 3rd trimesters, respectively) with healthy pregnant women (the average levels were 19.05 MUg/L, 28.47 MUg/L, and 39.86 MUg/L in the 1st, 2nd, and 3rd trimesters, respectively) significant differences in the levels of thrombomodulin were found in all three trimesters. By contrast, no statistically significant differences in the levels of vWF (both antigen and activity), t-PA, EPCR, EMPs, MMP-2, MMP-9, and TIMP-9 were found in any trimesters in the same group. CONCLUSIONS: Pregnancy and preeclampsia strongly influence the levels of studied markers. The findings of this work confirm the possible predictive potential of thrombomodulin and PA-1. PMID- 25807637 TI - An artificial aqueous humor as a standard matrix to assess drug concentration in the anterior chamber by high performance liquid chromatography methods. AB - BACKGROUND: The aim of the study was to recreate in-vitro artificial aqueous humor with the same physico-chemical properties of human aqueous humor to be used as a standard matrix in chromatography to assess drug concentration in the anterior and posterior chamber of the human eye. METHODS: The artificial aqueous humor was prepared according to the human aqueous humor chemical compositions reported in the literature. The artificial matrix was then analysed via the HPLC UV method and compared with aqueous humor from 15 patients who underwent cataract surgery. Known concentrations of widely-used ophthalmological drugs were added to the artificial aqueous humor in order to assess whether it can be used to explore ocular disposition towards topically or systemically administered drugs. RESULTS: No significant differences were found between the two examined aqueous humor types. There were no significant qualitative differences between examined fluids in terms of presence of ophthalmological drugs. CONCLUSIONS: The composition of artificial, in-vitro recreated aqueous humor was similar to that of the human kind. The absence of significant differences in the analysis of tested drugs both in the artificial and in human aqueous humor indicates that artificial aqueous humor may be used to generate a matrix-based standard curve for analytical method validation. PMID- 25807638 TI - Multiplex fluorescence quantitative polymerase chain reaction for simultaneous detection of hepatitis B virus, hepatitis C virus and human immunodeficiency virus. AB - BACKGROUND: To construct a multiplex fluorescence quantitative polymerase chain reaction (MFQ-PCR) system to simultaneously detect hepatitis B virus (HBV) DNA, hepatitis C virus (HCV) cDNA, and human immunodeficiency virus (HIV) cDNA to reduce the false positive and false negative results, therefore increasing the efficacy and accuracy of donor blood testing. The feasibility of the MFQ-PCR system was assessed by testing 58 clinical serum samples from hospitalized patients. METHODS: TaqMan probes designed specifically for the detection of HBV, HCV, and HIV viruses separately were put into the same MFQ-PCR tube and co amplified with the HBV target DNA, HCV target cDNA, and HIV target cDNA. RESULTS: In this new MFQ-PCR system, the detection limits were about 10 copies for each of standard plasmid DNAs of HBV, HCV, or HIV. In the test of 58 clinical serum samples, of which 23, 16, and 3 were positive for HBV, HCV, and HIV, respectively, by ELISA method, and 16 were normal controls, this new MFQ-PCR system detected 41 of 42 positive samples, and the 16 normal controls were all negative. The rate of consistency between the new system and ELISA was 98.3%. CONCLUSIONS: MFQ-PCR has the advantage of simultaneous detection of HBV, HCV and HIV viruses in clinical serum samples with high efficiency and accuracy. PMID- 25807639 TI - Antimicrobial effect of Australian antibacterial essential oils as alternative to common antiseptic solutions against clinically relevant oral pathogens. AB - BACKGROUND: The aim of the study was to examine the in vitro antibacterial activity of different oils in comparison to antiseptics against oral microorganisms. METHODS: The antimicrobial effect of tea tree oil (TTO), eucalyptus oil (EO), lemon grass oil (LGO), and a eucalyptus-based oil mixture (MXT) were tested in comparison to chlorhexidine digluconate (CHX), povidone iodine (BTA), and octenidine dihydrochloride (OCT). Oral bacterial strains and candida species using the agar diffusion test were used for the antimicrobial study. RESULTS: All tested oils showed antimicrobial potency against the tested biological indicators. In comparison of all tested substances the largest effective zones were measured for LGO, followed from MXT and CHX. TTO and EO were less effective against the tested microorganisms followed from BTA. CONCLUSIONS: The results of this study show that some essential oils have better antimicrobial properties than standard oral antiseptics. In a follow-up step, the ideal concentrations, the composition of essential oils, and the mode of application will be evaluated. The antibacterial efficacy of essential oils might be promising for use in clinical and oral hygiene applications. The cost reduction and availability particularly in rural areas with easy access to the originating plants might be advantageous factors to be considered. PMID- 25807640 TI - C-terminal agrin fragment (CAF) reflects renal function in patients suffering from severe sepsis or septic shock. AB - BACKGROUND: One of the main causes of acute kidney injury (AKI) in patients treated on an intensive care unit (ICU) is sepsis. The identification of new biomarkers indicating the early development and future course of AKI are of utmost medical interest. The C-terminal agrin fragment (CAF) is measurable in blood serum and might reflect kidney function. Therefore, this study evaluates CAF in patients presenting to an internal ICU with severe sepsis or septic shock. Serum levels of CAF are correlated with biomarkers of kidney function, markers of systemic inflammation, and the presence of AKI and renal replacement therapy (RRT). METHODS: 61 patients suffering from severe sepsis or septic shock were included during the first 24 hours of ICU treatment and blood samples for biomarker measurements, i.e., CAF, creatinine, cystatin C, procalcitonin (PCT), interleukin 6, C reactive protein (CRP), and white blood cells (WBC) were collected on the first day of intensive care treatment. The number of RRT days and the incidence of AKI were documented. RESULTS: 13% of the patients (8/61) suffered from SIRS/sepsis, 20% (12/61) from severe sepsis, and 67% (41/61) from septic shock. Serum levels of CAF significantly correlated with creatinine (r = 0.623, p < 0.001) and cystatin C (r = 0.578, p < 0.001). Multiple linear regression analyses adjusting CAF for inflammatory parameters (i.e., WBC, CRP, interleukin 6, PCT), age, and gender showed a strong correlation between CAF and creatinine (r = 0.643, p < 0.001). Serum levels of CAF were significantly associated with the need of RRT (area under the curve (AUC) = 0.772, 95% CI: 0.641-0.903, p = 0.002) and the incidence of AKI (AUC = 0.721, 95% CI: 591-0.850, p = 0.004) as indicated by ROC analysis. CONCLUSIONS: In patients suffering from severe sepsis and septic shock, serum levels of CAF were significantly associated with kidney function and RRT and were not influenced by severe septic conditions. PMID- 25807641 TI - Performance evaluation of four dominant anti-hepatitis B core antigen (HBcAb) kits in Japan for preventing de novo hepatitis B virus (HBV) infection. AB - BACKGROUND: The determination of antibody to hepatitis B core antigen (HBcAb) has become an important means of evaluating the risk factors of de novo hepatitis B virus (HBV) infection before starting intensive immunosuppressive drug therapies. Four dominant HBcAb determination reagents used in Japan were evaluated with HBcIgM, HBsAg, HBsAb, HBeAb, and HBV DNA reagents in order to study their clinical utility. METHODS: Four kinds of HBcAb reagent kits (HBcAb Total and HBcAb-IgG reagent) were evaluated with 526 clinical specimens, including 344 negative specimens, at Osaka University Hospital. The dynamic range of each kit was evaluated by testing serially diluted serum from pooled sera with high HBcAb concentration. RESULTS: The reagent that showed the largest dynamic range was the Lumipulse HBcAb-N (HBcAb-IgG reagent). Regarding clinical sensitivity and specificity, Centaur HBcAb (HBcAb Total reagent) gave several "doubtful negative" results and ARCHITECT HBcII (HBcAb Total reagent) had the most discrepant positive results. By comparing the cut-off-index distribution of negative specimens using a parameter of "distance from the mean to the cut-off divided by the SD", Centaur was determined to be the best (distance/SD = 12.65), with Lumipulse and Elecsys Anti-HBc (HBcAb Total reagent) in the second group (8.13 and 7.00, respectively), and ARCHITECT rated as the worst (3.25). CONCLUSIONS: In this evaluation, Elecsys and Lumipulse HBcAb kits showed good clinical sensitivity and specificity and were considered to be suitable for evaluating the risk factors of de novo HBV infection. PMID- 25807642 TI - Intestinal fatty acid binding protein (I-FABP) as a promising test for Crohn's disease: a preliminary study. AB - BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract from the mouth to the anus. The clinical course presents with remissions and activations. Also, clinical findings or endoscopic activity do not always reflect the overall appropriate disease activity. This is why specific markers are always an issue of concern for the diagnosis, prediction of relapse, and monitoring of CD activity. Fatty acid binding proteins (FABPs) are intracellular proteins that are expressed abundantly in several tissues. Intestinal FABP (I-FABP) is a plasma and urine marker that indicates intestinal damage. In this preliminary study, we aimed to determine whether serum I-FABP levels are a useful marker for CD. METHODS: Seventy-four patients with CD (41 active and 33 in remission) and 37 healthy controls were included in the study. The level of serum I-FABP was determined by ELISA. Crohn's disease activity index (CDAI) and CRP were used to assess the activity of Crohn's disease and to evaluate whether I-FABP is a useful laboratory marker. RESULTS: Serum I-FABP levels of patients with active disease were observed to be statistically higher than patients in the remission and control groups (p = 0.012 and p = 0.038, respectively). No statistically significant difference was observed among patients in the remission and control groups (p = 0.145). Correlation analysis showed a positive correlation between I-FABP and CDAI (r = 0.319, p = 0.006). In addition, a positive correlation was found between CRP and I-FABP levels. CONCLUSIONS: I-FABP seems to be a useful systemic marker for CD activity. PMID- 25807643 TI - Investigation of bacterial translocation in chronic ischemic heart failure in the rat. AB - BACKGROUND: Increased markers of systemic inflammation had been found in patients with acute heart failure. These and other findings led to the hypothesis of an increased rate of bacterial translocation in severe or acute heart failure, leading to systemic inflammation. The present study examined if bacterial translocation occurs under physiological conditions in rats and if its rate and spectrum changes in chronic compensated ischemic heart failure. METHODS: Myocardial infarction (MI) was induced by proximal ligation of the left anterior descending coronary artery or a sham operation was performed. Rats were followed up for six months and mesenteric lymph nodes of the surviving animals with large MI were excised and bacterial translocation was quantified by cultivating viable bacteria. RESULTS: Induction of a large MI led to a significant cardiac remodelling, elevated levels of atrial natriuretic peptide, and pulmonary oedema. There was no difference in the spectrum or in the rate of bacterial translocation compared with controls, neither comparing all cultured bacteria nor predefined subgroups (e.g., intestinal bacteria). CONCLUSIONS: Bacterial translocation is a physiological process with no gradual increase in chronic compensated heart failure in rats. PMID- 25807644 TI - Hematological and biochemical laboratory reference intervals for Zimbabwean adolescents. AB - BACKGROUND: Reference intervals are used as an aid in the interpretation of laboratory results. Most developing countries do not have reference intervals specific to adolescents. This study was aimed at establishing hematological and biochemical reference intervals for adolescents aged >= 12 years to < 18 years. METHODS: A community based, cross sectional study was conducted using the multistage sampling technique. Participants were enrolled from the UZ-UCSF research study catchment areas of Harare, Chitungwiza, and Mutoko. Samples were transported for analysis at the UZ-UCSF Central Laboratory under recommended conditions. The data analysis presented in this paper is for 302 adolescents aged >= 12 to < 18. Non-parametric statistical methods were used to estimate the 95% reference limits for the hematological and biochemical parameters, with the lower limit defined as the 2.5 percentile and the upper limit defined as the 97.5 percentile of the distribution. RESULTS: A total of 302 adolescents were included. Results show significant differences between males and females in hematological parameters except platelets, eosinophils, basophils, and red cell distribution width. The biochemical parameters which showed significant differences between males and females were phosphate, ALP, ALT, AST, GGT, and lipase. CONCLUSIONS: Hematological indices and liver function tests differ significantly by gender and this should be considered when defining normal intervals. PMID- 25807645 TI - EHEC, EPEC, and ETEC strains and their antibiotic resistance in drinking and tap water samples. AB - BACKGROUND: Investigating of the presence of Enterohemorrhagic E. coli (EHEC), Enterotoxigenic E. coli (ETEC), Enteropathogenic E. coli (EPEC) strains and their antibiotic resistance in natural spring waters and tap waters from two university hospitals, in Istanbul. METHODS: E. coli strains isolated from water samples were identified by polymerase chain reaction (PCR) method using stx-1, stx-2, eaeA genes specific for EHEC; eaeA, bfp genes specific for EPEC and lt, st genes specific for ETEC. Antibiotic susceptibility tests were done according to the Kirby-Bauer method using The Clinical and Laboratory Standards Institute (CLSI) criteria. RESULTS: E. coli strains were isolated from only five (2.7%) out of 184 water samples. Only one of the 36 E. coli strains isolated from these five water samples was found to be extended spectrum beta lactamase (ESBL) positive. According to PCR, ten E. coli strains isolated from one drinking water were identified as ETEC. Other than E. coli strains, coliforms and non-fermentative Gram negative bacteria were also isolated from waters. It was shown that 60 (81.1%) of these 74 strains isolated, other than E. coli, were found to be multiple resistant. CONCLUSIONS: Contrary to our expectations, it has been shown that natural spring waters (drinking waters) can be much more contaminated with fecal bacteria when compared with tap waters. The presence of pathogenic E. coli strains and antibiotic resistant Gram negative bacteria especially in drinking waters emphasize the importance of these types of studies. PMID- 25807646 TI - Evaluation of trace and toxic elements in the samples of different cigarettes and their impact on human health of Irish diabetes mellitus patients. AB - BACKGROUND: In the present study, trace and toxic elements were determined in scalp hair and blood samples of patients diagnosed with diabetes mellitus (DM) who are smokers living in Dublin, Ireland. These results were compared to age- and gender-matched healthy, non-smoker controls. In this study, these toxic metals (Cu, Cd, Fe, Ni, and Pb) were also determined in different components of imported branded cigarettes, including the filler tobacco (FT), filter (before and after normal smoking by a single volunteer), and ash. METHODS: The concentrations of trace and toxic elements were measured by inductively coupled plasma atomic emission spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked using certified reference materials and by the conventional wet acid digestion method on the same certified reference material and on real samples. The recovery of all the studied elements was found to be in the range of 96.41-99.7% in certified reference material. RESULTS: The results of this study showed that the mean values of cadmium, copper, iron, nickel, and lead were significantly higher (p < 0.001), in scalp hair and blood samples of diabetic patients as compared to referents of both genders. The smoker referents and DM patients have two to three times higher values of these elements than those subjects who were not smokers, whereas, the concentrations of zinc and chromium were lower in the scalp hair and blood samples of diabetic patients as compared to referents. The concentrations/percentage of trace and toxic metals in different components of cigarettes were calculated with respect to their total contents in FT of all branded cigarettes before smoking, while smoke concentration was calculated by subtracting the filter and ash contents from the filler tobacco content of each branded cigarette. CONCLUSIONS: This study showed that increased toxic elements and decreased essential elements as a result of cigarette smoking, are associated with diabetes mellitus. Therefore, these elements may play a role in the development and pathogenesis of diabetes mellitus. PMID- 25807647 TI - Comparison between Elecsys HBsAg II and Architect assays for quantification of serum hepatitis B surface antigen in Chinese patients with chronic hepatitis B. AB - BACKGROUND: Chronic hepatitis B (CHB) is an important global health problem. Recent innovations have rendered quantification of serum hepatitis B surface antigen (HBsAg) a valuable tool in hepatitis B virus (HBV) disease management and for determining the effectiveness of drug treatment. The aim of the present study was to compare the performances of the Elecsys HBsAg II and Abbott Architect HBsAg assays in Chinese patients with CHB, with predominantly genotypes B and C. METHODS: A dilution protocol was developed for the Elecsys assay to allow quantification of HBsAg levels. Sera were obtained from patients with various HBV genotypes, including HBV mutants, and longitudinal samples were obtained from patients undergoing antiviral treatment. RESULTS: There was a significant overall correlation between the Elecsys and Architect assays (r = 0.9881; p < 0.001). There were good correlations between the results of the two assays in terms of HBsAg levels in CHB samples (r = 0.9625-0.9974), in samples with low HBsAg levels (r = 0.9722, p < 0.001), across two genotypes (HBV genotype B, r = 0.9758, p < 0.001; HBV genotype C, r = 0.9943, p < 0.001), in samples with YMDD mutations (r = 0.9625, p < 0.001), and in samples from patients receiving anti-HBV treatment (r = 0.9974, p < 0.001). Bland-Altman analysis showed a discordance between the assays in all tested patients with CHB of 0.09 log IU/mL. CONCLUSIONS: Mean HBsAg levels detected by the Architect assay were higher than those obtained by the Elecsys assay. There was a good correlation between the results of the Elecsys HBsAg II and Abbott Architect HBsAg assays in patients with CHB, especially those with genotype C. PMID- 25807648 TI - Elevated serum total IgE alter the diagnostic performance of radio-immune assays for beta-lactam specific antibody dosing. AB - BACKGROUND: In vivo allergy tests and the detection of drug-specific antibodies are widely used in the diagnosis of beta-lactam induced immediate-type hypersensitivity reactions. The diagnostic performance of immunoenzymatic tests for the demonstration of serum-specific IgE (IgEs) antibodies is influenced by total IgE values (IgEt). The aim of this study was to investigate whether the result obtained by radioimmunoassays (RIA) for beta-lactams IgEs antibodies is correlated to IgEt. METHODS: 68 paired in vivo and in vitro tests were performed for the culprit drugs in 49 patients with suspected previous hypersensitivity reactions to beta-lactams. 14 controls who tolerated the tested antibiotics were similarly investigated. The dosing of IgEt was performed using the Immulite Immunoassay (Siemens). We detected IgEs using a sandwich-type RIA with sepharose as solid phase (Pathologie Cellulaire et Moleculaire en Nutrition, France) and anti-IgEs I(125)-labelled antibodies (Immunotech, Czech Republic). RESULTS: RIA IgEs sensitivity was 56.52% in patients with IgEt < 120 IU/mL and 90.90% in patients with IgEt > 120 IU/mL (p = 0.0052). All patients with IgEt > 500 IU/mL had positive RIA results. RIA-IgEs specificity was 90.90% for IgEt < 120 IU/mL and 66.66% for IgEt > 120 IU/mL. The linear equation that fits the relation between IgEt and IgEs is: IgEs = (IgEt + 81.644)/137.94, with a correlation coefficient of 0.4. CONCLUSIONS: Serum total IgE alter the diagnostic performance of radioimmunoassays for beta-lactam specific antibody dosing. Assays for the detection of both IgEt and IgEs need to be performed for each individual investigated, retrospectively, to confirm clinical immediate-type hypersensitivity reactions. PMID- 25807649 TI - High resolution melt analysis, DNA template quantity disparities and result reliability. AB - BACKGROUND: Disparities in DNA template quantity across sample wells is a common occurrence in PCR experiments and a frequent cause of bogus results in research and diagnostics. High Resolution Melt (HRM) analysis, a robust genotyping technique, was shown to be highly reproducible irrespective of the reaction volume and DNA template concentration used for PCR. The aim of this study is to determine if HRM can maintain its reproducibility/reliability when varying amounts of starting DNA templates are utilized for the upstream PCR. METHODS: Serial dilutions of differentially prepared DNA templates were amplified and subjected to HRM analysis using the ABI 7500 Fast Real Time PCR machine and the ABI HRM software v2.0.6. The first serial dilution set consisted of seven 1:2 serial dilutions of amplicon-enriched DNA templates from two samples of known genotypes at exon 9 of PIK3CA, while the second serial dilution set consisted of four 1:10 dilutions of two different template types from the same sample: original FFPE DNA template and amplicon-enriched DNA template. RESULTS: HRM analysis was reproducible across two- to one thousand-fold difference in starting DNA template in the upstream PCR, so long as the starting DNA template is of ample quality and quantity to give an adequate PCR amplification. CONCLUSIONS: HRM is highly reliable in the presence of a wide variation in the amount of starting template across wells for the upstream PCR, and the factor that determines HRM reproducibility is the adequacy of the PCR amplification. PMID- 25807650 TI - Association between glutathione S-transferase M1 and T1 polymorphisms and colorectal cancer risk in patients from Kazakhstan. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide and the incidence is increasing in developed as well as developing countries including Kazakhstan. Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. In this case-control study the influence of GSTM1 and GSTT1 polymorphisms on CRC risk in Kazakhstan population were evaluated. METHODS: Blood samples were collected from patients diagnosed with rectal or colon cancer (300 individuals) as well as a control cohort of healthy volunteers (300 individuals), taking into account the age, gender, ethnicity, and smoking habits of the CRC patients. Deletion polymorphisms were genotyped employing a multiplex PCR amplification method. Association between polymorphisms and CRC susceptibility risk was calculated using multivariate analysis and logistic regression for odd ratio (OR). RESULTS: The homozygous GSTM1 null genotype was associated with significantly increased risk of CRC (OR = 2.01, 95% CI = 1.45-2.79, p = 0.0001) while the homozygous GSST1 null genotype was not associated with the risk of developing CRC (OR = 1.10, 95% CI = 0.78-1.55, p = 0.001), but the heterozygous genotype correlated with CRC susceptibility (OR = 1.98, 95% CI = 1.30-3.00, p = 0.001). Also, separate analyses of each of the main ethnic groups (Kazakh and Russian) showed a strong association of GSTM1 null genotype with CRC risk (for Kazakhs OR = 2.36, 95% CI = 1.35-4.10, p = 0.006 and for Russians OR = 1.84, 95% CI = 1.17-2.89, p = 0.003). The CRC risk of GSTM1 null genotype in smokers was considerably higher (OR = 3.37, 95% CI = 1.78-6.38, p = 0.0007). The combination of the GSTM1 and GSTT1 null genotypes in combined mixed population of Kazakhstan showed a trend to increasing the risk of developing CRC (OR = 1.60, 95% CI = 1.00 2.56), but it was not statistically significant. CONCLUSIONS: In conclusion, the results of this case-control study for sporadic cases of CRC show that GSTM1 deletion polymorphisms can have predictive value for susceptibility to CRC (OR = 2.01, p = 0.0001) for the mixed population from Kazakhstan and for both main ethnic groups (Kazakhs and Russians (OR = 2.36 and OR = 1.84, respectively)). PMID- 25807651 TI - A comparison study between two analyzers for determining serum ferritin. AB - BACKGROUND: The measurement of serum ferritin (SF) is generally considered to be a reliable indicator of iron status in vivo. The accurate assessment of SF concentration promoted us to evaluate the analytical performance of two automated immunoassays. METHODS: A total of 125 different concentrations of clinical samples were routinely collected and determined by two analytical systems: the Architect i2000 system from Abbott Laboratories and the Cobas E601 from Roche Diagnostics. We evaluated the analytical performance of the two systems and compared the measurements of SF results, which covered the whole analytical range. RESULTS: The analytical performance and accuracy of the two systems were fairly good, and a satisfactory correlation was achieved between the two methods (r = 0.99), but Bland-Altman analysis suggested that the Cobas E601 was, on average, 60.6 ng/mL higher than the i2000, with wide limits of agreement (95% limits of agreement: -78.3 to 199.5 ng/mL). CONCLUSIONS: These findings suggested that the two methods had good correlation but were not interchangeable. Patients should always be monitored for SF with the same method and it should be indicated in the report. PMID- 25807652 TI - Elevated oxidative stress monitored via the albumin-thiol redox state is correlated with matrix metalloproteinase-3 elevation in patients with rheumatoid arthritis. AB - BACKGROUND: In rheumatoid arthritis (RA), matrix metalloproteinase-3 (MMP-3) and oxidative stress contribute to joint destruction. However, little is known about the relationship between MMP-3 and oxidative stress in RA. METHODS: We measured the albumin-thiol redox state as a marker of oxidative stress, MMP-3, and the DAS 28 score calculated using CRP values among forty-seven patients (9 males and 38 females) with RA. According to the serum MMP-3 levels, they were divided into two groups (group A: within normal ranges of 36.9-121.0 ng/mL for men and 17.3-59.7 ng/mL for women; group B: above normal ranges). RESULTS: The albumin-thiol redox state in group B was significantly oxidized compared with that in group A (p < 0.01). The percentage of oxidized albumin-thiol showed a positive correlation with serum MMP-3 (r = 0.52). DAS-28 and CRP were also correlated with the percentage of oxidized albumin-thiol (r = 0.46, r = 0.44). CONCLUSIONS: The albumin-thiol redox state was significantly oxidized in correlation with serum MMP-3 elevation in RA. PMID- 25807653 TI - Systemic mastocytosis with recurrent anaphylactic shock and multiple organ dysfunction failure. AB - BACKGROUND: Systemic mastocytosis (SM) is a rare neoplasm. The symptoms of this disease vary among patients. The authors describe a rare case of SM with recurrent anaphylactic shock and multiple organ dysfunction failure. METHODS: Hematologic investigation, bone marrow aspirate and biopsy, and cytogenetic analysis were performed. RESULTS: The patient was rescued with positive treatment, administered on prednisolone and H1/H2-receptor blocking agents. Corticosteroid and IFN-alpha treatment have no significant effect on tumor burden, but no more anaphylactic shock occurred. CONCLUSIONS: Cladribine and imatinib are recommended to treat SM patients to obtain a better therapeutic effect. Maybe allogeneic hematopoietic stem cell transplantation is a cure for SM. PMID- 25807654 TI - E255K and G250E mutation appearing in a patient with e19a2 chronic myeloid leukemia resistant to imatinib. AB - BACKGROUND: Chronic myeloid leukemia (CML) with the e19a2 transcript coding for p230 is a rare disease. ABL1 kinase domain mutations in CML with the e19a2 rearrangement were seldom reported. METHODS: The clinical characteristics of a 45 year-old Chinese female CML patient with e19a2 BCR/ABL1 transcript were described. The mutation on the ABL gene exons was determined by sequencing the cDNA of the MU-BCR-ABL fusion product. RESULTS: This patient developed an acquired resistance associated with two p-BCR/ABL1 mutations (E255K and G250E) during treatment with imatinib. CONCLUSIONS: Here, we report a CML patient with e19a2 transcripts, carrying E255K and G250E mutation and experience of nilotinib treatment. The MU-BCR/ABL1 mutation should be investigated after imatinib treatment failure. PMID- 25807655 TI - The significance of detection of serum miR-423-5p and miR-484 for diagnosis of colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is a severe disease with considerable morbidity and mortality. Stable presence of miRNAs in serum enables them to be biomarkers for early diagnosis and surveillance of the progress of CRC. METHODS: The blood samples of 53 CRC patients of I-IV stage pre therapy and 50 controlled healthy people were collected and total serum RNA was extracted. The level of miR 423-5p and miR-484 in serum were detected by qPCR. RESULTS: In stage I-II CRC, serum miR-423-5p was significantly elevated compared with the control, whereas miR-484 was attenuated. In stage III-IV, no significance difference in miR-423-5p level was found between CRC patients and the control, and miR-484 level increased dramatically. CONCLUSIONS: The study provides the possibility that the detection of miR-484-5p and miR-484 may be a useful method for early diagnosis and surveillance of the progress of CRC. PMID- 25807656 TI - Assessment of an expert system for the automated validation of electrophoretic profiles. AB - BACKGROUND: The Core-lab of the Greater Romagna Area Hub Laboratory carries out about 250,000 capillary electrophoresis assays/year. The huge workload demands the assessing of an Experimental Expert System (EES) capable to sort out the negative samples. METHODS: Capillarys 2 analyzer has been employed coupled with an EES (based on five simple rules) integrated with the electrophoretic test management software PhoresisCore for assessing the entire workload of a week (5,683 samples). The classification was compared with that of two expert laboratorians. RESULTS: The expert system automatically classified 2974 profiles as negative and no positive samples were erroneously classified as negative (negative predictive value: 100%). CONCLUSIONS: The EES sensitivity was 100% and the FTE required for the validation was reduced from 1.26 to 0.63. The EES could be easily implemented in routine activity embedded in a middleware or directly running in the analyzer improving the workflow. PMID- 25807657 TI - Rapid diagnostic tests apply for pediatric infections at outpatient clinic setting. AB - BACKGROUND: Early identification of the etiology of infection is beneficial. Most infections are treated as outpatients. However, facilities for rapid diagnosis are not available in clinic settings. METHODS: We applied Immunochromatography (IC) and Loop-mediated Isothermal Amplification (LAMP) methods to rapidly diagnose pathogens among 31 children with respiratory infection and 12 with gastroenteritis at a clinic in Saitama prefecture, Japan. Pathogens were then screened by multiplex conventional and real-time PCRs and bacterial culture. RESULTS: Respiratory pathogens were found in 64.5%. Despite the narrow spectrum, rapid tests identified pathogens in 28.6% of cases with a high agreement rate of 89.3% with PCR. Gastroenteritis pathogens were found in 66.7%. E. coli was positive in 3 cases and all were negative for verotoxin by LAMP. The agreement rate of IC and PCR assay was high, 100%. CONCLUSIONS: IC and LAMP are reliable and suitable methods in limited-resource settings for early pathogenic identification, which will help appropriate management, avoid unnecessary intervention, and cost saving. PMID- 25807658 TI - Avian influenza H7N9 and low thyroid hormone. PMID- 25807659 TI - Improving detection rates without influence on blood waste rate utilizing gray zone for hepatitis C virus antibody assay. PMID- 25807660 TI - Investigation of common blood cell parameters in prolonged closure time of PFA 100 test in Korean patients with various disease conditions. PMID- 25807661 TI - [Pharmacology in ancient Rome. First appearance, development, extension]. AB - The history of Roman pharmacology is ponctuated with ideological debates about relevance of this art. Thus, Hippocrates --a contemporary of Socrates who was teaching that "science of remedies and science of poisons are the same"--was given credit for favourable mood towards pharmaceuticals by Scribonius Largus on the basis of therapeutic complementarity. Among the Latin doctors of the late Roman Empire, Marcellus Empiricus and Caelius Aurelianus, Hippocrates appeared as an authority favourable towards medication, especially in a fictitious letter written by Marcellus to the Claudian emancipated slave Callistus. Likewise, popular philosophy has taken over the Socratic antinomy between remedia and uenena. Last but not least, Sextius Niger wrote a pharmacopoeia attested as an official source by Celsus and plentifully consulted by Pliny the Elder: the Naturalis historia allows to delimit Sextius' contribution to the recurring controversy about use of pharmaceuticals. In such a context, the antipharmaceutical argument entered by Asclepiades of Bithynia fulfils a provocative function, the historical impact of which needs to be assessed according to the present-day speculation about "useful, useless or dangerous medicines". PMID- 25807662 TI - [Lorraine pharmacy historians]. AB - The most known historian was Paul Dorveaux, but precursors were Husson during the 19th century and Grelot at the beginning of the 20th century. The best period for historical researchs was the twenty years between 1920 and 1940, then the creation of the "diplome d'Etat de docteur en pharmacie" at the end of the century. Two professors, Andre Meunier and Jean Martin, managed historical thesis. They leaved us useful thesis on the past of our profession. PMID- 25807663 TI - [Eugene-Humbert Guitard and French Institute of History of Science (1932-1939)]. AB - Named "membre-conseil" of the French Institute of History of Science in April 1932, Guitard gives there, from January 1935 to February 1939, a dozen history of pharmacy conferences. Those conferences will give birth to her especially valuable Manuel d'histoire de la litterature pharmaceutique, published in 1942 by Caffin. The author re-examines this intellectual adventure. PMID- 25807664 TI - [Cosmetic innovations in the Guerlain patents deposited in the XIXth century]. AB - The XIXth century was the century of the development of hygiene, cosmetics industry, chemistry and modern pharmacy. After the French revolution, a new legislation establishes a law of recognition of the property of the inventors on their inventions. This paper describes the content of patents and certificates deposited in the XIXth century at the INPI, french national institute of the industrial property, by the creators of Guerlain, a luxury brand of perfumes and cosmetics. This paper allows to discover the variety of the inventions which recovers whitening lotion, soaps, ingenious devices and new perfume substances. PMID- 25807665 TI - [An apothecary from the Cevennes region on the rolls of Oriental Pyrenees Army in 1793]. AB - In 1793 during the french Revolution, the decret of February 23rd orders a big recruitment of 300 000 people. The city of Ales (Cevennes) has to supply ninety seven soldiers to establish the battalion of the Gard. They will be allocated to the "Armee des Pyrenees-Orientales" (Army of the Eastern Pyrenees) which is going to defend the border with Spain. These armies have to face the influx of wounded persons but especially the devastation of the epidemics. Besides the soldiers, are enlisted the officers of health, the doctors, the surgeons and the pharmacists. So the city of Ales indicates to be of use to this army the youngest of the doctors, freshly honed of the university of Montpellier and two old pharmacists (51 y. and 61 y. old). They were allocated to the hospital of Narbonne where they worked to fight against the epidemics, in particular by the disinfection of rooms. The oldest of them succumbed to the disease. Two others, safe and sound income in their home town, played a notables' role. PMID- 25807666 TI - [Pharmacy, one of the emerging sources of new science of technology]. AB - Linking pharmacy and oenology seems to be paradox. The school of Medicine and Pharmacy owe their fame to the historical context of the Languedocian Universities. The role of their naturalist professors is less known. Dr Chaptal's thesis discusses the wine chemical constituents. In 1801 he published a book entitled "the Art of making, managing and perfecting wine", inventor of a distillation machine, his name become an eponym "the chaptalisation", which is specific process, for regions less exposed to sunlight, showing that sugar in the must is needed to obtain alcohol. Jules Emile Planchon, professor of botanic science at the Superior School of Pharmacy will discoverer the parasite disease of the phylloxera, a parasite that destroy vineyards. The cure will be the American grafting. The list of professors who worked on vineyards related frauds and diseases is long. Once Analytical chemistry has become part of the curriculum universities, pharmacists, started investigating wine analysis. It will be part of Bromatology, the science of food ingredients. Pharmacists were then able to carry out the first wine analyses sin their laboratory. It is at that time that Paul Jaulmes, professor of Analytical Chemistry who became Director of the international office of vineyards and Wine (OIV) proposed alongside Prof Negre, director of the National School of Agronomy, the initiation in 1955 of a new diploma oenology. As a renowned toxicologist, Prof. Jaulmes will lead the committee in charge of the oenology Standards. PMID- 25807667 TI - Histological pattern of thyroid gland neoplasms in Kano, Northern Nigeria. AB - BACKGROUND AND OBJECTIVE: Thyroid gland neoplasms occur globally with geographical variation in incidence and histopathological pattern related to age, sex, dietary and environmental factors. There is, however, no published histological study from northwestern Nigeria; hence, the need for this retrospective study to document the pattern in Kano. MATERIALS AND METHOD: This was a retrospective study of all histologically diagnosed thyroid neoplasms in the Department of Pathology, Aminu Kano Teaching Hospital (AKTH), Kano Nigeria, over a ten year period from 1st January, 2002 to 31st December, 2011. RESULTS: A total of 522 thyroid specimens (1.5% of all biopsies) were received over the ten year period. Thyroid neoplasms accounted for 157 (30.1%) of all the thyroid specimens, comprising 130 females (82.8%) and 27 males (17.2%) with female to male ratio of 4.8:1. The ages range from 15 to 80 years with a mean age of 35.8 years and peak occurrence in the 4th decade. There were 82 cases (52.2%) of thyroid adenoma (mostly follicular) while thyroid carcinoma accounted for 66 cases (42%). Papillary carcinoma predominated (53%) followed by follicular carcinoma (33.3%) and medullary carcinoma (9.1%). One case each (1.5%) of anaplastic carcinoma, squamous cell carcinoma and metastatic squamous cell carcinoma were seen. All the malignant tumours were epithelial and all except one were primary thyroid malignancy. CONCLUSION: Thyroid neoplasmis a common thyroid gland lesion in Kano with a striking female preponderance. Thyroid adenoma was the most common benign neoplasm while papillary carcinoma seen a decade earlier in females was the most common malignant thyroid neoplasm. The predominance of papillary carcinoma over follicular carcinoma is a reverse of the finding of an earlier clinicopatholgical study on thyroid gland diseases in Kano. PMID- 25807669 TI - Sexual behaviours and contraceptive use among female secondary school adolescents in a rural town in RiverS state, South-south Nigeria. AB - BACKGROUND: According to World Health Organization (WHO), adolescents are persons aged 10-19 years. They comprise nearly half of the world's population of about 7 billion and 85% of them live in developing countries. AIM: The aim of this study is to assess the sexual behaviours, practices and contraceptive use among secondary school adolescents in Elele, Rivers State, Nigeria. METHOD: A cross sectional descriptive study of 300 in-school adolescents in a rural community in Rivers State, South-South Nigeria, selected using multi-stage random sampling technique. RESULTS: There was a high awareness of contraception among respondents, 235 (78.3%), with condom, 207 (88.1%), having the highest awareness. About forty-five percent of respondents, (134), in this survey have had their first sexual debut and 84.3% of this number was sexually active in the last six months preceding this survey. The mean, median and the modal age of first sexual debut were; 12.0 + 2.8, 12.6, and 12.4 years respectively with the youngest age of initiation of sexual activity being 5 years. About two-thirds of those sexually active have multiple sexual partners. Contraceptive use was statistically higher among the sexually active respondents, (74.3%), than the sample study population, (30.3%), (Chi2 = 65.08, p = 0.000). Condom use at their last sexual debut, (58.2%), was significantly higher than use in their first sexual debut (31.3%), (Chi2 = 16.17, p = 0.000). The most commonly used contraceptive method was condom, (81.7%). CoNCLUSION: High risk sexual behaviour and increased sexual activity was prevalent in this age group. Efforts to promote sexuality education and contraceptive awareness should be intensified. PMID- 25807668 TI - The prevalence of clinical presentations and pathological characteristics of antrochoanal polyp. AB - OBJECTIVE: Antrochoanal polyps (ACPs) originating from the maxillary sinus, are considered as benign inflammatory lesions. In fact, these polyps are the hypertrophy of the mucous membrane of the maxillary sinus, which for unknown reasons grow through the maxillary sinus ostium towards the other portions of the nasal cavity and the choana, such a way that they may grow all the way to the nasopharynx and even oropharynx. ACP is usually unilateral however, the bilateral forms have been observed in some instances. Its most frequent clinical manifestations are nasal obstruction and rhinorrhea, whereas in many cases some other presentations such as epistaxis, dyspnea, and dysphagia, and weight loss have been also noticed. The aim of this study was to investigate the relative prevalence of clinical manifestations and pathological characteristics in 87 patients with ACPs during a period of 15 years in this hospital. METHODS: It was a descriptive cross-sectional study, accomplished retrospectively, and based on existing data in the records of the patients admitted in Imam Khomeini Hospital of Ahvaz. In this study, the patients above 16 years old have been considered as adults. Each patient's data were collected using a questionnaire. Data analysis was performed by the statistical SPSS software (descriptive statistics and Chi square test). RESULTS: 87 patients were registered with the diagnosis of ACP during 1999 and 2014. Out of these patients 60% were females and 40% were males. Predominant clinical manifestation was nasal obstruction with an incidence of 39%; and the least frequent manifestation was weight loss with an incidence of 0%. Moreover, the left nasal cavity was more involved with the incidence of 55%. Among the existing surgical techniques. Functional Endoscopic Sinus Surgery (FESS), Caldwell- Luc procedure, and combined approach were the most common applied techniques,with frequencies of 64%, 24% and 12%, respectively. Confidence Interval (CI) = 0.03 +/- 0.2, Odd ratio = 0.26, and p = 0.21. CONCLUSION: Nasal obstruction was the predominant clinical symptom of ACP. The left nasal cavity was more involved than the right-side. FESS was the commonest employed surgical procedure; and the inflammatory pattern has been the most pathological presentation. PMID- 25807670 TI - Role of warm saline mouth rinse in prevention of alveolar osteitis: a randomized controlled trial. AB - BACKGROUND: The present study was aimed at determining the role warm saline rinse in the prevention of alveolar osteitis following dental extractions. MATERIALS AND METHODS: Apparently patients aged 16 and above who were referred to the Oral Surgery Clinic of our institution, with an indication for non-surgical extraction of pathologic teeth were prospectively and uniformly randomized into warm saline group and control. The experimental group (n = 80) were instructed to gargle 6 times daily with warm saline and no such instructions were given to the second group (n = 80) to serve as controls. Information on demographic, indications for extraction, and development of alveolar osteitis were obtained and analyzed. Comparative statistics were done using Pearson's chi square or Fisher's exact test as appropriate. A p value of less than 0.05 was considered significant. RESULTS: The demographic and other baseline parameters such as indications for extractions were comparable among the study groups (p > 0.05). The overall prevalence of alveolar osteitis was 13.7%. There was a statistical significant difference between the study groups with respect to development of alveolar osteitis (X2 = 15.00, df = 1, p = 0.001).The risk of development of alveolar osteitis was 4 times higher in the control group (OR = 4.33, P = 0.001). CONCLUSION: Warm saline mouth rinse instruction is beneficial in the prevention of development of alveolar osteitis after dental extractions. PMID- 25807671 TI - Childhood rhabdomyosarcoma in Kano, Nigeria: a retrospective analysis of 52 cases. AB - BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma in children <= 15 years of age. There is, however, a paucity of reports on the pattern of its occurrence in Nigeria and other parts of Africa. OBJECTIVE: The aim of this review is to highlight the age and sex distribution, anatomical location and morphological characteristics of rhabdomyosarcoma among children in Kano, northwestern Nigeria. PATIENTS AND METHOD: This is a 14 year retrospective study of all cases of rhabdomyosarcomas occurring in children diagnosed at the Pathology Department of Aminu Kano Teaching Hospital, Kano, Nigeria. Clinical data obtained included sex, age, tumour site and histologic subtype. RESULTS: Fifty two children were seen with a male to female ratio of 1 : 1.3. The ages of these Patients ranged from 4 months to 15 years with a mean (SD) age of 6.99 (4.1) years and peak age frequency in the 0 to 5 years age group. The embryonal variant was the most common histological subtype (69%). The others were alveolar (27%) and pleomorphic (4%) variants. The head and neck was the most affected region (44%) and the most common primary site was the orbit (19.2%). CONCLUSION: Rhabdomyosarcoma is the most common childhood soft tissue sarcoma in Kano. It occurs in females more frequently than males and the most common histologic subtype is embryonal rhabdomyosarcoma affecting predominantly the orbit. PMID- 25807672 TI - Assessment of awareness, perception and utilization of health services among patients attending clinic at the Muslim Ummah Hospital, Kisi, South-west, Nigeria. AB - BACKGROUND: Health has been a prime concern of humanity since the dawn of history. People aspire to improve their health and also that of their household and communities. Healthcare utilization by the community is greatly influenced by their awareness and perception. METHODOLOGY: A descriptive study of the Awareness, Perception and Utilization of the Muslim Ummah Hospital, Kisi was carried out using a structured, interviewer administered questionnaire. Three hundred and eighty (380) participated in the study. A systematic sampling technique was utilized in sample selection. RESULT: The mean age of respondent was 36.9 + 2.95 years. Female respondents constituted 58.92% while the male counterpart were 41.08%. Awareness among the respondents is quite encouraging, as 198 (52%) of women respondents showed knowledge of the presence of the health center. A total of 38.1% (145) believed the service is very good while only 6.5% (25) considered it to be poor. On utilization profile 56.7% (215) had one time or the other attended the Outpatient Department; 43 (11.3%) for General Surgery, 7.4% (28) immunization, 15.4% (59) Delivery service and 9.2% (35) for Antenatal care. CONCLUSION: Health service utilization of the Muslim Ummah Comprehensive Hospital was shown to be greatly influenced by the community awareness of the service provided and their perception of the quality of service. PMID- 25807673 TI - Job-related risk factors for low back pain in adults attending a tertiary hospital in Uyo, Nigeria. AB - BACKGROUND: Low back pain is a common musculoskeletal disorder. However, there is very little information about low back pain in the general population in developing Countries. This study was aimed at identifying the job-related risk factors for low back pain in adults attending the General Out-patient Clinic of the University of Uyo Teaching Hospital, Uyo, Nigeria. METHODS: A cross-sectional study design was utilized. A structured questionnaire was used to obtain information from Four Hundred (400) consenting adults aged 18 years and above, attending the General Out-patient Clinic of University of Uyo Teaching Hospital from May 2011 to July 2011. The data obtained was analyzed using Epi Info statistical software version 3.2.2. RESULTS: The mean age of the subjects was 38 +/- 14.2 years. There were 176 male subjects and 224 female subjects in ratio 1:1.3. The prevalence of low back pain was 31%. Statistically significant job related risk factors were heavy lifting activity (Chi2 = 27.52, P = 0.0001) and stressful jobs (Chi2 = 29.57. P < 0.0001). Low job satisfaction (Chi2 = 1.22, P = 0.26) and prolonged sitting or bending (Chi2 = 0.28, P = 0.50) were not statistically significant. CONCLUSION: This study showed that stressful jobs, and jobs involving heavy lifting activity are significantly associated with low back pain. Health education on proper lifting techniques and the reduction of stress at work should be encouraged. PMID- 25807674 TI - Assessing medical students' perception of effective teaching and learning in Nigerian medical school. AB - BACKGROUND: Medical education is always in a state of dynamic equilibrium with continuous evolution of new techniques in teaching and learning. OBJECTIVES: Objective of this study is to determine medical students' perception on preferences of teaching and learning. METHODS: PARTICIPANTS: A total of 207 medical students participated in the study. Most (73.9%) of them were males while the modal age group was 23-25 years. Majority (57.5%) of the students belong the middle socioeconomic class and 65.7% resided within the hostel. RESULTS: Majority of the students (48.8%) believe two hours is enough to per lecture. Among the five different teaching-learning methods investigated, use of multimedia methods was found to be most effective. There exist a statistically significant association was found only in gender with regular oral examinations (Chi2 = 4.5, df = 1, p = 0.03) and socioeconomic class with dictation of lecture notes (Chi2 = 17.9, df = 9, p = 0.03). CONCLUSION: The present day medical student will end up as a good clinician if modern techniques of teaching and communication skills of the lecturers are adopted. PMID- 25807675 TI - Normal pregnancy and coagulation profile: from the first through the third trimester. AB - BACKGROUND: Normal pregnancy is a hypercoagulable state; a physiological safety valve aimed at preventing excessive maternal blood loss at delivery. OBJECTIVE: To evaluate the influence of normal pregnancy on blood coagulation and to explore changes in activity from the first through the third trimester. SUBJECT AND METHODS: Sixty (60) apparently healthy pregnant women (20 from each trimester) and 20 healthy non-pregnant age-matched controls were recruited. Each participant had Prothrombin time (PT). Activated partial thromboplastin time (APTT) and platelet count done. Multiple comparisons were made between control values and coagulation profile at different stages of pregnancy using the Bonferroni statistics. Results were expressed as means and standard deviations, p < 0.01 was significant at 95 % CI. Ethical approval for the study was obtained from the Institutional review board. RESULTS: The means of the APTT were significantly lower in the first, second and third trimesters compared with controls (35.59 +/- 4.95 seconds, 32.22 +/- 5.79 seconds and 29.60 +/- 3.66 seconds, respectively, vs. 40.55 +/- 5.95 seconds; p = 0.01). Correspondingly, the platelet count was significantly lower in the 3 trimester of pregnancy compared with controls (178.35 +/- 41.52 x 10(9)/L vs. 233.86 +/- 55.34 x 10(9)/L; p < 0.01) and equally with level in the 2nd trimester (178.35 +/- 41.52 x 10(9)/L vs. 232.10 +/- 48.67 x 10(9)/L; p < 0.01). CONCLUSION: The APTT and platelet counts are significantly lower in the 3 trimester of normal pregnancy. PMID- 25807676 TI - Preconception care in a southern Nigeria tertiary institution. AB - BACKGROUND: The concept of preconception care has been evident from ancient times, and had gained momentum over the past two to three decades especially in the developed world. However, this knowledge and practice is almost non-existent in developing countries like Nigeria. STUDY DESIGN: This was a cross sectional survey of 194 antenatal attendees at the University of Port Harcourt Teaching Hospital. RESULT: Only 35.05% of the respondent was aware of preconception care, however 86.60% of them thought it was important and should be encouraged in our society. CONCLUSION: The knowledge of preconception care was generally poor among the studied population and this is directly proportional to their educational status. Education of the girl child and improved counseling will advance preconception care in our environment. PMID- 25807677 TI - Evaluation of serum ferritin levels and blood counts in apparently normal individuals in Nnewi, South-east Nigeria. AB - INTRODUCTION: Serum ferritin levels as well as blood counts are variously affected in diverse disease conditions, particularly those characterized by inflammation. OBJECTIVE: To evaluate the relationship between serum ferritin levels and blood counts in apparently healthy Nigerian subjects. SUBJECTS AND METHODS: Five (5ml) of venous blood was collected for full blood count, malaria parasite, serum ferritin and C- reactive protein (CRP) estimation from 88 apparently healthy subjects. Those positive for malaria parasite (on blood film examination) or had elevated serum CRP were excluded. Statistical analysis was performed with SPSS version 16; (SPSS Inc., Chicago IL). Associations were tested between parameters using Pearson's correlation, set at a coefficient of p < 0.05. Ethical approval was obtained from the Institutional Review Board and all participants gave informed consent. RESULTS: The median, mean and modal ages of subjects were 23.50 years, 25.25 years and 16.00 years, respectively while the mean packed cell volume (PCV), total white blood cell (TWBC), platelet count and serum ferritin level were 0.37L/L, 7.10 x 10(9)/L, 246.39 x 10(9)/L and 18.35 ng/ml, respectively. Age of subjects varied significantly with serum ferritin, platelet count and TWBC (p > 0.05). The PCV, platelet count and TWBC varied significantly across the different age groups of the study population (p < 0.05), likewise the PCV in males, compared to females (p < 0.05). CONCLUSION: Serum ferritin level in our apparently healthy subjects is lower than previously reported but did not vary significantly with blood counts. PMID- 25807678 TI - Epidemiology and clinicopathological characteristics of gastric cancer--the Nigerian setting in view. AB - BACKGROUND: Gastric cancer is the 5th most common cancer globally and the 3rd most common killer cancer, although in Nigeria it is the 9th most common cancer with a dismal prognosis. AIM: To review the epidemiological and clinicopathological features of gastric cancer in Nigeria in the last two decades. MATERIALS AND METHODS: Original articles and review articles published about gastric cancer in Nigeria in the last two decades were reviewed. RESULTS: Most studies that have been done on gastric cancer in Nigeria, and which have been included in this review are hospital-based studies. With the exception of the lower prevalence of the disease and the younger peak age prevalence of gastric cancer in the Nigerian population, the epidemiological and clinicopathological features of gastric cancer are similar to those from other populations. Also, there has been an improvement in the overall survival of gastric cancer in Nigeria over the last three decades. CONCLUSION: The prevalence of gastric cancer in the Nigerian population has remained relatively low over the decades while it continues to share similar mode of presentation with other populations, with some improvement in prognosis. PMID- 25807679 TI - Secondary brain choriocarcinoma: a case report. AB - Choriocarcinoma metastasizes widely. One in every ten choriocarcinoma that leaves its primary site, metastasizes to the brain. This 27 years old patient presented with symptoms of space occupying lesion that was confirmed by CT-SCAN. There was no history of vaginal bleeding and amenorrhoea was concealed by unmarried patient. Chest X-ray was normal. Tumor was excised after craniotomy. Histology of tumor was that of secondary choriocarcinoma. Patient responded excellently to chemotherapy and was well one year after. We strongly recommend a high index of suspicion of choriocarcinoma in management of brain tumors. beta-HCG assay should be included in investigation of all patients with intracranial tumors irrespective of sex. PMID- 25807680 TI - Management of a fully edentulous mandible using an implant supported overdenture: a case report. AB - The choice for rehabilitation of an edentulous mandible by an implant supported overdenture is now the recommended minimally accepted option. This prosthesis has many advantages over conventional dentures and root or tooth supported overdentuers. We present a case of a failed conventional long span bridge which was treated satisfactorily using a four implant supported over denture and discuss our treatment option along with its advantages. This is a new and developing treatment option in our country. PMID- 25807681 TI - Utero-vaginal prolapse complicating pregnancy: a case report. AB - BACKGROUND: Uterovaginal prolapse in pregnancy is an infrequent but potentially harmful condition when not properly handled. There is no standard guideline on its management; however discretion is used to treat individual case on its merit. Vaginal delivery is possible but elective caesarean section seems a better alternative. METHOD: We present the case records of 24 year old Gravid 2 Para 1 + 0 (alive) who presented in labour with a second degree uterovaginal prolapse at term. Literature review using medline and manual library search was done. RESULT: She tested positive to HIV I and II: and had emergency caesarean section for dystocia with the delivery of a live 3.5kg female baby. She was managed conservatively on bed rest, local antiseptics and physiotherapy. She was however lost to follow up. CONCLUSION: Uterovaginal prolapsed in pregnancy is rare. Opinion is divided on delivery options but most are agreed on caesarean delivery and conservative follow up post partum. Prevention of pelvic organ prolapsed through antenatal care, supervised delivery, physiotherapy and fertility regulation remains key to favourable out-come. PMID- 25807682 TI - [Introduction]. PMID- 25807683 TI - [Giovanni Jervis, an intellectual of the second half of 20th century]. AB - Main issues in the scientific work of Giovanni Jervis (1933-2009), psychiatrist, psychoanalyst and psychologist, are outlined. Although he was one of the leading members of the movement for abolishing the psychiatric institutions in Italy from the '50s to the '70s, he distinguished himself for his critical and rigorously scientific approach to the problem. His research was characterized by an historical view of the development of psychological processes and psychopathological phenomena, and according to him psychology and psychiatry theories (and especially psychoanalysis) should always be considered as historically-determined attempts to understand the human mind. In the last period of his scientific activity, Jervis was particularly engaged in a critical analysis of postmodern and relativistic theories of science, and strenuously attacked at second-hand ways of dealing with scientific, social and political questions. PMID- 25807684 TI - Scientific method, history, Darwinism and laicism: a Giovanni Jervis's intellectual biography. AB - Some authors marked a change of perspective from the early to the late Jervis's thought, in terms of a supposed turn towards conservatism. That laid him open to criticism from some Leftist Italian intellectuals. The aim of this paper is to show that conservatism never was a Jervis's thought feature. Mainly, subjects and methods leading the development of his philosophical views suggest a continuity between earlier writings and later ones. All over his thought, in fact, the idea of preeminence of scientific method and historical contextualization convinced him about naturalistic approaches to human behavior, which came to support his Darwinism and laicism in approaching socio-psychological and socio-political issues. PMID- 25807685 TI - [Present and past: Jervis' interest for history]. AB - The mid-1970s saw in Italy a growing interest for the history of psychiatry, both among historians and psychiatrists, often in the context of the mounting struggle for the abolition of asylums. My aim here is to show the originality of Jervis' position in this regard. Already in 1967, in a period dominated by silence over the past of psychiatry, Jervis affirmed the importance of history for the critique of the present. His warning remained crucial in the following years; as the psychiatry looked at the past mostly in order to condemn it, Jervis emphasised the importance of understanding historical change, both in the distant and recent past. Looking at Jervis allows us to engage with history and memory, ideological diatribes and reassessments. It is in this perspective that several of his writings are examined here, encompassing both historical analyses and occasional autobiographical and personal notes. PMID- 25807686 TI - [Giovanni Jervis: critical conscience of the Italian psychiatric reform]. AB - Giovanni Jervis, was one of the protagonist of the Italian psychiatric reform and was greatly involved in all the phases of its development, but, with his typical intellectual rigours, he was also very critical not toward the law 180 which abolished the shame of psychiatric asylums, but rather toward the ways of leading and governing the global reform process. In this paper four aspects of Jervis critical evaluations are emphasised: a) the criticism toward a "totalitarian" conception considering practices and everyday institutional management as the unique ways to research problem solutions; b) the criticism toward a renewal process exclusively focused inside the psychiatric hospital, which led Jervis to organise one of the most important outside experience in the Reggio Emilia territory; c) the criticism toward a sociological conception of mental illness, disregarding the subjective, psychological and relational aspects of the psychic suffering; d) the criticism toward the inadequacy of the mental health workers formation, which must become the basis of a real transformation of the "public services culture". PMID- 25807687 TI - [Giovanni Jervis' thought about helping relationship]. AB - The author describes Giovanni Jervis' thought about helping relationship starting from considering how he received inspiration from Jervis himself in developing a way of practising psychiatry which is always careful and respectful of others and of everyday life policy. The construction of mental wellness is a dynamic process that is pursued all life long: it concerns the way we work as well, on the one hand to overcome or at least to mitigate mental disorders, on the other hand to preserve the mental endurance of a Mental Health Department and its workers. Institutional therapy therefore maintains with realism and without idealistic illusions this double "maturity" goal, without because of this indulging in pessimism on human nature and on incurability: these pessimisms too often have had and still have an auto-justifying function for doing nothing or doing wrong. PMID- 25807688 TI - [Pinocchio and the unattained identity: Jervis' contribution to child clinical psychology]. AB - Giovanni Jervis is mainly known as a psychiatrist, but he also worked on psychological methodology and tackled important issues in clinical psychology. This essay describes the concept of personal identity elaborated by Jervis and its importance in Child Clinical Psychology. The problems related to personal identity appear very early in Jervis' work, influenced by the ethnologist Ernesto De Martino. His first considerations are found in his Preface to The Adventures of Pinocchio by Carlo Collodi (1968), in which Jervis describes the unhappy upbringing, the anti-social behaviour, and the unattained identity of the wooden puppet. Subsequently, in Presenza e identith (1984), Fondamenti di Psicologia Dinamica (1993) and La conquista dell'identith (1997), Jervis dealt with the theme of identity from a Dynamic Psychology perspective, showing that the formation of personal identity is a basic aspect of the development of the individual that starts in early childhood. PMID- 25807689 TI - Illness, body and relationship: Giovanni Jervis and the field of clinical psychology. AB - Unlike most of his contemporaries, Jervis felt it was necessary to give new answers to last century's clinical psychology crisis. He managed to show the relevance that psychological knowledge coming from other sectors (such as philosophy, evolutionary biology, cybernetics, ethology and, nowadays, neuroscience) could have for clinical psychology. He realized that the clinical world was at risk of loosing its cultural models of reference and threatened to break up with the scientific tradition with which it had not been able to establish a profitable dialogue. Jervis' views on mental functioning allowed him to delimit the field of action of clinical psychology. The focus on pathology and existential distress suggested that correct clinical evaluation and diagnosis are at the core of the activity of clinical psychologists. The tension between relational expectations, self-deceptive aspects of identity and the bodily sources of mental life show the dynamic field on which clinical psychology can deploy its transformative action. PMID- 25807690 TI - [Dynamic psychology and psychoanalysis in Giovanni Jervis' thought]. AB - As against the background of an unconditioned reception of Darwinian theory and its developments, mainly in the field of ethology, a reflection deploys itself on complex theoretical themes, such as identity, consciousness and motivation. This leads Jervis to deal not only and not as much with psychoanalysis, as with a broader theoretical framework, labelled as "dynamic psychology". Contributions from different fields of contemporary psychological knowledge, particularly from cognitive sciences, personality and social psychology and developmental observations converge into this new framework. A proposal is made that is characterized by a peculiar critical sensitivity and is open to future developments. It is in this new light that Jervis was able to carry out a retrospective recognition of the century of Psychoanalysis. PMID- 25807691 TI - [Jervis and scientific research in psychoterapy: reflections on the problem of plurality of research methods]. AB - It is documented that psychotherapy and its scientific investigation interested Giovanni Jervis since the early 1960s. In this paper an aspect of psychotherapy research that attracted Jervis' interest is discussed. While there is more agreement on the hierarchy among the various methods of outcome research in psychotherapy, it is argued that in the field of process research the discussion on how the many process methods should relate to each other is still open. It is not clear which method is "superior" or "more useful" than others in understanding and measuring behaviour change. This problem is discussed also in its epistemological aspects, e.g., regarding the knowledge of "reality" (the patient's mind) and the eye(glasses) we have (the research methods or "lens" we use). A subdivision of the methods of psychotherapy process research into "thematic" and "structural" methods, used also for the classification of projective tests in personality psychology, is suggested. PMID- 25807692 TI - [Jervis and Timpanaro on psychoanalysis and materialism]. AB - Jervis and Timpanaro have been two influential figures of the Italian culture in the second half of the Twentieth Century. They never met, although they talked to each other regularly at a distance, as they shared many interests, in particular on the topics of the scientific status of psychoanalysis and on a coherent definition of materialism. Their epistemological and ontological views are clearly connected to Italian '60s and '70s philosophical climate dominated by the discussion on Marxism, and for this reason they might seem obsolete. However, especially from Jervis' views, one can draw important suggestions for the philosophy of human sciences, in the direction of a non-reductionist "scientism". PMID- 25807693 TI - Troubles with self-consciousness. Jervis on introspection and defense mechanisms. AB - Building on Sigmund Freud, Ernesto de Martino and cognitive sciences, Giovanni Jervis has outlined a view of introspective consciousness as primarily an activity of narrative re-appropriation of the outputs of the unconscious cognitive processing, emphasizing that such an activity is ruled by the primary need to construct an identity that is valid as much as possible. Thus Jervis has originally pursued an integration between the anti-introspectionist tradition in cognitive sciences and the psychodynamic investigation on defense mechanisms. This paper outlines Jervis' attempt to integrate these two traditions, and shows that it fits very well with recent developments of the theory-theory approach to self-knowledge. PMID- 25807694 TI - [The matter of human. Jervis, De Martino, Callieri]. AB - In this text we will examine the theoretical relationships between Ernesto De Martino's anthropological concept of "end of the world", and the experience of "end of the world" which has been investigated in some schizophrenic experiences by two Italian psychiatrists and collaborators of De Martino: Giovanni Jervis, who studied this experience in a clinical e biological perspective, and Bruno Callieri, who studied it in a psychopathological and phenomenological perspective. These complex relationships between De Martino, Jervis and Callieri are, on the other hand, an occasion for a more comprehensive meditation on the paradigms, and the underlying tasks, of today's human sciences. PMID- 25807695 TI - [Hermeneutics and relativism]. AB - Giovanni Jervis left us. There is only one way to cope with the irremediable separation: to give voice to what he said and wrote, by keeping open among us questions he asked, because they are also ours. In this dialogue with Giacomo Marramao let me begin with certain passages of the essay Psychoanalysis as a Critical Exercise that Jervis published in 1989. In the second part of the intervention I will try to explain why, in my opinion, hermeneutics cannot be equated with "relativism". PMID- 25807696 TI - [Darwin versus Marx? Reflections on a book by Giovanni Jervis]. AB - Giovanni Jervis'2002 book Individualismo e cooperazione. Psicologia della politica [Individualism and Cooperation: Psychology of Politics] is the outcome of a critical reflection begun by the author at the end of the 1970s in order to explore the manifestations and the problems of cooperation between individuals, and to identify some "universal" psychological factors that could define the role of psychology within politics and constitute an "objective foundation" of any human culture. Although Jervis was, so to speak,favoring Darwin against Marx, it is argued that,from his overall reasoning, several of his arguments actually are in favor of the inevitable "historicity" of individuals, due to the social conditioning they are subjected since birth: too often certain "universalistic" approaches transmit, together with scientific advances (or even without them), well identifiable ideological motives linked to precise and well defined historical and economic interests? PMID- 25807697 TI - [Introduction]. PMID- 25807698 TI - [Brief history of paleopathology in Italy]. AB - In the last decades, paleopathologists have developed a growing interest in archaeological, anthropological, and medical disciplines. However, although there have been satisfactory results, which are reflected in numerous publications at the international level and in academic credits that,for example, have led to the establishment of an autonomous Division of Paleopathology (unique in an Italian University) at the Faculty of Medicine in Pisa, the future seems not so bright. Indeed, the lack of general interest that Italian institutions have shown toward research and the reduction of ministerial financial support, will result not only in a lack of a generational turnover among researchers, but also in the suspension or closure of the few paleopathology courses that are now running, and in the layoff of the small but excellent study groups currently working in the field. PMID- 25807699 TI - [Tumors in paleopathology: evidences from mummies]. AB - The relative abundance of neoplastic lesions documented so far in paleopathological literature, distributed over a wide lapse of time and in different geographic areas, demonstrates that a number of tumours affected past populations. Nevertheless, if dozens of cases of tumors affecting the skeleton are reported, only afew records are documented in soft tissues. The rarity of tumors in mummies is a debated problem; short life span of past populations, scarcity of mummified remains arrived to us in comparison with skeletal remains and technical difficulties to detect neoplastic lesions in ancient tissues seem to be the main reasons of the rarity of findings. It is important to pay maximum attention to any little sign of neoplastic lesion in ancient human remains, in order to increase our limited knowledge about the type of tumours and relative incidence afflicting our ancestors. Comparison with modern data could help understand the evolution patterns of cancer in the history of Mankind. PMID- 25807700 TI - [Ancient DNA: principles and methodologies]. AB - Paleogenetics is providing increasing evidence about the biological characteristics of ancient populations. This paper examines the guiding principles and methodologies to the study of ancient DNA with constant references to the state of the art in this fascinating disciplin. PMID- 25807701 TI - [Paleopathology of Herculaneum's population (79 D.C.)]. AB - In 1982, some occasional excavations in the area corresponding to the ancient beach of Ercolano brought to light the rests of around 250 individuals, victims of the eruption of the Vesuvius. This exceptional recovery constitutes an essential patrimony for the reconstruction of the paleobiology and the paleopathology of the human populations in Roman epoch, in relationship not only to the style of life but also to the social and economic status. Notwithstanding the bone alterations due to the exposition to high temperature, the human remains present traces of illness. Among these we find rheumatic pathologies and arthrosis of the vertebral column. The high frequency of occupational markers (enthesopaties and sindesmopaties) suggests that the most part of the population (juveniles included) exercised hand work. Among the infectious pathologies we report cases of the tuberculosis and brucellosis. PMID- 25807702 TI - [The contribute of the trauma analysis to reconstruct the lifestyle of Castel Malnome community (Rome, I-II cent. A.C.)]. AB - The relations between fractures and living conditions of a population are important to reconstruct the biological status of a population. This work is focused on the description and interpretation of trauma in the skeletal remains: the sample consist of 218 individuals, coming from Roman imperial necropolis of Castel Malnome (I-II century AD). The trauma incidence has been considered by the calculation offrequencies per individual and per bone. The examination of the pattern offractures in the skeleton for this site indicates that the individuals are characterized by high level of trauma and reveals that ulna and ribs were the mostfrequently affected bones. The evidence of trauma in this population may reflect many factors about the lifestyle of individuals,for example their occupation and environmental conditions, moreover the state of healing of the injuries may also indicate the availability of treatments. PMID- 25807703 TI - [Palaeopathology in Roman Imperial age]. AB - The increasing attention of archaeological and anthropological research towards palaepathological studies has allowed to focus the examination of many skeletal samples on this aspect and to evaluate the presence of many diseases afflicting ancient populations. This paper describes the most interesting diseases observed in skeletal samples from some necropoles found in urban and suburban areas of Rome during archaeological excavations in the last decades, and dating back to the Imperial Age. The diseases observed were grouped into the following categories: articular diseases, traumas, infections, metabolic or nutritional diseases, congenital diseases and tumours, and some examples are reported for each group. Although extensive epidemiological investigation in ancient skeletal records is impossible, the palaeopathological study allowed to highlight the spread of numerous illnesses, many of which can be related to the life and health conditions of the Roman population. PMID- 25807704 TI - [Canonic recognitions and scientific investigations on the Mummies of Saints]. AB - The Mummies of Saints represent a peculiar category in Italian scene; they are very different for each type of mummification, suffer from numerous environmental interference and rituals,from conservation work or handling repeated over time. An analytical and critical review of all known cases and an inventory is presented. In the present work the topics of canonic recognitions is briefly considered. The study of the bodies of the Saints is characterized by particular techniques and by very close bonds that first puts the conservation of the venerable rest to analytical study of them. However, these investigations are of particular interest not only in the anthropological, paleopathological and biological profile but also from an historical, cultural, religious, literary and artistic point of view. PMID- 25807705 TI - [Bodies, mummies and texts for an history of embalming in Italy]. AB - In the early 80's, a systematic investigation was started of the series of mummies from Central and Southern Italy, in particular from important Renaissance depositions. Radiological exams were carried out on each individual, not only to determine the age at death of those subjects lacking any indication of age, but also to detect possible pathological findings. Furthermore, X-rays allow greater understanding of the techniques and the substances used for embalming, including the type of craniotomy, the partial or complete evisceration, and the identification of the embalming substances used to fill the body cavities. The great number of artificial mummies, examined by G. Fornaciari and his equipe, allowed the study of human embalming techniques, related to methods and procedures described by medical and non-medical authors in Early Modern age. The history of the art of mummification has been here reconstructed, from the 'clyster' techniques to the partial or total evisceration of the corpses, to the introvascular injection of drying and preserving liquors. PMID- 25807706 TI - [Skeleton or mummy: practices and structures for secondary burial in southern Italy in modern and contemporary age]. AB - The ancient concepts of death as duration and the practices of secondary burial,first analysed by Robert Hertz, still survive in many areas of southern Italy. According to these beliefs death was perceived not as a sudden event, but as a long-lasting process, during which the deceased person had to go through a transitory phase, passing from one state of existence to another. Recent archeological research documents the persistence of secondary burial rites in Southern Italy during the Modern Age. A survey conducted in the province of Messina in Eastern Sicily has identified two surviving architectural structures appointed for the treatment of the bodies: the 'sitting colatoio' aimed at favoring the skeletonisation and the 'horizontal colatoio' used to obtain mummification by dehydration. Both these structures controlled the corpse's decay and transformed the body in a stable and durable simulacra of the dead. PMID- 25807707 TI - [Egyptian mummies as anthropological artifacts]. AB - Ancient human remains like Egyptian mummified bodies cannot be considered on a physical anthropological perspective only. So severe and invasive were the operations on the body, so various were the materials involved in the preservation techniques, so complicated was the embalming and wrapping procedure according to specific rituals, that the final result, the mummy, is to be considered a highly composite product. The human remains are a relevant part of it indeed, but a very wide set of information can be taken.also from the other components, relating to environment, resources, technology, religious beliefs, cultural and technical traditions, skills and arts at the time of the individual's life. That a plain anthropological approach could not be exhaustive on cataloguing such a kind of archaeological finds emerged during the sessions of the scientific board charged by the Italian ICCD of defining a data track for filing anthropological remains as a special kind of cultural heritage. PMID- 25807708 TI - [Human remains in museums: research, preservation and communication. The experience of Turin University Museum of Anthropology and Etnography]. AB - The creation of large scientific collections has been an important development for anthropological and paleopathological research. Indeed the biological collections are irreplaceable reference systems for the biological reconstruction of past population. They also assume the important role of anthropological archives and, in the global description of man, permit the integration of historical data with those from bio-anthropolgical research. Thinking about the role of mummies and bones as scientific resources, best practice of preservation of ancient specimens should be of high priority for institution and researchers. By way of example, the authors mention their experience regarding ancient human remains preserved in the Museum of Anthropology and Ethnography at the University of Turin. PMID- 25807709 TI - [Medical research through historical resources. Talking objects: a case of a parasitic perineal monstrosity]. AB - A case of a parasitic perineal monstrosity from the collection of the Pathology Museum of the University of Florence, is described on the basis of the original medical records and illustrations. The surgeon Giorgio Pellizzari (1814-1894) first reported this extraordinary case of sacrococcygeal teratoma containing a rudimentary inferior limb. Reader of Descriptive Anatomy, Pellizzari was a well known Anatomy Dissector and Curator of the Physiological Museum of the Regio Arcispedale di Santa Maria Nuova in Florence. This report underlines the importance of studying the archive material in order to thoroughly comprehend a single museum talking object. This handling of matters will help to turn anatomical collections into a unique teaching toolfor modern medical practice and a noteworthy documentation of scientific, artistic and historical value. Through analysis of the original catalogue and investigation by means of modern scientific techniques, discovering the story behind the object becomes afeasible challenge. PMID- 25807710 TI - [Antique anatomical collections for contemporary museums]. AB - Anatomy and Pathology Museum collections display a great biological value and offer unique samples for research purposes. Pathological specimens may be investigated by means of modern radiological and molecular biology techniques in order to provide the etiological background of disease, with relevance to present day knowledge. Meanwhile, historical resources provide epidemiologic data regarding the socio-economic conditions of the resident populations, the more frequently encountered illnesses and dietary habits. These multidisciplinary approaches lead to more accurate diagnoses also allowing new strategies in cataloguing and musealization of anatomical specimens. Further, once these data are gathered, they may constitute the basis of riedited Museum catalogues feasible to be digitalized and displayed via the Web. PMID- 25807711 TI - [Comment on PMID 25807710]. PMID- 25807712 TI - [Betta E., L'altra genesi. Storia della fecondazione artificiale. Roma, Carocci, pp. 267]. PMID- 25807713 TI - Clark C. Z., Clark, O., The Remarkables. Endocrine Abnormalities in Art. University of California Medical Humanities Consortium, 2011 (series: Perspectives in medical Humanities). PMID- 25807714 TI - [Prospective study of microdiskectomy for lumbar disc herniation: evolution of pain, quality of life and satisfaction of Lebanese patients at short and long term follow-up]. AB - BACKGROUND AND PURPOSE: Lumbar disc herniation frequently affects young patients and is responsible for high rate of worker's compensation claims. The aim of this study is to evaluate at short and long-term the results of microdiscectomy in terms of pain control, quality of life and patient's satisfaction. METHODS: In this prospective study, 28 patients were enrolled and operated on by microdiscectomy for lumbar disc herniation. Three questionnaires were administered preoperatively. They evaluated the pain, the quality of life and the expectation of the patients. Four questionnaires were administered at six months and two years postoperatively evaluating pain, quality of life, results and satisfactions. RESULTS: A 62.3% and 53.2% improvement of low back pain at 6 months and 2 years respectively, and a 91.7% and 88.4% improvement of radicular pain were reported. A 73.2% and 79.8% improvement in quality of life was recorded respectively. Patient's expectation was evaluated at 3.85 and results estimated 3.24. Patient's satisfaction was 93.3% and 88.3% respectively. It was positively correlated to radicular pain, and inversely correlated to patient's expectations. CONCLUSION: Microdiscectomy for lumbar disc herniation offers a marked improvement in back and radicular pain. Quality of life is much improved. Although satisfaction is high, it is somewhat decreased for patients with high expectations. PMID- 25807715 TI - Short-term neonatal outcome in singleton, late preterm deliveries: a three-year experience at a single Lebanese center. AB - BACKGROUND: There has been a decrease in the mean gestational age at delivery worldwide mostly due to an increase in deliveries occurring at late preterm period (LPP) with a concomitant rise in the rate of morbidities among newborns delivered at this period. OBJECTIVES: To report the frequency of common short term neonatal morbidities in infants born at LPP (between 34(0/7) and 36(6/7) weeks' gestation) and to compare these frequencies with those of full-term infants born at our institution. MATERIALS & METHODS: A descriptive cohort study (2008-2010) at Makassed General Hospital. All deliveries occurring at LPP constituted the study group (n = 361), while births at or beyond 37 weeks' gestation were considered as controls (n = 2814). RESULTS: The average rate of deliveries in LPP was 11.4% for the entire study period. The rate of Neonatal Intensive Care Unit admissions, respiratory morbidities, sepsis, jaundice, hypothermia, hypoglycemia and overall neonatal morbidity were all significantly higher in LPP infants when compared to those at term (p-value < 0.013). CONCLUSION: In our cohort of Lebanese newborns delivered at LPP, significantly higher morbidities were encountered when compared to full-term newborns. Every possible effort should be exerted to avoid elective deliveries during LPP in order to curb the incidence of neonatal morbidities. PMID- 25807716 TI - What matters in the patients' decision to revisit the same primary care physician? AB - OBJECTIVE: To assess the priority of various aspects of the patient-primary care physician relationship in the decision to visit again that same physician. STUDY SETTINGS: A total of 400 community residents in Ras Beirut, Lebanon. STUDY DESIGN: A cross-sectional community based study sampled by a nonrandom sex education quota-based procedure. DATA COLLECTION: Participants were asked to fill a survey where they indicated the ranking of nine items by importance in their decision to revisit the same physician. The nine items were chosen from three categories of factors: professional expertise of the physician; characteristics of the patient-physician relationship, office organization. RESULTS: Having a physician that gives the patient adequate time for discussion prevailed as rank 1 and luxurious clinic ranked as 9th. Affordability was one of the main concerns among men, those with poor health and those of lower socioeconomic status. Accessibility of the physician's phone was considered highly important among women and those of lesser education status. CONCLUSIONS: This study emphasizes the importance of adequate time with the patient, accessibility and affordability of the physician in maintaining continuity of care and patient satisfaction, beyond mere medical expertise. PMID- 25807717 TI - Pruritus ani: more than a decade of personal experience in Lebanon. AB - INTRODUCTION: Pruritus ani is a common medical condition that is difficult to treat in the absence of obvious predisposing factors. Hereby, we report more than a ten-year experience in the management of pruritus ani stressing the importance of early detection, identification of the etiology, and management. METHODOLOGY: A total of 124 patients were managed in the surgical clinic. The follow-up was between 11 to 17 months. All patients had the symptoms for a period of time ranging between 6 and 40 months. Patients were treated according to their respective etiology. Medical cases like contact dermatitis and psoriasis were treated by applying proper topical ointments, while other cases like anal fissure and fistula were treated surgically. Idiopathic patients were treated by tattooing (injection to perianal skin with methylene blue). RESULTS & DISCUSSION: The majority of patients with known medical etiology responded favorably to conservative treatment (~ 92%). In addition, surgical management for anorectal disorders like hemorrhoids and fistula showed a consistent improvement (94%). However, patients who had their symptoms neglected for longtime or had used over the counter medication without a proper medical follow-up, experienced a lower success rate of cure (76%). CONCLUSION: Patients who were diagnosed and treated at first hand, showed better results than those who sought late medical advice and management (i.e. > 18 months). In light of the above, a multidisciplinary team approach consisting of a proctologist, a gastroenterologist and a dermatologist is recommended. PMID- 25807718 TI - Geometric indices of hip bone strength in male professional soccer players. AB - AIM OF THE STUDY: The aim of this study was to compare geometric indices of hip bone strength in male professional soccer players and controls. METHODS: Twenty three male professional soccer players and 21 male sedentary subjects whose ages range between 18 and 30 years participated in this study. Weight and height were measured, and body mass index (BMI) was calculated. Daily calcium intake and physical activity were evaluated using validated questionnaires. Hip bone mineral density was measured by dual-energy X-ray absorptiometry (DXA). To evaluate hip bone geometry, DXA scans were analyzed at the narrow-neck (NN), the intertrochanteric (IT) region and the femoral shaft (FS) by the Hip Structure Analysis (HSA) program. Cross sectional area (CSA), an index of axial compression strength, cross sectional moment of inertia (CSMI), an index of structural rigidity, section modulus (Z), an index of bending strength, cortical thickness (CT) and buckling ratio (BR) were measured from bone mass profiles. RESULTS: CSA, CSMI, Z and CT of the three regions (NN, IT and FS) were higher in soccer players compared to controls. After adjustment for either age, body weight, height or physical activity duration (h/week), CSA, CSMI, Z and CT of the three regions remained higher in soccer players compared to controls. CONCLUSION: This study suggests that, in young adult males, soccer practice is associated with greater axial strength, bending strength and structural rigidity indices at the hip. PMID- 25807719 TI - [Sleep quality is a determinant of hip bone mineral density in a group of young Lebanese men]. AB - INTRODUCTION: The aim of this study was to explore the relationship between sleep quality and bone mineral density (BMD) of the hip in a group of young Lebanese men. METHODS AND RESULTS: Fourteen Lebanese young men from 18 to 30 years (mean age 22.6 years) participated in this study. Weight and height were measured and body mass index (BMI) was calculated. BMD of the total hip (TH) and the femoral neck (FN) was measured by DXA. Daily protein intake (DPI), daily calcium intake (DCI) and sleep quality were evaluated by validated questionnaires. The Pittsburgh sleep quality index (PSQI) was used to assess sleep habits and quality; higher scores represent worse sleep quality. Weight, height, BMI, DCI, DPI and sleep duration were not correlated to BMD values. The Pittsburgh sleep quality index was negatively correlated to femoral neck BMD (r = -0.82; p < 0.001) and to TH BMD (r = -0.54; p < 0.05). CONCLUSION: This study suggests that poor sleep quality affects negatively BMD of the hip in young adult men. Our findings may lead to the development of better preventive approaches to osteoporosis. PMID- 25807720 TI - Hydatid disease: the Lebanese contribution. AB - Hydatid disease (HD) or cystic echinococcosis (CE) has been an important zoonotic disease causing medical, economic and public health problems in many parts of the world, including South America, North Africa, Turkey, and Middle Eastern countries. Humans as well as animals, primarily sheep and cattle, are infected by the ingestion of food, usually leafy vegetables, contaminated with the eggs (oncospheres) of the dog tapeworm Echinococcus granulosus. Hydatid cysts, which are the larval stage of the parasite, are located mostly in the liver and lungs of the infected host. Because of its chronic endemicity in Lebanon and neighboring countries, this disease has constituted an integral part of research studies conducted by medical doctors and researchers in Lebanon, mostly spearheaded by those at the American University of Beirut (AUB) and its medical center (AUBMC) since the early turn of the last century (1920s). Over 130 wide ranging studies were published; some were innovative e.g. the introduction of the once famous Indirect Haemagglutination (IHA) test for serodiagnosis, and the use of dilute cetrimide as a protoscolicidal agent during surgery. Although the incidence of HD is decreasing in our country, it has acquired increasing public health concern and is considered as an emerging or re-emerging disease in many parts of the world. In this review, we shed light on the numerous studies/publications done in Lebanon as a tribute to those researchers who have impacted the literature of HD in many aspects. The latter include epidemiology and ways of transmission, clinical features and radiological tools for diagnosis, serodiagnosis and immunology, and investigation of different therapeutic modalities for different aspects of the disease. Moreover, consolidating these studies in this review would hopefully represent the historic foundation for interested researchers and investigators, especially in this country, to pursue and build on such studies. The advances in technology, and the availability and utilization of new methodologies will hopefully help find more reliable and efficient ways for the diagnosis, and management of this disease. PMID- 25807722 TI - The cleft sternum: a possible role for pliable prosthetic reconstruction. AB - BACKGROUND: Faced with our intraoperative inability to primarily close a very wide isolated cleft sternum of a pediatric patient without causing cardiovascular decompensation, we describe our use of a synthetic material for partial approximation allowing muscular coverage. METHOD: We report an infant who was born with an isolated large complete sternal cleft where a trial of primary surgical repair had to be abandoned because of cardiovascular compromise. A similar difficulty was encountered in approximating the origins of both pectoralis major muscle flaps at the midline. Thus, a pliable synthetic patch was helpful in partially obliterating the widened sternal defect allowing successful muscular coverage. RESULT: Closure of a wide congenital sternal cleft using a synthetic material that partially obliterated an otherwise widely separated cleft sternum which was neither amenable for primary repair, nor by bilateral pectoralis major advancement alone, was possible. CONCLUSION: Strong prosthetic pliable material may offer a simple and useful procedure allowing obliteration of the widely separated cleft sternum not amenable for primary repair. PMID- 25807721 TI - [Laparoscopic treatment of vaginal agenesis: three cases]. AB - BACKGROUND: Ninety per cent of cases of congenital vaginal agenesis are represented by the Mayer-Rokitansky-Kuster-Hauser syndrome, the remaining 10% being represented by the testicular feminization syndrome and vaginal aplasia. Numerous surgical methods for the treatment of vaginal agenesis have been described. Neovagina construction by sigmoid colpoplasty seems to be the best surgical option as regards the anatomical and functional outcome. METHOD: We report the case of three patients operated of neovagina construction with a sigmoid graft by a laparoscopic-perineal approach. RESULTS: The surgical intervention lasted for 330 minutes, 210 minutes and 150 minutes respectively for the three patients. There were no perioperative complications. The duration of hospitalization was respectively 7, 4 and 6 days. The length of the neovagina was 15, 14 and 18 cm without retraction on the follow-up at 2 and 6 months. The vaginal wall maintained its patency allowing normal intercourse. The patients had normal sexual life after the surgery. CONCLUSION: Our results demonstrate the feasibility of laparoscopic-perineal neovagina construction by sigmoid colpoplasty when it is performed by experienced surgeons in gynecology and digestive laparoscopic surgery. PMID- 25807723 TI - [Bladder and bowel migration of staples used for inguinal hernia repair via transperitoneal laparoscopy]. AB - Introduction of foreign bodies inside abdominal cavity may migrate to hollow organs like bladder and bowel. This can occur after various laparoscopic or open abdominal and pelvic surgeries in which synthetic materials are used. We report an exceptional case of bladder and ileal migration of tackers used to fix mesh during laparoscopic transperitonel inguinal hernia repair in a 65-year-old man who presented for recurrent fever, dysuria, frequency and suprapubic pain. A laparotomy was done showing that some tackers which served to repair the hernia had migrated into ileon and bladder. We performed limited resection of involved ileum and bladder with complete disappearance of symptoms. PMID- 25807724 TI - Adalimumab-induced lichenoid drug eruption. AB - Tumor necrosis factor (TNF)-alpha inhibitors are being widely and increasingly used for the management of a spectrum of rheumatologic diseases that are refractory to conventional disease modifying anti-rheumatic drugs. Various cutaneous side effects have been reported after treatment with TNF-alpha inhibitors. We present a case report of a 26-year-old male patient who developed a lichenoid drug eruption few months after the initiation of adalimumab for the management of Crohn's disease. We also highlight the clinical and histopathologic differences between lichenoid drug eruptions and idiopathic lichen planus. PMID- 25807725 TI - Bellini duct carcinoma: two case reports. AB - We report two rare cases of Bellini duct carcinoma, a rare variant of renal cell carcinoma. CASE 1: The patient, a 73-year-old female, was admitted to the hospital for macroscopic hematuria and right flank pain. She was diagnosed to have a stage IV Bellini duct carcinoma. There was a progression of the disease despite chemotherapy. She died 21 months later. CASE 2: The patient, an 81-year old male, was admitted to the hospital for generalized fatigue, weight loss and left flank pain. He was diagnosed to have a stage IV Bellini duct carcinoma. The patient was treated with chemotherapy; he died six months later. We report the clinicopathological features of two cases of Bellini duct carcinoma in order to contribute to the related literature of this rare disease. PMID- 25807726 TI - Ovarian immature teratoma during pregnancy: a case report. AB - Germ cell tumors are derived from the primordial germ cells of the ovary and immature teratoma is the second most common germ cell malignancy. About 50% of pure immature teratomas of the ovary occur in women between the ages of 10 and 20 years, and they rarely occur in pregnancy. A 21-year-old woman, gravid 1, para 0, at 18 weeks of gestation, was incidentally diagnosed with a right ovarian mass 180 mm by 200 mm, 160 mm in diameter, during a prenatal ultrasound scanning. She underwent surgery by unilateral salpingo-oophorectomy and surgical staging. The result of pathology showed a stage 1a grade 1 immature teratoma of ovary. Her pregnancy continued until term. At 38 weeks she delivered with breech presentation a normal 2900 g male newborn by cesarean section. Although immature teratomas of ovary during pregnancy are rare, clinicians should consider their eventuality in younger pregnant women in asymptomatic cases. PMID- 25807727 TI - [Between furor and consumption: love, soul and body in medical and literary Western tradition]. AB - Love is a psychic force capable of converting itself into a real disease, as abundantly demostrated by the medical contemporary literature and by the interest of the law to the issue of protection of the objects of persecution of unrequited love. The dual nature of love, capable of harmful or sel- destructive metamorphoses, is a common topic of medical thought from Greek antiquity, even if it is openly thematized only from Late Antiquity and more deeply in Westerm medical medieval tradition. Nevertheless, it remains to analyze some aspects of the definition of lovesickness, especially in long-term perspective: what are the relations that lovesickness has with the more general category of medical melancholy? Is it a real disease or just one oftheforms of madness and fiury? Does it affect women more than men? Is it in some way linked to hysteria, greensickness, uterine fury and womb diseases as codified by medical and philosophical ancient thought? PMID- 25807728 TI - [Love trouble: armonies and imbalances of passions]. AB - Love trouble is a well described 'pathology' in Italian medieval literature, often indebted to the humoral medical theories of the School of Salerno, especially in the idea of love sickness as the result of the balance or imbalance ofthe four Hippocratic humors and of the cyclical pattern of the seasons and stages of life. Unbridled passions, not controlled by the 'amor cortese', deform bodies and torment souls and lead both men and women away from the search for a celestial balance, only guaranteed by the union of the heart spirit and bodily heat. PMID- 25807729 TI - [Melancholic disease and love between poetry and medicine in the Late Antiquity: Aegritudo Perdiccae (Ae.P.)]. AB - The article examines the topic of love and melancholic sickness in medicine and literature of Late Antiquity with special attention to the poem Aegritudo Perdiccae. In the Late Antiquity, medicine takes a new attitude to the disease of love, making it an indipendent disease, with specific physical and psychological symptoms. Many new features can be justified by the influence of Christian thought on medical theories. PMID- 25807730 TI - [A Roman soap opera: Justus' wife and love sickness]. AB - This paper presents a fiction rather than a story. Galen is called to visit Justus' wife, ill with a mysterious disease. The narrative of love sickness that afflicts her allows the author to draw an interesting picture of the social status of Roman women, the issues of reproduction and maritalbe trayal, and to shed light on magic practices for obtaining or preventing love affairs. PMID- 25807731 TI - [Love sickness in the Dialoghi d'amore by Leone Ebreo]. AB - The Dialoghi d'amore by Leone Ebreo is one of the most popular texts of an extended theoretical debate concerning the nature of love during early sixteenth century. At this time, this theme is already crystallized into two contrary approaches: one, derived from the classical and medical tradition, dwells upon many negative effects of love, understood as a form of sickness interfering with the correct exercise of reason; the other one regards love as the instrument of spiritual self-realization, the nexus by which the soul is finally reunited with God, its origin and ultimate aim. Leone's text certainly shares this second approach, but somewhere in the Dialoghi we can find a technical language derived from the medical tradition of the aegritudo amoris, undoubtedly known to Leone, who was a physician. This paper focuses on these passages, trying to show how the theme of lovesickness - although limited to a secondary rule - represents in this text a stage in the secular diffusion of a doctrine crossing so many different cultures and historic eras. PMID- 25807732 TI - [Phaedra's disease]. AB - The author hints at Phaedra's passion, described by Euripides, highlighting in particular the incest taboo. As well known, Phaedra in fact is love-sick for her own step-son Hippolytus, a human figure with a not well defined sexual identity. PMID- 25807733 TI - [Curing melancholia in sixteenth-century medical consilia between theory and practice]. AB - In this essay I analyze the development of the genre of the consilium at the end of the sixteenth century based on recent scholarship regarding the genres of early modern medical consilia and observationes. It is my conviction that for some late sixteenth-century physicians the consiliumn was becoming a hybrid genre in which elements of the already existing observatio were inserted into the structure of the consilium. To prove this point, I will consider the consilia of three physicians--Giambattista Da Monte, Girolamo Capivacci and Cristoforo Guarinoni--and a speciic illness, melancholy. I intend to show that while the diagnosis of symptoms, signs and causes of melancholy did not change for them, the attitude of these physicians toward the patient altered in the direction of a larger interest in the individual. PMID- 25807734 TI - [Figures of anima in the Odyssey]. AB - Feminine characters in the Odyssey show different aspects of the archetype: Mother and Anima (C.G. Jung). From an Analytical Psychology perspective the encounters of Odysseus with goddesses: Circe, Calypso, Ino are looked at as different and successive stages of the hero's way into the inconscious, who shows himself in feminine figures, being masculine the consciousness of the hero. Nausicaa is a new, nearly-human figure of Anima who appears after the symbolic death of Odysseus and leads him to the royal couple Alcinous-Arete: in front of them all he finds his new, reborn, personality by creating and narrating his own myth. PMID- 25807735 TI - [Women and madness in the Eneid]. AB - The article presents female cases of madness in Latin Vergilian Literature, comparing the Greek Dyonisian divine possession of the Maenads and Bacchae with the madness of Dido and Amata. Transcultural psychiatry is here proposed as a useful tool for reading the descriptions of the Aeneid - to try to understand every kind of world where barriers disappear between visible and invisible. PMID- 25807736 TI - [Comment on PMID 17152189]. PMID- 25807737 TI - [Paravicini Bagliani A. (a cura di), Terapie e guarigioni. Convegno internazionale di Storia della medicina (Ariano Irpino, 5-7 ottobre 2008). Firenze, Sismel, Edizioni del Galluzzo, 2010 (Edizione Nazionale La scuola medica salernitana), pp. XIV-418]. PMID- 25807738 TI - [Paravicini Bagliani A. (edited by), Le monde vegetal: mde'decine, botanique, symbolique. Firenze, Sismel, Edizioni del Galluzzo, 2009 (Micrologus' library), pp. V-495]. PMID- 25807739 TI - [Introduction]. PMID- 25807740 TI - [Fabiola's charitable activities: the Epistula 77 by Gerolamus]. AB - The fourth centwty is a century of innovation: beginning with the fierce persecution of Christians and ending with the order of an emperor to close the pagan temples. This is an important century for the history of medicine, too, as testifyied by the foundation of charitable institutions, a sort of antecedents of hospitals. Gerolamus in his Epistulae writes that "Fabiola has been the first one to build an hospital". The article discuss this testimony and the relation between Early Christianity and medical and charitable care. PMID- 25807741 TI - [Some notations on medical texts in Byzantium (IV-XII cent)]. AB - The aim of this article is outlining some of the most significant issues of the Byzantine medicine. In particular, it is highlighted the 'diagnostic of the fluids', an elaborate and meaningfull procedure applied to detect the state of the humors. PMID- 25807742 TI - [The chapter De Puero virgine (or de homine) of Liber medicinae ex animalibus by Sextus Placidus. Historical study, new critical edition and translation]. AB - The article offers an historical study, a new critical edition and the translation of the chapter De Puero virgine of Liber medicinae ex animalibus by Sextus Placitus, firstly edited by Sigerist and Howald in 1927. The book, dating to Late Antiquity, is part of a phyto -zootherapeutical corpus, trasmitted by the manuscript tradition in a single block of text whose central axis is represented by the Herbarium by Pseudo-Apuleius, the tractatus De herba vettonica attributed to Antonius Musa and the De taxone. Chapter 17 is devoted to pharmacological recipes whose ingredients are organic or human body parts; here is provided a critical edition based on the collation of three texts in the manuscript tradition, well testifying the particular vitality of medical prescription texts in Late Antiquity. PMID- 25807743 TI - [When no doctor is on call. Medical works for lay persons in late antiquity]. AB - The article offers a survey of the chief medical texts for lay persons in Latin, followed by a more detailed discussion of two examples, hare's brain for teething troubles and remedies for nosebleed. PMID- 25807744 TI - [Medical texts and professional deontology in the Late Antiquity]. AB - We analyze the peculiarities of the medicine in the Late Antiquity, researching the typology of medical texts and the physician's deontology during mental or incurable illness. PMID- 25807745 TI - [The Problemata by Cassius Iatrosophist: problems of dating and new discoveries]. AB - Nothing is known about Cassius Iatrophist, author of a collection of Problemata, which is medical oriented but has often affinities with the analogous texts of Pseudo-Aristoteles and Pseudo-Alexander of Aphrodisia. This is a provisory survey of the elements for a possible datation: as the surname of the author suggests a late compilation, the content of some problems has very high value and reveals surprisingly a close connection between ancient medicine and philology. PMID- 25807746 TI - [Assistance and care of the sick in early Christianity]. AB - Christianity presents a new vision of man (personalistic anthropology) and refers to the example and words of Jesus, highlighting the inseparable relationship between the love of God and the love of man. The article describes the assistance and care of the sick in the East and West in the early Christian centuries; the 'places of care'- nosokomia for the sicks, gerontokomia for the olders, brephotropia for abandoned children, orphanage structures; the managers of hospitals, ecclesistical dignitaries, lay personnel, monks, operators and employees. Christianity gave dignity to the sick and opportunity to serve humanity to the healthy. PMID- 25807747 TI - [Medicine after Galen]. AB - The article briefly traces the history of medicine in late antiquity, from Galen's death to the end of VIth century until the early VII century AD; it examines the medical literature, medical writers, anonymous literary production - synthesis of previous literature - recipe books and collections of simple drugs, comments, specialist books and literature in translation, the main characteristics of medical practice and training, and finally the influence of Christianity on the formation of scientific thought and on the new vocabulary of medical language. PMID- 25807748 TI - [The contribution of the ancient medicine to the Luxorius' text and to its exegesys (poem 302, 1-6 happ; with an appendix about V 7)]. AB - Luxorius' poem 302, written in Vandal Africa at the beginning of the VIth Century, about a physician named Marzinus, who knew the principles of the methodical and the dogmatic School, becames more clear in its meaning if it is read with an eye to the history of the Schools of Medicine in the Roman Empire and to the works by Cassius Felix and Caelius Aurelianus and if we suppose a recall by the author to the famous anatomist Marinus of Alexandria. PMID- 25807749 TI - [Vindicianus and the theory of temperaments]. AB - Vindicianus, in his Epistula to Pentadius, refers to a 'latinized' edition of an Hippocratic medical work which is not the De natura hominis nor any other Hippocratic text. The recent edition of the pseudohippocratic De pulsibus et de temperamentis corporis humani clearly proves that the Epistula is a translation of this text. The article discusses the question of the attribution of the Epistula, already problematized by J. Jouanna, its dating and its sources, surely including the pseudohippocratic De pulsibus et de temperamentis, but also a more ancient medical tradition, at least referring to Pseudoarist. Probl. 30,1. PMID- 25807750 TI - [Features and the need for patenting of medical developments]. AB - Modern health care is impossible to imagine without the constant development of the methodology of treatment; a fundamentally new methods or devices are often developed. In this case, there are many reasons for the need to protect copyright, and it is easy. The article describes: how and what can be patented, what are the main features and complexity of the organization of this process, what is needed to do this specifically? Actual examples are presented. PMID- 25807751 TI - [Modern conservative (citrate) therapy for urate calculi in the ureters]. AB - The results of conservative citrate therapy of 35 patients with urate calculi in ureter are presented. Due to the violation of the passage of urine in the upper urinary tract, the vast majority of patients (31 (88%)) underwent ureteral stenting to restore adequate flow of urine before treatment. In four patients, drainage of the upper urinary tract was not required. Citrate therapy allowed to achieve complete dissolution of calculi within 2 months in 25 (72%) patients. Another 14% of patients were able to reduce the size of the calculi, and in combination with contact ureterolithotripsy achieve complete discharge of calculi. Only in 14% of patients with urate calculi in ureter litholysis was ineffective. The used treatment option allows to avoid surgery in a large number of patients with urate lithiasis. PMID- 25807752 TI - [Clinical-biochemical and immunological parameters in the diagnosis and treatment of chronic pyelonephritis on the background of intercurrent diseases]. AB - Studies have shown that complicated chronic pyelonephritis in the active phase is characterized by structural and functional instability cytomembranes and decreased immunological resistance of the patient man. Supplement standard antibiotic treatment with ozone therapy antioxidant immunomodulation drug thus received immunobiochemical study. PMID- 25807753 TI - [Potentials of phytotherapy in the complex treatment of acute pyelonephritis]. AB - The purpose of this study was to increase the effectiveness of treatment of patients with acute pyelonephritis by incorporating of phytopreparation "Prolit Super Septo" in complex therapy. The study included 38 patients with acute primary pyelonephritis. All patients have received standard medical therapy, 21 of them (Group 2) have additionally received "Prolit Super Septo" 2 capsules 2 times a day for 1 month. Outcome measures included basic laboratory parameters, and results of bacteriological examination and immunological assessment of patients 12-14 and 28-30 days after initiation of therapy. Against the background of the therapy, positive dynamics of the level of leukocyturia and bacteriuria was detected in both groups; therapeutic effect, however, was more pronounced in the Group 2 treated with complex therapy: after the end of treatment, the proportion of sterile cultures was 85.7%, whereas in Group 1--70.6%. In addition, complex treatment had a positive effect on the immune status of patients, as evidenced by normalization of blood immunoglobulins, circulating immune complexes and C-reactive protein. The inclusion of "Prolit Super Septo" in the complex conservative treatment of patients with acute pyelonephritis promotes the development of an adequate immune response and the rapid elimination of the pathogens, thus preventing the development of purulent forms of the disease, or chronization of process. PMID- 25807754 TI - [Significance of macroanatomic variants of cavatesticuilar and renotesticular communications in the genesis of right testicular phlebectasia]. AB - The anatomical study of 188 retroperitoneal organocomplexes by direct methods of measurement and nonparametric Spearman correlation analysis explains the significance of different types of right cavatesticular and renotesticular communications in the genesis of expansion of right testicular vein. In 74% of cases, right testicular vein (TV) ends in the inferior vena cava (IVC), and in 26% of cases--in the right renal vein (RRV). When TV ends in IVC, quantity anomaly (doubling TV) is observed in 6.94% of cases; when TV ends in RRV, such anomaly is observed in 40.9% of cases. The width of right TV in the case of its end in IVC was 3.39 +/- 0.1 mm, and left TV--2.95 +/- 0.1 mm (n = 144), ie, right TV 0.5-1 mm wider than the left TV (P = 0.0008). Correlation analysis showed a weak relationship between the width of the right TV and lack of ostial valve at the end in IVC (r = -0.16, n = 144, P = 0.05). Associations of width of right TV with other factors (lack of ostial valves in the end in RRV, high location of RRV, width of the RRV, angle of return of TV to RRV, deposition of TV entry to the hilum of kidney or IVC) have not been reliably established. The moderate relationship between the width of right TV and type of entry of right inferior segmental renal vein in TV was established (r = 0.63; n = 6; P = 0.05). In a study, among all types of macroanatomical relationships with right TV, a single variant with important role in ectasia of TV was revealed--an entry of inferior segmental renal vein in the retroperitoneal segment of right TV. PMID- 25807755 TI - [Bladder tuberculosis stage 4: how to restore urination?]. AB - Reconstructive surgery for contracted bladder (bladder tuberculosis stage 4) was performed in 21 patients: women underwent cystectomy, and men underwent cystectomy and cystprostatectomy. The artificial bladder was formed using segment of the ileum by the Studer method with the implementation of ureteral-intestinal anastomosis by Nesbit or Wallace methods. Criteria for determining the bladder tuberculosis 4 stage, requiring the implementation of reconstructive surgery were as follows: bladder capacity of 100 ml or less (including general anesthesia); bladder volume--150 ml or less in the presence of vesicoureteral reflux. A good results were obtained in 17 (80.9%) patients. Results of 3 (14.2%) patients were regarded as satisfactory; one patient developed a stricture of ureterovaginal reservoir anastomosis, which required re-anastomosis; 1 patient formed a stricture of membranous urethra, which recurred after optical urethrotomy and required the implementation of anastomotic urethroplasty; and 1 patient had difficulty urinating, requiring intermittent catheterization. Poor result was recorded in 1 (4.7%) patient who was diagnosed with chronic renal failure progression, despite the lack of evidence of retention of the urinary tract and vesicoureteral reflux in the presence of spontaneous urination, and satisfactory bladder capacity. This fact was attributable to the antiretroviral therapy for HIV infection. PMID- 25807756 TI - [Some aspects of the treatment of persistent lower urinary tract infections in women]. AB - Chronic recurrent cystitis in women is a major socio-economic problem. In the pathogenesis of recurrent infection, violations of mechanisms of innate immunity of the bladder mucosa, and the persistence of microorganisms play an important role. The study included 43 women (mean age 39.5+/-1.2 years) with persistent lower urinary tract infection. The mean duration of disease was 6.5+/-1.8 years. Depending on the therapy, patients were divided into two groups. Patients in Group 1 (n = 20) have received only fosfomycin trimetamol 3 g every 10 days for 3 months, patients in group 2 (n = 23) have received the drug viferon(r) (rectal suppositories) 1 million IU per rectum 2 times per day at intervals of 12 hours for 20 days in addition to antibiotic therapy at the same dosage. The inclusion of immunomodulator in the complex therapy of persistent lower urinary tract infections contributed to the reduction of relapse rate by 1.5 times, and reduction of the number of patients with relapses by 4 times. PMID- 25807758 TI - [Magnetic resonance spectroscopy of the prostate: a description of the methodology and the own results]. AB - The first part of the article discusses the technical details of the magnetic resonance spectroscopy (MRS) of the prostate, postprocessing and assessment of the results; the second part of article presents a several own clinical examples, and describes the advantages and disadvantages of the methodology. Of all available clinical MRI techniques for the evaluation of the prostate multivoxel spectroscopy is the most difficult. Thus, even with abidance of all the technical aspects of the evaluation, it impossible to be sure absolutely that qualitative range of voxels of interest will be received. Upon receipt of quality results with interpretable spectra, it is still difficult to perform the differential diagnosis of cancer with benign changes. These complexities limit the widespread use of prostate MRS. In our opinion, the use of this method is most effective for a diagnosis of cancer localized in the peripheral zone of the prostate, and for the assessment of the dynamics of non-surgical treatment of the tumor. PMID- 25807757 TI - [Hormonal and metabolic disorders as systemic factor for the formation of urinary calculi]. AB - In patients suffering from urolithiasis, metabolic diagnostics often reveals abnormalities contributing to the formation of stones: hypocitraturia, hyper- and hypocalcemia, hypercalciuria, hypomagnesemia/hypomagnesuria, hyperoxalaturia, etc. Before surgery, complex biochemical examination of blood and 24 hourcollection urine in 82 patients with urolithiasis was performed. The analysis of the main laboratory parameters of carbohydrate, lipid, calcium and phosphorus and purine metabolism found the prevalence of violations of calcium and phosphorus metabolism in these patients. Dyslipidemia was diagnosed in 31 (37.8%) patients. There was a significant positive correlation between serum total cholesterol and serum total calcium (rs = 0.3315, P = 0.0103). Low serum calcium levels were associated with hyperoxalaturia (rs = -0.4270, P = 0.0295). There was a significant effect of natriuria on urinary excretion of oxalate (rs = 0.6107, P = 0.0001), Mg (rs = 0.4156, P = 0.0096) and K (rs = 0.5234, P = 0.00005). The study shows the role of magnesium in the prevention of recurrence and manifestation of urolithiasis. The combination of two or more types of hormonal and metabolic disorders increases the incidence of recurrent stones. Timely correction of hormonal-metabolic status allows to reduce the risk of stone formation, and hospitalization attributable to the complications associated. PMID- 25807759 TI - [Unsterile urine in health human--new paradigm in medicine]. AB - The 3-fold urine culture evaluation in healthy women (24) and men (28) was performed. In 100% of cases, various types of multicomponent aerobic-anaerobic microorganism associations were found. Dominant clusters in the urine of women incleded coagulase-negative staphylococci, Corynebacterium sp., Lactobacillus sp., Peptococcus sp., Propionibacterium sp., in men--coagulase negative staphylococci, Corynebacterium sp., Eubacterium sp. For aerobic microorganisms, level of bacteriuria in both groups was 10(2) CFU/ml, for most anaerobes-->=10(3) CFU/ml. Spectrum of microorganisms isolated from the urine was quite wide and variable. In women, number of assiociates in urine ranged from 3 to 10, in men- from 6 to 9, as well as individually--in each subject, the original range of microorganisms was not repeated in any other case. PMID- 25807761 TI - [Pharmacoeconomic study of using solifenacin for the treatment of urge urinary incontinence in patients with overactive bladder syndrome]. AB - Overactive bladder syndrome (OAB), accompanied by incontinence, is a relatively common disease. Currently, in the Russian Federation, unfortunately, management of patients with OAB includes the recommendations for symptomatic use of incontinence pads without pharmacotherapy. Along with this, the market is represented by a number of drugs that can reduce the occurrence of adverse symptoms associated with OAB syndrome. This study presents the pharmacoeconomic analysis of use of solifenacin for the treatment of patients with the OAB syndrome in Russia. Based on previous clinical studies, formal mathematical model for the development of OAB have been suggested, taking into account the concomitant symptoms (urinary incontinence), and complications (urinary tract infections, skin infections, depression and fractures). The model considers the direct medical and non-medical costs, as well as indirect social costs, arising from the traditional management of patients with OAB syndrome (no medication) and the use of solifenacin. As a result, it was found that the use of solifenacin is economically feasible option for the management of patients with OAB within 1 year, the difference in costs between these strategies per patient is 2,385 rubles. The use of solifenacin ceases to be a resource-saving if the cost of incontinence pads will reduced by more than half of the basic price included in the calculations, or if the effectiveness of solifenacin would be 15% lower than the value used in the basic model. PMID- 25807760 TI - [Revisiting the causes of low detection of M. tuberculosis in urine]. AB - The evaluation of potential anti-TB activity and bactericidal activity against opportunistic enterobacteria in urine of healthy people using the automated BACTEC MGIT 960 system for cultivation and determination of drug resistance of mycobacteria and culture on solid media was performed. It has been established that the urine of healthy people do not have bactericidal activity against M. tuberculosis and E. coli in vitro. The one of the possible reasons for the low detection of the pathogen in urogenital tuberculosis--asymptomatic bacteriuria- was identified. PMID- 25807763 TI - [Open and laparoscopic enucleation of renal tumor]. AB - In the structure of oncourological incidence in 2012, renal cancer continues to occupy one of the leading places among oncourological diseases. Radical nephrectomy was the traditional method of treatment of renal tumors. Currently, sparing operations, if technically possible, have become the standard treatment. Attempts to preserve the renal parenchyma during resection in difficult cases have contributed to the development of method of enucleation, which involves enucleating of renal tumor by blunt dissection with minimal damage of normal kidney tissues and intrarenal hemostasis by ligation of the third-order vessels surrounding the tumor. The team of authors presents own successful experience of open and laparoscopic enucleation of the renal tumors. PMID- 25807762 TI - [Renal cancer in the Primorye Territory. Risk factors]. AB - The epidemiological study in Vladivostok and Primorye Territory in period 1999 to 2013 was performed. In the structure of cancer incidence at the evaluated areas, renal cancer occupies fifth place among male population (5.7 and 5.3%, respectively), and 11th place (3.5%) among female population. The problem of renal cancer in this region and the administrative center is relevant due to the increasing incidence: a standardized measures in the period of 2009-2013 were 12.5 +/- 0.3 and 11.7 +/- 0.50/0000, respectively. The Increase of the incidence can be explained by the integrating influence of complex of changing demographics and health, social, hygienic and other factors. The questionnaire survey has become one of the main methods to identify risk factors for the development of the disease. Risk factors for renal cancer were identified by the case-control method. 231 patients with renal cancer (mean age 58.2 +/- 1.7 years) and 354 healthy men and women (mean age 57.4 +/- 2.2 years) underwent questionnaire survey. Specific risk factors for renal cancer were identified: migration (OR = 1.6, P = 0.0149); low socio-economic status (secondary-level education, income per family member less than 10,000 rubles, OR = 1.5, P = 0.0349); started smoking before 18 years of age (OR = 1.5, P = 0.0349); trade with physical activity and occupational hazards (car drivers, sailors, house-painters, OR = 2.0, P = 0.0000); occupational hazard: contact with oil products (OR = 1.6, P = 0.0262), contact with lead, asbestos, dyes (OR = 3.5, P = 0.0000); length of time worked with occupational hazard over 5 years (OR = 1.6, P = 0.0126); occupational hazard in the form of an underground work (OR = 8.0, P = 0.0000) and the presence of large amounts of dust (OR = 1.2, P = 0.0381); location of industrial enterprises within 2 kilometers from homesite (OR = 2.5, P = 0.0000). Based on the identified risk factors, predictive model for the assessment of individual risk and the formation of groups at risk for renal cancer was developed. PMID- 25807764 TI - [Diagnosis and treatment of local recurrence of prostate cancer using hystoscanning and high-intensity focused ultrasound in patients after radical prostatectomy]. AB - The study was aimed to the improvement of the diagnosis and treatment of patients with prostate cancer (PC). The study included 46 patients with recurrent prostate cancer after radical prostatectomy (RPE). The examination included contrast enhanced magnetic resonance imaging (endorectal coil 1.5T) and hystoscanning. All patients had local recurrence confirmed by the morphologically results of transrectal biopsy of the area of vesicourethral anastomosis. All patients underwent high-intensity focused ultrasound (HIFU). Before RPE, protate volume ranged from 21 to 102 cm3. The median age was 62 (46-68) years. PSA levels before a HIFU session ranged from 0.4 to 18 ng/ml. Nadir PSA level after 3 months of follow up was 0.1 ng/ml. Five-year disease-free survival in patients with locally recurrent prostate cancer after HIFU in the group of low cancer risk was 10 (81%), moderate risk--18 (57%), high risk--12 (42%). Contrast enhanced magnetic resonance imaging and hystoscanning are highly informative methods for diagnosis of local recurrence after radical prostatectomy, and HIFU can be categorized as highly effective treatment. PMID- 25807765 TI - [Mitomycin in the complex treatment of strictures of vesicourethral anastomosis after radical prostatectomy]. AB - The study involved 189 patients aged 40 to 80 years, which underwent retropubic radical prostatectomy for localized prostate cancer in the period from 2009 to 2013. 26 (13.8%) patients required repeated surgery due to the deterioration of urination. In primary detection or recurrent nature of the cicatrical process in vesico-urethral anastomosis, in places of dissection by urethrotomic knife (or transurethral resection), surgery was complemented by submucosal injection of mitomycin, previously diluted in saline to a concentration of not more than 0.2 mg/ml. Effectiveness of additional interstitial administration of mitomycin in primary application was 85%. Systemic infusion reactions have not been reported, that allows to consider this method as safe method for prevention of cicatricial complications. PMID- 25807766 TI - [Significance of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase and protein Ki-67 in prostate tumors]. AB - Immunohistochemical evaluation of localization of matrix metalloproteinase-9 (MMP 9) and an inhibitor of matrix metalloproteinase-1 (TIMP-1) and cell proliferative activity in the production Ki-67 protein in benign prostatic hyperplasia (BPH), and adenocarcinoma with different Gleason scores was performed. Moderate positive correlation between the Gleason scores and cell proliferation index usind Ki-67 antigen (rs = 0.674), moderate negative correlation between Gleason scores and levels of MMP-9 production (rs = -0.660), and weak significant negative correlation between the levels of cell proliferative activity and MMP-9 production by tumor cells (rs = -0.369) were established. Invasive properties of tumor cells, expressed in the destruction of type IV collagen in basement membrane and connective tissue of the stroma of the prostate, are associated with imbalance in MMP-9 protein, and blocking enzyme, TIMP-1; and TIMP-1 production is reduced significantly in adenocarcinomas with different Gleason scores compared with BPH. PMID- 25807767 TI - [Experience in the treatment of normogonadotropic infertility in men]. AB - This study presents an experience of application of follicle-stimulating drug in the treatment of men with normogonadotropic infertility. Patients of the study group have received standard treatment, including multivitamins, and additionally received follitropin-alpha (Gonal-f). They also underwent ultraviolet blood irradiation. Patients of comparison group were treated according to a standard scheme. All men underwent standard clinical and laboratory examination. The therapy consisting of follitropin alpha and ultraviolet blood irradiation in patients with infertility normalizes the function of endocrine glands, as indicated by an increase of testosterone levels, and decrease of prolactin and FSH levels. Moreover, there is a marked stimulation of spermatogenesis, as evidenced by a significant increase in the number of active sperm. The results of this study allow to recommend follitropin-alpha (Gonal-f) and ultraviolet blood irradiation for the correction of normogonadotropic treatment in men. PMID- 25807768 TI - [Chronobiological aspects of the use of complex "NeiroDoz" in patients with erectile dysfunction]. AB - The article presents the results of the study including 60 patients with erectile dysfunction, divided into four age groups: 20-30, 31-30, 41-50, and 51-60. All patients have received biocomplex "NeiroDoz" for two months 2 capsules 2 times a day. Clinical effectiveness was evaluated according to the ICF and ICEF questionnaires and according to the patient's subjective evaluation of the clinical efficacy; the psycho-emotional status of patients and changes in the chronograms were also analyzed. In all men with erectile dysfunction, pronounced desynchronosis and psycho-emotional disorders were revealed. The use of complex "NeiroDoz" allowed to correct erectile disorders and psycho-emotional status of patients, as well as to restore normal chronorithms in all groups of patients, regardless of age and severity of erectile dysfunction. PMID- 25807769 TI - [Transurethral electroenucleation of benign prostatic hyperplasia]. AB - Currently, the choice of treatment of benign prostatic hyperplasia (BPH) remains one of the most pressing issues of Urology. The study explored the potentials of monopolar electroenucleation of BPH using a monopolar electrode-pusher and standard equipment for transurethral resection. From January to May 2013, 38 patients with infravesical obstruction caused by large BPH underwent transurethral monopolar electroenucleation. The control group (n = 44) consisted of patients who underwent the traditional monopolar transurethral resection of the prostate of the same size. All patients underwent an identical complex of clinical laboratory tests in the preoperative period and 1, 6 and 12 months after surgery. The technical features of the new technique are presented, intraoperative complications are assessed, early and late results and complications are evaluated. It has been established that one of the significant advantages of this method is the ability to remove significant amounts of adenomatous tissue with low risk of bleeding complications. PMID- 25807771 TI - [Rehabilitation of patients with "forgotten" stents]. AB - The treatment of patients with large calculi, formed on both ends of the long standing stent, remains difficult problem of modern urology. We observed 6 patients with long-term (16 to 24 months) standing stents. Large calculi on both ends of the drain were detected in 5 patients, fragmentation of stent--in 1 patient. Indication for stenting was ureteral calculus in 4 patients, staghorn stone of the left kidney in one pregnant woman 26 years old, and the stent was installed during orthotopic cystoplasty in 1 patient. At the first stage, contact laser lithotripsy of calculus on cystic end of the stent was performed, and distal portion was removed with forceps. 2-3 weeks after, PCNL was performed and renal end of the stent was removed. Patient with fragmentation of stent underwent ureteroscopy, and parts of the drainage were removed. To remove the stent, on average 1.8 endourological intervention was required. Results of operations in all cases were successful. Endourological operations are an effective method for the treatment of patients with large calculi, formed at both ends of the "forgotten" stents. PMID- 25807770 TI - [Endoscopic treatment of vesicoureteral reflux in children]. AB - The one of the most common defects of the ureter-vesical segment in children is the condition, leading to a disorder of obturative function of this segment. Complications of vesicoureteral reflux include continuously recurrent pyelonephritis, reflux nephropathy. In this regard, the choice of the optimal treatment strategy based on minimal invasion is considered as one of the priorities of pediatric urology. The article presents the data obtained during the treatment of VUR in children of different ages in the Clinic of Reproductive Health FSBSI SCCH. A comparative evaluation of the results of endoscopic correction of vesicoureteral reflux depending on the kind of the bulking agent was performed. It was found that the use of endocorrection of reflux is highly effective surgical procedure, with the high number of positive results against the background of use of bulking agent "vantris". The study discriminates a group of patients with vesicoureteral reflux, intractable for endoscopic correction with cystoscopically normal structure of the orifices that allows to refer this method to the initial stage of treatment of the disease. PMID- 25807772 TI - [Ultrasound guided percutaneous nephrolithotripsy]. AB - The study was aimed to the evaluation of the effectiveness and results of ultrasound guided percutaneous nephrolithotripsy (PNL) for the treatment of patients with large stones in renal pelvis. The results of PNL in 138 patients who underwent surgery for kidney stones from 2011 to 2013 were analyzed. Seventy patients (Group 1) underwent surgery with combined ultrasound and radiological guidance, and 68 patients (Group 2)--only with ultrasound guidance. The study included patients with large renal pelvic stones larger than 2.2 cm, requiring the formation of a single laparoscopic approach. Using the comparative analysis, the timing of surgery, the number of intra- and postoperative complications, blood loss and length of stay were evaluated. Percutaneous access was successfully performed in all patients. Postoperative complications (exacerbation of chronic pyelonephritis, gross hematuria) were observed in 14.3% of patients in Group 1 and in 14.7% of patients in Group 2. Bleeding requiring blood transfusion, and injuries of adjacent organs were not registered. Efficacy of PNL in the Group 1 was 95.7%; 3 (4.3%) patients required additional interventions. In Group 2, the effectiveness of PNL was 94.1%, 4 (5.9%) patients additionally underwent extracorporeal lithotripsy. There were no significant differences in the effectiveness of PNL, the volume of blood loss and duration of hospitalization. Ultrasound guided PNL can be performed in large pelvic stones and sufficient expansion of renal cavities, thus reducing radiation exposure of patients and medical staff. PMID- 25807775 TI - [A prima constitutione foetus. The wit theory as a natural faculty in some medical sources of the late Renaissance]. AB - After publication of the Examen de ingenios para la ciencias of Juan Huarte de San Juan (Baeza 1575), Galen's theories on the inheritance of character traits were strongly recovered, especially in Italy, both by physician and philosophers. In this way it has been established an analogy between the natural generation and intellectual generation which will be the basis of seventeenth-century attempts to naturalize the mind. PMID- 25807773 TI - [Markers for non-invasive molecular genetic diagnosis of oncourological diseases]. AB - Currently, there is accumulated mass of data on the molecular-genetic disorders in prostate cancer (PCa), bladder cancer (BC) and renal cancer (RC). Tumor cells in these diseases are present in the urine sediment; their number is sufficient for molecular genetic analysis that makes possible the development of noninvasive diagnosis of oncourological diseases. A characteristic feature of PCa includes the overexpression of the PCA3 gene; assay kit ProgensaTM to quantify such overexpression has been developed; approximately 50% of tumors express a TMPRSS2 ERG chimeric oncogene. Combined analysis of PCA3 and TMPRSS2-ERG allows to detect PCa with a diagnostic accuracy of 84%, which is significantly higher than that of prostate specific antigen test. As a potential markers of BC, there are somatic mutations in FGFR3, PIK3CA, TERT genes in urine sediment, which are found in this disease with a frequency of about 60, 30 and 50%, respectively. The basis of the test system for DNA diagnosis of BC in urine sediment may include a definition of a combination of mutations in these genes with microsatellite instability. Aberrant methylation of the 5'-regulatory regions of tumor suppressor genes, integrated in the panel, also is considered as a tool in the diagnosis of RC (VHL, RASSF1, RARB2, CDH1), PCa (GSTP1, PTGS2, LGALS3) and BC (RASSF1, APC, SFRP2) after standardization of panels of loci investigated, sample preparation methods, bisulfite conversion, and the design of primers and probes. Thus, a test systems for molecular genetic diagnosis of oncourological diseases in urine sediment are currently available or may be developed in the near future. PMID- 25807776 TI - Rome's physician: Guido Baccelli and his legacy in the new Italian capital. AB - Many Italian physicians played a more or less relevant role in the military, social and political events which paved the way to and accompanied the birth of the unitary State, which 150th anniversary falls in 2011, but probably just one of them, Guido Baccelli (1832-1916), left so many traces in the very landscape of the present-day Italian capital. Even if the millions of tourists pouring into Rome every year are not aware of it, the vision and tenacity of this celebrated physician lay behind quite a lot of the most typical and popular places of the Eternal City. Baccelli, as a politician, took care of his home town with the same kindness and effectiveness he put, as a physician, in the care of the sick. PMID- 25807774 TI - [Treatment of exstrophy of bladder in adults]. AB - Exstrophy of bladder in adults is extremely rare, since such anomalies are usually underwent surgery in early childhood. Difficulties in the treatment of adult patients are associated with severe long-term changes of the mucosa and surrounding tissues, chronic urinary infection, as well as a large diastasis between pubic bones and inefficiency of osteotomy. The article describes the methodology and results of the surgery in a patient 33 years old with exstrophy epispadias after failed previous interventions. During the follow-up period of more than 5 years, there were no complications related to continent reservoir, reconstruction of the anterior abdominal wall, and urinary infection. Decrease in renal function was not observed. Thus, the cystectomy with formation of continent reservoir from the ileum is accompanied by a good functional and cosmetic results. Resection of vesical plate is justified due to severe long-term changes of the mucosa and the surrounding skin, as well as a high risk of malignancy. The use of polypropylene ? allows to reconstruct the anterior abdominal wall without osteotomy and provides a sufficient degree of its strengthening. PMID- 25807777 TI - [October the 1st 1777: Sigault executes the first symphysiotomy on a living woman]. AB - Hippocrates observed that in women, during childbirth, the iliac bones because of the failure of the joints disconnet and move away from their anchorage. In the 17th and 18h century, doctors plagued with severe and frequent mechanical dystocies, often fatal, devoted themselves to resolve these problem through measures aimed at obtaining a more modest growth of the fetus (thanks to an appropriate maternal nutrition, or induction of preterm birth) and both encouraging artificially and strengthening the natural pelvic collapse descripted by Hippocrates. They realized, but with little success, prophylactic measures (fumigation of the pelvis, local applications of emollients, fracture of the del coccyx in the female newborns, antepartum coitus), and absurd pharmacological remedies or resorted to intrapartum obstetric maneuvers, but they did non forget even to suggest the voluntary sterility to stunted or kyphotic women. The symphysiotomy on living women, officially performed for the first time by Dr. Sigault in 1777, in Paris (but certainly in 1774 by Prof. Ferrara in Naples) modified the obstetrical assistance. PMID- 25807778 TI - [Exercise of the medical profession between Fermo and Rome in modern age (XVII XVIII centuries). Peregrinatio medica and introduction of freshmen]. AB - The article regards the histor of medical profession between the county of Fermo and Rome in the Early Modern period. During the Seventeenth century the Medical Faculty of the University of Fermo became an important academic centre in the Papal State. During the second half of the Seventeenth century the link between the county of Fermo and the Roman capital became much stronger in the field of medical education and medical practice. Many physicians from Fermo moved to Rome to practise and to improve their professional knowledge. The peregrinatio medica is a strategicfactor towards understanding the development of the medical profession from an outlying area of the ecclesiastical territory to a centre of excellence as the Roman capital was for medicine in the Seventeenth and Early Eighteenth centuries. The medical licence was introduced by the Roman College of physicians as essential to qualifying for medical practice not only in Rome, but in all the provinces of the Papal State. This caused violent controversy between Rome and Fermo that lasted until the Early Nineteenth century. PMID- 25807779 TI - [Sports practice and body's limits in the Corpus Hippocraticum, Plato and Aristotle]. AB - We deal with ancient Greek texts (above all texts of the Corpus Hippocraticum, Plato and Aristotle) where the training and, in general, the way of life of the professional athletes are blamed, because of several reasons: 1) They are harmful to the health, because health is the consequence of an adequate balance between the four major body humours and between feeding and physical exercises; instead, illness comes when this balance is broken, either for lack or, as in the case of the athletes, due to an excess. 2) Bodies that the professional practice of sport makes, are neither beautiful nor harmonious, but deformed because of the overdeveloped muscles and the overspecialized training. 3) Athletes' way of life and training aim at the development of the physical strength and neglect the development of intellectual and moral qualities. PMID- 25807780 TI - [The Ehlers-Danlos syndrome: hystory of a clinical hendiadys]. AB - Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility, which results in easy bruising and abnormal scarring. The condition shows a phenotypic variance from milder to serious presentations. Complaints related to activity (hypermobility, dislocations, impaired balance), to pain (general pain, headache, jaw and tooth pain) and to skin (bruises, fragility, impaired wound healing) are frequent. It was first noted by Hippocrates in 400 BC in his writing 'Airs Water and Places' that the nomads Scythians had lax joints and multiple scars. Whereas the additional flexibility can give benefits in term of mobility and agility, adverse effects of tissue laxity and fragility can give rise to clinical consequences. We recognize that it is important that, in those hypermobility patients, who develop potentially debilitating symptoms of chronicfatigue or widespread pain, there should be prompt an appropriate intervention. PMID- 25807781 TI - [Intra-moenia: a historical and economical research]. AB - The so called free practice intra-moenia or ALPI (to be performed inside the public premises) is very popular among Italian doctors (quite so among patients). Our work aims to shed light both on true motives of such a success and on the degree of accomplishment of stated targets at its institution. We believe that its success among doctors is due both to the increase in providers' autonomy and to its economic advantages. Freedom of choice for patients is also increased (though just a minority of patients says that they have made recourse to intra moenia because they wanted to choose the doctor). The reduction of queues, one of the stated targets of ALPI, did not happen (as could be anticipated). Intra moenia may cause, moreover, induction of demand and defensive medicine. A regression analysis shows that the main explanatory factor of the recourse to ALPI is urgent need for treatment. The work, finally, in noting that there is a lack of sufficient administrative controls on ALPI, concludes that intra-moenia is hopefully a viable institution provided that more checks are done. PMID- 25807782 TI - [The representation of Italian psychiatry in Italian Treccani Encyclopedia in 1930's]. AB - The article reconstruct the situation of Italian psychiatry around 1930, using as unusual sources the pages of the Enciclopedia Italiana di Scienze, Lettere e Arti. This important work, conceived in 1925 and finished in 1937, is due - as well known - to the strong interest of Giovanni Gentile and to his capacity to involve in the project a great part of Italian intellectual world, without any ideological preclusion. The section devoted to Medical Sciences, including Psychiatry, was directed by Nicola Pende (1880-1970) and Giacinto Viola (1870 1943). A prevalent positivistic approach to science is well testified by their specific attention to preventive and social medicine, researches in Genetics and in biotypological constitutions. Psycopathological and psycological lemmas are very limited, underlying the medical disinterest towards contemporary philosophy and psycology. PMID- 25807783 TI - [The Hospital of Holy Spirit in Saxia of Rome during the XIII century examples for the study of an economic power's development]. AB - The author analyzes the development of the Holy Spirit hospital's economic power during the XIII century through some illustrative examples of original parchment documents, pontifical and private. After the hospital was founded by the pope Innocentius III and gifted of many properties, its charitable activity attracted the admiration and respect of many people, who, with donations and testamentary dispositions, not only around Rome, but also in several Italian regions and outside Italy, contributed to make it ever more powerful in an economic sense. PMID- 25807784 TI - [Medical practices in the migration novels in Spain]. AB - Starting from the analysis of three Spanish novels written by African authors emigrated in Spain, the article focuses on different medical practices adopted locally, in Africa and in Europe. El Metro, Mas alla del mar de arena and Rebeldia give the different disease treatments imagine, showing, on the one hand, the official medicine, and on the other hand, the traditional medicine. In some cases, it is emphasized little contradictions, doubts, and anxieties often experienced by immigrants, even when they are faced with the type of treatment to be undertaken. One of the many mosaic pieces of the world is highlighted: in fact, habits and cultures are very different in a society where more and more people with different physical appearance, language, religion, and customs live understanding that what "belongs" to the other is not necessarily something "distant" and extraneous, but something that can enrich our cultural identity for our open-mindedness. PMID- 25807785 TI - [Fire worship on Soratte: form prehistory to present days]. AB - Fire has always been involved in human thoughts, believes and actions. For many psychological reasons fire has been considered as living power: red as the human blood, warm as the human body, clearly shines in the night. Fire worship is very common, especially in regions where terrestrial fire is believed to be the image of the heavenly fire. Fire worship has represented the base for symbolic systems involved in the cultural-anthropological evolution of populations settled close to mount Soratte. Fire cults in this region have originated in independent and long-time separated contexts, according to available knowledge. Hirpi Sorani, ancient inhabitants of mount Soratte territory, celebrated Sorano Apollo by a famous fire walking ceremony, with a likely cathartic and apotropaic meaning, as reported by ancient Roman writers. The victory of Christianity over paganism caused the decline of these religious practices. The beginning of the XIX century witnessed the establishment ofa new kind of devotion to the Virgin Mary at the mount Soratte. Today, this religious piety-linked identity has weakened due to changes in lifestyles,from an agricultural to one based on outside home employment, and has been largely shifted on cultural and anthropological bases. In conclusion, fire worship at mount Soratte has evolved because of external influences and local inhabitants have reacted by asserting their own identity. PMID- 25807786 TI - [Bladder reconstruction using autologous bone marrow mesenchyaml stem cells seeded bladder acellelar matrix graft in a canine model]. AB - OBJECTIVE: To investigate the feasibility of autologous bone marrow mesenchymal stem cells(BMSCs) seeded on bladder acellular matrix graft (BAMG) for bladder reconstruction in a canine model. METHODS: This study included 25 mongrel dogs. Five dogs were sacrificed for the preparation of BAMG. Twenty dogs were randomly divided into two groups and received partial cystectomy. In group A, the bladder defect was repaired with unseeded BAMG. In group B, the bladder defect was repaired with autologous BMSCs-seeded BAMG. The bladders were retrieved and studied histologically and immunohistochemically at the time point of 1, 2, 4, 8, 12 weeks after surgery to evaluate tissue regeneration. RESULTS: All dogs survived the procedure. Histopathological examination in group B showed there was urothelium developed at the end of the 2 weeks. By 8 and 12 weeks all bladder wall components were regenerated in the repaired area, which were similar to normal bladder tissue. In group A, urothelium regeneration was observed at the end of the 4 weeks, whereas smooth muscle was still not well-formed by 12 weeks. CONCLUSION: Autologous BMSCs-seeded BAMG could promote the repair of bladder defect, which is superior to unseeded BAMG in regenerative properties. PMID- 25807787 TI - [Influence of exogenous nitric oxide on chondrogenic differentiation of adipose derived stem cells]. AB - OBJECTIVE: To determine the effects of exogenous nitric oxide (NO) donor sodium nitroprusside (SNP) on the proliferation and expression of related-gene of adipose-derived stem cells(ADSCs) and its role in chondrogenic differentiation of ADSCs. METHOD: Rat ADSCs were harvested and cultured, and then induced to osteogenic and adipogenic differentiations, detected with Alizarin red stained and Oil red O stain, respectively. The change of NO during chondrogenic differentiation of ADSCs was tested by NO detection kit. Cell counting kit-8 (CCK8) was used to detect the proliferation of ADSCs under different concentrations of SNP (0.25 mmol/L, 1.00 mmol/L, 4.00 mmol/L). Gene expression level of transformation growth factor (TGF-beta1) and specific gene of chondrogenic differentiation-signaling protein Smad3 and Collage II alPHA (Col-II alpha1), were detected by Real time- PCR (RT-PCR) method. RESULTS: Positive alizarin red staining and Oil red O staining were found after osteogenic and adipogenic induction of cultured ADSCs. Higher concentrations of NO were found in the supernatant of the experimental group with ADSCs chondrogenic differentiations compared with the controls (P<0.05). Low concentrations (0. 25 mmol/L, 1.00 mmol/L) of SNP showed no significant effects on cell proliferations (P>0.05), whereas high concentration (4. 00 mmol/L) of SNP inhibited cell proliferation (P<0.05). RT-PCR revealed that SNP inhibited the gene expression of TGF-beta1 mRNA and chondrogenic differentiation of specific gene Smad3 mRNA, Col II alpha1 mRNA. CONCLUSION: SNP can inhibit chondrogenic differentiations by suppressing the production of TGF-beta1 and inhibiting downstream of TGF-beta1 signaling pathways, thereby inhibiting ADSCs differentiation into chondrocytes. PMID- 25807788 TI - [Research on the relevance between the virulent genes differential expression and pathogenecity of Leptospira with microarray]. AB - OBJECTIVE: To find the change of virulent gene expression and to analyze the relevance between the virulent change and the gene expression. METHODS: Grouped guinea pigs were inoculated with 1 mL Leptospira cultured in vivo, Leptospira cultured in vitro and the Leptospira culture medium through abdominal subcutaneous respectively. The survival rate, body mass and temperature change of guinea pigs in different groups were measured within 15 d after the inoculation, then the survived guinea pigs were scarified, and the organ coefficient was also measured to know the virulence of Leptospira cultured in different environment. The amplified gene segments from Leptospira were used as probes and wrote the microarray. The total RNA was extracted from Leptospira standard strain cultured in culture medium and guinea pigs. After reverse transcription to cDNA, they were labeled with Cy3 and Cy5 respectively. Labeled cDNA was mixed and hybridized with the microarray. The hybridized mircroarray was scanned and analysed. RESULTS: The survival rate of inoculated guinea pig was different from group to group (in vivo group: 0%; in vitro group: 88.9%; culture medium group: 100%). The guinea pigs in vivo group had a higher temperature (P<0.05), lighter body mass (P<0.05), larger organ coefficient (P<0.05) and a more serious hemorrhage in lung. The genes from Leptospira: LA1027, LA1029, LA4004, LA3050, LA3540, LA0327, LA0378, LA1650, LA3937, LA2089, LA2144, LA3576, LA0011 and gene of Loa22 were up regulation after continuously cultured in guinea pigs. CONCLUSION: The pathogenic ability of Leptospira cultured in different environment is different and the gene expression of Leptospira is different between in vivo and in vitro as well. The understanding of the meaning of this change might help to know the pathogenecity of Leptospira. PMID- 25807789 TI - [Changes in expression of PYCARD gene and its transcript variant mRNA in peripheral blood mononuclear cells of patients with primary gout]. AB - OBJECTIVE: To determine the expression level and role of PYCARD [PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase recruitment domain (CARD), PYCARD] gene and its transcript variant mRNA in peripheral blood mononuclear cells (PBMCs) of patients with primary gout (PG). METHODS: PYCARD gene and its transcript variant mRNA were measured using reverse transcription-polymerase chain reaction (RT-PCR) in PBMCs. The expression of PYCARD gene and PYCARD-1,-2 mRNA in PBMCs was compared between the patients with acute phase PG (APPG) (n=44), non-acute phase PG (NAPPG) (n= 51) and healthy controls (HC) (n=87). PYCARD and NF-kappaB (p105/p50) protein expressions were measured using Western blot in the PBMCs of participants in the PG and HC groups. Routine blood tests and blood uric acid test were undertaken in all participants. Differences in the indicators were examined among the three groups. Correlations between the expression of PYCARD gene and PYCARD-1,-2 mRNA and other indicators were analyzed. RESULTS: The expression level of PYCARD gene, PYCARD-1,-2 mRNA was significantly higher in the APPG and NAPPG group than in the HC group (P<0.01). The NAPPG group had significantly higher levels of PYCARD gene transcript variant 2x mRNA and 2y mRNA in the HC and APPG groups (P<0.05). The expression of PYCARD and NF-kappaB (p105/p50) protein was significantly higher in the PG group compared with the HC group [(4.900 +/- 1.324) vs. (3.975 +/- 0.210) and (0.263 +/- 0.106) vs. (0.127 +/- 0.008), respectively P<0.05]. The expression level of PYCARD-2 mRNA and granulocyte were positively correlated in the NAPPG group. CONCLUSION: Abnormal expression of PYCARD gene and its transcript variant and PYCARD protein in PG patients suggests that PYCARD gene and its transcript variant may play an important role in regulating the inflammatory response of PG patients. PMID- 25807790 TI - [Preliminary study on the pathogenic mechanism of myoglobin-induced endoplasmic reticulum stress and apoptosis in crush syndrome]. AB - OBJECTIVE: To explore the pathogenic mechanism of myoglobin-induced endoplasmic reticulum stress (ERS) and apoptosis in tubular epithelial cells in acute kidney injury (AKI) mouse model of crush syndrome. METHODS: Eighteen C56BL/6 mice were randomly divided into control group, modeling 8 h group and modeling 24 h group. The AKI model of crush syndrome was established by intramuscular injection of 50% glycerol saline solution into thigh (8 microL/g), while equivalent volume of physiological saline was injected in control group. AKI was diagnosed when serum creatinine (sCr) level increased to double value of control group. The mice in the experimental groups were sacrificed at the time points of 8 h and 24 h after injection respectively. Serum Cr was detected and renal tissues was observed under electron microscopy. Apoptosis was detected by TUNEL technique. Marker proteins and mRNA of apoptosis and ERS were detected by immunohistochemistry and real-time PCR. Human kidney proximal tubular cell (HK-2) cells cultured in vitro were randomly divided into control, intervention 6 h and intervention 12 h groups. Control group were incubated in standard cell culture (DMEM/F12) and the two intervention groups were incubated in special DMEM/F12 in which ferrohemoglobin was added. After 6 h and 12 h incubation, the cells were collected and apoptosis was detected by flow cytometry. RESULTS: AKI model of crush syndrome was successfully established, which was proved with sCr doubling at the 8 h after the intramuscular injection of glycerol saline. Swelling of endoplasmic reticulum and mitochondria in proximal tubular epithelial cells was more obvious in the two model groups than that in control group. TUNEL staining showed the percentage of positive cells in AKI groups was higher than that in control group (P<0.05). Immunohistochemistry and real-time PCR showed the expressions of caspase3, caspase12 and CHOP in AKI groups were higher than those in control group (P<0.05). Flow cytometry showed cell apoptosis ratio was higher in model groups than control groiap (P<0.05). CONCLUSION: Myoglobin induced ERS and apoptosis may be involved in the pathogenesis of AKI in crush syndrome. PMID- 25807791 TI - [Regulatory effect of two component signal transduction system saeRS on the survival of Staphylococcus epidermidis]. AB - OBJECTIVE: To investigate the survival ability of Staphylococcus epidermidis (S. epidermidis) wildtype (WT), saeRS mutant (SAE) and saeRS complementary (SAEC) strains under different concentrations of glucose. METHODS: We measured the survival ability, biofilm forming ability, medium acidity and antimicrobial susceptibility of S. epidermidis in medium containing different concentrations of glucose. RESULTS: Compared with WT, the survival ability, biofilm forming ability and resistance to antibiotics (such as penicillin, oxacillin, gentamicin, ciprofloxacin and amikacin) of saeRS mutant increased significantly in response to glucose. SAE and SAEC showed the strongest survival ability and biofilm forming ability when grown in medium containing 14 mmol/L glucose and 28 mmol/L, respectively. WT showed no significant different survival and biofilm forming abilities when cultured with various concentrations of glucose. The medium acidity of saeRS mutant (pH=8.07) was lower than the WT (pH=7.0) in the presence of 14 mmol/L glucose. CONCLUSION: SaeRS may influence the survival ability of S. epidermidis by affecting glucose utilization. PMID- 25807792 TI - [The effect of electrical stimulation of nucleus tractus solitarius on cardiac nociception and its spinal cord mechanism in rat]. AB - OBJECTIVE: Examine the effect of electrical stimulation of nucleus tractus solitaries (NTS) on cardiac-somatic motor reflex (CMR) that induced by intrapericardial administration of capsaicin to clarify the spinal cord mechanism of NTS involved in cardiac nociception in rat. METHODS: SD rats were randomly divided into electrical stimulation, control, yohimbine and naloxone group and treated with elecetrical stimulation NTS alone, or with intrathecal injection of vehicle, saline, norepinephrine a2 receptors antagonist (yohimbine), opioid receptor antagonist (naloxone) respectively. RESULTS: Electrical stimulation of NTS (10, 20, 50 MA), the CMR response deceased in an intensity-dependent manner (P<0.05); intrathecal injection of vehicle, saline had no effect on the inhibition effect of electrical stimulation (P>0.05); intrathecal injection of yohimbine (20 microg, 50 microg) or naloxone (50 microg, 100 microg), reversed the inhibition effect of electrical stimulation (P<0.05); intrathecal injection of low dose of naloxone, the inhibition effect of electrical stimulation was potentiated. CONCLUSION: Electrical stimulation of NTS has inhibition effect on cardiac nociception, norepinephrine alpha2 receptors and opioid receptor in spinal cord involved in this descending inhibition, low dose of naloxone has synergetic effect with descending inhibition. PMID- 25807793 TI - [Promotive effect and its molecular mechanism of KLF5 on gemcitabine-induced apoptosis in human lung adenocarcinoma cell line H441]. AB - OBJECTIVE: To investigate the effects of kriippel-like factor 5 (KLF5) overexpression on gemcitabine (GEME)-induced lung adenocarcinoma cell apoptosis and its molecular mechanisms. METHODS: Lung adenocarcinoma cell line H441 were transfected with KLF5 plasmid or control plasmid. 68 h later, cells were treated with 100 nmol/L GEME for 4 h, then cell number counting and flow cytometry were applied to detect cell proliferation and apoptosis; Western blot were used to analyse the expression level of KLF5, RT-PCR were used to analyse the KLF5 gene, apoptosis-related genes CD95 and BAX; Immunofluorescence staining was performed to detect the expression level of apoptosis-related protein Caspase 3. RESULTS: The overexpressions of KLF5 protein were detected in cultured-lung adenocarcinoma cell line H441 cells when KLF5 plasmids were transfected 68 h. Further flow cytometry, overexpression of KLF5 in H441 cell line affected the biological process of apoptosis significantly. No significant changes of apoptosis and expression level of CD95 and BAX in H441 cells were observed by KLF5 overexpression without GEME treatment (P>0.05). Under GEME induction, the proportion of apoptotic cells and expression level of CD95 and BAX were increased significantly in H441 cells by KLF5 overexpression, compared with that of control (P<0.05); The overexpression of KLF5 restrained the proliferation of H441 cells; Immunofluorescence staining of Caspase 3 was also enhanced after KLF5 overexpression. CONCLUSION: Under GEME induction, the overexpression of KLF5 promoted the apoptosis of lung adenocarcinoma cell line H441 in vitro, possibly through the inhibition of cell proliferation and repair/activation of apoptosis pathway proteins, such as Caspase 3, CD95 and BAX. PMID- 25807794 TI - [Protective effect of ligustilide against low potassium induced apoptosis in cultured rat cerebellar granule neurons]. AB - OBJECTIVE: To investigate the effect of ligustilide (LIG) on low potassium induced apoptosis in primary cultured cerebellar granule neurons (CGN). METHODS: Apoptosis was induced by low potassium in cultured neonatal rat CGN in vitro. The CGN was divided into control/model/CGP54626 + LIG and LIG group. The neuronal viability of each group was measured by MTT assay. The protein expression levels of the key insulin-like growth factor 1 (IGF)-1 signaling effectors,including the phosphorylated IGF-1 receptor (IGF-1R), Akt, ERK1/2, CREB and activated caspase 3 were examined by Western blot analysis. RESULTS: LIG ranging from 2.5 to 20 micromol/L could protect against low potassium-induced apoptosis of CGN ini a concentration-dependent manner. 20 micromol/L LIG significantly induced upregulation of the phosphorylated levels of IGF-1, Akt, ERK1/2 and CREB, and downregulation of cleaved-caspase 3 expression, which could be blocked by a selective gamma-aminobutyric acid B (GABAs) receptor antagonist CGP54626. CONCLUSION: LIG concentration-dependently protects against low potassium-induced apoptosis in CGN at least partly through GABAa receptor activation and its downstream IGF-1 signaling pathway. PMID- 25807795 TI - [Tsc1 promoter methylation rate, mTOR expression in food-induced obese rat hypothalamus]. AB - OBJECTIVE: To investigate the methylation rate of tuberous sclerosis complex 1 (Tsc1) promoter and expression of mammalian target of rapamycin (mTOR) in food induced rat hypothalamus. METHODS: 16 male SD rats were divided into high fat diet induced group (8 rats) and normal control group (8 rats) feeding for 12 weeks. Body mass, mass of celiac fat, celiac fat/body mass were measured. Methylation of Tsc1 promoter, mRNA and protein expression of mTOR were detected by bisulfite sequencing method, RT-PCR and Western blot, respectively. RESULTS: Mass of celiac fat, celiac fat/body mass were higher in food-induced rat than that in control group. There were 11 methylation sites in SD rat hypothalamus. Obese group has significantly higher methylation rates (94.50% +/- 4.66%) than that of control group (86.60% +/- 3.49%) (P<0.002). The mRNA and protein expression of mTOR were noted lower in control group than in obese group (P<0.05). CONCLUSION: The increased methylation rate of Tsc1 promoter in food induced rat hypothalamus and up-regulated expression of mTOR, downstream gene of Tsc1 may promote the obesity. PMID- 25807796 TI - [Influence on the expression of RHOA and ROCK-II after global cerebral ischemia reperfusion in hippocampus by shenxiong huayu capsule]. AB - OBJECTIVE: To investigate the effect of Shenxiong Huayu capsule on the expression of hippocampal CA1 recombinant protein A (small GTP binding protein A, RHOA) and ROCK-2 (RHO associated protein kinase-2, ROCK-II). METHODS: Clean SD male rats (n=96), divided into three groups with 32 rats for each group, gavage was applied 7 days before modeling until the morning of the day to put to death. The groups included the normal control group (normal saline), global cerebral ischemia model group (normal saline) and Shenxiong Huayu capsule+global cerebral ischemia group (Shenxiong Huayu capsule 0.048 g/kg, was dissolved in 0.5 mL double distilled water, once a day, orally 0.3 mL/100 g). Modified Pulsinelli four-vessel occlusion model was constructed in global cerebral ischemia model and Shenxiong Huayu treatment groups and at 1, 3, 7, 14 d after successful modeling, water maze learning test was applied to evaluate the memory abilities of different groups, histopathological changes in HE staining, expression and protein content of RHOA and ROCK-II in immunohistochemical staining and Western blot was observed. RESULTS: At each time point, escape latency in model group was prolonged (P<0.05) when compared with that in normal control group, and that in Shenxiong Huayu was shorter (P<0.05) than that of model group, but still longer (P<0.05) than that of normal control group. HE staining showed that, compared with the normal group, model hippocampal CA1 reduced gradually from 1 d to 14 d; an increased survival neurons (P<0.05) in Shenxiong Huayu treatment group at each time points was observed, but still less than that in normal group (P<0.05); immunohistochemistry and Western blot analysis demonstrated that the expression of RHOA and ROCK-II in normal control group was not obvious, in model group was decreased after an initial increasing, and that in Shenxiong Huayu treatment group was lower than that of model group (P<0.05), but still higher than that in normal group (P<0.05). CONCLUSION: Shenxiong Huayu capsule improve neuronal damage induced by global ischemia, decreased the expression of hippocampal CA1 region of RHOA and ROCK-II. PMID- 25807797 TI - [Ambulatory arterial stiffness index and associated factors in patients with diabetic kidney disease]. AB - OBJECTIVE: To compare arterial stiffness between diabetic kidney disease and non diabetic kidney diseaseand to identify factors predicting ambulatory arterial stiffness index (AASI). METHODS: Forty-four patients with diabetic kidney disease (DKD group) and thirty-one patients with non-diabetic kidney disease (NDKD group) were recruited for this study. All of the participants had hypertension. The AASI (indirect reflex global arterial stiffness)and short-term blood pressure variability (BPV) were measured using a 24-h ambulatory BP monitoring, and compared.between DKD and NDKD groups using analyses of covariance, correlation analysis and multivariate linear regression model. RESULTS: DKD patients had significantly higher levels of AASI than NDKD patients (0.55 +/- 0.14 vs. 0.45 +/ 0.16, P < 0.05). The 24-h systolic and daytime systolic BP variability of DKD patients was also higher than NDKD patients. In DKD patients, the correlation analysis revealed that the AASI showed association with 24-h systolic BP variability (24 hSBPV), 24-h diastolic BP variability (24 hDBPV),daytime diastolic BP variability (dDBPV), nighttime systolic BP variability (nSBPV) and nighttime diastolic BP variability (nDBPV), and nDBPV and age showed strong associations with AASI. CONCLUSION: Although both DKD and NDKD patients suffered from arterial stiffness, greater AASI and short-term BPV was detected in DKD patients. AASI is associated with nDBPV and age. Optimal short-term BPV control in hypertensive type 2 diabetic patients with overt nephropathy may improve arterial elasticity. PMID- 25807798 TI - [Effects of 17beta-estradiol on the expression Caveolin-1 and type III collagen in the mouse lung fibroblast stimulated by SiO2]. AB - OBJECTIVE: To observe the effects of different concentration of 17P-estradiol (17p-E2) on the expression of Caveolin-1 and type 11 collagen in the mouse lung fibroblast stimulated by SiO2. METHODS: Fibroblast cells were devided into five groups: blank control group, Si02 (100 mg/L) group and SiOz (100 mg/L)+ different concentration of 17beta-E2 (10(-8),10(-6),10(-6) mol/L) groups. After treated with different concentration of 17beta-E2, for 48 h, the cells were collected, then the expression of Caveolin-1 and of type III collagen were examined with immunohistochemistry method. RESULTS: Compared with the blank control group, the expression of Caveolin-1 in mouse lung fibroblasts treated by SiO2 significantly decreased (P<0.05), While which in the SiO2 +17P-E2 group significantly increased as 17beta-E2 dose increased (P<0.05); There were significantly different in the expression of type III collagen among different groups (P<0.05), which in SiO2 group were evidently higher than that in the blank control group, while which in 17p-E2 groups decreased significantly, when compared with SiO2 group (P< 0.05); 17beta-E2 increased the expression of Caveolin-1 and decreased the expression of type 1f collagen in the dose dependent manner. Correlation analysis showed that 17p-E2 was positive correlated with the expression of Caveolin-1 (r=0.926, P<0.05), and negative correlated with the express of type Ill collagen (r = 0.914, P<0.05), and the expression of Caveolin-1 and the expression of type III collagen was negatively correlation (r = -0.887, P<0.05). CONCLUSION: 17beta-E2 may inhibit the expression of type III collagen by up-regulating the expression of Caveolin-1 in mouse lung fibroblast cell to play a role in the resistance of the lung fibrosis. PMID- 25807799 TI - [Effects of APOC3 polymorphisms on the plasma lipids in healthy adolescents with different body mass index]. AB - OBJECTIVE: To investigate the possible effects of apolipoprotein C I gene (APOC3) polymorphisms on plasma lipids in healthy adolescents with different body mass index (BMI). METHODS: Seven hundred and twenty three adolescents were divided into four groups according to BMI: group 1 CBMI= (17.80 +/- 0.75) kg/m2,n=180], group 2 [BMI = (19.39 +/- 0.32) kg/m2, n=182), group 3 [BMI= (20.68 +/- 0.43) kg/m2, n=1813 and group 4 [BMI= (23.40 +/- 2.05) kg/m2 ,n=180J. Fasting venous blood samples were collected, plasma lipids were determined and genome DNA was extracted for determining the genotypes of the APOC3 Sst I and -482C>T polymorphisms by PCR-RFLP. RESULTS: With the elevation of BMI, height and plasma high-density lipoprotein cholesterol decreased significantly (P<0.001 for both), body mass, waist circumference, hip circumference, waist/hip ratio, plasma triglycerides (TG), total cholesterol and low-density lipoprotein cholesterol levels increased significantly (P<0.001 for all). No significant differences in TG levels among Sst I genotypes were observed in group 1, group 2 and group 3; but in group 4, significant differences in TG levels among Sst I genotypes were observed, S2 carriers had higher TG levels than the adolescents with S1S1 genotype. No significant differences in plasma lipids among -482C>T genotypes were observed in all groups. CONCLUSION: The elevation of plasma TG levels by the S2 allele of APOC3 Sst I polymorphism is associated with BMI. It is possible that the reduction of body mass could favorably modulate the elevation of TG levels by S2 allele in healthy adolescents. PMID- 25807800 TI - [Effect of ingested immunoglobulin on sIgA expression in pediatric rotavirus enteritis]. AB - OBJECTIVE: To identify the effects of ingested anti-rotavirus immunoglobulin on enteric expressions of SIgA in pediatric rotavirus enteritis. METHODS: In this randomized, placebo controlled clinic trial, 100 patients of pediatric rotavirus enteritis who simultaneously received fluid replacement as basic therapy, were randomly divided into control and immunoglobulin treated groups. The patients in experimental group were given "ingested antirotavirus IgY". Stool sample was collected at day 1, 3, 5, 7, 9 and 11, the level of fecal SIgA was quantifies by radioimmunoassay kit, and fecal rotavirus shedding was detected by double sandwich ELISA. RESULTS: The frequency of diarrhea in immunoglobulin group was obviously less than that in control group (P<0.05). The mean course of diarrhea was (4.5 +/- 0.92) d in immunoglobulin group, and (5.8 +/- 1.68) d in control group (P=0.015). The fecal SIgA level in immunoglobulin group was higher than that in control group(P<0.05). The doubling time of SIgA level was the 3rd d in immunoglobulin group, and the 5th d in control group. The fecal rotavirus shedding in immunoglobulin group was obviously lower than that in control group (P < 0.05). CONCLUSION: Ingested anti-rotavirus immunoglobulin could promote the expression of enteric SIgA to remove rotavirus, achieving the benefit to release diarrhea in pediatric rotavirus enteritis. PMID- 25807801 TI - [Genotypes and in vitro antifungal susceptibility of Cryptococcus isolates in Sichuan Province]. AB - OBJECTIVE: To determine the genotypes and in vitro antifungal susceptibility of Cryptococcus strains isolated from Sichuan Province. METHODS: Ninety two clinical isolates of Cryptococcus spp. were collected from West China Hospital. Genotyping of the URA5 gene was accomplished by restriction fragment length polymorphism. The minimum inhibitory concentrations (MIC) of the isolates to 5 antifungals, including amphotericin B, flucytosine, fluconazole, itraconazole and voriconazole were determined by agar-based E-test method. The MIC50 and MIC90 were calculated based on MICs. RESULTS: Among the 92 clinical isolates, 91 were molecular type VN I and one was VG II. The susceptibility range, MIC50 and MICW, of the isolates to five antifungals were as follows: (<0.002-2) microg/mL, 0.19 microg/mL and 0.75 microg/mL for amphotericin B; (0.5-> 32) microg/mL, 4 microg/mL and 8 microg/mL for flucytosine; (0.5-32) microg/mL, 3 microg/mL and 8 microg/mL for uconazole; (0.064-2) microg/mL, 0.5 microg/mL and 1.5 microg/mL for itraconazole; (0.004 0.19) microg/mL, 0.047 microg/mL and 0.094 microg/mL for voriconazole. Three (3.3%) isolates were resistant to amphotericin B, 4 (4.3%) to flucytosine and 25 (27.2%) to itraconazole. No isolate was resistant to fluconazole and all isolates were susceptible to voriconazole. The isolate Cryprococcus gattii was resistant to flucytosine, while S-DD was resistant to fluconazole. There were significant differences in the MICs of the strains isolated from different periods. The MICs of the isolates to amphotericin B and flucytosine increased over time. CONCLUSION: VNI molecular type is the major genotype of Cryprococcus in Sichuan. All the agents have good in vitro activities against the tested strains except itraconazole. A few stains are resistant to amphotericin B and flucytosine. PMID- 25807802 TI - [Adhesion of Streptococcus mutans to removable denture crowns]. AB - OBJECTIVE: To determine adhesion of Streptococcus mutans (S. mutans) to different kinds of removable denture crowns for the purpose of minimizing influence of removable denture on oral environment. METHODS: Three kinds of removable denture crowns (single color synthetic resin teeth, alloy pin porcelain tooth and minute color synthetic resin teeth) were adsorbed S. mutans for 24 h in sterile saliva, The adhered bacteria were counted by means of sonic oscillation and bacteria coating. RESULTS: Highest level of adhesion was found on ,the single color synthetic resin teeth was adsorbed mostly, followed by alloy pin porcelain teeth. Minute color synthetic resin teeth had far less adhesion than the others (P<0.01). CONCLUSION: Minute color synthetic resin teeth have less adhesion of S. mutans, which may be associated with their lower level of surface free energy. PMID- 25807803 TI - [Reliability and validity of DSSI-23 scale in a rural elderly population]. AB - OBJECTIVE: To determine the reliability and validity of the Duke Social Support Index (DSSI)-23 scale in a rural elderly population. METHODS: A stratified cluster random sampling strategy was adopted to select 702 rural participants aged 60 years or over in Guangyuan. Those with severe hearing disorders or mental problems were excluded. The reliability and validity of DSSI-23 scale were evaluated using internal consistency, split-half reliability,content validity, convergent validity, discriminant validity and structure validity. RESULTS: The DSSI-23 had a Cronbach's alpha efficient of 0.881 and 0.918 split-half reliability. Item-scale correlation coefficients exceed 0.35 (P<0.01), except for item three. Satisfactory (100%) convergent validity and discriminant validity were found. Confirmatory Factor Analysis (CFA) demonstrated unsatisfactory fit with the theoretical model of the scale: chi2/df = 6.884, CFI=0.807, GFI=0.850, RMSEA=0.092. CONCLUSION: DSSI-23 scale has good reliability in the elderly population, but unsatisfactory validity. Further adjustments of the scale are needed. PMID- 25807804 TI - [Assessing quality of life of patients with stroke using EQ-5D and SF-12]. AB - OBJECTIVE: To compare.the results of EQ-SD and SF-12 for assessing health-related quality of life in stroke patients. METHODS: EQ-5D and SF-12 were administered to 598 ischemic stroke patients through face-to-face interviews. Differences in PCS 12 and MCS-12 scores across different levels of EQ-5D dimensions were tested using analysis of variance (ANOVA). The EQ-5D index and visual analogue scale/score (VAS) scores of respondents were compared between those with higher than and lower than median SF-12 scores using student t-test. Pearson correlations between PCS-12 and EQ-5D scores were tested. RESULTS: PCS-12 and MCA 12 scores varied across different levels of EQ-5D dimensional scores, except for pain/discomfort. EQ-5D and VAS scores varied between those with high and low SF 12 scores. No significant differences in EQ-5D index and VAS scores were found in the EQ-5D indicated healthy respondents between those with high and low SF-12 scores (P>0.05). PCS-12 was positively correlated with EQ-5D index and VAS scores, with r=0.15 (P<0.001) and r=0.33 (P< 0.001), respectively. MCS-12 was also positively correlated with EQ-5D index and VAS score, with r=0.17 (P<0.001) and r = 0.13 (P<0.001), respectively. CONCLUSION: Both instruments are valid measurements for assessing quality of life. The SF-12 appeared to be more sensitive to differences in health status. EQ-5D is preferable if both quality of life assessment and health economics study are to be conducted. PMID- 25807805 TI - [Research status of the pathogenesis of pre-eclampsia]. AB - Pre-eclampsia is a serious obstetric complication, not only affect maternal health, but also affect the long-term prognosis of offspring generation. Even though various theories on the pathogenesis of pre-eclampsia have been proposed in recent decades, it remains unclear due to the disadvantages in these theories. Therefore, the pathogenesis of pre-eclampsia keeps attracting a lot of research efforts in the field of obstetrics. In order to find the new break through points in the study of pre-eclampsia pathogenesis (pre-eclampsia related to genetic, epigenetic and expression changes of some genes), it is necessary to illustrate and understand the research status in this field, with integrating the related resources, updating the new progress, ideas and extensive research means. PMID- 25807810 TI - [Expression of p57(kip2) gene in placenta tissue of patients with pre-eclampsia]. PMID- 25807807 TI - [The Ala379Val polymorphism of platelet-activating factor acetylhydrolase gene in Chinese patients with pre-eclampsia]. AB - OBJECTIVE: To investigate the relationship between the Ala379Val polymorphism of the platelet-activating factor acetylhydrolase gene (PAF-AH) and pre-eclampsia (PE) in Chinese pregnant women. METHODS: A total of 592 subjects (210 patients with PE and 382 healthy pregnant women) in Chengdu area were included in this study. The Ala379Val polymorphism of the PAF-AH gene was determined by PCR amplification and restriction analysis. Plasma PAF-AH and high-density lipoprotein-associated PAF-AH (H-PAF-AH) activities were measured by the trichloroacetic acid precipitation method using PAF as substrate and (3 H-acetyl) PAF as tracer. Low-density lipoprotein-associated PAF-AH (L-PAF-AH) activity was obtained by subtracting H-PAF-AH activity from plasma PAF-AH activity. RESULTS: The frequencies of the A and V alleles at Ala379Val site were 0.890 and 0.110 in the patient group, and 0.865 and 0.135 in control group, respectively. No significant differences in the frequencies of the genotypes and alleles were observed between the two groups (P>0.05). However, the body mass index (BMI) and the ratio of L-PAF-AH to H-PAF-AH activities were significantly higher, and H-PAF AH activity was significantly lower, in patients with V alleles (AV + VV genotypes) compared to patients with AA homozygotes (P<0.05). CONCLUSION: The Ala379Val polymorphism of the PAF-AH gene was not associated with PE, but the V allele variation at this site might be associated with the increased BMI and the abnormal distribution of plasma PAF-AH activities in lipoproteins in patients with PE. PMID- 25807809 TI - [Interaction between GNB3 C825T and ACE I/D polymorphisms in pre-eclampsia]. AB - OBJECTIVE: To verify the hypothesis if interaction between the G protein beta3 subunit (GNB3) C825T polymorphism and angiotensin-I converting enzyme (ACE) insertion/deletion (I/D) could lead to the increased risk of pre-eclampsia. METHODS: Analyses of ACE and GNB3 genotypes were performed in 188 preeclamptic patients and 273 normal pregnant controls by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism in Chinese population, respectively. RESULTS: The distributions of alleles and genotypes for the GNB3 C825T and ACE I/D polymorphisms were not found to be significantly associathed with pre eclamptic status. No significant interaction of the influence of GNB3 T allele and ACE genotypes on the risk of pre-eclampsia was observed (OR 0.439-1.203, all P>0.05). However, we found that in homozygous 825T genotype carriers with the ACE II genotype in controls diastolic blood pressure (DBP) levels showed highest [(77.61 +/- 1.26) mmHg (1 mmHg=0.133 kPa)] among other three genotype combinations [TT/ID, (70.94 +/- 1.64) mmHg; CT/ID, (73.15 +/- 0.89) mmHg; CT/DD, (72.57 +/- 2.14) mmHg] (all P<0.05). No significant effect on systolic blood pressure (SBP) or DBP levels in the patients were observed. CONCLUSION: Our data suggest no significant interaction of the GNB3 825T allele carriers with the ACE I/D polymorphism in pre-eclampsia in Chinese population in Chengdu area. However there is the interaction of the two genes on DBP levels in pregnancy women without pre-eclampsia in the population. PMID- 25807811 TI - [Calculating Pearson residual in logistic regressions: a comparison between SPSS and SAS]. AB - OBJECTIVE: To compare the results of Pearson residual calculations in logistic regression models using SPSS and SAS. METHODS: We reviewed Pearson residual calculation methods, and used two sets of data to test logistic models constructed by SPSS and STATA. One model contained a small number of covariates compared to the number of observed. The other contained a similar number of covariates as the number of observed. RESULTS: The two software packages produced similar Pearson residual estimates when the models contained a similar number of covariates as the number of observed, but the results differed when the number of observed was much greater than the number of covariates. CONCLUSION: The two software packages produce different results of Pearson residuals, especially when the models contain a small number of covariates. Further studies are warranted. PMID- 25807806 TI - [Placental PHLDA2 gene imprinting in patients with pre-eclampsia]. AB - OBJECTIVE: To observe the imprinting status of maternally expressed gene pleckstrin homology-like domain, family A, member 2 (PHLDA2) in placental tissues from patients with pre-eclampsia. METHODS: Samples of placental tissues were collected from women with normal pregnancy (n=21) and pre-eclampsia (n=19). We examined two single nucleotide polymorphism (SNPs) which are prone to variation in PHLDA2: the C/T polymorphism in exon 1 and the G/A polymorphism in exon 2, corresponding to rs13390 (PHLDA2-1) and rs1056819 (PHLDA2-2), respectively. DNA PCR-direct sequencing and cDNA RT-PCR-direct sequencing were applied to detect the special-allelic imprinting status of PHLDA2. RESULTS: No heterozygote was found in placental tissues in relation to C/T polymorphism in PHLDA2 exon 1. Differences in heterozygote in relation to G/A polymorphism in PHLDA2 exon 2 were found between pre-eclampsia (4/19) and normal pregnancy(5/21), but without statistical significance. PHLDA2 cDNA from heterozygotes (PHLDA2-2) were all exclusively monoallelically expressed. CONCLUSION: Similargene polymorphism of PHLDA2 (PHLDA2-1 and PHLDA2-2) in placental tissues was found between pre eclampsia and normal pregnancies. No loss of imprinting (LOI) of PHLDA2 was found in this study. PMID- 25807808 TI - [Long noncoding RNA HOTAIR modulates the function of trophoblast cells in pre eclampsia]. AB - OBJECTIVE: To investigate the expression of long noncoding RNA (lncRNA) HOTAIR in pre-eclampsia (PE) placentas and its effect on trophoblast cells proliferation, invasion, and apoptosis. METHODS: The expression of HOTAIR was determined by qPCR for 23 severe PE and 23 normal pregnant women. qRT-PCR was used to detect the efficiency of overexpression and knock-down after the HTR-8/SVneo cells were transfected with HOTAIR overexpression and siRNAs targeting HOTAIR for 24-48 h, respectively. MTT and colony formation assays were used to test the proliferation of HTR-8/SVneo cells transfected. Transwell assay was used to show the migration and invasion ability of HTR-8/SVneo cells transfected. Flow cytometry assay was used to detect the cell apoptosis rate after treatment. Western blot assay was applied to detect the expression level of apoptotic proteins Caspase-3 and BCL-2. RESULTS: The level of HOTAIR in severe pre-eclampsia groups was significantly increased compared to normal pregnant placentas (P<0.05). The expression of HOTAIR in HTR-8/SVneo cells after transfected with pcDNA-HOTAIR was 51. 27-fold than that of control; while inhibition of HOTAIR was more than 95% in si-HOTAIR than that of control. According to the MTT and colony formation assays, we found that cells proliferation rate of cells were significantly decreased in overexpression HOTAIR group while increased in si- HOTARI group when compared with control, respectively. The transwell assay showed that the invasive capacity of HTR-8/SVneo cells in cells transfected with pcDNA-HOTAIR decreased, while increased in si-HOTAIR transfected cells when compared with that of control. The apoptosis rate in cells transfected with HOTAIR overexpression was apparently more than that of control, while less in cells treated with si-HOTAIR. Western blot assay showed that the Caspase-3 showed an obvious increase in HOTAIR overexpression group while decreased in si-HOTAIR group. And BCL-2 presented an opposite trend. CONCLUSION: HOTAIR is probably involved in the onset of preeclampsia by regulating proliferation, invasion and apoptosis of trophoblast cells. PMID- 25807812 TI - [The establishment and identification of GPx-1(P198L) gene systemic expression transgenic mice]. AB - OBJECTIVE: To generate systemic expression human cellular glutathione peroxidase 1 (GPx-1) (198Leu) transgenic mice model in order to investigate the functional variants in GPx-1 gene in oxidative stress-related diseases. METHODS: After linearization with BamnH I and Acc I, the transgenic construct GPx-1 (198Leu) was microinjected into the zygotes of C57BL/6J mice to generate transgenic mice, whose genotype was detected by PCR with specific primers. The GPx-1 gene expression profile was determined by Western blotting. RESULTS: 13 transgenic founder mice were successfully generated. Western blotting result showed that the protein expression level of 4 transgenic mice in hearts were higher than that of wild type mice. CONCLUSION: Human GPx-1PSL transgenic mice was successfully established. This kind of animal model is of significance for making further researches on oxidative stress-related diseases. PMID- 25807813 TI - [Pharmacokinetics study of injected doripenemin healthy volunteers]. AB - OBJECTIVE: To study the pharmacokinetics of injected doripenem in Chinese healthy volunteers, in order to optimize dosages for patients. METHODS: Twelve healthy volunteers were recruited in the threecross Latin square designed study. Participants received intravenous infusions of 0.25, 0.5 and 1.0 g doripenem sequentially in three periods at a random order. Plasma and urine doripenem were measured by HPLC-UV, using an internal standard method with meropenem for plasma samples and an external standard method for urine samples, respectively. Phoenix WinNonlin 6.1 pharmacokinetic software was used to calculate non-compartment pharmacokinetics parameters. SPSS 19.0 software was used for statistical analysis. RESULTS: A single dose infusion of 0.25, 0.5 and 1.0 g doripenemin 60 min produced the following respective parameters: Cmax (11.81 +/- 1.52), (22.80 +/- 3.80) and (47.26 +/- 8.38) microg/mL, Tmax (60.42 +/- 1.44), (58.33 +/- 5.77) and (60.00 +/- 0) min, t(1/2) (63.48 +/- 10.51), (69.12 +/- 16.72) and (69.30 +/- 11.71) min, AUC(0-1), (1100.86 +/- 150.04), (2111.50 +/- 359.58) and (4359.50 +/- 789.38) microg/(mL x min). Linear Regression and Confidence Interval analyses suggested a linear kinetic characteristic. Doripenem was mainly excreted through kidneys, with 24 h cumulative urine excretion rates ranging from 70% to 75% for the three doses of infusions. It was safe to administer doripenem through infusion in healthy volunteers. Adverse reactions occurred in 19.44% cases of infusions, although all were mild reactions. Tinnitus happened in two cases (8.33%) of infusions, which required close observations. CONCLUSION: Doripenem infusion possesses a linear kinetics. There is no need to adjust the regimenpatients. PMID- 25807815 TI - [Comparison of the efficacy and safety between TVT-O and TVT-O with biofeedback pelvic floor electrical stimulation on female stress urinary incontinence]. AB - OBJECTIVE: To compare the efficacy and safety between tension-free vaginal tape obturator technique (TVT-O) and TVT-O with biofeedback pelvic floor electrical stimulation on the therapy of female stress urinary incontinence. METHODS: In this prospective study, 120 female patients of female stress urinary incontinence were enrolled from January 2012 to December 2013. The patients were randomly assigned to two groups, 60 in group A received TVT-O alone, while 60 in group B not only received TVT-O but also received biofeedback pelvic floor electrical stimulation. All the patients were followed up for 12 months to assess the efficacy and safety of the two procedures. Subjective indices [total volume of urine (TV), the total frequency of urination (TOV), the total leakage of urine events (TL), urinary incontinence related quality of life questionnaire (I-QOL), International Advisory Committee on urinary incontinence urinary incontinence questionnaire short form scale (ICI-Q-SF)] and objective indices [Valsalva leak point pressure (VLPP), maximum flow rate (MFR), residual urine volume (RUV),pad test] were analyzed. RESULTS: Overall, the cure rate was 75% at 1 year follow-up for group A and 88.33% for group B (P<0.05). The effective rate was 16.67% for group A and 10% for group B (P<0.05). The ineffective rate was 8.33% for group A and 1.67% for group B (P<0.05). TV, I-QOL, ICI-Q-SF, VLPP and pad test in group B were superior to group A (P<0.05). CONCLUSION: Pelvic floor electrical stimulation biofeedback therapy could improve the curative effects of TVT-O on the treatment of female stress urinary incontinence. PMID- 25807814 TI - [Multi-center randomized control study on the effects of syndrome differentiated traditional Chinese medicine therapy on CKD 1-2 with chronic nephritis proteinuria]. AB - OBJECTIVE: To determine the effects of Syndrome Differentiated Chinese Medicine (TCM) Therapy on (CKD) 1-2 stage chronic kidney disease with proteinuria. METHODS: A prospective randomized control study was undertaken in 11 centers. A total of 396 chronic nephritis patients were divided into a treatment group (n=297) and a control group (n=99). Their TCM syndrome was classified as "Qi and Yin Deficiency of spleen and kidney" or "Qi and Yang Deficiency of spleen and kidney", with accompanying syndromes showing as "water and dampness", "damp heat", and "blood stasis". Patients in the treatment group took a dose of Chinese medicine daily in response to their syndromes, while the controls took 50 mg/d losartan. The course of treatment was 24 weeks. Changes of 24-hour urinary protein excretion and glomerular filtration rate (eGFR) before and after treatments (4, 8, 12, 16, 20, 24 weeks), as well as clinical efficacy (after 4, 16, 24 weeks treatments) were measured. RESULTS: 361 patients were included in the final program participants comply analysis (PPS). Patients in the treatment group showed gradual decreased 24-hour urinary protein excretion, whereas the controls remained unchanged. Significant differences in 24-hour urinary protein excretion appeared between the experimental and control group at week 20 and 24 (P<0.05). eGFR decreased in all of the patients after treatments (P=0.0014). At three follow-up points, patients in the treatment group had higher eGFR than the controls, but without statistical significance (P>0.05). Significant differences in clinical remission rate, marked effect rate and total effective rate were observed between the treatment and control groups at week 24 (P<0.001). CONCLUSION: Syndrome differentiated TCM therapy can reduce the level of proteinuria in CKD 1-2 nephritis patients, promoting clinical effectiveness and protecting renal functions. PMID- 25807816 TI - [Psychomanteum: Ancient walk to our unconscious]. PMID- 25807817 TI - [A letter about my passions--confessions of an ophthalmologist]. PMID- 25807818 TI - [Music therapy for patients with Parkinson's disease]. PMID- 25807821 TI - [Pisz forest animals]. PMID- 25807820 TI - [Pro-survival signaling pathways activated by BCR-ABL oncogene in chronic myelogenous leukemia cells: the role of the perk-EIF2alpha signal path and acetylation of p53]. PMID- 25807822 TI - [Nucleotide receptors--structure and function, history and perspectives]. AB - First nucleotide receptors were discovered by Geoffrey Burnstock in 70ties of the last century, as a purinoreceptors activated by ATP. It was further found that they may be activated both by purine and pyrimidine nucleotides and their name was changed to nucleotide receptors. They are divided into two fsamilies: P1, activated by adenosine and P2, activated by nucleotides which are further divided into P2X and P2Y subfamilies. P2X are ionotropic receptors activated by ATP, P2Y (as the P1) are metabotropic receptors coupled with protein G. P2Y receptors are activated by ATP, ADP, UTP, UDP and UDP-sugar derivatives. This review describes early history of extracellular nucleotide signaling studies and presents current knowledge of the particular nucleotide receptors subtypes. The article also describes the structure and functional roles of these receptors and speculates about future research and therapeutic directions in this field. PMID- 25807823 TI - [Nucleotide receptors and the cell motility]. AB - The ability to active motility is one of the fundamental features of both normal and pathologically transformed cells. The current paper de- scribes the role of nucleotide receptors in regulation of cell motility in higher organisms. Author focuses on those cells which actively move in the nucleotide gradients: immune system cells as well as glia cells. The impact of individual receptors in motility and current opinions on the role of signaling pathways activated by those receptors will be described. The source of nucleotides regulating motility will be proposed and role of extracellular nucleotides such as ATP, ADP, UTP and adenosine will be indicated. The role of ectoenzymes in creation of secondary nucleotide gradients regulating cell motility will also be indicated. Finally, the role of nucleotides in regulation of brain tumor cells will be described and perspective of possible therapeutic role of modulation nucleotide signaling influencing cell motility will be suggested. PMID- 25807824 TI - [Nucleotide receptors and actin cytoskeleton dynamics]. AB - Signaling cascades evoked by P2Y2 receptor plays an important role in the phenomena dependent on the actin cytoskeleton dynamics endocy-tosis, cell division, adhesion, intracellular transport and migration. P2Y2R coupled with G proteins, in response to ATP or UTP activates Rac1 and RhoA proteins important factors in actin cytoskeletal reorganization and regulates the level of phosphatidylinositol-4,5-bisphosphate (PIP2) that binds directly to a variety of actin regulatory proteins and modulates their function. The P2Y2 nucleotide receptor contains the integrin-binding domain enables it to interact selectively with alpha(v)beta3 and alpha(v)beta5 integrins and is required for G0-mediated Rac1 activation. Interaction with alpha(v)beta5 is necessary for coupling the P2Y2 receptor to G12 and subsequent activation of RhoA. PMID- 25807825 TI - [Involvement of nucleotide receptors in the regulation of vascular function]. AB - A novel function of ATP as a signal molecule was described nearly 50 years ago. Since then many receptors that could be activated via ATP, ADP, UTP, UDP and adenozine binding were discovered. The mechanism of signal transduction as well as quite complicated regulation of changes of extracellular nucleotides concentration is currently studied. Purinergic signaling in blood vessels is mostly engaged in vascular tone regulation thus maintaining proper blood pressure. ATP coreleased with noradrenaline from perivascular sympathetic nerves cause vasoconstriction whereas ATP in blood vessel lumen stimulate endothelial cells to release endothelium derived relaxing factor. Nucleotides and nucleosides contributes also to growth and differention of new blood vessels. Changes in purinergic signaling is commonly observed in cardiovascular diseases that plague our times, that is why nucleotide receptors seems to be good pharmacological target. PMID- 25807826 TI - [Nucleotide receptors and renal function]. AB - Kidney plays a key role in homeostasis of human body. It has heterogenic structure and is characterized by complicated vascular beds and numbers of sympathetic nerves endings. Nucleotides receptors are involved in the regulation of blood flow, a fundamental process for renal function. Plasma is filtrated in renal glomerulus and activity of nucleotides receptors located on cells of glomerular filter modifies the physi- cochemical properties of filter and affects the filtration process. Electrolytes, water and low molecular weight molecules are reabsorbed from tubular fluid or secreted into fluid in proximal and distal tubules. Glomerular filtration rate and activity of tubular processes are regulated via nucleotides receptors by glomerulotubularbalance and tubuloglomerular feedback. Nucleotides receptors are involved in systemic regulation of blood pressure and carbohydrate metabolism. PMID- 25807827 TI - Purinergic receptors in skeletal muscles in health and in muscular dystrophy. AB - The P2 purinergic (nucleotide) receptor super-family comprises of two families of protein. The P2X, which are channel-forming ionotropic receptors and the P2Y metabotropic receptors activating G protein-mediated signalling pathways. Members of both groups have been identified in skeletal muscle cells at different stages of differentiation. It is well documented that sequential expression and down regulation of particular P2 receptors on the surface of sarcolemma is closely associated with muscle maturation during embryogenesis and postnatal growth. P2 receptors are also involved in muscle regeneration following injury. Moreover, enhanced expression of specific purinergic receptors together with increased availability of extracellular ATP in dystrophic muscles are important elements of the dys- trophic pathophysiology considerably increasing severity. PMID- 25807828 TI - [Nucelotide receptors in cancer cells]. AB - Despite a great scientific effort, the causes, development as well as progression of many tumors still remains unknown. Since that, it is important to investigate possible mechanisms which may lead to better understanding of cancer biology. Nucleotide and adenosine receptors may be consider as a promising direction of anti-tumor scientific research. Nucleotide receptors P2 and adenosine receptors P1 forms a great family of proteins whose activity has been proved to be involved in many cellular processes vital for tumorogenesis. This review gives basic insights into the mechanisms of proproliferative as well as antiproliferative action of nucleotide receptors in tumor cells. PMID- 25807829 TI - [Nucleotide receptors in learning and neuronal plasticity]. AB - Nucleotide signalling plays an important role in neuronal plasticity and learning. Nucleotides are released at the synaptic terminals and may act pre- and postsynaptically by activating Pland P2 receptors. The A1 receptor, activated tonically by resting concentration of adenosine regulates basal neurotransmission. The A2A receptor is activated by increased adenosine levels and participates in plastic changes. ATP may act as an independent neurotransmitter on the P2X1 receptor, or via P2X3 subtype as a neuromodulator that affects NMDA receptor signalling. The G protein coupled P2Y receptors also evoke neuromodulatory effect on the neuronal plasticity, inhibiting LTD in prefrontal cortex. P2X7 receptor is responsible for communication between astrocytes and for synchronizing their activity. ATP and adenosine released by astrocytes act as neuromodulators both at the release site and heterosynaptically. Taken together, these multiple actions of nucleotides constitute a mechanism regulating homeostatic processes that are necessary for proper brain functioning: synaptic scaling and metaplasticity. PMID- 25807830 TI - [Recently identified GPR17 receptors--characteristics and role in pathology of the nervous system]. AB - Newly identified metabotropic GPR17 receptors are structurally related to purinergic P2Y receptors and cysteinyl leukotriene receptors. Re- cent studies showed that they play an important role in maturation of oligodendrocyte precursor cells. This review describes structure and pharmacological characterization of GPR17 receptors. It also summarizes knowledge about role of GPR17 receptors in physiology and patho- logy of nervous system, with special attention to remyelination processes. PMID- 25807831 TI - Clinical application of HE4 and CA125 in ovarian cancer type I and type II detection and differential diagnosis. AB - OBJECTIVES: The aim of this study was to assess the sensitivity and specificity of HE4 in detecting and differentiating between types I and II epithelial ovarian cancer (EOC) in comparison with CA125. MATERIAL AND METHODS: We measured HE4 and CA125 serum concentrations in 206 samples taken from patients operated in Gynecologic Oncology Department due to ovarian tumors. Ovarian cancer was confirmed in 89 cases divided into type I and type II. 52 healthy patients without any gynecological disease formed the control group. The sensitivity and specificity for type I and type II EOC detection and differentiating between both types was evaluated for HE4 and CA125. RESULTS: The HE4 and CA125 serum concentrations were significantly higher in type II than in type I EOC (p=0.008696, p=0.000243 respectively). The HE4 and CA125 sensitivity for type I and benign tumors differentiation was 63.16% for both of them and specificity was 87.29% vs 67.89% respectively. For CA125 these differences did not reach statistical significance. The HE4 sensitivity and specificity for type II and benign tumors differentiation were 87.14% and 96.61%, respectively and for CA125 these values were 82.86% and 94.07%, respectively. CONCLUSIONS: Pretreatment analysis of HE4 serum concentration is superior to CA125 in differential diagnosis of ovarian cancer subtypes (I and II). HE4 is superior to CA125 in detecting ovarian cancer type II. Neither HE4 nor CA125 is an effective diagnostic tool for type I ovarian cancer detection. A new highly specific and highly sensitive tumor marker for type I EOC is needed. PMID- 25807832 TI - The role of chemokine and non-chemokine factors in pain-related complaints in patients with endometrial cysts. AB - OBJECTIVES: Endometriosis is a chronic disease manifested as peritoneal endometrial implants and adhesions, as well as endometrial cysts, with pain as the dominant component. THE AIM: The aim of the study was to evaluate the role of chemokine (MCP-1, MCP-2, MIP-1, MIP-1 and RANTES) and non-chemokine (urocortin, ghrelin, and leptin) factors in the intensity of pelvic pain in women with endometrial cysts. MATERIAL AND METHODS: A total of 86 women, aged 18-38, treated laparoscopically between September 2009 and November 2012, due to adnexal changes, i.e. endometrial cysts and mature teratomas, were recruited for the study. On a numeric rating scale, i.e. PSS (Pain Sensation Scale--according to Johnson), the patients rated pain intensity. The level of pain-related stress was investigated with the Pain Distress Scale (PDS, according to Johnson). RESULTS: Medians for MCP-1, MCP-2, MIP-1, MIP-1 and RANTES concentrations were not statistically significantly different. The respondents rated pain intensity during menses as 6 and 3 points in the E and T groups, respectively (6 vs. 3 points; p=0.001). Statistically significant differences were also observed for pain intensity during work (apart from menses), (2 vs. 2 points, p=0,014) and during sexual intercourse (apart from menses) (3 vs. 1 points, p=0.006). Pain related stress levels were higher in the T group as compared to the E group (3 vs. 5 points; p=0.007). CONCLUSIONS: It seems safe to conclude that chemokines and leptin may play a significant role in the occurrence of pain complaints among women with endometrial cysts. Further research might result in implementation of new treatment methods for pain management, especially in terms of pharmacotherapy. PMID- 25807833 TI - Sexuality in women with polycystic ovary syndrome. AB - OBJECTIVES: This study aimed to compare sexual function and sexual response, attitude toward sexuality and relationships with sexual partners in women diagnosed with PCOS and healthy controls. MATERIAL AND METHODS: The study included 73 women (aged 23-42 years) diagnosed with PCOS using the Rotterdam criteria and 45 healthy controls. All participants completed a questionnaire assessing socioepidemiological parameters and sexual behavior. Validated instruments were used to assess hirsutism (Ferriman-Gallwey Scale), mental health status (General Health Questionnaire 12 [GHQ 12]), sexuality (Sexuality Scale [SS], Sexual Awareness Questionnaire [SAQ], Multidimensional Sexuality Questionnaire [MSQ], Multidimensional Sexual Self-Concept Questionnaire [MSSCQ]), and sexual function (Polish version of the Mell-Krat Scale [SFK/K Scale]). RESULTS: There were no statistically significant differences in the importance of sexual activity in both groups. Mean scores for the SFK/K Scale, SS, SAQ, MSQ, and MSSQ were similar among women with PCOS and controls, regardless of age. Similarly sexual needs and reactions were perceived in the same way by both groups. In contrast, women with PCOS rated themselves negatively as sexual partners more frequently than controls. CONCLUSIONS: Sexual function and sexual response, attitude toward sexuality as well as relationships with sexual partners were similar in PCOS subjects and healthy women. However, changes in physical appearance typically associated with PCOS result in deterioration of sexual function. Therefore, it is recommended that all PCOS patients should be referred to a sexual medicine specialist for consultation. PMID- 25807834 TI - [Comparison of carbetocin and oxytocin effectiveness for prevention of postpartum hemorrhage after caesarean delivery]. AB - OBJECTIVES: The aim of the study was to compare the effectiveness of carbetocin and oxytocin for prevention of postpartum hemorrhage (PPH) after caesarean section. MATERIAL AND METHODS: We analyzed data from 279 patients who received 100 MUg of carbetocin intravenously or 10 IU of oxytocin into the uterine muscle as a rudimentary treatment for prevention of PPH. RESULTS: Blood loss was statistically significantly higher (p=0.0136) in the entire study group as compared to the oxytocin group, and in cases when additional uterotonics were administered (p=0.0090). Also, we observed a statistically significantly correlation between the need for additional treatment and patient BMI. Patients with pre-pregnancy BMI of >=25 more often required additional medicaments after administration of carbetocin as compared to oxytocin (p=0.0077). We noted a statistically significantly higher rate of using additional treatment (p<0.05) after administering oxytocin into the uterine muscle as compared to intravenously given carbetocin (75% vs. 33%, respectively). CONCLUSIONS: 1. Carbetocin is more effective than oxytocin in the prevention of PPH and significantly reduces the necessity to administer therapeutic uterotonics during caesarean delivery. 2. Higher rates of additional treatment with uterotonics after the administration of carbetocin as compared to oxytocin in a group of patients after2 or more cesarean sections and women with BMI of >=25 require further studies in a target-selected larger sample size. 3. Based on our findings, it is not possible to conclude that 100 MUg of intravenous carbetocin is more effective than 10 IU of oxytocin given to the uterine muscle during caesarean delivery to prevent PPH. PMID- 25807835 TI - Pregnant women's diet composition and transitional milk fatty acids: factor analysis. AB - INTRODUCTION: The variation in the nutrients contained in the milk is the result of changes to the breast metabolism, placenta metabolism and the diet of pregnant women. Various factors influence fatty acid composition which are one of the major components of woman's breast milk. In our research, we wanted to determine the relationship between the components of the diet of and the transitional milk fatty acid composition mothers who delivered healthy full-term babies, preterm and small for gestational age neonates. MATERIALS AND METHODS: The study group comprised of 95 healthy women who were divided into three sub-groups: mothers of appropriate for gestational age (AGA) neonates (group A); mothers of preterm neonates (group B); and mothers who gave birth to small for gestational age (SGA) babies (Group C). The women's elements diet and the content of biochemical components were estimated based on the dietary questionnaire. The FAs in the mother's milk were analyzed using GCMS chromatography. The results of the studies of the dietary components and fatty acids of the milk underwent factor analysis. RESULTS: In group A, 10 correlations (5 positive and 5 negative) were found between the components of the mother's diet and the FAs in the milk (correlation varying from 0.285-0.366). In group B, only negative correlations were observed and these had higher absolute correlation values (0.354-0.500). The most correlations between dietary components and FAs in the milk were found in group C (0.537-0.800). CONCLUSION: Nature of the correlations between the variables examined in groups A, B and C are different. PMID- 25807836 TI - The importance of rs1021737 and rs482843 polymorphisms of cystathionine gamma lyase in the etiology of preeclampsia in the Caucasian population. AB - INTRODUCTION: Recently an increasing number of reports indicate the participation of genetic factors in the pathogenesis of preeclampsia (PE). The genes involved in the synthesis of nitric oxide that participates in the vasolidation, may play an important role in the development of this disorder. Hydrogen sulfide (H2S) which is produced by cystathionine gamma-lyase exhibits a similar effect to nitric oxide. It is suggested that certain polymorphisms of the CTH gene may participate in the development of chronic hypertension and preeclampsia. AIM OF THE STUDY: To evaluate the frequency of genotypes and alleles of rs1021737 and rs482843 polymorphisms of CTH gene in women with preeclampsia from Wielkopolska region. MATERIAL AND METHODS: The study group consisted of 60 patients with diagnosed preeclampsia, into the control group 120 healthy pregnant women were enrolled. The examined rs1021737 and rs482843 polymorphisms of CTH gene were determined using PCR-RFLP method. RESULTS: Analysis of rs482843 polymorphism in the CTH gene showed a statistically significant difference in the prevalence of mutated GG genotype (p<0.000001) and mutated G allele (p<0.000001) in the group of pregnant women with PE compared to the control group. There was no such correlation for the rs1021737 polymorphism. Furthermore, there are also no relationship between studied polymorphisms and selected clinical and biochemical parameters. CONCLUSIONS: The results of rs482843 polymorphism analysis suggest that mutated GG genotype predisposes to preeclampsia occurrence. There was no such relationship for the rs1021737 polymorphism of CTH gene. Hence, further studies based on the determination of CSE expression level in women with PE may confirm the observed relationship between the rs482843 polymorphism and the risk of preeclampsia. PMID- 25807837 TI - Evaluation of sonographic assessment of the progress of labor. AB - OBJECTIVE: To evaluate the practical application of intrapartum sonographic assessment of the progress of labor. MATERIAL AND METHODS: Eighty three full-term pregnant women who delivered at the Obstetrics and Gynecology Department were enrolled into this study. Transperineal ultrasonographic examinations were conducted with a convex transducer at the onset of active labor, yielding mid sagittal and coronal images. Three parameters were measured: 1) the angle between the long axis of the symphysis pubis and the line joining its lowest margin to the contour of the fetal head (angle of progression); 2) the distance between the presenting point and the line perpendicular to the symphysis pubis and passing through its lowest margin; 3) the fetal head-perineum distance. The relationship between measurement results and the period from examination to delivery was also analyzed. RESULTS: There were 73 vaginal deliveries and 10 women underwent a cesarean section due to failure to progress. The two groups (vaginal vs. cesarean delivery) differed significantly in terms of the angle of progression (131 vs. 110 degrees, respectively p<0.01) and the distance between the presenting point and the infrapubic line (34 vs. 20 mm, respectively p<0.01). The inter-group difference in fetal head-peritoneum distances (53 and 61 mm, respectively) was noticeable but non-significant (p>0.05). The study also demonstrated a relationship between all three of the measured values and the time to second labor phase completion. CONCLUSIONS: Ultrasonography may be useful in assessing the progress of labor as well as in predicting or early diagnosis of abnormal fetal head descent. PMID- 25807838 TI - [Practical implementation of recommendations concerning diagnostic procedures in gestational diabetes]. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with health consequences for both, the mother and her offspring. In Poland, the diagnosis of GDM is based on the recommendations of the Polish Gynecological Society (PTG) and is usually made by obstetricians. OBJECTIVE: The aim of the study was to assess practical implementation of PTG standards of GDM screening and diagnosis. MATERIAL AND METHODS: The study group consisted of 351 pregnant women consulted by a diabetologist: 102 patients between 2008-2010 (PTG guidelines of 2005) and 249 patients between 2011-2013 (PTG guidelines of 2011). Data concerning diagnostic procedures performed by obstetricians--time of diagnostic tests, fasting glucose levels, oral glucose tolerance test (OGTT) results, and GDM risk factors--were collected. Adherence to the diagnostic procedures was assessed. RESULTS: Adherence to the diagnostic guidelines for 2008-2010 was 42.2%. The most common errors were incorrect time of OGGT (36.4%) and wrong interpretation of glycaemia (34.1%). Between 2011-2013 incorrect diagnostic testing was detected in 78.3% of the affected women. The most common deviation was lack of OGTT at the beginning of pregnancy in women with GDM risk factors (91.3%). CONCLUSIONS: A considerable number of GDM women underwent incorrect diagnostic procedures. More precise description of GDM risk factors in PTG recommendations seems to be necessary. PMID- 25807839 TI - [Twin pregnancy as the risk factor for neonatal intraventricular hemorrhage]. AB - OBJECTIVES: The aim of this study was to find the perinatal risk factors of intravenricular hemorrhage in twin neonates. MATERIAL AND METHODS: A retrospective analysis of 203 twin pregnancies and deliveries between 2003 and 2009 was performed. Then data according birth state and neonatal complications in 406 twins were analyzed. Twin outcome was compared with the outcome of 105 singletons born at the same time and at the same gestational age as twins. RESULTS: Intraventricular hemorrhage was diagnosed in 116/406 (29%) of twins. IVH was found two times more often in the analyzed group than in singletons born at the same gestational age (29% vs. 18%, p = 0,03). In 96% I and II grade hemorrhage was diagnosed and in 4% III and IV grade hemorrhage in the Papille scale was found. CONCLUSIONS: 1) Intraventricular hemorrhage is found more often in twins than in singleton neonates born at the same gestational age. 2) IVH in twins correlate with preterm birth and low birth weight. IVH occur more often in twins with birth weight discordance and with too small maternal weight gain. PMID- 25807840 TI - Gender-specific implications for pharmacology in childbearing age and in postmenopausal women. AB - Women have three very important physiological functions that are not observed in men--menstruation, pregnancy and lactation. Each of these mechanisms influences pharmacokinetics and pharmacodynamics of many drugs. Individualization of pharmacotherapy is a major challenge of modern medicine. The differences in response to drug are responsible for the effectiveness of pharmacological treatment and the occurrence and severity of toxic effects and side effects. Therapeutic decision should be based not only on account of the dose-effect, but the consideration of gender, genetic and environmental differences affecting the final therapeutic effect. Many important differences between men and women like sex-based differences in normal physiology, or in the predisposition to a specific disease, can be due to genetic differences, the actions of the sex steroid hormones or an interaction between these factors. Women generally have a lower body mass, a reduced hepatic clearance, differences in activity of cytochrome P450 (CYP) enzymes (increase in CYP3A4, decrease in CYP2D6, CYP2C19 and CYP1A2) and different from men's rate of drug metabolism. Other important factors contributing to gender differences in the pharmacokinetics of drugs are conjugation, absorption, protein binding and urinary excretion. It still remains unexplained how gender differences affect the increased risk of side effects. This review is an attempt to assess the biological, physiological and hormonal basis of women differences in the pharmacokinetics and pharmacodynamics of many drugs. PMID- 25807841 TI - [The role of the Fanconi anemia pathway in the pathophysiology of ovarian cancer]. AB - We reviewed the literature on the relationship between the Fanconi anemia pathway (FA) and response to chemotherapy in patients with ovarian cancer. Despite continuous developments in medicine, ovarian cancer remains a challenge for both, physicians and researchers seeking ways to achieve better results of chemotherapy combined with other targeted therapies. Clinically relevant resistance to chemotherapy is a major problem in treating ovarian cancer. Researchers continue to investigate mechanisms responsible for drug resistance in order to develop better therapeutic methods against ovarian cancer. Among the resistance mechanisms, defects in DNA repair, including the FA pathway may be important in increasing the sensitivity of ovarian cancer cells to chemotherapy agents at the clinical level. A growing number of data has shown that disruption of the FA genes may be a useful predictor of OC sensitivity to chemotherapy agents whose activity is based on DNA crosslinking mechanisms. PMID- 25807842 TI - [Familial congenital diaphragmatic hernia with anencephly-exencephaly and spina bifida]. AB - Congenital Diaphragmatic Hernia (CDH) occurs with an estimated incidence of 1 to 2500 live births. Even though the exact etiology is still unknown, more and more often current research points out genetic factors as the possible cause of the defect. According to the latest data and the own experience 50-60% of CDH cases are isolated. The rest forms a group of CDH complicated by an additional anatomic defect or a genetic syndrome caused by a mutation of a single gene or the whole chromosome. We have presented a case study of a 32 years-old multigravida para 3, who has been referred to the Reference Centre of Prenatal Cardiology in 30 weeks of gestation due to the diagnosis of acrania with exencephaly, spina bifida and suspicion for CDH in a fetus. Although the patient's first child died due to CDH, the patient neither before nor during the pregnancy was getting a folic acid supplementation. Moreover, she has not agreed on a further cytogenetic testing or an advanced consultation with a clinical geneticist. The child died after delivery in a local hospital. The case was described to indicate the problem that the CDH diagnostic procedure is still missing a molecular genetic analysis especially in the cases of recurrent CDH. By saying that in the cases of CDH we should always strive to complete the molecular testing having in mind that by discovering pathogenesis and genes responsible for the formation of CDH we not only might improve the therapeutic methods but also find a way to prevent its development. PMID- 25807844 TI - Subclinical systemic and vascular inflammation detected by (18) F fluorodeoxyglucose positron emission tomography/computed tomography in patients with mild psoriasis. AB - Severe psoriasis is a systemic inflammatory disease involving major arteries and internal organs. The association between psoriasis and arterial inflammation, however, has been noted mostly in patients with moderate to severe psoriasis. Therefore, it is still not clear whether mild psoriasis also increases the arterial inflammation and cardiovascular disease. In this study, we aimed to investigate systemic inflammation using (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients with mild psoriasis. In a nested case-control study, FDG-PET/CT findings of 10 patients with mild chronic plaque psoriasis involving a body surface area of less than 5% were compared with those of 10 age- and sex-matched healthy controls. The degree of FDG uptake in the large arteries (ascending aorta, aortic arch, descending aorta, suprarenal abdominal aorta and infrarenal abdominal aorta,) and liver were analyzed using the maximum target-to-background ratios (TBR). There were no significant demographic differences between the psoriasis patients and the control subjects (P > 0.05). Patients with psoriasis showed higher maximum TBR than healthy controls in all examined arterial segments, with statistical significance reached in the suprarenal abdominal aorta (P < 0.05), ascending thoracic aorta (P < 0.01) and infrarenal abdominal aorta (P < 0.05), and in the liver (P < 0.05). The "candy cane sign", which represents typical arterial inflammation of the thoracic aorta, was noted upon PET in the majority of psoriasis cases. In conclusion, mild psoriasis is also associated with arterial and hepatic inflammation, which can be readily demonstrated by using FDG-PET/CT. PMID- 25807845 TI - Dialysis Withdrawal: Impact and Evaluation of a Multidisciplinary Deliberation Within an Ethics Committee as a Shared-Decision-Making Model. AB - Since dialysis withdrawal in maintenance dialysis patients with limited life expectancy results always in short-term death, nephrologists need a referenced process to make their decision. This study reviews 8 years of operation of an Ethics Committee in Nephrology (ECN). The ECN, within a multidisciplinary team, once a month explores cases reported by caregivers when maintaining dialysis seems not to be in the patient's best interest. Discussion is required when the vital prognosis is engaged by the evolution of the chronic kidney disease (CKD) or the occurrence of an acute medical event. Data are analyzed using a discussion guide. The informed decision is completed with an appropriated palliative care project involving the patient, and recorded in their file. Since 2006, the ECN has deliberated yearly for 10 sessions on 6-18 cases, concerning 380 identified maintenance dialysis patients. Characteristics of the population, cases, sessions and proposals are recorded and analyzed. The only variable associated with dialysis withdrawal was having at least one new comorbid condition. End of life is supported with the help of the palliative care team in the hospital or exceptionally at home. The ECN, through a multidisciplinary deliberation and resolution process, proposes an ethical shared-decision-making model ensuring that dialysis withdrawal follows professional guidelines, and is registered as a method for evaluating professional practice (EPP). Annual activity reports are submitted to the Hospital's Medical Evaluation and Quality Unit. Benefits are individual and collective for patients, relatives and caregivers. Prospects for reducing non-implemented decisions and identifying cases earlier would improve the Committee effectiveness. PMID- 25807843 TI - The Warburg effect in mycobacterial granulomas is dependent on the recruitment and activation of macrophages by interferon-gamma. AB - Granulomas are the hallmark of mycobacterial disease. Here, we demonstrate that both the cell recruitment and the increased glucose consumption in granulomatous infiltrates during Mycobacterium avium infection are highly dependent on interferon-gamma (IFN-gamma). Mycobacterium avium-infected mice lacking IFN-gamma signalling failed to developed significant inflammatory infiltrations and lacked the characteristic uptake of the glucose analogue fluorine-18-fluorodeoxyglucose (FDG). To assess the role of macrophages in glucose uptake we infected mice with a selective impairment of IFN-gamma signalling in the macrophage lineage (MIIG mice). Although only a partial reduction of the granulomatous areas was observed in infected MIIG mice, the insensitivity of macrophages to IFN-gamma reduced the accumulation of FDG. In vivo, ex vivo and in vitro assays showed that macrophage activated by IFN-gamma displayed increased rates of glucose uptake and in vitro studies showed also that they had increased lactate production and increased expression of key glycolytic enzymes. Overall, our results show that the activation of macrophages by IFN-gamma is responsible for the Warburg effect observed in organs infected with M. avium. PMID- 25807848 TI - Special Issue: Renal Transplant Case Series 2014. Introduction. PMID- 25807847 TI - Relation between virulence of Vibrio anguillarum strains and response to the host factors mucin, bile salts and cholesterol. AB - AIMS: In this study, we investigated the responsiveness of 15 Vibrio anguillarum strains to three host factors (mucin, bile salts and cholesterol). METHODS AND RESULTS: Three virulence-related phenotypes were investigated in this respect, i.e. motility, biofilm formation and exopolysaccharide production. Almost all V. anguillarum strains showed a significantly increased motility in the presence of either of the three host factors. Only five of the strains showed increased biofilm formation in the presence of host factors and only three strains showed increased exopolysaccharide production in the presence of the host factors. CONCLUSIONS: There were no significant correlations between the three putatively virulence-linked phenotypes (in the absence of host factors) and virulence to sea bass larvae. There was no correlation between responsiveness to the host factors (percentage increase in motility, biofilm formation or exopolysaccharide production in the presence of the three host factors) and virulence to sea bass larvae. However, the responses of these virulence-related phenotypes upon the addition of either of the three host factors were significantly correlated with each other. This result suggests that the mechanisms by which V. anguillarum responds to these three host factors is linked. SIGNIFICANCE AND IMPACT OF THE STUDY: Although the mechanism by which V. anguillarum responds to the host factors mucin, bile salts and cholesterol seems to be linked, there is no correlation between host factor responsiveness and virulence towards sea bass larvae. This emphasizes that one should be careful when extrapolating results obtained for one particular strain to reach general conclusions on a species of pathogenic bacteria. PMID- 25807846 TI - ALSUntangled No. 27: Precision Stem Cell. PMID- 25807849 TI - Managing psychosis in a renal transplant recipient with bipolar affective disorder and allograft rejection. AB - Management of mental health issues in the post-transplant setting can be difficult given the potential for medication related neurotoxicity. The lack of established guidelines in this area further compounds this difficulty. The current report details the course of patient with stable bipolar affective disorder prior to renal transplantation, who developed de novo psychosis post transplantation as an adverse effect of her tacrolimus therapy. The patient was unable to take her usual oral immunosuppressants due to the severity of her psychosis and she eventually required alemtuzumab parenterally as rescue therapy from rejection. This case highlights the diagnostic and therapeutic challenges when dealing with transplant recipients with significant psychosis. PMID- 25807850 TI - Nocardiosis presenting as a lung mass in a kidney transplant recipient. AB - Nocardiosis is a potentially life-threatening disease in renal transplant recipients. It is an uncommon infection with high lethality if left untreated. We report a case of a 67 year-old kidney transplant recipient who developed pulmonary nocardiosis and presented with pleural effusion along with an underlying lung mass, which was successfully treated with trimethoprim sulphamethoxazole in conjunction with a reduction in immunosuppressive therapy. Five months later, graft function remains stable with complete regression of radiological abnormalities and absence of symptoms. Nocardiosis should be suspected in the presence of pulmonary symptoms in a transplant patient with unusual radiological presentation. PMID- 25807852 TI - Galactose therapy reduces proteinuria in patients with recurrent focal segmental glomerulosclerosis after kidney transplantation. AB - Primary focal segmental glomerulosclerosis is an important cause of end-stage kidney disease with a high rate of recurrent disease after kidney transplantation. Current therapy achieves remission in only half of patients. Recent interest has focused on the potential role of galactose in binding and inactivating the putative circulating permeability factor, supported by in vitro and clinical case report studies. Orally active and without major adverse effects, galactose has a favourable treatment profile compared with current immunosuppressive treatment options. We describe our experience using galactose therapy in two patients with recurrent focal segmental glomerulosclerosis after renal transplantation. Galactose was associated with symptomatic improvement and stabilization of graft function in one case; the other case was complicated by concurrent malignancy. In both cases, we observed a marked reduction in proteinuria with galactose treatment. PMID- 25807851 TI - Angiotensin II type 1 receptor antibody precipitating acute vascular rejection in kidney transplantation. AB - Atypical non HLA antibodies are increasingly recognised as causes of immunological injury in allotransplantation. In this report we describe a non HLA sensitized male renal allograft recipient who developed acute vascular rejection on a "for cause" biopsy (Banff v2, g2, ptc 3) at day 4 post first renal allograft in the presence of elevated angiotensin II type 1 receptor antibodies (AT1R-Ab level 14.1). The acute rejection was treated with pulse corticosteroid therapy, anti-thymocyte globulin (ATG * 6), plasma exchange (1.5 plasma volume replacement x6) and oral candesartan. Serum creatinine improved and follow up biopsy confirmed resolution of rejection following treatment. AT1R-Ab should be considered when rejection is diagnosed in the absence of HLA antibodies. PMID- 25807853 TI - Renal allograft re-use and herpetic re-infection. AB - A middle-aged man received a kidney transplant from a deceased multi-organ donor. The recipient suffered cardiac arrest several days post-operatively and sustained hypoxic brain injury and was declared brain dead. Following the family's consent, the allograft kidney was retrieved and re-transplanted into a man with end-stage renal failure secondary to reflux nephropathy. The liver was not transplanted due to suspicion of fatty changes based on macroscopic appearance. After transplantation of other organs, liver histology revealed coagulative parenchymal necrosis with nuclear inclusions and moderate parenchymal cholestasis, suggestive of herpes viral hepatitis. Renal implantation biopsy showed histiocytes with enlarged nuclei containing viral inclusions in the capsular fibrous tissue, with positive immunostaining for herpes simplex virus (HSV). Anti-viral therapy was commenced immediately after obtaining histological evidence of donor HSV infection. Our recipient had pre-formed immunoglobulin G antibodies to HSV-1 and HSV-2, and was immunoglobulin M negative pre-transplant. HSV viraemia was detected day 5 post-transplant with a viral load of 7688 copies/mL by polymerase chain reaction assay. The recipient completed a 30 day course of intravenous ganciclovir before switching to oral valganciclovir as standard cytomegalovirus prophylaxis. The HSV polymerase chain reaction became undetectable on day 7 of intravenous ganciclovir and has remained undetectable. The patient remains well 9 months post-transplant with an estimated glomerular filtration rate of 61 mL/min per 1.73 m(2). Although renal allograft re-use has been shown to be technically possible with a good outcome in this recipient, this does raise issues including assessment of allografts that have undergone repeated severe ischaemic insults and the potential of transmission of infections. PMID- 25807854 TI - Bortezomib in ABO-incompatible kidney transplant desensitization: a case report. AB - Positive B cell crossmatch accompanied by high levels of pre-transplant human leukocyte antigen donor-specific antibodies are associated with adverse graft outcomes in kidney transplant recipients. Targeting plasma cells, the main antibody producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We report using a combination of bortezomib and plasmapheresis to desensitize a highly sensitized kidney transplant recipient for an ABO-incompatible living donor kidney transplant. The flow cytometric B cell crossmatch was positive on presentation. After treatment, the anti-A titres fell from 1:64 to 1:4, and a negative B flow cytometric crossmatch was achieved prior to transplantation. The combined approach of bortezomib to abrogate antibody production at the plasma cell level, followed by plasmapheresis and low dose intravenous immunoglobulin to remove in-circulation alloantibodies, has proven to be effective in our case. Bortezomib may play a role in highly sensitized renal transplants. PMID- 25807855 TI - Numerical and in vitro investigation of a novel mechanical circulatory support device installed in the descending aorta. AB - Traditional implantation techniques of assist devices from the apex of left ventricle to the ascending or descending aorta are highly invasive and carry substantial complications for end-stage heart failure patients. This study has shown that the descending aorta can be a promising location to install an implantable mechanical circulatory support with minimally invasive surgery. Herein, the hemodynamic effect of an in-house prototyped pump implanted in the descending aorta was investigated numerically as well as experimentally. The objective of the experimental study is met by using the in-house simulator of the cardiovascular loop replicating congestive heart failure conditions. The objective of the numerical study was met by using the modified version of the concentrated lumped parameter model developed by the same team. The results show that the pump placement in the descending aorta can lead to an improvement in pulsatility. The pressure drop, generated at the upstream of the pump, facilitates the cardiac output as a result of after-load reduction, but at the same time, it induces a slight drop in the carotid as well as the coronary perfusion. The pressure rise, generated at the downstream of the pump, improves the blood perfusion in the renal circulation. PMID- 25807857 TI - Surgical precision and non-operative treatment of colorectal cancer: the 'H' factor concept. PMID- 25807856 TI - Correspondence of physical activity and fruit/vegetable consumption among prostate cancer survivors and their spouses. AB - A healthy diet and physical activity are recommended for prostate cancer survivors. Interdependence theory suggests that the spousal relationship influences those health behaviours and the degree of correspondence may be an indicator of this influence. This study evaluated the correspondence between prostate cancer survivors and spouses regarding physical activity and fruit/vegetable consumption. Baseline data from an ongoing randomised control trial were utilised. Men who had been treated for prostate cancer within the past year and their partners (N = 132 couples) completed self-report measures of physical activity, fruit/vegetable consumption, relationship satisfaction and support for partner's healthy diet and physical activity. Couples reported similar fruit/vegetable consumption and physical activity as indicated by high levels of correspondence. Greater fruit/vegetable correspondence was related to higher relationship satisfaction (F = 4.14, P = 0.018) and greater patient (F = 13.29, P < 0.001) and spouse-rated support (F = 7.2, P < 0.001). Greater physical activity correspondence was related to greater patient (F = 3.57, P = 0.028) and spouse-rated support (F = 4.59, P = 0.031). Prostate cancer survivors and spouses may influence each other's diet and exercise behaviours. Couple-based interventions may promote healthy behaviours among this population. PMID- 25807858 TI - AAV-mediated expression of BAG1 and ROCK2-shRNA promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury. AB - A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion. PMID- 25807859 TI - Cryptosporidium parvum Caused a Large Outbreak Linked to Frisee Salad in Finland, 2012. AB - Over 250 individuals fell ill in five outbreaks caused by Cryptosporidium parvum in Finland, October-November 2012. The cases were connected by lunch meals at restaurants in four different cities. In two outbreaks, the same C. parvumIIdA17G1 subtype was found in patients' stool samples which supports a single source of infection. Frisee salad was the only common food item served at the restaurants, and consumption of lunch salad containing the frisee salad was associated with the illness. Lunch customers who responded that they had eaten lunch salad were three times more likely to have become ill than those who had not answered whether they had eaten the salad or not (RR 2.66; 95% Cl 1.02-6.9, P value <0.01). Cryptosporidiosis should be considered as a causal agent in long lasting watery diarrhoea combined with abdominal cramps, and clinical samples should be tested for Cryptosporidium at the same time bacteria and viruses are tested. Measures to prevent contamination of 'ready-to-eat vegetables' with Cryptosporidium oocysts and methods to test frozen food samples should be developed. PMID- 25807860 TI - Non-anaemic iron deficiency in pregnancy: the views of health service users and health care professionals. AB - BACKGROUND: The prevalence of anaemia in pregnancy in Europe is 25% and that resulting from iron deficiency is estimated at 40%. The maternal and fetal morbidity of non-anaemic iron deficiency (NAID) in pregnancy is likely to be significant. OBJECTIVES: To determine the views and opinions of health service users and clinicians concerning NAID in pregnancy in order to inform future research. METHODS: Two semi-structured focus groups were carried out to determine health service users' views on anaemia and NAID in pregnancy. A questionnaire was administered to obstetricians, haematologists, midwives and anaesthetists to elucidate their views on NAID in pregnancy. RESULTS: The study indicated that health service users and clinicians were interested in implementing testing for NAID in pregnancy with serum ferritin, if proven to be effective at reducing the effects of anaemia and improving maternal and neonatal outcomes. Clinicians had reservations in the use of intravenous iron supplementation for NAID in pregnancy. CONCLUSION: NAID is now accepted as a target condition for research by health service users and clinicians. The focus of future research should be on screening for NAID and its treatment. PMID- 25807861 TI - Sarcopenia is an independent risk factor of dysphagia in hospitalized older people. AB - AIM: Sarcopenia can cause varying physical function disorders, including dysphagia. Malnutrition, a potential result of dysphagia, can also cause sarcopenia. However, the association between sarcopenia and dysphagia is not fully understood, despite evidence suggesting correlations between deglutition disorders and degenerative loss of muscle mass. The present study investigated the prevalence of dysphagia among patients with sarcopenia, and the association between the two conditions. METHODS: We included 224 older adults (mean age 82.5 +/- 8.4 years; 37.9% men). Individuals who had a stroke or other diseases that could directly cause dysphagia were excluded. Logistic regression analyses were carried out after adjusting for potential causes of sarcopenia, including malnutrition, a low activity of daily living levels and aging, to investigate the relationship between the skeletal muscle index (SMI), prevalence of sarcopenia diagnosed based on a low SMI and grip strength, and swallowing functions. The Mini-Nutritional Assessment short form was used to assess their nutritional status, and the Barthel Index was used to evaluate their activities of daily living. RESULTS: The prevalences of sarcopenia and dysphagia were 76.8% and 30.0%, respectively. Multivariate analysis showed that Barthel Index, SMI and presence of sarcopenia were significant independent factors for the prevalence of dysphagia, after adjusting for sex, age and nutritional status. Furthermore, subgroup analysis showed that SMI in males, and both hand-grip strength and SMI in females were lower in dysphagic subjects than in non-dysphagic subjects (P <= 0.01). CONCLUSION: Sarcopenia was an independent risk factor for dysphagia among older individuals. However, further studies are required to define causality. PMID- 25807862 TI - Are the Public Health Responsibility Deal alcohol pledges likely to improve public health? An evidence synthesis. AB - AIMS: The English Public Health Responsibility Deal (RD) is a public-private partnership involving voluntary pledges between industry, government and other actors in various areas including alcohol, and designed to improve public health. This paper reviews systematically the evidence underpinning four RD alcohol pledges. METHODS: We conducted a systematic review of reviews of the evidence underpinning interventions proposed in four RD alcohol pledges, namely alcohol labelling, tackling underage alcohol sales, advertising and marketing alcohol, and alcohol unit reduction. In addition, we included relevant studies of interventions where these had not been covered by a recent review. RESULTS: We synthesized the evidence from 14 reviews published between 2002 and 2013. Overall, alcohol labelling is likely to be of limited effect on consumption: alcohol unit content labels can help consumers assess the alcohol content of drinks; however, labels promoting drinking guidelines and pregnancy warning labels are unlikely to influence drinking behaviour. Responsible drinking messages are found to be ambiguous, and industry-funded alcohol prevention campaigns can promote drinking instead of dissuading consumption. Removing advertising near schools can contribute to reducing underage drinking; however, community mobilization and law enforcement are most effective. Finally, reducing alcohol consumption is more likely to occur if there are incentives such as making lower-strength alcohol products cheaper. CONCLUSIONS: The most effective evidence-based strategies to reduce alcohol-related harm are not reflected consistently in the RD alcohol pledges. The evidence is clear that an alcohol control strategy should support effective interventions to make alcohol less available and more expensive. PMID- 25807863 TI - Retroflexion-assisted endoscopic mucosal resection: a useful and safe method for removal of low rectal laterally spreading tumors. AB - BACKGROUND AND AIM: Lesions below or involving the dentate line cannot be removed by standard forward-viewing endoscopic mucosal resection (EMR). Data about retroflexion technique applied during EMR for low rectal laterally spreading tumors (LSTs) are quite limited. Therefore, we aimed to determine the efficacy and safety of retroflexion-assisted EMR (REMR) for the removal of large LSTs from the lower rectum. PATIENTS AND METHODS: EMR employing a complete retroflexion technique was performed in 49 consecutive patients (28 men, 21 women; mean age 51.8 years) with low rectal LSTs that were considered unresectable by conventional forward-viewing EMR due to the narrow and poor endoscopic view. Colonoscopy follow-up data were collected after resection. RESULTS: The low rectal LSTs had a median size of 51 mm (range 30-85 mm). All the tumors were successfully resected in two sessions (median procedure time 57.4 min, range 29 126 min). Procedure-related early bleeding occurred in 14 patients, and delayed hemorrhage occurred in four patients. Serious complications such as perforation or anal dysfunction were not observed, and any procedure-related bleeding was well controlled. The median follow-up period was 8.4 months (range 3-36 months). Nine patients (nine out of 49, 18.4%) experienced recurrence based on follow-up colonoscopy examinations, and the recurrent lesion was completely eradicated by additional endoscopic treatments. CONCLUSIONS: This is the first pilot study to evaluate the efficacy and safety of REMR for removal of low rectal LSTs. The short-term outcomes observed in this study indicate that REMR is a valuable method for the removal of low rectal LSTs. However, further studies evaluating the long-term efficacy and comparing REMR with other interventional therapies are needed. PMID- 25807864 TI - Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting. PMID- 25807866 TI - Availability of Alternatives and the Processing of Scalar Implicatures: A Visual World Eye-Tracking Study. AB - Two visual world experiments investigated the processing of the implicature associated with some using a "gumball paradigm." On each trial, participants saw an image of a gumball machine with an upper chamber with orange and blue gumballs and an empty lower chamber. Gumballs dropped to the lower chamber, creating a contrast between a partitioned set of gumballs of one color and an unpartitioned set of the other. Participants then evaluated spoken statements, such as "You got some of the blue gumballs." Experiment 1 investigated the time course of the pragmatic enrichment from some to not all when the only utterance alternatives available to refer to the different sets were some and all. In Experiment 2, the number terms two, three, four, and five were also included in the set of alternatives. Scalar implicatures were delayed relative to the interpretation of literal statements with all only when number terms were available. The results are interpreted as evidence for a constraint-based account of scalar implicature processing. PMID- 25807865 TI - Healthcare workers' willingness to work during an influenza pandemic: a systematic review and meta-analysis. AB - To estimate the proportion of healthcare workers (HCWs) willing to work during an influenza pandemic and identify associated risk factors, we undertook a systematic review and meta-analysis compliant with PRISMA guidance. Databases and grey literature were searched to April 2013, and records were screened against protocol eligibility criteria. Data extraction and risk of bias assessments were undertaken using a piloted form. Random-effects meta-analyses estimated (i) pooled proportion of HCWs willing to work and (ii) pooled odds ratios of risk factors associated with willingness to work. Heterogeneity was quantified using the I(2) statistic, and publication bias was assessed using funnel plots and Egger's test. Data were synthesized narratively where meta-analyses were not possible. Forty-three studies met our inclusion criteria. Meta-analysis of the proportion of HCWs willing to work was abandoned due to excessive heterogeneity (I(2) = 99.2%). Narrative synthesis showed study estimates ranged from 23.1% to 95.8% willingness to work, depending on context. Meta-analyses of specific factors showed that male HCWs, physicians and nurses, full-time employment, perceived personal safety, awareness of pandemic risk and clinical knowledge of influenza pandemics, role-specific knowledge, pandemic response training, and confidence in personal skills were statistically significantly associated with increased willingness. Childcare obligations were significantly associated with decreased willingness. HCWs' willingness to work during an influenza pandemic was moderately high, albeit highly variable. Numerous risk factors showed a statistically significant association with willingness to work despite significant heterogeneity between studies. None of the included studies were based on appropriate theoretical constructs of population behaviour. PMID- 25807867 TI - Efficacy and tolerance assessment of a new type of dermocosmetic in infants and children with moderate atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is an inflammatory and pruritic skin disorder. OBJECTIVES: To assess the efficacy and tolerance of a new emollient (SBT complex) in subjects with moderate AD. METHODS: Subjects received twice daily for 168 days (6 months) either SBT complex or emollient base adjunctively or alternately with topical corticosteroids or calcineurin inhibitors. Evolution of AD was assessed throughout the study using usual AD assessment criteria including SCORAD and PO SCORAD. Quality of life was assessed at Day 0 and Day 168. RESULTS: At Day 168, a significant decrease with SBT complex was observed for the SCORAD and the PO SCORAD scores (P < 0.05), the primary efficacy criteria. A total of 76% of SBT complex subjects did not relapse and time-to-relapse increased compared to the emollient base subjects. Intensity, dryness, and quality of life (P < 0.05) had improved in subjects using SBT complex. The product was well tolerated with less physical and functional signs in the SBT than in the emollient base group. CONCLUSION: The new emollient dermocosmetic SBT complex applied adjunctively or alternately with topical AD treatments significantly improved AD without any safety concerns. SBT complex may play an important role in the restoration of the natural skin barrier. PMID- 25807869 TI - Anatomic relationship of the proximal nail matrix to the extensor hallucis longus tendon insertion. AB - BACKGROUND: The purpose of this study was to delineate the relationship of the terminal extensor hallucis longus tendon insertion to the proximal limit of the nail matrix of the great toe. MATERIAL AND METHODS: Fifty fresh-frozen human cadaver great toes with no evidence of trauma (average age, 62.5 years; 29 males and 21 females) were used for this study. Under 25X magnification, the proximal limit of the nail matrix and the terminal bony insertion of the extensor hallucis longus tendons were identified. The distance from the terminal tendon insertion to the nail matrix was ascertained using precision calipers, an optical microscope, and autocad((r)) software for windows. Twenty-five great toes were placed in a neutral formalin solution and further analysed by histological longitudinal-sections. The specimens were stained with haematoxylin and eosin and examined microscopically to determine the presence of the extensor hallucis longus tendon along the dorsal aspect of the distal phalanx of each great toe. RESULTS: The main result we found in great toes was that the extensor tendon is between the matrix and the phalanx and extends dorsally to the distal aspect of the distal phalanx in all, 100%, specimens. The nail matrix of the great toe is not attached to the periosteum of the dorsal aspect of the base of the distal phalanx as is the case for fingers, because the extensor hallucis tendon is plantar or directly underneath the nail matrix and the tendon is dorsal to the bone. CONCLUSIONS: We have found that the extensor tendon is between the matrix and the phalanx and extends dorsally to the distal aspect of the distal phalanx. The nail matrix of the great toe is not attached to the periosteum of the dorsal aspect of the base of distal phalanx as is the case in fingers, because the extensor hallucis tendon is plantar or directly underneath the nail matrix and the tendon is dorsal to the bone. Our anatomic study demonstrates that the proximal limit of the matrix and nail bed of the human great toe are dorsal and overlapping the terminal extensor hallucis longus tendon until its distal bony insertion in all specimens. PMID- 25807868 TI - Emergency physician perceptions of medically unnecessary advanced diagnostic imaging. AB - OBJECTIVES: The objective was to determine emergency physician (EP) perceptions regarding 1) the extent to which they order medically unnecessary advanced diagnostic imaging, 2) factors that contribute to this behavior, and 3) proposed solutions for curbing this practice. METHODS: As part of a larger study to engage physicians in the delivery of high-value health care, two multispecialty focus groups were conducted to explore the topic of decision-making around resource utilization, after which qualitative analysis was used to generate survey questions. The survey was extensively pilot-tested and refined for emergency medicine (EM) to focus on advanced diagnostic imaging (i.e., computed tomography [CT] or magnetic resonance imaging [MRI]). The survey was then administered to a national, purposive sample of EPs and EM trainees. Simple descriptive statistics to summarize physician responses are presented. RESULTS: In this study, 478 EPs were approached, of whom 435 (91%) completed the survey; 68% of respondents were board-certified, and roughly half worked in academic emergency departments (EDs). Over 85% of respondents believe too many diagnostic tests are ordered in their own EDs, and 97% said at least some (mean = 22%) of the advanced imaging studies they personally order are medically unnecessary. The main perceived contributors were fear of missing a low-probability diagnosis and fear of litigation. Solutions most commonly felt to be "extremely" or "very" helpful for reducing unnecessary imaging included malpractice reform (79%), increased patient involvement through education (70%) and shared decision-making (56%), feedback to physicians on test-ordering metrics (55%), and improved education of physicians on diagnostic testing (50%). CONCLUSIONS: Overordering of advanced imaging may be a systemic problem, as many EPs believe a substantial proportion of such studies, including some they personally order, are medically unnecessary. Respondents cited multiple complex factors with several potential high-yield solutions that must be addressed simultaneously to curb overimaging. PMID- 25807870 TI - Efficacy and safety of a lindane 1% treatment regimen for scabies, confirmed by dermoscopy-guided skin scraping with microscopic examination. AB - BACKGROUND: This is the first study investigating scabies treatment since 1992 to involve examination of patients with microscopically confirmed scabies. AIM: To assess the efficacy of 1% lindane cream in treating microscopically confirmed scabies, and to determine the utility of dermoscopy-guided skin scraping with microscopic examination (DSGSS-ME) in evaluating the efficacy of scabies treatment. METHODS: This retrospective study analysed patients treated for scabies between January 2012 and December 2013. From the hospital database, 287 cases of scabies were identified and 50 were enrolled in the study. Patients were treated with 1% lindane cream twice weekly (days 0 and 1) and were evaluated with DSGSS-ME on day 7. Treatment and evaluations were repeated once weekly until a negative DSGSS-ME result was obtained. RESULTS: The cumulative efficacy of lindane 1% cream was 40% (20/50) after 1 week, 88% (44/50) after 2 weeks and 98% (49/50) after 3 weeks of treatment. There was a statistically significant difference between the 1- and 2-week (P = 0.03), and 1- and 3-week (P = 0.02) treatments. A total of 90 post-treatment DSGSS-MEs were performed, with a sensitivity of 97.3% (95% CI 85.8-99.9) and a negative predictive value of 98.2% (95% CI 90.1-100). Specificity and positive predictive value were 100%, as this procedure cannot yield false-positive results, because it relies on finding mites, eggs or faeces. CONCLUSIONS: We suggest that a twice-weekly schedule (on consecutive days) of 1% lindane treatment lasting at least 2 weeks is required to clear scabies. DSGSS-ME appears to be a good method to evaluate the efficacy of scabies treatment. This study introduces a safe and effective method to treat scabies, and to accurately monitor infestation status in patients. PMID- 25807872 TI - Practice makes perfect: Training the interpretation of emotional ambiguity. AB - The interpretation of emotionally ambiguous words, sentences, or scenarios can be altered through training procedures that are collectively called cognitive bias modification for interpretation (CBM-I). In three experiments, we systematically manipulated the nature of the training in order to discriminate between emotional priming and ambiguity resolution accounts of training effects. In Experiment 1 participants completed word fragments that were consistently related to either a negative or benign interpretation of an ambiguous sentence. In a subsequent semantic priming task they demonstrated an interpretation bias, in that they were faster to identify relatedness of targets that were associated with the training congruent meaning of an emotionally ambiguous homograph. We then manipulated the training sentences to show that interpretation bias was eliminated when participants simply completed valenced word fragments following unrelated sentences (Experiment 2), or completed fragments that were related to emotional but unambiguous sentences (Experiment 3). Only when participants were required to actively resolve emotionally ambiguous sentences during training did changes in interpretation emerge at test. Findings suggest that CBM-I achieves its effects by altering a production rule that aids the selection of meaning from emotionally ambiguous alternatives, in line with an ambiguity resolution account. PMID- 25807871 TI - Patient-derived olfactory mucosa for study of the non-neuronal contribution to amyotrophic lateral sclerosis pathology. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease which currently has no cure. Research using rodent ALS models transgenic for mutant superoxide dismutase 1 (SOD1) has implicated that glial-neuronal interactions play a major role in the destruction of motor neurons, but the generality of this mechanism is not clear as SOD1 mutations only account for less than 2% of all ALS cases. Recently, this hypothesis was backed up by observation of similar effects using astrocytes derived from post-mortem spinal cord tissue of ALS patients which did not carry SOD1 mutations. However, such necropsy samples may not be easy to obtain and may not always yield viable cell cultures. Here, we have analysed olfactory mucosa (OM) cells, which can be easily isolated from living ALS patients. Disease-specific changes observed when ALS OM cells were co cultured with human spinal cord neurons included decreased neuronal viability, aberrant neuronal morphology and altered glial inflammatory responses. Our results show the potential of OM cells as new cell models for ALS. PMID- 25807874 TI - A literature review of factors related to hospital nurses' health-related quality of life. AB - AIM: To conduct a literature review in order to determine the predictors of nurses' health-related quality of life and to clarify the implications for nursing management and future study in this area. BACKGROUND: Good health is essential to the performance of health care workers. EVALUATION: Relevant studies were retrieved from PubMed, Medline, CINAHL, the Japan Medical Abstract Society, and the Technology Information Aggregator, Electronic. The studies selected for this review were published in English or Japanese between 1995 and 2012, investigated nurses' health-related quality of life. The identified predictive factors of each study were categorised according to type. KEY ISSUES: Based on the criteria, 22 studies were reviewed. The predictive factors of nurses' health related quality of life were classified into eight categories. CONCLUSIONS: Age and occupational stress should be considered when examining unknown predictive factors of nurses' health-related quality of life. In addition, it may be useful to adopt a conceptual framework and consider patient and organisational factors in future research. IMPLICATIONS FOR NURSING MANAGEMENT: It is necessary to identify nurses' occupational stressors and consider age during job placement in order to support their health. PMID- 25807875 TI - Is a Bioprosthetic Valve in the Aortic Position Desirable with a Continuous Flow LVAD? AB - Commissural fusion of the native aortic valve in a patient with a continuous flow left ventricular assist device (LVAD) is a known phenomenon. This may result in aortic insufficiency (AI) leading to symptomatic heart failure. In patients with AI at the time of LVAD implantation, repairing, or replacing the aortic valve is advisable. We describe a patient who had a severe dilated cardiomyopathy and moderate AI who underwent implantation of an LVAD and aortic valve replacement with a bioprosthesis that subsequently developed commissural fusion which was found at the time of heart transplantation. This case highlights the conundrum of the management of AI in patients requiring LVAD support. PMID- 25807876 TI - Reply: To PMID 24975775. PMID- 25807877 TI - The Role of Conflict Identification and Management in Sustaining Community Collaboration: Report on a Four-Year Exploratory Study. AB - Community collaboration has become increasingly common in behavioral health services. Conflict is likely to occur in any community coalition bringing together organizations with differing mandates, missions, and histories. However, research on how coalitions identify and handle conflict, and on the impact of conflict on sustainability is scarce. An exploratory study examined conflict in two federally funded children's "systems of care" using site visits and concept mapping to describe differences in how sites conceptualize and respond to conflict. Results suggest that unacknowledged and unaddressed conflict can negatively affect the development and sustainability of sites, and that focusing on cooperation may, paradoxically, make it more difficult to acknowledge conflict and to implement conflict transformation processes. Implications for behavioral health administrators are discussed, including potential interventions that could address these issues. PMID- 25807873 TI - Tempering allorecognition to induce transplant tolerance with chemically modified apoptotic donor cells. AB - The development of organ transplantation as a therapy for end-stage organ failure is among the most significant achievements of 20th century medicine, but chronic rejection remains a barrier to achieving long-term success. Current therapeutic regimens consist of immunosuppressive drugs that are efficient at delaying rejection but are associated with significant risks such as opportunistic infections, toxicity, and malignancy. Thus, the induction of specific immune tolerance to transplant antigens is the coveted aim of researchers. The use of 1 ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI)-treated, autoantigen-coupled syngeneic leukocytes has been developed as a specific immunotherapy in preclinical models of autoimmunity and is currently in a phase II clinical trial for the treatment of multiple sclerosis. In this review, we discuss the use of allogeneic ECDI-treated apoptotic donor leukocytes (allo-ECDI-SP) as a strategy for inducing antigen-specific tolerance in allogeneic transplantation. Allo-ECDI SP therapy induces long-term systemic immune tolerance to transplant antigens by subverting alloimmune recognition and exploiting apoptotic cell uptake pathways to recapitulate innate mechanisms of peripheral tolerance. Lastly, we discuss potential indications and challenges for transitioning allo-ECDI-SP therapy into clinical practice. PMID- 25807878 TI - Reduction of Radiation Exposure in Atrial Fibrillation Ablation Using a New Image Integration Module: A Prospective Randomized Trial in Patients Undergoing Pulmonary Vein Isolation. AB - INTRODUCTION: Recently, a new image integration module (IIM, CartoUnivuTM Module) has been introduced to combine and merge fluoroscopy images with 3-dimensional (3D)-electroanatomical maps (Carto(r) 3 System) into an accurate 3D view. The aim of the study was to investigate the influence of IIM on the fluoroscopy exposure during pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) in a prospective randomized trial. METHODS AND RESULTS: Between June and November 2014, a total of 60 patients with PAF (73.3% male, 64.0 +/- 9.2 years), who underwent PVI with the endpoint of unexcitability of the ablation line, were randomized to either a conventional 3D mapping system (Carto(r) 3 System) or to an additional IIM on the basis of an assumed reduction of fluoroscopy exposure by the use of IIM. There were no significant differences in baseline characteristics. The median ablation procedure time was identical in both groups (140.7 +/- 27.8 minutes vs. 140.8 +/- 39.5 minutes; P = 0.851). A significant decrease of mean fluoroscopy time from 11.9 +/- 2.1 to 7.4 +/- 2.6 minutes (P < 0.0006) and median fluoroscopy dose from 882.9 to 476.5 cGycm(2) (P < 0.001) was achieved. The main reduction of radiation could be realized during creation of the 3D-map. No major complications occurred during the procedures. After a median follow-up of 125.7 +/- 45.6 days 80% of the patients were free from any atrial arrhythmias. CONCLUSION: CartoUnivuTM module easily integrates into the workflow of PVI with the endpoint of unexcitability of the ablation line without prolonging the procedure time. It is associated with a marked reduction in fluoroscopic dose when compared to a conventional 3D mapping system. PMID- 25807879 TI - Involvement of 5-HT3 and 5-HT4 receptors in colonic motor patterns in rats. AB - BACKGROUND: Colonic migrating motor complexes in the rat constitute two distinct propulsive motor patterns, pan-colonic rhythmic long distance contractions (LDCs), and rhythmic propulsive motor complexes (RPMCs) occurring primarily in the mid/distal colon. Interstitial cells of Cajal govern their rhythmicity, but their occurrence is dependent on neural programs. Our aim was to investigate the involvement of 5-HT3 and 5-HT4 receptors in the generation and pharmacological control of the motor patterns. METHODS: Effects of 5-HT-related drugs on colonic motor patterns were analyzed through spatio-temporal maps created from video recordings of whole organ motility. KEY RESULTS: 5-HT3 antagonists abolished RPMCs and LDCs. 5-HT4 agonists inhibited LDCs; they promoted RPMCs, which was blocked by the 5-HT4 antagonist GR 125487. 5-HT and the 5-HT3 agonist m-CPBG strongly inhibited LDCs and RPMCs. CONCLUSIONS & INFERENCES: The generation of LDCs involves ongoing 5-HT release acting on 5-HT3 and 5-HT4 receptors. The spontaneous generation of RPMCs involves ongoing 5-HT release acting on 5-HT3 but not 5-HT4 receptors. Prucalopride and mosapride promote RPMCs, an effect that is inhibited by the 5-HT4 receptor antagonist GR 125487. A 5-HT3 agonist does not promote RPMCs. Segmentation, including a pattern of sequential segmental activity not previously described, can occur without significant involvement of 5-HT3 and 5-HT4 receptors. 5-HT and a 5-HT3 agonist are strongly inhibitory indicating that 5-HT receptors are present in inhibitory pathways which are normally not involved in the generation of spontaneous or distention-induced motor patterns. PMID- 25807880 TI - On the Eicosanoid Trail with John Vane and Jack McGiff: 1974-1976. A personal reminiscence. AB - In this brief personal reminiscence I comment upon the friendship and mutual understanding that arose between two great scientists and co-travellers, John Vane and Jack McGiff. I relate the events that led up to their meeting and focus on the brief period of time when they worked together on eicosanoid pharmacology in the UK. PMID- 25807881 TI - Growth hormone deficiency after childhood bone marrow transplantation with total body irradiation: interaction with adiposity and age. AB - OBJECTIVE: Bone marrow transplantation with total body irradiation (BMT/TBI) has adverse effects on growth, growth hormone status and adiposity. We investigated the GH-IGF-I axis in relation to adiposity. DESIGN: Cross-sectional case control study. PATIENTS: BMT/TBI survivors (n = 22) and short stature control participants (n = 19), all GH-naive or off GH treatment >3 months. MEASUREMENTS: Auxology, DEXA scans and GH-IGF-I axis investigation: (i) 12-h overnight GH profiles; (ii) insulin tolerance test (ITT); and (iii) IGF-I generation test. ANALYSIS: auto-deconvolution of GH profile data and comparison of quantitative parameters using ANOVA. RESULTS: Eighty-two percent of BMT/TBI survivors had growth hormone deficiency (GHD) using ITT. GH profile area-under-the-curve (GH AUC) was reduced in BMT/TBI survivors vs short stature control participants [geometric mean (range) 209 (21-825) vs 428 (64-1400) mcg/l/12 h, respectively, P = 0.007]. GHD was more marked in those who had additional cranial irradiation (CRT) [ITT peak 1.4 (0.2-3.0) vs TBI only 4.1 (1.1-14.8) mcg/l, P = 0.036]. GHD was more marked at the end of growth in BMT/TBI survivors vs short stature control participants (GH-AUC 551 (64-2474) vs 1369 (192-4197) mcg/l/12 h, respectively, P = 0.011) and more prevalent (9/11 vs 1/9, respectively, P = 0.005). GH profile data were consistent with ITT results in 80% of participants. IGF-I generation tests were normal. BMT/TBI survivors still demonstrated lower GH levels after adjustment for adiposity (fat-adjusted mean difference for GH-AUC 90.9 mcg/l/12 h, P = 0.025). CONCLUSIONS: GHD was more prevalent in BMT/TBI survivors than expected for the CRT dose in TBI, worsened with time and persisted into adulthood. GHD could not be explained by adiposity. There was no evidence of GH neurosecretory dysfunction or resistance after BMT/TBI. PMID- 25807882 TI - Antimicrobial effects of essential oils, nisin, and irradiation treatments against Listeria monocytogenes on ready-to-eat carrots. AB - The study aimed at using essential oil (EO) alone or combined EO with nisin and low dose gamma-irradiation to evaluate their antibacterial effect against Listeria monocytogenes during storage of carrots at 4 degrees C. Minicarrots were inoculated with L. monocytogenes at a final concentration of approximately 7 log CFU/g. Inoculated samples were coated by nisin at final concentration of 10(3) International Unit (IU)/mL or individual mountain savory EO or carvacrol at final concentration of 0.35%, w/w) or nisin plus EO. The samples were then irradiated at 0, 0.5, and 1.0 kGy. The treated samples were kept at 4 degrees C and microbial analysis of samples were conducted at days 1, 3, 6, and 9. The results showed that coating carrots by carvacrol plus nisin or mountain savory plus nisin and then irradiating coated carrots at 1 kGy could reduce L. monocytogenes by more than 3 log at day 1 and reduced it to undetectable level from day 6. Thus, the combined treatments using nisin plus carvacrol or nisin plus mountain savory and irradiation at 1.0 kGy could be used as an effective method for controlling L. monocytogenes in minicarrots. PMID- 25807883 TI - Do Obese Individuals With Hypertension Have More Difficult-to-Control Blood Pressure and End Organ Damage Than Their Nonobese Counterparts? AB - The authors assessed whether individuals with elevated body mass index (BMI) and hypertension had more difficult-to-control blood pressure (BP) and more evidence of end organ damage using data collected prospectively over 11 years from a secondary care hypertension clinic. A total of 1114 individuals were divided by BMI criteria into normal (n=207), overweight (n=440), and obese (n=467). Mean daytime, nighttime, and 24-hour systolic BP and diastolic BP were similar in all groups. There was less nocturnal dip in obese compared with overweight groups (P=.025). Individuals with a normal BMI were taking fewer antihypertensive medications than those in the obese group (P=.01). Individuals classified as obese had a higher left ventricular mass index than those with a normal BMI (female, P=.028; male, P<.001); this relationship remained after multivariate linear regression. Obese individuals with hypertension required more medication to achieve similar mean ambulatory BP values, had less nocturnal dip in BP, and had a higher prevalence of left ventricular hypertrophy. As such, obese patients are at potentially increased risk of cardiovascular events. PMID- 25807884 TI - Absent right superior caval vein in situs solitus. AB - Introduction In up to 0.07% of the general population, the right anterior cardinal vein obliterates and the left remains open, creating an absent right superior caval vein and a persistent left superior caval vein. Absent right superior caval vein is associated with additional congenital heart disease in about half the patients. We wished to study the consequences of absent right superior caval vein as an incidental finding on prenatal ultrasonic malformation screening. Material and methods This is a retrospective case series study of all foetuses diagnosed with absent right superior caval vein at the national referral hospital, Rigshospitalet, Denmark, from 2009 to 2012. RESULTS: In total, five cases of absent right superior caval vein were reviewed. No significant associated cardiac, extra-cardiac, or genetic anomalies were found. Postnatal echocardiographies confirmed the diagnosis and there were no postnatal complications. All children were found to have healthy hearts at follow-up. CONCLUSIONS: In all cases, the findings proved to be a benign condition with no clinical manifestations or complications. Although isolated absent right superior caval vein does not seem to affect the outcome, associated anomalies may be serious. Absent right superior caval vein should, therefore, prompt a search for additional malformations. Furthermore, the diagnosis of an isolated absent right superior caval vein is important, because knowledge of the anomaly can prevent future problems when invasive procedures are necessary. PMID- 25807885 TI - Libman-Sacks Endocarditis: Detection, Characterization, and Clinical Correlates by Three-Dimensional Transesophageal Echocardiography. AB - BACKGROUND: Libman-Sacks endocarditis, characterized by Libman-Sacks vegetations, is common in patients with systemic lupus erythematosus and is commonly complicated with embolic cerebrovascular disease. Thus, accurate detection of Libman-Sacks vegetations may lead to early therapy and prevention of their associated complications. Although two-dimensional (2D) transesophageal echocardiography (TEE) has high diagnostic value for detection of Libman-Sacks vegetations, three-dimensional (3D) TEE may allow improved detection, characterization, and clinical correlations of Libman-Sacks vegetations. METHODS: Twenty-nine patients with systemic lupus erythematosus (27 women; mean age, 34 +/ 12 years) prospectively underwent 40 paired 3D and 2D transesophageal echocardiographic studies and assessment of cerebrovascular disease manifested as acute clinical neurologic syndromes, neurocognitive dysfunction, or focal brain injury on magnetic resonance imaging. Initial and repeat studies in patients were intermixed in a blinded manner with paired studies from healthy controls, deidentified, coded, and independently interpreted by experienced observers unaware of patients' clinical and imaging data. RESULTS: The results of 3D TEE compared with 2D TEE were more often positive for mitral or aortic valve vegetations, and 3D TEE detected more vegetations per study and determined larger sizes of vegetations (P <= .03 for all). Also, 3D TEE detected more vegetations on the anterior mitral leaflet, anterolateral and posteromedial scallops, and ventricular side or both atrial and ventricular sides of the leaflets (P < .05 for all). In addition, 3D TEE detected more vegetations on the aortic valve left and noncoronary cusps, coronary cusps' tips and margins, and aortic side or both aortic and ventricular sides of the cusps (P <= .01 for all). Furthermore, 3D TEE more often detected associated mitral or aortic valve commissural fusion (P = .002). Finally, 3D TEE detected more vegetations in patients with cerebrovascular disease (P = .01). CONCLUSIONS: Three-dimensional TEE provides clinically relevant additive information that complements 2D TEE for the detection, characterization, and association with cerebrovascular disease of Libman-Sacks endocarditis. PMID- 25807886 TI - Clinical significance of peripheral zone thickness in men with lower urinary tract symptoms/benign prostatic hyperplasia. AB - OBJECTIVE: To evaluate the clinical impact of prostate peripheral zone thickness (PZT), based on presumed circle area ratio (PCAR) theory, on urinary symptoms in men with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) as a novel prostate parameter. PATIENTS AND METHODS: Medical records were obtained from a prospective database of first-visit men with LUTS/BPH. Age, international prostate symptom score (IPSS), overactive bladder symptom score (OABSS), maximum urinary flow rate (Qmax ), and post-void residual urine volume (PVR) were assessed. Total prostate volume (TPV), transition zone volume (TZV), transition zone index (TZI), and PZT were measured by transrectal ultrasonography. Reliability analysis was also performed. RESULTS: In all, 1009 patients were enrolled for the analysis. The mean (sd) PZT was 11.10 (2.50) mm, and patients were classified into three groups PZT thickness groups; PZT <9.5 mm, >=9.5 to <13 mm, and >=13 mm. As the PZT became smaller, all urinary symptom scores including IPSS, quality of life (QoL), and OABSS significantly increased. Uroflowmetry variables, such as Qmax and PVR, also showed significant differences. PZT showed a high intra-class correlation coefficient (0.896). Multivariate analysis revealed that the PZT was independently associated with IPSS (P < 0.001), QoL (P = 0.003), OABSS (P = 0.001), and PVR (P = 0.001), but PZT influence on Qmax was only of borderline significance (P = 0.055). CONCLUSION: PZT is a novel, easy-to measure prostate parameter that is significantly associated with urinary symptoms. Our present findings suggest that clinical usefulness of PZT should be further validated for managing men with LUTS/BPH. PMID- 25807887 TI - Feasibility of antibody-poly(glutamic acid) complexes: preparation of high concentration antibody formulations and their pharmaceutical properties. AB - Development of high-concentration antibody formulations for subcutaneous administration remains challenging. Recently, a precipitation-redissolution method was proposed to prepare suspensions or precipitates of salt-dissociable protein-poly(amino acid) complexes. To elucidate the utility of this method for protein therapy, we investigated the feasibility of a precipitation-redissolution method using poly(amino acid) for high-concentration antibody formulation. Omalizumab and adalimumab formulations of 150 mg/mL could be prepared using poly l-glutamic acid (polyE) from low-concentration stock solutions. Enzyme-linked immunosorbent assay, circular dichroism, and size-exclusion chromatography revealed that the formation of antibody-polyE complex and precipitation redissolution process did not significantly affect the immunoreactivity or secondary structure of the antibodies. The precipitation-redissolution method was less time-consuming and more effective than lyophilization-redissolution, evaporation-redissolution, and ultrafiltration from the viewpoint of final yield. Scalability was confirmed from 400 MUL to 1.0 L. The general toxicity and pharmacokinetic profiles of the antibody-polyE complex formulations were similar to those of conventional antibody formulations. These results suggested that the precipitation-redissolution method using poly(amino acid) has great potential as a concentration method for antibody formulation and medicinal use. PMID- 25807888 TI - Relation between chemotaxis and consumption of amino acids in bacteria. AB - Chemotaxis enables bacteria to navigate chemical gradients in their environment, accumulating toward high concentrations of attractants and avoiding high concentrations of repellents. Although finding nutrients is likely to be an important function of bacterial chemotaxis, not all characterized attractants are nutrients. Moreover, even for potential nutrients, the exact relation between the metabolic value of chemicals and their efficiency as chemoattractants has not been systematically explored. Here we compare the chemotactic response of amino acids with their use by bacteria for two well-established models of chemotactic behavior, Escherichia coli and Bacillus subtilis. We demonstrate that in E. coli chemotaxis toward amino acids indeed strongly correlates with their utilization. However, no such correlation is observed for B. subtilis, suggesting that in this case, the amino acids are not followed because of their nutritional value but rather as environmental cues. PMID- 25807889 TI - Factors affecting perioperative mortality in tetralogy of Fallot. AB - BACKGROUND: We evaluated the preoperative, operative and postoperative risk factors affecting early mortality in patients who underwent total correction of tetralogy of Fallot (TOF). METHODS: One hundred and twenty-two TOF patients who underwent reparative surgery between January 2010 and November 2013 were enrolled in the study. RESULTS: Mean patient age and weight was 2.3 +/- 2.5 years and 11.3 +/- 6.4 kg, respectively. Cardiac catheterization was performed in 101 patients (83%),and coronary anomalies were found in 11 patients. Mean McGoon index, pulmonary annulus z-score, main pulmonary artery z-score, left pulmonary artery z score and right pulmonary artery z-score were 2.0 +/- 0.4, -1.85 +/- 1.54, -2.84 +/- 2.06, 1.17 +/- 1.73, and 0.74 +/- 1.57, respectively. Total reparative surgery with a transannular patch was performed in 97 patients (79.6%); the rest underwent valve-sparing surgery. Median duration of postoperative mechanical ventilation, intensive care and hospital stay were 19 h, 3 days and 9 days, respectively. Extracorporeal membrane oxygenation (ECMO) was required in 10 patients in the postoperative early period. Arrhythmias occurring in the early postoperative period were junctional ectopic tachycardia (n = 13), complete atrioventricular block(n = 10; permanent epicardial pacemaker implanted in four) and ventricular tachycardia (n = 4). Nine patients died in the early postoperative period (7.3%). Parameters found to be associated with increased mortality were low preoperative oxygen saturation; high right ventricular/aortic pressure ratio immediately after surgery; presence of coronary anomaly; requirement of postoperative ECMO; and pacemaker (P = 0.02, P = 0.04, P = 0.01, P = 0.0001, P = 0.03, respectively). CONCLUSIONS: Poor preoperative oxygenation, presence of coronary anomaly, complete AV block in the early postoperative period, high RV pressure and requirement of ECMO appear to be the most significant factors that affect early mortality in the surgical treatment of TOF. Appropriate preoperative assessment, correct surgical strategies and attentive intensive care monitoring are required in order to reduce mortality. PMID- 25807890 TI - Preparation and preliminary dialysis performance research of polyvinylidene fluoride hollow fiber membranes. AB - In this study, the separation properties of Polyvinylidene fluoride (PVDF) hollow fiber hemodialysis membranes were improved by optimizing membrane morphology and structure. The results showed that the PVDF membrane had better mechanical and separation properties than Fresenius Polysulfone High-Flux (F60S) membrane. The PVDF membrane tensile stress at break, tensile elongation and bursting pressure were 11.3 MPa, 395% and 0.625 MPa, respectively. Ultrafiltration (UF) flux of pure water reached 108.2 L?h-1?m-2 and rejection of Albumin from bovine serum was 82.3%. The PVDF dialyzers were prepared by centrifugal casting. The influences of membrane area and simulate fluid flow rate on dialysis performance were investigated. The results showed that the clearance rate of urea and Lysozyme (LZM) were improved with increasing membrane area and fluid flow rate while the rejection of albumin from bovine serum (BSA) had little influence. The high-flux PVDF dialyzer UF coefficient reached 62.6 mL/h/mmHg. The PVDF dialyzer with membrane area 0.69 m2 has the highest clearance rate to LZM and urea. The clearance rate of LZM was 66.8% and urea was 87.7%. PMID- 25807891 TI - A Randomized Controlled Trial for Children With Childhood Apraxia of Speech Comparing Rapid Syllable Transition Treatment and the Nuffield Dyspraxia Programme-Third Edition. AB - PURPOSE: This randomized controlled trial compared the experimental Rapid Syllable Transition (ReST) treatment to the Nuffield Dyspraxia Programme-Third Edition (NDP3; Williams & Stephens, 2004), used widely in clinical practice in Australia and the United Kingdom. Both programs aim to improve speech motor planning/programming for children with apraxia of speech (CAS), but they differ in types of stimuli used, level of stimulus complexity at initiation of treatment, and the principles of motor learning that they apply. METHOD: Treatment was delivered to 26 children with mild to severe CAS aged 4-12 years through trained and supervised speech-language pathology students in 1-hr sessions, 4 days a week for 3 weeks at a university clinic. Articulation and prosodic accuracy were assessed at pretreatment, 1 week, 1 month, and 4 months posttreatment using blinded independent assessors to compare treatment, maintenance, and generalization effects. RESULTS: The ReST and NDP3 treatments demonstrated large treatment effects. ReST maintained treatment gains from 1-week to 4-months posttreatment more effectively than the NDP3. Significant generalization to untreated stimuli was observed for both ReST and NDP3. CONCLUSIONS: ReST and NDP3 have strong evidence of treatment and generalization gains in children with CAS when delivered intensively. Overall, ReST has greater external evidence from multiple sources but both treatments have support for clinical use. PMID- 25807896 TI - Antiplatelet and invasive treatment in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and acute coronary syndrome. The safety of aspirin. AB - WHAT IS KNOWN AND OBJECTIVE: Aspirin is an important drug in acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI). However, its use is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (risk for haemolytic anaemia). We report the management of 2 patients with class II G6PD deficiency and non-ST-segment elevation ACS (NSTE-ACS). CASE DESCRIPTION: The two patients were safely and efficiently treated with dual antiplatelet treatment (DAPT, aspirin plus ticagrelor) and PCI using new generation drug-eluting stent (DES) despite G6PD deficiency. WHAT IS NEW AND CONCLUSION: NSTE-ACS management with DAPT and DES is probably safe and effective in class II G6PD-deficient patients. PMID- 25807892 TI - EphrinB2 controls vessel pruning through STAT1-JNK3 signalling. AB - Angiogenesis produces primitive vascular networks that need pruning to yield hierarchically organized and functional vessels. Despite the critical importance of vessel pruning to vessel patterning and function, the mechanisms regulating this process are not clear. Here we show that EphrinB2, a well-known player in angiogenesis, is an essential regulator of endothelial cell death and vessel pruning. This regulation depends upon phosphotyrosine-EphrinB2 signalling repressing c-jun N-terminal kinase 3 activity via STAT1. JNK3 activation causes endothelial cell death. In the absence of JNK3, hyaloid vessel physiological pruning is impaired, associated with abnormal persistence of hyaloid vessels, defective retinal vasculature and microphthalmia. This syndrome closely resembles human persistent hyperplastic primary vitreus (PHPV), attributed to failed involution of hyaloid vessels. Our results provide evidence that EphrinB2/STAT1/JNK3 signalling is essential for vessel pruning, and that defects in this pathway may contribute to PHPV. PMID- 25807895 TI - Daily differential expression of melatonin-related genes and clock genes in rat cumulus-oocyte complex: changes after pinealectomy. AB - This study investigated the maturational stage (immature and mature ovaries) differences of mRNA expression of melatonin-forming enzymes (Aanat and Asmt), melatonin membrane receptors (Mt1 and Mt2) and putative nuclear (Roralpha) receptors, and clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2) in cumulus oocyte complexes (COC) from weaning Wistar rats. We also examined the effects of pinealectomy and of melatonin pharmacological replacement on the daily expression of these genes in COC. qRT-PCR analysis revealed that in oocytes, the mRNA expression of Asmt, Mt2, Clock, Bmal1, Per2, and Cry1 were higher (P < 0.05) in immature ovaries than in the mature ones. In cumulus cells, the same pattern of mRNA expression for Asmt, Aanat, Roralpha, Clock, Per1, Cry1, and Cry2 genes was observed. In oocytes, pinealectomy altered the daily mRNA expression profiles of Asmt, Mt1, Mt2, Clock, Per1, Cry1, and Cry2 genes. In cumulus cells, removal of the pineal altered the mRNA expression profiles of Mt1, Mt2, Roralpha, Aanat, Asmt, Clock, Bmal1, Per2, Cry1, and Cry2 genes. Melatonin treatment partially or completely re-established the daily mRNA expression profiles of most genes studied. The mRNA expression of melatonin-related genes and clock genes in rat COC varies with the maturational stage of the meiotic cellular cycle in addition to the hour of the day. This suggests that melatonin might act differentially in accordance with the maturational stage of cumulus/oocyte complex. In addition, it seems that circulating pineal melatonin is very important in the design of the daily profile of mRNA expression of COC clock genes and genes related to melatonin synthesis and action. PMID- 25807894 TI - Ablating hedgehog signaling in tenocytes during development impairs biomechanics and matrix organization of the adult murine patellar tendon enthesis. AB - Restoring the native structure of the tendon enthesis, where collagen fibers of the midsubstance are integrated within a fibrocartilaginous structure, is problematic following injury. As current surgical methods fail to restore this region adequately, engineers, biologists, and clinicians are working to understand how this structure forms as a prerequisite to improving repair outcomes. We recently reported on the role of Indian hedgehog (Ihh), a novel enthesis marker, in regulating early postnatal enthesis formation. Here, we investigate how inactivating the Hh pathway in tendon cells affects adult (12 week) murine patellar tendon (PT) enthesis mechanics, fibrocartilage morphology, and collagen fiber organization. We show that ablating Hh signaling resulted in greater than 100% increased failure insertion strain (0.10 v. 0.05 mm/mm, p<0.01) as well as sub-failure biomechanical deficiencies. Although collagen fiber orientation appears overtly normal in the midsubstance, ablating Hh signaling reduces mineralized fibrocartilage by 32%, leading to less collagen embedded within mineralized tissue. Ablating Hh signaling also caused collagen fibers to coalesce at the insertion, which may explain in part the increased strains. These results indicate that Ihh signaling plays a critical role in the mineralization process of fibrocartilaginous entheses and may be a novel therapeutic to promote tendon-to-bone healing. PMID- 25807897 TI - Implementation of HPV-testing for cervical cancer screening in programmatic contexts: The Jujuy demonstration project in Argentina. AB - The aim of this article is to present results of programmatic introduction of HPV testing with cytologic triage among women 30 years and older in the province of Jujuy, Argentina, including description of the planning phase and results of program performance during the first year. We describe the project implementation process, and calculate key performance indicators using SITAM, the national screening information system. We also compare disease detection rates of HPV testing in 2012 with cytology as performed during the previous year. HPV testing with cytology triage was introduced through a consensus-building process. Key activities included establishment of algorithms and guidelines, creating the HPV laboratory, training of health professionals, information campaigns for women and designing the referral network. By the end of 2012, 100% (n = 270) of public health care centers were offering HPV testing and 22,834 women had been HPV tested, 98.5% (n = 22,515) were 30+. HPV positivity among women over 30 was 12.7%, 807 women were HPV+ and had abnormal cytology, and 281 CIN2+ were identified. CIN2+ detection rates was 1.25 in 2012 and 0.62 in 2011 when the program was cytology based (p = 0.0002). This project showed that effective introduction of HPV testing in programmatic contexts of low-middle income settings is feasible and detects more disease than cytology. PMID- 25807898 TI - EMMPRIN regulates beta1 integrin-mediated adhesion through Kindlin-3 in human melanoma cells. AB - EMMPRIN is known to promote tumor invasion through extracellular matrix (ECM) degradation. Here we report that EMMPRIN can regulate melanoma cell adhesion to the ECM through an interaction with beta1 integrin involving kindlin-3. In this study, EMMPRIN knockdown in the human melanoma cell line M10 using siRNA decreased cell invasion and significantly increased cell adhesion and spreading. A morphological change from a round to a spread shape was observed associated with enhanced phalloidin-labelled actin staining. In situ proximity ligation assay and co-immunoprecipitation revealed that EMMPRIN silencing increased the interaction of beta1 integrin with kindlin-3, a focal adhesion protein. This was associated with an increase in beta1 integrin activation and a decrease in the phosphorylation of the downstream integrin kinase FAK. Moreover, the expression at both the transcript and protein level of kindlin-3 and of beta1 integrin was inversely regulated by EMMPRIN. EMMPRIN did not regulate either talin expression or its interaction with beta1 integrin. These results are consistent with our in vivo demonstration that EMMPRIN inhibition increased beta1 integrin activation and its interaction with kindlin-3. To conclude, these findings reveal a new role of EMMPRIN in tumor cell migration through beta1 integrin/kindlin-3-mediated adhesion pathway. PMID- 25807893 TI - Intasome architecture and chromatin density modulate retroviral integration into nucleosome. AB - BACKGROUND: Retroviral integration depends on the interaction between intasomes, host chromatin and cellular targeting cofactors as LEDGF/p75 or BET proteins. Previous studies indicated that the retroviral integrase, by itself, may play a role in the local integration site selection within nucleosomal target DNA. We focused our study on this local association by analyzing the intrinsic properties of various retroviral intasomes to functionally accommodate different chromatin structures in the lack of other cofactors. RESULTS: Using in vitro conditions allowing the efficient catalysis of full site integration without these cofactors, we show that distinct retroviral integrases are not equally affected by chromatin compactness. Indeed, while PFV and MLV integration reactions are favored into dense and stable nucleosomes, HIV-1 and ASV concerted integration reactions are preferred into poorly dense chromatin regions of our nucleosomal acceptor templates. Predicted nucleosome occupancy around integration sites identified in infected cells suggests the presence of a nucleosome at the MLV and HIV-1 integration sites surrounded by differently dense chromatin. Further analyses of the relationships between the in vitro integration site selectivity and the structure of the inserted DNA indicate that structural constraints within intasomes could account for their ability to accommodate nucleosomal DNA and could dictate their capability to bind nucleosomes functionally in these specific chromatin contexts. CONCLUSIONS: Thus, both intasome architecture and compactness of the chromatin surrounding the targeted nucleosome appear important determinants of the retroviral integration site selectivity. This supports a mechanism involving a global targeting of the intasomes toward suitable chromatin regions followed by a local integration site selection modulated by the intrinsic structural constraints of the intasomes governing the target DNA bending and dictating their sensitivity toward suitable specific nucleosomal structures and density. PMID- 25807900 TI - Response to Dylan Mordaunt and Alisha McLauchlan. PMID- 25807899 TI - Transforming growth factor-beta released by apoptotic white blood cells during red blood cell storage promotes transfusion-induced alloimmunomodulation. AB - BACKGROUND: Red blood cell (RBC) alloimmunization is a major immunologic risk of transfusion. However, RBC storage facilitates white blood cell (WBC) apoptosis and apoptotic cells have immunomodulatory properties. We investigated the behavior of WBCs, and apoptosis in particular, in RBC units during storage and then studied the impact of WBC apoptosis on the modulation of posttransfusion alloimmunization in RBC products stored short term. STUDY DESIGN AND METHODS: We used a mouse model of alloimmunization to transfused HEL-ovalbumin-Duffy (HOD) surface antigen expressed specifically on RBCs. The presence of circulating anti HOD immunoglobulin G detected by flow cytometry confirmed immunization to HOD+ RBCs. WBC apoptosis and factors released by apoptotic WBCs during storage were determined and in particular the role of transforming growth factor (TGF)-beta was assessed on RBC alloimmunization. RESULTS: In blood stored 72 hours, 30% of WBCs were apoptotic, and transfusion of short-term-stored blood resulted in lesser immunization than did fresh blood or stored leukoreduced (LR) RBCs. WBCs undergoing apoptosis released during short-term storage factors modulating RBC alloimmunization. Indeed apoptotic cell-released factors modulate alloimmunization whereas exogenous apoptotic cells directly transfused with LR RBCs did not. While microparticles released during RBC storage had no immunomodulatory role, TGF-beta found in the supernatant of stored blood demonstrated the capacity to favor Treg polarization of naive CD4+CD25- T cells in vitro and limited RBC alloimmunization in vivo. Indeed, addition of recombinant TGF-beta to stored LR RBC transfusion strongly limited posttransfusion RBC alloimmunization. CONCLUSION: Our findings show that short term storage of non-LR blood facilitates WBC apoptosis therefore releasing TGF beta that modulates posttransfusion RBC alloimmunization. PMID- 25807902 TI - Effectiveness of full- and partial-mouth disinfection on halitosis in periodontal patients. AB - To compare the effectiveness of full- and partial-mouth disinfection for halitosis control, patients were assigned to treatment with full-mouth therapy (complete scaling and root planing in one stage within 24 h) or conventional therapy in quadrants (scaling and root planing performed by quadrant over a period of 4 weeks) (n = 90 for each group). Both groups were then subdivided: half the patients scraped their tongue daily and half did not. The patients were then evaluated by halimeter, organoleptic testing, and tongue coating index. Halimeter evaluation showed greater reduction of sulfide gases after full-mouth therapy than after conventional therapy (P < 0.001). However, organoleptic testing and the tongue coating index showed no difference among the four treatment groups. There was also no difference in relation to tongue scraping. In conclusion, halimeter evaluation showed that the reduction in volatile sulfur compounds was significantly greater after full-mouth therapy than after conventional therapy. However, this difference was not observed in organoleptic evaluation. PMID- 25807901 TI - Urine biomarkers for necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in premature neonates. Despite decades of investigation, treating clinicians are still not able to determine which premature infants are at greatest risk of developing NEC and which of the affected infants will develop severe NEC requiring operation. A biomarker is a specific molecular indicator that can be used to identify or measure the progress of a disease. Many potential biomarkers have been studied for their potential relevance to NEC. Those showing promise include C-reactive protein, intestinal fatty acid-binding protein, platelet-activating factor and many others. None to date have achieved sufficient predictive value to be clinically useful. Distinguishing between the specific changes in NEC and the non-specific inflammation of sepsis has proven challenging. Urine is a particularly attractive site for potential biomarkers. It can be collected readily and non-invasively, and it is a rich source of both proteins and peptides. Preliminary work has revealed some promising biomarkers of NEC in urine. Combined with clinical data, they have been shown to be highly predictive in small series of patients. Advances in high-throughput molecular analysis have opened the door to finding biomarkers that may meaningfully improve the outcome of infants at risk for NEC. PMID- 25807903 TI - Effects of bovine lactoferrin in surgically created bone defects on bone regeneration around implants. AB - The aim of this experimental study was to evaluate the effect of bovine lactoferrin (bLF)-loaded gelatin microspheres (GM) used in combination with anorganic bovine bone on bone regeneration in surgically created bone defects around tooth implants. Twenty-four uniform bone defects were created in the frontal bone via an extraoral approach in 12 domestic pigs. Twenty-four implants were placed at the center of the defects. In eight animals one of these defects was filled with 0.3 mL anorganic bovine bone while the other was left empty. In four animals, all defects were filled with 3 mg/defect bLF-loaded GM and anorganic bovine bone. All the defects were covered with collagen membranes. All animals were sacrificed after 10 weeks of healing, and the implants with the surrounding bone defects were removed en bloc. Undecalcified sections were prepared for histomorphometric analysis. The mean total area of hard tissue was 26.9 +/- 6.0% in the empty defect group, 31.8 +/- 8.4% in the graft group, and 47.6 +/- 5.0% in the lactoferrin group (P < 0.001). The mean area of newly formed bone was 26.9 +/- 6.0% in the empty defect group, 22.4 +/- 8.2% in the graft group, and 46.1 +/- 5.1% in the lactoferrin group (P < 0.001). The mean residual graft area was 9.4 +/- 3.2% in the graft group and 1.5 +/- 0.6% in the lactoferrin group (P < 0.001). The mean proportion of bone-implant contact in the defect region was 21.9 +/- 8.4% in the empty defect group, 26.9 +/- 10.1% in the graft group and 29.9 +/- 10.3% in the lactoferrin group (P = 0.143). These data indicate that a combination of 3 mg bLF-loaded GM and bovine-derived HA promotes bone regeneration in defects around implants. PMID- 25807904 TI - Effect of sodium sulfite, carboxylic monomer, and phosphoric acid etching on bonding of tri-n-butylborane initiated resin to human enamel. AB - The purpose of the present study is evaluation of bonding durability of tri-n butylborane (TBB) initiated resin without 4-methacryloyloxyethyl trimellitate anhydride (4-META) joined to human enamel. Ground human enamel was bonded with TBB resin under six surface conditions: 1) as ground, 2) primed with Teeth Primer, 3) sodium sulfite solution, 4) 4-META solution, 5) acetone-water, and 6) phosphoric acid etching. Pre- and post-thermocycling bond strengths and change in strength after thermocycling were compared. Etching enamel with 35-45% phosphoric acid enhanced bonding durability between enamel and TBB-initiated resin. Priming with Teeth Primer or 4-META solution improved bond strength between enamel and TBB-initiated resin. Sodium sulfite had little effect on enamel bonding in the present bonding systems. PMID- 25807905 TI - Effect of a novel fluorapatite-forming calcium phosphate cement with calcium silicate on osteoblasts in comparison with mineral trioxide aggregate. AB - We compared the effects of treatment with fluorapatite-forming calcium phosphate cement (FA-forming CPC) containing tricalcium silicate (TCS) and those of mineral trioxide aggregate (MTA), the gold standard endodontic cement, on cultured osteoblast-like cells (ROS 17/2.8 cells; ROS cells). The FA-forming CPC powder consisted of 61.29% CaHPO4, 32.26% CaCO3, and 6.45% NaF. One part TCS was combined with nine parts FA-forming CPC powder to make FA-forming CPC with TCS. A 1.5-M phosphate solution was mixed as a cement liquid with a powder/liquid ratio of 2.22. Cell culture was carried out using cell culture inserts, whereby each test material was put on a porous membrane insert in the cell culture plate. Proliferation, morphologic changes, and alkaline phosphatase activity in ROS cells were measured in the presence of FA-forming CPC with TCS and MTA and compared. The logarithmic growth phase and cellular morphologic changes in ROS cells were identical in all experimental groups. Additionally, no significant difference in alkaline phosphatase activity was noted in ROS cells exposed to FA forming CPC with TCS and those exposed to MTA. In conclusion, FA-forming CPC with TCS has characteristics identical to those of MTA under the present experimental conditions and may thus be useful for endodontic applications. PMID- 25807906 TI - Associations of interleukin (IL)-1beta, IL-1 receptor antagonist, and IL-10 with dental caries. AB - Streptococcus mutans is important in dental caries. Although the role of cytokines in the pathogenesis of dental caries is not clear, components of S. mutans were found to stimulate production of pro-inflammatory cytokines. We examined the associations of interleukin (IL)-1beta, IL-1 receptor antagonist (IL 1ra), and IL-10 with dental caries. Unstimulated whole saliva and blood samples were obtained from 108 children aged 6-12 years with high caries (decayed, missing, or filled teeth [dmft/DMFT] index >4, n = 37), moderate caries (dmft/DMFT = 1-4, n = 37), or caries-free (dmft/DMFT = 0, n = 34). S. mutans level was classified as low (<10(5) colony-forming units [CFU]/mL) or high (>=10(5) CFU/mL). Saliva and serum concentrations of IL-1beta, IL-1ra, and IL-10 were determined by ELISA. IL-1beta, IL-1ra, and IL-10 gene polymorphisms were genotyped using PCR and restriction fragment length polymorphism analysis. The chi-square, Mann-Whitney U, one-way ANOVA, posthoc, Fisher's exact, and t tests were used in statistical analysis. Dental caries was not correlated with salivary or serum concentrations of the studied cytokines. S. mutans level positively correlated with saliva IL-1beta concentration and inversely correlated with saliva IL-1ra concentration. There was no correlation of IL-1beta, IL-1ra, or IL 10 gene polymorphisms with dental caries. S. mutans is important in stimulating saliva IL-1beta and inhibiting IL-1ra. Future studies of associations between cytokines and dental caries should investigate additional cytokines and enroll a larger number of participants. PMID- 25807907 TI - Prevalence and risk factors for non-carious cervical lesions in children attending special needs schools in India. AB - We assessed the prevalence and risk factors for development of non-carious cervical lesions (NCCLs) in children attending special needs schools in India. The participants were 395 children aged 12-15 years with disabilities in learning, communication, physical function, and/or development. A questionnaire was designed in order to collect information on sociodemographic characteristics, oral hygiene practices, dietary habits, and risk factors for NCCLs. The chi square test, bivariate analysis, and logistic regression analysis were used to analyze the data. Presence of NCCLs was associated with use of toothpowder or other materials for teeth cleaning, use of harder toothbrushes, use of a horizontal scrub technique for toothbrushing, consumption of a vegetarian diet, and greater consumption of lemon. The overall prevalence of NCCLs was 22.7%. Most lesions involved minimal loss of contour or defects <1 mm in depth. The prevalence of non-carious cervical lesions was slightly higher than the global average. Effective policies should be developed for oral health care among children attending special needs schools. PMID- 25807908 TI - CD105 expression in oral capillary hemangiomas and cavernous hemangiomas. AB - Capillary hemangioma (capillary lobular hemangioma) and cavernous hemangioma (venous malformation) are relatively common oral tumors/malformations and are characterized by increased numbers of normal and abnormal blood vessels. However, the causes of these lesions are not well understood. CD105 (endoglin) is predominantly expressed in proliferating blood endothelial cells (ECs). We analyzed expressions of CD105, CD34, von Willebrand factor, Ki-67, cyclooxygenase 2 (COX-2), and vascular endothelial growth factor (VEGF)-A in 31 capillary hemangiomas and 34 cavernous hemangiomas. Staining scores were calculated as the product of the proportion score and intensity score. Morphologically normal oral mucosa specimens (n = 10) were simultaneously evaluated as normal controls. As compared with cavernous hemangiomas and normal controls, capillary hemangiomas had higher staining scores for CD105, VEGF-A, and COX-2. The Ki-67 labeling index was significantly higher in capillary hemangiomas than in cavernous hemangiomas and normal controls (P < 0.01). These findings suggest that the biological characteristics of capillary and cavernous hemangiomas are quite different. The ECs of capillary hemangiomas actively proliferated and were generally regulated by VEGF-A. In contrast, the ECs of cavernous hemangiomas lacked proliferative activity. These results suggest that angiogenesis and vasodilatation of pre existing blood vessels are important in the development of capillary hemangioma and cavernous hemangioma, respectively. PMID- 25807909 TI - Feasibility study of a salivary occult blood test to correlate with periodontal measures as indicators of periodontal inflammation in a population of pregnant women. AB - The purpose of this feasibility study was to investigate the correlation of a salivary occult blood test (SOBT) with traditional periodontal measures to assess the feasibility of the SOBT as a measure of periodontal inflammation in a population of women during pregnancy. Considering the limitations of the previous SOBT studies, this study evaluated correlation of the Perioscreen Sunstar SOBT with traditional measures from a full mouth periodontal examination. Data were collected 3 times during pregnancy (12-14, 24-28, and 36 weeks) from women participating in an ongoing study of pregnancy and inflammation. Descriptive statistics and correlations were generated for SOBT scores with periodontal measures. Preliminary data were analyzed from 7 women with 3 visits, 7 with 2, and 9 with 1 visit. For these 44 visits' data, the mean percent of sites with bleeding on probing (BOP) for SOBT scores = 0, 2, and 5 was 58% +/- 18%, 68% +/- 14%, and 72% +/- 19%, respectively. Correlations for percent of sites with BOP and continuous SOBT score was 0.301, P-value = 0.0469 and dichotomous SOBT was 0.32, P-value = 0.0339. Results for feasibility, measured as recruitment of participants, acceptance of protocols, distribution of periodontal inflammation and preliminary correlations, support SOBT as a correlated marker of periodontal inflammation in this population of pregnant women. PMID- 25807910 TI - Diagnosis, PET/CT imaging, and treatment of extranodal non-Hodgkin lymphoma in keratinized gingiva: a case report. AB - A 58-year-old patient who smoked and had uncontrolled type 2 diabetes mellitus was referred to our clinic. The patient had a suspicious asymptomatic lesion that was diagnosed as B-cell non-Hodgkin lymphoma (NHL). Immunohistochemistry revealed intense and diffuse expression of CD20, CD10, BCL-6, and Ki-67. A positron emission tomography/computed tomography (PET/CT) scan showed focal pathological uptake of F-18-fluorodeoxyglucose only in the subcutaneous tissue anterior to the left maxillary sinus. After lesion excision and five courses of chemotherapy, PET/CT scans demonstrated complete resolution of the lesion. Smoking, uncontrolled diabetes mellitus, and periodontal disease might be predisposing factors for oral NHL. PMID- 25807911 TI - Angioleiomyoma of the cheek: a case report. AB - Angioleiomyoma is a form of subcutaneous vascular leiomyoma that usually occurs in the extremities. Leiomyoma of the oral cavity represents only 0.4% of soft tissue neoplasms and 0.06% of leiomyomas. Isolated cases of angioleiomyoma have been reported in the knee and lower thigh, gastrointestinal tract, genital and renal tract, and brain. Histopathologic examination by biopsy is necessary to establish a diagnosis, and immunohistochemical staining, along with conventional hematoxylin-eosin staining, is important. The differential diagnosis includes hemangioma and angiosarcoma. At present, surgical resection is the standard therapy for leiomyoma, and recurrence is extremely rare. We report a rare case of angioleiomyoma of the cheek in a 45-year-old man. The postoperative course was uneventful, without complications. PMID- 25807912 TI - The effect of pupillary dilatation on IOL power measurement by using the IOLMaster. AB - The aim of this study is to assess the agreement of IOL power and ocular biometry measurements before and after pupillary dilatation by using the IOLMaster. This was the prospective nonrandomized cohort study. Measurements were taken with the IOLMaster ((r)) (Carl Zeiss Meditec AG, Jena, Germany) from healthy volunteers at the Department of Ophthalmology, King Chulalongkorn Memorial Hospital. Axial length (AL), keratometry both flattest and steepest (K1, K2), and anterior chamber depth (ACD) were measured before and after the dilatation of the pupil with 1 % tropicamide. The IOL power was calculated using the Sanders-Retzlaff Kraff/Theoretical (SRK/T) formula. The mean difference of each parameter was assessed by Bland-Altman plot analysis. 384 eyes from 195 healthy volunteers were measured. The mean age of the patients was 52.39 +/- 1.02 years (range 21-79). Pupillary dilatation had no significant effect on AL (p = 0.07), keratometry [steepest K (p = 0.95) and flattest K (p = 0.17)], and IOL power (Alcon SN60WF) (p = 0.40) obtained from the IOLMaster. However, ACD was significantly increased post-dilatation (p < 0.05). The Bland-Altman plot indicated good concordance in nearly all parameters except ACD. For ACD measurements, the 95 % limit of agreement between pre-dilatation and post-dilatation was -0.47 to 0.23 mm; therefore, 92.2 % of the measurement differences were with a LoA of -0.47 to 0.23 mm. There were no eyes that could not be measured by the IOLMaster. The dilatation of the pupil had no significant effect on AL, keratometry measurements, and SRK/T calculated IOL power. However, the ACD significantly increased post-dilatation. PMID- 25807913 TI - Cost-effectiveness of fracture prevention in rural women with limited access to dual-energy X-ray absorptiometry. AB - A reduced reimbursement for office-based dual-energy X-ray absorptiometry (DXA) is likely to exacerbate the burden of fractures in rural areas. Our cost effective analysis suggests that, in areas where access to DXA is limited, treatment for women at high clinical risk for fractures could both improve health and save money. INTRODUCTION: To evaluate the cost-effectiveness of various fracture prevention strategies for rural women with limited access to dual-energy X-ray absorptiometry (DXA). METHODS: A Markov model was developed using data from the published literature and the Manitoba Bone Density Program. The participants were a simulated cohort of rural women aged 65 years with travel distance between 10 and 24 mi to the nearest DXA site. The evaluated strategies were (1) watchful waiting, (2) bone mineral density (BMD)-based strategy (i.e., DXA screening followed by pharmacotherapy based on BMD), and (3) clinical risk factor (CRF) based strategy (i.e., pharmacotherapy for women at high risk for fractures by the World Health Organization Fracture Risk Assessment Tool [FRAX]). The outcome was an incremental cost-effectiveness ratio (ICER) measured by cost per quality adjusted life-year (QALY) gained. The analysis was preformed from a societal perspective over a lifetime horizon. RESULTS: In the base-case analysis, the BMD based strategy had an ICER of $6000 per QALY gained. For those with travel distance between 25 and 39 mi, the BMD-based strategy would have an ICER of $140,800 per QALY gained. For those with travel distance greater than 40 mi, the CRF-based strategy would be more effective and less costly than other strategies. CONCLUSIONS: In areas where DXA is readily available, DXA screening followed by pharmacotherapy guided by BMD would be preferred. In areas with more limited access to DXA, pharmacotherapy for women at high clinical risk for fractures based on FRAX could both improve health and save money from the societal perspective. PMID- 25807915 TI - Highly Efficient Chirality Transfer from Diamines Encapsulated within a Self Assembled Calixarene-Salen Host. AB - A calix[4]arene host equipped with two bis-[Zn(salphen)] complexes self-assembles into a capsular complex in the presence of a chiral diamine guest with an unexpected 2:1 ratio between the host and the guest. Effective chirality transfer from the diamine to the calix-salen hybrid host is observed by circular dichroism (CD) spectroscopy, and a high stability constant K2,1 of 1.59*10(11) M(-2) for the assembled host-guest ensemble has been determined with a substantial cooperativity factor alpha of 6.4. Density functional calculations are used to investigate the origin of the stability of the host-guest system and the experimental CD spectrum compared with those calculated for both possible diastereoisomers showing that the M,M isomer is the one that is preferentially formed. The current system holds promise for the chirality determination of diamines, as evidenced by the investigated substrate scope and the linear relationship between the ee of the diamine and the amplitude of the observed Cotton effects. PMID- 25807916 TI - Determinants of spatial behavior of a tropical forest seed predator: The roles of optimal foraging, dietary diversification, and home range defense. AB - Specialized seed predators in tropical forests may avoid seasonal food scarcity and interspecific feeding competition but may need to diversify their daily diet to limit ingestion of any given toxin. Seed predators may, therefore, adopt foraging strategies that favor dietary diversity and resource monitoring, rather than efficient energy intake, as suggested by optimal foraging theory. We tested whether fine-scale space use by a small-group-living seed predator-the bald-faced saki monkey (Pithecia irrorata)-reflected optimization of short-term foraging efficiency, maximization of daily dietary diversity, and/or responses to the threat of territorial encroachment by neighboring groups. Food patches across home ranges of five adjacent saki groups were widely spread, but areas with higher densities of stems or food species were not allocated greater feeding time. Foraging patterns-specifically, relatively long daily travel paths that bypassed available fruiting trees and relatively short feeding bouts in undepleted food patches-suggest a strategy that maximizes dietary diversification, rather than "optimal" foraging. Travel distance was unrelated to the proportion of seeds in the diet. Moreover, while taxonomically diverse, the daily diets of our study groups were no more species-rich than randomly derived diets based on co-occurring available food species. Sakis preferentially used overlapping areas of their HRs, within which adjacent groups shared many food trees, yet the density of food plants or food species in these areas was no greater than in other HR areas. The high likelihood of depletion by neighboring groups of otherwise enduring food sources may encourage monitoring of peripheral food patches in overlap areas, even if at the expense of immediate energy intake, suggesting that between-group competition is a key driver of fine-scale home range use in sakis. PMID- 25807914 TI - Hyponatremia and osteoporosis: reappraisal of a novel association. AB - Age was a modifier of the independent association between hyponatremia and osteoporosis (OP). Risk of OP was the highest in the youngest age group as compared to older patients. A longer duration of hyponatremia revealed a similar association with OP in all anatomical sites. INTRODUCTION: Epidemiologic studies provide conflicting results on the relationship between hyponatremia and OP. Our aim is to test the modification effect of age on the relationship between hyponatremia and OP at various anatomical sites in a large patient population. METHODS: This is a cross-sectional observation of consecutive patients with available bone densitometry, demographic, clinical, and laboratory data from 2001 to 2013 at a single center. OP was defined as a bone mineral density of <=2.5 standard deviations below the mean peak bone mass of young, healthy adults. Hyponatremia was defined as serum sodium <=135 mmol/L. Multiple logistic regressions were used to calculate adjusted odds ratio (OR). RESULTS: Overall, 24,784 patients were included. There were 4549 males (18.4 %). Hyponatremia was present in 703 patients (2.8 %), femoral neck OP in 2603 (10.5 %), total hip OP in 1885 (7.5 %), and lumbar OP in 4830 (19.5 %). Total hip OP occurred in 17.6 % (n = 124) of patients with hyponatremia as compared to 6.6 % (n = 880) of patients with sodium level of "140-145" mmol/L (P < 0.001). After multivariable adjustments, hyponatremia was associated with 2.46-fold higher odds of total hip OP (95 % CI, 1.36 to 4.46) in age <55 years, 1.96-fold (1.13 to 3.41) in age 55 to 67 years, and 1.55-fold (1.13 to 2.12) in age >67 years (age-sodium category interaction P value = 0.002). CONCLUSIONS: Age appeared as a modifier of the independent association between hyponatremia and OP. Risk of OP was the highest in the youngest age group as compared to older patients. PMID- 25807917 TI - Multiplex sequencing for EZH2, CD79B, and MYD88 mutations using archival cytospin preparations from B-cell non-Hodgkin lymphoma aspirates previously tested for MYC rearrangement and IGH/BCL2 translocation. AB - BACKGROUND: Gene rearrangements and specific translocations define some B-cell non-Hodgkin lymphoma (NHL) subtypes. Genome-wide mutational studies have revealed recurrent point mutations with prognostic implications. The goals of this study were to evaluate the feasibility of applying a multiplex mutation assay to archival cytospin preparations (CPs) and to investigate the rate of EZH2, CD79B, and MYD88 mutations in B-cell NHL samples previously tested for MYC rearrangement and/or IGH/BCL-2 translocation. METHODS: DNA was extracted from archival CPs of B cell NHL cases with previous fluorescence in situ hybridization (FISH) assays for MYC rearrangement and/or IGH/BCL-2 translocation. Multiplex sequencing was performed for the detection of EZH2 (Y641), CD79B (Y196), and MYD88 (L265) mutations. Sanger sequencing was applied to samples with positive results and failed assays. RESULTS: Eighty-eight archival CPs were available from 40 patients. Alterations detected by FISH were: MYC rearrangement (10 cases), IGH/BCL-2 translocations (21 cases), dual translocations (6 cases), and other abnormalities for IGH/BCL-2 (23 cases) and for MYC (16 cases). DNA concentration ranged from 1.88 to 62.85 ng/uL (mean, 9.46 ng/uL). Successful results were obtained in 88.0% of the specimens submitted to multiplex sequencing. With Sanger sequencing, 2 additional mutated cases were found, and all cases with mutations were confirmed. Eight specimens showed mutations: 6 for EZH2, 1 for CD79B, and 1 for MYD88. Among them, 5 cases showed concurrent MYC and/or IGH/BCL-2 translocations and 2 revealed abnormal signals of IGH/BCL-2 and MYC. CONCLUSIONS: CPs archived for up to 6 years are a reliable source of high-quality genomic material for multiplex sequencing. Almost all B-cell NHL with point mutations showed concurrent chromosomal abnormalities. PMID- 25807918 TI - Localization and dynamics of long-lived excitations in colloidal semiconductor nanocrystals with dual quantum confinement. AB - Semiconductor nanocrystals consisting of a quantum dot (QD) core and a quantum well (QW) shell, where the QD and QW are separated by a tunneling barrier, offer a unique opportunity to engineer the photophysical properties of individual nanostructures. Using the thicknesses of the corresponding layers, the excitons of the first and second excited states can be separated spatially, localizing one state to the QD and the other to the QW. Thus the wave function overlap of the two states can be minimized, suppressing non-radiative thermalization between the two wells, which in turn leads to radiative relaxation from both states. The molecular analogy to such dual emission would be the inhibition of internal conversion, a special case that violates Kasha's rule. Using nanosecond time resolved spectroscopy of QDQW CdSe/ZnS onion-like nanocrystals, an intermediate regime of exciton separation and suppressed thermalization is identified where the non-radiative relaxation of the higher-energy state is slowed, but not completely inhibited. In this intermediate thermalization regime, the temporal evolution of the delayed emission spectra resulting from trapped carriers mimic the dynamics of such states in nanocrystals that consist of only a QD core. In stark contrast, when a higher-energy metastable state exists in the QW shell due to strongly suppressed interwell thermalization, the spectral dynamics of the long-lived excitations in the QD and QW, which are spectrally distinct, are amplified and differ from each other as well as from those in the core-only nanocrystals. This difference in spectral dynamics demonstrates the utility of exploiting well-defined exciton localization to study the nature and spatial dependence of the intriguing photophysics of colloidal semiconductor nanocrystals, and illustrates the power of nanosecond gated luminescence spectroscopy in illuminating complex relaxation dynamics which are entirely masked in steady-state or ultrafast spectroscopy. PMID- 25807920 TI - Perineal and vaginal tears are clinical markers for occult levator ani trauma: a retrospective observational study. AB - OBJECTIVES: Levator avulsion has been shown to be associated with anterior and central compartment prolapse and is a risk factor for prolapse recurrence. Diagnosis in the delivery room is usually impossible, as levator avulsion is commonly occult. The objective of this study was to determine if vaginal and major perineal tears are clinical markers of levator trauma as diagnosed by four dimensional (4D) translabial ultrasound 3-6 months postpartum. METHODS: This was a retrospective observational study using data obtained in two perinatal trials. A total of 774 women seen, on average, 5 (range, 2.3-22.4) months after their first delivery of a term singleton cephalic baby underwent a standardized interview, clinical assessment and 4D translabial ultrasound examination. Clinical data were obtained from the institutional obstetric database, including information on vaginal and perineal tears. Levator avulsion was diagnosed using tomographic ultrasound, with operators blinded to the clinical data. RESULTS: Both third- and fourth-degree perineal tears and vaginal sidewall tears were independently associated with levator avulsion (P = 0.004 and P = 0.012, respectively). The odds ratio for avulsion in women suffering from such overt trauma was 3.44 (95% CI, 1.47-8.03) for third-/fourth-degree perineal tears and 3.35 (95% CI, 1.30-8.61) for vaginal sidewall tears. CONCLUSIONS: Vaginal sidewall and third-/fourth-degree perineal tears were found to be independent clinical indicators of an increased risk of levator trauma, as diagnosed by 4D translabial ultrasound 3-6 months postpartum. Such clinical markers may become useful in the identification of women at high risk of levator trauma and future pelvic floor disorders. PMID- 25807921 TI - Characterization of the constituents in rat plasma after oral administration of radix polygoni multiflori extracts by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry method was established to detect as many constituents in rat plasma as possible after oral administration of Radix polygoni multiflori (RPM) extract. A C18 column (150 * 2.0 mm, 4 um) was adopted to separate the samples, and mass spectra were acquired in negative modes. The fingerprints of RPM extract were established, resulting in 39 components being detected. Among these compounds, 29 were identified by comparing the retention times and mass spectral data with those of reference standards and relevant references, and eight compounds were separated and detected in RPM for the first time. In vivo, 23 compounds were observed in dosed rat plasma, 16 of 23 compounds were indicated as prototype components of RPM, and seven compounds were predicted to be metabolites of RPM. A high-speed and sensitive method was developed and was successfully utilized for screening and characterizing the ingredients and metabolites of RPM. PMID- 25807919 TI - Quantitative description of radiofrequency (RF) power-based ratiometric chemical exchange saturation transfer (CEST) pH imaging. AB - Chemical exchange saturation transfer (CEST) MRI holds great promise for the imaging of pH. However, routine CEST measurement varies not only with the pH dependent chemical exchange rate, but also with CEST agent concentration, providing pH-weighted information. Conventional ratiometric CEST imaging normalizes the confounding concentration factor by analyzing the relative CEST effect from different exchangeable groups, requiring CEST agents with multiple chemically distinguishable labile proton sites. Recently, a radiofrequency (RF) power-based ratiometric CEST MRI approach has been developed for concentration independent pH MRI using CEST agents with a single exchangeable group. To facilitate quantification and optimization of the new ratiometric analysis, we quantified the RF power-based ratiometric CEST ratio (rCESTR) and derived its signal-to-noise and contrast-to-noise ratios. Using creatine as a representative CEST agent containing a single exchangeable site, our study demonstrated that optimized RF power-based ratiometric analysis provides good pH sensitivity. We showed that rCESTR follows a base-catalyzed exchange relationship with pH independent of creatine concentration. The pH accuracy of RF power-based ratiometric MRI was within 0.15-0.20 pH units. Furthermore, the absolute exchange rate can be obtained from the proposed ratiometric analysis. To summarize, RF power-based ratiometric CEST analysis provides concentration-independent pH sensitive imaging and complements conventional multiple labile proton group-based ratiometric CEST analysis. PMID- 25807922 TI - The discovery of the synovial lymphatic stomata and lymphatic reabsorption in knee effusion. AB - To illustrate the mechanism of lymphatic reabsorption in knee joint effusion. The current investigation employed transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques to reveal the ultrastructure of the knee synovial membrane in New Zealand rabbits and human. Ultrastructural changes of the synovial lymphatic stomata were observed by using trypan blue absorption and sodium hydroxide (NaOH) digestion methods, and the animal models of synovitis. New Zealand rabbits and human synovial membranes were composed of two types of synovial cells: type A and type B. No lymphatic stomata were found among type A synovial cells, whereas lymphatic stomata with the diameters ranging 0.74 3.26 um were found in type B synovial cells, and some stomata were closed. After the NaOH digestion, a number of sieve pores, similar to lymphatic stomata in size and shape, were observed in the dense fibrous connective tissue underneath the type B synovial cells. After injecting trypan blue into the rabbit knee joint cavity, absorption of trypan blue through the lymphatic stomata was observed, suggesting the absorption function of the synovial lymphatic stomata. In the rabbit knee joint synovitis models, the synovial lymphatic stomata diameter enlarged. Some macrophages migrated from the lymphatic stomata, indicating that the synovial lymphatic stomata were involved in the joint effusion absorption and inflammatory response. Our study is the first to report the existence of synovial lymphatic stomata in the New Zealand rabbits and human knee joints. Lymphatic stomata may have an important role in the reabsorption of joint effusion. PMID- 25807923 TI - Why on the snow? Winter emergence strategies of snow-active Chironomidae (Diptera) in Poland. AB - A long-term study of adult non-biting midges (Chironomidae) active in winter on the snow in mountain areas and lowlands in Poland yielded 35 species. The lowland and mountain communities differed significantly in their specific composition. The mountain assemblage was found to be more diverse and abundant, with a substantial contribution from the subfamily Diamesinae, whereas Orthocladiinae predominated in the lowlands. Orthocladius wetterensis Brundin was the most characteristic and superdominant species in the winter-active chironomid communities in both areas. Only a few specimens and species of snow-active chironomids were recorded in late autumn and early winter. The abundance of chironomids peaked in late February in the mountain and lowland areas with an additional peak in the mountain areas in early April. However, this second peak of activity consisted mainly of Orthocladiinae, as Diamesinae emerged earliest in the season. Most snow-active species emerged in mid- and late winter, but their seasonal patterns differed between the 2 regions as a result of the different species composition and the duration of snow cover in these regions. Spearman's rank correlation coefficient tests yielded positive results between each season and the number of chironomid individuals recorded in the mountain area. A positive correlation between air temperature, rising to +3.5 degrees C, and the number of specimens recorded on the snow in the mountain community was statistically significant. The winter emergence and mate-searching strategies of chironomids are discussed in the light of global warming, and a brief compilation of most important published data on the phenomena studied is provided. PMID- 25807924 TI - Stable and Low-Threshold Optical Gain in CdSe/CdS Quantum Dots: An All-Colloidal Frequency Up-Converted Laser. AB - An all-solution processed and all-colloidal laser is demonstrated using tailored CdSe/CdS core/shell quantum dots, which exhibit highly stable and low-threshold optical gain owing to substantially suppressed non-radiative Auger recombination. PMID- 25807925 TI - Mechanoluminescence, thermoluminescence, photoluminescence studies on Ca3Y2Si3O12:RE(3+) (RE(3+) = Dy(3+) and Eu(3+)) phosphors. AB - Dy(3+) and Eu(3+) activated Ca3Y2Si3O12 phosphors were synthesized by the solid state synthesis method. The phosphors were characterized by X-ray diffraction (XRD), mechanoluminescence (ML), thermoluminescence (TL) and photoluminescence (PL) to determine structure and luminescence. For ML glow curves, only one peak was observed, as only one type of luminescence centre was formed during irradiation. The Ca3Y2Si3O12:Dy(3+) TL glow curve showed a single peak at 151.55 degrees C and the Ca3Y2Si3O12:Eu(3+) TL glow curve peaked at 323 degrees C with a small peak at 192 degrees C, indicating that two types of traps were activated. The trapping parameters for both the samples were calculated using Chen's peak shape method. Dy(3+)-activated Ca3Y2Si3O12 showed emission at 482 and 574 nm when excited by a 351 nm excitation wavelength, whereas the Eu(3+) activated Ca3 Y2Si3O12 phosphor PL emission spectra showed emission peaks at 613 nm, 591 nm, 580 nm when excited at 395 nm wavelength. When excited at 466 nm, prominent emission peaks were observed at their respective positions with very slight shifts. PMID- 25807926 TI - Insulin treatment restores glutamate (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor function in the hippocampus of diabetic rats. AB - Type 1 diabetes is associated with cognitive dysfunction. Cognitive processing, particularly memory acquisition, depends on the regulated enhancement of expression and function of glutamate receptor subtypes in the hippocampus. Impairment of memory was been detected in rodent models of type 1 diabetes induced by streptozotocin (STZ). This study examines the functional properties of synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the expression of synaptic molecules that regulate glutamatergic synaptic transmission in the hippocampus of STZ-diabetic rats. The AMPA receptor mediated miniature excitatory postsynaptic currents (mEPSCs) and single-channel properties of synaptosomal AMPA receptors were examined after 4 weeks of diabetes induction. Results show that amplitude and frequency of mEPSCs recorded from CA1 pyramidal neurons were decreased in diabetic rats. In addition, the single channel properties of synaptic AMPA receptors from diabetic rat hippocampi were different from those of controls. These impairments in synaptic currents gated by AMPA receptors were accompanied by decreased protein levels of AMPA receptor subunit GluR1, the presynaptic protein synaptophysin, and the postsynaptic anchor protein postsynaptic density protein 95 in the hippocampus of diabetic rats. Neural cell adhesion molecule (NCAM), an extracellular matrix molecule abundantly expressed in the brain, and the polysialic acid (PSA) attached to NCAM were also downregulated in the hippocampus of diabetic rats. Insulin treatment, when initiated at the onset of diabetes induction, reduced these effects. These findings suggest that STZ-induced diabetes may result in functional deteriorations in glutamatergic synapses in the hippocampus of rats and that these effects may be reduced by insulin treatment. PMID- 25807927 TI - Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended release tablets in healthy Japanese subjects without co-administration of an opioid antagonist. AB - This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0 inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3 glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing. PMID- 25807930 TI - Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic profiling of protein lipidation during vertebrate development. AB - Novel multifunctional reagents were applied in combination with a lipid probe for affinity enrichment of myristoylated proteins and direct detection of lipid modified tryptic peptides by mass spectrometry. This method enables high confidence identification of the myristoylated proteome on an unprecedented scale in cell culture, and allowed the first quantitative analysis of dynamic changes in protein lipidation during vertebrate embryonic development. PMID- 25807928 TI - Voxel-based morphometric magnetic resonance imaging (MRI) postprocessing in MRI negative epilepsies. AB - OBJECTIVE: In the presurgical workup of magnetic resonance imaging (MRI)-negative (MRI(-) or "nonlesional") pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel-based MRI postprocessing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI(-) surgical candidates. METHODS: Included in this retrospective study was a consecutive cohort of 150 MRI(-) surgical patients. MAP was performed on T1 weighted MRI, with comparison to a scanner-specific normal database. Review and analysis of MAP were performed blinded to patients' clinical information. The pertinence of MAP(+) areas was confirmed by surgical outcome and pathology. RESULTS: MAP showed a 43% positive rate, sensitivity of 0.9, and specificity of 0.67. Overall, patients with the MAP(+) region completely resected had the best seizure outcomes, followed by the MAP(-) patients, and patients who had no/partial resection of the MAP(+) region had the worst outcome (p < 0.001). Subgroup analysis revealed that visually identified subtle findings are more likely correct if also MAP(+) . False-positive rate in 52 normal controls was 2%. Surgical pathology of the resected MAP(+) areas contained mainly non-balloon-cell focal cortical dysplasia (FCD). Multiple MAP(+) regions were present in 7% of patients. INTERPRETATION: MAP can be a practical and valuable tool to: (1) guide the search for subtle MRI abnormalities and (2) confirm visually identified questionable abnormalities in patients with PFE due to suspected FCD. A MAP(+) region, when concordant with the patient's electroclinical presentation, should provide a legitimate target for surgical exploration. PMID- 25807931 TI - Letter to the editor by the authors of Exact Calculation of Power and Sample Size in Bioequivalence Studies Using Two One-sided Tests, Pharmaceutical Statistics, DOI: 10.1002/pst.1666. AB - This article reflects the views of the authors and should not be construed to be those of the US Food and Drug Administration. PMID- 25807933 TI - Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype. AB - Lactate dehydrogenase B (LDHB) is widely expressed in adult somatic tissue and is one of the two subunits of lactate dehydrogenase, which is the key glycolytic enzyme and catalyzes the interconversion of pyruvate and lactate. However, the roles of LDHB in glycolysis and tumor progression were obscure in different types of cancer. Here, we determined the roles of LDHB in pancreatic cancer development and progression. We found suppressed expression of LDHB in pancreatic cancer which was due to promoter hypermethylation and deceased expression of LDHB led to glycolytic transition. Functional analysis revealed that suppressed expression of LDHB promoted pancreatic cancer cells proliferation, invasion, and migration in hypoxia. Thus, LDHB might function as a suppressor of glycolysis and suppressed pancreatic cancer progression. PMID- 25807932 TI - Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection. AB - Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naive patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naive patients, 85% and 77% had a >= 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. PMID- 25807936 TI - Antimicrobial benzodiazepine-based short cationic peptidomimetics. AB - Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic 'back', and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 ug/ml against Staphylococcus aureus and 25 ug/ml against Escherichia coli, similar to the well-known antimicrobial peptide MSI-78. In contrast to MSI-78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications. PMID- 25807937 TI - Divalent cation-aided identification of physico-chemical properties of metal ions that stabilize RNA G-quadruplexes. AB - DNA and RNA sequences rich in guanosines (G) can form a four-stranded secondary structure known as a G-quadruplex (GQ), which plays a role in regulation of gene expression at the transcription and translation level. Both DNA and RNA GQs typically use the monovalent K(+) ion for stabilization of the structures. However, the fundamental reasons for K(+) acting as the most stabilizing metal ion for RNA GQs are not known. To identify the properties of a metal ion that stabilizes an RNA GQ we investigated the effect of alkaline earth metal cations and a set of divalent transition metal ions on two previously identified highly stable RNA GQs. Our results based upon circular dichroism and RNase T1 structure mapping data reveal that the RNA GQs are destabilized in the presence of the tested divalent metal cations. The destabilizing effect of a divalent metal cation is reversible upon increasing K(+) concentration. Results show that ionic radius, hydration energy, and binding strength towards the hard ligand (guanine O(6)) are important factors that determine a metal ion's ability to stabilize an RNA GQ. Additionally, the tested set of divalent metal cations incongruously affects RNA and DNA GQs. PMID- 25807935 TI - FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. AB - Primary spontaneous pneumothorax (PSP) is a significant clinical problem, affecting tens of thousands patients annually. Germline mutations in the FLCN gene have been implicated in etiology of familial PSP (FPSP). Most of the currently identified FLCN mutations are small indels or point mutations that detected by Sanger sequencing. The aim of this study was to determine large FLCN deletions in PSP families that having no FLCN sequence-mutations. Multiplex ligation-dependent probe amplification (MLPA) assays and breakpoint analyses were used to detect and characterize the deletions. Three heterozygous FLCN intragenic deletions were identified in nine unrelated Chinese families including the exons 1-3 deletion in two families, the exons 9-14 deletion in five families and the exon 14 deletion in two families. All deletion breakpoints are located in Alu repeats. A 5.5 Mb disease haplotype shared in the five families with exons 9-14 deletion may date the appearance of this deletion back to approximately 16 generations ago. Evidences for founder effects of the other two deletions were also observed. This report documents the first identification of founder mutations in FLCN, as well as expands mutation spectrum of the gene. Our findings strengthen the view that MLPA analysis for intragenic deletions/duplications, as an important genetic testing complementary to DNA sequencing, should be used for clinical molecular diagnosis in FPSP. PMID- 25807934 TI - Prognostic performance of inflammation-based prognostic indices in patients with resectable colorectal liver metastases. AB - A range of prognostic cellular indices of the systemic inflammatory response, namely the neutrophil-lymphocyte ratio (NLR), derived NLR (dNLR), platelet lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) and prognostic nutritional index (PNI), have been developed and found to have prognostic utility across varied malignancies. The current study is the first to examine the prognostic value of these six inflammatory scores in patients with resectable colorectal liver metastases (CRLM). Data from 302 consecutive patients undergoing surgery for resectable CRLM were evaluated. The prognostic influence of clinicopathological variables and the inflammatory scores NLR, dNLR, PLR, LMR, COP-NLR and PNI upon overall survival (OS) and cancer-specific survival (CSS) were determined by log rank analysis and univariate and multivariate Cox regression analyses. High preoperative NLR was the only inflammatory variable independently associated with shortened OS (HR 1.769, 95 % CI 1.302-2.403, P < 0.001) or CSS (HR 1.927, 95 % CI 1.398-2.655, P < 0.001) following metastasectomy. When NLR was replaced by dNLR in analyses, high dNLR was independently associated with shortened OS (HR 1.932, 95 % CI 1.356-2.754, P < 0.001) and CSS (HR 1.807, 95 % CI 1.209-2.702, P = 0.004). The inflammatory scores PLR, LMR, COP-NLR and PNI demonstrated no independent association with either overall or cancer-specific survival in the study population. Our findings support high preoperative NLR and dNLR as independent prognostic factors for poor outcome in patients undergoing CRLM resection, with prognostic value superior to other cellular-based systemic inflammatory scores. PMID- 25807938 TI - Use of patient registries and administrative datasets for the study of pediatric cancer. AB - Analysis of data from large administrative databases and patient registries is increasingly being used to study childhood cancer care, although the value of these data sources remains unclear to many clinicians. Interpretation of large databases requires a thorough understanding of how the dataset was designed, how data were collected, and how to assess data quality. This review will detail the role of administrative databases and registry databases for the study of childhood cancer, tools to maximize information from these datasets, and recommendations to improve the use of these databases for the study of pediatric oncology. PMID- 25807939 TI - What Is the Relationship Between Morning Symptoms and Measures of Disease Activity in Patients With Rheumatoid Arthritis? AB - OBJECTIVE: Little is known about the relationship between morning symptoms of rheumatoid arthritis (RA) and measures of disease activity currently used to assess RA. Information available from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-2) study was used to investigate these relationships. METHODS: CAPRA-2 included 350 patients with RA who were symptomatic despite treatment with disease-modifying antirheumatic drugs, randomized 2:1 to additional treatment with a 5-mg daily dose of delayed-release prednisone or placebo. Pearson's correlations were used to evaluate the relationships between change from baseline in symptoms (duration of morning stiffness, severity of morning stiffness, and intensity of pain on waking) and measures of disease activity (the American College of Rheumatology 20% improvement criteria [ACR20], the Disease Activity Score in 28 joints [DAS28], and the Health Assessment Questionnaire disability index). Correlations were defined as weak (<0.3), moderate (0.3-0.7), or strong (>0.7). RESULTS: There was a strong correlation between the severity of morning stiffness and the intensity of morning pain (Pearson's correlation 0.91, P < 0.001). There was a weak correlation between the duration of morning stiffness and measures of disease activity (0.24-0.28), with moderate correlations between the severity of morning stiffness or intensity of pain on waking and DAS28 or ACR20 scores (0.44-0.48). Severity of morning stiffness showed less variability and a greater effect size than did duration of morning stiffness. CONCLUSION: Morning symptoms and measures of disease activity show weak to moderate correlations. Severity of morning stiffness showed less variability and greater effect size than did duration of morning stiffness. These findings suggest that severity is the preferred construct to measure the impact of morning stiffness in patients with RA, information that is not fully captured in the RA core set. PMID- 25807940 TI - Anti-resorptive Drugs and their Impact on Maxillofacial Bone among Cancer Patients. AB - This article aims to give an overview on etiology, diagnosis and treatment options of osteonecrosis of the jaw bone among cancer patients receiving anti resorptive drugs (ARDs). The physiologic bone function of continuous resorption and buildup is modified by the use of ARDs. Although ARDs proved to reduce pain and to improve the quality of life in patients with metastasizing bone disease, side effects such as medication related osteonecrosis of jaw bone (MRONJ) have been frequently reported since ARDs were firstly introduced. The new generation of ARDs such as Denosumab is associated with the same incidence of MRONJ among cancer patients. The etiology of MRONJ is not entirely understood and many hypotheses have been proposed. ARDs can modify the hard tissues directly by accumulation in the bone, or indirectly by suppression of the osteoclasts, inhibition of angiogenesis and vascularity. Some ARDs such as Bisphosphonates have reportedly the capacity to interfere directly and indirectly with the bone physiology. MRONJ can be a debilitating disease with non healing freely exposed bone in the oral cavity in patients, who already suffer from a primary cancerous disease. Knowledge of MRONJ as a potential side effect of ARDs is crucial for health professionals treating patients with bone modulating drugs. PMID- 25807942 TI - Targeting microRNAs in Pathological Hypertrophy and Cardiac Failure. AB - MicroRNAs (miRNAs) are a novel class of endogenous, short, non-coding, posttranscriptional RNAs, which play important roles in regulating lots of important biological functions. Evidences show that altered expression of miRNAs are involved in pathological hypertrophy and cardiac failure, making it possible to target miRNAs as a novel therapy. In this review, we focus on very recent progresses in the regulation of miRNAs in pathological hypertrophy and cardiac failure. In addition, we also discuss the potential of using miRNAs as a new therapy for pathological hypertrophy and cardiac failure. PMID- 25807941 TI - MicroRNA Therapeutics: the Next Magic Bullet? AB - MicroRNAs are short noncoding 18-25 nucleotide long RNA which bind and inhibit mRNA. Currently, there are over 1000 known human microRNAs, and microRNAs control over 50% of mammalian protein coding genes. MicroRNAs can be overexpressed or repressed in different diseases and inhibition or replacement of microRNAs is a promising area of study for therapeutics. Here we review the current knowledge of microRNA therapy, and discuss ways in which they can be utilized. We also discuss different methods of delivery of miRNA, and current clinical trials of microRNA based therapies for disease. Finally we discuss the current limitations in the field, and how these limitations are being overcome. PMID- 25807943 TI - MicroRNA Therapeutics for Cardiac Regeneration. AB - It is estimated that a typical myocardial infarction results in the loss of approximately one billion functional cardiomyocytes, which are replaced by a non contractile fibrous scar, eventually leading to heart failure. The currently available surgical, drug, and device-based therapies cannot reverse the loss of functional myocardium, which is the fundamental cause of the problem. As a result of this lack of an available medical solution, heart failure has evolved into a global epidemic. Therefore, the development of regenerative therapeutic strategies to halt the progression of ischemic heart disease to advanced heart failure has become one of the most urgent medical needs of this century. This review first addresses the extremely limited endogenous regenerative capacity of the mammalian heart, and the benefits and limitations of stem cell-based therapies for cardiac repair. Then it discusses the known roles of microRNAs after cardiac injury and the possibility of employing microRNAs to enhance cardiac regeneration. PMID- 25807944 TI - Use of microRNAs as Anti-Atherosclerosis. AB - MicroRNAs are a class of non-coding RNA molecules that have been reported to play a crucial role in cell signaling via post-transcriptional regulation of gene expression. There is increasing evidence showing that this class of RNA is involved in the pathogenesis of cardiovascular diseases, including atherosclerosis. More recently, it has been demonstrated that microRNAs can function to protect against the development of atherosclerosis. The primary goal of this review is to discuss the discovery, mechanism, and therapeutic use of microRNA molecules as atheroprotective agents. PMID- 25807945 TI - MicroRNAs Contribute to Hepatocellular Carcinoma. AB - Hepatocellular carcinoma is a leading unnatural death worldwide, and it causes second most common cancer related death. Hepatocellular carcinoma development is distinct from other types of cancer, which is usually based on hepatic cirrhosis resulted from various etiologies including viral hepatitis, non-alcoholic liver diseases and alcohol abuse. MicroRNAs (miRNAs) are a group of small, non-coding sequences with approximate 20~ bp in length, which post-transcriptionally regulates target genes to control multiple biological activities. Recent studies have indicated that miRNAs contribute to hepatocellular carcinoma, indicating that targeting miRNAs might be a novel therapeutic strategy for the management of hepatocellular carcinoma. In this review, we summarized recent advances in the role of miRNAs in hepatocellular carcinoma, and also discussed the potential therapeutic and prognostic values of miRNAs in hepatocellular carcinoma. PMID- 25807946 TI - The Translocator Protein 18 kDa (TSPO) and Its Role in Mitochondrial Biology and Psychiatric Disorders. AB - The translocator protein 18 kDa (TSPO) is localized in the outer mitochondrial membrane of many cell types and its expression is found to be up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions, and neurological diseases, e.g. amyotrophic lateral sclerosis (ALS). Its primary function is to mediate the transport of cholesterol into the inner compartments of mitochondria. Moreover, TSPO is interacting and building up functional complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC), the adenine nucleotide transporter (ANT), hexokinase I and II and Glycogen synthase kinase 3 beta (GSK3beta). This mini review will focus on the role of TSPO as a central regulator of mitochondrial function with regard to pathologic states and as a target for new therapeutic strategies for the treatment of psychiatric disorders. PMID- 25807947 TI - Cdk5: a key player at neuronal synapse with diverse functions. AB - The development and function of neuronal synapses are orchestrated by various extrinsic factors through intracellular signaling cascades that often involve protein kinases. One important kinase at the synapse is the proline-directed serine/ threonine kinase Cdk5. Although early pharmacological and genetic studies have pointed out the critical role of Cdk5 in regulating synapse function, the precise mechanisms have only been unraveled in recent years through the identification and characterization of multiple substrates. Emerging studies also indicate that Cdk5 dysregulation is linked to mitochondrial dysfunction. This review focuses on recent progress in our understanding of the multiple roles of Cdk5 in mitochondrial function, synapse development and plasticity through phosphorylation of specific substrates at different cellular compartments. PMID- 25807948 TI - Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of pharmacotherapy. AB - Bipolar disorder is a common, chronic, and complex mental illness. Bipolar disorder is frequently comorbid with primary mitochondrial and metabolic disorders, and studies have implicated mitochondrial dysfunction in its pathophysiology. In the brains of people with bipolar disorder, high-energy phosphates are decreased, lactate is elevated and pH decreased, which together suggest a shift toward glycolysis for energy production. Furthermore, oxidative stress is increased, and calcium signalling dysregulated. Additionally there is downregulation of the expression of mitochondrial complexes, especially complex I. The therapeutic effects of some bipolar disorder drugs have recently been shown to be related to these mechanisms. In this review we will evaluate current research on the interactions between mitochondrial dysfunction and bipolar disorder pathology. We will then appraise the current literature describing the effects of bipolar disorder drugs on mitochondrial function, and discuss ramifications for future research. PMID- 25807949 TI - Carers' responses to shifting identity in dementia in Iris and Away From Her: cultivating stability or embracing change? AB - An emphasis on supporting and maintaining self-identity in people who have dementia for as long as possible has gone hand in hand with the revitalisation of dementia interventions, services and empowerment. However, recognition of the need for change, adaptation and personal growth is as necessary when living with dementia as at any other time in people's lives. Those who care for people with dementia must constantly navigate this tension between continuity and change within the context of memory loss, knowing when to respond by reinforcing the 'self' they have known over time, and when it may be better to respond by acknowledging the changes that have taken place in that 'self'. The creative arts are avenues for the exploration of the caring relationship under these conditions, conveying the challenges and stimulating audiences to ask how they themselves might choose to respond in a similar situation. This article considers how the scenarios of two noted films, Iris (dir. Richard Eyre, 2001 UK)) and Away From Her (dir. Sarah Polley, 2006 Can), present the dilemmas of identity and caring. In both, a husband cares for a wife experiencing cognitive decline, but responds differently in each to her shifting needs and experience of identity. We argue that the two films reveal complementary and provocative perspectives on this situation. They offer no easy answers, but provide insights into the everyday decisions characteristic of caring for someone who has dementia. PMID- 25807951 TI - Simultaneous Occurrence of Glandular and Neuroendocrine Components in Lymph Node Metastasis of Gastric MANEC. PMID- 25807950 TI - What has happened to suicides during the Greek economic crisis? Findings from an ecological study of suicides and their determinants (2003-2012). AB - OBJECTIVES: There is a controversy about the impact of economic crisis on suicide rates in Greece. We analysed recent suicide data to identify who has been most affected and the relationships to economic and labour market indicators. SETTING: Greece. PRIMARY AND SECONDARY OUTCOME MEASURES: Age-specific and sex-specific suicide rates in Greece for the period 2003-2012 were calculated using data provided by the Hellenic Statistical Authority. We performed a join-point analysis to identify discontinuities in suicide trends between 2003 and 2010, prior to austerity, and in 2011-2012, during the period of austerity. Regression models were used to assess relationships between unemployment, Gross Domestic Product (GDP) and suicide rates for the entire period by age and sex. RESULTS: The mean suicide rate overall rose by 35% between 2010 and 2012, from 3.37 to 4.56/100,000 population. The suicide mortality rate for men increased from 5.75 (2003-2010) to 7.43/100,000 (2011-2012; p<0.01). Among women, the suicide rate also rose, albeit less markedly, from 1.17 to 1.55 (p=0.03). When differentiated by age group, suicide mortality increased among both sexes in the age groups 20 59 and >60 years. We found that each additional percentage point of unemployment was associated with a 0.19/100,000 population rise in suicides (95% CI 0.11 to 0.26) among working age men. CONCLUSIONS: We found a clear increase in suicides among persons of working age, coinciding with austerity measures. These findings corroborate concerns that increased suicide risk in Greece is a health hazard associated with austerity measures. PMID- 25807953 TI - Professional Pitchers With Glenohumeral Internal Rotation Deficit (GIRD) Display Greater Humeral Retrotorsion Than Pitchers Without GIRD. AB - BACKGROUND: Dominant shoulder glenohumeral internal rotation deficit (GIRD) has been associated with pitching arm injuries. The relationship of humeral torsion on development of GIRD is not clear. HYPOTHESIS: Pitchers displaying GIRD will display greater humeral retrotorsion when compared with those without GIRD. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Humeral torsion and shoulder range of motion (ROM) were measured in 222 professional pitchers before spring training from 2009 to 2012. Shoulder external rotation (ER) and internal rotation (IR) ROM were assessed in 90 degrees of abduction with the scapula stabilized. Humeral torsion was measured via ultrasound using previously described and validated methods. Side-to-side differences in total arc of motion (ER + IR), ER, and IR ROM and humeral torsion were calculated as nondominant minus dominant arm measures for analysis. Pitchers were classified as having GIRD if their dominant arm displayed an IR deficit >=15 degrees concomitant with a total arc of motion deficit >=10 degrees compared with their nondominant arm. A mixed-model analysis of variance (side * GIRD) was used to compare dominant and nondominant humeral torsion between pitchers with GIRD (n = 60) and those without GIRD (n = 162). Independent t tests were used to compare the side-to-side difference in humeral torsion between pitchers with GIRD and those without GIRD (alpha = 0.05). RESULTS: Pitchers with GIRD displayed significantly less humeral torsion (ie, greater retrotorsion) in their dominant arm as compared with those without GIRD (GIRD = 4.5 degrees +/- 11.8 degrees , no GIRD = 10.4 degrees +/- 11.7 degrees ; P = .002). Pitchers with GIRD also displayed a greater side-to side difference in humeral torsion (GIRD = 19.5 degrees +/- 11.9 degrees , no GIRD = 12.3 degrees +/- 12.4 degrees ; P = .001). However, pitchers with GIRD did not display an increase in dominant ER ROM (dominant ER = 131.8 degrees +/- 14.3 degrees , nondominant ER 126.6 degrees +/- 13.1 degrees ) when compared with those without GIRD (dominant ER = 132.0 degrees +/- 14.2 degrees , nondominant ER 122.6 degrees +/- 13.1 degrees ; P = .03). Pitchers with GIRD displayed expected alterations in ROM (IR = 28.8 degrees +/- 9.6 degrees , total arc = 160.6 degrees +/- 15.4 degrees ; P < .01 for both) when compared with those without GIRD (IR = 39.9 degrees +/- 9.9 degrees , total arc = 171.2 degrees +/- 15.5 degrees ). CONCLUSION: Pitchers with GIRD displayed greater side-to-side differences and dominant humeral retrotorsion as compared with those without GIRD. The greater humeral retrotorsion may place greater stress on the posterior shoulder resulting in ROM deficits. Pitchers with greater humeral retrotorsion appear to be more susceptible to developing ROM deficits associated with injury and may need increased monitoring and customized treatment programs to mitigate their increased injury risk. PMID- 25807952 TI - Medial patellofemoral ligament tears in the setting of multiligament knee injuries rarely cause patellar instability. AB - BACKGROUND: Multiligament knee injuries (MLKIs) can also involve the medial patellofemoral ligament (MPFL), but there is a paucity of information regarding prevalence and relevance of MPFL involvement in this setting. PURPOSE: (1) To identify the prevalence of MPFL injury in MLKIs, (2) to determine whether an MPFL tear results in symptomatic patellar instability, and (3) to report clinical and functional outcomes of patients with and without MPFL tears after MLKI surgical reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The records of all patients who underwent surgical reconstruction of MLKI (defined as a grade 3 injury of >=2 ligaments) at a single institution from 2007 to 2010 were reviewed. Age, sex, knee dislocation classification (according to Schenck), and MRI findings were documented. All preoperative MRI scans were reviewed by an experienced musculoskeletal radiologist to determine the presence or absence of MPFL involvement. If an MPFL tear was present, its anatomic location and severity as well as the presence of patellar or lateral femoral condyle bone bruises were documented. Inclusion criteria included (1) MLKI treated at a single institution, (2) presence of MPFL tear on preoperative MRI, and (3) minimum 2-year clinical follow-up. Patellar instability symptoms were assessed with the Kujala Knee Questionnaire. Functional outcomes were measured using the International Knee Documentation Committee (IKDC) score. IKDC scores were compared between patients who sustained MLKIs with and without MPFL tears. There were 21 patients in each group. RESULTS: Over the 4-year study period, 30 of 51 patients (59%) treated surgically for a MLKI had MRI evidence of an MPFL tear. Nine were lost to follow up, leaving 21 patients for review. There were 13 complete (62%), 5 high-grade partial (24%), and 3 partial (14%) MPFL tears. Sixteen of 21 tears (76%) occurred at the proximal third, with the remainder exhibiting diffuse signal abnormality consistent with tearing throughout the length of the MPFL. The superficial medial collateral ligament was involved in all patients. In no case was the MPFL repaired or reconstructed. At mean follow-up of 3.6 years (range, 2.0-5.7 years), only 1 of 21 patients (5%) complained of patellofemoral instability symptoms whereas 20 of 21 patients (95%) did not experience patellar subluxation or dislocation. No significant difference was found when IKDC scores were compared between patients with and without an MPFL tear (mean +/- SD, 65.5 +/- 22.9 vs 79.4 +/- 16.1; P = .07). CONCLUSION: MPFL tears occur frequently in patients with MLKI but rarely cause instability. In the majority of cases, MPFL tears do not need to be addressed at the time of surgery. PMID- 25807954 TI - Spitz nevus on the palm with crista transverse dots/dotted lines revealed by dermoscopic examination. PMID- 25807955 TI - Development of a Quantitative PCR Assay for Differentiating the Agent of Heartwater Disease, Ehrlichia ruminantium, from the Panola Mountain Ehrlichia. AB - Panola Mountain Ehrlichia (PME) is an emerging Ehrlichia sp. reported in ten US states. Based on the sequence homology of all known genes, PME is closely related to Ehrlichia ruminantium (ER), the causative agent of heartwater. Heartwater is an economically important tick-borne disease of cattle, sheep and goats responsible for stock losses in sub-Saharan Africa. Unfortunately, ER was imported to the Caribbean islands in the 19th century, and the presence of this foreign animal disease in the Caribbean poses a threat to the US mainland. If introduced, a heartwater outbreak would cause massive losses of naive livestock. The serologic assay of choice to diagnose heartwater is cross-reactive with Ehrlichia spp., including PME, as we demonstrate here, which would confound disease surveillance in the event of a heartwater outbreak. The purpose of this study was to develop a diagnostic assay capable of rapidly distinguishing between these pathogens. Using synthetic MAP-1B peptides for ER and PME, we tested the cross-reactivity of this assay using sera from infected livestock. The MAP-1B ELISA cannot distinguish between animals infected with PME and ER. Therefore, a dual-plex TaqmanTM qPCR assay targeting the groEL gene of PME and ER was developed and validated. Primers were designed that are conserved among all known strains of ER, allowing for the amplification of strains from the Caribbean and Africa. The assay is highly sensitive (10 copies of DNA) and specific. This assay distinguishes between infection with PME and ER and will be a valuable tool in the event of heartwater outbreak on the US mainland, or for epidemiological studies involving either disease-causing organism. PMID- 25807957 TI - Ferulic acid reverses the cognitive dysfunction caused by amyloid beta peptide 1 40 through anti-oxidant activity and cholinergic activation in rats. AB - Cholinergic dysfunction and oxidation stress are the dominant mechanisms of memory deficit in Alzheimer's disease (AD). This study describes how ferulic acid (FA) ameliorates cognitive deficits induced by mecamylamine (MECA), scopolamine (SCOP), central acetylcholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A) and amyloid beta peptide (Abeta1-40). This study also elucidates the role of anti-oxidant enzymes and cholinergic marker acetylcholinesterase (AChE) in the reversal of FA from Abeta1-40-induced cognitive deficits in rats. At 100 mg/kg, FA attenuated impairment induced by MECA and SCOP plus MECA; however, this improvement was not blocked by the peripheral muscarinic receptor antagonist scopolamine methylbromide (M-SCOP). At 100 and 300 mg/kg, FA also attenuated the impairment of inhibitory passive avoidance induced by AF64A. Further, FA attenuated the performance impairment and memory deficit induced by Abeta1-40 in rats, as did vitamin E/C. FA reversed the deterioration of superoxide dismutase (SOD) and AChE activities, and the glutathione disulfide (GSSG) and glutathione (GSH) levels in the cortex and hippocampus. Vitamin E/C only selectively reversed deterioration in the hippocampus. We suggest that FA reduced the progression of cognitive deficits by activating central muscarinic and nicotinic receptors and anti-oxidant enzymes. PMID- 25807956 TI - The pharmacokinetics of peginterferon lambda-1a following single dose administration to subjects with impaired renal function. AB - AIMS: This open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda). METHODS: Subjects (age 18-75 years, BMI 18-35 kg m(-2) ) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 ug) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups. RESULTS: With decreasing eGFR, Lambda exposure (Cmax , AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml( 1) h), Lambda exposure estimates (AUC) were slightly increased in the mild RI group (geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Lambda was generally well tolerated. CONCLUSIONS: The results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD. PMID- 25807958 TI - ERRATUM: "Effect of the semen extract of Thuja orientalis on inflammatory responses in transient focal cerebral ischemia rat model and LPS-stimulated BV-2 microglia". PMID- 25807959 TI - Ginsenoside Rg1 downregulates the shear stress induced MCP-1 expression by inhibiting MAPK signaling pathway. AB - Ginsenoside Rg1 has been reported to possess anti-inflammatory activities, but the effects of Rg1 on the shear induced MCP-1 upregulation mechanism on endothelial cells (ECs) remain to be determined. In this study, we show that Rg1 down modulates shear induced pro-inflammatory cytokine MCP-1 gene expression and monocytes adhesion without potential cell toxicity. The negative effects on monocytes adhesion is due to a decrease in MCP-1 protein release. Furthermore, the inhibitory effect of Rg1 on the phosphorylation level of ERK, p38, and JNK mitogen-activated protein kinase (MAPK) induced by shear stress (SS) is similar with that of specific chemical inhibitors for MAPK pathways activation. These results demonstrate that ginsenoside Rg1 inhibits the shear induced inflammation by suppressing the MAPK pathway. This suggests that Rg1 may serve as a novel anti inflammatory agent for inflammation-induced cardiovascular diseases treatment. PMID- 25807960 TI - A retrospective view of concussion in American football, 1900-1959: What was suggested then we now know. AB - While published work and media attention about football-related concussion in the USA have increased exponentially in the past few years, these injuries have in fact been written about for over a century. In this work, we undertook a selective review of the PubMed database of the published reports on concussion in football prior to 1960, with attention to the definitions used, physician attitudes, epidemiology, return to play criteria and recommendations and concerns related to long-term outcomes. Search inclusion criteria were English language, publication between the years 1900 and 1959 and studies written by healthcare professionals treating football-related injuries. Twenty-six studies met the inclusion criteria for this review, and the findings are grouped by topic area and detailed chronologically. Early sports medicine physicians struggled with many of the same issues faced today by clinicians such as honest reporting of symptoms by athletes, lack of uniform diagnosis and treatment and ambiguity over maximum 'safe' number of lifetime concussions. PMID- 25807961 TI - Thrombosis in thrombocythemic Ph- myeloproliferations is associated with higher platelet count prior to the event: results of analyses of prothrombotic risk factors from a registry of patients treated with anagrelide. AB - Controversies still exist regarding definition of the thrombotic risks in Ph- (BCR/ABL1-) myeloproliferative disorders with thrombocythemia (MPD-T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD-T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 * 10(9)/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2(V617F) mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V 'Leiden' and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (+/- aspirin), we documented a decrease in both venous (6.7-fold) and arterial events (1.8-fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value. PMID- 25807962 TI - Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success--a personal perspective. AB - Fifty years after the discovery of adeno-associated virus (AAV) and more than 30 years after the first gene transfer experiment was conducted, dozens of gene therapy clinical trials are in progress, one vector is approved for use in Europe, and breakthroughs in virus modification and disease modeling are paving the way for a revolution in the treatment of rare diseases, cancer, as well as HIV. This review will provide a historical perspective on the progression of AAV for gene therapy from discovery to the clinic, focusing on contributions from the Samulski lab regarding basic science and cloning of AAV, optimized large-scale production of vectors, preclinical large animal studies and safety data, vector modifications for improved efficacy, and successful clinical applications. PMID- 25807965 TI - Blood Vessels in Allotransplantation. AB - Human vascularized allografts are perfused through blood vessels composed of cells (endothelium, pericytes, and smooth muscle cells) that remain largely of graft origin and are thus subject to host alloimmune responses. Graft vessels must be healthy to maintain homeostatic functions including control of perfusion, maintenance of permselectivity, prevention of thrombosis, and participation in immune surveillance. Vascular cell injury can cause dysfunction that interferes with these processes. Graft vascular cells can be activated by mediators of innate and adaptive immunity to participate in graft inflammation contributing to both ischemia/reperfusion injury and allograft rejection. Different forms of rejection may affect graft vessels in different ways, ranging from thrombosis and neutrophilic inflammation in hyperacute rejection, to endothelialitis/intimal arteritis and fibrinoid necrosis in acute cell-mediated or antibody-mediated rejection, respectively, and to diffuse luminal stenosis in chronic rejection. While some current therapies targeting the host immune system do affect graft vascular cells, direct targeting of the graft vasculature may create new opportunities for preventing allograft injury and loss. PMID- 25807966 TI - Stage-specific direct health care costs in patients with cutaneous malignant melanoma. AB - BACKGROUND: Clinical stage at diagnosis is a strong prognostic factor for death in cutaneous malignant melanoma (CMM), with worse prognosis at higher stages. However, few studies have investigated how direct health care cost per patient varies with clinical stage. OBJECTIVE: The aim of this study was to determine the stage-specific direct health care costs for CMM patients compared to the health care costs in the general population in the County of Ostergotland, Sweden. METHODS: Cutaneous malignant melanoma patients in the County of Ostergotland diagnosed 2005-2012 were identified from the Swedish cancer registry. Information on clinical stage was collected from the Swedish Melanoma Register (SMR) and cost data from the Cost per Patient database (CPP) for 1075 CMM patients in Ostergotland. CPP contains costs associated with all health care contacts per patient including inpatient, outpatient and primary care. The CMM-related costs were defined as the difference in mean health care costs between CMM patients and general population. RESULTS: The first year after CMM diagnosis, the average health care costs for CMM patients were 2.8 times higher than in the general population. The health care cost ratio varied from 2.0 (stage I) to 10.1 (stage IV) and the CMM-related costs per patient-year varied from ?2 670 (stage I) to ?29 291 (stage IV). The mean health care costs decreased over time but remained significantly higher than in the general population for all clinical stages. During the first year after diagnosis, patients in clinical stage III-IV (7% of CMM patients) accounted for 27% of the total CMM-related health care costs. CONCLUSIONS: The direct health care costs for CMM patients were significantly higher than in the general population independent of clinical stage. CMM patients diagnosed in clinical stage III-IV were associated with particularly high costs and the health care system may save resources by finding CMM patients in earlier stages. PMID- 25807967 TI - Poor accuracy of the eosinophil count of hematology instruments limits the use of eosinopenia as a marker of bacterial infection or increased mortality. PMID- 25807964 TI - A novel missense mutation nt737T>G of JK gene with Jk(a-b-) phenotype in Chinese blood donors. AB - OBJECTIVES: The aim of this study was to investigate the molecular mechanism of the JK-null phenotype in the Chinese population. BACKGROUND: The Jk(a-b-) phenotype is vanishingly rare and the molecular basis differs between ethnic groups. The information regarding the molecular basis of JK-null alleles in the Chinese population is limited. MATERIALS AND METHODS: Three unrelated Jk(a-b-) phenotype donors were selected from 52 260 randomly blood samples through the urea lysis test and serological analysis. The JK gene-coding regions were amplified by the polymerase chain reaction and the products were sequenced directly. RESULTS: Sequencing results revealed that one sample of JK(*) B alleles carried the well-known Polynesian Jk(a-b-) mutation IVS5-1g>a. Another null allele, also on the JK(*) B background, presented with two heterozygous missense mutation, including nt222C>A(Asn74Lys) in exon 5 and nt896G>A(Gly299Glu) in exon 9. The third null allele carried two heterozygous missense mutations, nt222C>A and a novel allele nt737T>G(Leu246Arg) in exon 8. The family investigation revealed that the proband was JK(*) A(737T>G)/JK(*) B(222C>A). CONCLUSION: The Jk(a-b-) phenotype in the Chinese population shows several different molecular mechanisms. A novel missense mutation nt737T>G of JK gene was found as associated with Jk(a-b-) phenotype. PMID- 25807963 TI - Validation of the English translation of the low anterior resection syndrome score. AB - AIM: Many patients having anterior resection for rectal cancer suffer from severe long-term bowel dysfunction, known as low anterior resection syndrome (LARS). The LARS score was developed in Denmark, and Swedish, Spanish and German versions have been validated. The aim of this study was to validate the English translation of the LARS score in British rectal cancer patients. METHOD: Rectal cancer patients who underwent an anterior resection in 12 UK centres received the LARS score questionnaire, the EORTC QLQ-C30 and a single ad hoc quality of life question. A subgroup of patients received the LARS score questionnaire twice. RESULTS: The response rate was 80% and 451 patients were included in the analyses. A strong association between LARS score and quality of life (convergent validity) was found (P < 0.01), discriminative validity was good (P < 0.02) and the test-retest reliability was high (intraclass correlation coefficient 0.83). CONCLUSION: The English translation of the LARS score has shown good psychometric properties comparable with recently published results from an international multicentre study. Thus, the English translation of the LARS score can be considered a valid and reliable tool for measuring LARS. PMID- 25807969 TI - Influence of Ventricular Assist Devices Equipment Wear on Body Posture. PMID- 25807968 TI - Serum Cytokine Profiling of Leukocytapheresis in Pediatric Ulcerative Colitis. PMID- 25807970 TI - Associations between sex and incident chronic kidney disease in a prospective diabetic cohort. AB - AIM: Women with diabetes have a higher prevalence of chronic kidney disease (CKD) risk factors compared with men, but whether they are at higher risk for incident CKD remains uncertain. METHODS: This was a prospective, observational cohort study of 1464 patients with diabetes and normal renal function, recruited from primary care clinics at a vertically integrated healthcare system in Seattle, WA, USA. The primary predictor was sex. Incident CKD was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m(2) by Chronic Kidney Disease-Epidemiology equations or sex-specific microalbuminuria (urine albumin/creatinine ratio >=25 mg/g for women or >=17 mg/g for men). RESULTS: Of the 1464 patients (52.0% women), CKD incidence rates were 154.0 and 144.3 cases per 1000 patient-years for women and men, respectively. In the competing risks regression, women had an increased risk of incident CKD (sub-hazard ratio 1.37, 95% confidence interval (CI) 1.17, 1.60) compared with men after adjustment for demographics, baseline eGFR and duration of diabetes, which persisted after additional adjustment for CKD risk factors, depressive symptoms and diabetes self care (sub-hazard ratio 1.35, 95% CI 1.15, 1.59). Sex differences in incident CKD were consistent across age groups and appeared to be driven by differences in the development of low eGFR rather than microalbuminuria. CONCLUSION: Women with diabetes had a higher risk of incident CKD compared with men, which could not be entirely explained by differences in biologic CKD risk factors, depression or diabetes self-care. Additional work is needed determine if these sex differences contribute to worse outcomes in women with diabetes. PMID- 25807972 TI - Helicobacter pylori-negative gastric cancer: characteristics and endoscopic findings. AB - Helicobacter pylori (H. pylori) leads to chronic gastritis and eventually causes gastric cancer. The prevalence of H. pylori infection is gradually decreasing with improvement of living conditions and eradication therapy. However, some reports have described cases of H. pylori-negative gastric cancers (HpNGC), and the prevalence was 0.42-5.4% of all gastric cancers. Diagnostic criteria of HpNGC vary among the different reports; thus, they have not yet been definitively established. We recommend negative findings in two or more methods that include endoscopic or pathological findings or serum pepsinogen test, and negative urease breath test or serum immunoglobulin G test and no eradication history the minimum criteria for diagnosis of HpNGC. The etiology of gastric cancers, excluding H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations, but the main causal factor of HpNGC is still unclear. Regarding the characteristics of HpNGC, the undifferentiated type (UD-type) is more frequent than the differentiated type (D-type). The UD-type is mainly signet ring-cell carcinoma that presents as a discolored lesion in the lower or middle part of the stomach in relatively young patients. The gross type is flat or depressed. The D-type is mainly gastric adenocarcinoma of the fundic gland type that presents as a submucosal tumor-like or flat or depressed lesion in the middle and upper part of the stomach in relatively older patients. Early detection of HpNGC enables minimally invasive treatment which preserves the patient's quality of life. Endoscopists should fully understand the characteristics and endoscopic findings of HpNGC. PMID- 25807971 TI - Association between modification of phenolic profiling and development of wine color during alcohol fermentation. AB - To solve the problem of wine color instability in western China, different additives (the maceration enzymes Vinozym G and Ex-color, yeasts VR5 and Red Star, and commercial tannins) were added during alcoholic fermentation of Syrah (Vitis vinifera L.). The phenolic profile and color characteristics of wine were examined using high performance liquid chromatography mass spectrometry and CIELAB, respectively. The results showed that the combination of the enzyme Ex color with the Red Star yeast eased the release of non-anthocyanins from grape berries into wine, whereas the use of enzyme Vinozym G and VR5 yeast enhanced the concentration of anthocyanins and achieved a higher red hue (a* value) and a lower yellow hue (b* value) in the wine. The addition of commercial tannins greatly promoted the level of gallic acid in the wine and led to a relatively higher concentration of anthocyanins. Partial least-squares regression analysis was used to find out the major phenolics, which were in close relation with color parameters; principal component analysis was used to evaluate the contribution of different winemaking techniques to wine color. The combination of these 2 analytic methods indicated that Vinozym G and VR5 yeast together with commercial tannins should be an appropriate combination to enhance the stability of wine color during alcohol fermentation, which was related to a significant increase in cyanidin-3-O-(6-O-acetyl)-glucoside, cyanidin-3-O-(6-O-coumaryl)-glucoside, trans peonidin-3-O-(6-O-coumaryl)-glucoside, trans-malvidin-3-O-(6-O-coumaryl) glucoside, and malvidin-3-O-(6-O-acetyl)-glucoside-pyruvic acid, all of which played an important role in stabilizing wine color. PMID- 25807974 TI - Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group. AB - Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma-associated, or large granular lymphocyte (LGL) leukaemia-associated PRCA, which is thought to be immune-mediated. To explore the overall long-term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma associated and 14 LGL leukaemia-associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma-associated and LGL leukaemia-associated PRCA were 142.1 and 147.8 months, respectively. Twenty-two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA. PMID- 25807973 TI - How Children and Adults Represent God's Mind. AB - For centuries, humans have contemplated the minds of gods. Research on religious cognition is spread across sub-disciplines, making it difficult to gain a complete understanding of how people reason about gods' minds. We integrate approaches from cognitive, developmental, and social psychology and neuroscience to illuminate the origins of religious cognition. First, we show that although adults explicitly discriminate supernatural minds from human minds, their implicit responses reveal far less discrimination. Next, we demonstrate that children's religious cognition often matches adults' implicit responses, revealing anthropomorphic notions of God's mind. Together, data from children and adults suggest the intuitive nature of perceiving God's mind as human-like. We then propose three complementary explanations for why anthropomorphism persists in adulthood, suggesting that anthropomorphism may be (a) an instance of the anchoring and adjustment heuristic; (b) a reflection of early testimony; and/or (c) an evolutionary byproduct. PMID- 25807976 TI - Tatumella saanichensis sp. nov., isolated from a cystic fibrosis patient. AB - Polyphasic taxonomic analysis was performed on a clinical isolate (NML 06-3099T) from a cystic fibrosis patient, including whole-genome sequencing, proteomics, phenotypic testing, electron microscopy, chemotaxonomy and a clinical investigation. Comparative whole-genome sequence analysis and multilocus sequence analysis (MLSA) between Tatumella ptyseos ATCC 33301T and clinical isolate NML 06 3099T suggested that the clinical isolate was closely related to, but distinct from, the species T. ptyseos. By 16S rRNA gene sequencing, the clinical isolate shared 98.7 % sequence identity with T. ptyseos ATCC 33301T. A concatenate of six MLSA loci (totalling 4500 bp) revealed < 93.9 % identity between T. ptyseos ATCC 33301T, other members of the genus and the clinical isolate. A whole-genome sequence comparison between NML 06-3099T and ATCC 33301T determined that the average nucleotide identity was 76.24 %. The overall DNA G+C content of NML 06 3099T was 51.27 %, consistent with members of the genus Tatumella. By matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS analysis, NML 06-3099T had a genus-level match, but not a species-level match, to T. ptyseos. By shotgun proteomics, T. ptyseos ATCC 33301T and NML 06-3099T were found to have unique proteomes. The two strains had similar morphologies and multiple fimbriae, as observed by transmission electron microscopy, but were distinguishable by phenotypic testing. Cellular fatty acids found were typical for members of the Enterobacteriaceae. NML 06-3099T was susceptible to commonly used antibiotics. Based on these data, NML 06-3099T represents a novel species in the genus Tatumella, for which the name Tatumella saanichensis sp. nov. is proposed (type strain NML 06-3099T = CCUG 55408T = DSM 19846T). PMID- 25807975 TI - Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. AB - Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using (2) H3 -leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions. PMID- 25807977 TI - Sphingobium phenoxybenzoativorans sp. nov., a 2-phenoxybenzoic-acid-degrading bacterium. AB - A Gram-stain-negative, aerobic, yellow-pigmented, rod-shaped bacterium, designated strain SC_3T, was isolated from pesticide-contaminated soil sediment. The strain was able to mineralize 2-phenoxybenzoic acid. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain SC_3T formed a monophyletic lineage in the genus Sphingobium, and showed highest similarity to the type strains of Sphingobium abikonense (97.0 %), followed by Sphingobium lactosutens (96.8 %) and Sphingobium cloacae (96.7 %). The DNA-DNA relatedness between strain SC_3T and its closest phylogenetic neighbours was lower than 70 %. The major fatty acids (>5 % of the total) were summed feature 8 (comprising C18:1omega7c/C18:1omega6c), summed feature 3 (comprising C16:1omega7c/C16:1omega6c), C14:0 2-OH, C16:0 and C17:1omega6c. The predominant quinone was ubiquinone Q-10, and the major polyamine was spermidine. The polar lipid profile contained diphosphatidylglycerol (DPG), sphingoglycolipid (SGL), phosphatidylethanolamine (PDME), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylmonomethylethanolamine (PMME), an unknown aminolipid (AL), two unknown lipids (L1, L2) and several unknown phospholipids (PL1-6). The genomic DNA G+C content of strain SC_3T was 62.9 mol%. On the basis of phenotypic, chemotaxonomic, phylogenetic and genotypic data, strain SC_3T represents a novel species of the genus Sphingobium, for which the name Sphingobium phenoxybenzoativorans sp. nov. is proposed. The type strain is SC_3T ( = CCTCC AB 2014349T = KACC 42448T). PMID- 25807978 TI - Methanobacterium aggregans sp. nov., a hydrogenotrophic methanogenic archaeon isolated from an anaerobic digester. AB - A novel, strictly anaerobic, hydrogenotrophic methanogen, strain E09F.3T, was isolated from a commercial biogas plant in Germany. Cells of E09F.3T were Gram stain-negative, non-motile, slightly curved rods, long chains of which formed large aggregates consisting of intertwined bundles of chains. Cells utilized H2+CO2 and, to a lesser extent, formate as substrates for growth and methanogenesis. The optimal growth temperature was around 40 degrees C; maximum growth rate was obtained at pH around 7.0 with approximately 6.8 mM NaCl. The DNA G+C content of strain E09F.3T was 39.1 mol%. Phylogenetic analyses based on 16S rRNA and mcrA gene sequences placed strain E09F.3T within the genus Methanobacterium. On the basis of 16S rRNA gene sequence similarity, strain E09F.3T was closely related to Methanobacterium congolense CT but morphological, physiological and genomic characteristics indicated that strain E09F.3T represents a novel species. The name Methanobacterium aggregans sp. nov. is proposed for this novel species, with strain E09F.3T ( = DSM 29428T = JCM 30569T) as the type strain. PMID- 25807979 TI - Lactobacillus mixtipabuli sp. nov. isolated from total mixed ration silage. AB - Using a polyphasic taxonomic approach, we investigated three bacterial strains - IWT30T, IWT8 and IWT75 - isolated from total mixed ration silage prepared in Hachimantai, Iwate, Japan. The isolates comprised Gram-stain positive, non motile, non-spore-forming, catalase-negative, rod-shaped bacteria. Good growth occurred at 15-45 degrees C and at pH 4.0-7.5. Their major cellular fatty acids were C18:1omega9c and C19:1 cyclo 9,10.The G+C content of genomic DNA of strain IWT30T was 44.6 mol%. Comparative 16S rRNA gene sequence analysis showed that these novel strains belonged to the genus Lactobacillus. These strains shared 100 % 16S rRNA gene sequence similarity and were most closely related to the type strains of Lactobacillus silagei, Lactobacillus odoratitofui, Lactobacillus similis, Lactobacillus collinoides, Lactobacillus paracollinoides and Lactobacillus kimchicus, with sequence similarity values of 99.5, 98.8, 98.7, 97.8, 97.8 and 96.8 %, respectively. The level of DNA-DNA relatedness between these strains and their closest phylogenetic neighbours was less than 30 %. On the basis of additional phylogenetic analysis of pheS and rpoA gene sequences and phenotypic and chemotaxonomic characteristics, we conclude that these three strains represent a novel species of the genus Lactobacillus, for which we propose the name Lactobacillus mixtipabuli sp. nov. The type strain is IWT30T ( = JCM 19805T = DSM 28580T). PMID- 25807980 TI - Individual heterogeneity in life histories and eco-evolutionary dynamics. AB - Individual heterogeneity in life history shapes eco-evolutionary processes, and unobserved heterogeneity can affect demographic outputs characterising life history and population dynamical properties. Demographic frameworks like matrix models or integral projection models represent powerful approaches to disentangle mechanisms linking individual life histories and population-level processes. Recent developments have provided important steps towards their application to study eco-evolutionary dynamics, but so far individual heterogeneity has largely been ignored. Here, we present a general demographic framework that incorporates individual heterogeneity in a flexible way, by separating static and dynamic traits (discrete or continuous). First, we apply the framework to derive the consequences of ignoring heterogeneity for a range of widely used demographic outputs. A general conclusion is that besides the long-term growth rate lambda, all parameters can be affected. Second, we discuss how the framework can help advance current demographic models of eco-evolutionary dynamics, by incorporating individual heterogeneity. For both applications numerical examples are provided, including an empirical example for pike. For instance, we demonstrate that predicted demographic responses to climate warming can be reversed by increased heritability. We discuss how applications of this demographic framework incorporating individual heterogeneity can help answer key biological questions that require a detailed understanding of eco-evolutionary dynamics. PMID- 25807981 TI - Parents' perceptions of microneedle-mediated monitoring as an alternative to blood sampling in the monitoring of their infants. AB - OBJECTIVES: Microneedle (MN) arrays could offer a pain-free, minimally invasive approach to monitoring. This is envisaged to be particularly beneficial for younger patients, but parents' views to date are unknown. The aim of this study was to explore parental perceptions of MN-mediated ISF monitoring, as an alternative to the use of conventional blood sampling, and to understand the important factors for technique approval. METHODS: Semi-structured interviews were conducted with parents with recent experience of a premature birth. Recruitment was through the Northern Ireland premature infant charity, Tinylife. Interviews progressed until data saturation was reached and thematic analysis employed. KEY FINDINGS: The study included 16 parents. Parental support for MN mediated monitoring was evident, alongside the unpopularity of traditional blood sampling in neonates. Factors facilitating MN approval included the opportunity for pain reduction, the simplicity of the procedure, the potential for increased parental involvement and the more favourable appearance, owing to the minute size of MNs and similarities with a sticking plaster. Confirmation of correct application, a pain-free patch removal and endorsement from trusted healthcare professionals were important. CONCLUSION: These findings will inform researchers in the field of MN development and enlighten practitioners regarding parental distress resulting from conventional blood sampling. Further work is necessary to understand MN acceptability among practitioners. This work should assist in the development of an acceptable MN device and facilitate the reduction of parental distress. AUTHOR: The abbreviations section has been deleted, and the full forms of the terms mentioned therein have been incorporated in the text. Please confirm if this is okay. PMID- 25807983 TI - Exploring competencies: a qualitative study of Chinese nurse managers. AB - AIM: To identify core competencies needed in the transition of nurse managers on the way to excellence. BACKGROUND: There is growing recognition of the importance of nurse managers in hospitals. Most managers still learn through their failures and few studies have described the perceptions of nurse managers in China. It is vital to understand what competencies Chinese nurse managers should have in order to establish suitable training programmes and improve their management skills. METHOD: A phenomenological approach that included in-depth interviews with 12 nurse managers in six Chinese hospitals was conducted. RESULTS: The transition to management included four phases: the adaptive phase, the running-in and stable phase, the stagnation phase and the maturation phase. CONCLUSION: In order to fulfil their clinical responsibilities, nurse managers need to develop multifaceted competencies, specifically in communication and stress management. Ideally, nurse managers should progress through the four phases mentioned above to achieve excellence. IMPLICATIONS: There is a requirement for utilising various methods for nurse managers in adapting new roles, improving communication and relieving stress. PMID- 25807982 TI - Methamphetamine acutely inhibits voltage-gated calcium channels but chronically up-regulates L-type channels. AB - In neurons, calcium (Ca(2+) ) channels regulate a wide variety of functions ranging from synaptic transmission to gene expression. They also induce neuroplastic changes that alter gene expression following psychostimulant administration. Ca(2+) channel blockers have been considered as potential therapeutic agents for the treatment of methamphetamine (METH) dependence because of their ability to reduce drug craving among METH users. Here, we studied the effects of METH exposure on voltage-gated Ca(2+) channels using SH-SY5Y cells as a model of dopaminergic neurons. We found that METH has different short- and long term effects. A short-term effect involves immediate (< 5 min) direct inhibition of Ca(2+) ion movements through Ca(2+) channels. Longer exposure to METH (20 min or 48 h) selectively up-regulates the expression of only the CACNA1C gene, thus increasing the number of L-type Ca(2+) channels. This up-regulation of CACNA1C is associated with the expression of the cAMP-responsive element-binding protein (CREB), a known regulator of CACNA1C gene expression, and the MYC gene, which encodes a transcription factor that putatively binds to a site proximal to the CACNA1C gene transcription initiation site. The short-term inhibition of Ca(2+) ion movement and later, the up-regulation of Ca(2+) channel gene expression together suggest the operation of cAMP-responsive element-binding protein- and C MYC-mediated mechanisms to compensate for Ca(2+) channel inhibition by METH. Increased Ca(2+) current density and subsequent increased intracellular Ca(2+) may contribute to the neurodegeneration accompanying chronic METH abuse. Methamphetamine (METH) exposure has both short- and long-term effects. Acutely, methamphetamine directly inhibits voltage-gated calcium channels. Chronically, neurons compensate by up-regulating the L-type Ca(2+) channel gene, CACNA1C. This compensatory mechanism is mediated by transcription factors C-MYC and CREB, in which CREB is linked to the dopamine D1 receptor signaling pathway. These findings suggest Ca(2+) -mediated neurotoxicity owing to over-expression of calcium channels. PMID- 25807984 TI - Risks inherent to mitochondrial replacement. PMID- 25807987 TI - RNA metabolism: putting the brake on the UPR. AB - The unfolded protein response (UPR) is a major signaling cascade that determines cell fate under conditions of endoplasmic reticulum (ER) stress. The kinetics and amplitude of UPR responses are tightly controlled by several feedback loops and the expression of positive and negative regulators. In this issue of EMBO Reports, the Wilkinson lab uncovers a novel function of nonsense-mediated RNA decay (NMD) in fine-tuning the UPR. NMD is an mRNA quality control mechanism known to destabilize aberrant mRNAs that contain premature termination codons. In this work, NMD was shown to determine the threshold of stress necessary to activate the UPR, in addition to adjusting the amplitude of downstream responses and the termination phase. These effects were mapped to the control of the mRNA stability of IRE1, a major ER stress transducer. This study highlights the dynamic crosstalk between mRNA metabolism and the proteostasis network demonstrating the physiological relevance of normal mRNA regulation by the NMD pathway. PMID- 25807988 TI - Symptoms Before Sudden Arrhythmic Death Syndrome: A Nationwide Study Among the Young in Denmark. AB - INTRODUCTION: No studies in an unselected and nationwide setting have characterized the symptoms and medical history of patients with sudden arrhythmic death syndrome (SADS). The aim of this study was to identify and describe the symptoms and medical history of patients before the presentation of SADS. METHODS AND RESULTS: We have previously identified all of the autopsied sudden cardiac deaths (SCD; n = 314) in Danes aged 1-35 years between 2000 and 2006. After comprehensive pathological and toxicological investigation did not reveal a cause of SCD, 136 of the patients were identified as SADS. The National Patient Registry was utilized to obtain information on all in- and outpatient activity in Danish hospitals. All medical records from hospitals and general practitioners, including death certificates and autopsy reports were reviewed. Before death, 48 (35%) SADS patients had cardiac symptoms; among these, 30 (22%) had contacted the healthcare system. Antecedent symptoms (symptoms >24 hours before death) were present in 34 (25%) patients. Prodromal symptoms (symptoms <=24 hours before death) were present in 23 (17%) patients. Cardiac symptoms included chest pain (n = 16, 12%), dyspnea (n = 18, 13%), palpitations (n = 2, 1%), presyncope/syncope (n = 23, 17%), and aborted SCD (n = 2, 1%). In addition, seizures (n = 25, 18%) were prevalent. In 61 (45%) SADS cases, no previous medical history were recorded. CONCLUSION: In this unselected, nationwide study of 136 young SADS patients, 35% had experienced cardiac symptoms before death, most commonly presyncope/syncope, but only one out of five had contacted a healthcare provider with cardiac symptoms. PMID- 25807989 TI - Increased Neutrophil to Lymphocyte Ratio in Patients With Resistant Hypertension. AB - Resistant hypertension (RHT) is an important disease that causes an increase in cardiovascular risk, yet its etiology remains unclear. The authors aimed to investigate neutrophil/lymphocyte ratio (NLR) as an inflammation marker in patients with RHT. A total of 150 patients were included in the study and grouped according to their office and ambulatory blood pressure measurements. They were classified as having normotension (NT), controlled hypertension (CHT), or RHT. The RHT group had a significantly higher NLR than the CHT group (P=.03), and NLRs of both hypertension groups were significantly higher than those in the NT group (P<.001, for both). NLR and neutrophil count were found to be independent correlates for RHT in multivariate analysis (P<.001). NLR and neutrophil count are increased in RHT patients than both CHT and NT patients. This finding, which is defined for the first time in patients with RHT, may imply the importance of inflammation in blood pressure control. PMID- 25807985 TI - Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function. AB - Decreased nitric oxide (NO) bioavailability underlies a number of cardiovascular pathologies, including hypertension. The shear stress exerted by flowing blood is the main determinant of NO release. Rap1 promotes integrin- and cadherin-mediated signaling. Here, we show that Rap1 is a critical regulator of NO production and endothelial function. Rap1 deficiency in murine endothelium attenuates NO production and diminishes NO-dependent vasodilation, leading to endothelial dysfunction and hypertension, without deleterious effects on vessel integrity. Mechanistically, Rap1 is activated by shear stress, promotes the formation of the endothelial mechanosensing complex-comprised of PECAM-1, VE-cadherin and VEGFR2- and downstream signaling to NO production. Our study establishes a novel paradigm for Rap1 as a regulator of mechanotransduction. PMID- 25807990 TI - Familial hypercholesterolaemia with tuberous and tendinous xanthomas: case report and mutation analysis. AB - Xanthomas are important clinical manifestations of disordered lipid metabolism, which are mostly found in patients with familial hypercholesterolaemia (FH), an inherited disorder that is predominantly caused by mutations in the low-density lipoprotein receptor gene (LDLR). Tuberous and tendinous xanthomas with wide distribution and large size are rare; however, they may indicate the severity of FH, and tend to be found in homozygous FH. In this study, we investigated the clinical and genetic aspects of a young patient with FH presenting with multiple large masses in various locations. The lesions on the elbows and buttocks were locally excised and subsequently confirmed by biopsy to be xanthomas. Genetic analysis further confirmed that the patient was compound heterozygous for two mutations in both alleles of the LDLR gene. This rare case of compound heterozygous FH presenting with multiple large and widely distributed xanthomas provides a better understanding of FH and xanthomas. PMID- 25807986 TI - The unfolded protein response is shaped by the NMD pathway. AB - Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), an essential adaptive intracellular pathway that relieves the stress. Although the UPR is an evolutionarily conserved and beneficial pathway, its chronic activation contributes to the pathogenesis of a wide variety of human disorders. The fidelity of UPR activation must thus be tightly regulated to prevent inappropriate signaling. The nonsense-mediated RNA decay (NMD) pathway has long been known to function in RNA quality control, rapidly degrading aberrant mRNAs, and has been suggested to regulate subsets of normal mRNAs. Here, we report that the NMD pathway regulates the UPR. NMD increases the threshold for triggering the UPR in vitro and in vivo, thereby preventing UPR activation in response to normally innocuous levels of ER stress. NMD also promotes the timely termination of the UPR. We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1alpha, whose NMD dependent degradation partly underpins this process. Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD's ability to regulate normal mRNAs. PMID- 25807991 TI - Shifting elasmobranch community assemblage at Cocos Island--an isolated marine protected area. AB - Fishing pressure has increased the extinction risk of many elasmobranch (shark and ray) species. Although many countries have established no-take marine reserves, a paucity of monitoring data means it is still unclear if reserves are effectively protecting these species. We examined data collected by a small group of divers over the past 21 years at one of the world's oldest marine protected areas (MPAs), Cocos Island National Park, Costa Rica. We used mixed effects models to determine trends in relative abundance, or probability of occurrence, of 12 monitored elasmobranch species while accounting for variation among observers and from abiotic factors. Eight of 12 species declined significantly over the past 2 decades. We documented decreases in relative abundance for 6 species, including the iconic scalloped hammerhead shark (Sphyrna lewini) (-45%), whitetip reef shark (Triaenodon obesus) (-77%), mobula ray (Mobula spp.) (-78%), and manta ray (Manta birostris) (-89%), and decreases in the probability of occurrence for 2 other species. Several of these species have small home ranges and should be better protected by an MPA, which underscores the notion that declines of marine megafauna will continue unabated in MPAs unless there is adequate enforcement effort to control fishing. In addition, probability of occurrence at Cocos Island of tiger (Galeocerdo cuvier), Galapagos (Carcharhinus galapagensis), blacktip (Carcharhinus limbatus), and whale (Rhincodon typus) sharks increased significantly. The effectiveness of MPAs cannot be evaluated by examining single species because population responses can vary depending on life history traits and vulnerability to fishing pressure. PMID- 25807992 TI - Distinct sustained structural and functional effects of interleukin-33 and interleukin-25 on the airways in a murine asthma surrogate. AB - Interleukin-25 (IL-25) and IL-33, which belong to distinct cytokine families, induce and promote T helper type 2 airway inflammation. Both cytokines probably play a role in asthma, but there is a lack of direct evidence to clarify distinctions between their functions and how they might contribute to distinct 'endotypes' of disease. To address this, we made a direct comparison of the effects of IL-25 and IL-33 on airway inflammation and physiology in our established murine asthma surrogate, which involves per-nasal, direct airway challenge. Intranasal challenge with IL-33 or IL-25 induced inflammatory cellular infiltration, collagen deposition, airway smooth muscle hypertrophy, angiogenesis and airway hyper-responsiveness, but neither increased systemic production of IgE or IgG1. Compared with that of IL-25, the IL-33-induced response was characterized by more sustained laying down of extracellular matrix protein, neoangiogenesis, T helper type 2 cytokine expression and elevation of tissue damping. Hence, both IL-25 and IL-33 may contribute significantly and independently to asthma 'endotypes' when considering molecular targets for the treatment of human disease. PMID- 25807994 TI - Effect of late-onset fetal growth restriction on organization of behavioral state in infants. AB - BACKGROUND: The aim of this study was to analyze whether late-onset fetal growth restriction (FGR) alters regulatory capability in infants, and whether this can be detected using both the neonatal behavior assessment scale (NBAS) and brainstem auditory-evoked potentials (BAEP). METHODS: The diagnosis of FGR was made on Doppler examination in the third trimester of pregnancy. NBAS and BAEP measurement were performed at 1 month of corrected postnatal age. RESULTS: The group with late-onset FGR was integrated with 17 infants and the control group consisted of 14 subjects. The NBAS range of state score, which reflects organization of behavioral state, was low in infants with late-onset FGR. No differences were found in BAEP between groups. No association between NBAS and BAEP was detected. CONCLUSION: Late-onset FGR has a deleterious effect on NBAS range of state, but possibly does not alter BAEP response. It is proposed that regulatory capabilities in the neonatal period play a primary role in subtle cognitive difficulties in infants with late-onset FGR in the long term. PMID- 25807996 TI - First surgery for pancreatic neuroendocrine tumours in a patient with MEN1: enucleation versus disease-modifying surgery. AB - Pancreatic neuroendocrine tumours (PNETs) are the second most common manifestation of MEN1, affecting up to 80% of patients. The secretion of peptide hormones by PNETs causes clinical syndromes requiring therapeutic intervention. Malignant progression of PNETs is a leading cause of mortality in patients with MEN1. The goal of surgery, when required, is to alleviate a biochemical syndrome or to treat established tumour(s) to reduce the risk of local progression or metastases against the background of preservation of pancreatic function. Determining the need and optimum timing for an operative intervention is complex and requires an approach individualized for each patient. When a clinically significant biochemical syndrome is confirmed, the time course to surgery is clear. In patients with a potentially malignant PNET, the decision as to when to intervene is more challenging. In all cases surgical treatment carries the potential for harm, of more than usual concern because many of the patients are young. In this study, we explain an approach to the surgical treatment of MEN1 patients with biochemical or radiological evidence of PNETs where other manifestations of the syndrome are either treated or controlled and the patient lacks comorbidity that would preclude pancreatic surgery. In each scenario we present, a normal serum gastrin will be assumed as the surgical approach to this usually duodenal manifestation of MEN1 is significantly different to the management of other PNETs. PMID- 25807993 TI - Verbascoside down-regulates some pro-inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase SHP-1 in the U937 cell line. AB - Polyphenols are the major components of many traditional herbal remedies, which exhibit several beneficial effects including anti-inflammation and antioxidant properties. Src homology region 2 domain-containing phosphatase-1 (SHP-1) is a redox sensitive protein tyrosine phosphatase that negatively influences downstream signalling molecules, such as mitogen-activated protein kinases, thereby inhibiting inflammatory signalling induced by lipopolysaccharide (LPS). Because a role of transforming growth factor beta-activated kinase-1 (TAK1) in the upstream regulation of JNK molecule has been well demonstrated, we conjectured that SHP-1 could mediate the anti-inflammatory effect of verbascoside through the regulation of TAK-1/JNK/AP-1 signalling in the U937 cell line. Our results demonstrate that verbascoside increased the phosphorylation of SHP-1, by attenuating the activation of TAK-1/JNK/AP-1 signalling. This leads to a reduction in the expression and activity of both COX and NOS. Moreover, SHP-1 depletion deletes verbascoside inhibitory effects on pro-inflammatory molecules induced by LPS. Our data confirm that SHP-1 plays a critical role in restoring the physiological mechanisms of inducible proteins such as COX2 and iNOS, and that the down-regulation of TAK-1/JNK/AP-1 signalling by targeting SHP-1 should be considered as a new therapeutic strategy for the treatment of inflammatory diseases. PMID- 25807995 TI - Emergency physician perceptions of shared decision-making. AB - OBJECTIVES: Despite the potential benefits of shared decision-making (SDM), its integration into emergency care is challenging. Emergency physician (EP) perceptions about the frequency with which they use SDM, its potential to reduce medically unnecessary diagnostic testing, and the barriers to employing SDM in the emergency department (ED) were investigated. METHODS: As part of a larger project examining beliefs on overtesting, questions were posed to EPs about SDM. Qualitative analysis of two multispecialty focus groups was done exploring decision-making around resource use to generate survey items. The survey was then pilot-tested and revised to focus on advanced diagnostic imaging and SDM. The final survey was administered to EPs recruited at four emergency medicine (EM) conferences and 15 ED group meetings. This report addresses responses regarding SDM. RESULTS: A purposive sample of 478 EPs from 29 states were approached, of whom 435 (91%) completed the survey. EPs estimated that, on average, multiple reasonable management options exist in over 50% of their patients and reported employing SDM with 58% of such patients. Respondents perceived SDM as a promising solution to reduce overtesting. However, despite existing research to the contrary, respondents also commonly cited beliefs that 1) "many patients prefer that the physician decides," 2) "when offered a choice, many patients opt for more aggressive care than they need," and 3) "it is too complicated for patients to know how to choose." CONCLUSIONS: Most surveyed EPs believe SDM is a potential high-yield solution to overtesting, but many perceive patient-related barriers to its successful implementation. PMID- 25807997 TI - Long-term efficacy of biofeedback therapy in patients with dyssynergic defecation: results of a median 44 months follow-up. AB - BACKGROUND: The beneficial effect of biofeedback therapy (BFT) over a period of more than 2 years has not been studied in a large group of patients. The aim of this study was to evaluate the long-term efficacy of BFT for dyssynergic defecation (DD). METHODS: We evaluated the results for 347 consecutive constipated patients with DD who underwent BFT for a median of five sessions between 2004 and 2009. Initial responses were assessed immediately after the completion of BFT. A responder was defined as a subject with at least a three point improvement from before to after BFT on an 11-point global bowel satisfaction (GBS) scale, or a two-point improvement if the baseline GBS was more than six points. The probability of remaining a responder was estimated by non parametric maximum likelihood estimation. KEY RESULTS: The initial response rate to BFT was 72.3% (n = 251), Parkinson's disease and higher baseline GBS scores were associated with initial non-response. The long-term efficacy of BFT was analyzed in 103 patients who were followed up for more than 6 months; the initial effects of BFT were maintained in 85 of the patients (82.5%) during a median of 44 months of follow-up (IQR = 12-68). The probability of remaining a responder was 60% at 2 years, and 58% at 5 years. CONCLUSIONS & INFERENCES: The efficacy of BFT is maintained for more than 2 years after BFT in a considerable proportion of constipated patients with DD. BFT is effective and durable treatment for managing DD. PMID- 25808000 TI - Correction to 'Ancient DNA and the tropics: a rodent's tale'. AB - The present erratum is in regards to our article entitled 'Ancient DNA and the tropics: a rodent's tale'. We were made aware of problems with some of the ancient sequences submitted to GenBank and conducted a systematic review of all the files used in our study. We discovered that, unfortunately, an incorrect file was sent to GenBank and was also used in some of our downstream analyses. We immediately contacted GenBank, explained the situation and corrected the file. We have redone some analyses with the correct file and describe these changes below. PMID- 25807998 TI - PfSR1 controls alternative splicing and steady-state RNA levels in Plasmodium falciparum through preferential recognition of specific RNA motifs. AB - Plasmodium species have evolved complex biology to adapt to different hosts and changing environments throughout their life cycle. Remarkably, these adaptations are achieved by a relatively small genome. One way by which the parasite expands its proteome is through alternative splicing (AS). We recently identified PfSR1 as a bona fide Ser/Arg-rich (SR) protein that shuttles between the nucleus and cytoplasm and regulates AS in Plasmodium falciparum. Here we show that PfSR1 is localized adjacent to the Nuclear Pore Complex (NPC) clusters in the nucleus of early stage parasites. To identify the endogenous RNA targets of PfSR1, we adapted an inducible overexpression system for tagged PfSR1 and performed RNA immunoprecipitation followed by microarray analysis (RIP-chip) to recover and identify the endogenous RNA targets that bind PfSR1. Bioinformatic analysis of these RNAs revealed common sequence motifs potentially recognized by PfSR1. RNA EMSAs show that PfSR1 preferentially binds RNA molecules containing these motifs. Interestingly, we find that PfSR1 not only regulates AS but also the steady-state levels of mRNAs containing these motifs in vivo. PMID- 25807999 TI - New insights into Brunner syndrome and potential for targeted therapy. AB - We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms. PMID- 25808001 TI - Negative impact of manganese on honeybee foraging. AB - Anthropogenic accumulation of metals such as manganese is a well-established health risk factor for vertebrates. By contrast, the long-term impact of these contaminants on invertebrates is mostly unknown. Here, we demonstrate that manganese ingestion alters brain biogenic amine levels in honeybees and fruit flies. Furthermore, we show that manganese exposure negatively affects foraging behaviour in the honeybee, an economically important pollinator. Our findings indicate that in addition to its direct impact on human health, the common industrial contaminant manganese might also have indirect environmental and economical impacts via the modulation of neuronal and behavioural functions in economically important insects. PMID- 25808002 TI - Transgenerational effects modulate density-dependent prophylactic resistance to viral infection in a lepidopteran pest. AB - There is an increasing appreciation of the importance of transgenerational effects on offspring fitness, including in relation to immune function and disease resistance. Here, we assess the impact of parental rearing density on offspring resistance to viral challenge in an insect species expressing density dependent prophylaxis (DDP); i.e. the adaptive increase in resistance or tolerance to pathogen infection in response to crowding. We quantified survival rates in larvae of the cotton leafworm (Spodoptera littoralis) from either gregarious- or solitary-reared parents following challenge with the baculovirus S. littoralis nucleopolyhedrovirus. Larvae from both the parental and offspring generations exhibited DDP, with gregarious-reared larvae having higher survival rates post-challenge than solitary-reared larvae. Within each of these categories, however, survival following infection was lower in those larvae from gregarious-reared parents than those from solitary-reared, consistent with a transgenerational cost of DDP immune upregulation. This observation demonstrates that crowding influences lepidopteran disease resistance over multiple generations, with potential implications for the dynamics of host-pathogen interactions. PMID- 25808003 TI - Brain serotonin deficiency leads to social communication deficits in mice. AB - A deficit in brain serotonin is thought to be associated with deteriorated stress coping behaviour, affective disorders and exaggerated violence. We challenged this hypothesis in mice with a brain-specific serotonin depletion caused by a tryptophan hydroxylase 2 (TPH2) deficiency. We tested TPH2-deficient (Tph2(-/-)) animals in two social situations. As juveniles, Tph2(-/-) mice displayed reduced social contacts, whereas ultrasonic vocalizations (USVs) were unchanged within same-sex same-genotype pairings. Interestingly, juvenile females vocalized more than males across genotypes. Sexually naive adult males were exposed to fresh male or female urine, followed by an interaction with a conspecific, and re exposed to urine. Although Tph2(-/-) mice showed normal sexual preference, they were hyper-aggressive towards their interaction partners and did not vocalize in response to sexual cues. These results highlight that central serotonin is essential for prosocial behaviour, especially USV production in adulthood, but not for sexual preference. PMID- 25808004 TI - Animal personality as a cause and consequence of contest behaviour. AB - We review the evidence for a link between consistent among-individual variation in behaviour (animal personality) and the ability to win contests over limited resources. Explorative and bold behaviours often covary with contest behaviour and outcome, although there is evidence that the structure of these 'behavioural syndromes' can change across situations. Aggression itself is typically repeatable, but also subject to high within-individual variation as a consequence of plastic responses to previous fight outcomes and opponent traits. Common proximate mechanisms (gene expression, endocrine control and metabolic rates) may underpin variation in both contest behaviour and general personality traits. Given the theoretical links between the evolution of fighting and of personality, we suggest that longitudinal studies of contest behaviour, combining behavioural and physiological data, would be a useful context for the study of animal personalities. PMID- 25808005 TI - Involving patients in health care: the process matters. PMID- 25808006 TI - Xenobiotic metabolizing enzymes in human skin and SkinEthic reconstructed human skin models. AB - Skin metabolism is becoming a major consideration in the development of new cosmetic ingredients, skin being the first organ exposed to them. In order to replace limited samples of Excised human skin (EHS), in vitro engineered human skins have been developed. 3D models are daily used to develop and evaluate new cosmetic ingredients and have to be characterized and compared with EHS in terms of metabolic capabilities. This work presents the determination of apparent catalytic parameters (apparent Vmax, Km and the ratio Vmax/Km) in 3D models compared with EHS for cytochrome P450 dependent monooxygenase isoforms involved in drug metabolism, esterases, alcohol dehydrogenases, aldehyde dehydrogenases, peroxidases, glutathione S-transferases, N-acetyl transferases, uridinyl diphosphate glucuronyl transferases and sulfotransferases. Results show that all these enzymes involved in the metabolism of xenobiotics are expressed and functional in the EHS and 3D models. Also, the Vmax/Km ratios (estimating the intrinsic metabolic clearances) show that the metabolic abilities are the most often comparable between the skin models and EHS. These results indicate that the 3D models can substitute themselves for EHS to select cosmetic ingredients on the basis of their metabolism, efficacy or/and safety. PMID- 25808009 TI - DSM-5 two years later: facts, myths and some key open issues. PMID- 25808008 TI - Subtherapeutic serum quetiapine concentrations after absorption inhibition by binding resins: a case report. AB - WHAT IS KNOWN AND OBJECTIVE: Polystyrene sulfonate and sevelamer are binding resins that are used in the treatment of, respectively, hyperkalemia and hyperphosphatemia. It is unknown whether these resins interact with the antipsychotic quetiapine. CASE SUMMARY: We report on a woman with unexplainable low serum quetiapine concentrations who also used the binding resins polystyrene sulfonate and sevelamer. An In vitro binding assay showed binding of quetiapine by these resins. Separation of the ingestion times of quetiapine and the binding resins resulted in increased serum levels in this patient. WHAT IS NEW AND CONCLUSION: Polystyrene sulfonate and sevelamer are able to bind quetiapine. Healthcare professionals should be aware of this potential drug-drug interaction as this could lead to antipsychotic treatment failure. PMID- 25808007 TI - In vitro activity of dolutegravir against wild-type and integrase inhibitor resistant HIV-2. AB - BACKGROUND: Dolutegravir recently became the third integrase strand transfer inhibitor (INSTI) approved for use in HIV-1-infected individuals. In contrast to the extensive dataset for HIV-1, in vitro studies and clinical reports of dolutegravir for HIV-2 are limited. To evaluate the potential role of dolutegravir in HIV-2 treatment, we compared the susceptibilities of wild-type and INSTI-resistant HIV-1 and HIV-2 strains to the drug using single-cycle assays, spreading infections of immortalized T cells, and site-directed mutagenesis. FINDINGS: HIV-2 group A, HIV-2 group B, and HIV-1 isolates from INSTI-naive individuals were comparably sensitive to dolutegravir in the single cycle assay (mean EC50 values = 1.9, 2.6, and 1.3 nM, respectively). Integrase substitutions E92Q, Y143C, E92Q + Y143C, and Q148R conferred relatively low levels of resistance to dolutegravir in HIV-2ROD9 (2- to 6-fold), but Q148K, E92Q + N155H, T97A + N155H and G140S + Q148R resulted in moderate resistance (10- to 46-fold), and the combination of T97A + Y143C in HIV-2ROD9 conferred high-level resistance (>5000-fold). In contrast, HIV-1NL4-3 mutants E92Q + N155H, G140S + Q148R, and T97A + Y143C showed 2-fold, 4-fold, and no increase in EC50, respectively, relative to the parental strain. The resistance phenotypes for E92Q + N155H, and G140S + Q148R HIV-2ROD9 were also confirmed in spreading infections of CEM-ss cells. CONCLUSIONS: Our data support the use of dolutegravir in INSTI naive HIV-2 patients but suggest that, relative to HIV-1, a broader array of replacements in HIV-2 integrase may enable cross-resistance between dolutegravir and other INSTI. Clinical studies are needed to evaluate the efficacy of dolutegravir in HIV-2-infected individuals, including patients previously treated with raltegravir or elvitegravir. PMID- 25808010 TI - Novel anticoagulants and antiplatelet agents; a guide for the urologist. AB - Novel oral anti-coagulants (NOACs) are increasingly being used in clinical practice and are set to almost entirely replace the vitamin K antagonists, such as warfarin, in the near future. Similarly, new antiplatelet agents are now regularly used in place of older agents, such as aspirin and clopidogrel. In an ageing population, with an increasing burden of complex comorbidities, urologists will frequently encounter patients who will be using such agents. Some background knowledge, and an understanding, of these drugs and the issues that surround their usage, is essential. The present article will provide readers with an understanding of these new drugs, including their mechanisms of action, the up-to date evidence justifying their recent introduction into clinical practice and the appropriate interval for stopping them before surgery. It will also consider the risks of perioperative bleeding for patients taking these drugs and the risks of venous thromboembolism in those in whom they are stopped. Strategies to manage anticoagulant-associated bleeding are discussed. PMID- 25808011 TI - Financial implications of RHD genotyping of pregnant women with a serologic weak D phenotype. AB - BACKGROUND: Hemolytic disease of the fetus and newborn, classically caused by maternal-fetal incompatibility of the Rh blood group D antigen, can be prevented by RhIG prophylaxis. While prophylactic practices for pregnant women with serologic weak D phenotypes vary widely, RHD genotyping could provide clear guidance for management. This analysis evaluated the financial implications of using RHD genotyping to guide RhIG prophylaxis among pregnant females. STUDY DESIGN AND METHODS: A Markov-based model was constructed to evaluate the costs of RHD genotyping for pregnant females with serologic weak D phenotypes to inform RhIG prophylaxis. Using a comparison strategy of managing these women conservatively as D-, direct medical costs were assessed over 10- and 20-year periods for a simulated population of US women. One-way and probabilistic sensitivity analyses were used to assess the robustness of conclusions. RESULTS: Using base-case variables, RHD genotyping for pregnant women with serologic weak D phenotypes is expected to marginally reduce overall costs. RHD genotyping these patients, rather than conservatively managing them as D-, would be cost-saving when the cost of genotyping is below $256. Genotyping would decrease net costs among non-Hispanic Caucasian females (-$0.17/pregnancy), but would increase costs among non-Hispanic African Americans (+$0.51/pregnancy), non-Hispanic American Indian/Alaskans (+$0.10/pregnancy), and Hispanics (+$0.37/pregnancy). Incorporating RHD genotyping would not significantly impact costs among Asians and Hawaiians/Pacific Islanders. CONCLUSIONS: Using RHD genotyping to guide RhIG prophylaxis among pregnant women with serologic weak D phenotypes may be clinically beneficial without increasing overall costs. PMID- 25808012 TI - Algorithm-based multidisciplinary treatment approach for rectourethral fistula. AB - PURPOSE: The purpose of this study is to report the outcomes of an algorithm based multidisciplinary treatment approach to rectourethral fistula. METHODS: This study is a retrospective review of a prospectively collected database at a tertiary center of all consecutive patients treated between 2003 and 2013. RESULTS: Thirty males (mean age 63 years) were reviewed. Prostate cancer treatment was the most common fistula etiology (97%). Urinary drainage consisted of urethral catheter in all patients and suprapubic catheter in 14 (47%). The rate of fecal diversion was 67%. During a mean follow-up of 72 months, healing rate was 90% and recurrence rate 0%. Spontaneous healing was achieved in 14 patients (47%): 8 (27%) without fecal diversion and 6 (20%) following fecal diversion. Thirteen patients (43%) required definitive intervention. The majority of operated patients underwent transanal or transperineal flap (endorectal, dartos, or gracilis) successfully. Only 2 patients (7%) required an abdominal approach (positive oncologic margins or non-functioning bladder). Fifteen out of the 20 patients (75%) who underwent fecal diversion had stoma closure with an overall permanent stoma rate of 17%. Long-term urinary incontinence was noted in 11 patients (37%). Six patients (20%) required permanent urinary diversion or drainage catheters. CONCLUSIONS: Algorithm-based treatment approach for rectourethral fistula is useful in the management of this rare condition. Selective fecal diversion is possible, and majority of patients who require definitive intervention can be treated with a transanal or transperineal approach. The rate of permanent stoma is low, but long-term urinary dysfunction is frequent. PMID- 25808013 TI - Influence of extent of lymph node dissection on survival for patients with pT2 colon cancer. AB - PURPOSE: The optimal extent of lymph node dissection for early-stage colon cancer (CC) remains undefined. This study assessed the influence of the extent of lymph node dissection on overall survival (OS) in patients with pT2 CC. METHODS: We retrospectively examined data from the multi-institutional registry system of the Japanese Society for Cancer of the Colon and Rectum and used a propensity score matching method to balance potential confounders of lymph node dissection. We extracted 463 matched pairs from 1433 patients who underwent major resections for pT2 CC between 1995 and 2004. RESULTS: Lymph node metastasis was found in 301 (21.0%) of 1433 patients with pT2 CC. In this cohort, significant independent risk factors for lymph node metastasis were lymphatic invasion and venous invasion. Patients who underwent D3 or D2 lymph node dissection did not significantly differ in OS, either among the propensity score-matched cohort (estimated hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.536-1.346, P = 0.484) or in the cohort as a whole (HR 0.720, 95% CI 0.492-1.052, P = 0.089). CONCLUSIONS: For patients with pT2 CC, D3 lymph node dissection did not add to OS. D2 lymph node dissection may be adequate for pT2 CC. PMID- 25808014 TI - Chaperone-Like Activity of a Bacterioferritin Comigratory Protein from Thermococcus kodakaraensis KOD1. AB - Peroxiredoxins (Prxs) are ubiquitous and conserved proteins that can catalyze the reduction of inorganic and organic hydroperoxides to protect against damage by reactive oxygen species. In this study, a Prx subfamily member, and specifically a bacterioferritin comigratory protein from hyperthermophilic Thermococcus kodakaraensis KOD1 (TkBcp), was overexpressed, purified and characterized. Based on the conserved cysteine (Cys) residues in its amino acids sequence, TkBcp can be grouped into 1-Cys Prx family. Size exclusion chromatography analysis showed that TkBcp exists in three oligomeric forms: 700 kDa, 70 kDa, and 20 kDa. The peroxidase function was found to predominate in the lowmolecular- weight (MW) form, whereas the high-MW complex has the chaperone function. Oxidative reagents caused the protein structure of TkBcp to shift from low-MW form to high-MW complexes, whereas reducing reagents caused a shift in the reverse direction. Furthermore, the high-MW form of TkBcp preferred to tightly bind DNA. The relationship of TkBcp with other homologs was also examined. PMID- 25808015 TI - (2R,3S)-Pinobanksin-3-cinnamate improves cognition and reduces oxidative stress in rats with vascular dementia. AB - This study investigated the neuroprotective effects of (2R,3S)-pinobanksin-3 cinnamate (PNC) in rats with occlusion-damaged bilateral common carotid arteries. Administration with PNC (5 and 10 mg/kg/day) for 5 weeks significantly improved the behavioral performance of rats with vascular dementia, as showed in the Morris water maze test by shortening the escape latency and latency of crossing, completing more platform crossings, as well as spending more time in the target zone. Further evaluations found that PNC could markedly decrease malondialdehyde levels, enhance superoxide dismutase activity and glutathione levels, and decrease the release of cytochrome c as well as the activities of caspases. Moreover, PNC increased Nrf2 and anti-apoptotic bcl-2 protein expression, while Nox1 and pro-apopotic bax protein expression was decreased. PNC may exert its neuroprotective effects through counteracting oxidative stress and has the potential to treat vascular dementia. PMID- 25808016 TI - Incidence and clinical features of recurrent Vogt-Koyanagi-Harada disease in Japanese individuals. AB - PURPOSE: Our aim was to determine the recurrence rate of inflammation in Vogt Koyanagi-Harada (VKH) disease and to describe its clinical features. METHODS: We retrospectively evaluated patients diagnosed as having VKH disease with exudative retinal detachment at the Osaka University Hospital or the Japanese Community Healthcare Organization, Osaka Hospital, between 1998 and 2012. All patients received high-dose corticosteroid therapy as the initial treatment and were followed for at least 6 months. Demographic data, including age, sex, visual acuity (VA) levels at initial presentation and at 1 year after initial therapy, treatment received, and recurrent episodes were reviewed. RESULTS: Fifty-five consecutive patients with VKH disease were identified (36 women; mean age 38.6 +/ 10.4 years). Fourteen patients (25.5 %) had recurrent inflammation, which manifested as posterior uveitis in eight and as anterior uveitis in six of the patients. Recurrent posterior segment inflammation was more likely to develop in patients whose VA at initial presentation was poor (P = 0.039) and in whom orally administered corticosteroid was tapered rapidly (to 30 mg within 3 weeks or less, to 20 mg within 2 months or less, and to 10 mg within 3 months or less) (P = 0.006, P = 0.066, and P = 0.041, respectively). CONCLUSIONS: About 25 % of patients with VKH disease had recurrent inflammation. Poor initial VA and rapid tapering of the corticosteroid were associated with posterior recurrence. PMID- 25808018 TI - Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients. AB - AIMS: The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics. METHODS: Twenty patients (m/f 15/5, age 25-86 years, body weight 60-121 kg, APACHE II 7-40, estimated glomerular filtration rate 19 157 ml min(-1) , albumin 11.7-30.1 g l(-1) , total bilirubin <0.1-36.1 mg dl(-1) ) treated with intravenous ceftriaxone were recruited from two ICUs. Timed plasma samples were obtained using an opportunistic study protocol. Ceftriaxone concentrations were determined by high-performance liquid chromatography; unbound concentrations were determined after ultrafiltration using a new method which maintains physiological pH and temperature. The pharmacokinetics was described by a one-compartment model, the protein-binding characteristics by Michaelis-Menten kinetics. RESULTS: For total drug, the volume of distribution was 20.2 l (median; interquartile range 15.6-24.5 l), the half-life 14.5 h (10.0-25.5 h) and the clearance 0.96 l h(-1) (0.55-1.28 l h(-1) ). The clearance of unbound drug was 1.91 l h(-1) (1.46-6.20 l h(-1) ) and linearly correlated with estimated glomerular filtration rate (slope 0.85, y-intercept 0.24 l h(-1) , r(2) = 0.70). The unbound fraction was higher in ICU patients (33.0%; 20.2-44.5%) than reported in healthy volunteers, particularly when renal impairment or severe hyperbilirubinaemia was present. In all patients, unbound concentrations during treatment with ceftriaxone 2 g once daily remained above the EUCAST susceptibility breakpoint (<=1 mg l(-1) ) throughout the whole dosing interval. CONCLUSIONS: Protein binding of ceftriaxone is reduced and variable in ICU patients due to hypoalbuminaemia, but also to altered binding characteristics. Despite these changes, the pharmacokinetics of unbound ceftriaxone is governed by renal function. For patients with normal or reduced renal function, standard doses are sufficient. PMID- 25808017 TI - Intravitreal injection of melphalan for intraocular retinoblastoma. AB - PURPOSE: To investigate the safety and efficacy of intravitreal injection of melphalan for retinoblastoma. METHODS: A retrospective chart review of all patients who were administered intravitreal injections of melphalan for retinoblastoma between 1990 and 2011. A total of 264 eyes of 250 patients were included. All ocular adverse events, systemic prognosis, ocular prognosis, and visual acuity were investigated. RESULTS: The total number of intravitreal injections administered was 1,067; each eye received between one and 25 injections. A postoperative subconjunctival tumor developed in one eye. None of the eyes suffered infections or uveitis, and all other adverse events including chorioretinal atrophy displayed incidences of less than 1.5 %. At 5 postoperative years, the cumulative incidence of cataract surgery was 3.1 % among the eyes that were treated without ocular hyperthermia. Distant metastasis or intracranial invasion occurred in 11 patients, all of whom had high-risk pathological factors for metastasis such as optic nerve invasion, but refused to receive adjuvant chemotherapy. Sixty-eight percent of the eyes achieved complete vitreous seed remission, but recurrence occurred in 19 % of these eyes after 10.0 +/- 4.9 months. In addition, 47 and 27 % of the eyes without primary macular tumors retained visual acuity of >0.5 and >1.0, respectively. CONCLUSIONS: The risk of extraocular tumor spreading following intravitreal injections is low, and other adverse events are rare. Sixty-eight percent of the treated eyes achieved complete vitreous seed remission, and about half of them retained practical levels of vision. The intravitreal injection of melphalan is a safe and effective treatment for vitreous seeds. PMID- 25808021 TI - Looking, and thinking, about your genome like real estate: location, location, location. PMID- 25808019 TI - Acute kidney injury is associated with bronchopulmonary dysplasia/mortality in premature infants. AB - BACKGROUND: Acute kidney injury (AKI) impairs electrolyte balance, alters fluid homeostasis and decreases toxin excretion. More recent data suggest it also affects the physiology of distant organs. METHODS: We performed a prospective cohort study which invloved 122 premature infants [birth weight (BW) <=1200 g and/or gestational age (GA) <31 weeks] to determine relationships between AKI and bronchopulmonary dysplasia (BPD)/mortality. Days until oxygen discontinuation was compared between those with and without AKI in survivors who received oxygen for >=24 h. RESULTS: Acute kidney disease, defined by a rise in serum creatinine (SCr) of >=0.3 mg/dl or an increase in SCr of >=150%, occurred in 36/122 (30%) of the premature infants. Those with AKI had a 70% higher risk of oxygen requirement or of dying at 28 days of life [relative risk (RR) 1.71, 95% confidence interval (CI) 1.22-2.39; p < 0.002]. This association remained after controlling for GA, pre-eclampsia, 5 min Apgar score and percentage maximum weight change (max % weight Delta) in the first 4 days (RR 1.45, 95% CI 1.07-1.97); p < 0.02). Similar findings were noted for receipt of mechanical ventilation/death by day 28 (adjusted RR 1.53, 95% CI 1.05-2.22; p < 0.03). Those without AKI were 2.5-fold more likely to come off oxygen [hazard ratio (HR) 1.3-5; p < 0.02) than those with AKI, even when controlling for GA, pre-eclampsia, 5 min Apgar and max % weight Delta (multivariate HR 2.0, 95% CI 0.9-4.0; p < 0.06). CONCLUSIONS: In premature infants, AKI is associated with BPD/mortality. As AKI could lead to altered lung physiology, interventions to ameliorate AKI could improve long-term BPD. PMID- 25808020 TI - Can apoptosis and necrosis coexist in ejaculated human spermatozoa during in vitro semen bacterial infection? AB - PURPOSE: To evaluate whether ejaculated human spermatozoa undergo complete apoptosis or necrosis during experimental semen bacterial infection in vitro. METHODS: Apoptotic markers, including mitochondrial transmembrane potential (DeltaPsim), phosphatidylserine (PS) externalization, and DNA fragmentation, have been detected simultaneously in ejaculated human sperm after their incubation with a known pathogenic (Escherichia coli), as well as with conditionally pathogenic bacterial strains (Staphylococcus haemolyticus, Bacteroides ureolyticus) and/or leukocytes. The DeltaPsim and translocation of PS was evaluated using the JC-1 and Annexin V binding tests, respectively. A modified TUNEL assay with additional staining for sperm viability was used to detect the DNA fragmentation level. RESULTS: The exposure of ejaculated spermatozoa to bacterial strains was associated with a simultaneous decrease in the percentage of sperm with normal DeltaPsim and an increase in the proportion of Annexin V positive sperm. Additionally, in the presence of S. haemolyticus, B. ureolyticus and/or leukocytes, a significant increase in the percentage of live TUNEL positive (apoptotic) as well as dead TUNEL-positive (necrotic) sperm cells was also observed. CONCLUSIONS: The cellular death observed in spermatozoa in the presence of inflammatory mediators may be due to both apoptosis and necrosis. Here, we demonstrate for the first time that direct contact of conditionally pathogenic bacteria with ejaculated human sperm may play an even greater role in the promotion of apoptosis than in case of some pathogenic bacterial strains. These findings suggest that significant bacteriospermia and leukocytospermia may be direct causes of subfertility or additional negative factors worsening the prognosis of fertility in natural and assisted procreation. PMID- 25808022 TI - Diffusion of childbearing within cohabitation. AB - The article analyzes the diffusion of childbearing within cohabitation in Norway, using municipality data over a 24-year period (1988-2011). Research has found substantial spatial heterogeneity in this phenomenon but also substantial spatial correlation, and the prevalence of childbearing within cohabitation has increased significantly over time. We consider several theoretical perspectives and implement a spatial panel model that allows accounting for autocorrelation not only on the dependent variable but also on key explanatory variables, and hence identifies the key determinants of diffusion of childbearing within cohabitation across space and over time. We find only partial support for the second demographic transition as a theory able to explain the diffusion of childbearing within cohabitation. Our results show that at least in the first phase of the diffusion (1988-1997), economic difficulties as measured by increased unemployment among men contributed to the diffusion of childbearing within cohabitation. However, the most important driver for childbearing within cohabitation is expansion in education for women. PMID- 25808023 TI - Understanding Disease-Drug Interactions in Cancer Patients: Implications for Dosing Within the Therapeutic Window. AB - The human inflammatory response can result in the alteration of drug clearance through effects on metabolizing enzymes or transporters. In this article we briefly review the theory of how cancer can lead to indirect changes in drug metabolism, review acute phase proteins and cytokines as markers of changes in cytochrome P450 (CYP) activity in cancer patients, and provide clinical case examples of how the inflammation in advanced cancer patients can lead to altered CYP-mediated drug clearance. PMID- 25808024 TI - Melatonin regulates the autophagic flux via activation of alpha-7 nicotinic acetylcholine receptors. AB - Our previous study suggested that melatonin-mediated neuroprotective effects are related with the activation of autophagy. However, the mechanism of melatonin mediated autophagic activation in prion-mediated mitochondrial damage is not reported. Alpha-7 nicotinic acetylcholine receptors (alpha7nAchR) is a member of nicotinic acetylcholine receptors, and alpha7nAchR activation regulates via melatonin. Thus, we hypothesized that melatonin-mediated neuroprotective effect related with to autophagy pathway as a result of alpha7nAchR regulation. Inactivation of alpha7nAchR inhibited melatonin-mediated autophagic activation and protective effect against prion-mediated mitochondrial neurotoxicity. Also, knockdown of ATG5 blocked the melatonin-mediated neuroprotection and did not influence to the activation of alpha7nAchR caused by melatonin. This report is the first study demonstrating that melatonin-mediated autophagic activation regulates via modulation of alpha7nAchR signals, and upregulation of alpha7nAchR signals induced by melatonin plays a pivotal role in neuroprotection of prion mediated mitochondrial neurotoxicity. Our results suggested that regulator of alpha7 nAChR signals including melatonin may have used for neuroprotective strategies for the neurodegenerative disorders including prion diseases. PMID- 25808025 TI - Exhalation pattern changes during fasting and low dose glucose treatment in rats. AB - The analysis of exhaled metabolites has become a promising field of research in recent decades. Several volatile organic compounds reflecting metabolic disturbance and nutrition status have even been reported. These are particularly important for long-term measurements, as needed in medical research for detection of disease progression and therapeutic efficacy. In this context, it has become urgent to investigate the effect of fasting and glucose treatment for breath analysis. In the present study, we used a model of ventilated rats that fasted for 12 h prior to the experiment. Ten rats per group were randomly assigned for continuous intravenous infusion without glucose or an infusion including 25 mg glucose per 100 g per hour during an observation period of 12 h. Exhaled gas was analysed using multicapillary column ion-mobility spectrometry. Analytes were identified by the BS-MCC/IMS database (version 1209; B & S Analytik, Dortmund, Germany). Glucose infusion led to a significant increase in blood glucose levels (p < 0.05 at 4 h and thereafter) and cardiac output (p < 0.05 at 4 h and thereafter). During the observation period, 39 peaks were found collectively. There were significant differences between groups in the concentration of ten volatile organic compounds: p < 0.001 at 4 h and thereafter for isoprene, cyclohexanone, acetone, p-cymol, 2-hexanone, phenylacetylene, and one unknown compound, and p < 0.001 at 8 h and thereafter for 1-pentanol, 1-propanol, and 2 heptanol. Our results indicate that for long-term measurement, fasting and the withholding of glucose could contribute to changes of volatile metabolites in exhaled air. PMID- 25808026 TI - Molecular encryption and reconfiguration for remodeling of dynamic hydrogels. AB - Dynamic materials have been widely studied for regulation of cell adhesion that is important to a variety of biological and biomedical applications. These materials can undergo changes mainly through one of the two mechanisms: ligand release in response to chemical, physical, or biological stimuli, and ligand burial in response to mechanical stretching or the change of electrical potential. This study demonstrates an encrypted ligand and a new hydrogel that are capable of inducing and inhibiting cell adhesion, which is controlled by molecular reconfiguration. The ligand initially exhibits an inert state; it can be reconfigured into active and inert states by using unblocking and recovering molecules in physiological conditions. Since molecular reconfiguration does not require the release of the ligand from the hydrogels, inhibiting and inducing cell adhesion on the hydrogels can be repeated for multiple cycles. PMID- 25808027 TI - Experimental Infection of Domestic Pigs with African Swine Fever Virus Lithuania 2014 Genotype II Field Isolate. AB - An experimental infection was conducted to evaluate horizontal transmission, clinical, virological and humoral response induced in domestic pigs infected with African swine fever (ASF) genotype II virus circulating in 2014 into the European Union (EU). Ten naive pigs were placed in contact with eight pigs experimentally inoculated with the Lithuanian LT14/1490 ASF virus (ASFV) responsible for the first ASF case detected in wild boar in Lithuania in January 2014. Clinical examination and rectal temperature were recorded each day. Blood sampling from every animal was carried out twice weekly. Blood samples were examined for presence of ASF virus-specific antibodies and for determining the ASFV viral load. From the obtained results, it was concluded that the Lithuanian ASFV induced an acute disease which resulted in 94, 5% mortality. The disease was easily detected by real-time PCR prior to the onset of clinical signs and 33% of the animals seroconverted. All findings were in accordance with observations previously made in domestic pigs and wild boar when infected with ASF genotype II viruses characterized by a high virulence. One in-contact pig remained asymptomatic and survived the infection. The role of such animals in virus transmission would need further investigation. PMID- 25808028 TI - Rates of climatic niche evolution are correlated with species richness in a large and ecologically diverse radiation of songbirds. AB - By employing a recently inferred phylogeny and museum occurrence records, we examine the relationship of ecological niche evolution to diversification in the largest family of songbirds, the tanagers (Thraupidae). We test whether differences in species numbers in the major clades of tanagers can be explained by differences in rate of climatic niche evolution. We develop a methodological pipeline to process and filter occurrence records. We find that, of the ecological variables examined, clade richness is higher in clades with higher climatic niche rate, and that this rate is also greater for clades that occupy a greater extent of climatic space. Additionally, we find that more speciose clades contain species with narrower niche breadths, suggesting that clades in which species are more successful at diversifying across climatic gradients have greater potential for speciation or are more buffered from the risk of extinction. PMID- 25808031 TI - Erratum to: A Stable Human-Cell System Overexpressing Cystic Fibrosis Transmembrane Conductance Regulator Recombinant Protein at the Cell Surface. PMID- 25808032 TI - Critical Role of a Loop at C-Terminal Domain on the Conformational Stability and Catalytic Efficiency of Chondroitinase ABC I. AB - We used a combination of protein engineering and spectroscopic methods to investigate the effect of a long length loop on the conformational stability and activity of chondroitinase ABC I. This study involves manipulation of interactions around Asp(689) as a key residue in the central region of the loop containing residues 681-695 located at C-terminal domain of the enzyme. According to the equilibrium unfolding experiments and considering thermodynamic m value and DeltaG(H2O), we found that the folded state of H700N, L701T, and H700N/L701T are more compact relative to the folded state of wild-type protein and they become stabilized upon mutation. However, the compactness and stability of other variants are less than those of wild-type protein. According to enzyme activity measurements, we found that the catalytic efficiency of structurally stabilized variants is decreased, while that of destabilized mutants is improved. PMID- 25808033 TI - Myocardial metabolism in diabetic cardiomyopathy: potential therapeutic targets. AB - SIGNIFICANCE: Cardiovascular complications in diabetes are particularly serious and represent the primary cause of morbidity and mortality in diabetic patients. Despite early observations of cardiac dysfunction in diabetic humans, cardiomyopathy unique to diabetes has only recently been recognized. RECENT ADVANCES: Research has focused on understanding the pathogenic mechanisms underlying the initiation and development of diabetic cardiomyopathy. Emerging data highlight the importance of altered mitochondrial function as a major contributor to cardiac dysfunction in diabetes. Mitochondrial dysfunction occurs by several mechanisms involving altered cardiac substrate metabolism, lipotoxicity, impaired cardiac insulin and glucose homeostasis, impaired cellular and mitochondrial calcium handling, oxidative stress, and mitochondrial uncoupling. CRITICAL ISSUES: Currently, treatment is not specifically tailored for diabetic patients with cardiac dysfunction. Given the multifactorial development and progression of diabetic cardiomyopathy, traditional treatments such as anti-diabetic agents, as well as cellular and mitochondrial fatty acid uptake inhibitors aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose may not adequately target all aspects of this condition. Thus, an alternative treatment such as resveratrol, which targets multiple facets of diabetes, may represent a safe and promising supplement to currently recommended clinical therapy and lifestyle changes. FUTURE DIRECTIONS: Elucidation of the mechanisms underlying the initiation and progression of diabetic cardiomyopathy is essential for development of effective and targeted treatment strategies. Of particular interest is the investigation of alternative therapies such as resveratrol, which can function as both preventative and mitigating agents in the management of diabetic cardiomyopathy. PMID- 25808034 TI - Intramembranous bone regeneration differs among common inbred mouse strains following marrow ablation. AB - Various intact and post-injury bone phenotypes are heritable traits. In this study, we sought to determine if intramembranous bone regeneration following marrow ablation differed among common inbred mouse strains and to identify how early the differences appear. We found a ~four-fold difference in the regenerated bone volume 21 days after marrow ablation in females from four inbred mouse strains: FVB/N (15.7 +/- 8.1%, mean and standard deviation), C3H/He (15.5 +/- 4.2%), C57BL/6 (12.2 +/- 5.2%), and BALB/c (4.0 +/- 4.4%); with BALB/c different from FVB/N (p = 0.007) and C3H/He (p = 0.002). A second experiment showed that FVB/N compared to BALB/c mice had more regenerated bone 7 and 14 days after ablation (p < 0.001), while at 21 days FVB/N mice had a greater fraction of mineralizing surface (p = 0.008) without a difference in mineral apposition rate. Thus, differences among strains are evident early during intramembranous bone regeneration following marrow ablation and appear to be associated with differences in osteogenic cell recruitment, but not osteoblast activity. The amount of regenerating bone was not correlated with other heritable traits such as the intact bone phenotype or soft tissue wound healing, suggesting that there may be independent genetic pathways for these traits. PMID- 25808035 TI - Small carcinomas involving less than one-quarter of the rectal circumference: local excision is still associated with a high risk of nodal positivity. AB - AIM: A study was carried out to determine the relationship between mesorectal lymph nodal involvement and T stage in a group of patients with a rectal cancer involving less than one-quarter of the rectal circumference, such as might be selected for local excision. METHOD: The data of patients having rectal resection between 2010 and 2014 were prospectively entered in a rectal carcinoma registry. A model for describing tumours involving less than one quadrant of the rectal circumference was created to facilitate the evaluation process. RESULTS: In all, 304 patients were included in the study. In 68 (22.4%) a small tumour (< 1 quadrant involved) was found. Of these, 26.5% had positive mesorectal lymph nodes (N+). In lesions of Stage ypT0 cancer 12.5% patients were node positive, in Stage Tis and T1 tumours there was no case of node positivity, but in Stage T2 and Stage T3 cancers the incidence of node positivity was 27.5% and 64%. CONCLUSION: The study demonstrated that, even for small tumours involving only one rectal quadrant, the risk of lymph nodal involvement was about 25%. Had the patients undergone local excision the treatment would have been incomplete. PMID- 25808036 TI - Geometric complexity is increased in in vitro activated platelets. AB - This article investigates the use of computerized fractal analysis for objective characterization of the complexity of platelets in vitro stimulated by low level thrombin (0.02 U mL(-1) ), collected from healthy individuals and observed by means of transmission electron microscopy. Platelet boundaries were extracted by means of automatically image analysis. Local fractal dimension was evaluated by the box-counting technique (measure of geometric complexity of the platelet outline). The results showed that the platelet boundary is fractal when observed by transmission electron microscopy and that, after an in vitro platelet activation test, the shape of platelets present increased geometric complexity in comparison to the no stimulated platelets (P < 0.001), with 100% correct classification. Computerized fractal analysis of platelet shape by transmission electron microscopy can provide accurate, quantitative, data to study platelet activation. The results may play important roles in the evaluation of the platelets status in pathological conditions, like as atherosclerosis and diabetes mellitus, where in in vivo activated platelets have been described. PMID- 25808038 TI - Dose effect on the uptake and accumulation of hydroxytyrosol and its metabolites in target tissues in rats. AB - Hydroxytyrosol (HT) is the most prominent phenolic compound of virgin olive oil and due to its scientifically validated biological activities it is entering to the market as a potentially useful supplement for cardiovascular disease prevention. The aim of the present study was to investigate the relationship between the HT dose intake and its tissue uptake in rats, and thus, providing complementary information in relation to the target-dose relationship. Rats were given a refined olive oil enriched with HT at different doses (1, 10, and 100 mg/kg) and they were sacrificed after 5 h to ensure the cell tissue uptake of HT and its metabolites. Plasma samples and different organs as liver, kidney, heart and brain were obtained, and HT metabolites were analyzed by UPLC-MS/MS. The results showed that HT and its metabolites could be accumulated in a dose dependent manner basically in the liver, kidney, and brain and were detected in these tissues even at nutritionally relevant human doses. The detection of free HT in liver and kidney was noteworthy. To date, this appears to be the only biologically active form, and thus, it provides relevant information for optimizing the potential applications of HT to prevent certain hepatic and renal diseases. In recent years, HT and its derivatives have led to a great interest from the virgin olive oil producers and manufacturers of nutraceutical supplements. The increasing interest in HT is mainly due to the European Food Safety Agency (EFSA) Panel on Dietetic Products, Nutrition, and Allergies (NDA) scientific opinion that established a cause-and-effect relationship between the consumption of olive oil polyphenols and protection of LDL particles from oxidative damage . Based on this positive opinion, the health claim "Olive oil polyphenols contribute to the protection of blood lipids from oxidative stress" was included in the list of health claims , being the only authorized health claim in the European Union regarding polyphenols and health. PMID- 25808039 TI - Genital melanocytic naevus on lichen sclerosus: an uncommon occurrence and a management proposal. AB - BACKGROUND: Melanocytic naevi located in special sites, such as the vulvar mucosa might present peculiar clinical and dermatoscopic features. OBJECTIVES: We describe a management proposal of a genital naevus associated with inflammatory disorders that aims to facilitate the clinical and pathologic diagnosis. METHODS: Videodermoscopy of a genital naevus associated with lichen sclerosus of an 8-year old girl, was carried out before and 2 months after treatment with topical steroids. An excisional biopsy and immunohistochemical studies with HMB-45, MART 1 and molecular studies with p 16 staining were performed. RESULTS: The features of the melanocytic lesion associated with lichen sclerosus were troublesome on the basis of clinical and videodermoscopic evaluation. Histopathologic and immunohistochemical examination performed after topical treatment, showed a compound melanocytic naevus with an underlying inflammation consistent with lichen sclerosus. CONCLUSIONS: The evaluation of genital naevi should take into account the presence of inflammatory disorders, not uncommon in such location. Treatment of the latter and short follow-up of the patients, can avoid over diagnosis of malignancies and extensive surgical procedures. PMID- 25808040 TI - Ling et al.'s 'Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder'. PMID- 25808041 TI - Directing the deformation paths of soft metamaterials with prescribed asymmetric units. AB - By prescribing asymmetric ligaments with different arrangements in elastomeric porous membranes of pre-twisted kagome lattices, the buckling instability is avoided, allowing for smooth and homogenous structural reconfiguration in a deterministic fashion. The stress-strain behaviors and negative Poisson's ratios can be tuned by the pre-twisting angles. PMID- 25808042 TI - Relationship Between Short-Term Blood Pressure Variability and Subclinical Renal Damage in Essential Hypertensive Patients. AB - The authors aimed to analyze the relationship between subclinical renal damage, defined as the presence of microalbuminuria or an estimated glomerular filtration rate (eGFR) between 30 mL/min/1.73 m(2) and 60 mL/min/1.73 m(2) and short-term blood pressure (BP) variability, assessed as average real variability (ARV), weighted standard deviation (SD) of 24-hour BP, and SD of daytime and nighttime BP. A total of 328 hypertensive patients underwent 24-hour ambulatory BP monitoring, 24-hour albumin excretion rate determination, and eGFR calculation using the Chronic Kidney Disease Epidemiology Collaboration equation. ARV of 24 hour systolic BP (SBP) was significantly higher in patients with subclinical renal damage (P=.001). This association held (P=.04) after adjustment for potential confounders. In patients with microalbuminuria, ARV of 24-hour SBP, weighted SD of 24-hour SBP, and SD of daytime SBP were also independently and inversely related to eGFR. These results seem to suggest that in essential hypertension, short-term BP variability is independently associated with early renal abnormalities. PMID- 25808043 TI - Association among number, order and type of siblings and adolescent mental health at age 12. AB - BACKGROUND: Although the sibling relationship is a unique one, the effects of the number and type of siblings on mental health among adolescents have not been reported. METHODS: Japanese children (total, 9276; boys, 4654; girls, 4622), all 12 years old, and from the Japanese Toyama Birth Cohort Study, were followed up until 2002. Subject self-reported mental health was obtained from the Japanese version of the Dartmouth Primary Care Co-operative Project (COOP) charts. The associations between number and type of siblings and self-reported mental health were examined. RESULTS: There was a significant difference in mental health between different sibling pairs, with brother pairs and brother/sister pairs having a positive effect on adolescent mental health, compared with those in sister pairs. Girls with brothers had better self-reported mental health than those without. The adjusted OR of good mental health was 1.44 (95%CI:1.00-2.08) for those with an older brother and 1.67 (95%CI: 1.17-2.38) for those with a younger brother compared with those without. Boys with a younger sister had a higher OR of good self-reported health than those without (OR, 1.62; 95%CI: 1.08 2.43). CONCLUSIONS: Children with siblings had better mental health status than those without, which has practical implications for Asian countries and worldwide considering the declining fertility. PMID- 25808044 TI - The development of a virtual 3D model of the renal corpuscle from serial histological sections for E-learning environments. AB - Histology is a core subject in the anatomical sciences where learners are challenged to interpret two-dimensional (2D) information (gained from histological sections) to extrapolate and understand the three-dimensional (3D) morphology of cells, tissues, and organs. In gross anatomical education 3D models and learning tools have been associated with improved learning outcomes, but similar tools have not been created for histology education to visualize complex cellular structure-function relationships. This study outlines steps in creating a virtual 3D model of the renal corpuscle from serial, semi-thin, histological sections obtained from epoxy resin-embedded kidney tissue. The virtual renal corpuscle model was generated by digital segmentation to identify: Bowman's capsule, nuclei of epithelial cells in the parietal capsule, afferent arteriole, efferent arteriole, proximal convoluted tubule, distal convoluted tubule, glomerular capillaries, podocyte nuclei, nuclei of extraglomerular mesangial cells, nuclei of epithelial cells of the macula densa in the distal convoluted tubule. In addition to the imported images of the original sections the software generates, and allows for visualization of, images of virtual sections generated in any desired orientation, thus serving as a "virtual microtome". These sections can be viewed separately or with the 3D model in transparency. This approach allows for the development of interactive e-learning tools designed to enhance histology education of microscopic structures with complex cellular interrelationships. Future studies will focus on testing the efficacy of interactive virtual 3D models for histology education. PMID- 25808045 TI - Non-enzymatic Glycation of Almond Cystatin Leads to Conformational Changes and Altered Activity. AB - The non-enzymatic reaction between proteins and reducing sugars, known as glycation, leads to the formation of inter and intramolecular cross-links of proteins. Stable end products called as advanced Maillard products or advanced glycation end products (AGEs) have received tremendous attention since last decades. It was suggested that the formation of AGEs not only modify the conformation of proteins but also induces altered biological activity. In this study, cystatin purified from almond was incubated with three different sugars namely D-ribose, fructose and lactose to monitor the glycation process. Structural changes induced in cystatin on glycation were studied using UV-visible spectroscopy, fluorescence spectroscopy, CD and FTIR techniques. Glycated cystatin was found to migrate slower on electrophoresis as compared to control cystatin. Biological activity data of glycated cystatin showed that D-ribose was most effective in inducing conformational changes with maximum altered activity. PMID- 25808047 TI - Construct of Dialysis Employee Satisfaction: Acquiring Satisfaction Factors and Their Contributions. AB - We developed a construct of dialysis employees' satisfaction as an assessment framework and identified the crucial factors that contribute to overall job satisfaction. We also seek to capture some important characteristics of dialysis professionals' job satisfaction/dissatisfaction in Japan. A questionnaire was developed, including 35 facet-specific job-related satisfaction and 10 general satisfaction items in closed-ended questions. A questionnaire-based survey was conducted between August and October 2013. A total of 799 valid responses (87% of response rate) were collected from 46 physicians, 470 nurses and 251 technologists in the dialysis department of 43 facilities in Japan. Five satisfaction factors were derived by applying principal component analysis with 61% of cumulative variance accounted for. Physicians, nurses and technologists in the dialysis department shared a similar trend of job satisfaction that they were more satisfied with leadership, and communication and teamwork among the five factors, whereas their satisfaction level was relatively low with salary and welfare conditions. Physicians expressed the strongest satisfaction with any factor while nurses were the least satisfied. Nurses' and technologists' overall job satisfaction was mostly determined by satisfaction with self-actualization, and work demands and workload. A five-factor construct of dialysis employee satisfaction was identified. Overall job satisfaction of dialysis nurses and technologists were not overly high in Japan, and this seems to be caused by their relatively low satisfaction with self-actualization and with work demands and workload. Therefore, it is suggested that their work conditions and environment must be improved to support their self-actualization and to reduce their workload. PMID- 25808046 TI - A reliable model for gamma oscillations in hippocampal tissue. AB - Gamma oscillations (30-100 Hz) reflect a fast brain rhythm that provides a fundamental mechanism of complex neuronal information processing in the hippocampus and in the neocortex in vivo. Gamma oscillations have been implicated in higher brain functions, such as sensory perception, motor activity, and memory formation. Experimental studies on synaptic transmission and bioenergetics underlying gamma oscillations have primarily used acute slices of the hippocampus. This study tests whether organotypic hippocampal slice cultures of the rat provide an alternative model for cortical gamma oscillations in vitro. Our findings are that 1) slice cultures feature well-preserved laminated architecture and neuronal morphology; 2) slice cultures of different maturation stages (7-28 days in vitro) reliably express gamma oscillations at about 40 Hz as induced by cholinergic (acetylcholine) or glutamatergic (kainate) receptor agonists; 3) the peak frequency of gamma oscillations depends on the temperature, with an increase of ~ 3.5 Hz per degree Celsius for the range of 28-36 degrees C; 4) most slice cultures show persistent gamma oscillations for ~ 1 hr during electrophysiological local field potential recordings, and later alterations may occur; and 5) in slice cultures, glucose at a concentration of 5 mM in the recording solution is sufficient to power gamma oscillations, and additional energy substrate supply with monocarboxylate metabolite lactate (2 mM) exclusively increases the peak frequency by ~ 4 Hz. This study shows that organotypic hippocampal slice cultures provide a reliable model to study agonist induced gamma oscillations at glucose levels near the physiological range. PMID- 25808048 TI - Endoscopic band ligation with double-balloon endoscopy for treatment of jejunal Dieulafoy's lesion. PMID- 25808049 TI - Inpatient treatment has no impact on the core thoughts and perceptions in adolescents with anorexia nervosa. AB - AIM: Examine changes in core perceptions and thoughts during the weight restoration phase of inpatient treatment for adolescents with anorexia nervosa. METHOD: Forty-four adolescents with anorexia nervosa consecutively admitted (2009 2012) to an inpatient paediatric-psychiatric unit specializing in eating disorders. The programme consisted of a complete inpatient intervention combining weight restoration by structured supervised meals with individual and group cognitive-behavioural therapy, parental training/family intervention and educational activities, followed by a half-way day-treatment weight-stabilizing phase and progressive reintroduction to the community. The study focused on changes from hospital admission to discharge in patients' responses to self report questionnaires on eating disorder symptoms, depression, anxiety and suicidal ideation. RESULTS: No significant changes in core anorexic thoughts and perceptions as Body dissatisfaction, Drive for thinness, Weight concern and Shape concern were noted. However, a reduction in the general severity of eating disorder symptoms (including Restraint and Eating concern) was observed, mainly related to the treatment structure. Levels of depression significantly decreased but remained within pathological range. We also found a concerning increase in suicidal ideation not correlated with a concomitant increase in depressive symptomatology. CONCLUSIONS: Inpatient treatment of anorexia nervosa in adolescents does not significantly modify core anorexic thoughts and perceptions. This may explain the high relapse rates. Changes in core beliefs may be crucial for recovery and prevention of relapse in anorexia nervosa at this critical age. This study may have clinical implications for the development of better treatment strategies to target the gap between disturbed thoughts and distorted perceptions - the core aspects of anorexia nervosa and physical recovery during and after the weight restoration phase. PMID- 25808050 TI - Clinical and quality evaluation of apheresis vs random-donor platelet concentrates stored for 7 days. AB - BACKGROUND AND OBJECTIVES: The clinical efficacy of different types of platelets remains under debate. We conducted a pilot study to prospectively evaluate the impact of subsequent storage on the in vitro quality and post-transfusion outcome of apheresis prepared platelets (APCs) vs random donor platelets (RDPs). MATERIALS AND METHODS: We studied 30 units of APCs, and 30 units of RDPs. We performed assays on days 1, 3, 5 and 7, evaluating ADP aggregation, platelet count and pH. Fifteen thrombocytopenic patients with haematologic conditions were evaluated. Each patient received prophylactic transfusions of both components, and their post-transfusion platelet increments were compared. Twenty-five transfusions were apheresis prepared, and 35 transfusions were received as RDPs. None of the RDPs were leukoreduced. RESULTS: The median platelet counts for APCs on days 1, 3, 5 and 7 were; 2070, 1990, 1680 and 1240 * 10(3) uL(-1) , respectively, and were; 1290, 850, 499 and 284 * 10(3) uL(-1) , respectively for RDPs. The pH of all units was more than 6.2. Both groups demonstrated a significant decrease of ADP aggregation after 3 days of storage (P < 0.05). However, APCs provided satisfactory increments for 90.9% of transfusions. On the sixth and seventh days of storage, APCs provided significantly higher platelet increments (18.7 * 10(3) uL(-1) ) compared with RDPs (3.20 * 10(3) uL(-1) ) (P < 0.05). Significantly longer transfusion intervals were also achieved with APCs (P < 0.05). CONCLUSION: Although other variables may have confounded the results, subsequent storage of APCs appeared to provide higher increments with longer intervals of transfusion compared with RDPs. Future prospective studies are needed, adjusting for other possible confounding variables. PMID- 25808051 TI - Proficiency and Linguistic Complexity Influence Speech Motor Control and Performance in Spanish Language Learners. AB - PURPOSE: Second-language (L2) production requires greater cognitive resources to inhibit the native language and to retrieve less robust lexical representations. The current investigation identifies how proficiency and linguistic complexity, specifically syntactic and lexical factors, influence speech motor control and performance. METHOD: Speech movements of 29 native English speakers with low or high proficiency in Spanish were recorded while producing simple and syntactically complex sentences in English and Spanish. Sentences were loaded with cognate (e.g., baby-bebe) or noncognate (e.g., dog-perro) words. Effects of proficiency, lexicality (cognate vs. noncognate), and syntactic complexity on maximum speed, range of movement, duration, and speech movement variability were examined. RESULTS: In general, speakers with lower L2 proficiency differed in their speech motor control and performance from speakers with higher L2 proficiency. Speakers with higher L2 proficiency generally had less speech movement variability, shorter phrase durations, greater maximum speeds, and greater ranges of movement. In addition, lexicality and syntactic complexity affected speech motor control and performance. CONCLUSIONS: L2 proficiency, lexicality, and syntactic complexity influence speech motor control and performance in adult L2 learners. Information about relationships between speech motor control, language proficiency, and cognitive-linguistic demands may be used to assess and treat bilingual clients and language learners. PMID- 25808052 TI - Cognitive Frailty: A Systematic Review of Epidemiological and Neurobiological Evidence of an Age-Related Clinical Condition. AB - Advancing age is the focus of recent studies on familial and sporadic Alzheimer's disease (AD), suggesting a prolonged pre-clinical phase several decades before the onset of dementia symptoms. Influencing some age-related conditions, such as frailty, may have an impact on the prevention of late-life cognitive disorders. Frailty reflects a nonspecific state of vulnerability and a multi-system physiological change with increased risk for adverse health outcomes in older age. In this systematic review, frailty indexes based on a deficit accumulation model were associated with late life cognitive impairment and decline, incident dementia, and AD. Physical frailty constructs were associated with late-life cognitive impairment and decline, incident AD and mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology in older persons with and without dementia, thus also proposing cognitive frailty as a new clinical condition with co-existing physical frailty and cognitive impairment in non demented older subjects. Considering both physical frailty and cognitive impairment as a single complex phenotype may be central in the prevention of dementia and its subtypes with secondary preventive trials on cognitive frail older subjects. The mechanisms underlying the cognitive-frailty link are multi factorial, and vascular, inflammatory, nutritional, and metabolic influences may be of major relevance. There is a critical need for randomized controlled trials of intervention investigating the role of nutrition and/or physical exercise on cognitive frail subjects with the progression to dementia as primary outcome. These preventive trials and larger longitudinal population-based studies targeting cognitive outcomes could be useful in further understanding the cognitive-frailty interplay in older age. PMID- 25808053 TI - Translating knowledge into best practice care bundles: a pragmatic strategy for EBP implementation via moving postprocedural pain management nursing guidelines into clinical practice. AB - AIMS AND OBJECTIVES: To describe quantitative and qualitative best evidence as sources for practical interventions usable in daily care delivery in order to integrate best evidence into clinical decision-making at local practice settings. To illustrate the development, implementation and evaluation of a pain management nursing care bundle based on a clinical practice guideline via a real-world clinical exemplar. BACKGROUND: Successful implementation of evidence-based practice requires consistent integration of best evidence into daily clinical decision-making. Best evidence comprises high-quality knowledge summarised in systematic reviews and translated into guidelines. However, consistent integration of guidelines into care delivery remains challenging, partly due to guidelines not being in a usable form for daily practice or relevant for the local context. DESIGN: A position paper with a clinical exemplar of a nurse-led, evidence-based quality improvement project to design, implement and evaluate a pain management care bundle translated from a national nursing guideline. METHODS: A pragmatic approach to integrating guidelines into daily practice is presented. Best evidence from a national nursing guideline was translated into a pain management care bundle and integrated into daily practice in 15 medical surgical (med-surg) units of nine hospitals of a large university hospital system in Finland. CONCLUSIONS: Translation of best evidence from guidelines into usable form as care bundles adapted to the local setting may increase implementation and uptake of guidelines and improve quality and consistency of care delivery. RELEVANCE TO CLINICAL PRACTICE: A pragmatic approach to translating a nursing guideline into a pain management care bundle to incorporate best evidence into daily practice may help achieve more consistent and equitable integration of guidelines into care delivery, and better quality of pain management and patient outcomes. PMID- 25808054 TI - Oxide nanomembrane hybrids with enhanced mechano- and thermo-sensitivity for semitransparent epidermal electronics. AB - Oxide nanomembrane hybrids with enhanced mechano- and thermo-sensitivity for semitransparent epidermal electronics are developed. The use of nanomaterials (single wall nanotubes and silver nanoparticles) embedded in the oxide nanomembranes significantly enhances mechanical and thermal sensitivities. These mechanical and thermal sensors are utilized in wheelchair control and hypothermia detection, which are useful for patients with strokes. PMID- 25808055 TI - Health-related quality of life among prescription opioid-dependent patients: Results from a multi-site study. AB - BACKGROUND: Although prescription opioid use disorder has recently increased sharply in the United States, relatively little is known about the general well being of this population. Assessment of quality of life in patients with substance use disorders has been recommended to improve clinical care. OBJECTIVES: Health-related quality of life was examined in prescription opioid dependent patients at entry to a national multi-site clinical trial, to compare quality of life scores in the study sample to other populations; further, background variables associated with quality of life in the literature were examined. METHODS: Prescription opioid-dependent patients (N = 653) were compared to general populations on the Medical Outcome Study Short Form-36 (SF-36) quality of life measure; and the association between patient background variables and quality of life was examined. RESULTS: Compared to a general population, the current sample of prescription opioid-dependent patients had worse physical (-1.7 points, p < .001) and mental quality of life (-12.3 points, p < .001) as measured by the SF-36, similar to other opioid-use disorder populations. Within our sample, women showed more impairment than men in mental quality of life (-4.3 points, p < .001); older patients scored worse on physical (-5.2 points, p < .001), but not mental, quality of life. Chronic pain was associated with poorer physical quality of life (-9.0 points, p < .001). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The growing focus on wellness underscores the importance of measuring quality of life in addition to substance use outcomes. Routine assessment of health-related quality of life can add an important dimension to overall evaluation of patients' treatment response. PMID- 25808057 TI - Improved in vitro human tumor models for cancer gene therapy. AB - Developing effective anticancer treatments is a particular challenge, as agents must contend with not only the target cellular biology, but also with the complex tumor microenvironment. Here we discuss various in vitro strategies that have sought to address this issue, with a particular focus on new methodologies that utilize clinical samples in basic research and their application in gene therapy and virotherapy. PMID- 25808058 TI - Polymorphism in new thienothiophene-thiazolothiazole organic semiconductors. AB - Charge transport in organic semiconductors is heavily influenced by their solid state packing. To separate intermolecular packing effects from molecular electronic effects, we have synthesized two polymorphs of crystalline thienothiophene-thiazolothiazole trimers and studied them by DFT calculations, optical spectroscopy, single-crystal X-ray diffraction and charge-transport measurements in field-effect transistors. One polymorph was found to be a p-type semiconductor with a hole mobility of 3.3*10(-3) cm(2) V(-1) s(-1) , while the other was insulating. The different charge-transport behavior and optical properties of the two polymorphs are strongly related to the topology of their pi stacks. Subtle differences between the polymorphs, including S???S close contacts and bond-length alternation are also discussed for their possible effects on charge transport. PMID- 25808056 TI - Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. AB - OBJECTIVE: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools. METHODS: Because biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays. RESULTS: Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group. INTERPRETATION: The cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS. PMID- 25808060 TI - Relationship between vitamin D status and response to hepatitis C virus therapy. PMID- 25808059 TI - A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS dependent regulation of stress resistance and longevity. AB - Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS. PMID- 25808061 TI - DNA methylation in individuals with anorexia nervosa and in matched normal-eater controls: A genome-wide study. AB - OBJECTIVE: Evidence associates anorexia nervosa (AN) with epigenetic alterations that could contribute to illness risk or entrenchment. We investigated the extent to which AN is associated with a distinct methylation profile compared to that seen in normal-eater women. METHOD: Genome-wide methylation profiles, obtained using DNA from whole blood, were determined in 29 women currently ill with AN (10 with AN-restrictive type, 19 with AN-binge/purge type) and 15 normal-weight, normal-eater control women, using 450 K Illumina bead arrays. RESULTS: Regardless of type, AN patients showed higher and less-variable global methylation patterns than controls. False Discovery Rate corrected comparisons identified 14 probes that were hypermethylated in women with AN relative to levels obtained in normal eater controls, representing genes thought to be associated with histone acetylation, RNA modification, cholesterol storage and lipid transport, and dopamine and glutamate signaling. Age of onset was significantly associated with differential methylation in gene pathways involved in development of the brain and spinal cord, while chronicity of illness was significantly linked to differential methylation in pathways involved with synaptogenesis, neurocognitive deficits, anxiety, altered social functioning, and bowel, kidney, liver and immune function. DISCUSSION: Although pre-existing differences cannot be ruled out, our findings are consistent with the idea of secondary alterations in methylation at genomic regions pertaining to social-emotional impairments and physical sequelae that are commonly seen in AN patients. Further investigation is needed to establish the clinical relevance of the affected genes in AN, and, importantly, reversibility of effects observed with nutritional rehabilitation and treatment. PMID- 25808062 TI - Longitudinal growth and health outcomes in nutritionally at-risk children who received long-term nutritional intervention. AB - BACKGROUND: The benefits of short-term oral nutritional supplementation (ONS) in undernourished children are well-established. The benefits of long-term ONS in promoting longitudinal growth and health in children who are at risk of undernutrition have not been reported previously. METHODS: In this 48-week prospective, single-arm, multicentre trial, 200 Filipino children aged 3-4 years with weight-for-height percentiles from 5th to 25th (WHO Child Growth Standards) were enrolled. Parents received dietary counselling at baseline, and at weeks 4 and 8. Two servings of ONS (450 mL) were consumed daily, providing 450 kcal, 13.5 g protein and micronutrients. Weight, height, dietary intake using 24-h dietary recalls, and physical activity and appetite using the visual analogue scales were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48. The number of sick days for acute illnesses was collected over the study period. RESULTS: At baseline, mean age was 41.2 months with 50% being male. Weight-for-height percentiles showed the greatest increase in the first 4 weeks (12.1 and 12.8 percentiles, respectively, P < 0.0001) and remained significantly higher than baseline (P < 0.0001) but were relatively stable from week 4 onwards. Height-for age percentiles increased steadily over time and became significantly higher than baseline from week 24 onwards (P < 0.0001). Appetite and physical activity scores at all post-baseline visits improved from baseline (P < 0.0001), and a reduction in the number of sick days from week 16 onwards was also observed (P < 0.0001). Higher parental education level, being male and higher baseline weight-for-height percentiles were significantly associated with higher ponderal and linear growth over time in repeated measures analysis of covariance. CONCLUSIONS: Intervention consisting of initial dietary counselling and continued ONS helped sustain normal growth after a catch-up growth in nutritionally at-risk children. PMID- 25808064 TI - Monitoring processing style: to see or not to see. PMID- 25808063 TI - Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. AB - Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored. PMID- 25808065 TI - Properties of serial ultrasound clinical diagnostic pathway in suspected appendicitis and related computed tomography use. AB - OBJECTIVES: The primary objective was to determine the diagnostic accuracy of a serial ultrasound (US) clinical diagnostic pathway to detect appendicitis in children presenting to the emergency department (ED). The secondary objective was to examine the diagnostic performance of the initial and interval US and to compare the accuracy of the pathway to that of the initial US. METHODS: This was a prospective cohort study of 294 previously healthy children 4 to 17 years old with suspected appendicitis and baseline pediatric appendicitis scores of >=2, who were managed with the serial US clinical diagnostic pathway. This pathway consisted of an initial US followed by a clinical reassessment in each patient and an interval US and surgical consultation in patients with equivocal initial US and persistent concern about appendicitis. The USs were interpreted by published criteria as positive, negative, or equivocal for appendicitis. Children in whom this pathway did not rule in or rule out appendicitis underwent computed tomography (CT). Cases with missed appendicitis, negative operations, and CTs after the pathway were considered inaccurate. The primary outcome was the diagnostic accuracy of the serial US clinical diagnostic pathway. The secondary outcomes included the test performance of the initial and interval US imaging studies. RESULTS: Of the 294 study children, 111 (38%) had appendicitis. Using the serial US clinical diagnostic pathway, 274 of 294 children (93%, 95% confidence interval [CI] = 90% to 96%) had diagnostically accurate results: 108 of the 111 (97%) appendicitis cases were successfully identified by the pathway without CT scans (two missed and one CT), and 166 of the 183 (91%) negative cases were ruled out without CT scans (14 negative operations and three CTs). The sensitivity of this pathway was 108 of 111 (97%, 95% CI = 94% to 100%), specificity 166 of 183 (91%, 95% CI = 87% to 95%), positive predictive value 108 of 125 (86%; 95% CI = 79% to 92%), and negative predictive value 166 of 169 (98%, 95% CI = 96% to 100%). The diagnostic accuracy of the pathway was higher than that of the initial US alone (274 of 294 vs. 160 of 294; p < 0.0001). Of 123 patients with equivocal initial US, concern about appendicitis subsided on clinical reassessment in 73 (no surgery and no missed appendicitis). Of 50 children with persistent symptoms, 40 underwent interval US and 10 had surgical consultation alone. The interval US confirmed or ruled out appendicitis in 22 of 40 children (55.0%) with equivocal initial US, with one false-positive interval US. CONCLUSIONS: The serial US clinical diagnostic pathway in suspected appendicitis has an acceptable diagnostic accuracy that is significantly higher than that of the initial US and results in few CT scans. This approach appears most useful in children with equivocal initial US, in whom the majority of negative cases were identified at clinical reassessment and appendicitis was diagnosed by interval US or surgical consultation in most study patients. PMID- 25808066 TI - Transforming the nursing profession in Saudi Arabia. AB - AIM: To discuss the impact of health-care policies and regulations on hospitals' journey towards the Magnet designation in Saudi Arabia. BACKGROUND: Saudi Arabia, like many other countries, faces several challenges in achieving 'the Gold Standard' in nursing practice. Centralised management, the absence of a regulatory professional body, lack of a national benchmarking database and a nursing shortage are all major challenges in advancing nursing practice. KEY ISSUE: The presence of two Magnet-designated hospitals in Saudi Arabia (not affiliated with the Ministry of Health) is an opportunity to explore how this has been achieved within the organisational and professional context. The nursing leaders in the Ministry of Health could be accountable to address the barriers in advancing nursing practice and to raise nursing awareness regarding the adoption of a new culture of excellence. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers in the Ministry of Health hospitals are encouraged to assess the hospitals' readiness to apply for Magnet status. Their readiness must include having a high level of nursing satisfaction and low turnover rate, which goes along with assessing cultural and organisational climates to understand the gaps in work environment and driving evidence of readiness toward achieving Magnet status. CONCLUSION: Health-care policies and regulations, both nationally and globally, can result in several challenges to achieving 'the Gold Standard' in nursing practice. These challenges may not be possible to resolve within an organisational level. Collaborative effort and transformational changes are needed to drive the nursing profession toward the best outcomes for our patients and nurses. PMID- 25808068 TI - Rapid Generation and Safe Use of Carbenes Enabled by a Novel Flow Protocol with In-line IR spectroscopy. AB - A powerful new continuous process for the formation and use of donor/acceptor substituted carbenes is described. The safety profile of diazo group transfer on methyl phenylacetate was determined including kinetic studies in batch and in flow using in-line IR analysis. Batch work-up and liquid chromatography were circumvented by developing an optimized liquid/liquid flow separation method providing aryl diazoacetates in high purity. Fast screening of reaction conditions in flow with in-line IR analysis allowed rapid reaction optimization. Finally, a multistep process of diazo group transfer, extraction, separation and subsequent diazo decomposition combined with multiple X-H insertion reactions was established. PMID- 25808067 TI - Mechanistic investigations of the catalytic formation of lactams from amines and water with liberation of H2. AB - The mechanism of the unique lactam formation from amines and water with concomitant H2 liberation with no added oxidant, catalyzed by a well-defined acridine-based ruthenium pincer complex was investigated in detail by both experiment and DFT calculations. The results show that a dearomatized form of the initial complex is the active catalyst. Furthermore, reversible imine formation was shown to be part of the catalytic cycle. Water is not only the oxygen atom source but also acts as a cocatalyst for the H2 liberation, enabled by conformational flexibility of the acridine-based pincer ligand. PMID- 25808071 TI - Predictive accuracy of single- and multi-slice MRI for the estimation of total visceral adipose tissue in overweight to severely obese patients. AB - The quantification of visceral adipose tissue (VAT) is increasingly being considered for risk assessment and treatment monitoring in obese patients, but is generally time-consuming. The goals of this work were to semi-automatically segment and quantify VAT areas of MRI slices at previously proposed anatomical landmarks and to evaluate their predictive power for whole-abdominal VAT volumes on a relatively large number of patients. One-hundred and ninety-seven overweight to severely obese patients (65 males; body mass index, 33.3 +/- 3.5 kg/m(2); 132 females; body mass index, 34.3 +/- 3.2 kg/m(2)) underwent MRI examination. Total VAT volumes (VVAT-T ) of the abdominopelvic cavity were quantified by retrospective analysis of two-point Dixon MRI data (active-contour segmentation, visual correction and histogram analysis). VVAT-T was then compared with VAT areas determined on one or five slices defined at seven anatomical landmarks (lumbar intervertebral spaces, umbilicus and femoral heads) and corresponding conversion factors were determined. Statistical measures were the coefficients of variation and standard deviations sigma1 and sigma5 of the difference between predicted and measured VAT volumes (Bland-Altman analysis). VVAT-T was 6.0 +/- 2.0 L (2.5-11.2 L) for males and 3.2 +/- 1.4 L (0.9-7.7 L) for females. The analysis of five slices yielded a better agreement than the analysis of single slices, required only a little extra time (4 min versus 2 min) and was substantially faster than whole-abdominal assessment (24 min). Best agreements were found at intervertebral spaces L3-L4 for females (sigma5/1 = 523/608 mL) and L2-L3 for males (sigma5/1 = 613/706 mL). Five-slice VAT volume estimates at the level of lumbar disc L3-L4 for females and L2-L3 for males can be obtained within 4 min and were a reliable predictor for abdominopelvic VAT volume in overweight to severely adipose patients. One-slice estimates took only 2 min and were slightly less accurate. These findings may contribute to the implementation of analytical methods for fast and reliable (routine) estimation of VAT volumes in obese patients. PMID- 25808072 TI - Supramolecular interaction of 18-crown-6 ether with mesalazine and spectrofluorimetric determination of mesalazine in pharmaceutical formulations. AB - The supramolecular interaction of protonated mesalazine (MSZ) and 18-crown-6 ether (18C6) has been examined by Ultraviolet-visible, FT-IR and fluorescence spectroscopy. The formation of the inclusion complex has been confirmed based on the changes of the spectral properties. The MSZ-18C6 host-guest complex formed in (1:1) stoichiometry and the inclusion constant (K = 1.411 * 10(2) L mol(-1)) was ascertained by the typical double reciprocal plots. Furthermore, the thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ) of (MSZ-18C6) were obtained. Based on the remarkable enhancement of the fluorescence intensity of MSZ produced through complex formation, a simple, accurate, rapid and highly sensitive spectrofluorometric method for the determination of MSZ in aqueous solution in the presence of 18C6 was developed. The measurement of relative fluorescence intensity was carried with excitation at 298 nm, emission 410 nm. All variables affecting the reactions were studied and optimized. Beer's law was obeyed in the concentration range of 0.1-0.9 ug/mL. The absorbance was found to increase linearly with increasing concentration of MSZ. The molar absorptivity, Sandell sensitivity, limit of detection (LOD) and limit of quantification (LOQ) were calculated. The validity of the described method was assessed, and the method was successfully applied to the determination of MSZ in its pharmaceutical formulation. In addition, a solid inclusion complex was synthesized by the coprecipitation method. PMID- 25808073 TI - Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers, and fathers. AB - BACKGROUND: The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) gene has been reported to play a critical role in the pathogenesis of neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results are inconclusive. In this study, we performed a meta-analysis in three groups to investigate the association between the MTHFR C677T polymorphism and NTD risk. METHODS: A computer retrieval of PubMed, Cochrane Library, CBM, and Embase for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analyzed with STATA (Version 13.0). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. A test for heterogeneity, a sensitivity analysis, and an assessment of publication bias were performed in our meta-analysis. RESULTS: Forty articles were included in this meta-analysis: 13 studies for Group A: 1329 NTD patients versus 2965 healthy controls; 34 studies for Group B: 3018 mothers with NTD progeny versus 8746 healthy controls; three studies for Group C: 157 fathers with NTD progeny versus 705 healthy controls. The analysis results show: allele contrast in NTD patients: OR = 1.445, 95% CI [1.186, 1.760]; allele contrast in mothers: OR = 1.342, 95% CI [1.166, 1.544]; allele contrast in fathers: OR = 1.062, 95% CI [0.821, 1.374]. CONCLUSION: We found no association between any of the fathers' genotypes and NTDs, whereas a significant correlation between MTHFR C677T polymorphism and NTD risk was found in NTD patients and in their mother. PMID- 25808075 TI - Clinical picture, outcome and predictive factors of lymphoma in Sjogren syndrome. AB - The intrinsic and complex nature of primary Sjogren's syndrome (pSS) makes it difficult to identify risk factors that can predict the development and outcome of non-Hodgkin's lymphoma (NHL), yet patients at high risk for such complication seem to bear certain clinic-serological characteristics that render them a unique profile. In the last decade, research focusing on B-cell hyperactivity as the hallmark of pSS-related lymphoproliferation has shed light on certain biological and molecular factors that participate in disease evolution and lymphoma development, thus indicating possible predictors of lymphoma development and outcome. In this review, we explore all the available data concerning the clinical picture, risk prognostication and outcome of pSS-associated NHLs. PMID- 25808074 TI - Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens. AB - This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412. PMID- 25808076 TI - Transposable elements in cancer and other human diseases. AB - Transposable elements (TEs) are mobile DNA sequences representing a substantial fraction of most genomes. Through the creation of new genes and functions, TEs are important elements of genome plasticity and evolution. However TE insertion in human genomes may be the cause of genetic dysfunction and alteration of gene expression contributing to cancer and other human diseases. Besides the chromosome rearrangements induced by TE repeats, this mini-review shows how gene expression may be altered following TE insertion, for example by the creation of new polyadenylation sites, by the creation of new exons (exonization), by exon skipping and by other modification of alternative splicing, and also by the alteration of regulatory sequences. Through the correlation between TE mobility and the methylation status of DNA, the importance of chromatin regulation is evident in several diseases. Finally this overview ends with a brief presentation of the use of TEs as biotechnology tools for insertional mutagenesis screening and gene therapy with DNA transposons. PMID- 25808077 TI - The Loss of BKV-specific Immunity From Pretransplantation to Posttransplantation Identifies Kidney Transplant Recipients at Increased Risk of BKV Replication. AB - Quantification of BKV-load and BKV-specific immunity have been evaluated to monitor BKV-replication and outcomes in kidney transplant recipients (KTRs) with BKV-infection. However, it remains crucial to better understand how immune markers can predict the risk for later infection. We studied all KTRs between 2008 and 2011. Twenty-four KTRs were diagnosed with BKV-replication and a control group of 127 KTRs was used for comparison. Samples were collected before at +1, +2, and +3 months posttransplantation. BKV-specific and alloreactive T cells were measured using an interferon-gamma Elispot assay. The extent of immunosuppression was quantified by lymphocyte subpopulations and interferon-gamma levels. KTRs with a loss of BKV-specific T cells directed to Large T-antigen from pretransplantation to posttransplantation were at increased risk of BKV replication (p < 0.001). In contrast, KTRs with stable/rising BKV-specific T cells were more likely not to develop BKV-replication (p < 0.05). KTRs developing BKV-replication showed significantly lower CD3+, CD4+, CD8+ T cells and interferon-gamma levels posttransplantation, but significantly higher alloreactive T cells (p < 0.05). Monitoring pretransplant and posttransplant BKV specific T cells is suggested a sensitive marker to identify KTRs at increased risk of BKV-replication. Increased susceptibility to immunosuppression predisposes KTRs to a loss of protective BKV-specific immunity that results in impaired virus control and BKV-replication. PMID- 25808079 TI - Tumor-targeted and immune-targeted monoclonal antibodies: Going from passive to active immunotherapy. AB - Monoclonal antibodies (mAbs) have inaugurated the concepts of tumor-targeted therapy and personalized medicine. A new family of mAbs is currently emerging in the clinic, which target immune cells rather than cancer cells. These immune targeted therapies have recently demonstrated long-term tumor responses in adults with refractory/relapsing metastatic solid tumors. Pediatric cancers are different from their adult counterparts in terms of histological features and immune infiltrates. However, the same immune checkpoint targets can be expressed within the microenvironment of pediatric tumors. The benefits of immune checkpoint blockade in pediatric cancers are currently under evaluation in early phase clinical trials. PMID- 25808078 TI - Trends in the precipitation and crystallization behavior of supersaturated aqueous solutions of poorly water-soluble drugs assessed using synchrotron radiation. AB - Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly soluble compounds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystallization tendency of six structural analogues belonging to the dihydropyridine class, in an aqueous environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy. The crystallization behavior of precipitates generated from supersaturated solutions of the active pharmaceutical ingredients was found to be highly variable ranging from immediate to several hours in the absence of polymers. Polymers with intermediate hydrophilicity/hydrophobicity were found to substantially delay crystallization, whereas strongly hydrophilic or hydrophobic polymers were largely ineffective. Nuclear magnetic resonance spectroscopy experiments supported the supposition that polymers need to have affinity for both the drug-rich precipitate and the aqueous phase in order to be effective crystallization inhibitors. This study highlights the variability in the crystallization tendency of different compounds and provides insight into the mechanism of inhibition by polymeric additives. PMID- 25808080 TI - A case study of bats and white-nose syndrome demonstrating how to model population viability with evolutionary effects. AB - Ecological factors generally affect population viability on rapid time scales. Traditional population viability analyses (PVA) therefore focus on alleviating ecological pressures, discounting potential evolutionary impacts on individual phenotypes. Recent studies of evolutionary rescue (ER) focus on cases in which severe, environmentally induced population bottlenecks trigger a rapid evolutionary response that can potentially reverse demographic threats. ER models have focused on shifting genetics and resulting population recovery, but no one has explored how to incorporate those findings into PVA. We integrated ER into PVA to identify the critical decision interval for evolutionary rescue (DIER) under which targeted conservation action should be applied to buffer populations undergoing ER against extinction from stochastic events and to determine the most appropriate vital rate to target to promote population recovery. We applied this model to little brown bats (Myotis lucifugus) affected by white-nose syndrome (WNS), a fungal disease causing massive declines in several North American bat populations. Under the ER scenario, the model predicted that the DIER period for little brown bats was within 11 years of initial WNS emergence, after which they stabilized at a positive growth rate (lambda = 1.05). By comparing our model results with population trajectories of multiple infected hibernacula across the WNS range, we concluded that ER is a potential explanation of observed little brown bat population trajectories across multiple hibernacula within the affected range. Our approach provides a tool that can be used by all managers to provide testable hypotheses regarding the occurrence of ER in declining populations, suggest empirical studies to better parameterize the population genetics and conservation-relevant vital rates, and identify the DIER period during which management strategies will be most effective for species conservation. PMID- 25808082 TI - Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti T lymphocyte globulin in kidney transplantation from donation after cardiac death: a retrospective cohort study. AB - AIM: To compare the efficacy and safety between rabbit anti-thymocyte globulin (Thymoglobulin) and anti-T lymphocyte globulin (ATG-Fresenius, ATG-F) in donation after cardiac death (DCD) kidney transplantation. METHODS: We retrospectively analyzed 255 cases of DCD kidney transplantation performed at our hospital from February 2007 to October 2013. The patients were divided into two groups based on their induction therapies with Thymoglobulin (n = 188) or ATG-F (n = 67). Clinical data were collected and compared between the two groups. RESULTS: Delayed graft function (DGF) occurred in 36 (19.1%) patients in the Thymoglobulin group versus 17 (25.4%) patients in the ATG-F group (P = 0.281). However, if we subgroup the patients with increased risk factors for DGF, the DGF rate was 9/40 (22.5%) in the Thymoglobulin group versus 9/16 (56.3%) in the ATG-F group (P = 0.015). Duration of DGF was significantly shorter in the Thymoglobulin group (11.7 days vs. 16.1 days). The acute rejection rate was significantly lower in the Thymoglobulin group (9.6% vs. 19.4%, P = 0.035). One-year graft and patient survival were both comparable between the Thymoglobulin and ATG-F groups. The adjusted odds ratio of DGF was 4.283 (1.137-16.13) between the ATG-F and Thymoglobulin groups in patients with increased risk factors for DGF. CONCLUSION: Compared with ATG-F, Thymoglobulin may reduce duration of DGF and acute rejection rate after DCD kidney transplantation. Moreover, Thymoglobulin significantly reduced DGF in patients with increased risk factors for DGF. PMID- 25808081 TI - Early pregnancy maternal vitamin D concentrations and risk of gestational diabetes mellitus. AB - BACKGROUND: While associations of vitamin D deficiency with type 2 diabetes have been well demonstrated, investigations of vitamin D and risk of gestational diabetes mellitus (GDM) reported inconsistent findings. We examined associations of vitamin D status with GDM. METHODS: In a nested case-cohort study (135 GDM cases and 517 non-GDM controls), we measured maternal serum vitamin D status (total 25[OH]D and 25[OH]D3 ) in early pregnancy (16 weeks on average) using liquid chromatography-tandem mass spectroscopy. GDM was diagnosed according to the American Diabetes Association guidelines. We calculated adjusted odds ratios and 95% confidence intervals (CIs) using logistic regression models. RESULTS: GDM cases had lower mean total 25[OH]D (27.3 vs. 29.3 ng/mL) and 25[OH]D3 (23.9 vs. 26.7 ng/mL) concentrations compared with women who did not develop GDM (both P values < 0.05). Overall, 25[OH]D3 concentrations, but not total 25[OH]D concentrations, were significantly associated with GDM risk. A 5-ng/mL increase in 25[OH]D3 concentration was associated with a 14% decrease in GDM risk (P-value = 0.02). Women in the lowest quartile for 25[OH]D3 concentration had a twofold [95% CI 1.15, 3.58] higher risk of GDM compared with women in the highest quartile (P-value for trend < 0.05). CONCLUSIONS: Early pregnancy vitamin D status, particularly 25[OH]D3 , is inversely associated with GDM risk. PMID- 25808084 TI - Physiochemical properties, microstructure, and probiotic survivability of nonfat goats' milk yogurt using heat-treated whey protein concentrate as fat replacer. AB - There is a market demand for nonfat fermented goats' milk products. A nonfat goats' milk yogurt containing probiotics (Lactobacillus acidophilus, and Bifidobacterium spp.) was developed using heat-treated whey protein concentrate (HWPC) as a fat replacer and pectin as a thickening agent. Yogurts containing untreated whey protein concentrate (WPC) and pectin, and the one with only pectin were also prepared. Skim cows' milk yogurt with pectin was also made as a control. The yogurts were analyzed for chemical composition, water holding capacity (syneresis), microstructure, changes in pH and viscosity, mold, yeast and coliform counts, and probiotic survivability during storage at 4 degrees C for 10 wk. The results showed that the nonfat goats' milk yogurt made with 1.2% HWPC (WPC solution heated at 85 degrees C for 30 min at pH 8.5) and 0.35% pectin had significantly higher viscosity (P < 0.01) than any of the other yogurts and lower syneresis than the goats' yogurt with only pectin (P < 0.01). Viscosity and pH of all the yogurt samples did not change much throughout storage. Bifidobacterium spp. remained stable and was above 10(6) CFU g(-1) during the 10 wk storage. However, the population of Lactobacillus acidophilus dropped to below 10(6) CFU g(-1) after 2 wk of storage. Microstructure analysis of the nonfat goats' milk yogurt by scanning electron microscopy revealed that HWPC interacted with casein micelles to form a relatively compact network in the yogurt gel. The results indicated that HWPC could be used as a fat replacer for improving the consistency of nonfat goats' milk yogurt and other similar products. PMID- 25808083 TI - Recent insights into the actions of IGFBP-6. AB - IGFBP-6 is an O-linked glycoprotein that preferentially binds IGF-II over IGF-I. It is a relatively selective inhibitor of IGF-II actions including proliferation, survival and differentiation of a wide range of cells. IGFBP-6 has recently been shown to have a number of IGF-independent actions, including promotion of apoptosis in some cells and inhibition of angiogenesis. IGFBP-6 also induces migration of tumour cells including rhabdomyosarcomas by an IGF-independent mechanism. This chemotactic effect is mediated by MAP kinases. IGFBP-6 binds to prohibitin-2 on the cell surface and the latter is required for IGFBP-6-induced migration by a mechanism that is independent of MAP kinases. IGFBP-6 may enter the nucleus and modulate cell survival and differentiation. IGFBP-6 expression is decreased in a number of cancer cells and it has been postulated to act as a tumour suppressor. IGFBP-6 expression is increased in a smaller number of cancers, which may reflect a compensatory mechanism to control IGF-II actions or IGF-independent actions. The relative balance of IGF-dependent and IGF independent actions of IGFBP-6 in vivo together with the related question regarding the roles of IGFBP-6 binding to IGF and non-IGF ligands are keys to understanding the physiological role of this protein. PMID- 25808085 TI - Selection of cell-type specific antibodies on tissue-sections using phage display. AB - With the advent of modern technologies enabling single cell analysis, it has become clear that small sub-populations of cells or even single cells can drive the phenotypic appearance of tissue, both diseased and normal. Nucleic acid based technologies allowing single cell analysis has been faster to mature, while technologies aimed at analysing the proteome at a single cell level is still lacking behind, especially technologies which allow single cell analysis in tissue. Introducing methods, that allows such analysis, will pave the way for discovering new biomarkers with more clinical relevance, as these may be unique for microenvironments only present in tissue and will avoid artifacts introduced by in vitro studies. Here, we introduce a technology enabling biomarker identification on small sub-populations of cells within a tissue section. Phage antibody libraries are applied to the tissue sections, followed by washing to remove non-bound phage particles. To eliminate phage antibodies binding to antigens ubiquitously expressed and retrieve phage antibodies binding specifically to antigens expressed by the sub-population of cells, the area of interest is protected by a 'shadow stick'. The phage antibodies on the remaining areas on the slide are exposed to UV light, which introduces cross-links in the phage genome, thus rendering them non-replicable. In this work we applied the technology, guided by CD31 expressing endothelial cells, to isolate recombinant antibodies specifically binding biomarkers expressed either by the cell or in the microenvironment surrounding the endothelial cell. PMID- 25808086 TI - Optimal Design of Litz Wire Coils With Sandwich Structure Wirelessly Powering an Artificial Anal Sphincter System. AB - Transcutaneous energy transfer system (TETS) is widely used to energize implantable biomedical devices. As a key part of the TETS, a pair of applicable coils with low losses, high unloaded Q factor, and strong coupling is required to realize an efficient TETS. This article presents an optimal design methodology of planar litz wire coils sandwiched between two ferrite substrates wirelessly powering a novel mechanical artificial anal sphincter system for treating severe fecal incontinence, with focus on the main parameters of the coils such as the wire diameter, number of turns, geometry, and the properties of the ferrite substrate. The theoretical basis of optimal power transfer efficiency in an inductive link was analyzed. A set of analytical expressions are outlined to calculate the winding resistance of a litz wire coil on ferrite substrate, taking into account eddy-current losses, including conduction losses and induction losses. Expressions that describe the geometrical dimension dependence of self- and mutual inductance are derived. The influence of ferrite substrate relative permeability and dimensions is also considered. We have used this foundation to devise an applicable coil design method that starts with a set of realistic constraints and ends with the optimal coil pair geometries. All theoretical predictions are verified with measurements using different types of fabricated coils. The results indicate that the analysis is useful for optimizing the geometry design of windings and the ferrite substrate in a sandwich structure as part of which, in addition to providing design insight, allows speeding up the system efficiency-optimizing design process. PMID- 25808088 TI - Chemical fingerprint of Ganmaoling granule by double-wavelength ultra high performance liquid chromatography and ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry. AB - A method incorporating double-wavelength ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry was developed for the investigation of the chemical fingerprint of Ganmaoling granule. The chromatographic separations were performed on an ACQUITY UPLC HSS C18 column (2.1 * 50 mm, 1.8 MUm) at 30 degrees C using gradient elution with water/formic acid (1%) and acetonitrile at a flow rate of 0.4 mL/min. A total of 11 chemical constituents of Ganmaoling granule were identified from their molecular weight, UV spectra, tandem mass spectrometry data, and retention behavior by comparing the results with those of the reference standards or literature. And 25 peaks were selected as the common peaks for fingerprint analysis to evaluate the similarities among 25 batches of Ganmaoling granule. The results of principal component analysis and orthogonal projection to latent structures discriminant analysis showed that the important chemical markers that could distinguish the different batches were revealed as 4,5-di-O-caffeoylquinic acid, 3,5-di-O caffeoylquinic acid, and 4-O-caffeoylquinic acid. This is the first report of the ultra high performance liquid chromatography chemical fingerprint and component identification of Ganmaoling granule, which could lay a foundation for further studies of Ganmaoling granule. PMID- 25808090 TI - Primary osteomyelofibrosis and an XX-male genotype. AB - A 62-yr-old man with two healthy daughters was diagnosed with osteomyelofibrosis. To our surprise, a female XX-karyotype was observed in bone marrow and confirmed in PHA-stimulated T-lymphocytes from peripheral blood. Further molecular genetic investigation revealed a submicroscopic translocation between the short arm of X and Y, which leads to an XX-male genotype based on an unbalanced translocation X;Y. This rare coincidence was further accentuated as the USP9Y gene, suspected to be to be involved in sperm cell production, was absent, but no azoospermia was present. In general, routine cytogenetics may result in findings that need to be further delineated and, as here, lead to a rare observation. PMID- 25808091 TI - TriAxial perineal evaluation score: the male version. PMID- 25808089 TI - Characterisation of the contractile dynamics of the resting ex vivo urinary bladder of the pig. AB - OBJECTIVES: To characterise the area and movements of ongoing spontaneous localised contractions in the resting porcine urinary bladder and relate these to ambient intravesical pressure (Pves ), to further our understanding of their genesis and role in accommodating incoming urine. MATERIALS AND METHODS: We used image analysis to quantify the areas and movements of discrete propagating patches of contraction (PPCs) on the anterior, anterolateral and posterior surfaces of the urinary bladders of six pigs maintained ex vivo with small incremental increases in volume. We then correlated the magnitude of Pves and cyclic changes in Pves with parameters derived from spatiotemporal maps. RESULTS: Contractile movements in the resting bladder consisted only of PPCs that covered around a fifth of the surface of the bladder, commenced at various sites, and were of ~6 s in duration. They propagated at around 6 mm/s, mainly across the anterior and lateral surface of the bladder by various, sometimes circular, routes in a quasi-stable rhythm, and did not traverse the trigone. The frequencies of these rhythms were low (3.15 cycles/min) and broadly similar to those of cyclic changes in Pves (3.55 cycles/min). Each PPC was associated with a region of stretching (positive strain rate) and these events occurred in a background of more constant strain. The amplitudes of cycles in Pves and the areas undergoing PPCs increased after a sudden increase in Pves but the frequency of cycles of Pves and of origin of PPCs did not change. Peaks in Pves cycles occurred when PPCs were traversing the upper half of the bladder, which was more compliant. The velocity of propagation of PPCs was similar to that of transverse propagation of action potentials in bladder myocytes and significantly greater than that reported in interstitial cells. The size of PPCs, their frequency and their rate of propagation were not affected by intra-arterial dosage with tetrodotoxin or lidocaine. CONCLUSIONS: The origin and duration of PPCs influence both Pves and cyclic variation in Pves . Hence, propagating rather than stationary areas of contraction may contribute to overall tone and to variation in Pves . Spatiotemporal mapping of PPCs may contribute to our understanding of the generation of tone and the basis of clinical entities such as overactive bladder, painful bladder syndrome and detrusor overactivity. PMID- 25808092 TI - Pigmented macule on the nipple. PMID- 25808087 TI - Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. AB - Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro epileptic brain insult. PMID- 25808093 TI - Contact sensitivity in patients with recalcitrant atopic dermatitis. AB - Patients with atopic dermatitis are usually responsive to conventional treatment such as topical steroids; however, they are sometimes refractory to the treatment. The influence of contact sensitivities on the course of patients with recalcitrant atopic dermatitis is not known. The aim of this study was to investigate whether contact sensitivities affect the course of patients with recalcitrant atopic dermatitis. We evaluated 45 patients with atopic dermatitis who had failed conventional therapy. Patch testing was performed with the Japanese standard series, metal series and/or suspected items. A total of 15 patients had a positive patch test reaction to at least one allergen. The most common allergens were nickel, topical drugs and rubber accelerators. Avoidance of products or food containing allergic substances greatly or partially improved skin symptoms in nine patients. These results suggest that contact allergens and metals may be critical factors causing eczematous lesions in patients with recalcitrant atopic dermatitis. PMID- 25808095 TI - Atopy-related skin rash in a normal population of infants: Distribution and rates for 50 separate skin regions: Cohort study from 4 months to 3.5 years. AB - Analysis of the rash in a normal population of infants may give new information that is different from clinical observation of atopic dermatitis (AD). For this purpose, a cohort study was undertaken on infants at 4 months, 10 months and 3.5 years. Infants who attended the local health center for health check were the subjects. Rash related to AD, dryness, scaling, erythema, papules, exudation and crusts was recorded in 50 skin regions and divided into three degrees. Examination was performed twice a month for a year at each age. The 777 infants who attended all three examinations were analyzed in this report. Rash-positive regions were 14.7% on average at 4 months and decreased with age. Prevalence of rash-positive infants was 93.6% at 4 months and also decreased with age. The main findings are as follows. First, rash was more frequent and more severe in younger infants. This seems to suggest that AD in early infancy is initiated and developed by immune immaturity, and is resolved by its maturation. Second, rash involved preferentially air-exposed and air-closed skin in younger infants. This seems to be evidence that the epidermis of young infants is easily responsive to both dryness and wetness. Third, some regions did not show age-dependent reduction of rash rate in younger infants. Those regions are probably irritated by saliva and urine or rubbing and scratching. PMID- 25808094 TI - AZT resistance alters enzymatic properties and creates an ATP-binding site in SFVmac reverse transcriptase. AB - BACKGROUND: The replication of simian foamy virus from macaques can be inhibited by the nucleoside reverse transcriptase inhibitor azidothymidine (AZT, zidovudine). Four substitutions in the protease-reverse transcriptase (PR-RT) protein (K211I, I224T, S345T, E350K) are necessary to obtain highly AZT resistant and fully replication competent virus. AZT resistance is based on the excision of the incorporated AZTMP in the presence of ATP. I224T is a polymorphism which is not essential for AZT resistance per se, but is important for regaining efficient replication of the resistant virus. RESULTS: We constructed PR-RT enzymes harboring one to four amino acid substitutions to analyze them biochemically and to determine their ability to remove the incorporated AZTMP. S345T is the only single substitution variant exhibiting significant AZTMP excision activity. Although K211I alone showed no AZTMP excision activity, excision efficiency doubled when K211I was present in combination with S345T and E350K. K211I also decreased nucleotide binding affinity and increased fidelity. NMR titration experiments revealed that a truncated version of the highly AZT resistant mt4 variant, comprising only the fingers-palm subdomains was able to bind ATP with a KD-value of ca. 7.6 mM, whereas no ATP binding could be detected in the corresponding wild type protein. We could show by NMR spectroscopy that S345T is responsible for ATP binding, probably by making a tryptophan residue accessible. CONCLUSION: Although AZT resistance in SFVmac is based on excision of the incorporated AZTMP like in HIV-1, the functions of the resistance substitutions in SFVmac PR-RT appear to be different. No mutation resulting in an aromatic residue like F/Y215 in HIV, which is responsible for pi-pi-stacking interactions with ATP, is present in SFVmac. Instead, S345T is responsible for creating an ATP binding site, probably by making an already existing tryptophan more accessible, which in turn can interact with ATP. This is in contrast to HIV-1 RT, in which an ATP binding site is present in the WT RT but differs from that of the AZT resistant enzyme. PMID- 25808096 TI - Impact of periodic endoscopy on incidentally diagnosed gastric gastrointestinal stromal tumors: findings in surgically resected and confirmed lesions. AB - BACKGROUND: Although gastric gastrointestinal stromal tumors (GISTs) are usually identified by endoscopic examinations, the diagnostic value of endoscopy has not been fully evaluated. We assessed the diagnostic performance of endoscopy for gastric GISTs according to lesion characteristics. Furthermore, the benefits of periodic endoscopy prior to diagnosis of gastric GISTs were evaluated. METHODS: We reviewed patients who underwent surgery for gastric GISTs at Severance Hospital, Seoul, Korea, between January 2008 and April 2014. In addition, we administered a questionnaire to determine the usage of periodic endoscopic inspection and the period from the penultimate endoscopy to the diagnosis. RESULTS: Of 174 included patients, 109 (62.4 %) showed intraluminally growing GISTs and 65 (37.4 %) showed extraluminally growing GISTs. The proportions of lesions that were initially diagnosed via endoscopy were 99.1 % for intraluminally growing GISTs and 49.2 % for extraluminally growing GISTs (P < 0.001). In patients with intraluminally growing GISTs, patients who had undergone endoscopy within 3 years prior to the diagnosis showed smaller tumor sizes (P = 0.015) and fewer tumors with ulceration (7.1 vs. 28.4 %, P = 0.021). The proportion of GISTs with a high mitotic index did not differ according to the usage of periodic endoscopy (P = 0.639). In contrast, lesion characteristics of the extraluminally growing GISTs did not differ according to whether an endoscopy was performed within 3 years prior to the diagnosis. CONCLUSIONS: Endoscopic examinations had a limited role in the diagnosis of extraluminally growing GISTs. However, periodic endoscopy was associated with relatively earlier detection of growth in intraluminal gastric GISTs. PMID- 25808097 TI - Pyruvate Kinase M2 Modulates Esophageal Squamous Cell Carcinoma Chemotherapy Response by Regulating the Pentose Phosphate Pathway. AB - BACKGROUND: Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates the Warburg effect and is necessary for tumor growth. However, its role in chemoresistance has not been fully elucidated. METHODS: PKM2 expression was examined by immunohistochemistry in 205 tissue samples from thoracic esophageal squamous cell carcinoma patients who had undergone curative surgery (100 patients with surgery alone and 105 patients with preoperative chemotherapy). The relationship between PKM2 expression and clinicopathological factors, including chemotherapy response was examined. In vitro assays were performed to determine the mechanism of PKM2-related chemoresistance, using esophageal squamous cell carcinoma cell lines. RESULTS: PKM2 expression significantly correlated with tumor cell differentiation, tumor depth, and tumor stage. Strong PKM2 expression significantly correlated with decreased survival rates and poor response to chemotherapy. In vitro assays showed that PKM2 inhibition significantly decreased cisplatin resistance and increased apoptosis. In siPKM2-transfected cells, pyruvate kinase activity paradoxically increased, followed by increased intracellular reactive oxygen species levels. The ratio of NADPH/NADP, which is an indicator of glucose influx into pentose phosphate pathway (PPP), significantly decreased in siPKM2-transfected cells upon cisplatin treatment compared with control cells. CONCLUSIONS: PKM2 expression is associated with esophageal squamous cell carcinoma chemoresistance. PKM2 inhibition can restore cisplatin sensitivity by inactivating PPP. PMID- 25808098 TI - Bilateral risk-reduction mastectomy in BRCA1 and BRCA2 mutation carriers: a meta analysis. AB - BACKGROUND: Women with BRCA1 and BRCA2 mutations have substantially elevated risk of developing breast cancer. The aim of this study was to clarify the role of bilateral risk-reducing mastectomy (BRRM) in reducing breast cancer risk in women carriers of BRCA1 and BRCA2 mutations. METHODS: The Pubmed, MEDLINE and Scopus databases were searched to retrieve articles written in the English language. Two investigators independently extracted the characteristics and results of the selected studies. Only prospective trials with available absolute numbers of breast cancer and death events were included. Pooled hazard ratio (HR) with 95 % confidence interval (CI) was calculated using fixed or random effects model. RESULTS: Meta-analysis of four prospective studies, including 2635 patients, demonstrated a significant risk reduction of breast cancer incidence in BRCA1 and BRCA2 mutation carriers receiving BRRM (HR 0.07; 95 % CI 0.01-0.44; p = 0.004). Among patients without previous risk-reducing salpingo-oophorectomy, a significant benefit was similarly recorded (HR 0.06; 95 % CI 0.01-0.41; p = 0.005). CONCLUSIONS: Performing BRRM may lead to highly significant risk reduction of breast cancer in BRCA1 and BRCA2 mutation carriers. These data allow clinicians to discuss more in-depth with patients all the available options in order to design better management strategies. PMID- 25808099 TI - A Predictive Score for Secondary Cytoreductive Surgery in Recurrent Ovarian Cancer (SeC-Score): A Single-Centre, Controlled Study for Preoperative Patient Selection. AB - BACKGROUND: The standard treatments of patients with platinum-sensitive recurrent ovarian cancer (ROC) remains poorly defined. Chemotherapy (CT) and secondary cytoreductive surgery (SCS) represent both valid options, even if several studies demonstrated a greater survival benefit, with survival rates up to 62 months, for platinum-sensitive patients undergoing complete SCS. The purpose of the present study was to develop a predictive model, named SeC-Score (SeC-s), to assess the risk of optimal SCS, including, for the first time in literature, HE4. METHODS: All patients affected by suspicious ROC at radiologic imaging, referred to the Department of Gynecology of Campus Bio-medico of Rome, were prospectively included in the study. The preoperative variables considered in our predictive model were: age, residual tumour (RT) at primary cytoreduction (0 vs. >0 cm), preoperative CA125 and HE4, and ascites at recurrence. After exploratory laparotomy, patients were submitted to secondary SCS (Group A) or addressed to CT (Group B). RESULTS: A total of 135 patients with ROC were considered for the analysis. Preoperative CA125, HE4, ascites, and RT at first surgery were found statistically significant and included into a multivariate logistic regression model to determine the risk to not optimal SCS. In the overall cohort of patients, SeC-s reported sensitivity and specificity of 82 and 83 %, respectively (PPV = 0.79, NPV = 0.81). CONCLUSIONS: Our data support the use of SeC-s to preoperative triage patients suitable of optimal SCS, even if external validation is needed. PMID- 25808100 TI - Prognostic Significance of Tumor-Positive Internal Mammary Sentinel Lymph Nodes in Breast Cancer: A Multicenter Cohort Study. AB - INTRODUCTION: The introduction of the sentinel lymph node biopsy (SLNB) in breast cancer has renewed interest in lymphatic drainage to the internal mammary (IM) nodes. The clinical impact of tumor positive IM nodes is not completely clear. This study evaluated the incidence and impact on overall survival of metastatic IM SLNs. METHODS: Between 1997 and 2010, 3685 patients underwent surgery including SLNB for primary breast cancer following an intratumoral or peritumoral radioactive-tracer injection. The presence of lymph node metastases was categorized according to the TNM-classification. Cumulative overall survival was estimated and the influence of metastases in the IM nodes and other factors was assessed by Cox-regression-analysis. RESULTS: In 754 patients (20.5 %) ipsilateral IM lymph nodes were visualized on preoperative lymphoscintigraphy, retrieval rate of IM SLNs was 81.0 %. IM metastases were detected in 130 patients (21.3 % of retrieved SLNs and 3.5 % of all patients respectively). The presence of IM metastases was associated with axillary metastases (p < 0.001). After a median follow-up of 61.2 months, 10.9 % of patients had died. In a multivariate analysis IM metastases did not have a significant effect on overall survival [HR] 1.20; CI: 0.73-1.98. In patients without axillary metastases (n = 2398), the presence of IM metastases (n = 43) was associated with worse survival [HR] 2.68; 95 % CI: 1.30-5.54. CONCLUSION: Overall, the presence of IM metastases did not effect overall survival independent of other prognostic factors including axillary metastases. However, the small subgroup of patients who had IM metastases alone had worse outcome than patients without any regional lymph node metastases. PMID- 25808101 TI - Resurfacing of the humeral head: An analysis of the bone stock and osseous integration under the implant. AB - Cementless-surface-replacement-arthroplasty (CSRA) of the shoulder aims for functional joint restoration with minimal bone loss. Good clinical results have been reported, but due to the radiopaque metal shell no data is available on the structure, osseous integration, and bone stock under the implant. 14 hemi-CSRAs (4 manufacturers) with two geometries (crown [n = 7]/ stem [n = 7] fixation) were retrieved from patients undergoing revision due to glenoidal erosion. Histological sections cutting through the implant centre and bone were analysed. Quantitative histomorphometry evaluated the bone-implant-contact and compared the bone-area to native humeral retrievals (n = 7). The bone-implant-interface was further assessed by scanning-electron-microscopy (SEM) and energy-dispersive-x ray (EDX). Qualitative histology revealed a reduced and inhomogeneous bone stock. Obvious signs of stress shielding were observed with bone predominantly visible at the stem and implant rim. Quantitative histomorphometry confirmed the significantly reduced bone-area (9.2 +/- 3.9% [crown 9.9 +/- 4.3%, stem 8.6 +/- 3.6%]) compared to native humeri (21.2 +/- 9.1%; p < 0.05). Bone-implant-contact was 20.5 +/- 5.8% (crown 21.8 +/- 6.2%, stem 19.2 +/- 5.6%) which was confirmed by SEM and EDX. Altogether, CRSA shows satisfactory bone ingrowth at the interface suggesting sufficient primary stability to allow osseous integration. However, clear signs of stress shielding with an inhomogeneous and reduced bone stock were observed. The impact on the long-term-results is unclear requiring further investigation. PMID- 25808103 TI - A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of long-term treatment with prucalopride. AB - BACKGROUND: Randomized trials have confirmed the efficacy of prucalopride for the treatment of chronic constipation up to 12 weeks. This study aimed to assess the efficacy of prucalopride over a 24-week period (ClinicalTrials.gov: NCT01424228). METHODS: Adults with chronic constipation and <=2 spontaneous complete bowel movements (SCBMs)/week were randomized to receive prucalopride 2 mg or placebo daily for 24 weeks. The primary endpoint was the proportion of patients achieving a mean of >=3 SCBMs/week over the treatment period, assessed using daily e diaries. Secondary outcomes and safety parameters were assessed throughout the study. KEY RESULTS: Overall, 361 patients were randomized and received prucalopride or placebo. Baseline characteristics were similar in the prucalopride (N = 181) and placebo (N = 180) groups. Mean age was 48.9 years (standard deviation, 16.0) and most patients were women. The proportion of participants achieving the primary endpoint was not statistically different between the prucalopride and placebo groups (25.1% vs 20.7%; p = 0.367). There was also no statistically significant difference between groups over the first 12 week period (prucalopride, 25.1%; placebo, 20.1%; p = 0.341). There were no statistically significant differences between groups for most secondary endpoints. No new safety concerns were identified. CONCLUSIONS & INFERENCES: This trial did not show statistically significant improvements in primary or secondary outcomes with prucalopride compared with placebo over 24 or 12 weeks. This is in contrast to the results of four previous 12-week trials, which demonstrated prucalopride to be significantly more effective than placebo. An extensive evaluation did not provide an explanation for the null efficacy results of this study. PMID- 25808105 TI - Sensory regulation of spontaneous limb movements in the midstage embryonic chick. AB - It is becoming increasingly apparent that somatosensation plays an important role in regulating prenatal movement and developmental plasticity. Numerous studies performed on embryonic chicks and perinatal rats are beginning to implicate proprioception to be particularly important in modulating motility very soon after afferent connections are made in the spinal cord. In this report, we demonstrate new approaches in the chick embryo to explore the role of sensation in modulating embryonic movement. Force recordings from the legs of chick embryos on E9 and E11, during spontaneous motility, demonstrate changes in sensory regulation consistent with the concept that sensory regulation is functioning one day after sensory synapse formation and that the complexity of this regulation increases by E11. Additionally, we present new video data showing activation of embryonic motility on E5 and E9 in embryos expressing channelrhodopsin in the spinal cord as a novel way to approach the issues of sensorimotor development. PMID- 25808102 TI - Unbreak my heart: targeting mitochondrial autophagy in diabetic cardiomyopathy. AB - SIGNIFICANCE: Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. RECENT ADVANCES: Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. CRITICAL ISSUES: Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed "mitophagy," is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. FUTURE DIRECTIONS: This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically. PMID- 25808106 TI - Macrophages play an essential role in antigen-specific immune suppression mediated by T CD8+ cell-derived exosomes. AB - Murine contact sensitivity (CS) reaction could be antigen-specifically regulated by T CD8(+) suppressor (Ts) lymphocytes releasing microRNA-150 in antibody light chain-coated exosomes that were formerly suggested to suppress CS through action on macrophages (Mphi). The present studies investigated the role of Mphi in Ts cell-exosome-mediated antigen-specific suppression as well as modulation of Mphi antigen-presenting function in humoral and cellular immunity by suppressive exosomes. Mice depleted of Mphi by clodronate liposomes could not be tolerized and did not produce suppressive exosomes. Moreover, isolated T effector lymphocytes transferring CS were suppressed by exosomes only in the presence of Mphi, demonstrating the substantial role of Mphi in the generation and action of Ts cell regulatory exosomes. Further, significant decrease of number of splenic B cells producing trinitrophenyl (TNP) -specific antibodies with the alteration of the ratio of serum titres of IgM to IgG was observed in recipients of exosome treated, antigen-pulsed Mphi and the significant suppression of CS was demonstrated in recipients of exosome-treated, TNP-conjugated Mphi. Additionally, exosome-pulsed, TNP-conjugated Mphi mediated suppression of CS in mice pre treated with a low-dose of cyclophosphamide, suggesting de novo induction of T regulatory (Treg) lymphocytes. Treg cell involvement in the effector phase of the studied suppression mechanism was proved by unsuccessful tolerization of DEREG mice depleted of Treg lymphocytes. Furthermore, the inhibition of proliferation of CS effector cells cultured with exosome-treated Mphi in a transmembrane manner was observed. Our results demonstrated the essential role of Mphi in antigen specific immune suppression mediated by Ts cell-derived exosomes and realized by induction of Treg lymphocytes and inhibition of T effector cell proliferation. PMID- 25808107 TI - Residues of different gel formulations on dentinal walls: A SEM/EDS analysis. AB - The aim of this study was to evaluate the presence of residues of sodium hypochlorite gel, chlorhexidine gel, and EDTA gel on dentinal walls after canal preparation through chemical SEM- elemental chemical microanalysis (EDS) analysis. Forty-eight single-rooted teeth were selected. They had their crowns sectioned and were instrumented with a reciprocating system. The canals were irrigated with 5 mL of saline solution during root canal preparation. After instrumentation, the root canals were irrigated with 3 mL 17% EDTA followed by 1 min of ultrasonic passive activation (3* 20 sec) to remove the smear layer, and then irrigated with 3 mL of saline solution. The specimens were randomized into three groups (n = 12) according to the chemical substance that filled the root canal for 30 min: GI: 5.5% sodium hypochlorite gel; GII: 2% chlorhexidine gel; GIII: 24% EDTA gel; Negative control group: no substance was used. Then, the root canals were irrigated with 6 mL of saline solution followed by 1 min of ultrasonic passive activation (3* 20 sec). After ultrasonic activation, the canals were irrigated with 2 mL saline. The roots were sectioned, and the percentage of each chemical element present in the samples was analyzed through chemical SEM-EDS microanalysis. All experimental groups showed a significantly higher percentage of chemical elements (Na and/or Cl) than the control group (P < 0.03). This in vitro study has shown that, regardless of chemical solutions used even after the final irrigation protocol, chemical residues of different substances remained attached to the root canal walls. PMID- 25808104 TI - The self-reported Physical Activity Scale for the Elderly (PASE) is a valid and clinically applicable measure in lung cancer. AB - PURPOSE: Physical activity (PA) is an important outcome in lung cancer; however, there is lack of consensus as to the best method for assessment. The Physical Activity Scale for the Elderly (PASE) is a commonly used questionnaire. The aim of this study was to assess the clinimetric properties of the PASE in lung cancer, specifically validity, predictive utility and clinical applicability (floor/ceiling effects, responsiveness and minimal important difference [MID]). METHODS: This is a prospective observational study. Sixty-nine participants (62 % male, median [IQR] age 68 years [61-74]) with lung cancer completed the PASE at diagnosis at 2, 4 and 6 months. Additional measures included movement sensors (steps/day), physical function, health-related quality of life, functional capacity (6-min walk distance [6MWD]), and muscle strength. Spearman's rank correlation coefficient was used to assess relationships. Linear regression analyses were conducted to determine predictive utility of the PASE for health status at 6 months. Responsiveness (effect size) and MID (distribution-based estimation) were calculated. RESULTS: The PASE was administered on 176 occasions. The PASE had moderate convergent validity with movement sensors (rho = 0.50 [95 %CI = 0.29-0.66], p < 0.005) and discriminated between participants classed as sedentary/insufficient/sufficient according to PA guidelines (p < 0.005). The PASE had fair-moderate construct validity with measures of physical function (rho = 0.57 [95 %CI = 0.46-0.66], p < 0.005), 6MWD (rho = 0.40 [95 %CI = 0.23-0.55], p < 0.005), and strength (rho = 0.37 [95 %CI = 0.18-0.54], p < 0.005). The PASE (at diagnosis) exhibited predictive utility for physical function (Bcoef = 0.35, p = 0.008) and quality of life (Bcoef = 0.35, p = 0.023) at 6 months. A small floor effect was observed (3 %); however, there was no ceiling effect. There was a small responsiveness to change (effect size = 0.23) and MID between 17 and 25 points. CONCLUSIONS: The PASE is a valid measure of self-reported PA in lung cancer. PMID- 25808108 TI - Waldenstrom macroglobulinemia: 2015 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with >=10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients. RISK STRATIFICATION: Age, hemoglobin level, platelet count, beta2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. RISK ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Management of Refractory Disease: Bortezomib, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. PMID- 25808109 TI - Nursing Outcomes for the Diagnosis Impaired Tissue Integrity (00044) in Adults With Pressure Ulcer. AB - PURPOSE: The study aims to validate nursing outcomes from the Nursing Outcomes Classification (NOC) related to the nursing diagnosis of impaired tissue integrity (00044) in adults with pressure ulcer (PU). METHODS: It was a consensus validation study using the focus group technique. Data were analyzed by descriptive statistics, and NOCs that obtained 100% consensus were considered validated. FINDINGS: Of the 16 NOCs evaluated, nine were validated. CONCLUSIONS: The NOCs validated may identify the effectiveness, impact, and quality of interventions, making it possible to maintain or change the care planning of PU patients. IMPLICATIONS FOR NURSING PRACTICE: This work may serve to contribute to the future development of NOC, making it possible to evaluate the outcomes of PU patients in terms of the interventions performed in nursing practice. PMID- 25808110 TI - FOXP3+ and CD39+ regulatory T cells in subtypes of cutaneous lupus erythematosus. AB - BACKGROUND: Lupus erythematosus (LE) is an autoimmune disease in which regulatory T cells play a pathogenetic role. OBJECTIVES: We aimed to assess and compare the quantities of lesional Tregs in subtypes of cutaneous LE (CLE) including chronic discoid LE (CDLE), LE tumidus (LET) and subacute CLE (SCLE). METHODS: Thirty-nine patients with CLE were enrolled in the study. Immunohistochemistry was performed for CD4, CD8, FOXP3 and CD39. RESULTS: We studied nine CDLE patients, 21 LET patients and nine patients with SCLE. SCLE lesions [37 (0-134)] showed a significantly (P = 0.024) decreased percentage of CD4+ cells when compared with CDLE [125 (0-146)] and LET [124 (0-240)] lesions. Moreover, the CD4/CD8 ratio in SCLE lesions [0.7 (0.5-1.8)] was significantly (P = 0.027) decreased when compared with CDLE [1.9 (1.5-2.8)] and LET [1.6 (0.8-2.9)] lesions. FOXP3 immunopositivity was significantly (P = 0.017) decreased in LET [0 (0-6)] and SCLE [1 (0-2)] lesions when compared with CDLE [6 (0-38)]. Moreover, in LET [2 (0 6)] and SCLE [2 (0-2)], we observed a significantly (P = 0.0049) diminished CD39 immunoreactivity when compared with CDLE [4 (2-12)]. CD4+ cell count is a significant (P = 0.0133) negative predictor for the diagnosis of SCLE (Odds ratio 0.978, 95% CI 0.960-0.99). CONCLUSIONS: Our data indicate that there are differences in quantities of lesional T helper cells, CD4/CD8 ratio and Tregs among subtypes of CLE. Interestingly, a more significant decrease in Tregs, which likely reflects greater loss of immune-tolerance, is observed in the more photosensitive subtypes of CLE such as SCLE and LET. PMID- 25808112 TI - Superstructure of a substituted zeolitic imidazolate metal-organic framework determined by combining proton solid-state NMR spectroscopy and DFT calculations. AB - We report the supercell crystal structure of a ZIF-8 analog substituted imidazolate metal-organic framework (SIM-1) obtained by combining solid-state nuclear magnetic resonance and powder X-ray diffraction experiments with density functional theory calculations. PMID- 25808111 TI - Expression of nuclear matrix proteins binding matrix attachment regions in prostate cancer. PARP-1: New player in tumor progression. AB - Prostate cancer (PCa) displays infrequent point mutations, whereas genomic rearrangements are highly prevalent. In eukaryotes, the genome is compartmentalized into chromatin loop domains by the attachment to the nuclear matrix (NM), and it has been demonstrated that several recombination hot spots are situated at the base of loops. Here, we have characterized the binding between NM proteins and matrix attachment regions (MARs) in PCa. Nontumor and 44 PCa tissues were analyzed. More aggressive tumors were characterized by an increase in the complexity of the NM protein patterns that was synchronous with a decrease in the number of proteins binding the MAR sequences. PARP-1 was the protein that showed the most evident changes. The expression of the PARP-1 associated with NM increased and it was dependent on tumor aggressiveness. Immunohistochemical analysis showed that the protein was significantly overexpressed in tumor cells. To explore the role of PARP-1 in PCa progression, PCa cells were treated with the PARP inhibitor, ABT-888. In androgen-independent PC3 cells, PARP inhibition significantly decreased cell viability, migration, invasion, chromatin loop dimensions and histone acetylation. Collectively, our study provides evidence that MAR-binding proteins are involved in the development and progression of PCa. PARP could play a key role in the compartmentalization of chromatin and in the development of the more aggressive phenotype. Thus, PARP can no longer be viewed only as an enzyme involved in DNA repair, but that its role in chromatin modulation could provide the basis for a new therapeutic approach to the treatment of PCa. PMID- 25808113 TI - Inhaled corticosteroids: potency, dose equivalence and therapeutic index. AB - Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies. For synthetic corticosteroid analogues it is commonly assumed that the therapeutic index cannot be improved by increasing their glucocorticoid receptor binding affinity. The validity of this assumption, particularly for inhaled corticosteroids, has not been fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this can be dissociated from their potential to cause systemic adverse effects. The molecular structural features that increase glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity. However, in addition, these structural modifications also result in physicochemical and pharmacokinetic changes that can enhance targeting to the airways and reduce systemic exposure. As a consequence, potency and therapeutic index can be correlated. However, this consideration is not reflected in asthma treatment guidelines that classify inhaled corticosteroid formulations as low-, mid- and high dose, and imbed a simple dose equivalence approach where potency is not considered to affect the therapeutic index. This article describes the relationship between potency and therapeutic index, and concludes that higher potency can potentially improve the therapeutic index. Therefore, both efficacy and safety should be considered when classifying inhaled corticosteroid regimens in terms of dose equivalence. The historical approach to dose equivalence in asthma treatment guidelines is not appropriate for the wider range of molecules, potencies and device/formulations now available. A more robust method is needed that incorporates pharmacological principles. PMID- 25808114 TI - Fossil-based comparative analyses reveal ancient marine ancestry erased by extinction in ray-finned fishes. AB - The marine-freshwater boundary is a major biodiversity gradient and few groups have colonised both systems successfully. Fishes have transitioned between habitats repeatedly, diversifying in rivers, lakes and oceans over evolutionary time. However, their history of habitat colonisation and diversification is unclear based on available fossil and phylogenetic data. We estimate ancestral habitats and diversification and transition rates using a large-scale phylogeny of extant fish taxa and one containing a massive number of extinct species. Extant-only phylogenetic analyses indicate freshwater ancestry, but inclusion of fossils reveal strong evidence of marine ancestry in lineages now restricted to freshwaters. Diversification and colonisation dynamics vary asymmetrically between habitats, as marine lineages colonise and flourish in rivers more frequently than the reverse. Our study highlights the importance of including fossils in comparative analyses, showing that freshwaters have played a role as refuges for ancient fish lineages, a signal erased by extinction in extant-only phylogenies. PMID- 25808115 TI - Response to Letter to the Editor from Dr. Guilford. PMID- 25808118 TI - Review lipopeptides biosurfactants: Mean classes and new insights for industrial, biomedical, and environmental applications. AB - Lipopeptides are microbial surface active compounds produced by a wide variety of bacteria, fungi, and yeast. They are characterized by high structural diversity and have the ability to decrease the surface and interfacial tension at the surface and interface, respectively. Surfactin, iturin, and fengycin of Bacillus subtilis are among the most popular lipopeptides. Lipopepetides can be applied in diverse domains as food and cosmetic industries for their emulsification/de emulsification capacity, dispersing, foaming, moisturizing, and dispersing properties. Also, they are qualified as viscosity reducers, hydrocarbon solubilizing and mobilizing agents, and metal sequestering candidates for application in environment and bioremediation. Moreover, their ability to form pores and destabilize biological membrane permits their use as antimicrobial, hemolytic, antiviral, antitumor, and insecticide agents. Furthermore, lipopeptides can act at the surface and can modulate enzymes activity permitting the enhancement of the activity of certain enzymes ameliorating microbial process or the inhibition of certain other enzymes permitting their use as antifungal agents. This article will present a detailed classification of lipopeptides biosurfactant along with their producing strain and biological activities and will discuss their functional properties and related applications. PMID- 25808116 TI - The effect of flaxseed dose on circulating concentrations of alpha-linolenic acid and secoisolariciresinol diglucoside derived enterolignans in young, healthy adults. AB - PURPOSE: The primary endpoint was to determine the plasma concentration of alpha linolenic acid (ALA), and its metabolites, following milled flaxseed consumption at four doses. Secondary outcomes focused on plasma enterolignan concentrations and the effects on tolerability, platelet aggregation, plasma lipids and urinary thromboxane levels. METHODS: Healthy, younger adults (n = 34; 18-49 years old) were randomized into four groups consuming one muffin daily for 30 days fortified with 10, 20, 30 or 40 g of milled flaxseed. Blood and urine were collected at baseline and 4 weeks. RESULTS: Plasma ALA concentrations increased with all flaxseed doses (P < 0.01), except the 20 g/day dose (P = 0.10), yet there was no significant dose-dependent response (P = 0.81). Only with the 30 g/day diet were n-3 polyunsaturated fatty acids (P = 0.007), and eicosapentaenoic acid (EPA) (P = 0.047) increased from baseline values. Docosapentaenoic acid and docosahexaenoic acid were not detected at any dose. Plasma total enterolignan concentrations significantly increased over time in all treatment groups, yet despite a dose dependent tendency, no between-group differences were detected (P = 0.22). Flaxseed was well tolerated, even at the highest dose, as there were no reported adverse events, changes in cholesterol, platelet aggregation or urinary 11 dehydro-thromboxane B2. CONCLUSIONS: In healthy, younger adults, 10 g/day of milled flaxseed consumption is sufficient to significantly increase circulating ALA and total enterolignan concentrations; however, 30 g/day is required to convert ALA to EPA. Although all doses were well tolerated, 40 g/day is too low to attenuate cholesterol in this population. PMID- 25808117 TI - Fructose only in pregnancy provokes hyperinsulinemia, hypoadiponectinemia, and impaired insulin signaling in adult male, but not female, progeny. AB - PURPOSE: Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Recently, we found that an intake of fructose (10 % wt/vol) throughout gestation produces impaired fetal leptin signaling and hepatic steatosis. Therefore, we have investigated whether fructose intake during pregnancy produces subsequent changes in the progeny, when adult. METHODS: Fed 261-day-old male and female descendants from fructose-fed, control or glucose-fed mothers were used. Plasma was used to analyze glucose, insulin, leptin, and adiponectin. Hepatic expression of proteins related to insulin signaling was determined. RESULTS: Fructose intake throughout pregnancy did not produce alterations in the body weight of the progeny. Adult male progeny of fructose-fed mothers had elevated levels of insulin without a parallel increase in phosphorylation of protein kinase B. However, they displayed an augmented serine phosphorylation of insulin receptor substrate-2, indicating reduced insulin signal transduction. In agreement, adiponectin levels, which have been positively related to insulin sensitivity, were lower in male descendants from fructose-fed mothers than in the other two groups. Furthermore, mRNA levels for insulin-responsive genes were not affected (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) or they were decreased (sterol response element-binding protein-1c) in the livers of male progeny from fructose supplemented rats. On the contrary, adult female rats from fructose-fed mothers did not exhibit any of these disturbances. CONCLUSION: Maternal fructose, but not glucose, intake confined to the prenatal stage provokes impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia in adult male, but not female, progeny. PMID- 25808119 TI - A novel hematopoietic progenitor cell mobilization and collection algorithm based on preemptive CD34 enumeration. AB - BACKGROUND: The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed "poor mobilizers" with granulocyte colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. STUDY DESIGN AND METHODS: To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. RESULTS: Significant differences (p <= 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. CONCLUSION: Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product. PMID- 25808120 TI - Visualized absorption of anti-atherosclerotic dipeptide, Trp-His, in Sprague Dawley rats by LC-MS and MALDI-MS imaging analyses. AB - SCOPE: The basic dipeptide, Trp-His, was found to show an in vivo anti atherosclerotic effect when orally administered to apo E-deficient mice. In addition, this dipeptide causes vasorelaxation in contracted rat aorta via suppression of intracellular Ca(2+) signaling cascades. In this study, we attempted to determine whether Trp-His can be absorbed after single oral administration in Sprague-Dawley (SD) rats. METHODS AND RESULTS: Trp-His and His Trp (10 or 50 mg/kg) was orally administered to 8-week-old male SD rats. Both peptides in plasma were assayed by LC-MS/MS in combination with 2,4,6 trinitrobenzene sulfonate derivatization technique. In vitro transport experiments using Caco-2 cell monolayers were performed to evaluate the apparent permeability (Papp ). A phytic acid-aided MALDI-MS imaging (MSI) was conducted to visualize the distribution of dipeptides in the rat intestinal membrane. Trp-His was absorbed intact into SD rat blood, showing a maximal level at 1 h after administration at 10 mg/kg dose (Cmax , 28.7 +/- 8.9 pmol/mL-plasma; area under the curve, 71.3 +/- 18.7 pmol.h/mL-plasma). In contrast, His-Trp was surprisingly not detected, although the Papp was compatible to that of Trp-His. MSI analysis provided crucial evidence that Trp-His was visualized in the overall intestinal membrane. The Trp-His peptide was not visualized in the presence of Gly-Sar, which is a model peptide that is transported via the intestinal proton-coupled peptide transporter 1 (PepT1) transporter. The His-Trp molecular ion was not observed at the intestinal membrane. The MSI analysis illustrated that there is no absorption of His-Trp due to its unexpected hydrolysis by brush border proteases. CONCLUSION: To the best of our knowledge, this is the first study demonstrating that the vasoactive Trp-His is preferably transported across the rat intestinal membrane by PepT1 and is absorbed intact into the circulation. However, no absorption of His-Trp, a reverse sequence of absorbable Trp-His, is observed owing to hydrolysis by intestinal proteases. This suggests that the bioavailability of peptides may be determined in part by their protease resistance in the intestinal membrane. PMID- 25808121 TI - Effects of low oxygen levels on G2-specific cytogenetic low-dose hyper radiosensitivity in irradiated human cells. AB - Low-dose hyper-radiosensitivity (HRS) has been reported in normal human lymphoblastoid cell lines for exposures at <= 20 cGy, but the cytogenetic effects of oxygen (O2 ) levels in tissue culture medium on HRS have not been evaluated. We asked whether HRS was lost in G2-irradiated cells grown in atmospheres of 2.5% or 5% O2 , compared to responses by cells cultured in ambient O2 (21%). The results indicate a loss of HRS when cells are cultured and irradiated either in 2.5% or 5% O2 . We then evaluated whether low O2 levels either before or after exposure were responsible for the loss of HRS. For cells irradiated in 5% O2 , subsequent immediate re-oxygenation to ambient O2 levels restored the HRS effect, while cells cultured and irradiated at ambient O2 levels and then transferred to 5% O2 exhibited little or no HRS, indicating that ambient O2 levels after, but not before, radiation substantially affect the amounts of cytogenetic damage. HRS was not observed when cells were irradiated in G1. At doses of 40-400 cGy there was significantly less cytogenetic damage when cells were recovering from radiation at low O2 levels than at ambient O2 levels. Here we provide the first cytogenetic evidence for the loss of HRS at low O2 levels in G2-irradiated cells; these results suggest that at low O2 levels for all doses evaluated there is either less damage to DNA, perhaps because of lower amounts of reactive oxygen species, or that DNA damage repair pathways are activated more efficiently. PMID- 25808122 TI - Objective and subjective image quality of primary and recurrent squamous cell carcinoma on head and neck low-tube-voltage 80-kVp computed tomography. AB - INTRODUCTION: To investigate low-tube-voltage 80-kVp computed tomography (CT) of head and neck primary and recurrent squamous cell carcinoma (SCC) regarding objective and subjective image quality. METHODS: We retrospectively evaluated 65 patients (47 male, 18 female; mean age: 62.1 years) who underwent head and neck dual-energy CT (DECT) due to biopsy-proven primary (n = 50) or recurrent (n = 15) SCC. Eighty peak kilovoltage and standard blended 120-kVp images were compared. Attenuation and noise of malignancy and various soft tissue structures were measured. Tumor signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Subjective image quality was rated by three reviewers using 5 point grading scales regarding overall image quality, lesion delineation, image sharpness, and image noise. Radiation dose was assessed as CT dose index volume (CTDIvol). Interobserver agreement was calculated using intraclass correlation coefficient (ICC). RESULTS: Mean tumor attenuation (153.8 Hounsfield unit (HU) vs. 97.1 HU), SNR (10.7 vs. 8.3), CNR (8.1 vs. 4.8), and subjective tumor delineation (score, 4.46 vs. 4.13) were significantly increased (all P < 0.001) with 80-kVp acquisition compared to standard blended 120-kVp images. Noise of all measured structures was increased in 80-kVp acquisition (P < 0.001). Overall interobserver agreement was good (ICC, 0.86; 95 % confidence intervals: 0.82 0.89). CTDIvol was reduced by 48.7 % with 80-kVp acquisition compared to standard DECT (4.85 +/- 0.51 vs. 9.94 +/- 0.81 mGy cm, P < 0.001). CONCLUSIONS: Head and neck CT with low-tube-voltage 80-kVp acquisition provides increased tumor delineation, SNR, and CNR for CT imaging of primary and recurrent SCC compared to standard 120-kVp acquisition with an accompanying significant reduction of radiation exposure. PMID- 25808125 TI - Red blood cell distribution width as a link between ineffective erythropoiesis and chronic inflammation in heart failure. PMID- 25808124 TI - Progressive thrombosis of small saccular aneurysms filled with contrast immediately after coil embolization: analysis of related factors and long-term follow-up. AB - INTRODUCTION: Although it is well-known that incomplete occlusion of aneurysms after coil embolization predisposes to later recanalization, not all aneurysms will be fully occluded by coiling. In follow-up, we evaluated outcomes of small aneurysms (<10 mm) that showed filling of the sac with contrast immediately after coil embolization and assessed factors implicated in subsequent progressive thrombosis. METHODS: Between January 2008 and December 2010, a total of 1035 aneurysms in 898 patients were treated by endovascular coiling. Of these, 210 small aneurysms displayed filling of the sac by contrast immediately after coil embolization. Time-of-flight magnetic resonance angiography (TOF-MRA; at 6, 12, 24, and 36 months) and digital subtraction angiography (as needed) were used for postoperative monitoring. Complete occlusion of these aneurysms at the 6-month follow-up point was attributed to progressive thrombosis. RESULTS: In 186 (88.5 %) of the 210 aneurysms that showed filling of the sac with contrast, complete occlusion was observed on follow-up imaging studies at 6 months. Multiple logistic regression analysis indicated that progressive thrombosis was linked to aneurysmal neck diameter <=4 mm (p < 0.001) and packing density >30 % (p = 0.016). Aneurysms originating from non-branching vessels were of marginal statistical significance (p = 0.056). In 179 progressively thrombosed aneurysms with follow-up evaluations of >=12 months (mean, 31.9 +/- 7.6 months), 168 aneurysms (93.9 %) exhibited stable occlusion, whereas minor recanalization was observed in 6 (3.3 %) instances, and major recanalization occurred in 5 (2.8 %). CONCLUSIONS: In aneurysms where filling of the sac with contrast was demonstrable after coil embolization, aneurysms with small neck diameters or high coil packing density, and non-branching aneurysms seem predisposed to progressive intra aneurysmal thrombosis over the course of time. PMID- 25808123 TI - Hidden spondylolisthesis: unrecognized cause of low back pain? Prospective study about the use of dynamic projections in standing and recumbent position for the individuation of lumbar instability. AB - INTRODUCTION: Dynamic X-rays (DXR) are widely recognized as an effective method to detect lumbar instability (LI). They are usually performed with the patient in standing position (SDXR). In our opinion, standing position inhibits micromovements of the lumbar segment interested by the listhesis, thanks to paravertebral muscles antalgic contraction and augmented tone. We aim to demonstrate that DXR in recumbent position (RDXR), reducing the action of paravertebral muscles, can discover hypermovements not evidenced in SDXR. METHODS: Between January 2011 and January 2013, we studied 200 consecutive patients with lumbar degenerative disease with MRI, SDXR, and RDXR. We aimed to find a correlation between low back or radicular pain and the presence of a spondylolisthesis not showed by the SDXR, but showed by the RDXR. RESULTS: We analysed 200 patients: of the 133 not pathologic in SDXR, 43 patients (32.3 %) showed an hypermovement in RDXR (p = 0.0001) without any significant correlation between hidden listhesis and age, sex, or level involved. CONCLUSIONS: The aim of our study is to determine whether in patients with lumbalgy without evidence of listhesis in SDXR, pain can be attributed to a faccettal syndrome or to a spondylolisthesis. Consequence of pain is augmented muscular tone of the paravertebral musculature, particularly in standing position. Augmented muscular tone tries to inhibit the pain generator, attempting to limit the slippage of the involved segment. In patients examined in RDXR, the tone of paravertebral musculature is reduced, showing the hidden spondylolisthesis. PMID- 25808126 TI - Renin - a historical biomarker of heart failure - . PMID- 25808127 TI - Development of a chemically defined in vitro culture system to effectively stimulate the proliferation of adult human dermal fibroblasts. AB - Despite the fact that dermal fibroblasts are a practical model for research related to cell physiology and cell therapy, an in vitro culture system excluding serum, which complicates standardization and specificity and induces variability and unwanted effects, does not exist. We tried to establish a CDCS that supports effective proliferation of aHDFs. KDMEM supplemented with 5% (v/v) KSR, 12 ng/ml bFGF, 5 ng/ml EGF and 1 MUg/ml hydrocortisone supported sufficient proliferation of aHDFs for 1 week. However, aHDF proliferation was decreased greatly after subculture. This problem could be overcome by culturing aHDFs in CDCM in culture plates coated with 10 MUg/ml FN. Long-term culture of aHDFs was achieved using CDCM and FN-coated culture plates for 7 weeks. The optimized CDCS increased the proliferation of aHDFs significantly, without any increase in the senescence rate or alteration in morphology of aHDFs, despite long-term culture. In conclusion, we established a CDCS that improved proliferation of aHDFs while inhibiting cellular senescence. The CDCS will contribute to advances in various future research related to clinical skin regeneration. PMID- 25808128 TI - AIDS is not over. PMID- 25808129 TI - Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory. AB - The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus. PMID- 25808130 TI - Screening for secondhand smoke in schoolchildren in Japan. AB - BACKGROUND: There is no systematic screening for secondhand smoke exposure in children. METHODS: In 2002, we began a secondhand smoke screening (SSS) program for grade 4 elementary schoolchildren with the cooperation of public administration. The SSS program consisted of urinary cotinine measurement in children and a questionnaire survey of their parents. RESULTS: More than 1200 schoolchildren were enrolled in this program annually. The level of urinary cotinine in 30% of the children was >5 ng/mL, whereas in half of them it was undetectable. The major risk factor affecting cotinine level was mother's smoking. Average cotinine was significantly high in children who had a history of "short stature", "decayed tooth and/or periodontal disease," and "frequent stridor". In addition, the highest level of cotinine was detected in children whose father and/or mother smoked in the living room and the lowest level of cotinine was detected in children whose father and/or mother smoked on the veranda or outside the door. These levels, however, were two-fivefold higher than in children whose parents did not smoke. On follow-up questionnaire survey 4 years after initial SSS, significant elevated motivation for smoking cessation was noted. CONCLUSIONS: The SSS program is a very simple mass screen that can be done using only a urine test and is very effective for motivating parents to stop smoking with regard to cost benefit. PMID- 25808131 TI - Expression of antimicrobial peptides and interleukin-8 during early stages of inflammation: An experimental gingivitis study. AB - BACKGROUND AND OBJECTIVES: In the oral cavity, the epithelial surface is constantly exposed to a number of different microorganisms that are organized in a well-structured biofilm. The aim of this study was to monitor gingival expression of antimicrobial peptides (AMPs) and interleukin-8 (IL-8) in an early gingivitis model. MATERIAL AND METHODS: Experimental gingivitis was allowed to develop in healthy volunteers (n = 17). Bleeding on probing (BOP%) and gingival crevicular fluid volume (GCF) were assessed at baseline and day 1, 3, 5, 7 and 14. Expression of AMPs (human beta-defensin-2, hBD-2; CC-chemokine ligand 20, CCL20; psoriasin, pso/S100A7) and IL-8 was analyzed by immunohistochemistry in gingival biopsies. In addition, hBD-2 and IL-8 protein expression was monitored in GCF using the ELISA technology. RESULTS: Experimental gingivitis gradually developed with an increase in BOP scores and GCF volume over time. In GCF, elevated concentrations of hBD-2 and IL-8 were monitored at day 1, 5 and 7 (p <= 0.0002). Immunohistochemical analysis of gingival sections demonstrated increased staining for hBD-2 at day 3, whereas the CCL20, pso/S100A7, and IL-8 expression was increased at later time points (p < 0.05). CONCLUSION: For the first time, this study showed the time-dependent regulation of AMPs, following clinical signs of experimentally induced gingival inflammation. Differential temporal expression for AMPs may ensure a constant antimicrobial activity against changes in the bacterial composition of the growing dental biofilm. PMID- 25808132 TI - Gender differences in one-year outcomes of first-presentation psychosis patients in inner-city UK Early Intervention Services. AB - AIM: Men and women have historically been shown to differ in their presentation and outcome of psychotic disorders and thus are likely to have different treatment needs. It is unclear whether Early Intervention Services (EIS) are able to provide equitable care for both men and women presenting for the first time with psychosis. The main aim of this study was to explore gender differences for first-presentation psychosis patients at the time of their referral to inner-city EIS and their outcomes 1 year later. METHODS: Audit data were utilized from 1098 first-presentation psychosis patients from seven EIS across London, UK, collected via the computerized MiData package. Binary logistic regression was employed to detect potential associations between gender and (i) initial clinical presentation (including duration of untreated psychosis, pathways to care, risk behaviours); and (ii) 1-year clinical and functional outcomes. RESULTS: At entry to EIS, male patients presented with more violent behaviour whereas female patients had more suicide attempts. Following 1 year of EIS care, men still presented as more violent towards others whereas women were more likely to have been admitted to a psychiatric ward. CONCLUSION: Gender differences in clinical outcome, service use and risk behaviours were apparent within the first year of specialist psychosis care. This may be partly due to the different pathways to care taken by men and women and differences in clinical presentation. Greater focus on the specific needs of each gender by EIS in detection and intervention is required to improve equality of outcome. PMID- 25808133 TI - Statistical dictionaries for hypothetical in silico model of the early-stage intermediate in protein folding. AB - The polypeptide chain folding process appears to be a multi-stage phenomenon. The scientific community has recently devoted much attention to early stages of this process, with numerous attempts at simulating them--either experimentally or in silico. This paper presents a comparative analysis of the predicted and observed results of folding simulations. The proposed technique, based on statistical dictionaries, yields a global accuracy of 57%--a marked improvement over older approaches (with an accuracy of approximately 46%). PMID- 25808134 TI - Guidelines for the analysis of free energy calculations. AB - Free energy calculations based on molecular dynamics simulations show considerable promise for applications ranging from drug discovery to prediction of physical properties and structure-function studies. But these calculations are still difficult and tedious to analyze, and best practices for analysis are not well defined or propagated. Essentially, each group analyzing these calculations needs to decide how to conduct the analysis and, usually, develop its own analysis tools. Here, we review and recommend best practices for analysis yielding reliable free energies from molecular simulations. Additionally, we provide a Python tool, alchemical-analysis.py, freely available on GitHub as part of the pymbar package (located at http://github.com/choderalab/pymbar), that implements the analysis practices reviewed here for several reference simulation packages, which can be adapted to handle data from other packages. Both this review and the tool covers analysis of alchemical calculations generally, including free energy estimates via both thermodynamic integration and free energy perturbation-based estimators. Our Python tool also handles output from multiple types of free energy calculations, including expanded ensemble and Hamiltonian replica exchange, as well as standard fixed ensemble calculations. We also survey a range of statistical and graphical ways of assessing the quality of the data and free energy estimates, and provide prototypes of these in our tool. We hope this tool and discussion will serve as a foundation for more standardization of and agreement on best practices for analysis of free energy calculations. PMID- 25808136 TI - Postoperative abdominal collections drainage: Percutaneous versus guided by endoscopic ultrasound. AB - BACKGROUND AND AIM: Postoperative fluid collections (POFC) have high mortality. Percutaneous drainage (PD) is the preferred treatment modality. Drainage guided by endoscopic ultrasound (EUS-GD) represents a good alternative. The aim of the present study was to compare clinical success and complication rates of EUS-GD versus PD. METHODS: Data collected prospectively were analyzed in a retrospective manner. Patients with POFC from October 2008 to November 2013 were included. All collections were drained percutaneously or by EUS-GD. RESULTS: Sixty-three procedures in 43 patients with POFC were analyzed; 13 patients were drained using EUS-GD and 32 patients with PD. Two patients assigned initially to the PD group were reassigned to EUS-GD. Surgery procedures most often related to the collections were intestinal reconnection, distal pancreatectomy, biliary digestive bypass, and exploratory laparotomy. Technical success (100% vs 91%; P = 0.25), clinical success (100% vs 84%; P = 0.13), recurrence (31% vs 25%; P = 0.69), hospital stay days (median 22 vs 27; P = 0.35), total costs (8328 +/- 1600 USD vs 11 047 +/- 1206 USD; P = 0.21), complications (0% vs 6%; P = 0.3), and mortality (8% vs 6%; P = 0.9) were each evaluated in the EUS-GD and PD groups, respectively. In the PD group one death was related to the procedure. CONCLUSIONS: EUS-GD is as effective and safe as PD in patients with POFC. The advantage of not requiring external drainage and a trend to higher clinical success and lower total costs must be considered. PMID- 25808137 TI - Vocabulary Instruction on Sesame Street: A Content Analysis of the Word on the Street Initiative. AB - PURPOSE: Authors of this content analysis examined how Sesame Street's Word on the Street initiative aligns with research-based practices for selecting and teaching vocabulary to young children and considered how speech-language pathologists can use educational media to supplement traditional vocabulary instruction. METHOD: Study authors used a well-established vocabulary selection hierarchy to analyze 170 target words across 7 seasons of Word on the Street to judge appropriateness for preschool vocabulary instruction. The authors then coded vocabulary instruction across 96 episodes to determine frequency and types of teaching strategies used within this educational program. RESULTS: Target word selection was appropriate in 77% of episodes. Some instructional strategies were used frequently (e.g., exposure to a word, examples, and nonexamples), whereas others were used rarely (e.g., definitions, active learning). Across episodes, there was substantial variability in how many opportunities children had to learn words. CONCLUSIONS: Vocabulary instruction during Word on the Street could be improved by targeting only high-utility words, maximizing learning opportunities during all segments, and increasing strategies that promote deep processing. Although research is needed to examine word learning during Word on the Street, speech-language pathologists may find selected segments targeting Tier 2 words useful for augmenting traditional intervention approaches. PMID- 25808135 TI - Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3). AB - Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Calpha helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments. PMID- 25808139 TI - High Uric Acid Levels During Pregnancy Linked to Increased Risk for Future Atherosclerotic-Related Hospitalization. AB - The aim of this study was to examine the association between uric acid (UA) level during pregnancy and future maternal hospitalization for atherosclerotic-related morbidity. A case-control study was conducted including women who delivered between the years 2000 to 2012 and subsequently developed atherosclerotic morbidity at least 1 year after their last delivery (n=588) and controls (n=3645). The mean follow-up duration was 57.8+/-35.6 months and 77+/-43.4 months, respectively. Cox proportional hazards models were used to estimate the adjusted hazard ratios for hospitalizations. A significant linear association was documented between UA during pregnancy and long-term maternal-related atherosclerotic morbidity. A Cox proportional hazard model, controlling for the confounders gestational hypertension, gestational diabetes mellitus, obesity, maternal age, creatinine level, and gestational week at index pregnancy showed that UA >=5.6 mg/dL during pregnancy remained independently associated with long term total hospitalization (adjusted hazard ratio, 1.47; 95% confidence interval, 1.16-1.86; P<.001). High UA level during pregnancy may predict maternal atherosclerotic morbidity. PMID- 25808138 TI - Development and validation of a high performance liquid chromatography method for determination of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non nucleoside reverse transcriptase inhibitor and its application to a pharmacokinetic study in rats. AB - A sensitive and selective high-performance liquid chromatographic (HPLC) method for determination of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non nucleoside reverse transcriptase inhibitor in rat plasma, was developed and validated. Chromatographic separation of W-1 and megestrol acetate (internal standard) was achieved on a reversed-phase C18 column at 25 degrees C. The mobile phase was consisted of acetonitrile-water (60:40, v/v) and pumped at a flow rate of 1.0 mL/min. The ultraviolet (UV) detector was set at the absorption wavelength of 284 nm. The calibration curve for W-1 was linear over the concentration range of 0.01-8 ug/mL and the lower limit of quantification was 10 ng/mL. The intra- and inter-day precision and accuracy were <8.9 and 5.3%, respectively. The extraction recoveries ranged from 97.9 to 101.6%. The validated HPLC method was successfully applied to a pharmacokinetic study of W-1 in rats. PMID- 25808140 TI - Mesenchymal Stromal Cell-Like Cells Set the Balance of Stimulatory and Inhibitory Signals in Monocyte-Derived Dendritic Cells. AB - The major reservoir of human multipotent mesenchymal stem/stromal cells (MSCs) is the bone marrow (BM) with the capability to control hematopoietic stem cell development. The regenerative potential of MSCs is associated with enhanced endogenous repair and healing mechanisms that modulate inflammatory responses. Our previous results revealed that MSC-like (MSCl) cells derived from pluripotent human embryonic stem cells resemble BM-derived MSCs in morphology, phenotype, and differentiating potential. In this study, we investigated the effects of MSCl cells on the phenotype and functions of dendritic cells (DCs). To assess how antiviral immune responses could be regulated by intracellular pattern recognition receptors of DCs in the presence of MSCl cells, we activated DCs with the specific ligands of retinoic acid-inducible gene-I (RIG-I) helicases and found that activated DCs cocultured with MSCl cells exhibited reduced expression of CD1a and CD83 cell surface molecules serving as phenotypic indicators of DC differentiation and activation, respectively. However, RIG-I-mediated stimulation of DCs through specific ligands in the presence of MSCl cells resulted in significantly higher expression of the costimulatory molecules, CD80 and CD86, than in the presence of BM-MSCs. In line with these results, the concentration of IL-6, IL-10, and CXCL8 was increased in the supernatant of the DC-MSCl cocultures, while the secretion of TNF-alpha, CXCL10, IL-12, and IFNgamma was reduced. Furthermore, the concerted action of mechanisms involved in the regulation of DC migration resulted in the blockade of cell migration, indicating altered DC functionality mediated by MSCl cell-derived signals and mechanisms resulting in a suppressive microenvironment. PMID- 25808145 TI - Digital acrometastasis. PMID- 25808146 TI - New synthesis method for sultone derivatives: synthesis, crystal structure and biological evaluation of S-CA. AB - There has been no remarkable progress in the synthesis of sultones in recent years. To facilitate more detailed studies of this functional group, we found a new method to synthesize the sulfonic acid lactone derivatives and finish its ring-closing reaction. A new sultone derivative, (E)-ethyl 4-oxo-6-styryl-3,4 dihydro-1,2-oxathiine-5-carboxylate 2,2-dioxide (S-CA), was synthesized and structurally identified by 1H-NMR, 13C-NMR, HMQC and X-ray single crystal diffraction analysis. The new rapid synthesis extended the method of ring-closing reaction of sulfonic acid lactone derivatives. The angiogenesis activities of S CA were evaluated by the chick chorioallantoic membrane (CAM) model. It could selectively suppress small angiogenesis in CAM, without influencing either middle and large angiogenesis. In addition, anticancer efficacy of S-CA was evaluated in vivo using a murine sarcoma S180 model. Reduction of the tumor weight and tumor HE staining regions demonstrated that S-CA (10 mg/kg, intraperitoneal injection) had potent inhibition effects and a 44.71% inhibitory rate in S180 mice. Moreover, an acute toxicity test showed that the LD50 value of S-CA via intraperitoneal injection was 25.624 mg/kg. PMID- 25808147 TI - Secondary metabolite localization by autofluorescence in living plant cells. AB - Autofluorescent molecules are abundant in plant cells and spectral images offer means for analyzing their spectra, yielding information on their accumulation and function. Based on their fluorescence characteristics, an imaging approach using multiphoton microscopy was designed to assess localization of the endogenous fluorophores in living plant cells. This method, which requires no previous treatment, provides an effective experimental tool for discriminating between multiple naturally-occurring fluorophores in living-tissues. Combined with advanced Linear Unmixing, the spectral analysis extends the possibilities and enables the simultaneous detection of fluorescent molecules reliably separating overlapping emission spectra. However, as with any technology, the possibility for artifactual results does exist. This methodological article presents an overview of the applications of tissular and intra-cellular localization of these intrinsic fluorophores in leaves and fruits (here for coffee and vanilla). This method will provide new opportunities for studying cellular environments and the behavior of endogenous fluorophores in the intracellular environment. PMID- 25808148 TI - (-)-Tarchonanthuslactone exerts a blood glucose-increasing effect in experimental type 2 diabetes mellitus. AB - A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant. PMID- 25808149 TI - Design, synthesis and insecticidal activity of novel phenylurea derivatives. AB - A series of novel phenylurea derivatives were designed and synthesized according to the method of active groups linkage and the principle of aromatic groups bioisosterism in this study. The structures of the novel phenylurea derivatives were confirmed based on ESI-MS, IR and 1H-NMR spectral data. All of the compounds were evaluated for the insecticidal activity against the third instars larvae of Spodoptera exigua Hiibner, Plutella xyllostella Linnaeus, Helicoverpa armigera Hubner and Pieris rapae Linne respectively, at the concentration of 10 mg/L. The results showed that all of the derivatives displayed strong insecticidal activity. Most of the compounds presented higher insecticidal activity against S. exigua than the reference compounds tebufenozide, chlorbenzuron and metaflumizone. Among the synthesized compounds, 3b, 3d, 3f, 4b and 4g displayed broad spectrum insecticidal activity. PMID- 25808151 TI - Synthesis of novel dihydropyridothienopyrimidin-4,9-dione derivatives. AB - A novel molecular scaffold, dihydropyridothienopyrimidin-4,9-dione, was synthesized from benzylamine or p-methoxybenzylamine in six steps involving successive ring closure to form a fused ring system composed of dihydropyridone, thiophene and pyrimidone. The pharmacological versatility of the dihydropyridothenopyrimidin-4,9-dione scaffold was demonstrated by inhibitory activity against metabotropic glutamate receptor subtype 1 (mGluR1), which shows that the title compounds can serve as an interesting scaffold for the discovery of potential bioactive molecules for the treatment of human diseases. PMID- 25808150 TI - Comparison of two species of Notopterygium by GC-MS and HPLC. AB - Notopterygii Rhizoma et Radix (Qianghuo), including Notopterygium incisum Ting ex H. T. Chang (NI) and Notopterygium franchetii H. de Boiss (NF), is an important traditional Chinese medicine. Of these two plants, NI, is more commonly used and has a much higher price in the marketplace. To compare these two plants, a combination of gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) was carried out, thus obtaining an overall characterization for both volatile and none-volatile compounds. Combined with hierarchical cluster analysis (HCA) and principal component analysis, GC-MS was successfully applied to distinguish NF and NI. The chemical constitutes of volatile oil in NI and NF were firstly compared in detail, and 1R-alpha-pinene, beta-pinene and 4-isopropyl-1-methyl-1,4-cyclohexadiene had great contribution to the discrimination. Fingerprints of 14 batches of Qinghuo samples were also established based on HPLC, and an obvious difference was found between the two species. The chromatographic fingerprints were further analyzed by similarity analysis and HCA. The present study is the first reported evaluation of two origins of Notopterygii Rhizoma et Radix by GC-MS and HPLC, which will facilitate quality control and its clinical application. PMID- 25808152 TI - Determination of the molecular weight of low-molecular-weight heparins by using high-pressure size exclusion chromatography on line with a triple detector array and conventional methods. AB - The evaluation of weight average molecular weight (Mw) and molecular weight distribution represents one of the most controversial aspects concerning the characterization of low molecular weight heparins (LMWHs). As the most commonly used method for the measurement of such parameters is high performance size exclusion chromatography (HP-SEC), the soundness of results mainly depends on the appropriate calibration of the chromatographic columns used. With the aim of meeting the requirement of proper Mw standards for LMWHs, in the present work the determination of molecular weight parameters (Mw and Mn) by HP-SEC combined with a triple detector array (TDA) was performed. The HP-SEC/TDA technique permits the evaluation of polymeric samples by exploiting the combined and simultaneous action of three on-line detectors: light scattering detectors (LALLS/RALLS); refractometer and viscometer. Three commercial LMWH samples, enoxaparin, tinzaparin and dalteparin, a gamma-ray depolymerized heparin (gamma-Hep) and its chromatographic fractions, and a synthetic pentasaccharide were analysed by HP SEC/TDA. The same samples were analysed also with a conventional HP-SEC method employing refractive index (RI) and UV detectors and two different chromatographic column set, silica gel and polymeric gel columns. In both chromatographic systems, two different calibration curves were built up by using (i) gamma-Hep chromatographic fractions and the corresponding Mw parameters obtained via HP-SEC/TDA; (ii) the whole gamma-Hep preparation with broad Mw dispersion and the corresponding cumulative distribution function calculated via HP-SEC/TDA. In addition, also a chromatographic column calibration according to European Pharmacopoeia indication was built up. By comparing all the obtained results, some important differences among Mw and size distribution values of the three LMWHs were found with the five different calibration methods and with HP SEC/TDA method. In particular, the detection of the lower molecular weight components turned out to be the most critical aspect. Whereas HP-SEC/TDA may underestimate species under 2 KDa when present in low concentration, other methods appeared to emphasize their content. PMID- 25808153 TI - Docking and antiherpetic activity of 2-aminobenzo[de]-isoquinoline-1,3-diones. AB - As part of our search for new compounds having antiviral effects, the prepared 2 aminonaphthalimide series was examined for its activity against the herpes simplex viruses HSV-1 and HSV-2. This represents the first study of the antiviral effects of this class of compounds. The new series of 2-amino-1H benzo[de]isoquinoline-1,3-diones was examined against HSV-1 and HSV-2 using a cytopathic effect inhibition assay. In terms of effective concentration (EC50), furaldehyde, thiophene aldehyde and allyl isothiocyanide derivatives 14-16 showed potent activity against HSV-1 (EC50 = 19.6, 16.2 and 17.8 MUg/mL), compared to acyclovir as a reference drug (EC50 = 1.8 MUg/mL). Moreover, 14 and 15 were found to exhibit valuable activity against HSV-2. Many of the tested compounds demonstrated weak to moderate EC50 values relative to their inactive parent compound (2-amino-1H-benzo[de]isoquinoline-1,3-dione), while compounds 7, 9, 13, 14, 15, 16, 21 and 22 were the most active set of antiviral compounds throughout this study. The cytotoxicity (CC50), EC50, and the selectivity index (SI) values were determined. In a molecular docking study, the ligand-receptor interactions of compounds 1-24 and their parent with the HSV-1 thymidine kinase active site were investigated using the Molegro Virtual Docker (MVD) software. Based on the potent anti-HSV properties of the previous naphthalimide condensate products, further exploration of this series of 2-amino-1H-benzo[de]isoquinoline-1,3-diones is warranted. PMID- 25808154 TI - Functional characterization of individual- and mixed-Burgundian Saccharomyces cerevisiae isolates for fermentation of Pinot noir. AB - Pinot noir has traditionally been fermented by native flora of multiple yeasts producing a complex combination of aromas and flavors. With the use of industrial dry yeasts, winemakers gained enological reliability and consistency in their wines, but lost diversity and complexity. This research evaluated the use of co culturing yeasts to fulfill this dual role. Fermentations of Burgundian Saccharomyces cerevisiae isolates and their mixtures were evaluated for their enological characteristics and production of volatile compounds, at 22 degrees C and 27 degrees C. The novel isolates were genetically unique and enologically equivalent to the industrial strains. Analysis of variance and principal component analysis of 25 headspace volatiles revealed differences among the yeasts and between the fermentation temperatures. Wines from the mixed-Burgundian isolates were most similar to one another and could be differentiated from the industrial strains at both 22 degrees C and 27 degrees C. Mixed-Burgundian wines at both temperatures had higher concentrations of ethyl esters and acetate esters, compared to the industrial strains which had higher concentrations of higher alcohols at 27 degrees C and higher concentration of other ethyl esters at 22 degrees C. Given the unique profiles of the co-cultured wines, this research offers winemakers a strategy for producing wines with unique and more complex characters without the risk of spontaneous fermentations. PMID- 25808155 TI - Antiviral activity of a nanoemulsion of polyprenols from ginkgo leaves against influenza A H3N2 and hepatitis B virus in vitro. AB - In order to improve the bioavailability levels of polyprenols (derived from ginkgo leaves (GBP)) in the human body, a GBP nanoemulsion was prepared, and its antiviral activity was evaluated against influenza A H3N2 and hepatitis B virus in vitro. METHODS: A GBP nanoemulsion was prepared by inversed-phase emulsification (IPE). Next, we investigated the antiviral activity of the GBP nanoemulsion on influenza A H3N2 and hepatitis B virus in vitro by the MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenlytetrezolium bromide) method. ELISA and the fluorescent quantitative PCR method were used to measure the content of HBsAg, HBeAg and DNA virus in human samples. RESULTS: The GBP nanoemulsion exhibited uniformity at an average particle size 97 nm with a hydrophilic-lipophilic balance (HLB) of 9.5. GBP is non-toxic to normal cells, hepatitis B virus DNA, hepatitis B virus antigen and HepG2215. Furthermore, GBP could reach a 70% virucidal activity and a 74.9% protection rate (*** p < 0.001) on MDCK cells infected with H3N2 virus at a high concentration of 100 MUg/mL. GBP had a good inhibition rate on HBsAg (52.11%, ** p < 0.01) at 50 MUg/mL and Day 9 of incubation, and a 67.32% inhibition effect on HBeAg at a high concentration of 100 MUg/mL and Day 9. GBP had good inhibition on HBV DNA with CT 18.6 and lower copies (** p < 0.01) at a middle concentration of 12.5 to 25 MUg/mL. CONCLUSIONS: The GBP nanoemulsion was very stable and non-toxic and had very strong antiviral activity against influenza A H3N2 and hepatitis B virus in vitro. The inhibitory effects and reactive mechanisms were similar to the drug, 3TC; by lengthening the incubation time and increasing the drug concentration, GBP has promising potential as an antiviral drug. PMID- 25808157 TI - A review of herbal medicines in wound healing. AB - Herbs have been integral to both traditional and non-traditional forms of medicine dating back at least 5000 years. The enduring popularity of herbal medicines may be explained by the perception that herbs cause minimal unwanted side effects. More recently, scientists increasingly rely on modern scientific methods and evidence-based medicine to prove efficacy of herbal medicines and focus on better understanding of mechanisms of their action. However, information concerning quantitative human health benefits of herbal medicines is still rare or dispersed, limiting their proper valuation. Preparations from traditional medicinal plants are often used for wound healing purposes covering a broad area of different skin-related diseases. Herbal medicines in wound management involve disinfection, debridement, and provision of a suitable environment for aiding the natural course of healing. Here we report on 22 plants used as wound healing agents in traditional medicine around the world. The aim of this review is therefore to review herbal medicines, which pose great potential for effective treatment of minor wounds. PMID- 25808158 TI - Anticoagulant-induced pseudothrombocytopenia in blood donors. PMID- 25808156 TI - Reduction of false positives in structure-based virtual screening when receptor plasticity is considered. AB - Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries. PMID- 25808159 TI - Defining the key clinical indicators for ineffective breathing pattern in paediatric patients: a meta-analysis of accuracy studies. AB - AIMS AND OBJECTIVES: The purpose of this study was to identify the key clinical indicators of ineffective breathing pattern among paediatric patients. BACKGROUND: When nurses perform clinical reasoning, certain characteristics represent the clinical indicators necessary to confirm the presence of a particular diagnosis. Some quantitative studies have reported the prevalence of ineffective breathing pattern in different samples of patients. However, these findings should be synthesised. DESIGN: Meta-analysis of quantitative nursing studies. METHODS: Studies were identified via systematic searches of CINAHL, LILACS, PubMed and Scopus using the key search terms 'ineffective', 'breathing' and 'pattern'. Additional quality-related inclusion criteria were gleaned from the Cochrane Collaboration for Systematic Reviews of Diagnostic Test Accuracy, the Standards for Reporting of Diagnostic Accuracy and the Quality Assessment of Diagnostic Accuracy Studies. The pertinent results from each study were extracted and analysed via meta-analysis. RESULTS: Six studies using paediatric populations met the inclusion criteria. Summary measures indicated that the following defining characteristics had the highest accuracy values for ineffective breathing pattern among children: bradypnoea, dyspnoea, nasal flaring, orthopnoea, tachypnoea and the use of accessory muscles to breathe. CONCLUSION: This meta-analysis provides information regarding the accuracy of the clinical indicators of ineffective breathing pattern from studies sampling diverse paediatric populations. RELEVANCE TO CLINICAL PRACTICE: Nurses can better use clinical indicators to infer the presence of ineffective breathing pattern when they are aware of the most relevant defining characteristics. Nursing students and professionals can also improve their critical thinking abilities and diagnostic reasoning based on these findings. PMID- 25808160 TI - Effects of moderate intensity static magnetic fields on human bone marrow-derived mesenchymal stem cells. AB - This study aimed to explore effects of static magnetic fields (SMFs) of moderate intensity (3-50 mT) as biophysical stimulators of proliferation and osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells (MSCs). MSCs were exposed to SMFs of three intensities: 3, 15, and 50 mT. Proliferation was assessed by cell counting and bromodeoxyuridine incorporation, and differentiation by measuring alkaline phosphatase (ALP) activity, calcium content, mineralized nodule formation, and transcripts of osteogenic markers. Moderate intensity SMFs increased cell proliferation, ALP activity, calcium release, and mineralized nodule formation in a dose- and time-dependent manner, which peaked at 15 mT. In the same manner, they upregulated expression of osteogenic marker genes such as ALP, bone sialoprotein 2 (BSP2), collagen1a1 (COL1a1), osteocalcin (OCN), osteonectin (ON), osteopontin (OPN), osterix (OSX), and runt-related transcription factor 2 (RUNX2) with peak at 15 mT after 14 or 21 days of exposure. Results demonstrate that moderate intensity SMFs promote proliferation and osteoblastic differentiation of MSCs. This effect could help to improve MSC responses during osseointegration between a dental implant and surrounding bone. PMID- 25808161 TI - Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores. AB - CONTEXT: The expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. OBJECTIVE: To investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. DESIGN: Prospective two-centre study. PATIENTS AND MEASUREMENTS: We analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n = 54) and metastatic (n = 27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. RESULTS: Sstr2 was the commonest sstr expressed (65.4%) and was co-expressed with sstr3 and sstr5 in 32.1% and 24.7% of the specimens, respectively. In 67 of 81 specimens (82.7%), there was concordance of sstr2 immunohistochemistry with SRS findings (P < 0.001). D2R was expressed in only 8 of 23 (34.8%) GI-NENs while was co-expressed with sstr2 in all cases. SRS grade, as per Krenning scale, was higher in metastatic foci, large-size (>2 cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r = 0.6, P < 0.001) and D2R (r = 0.5, P < 0.001) IHC intensity scores than tumour size (r = 0.4, P < 0.001) and sstr3 (r = 0.4, P < 0.001) intensity score. CONCLUSIONS: Sstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours. PMID- 25808163 TI - Enteric fever and its impact on returning travellers. AB - Enteric fever, a systemic illness, is caused by Salmonella enterica serovar Typhi or S. enterica serovar Paratyphi A, B or C. The organism is transmitted to humans by the faecal oral route and is endemic in countries with poor sanitation and lacking clean drinking water. There are around 27 million individuals infected with S. Typhi worldwide annually. Enteric fever is a particular problem in travellers to endemic areas, especially those visiting friends and relatives. Currently, the two main vaccines recommended for travellers are the Vi polysaccharide vaccine and the oral Ty21a vaccine. These internationally licensed vaccines are safe and effective against S. Typhi. However, there is currently no commercially available vaccine against S. Paratyphi, which is increasingly reported as a cause of enteric fever. Vaccine uptake and taking appropriate precautions are poor in travellers visiting friends and relatives abroad; this problem requires addressing. Ciprofloxacin is no longer recommended for empirical treatment of infection because of increasing reports of resistance, especially from South Asia. Ceftriaxone and azithromycin are currently the most commonly used antimicrobials for empirical treatment of enteric fever but resistance to both these agents is emerging. PMID- 25808162 TI - Atypical hemispheric specialization for faces in infants at risk for autism spectrum disorder. AB - Among the many experimental findings that tend to distinguish those with and without autism spectrum disorder (ASD) are face processing deficits, reduced hemispheric specialization, and atypical neurostructural and functional connectivity. To investigate the earliest manifestations of these features, we examined lateralization of event-related gamma-band coherence to faces during the first year of life in infants at high risk for autism (HRA; defined as having an older sibling with ASD) who were compared with low-risk comparison (LRC) infants, defined as having no family history of ASD. Participants included 49 HRA and 46 LRC infants who contributed a total of 127 data sets at 6 and 12 months. Electroencephalography was recorded while infants viewed images of familiar/unfamiliar faces. Event-related gamma-band (30-50 Hz) phase coherence between anterior-posterior electrode pairs for left and right hemispheres was computed. Developmental trajectories for lateralization of intra-hemispheric coherence were significantly different in HRA and LRC infants: by 12 months, HRA infants showed significantly greater leftward lateralization compared with LRC infants who showed rightward lateralization. Preliminary results indicate that infants who later met criteria for ASD were those that showed the greatest leftward lateralization. HRA infants demonstrate an aberrant pattern of leftward lateralization of intra-hemispheric coherence by the end of the first year of life, suggesting that the network specialized for face processing may develop atypically. Further, infants with the greatest leftward asymmetry at 12 months where those that later met criteria for ASD, providing support to the growing body of evidence that atypical hemispheric specialization may be an early neurobiological marker for ASD. PMID- 25808164 TI - Cellular innate immunity and restriction of viral infection: implications for lentiviral gene therapy in human hematopoietic cells. AB - Hematopoietic gene therapy has tremendous potential to treat human disease. Nevertheless, for gene therapy to be efficacious, effective gene transfer into target cells must be reached without inducing detrimental effects on their biological properties. This remains a great challenge for the field as high vector doses and prolonged ex vivo culture conditions are still required to reach significant transduction levels of clinically relevant human hematopoietic stem and progenitor cells (HSPCs), while other potential target cells such as primary macrophages can hardly be transduced. The reasons behind poor permissiveness of primary human hematopoietic cells to gene transfer partly reside in the retroviral origin of lentiviral vectors (LVs). In particular, host antiviral factors referred to as restriction factors targeting the retroviral life cycle can hamper LV transduction efficiency. Furthermore, LVs may activate innate immune sensors not only in differentiated hematopoietic cells but also in HSPCs, with potential consequences on transduction efficiency as well as their biological properties. Therefore, better understanding of the vector-host interactions in the context of hematopoietic gene transfer is important for the development of safer and more efficient gene therapy strategies. In this review, we briefly summarize the current knowledge regarding innate immune recognition of lentiviruses in primary human hematopoietic cells as well as discuss its relevance for LV-based ex vivo gene therapy approaches. PMID- 25808165 TI - Effects of air pollution-related heavy metals on the viability and inflammatory responses of human airway epithelial cells. AB - Various metals produced from human activity are ubiquitously detected in ambient air. The metals may lead to induction and/or exacerbation of respiratory diseases, but the significant metals and factors contributing to such diseases have not been identified. To compare the effects of each metal and different oxidation states of metals on human airway, we examined the viability and production of interleukin (IL)-6 and IL-8 using BEAS-2B cell line, derived from human airway epithelial cells. Airway epithelial cells were exposed to Mn(2+), V(4+), V(5+), Cr(3+), Cr(6+), Zn(2+), Ni(2+), and Pb(2+) at a concentration of 0.5, 5, 50, or 500 MUmol/L for 24 hours. Mn and V decreased the cell viability in a concentration-dependent manner, and V(5+) tended to have a greater effect than V(4+). The Cr decreased the cell viability, and (Cr(+6)) at concentrations of 50 and 500 MUmol/L was more toxic than (Cr(+3)). Zn at a concentration of 500 MUmol/L greatly decreased the cell viability, whereas Ni at the same concentration increased it. Pb produced fewer changes. Mn and Ni at a concentration of 500 MUmol/L induced the significant production of IL-6 and IL-8. However, most of the metals including (V(+4), V(+5)), (Cr(+3), Cr(+6)), Zn, and Pb inhibited the production of both IL-6 and IL-8. The present results indicate that various heavy metals have different effects on toxicity and the proinflammatory responses of airway epithelial cells, and those influences also depend on the oxidation states of the metals. PMID- 25808166 TI - GPs' perceptions and experiences of public awareness campaigns for cancer: a qualitative enquiry. AB - BACKGROUND: Public awareness campaigns for cancer are used to alert the UK population to symptoms which, if experienced, should be discussed with their general practitioner (GP). More timely diagnosis of cancer is assumed possible if patients with the appropriate symptoms present to GPs and GPs recognise the need to act on these symptoms. OBJECTIVE: To investigate GPs' perceptions and experiences of public awareness campaigns for cancer. METHODS: Semi-structured interviews with 55 GPs from practices in the North and North East of England and Greater London. Interviews were recorded and transcribed verbatim. Repeated reading of GP transcripts engendered thematic analysis and co-coding ensured legitimacy of findings. RESULTS: Participants supported the underpinning ethos of public health campaigns and articulated a commitment to engaging with patients with respect to cancer warning signs and symptoms despite the common perception that public awareness campaigns increased numbers of consultations. Tensions were evident with regard to increased demands on GP time and primary care resources during a period of major upheaval within the NHS. Concern was raised that some patients remain outwith the reach of campaign messages. The complexity of addressing how public health messages compete with other issues in people's lives was identified as challenging. CONCLUSIONS: General practitioners provided insight into why some members of the general public do not engage with public health messages. Public health/primary care interaction that incorporates GPs' knowledge of their patient populations could advance the search for solutions to a more robust approach to earlier cancer recognition and referral in primary care. PMID- 25808170 TI - Current status of chemically synthesized inhibitors of Ebola virus. AB - The current Ebola virus outbreak is unprecedented in its scope and international impact. Given that there are currently no approved antivirals to treat Ebola virus, there is urgency to conduct more rapid development and evaluation of Ebola antivirals. Recently, the World Health Organization identified a number of antivirals as high priority to include AVI-6002 (AVI-7537 and AVI-7539), BCX4430, brincidofovir, favipiravir, and TKM-100802. This review describes these chemically synthesized inhibitors of Ebola virus, relevant patent development and gives an update on their current status. PMID- 25808167 TI - Survival curves to support quality improvement in hospitals with excess 30-day mortality after acute myocardial infarction, cerebral stroke and hip fracture: a before-after study. AB - OBJECTIVES: To evaluate survival curves (Kaplan-Meier) as a means of identifying areas in the clinical pathway amenable to quality improvement. DESIGN: Observational before-after study. SETTING: In Norway, annual public reporting of nationwide 30-day in-and-out-of-hospital mortality (30D) for three medical conditions started in 2011: first time acute myocardial infarction (AMI), stroke and hip fracture; reported for 2009. 12 of 61 hospitals had statistically significant lower/higher mortality compared with the hospital mean. PARTICIPANTS: Three hospitals with significantly higher mortality requested detailed analyses for quality improvement purposes: Telemark Hospital Trust Skien (AMI and stroke), Ostfold Hospital Trust Fredrikstad (stroke), Innlandet Hospital Trust Gjovik (hip fracture). OUTCOME MEASURES: Survival curves, crude and risk-adjusted 30D before (2008-2009) and after (2012-2013). INTERVENTIONS: Unadjusted survival curves for the outlier hospitals were compared to curves based on pooled data from the other hospitals for the 30-day period 2008-2009. For patients admitted with AMI (Skien), stroke (Fredrikstad) and hip fracture (Gjovik), the curves suggested increased mortality from the initial part of the clinical pathway. For stroke (Skien), increased mortality appeared after about 8 days. The curve profiles were thought to reflect suboptimal care in various phases in the clinical pathway. This informed improvement efforts. RESULTS: For 2008-2009, hospital-specific curves differed from other hospitals: borderline significant for AMI (p=0.064), highly significant (p<=0.005) for the remainder. After intervention, no difference was found (p>0.188). Before-after comparison of the curves within each hospital revealed a significant change for Fredrikstad (p=0.006). For the three hospitals, crude 30D declined and they were non-outliers for risk-adjusted 30D for 2013. CONCLUSIONS: Survival curves as a supplement to 30D may be useful for identifying suboptimal care in the clinical pathway, and thus informing design of quality improvement projects. PMID- 25808168 TI - Expression of the IL-11 Gene in Metastatic Cells Is Supported by Runx2-Smad and Runx2-cJun Complexes Induced by TGFbeta1. AB - In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFbeta1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes in IL-11 expression. The IL-11 gene has Runx2, AP-1 sites and Smad binding elements located on the IL-11 promoter. Here, we demonstrated that Runx2-c-Jun as well as Runx2-Smad complexes upregulate IL-11 expression. Functional studies identified a significant loss of IL-11 expression in PC3 cells in the presence of the Runx2-HTY mutant protein, a mutation that disrupts Runx2 Smad signaling. In response to TGFbeta1 and in the presence of Runx2, we observed a 30-fold induction of IL-11 expression, accompanied by increased c-Jun binding to the IL-11 promoter. Immunoprecipitation and in situ co-localization studies demonstrated that Runx2 and c-Jun form nuclear complexes in PC3 cells. Thus, TGFbeta1 signaling induces two independent transcriptional pathways - AP-1 and Runx2. These transcriptional activators converge on IL-11 as a result of Runx2 Smad and Runx2-c-Jun interactions to amplify IL-11 gene expression that, together with Runx2, supports the osteolytic pathology of cancer induced bone disease. PMID- 25808169 TI - D-cycloserine combined with cue exposure therapy fails to attenuate subjective and physiological craving in cocaine dependence. AB - BACKGROUND: Based on preclinical studies showing that the partial N-methyl-D aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of cocaine self-administration and cocaine-induced conditioned place preference, we evaluated whether 50 mg of DCS would reduce craving to cocaine cues when combined with cue exposure (CE) in cocaine dependent humans. METHODS: In this double-blind placebo-controlled pilot study, 47 cocaine dependent participants were randomized to DCS or placebo (PBO), plus CE. Participants received DCS or PBO 30 minutes prior to two CE sessions, conducted one day apart. Craving and heart rate was assessed prior to CE sessions, during CE trials, and after CE trials. These measures were assessed again at a 1-week follow-up (session 3) after the second CE session. RESULTS: DCS failed to significantly attenuate cocaine cue reactivity based on subjective craving and physiological reactivity (heart rate) compared to PBO. The CE protocol, consisting of repeated exposure to drug cues combined with skills training, resulted in extinction to cocaine cues as suggested by decreased craving within and between sessions in both treatment conditions. All participants exhibited elevated heart rate with repeated exposures, demonstrating a potentiation in heart rate between sessions. CONCLUSIONS: 50 mg of DCS may not be effective for extinguishing reactivity to drug cues for individuals with cocaine dependence. SCIENTIFIC SIGNIFICANCE: Future studies examining the effect of DCS on facilitating extinction to drug cues should examine variations in cue exposure length, number of CE presentations, and timing of DCS dose administration prior to cue exposures, which may differentially impact drug cue reactivity. PMID- 25808172 TI - Characterization of five putative aspartate aminotransferase genes in the N2 fixing heterocystous cyanobacterium Anabaena sp. strain PCC 7120. AB - Aspartate and glutamate are two key amino acids used in biosynthesis of many amino acids that play vital role in cellular metabolism. Aspartate aminotransferases (AspATs) are required for channelling nitrogen (N(2)) between Glu and Asp in all life forms. Biochemical and genetic characterization of AspATs have been lacking in N(2)-fixing cyanobacteria. In this report, five putative AspAT genes (alr1039, all2340, alr2765, all4327 and alr4853) were identified in the N(2)-fixing heterocystous cyanobacterium Anabaena sp. PCC 7120. Five recombinant C-terminal hexahistidine-tagged AspATs (AspAT-H(6)) were overexpressed in Escherichia coli and purified to homogeneity. Biochemical analysis demonstrated that these five putative AspATs have authentic AspAT activity in vitro using aspartate as an amino donor. However, the enzymic activities of the five AspATs differed in vitro. Alr4853-H(6) showed the highest AspAT activity, while the enzymic activity for the other four AspATs ranged from 6.5 to 53.7 % activity compared to Alr4853 (100 %). Genetic characterization of the five AspAT genes was also performed by inactivating each individual gene. All of the five AspAT knockout mutants exhibited reduced diazotrophic growth, and alr4853 was further identified to be a Fox gene (requiring fixed N(2) for growth in the presence of oxygen). Four out of five P(aspAT)-gfp transcriptional fusions were constitutively expressed in both diazotrophic and nitrate-dependent growth conditions. Quantitative reverse transcriptase PCR showed that alr4853 expression was increased by 2.3-fold after 24 h of N(2) deprivation. Taken together, these findings add to our understanding of the role of AspATs in N(2)-fixing within heterocystous cyanobacteria. PMID- 25808171 TI - Dual orientation of the outer membrane lipoprotein Pal in Escherichia coli. AB - Peptidoglycan associated lipoprotein (Pal) of Escherichia coli (E. coli) is a characteristic bacterial lipoprotein, with an N-terminal lipid moiety anchoring it to the outer membrane. Since its discovery over three decades ago, Pal has been well studied for its participation in the Tol-Pal complex which spans the periplasm and has been proposed to play important roles in bacterial survival, pathogenesis and virulence. Previous studies of Pal place the lipoprotein in the periplasm of E. coli, allowing it to interact with Tol proteins and the peptidoglycan layer. Here, we describe for the first time, a subpopulation of Pal which is present on the cell surface of E. coli. Flow cytometry and confocal microscopy detect anti-Pal antibodies on the surface of intact E. coli cells. Interestingly, Pal is surface exposed in an 'all or nothing' manner, such that most of the cells contain only internal Pal, with fewer cells ( < 20 %) exhibiting surface Pal. PMID- 25808177 TI - Role of microenvironment on neuroblastoma SK-N-AS SDHB-silenced cell metabolism and function. AB - In solid tumors, neoplastic cells grow in contact with the so-called tumor microenvironment. The interaction between tumor cells and the microenvironment causes reciprocal metabolic reprogramming and favorable conditions for tumor growth and metastatic spread. To obtain an experimental model resembling the in vivo conditions of the succinate dehydrogenase B subunit (SDHB)-mutated paragangliomas (PGLs), we evaluated the effects of SDHB silencing on metabolism and proliferation in the human neuroblastoma cell line (SK-N-AS), cultured alone or in association with human fibroblasts. Silencing caused a 70% decrease in protein expression, an almost complete loss of the complex specific enzymatic activity, and a significant increase in HIF1alpha and HIF2alpha expression; it thus resembled the in vivo tumor cell phenotype. When compared with WT SK-N-AS cells, SDHB-silenced cells showed an altered metabolism characterized by an unexpected significant decrease in glucose uptake and an increase in lactate uptake. Moreover, silenced cells exhibited a significant increase in cell proliferation and metalloproteinase activity. When co-cultured with human fibroblasts, control cells displayed a significant decrease in glucose uptake and a significant increase in cell proliferation as compared with their mono-cultured counterparts. These effects were even more evident in co-cultured silenced cells, with a 70% decrease in glucose uptake and a 92% increase in cell proliferation as compared to their mono-cultured counterparts. The present data indicate for the first time, to our knowledge, that SDHB impairment causes metabolic and functional derangement of neural-crest-derived tumor cells and that the microenvironment, here represented by fibroblasts, strongly affects their tumor metabolism and growth capacity. PMID- 25808176 TI - Novelty and Inductive Generalization in Human Reinforcement Learning. AB - In reinforcement learning (RL), a decision maker searching for the most rewarding option is often faced with the question: What is the value of an option that has never been tried before? One way to frame this question is as an inductive problem: How can I generalize my previous experience with one set of options to a novel option? We show how hierarchical Bayesian inference can be used to solve this problem, and we describe an equivalence between the Bayesian model and temporal difference learning algorithms that have been proposed as models of RL in humans and animals. According to our view, the search for the best option is guided by abstract knowledge about the relationships between different options in an environment, resulting in greater search efficiency compared to traditional RL algorithms previously applied to human cognition. In two behavioral experiments, we test several predictions of our model, providing evidence that humans learn and exploit structured inductive knowledge to make predictions about novel options. In light of this model, we suggest a new interpretation of dopaminergic responses to novelty. PMID- 25808179 TI - Rethinking the capsid proteins of enveloped viruses: multifunctionality from genome packaging to genome transfection. AB - Regardless of the debate on whether there is a place for viruses in the tree of life, it is consensual that they co-evolve with their hosts under the pressure of genome minimization. The abundance of multifunctional viral structural proteins is a consequence of this pressure. The molecular key to multifunctionality is the existence of intrinsically disordered domains together with ordered domains in the same protein. Capsid proteins, the hallmark of viruses, are not exceptions because they have coexisting ordered and disordered domains that are crucial for multifunctionality. It is also frequent to find supercharged proteins (i.e. proteins for which the net charge per unit molecular mass is > +0.75/kDa) among viral capsid proteins. All flaviviruses having annotated proteins in the ExPASy Viralzone database have supercharged capsid proteins. Moreover, cell-penetrating sequences/domains are frequent in viral proteins, even when they are not supercharged. Altogether, the findings strongly suggest that the ability to translocate membranes was acquired, conserved and optimized throughout the evolution of some viral proteins as part of their multifunctionality. The fitness of capsid proteins to translocate membranes carrying genomes was experimentally demonstrated with dengue virus capsid protein. This protein is potentially able to help the fusion process and translocate the RNA genome across the hemifused membrane formed by the viral envelope and the endosomal membrane. In addition, one of the cell-penetrating domains of the capsid protein also has antibacterial activity. This may be reminiscent of parasitic bacteria-bacteria competition for the same host and shed light on the origins of enveloped viruses. PMID- 25808178 TI - Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria. AB - Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function, just like germline SDH-deficiency does. PMID- 25808181 TI - Comparison of the Stability of Functionalized GaN and GaP. AB - Surface functionalization via 1 H,1 H,2 H,2H-perfluoro octanephosphonic acid was done in the presence of phosphoric acid to provide a simplified surface passivation technique for gallium nitride (GaN) and gallium phosphide (GaP). In an effort to identify the leading causes of surface instabilities, hydrogen peroxide was utilized as an additional chemical modification to cap unsatisfied bonds. The stability of the surfaces was studied in an aqueous environment and subsequently characterized. A physical characterization was carried out to evaluate the surface roughness and water hydrophobicity pre and post stability testing via atomic force microscopy and water goniometry. Surface-chemistry changes and solution leaching were quantified by X-ray photoelectron spectroscopy and inductively coupled plasma mass spectrometry. The results indicate a sensitivity to hydroxyl terminated species for both GaN and GaP under aqueous environments, as the increase of the degree of leaching was more significant for hydrogen peroxide treated samples. The results support the notion that hydroxyl species act as precursors to gallium oxide formation and lead to subsequent instability in aqueous solutions. PMID- 25808180 TI - Sex-specific effects of protein and carbohydrate intake on reproduction but not lifespan in Drosophila melanogaster. AB - Modest dietary restriction extends lifespan (LS) in a diverse range of taxa and typically has a larger effect in females than males. Traditionally, this has been attributed to a stronger trade-off between LS and reproduction in females than in males that is mediated by the intake of calories. Recent studies, however, suggest that it is the intake of specific nutrients that extends LS and mediates this trade-off. Here, we used the geometric framework (GF) to examine the sex specific effects of protein (P) and carbohydrate (C) intake on LS and reproduction in Drosophila melanogaster. We found that LS was maximized at a high intake of C and a low intake of P in both sexes, whereas nutrient intake had divergent effects on reproduction. Male offspring production rate and LS were maximized at the same intake of nutrients, whereas female egg production rate was maximized at a high intake of diets with a P:C ratio of 1:2. This resulted in larger differences in nutrient-dependent optima for LS and reproduction in females than in males, as well as an optimal intake of nutrients for lifetime reproduction that differed between the sexes. Under dietary choice, the sexes followed similar feeding trajectories regulated around a P:C ratio of 1:4. Consequently, neither sex reached their nutritional optimum for lifetime reproduction, suggesting intralocus sexual conflict over nutrient optimization. Our study shows clear sex differences in the nutritional requirements of reproduction in D. melanogaster and joins the growing list of studies challenging the role of caloric restriction in extending LS. PMID- 25808182 TI - Childhood trauma and cortisol awakening response in symptomatic patients with anorexia nervosa and bulimia nervosa. AB - OBJECTIVE: Exposure to trauma during childhood is a risk factor for eating disorders (EDs) in adulthood. The biological mechanisms underlying such increased risk seem to involve the endogenous stress response system (i.e., the hypothalamic-pituitary-adrenal [HPA] axis), which undergoes trauma-induced functional changes that may persist later in life. In the present study, we examined the effects of childhood trauma experiences on HPA-axis activity, comparing saliva cortisol awakening response (CAR) in adult patients with anorexia nervosa (AN) or bulimia nervosa (BN) with CAR in adult healthy controls. METHOD: Twenty-three patients with symptomatic AN, 21 patients with symptomatic BN, and 29 healthy women collected saliva samples at awakening and again after 15, 30, and 60 min. Participants also completed the Childhood Trauma Questionnaire and eating-related psychopathological rating scales. RESULTS: According to the Childhood Trauma Questionnaire, 13 individuals with AN and 12 individuals with BN, but none of the healthy women, reported childhood maltreatment. Compared with the control group, the non-maltreated AN patient group exhibited an enhanced CAR, whereas the group of non-maltreated BN patients showed a normal CAR. Moreover, both AN and BN patient groups with childhood maltreatment exhibited statistically significant blunting of CAR compared with non-maltreated groups. DISCUSSION: The present findings add to the evidence supporting the concept that there is a dysregulation of HPA-axis activity in symptomatic patients with EDs and suggest that childhood trauma exposure may contribute to such dysregulation. PMID- 25808183 TI - What big data can and cannot tell us about emergency department quality for urolithiasis. PMID- 25808187 TI - The cost-effectiveness of identifying and treating malnutrition in hospitals: a systematic review. AB - BACKGROUND: Disease-related malnutrition is known to have significant clinical and economic consequences. This systematic review of recent evidence aimed to establish the cost-effectiveness of identifying and treating malnutrition in the hospital setting. METHODS: A search of four electronic databases and the Internet was conducted for relevant publications from 2003 to 2013. The search strategy considered both nutritional care and healthcare costs. Hospitalised adults with, or at risk of malnutrition, were the focus of the review. Eligibility criteria included publications of original research to identify or treat malnutrition through usual care. Studies with a focus on enteral and parenteral nutrition interventions were beyond the scope of the review. Methodological quality was assessed using the Consensus on Health Economic Criteria checklist. RESULTS: Of the 1174 records identified through database searching, 19 full-text articles were assessed for eligibility. Three studies were included in the final review, highlighting the absence of recent high quality cost-effectiveness studies in this field. One economic modelling study and two prospective clinical trials were included of moderate to high methodological quality. CONCLUSIONS: Definite conclusions could not be drawn regarding the cost-effectiveness of individual interventions because of the heterogeneity of treatments, controls and populations. The present review highlights an evidence gap in the care of malnourished hospitalised adults, limiting the ability of clinicians and healthcare managers to make informed, cost-effective treatment decisions. Further economic evaluations are needed and should be considered as a routine component of future research. PMID- 25808185 TI - Development and characterization of spray dried microparticles for pulmonary delivery of antifungal drug. AB - Invasive pulmonary aspergillosis is a life threatening fungal infection mainly caused by Aspergillus species. Available treatment strategy against pulmonary aspergillosis is having very limited applicability, due to its toxicity and low circulation half-life. Pulmonary drug delivery is one of the strategies that can minimize these pitfalls. In the present study, polymeric and lipidic nanoparticles of amphotericin B were prepared by spray drying technique using hydroxypropylmethylcellulose (HPMC) and stearylamine with oleic acid respectively. Formulations were characterized for particle size, zeta potential, entrapment efficiency, in-vitro release studies, uptake analysis and in-vivo bio distribution studies. Developed polymeric and nanostructured lipid carriers (NLCs) were found in submicron size (600-700nm) and spherical in shape. Studies suggested that NLCs have better entrapment efficiency (77.1+/-5.5 %) as compared to HPMC carrier (71.28+/-5.22 %). Both formulations provided sustained drug release (HPMC, 82.05% releases up to 32 hrs and NLC, 88.2 % up to 40 hrs) and reduced dose dumping that may be helpful to reduce the toxicity and improve patient compliance. In-vitro antifungal studies suggested that stearylamine formulations exhibited better antifungal activity over control and HPMC formulations. Pharmacokinetic and organ distribution studies also support our hypothesis i.e. localized drug delivery for prolong period, improving the therapeutic effectiveness of the encapsulated drug against pulmonary aspergillosis. Studies suggested that drug delivery by pulmonary route is beneficial for local action in lungs. PMID- 25808184 TI - Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis. AB - Matrix metalloproteinases (MMPs) participate in tissue repair after acute injury, but also participate in cancer by promoting a protumorigenic microenvironment. Previously, we reported on a key role for MMP10 in mouse liver regeneration. Herein, we investigated MMP10 expression and function in human hepatocellular carcinoma (HCC) and diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. MMP10 was induced in human and murine HCC tissues and cells. MMP10-deficient mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic, C-X-C chemokine receptor-4 (CXCR4), was reduced in DEN-induced MMP10-deficient mice livers. Human HCC cells stably expressing MMP10 had increased CXCR4 expression and migratory capacity. Pharmacological inhibition of CXCR4 significantly reduced MMP10-stimulated HCC cell migration. Furthermore, MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand, stromal-derived factor-1 (SDF1), through the extracellular signal-regulated kinase 1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter. CONCLUSION: MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis. To our knowledge, this is the first report addressing the role of a MMP in hepatocarcinogenesis in the corresponding genetic mouse model. PMID- 25808186 TI - The "New Polyethylene Glycol Dilemma": Polyethylene Glycol Impurities and Their Paradox Role in mAb Crystallization. AB - Polyethylene glycols (PEG) represent the most successful and frequently applied class of excipients used for protein crystallization. PEG auto-oxidation and formation of impurities such as peroxides and formaldehydes that foster protein drug degradation is known. However, their effect on mAb crystallization has not been studied in detail before. During the present study, a model IgG1 antibody (mAb1) was crystallized in PEG solutions. Aggregate formation was observed during crystallization and storage that was ascribed to PEG degradation products. Reduction of peroxide and formaldehyde levels prior to crystallization by vacuum and freeze-drying was investigated for its effect on protein degradation. Vacuum drying was superior in removal of peroxides but inferior in reducing formaldehyde residues. Consequently, double purification allowed extensive removal of both impurities. Applying of purified PEG led to 50% lower aggregate fractions. Surprisingly, PEG double purification or addition of methionine prior to crystallization prevented crystal formation. With increased PEG concentration or spiking with peroxides and formaldehydes, crystal formation could be recovered again. With these results, we demonstrate that minimum amounts of oxidizing impurities and thus in consequence chemically altered proteins are vital to initiate mAb1 crystallization. The present study calls PEG as good precipitant for therapeutic biopharmaceuticals into question. PMID- 25808188 TI - Effects of compression at myofascial trigger points in patients with acute low back pain: A randomized controlled trial. AB - BACKGROUND: Although there is some evidence that massage therapy, especially compression at myofascial trigger points (MTrPs), is effective for sub-acute and chronic low back pain, the effectiveness of massage therapy with compression at MTrPs for acute low back pain has not been studied. METHODS: To evaluate the effectiveness of compression at MTrPs for acute low back pain, 63 patients with acute low back pain were randomly assigned to one of three groups: the MTrP group who received compression at MTrPs (N = 23), the non-MTrP group who received compression at non-trigger points (N = 21), and the effleurage massage group who received superficial massage (N = 19). The patients received the assigned treatment 3 times/week for 2 weeks. The subjective pain intensity in static and dynamic conditions and disability caused by low back pain were measured by the visual analogue scale (VAS) and Roland-Morris questionnaire (RMQ), respectively; along with the range of motion (ROM) at the lumbar region and pressure pain threshold (PPT) at trigger points before treatment (baseline), 1 week after the start of treatment, and 1 month after the end of treatment (follow-up). RESULTS: Static and dynamic VAS score, PPT and ROM were significantly improved in the MTrP group compared with those in the non-MTrP and effleurage groups. CONCLUSIONS: These results indicate that compression at MTrPs is effective to treat acute low back pain compared with compression at non-MTrPs and superficial massage. For this article, a commentary is available at the Wiley Online Library. PMID- 25808189 TI - Asymmetric 1,2-perfluoroalkyl migration: easy access to enantioenriched alpha hydroxy-alpha-perfluoroalkyl esters. AB - This study has led to the development of a novel, highly efficient, 1,2-perfluoro alkyl/-aryl migration process in reactions of hydrate of 1-perfluoro-alkyl/-aryl 1,2-diketones with alcohols, which are promoted by a Zn(II)/bisoxazoline and form alpha-perfluoro-alkyl/-aryl-substituted alpha-hydroxy esters. With (-)-8 phenylmenthol as the alcohol, the corresponding menthol esters are generated in high yields with excellent levels of diastereoselectivity. The mechanistic studies show that the benzilic ester-type rearrangement reaction takes place via an unusual 1,2-migration of electron-deficient trifluoromethyl group rather than the phenyl group. The overall process serves as a novel, efficient, and simple approach for the synthesis of highly enantioenriched, biologically relevant alpha hydroxy-alpha-perfluoroalkyl carboxylic acid derivatives. PMID- 25808191 TI - Ln0.5 A0.5 MnO3 (Ln=Lanthanide, A= Ca, Sr) Perovskites Exhibiting Remarkable Performance in the Thermochemical Generation of CO and H2 from CO2 and H2 O. AB - Perovskite oxides of the Ln0.5 A0.5 MnO3 (Ln=lanthanide, A=Sr, Ca) family have been investigated for the thermochemical splitting of H2 O and CO2 to produce H2 and CO respectively. The amounts of O2 and CO produced strongly depend on the size of the rare earth ions and alkaline earth ions. The manganite with the smallest rare earth possessing the highest distortion and size disorder as well as the smallest tolerance factor, gives out the maximum amount of O2 , and, hence, the maximum amount of CO. Thus, the best results are found with Y0.5 Sr0.5 MnO3 , which possesses the highest distortion and size disorder. Y0.5 Sr0.5 MnO3 shows remarkable fuel production activity even at the reduction and oxidation temperatures as low as 1200 degrees C and 900 degrees C, respectively. PMID- 25808190 TI - Imaging chemical exchange saturation transfer (CEST) effects following tumor selective acidification using lonidamine. AB - Increased lactate production through glycolysis in aerobic conditions is a hallmark of cancer. Some anticancer drugs have been designed to exploit elevated glycolysis in cancer cells. For example, lonidamine (LND) inhibits lactate transport, leading to intracellular acidification in cancer cells. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on intracellular pH. Amine and amide concentration-independent detection (AACID) and apparent amide proton transfer (APT*) represent two recently developed CEST contrast parameters that are sensitive to pH. The goal of this study was to compare the sensitivity of AACID and APT* for the detection of tumor-selective acidification after LND injection. Using a 9.4-T MRI scanner, CEST data were acquired in mice approximately 14 days after the implantation of 10(5) U87 human glioblastoma multiforme (GBM) cells in the brain, before and after the administration of LND (dose, 50 or 100 mg/kg). Significant dose dependent LND-induced changes in the measured CEST parameters were detected in brain regions spatially correlated with implanted tumors. Importantly, no changes were observed in T1- and T2-weighted images acquired before and after LND treatment. The AACID and APT* contrast measured before and after LND injection exhibited similar pH sensitivity. Interestingly, LND-induced contrast maps showed increased heterogeneity compared with pre-injection CEST maps. These results demonstrate that CEST contrast changes after the administration of LND could help to localize brain cancer and monitor tumor response to chemotherapy within 1 h of treatment. The LND CEST experiment uses an anticancer drug to induce a metabolic change detectable by endogenous MRI contrast, and therefore represents a unique cancer detection paradigm which differs from other current molecular imaging techniques that require the injection of an imaging contrast agent or tracer. PMID- 25808192 TI - Whole-body muscle magnetic resonance imaging in SEPN1-related myopathy shows a homogeneous and recognizable pattern. AB - INTRODUCTION: The aim of this study was to delineate the spectrum of muscle involvement in patients with a myopathy due to mutations in SEPN1 (SEPN1-RM). METHODS: Whole-body magnetic resonance imaging (WBMRI) was used in 9 patients using T1-weighted turbo spin-echo (T1-TSE) sequences and short tau inversion recovery (STIR) in 5 patients. RESULTS: Analysis of signal and volume abnormalities by T1-TSE sequences in 109 muscles showed a homogeneous pattern characterized by a recognizable combination of atrophy and signal abnormalities in selected muscles of the neck, trunk, pelvic girdle, and lower limbs. Severe wasting of sternocleidomastoid muscle and atrophy of semimembranosus were detected. Selective paraspinal, gluteus maximus, and thigh muscle involvement was also observed. The lower leg was less constantly affected. CONCLUSIONS: WBMRI scoring of altered signal and atrophy in muscle can be represented by heatmaps and is associated with a homogeneous, recognizable pattern in SEPN1-RM, distinct from other genetic muscle diseases. PMID- 25808194 TI - KDIGO Guidelines and Kidney Transplantation: Is the Cystatin-C Based Recommendation Relevant? AB - The KDIGO guidelines propose a new approach to diagnose chronic kidney disease (CKD) based on estimated glomerular filtration rate (GFR). In patients with a GFR value comprised between 45 and 59 mL/min/1.73 m(2) as estimated by the CKD-EPI creatinine equation (eGFRcreat ), it is suggested to confirm the diagnosis with a second estimation using the CKD-EPI cystatin C-based equations (eGFRcys /eGFRcreat-cys) . We sought to determine whether this new diagnostic strategy might extend to kidney transplant recipients (KTR) and help to identify those with decreased GFR. In 670 KTR for whom a measured GFR was available, we simulated the detection of CKD using the two-steps approach recommended by the guidelines in comparison to the conventional approach relying on creatinine equation. One hundred forty-five patients with no albuminuria had eGFRcreat between 45 and 59 mL/min/1.73 m(2) . Among them, 23% had inulin clearance over 60 mL/min/1.73 m(2) and were thus incorrectly classified as CKD patients. When applying the Kidney Disease: Improving Global Outcomes (KDIGO) strategy, 138 patients were confirmed as having a GFR below 60 mL/min with eGFRcreat-cys . However, 21% of them were misclassified in reference to measured GFR. Our data do no not support the use of cystatin C as a confirmatory test of stage 3 A CKD in KTR. PMID- 25808193 TI - Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. AB - Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria. PMID- 25808195 TI - A strategy to improve treatment-related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays. AB - BACKGROUND: Treatment-related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world. PROCEDURE: A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper-middle income country, and Dana-Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced-intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact. RESULTS: The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995-2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P < 0.001), and event-free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy >=4 weeks delayed predicted markedly inferior disease-free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high income countries. CONCLUSIONS: Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. PMID- 25808197 TI - Clear cell carcinoid of the appendix: Report of two cases with literature review. AB - The clear cell/lipid-rich change has been described in neuroendocine tumors in several organs, but rarely observed in the appendix. In this study, we describe the morphologic, immunohistochemical features of incidentally discovered appendiceal carcinoids entirely represented by clear cells in a 22-year-old man and a 52-year-old woman. Ultrastructual examination demonstrated abundant lipid droplets and dense core granules. The mechanism leading to lipid accumulation in the cytoplasm has not been discovered, but degenerative processes following recurrent inflammatory change might be considered. This uncommon variant of appendiceal classic carcinoid tumors may bear a superficial resemblance to goblet carcinoid and/or appendiceal metastases from clear cell carcinoma. Awareness of clear cell carcinoid of the appendix will prevent incorrect diagnosis and unnecessary aggressive management. PMID- 25808198 TI - Increased incidence of admissions for anaphylaxis in Spain 1998-2011. AB - We report on trends in anaphylaxis admissions in the Spanish hospital system during the period 1998-2011. Data on admissions for anaphylaxis were obtained from the Spanish Information System for Hospital Data for the period 1998-2011. Patients were selected using the codes for anaphylaxis in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Poisson regression models were used to estimate incidence rate ratios. We recorded a 1.89-fold increase in admissions for anaphylaxis in Spanish hospitals during the study period, particularly in patients aged 0-14 years (1.65- to 3.22 fold until 2009 and 4.09- to 12.59-fold until 2011) and in food anaphylaxis in all age groups (2.78-fold until 2009 and 8.74-fold until 2011). The incidence of anaphylaxis is perceived as having increased in recent years, especially anaphylaxis caused by food and anaphylaxis affecting the pediatric population. PMID- 25808196 TI - Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR inhibitor and low dosed interferon alpha in prostate cancer cells. AB - A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNalpha) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin alpha and beta subtypes were investigated by flow cytometry, western blotting and RT-PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNalpha blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNalpha might be a promising option to counteract resistance development and improve outcome in PCa patients. PMID- 25808199 TI - Alkynyl-protected Au23 nanocluster: a 12-electron system. AB - A 23-gold-atom nanocluster was prepared by NaBH4-mediated reduction of a solution of PhC=CAu and Ph3PAuSbF6 in CH2Cl2. The cluster composition was determined to be [Au23(PhC=C)9(Ph3P)6](2+) and single-crystal X-ray diffraction revealed that the cluster has an unprecedented Au17 kernel protected by three PhC2-Au-C2 (Ph)-Au-C2 Ph motifs and six Ph3P groups. The Au17 core can be viewed as the fusion of two Au10 units sharing a Au3 triangle. Electronic structure analysis from DFT calculations suggests that the stability of this unusual 12-electron cluster is a result of the splitting of the superatomic 1D orbitals under D3h symmetry of the Au17 kernel. The discovery and determination of the structure of the Au23 cluster demonstrates the versatility of the alkynyl ligand in leading to the formation of new cluster compounds. PMID- 25808200 TI - Exploring educational disparities in risk of preterm delivery: a comparative study of 12 European birth cohorts. AB - BACKGROUND: An association between education and preterm delivery has been observed in populations across Europe, but differences in methodology limit comparability. We performed a direct cross-cohort comparison of educational disparities in preterm delivery based on individual-level birth cohort data. METHODS: The study included data from 12 European cohorts from Denmark, England, France, Lithuania, the Netherlands, Norway, Italy, Portugal, and Spain. The cohorts included between 2434 and 99 655 pregnancies. The association between maternal education and preterm delivery (22-36 completed weeks of gestation) was reported as risk ratios, risk differences, and slope indexes of inequality with 95% confidence intervals (CIs). RESULTS: Singleton preterm live delivery proportion varied between 3.7% and 7.5%. There were large variations between the cohorts in the distribution of education and maternal characteristics. Nevertheless, there were similar educational differences in risk of preterm delivery in 8 of the 12 cohorts with slope index of inequality varying between 2.2 [95% CI 1.1, 3.3] and 4.0 [95% CI 1.4, 6.6] excess preterm deliveries per 100 singleton deliveries among the educationally most disadvantaged, and risk ratio between the lowest and highest education category varying from 1.4 [95% CI 1.1, 1.8] to 1.9 [95% CI 1.2, 3.1]. No associations were found in the last four cohorts. CONCLUSIONS: Educational disparities in preterm delivery were found all over Europe. Despite differences in the distributions of education and preterm delivery, the results were remarkably similar across the cohorts. For those few cohorts that did not follow the pattern, study and country characteristics did not explain the differences. PMID- 25808201 TI - Simulation of Ventricular, Cavo-Pulmonary, and Biventricular Ventricular Assist Devices in Failing Fontan. AB - Considering the lack of donors, ventricular assist devices (VADs) could be an alternative to heart transplantation for failing Fontan patients, in spite of the lack of experience and the complex anatomy and physiopathology of these patients. Considering the high number of variables that play an important role such as type of Fontan failure, type of VAD connection, and setting (right VAD [RVAD], left VAD [LVAD], or biventricular VAD [BIVAD]), a numerical model could be useful to support clinical decisions. The aim of this article is to develop and test a lumped parameter model of the cardiovascular system simulating and comparing the VAD effects on failing Fontan. Hemodynamic and echocardiographic data of 10 Fontan patients were used to simulate the baseline patients' condition using a dedicated lumped parameter model. Starting from the simulated baseline and for each patient, a systolic dysfunction, a diastolic dysfunction, and an increment of the pulmonary vascular resistance were simulated. Then, for each patient and for each pathology, the RVAD, LVAD, and BIVAD implantations were simulated. The model can reproduce patients' baseline well. In the case of systolic dysfunction, the LVAD unloads the single ventricle and increases the cardiac output (CO) (35%) and the arterial systemic pressure (Pas) (25%). With RVAD, a decrement of inferior vena cava pressure (Pvci) (39%) was observed with 34% increment of CO, but an increment of the single ventricle external work (SVEW). With the BIVAD, an increment of Pas (29%) and CO (37%) was observed. In the case of diastolic dysfunction, the LVAD increases CO (42%) and the RVAD decreases the Pvci, while both increase the SVEW. In the case of pulmonary vascular resistance increment, the highest CO (50%) and Pas (28%) increment is obtained with an RVAD with the highest decrement of Pvci (53%) and an increment of the SVEW but with the lowest VAD power consumption. The use of numerical models could be helpful in this innovative field to evaluate the effect of VAD implantation on Fontan patients to support patient and VAD type selection personalizing the assistance. PMID- 25808203 TI - Steatocystoma multiplex with hair shaft abnormalities. AB - Steatocystoma multiplex (SM) is an unusual benign disorder of the pilosebaceous duct characterized by multiple cysts with little or no nail and hair involvement. We report a 30-year-old woman with multiple cystic nodules located on the neck, axillae and forearms as well as patchy scalp alopecia. Histopathological examination of the lesions was diagnostic of SM. Trichoscopy revealed pili torti and pili canaliculi. This patient represents an unusual clinical presentation of SM because of the presence of hair abnormalities. PMID- 25808202 TI - The Rural Obstetric Workforce in US Hospitals: Challenges and Opportunities. AB - PURPOSE: The purpose of this study was to describe the types and combinations of clinicians who are delivering babies in rural hospitals, their employment status, the relationship between hospital birth volume and staffing models, and the staffing challenges faced by rural hospitals. METHODS: We conducted a telephone survey of 306 rural hospitals in 9 states: Colorado, Iowa, Kentucky, New York, North Carolina, Oregon, Vermont, Washington, and Wisconsin, from November 2013 to March 2014 to assess their obstetric workforce. Bivariate associations between hospitals' annual birth volume and obstetric workforce characteristics were examined, as well as qualitative analysis of workforce changes and staffing challenges. FINDINGS: Hospitals with lower birth volume (<240 births per year) are more likely to have family physicians and general surgeons attending deliveries, while those with a higher birth volume more frequently have obstetricians and midwives attending deliveries. Reported staffing challenges include scheduling, training, census fluctuation, recruitment and retention, and intrahospital relationships. CONCLUSIONS: Individual hospitals working in isolation may struggle to address staffing challenges. Federal and state policy makers, regional collaboratives, and health care delivery systems can facilitate solutions through programs such as telehealth, simulation training, and interprofessional education. PMID- 25808204 TI - Arginine: Its pKa value revisited. AB - Using complementary approaches of potentiometry and NMR spectroscopy, we have determined that the equilibrium acid dissociation constant (pKa value) of the arginine guanidinium group is 13.8 +/- 0.1. This is substantially higher than that of ~ 12 often used in structure-based electrostatics calculations and cited in biochemistry textbooks. The revised intrinsic pKa value helps explains why arginine side chains in proteins are always predominantly charged, even at pH values as great as 10. The high pKa value also reinforces the observation that arginine side chains are invariably protonated under physiological conditions of near neutral pH. This occurs even when the guanidinium moiety is buried in a hydrophobic micro-environment, such as that inside a protein or a lipid membrane, thought to be incompatible with the presence of a charged group. PMID- 25808206 TI - Changes in volatile compounds and some physicochemical properties of European cranberrybush (Viburnum opulus L.) during ripening through traditional fermentation. AB - The changes in volatile compounds and some physicochemical properties of European Cranberrybush (Viburnum opulus L.) were investigated during traditional fermentation. Using the principal component analysis (PCA), relations between volatile compounds and fermentation were associated with dynamics of these compounds. In total, 58 volatile compounds were identified, 3-methylbutanoic acid (25.4% to 66.4% of identified volatile compounds) being the major constituent in raw, 2-, 3-, and 4-mo fermented European Cranberrybush fruits, while 2-octanone was dominant in 1-mo fermented sample with a 30% of the total identified volatiles. The amount of total volatile compounds was increased in the 1st month of fermentation and then decreased gradually in the following months. Acids were the dominant volatile compounds in raw and 3- to 4-mo fermented European Cranberrybush. Ketones and alcohols had the highest percentage in total volatile compounds in the 2nd and 3rd months of fermentation, respectively. PMID- 25808205 TI - Function and Mechanisms of Autophagy in Brain and Spinal Cord Trauma. AB - SIGNIFICANCE: Traumatic brain injury (TBI) and spinal cord injury (SCI) are major causes of death and long-term disability worldwide. Despite important pathophysiological differences between these disorders, in many respects, mechanisms of injury are similar. During both TBI and SCI, some cells are directly mechanically injured, but more die as a result of injury-induced biochemical changes (secondary injury). Autophagy, a lysosome-dependent cellular degradation pathway with neuroprotective properties, has been implicated both clinically and experimentally in the delayed response to TBI and SCI. However, until recently, its mechanisms and function remained unknown, reflecting in part the difficulty of isolating autophagic processes from ongoing cell death and other cellular events. RECENT ADVANCES: Emerging data suggest that depending on the location and severity of traumatic injury, autophagy flux--defined as the progress of cargo through the autophagy system and leading to its degradation- may be either increased or decreased after central nervous system trauma. CRITICAL ISSUES: While increased autophagy flux may be protective after mild injury, after more severe trauma inhibition of autophagy flux may contribute to neuronal cell death, indicating disruption of autophagy as a part of the secondary injury mechanism. FUTURE DIRECTIONS: Augmentation and/or restoration of autophagy flux may provide a potential therapeutic target for treatment of TBI and SCI. Development of those treatments will require thorough characterization of changes in autophagy flux, its mechanisms and function over time after injury. PMID- 25808208 TI - Development and Validation of Statistical Models of Femur Geometry for Use with Parametric Finite Element Models. AB - Statistical models were developed that predict male and female femur geometry as functions of age, body mass index (BMI), and femur length as part of an effort to develop lower-extremity finite element models with geometries that are parametric with subject characteristics. The process for developing these models involved extracting femur geometry from clinical CT scans of 62 men and 36 women, fitting a template finite element femur mesh to the surface geometry of each patient, and then programmatically determining thickness at each nodal location. Principal component analysis was then performed on the thickness and geometry nodal coordinates, and linear regression models were developed to predict principal component scores as functions of age, BMI, and femur length. The average absolute errors in male and female external surface geometry model predictions were 4.57 and 4.23 mm, and the average absolute errors in male and female thickness model predictions were 1.67 and 1.74 mm. The average error in midshaft cortical bone areas between the predicted geometries and the patient geometries was 4.4%. The average error in cortical bone area between the predicted geometries and a validation set of cadaver femur geometries across 5 shaft locations was 2.9%. PMID- 25808209 TI - The Mechanical, Structural, and Compositional Changes of Tendon Exposed to Elastase. AB - The mechanical response of tendon is dependent on the interaction of structural molecules that constitute the extracellular matrix. However, little is known about the role of elastic fibers that are present in this structure. Elastase treatments have been used to elucidate the mechanical role of elastic fibers in numerous tissues. Here, we show that a standard elastase treatment affects the mechanical properties of tendon, including the ultimate tensile strength and failure strain. Moreover, elastase-treated specimens exhibit significant structural and compositional changes including crimp undulation and release of glycosaminoglycans. These data demonstrate that a common elastase treatment has a complex digestion profile that influences the structure-function relationship of tendon. Thus, defining the mechanical role of elastic fibers in tendon using this technique is challenging. This introduces new and exciting questions regarding the function of elastic fibers in tendon, which may not be as well understood as previously thought. PMID- 25808207 TI - An integrated map of HIV genome-wide variation from a population perspective. AB - BACKGROUND: The HIV pandemic is characterized by extensive genetic variability, which has challenged the development of HIV drugs and vaccines. Although HIV genomes have been classified into different types, groups, subtypes and recombinants, a comprehensive study that maps HIV genome-wide diversity at the population level is still lacking to date. This study aims to characterize HIV genomic diversity in large-scale sequence populations, and to identify driving factors that shape HIV genome diversity. RESULTS: A total of 2996 full-length genomic sequences from 1705 patients infected with 16 major HIV groups, subtypes and circulating recombinant forms (CRFs) were analyzed along with structural, immunological and peptide inhibitor information. Average nucleotide diversity of HIV genomes was almost 50% between HIV-1 and HIV-2 types, 37.5% between HIV-1 groups, 14.7% between HIV-1 subtypes, 8.2% within individual HIV-1 subtypes and less than 1% within single patients. Along the HIV genome, diversity patterns and compositions of nucleotides and amino acids were highly similar across different groups, subtypes and CRFs. Current HIV-derived peptide inhibitors were predominantly derived from conserved, solvent accessible and intrinsically ordered structures in the HIV-1 subtype B genome. We identified these conserved regions in Capsid, Nucleocapsid, Protease, Integrase, Reverse transcriptase, Vpr and the GP41 N terminus as potential drug targets. In the analysis of factors that impact HIV-1 genomic diversity, we focused on protein multimerization, immunological constraints and HIV-human protein interactions. We found that amino acid diversity in monomeric proteins was higher than in multimeric proteins, and diversified positions were preferably located within human CD4 T cell and antibody epitopes. Moreover, intrinsic disorder regions in HIV-1 proteins coincided with high levels of amino acid diversity, facilitating a large number of interactions between HIV-1 and human proteins. CONCLUSIONS: This first large scale analysis provided a detailed mapping of HIV genomic diversity and highlighted drug-target regions conserved across different groups, subtypes and CRFs. Our findings suggest that, in addition to the impact of protein multimerization and immune selective pressure on HIV-1 diversity, HIV-human protein interactions are facilitated by high variability within intrinsically disordered structures. PMID- 25808211 TI - Leak in Perseus workstation after complete check sequences. PMID- 25808210 TI - Prognostic implication of CD57, CD16, and TGF-beta expression in oral squamous cell carcinoma. AB - BACKGROUND: Natural killer (NK) cells are important immune effector cells against tumors especially in the absence or reducing MHC class I antigen. Downregulation of CD16 receptor is accompanied by decreasing NK cell-killing activity. It has also been shown that some of tumor cells can evade from immune system through producing transforming growth factor beta (TGF-beta) and affect prognosis. The objective of this study was to evaluate the prognostic significance of CD57(+) and CD16(+) cells and TGF-beta expression in samples of oral squamous cell carcinoma (OSCC). METHODS: CD57, CD16, and TGF-beta expressions were examined immunohistochemically in 57 cases of OSCC. The relationship between markers' expression and clinicopathologic data using bivariate and multivariate analysis was assessed. RESULTS: Multivariate analysis revealed that CD57 expression [HR 17.34 (95% CI 3.815-78.830); P < 0.001] and mode of invasion [HR 0.362 (95% CI 0.138-0.947); P = 0.038] correlated with survival rate, but no relation between CD57 expression and mode of invasion was seen (P = 0.96). Furthermore, no correlation between CD57, CD16, and TGF-beta expression was found. CONCLUSION: These findings suggest that CD57 expression and mode of invasion are independent prognostic factors of survival in OSCC patients. PMID- 25808212 TI - Borderline personality pathology in young people at ultra high risk of developing a psychotic disorder. AB - AIM: The association between borderline personality disorder and the ultra high risk (UHR) for psychosis state is unclear. The following study aimed to investigate the type of attenuated psychotic symptoms and prevalence of borderline personality pathology in a sample of UHR young people. Additionally, the study aimed to explore whether borderline personality pathology influenced the transition rate to psychosis. METHODS: Medical records from Orygen Youth Health between 2007 and 2009 were examined. There were 180 patients who met UHR criteria and were included for analysis. Most patients were females (62.8%) and age ranged from 15 to 24 years. RESULTS: A quarter (25.2%) of UHR patients endorsed items consistent with borderline personality pathology. UHR patients with borderline personality pathology experienced a range of attenuated psychotic symptoms and could not be statistically differentiated from UHR patients with less significant or without borderline personality pathology. Borderline personality pathology did not increase or decrease the risk of developing a psychotic disorder. The absence of depression was the only predictor of psychosis. CONCLUSIONS: Many UHR patients present with concurrent borderline personality features. The psychotic experiences reported by UHR patients with borderline personality features were not limited to paranoid ideation, supporting the idea that borderline personality disorder may include a wider range of psychotic symptoms than previously thought. It is further possible that the psychotic symptoms experienced in this group could also be indicative of an emerging psychotic disorder. PMID- 25808213 TI - Ultrafast helicity control of surface currents in topological insulators with near-unity fidelity. AB - In recent years, a class of solid-state materials, called three-dimensional topological insulators, has emerged. In the bulk, a topological insulator behaves like an ordinary insulator with a band gap. At the surface, conducting gapless states exist showing remarkable properties such as helical Dirac dispersion and suppression of backscattering of spin-polarized charge carriers. The characterization and control of the surface states via transport experiments is often hindered by residual bulk contributions. Here we show that surface currents in Bi2Se3 can be controlled by circularly polarized light on a picosecond timescale with a fidelity near unity even at room temperature. We reveal the temporal separation of such ultrafast helicity-dependent surface currents from photo-induced thermoelectric and drift currents in the bulk. Our results uncover the functionality of ultrafast optoelectronic devices based on surface currents in topological insulators. PMID- 25808215 TI - Anomalous Circle of Willis with Vertigo. PMID- 25808214 TI - Acute sacral nerve stimulation reduces visceral mechanosensitivity in Rat through spinal opioid pathway. AB - BACKGROUND: Sacral nerve stimulation (SNS) is an alternative surgical treatment of refractory urge incontinence and/or fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS remain poorly understood. The aim of this experimental study was to evaluate the effect of SNS on visceral mechanosensitivity in rats. METHODS: Anesthetized Sprague-Dawley rats were treated with SNS or sham stimulation. SNS was performed by implanting an electrode close to the sacral nerve root S1. Rats were administered either a non selective opioid receptor antagonist (naloxone) or a nitric oxide synthase inhibitor (L-NAME). Colonic mechanosensitivity was evaluated using the variation of arterial blood pressure as a spino-bulbar reflex in response to graded isobaric colorectal distension (CRD). C-fos immunoreactive neurons were quantified in spinal and supraspinal sites. MU-opioid receptor (MOR) internalization was counted in the sacral spinal cord with sham or effective SNS in response to CRD. KEY RESULTS: SNS reduced visceral mechanosensitivity in response to CRD. This effect was reversed by intrathecal and intraveinous naloxone administration. In both models, CRD induced increased c-fos immunoreactivity in the dorsal horn neurons of the sacral spinal cord and supraspinal areas. This increase was prevented by SNS. MOR internalization was significantly higher in stimulated group. CONCLUSIONS & INFERENCES: SNS impacts on visceral mechanosensitivity by decreasing the spino-bulbar reflex in response to CRD. Spinal opioid receptors are likely involved in this effect. PMID- 25808216 TI - Resveratrol treatment restores peripheral insulin sensitivity in diabetic mice in a sirt1-independent manner. AB - SCOPE: Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice. METHODS AND RESULTS: We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2(-/-)) mice and streptozotocin (STZ) injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice. CONCLUSION: Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes. PMID- 25808217 TI - Effect of new curcumin-containing nanostructured lipid dispersions on human keratinocytes proliferative responses. AB - This study describes the production and characterization of nanostructured lipid dispersions (NLDs) containing curcumin (CUR) as new tools for curcumin topical delivery. Four types of NLDs based on monoolein in association with different emulsifiers were produced: Na cholate and poloxamer 407 (NLD1), poloxamer alone (NLD2), the mixture of Na cholate and Na caseinate (NLD3) and Na cholate alone (NLD4). Morphology and dimensional distribution of lipid dispersions were investigated by cryo-TEM and photon correlation spectroscopy (PCS). In vitro studies based on Franz cell, membrane nylon and stratum corneum-epidermis (SCE) were carried out to compare the four NLDs in terms of cytotoxicity in human keratinocytes and CUR diffusion. Our PCS studies showed differences in particles diameter among the different NLDs. In addition, cytotoxicity results in HaCaT cells evidenced that NLD1 and NLD2 were toxic at doses over 1 MUm. Therefore, cryo-TEM was determined only for NLD3 and NLD4 showing that CUR did not affect their structure. Diffusion measurement in SCE and nylon membrane evidenced that CUR had a time-delayed release for NLD4. The 'wound healing' effect of NLD3 and NLD4 with and without CUR analysed keratinocytes in vitro, and a clear inhibition of cell proliferation/migration by CUR was observed. This effect was mediated by the inhibition of cyclin D1 expression as a consequence of the impaired NFkB activation. This study confirms the antiproliferative properties of CUR and evidenced a new possible model of CUR topical delivery for hyperproliferative cutaneous diseases such as psoriasis. PMID- 25808218 TI - Case of lichen planus pigmentosus with unique distribution. PMID- 25808219 TI - The Effectiveness and Efficiency of Nursing Care Documentation Using the SIMPRO Model. AB - PURPOSE: The study aims to develop and test the effectiveness and efficiency of the SIMPRO. SIMPRO was developed with NANDA-I, Nursing Intervention Classification, and Nursing Outcome Classification nursing language. METHOD: The research was divided into two parts, in which we used two different designs incremental and quasi-experimental design. Two hundred fifty-five samples of nursing documentations were randomly assessed with computer-assisted clustering out of 1,040 nursing records of discharged patients. Data were analyzed using Wilcoxon test to compare each elements of evaluation before and after the implementation of the system. RESULT: SIMPRO improved the quality of documentation (p = .0001) and time efficiency (p = .0001). CONCLUSION: SIMPRO increased the quality and functions of the decision support system in delivering nursing care as well as in nursing management. TUJUAN: Penelitian ini bertujuan untuk mengembangkan dan menguji keefektifan dan efisiensi SIMPRO. SIMPRO adalah sistem informasi manajemen keperawatan yang dikembangkan dengan menggunakan NANDA I, Nursing Intervention Classification dan Nursing Outcome Classification. METODE: Penelitian ini dibagi menjadi dua tahap yang menggunakan desain incremental dan kuasi-eksperimental. 255 sampel dokumentasi keperawatan diambil secara acak dengan menggunakan klustering yang dibantu dengan komputer dari 1040 catatan keperawatan pasien yang sudah pulang. Data dianalisis dengan Uji Wilcoxon untuk membandingkan masing-masing elemen sebelum dan sesudah implementasi sistem. HASIL: SIMPRO memperbaiki kualitas dokumentasi (p = .0001) dan efisiensi (p = .0001). KESIMPULAN: SIMPRO meningkatkan kualitas dan fungsi sistem dukungan dalam memberikan asuhan keperawatan dan manajemen keperawatan. PMID- 25808220 TI - Efficient and generalized processing of multidimensional NUS NMR data: the NESTA algorithm and comparison of regularization terms. AB - The advantages of non-uniform sampling (NUS) in offering time savings and resolution enhancement in NMR experiments have been increasingly recognized. The possibility of sensitivity gain by NUS has also been demonstrated. Application of NUS to multidimensional NMR experiments requires the selection of a sampling scheme and a reconstruction scheme to generate uniformly sampled time domain data. In this report, an efficient reconstruction scheme is presented and used to evaluate a range of regularization algorithms that collectively yield a generalized solution to processing NUS data in multidimensional NMR experiments. We compare l1-norm (L1), iterative re-weighted l1-norm (IRL1), and Gaussian smoothed l0-norm (Gaussian-SL0) regularization for processing multidimensional NUS NMR data. Based on the reconstruction of different multidimensional NUS NMR data sets, L1 is demonstrated to be a fast and accurate reconstruction method for both quantitative, high dynamic range applications (e.g. NOESY) and for all J coupled correlation experiments. Compared to L1, both IRL1 and Gaussian-SL0 are shown to produce slightly higher quality reconstructions with improved linearity in peak intensities, albeit with a computational cost. Finally, a generalized processing system, NESTA-NMR, is described that utilizes a fast and accurate first-order gradient descent algorithm (NESTA) recently developed in the compressed sensing field. NESTA-NMR incorporates L1, IRL1, and Gaussian-SL0 regularization. NESTA-NMR is demonstrated to provide an efficient, streamlined approach to handling all types of multidimensional NMR data using proteins ranging in size from 8 to 32 kDa. PMID- 25808221 TI - Water-soluble polymeric chemosensor for selective detection of Hg(2+) in aqueous solution using rhodamine-based modified poly(acrylamide-acrylic acid). AB - We report the fabrication of a novel easily available turn-on fluorescent water soluble polymeric chemosensor for Hg(2+) ions that was simply prepared by micellar free radical polymerization of a water-insoluble organic rhodamine-based Hg(2+)-recognizing monomer (GR6GH), with hydrophilic monomers acrylamide (AM) and acrylic acid (AA). The chemical structure of the polymeric sensor was characterized by FT-IR and (1)H NMR spectroscopy. The apparent viscosity average molecular weight Meta of poly(acrylamide-acrylic acid) [poly(AM-NaAA)] and the water-soluble polymeric chemosensor poly(AM-NaAA-GR6GH) were 1.76 * 10(6) and 6.84 * 10(4) g/mol, respectively. Because of its amphiphilic property, the water soluble polymeric chemosensor can be used as a chemosensor in aqueous media. Upon addition of Hg(2+) ions to an aqueous solution of poly(AM-NaAA-GR6GH), fluorescence enhancements were observed instantly. Moreover, other metal ions did not induce obvious changes to the fluorescence spectra. This approach may provide an easily measurable and inherently sensitive method for Hg(2+) ion detection in environmental and biological applications. PMID- 25808222 TI - A KRT1 gene mutation related to epidermolytic ichthyosis in a Chinese family. AB - We report a Chinese family with members affected by epidermolytic ichthyosis (EI), caused by KRT gene mutations. The proband was a 14-year-old boy who had simultaneous appearance of nephroblastoma and epidermolytic ichthyosis (EI). Both the patient and his mother exhibited the specific clinical and pathological manifestations of EI. We analysed all exons and flanking sequences of the KRT1 and KRT10 genes using PCR, and found that the proband and his mother had a G>C transition at nucleotide position 1432 in exon 7 of KRT1, resulting in an amino acid substitution of glutamate (GAA) to glutamine (CAA) at codon 478 (E478Q). The KRT10 gene had no mutations. PMID- 25808223 TI - Glia Open Access Database (GOAD): A comprehensive gene expression encyclopedia of glia cells in health and disease. AB - Recently, the number of genome-wide transcriptome profiles of pure populations of glia cells has drastically increased, resulting in an unprecedented amount of data that offer opportunities to study glia phenotypes and functions in health and disease. To make genome-wide transcriptome data easily accessible, we developed the Glia Open Access Database (GOAD), available via www.goad.education. GOAD contains a collection of previously published and unpublished transcriptome data, including datasets from isolated microglia, astrocytes and oligodendrocytes both at homeostatic and pathological conditions. It contains an intuitive web based interface that consists of three features that enable searching, browsing, analyzing, and downloading of the data. The first feature is differential gene expression (DE) analysis that provides genes that are significantly up and down regulated with the associated fold changes and p-values between two conditions of interest. In addition, an interactive Venn diagram is generated to illustrate the overlap and differences between several DE gene lists. The second feature is quantitative gene expression (QE) analysis, to investigate which genes are expressed in a particular glial cell type and to what degree. The third feature is a search utility, which can be used to find a gene of interest and depict its expression in all available expression data sets by generating a gene card. In addition, quality guidelines and relevant concepts for transcriptome analysis are discussed. Finally, GOAD is discussed in relation to several online transcriptome tools developed in neuroscience and immunology. In conclusion, GOAD is a unique platform to facilitate integration of bioinformatics in glia biology. PMID- 25808225 TI - Downregulation of the vascular renin-angiotensin system by aerobic training - focus on the balance between vasoconstrictor and vasodilator axes - . AB - BACKGROUND: Hyperactivity of the renin-angiotensin system (RAS) and functional deficits in hypertension are reduced after exercise training. We evaluate in arteries, kidney and plasma of hypertensive rats the sequential effects of training on vascular angiotensinogen, Ang II and Ang (1-7) content. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were trained or kept sedentary (S) for 3 months. After hemodynamic measurements (weeks 0, 1, 2, 4, 8 and 12), blood, arteries and kidneys were obtained to quantify the angiotensin content (HPLC) and angiotensinogen expression (Western Blotting). SHR S vs. WKY-S exhibited elevated pressure, increased angiotensinogen and angiotensins' content in the renal artery with a high Ang II/Ang (1-7) ratio (~5 fold higher than in the femoral artery, kidney and plasma, and 14-fold higher than in the aorta). Training promptly reduced angiotensinogen expression and downregulated the RAS in the renal SHR artery (1st-12th week), with a specific reduction of the vasoconstrictor axis; significant reduction of the AngII/Ang (1 7) ratio (36%, T4-T8) occurred simultaneously with significant pressure fall (5%). In other SHR arteries, plasma and kidneys and in all WKY tissues, T-induced AngII and Ang (1-7) reductions were proportional, maintaining the AngII/Ang (1-7) ratio. CONCLUSIONS: Vascular RAS is not equally expressed in vessels, having crucial importance in the renal artery. In the renal SHR artery, training downregulates the vasoconstrictor and preserves the vasodilator axis while in other tissues and plasma training reduces both RAS axes, thus maintaining the vasoconstriction/vasodilatation balance in a lower level. PMID- 25808224 TI - Linking anthropogenic resources to wildlife-pathogen dynamics: a review and meta analysis. AB - Urbanisation and agriculture cause declines for many wildlife, but some species benefit from novel resources, especially food, provided in human-dominated habitats. Resulting shifts in wildlife ecology can alter infectious disease dynamics and create opportunities for cross-species transmission, yet predicting host-pathogen responses to resource provisioning is challenging. Factors enhancing transmission, such as increased aggregation, could be offset by better host immunity due to improved nutrition. Here, we conduct a review and meta analysis to show that food provisioning results in highly heterogeneous infection outcomes that depend on pathogen type and anthropogenic food source. We also find empirical support for behavioural and immune mechanisms through which human provided resources alter host exposure and tolerance to pathogens. A review of recent theoretical models of resource provisioning and infection dynamics shows that changes in host contact rates and immunity produce strong non-linear responses in pathogen invasion and prevalence. By integrating results of our meta analysis back into a theoretical framework, we find provisioning amplifies pathogen invasion under increased host aggregation and tolerance, but reduces transmission if provisioned food decreases dietary exposure to parasites. These results carry implications for wildlife disease management and highlight areas for future work, such as how resource shifts might affect virulence evolution. PMID- 25808227 TI - Development of an Image-Based Modeling System to Investigate Evolutional Geometric Changes of a Stent Graft in an Abdominal Aortic Aneurysm. AB - BACKGROUND: Quantification of geometric changes of the stent graft (SG) in abdominal aortic aneurysm has been required for follow up of endovascular aneurysm repair (EVAR). The aim was to develop an image-based modeling system (V Modeler) to investigate these changes over time. METHODS AND RESULTS: V-Modeler was applied to investigate the migration of the SG. Three sets of computed tomography images were taken at 3 different times: (1) 5 days after the implantation; (2) 7 months later when the unilateral leg migrated upward; and (3) 10 months later when the limb had migrated into the common iliac aneurysm resulting in a type 1b endoleak. A spline function was used to represent the center lines of the SG to track its evolutional geometric changes in a three dimensional manner. The characteristics of vascular geometry, as well as the SG geometry using geometric parameters such as length, curvature, torsion, angle of tangent vector (ATV), and migrated length, was evaluated. It was observed that the strong peak of the curvature in the distal area appeared, and a conversion of the torsion disappeared chronologically. CONCLUSIONS: The V-Modeler was developed, which not only can extract vascular geometry but also can identify geometric parameter, such as curvature, torsion, and ATV, to predict adverse events following EVAR. PMID- 25808226 TI - Association between endothelial function (assessed on reactive hyperemia peripheral arterial tonometry) and obstructive sleep apnea, visceral fat accumulation, and serum adiponectin. AB - BACKGROUND: Visceral obesity, low adiponectin, and severe obstructive sleep apnea (OSA) are associated with cardiovascular diseases, but the interactions among these factors on endothelial dysfunction are not well known. METHODS AND RESULTS: Endothelial function in 133 patients after polysomnography was evaluated as reactive hyperemia index (RHI) on reactive hyperemia peripheral arterial tonometry. Visceral obesity was defined as visceral fat area >=100 cm(2)on computed tomography. RHI was significantly correlated with apnea hypopnea index (AHI), visceral fat area, and serum adiponectin (r=-0.24, P=0.0055, r=-0.19, P=0.031, and r=0.20, P=0.019, respectively). RHI in patients with visceral obesity was significantly decreased in the presence of severe OSA (AHI >=30; P=0.042). On multivariate regression analysis, only severe OSA remained as an independent predictive factor of RHI (P=0.024, R(2)=5.4%). RHI in patients with severe OSA (n=44) was significantly improved after 3 months of continuous positive airway pressure (CPAP) treatment (1.78+/-0.40 before CPAP vs. 2.00+/ 0.53 after CPAP, P=0.013), similarly to those with AHI <30 (P=0.45). CONCLUSIONS: Severe OSA, but not visceral fat area or serum adiponectin, was independently associated with endothelial function according to RHI. In addition, impaired endothelial function was reversible following 3 months of CPAP treatment. PMID- 25808228 TI - Li Intercalation into a beta-MnO2 Grain Boundary. AB - MnO2 is well-known for its technological applications including Li ion, Li-air batteries, and electrochemical capacitors. Compared to the bulk material, nanostructuring of rutile (beta-)MnO2 has been shown to vastly improve its electrochemical properties and performance. While the bulk material cannot readily intercalate Li, nanostructured mesoporous samples exhibit good Li intercalation. This observation is not yet fully understood. In this work, we use state-of-the-art theoretical techniques to investigate Li intercalation and migration at the beta-MnO2 Sigma 5(210)/[001] grain boundary (GB). We show how large tunnel structures in the GB can promote Li intercalation with voltages of up to 3.83 eV compared to the experimental value of 3.00 eV. Conversely, small tunnel structures resulting from overcoordination of ions at the GB can hinder Li intercalation with significantly reduced voltages. The size and shape of these tunnels also strongly influence the energetics of Li migration with energy barriers ranging from 0.15 to 0.89 eV, compared to a value for the bulk of 0.17 eV. Our results illustrate how GBs with large, open tunnel structures may promote electrochemical performance and could be a contributing factor to the excellent performance of nanostructured beta-MnO2. PMID- 25808229 TI - The microbiota in inflammatory bowel disease. AB - This review explores our current understanding of the complex interaction between environmental risk factors, genetic traits and the development of inflammatory bowel disease. The primacy of environmental risk factors is illustrated by the rapid increase in the incidence of the disease worldwide. We discuss how the gut microbiota is the proximate environmental risk factor for subsequent development of inflammatory bowel disease. The evolving fields of virome and mycobiome studies will further our understanding of the full potential of the gut microbiota in disease pathogenesis. Manipulating the gut microbiota is a promising therapeutic avenue. PMID- 25808230 TI - Colorectal distention induces acute and delayed visceral hypersensitivity: role of peripheral corticotropin-releasing factor and interleukin-1 in rats. AB - BACKGROUND: Most studies evaluating visceral sensation measure visceromotor response (VMR) to colorectal distention (CRD). However, CRD itself induces visceral sensitization, and little is known about the detailed characteristics of this response. The present study tried to clarify this question. METHODS: VMR was determined by measuring abdominal muscle contractions as a response to CRD in rats. The CRD set consisted of two isobaric distentions (60 mmHg for 10 min twice, with a 30-min rest), and the CRD set was performed on two separate days, i.e., days 1 and 3, 8. RESULTS: On day 1, VMR to the second CRD was increased as compared with that to the first CRD, which is the acute sensitization. VMR to the first CRD on day 3 returned to the same level as that to the first CRD on day 1, and total VMR, i.e., the whole response to the CRD set, was not different between day 1 and day 3. However, total VMR was significantly increased on day 8 as compared with that on day 1, suggesting CRD induced the delayed sensitization. Intraperitoneally administered astressin (200 ug/kg), a corticotropin-releasing factor receptor antagonist, at the end of the first CRD blocked the acute sensitization, but anakinra (20 mg/kg, intraperitoneally), an interleukin-1 receptor antagonist, did not modify it. Astressin (200 ug/kg, twice before CRD on day 8) did not alter the delayed sensitization, but anakinra (20 mg/kg, twice) abolished it. CONCLUSIONS: CRD induced both acute sensitization and delayed sensitization, which were mediated through peripheral corticotropin-releasing factor and interleukin-1 pathways, respectively. PMID- 25808233 TI - Editorial Comment to Endoglin expression in upper urinary tract urothelial carcinoma is associated with intravesical recurrence after radical nephroureterectomy. PMID- 25808232 TI - Silver oxide-containing hydroxyapatite coating supports osteoblast function and enhances implant anchorage strength in rat femur. AB - Antibacterial silver with hydroxyapatite (Ag-HA) is a promising coating material for imparting antibacterial properties to implants. We previously reported that 3% (w/w) silver with HA (3% Ag-HA) has both antibacterial activity and osteoconductivity. In this study, we investigated the effects of Ag-HA on the in vitro osteoblast function and the in vivo anchorage strength and osteoconductivity of implants. Production of the osteoblast marker alkaline phosphatase, but not cytotoxicity, was observed in cells of the osteoblast cell line MC3T3-E1 cultured on the 3% Ag-HA-coated surface. These results were similar to those observed with silver-free HA coating. In contrast, a significant high level of cytotoxicity was observed when the cells were cultured on a 50% Ag-HA coated surface. The anchorage strength of implants inserted into the femur of Sprague-Dawley (SD) rats was enhanced by coating the implants with 3% Ag-HA. On the 3% Ag-HA-coated surface, both metaphyseal and diaphyseal areas were largely covered with new bone and had adequate osteoconductivity. These results suggest that 3% Ag-HA, like conventional HA, promotes osteogenesis by supporting osteoblast viability and function and thereby contributes to sufficient anchorage strength of implants. Application of 3% Ag-HA, which combines the osteoconductivity of HA and the antibacterial activity of silver, to prosthetic joints will help prevent postoperative infections. PMID- 25808231 TI - Durable remission with rituximab in a patient with an unusual variant of Castleman's disease with myelofibrosis-TAFRO syndrome. PMID- 25808234 TI - Impact of smoking on the surgical outcome of Crohn's disease: a propensity-score matched National Surgical Quality Improvement Program analysis. AB - AIM: Smoking is known to have a deleterious effect on Crohn's disease (CD). The present study addressed the specific impact of smoking on the outcome of surgery for CD. METHOD: A review of the National Surgical Quality Improvement Program (NSQIP) database (2005-2012) identified 7631 patients with CD who underwent surgical resection. Patients were stratified based on smoking status and were compared with univariate statistical tests. Generalized linear regression and multiple logistic regressions were used to model the impact of smoking on the surgical outcome [length of stay (LOS), mortality, postoperative complications and readmission]. To confirm the validity of the regression models and to evaluate the influence of smoking in comparable patient cohorts, a propensity score match was also performed. RESULTS: There were 2047 (26.8%) patients with CD identified as current smokers, and 5584 (74.2%) identified as non- or ex-smokers. Smokers were more likely to have a pulmonary comorbidity, preoperative weight loss and a higher American Society of Anesthesiologists classification. No differences in mortality were observed between smokers and non- or ex-smokers in univariate analysis. In multivariate analysis, smoking status was not significantly associated with LOS. Morbidity (OR 1.20, P = 0.003), particularly infectious (OR 1.30, P < 0.001) and pulmonary (OR 1.87, P < 0.001) complications, and readmission (OR 1.58, P = 0.004) were significantly associated with smoking status. These findings were validated on propensity-score matching analysis. CONCLUSION: In patients with CD, the detrimental effects of smoking on surgical outcomes are driven by infectious and pulmonary complications, and by an increased likelihood of readmission. PMID- 25808235 TI - Familial cutaneous leiomyomatosis in multiple generations with varied morphological presentations. PMID- 25808238 TI - In vivo determination of the volatile metabolites of saprotroph fungi by comprehensive two-dimensional gas chromatography. AB - In this work, we discuss the use of multiway principal component analysis combined with comprehensive two-dimensional gas chromatography to study the volatile metabolites of the saprophytic fungus Memnoniella sp. isolated in vivo by headspace solid-phase microextraction. This fungus has been identified as having the ability to induce plant resistance against pathogens, possibly through its volatile metabolites. Adequate culture media were inoculated, and its headspace was then sampled with a solid-phase microextraction fiber and chromatographed every 24 h over seven days. The raw chromatogram processing using multiway principal component analysis allowed the determination of the inoculation period, during which the concentration of volatile metabolites was maximized, as well as the discrimination of the appropriate peaks from the complex culture media background. Several volatile metabolites not previously described in the literature on biocontrol fungi were observed, as well as sesquiterpenes and aliphatic alcohols. These results stress that, due to the complexity of multidimensional chromatographic data, multivariate tools might be mandatory even for apparently trivial tasks, such as the determination of the temporal profile of metabolite production and extinction. However, when compared with conventional gas chromatography, the complex data processing yields a considerable improvement in the information obtained from the samples. PMID- 25808236 TI - Evaluation of new automated hematopoietic progenitor cell analysis in the clinical management of peripheral blood stem cell collections. AB - BACKGROUND: Successful peripheral blood stem cell transplantation (PBSCT) depends on the collection and infusion of adequate numbers of peripheral blood progenitor cells (PBPCs). Several predictors of PBPC yield are used currently, including white blood cell (WBC) count and CD34 analysis. This study evaluated the utility of the new automated hematopoietic progenitor cell count available on Sysmex XN hematology analyzers (XN-HPCs) in PBSCT. STUDY DESIGN AND METHODS: The performance characteristics of XN-HPC, CD34+, and WBC analysis were compared using 107 matched peripheral blood and apheresis samples. RESULTS: Good correlation was observed between XN-HPC and CD34+ cell counts in peripheral blood (r = 0.88; slope, 0.81) and apheresis collections (r = 0.91; slope, 0.89). Moreover, peripheral blood XN-HPC and CD34 analysis showed comparable ability to predict successful PBPC harvests (>=2 * 10(6) CD34+ cells/kg). At a cutoff of 20 * 10(6) progenitor cells/L, peripheral blood XN- HPC and CD34 analysis both showed negative predictive values (NPVs) of 100% and positive predictive values (PPVs) of 55.4 and 63%, respectively. Using an optimized cutoff of 38 * 10(6) progenitor cells/L, derived from receiver operating characteristic analysis, the PPV for XN-HPC and CD34 analysis increased to 71.4 and 78.9%, respectively, with relatively unchanged NPVs (XN-HPC 97.7%, CD34+ 98.0%). In contrast, the correlation between peripheral blood WBC and CD34 analysis was poor (r = 0.48; slope, 669.85), and the peripheral blood WBC count (cutoff, 10 * 10(9) /L) was a poor predictor of PBPC harvest (NPV 60%, PPV 43.1%). CONCLUSION: XN-HPC compares favorably with CD34 analysis and may be a surrogate for CD34 analysis to predict optimal timing of PBPC collections. PMID- 25808237 TI - [Knowledge of guidelines for anticoagulation management of patients with atrial fibrillation]. AB - INTRODUCTION: In Germany, about 1 million people are affected by atrial fibrillation (AF). Morbidity and mortality are high especially due to the risk of thromboembolic events. A valid risk stratification by the CHADS2 criteria is critical regarding the indication for anticoagulation and thus to improve prognosis. To what extent these criteria and guidelines are known and have been implemented among cardiologists and general practitioners in Germany has not been evaluated so far. METHODS: A total of 558 cardiologists (46.8 %) and general practitioners (52.5 %) were surveyed during the annual meeting of the German Society of Cardiology or in writing in a representative sample of German general practitioners. RESULTS: Compared to 51.8 % of general practitioners, 87.6 % of cardiologists (p < 0.001) claimed to know the CHADS2 criteria. In the total cohort, CHADS2 criteria were correctly identified as risk factors by 55.6-86.9 %. Cardiologists had significantly better knowledge of these criteria (63.6-91.2 % vs. 55.6-86.9 %, p < 0.001). A previous history of cerebral stroke was known to be a risk factor in almost all physicians in contrast to heart failure (47.3 % of cardiologists vs. 36.0 % of general practitioners, p < 0.001). Physicians who had attended a training course on anticoagulation and atrial fibrillation (n = 380) in the 2 years prior to the survey performed significantly better (p = 0.007) than those without training (n = 173). CONCLUSION: While the majority of cardiologists knew the CHADS2 criteria and the related guidelines, these criteria were less known in the primary care sector. Nevertheless, even cardiologists do not always apply the guidelines for anticoagulation in AF correctly. Participants of training courses had a significantly better knowledge of these guidelines. PMID- 25808239 TI - Midkine and Pleiotrophin in the Treatment of Neurodegenerative Diseases and Drug Addiction. AB - Pleiotrophin (PTN) and Midkine (MK) are neurotrophines with documented protective actions in experimental models of neurodegenerative diseases and beneficial effects on toxicity and addictive behaviours related to drug abuse. Concerning the latter, both PTN and MK prevent the neurotoxic effects of amphetamine on nigrostriatal pathways and endogenous PTN also limits amphetamine reward. Moreover, endogenous PTN overexpression in the prefontral cortex abolishes alcohol- induced conditioned place preference. This review summarizes the existing patents for using PTN and MK in the treatment and diagnosis of neuropsychiatric disorders with a focus on neurotoxicity, neurodegeneration and substance use disorders. We have also reviewed the mechanism of action of PTN and MK and summarized existing patents on downstream modulators in their signaling pathways for the same indications. PMID- 25808241 TI - Patterns of biomechanical demands are associated with musculoskeletal pain in the beginning of professional life: a population-based study. AB - OBJECTIVES: This study aimed to describe patterns of occupational biomechanical demands in the beginning of professional life and to quantify their association with the presence and intensity of regional musculoskeletal pain. METHODS: Cross sectional data from 21-year-old participants were collected during the third wave of the EPITeen cohort study (N=1733, 37.5% were workers). Ten different work related biomechanical tasks were characterized. Latent class analysis was conducted to identify empirical patterns of occupational biomechanical demands. The presence and intensity of regional musculoskeletal pain in the previous year were also evaluated. RESULTS: Four patterns of occupational biomechanical demands were found: "low demands", "sitting demands", "repetitive and asymmetric demands", and "high and vibrational demands". When compared to workers with low demands, those with repetitive and asymmetric demands or high and vibrational demands presented 80% higher adjusted odds ratio (OR adj) of reporting neck/shoulder pain. High and vibrational demands occupations were significantly associated with upper-/lower-back pain in comparison to low demands [OR adj1.80, 95% confidence interval (95% CI%) 1.09-2.96]. In addition, workers with sitting demands were more likely to report any or severe upper-/lower-back pain [OR adj1.56 (95% CI 0.99-2.45) and 1.66 (95% CI 1.03-2.66), respectively] when compared to those with low demands. CONCLUSIONS: Patterns of high work-related physical demands were associated with the presence of neck/shoulder pain and severity of upper-/lower-back pain. This emphasizes that even short-term biomechanical exposures at the workplace may be involved in the etiology of musculoskeletal complaints. PMID- 25808240 TI - Horizontal Basal Cell-Specific Deletion of Pax6 Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury. AB - In the mammalian olfactory epithelium (OE), olfactory receptor neurons (ORNs) are continuously regenerated throughout the animal's lifetime. Horizontal basal cells (HBCs) in the OE express the epithelial marker keratin 5 (K5) and the stem cell marker Pax6 and are considered relatively quiescent tissue stem cells in the OE. Pax6 is a key regulator of several developmental processes in the central nervous system and in sensory organs. Although Pax6 is expressed in the OE, its precise role remains unknown, particularly with respect to stem cell-like HBCs. To investigate the function of Pax6 in the developmental and regenerative processes in the OE, we generated conditional Pax6-knockout mice carrying a loxP-floxed Pax6 gene. Homozygous Pax6-floxed mice were crossed with K5-Cre transgenic mice to generate HBC-specific Pax6-knockout (Pax6-cKO) mice. We confirmed that the deletion of Pax6 expression in HBCs was sufficiently achieved in zone 1 of the OE in Pax6-cKO mice 3 days after methimazole-induced severe damage. In this condition, regeneration of the OE was dramatically impaired; both OE thickness and the number of ORNs were significantly decreased in the regenerated OE of Pax6 cKO mice. These results suggest that Pax6 expression is essential for HBCs to differentiate into neuronal cells during the regeneration process following severe injury. PMID- 25808242 TI - The role of the gastrointestinal epithelium as a possible pathway for the transfer of nutrients to the embryo's circulation. AB - The endodermal cells of the human yolk sac (YS) produce non-nucleated erythrocytes (NNEs) and numerous serum proteins that are transiently storage within the YS cavity. After their transfer via the vitelline duct to the embryo gastrointestinal lumen, the nutrients' final fate is unknown. With the aim of investigate how erythroid cells and nutrients are conveyed to embryo circulation, we studied, using a morphological and immunohistochemical approach, the embryo anatomy and the serum protein alpha-fetoprotein (AFP) presence, in 15 human embryos and their YS, collected from tubal pregnancies from 4 to 8 wpf. We observed at 5 wpf, a strong AFP staining in the endodermal cells of the YS, thereafter AFP was only present in the YS cavity and the gastrointestinal lumen. During 7 wpf, AFP expression declined and disappeared, concomitant with YS regression. Between 5 and 7 wpf, NNEs were observed in the gastrointestinal cavity, where they accumulate in the stomach. Here, the cells were attached to the endodermal epithelial cells or were free in the lumen. By scanning electron microscopy, we identified signs of NNEs phagocytized by endodermal cells. Those NNEs free in the lumen, after hemolysis, were probably removed by endocytosis (cell debris). Taking all together, we postulate that after reaching the endodermal epithelial cells of the stomach, nutrients are transferred to the embryo by a phagocytic/endocytic mechanism that is operative until the end of 6 wpf. After absorption, NNEs are probably degraded within phagosomes, nutrients delivered to the cell cytoplasm and then transported towards the embryonic circulation. PMID- 25808243 TI - Helicobacter pylori infection in psoriasis: results of a clinical study and review of the literature. AB - BACKGROUND: Data from the literature concerning the role of Helicobacter pylori (H. pylori) infection in psoriasis are still conflicting. This study was carried out to evaluate prevalence of H. pylori in patients with mild to severe psoriasis, correlation between H. pylori infection and severity of psoriasis, and effect of H. pylori eradication on the clinical course of psoriasis. METHODS: Two hundred and ten patients with psoriasis and 150 healthy controls were screened for H. pylori through [(13) C] urea breath test at baseline (T0). All patients with psoriasis received standardized phototherapy treatment, and those infected by H. pylori were also treated with a 1-week triple therapy, then they were all re-evaluated four weeks later at the end of therapy (T5). RESULTS: The prevalence of H. pylori was not higher in psoriasis than in the control group (20.27 vs. 22%; P > 0.05). Patients infected by H. pylori showed more severe psoriasis than uninfected patients (psoriasis area and severity index score 17.9 +/- 7.1 vs. 13.7 +/- 6.9; P = 0.04), and patients who received successful eradication of H. pylori infection showed a greater improvement of psoriasis than the others (psoriasis area and severity index score at T5 in patients infected by H. pylori was 8.36 +/- 3.76, in uninfected patients was 10.85 +/- 3.49; P = 0.006). CONCLUSIONS: Patients with mild to severe psoriasis do not show a greater prevalence of H. pylori infection; however, H. pylori seems able to affect the clinical severity of psoriasis. PMID- 25808245 TI - Crystal structure analyses of azasulfuryltripeptides reveal potential for gamma turn mimicry. AB - Azasulfurylpeptides feature an amino acid residue in which the CalphaH and the carbonyl are replaced respectively by a nitrogen atom and a sulfonyl group. Insight into the conformational preferences of azasulfurylpeptides containing an azasulfurylglycine (AsG) residue has been pursued using X-ray analysis in the solid state. Crystals of N-(Boc)-Pro-AsG-Val-OMe (10) and N-(Cbz)-Ala-AsG-D-Phe Ot-Bu (11) showed tetrahedral geometries about the sulfur atom with the omega torsion angle preferring a staggered conformation. Furthermore, the phi and psi torsion angles of the central azasulfuryl residue were respectively within close proximity to those of ideal inverse and classical gamma-turns. In the crystal lattice, azasulfurylpeptide 11 engaged in intermolecular hydrogen bonds between the sulfonyl oxygen and hydrazide hydrogen in an antiparallel orientation. PMID- 25808244 TI - The Public Health Responsibility deal: has a public-private partnership brought about action on alcohol reduction? AB - BACKGROUND AND AIMS: The Public Health Responsibility Deal (RD) in England is a public-private partnership involving voluntary pledges between industry, government and other organizations, with the aim of improving public health. This paper aims to evaluate what action resulted from the RD alcohol pledges. METHODS: We analysed publically available data on organizations' plans and progress towards achieving key alcohol pledges of the RD. We assessed the extent to which activities pledged by signatories could have been brought about by the RD, as opposed to having happened anyway (the counterfactual), using a validated coding scheme designed for the purpose. RESULTS: Progress reports were submitted by 92% of signatories in 2013 and 75% of signatories in 2014, and provided mainly descriptive feedback rather than quantifiable performance metrics. Approximately 14% of 2014 progress reports were identical to those presented in 2013. Most organizations (65%) signed pledges that involved actions to which they appear to have been committed already, regardless of the RD. A small but influential group of alcohol producers and retailers reported taking measures to reduce alcohol units available for consumption in the market. However, where reported, these measures appear to involve launching and promoting new lower-alcohol products rather than removing units from existing products. CONCLUSIONS: The RD is unlikely to have contributed significantly to reducing alcohol consumption, as most alcohol pledge signatories appear to have committed to actions that they would have undertaken anyway, regardless of the RD. Irrespective of this, there is considerable scope to improve the clarity of progress reports and reduce the variability of metrics provided by RD pledge signatories. PMID- 25808246 TI - Serenity: Violence, Inequality, and Recovery on the Edge of Mexico City. AB - Over the last decade, there has been a sharp increase in drug addiction in Mexico, especially among the urban poor. During the same period, unregulated residential treatment centers for addiction, known as anexos, have proliferated throughout the country. These centers are utilized and run by marginalized populations and are widely known to engage in physical violence. Based on long term ethnographic research in Mexico City, this article describes why anexos emerged, how they work, and what their prevalence and practices reveal about the nature of recovery in a context where poverty, drugs, and violence are existential realities. Drawing attention to the dynamic relationship between violence and recovery, pain, and healing, it complicates categories of violence and care that are presumed to have exclusive meaning, illuminating the divergent meanings of, and opportunities for, recovery, and how these are socially configured and sustained. PMID- 25808247 TI - Determination of corilagin in rat plasma using a liquid chromatography electrospray ionization tandem mass spectrometric method. AB - A sensitive and simple liquid chromatography-tandem mass spectrometric (HPLC MS/MS) method for the determination of corilagin in rat plasma has been developed. Samples were prepared with protein precipitation method and analyzed with a triple quadrupole tandem mass spectrometer. We employed negative electrospray ionization as the ionization source and the analytes were detected in multiple reaction monitoring mode. Separation was achieved on a C8 column eluted with mobile phase consisting of methanol-0.1% formic acid in a gradient mode at the flow rate of 0.3 mL/min. The total run time was 7.0 min.This method was proved to have good linearity in the concentration range of 2.5-1000.0 ng/mL. The lower limit of quantification of corilagin was 2.5 ng/mL. The intra- and inter-day relative standard deviationa across three validation runs for four concentration levels were both <9.8%. The relative error was within +/-6.0%. This assay offers advantages in terms of expediency and suitability for the analysis of corilagin in rat plasma. The practical utility of this new HPLC-MS/MS method was confirmed in pilot plasma concentration studies in rats following oral administration. PMID- 25808248 TI - Learning and teaching Emotional Logic in Zimbabwe: A lifelong learning emotional literacy training package that promotes healthy adjustment in resource-poor settings. AB - This article describes an innovative, rapidly effective, low cost, health promoting educational input that can strengthen social systems to support the social and emotional development of orphan children. The training project took place in a resource-poor area of rural southern Zimbabwe. The teaching was found to be culturally relevant and transferable, to the extent that several of the learners progressed to become tutors, training others to use the method in local languages. The method promotes healthy adjustment, emotional resilience and intelligent decision-making for health. By reducing chronic stress in orphans and their carers, lifelong learning may improve immune function. PMID- 25808249 TI - Advances in computer simulation of genome evolution: toward more realistic evolutionary genomics analysis by approximate bayesian computation. AB - NGS technologies present a fast and cheap generation of genomic data. Nevertheless, ancestral genome inference is not so straightforward due to complex evolutionary processes acting on this material such as inversions, translocations, and other genome rearrangements that, in addition to their implicit complexity, can co-occur and confound ancestral inferences. Recently, models of genome evolution that accommodate such complex genomic events are emerging. This letter explores these novel evolutionary models and proposes their incorporation into robust statistical approaches based on computer simulations, such as approximate Bayesian computation, that may produce a more realistic evolutionary analysis of genomic data. Advantages and pitfalls in using these analytical methods are discussed. Potential applications of these ancestral genomic inferences are also pointed out. PMID- 25808250 TI - Risk of cancer among children with birth defects: a novel approach. AB - BACKGROUND: Associations between birth defects (BDs) and childhood cancers have been studied previously and have identified several specific birth defect-cancer associations. No studies have examined the risk after exclusion of known associations. METHODS: We analyzed data from high-quality population-based registers of BDs and cancers for Western Australian births 1982 to 2007. The cohort comprised 641,036 babies still alive at 90 days. Two experts independently reviewed all 120 births with a BD and a cancer to determine whether the cancer was congenital, caused by the BD, known to be associated with the BD or otherwise. These categories were used in sensitivity analyses. Cox regression was used to estimate hazard ratios (HRs) for any cancer and specific cancers associated with any BD and specific BDs. RESULTS: The HR for any cancer among children with any BD was 1.96 (95% confidence interval, 1.59-2.43). The HR for any cancer among children with a BD not known to be related to a cancer (n = 57) was 1.19 (95% confidence interval, 0.91-1.56). The HR for the latter association among children diagnosed with cancer before 5 years of age was 1.74 (95% confidence interval, 1.28-2.37). CONCLUSION: This novel approach aimed to prevent inflated HRs arising from reverse causation, and allow identification of associations beyond those already well documented. Larger studies using this method are needed to explore currently undocumented associations between BDs and cancers. PMID- 25808252 TI - Celebrate World Hypertension Day (WHD) on May 17, 2015, and contribute to improving awareness of hypertension. PMID- 25808253 TI - Facilitating patients with disorders of consciousness to sit without trunk support: a qualitative study. AB - AIMS AND OBJECTIVES: This study aimed to clarify why and how clinical nurses facilitate sitting without trunk support among patients with disorders of consciousness. BACKGROUND: Recent attention has focused on encouraging patients with disorders of consciousness to sit without trunk support, but no reports describe this intervention among patients with poor awareness and physical disuse. DESIGN: Qualitative research design. METHODS: We enrolled five clinical nurses with interventional experience in rehabilitating patients with disorders of consciousness to sit without trunk support. Participant observation and semi structured interviews were used to collect data. The data were analysed by text mining method. RESULTS: Three reasons for nursing in the sitting position were identified: to raise the patient's body to assess the recovery of activities of daily living, to adjust their circadian rhythm and encourage the will to sit, and to make it easier to breathe. Five practices were identified: moving the patient to the prone position to sit in safety and comfort, developing postural stability by improving the flexibility of the lower limbs, improving the flexibility of the hip joints, developing trunk balance and encouraging hand use for stability, and ensuring safety by terminating the sitting practice when symptoms of respiratory failure, heart failure, or excessive tiredness developed. CONCLUSIONS: The rationale for nursing patients with disorders of consciousness to sit without trunk support was to establish a foundation for independent living. This was achieved by preparing patient's disused body for activity by improving the flexibility of hip joint in the prone position. This represents a new intervention for patients with disorders of consciousness that could facilitate independent living. RELEVANCE TO CLINICAL PRACTICE: This study provides empirical and practical evidence from nurses who perform novel clinical interventions that specifically promote independent living. Further accumulation of quantitative clinical results and physiological verification are required. PMID- 25808251 TI - The clinical utility of serum anti-Mullerian hormone in the follow-up of ovarian adult-type granulosa cell tumors--A comparative study with inhibin B. AB - Ovarian adult-type granulosa cell tumors (AGCTs) require prolonged follow-up, but evidence regarding the optimal follow-up marker is lacking. The objective of our study was to validate the clinical usefulness of serum anti-Mullerian hormone (AMH) and the current marker inhibin B as single and combined markers of AGCTs. We conducted a longitudinal, partially prospective cohort study of 123 premenopausal and postmenopausal AGCT patients with a median follow-up time of 10.5 years (range 0.3-50.0 years). Serum AMH and inhibin B levels were measured from 560 pretreatment and follow-up serum samples by using immunoenzymometric assays. We found that serum AMH and inhibin B levels were significantly elevated in patients with primary or recurrent AGCTs. The levels of both markers positively correlated to tumor size (p < 0.05). AMH and inhibin B performed similarly in receiving operator characteristic analyses; area under the curve (AUC) values were 0.92 [95% confidence interval (CI) 0.88-0.95] for AMH, and 0.94 (95% CI 0.90-0.96) for inhibin B. AMH was highly sensitive (92%) and specific (81%) in detecting a macroscopic AGCT. However, in AUC comparison analyses, the combination of the markers was superior to inhibin B alone. In conclusion, serum AMH is a sensitive and specific marker of AGCT, and either AMH or inhibin B can be monitored during follow-up. However, combining AMH and inhibin B in AGCT patient follow-up improves the detection of recurrent disease. PMID- 25808254 TI - Plasma H2S predicts coronary artery lesions in children with Kawasaki disease. AB - BACKGROUND: The aim of this study was to determine whether plasma hydrogen sulfide (H2S) is a biomarker for predicting coronary artery lesions (CAL) in children with Kawasaki disease (KD). METHODS: A prospective study was conducted on 50 KD patients and 27 healthy children. Plasma H2 S was analyzed at the acute stage. Plasma H2S was detected using the sensitive electrode method, and receiver operating characteristic curve (ROC) analysis was carried out. RESULTS: Plasma H2S in KD patients at the acute stage was significantly lower than that of controls. CAL patients had reduced plasma H2S at acute stage compared with the non-CAL patients. A plasma H2S cut-off of 31.2 umol/L provided a sensitivity of 81% and a specificity of 62.5% for predicting coronary injuries in KD. Optimal specificity and sensitivity were obtained when using plasma H2S to predict CAL in KD children. CONCLUSION: Plasma H2S level in the acute period is a potentially useful biomarker for predicting CAL in KD children. PMID- 25808255 TI - Precipitation of ventricular bigeminy by DMSO during autologous haematopoietic stem cell transplantation. PMID- 25808256 TI - Improving recorded volume in mesial temporal lobe by optimizing stereotactic intracranial electrode implantation planning. AB - PURPOSE: Intracranial electrodes are sometimes implanted in patients with refractory epilepsy to identify epileptic foci and propagation. Maximal recording of EEG activity from regions suspected of seizure generation is paramount. However, the location of individual contacts cannot be considered with current manual planning approaches. We propose and validate a procedure for optimizing intracranial electrode implantation planning that maximizes the recording volume, while constraining trajectories to safe paths. METHODS: Retrospective data from 20 patients with epilepsy that had electrodes implanted in the mesial temporal lobes were studied. Clinical imaging data (CT/A and T1w MRI) were automatically segmented to obtain targets and structures to avoid. These data were used as input to the optimization procedure. Each electrode was modeled to assess risk, while individual contacts were modeled to estimate their recording capability. Ordered lists of trajectories per target were obtained. Global optimization generated the best set of electrodes. The procedure was integrated into a neuronavigation system. RESULTS: Trajectories planned automatically covered statistically significant larger target volumes than manual plans [Formula: see text]. Median volume coverage was [Formula: see text] for automatic plans versus [Formula: see text] for manual plans. Furthermore, automatic plans remained at statistically significant safer distance to vessels [Formula: see text] and sulci [Formula: see text]. Surgeon's scores of the optimized electrode sets indicated that 95% of the automatic trajectories would be likely considered for use in a clinical setting. CONCLUSIONS: This study suggests that automatic electrode planning for epilepsy provides safe trajectories and increases the amount of information obtained from the intracranial investigation. PMID- 25808257 TI - Improving GRAPPA reconstruction by frequency discrimination in the ACS lines. AB - PURPOSE: GRAPPA is a well-known parallel imaging method that recovers the MR magnitude image from aliasing by using a weighted interpolation of the data in k space. To estimate the optimal reconstruction weights, GRAPPA uses a band along the center of the k-space where the signal is sampled at the Nyquist rate, the so called autocalibrated (ACS) lines. However, while the subsampled lines usually belong to the medium- to high-frequency areas of the spectrum, the ACS lines include the low-frequency areas around the DC component. The use for estimation and reconstruction of areas of the k-space with very different features may negatively affect the final reconstruction quality. We propose a simple, yet powerful method to eliminate reconstruction artifacts, based on the discrimination of the low-frequency spectrum. METHODS: The proposal to improve the estimation of the weights lays on a proper selection of the coefficients within the ACS lines, which advises discarding those points around the DC component. A simple approach is the elimination of a square window in the center of the k-space, although more developed approaches can be used. RESULTS: The method is tested using real multiple-coil MRI acquisitions. We empirically show this approach achieves great enhancement rates, while keeping the same complexity of the original GRAPPA and reducing the g-factor. The reconstruction is even more accurate when combined with other reconstruction methods. Improvement rates of 35% are achieved for 32 ACS and acceleration rate of 3. CONCLUSIONS: The method proposed highly improves the accuracy of the GRAPPA coefficients and therefore the final image reconstruction. The method is fully compatible with the original GRAPPA formulation and with other optimization methods proposed in literature, and it can be easily implemented into the commercial scanning software. PMID- 25808258 TI - A Hybrid Adenoviral Vector System Achieves Efficient Long-Term Gene Expression in the Liver via piggyBac Transposition. AB - Much research has gone into the development of hybrid gene delivery systems that combine the broad tropism and efficient transduction of adenoviral vectors with the ability to achieve stable expression of cargo genes. In addition to gene therapy applications, such a system has considerable advantages for studies of gene function in vivo, permitting fine-tuned genetic manipulation with higher throughput than can be achieved using standard transgenic and DNA targeting techniques. Existing strategies are limited, however, by low integration efficiencies, small cargo capacity, and/or a dependence on target cell division. The utility of this approach could be enhanced by a system that provides all of the following: (1) efficient delivery, (2) stable expression in a high percentage of target cells (whether mitotic or not), (3) large cargo capacity, (4) flexibility to use with a wide range of additional experimental conditions, and (5) simple experimental technique. Here we report the initial characterization of a hybrid system that meets these criteria by utilizing piggyBac (PB) transposition to achieve genomic integration from adenoviral vectors. We demonstrate stable expression of an adenovirus (Ad)-PB-delivered reporter gene in ~20-40% of hepatocytes following standard tail vein injection. Its high efficiency and flexibility relative to existing hybrid adenoviral gene delivery approaches indicate a considerable potential utility of the Ad-PB system for therapeutic gene delivery and in vivo studies of gene function. PMID- 25808259 TI - Involvement of ICAM-1 in impaired spermatogenesis after busulfan treatment in mice. AB - Expression of adherence proteins, such as P-cadherin, has been identified in the normal testis and changed in impaired testis induced by alkylating agents. Intercellular adhesion molecule-1 (ICAM-1), a member of the immunoglobulin superfamily of cell adhesion molecules, is a constituent component of the blood testis barrier and a multifunctional molecule in homeostasis of spermatogenesis. However, the distribution of ICAM-1 in the testis of mice and expression changes after busulfan treatment remain unclear. In this study, ICAM-1 immunoreaction was detected in Sertoli and germinal cells, particularly in spermatogonia, and elongating and elongated spermatids of normal testes. Accompanied with degeneration of spermatogenesis (decrease in testicular and epididymal weights, as well as loss of germ cells in histological morphology), ICAM-1 expression declined significantly in the seminiferous tubules during a 4-week experimental period, particularly in the first 2 weeks (40 mg kg(-1) busulfan, single injection). Compared with the control group, busulphan-treated testes showed a significant increase in lipid peroxidation during weeks 1 and 2. Thus, ICAM-1 may play an important role in the homeostasis of spermatogenesis, and busulfan treatment can lead to adhesion disintegration. PMID- 25808261 TI - Some Anti-Inflammatory Agents Inhibit Esterase Activities of Human Carbonic Anhydrase Isoforms I and II: An In Vitro Study. AB - Carbonic anhydrases (CAs) are known as a drug-target enzymes. The inhibitors of the enzyme are important compounds for discovering new therapeutic agents and understanding in detail protein-drug interactions at the molecular level. For this purpose, the in vitro effects of some anti-inflammatory agents such as tenoxicam, fluorometholone acetate, and dexamethasone were investigated on esterase activity of human erythrocyte CA-I and CA-II in this study. hCA-I and hCA-II were purified by affinity chromatography with a yield of 47.25% and 87%, and a specific activity of 642.8 EU/mg proteins and 5576.9 EU/mg proteins, respectively. SDS-PAGE was performed to determine the purity of the enzymes. Inhibitory effects of the drugs on hCA-I and hCA-II were determined by spectrophotometric method. IC50 values for hCA-I and hCA-II were 0.198, 2.18, 11.7, 0.11, 17.5 and 14 MUm using tenoxicam, fluorometholone acetate, and dexamethasone, respectively. For fluorometholone acetate and dexamethasone, Ki values from Lineweaver-Burk plots were obtained as 1.044 and 21.2 MUm (noncompetitive) for hCA-I and 9.98 and 8.66 MUm (non-competitive) for hCA-II. In conclusion, tenoxicam, fluorometholone acetate, and dexamethasone showed potent inhibitory effects on esterase activity of hCA-I and hCA-II isozymes under in vitro conditions. PMID- 25808260 TI - The controversial role of food allergy in infantile colic: evidence and clinical management. AB - Food allergies (FAs) are an increasing problem in Western countries, affecting up to 10% of young children. FAs are frequently associated with gastrointestinal manifestations. The role of FAs as a potential causative factor for infantile colic (IC) is still controversial. We report the most recent evidence on the pathogenesis, clinical and diagnostic aspects of FA-induced infantile colic (IC) and suggest a stepwise diagnostic approach. We selected articles on clinical and immunologic features, pathogenesis and management of FAs and IC from of 1981 to 2015. Original and review articles were identified through selective searches performed on PubMed, using the following terms: colic, infantile colic, food allergy and infantile colic, infantile colic treatment. The possible relationship between FAs and IC derives from the presence of dysmotility with visceral hypersensitivity and dysbiosis, demonstrated in both conditions, and the clinical response to dietary interventions. Unfortunately, the design of the studies, poor characterization of atopy and different dietary approaches limit the understanding of the importance of FAs in subjects with IC. The role of FAs in IC subjects without other symptoms of atopy remains controversial. However, where there is a suspicion of FAs, a short trial with an extensively hydrolyzed cow's proteins formula or, if breast fed, with maternal elimination diet may be considered a reasonable option. PMID- 25808263 TI - Comparison of clinical characteristics of tuberculosis between two age groups at an Italian Tertiary Hospital. AB - Differences in clinical characteristics and outcome between elderly (>60 years) and younger (18-59 years) tuberculosis (TB) patients were retrospectively evaluated. Alcohol abuse, radiological evidence of cavitation, and cough at presentation were more frequent among younger patients. Older patients were more likely to have comorbidities, disseminated TB, longer duration of symptoms and higher TB-related mortality (19 vs 0%). Very old patients (>=80 years) showed increased liver toxicity and hospital acquired infections compared to patients aged 60-79 years. PMID- 25808262 TI - Impact of serology and molecular methods on improving the microbiologic diagnosis of infective endocarditis in Egypt. AB - BACKGROUND: Conventional diagnosis of infective endocarditis (IE) is based mainly on culture-dependent methods that may fail because of antibiotic therapy or fastidious microorganisms. OBJECTIVES: We aimed to evaluate the added values of serological and molecular methods for diagnosis of infective endocarditis. PATIENTS AND METHODS: One hundred and fifty-six cases of suspected endocarditis were enrolled in the study. For each patient, three sets of blood culture were withdrawn and serum sample was collected for Brucella, Bartonella and Coxiella burnetii antibody testing. Galactomannan antigen was added if fungal endocarditis was suspected. Broad range PCR targeting bacterial and fungal pathogens were done on blood culture bottles followed by sequencing. Culture and molecular studies were done on excised valve tissue when available. RESULTS: One hundred and thirty two cases were diagnosed as definite IE. Causative organisms were detected by blood cultures in 40 (30.3 %) of cases. Blood culture-negative endocarditis (BCNE) represented 69.7 %. Of these cases, PCR followed by sequencing on blood and valvular tissue could diagnose five cases of Aspergillus flavus. Eleven patients with BCNE (8.3 %) were diagnosed as zoonotic endocarditis by serology and PCR including five cases of Brucella spp, four cases of Bartonella spp and two cases of Coxiella burnetii. PCR detected three cases of Brucella spp and two cases of Bartonella spp, while cases of Coxiella burnetii were PCR negative. The results of all diagnostic tools decreased the percentage of non-identified cases of BCNE from 69.7 to 49.2 %. CONCLUSION: Our data underline the role of serologic and molecular tools for the diagnosis of blood culture-negative endocarditis. PMID- 25808264 TI - Vasculitis secondary to anti-C1q antibodies induced by Toxocariasis. AB - INTRODUCTION: Vasculitides occurring during parasitic infection are rare and may imply different mechanisms. METHODS: A case report of cutaneous vasculitis and visceral damage during a larva migrans syndrome. RESULTS: We report the case of a 64-year-old man who developed a purpura along with fever, respiratory failure, abdominal pain and myalgia. Immunological screening showed a high titer of both antinuclear antibodies and anti-double-stranded DNA antibodies along with anti C1q antibodies. Toxocara canis serology returned highly positive with a positive western-blot. The use of antiparasitic drugs in combination with corticosteroids resulted in a dramatic improvement in the patient's condition. CONCLUSIONS: Clinicians should be aware of the systemic complications that may occur during Toxocara canis infection, including vasculitis and immunological disorder. PMID- 25808265 TI - Numerical Estimation in Children With Autism. AB - Number skills are often reported anecdotally and in the mass media as a relative strength for individuals with autism, yet there are remarkably few research studies addressing this issue. This study, therefore, sought to examine autistic children's number estimation skills and whether variation in these skills can explain at least in part strengths and weaknesses in children's mathematical achievement. Thirty-two cognitively able children with autism (range = 8-13 years) and 32 typical children of similar age and ability were administered a standardized test of mathematical achievement and two estimation tasks, one psychophysical nonsymbolic estimation (numerosity discrimination) task and one symbolic estimation (numberline) task. Children with autism performed worse than typical children on the numerosity task, on the numberline task, which required mapping numerical values onto space, and on the test of mathematical achievement. These findings question the widespread belief that mathematical skills are generally enhanced in autism. For both groups of children, variation in performance on the numberline task was also uniquely related to their academic achievement, over and above variation in intellectual ability; better number-to space mapping skills went hand-in-hand with better arithmetic skills. Future research should further determine the extent and underlying causes of some autistic children's difficulties with regards to number. PMID- 25808266 TI - Off-resonance saturation ratio obtained with ultrashort echo time-magnetization transfer techniques is sensitive to changes in static tensile loading of tendons and degeneration. AB - BACKGROUND: To determine if off-saturation ratio (OSR) measured with the ultrashort echo time magnetization transfer (UTE-MT) sequence could differentiate between tendons under different states of tensile load and to compare these changes between normal versus degenerated tendons. METHODS: Fourteen tendons were imaged at 3 Tesla before and during the application of 0.5-1 kg tension. A two dimensional (2D) -UTE-MT sequence with 1.5, 3, and 5 kHz frequency offsets was used on nine tendons and a 3D-UTE-MT sequence with 1.5 kHz frequency offset was used on five tendons. OSR was calculated and compared for each condition. Histologic correlation was performed using light microscopy. RESULTS: In general, OSR increased after the application of tension. Mean increase of 2D OSR was 0.035 (95% confidence interval [CI], 0.013-0.056) at 1.5 kHz offset (P < 0.01), 0.031 (95% CI, 0.023-0.040) at 3 kHz offset (P < 0.01), and 0.013 (95% CI, -0.013 0.027) at 5 kHz offset (P = 0.07) from pre- to posttension states. Mean increase of 3D OSR was 0.026 (95% CI, 0.008-0.044) at a 1.5 kHz offset (P = 0.02) from pre to posttension states. Mean decrease of 2D OSR at 1.5 kHz offset was 0.074-0.087 when comparing normal versus degenerated tendons (P < 0.01). CONCLUSION: OSR as measured with 2D or 3D UTE-MT sequences can detect the changes in hydration seen when tendons are placed under two different states of tensile load, but these changes are smaller than those encountered when comparing between normal versus pathologic tendons. Lower off-resonance saturation frequencies (3 kHz or less) are more sensitive to these changes than higher off-resonance saturation frequencies. PMID- 25808267 TI - Suicidal ideation and suicide attempts in five groups with different severities of gambling: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - BACKGROUND AND OBJECTIVES: Problem and pathological gamblers show high rates of suicidal behavior. However, previous research of suicide among this population has been inconsistent. Discrepancies may stem from methodological issues, including variable use of suicide nomenclature and selection bias in study samples. Furthermore, earlier research has rarely examined gambling severity aside from problem or pathological categories. This study utilized subgroups derived from a nationally representative data set, examining different characteristics of suicidal behavior and several gambling levels, including subclinical groups. METHODS: Participants included 13,578 individuals who participated in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and provided information on gambling behavior, lifetime suicidal ideation, and/or lifetime suicide attempts. Five gambling groups were derived using DSM-IV criteria for pathological gambling; non-gambling, low-risk gambling, at-risk gambling, problem gambling, and pathological gambling. RESULTS: Problem gambling was associated with suicidal ideation [adjusted odds ratio (AOR) = 1.64, 95% confidence interval (CI) = 1.19-2.26] and suicide attempts [(AOR) = 2.42, 95% (CI) = 1.60-3.67] after adjustment for sociodemographic variables. Pathological gambling was associated with suicidal ideation [(AOR) = 2.86, 95% (CI) = 1.98-4.11] and suicide attempts [(AOR) = 2.77, 95% (CI) = 1.72-4.47) after adjustment for sociodemographic variables. DISCUSSION, CONCLUSIONS, AND SCIENTIFIC SIGNIFICANCE: Our results from this population sample reinforce increased rates of suicidal behavior amongst smaller, clinical samples of problem and pathological gamblers. Education for providers about gambling is recommended, including screening for gambling-related symptoms such as suicidal behavior. PMID- 25808268 TI - The Structural Influence of Graphene Oxide on Its Fragmentation during Laser Desorption/Ionization Mass Spectrometry for Efficient Small-Molecule Analysis. AB - The structural influence of graphene oxide (GO) on laser desorption/ionization mass spectrometry (LDI-MS) analysis of small molecules was systematically investigated by using size-fractionated GO. For fractionation of GO, pH-assisted centrifugation, sequential vacuum filtration, and sonochemical cutting processes were employed and the size-fractionated GO was thoroughly characterized to understand their size-dependent optochemical properties. Then, the fractionated GO was applied to the analysis of various small molecules by LDI-MS to investigate the relationship between their optochemical properties and LDI-MS performance. We found that large GO sheets (>0.5 MUm) were more prone to fragmentation under laser irradiation during LDI-MS analysis than small GO sheets (<0.5 MUm). In this regard, the LDI-MS analysis efficiency of various small molecules was significantly improved by using nanosized GO (NGO) as a matrix without background interference. In particular, NGO was successfully applied to the sensitive detection of hydrophobic pollutant molecules without requiring any surface-functionalization, enrichment, and separation process. Therefore, the present study could provide important basic information and be a practical tool for the development of simple and efficient LDI-MS platforms by using GO derivatives. PMID- 25808270 TI - Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research. AB - The tissue:plasma partition coefficients (Kp ) are good indicators of the extent of tissue distribution. Therefore, advanced tissue composition-based models were used to predict the Kp values of drugs under in vivo conditions on the basis of in vitro and physiological input data. These models, however, focus on animal tissues and do not challenge the predictions with human tissues for drugs. The first objective of this study was to predict the experimentally determined Kp values of seven human tissues for 26 drugs. In all, 95% of the predicted Kp values are within 2.5-fold error of the observed values in humans. Accordingly, these results suggest that the tissue composition-based model used in this study is able to provide accurate estimates of drug partitioning in the studied human tissues. Furthermore, as the Kp equals to the ratio of total concentration between tissue and plasma, or the ratio of unbound fraction between plasma (fup ) and tissue (fut ), this parameter Kp would deviate from the unity. Therefore, the second objective was to examine the corresponding relationships between fup and fut values experimentally determined in humans for several drugs. The results also indicate that fup may significantly deviate to fut ; the discrepancies are governed by the dissimilarities in the binding and ionization on both sides of the membrane, which were captured by the tissue composition-based model. Hence, this violated the basic assumption in in vivo pharmacokinetics-pharmacodynamics (PK/PD) research, since the free drug concentration in tissue and plasma was not equal particularly for the ionizable drugs due to the pH gradient effect on the fraction of unionized drug in plasma (fuip ) and tissue (fuit ) (i.e., fup * fuip * total plasma concentration = fut * fuit * total tissue concentration, and, hence, the free drug concentration in plasma and tissue differed by fuip/fuit). Therefore, this assumption should be adjusted for the ionized drugs, and, hence, a mathematical correction to the basic assumption of similar free drug concentration in plasma and tissues can be derived from the tissue composition based model. Note that this assumption will be further challenged in a dynamic in vivo system in a companion manuscript. Overall, this study was a first attempt to predict the in vivo Kp values for specific human tissues by considering separately the effect of fup and fut , with the aim of facilitating the use of physiologically-based PK (PBPK) model in PK/PD studies. PMID- 25808271 TI - Why do we need a child psychiatric nursing specialty? PMID- 25808269 TI - An exploratory examination of patient and parental self-efficacy as predictors of weight gain in adolescents with anorexia nervosa. AB - OBJECTIVE: To determine whether increases in adolescent or parental self-efficacy predicted subsequent weight gain in two different therapies for adolescent anorexia nervosa (AN). METHOD: Participants were 121 adolescents with AN (M = 14.4 years, SD = 1.6), from a two-site randomized clinical trial for family-based treatment (FBT) and individual adolescent focused therapy (AFT). Both adolescent and parental self-efficacy were assessed at baseline and sessions 2, 4, 6, and 8. Adolescent self-efficacy was assessed using a generic measure of self-efficacy, while parental self-efficacy was assessed using a measure specific to the recovery of an eating disorder. Weight was assessed at baseline, sessions 1 through 8, and end of treatment. Mixed-effects models were used to evaluate the relation between patient and parent self-efficacy and subsequent weight gain, controlling for weight at the previous time point. RESULTS: For families who received FBT, greater within-treatment increases in parental self-efficacy predicted greater subsequent adolescent weight gain compared to those who received FBT with lesser change in parental self-efficacy and those who received AFT. Interestingly, adolescent self-efficacy did not significantly predict subsequent weight gain. DISCUSSION: Greater increases in parental self-efficacy predicted significantly greater subsequent weight gain for adolescents who received FBT, but the same was not true for adolescents who received AFT. Neither overall level nor change in adolescent self-efficacy significantly predicted subsequent weight gain in either treatment group. These findings emphasize the importance of increasing parental self-efficacy in FBT in order to impact adolescent weight outcomes. PMID- 25808272 TI - Stressful life events, worry, and rumination predict depressive and anxiety symptoms in young adolescents. AB - PROBLEM: Depression and anxiety are highly prevalent and frequently comorbid mental health disorders that often manifest during childhood and adolescence. The purpose of this study was to prospectively examine potential common underlying mechanisms predicting the development of depressive and anxiety symptoms to identify mutual underlying modifiable risk factors to target with mental health promotion and prevention interventions. METHODS: A community-based sample of 11- to 15-year-old adolescents participated in a prospective, longitudinal pilot study with three waves of data collection over a 6-month period. FINDINGS: At baseline, stressful life events, worry, and rumination accounted for 35% of the variance in anxiety scores (adjusted R(2) = 0.28) and 58% of the variance in depressive symptoms (adjusted R(2) = 0.53), while at Time 3 (T3; 6 months post baseline) these variables accounted for 63% of the variance in anxiety scores (adjusted R(2) = 0.59) and 45% of the variance in depressive symptoms (adjusted R(2) = 0.39). After controlling for baseline values, increases in stress, worry, and rumination were predictive of both depressive and anxiety symptoms at T3. CONCLUSIONS: Study findings point to the importance of prevention and early intervention programs including content addressing stress management, rumination, and worry. PMID- 25808273 TI - A review of depression and quality of life outcomes in adolescents post bariatric surgery. AB - TOPIC: A systematic review: Depression and quality of life of adolescents after bariatric surgery. PURPOSE: Reported changes in depression and quality of life among adolescents after bariatric surgery were assessed, along with the choice of tools, length of follow-up, and age and gender trends. SOURCES USED: Medical and psychosocial electronic databases. CONCLUSIONS: The majority of published studies of adolescents post bariatric surgery showed a positive reduction in depression and improvements in quality of life regardless of the amount of weight lost or type of surgery performed. Four studies measured changes only within the first year and three within 2 years; it is unknown if positive psychological benefits persisted. Patients' ages ranged from 9 to 20 years, with an average age of 16.6. A 7:3 female/male ratio presented for surgery. Three depression and six quality of life instruments were utilized; two instruments were validated for adult use only. Consistent qualitative and quantitative measures of psychological issues and quality of life specific to adolescents are necessary. Multicenter longitudinal studies are warranted to more effectively track outcomes and patients needing more support. Thus informed, a nurse or health practitioner can better advocate for the patient during the preoperative, postoperative, and follow-up periods. PMID- 25808274 TI - Autoimmune spontaneous chronic urticaria and generalized myasthenia gravis in a patient with polyglandular autoimmune syndrome type 3. AB - INTRODUCTION: Autoimmune polyglandular syndromes (APS) are a group of disorders characterized by the presence of autoimmune processes in several endocrine and non-endocrine organs that are classified into 4 types. METHODS: We describe the case of a woman affected with APS type 3 who presented initially with Hashimoto thyroiditis and pernicious anemia and subsequently developed autoimmune chronic urticaria, myasthenia gravis, and type 1 diabetes mellitus. RESULTS: This patient had a combination of components of APS types 3b, 3a, and 3c. She was referred for evaluation of chronic spontaneous urticaria and subsequently developed severe generalized myasthenia gravis, which was apparently unmasked by antihistamines used to control urticaria. CONCLUSIONS: Patients with APS should have a more thorough evaluation to better clarify their autoimmune background. Early detection of autoantibodies and latent organ-specific dysfunction may help physicians take appropriate action to prevent full-blown disease. PMID- 25808275 TI - Real-world outcomes in patients with depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia. AB - INTRODUCTION: This study compared treatment outcomes in patients with major depressive disorder treated with either duloxetine with a daily dose of <=60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. METHODS: This post-hoc analysis of data from a 6-month prospective observational study involving 1,549 major depressive disorder patients without sexual dysfunction focused on a subgroup of patients from East Asia (n = 587). Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS SR16 ), whereas quality of life (QoL) was measured using EuroQoL instruments. PPS were rated using the modified Somatic Symptom Inventory. Multiple regression analyses were performed to compare the treatment outcomes. RESULTS: Duloxetine treated patients had higher odds of achieving remission (odds ratio = 2.578, P < 0.001) and response (odds ratio = 2.704, P < 0.001) during follow-up, compared with SSRI-treated patients. They also had lower levels of disease severity and higher levels of QoL during follow-up. A similar pattern was observed in each subgroup of patients with and without PPS at baseline, but the effects of duloxetine relative to SSRIs were in general greater in patients with PPS. DISCUSSION: Patients treated with duloxetine had better treatment outcomes in terms of remission, response, depressive symptoms, and QoL, compared with SSRIs. Treatment with duloxetine may have additional advantages for patients with concurrent PPS. PMID- 25808276 TI - Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice. AB - The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN(+/-) and MSTN(-/-) mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN(+/+) and MSTN(-/-) mice, MSTN(+/-) mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity. PMID- 25808277 TI - Palladium-catalyzed three-component cascade reaction: facial access to densely functionalized indolizines. AB - A palladium-catalyzed three-component cascade reaction of 2-(2-enynyl)pyridines with nucleophiles and allyl halides has been developed, enabling the synthesis of densely functionalized indolizines in moderate to good yields. The newly developed methodology offers several practical advantages, including operational simplicity, ready availability of starting materials, and mild reaction conditions. PMID- 25808278 TI - Transplanting Kidneys from Deceased Donors With Severe Acute Kidney Injury. AB - Our aim was to determine outcomes with transplanting kidneys from deceased donors with acute kidney injury, defined as a donor with terminal serum creatinine >=2.0 mg/dL, or a donor requiring acute renal replacement therapy. We included all patients who received deceased donor kidney transplant from June 2004 to October 2013. There were 162 AKI donor transplant recipients (21% of deceased donor transplants): 139 in the standard criteria donor (SCD) and 23 in the expanded criteria donor (ECD) cohort. 71% of the AKI donors had stage 3 (severe AKI), based on acute kidney injury network (AKIN) staging. Protocol biopsies were done at 1, 4, and 12 months posttransplant. One and four month formalin-fixed paraffin embedded (FFPE) biopsies from 48 patients (24 AKI donors, 24 non-AKI) underwent global gene expression profiling using DNA microarrays (96 arrays). DGF was more common in the AKI group but eGFR, graft survival at 1 year and proportion with IF/TA>2 at 1 year were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (p-value <0.005; FDR <10%), but by 4 months there were no differences. Transplanting selected kidneys from deceased donors with AKI is safe and has excellent outcomes. PMID- 25808279 TI - Intramuscular pH modulates glutamate-evoked masseter muscle pain magnitude in humans. AB - BACKGROUND: This study was conducted to determine whether glutamate-evoked jaw muscle pain is modulated by the acidity and temperature of the solution injected. METHODS: Thirty two participants participated and received injections of high temperature acidic (HT-A) glutamate (pH 4.8, 48 degrees C), high-temperature neutral (HT-N) glutamate (pH 7.0, 48 degrees C) and neutral temperature neutral (NT-N) glutamate (pH 7.0, 38 degrees C) solutions (0.5 mL) into the masseter muscle. Pain intensity was assessed with an electronic visual analogue scale (eVAS). Numerical rating scale (NRS) scores of unpleasantness and temperature perception, pain-drawing areas, mechanical sensitivity and pressure pain thresholds (PPT) were also measured. Participants filled out the McGill Pain Questionnaire (MPQ). One or two way ANOVAs were used for data analyses. RESULTS: Injection of HT-A glutamate solutions significantly increased the area under the VAS-time curve compared with injection of HT-N glutamate and NT-N glutamate solution (p < 0.040). The duration of glutamate-evoked pain was significantly longer when HT-A glutamate was injected than when NT-N glutamate was injected (p < 0.017). No significant effects of acidity were detected on pain drawings, NRS unpleasantness and heat perception, but there was a significant effect of acidity on MPQ scores and mechanical sensitivity. CONCLUSION: Acidity and temperature modulate glutamate-evoked jaw muscle pain suggesting an interaction between acid sensing and glutamate receptors which could be of importance for understanding clinical muscle pain conditions. PMID- 25808282 TI - Oxidation of organosilanes with nanoporous copper as a sustainable non-noble metal catalyst. AB - Although many noble-metal catalysts have been used for the oxidation of organosilanes, there has been less success with non-noble-metal catalysts. Here, unsupported nanoporous copper (np-Cu) is used to catalyze the oxidation of organosilanes under mild conditions. It is the first time that this reaction has been achieved with a heterogeneous copper catalyst with high activity and selectivity. Both water and alcohols are used as oxidants and the corresponding organosilanols and organosilyl ethers are obtained in high yield. The possible mechanism was obtained by kinetic studies. The catalyst could be reused at least five times without evident loss of activity. As a novel green catalyst np-Cu should play a unique role in organic synthesis. PMID- 25808281 TI - Physically cross-linked hydrogels of beta -cyclodextrin polymer and poly(ethylene glycol)-cholesterol as delivery systems for macromolecules and small drug molecules. AB - An injectable hydrogel based on the inclusion complexation of polymerized beta cyclodextrin (pbeta-CD) and cholesterol terminated poly(ethylene glycol) (PEG chol) was developed and used as a delivery system for both macromolecules and small drugs. The hydrogel was characterized by different analyses including X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. The effects of pbeta-CD/PEG-chol ratio and PEG-chol architecture on the hydrogel properties were also investigated. Cytotoxicity of the hydrogel was evaluated in NIH 3T3 fibroblasts using MTS assay. The hydrogel had an elastic behavior even at high temperature since the gelation temperature was observed at 68 degrees C. The highest hydrogel strength and stability were observed for the 8-armed PEG chol at a pbeta-CD/PEG-chol ratio of 1:1, w/w. Hydrogel degradation in phosphate buffered saline occurred by gradual erosion over the course of two months. IgG, a model hydrophilic macromolecule and riluzole, a model hydrophobic small drug were incorporated into the hydrogel and quantitatively released in a sustained fashion. The released IgG maintained its bioactivity confirming the absence of deleterious effects on protein structure during loading and release. The hydrogels showed no toxicity on NIH 3T3 fibroblasts confirming their biocompatibility. These results confirm the potential of pbeta-CD/PEG-chol hydrogel as a versatile delivery system for drugs of different molecular weights and nature. PMID- 25808280 TI - Investigation of Drug Release from PEO Tablet Matrices in the Presence of Vitamin E as Antioxidant. AB - The objective of this study was to investigate the influence of drug type on the release of drug from PEO matrix tablets accompanied with the impact of vitamin E succinate as antioxidant. The result showed that the presence of vitamin E promoted a stable release rate of soluble drug propranolol HCl from aged PEO matrix tablets, which was similar to fresh sample, regardless of molecular weight (MW) of PEO. However, the influence of the presence of vitamin E on the release rate of partially soluble drug, theophylline, was dependent on the MW of PEO; i.e., fast and unstable drug release was obtained in the case of low MW PEO 750 whereas stable drug release was obtained in the case of high MW PEO 303. The release of low water-soluble drug zonisamide was stable regardless of both the presence of vitamin E and the MW of PEO. The presence of vitamin E slightly slowed the release of zonisamide from aged PEO 303 matrices but not PEO 750 matrices. Therefore, in order to achieve a suitable controlled release profile from PEO matrices, not only the presence of vitamin E but also the solubility of the drug and the MW of polyox should be considered. PMID- 25808283 TI - Acute Treatment With XMetA Activates Hepatic Insulin Receptors and Lowers Blood Glucose in Normal Mice. AB - It has been proposed that monoclonal antibodies may become therapeutics for metabolic diseases such as diabetes mellitus. We have previously characterized an allosteric monoclonal antibody to the human insulin receptor (IR), XMetA, that activated metabolic signaling leading to enhanced glucose transport in cultured cells, and chronically reduced fasting blood glucose levels in mouse models of diabetes mellitus. Under acute dosing conditions, the large size of an IR-binding antibody like XMetA (~ 150 kDa) could lead to a more rapid access into liver, an insulin sensitive tissue with well-fenestrated capillaries, when compared to other insulin sensitive tissues with non-fenestrated capillaries, such as muscle and adipose. Thus, in the present study we administered XMetA (10 mg/kg) and insulin (0.5 U/kg) via IV injection, and for 90 min compared their effects on blood glucose lowering and IR activation in three of the major insulin-sensitive tissues of the normal fasted mouse: liver, adipose, and muscle. Like insulin, XMetA lowered blood glucose levels, although the effect was less rapid. Insulin activated IR autophosphorylation and Akt phosphorylation in liver, fat, and muscle. In contrast, IR activation by XMetA was primarily observed in the liver. Both insulin and XMetA lowered beta-hydroxybutyrate levels in plasma; however, only insulin reduced both non-esterified fatty acids (NEFA) and glycerol concentrations. These data indicate that, in normal mice, acute glucose regulation by XMetA is largely mediated by its action on the liver. PMID- 25808284 TI - Nosocomial hepatitis C virus transmission from tampering with injectable anesthetic opioids. AB - The extent of provider-to-patient hepatitis C virus (HCV) transmission from diversion, self-injection, and substitution ("tampering") of anesthetic opioids is unknown. To quantify the contribution of opioid tampering to nosocomial HCV outbreaks, data from health care-related HCV outbreaks occurring in developed countries from 1990 to 2012 were collated, grouped, and compared. Tampering was associated with 17% (8 of 46) of outbreaks, but 53% (438 of 833) of cases. Of the tampering outbreaks, six (75%) involved fentanyl, five (63%) occurred in the United States, and one each in Australia, Israel, and Spain. Case counts ranged from 5 to 275 in the tampering outbreaks (mean, 54.8; median, 25), and 1-99 in the nontampering outbreaks (mean, 10.4; median, 5); between them, the difference in mean ranks of counts was significant (P < 0.01). To estimate HCV transmission risks from tampering, risk-assessment models were constructed, and these risks compared with those from surgery. HCV transmission risk from exposure to an opioid preparation tampered by a provider of unknown HCV infection status who is a person who injects drugs (PWID; 0.62%; standard error [SE] = 0.38%) exceeds 16,757 times the risk from surgery by a surgeon of unknown HCV infection status (0.000037%; SE = 0.000029%) and 135 times by an HCV-infected surgeon (0.0046%; SE = 0.0033%). To pose a 50% patient transmission risk, an infected surgeon may take 30 years, compared to <1 year for a PWID tamperer, and weeks or days for a PWID tamperer who intensifies access to opioids. CONCLUSION: Disproportionately, many cases of HCV infection from nosocomial outbreaks were attributable to provider tampering of anesthetic opioids. Transmission risk from tampering is substantially higher than from surgery. PMID- 25808287 TI - Investigation of maximum local specific absorption rate in 7 T magnetic resonance with respect to load size by use of electromagnetic simulations. AB - Local specific absorption rate (SAR) evaluation in ultra high field (UHF) magnetic resonance (MR) systems is a major concern. In fact, at UHF, radiofrequency (RF) field inhomogeneity generates hot-spots that could cause localized tissue heating. Unfortunately, local SAR measurements are not available in present MR systems; thus, electromagnetic simulations must be performed for RF fields and SAR analysis. In this study, we used three-dimensional full-wave numerical electromagnetic simulations to investigate the dependence of local SAR at 7.0 T with respect to subject size in two different scenarios: surface coil loaded by adult and child calves and quadrature volume coil loaded by adult and child heads. In the surface coil scenario, maximum local SAR decreased with decreasing load size, provided that the RF magnetic fields for the different load sizes were scaled to achieve the same slice average value. On the contrary, in the volume coil scenario, maximum local SAR was up to 15% higher in children than in adults. PMID- 25808285 TI - Probiotics as potential antioxidants: a systematic review. AB - Probiotics are known for their health beneficial effects and are established as dietary adjuncts. Probiotics have been known for many beneficial health effects. In this view, there is interest to find the potential probiotic strains that can exhibit antioxidant properties along with health benefits. In vitro and in vivo studies indicate that probiotics exhibit antioxidant potential. In this view, consumption of probiotics alone or foods supplemented with probiotics may reduce oxidative damage, free radical scavenging rate, and modification in activity of crucial antioxidative enzymes in human cells. Incorporation of probiotics in foods can provide a good strategy to supply dietary antioxidants, but more studies are needed to standardize methods and evaluate antioxidant properties of probiotics before they can be recommended for antioxidant potential. In this paper, the literature related to known antioxidant potential of probiotics and proposing future perspectives to conduct such studies has been reviewed. PMID- 25808288 TI - Earlier initiation of antibiotic therapy: Does prophylaxis offer greater benefit in AML? PMID- 25808289 TI - Organocatalytic Enantioselective Oxidative C-H Alkenylation and Arylation of N Carbamoyl Tetrahydropyridines and Tetrahydro-beta-carbolines. AB - The first organocatalytic enantioselective C-H alkenylation and arylation reactions of N-carbamoyl tetrahydropyridines and tetrahydro-beta-carbolines (THCs) are described. The metal-free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse alpha-substituted tetrahydropyridines and THCs in good yields with excellent regio- and enantioselectivities. Preliminary control experiments provide important insights into the reaction mechanism. PMID- 25808290 TI - Expression of cytokeratins in enamel organ, junctional epithelium and epithelial cell rests of Malassez. AB - BACKGROUND AND OBJECTIVE: After tooth formation is complete, it is suggested that continuity exists between the epithelial cell rests of Malassez (ERM), reduced enamel epithelium (REE) and subsequently the junctional epithelium. However, the junctional epithelium was reported to differ from REE and ERM. The developmental relationships between and among them remain controversial. Therefore, in the present study we examined the expression of cytokeratins in the three types of epithelia to investigate the epithelial phenotypes. MATERIAL AND METHODS: The maxillae of Wistar rats, 1, 2, 3 and 7 wk of age, were used, and the expression of CK14, CK17, CK19, CK10/CK13 and AE1/AE3 was detected using immunoperoxidase techniques. RESULTS: There was negative staining for CK10/CK13 in all the epithelia. ERM stained strongly for AE1/AE3, CK14, CK17 and CK19. During the transformation of inner enamel epithelial (IEE) cells into reduced ameloblasts and subsequently into junctional epithelium, strong staining for CK14 was evident in IEE, REE and junctional epithelium, whereas the expression of AE1/AE3 and of CK19 were initially negative in IEE and then strong in REE and junctional epithelium, respectively. In particular, the expression of CK17 was strongly positive in ERM and REE, but was negative in IEE and junctional epithelium. CONCLUSION: ERM are of odontogenic origin and junctional epithelium has an epithelial phenotype different from REE and ERM. This is the first report to demonstrate that CK17 can be used as a marker to distinguish junctional epithelium from ERM. PMID- 25808291 TI - Enzyme kinetics: the whole picture reveals hidden meanings. AB - The methodology adopted by Michaelis and Menten in 1913 is still routinely used to characterize the catalytic power and selectivity of enzymes. These kinetic measurements must be performed soon after the purified enzyme is mixed with a large excess of substrate. Other time scales and solution compositions are no less physiologically relevant, but fall outside the range of applicability of the classical formalism. Here we show that the complete picture of an enzyme's mode of function is critically obscured by the limited scope of conventional kinetic analysis, even in the simplest case of a single active site without inhibition. This picture is now unveiled in a mathematically closed form that remains valid over the reaction time for all combinations of enzyme/substrate concentrations and rate constants. Algebraic simplicity is maintained in the new formalism when stationary reaction phases are considered. By achieving this century-old objective, the otherwise hidden role of the reversible binding step is revealed and atypical kinetic profiles are explained. Most singular kinetic behaviors are identified in a critical region of conditions that coincide with typical cell conditions. Because it is not covered by the Michaelis-Menten model, the critical region has been missed until now by low- and high-throughput screenings of new drugs. New possibilities are therefore raised for novel and once-promising inhibitors to therapeutically target enzymes. PMID- 25808293 TI - Anatomically structured burst spiking of thalamic reticular nucleus cells: implications for distinct modulations of sensory processing in lemniscal and non lemniscal thalamocortical loop circuitries. AB - The thalamic reticular nucleus (TRN) occupies a highly strategic position to modulate sensory processing in the thalamocortical loop circuitries. It has been shown that TRN visual cells projecting to first- and higher-order thalamic nuclei have distinct levels of burst spiking, suggesting the possibility that the TRN exerts differential influences on information processing in first- and higher order thalamic nuclei that compose the lemniscal and non-lemniscal sensory systems, respectively. To determine whether this possibility could extend across sensory modalities, the present study examined activities of TRN auditory cells projecting to the ventral and dorsal divisions (first- and higher-order auditory thalamic nuclei) of the medial geniculate nucleus (TRN-MGV and TRN-MGD cells) in anesthetized rats, using juxta-cellular recording and labeling techniques. Burst spiking of TRN-MGV cells consisted of larger numbers of spikes with shorter inter spike intervals as compared with that of TRN-MGD cells in auditory response evoked by noise burst stimuli. Similar distinctions, although not statistically significant, were observed in spontaneous activity. Furthermore, the features of burst spiking varied in association with the topographies of cell body and terminal field locations. These features of burst spiking are similar to those observed in the two types of TRN visual cells. First- and higher-order thalamic nuclei are known to have distinct levels of burst spiking across sensory modalities. Taken together, it is suggested that the distinctions in burst spiking in the TRN, in conjunction with those in thalamic nuclei, could constitute distinct circuitries for lemniscal and non-lemniscal sensory processing in the thalamocortical loop. PMID- 25808292 TI - Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of beclometasone dipropionate/formoterol fumarate in adolescent asthma. AB - AIM: The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma. METHODS: This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 ug and 24 ug, for each treatment, respectively. Assessments were performed over 8 hours. RESULTS: In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80-1.25, both for beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively. CONCLUSIONS: In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting beta2 -adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults. PMID- 25808294 TI - Assessing the alignment of sexual and natural selection using radiomutagenized seed beetles. AB - A major unsolved question in evolutionary biology concerns the relationship between natural and sexual selection. Sexual selection might augment natural selection, for example if mutations that harm female fecundity also reduce male mating success. Conversely, sexual selection might favour traits that impair naturally selected fitness components. We induced detrimental mutations in Callosobruchus maculatus beetles using X-ray irradiation and then experimentally measured the effect of precopulatory sexual selection on offspring number and survival rate. Sexual selection treatment had a negative effect on egg-to-adult survivorship, although the number of progeny reaching adulthood was unaffected, perhaps because eggs and juveniles that failed to develop lessened competition on the survivors. We hypothesize that the negative effect of sexual selection arose because sexually competitive males transmitted a smaller nuptial gift or carried alleles that conferred reduced survival. Although we found no evidence that sexual selection on males can purge alleles that are detrimental to naturally selected fitness components, such benefits might exist in other environmental or genetic contexts. PMID- 25808295 TI - Mirror syndrome associated with fetal transient abnormal myelopoiesis in Down syndrome. PMID- 25808296 TI - Precautionary allergen labelling: perspectives from key stakeholder groups. AB - Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counterproductive for consumers with food allergies. This review aims to summarize the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimization goals. The lack of agreed reference doses has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk-taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision-making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach and its limitations. Consumers with food allergy then need to be educated to undertake individualized risk assessments in relation to any PAL present. PMID- 25808297 TI - Long-term follow up of 103 ankylosed permanent incisors surgically treated with decoronation--a retrospective cohort study. AB - BACKGROUND/AIM: Decoronation is a technique developed in 1984 to remove ankylosed teeth and increase marginal bone levels in young, growing individuals. This retrospective cohort study evaluates marginal bone development after decoronation in relation to gender and age at treatment. MATERIALS AND METHODS: The study evaluated all 95 patients with 103 ankylosed permanent incisors treated with decoronation at the Eastmaninstitutet Department of Pediatric Dentistry during 1978-1999. Mean age of the patients was 10.7 years (6.8-17.8) at the time of trauma and 14.9 years (9.3-22.0) at decoronation. The mean follow-up period was 4.6 years (1.0-19.3 years). The study evaluated development of the marginal alveolar bone level with a three-point scoring system: 1 = Unchanged or reduced alveolar bone level, 2 = A moderate increase in alveolar bone level, and 3 = A considerable increase in alveolar bone level. The final group for statistical evaluation comprised 75 patients: 56 boys and 19 girls who had only one tooth decoronated. Kappa statistics showed almost complete agreement between the two observers (kappa = 0.90). RESULTS: Bone level changes were significantly correlated (P < 0.05) to gender and age at treatment. In decoronations performed after the age of 16, bone levels were unchanged or reduced, while decoronations performed at a mean age of 14.6 years in boys and 13 years in girls yielded a considerable increase in bone levels. CONCLUSION: This study indicates that age at decoronation is an important factor for favorable development of the alveolar ridge and that decoronation should be performed earlier in girls. PMID- 25808298 TI - Operational models of infrastructure resilience. AB - We propose a definition of infrastructure resilience that is tied to the operation (or function) of an infrastructure as a system of interacting components and that can be objectively evaluated using quantitative models. Specifically, for any particular system, we use quantitative models of system operation to represent the decisions of an infrastructure operator who guides the behavior of the system as a whole, even in the presence of disruptions. Modeling infrastructure operation in this way makes it possible to systematically evaluate the consequences associated with the loss of infrastructure components, and leads to a precise notion of "operational resilience" that facilitates model verification, validation, and reproducible results. Using a simple example of a notional infrastructure, we demonstrate how to use these models for (1) assessing the operational resilience of an infrastructure system, (2) identifying critical vulnerabilities that threaten its continued function, and (3) advising policymakers on investments to improve resilience. PMID- 25808299 TI - Medical Education to Improve Rural Population Health: A Chain of Evidence From Alabama. AB - PURPOSE: To provide evidence that medical education is associated with population health in order to support adaptation of medical school programs to address populations with health disparities. We explored medical education efforts, local physician supply, and life expectancy in Alabama. METHODS: County-level public data of the number of students accepted to medical schools in 2008 and 2011, primary care physicians, life expectancy, and demographic/contextual variables were analyzed to develop a model for hypothesized associations. Correlational analysis, ANCOVA modeling, and path analysis were employed to identify, reduce, and organize significant variables in this cross-sectional ecologic study. FINDINGS: The path model, which met criteria for goodness of fit, found significant relationships among medical students per 10,000 population, primary care physicians per 10,000 population, life expectancy, and contextual variables for rurality and poverty. ANCOVA models showed that geographic region was significant. CONCLUSIONS: Within limitations of the study design, these findings support the proposition that the number of medical students produced in a county is related to the number of primary care physicians, which is related to life expectancy. Recommendations are to confirm the findings in other populations and inform public health policy concerning the utility of medical education to address population health by producing local medical students. PMID- 25808300 TI - Quantification of Shear-Induced Platelet Activation: High Shear Stresses for Short Exposure Time. AB - Thrombosis and thromboembolism are the life-threatening clinical complications for patients supported or treated with prosthetic cardiovascular devices. The high mechanical shear stress within these devices is believed to be the major contributing factor to cause platelet activation (PA) and function alteration, leading to thrombotic events. There have been limited quantitative data on how the high mechanical shear stress causes platelet activation. In this study, shear induced PA in the ranges of well-defined shear stress and exposure time relevant to cardiovascular devices was quantitatively characterized for human blood using two novel flow-through Couette-type blood shearing devices. Four markers of platelet activation-surface P-selectin (CD62p), platelet-derived microparticles (PMPs), platelet-monocyte aggregation (PMA), and soluble P-selectin-were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The results indicated that PA induced by high shear stresses with short exposure time could be reliably detected with surface P-selectin, and, to a lesser extent, PMPs rather than soluble P-selectin. It was also verified that PMA can be a highly sensitive indirect marker of platelet activation. The quantitative relationship between percentage of activated platelets indicated by surface P selectin expression and shear stress/exposure time follows well the power law functional form. The coefficients of the power law models of PA based on surface P-selectin expression were derived. PMID- 25808301 TI - Stardust memories. PMID- 25808302 TI - Computational analysis of cell images. PMID- 25808307 TI - Sebaceous carcinoma in association with actinic keratosis: A report of two cases with an immunohistochemical study. AB - We report two cases of sebaceous carcinoma associated with actinic keratosis (AK) with an immunohistochemical study, which suggests the possibility that sebaceous carcinoma really does develop within AK. Case 1 had sebaceous carcinoma arising within the atrophic type AK and case 2 had sebaceous carcinoma associated with bowenoid AK in the periphery and some parts of the overlying epidermis of the lesion. PMID- 25808308 TI - Mitochondrial Function and Diabetes: Consequences for Skeletal and Cardiac Muscle Metabolism. AB - SIGNIFICANCE: An early hallmark in the development of type 2 diabetes is the resistance to the effect of insulin in skeletal muscle and in the heart. Since mitochondrial function was found to be diminished in patients with type 2 diabetes, it was suggested that this defect might be involved in the etiology of insulin resistance. Although several hypotheses were suggested, yet unclear is the mechanistic link between these two phenomena. RECENT ADVANCES: Herein, we review the evidence for disturbances in mitochondrial function in skeletal muscle and the heart in the diabetic state. Also the mechanisms involved in improving mitochondrial function are considered and, whenever possible, human data is cited. CRITICAL ISSUES: Reported evidence shows that interventions that improve skeletal muscle mitochondrial function also improve insulin sensitivity in humans. In the heart, available data from animal studies suggests that enhancement of mitochondrial function can reverse aging-induced changes in heart function, and can be protective against cardiomyopathy and heart failure. FUTURE DIRECTIONS: Mitochondria and their functions can be targeted with the aim of improving skeletal muscle insulin sensitivity and cardiac function. However, human clinical intervention studies are needed to fully substantiate the potential of mitochondria as a target to prevent cardiometabolic disease. PMID- 25808309 TI - Intellectual Profiles in Children With ADHD and Comorbid Learning and Motor Disorders. AB - OBJECTIVE: Neurodevelopmental disorders, including Reading Disorder, Disorder of Written Expression, and Developmental Coordination Disorder, often co-occur with ADHD. Although research has identified increased functional impairment in the presence of these comorbid diagnoses, few direct comparisons of intellectual profiles have been conducted. Thus, the present study examined Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) profiles of children with ADHD alone and with comorbid neurodevelopmental disorders. METHOD: Participants included 296 children with ADHD, ADHD with Developmental Coordination Disorder, and ADHD with Reading Disorder and/or Disorder of Written Expression. RESULTS: Comparisons of these groups suggests children with ADHD and language-based Learning Disorders have poorer working memory than children with only ADHD. Furthermore, children with ADHD and Developmental Coordination Disorder perform relatively better on verbal compared with perceptual reasoning indexes. CONCLUSION: These intellectual profiles may have utility in identifying cognitive weaknesses inherent to these disorders and may be used to guide treatment intervention. PMID- 25808310 TI - Association Between Altitude and Regional Variation of ADHD in Youth. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of altitude on rates of ADHD. As decreased dopamine (DA) activity has been reported with ADHD and hypoxia has shown to be associated with increased DA, we hypothesized that states at higher altitudes would have lower rates of ADHD. METHOD: State estimates from the 2007 National Survey of Children's Health (NSCH) report and 2010 National Survey of Children with Special Health Care Needs (NS-CSHCN) report were used to extract the percentages of youth ages 4 to 17 diagnosed with ADHD. RESULTS: Both the datasets independently revealed that the prevalence of ADHD decreases with increasing altitude ( R2 = .38, p < .001; R2 = .31, p < .001), respectively. This study controlled for potential confounds (e.g., low birth weight, ethnicity, and household size). CONCLUSION: These findings suggest a need for further investigation into the extent by which altitude may serve as a protective factor for ADHD. PMID- 25808311 TI - Constructing and evaluating a validity argument for the final-year ward simulation exercise. AB - The authors report final-year ward simulation data from the University of Dundee Medical School. Faculty who designed this assessment intend for the final score to represent an individual senior medical student's level of clinical performance. The results are included in each student's portfolio as one source of evidence of the student's capability as a practitioner, professional, and scholar. Our purpose in conducting this study was to illustrate how assessment designers who are creating assessments to evaluate clinical performance might develop propositions and then collect and examine various sources of evidence to construct and evaluate a validity argument. The data were from all 154 medical students who were in their final year of study at the University of Dundee Medical School in the 2010-2011 academic year. To the best of our knowledge, this is the first report on an analysis of senior medical students' clinical performance while they were taking responsibility for the management of a simulated ward. Using multi-facet Rasch measurement and a generalizability theory approach, we examined various sources of validity evidence that the medical school faculty have gathered for a set of six propositions needed to support their use of scores as measures of students' clinical ability. Based on our analysis of the evidence, we would conclude that, by and large, the propositions appear to be sound, and the evidence seems to support their proposed score interpretation. Given the body of evidence collected thus far, their intended interpretation seems defensible. PMID- 25808312 TI - Antioxidant activity and sensory evaluation of a rosmarinic acid-enriched extract of Salvia officinalis. AB - An extract of Salvia officinalis (garden sage) was prepared using supercritical carbon dioxide (SC-CO2 ) extraction, followed by hot water extraction. The resulting extract was enriched in polyphenols, including rosmarinic acid (RA), which has shown promising health benefits in animals. The extract contained RA at a concentration of 28.4 mg/g, representing a significant enrichment from the RA content in sage leaves. This extract was incorporated into oil-in-water emulsions as a source of lipid antioxidants and compared to emulsions containing pure rosmarinic acid. Both treatments were effective in suppressing lipid oxidation. The extract was evaluated by a trained sensory panel in a tea formulation. While the panel could discriminate among extract-treated and control samples, panelists demonstrated high acceptability of the sage extract in a tea. PMID- 25808313 TI - A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape. AB - BACKGROUND: Presentation of identical HIV-1 peptides by closely related Human Leukocyte Antigen class I (HLAI) molecules can select distinct patterns of escape mutation that have a significant impact on viral fitness and disease progression. The molecular mechanisms by which HLAI micropolymorphisms can induce differential HIV-1 escape patterns within identical peptide epitopes remain unknown. RESULTS: Here, we undertook genetic and structural analyses of two immunodominant HIV-1 peptides, Gag180-188 (TPQDLNTML, TL9-p24) and Nef71-79 (RPQVPLRPM, RM9-Nef) that are among the most highly targeted epitopes in the global HIV-1 epidemic. We show that single polymorphisms between different alleles of the HLA-B7 superfamily can induce a conformational switch in peptide conformation that is associated with differential HLAI-specific escape mutation and immune control. A dominant R71K mutation in the Nef71-79 occurred in those with HLA-B*07:02 but not B*42:01/02 or B*81:01. No structural difference in the HLA-epitope complexes was detected to explain this observation. CONCLUSIONS: These data suggest that identical peptides presented through very similar HLAI landscapes are recognized as distinct epitopes and provide a novel structural mechanism for previously observed differential HIV-1 escape and disease progression. PMID- 25808314 TI - Ascorbic acid modulates cell migration in differentiated HL-60 cells and peripheral blood leukocytes. AB - SCOPE: The impact of L-ascorbic acid (L-AA) on the chemokinesis (CK) and chemotaxis (CT) of HL-60 cells and polymorphonuclear cells (PMN) was investigated. METHODS AND RESULTS: HL-60 cells were differentiated with DMSO, retinoic acid (RA), vitamin D, or L-AA. Chemokinesis and chemotaxis of differentiated HL-cells were assayed. Vitamin D3-treated HL-60 cells (dHL-60vitD3 cells) and RA-treated cells (dHL-60RA cells) acquired monocyte/macrophage-like and neutrophil-like phenotypes, respectively. DMSO induced the differentiation of an intermediate phenotype (dHL-60DMSO cells), whereas L-AA downregulated neutrophil markers (dHL-60L-AA cells). dHL-60DMSO cells had increased CK and potent CT in gradients of IL-8 and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). dHL-60RA cells and dHL-60L-AA cells migrated less toward IL-8 and fMLP; dHL-60vitD3 cells preferably responded to fMLP. L-AA enhanced CK of dHL-60DMSO cells and was a weak chemo-attractant. In human leukocytes, IL-8 and fMLP triggered receptor-mediated chemotaxis. CXCR2 and fMLPR were downregulated by IL 8 and fMLP, respectively. L-AA stimulated chemotaxis although significantly less than IL-8 and fMLP. IL-8 targeted chemotaxis was enhanced both in HL-60 cells and leukocytes when cells were incubated with L-AA. CONCLUSION: L-AA modulated chemokinesis and had significant chemo-attractant properties, which were independent on fMLP or IL-8 receptors. The results suggest that L-AA improves leukocyte function in innate immune responses. PMID- 25808316 TI - Diagnostic accuracy of patch test in children with food allergy. AB - BACKGROUND: The gold standard test for confirming whether a child has clinical hypersensitivity reactions to foods is the oral food challenge. Therefore, there is increasing interest in simpler diagnostic markers of food allergy, especially in children, to avoid oral food challenge. The goal of this study was to assess the diagnostic accuracy of atopy patch test in comparison with oral food challenge. METHODS: We investigated 243 children (mean age, 51 months) referred for evaluation of suspected egg or cow's milk allergy. Skin prick test and atopy patch test were carried out, and after a 2 weeks elimination diet, oral food challenge was performed. RESULTS: Two hundred and forty-three children underwent OFC to the suspected food. We found clinically relevant food allergies in 40 (65%) children to egg and in 22 (35%) to cow's milk. The sensitivity of skin prick test for both milk and egg was 92%, specificity 91%, positive predictive value 35%, and negative predictive value of 93%. Sensitivity, specificity, positive predictive value, and negative predictive value of atopy patch test for both milk and egg were 21%, 73%, 20%, and 74%, respectively. CONCLUSION: Our study suggests that there is insufficient evidence for the routine use of atopy patch test for the evaluation of egg and cow's milk allergy. OFC remains gold standard for the diagnosis of egg and milk allergy even in the presence of high costs in terms of both time and risks during application. PMID- 25808315 TI - Activated NKT cells imprint NK-cell differentiation, functionality and education. AB - NK cells represent a vital component of the innate immune system. The recent discoveries demonstrating that the functionality of NK cells depends on their differentiation and education status underscore their potential as targets for immune intervention. However, to exploit their full potential, a detailed understanding of the cellular interactions involved in these processes is required. In this regard, the cross-talk between NKT cells and NK cells needs to be better understood. Our results provide strong evidence for NKT cell-induced effects on key biological features of NK cells. NKT-cell activation results in the generation of highly active CD27(high) NK cells with improved functionality. In this context, degranulation activity and IFNgamma production were mainly detected in the educated subset. In a mCMV infection model, we also demonstrated that NKT-cell stimulation induced the generation of highly functional educated and uneducated NK cells, crucial players in viral control. Thus, our findings reveal new fundamental aspects of the NKT-NK cell axis that provide important hints for the manipulation of NK cells in clinical settings. PMID- 25808317 TI - Role of social media and the Internet in pathways to care for adolescents and young adults with psychotic disorders and non-psychotic mood disorders. AB - AIMS: Although psychosis often occurs during adolescence, there has been little research on how the ubiquitously used Internet and social media could impact pathways to care. We examined how youth with psychotic spectrum disorders (PSD) versus non-psychotic mood disorders (NPMD) use online resources in the early illness stages. METHODS: Social media use and pathways to care data were collected using a semi-structured interview from 80 youth (PSD = 40 and NPMD = 40) aged 12-21 years within 2 years of symptom onset. RESULTS: A total of 97.5% of participants (mean age = 18.3 years) regularly used social media, spending approximately 2.6 +/- 2.5 h per day online. There were 22.4% of our sample (PSD = 19.4%, NPMD = 25.0%, P = 0.56) who reported waiting to reach out for help believing that symptoms would disappear. A total of 76.5% (PSD = 67.5%, NPMD = 85.0%, P = 0.06) noticed social media habit changes during symptom emergence. Thirty per cent reported discussing their symptoms on social media (PSD = 22.5%, NPMD = 37.5%, P = 0.14). NPMD patients sought information most on how to stop symptoms (40.0% vs. 13.5%, P = 0.01), while PSD youth were more commonly interested in what caused their symptoms (21.6% vs. 15.0%, P = 0.45). More PSD patients (42.9% vs. 25.0%, P = 0.10) would prefer to receive mental health information via the Internet. Altogether, 63.6% (PSD = 64.9%, NPMD = 62.5%, P = 0.83) were amenable to clinicians proactively approaching them via social media during symptom emergence. A total of 74.3% (PSD = 78.4%, NPMD = 70.0%, P = 0.40) liked the idea of obtaining help/advice from professionals via social media. CONCLUSIONS: The Internet and social media provide an unparalleled opportunity to supplement and potentially transform early intervention services, and acceptance of this approach appears to be high. PMID- 25808319 TI - Determination of bergenin based on the electrochemiluminescence quenching of tris(2,2'-bipyridine)-ruthenium(II). AB - Quenching effects of bergenin, based on the electrochemiluminescence (ECL) of the tris(2,2'-bipyridyl)-ruthenium(II) (Ru(bpy)3(2+))/tri-n-propylamine (TPrA) system in aqueous solution, is been described. The quenching behavior can be observed with a 100-fold excess of bergenin over Ru(bpy)3(2+). In the presence of 0.1 m TPrA, the Stern-Volmer constant (KSV ) of the ECL quenching is as high as 1.16 * 10(4) M(-1) for bergenin. The logarithmic plot of the inhibited ECL versus logarithmic plot of the concentration of bergenin was linear over the range 3.0 * 10(-6)-1.0 * 10(-4) mol/L. The corresponding limit of detection was 6.0 * 10(-7) mol/L for bergenin (S/N = 3). In the mechanism of quenching it is believed that the competition of the active free radicals between Ru(bpy)3(2+)/TPrA and bergenin was the key factor for the ECL inhibition of the system. Photoluminescence, cyclic voltammetry, coupled with bulk electrolysis, supports the supposition mechanism of the Ru(bpy)3(2+)/TPrA-bergenin system. PMID- 25808318 TI - Metallothionein 2A affects the cell respiration by suppressing the expression of mitochondrial protein cytochrome c oxidase subunit II. AB - Metallothioneins (MT) are involved in a broad range of cellular processes and play a major role in protection of cells towards various stressors. Two functions of MTs, namely the maintaining of the homeostasis of transition metal ions and the redox balance, are directly linked to the functioning of mitochondria. Dyshomeostasis of MTs is often related with malfunctioning of mitochondria; however, the mechanism by which MTs affect the mitochondrial respiratory chain is still unknown. We demonstrated that overexpression of MT-2A in HEK cell line decreased the oxidative phosphorylation capacity of the cells. HEK cells overexpressing MT-2A demonstrated reduced oxygen consumption and lower cellular ATP levels. MT-2A did not affect the number of mitochondria, but reduced specifically the level of cytochrome c oxidase subunit II protein, which resulted in lower activity of the complex IV. PMID- 25808320 TI - Grounded theory methodology--narrativity revisited. AB - This article aims to illuminate the role of narrativity in Grounded Theory Methodology and to explore an approach within Grounded Theory Methodology that is sensitized towards aspects of narrativity. The suggested approach takes into account narrativity as an aspect of the underlying data. It reflects how narrativity could be conceptually integrated and systematically used for shaping the way in which coding, category development and the presentation of results in a Grounded Theory Methodology study proceed. PMID- 25808321 TI - Quantitative assessment of small bowel motility in patients with Crohn's disease using dynamic MRI. AB - BACKGROUND: Assessment of motility alterations by functional magnetic resonance imaging (MRI) contributes to improved evaluation of inflammatory bowel disease. The aim of the study was to quantify motility in inflammatory bowel segments and to compare motility alterations with MR-based parameters for activity of inflammation in Crohn's disease (CD). METHODS: Thirty consecutive patients with CD underwent bowel MRI which included a dynamic sequence for automatic generation of parametric maps facilitating quantification of bowel motility. Mean motility score (MMS) of small bowel segments with signs of inflammation was measured and compared with MMS of the whole gastrointestinal tract (GI tract). MRI-based score of inflammatory activity and lesion length were correlated with the MMS ratio of inflammatory small bowel lesion and whole GI tract. KEY RESULTS: Inflammatory bowel segments showed a mean value of MMSs of 1080, whereas the whole GI tract showed a mean value of MMSs of 2839 (p < 0.0001). Decrease in motility ranged between 20 and 87% in inflammatory bowel segments compared to the MMS of the whole GI tract. The MMS ratio of an inflammatory small bowel segment and whole GI tract showed negative correlation with MR activity score (r = -0.5921, p = 0.0003) and length of the lesion (r = -0.3495, p = 0.0462). CONCLUSIONS & INFERENCES: Quantitative assessment of motility alterations by means of motility scoring in small bowel segments affected by CD provides additional information on inflammatory activity. PMID- 25808325 TI - Intrinsic dynamics of the regional community. AB - Patterns of diversity within large regional biotas express the outcomes of processes, operating on both regional and local scales, that influence evolutionary diversification as well as the distribution and abundance of species. Regional analyses of species distributions suggest that neither ecological sorting of species based on their adaptations to the physical environment, nor interactions between competing species, adequately explain patterns of species richness. Potentially competing species appear to utilise broadly overlapping resources with similar proficiency. Phylogenetic and phylogeographic analyses reveal that species abundances and distributions within regions vary independently of evolutionary relationship. This implies the existence of dynamic, species-specific controls on population growth, as could be applied by specialised pathogens or other antagonists. Here, I argue that the changing balance of coevolved interactions between hosts and their antagonists shapes the distribution and abundance of individual host populations as well as patterns of local species richness. Geographical expansion creates allopatric populations and thereby could promote diversification; contraction ultimately leads to extinction. This taxon-cycle dynamic links regional diversity and distribution to intrinsic biological interactions independently of extrinsic ecological conditions. These hypotheses emphasise the central importance of investigating the impacts of pathogens on species abundance and distribution, and the potential consequences of coevolutionary changes in pathogen-host relationships for species formation and extinction. PMID- 25808324 TI - Interactome analysis of herpes simplex virus 1 envelope glycoprotein H. AB - Herpes simplex virus 1 (HSV-1) envelope glycoprotein H (gH) is important for viral entry into cells and nuclear egress of nucleocapsids. To clarify additional novel roles of gH during HSV-1 replication, host cell proteins that interact with gH were screened for by tandem affinity purification coupled with mass spectrometry-based proteomics in 293T cells transiently expressing gH. This screen identified 123 host cell proteins as potential gH interactors. Of these proteins, general control nonderepressive-1 (GCN1), a trans-acting positive effector of GCN2 kinase that regulates phosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha), was subsequently confirmed to interact with gH in HSV-1-infected cells. eIF2alpha phosphorylation is known to downregulate protein synthesis, and various viruses have evolved mechanisms to prevent the accumulation of phosphorylated eIF2alpha in infected cells. Here, it was shown that GCN1 knockdown reduces phosphorylation of eIF2alpha in HSV-1 infected cells and that the gH-null mutation increases eIF2alpha in HSV-1 infected cells, whereas gH overexpression in the absence of other HSV-1 proteins reduces eIF2alpha phosphorylation. These findings suggest that GCN1 can regulate eIF2alpha phosphorylation in HSV-1-infected cells and that the GCN1-binding viral partner gH is necessary and sufficient to prevent the accumulation of phosphorylated eIF2alpha. Our database of 123 host cell proteins potentially interacting with gH will be useful for future studies aimed at unveiling further novel functions of gH and the roles of cellular proteins in HSV-1-infected cells. PMID- 25808328 TI - IJP open--one year later. PMID- 25808322 TI - Metastasis suppressor NME1 regulates melanoma cell morphology, self-adhesion and motility via induction of fibronectin expression. AB - Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility and invasion in vitro and metastasis in vivo, but the underlying molecular mechanisms are not completely understood. Herein, we report a novel mechanism through which NME1 controls melanoma cell morphology via upregulation of the extracellular matrix (ECM) protein fibronectin. Expression of NME1 strongly suppressed cell motility in melanoma cell lines 1205LU and M14. The resulting sedentary phenotype was associated with a more flattened appearance and marked increases in actin stress fibre and focal adhesion formation. NME1-induced focal adhesions were colocalized with dense deposits of fibronectin, which were absent or minimal in the corresponding NME1-deficient parental lines. NME1 was a strong inducer of fibronectin mRNA and protein expression, shown with reciprocal approaches of forced NME1 expression and shRNA-mediated knock-down. Increased synthesis and ECM deposition of fibronectin was necessary for NME1-induced cell spreading, as knock-down of fibronectin opposed the effects of NME1 on cell morphology. Fibronectin knock-down also reversed the ability of NME1 to promote aggregation when cells were plated on a non-adherent substratum. Similarly, inhibiting activation of the fibronectin receptor integrin alpha4beta1 with an anti-alpha4 antibody reversed the motility-suppressing effect of NME1. A positive correlation was observed between NME1 and fibronectin mRNA in clinical biopsies of normal skin, benign nevi and primary melanomas, but not in metastatic forms, suggesting the NME1/fibronectin axis represents a barrier to melanoma progression. In summary, these findings indicate fibronectin is an important effector of the motility-suppressing function of NME1 in melanoma cells. PMID- 25808326 TI - An energy theory of glaucoma. AB - A radial array of fortified astrocytes (FASTs) is the load bearing structure of the rat optic nerve head (ONH). At the retinal end the ONH is suspended on a fluid filled extracellular space occupied by modified pigment cells which generate a glomerular-like formation of villi. We propose that regulation of fluid in and out of this space may contribute to buffering the normal fluctuations of intraocular pressure. The energy requirement for the fluid transfer process is provided by the dense vascularity of the ONH and is reflected in the giant mitochondria of the FASTs. We propose that glaucoma occurs when a maintained rise in pressure overwhelms the capacity of this regulatory system. Under these circumstances the FAST array becomes detached from its anchorage in the surrounding ONH sheath. Progressively driven backwards by the pressure, the FASTs degenerate. We propose that the degeneration of the FASTs is associated with ischemic damage caused by the backward stretching of their blood supply. Retraction of the FAST processes deprives the retinal ganglion cell axons of their energy support, resulting in axotomy. We consider that our previously observed rescue of axons and FASTs by transplantation of olfactory ensheathing cells is due to replacement of this lost energy source. PMID- 25808329 TI - Correction note. PMID- 25808323 TI - Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons. AB - Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons. PMID- 25808330 TI - The case of Alix: a psychoanalytic transformation when a baby makes three. PMID- 25808331 TI - Discussion of 'The case of Alix: a psychoanalytic transformation when a baby makes three'. PMID- 25808332 TI - Discussion of 'The case of Alix: a psychoanalytic transformation when a baby makes three'. PMID- 25808333 TI - Reason and passion: a tribute to Hanna Segal. PMID- 25808335 TI - Effect of pi-pi+ stacking on the layering of ionic liquids confined to an amorphous carbon surface. AB - In the current paper, AFM studies were conducted on nanometer-thick ionic liquids (ILs) confined to an amorphous carbon (AC) surface, which is critical to the design of the next-generation media lubricant for hard disk drives (HDDs). The results indicated that the existence of the delocalized ring in the cation is critical to layering of ILs. Extended layering was observed only when there is imidazolium ring in the cation. When the imidazolium ring is replaced by an aliphatic moiety, "drop-on-layer" (dewetting) structure was observed. On the basis of the experimental results, we proposed that pi-pi+ stacking between sp(2) carbon in the AC and the imidazolium cation in the ILs is the key to the extended layering of ILs at the ILs/AC interface. PMID- 25808336 TI - Quantitative analysis of three-dimensional fibrillar collagen microstructure within the normal, aged and glaucomatous human optic nerve head. AB - The aim of this study was to quantify connective tissue fibre orientation and alignment in young, old and glaucomatous human optic nerve heads (ONH) to understand ONH microstructure and predisposition to glaucomatous optic neuropathy. Transverse (seven healthy, three glaucomatous) and longitudinal (14 healthy) human ONH cryosections were imaged by both second harmonic generation microscopy and small angle light scattering (SALS) in order to quantify preferred fibre orientation (PFO) and degree of fibre alignment (DOFA). DOFA was highest within the peripapillary sclera (ppsclera), with relatively low values in the lamina cribrosa (LC). Elderly ppsclera DOFA was higher than that in young ppsclera (p < 0.00007), and generally higher than in glaucoma ppsclera. In all LCs, a majority of fibres had preferential orientation horizontally across the nasal-temporal axis. In all glaucomatous LCs, PFO was significantly different from controls in a minimum of seven out of 12 LC regions (p < 0.05). Additionally, higher fibre alignment was observed in the glaucomatous inferior temporal LC (p < 0.017). The differences between young and elderly ONH fibre alignment within regions suggest that age-related microstructural changes occur within the structure. The additional differences in fibre alignment observed within the glaucomatous LC may reflect an inherent susceptibility to glaucomatous optic neuropathy, or may be a consequence of ONH remodelling and/or collapse. PMID- 25808338 TI - Rectangle-capped and tilted micropillar array for enhanced anisotropic anti shearing in biomimetic adhesion. AB - Dry adhesion observed in the feet of various small creatures has attracted considerable attention owing to the unique advantages such as self-cleaning, adaptability to rough surfaces along with repeatable and reversible adhesiveness. Among these advantages, for practical applications, proper detachability is critical for dry adhesives with artificial microstructures. In this study, we present a microstructured array consisting of both asymmetric rectangle-capped tip and tilted shafts, which produce an orthogonal anisotropy of the shearing strength along the long and short dimensions of the tip, with a maximum anti shearing in the two directions along the longer dimension. Meanwhile, the tilt feature can enhance anisotropic shearing adhesion by increasing shearing strength in the forward shearing direction and decreasing strength in the reverse shearing direction along the short dimension of the tip, leading to a minimum anti shearing in only one of the two directions along the shorter dimension of the rectangular tip. Such a microstructured adhesive with only one weak shearing direction, leading to well-controlled attachment and detachment of the adhesive, is created in our experiment by conventional double-sided exposure of a photoresist followed by a moulding process. PMID- 25808337 TI - The dynamic balance of import and export of zinc in Escherichia coli suggests a heterogeneous population response to stress. AB - Zinc is essential for life, but toxic in excess. Thus all cells must control their internal zinc concentration. We used a systems approach, alternating rounds of experiments and models, to further elucidate the zinc control systems in Escherichia coli. We measured the response to zinc of the main specific zinc import and export systems in the wild-type, and a series of deletion mutant strains. We interpreted these data with a detailed mathematical model and Bayesian model fitting routines. There are three key findings: first, that alternate, non-inducible importers and exporters are important. Second, that an internal zinc reservoir is essential for maintaining the internal zinc concentration. Third, our data fitting led us to propose that the cells mount a heterogeneous response to zinc: some respond effectively, while others die or stop growing. In a further round of experiments, we demonstrated lower viable cell counts in the mutant strain tested exposed to excess zinc, consistent with this hypothesis. A stochastic model simulation demonstrated considerable fluctuations in the cellular levels of the ZntA exporter protein, reinforcing this proposal. We hypothesize that maintaining population heterogeneity could be a bet-hedging response allowing a population of cells to survive in varied and fluctuating environments. PMID- 25808339 TI - Periodic traction in migrating large amoeba of Physarum polycephalum. AB - The slime mould Physarum polycephalum is a giant multinucleated cell exhibiting well-known Ca(2+)-dependent actomyosin contractions of its vein network driving the so-called cytoplasmic shuttle streaming. Its actomyosin network forms both a filamentous cortical layer and large fibrils. In order to understand the role of each structure in the locomotory activity, we performed birefringence observations and traction force microscopy on excised fragments of Physarum. After several hours, these microplasmodia adopt three main morphologies: flat motile amoeba, chain types with round contractile heads connected by tubes and motile hybrid types. Each type exhibits oscillations with a period of about 1.5 min of cell area, traction forces and fibril activity (retardance) when fibrils are present. The amoeboid types show only peripheral forces while the chain types present a never-reported force pattern with contractile rings far from the cell boundary under the spherical heads. Forces are mostly transmitted where the actomyosin cortical layer anchors to the substratum, but fibrils maintain highly invaginated structures and contribute to forces by increasing the length of the anchorage line. Microplasmodia are motile only when there is an asymmetry in the shape and/or the force distribution. PMID- 25808340 TI - An anthropologically based model of the impact of asymptomatic cases on the spread of Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae (GC) remains a serious burden in many high-sexual-activity, undertreated populations. Using empirical data from a 2009 study of GC burden among pastoralists in Kaokoveld, Namibia, we expand the standard gonorrhoea transmission model by using locally derived sexual contact data to explore transmission dynamics in a population with high rates of partner exchange and low treatment-seeking behaviour. We use the model to generate ball-park estimates for transmission probabilities and other parameter values for low-level (i.e. less than approx. 1200 copies/20 ul PCR reaction) asymptomatic infections, which account for 74% of all GC infections found in Kaokoveld in 2009, and to describe the impact of asymptomatic, low-level infections on overall prevalence patterns. Our results suggest that GC transmission probabilities are higher than previously estimated, that untreated infections take longer to clear than previously estimated and that a high prevalence of low-level infections is partially due to larger numbers of untreated, asymptomatic infections. These results provide new insights into the natural history of GC and the challenge of syndromic management programmes for the eradication of endemic gonorrhoea. PMID- 25808342 TI - Multicomponent model of deformation and detachment of a biofilm under fluid flow. AB - A novel biofilm model is described which systemically couples bacteria, extracellular polymeric substances (EPS) and solvent phases in biofilm. This enables the study of contributions of rheology of individual phases to deformation of biofilm in response to fluid flow as well as interactions between different phases. The model, which is based on first and second laws of thermodynamics, is derived using an energetic variational approach and phase field method. Phase-field coupling is used to model structural changes of a biofilm. A newly developed unconditionally energy-stable numerical splitting scheme is implemented for computing the numerical solution of the model efficiently. Model simulations predict biofilm cohesive failure for the flow velocity between [Formula: see text] and [Formula: see text] m s(-1) which is consistent with experiments. Simulations predict biofilm deformation resulting in the formation of streamers for EPS exhibiting a viscous-dominated mechanical response and the viscosity of EPS being less than [Formula: see text]. Higher EPS viscosity provides biofilm with greater resistance to deformation and to removal by the flow. Moreover, simulations show that higher EPS elasticity yields the formation of streamers with complex geometries that are more prone to detachment. These model predictions are shown to be in qualitative agreement with experimental observations. PMID- 25808344 TI - kappa-Opioid receptors are involved in enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning. AB - BACKGROUND: The combination of various interventions to obtain enhanced cardioprotection is always an important area of research focus. This randomized experiment was designed to assess whether combined fentanyl and limb remote ischemic postconditioning produced enhanced protection against myocardial ischemia/reperfusion injury in an in vivo rat model, and to determine if kappa opioid receptors were implicated in the cardioprotection of these interventions. METHODS: Seventy-two rats were exposed to a 30-min myocardial ischemia followed by a 180-min reperfusion. Half of the rats (36) were randomized into four different groups receiving control treatment, fentanyl postconditioning, limb remote ischemic postconditioning, and combined fentanyl and limb remote ischemic postconditioning. The remaining 36 rats were also randomized into four groups receiving the same interventions as the above groups following the intravenous administration of a kappa-opioid receptor antagonist, nor-binaltorphimine, before myocardial ischemia. At the end of reperfusion, both serum cardiac troponin I and infarct size were determined. RESULTS: Both fentanyl postconditioning and limb remote ischemic postconditioning significantly decreased the infarct size and serum cardiac troponin I level, and combined fentanyl and limb remote ischemic postconditioning produced enhanced cardioprotection on the infarct size-sparing effect. The use of nor-binaltorphimin to block kappa-opioid receptors eliminated cardioprotection by fentanyl postconditioning and enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning, but did not change cardioprotection by limb remote ischemic postconditioning. CONCLUSIONS: Combined fentanyl and limb remote ischemic postconditioning produced enhanced protection against myocardial ischemia/reperfusion injury. kappa-Opioid receptors are essential for cardioprotection by fentanyl postconditioning and enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning; however, they do not play a pivotal role in cardioprotection by limb remote ischemic postconditioning. PMID- 25808345 TI - The effective bolus dose of remifentanil to facilitate laryngeal mask airway insertion during inhalation induction of sevoflurane in children. AB - PURPOSE: The additional administration of remifentanil during inhalation induction with sevoflurane could provide better conditions for laryngeal mask airway (LMA) insertion than sevoflurane alone. This study was designed to evaluate the 50 % effective bolus dose (ED50) and 95 % effective bolus dose (ED95) of remifentanil required for LMA insertion in children during inhalation induction with sevoflurane. METHODS: Pediatric patients aged 3-12 years requiring general anesthesia were recruited. A predetermined dose of remifentanil was injected over 30 s after the induction of general anesthesia with sevoflurane. LMA insertion was attempted 60 s after remifentanil injection. The dose of remifentanil was determined using the Dixon's up-and-down method, starting from 0.5 MUg/kg (step size of 0.05 MUg/kg). RESULTS: The study was conducted until seven cross-over points and 29 children were collected. The ED50 of remifentanil for successful LMA insertion during sevoflurane inhalation induction in children was 0.168 +/- 0.035 MUg/kg using Dixon's method. In addition, the ED50 and ED95 of remifentanil from the probit analysis were 0.176 MUg/kg (95 % confidence limits, 0.102-0.216 MUg/kg) and 0.268 MUg/kg (95 % confidence limits, 0.223-0.659 MUg/kg), respectively. CONCLUSION: The ED50 and ED95 of remifentanil for successful LMA insertion in children were estimated to be 0.176 (0.168) and 0.268 MUg/kg during inhalation induction with 2.1 % sevoflurane. PMID- 25808346 TI - Effect of mycophenolic acid on proliferation of dermal papilla cells and induction of anagen hair follicles. AB - BACKGROUND: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, has anti-inflammatory effects, and is widely used as an immunomodulatory agent. However, the beneficial effect of MPA in hair-loss disorders is not fully understood. AIM: To investigate the direct effect of MPA on dermal papilla cells (DPCs), and to examine the hair growth-stimulating effects of MPA topically applied to mouse skin. METHODS: Cultured DPCs were treated with various concentrations of MPA and analysed by MTT assay. Expressions of hair growth related genes, including Wnt/beta-catenin pathway-related genes and cellular apoptosis-regulating genes, such as Bcl-2, Bax and caspase-9, were examined using reverse transcription (RT)-PCR and western blotting. The Wnt/extracellular signal regulated kinase (ERK) pathway was analysed by western blotting. The effect of topically applied MPA on anagen hair follicle induction after microneedle (MN) treatment with or without minoxidil (MXD) was evaluated by histopathological examination and RT-PCR. RESULTS: MPA showed a promoting effect on DPC proliferation, which was associated with increased Axin2 transcription levels. In addition, phospho-ERK protein was detected in the MPA-treated DPCs. An increased Bcl-2/Bax transcript ratio contributed to cellular proliferation, and this was maintained in the MPA-treated environment. Topically applied MPA promoted anagen hair follicle induction in mice. The effect of MPA on hair follicles was compatible with that of MXD, and this effect was accelerated by MN treatment. CONCLUSIONS: MPA promotes proliferation of DPCs and induction of anagen hair follicles in mice. This finding raises the possibility that MPA could be used as a treatment option for hair-loss disorders. PMID- 25808347 TI - Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients >=60 years old. AB - Older patients with acute myeloid leukemia (AML) have poor outcomes with standard induction chemotherapy. We retrospectively reviewed our institute's experience with epigenetic (Epi) versus cytarabine- and anthracycline-based intensive chemotherapy (IC) as induction in newly diagnosed AML patients aged 60 years and older. One hundred sixty-seven patients (n = 84, IC; n = 83, Epi) were assessed; 69 patients received decitabine and 14 azacitidine. Baseline characteristics between the IC and Epi patient cohorts were not statistically different except for age, initial white blood cell count, and comorbidity index. Overall response rate (ORR, 50% vs. 28%, respectively, P < 0.01) and complete response rate (CRR, 43% vs. 20%, respectively, P < 0.01) were superior following IC vs. Epi. Although univariate analysis demonstrated longer overall survival after IC (10.7 vs. 9.1 months, P = 0.012), multivariate analysis showed no independent impact of induction treatment. Treatment-related mortality was not statistically different in the two groups. Outcomes of patients with secondary, poor cytogenetic risk, FLT-3 mutated AML, or relapsed/refractory disease after IC or Epi were not significantly different. Outcomes of patients receiving IC versus a 10-day decitabine regimen (n = 63) also were not significantly different. Our results suggest that IC and Epi therapy are clinically equivalent approaches for upfront treatment of older patients with AML and that other factors (feasibility, toxicity, cost, etc.) should drive treatment decisions. Prospective randomized trials to determine the optimal induction approach for specific patient subsets are needed. PMID- 25808343 TI - Hierarchical analysis and multi-scale modelling of rat cortical and trabecular bone. AB - The aim of this study was to explore the hierarchical arrangement of structural properties in cortical and trabecular bone and to determine a mathematical model that accurately predicts the tissue's mechanical properties as a function of these indices. By using a variety of analytical techniques, we were able to characterize the structural and compositional properties of cortical and trabecular bones, as well as to determine the suitable mathematical model to predict the tissue's mechanical properties using a continuum micromechanics approach. Our hierarchical analysis demonstrated that the differences between cortical and trabecular bone reside mainly at the micro- and ultrastructural levels. By gaining a better appreciation of the similarities and differences between the two bone types, we would be able to provide a better assessment and understanding of their individual roles, as well as their contribution to bone health overall. PMID- 25808341 TI - Mammalian synthetic biology: emerging medical applications. AB - In this review, we discuss new emerging medical applications of the rapidly evolving field of mammalian synthetic biology. We start with simple mammalian synthetic biological components and move towards more complex and therapy oriented gene circuits. A comprehensive list of ON-OFF switches, categorized into transcriptional, post-transcriptional, translational and post-translational, is presented in the first sections. Subsequently, Boolean logic gates, synthetic mammalian oscillators and toggle switches will be described. Several synthetic gene networks are further reviewed in the medical applications section, including cancer therapy gene circuits, immuno-regulatory networks, among others. The final sections focus on the applicability of synthetic gene networks to drug discovery, drug delivery, receptor-activating gene circuits and mammalian biomanufacturing processes. PMID- 25808350 TI - Management of acute sigmoid volvulus: short- and long-term results. AB - AIM: The best form of prophylactic management of a decompressed sigmoid volvulus (SV) is controversial especially in the elderly. We have studied our experience with this condition to assess the short- and long-term results of SV management. METHOD: All patients treated for SV in our department between 2003 and 2013 were retrospectively included. Emergency decompression was attempted in all patients in whom there was no sign of peritonitis. Planned surgical resection was the procedure of choice in young patients. Percutaneous endoscopic colopexy (PEC) was used in high surgical risk patients. RESULTS: There were 65 patients (45 males) of median age 71.5 (24-99) years. Non-surgical reduction was performed in 62 with a success rate of 95% (59/62). Recurrence after initial decompression was 67% at a median follow-up of 5 (1-14) years. A prophylactic surgical resection was performed with primary anastomosis in 33 patients. There were no deaths and the major morbidity rate was 6%. At a mean follow-up of 62 months, only 1 (3%) patient had had a recurrence (at 130 months). PEC was performed in six patients of median age 90 (84-99) years and with a median American Society of Anesthesiologists score of 4. Complications included local site infection (n = 2), pain (n = 1) and abdominal wall bleeding (n = 1). After a median follow-up of 2 (1-4) years, three patients died from medical causes and one recurrence occurred 13 months after removal of the PEC tube. CONCLUSION: Prophylactic treatment after initial decompression of SV results in a low rate of recurrence. Planned sigmoid resection is safe and effective. In frail elderly patients, PEC is satisfactory. PMID- 25808349 TI - Venous tumor thrombus consistency is not predictive of survival in patients with renal cell carcinoma: A retrospective study of 147 patients. AB - OBJECTIVES: To evaluate the prognostic role of venous tumor thrombus consistency in patients with renal cell carcinoma. METHODS: A retrospective evaluation of the data of patients with renal cell carcinoma and a tumor thrombosis submitted to surgery from 2000 to 2013 was carried out. Histological slides were revised by two uropathologists, blinded of the clinical outcome, to assess venous tumor thrombus consistency classified as solid venous tumor thrombus consistency or friable venous tumor thrombus consistency. The statistical correlation between venous tumor thrombus consistency and other adverse features was assessed. Then the predictive ability of an integrated prognostic model, generated by Cox regression and random survival forest, was evaluated, with and without the inclusion of venous tumor thrombus consistency, by integrated Brier score, dynamic receiver operating characteristic curves, integrated discrimination improvement index and category-less net reclassification index. RESULTS: The data of 147 patients were analyzed, 79 with a solid venous tumor thrombus consistency and 68 with a friable venous tumor thrombus consistency, followed for a median period of 40.5 months. Venous tumor thrombus consistency was assessed with a high interobserver agreement (145/147 cases). The presence of a friable venous tumor thrombus consistency was associated with some adverse prognostic factors (symptoms, lymphnodal and distant metastasis, larger tumor diameter, higher cephalad thrombosis level, necrosis, microvascular invasion) and to a worse cancer-specific and overall survival at univariate analysis. However, venous tumor thrombus consistency was not predictive of survival, and did not improve the performance of a multivariable model that included a set of informative predictors. CONCLUSION: Venous tumor thrombus consistency does not seem to have an independent prognostic role in patients with renal cell carcinoma. PMID- 25808352 TI - Redisplacement after reduction with intramedullary nails in surgery of intertrochanteric fracture: cause analysis and preventive measures. AB - OBJECTIVE: During the implantation of intramedullary nail in surgery of intertrochanteric fracture, the fact that the originally satisfactory reduction may incur redisplacement remains a major concern. In this article, we will analyze the reasons of redisplacement and describe some methods that can improve the quality of reduction. METHODS: From January 2012 to October 2014, 67 patients with intertrochanteric fracture were treated using Gamma3 or PFNA system. All the surgical procedures were monitored by fluoroscopy on the AP and lateral views, and the X-ray films were used to evaluate all cases. RESULTS: Redisplacement occurred in ten cases intraoperatively. According to the fracture type, re occurring deformities appeared in 31-A2 and 31-A3 commonly, 6 and 3 cases. We found the redisplacement emerged usually in operative procedure and some manipulations should be taken to obtain an anatomic reduction. CONCLUSIONS: When reduction is achieved in the surgery of intertrochanteric fracture, surgeons tend to overlook the occurrence of redisplacement, or not to treat it that has emerged timely. Internal fixation in nonanatomic reduction may increase the likelihood of fixation failure postoperatively. For the importance of accurate reduction of the fracture, once redisplacement occurs during the surgery, some methods or tricks are applicable to it to restore the anatomic reduction. PMID- 25808351 TI - Red blood cell storage affects the stability of cytosolic native protein complexes. AB - BACKGROUND: Refrigerated storage of red blood cell (RBC) units promotes the progressive accumulation of the so-called storage lesions, a widespread series of alterations to morphology, metabolism, and proteome integrity of stored RBCs. However, while storage lesions targeting the RBC membrane fraction have been widely documented, the cytosolic fraction is as yet an underinvestigated cause of the technical inconveniences related to the high abundance of hemoglobin. STUDY DESIGN AND METHODS: By exploiting a recently ideated preparative two-dimensional clear native electrophoresis, followed by mass spectrometry analysis, we could monitor the changes of soluble multiprotein complexes (MPCs) in RBCs after 0, 21, and 35 days of storage under standard blood banking conditions. RESULTS: Data indicate a substantial storage-dependent alteration of RBC MPCs, particularly of those involved in energy and redox metabolism, confirming previous evidence about the progressive dysregulation of these pathways in long-stored units. CONCLUSION: The use of native gel-based proteomics to investigate MPCs present in the RBC cytosolic fraction proved to be a powerful tool. Results collected represent a preliminary advance in the knowledge of the key role of native cytosolic MPCs in context of RBC storage lesion. Multiprotein organization and interacting partners of some key enzymes have been found to change during storage duration, suggesting that future studies will be needed to assess whether such alterations could influence their activity and efficiency. PMID- 25808353 TI - Paediatric anogenital Crohn's disease 11 years after Lichen planus - same background for two different entities? PMID- 25808354 TI - New sulfonate composite functionalized with multiwalled carbon nanotubes with cryogel solid-phase extraction sorbent for the determination of beta-agonists in animal feeds. AB - A new mixed-mode cation-exchange sulfonate composite functionalized with multiwalled carbon nanotubes with polyvinyl alcohol cryogel was fabricated and used for the first time as a solid-phase extraction sorbent for the determination of beta-agonists in animal feeds. Feed samples were extracted with 0.20 M phosphoric acid and methanol (1:4, v/v) using ultrasonication, cleaned-up using the developed sorbent to which the beta-agonists bound then finally eluted with 5.0% ammonia in methanol and analyzed by high-performance liquid chromatography. Various parameters that affected the extraction efficiency were optimized. Under the optimal conditions, the developed sorbent strongly interacted with beta agonists by cationic exchange and hydrophobic and hydrophilic interactions, that provided a high extraction efficiency in the range of 92.8 +/- 3.7-104.4 +/- 2.3% over a range of 0.04-2.0 mg/kg for salbutamol and ractopamine, and 0.40-8.0 mg/kg for clenbuterol. The relative standard deviations were less than 6.0%. The developed method was successfully applied for the determination of beta-agonists in various types of animal feed and effectively reduced any matrix interference. PMID- 25808355 TI - Novel alleles of the transforming growth factor beta-1 regulatory region and exon 1. AB - Transforming growth factor beta-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiologic and pathogenic processes with pleiotropic effects. Regulatory activity for this gene has been shown for 3.0 kb between positions -2665 and +423 from its translational start site. At least 17 TGFB1 regulatory region and exon 1 alleles have been defined on the basis of 18 polymorphic sites. Polymorphisms in TGFB1's regulatory region have been associated with differential levels of expression of this cytokine and to genetic risk in cancer and transplantation. In this report, we present 19 novel TGFB1 regulatory region and exon 1 alleles: p018-p036. Amplification of TGFB1's regulatory region was performed with an in-house protocol, and novel alleles were defined by either allele-specific amplification and/or molecular cloning of the amplicons, followed by sequencing in isolation. Three of these novel alleles (p018, p019, and p020) are shown to be formed by novel combinations of the aforementioned known polymorphic positions. Another 16 novel alleles are shown to carry additional known and unknown single-nucleotide polymorphisms. Polymorphism in TGFB1's regulatory region could have an impact on important processes, including embryogenesis, hematopoiesis, carcinogenesis, angiogenesis, fibrosis, immune responses, and transplantation, making its characterization necessary. PMID- 25808357 TI - Preserved somatosensory conduction in a patient with complete cervical spinal cord injury. AB - OBJECTIVE: Neurophysiological investigation has shown that patients with clinically complete spinal cord injury can have residual motor sparing ("motor discomplete"). In the current study somatosensory conduction was assessed in a patient with clinically complete spinal cord injury and a novel methodology for assessing such preservation is described, in this case indicating "sensory discomplete" spinal cord injury. METHODS: Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to examine the somatosensory system in a healthy subject and in a subject with a clinically complete cervical spinal cord injury, by applying tactile stimulation above and below the level of spinal cord injury, with and without visual feedback. RESULTS: In the participant with spinal cord injury, somatosensory stimulation below the neurological level of the lesion gave rise to BOLD signal changes in the corresponding areas of the somatosensory cortex. Visual feedback of the stimulation strongly modulated the somatosensory BOLD signal, implying that cortico-cortical rather than spino-cortical connections can drive activity in the somatosensory cortex. Critically, BOLD signal change was also evident when the visual feedback of the stimulation was removed, thus demonstrating sensory discomplete spinal cord injury. CONCLUSION: Given the existence of sensory discomplete spinal cord injury, preserved but hitherto undetected somatosensory conduction might contribute to the unexplained variability related to, for example, the propensity to develop decubitus ulcers and neuropathic pain among patients with clinically complete spinal cord injury. PMID- 25808356 TI - A Paracrine Mechanism Accelerating Expansion of Human Induced Pluripotent Stem Cell-Derived Hepatic Progenitor-Like Cells. AB - Hepatic stem/progenitor cells in liver development have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In this study, we focused on the cell surface molecules of human induced pluripotent stem (iPS) cell-derived hepatic progenitor-like cells (HPCs) and analyzed how these molecules modulate expansion of these cells. Human iPS cells were differentiated into immature hepatic lineage cells by cytokines. In addition to hepatic progenitor markers (CD13 and CD133), the cells were coimmunostained for various cell surface markers (116 types). The cells were analyzed by flow cytometry and in vitro colony formation culture with feeder cells. Twenty types of cell surface molecules were highly expressed in CD13(+)CD133(+) cells derived from human iPS cells. Of these molecules, CD221 (insulin-like growth factor receptor), which was expressed in CD13(+)CD133(+) cells, was quickly downregulated after in vitro expansion. The proliferative ability was suppressed by a neutralizing antibody and specific inhibitor of CD221. Overexpression of CD221 increased colony-forming ability. We also found that inhibition of CD340 (erbB2) and CD266 (fibroblast growth factor-inducible 14) signals suppressed proliferation. In addition, both insulin-like growth factor (a ligand of CD221) and tumor necrosis factor-like weak inducer of apoptosis (a ligand of CD266) were provided by feeder cells in our culture system. This study revealed the expression profiles of cell surface molecules in human iPS cell-derived HPCs and that the paracrine interactions between HPCs and other cells through specific receptors are important for proliferation. PMID- 25808358 TI - Fatigue is a major issue for children and adolescents with physical disabilities. AB - AIM: This study aimed to investigate fatigue, and its correlates, in children and adolescents with physical disabilities. METHOD: Sixty-five young people aged 8 to 17 years (35 males, 30 females; mean age 13y 2mo, SD 2y 8mo) with mild to moderate physical disabilities (Gillette Functional Assessment Questionnaire levels 7-10) were recruited. Self-reported fatigue was measured using the PedsQL Multidimensional Fatigue Scale. Physical activity was measured using 7-day hip worn accelerometer. Associations between fatigue, physical activity, and socio demographic characteristics were examined using analysis of covariance, with significance (alpha) set at 0.05. Results were compared with normative data from other paediatric populations. RESULTS: Among children with physical disabilities, fatigue was associated with being physically inactive (F-statistic=4.42, p=0.040), female (F=4.37, p=0.042), and of low socio-economic status (F=3.94, p=0.050). Fatigue was not associated with age, weight status, or functional impairment. Young people with physical disabilities experienced high levels of fatigue compared with other paediatric health populations, and comparable to the paediatric cancer population. INTERPRETATION: Fatigue is an important issue for young people with physical disabilities. Clinicians and researchers working with this group should be mindful that fatigue is likely to impact on an individual's ability to undertake new treatment regimens or interventions. Interventions aimed at reducing fatigue are warranted. Increasing physical activity might play a role in reducing fatigue. PMID- 25808359 TI - Ambivalence in Narrative Therapy: A Comparison Between Recovered and Unchanged Cases. AB - Research on the identification of poor outcome predictors is crucial for the prevention of therapeutic failure. Previous research suggests that clients' persistent ambivalence is one possible path to unsuccessful psychotherapy. The present study analyses ambivalence--here operationalized as return-to-the-problem markers (RPMs)--in five recovered and five unchanged cases of narrative psychotherapy for major depression. The results suggest that both recovered and unchanged cases presented a similar proportion of RPMs at baseline and a decreasing pattern of these ambivalence markers throughout therapy. However, the decreasing was more accentuated in recovered than in unchanged cases, and at the end of the treatment, the proportion of RPMs of the unchanged cases was significantly higher. The results are discussed in light of previous research on ambivalence in psychotherapy, focusing on the meaning of ambivalence and its clinical implications. KEY PRACTITIONER MESSAGE: Ambivalence towards change, here operationalized as RPMs, seems to be a common process in both recovered and unchanged cases, perhaps signalling the uncertainty and anxiety that change may elicit. Although the number of RPMs decreased in both the recovered and unchanged cases, this reduction was significantly higher in the recovered group. Moreover, at the end of therapy, the recovered group revealed a significantly lower proportion of RPMs than the unchanged group, suggesting that ambivalence resolution (or lack thereof) may play a determining role in the therapy's evolution and outcome. RPMs in later stages of therapy may be operationalized as 'red flags' for the therapist to acknowledge the client's stuckness and adapt his or her intervention efforts, turning these instances into developmental opportunities. PMID- 25808360 TI - The health consequences of injecting tablet preparations: foreign body pulmonary embolization and pulmonary hypertension among deceased injecting drug users. AB - AIMS: To determine: (1) the characteristics of cases presenting to the Department of Forensic Medicine Sydney (1997-2013) with foreign body pulmonary embolization; (2) the extent and locations of embolization; and (3) the relationship between extent, and use of other injection sites, with pathology. DESIGN: Analysis of consecutive case presentations with foreign body pulmonary embolization. SETTING/PARTICIPANTS: Sydney, Australia, with a total of 373 cases (271 males, 102 females). MEASUREMENTS: Full autopsy reports, microscopy of tissue samples, and full toxicology. The extent and locations of embolization, inflammatory responses, clinical signs of pulmonary hypertension and signs of right-sided heart failure were examined. FINDINGS: Cases increased from three (1997) to 58 (2013). In 43.4%, foreign particles were moderate-abundant in extent. Cases with moderate-abundant emboli were more likely to have injection sites other than the cubital fossa [odds ratio (OR) = 2.4]. In 6.9% of cases emboli were also found in other organs. A foreign body inflammatory response was present in 45.3%, vascular scarring in 8.0%, signs of pulmonary hypertension in 10.2% and signs of right sided heart pathology in 5.4%. Cases with moderate-abundant deposition were more likely to have emboli in other organs (OR = 7.9), a foreign body inflammatory response (OR = 5.3), vascular scarring (OR = 3.4), signs of pulmonary hypertension (OR = 5.4) and right-sided heart pathology (OR = 5.3). CONCLUSIONS: Cases of foreign body pulmonary embolization (resulting from injecting crushed tablets meant for oral use, such as benzodiazepines and pharmaceutical opioids) in Sydney, Australia increased markedly from 1997 to 2013. In a large proportion there were clinical consequences. More extensive embolization was associated with higher levels of pulmonary hypertension and right-sided heart pathology. PMID- 25808361 TI - Modulation of cluster incorporation specificity in a de novo iron-sulfur cluster binding peptide. AB - iron-sulfur cluster binding proteins perform an astounding variety of functions, and represent one of the most abundant classes of metalloproteins. Most often, they constitute pairs or chains and act as electron transfer modules either within complex redox enzymes or within small diffusible proteins. We have previously described the design of a three-helix bundle that can bind two clusters within its hydrophobic core. Here, we use single-point mutations to exchange one of the Cys ligands coordinating the cluster to either Leu or Ser. We show that the mutants modulate the redox potential of the clusters and stabilize the [3Fe-4S] form over the [4Fe-4S] form, supporting the use of model iron-sulfur cluster proteins as modules in the design of complex redox enzymes. PMID- 25808363 TI - UHPLC-MS/MS quantification of buprenorphine, norbuprenorphine, methadone, and glucuronide conjugates in umbilical cord plasma. AB - Opioid use during pregnancy can result in the newborn being physically dependent on the substance, thus experiencing drug withdrawal, termed neonatal abstinence syndrome (NAS). Buprenorphine and methadone are two drugs used to treat opioid withdrawal and are approved for use in pregnancy. Quantification of these compounds in umbilical cord plasma would help assess in utero exposure of neonates in cases of buprenorphine or methadone use during pregnancy. An LC-MS/MS method using solid-phase extraction sample preparation was developed and validated for the simultaneous quantification of methadone, buprenorphine, norbuprenorphine, and glucuronide metabolites in umbilical cord plasma. The average accuracy (percentage error) and precision (relative standard deviation) were <15% for each validated concentration. Our data establishes a 2 week maximum freezer storage window in order to achieve the most accurate cord plasma concentrations of these analytes. Additionally, we found that the umbilical cord tissue analysis was less sensitive compared with analysis with umbilical cord blood plasma, indicating that this may be a more appropriate matrix for determination of buprenorphine and metabolite concentrations. This method was successfully applied to the analysis of cord blood from women with known buprenorphine or methadone use during pregnancy. PMID- 25808366 TI - Benefits and Challenges of a Nurse-Midwife Fellowship: A Review of the Ruth B. Stifel Fellowship Program at The Midwife Center for Birth and Women's Health. AB - New graduate nurse-midwives are looking for a bridge between their education and clinical practice, whereas birth centers often have a difficult time recruiting midwives to hire. At the same time, women are seeking birth center and midwifery care in growing numbers. A well-designed fellowship program helps address all of these needs in a supported, safe way. This article describes one birth center's fellowship program and the benefits and challenges of the program. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 25808365 TI - rs1801133C>T polymorphism in MTHFR is a risk factor for nonsyndromic cleft lip with or without cleft palate in the Brazilian population. AB - BACKGROUND: The MTHFR rs1801131A>C and rs1801133C>T variants have been analyzed as putative genetic risk factors for oral clefts within various populations worldwide. METHODS: To test the role of these polymorphisms in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in the Brazilian population, we conducted a study combining a Family-Based Association Test (transmission disequilibrium test) and a structured association analysis (case-control study) based on the individual ancestry proportions. The rs1801131 and rs1801133 were initially analyzed in 197 case-parent trios by transmission disequilibrium test, and polymorphisms showing significant association with NSCL/P were subsequently studied in independent sample composed of 318 isolated samples of NSCL/P and 598 healthy controls in a case-control approach. Genomic ancestry was characterized by a set of 40 biallelic short insertion/deletion markers. RESULTS: A strong overtransmission of the T allele of rs1801133 was observed in case-parent trios of NSCL/P (p = 0.002), but no preferential parent-of-origin transmission was detected. No association of rs1801131 polymorphism with NSCL/P was observed. The structured case-control analysis supported that the T allele was significantly more frequent in the NSCL/P group (odds ratio: 1.37; 95% CI: 1.12-1.69; p = 0.002) than in the control group. Both polymorphisms were in linkage disequilibrium (D' = 0.94 and r(2) = 0.79), and haplotype-transmission disequilibrium test for allelic combination of rs1801131 and rs1801133 showed a significant overtransmission of haplotype A-T to the affected NSCL/P offspring (p = 0.001). CONCLUSION: Our findings provide evidences for the involvement of rs1801133 in the development of NSCL/P in the Brazilian population. PMID- 25808364 TI - Exercise capacity in children and adolescents with corrected congenital heart disease. AB - Congenital heart disease promotes hemodynamic changes that can contribute to reduce exercise capacity. The aim of the study was to evaluate the exercise capacity of children and adolescents with cyanotic congenital heart disease and to assess respiratory muscle strength, plasma levels of B-type natriuretic peptide and ventricular ejection fraction, as well the associations between these variables. Cross-sectional study that evaluated 48 patients between 6 and 18 years-old that underwent a six-minute walk test (6MWT), respiratory muscle strength, dosage of B-type natriuretic peptide and echocardiography. The mean age was 13.3 +/- 4.1 years, and the most prevalent heart disease was tetralogy of Fallot (54.2 %). The average distance walked was 452.7 +/- 73.2 m, significantly below the predicted (69 %) (p < 0.001). The maximum inspiratory pressure was above the predicted result (111.4 %), average 58.2 +/- 22.3 (p = 0.56), and the maximum expiratory pressure was 63.2 +/- 23.3 cm H2O, significantly below the predicted (63 %) (p < 0.001). The level of B-type natriuretic peptide was elevated in all patients, with a median of 2087.17 (502.54-4,768.05). The ventricular ejection fraction showed a median of 65.9 (41-100). There was no correlation between the 6MWT, ventricular ejection fraction (r = -0.05; p = 0.72), inspiratory muscle strength (r = 0.03; p = 0.81), expiratory muscle strength (r = 0.09; p = 0.05) and B-type natriuretic peptide (r = -0.04; p = 0.77). Children and adolescents with cyanotic congenital heart disease present a lower exercise capacity and expiratory muscle strength. No associations were found between exercise capacity, respiratory muscle strength, B-type natriuretic peptide and left ventricular ejection fraction. PMID- 25808368 TI - Differences between abusive head trauma and physical abuse in Japan. AB - BACKGROUND: We examined differences in characteristics between abusive head trauma (AHT) and physical abuse (PA). METHODS: We examined 45 AHT patients and 119 PA patients during the period 1 April 2000-31 March 2014, at Kanagawa Children's Medical Center (Kanagawa, Japan). We compared patient age, young maternal or parental age, being the first child, child factors (chronic illness, developmental disabilities and preterm birth), parental factors (substance abuse/alcohol abuse and depression or other mental illness), environmental factors (single-parent home, non-biologically related man living in the home and family or intimate partner violence). Logistic regression was used to examine predictors of differences between AHT and PA for children <1 year of age. RESULTS: There were differences in characteristics between AHT and PA in those <1 year old in child factors (OR, 3.47; 95%CI: 1.01-11.9) and environmental factors (OR, 14.2; 95%CI: 1.45-139). CONCLUSIONS: The risk factors for AHT differ from those of PA. We speculate that AHT is not merely physical abuse of young infants; the characteristics of AHT differ significantly from those of PA. These observations are important for understanding and thereby preventing child abuse. PMID- 25808367 TI - Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis. AB - The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint is associated with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats, and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes, and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose, and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with P = e(-13) to e(-36) . Cell cycle expression networks show species, sex and tissue variability, and they are enriched in mRNA transcripts associated with mitosis, many of which are associated with chromosomal instability. PMID- 25808369 TI - Perfusion computed tomography to assist decision making for stroke thrombolysis. AB - The use of perfusion imaging to guide selection of patients for stroke thrombolysis remains controversial because of lack of supportive phase three clinical trial evidence. We aimed to measure the outcomes for patients treated with intravenous recombinant tissue plasminogen activator (rtPA) at a comprehensive stroke care facility where perfusion computed tomography was routinely used for thrombolysis eligibility decision assistance. Our overall hypothesis was that patients with 'target' mismatch on perfusion computed tomography would have improved outcomes with rtPA. This was a prospective cohort study of consecutive ischaemic stroke patients who fulfilled standard clinical/non-contrast computed tomography eligibility criteria for treatment with intravenous rtPA, but for whom perfusion computed tomography was used to guide the final treatment decision. The 'real-time' perfusion computed tomography assessments were qualitative; a large perfusion computed tomography ischaemic core, or lack of significant perfusion lesion-core mismatch were considered relative exclusion criteria for thrombolysis. Specific volumetric perfusion computed tomography criteria were not used for the treatment decision. The primary analysis compared 3-month modified Rankin Scale in treated versus untreated patients after 'off-line' (post-treatment) quantitative volumetric perfusion computed tomography eligibility assessment based on presence or absence of 'target' perfusion lesion-core mismatch (mismatch ratio >1.8 and volume >15 ml, core <70 ml). In a second analysis, we compared outcomes of the perfusion computed tomography-selected rtPA-treated patients to an Australian historical cohort of non-contrast computed tomography-selected rtPA-treated patients. Of 635 patients with acute ischaemic stroke eligible for rtPA by standard criteria, thrombolysis was given to 366 patients, with 269 excluded based on visual real time perfusion computed tomography assessment. After off-line quantitative perfusion computed tomography classification: 253 treated patients and 83 untreated patients had 'target' mismatch, 56 treated and 31 untreated patients had a large ischaemic core, and 57 treated and 155 untreated patients had no target mismatch. In the primary analysis, only in the target mismatch subgroup did rtPA-treated patients have significantly better outcomes (odds ratio for 3 month, modified Rankin Scale 0-2 = 13.8, P < 0.001). With respect to the perfusion computed tomography selected rtPA-treated patients (n = 366) versus the clinical/non-contrast computed tomography selected rtPA-treated patients (n = 396), the perfusion computed tomography selected group had higher adjusted odds of excellent outcome (modified Rankin Scale 0-1 odds ratio 1.59, P = 0.009) and lower mortality (odds ratio 0.56, P = 0.021). Although based on observational data sets, our analyses provide support for the hypothesis that perfusion computed tomography improves the identification of patients likely to respond to thrombolysis, and also those in whom natural history may be difficult to modify with treatment. PMID- 25808370 TI - Disconnection of network hubs and cognitive impairment after traumatic brain injury. AB - Traumatic brain injury affects brain connectivity by producing traumatic axonal injury. This disrupts the function of large-scale networks that support cognition. The best way to describe this relationship is unclear, but one elegant approach is to view networks as graphs. Brain regions become nodes in the graph, and white matter tracts the connections. The overall effect of an injury can then be estimated by calculating graph metrics of network structure and function. Here we test which graph metrics best predict the presence of traumatic axonal injury, as well as which are most highly associated with cognitive impairment. A comprehensive range of graph metrics was calculated from structural connectivity measures for 52 patients with traumatic brain injury, 21 of whom had microbleed evidence of traumatic axonal injury, and 25 age-matched controls. White matter connections between 165 grey matter brain regions were defined using tractography, and structural connectivity matrices calculated from skeletonized diffusion tensor imaging data. This technique estimates injury at the centre of tract, but is insensitive to damage at tract edges. Graph metrics were calculated from the resulting connectivity matrices and machine-learning techniques used to select the metrics that best predicted the presence of traumatic brain injury. In addition, we used regularization and variable selection via the elastic net to predict patient behaviour on tests of information processing speed, executive function and associative memory. Support vector machines trained with graph metrics of white matter connectivity matrices from the microbleed group were able to identify patients with a history of traumatic brain injury with 93.4% accuracy, a result robust to different ways of sampling the data. Graph metrics were significantly associated with cognitive performance: information processing speed (R(2) = 0.64), executive function (R(2) = 0.56) and associative memory (R(2) = 0.25). These results were then replicated in a separate group of patients without microbleeds. The most influential graph metrics were betweenness centrality and eigenvector centrality, which provide measures of the extent to which a given brain region connects other regions in the network. Reductions in betweenness centrality and eigenvector centrality were particularly evident within hub regions including the cingulate cortex and caudate. Our results demonstrate that betweenness centrality and eigenvector centrality are reduced within network hubs, due to the impact of traumatic axonal injury on network connections. The dominance of betweenness centrality and eigenvector centrality suggests that cognitive impairment after traumatic brain injury results from the disconnection of network hubs by traumatic axonal injury. PMID- 25808371 TI - The effect of early visual deprivation on the neural bases of multisensory processing. AB - Developmental vision is deemed to be necessary for the maturation of multisensory cortical circuits. Thus far, this has only been investigated in animal studies, which have shown that congenital visual deprivation markedly reduces the capability of neurons to integrate cross-modal inputs. The present study investigated the effect of transient congenital visual deprivation on the neural mechanisms of multisensory processing in humans. We used functional magnetic resonance imaging to compare responses of visual and auditory cortical areas to visual, auditory and audio-visual stimulation in cataract-reversal patients and normally sighted controls. The results showed that cataract-reversal patients, unlike normally sighted controls, did not exhibit multisensory integration in auditory areas. Furthermore, cataract-reversal patients, but not normally sighted controls, exhibited lower visual cortical processing within visual cortex during audio-visual stimulation than during visual stimulation. These results indicate that congenital visual deprivation affects the capability of cortical areas to integrate cross-modal inputs in humans, possibly because visual processing is suppressed during cross-modal stimulation. Arguably, the lack of vision in the first months after birth may result in a reorganization of visual cortex, including the suppression of noisy visual input from the deprived retina in order to reduce interference during auditory processing. PMID- 25808374 TI - Preparation of red blood cell concentrates and plasma units from whole blood held overnight using a hollow-fibre separation system. AB - BACKGROUND: The ErySep system represents an alternative to centrifuge-based whole blood (WB) separation, using gravity and filtration through hollow-fibres (0.2 um pore size) to produce red blood cell (RBC) and plasma components. The aim of this study was to characterise the quality of ErySep RBC and plasma units compared with standard products from WB held overnight. METHODS/MATERIALS: Two ABO compatible WB units (n = 24) were pooled and split to produce matched products. One of the WB units was separated into components using the ErySep system (ErySep; n = 12), whereas the other units were separated by centrifugation (control; n = 12). RBC units were stored at 2-6 degrees C and assessed for in vitro quality over 42 days of storage. Plasma was frozen at -30 degrees C and tested upon thawing. RESULTS: Processing WB with the ErySep system took longer than controls. The ErySep RBC units were of an appropriate volume (307 +/- 17 mL) and contained sufficient Hb (50 +/- 2 g unit(-1) ). ErySep RBC components contained more microparticles relative to controls at expiry. The plasma volume, total protein, coagulation factor activity (fibrinogen, FV, FVIII) and number of microparticles was lower in the ErySep units compared with controls. CONCLUSION: Following overnight hold of WB, the ErySep system was capable of producing RBC components that met specifications. However, the ErySep plasma components did not meet quality specifications. PMID- 25808373 TI - Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. AB - A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option. PMID- 25808372 TI - PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia. AB - Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes alpha-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. PMID- 25808376 TI - The eighth international orthodontic congress. PMID- 25808375 TI - Immunoprofiling for prognostic assessment of colon cancer: a novel complement to ultrastaging. AB - BACKGROUND: Although AJCC/TNM staging remains the gold standard for prognostic assessment of colon cancer, stage-specific outcomes vary. We therefore prospectively evaluated the prognostic role of immunoprofiling. METHODS: Our cohort included 35 patients from an ongoing prospective trial of ultrastaging for colon cancer. Specimens were analyzed for T cell markers (CD3, CD4, CD8, and FoxP3). The number of tumor-infiltrating lymphocytes was analyzed at the tumor's margin and center and correlated with AJCC/TNM stage, clinicopathologic variables, and disease-free survival. RESULTS: There was a significant inverse association between number of CD3(+) cells in the tumor center and tumor stage (P = 0.05). The tumor center/margin ratio of CD3(+) cells also showed an inverse but non-significant relationship with nodal involvement (P = 0.07). Body mass index was inversely associated with numbers of CD3(+)(P = 0.04) and CD8(+)(P = 0.02) cells. Longer disease-free survival was correlated with higher CD8+ counts (P = 0.07), lower CD4(+)/CD8(+) ratios (P = 0.008), and higher CD8(+)/FoxP3(+) ratios (P = 0.02). CONCLUSIONS: This is the first prospective validation of immunoprofiling in patients whose colon cancer is staged with strict surgical and pathology quality measures. The apparent correlation between immunophenotypic response and clinical outcome warrants evaluation in a larger prospective trial. PMID- 25808378 TI - Crevicular alkaline phosphatase activity during the application of two patterns of orthodontic forces. AB - OBJECTIVE: The objective of this study was to test the hypothesis that using a gradually increasing orthodontic force would induce an increased activity of osteoblasts compared to a relatively constant orthodontic force. PARTICIPANTS AND METHODS: Twelve orthodontic patients participated in this study. In a split mouth design, one maxillary canine undergoing distal movement received a relatively constant continuous retraction force, while the contralateral canine received a gradually increasing retraction force. Gingival crevicular fluid (GCF) samples were collected from both experimental sites at weekly intervals and analysed spectrophotometrically for the activity of alkaline phosphatase enzyme, which was used as a biological marker for osteoblastic activity. RESULTS: With the exception of the maxillary first molar receiving gradually increasing orthodontic force, the results revealed a consistent pattern of alkaline phosphatase activity. This pattern included an initial rise from baseline to the first week, then a peak in the second week. This peak was followed by a reduction in enzyme activity in the third week. The overall increases in enzyme activity at the maxillary canines and the maxillary first molars in the relatively constant force group were 179.76% and 332.90%, respectively. The overall increases in enzyme activity at the maxillary canines and the maxillary first molars in the gradually increasing force group were 304.81% and 493.08%, respectively. CONCLUSION: The use of gradually increasing orthodontic force induces increased activity of osteoblasts during the initial stage of orthodontic tooth movement compared to that induced by a relatively constant orthodontic force. PMID- 25808380 TI - The effect of canine characteristics and symmetry on perceived smile attractiveness when canine teeth are substituted for lateral incisors. AB - OBJECTIVES: To determine the effect of canine tooth characteristics and symmetry on perceived smile attractiveness when maxillary canine teeth are substituted for missing lateral incisors. DESIGN: Prospective, cross-sectional study. SETTING: Non-clinical study undertaken from Leeds Dental Institute, UK. PARTICIPANTS AND METHODS: A composite full-face image of a smiling female was used to display various dentitions; a control image with an 'ideal' smile, plus six further images substituting the maxillary lateral incisors with canine teeth either unilaterally or bilaterally with varying size, shape, colour and gingival margin level. The seven images were shown to orthodontists (n = 30), dentists (n = 30) and lay people (n = 30) who were asked to rate smile attractiveness using a visual analogue scale. RESULTS: Dental professionals rated smiles with canine substitution for lateral incisor agenesis to be significantly less attractive than an ideal smile unless the substituted canine teeth approximated the lateral incisor in terms of size, shape, colour and gingival margin. Lay people did not find smiles where canine teeth were substituted for lateral incisors significantly more or less attractive than an ideal smile regardless of the canine tooth characteristics. Dental professionals were significantly more perceptive than lay people to the deviation from ideal smile aesthetics due to canine substitution. Smiles with unilateral canine substitution were not found to be significantly less attractive than bilateral canine substitution by all groups. CONCLUSIONS: Canine characteristics and observer status will affect how canine substitution for lateral incisor agenesis is viewed in terms of aesthetic outcome. PMID- 25808379 TI - Natural reference structures in the human maxilla: a systematic search in children with tantalum implants. AB - OBJECTIVE: The aim of the study was to locate stable natural reference structures (NRS) in the maxilla as seen on lateral cephalometric radiographs. DESIGN: Retrospective radiographic analysis. MATERIALS AND METHOD: Paired serial lateral cephalometric radiographs of 27 children (aged 7.1-13.5 years at the initial radiograph and a mean interval of 3.9 years between radiographs) with a minimum of three Bjork-type tantalum implant markers in the left maxilla were examined for the presence of NRS. The pairs of radiographs were converted to digital image format, superimposed and registered using stable implants. Potential NRS were located by visual examination of the superimposed images and tested for morphological and spatial stability using automated computer-based analysis employing cross-correlation. RESULTS: NRS were detected in 24 of the 27 subjects (median: 4; range: 1-9 NRS). The number of NRS was statistically significantly negatively correlated with the interval between the radiographs (rrank = -0.422; P = 0.03), but not significantly correlated with the age at the initial radiograph (rrank = 0.23; P = 0.26). Those NRS found above the nasal floor were both morphologically and spatially stable over periods of several years. The most conspicuous of these were the mid-portion of the anterior contour of the zygomatic process beyond 9 years of age and the junction of the corticated walls of the infra-orbital canal with the internal surface of the maxilla. CONCLUSIONS: This study has demonstrated the existence of several NRS visible on the lateral cephalometric image of the maxillae. The most prominent NRS should be sufficient in most cases to permit accurate orientation of serial cephalometric radiographs. PMID- 25808381 TI - Lower incisor extraction treatment with the Invisalign(r) technique: three case reports. AB - The extraction of a lower incisor can lead to satisfactory orthodontic results for patients with moderate to severe lower incisor crowding. Invisalign((r)) is a treatment modality for such treatments, moving teeth with precision and reducing inconvenience for the patient. Three case reports are presented in this article supporting the above statements. PMID- 25808382 TI - A modified occlusal wafer for managing partially dentate orthognathic patients--a case series. AB - A multidisciplinary approach is essential in orthognathic surgery to achieve stable and successful outcomes. The model surgery planning is an important aspect in achieving the desired aims. An occlusal wafer used at the time of surgery aids the surgeon during correct placement of the jaws. When dealing with partially dentate patients, the design of the occlusal wafer requires modification to appropriately position the jaw. Two cases with partially dentate jaws are presented in which the occlusal wafer has been modified to provide stability at the time of surgery. PMID- 25808383 TI - The William Houston gold medal of the Royal College of Surgeons of Edinburgh and British Orthodontic Society cases prize 2013. AB - This paper describes the orthodontic treatment of two cases presented by the winner of the William Houston gold medal at the Membership in Orthodontics examination at the Royal College of Surgeons of Edinburgh and which also won the British Orthodontic Society (BOS) cases prize in 2013. The first case describes the management of a 20-year-old female patient with a Class II division 2 malocclusion complicated by moderate upper and severe lower arch crowding, increased overjet and overbite, a crossbite and centreline discrepancies. Treatment involved a combination of a transpalatal arch, temporary anchorage devices and fixed appliances. The second case describes the management of a 15 year-old male patient with a Class I malocclusion complicated by crossbites affecting the right buccal segment and UR2, an associated mandibular displacement forward and to the right, mild upper arch crowding and a centreline discrepancy. Treatment involved a combination of a quad-helix, headgear and fixed appliances. PMID- 25808390 TI - Obsession with evidence-based studies. PMID- 25808384 TI - The simple class II and class III corrector: three case reports. AB - This article illustrates three case reports which describe a very simple appliance that is used to correct both class II and class III buccal segments. A class I molar relationship is achieved within 2-6 months. Hundreds of cases have been treated with these appliances over a number of years at Queen's Hospital, Burton upon Trent with great success. PMID- 25808391 TI - Investigating interoception and body awareness in adults with and without autism spectrum disorder. AB - This study aimed to investigate the current gap in the literature with regard to how adults with and without Autism Spectrum Disorder (ASD) interpret elements of the interoceptive sense, which includes thirst, hunger, temperature, satiety, and the prediction of onset of illness. Adults with a diagnosed ASD (n = 74; 36 males, 38 females) were compared to a control group (n = 228; 53 males, 174 females, 1 unspecified) in their self-reported perceptions of body awareness utilizing the Body Awareness Questionnaire (BAQ) and thirst awareness using the Thirst Awareness Scale (TAS). Those in the ASD group reported a clinically significant lower body and thirst awareness compared to the control group, and this was a large effect (BAQ; d = -1.26, P < 0.001; TAS; d = -1.02, P < 0.001). These findings are of clinical importance, as difficulty with sensing internal bodily states could theoretically impact on the physical and mental health, social interactions and self-awareness of adults with ASD. PMID- 25808392 TI - The Effect of a Quality Improvement Intervention on Variability of Measurements of Left Ventricular Dimensions in a Pediatric Echocardiography Laboratory. AB - OBJECTIVE: To assess the effect of a multifaceted quality improvement intervention on variability of left ventricular dimensions as measured on pediatric echocardiograms. METHODS: Variability of measurements of left ventricular dimensions was assessed using percent error before a multifaceted educational intervention. Sonographers attended group sessions, used visual prompts and received individual feedback regarding the proper technique for measuring the left ventricle. Variability was reassessed following the intervention. RESULTS: Sonographers were more likely to use proper measurement technique (38% vs. 62%, P = .017) after the educational intervention. The percent error of the left ventricular end systolic measurement decreased significantly (12.4% to 8.8%, P = .002). The percent error of the left ventricular end diastolic measurement showed a trend toward a decrease (7.7% to 5.8%, P = .067). There was no significant improvement in percent error for other measurements. Use of correct technique and sonographer experience of less than 5 years predicted decreased percent error. CONCLUSION: A multifaceted educational intervention can be used to improve measurement variability in pediatric echocardiography laboratories. PMID- 25808393 TI - Patient understanding of drug risks: an evaluation of medication guide assessments. AB - PURPOSE: When a Medication Guide (MG) is part of Risk Evaluation and Mitigation Strategy (REMS), manufacturers assess the effectiveness of MGs through patient surveys, which have not undergone systematic evaluation. We aimed to characterize knowledge rates from these patient surveys, describe their design and respondent characteristics, and explore predictors of acceptable knowledge rates. METHODS: We analyzed MG assessments submitted to the Food and Drug Administration from September 2008 through June 2012. We evaluated the prevalence of specific characteristics, and calculated knowledge rates, whereby we defined "acceptable knowledge" when >= 80% of respondents correctly answered questions about the primary drug risk. Univariate logistic models were used to investigate the predictors of acceptable knowledge rates. RESULTS: We analyzed the first completed MG assessment for each drug with a patient survey, resulting in 66 unique MG assessments. The mean knowledge rate was 63.8%, with 20 MG assessments (30.3%) achieving the 80% threshold. Compared to assessments that did not reach acceptable knowledge rates, those that did were more likely associated with additional REMS elements (e.g. Elements to Assure Safe Use or Communication Plans). Other factors, including mean age, reading or understanding the MG, and being offered or accepting counseling were not associated with knowledge rates. There was considerable variation in the design of MG assessments. CONCLUSIONS: Most MG assessments did not reach the 80% knowledge threshold, but those associated with additional interventions were more likely to achieve it. Our study highlights the need to improve patient-directed information and the methods of assessing it. PMID- 25808395 TI - Erratum to: Health Economic Evaluation of Paricalcitol((r)) Versus Cinacalcet + Calcitriol (Oral) in Italy. PMID- 25808394 TI - Effect of the gastrointestinal prokinetic agent erythromycin on the pharmacokinetics of pregabalin controlled-release in healthy individuals: a phase I, randomized crossover trial. AB - BACKGROUND AND OBJECTIVES: The controlled-release (CR) formulation of pregabalin is designed to remain in the stomach for a prolonged period while slowly releasing pregabalin for absorption in the small intestine. This study evaluated the effect of the gastrointestinal prokinetic agent, erythromycin, on the pharmacokinetics of a single dose of pregabalin CR 330 mg administered following an evening meal and the safety and tolerability of a single dose of pregabalin CR 330 mg when administered with and without multiple doses of erythromycin 500 mg. METHODS: This was a phase I, open-label, randomized, two-period, two-treatment crossover study. Participants received (in a randomized sequence) a single oral dose of pregabalin CR 330 mg alone and pregabalin CR 330 mg co-administered with multiple doses of erythromycin 500 mg. The CR formulation was administered immediately following a standardized 600-750 calorie 30 % fat evening meal. Erythromycin 500 mg was administered orally approximately 1 h prior to pregabalin CR, as well as 6 and 12 h following the first erythromycin dose. Blood samples were collected up to 48 h post-pregabalin CR dose. Pharmacokinetic parameters were estimated from concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout. RESULTS: Eighteen healthy participants (aged 19-52 years) received pregabalin CR. Co-administration of pregabalin CR with erythromycin resulted in a 17 % decrease in total exposure [area under the plasma concentration-time curve from zero to infinity (AUCinfinity)] and a 13 % decrease in peak plasma concentrations (C max) relative to pregabalin CR administered alone. The 90 % CI for the ratio of the adjusted geometric mean AUCinfinity was 76.5-89.2 % (outside the 80-125 % range prespecified for bioequivalence). Adverse events were of mild to moderate severity and the adverse event profile was similar for pregabalin CR administered with and without erythromycin. CONCLUSION: Co-administration of multiple high doses of erythromycin resulted in 17 % lower pregabalin exposure for a single dose of pregabalin CR 330 mg than for pregabalin CR 330 mg administered alone. Although the two treatments did not achieve formal bioequivalence, the impact of co-administered erythromycin treatment was small and not considered clinically relevant. PMID- 25808396 TI - The association between sleep disturbances and alcohol relapse: A 12-month observational cohort study. AB - BACKGROUND: Sleep disturbances are extremely common in alcohol recovery. Systematic research into the relationship between alcohol relapse and sleep disturbances using validated scales and accounting for potential confounders is lacking. METHODS: Patients admitted to a 1-month residential addiction treatment program were administered the Pittsburg Sleep Quality Index (PSQI) at admission/discharge. In addition, the Alcohol Use Disorders Identification Test (AUDIT), Patient Health Questionnaire-9 (PHQ-9), and Pennsylvania Alcohol Craving Scale (PACS) were administered. Patients were contacted every 3 months over 1 year following discharge. Associations of clinical factors with time until relapse were examined using univariate Cox proportional hazard models. RESULTS: One-hundred and nineteen patients with alcohol use disorders met inclusion criteria (mean age 50.6 +/- 13.2 years, 57% male), relapse data were available for 81 patients. Eighty percent of subjects had other psychiatric diagnoses, 66.3% had sleep disturbances at the time of admission, and 57.1% were using hypnotics; 49.1% of patients had sleep disturbances at discharge. Sleep disturbances at admission and discharge were not associated with alcohol relapse at 12 months (OR = 1.00, 95% CI = 0.89-1.13; p = 0.95 and OR = 0.97, 95% CI = 0.86-1.09; p = 0.61). The PSQI sub-scale scores were also not associated with relapse at 12 months. The use of alcohol to help fall asleep (OR = 3.26, 95% CI = 1.33-7.95; p = 0.008), hypnotic use at admission (OR = 4.03, 95% CI = 1.63-9.97; p = 0.002) and age (OR = 1.03, 95% CI = 1.00-1.06; p = 0.035) were associated with relapse over 12 months. CONCLUSION: In patients completing a residential treatment program, sleep disturbances as measured by the PSQI were not associated with alcohol relapse at 12 months. Alcohol use as a hypnotic and hypnotic use at admission were associated with subsequent relapse. PMID- 25808398 TI - The Acidity of the HBr/AlBr3 System: Stabilization of Crystalline Protonated Arenes and Their Acidity in Bromoaluminate Ionic Liquids. AB - Bulk protonated mesitylene, toluene, and benzene bromoaluminate salts were stabilized and characterized in the superacidic system HBr/n AlBr3 with NMR spectroscopy and X-ray analysis of [HC6 H3 (CH3 )3 ](+) [AlBr4 ](-) (1), [HC6 H5 (CH3 )](+) [AlBr4 ](-) (2), and [C6 H7 ](+) [Al2 Br7 ](-) ?C6 H6 (3). Protonation attempts in bromoaluminate ILs led to a complete protonation of mesitylene, and a protonation degree of up to 15 % for toluene in the IL BMP(+) [Al2 Br7 ](-) . Benzene could only be protonated in the more acidic IL BMP(+) [Al3 Br10 ](-) , with a degree of 25 %. Protonation attempts on aromatics provide evidence that the bromoaluminate ILs tolerate superacidic environments. On the basis of the absolute Bronsted acidity scale, quantum chemical calculations confirmed the superacidic properties, and rank the acidities in ILs down to a pHabs value of 164 with an error of less than one pH unit compared with experimental findings. The neat AlBr3 /HBr system even may reach acidities down to pHabs 163. PMID- 25808397 TI - Lack of association of oral calcium supplementation with coronary artery calcification in rheumatoid arthritis. AB - OBJECTIVE: To investigate the association between oral calcium supplementation and coronary artery calcification among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD). METHODS: This study was conducted as a nested, prospective cohort study of RA patients without known CVD. The daily supplemental calcium dose was ascertained from each patients' list of prescription and over-the-counter medications at baseline and at visit 2 (median 20 months postbaseline). The coronary artery calcium (CAC) score, a measure of coronary atherosclerosis, was assessed by cardiac multidetector row computed tomography at baseline and at visit 3 (median 39 months postbaseline). The association between calcium supplementation and CAC was explored. RESULTS: Among the 145 RA patients studied, 42 (28%) were taking >=1,000 mg/day of supplemental calcium at baseline. A CAC score of >100 units was seen in 44 patients (30%) at baseline and 50 patients (34%) at followup. Baseline CAC scores of >100 units were significantly less frequent in patients receiving the higher dosage (>=1,000 mg/day) of supplemental calcium than in those receiving the lower dosage (<1,000 mg/day) (odds ratio [OR] 0.28, 95% confidence interval [95% CI] 0.11-0.74); this association remained significant after adjustment for relevant confounders (adjusted OR 0.30, 95% CI 0.09-0.93). Similarly, at the third study visit, CAC scores of >100 units were less frequent in the higher supplemental calcium dose group compared to the lower dose group (OR 0.41, 95% CI 0.18-0.95); however, after adjustment for relevant confounders, the statistical significance of this association was lost (adjusted OR 0.39, 95% CI 0.14-1.12). No effect of sex heterogeneity was seen in the association of calcium supplementation with coronary artery calcification, and no change in the CAC score over time was observed. CONCLUSION: Higher levels of oral calcium supplementation were not associated with an increased risk of coronary atherosclerosis, as measured by the CAC score, in this RA cohort. PMID- 25808401 TI - Necrotizing myopathy caused by central hypothyroidism. PMID- 25808399 TI - Prevalence of and familial influences on purging disorder in a community sample of female twins. AB - OBJECTIVE: Purging disorder (PD) was recently included as an otherwise specified feeding or eating disorder (OSFED) in the DSM-5; however, limited information is available on its prevalence, and its etiology is unknown. METHOD: Data from 1,790 monozygotic and 1,440 dizygotic European American female twins (age range = 18-29 years) from the Missouri Adolescent Female Twin Study were used to investigate prevalence and familial influences for PD. A structured clinical interview assessed lifetime DSM-IV criteria for eating disorders and PD. After adjustment for age, twin correlations and biometrical twin models were used to estimate familial (i.e., genetic plus shared environmental) influences on PD. RESULTS: One hundred and twenty one (3.77%; 95% CI: 3.14, 4.49) women met criteria for lifetime PD. Twin correlations suggested that genetic, shared environmental, and nonshared environmental factors influenced liability to PD. Nonshared environmental factors accounted for 56% [35%, 79%] of the variance in PD. Although familial effects accounted for a significant proportion of variance (44% [21%, 65%]), it was not possible to disentangle the independent contributions of additive genetic effects (20% [0%, 65%]) and shared environmental effects (24% [0%, 57%]). DISCUSSION: PD is a prevalent form of eating pathology. Familial factors are relevant to the development of PD but do not demonstrate the magnitude of heritable factors found for other eating disorders. PMID- 25808400 TI - Diphenyl phosphine oxide-1-sensitive K(+) channels contribute to the vascular tone and reactivity of resistance arteries from brain and skeletal muscle. AB - OBJECTIVE: Many types of vascular smooth muscle cells exhibit prominent KDR currents. These KDR currents may be mediated, at least in part, by KV1.5 channels, which are sensitive to inhibition by DPO-1. We tested the hypothesis that DPO-1-sensitive KDR channels regulate the tone and reactivity of resistance sized vessels from rat brain (MCA) and skeletal muscle (GA). METHODS: Middle cerebral and gracilis arteries were isolated and subjected to three kinds of experimental analysis: (i) western blot/immunocytochemistry; (ii) patch clamp electrophysiology; and (iii) pressure myography. RESULTS: Western blot and immunocytochemistry experiments demonstrated KV1.5 immunoreactivity in arteries and smooth muscle cells isolated from them. Whole-cell patch clamp experiments revealed smooth muscle cells from resistance-sized arteries to possess a KDR current that was blocked by DPO-1. Resistance arteries constricted in response to increasing concentrations of DPO-1. DPO-1 enhanced constrictions to PE and serotonin in gracilis and middle cerebral arteries, respectively. When examining the myogenic response, we found that DPO-1 reduced the diameter at any given pressure. Dilations in response to ACh and SNP were reduced by DPO-1. CONCLUSION: We suggest that KV1.5, a DPO-1-sensitive KDR channel, plays a major role in determining microvascular tone and the response to vasoconstrictors and vasodilators. PMID- 25808403 TI - Sore throat in primary care project: a clinical score to diagnose viral sore throat. AB - OBJECTIVE: Viral agents cause the majority of sore throats. However, there is not currently a score to diagnose viral sore throat. The aims of this study were (i) to find the rate of bacterial and viral causes, (ii) to show the seasonal variations and (iii) to form a new scoring system to diagnose viral sore throat. METHODS: A throat culture for group A beta haemolytic streptococci (GABHS) and a nasopharyngeal swab to detect 16 respiratory viruses were obtained from each patient. Over a period of 52 weeks, a total of 624 throat cultures and polymerase chain reaction analyses were performed. Logistic regression analysis was performed to find the clinical score. RESULTS: Viral infection was found in 277 patients (44.3%), and GABHS infection was found in 116 patients (18.5%). An infectious cause was found in 356 patients (57.1%). Rhinovirus was the most commonly detected infectious agent overall (highest in November, 34.5%), and the highest GABHS rate was in November (32.7%). Analysis of data provided a scoring system, called the Mistik Score, to diagnose viral sore throat. The predictive model for positive viral analysis included the following variables: absence of headache, stuffy nose, sneezing, temperature of >=37.5 degrees C on physical examination, and the absence of tonsillar exudate and/or swelling. The probability of a positive viral analysis for a score of 5 was 82.1%. CONCLUSION: The Mistik Score may be useful to diagnose viral sore throat. We suggest its use either alone or in combination with the Modified Centor Score. PMID- 25808402 TI - The life-extending effect of dietary restriction requires Foxo3 in mice. AB - Forkhead box O (Foxo) transcription factors may be involved in the salutary effect of dietary restriction (DR). This study examined the role of Foxo3 in lifespan extension and cancer suppression in DR mice. Wild-type (WT) and Foxo3 knockout heterozygous ((+/-) ) and homozygous ((-/-) ) mice were subjected to a 30% DR regimen initiated at 12 weeks of age. Control mice were fed ad libitum (AL) throughout the study. In contrast to WT mice, DR did not significantly extend the lifespan of Foxo3(+/-) or Foxo3(-/-) mice. However, DR reduced the prevalence of tumors at death in WT, Foxo3(+/-) , and Foxo3(-/-) mice. These results indicate the necessity of Foxo3 for lifespan extension but not cancer suppression by DR. The findings in Foxo3(+/-) mice contrast with those in Foxo1(+/-) mice reported previously by our laboratory suggest differential regulation of cancer and lifespan by DR via Foxo1 and Foxo3. PMID- 25808406 TI - Improving singlet oxygen resistance during photochemical water oxidation by cobalt porphyrin catalysts. AB - Enabling the production of solar fuels on a global scale through artificial photosynthesis requires the development of water oxidation catalysts with significantly improved stability. The stability of photosystems is often reduced owing to attack by singlet oxygen, which is produced during light harvesting. Here, we report photochemical water oxidation by CoFPS, a fluorinated Co porphyrin designed to resist attack by singlet oxygen. CoFPS exhibits significantly improved stability relative to its non-fluorinated analogue, as shown by a large increase in turnover numbers. This increased stability results from resistance of CoFPS to attack by singlet oxygen, the formation of which was monitored in situ by using 9,10-diphenylanthracene as a chemical probe. Dynamic light scattering (DLS) confirms that CoFPS remains homogeneous, proving its stability during water oxidation catalysis. PMID- 25808404 TI - Association involving serotonin transporter gene linked polymorphic region and bipolar disorder type 1 in Iranian population. AB - INTRODUCTION: Serotonin transporter gene linked polymorphic region, also called 5HTTLPR, is a candidate in the genetics of bipolar disorder; however, the results of previous association studies are inconsistent. Several explanations have been proposed for that inconsistency; among them are the existing differences both in the genetic basis of bipolar disorder subtypes and the genetic backgrounds of the studied populations. We aimed to investigate the association of 5HTTLPR with bipolar disorder type I (BP-1) in Iranian population. METHODS: In this case control study, 146 patients with BP-1 and 165 controls were recruited. The patients were selected through the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition. It was required that the patients do not have any present history of general medical conditions, substance abuse, and concurrent major psychiatric disorders. The polymorphism was evaluated by blood sampling and subsequent DNA extraction, polymerase chain reaction, and agarose gel electrophoresis. Chi-square test was used for analyzing allelic and genotype frequencies and two-tailed P values were obtained. RESULTS: The S allele was significantly more frequent in the BP-1 patients compared with the controls (P = 0.02, S allele odds ratio = 1.5, confidence interval 95% = 1.06-2.11). DISCUSSION: Our statistically significant results suggest that the role of 5HTTLPR in the pathogenesis of BP-1 needs to be clarified by further scrutiny in Iranian population and other populations of Near East. PMID- 25808405 TI - Kaempferol Promotes Transplant Tolerance by Sustaining CD4+FoxP3+ Regulatory T Cells in the Presence of Calcineurin Inhibitor. AB - Calcineurin inhibitor cyclosporine is widely used as an immunosuppressant in clinic. However, mounting evidence has shown that cyclosporine hinders tolerance induction by dampening Tregs. Therefore, it is of paramount importance to overcome this pitfall. Kaempferol was reported to inhibit DC function. Here, we found that kaempferol delayed islet allograft rejection. Combination of kaempferol and low-dose, but not high-dose, of cyclosporine induced allograft tolerance in majority of recipient mice. Although kaempferol plus either dose of cyclosporine largely abrogated proliferation of graft-infiltrating T cells and their CTL activity, both proliferation and CTL activity in mice treated with kaempferol plus low-dose, but not high-dose, cyclosporine reemerged rapidly upon treatment withdrawal. Kaempferol increased CD4+FoxP3+ Tregs both in transplanted mice and in vitro, likely by suppressing DC maturation and their IL-6 expression. Reduction in Tregs by low dose of cyclosporine was reversed by kaempferol. Kaempferol-induced Tregs exhibited both allospecific and non-allospecific suppression. Administering IL-6 abrogated allograft tolerance induced by kaempferol and cyclosporine via diminishing CD4+FoxP3+ Tregs. Thus, for the first time, we demonstrated that kaempferol promotes transplant tolerance in the presence of low dose of cyclosporine, which allows for sufficient Treg generation while minimizing side effects, resulting in much-needed synergy between kaempferol and cyclosporine. PMID- 25808409 TI - Model for end-stage liver disease-based allocation system: On the right path, but not there yet. PMID- 25808408 TI - Targeted inhibition of osteosarcoma tumor growth by bone marrow-derived mesenchymal stem cells expressing cytosine deaminase/5-fluorocytosine in tumor bearing mice. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are considered as an attractive approach for gene or drug delivery in cancer therapy. In the present study, the ability of human bone marrow-derived MSCs expressing the cytosine deaminase/5 fluorocytosine prodrug (CD/5-FC MSCs) to target the human osteosarcoma cell line Cal72 was evaluated. METHODS: The stable CD/5-FC MSC cell line was established by transfection of pEGFP containing the cytosine deaminase gene into MSCs with G418 selection. The anti-tumor effect was verified by a bystander effect assay in vitro and co-injection of Cal72 and CD/5-FC MSCs in cancer-bearing mice. RESULTS: The therapeutic CD/5-FC MSCs retained the characteristics of multipotent cells, such as differentiation into adipocytes/osteocytes and expression of mesenchymal markers (CD90 and CD44), and showed migration toward Cal72 cells to a greater extent than the native MSCs. The bystander effect assay showed that the CD/5-FC MSCs significantly augmented Cal72 cytotoxicity in direct co-culture and in the presence of 5-FC through the application of conditioned medium. In osteosarcoma bearing mice, the CD/5-FC MSCs inhibited tumor growth compared to control mice subcutaneously injected with only Cal72 cells. CONCLUSIONS: Taken together, these findings suggest that CD/5-FC MSCs may be suitable for targeting human osteosarcoma. PMID- 25808411 TI - TMS-induced motor evoked potentials in Wilson's disease: a systematic literature review. AB - Wilson's disease (WD) is a metabolic brain disease resulting from improper copper metabolism. Although pyramidal symptoms are rarely observed, subclinical injury is highly possible as copper accumulates in all brain structures. The usefulness of motor evoked potentials (MEPs) in pyramidal tracts damage evaluation still appears to be somehow equivocal. We searched for original papers assessing the value of transcranial magnetic stimulation elicited MEPs with respect to motor function of upper and lower extremity in WD. We searched PubMed for original papers evaluating use of MEPs in WD using key words: "motor evoked potentials Wilson's disease" and "transcranial magnetic stimulation Wilson's disease." We found six articles using the above key words. One additional article and one case report were found while viewing the references lists. Therefore, we included eight studies. Number of patients in studies was low and their clinical characteristic was variable. There were also differences in methodology. Abnormal MEPs were confirmed in 20-70% of study participants. MEPs were not recorded in 7.6-66.7% of patients. Four studies reported significantly increased cortical excitability (up to 70% of patients). Prolonged central motor conduction time was observed in four studies (30-100% of patients). One study reported absent or prolonged central motor latency in 66.7% of patients. Although MEPs may be abnormal in WD, this has not been thoroughly assessed. Hence, further studies are indispensable to evaluate MEPs' usefulness in assessing pyramidal tract damage in WD. PMID- 25808410 TI - Different Impact Of Antiretroviral Drugs On Bone Differentiation In An In Vitro Model. AB - Recently increasing emphasis is placed on preventive health and management of chronic comorbidities avoiding long-term toxicities of antiretroviral therapy (ART). Drawing from this background we decided to use the Saos-2, osteosarcoma cell line, as a cellular model, to evaluate the effects of some antiretroviral drugs such as abacavir (ABC), tenofovir (TDF), efavirenz (EFV), etravirine (ETR), and darunavir (DRV), on bone differentiation related pathways. According to our observation, treatment with TDF and ABC affects the ability of the cells to produce calcium deposits with a reduced expression of type I collagen gene and p21 mRNA, also increasing the activity of Wnt3a related pathway. On the other hand treatment with EFV and DRV was not related to any significant reduction of calcium deposits but displayed a decrease in the expression of Wnt3a at day 14 and Type I Collagen at day 7 compared with untreated cells, even if this last down regulation was not confirmed at day 14. Instead ETR administration to Saos-2 cells increases the calcium deposits collagen type I production, as a result of Wnt3a mRNA overexpression, and of an upregulation of collagen type I expression, being also the only drug able to increase the expression of p21 cdk inhibitor as further marker of terminal differentiation. In summary these data suggest the potential negative interference of TDF and ABC on bone differentiation. DRV and EFV partially affect collagen type I production, instead ETR facilitates a positive bone balance as a result of an increased osteoblasts terminal differentiation. PMID- 25808412 TI - Photoresponsive molecularly imprinted hydrogel casting membrane for the determination of trace tetracycline in milk. AB - This study aimed to develop a photoresponsive molecularly imprinted hydrogel (MIH) casting membrane for the determination of trace tetracycline (TC) in milk. This MIH casting membrane combined the specificity of MIHs, the photoresponsive properties of azobenzene, and the portable properties of a membrane. Photoresponsive TC-imprinted MIHs were initially fabricated and then cast on sodium dodecyl sulfonate polyacrylamide gel. After TC removal, a photoresponsive MIH casting membrane was obtained. The photoresponsive properties of the MIH casting membrane were robust, and no obvious photodegradation was observed after 20 cycles. The MIH casting membrane displayed specific affinity to TC upon alternate irradiation at 365 and 440 nm; it could quantitatively uptake and release TC. The TC concentration (0.0-2.0 * 10(-4) mol l(-1)) in aqueous solution displayed a linear relationship with the photoisomerization rate constant of azobenzene within the MIH casting membrane. As such, a quick detection method for trace TC in aqueous foodstuff samples was established. The recovery of this method for TC in milk was investigated with a simple pretreatment of milk, and a high recovery of 100.54-106.35% was obtained. Therefore, the fabricated membrane can be used as a portable molecular sensor that can be easily recycled. PMID- 25808414 TI - Structural transformation: assembly of an otherwise inaccessible DNA nanocage. AB - A strategy of structural transformation for the assembly of DNA nanocages that can not be assembled directly is described. In this strategy, a precursor DNA nanocage is assembled first and then is isothermally transformed into a desired, complicated nanocage. A dramatic, conformational change accompanies the transformation. This strategy has been proven to be successful by native polyacrylamide gel electrophoresis (PAGE) and cryogenic electron microscopy (cryoEM) imaging. We expect that the strategy of structural transformation will be useful for the assembly of many otherwise inaccessible DNA nanostructures and help to increase the structural complexity of DNA nanocages. PMID- 25808413 TI - Growth patterns during and after treatment in patients with pediatric ALL: A meta analysis. AB - BACKGROUND: Survivors of pediatric acute lymphoblastic leukemia (ALL) have a significantly higher body mass index (BMI) than their peers. Understanding the critical time periods in which patients with pediatric ALL are vulnerable to unhealthy weight gain will lay the groundwork for developing effectively timed interventions. PROCEDURE: We determined the growth patterns of patients with pediatric ALL during and after treatment through the conduct of a systematic review and meta-analysis. A search of MEDLINE, Scopus, and Web of Science was performed from its inception through May 2014. Studies met the inclusion criteria if they included at least 10 patients of pediatric ALL, and longitudinally assessed BMI at diagnosis and at least one time point after diagnosis RESULTS: Twenty-one studies met the inclusion criteria for the systematic review and 16 were included in meta-analysis. The mean increase in BMI z-score during treatment in 1,514 patients with pediatric ALL was 0.81 (95% CI: 0.25-1.38). Specifically, patients experienced substantial weight gain in early treatment (Delta = 0.41, 95% CI: -0.34, 1.17) and again during maintenance (Delta = 0.34, 95% CI:-0.22, 0.90). The mean increase in BMI z-score ranged between 0.52 and 0.89 beyond treatment completion. Subgroup analyses found unhealthy weight gain occurred regardless of patients' receipt of cranial radiation therapy, sex, and, weight status at diagnosis. CONCLUSIONS: Patients with pediatric ALL experience unhealthy weight gain early in treatment, and increases in weight are maintained beyond treatment completion. Preventing early onset of obesity is a priority for improving the care and outcomes for patients with pediatric ALL. PMID- 25808416 TI - Transglutaminase 2 interactions with extracellular matrix proteins as probed with celiac disease autoantibodies. AB - Transglutaminases have been implicated in various human diseases. A prominent example is the involvement of transglutaminase 2 (TG2) in the gluten-sensitive enteropathy celiac disease, where the enzyme is both the target of autoantibodies and responsible for the generation of immunogenic gluten epitopes. Here, we aimed to characterize the microenvironment of TG2 in the extracellular matrix (ECM) in order to gain insights into the antigenic structures that are recognized by autoantibodies in celiac disease. A panel of TG2-specific mAbs established from gut plasma cells of celiac disease patients was employed as probes to characterize the interactions between TG2 and ECM constituents. With immunofluorescence staining, microplate protein-binding and surface plasmon resonance assays, we found that the main epitope (epitope 1) recognized by TG2 specific gut plasma cells overlaps with the fibronectin (FN)-binding site of TG2. Furthermore, we found that the same TG2 amino acids that are involved in binding of epitope 1 mAbs are also important for efficient binding of FN. Notably, epitope 1 mAbs recognize TG2 in tissue sections, suggesting that some TG2 in the extracellular matrix has interaction partners in addition to FN. We demonstrate that collagen VI is a strong candidate, on the basis of its tissue expression pattern and ability to bind TG2. Collagen VI may thus serve as a matrix for deposition of TG2 in a context that can also be recognized by epitope 1-targeting autoantibodies. PMID- 25808417 TI - Clinical significance of the new cardiovascular risk markers in diabetes mellitus. AB - The prevalence of type 2 diabetes mellitus (T2DM) has risen in recent decades, and cardiovascular disease (CVD) remains the leading cause of death in this population. Several studies have shown that, in clinical practice, identifying diabetic patients at high risk for CVD is essential, since these patients benefit from aggressive strategies to achieve a greater risk reduction. In recent years, new markers of CV risk have been added to the list of those already known. These new emerging markers, such as inflammatory, bone and hormonal markers, act as new indicators of subclinical atherosclerosis and CV mortality. Therefore, we reviewed the ongoing scientific research on these new biomarkers and discuss their clinical impact on the identification of T2DM patients at high CV risk. PMID- 25808415 TI - The World at 7:00: Comparing the Experience of Situations Across 20 Countries. AB - The purpose of this research is to quantitatively compare everyday situational experience around the world. Local collaborators recruited 5,447 members of college communities in 20 countries, who provided data via a Web site in 14 languages. Using the 89 items of the Riverside Situational Q-sort (RSQ), participants described the situation they experienced the previous evening at 7:00 p.m. Correlations among the average situational profiles of each country ranged from r = .73 to r = .95; the typical situation was described as largely pleasant. Most similar were the United States/Canada; least similar were South Korea/Denmark. Japan had the most homogenous situational experience; South Korea, the least. The 15 RSQ items varying the most across countries described relatively negative aspects of situational experience; the 15 least varying items were more positive. Further analyses correlated RSQ items with national scores on six value dimensions, the Big Five traits, economic output, and population. Individualism, Neuroticism, Openness, and Gross Domestic Product yielded more significant correlations than expected by chance. Psychological research traditionally has paid more attention to the assessment of persons than of situations, a discrepancy that extends to cross-cultural psychology. The present study demonstrates how cultures vary in situational experience in psychologically meaningful ways. PMID- 25808418 TI - Obstructive Sleep Apnoea Syndrome and Diabetes. Fortuitous Association or Interaction? AB - This review explores the relation between obstructive sleep apnoea syndrome (OSAS) and diabetes. It aims to address the following issues: 1. the epidemiological evidence of the association between OSAS and type 2 diabetes; 2. the independence of this association from the comorbidities shared by the two conditions; 3. the chronological and quantitative characteristics of this association (Which comes first? Is there severity interdependence? Is treatment of one condition able to modify the natural history of the other?); 4. the mechanisms that make interaction plausible; 5. the impact of the OSAS-diabetes relation on micro- and macrovascular diabetic complications. OSAS is common in type 2 diabetes. Despite the association being affected by the confounding action of type 2 diabetes comorbidities (also risk factors for OSAS), it does not seem to be fully attributable to them. There is also a relation between OSAS severity and glucose metabolism alteration. A link between OSAS and insulin resistance appears early, prior to impaired glucose tolerance and the onset of diabetes. Therefore, a debate is ongoing on the pathogenetic role of OSAS in type 2 diabetes development and any consequent relevance to diabetes treatment with no conclusive evidence to date. A multiplicity of hypothetical mechanisms may mediate this relation. Most experimental findings support sympathetic activation and changes in chemoreflex sensitivity based on the interaction between chemoreflex and baroreflex. Some studies suggest bidirectional relationship between OSAS and diabetes, additive or synergistic effects for diabetic complications and a reciprocal enhancement in their impact on hypertension and cardiovascular disease. Clarification of these items could benefit diabetes management and prevention of diabetic cardiovascular complications. PMID- 25808419 TI - Treatment options for post-transplantation diabetes mellitus. AB - Treatment options for management of post-transplantation diabetes mellitus (PTDM) are limited with regards to the availability of strong clinical evidence base. This is a concern as PTDM is common after solid organ transplantation and associated with poor clinical outcomes. PTDM and type 2 diabetes mellitus are distinct pathophysiological entities that have important differences with regards to aetiology, clinical course and management. Therefore, any clinical evidence of treatment benefit from the general population with type 2 diabetes mellitus may not be directly translated to the solid organ transplant recipient. In addition, the potential risk and benefit of using many of these therapeutic agents must take account of the complicated post-transplantation milieu of immunosuppression. While there is reasonable evidence base for treatment of diabetes mellitus in the general population, the same is not true in a post-transplantation setting. In this article the treatment options available for PTDM will be discussed, with a transplant-specific focus on the pros and cons of each particular component of the glucose lowering therapy armoury. PMID- 25808420 TI - Dynamic studies of human corneal fibroblasts. PMID- 25808422 TI - Dendritic connectivity shapes spatial patterns of genetic diversity: a simulation based study. AB - Landscape features notoriously affect spatial patterns of biodiversity. For instance, in dendritic ecological networks (such as river basins), dendritic connectivity has been proposed to create unique spatial patterns of biodiversity. Here, we compared genetic datasets simulated under a lattice-like, a dendritic and a circular landscape to test the influence of dendritic connectivity on neutral genetic diversity. The circular landscape had a level of connectivity similar to that of the dendritic landscape, so as to isolate the influence of dendricity on genetic diversity. We found that genetic diversity and differentiation varied strikingly among the three landscapes. For instance, the dendritic landscape generated higher total number of alleles and higher global Fst than the lattice-like landscape, and these indices also varied between the dendritic and the circular landscapes, suggesting an effect of dendricity. Furthermore, in the dendritic landscape, allelic richness was higher in highly connected demes (e.g. confluences in rivers) than in low-connected demes (e.g. upstream and downstream populations), which was not the case in the circular landscape, hence confirming the major role of dendricity. This led to bell-shaped distributions of allelic richness along an upstream-downstream gradient. Conversely, genetic differentiation (Fst ) was lower in highly than in low connected demes (which was not observed in circular landscape), and significant patterns of isolation by distance (IBD) were also observed in the dendritic landscape. We conclude that in dendritic networks, the combined influence of dendricity and connectivity generates unique spatial patterns of neutral genetic diversity, which has implications for population geneticists and conservationists. PMID- 25808421 TI - Statins are associated with a reduced risk of cholangiocarcinoma: a population based case-control study. AB - AIMS: Cholangiocarcinoma (CCA) is the second most common primary liver cancer in the world. Due to the lack of effective treatments, the survival rate of CCA is low and it is usually considered difficult to diagnose early. To date, no effective strategies for the prevention of CCA have been developed. Statins are cholesterol-lowering agents which possess pleiotropic properties and the use of statins may reduce cancer risk. The aim of the study was to investigate the effect of statin use on the risk of CCA. METHODS: We used nationwide insurance data to perform a case-control study including 3174 CCA patients diagnosed in 2002-2011 and 3174 propensity score matched controls. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated to assess the association between CCA risk and statin use by type of statin and dose. RESULTS: Patients with CCA were slightly younger than controls with mean ages of 67.4 (SD 12.3) and 68.5 (SD 13.2) years (P = 0.001), respectively, and had less users of statins (22.7 vs. 26.5%, P < 0.001). The overall adjusted OR of statin use associated CCA was 0.80 (95% CI 0.71, 0.90) and lowered for those with longer medications. The OR ranged from 0.65 to 0.77. Stronger dose-response association was seen when using lovastatin. CONCLUSIONS: Statin use is associated with reduced risk of CCA and there is a dose-response relationship between the use of statins and risk of CCA. PMID- 25808423 TI - Nursing researchers' modifications of Ricoeur's hermeneutic phenomenology. AB - Paul Ricoeur's hermeneutic phenomenology has proved to be very helpful in guiding nursing researchers' qualitative analysis of interview transcripts. Modifying Ricoeur's philosophy, a number of nursing researchers have developed their own interpretive methods and shared them, along with their experience, with research community. Major contributors who published papers directly presenting their modifications of Ricoeur's theory include Rene Geanellos (2000), Lena Wiklund, Lisbet Lindholm and Unni A. Lindstrom (2002), Anders Lindseth and Astrid Norberg (2004) and Pia Sander Dreyer and Birthe D Pedersen (2009). The aim of this article was to delineate differences among these methods. Descriptive presentation of each method side by side makes clear the differences among them. In addition, Ricoeur's hermeneutic theory is portrayed and compared with the modifications. It is believed that differences that are found can stimulate further thoughts on how to apply Ricoeur's theory in qualitative research in nursing. PMID- 25808425 TI - Clarifying the effect of behavioral and clinical factors on traumatic dental injuries in childhood: a hierarchical approach. AB - AIM: To explore associations between traumatic dental injuries (TDI) in Brazilian preschool children and clinical, behavioral, and socio-demographic factors using a hierarchical approach. MATERIAL AND METHODS: A cross-sectional study was conducted involving 1316 children aged 0-5 years at public preschools in the city of Canoas (southern Brazil). Demographic (sex and age), socioeconomic (mother's schooling, income and family structure) and behavioral (use of pacifier, breastfeeding duration and bottle use at 12 months) factors were collected through a questionnaire. TDI (Andreasen criteria) and malocclusion (overjet and anterior open bite) were recorded by trained and calibrated examiners. Poisson regression was employed to determine factors associated with TDI using a hierarchical approach. RESULTS: The prevalence of TDI was 13.3%. In the final model, the probability of TDI was 50% higher in children who used a pacifier (PR: 1.50; 95% CI: 1.08-2.10), 77% higher in children with overjet between 3 and 5 mm (PR: 1.77; 95% CI: 1.22-2.57) and nearly threefold higher in children with overjet > 5 mm (PR: 2.73; 95% CI: 1.77-4.20) compared with children with overjet <= 2 mm. Additional analysis demonstrated that overjet represented the pathway by which pacifier use was associated with TDI. CONCLUSION: Pacifier use is strongly associated with the occurrence of TDI in the primary dentition, and accentuated overjet represents a pathway to this association. These findings suggest the need for prevention strategies that address early counseling on pacifier use to reduce the occurrence of TDI. PMID- 25808424 TI - Cell-specific regulation of neuronal activity by endogenous production of nitric oxide. AB - Nitric oxide (NO) is a key regulator of neuronal excitability in the nervous system. While most studies have investigated its role as an intercellular messenger/modulator, less is known about potential physiological roles played by NO within NO-producing neurons. We showed previously that intrinsic production of NO within B5 neurons of the pond snail Helisoma trivolvis increased neuronal excitability by acting on three ionic conductances. Here we demonstrate that intrinsically produced NO affected two of the same conductances in another buccal neuron, B19, where it had the opposite, namely inhibitory, effect on neuronal activity. Using single-cell RT-PCR, we show that B19 neurons express NO synthase (NOS) mRNA. The inhibition of intrinsic NO production with NOS inhibitors caused membrane potential depolarization, transient spiking and an increase in input resistance. Inhibition of the main intracellular receptor of NO, soluble guanylyl cyclase, had similar effects on the parameters mentioned above. An investigation of the effects of NO on ion channels revealed that intrinsic NO mediated neuronal hyperpolarization by activating voltage-gated calcium channels that in turn caused the tonic opening of apamin-sensitive calcium-activated potassium channels. The analysis of action potentials in B5 and B19 neurons suggested that the opposite effects on neuronal excitability elicited by intrinsic NO were probably determined by differences in the ionic conductances that shape their action potentials. In summary, we describe a mechanism by which B19 neurons utilise intrinsically produced NO in a cell-type-specific fashion to decrease their neuronal activity, highlighting an important physiological role of NO within NO-producing neurons. PMID- 25808426 TI - The Effect of Occupation-based Cognitive Rehabilitation for Traumatic Brain Injury: A Meta-analysis of Randomized Controlled Trials. AB - Traumatic brain injury (TBI) is the leading cause of death and disability among people younger than 35 years in the United States. Cognitive difficulty is a common consequence of TBI. To address cognitive deficits of patients with TBI, various cognitive rehabilitation approaches have been used for the clinical setting. The purpose of this study was to investigate the overall effect of occupation-based cognitive rehabilitation on patients' improvement in cognitive performance components, activity of daily living (ADL) performance, and values, beliefs and spirituality functions of patients with TBI. The papers used in this study were retrieved from the Cochrane Database, EBSCO (CINAHL), PsycINFO, PubMed and Web of Science published between 1997 and 2014. The keywords for searching were cognitive, rehabilitation, occupation, memory, attention, problem-solving, executive function, ADL, values, beliefs, spirituality, randomized controlled trials and TBI. For the meta-analysis, we examined 60 effect sizes from nine studies that are related to the occupation-based cognitive rehabilitation on persons with TBI. In persons with TBI, overall mental functions, ADL, and values, beliefs and spirituality were significantly improved in the groups that received occupation-based cognitive rehabilitation compared with comparison groups (mean d = 0.19, p < .05). Evidence from the present meta-analytic study suggests that occupation-based cognitive rehabilitation would be beneficial for individuals with TBI for improving daily functioning and positively be able to affect their psychosocial functions. Collecting many outcome measures in studies with relatively few participants and the final data are less reliable than the whole instrument itself. Future research should evaluate the effectiveness of specific occupation-based cognitive rehabilitations programmes in order to improve consistency among rehabilitation providers. PMID- 25808427 TI - Will the Occupational Safety and Health Administration's Proposed Standards for Occupational Exposure to Respirable Crystalline Silica Reduce Workplace Risk? AB - The Occupational Safety and Health Administration (OSHA) is developing regulations to amend existing standards for occupational exposure to respirable crystalline silica by establishing a new permissible exposure limit as well as a series of ancillary provisions for controlling exposure. This article briefly reviews OSHA's proposed regulatory approach and the statutory authority on which it is based. It then evaluates OSHA's preliminary determination of significant risk and its analysis of the risk reduction achievable by its proposed controls. It recognizes that OSHA faces multiple challenges in devising a regulatory approach that reduces exposures and health risks and meets its statutory goal. However, the greatest challenge to reducing risks associated with silica exposure is not the lack of incentives (for either employers or employees) but rather lack of information, particularly information on the relative toxicity of different forms of silica. The article finds that OSHA's proposed rule would contribute little in the way of new information, particularly since it is largely based on information that is at least a decade old--a significant deficiency, given the rapidly changing conditions observed over the last 45 years. The article concludes with recommendations for alternative approaches that would be more likely to generate information needed to improve worker health outcomes. PMID- 25808428 TI - Complications of a High-flow Access and Its Management. AB - A high-flow access has been defined as one with a flow >1-1.5 l/minute or as one where the access flow is >20% of the cardiac output. Although it may be asymptomatic, it can be associated with cardiopulmonary complications, aneurysms, central vein stenosis and the distal hypoperfusion ischemic syndrome in some patients. The decision for surgical intervention should be made after careful medical optimization especially in patients with high output cardiopulmonary compromise. In this review, we present a summary of current knowledge about the pathophysiology of a high-flow fistula, followed by a concise, comprehensive synopsis of current medical and surgical therapy. PMID- 25808429 TI - Nocturnal GERD - a risk factor for rhinitis/rhinosinusitis: the RHINE study. AB - BACKGROUND: It has been suggested that gastroesophageal reflux disease (GERD) is a risk factor for developing rhinitis/rhinosinusitis, but data are lacking. This is a prospective 10-year follow-up study of a large multicenter cohort from Northern Europe, evaluating the relationship between nocturnal GERD and noninfectious rhinitis (NIR). METHODS: The study comprised 5417 subjects born between 1945 and 1973, who answered a questionnaire in 1999-2001 and again in 2010-2012. Noninfectious rhinitis was defined as having nasal obstruction, secretion, and/or sneezing without having the common cold. Odds ratios for developing NIR in relation to age, gender, BMI, smoking, asthma, and nocturnal GERD were calculated. RESULTS: During the 10-year observation period, 1034 subjects (19.1%) developed NIR. Subjects reporting nocturnal gastroesophageal reflux in both 1999 and 2010 had more NIR in 2010 (2.8% vs 1.2%, P < 0.001). There was a significant dose-response relationship between the number of reflux episodes/week in 1999 and the risk of having NIR in 2010, P = 0.02. In the multiple regression adjusted for age, gender, BMI, tobacco smoke, and asthma, those with nocturnal GERD in 1999 (>=3 episodes of nocturnal gastroesophageal reflux symptoms per week) had an OR of 1.6 (95% CI 1.0-2.5, P = 0.03) to develop NIR in 2010. Smoking was associated both with an increased risk of developing NIR (30.7% vs 24.0%, P < 0.001) and with the development of nocturnal GERD. CONCLUSION: This large, population-based, 10-year study indicates that nocturnal GERD was a risk factor for noninfectious rhinitis/rhinosinusitis. GERD should therefore be considered in patients with rhinitis of known and unknown origin. PMID- 25808430 TI - Super-resolved calibration-free flow cytometric characterization of platelets and cell-derived microparticles in platelet-rich plasma. AB - Importance of microparticles (MPs), also regarded as extracellular vesicles, in many physiological processes and clinical conditions motivates one to use the most informative and precise methods for their characterization. Methods based on individual particle analysis provide statistically reliable distributions of MP population over characteristics. Although flow cytometry is one of the most powerful technologies of this type, the standard forward-versus-side-scattering plots of MPs and platelets (PLTs) overlap considerably because of similarity of their morphological characteristics. Moreover, ordinary flow cytometry is not capable of measurement of size and refractive index (RI) of MPs. In this study, we 1) employed the potential of the scanning flow cytometer (SFC) for identification and characterization of MPs from light scattering; 2) suggested the reference method to characterize MP morphology (size and RI) with high precision; and 3) determined the lowest size of a MP that can be characterized from light scattering with the SFC. We equipped the SFC with 405 and 488 nm lasers to measure the light-scattering profiles and side scattering from MPs, respectively. The developed two-stage method allowed accurate separation of PLTs and MPs in platelet-rich plasma. We used two optical models for MPs, a sphere and a bisphere, in the solution of the inverse light-scattering problem. This solution provides unprecedented precision in determination of size and RI of individual spherical MPs-median uncertainties (standard deviations) were 6 nm and 0.003, respectively. The developed method provides instrument-independent quantitative information on MPs, which can be used in studies of various factors affecting MP population. PMID- 25808431 TI - Point-of-care ultrasound education for non-physician clinicians in a resource limited emergency department. AB - OBJECTIVE: To describe the outcomes and curriculum components of an educational programme to train non-physician clinicians working in a rural, Ugandan emergency department in the use of POC ultrasound. METHODS: The use of point-of-care ultrasound was taught to emergency care providers through lectures, bedsides teaching and hands-on practical sessions. Lectures were tailored to care providers' knowledge base and available therapeutic means. Every ultrasound examination performed by these providers was recorded over 4.5 years. Findings of these examinations were categorised as positive, negative, indeterminate or procedural. Other radiologic studies ordered over this same time period were also recorded. RESULTS: A total of 22,639 patients were evaluated in the emergency department by emergency care providers, and 2185 point-of-care ultrasound examinations were performed on 1886 patients. Most commonly used were the focused assessment with sonography in trauma examination (53.3%) and echocardiography (16.4%). Point-of-care ultrasound studies were performed more frequently than radiology department-performed studies. Positive findings were documented in 46% of all examinations. CONCLUSIONS: We describe a novel curriculum for point-of care ultrasound education of non-physician emergency practitioners in a resource limited setting. These non-physician clinicians integrated ultrasound into clinical practice and utilised this imaging modality more frequently than traditional radiology department imaging with a large proportion of positive findings. PMID- 25808432 TI - Typology of Couples Entering Alcohol Behavioral Couple Therapy: An Empirical Approach and Test of Predictive Validity on Treatment Response. AB - This study aimed to examine whether classification of couples in which one partner has an alcohol problem is similar to that reported in the general couples literature. Typologies of couples seeking alcohol behavioral couple therapy (ABCT) were developed via hierarchical cluster analysis using behavioral codes of couple interactions during their first ABCT session. Four couples types based on in-session behavior were established reliably, labeled avoider, validator, hostile, and ambivalent-detached. These couple types resembled couples types found in previous research. Couple type was associated with baseline relationship satisfaction, but not alcohol use. Results suggest heterogeneity in couples with alcohol problems presenting to treatment; further study is needed to investigate the function of alcohol within these different types. PMID- 25808433 TI - Fabrication of continuous flow microfluidics device with 3D electrode structures for high throughput DEP applications using mechanical machining. AB - Microfluidics is the combination of micro/nano fabrication techniques with fluid flow at microscale to pursue powerful techniques in controlling and manipulating chemical and biological processes. Sorting and separation of bio-particles are highly considered in diagnostics and biological analyses. Dielectrophoresis (DEP) has offered unique advantages for microfluidic devices. In DEP devices, asymmetric pair of planar electrodes could be employed to generate non-uniform electric fields. In DEP applications, facing 3D sidewall electrodes is considered to be one of the key solutions to increase device throughput due to the generated homogeneous electric fields along the height of microchannels. Despite the advantages, fabrication of 3D vertical electrodes requires a considerable challenge. In this study, two alternative fabrication techniques have been proposed for the fabrication of a microfluidic device with 3D sidewall electrodes. In the first method, both the mold and the electrodes are fabricated using high precision machining. In the second method, the mold with tilted sidewalls is fabricated using high precision machining and the electrodes are deposited on the sidewall using sputtering together with a shadow mask fabricated by electric discharge machining. Both fabrication processes are assessed as highly repeatable and robust. Moreover, the two methods are found to be complementary with respect to the channel height. Only the manipulation of particles with negative-DEP is demonstrated in the experiments, and the throughput values up to 105 particles / min is reached in a continuous flow. The experimental results are compared with the simulation results and the limitations on the fabrication techniques are also discussed. PMID- 25808434 TI - Biomarkers: a framework driving advances in oncology. PMID- 25808435 TI - An individual reference limit for 'early' diagnosis of metastatic breast cancer during postoperative follow-up. AB - AIMS: This study is a clinical pilot study with the principal aim to investigate the accuracy of a panel of serum tumor markers for the early diagnosis of relapses. We propose a systematic use of serum CEA-TPA-CA15.3 tumor marker panel and criteria in order to make it an accurate tool for a postoperative breast cancer monitoring. MATERIALS & METHODS: 204 disease free breast cancer patients after mastectomy were intensively monitored with serial serum determination of CEA, CA15.3 and TPA. RESULTS: During a mean follow-up of 3.7 years the sensitivity of the CEA-TPA-CA15.3 tumor marker panel was 93%, the specificity was 97.6% and the rate of false 'warning signals' per year of follow-up was 9 per 100 patients. CONCLUSIONS: Our results show that the proposed tool is promising for a postoperative monitoring of breast cancer patients. PMID- 25808436 TI - C-type natriuretic peptide and its precursor: potential markers in human prostate cancer. AB - AIM: Seminal plasma offer a more organ-specific matrix for markers in prostatic disease. We hypothesized that C-type natriuretic peptide (CNP) expression may constitute such a new target. METHODS: Patients with benign prostatic hyperplasia, clinically localized and metastatic prostate cancer were examined for CNP and CNP precursor (proCNP) concentrations in blood and seminal plasma. Furthermore, CNP and the CNP receptor (NPR-B) mRNA contents in tissue from prostate and seminal vesicles were analyzed by qPCR. RESULTS: CNP and NPR-B concentrations decreased with increasing tumor burden (p = 0.0027 and p = 0.0096, respectively). In contrast, seminal plasma CNP and proCNP concentrations were markedly increased with increased tumor burden (p < 0.0001 and p < 0.0001, respectively). CONCLUSION: CNP/proCNP could be new markers in human prostate cancer. PMID- 25808437 TI - Plasma fibrinogen and blood platelet counts are associated with response to neoadjuvant therapy in esophageal cancer. AB - AIM: To investigate coagulatory factors in predicting response to neoadjuvant therapy (NeoTr) in esophageal cancer (EC). METHODS: We investigated the relevance of coagulatory factors in 84 EC patients (56 adenocarcinomas, 28 squamous cell cancer) who received NeoTr. Plasma fibrinogen (PFR), peripheral blood platelet counts (PBPC) and C-reactive protein (CRP) were determined before NeoTr. Response was classified as tumor regression grades. RESULTS: Patients with good response to NeoTr had significantly higher PFR (p = 0.006), CRP (p = 0.002) and PBPC levels (p = 0.034) when compared with others. Only, PFR remained an independent factor influencing tumor regression (p = 0.0064, coefficient of regression: 0.003). No association with survival was observed. CONCLUSION: PFR and to a lesser extent PBPC and CRP might be considered as a predictive marker for the response to NeoTr in EC. PMID- 25808439 TI - Pluripotency transcription factors in the pathogenesis of colorectal cancer and implications for prognosis. AB - The cancer stem cell hypothesis argues that cancers depend on a specific type of cells, representing usually a small percentage of the total cancer cell population, termed cancer stem cells (or tumor-initiating cells) for their development and propagation. In colorectal cancer these cells express specific surface proteins such as CD133 and CD44 and can recapitulate the whole tumor. Besides expression of these surface markers, stem cells are associated with a network of pluripotency transcription factors, such as Oct4 and Sox2, which is present in them. Pluripotency factors are normally active in early development and characterize primitive cells, able to give rise to all different cell and tissue types of the three embryonic layers. In this review I will discuss the relationship of these factors with pathogenic lesions in colorectal cancer and their prognostic implications. PMID- 25808438 TI - Personalized treatment for patients with colorectal cancer: role of biomarkers. AB - The systemic treatment of patients with colorectal cancer (CRC) has traditionally been based on clinical and tumor histological criteria. Recently however, several prognostic and predictive biomarkers have been proposed for patients with newly diagnosed CRC, including the subgroup with stage II disease. Among the best validated prognostic biomarkers for CRC are CEA levels, MS instability status and certain gene signatures. Although no biomarker currently exists for identifying patients likely to benefit from chemotherapy, the mutational status of KRAS and NRAS is used to predict response to cetuximab and panitumumab. For upfront identification of patients at high risk of suffering from severe therapy-related toxicity, specific variants of dihydropyrimidine dehydrogenase may be measured for predicting toxicity from fluoropyrimidines and uridine diphosphate glucuronosyltransferase*28 (UGT1A1*28) for predicting toxicity from irinotecan. PMID- 25808440 TI - Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status: alternative biomarkers and therapeutic strategies. AB - Patients with metastatic colorectal cancer have a very poor prognosis. Incorporation of targeted molecular therapies, such as the anti-EGFR receptor monoclonal antibodies cetuximab and panitumumab, into treatment regimens has improved outcomes for patients with wild-type RAS tumors. Yet, response rates remain low and overall survival times are short. Increased understanding of oncogenic signaling pathways within the tumor, and how these are regulated by the inflammatory tumor microenvironment, is a priority to facilitate the development of biomarkers to better guide the use of existing therapies and to develop new ones. Here, we review recent preclinical and clinical progress in the development of biomarkers for predicting response to anti-EGFR therapy in metastatic colorectal cancer. PMID- 25808441 TI - Zinc isotopes: a novel approach to biomarkers of breast cancer? PMID- 25808442 TI - Poor prognosis of constitutive gamma-H2AX expressing triple-negative breast cancers is associated with telomere length. AB - AIM: Here, we set out to establish whether endogenous gamma-H2AX is a biomarker in triple-negative breast cancer. METHODS: We explored the association of gamma H2AX with mutation status and sensitivity to 139 different anticancer drugs in up to 41 breast cancer cell lines. Further, we correlated gamma-H2AX expression in breast cancer tumor tissues with telomere length. RESULTS: gamma-H2AX positive breast cancer cells exhibit more mutations, and - when p53 mutated - have shorter telomeres. In breast cancer patients gamma-H2AX is also related to shorter telomeres, which was in turn associated with poorer prognosis of triple-negative breast cancer patients. CONCLUSION: Thus, endogenous gamma-H2AX is associated with short telomeres, which might offer a specific target for therapy for triple negative breast cancer patients. PMID- 25808443 TI - Study of NGEP expression pattern in cancerous tissues provides novel insights into prognostic marker in prostate cancer. AB - AIM: The aim of this study was to produce a novel polyclonal antibody against extracellular domain of NGEP protein and explore its role in prognosis of prostate cancer. MATERIALS & METHODS: Polyclonal antibodies against two peptides (NGEP-p1 and NGEP-p2) derived extracellular domains of NGEP were prepared and the intensity and distribution of NGEP expression analyzed in large series of prostate tissue specimens. RESULTS: We found a significant inverse correlation between NGEP expression and prognostic features such as Gleason score, pathologic tumor stage and prostate-specific antigen level using anti-NGEP-p2 antibody. CONCLUSION: The results indicate that the high level of expression could be associated with good prognosis in prostate cancer. However, additional studies are required to evaluate NGEP as an independent prognostic factor for prostate carcinoma. PMID- 25808444 TI - Rs4948496 within ARID5B gene is associated with clinical features of systemic lupus erythematosus in the Chinese Han population. AB - In our previous meta-analysis of genome-wide association study, we identified the single nucleotide polymorphism (SNP) rs4948496 (P = 5.1 * 10(-11) , odds ratio [OR] = 0.85) within the ARID5B gene associated with systemic lupus erythematosus (SLE) in a Chinese population. To investigate its association with disease subphenotypes, we further analyzed the genotype data of rs4948496 in 4348 cases and 6679 controls from our previous meta-analysis and an independent replication cohort in this study. The SNP rs4948496 was significantly associated with SLE (P = 1.61 * 10(-5) , OR = 0.88, 95% confidence interval [CI] = 0.83-0.93) in our group. In case-only study, the genotype of rs4948496 was associated with antinuclear antibodies (P = 0.03, OR = 0.81, 95% CI = 0.68-0.98) and anti-RNP (P = 0.03, OR = 0.86, 95% CI = 0.76-0.99). This study showed that rs4948496 in ARID5B is associated with several subphenotypes of SLE and this gene may cause the complicacy of clinical features. PMID- 25808445 TI - Locking Away "Recidivism". AB - The etymology of the word recidivism is explored as is its use in the psychiatric literature and other areas. This paper revisits a proposal to stop using the word to describe hospital readmission and substance use relapse since the origin of the word and predominant meaning reflect crime and acts that offend society. Public policy makers and leaders should be careful to not misuse the word and unwittingly stigmatize persons with mental illness and substance use disorders. PMID- 25808448 TI - Formation of vitamin E emulsion stabilized by octenylsuccinic starch: factors affecting particle size and oil load. AB - Vitamin E (VE) emulsions were formed by adding VE acetate in an octenylsuccinic (OS) starch solution with distilled water and homogenizing with a microfluidizer at 20000 psi. The objective of this study was to investigate the effects of total concentration of starch and oil, ratio of oil to starch, pH value, and free OS content on emulsion properties. A method using HPLC was developed to analyze VE in emulsion, and the results were used to estimate the amount of surface VE oil. Lower total concentration of starch and oil and lower ratio of oil to starch resulted in more stable emulsions, whereas differences in the pH between 3 and 8 had little effect. Free OS content increased with greater particle size and decreased oil load. Increasing the number of passes reduced the initial particle size of the emulsion but increased free OS content. PMID- 25808449 TI - The CRISPR/Cas9 system inactivates latent HIV-1 proviral DNA. AB - BACKGROUND: Highly active antiretroviral therapy (HAART) has transformed HIV-1 infection from a deadly disease to a manageable chronic illness, albeit does not provide a cure. The recently developed genome editing system called CRISPR/Cas9 offers a new tool to inactivate the integrated latent HIV-1 DNA and may serve as a new avenue toward cure. FINDINGS: We tested 10 sites in HIV-1 DNA that can be targeted by CRISPR/Cas9. The engineered CRISPR/Cas9 system was introduced into the JLat10.6 cells that are latently infected by HIV-1. The sequencing results showed that each target site in HIV-1 DNA was efficiently mutated by CRISPR/Cas9 with the target site in the second exon of Rev (called T10) exhibiting the highest degree of mutation. As a result, HIV-1 gene expression and virus production were significantly diminished with T10 causing a 20-fold reduction. CONCLUSIONS: The CRISPR/Cas9 complex efficiently mutates and deactivates HIV-1 proviral DNA in latently infected Jurkat cells. Our results also revealed a highly efficient Cas9 target site within the second exon of Rev that represents a promising target to be further explored in the CRISPR/Cas9-based cure strategy. PMID- 25808450 TI - How can we increase physical activity and exercise among youth experiencing first episode psychosis? A systematic review of intervention variables. AB - AIMS: To review intervention variables and outcomes of studies designed to increase physical activity or exercise participation among people experiencing first-episode psychosis. METHODS: A systematic review of electronic databases was conducted from inception to November 2014. RESULTS: Eleven eligible studies describing 12 interventions were included (n = 351; 14-35 years) incorporating health coaching (n = 5), exercise prescriptions based on physiological parameters (e.g. heart rate) (n = 3), supervised, individually tailored programmes (n = 2), an Internet-delivered intervention and a yoga intervention. The majority of the interventions were delivered over 12 weeks (n = 6) and in community settings (n = 11). Five studies assessed aerobic capacity (VO2 max or VO2 peak) and three studies assessed self-reported physical activity levels. CONCLUSIONS: Considerable heterogeneity in the design, implementation and assessment of interventions was found. There is an urgent need to better understand how physical activity can be increased in line with the internationally endorsed HeaL (Healthy Active Lives) Declaration 5-year physical activity target. PMID- 25808446 TI - Brachypodium as an emerging model for cereal-pathogen interactions. AB - BACKGROUND: Cereal diseases cause tens of billions of dollars of losses annually and have devastating humanitarian consequences in the developing world. Increased understanding of the molecular basis of cereal host-pathogen interactions should facilitate development of novel resistance strategies. However, achieving this in most cereals can be challenging due to large and complex genomes, long generation times and large plant size, as well as quarantine and intellectual property issues that may constrain the development and use of community resources. Brachypodium distachyon (brachypodium) with its small, diploid and sequenced genome, short generation time, high transformability and rapidly expanding community resources is emerging as a tractable cereal model. SCOPE: Recent research reviewed here has demonstrated that brachypodium is either susceptible or partially susceptible to many of the major cereal pathogens. Thus, the study of brachypodium-pathogen interactions appears to hold great potential to improve understanding of cereal disease resistance, and to guide approaches to enhance this resistance. This paper reviews brachypodium experimental pathosystems for the study of fungal, bacterial and viral cereal pathogens; the current status of the use of brachypodium for functional analysis of cereal disease resistance; and comparative genomic approaches undertaken using brachypodium to assist characterization of cereal resistance genes. Additionally, it explores future prospects for brachypodium as a model to study cereal-pathogen interactions. CONCLUSIONS: The study of brachypodium-pathogen interactions appears to be a productive strategy for understanding mechanisms of disease resistance in cereal species. Knowledge obtained from this model interaction has strong potential to be exploited for crop improvement. PMID- 25808451 TI - Well-Dispersed and Size-Controlled Supported Metal Oxide Nanoparticles Derived from MOF Composites and Further Application in Catalysis. AB - Supported metal oxide nanoparticles are important in heterogeneous catalysis; however, the ability to tailor their size, structure, and dispersion remains a challenge. A strategy to achieve well-dispersed and size-controlled supported metal oxides through the manageable growth of a metal organic framework (Cu-BTC) on TiO2 followed by pyrolysis is described. PMID- 25808453 TI - Household air pollution and personal exposure risk of polycyclic aromatic hydrocarbons among rural residents in Shanxi, China. AB - Polycyclic aromatic hydrocarbons (PAHs) are a group of pollutants of widespread concerns. Gaseous and size-segregated particulate-phase PAHs were collected in indoor and outdoor air in rural households. Personal exposure was measured and compared to the ingestion exposure. The average concentrations of 28 parent PAHs and benzo(a)pyrene (BaP) were 9000 +/- 8390 and 131 +/- 236 ng/m(3) for kitchen, 2590 +/- 2270 and 43 +/- 95 ng/m(3) for living room, and 2800 +/- 3890 and 1.6 +/ 0.7 ng/m(3) for outdoor air, respectively. The mass percent of high molecular weight (HMW) compounds with 5-6 rings contributed 1.3% to total 28 parent PAHs. Relatively higher fractions of HMW PAHs were found in indoor air compared to outdoor air. Majorities of particle-bound PAHs were found in the finest PM0.25 , and the highest levels of fine PM0.25 -bound PAHs were in the kitchen using peat and wood as energy sources. The 24-h personal PAH exposure concentration was 2100 +/- 1300 ng/m(3) . Considering energies, exposures to those using wood were the highest. The PAH inhalation exposure comprised up to about 30% in total PAH exposure through food ingestion and inhalation, and the population attributable fraction (PAF) for lung cancer in the region was 0.85%. The risks for inhaled and ingested intakes of PAHs were 1.0 * 10(-5) and 1.1 * 10(-5) , respectively. PMID- 25808452 TI - Seeing through the dark: New insights into the immune regulatory functions of vitamin A. AB - The importance of vitamin A for host defense is undeniable and the study of its mechanisms is paramount. Of the estimated 250 million preschool children who are vitamin A-deficient (VAD), 10% will die from their increased susceptibility to infectious disease. Vitamin A supplementation was established in the 1980s as one of the most successful interventions in the developing world. Understanding how vitamin A controls immunity will help curb the mortality and morbidity associated with vitamin A deficiency and exploit the immune-enhancing capacity of vitamin A to heighten host resistance to infectious disease. The discoveries that retinoic acid (RA) imprints the homing of leukocytes to the gut and enhances the induction of regulatory T cells, highlighted a potential role for RA in mucosal tolerance. However, more recently emerging data tell of a more profound systemic impact of RA on leukocyte function and commitment. In animal models using genetic manipulation of RA signaling, we learned when and how RA controls T cell fate. Here, we review the role for RA as a critical checkpoint regulator in the differentiation of CD4(+) T cells within the immune system. PMID- 25808456 TI - Journal of clinical monitoring and computing 2014 end of year summary: near infrared spectroscopy (NIRS). PMID- 25808455 TI - Cardiac output monitoring in severe aortic stenosis: Which technologies are reliable? PMID- 25808454 TI - Influences of different vasopressors on stroke volume variation and pulse pressure variation. AB - Pulse pressure variation (PPV) and stroke volume variation (SVV) during mechanical ventilation have been shown to be effective parameters to predict preload responsiveness. Although induced hypertension decreases PPV and SVV, the influences of different vasopressors on PPV and SVV are unknown. 94 patients undergoing elective otologic surgery were randomly divided into three groups: Group P (patients were given phenylephrine), Group D (patients were given dopamine), Group E (patients were given ephedrine). When surgery was ongoing and the circulation state was stable, patients were given the vasopressor to increase the systolic arterial pressure (SAP) to the pre-calculated levels: low level, 10 % < DeltaSAP <= 20 %; medium level, 20 % < DeltaSAP <= 30 %; high level, 30 % < DeltaSAP <= 40 %. When invasive arterial pressure reached the target value, PPV, SVV and other parameters were recorded. Dopamine decreased the PPV and SVV more significantly than ephedrine, but less significantly than phenylephrine. The influences of phenylephrine, dopamine and ephedrine on SVV and PPV are different due to their different pharmacological mechanisms. PMID- 25808457 TI - Comparison of colorimetric and chemiluminescent enzyme-linked immunosorbent assay for the detection of endosulfan in food samples. AB - Pesticides have become part of food protection since their inception. Endosulfan, an organochlorine insecticide, has been used against insect pests such as whiteflies, aphids, red spiders and mites. Methods of immunochemical assays have been devised for the determination and analysis of pesticides and commonly used for the analysis of contaminants in food, water, soil and body fluids. Chicken IgY antibodies raised against endosulfan haptens were used for the detection of endosulfan. We have compared colorimetric (CO) and chemiluminescence (CL) enzyme linked immunosorbent assay (ELISA) techniques for the detection of endosulfan isomers in a food matrix. CL ELISA assay was found to be more sensitive than CO assay. The mean recovery was 81.2-95.6% for alpha- and beta-endosulfan-spiked food samples with 2.8-4.6% relative standard deviation. The detection of the endosulfan isomers was linear in the range 100 ug/mL-5 fg/mL, with a limit of detection at 100 ug/mL and 5 fg/mL for the CL ELISA method and 100 ug/mL and 1 ng/mL for the CO ELISA method respectively. These methods can be used for the rapid and reliable detection of organochlorine pesticide endosulfan. PMID- 25808459 TI - Seizure-Precipitating Factors in Relation to medical Recommendations: Especially Those Limiting Physical Activity. AB - Identification of factors precipitating epileptic seizures should always have practical implications and should always result in special recommendations given to patients. The purpose of our study is to analyze the relation between seizure triggering factors and restrictive recommendations involving limitation of physical activity in particular. The research group consisted of 407 children hospitalized due to seizures. Their precipitants were identified in 27.5% of the patients. The most common included infection/fever, stress, and flashing lights. Although sport was documented as a precipitant in only 3.4% of all children, 8.1% of the investigated group were recommended to limit physical activity. As some episodes of epileptic seizures are reported to be provoked by sport, multiple restrictions are imposed on children. In the light of the worldwide academic literature and the present study, the recommendation of limiting sports activity is no longer supported. PMID- 25808458 TI - Effect of climate change on vector-borne disease risk in the UK. AB - During the early part of the 21st century, an unprecedented change in the status of vector-borne disease in Europe has occurred. Invasive mosquitoes have become widely established across Europe, with subsequent transmission and outbreaks of dengue and chikungunya virus. Malaria has re-emerged in Greece, and West Nile virus has emerged throughout parts of eastern Europe. Tick-borne diseases, such as Lyme disease, continue to increase, or, in the case of tick-borne encephalitis and Crimean-Congo haemorrhagic fever viruses, have changed their geographical distribution. From a veterinary perspective, the emergence of Bluetongue and Schmallenberg viruses show that northern Europe is equally susceptible to transmission of vector-borne disease. These changes are in part due to increased globalisation, with intercontinental air travel and global shipping transport creating new opportunities for invasive vectors and pathogens. However, changes in vector distributions are being driven by climatic changes and changes in land use, infrastructure, and the environment. In this Review, we summarise the risks posed by vector-borne diseases in the present and the future from a UK perspective, and assess the likely effects of climate change and, where appropriate, climate-change adaptation strategies on vector-borne disease risk in the UK. Lessons from the outbreaks of West Nile virus in North America and chikungunya in the Caribbean emphasise the need to assess future vector-borne disease risks and prepare contingencies for future outbreaks. Ensuring that adaptation strategies for climate change do not inadvertently exacerbate risks should be a primary focus for decision makers. PMID- 25808461 TI - Has the Research Excellence Framework killed creativity? PMID- 25808460 TI - High butyric acid amounts induce oxidative stress, alter calcium homeostasis, and cause neurite retraction in nerve growth factor-treated PC12 cells. AB - Butyric acid (BA) is a common secondary metabolite by-product produced by oral pathogenic bacteria and is detected in high amounts in the gingival tissue of patients with periodontal disease. Previous works have demonstrated that BA can cause oxidative stress in various cell types; however, this was never explored using neuronal cells. Here, we exposed nerve growth factor (NGF)-treated PC1(2) cells to varying BA concentrations (0.5, 1.0, 5.0 mM). We measured total heme, H(2)O(2), catalase, and calcium levels through biochemical assays and visualized the neurite outgrowth after BA treatment. Similarly, we determined the effects of other common periodontal short-chain fatty acids (SCFAs) on neurite outgrowth for comparison. We found that high (1.0 and 5.0 mM) BA concentrations induced oxidative stress and altered calcium homeostasis, whereas low (0.5 mM) BA concentration had no significant effect. Moreover, compared to other SCFAs, we established that only BA was able to induce neurite retraction. PMID- 25808462 TI - Piloting yoga and assessing outcomes in a residential behavioural health unit. AB - This study examined if adolescents on a residential behavioural health unit would participate in a yoga intervention. Yoga has been used as a mind-body practice for more than 2000 years; however, studies are limited regarding its effects on adolescents with mental illness on an inpatient unit. Yoga was added, twice weekly, to the program schedule. Trait Emotional Intelligence Questionnaire Adolescent Short Form (TEIQue-ASF) scores were measured over 8 weeks. Additional measures included daily numbers of quiet times, time outs, and point card scores. Twenty-two adolescents completed the study. The TEIQue-ASF assessment was able to detect changes in total scores over 8 weeks. Increased yoga participation was related to higher values of the TEIQue-ASF subdomain of sociability, increase in weekly point card totals, a decrease in behavioural time outs, and a decrease in combined behavioural interventions at various time points throughout the programme. This study was relevant because it was conducted on an adolescent inpatient unit. It provides support that yoga, as part of a residential programme, is a feasible intervention for adolescents with mental illness. Changes in the various measures cannot be directly linked to yoga because of lack of a comparison group. Additional studies with a larger sample, and randomization, are needed to evaluate the potential benefits of yoga and to determine if changes to the TEIQue-ASF can be attributed to yoga or other behavioural-based interventions. Little is known about how yoga will impact behavioural health outcomes for adolescents with mental illness in an inpatient setting. This study examined if adolescents on a residential behavioural health unit would participate in a yoga intervention to address emotional regulation. A single cohort study design was used. Yoga was added to the programme schedule twice weekly. Trait Emotional Intelligence Questionnaire-Adolescent Short Form (TEIQue-ASF) scores and additional behavioural measures were tracked over 8 weeks. Adolescents participated in yoga, with a higher participation rate for girls compared with boys. The TEIQue-ASF assessment detected changes in total score over 8 weeks. Increased yoga participation was related to higher values of the TEIQue-ASF subdomain of sociability, increase in weekly point card totals, and a decrease in combined behavioural interventions at various time points throughout the programme. This study was relevant because it was conducted on an adolescent inpatient unit. Further studies are needed to determine if changes can be attributed to yoga or other behavioural-based interventions. If supported by further studies, yoga has the potential to be a complimentary therapy that can be integrated into the multidisciplinary treatment approach for mental health patients. PMID- 25808463 TI - Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 Signalling. AB - Vascular endothelial growth factor receptor-2 (VEGFR-2) and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signalling are important for tumor angiogenesis and metastasis. In this study, we identified (3 (2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol (LCB03-0110) as a potent angiogenesis inhibitor. LCB03-0110 inhibited VEGFR-2 and JAK/STAT3 signalling in primary cultured human endothelial cells and cancer cells. An in vitro kinase assay and molecular modelling revealed that LCB03-0110 inhibited VEGFR-2, c-SRC and TIE-2 kinase activity via preferential binding at the ATP binding site of their kinases. LCB03-0110 successfully occupied the hydrophobic pocket of VEGFR-2, c-SRC and TIE-2. LCB03-0110 also inhibited hypoxia-induced HIF/STAT3 and EGF- or angiopoietin-induced signalling cascades. In addition, LCB03-0110 inhibited VEGF-induced proliferation, viability, migration and capillary-like tube formation. LCB03-0110 also suppressed the sprouting of endothelial cells in the rat aorta and the formation of new blood vessels in the mouse Matrigel plug assay, but also suppressed pulmonary metastasis and tumor xenograft in mice. Our results suggest that LCB03-0110 is a potential candidate small molecule for blocking angiogenesis mediated by aberrant activation of VEGFR 2 and JAK/STAT3 signalling. PMID- 25808465 TI - Ultrasonographic appearance of normal and injured lateral patellar ligaments in the equine stifle. AB - REASONS FOR PERFORMING STUDY: Ultrasound is widely used in horses with stifle lameness, yet limited information is available regarding the appearance of normal and injured lateral patellar ligaments (LPL). OBJECTIVES: To map the normal ultrasonographic appearance of the LPL. To describe the clinical and ultrasonographic features of LPL injuries. STUDY DESIGN: Descriptive study of healthy horses and retrospective case series. METHODS: Twelve horses without stifle lameness underwent ultrasonographic examination of bilateral LPLs and ultrasonographic features were recorded. Eighteen horses with LPL injury were identified from 1999 to 2011. RESULTS: The normal LPL changes in appearance from origin to insertion. It shows ill-defined margins at the patella, becomes flattened and bilobed over the lateral trochlear ridge, is oval-triangular shaped with variable echogenicity and fibre pattern distal to the LTR, and becomes tapered with striations at the tibial insertion. LPL injury was identified in 18 horses of multiple breeds and uses. All injuries were acute, and 12 had wounds. Eleven horses were severely lame (grade 4-5/5). Ultrasonographic lesions were severe in 78% of cases. The mid to insertional portion of the LPL was most often affected. Radiography showed fractures of the tibial tuberosity (n = 6), patella (n = 4) and lateral trochlear ridge (n = 1). Fractures involved LPL attachments in 9 horses. Five were treated for osteomyelitis and one for synovial sepsis. Recheck ultrasound in 4 horses showed minimal to no change in the appearance of LPL injuries. Nine horses returned to riding, one continued as a broodmare, 2 were retired, one became a broodmare, 2 were lost to follow-up and 3 were subjected to euthanasia owing to concurrent injuries. CONCLUSION: Normal variations in shape, echogenicity and fibre pattern of the LPL are important considerations to prevent false positive diagnoses during ultrasonography. LPL injuries were often severe and associated with craniolateral stifle trauma. Prognosis varied from good to guarded in horses without additional severe injuries. PMID- 25808464 TI - Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics. AB - Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and also controls the levels of endogenous transcripts. Here we show that when human cells are treated with clinically used chemotherapeutic compounds, NMD activity declines partly as a result of the proteolytic production of a dominant-interfering form of the key NMD factor UPF1. Production of cleaved UPF1 functions to upregulate genes involved in the response to apoptotic stresses. The biological consequence is the promotion of cell death. Combined exposure of cells to a small-molecule inhibitor of NMD, NMDI-1, and the chemotherapeutic doxorubicin leads to enhanced cell death, while inhibiting UPF1 cleavage protects cells from doxorubicin challenge. We propose a model to explain why the expression levels of genes producing mRNAs of diverse structure that encode proteins of diverse function are under the purview of NMD. PMID- 25808468 TI - Bridging the reductive and the synthetic: some reflections on the clinical implications of synchronicity. AB - When Jung introduced the concepts of synchronicity and the psychoid unconscious, he expanded analytical psychology into decidedly uncanny territory. Despite the early interest shown by Freud, anomalous phenomena such as telepathy have become a taboo subject in psychoanalysis. Today, however, there is an increasing interest in thought transference and synchronicity, thus opening the way for a fruitful exchange between different psychoanalytical schools on their clinical implications. I propose to examine some of the ambiguities of Jung's thinking, to clarify how we define synchronicity, the relationship between synchronicities and parapsychological events, and their clinical significance. At the present moment, we are still unsure if such events should be considered as normal and a way of facilitating individuation, or as an indication of psychopathology in the patient or in the analyst, just as we are uncertain about the particular characteristics of the intersubjective field that can lead to synchronicities. Making use of the typology of mind-matter correlations presented by Atmanspacher and Fach, and the distinction they draw between acategorial and non-categorial states of mind, I will use two clinical vignettes to illustrate the different states of mind in analyst and analysand that can lead to synchronicities. In particular I will focus on the relationship between analytical reverie and synchronicity. PMID- 25808469 TI - Demons, voices and virtual realities in adolescence-an exploration of zeitgeist, culture and cultural complexes. AB - This paper contrasts two aspects of the adolescent's sojourn in the metaphorical landscape of the borderland. Either this 'dance with death' can prove life affirming and serve individuation as the intensity of being poised on the cusp between life and death negates numbing dissociation, or it can spiral into madness and suicide when the adolescent gets trapped in a mimetic hall of mirrors. This paper considers both the oscillations between mimesis and alterity, and how culture and cultural complexes may define expressions of distress. It concludes with the question of whether one can-and whether one should-make sense of the demons from the other side; and whether they are psychotic, pseudo psychotic or dissociative manifestations as they emerge during the course of therapy. PMID- 25808470 TI - Virtual reality and the psyche. Some psychoanalytic approaches to media addiction. AB - This paper explores the ramifications of excessive use of media on personality development, the development of symbolic and thinking functions and on psychic reality. In doing so, the questions of whether there are specific media objects possessing an intrinsic symbolic quality, and which attachments in the inner world of a child/adolescent can be mobilized or destroyed are discussed. By selecting specific material, computer gamers use their game to activate the field of a personal psychic reality. Hereby, they attempt some kind of self-healing. However, after leaving the game, conflicts and traumata re-enacted but unresolved in the game disappear from their temporary representation without generating any resonance in the gamer's psychic experience. Consequently, although states of mind and affects are activated in the computer game, their processing and integration fail; the game results in a compulsive repetition. The construction and consolidation of retrievable maturation and structural development, the representation of the unrepresentable, succeed in the context of the triangulating analytic relationship, initially through a jointly performed symbolic and narrative re-experience or the recreation of the game. Theoretical considerations are illustrated by means of clinical vignettes. PMID- 25808471 TI - Lost in (cyber)space: finding two adolescent boys hiding from their own humanity. AB - This article explores the intense psychological effects of compulsive Internet use, which has become increasingly common among adolescent boys and young men. Two cases are presented and discussed to illustrate some of the psychic distortions around thinking and feeling, as these occurred in the analysis of a mid-adolescent boy and of another patient in later adolescence. A kind of narcissistic omnipotence grounded in magical thinking appeared to take root in their minds, and it led to an avoidant pattern in relationships because of such strong wishes for both distance and control. A short review of the conceptual origins of magical thinking underscores its continued relevance because so many now engage with the Internet. In addition, Anzieu's idea of the 'skin ego' is applied to the clinical case material to provide a theoretical framework for the developmental challenges that can appear in adolescent boys who seek to use the Internet as a form of psychic container. Emerging problems that immersion in the Internet might bring into our practices, for example the depleting effects of massive projective identification, are considered and discussed, along with the obvious ways in which using the Internet can be beneficial for connecting with others, for creating new platforms of expression, and for education. PMID- 25808466 TI - Coevolution of radial glial cells and the cerebral cortex. AB - Radial glia cells play fundamental roles in the development of the cerebral cortex, acting both as the primary stem and progenitor cells, as well as the guides for neuronal migration and lamination. These critical functions of radial glia cells in cortical development have been discovered mostly during the last 15 years and, more recently, seminal studies have demonstrated the existence of a remarkable diversity of additional cortical progenitor cell types, including a variety of basal radial glia cells with key roles in cortical expansion and folding, both in ontogeny and phylogeny. In this review, we summarize the main cellular and molecular mechanisms known to be involved in cerebral cortex development in mouse, as the currently preferred animal model, and then compare these with known mechanisms in other vertebrates, both mammal and nonmammal, including human. This allows us to present a global picture of how radial glia cells and the cerebral cortex seem to have coevolved, from reptiles to primates, leading to the remarkable diversity of vertebrate cortical phenotypes. PMID- 25808472 TI - Inwardizing Rilke's dog of 'divine inseeing' into itself. AB - The article explores a text of the poet R.M. Rilke in the manner of Psychology as the Discipline of Interiority (PDI). PDI, developed mainly in the writings of Wolfgang Giegerich, refers to the 'speculative turn' within analytical psychology. The speculative turn involves an interpretative stance that strictly adheres to Jung's seminal insight into psychology's lack of an empirically objective, Archimedean vantage-point outside of or beyond the psyche. The paper aims to demonstrate that, for all its beauty, the account of interiority that is celebrated in the passage from Rilke is self-contradictory. This is due to its being naively conceived as the undialectical opposite of an external viewpoint that it is unable to overcome. Whereas Rilke merely imagines interiority by means of the visual image of his getting inside a dog as one passes by, the interpretative approach taken in this article thinks interiority by reflecting Rilke's text into itself in the speculative manner that is provided for and required by Jung's insight into psychology's lack of an Archimedean vantage point. If we interpret the text in this way, an understanding of interiority that is truly in accord with its concept is opened up and a main aspect of psychology as the discipline of interiority is performatively demonstrated. PMID- 25808473 TI - The bark and bite of the logically negative soul: further reflections on Rilke's dog of 'divine inseeing'. AB - Following on the approach taken in the previous essay, this article critically reflects Rilke's account of his having imaginatively entered into the interior of a passing dog more deeply into itself. In doing so, it illustrates the concepts of logical negativity and absolute negative interiorization, which are core concepts of the speculative turn within analytical psychology that is known by the name 'psychology as the discipline of interiority'. Just as analytical psychology often thinks in terms of the alchemical figure of 'the stone that is not a stone', so in this article the bark and bite of a logically negative 'dog that is not a dog' is grappled with. Further insights into what is meant by the author's phrase, 'the Archimedean-less interiority of the soul', are imparted. PMID- 25808481 TI - Donor-acceptor small molecules for organic photovoltaics: single-atom substitution (Se or S). AB - Two isostructural low-band-gap small molecules that contain a one-atom substitution, S for Se, were designed and synthesized. The molecule 7,7'-[4,8 bis(2-ethylhexyloxy)benzo[1,2-b:4,5-b']dithiophene]bis[6-fluoro-4-(5'-hexyl-2,2' bithiophen-5-yl)benzo[c][1,2,5]thiadiazole] (1) and its selenium analogue 7,7' [4,8-bis(2-ethylhexyloxy)benzo[1,2-b:4,5-b']dithiophene]bis[6-fluoro-4-(5'-hexyl 2,2'-bithiophen-5-yl)benzo[c][1,2,5]selenodiazole] (2) are both based on the electron-rich central unit benzo[1,2-b:4,5-b']dithiophene. The aim of this work was to investigate the effect of one-atom substitution on the optoelectronic properties and photovoltaic performance of devices. Theoretical calculations revealed that this one-atom variation has a small but measurable effect on the energy of frontier molecular orbital (HOMO and LUMO), which, in turn, can affect the absorption profile of the molecules, both neat and when mixed in a bulk heterojunction (BHJ) with PC71BM. The Se-containing variant 2 led to higher efficiencies [highest power conversion efficiency (PCE) of 2.6%] in a standard organic photovoltaic architecture, when combined with PC71BM after a brief thermal annealing, than the S-containing molecule 1 (highest PCE of 1.0%). Studies of the resulting morphologies of BHJs based on 1 and 2 showed that one atom substitution could engender important differences in the solubilities, which then influenced the crystal orientations of the small molecules within this thin layer. Brief thermal annealing resulted in rotation of the crystalline grains of both molecules to more energetically favorable configurations. PMID- 25808482 TI - Bone union and remodelling of the non-ossified segment in thoracic ossification of the posterior longitudinal ligament after posterior decompression and fusion surgery. AB - PURPOSE: The motion at the non-ossified segment of the ossification of the posterior longitudinal ligament (OPLL) is thought to be highly correlated to aggravation of symptoms of myelopathy. The rationale for posterior decompression with instrumented fusion (PDF) surgery is to limit the motion of the non-ossified segment of OPLL by stabilization. The purpose of the present study was to elucidate the course of bone union and remodelling of the non-ossified segment of thoracic OPLL (T-OPLL) after PDF surgery. METHODS: A total of 29 patients who underwent PDF surgery for T-OPLL were included in this study. We measured the thickness of the OPLLs by determining the thickest part of the OPLL in the sagittal multi-planer reconstruction CT images pre- and post-operatively. Five experienced spine surgeons independently performed CT measurements of OPLL thickness twice. Japanese Orthopaedic Association score for thoracic myelopathy was measured as clinical outcome measure. RESULTS: Non-ossified segment of OPLLs fused in 24 out of 29 (82.8 %) patients. The average thickness of the OPLL at its thickest segment was 8.0 mm and decreased to 7.3 mm at final follow-up. The decrease in ossification thickness was significantly larger in the patients who showed fusion of non-ossified segments of OPLL compared with that in the patients did not show fusion. There was no significant correlation between the clinical outcome and the decrease in thickness of the OPLLs. CONCLUSION: The results of this study showed that remodelling of the OPLLs, following fusion of non-ossified segment of OPLLs, resulted in a decreased OPLL thickness, with potential for a reduction of spinal cord compression. PMID- 25808484 TI - Lateral access surgery: a decade of innovation. PMID- 25808485 TI - Dark-violaceous lesions on the dorsa of both hands. PMID- 25808483 TI - Evaluation of TLICS for thoracolumbar fractures. AB - PURPOSE: Thoracolumbar Injury Classification and Severity Score (TILCS), facilitates the communication between physicians, and guides to treatment decision with better outcome. A composite injury severity score is calculated from these characteristics stratifying patients into operative and non-operative treatment. Aim of this study is to identify the effectiveness of TLICS scoring for thoracolumbar vertebral fractures without neurological deficits and the efficacy of conservative treatment in patients with TILCS 4. METHODS: 58 patients with thoracolumbar fracture were included. 38 patients with TLICS 1-3 (group A) and 20 patients with TLICS 4 (group B) treated conservatively, were evaluated with traditional two-plain radiographic examination, CT-scan and MRI. The pain and functional scales were used in the clinical evaluation. Local kyphosis angle, sagittal index and height loss percentage were measured in the radiologic evaluation. Mean follow-up period was 28 months. Post-fracture and follow-up values were compared. Functional scores and clinical outcomes of the groups were compared. RESULTS: The mean pain (1 = worse pain, reverse-VAS) and functional scores at the final follow-up were 8.2 and 86 points, respectively (group A), 6.4 and 76 points (group B). The mean period for returning to work was 3.2 (group A) and 3.8 months (group B). Comparing the two groups did not demonstrate any statistical difference of their clinical and functional outcomes. CONCLUSION: The study's results demonstrate that conservative treatment for TLICS 4 thoracolumbar fractures can be safely applied. The conservative treatment of cases scoring TLICS 4 is equally effective to those scoring <=3. PMID- 25808486 TI - Perioperative use of iloprost in cardiac surgery patients diagnosed with heparin induced thrombocytopenia-reactive antibodies or with true HIT (HIT-reactive antibodies plus thrombocytopenia): An 11-year experience. AB - Thrombocytopenia and thromboembolism(s) may develop in heparin immune-mediated thrombocytopenia (HIT) patients after reexposure to heparin. At the Onassis Cardiac Surgery Center, 530 out of 17,000 patients requiring heart surgery over an 11-year period underwent preoperative HIT assessment by ELISA and a three point heparin-induced platelet aggregation assay (HIPAG). The screening identified 110 patients with HIT-reactive antibodies, out of which 46 were also thrombocytopenic (true HIT). Cardiac surgery was performed in HIT-positive patients under heparin anticoagulation and iloprost infusion. A control group of 118 HIT-negative patients received heparin but no iloprost during surgery. For the first 20 patients, the dose of iloprost diminishing the HIPAG test to <=5% was determined prior to surgery by in vitro titration using the patients' own plasma and donor platelets. In parallel, the iloprost "target dose" was also established for each patient intraoperatively, but before heparin administration. Iloprost was infused initially at 3 ng/kg/mL and further adjusted intraoperatively, until ex vivo aggregation reached <=5%. As a close correlation was observed between the "target dose" identified before surgery and that established intraoperatively, the remaining 90 patients were administered iloprost starting at the presurgery identified "target dose." This process significantly reduced the number of intraoperative HIPAG reassessments needed to determine the iloprost target dose, and reduced surgical time, while maintaining similar primary clinical outcomes to controls. Therefore, infusion of iloprost throughout surgery, under continuous titration, allows cardiac surgery to be undertaken safely using heparin, while avoiding life-threatening iloprost-induced hypotension in patients diagnosed with HIT-reactive antibodies or true HIT. PMID- 25808487 TI - Absence of the ileocolic artery: Microsurgical implications in reconstruction of the esophagus with the free ileocolon flap. PMID- 25808489 TI - A short splicing isoform of afadin suppresses the cortical axon branching in a dominant-negative manner. AB - Precise wiring patterns of axons are among the remarkable features of neuronal circuit formation, and establishment of the proper neuronal network requires control of outgrowth, branching, and guidance of axons. R-Ras is a Ras-family small GTPase that has essential roles in multiple phases of axonal development. We recently identified afadin, an F-actin-binding protein, as an effector of R Ras mediating axon branching through F-actin reorganization. Afadin comprises two isoforms--l-afadin, having the F-actin-binding domain, and s-afadin, lacking the F-actin-binding domain. Compared with l-afadin, s-afadin, the short splicing variant of l-afadin, contains RA domains but lacks the F-actin-binding domain. Neurons express both isoforms; however, the function of s-afadin in brain remains unknown. Here we identify s-afadin as an endogenous inhibitor of cortical axon branching. In contrast to the abundant and constant expression of l-afadin throughout neuronal development, the expression of s-afadin is relatively low when cortical axons branch actively. Ectopic expression and knockdown of s-afadin suppress and promote branching, respectively. s-Afadin blocks the R-Ras-mediated membrane translocation of l-afadin and axon branching by inhibiting the binding of l-afadin to R-Ras. Thus s-afadin acts as a dominant-negative isoform in R-Ras afadin-regulated axon branching. PMID- 25808488 TI - The FHA domain determines Drosophila Chk2/Mnk localization to key mitotic structures and is essential for early embryonic DNA damage responses. AB - DNA damage responses, including mitotic centrosome inactivation, cell-cycle delay in mitosis, and nuclear dropping from embryo cortex, maintain genome integrity in syncytial Drosophila embryos. A conserved signaling kinase, Chk2, known as Mnk/Loki, is essential for the responses. Here we demonstrate that functional EGFP-Mnk expressed from a transgene localizes to the nucleus, centrosomes, interkinetochore/centromere region, midbody, and pseudocleavage furrows without DNA damage and in addition forms numerous foci/aggregates on mitotic chromosomes upon DNA damage. We expressed EGFP-tagged Mnk deletion or point mutation variants and investigated domain functions of Mnk in vivo. A triple mutation in the phosphopeptide-binding site of the forkhead-associated (FHA) domain disrupted normal Mnk localization except to the nucleus. The mutation also disrupted Mnk foci formation on chromosomes upon DNA damage. FHA mutations and deletion of the SQ/TQ-cluster domain (SCD) abolished Mnk transphosphorylations and autophosphorylations, indicative of kinase activation after DNA damage. A potent NLS was found at the C-terminus, which is required for normal Mnk function. We propose that the FHA domain in Mnk plays essential dual functions in mediating embryonic DNA damage responses by means of its phosphopeptide-binding ability: activating Mnk in the nucleus upon DNA damage and recruiting Mnk to multiple subcellular structures independently of DNA damage. PMID- 25808490 TI - Preventing farnesylation of the dynein adaptor Spindly contributes to the mitotic defects caused by farnesyltransferase inhibitors. AB - The clinical interest in farnesyltransferase inhibitors (FTIs) makes it important to understand how these compounds affect cellular processes involving farnesylated proteins. Mitotic abnormalities observed after treatment with FTIs have so far been attributed to defects in the farnesylation of the outer kinetochore proteins CENP-E and CENP-F, which are involved in chromosome congression and spindle assembly checkpoint signaling. Here we identify the cytoplasmic dynein adaptor Spindly as an additional component of the outer kinetochore that is modified by farnesyltransferase (FTase). We show that farnesylation of Spindly is essential for its localization, and thus for the proper localization of dynein and its cofactor dynactin, to prometaphase kinetochores and that Spindly kinetochore recruitment is more severely affected by FTase inhibition than kinetochore recruitment of CENP-E and CENP-F. Molecular replacement experiments show that both Spindly and CENP-E farnesylation are required for efficient chromosome congression. The identification of Spindly as a new mitotic substrate of FTase provides insight into the causes of the mitotic phenotypes observed with FTase inhibitors. PMID- 25808492 TI - Multisite phosphorylation of the NDC80 complex gradually tunes its microtubule binding affinity. AB - Microtubule (MT) attachment to kinetochores is vitally important for cell division, but how these interactions are controlled by phosphorylation is not well known. We used quantitative approaches in vitro combined with molecular dynamics simulations to examine phosphoregulation of the NDC80 complex, a core kinetochore component. We show that the outputs from multiple phosphorylation events on the unstructured tail of its Hec1 subunit are additively integrated to elicit gradual tuning of NDC80-MT binding both in vitro and in silico. Conformational plasticity of the Hec1 tail enables it to serve as a phosphorylation-controlled rheostat, providing a new paradigm for regulating the affinity of MT binders. We also show that cooperativity of NDC80 interactions is weak and is unaffected by NDC80 phosphorylation. This in vitro finding strongly supports our model that independent molecular binding events to MTs by individual NDC80 complexes, rather than their structured oligomers, regulate the dynamics and stability of kinetochore-MT attachments in dividing cells. PMID- 25808491 TI - Integrin alpha3beta1 regulates kidney collecting duct development via TRAF6 dependent K63-linked polyubiquitination of Akt. AB - The collecting system of the kidney develops from the ureteric bud (UB), which undergoes branching morphogenesis, a process regulated by multiple factors, including integrin-extracellular matrix interactions. The laminin (LM)-binding integrin alpha3beta1 is crucial for this developmental program; however, the LM types and LM/integrin alpha3beta1-dependent signaling pathways are poorly defined. We show that alpha3 chain-containing LMs promote normal UB branching morphogenesis and that LM-332 is a better substrate than LM-511 for stimulating integrin alpha3beta1-dependent collecting duct cell functions. We demonstrate that integrin alpha3beta1-mediated cell adhesion to LM-332 modulates Akt activation in the developing collecting system and that Akt activation is PI3K independent but requires decreased PTEN activity and K63-linked polyubiquitination. We identified the ubiquitin-modifying enzyme TRAF6 as an interactor with the integrin beta1 subunit and regulator of integrin alpha3beta1 dependent Akt activation. Finally, we established that the developmental defects of TRAF6- and integrin alpha3-null mouse kidneys are similar. Thus K63-linked polyubiquitination plays a previously unrecognized role in integrin alpha3beta1 dependent cell signaling required for UB development and may represent a novel mechanism whereby integrins regulate signaling pathways. PMID- 25808493 TI - Prostaglandins regulate nuclear localization of Fascin and its function in nucleolar architecture. AB - Fascin, a highly conserved actin-bundling protein, localizes and functions at new cellular sites in both Drosophila and multiple mammalian cell types. During Drosophila follicle development, in addition to being cytoplasmic, Fascin is in the nuclei of the germline-derived nurse cells during stages 10B-12 (S10B-12) and at the nuclear periphery during stage 13 (S13). This localization is specific to Fascin, as other actin-binding proteins, Villin and Profilin, do not exhibit the same subcellular distribution. In addition, localization of fascin1 to the nucleus and nuclear periphery is observed in multiple mammalian cell types. Thus the regulation and function of Fascin at these new cellular locations is likely to be highly conserved. In Drosophila, loss of prostaglandin signaling causes a global reduction in nuclear Fascin and a failure to relocalize to the nuclear periphery. Alterations in nuclear Fascin levels result in defects in nucleolar morphology in both Drosophila follicles and cultured mammalian cells, suggesting that nuclear Fascin plays an important role in nucleolar architecture. Given the numerous roles of Fascin in development and disease, including cancer, our novel finding that Fascin has functions within the nucleus sheds new light on the potential roles of Fascin in these contexts. PMID- 25808496 TI - Significance of R1 resection margin in colon cancer resections in the modern era. AB - AIM: Circumferential resection margin involvement (R1) in rectal cancer is a predictive factor for poor prognosis. The aim of this study was to confirm the prognostic significance of R1 in colon cancer resection and to establish whether the introduction of laparoscopic colorectal surgery influenced this. METHOD: Prospectively collected data on a patient pathway data manager for sequential patients with colon cancer treated at our specialist unit from January 2005 to December 2010 were analysed. There were 1110 colonic resections (elective 865; emergency 245). A circumferential resection margin involvement of < 1 mm was considered positive. RESULTS: The total R1 rate was 13.3% (elective 10.4%; emergency 23.6%; P < 0.001). Other statistically significant risk factors for an R1 resection included tumour perforation (P < 0.001), poorly differentiated carcinoma (P < 0.001), T4 tumour (P < 0.001), vascular invasion (P < 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001) and palliative resection (P < 0.001). Over half of the elective resections were undertaken laparoscopically (486/865; 56.2%). When compared with elective open resection (379/865; 43.8%), the R1 rate was similar (P = 0.491) with similar disease-free survival (DFS) and overall survival (OS). The overall relapse rate was 18.9% in R0 and 55.5% in R1 resections (P < 0.001). Kaplan-Meier survival analysis showed significant improvements in DFS and OS in R0 over R1 patients. CONCLUSION: The R1 margin in colon cancer resection is an important marker for advanced disease and a prognostic factor for DFS and OS. The introduction of laparoscopic surgery has not influenced the outcome in our unit despite a complex case mix. PMID- 25808494 TI - Expression, sorting, and segregation of Golgi proteins during germ cell differentiation in the testis. AB - The molecular basis of changes in structure, cellular location, and function of the Golgi apparatus during male germ cell differentiation is unknown. To deduce cognate Golgi proteins, we isolated germ cell Golgi fractions, and 1318 proteins were characterized, with 20 localized in situ. The most abundant protein, GL54D of unknown function, is characterized as a germ cell-specific Golgi-localized type II integral membrane glycoprotein. TM9SF3, also of unknown function, was revealed to be a universal Golgi marker for both somatic and germ cells. During acrosome formation, several Golgi proteins (GBF1, GPP34, GRASP55) localize to both the acrosome and Golgi, while GL54D, TM9SF3, and the Golgi trafficking protein TMED7/p27 are segregated from the acrosome. After acrosome formation, GL54D, TM9SF3, TMED4/p25, and TMED7/p27 continue to mark Golgi identity as it migrates away from the acrosome, while the others (GBF1, GPP34, GRASP55) remain in the acrosome and are progressively lost in later steps of differentiation. Cytoplasmic HSP70.2 and the endoplasmic reticulum luminal protein-folding enzyme PDILT are also Golgi recruited but only during acrosome formation. This resource identifies abundant Golgi proteins that are expressed differentially during mitosis, meiosis, and postacrosome Golgi migration, including the last step of differentiation. PMID- 25808497 TI - Morphological analysis of the effects of intraoperative transrectal compression of the prostate during high-intensity focused ultrasound for localized prostate cancer. AB - OBJECTIVES: To evaluate the effects of transrectal compression of the prostate for intra-operative prostatic swelling and intraprostatic point shift during high intensity focused ultrasound treatment of localized prostate cancer. METHODS: Patients treated with whole-gland high-intensity focused ultrasound as primary monotherapy for localized prostate cancer were enrolled in the study. Using the standard and compression method, the volumes of degassed water in the balloon covering the high-intensity focused ultrasound probe were 50 mL and 80-160 mL, respectively. To identify prostatic swelling and shift during high-intensity focused ultrasound and the volume occupied by the non-enhanced area, three dimensional prostate models were reconstructed using ultrasound and contrast enhanced magnetic resonance imaging. RESULTS: In comparison with the standard (n = 40) and compression (n = 48) methods, intraoperative increase in the prostate volume (21% vs 5.3%; P = 0.044), intraprostatic point shift (4 mm vs 2 mm, P = 0.040 in the transition zone; 3 mm vs 0 mm; P = 0.001 in the peripheral zone) and the volume occupied by the non-enhanced area (89% vs 96%; P = 0.001) were significantly suppressed. The biochemical disease-free survival rate in patients treated using the compression method was significantly improved relative to the standard method (92.6% vs 76.5%; P = 0.038). Regarding complications, there was no significant difference in the rate of urethral stricture (P = 0.9), urinary tract infection (P = 0.9), incontinence (P = 0.3), erectile dysfunction (P = 0.9) or recto-urethral fistula between the patients treated using the standard and compression methods. CONCLUSIONS: Intraoperative transrectal compression suppresses intraoperative increase in the prostate volume and intraprostatic point shift during high-intensity focused ultrasound, having the potential to achieve precise whole-gland and lesion-targeted focal therapy. PMID- 25808495 TI - Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal. AB - The mammalian intestinal epithelium is one of the most rapidly self-renewing tissues in the body, and its integrity is preserved through strict regulation. The RNA-binding protein (RBP) ELAV-like family member 1 (CELF1), also referred to as CUG-binding protein 1 (CUGBP1), regulates the stability and translation of target mRNAs and is implicated in many aspects of cellular physiology. We show that CELF1 competes with the RBP HuR to modulate MYC translation and regulates intestinal epithelial homeostasis. Growth inhibition of the small intestinal mucosa by fasting in mice was associated with increased CELF1/Myc mRNA association and decreased MYC expression. At the molecular level, CELF1 was found to bind the 3'-untranslated region (UTR) of Myc mRNA and repressed MYC translation without affecting total Myc mRNA levels. HuR interacted with the same Myc 3'-UTR element, and increasing the levels of HuR decreased CELF1 binding to Myc mRNA. In contrast, increasing the concentrations of CELF1 inhibited formation of the [HuR/Myc mRNA] complex. Depletion of cellular polyamines also increased CELF1 and enhanced CELF1 association with Myc mRNA, thus suppressing MYC translation. Moreover, ectopic CELF1 overexpression caused G1-phase growth arrest, whereas CELF1 silencing promoted cell proliferation. These results indicate that CELF1 represses MYC translation by decreasing Myc mRNA association with HuR and provide new insight into the molecular functions of RBPs in the regulation of intestinal mucosal growth. PMID- 25808498 TI - Demonstration of uniformity of calcium absorption in adult dogs and cats. AB - A meta-analysis was conducted to understand quantitative aspects of calcium (Ca) and phosphorus (P) absorption in adult dogs and cats. 34 studies in dogs and 14 studies in cats met the criteria for inclusion in the meta-analysis. Intake and faecal excretion values of Ca and P were subjected to a modified Lucas test and subsequent regression analyses. According to the current scientific consensus, Ca true digestibility (absorption) should increase at low Ca intake and decrease at high Ca intake. If true, this should result in a nonlinear relationship between the percentage of Ca excreted and dietary Ca intake. The present meta-analysis showed a highly significant linear relationship (p < 0.0001) between Ca intake and Ca excretion suggesting a lack of systematic quantitative adaptation in true Ca digestibility. This finding suggests either that the time period covered by standard digestion trials is too short to induce adaptation mechanisms or that dogs and cats at maintenance will not efficiently alter quantitative Ca absorption percentage according to the amount ingested. If the latter is true, a dietary Ca supply differing greatly from the recommended dietary intake might impair the health of cats and dogs when fed long term. The data plots for P intake and faecal excretion were less uniform suggesting other factors not just dietary intake influence faecal P excretion. In adult cats, the dietary Ca:P ratio strongly influenced the true digestibility of P, whereas this effect was less marked in adult dogs. Faecal P excretion was significantly correlated to faecal Ca excretion in both species (p < 0.0001), and surprisingly, the level of P intake did not appear to be an important determinant of true digestibility of P. PMID- 25808500 TI - Pathophysiology of neuropsychiatric disorders: moving forward. PMID- 25808499 TI - Acquired ataxias: the clinical spectrum, diagnosis and management. AB - Acquired ataxias represent a large group of disorders defined by the common clinical feature of ataxia and the absence of a clear genetic basis for it. Based on the aetiology, the group can be subdivided into autoimmune, toxic, infectious and vitamin deficiency causes. Cerebellar ataxia may occur as an isolated syndrome in this spectrum of disorders but is often accompanied by additional neurological manifestations. Clinical work-up is challenging and mainly includes biochemical analyses, whereas imaging is of minor significance. Diagnosis is essential as many of these disorders represent potential treatable conditions and early therapy may prevent progressive cerebellar ataxia. The clinical findings, the implications for diagnosis and management of this heterogeneous group of disorders are discussed in this review. PMID- 25808501 TI - Dalfampridine in hereditary spastic paraplegia: a prospective, open study. AB - Our aim was to support the use of dalfampridine as a treatment for patients affected with hereditary spastic paraplegia (HSP). We performed a prospective, uncontrolled, proof of concept, open trial. We included 12 HSP patients defining the total group (TG) who received dalfampridine 10 mg twice daily for 2 weeks. Efficacy assessment was based on walking ability improvement. The Timed-25-Foot Walk Test, the Spastic Paraplegia Rating Scale (SPRS), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) were performed before and after treatment. Safety assessment was based on adverse events occurrence. A significant improvement in SPRS (p = 0.0195) and MSWS-12 (p = 0.0429) was noted after treatment in the TG. No serious adverse events were noted. This interventional study provides encouraging results supporting the use of dalfampridine in HSP. PMID- 25808502 TI - Redefining phenotypes associated with mitochondrial DNA single deletion. AB - Progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and "KSS spectrum" (a category of which classic KSS represents the most severe extreme). The criteria for "KSS spectrum" include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials. PMID- 25808504 TI - The influence of previous infections and antichlamydia pneumoniae seropositivity on functional outcome in ischemic stroke patients: results from the IN2 study. AB - Although a growing attention is being paid to acute ischemic stroke patients, the correlation between clinical outcome and infectious events in this population has been poorly investigated. 749 ischemic stroke (mean age 71 years old, males 56%) patients were enrolled in this prospective case-control study by 11 Italian Stroke Units. Demographic data, vascular risk factors, previous infections and post-stroke infections (PSIs) were recorded. Blood samples were collected and the enzyme-linked immunoassay was chosen to measure Chlamydia pneumoniae IgG and IgA plasma antibodies (antibody titers were classified with specific cut-off levels: IgA > 1:16 and IgG > 1:64). Early poor outcome was defined as mRS score >2 at discharge, while poor outcome at 6-month follow-up. Univariate and multivariate analyses were performed. Median NIHSS was 7, IgA and IgG antichlamydia pneumoniae seropositivities were observed in 308 (37.1%) and 207 (23.6%) patients, respectively. Multivariate analyses showed significant correlations between PSIs and NIHSS (RR: 1.06; 95% CI 1.02-1.09; p < 0.001) and PSIs and IgA antichlamydia pneumoniae seropositivity (RR: 3.84; 95% CI 2.53-5.84; p < 0.001). Significant disability was associated with baseline NIHSS (RR: 1.32; 95% CI 1.16-1.50; p < 0.001), IgA (RR: 2.67; 95% CI 1.06-6.70; p = 0.035) and IgG antichlamydia (RR: 5.75; 95% CI 1.83-18.03; p = 0.003) seropositivity and atrial fibrillation (RR: 2.58; 95% CI 1.81-3.67; p < 0.001). While previous infections were not associated with functional outcome, antichlamydia antibodies play a negative role in ischemic stroke patients. Preventive strategies may reduce the stroke burden and improve the clinical outcome. PMID- 25808505 TI - Vestibulocochlear nerve infarction documented with diffusion-weighted MRI. PMID- 25808503 TI - Recent imaging advances in neurology. AB - Over the recent years, the application of neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) has considerably advanced the understanding of complex neurological disorders. PET is a powerful molecular imaging tool, which investigates the distribution and binding of radiochemicals attached to biologically relevant molecules; as such, this technique is able to give information on biochemistry and metabolism of the brain in health and disease. MRI uses high intensity magnetic fields and radiofrequency pulses to provide structural and functional information on tissues and organs in intact or diseased individuals, including the evaluation of white matter integrity, grey matter thickness and brain perfusion. The aim of this article is to review the most recent advances in neuroimaging research in common neurological disorders such as movement disorders, dementia, epilepsy, traumatic brain injury and multiple sclerosis, and to evaluate their contribution in the diagnosis and management of patients. PMID- 25808506 TI - Western immunoblotting as a new tool for investigating direct antiglobulin test negative autoimmune hemolytic anemias. AB - BACKGROUND: Direct antiglobulin test-negative (DAT(-)) autoimmune hemolytic anemia, characterized by hemolysis without detectable immunoglobulin or complement on patient red blood cells (RBCs), poses a diagnostic challenge. To select therapy, classification of the hemolysis as immune- or non-immune-mediated is important. We developed a method using Western immunoblot (WB) to classify DAT(-) patients by measuring and comparing levels of RBC immunoglobulin (Ig)G to normal donors. STUDY DESIGN AND METHODS: RBC samples from 42 normal donors were made into ghosts and analyzed by WB and densitometry to establish a normal mean relative quantity of IgG (RQIgG) on the RBCs. RQIgG on eight DAT(-) and eluate negative patients with hemolytic anemia was determined and compared to RQIgG on normal RBCs. RESULTS: RQIgG of 42 normal donors indicated a calculated mean +/- SD of 0.0016 +/- 0.0015 and we used a cutoff of 0.0047, the mean + 2SD. This was compared with a receiver operating curve cutoff of 0.0041 with 100% sensitivity and 93% specificity. Of the eight patients tested, three were classified as non immune-mediated (one had pyruvate kinase deficiency) and five as immune-mediated. Two of the patients in the latter group underwent splenectomy, followed by remission. CONCLUSION: WB analysis is more sensitive than conventional test tube DAT or elution analysis. Our assay confirms: 1) previous studies showing normal RBCs are sensitized with IgG, perhaps due to natural autoantibody to senescence; 2) that some normal RBCs have increased levels of IgG without signs of disease; and 3) that WB distinguishes between non-immune- and immune-mediated hemolytic anemia in DAT(-) patients and may be useful for clinical diagnosis. PMID- 25808507 TI - Development and validation of a liquid chromatography with tandem mass spectrometry method for the quantification of vitisin B in rat plasma and urine. AB - A new, rapid, and sensitive liquid chromatography with tandem mass spectrometry method was developed for the determination of vitisin B and validated in rat plasma and urine using carbamazepine as an internal standard. The plasma (0.05 mL) or urine (0.2 mL) samples were extracted by liquid-liquid extraction with ethyl acetate and separated on an Eclipse Plus C18 column (100 * 4.6 mm, 3.5 MUm) with a mobile phase consisting of acetonitrile and 0.1% formic acid water (60:40, v/v) at a flow rate of 0.7 mL/min. Detection and quantification were performed by mass spectrometry in selected reaction-monitoring mode with positive electrospray ionization. The calibration curves were recovered over the concentration ranges of 10-5000 ng/mL (correlation coefficients, r>=0.9833) in plasma and 5-2500 ng/mL (r>=0.9977) in urine, respectively. All validation data, including the specificity, precision, accuracy, recovery, and stability, conformed to the acceptance requirements. No matrix effects were observed. The developed method was successfully applied to pharmacokinetic studies of vitisin B following intravenous administration of 0.5 and 1 mg/kg and intraperitoneal injection of 5, 10, and 25 mg/kg to rats. This is the first report on the pharmacokinetic properties of vitisin B. The results provide a meaningful basis to evaluate preclinical or clinical applications of vitisin B. PMID- 25808509 TI - Association of CYP450 single nucleotide polymorphisms with the efficacy of epidural ropivacaine during mastectomy. AB - BACKGROUND: Ropivacaine is frequently used for local anesthesia in the clinic and is metabolized by cytochrome P450 (CYP450) in the liver. CYP450 polymorphisms may alter the therapeutic efficacy of drugs in patients. In this study, we selected six CYP450 polymorphisms from the dbSNP and HapMap databases, using a combination of functional analysis and Tag SNP strategies and examined these polymorphisms for association with the efficacy of epidural ropivacaine in patients during mastectomy. METHODS: A total of 256 patients with breast cancer received thoracic epidural anesthesia with ropivacaine for elective mastectomy with axillary lymph node clearance. Blood samples from patients were genotyped using the SNaPshot method. RESULTS: We found that patients with rs11636419 AG and GG genotypes required lower doses of epidural ropivacaine than patients with the AA genotype (corrected P = 0.024 and P < 0.001, respectively). Similarly, patients with rs17861162 CG and GG genotypes required lower doses of epidural ropivacaine than those with the CC genotype (corrected P = 0.018 and P < 0.001, respectively). There was no statistically significant association between the other four single nucleotide polymorphisms (SNPs) and total or mean ropivacaine dose, the onset of ropivacaine, or the initial dose of lidocaine. CONCLUSIONS: Our present data demonstrate that CYP1A2 SNPs rs11636419 and rs17861162 alter the sensitivity of epidural ropivacaine in patients undergoing breast cancer surgery. As such, detection of these two CYP1A2 SNPs may aid in the development of effective personalized treatments for breast cancer patients. PMID- 25808508 TI - A novel method for the purification of inositol phosphates from biological samples reveals that no phytate is present in human plasma or urine. AB - Inositol phosphates are a large and diverse family of signalling molecules. While genetic studies have discovered important functions for them, the biochemistry behind these roles is often not fully characterized. A key obstacle in inositol phosphate research in mammalian cells has been the lack of straightforward techniques for their purification and analysis. Here we describe the ability of titanium dioxide (TiO2) beads to bind inositol phosphates. This discovery allowed the development of a new purification protocol that, coupled with gel analysis, permitted easy identification and quantification of InsP6 (phytate), its pyrophosphate derivatives InsP7 and InsP8, and the nucleotides ATP and GTP from cell or tissue extracts. Using this approach, InsP6, InsP7 and InsP8 were visualized in Dictyostelium extracts and a variety of mammalian cell lines and tissues, and the effects of metabolic perturbation on these were explored. TiO2 bead purification also enabled us to quantify InsP6 in human plasma and urine, which led to two distinct but related observations. Firstly, there is an active InsP6 phosphatase in human plasma, and secondly, InsP6 is undetectable in either fluid. These observations seriously question reports that InsP6 is present in human biofluids and the advisability of using InsP6 as a dietary supplement. PMID- 25808510 TI - Up-regulation of miR-26a promotes neurite outgrowth and ameliorates apoptosis by inhibiting PTEN in bupivacaine injured mouse dorsal root ganglia. AB - Local anesthetic of bupivacaine may inhibit neurite outgrowth and induce apoptosis in mouse dorsal root ganglia (DRG) neurons. In this work, we intended to investigate the functional role of microRNA 26a (miR-26a) in regulating bupivacaine-induced nerve injury in DRG neurons. DRG neurons were extracted from C57BL/6 mice and cultured in vitro. Bupivacaine was applied in vitro and it induced apoptosis, inhibited neurite growth, and significantly down-regulated miR 26a gene in DRG neurons. MiR-26a mimic was then used to up-regulate miR-26a expression in DRG neurons. We found that miR-26a up-regulation promoted neurite outgrowth and reduced apoptosis in bupivacaine-injured DRG neurons. Luciferase assay and Western blot confirmed that Phosphatase and tensin homolog (PTEN) was down-stream target of miR-26a in DRG neurons. Ectopic PTEN up-regulation was then able to reverse the protective effect of miR-26a overexpression on bupivacaine induced nerve injury in DRG neurons. Overall, this work demonstrated that miR-26a had a functional role in regulating bupivacaine-induced nerve injury in DRG neurons. Up-regulating miR-26a to suppress PTEN signaling pathway may be an effective method to protect local anesthetic-induced nerve injury in spinal cord. PMID- 25808511 TI - 4-Fluoroamphetamine in the Netherlands: more than a one-night stand. AB - AIMS: To investigate the temporal pattern of appearance of a new psychoactive substance (4-fluoroamphetamine) on the Dutch drug market, as well as its patterns of use and effects. DESIGN: Data from the Drug Information and Monitoring System (DIMS) was used to investigate the emergence of 4-fluoroamphetamine on the Dutch drug market. An on-line questionnaire was used to study its patterns of use and effects. SETTING: Dutch drug-related websites and social media. PARTICIPANTS: A convenience sample of 249 life-time 4-fluoroamphetamine users was recruited through the internet. MEASUREMENTS: Samples containing 4-fluoroamphetamine were extracted from the DIMS database for further investigation. Patterns of use, settings of use and the subjective effects of 4-fluoroamphetamine, amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) were investigated with the on-line questionnaire. FINDINGS: 4-Fluoroamphetamine was first encountered on the Dutch drug market, sold mainly as amphetamine or ecstasy (MDMA), between 2007 and 2009. These misrepresented drug samples declined when the MDMA and amphetamine markets recovered after a period of shortage, whereas purposefully bought 4 fluoroamphetamine samples showed an increase. Survey results showed that 4 fluoroamphetamine is used predominantly [77.1%, 95% confidence interval (CI) = 72.0-82.3] for its specific effects, rather than its legal status (17.7%, 95% CI = 10.7-22.1). The subjective effects of 4-fluoroamphetamine were compared with those of amphetamine and MDMA. Subjective effect scores of 4-fluoroamphetamine ranged between those of amphetamine and MDMA. CONCLUSIONS: The stimulant 4 fluoroamphetamine is increasingly popular in the Netherlands, which might be due to its subjective effects profile, which lies intermediate between amphetamine and MDMA. PMID- 25808512 TI - Valproate-induced enuresis: a prospective study. AB - AIM: The aim of this study was to determine the frequency and characteristics of secondary enuresis in children initiated on valproate treatment. METHOD: This was a prospective study conducted in children aged 5 to 12 years with suspected newly diagnosed epilepsy and maintained on valproate for at least 1 month. Adverse events spontaneously reported by parents were recorded at each follow-up visit. In addition, we specifically asked about enuresis and other side effects known to occur with valproate treatment. We assessed the frequency of enuresis and its association with a number of variables. RESULTS: Seventy-two children (43 males and 29 females) with a mean age of 8 years 7 months (range 5-12y) were included in this study. Secondary enuresis developed in 17 (24%) of these children after, on average, 19.8 days of exposure to valproate. The data obtained from a multivariate analysis indicate that age was the only significant factor in predicting the development of enuresis. Enuresis ceased in all children after discontinuation of valproate use, and in 10 out of 11 children still on the drug. INTERPRETATION: Secondary enuresis is a common adverse event associated with valproate use in children, which is not usually spontaneously reported and is reversible in most cases. PMID- 25808513 TI - Molecular docking and dynamics simulations on the interaction of cationic porphyrin-anthraquinone hybrids with DNA G-quadruplexes. AB - A series of cationic porphyrin-anthraquinone hybrids bearing either pyridine, imidazole, or pyrazole rings at the meso-positions have been investigated for their interaction with DNA G-quadruplexes by employing molecular docking and molecular dynamics simulations. Three types of DNA G-quadruplexes were utilized, which comprise parallel, antiparallel, and mixed hybrid topologies. The porphyrin hybrids have a preference to bind with parallel and mixed hybrid structures compared to the antiparallel structure. This preference arises from the end stacking of porphyrin moiety following G-stem and loop binding of anthraquinone tail, which is not found in the antiparallel due to the presence of diagonal and lateral loops that crowd the G-quartet. The binding to the antiparallel, instead, occurred with poorer affinity through both the loop and wide groove. All sites of porphyrin binding were confirmed by 6 ns molecular dynamics simulation, as well as by the negative value of the total binding free energies that were calculated using the MMPBSA method. Free energy analysis shows that the favorable contribution came from the electrostatic term, which supposedly originated from the interaction of either cationic pyridinium, pyrazole, or imidazole groups and the anionic phosphate backbone, and also from the van der Waals energy, which primarily contributed through end stacking interaction. PMID- 25808514 TI - Solid-state 31P NMR investigation on the status of guanine nucleotides in paclitaxel-stabilized microtubules. AB - Microtubule dynamics is a target for many chemotherapeutic drugs. In order to understand the biochemical effects of paclitaxel on the GTPase activity of tubulin, the status of guanine nucleotides in microtubules was investigated by (31)P cross-polarization magic angle spinning (CPMAS) NMR. Microtubules were freshly prepared in vitro in the presence of paclitaxel and then lyophilized in sucrose buffer for solid-state NMR experiments. A (31)P CPMAS NMR spectrum with the SNR of 25 was successfully acquired from the lyophilized microtubule sample. The broadness of the (31)P spectral lines in the spectrum indicates that the molecular environments around the guanine nucleotides inside tubulin may not be as crystalline as reported by many diffraction studies. Deconvolution of the spectrum into four spectral components was carried out in comparison with the (31)P NMR spectra obtained from five control samples. The spectral analysis suggested that about 13% of the nucleotides were present as GTP and 37% as GDP in the beta-tubulin (E-site) of the microtubules. It was found that most of the GDPs were present as GDP-Pi complex in the microtubules, which seems to be one of the effects of paclitaxel binding. PMID- 25808515 TI - Molecular weight characterization of high molecular weight dextran with multiangle light scattering in on-line and off-line mode. AB - This work reports the molecular weight (MW) analysis of high MW dextran using multiangle light scattering (MALS) in both chromatography and automated batch measurement mode. The results show that the chromatographic columns alter the high MW native dextran and cause underestimation of the MW as a consequence. Alternatively, a batch MALS measurement (without columns) provides more accurate MW values. The batch MALS measurement was automated with the incorporation of an automatic sample dilution and injection device. This automation reduces the sample preparation time and minimizes concentration errors introduced by manual sample dilution. To the best of our knowledge, this is the first study using an automated batch MALS in the analysis of high MW dextran. PMID- 25808516 TI - Proton transfer reaction-mass spectrometry: online and rapid determination of volatile organic compounds of microbial origin. AB - Analytical tools for the identification and quantification of volatile organic compounds (VOCs) produced by microbial cultures have countless applications in an industrial and research context which are still not fully exploited. The various techniques for VOC analysis generally arise from the application of different scientific and technological philosophies, favoring either sample throughput or chemical information. Proton transfer reaction-mass spectrometry (PTR-MS) represents a valid compromise between the two aforementioned approaches, providing rapid and direct measurements along with highly informative analytical output. The present paper reviews the main applications of PTR-MS in the microbiological field, comprising food, environmental, and medical applications. PMID- 25808517 TI - Genome-wide investigation of the genes involved in nicotine metabolism in Pseudomonas putida J5 by Tn5 transposon mutagenesis. AB - Pseudomonas putida J5 is an efficient nicotine-degrading bacterial strain isolated from the tobacco rhizosphere. We successfully performed a comprehensive whole-genome analysis of nicotine metabolism-associated genes by Tn5 transposon mutagenesis in P. putida J5. A total of 18 mutants with unique insertions screened from 16,324 Tn5-transformants failed to use nicotine as the sole carbon source. Flanking sequences of the Tn5 transposon were cloned with a shotgun method from all of the nicotine-growth-deficient mutants. The potentially essential products of mutated gene were classified as follows: oxidoreductases, protein and metal transport systems, proteases and peptidases, transcriptional and translational regulators, and unknown proteins. Bioinformatic analysis of the Tn5 insertion sites indicated that the nicotine metabolic genes were separated and widely distributed in the genome. One of the mutants, M2022, was a Tn5 insert into a gene encoding a homolog of 6-hydroxy-L-nicotine oxidase, the second enzyme of nicotine metabolism in Arthrobacter nicotinovorans. Genetic and biochemical analysis confirmed that three open reading frames (ORFs) from an approximately 13 kb fragment recovered from the mutant M2022 were responsible for the transformation of nicotine to 3-succinoyl-pyridine via pseudooxynicotine and 3 succinoyl semialdehyde-pyridine, the first three steps of nicotine degradation. Further research on these mutants and the Tn5-inserted genes will help us characterize nicotine metabolic processes in P. putida J5. PMID- 25808518 TI - 16S rRNA gene high-throughput sequencing data mining of microbial diversity and interactions. AB - The ubiquitous occurrence of microorganisms gives rise to continuous public concerns regarding their pathogenicity and threats to human environment, as well as potential engineering benefits in biotechnology. The development and wide application of environmental biotechnology, for example in bioenergy production, wastewater treatment, bioremediation, and drinking water disinfection, have been bringing us with both environmental and economic benefits. Strikingly, extensive applications of microscopic and molecular techniques since 1990s have allowed engineers to peep into the microbiology in "black box" of engineered microbial communities in biotechnological processes, providing guidelines for process design and optimization. Recently, revolutionary advances in DNA sequencing technologies and rapidly decreasing costs are altering conventional ways of microbiology and ecology research, as it launches an era of next-generation sequencing (NGS). The principal research burdens are now transforming from traditional labor-intensive wet-lab experiments to dealing with analysis of huge and informative NGS data, which is computationally expensive and bioinformatically challenging. This study discusses state-of-the-art bioinformatics and statistical analyses of 16S ribosomal RNA (rRNA) gene high throughput sequencing (HTS) data from prevalent NGS platforms to promote its applications in exploring microbial diversity of functional and pathogenic microorganisms, as well as their interactions in biotechnological processes. PMID- 25808519 TI - Nutrient removal and biogas upgrading by integrating freshwater algae cultivation with piggery anaerobic digestate liquid treatment. AB - An integrated approach that combined freshwater microalgae Scenedesmus obliquus (FACHB-31) cultivation with piggery anaerobic digestate liquid treatment was investigated in this study. The characteristics of algal growth, biogas production, and nutrient removal were examined using photobioreactor bags (PBRbs) to cultivate S. obliquus (FACHB-31) in digestate with various digestate dilutions (the concentration levels of 3200, 2200, 1600, 1200, 800, and 400 mg L(-1) chemical oxygen demand (COD)) during 7-day period. The effects of the level of pollutants on nutrient removal efficiency and CO2 removal process were investigated to select the optimum system for effectively upgrade biogas and simultaneously reduce the nutrient content in digestate. The treatment performance displayed that average removal rates of COD, total nitrogen (TN), total phosphorous (TP), and CO2 were 61.58-75.29, 58.39-74.63, 70.09-88.79, and 54.26-73.81 %, respectively. All the strains grew well under any the dilution treatments. With increased initial nutrient concentration to a certain range, the CO4 content (v/v) of raw biogas increased. Differences in the biogas enrichment of S. obliquus (FACHB-31) in all treatments mainly resulted from variations in biomass productivity and CO2 uptake. Notably, the diluted digestate sample of 1600 mg L(-1) COD provided an optimal nutrient concentration for S. obliquus (FACHB-31) cultivation, where the advantageous nutrient and CO2 removals, as well as the highest productivities of biomass and biogas upgrading, were revealed. Results showed that microalgal biomass production offered real opportunities to address issues such as CO2 sequestration, wastewater treatment, and biogas production. PMID- 25808520 TI - Glucose consumption rate critically depends on redox state in Corynebacterium glutamicum under oxygen deprivation. AB - Rapid sugar consumption is important for the microbial production of chemicals and fuels. Here, we show that overexpression of the NADH dehydrogenase gene (ndh) increased glucose consumption rate in Corynebacterium glutamicum under oxygen deprived conditions through investigating the relationship between the glucose consumption rate and intracellular NADH/NAD(+) ratio in various mutant strains. The NADH/NAD(+) ratio was strongly repressed under oxygen deprivation when glucose consumption was accelerated by the addition of pyruvate or sodium hydrogen carbonate. Overexpression of the ndh gene in the wild-type strain under oxygen deprivation decreased the NADH/NAD(+) ratio from 0.32 to 0.13, whereas the glucose consumption rate increased by 27%. Similarly, in phosphoenolpyruvate carboxylase gene (ppc)- or malate dehydrogenase gene (mdh)-deficient strains, overexpression of the ndh gene decreased the NADH/NAD(+) ratio from 1.66 to 0.37 and 2.20 to 0.57, respectively, whereas the glucose consumption rate increased by 57 and 330%, respectively. However, in a lactate dehydrogenase gene (L-ldhA) deficient strain, although the NADH/NAD(+) ratio decreased from 5.62 to 1.13, the glucose consumption rate was not markedly altered. In a tailored D-lactate producing strain, which lacked ppc and L-ldhA genes, but expressed D-ldhA from Lactobacillus delbrueckii, overexpression of the ndh gene decreased the NADH/NAD(+) ratio from 1.77 to 0.56, and increased the glucose consumption rate by 50%. Overall, the glucose consumption rate was found to be inversely proportional to the NADH/NAD(+) ratio in C. glutamicum cultured under oxygen deprivation. These findings could provide an option to increase the productivity of chemicals and fuels under oxygen deprivation. PMID- 25808521 TI - Y-craniosynostosis by premature fusion of the metopic and coronal sutures: a new nosological entity or a variety of Saethre-Chotzen syndrome? AB - BACKGROUND: New forms and varieties of craniosynostoses are continuously identified due to the current increased interest of clinicians and genetists especially since the introduction of microarray-based comparative genomic hybridization (Array-CGH) techniques in the diagnostic setting of patients with craniofacial anomalies. METHODS: In this report, we describe the case of an infant who associated the early fusion of the metopic and both the coronal sutures. The interaction of the early fusion of the anterior group of the main cranial sutures gave the infant a particular clinical phenotypes with a Y configuration of the frontal bone and a globally reduced size of the skull. Such a deformity was observed in utero and was subsequently confirmed by the postnatal imaging of the head. RESULTS: This phenotype was never described previously in antenatal period to our knowledge. The array-CGH showed a heterozygous 9.0 Mb deletion in the chromosomal region 7p21.1p21.3 encompassing approximately 25 other genes, spanning from THSD7A to TWIST1/FERD3L. CONCLUSION: This case further illustrates the variability of the clinical spectrum of craniofacial disorders associated with TWIST1 abnormalities. It is important to note that the Saethre Chotzen syndrome caused by microdeletion is generally characterized by a mental disability. However, of interest, the postoperative psychomotor development of the child considered hereby was within the normal limits. PMID- 25808522 TI - Facilitating access to prenatal care through an interprofessional student-run free clinic. AB - INTRODUCTION: Addressing the persistent challenge of inadequate prenatal care requires innovative solutions. Student-run free health centers are poised to rise to this challenge. The Shade Tree Clinic Early Pregnancy Program, jointly operated by university medical and nursing programs, functions as an ongoing access-to-care portal for pregnant women without health insurance. The clinic is run by medical students and nurse-midwifery students and uses a service-based learning model that allows students to work and learn in supervised, interprofessional teams while providing evidence-based prenatal care. METHODS: All data reported in this paper were obtained from a retrospective chart review of women served by the prenatal clinic. These data are descriptive in nature, and include the patient demographics and services provided by the clinic to 152 women between the years of 2010-2013. RESULTS: During this time period, the clinic served a demographically diverse clientele. Approximately half lacked documentation of legal immigration status. The majority of women seeking care were in their first trimester of pregnancy and had previously given birth. Several women had medical or obstetric complications that required timely referral to specialist care; and many women received treatment for infection and other primary care concerns. DISCUSSION: Shade Tree Clinic provides the basic components of prenatal care and assists women with other medical needs. Women also receive help when applying for and accessing public maternity insurance, and the clinic facilitates entry to any necessary specialist care while that insurance is processed. In many cases, necessary and time-sensitive care would be delayed if Shade Tree Clinic's prenatal services were not available. In addition, the clinic presents a valuable opportunity for interprofessional socialization, increased respect, and improved collaboration between students in different but complementary professions, which is an important experience while we move to meet national goals for interprofessional care among health professionals. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 25808523 TI - Childbirth expense support and small-for-gestational-age infants in Japan. AB - BACKGROUND: Poor nutritional status during the fetal period could cause perinatal and lifelong health disadvantages in neonates. The aim of this study was to investigate the background of pregnant women receiving childbirth expense support (CES), pregnancy outcome, and neonatal anthropometric data. METHODS: A retrospective cohort study was conducted using 823 antenatal and delivery records in a perinatal center located in one of the poorest areas in Japan. Neonates who were small for gestational age (SGA) were compared between the CES and the non CES groups. RESULTS: The incidences of low birthweight (LBW) and SGA were significantly higher in the group receiving CES (14.6% and 14.6%, respectively). The adjusted OR of CES was 2.78 (95%CI: 1.32-5.87) and the adjusted OR of maternal smoking was 5.03 (95%CI: 2.74-9.21), indicating that CES and maternal smoking were directly associated with SGA. CONCLUSIONS: CES recipients had a higher prevalence of SGA infants. CES was independently associated with SGA. Previous studies have shown that smoking is a major risk factor for SGA. Further studies are needed to identify risk factors of SGA specific to CES recipients. PMID- 25808525 TI - Improving PET Evaluation of Brain Tumors. PMID- 25808526 TI - Benign paroxysmal positional vertigo is associated with an increased risk of fracture: a population-based cohort study. AB - STUDY DESIGN: A nationwide, population-based, retrospective cohort study. OBJECTIVES: To investigate whether benign paroxysmal positional vertigo (BPPV) is associated with an increased risk of fracture. BACKGROUND : Benign paroxysmal positional vertigo is a brief rotational vertigo induced by head position change that may increase the risk of falls and, therefore, fracture. METHODS: Data from the Taiwan National Health Insurance Research Database were used for this study. We selected a case cohort comprising 3796 patients aged over 20 years who were newly diagnosed with BPPV between 2000 and 2006. In addition, we randomly selected a control cohort of 15 184 individuals without BPPV. Patients with BPPV were matched to individuals in the control group according to sex, age, and index year. A Cox proportional hazard regression was performed to compute the hazard ratio of fracture, after adjusting for demographic characteristics and comorbidities. RESULTS: The prevalence of comorbidities was higher among patients with BPPV. After adjusting for age, sex, and comorbidities, patients with BPPV exhibited a 1.14-fold (95% confidence interval [CI]: 1.04, 1.25; P<.01) higher risk of fracture than those without BPPV. Trunk fracture (vertebra, rib, and pelvis) was the fracture type with the highest adjusted hazard ratio (1.24; 95% CI: 1.06, 1.45; P<.01) in patients with BPPV relative to those without BPPV. An analysis stratified according to demographic factors revealed that men with BPPV exhibited a 1.43-fold (95% CI: 1.22, 1.66; P<.001) higher risk of fracture. Patients with BPPV aged over 65 years exhibited a significantly higher risk of fracture (adjusted hazard ratio = 1.17; 95% CI: 1.03, 1.33; P<.05) than did those without BPPV. CONCLUSION: Patients with BPPV exhibited a higher risk of fracture than did those without BPPV. LEVEL OF EVIDENCE: Prognosis, level 2b. PMID- 25808527 TI - A consensus definition of running-related injury in recreational runners: a modified Delphi approach. AB - STUDY DESIGN: Delphi study. OBJECTIVE: To reach a consensus definition of running related injury in recreational runners through a modified Delphi approach. BACKGROUND: Many studies have suggested the need for a standardized definition of running-related injury to provide uniformity to injury surveillance in running. METHODS: We invited 112 researchers from running-related injury studies identified in a previous systematic review to classify words and terms frequently used in definitions of running-related injury in an online form during 3 rounds of study. In the last round, participants were asked to approve or disapprove the consensus definition. We considered an agreement level of at least 75% to be a consensus. RESULTS: Thirty-eight participants agreed to participate in the study. The response rates were 94.7% (n = 36) for the first round, 83.3% (n = 30) for the second round, and 86.7% (n = 26) for the third round. A consensus definition of running-related injury was reached, with 80% of participants approving the following: "Running-related (training or competition) musculoskeletal pain in the lower limbs that causes a restriction on or stoppage of running (distance, speed, duration, or training) for at least 7 days or 3 consecutive scheduled training sessions, or that requires the runner to consult a physician or other health professional." CONCLUSION: The proposed standardized definition of running related injury could assist in standardizing the definitions used in sport science research and facilitate between-study comparisons. Future studies testing the validity of the proposed consensus definition, as well as its accurate translation to other languages, are also needed. PMID- 25808528 TI - Descriptors used to define running-related musculoskeletal injury: a systematic review. AB - STUDY DESIGN: Systematic review. OBJECTIVES: To systematically review the descriptors used to define running-related musculoskeletal injury and to analyze the implications of different definitions on the results of studies. BACKGROUND : Studies have developed their own definitions of running-related musculoskeletal injuries based on different criteria. This may affect the rates of injury, which can be overestimated or underestimated due to the lack of a standard definition. METHODS: Searches were conducted in the Embase, PubMed, CINAHL, SPORTDiscus, LILACS, and SciELO databases, without limits on date of publication and language. Only articles that reported a definition of running-related injury were included. The definitions were classified according to 3 domains and subcategories: (1) presence of physical complaint (symptom, body system involved, region), (2) interruption of training or competition (primary sports involved, extent of injury, extent of limitation, interruption, period of injury), and (3) need for medical assistance. Spearman rank correlation was performed to evaluate the correlation between the completeness of definitions and the rates of injury reported in the studies. RESULTS: A total of 48 articles were included. Most studies described more than half of the subcategories, but with no standardization between the terms used within each category, showing that there is no consensus for a definition. The injury rates ranged between 3% and 85%, and tended to increase with less specific definitions. CONCLUSION: The descriptors commonly used by researchers to define a running-related injury vary between studies and may affect the rates of injuries. The lack of a standardized definition hinders comparison between studies and rates of injuries. PMID- 25808529 TI - Muscle force cannot be directly inferred from muscle activation: illustrated by the proposed imbalance of force between the vastus medialis and vastus lateralis in people with patellofemoral pain. AB - SYNOPSIS: Muscle force cannot be directly inferred from neural drive assessed using electromyography (EMG). Although the limitations associated with inferring force from EMG are well known, this has received little attention in the clinical literature. This commentary discusses these limitations within the context of the imbalance of force production between the vastus medialis (VM) and vastus lateralis (VL) muscles, which has been speculated to contribute to the development and/or persistence of patellofemoral pain. The balance of neural drive between vasti muscles is most frequently measured with 2 approaches: (1) the onset of VM EMG relative to that of the VL, and (2) the ratio of the EMG signal amplitude of the VM and VL. Here, we demonstrate that this classical approach cannot determine whether an imbalance of force exists between the VM and VL. Considerations such as altered electromechanical delay (time between the onsets of muscle activation and patellar motion) in people with patellofemoral pain may lead to a reconsideration of the classical interpretation of the onset of VM EMG signal relative to that of the VL. Also, beyond the amplitude of the neural drive, muscle force depends on several biomechanical factors (eg, specific tension and physiological cross-sectional area). Therefore, the VL/VM activation ratio does not provide information about the VL/VM force ratio, which is ultimately the most important information from a clinical perspective. Although the literature includes defenses for both the existence and absence of this force imbalance in people with patellofemoral pain, a reconsideration of the methods used to assess this imbalance is needed. PMID- 25808524 TI - The SWI/SNF ATPases Are Required for Triple Negative Breast Cancer Cell Proliferation. AB - The Brahma (BRM) and Brahma-related Gene 1 (BRG1) ATPases are highly conserved homologs that catalyze the chromatin remodeling functions of the multi-subunit human SWI/SNF chromatin remodeling enzymes in a mutually exclusive manner. SWI/SNF enzyme subunits are mutated or missing in many cancer types, but are overexpressed without apparent mutation in other cancers. Here, we report that both BRG1 and BRM are overexpressed in most primary breast cancers independent of the tumor's receptor status. Knockdown of either ATPase in a triple negative breast cancer cell line reduced tumor formation in vivo and cell proliferation in vitro. Fewer cells in S phase and an extended cell cycle progression time were observed without any indication of apoptosis, senescence, or alterations in migration or attachment properties. Combined knockdown of BRM and BRG1 showed additive effects in the reduction of cell proliferation and time required for completion of cell cycle, suggesting that these enzymes promote cell cycle progression through independent mechanisms. Knockout of BRG1 or BRM using CRISPR/Cas9 technology resulted in the loss of viability, consistent with a requirement for both enzymes in triple negative breast cancer cells. PMID- 25808530 TI - The efficacy of manual therapy for rotator cuff tendinopathy: a systematic review and meta-analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: To evaluate the efficacy of manual therapy (MT) for patients with rotator cuff (RC) tendinopathy. BACKGROUND: Rotator cuff tendinopathy is a highly prevalent musculoskeletal disorder, for which MT is a common intervention used by physical therapists. However, evidence regarding the efficacy of MT is inconclusive. METHODS: A literature search using terms related to shoulder, RC tendinopathy, and MT was conducted in 4 databases to identify randomized controlled trials that compared MT to any other type of intervention to treat RC tendinopathy. Randomized controlled trials were assessed with the Cochrane risk-of-bias tool. Meta analyses or qualitative syntheses of evidence were performed. RESULTS: Twenty-one studies were included. The majority had a high risk of bias. Only 5 studies had a score of 69% or greater, indicating a moderate to low risk of bias. A small but statistically significant overall effect for pain reduction of MT compared with a placebo or in addition to another intervention was observed (n = 406), which may or may not be clinically important, given a mean difference of 1.1 (95% confidence interval: 0.6, 1.6) on a 10-cm visual analog scale. Adding MT to an exercise program (n = 226) significantly decreased pain (mean difference, 1.0; 95% confidence interval: 0.7, 1.4), as reported on a 10-cm visual analog scale, which may or may not be clinically important. Based on qualitative analyses, it is unclear whether MT used alone or added to an exercise program improves function. CONCLUSION: For patients with RC tendinopathy, based on low- to moderate-quality evidence, MT may decrease pain; however, it is unclear whether it can improve function. More methodologically sound studies are needed to make definitive conclusions. LEVEL OF EVIDENCE: Therapy, level 1a-. PMID- 25808532 TI - Reconciling evidence-based practice and cultural competence in mental health services: introduction to a special issue. AB - The calls for evidence-based practice (EBP) and cultural competence (CC) represent two increasingly influential mandates within the mental health professions. Advocates of EBP seek to standardize clinical practice by ensuring that only treatment techniques that have demonstrated therapeutic outcomes under scientifically controlled conditions would be adopted and promoted in mental health services. Advocates of CC seek to diversify clinical practice by ensuring that treatment approaches are designed and refined for a multicultural clientele that reflects a wide variety of psychological orientations and life experiences. As these two powerful mandates collide, the fundamental challenge becomes how to accommodate substantive cultural divergences in psychosocial experience using narrowly prescriptive clinical practices and approaches, without trivializing either professional knowledge or cultural difference. In this Introduction to a special issue of Transcultural Psychiatry, the virtue of an interdisciplinary conversation between and among anthropologists, psychologists, psychiatrists, and social work researchers in addressing these tensions is extolled. PMID- 25808531 TI - Altered gait characteristics in individuals with knee osteoarthritis and self reported knee instability. AB - STUDY DESIGN: Experimental laboratory study. OBJECTIVE: To characterize the differences in lower extremity gait biomechanics in individuals who have knee osteoarthritis (OA) with and without self-reported knee instability. BACKGROUND: Individuals with knee OA who experience episodes of knee instability often report gait difficulties that interfere with their daily lives. A better understanding of the alterations in gait biomechanics may help to mitigate symptomatic knee instability in this patient population. METHODS: Seventeen participants with knee OA and self-reported knee instability and 36 participants with knee OA and no self-reported knee instability underwent instrumented gait analysis on level ground. Knee-specific symptoms and functional limitations were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS: Knee instability was associated with greater odds of reporting moderate to severe gait related pain (odds ratio = 6.0; 95% confidence interval: 1.2, 28.9) and moderate to severe difficulty when walking on flat surfaces (odds ratio = 10.7; 95% confidence interval: 1.7, 69.2). During early stance, the group with self reported knee instability walked with a greater knee flexion excursion (P = .02) and a smaller lower extremity support moment (P<.01), due to reduced contributions from the hip extensors (P<.01) and ankle plantar flexors (P = .04). The group with self-reported knee instability also walked with a greater knee extensor contribution to the lower extremity support moment (P = .04) during the initial knee extension phase of gait compared to their counterparts with good knee stability. CONCLUSION: These findings suggest that self-reported knee instability is associated with significant alterations in hip, knee, and ankle joint function during the stance phase of gait in individuals with knee OA. PMID- 25808533 TI - Molecular action of metformin in hepatocytes: an updated insight. AB - Although, metformin is a drug of the first choice in the treatment of type 2 diabetes mellitus, its molecular action is not fully determined. It is widely accepted that the antihyperglycemic effect of metformin is a result of a decrease in hepatic glucose production, and several cellular targets of the drug have been proposed. The reduction of gluconeogenesis evoked by metformin may be a result of an energy deficit evoked through the inhibition of mitochondrial respiratory chain complex I and/or increased cytosolic redox state and decreased mitochondrial redox state elicited by the inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD). Metformin mediated reduction of hepatic gluconeogenesis was found to be AMP-activated protein kinase (AMPK) dependent and independent, including the inhibition of gluconeogenesis gene expression and allosteric regulation of key gluconeogenesis enzymes. Recently, it was reported that inhibition of mGPD by metformin decreases the level of dihydroxyacetone phosphate and reduces the conversion of lactate to pyruvate, that in consequence diminishes the utilization of glycerol and lactate for gluconeogenesis. The purpose of this paper is to discus molecular mechanisms responsible for the metabolic action of metformin. PMID- 25808534 TI - Introduction to the review articles by ICADA on the pathogenesis of atopic dermatitis in dogs. PMID- 25808535 TI - Review: Lymphocytes, cytokines, chemokines and the T-helper 1-T-helper 2 balance in canine atopic dermatitis. AB - BACKGROUND: The development of atopic dermatitis (AD) and other cutaneous hypersensitivities involves the activation and differentiation of allergen specific lymphocytes. Although hypersensitivity is often considered to be a 'T helper 2-polarized' lymphocyte response, recent evidence suggests that clinical disease is associated with the development of multiple lymphocyte phenotypes. OBJECTIVES: The purpose of this paper is to review recent advances in the understanding of the roles of lymphocytes, cytokines and noncytokine factors in the pathogenesis of canine AD. METHODS: Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed in this update. Where necessary, older articles were included for background information. RESULTS: The development of canine AD is associated with changes in both cutaneous and circulating lymphocyte populations. These lymphocyte responses are characterized by the production of a complex variety of cytokines, including not only T-helper 2 but also T-helper 1, T-helper 17 and regulatory T-cell responses. In addition, microarray gene expression analysis has enabled the identification of a number of noncytokine factors that appear to be associated with atopic inflammation. These include the calcium-binding protein S100A8, serum amyloid A and a number of protease inhibitors, as well as genes involved in epidermal barrier formation, innate immunity receptors, cell cycle proteins and apoptosis. CONCLUSIONS: The development of AD in dogs is characterized by the development of a delicate balance between a variety of T cell phenotypes and inflammatory mediators, including cytokines, chemokines and noncytokine factors. PMID- 25808536 TI - Glycogen synthase kinase 3 regulates acrosomal exocytosis in mouse spermatozoa via dynamin phosphorylation. AB - The dynamin family of GTPases has been implicated as novel regulators of the acrosome reaction, a unique exocytotic event that is essential for fertilization. Dynamin activity during the acrosome reaction is accompanied by phosphorylation of key serine residues. We now tested the hypothesis that glycogen synthase kinase 3 (GSK3) is the protein kinase responsible for dynamin phosphorylation at these phosphosites in mouse spermatozoa. Pharmacologic inhibition of GSK3 in mature mouse spermatozoa (CHIR99021: IC50 = 6.7 nM) led to a significant reduction in dynamin phosphorylation (10.3% vs. 27.3%; P < 0.001), acrosomal exocytosis (9.7% vs. 25.7%; P < 0.01), and in vitro fertilization (53% vs. 100%; P < 0.01). GSK3 was shown to be present in developing germ cells where it colocalized with dynamin in the peri-acrosomal domain. However, additional GSK3 was acquired by maturing mouse spermatozoa within the male reproductive tract, via a novel mechanism involving direct interaction of sperm heads with extracellular structures known as epididymal dense bodies. These data reveal a novel mode for the cellular acquisition of a protein kinase and identify a key role for GSK3 in the regulation of sperm maturation and acrosomal exocytosis. PMID- 25808537 TI - Islet amyloid polypeptide exerts a novel autocrine action in beta-cell signaling and proliferation. AB - The toxic effects of human islet amyloid polypeptide (IAPP) on pancreatic islets have been widely studied. However, much less attention has been paid to the physiologic actions of IAPP on pancreatic beta cells, which secrete this peptide together with insulin upon glucose stimulation. Here, we aimed to explore the signaling pathways and mitogenic actions of IAPP on beta cells. We show that IAPP activated Erk1/2 and v-akt murine thymoma viral oncogene homolog 1 (Akt) at the picomolar range (10-100 pM) in mouse pancreatic islets and MIN6 beta cells cultured at low glucose concentrations. In contrast, IAPP decreased the induction of these pathways by high glucose levels. Consistently, IAPP induced a 1.7-fold increase of beta-cell proliferation at low-glucose conditions, whereas it reduced beta-cell proliferation at high glucose levels. Strikingly, the specific antagonist of the IAPP receptor AC187 (100 nM) decreased the activation of Erk1/2 and Akt and reduced beta-cell proliferation by 24% in glucose-stimulated beta cells, uncovering a key role of endogenously released IAPP in beta-cell responses to glucose. We conclude that exogenously added IAPP exerts a dual effect on beta cell mitogenic signaling and proliferation, depending on the glucose concentration. Importantly, secreted IAPP contributes to the signaling and mitogenic response of beta cells to glucose through an autocrine mechanism. PMID- 25808539 TI - Improvements, trends, and new ideas in molecular docking: 2012-2013 in review. AB - Molecular docking is a computational method for predicting the placement of ligands in the binding sites of their receptor(s). In this review, we discuss the methodological developments that occurred in the docking field in 2012 and 2013, with a particular focus on the more difficult aspects of this computational discipline. The main challenges and therefore focal points for developments in docking, covered in this review, are receptor flexibility, solvation, scoring, and virtual screening. We specifically deal with such aspects of molecular docking and its applications as selection criteria for constructing receptor ensembles, target dependence of scoring functions, integration of higher-level theory into scoring, implicit and explicit handling of solvation in the binding process, and comparison and evaluation of docking and scoring methods. PMID- 25808538 TI - Extracellular matrix remodeling and its contribution to protective adaptation following lengthening contractions in human muscle. AB - This study determined the contribution of extracellular matrix (ECM) remodeling to the protective adaptation of human skeletal muscle known as the repeated-bout effect (RBE). Muscle biopsies were obtained 3 hours, 2 days, and 27 days following an initial bout (B1) of lengthening contractions (LCs) and 2 days following a repeated bout (B2) in 2 separate studies. Biopsies from the nonexercised legs served as controls. In the first study, global transcriptomic analysis indicated widespread changes in ECM structural, deadhesive, and signaling transcripts, 3 hours following LC. To determine if ECM remodeling is involved in the RBE, we conducted a second study by use of a repeated-bout paradigm. TNC immunoreactivity increased 10.8-fold following B1, was attenuated following B2, and positively correlated with LC-induced strength loss (r(2) = 0.45; P = 0.009). Expression of collagen I, III, and IV (COL1A1, COL3A1, COL4A1) transcripts was unchanged early but increased 5.7 +/- 2.5-, 3.2 +/- 0.9-, and 2.1 +/- 0.4-fold (P < 0.05), respectively, 27 days post-B1 and were unaffected by B2. Likewise, TGF-beta signaling demonstrated a delayed response following LC. Satellite cell content increased 80% (P < 0.05) 2 days post-B1 (P < 0.05), remained elevated 27 days post-B1, and was unaffected by B2. Collectively, the data suggest sequential ECM remodeling characterized by early deadhesion and delayed reconstructive activity that appear to contribute to the RBE. PMID- 25808540 TI - Impact of antibiotic exposure on the risk of colorectal cancer. AB - PURPOSE: Gut microbiota has been postulated to serve as a significant promoter of CRC formation, and colonic dysbiosis was previously reported in CRC tissue. Our aim was to evaluate the association between the type and cumulative duration of antibiotic exposure and CRC risk. METHODS: We conducted a nested case-control study using a large population-based database from the UK. Cases were defined as those with any medical code of CRC. Subjects with known familial CRC syndromes or IBD were excluded from the study. For every case, four eligible controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy before index date. Adjusted ORs and 95%CIs were estimated using conditional logistic regression analysis. RESULTS: A total of 20,990 cases and 82,054 controls were identified. The adjusted OR for CRC among subjects first exposed to penicillins >10 years prior to index date was 1.11 (95%CI 1.02-1.20). The risk increased significantly with the number of penicillin exposures up to 1.20 (95%CI 1.11-1.31) for >10 courses. The risk also increased with the average number of penicillin treatments per-year (exposure intensity) with an OR of 1.04 (95%CI 1.01-1.08) per one additional treatment per year. Exposure to anti-viral or anti-fungal therapy was not associated with CRC risk. CONCLUSIONS: Past exposure to multiple courses of penicillins is related to a modest elevation in CRC risk. PMID- 25808542 TI - Highly active phosphine-free bifunctional iron complex for hydrogenation of bicarbonate and reductive amination. AB - Based on a "transition metal frustrated Lewis pair" approach, a cyclopentadienone iron tricarbonyl complex has been designed and applied in the reductive amination and hydrogenation of bicarbonate. This well-defined phosphine-free complex displays the best activities reported to date for an iron complex in the reduction of bicarbonate into formate and in reductive amination. PMID- 25808543 TI - Fabrication of supramolecular semiconductor block copolymers by ring-opening metathesis polymerization. AB - omega-Telechelic poly(p-phenylene vinylene) species (PPVs) are prepared by living ring-opening metathesis polymerization of a [2.2]paracyclophane-1,9-diene in the presence of Hoveyda-Grubbs 2nd generation initiator, with terminating agents based on N(1) ,N(3) -bis(6-butyramidopyridin-2-yl)-5-hydroxyisophthalamide (Hamilton wedge), cyanuric acid, Pd(II) -SCS-pincer, or pyridine moieties installing the supramolecular motifs. The resultant telechelic polymers are self assembled into supramolecular block copolymers (BCPs) via metal coordination or hydrogen bonding and analyzed by (1) H NMR spectroscopy. The optical properties are examined, whereby individual PPVs exhibit similar properties regardless of the nature of the end group. Upon self-assembly, different behaviors emerge: the hydrogen-bonding BCP behaves similarly to the parent PPVs whereas the metallosupramolecular BCP demonstrates a hypsochromic shift and a more intense emission owing to the suppression of aggregation. These results demonstrate that directional self-assembly can be a facile method to construct BCPs with semiconducting networks, while combating solubility and aggregation. PMID- 25808541 TI - A Protocol for Diagnosing the Effect of Calibration Priors on Posterior Time Estimates: A Case Study for the Cambrian Explosion of Animal Phyla. AB - We present a procedure to test the effect of calibration priors on estimated times, which applies a recently developed calibration-free approach (RelTime) method that produces relative divergence times for all nodes in the tree. We illustrate this protocol by applying it to a timetree of metazoan diversification (Erwin DH, Laflamme M, Tweedt SM, Sperling EA, Pisani D, Peterson KJ. 2011. The Cambrian conundrum: early divergence and later ecological success in the early history of animals. Science 334:1091-1097.), which placed the divergence of animal phyla close to the time of the Cambrian explosion inferred from the fossil record. These analyses revealed that the two maximum-only calibration priors in the pre-Cambrian are the primary determinants of the young divergence times among animal phyla in this study. In fact, these two maximum-only calibrations produce divergence times that severely violate minimum boundaries of almost all of the other 22 calibration constraints. The use of these 22 calibrations produces dates for metazoan divergences that are hundreds of millions of years earlier in the Proterozoic. Our results encourage the use of calibration-free approaches to identify most influential calibration constraints and to evaluate their impact in order to achieve biologically robust interpretations. PMID- 25808545 TI - Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells-derived and fetal hepatocytes. AB - The liver is the main organ responsible for the modification, clearance, and transformational toxicity of most xenobiotics owing to its abundance in cytochrome P450 (CYP450) enzymes. However, the scarcity and variability of primary hepatocytes currently limits their utility. Human pluripotent stem cells (hPSCs) represent an excellent source of differentiated hepatocytes; however, current protocols still produce fetal-like hepatocytes with limited mature function. Interestingly, fetal hepatocytes acquire mature CYP450 expression only postpartum, suggesting that nutritional cues may drive hepatic maturation. We show that vitamin K2 and lithocholic acid, a by-product of intestinal flora, activate pregnane X receptor (PXR) and subsequent CYP3A4 and CYP2C9 expression in hPSC-derived and isolated fetal hepatocytes. Differentiated cells produce albumin and apolipoprotein B100 at levels equivalent to primary human hepatocytes, while demonstrating an 8-fold induction of CYP450 activity in response to aryl hydrocarbon receptor (AhR) agonist omeprazole and a 10-fold induction in response to PXR agonist rifampicin. Flow cytometry showed that over 83% of cells were albumin and hepatocyte nuclear factor 4 alpha (HNF4alpha) positive, permitting high-content screening in a 96-well plate format. Analysis of 12 compounds showed an R(2) correlation of 0.94 between TC50 values obtained in stem cell-derived hepatocytes and primary cells, compared to 0.62 for HepG2 cells. Finally, stem cell-derived hepatocytes demonstrate all toxicological endpoints examined, including steatosis, apoptosis, and cholestasis, when exposed to nine known hepatotoxins. CONCLUSION: Our work provides fresh insights into liver development, suggesting that microbial-derived cues may drive the maturation of CYP450 enzymes postpartum. Addition of these cues results in the first functional, inducible, hPSC-derived hepatocyte for predictive toxicology. PMID- 25808544 TI - Hexokinase plays a critical role in deoxynivalenol (DON) production and fungal development in Fusarium graminearum. AB - Fusarium graminearum, the causal agent of Fusarium head blight, is a common pathogen on small grain cereals worldwide and produces various trichothecenes [deoxynivalenol (DON) is predominant] during infection. A previous study has revealed that DON production is positively correlated with the occurrence of carbendazim (MBC) resistance. Here, we identified and characterized two putative genes encoding hexokinase in F. graminearum (FgHXK1 and FgHXK2), which is a rate limiting enzyme in DON biosynthesis. The expression level of hexokinase genes and the production of pyruvate, which is the precursor of DON, were up-regulated in the MBC-resistant strain, indicating that hexokinase genes might be involved in increased DON production. Phylogenetic and comparative analyses indicated that FgHXK1 was the predominant hexokinase gene. Gene disruption showed that DeltaFgHXK1 severely affected DON production, indicating that FgHXK1 played a role in the regulation of DON biosynthesis. Morphological characterization showed that DeltaFgHXK1 led to inhibited vegetative growth and conidiation. Sensitivity tests to MBC and various stresses indicated that both DeltaFgHXK1 and DeltaFgHXK2 mutants showed no significant difference from parental strains. Pathogencity assays showed that DeltaFgHXK1 mutants lost virulence on wheat head and corn stigma; however, they showed no change in sexual reproduction. The FgHXK1 overexpressing transformants were obtained subsequently. Their pyruvate and DON production was confirmed to be increased, indicating that FgHXK1 positively regulated DON biosynthesis. Although additional defects appeared in overexpression mutants, MBC sensitivity showed no change. All of the results indicated that the transcriptional level of FgHXK1 regulated DON biosynthesis, but showed no direct relationship with MBC resistance. PMID- 25808546 TI - IL-33 Exacerbates Periodontal Disease through Induction of RANKL. AB - Cytokines mediate the balance between protective and destructive immunity in periodontitis. We sought to investigate the role of IL-33 in periodontitis. The expression of IL-33 in gingival tissue from healthy controls (n = 10) and patients with chronic periodontitis (n = 17) was investigated. Based on a murine model of periodontal disease, the function of IL-33 was determined first by administration of exogenous IL-33 and second by inhibition of IL-33 signaling using mice deficient in the IL-33 receptor ST2. Alveolar bone level, serum antibody, and lymphocyte responses were assessed in the murine model. Expression of IL-33 and ST2 was elevated in gingival tissues from patients with chronic periodontitis as compared with healthy tissues (P < 0.05). Similarly, Il33 expression was higher in periodontal tissues of Porphyromonas gingivalis-infected mice as compared with sham-infected controls (P < 0.05). IL-33 treatment of P. gingivalis-infected mice significantly exacerbated alveolar bone loss when compared with infection or IL-33 treatment alone (P < 0.001). Conversely, P. gingivalis infection-induced alveolar bone loss was attenuated in mice lacking ST2. The percentages of T and B lymphocytes expressing nuclear factor kappaB ligand (RANKL) in the gingival tissues and T lymphocytes expressing RANKL in the cervical draining lymph nodes were higher in IL-33-treated P. gingivalis-infected mice versus phosphate buffered saline-treated P. gingivalis-infected controls (all P < 0.001). Targeting the RANKL pathway by osteoprotegerin administration abrogated periodontal bone destruction in P. gingivalis-infected, IL-33-treated mice. These data demonstrate a previously unrecognized role for IL-33 in exacerbating bone loss in a RANKL-dependent manner in the context of bacterial infection and suggest that this pathway may be amenable to manipulation as a novel therapeutic target in periodontitis. PMID- 25808548 TI - Post-Translational Modifications of Histones in Human Sperm. AB - We examined the levels and distribution of post-translationally modified histones and protamines in human sperm. Using western blot immunoassay, immunofluorescence, mass spectrometry (MS), and FLIM-FRET approaches, we analyzed the status of histone modifications and the protamine P2. Among individual samples, we observed variability in the levels of H3K9me1, H3K9me2, H3K27me3, H3K36me3, and H3K79me1, but the level of acetylated (ac) histones H4 was relatively stable in the sperm head fractions, as demonstrated by western blot analysis. Sperm heads with lower levels of P2 exhibited lower levels of H3K9ac, H3K9me1, H3K27me3, H3K36me3, and H3K79me1. A very strong correlation was observed between the levels of P2 and H3K9me2. FLIM-FRET analysis additionally revealed that acetylated histones H4 are not only parts of sperm chromatin but also appear in a non-integrated form. Intriguingly, H4ac and H3K27me3 were detected in sperm tail fractions via western blot analysis. An appearance of specific histone H3 and H4 acetylation and H3 methylation in sperm tail fractions was also confirmed by both LC-MS/MS and MALDI-TOF MS analysis. Taken together, these data indicate that particular post-translational modifications of histones are uniquely distributed in human sperm, and this distribution varies among individuals and among the sperm of a single individual. PMID- 25808547 TI - Is there a potential consumer market for low-sodium fermented sausages? AB - The NaCl levels in dry fermented sausages were reduced by 50% or were substituted with KCl, CaCl2 , or a blend of KCl and CaCl2 (1:1). The quality, safety, and the potential consumer market of dry fermented sausages were assessed. Neither 50% reduction of the NaCl content nor the substitution of 50% of the NaCl with KCl influenced the fermentation and maturation process. However, when CaCl2 was used as the substitute salt (50%), there was a significant decrease in pH, an increase in the water activity, and a decrease in lactic acid and micrococcus bacterial counts. Overall, the sensory acceptance decreased in dry fermented sausages with reduced sodium content. However, cluster analysis and internal preference mapping revealed potential for commercialization of samples with 50% of the NaCl content substituted with KCl or with a mixture of KCl and CaCl2 (1:1). PMID- 25808549 TI - Food Sources of Protein and Risk of Incident Gout in the Singapore Chinese Health Study. AB - OBJECTIVE: Prospective studies evaluating diet in relation to the risk of gout in Asian populations are lacking. The purpose of this study was to examine the relationship between the consumption of dietary protein from each of its major sources and the risk of gout in a Chinese population. METHODS: We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese adults who were 45-74 years old at recruitment during the years 1993-1998. Habitual diet information was collected via a validated semiquantitative food frequency questionnaire, and physician-diagnosed gout was self-reported during 2 followup interviews up to the year 2010. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs), with adjustment for potential confounders, among 51,114 eligible study participants who were free of gout at baseline and responded to our followup interviews. RESULTS: A total of 2,167 participants reported physician-diagnosed gout during the followup period. The multivariate-adjusted HRs (with 95% CIs) of gout, comparing the first quartile with the fourth quartile, were as follows: 1.27 (1.12-1.44; P for trend < 0.001) for total protein, 1.27 (1.11-1.45; P for trend < 0.001) for poultry, 1.16 (1.02-1.32; P for trend = 0.006) for fish and shellfish, 0.86 (0.75-0.98; P for trend = 0.018) for soy food, and 0.83 (0.73 0.95; P for trend = 0.012) for nonsoy legumes. No statistically significant associations were found with protein intake from other sources (red meat, eggs, dairy products, grains, or nuts and seeds). CONCLUSION: In this Chinese population living in Singapore, higher total dietary protein intake from mainly poultry and fish/shellfish was associated with an increased risk of gout, while dietary intake of soy and nonsoy legumes was associated with a reduced risk of gout. PMID- 25808550 TI - Analysis of muscle fiber clustering in the diaphragm muscle of sarcopenic mice. AB - INTRODUCTION: Sarcopenia likely comprises muscle fiber denervation and re innervation, resulting in clustering of muscle fibers of the same type (classified by myosin heavy chain isoform composition). Development of methodology to quantitatively evaluate clustering of muscle fibers according to fiber type is necessary. METHODS: Fiber type specific immunofluorescence histology was used to quantify fiber clustering in murine diaphragm muscle (n = 15) at ages 6 and 24 months. RESULTS: With age, fiber type clustering is evidenced by fiber type specific changes in distances between fibers, specifically a 14% decrease to the closest fiber for type I and 24% increase for type IIx and/or IIb fibers (P < 0.001). Additionally, a 34% increase to the 3 closest type IIx and/or IIb fibers was found (P < 0.001). CONCLUSIONS: This novel method of analyzing fiber type clustering may be useful in examining pathophysiological conditions of motor unit loss in neuromuscular disorders, myopathies, dystrophies, injuries, or amyotrophic lateral sclerosis. PMID- 25808553 TI - The perlecan fragment LG3 regulates homing of mesenchymal stem cells and neointima formation during vascular rejection. AB - Transplant vasculopathy is associated with neointimal accumulation of recipient derived mesenchymal stem cells. Increased circulating levels of LG3, a C-terminal fragment of perlecan, were found in renal transplant patients with vascular rejection. Here, we evaluated whether LG3 regulates the migration and homing of mesenchymal stem cells and the accumulation of recipient-derived neointimal cells. Mice were transplanted with a fully-MHC mismatched aortic graft followed by intravenous injection of recombinant LG3. LG3 injections increased neointimal accumulation of alpha-smooth muscle actin positive cells. When green fluorescent protein (GFP)-transgenic mice were used as recipients, LG3 injection favored accumulation of GFP+ cells to sites of neointima formation. LG3 increased horizontal migration and transmigration of mouse and human MSC in vitro and led to increased ERK1/2 phosphorylation. Neutralizing beta1 integrin antibodies or use of mesenchymal stem cells from alpha2 integrin-/- mice decreased migration in response to recombinant LG3. Reduced intima-media ratios and decreased numbers of neointimal cells showing ERK1/2 phosphorylation were found in alpha2-/- recipients injected with recombinant LG3. Collectively, our results suggest that LG3, through interactions with alpha2beta1 integrins on recipient-derived cells leading to activation of ERK1/2 and increased migration, favors myointimal thickening. PMID- 25808551 TI - Integrative models of vascular remodeling during tumor growth. AB - Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. WIREs Syst Biol Med 2015, 7:113-129. doi: 10.1002/wsbm.1295 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. PMID- 25808552 TI - Antithrombotic treatment at onset of stroke with atrial fibrillation, functional outcome, and fatality: a systematic review and meta-analysis. AB - BACKGROUND: In atrial fibrillation-associated stroke, conflicting data exist regarding association between therapeutic vitamin K-antagonist anticoagulation (International Normalized Ratio 2-3) and early death and functional outcome, and few data exist relating to late outcome in ischemic and haemorrhagic atrial fibrillation-stroke. AIM: We performed a systematic review and meta-analysis of oral anticoagulation at stroke onset, death and functional outcome. METHODS: We performed a systematic review, searching multiple sources. Studies were included if outcomes in atrial fibrillation-associated stroke were reported stratified by pre-stroke antithrombotic status, with documented International Normalized Ratio at onset. Outcomes were survival and good functional outcome (modified Rankin score 0-2) at discharge/30 days, and at one-year. RESULTS: Of eight studies (3552 patients) in ischemic stroke, International Normalized Ratio >= 2 compared with other treatments (International Normalized Ratio < 2, antiplatelet, or no antithrombotic) was associated with good outcome [pooled odds ratio 1.9 (95% confidence interval) 1.5-2.5, P < 0.001] and improved survival at 30 days discharge (pooled odds ratio for death 0.4, confidence interval 0.2-0.5, P < 0.001). The net benefit remained after inclusion of haemorrhagic stroke (odds ratio for good outcome 1.89, confidence interval 1.45-2.46, P < 0.001). At one year, improved functional outcome for International Normalized Ratio >= 2 (pooled odds ratio 1.7, confidence interval 1.0-2.7, P = 0.04) and survival (odds ratio for death 0.5, confidence interval 0.4-0.8, P = 0.001) were also observed. CONCLUSIONS: Therapeutic International Normalized Ratio at stroke onset was associated with early and late improved survival and functional recovery suggesting sustained benefit for warfarin anticoagulation for stroke outcome in atrial fibrillation patients. Long-term outcome data following stroke in patients taking new oral anticoagulants is required. PMID- 25808554 TI - Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease. AB - The main hallmarks of Alzheimer's disease (AD) are senile plaques, neurofibrillary tangles and neuronal death. The McGill-R-Thy1-APP rat is one of the few transgenic rat models of AD that displays progressive amyloid pathology. This study aimed to further characterise this rat model, focusing on the pathological changes in the hippocampal formation and the parahippocampal region. These structures, that are important for episodic memory and spatial navigation, are affected in the early stages of the disease. This study used unbiased stereology to investigate possible neuronal loss in the CA1, subiculum and entorhinal cortex of 18-month-old homozygous McGill-R-Thy1-APP rats, and also quantified the plaque load in all the areas of the hippocampal formation and parahippocampal region from 9 to 18 months old. A significant reduction of neurons at 18 months was only seen in the subiculum. The first plaque pathology was seen at 9 months in the subiculum. Although the quantified plaque load was variable between animals, the pattern of spatiotemporal progression was similar for all animals. The spread of plaque pathology mainly affected anatomically connected regions. Overall, the plaque pathology observed in the transgenic rats was similar to the early phases of amyloid beta (Abeta)-deposition described in human patients. The findings here thus indicate that the McGill-R-Thy1-APP rat could be a good model of the Abeta pathology in AD, but less so with respect to neuron loss. PMID- 25808556 TI - Thermal acclimation modulates the impacts of temperature and enrichment on trophic interaction strengths and population dynamics. AB - Global change affects individual phenotypes and biotic interactions, which can have cascading effects up to the ecosystem level. However, the role of environmentally induced phenotypic plasticity in species interactions is poorly understood, leaving a substantial gap in our knowledge of the impacts of global change on ecosystems. Using a cladoceran-dragonfly system, we experimentally investigated the effects of thermal acclimation, acute temperature change and enrichment on predator functional response and metabolic rate. Using our experimental data, we next parameterized a population dynamics model to determine the consequences of these effects on trophic interaction strength and food-chain stability. We found that (1) predation and metabolic rates of the dragonfly larvae increase with acute warming, (2) warm-acclimated larvae have a higher maximum predation rate than cold-acclimated ones, and (3) long-term interaction strength increases with enrichment but decreases with both acclimation and acute temperatures. Overall, our experimental results show that thermal acclimation can buffer negative impacts of environmental change on predators and increase food web stability and persistence. We conclude that the effect of acclimation and, more generally, phenotypic plasticity on trophic interactions should not be overlooked if we aim to understand the effects of climate change and enrichment on species interaction strength and food-web stability. PMID- 25808555 TI - Favorable effects of clearly defined interventions by parents at the start of treatment of adolescents with restrictive eating disorders. AB - OBJECTIVE: To study the effect of clearly defined and decisive parental interventions at the start of treatment of restrictive eating disorders (ED) in adolescents. METHOD: Forty-seven adolescents with ED (anorexia nervosa = 6, bulimia nervosa = 1, EDNOS = 40) and their families participated. Parents were advised to (1) keep the adolescent home from school, (2) eat all meals together with the adolescent, (3) prevent any form of exercise, and (4) prevent vomiting during the first week of treatment. Weight change was followed up to three months and EDE-Q administered at start of treatment and at three months. RESULTS: Thirty (64%) of the families accomplished all four interventions during the first week of treatment. Their adolescents gained ~ 1 kg of weight at one week, 2 kg at one month, and 4 kg at three months while adolescents in families who did not accomplish all four interventions gained only 1.4 kg up to three months. Scores on the EDE-Q decreased during treatment and in adolescents of families who accomplished all four interventions they were in the range of a reference population. DISCUSSION: Decisive parental management of eating disturbed behaviors at the start of treatment of adolescents with ED promotes later clinical outcome. The finding supports the view that family based therapies are effective in adolescent ED. Results has to be followed up for evaluation of the long term effects of this type of intervention. PMID- 25808557 TI - Remembering Stephanie. PMID- 25808558 TI - The longer term impact of a novel rural mental health recruitment strategy: A quasi-experimental study. AB - INTRODUCTION: This study examines the longer term impact of the Gippsland Mental Health Vacation School program, an initiative designed to orientate preregistration allied health and nursing students to rural mental health employment and career opportunities. METHODS: Student participants from vacation schools held from July 2010 to August 2013 were invited to complete on-line surveys prior to, immediately following and 6 months after the event. Participant rating of Interest in rural work, mental health work and rural mental health work and responses to the student attitudes to rural practice and life questionnaire were analyzed using repeated measure analyses of variance. RESULTS: There was a large and significant positive increase in pre to post scores for student interest and attitudes to working in and career in the rural mental health sector. These gains in interest and attitudes fell away by approximately 50% in the six months following the program. The changes in attitudes toward rural work remained significant six months after the program, while attitudes to rural life at six months following the program were not-significantly different to the preprogram scores. CONCLUSIONS: The findings highlight that although a short term program designed to attract students to rural mental health work can positively change participants' interest in and attitudes toward rural work and life, the change diminishes over time. However, interest in rural work and career and rural work attitudes generally maintain significant improvement in the longer term. These differential findings have important implications for developing strategies to overcome rural mental health workforce shortages. PMID- 25808560 TI - Direct Hydrothermal Synthesis of Carbonaceous Silver Nanocables for Electrocatalytic Applications. AB - This study demonstrates a facile but efficient hydrothermal method for the direct synthesis of both carbonaceous silver (Ag@C core-shell) nanocables and carbonaceous nanotubes under mild conditions (<180 degrees C). The carbonaceous tubes can be formed by removal of the silver cores via an etching process under temperature control (60-140 degrees C). The structure and composition are characterized using various advanced microscopic and spectroscopic techniques. The pertinent variables such as temperature, reaction time, and surfactants that can affect the formation and growth of the nanocables and nanotubes are investigated and optimized. It is found that cetyltrimethylammonium bromide plays multiple roles in the formation of Ag@C nanocables and carbonaceous nanotubes including: a shape controller for metallic Ag wires and Ag@C cables, a source of Br(-) ions to form insoluble AgBr and then Ag crystals, an etching agent of silver cores to form carbonaceous tubes, and an inducer to refill silver particles into the carbonaceous tubes to form core-shell structures. The formation mechanism of carbonaceous silver nanostructures depending upon temperature is also discussed. Finally, the electrocatalytic performance of the as-prepared Ag@C nanocables is assessed for the oxidation reduction reaction and found to be very active but much less costly than the commonly used platinum catalysts. The findings should be useful for designing and constructing carbonaceous-metal nanostructures with potential applications in conductive materials, catalysts, and biosensors. PMID- 25808559 TI - Synthesis and application of nanohybrids based on upconverting nanoparticles and polymers. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) have been an emerging and exciting research field in recent years due to their unique luminescent properties of converting near-infrared light to shorter wavelength radiation. UCNPs offer excellent prospects in luminescent labeling, displays, bioimaging, bioassays, drug delivery, sensors, and anticounterfeiting applications. Along with the abundant studies and rapid progress in this area, UCNPs are promising to be a new class of luminescent probe owing to their special advantages over the conventional organic dyes and quantum dots. Among them, polymers play an important role to improve properties or endow new function of UCNPs such as for matrix materials, water solubility, linking active targeting molecules, biocompatibility, and stimuli-responsive behavior. This article briefly reviews the compositions, optical mechanisms, architectures of upconversion nanocrystals and highlights the works on various functional UCNPs/polymer nanohybrids as well as many new interesting fruits in applications. PMID- 25808562 TI - Predicting Vaccination Intention and Benefit and Risk Perceptions: The Incorporation of Affect, Trust, and Television Influence in a Dual-Mode Model. AB - Major health behavior change models tend to consider health decisions as primarily resulting from a systematic appraisal of relevant beliefs, such as the perceived benefits and risks of a pharmacological intervention. Drawing on research from the disciplines of risk management, communication, and psychology, this study proposed the inclusion of a heuristic route in established theory and tested the direction of influence between heuristic and systematic process variables. Affect and social trust were included as key heuristics in the proposed dual-mode framework of health decision making. Furthermore, exposure to health-related coverage on television was considered potentially influential over both heuristic and systematic process variables. To test this framework, data were collected from a national probability sample of 584 adults in the United States in 2012 regarding their decision to vaccinate against a hypothetical avian flu. The results provided some support for the bidirectional influence between heuristic and systematic processing. Affect toward flu vaccination and trust in the Food and Drug Administration were found to be powerful predictors of vaccination intention, enhancing intention both directly and indirectly via certain systematic process variables. The direction of influence between perceived susceptibility and severity, on the one hand, and affect, on the other, is less clear, suggesting the need for further research. Contrary to the opinion of media critics, exposure to televised health coverage was negatively associated with the perceived risks of vaccination. Results from this study carry theoretical and practical implications, and applying this model to the acceptance of different health interventions constitutes an area for future inquiries. PMID- 25808561 TI - MRI guided focused ultrasound robotic system for the treatment of gynaecological tumors. AB - BACKGROUND: A novel MRI-conditional robot that navigates focused ultrasound (FUS) for the treatment of gynaecological tumors endovaginally was developed. METHODS: The robotic system has two PC-controlled axes (linear and angular). The robotic system was manufactured using a digital manufacturing 3D printer using acrylonitrile butadiene styrene (ABS) plastic. Evaluation of the device was performed in a 1.5T MRI using excised porcine tissue. RESULTS: The robotic system was successfully tested for MRI safety and compatibility. The robotic system has been tested for its functionality for creating multiple (overlapping) lesions in an in vitro model. CONCLUSIONS: An MRI-conditional FUS robotic system was developed that has the potential to create thermal lesions with the intention of treating gynaecological tumors. In the future a third axis will be needed that lifts the robot up or down in order to access vaginas which are at a variable height from the MRI table. PMID- 25808563 TI - Treatment of equine metabolic syndrome: A clinical case series. AB - REASONS FOR PERFORMING STUDY: Treatment of equine metabolic syndrome (EMS) is essential to improve insulin sensitivity and reduce the risk of laminitis. Calorie restriction and increased exercise are the mainstays of treatment but there is potential for poor owner compliance. OBJECTIVES: To determine whether significant weight loss accompanied by improvements in measures of insulin sensitivity can be achieved in horses and ponies with EMS managed by their owners in their normal environment under veterinary guidance. STUDY DESIGN: Retrospective clinical case series. METHODS: Horses and ponies attending 2 university hospitals for investigation and treatment of suspected EMS were eligible for inclusion in the study. Animals underwent a clinical examination, basal and dynamic endocrine testing; those with pituitary pars intermedia dysfunction (PPID) were excluded. Owners were given individually tailored diet and exercise programmes to follow for between 3 and 6 months. After the treatment period, clinical examination and endocrine tests were repeated and results compared to the initial assessment. RESULTS: Nineteen animals were recruited to the study, 17 with a history of laminitis. All animals showed a reduction in body condition score (P<0.001) and 18/19 had a reduction in bodyweight (P<0.001) between assessments. There were significant (P<0.05) reductions in basal insulin, insulin at 45 min during a combined glucose insulin tolerance test (CGIT), time for blood glucose concentration to return to baseline during a CGIT and mean area under the glucose curve. CONCLUSIONS: A diet and exercise programme tailored to the needs of the individual animal and implemented by the owner results in weight loss accompanied by improvements in insulin sensitivity. PMID- 25808564 TI - FcWRKY70, a WRKY protein of Fortunella crassifolia, functions in drought tolerance and modulates putrescine synthesis by regulating arginine decarboxylase gene. AB - WRKY comprises a large family of transcription factors in plants, but most WRKY members are still poorly understood. In this study, we report functional characterization of a Group III WRKY gene (FcWRKY70) from Fortunella crassifolia. FcWRKY70 was greatly induced by drought and abscisic acid, but slightly or negligibly by salt and cold. Overexpression of FcWRKY70 in tobacco (Nicotiana nudicaulis) and lemon (Citrus lemon) conferred enhanced tolerance to dehydration and drought stresses. Transgenic tobacco and lemon exhibited higher expression levels of ADC (arginine decarboxylase), and accumulated larger amount of putrescine in comparison with wild type (WT). Treatment with D-arginine, an inhibitor of ADC, caused transgenic tobacco plants more sensitive to dehydration. Knock-down of FcWRKY70 in kumquat down-regulated ADC abundance and decreased putrescine level, accompanied by compromised dehydration tolerance. The promoter region of FcADC contained two W-box elements, which were shown to be interacted with FcWRKY70. Taken together, our data demonstrated that FcWRKY70 functions in drought tolerance by, at least partly, promoting production of putrescine via regulating ADC expression. PMID- 25808567 TI - Effects of different sulphur amino acids and dietary electrolyte balance levels on performance, jejunal morphology, and immunocompetence of broiler chicks. AB - As alterations of dietary electrolyte balance (DEB) can influence amino acid metabolism via changes the ions incur in their configurations, performance and immunological responses of broiler chicks might be affected. So, the current study was carried out to investigate the effects of different levels of sulphur amino acids (SAA) and DEB on performance, jejunal morphology and immunocompetence of broiler chicks. A total of 360 1-day-old male Ross 308 broiler chicks were randomly assigned to nine experimental treatments with four replicates of 10 birds each. Experimental treatments consisted of three levels of SAA (100, 110, and 120% of NRC recommendation, provided by methionine supplementation in diets with the same cysteine level) and three levels of DEB (150, 250, and 350 mEq/kg) that were fed during the entire of trial in a 3 * 3 factorial arrangement. Results showed that the relative weights of intestine and abdominal fat were decreased markedly (p < 0.001) with increasing levels of SAA and DEB respectively. Antibody titre against sheep red blood cell was neither individually nor in combination influenced by supplementation of SAA or DEB. Nevertheless, a decrease in DEB level led to a suppression in heterophile (p < 0.05) and an increase in lymphocyte counts (p = 0.06); consequently, heterophile to lymphocyte ratio was significantly decreased (p < 0.05) by decremental levels of DEB. Albumin to globulin ratio was increased after inclusion of at least 10% SAA (p < 0.001) and 150 mEq DEB/kg in the diet (p = 0.11). Although feeding high DEB level led to a remarkable decrease in villus height (p < 0.01) and goblet cell numbers (p < 0.001), supplementing the highest level of SAA improved the height of jejunal villus. During the entire trial period, average daily feed intake (ADFI) was increased by incremental SAA levels (p < 0.05). However, inclusion of 150 mEq/kg led to not only a remarkable increase (p < 0.0001) in both ADFI and average daily weight gain (ADWG) but also to improved (p < 0.001) feed conversion ratio (FCR) both during the growing and over the entire trial periods. The present findings indicated that inclusion of low DEB decreased the heterophile to lymphocyte ratio and improved both the albumin to globulin ratio and intestinal health indices. The best growth performance was obtained with 150 mEq DEB/kg in the diet for each level of SAA. PMID- 25808565 TI - Self-Compassion as a prospective predictor of PTSD symptom severity among trauma exposed U.S. Iraq and Afghanistan war veterans. AB - U.S. combat veterans of the Iraq and Afghanistan wars have elevated rates of posttraumatic stress disorder (PTSD) compared to the general population. Self compassion, characterized by self-kindness, a sense of common humanity when faced with suffering, and mindful awareness of suffering, is a potentially modifiable factor implicated in the development and maintenance of PTSD. We examined the concurrent and prospective relationship between self-compassion and PTSD symptom severity after accounting for level of combat exposure and baseline PTSD severity in 115 Iraq and Afghanistan war veterans exposed to 1 or more traumatic events during deployment. PTSD symptoms were assessed using the Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) at baseline and 12 months (n =101). Self compassion and combat exposure were assessed at baseline via self-report. Self compassion was associated with baseline PTSD symptoms after accounting for combat exposure (beta = -.59; p < .001; DeltaR(2) = .34; f(2) = .67; large effect) and predicted 12-month PTSD symptom severity after accounting for combat exposure and baseline PTSD severity (beta = -.24; p = .008; DeltaR(2) = .03; f(2) = .08; small effect). Findings suggest that interventions that increase self-compassion may be beneficial for treating chronic PTSD symptoms among some Iraq and Afghanistan war veterans. PMID- 25808566 TI - Macrophages and dendritic cells: the usual suspects in atherogenesis. AB - Atherosclerosis, the major risk factor for cardiovascular disease (CVD) and the leading cause of death worldwide, is a multifactorial chronic inflammatory disease, which, clinically manifests from early lipid-rich lesions to plaque rupture and/or thrombosis in the arterial wall. The myeloid cell compartment, including macrophages and dendritic cells (DCs), is long known to contribute to the initiation and progression of atherosclerosis. However their complex phenotypic heterogeneity hampers our full understanding of their role. Here, we review the biological and functional versatility of the myeloid cells in atherosclerosis. Several distinct subsets of macrophages and myeloid cells have been identified in atherosclerotic plaques, including subsets that are specific to atherosclerosis itself. Our ability to target them therapeutically is still limited. The challenge for the future will be the definition of treatments that target specific myeloid subsets to prevent the activation of pro-atherogenic myeloid cell subsets while preserving the anti-atherogenic and repairable function of myeloid cells. PMID- 25808568 TI - In the eyes of the beholder: Understanding subtypes of social withdrawal among young Chinese children. AB - In this commentary on Ding et al. (Brit. J. Dev. Psychol., 2015; 33, 159-173), we focus on the following: (1) the authors' use of vignettes portraying various prototypes of withdrawn children and (2) the cultural interpretation of their findings. We end with some suggestions for future research. PMID- 25808571 TI - 1D NMR Homodecoupled (1)H Spectra with Scalar Coupling Constants from 2D NemoZS DIAG Experiments. AB - A two-dimensional liquid-state NMR experiment cleanly separating chemical shifts and scalar couplings information is introduced. This DIAG experiment takes advantage of a drastic reduction of the spectral window in the indirect dimension to be quickly recorded and of a new non-equidistant modulation of the selective pulse to improve the sensitivity of the broadband homodecoupling Zangger-Sterk sequence element by one order of magnitude. A simple automatic analysis results in 1D spectra displaying singlets and lists of the scalar couplings for first order multiplets. This facilitates the analysis of 1D spectra by resolving multiplets based on their differences in chemical shifts and coupling structures. PMID- 25808569 TI - Serpentine supravenous hyperpigmentation resulting from vinorelbine administration. PMID- 25808570 TI - Treatment effect with anti-RAGE F(ab')2 antibody improves hind limb angiogenesis and blood flow in Type 1 diabetic mice with left femoral artery ligation. AB - We investigated treatment with a receptor for advanced glycation endproduct (RAGE) blocking antibody on angiogenic response to hind limb ischemia in diabetic mice. Streptozotocin treated C57BL/6 mice received either murine monoclonal anti RAGE F(ab')2 intraperitoneally (n=10) or saline (n=9) for 9 weeks. Diabetic plus 10 non-diabetic C57BL/6 mice underwent left femoral artery ligation and 5 days later angiogenesis imaging with (99m)Tc-Arg-Gly-Asp (RGD) nanoSPECT/CT. Twenty four days later, hind limb blood flow was measured with ultrasound, the mice were euthanized, and tissue was taken for immunohistochemistry. The angiogenic imaging signal in ischemic limbs was higher in RAGE-ab treated versus saline treated mice at day 5 (3.1+/-1.4 vs 1.68+/-0.35, p=0.02) and blood flow was higher at day 24 (1.49+/-0.5 vs 0.61+/-0.39, p=0.04). Immunohistochemistry of ischemic muscles showed greater capillary density in the RAGE-ab treated group versus the vehicle treated group (p<0.001) (NS from non-diabetic mice). In conclusion, treatment with anti-RAGE F(ab')2 in diabetic mice improves neovascularization in the ischemic leg. PMID- 25808572 TI - Efficacy and safety of lornoxicam vs ibuprofen in primary dysmenorrhea: a randomized, double-blind, double dummy, active-controlled, cross over study. AB - OBJECTIVES: Study was planned to evaluate the efficacy and safety of lornoxicam in moderate to severe menstrual pain due to primary dysmenorrhea. STUDY DESIGN: This doubled blind, double dummy, randomized, comparable study of lornoxicam versus ibuprofen was conducted at Sir Takhtsinghji General Hospital, Bhavnagar, Gujarat, India. Total 57 primary dysmenorrhea participants having mean age+/ standard deviation (SD) of 19.2+/-2.08 were analyzed. The participants were randomly allocated to either lornoxicam 8 mg or ibuprofen 400mg two times a day for maximum of three days on two consecutive menstrual periods. The different medication was taken on each cycle. The analgesic efficacy was compared by a total area under pain relief score to 4 and 8h, pain intensity difference, sum of pain intensity difference to 4 and 8h, peak pain intensity difference to 4 and 8h, peak pain relief to 4 and 8h, total medication consumption, rescue medication and participant global evaluation. Adverse effects were recorded in both groups. RESULTS: In both treatments, efficacy parameters were significantly reduced at measured time points as compared to baseline. No significant difference was observed between lornoxicam and ibuprofen in terms of efficacy parameters: total area under pain relief to 4h (8.0+/-2.6 vs 8.3+/-2.7), total area under pain relief to 8h (22.4+/-4.6 vs 23.0+/-4.4), sum of pain intensity difference to 4h ( 5.7+/-1.9 vs -6.0+/-2.0), sum of pain intensity difference to 8h (-17.5+/-3.3 vs 17.8+/-3.5), peak pain relief to 4h (3.4+/-0.8 vs 3.5+/-0.8), peak pain relief to 8h (3.9+/-0.5 vs 3.9+/-0.4), peak pain intensity difference to 4h (-2.6+/-0.7 vs 2.7+/-0.7), peak pain intensity difference to 8h (-3.3+/-0.6 vs -3.3+/-0.6). Total medication consumption, a requirement of rescue medication and global evaluation of efficacy were comparable in both groups. The incidence of adverse effect was also similar in both groups. CONCLUSIONS: Lornoxicam appears to be a new therapeutic agent for the treatment of primary dysmenorrhea. PMID- 25808574 TI - Serum heparanase levels: A protective marker against digital ulcers in patients with systemic sclerosis. AB - Heparanase is an endo-beta-D-glucuronidase cleaving heparan sulfate side-chains of heparin sulfate proteoglycans, which is involved in wound healing, inflammation, neovascularization and tumor progression through the degradation and remodeling of the extracellular matrix and the release of sequestered pro angiogenic factors. Because heparanase-mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), we investigated the clinical correlation of serum heparanase levels in patients with this disease. Serum heparanase levels were significantly higher in SSc patients than in healthy individuals, while comparable between diffuse cutaneous SSc and limited cutaneous SSc subgroups. On the other hand, SSc patients with digital ulcers had serum heparanase levels significantly lower than those without. These results suggest that serum heparanase levels may be elevated in SSc patients reflecting the contribution of heparanase-dependent biological processes to the development of SSc. SSc patients with high serum heparanase levels may be protected from the development of digital ulcers due to the increased release of sequestered pro angiogenic factors such as vascular endothelial growth factor. Therefore, serum heparanase levels may serve as a protective marker against digital ulcers in SSc patients. PMID- 25808573 TI - Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships. AB - Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses an appropriate PKC binding domain. PMID- 25808576 TI - Involvement of membrane proteins and ion channels on the self-rotation of human cells in a non-rotating AC electric field. AB - Dielectrophoresis is a force that has been exploited in microsystems for label free characterization and separation of cells, when their electrical signature is known. However, the polarization effect of cells at the transmembrane protein level is not well established. In this work, we have use the self-rotation effect of cells in a non-rotating field, known as the "Quincke effect," in order to measure the maximum rotation frequency (frotmax ) of different cell populations when modifying the composition of their membrane. We investigated the influence of active ionic transportation of membrane protein concentration on frotmax of HEK cells. Our results show that ionic transportation is responsible for the reduction of conductivity within the cytoplasm, which results in higher frotmax . However, the influence of the concentration of proteins in the membrane, achieved by silencing gene expression in cancer cells, changes significantly frotmax , which is not explained by the changes of ionic conductivity within the cell. PMID- 25808578 TI - BREMSO: a simple score to predict early the natural course of multiple sclerosis. AB - BACKGROUND AND PURPOSE: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. METHODS: An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. RESULTS: Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS>= third quartile vs. <= first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. CONCLUSIONS: BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting. PMID- 25808577 TI - Botulinum toxin A injections and occupational therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial. AB - AIM: To investigate the effects of repeated botulinum toxin A (BoNT-A) injections combined with occupational therapy, including a splint, compared with occupational therapy alone on hand function in children with unilateral spastic cerebral palsy (USCP), in all International Classification of Functioning, Disability and Health (ICF) domains. METHOD: This was a randomized controlled study, population-based and evaluator-blinded for primary outcome (October 2004 to September 2010). Twenty children (14 males; median age 3y 1mo) with USCP, recruited at a rehabilitation centre in Sweden, were assigned to one of two parallel groups using concealed allocation. In the course of one year, 10 children received occupational therapy, while 10 received repeated BoNT-A plus occupational therapy (BoNT-A/OT). Primary outcome (Assisting Hand Assessment [AHA]), and secondary outcome measures (range of movement [ROM], and Canadian Occupational Performance Measure), were measured at baseline, 3, 6, 9, and 12 months. RESULTS: AHA revealed a superior effect in the BoNT-A/OT group at 12 months: 6 out of 10 improved compared with 1 out of 10 in the occupational therapy group (p<0.03). A 95% Peskun exact confidence interval for the difference in proportions is given as 0.01 to 0.81. Secondary outcomes improved in both groups. INTERPRETATION: Repeated BoNT-A/OT appeared superior to occupational therapy alone for bimanual performance in young children with USCP. Active ROM and goal performance improved in both groups. PMID- 25808579 TI - A very simple high-performance liquid chromatographic method with fluorescence detection for the determination of gemifloxacin in human breast milk. AB - A high-performance liquid chromatographic method with fluorescence detection was developed and validated for the determination of gemifloxacin in human breast milk. The proposed method allows the determination of gemifloxacin in breast milk samples without complex sample preparation. The samples were mixed with a mobile phase and filtered with a 0.45 um polytetrafluoroethylene filter before analysis. Chromatographic separation was carried out on a C18 column (150 * 4.6 mm, 5 um I.D.) using methanol:50 mM ortho-phosphoric acid solution (40:60) as the mobile phase with a 1.0 mL/min flow rate. Quantitation was performed using fluorescence detection with an excitation wavelength at 272 nm and an emission wavelength at 395 nm. The linear range was found to be 0.1-2.5 ug/mL. The method was applied successfully for the determination of gemifloxacin in breast milk obtained from a breastfeeding mother after oral administration of a single tablet that included 320 mg gemifloxacin per gemifloxacin tablet. PMID- 25808575 TI - Kinetics of peptide folding in lipid membranes. AB - Despite our extensive understanding of water-soluble protein folding kinetics, much less is known about the folding dynamics and mechanisms of membrane proteins. However, recent studies have shown that for relatively simple systems, such as peptides that form a transmembrane alpha-helix, helical dimer, or helix turn-helix, it is possible to assess the kinetics of several important steps, including peptide binding to the membrane from aqueous solution, peptide folding on the membrane surface, helix insertion into the membrane, and helix-helix association inside the membrane. Herein, we provide a brief review of these studies and also suggest new initiation and probing methods that could lead to improved temporal and structural resolution in future experiments. PMID- 25808581 TI - Ablation of human skin mast cells in situ by lysosomotropic agents. AB - Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell-mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu-Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells. PMID- 25808580 TI - Identification and characterization of diverse groups of endogenous retroviruses in felids. AB - BACKGROUND: Endogenous retroviruses (ERVs) are genetic elements with a retroviral origin that are integrated into vertebrate genomes. In felids (Mammalia, Carnivora, Felidae), ERVs have been described mostly in the domestic cat, and only rarely in wild species. To gain insight into the origins and evolutionary dynamics of endogenous retroviruses in felids, we have identified and characterized partial pro/pol ERV sequences from eight Neotropical wild cat species, belonging to three distinct lineages of Felidae. We also compared them with publicly available genomic sequences of Felis catus and Panthera tigris, as well as with representatives of other vertebrate groups, and performed phylogenetic and molecular dating analyses to investigate the pattern and timing of diversification of these retroviral elements. RESULTS: We identified a high diversity of ERVs in the sampled felids, with a predominance of Gammaretrovirus related sequences, including class I ERVs. Our data indicate that the identified ERVs arose from at least eleven horizontal interordinal transmissions from other mammals. Furthermore, we estimated that the majority of the Gamma-like integrations took place during the diversification of modern felids. Finally, our phylogenetic analyses indicate the presence of a genetically divergent group of sequences whose position in our phylogenetic tree was difficult to establish confidently relative to known retroviruses, and another lineage identified as ERVs belonging to class II. CONCLUSIONS: Retroviruses have circulated in felids along with their evolution. The majority of the deep clades of ERVs exist since the primary divergence of felids' base and cluster with retroviruses of divergent mammalian lineages, suggesting horizontal interordinal transmission. Our findings highlight the importance of additional studies on the role of ERVs in the genome landscaping of other carnivore species. PMID- 25808582 TI - Current Australasian practice for diagnosis and management of idiopathic pulmonary fibrosis: Where are we now? AB - BACKGROUND AND OBJECTIVE: Recent international consensus statements have refined evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). This study sought to investigate how closely these guidelines are adhered to and to compare current practices with those of a similar cohort 15 years ago. METHODS: A questionnaire on IPF diagnosis and management was distributed to respiratory physicians practising in Australia and New Zealand, in 2012-2013, and results were compared with a similar survey conducted in 1999. RESULTS: A total of 172 and 144 questionnaires were completed in 1999 and 2012-2013, respectively. The most important investigations in both survey populations were high-resolution computed tomography scans, spirometry, diffusing capacity for carbon monoxide, chest X-ray, static lung volumes and autoimmune serology. In 1999, physicians were more likely to perform arterial blood gases, bronchoalveolar lavage and transbronchial lung biopsy. In the 2012 2013 cohort, 6-min walk tests and pulse oximetry were more widely utilized. Treatment choices differed considerably between the two survey populations. In 1999, the majority would offer a steroid-based regimen, whereas most would not use any specific treatment or would refer for trial participation in 2012-2013. CONCLUSIONS: Approach to IPF diagnosis and management is not uniform and has changed over 15 years. Surveyed respiratory physicians were generally practising in accordance with clinical guidelines, although significant variation in practice was identified in both cohorts. This study identifies the need to standardize care of IPF patients across Australia and New Zealand. PMID- 25808584 TI - Non-injection-site necrotic skin lesions complicating postoperative heparin thromboprophylaxis. AB - The patient case we present is a definite case of HIT from both clinical and serological perspectives. The 4Ts score was eventually 8/8 (maximum) based upon thrombocytopenia (88% platelet count fall to nadir of 58 * 109/L), appropriate timing (onset on Day 5 post-intraoperative UFH exposure), thrombosis (right lower limb DVTs, skin necrosis, anaphylactoid reaction to IV heparin, right hallux ischemic necrosis), and no plausible alternative explanation for thrombocytopenia. In addition, the patient had a strong positive SRA and PF4 dependent ELISA. Although necrotizing skin lesions distant from heparin injection sites are not a common consequence of HIT, their occurrence in this patient-along with previous supportive literature [11-13]-indicate that these lesions should be considered rare manifestations of HIT. Moreover, the distinct localization of the unusual necrotic skin rash to the right limb suggests that a low flow state due to the arterial obstruction or perhaps even as a result of an underlying venous thrombus, both of which were present in our patient, could play a key pathophysiological role in predisposing to this unusual complication of HIT. PMID- 25808585 TI - Femoral perfusion after pulsed electromagnetic field stimulation in a steroid induced osteonecrosis model. AB - This study was designed to evaluate femoral perfusion after pulsed electromagnetic field (PEMF) stimulation in a steroid-induced osteonecrosis rabbit model by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Steroid-induced osteonecrosis was produced by single intramuscular injection of methylprednisolone in 15 rabbits. Eight rabbits underwent PEMF stimulation (PEMF group) and seven did not (control group). DCE-MRI was performed before PEMF stimulation, immediately before steroid administration, and 1, 5, 10, and 14 days after steroid administration. Regions of interest were set in the bilateral proximal femora. Enhancement ratio (ER), initial slope (IS), and area under the curve (AUC) were analyzed. ER, IS, and AUC in the control group significantly decreased after steroid administration compared with before administration (P<0.05). In PEMF group, IS significantly decreased; however, ER and AUC showed no significant differences after steroid administration compared with before. ER and IS in PEMF group were higher than in control group until 10th day, and AUC was higher until 5th day after steroid administration (P<0.05). PEMF stimulation restrains the decrease in blood flow after steroid administration. PMID- 25808583 TI - Polysaccharide fraction isolated from Passiflora edulis inhibits the inflammatory response and the oxidative stress in mice. AB - OBJECTIVES: The aim of the study was to investigate the anti-inflammatory, antioxidant and antinociceptive actions of PFPe, a polysaccharide fraction isolated from the dried fruit of the Passiflora edulis. METHODS: Animals were pretreated with PFPe (0.3, 1 or 3 mg/kg, i.p.) 1 h before induction of paw oedema by carrageenan, histamine, serotonin, compound 48/80 or prostaglandin E2 (PGE2). Neutrophil migration and vascular permeability were measured after carrageenan injection into the peritoneum, and the action of the PFPe on the tumour necrosis factor-alpha, interleukin-1 beta (IL-1beta), myeloperoxidase (MPO), glutathione (GSH) and malondialdehyde (MDA) levels was also evaluated. To assay nociception, we examined acetic acid-induced writhing, formalin-induced paw licking and response latency in the hot plate test. KEY FINDINGS: Pretreatment with PFPe significantly inhibited carrageenan-induced paw oedema. PFPe also reduced paw oedema induced by compound 48/80, histamine, serotonin, and PGE2 and compound 48/80-induced vascular permeability. In addition, PFPe significantly reduced the MPO activity, MDA and GSH concentrations, and IL-1beta level. In the nociception tests, PFPe reduced acetic acid-induced writhing and formalin-induced paw licking and did not increase the response latency time. CONCLUSIONS: Our results suggest that PFPe administration reduces the inflammatory response by modulation of the liberation or synthesis of histamine and serotonin, by reduction of neutrophil migration, IL-1beta levels, and oxidative stress and nociception. PMID- 25808587 TI - Day-case closure of ileostomy: feasible, safe and efficient. AB - AIM: Over 5000 loop ileostomy closures were performed in the UK in 2013 with a median inpatient stay of 5 days. Previously we have successfully implemented a 23 h protocol for loop ileostomy closure which was modified for same-day discharge. We present our early experience of day-case loop ileostomy closure. METHOD: A specific patient pathway for day-case discharge following loop ileostomy closure was implemented with inclusion criteria to conform with British Association of Day Surgery guidelines. Exclusion criteria included postoperative chemoradiotherapy, multiple comorbidities and social care needs. Follow-up consisted of telephone contact (24 and 72 h after discharge) and a routine outpatient appointment. Patients were provided with a 24-h contact point in case of emergency. RESULTS: Fifteen (12 male) patients were enrolled of median age 67 (39-80) years. The median operating time was 41 (23-80) min. The indication for ileostomy formation was to cover a low anterior resection for adenocarcinoma (13), reversal of Hartmann's procedure (1) and functional bowel disorder (1). The median interval from the primary procedure to day-case loop ileostomy closure was 8 (3-14) months. Every patient was discharged on the day of surgery. There were no complications related to the surgery and there was one readmission due to a urinary tract infection. The median length of follow-up was 4 (2-16) months. CONCLUSION: Our early experience shows that day-case loop ileostomy closure is feasible, safe and efficient. This protocol will become standard within our institution for suitable patients, saving on average five inpatient bed days per patient. PMID- 25808590 TI - Nursing home nurses conceptualize how to care for residents with cardiac vulnerability. AB - BACKGROUND: With ageing, older people face cardiovascular problems as the major cause of disability and death. Although immediate medical attention is a major factor in determining outcomes of cardiac problems, lack of personnel (i.e. registered nurse, certified nursing assistant and home care aide) in nursing homes without residing doctor limits the awareness of such problems, thus making it difficult to initiate timely and appropriate intervention. AIM: The aim of this study was to conceptualize critical care for nursing home residents with cardiac vulnerability and develop practical knowledge in nursing practice. METHODS: Conventional content analysis was performed on date from interviews with 30 nurses from 10 nursing homes in South Korea between July and November 2010. RESULTS: The analysis revealed three major cardiac problems resulting from residents' cardiac vulnerability: angina, myocardial infarction (MI) and cardiogenic shock. Through content analysis, we extracted 6 themes and 21 subthemes for nurses' conceptualization of critical care for nursing home residents with cardiac vulnerability. In nursing homes without a residing doctor, nurses assessed the physical, functional and cognitive conditions along with the responses and symptoms of residents when emergency situations related to the cardiac problems occurred. Moreover, with a lack of infrastructures of a hospital, nurses provided critical care to the elderly by using personal practice strategies based on their personal experience in facilities along with practical knowledge of nurses while following the management principles of emergencies. CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: We found that nurses conceptualized critical nursing care for cardiac problems at nursing homes, which are different from those of general hospitals. The results of this study will provide basis for the development of care guidelines and educational materials that can be used by novice nurses or nursing students. PMID- 25808589 TI - Comparison of childhood cancer survivors' nutritional intake with US dietary guidelines. AB - BACKGROUND: Despite improved survival, childhood cancer survivors experience significantly elevated risk of premature mortality and serious morbidity due to chronic health conditions. Poor diet quality can exacerbate chronic health conditions in the survivors but their nutritional intake has not been adequately studied. PROCEDURE: We assessed the Healthy Eating Index 2010 (HEI-2010) in 22 survivors of pediatric acute lymphoblastic leukemia and lymphoma (median age = 11.7 years) and compared survivors' dietary intake to the 2010 Dietary Guidelines for Americans. Dietary data were collected using repeated 24 hr dietary recalls over a 1-year period, which were averaged to estimate habitual intake. RESULTS: The mean HEI-2010 in childhood cancer survivors was 52.7, about 50 percent of the maximum score. Long-term survivors (time from diagnosis >=10 years) had a significantly lower HEI-2010 than recent survivors (time from diagnosis <5 years) (beta = -11.5, 95% CI: -22.1, -0.9, P = 0.047). For individual food groups and nutrients, survivors had a particularly poor adherence to green vegetables and beans, total vegetables, and whole fruits. None of the survivors met the guidelines for dietary fiber and potassium intake. Only 4%, 19%, 24%, and 29% met the guidelines for vitamin D, sodium, calcium, and saturated fat intake. The average intake in relative to the recommended intake was 32% for vitamin D, 50% for potassium, 63% for fiber, and 85% for calcium, but was 115% for saturated fat and 143% for sodium. CONCLUSIONS: Childhood cancer survivors, in particular long term survivors, have a poor adherence to the US dietary guidelines. PMID- 25808591 TI - Internet diabetes management: a practical approach. PMID- 25808588 TI - Pregnancy outcome after TNF-alpha inhibitor therapy during the first trimester: a prospective multicentre cohort study. AB - AIMS: TNF-alpha inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-alpha inhibitors. METHODS: Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS: In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS: TNF-alpha inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-alpha inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs. PMID- 25808592 TI - Extensive functional analyses of RHD splice site variants: Insights into the potential role of splicing in the physiology of Rh. AB - BACKGROUND: Among more than 300 mutated alleles identified so far within the RHD gene, almost 40 are assumed to alter cellular splicing and therefore may have a direct effect on Rh phenotype both at the quantitative and at the qualitative levels. Functional data are, however, mostly unavailable to assess the direct involvement of splicing defect in the underlying physiology. STUDY DESIGN AND METHODS: We generated plasmid constructs to carry out an exhaustive investigation of 38 RHD variants located within or in the vicinity of exon-intron junctions by a minigene splicing assay, further characterized the transcript structures by sequencing, and identified cryptic sites activated by the genetic defect. Bioinformatics predictions were carried out in parallel and compared with the functional data. RESULTS: For the first time we demonstrate that a product including the full-length Exon 9 is transcribed in the presence of the c.1227G>A substitution frequently carried by Asians with DEL phenotype and confirmed that splicing is altered in the RHD*weak D Type 2 allele, a rare variant most commonly found in Caucasians. CONCLUSION: Overall we 1) show significant correlation between functional analyses, bioinformatics predictions, and phenotypes, when available, especially for variants in close proximity of the consensus splice sites; 2) classify the variations as splicing or nonsplicing variants; and 3) provide functional data to further improve bioinformatics splicing tools. Conversely assessment of seven silent exonic variants was mainly inconclusive. PMID- 25808595 TI - Erratum to: Biophysical Interactions of Novel Oleic Acid Conjugate and its Anticancer Potential in HeLa Cells. PMID- 25808594 TI - DFT studies of the photophysical properties of fluorescent and semiconductor polycyclic benzimidazole derivatives. AB - The photophysical and electrochemical properties of eleven polycyclic benzimidazole fused organic pigments (four based on phthalic anhydride, four based on naphthalic anhydride and three based naphthalene tetra carboxylic acid dianhydride) were investigated using density functional theory and time dependent density functional theory methods (B3LYP/6-31G(d) and M06/6-31G(d)). The predicted geometries are comparable using both functionals. The electrochemical properties are in good agreement with the experimental results. However, the experimental absorption-emission properties are closer to the values computed using the M06/6-31G(d) method. Both the methods perform equally well in explaining the intramolecular charge transfer characteristics. This work can help to understand the modern age functional materials at molecular level and to design new molecules. PMID- 25808593 TI - Mitochondrial protein import receptors in Kinetoplastids reveal convergent evolution over large phylogenetic distances. AB - Mitochondrial protein import is essential for all eukaryotes and mediated by hetero-oligomeric protein translocases thought to be conserved within all eukaryotes. We have identified and analysed the function and architecture of the non-conventional outer membrane (OM) protein translocase in the early diverging eukaryote Trypanosoma brucei. It consists of six subunits that show no obvious homology to translocase components of other species. Two subunits are import receptors that have a unique topology and unique protein domains and thus evolved independently of the prototype receptors Tom20 and Tom70. Our study suggests that protein import receptors were recruited to the core of the OM translocase after the divergence of the major eukaryotic supergroups. Moreover, it links the evolutionary history of mitochondrial protein import receptors to the origin of the eukaryotic supergroups. PMID- 25808596 TI - Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells. AB - Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-alpha and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF alpha or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFkappaB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-alpha with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFkappaB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN. PMID- 25808598 TI - An Amide-Functionalized Dynamic Metal-Organic Framework Exhibiting Visual Colorimetric Anion Exchange and Selective Uptake of Benzene over Cyclohexane. AB - A novel porous metal-organic framework (MOF) architecture is formed by a neutral amide-functionalized ligand and copper(II). Upon desolvation, this compound undergoes a dynamic structural transformation from a one-dimensional (1D) porous phase to a two-dimensional (2D) non-porous phase that shows selective uptake of benzene over cyclohexane. The as-synthesized compound also acts as a visual colorimetric anion sensor for thiocyanate. PMID- 25808597 TI - Immunocytochemical results for HER2 and Ki67 in breast cancer touch-smear cell specimens are reliable. AB - BACKGROUND: Re-evaluation of the subtype of recurrent breast cancer is necessary for deciding the treatment approach, but it is often not performed due to the difficulty of obtaining tissue specimens from a recurrent lesion, etc. However, when a recurrent lesion is close to the body surface, fine-needle aspiration cells (FNA cells) can be easily obtained, and immunocytochemical (ICC) analysis of hormone receptors expression in FNA cells is said to be highly reliable. However, there is no consensus regarding ICC analysis of human epidermal growth factor receptor type 2 (HER2) expression and the Ki67 index using FNA cells. METHODS: Touch-smear cells (TSC) were prepared from resected specimens from 36 patients with primary invasive ductal carcinoma of the breast. The TSC were fixed in 95 % ethanol and subjected to ICC analysis for HER2 using HercepTestTM (Dako) and Ki67 using MIB-1TM (Dako). HER2 expression and the Ki67 index for the TSC were compared with the results of immunohistochemical analysis of histological section (HS). Statistical analyses used the kappa test and Pearson's correlation coefficients. RESULTS: HER2 and Ki67 were analyzed in TSC from 36 and 28 patients, respectively. The HER2 expression scores in the TSC and HS groups showed good agreement (kappa value =0.640) and significant correlation (correlation coefficient =0.860, p < 0.001). The Ki67 indexes in the TSC and HS groups also showed significant correlation (correlation coefficient =0.861, p < 0.001). CONCLUSIONS: The reliability of ICC analysis of HER2 expression and the Ki67 index using TSC were recognized. PMID- 25808599 TI - Does prospective memory influence quality of life in community-dwelling older adults? AB - Older adults commonly experience declines in prospective memory, which describes one's ability to "remember to remember," and can adversely affect instrumental activities of daily living and healthcare compliance. However, the extent to which prospective memory failures may influence quality of life in typically aging older adults is not well understood. One-hundred and four community dwelling older Australians (aged 50 to 82 years) were administered a comprehensive, neuropsychological battery that included the Memory for Intentions Screening Test (MIST), Prospective and Retrospective Memory Questionnaire (PRMQ), Instrumental Activities of Daily Living Questionnaire (IADLQ), and World Health Organization Quality of Life-8 (WHOQOL-8). Multiple regressions controlling for negative affect, medical comorbidities, and other neurocognitive functions revealed an interaction between prospective memory and instrumental activities of daily living in the concurrent prediction of quality of life. Among the 39 older adults who reported multiple problems on the IADLQ, lower performance-based prospective memory (MIST) and higher self-reported prospective memory failures in daily life (PRMQ) were significantly associated with lower quality of life (WHOQOL-8). Conversely, no significant associations were observed between prospective memory and quality of life in the 65 participants without IADL problems. Prospective memory difficulties adversely impact quality of life in community-dwelling older adults who experience problems independently managing their instrumental activities of daily living. These findings extend prior literature showing that prospective memory plays a unique role in the real-world outcomes of older adults and clinical populations and highlight the need to develop effective strategies to enhance prospective memory functioning in these vulnerable groups. PMID- 25808601 TI - Body-Mass Scaling of Metabolic Rate: What are the Relative Roles of Cellular versus Systemic Effects? AB - The reason why metabolic rate often scales allometrically (disproportionately) with body mass has been debated for decades. A critical question concerns whether metabolic scaling is controlled intrinsically at the intracellular level or systemically at the organismal level. Recently, the relative importance of these effects has been tested by examining the metabolic rates of cultured dermal fibroblast and skeletal muscle cells in relation to donor body mass of a variety of birds and mammals. The lack of a relationship between in vitro cellular metabolic rates and body mass suggests that systemic effects, not intrinsic cellular effects are responsible for allometric metabolic scaling observed in whole organisms. Influential resource-transport network theory claims that the most important systemic effect involved is body-size related resource-supply limits to metabolizing cells. However, comparisons of in vitro cellular metabolic rates with scaling relationships for in vivo (basal) metabolic rates suggest that other systemic effects, such as body-size dependent biological regulation and tissue composition may also have major, perhaps more important effects. Furthermore, systemic effects must ultimately act at the cellular level, for example, by induced variation in the function, structure and intracellular densities of mitochondria. The mechanistic pathways involved require further study. PMID- 25808603 TI - The F-box protein Fbp1 functions in the invasive growth and cell wall integrity mitogen-activated protein kinase (MAPK) pathways in Fusarium oxysporum. AB - F-box proteins determine substrate specificity of the ubiquitin-proteasome system. Previous work has demonstrated that the F-box protein Fbp1, a component of the SCF(Fbp1) E3 ligase complex, is essential for invasive growth and virulence of the fungal plant pathogen Fusarium oxysporum. Here, we show that, in addition to invasive growth, Fbp1 also contributes to vegetative hyphal fusion and fungal adhesion to tomato roots. All of these functions have been shown previously to require the mitogen-activated protein kinase (MAPK) Fmk1. We found that Fbp1 is required for full phosphorylation of Fmk1, indicating that Fbp1 regulates virulence and invasive growth via the Fmk1 pathway. Moreover, the Deltafbp1 mutant is hypersensitive to sodium dodecylsulfate (SDS) and calcofluor white (CFW) and shows reduced phosphorylation levels of the cell wall integrity MAPK Mpk1 after SDS treatment. Collectively, these results suggest that Fbp1 contributes to both the invasive growth and cell wall integrity MAPK pathways of F. oxysporum. PMID- 25808604 TI - Current resources for evidence-based practice, May/June 2015. PMID- 25808602 TI - Intravesical hyaluronic acid treatment improves bacterial cystitis and reduces cystitis-induced hypercontractility in rats. AB - OBJECTIVE: To investigate the effect of intravesical hyaluronic acid on Escherichia coli-induced cystitis and cystitis-induced hypercontractility in rats. METHODS: Bacterial cystitis was induced in Wistar female rats by intravesical inoculation of E. coli. Isotonic saline was instilled in the control group (n = 6). The rats were either non-treated, treated with gentamycin (4 mg/kg, 5 days) or treated intravesically with hyaluronic acid (0.5 mL, 0.5%). On the eighth day, the bladder tissues were excised for histological examination, and the measurements of myeloperoxidase, superoxide dismutase and catalase activities. Contraction/relaxation responses to carbachol, isoprotrenol and papaverine were studied. RESULTS: Tissue myeloperoxidase activity was increased, but superoxide dismutase and catalase activities were decreased in bacterial cystitis, while hyaluronic acid treatment reversed these changes. In the hyaluronic acid-treated group, healing of the uroepithelium was observed, while decreased inflammatory cell infiltration was obvious in gentamycin-treated group. E. coli-induced cystitis in all rats resulted in increased contraction responses to carbachol compared with controls (P < 0.01). Treatment with hyaluronic acid, but not gentamycin, significantly (P < 0.05) depressed hypercontractility at maximum carbachol concentrations. In all rats with cystitis, papaverine-induced relaxation was increased, whereas isoproterenol-induced relaxation curves were not different between the studied groups. CONCLUSION: Gentamycin treatment, despite its ameliorative effect on inflammation, had no impact on the contractile dysfunction of the injured bladder. Intravesical hyaluronic acid, in addition to its supportive role in the healing of the epithelium, seems to lower the increased threshold for contraction and to reduce oxidative stress. These findings support a potential role for hyaluronic acid in the treatment of bacterial cystitis. PMID- 25808600 TI - Non-typhoidal Salmonella Typhimurium ST313 isolates that cause bacteremia in humans stimulate less inflammasome activation than ST19 isolates associated with gastroenteritis. AB - Salmonella is an enteric pathogen that causes a range of diseases in humans. Non typhoidal Salmonella (NTS) serovars such as Salmonella enterica serovar Typhimurium generally cause a self-limiting gastroenteritis whereas typhoidal serovars cause a systemic disease, typhoid fever. However, S. Typhimurium isolates within the multi-locus sequence type ST313 have emerged in sub-Saharan Africa as a major cause of bacteremia in humans. The S. Typhimurium ST313 lineage is phylogenetically distinct from classical S. Typhimurium lineages, such as ST19, that cause zoonotic gastroenteritis worldwide. Previous studies have shown that the ST313 lineage has undergone genome degradation when compared to the ST19 lineage, similar to that observed for typhoidal serovars. Currently, little is known about phenotypic differences between ST313 isolates and other NTS isolates. We find that representative ST313 isolates invade non-phagocytic cells less efficiently than the classical ST19 isolates that are more commonly associated with gastroenteritis. In addition, ST313 isolates induce less Caspase-1-dependent macrophage death and IL-1beta release than ST19 isolates. ST313 isolates also express relatively lower levels of mRNA of the genes encoding the SPI-1 effector sopE2 and the flagellin, fliC, providing possible explanations for the decrease in invasion and inflammasome activation. The ST313 isolates have invasion and inflammatory phenotypes that are intermediate; more invasive and inflammatory than Salmonella enterica serovar Typhi and less than ST19 isolates associated with gastroenteritis. This suggests that both phenotypically and at the genomic level ST313 isolates are evolving signatures that facilitate a systemic lifestyle in humans. PMID- 25808605 TI - Molecular signalling pathways in canine gliomas. AB - In this study, we determined the expression of key signalling pathway proteins TP53, MDM2, P21, AKT, PTEN, RB1, P16, MTOR and MAPK in canine gliomas using western blotting. Protein expression was defined in three canine astrocytic glioma cell lines treated with CCNU, temozolamide or CPT-11 and was further evaluated in 22 spontaneous gliomas including high and low grade astrocytomas, high grade oligodendrogliomas and mixed oligoastrocytomas. Response to chemotherapeutic agents and cell survival were similar to that reported in human glioma cell lines. Alterations in expression of key human gliomagenesis pathway proteins were common in canine glioma tumour samples and segregated between oligodendroglial and astrocytic tumour types for some pathways. Both similarities and differences in protein expression were defined for canine gliomas compared to those reported in human tumour counterparts. The findings may inform more defined assessment of specific signalling pathways for targeted therapy of canine gliomas. PMID- 25808606 TI - Simplified procedure for the immediate loading of a complete fixed prosthesis supported by four implants in the maxillary jaw: a 2-year prospective study. AB - PURPOSE: The aim of this study was to verify the reliability of a system for the fixed retention of complete maxillary prostheses supported by four implants with a follow-up of 2 years. MATERIAL AND METHODS: Patients were treated between September 2009 and December 2010 with four Straumann Bone Level SLActive implants supporting a complete prosthesis (CPs). The two distal implants were positioned mesially to the maxillary sinus and with a mesio-distal inclination <= 30 degrees in order to reduce the distal prosthesis cantilever. An immediate loading surgical protocol was used. The CPs were planned to be fixed to multibase abutments to test their retention for a fixed rehabilitation. Clinical and radiographic parameters as probing pocket depth (PPD), bleeding score (mBI), plaque index (PI), and marginal bone loss (MBL) were assessed at a 1- and 2-year follow-up visits. Moreover, any biological and prosthodontic maintenance events were recorded. Clinical and radiographic parameters changes were analyzed. RESULTS: Twenty-one patients treated with a total of 84 implants completed the 2 year examination period. Four patients were lost to follow up. No technical complication was recorded. Also, no implant, reconstruction, or abutment failures were observed. Therefore, an implant and prosthetic survival rate of 100% were achieved after 2 years. The mean periodontal parameter scores after 2 years of function were 2.6 mm for PPD (SD 0.8 mm), 0.3 for mBI (SD 0.5 mm), and 1.2 for PI (SD 0.4 mm) indexes, respectively. In addition, the mean MBL score measured at the 2-year follow-up visit was -0.34 mm (SD of -0.45 mm). Furthermore, no peri implant soft tissue inflammation or peri-implant infection was observed. CONCLUSIONS: It has been shown that immediate loading of four implants positioned anteriorly to the maxillary sinus could be a reliable treatment procedure to support fixed complete restorations. PMID- 25808608 TI - Rapid increase in multidrug-resistant enteric bacilli blood stream infection after prostate biopsy - A 10-year population-based cohort study. AB - BACKGROUND: Bloodstream infection following a transrectal prostate biopsy is a well-known and feared complication. Previous studies have shown an increase in multi-resistant bacterial infections as a consequence of higher usage of antibiotics in investigated populations. Our aim was to analyze bacterial resistance patterns in positive blood cultures, after prostate biopsies in Stockholm, Sweden, where the use of antibiotics has been low and decreasing during the last 10 years. METHODS: From the three pathology laboratories in Stockholm, reports of prostate examinations were retrieved (n = 56,076) from 2003 to 2012. By linking men to the National Patient Register all but prostate core biopsies were excluded (n = 12,024). Prostate biopsies in men younger than 30 years of age were excluded (n = 5) leaving 44,047 biopsies for analysis. From laboratory information systems data regarding blood cultures were retrieved. Proportions of blood cultures within 30 days by year were calculated. Crude and adjusted logistic regression models were used to estimate ORs. RESULTS: In total, 44,047 prostate biopsies were performed in 32,916 men over 10 years. On 620 occasions a blood culture was drawn within 30 days of the biopsy; 266 of these were positive. The proportions with positive blood cultures in 2003 and 2012 were 0.38 and 1.14%, respectively. The proportion of multidrug-resistant bacteria increased significantly during the study. In the crude and the adjusted analysis, the year of biopsy and Charlson Comorbidity Index were associated with the risk of having a positive blood culture. CONCLUSION: Multidrug-resistant enteric bacilli are becoming a problem in Sweden, despite low antimicrobial use. Men need to be informed about the increasing risks of infectious complications of transrectal prostate biopsy. One out of 50 men undergoing a prostate biopsy will develop symptoms suggestive of a bloodstream infection after the biopsy and one in 100 men will have a positive blood culture. PMID- 25808610 TI - Clinical value of flow cytometric assessment of dendritic cell subsets in peripheral blood after solid organ transplantation. PMID- 25808609 TI - Laser trapping of colloidal metal nanoparticles. AB - Optical trapping using focused laser beams (laser tweezers) has been proven to be extremely useful for contactless manipulation of a variety of small objects, including biological cells, organelles within cells, and a wide range of other dielectric micro- and nano-objects. Colloidal metal nanoparticles have drawn increasing attention in the field of optical trapping because of their unique interactions with electromagnetic radiation, caused by surface plasmon resonance effects, enabling a large number of nano-optical applications of high current interest. Here we try to give a comprehensive overview of the field of laser trapping and manipulation of metal nanoparticles based on results reported in the recent literature. We also discuss and describe the fundamentals of optical forces in the context of plasmonic nanoparticles, including effects of polarization, optical angular momentum, and laser heating effects, as well as the various techniques that have been used to trap and manipulate metal nanoparticles. We conclude by suggesting possible directions for future research. PMID- 25808611 TI - Baclofen as an anti-craving agent for adolescent inhalant dependence syndrome. PMID- 25808607 TI - Influence of early trauma on features of schizophrenia. AB - AIM: This proof-of-concept study examined if early trauma influences features of schizophrenia, consistent with hypothalamic-pituitary-adrenal (HPA) axis activation. METHODS: Early trauma and current perceived stress were assessed in 28 treated schizophrenia cases, along with salivary cortisol, brain volumes, cognition and symptoms. RESULTS: Early trauma predicted more positive (r = .66, P = .005) and dysthymia symptoms (r -.65, P = .007), but less negative symptoms (r = -.56, P = .023), as well as reduced whole brain volumes (r = .50, P = .040) and increased amygdala to whole brain volume ratios (r = .56, P = .018). Larger volume reductions accompanied cortisol levels: evening values predicted smaller whole brain and hippocampal volumes whereas afternoon levels only significantly predicted smaller brain volumes in women. Sex differences were demonstrated between early trauma and cognition, with better cognition in traumatized women than other women and no male effects. Current perceived stress was related to dysthymia (especially in women) and diminished sense of purpose and social drive (especially in men). CONCLUSIONS: These results suggest that early trauma and current stress impact features of schizophrenia, consistent with stress sensitization and increased dopamine activity for treatment refractory positive symptoms, as well as the cascade of increased morning cortisol, reduced brain volumes, and depressive and deficit symptoms. Conversely, cognitive deficits and negative symptoms may arise from a distinct diathesis. The sex differences accord with the literature on human HPA function and stress responses. Early trauma may be a stressor in the aetiopathophysiology of schizophrenia, particularly for cases with treatment refractory positive symptoms, and may guide future treatment development. PMID- 25808612 TI - Investigation of Multiple Frequency Ranges Using Discrete Wavelet Decomposition of Resting-State Functional Connectivity in Mild Traumatic Brain Injury Patients. AB - The aim of this study was to investigate if discrete wavelet decomposition provides additional insight into resting-state processes through the analysis of functional connectivity within specific frequency ranges within the default mode network (DMN) that may be affected by mild traumatic brain injury (mTBI). Participants included 32 mTBI patients (15 with postconcussive syndrome [PCS+] and 17 without [PCS-]). mTBI patients received resting-state functional magnetic resonance imaging (rs-fMRI) at acute (within 10 days of injury) and chronic (6 months postinjury) time points and were compared with 31 controls (healthy control [HC]). The wavelet decomposition divides the time series into multiple frequency ranges based on four scaling factors (SF1: 0.125-0.250 Hz, SF2: 0.060 0.125 Hz, SF3: 0.030-0.060 Hz, SF4: 0.015-0.030 Hz). Within each SF, wavelet connectivity matrices for nodes of the DMN were created for each group (HC, PCS+, PCS-), and bivariate measures of strength and diversity were calculated. The results demonstrate reduced strength of connectivity in PCS+ patients compared with PCS- patients within SF1 during both the acute and chronic stages of injury, as well as recovery of connectivity within SF1 across the two time points. Furthermore, the PCS- group demonstrated greater network strength compared with controls at both time points, suggesting a potential compensatory or protective mechanism in these patients. These findings stress the importance of investigating resting-state connectivity within multiple frequency ranges; however, many of our findings are within SF1, which may overlap with frequencies associated with cardiac and respiratory activities. PMID- 25808613 TI - Atypical antipsychotic initiation and the risk of type II diabetes in children and adolescents. AB - PURPOSE: To estimate the risk of type II diabetes (T2DM) in children and adolescents initiating atypical antipsychotic (AAP) therapy. METHODS: We conducted a retrospective cohort study using a new user design approach. Medical and pharmacy claims data between 1 January 2007 and 31 December 2009 for dependents ages 4 to 18 from an employed, commercially insured population from across the USA were included. AAP exposure was defined in the presence of a pharmacy claim preceded by at least six months of AAP-free history. We used propensity score (PS) methodology to identify and match incident AAP users and non-users. New-onset T2DM, was defined based on medical and pharmacy claims. Follow-up was extended until the date of new-onset T2DM or the end of the study period. The risk of T2DM was evaluated in an intent to treat fashion using the Kaplan-Meier estimator and Cox proportional hazard regression that provided hazard ratio (HR) and associated 95% confidence interval (CI). RESULTS: Our study population included 6236 new AAP users and 22 080 non-users. In this PS-matched sample, the estimated risk of T2DM was twice as high in AAP users as non-users (HR 2.18, 95% CI 1.45-3.29). Noticeable risk differences between AAP-treated and control groups materialized within four months of AAP initiation and became constant after six months until the end of the follow-up. CONCLUSIONS: Children and adolescents who were prescribed an AAP medication had a two times higher risk of developing T2DM; our study raises questions about continued AAP use in children and adolescents. PMID- 25808614 TI - TNFalpha Post-Translationally Targets ZnT2 to Accumulate Zinc in Lysosomes. AB - Mammary epithelial cells undergo widespread lysosomal-mediated cell death (LCD) during early mammary gland involution. Recently, we demonstrated that tumor necrosis factor-alpha (TNFalpha), a cytokine released during early involution, redistributes the zinc (Zn) transporter ZnT2 to accumulate Zn in lysosomes and activate LCD and involution. The objective of this study is to determine how TNFalpha retargets ZnT2 to lysosomes. We tested the hypothesis that TNFalpha signaling dephosphorylates ZnT2 to uncover a highly conserved dileucine motif (L294L) in the C-terminus of ZnT2, allowing adaptor protein complex-3 (AP-3) to bind and traffic ZnT2 to lysosomes. Confocal micrographs showed that TNFalpha redistributed wild-type (WT) ZnT2 from late endosomes (Pearson's coefficient = 0.202 +/- 0.05 and 0.097 +/- 0.03; P<0.05) to lysosomes (0.292 +/- 0.03 and 0.649 +/- 0.03; P<0.0001), which increased lysosomal Zn (P<0.0001) and activated LCD (P<0.0001) compared to untreated cells. Mutation of the dileucine motif (L294V) eliminated the ability of TNFalpha to redistribute ZnT2 from late endosomes to lysosomes, increase lysosomal Zn, or activate LCD. Moreover, TNFalpha increased (P<0.05) AP-3 binding to wt ZnT2 but not to L294V immunoprecipitates. Finally, using phospho- and dephospho-mimetics of predicted phosphorylation sites (T281, T288, and S296), we found that dephosphorylated S296 was required to target ZnT2 to accumulate Zn in lysosomes and activate LCD. Our findings suggest that women with variation in the C-terminus of ZnT2 may be at risk for inadequate involution and breast disease due the inability to traffic ZnT2 to lysosomes. PMID- 25808615 TI - Achievement of 1 H-19 F heteronuclear experiments using the conventional spectrometer with a shared single high band amplifier. AB - The (1)H-(19) F heteronuclear NMR experiments were achieved using the conventional spectrometer equipped with a single high band amplifier and a (1)H/(19)F/(13) C double-tuned probe. Although double high band amplifiers are generally required to perform such experiments, a simple modification of pathway in the conventional spectrometer was capable of acquiring various (1)H-(19)F heteronuclear spectra. The efficiency of the present technique was demonstrated in an application for (19)F{(1)H} and (1)H{(19)F} saturation transfer difference experiments. PMID- 25808616 TI - Effect of neohesperidin dihydrochalcone on the activity and stability of alpha amylase: a comparative study on bacterial, fungal, and mammalian enzymes. AB - Neohesperidin dihydrochalcone (NHDC) was recently introduced as an activator of mammalian alpha-amylase. In the current study, the effect of NHDC has been investigated on bacterial and fungal alpha-amylases. Enzyme assays and kinetic analysis demonstrated the capability of NHDC to significantly activate both tested alpha-amylases. The ligand activation pattern was found to be more similar between the fungal and mammalian enzyme in comparison with the bacterial one. Further, thermostability experiments indicated a stability increase in the presence of NHDC for the bacterial enzyme. In silico (docking) test locates a putative binding site for NHDC on alpha-amylase surface in domain B. This domain shows differences in various alpha-amylase types, and the different behavior of the ligand toward the studied enzymes may be attributed to this fact. PMID- 25808618 TI - Palladium-catalyzed aminocarbonylation of N-chloroamines with boronic acids. AB - Aryl (pseudo)halide-based (C-X) carbonylation reactions have been extensively studied during the past few decades. From both academic and synthetic points of view, the carbonylative transformation of N-X bonds represents an interesting and attractive area of investigation. In light of this, the first carbonylative cross coupling between N-chloroamines and organoboronic acids has been developed. This new type of aminocarbonylation proceeds at mild temperatures (45-55 degrees C) with 2 mol % Pd/C (10 wt %) as the ligand-free catalyst. Not only arylboronic acids, but also alkenyl- and alkylboronic acids can be applied as the substrates and bromide and iodide substituents in the substrates are well tolerated. Initial mechanistic investigations have also been performed. PMID- 25808617 TI - Computational analysis of spiro-oxindole inhibitors of the MDM2-p53 interaction: insights and selection of novel inhibitors. AB - Since MDM2 is an inhibitor of the p53 tumor suppressor, disrupting the MDM2-p53 interaction is a promising approach for cancer therapy. Here, we used molecular dynamics simulations followed by free energy decomposition analysis to study conformational changes in MDM2 induced by three known spiro-oxindole inhibitors. Analysis of individual energy terms suggests that van der Waals and electrostatic interactions explain much of the binding affinities of these inhibitors. Binding free energies calculated for the three inhibitors using the molecular mechanics generalized Born surface area model were consistent with experimental data, suggesting the validity of this approach. Based on this structure-function analysis, several novel spiro-oxindole derivatives were selected and evaluated for their ability to block the MDM2-p53 interaction in vitro. These results suggest that combining in silico and experimental techniques can provide insights into the structure-function relationships of MDM2 inhibitors and guide the rational design of anticancer drugs targeting the MDM2-p53 interaction. PMID- 25808619 TI - Combined free flaps with arteriovenous loops for reconstruction of extensive thoracic defects after sternal osteomyelitis. AB - BACKGROUND: Various local flaps have been described for patients suffering from sternal osteomyelitis and are regarded as a standard procedure for defect reconstruction. In contrast, the use of microsurgical free flaps has been reported anecdotally only. We present our experiences with the combination of an arteriovenous loop and a free flap transfer in defects larger than half of the sternum. METHODS: Between January 2012 and October 2014, eight patients with a mean age of 68 years who suffered from extensive deep sternal osteomyelitis were operated in a consecutive series. After radical surgical debridement, the defect size comprised all three thirds of the sternum. Defect reconstruction was achieved by means of free flap transplantation using the vastus lateralis myocutaneous flap, rectus abdominis, and bipedicled latissimus dorsi/parascapular flap. As local recipient vessels were depleted in all patients, the pedicle of the flap was anastomosed to a high-flow and short-length subclavian arteriovenous loop as recipient vessel in all cases. RESULTS: The immediate postoperative course in all patients was uneventful despite one axonal injury to the femoral nerve at the donor site. There was no partial or total flap loss. During a mean follow-up of 9 months, one patient suffered from a local infection at the donor site. In all patients, a successful defect reconstruction could be achieved. CONCLUSION: Depletion of local recipient vessels as an obstacle for free flap reconstruction can be overcome by creating an arteriovenous loop. Even extensive defects are adequate for defect reconstruction using a single or, in extreme cases, bipedicled free flap. PMID- 25808621 TI - Removal of ENT foreign bodies in children. PMID- 25808625 TI - Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice. AB - The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up-regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high-fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2 mediated up-regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up-regulation. CONCLUSION: Sphk2 is transcriptionally up-regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism. PMID- 25808626 TI - Safety and Effectiveness of Highly Active Antiretroviral Therapy in Treatment Naive HIV Patients: Preliminary Findings of a Cohort Event Monitoring Study in Belarus. AB - BACKGROUND AND OBJECTIVE: Antiretroviral drugs have well-documented evidence based favorable benefit-risk ratios. Although various studies have investigated and characterized the safety profile of antiretroviral medicines, there are a limited number of studies evaluating the safety of first-line antiretroviral therapy (ART) in patients with a specific co-morbidity. A cohort event monitoring (CEM) study of the safety and effectiveness of antiretroviral medicines in a target population that has a significant level of co-morbidities (chronic infectious diseases, peripheral blood cytopenias) was implemented. The aim was to evaluate the safety profile of the highly active ART (HAART) in the target population and subpopulations with risk factors, to optimize the monitoring and decision-making procedure for subgroups of patients with specific types of co morbidity, and to implement a more vigilant approach to therapy management in risk groups of patients. METHODS: Prospective observational CEM was implemented among HAART-naive HIV-positive patients at four clinical sites from December 2012. Eligible patients were those starting first-line HAART. Close medical supervision of all enrolled patients, with regular clinical and laboratory monitoring, was provided by healthcare professionals within 1 year after commencement of therapy. Standardized forms were used for data collection on initial and subsequent visits. All objective or subjective deviations in condition (events) were assessed for a causal relationship with ART, and for severity, seriousness, reversibility, preventability, and pre-existing risk factors in the case of adverse drug reactions (ADRs). RESULTS: A total of 518 HAART-naive HIV-positive patients were enrolled in the CEM study. Of these patients, 65% (337) experienced one or several ADRs related to one or more components of HAART. Most of the ADRs reported were non-serious, expected, common (very common), transient (correctable), or reversible. The most common were hematotoxic, hepatotoxic, and neurotoxic adverse reactions. In several cases, some types of toxicities, associated with zidovudine, efavirenz, and nevirapine, had a high level of severity, necessitating hospitalization and drug regimen or single-agent substitution. Severe cases of hematological, hepatobiliary, and psychiatric toxicities were associated with pre-existing risk factors. CONCLUSION: CEM is an effective tool for safety and effectiveness monitoring and could be successfully implemented for intensive study of important safety issues and for overcoming knowledge gaps regarding safety. In order to achieve a favorable benefit-risk ratio for HAART in the specific sections of the population with pre-existing risk factors for development of ART toxicities, more vigilant consideration and careful assessment before therapy is commenced and further regular monitoring of key laboratory parameters is required. PMID- 25808624 TI - The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells. AB - Activation of genes promoting aerobic glycolysis and suppression of mitochondrial oxidative phosphorylation is one of the hallmarks of cancer. The RUNX2 transcription factor mediates breast cancer (BC) metastasis to bone and is regulated by glucose availability. But, the mechanisms by which it regulates glucose metabolism and promotes an oncogenic phenotype are not known. RUNX2 expression in luminal BC cells correlated with lower estrogen receptor-alpha (ERalpha) levels, anchorage-independent growth, expression of glycolytic genes, increased glucose uptake, and sensitivity to glucose starvation, but not to inhibitors of oxidative phosphorylation. Conversely, RUNX2 knockdown in triple negative BC cells inhibited mammosphere formation and glucose dependence. RUNX2 knockdown resulted in lower LDHA, HK2, and GLUT1 glycolytic gene expression, but upregulation of pyruvate dehydrogenase-A1 (PDHA1) mRNA and enzymatic activity, which was consistent with lower glycolytic potential. The NAD-dependent histone deacetylase, SIRT6, a known tumor suppressor, was a critical regulator of these RUNX2-mediated metabolic changes. RUNX2 expression resulted in elevated pAkt, HK2, and PDHK1 glycolytic protein levels that were reduced by ectopic expression of SIRT6. RUNX2 also repressed mitochondrial oxygen consumption rates (OCR), a measure of oxidative phosphorylation (respiration). Overexpression of SIRT6 increased respiration in RUNX2-positive cells, but knockdown of SIRT6 in cells expressing low RUNX2 decreased respiration. RUNX2 repressed SIRT6 expression at both the transcriptional and post-translational levels and endogenous SIRT6 expression was lower in malignant BC tissues or cell lines that expressed high levels of RUNX2. These results support a hypothesis whereby RUNX2-mediated repression of the SIRT6 tumor suppressor regulates metabolic pathways that promote BC progression. PMID- 25808627 TI - Potential Use of Bacterial Community Succession in Decaying Human Bone for Estimating Postmortem Interval. AB - Bacteria are taphonomic agents of human decomposition, potentially useful for estimating postmortem interval (PMI) in late-stage decomposition. Bone samples from 12 individuals and three soil samples were analyzed to assess the effects of decomposition and advancing time on bacterial communities. Results indicated that partially skeletonized remains maintained a presence of bacteria associated with the human gut, whereas bacterial composition of dry skeletal remains maintained a community profile similar to soil communities. Variation in the UniFrac distances was significantly greater between groups than within groups (p < 0.001) for the unweighted metric and not the weighted metric. The members of the bacterial communities were more similar within than between decomposition stages. The oligotrophic environment of bone relative to soft tissue and the physical protection of organic substrates may preclude bacterial blooms during the first years of skeletonization. Therefore, community membership (unweighted) may be better for estimating PMI from skeletonized remains than community structure (weighted). PMID- 25808629 TI - First experience of simultaneous PET/MRI for the early detection of cardiac involvement in patients with Anderson-Fabry disease. AB - PURPOSE: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder associated with severe multiorgan dysfunction and premature death. Early diagnosis and treatment strategies play a key role in patient outcome. We investigated the potential role of hybrid PET/MR imaging in the assessment of early cardiac involvement in AFD patients. METHODS: Thirteen AFD patients without cardiac symptoms and with normal left ventricular function underwent simultaneous cardiac PET/MR imaging after administration of (18)F-FDG. Cardiac FDG uptake was quantified by measuring the standardized uptake value in 17 myocardial segments in each subject. The coefficient of variation (COV, i.e. the standard deviation divided by the average) of the uptake of the 17 segments was calculated as an index of heterogeneity in the heart. RESULTS: Six patients exhibited focal late gadolinium enhancement (LGE) indicating intramyocardial fibrosis, and four of these also had positive short inversion time inversion recovery (STIR) sequences. All patients with LGE and positive STIR MR images showed focal FDG uptake in the corresponding myocardial segments indicating inflammation. Of the seven patients with negative LGE and STIR images, five showed homogeneous FDG cardiac uptake and two showed heterogeneous FDG uptake. The COV was significantly greater in patients with focal FDG uptake (0.25 +/- 0.02) than in those without (0.14 +/- 0.07, p < 0.01). CONCLUSION: PET/MR imaging is clinically feasible for the early detection of cardiac involvement in patients with AFD. Further studies evaluating the role of hybrid PET/MR imaging in management of the disease in larger patient populations are warranted. PMID- 25808628 TI - Specific Preferences in Lineage Choice and Phenotypic Plasticity of Glioma Stem Cells Under BMP4 and Noggin Influence. AB - Although BMP4-induced differentiation of glioma stem cells (GSCs) is well recognized, details of the cellular responses triggered by this morphogen are still poorly defined. In this study, we established several GSC-enriched cell lines (GSC-ECLs) from high-grade gliomas. The expansion of these cells as adherent monolayers, and not as floating neurospheres, enabled a thorough study of the phenotypic changes that occurred during their differentiation. Herein, we evaluated GSC-ECLs' behavior toward differentiating conditions by depriving them of growth factors and/or by adding BMP4 at different concentrations. After analyzing cellular morphology, proliferation and lineage marker expression, we determined that GSC-ECLs have distinct preferences in lineage choice, where some of them showed an astrocyte fate commitment and others a neuronal one. We found that this election seems to be dictated by the expression pattern of BMP signaling components present in each GSC-ECL. Additionally, treatment of GSC-ECLs with the BMP antagonist, Noggin, also led to evident phenotypic changes. Interestingly, under certain conditions, some GSC-ECLs adopted an unexpected smooth muscle-like phenotype. As a whole, our findings illustrate the wide differentiation potential of GSCs, highlighting their molecular complexity and paving a way to facilitate personalized differentiating therapies. PMID- 25808630 TI - Specific efficacy of peptide receptor radionuclide therapy with (177)Lu octreotate in advanced neuroendocrine tumours of the small intestine. AB - PURPOSE: Increasing evidence supports the value of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours (NET), but there are limited data on its specific efficacy in NET of small intestinal (midgut) origin. This study aims to define the benefit of PRRT with (177)Lu octreotate for this circumscribed entity derived by a uniformly treated patient cohort. METHODS: A total of 61 consecutive patients with unresectable, advanced small intestinal NET G1-2 stage IV treated with (177)Lu-octreotate (4 intended cycles at 3-month intervals, mean activity per cycle 7.9 GBq) were analysed. Sufficient tumour uptake on baseline receptor imaging and either documented tumour progression (n = 46) or uncontrolled symptoms (n = 15) were prerequisites for treatment. Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Assessment of survival was performed using Kaplan-Meier curves and Cox proportional hazards model for uni- and multivariate analyses. Toxicity was assessed according to standardized follow-up laboratory work-up including blood counts, liver and renal function, supplemented with serial (99m)Tc diethylenetriaminepentaacetic acid (DTPA) clearance measurements. RESULTS: The median follow-up period was 62 months. Reversible haematotoxicity (>= grade 3) occurred in five patients (8.2%). No significant nephrotoxicity (>= grade 3) was observed. Treatment response according to modified SWOG criteria consisted of partial response in 8 (13.1%), minor response in 19 (31.1%), stable disease in 29 (47.5%) and progressive disease in 5 (8.2%) patients. The disease control rate was 91.8%. Median progression-free survival (PFS) and overall survival (OS) was 33 [95% confidence interval (CI) 25-41] and 61 months (95% CI NA), respectively. Objective response was associated with longer survival (p = 0.005). Independent predictors of shorter PFS were functionality [hazard ratio (HR) 2.1, 95% CI 1.0 4.5, p = 0.05] and high plasma chromogranin A (CgA) levels > 600 ng/ml (HR 2.9, 95% CI 1.5-5.5, p < 0.001) at baseline. CONCLUSION: PRRT is well tolerated and very effective in advanced well-differentiated small intestinal (midgut) NET. A high disease control rate and long PFS can be achieved with this modality after failure of standard biotherapy with somatostatin analogues. Tumour functionality and high plasma CgA appear to be independent predictors of unfavourable patient outcome. PMID- 25808632 TI - 18F-Fluorocholine PET/CT as a complementary tool in the follow-up of low-grade glioma. PMID- 25808631 TI - (18)F-Fluorocholine PET/CT for early response assessment in patients with metastatic castration-resistant prostate cancer treated with enzalutamide. AB - PURPOSE: We investigated the role of (18)F-methylcholine (FCH) PET/CT in the early evaluation of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide. METHODS: The study group comprised 36 patients with a median age of 72 years (range 48-90 years) who were treated with enzalutamide 160 mg once daily after at least one chemotherapeutic regimen with docetaxel. Patients were evaluated monthly for serological prostate-specific antigen (PSA) response. FCH PET/CT was performed at baseline and repeated after 3 6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: At a median follow-up of 24.2 months (range 1.8-27.3 months), 34 patients were evaluable for early FCH PET/CT evaluation of response, and of these 17 showed progressive disease (PD) and 17 had stable disease or a partial response. A decrease in PSA level of more than 50% was observed in 21 patients. Early FCH PET/CT PD predicted radiological PD 3 months in advance of CT in 12 of 18 patients (66%) and was discordant with the decrease in PSA level in 13 patients. In 6 of these, biochemical PD was confirmed in 2 months. In multivariate analysis, only decrease in PSA level and FCH PET/CT were significant predictors of PFS (p = 0.0005 and p = 0.029, respectively), whereas decrease in PSA level alone was predictive of OS (p = 0.007). CONCLUSION: This is one of the first studies to evaluate the role of FCH PET/CT as an early predictor of outcome in mCRPC patients treated with enzalutamide. Our preliminary results suggest that the combination of FCH PET/CT and decrease in PSA level could be a valid tool to predict PFS in mCRPC patients. PSA remains the single most important prognostic factor, while FCH PET/CT does not add more information on OS beyond that obtained from PSA. Further studies in larger populations are needed to confirm these data and to clarify the role of FCH PET/CT in predicting response to enzalutamide in mCRPC patients. PMID- 25808633 TI - Experiences of coercion to sterilize and forced sterilization among women living with HIV in Latin America. AB - INTRODUCTION: Forced and coerced sterilization is an internationally recognized human rights violation reported by women living with HIV (WLHIV) around the globe. Forced sterilization occurs when a person is sterilized without her knowledge or informed consent. Coerced sterilization occurs when misinformation, intimidation tactics, financial incentives or access to health services or employment are used to compel individuals to accept the procedure. METHODS: Drawing on community-based research with 285 WLHIV from four Latin American countries (El Salvador, Honduras, Mexico and Nicaragua), we conduct thematic qualitative analysis of reports of how and when healthcare providers pressured women to sterilize and multivariate logistic regression to assess whether social and economic characteristics and fertility history were associated with pressure to sterilize. RESULTS: A quarter (23%) of the participant WLHIV experienced pressure to sterilize post-diagnosis. WLHIV who had a pregnancy during which they (and their healthcare providers) knew their HIV diagnosis were almost six times more likely to experience coercive or forced sterilization than WLHIV who did not have a pregnancy with a known diagnosis (OR 5.66 CI 95% 2.35-13.58 p<=0.001). WLHIV reported that healthcare providers told them that living with HIV annulled their right to choose the number and spacing of their children and their contraceptive method, employed misinformation about the consequences of a subsequent pregnancy for women's and children's health, and denied medical services needed to prevent vertical (mother-to-child) HIV transmission to coerce women into accepting sterilization. Forced sterilization was practiced during caesarean delivery. CONCLUSIONS: The experiences of WLHIV indicate that HIV related stigma and discrimination by healthcare providers is a primary driver of coercive and forced sterilization. WLHIV are particularly vulnerable when seeking maternal health services. Health worker training on HIV and reproductive rights, improving counselling on HIV and sexual and reproductive health for WLHIV, providing State mechanisms to investigate and sanction coercive and forced sterilization, and strengthening civil society to increase WLHIV's capacity to resist coercion to sterilize can contribute to preventing coercive and forced sterilization. Improved access to judicial and non-judicial mechanisms to procure justice for women who have experienced reproductive rights violations is also needed. PMID- 25808635 TI - Quality of life in amyotrophic lateral sclerosis patients and caregivers: Impact of assistive communication from early stages. AB - INTRODUCTION: In this study we performed a longitudinal investigation to assess the impact of early introduction of assistive communication devices (ACDs) on quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients and their caregivers. METHODS: Patients were followed for 7-10 months (3 evaluation periods). Bulbar-onset ALS patients (N = 27) and paired caregivers (N = 17) were included. Fifteen randomly selected patients received early support in ACD use. Patients were assessed using the ALS Functional Rating Scale-revised (ALSFRS-R), the McGill QoL (MQoL), the Communication Effectiveness Index (CETI), and performance in writing; and caregivers were assessed with the MQoL and World Health Organization Quality of Life questionnaire (WHOQOL-BREF). RESULTS: Patients with early support had higher MQoL Psychological and MQoL Existential well-being domains; caregivers had higher MQoL Support domain and their MQoL Psychological domain positively associated with patient CETI. Most patients could communicate using a touchscreen keyboard to write, even when handwriting and speech were not possible. CONCLUSION: Early intervention with an ACD seems to have a positive impact on QoL and gives patients the opportunity to improve skills for communication in later disease stages. PMID- 25808634 TI - Brief Report: Childhood-Onset Systemic Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study Group Registry. AB - OBJECTIVE: To describe the initial features and long-term outcomes of childhood onset small vessel and medium vessel systemic necrotizing vasculitides (SNVs), including antineutrophil cytoplasmic antibody-associated vasculitides (AAVs) and polyarteritis nodosa (PAN). METHODS: Data on patients with childhood-onset SNV registered in the French Vasculitis Study Group database were reviewed for demographic characteristics, clinical, laboratory, and histologic features, and outcomes. Disease activity was assessed with the Birmingham Vasculitis Activity Score and the Paediatric Vasculitis Activity Score, and damage was scored using the Vasculitis Damage Index. Relapse and survival rates and causes of death were analyzed. RESULTS: Fifty-six patients (35 with AAV and 21 with PAN) (median age at database enrollment 14 years [range 2-17]) were included in the study. The median duration of followup was 96 months (range 1-336); two-thirds of the patients were followed up beyond 18 years of age. Six patients (11%) died, mostly of SNV-related causes. Relapse rates ranged from 33% for microscopic polyangiitis to 50% for eosinophilic granulomatosis with polyangiitis (Churg-Strauss) and 83% for granulomatosis with polyangiitis (Wegener's), with similar rates among AAV and PAN patients (76% and 75%, respectively); neither overall survival nor relapse-free survival differed significantly between the 2 disease groups. Rates of relapse increased after 18 years of age, both among patients with AAV and among patients with PAN. At the last followup evaluation, AAV patients had more major flares and more severe accrued damage compared with PAN patients. CONCLUSION: Despite similar relapse rates, patients with childhood-onset AAVs experienced more major flares with more cumulative damage than those with pediatric PAN. Treatments aimed at reducing the rates of mortality and relapse in this patient group need to be developed and assessed. PMID- 25808636 TI - Impact and effectiveness of risk mitigation strategies on the insurability of nanomaterial production: evidences from industrial case studies. AB - Workers involved in producing nanomaterials or using nanomaterials in manufacturing plants are likely to have earlier and higher exposure to manufactured/engineered nanomaterials (ENM) than the general population. This is because both the volume handled and the probability of the effluence of 'free' nanoparticles from the handled volume are much higher during a production process than at any other stage in the lifecycle of nanomaterials and nanotechnology enabled products. Risk assessment (RA) techniques using control banding (CB) as a framework for risk transfer represents a robust theory but further progress on implementing the model is required so that risk can be transferred to insurance companies. Following a review of RA in general and hazard measurement in particular, we subject a Structural Alert Scheme methodology to three industrial case studies using ZrO2 , TiO2 , and multi-walled carbon nanotubes (MWCNT). The materials are tested in a pristine state and in a remediated (coated) state, and the respective emission and hazard rates are tested alongside the material performance as originally designed. To our knowledge, this is the first such implementation of a CB RA in conjunction with an ENM performance test and offers both manufacturers and underwriters an insight into future applications. PMID- 25808639 TI - Lump on the lower eyelid due to hyaluronic acid filler. PMID- 25808638 TI - siRNA mediated knockdown of tissue factor expression in pigs for xenotransplantation. AB - Acute vascular rejection (AVR), in particular microvascular thrombosis, is an important barrier to successful pig-to-primate xenotransplantation. Here, we report the generation of pigs with decreased tissue factor (TF) levels induced by small interfering (si)RNA-mediated gene silencing. Porcine fibroblasts were transfected with TF-targeting small hairpin (sh)RNA and used for somatic cell nuclear transfer. Offspring were analyzed for siRNA, TF mRNA and TF protein level. Functionality of TF downregulation was investigated by a whole blood clotting test and a flow chamber assay. TF siRNA was expressed in all twelve liveborn piglets. TF mRNA expression was reduced by 94.1 +/- 4.7% in TF knockdown (TFkd) fibroblasts compared to wild-type (WT). TF protein expression in PAEC stimulated with 50 ng/mL TNF-alpha was significantly lower in TFkd pigs (mean fluorescence intensity TFkd: 7136 +/- 136 vs. WT: 13 038 +/- 1672). TF downregulation significantly increased clotting time (TFkd: 73.3 +/- 8.8 min, WT: 45.8 +/- 7.7 min, p < 0.0001) and significantly decreased thrombus formation compared to WT (mean thrombus coverage per viewing field in %; WT: 23.5 +/- 13.0, TFkd: 2.6 +/- 3.7, p < 0.0001). Our data show that a functional knockdown of TF is compatible with normal development and survival of pigs. TF knockdown could be a valuable component in the generation of multi-transgenic pigs for xenotransplantation. PMID- 25808637 TI - Symptomatic intracranial hemorrhage in the ALIAS Multicenter Trial: relationship to endovascular thrombolytic therapy. AB - BACKGROUND: In the ALIAS (Albumin in Acute Stroke) Part 2 Multicenter Trial, 85% of subjects received standard-of-care intravenous tissue plasminogen activator, and 21% received some form of endovascular thrombolysis. The overall rate of symptomatic intracranial hemorrhage was within the expected range but was higher in albumin-treated subjects than in saline-treated subjects. AIMS AND METHODS: Using the trial's Public Use Dataset, we analyzed factors contributing to symptomatic and asymptomatic intracranial hemorrhage in the 'safety sample' of 830 subjects. RESULTS: Four hundred sixteen subjects received albumin therapy, and 414 received saline. Intravenous tissue plasminogen activator was given to 68.2%; intravenous tissue plasminogen activator plus endovascular intervention in 16.4%; and endovascular therapy alone in 43%. Symptomatic intracranial hemorrhage occurred in 41 subjects - within the first 12 h in one-third of cases, and within the first day in ~60%. Intravenous tissue plasminogen activator had been used in 78% of symptomatic intracranial hemorrhage subjects - no higher than in the overall cohort. In contrast, 48.8% of subjects with symptomatic intracranial hemorrhage had received endovascular therapy - a rate markedly higher than the 20.7% rate for the entire cohort (P = 0.0001). Sixty-eight point three percent of subjects with symptomatic intracranial hemorrhage had received albumin, and 31.7% saline (risk ratio 2.14, P = 0.025). Other factors associated with symptomatic intracranial hemorrhage were baseline NIHSS and ASPECTS scores and the SEDAN score. Forty-one point four percent of subjects with symptomatic intracranial hemorrhage died. The odds ratio for symptomatic intracranial hemorrhage was 3.89 (95% confidence interval 2.04-7.41) with endovascular therapy and 2.15 (confidence interval 1.08-4.25) with albumin. CONCLUSIONS: Endovascular thrombolysis was the major factor predisposing to symptomatic intracranial hemorrhage, and albumin contributed to this predisposition. The latter may be mediated by albumin's influence on platelet aggregation or collateral perfusion. PMID- 25808640 TI - Effects of diurnal temperature variation on microbial community and petroleum hydrocarbon biodegradation in contaminated soils from a sub-Arctic site. AB - Contaminated soils are subject to diurnal and seasonal temperature variations during on-site ex-situ bioremediation processes. We assessed how diurnal temperature variations similar to that in summer at the site from which petroleum hydrocarbon-contaminated soil was collected affect the soil microbial community and the extent of biodegradation of petroleum hydrocarbons compared with constant temperature regimes. Microbial community analyses for 16S rRNA and alkB genes by pyrosequencing indicated that the microbial community for soils incubated under diurnal temperature variation from 5 degrees C to 15 degrees C (VART5-15) evolved similarly to that for soils incubated at constant temperature of 15 degrees C (CST15). In contrast, under a constant temperature of 5 degrees C (CST5), the community evolved significantly different. The extent of biodegradation of C10 C16 hydrocarbons in the VART5-15 systems was 48%, comparable with the 41% biodegradation in CST15 systems, but significantly higher than CST5 systems at 11%. The enrichment of Gammaproteobacteria was observed in the alkB gene harbouring communities in VART5-15 and CST15 but not in CST5 systems. However, the Actinobacteria was abundant at all temperature regimes. The results suggest that changes in microbial community composition as a result of diurnal temperature variations can significantly influence petroleum hydrocarbon bioremediation performance in cold regions. PMID- 25808642 TI - Impact of intensive treatment on serum methylglyoxal levels among individuals with screen-detected type 2 diabetes: the ADDITION-Denmark study. AB - AIMS: Methylglyoxal (MG) has been implicated in the development of micro- and macrovascular diabetic complications, but it remains unclear how current treatments of type 2 diabetes affect its circulating levels. METHODS: In the Danish arm of the ADDITION trial, we (a) described serum MG levels at baseline and at 6-year follow-up among individuals with screen-detected type 2 diabetes, (b) examined the effect of intensive multifactorial treatment compared with routine care on MG, (c) examined the associations between MG and risk factors at baseline and at follow-up and (d) examined the associations between changes in MG and changes in risk factors. RESULTS: Patients in both treatment arms experienced a significant decline in MG from baseline to follow-up, with no effect of allocation to intensive treatment. In cohort analyses, MG was associated with smoking and fasting glucose at baseline and smoking and LDL cholesterol at follow up. Compared with patients receiving no lipid-lowering treatment, patients receiving lipid-lowering treatment had higher MG at follow-up, and those initiating lipid-lowering treatment experienced a less pronounced decline in MG. CONCLUSIONS: Further studies are required to explore any possible effects of the observed decrease in MG in type 2 diabetes patients as well as the potential interplay between MG, lipids, lipid-lowering treatment and smoking. PMID- 25808641 TI - Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site. AB - AIMS: Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory properties. We tested the ability of MSCs to delay islet allograft rejection. METHODS: Mesenchymal stem cells were generated in vitro from C57BL/6 and BALB/c mice bone marrow, and their immunomodulatory properties were tested in vitro. We then tested the effect of a local or systemic administration of heterologous and autologous MSCs on graft survival in a fully allogeneic model of islet transplantation (BALB/c islets into C57BL/6 mice). RESULTS: In vitro, autologous, but not heterologous, MSCs abrogated immune cell proliferation in response to alloantigens and skewed the immune response toward a Th2 profile. A single dose of autologous MSCs co-transplanted under the kidney capsule with allogeneic islets delayed islet rejection, reduced graft infiltration, and induced long-term graft function in 30 % of recipients. Based on ex vivo analysis of recipient splenocytes, the use of autologous MSCs did not appear to have any systemic effect on the immune response toward graft alloantigens. The systemic injection of autologous MSCs or the local injection of heterologous MSCs failed to delay islet graft rejection. CONCLUSION: Autologous, but not heterologous, MSCs showed multiple immunoregulatory properties in vitro and delayed allograft rejection in vivo when co-transplanted with islets; however, they failed to prevent rejection when injected systemically. Autologous MSCs thus appear to produce a local immunoprivileged site, which promotes graft survival. PMID- 25808643 TI - Psychometric properties of the revised Malay version Medical Outcome Study Social Support Survey using confirmatory factor analysis among postpartum mothers. AB - INTRODUCTION: Social support is an essential component for the physical and emotional well-being of postpartum mothers. The objective of this study is to determine the psychometric properties of the revised Malay version Medical Outcome Study (MOS) Social Support Survey using a confirmatory validity approach. METHODS: A cross-sectional study was conducted involving 144 postpartum mothers attending Obstetric and Gynecology Clinic, Universiti Sains Malaysia Hospital. Construct validity and internal consistency assessment was performed after the translation, content validity and face validity process. The data were analyzed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA) and AMOS 20.0 (SPSS Inc., Chicago, IL, USA). RESULTS: The original questionnaire consists of four domains (emotional/informational support, tangible support, affectionate support and positive social interaction) and 19 items. Affectionate support domain with three items only was treated as a separate construct and was not included in the factor analysis. The final confirmatory model with three constructs and 13 items demonstrated acceptable factor loadings, domain to domain correlation and best fit; (chi2[df]=1.665 [61]; P-value=0.001; Tucker-Lewis Index=0.944; comparative fit index=0.956; root mean square error of approximation=0.068). Composite reliability, average variance extracted and Cronbach's alpha of the domains ranged from 0.649 to 0.903; 0.390 to 0.699; 0.616 to 0.902, respectively. CONCLUSION: The study suggested that the four-factor model with 16 items (including one separate factor of affectionate) of the revised Malay version MOS Social Support Survey was acceptable to be used to measure social support after childbirth because it is valid, reliable and simple. PMID- 25808645 TI - Electrophysiological and morphological properties of neurons in the prepositus hypoglossi nucleus that express both ChAT and VGAT in a double-transgenic rat model. AB - Although it has been proposed that neurons that contain both acetylcholine (ACh) and gamma-aminobutyric acid (GABA) are present in the prepositus hypoglossi nucleus (PHN), these neurons have not been characterized because of the difficulty in identifying them. In the present study, PHN neurons that express both choline acetyltransferase and the vesicular GABA transporter (VGAT) were identified using double-transgenic rats, in which the cholinergic and inhibitory neurons express the fluorescent proteins tdTomato and Venus, respectively. To characterize the neurons that express both tdTomato and Venus (D+ neurons), the afterhyperpolarization (AHP) profiles and firing patterns of these neurons were investigated via whole-cell recordings of brainstem slice preparations. Regarding the three AHP profiles and four firing patterns that the D+ neurons exhibited, an AHP with an afterdepolarization and a firing pattern that exhibited a delay in the generation of the first spike were the preferential properties of these neurons. In the three morphological types classified, the multipolar type that exhibited radiating dendrites was predominant among the D+ neurons. Immunocytochemical analysis revealed that the VGAT-immunopositive axonal boutons that expressed tdTomato were primarily located in the dorsal cap of inferior olive (IO) and the PHN. Although the PHN receives cholinergic inputs from the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus, D+ neurons were absent from these brain areas. Together, these results suggest that PHN neurons that co-express ACh and GABA exhibit specific electrophysiological and morphological properties, and innervate the dorsal cap of the IO and the PHN. PMID- 25808644 TI - Factors associated with willingness to participate in a pharmacologic addiction treatment clinical trial among people who use drugs. AB - BACKGROUND AND OBJECTIVES: Although new medications are needed to address the harms of drug addiction, rates of willingness to participate in addiction treatment trials among people who use drugs (PWUD), have not been well characterized. METHODS: One thousand twenty PWUD enrolled in two community recruited cohorts in Vancouver, Canada, were asked whether they would be willing to participate in a pharmacologic addiction treatment trial. Logistic regression was used to identify factors independently associated with a willingness to participate. RESULTS: Among the 1,020 PWUD surveyed between June 1, 2013 and November 30, 2013, 58.3% indicated a willingness to participate. In multivariate analysis, factors independently associated with a willingness to participate in a pharmacologic addiction treatment trial included: daily heroin injection (Adjusted Odds Ratio [AOR] = 1.75; 95% Confidence Interval [CI]: 1.13 - 2.72); daily crack smoking (AOR = 1.81; 95% CI: 1.23 - 2.66); sex work involvement (AOR = 2.22; 95% CI: 1.21 - 4.06); HIV seropositivity (AOR = 1.49; 95% CI: 1.15 - 1.94); and methadone maintenance therapy participation (AOR = 1.77; 95% CI: 1.37 2.30). DISCUSSION AND CONCLUSIONS: High rates of willingness to participate in a pharmacologic addiction treatment trial were observed in this setting. Importantly, high-risk drug and sexual activities were positively associated with a willingness to participate, which may suggest a desire for new treatment interventions among PWUD engaged in high-risk behavior. SCIENTIFIC SIGNIFICANCE: These results highlight the viability of studies seeking to enroll representative samples of PWUD engaged in high-risk drug use. PMID- 25808647 TI - A prospective study of effects of prenatal maternal stress on later eating disorder manifestations in affected offspring: preliminary indications based on the Project Ice Storm cohort. AB - BACKGROUND: Research associates maternal stress exposures (especially when occurring late in gestation) with heightened risk of subsequent emotional and behavioral problems in affected offspring. However, as yet, no study has examined the association between prenatal maternal stress (PNMS) and affected children's risk of anorexia- or bulimia-type eating disturbances. OBJECTIVE: To study the influences of PNMS on later disordered eating in exposed offspring. METHOD: We used the Eating Attitudes Test (EAT)-26 to measure eating attitudes and behaviors in 54 thirteen-year olds whose mothers had been exposed, while pregnant with these children, to the 1998 Quebec Ice Storm-a natural disaster regarded as a model of exposure to severe environmental stress. Mothers' stress was measured shortly after exposure to the storm using established indices of objective and subjective stress. RESULTS: Hierarchical multiple linear regression analyses indicated that once variance owing to children's body mass index and sex was accounted for, stress exposures during the third trimester of pregnancy predicted elevated EAT-26 scores in affected children-perhaps even more so when levels of objective stress were high. DISCUSSION: Third trimester exposure to PNMS, especially when objectively severe, seems to be associated with increased eating disorder-linked manifestations in affected early adolescents. PMID- 25808646 TI - E-waste environmental contamination and harm to public health in China. AB - The adverse effects of electronic waste (e-waste) on the human body have stirred up concern in recent years. China is one of the countries that confront serious pollution and human exposure of e-waste, and the majority of the population is exposed to potentially hazardous substances that are derived from informal e waste recycling processes. This study reviews recent reports on human exposure to e-waste in China, with particular focus on exposure routes (e.g., inhalation and ingestion) and several toxicities of human (e.g., endocrine system, respiratory system, reproductive system, developmental toxicity, neurotoxicity, and genetic toxicity). Pieces of evidence that associate e-waste exposure with human health effects in China are assessed. The role of toxic heavy metals (e.g., lead, cadmium, chromium, mercury, and nickel) and organic pollutants (e.g., polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyl (PCBs), polycyclic aromatic hydrocarbons (PAHs), polybrominated biphenyls (PBBs), polyhalogenated aromatic hydrocarbons (PHAHs), bisphenol A (BPA)) on human health is also briefly discussed. PMID- 25808648 TI - Creating an Inclusive Society... How Close are We in Relation to Autism Spectrum Disorder? A General Population Survey. AB - BACKGROUND: Children with autism spectrum disorder are increasingly educated in mainstream classrooms in the United Kingdom (Wilkinson & Twist, Autism and Educational Assessment: UK Policy and Practice. NFER, Slough, 2010), and some employers are now specifically seeking out staff on the autism spectrum. Does that mean that we are living in an 'inclusive society' [United Nations Department of Economic and Social Affairs (UNDESA), Creating an Inclusive Society: Practical Strategies to Promote Social Integration 2008], in the sense that inequalities are reduced and full economic, social and cultural participation is advanced for individuals with autism? METHODS: A general population survey was conducted to assess how close we, as a society, are to an inclusive society for individuals with autism in Northern Ireland. Public attitudes were examined to (i) visibility and social interaction, (ii) aetiology, needs and interventions, and (iii) rights and resources. RESULTS: A stratified, representative sample of 1204 adults took part in the survey; of these, 989 were aware of autism and their attitudes and behavioural projections reflected a mix of acceptance and denunciation. The level of confusion with regard to interventions reflected the general uncertainty within UK policy regarding meeting the needs of individuals on the autism spectrum (International Journal of Disability, Development and Education 61, 134, 2014a). CONCLUSION: Therefore, it seems that inclusion is working to an extent, but more clarity is needed with regard to adequate education, intervention and support for individuals with autism. PMID- 25808649 TI - Is there a Role for Bevacizumab in Non-Glial Tumors? AB - Angiogenesis is one of the hallmarks of cancer, including brain tumors. The vascular endothelial growth factor (VEGF) family and their receptors are of utmost importance in the complex interaction between pro- and anti-angiogenic factors, and have a crucial role in tumor angiogenesis. Up to date, targeting the VEGF pathway with specific drugs has yielded interesting results in oncology. In particular bevacizumab (Bev), a humanized monoclonal antibody against VEGF-A, has been approved by the Food and Drug Administration (FDA) for use in recurrent glioblastomas failing standard radiochemotherapy. Bevacizumab is now being extensively investigated in several non-glial brain tumors, such as vestibular schwannomas, meningiomas, ependymomas, medulloblastomas and miscellaneous histotypes. The aim of this review is to reevaluate the literature on the use of Bev in non-glial brain tumors. PMID- 25808650 TI - The link between Hepatic Vitamin A Metabolism and Nonalcoholic Fatty Liver Disease. AB - The liver is essential for the control of glucose and lipid metabolism. Excessive accumulation of fat in the liver disturbs its function and leads to the development of fatty liver diseases. The nonalcoholic fatty liver disease (NAFLD) is a common type of fatty liver disease found in patients who have not consumed significant amount of alcohol. Multiple factors and cell types contribute to the development and progression of NAFLD. Diets contain macronutrients with energy and micronutrients with regulatory roles. As an essential micronutrient, vitamin A (VA), plays critical roles in various physiological functions including the regulation of glucose and lipid homeostasis in the liver. The body's VA is mainly stored in quiescent hepatic stellate cells (HSCs) in the liver. Hepatocytes actively metabolize VA, and change glucose and lipid metabolism in response to VA metabolites. Interestingly, the activated HSCs lose their VA content and contribute to the NAFLD progression. Significant number of studies have been conducted to investigate the link between VA metabolism and NAFLD development. This review is to summarize current literatures that discuss the changes of VA metabolism occurring locally between hepatocytes and HSCs, and intracellularly in hepatocytes during the course of NAFLD development. It appears that factors derived from HSCs and hepatocytes mutually affect each other, which contributes to NAFLD development. Additionally, this review discusses the potential mechanism by which excessive VA metabolism increases lipogenesis and contributes to fat accumulation in hepatocytes. It offers potential future directions for the study of the role of VA metabolism in the NAFLD development. PMID- 25808652 TI - Targeting Angiogenic Pathways in Colorectal Cancer: Complexities, Challenges and Future Directions. AB - Colorectal cancer (CRC) is one of the commonest cancers in the world. During the last decade, the development of targeted therapies has given cancer treatment a novel direction in management of metastatic CRC (mCRC) and has enriched the therapeutic armamentarium in the management of this disease. In mCRC, targeting angiogenesis via the vascular endothelial growth factor (VEGF) pathway has been of particular interest based on the favourable survival benefit demonstrated by bevacizumab in clinical trials. More recently, large phase III studies have shown clinical efficacy for the new antiangiogenic agents aflibercept and regorafenib. However, the results of pre-clinical and clinical studies of other anti angiogenic agents have been disappointing. Furthermore, the benefits from angiogenic inhibitors (AIs) in an unselected patient population are modest. Research into predictive biomarkers is therefore essential, but has, to date, been unsuccessful. Nevertheless, aflibercept and regorafenib have been shown to benefit both bevacizumab naive and refractory patients, suggesting that acquired resistance to AIs can be potentially reversed. This review describes the most recent advances in development of AIs in mCRC with particular focus on aflibercept and regorafenib, the existing challenges for the evaluation of these agents in clinical practice and potential strategies in designing clinical trials that could lead to the discovery of clinically meaningful biomarkers. PMID- 25808651 TI - A Comprehensive Review on miR-200c, A Promising Cancer Biomarker with Therapeutic Potential. AB - MicroRNAs (miRNAs) are small single stranded non coding RNA molecules (~22 nucleotides) which impede protein production by directly interacting with 3'untranslated regions of the target mRNAs. Interestingly, miR-200c is often dysregulated in various cancers that normally exhibits tumor suppressive behavior by blocking epithelial to mesenchymal transition (EMT) of cancer cells. However, elevation of miR-200c in various cancer tissues contradicts the tumor suppressive role of this microRNA. This review addresses the molecular mechanisms involved in the regulation of the endogenous level of miR-200c in various cancers such as breast, ovarian, prostate, endometrial, lungs, colon, pancreatic, etc. and its differential role in regulation of proliferation and EMT phenotype of cancer cells. Further, this review discusses whether abnormal level of miR-200c in cancer tissues or in blood circulation can be used as a biomarker. Importantly, how the level of miR-200c can be used to predict the effectiveness of the cancer therapy is also discussed. Accumulating evidences suggest that use of miR-200c alone may not be sufficient for treatment of cancer patients, but the combination of miR-200c with an anti-proliferating drug could be a better choice to prevent invasiveness of cancers as well as tumor growth both in primary and in metastatic sites. This article also proposes that the tumor microenvironment may have a role in influencing epigenetic silencing of miR-200c expression. PMID- 25808653 TI - Why is intracellular ice lethal? A microscopical study showing evidence of programmed cell death in cryo-exposed embryonic axes of recalcitrant seeds of Acer saccharinum. AB - BACKGROUND AND AIMS: Conservation of the genetic diversity afforded by recalcitrant seeds is achieved by cryopreservation, in which excised embryonic axes (or, where possible, embryos) are treated and stored at temperatures lower than -180 degrees C using liquid nitrogen. It has previously been shown that intracellular ice forms in rapidly cooled embryonic axes of Acer saccharinum (silver maple) but this is not necessarily lethal when ice crystals are small. This study seeks to understand the nature and extent of damage from intracellular ice, and the course of recovery and regrowth in surviving tissues. METHODS: Embryonic axes of A. saccharinum, not subjected to dehydration or cryoprotection treatments (water content was 1.9 g H2O g(-1) dry mass), were cooled to liquid nitrogen temperatures using two methods: plunging into nitrogen slush to achieve a cooling rate of 97 degrees C s(-1) or programmed cooling at 3.3 degrees C s( 1). Samples were thawed rapidly (177 degrees C s(-1)) and cell structure was examined microscopically immediately, and at intervals up to 72 h in vitro. Survival was assessed after 4 weeks in vitro. Axes were processed conventionally for optical microscopy and ultrastructural examination. KEY RESULTS: Immediately following thaw after cryogenic exposure, cells from axes did not show signs of damage at an ultrastructural level. Signs that cells had been damaged were apparent after several hours of in vitro culture and appeared as autophagic decomposition. In surviving tissues, dead cells were sloughed off and pockets of living cells were the origin of regrowth. In roots, regrowth occurred from the ground meristem and procambium, not the distal meristem, which became lethally damaged. Regrowth of shoots occurred from isolated pockets of surviving cells of peripheral and pith meristems. The size of these pockets may determine the possibility for, the extent of and the vigour of regrowth. CONCLUSIONS: Autophagic degradation and ultimately autolysis of cells following cryo-exposure and formation of small (0.2-0.4 um) intracellular ice crystals challenges current ideas that ice causes immediate physical damage to cells. Instead, freezing stress may induce a signal for programmed cell death (PCD). Cells that form more ice crystals during cooling have faster PCD responses. PMID- 25808654 TI - Substantial variation in leaf senescence times among 1360 temperate woody plant species: implications for phenology and ecosystem processes. AB - BACKGROUND AND AIMS: Autumn leaf senescence marks the end of the growing season in temperate ecosystems. Its timing influences a number of ecosystem processes, including carbon, water and nutrient cycling. Climate change is altering leaf senescence phenology and, as those changes continue, it will affect individual woody plants, species and ecosystems. In contrast to spring leaf out times, however, leaf senescence times remain relatively understudied. Variation in the phenology of leaf senescence among species and locations is still poorly understood. METHODS: Leaf senescence phenology of 1360 deciduous plant species at six temperate botanical gardens in Asia, North America and Europe was recorded in 2012 and 2013. This large data set was used to explore ecological and phylogenetic factors associated with variation in leaf senescence. KEY RESULTS: Leaf senescence dates among species varied by 3 months on average across the six locations. Plant species tended to undergo leaf senescence in the same order in the autumns of both years at each location, but the order of senescence was only weakly correlated across sites. Leaf senescence times were not related to spring leaf out times, were not evolutionarily conserved and were only minimally influenced by growth habit, wood anatomy and percentage colour change or leaf drop. These weak patterns of leaf senescence timing contrast with much stronger leaf out patterns from a previous study. CONCLUSIONS: The results suggest that, in contrast to the broader temperature effects that determine leaf out times, leaf senescence times are probably determined by a larger or different suite of local environmental effects, including temperature, soil moisture, frost and wind. Determining the importance of these factors for a wide range of species represents the next challenge for understanding how climate change is affecting the end of the growing season and associated ecosystem processes. PMID- 25808656 TI - Pollen dispersal and breeding structure in a hawkmoth-pollinated Pampa grasslands species Petunia axillaris (Solanaceae). AB - BACKGROUND AND AIMS: The evolution of selfing is one of the most common transitions in flowering plants, and this change in mating pattern has important systematic and ecological consequences because it often initiates reproductive isolation and speciation. Petunia axillaris (Solanaceae) includes three allopatric subspecies widely distributed in temperate South America that present different degrees of self-compatibity and incompatibility. One of these subspecies is co-distributed with P. exserta in a restricted area and presents a complex, not well-understood mating system. Artificial crossing experiments suggest a complex system of mating in this sympatric area. The main aims of this study were to estimate the pollen dispersal distance and to evaluate the breeding structure of P. axillaris subsp. axillaris, a hawkmoth-pollinated taxon from this sympatric zone. METHODS: Pollen dispersal distance was compared with nearest neighbours distance, and the differentiation in the pollen pool among mother plants was estimated. In addition, the correlation between genetic differentiation and spatial distance among plants was tested. All adult individuals (252) within a space of 2800 m(2) and 15 open-pollinated progeny (285 seedlings) were analysed. Genetic analyses were based on 12 polymorphic microsatellite loci. KEY RESULTS: A high proportion of self-pollination was found, indicating a mixed-mating system. The maximum pollen dispersal distance was 1013 m, but most pollination events (96 %) occurred at a distance of 0 m, predominantly in an inbreeding system. Both parents among sampled individuals could be identifed in 60-85 % of the progeny. CONCLUSIONS: The results show that most pollen dispersal in the hawkmoth-pollinated P. axillaris subsp. axillaris occurs within populations and there is a high proportion of inbreeding. This mating system appears to favour species integrity in a secondary contact zone with the congener species P. exserta. PMID- 25808655 TI - Interplay between vitamin E and phosphorus availability in the control of longevity in Arabidopsis thaliana. AB - BACKGROUND AND AIMS: Vitamin E helps to control the cellular redox state by reacting with singlet oxygen and preventing the propagation of lipid peroxidation in thylakoid membranes. Both plant ageing and phosphorus deficiency can trigger accumulation of reactive oxygen species, leading to damage to the photosynthetic apparatus. This study investigates how phosphorus availability and vitamin E interact in the control of plant longevity in the short-lived annual Arabidopsis thaliana. METHODS: The responses of tocopherol cyclase (VTE1)- and gamma tocopherol methyltransferase (VTE4)-null mutants to various levels of phosphorus availability was compared with that of wild-type plants. Longevity (time from germination to rosette death) and the time taken to pass through different developmental stages were determined, and measurements were taken of photosynthetic efficiency, pigment concentration, lipid peroxidation, vitamin E content and jasmonate content. KEY RESULTS: The vte1 mutant showed accelerated senescence under control conditions, excess phosphorus and mild phosphorus deficiency, suggesting a delaying, protective effect of alpha-tocopherol during plant senescence. However, under severe phosphorus deficiency the lack of alpha tocopherol paradoxically increased longevity in the vte1 mutant, while senescence was accelerated in wild-type plants. Reduced photoprotection in vitamin E deficient mutants led to increased levels of defence chemicals (as indicated by jasmonate levels) under severe phosphorus starvation in the vte4 mutant and under excess phosphorus and mild phosphorus starvation in the vte1 mutant, indicating a trade-off between the capacity for photoprotection and the activation of chemical defences (jasmonate accumulation). CONCLUSIONS: Vitamin E increases plant longevity under control conditions and mild phosphorus starvation, but accelerates senescence under severe phosphorus limitation. Complex interactions are revealed between phosphorus availability, vitamin E and the potential to synthesize jasmonates, suggesting a trade-off between photoprotection and the activation of chemical defences in the plants. PMID- 25808657 TI - The role of pollinators in maintaining variation in flower colour in the Rocky Mountain columbine, Aquilegia coerulea. AB - BACKGROUND AND AIMS: Flower colour varies within and among populations of the Rocky Mountain columbine, Aquilegia coerulea, in conjunction with the abundance of its two major pollinators, hawkmoths and bumble-bees. This study seeks to understand whether the choice of flower colour by these major pollinators can help explain the variation in flower colour observed in A. coerulea populations. METHODS: Dual choice assays and experimental arrays of blue and white flowers were used to determine the preference of hawkmoths and bumble-bees for flower colour. A test was made to determine whether a differential preference for flower colour, with bumble-bees preferring blue and hawkmoths white flowers, could explain the variation in flower colour. Whether a single pollinator could maintain a flower colour polymorphism was examined by testing to see if preference for a flower colour varied between day and dusk for hawkmoths and whether bumble-bees preferred novel or rare flower colour morphs. KEY RESULTS: Hawkmoths preferred blue flowers under both day and dusk light conditions. Naive bumble-bees preferred blue flowers but quickly learned to forage randomly on the two colour morphs when similar rewards were presented in the flowers. Bees quickly learned to associate a flower colour with a pollen reward. Prior experience affected the choice of flower colour by bees, but they did not preferentially visit novel flower colours or rare or common colour morphs. CONCLUSIONS: Differences in flower colour preference between the two major pollinators could not explain the variation in flower colour observed in A. coerulea. The preference of hawkmoths for flower colour did not change between day and dusk, and bumble-bees did not prefer a novel or a rare flower colour morph. The data therefore suggest that factors other than pollinators may be more likely to affect the flower colour variation observed in A. coerulea. PMID- 25808659 TI - Ultrafast Graphene Growth on Insulators via Metal-Catalyzed Crystallization by a Laser Irradiation Process: From Laser Selection, Thickness Control to Direct Patterned Graphene Utilizing Controlled Layer Segregation Process. AB - Despite the vast progress in chemical vapor deposition (CVD) graphene grown on metals, the transfer process is still a major bottleneck, being not devoid of wrinkles and polymer residues. In this paper, a structure is introduced to directly synthesize few layer graphene on insulating substrates by a laser irradiation heating process. The segregation of graphene layers can be manipulated by tuning the metal layer thickness and laser power at different scanning rates. Graphene deposition and submicrometer patterning resolution can be achieved by patterning the intermediate metal layer using standard lithography methods in order to overcome the scalability issue regardless the resolution of the laser beam. The systematic analysis of the process based on the formation of carbon microchannels by the laser irradiation process can be extended to several materials, thicknesses, and methods. Furthermore, hole and electron mobilities of 500 and 950 cm(2) V(-1) s(-1) are measured. The laser-synthesized graphene is a step forward along the direct synthesis route for graphene on insulators that meets the criteria for photonics and electronics. PMID- 25808661 TI - sRNAs in bacterial type I and type III toxin-antitoxin systems. AB - Toxin-antitoxin (TA) loci consist of two genes: a stable toxin whose overexpression kills the cell or causes growth stasis and an unstable antitoxin that neutralizes the toxin action. Currently, five TA systems are known. Here, we review type I and type III systems in which the antitoxins are regulatory RNAs. Type I antitoxins act by a base-pairing mechanism on toxin mRNAs. By contrast, type III antitoxins are RNA pseudoknots that bind their cognate toxins directly in an RNA-protein interaction. Whereas for a number of plasmid-encoded systems detailed information on structural requirements, kinetics of interaction with their targets and regulatory mechanisms employed by the antitoxin RNAs is available, the investigation of chromosomal systems is still in its infancy. Here, we summarize our current knowledge on that topic. Furthermore, we compare factors and conditions that induce antitoxins or toxins and different mechanisms of toxin action. Finally, we discuss biological roles for chromosome-encoded TA systems. PMID- 25808660 TI - Peripapillary retinal nerve fiber layer thickness in bipolar disorder. AB - BACKGROUND: To compare peripapillary retinal nerve fiber layer thickness (RNFLT) between patients with bipolar disorder and a control group by optical coherence tomography (OCT). METHODS: This prospective comparative case series included 60 eyes of 30 patients with bipolar disorder and 60 eyes of 30 age-matched healthy control subjects. Using OCT, peripapillary RNFLT of the 4 quadrants and the mean of them was compared between the two groups. Variables such as age of onset, duration, smoking, psychosis, mania and depression episodes in the case group and their relationships with RNFLT were evaluated by OCT. RESULTS: Mean RNFLT was 99 +/- 8 in the case group, significantly less than the 106 +/- 8 mMU in the control group (p = 0.001). The inferior, superior, and nasal quadrants in the case and control groups showed significant difference in RNFLT (p < 0.001) (p = 0.040) (p = 0.005); however, the temporal quadrant was not reduced significantly, compared to the control value (p = 0.907). Moreover, the only variable showing significant relation with RNFLT was duration of bipolar disorder (p = 0.040). CONCLUSION: Reduction of peripapilary RNFLT occurs in patients with bipolar disorder, and is related to the duration of disease. RNFLT can be a beneficial value for studying neurodegenerative changes over time towards detecting the severity and duration of disorder. PMID- 25808658 TI - Spatial and temporal regulation of the metabolism of reactive oxygen and nitrogen species during the early development of pepper (Capsicum annuum) seedlings. AB - BACKGROUND AND AIMS: The development of seedlings involves many morphological, physiological and biochemical processes, which are controlled by many factors. Some reactive oxygen and nitrogen species (ROS and RNS, respectively) are implicated as signal molecules in physiological and phytopathological processes. Pepper (Capsicum annuum) is a very important crop and the goal of this work was to provide a framework of the behaviour of the key elements in the metabolism of ROS and RNS in the main organs of pepper during its development. METHODS: The main seedling organs (roots, hypocotyls and green cotyledons) of pepper seedlings were analysed 7, 10 and 14 d after germination. Activity and gene expression of the main enzymatic antioxidants (catalase, ascorbate-glutathione cycle enzymes), NADP-generating dehydrogenases and S-nitrosoglutathione reductase were determined. Cellular distribution of nitric oxide ((.)NO), superoxide radical (O2 (.-)) and peroxynitrite (ONOO(-)) was investigated using confocal laser scanning microscopy. KEY RESULTS: The metabolism of ROS and RNS during pepper seedling development was highly regulated and showed significant plasticity, which was co ordinated among the main seedling organs, resulting in correct development. Catalase showed higher activity in the aerial parts of the seedling (hypocotyls and green cotyledons) whereas roots of 7-d-old seedlings contained higher activity of the enzymatic components of the ascorbate glutathione cycle, NADP isocitrate dehydrogenase and NADP-malic enzyme. CONCLUSIONS: There is differential regulation of the metabolism of ROS, nitric oxide and NADP dehydrogenases in the different plant organs during seedling development in pepper in the absence of stress. The metabolism of ROS and RNS seems to contribute significantly to plant development since their components are involved directly or indirectly in many metabolic pathways. Thus, specific molecules such as H2O2 and NO have implications for signalling, and their temporal and spatial regulation contributes to the success of seedling establishment. PMID- 25808662 TI - Molecular characterisation of clinical Cryptococcus neoformans and Cryptococcus gattii isolates from Sichuan province, China. AB - Previous reports on the molecular characteristics of clinical isolates of Cryptococcus species in China have focused on isolates from southeast China. To obtain a more detailed molecular epidemiology, a total of 92 cryptococcal isolates were collected from Sichuan province. A total of 24 isolates from 12 other provinces were collected for comparative study. Genotypes and mating types of 116 Cryptococcus isolates were determined. Among the 116 isolates, 43 isolates (19 isolates from Sichuan and 24 isolates outside of Sichuan) were analysed by multi-locus sequence typing (MLST). All 116 clinical isolates were mating type alpha. Most isolates (114/116) were molecular type VNI and the remaining two isolates were VGI and VGII respectively. MLST results revealed five sequence types (STs) of C. neoformans including two novel STs, with most isolates identified as ST5. The two C. gattii isolates identified in our study were ST44 and ST159. Based on our report and previous studies, there are 15 C. neoformans STs in China which can be divided into three subgroups. The C. gattii isolate from Sichuan could be a scattered subtype of VGII (ST44). Our findings demonstrated that C. neoformans isolates in Sichuan are genetically homogeneous, and ST5 is the epidemic clone of C. neoformans in China. PMID- 25808663 TI - Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik-Fields Reaction. AB - Polyacrylamides containing pendant aminobisphosphonate groups are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and a multicomponent postpolymerization functionalization reaction. A Moedritzer-Irani reaction installs the phosphonic acid groups on well-defined, RAFT-generated polymers bearing a pendant amine. An alternate route to the same materials is developed utilizing a three-component Kabachnik-Fields reaction and subsequent dealkylation. Kinetics of the RAFT polymerization of the polymer precursor are studied. Successful functionalization is demonstrated by NMR and FTIR spectroscopy and elemental analysis of the final polymers. PMID- 25808665 TI - Exposure to secondhand smoke in the home and mental health in children: a population-based study. AB - OBJECTIVES: To examine the association between exposure to secondhand smoke (SHS) in the home and mental health among children. METHODS: Cross-sectional study of 2357 children representative of the Spanish population aged 4-12 years in 2011 2012. Duration of SHS exposure in children was reported by parents. Probable mental disorder was defined as a score>90th centile in the parental version of the Strengths and Difficulties Questionnaire (SDQ). Statistical analysis was performed with logistic regression and adjusted for sociodemographic variables, lifestyle, neighbourhood environment and family characteristics, including parental mental health. RESULTS: Among study participants, 6.9% (95% CI 5.7% to 8.0%) were exposed to SHS in the home for <1 h/day and 4.5% (95% CI 3.5% to 5.5%) for >=1 h/day. Compared to children not habitually exposed to SHS, the multivariate ORs for probable mental disorder were 1.49 (95% CI 0.85 to 2.62) for SHS exposure<1 h/day and 2.73 (95% CI 1.38 to 5.41) for SHS exposure>=1 h/day (p for linear trend=0.002). The corresponding ORs for attention-deficit and hyperactivity disorder (ADHD) were 2.18 (95% CI 1.30 to 3.64) for <1 h/day exposure and 3.14 (95% CI 1.63 to 6.04) for >=1 h/day exposure (p for linear trend<0.001). No association was found between SHS and the rest of the components of the SDQ. CONCLUSIONS: Among children, SHS exposure in the home during >=1 h/day is associated with a higher frequency of mental disorder. This association was mostly due to the impact of SHS on ADHD. PMID- 25808664 TI - Inactivation of HDAC1 or HDAC2 induces gamma globin expression without altering cell cycle or proliferation. AB - Other than hydroxyurea, no pharmacologic agents are clinically available for fetal hemoglobin (HbF) induction in sickle cell disease (SCD). An optimal candidate would induce HbF without causing cell cycle inhibition and would act independently of hydroxyurea in order to yield additional HbF induction when combined. We explored whether inhibition of histone deacetylase (HDAC) 1 or HDAC2 could achieve these goals. In human erythroid progenitor cells, shRNA knockdown of the HDAC1 or HDAC2 genes induced gamma globin, without altering cellular proliferation in vitro, and without altering cell cycle phase. Treatment with hydroxyurea in combination with HDAC2 knockdown yielded a further increase in gamma globin expression. Additionally, when CD34+ cells were treated with both hydroxyurea and MS-275 (an inhibitor of HDAC 1, 2, and 3), an additive induction of relative gamma globin expression was achieved. Our findings support further clinical investigation of HDAC inhibitors in combination with hydroxyurea in SCD patients. PMID- 25808666 TI - The impact of the Malaysian minimum cigarette price law: findings from the ITC Malaysia Survey. AB - OBJECTIVES: Study the effects of the 2011 Malaysian minimum price law (MPL) on prices of licit and illicit cigarette brands. Identify barriers to the MPL achieving positive public health effects. METHODS: The International Tobacco Control Project's Southeast Asia survey collected information on Malaysian smokers' cigarette purchases (n=7520) in five survey waves between 2005 and 2012. Consumption-weighted comparisons of proportions tests and adjusted Wald tests were used to evaluate changes over time in violation rates of the inflation adjusted MPL, the proportion of illicit cigarette purchases and mean prices. RESULTS: After the passage of the MPL, the proportion of licit brand cigarette purchases that were below the inflation-adjusted 2011 minimum price level fell substantially (before 3.9%, after 1.8%, p=0.002), while violation of the MPL for illicit brand cigarette purchases was unchanged (before 89.8%, after 91.9%, p=0.496). At the same time, the mean real price of licit cigarettes rose (p=0.006), while the mean real price of illicit cigarettes remained unchanged (p=0.134). The proportion of illicit cigarette purchases rose as well (before 13.4%, after 16.5%, p=0.041). DISCUSSION: The MPL appears not to have meaningfully changed cigarette prices in Malaysia, as licit brand prices remained well above and illicit brand prices remained well below the minimum price level before and after MPL's implementation. The increasing proportion of illicit cigarettes on the market may have undermined any positive health effects of the Malaysian MPL. The illicit cigarette trade must be addressed before a full evaluation of the Malaysian MPL's impact on public health can take place. The authors encourage the continued use of specific excise tax increases to reliably increase the price and decrease the consumption of cigarettes in Malaysia and elsewhere. PMID- 25808667 TI - Effects of brand variants on smokers' choice behaviours and risk perceptions. AB - BACKGROUND: Australian tobacco companies have introduced evocative variant names that could re-create the aspirational connotations plain packaging aims to remove. To inform future regulation, we explored how brand descriptors affected smokers' responses to plain packs featuring different variant name combinations. METHODS: An online survey of 254 daily smokers or social smokers aged between 18 and 34 used a within-subjects best-worst experiment to estimate the relative effects of variant names. A 2*4*4*4 design contained four attributes: quality (premium or none), taste (smooth, fine, rich or none) connotation (classic, midnight, infinite or none) and colour (red, blue, white or none). In a between subjects component, respondents evaluated one of two alternative packs according to its perceived harm and ease of quitting. RESULTS: The most important variant attribute was connotation, followed by taste, colour and quality; within these attributes, the most attractive descriptors were 'classic' and 'smooth'. We identified four distinct segments that differed significantly in their sociodemographic attributes and variant preferences, although not in their perceptions of the harm or quitting ease associated with two different variants. CONCLUSIONS: Some descriptors significantly enhance the appeal of tobacco products among different groups of smokers and may undermine plain packaging's dissuasive intent. Policymakers should explicitly regulate variant names to avoid the 'poetry on a package' evident in Australia. Options include disallowing new descriptors, limiting the number of descriptors permitted or banning descriptors altogether. PMID- 25808668 TI - Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells. AB - To identify immunological mechanisms that govern distinct clinical phases of a chronic hepatitis B virus (HBV) infection-immune tolerant (IT), immune active (IA), inactive carrier (IC), and hepatitis B e antigen (HBeAg)-negative (ENEG) hepatitis phases-we performed a systems biology study. Serum samples from untreated chronic HBV patients (n = 71) were used for multiplex cytokine measurements, quantitative hepatitis B surface antigen (HBsAg), HBeAg levels, HBV genotype, and mutant analysis. Leukocytes were phenotyped using multicolor flow cytometry, and whole-blood transcriptome profiles were generated. The latter were compared with liver biopsy transcriptomes from IA (n = 16) and IT (n = 3) patients. HBV viral load as well as HBeAg and HBsAg levels (P < 0.001), but not leukocyte composition, differed significantly between distinct phases. Serum macrophage chemotactic protein 1, interleukin-12p40, interferon (IFN)-gamma inducible protein 10, and macrophage inflammatory protein 1 beta levels were different between two or more clinical phases (P < 0.05). Comparison of blood transcriptomes identified 64 differentially expressed genes. The gene signature distinguishing IA from IT and IC patients was predominantly composed of highly up regulated immunoglobulin-encoding genes. Modular repertoire analysis using gene sets clustered according to similar expression patterns corroborated the abundant expression of B-cell function-related genes in IA patients and pointed toward increased (ISG) transcript levels in IT patients, compared to subsequent phases. Natural killer cell activities were clustered in clinical phases with biochemical liver damage (IA and ENEG phases), whereas T-cell activities were higher in all phases, compared to IT patients. B-cell-related transcripts proved to be higher in biopsies from IA versus IT patients. CONCLUSION: HBV clinical phases are characterized by distinct blood gene signatures. Innate IFN and B-cell responses are highly active during the IT and IA phases, respectively. This suggests that the presumed immune tolerance in chronic HBV infections needs to be redefined. PMID- 25808669 TI - Caregivers of patients with disorder of consciousness: burden, quality of life and social support. AB - OBJECTIVE: To evaluate quality of life (QoL) and its predictors, psychological burden and level of perceived social support in caregivers of patients with disorder of consciousness. MATERIALS & METHODS: World Health Organization Quality of Life-Bref (WHOQOL-BREF), State Trait Anxiety Inventory-Y (STAI-Y), Beck Depression Inventory (BDI-II), Prolonged Grief Disorder Questionnaire, Coping Orientations to Problem Experiences, State-Trait Anger Expression Inventory-2 (STAXI-2), and the Medical Outcome Study Social Support Survey (MOS-SSS) were administered. One-sample t-tests were performed to compare WHOQOL-BREF, STAI-Y and STAXI-2 mean scores to the respective normative sample (NS). Pearson correlation was calculated between time dedicated to patient's care, WHOQOL-BREF, BDI-II, STAI-Y and MOS-SSS scores. Hierarchical multiple regression analyses were performed to evaluate which variables have predictive power on QoL. RESULTS: A total of 129 caregivers, 68.2% female, mean age 52.8 years, were enrolled. Three WHOQOL-BREF domains were significantly lower. Anxiety and anger were in line with NS. 28.7% of the sample reported high level of depressive symptoms; 20.9% satisfied the prolonged grief disorder criteria. No differences emerged between caregivers and chronic ill patients' scores at MOS-SSS. STAI-Y, BDI-II and WHOQOL BREF scores positively correlated. MOS-SSS domains inversely correlate with BDI II scores. BDI-II results the most relevant predictor of QoL. CONCLUSIONS: Study results provided innovative information about caregivers' poor QoL, difficulties in social support and high levels of burden. Time dedicated to care is not strictly related to burden, while social support perceived is highly associated with caregivers' depressive symptoms that are strong predictor of poor QoL. Supportive intervention able to integrate psychological, social and environmental levels is needed. PMID- 25808671 TI - Comparison of robotic approach, laparoscopic approach and laparotomy in treating epithelial ovarian cancer. AB - BACKGROUND: The purpose of this study was to evaluate the feasibility of robotic surgery and compare its surgical outcomes with those of laparoscopic surgery and laparotomy, with regard to performing staging surgery to manage ovarian cancer. METHODS: One hundred and thirty-eight women who received surgical staging procedures for treatment of stage IA-IIIC epithelial ovarian cancer and borderline tumours were retrospectively included in the study. All enrolled cases were reviewed for patient demographics, peri-operative parameters, complications and survival. RESULTS: The operation time and blood loss was significantly reduced in the robotic and laparoscopic groups. Moreover, robotic surgery was associated with decreased postoperative pain score. The length of hospital stay and time to full diet resumption were also shortened for those who underwent robotic and laparoscopic procedures. Survival analysis and complication rates were similar between the two groups. CONCLUSION: Robotic surgery is a feasible alternative in managing ovarian cancer as long as there is careful consideration given to patient selection. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25808670 TI - Site-selective modification of peptides: From "customizable units" to novel alpha aryl and alpha-alkyl glycine derivatives, and components of branched peptides. AB - The creation of peptide libraries by site-selective modification of a few peptide substrates would increase the efficiency of discovery processes, but still is a real synthetic challenge. The site-selective modification of small peptides at serine or threonine residues, by using a short scission-addition procedure, allows the preparation of peptides with unnatural alpha-aryl glycines. In a similar way, the scission of hydroxyproline residues is the key step in the production of optically pure alpha-alkyl glycines which are precursors or components of branched peptides. With these versatile processes, a single peptide can be transformed into a variety of peptide derivatives. The process takes place under mild conditions, and good global yields are obtained. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 650-662, 2015. PMID- 25808672 TI - Critical incident history questionnaire replication: frequency and severity of trauma exposure among officers from small and midsize police agencies. AB - Frequency and severity of trauma exposure are thought to influence posttraumatic reactions. Weiss et al.'s Critical Incident History Questionnaire (CIHQ; 2010) measures these variables among law enforcement officers; they reported findings using a sample of officers from large urban departments. We noted the need for replication studies utilizing samples from smaller and rural police agencies. The purpose of this study was to replicate the CIHQ findings from Weiss et al. using a sample (N = 193) of officers from small and midsize police departments and officers whose duties include policing rural and isolated jurisdictions. Frequency and severity findings were similar to those reported by Weiss et al. (). Regarding frequency, the present study found the critical incident exposure mean score was 188.5, compared to 168.5 from Weiss et al. (). Making a mistake that kills or injures a colleague had the highest mean nomothetic severity rating in both studies. Among the various variables examined in this study, PTSD symptoms demonstrated the strongest association with the exposure indices, based on Spearman rank correlations (r = .26-.46). PMID- 25808673 TI - Dielectrophoresis chips improve PCR detection of the food-spoiling yeast Zygosaccharomyces rouxii in apple juice. AB - Dielectrophoretic (DEP) manipulation of cells present in real samples is challenging. We show in this work that an interdigitated DEP chip can be used to trap and wash a population of the food-spoiling yeast Zygosaccharomyces rouxii that contaminates a sample of apple juice. By previously calibrating the chip, the yeast population loaded is efficiently trapped, washed, and recovered in a small-volume fraction that, in turn, can be used for efficient PCR detection of this yeast. DEP washing of yeast cells gets rid of PCR inhibitors present in apple juice and facilitates PCR analysis. This and previous works on the use of DEP chips to improve PCR analysis show that a potential use of DEP is to be used as a treatment of real samples prior to PCR. PMID- 25808674 TI - Eosinophilia in asthma: the easy way is not always the best. PMID- 25808675 TI - Stratification of patients with severe asthma. PMID- 25808677 TI - A Risk Assessment Scheme of Infection Transmission Indoors Incorporating the Impact of Resuspension. AB - A new risk assessment scheme was developed to quantify the impact of resuspension to infection transmission indoors. Airborne and surface pathogenic particle concentration models including the effect of two major resuspension scenarios (airflow-induced particle resuspension [AIPR] and walking-induced particle resuspension [WIPR]) were derived based on two-compartment mass balance models and validated against experimental data found in the literature. The inhalation exposure to pathogenic particles was estimated using the derived airborne concentration model, and subsequently incorporated into a dose-response model to assess the infection risk. Using the proposed risk assessment scheme, the influences of resuspension towards indoor infection transmission were examined by two hypothetical case studies. In the case of AIPR, the infection risk increased from 0 to 0.54 during 0-0.5 hours and from 0.54 to 0.57 during 0.5-4 hours. In the case of WIPR, the infection risk increased from 0 to 0.87 during 0-0.5 hours and from 0.87 to 1 during 0.5-4 hours. Sensitivity analysis was conducted based on the design-of-experiments method and showed that the factors that are related to the inspiratory rate of viable pathogens and pathogen virulence have the most significant effect on the infection probability under the occurrence of AIPR and WIPR. The risk assessment scheme could serve as an effective tool for the risk assessment of infection transmission indoors. PMID- 25808676 TI - The Relationship Between the Social Environment and Lifestyle-Related Physical Activity in a Low-Income African American Inner-City Southern Neighborhood. AB - The social ecological model was used to examine individual, interpersonal, and neighborhood characteristics related to lifestyle-related physical activity (PA) in a low-income African American (AA) population in New Orleans, Louisiana. Interviewers administered surveys to randomly-sampled household participants from three low-income, AA neighborhoods in New Orleans, Louisiana. Questions included the social and physical environment, physical activity, interpersonal factors, demographics, height and weight. Logistic regression multivariable models were built predicting whether the respondent met PA guidelines, controlling for neighborhood. Females were less as likely to engage in lifestyle-related PA compared to males (OR 0.46, CI 0.30-0.70). Support specific for PA was correlated with engaging in lifestyle-related PA (OR 1.45, CI 1.14-1.83). The individual and social environment should be considered for increasing PA in AA. Interventions targeting the AA population could consider ways of enhancing social support for PA. PMID- 25808678 TI - Activation of the signalling mucin MoMsb2 and its functional relationship with Cbp1 in Magnaporthe oryzae. AB - Various surface signals are recognized by Magnaporthe oryzae to activate the Pmk1 MAP kinase that is essential for appressorium formation and invasive growth. One of upstream sensors of the Pmk1 pathway is the MoMsb2 signalling mucin. However, the activation of MoMsb2 and its relationship with other sensors is not clear. In this study, we showed that the cleavage and transmembrane domains are essential for MoMsb2 functions. Cleavage of MoMsb2 was further confirmed by western blot analysis, and five putative cleavage sites were functionally characterized. Expression of the extracellular region alone partially rescued the defects of Momsb2 in appressorium formation and virulence. The cytoplasmic region of MoMsb2, although dispensable for appressorium formation, was more important for penetration and invasive growth. Interestingly, the Momsb2 cbp1 double mutant deleted of both mucin genes was blocked in Pmk1 activation. It failed to form appressoria on artificial surfaces and was non-pathogenic. In addition, we showed that MoMsb2 interacts with Ras2 but not with MoCdc42 in co-immunoprecipitation assays. Overall, results from this study indicated that the extracellular and cytoplasmic regions of MoMsb2 have distinct functions in appressorium formation, penetration and invasive growth, and MoMsb2 has overlapping functions with Cbp1 in recognizing environmental signals for Pmk1 activation. PMID- 25808680 TI - Combination of hollow-fiber-supported liquid membrane and dispersive liquid liquid microextraction as a fast and sensitive technique for the extraction of pesticides from grape juice followed by high-performance liquid chromatography. AB - The simultaneous use of a hollow-fiber-supported liquid membrane and dispersive liquid-liquid microextraction for the determination of pesticides directly in grape juice was investigated. The detection and quantification were performed by liquid chromatography with diode array detection. The optimum extraction condition was reached by filling the pores of the membrane wall with dodecanol and using hexane/acetone as extraction/dispersion solvents. Salt addition had a highly negative effect on the extraction efficiency and the optimum extraction time was 60 min. The volume of hexane/acetone mixture and the sample pH did not affect the signal at the levels studied. Therefore, an intermediate amount of these solvents (250 MUL; 1:7.5 v/v) and pH 6 were selected. The optimum desorption condition was obtained with acetonitrile and 10 min of desorption time. The linear working range varied from 58 to 500 MUg/L (parathion-methyl), 62 500 MUg/L (difenoconazole) and 107-500 MUg/L (chlorpyrifos), with correlation coefficients ranging from 0.9980-0.9942. The limits of detection and quantification found were, respectively, 17 and 58 MUg/L for parathion-methyl, 19 and 62 MUg/L for difenoconazole and 32 and 107 MUg/L for chlorpyrifos. The relative standard deviation ranged between 3.5 and 11.2%. PMID- 25808679 TI - Effects of bergamot essential oil and its extractive fractions on SH-SY5Y human neuroblastoma cell growth. AB - OBJECTIVES: The goals were to investigate the mechanisms underlying the antiproliferative effects of bergamot essential oil (BEO) and to identify the compounds mainly responsible for its SH-SY5Y cells growth rate inhibition. METHODS: Five BEO extractive fractions (BEOs) differing in their chemical composition were used. Cell proliferation was determined by 3-(4,5 dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell count assays. Trypan blue exclusion test and Annexin V/PI staining were performed to assess their cytotoxic activity. Genotoxicity was detected by comet assay. The cell cycle was checked cytofluorimetrically. Reactive oxygen species (ROS) and Deltapsim were measured fluorimetrically. Western blotting analyses for some apoptosis-related proteins were carried out. KEY FINDINGS: Treatment of SH-SY5Y cells with some types of BEOs decreased cell growth rate by a mechanism correlated to both apoptotic and necrotic cell death. Coloured BEOs act by increasing ROS generation, responsible for the drop in Deltapsim, and modulate p38 and extracellular signal-regulated kinases (ERK 1/2) mitogen-activated protein kinases, p53, Bcl-2 and Bax signalling pathways. Finally, we identify bergamottin and 5-geranyloxy-7-methoxycoumarin as the bioactive molecules that could play a pivotal role in the antiproliferative effects exerted by coloured BEOs. CONCLUSIONS: Our study provides novel insights into the field of the antiproliferative effects of BEO, which could be exploited in the context of a multitarget pharmacological strategy. PMID- 25808681 TI - Altered levels of LIL3 isoforms in Arabidopsis lead to disturbed pigment-protein assembly and chlorophyll synthesis, chlorotic phenotype and impaired photosynthetic performance. AB - Light-harvesting complex (LHC)-like (LIL) proteins contain two transmembrane helices of which the first bears a chlorophyll (Chl)-binding motif. They are widespread in photosynthetic organisms, but almost nothing is known about their expression and physiological functions. We show that two LIL3 paralogues (LIL3:1 and LIL3:2) in Arabidopsis thaliana are expressed in photosynthetically active tissues and their expression is differentially influenced by light stress. Localization studies demonstrate that both isoforms are associated with subcomplexes of LHC antenna of photosystem II. Transgenic plants with reduced amounts of LIL3:1 exhibited a slightly impaired growth and have reduced Chl and carotenoid contents as compared to wild-type plants. Ectopic overexpression of either paralogue led to a developmentally regulated switch to co-suppression of both LIL3 isoforms, resulting in a circular chlorosis of the leaf rosettes. Chlorotic sectors show severely diminished levels of LIL3 isoforms and other proteins, and thylakoid morphology was changed. Additionally, the levels of enzymes involved in Chl biosynthesis are altered in lil3 mutant plants. Our data support a role of LIL3 paralogues in the regulation of Chl biosynthesis under light stress and under standard growth conditions as well as in a coordinated ligation of newly synthesized and/or rescued Chl molecules to their target apoproteins. PMID- 25808683 TI - Acute management of shoulder dislocations. PMID- 25808685 TI - Prenatal diagnosis of musculoskeletal conditions. AB - Ultrasonography is a safe, cost-effective tool used to prenatally detect common musculoskeletal conditions, including clubfoot, skeletal dysplasias, limb-length discrepancies, spinal abnormalities, and hand and other upper extremity deformities. With increased detection of such abnormalities, prenatal parental counseling by orthopaedic surgeons is being requested more frequently. Counseling is important for family education on prognosis and treatment options. A thorough understanding of the common musculoskeletal conditions diagnosed on prenatal ultrasonography, classification of these conditions, and the correlations of these classifications to postnatal severity allows the orthopaedic surgeon to conduct well-informed counseling sessions with families. Accurate information and counseling aids parents in understanding their child's diagnosis, assists clinicians in planning treatment algorithms, and optimizes family preparedness. PMID- 25808684 TI - Obesity, orthopaedics, and outcomes. PMID- 25808686 TI - Thoracic outlet syndrome. AB - Thoracic outlet syndrome is a well-described disorder caused by thoracic outlet compression of the brachial plexus and/or the subclavian vessels. Neurogenic thoracic outlet syndrome is the most common manifestation, presenting with pain, numbness, tingling, weakness, and vasomotor changes of the upper extremity. Vascular complications of thoracic outlet syndrome are uncommon and include thromboembolic phenomena and swelling. The clinical presentation is highly variable, and no reproducible study exists to confirm the diagnosis; instead, the diagnosis is based on a physician's judgment after a meticulous history and physical examination. Both nonsurgical and surgical treatment methods are available for thoracic outlet syndrome. Whereas nonsurgical management appears to be effective in some persons, surgical treatment has been shown to provide predictable long-term cure rates for carefully selected patients. In addition, physicians who do not regularly treat patients with thoracic outlet syndrome may not have an accurate view of this disorder, its treatment, or the possible success rate of treatment. PMID- 25808682 TI - Designing and evaluating health systems level hypertension control interventions for African-Americans: lessons from a pooled analysis of three cluster randomized trials. AB - OBJECTIVES: African-Americans (AAs) have a high prevalence of hypertension and their blood pressure (BP) control on treatment still lags behind other groups. In 2004, NHLBI funded five projects that aimed to evaluate clinically feasible interventions to effect changes in medical care delivery leading to an increased proportion of AA patients with controlled BP. Three of the groups performed a pooled analysis of trial results to determine: 1) the magnitude of the combined intervention effect; and 2) how the pooled results could inform the methodology for future health-system level BP interventions. METHODS: Using a cluster randomized design, the trials enrolled AAs with uncontrolled hypertension to test interventions targeting a combination of patient and clinician behaviors. The 12 month Systolic BP (SBP) and Diastolic BP (DBP) effects of intervention or control cluster assignment were assessed using mixed effects longitudinal regression modeling. RESULTS: 2,015 patients representing 352 clusters participated across the three trials. Pooled BP slopes followed a quadratic pattern, with an initial decline, followed by a rise toward baseline, and did not differ significantly between intervention and control clusters: SBP linear coefficient = -2.60+/-0.21 mmHg per month, p<0.001; quadratic coefficient = 0.167+/- 0.02 mmHg/month, p<0.001; group by time interaction group by time group x linear time coefficient=0.145 +/- 0.293, p=0.622; group x quadratic time coefficient= -0.017 +/- 0.026, p=0.525). RESULTS were similar for DBP. The individual sites did not have significant intervention effects when analyzed separately. CONCLUSION: Investigators planning behavioral trials to improve BP control in health systems serving AAs should plan for small effect sizes and employ a "run-in" period in which BP can be expected to improve in both experimental and control clusters. PMID- 25808687 TI - Management of osteoporosis in spine surgery. AB - Osteoporosis is a burgeoning clinical problem that is characterized by decreased bone strength and density. It predisposes patients to fragility fractures and debilitating spine deformities. Several complications are associated with spine surgery in patients with osteoporosis, and there is currently no treatment algorithm to guide the spine surgeon. A multidisciplinary approach to treatment of patients with osteoporosis and spine deformity or fracture is encouraged, and preoperative planning is crucial for successful surgical outcomes. Several surgical techniques have been developed to treat osteoporosis-related deformities, including posterior instrumentation with fusion. However, achieving fixation and fusion in these patients can be difficult secondary to poor bone stock. Augmentation methods to improve pedicle screw fixation have evolved, including instrumentation at multiple levels, bioactive cement augmentation, and fenestrated or expandable pedicle screws, but their impact on clinical outcomes remains unknown. Management of osteoporosis in patients undergoing spine surgery is challenging, but with appropriate patient selection, medical optimization, and surgical techniques, these patients can experience pain relief, deformity correction, and improved function. PMID- 25808688 TI - Endogenous cell homing for intervertebral disk regeneration. PMID- 25808689 TI - Errata. PMID- 25808690 TI - Crestal bone changes in macrogeometrically similar implants with the implant abutment connection at the crestal bone level or 2.5 mm above: a prospective randomized clinical trial. AB - OBJECTIVE: Crestal bone loss around dental implants is a criterion for success as this could prevent loss of implant and superstructure. The macrogeometry of the implant could influence bone remodelling when the implant-abutment connection is placed at crestal bone level or above. The aim of this study was to evaluate crestal bone remodelling in a randomized clinical prospective trial in macrogeometrically similar implants with the prosthetic connection at the crestal bone level and 2.5 mm above. The null hypothesis was that there was no difference in crestal bone loss after 1 year of early loading. MATERIAL AND METHODS: Patients were referred to Academic Centre of Dentistry Amsterdam for implant placement. Patients were subjected to inclusion and exclusion criteria and received a minimum of two implants: an implant with the prosthetic abutment connection at the crestal bone level (minimized collar [MC], bone level) and one with the prosthetic abutment connection 2.5 mm supracrestal (long collar [LC], tissue level). The mesial or distal location of each implant type was blinded for the patient and randomized. The implants were loaded splinted after 3 weeks of healing. The primary outcome was bone-level change assessed after 1 year of loading. RESULTS: Thirty-three patients fulfilled the inclusion criteria. Thirty nine Thommen SPI ELEMENT LC implants and 39 MC were placed, and each fixed dental prosthesis was supported by one LC and one MC implant. The intraclass correlation of measures performed by the first and second X-ray examiner was as follows: on the mesial side of the MC implant 0.990 (0.980-0.995; 95% confidence interval [CI]), 0.980 (0.962-0.990; 95% CI) on the distal side of the MC implant, 0.979 (0.959-0.989; 95% CI) and 0.988 (0.978-0.994; 95% CI) on the mesial and distal side of the LC implant, respectively. The mean bone loss of the MC implant was 0.4 +/- 0.4 mm. The mean bone loss of the LC implant was 0.2 +/- 0.5 mm. The paired samples t-test showed a statistically significant difference (P < 0.05) between the MC and LC implants. CONCLUSION: Dental implants at bone level show statistically significantly (P < 0.05) more crestal bone change after 1 year of loading than a tissue-level implant. PMID- 25808692 TI - Vascular considerations in foot and ankle free tissue transfer: Analysis of 231 free flaps. AB - OBJECTIVE: Successful foot and ankle soft tissue reconstruction is dependent on a clear understanding of the vascular supply to the foot. The aim of this study was to identify risk factors for reconstructive failure following foot and ankle free tissue transfer. METHODS: The authors retrospectively reviewed their 17-year institutional experience with 231 foot and ankle free flaps performed in 225 patients to determine predictors of postoperative foot ischemia and flap failure. Postoperative foot ischemia was defined as ischemia resulting in tissue necrosis, separate from the reconstruction site. RESULTS: Six (3%) patients developed postoperative foot ischemia, and 28 (12%) patients experienced flap failure. Chronic ulceration (P = 0.02) and an elevated preoperative platelet count (P = 0.04) were independent predictors of foot ischemia. The presence of diabetes was predictive of flap failure (P = 0.05). Flap failure rates were higher in the setting of an abnormal preoperative angiogram (P = 0.04), although the type and number of occluded arteries did not influence outcome. Foot ischemia was more frequent following surgical revascularization in conjunction with free tissue transfer and the use of the distal arterial bypass graft for flap anastomosis (P < 0.01). Overall, no differences were observed in foot ischemia (P = 0.17) and flap failure (P = 0.75) rates when the flap anastomosis was performed to the diseased artery noted on angiography, compared with an unobstructed native tibial artery. CONCLUSIONS: Foot and ankle free tissue transfer may be performed with a low incidence of foot ischemia. Patients with diabetes, chronic ulceration, and an elevated preoperative platelet count are at higher risk for reconstructive failure. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:276-283, 2016. PMID- 25808691 TI - Educational inequalities in hospitalization attributable to alcohol: a population based longitudinal study of changes during the period 2000-07. AB - AIMS: To estimate the relative risk of hospitalization from alcohol-related causes among men and women in Finland across different educational categories, and to determine whether these differentials changed following a large reduction in alcohol prices in 2004. DESIGN AND MEASUREMENTS: A register-based longitudinal study of hospitalizations. We used repeated-measures analysis to estimate alcohol attributable hospitalization rates and assessed effects of the reduction in alcohol prices by comparing two 4-year periods (2000-03 and 2004-07). SETTING: Finland. PARTICIPANTS: A representative sample of the residents of Finland aged 30-79 years in the period 2000-07 (n = 470,627). FINDINGS: There was a clear gradient across educational levels in alcohol-attributable hospitalizations: the incidence rate ratios among men and women with basic education were 1.70 [95% confidence interval (CI) = 1.32, 2.20] and 1.96 (95% CI = 1.36, 2.84), respectively, compared with those with upper-tertiary education. After allowing for the long-term trend, there were no significant changes between the two follow up periods either among men with an upper tertiary education or among women in any educational level, whereas the rate increased by 21% (95% CI = 5, 41), 16% (95% CI = 6, 27) and 10% (95% CI = 2, 18), respectively, among men with a lower tertiary, secondary and basic education. However, these differences in changes were not statistically significant. CONCLUSIONS: Lower-level education is associated with a substantially increased risk of alcohol-related hospitalization among men and women in Finland, even when adjusted for age, economic activity and income. The results do not provide strong evidence that the 2004 price reduction had differential effects by education. PMID- 25808695 TI - Pigmented purpuric dermatosis-like sarcoidosis. AB - Sarcoidosis is a chronic multisystem granulomatous disease of unknown origin. Recently, a purpuric variant of cutaneous sarcoidosis resembling pigmented purpuric dermatosis (PPD) has been documented. Herein, we describe another unusual case with clinical features mimicking PPD, characterized by brownish macules and flat-topped papules with a slightly purpuric component on the legs and dorsum of the feet and histopathological features consistent with sarcoidosis. We designated this unusual clinical presentation as "PPD-like sarcoidosis". PMID- 25808693 TI - Beryllium Concentrations at European Workplaces: Comparison of 'Total' and Inhalable Particulate Measurements. AB - A field study was carried out in order to derive a factor for the conversion of historic worker exposure data on airborne beryllium (Be) obtained by sampling according to the 37-mm closed faced filter cassette (CFC) 'total' particulate method into exposure concentration values to be expected when sampling using the 'Gesamtstaubprobenahmesystem' (GSP) inhalable sampling convention. Workplaces selected to represent the different copper Be work processing operations that typically occur in Germany and the EU were monitored revealing a broad spectrum of prevailing Be size distributions. In total, 39 personal samples were taken using a 37-mm CFC and a GSP worn side by side for simultaneous collection of the 'total' dust and the inhalable particulates, respectively. In addition, 20 static general area measurements were carried out using GSP, CFC, and Respicon samplers in parallel, the latter one providing information on the extra-thoracic fraction of the workplace aerosol. The study showed that there is a linear relationship between the concentrations measured with the CFC and those measured with the GSP sampler. The geometric mean value of the ratios of time-weighted average concentrations determined from GSP and CFC samples of all personal samples was 2.88. The individual values covered a range between 1 and 17 related to differences in size distributions of the Be-containing particulates. This was supported by the area measurements showing that the conversion factor increases with increasing values of the extra-thoracic fraction covering a range between 0 and 79%. PMID- 25808696 TI - Practical application of color Doppler ultrasonography in patients with ejaculatory dysfunction. AB - We describe two cases in which dynamic analysis of ejaculation using color Doppler ultrasonography was useful in diagnosis of ejaculatory dysfunction and planning of therapy. The first patient was a 32-year-old man with a diagnosis of retrograde ejaculation. A bladder neck collagen injection was carried out, as the main cause was thought to be the bladder neck remaining open during ejaculation. The patient had antegrade ejaculation 1 week later. The second patient was a 48 year-old man with a diagnosis of anorgasmia accompanied by decreased seminal emission and insufficient function of the rhythmic pelvic striated muscles. The patient was prescribed etilefrine hydrochloride 15 mg/day. The symptom improved 2 weeks after starting this drug. These cases suggest that the use of color Doppler ultrasonography during ejaculation can improve the understanding of ejaculatory dysfunction and therapy for this condition. PMID- 25808697 TI - Recombinant Human Plasminogen Activator Inhibitor-1 Promotes Cementogenic Differentiation of Human Periodontal Ligament Stem Cells. AB - The periodontium, consisting of gingiva, periodontal ligament (PDL), cementum, and alveolar bone, is necessary for the maintenance of tooth function. Specifically, the regenerative abilities of cementum with inserted PDL are important for the prevention of tooth loss. Periodontal ligament stem cells (PDLSCs), which are located in the connective tissue PDL between the cementum and alveolar bone, are an attractive candidate for hard tissue formation. We investigated the effects of recombinant human plasminogen activator inhibitor-1 (rhPAI-1) on cementogenic differentiation of human PDLSCs (hPDLSCs) in vitro and in vivo. Untreated and rhPAI-1-treated hPDLSCs mixed with hydroxyapatite/tricalcium phosphate (HA/TCP) and dentin matrix were transplanted subcutaneously into the dorsal surface of immunocompromised mice to assess their capacity for hard tissue formation at 8 and 10 weeks posttransplantation. rhPAI-1 accelerated mineral nodule formation and increased the mRNA expression of cementoblast-associated markers in hPDLSCs. We also observed that rhPAI-1 upregulated the levels of osterix (OSX) and cementum protein 1 (CEMP1) through Smad2/3 and p38 pathways, whereas specific inhibitors of Smad3 and p38 inhibited the enhancement of mineralization of hPDLSCs by rhPAI-1. Furthermore, transplantation of hPDLSCs with rhPAI-1 showed a great ability to promote cementogenic differentiation. Notably, rhPAI-1 induced hPDLSCs to regenerate cementum-like tissue with PDL fibers inserted into newly formed cementum-like tissue. These results suggest that rhPAI-1 may play a key role in cementogenic differentiation of hPDLSCs. rhPAI-1 with hPDLSCs may be a good candidate for future clinical applications in periodontal tissue regeneration and possibly in tooth root bioengineering. PMID- 25808699 TI - Variation in health care for children and young people with cerebral palsies: a retrospective multicentre audit study. AB - AIM: To explore the provision and variations in care for children and young people with cerebral palsies (CP) registered with the population-based North of England Collaborative Cerebral Palsy Survey (NECCPS). METHOD: This is a retrospective multicentre record audit of 389 children with CP (220 males, 148 females, 21 no data; median age at time of audit 12y 3mo), born between 1995 and 2002. Data were collected on cranial magnetic resonance imaging (MRI), hip and spine surveillance and management, and pain presence and management. Variations over time and between the districts in the north of England (Northumberland, North and West Cumbria, North and South Tyneside, Newcastle-upon-Tyne, Gateshead, Sunderland, Durham, Darlington, Bishop Auckland, Hartlepool, Stockton-on-Tees, Middlesbrough, Redcar, and Cleveland), and by socio-economic status (SES) (estimated from the Index of Multiple Deprivation [IMD] 2004) were estimated by generalized estimating equations. RESULTS: There was significant variation between districts in access to MRI (p<0.001), orthopaedic surgeons (p=0.005), recording state of spine (p<0.001), and discussions about pain (p<0.001). Fifty seven per cent (95% CI 52-62) had evidence of a reported MRI brain scan, the proportion of which increased over time (p<0.001). Sixty-seven per cent (95% CI 62-71) had a discussion about pain recorded. Of those in pain, 87% (95% CI 80-93) had a pain management plan. The proportion with documented discussion about pain increased with increasing SES (p=0.04). INTERPRETATION: The provision of care for children with CP in the north of England varies between districts. Internationally agreed, evidence-based standards are urgently needed to ensure more equitable health care and improved outcomes for all. PMID- 25808698 TI - Birth defects in a cohort of infants born to HIV-infected women in Spain, 2000 2009. AB - BACKGROUND: Antiretroviral therapy (ART) in pregnancy has resulted in a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV. However the safety of in utero ART exposure in newborns remains a concern. METHODS: A multicenter prospective observational study of HIV-infected mother and their infants was performed in Madrid, Spain, from 2000 to 2009. Children had regular visits with clinical examination according to protocol until the age of 24 months. An abdominal ultrasound and an echocardiogram were scheduled during follow up. Birth defects (BDs) were registered according to European Surveillance of Congenital Anomalies (EUROCAT). RESULTS: A total of 897 live births from 872 mothers were included. Overall the birth defects prevalence observed was 6.9% (95% CI 5.4-9.1).The most commonly reported birth defects types were in genital organs and urinary system (19 cases, 30.6%) and cardiovascular system (17 cases, 27.4%). There was no increased risk for infants exposed in the first trimester to ARVs compared with unexposed infants. No significant associations were observed between exposure to any individual antiretroviral agent during pregnancy and birth defects CONCLUSION: A higher prevalence of BDs was observed, higher than previously reported. In utero exposure to ART was not proved to be a major risk factor of birth defects in infants. However the relatively small number of patients is a major limitation of this study. PMID- 25808700 TI - Head and pelvic movement asymmetry during lungeing in horses with symmetrical movement on the straight. AB - REASONS FOR PERFORMING STUDY: Lungeing is commonly used as part of standard lameness examinations in horses. Knowledge of how lungeing influences motion symmetry in sound horses is needed. OBJECTIVES: The aim of this study was to objectively evaluate the symmetry of vertical head and pelvic motion during lungeing in a large number of horses with symmetric motion during straight line evaluation. STUDY DESIGN: Cross-sectional prospective study. METHODS: A pool of 201 riding horses, all functioning well and considered sound by their owners, were evaluated in trot on a straight line and during lungeing to the left and right. From this pool, horses with symmetric vertical head and pelvic movement during the straight line trot (n = 94) were retained for analysis. Vertical head and pelvic movements were measured with body mounted uniaxial accelerometers. Differences between vertical maximum and minimum head (HDmax, HDmin) and pelvic (PDmax, PDmin) heights between left and right forelimb and hindlimb stances were compared between straight line trot and lungeing in either direction. RESULTS: Vertical head and pelvic movements during lungeing were more asymmetric than during trot on a straight line. Common asymmetric patterns seen in the head were more upward movement during push-off of the outside forelimb and less downward movement during impact of the inside limb. Common asymmetric patterns seen in the pelvis were less upward movement during push-off of the outside hindlimb and less downward movement of the pelvis during impact of the inside hindlimb. Asymmetric patterns in one lunge direction were frequently not the same as in the opposite direction. CONCLUSIONS: Lungeing induces systematic asymmetries in vertical head and pelvic motion patterns in horses that may not be the same in both directions. These asymmetries may mask or mimic fore- or hindlimb lameness. PMID- 25808701 TI - Experimentally induced thyrotoxicosis leads to increased connectivity in temporal lobe structures: a resting state fMRI study. AB - Adult onset hyperthyroidism may impact on different cognitive domains, including attention and concentration, memory, perceptual function, language and executive function. Previous PET studies implicated changed functionality of limbic regions, the temporal and frontal lobes in hyperthyroidism, whereas it is unknown whether cognitive effects of hyperthyroidism may be due to changed brain connectivity. This study aimed to investigate the effect of experimentally induced short-term hyperthyroidism thyrotoxicosis on resting-state functional connectivity using functional magnetic resonance imaging. Twenty-nine healthy male right-handed subjects were examined twice, once prior and once after 8 weeks of oral administration of 250 MUg levothyroxine per day. Resting-state fMRI was subjected to graph-theory based analysis methods to investigate whole-brain intrinsic functional connectivity. Despite a lack of subjective changes noticed by the subjects significant thyrotoxicosis was confirmed in all subjects. This induced a significant increase in resting-state functional connectivity specifically in the rostral temporal lobes (0.05 FDR corrected at the cluster level), which is caused by an increased connectivity to the cognitive control network. The increased connectivity between temporal poles and the cognitive control network shown here under experimental conditions supports an important function of thyroid hormones in the regulation of paralimbic structures. PMID- 25808703 TI - Editorial Comment to Intravesical hyaluronic acid treatment improves bacterial cystitis and reduces cystitis-induced hypercontractility in rats. PMID- 25808704 TI - Ionizing radiation increases primary cilia incidence and induces multiciliation in C2C12 myoblasts. AB - Primary cilia act as physical-chemical sensors and their functions include the perception of the extracellular milieu, regulation of organogenesis, and cell polarity. In general, these cells are monociliated and the single cilium possesses diverse receptors and channels which are involved in morphogenesis and growth signaling, and are, therefore, important for cell proliferation and differentiation. In this study, we used an in vitro model of C2C12 myoblasts to evaluate the effect of DNA damage induced by gamma ionizing radiation on primary cilia incidence. A significantly higher number of ciliated cells were observed after 1 day post-irradiation with 2-20 Gy when compared with non-irradiated cells. After 3 days post-irradiation, the cilia incidence in cells had decreased slightly when treated with 2, 6, and 10 Gy, although an increase in incidence rate was observed in cells treated with 20 Gy. Multi-ciliated cells were also detected in myoblasts irradiated with 10 and 20 Gy but not in non-irradiated cells or after low irradiation (2-6 Gy). Irradiation also caused a dose-dependent decrease in cell viability and proliferation and corresponding cell cycle arrest. Furthermore, an activation of caspases 3/7, 8, and 9 was observed after higher radiation (10 and 20 Gy) with increased apoptosis. Together, our results show that irradiation by gamma rays promotes myoblast ciliogenesis, with pronounced effects observed after 3 days post-irradiation. We conclude that irradiation doses of 10 and 20 Gy are sufficient to induce cell death and are responsible for the formation of multiple cilia originating from multiple basal bodies. PMID- 25808702 TI - Adipocyte glucocorticoid receptors mediate fat-to-brain signaling. AB - Stress-related (e.g., depression) and metabolic pathologies (e.g., obesity) are important and often co-morbid public health concerns. Here we identify a connection between peripheral glucocorticoid receptor (GR) signaling originating in fat with the brain control of both stress and metabolism. Mice with reduced adipocyte GR hypersecrete glucocorticoids following acute psychogenic stress and are resistant to diet-induced obesity. This hypersecretion gives rise to deficits in responsiveness to exogenous glucocorticoids, consistent with reduced negative feedback via adipocytes. Increased stress reactivity occurs in the context of elevated hypothalamic expression of hypothalamic-pituitary-adrenal (HPA) axis excitatory neuropeptides and in the absence of altered adrenal sensitivity, consistent with a central cite of action. Our results identify a novel mechanism whereby activation of the adipocyte GR promotes peripheral energy storage while inhibiting the HPA axis, and provide functional evidence for a fat-to-brain regulatory feedback network that serves to regulate not just homeostatic energy balance but also responses to psychogenic stimuli. PMID- 25808705 TI - The Role of Maternal Gestational Diabetes in Inducing Fetal Endothelial Dysfunction. AB - Gestational diabetes mellitus (GDM) is known to be associated with fetal endothelial dysfunction, however, the mechanisms are not fully understood. This study examines the effect of maternal diabetes on fetal endothelial function and gene expression under physiological glucose conditions (5 mM). Human umbilical vein endothelial cell (HUVEC) isolated from diabetic mothers (d.HUVEC) grew more slowly than HUVEC isolated from healthy mothers (c.HUVEC) and had delayed doubling time despite increased levels of total vascular endothelial growth factor (VEGF) expression and protein production as determined by real-time PCR and ELISA respectively. Using western blot, the levels of antiproliferative VEGF165b isoform were increased in d.HUVEC relative to c.HUVEC. Successful VEGF165b knockdown by small interfering RNA (siRNA) resulted in increased proliferation of d.HUVEC measured by MTT, compared with negative siRNA control, to similar levels measured in c.HUVEC. In addition, d.HUVEC generated excess levels of ROS as revealed by 2',7' Dichlorodihydrofluorescein Diacetate (DCFH-DA) and Nitrotetrazolium blue (NBT). Using microarray, 102 genes were differentially overexpressed between d.HUVEC versus c.HUVEC (>1.5-fold change; P < 0.05). Functional clustering analysis of these differentially expressed genes revealed participation in inflammatory responses (including adhesion) which may be related to pathological outcomes. Of these genes, ICAM-1 was validated as upregulated, confirming microarray results. Additional confirmatory immunofluorescence staining revealed increased protein expression of ICAM-1 compared with c.HUVEC which was reduced by vitamin C treatment (100 MUM). Thus, maternal diabetes induces persistent alterations in fetal endothelial function and gene expression following glucose normalization and antioxidant treatment could help reverse endothelium dysfunction. PMID- 25808707 TI - Future directions in urological oncology. PMID- 25808706 TI - Mapping the expression of epithelial hair follicle stem cell-related transcription factors LHX2 and SOX9 in the human hair follicle. AB - In the murine hair follicle (HF), the transcription factors LHX2 and SOX9 are implicated in epithelial hair follicle stem cell (eHFSC) self-renewal and the maintenance of eHFSC niche characteristics. However, the exact expression patterns of LHX2 and SOX9 in the human HF are unclear. Therefore, we have quantitatively mapped the localisation of known human eHFSC markers keratin 15 (K15) and keratin 19 (K19) in the outer root sheath (ORS) of male occipital scalp anagen HFs and related this to the localisation of LHX2 and SOX9 protein expression. As expected, K15(+) and K19(+) cells represented two distinct progenitor cell populations in the bulge and in the proximal bulb ORS (pbORS). Interestingly, cell fluorescence for K19 was significantly stronger within the pbORS versus the bulge, and vice versa for K15, describing a hitherto unrecognised differential expression pattern. LHX2 and SOX9 expressing cells were distributed throughout the ORS, including the bulge, but were not restricted to it. SOX9 expression was most prominent in the ORS immediately below the human bulge, whereas LHX2(+) cells were similarly distributed between the sub-bulge and pbORS, that is compartments not enriched with quiescent eHFSCs. During catagen development, the intensity of LHX2 and SOX9 protein expression increased in the proximal HF epithelium. Double immunostaining showed that the majority of SOX9(+) cells in the human anagen HF epithelium did not co-express K15, K19 or LHX2. This expression profile suggests that LHX2 and SOX9 highlight distinct epithelial progenitor cell populations, in addition to K15(+) or K19(+) cells, that could play an important role in the maintenance of the human HF epithelium. PMID- 25808709 TI - The need for standardised reporting of complications. Re: Minimum 5-years follow up of 1138 consecutive laparoscopic radical prostatectomies. PMID- 25808708 TI - Time to replace prostate-specific antigen (PSA) with the Prostate Health Index (PHI)? Yet more evidence that the PHI consistently outperforms PSA across diverse populations. PMID- 25808710 TI - Cardiopulmonary exercise testing: fortune-teller or guardian angel? PMID- 25808711 TI - A urologists' guide to the multi-parametric magnetic resonance imaging (mpMRI) galaxy. PMID- 25808712 TI - A three-dimensional window into the body? PMID- 25808714 TI - Hybrid Films of Graphene and Carbon Nanotubes for High Performance Chemical and Temperature Sensing Applications. AB - A hybrid composite material of graphene and carbon nanotube (CNT) for high performance chemical and temperature sensors is reported. Integration of 1D and 2D carbon materials into hybrid carbon composites is achieved by coupling graphene and CNT through poly(ionic liquid) (PIL) mediated-hybridization. The resulting CNT/PIL/graphene hybrid materials are explored as active materials in chemical and temperature sensors. For chemical sensing application, the hybrid composite is integrated into a chemo-resistive sensor to detect a general class of volatile organic compounds. Compared with the graphene-only devices, the hybrid film device showed an improved performance with high sensitivity at ppm level, low detection limit, and fast signal response/recovery. To further demonstrate the potential of the hybrid films, a temperature sensor is fabricated. The CNT/PIL/graphene hybrid materials are highly responsive to small temperature gradient with fast response, high sensitivity, and stability, which may offer a new platform for the thermoelectric temperature sensors. PMID- 25808715 TI - Intermittent ulnar nerve compression due to accessory abductor digiti minimi muscle: Crucial diagnostic role of nerve ultrasound. PMID- 25808713 TI - Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study. AB - AIMS: Regulatory review time has been associated with post-market medication safety issues in the United States. Our objective was to evaluate whether regulatory review time and near deadline approval are associated with post-market safety events (PMSEs) for novel medicines approved by the European Medicines Agency (EMA). METHODS: We performed a cross-sectional analysis of all novel medicines approved by the EMA through the centralized authorization procedure between 2001 and 2010. PMSEs were defined as withdrawals and communications identified through Dear Healthcare Professional Communications (DHPCs). Regulatory review time was defined as the time that elapsed between the start of the assessment procedure and approval. Near regulatory deadline approval was defined as approval within the 30 days before the EMA's 210 day regulatory deadline. RESULTS: Among 161 eligible medicines, PMSEs were identified for 49 (30.4%), 44 of which were DHPCs, five of which were withdrawals. Median regulatory review time was 337 days (IQR 276-406) and was not associated with PMSEs (P = 0.57). However, when categorized by regulatory review speed tertile, there were differences in risk of PMSEs, with higher rates among medicines in the middle tertile (25 of 55, 45.4%; P = 0.01). Finally, 26 medicines were approved near the 210 day regulatory deadline, but were not more likely to have PMSEs (38.5% vs. 28.7%; P = 0.32). CONCLUSIONS: Neither faster EMA regulatory review speed nor approval near regulatory deadlines was associated with greater likelihood of PMSEs among recently approved novel medicines. PMID- 25808716 TI - Longitudinal diffusion-weighted imaging changes in children with small bowel Crohn's disease: preliminary experience. AB - PURPOSE: Crohn's disease has been associated with restricted diffusion in diseased small bowel segments on diffusion-weighted imaging (DWI). However, data addressing longitudinal changes in DWI findings and their potential clinical ramifications in the pediatric population are lacking. The purpose of this study was to follow DWI changes in diseased small bowel segments between serial magnetic resonance enterography (MRE) examinations, and to correlate these changes with other imaging parameters and clinical status. METHODS: This retrospective study evaluated patients less than 21 years of age undergoing serial MRE examinations including DWI for Crohn's disease involving the small bowel. All patients carried a diagnosis of Crohn's disease established by pathology or corroborative clinical and imaging findings. Longitudinal changes in mean apparent diffusion coefficient (ADC) values within the wall of affected small bowel lesions were recorded and normalized to both unaffected bowel and skeletal muscle. ADC changes were correlated with qualitative imaging phenotype, as reflected by a defined set of non-DWI imaging parameters, as well as with clinical disease activity. RESULTS: Seventeen lesions were evaluated longitudinally, distributed among 13 patients (9 boys and 4 girls, mean age at baseline 16.6 years), each of whom had two sequential MRE examinations. Lesions demonstrating a fibrostenotic imaging phenotype at follow-up MRE had a significantly lower change in mean ADC value between examinations than lesions that did not have a fibrostenotic imaging phenotype (p = 0.0005), an effect that persisted when ADC values were normalized to unaffected bowel and skeletal muscle. Across all studies, lesions with a fibrostenotic imaging phenotype had lower ADC values than those with an inflammatory imaging phenotype, which were in turn lower than those with a normal imaging phenotype (p = 0.0001). CONCLUSION: Patterns of longitudinal DWI changes in Crohn's disease may differ among small bowel lesions depending upon their specific natural histories. These findings may assist in the evaluation of the ADC value as a potential imaging surrogate when evaluating lesion status, particularly as it pertains to relative contributions of inflammation and fibrosis. PMID- 25808718 TI - Comparing Subjective Ratings of Sexual Arousal and Desire in Partnered Sexual Activities from Women of Different Sexual Orientations. AB - Little is known about non-monosexual women's sexual arousal and desire. Typically, bisexual women have been excluded from research on sexual arousal and desire, whereas mostly heterosexual and mostly lesbian women have been placed into monosexual categories. This research (1) compared the subjective sexual arousal and desire of self-identified heterosexual, mostly heterosexual, bisexual, mostly lesbian, and lesbian women in partnered sexual activities with men and with women, and (2) compared within-group differences for subjective sexual arousal and desire with men versus women for the five groups. Participants included 388 women (M age = 24.40, SD = 6.40, 188 heterosexual, 53 mostly heterosexual, 64 bisexual, 32 mostly lesbian, 51 lesbian) who filled out the Sexual Arousal and Desire Inventory (SADI). Sexual orientation was associated with sexual arousal and desire in sexual activities with both men and with women. Bisexuals reported higher sexual arousal and desire for women than heterosexuals and lesbians, while lesbians reported lower sexual arousal and desire with men than the other groups. Heterosexuals and mostly heterosexuals scored higher on the male than on the female motivational dimension of the SADI, while the reverse was found for lesbians and mostly lesbians. Findings indicate that non monosexuals have higher sexual arousal and desire in sexual activities with women than monosexuals. Further, bisexual women did not differentiate their sexual arousal with men versus women, while the other sexual orientation groups differentiated in terms of their motivation to engage in sexual activity. These findings may have implications for how female sexual orientation is conceptualized. PMID- 25808717 TI - Social disadvantage and exposure to lower priced alcohol in off-premise outlets. AB - INTRODUCTION AND AIMS: Greater concentrations of off-premise alcohol outlets are found in areas of social disadvantage, exposing disadvantaged populations to excess risk for problems such as assault, child abuse and intimate partner violence. This study examines whether the outlets to which they are exposed also sell cheaper alcohol, potentially further contributing to income-related health disparities. DESIGN AND METHODS: We conducted unobtrusive observations in 295 off premise outlets in Melbourne, Australia, randomly selected using a spatial sample frame. In semi-logged linear regression models, we related the minimum purchase price for a 750 mL bottle of wine to a national index of socioeconomic advantage for the census areas in which the outlets were located. Other independent variables characterised outlet features (e.g. volume, chain management) and conditions of the local alcohol market (adjacent outlet characteristics, neighbourhood characteristics). RESULTS: A one decile increase in socioeconomic advantage was related to a 1.3% increase in logged price. Larger outlets, chains, outlets adjacent to chains, outlets in greater proximity to the nearest neighbouring outlet and those located in areas with more students also had cheaper alcohol. DISCUSSION AND CONCLUSIONS: Not only are disadvantaged populations exposed to more outlets, the outlets to which they are exposed sell cheaper alcohol. This finding appears to be consistent with the spatial dynamics of typical retail markets. PMID- 25808719 TI - Acute Effects of Intoxication and Arousal on Approach/Avoidance Biases Toward Sexual Risk Stimuli in Heterosexual Men. AB - This study tested the effects of alcohol intoxication and physiological arousal on cognitive biases toward erotic stimuli and condoms. Ninety-seven heterosexual men were randomized to 1 of 6 independent conditions in a 2 (high arousal or control) * 3 (alcohol target BAC = 0.08, placebo, or juice control) design and then completed a variant of the Approach-Avoidance Task (AAT). The AAT assessed reaction times toward approaching and avoiding erotic stimuli and condoms with a joystick. Consistent with hypotheses, the alcohol condition exhibited an approach bias toward erotic stimuli, whereas the control and placebo groups exhibited an approach bias toward condom stimuli. Similarly, the participants in the high arousal condition exhibited an approach bias toward erotic stimuli and the low arousal control condition exhibited an approach bias toward condoms. The results suggest that acute changes in intoxication and physiological arousal independently foster biased responding toward sexual stimuli and these biases are associated with sexual risk intentions. PMID- 25808721 TI - Misrepresentation of evidence favoring early normalizing surgery for atypical sex anatomies. PMID- 25808720 TI - Bidirectional associations between alcohol use and sexual risk-taking behavior from adolescence into young adulthood. AB - Overwhelming evidence indicates that sexual risk-taking behavior and alcohol use are linked, but the nature, strength, and timing of these relations may differ between gender and racial subgroups. These issues were addressed by examining the course and interrelations of both behaviors from adolescence into young adulthood, as well as how these patterns differed between both men and women and between Blacks and Whites. Data came from a representative, community-based sample of 1867 urban participants surveyed up to 5 times over a 15-year period. Although both prospective and trajectory analyses showed that adolescent involvement in one behavior predicted later involvement in the other, most patterns were moderated by gender, race, or both. In general, positive, bidirectional associations were discovered among men and Whites. Among women, adolescent sexual risk-taking behavior positively predicted later drinking, but not vice versa. For Blacks, adolescent alcohol use was inconsistently related to later sexual risk-taking behavior, and adolescent sexual risk-taking negatively predicted later alcohol use. Results suggest that associations between sexual risk-taking behavior and alcohol use are more complex than previously thought and that an adequate understanding of these links must account for both gender and racial differences. PMID- 25808722 TI - The heritability of blood donation: a population-based nationwide twin study. AB - BACKGROUND: Voluntary blood donation is believed to be mostly motivated by altruism. Because studies have suggested that altruistic personality is determined by both genetic and environmental factors, we speculated that willingness to donate blood could also be governed by constitutional factors. This hypothesis was tested in a study among Danish twins. STUDY DESIGN AND METHODS: The nationwide Danish Twin Register, which is virtually complete for all twins born since 1968, was linked with Danish portion of the Scandinavian Donation and Transfusion (SCANDAT) Database, which includes information on all active Danish blood donors from 2002 to 2012, to establish blood donor status for Danish twins, who at age 17 years became eligible for donation in 2002 or later. Casewise concordance in monozygotic (MZ) and dizygotic (DZ) twins were presented and heritability was estimated in Mx by variance component analysis in a liability threshold model. RESULTS: A total of 274 MZ and 484 same-sex DZ twins age 17 to 27 years were identified as donors in SCANDAT. There was no difference between MZ and DZ twins with regard to age at first donation or number of donations. Casewise concordance rates were 0.61 (95% confidence interval [CI], 0.56-0.67) and 0.41 (95% CI, 0.36-0.47) in MZ and DZ twin pairs, respectively. Heritability analysis using the ACE model found that additive genetic and shared environmental effects accounted for 0.53 (95% CI, 0.33-0.73) and 0.28 (95% CI, 0.10-0.45) of the variance in the motivation to donate blood, respectively. CONCLUSION: Becoming a volunteer blood donor is determined by both genetic and environmental factors shared within families. PMID- 25808723 TI - miR-544 Regulates Dairy Goat Male Germline Stem Cell Self-Renewal via Targeting PLZF. AB - The balance between the self-renewal and differentiation of male germline stem cells (mGSCs) is critical for the initiation and maintenance of mammalian spermatogenesis. The promyelocytic leukemia zinc finger (PLZF), a zinc finger protein, is a critical factor for maintaining the self-renewal of mGSCs, so, evaluation of the PLZF pathway in mGSCs may provide a deeper insight into mammalian spermatogenesis. miRNA was also an important regulating factor for the self-renewal and differentiation of mGSCs; however, there is currently no data indicating that which miRNA regulate the self-renewal and differentiation of mGSCs via PLZF. Here, we predicted the prospective miRNA targeting to PLZF using the online Bioinformatics database-Targetscan, and performed an analysis of the dual-luciferase recombinant vector, psiCHCEKTM-2-PLZF-3'UTR. miR-544 mimics (miR 544m), miR-544 inhibitors (miR-544i), Control (NC, scrambled oligonucleotides transfection), pPLZF-IRES2-EGFP or PLZF siRNA were transfected into mGSCs; the cells proliferation was evaluated by BRDU incorporation assay and flow cytometry, and the mGSC marker, GFRa1, PLZF, KIT, DAZL, and VASA expression were analyzed by RT-qPCR, immunofluorescence and Western blot. The results showed that miR-544 regulates dairy goat male germline stem cell self-renewal via targeting PLZF. Our study identifies a new regulatory pathway for PLZF and expands upon the PLZF regulatory network in mGSCs. PMID- 25808724 TI - Evaluating Breast Cancer Health System Between Countries: The Use of USA/SEER and Brazilian Women as a Cohort Sample. PMID- 25808725 TI - Refugee children's play: Before and after migration to Australia. AB - AIM: Play is vital to children's development, health and resilience. Play modulates cognitive, emotional and social well-being. Children constitute approximately half of all humanitarian refugee entrants resettled in Australia. Refugee children are commonly victims and witnesses of war and persecution, living across resource-poor environs during transit. Little is known about the effects of refugee migration on play. This study explores how refugee children engaged in play pre-migration (in their home country) and post-migration (Australia). METHODS: Refugee children attending the Refugee Health Clinic of a tertiary children's hospital were invited to complete a qualitative descriptive study of play. The children were asked to draw how they played pre- and post migration. Drawings were analysed for (i) the presence of play; (ii) location of play; and (iii) drawing detail. RESULTS: Nineteen refugee children were recruited (mean age 8.5 years +/- standard deviation 6.4 months). Significantly fewer children drew play pre- versus post-migration (11/19, 58% vs. 18/19, 95% P < 0.03). Girls had greater comparative changes in play with migration (pre: 2/8, 25% vs. post: 7/8, 87%, P = 0.06), trending to significance. Of those children who drew play, almost all drew playing outside (pre-migration: 10/11, 90.9%; post migration: 17/18, 94.4%). Drawings showed equivalent detail pre- and post migration. CONCLUSION: Resettled refugee children, especially girls, demonstrated limited play pre-migration, with higher levels of engagement post-resettlement. Facilitating opportunities for variety of play may strengthen positive resettlement outcomes for children and parents. Larger longitudinal studies examining play in refugee children and associations with physical, development and psychological well-being are warranted. PMID- 25808726 TI - Registered nurses with disabilities: legal rights and responsibilities. AB - PURPOSE: The purpose of this legal case review and analysis was to determine what kinds of cases involving nurses with disabilities are typically brought to attorneys, which cases tend to be successful, and how and when a nurse with a disability should pursue legal action. DESIGN: The review used the standard legal case analysis method to analyze legal cases that have been brought by registered nurses (RNs) with physical or sensory disabilities from 1995 to 2013. The cases span the period following the enactment of the Americans With Disabilities Act (ADA) of 1990 through the ADA Amendments Act (ADAAA) of 2008. METHODS: A nurse attorney reviewed the background material to find every case involving an RN with a disability, excluding those with mental health disabilities or substance abuse issues. Case analysis was conducted using standard legal case analysis procedures. Fifty-six cases were analyzed. FINDINGS: The cases were categorized into five types of legal claims: (a) disability discrimination (84%); (b) failure to accommodate (46%); (c) retaliation (12.5%); (d) association (3.6%); and (e) hostile work environment (7%). The cases were largely unsuccessful, particularly those brought under the ADA instead of the ADAAA. CONCLUSIONS: The case analysis revealed that several cases brought by RNs with disabilities using the ADA might have been successful under the ADAAA. In addition, the case analysis has provided vital information for administrators, leaders, and clinical nurses regarding when a case is appropriate for legal action. These findings from this review will help nurses recognize when they are being treated in a discriminatory way in the workplace, what their legal rights and responsibilities are, and at what point they should pursue legal action. CLINICAL RELEVANCE: This review has relevance to all RNs working in clinical and academic settings who may have a congenital or acquired physical or sensory disability. PMID- 25808727 TI - Molecular profiling of sepsis in mice using Fourier Transform Infrared Microspectroscopy. AB - Sepsis is a life threatening condition resulting from a high burden of infection. It is a major health care problem and associated with inflammation, organ dysfunction and significant mortality. However, proper understanding and delineating the changes that occur during this complex condition remains a challenge. A comparative study involving intra-peritoneal injection of BALB/c mice with Salmonella Typhimurium (infection), lipopolysaccharide (endotoxic shock) or thioglycollate (sterile peritonitis) was performed. The changes in organs and sera were profiled using immunological assays and Fourier Transform Infrared (FTIR) micro-spectroscopy. There is a rapid rise in inflammatory cytokines accompanied with lowering of temperature, respiratory rate and glucose amounts in mice injected with S. Typhimurium or lipopolysaccharide. FTIR identifies distinct changes in liver and sera: decrease in glycogen and protein/lipid ratio and increase in DNA and cholesteryl esters. These changes were distinct from the pattern observed in mice treated with thioglycollate and the differences in the data obtained between the three models are discussed. The combination of FTIR spectroscopy and other biomarkers will be valuable in monitoring molecular changes during sepsis. PMID- 25808730 TI - Sirkka-Liisa Leinonen. PMID- 25808729 TI - Plasma folate levels in early to mid pregnancy after a nation-wide folic acid supplementation program in areas with high and low prevalence of neural tube defects in China. AB - BACKGROUND: Folic acid supplementation is recommended for all women of child bearing age to prevent neural tube defects (NTDs). A nation-wide folic acid supplementation program was implemented in rural areas of China since 2009; however, changes in plasma folate levels in pregnant women were unknown. METHODS: A cross-sectional survey was conducted in 2011 to 2012, with 1736 pregnant women enrolled, and results were compared with a previous survey in 2002 to 2004. A microbiological method was used to determine plasma folate levels. Preprogram and postprogram median plasma folate concentrations were compared while stratified by prevalence of NTDs and residence. RESULTS: In the high NTD prevalence population, plasma folate concentration increased to 33.4 (18.7, 58.4) nmol/L in the postprogram sample, which is 2.9 times of the preprogram. In the low NTD prevalence population, plasma folate increased to 67.9 (44.5, 101.9) nmol/L, which is 1.9 times of the preprogram. Gaps remained in plasma folate levels with respect to prevalence of NTDs and residence. Folic acid supplementation has a strong impact on plasma folate concentrations. Earlier supplementation (before the last menstrual period), increased supplementation frequency and more total days of supplementation were associated with a higher plasma folate concentration as demonstrated in both the high- and low-prevalence populations. CONCLUSION: Plasma folate levels among pregnant Chinese women increased dramatically after the nation-wide folic acid supplementation program in both rural and urban areas, and in populations of high and low NTD prevalence. The nation-wide program should have a component to ensure that supplementation begins before pregnancy. PMID- 25808728 TI - DNA Methylome Signature in Synoviocytes From Patients With Early Rheumatoid Arthritis Compared to Synoviocytes From Patients With Longstanding Rheumatoid Arthritis. PMID- 25808731 TI - Valence bond and enzyme catalysis: a time to break down and a time to build up. AB - Understanding enzyme catalysis and developing ability to control of it are two great challenges in biochemistry. A few successful examples of computational based enzyme design have proved the fantastic potential of computational approaches in this field, however, relatively modest rate enhancements have been reported and the further development of complementary methods is still required. Herein we propose a conceptually simple scheme to identify the specific role that each residue plays in catalysis. The scheme is based on a breakdown of the total catalytic effect into contributions of individual protein residues, which are further decomposed into chemically interpretable components by using valence bond theory. The scheme is shown to shed light on the origin of catalysis in wild-type haloalkane dehalogenase (wt-DhlA) and its mutants. Furthermore, the understanding gained through our scheme is shown to have great potential in facilitating the selection of non-optimal sites for catalysis and suggesting effective mutations to enhance the enzymatic rate. PMID- 25808732 TI - Assessment of STR Typing Success Rate in Soft Tissues from Putrefied Bodies Based on a Quantitative Grading System for Putrefaction. AB - To date, there is no systematic investigation of the association of short tandem repeat (STR) typing success rate in soft tissues with different signs of putrefaction. Herein, putrefaction was rated using a newly developed 19-parameter system in soft tissues from a collective of 68 decaying bodies, and DNA yield was determined in 408 samples. DNA integrity was rated using a self-devised pentaplex PCR generating an "integrity score" (Si). STR typing success rate was then assessed for selected cases. DNA yield and Si differed significantly between tissues with kidney on average exhibiting the highest Si values. Statistical analysis revealed that nine parameters were significantly and positively correlated with Si . The observed values for each of these nine parameters were summed up to generate a putrefaction score (Sp) for each sample. Our results show that STR typing success rate can be predicted based on Sp before expensive multiplex STR profiling is performed. PMID- 25808733 TI - Bisphosphonate exposure and osteonecrosis of the jaw. PMID- 25808734 TI - Bisphosphonate exposure and osteonecrosis of the jaw. PMID- 25808736 TI - Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration. AB - BACKGROUND: Genomic integration, an obligate step in the HIV-1 replication cycle, is blocked by the integrase inhibitor raltegravir. A consequence is an excess of unintegrated viral DNA genomes, which undergo intramolecular ligation and accumulate as 2-LTR circles. These circularized genomes are also reliably observed in vivo in the absence of antiviral therapy and they persist in non dividing cells. However, they have long been considered as dead-end products that are not precursors to integration and further viral propagation. RESULTS: Here, we show that raltegravir action is reversible and that unintegrated viral DNA is integrated in the host cell genome after raltegravir removal leading to HIV-1 replication. Using quantitative PCR approach, we analyzed the consequences of reversing prolonged raltegravir-induced integration blocks. We observed, after RAL removal, a decrease of 2-LTR circles and a transient increase of linear DNA that is subsequently integrated in the host cell genome and fuel new cycles of viral replication. CONCLUSIONS: Our data highly suggest that 2-LTR circles can be used as a reserve supply of genomes for proviral integration highlighting their potential role in the overall HIV-1 replication cycle. PMID- 25808738 TI - Circadian gene expression and extremely low-frequency magnetic fields: an in vitro study. AB - It is well known that circadian clocks are mainly regulated by light targeting signaling pathways in the hypothalamic suprachiasmatic nucleus. However, an entrainment mediated by non-photic sensory stimuli was also suggested for peripheral clocks. Exposure to extremely low frequency (ELF) electromagnetic fields might affect circadian rhythmicity. The goal of this research was to investigate effects of ELF magnetic fields (ELF-MF) on circadian clock genes in a human fibroblast cell line. We found that an ELF-MF (0.1 mT, 50 Hz) exposure was capable of entraining expression of clock genes BMAL1, PER2, PER3, CRY1, and CRY2. Moreover, ELF-MF treatment induced an alteration in circadian clock gene expression previously entrained by serum shock stimulation. These results support the hypothesis that ELF-MF may be able to drive circadian physiologic processes by modulating peripheral clock gene expression. PMID- 25808737 TI - Visualization of pulmonary clearance mechanisms via noninvasive optical imaging validated by near-infrared flow cytometry. AB - In vivo optical imaging with near-infrared (NIR) probes is an established method of diagnostics in preclinical and clinical studies. However, the specificities of these probes are difficult to validate ex vivo due to the lack of NIR flow cytometry. To address this limitation, we modified a flow cytometer to include an additional NIR channel using a 752 nm laser line. The flow cytometry system was tested using NIR microspheres and cell lines labeled with a combination of visible range and NIR fluorescent dyes. The approach was verified in vivo in mice evaluated for immune response in lungs after intratracheal delivery of the NIR contrast agent. Flow cytometry of cells obtained from the lung bronchoalveolar lavage demonstrated that the NIR dye was taken up by pulmonary macrophages as early as 4-h post-injection. This combination of optical imaging with NIR flow cytometry extends the capability of imaging and enables complementation of in vivo imaging with cell-specific studies. PMID- 25808740 TI - The influence of adolescent eating disorders or disordered eating behaviors on socioeconomic achievement in early adulthood. AB - OBJECTIVE: Much research documents the etiology and health consequences of adolescent eating disorders (ED), but very little is known about the long-term effects of EDs on the transition to adulthood. This study explores gender differences in the influence of EDs or disordered eating behaviors (DEB) on measures of socioeconomic independence in early adulthood. METHOD: Using the National Longitudinal Study of Adolescent Health (Add Health), this study compares individuals who self-identified as have been diagnosed with an ED or engaged in DEBs in late adolescence to those without ED or DEB on three measures of socioeconomic independence during early adulthood, including educational attainment, income, and likelihood of owning a home. This study uses multiple regression techniques and attempts to account for early-life conditions and health outcomes associated with EDs and DEBs. RESULTS: For females, ED or DEB in late adolescence had a statistically significant, negative association with educational attainment (coefficient = -0.20, p = .05), personal income (coefficient = -0.12, p < .05) and odds of owning a home (odds ratio = 0.73, p < .02) in early adulthood. For males, ED or DEB was not associated with socioeconomic attainment. DISCUSSION: Our findings suggest that EDs and DEBs are negatively associated with socioeconomic achievement during early adulthood for females, but not for males. EDs or DEBs during adolescence may set individuals on a different trajectory whereby they do not have the same life chances or opportunities for success in adulthood. These results confirm the public health message that EDs or DEBs have lasting negative consequences for women. PMID- 25808739 TI - Prostate cancer marker panel with single cell sensitivity in urine. AB - BACKGROUND: Over one million men undergo prostate biopsies annually in the United States, a majority of whom due to elevated serum PSA. More than half of the biopsies turn out to be negative for prostate cancer (CaP). The limitations of both the PSA test and the biopsy procedure have led to the development for more precise CaP detection assays in urine (e.g., PCA3, TMPRSS2-ERG) or blood (e.g., PHI, 4K). Here, we describe the development and evaluation of the Urine CaP Marker Panel (UCMP) assay for sensitive and reproducible detection of CaP cells in post-digital rectal examination (post-DRE) urine. METHODS: The cellular content of the post-DRE urine was captured on a translucent filter membrane, which is placed on Cytoclear slides for direct evaluation by microscopy and immuno-cytochemistry (ICC). Cells captured on the membrane were assayed for PSA and Prostein expression to identify prostate epithelial cells, and for ERG and AMACR to identify prostate tumor cells. Immunostained cells were analyzed for quantitative and qualitative features and correlated with biopsy positive and negative status for malignancy. RESULTS: The assay was optimized for single cell capture sensitivity and downstream evaluations by spiking a known number of cells from established CaP cell lines, LNCaP and VCaP, into pre-cleared control urine. The cells captured from the post-DRE urine of subjects, obtained prior to biopsy procedure, were co-stained for ERG, AMACR (CaP specific), and Prostein or PSA (prostate epithelium specific) rendering a whole cell based analysis and characterization. A feasibility cohort of 63 post-DRE urine specimens was assessed. Comparison of the UCMP results with blinded biopsy results showed an assay sensitivity of 64% (16 of 25) and a specificity of 68.8% (22 of 32) for CaP detection by biopsy. CONCLUSIONS: This pilot study assessing a minimally invasive CaP detection assay with single cell sensitivity cell-capture and characterization from the post-DRE urine holds promise for further development of this novel assay platform. Prostate 75: 969-975, 2015. (c) 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc. PMID- 25808741 TI - Effects of candesartan in acute stroke on vascular events during long-term follow up: results from the Scandinavian Candesartan Acute Stroke Trial (SCAST). AB - BACKGROUND: Randomized-controlled trials have shown no beneficial short-term effects of blood pressure lowering treatment in the acute phase of stroke. AIM: We aimed to see whether blood pressure lowering treatment with candesartan in the acute phase can lead to benefits that become apparent over a longer period of follow-up. METHODS: The Scandinavian Candesartan Acute Stoke Trial was a randomized- and placebo-controlled trial of candesartan in 2,029 patients with acute stroke and systolic blood pressure >=140 mmHg. Trial treatment was given for seven-days, and the primary follow-up period was six-months. We have used the national patient registries and the cause of death registries in the Scandinavian countries to collect data on vascular events and deaths up to three-years from randomization. The primary end-point was the composite of stroke, myocardial infarction, or vascular death, and we used Cox proportional hazards regression model for analysis. RESULTS: Long-term data were available for 1,256 of the 1,286 patients (98%) from Scandinavia. The risk of the primary composite end-point did not differ significantly between the groups (candesartan 178/632 events, placebo 203/624 events, hazard ratio = 0.87, 95% confidence interval 0.71-1.07). There were also no statistically significant differences for the secondary end-points stroke and all-cause death, or in any of the pre-specified subgroups. CONCLUSIONS: Treatment with candesartan in the acute phase of stroke was not associated with clear long-term clinical benefits. This result supports the conclusion from trials with short-term follow-up, that blood pressure lowering treatment with candesartan should not be given routinely to patients with acute stroke and raised blood pressure. PMID- 25808743 TI - Assessing Major Accident Risks to Support Land-Use Planning Using a Severity Vulnerability Combination Method: A Case Study in Dagushan Peninsula, China. AB - Major accident risks posed by chemical hazards have raised major social concerns in today's China. Land-use planning has been adopted by many countries as one of the essential elements for accident prevention. This article aims at proposing a method to assess major accident risks to support land-use planning in the vicinity of chemical installations. This method is based on the definition of risk by the Accidental Risk Assessment Methodology for IndustrieS (ARAMIS) project and it is an expansion application of severity and vulnerability assessment tools. The severity and vulnerability indexes from the ARAMIS methodology are employed to assess both the severity and vulnerability levels, respectively. A risk matrix is devised to support risk ranking and compatibility checking. The method consists of four main steps and is presented in geographical information-system-based maps. As an illustration, the proposed method is applied in Dagushan Peninsula, China. The case study indicated that the method could not only aid risk regulations on existing land-use planning, but also support future land-use planning by offering alternatives or influencing the plans at the development stage, and thus further enhance the roles and influence of land-use planning in the accident prevention activities in China. PMID- 25808742 TI - Practice Leadership at the Front Line in Supporting People with Intellectual Disabilities and Challenging Behaviour: A Qualitative Study of Registered Managers of Community-based, Staffed Group homes. AB - BACKGROUND: The front-line management role in services for people with intellectual disabilities remains rather under-researched. The aim of this study was to examine the experiences of registered managers in services for adults with intellectual disability who exhibit challenging behaviour. METHOD: Interviews, primarily focussed upon staff practice, were conducted with 19 managers of staffed group homes in SE England. Transcripts were analysed using interpretive phenomenological analysis. RESULTS: Five groups of themes emerged: monitoring staff performance, supporting new ways of working, shaping staff performance, influence of external and employing agencies, and importance of participants' personal values and experiences. CONCLUSION: The themes identified contribute to a conceptual framework for thinking about front-line management/practice leadership. The limitations, and potential implications, of the findings are discussed. PMID- 25808744 TI - Epidemiologic link between tuberculosis and cigarette/biomass smoke exposure: Limitations despite the vast literature. AB - The geographic overlap between the prevalence of cigarette smoke (CS) exposure and tuberculosis (TB) in the world is striking. In recent years, relatively large number of studies has linked cigarette or biomass fuel smoke exposure and various aspects of TB. Our goals are to summarize the significance of the known published studies, graphically represent reports that quantified the association and discuss their potential limitations. PubMed searches were performed using the key words 'tuberculosis' with 'cigarette', 'tobacco', 'smoke' or 'biomass fuel smoke.' The references of relevant articles were examined for additional pertinent papers. A large number of mostly case-control and cross-sectional studies significantly associate both direct and second-hand smoke exposure with tuberculous infection, active TB, and/or more severe and lethal TB. Fewer link biomass fuel smoke exposure and TB. While a number of studies interpreted the association with multivariate analysis, other confounders are often not accounted for in these analyses. It is also important to emphasize that these retrospective studies can only show an association and not any causal link. We further explored the possibility that even if CS exposure is a risk factor for TB, several mechanisms may be responsible. Numerous studies associate cigarette and biomass smoke exposure with TB but the mechanism(s) remains largely unknown. While the associative link of these two health maladies is well established, more definitive, mechanistic studies are needed to cement the effect of smoke exposure on TB pathogenesis and to utilize this knowledge in empowering public health policies. PMID- 25808745 TI - Characteristics of women in a prison mental health assessment unit in England and Wales (2008-2010). AB - BACKGROUND: The high prevalence of mental disorders among women in prison is recognised worldwide. In England and Wales, successive governments and independent reports have argued that the equivalent of community care in prisons is acceptable but that some mental health assessment units (MHAUs), staffed by professional clinicians, should remain. These have not been researched. AIMS: This paper aimed to explore patterns of use of a MHAU in a women's prison in England and to test the hypothesis that it was being used only, as intended--to hold women pending transfer to a health service hospital or in a bona fide crisis. METHODS: Anonymised data on all women transferred to one MHAU between 1 January 2008 and 31 August 2010 were obtained from the prison files and subjected to descriptive analysis. RESULTS: Less than a third of these women were transferred to an outside hospital; this group stayed longest in the unit. An overlapping group of 52% of the women was under a special assessment, care in custody and teamwork protocol because of suicide or serious self-harm risk. Thus, 188 (68%) admissions fulfilled national protocol criteria for MHAU admissions. Two in five women admitted were released or returned to ordinary prison locations. Nevertheless, over 80% of the women were known to external mental health services, and 64 (30%) were so unwell on arrival in prison that they were transferred directly to the MHAU. Over a third of admissions were of women admitted more than once during the 32 months of study, and this was significantly more likely after release from prison directly to the community. CONCLUSIONS: Our hypothesis was not sustained, and it seems unlikely that this prison MHAU is unique in being used outside its strict remit. A shift from studying the epidemiology of mental disorder in prisons to the epidemiology of mental health needs could benefit this vulnerable group and the wider community alike. PMID- 25808746 TI - Hepatocyte nuclear factor 4alpha suppresses the aggravation of colon carcinoma. AB - Hepatocyte nuclear factor 4-alpha (HNF4alpha), a nuclear receptor, is expressed at lower levels in colon carcinoma tissues than in adjacent normal tissues. However, the relation between HNF4alpha and colon cancer progression and the underlying molecular mechanisms remain unclear. Here, we investigated the role of HNF4alpha in the progression of colon carcinoma. We showed that HNF4alpha mRNA and protein were downregulated in colon carcinoma specimens. HNF4alpha expression was related to pT classification (P < 0.001), lymph node metastasis (P = 0.002), distant metastasis (P < 0.001) and clinical stage (P < 0.001) in colon carcinoma patients. Patients with low or negative HNF4alpha expression had worse 3-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.005) than patients with high HNF4alpha expression. Low HNF4alpha expression was an independent prognostic factor for 3-year PFS (hazard ratio 2.94; 95% confidence interval 1.047-8.250; P = 0.041). Ectopic expression of HNF4alpha inhibited colon carcinoma cell (HT29, LoVo, and SW480) proliferation, migration, and invasion, induced G2/M phase arrest and promoted apoptosis. Ectopic expression of HNF4alpha upregulated E-cadherin and downregulated vimentin in vitro, and suppressed SW480 xenograft tumor growth and liver metastasis in vivo. Furthermore, HNF4alpha overexpression downregulated the expression of snail, slug and twist. HNF4alpha inhibited EMT through its effect on the Wnt/beta-catenin signaling pathway, and HNF4alpha downregulation may be mediated by promoter methylation in cancer tissues. Our results suggest that downregulation of HNF4alpha plays a critical role in the aggravation of colon carcinoma possibly by promoting EMT via the Wnt/beta-catenin signaling pathway and by affecting apoptosis and cell cycle progression. PMID- 25808747 TI - Vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in a Korean population. AB - BACKGROUND: Vitamin D receptor (VDR) has been suggested to play a role in the pathogenesis of type 1 diabetes mellitus (T1DM). There has been no case-control study examining the association between VDR polymorphisms and T1DM among Korean subjects with a low incidence of T1DM. METHODS: Eighty-one T1DM patients and 113 unrelated healthy controls with no history of DM or other autoimmune diseases were investigated at either Pusan National University Children's Hospital or Korea University Anam Hospital between March 2009 and September 2013. Polymerase chain reaction-restriction fragment length polymorphism was utilized to genotype single nucleotide substitutions at TaqI, BsmI, and ApaI alleles. RESULTS: All frequencies in T1DM and control subjects were in Hardy-Weinberg equilibrium, although ApaI in controls and TaqI in T1DM showed relatively weak equilibrium. TaqI and BsmI differences were significant (P = 0.045 and P = 0.012, respectively) after applying Bonferroni correction. The TT genotype carrier frequency among controls was higher than among the T1DM patients (P = 0.015; OR, 2.98; 95%CI: 1.19-7.42). T allele frequency was higher among controls than T1DM patients (P = 0.019; OR, 2.78; 95%CI: 1.15-6.72). The frequency of bb genotype carriers among controls was higher than among T1DM patients (P = 0.004; OR, 4.13; 95%CI: 1.4-12.10). The frequency of the b allele among controls was higher than that among T1DM patients (P = 0.016; OR, 3.20; 95%CI: 1.19-8.60). CONCLUSIONS: T and b TaqI and BsmI alleles are protective against T1DM in Korean subjects. PMID- 25808748 TI - How job demands affect absenteeism? The mediating role of work-family conflict and exhaustion. AB - PURPOSE: To investigate how psychosocial factors (such as job demands and work family conflict) produce absenteeism in the workplace, using the health impairment process of the job demands-resources model. According to this model, job demands lead to burnout (often measured with the emotional exhaustion component), which in turn could lead to outcomes (such as absenteeism). Work family conflict (WFC) was also studied, because of contradictory results collected in the existing literature on absenteeism in the workplace, regarding the role of WFC in causing absenteeism. METHODS: Data were collected on 245 workers using both subjective (questionnaire on psychological risk factors and work-related health) and objective data (sickness leave frequency records). To test the hypothesis that job demands and WFC contribute to absenteeism in the workplace, a subsequent mediation analysis was used, which analysed both (a) the subsequent mediation of WFC and emotional exhaustion and (b) the separate roles played by the mediators proposed (WFC and emotional exhaustion). RESULTS: Job demands affect absenteeism through the subsequent mediation of WFC and emotional exhaustion. In addition, emotional exhaustion mediates the relationship between job demands and absenteeism, while WFC does not. CONCLUSION: In conclusion, subsequent mediation highlights the role of emotional exhaustion in causing absenteeism; in fact, when emotional exhaustion is included in the analysis, job demands are associated with higher levels of absenteeism. The results of this study suggest that without the concurrent contribution of emotional exhaustion, WFC does not influence absenteeism in the workplace. Our findings are useful for organizations that aim to reduce absenteeism. PMID- 25808749 TI - Effects of electromagnetic fields exposure on plasma hormonal and inflammatory pathway biomarkers in male workers of a power plant. AB - PURPOSE: The potential health risks of electromagnetic fields (EMFs) have currently raised considerable public concerns. The aim of this study was to evaluate the effects of EMF exposure on levels of plasma hormonal and inflammatory pathway biomarkers in male workers of an electric power plant. METHODS: Seventy-seven male workers with high occupational EMF exposure and 77 male controls with low exposure, matched by age, were selected from a cross sectional study. Moreover, high EMF exposure group was with walkie-talkies usage and exposed to power frequency EMF at the work places for a longer duration than control group. A questionnaire was applied to obtain relevant information, including sociodemographic characteristics, lifestyle factors, and EMF exposures. Plasma levels of testosterone, estradiol, melatonin, NF-kappaB, heat-shock protein (HSP) 70, HSP27, and TET1 were determined by an enzyme-linked immunosorbent assay. RESULTS: EMF exposure group had statistically significantly lower levels of testosterone (beta = -0.3 nmol/L, P = 0.015), testosterone/estradiol (T/E2) ratio (beta = -15.6, P = 0.037), and NF-kappaB (beta = -20.8 ng/L, P = 0.045) than control group. Moreover, joint effects between occupational EMF exposure and employment duration, mobile phone fees, years of mobile phone usage, and electric fees on levels of testosterone and T/E2 ratio were observed. Nevertheless, no statistically significant associations of EMF exposures with plasma estradiol, melatonin, HSP70, HSP27, and TET1 were found. CONCLUSIONS: The findings showed that chronic exposure to EMF could decrease male plasma testosterone and T/E2 ratio, and it might possibly affect reproductive functions in males. No significant associations of EMF exposure with inflammatory pathway biomarkers were found. PMID- 25808752 TI - The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated endochondral ossification. AB - Indian hedgehog (Ihh) regulates endochondral ossification in both a parathyroid hormone-related protein (PTHrP)-dependent and -independent manner by activating transcriptional mediator Gli2. However, the molecular mechanisms underlying these processes remain elusive. Here by using in vivo microarray analysis, we identify forkhead box C1 (Foxc1) as a transcriptional partner of Gli2. Foxc1 stimulates expression of Ihh target genes, including PTHrP and Col10a1, through its physical and functional interaction with Gli2. Conversely, a dominant negative Foxc1 inhibits the Ihh target gene expression. In a spontaneous loss of Foxc1 function mouse (Foxc1(ch/ch)), endochondral ossification is delayed and the expression of Ihh target genes inhibited. Moreover, the pathological Foxc1 missense mutation observed in the Axenfeld-Rieger syndrome impairs Gli2-Foxc1 association as well as Ihh function. Our findings suggest that Foxc1 is an important transcriptional partner of Ihh-Gli2 signalling during endochondral ossification, and that disruption of the Foxc1-Gli2 interaction causes skeletal abnormalities observed in the Axenfeld-Rieger syndrome. PMID- 25808753 TI - Pre-diabetes and well-controlled diabetes are not associated with periodontal disease: the SHIP Trend Study. AB - AIM: To examine associations of pre-diabetes and well-controlled diabetes with periodontitis. MATERIALS AND METHODS: The Study of Health in Pomerania (SHIP) Trend is a cross-sectional survey in North-Eastern Germany including 3086 participants (49.4% men; age 20-82 years). Clinical attachment loss (CAL) and periodontal probing depth (PPD) were assessed applying a random half-mouth protocol. The number of teeth was determined. Pre-diabetes comprised impaired fasting glucose and impaired glucose tolerance. Previously known diabetes was defined as well controlled if glycated haemoglobin (HbA1c) was <7.0%. Participants were categorized as follows: normal glucose tolerance (NGT), pre diabetes, newly detected type 2 diabetes (T2DM), known T2DM with HbA1c<7.0% and known T2DM with HbA1c>=7.0%. RESULTS: Pre-diabetes was neither associated with mean CAL and PPD in multivariable adjusted linear regression models nor with edentulism (OR = 1.09 (95%-CI: 0.69-1.71)) and number of teeth (OR = 0.96 (95% CI: 0.75-1.22), lowest quartile versus higher quartiles) in logistic regression models. Associations with mean CAL and edentulism were stronger in poorly controlled previously known diabetes than in well-controlled previously known diabetes (for edentulism: OR = 2.19 (95%-CI: 1.18-4.05), and OR = 1.40 (95%-CI: 0.82-2.38), respectively, for comparison with NGT). CONCLUSIONS: Periodontitis and edentulism were associated with poorly controlled T2DM, but not with pre diabetes and well-controlled diabetes. PMID- 25808755 TI - Double-digest RAD sequencing using Ion Proton semiconductor platform (ddRADseq ion) with nonmodel organisms. AB - Research in evolutionary biology involving nonmodel organisms is rapidly shifting from using traditional molecular markers such as mtDNA and microsatellites to higher throughput SNP genotyping methodologies to address questions in population genetics, phylogenetics and genetic mapping. Restriction site associated DNA sequencing (RAD sequencing or RADseq) has become an established method for SNP genotyping on Illumina sequencing platforms. Here, we developed a protocol and adapters for double-digest RAD sequencing for Ion Torrent (Life Technologies; Ion Proton, Ion PGM) semiconductor sequencing. We sequenced thirteen genomic libraries of three different nonmodel vertebrate species on Ion Proton with PI chips: Arctic charr Salvelinus alpinus, European whitefish Coregonus lavaretus and common lizard Zootoca vivipara. This resulted in ~962 million single-end reads overall and a mean of ~74 million reads per library. We filtered the genomic data using Stacks, a bioinformatic tool to process RAD sequencing data. On average, we obtained ~11,000 polymorphic loci per library of 6-30 individuals. We validate our new method by technical and biological replication, by reconstructing phylogenetic relationships, and using a hybrid genetic cross to track genomic variants. Finally, we discuss the differences between using the different sequencing platforms in the context of RAD sequencing, assessing possible advantages and disadvantages. We show that our protocol can be used for Ion semiconductor sequencing platforms for the rapid and cost-effective generation of variable and reproducible genetic markers. PMID- 25808756 TI - Highly conductive and ultrastretchable electric circuits from covered yarns and silver nanowires. AB - Stretchable electronics, as a promising research frontier, has achieved progress in a variety of sophisticated applications. The realization of stretchable electronics frequently involves the demand for a stretchable conductor as an electrical circuit. However, it still remains a challenge to fabricate high performance (working strain exceeding 200%) stretchable conductors. Here, we present for the first time a facile, cost-effective, and scalable method for manufacturing ultrastretchable composite fibers with a "twining spring" configuration: cotton fibers twining spirally around a polyurethane fiber. The composite fiber possesses a high conductivity up to 4018 S/cm, which remains as high as 688 S/cm at 500% tensile strain. In addition, the conductivity of the composite fiber (initial conductivity of 4018 S/cm) remains perfectly stable after 1000 bending events and levels off at 183 S/cm after 1000 cyclic stretching events of 200% strain. Stretchable LED arrays are integrated efficiently utilizing the composite fibers as a stretchable electric wiring system, demonstrating the potential applications in large-area stretchable electronics. The biocompatibility of the composite fiber is verified, opening up its prospects in the field of implantable devices. Our fabrication strategy is also versatile for the preparation of other specially functionalized composite fibers with superb stretchability. PMID- 25808757 TI - Scyphomedusae of the Mediterranean: state of the art and future perspectives. AB - Scyphomedusae (Phylum Cnidaria, Class Scyphozoa) are perceived as a nuisance due to their sudden outbreaks that negatively affect human activities (particularly tourism and fisheries) mainly because of their stings. A brief review of the history of scyphozoan blooms in the Mediterranean and updated information available after 2010 point to an increase in scyphozoan outbreaks. Whilst the negative effects on public health, aquaculture, coastal industrial activities and fisheries operations are undeniable, the effects on the ecosystem are not well defined. We focus on the trophic interactions between scyphomedusae and fish, highlighting that the negative effects of scyphomedusae on fish stocks exerted through direct predation on early life stages of fish and competition for plankton are at present speculative. In favor of a positive effect of scyphomedusae on fish populations, the reports of predation upon scyphozoans are increasing, which suggests that predators may benefit from the availability of scyphozoans by shifting their diet toward jelly prey. Additionally, scyphomedusae may provide nursery habitats to early life stages of ecologically and economically important forage fishes and other organisms which shelter underneath their bells. Together with these ecosystem services, compounds extracted from scyphozoan tissues and venoms are having a variety of biomedical applications and are likely to contribute to treat a growing number of diseases, including cancer. Our analysis highlights that a re-evaluation of the balance between "positive" and "negative" effects of scyphomedusae on the ecosystem and human activities is needed and provides indications on potential directions for future studies. PMID- 25808754 TI - Spirituality attenuates the association between depression symptom severity and meaning in life. AB - OBJECTIVES: This cross-sectional study examined whether spirituality moderates the association between depression symptom severity and meaning in life among treatment-seeking adults. METHOD: Participants were 55 adults (>=60 years of age) newly seeking outpatient mental health treatment for mood, anxiety, or adjustment disorders. Self-report questionnaires measured depression symptom severity (Patient Health Questionnaire-9), spirituality (Spirituality Transcendence Index), and meaning in life (Geriatric Suicide Ideation Scale-Meaning in Life subscale). RESULTS: Results indicated a significant interaction between spirituality and depression symptom severity on meaning in life scores (beta = .26, p = .02). A significant negative association between depression symptom severity and meaning in life was observed at lower but not the highest levels of spirituality. CONCLUSION: In the presence of elevated depressive symptomatology, those participants who reported high levels of spirituality reported comparable levels of meaning in life to those without elevated depressive symptomatology. Assessment of older adult patients' spirituality can reveal ways that spiritual beliefs and practices can be can be incorporated into therapy to enhance meaning in life. PMID- 25808758 TI - Assembly of Fluorinated Quaternary Stereogenic Centers through Catalytic Enantioselective Detrifluoroacetylative Aldol Reactions. AB - A Cu-catalyzed asymmetric detrifluoroacetylative aldol addition reaction of 2 fluoro-1,3-diketones/hydrates to aldehydes in the presence of base and chiral bidentate ligand was developed. The reaction was carried out under convenient conditions and tolerated a wide range of substrates, resulting in fluorinated quaternary stereogenic alpha-fluoro-beta-hydroxy ketone products with good chemical yields, diastereo- and enantioselectivities. This catalytic asymmetric detrifluoroacetylative aldol addition reaction provides a new approach for the preparation of biologically relevant products containing C-F quaternary stereogenic centers. PMID- 25808751 TI - Oscillations, Timing, Plasticity, and Learning in the Cerebellum. AB - The highly stereotyped, crystal-like architecture of the cerebellum has long served as a basis for hypotheses with regard to the function(s) that it subserves. Historically, most clinical observations and experimental work have focused on the involvement of the cerebellum in motor control, with particular emphasis on coordination and learning. Two main models have been suggested to account for cerebellar functioning. According to Llinas's theory, the cerebellum acts as a control machine that uses the rhythmic activity of the inferior olive to synchronize Purkinje cell populations for fine-tuning of coordination. In contrast, the Ito-Marr-Albus theory views the cerebellum as a motor learning machine that heuristically refines synaptic weights of the Purkinje cell based on error signals coming from the inferior olive. Here, we review the role of timing of neuronal events, oscillatory behavior, and synaptic and non-synaptic influences in functional plasticity that can be recorded in awake animals in various physiological and pathological models in a perspective that also includes non-motor aspects of cerebellar function. We discuss organizational levels from genes through intracellular signaling, synaptic network to system and behavior, as well as processes from signal production and processing to memory, delegation, and actual learning. We suggest an integrative concept for control and learning based on articulated oscillation templates. PMID- 25808759 TI - The Androgenic Alopecia Protective Effects of Forsythiaside-A and the Molecular Regulation in a Mouse Model. AB - This study examined the inhibitory effect of forsythiaside-A, a natural substance derived from Forsythia suspensa (F. suspensa), on entry into catagen induced by dihydrotestosterone (DHT) in an androgenic alopecia mouse model. In vitro experiment comparing finasteride with forsythiaside-A showed that forsythiaside-A treatment resulted in a 30% greater inhibition of DHT-induced apoptosis in human hair dermal papilla cell (HHDPCs) and human keratinocytes (HaCaTs). In vivo experiment showed that mouse hair density and thickness were increased by 50% and 30%, respectively, in the forsythiaside-A-treated group when compared to a DHT group. Tissue histological results revealed that the forsythiaside-A-treated group had an increase in size and shape of the hair follicles and a 1.5 times increase in the follicle anagen/telogen ratio when compared to the finasteride group. Western blot examination of TGF-beta2 expression related to apoptosis signaling in mouse skin verified that forsythiaside-A reduced the expression of TGF-beta2 by 75% and suppressed apoptosis by reducing the expression of caspase-9 by 40%, and caspase-3 by 53%, which play an roles up-regulator in the apoptosis signal. The forsythiaside-A group also showed a 60% increase in the Bcl-2/Bax ratio, which is a factor related to mitochondrial apoptosis. Our results indicated that forsythiaside-A prevents apoptosis by similar mechanism with finasteride, but forsythiaside-A is more effective than finasteride. In summary, forsythiaside-A controlled the apoptosis of hair cells and retarded the entry into the catagen phase and therefore represents a natural product with much potential for use as a treatment for androgenic alopecia. PMID- 25808760 TI - Application of the Transtheoretical Model to Cervical Cancer Screening in Latina Women. AB - This study examined the relationship between the intention to receive Pap tests for cervical cancer screening, as related to the transtheoretical model of behavior change, and self-efficacy, and perceived barriers and benefits among Latina women. A sample of 121 Latina women recruited from a University campus completed validated questionnaires. Over half the participants (62 %) reported engaging in regular cervical screening. The greatest self-efficacy scores were observed among women in the action/maintenance phase, and the least self-efficacy was observed among women in the no-intention phases of behavior change. There was also a gradient in perceived barriers and the stages of change, women in precontemplative/relapse perceived significantly higher barriers than those in contemplation/preparation and action/maintenance. This study identifies a high risk group of Latina women and demonstrates a need for culturally targeted Pap screening interventions using validated and theoretically driven behavior change interventions focusing on perceived barriers and benefits, and self-efficacy. PMID- 25808761 TI - Determinants of Subjective Social Status and Health Among Latin American Women Immigrants in Spain: A Qualitative Approach. AB - This qualitative study was carried out to better understand factors that determine the subjective social status of Latin Americans in Spain. The study was conducted following a theoretical framework and forms part of broader study on subjective social status and health. Ten immigrant participants engaged in semi structured interviews, from which data were collected. The study results show that socioeconomic aspects of the crisis and of policies adopted have shaped immigrant living conditions in Spain. Four major themes that emerged from the analysis were related to non-recognition of educational credentials, precarious working conditions, unemployment and loneliness. These results illustrate the outcomes of current policies on health and suggest a need for health professionals to orient practices toward social determinants, thus utilizing evaluations of subjective social status to reduce inequalities in health. PMID- 25808762 TI - Ultra-sensitive nanofiber fluorescence detection in a microfluidic chip. AB - We report an ultra-sensitive and robust fluorescence sensor made by using a biconical taper with a waist diameter of 720 nm for both excitation and fluorescence collection. To enhance the stability of the fluorescence sensor, the biconical taper has been embedded in a 125 um wide microchannel with a detection length of 2.5 cm. Investigated by measuring the fluorescence intensity of rhodamine 6G (R6G), the sensor shows a detection limit down to 100 pM, with excellent reversibility in a concentration range of 0-10 nM. The sensor has also been applied to quantum dot (QD)-labeled streptavidin measurements, yielding a detection sensitivity down to 10 pM for QDs. In addition, the small sample volume (ca. 500 nL), high sampling throughput, and seamless connection between the biconical taper and standard optical fibers offer a number of attractive advantages for chemical and biosensing applications. PMID- 25808763 TI - MEMS sensor technologies for human centred applications in healthcare, physical activities, safety and environmental sensing: a review on research activities in Italy. AB - Over the past few decades the increased level of public awareness concerning healthcare, physical activities, safety and environmental sensing has created an emerging need for smart sensor technologies and monitoring devices able to sense, classify, and provide feedbacks to users' health status and physical activities, as well as to evaluate environmental and safety conditions in a pervasive, accurate and reliable fashion. Monitoring and precisely quantifying users' physical activity with inertial measurement unit-based devices, for instance, has also proven to be important in health management of patients affected by chronic diseases, e.g., Parkinson's disease, many of which are becoming highly prevalent in Italy and in the Western world. This review paper will focus on MEMS sensor technologies developed in Italy in the last three years describing research achievements for healthcare and physical activity, safety and environmental sensing, in addition to smart systems integration. Innovative and smart integrated solutions for sensing devices, pursued and implemented in Italian research centres, will be highlighted, together with specific applications of such technologies. Finally, the paper will depict the future perspective of sensor technologies and corresponding exploitation opportunities, again with a specific focus on Italy. PMID- 25808764 TI - New calibration method using low cost MEM IMUs to verify the performance of UAV borne MMS payloads. AB - Spatial information plays a critical role in remote sensing and mapping applications such as environment surveying and disaster monitoring. An Unmanned Aerial Vehicle (UAV)-borne mobile mapping system (MMS) can accomplish rapid spatial information acquisition under limited sky conditions with better mobility and flexibility than other means. This study proposes a long endurance Direct Geo referencing (DG)-based fixed-wing UAV photogrammetric platform and two DG modules that each use different commercial Micro-Electro Mechanical Systems' (MEMS) tactical grade Inertial Measurement Units (IMUs). Furthermore, this study develops a novel kinematic calibration method which includes lever arms, boresight angles and camera shutter delay to improve positioning accuracy. The new calibration method is then compared with the traditional calibration approach. The results show that the accuracy of the DG can be significantly improved by flying at a lower altitude using the new higher specification hardware. The new proposed method improves the accuracy of DG by about 20%. The preliminary results show that two-dimensional (2D) horizontal DG positioning accuracy is around 5.8 m at a flight height of 300 m using the newly designed tactical grade integrated Positioning and Orientation System (POS). The positioning accuracy in three-dimensions (3D) is less than 8 m. PMID- 25808765 TI - Tracking systems for virtual rehabilitation: objective performance vs. subjective experience. A practical scenario. AB - Motion tracking systems are commonly used in virtual reality-based interventions to detect movements in the real world and transfer them to the virtual environment. There are different tracking solutions based on different physical principles, which mainly define their performance parameters. However, special requirements have to be considered for rehabilitation purposes. This paper studies and compares the accuracy and jitter of three tracking solutions (optical, electromagnetic, and skeleton tracking) in a practical scenario and analyzes the subjective perceptions of 19 healthy subjects, 22 stroke survivors, and 14 physical therapists. The optical tracking system provided the best accuracy (1.074 +/- 0.417 cm) while the electromagnetic device provided the most inaccurate results (11.027 +/- 2.364 cm). However, this tracking solution provided the best jitter values (0.324 +/- 0.093 cm), in contrast to the skeleton tracking, which had the worst results (1.522 +/- 0.858 cm). Healthy individuals and professionals preferred the skeleton tracking solution rather than the optical and electromagnetic solution (in that order). Individuals with stroke chose the optical solution over the other options. Our results show that subjective perceptions and preferences are far from being constant among different populations, thus suggesting that these considerations, together with the performance parameters, should be also taken into account when designing a rehabilitation system. PMID- 25808767 TI - Wavelength-adaptive dehazing using histogram merging-based classification for UAV images. AB - Since incoming light to an unmanned aerial vehicle (UAV) platform can be scattered by haze and dust in the atmosphere, the acquired image loses the original color and brightness of the subject. Enhancement of hazy images is an important task in improving the visibility of various UAV images. This paper presents a spatially-adaptive dehazing algorithm that merges color histograms with consideration of the wavelength-dependent atmospheric turbidity. Based on the wavelength-adaptive hazy image acquisition model, the proposed dehazing algorithm consists of three steps: (i) image segmentation based on geometric classes; (ii) generation of the context-adaptive transmission map; and (iii) intensity transformation for enhancing a hazy UAV image. The major contribution of the research is a novel hazy UAV image degradation model by considering the wavelength of light sources. In addition, the proposed transmission map provides a theoretical basis to differentiate visually important regions from others based on the turbidity and merged classification results. PMID- 25808766 TI - Sensing in the collaborative Internet of Things. AB - We are entering a new era of computing technology, the era of Internet of Things (IoT). An important element for this popularization is the large use of off-the shelf sensors. Most of those sensors will be deployed by different owners, generally common users, creating what we call the Collaborative IoT. This collaborative IoT helps to increase considerably the amount and availability of collected data for different purposes, creating new interesting opportunities, but also several challenges. For example, it is very challenging to search for and select a desired sensor or a group of sensors when there is no description about the provided sensed data or when it is imprecise. Given that, in this work we characterize the properties of the sensed data in the Internet of Things, mainly the sensed data contributed by several sources, including sensors from common users. We conclude that, in order to safely use data available in the IoT, we need a filtering process to increase the data reliability. In this direction, we propose a new simple and powerful approach that helps to select reliable sensors. We tested our method for different types of sensed data, and the results reveal the effectiveness in the correct selection of sensor data. PMID- 25808768 TI - Water area extraction using RADARSAT SAR imagery combined with Landsat imagery and terrain information. AB - This paper exploits an effective water extraction method using SAR imagery in preparation for flood mapping in unpredictable flood situations. The proposed method is based on the thresholding method using SAR amplitude, terrain information, and object-based classification techniques for noise removal. Since the water areas in SAR images have the lowest amplitude value, the thresholding method using SAR amplitude could effectively extract water bodies. However, the reflective properties of water areas in SAR imagery cannot distinguish the occluded areas caused by steep relief and they can be eliminated with terrain information. In spite of the thresholding method using SAR amplitude and terrain information, noises which interfered with users' interpretation of water maps still remained and the object-based classification using an object size criterion was applied for the noise removal and the criterion was determined by a histogram based technique. When only using SAR amplitude information, the overall accuracy was 83.67%. However, using SAR amplitude, terrain information and the noise removal technique, the overall classification accuracy over the study area turned out to be 96.42%. In particular, user accuracy was improved by 46.00%. PMID- 25808769 TI - Beamforming and power control in sensor arrays using reinforcement learning. AB - The use of beamforming and power control, combined or separately, has advantages and disadvantages, depending on the application. The combined use of beamforming and power control has been shown to be highly effective in applications involving the suppression of interference signals from different sources. However, it is necessary to identify efficient methodologies for the combined operation of these two techniques. The most appropriate technique may be obtained by means of the implementation of an intelligent agent capable of making the best selection between beamforming and power control. The present paper proposes an algorithm using reinforcement learning (RL) to determine the optimal combination of beamforming and power control in sensor arrays. The RL algorithm used was Q learning, employing an epsilon-greedy policy, and training was performed using the offline method. The simulations showed that RL was effective for implementation of a switching policy involving the different techniques, taking advantage of the positive characteristics of each technique in terms of signal reception. PMID- 25808770 TI - Development of a capacitive ice sensor to measure ice growth in real time. AB - This paper presents the development of the capacitive sensor to measure the growth of ice on a fuel pipe surface in real time. The ice sensor consists of pairs of electrodes to detect the change in capacitance and a thermocouple temperature sensor to examine the ice formation situation. In addition, an environmental chamber was specially designed to control the humidity and temperature to simulate the ice formation conditions. From the humidity, a water film is formed on the ice sensor, which results in an increase in capacitance. Ice nucleation occurs, followed by the rapid formation of frost ice that decreases the capacitance suddenly. The capacitance is saturated. The developed ice sensor explains the ice growth providing information about the icing temperature in real time. PMID- 25808771 TI - Soil water content assessment: critical issues concerning the operational application of the triangle method. AB - Knowledge of soil water content plays a key role in water management efforts to improve irrigation efficiency. Among the indirect estimation methods of soil water content via Earth Observation data is the triangle method, used to analyze optical and thermal features because these are primarily controlled by water content within the near-surface evaporation layer and root zone in bare and vegetated soils. Although the soil-vegetation-atmosphere transfer theory describes the ongoing processes, theoretical models reveal limits for operational use. When applying simplified empirical formulations, meteorological forcing could be replaced with alternative variables when the above-canopy temperature is unknown, to mitigate the effects of calibration inaccuracies or to account for the temporal admittance of the soil. However, if applied over a limited area, a characterization of both dry and wet edges could not be properly achieved; thus, a multi-temporal analysis can be exploited to include outer extremes in soil water content. A diachronic empirical approach introduces the need to assume a constancy of other meteorological forcing variables that control thermal features. Airborne images were acquired on a Sicilian vineyard during most of an entire irrigation period (fruit-set to ripening stages, vintage 2008), during which in situ soil water content was measured to set up the triangle method. Within this framework, we tested the triangle method by employing alternative thermal forcing. The results were inaccurate when air temperature at airborne acquisition was employed. Sonic and aerodynamic air temperatures confirmed and partially explained the limits of simultaneous meteorological forcing, and the use of proxy variables improved model accuracy. The analysis indicates that high spatial resolution does not necessarily imply higher accuracies. PMID- 25808772 TI - Multi-layer sparse representation for weighted LBP-patches based facial expression recognition. AB - In this paper, a novel facial expression recognition method based on sparse representation is proposed. Most contemporary facial expression recognition systems suffer from limited ability to handle image nuisances such as low resolution and noise. Especially for low intensity expression, most of the existing training methods have quite low recognition rates. Motivated by sparse representation, the problem can be solved by finding sparse coefficients of the test image by the whole training set. Deriving an effective facial representation from original face images is a vital step for successful facial expression recognition. We evaluate facial representation based on weighted local binary patterns, and Fisher separation criterion is used to calculate the weighs of patches. A multi-layer sparse representation framework is proposed for multi intensity facial expression recognition, especially for low-intensity expressions and noisy expressions in reality, which is a critical problem but seldom addressed in the existing works. To this end, several experiments based on low resolution and multi-intensity expressions are carried out. Promising results on publicly available databases demonstrate the potential of the proposed approach. PMID- 25808773 TI - Location detection and tracking of moving targets by a 2D IR-UWB radar system. AB - In indoor environments, the Global Positioning System (GPS) and long-range tracking radar systems are not optimal, because of signal propagation limitations in the indoor environment. In recent years, the use of ultra-wide band (UWB) technology has become a possible solution for object detection, localization and tracking in indoor environments, because of its high range resolution, compact size and low cost. This paper presents improved target detection and tracking techniques for moving objects with impulse-radio UWB (IR-UWB) radar in a short range indoor area. This is achieved through signal-processing steps, such as clutter reduction, target detection, target localization and tracking. In this paper, we introduce a new combination consisting of our proposed signal processing procedures. In the clutter-reduction step, a filtering method that uses a Kalman filter (KF) is proposed. Then, in the target detection step, a modification of the conventional CLEAN algorithm which is used to estimate the impulse response from observation region is applied for the advanced elimination of false alarms. Then, the output is fed into the target localization and tracking step, in which the target location and trajectory are determined and tracked by using unscented KF in two-dimensional coordinates. In each step, the proposed methods are compared to conventional methods to demonstrate the differences in performance. The experiments are carried out using actual IR-UWB radar under different scenarios. The results verify that the proposed methods can improve the probability and efficiency of target detection and tracking. PMID- 25808774 TI - Human detection based on the generation of a background image by using a far infrared light camera. AB - The need for computer vision-based human detection has increased in fields, such as security, intelligent surveillance and monitoring systems. However, performance enhancement of human detection based on visible light cameras is limited, because of factors, such as nonuniform illumination, shadows and low external light in the evening and night. Consequently, human detection based on thermal (far-infrared light) cameras has been considered as an alternative. However, its performance is influenced by the factors, such as low image resolution, low contrast and the large noises of thermal images. It is also affected by the high temperature of backgrounds during the day. To solve these problems, we propose a new method for detecting human areas in thermal camera images. Compared to previous works, the proposed research is novel in the following four aspects. One background image is generated by median and average filtering. Additional filtering procedures based on maximum gray level, size filtering and region erasing are applied to remove the human areas from the background image. Secondly, candidate human regions in the input image are located by combining the pixel and edge difference images between the input and background images. The thresholds for the difference images are adaptively determined based on the brightness of the generated background image. Noise components are removed by component labeling, a morphological operation and size filtering. Third, detected areas that may have more than two human regions are merged or separated based on the information in the horizontal and vertical histograms of the detected area. This procedure is adaptively operated based on the brightness of the generated background image. Fourth, a further procedure for the separation and removal of the candidate human regions is performed based on the size and ratio of the height to width information of the candidate regions considering the camera viewing direction and perspective projection. Experimental results with two types of databases confirm that the proposed method outperforms other methods. PMID- 25808775 TI - Development of a microfluidic-based optical sensing device for label-free detection of circulating tumor cells (CTCs) through their lactic acid metabolism. AB - This study reports a microfluidic-based optical sensing device for label-free detection of circulating tumor cells (CTCs), a rare cell species in blood circulation. Based on the metabolic features of cancer cells, live CTCs can be quantified indirectly through their lactic acid production. Compared with the conventional schemes for CTC detection, this label-free approach could prevent the biological bias due to the heterogeneity of the surface antigens on cancer cells. In this study, a microfluidic device was proposed to generate uniform water-in-oil cell-encapsulating micro-droplets, followed by the fluorescence based optical detection of lactic acid produced within the micro-droplets. To test its feasibility to quantify cancer cells, experiments were carried out. Results showed that the detection signals were proportional to the number of cancer cells within the micro-droplets, whereas such signals were insensitive to the existence and number of leukocytes within. To further demonstrate its feasibility for cancer cell detection, the cancer cells with known cell number in a cell suspension was detected based on the method. Results revealed that there was no significant difference between the detected number and the real number of cancer cells. As a whole, the proposed method opens up a new route to detect live CTCs in a label-free manner. PMID- 25808776 TI - Broadband and high sensitive time-of-flight diffraction ultrasonic transducers based on PMNT/epoxy 1-3 piezoelectric composite. AB - 5-6 MHz PMNT/epoxy 1-3 composites were prepared by a modified dice-and-fill method. They exhibit excellent properties for ultrasonic transducer applications, such as ultrahigh thickness electromechanical coupling coefficient k(t) (85.7%), large piezoelectric coefficient d33 (1209 pC/N), and relatively low acoustic impedance Z (1.82 * 107 kg/(m2.s)). Besides, two types of Time-of-Flight Diffraction (TOFD) ultrasonic transducers have been designed, fabricated, and characterized, which have different matching layer schemes with the acoustic impedance of 4.8 and 5.7 * 106 kg/(m2.s), respectively. In the detection on a backwall of 12.7 mm polystyrene, the former exhibits higher detectivity, the relative pulse-echo sensitivity and -6 dB relative bandwidth are -21.93 dB and 102.7%, respectively, while the later exhibits broader bandwidth, the relative pulse-echo sensitivity and -6 dB relative bandwidth are -24.08 dB and 117.3%, respectively. These TOFD ultrasonic transducers based on PMNT/epoxy 1-3 composite exhibit considerably improved performance over the commercial PZT/epoxy 1-3 composite TOFD ultrasonic transducer. PMID- 25808777 TI - Successful ABO-incompatible living-related intestinal transplantation: a 2-year follow-up. AB - ABO-incompatible intestinal transplantation has rarely been performed due to poor patient outcomes. Herein we present a case of successful ABO-incompatible intestinal transplantation with a 2-year follow-up. A 16-year-old female with a history of extensive bowel resection received an ABO-incompatible living donor bowel graft from her father (blood type AB graft into a type A recipient). Posttransplant immunosuppression consisted of an initial anti-CD20, plasmapheresis/intravenous immunoglobulin before transplantation, followed by an anti-thymocyte globulin (ATG) induction and splenectomy, and maintenance with tacrolimus and prednisone. Her postoperative course was remarkable for a single episode of rejection on day 14 which responded promptly to treatment with methyprednisolone and ATG. Three months after transplantation, the patient developed an abdominal abscess requiring open surgical drainage. No viral infections were encountered. Posttransplant anti-B antibody titers and anti-B7 donor-specific antibody levels remained low. At a 2-year follow-up, the patient showed a progressive weight gain of 5.0 kg. This case illustrates that ABO incompatible living-related bowel transplantation is immunologically feasible and is associated with good outcomes for the recipient. The management of blood type antibodies and the use of adequate immunosuppression in the early period of the procedure may be the keys to the success of future cases. PMID- 25808778 TI - A portable and integrated instrument for cell manipulation by dielectrophoresis. AB - The physical manipulation of biological cells is a key point in the development of miniaturized systems for point-of-care analyses. Dielectrophoresis (DEP) has been reported by several laboratories as a promising method in biomedical research for label-free cell manipulation without physical contact, by exploiting the dielectric properties of cells suspended in a microfluidic sample, under the action of high-gradient electric fields. In view of a more extended use of DEP phenomena in lab-on-chip devices for point-of-care settings, we have developed a portable instrument, integrating on the same device the microfluidic biochip for cell manipulation and all the laboratory functions (i.e., DEP electric signal generation, microscopic observation of the biological sample under test and image acquisition) that are normally obtained by combining different nonportable standard laboratory instruments. The nonuniform electric field for cell manipulation on the biochip is generated by microelectrodes, patterned on the silicon substrate of microfluidic channels, using standard microfabrication techniques. Numerical modeling was performed to simulate the electric field distribution, quantify the DEP force, and optimize the geometry of the microelectrodes. The developed instrument includes an electronic board, which allows the control of the electric signal applied to electrodes necessary for DEP, and a miniaturized optical microscope system that allows visual inspection and eventually cell counting, as well as image and video recording. The system also includes the control software. The portable and integrated platform described in this work therefore represents a complete and innovative solution of applied research, suitable for many biological applications. PMID- 25808779 TI - Analysis of the tomato leaf transcriptome during successive hemibiotrophic stages of a compatible interaction with the oomycete pathogen Phytophthora infestans. AB - The infection of plants by hemibiotrophic pathogens involves a complex and highly regulated transition from an initial biotrophic, asymptomatic stage to a later necrotrophic state, characterized by cell death. Little is known about how this transition is regulated, and there are conflicting views regarding the significance of the plant hormones jasmonic acid (JA) and salicylic acid (SA) in the different phases of infection. To provide a broad view of the hemibiotrophic infection process from the plant perspective, we surveyed the transcriptome of tomato (Solanum lycopersicum) during a compatible interaction with the hemibiotrophic oomycete Phytophthora infestans during three infection stages: biotrophic, the transition from biotrophy to necrotrophy, and the necrotrophic phase. Nearly 10 000 genes corresponding to proteins in approximately 400 biochemical pathways showed differential transcript abundance during the three infection stages, revealing a major reorganization of plant metabolism, including major changes in source-sink relations, as well as secondary metabolites. In addition, more than 100 putative resistance genes and pattern recognition receptor genes were induced, and both JA and SA levels and associated signalling pathways showed dynamic changes during the infection time course. The biotrophic phase was characterized by the induction of many defence systems, which were either insufficient, evaded or suppressed by the pathogen. PMID- 25808780 TI - Pes planus and paediatric obesity: a systematic review of the literature. AB - Children with obesity report musculoskeletal pain more than normal-weight children; this may be linked with literature suggesting children with obesity have higher prevalence of pes planus (flatfoot). To further elucidate whether this relation occurs, we conducted a systematic literature review on the co occurrence of pes planus and paediatric obesity. Empirical articles published until September 2013 were obtained through an electronic search of MEDLINE and SPORTDiscus; included articles examined the association between body weight and pes planus in children. Thirteen cross-sectional studies of varied designs were identified. Methods used to diagnose pes planus varied between studies: imaging modalities, anthropometric measurements and clinical examination. Across all studies, pes planus prevalence among children with obesity ranged widely from 14 to 67%. Nearly all studies indicated increasing pes planus in children with increasing weight. No studies evaluated pain/complications related to pes planus. Our review suggests increased prevalence of pes planus among children with obesity or increasing weight status. Because of differing methodologies, lack of consensus regarding the pes planus definition, the dearth of investigation into pain/complications and the few existing studies, more research is needed to determine a relation between children's body weight, pes planus and associated effects on pain and function. PMID- 25808781 TI - Cognitive, psychophysical, and neural correlates of vulvar pain in primary and secondary provoked vestibulodynia: a pilot study. AB - INTRODUCTION: Provoked vestibulodynia (PVD) is a common condition characterized by localized, provoked pain that can be present since first vaginal penetration attempt (primary) or can develop after a period of pain-free penetration (secondary). Research has demonstrated psychosocial and psychophysical differences between women with these subtypes of PVD, but the question of whether neural responses to pain also differ remains to be investigated. AIM: This study aims to examine whether cognitive, psychophysical, and neural responses to vulvar pressure pain differ between women with PVD1 and PVD2. METHODS: Women with PVD1 and PVD2 were compared for group differences using multiple modalities, including questionnaires, psychophysical testing, and neuroimaging. Pain ratings were held constant across groups, rather than amount of pressure applied. MAIN OUTCOME MEASURES: Demographics, sexual functioning, four questionnaires examining anxiety and catastrophizing, quantitative sensory testing at the vulvar vestibule using a vulvalgesiometer, and functional and structural magnetic resonance imaging (MRI). RESULTS: Findings suggest that women with PVD1 are more anxious and that they catastrophize more about their vulvar and nonvulvar pain than women with PVD2. Overall, MRI results demonstrated structural and functional similarities to other chronic pain findings for both groups of women. Gray matter (GM) density also differed between groups: women with PVD1 showed significant decreases in GM throughout areas associated with pain processing. Functionally, between-groups differences were found during painful vulvar stimulation despite lower pressures applied to the vulva for women with PVD1 because of their heightened sensitivity; the determination of the level of vulvar pressure to elicit pain was based on subjective ratings. CONCLUSIONS: Findings are limited by sample size and liberal alpha values; however, future research is certainly warranted based on the preliminary findings of this study suggesting both similarities and differences between PVD1 and PVD2. Overall, women with PVD1 seem to fare worse on several pain-related and psychosocial variables compared with women with PVD2. PMID- 25808782 TI - Liver transplantation for hepatocellular carcinoma comparing the Milan, UCSF, and Asan criteria: long-term follow-up of a Western single institutional experience. AB - BACKGROUND: In patients with hepatocellular carcinoma (HCC), the outcome after liver transplantation (LT) is excellent if tumor characteristics are within the Milan criteria (MC). Expanded Asan criteria (AC) have not yet been validated in Western countries. METHODS: A total of 76 patients with HCC underwent LT. Patients were divided and compared according to Milan, UCSF, and Asan criteria. Differences between pre- and post-operative assessment were evaluated. Overall survival (OS) and disease-free survival (DFS) were compared between groups. Predictors of recurrence were investigated. RESULTS: Asan criteria provided 26% and 15% more criteria-fitting patients than MC and UCSF pre-operatively while 49% and 35% at pathological evaluation. Discrepancy between pre- and post-operative evaluation was 32% for MC, 33% for UCSF, and 18% for AC (p = 0.06). After a median follow-up of 70.5 months, patients exceeding MC but fulfilling Asan had comparable 5-yr OS and DFS to patients fulfilling MC (p = 0.17; p = 0.29). Patients exceeding UCSF but fulfilling AC had comparable 5-yr OS and DFS to patients fulfilling UCSF (p = 0.26; p = 0.32). Number of nodules, macro-vascular invasion, capsular invasion, and exceeding AC predicted recurrence at multivariate analysis (p = 0.01, 0.03, 0.01, 0.02, respectively). CONCLUSIONS: The extension to AC allows increasing the number of patients eligible for LT without affecting OS and DFS. PMID- 25808783 TI - Examination of smoking inflexibility as a mechanism linking anxiety sensitivity and severity of smoking behavior. AB - BACKGROUND AND OBJECTIVES: Anxiety sensitivity is associated with smoking processes and poorer clinical outcomes. Yet, the specific mechanisms underlying this association are unclear. Smoking-specific avoidance and inflexibility (AIS) is a construct implicated in multiple manifestations of mood regulation that may underlie smoking severity. The current study examined whether AIS accounted for (ie, statistically mediated) the relationship between anxiety sensitivity and multiple indices of smoking severity. METHODS: Baseline self-report data were collected among treatment-seeking smokers (N = 396; 48% female; Mage = 37.8 years) taking part in a larger intervention study. Gender, smoking-related medical history, Axis I diagnoses, hazardous alcohol use, substance abuse/dependence, and negative affectivity were statistically controlled in analyses. RESULTS: Anxiety sensitivity was indirectly related to all smoking severity variables, with the exception of nicotine dependence, through its relation with AIS. DISCUSSION AND CONCLUSIONS: These findings provide initial evidence suggesting AIS may be an important construct in better understanding anxiety sensitivity-smoking relations. SCIENTIFIC SIGNIFICANCE: Results suggest the importance of AIS as a malleable target for smoking cessation intervention. PMID- 25808784 TI - Novel mutations in GJB6 and GJB2 in Clouston syndrome. AB - Clouston syndrome (CS; also termed hidrotic ectodermal dysplasia) is a rare autosomal dominant genetic skin disorder, characterized by alopecia, nail dystrophy, and palmoplantar hyperkeratosis. Mutations in the GJB6 gene, which encodes the gap junction protein connexin 30, have been shown to cause this disorder. To date, four mutations of GJB6 have been found in patients with CS: G11R, V37E, D50N and A88V. Mutations in GJA1 (V41L) and GJB2 (R127H) are also related to CS. We found a novel missense mutation, N14S, in GJB6 and the previously identified F191L mutation in GJB2 (Cx26) in a proband with CS in a Han Chinese pedigree; these mutations were not found in 200 ethnically matched nonconsanguineous Han Chinese controls. PMID- 25808785 TI - Biogenesis of Pseudomonas aeruginosa type IV pili and regulation of their function. AB - Type IV pili (T4P) are bacterial virulence factors involved in a wide variety of functions including deoxyribonucleic acid uptake, surface attachment, biofilm formation and twitching motility. While T4P are common surface appendages, the systems that assemble them and the regulation of their function differ between species. Pseudomonas aeruginosa, Neisseria spp. and Myxococcus xanthus are common model systems used to study T4P biology. This review focuses on recent advances in P. aeruginosa T4P structural biology, and the regulatory pathways controlling T4P biogenesis and function. PMID- 25808786 TI - Dermoscopy of prurigo nodularis. AB - The diagnosis of prurigo nodularis is mainly clinical, based on its distinctive features. However, in some cases it may be difficult to differentiate it from other nodular dermatoses only on the clinical basis, thus requiring histopathological examination to reach a definitive diagnosis. The aim of this study was to describe for the first time the dermoscopic features of prurigo nodularis and the useful contribution of dermoscopy in the differential diagnosis of such dermatoses. Fourteen patients with histopathologically proven prurigo nodularis were included in the study. The results of our study suggest that the detection of a "white starburst pattern" surrounding brown-reddish/brown yellowish crust(s), erosion(s) and/or hyperkeratosis/scales is a useful clue to support the clinical diagnosis of prurigo nodularis, distinguishing it from the other main differential diagnoses. PMID- 25808787 TI - Biomedical applications of gold nanomaterials: opportunities and challenges. AB - In the past few years, there has been an unprecedented development of gold nanomaterials (AuNMs) for potential clinical applications. Owing to their advantageous physical, chemical, and biological properties, AuNMs have attracted great attention in the nanomedicine arena for applications in biological sensing, biomedical imaging, drug delivery, and photothermal therapy. Their tunable size, shape, and surface characteristics coupled with excellent biocompatibility render them ideal candidates for translation from bench-top to bedside. This review summarizes the recent research on the applications of AuNM with a focus on biomedical diagnostics and therapeutics. The bio-interaction of these NM with cells and their in vivo responses are presented. After reviewing these potential applications, future challenges and prospects are discussed and the suitability of how AuNMs are used as effective tools in clinical medicine is assessed. PMID- 25808788 TI - Dendritic cells enhance UHMWPE wear particle-induced osteoclast differentiation of macrophages. AB - Ultra-high molecular weight polyethylene (UHMWPE) has been widely used in large joint replacement. Osteolysis induced by the UHMWPE wear particles is one of the main causes of replacement failure. This study aims to elucidate whether dendritic cells play a role in UHMWPE particle-induced osteolysis. An in vitro Raw 264.7 and DC 2.4 coculture system was employed to examine the effects of dendritic cells on the inflammatory and osteoclastogenic responses of Raw 264.7 toward UHMWPE particles. The expression of cytokines, NF-kappaB, and osteoclast marker genes was analyzed by ELISA, western blot, or quantitative PCR. The osteoclast differentiation was measured by TRAP staining and flow cytometry. UHMWPE particles induced Raw 264.7 cells to differentiate into osteoclasts, which was enhanced by coculturing with DC 2.4 cells. DC 2.4 cells augmented UHMWPE particle-elicited activation of NF-kappaB signaling, higher levels of TNF-alpha and MCP-1, and an increased expression of MMP-9, Calcr, and Ctsk, though DC 2.4 coculture alone did not significantly cause the aforementioned changes. These results suggest that dendritic cells, among other immune cells recruited by UHMWPE particle induced inflammation, could further exacerbate inflammation and osteolysis. PMID- 25808789 TI - Simple and rapid determination of N(6)-(Delta(2)-isopentenyl)adenine, zeatin, and dihydrozeatin in plants using on-line cleanup liquid chromatography coupled with hybrid quadrupole-Orbitrap high-resolution mass spectrometry. AB - A simple and rapid method was developed for the determination of three free cytokinins, namely, N(6)-(Delta(2)-isopentenyl)adenine, zeatin, and dihydrozeatin, in plants using TurboFlow on-line cleanup liquid chromatography combined with hybrid quadrupole-Orbitrap high-resolution mass spectrometry. The samples were extracted using acetonitrile, and then the extract was purified on a C18-p column, in which the sample matrix was removed and the analytes were retained. Subsequently, the analytes were eluted from the extraction column onto the analytical column (Hypersil Gold C18 column) prior to chromatographic separation and hybrid Q-Orbitrap detection using the targeted-MS(2) scan mode. The linearity was satisfactory with a correlation coefficient of >0.999 at concentrations ranging from 5-5000 pg/mL. The limits of quantification for the analytes ranged from 4.2-5.2 pg/mL. The intra- and inter-day average recoveries of analytes fortified at three levels ranged from 85.4-108.2%, and the intra- and inter-day relative standard deviations ranged from 4.04-8.57%. The method was successfully applied for the determination of free cytokinins in different tissue samples of Oryza sativa and Arabidopsis thaliana. PMID- 25808790 TI - The shared experience of adolescent and young adult cancer patients and their caregivers. AB - OBJECTIVE: We examined the interdependent, dyadic, mental health of adolescent and young adult (AYA) cancer patients and their caregivers. Our aims were as follows: (1) to investigate the degree to which patients' and caregivers' subjective perceptions of illness severity are congruent with objective severity (i.e., medical indicators), (2) to compare patients' and caregivers' subjective perceptions of illness severity and cancer-related posttraumatic stress symptoms (PTSS), and (3) to evaluate whether subjective perceptions of illness severity are linked to patients' and caregivers' cancer-related PTSS. METHODS: The AYA cancer patients (n = 110; ages 12-24 years; 52% male) undergoing active treatment at an outpatient clinic and their caregivers (n = 110; 97% parents; ages 24-68 years; 89% female) independently reported their PTSS and subjective illness severity. RESULTS: Overall, neither patients' nor caregivers' reports of subjective illness severity were associated with objective illness severity. Caregivers reported higher PTSS than did patients and higher illness severity than younger, but not older, patients. Actor-partner interdependence model analyses indicated that AYA patients' subjective illness severity is the strongest predictor of their own PTSS and is a significant correlate of their caregivers' PTSS. Caregivers' subjective illness severity is associated with their own PTSS only. Results remained robust after controlling for demographic and illness characteristics. CONCLUSIONS: The AYA patients' and caregivers' illness perceptions are distinct from each other and from objective medical indicators of illness severity. Patients' reports of subjective illness severity may be a marker for their own and their caregivers' mental health. Patient care and efficacious psychosocial interventions may require consideration of both patients' and caregivers' subjective perceptions of illness severity. PMID- 25808791 TI - Clinical high risk for psychosis: gender differences in symptoms and social functioning. AB - AIM: Schizophrenia is a heterogeneous disorder that presents differently in men and women: men show a higher propensity to negative symptoms, lower social functioning, earlier age at onset and co-morbid substance abuse, whereas women display more affective symptoms. It is unknown whether these differences extend to subjects at high risk (HR) of psychosis. Thus, the aim of the present study was to address this question. METHODS: Clinical symptoms and functioning were assessed using structured interviews in 239 HR subjects (female, n = 80). The definition of being at HR was based on the criteria used in the European Prediction of Psychosis Study (EPOS). RESULTS: Men displayed more pronounced negative symptoms, higher rates of past substance abuse disorders and higher deficits in social functioning. No gender difference was found for depression, which affected almost 50% of the cohort, or age at onset for the fulfilment of HR criteria. CONCLUSION: The higher impairment in specific symptoms observed in male schizophrenia patients was also present in subjects at HR for psychosis. Further studies are required to determine whether these symptoms are gender-specific predictors of transition to psychosis and whether they warrant gender-specific interventions. The high propensity to depression in the present cohort, which was particularly pronounced in the male cohort compared with the general population, in conjunction with the observed increase in negative symptoms and functional impairment, should alert clinicians to the necessity for the identification and treatment of HR subjects, irrespective of the degree to which these features are associated with transition risk. PMID- 25808792 TI - Management of chronic lymphocytic leukemia (CLL) in the era of B-cell receptor signal transduction inhibitors. AB - The treatment of patients with chronic lymphocytic leukemia (CLL), an indolent B cell lymphoma is in the midst of a transformation. There are a large number of promising new therapeutic agents and cellular therapies being studied which exhibit remarkable activity, favorable toxicity profiles, convenient administration schedules, and treatment options are rapidly expanding. The recent advances in the management of CLL exemplify the value of translational medicine. This review highlights key aspects of B-cell receptor (BCR) signaling in relation to novel inhibitors of the BCR signaling pathway, currently at various stages of preclinical and clinical development. PMID- 25808793 TI - Two different approaches for novel extracapsular cranial cruciate ligament reconstruction: an in vitro kinematics study. AB - OBJECTIVE: To analyse the best combination of isometric points with the best kinematic results between two different approaches of TightRope(r) cranial cruciate ligament reconstruction. MATERIALS AND METHODS: Cranial drawer, cranial tibial thrust, internal/external, range of motion and varus/valgus tests were passively performed in different stifle conditions: cranial cruciate ligament intact/deficient, after F2-T2/F2-T3 TR reconstruction at 22-44-99 N of tension. Data were acquired by a custom-made navigation system. RESULTS: The cranial drawer test showed recovery of laxity only at 99 N in both approaches. Significant laxity reduction (cranial tibial thrust) was present at only the F2 T2 point. Differences were noted in internal/external and varus/valgus rotation between the cranial cruciate ligament-intact and TightRope(r) stifles at all of the implant tensions. The range of motion underlined significantly lower laxity values following the F2-T2/F2-T3 reconstruction at all of the evaluated implant tensions. CLINICAL SIGNIFICANCE: The best isometric site was at the F2-T2 point, however significant differences in the amount of laxity between the two techniques were limited to the cranial tibial thrust and internal/external test. The F2-T2 technique was the best consideration for clinical application because it is relatively easy to perform, repeatable and results in good stifle stability with low morbidity and complications. PMID- 25808794 TI - Fractional photothermolysis treatment of digital cutis laxa reverses hand disability. AB - In this case study, we present a safe and novel treatment for a patient with soft tissue hand disability caused by severe and chronic lupus and cutis laxa (CL). This patient was a woman in her 50s with a 20-year history of systemic lupus erythematous (SLE) and multiple sclerosis who developed hand disability because of the drastic loss of firmness in her soft tissue, extending from the dermis down to the ligaments. The likely cause was CL with SLE synovitis, exacerbated by corticosteroid tapering. Fractional photothermolysis (FP) LASER (Fraxel DUAL 1550/1927; Solta Medical) therapy profoundly alleviated her joint locking in addition to improving the firmness of the overlying skin to reverse her hand disability. This case illustrates a novel approach to CL hand treatment and the profound impact the treatment had on the patient's disabled hand. FP therapy is quick and safe, and its medical application to skin and joints should be further explored. PMID- 25808795 TI - Short-term pilot study of the effect of sleeve gastrectomy on food preference. AB - The effect of vertical sleeve gastrectomy (VSG) on food preference has not been examined in humans, but VSG decreases preference for fat and calorically dense foods in rodents. A validated Food Preference Questionnaire (FPQ) assessed food preference changes before and 6 weeks after VSG in humans. The FPQ was completed before and 43 +/- 19 days (Mean +/- SD) after VSG. Fifteen subjects (14 females) completed the study. Hedonic ratings decreased for foods high in fat and sugar (p = 0.002) and high in fat and complex carbohydrate (p = 0.007). Fat preference (p = 0.048) decreased, VSG reduced preference for calorically dense foods high in fat, sugar, and complex carbohydrate, and these changes may contribute to the weight loss with VSG. PMID- 25808798 TI - Creating the future of public health nursing: a call to action. PMID- 25808797 TI - Modulatory effect of cadmium on the expression of phospholipase A2 and proinflammatory genes in rat testis. AB - Cadmium (Cd) is a toxic metal that is hazardous to health, and its exposure showed a significant reduction in mitochondrial phospholipid function in the rat testes. Cd induction enhanced phospholipases (PLA2 s) activities, specifically the secretory PLA2 and cytosolic PLA2 . There was a reduction in mitochondrial membrane potential and significant decline in the respiratory complexes, which was confirmed by 2D blue native gel. The mRNA expression of cyclooxygenase and proinflammatory cytokine genes interleukin (IL)-1, IL-6, tumor necrosis factor alpha, inducible nitric oxide synthase, and interferon-gamma increased and that of anti-inflammatory cytokine IL-10 reduced with Cd exposure in a time-dependent manner. The gene expression of the proapoptotic factor Bax was elevated, and in parallel, the antiapoptotic factor Bcl2 was down-regulated. Hence, this study explored the testes under Cd toxicity and observed alterations in PLA2 s and mitochondrial membrane composition/function and further explored the impact of these alterations on proinflammation and apoptosis. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1176-1184, 2016. PMID- 25808796 TI - Identifying the Bariatric Patient at Risk for Pulmonary Embolism: Prospective Clinical Trial Using Duplex Sonography and Blood Screening. AB - BACKGROUND: Thromboembolic complications continue to be one of the main reasons for perioperative mortality in bariatric surgery. There is no consensus on which is the safest and most effective thromboprophylaxis. This prospective study aims to evaluate the significance of thrombophilia screening and a venous duplex sonography in bariatric patients. METHODS: One hundred one patients were tested for coagulopathies (activated protein C (APC) resistance, factor II, antithrombin (AT)III, protein S and C). Perioperatively, the patients underwent a venous duplex sonography. A multimodal thromboprophylaxis protocol was set up: 2* 40 mg enoxaparin sodium per day and sequential pneumatic compressions of the lower extremities. RESULTS: In six patients, we identified previously unknown risk factors for thromboembolic complications. Protein S deficiency is found significantly more often in obese patients than in the general population. There are numerous risk factors which, in themselves, increase the risk of venous thromboembolism. In obese patients with obstructive sleep apnea or diabetes mellitus, thrombophilia is found significantly more often than in patients without these diseases. No postoperative thromboses occurred. CONCLUSIONS: The bariatric patient is a potential high-risk patient for venous thromboembolism. Thrombophilia is found significantly more often in obese patients than in the general population. Conceivably, existing conditions such as obstructive sleep apnea and diabetes mellitus have until today been underestimated regarding the entailing thrombosis risk. Thrombophilia screening and duplex sonography are possibilities for identifying patients at risk. The advantage of a reduced risk thanks to an adapted thromboprophylaxis based on the patient's individual risk profile justifies the relative increase in time and cost. PMID- 25808799 TI - Signaling pathways and mechanisms of hypoxia-induced autophagy in the animal cells. AB - Hypoxia occurs in a series of supraphysiological circumstances, for instance, sleep disorders, myocardial infarction and cerebral stroke, that can induce a systematic inflammatory response. Such a response may then lead to a widespread dysfunction and cell injury. Autophagy, a cellular homeostatic process that governs the turnover of damaged organelles and proteins, can be triggered by multiple forms of extra- and intracellular stress, for example, hypoxia, nutrient deprivation and reactive oxygen specie. Central to this process is the formation of double-membrane vesicles, thereby autophagosomes sequester portions of cytosol and deliver them to the lysosomes for a breakdown. In recent years, several distinct oxygen-sensing pathways that regulate the cellular response to autophagy have been defined. For instance, hypoxia influences autophagy in part through the activation of the hypoxia-inducible factor (HIF)-dependent pathways. In chronic and moderate hypoxia, autophagy plays a protective role by mediating the removal of the damaged organelles and protein. Moreover, three additional oxygen sensitive signaling pathways are also associated with the activation of autophagy. These include mammalian target of rapamycin (mTOR) kinase, unfolded protein response (UPR)- and PKCdelta-JNK1-dependent pathways. Contrary to the protective effects of autophagy, during rapid and severe oxygen fluctuations, autophagy may be detrimental and induce cell death. In this review, we highlight a serious of recent advances on how autophagy is regulated at the molecular level and on final consequences of cell under different hypoxic environment. PMID- 25808800 TI - MicroRNA-29 family expression and its relation to antiviral immune response and viro-immunological markers in HIV-1-infected patients. AB - BACKGROUND: Several in vitro studies suggested the microRNA-29 (miRNA-29) family is involved in regulating HIV-1 and modulating the expression of interleukin (IL) 32, an anti-HIV-1 cytokine. METHODS: To investigate the contribution of the miRNA 29 family to HIV-1 infection in vivo, we compared miRNA-29 expression in PBMC collected from 58 HIV-1-infected patients, naive for antiretroviral therapy, and 21 gender- and age-matched HIV-1 seronegative healthy donors, using RT-Taqman assays. The relation between miRNA-29 levels and HIV-1 viro-immunological markers and the activation rate of antiviral immune response were also evaluated. In addition, we profiled miRNA-29 expression in CD4+ T lymphocytes and CD14+ monocytes collected from 5 antiretroviral treated HIV-1 infected patients. RESULTS: miRNA-29b levels were higher in HIV-1-infected patients than in the control group (p < 0.001). There were no correlations with either HIV-1 RNA levels or CD4+ T count, whereas a significant correlation was found between miRNA 29-a/c levels and integrated HIV-1 DNA (miRNA-29a: p = 0.009, r = -0.448; miRNA 29c: p = 0.029; r = -0.381). When the HIV-1-infected patients were grouped on the basis of their plasma HIV-1 RNA and CD4+ T cell count, we also found that patients expressing the lowest levels of miRNA-29c showed high viraemia, low CD4+ T cell count and high levels of integrated HIV-1 DNA. Moreover, miRNA-29b levels were correlated with those of IL-32nonalpha (p = 0.028; r = -0.298). Patients expressing higher levels of miRNA-29b showed lower levels of MxA, an interferon stimulated gene, also induced by IL-32 (p = 0.006 r = -0.397). Lastly, we found that CD4+ T lymphocytes and CD14+ monocytes shared similar miRNA-29a/b/c expression patterns but the amount of miRNA-29a/b/c, IL-32 isoforms and MxA were highly variable in these two cellular subsets. CONCLUSIONS: The miRNA-29 family could influence the clinical progression of HIV-1 infection, the HIV-1 proviral load and the innate immune response against HIV-1. PMID- 25808801 TI - An n=1 case report of a child with autism improving on antibiotics and a father's quest to understand what it may mean. AB - The author, a parent of a child with autism, describes an n=1 case in which his child's autism symptoms dramatically and rapidly improved following administration of a common antibiotic. The author asserts that this finding is not unusual in the autism population and that, when combined with prior recent medical research, suggests that a link between autism and the microbiome in some children is not just plausible, but in fact likely for some meaningful percentage of cases. The author argues for increased funding for a more thorough examination of links between autism and the microbiome and poses a series of questions to be further examined in future research. PMID- 25808805 TI - Frere Jacques/Dormez vous? Dormancy, an intriguing phenomenon shared by many forms of life. PMID- 25808807 TI - Magnetic resonance imaging pattern recognition in sporadic inclusion-body myositis. AB - INTRODUCTION: In sporadic inclusion-body myositis (IBM), additional tools are needed to confirm the diagnosis, particularly in clinically atypical or pathologically unproven patients. The aims of this study were to define the pattern of muscle MRI in IBM and to assess its accuracy in differentiating IBM from other myopathies that overlap with it clinically or pathologically. METHODS: Blind assessment was done on the scans of 17 definite IBM, 2 possible IBM, and 118 patients with other myopathies. RESULTS: The diagnostic accuracy to detect definite IBM was 95% for the typical pattern (with 100% specificity) and 97% for both typical and consistent patterns (with 97% specificity). CONCLUSIONS: Muscle MRI is an accurate tool for diagnostic work-up of suspected IBM patients and may be particularly helpful in patients with early disease or who lack the classical IBM pathology. PMID- 25808802 TI - Predicting Outcome after Pediatric Traumatic Brain Injury by Early Magnetic Resonance Imaging Lesion Location and Volume. AB - Brain lesions after traumatic brain injury (TBI) are heterogeneous, rendering outcome prognostication difficult. The aim of this study is to investigate whether early magnetic resonance imaging (MRI) of lesion location and lesion volume within discrete brain anatomical zones can accurately predict long-term neurological outcome in children post-TBI. Fluid-attenuated inversion recovery (FLAIR) MRI hyperintense lesions in 63 children obtained 6.2+/-5.6 days postinjury were correlated with the Glasgow Outcome Scale Extended-Pediatrics (GOS-E Peds) score at 13.5+/-8.6 months. FLAIR lesion volume was expressed as hyperintensity lesion volume index (HLVI)=(hyperintensity lesion volume / whole brain volume)*100 measured within three brain zones: zone A (cortical structures); zone B (basal ganglia, corpus callosum, internal capsule, and thalamus); and zone C (brainstem). HLVI-total and HLVI-zone C predicted good and poor outcome groups (p<0.05). GOS-E Peds correlated with HLVI-total (r=0.39; p=0.002) and HLVI in all three zones: zone A (r=0.31; p<0.02); zone B (r=0.35; p=0.004); and zone C (r=0.37; p=0.003). In adolescents ages 13-17 years, HLVI total correlated best with outcome (r=0.5; p=0.007), whereas in younger children under the age of 13, HLVI-zone B correlated best (r=0.52; p=0.001). Compared to patients with lesions in zone A alone or in zones A and B, patients with lesions in all three zones had a significantly higher odds ratio (4.38; 95% confidence interval, 1.19-16.0) for developing an unfavorable outcome. PMID- 25808809 TI - Movement towards enhancing self-management and exercise prescription through use of the OMNI Walk/Run Rating of Perceived Exertion scale. PMID- 25808808 TI - Regulation of MDM2 Stability After DNA Damage. AB - Cells in our body are constantly exposed to various stresses and threats to their genomic integrity. The tumor suppressor protein p53 plays a critical role in successful defense against these threats by inducing apoptotic cell death or cell cycle arrest. In unstressed conditions, p53 levels and activity must be kept low to prevent lethal activation of apoptotic and senescence pathways. However, upon DNA damage or other stressors, p53 is released from its inhibitory state to induce an array of apoptosis and cell cycle genes. Conversely, inactivation of p53 could promote unrestrained tumor proliferation and failure to appropriately undergo apoptotic cell death, which could, in turn, lead to carcinogenesis. The ubiquitin E3 ligase MDM2 is the most critical inhibitor of p53 that determines the cellular response to various p53-activating agents, including DNA damage. MDM2 activity is controlled by post-translational modifications, especially phosphorylation. However, accumulating evidence suggests that MDM2 is also regulated at the level of protein stability, which is controlled by the ubiquitin proteasome pathway. Here, we discuss how MDM2 can be regulated in response to DNA damage with particular focus on the regulation of MDM2 protein stability. PMID- 25808810 TI - Senescent dermal fibroblasts enhance stem cell migration through CCL2/CCR2 axis. AB - During aging, increases in the number of senescent cells are seen in various tissues. On the other hand, stem cells play crucial roles in tissue repair and homeostasis. Therefore, it is likely that stem cells give rise to new cells that replace senescent cells. However, how stem cells contribute to homeostasis in the dermis has not been elucidated. Here, we investigated the effects of factors secreted from senescent fibroblasts on stem cells. We found that senescent human dermal fibroblast (HDF) conditioned medium (CM) significantly enhanced stem cell migration compared with young HDF CM. The senescent HDF CM strongly secreted chemokine ligand 2 (CCL2). Furthermore, CCL2 was found to enhance stem cell migration, and the inhibition of CCR2, a receptor for CCL2, reduced stem cell migration. These results suggest that senescent fibroblasts recruit stem cells by secreting various factors and that the CCL2/CCR2 axis is one of the mechanisms underlying this phenomenon. PMID- 25808812 TI - Editorial Comment to Exploration of risk factors predicting outcomes for primary T1 high-grade bladder cancer and validation of the Spanish Urological Club for Oncological Treatment scoring model: Long-term follow-up experience at a single institute. PMID- 25808811 TI - Maintaining Moderate Platelet Aggregation and Improving Metabolism of Endothelial Progenitor Cells Increase the Patency Rate of Tissue-Engineered Blood Vessels. AB - Small-diameter tissue-engineered blood vessels (TEBVs) have been associated with low, long-term patency rates primarily because of acute thrombosis in early stages and an inability to achieve early endothelialization. Platelets and endothelial progenitor cells (EPCs) play a key role in these processes. A nano delayed-release 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) bound TEBV was implanted in rat carotid arteries for 3 months. AICAR-bound TEBVs had a high patency rate compared with control TEBVs after 3 months. We found that AICAR maintained moderate platelet aggregation in vivo. In vitro data indicated that AICAR inhibits the release of 5-hydroxytryptamine and thromboxane A2 in activating platelets to reduce platelet aggregation. Then, we confirmed that AICAR strengthens the EPC energy state, which results in earlier endothelialization. The homing, migration, and paracrine function of EPCs were enhanced by AICAR in vitro. Besides, AICAR can contribute to the migration of endothelial cells near the anastomosis. The cellularization of TEBVs at different time points was observed too. In conclusion, our study suggests that the application of nanodelivery material containing AICAR can effectively improve small-diameter TEBVs by maintaining moderate platelet aggregation and improving metabolism of EPCs. PMID- 25808813 TI - Direct Solvent-Derived Polymer-Coated Nitrogen-Doped Carbon Nanodots with High Water Solubility for Targeted Fluorescence Imaging of Glioma. AB - Cancer imaging requires biocompatible and bright contrast-agents with selective and high accumulation in the tumor region but low uptake in normal tissues. Herein, 1-methyl-2-pyrrolidinone (NMP)-derived polymer-coated nitrogen-doped carbon nanodots (pN-CNDs) with a particle size in the range of 5-15 nm are prepared by a facile direct solvothermal reaction. The as-prepared pN-CNDs exhibit stable and adjustable fluorescence and excellent water solubility. Results of a cell viability test (CCK-8) and histology analysis both demonstrate that the pN-CNDs have no obvious cytotoxicity. Most importantly, the pN-CNDs can expediently enter glioma cells in vitro and also mediate glioma fluorescence imaging in vivo with good contrast via elevated passive targeting. PMID- 25808814 TI - Informed herbivore movement and interplant communication determine the effects of induced resistance in an individual-based model. AB - 1. Plant induced resistance to herbivory affects the spatial distribution of herbivores, as well as their performance. In recent years, theories regarding the benefit to plants of induced resistance have shifted from ideas of optimal resource allocation towards a more eclectic set of theories that consider spatial and temporal plant variability and the spatial distribution of herbivores among plants. However, consensus is lacking on whether induced resistance causes increased herbivore aggregation or increased evenness, as both trends have been experimentally documented. 2. We created a spatial individual-based model that can describe many plant-herbivore systems with induced resistance, in order to analyse how different aspects of induced resistance might affect herbivore distribution, and the total damage to a plant population, during a growing season. 3. We analyse the specific effects on herbivore aggregation of informed herbivore movement (preferential movement to less-damaged plants) and of information transfer between plants about herbivore attacks, in order to identify mechanisms driving both aggregation and evenness. We also investigate how the resulting herbivore distributions affect the total damage to plants and aggregation of damage. 4. Even, random and aggregated herbivore distributions can all occur in our model with induced resistance. Highest levels of aggregation occurred in the models with informed herbivore movement, and the most even distributions occurred when the average number of herbivores per plant was low. With constitutive resistance, only random distributions occur. Damage to plants was spatially correlated, unless plants recover very quickly from damage; herbivore spatial autocorrelation was always weak. 5. Our model and results provide a simple explanation for the apparent conflict between experimental results, indicating that both increased aggregation and increased evenness of herbivores can result from induced resistance. We demonstrate that information transfer from plants to herbivores, and from plants to neighbouring plants, can both be major factors in determining non-random herbivore distributions. PMID- 25808816 TI - Ketoconazole Treatment Decreases the Viability of Immortalized Pituitary Cell Lines Associated with an Increased Expression of Apoptosis-Related Genes and Cell Cycle Inhibitors. AB - Ketoconazole, which was initially developed as an antifungal agent, is a potent inhibitor of adrenal steroidogenesis and has therefore been used in the management of Cushing's disease. Surprisingly, the reduction of cortisol levels during ketoconazole treatment is not accompanied by the expected elevation in plasma adrenocorticotrophic hormone (ACTH) at the loss of negative cortisol feedback from corticotrophic cells, suggesting a direct effect of ketoconazole on these cells. To characterize the direct effects of ketoconazole, we evaluated its in vitro effect on cell viability using the pituitary tumoural cell lines AtT-20 (which secretes ACTH), GH3 (which secretes growth hormone and prolactin) and alphaT3.1 (which secretes alpha-subunit) and we also determined the expression levels of genes involved in apoptosis and DNA replication by the quantitative reverse transcription polymerase chain reaction (qRT-PCR). We also evaluated ACTH levels in AtT-20 cells during ketoconazole treatment. We observed a ketoconazole concentration-dependent decrease in pituitary cell viability and reduced ACTH levels in AtT-20 cells after removal of the drug. We also observed increased expression of cell death receptors (e.g. Fas, tumour necrosis factor receptor) and caspases (e.g., caspase-6, caspase-7, caspase-9), suggesting activation of the apoptosis pathway. In addition, we observed increased gene expression of the cell cycle inhibitors p21 and p27 in GH3 cells and increased expression of p21 in alphaT3.1 cells. In conclusion, our findings suggest that ketoconazole significantly reduces cell viability in a concentration-dependent manner in pituitary tumour cell lines and is associated with an increase in apoptosis- and cell cycle regulation-related gene expression. PMID- 25808815 TI - Maternal use of flaxseed oil during pregnancy and lactation prevents morphological alterations in pancreas of female offspring from rat dams with experimental diabetes. AB - Nutritional recommendations have promoted the increased need to consume n-3 polyunsaturated fatty acids. Flaxseed is the richest dietary source of n-3 fatty acids among plant sources and is widely used for its edible oil. This study aimed to investigate whether maternal use of flaxseed oil has effects on pancreas morphology in the female offspring of diabetic mothers. Female Wistar rats (n = 12) were induced into diabetes by a high-fat diet and low dose of streptozotocin. After confirmation of the diabetes, rats were mated, and once pregnancy was confirmed, they were allocated into three groups (n = 6): high-fat group (HG); flaxseed oil group (FOG); and control group (CG) (non-diabetic rats). At weaning, female offspring (n = 6/group) received standard chow diet. The animals were euthanized at 180 days. Pancreas was collected for histomorphometric and immunohistochemistry analysis. HG showed hypertrophy of pancreatic islets (P < 0.0001), whereas FOG offspring had islets with smaller diameters compared to HG (P < 0.0001). HG offspring showed higher percentage of larger (P = 0.0061) and lower percentage of smaller islets (P = 0.0036). HG showed lower islet insulin immunodensity at 180 days (P < 0.0001), whereas FOG was similar to CG (P < 0.0001). Flaxseed oil reduced the damage caused by maternal hyperglycaemia, promoting normal pancreas histomorphometry and beta-cell mass in female offspring. PMID- 25808817 TI - Vibrational and thermal analyses of multicomponent crystal forms of the anti-HIV drugs lamivudine and zalcitabine. AB - The vibrational and thermal characterizations of four multicomponent molecular crystals of lamivudine, namely, lamivudine hydrochloride anhydrate (1), lamivudine hydrochloride monohydrate (2), lamivudine duplex I (3), with a 8:2:2:1:4 lamivudine:maleic acid:HCl:(CH3)2CHOH:H2O stoichiometry, being all three more soluble in water than the commercial solid form of lamivudine, and lamivudine maleate (4), have been performed here by infrared (IR) and Raman spectroscopy, differential scanning calorimetry (DSC), and thermogravimetry (TG). Furthermore, the vibrational spectra of zalcitabine hydrochloride (5), isostructural to 1 but with a methylene moiety in the 3'-position of the five membered ring instead of sulfur in lamivudine, have also been measured in order to point out the role of this molecular substitution and conformation in the vibrational modes of the salts. In fact, scattering bands at the high frequency range relative to CH stretching modes are not superimposable in the Raman spectra of 1 and 5, even though these crystal forms are assembled with the same molecular conformation and intermolecular packing. At the same time, the structural similarity between 1 and 5 can be reflected in their IR spectra, as in the carbonyl and iminium stretching bands shifted to lower frequencies as consequence of their hydrogen bonding engagement. Furthermore, a scattering band at 3057 cm( 1) is observed only in the Raman spectra of crystal forms present with their 5' CH2OH moiety in-gauche conformation, namely, 2-4. It is absent in the Raman spectra of 1 and 5 whose 5'-CH2OH moiety adopts (+)gauche conformation. In-gauche conformation, the 5'-OH oxygen is pointed toward one of the two aromatic CH hydrogens. Consequently, there is formation of an intramolecular hydrogen bond between them, shifting the aromatic CH stretching band to a lower frequency. The DFT calculations have also revealed in-phase and out-of-phase couplings of the two aromatic CH stretchings in the Raman spectra of 1, which is without intramolecular hydrogen bond due to (+)gauche conformation of 5'-CH2OH moiety. Both coupled vibrational modes are observed in the corresponding experimental spectrum as a single peak because of their similar frequencies. On contrary, aromatic CH stretching modes are not coupled in 2 due to the intramolecular hydrogen bond, resulting in resolution of the Raman bands. Thermal events in DSC and TG curves of 1 and 2 are also in agreement with crystal stoichiometry as observed from single-crystal X-ray diffraction analysis. PMID- 25808819 TI - Construction of a biocathode using the multicopper oxidase from the hyperthermophilic archaeon, Pyrobaculum aerophilum: towards a long-life biobattery. AB - OBJECTIVES: The life of biobatteries remains an issue due to loss of enzyme activity over time. In this study, we sought to develop a biobattery with a long life using a hyperthermophilic enzyme. RESULTS: We hypothesized that use of such hyperthermophilic enzymes would allow for the biofuel cells to have a long battery life. Using pyrroloquinoline quinone-glucose dehydrogenase and the multicopper oxidase from Pyrobaculum aerophilum, we constructed an anode and cathode. The maximum output was 11 MUW at 0.2 V, and the stability of the both electrode was maintained at 70 % after 14 days. CONCLUSION: The biofuel cells that use hyperthermophilic enzymes may prolong their life. PMID- 25808820 TI - Recent advances in phosphate biosensors. AB - A number of biosensors have been developed for phosphate analysis particularly, concerning its negative impact within the environmental and biological systems. Enzymatic biosensors comprising either a single or multiple enzymatic system have been extensively used for the direct and indirect analysis of phosphate ions. Furthermore, some non-enzymatic biosensors, such as affinity-based biosensors, provide an alternative analytical approach with a higher selectivity. This article reviews the recent advances in the field of biosensor developed for phosphate estimation in clinical and environmental samples, concerning the techniques involved, and the sensitivity toward phosphate ions. The biosensors have been classified and discussed on the basis of the number of enzymes used to develop the analytical system, and a comparative analysis has been performed. PMID- 25808818 TI - Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. AB - AIMS: The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo. METHODS: The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers. RESULTS: Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control. CONCLUSION: Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance. PMID- 25808821 TI - Fibrin Sealants and Quilting Suture for Prevention of Seroma Formation Following Latissimus Dorsi Muscle Harvest: A Systematic Review and Meta-analysis. AB - PURPOSE: Despite popular use of fibrin sealants and quilting sutures for prevention of seroma formation at the donor site of the latissimus dorsi (LD) muscle flap, there is still no consensus regarding their efficacy. The present review estimates the potential benefits of fibrin and quilting suture for reducing seroma-related morbidity following LD muscle harvest. METHODS: Using Medline, Ovid, and Cochrane databases, two-arm studies evaluating the efficacy of fibrin sealants, quilting suture, or their combination for prevention of seroma formation following LD muscle transfer were searched. The outcome measure was the incidence of seroma, total drainage volume from the back, periods of drainage in situ, volume of seroma, and frequency of aspiration for treatment of seroma. The efficacy on reducing the seroma-related morbidity for each procedure was estimated by meta-analytic methodology. RESULTS: Fourteen studies were analyzed. Fibrin alone failed to reduce seroma-related morbidities compared with no intervention, while fibrin instillation combined with quilting suture halved the risk of seroma formation (relative risk (RR): 0.51, 95 % CI 0.12-2.16) and significantly reduced total drainage volume (mean difference (MD); -320.80, 95 % CI -389.92 to -251.68) and drain indwelling periods (MD -1.62, 95 % CI -2.91 to 0.33) compared with quilting suture alone. Quilting suture had significant protective effects on reducing the risk of seroma formation (RR 0.38, 95 % CI 0.19-0.75), total drainage volume (MD -284.10, 95 % CI -474.61 to -93.60), and drain indwelling periods (MD -3.65, 95 % CI -5.43 to -1.87), and its efficacy was enhanced by combining with fibrin. CONCLUSIONS: According to this review, both fibrin and quilting sutures contributed in varying degrees to reducing seroma related morbidity following LD muscle transfer, and their combination can have a synergistic effect. Although large-scaled, randomized studies are needed, the combination of both procedures may be considered an effective option for minimizing the risk of seroma. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25808822 TI - Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single-centre study with focus on emerging pathogens. AB - With increased use of expanded-spectrum triazoles for antifungal prophylaxis, the epidemiology of invasive fungal infections (IFIs) after allogeneic haematopoietic stem cell transplantation (HSCT) continues to evolve. To define the contemporary epidemiology of IFIs in this population, we reviewed all European Organization for Research and Treatment of Cancer-Mycoses Study Group proven and probable IFIs in adults transplanted from 2002 to 2011 and determined the incidence and risk factors for IFI and post-IFI mortality. All patients received antifungal prophylaxis. Fifty-three (14%) of 378 allogeneic HSCT recipients developed an IFI. There were 62 IFI episodes, of which aspergillosis (n = 31; 50%) and candidaemia (n = 15; 24%) were most common. Sixteen episodes (26%) were caused by other fungi, including Mucorales (n = 6; 10%) and the following uncommon pathogens: Trichosporon asahii, Arthrographis sp., Cladosporium sp., Geosmithia argillacea and Hormographiella aspergillata. Independent IFI risk factors were hospitalisation in an intensive care unit [ICU; odds ratio (OR) = 6.0], graft versus-host disease (OR = 5.3), central venous catheter use (OR = 5.2) and hypoalbuminaemia (OR = 0.3 g(-1) dl(-1) increase in albumin). The 90-day mortality rate after IFI was 57%. Non-cytomegalovirus systemic viral co-infection (OR = 3.5) and stay in an ICU (OR = 2.9) were independent risk factors for death. Despite antifungal prophylaxis, IFIs remain common after allogeneic HSCT and previously uncommon pathogens are emerging. PMID- 25808823 TI - Exposure to occupational therapy as a factor influencing recruitment to the profession. AB - AIM: This article provides insight into the impact that exposure to an occupational therapist, in personal capacity or via a professional interaction, has on the decision to enter an occupational therapy undergraduate programme. METHODS: A quantitative survey was completed by 139 occupational therapy students. The survey tool focussed on the students' exposure to a range of allied health professions (e.g. occupational therapy, physiotherapy, psychology) and investigated how exposure to occupational therapy had influenced their decision to enter the programme. RESULTS: The results indicated that over 70% of respondents had personal professional exposure to occupational therapy prior to making a career decision. Exposure most frequently involved occupational therapy intervention of a friend or family member. The majority of students who had professional exposure to occupational therapy (e.g. family, self, friend received occupational therapy) identified that it was the most influential factor in their career choice. Forty per cent of the occupational therapy students did not enter the programme straight from school and the influence of 'working with an occupational therapist' was noteworthy for mature aged students. CONCLUSION: Occupational therapists need to consider that every interaction they have with the community provides valuable information regarding the profession and gives insight into occupational therapy as a potential career path for other people. Additionally, the current research identifies there were differences in the impact, type and number of exposures for different student groups, and this potentially offers some insight into ways in which occupational therapy could target specific groups within the community to increase future diversity in the profession. PMID- 25808824 TI - Tumor necrosis factor inhibitor therapy for hepatitis B virus-infected individuals: How loud is the alarm bell? PMID- 25808825 TI - Primary neuroendocrine tumor of the breast. PMID- 25808826 TI - Increased SPHK2 Transcription of Human Colon Cancer Cells in Serum-Depleted Culture: The Involvement of CREB Transcription Factor. AB - Sphingosine kinases (SPHK) are important to determine cells' fate by producing sphingosine 1-phosphate. Reportedly, exogenous SPHK2 overexpression induces cell cycle arrest or cell death. However, the regulatory mechanism of SPHK2 expression has not been fully elucidated. Here, we analyzed this issue using human colon cancer cell lines under various stress conditions. Serum depletion (FCS(-)) but not hypoxia and glucose depletion increased mRNA, protein and enzyme activity of SPHK2 but not SPHK1. In HCT116 cells mostly used, SPHK2 activity was predominant over SPHK1, and serum depletion increased both nuclear and cytoplasmic SPHK2 activity. Based on previous reports analyzing cellular response after serum depletion, the temporal changes of intracellular signaling molecules and candidate transcription factors for SPHK2 were examined using serum-depleted HCT116 cells, and performed transfection experiments with siRNA or cDNA of candidate transcription factors. Results showed that the rapid and transient JNK activation followed by CREB activation was the major regulator of increased SPHK2 transcription in FCS(-) culture. EMSA and ChIP assay confirmed the direct binding of activated CREB to the CREB binding site of 5' SPHK2 promoter region. Colon cancer cells examined continued to grow in FCS(-) culture, although mildly, while hypoxia and glucose depletion suppressed cell proliferation or induced cell death, suggesting the different role of SPHK2 in different stress conditions. Because of the unique relationship observed after serum depletion, we examined effects of siRNA for SPHK2, and found the role of SPHK2 as a growth or survival factor but not a cell proliferation inhibitor in FCS(-) culture. PMID- 25808829 TI - An infrared sensor analysing label-free the secondary structure of the Abeta peptide in presence of complex fluids. AB - The secondary structure change of the Abeta peptide to beta-sheet was proposed as an early event in Alzheimer's disease. The transition may be used for diagnostics of this disease in an early state. We present an Attenuated Total Reflection (ATR) sensor modified with a specific antibody to extract minute amounts of Abeta peptide out of a complex fluid. Thereby, the Abeta peptide secondary structure was determined in its physiological aqueous environment by FTIR-difference spectroscopy. The presented results open the door for label-free Alzheimer diagnostics in cerebrospinal fluid or blood. It can be extended to further neurodegenerative diseases. An immunologic ATR-FTIR sensor for Abeta peptide secondary structure analysis in complex fluids is presented. PMID- 25808830 TI - Multiplexed gene transfer to a human T-cell line by combining Sleeping Beauty transposon system with methotrexate selection. AB - Engineered human T-cells are a promising therapeutic modality for cancer immunotherapy. T-cells expressing chimeric antigen receptors combined with additional genes to enhance T-cell proliferation, survival, or tumor targeting may further improve efficacy but require multiple stable gene transfer events. Methods are therefore needed to increase production efficiency for multiplexed engineered cells. In this work, we demonstrate multiplexed, non-viral gene transfer to a human T-cell line with efficient selection (~ 50%) of cells expressing up to three recombinant open reading frames. The efficient introduction of multiple genes to T-cells was achieved using the Sleeping Beauty transposon system delivered in minicircles by nucleofection. We demonstrate rapid selection for engineered cells using methotrexate (MTX) and a mutant human dihydrofolate reductase resistant to methotrexate-induced metabolic inhibition. Preferential amplification of cells expressing multiple transgenes was achieved by two successive rounds of increasing MTX concentration. This non-viral gene transfer method with MTX step selection can potentially be used in the generation of clinical-grade T-cells housing multiplexed genetic modifications. PMID- 25808828 TI - Methods of genomic competency integration in practice. AB - PURPOSE: Genomics is increasingly relevant to health care, necessitating support for nurses to incorporate genomic competencies into practice. The primary aim of this project was to develop, implement, and evaluate a year-long genomic education intervention that trained, supported, and supervised institutional administrator and educator champion dyads to increase nursing capacity to integrate genomics through assessments of program satisfaction and institutional achieved outcomes. DESIGN: Longitudinal study of 23 Magnet Recognition Program(r) Hospitals (21 intervention, 2 controls) participating in a 1-year new competency integration effort aimed at increasing genomic nursing competency and overcoming barriers to genomics integration in practice. METHODS: Champion dyads underwent genomic training consisting of one in-person kick-off training meeting followed by monthly education webinars. Champion dyads designed institution-specific action plans detailing objectives, methods or strategies used to engage and educate nursing staff, timeline for implementation, and outcomes achieved. Action plans focused on a minimum of seven genomic priority areas: champion dyad personal development; practice assessment; policy content assessment; staff knowledge needs assessment; staff development; plans for integration; and anticipated obstacles and challenges. Action plans were updated quarterly, outlining progress made as well as inclusion of new methods or strategies. Progress was validated through virtual site visits with the champion dyads and chief nursing officers. Descriptive data were collected on all strategies or methods utilized, and timeline for achievement. Descriptive data were analyzed using content analysis. FINDINGS: The complexity of the competency content and the uniqueness of social systems and infrastructure resulted in a significant variation of champion dyad interventions. CONCLUSIONS: Nursing champions can facilitate change in genomic nursing capacity through varied strategies but require substantial training in order to design and implement interventions. CLINICAL RELEVANCE: Genomics is critical to the practice of all nurses. There is a great opportunity and interest to address genomic knowledge deficits in the practicing nurse workforce as a strategy to improve patient outcomes. Exemplars of champion dyad interventions designed to increase nursing capacity focus on improving education, policy, and healthcare services. PMID- 25808831 TI - Finafloxacin: first global approval. AB - Finafloxacin is a fluoroquinolone antimicrobial agent that exhibits optimum efficacy in slightly acidic environments. It is being developed by MerLion Pharmaceuticals to treat serious bacterial infections associated with an acidic environment, including urinary tract infections and Helicobacter pylori infections. An otic suspension of finafloxacin (XtoroTM), developed by Alcon (a division of Novartis), was recently approved in the USA for the treatment of acute otitis externa, and a Common Technical Document for this indication was also filed in Canada. Oral and/or intravenous formulations are in phase I and II evaluation in uncomplicated urinary tract infections (Germany and Singapore), complicated urinary tract infections and pyelonephritis (Germany and Poland) and H. pylori infection (Germany). This article summarizes the milestones in the development of finafloxacin leading to this first approval for otitis externa. PMID- 25808827 TI - Outcome comparison of very preterm infants cared for in the neonatal intensive care units in Australia and New Zealand and in Canada. AB - AIM: To compare risk-adjusted neonatal intensive care unit outcomes between regions of similar population demography and health-care systems in Australia-New Zealand and Canada to generate meaningful hypothesis for outcome improvements. METHODS: Retrospective study of data from preterm infants (<32 weeks gestational age) cared for in 29 ANZNN (Australian and New Zealand Neonatal Network) and 26 Canadian Neonatal Network (CNN) intensive care unit admitted between 2005 and 2007. Moribund infants or those with major congenital malformation were excluded. RESULTS: The 9995 ANZNN infants had a higher gestational age (29 vs. 28 weeks, P < 0.0001), lower rate of outborn status (13.2% vs. 19.1%, P < 0.0001) and Apgar score <7 at 5 min (14.8% vs. 21.6%, P < 0.0001) than their 7141 CNN counterparts. After adjustment, ANZNN and CNN infants had a similar likelihood of survival (adjusted odds ratio (AOR) 1.01 (0.88, 1.16)), but ANZNN infants were at lower risk of severe retinopathy (AOR 0.71 (0.61, 0.83)), severe ultrasound neurological injury (AOR 0.68 (0.59, 0.78)), necrotising enterocolitis (AOR 0.65 (0.56, 0.76)), chronic lung disease (AOR 0.67 (0.62, 0.73)) and late-onset sepsis (AOR 0.83 (0.76, 0.91)). ANZNN infants were at a higher risk of pulmonary air leak (AOR 1.20 (1.01, 1.42)), early-onset sepsis (AOR 1.33 (1.02, 1.74)). More ANZNN infants received any respiratory support (AOR 1.27 (1.14, 1.41)) and continuous positive airway pressure as sole respiratory support (AOR 2.50 (2.27, 2.70)). CONCLUSIONS: Despite similarities in settings, ANZNN infants fared better in most measures. Outcome disparities may be related to differences in tertiary service provision, referral and clinical practices. PMID- 25808832 TI - Migraine and risk of ischaemic heart disease: a systematic review and meta analysis of observational studies. AB - BACKGROUND AND PURPOSE: Several studies have assessed the risk of ischaemic heart diseases in migraineurs, drawing different conclusions. To define and update the issue, a systematic review and meta-analysis of the available observational studies was performed. METHODS: PubMed and EMBASE were systematically searched up to April 2014 for observational studies dealing with the risk of any form of ischaemic heart disease in migraineurs. Studies assessing migraine as exposure and several types of ischaemic heart disease as outcomes were included in the analysis. A random effects model was used to pool the effect sizes. RESULTS: Out of 3348 records, 15 studies (one case-control, one cross-sectional and 13 cohort studies) were identified and were included in the meta-analysis. The pooled analysis indicated an increased risk of myocardial infarction (pooled adjusted effect estimate 1.33, 95% confidence interval 1.08-1.64; P = 0.007) and of angina (pooled adjusted effect estimate 1.29, 95% confidence interval 1.17-1.43; P < 0.0001) in migraineurs compared to non-migraineurs. CONCLUSIONS: Based on our data indicating an association of migraine with myocardial infarction and angina and on previous data showing an association of migraine, and particularly migraine with aura, with an increased risk for stroke, migraine can be appropriately considered an overall risk factor for cardiovascular diseases. PMID- 25808834 TI - Placenta previa and risk of major congenital malformations among singleton births in Finland. AB - BACKGROUND: Placenta previa has been associated with adverse birth outcomes, but its association with congenital malformations is inconclusive. We examined the association between placenta previa and major congenital malformations among singleton births in Finland. METHODS: We performed a retrospective population register-based study on all singletons born at or after 22+0 weeks of gestation in Finland during 2000 to 2010. We linked three national health registers: the Finnish Medical Birth Register, the Hospital Discharge Register, and the Register of Congenital Malformations, and examined several demographic and clinical characteristics among women with and without placenta previa, in association with major congenital malformations. We estimated adjusted odds ratios and 95% confidence intervals using multivariable logistic regression models. RESULTS: The prevalence of placenta previa was estimated as 2.65 per 1000 singleton births in Finland (95% confidence interval, 2.53-2.79). Overall, 6.2% of women with placenta previa delivered a singleton infant with a major congenital malformation, compared with 3.8% of unaffected women (p <= 0.001). Placenta previa was positively associated with almost 1.6-fold increased risk of major congenital malformations in the offspring, after controlling for maternal age, parity, fetal sex, smoking, socio-economic status, chorionic villus biopsy, In vitro fertilization, pre-existing diabetes, depression, preeclampsia, and prior caesarean section (adjusted odds ratio = 1.55; 95% confidence interval, 1.27 1.90). CONCLUSION: Using a large population-based study, we found that placenta previa was weakly, but significantly associated with an increased risk of major congenital malformations in singleton births. Future studies should examine the association between placenta previa and individual types of congenital malformations, specifically in high-risk pregnancies. PMID- 25808833 TI - Epitope Specificity Determines Pathogenicity and Detectability of Anti-Platelet Derived Growth Factor Receptor alpha Autoantibodies in Systemic Sclerosis. AB - OBJECTIVE: To identify the epitopes recognized by autoantibodies targeting platelet-derived growth factor receptor alpha (PDGFRalpha) in systemic sclerosis (SSc) and develop novel assays for detection of serum anti-PDGFRalpha autoantibodies. METHODS: Epstein-Barr virus-immortalized B cells from 1 patient with SSc (designated PAM) were screened for expression of IgG binding to PDGFRalpha and induction of reactive oxygen species in fibroblasts. The variable regions of anti-PDGFRalpha IgG were cloned into an IgG expression vector to generate distinct recombinant human monoclonal autoantibodies (mAb), which were characterized by binding and functional assays. The epitopes of anti-PDGFRalpha recombinant human mAb were defined by molecular docking, surface plasmon resonance binding assays, screening of a conformational peptide library spanning the PDGFRalpha extracellular domains, and expression analyses of alanine-scanned PDGFRalpha mutants. Direct or competitive enzyme-linked immunosorbent assays were established to detect all serum anti-PDGFRalpha autoantibodies or, selectively, the agonistic ones. RESULTS: Three types of anti-PDGFRalpha recombinant human mAb, with the same VH but distinct VL chains, were generated. Nonagonistic VH PAM Vkappa 13B8 recognized 1 linear epitope, whereas agonistic VH PAM-Vlambda 16F4 and VH PAM-Vkappa 16F4 recognized 2 distinct conformational epitopes. Serum anti PDGFRalpha antibodies were detected in 66 of 70 patients with SSc, 63 of 130 healthy controls, 11 of 26 patients with primary Raynaud's phenomenon (RP), and 13 of 29 patients with systemic lupus erythematosus (SLE). Serum VH PAM-Vkappa 16F4-like antibodies were found in 24 of 34 patients with SSc, but not in healthy controls, patients with primary RP, or patients with SLE. Peptides composing the VH PAM-Vkappa 16F4 epitope inhibited PDGFRalpha signaling triggered by serum IgG from SSc patients. CONCLUSION: Agonistic anti-PDGFRalpha autoantibodies are enriched in SSc sera and recognize specific conformational epitopes that can be used to discriminate agonistic from nonagonistic antibodies and block PDGFRalpha signaling in patients with SSc. PMID- 25808835 TI - One-pot synthesis of highly emissive dipyridinium dihydrohelicenes. AB - Condensation of a pyridyl-2-carbaldehyde derivative with 2-(bromoethyl)amine hydrobromide gave tetracyclic pyrido[1,2-a]pyrido[1',2':3,4]imidazo-[2,1-c]-6,7 dihydropyrazinium dications in excellent yields. Crystal structures and NOE data demonstrated the helical character of the dications, the dihedral angles between the two pyrido groups ranging from 28-45 degrees . An intermediate in the synthesis was also characterized. A much brighter emission compared to literature helicenes has been found, with quantum yields as high as 60 % in the range of lambda=460-600 nm. Preliminary cytotoxicity studies against HT-29 cancer cells demonstrated moderate-to-good activity, with IC50 values 12-30* that of cisplatin. PMID- 25808837 TI - Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC. AB - Lung cancer is the most common cancer worldwide and on top of that has a very poor prognosis, which is reflected by a 5-year survival rate of 5% to 15%. Radiotherapy is an integral part of most treatment regimens for this type of tumor, often combined with radiosensitizing cytotoxic drugs. In this study, we identified many genes that could potentially be exploited for targeted radiosensitization using a genome-wide siRNA screen in non-small cell lung cancer (NSCLC) cells. The screen identified 433 siRNAs that potentially sensitize lung cancer cells to radiation. Validation experiments showed that knockdown of expression of Forkhead box M1 (FOXM1) or microtubule-associated serine/threonine kinase-like (MASTL) indeed causes radiosensitization in a panel of NSCLC cells. Strikingly, this effect was not observed in primary human fibroblasts, suggesting that the observed radiosensitization is specific for cancer cells. Phosphoproteomics analyses with and without irradiation showed that a number of cell-cycle-related proteins were significantly less phosphorylated after MASTL knockdown in comparison to the control, while there were no changes in the levels of phosphorylation of DNA damage response proteins. Subsequent analyses showed that MASTL knockdown cells respond differently to radiation, with a significantly shortened G2-M phase arrest and defects in cytokinesis, which are followed by a cell-cycle arrest. In summary, we have identified many potential therapeutic targets that could be used for radiosensitization of NSCLC cells, with MASTL being a very promising and druggable target to combine with radiotherapy. PMID- 25808836 TI - Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus. AB - Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation. PMID- 25808838 TI - A laser photoacoustic analysis of residual CO2 and H2O in larch stems. AB - Every so often, the results obtained from investigations into the effects of varying environmental conditions on the tree growth rate at the same sites and on the change in the carbon balance in plants, using traditional methods, are found to differ widely. We believe that the reason for the ambiguity of the data has to do with failure to account for the role of the residual CO2 (and H2O) in the tree wood exhibiting a climate response. In our earlier work, the results of a laser photoacoustic gas analysis of CO2 and H2O vacuum-desorbed from disc tree rings of evergreen conifer trees were presented. In this paper, laser photoacoustic measurements of tree ring gases in deciduous conifer trees and CO2 carbon isotope composition determined by means of a mass spectrometer are given. Conclusions are made regarding the response of annual larch CO2 disc tree ring distributions to climatic parameters (temperatures and precipitation). The data about the CO2 disc content for different sites are compared. PMID- 25808839 TI - Tracking traction force changes of single cells on the liquid crystal surface. AB - Cell migration is a key contributor to wound repair. This study presents findings indicating that the liquid crystal based cell traction force transducer (LCTFT) system can be used in conjunction with a bespoke cell traction force mapping (CTFM) software to monitor cell/surface traction forces from quiescent state in real time. In this study, time-lapse photo microscopy allowed cell induced deformations in liquid crystal coated substrates to be monitored and analyzed. The results indicated that the system could be used to monitor the generation of cell/surface forces in an initially quiescent cell, as it migrated over the culture substrate, via multiple points of contact between the cell and the surface. Future application of this system is the real-time assaying of the pharmacological effects of cytokines on the mechanics of cell migration. PMID- 25808841 TI - Label-free sensing of adenosine based on force variations induced by molecular recognition. AB - We demonstrate a simple force-based label-free strategy for the highly sensitive sensing of adenosine. An adenosine ssDNA aptamer was bound onto an atomic force microscopy (AFM) probe by covalent modification, and the molecular-interface adsorption force between the aptamer and a flat graphite surface was measured by single-molecule force spectroscopy (SMFS). In the presence of adenosine, the molecular recognition between adenosine and the aptamer resulted in the formation of a folded, hairpin-like DNA structure and hence caused a variation of the adsorption force at the graphite/water interface. The sensitive force response to molecular recognition provided an adenosine detection limit in the range of 0.1 to 1 nM. The addition of guanosine, cytidine, and uridine had no significant interference with the sensing of adenosine, indicating a strong selectivity of this sensor architecture. In addition, operational parameters that may affect the sensor, such as loading rate and solution ionic strength, were investigated. PMID- 25808842 TI - Effect of dental cements on peri-implant microbial community: comparison of the microbial communities inhabiting the peri-implant tissue when using different luting cements. AB - BACKGROUND: Cementing dental restorations on implants poses the risk of undetected excess cement. Such cement remnants may favor the development of inflammation in the peri-implant tissue. The effect of excess cement on the bacterial community is not yet known. The aim of this study was to analyze the effect of two different dental cements on the composition of the microbial peri implant community. METHODS: In a cohort of 38 patients, samples of the peri implant tissue were taken with paper points from one implant per patient. In 15 patients, the suprastructure had been cemented with a zinc oxide-eugenol cement (Temp Bond, TB) and in 23 patients with a methacrylate cement (Premier Implant Cement, PIC). The excess cement found as well as suppuration was documented. Subgingival samples of all patients were analyzed for taxonomic composition by means of 16S amplicon sequencing. RESULTS: None of the TB-cemented implants had excess cement or suppuration. In 14 (61%) of the PIC, excess cement was found. Suppuration was detected in 33% of the PIC implants without excess cement and in 100% of the PIC implants with excess cement. The taxonomic analysis of the microbial samples revealed an accumulation of oral pathogens in the PIC patients independent of the presence of excess cement. Significantly fewer oral pathogens occurred in patients with TB compared to patients with PIC. CONCLUSION: Compared with TB, PIC favors the development of suppuration and the growth of periodontal pathogens. PMID- 25808843 TI - High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer. AB - BACKGROUND: Colorectal cancer with metastases limited to the liver (liver-limited mCRC) is a distinct clinical subset characterized by possible cure with surgery. We performed high-depth sequencing of over 750 cancer-associated genes and copy number profiling in matched primary, metastasis and normal tissues to characterize genomic progression in 18 patients with liver-limited mCRC. RESULTS: High depth Illumina sequencing and use of three different variant callers enable comprehensive and accurate identification of somatic variants down to 2.5% variant allele frequency. We identify a median of 11 somatic single nucleotide variants (SNVs) per tumor. Across patients, a median of 79.3% of somatic SNVs present in the primary are present in the metastasis and 81.7% of all alterations present in the metastasis are present in the primary. Private alterations are found at lower allele frequencies; a different mutational signature characterized shared and private variants, suggesting distinct mutational processes. Using B allele frequencies of heterozygous germline SNPs and copy number profiling, we find that broad regions of allelic imbalance and focal copy number changes, respectively, are generally shared between the primary tumor and metastasis. CONCLUSIONS: Our analyses point to high genomic concordance of primary tumor and metastasis, with a thick common trunk and smaller genomic branches in general support of the linear progression model in most patients with liver-limited mCRC. More extensive studies are warranted to further characterize genomic progression in this important clinical population. PMID- 25808844 TI - Predictors of caregiver burden across the home-based palliative care trajectory in Ontario, Canada. AB - Family caregivers of patients enrolled in home-based palliative care programmes provide unpaid care and assistance with daily activities to terminally ill family members. Caregivers often experience caregiver burden, which is an important predictor of anxiety and depression that can extend into bereavement. We conducted a longitudinal, prospective cohort study to comprehensively assess modifiable and non-modifiable patient and caregiver factors that account for caregiver burden over the palliative care trajectory. Caregivers (n = 327) of patients with malignant neoplasm were recruited from two dedicated home-based palliative care programmes in Southern Ontario, Canada from 1 July 2010 to 31 August 2012. Data were obtained from bi-weekly telephone interviews with caregivers from study admission until death, and from palliative care programme and home-care agency databases. Information collected comprised patient and caregiver demographics, utilisation of privately and publicly financed resources, patient clinical status and caregiver burden. The average age of the caregivers was 59.0 years (SD: 13.2), and almost 70% were female. Caregiver burden increased over time in a non-linear fashion from study admission to patient death. Increased monthly unpaid care-giving time costs, monthly public personal support worker costs, emergency department visits and low patient functional status were associated with higher caregiver burden. Greater use of hospice care was associated with lower burden. Female caregivers tended to report more burden compared to men as death approached, and burden was higher when patients were male. Low patient functional status was the strongest predictor of burden. Understanding the influence of modifiable and non-modifiable factors on the experience of burden over the palliative trajectory is essential for the development and targeting of programmes and policies to support family caregivers and reduce burden. Supporting caregivers can have benefits such as improved caregiver health outcomes, and enhancing their ability to meet care-giving demands, thereby potentially allowing for longer patient care in the home setting. PMID- 25808846 TI - Light depolarization measurements in malaria: A new job for an old friend. AB - The use of flow cytometry in malaria research has increased over the last decade. Most approaches use nucleic acid stains to detect parasite DNA and RNA and require complex multi-color, multi-parameter analysis to reliably detect infected red blood cells (iRBCs). We recently described a novel and simpler approach to parasite detection based on flow cytometric measurement of scattered light depolarization caused by hemozoin (Hz), a pigment formed by parasite digestion of hemoglobin in iRBCs. Depolarization measurement by flow cytometry was described in 1987; however, patent issues restricted its use to a single manufacturer's hematology analyzers until 2009. Although we recently demonstrated that depolarization measurement of Hz, easily implemented on a bench top flow cytometer (Cyflow), provided useful information for malaria work, doubts regarding its application and utility remain in both the flow cytometry and malaria communities, at least in part because instrument manufacturers do not offer the option of measuring depolarized scatter. Under such circumstances, providing other researchers with guidance as to how to do this seemed to offer the most expeditious way to resolve the issue. We accordingly examined how several commercially available flow cytometers (CyFlow SL, MoFLo, Attune and Accuri C6) could be modified to detect depolarization due to the presence of free Hz on solution, or of Hz in leukocytes or erythrocytes from rodent or human blood. All were readily adapted, with substantially equivalent results obtained with lasers emitting over a wide wavelength range. Other instruments now available may also be modifiable for Hz measurement. Cytometric detection of Hz using depolarization is useful to study different aspects of malaria. Adding additional parameters, such as DNA content and base composition and RNA content, can demonstrably provide improved accuracy and sensitivity of parasite detection and characterization, allowing malaria researchers and eventually clinicians to benefit from cytometric technology. PMID- 25808848 TI - Understanding Variations of Soil Mapping Units and Associated Data for Forensic Science. AB - Soil samples have potential to be useful in forensic investigations, but their utility may be limited due to the inherent variability of soil properties, the wide array of analytical methods, and complexity of data analysis. This study examined the differentiation of similar soils based on both gross (texture, color, mineralogy) and explicit soil properties (elemental composition, cation exchange, Fe-oxyhydroxides). Soils were collected from Fallbrook and adjacent map units from Riverside and San Diego Counties in California. Samples were characterized using multiple techniques, including chemical extracts, X-ray diffraction (XRD), and Fourier transform infrared spectroscopy. Results were analyzed using multiple analytical approaches to compare counties and land uses. Some analyses (XRD, extractions) were better at distinguishing among samples than others (color, texture). Ratios of rare earth elements were particularly useful for distinguishing samples between counties. This potential to "fingerprint" soils illustrates the usefulness of a comprehensive soil database for criminal investigators. PMID- 25808847 TI - Separating water-potential induced swelling and shrinking from measured radial stem variations reveals a cambial growth and osmotic concentration signal. AB - The quantification of cambial growth over short time periods has been hampered by problems to discern between growth and the swelling and shrinking of a tree stem. This paper presents a model, which separates cambial growth and reversible water potential induced diurnal changes from simultaneously measured whole stem and xylem radial variations, from field-measured Scots pine trees in Finland. The modelled growth, which includes osmotic concentration changes, was compared with (direct) dendrometer measurements and microcore samples. In addition, the relationship of modelled growth and dendrometer measurements to environmental factors was analysed. The results showed that the water-potential induced changes of tree radius were successfully separated from stem growth. Daily growth predicted by the model exhibited a high correlation with the modelled daily changes of osmotic concentration in phloem, and a temperature dependency in early summer. Late-summer growth saw higher dependency on water availability and temperature. Evaluation of the model against dendrometer measurements showed that the latter masked a true environmental signal in stem growth due to water potential induced changes. The model provides better understanding of radial growth physiology and offers potential to examine growth dynamics and changes due to osmotic concentration, and how the environment affects growth. PMID- 25808849 TI - Impact of worsening renal function related to medication in heart failure. AB - AIMS: Renal failure is a major challenge in treating heart failure (HF) patients. HF medication may deteriorate renal function, but the impact thereof on outcome is unknown. We investigated the effects of HF medication on worsening renal function (WRF) and the relationship to outcome. METHODS AND RESULTS: This post hoc analysis of TIME-CHF (NT-proBNP-guided vs. symptom-guided management in chronic HF) included patients with LVEF <=45% and >=1 follow-up visit (n = 462). WRF III was defined as a rise in serum creatinine >=0.5 mg/dL (i.e. 44.2 umol/L) at any time during the first 6 months. Four classes of medication were considered: loop diuretics, beta-blockers, renin-angiotensin system (RAS) blockers, and spironolactone. Functional principal component analysis of daily doses was used to comprehend medication over time. All-cause mortality after 18 months was the primary outcome. Interactions between WRF, medication, and outcome were tested. Patients with WRF III received on average higher loop diuretic doses (P = 0.0002) and more spironolactone (P = 0.02), whereas beta-blockers (P = 0.69) did not differ and lower doses of RAS-blockers were given (P = 0.09). There were significant interactions between WRF III, medicationn and outcome. Thus, WRF III was associated with poor prognosis if high loop diuretic doses were given (P = 0.001), but not with low doses (P = 0.29). The opposite was found for spironolactone (poor prognosis in the case of WRF III with no spironolactone, P <0.0001; but not with spironolactone, P = 0.31). Beta-blockers were protective in all patients (P <0.001), but most in those with WRF III (P <0.05 for interaction). RAS-blockade was associated with improved outcome (P = 0.006), irrespective of WRF III. CONCLUSION: Based on this analysis, it may be hypothesized that high doses of loop diuretics might have detrimental effects, particularly in combination with significant WRF, whereas spironolactone and beta blockers might be protective in patients with WRF. PMID- 25808845 TI - High Bone Mass-Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo. AB - Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). We previously reported the creation of two Lrp5 HBM knock-in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock-in mice are resistant to SOST- or DKK1-induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes ((8kb) Dmp1-SOST) or mouse DKK1 in osteoblasts and osteocytes ((2.3kb) Col1a1-Dkk1). We observed that the (8kb) Dmp1-SOST transgene significantly lowered whole-body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone-formation rate (BFR) in wild-type mice but not in mice with Lrp5 p.G171V and p.A214V alleles. The (2.3kb) Col1a1-Dkk1 transgene significantly lowered whole-body BMD, BMC, and vertebral BV/TV in wild-type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM-causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1. PMID- 25808850 TI - Knockdown of the ionotropic gamma-aminobutyric acid receptor (GABAR) RDL gene decreases fipronil susceptibility of the small brown planthopper, Laodelphax striatellus (Hemiptera: Delphacidae). AB - Insect gamma-aminobutyric acid receptors (GABARs) are important molecular targets of cyclodiene and phenylpyrazole insecticides. Previously GABARs encoding rdl (resistant to dieldrin) genes responsible for dieldrin and fipronil resistance were identified in various economically important insect pests. In this study, we cloned the open reading frame cDNA sequence of rdl gene from fipronil-susceptible and fipronil-resistant strains of Laodelphax striatellus (Lsrdl). Sequence analysis confirmed the presence of a previously identified resistance-conferring mutation. Different alternative splicing variants of Lsrdl were noted. Injection of dsLsrdl reduced the mRNA abundance of Lsrdl by 27-82%, and greatly decreased fipronil-induced mortality of individuals from both susceptible and resistant strains. These data indicate that Lsrdl encodes a functional RDL subunit that mediates susceptibility to fipronil. Additionally, temporal and spatial expression analysis showed that Lsrdl was expressed at higher levels in eggs, fifth-instar nymphs, and female adults than in third-instar and fourth-instar nymphs. Lsrdl was predominantly expressed in the heads of 2-day-old female adults. All these results provide useful background knowledge for better understanding of fipronil resistance related ionotropic GABA receptor rdl gene expressed variants and potential functional differences in insects. PMID- 25808853 TI - FOXA1 modulates EAF2 regulation of AR transcriptional activity, cell proliferation, and migration in prostate cancer cells. AB - BACKGROUND: ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor in the prostate. However, the mechanisms underlying tumor suppressive function of EAF2 are still largely unknown. Identification of factors capable of modulating EAF2 function will help elucidate the mechanisms underlying EAF2 tumor suppressive function. METHODS: Using eaf-1(the ortholog of EAF2) mutant C. elegans model, RNAi screen was used to identify factors on the basis of their knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans. In human cells, the interaction of EAF2 with FOXA1 and the effect of EAF2 on the FOXA1 protein levels were determined by co immunoprecipitation and protein stability assay. The effect of EAF2 and/or FOXA1 knockdown on the expression of AR-target genes was determined by real-time RT-PCR and luciferase reporter assays. The effect of EAF2 and/or FOXA1 knockdown on LNCaP human prostate cancer cell proliferation and migration was tested using BrdU assay and transwell migration assay. RESULTS: RNAi screen identified pha-4, the C. elegans ortholog of mammalian FOXA1, on the basis of its knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans causing sterility. EAF2 co-immunoprecipitated with FOXA1. EAF2 knockdown enhanced endogenous FOXA1 protein level, whereas transfected GFP-EAF2 down regulated the FOXA1 protein. Also, EAF2 knockdown enhanced the expression of AR target genes, cell proliferation, and migration in LNCaP cells. However, FOXA1 knockdown inhibited the effect of EAF2 knockdown on AR-target gene expression, cell proliferation, and migration in LNCaP cells, suggesting that FOXA1 can modulate EAF2 regulation of AR transcriptional activation, cell proliferation, and migration. CONCLUSIONS: These findings suggest that regulation of the AR signaling pathway, cell proliferation, and migration through FOXA1 represents an important mechanism of EAF2 suppression of prostate carcinogenesis. PMID- 25808855 TI - Statistical analysis plan (SAP) for Shared Team Approach between Nurses and Doctors For Improved Risk Factor Management (STANDFIRM): a randomised controlled trial. PMID- 25808854 TI - Negative affect prior to and following overeating-only, loss of control eating only, and binge eating episodes in obese adults. AB - OBJECTIVE: The objective was to examine the trajectory of five types of negative affect (global negative affect, fear, guilt, hostility, sadness) prior to and following three types of eating episodes (overeating in the absence of loss of control [OE-only], loss of control eating in the absence of overeating [LOC only], and binge eating) among obese adults using ecological momentary assessment (EMA). METHOD: Fifty obese adults (84% female) completed a two-week EMA protocol during which they were asked to record all eating episodes and rate each episode on continua of overeating and loss of control. Momentary measures of global negative affect, fear, guilt, hostility, and sadness were assessed using an abbreviated version of the Positive and Negative Affect Schedule (PANAS). Trajectories for each of the five types of negative affect were modeled prior to and following episodes of OE-only, LOC-only, and binge eating. RESULTS: Consistent with previous findings, global negative affect and Guilt increased prior to and decreased following binge eating episodes (all ps < .05). Guilt also decreased following OE-only episodes (p < .05). DISCUSSION: These results are consistent with the affect regulation model of binge eating and suggest that binge eating may function to regulate global negative affect, and more specifically, guilt among obese adults. These data suggest that the relationship between negative affect and binge eating may not be unique to individuals with clinical eating disorders and indicate that targeting negative affect may be an effective strategy for the treatment of binge eating in the context of obesity. PMID- 25808856 TI - Nager syndrome and Pierre Robin sequence. AB - Nager syndrome is considered a rare genetic syndrome characterized by craniofacial and radial anomalies. Pierre Robin sequence is a triad that includes micrognathia, cleft palate and glossoptosis. The present patient had typical findings of Nager syndrome and Pierre Robin sequence. He progressed to severe respiratory distress, requiring mechanical ventilation and tracheostomy. At 1 year and 11 months, he had episodes of cardiorespiratory arrest and died. In the literature review, we identified the clinical description of 44 patients with Nager syndrome. Among them, 93.1% had micrognathia, 38.6% cleft palate and 11.3% glossoptosis. Only one (2.3%) had all three features, as observed in the present patient. Therefore, despite the fact that the features of Pierre Robin sequence are common, there are few patients who have the complete triad. It is noteworthy, however, that they may be associated with respiratory distress, which may put the patient's life at risk. PMID- 25808859 TI - Approximations for Estimating Change in Life Expectancy Attributable to Air Pollution in Relation to Multiple Causes of Death Using a Cause Modified Life Table. AB - There is considerable debate as to the most appropriate metric for characterizing the mortality impacts of air pollution. Life expectancy has been advocated as an informative measure. Although the life-table calculus is relatively straightforward, it becomes increasingly cumbersome when repeated over large numbers of geographic areas and for multiple causes of death. Two simplifying assumptions were evaluated: linearity of the relation between excess rate ratio and change in life expectancy, and additivity of cause-specific life-table calculations. We employed excess rate ratios linking PM2.5 and mortality from cerebrovascular disease, chronic obstructive pulmonary disease, ischemic heart disease, and lung cancer derived from a meta-analysis of worldwide cohort studies. As a sensitivity analysis, we employed an integrated exposure response function based on the observed risk of PM2.5 over a wide range of concentrations from ambient exposure, indoor exposure, second-hand smoke, and personal smoking. Impacts were estimated in relation to a change in PM2.5 from 19.5 MUg/m(3) estimated for Toronto to an estimated natural background concentration of 1.8 MUg/m(3) . Estimated changes in life expectancy varied linearly with excess rate ratios, but at higher values the relationship was more accurately represented as a nonlinear function. Changes in life expectancy attributed to specific causes of death were additive with maximum error of 10%. Results were sensitive to assumptions about the air pollution concentration below which effects on mortality were not quantified. We have demonstrated valid approximations comprising expression of change in life expectancy as a function of excess mortality and summation across multiple causes of death. PMID- 25808857 TI - Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis. AB - Cathepsin B is a cysteine proteinase that primarily functions as an endopeptidase within endolysosomal compartments in normal cells. However, during tumoral expansion, the regulation of cathepsin B can be altered at multiple levels, thereby resulting in its overexpression and export outside of the cell. This may suggest a possible role of cathepsin B in alterations leading to cancer progression. The aim of this study was to determine the contribution of intracellular and extracellular cathepsin B in growth, tumorigenesis, and invasion of colorectal cancer (CRC) cells. Results show that mRNA and activated levels of cathepsin B were both increased in human adenomas and in CRCs of all stages. Treatment of CRC cells with the highly selective and non-permeant cathepsin B inhibitor Ca074 revealed that extracellular cathepsin B actively contributed to the invasiveness of human CRC cells while not essential for their growth in soft agar. Cathepsin B silencing by RNAi in human CRC cells inhibited their growth in soft agar, as well as their invasion capacity, tumoral expansion, and metastatic spread in immunodeficient mice. Higher levels of the cell cycle inhibitor p27(Kip1) were observed in cathepsin B-deficient tumors as well as an increase in cyclin B1. Finally, cathepsin B colocalized with p27(Kip1) within the lysosomes and efficiently degraded the inhibitor. In conclusion, the present data demonstrate that cathepsin B is a significant factor in colorectal tumor development, invasion, and metastatic spreading and may, therefore, represent a potential pharmacological target for colorectal tumor therapy. PMID- 25808860 TI - Genomic analysis of a migratory divide reveals candidate genes for migration and implicates selective sweeps in generating islands of differentiation. AB - Differential gene flow, reductions in diversity following linked selection and/or features of the genome can structure patterns of genomic differentiation during the process of speciation. Possible sources of reproductive isolation are well studied between coastal and inland subspecies groups of Swainson's thrushes, with differences in seasonal migratory behaviour likely playing a key role in reducing hybrid fitness. We assembled and annotated a draft reference genome for this species and generated whole-genome shotgun sequence data for populations adjacent to the hybrid zone between these groups. We documented substantial genomewide heterogeneity in relative estimates of genetic differentiation between the groups. Within population diversity was lower in areas of high relative differentiation, supporting a role for selective sweeps in generating this pattern. Absolute genetic differentiation was reduced in these areas, further suggesting that recurrent selective sweeps in the ancestral population and/or between divergent populations following secondary contact likely occurred. Relative genetic differentiation was also higher near centromeres and on the Z chromosome, suggesting that features of the genome also contribute to genomewide heterogeneity. Genes linked to migratory traits were concentrated in islands of differentiation, supporting previous suggestions that seasonal migration is under divergent selection between Swainson's thrushes. Differences in migratory behaviour likely play a central role in the speciation of many taxa; we developed the infrastructure here to permit future investigations into the role several candidate genes play in reducing gene flow between not only Swainson's thrushes but other species as well. PMID- 25808861 TI - Rapid Identification of Steroidal Saponins in Trillium tschonoskii Maxim by Ultraperformance Liquid Chromatography Coupled to Electrospray Ionisation Quadrupole Time-of-Flight Tandem Mass Spectrometry. AB - INTRODUCTION: Steroidal saponins in Trillium tschonoskii Maxim have many biological activities, including immunological regulation and anti-tumour. Comprehensive ingredient identification is critical for understanding its pharmacological mechanism and establishing quality control protocols. However, it is a challenging problem because of the complexity of steroidal saponins. OBJECTIVES: To develop a UPLC-MS method for identifying and characterising steroidal saponins in the root and rhizome of T. tschonoskii. METHODS: Methanolic extracts of T. tschonoskii were analysed by using ultraperformance liquid chromatography coupled to electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI/QTOF/MS). The UPLC experiments were performed by means of a reversed-phase C18 -column and a binary mobile phase system consisting of water and acetonitrile with formic acid under gradient elution conditions. For the UPLC-MS measurements, positive and negative ion modes were used in order to obtain better tandem mass spectra and high-resolution mass spectra. RESULTS: Based on retention times, accurate mass and mass spectrometric fragmentation, a total of 31 saponins distributed over eight steroidal aglycone skeletons were identified or tentatively elucidated from T. tschonoskii. CONCLUSION: The UPLC-ESI/QTOF/MS method has proven to be a powerful tool for rapid identification of steroidal saponins in T. tschonoskii without tedious and time-consuming isolation of pure constituents. PMID- 25808858 TI - Perspectives on biologically active camptothecin derivatives. AB - Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects. PMID- 25808862 TI - Remaining root dentin thickness in mesiobuccal canals of maxillary first molars after attempted removal of broken instrument fragments. AB - The aim was to measure the minimal thickness of the remaining canal wall dentine in the mesiobuccal roots of maxillary first molars using a virtual model to simulate the attempt to remove fractured instruments. Thirty-seven molars were scanned by micro-computed tomography. The application framework for the simulation of the attempt to remove a broken instrument was constructed. The staging platform was created and followed by the use of ultrasonic tips to trephine dentine around the fragment to reveal the coronal 1.5 mm. The minimum canal wall thickness in the mesiobuccal roots was then measured. The concavity groove was found on all the distal aspects of the mesiobuccal root. The minimum thickness of the remaining canal wall distally to the canal was significantly thinner than mesially to the canals when sizes 25/0.06 and 25/0.02 instruments were broken at 3 and 5 mm away from the canal orifice. When the sizes 20/0.02 and 25/0.06 instruments were broken at 5 mm away from the canal orifice, the minimum thickness of the distal dentine wall was only 300-400 MUm which was significantly less than when the instrument was broken at 3 mm. PMID- 25808864 TI - Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR Ligand Off-Rates Measurements on Living Cells. AB - The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the peptide-MHC (pMHC) on cells is a key parameter for cell-mediated immunity. Yet a fundamental feature of most tumor antigen-specific CD8(+) T cells is that this avidity is low. In this study, we addressed the need to identify and select tumor specific CD8(+) T cells of highest avidity, which are of the greatest interest for adoptive cell therapy in patients with cancer. To identify these rare cells, we developed a peptide-MHC multimer technology, which uses reversible Ni(2+) nitrilotriacetic acid histidine tags (NTAmers). NTAmers are highly stable but upon imidazole addition, they decay rapidly to pMHC monomers, allowing flow cytometric-based measurements of monomeric TCR-pMHC dissociation rates of living CD8(+) T cells on a wide avidity spectrum. We documented strong correlations between NTAmer kinetic results and those obtained by surface plasmon resonance. Using NTAmers that were deficient for CD8 binding to pMHC, we found that CD8 itself stabilized the TCR-pMHC complex, prolonging the dissociation half-life several fold. Notably, our NTAmer technology accurately predicted the function of large panels of tumor-specific T cells that were isolated prospectively from patients with cancer. Overall, our results demonstrated that NTAmers are effective tools to isolate rare high-avidity cytotoxic T cells from patients for use in adoptive therapies for cancer treatment. PMID- 25808863 TI - Training-induced dynamic changes in left atrial reservoir, conduit, and active volumes in professional soccer players. AB - PURPOSE: Although left atrial (LA) enlargement is a recognized component of athlete's heart, dynamic cavity changes occurring during the training period remain to be elucidated. We aimed to investigate the adaptive changes of LA reservoir, conduit, and active volumes in elite athletes vs. controls and their response to different training loads. METHODS: LA maximum, pre-P, and minimum volumes were assessed in 26 top-level athletes and 23 controls. In athletes, LA volumes were measured at pre-, mid-, end-training, and post-detraining time points using conventional 2D echocardiography. RESULTS: Athletes had larger maximum (27.5 +/- 3.2 vs. 20.3 +/- 5.8 mL/m(2), p = 0.001), pre-P (11.5 +/- 0.9 vs. 9.8 +/- 2.2 mL/m(2), p = 0.001), and minimum (6.6 +/- 0.9 vs. 5.0 +/- 1.2 mL/m(2), p < 0.001) LA indexed volumes, compared with controls. Total and passive emptying volume indices were also larger in athletes compared with controls (18.7 +/- 3.1 vs. 15.3 +/- 4.9 mL/m(2), p < 0.05 and 13.8 +/- 2.9 vs. 10.5 +/- 4.6 mL/m(2), p < 0.05, respectively), while active emptying volume was similar (p = 0.74). During training, LA maximum (p < 0.0001), pre-P (p < 0.0001), minimum (p < 0.0001), total (p < 0.005), and passive (p < 0.05) emptying volume indices progressively increased, while active emptying volume (p = 0.10) and E/e' ratio (p = 0.32) remained unchanged. After detraining, LA volume measurements were not different from pre-training ones. End-training left ventricular mass index was the only independent predictor of the respective maximum LA volume (beta = 0.74, p < 0.005). CONCLUSIONS: Top-level athletes exhibit a dynamic morphological and functional LA remodeling, induced by training, with an increase in reservoir and conduit volumes, but stable active volume. LA remodeling is closely associated with left ventricular adaptation to exercise and both completely regress after detraining. PMID- 25808865 TI - PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy. AB - Whole-exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveals that 5% to 7% of tumors harbor promyelocytic leukemia zinc finger (PLZF) protein homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide-resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways, including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT. This acquired mechanism together with the finding of genetic loss in CRPC implicates PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. PMID- 25808867 TI - MMP16 Mediates a Proteolytic Switch to Promote Cell-Cell Adhesion, Collagen Alignment, and Lymphatic Invasion in Melanoma. AB - Lymphatic invasion and accumulation of continuous collagen bundles around tumor cells are associated with poor melanoma prognosis, but the underlying mechanisms and molecular determinants have remained unclear. We show here that a copy-number gain or overexpression of the membrane-type matrix metalloproteinase MMP16 (MT3 MMP) is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. In cultured WM852 melanoma cells derived from human melanoma metastasis, silencing of MMP16 resulted in cell surface accumulation of the MMP16 substrate MMP14 (MT1-MMP) as well as L1CAM cell adhesion molecule, identified here as a novel MMP16 substrate. When limiting the activities of these trans-membrane protein substrates toward pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP16 supported nodular-type growth of adhesive collagen surrounded melanoma cell nests, coincidentally steering cell collectives into lymphatic vessels. These results uncover a novel mechanism in melanoma pathogenesis, whereby restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, revealing MMP16 as a putative indicator of adverse melanoma prognosis. PMID- 25808866 TI - Development of Resistance to EGFR-Targeted Therapy in Malignant Glioma Can Occur through EGFR-Dependent and -Independent Mechanisms. AB - Epidermal growth factor receptor (EGFR) is highly amplified, mutated, and overexpressed in human malignant gliomas. Despite its prevalence and growth promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Using combined genetic and pharmacologic interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors, although they could efficiently inhibit EGFR* autophosphorylation in vitro and in vivo. This is in contrast with the genetic suppression of EGFR* induction that led to significant tumor regression and prolonged animal survival. However, despite their initial response to genetic EGFR* extinction, all tumors would relapse and propagate independent of EGFR*. We further showed that EGFR*-independent tumor cells existed prior to treatment and were responsible for relapse following genetic EGFR* suppression. And, the addition of a PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our findings shed mechanistic insight into EGFR drug resistance in glioma and provide a platform to test therapies targeting aberrant EGFR signaling in this setting. PMID- 25808869 TI - Manic fringe promotes a claudin-low breast cancer phenotype through notch mediated PIK3CG induction. AB - Claudin-low breast cancer (CLBC) is a poor prognosis disease biologically characterized by stemness and mesenchymal features. These tumors disproportionately affect younger patients and women with African ancestry, causing significant morbidity and mortality, and no effective targeted therapy exists at present. CLBC is thought to originate from mammary stem cells, but little is known on how or why these tumors express a stable epithelial-to mesenchymal transition phenotype, or what are the driving forces of this disease. Here, we report that Manic Fringe (Mfng), which encodes an O-fucosylpeptide 3 beta-N-acetylglucosaminyltransferase known to modify EGF repeats in the Notch extracellular domain, is highly expressed in CLBC and functions as an oncogene in this context. We show that Mfng modulates Notch activation in human and mouse CLBC cell lines, as well as in mouse mammary gland. Mfng silencing in CLBC cell lines reduced cell migration, tumorsphere formation, and in vivo tumorigenicity associated with a decrease in the stem-like cell population. Mfng deletion in the Lfng(flox/flox);MMTV-Cre mouse model, in which one-third of mammary tumors resemble human CLBC, caused a tumor subtype shift away from CLBC. We identified the phosphoinositide kinase Pik3cg as a direct transcriptional target of Mfng facilitated RBPJkappa-dependent Notch signaling. Indeed, pharmacologic inhibition of PI3Kgamma in CLBC cell lines blocked migration and tumorsphere formation. Taken together, our results define Mfng as an oncogene acting through Notch mediated induction of Pik3cg. Furthermore, they suggest that targeting PI3Kgamma may prove beneficial for the treatment of CLBC subtype. PMID- 25808868 TI - Decoy Receptor DcR1 Is Induced in a p50/Bcl3-Dependent Manner and Attenuates the Efficacy of Temozolomide. AB - Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-kappaB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-kappaB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-kappaB1. A conserved NF-kappaB-binding sequence (kappaB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IkappaB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy. PMID- 25808871 TI - Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis. AB - Semaphorins play important regulatory roles in diverse processes such as axon guidance, angiogenesis, and immune responses. We find that semaphorin-3C (sema3C) induces the collapse of the cytoskeleton of lymphatic endothelial cells (LEC) in a neuropilin-2-, plexin-D1-, and plexin-A1-dependent manner, while most other semaphorins, including antiangiogenic semaphorins such as sema3A do not. Sema3C is cleaved, like other class-3 semaphorins, by furin-like pro-protein convertases (FPPC). Cleaved sema3C (p65-Sema3C) was unable to induce the collapse of the cytoskeleton of LEC. FPPC are strongly upregulated in tumor cells. In order to examine the effects of full-length sema3C on tumor progression, we therefore generated an active point mutated furin cleavage-resistant sema3C (FR-sema3C). FR sema3C inhibited potently proliferation of LEC and to a lesser extent proliferation of human umbilical vein-derived endothelial cells. FR-sema3C also inhibited VEGF-C-induced phosphorylation of VEGFR-3, ERK1/2, and AKT. Expression of recombinant FR-sema3C in metastatic, triple-negative LM2-4 breast cancer cells did not affect their migration or proliferation in vitro. However, tumors derived from FR-sema3C-expressing LM2-4 cells implanted in mammary fat pads developed at a slower rate, contained a lower concentration of blood vessels and lymph vessels, and metastasized much less effectively to lymph nodes. Interestingly, p65-Sema3C, but not FR-sema3C, rendered A549 lung cancer cells resistant to serum deprivation, suggesting that previously reported protumorigenic activities of sema3C may be due to p65-Sema3C produced by tumor cells. Our observations suggest that FR-sema3C may be further developed into a novel antitumorigenic drug. PMID- 25808874 TI - A rare case of splenic lymphoma in a patient with polymyositis manifesting as gastric variceal bleeding. AB - We report an unusual case of upper gastrointestinal bleeding due to isolated gastric variceal bleeding in a patient with splenomegaly who was subsequently diagnosed with diffuse large B-cell lymphoma. The patient is a 47-year-old male with a history of polymyositis who presented to the emergency room with complaints of lightheadedness and melena for 2 days. On initial presentation, the patient had positive orthostatic vital signs. He was found to be anemic with presenting hemoglobin of 5.8 g/dl (compared with 13.4 g/dl 4 months prior to presentation). The patient was aggressively resuscitated with intravenous fluid and blood transfusions. An emergency esophagogastroduodenoscopy was performed which showed isolated gastric varices in the fundus of the stomach, with no active bleeding or high-risk stigmata. Abdominal computed tomography revealed focal splenic vein thrombosis and splenomegaly with ill-defined hypodensities. Portal and superior mesenteric veins were patent. Mild edema was seen surrounding the spleen and non-specific abdominal lymphadenopathy was also reported. A surgical consultation recommended an urgent splenectomy. Pathology of the removed spleen revealed diffuse large B-cell lymphoma. Positron emission tomography computed tomography revealed lymphomatous disease in the thorax, abdomen, pelvis and bone marrow. The patient was subsequently started on chemotherapy. PMID- 25808872 TI - Tenascin-C Protects Cancer Stem-like Cells from Immune Surveillance by Arresting T-cell Activation. AB - Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here, we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSCs were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T-cell receptor-dependent T-cell activation, proliferation, and cytokine production. Mechanistically, TNC interacted with alpha5beta1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T-cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system. PMID- 25808873 TI - Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer. AB - Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation. PMID- 25808870 TI - CDK2 Inhibition Causes Anaphase Catastrophe in Lung Cancer through the Centrosomal Protein CP110. AB - Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacologic targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. Mechanisms of CDK2 mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced anaphase catastrophe of lung cancer cells. In contrast, CP110 overexpression antagonized CDK2 inhibitor mediated anaphase catastrophe. Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. Thus, CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe. Independent examination of murine and human paired normal-malignant lung tissues revealed marked upregulation of CP110 in malignant versus normal lung. Human lung cancers with KRAS mutations had significantly lower CP110 expression as compared with KRAS wild-type cancers. Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations. PMID- 25808877 TI - Standards for reporting chronic periodontitis prevalence and severity in epidemiologic studies: Proposed standards from the Joint EU/USA Periodontal Epidemiology Working Group. AB - Periodontal diseases are common and their prevalence varies in different populations. However, prevalence estimates are influenced by the methodology used, including measurement techniques, case definitions, and periodontal examination protocols, as well as differences in oral health status. As a consequence, comparisons between populations are severely hampered and inferences regarding the global variation in prevalence can hardly be drawn. To overcome these limitations, the authors suggest standardized principles for the reporting of the prevalence and severity of periodontal diseases in future epidemiological studies. These principles include the comprehensive reporting of the study design, the recording protocol, and specific subject-related and oral data. Further, a range of periodontal data should be reported in the total population and within specific age groups. Periodontal data include the prevalence and extent of clinical attachment loss (CAL) and probing depth (PD) on site and tooth level according to specific thresholds, mean CAL/PD, the CDC/AAP case definition, and bleeding on probing. Consistent implementation of these standards in future studies will ensure improved reporting quality, permit meaningful comparisons of the prevalence of periodontal diseases across populations, and provide better insights into the determinants of such variation. PMID- 25808876 TI - Ternary metal fluorides as high-energy cathodes with low cycling hysteresis. AB - Transition metal fluorides are an appealing alternative to conventional intercalation compounds for use as cathodes in next-generation lithium batteries due to their extremely high capacity (3-4 times greater than the current state-of the-art). However, issues related to reversibility, energy efficiency and kinetics prevent their practical application. Here we report on the synthesis, structural and electrochemical properties of ternary metal fluorides (M(1)yM(2)(1 y)F(x): M(1), M(2) = Fe, Cu), which may overcome these issues. By substituting Cu into the Fe lattice, forming the solid-solution Cu(y)Fe(1-y)F(2), reversible Cu and Fe redox reactions are achieved with surprisingly small hysteresis (<150 mV). This finding indicates that cation substitution may provide a new avenue for tailoring key electrochemical properties of conversion electrodes. Although the reversible capacity of Cu conversion fades rapidly, likely due to Cu(+) dissolution, the low hysteresis and high energy suggest that a Cu-based fluoride cathode remains an intriguing candidate for rechargeable lithium batteries. PMID- 25808878 TI - Characterization of Listeria monocytogenes from three countries and antibiotic resistance differences among countries and Listeria monocytogenes serogroups. AB - A total of 104 Listeria monocytogenes isolates from 330 fish samples from three countries were characterized by multiplex PCR for serogrouping and virulence markers determination and tested for antibiotics resistance. A 53.8% of the isolates belonged to serogroup 1/2a, 3a; 32% belonged to 1/2b, 3b, 7; 14.4% belonged to 4b, 4d, 4e and 1% belonged to 1/2c, 3c. All isolates exhibited resistance to at least one antibiotic but the resistance rates varied among countries. The isolates exhibited high resistance to penicillin, rifampicin, clindamycin, erythromycin and tetracycline, but low resistance to amoxicillin clavulanic acid, streptomycin, sulfamethoxazole-trimethoprim, gentamicin, chloramphenicol and kanamycin. When comparing countries, the resistance rate for rifampicin, clindamycin, erythromycin, tetracycline, amoxicillin-clavulanic acid varied among countries. When comparing serogroup, 1/2a, 3a exhibited the highest resistance to clindamycin, erythromycin, tetracycline and vancomycin while serogroup 4b, 4d, 4e exhibited the highest resistance to amoxicillin-clavulanic acid. All isolates carried inlA, inlC, inlJ and lmo2672. Listeriolysin S was carried by 42 and 30% of 4b and 1/2b isolates respectively. Significance and impact of the study: This is one of few studies to correlate antibiotic resistance with Listeria monocytogenes serogroups. The study also compared the antibiotic resistance and serogroups of L. monocytogenes isolates from three countries in one single study. The findings of this study will be helpful in improving data on the antibiotics resistance of L. monocytogenes in developing countries and enriches the epidemiological and public health studies of L. monocytogenes. PMID- 25808879 TI - Social networks and links to isolation and loneliness among elderly HCBS clients. AB - OBJECTIVES: The purpose of this study was to explore the network types of HCBS clients based on the structural characteristics of their social networks. We also examined how the network types were associated with social isolation, relationship quality and loneliness. METHOD: Forty personal interviews were carried out with HCBS clients to assess the structure of their social networks as indicated by frequency of contact with children, friends, family and participation in religious and community organizations. Hierarchical cluster analysis was conducted to identify network types. RESULTS: Four network types were found including: family (n = 16), diverse (n = 8), restricted (n = 8) and religious (n = 7). Family members comprised almost half of participants' social networks, and friends comprised less than one-third. Clients embedded in family, diverse and religious networks had significantly more positive relationships than clients embedded in restricted networks. Clients embedded in restricted networks had significantly higher social isolation scores and were lonelier than clients in diverse and family networks. DISCUSSION: The findings suggest that HCBS clients' isolation and loneliness are linked to the types of social networks in which they are embedded. The findings also suggest that clients embedded in restricted networks are at high risk for negative outcomes. PMID- 25808880 TI - Motion-driven electrochromic reactions for self-powered smart window system. AB - The self-powered system is a promising concept for wireless networks due to its independent and sustainable operations without an external power source. To realize this idea, the triboelectric nanogenerator (TENG) was recently invented, which can effectively convert ambient mechanical energy into electricity to power up portable electronics. In this work, a self-powered smart window system was realized through integrating an electrochromic device (ECD) with a transparent TENG driven by blowing wind and raindrops. Driven by the sustainable output of the TENG, the optical properties, especially the transmittance of the ECD, display reversible variations due to electrochemical redox reactions. The maximum transmittance change at 695 nm can be reached up to 32.4%, which is comparable to that operated by a conventional electrochemical potentiostat (32.6%). This research is a substantial advancement toward the practical application of nanogenerators and self-powered systems. PMID- 25808881 TI - Formation of BN Isosteres of Azo Dyes by Ring Expansion of Boroles with Azides. AB - Herein, we present the results of our investigations on the effect of ortho substitution of aryl azides on the ring-expansion reaction of boroles, five membered unsaturated boron heterocycles. These studies led to the isolation of the first 1,2-azaborinine-substituted azo dyes, which are bright yellow solids. One of the derivatives, (E)-2-mesityl-1-(mesityldiazenyl)-3,4,5,6-tetraphenyl-1,2 azaborinine, was found to be unstable in solution and to transform through a Jacobsen-like reaction into an indazole and 1-hydro-1,2-azaborinine. DFT calculations were performed to shed light on possible mechanisms to rationalize the unexpected azo-azaborinine formation and to draw conclusions about the role played by the ortho substituents in the reaction. PMID- 25808882 TI - Medical Disaster: Why Ken Mattingly Can't Have Measles in Apollo 13. AB - The film Apollo 13 depicts denial of illness and refusal of health care as key components of American masculinity. In the film, male astronauts and mission controllers deny vulnerability to measles and to urinary infections, as well as the need to sleep, to prove their manliness. This is symbolized by their ridicule of flight surgeon Dr. Chuck. Conversely, the astronauts' wives are depicted admitting vulnerability, especially insomnia. Thus, the film exploits and reinforces existing strands of American culture that view admission of illness and help-seeking as appropriate for women but not men, reinforcing denial and noncompliance as desirable male behaviors. PMID- 25808883 TI - Review of the Safety and Efficacy of Moringa oleifera. AB - Moringa oleifera leaves, seeds, bark, roots, sap, and flowers are widely used in traditional medicine, and the leaves and immature seed pods are used as food products in human nutrition. Leaf extracts exhibit the greatest antioxidant activity, and various safety studies in animals involving aqueous leaf extracts indicate a high degree of safety. No adverse effects were reported in association with human studies. Five human studies using powdered whole leaf preparations of M. oleifera have been published, which have demonstrated anti-hyperglycemic (antidiabetic) and anti-dyslipidemic activities. These activities have been confirmed using extracts as well as leaf powders in animal studies. A rapidly growing number of published studies have shown that aqueous, hydroalcohol, or alcohol extracts of M. oleifera leaves possess a wide range of additional biological activities including antioxidant, tissue protective (liver, kidneys, heart, testes, and lungs), analgesic, antiulcer, antihypertensive, radioprotective, and immunomodulatory actions. A wide variety of polyphenols and phenolic acids as well as flavonoids, glucosinolates, and possibly alkaloids is believed to be responsible for the observed effects. Standardization of products is an issue. However, the results of published studies to date involving M. oleifera are very promising. Additional human studies using standardized extracts are highly desirable. PMID- 25808885 TI - Biodiversity gains from efficient use of private sponsorship for flagship species conservation. AB - To address the global extinction crisis, both efficient use of existing conservation funding and new sources of funding are vital. Private sponsorship of charismatic 'flagship' species conservation represents an important source of new funding, but has been criticized as being inefficient. However, the ancillary benefits of privately sponsored flagship species conservation via actions benefiting other species have not been quantified, nor have the benefits of incorporating such sponsorship into objective prioritization protocols. Here, we use a comprehensive dataset of conservation actions for the 700 most threatened species in New Zealand to examine the potential biodiversity gains from national private flagship species sponsorship programmes. We find that private funding for flagship species can clearly result in additional species and phylogenetic diversity conserved, via conservation actions shared with other species. When private flagship species funding is incorporated into a prioritization protocol to preferentially sponsor shared actions, expected gains can be more than doubled. However, these gains are consistently smaller than expected gains in a hypothetical scenario where private funding could be optimally allocated among all threatened species. We recommend integrating private sponsorship of flagship species into objective prioritization protocols to sponsor efficient actions that maximize biodiversity gains, or wherever possible, encouraging private donations for broader biodiversity goals. PMID- 25808886 TI - The forgotten flies: the importance of non-syrphid Diptera as pollinators. AB - Bees, hoverflies and butterflies are taxa frequently studied as pollinators in agricultural and conservation contexts. Although there are many records of non syrphid Diptera visiting flowers, they are generally not regarded as important pollinators. We use data from 30 pollen-transport networks and 71 pollinator visitation networks to compare the importance of various flower-visiting taxa as pollen-vectors. We specifically compare non-syrphid Diptera and Syrphidae to determine whether neglect of the former in the literature is justified. We found no significant difference in pollen-loads between the syrphid and non-syrphid Diptera. Moreover, there was no significant difference in the level of specialization between the two groups in the pollen-transport networks, though the Syrphidae had significantly greater visitation evenness. Flower visitation data from 33 farms showed that non-syrphid Diptera made up the majority of the flower-visiting Diptera in the agricultural studies (on average 82% abundance and 73% species richness), and we estimate that non-syrphid Diptera carry 84% of total pollen carried by farmland Diptera. As important pollinators, such as bees, have suffered serious declines, it would be prudent to improve our understanding of the role of non-syrphid Diptera as pollinators. PMID- 25808884 TI - Post-determined emotion: motor action retrospectively modulates emotional valence of visual images. AB - Upward and downward motor actions influence subsequent and ongoing emotional processing in accordance with a space-valence metaphor: positive is up/negative is down. In this study, we examined whether upward and downward motor actions could also affect previous emotional processing. Participants were shown an emotional image on a touch screen. After the image disappeared, they were required to drag a centrally located dot towards a cued area, which was either in the upper or lower portion of the screen. They were then asked to rate the emotional valence of the image using a 7-point scale. We found that the emotional valence of the image was more positive when the cued area was located in the upper portion of the screen. However, this was the case only when the dragging action was required immediately after the image had disappeared. Our findings suggest that when somatic information that is metaphorically associated with an emotion is linked temporally with a visual event, retrospective emotional integration between the visual and somatic events occurs. PMID- 25808887 TI - Predator experience overrides learned aversion to heterospecifics in stickleback species pairs. AB - Predation risk can alter female mating decisions because the costs of mate searching and selecting attractive mates increase when predators are present. In response to predators, females have been found to plastically adjust mate preference within species, but little is known about how predators alter sexual isolation and hybridization among species. We tested the effects of predator exposure on sexual isolation between benthic and limnetic threespine sticklebacks (Gasterosteus spp.). Female discrimination against heterospecific mates was measured before and after females experienced a simulated attack by a trout predator or a control exposure to a harmless object. In the absence of predators, females showed increased aversion to heterospecifics over time. We found that predator exposure made females less discriminating and precluded this learned aversion to heterospecifics. Benthic and limnetic males differ in coloration, and predator exposure also affected sexual isolation by weakening female preferences for colourful males. Predator effects on sexual selection were also tested but predators had few effects on female choosiness among conspecific mates. Our results suggest that predation risk may disrupt the cognitive processes associated with mate choice and lead to fluctuations in the strength of sexual isolation between species. PMID- 25808888 TI - Elucidating the significance of spatial memory on movement decisions by African savannah elephants using state-space models. AB - Spatial memory facilitates resource acquisition where resources are patchy, but how it influences movement behaviour of wide-ranging species remains to be resolved. We examined African elephant spatial memory reflected in movement decisions regarding access to perennial waterholes. State-space models of movement data revealed a rapid, highly directional movement behaviour almost exclusively associated with visiting perennial water. Behavioural change point (BCP) analyses demonstrated that these goal-oriented movements were initiated on average 4.59 km, and up to 49.97 km, from the visited waterhole, with the closest waterhole accessed 90% of the time. Distances of decision points increased when switching to different waterholes, during the dry season, or for female groups relative to males, while selection of the closest waterhole decreased when switching. Overall, our analyses indicated detailed spatial knowledge over large scales, enabling elephants to minimize travel distance through highly directional movement when accessing water. We discuss the likely cognitive and socioecological mechanisms driving these spatially precise movements that are most consistent with our findings. By applying modern analytic techniques to high resolution movement data, this study illustrates emerging approaches for studying how cognition structures animal movement behaviour in different ecological and social contexts. PMID- 25808889 TI - Susceptibility of amphibians to chytridiomycosis is associated with MHC class II conformation. AB - The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) can cause precipitous population declines in its amphibian hosts. Responses of individuals to infection vary greatly with the capacity of their immune system to respond to the pathogen. We used a combination of comparative and experimental approaches to identify major histocompatibility complex class II (MHC-II) alleles encoding molecules that foster the survival of Bd-infected amphibians. We found that Bd resistant amphibians across four continents share common amino acids in three binding pockets of the MHC-II antigen-binding groove. Moreover, strong signals of selection acting on these specific sites were evident among all species co existing with the pathogen. In the laboratory, we experimentally inoculated Australian tree frogs with Bd to test how each binding pocket conformation influences disease resistance. Only the conformation of MHC-II pocket 9 of surviving subjects matched those of Bd-resistant species. This MHC-II conformation thus may determine amphibian resistance to Bd, although other MHC-II binding pockets also may contribute to resistance. Rescuing amphibian biodiversity will depend on our understanding of amphibian immune defence mechanisms against Bd. The identification of adaptive genetic markers for Bd resistance represents an important step forward towards that goal. PMID- 25808893 TI - All roads lead to Rome, even in African savannah elephants--or do they? PMID- 25808890 TI - Tracing the genetic origin of Europe's first farmers reveals insights into their social organization. AB - Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis is yet unclear. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starcevo and LBK sites (seventh/sixth millennia BC) from the Carpathian Basin and southeastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early southeastern European and Carpathian Basin farming cultures on Central European populations of the sixth fourth millennia BC. Comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through southeastern Europe and the Carpathian Basin into Central Europe. However, our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting a system of patrilineal descent and patrilocal residential rules among the early farmers. PMID- 25808891 TI - Na+/K+-ATPase resistance and cardenolide sequestration: basal adaptations to host plant toxins in the milkweed bugs (Hemiptera: Lygaeidae: Lygaeinae). AB - Despite sequestration of toxins being a common coevolutionary response to plant defence in phytophagous insects, the macroevolution of the traits involved is largely unaddressed. Using a phylogenetic approach comprising species from four continents, we analysed the ability to sequester toxic cardenolides in the hemipteran subfamily Lygaeinae, which is widely associated with cardenolide producing Apocynaceae. In addition, we analysed cardenolide resistance of their Na(+)/K(+)-ATPases, the molecular target of cardenolides. Our data indicate that cardenolide sequestration and cardenolide-resistant Na(+)/K(+)-ATPase are basal adaptations in the Lygaeinae. In two species that shifted to non-apocynaceous hosts, the ability to sequester was secondarily reduced, yet Na(+)/K(+)-ATPase resistance was maintained. We suggest that both traits evolved together and represent major coevolutionary adaptations responsible for the evolutionary success of lygaeine bugs. Moreover, specialization on cardenolides was not an evolutionary dead end, but enabled this insect lineage to host shift to cardenolide-producing plants from distantly related families. PMID- 25808894 TI - The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach? AB - Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and tipically affecting a variety of bodily systems including the immune system. Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system. Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients. Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration. This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting. PMID- 25808892 TI - Binding space and time through action. AB - Space and time are intimately coupled dimensions in the human brain. Several lines of evidence suggest that space and time are processed by a shared analogue magnitude system. It has been proposed that actions are instrumental in establishing this shared magnitude system. Here we provide evidence in support of this hypothesis, by showing that the interaction between space and time is enhanced when magnitude information is acquired through action. Participants observed increases or decreases in the height of a visual bar (spatial magnitude) while judging whether a simultaneously presented sequence of acoustic tones had accelerated or decelerated (temporal magnitude). In one condition (Action), participants directly controlled the changes in bar height with a hand grip device, whereas in the other (No Action), changes in bar height were externally controlled but matched the spatial/temporal profile of the Action condition. The sign of changes in bar height biased the perceived rate of the tone sequences, where increases in bar height produced apparent increases in tone rate. This effect was amplified when the visual bar was actively controlled in the Action condition, and the strength of the interaction was scaled by the magnitude of the action. Subsequent experiments ruled out that this was simply explained by attentional factors, and additionally showed that a monotonic mapping is also required between grip force and bar height in order to bias the perception of the tones. These data provide support for an instrumental role of action in interfacing spatial and temporal quantities in the brain. PMID- 25808895 TI - Monoamine Oxidase Inhibitors Extracted from Tobacco Smoke as Neuroprotective Factors for Potential Treatment of Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of mainly the nigrostriatal dopaminergic neurons, which leads to motor dysfunction. Although, most of the drugs are currently used for symptomatic treatment, there are at least three FDA-approved drugs for the treatment of PD that have been suggested preclinically to have neuroprotective effects. Among these drugs are monoamine oxidase (MAO) type B inhibitors such as selegiline and rasagiline, and non-ergot derivative dopamine agonist, pramipexole. In this review article, we focused on the potential uses of non-selective reversible MAO inhibitor, 2,3,6-trimethyl-1,4-naphthoquinone, from flue-cured tobacco leaves extract and two beta- carboline alkaloids (harman and norharman) as potent, reversible and non-selective MAO inhibitors for the treatment of PD. In addition, we discussed the potential uses of farnesol as a potent inhibitor of MAO-B and farnesylacetone as a less potent selective MAO-B inhibitor. Furthermore, adducts of 1,2,3,4-tetrahydroisoquinoline have shown to have competitive inhibitory effects for both MAO-A and MAO-B. These inhibitors have potential neuroprotective effects, which might be mediated at least through nerve growth factor, neurotrophin 3, brain derived neurotrophic factor, and glial-cell-line-derived neurotrophic factor. We suggest here the neuroprotective implication of extracted MAO inhibitors from smoke tobacco; however, it is important to note that there are several existing compounds in tobacco smoke that have toxic effects in the brain, these include and not limited to the induction of neuropathological features observed in individuals suffering from Alzheimer's disease and dementia. PMID- 25808896 TI - Improvement of Depression and Anxiety After Discontinuation of Long- Term Efavirenz Treatment. AB - Neuropsychiatric symptoms in human immunodeficiency virus (HIV)-infected patients may be a late complication of efavirenz treatment. This study: 1) assessed the level of neuropsychiatric symptoms in HIV-infected patients on long-term efavirenz therapy; 2) explored the effect of a switch to non-efavirenz containing anti-retroviral treatment on neuropsychiatric symptoms. A consecutive series of 47 HIV-infected participants on long-term efavirenz treatment were included in an observational clinical trial. Participants completed three self-report questionnaires on neuropsychiatric symptoms. Patients switching to a non efavirenz regimen were retested 2 weeks and 3 months after switching. Data were analyzed using repeated measures ANOVA to assess the effect of switching over time. A change in the percentage of patients scoring above norm scores after switching was analyzed using Chi square. Neuropsychiatric symptoms were common among HIV-infected patients on long-term efavirenz therapy, mainly depression, anxiety, stress, insufficiency in thinking and paranoia. After switching, these symptoms improved significantly to (near) normal levels. Our results show that neuropsychiatric symptoms are common among HIV-infected subjects and may be caused by long-term efavirenz use. Neuropsychiatric assessment, such as the Depression, Anxiety and Stress scale and Symptom Checklist 90, can identify those that may benefit from the discontinuation of efavirenz. PMID- 25808897 TI - Peroxisome Proliferator Activated Receptor Gamma Coactivator 1 Alpha: An Emerging Target for Neuroprotection in Parkinson's Disease. AB - Mutations in mitochondrial genes, oxidative insults, imbalance in redox mechanisms and dysregulated mitophagy are some of the leading causes for mitochondrial dysfunction and subsequent neurodegeneration in Parkinson's disease. Targeting mitochondrial dysfunction and prolonging neuronal survival could potentially prove to be useful neuroprotective strategies. In some recent investigations, peroxisome proliferator activated receptor gamma coactivator 1 alpha mediated mitochondrial biogenesis and its ability to restore reactive oxygen species-detoxifying enzymes have been observed in preclinical studies. In this review, we discuss about physiological importance of peroxisome proliferator activated receptor gamma coactivator 1 alpha along with a list of its activators that could prove useful as possible neuroprotectants in Parkinson's disease. PMID- 25808899 TI - The causes of variation in the presence of genetic covariance between sexual traits and preferences. AB - Mating traits and mate preferences often show patterns of tight correspondence across populations and species. These patterns of apparent coevolution may result from a genetic association between traits and preferences (i.e. trait-preference genetic covariance). We review the literature on trait-preference covariance to determine its prevalence and potential biological relevance. Of the 43 studies we identified, a surprising 63% detected covariance. We test multiple hypotheses for factors that may influence the likelihood of detecting this covariance. The main predictor was the presence of genetic variation in mate preferences, which is one of the three main conditions required for the establishment of covariance. In fact, 89% of the nine studies where heritability of preference was high detected covariance. Variables pertaining to the experimental methods and type of traits involved in different studies did not greatly influence the detection of trait preference covariance. Trait-preference genetic covariance appears to be widespread and therefore represents an important and currently underappreciated factor in the coevolution of traits and preferences. PMID- 25808898 TI - Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study. AB - Recent cross-sectional studies suggest an important role for transitional B lymphocytes (CD19 + CD24hiCD38hi) in promoting transplant tolerance, and protecting from late antibody-mediated rejection (ABMR). However, prospective studies are lacking. This study enrolled 73 de novo transplant recipients, and collected serial clinical, immunological and biochemical information over 48 +/- 6 months. Cell phenotyping was conducted immediately prior to transplantation, and then on five occasions during the first year posttransplantation. When modeled as a time-dependent covariate, transitional B cell frequencies (but not total B cells or "regulatory" T cells) were associated with protection from acute rejection (any Banff grade; HR: 0.60; 95% CI: 0.37-0.95; p = 0.03). No association between transitional B cell proportions and either de novo donor specific or nondonor-specific antibody (dnDSA; dnNDSA) formation was evident, although preserved transitional B cell proportions were associated with reduced rejection rates in those patients developing dnDSA. Three episodes of ABMR occurred, all in the context of nonadherence, and all associated with in vitro anti-HLA T cell responses in an ELISPOT assay (p = 0.008 versus antibody-positive patients not experiencing ABMR). This prospective study supports the potential relevance of transitional ("regulatory") B cells as a biomarker and therapeutic intervention in transplantation, and highlights relationships between humoral immunity, cellular immunity and nonadherence. PMID- 25808900 TI - Hypersexuality and high sexual desire: exploring the structure of problematic sexuality. AB - INTRODUCTION: The concept of hypersexuality has been accompanied by fierce debates and conflicting conclusions about its nature. One of the central questions under the discussion is a potential overlap between hypersexuality and high sexual desire. With the relevant research in its early phase, the structure of hypersexuality remains largely unknown. AIM: The aim of the present study was to systematically explore the overlap between problematic sexuality and high sexual desire. METHODS: A community online survey was carried out in Croatia in 2014. The data were first cluster analyzed (by gender) based on sexual desire, sexual activity, perceived lack of control over one's sexuality, and negative behavioral consequences. Participants in the meaningful clusters were then compared for psychosocial characteristics. To complement cluster analysis (CA), multigroup confirmatory factor analysis (CFA) of the same four constructs was carried out. MAIN OUTCOME MEASURES: Indicators representing the proposed structure of hypersexuality were included: sexual desire, frequency of sexual activity, lack of control over one's sexuality, and negative behavioral outcomes. Psychosocial characteristics such as religiosity, attitudes toward pornography, and general psychopathology were also evaluated. RESULTS: CA pointed to the existence of two meaningful clusters, one representing problematic sexuality, that is, lack of control over one's sexuality and negative outcomes (control/consequences cluster), and the other reflecting high sexual desire and frequent sexual activity (desire/activity cluster). Compared with the desire/activity cluster, individuals from the control/consequences cluster reported more psychopathology and were characterized by more traditional attitudes. Complementing the CA findings, CFA pointed to two distinct latent dimensions-problematic sexuality and high sexual desire/activity. CONCLUSION: Our study supports the distinctiveness of hypersexuality and high sexual desire/activity, suggesting that problematic sexuality might be more associated with the perceived lack of personal control over sexuality and moralistic attitudes than with high levels of sexual desire and activity. PMID- 25808901 TI - Doxorubicin interactions with bovine serum albumin revealed by microdialysis with on-line laser-induced fluorescence detection at subpicogram level. AB - Doxorubicin (DOX) is an effective antitumor drug employed for treatment of a wide range of cancers types such as neuroblastoma, osteosarcoma, breast and esophageal carcinomas. On the other hand, the cumulative dose is restricted (300-550 mg/m(2)) and its amount administered to a patient has to be closely controlled due to its cardiotoxicity. To understand the mechanisms of the DOX side effects as well as to reveal the ways how to reduce its adverse impact on cardiomyocytes, the interactions with particular components of the blood and tissues have to be studied in greater detail. In this work, microdialysis technique was optimized to extract DOX from samples and subsequently monitor its interaction with BSA. Finally, the microdialysis probe was connected on-line to the LIF detector to ensure the real-time detection. The best flow rate was 1 MUL/min and after 120 min of microdialysis 28% of the DOX was dialyzed out from the sample. The results from investigation of the DOX-BSA interaction indicate that the interaction occurs in less than 30 min, causing marked decrease in the amount of DOX extracted by microdialysis. PMID- 25808904 TI - Integrative network analysis: bridging the gap between Western medicine and traditional Chinese medicine. PMID- 25808903 TI - Physical activity, sleep duration and metabolic health in children fluctuate with the lunar cycle: science behind the myth. AB - Behaviours of several animal species have been linked to lunar periodicity. Evidence for such links in humans is weak; however, recently, shorter sleep duration was reported around full moon in two small samples of adults. As restrictions in sleep duration have been shown to adversely affect glucose regulation and physical activity to improve glucose regulation, one could speculate that cardiometabolic risk factors might also be affected by the lunar phase. We retrospectively examined 795 Danish children, aged 8-11 years, with more than 13,000 24-h accelerometer recordings of activity and sleep as well as 2000 measurements of different cardiometabolic risk factors, including insulin sensitivity, appetite hormones and blood pressure, during nine lunar phases. During the period around full moon, children were 5.0 and 3.2 min per day less active, slept 2.4 and 4.1 min per night longer, had 0.03 and 0.05 higher homeostatic model assessment of insulin resistance and 0.6 and 0.8 mmHg higher mean arterial blood pressure compared with days around half moon and new moon, respectively (all P <= 0.02). Furthermore, ghrelin was lower and leptin was higher during the period around full moon compared with days around half moon (both P < 0.001). The results suggest that physical activity rather than sleep is responsible for the metabolic alterations observed around full moon. However, we have no understanding of potential mechanisms that may mediate a potential true link between childhood behaviour and the lunar cycle or confounders that may explain this, apparently leading to fluctuation in a number of cardiometabolic risk markers conjointly with lunar phases. PMID- 25808902 TI - Molecular evolution of the CYP2D subfamily in primates: purifying selection on substrate recognition sites without the frequent or long-tract gene conversion. AB - The human cytochrome P450 (CYP) 2D6 gene is a member of the CYP2D gene subfamily, along with the CYP2D7P and CYP2D8P pseudogenes. Although the CYP2D6 enzyme has been studied extensively because of its clinical importance, the evolution of the CYP2D subfamily has not yet been fully understood. Therefore, the goal of this study was to reveal the evolutionary process of the human drug metabolic system. Here, we investigate molecular evolution of the CYP2D subfamily in primates by comparing 14 CYP2D sequences from humans to New World monkey genomes. Window analysis and statistical tests revealed that entire genomic sequences of paralogous genes were extensively homogenized by gene conversion during molecular evolution of CYP2D genes in primates. A neighbor-joining tree based on genomic sequences at the nonsubstrate recognition sites showed that CYP2D6 and CYP2D8 genes were clustered together due to gene conversion. In contrast, a phylogenetic tree using amino acid sequences at substrate recognition sites did not cluster the CYP2D6 and CYP2D8 genes, suggesting that the functional constraint on substrate specificity is one of the causes for purifying selection at the substrate recognition sites. Our results suggest that the CYP2D gene subfamily in primates has evolved to maintain the regioselectivity for a substrate hydroxylation activity between individual enzymes, even though extensive gene conversion has occurred across CYP2D coding sequences. PMID- 25808905 TI - A systematic literature review on the effectiveness of eurythmy therapy. AB - BACKGROUND: Eurythmy therapy is a movement therapy of anthroposophic medicine that can have effects on a person's physical body, spirit, and soul. OBJECTIVE: The aim of this publication was to update and summarize the relevant literature on the effectiveness of eurythmy in a therapeutic context since 2008. SEARCH STRATEGY: Different databases like PubMed, MEDPILOT, Research Gate, The Cochrane Library, DIMDI, Arthe and also the journal databases Der Merkurstab and the European Journal of Integrative Medicine were searched for prospective and retrospective clinical trials in German or English language. INCLUSION CRITERIA: There were no limitations for indication, considered outcome or age of participants. DATA EXTRACTION AND ANALYSIS: Studies were evaluated with regard to their description of the assembly process and treatment, adequate reporting of follow-ups, and equality of comparison groups in controlled trials. RESULTS: Eleven studies met the inclusion criteria. These included two single-arm, non controlled pilot studies, two publications on the same non-randomized controlled trial and one case study; six further studies referred to a prospective cohort study, the Anthroposophic Medicine Outcome Study. Most of these studies described positives treatment effects with varying effect sizes. The studies were heterogynous according to the indications, age groups, study design and measured outcome. The methodological quality of the studies varied considerably. There were no clear improvements since 2008, when the recommendations were published in the first review. CONCLUSION: Eurythmy seems to be a beneficial add-on in a therapeutic context that can improve the health conditions of affected persons. More methodologically sound studies are needed to substantiate this positive impression. PMID- 25808907 TI - Detection of early cartilage deterioration associated with meniscal tear using T1rho mapping magnetic resonance imaging. AB - BACKGROUND: In patients with degenerative meniscal tears, subclinical cartilage degeneration may be present even if gross morphological changes are not evident. The aim of this study was to detect occult cartilage degeneration using T1rho MRI mapping in patients with meniscal tears without obvious radiographic osteoarthritis (OA). METHODS: A total of 22 subjects with degenerative meniscal tears in the early stages of osteoarthritis [Kellgren-Lawrence (KL) grade of 0-2] and 19 healthy subjects as the control group were examined. The femoral condyle was divided into four 30 degrees wedges (-30 degrees -0 degrees anteriorly, 0 degrees -30 degrees , 30 degrees -60 degrees and 60 degrees -90 degrees posteriorly), and each area of cartilage was further divided into superficial and deep layers of equal thickness. The tibial side was divided into anterior and posterior areas with superficial and deep layers in each. The mean T1rho values (ms) in each area were calculated. RESULTS: On the femoral side, T1rho values of the superficial and deep regions (-30 degrees -0 degrees , 0 degrees -30 degrees and 30 degrees -60 degrees ) in the meniscal tear group were significantly higher than those in the control group [superficial (-30 degrees -0 degrees ): 49.0 +/- 4.0 (meniscal tear group) vs 45.1 +/- 2.1 (control group), deep (-30 degrees -0 degrees ): 45.2 +/- 3.3 vs 39.5 +/- 5.0, superficial (0 degrees -30 degrees ): 54.5 +/- 5.3 vs 47.4 +/- 5.7, deep (0 degrees -30 degrees ): 46.8 +/- 4.0 vs 40.7 +/- 6.3, superficial (30 degrees -60 degrees ): 50.5 +/- 3.1 vs 47.1 +/- 5.7]. On the tibial side, the meniscal tear group had significantly higher T1rho values superficially in both anterior and posterior regions compared with the control group [superficial (anterior): 52.0 +/- 4.3 vs 46.7 +/- 5.4, superficial (posterior): 53.1 +/- 5.1 vs 46.0 +/- 4.9]. Moreover, these significant differences were observed when comparing patients in the meniscal tear group with KL grades of 0 or 1 and the control group. CONCLUSIONS: Our study suggested that early biochemical changes in cartilage associated with degenerative meniscal tears occur first in the superficial zones in areas of contact during slight flexion. Characterising the early relationship between cartilage degeneration and degenerative meniscal tears using T1rho MRI mapping may be of clinical benefit and provide further evidence linking meniscal injury to OA. PMID- 25808908 TI - Determining the authenticity of athlete urine in doping control by DNA analysis. AB - The integrity of urine samples collected from athletes for doping control is essential. The authenticity of samples may be contested, leading to the need for a robust sample identification method. DNA typing using short tandem repeats (STR) can be used for identification purposes, but its application to cellular DNA in urine has so far been limited. Here, a reliable and accurate method is reported for the successful identification of urine samples, using reduced final extraction volumes and the STR multiplex kit, Promega(r) PowerPlex ESI 17, with capillary electrophoretic characterisation of the alleles. Full DNA profiles were obtained for all samples (n = 20) stored for less than 2 days at 4 degrees C. The effect of different storage conditions on yield of cellular DNA and probability of obtaining a full profile were also investigated. Storage for 21 days at 4 degrees C resulted in allelic drop-out in some samples, but the random match probabilities obtained demonstrate the high power of discrimination achieved through targeting a large number of STRs. The best solution for long term storage was centrifugation and removal of supernatant prior to freezing at 20 degrees C. The method is robust enough for incorporation into current anti doping protocols, and was successfully applied to 44 athlete samples for anti doping testing with 100% concordant typing. PMID- 25808906 TI - Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer's disease. AB - Sporadic Alzheimer's disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid beta- (Abeta(1-42)) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (<=3 months/acute, >=3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (>=1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Abeta(1-42) accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Abeta(1-42) positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD. PMID- 25808910 TI - Living related transplantation for MSUD--caution, or a new path forward? PMID- 25808911 TI - Pursuing distributive justice in pediatric lung transplantation. PMID- 25808909 TI - Magnetoencephalography Slow-Wave Detection in Patients with Mild Traumatic Brain Injury and Ongoing Symptoms Correlated with Long-Term Neuropsychological Outcome. AB - Mild traumatic brain injury (mTBI) is common in the United States, accounting for as many as 75-80% of all TBIs. It is recognized as a significant public health concern, but there are ongoing controversies regarding the etiology of persistent symptoms post-mTBI. This constellation of nonspecific symptoms is referred to as postconcussive syndrome (PCS). The present study combined results from magnetoencephalography (MEG) and cognitive assessment to examine group differences and relationships between brain activity and cognitive performance in 31 military and civilian individuals with a history of mTBI+PCS and 33 matched healthy control subjects. An operator-free analysis was used for MEG data to increase reliability of the technique. Subjects completed a comprehensive neuropsychological assessment, and measures of abnormal slow-wave activity from MEG were collected. Results demonstrated significant group differences on measures of executive functioning and processing speed. In addition, significant correlations between slow-wave activity on MEG and patterns of cognitive functioning were found in cortical areas, consistent with cognitive impairments on exams. Results provide more objective evidence that there may be subtle changes to the neurobiological integrity of the brain that can be detected by MEG. Further, these findings suggest that these abnormalities are associated with cognitive outcomes and may account, at least in part, for long-term PCS in those who have sustained an mTBI. PMID- 25808912 TI - Comparative analysis of the antioxidant properties of Icelandic and Hawaiian lichens. AB - Antioxidant activity of symbiotic organisms known as lichens is an intriguing field of research because of its strong contribution to their ability to withstand extremes of physical and biological stress (e.g. desiccation, temperature, UV radiation and microbial infection). We present a comparative study on the antioxidant activities of 76 Icelandic and 41 Hawaiian lichen samples assessed employing the DPPH- and FRAP-based antioxidant assays. Utilizing this unprecedented sample size, we show that while highest individual sample activity is present in the Icelandic dataset, the overall antioxidant activity is higher for lichens found in Hawaii. Furthermore, we report that lichens from the genus Peltigera that have been described as strong antioxidant producers in studies on Chinese, Russian and Turkish lichens also show high antioxidant activities in both Icelandic and Hawaiian lichen samples. Finally, we show that opportunistic sampling of lichens in both Iceland and Hawaii will yield high numbers of lichen species that exclusively include green algae as photobiont. PMID- 25808913 TI - Schizophrenia and hallucinogen persisting perception disorder: A clinical investigation. AB - BACKGROUND AND OBJECTIVES: We compared characteristics of schizophrenia patients with prior LSD use who developed hallucinogen persisting perception disorder (SCH+HPPD) with those who did not (SCH-HPPD). METHODS: Data were collected for 37 subjects in the SCH+HPPD group and 43 subjects in the SCH-HPPD group. RESULTS: Socio-demographics and positive symptom scores were similar between groups. Individuals in the SCHIZO+HPPD group scored lower on general psychopathology and negative symptoms scores. DISCUSSION AND CONCLUSIONS: Individuals with schizophrenia and HPPD present with less severe psychopathology, despite persistent perceptual disturbances. SCIENTIFIC SIGNIFICANCE: Our findings highlight the importance of further research into this subset of patients. PMID- 25808914 TI - Four-stage dissolved oxygen strategy based on multi-scale analysis for improving spinosad yield by Saccharopolyspora spinosa ATCC49460. AB - Dissolved oxygen (DO) is an important influencing factor in the process of aerobic microbial fermentation. Spinosad is an aerobic microbial-derived secondary metabolite. In our study, spinosad was used as an example to establish a DO strategy by multi-scale analysis, which included a reactor, cell and gene scales. We changed DO conditions that are related to the characteristics of cell metabolism (glucose consumption rate, biomass accumulation and spinosad production). Consequently, cell growth was promoted by maintaining DO at 40% in the first 24 h and subsequently increasing DO to 50% in 24 h to 96 h. In an in depth analysis of the key enzyme genes (gtt, spn A, spn K and spn O), expression of spinosad and specific Adenosine Triphosphate (ATP), the spinosad yield was increased by regulating DO to 30% within 96 h to 192 h and then changing it to 25% in 192 h to 240 h. Under the four-phase DO strategy, spinosad yield increased by 652.1%, 326.1%, 546.8%, and 781.4% compared with the yield obtained under constant DO control at 50%, 40%, 30%, and 20% respectively. The proposed method provides a novel way to develop a precise DO strategy for fermentation. PMID- 25808915 TI - The role of socio-economic status and perinatal factors in racial disparities in the risk of cerebral palsy. AB - AIM: To determine whether racial disparities in cerebral palsy (CP) risk among US children persist after controlling for socio-economic status (SES) (here indicated by maternal education) and perinatal risk factors. METHOD: A population based birth cohort study was conducted using the Autism and Developmental Disabilities Monitoring Network surveillance and birth data for 8-year-old children residing in multi-county areas in Alabama, Georgia, Missouri, and Wisconsin between 2002 and 2008. The birth cohort comparison group included 458 027 children and the case group included 1570 children with CP, 1202 with available birth records. chi(2) tests were performed to evaluate associations and logistic regression was used to calculate relative risks (RR) and adjusted odds ratios (OR) with 95% confidence intervals (CI). RESULTS: The risk of spastic CP was more than 50% higher for black versus white children (RR 1.52, 95% CI 1.33 1.73), and this greater risk persisted after adjustment for SES (OR 1.35, 95% CI 1.18-1.55), but not after further adjustment for preterm birth and size for gestational age. The protective effect of maternal education remained after adjustment for race/ethnicity and perinatal factors. INTERPRETATION: Maternal education appears to independently affect CP risk but does not fully explain existing racial disparities in CP prevalence in the US. PMID- 25808917 TI - Combination of EUTOS score and 3-month BCR-ABL transcript level identifies a group of good-risk chronic myeloid leukemia patients with favorable response to frontline imatinib therapy. PMID- 25808916 TI - Our 2015 approach to invasive pulmonary aspergillosis. AB - At the University Hospital of Cologne, in general two patient groups at high risk for invasive aspergillosis receive posaconazole prophylaxis: Acute myelogenous leukaemia patients during remission induction chemotherapy and allogeneic haematopoietic stem cell transplant recipients. Other patients at risk undergo serum galactomannan testing three times weekly. At 72-96 h of persisting fever despite broad-spectrum antibiotics, or at onset of lower respiratory tract symptoms a thoracic computed tomography (CT) scan is performed. Without lung infiltrates on CT, IPA is ruled out. In lung infiltrates not suggestive for IPA mycological confirmation is pursued. In patients without posaconazole prophylaxis empiric caspofungin will be considered. CT findings typical for IPA prompt targeted treatment, and mycological confirmation. Bronchoalveolar lavage (BAL) is most important for cultural identification and susceptibility testing, and facilitates diagnosing other pathogens. BAL performance is virtually independent of platelet counts. If despite suggestive infiltrates BAL does not yield the diagnosis, CT-guided biopsy follows as soon as platelet counts allow. Surgery can also be beneficial in diagnosis and treatment of IPA. If the diagnosis of IPA is not established, mucormycosis is a valid concern. In patients with breakthrough IPA during posaconazole prophylaxis liposomal amphotericin B is the drug of choice. If no posaconazole prophylaxis was given, voriconazole is the treatment of choice for IPA. PMID- 25808918 TI - United Network for Organ Sharing regional variations in appeal denial rates with non-standard Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease exceptions: support for a national review board. AB - Although it has been generally recognized that there are inconsistencies among Regional Review Boards in the assignment of points for model for end-stage liver disease (MELD)/pediatric end-stage liver disease (PELD) exception patients with resulting considerable variation in appeal denial rates, data to actually prove this have been limited. We reviewed 6533 MELD/PELD exception applications submitted between 2005 and 2008, calculated the variation in approval/denial rates, and followed these cases through mid-2013 to assess the effects on patient outcomes. We found highly significant regional variations in denial rates for appeals by exception patients and in transplantation rates. The odds of transplant for patients whose appeals are approved is 2.45 times that of patients not approved; that this effect does not vary by region suggests that the variation in transplant rates is driven, at least in part, by the variation in appeal denial rates. Health deterioration or death accounts for more than two thirds of wait list removals among patients removed for reasons other than transplant. Our findings add to the weight of evidence that a national review board that uses current clinical expertise, peer review literature, and data to consistently assign priority could reduce regional inequities and move toward equitable allocation of organs and compliance with the United States Department of Health & Human Services Final Rule. PMID- 25808919 TI - Cell wall composition profiling of parasitic giant dodder (Cuscuta reflexa) and its hosts: a priori differences and induced changes. AB - Host plant penetration is the gateway to survival for holoparasitic Cuscuta and requires host cell wall degradation. Compositional differences of cell walls may explain why some hosts are amenable to such degradation while others can resist infection. Antibody-based techniques for comprehensive profiling of cell wall epitopes and cell wall-modifying enzymes were applied to several susceptible hosts and a resistant host of Cuscuta reflexa and to the parasite itself. Infected tissue of Pelargonium zonale contained high concentrations of de esterified homogalacturonans in the cell walls, particularly adjacent to the parasite's haustoria. High pectinolytic activity in haustorial extracts and high expression levels of pectate lyase genes suggest that the parasite contributes directly to wall remodeling. Mannan and xylan concentrations were low in P. zonale and in five susceptible tomato introgression lines, but high in the resistant Solanum lycopersicum cv M82, and in C. reflexa itself. Knowledge of the composition of resistant host cell walls and the parasite's own cell walls is useful in developing strategies to prevent infection by parasitic plants. PMID- 25808920 TI - delta-Catenin interacts with LEF-1 and negatively regulates its transcriptional activity. AB - delta-Catenin and beta-catenin belong to different subfamilies of armadillo proteins but share some common binding partners, such as E-cadherin. This is the first study that demonstrated a novel common binding partner for delta-catenin and beta-catenin, lymphoid enhancer factor-1 (LEF-1). We found that the N terminus of delta-catenin (amino acids 85-325) bound to the middle region of LEF 1 unlike beta-catenin. Overexpressed delta-catenin entered the nucleus and inhibited LEF-1-mediated transcriptional activity in Bosc23 and DLD-1 cell lines. The current study provided novel insights that will provide a better understanding of the effects of delta-catenin on Wnt/LEF-1-mediated transcriptional activity. PMID- 25808921 TI - Reliable change in neuropsychological assessment of breast cancer survivors. AB - BACKGROUND: The purpose of this study was to enhance the current understanding and interpretation of longitudinal change on tests of neurocognitive function in individuals with cancer. Scores on standard neuropsychological instruments may be impacted by practice effects and other random forms of error. METHODS: The current study assessed the test-retest reliability of several tests and overarching cognitive domains comprising a neurocognitive battery typical of those used for research and clinical evaluation using relevant time frames. Practice effect-adjusted reliable change confidence intervals for test-retest difference scores based on a sample of patient-matched healthy controls are provided. RESULTS: By applying reliable change confidence intervals to scores from two samples of breast cancer patients at post-treatment follow-up assessment, meaningful levels of detectable change in cognitive functioning in breast cancer survivors were ascertained and indicate that standardized neuropsychological instruments may be subject to limitations in detection of subtle cognitive dysfunction over clinically relevant intervals, especially in patient samples with average to above average range baseline functioning. CONCLUSIONS: These results are discussed in relation to reported prevalence of cognitive change in breast cancer patients along with recommendations for study designs that enhance detection of treatment effects. PMID- 25808922 TI - Carbon-Based Sorbents with Three-Dimensional Architectures for Water Remediation. AB - Over the past decade, carbon-based 3D architectures have received increasing attention in science and technology due to their fascinating properties, such as a large surface area, macroscopic bulky shape, and interconnected porous structures, enabling them to be one of the most promising materials for water remediation. This review summarizes the recent development in design, preparation, and applications of carbon-based 3D architectures derived from carbon nanotubes, graphene, biomass, or synthetic polymers for water treatment. After a brief introduction of these materials and their synthetic strategies, their applications in water treatment, such as the removal of oils/organics, ions, and dyes, are summarized. Finally, future perspective directions for this promising field are also discussed. PMID- 25808923 TI - Public Health Nursing Activities: Visible or Invisible? AB - OBJECTIVE: To promote visibility of public health nurses (PHNs), this study identified public health nursing activities and explored PHN perceptions of the impact of their activities on the health of the communities they serve. DESIGN AND SAMPLE: Two surveys with questions focusing on PHN activities were made available electronically. Following the initial survey, the second survey had more detailed questions about PHN activities, including time spent and frequency of activities as well as open-ended questions. Sixty staff level PHNs, representing 29 states, completed the first survey; 49 completed the second survey. MEASURES: Demographic variables and PHN activities were analyzed by population, setting, program, intervention, essential services, and prevention level using descriptive statistics. Themes or categories were determined through a content analysis of responses to three open-ended questions. RESULTS: PHNs reported a wide variety of activities that included: (1) individual/family, community, and systems intervention levels, (2) primary, secondary, and tertiary prevention, and (3) all 10 Public Health Essential Services. PHNs perceived they perform work that is essential for community health. CONCLUSION: PHNs do work that is both visible and invisible. PHNs need to be proactive in promoting all their work to increase the visibility of their contributions to population health. PMID- 25808924 TI - Nutrient Sensing Overrides Somatostatin and Growth Hormone-Releasing Hormone to Control Pulsatile Growth Hormone Release. AB - Pharmacological studies reveal that interactions between hypothalamic inhibitory somatostatin and stimulatory growth hormone-releasing hormone (GHRH) govern pulsatile GH release. However, in vivo analysis of somatostatin and GHRH release into the pituitary portal vasculature and peripheral GH output demonstrates that the withdrawal of somatostatin or the appearance of GHRH into pituitary portal blood does not reliably dictate GH release. Consequently, additional intermediates acting at the level of the hypothalamus and within the anterior pituitary gland are likely to contribute to the release of GH, entraining GH secretory patterns to meet physiological demand. The identification and validation of the actions of such intermediates is particularly important, given that the pattern of GH release defines several of the physiological actions of GH. This review highlights the actions of neuropeptide Y in regulating GH release. It is acknowledged that pulsatile GH release may not occur selectively in response to hypothalamic control of pituitary function. As such, interactions between somatotroph networks, the median eminence and pituitary microvasculature and blood flow, and the emerging role of tanycytes and pericytes as critical regulators of pulsatility are considered. It is argued that collective interactions between the hypothalamus, the median eminence and pituitary vasculature, and structural components within the pituitary gland dictate somatotroph function and thereby pulsatile GH release. These interactions may override hypothalamic somatostatin and GHRH-mediated GH release, and modify pulsatile GH release relative to the peripheral glucose supply, and thereby physiological demand. PMID- 25808927 TI - Development and implementation of a peer mentoring program for early career gerontological faculty. AB - PURPOSE: The Hartford Gerontological Nursing Leaders (HGNL) formerly known as the Building Academic Geriatric Nursing Capacity Initiative (BAGNC), in conjunction with the National Hartford Centers of Gerontological Nursing Excellence (NHCGNE), developed and executed a peer mentoring program beginning in 2011 to enhance both (a) the experience of newly selected scholars and fellows to the NHCGNE and (b) the ongoing professional development of HGNL members. The purpose of this article is to describe key strategies used to develop and execute the peer mentoring program and to present formative program evaluation. DESIGN: The program was launched in January 2011 with seven peer mentor and mentee matches. In June 2012, the peer mentoring committee solicited feedback on the development of the peer mentoring program and changes were made for the subsequent cohorts. FINDINGS: An additional 12 matches were made in the following 2 years (2012 and 2013), for a total of 31 matches to date. We have learned several key lessons from our three cohorts regarding how to structure, implement, and carefully evaluate a peer mentoring program. CONCLUSIONS: Informal evaluation of our peer mentoring program noted several challenges for both peer mentors and mentees. Having knowledge of and addressing those challenges may increase the overall quality and effectiveness of peer mentoring programs and, in turn, benefit academic nursing by strengthening the faculty workforce. CLINICAL RELEVANCE: Findings from development and implementation of a peer mentoring program for gerontological faculty could lead to new and adaptable programs in a variety of clinical and education settings. PMID- 25808925 TI - Effect of Local Sustainable Release of BMP2-VEGF from Nano-Cellulose Loaded in Sponge Biphasic Calcium Phosphate on Bone Regeneration. AB - Bone regeneration is a coordinated process mainly regulated by multiple growth factors. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and bone morphogenetic proteins (BMPs) induce osteogenesis during bone healing process. The aim of this study was to investigate how these growth factors released locally and sustainably from nano-cellulose (NC) simultaneously effect bone formation. A biphasic calcium phosphate (BCP)-NC-BMP2-VEGF (BNBV) scaffold was fabricated for this purpose. The sponge BCP scaffold was prepared by replica method and then loaded with 0.5% NC containing BMP2-VEGF. Growth factors were released from NC in a sustainable manner from 1 to 30 days. BNBV scaffolds showed higher cell attachment and proliferation behavior than the other scaffolds loaded with single growth factors. Bare BCP scaffolds and BNBV scaffolds seeded with rat bone marrow mesenchymal stem cells were implanted ectopically and orthotopically in nude mice for 4 weeks. No typical bone formation was exhibited in BNBV scaffolds in ectopic sites. BMP2 and VEGF showed positive effects on new bone formation in BNBV scaffolds, with and without seeded stem cells, in the orthotopic defects. This study demonstrated that the BNBV scaffold could be beneficial for improved bone regeneration. Stem cell incorporation into this scaffold could further enhance the bone healing process. PMID- 25808928 TI - Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity. AB - The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal-regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, betaarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward betaarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)-dependent ERK pathway via atypical PKC isoforms PKCzeta and PKCiota. PMID- 25808930 TI - PDZ Protein Regulation of G Protein-Coupled Receptor Trafficking and Signaling Pathways. AB - G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membrane-associated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI 3], Na(+)/H(+) exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domain-containing kidney protein 1, and PDZ domain-containing kidney protein 2), Golgi-associated PDZ proteins (Galpha-binding protein interacting protein, C terminus and CFTR-associated ligand), PDZ domain-containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)-homology RhoGEFs (PDZ domain-containing RhoGEF and leukemia-associated RhoGEF), RGS3 and RGS12, spinophilin and neurabin-1, SRC homology 3 domain and multiple ankyrin repeat domain (Shank) proteins (Shank1, Shank2, and Shank3), partitioning defective proteins 3 and 6, multiple PDZ protein 1, Tamalin, neuronal nitric oxide synthase, syntrophins, protein interacting with protein kinase C alpha 1, syntenin-1, and sorting nexin 27. PMID- 25808931 TI - Simultaneous biodegradation of bisphenol A and a biogenic substrate in semi continuous activated sludge reactors. AB - In this work, the simultaneous degradation of BPA and cheese whey (CW) in semi continuous activated sludge reactors was studied. The acclimation process and microbial growth on BPA, CW and BPA + CW were analyzed. In addition, the effect of increasing CW concentration on the BPA degradation by acclimated activated sludge was also studied. In order to reduce the factors involved in the analysis of the simultaneous degradation of BPA and CW, the effect of bisphenol A (BPA) on activated sludge not previously exposed to BPA (native activated sludge) was studied. Results demonstrate that BPA concentrations lower than 40 mg l(-1) had a negligible effect on the growth of native activated sludge. In the semi continuous reactors, the presence of CW increased the acclimation time to 40 mg l(-1) of BPA. Once the capability of degrading BPA was acquired, the removal of BPA was not affected by the presence of CW. Increasing the CW concentration did not affect the removal of BPA by the acclimated activated sludge. Additionally, the CW consumption was not modified by the presence of BPA. Kinetic and stoichiometric coefficients reported in the present work can be useful in developing mathematical models to describe the simultaneous aerobic biodegradation of a biogenic substrate, such as CW, and BPA by activated sludge. PMID- 25808932 TI - Visual inspection is not a substitute for anthropometry in screening for nutritional status and growth in sick children. PMID- 25808933 TI - Androgens, hair loss and eugenics: a tale of discovery and American social history. PMID- 25808934 TI - Relevance of blood cultures in acute pyelonephritis in a single-center retrospective study. AB - Pyelonephritides are frequently encountered diagnosis in Emergency Departments. Urinalyses have a central place in the management of this situation but the usefulness of blood cultures is not clear. We conducted a single-center retrospective study of 24 months to study the microbiological relevance of blood cultures in pyelonephritis. We included patients with blood cultures (BC) and urine cultures (UC) drawn at the same time, if they were not exposed to antibiotics prior to these tests. Of our 264 patients, 39 (15 %) had no bacteriological documentation. There were 83 (31 %) bacteremic patients. Seven patients had contaminated or sterile UC with positive BC. Four patients had positive UC and BC with the latter allowing identification of a pathogen absent from the UC (n = 1) or identifying the main pathogen in three cases. A total of 11 patients theoretically benefited from BC representing 4.2 % of our population. Excluding one patient who was known to be infected with multi-drug resistant bacteria, all empirical antibiotics regimens were effective against the identified pathogens. We did not reveal any significant therapeutic impact of blood cultures in the management of pyelonephritis, when BC and UC are performed before any antimicrobials treatment. PMID- 25808936 TI - What's the diagnosis? Organisational culture and palliative care delivery in residential aged care in New Zealand. AB - Organisational culture has been shown to impact on resident outcomes in residential aged care (RAC). This is particularly important given the growing number of residents with high palliative care needs. The study described herein (conducted from January 2013 to March 2014) examined survey results from a convenience sample of 46 managers, alongside interviews with a purposively selected sample of 23 bereaved family members in order to explore the perceptions of organisational culture within New Zealand RAC facilities in one large urban District Health Board. Results of the Organisational Culture Assessment Instrument (OCAI) completed by managers indicated a preference for a 'Clan' and the structured 'Hierarchy' culture. Bereaved family interviews emphasised both positive and negative aspects of communication, leadership and teamwork, and relationship with residents. Study results from both managers' OCAI survey scores and next of kin interviews indicate that while the RAC facilities are culturally oriented towards providing quality care for residents, they may face barriers to adopting organisational processes supportive of this goal. PMID- 25808929 TI - Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation. AB - The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre- and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation. PMID- 25808937 TI - Physical therapy management for balance deficits in children with hearing impairments: A systematic review. AB - Childhood hearing impairment is a significant problem, associated with long-term academic, communicative and physical impairments. Studies have shown that children with hearing loss also present with balance and/or vestibular deficits along with complain of frequent falls. Various interventions have been studied to improvise postural control and balance in these children on different outcome measures. This review will provide the existing evidence on interventions to improve vestibular and/or balance functions. Three trials met our study criteria with PEDro score >=6, and data were extracted, entered by two independent review authors. Though there was variability with regard to the focus and intensity of the intervention, subject characteristics and in outcome measures, vestibular rehabilitation has a positive influence on functional independence. Heterogeneity in the studies limits the comparisons of intervention programmes. We conclude that there was considerable evidence for a positive effect on balance outcomes among the hearing-impaired population with vestibular deficits. Further investigations of high-quality studies are needed to determine to compare interventions for improving vestibular deficits in hearing-impaired children. PMID- 25808935 TI - Ex vivo investigations on the potential of optical coherence tomography (OCT) as a diagnostic tool for reproductive medicine in a bovine model. AB - Routine infertility investigations in the male and female include imaging techniques such as ultrasonography and endoscopy (fertiloscopy). However, these techniques lack the resolution to localize vital sperm or to reveal detailed morphological analysis of the oviduct which is often the cause of infertility in females. Therefore we set out to evaluate the efficiency of optical coherence tomography (OCT) as a diagnostic imaging tool for micron-scale visualization of the male and female genital tract. Using the bovine as a model, the optical features of the Telesto(TM) , Ganymede(TM) (both Thorlabs) and Niris(TM) (Imalux) OCT imaging systems were compared. PMID- 25808938 TI - Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells. AB - The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy 2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF 7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 +/- 0.71 MUg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis. PMID- 25808941 TI - Bile acid hepatotoxicity: Epigenetics comes to the rescue. PMID- 25808940 TI - Patient-Reported Outcomes After a Switch to a Single-Tablet Regimen of Rilpivirine, Emtricitabine, and Tenofovir DF in HIV-1-Positive, Virologically Suppressed Individuals: Additional Findings From a Randomized, Open-Label, 48 Week Trial. AB - BACKGROUND: Patient-reported outcomes (PROs) can provide important information about treatment tolerability in HIV-1-infected patients. OBJECTIVE: The aim of this study was to evaluate PROs following switching from a boosted protease inhibitor-based regimen to the single-tablet regimen (STR) of rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in the 48 week open-label Switching Boosted PI to Rilpivirine in Combination with Truvada as a Single-Tablet Regimen (SPIRIT) trial. METHODS: In the open-label SPIRIT trial, patients were randomized to receive an STR of RPV/FTC/TDF (n = 317) for 48 weeks or stay on their baseline regimen of a ritonavir-boosted protease inhibitor and two nucleoside/nucleotide analog reverse transcriptase inhibitors (PI + RTV + 2NRTIs, n = 159) for 24 weeks before switching to RPV/FTC/TDF for another 24 weeks. PRO assessments included the HIV Treatment Satisfaction Questionnaire (TSQ) and the HIV Symptom Index Questionnaire (SIQ). RESULTS: At week 24, the mean HIV TSQ improvement from baseline was significantly greater in the RPV/FTC/TDF group than the PI + RTV + 2NRTIs group (p < 0.001). On the HIV SIQ, the percentage of patients reporting a shift from 'symptom' to 'no symptom' was significantly greater with RPV/FTC/TDF treatment compared with PI + RTV + 2NRTIs for all items (all p <= 0.01), with total within-group occurrence of 13/20 symptoms significantly decreasing from baseline for RPV/FTC/TDF patients. In the delayed switch group, significantly fewer patients reported diarrhea and sleep problems at week 48 vs. week 24. CONCLUSIONS: These data suggest that switching to the STR RPV/FTC/TDF from a PI-based multi-pill regimen is associated with greater patient-reported treatment satisfaction and improved tolerability in HIV 1-infected, virologically suppressed individuals. PMID- 25808943 TI - Lamellar ichthyosis with pseudoexon activation in the transglutaminase 1 gene. AB - We report a case of a 12-year-old boy who was born as a collodion baby after which thick scales developed on his entire body surface. His younger brother showed a similar skin condition. Arcuate-shaped, large, brownish scales covered his face with ectropion. His lower legs were also covered with larger thick, brownish, plate-like scales, but other areas were covered with smaller scales. Next-generation sequencing for exons and splice sites detected a stop-gain TGM1 mutation leading to p.R71* in transglutaminase 1 (TG1). Another mutation identified was a cryptic mutation in intron 3 that activated a pseudoexon, which was detected by RNA-based analysis of hair bulbs. The deep intronic mutation caused another truncation mutation, p.N171Tfs(*) 45, in TG1. An in situ TG1 assay demonstrated that TG1 activity was totally lost in this case. Thus, we conclude that the severe phenotype of the patient developed due to those novel compound heterozygous null truncation mutations in TGM1. PMID- 25808944 TI - Simultaneous determination of capecitabine and its three nucleoside metabolites in human plasma by high performance liquid chromatography-tandem mass spectrometry. AB - Capecitabine (Cape) is a prodrug that is metabolized into 5'-deoxy-5 fluorocytidine (DFCR), 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5-FU) after oral administration. A liquid chromatography-tandem mass spectrometry method for the simultaneous determination of capecitabine and its three metabolites in human plasma was developed and validated. The ex vivo conversion of DFCR to DFUR in human blood was investigated and an appropriate blood sample handling condition was recommended. Capecitabine and its metabolites were extracted from 100 MUL of plasma by protein precipitation. Adequate chromatographic retention and efficient separation were achieved on an Atlantis dC18 column under gradient elution. Interferences from endogenous matrix and the naturally occurring heavy isotopic species were avoided. Detection was performed in electrospray ionization mode using a polarity-switching strategy. The method was linear in the range of 10.0-5000 ng/mL for Cape, DFCR, and DFUR, and 2.00-200 ng/mL for 5-FU. The LLOQ was established at 10.0 ng/mL for Cape, DFCR, and DFUR, and 2.00 ng/mL for 5-FU. The inter- and intra-day precisions were less than 13.5%, 11.1%, 9.7%, and 11.4%, and the accuracy was in the range of -13.2% to 1.6%, -2.4% to 2.5%, -7.1% to 8.2%, and -2.0% to 3.8% for Cape, DFCR, DFUR, and 5 FU, respectively. The matrix effect was negligible under the current conditions. The mean extraction recoveries were within 105-115%, 92.6-101%, 94.0-100%, and 85.1-99.9% for Cape, DFCR, DFUR, and 5-FU, respectively. Stability testing showed that the four analytes remained stable under all relevant analytical conditions. This method has been applied to a clinical bioequivalence study. PMID- 25808939 TI - Cerebrospinal fluid Abeta42 levels and APP processing pathway genes in Parkinson's disease. AB - BACKGROUND: Of recent interest is the finding that certain cerebrospinal fluid (CSF) biomarkers traditionally linked to Alzheimer's disease (AD), specifically amyloid beta protein (Abeta), are abnormal in PD CSF. The aim of this exploratory investigation was to determine whether genetic variation within the amyloid precursor protein (APP) processing pathway genes correlates with CSF Abeta42 levels in Parkinson's disease (PD). METHODS: Parkinson's disease (n = 86) and control (n = 161) DNA were genotyped for 19 regulatory region tagging single nucleotide polymorphisms (SNPs) within nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN, and APH1B) involved in the cleavage of APP. The SNP genotypes were tested for their association with CSF biomarkers and PD risk while adjusting for age, sex, and APOE E4 status. RESULTS: Significant correlation with CSF Abeta42 levels in PD was observed for two SNPs, (APP rs466448 and APH1B rs2068143). Conversely, significant correlation with CSF Abeta42 levels in controls was observed for three SNPs (APP rs214484, rs2040273, and PSEN1 rs362344). CONCLUSIONS: In addition, results of this exploratory investigation suggest that an APP SNP and an APH1B SNP are marginally associated with PD CSF Abeta42 levels in APOE E4 noncarriers. Further hypotheses generated include that decreased CSF Abeta42 levels are in part driven by genetic variation in APP processing genes. Additional investigation into the relationship between these findings and clinical characteristics of PD, including cognitive impairment, compared with other neurodegenerative diseases, such as AD, are warranted. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 25808945 TI - Loss of MicroRNA-101 Promotes Epithelial to Mesenchymal Transition in Hepatocytes. AB - Epithelial-to-mesenchymal transition (EMT) has been implicated in embryonic development and various pathological events. However, the involvement of microRNA in the process of EMT remains to be fully defined in hepatocyte. ZEB1 is a well known transcriptional repressor of E-cadherin and plays a major role in triggering EMT during organ fibrosis and cancer cell metastasis. Computational microRNA target predictions detect a conserved sequence matching to miR-101 in the 3'UTR of ZEB1 mRNA. Our results confirm that miR-101 suppresses ZEB1 expression by targeting the predicted site of ZEB1 3'UTR. Subsequent investigations show that miR-101 is significantly downregulated in the cultured hepatocytes undergoing EMT and in the hepatocytes isolated from fibrotic liver. Along with the loss of miR-101, the ZEB1 expression increases simultaneously in hepatocytes. In addition, miR-101 levels in HCC cell lines are negatively associated with the ZEB1 productions and the metastatic potentials of tumor cells. Mechanistically, we demonstrate that miR-101 significantly inhibits the TGF-beta1-induced EMT in hepatocytes, whereas inhibition of miR-101 promotes the EMT process as indicated by the changes of morphology, cell migration, and the expression profiles of EMT markers. In the fibrotic liver, ectopic expression of miR-101 can significantly downregulate ZEB1 in the hepatocyte and thereby reduces the mesenchymal marker expression. Moreover, miR-101 significantly inhibits the proliferation and migration of HCC cell. Our results demonstrate that miR-101 regulates HCC cell phenotype by upregulating the epithelial marker genes and suppressing the mesenchymal ones. PMID- 25808948 TI - Abstracts of the Fifth Annual Meeting of the Italian Association for the Study of the Peripheral Nervous System (ASNP). PMID- 25808946 TI - The heterotrimeric G-protein beta subunit, AGB1, plays multiple roles in the Arabidopsis salinity response. AB - Salinity stress includes both osmotic and ionic toxicity. Sodium homeostasis is influenced by Na(+) uptake and extrusion, vacuolar Na(+) compartmentation and root to shoot Na(+) translocation via transpiration. The knockout mutant of the Arabidopsis heterotrimeric G-protein Gbeta subunit, agb1, is hypersensitive to salt, exhibiting a leaf bleaching phenotype. We show that AGB1 is mainly involved in the ionic toxicity component of salinity stress and plays roles in multiple processes of Na(+) homeostasis. agb1 mutants accumulate more Na(+) and less K(+) in both shoots and roots of hydroponically grown plants, as measured by inductively coupled plasma atomic emission spectrometry. agb1 plants have higher root to shoot translocation rates of radiolabelled (24) Na(+) under transpiring conditions, as a result of larger stomatal apertures and increased stomatal conductance. (24) Na(+) tracer experiments also show that (24) Na(+) uptake rates by excised roots of agb1 and wild type are initially equal, but that agb1 has higher net Na(+) uptake at 90 min, implicating possible involvement of AGB1 in the regulation of Na(+) efflux. Calcium alleviates the salt hypersensitivity of agb1 by reducing Na(+) accumulation to below the toxicity threshold. Our results provide new insights into the regulatory pathways underlying plant responses to salinity stress, an important agricultural problem. PMID- 25808950 TI - Selenium-Catalyzed C(sp3)-H Acyloxylation: Application in the Expedient Synthesis of Isobenzofuranones. AB - Oxidative Se-catalyzed C(sp3)-H bond acyloxylation has been used to construct a diverse array of isobenzofuranones from simple ortho-allyl benzoic acid derivatives. The synthetic procedure employs mild reaction conditions and gives high chemoselectivity enabled by an inexpensive organodiselane catalyst. The presented approach offers a new synthetic pathway toward the core structures of phthalide natural products. PMID- 25808949 TI - Eco-dialysis: the financial and ecological costs of dialysis waste products: is a 'cradle-to-cradle' model feasible for planet-friendly haemodialysis waste management? AB - BACKGROUND: Approximately 2 million chronic haemodialysis patients produce over 2,000,000 tons of waste per year that includes about 600,000 tons of potentially hazardous waste. The aim of the present study was to analyse the characteristics of the waste that is produced through chronic haemodialysis in an effort to identify strategies to reduce its environmental and financial impact. METHODS: The study included three dialysis machines and disposables for bicarbonate dialysis, haemodiafiltration (HFR) and lactate dialysis. Hazardous waste is defined as waste that comes into contact with bodily fluids. The weight and cost of waste management was evaluated by various policies of differentiation, ranging from a careful-optimal differentiation to a careless one. The amount of time needed for optimal management was recorded in 30 dialysis sessions. Non-hazardous materials were assessed for potential recycling. RESULTS: The amount of plastic waste that is produced per dialysis session ranges from 1.5 to 8 kg (from 1.1 to 8 kg of potentially hazardous waste), depending upon the type of dialysis machine and supplies, differentiation and emptying policies. The financial cost of waste disposal is high, and is mainly related to hazardous waste disposal, with costs ranging from 2.2 to 16 Euro per session (2.7-21 USD) depending on the waste management policy. The average amount of time needed for careful, optimal differentiation disposal is approximately 1 minute for a haemodialysis session and 2 minutes for HFR. The ecological cost is likewise high: less than one-third of non-hazardous waste (23-28%) is potentially recyclable, while the use of different types of plastic, glues, inks and labels prevents the remaining materials from being recycled. CONCLUSION: Acknowledging the problem of waste management in dialysis could lead to savings of hundreds of millions of Dollars and to the reuse and recycling of hundreds of tons of plastic waste per year on a world-wide scale with considerable financial and ecological savings. PMID- 25808947 TI - The impact of psychosocial stress on healthy skin. AB - Dermatologists are only too aware of the significant role psychosocial stress plays in the exacerbation of skin disease; indeed, it is often the first precipitant patients mention when they attend outpatient clinics. Of late, research has focused on understanding the 'brain-skin' axis, a complex interplay between the nervous and immune systems and the skin. In particular, there is an evolving body of literature exploring the underlying pathophysiological mechanisms by which psychosocial stress influences skin homeostasis. This article provides a broad overview of the literature, emphasizing the importance of individual stress perception and summarizing the varied roles of the major cutaneous stress-response pathways. Both central [the hypothalamic-pituitary adrenal (HPA) axis and the locus ceruleus-norepinephrine (LC-NE) sympathetic adrenomedullary system] and peripheral (the intracutaneous HPA axis and the release of mediators from peripheral sensory and autonomic nerves) pathways are discussed. Moreover, how activation of these pathways affects the skin's immune system, barrier function, wound healing and susceptibility to infection is reviewed. Although this field of research is rapidly expanding, several important questions remain unanswered, including: what is the precise role of mast cells in the cutaneous stress response?; what is the role of regulatory T-cells?; can therapeutic intervention be harnessed to prevent the stress-induced exacerbation of skin disease? It is anticipated that an improved understanding of the underlying mechanisms through which psychosocial stress affects the homeostasis of healthy skin will not only increase knowledge of the brain-skin axis but will also improve the holistic management of stress-responsive cutaneous disease. PMID- 25808952 TI - At Home on the Range? Lay Interpretations of Numerical Uncertainty Ranges. AB - Numerical uncertainty ranges are often used to convey the precision of a forecast. In three studies, we examined how users perceive the distribution underlying numerical ranges and test specific hypotheses about the display characteristics that affect these perceptions. We discuss five primary conclusions from these studies: (1) substantial variation exists in how people perceive the distribution underlying numerical ranges; (2) distributional perceptions appear similar whether the uncertain variable is a probability or an outcome; (3) the variation in distributional perceptions is due in part to individual differences in numeracy, with more numerate individuals more likely to perceive the distribution as roughly normal; (4) the variation is also due in part to the presence versus absence of common cues used to convey the correct interpretation (e.g., including a best estimate increases perceptions that the distribution is roughly normal); and (5) simple graphical representations can decrease the variance in distributional perceptions. These results point toward significant opportunities to improve uncertainty communication in climate change and other domains. PMID- 25808951 TI - Optimal population prediction of sandhill crane recruitment based on climate mediated habitat limitations. AB - 1. Prediction is fundamental to scientific enquiry and application; however, ecologists tend to favour explanatory modelling. We discuss a predictive modelling framework to evaluate ecological hypotheses and to explore novel/unobserved environmental scenarios to assist conservation and management decision-makers. We apply this framework to develop an optimal predictive model for juvenile (<1 year old) sandhill crane Grus canadensis recruitment of the Rocky Mountain Population (RMP). We consider spatial climate predictors motivated by hypotheses of how drought across multiple time-scales and spring/summer weather affects recruitment. 2. Our predictive modelling framework focuses on developing a single model that includes all relevant predictor variables, regardless of collinearity. This model is then optimized for prediction by controlling model complexity using a data-driven approach that marginalizes or removes irrelevant predictors from the model. Specifically, we highlight two approaches of statistical regularization, Bayesian least absolute shrinkage and selection operator (LASSO) and ridge regression. 3. Our optimal predictive Bayesian LASSO and ridge regression models were similar and on average 37% superior in predictive accuracy to an explanatory modelling approach. Our predictive models confirmed a priori hypotheses that drought and cold summers negatively affect juvenile recruitment in the RMP. The effects of long-term drought can be alleviated by short-term wet spring-summer months; however, the alleviation of long-term drought has a much greater positive effect on juvenile recruitment. The number of freezing days and snowpack during the summer months can also negatively affect recruitment, while spring snowpack has a positive effect. 4. Breeding habitat, mediated through climate, is a limiting factor on population growth of sandhill cranes in the RMP, which could become more limiting with a changing climate (i.e. increased drought). These effects are likely not unique to cranes. The alteration of hydrological patterns and water levels by drought may impact many migratory, wetland nesting birds in the Rocky Mountains and beyond. 5. Generalizable predictive models (trained by out-of-sample fit and based on ecological hypotheses) are needed by conservation and management decision-makers. Statistical regularization improves predictions and provides a general framework for fitting models with a large number of predictors, even those with collinearity, to simultaneously identify an optimal predictive model while conducting rigorous Bayesian model selection. Our framework is important for understanding population dynamics under a changing climate and has direct applications for making harvest and habitat management decisions. PMID- 25808953 TI - Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice. AB - Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes. In the hematopoietic compartment there is selection for the BALB mtDNA haplotype, a phenotype that can be modified by allelic variants of Gimap3. Gimap3 is a tail-anchored member of the GTPase of the immunity-associated protein (Gimap) family of protein scaffolds important for leukocyte development and survival. Here we show how the expression of two murine Gimap3 alleles from Mus musculus domesticus and M. m. castaneus differentially affect mtDNA segregation. The castaneus allele has incorporated a uORF (upstream open reading frame) in-frame with the Gimap3 mRNA that impairs translation and imparts a negative effect on the steady-state protein abundance. We found that quantitative changes in the expression of Gimap3 and the paralogue Gimap5, which encodes a lysosomal protein, affect mtDNA segregation in the mouse hematopoietic tissues. We also show that Gimap3 localizes to the endoplasmic reticulum and not mitochondria as previously reported. Collectively these data show that the abundance of protein scaffolds on the endoplasmic reticulum and lysosomes are important to the segregation of the mitochondrial genome in the mouse hematopoietic compartment. PMID- 25808956 TI - PET/CT in External Beam Radiation Therapy Dose Planning. PMID- 25808954 TI - Limited portability of G-patch domains in regulators of the Prp43 RNA helicase required for pre-mRNA splicing and ribosomal RNA maturation in Saccharomyces cerevisiae. AB - The Prp43 DExD/H-box protein is required for progression of the biochemically distinct pre-messenger RNA and ribosomal RNA (rRNA) maturation pathways. In Saccharomyces cerevisiae, the Spp382/Ntr1, Sqs1/Pfa1, and Pxr1/Gno1 proteins are implicated as cofactors necessary for Prp43 helicase activation during spliceosome dissociation (Spp382) and rRNA processing (Sqs1 and Pxr1). While otherwise dissimilar in primary sequence, these Prp43-binding proteins each contain a short glycine-rich G-patch motif required for function and thought to act in protein or nucleic acid recognition. Here yeast two-hybrid, domain-swap, and site-directed mutagenesis approaches are used to investigate G-patch domain activity and portability. Our results reveal that the Spp382, Sqs1, and Pxr1 G patches differ in Prp43 two-hybrid response and in the ability to reconstitute the Spp382 and Pxr1 RNA processing factors. G-patch protein reconstitution did not correlate with the apparent strength of the Prp43 two-hybrid response, suggesting that this domain has function beyond that of a Prp43 tether. Indeed, while critical for Pxr1 activity, the Pxr1 G-patch appears to contribute little to the yeast two-hybrid interaction. Conversely, deletion of the primary Prp43 binding site within Pxr1 (amino acids 102-149) does not impede rRNA processing but affects small nucleolar RNA (snoRNA) biogenesis, resulting in the accumulation of slightly extended forms of select snoRNAs, a phenotype unexpectedly shared by the prp43 loss-of-function mutant. These and related observations reveal differences in how the Spp382, Sqs1, and Pxr1 proteins interact with Prp43 and provide evidence linking G-patch identity with pathway specific DExD/H-box helicase activity. PMID- 25808957 TI - SPECT-CT in Radiotherapy Planning, with Main Reference to Patients with Breast Cancer. AB - The aim of modern intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) is to define the target areas including the smallest non-invaded margins, thus reducing the radiation dose to radiosensitive organs. To reach this goal, these methods require a more precise target delineation by imaging to better define the viable part of the tumor. Image-guided selection and demarcation of Gross Tumor Volume (GTV), Clinical Target Volume (CTV) and Organs at Risk (OAR) are the main steps to reach a satisfactory radiation treatment plan. Hybrid machines, such as PET-CT, SPECT-CT and, more recently, PET-MRI, may significantly increase diagnostic accuracy improving either sensitivity and specificity achievable alone by the single constituents of the hybrid tools. While the implementation contribution of PET-CT in radiotherapy, with respect to CT stand alone, has been extensively and successfully investigated, few papers have been at present written on the possible role of SPECT-CT for the same purpose. With an identical contribution to CT, SPECT may give similar information with respect to PET, when suitable radiopharmaceuticals are available. In particular, SPECT may provide additional information to CT, better defining the viable tumor mass; as a consequence, a more effective delineation of the GTV, saving the maximum normal tissue as possible, may be allowed. In this paper, we review some of the most important applications of SPECT-CT in oncology, as a premise to its possible utilization in tumor target definition in radiotherapy. In particular, we discuss sentinel lymph node (SLN) detection, tumor imaging with cationic lipophilic radiotracers, as (99m)Tc-methoxyisobutylisonitrile (MIBI) and (99m)Tc-tetrofosmin (TF) in breast cancer, thymoma, and lung cancer, (99m)Tcmethylene diphosphonate (MDP) for bone scan, (131)Iodine and (123)Iodine in differentiated thyroid cancer (DTC), as useful methods to optimize GTV and CTV definition. A reflection on the possible role in radiotherapy of other radiotracers labeled with gamma emitters, such as In-111 pentreotide has also been included. PMID- 25808958 TI - Planning of External Beam Radiotherapy for Prostate Cancer Guided by PET/CT. AB - In this paper, we give an overview of articles on non-choline tracers for PET/CT for patients with prostate cancer and planning of radiotherapy guided by PET/CT. Nineteen articles described (11)C-Acetate PET/CT. Of 629 patients 483 (77%, 95% CI 74% - 80%) had positive (11)C-Acetate PET/CT scans. Five articles described (18)F-FACBC PET/CT. Of 174 patients, 127 (73%, 95% CI 68% - 78%) had positive scans. Both tracers detected local lesions, lesions in regional lymph nodes, and distant organs. Ten articles described (18)F-NaF PET/CT and found that 1289 of 3918 patients (33%) had positive reactive lesions in bones. PET/CT scan can guide external beam radiotherapy (EBRT) planning for patients with loco-regional prostate cancer. In six studies with 178 patients with localized prostate cancer, PET/CT pointed out dominant intraprostatic lesions (DIL). Oncologists gave EBRT to the whole prostate and a simultaneously integrated boost to the DIL. Four studies with 254 patients described planning of EBRT for patients with PETpositive lymph nodes. After the EBRT, 15 of 29 node-positive patients remained in remission for median 28 months (range 14 to 50 months). Most articles describe (11)C- and (18)F-Choline PET/CT. However, (11)C-Acetate and (18)F-FACBC may also be useful tracers for PET/CT. Planning of radiotherapy guided by MRI or PET/CT is an investigational method for localized prostate cancer. Current clinical controlled trials evaluate whether the method improves overall survival. PMID- 25808955 TI - Cuticle integrity and biogenic amine synthesis in Caenorhabditis elegans require the cofactor tetrahydrobiopterin (BH4). AB - Tetrahydrobiopterin (BH4) is the natural cofactor of several enzymes widely distributed among eukaryotes, including aromatic amino acid hydroxylases (AAAHs), nitric oxide synthases (NOSs), and alkylglycerol monooxygenase (AGMO). We show here that the nematode Caenorhabditis elegans, which has three AAAH genes and one AGMO gene, contains BH4 and has genes that function in BH4 synthesis and regeneration. Knockout mutants for putative BH4 synthetic enzyme genes lack the predicted enzymatic activities, synthesize no BH4, and have indistinguishable behavioral and neurotransmitter phenotypes, including serotonin and dopamine deficiency. The BH4 regeneration enzymes are not required for steady-state levels of biogenic amines, but become rate limiting in conditions of reduced BH4 synthesis. BH4-deficient mutants also have a fragile cuticle and are generally hypersensitive to exogenous agents, a phenotype that is not due to AAAH deficiency, but rather to dysfunction in the lipid metabolic enzyme AGMO, which is expressed in the epidermis. Loss of AGMO or BH4 synthesis also specifically alters the sensitivity of C. elegans to bacterial pathogens, revealing a cuticular function for AGMO-dependent lipid metabolism in host-pathogen interactions. PMID- 25808959 TI - Hypoxia PET Tracers in EBRT Dose Planning in Head and Neck Cancer. AB - Over the years, external beam radiotherapy (EBRT) has been used in the treatment management of many malignancies, including head and neck squamous cell carcinomas (HNSCC). Hypoxia is a common feature in HNSCC. Hypoxic segments in HNSCC have proven to be more resistant to radiotherapy. The ability to identify hypoxia using SPECT and PET tracers has been investigated since the late 1970s. Nitroimidazole-based compounds labelled with positron emitters have been developed to more specifically image hypoxia. This article reviews the current data from research publications on(18)F-FMISO, (18)F-FAZA, (18)F-EF5 and (64)Cu ATSM. PMID- 25808960 TI - The Current Role of PET/CT in Radiotherapy Planning. AB - Positron Emission Tomography (PET) is increasingly being used in radiotherapy planning, with the development of hybrid imaging technology such as PET/CT allowing more accurate volumes being generated for treatment with external beam radiation. This article will discuss the use of FDG PET in radiotherapy planning of various types of malignancies, as well as some pitfalls and practicalities of integrating PET/CT into radiotherapy planning. PMID- 25808961 TI - The Use of 68Ga-DOTA-(Tyr3)-Octreotate PET/CT for Improved Target Definition in Radiotherapy Treatment Planning of Meningiomas - A Case Report. AB - Due to somatostatin receptor expression in meningiomas, PET with somatostatin analogs appears to be useful in radiotherapy treatment planning. We report the case of a 63-year-old man diagnosed with meningioma of the left frontal lobe in 2011. He underwent total tumor excision (pathology was atypical meningioma WHO 2) and radiotherapy, but one year after the completion of treatment, he complained about diplopia and left upper eyelid ptosis. The MRI showed a new parasagittal lesion and the patient received stereotactic radiotherapy. Few weeks later, two new lesions were found - one in the sella turcica region and the other adjacent to the greater wing of the right sphenoid bone. The patient underwent transsphenoidal biopsy, but was not qualified for neurosurgery due to high risk of bleeding. In the radiotherapy treatment planning, we used a fusion of MRI and 68Ga-DOTA-(Tyr3)-octreotate PET/CT images. The patient received stereotactic radiotherapy, first to the parasellar lesion and then to the progressing tumor adjoining the sphenoid bone. In both cases, PET/CT scans helped to define the target, its volume being bigger on PET/CT than on MRI images. In patients with meningiomas, 68-Ga-DOTA-(Tyr3)-octreotate PET/CT can be considered as a useful imaging modality in radiotherapy treatment planning, which helps to visualize the tumor extension and to define the target. PMID- 25808962 TI - Real-time 2D visualization of metabolic activities in zebrafish embryos using a microfluidic technology. AB - Non-invasive and real-time visualization of metabolic activities in living small model organisms such as embryos and larvae of zebrafish has not yet been attempted largely due to profound analytical limitations of existing technologies. Historically, our capacity to examine oxygen gradients surrounding eggs and embryos has been severely limited, so much so that to date, most of the articles characterizing in situ oxygen gradients have described predominantly mathematical simulations. These drawbacks can, however, be experimentally addressed by an emerging field of microfluidic Lab-on-a-Chip (LOC) technologies combined with sophisticated optoelectronic sensors. In this work, we outline a proof-of-concept approach utilizing microfluidic living embryo array system to enable in situ Fluorescence Ratiometric Imaging (FRIM) on developing zebrafish embryos. The FRIM is an innovative method for kinetic quantification of the temporal patterns of aqueous oxygen gradients at a very fine scale based on signals coming from an optical sensor referred to as a sensor foil. We envisage that future integration of microfluidic chip-based technologies with FRIM represents a noteworthy direction to miniaturize and revolutionize research on metabolism and physiology in vivo. PMID- 25808963 TI - Effects of TBEP on the induction of oxidative stress and endocrine disruption in Tm3 Leydig cells. AB - The flame retardant tris (2-butoxyethyl) phosphate (TBEP) is a frequently detected contaminant in the environment. In the cultured TM3 cells (originated from ATCC), effects of TBEP on the induction of oxidative stress and endocrine disruption were evaluated. It was observed that exposure to 100 MUg/mL TBEP for 24 h significantly reduced the viability of TM3 cells. The mRNA levels of genes related to oxidative stress including Sod, Gpx1, Cat, and Gsta1 were changed in a dose-dependent and/or time-dependent manner after exposure to 30 and 100 MUg/mL TBEP for 6, 12, or 24 h. Moreover, notable decrease in glutathione (GSH) contents and increases in oxidized glutathione (GSSG) contents as well as the antioxidant enzyme activities like superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase were found in the group treated with 100 MUg/mL TBEP for 24 h, indicating that TBEP induced oxidative stress in TM3 Leydig cells. In addition, the expression of genes related to testosterone (T) synthesis including cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), cytochrome P450 17alpha-hydroxysteroid dehydrogenase (P450-17alpha), and 17beta hydroxysteroid dehydrogenase (17beta-HSD) and T levels in medium were remarkably declined by the treatment of 100 MUg/mL TBEP for 24 h. And TBEP could inhibit the expression of P450-17alpha and 17beta-HSD and T levels up-regulated by hCG in TM3 cells. Taken together, these findings indicated that TBEP can induce oxidative stress and alter steroidogenesis in TM3 cells. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1276-1286, 2016. PMID- 25808964 TI - The economic significance of orthopaedic infections. AB - Musculoskeletal infections are a leading cause of patient morbidity and rising healthcare expenditures. The incidence of musculoskeletal infections, including soft-tissue infections, periprosthetic joint infection, and osteomyelitis, is increasing. Cases involving both drug-resistant bacterial strains and periprosthetic joint infection in total hip and total knee arthroplasty are particularly costly and represent a growing economic burden for the American healthcare system. With the institution of the Affordable Care Act, there has been an increasing drive in the United States toward rewarding healthcare organizations for their quality of care, bundling episodes of care, and capitating approaches to managing populations. In current reimbursement models, complications following the index event, including infection, are not typically reimbursed, placing the burden of caring for infections on the physician, hospital, or accountable care organization. Without the ability to risk-stratify patient outcomes based on patient comorbidities that are associated with a higher incidence of musculoskeletal infection, healthcare organizations are disincentivized to care for moderate- to high-risk patients. Reducing the cost of treating musculoskeletal infection also depends on incentivizing innovations in infection prevention. PMID- 25808965 TI - Best practices for centers of excellence in addressing periprosthetic joint infection. AB - Periprosthetic joint infection is a rare and devastating complication. Management of this complication often requires a multidisciplinary approach similar to that used for the care of patients with cancer. Several studies have reported better outcomes following total joint arthroplasties performed at specialized hospitals than those performed at general hospitals. Specialized institutions use care pathways that aid the multidisciplinary team in decision making. During the recent Musculoskeletal Infection symposium, specific issues were discussed with regard to the treatment of periprosthetic joint infection, including medical optimization, systematic approaches to infection management, and the importance of establishing registries to aid in the creation of Centers of Excellence. A Center of Excellence in periprosthetic infection could provide better overall outcomes with lower financial, physical, and emotional costs to patients. PMID- 25808966 TI - Conventional diagnostic challenges in periprosthetic joint infection. AB - Periprosthetic joint infection remains a clinical challenge with no benchmark for diagnosis. The diagnosis is based on many different clinical variables that may be difficult to interpret, especially in the setting of chronic systemic disease. Synovial fluid aspiration, diagnostic imaging, traditional culture, peripheral serum inflammatory markers, and intraoperative frozen sections each have their limitations but continue to be the mainstay for diagnosis of periprosthetic joint infection. As molecular- and biomarker-based technologies improve, the way we interpret and diagnose periprosthetic joint infection will ultimately change and may even improve diagnostic accuracy and turnaround time. Future research on this topic should be focused on improving diagnostic criteria for low-virulence organisms, improving interpretation of intraoperative frozen sections, and establishing improved synovial fluid and peripheral serum biomarker profiles for periprosthetic joint infection. PMID- 25808968 TI - Novel developments in the prevention, diagnosis, and treatment of periprosthetic joint infections. AB - Periprosthetic joint infection (PJI) is one of the most challenging complications compromising the outcome of an otherwise successful operation. Considerable efforts have been invested in the recent years to address paradigm shifts in our understanding of the complex microbiological phenomena that contribute to the pathophysiology of PJI, such as microbial adherence, biofilm formation, and resistance to antibiotics. This article is an introduction to some of the recent advancements in the prevention, diagnosis, and treatment of PJI. It describes how industry, academic researchers, and government are increasing collaboration to address PJI through development of novel technologies, therapeutic strategies, and regulatory science that specifically target the unique biofilm-associated aspects of its pathogenesis. PMID- 25808967 TI - Molecular diagnostics. AB - Orthopaedic infections are complex conditions that require immediate diagnosis and accurate identification of the causative organisms to facilitate appropriate management. Conventional methodologies for diagnosis of these infections sometimes lack accuracy or sufficient rapidity. Molecular diagnostics is an emerging area of bench-to-bedside research in orthopaedic infections. Examples of promising molecular diagnostics include measurement of a specific biomarker in the synovial fluid, polymerase chain reaction-based detection of bacterial genes, and metabolomic determination of responses to orthopaedic infection. PMID- 25808969 TI - A clinical perspective on musculoskeletal infection treatment strategies and challenges. AB - Orthopaedic implants improve the quality of life of patients, but the risk of postoperative surgical site infection poses formidable challenges for clinicians. Future directions need to focus on prevention and treatment of infections associated with common arthroplasty procedures, such as the hip, knee, and shoulder, and nonarthroplasty procedures, including trauma, foot and ankle, and spine. Novel prevention methods, such as nanotechnology and the introduction of antibiotic-coated implants, may aid in the prevention and early treatment of periprosthetic joint infections with goals of improved eradication rates and maintaining patient mobility and satisfaction. PMID- 25808970 TI - Capturing orthopaedic surgical site infection data and assessing dental recommendations with respect to total joint arthroplasty. AB - Greater documentation of patient history and clinical course is crucial for identifying factors that can influence surgical outcomes. The Centers for Medicare and Medicaid Services have already begun public reporting of hospital data on readmission, complication, and infection rates and will soon launch a website to make physician-specific outcomes data public. The orthopaedic community has the opportunity to lead the way in ensuring that adequate and accurate data is collected to facilitate appropriate comparisons that are based on patients' true risk of complications and the complexity of treatment. Several studies have reported a link between oral pathogens and periprosthetic infection, although it remains unclear whether organisms unique to dental tissues are also present in osteoarthritic joints and tissues affected by periprosthetic joint infection. The American Academy of Orthopaedic Surgeons and the American Dental Association are aware of these concerns and have created guidelines for antibiotic prophylaxis in patients who have undergone total hip or knee arthroplasty and require high-risk dental procedures. Because these guidelines have received considerable criticism, recommendations that are based on scientific and case-controlled clinical studies and provide effective guidance on this important subject are needed. PMID- 25808971 TI - Surgical site infection risk factors and risk stratification. AB - Preoperative identification of the risk factors for surgical site infection and patient risk stratification are essential for deciding whether surgery is appropriate, educating patients on their individual risk of complications, and managing postoperative expectations. Early identification of these factors is also necessary to help guide both patient medical optimization and perioperative care planning. Several resources are currently available to track and analyze healthcare-associated infections, including the Centers for Disease Control and Prevention's National Healthcare Safety Network. In addition, the Centers for Disease Control and Prevention and the American Academy of Orthopaedic Surgeons are exploring collaborative opportunities for the codevelopment of a hip and/or knee arthroplasty national quality measure for periprosthetic joint infection. PMID- 25808973 TI - Mitochondrias' sense of SNO: pathway to cardioprotection in ischaemic preconditioning. PMID- 25808972 TI - PKC-beta activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis. AB - AIMS: Clinical observations showed a correlation between accelerated atherosclerosis in diabetes and high plasmatic level of IL-18, a pro-inflammatory cytokine. IL-18 enhances the production of inflammatory cytokines and cellular adhesion molecules contributing to atherosclerotic plaque formation and instability. Previous studies indicated that protein kinase C (PKC)-beta inhibition prevented macrophage-induced cytokine expression involved in diabetic (DM) atherosclerotic plaque development. However, the role of PKC-beta activation on IL-18/IL-18-binding protein (IL-18BP) pathway causing endothelial dysfunction and monocyte adhesion in diabetes has never been explored. METHODS AND RESULTS: Apoe(-/-) mice were rendered DM and fed with western diet containing ruboxistaurin (RBX), a PKC-beta inhibitor. After 20 weeks, atherosclerotic plaque composition was quantified. Compared with non-diabetic, DM mice exhibited elevated atherosclerotic plaque formation, cholestoryl ester content and macrophage infiltration, as well as reduced IL-18BP expression in the aorta which was prevented with RBX treatment. Endothelial cells (ECs) and macrophages were exposed to normal or high glucose (HG) levels with or without palmitate and recombinant IL-18 for 24 h. The combined HG and palmitate condition was required to increase IL-18 expression and secretion in macrophages, while it reduced IL 18BP expression in EC causing up-regulation of the vascular cell adhesion molecule (VCAM)-1 and monocyte adhesion. Elevated VCAM-1 expression and monocyte adherence were prevented by siRNA, RBX, and IL-18 neutralizing antibody. CONCLUSION: Our study unrevealed a new mechanism by which PKC-beta activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes. PMID- 25808974 TI - Syndecan-4: a novel regulator of collagen synthesis and deposition in the pressure-overloaded myocardium. PMID- 25808975 TI - A step closer to cardiac optogenetics in vivo. PMID- 25808976 TI - The Function of Twisted Gastrulation in Regulating Osteoclast Differentiation is Dependent on BMP Binding. AB - Proper regulation of osteoclast (OCL) function is critical for normal bone homeostasis. Bone morphogenetic protein (BMP) signaling and its regulation have been shown to have direct effects on OCL differentiation and activity. One of the major modulators of BMP signaling in the extracellular space is the secreted protein twisted gastrulation (TWSG1), which can inhibit BMP signaling and OCL differentiation. In this study we examine specific N-terminal regions of TWSG1 protein that have been previously proposed as BMP binding sites to determine whether TWSG1 binding to BMPs is required for its inhibitory effects on OCLs. We demonstrate that overexpression of wild type TWSG1 suppresses osteoclastogenesis, while overexpression of mutant TWSG1 proteins (W66A and N80Q/N146Q mutants), which cannot bind BMPs, leads to increased BMP signaling, enhanced osteoclastogenesis, increased resorptive activity, and expression of OCL-specific genes. Our results show that BMP binding is required for TWSG1-mediated inhibition of OCL formation and function, and validate the critical functional regions within the TWSG1 protein for these interactions. PMID- 25808977 TI - Identification of Missing Norwegian World War II Soldiers, in Karelia Russia. AB - This article presents the multidisciplinary effort in trying to identify the skeletal remains of 100 Norwegian soldiers serving in the German army, killed in Karelia Russia in 1944, from the recovery of the remains through the final identification using DNA. Of the 150 bone samples sent for DNA testing, 93 DNA profiles were obtained relating to 57 unique individuals. The relatives could not be directly contacted as the soldiers were considered as traitors to Norway; therefore, only 45 reference samples, relating to 42 cases of the missing, were donated. DNA matches for 14 soldiers and 12 additional body part re-associations for these individuals were found. Another 24 bone samples were re-associated with 16 individuals, but no familial match was found. More than six decades after the end of WWII, DNA analysis can significantly contribute to the identification of the remains. PMID- 25808978 TI - Interactions between genotype and environment drive the metabolic phenotype within Escherichia coli isolates. AB - To gain insights into the adaptation of the Escherichia coli species to different environments, we monitored protein abundances using quantitative proteomics and measurements of enzymatic activities of central metabolism in a set of five representative strains grown in four contrasted culture media including human urine. Two hundred and thirty seven proteins representative of the genome-scale metabolic network were identified and classified into pathway categories. We found that nutrient resources shape the general orientation of metabolism through coordinated changes in the average abundances of proteins and in enzymatic activities that all belong to the same pathway category. For example, each culture medium induces a specific oxidative response whatever the strain. On the contrary, differences between strains concern isolated proteins and enzymes within pathway categories in single environments. Our study confirms the predominance of genotype by environment interactions at the proteomic and enzyme activity levels. The buffering of genetic variation when considering life-history traits suggests a multiplicity of evolutionary strategies. For instance, the uropathogenic isolate CFT073 shows a deregulation of iron demand and increased oxidative stress response. PMID- 25808979 TI - Directed evolution of a beta-1,3-1,4-glucanase from Bacillus subtilis MA139 for improving thermal stability and other characteristics. AB - In order to improve some characteristics of a beta-1,3-1,4-glucanase from Bacillus subtilis MA139, directed evolution was conducted in this study. After error-prone PCR, the beta-1,3-1,4-glucanase gene, glu-opt, was cloned into the vector pBGP1 and transformed into Pichia pastoris X-33 to construct a mutant library. Three variants named as 7-32, 7-87, and 7-115 were screened from 8000 colonies. Amino-acid sequence analysis showed that these mutants had one or two amino-acid substitutions (7-32: T113S, 7-87: M44V/N53H, and 7-115: N157D). The variants were over-expressed in P. pastoris by methanol induction. After purification of the enzyme proteins, the characteristics of the variants were analyzed in detail. It indicated that these mutant enzymes had broader ranges of pH value and better pH stability than the wild-type enzyme. The mutant enzyme 7 87 had the best ability to tolerate an acid environment (pH 2.0), while the wild type enzyme had no activity under this condition. Moreover, all these mutants demonstrated improved thermal stability. In particular, the mutant enzyme 7-32 had residual enzymatic activity of 60% and 40% after being incubated at 80 degrees C and 90 degrees C for 10 min. While, the wild-type enzyme had no residual enzymatic activity after being incubated at 80 degrees C for 4 min. In addition, the mutant enzymes had better tolerance to some chemicals than the wild type enzyme. The improved stability could enhance the prospects for this enzyme to have use in the feed industry to reduce the effects of the anti-nutritional factor beta-glucan. PMID- 25808980 TI - Antimicrobial photodynamic effect to treat residual pockets in periodontal patients: a randomized controlled clinical trial. AB - AIM: A randomized controlled clinical trial was designed to evaluate the efficacy of the photodynamic therapy (PDT) in the treatment of residual pockets of chronic periodontitis patients. MATERIAL AND METHODS: Thirty-four patients with at least four residual periodontal pockets undergoing maintenance care were included and randomly assigned to test group (PDT, n = 18) or control group (sham procedure, n = 16). The intervention was performed at baseline, 3, 6 and 12 months. Clinical parameters such as pocket probing depth (PPD), clinical attachment level (CAL), bleeding on probing (BoP) and plaque index (PI) were measured before intervention and after 3, 6 and 12 months. Subgingival samples were obtained at baseline, and after 7 days, 3, 6 and 12 months to quantify Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia by real-time polimerase chain reaction (PCR). RESULTS: All clinical variables showed significant improvement during the study, but there was no significant difference between test and control groups. The microbiological analyses showed no differences between groups at any time during the study. CONCLUSION: Within the limits of this clinical trial and considering the laser and photosensitizer protocol used, PDT failed to demonstrate additional clinical and bacteriological benefits in residual pockets treatment. PMID- 25808981 TI - Computer-Aided Assessment of Spinal Inflammation on Magnetic Resonance Images in Patients With Spondyloarthritis. AB - OBJECTIVE: To evaluate a computer-aided approach to the assessment of spinal inflammation on magnetic resonance imaging (MRI) in spondyloarthritis as compared to visual assessment. METHODS: Following institutional ethics approval, 32 patients (mean +/- SD age 35.3 +/- 10.2 years) with active ankylosing spondylitis underwent treatment with methotrexate and infliximab for 30 weeks. Spinal MRI examination (T1-weighted, T2-weighted fat-suppressed, and postcontrast T1 weighted fat-suppressed sagittal sequences using a 1.5T MRI system) was performed at baseline and at 30 weeks. Following manual identification of the vertebral corners, vertebral body segmentation was performed using a deformable model that automatically isolated the 4 vertebral corner areas, allowing automatic measurement of the relative mean corner intensity of each vertebral corner before and after treatment. Quantitative computer-aided assessment of spinal inflammation was compared with a semiquantitative visual assessment of spinal inflammation (the Berlin method). RESULTS: Computer-aided quantification was quick and highly reliable, and it identified increases in vertebral corner edema or enhancement that were significantly decreased following treatment (P < 0.5). For computer-aided analysis, there was excellent inter- and intrarater correlation of both corner edema and enhancement (intraclass correlation coefficients [ICCs] >0.99), and the correlations were better than those for visual analysis (ICCs 0.83-0.96). For computer-aided analysis, the standardized response mean was 1.67 for corner edema and 1.64 for enhancement, as compared to 1.20 and 1.18, respectively, for visual analysis. Computer-aided quantification of MRI data correlated better (r = 0.50-0.53, P < 0.01) with clinical features of spinal disease activity pre- and posttreatment than did visual analysis of spinal inflammation (r = 0.37-0.43, P > 0.02). CONCLUSION: Computer-aided assessment of spinal inflammation in spondyloarthritis is quick, reliable, and sensitive and correlates better with clinical disease activity than does visual assessment by the Berlin method. PMID- 25808983 TI - SNP genotyping and population genomics from expressed sequences - current advances and future possibilities. AB - With the rapid increase in production of genetic data from new sequencing technologies, a myriad of new ways to study genomic patterns in nonmodel organisms are currently possible. Because genome assembly still remains a complicated procedure, and because the functional role of much of the genome is unclear, focusing on SNP genotyping from expressed sequences provides a cost effective way to reduce complexity while still retaining functionally relevant information. This review summarizes current methods, identifies ways that using expressed sequence data benefits population genomic inference and explores how current practitioners evaluate and overcome challenges that are commonly encountered. We focus particularly on the additional power of functional analysis provided by expressed sequence data and how these analyses push beyond allele pattern data available from nonfunction genomic approaches. The massive data sets generated by these approaches create opportunities and problems as well - especially false positives. We discuss methods available to validate results from expressed SNP genotyping assays, new approaches that sidestep use of mRNA and review follow-up experiments that can focus on evolutionary mechanisms acting across the genome. PMID- 25808982 TI - EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease. AB - BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI 0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak. PMID- 25808984 TI - Multiresponse Optimisation Applied to the Development of a TLC Autography for the Detection of Tyrosinase Inhibitors. AB - INTRODUCTION: Autographic methods are useful tools to detect bioactive compounds in complex matrixes. Experimental design and optimisation techniques were implemented for the development of an autographic assay suitable for the detection of tyrosinase inhibitors. OBJECTIVES: To develop an autographic assay to detect tyrosinase inhibitors using gel entrapped enzyme, experimental design and response surface methodology (RSM) to optimise conditions with a minimum number of experiments. METHODS: Gel entrapment was used for the assay and the effects of four factors on the sensitivity and the detection limit for known inhibitors of the enzyme were evaluated. The factors were: tyrosinase amount (TA), L-tyrosine amount (LTA), incubation time and incubation temperature. RESULTS: The assay allowed the detection of kojic acid in an extract of Calamagrostis viridiflavescens (Poir.) Steud spiked with 0.1% w/w. CONCLUSION: The developed assay is able to detect tyrosinase inhibitors present in complex matrixes in a reproducible way. PMID- 25808985 TI - Territory and fiber orientation of vastus medialis motor units: A Surface electromyography investigation. AB - INTRODUCTION: The aim of this study was to determine whether muscle fibers innervated by single motor neurons are confined in small subvolumes of the vastus medialis (VM) and if motor unit fiber orientation depends on their position within the muscle. METHODS: Single motor units were identified from a grid of surface electrodes. The size of their surface representation and fiber orientation were extracted using an algorithm validated on simulated signals. RESULTS: The action potentials of 77 motor units were represented locally on the skin (10th-90th percentiles: 14-25 mm). According to simulations, this indicates territories smaller than 11.8-64.8 mm. Motor units in distal regions of VM had fibers at a greater angle than those in proximal regions (R = -0.54, P < 0.001). CONCLUSION: Motor units with small territories and varying fiber orientations may be an anatomical predisposition to regulate how regions within VM apply forces to the patella. This could help to redistribute loads within the joint in painful conditions. PMID- 25808987 TI - Effects of biliopancreatic diversion on diurnal leptin, insulin and free fatty acid levels. AB - BACKGROUND: Free fatty acid (FFA) levels are raised in obesity as a consequence of increased production and reduced clearance. They may link obesity with insulin resistance. Bariatric surgery can result in considerable weight loss and reduced insulin resistance, but the mechanism of action is not well understood. Although drugs such as metformin that lower insulin resistance can contribute to weight loss, a better understanding of the links between obesity, weight loss and changes in insulin resistance might lead to new approaches to patient management. METHODS: Variations in circulating levels of leptin, insulin and FFAs over 24 h were studied in severely obese (body mass index over 40 kg/m(2) ) women before and 6 months after biliopancreatic diversion (BPD). Body composition was measured by dual-energy X-ray absorptiometry. A euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. Levels of insulin, leptin and FFAs were measured every 20 min for 24 h. Pulsatile hormone and FFA analyses were performed. RESULTS: Among eight patients studied, insulin sensitivity more than doubled after BPD, from mean(s.d.) 39.78(7.74) to 96.66(27.01) mmol per kg fat free mass per min, under plasma insulin concentrations of 102.29(9.60) and 93.61(9.95) uunits/ml respectively. The secretory patterns of leptin were significantly different from random but not statistically different before and after BPD, with the exception of the pulse height which was reduced after surgery. Both plasma insulin and FFA levels were significantly higher throughout the study day before BPD. Based on Granger statistical modelling, lowering of daily FFA levels was linked to decreased circulating leptin concentrations, which in turn were related to the lowering of daily insulin excursions. Multiple regression analysis indicated that FFA level was the only predictor of leptin level. CONCLUSION: Lowering of circulating levels of FFAs after BPD may be responsible for the reduction in leptin secretion, which in turn can decrease circulating insulin levels. Surgical relevance Insulin resistance is a common feature of obesity and type II diabetes. These patients are also relatively insensitive to the biological effects of leptin, a satiety hormone produced mainly in subcutaneous fat. Biliopancreatic diversion, a malabsorptive bariatric operation that drastically reduces circulating lipid levels, improves insulin resistance independently of weight loss. The mechanism of action, however, has still to be elucidated. This study demonstrated that normalization of insulin sensitivity after bariatric surgery was associated with a reduction in 24-h free fatty acid concentrations and changes in the pattern of leptin peaks in plasma. Bariatric surgery improves the metabolic dysfunction of obesity, and this may be through a reduction in circulating free fatty acids and modification of leptin metabolism. PMID- 25808988 TI - Enhancement of Haemophilus parasuis serovar 5 yields by medium optimization. AB - The purpose of this study was to optimize the medium components for high productivity of Haemophilus parasuis serovar 5 through statistical approach. Plakett-Burman experimental design was initially applied to identify the factors that influenced the biomass of H. parasuis. Based on the response surface and canonical analyses, the optimum concentrations of the critical components were obtained as follows: 43.55 g l(-1) , yeast extract; 1.05 g l(-1) , sodium chloride; 11.63% (v/v), phosphate buffer; 10% (v/v), bovine serum; and 20 MUg l( 1) , nicotinamide adenine dinucleotide. The number of viable cells of H. parasuis reached 4.7*10(9) CFU ml(-1) and the productivity was 4.7*10(9) CFU ml(-1) h(-1) after cultivation in the optimal medium in 3 l fermentor, increasing 2.5 times and 3.9 times more than that in tryptone soy broth medium, respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report on statistical optimization of medium components for the fermentation of Haemophilus parasuis serovar 5. The improved medium was highly efficient, less expensive (its cost was $1.16 l(-1) , while that of tryptone soy broth was $4.00 l(-1) ) and has been used for large-scale production in Wuhan Keqian Animal Biology Product Co. Ltd, China, and it will improve the industrialization of H. parasuis worldwide. PMID- 25808986 TI - DNA copy number profiling reveals different patterns of chromosomal instability within colorectal cancer according to the age of onset. AB - Chromosomal instability resulting in copy number alterations is a hallmark of colorectal cancer (CRC). However, few studies have attempted to characterize the chromosomal changes occurring in early-onset CRC in order to compare them with those taking place within the more extensively studied late-onset CRC subset. Our aim was to characterize the genomic profiles of these two groups of colorectal tumors and to compare them to each other. Array comparative genomic hybridization profiling of 146 colorectal tumors (60 early-onset and 86 late-onset) in combination with an unsupervised analysis was used to define common and specific copy number alterations. We found a number of important differences between the chromosomal instability profiles of each age subset. Thus, losses at 1p36, 1p12, 1q21, 9p13, 14q11, 16p13, and 16p12 were significantly more frequent in younger patients, whereas gains at 7q11 and 7q22 were more frequent in older patients. Moreover, the unsupervised analysis stratified the tumors into two clusters, each one of which was enriched in patients from one of the age subsets. Our findings confirm the existence of substantial differences between the chromosomal instability profiles of the two groups which are more important from a qualitative point of view. Further studies are needed to understand the clinicopathological implications of these dissimilarities. PMID- 25808989 TI - Long-term outcome of native tissue reconstructive vaginal surgery for advanced pelvic organ prolapse at 86 months: Hysterectomy versus hysteropexy. AB - AIM: To evaluate and compare the long-term outcome of sacrospinous ligament fixation (SSF) in combination with various other compartment defect native tissue repairs with hysterectomy or hysteropexy. METHODS: Medical records of 159 patients who underwent surgery for pelvic organ prolapse (POP) between April 2004 and August 2008 were reviewed retrospectively. Patients were assessed at baseline and at 5-year postoperative follow-up. SSF, anterior (AC) and posterior colporrhaphy (PC), both with and without hysterectomy, were performed. Primary outcome was objective cure (POP quantification system [POP-Q] <=1) and subjective cure (negative response to questions 2 and 3 on Pelvic Organ Prolapse Distress Inventory 6 [POPDI-6]). Subanalysis was done on patients who had uterus preserved compared with those with vaginal hysterectomy. RESULTS: Postoperative data were available for 146 patients: 120 in the hysterectomy group and 26 in the hysteropexy group. Mean age, parity, postmenopausal status and mean operating time in the hysterectomy group were significantly higher than in the hysteropexy group. At median follow-up of 86 months, objective cure at overall compartments for all patients was 67.8%, and for subjective cure, this was 64.4%. There was no difference in the adjusted odds ratio for objective and subjective cure rates in both groups, but the hysterectomy group had a significantly lower mean total POPDI-6 score. CONCLUSION: SSF plus AC and PC have a low reoperation rate despite a moderate success rate at 7-year follow-up. There was no difference in the adjusted objective, subjective success rates and sexual function between sacrospinous hysteropexy and hysterectomy. The hysterectomy group, however, had fewer bothersome prolapse symptoms. PMID- 25808990 TI - Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions. AB - Receptor families of the innate immune response engage in 'cross-talk' to tailor optimal immune responses against invading pathogens. However, these responses are subject to multiple levels of regulation to keep in check aberrant inflammatory signals. Here, we describe a role for the orphan receptor interleukin-17 receptor D (IL-17RD) in negatively regulating Toll-like receptor (TLR)-induced responses. Deficiency of IL-17RD expression in cells leads to enhanced pro-inflammatory signalling and gene expression in response to TLR stimulation, and Il17rd(-/-) mice are more susceptible to TLR-induced septic shock. We demonstrate that the intracellular Sef/IL-17R (SEFIR) domain of IL-17RD targets TIR adaptor proteins to inhibit TLR downstream signalling thus revealing a paradigm involving cross regulation of members of the IL-17R and TLR families. PMID- 25808992 TI - What Challenges Manual Workers' Ability to Cope with Back Pain at Work, and What Influences Their Decision to Call in Sick? AB - INTRODUCTION: Although back pain (BP) is a very common cause for sickness absence, most people stay at work during BP episodes. Existing knowledge on the factors influencing the decision to stay at work despite pain is limited. The aim of this study was to explore challenges for coping with BP at work and decisive factors for work attendance among workers with high physical work demands. METHODS: Three focus groups (n = 20) were conducted using an explorative inductive method. Participants were public-employed manual workers with high physical work demands. All had personal BP experience. Thematic analysis was used for interpretation. Results were matched with the Flags system framework to guide future recommendations. RESULTS: Workers with BP were challenged by poor physical work conditions and a lack of supervisor support/trust (i.e. lack of adjustment latitude). Organization of workers into teams created close co-worker relationships, which positively affected BP coping. Workers responded to BP by applying helpful individual adjustments to reduce or prevent pain. Traditional ergonomics was considered inconvenient, but nonetheless ideal. When pain was not decisive, the decision to call in sick was mainly governed by workplace factors (i.e. sick absence policies, job strain, and close co-workers relationships) and to a less degree by personal factors. CONCLUSION: Factors influencing BP coping at work and the decision to report sick was mainly governed by factors concerning general working conditions. Creating a flexible and inclusive working environment guided by the senior management and overall work environment regulations seems favourable. PMID- 25808991 TI - Workstyle and Musculoskeletal Discomfort (MSD): Exploring the Influence of Work Culture in Malaysia. AB - PURPOSE: Workstyle can be defined as an individual pattern of cognitions, behaviours and physiological reactivity that can occur while performing job tasks. Workstyle has been associated with the development of musculoskeletal disorders (MSDs) amongst office workers in developed countries. However, little is known about the contribution of workstyle on MSDs in developing countries such as Malaysia. The objective of this cross-sectional study was to examine the relationship between workstyle and musculoskeletal discomfort in a sample of office workers in Malaysia. METHODS: Office workers (N = 417; response rate 65.5 %) from four organisations completed a survey measuring physical and psychosocial hazards, job satisfaction, work-life balance, workstyle, and MSD discomfort levels. Hierarchical regression analyses were undertaken to examine predictors associated with self-reported musculoskeletal discomfort, and more specifically the relationship between workstyle and MSD discomfort. RESULTS: Musculoskeletal discomfort was significantly associated with working through pain, mental health, physical demands, gender and work-life balance (R (2) = 50.2, adjusted R (2) = 0.48; F (13, 324) = 25.09, p = 0.001). Working through pain is the strongest risk factor associated with MSD discomfort (beta = 0.49, p = 0.001) compared to other potential risk factors. CONCLUSIONS: Working through pain is influenced by work, social culture and religious beliefs. Workplace MSDs interventions that focus on the impact of physical and psychosocial hazards with emphasis on addressing adverse workstyles should take into account aspects related to work and social culture of the target population. Changes are recommended at both employee and management levels such as better communications and understanding concerning workplace problems with regards to minimizing MSDs at work. PMID- 25808995 TI - Anandamide reduces the ejaculatory threshold of sexually sluggish male rats: possible relevance for human lifelong delayed ejaculation disorder. AB - INTRODUCTION: The sexually sluggish (SLG) male rat has been proposed as an animal model for the study of lifelong delayed ejaculation, a sexual dysfunction for which no treatment is available. Low endocannabinoid anandamide (AEA) doses facilitate sexual behavior display in normal sexually active and in noncopulating male rats through the activation of CB1 receptors. AIM: To establish whether low AEA doses reduced the ejaculatory threshold of SLG male rats by acting at CB1 receptors. METHODS: SLG male rats were intraperitoneally injected with different doses of AEA (0.1-3.0 mg/kg), the CB1 receptor antagonist AM251 (0.1-3.0 mg/kg), or their vehicles and tested for copulatory behavior during 60 minutes. Animals receiving AEA effective doses were subjected to a second sexual behavior test, 7 days later under drug-free conditions. To determine the participation of CB1 receptors in AEA-induced actions, SLG rats were pretreated with AM251 prior to AEA. MAIN OUTCOME MEASURES: The sexual parameters, intromission latency, number of mounts and intromissions, ejaculation latency, and interintromission interval. RESULTS: All sexual behavior parameters of SLG rats were significantly increased when compared with normal sexually experienced animals. Low AEA doses (0.3 and 1 mg/kg) significantly lowered the ejaculatory threshold of SLG rats, reducing the number of pre-ejaculatory intromissions and ejaculation latency. IL, M number, and locomotor activity were unaffected by AEA. Facilitation of the ejaculatory response of SLG rats disappeared 7 days after AEA injection. AM251 lacked an effect on copulation of SLG rats but blocked the AEA-induced lowering of the ejaculatory threshold. CONCLUSIONS: AEA appears to specifically target the ejaculatory threshold of SLG rats through the activation of CB1 receptors. This specificity along with the fact that AEA's effects are exerted acutely and at low doses makes this drug emerge as a promising treatment for the improvement of the ejaculatory response in men with primary delayed ejaculation. PMID- 25808994 TI - Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA. AB - Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase >=1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR. PMID- 25808996 TI - Palladium(II)/Bronsted Acid-Catalyzed Enantioselective Oxidative Carbocyclization Borylation of Enallenes. AB - An enantioselective oxidative carbocyclization-borylation of enallenes that is catalyzed by palladium(II) and a Bronsted acid was developed. Biphenol-type chiral phosphoric acids were superior co-catalysts for inducing the enantioselective cyclization. A number of chiral borylated carbocycles were synthesized in high enantiomeric excess. PMID- 25808997 TI - Insulin-like growth factor-1 (IGF-1) promotes myoblast proliferation and skeletal muscle growth of embryonic chickens via the PI3K/Akt signalling pathway. AB - During embryonic development, IGF-1 fulfils crucial roles in skeletal myogenesis. However, the involvement of IGF-1-induced myoblast proliferation in muscle growth is still unclear. In the present study, we have characterised the role of IGF-1 in myoblast proliferation both in vitro and in vivo and have revealed novel details of how exogenous IGF-1 influences myogenic genes in chicken embryos. The results show that IGF-1 significantly induces the proliferation of cultured myoblasts in a dose-dependent manner. Additionally, the IGF-1 treatment significantly promoted myoblasts entering a new cell cycle and increasing the mRNA expression levels of cell cycle-dependent genes. However, these effects were inhibited by the PI3K inhibitor LY294002 and the Akt inhibitor KP372-1. These data indicated that the pro-proliferative effect of IGF-1 was mediated in response to the PI3K/Akt signalling pathway. Moreover, we also showed that exogenous IGF-1 stimulated myoblast proliferation in vivo. IGF-1 administration obviously promoted the incorporation of BrdU and remarkably increased the number of PAX7-positive cells in the skeletal muscle of chicken embryos. Administration of IGF-1 also significantly induced the upregulation of myogenic factors gene, the enhancement of c-Myc and the inhibition of myostatin (Mstn) expression. These findings demonstrate that IGF-1 has strong activity as a promoter of myoblast expansion and muscle fiber formation during early myogenesis. Therefore, this study offers insight into the mechanisms responsible for IGF-1-mediated stimulation of embryonic skeletal muscle development, which could have important implications for the improvement of chicken meat production. PMID- 25808998 TI - IDENTIFICATION AND EXPRESSION ANALYSIS OF VITELLOGENIN RECEPTOR FROM THE WILD SILKWORM, Bombyx mandarina. AB - The vitellogenin receptor (VgR) plays a key role on embryonic development in oviparous animals. Here, we cloned a VgR gene, which was identified from the wild silkworm Bombyx mandarina (BmaVgR) using reverse transcriptase polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). Sequence analysis revealed that BmaVgR is 5,861 bp long with an open reading frame encoded by 1,811 amino acid residues. The predicted amino acid sequence has 99.7 and 98.2% identity with the VgRs of Actias selene and Bombyx mori, respectively. The class B domain sequence of BmaVgR was cloned and expressed in Escherichia coli, and purified by a Ni-NTA column. Polyclonal antibodies were produced against the purified recombinant protein, and titer of the antibody was about 1:12,800 measured by enzyme-linked immunosorbent assay (ELISA). Western blot and RT-qPCR showed that BmaVgR was expressed in the ovary and fat body of female larvae and the ovary of moth, and the expression level was highest at the third day and then declined from third day to seventh in fat body of pupa. After knockdown of the BmaVgR gene through RNA interference (RNAi), other three BmaVgR-related genes (Vg, egg-specific protein, and low molecular weight lipoprotein LP gene) were all downregulated significantly. PMID- 25808999 TI - Size control: the developmental physiology of body and organ size regulation. AB - The developmental regulation of final body and organ size is fundamental to generating a functional and correctly proportioned adult. Research over the last two decades has identified a long list of genes and signaling pathways that, when perturbed, influence final body size. However, body and organ size are ultimately a characteristic of the whole organism, and how these myriad genes and pathways function within a physiological context to control size remains largely unknown. In this review, we first describe the major size-regulatory signaling pathways: the Insulin/IGF-, RAS/RAF/MAPK-, TOR-, Hippo-, and JNK-signaling pathways. We then explore what is known of how these pathways regulate five major aspects of size regulation: growth rate, growth duration, target size, negative growth and growth coordination. While this review is by no means exhaustive, our goal is to provide a conceptual framework for integrating the mechanisms of size control at a molecular-genetic level with the mechanisms of size control at a physiological level. PMID- 25809000 TI - Detection of GHRP-2 and GHRP-6 in urine samples from athletes. PMID- 25809002 TI - Cell culture models for study of differentiated adipose cells. AB - Adipose cells are an important source of mesenchymal stem cells and are important for direct use in research on lipid metabolism and obesity. In addition to use of primary cultures, there is increasing interest in other sources of larger numbers of cells, using approaches including induced pluripotent stem cell differentiation and viral immortalisation. PMID- 25809003 TI - Parent questionnaires measuring feeding disorders in preschool children: a systematic review. AB - AIM: Preschool feeding disorders are common and debilitating and are associated with a range of developmental and medical issues. Parent report allows assessment of feeding in a naturalistic environment over time, with advantages over time limited, clinic-based observations. However, little is understood about the limitations and advantages of current parent-report measures. We aimed to systematically review the psychometrics and clinometrics of parent-administered feeding questionnaires. METHOD: Five search engines were used to identify questionnaires that met inclusion criteria, i.e. being norm-or criterion referenced, child focused, appropriate for preschool children, and measured two or more feeding domains (e.g. dysphagia/oral motor delay, food refusal). RESULTS: In total 3535 abstracts were identified and 215 full-text articles were evaluated. Five questionnaires met the criteria. The Behavioral Pediatrics Feeding Assessment Scale (BPFAS) was the most reliable questionnaire identified, with good test-retest reliability and internal consistency. More predictive and concurrent validity data was available for the BPFAS, the Mealtime Behavior Questionnaire, and the Montreal Children's Hospital Feeding Scale than for other measures. INTERPRETATION: Further research is needed on the psychometric properties of feeding questionnaires used in research and clinical practice. To date, the BPFAS has the most comprehensive reliability and validity data of any parent-administered feeding questionnaire for preschool children. PMID- 25809001 TI - Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene. AB - BACKGROUND: The asymptomatic carriers of the Leucine rich repeat kinase 2 (LRRK2) G2019S mutation represent a population at risk for developing PD. The aim of this study was to assess differences in nonmotor symptoms between nonmanifesting carriers and noncarriers of the G2019S mutation. METHODS: Two hundred fifty-three subjects participated in this observational cross-sectional multicenter study. Standard questionnaires assessing anxiety, depression, cognition, smell, nonmotor symptoms, and rapid eye movement (REM) sleep behavior were administered. Analyses were adjusted for age, sex, family relations, education, and site. RESULTS: One hundred thirty-four carriers were identified. Carriers had higher nonmotor symptoms score on the Nonmotor symptoms (NMS) questionnaire (P = 0.02). These findings were amplified in carriers older than age 50 y, with higher nonmotor symptoms scores and trait anxiety scores (P < 0.03). CONCLUSIONS: In this cross section study, carriers of the G2019S LRRK2 mutation endorsed subtle nonmotor symptoms. Whether these are early features of PD will require a longitudinal study. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 25809007 TI - Proteomic and functional profiles of a follicle-stimulating hormone positive human nonfunctional pituitary adenoma. AB - Nonfunctional pituitary adenoma (NFPA) is highly heterogeneous with different hormone-expressed subtypes in NFPA tissues including follicle-stimulating hormone (FSH) positive, luteinizing hormone-positive, FSH/luteinizing hormone-positive, and negative types. To analyze in-depth the variations in the proteomes among different NFPA subtypes for our long-term goal to clarify molecular mechanisms of NFPA and to detect tumor biomarker for personalized medicine practice, a reference map of proteome of a human FSH-expressed NFPA tissue was described here. 2DE and PDQuest image analysis were used to array each protein. MALDI-TOF PMF and human Swiss-Prot databases with MASCOT search were used to identify each protein. A good 2DE pattern with high level of between-gel reproducibility was attained with an average positional deviation 1.98 +/- 0.75 mm in the IEF direction and 1.62 +/- 0.68 mm in the SDS-PAGE direction. Approximately 1200 protein spots were 2DE-detected and 192 redundant proteins that were contained in 141 protein spots were PMF-identified, representing 107 nonredundant proteins. Those proteins were located in cytoplasm, nucleus, plasma membrane, extracellular space, and so on, and those functioned in transmembrane receptor, ion channel, transcription/translation regulator, transporter, enzyme, phosphatase, kinase, and so on. Several important pathway networks were characterized from those identified proteins with DAVID and Ingenuity Pathway Analysis systems, including gluconeogenesis and glycolysis, mitochondrial dysfunction, oxidative stress, cell cycle alteration, MAPKsignaling system, immune response, TP53-signaling, VEGF signaling, and inflammation signaling pathways. Those resulting data contribute to a functional profile of the proteome of a human FSH-positive NFPA tissue, and will serve as a reference for the heterogeneity analysis of NFPA proteomes. PMID- 25809008 TI - Hospital environment fungal contamination and aspergillosis risk in acute leukaemia patients in Sousse (Tunisia). AB - Hospital environment is considered the main source of invasive aspergillosis (IA) in leukemic patients. This study aimed to describe Aspergillus colonisation in leukemic patients and their hospital environment and to test whether Aspergillus environmental contamination was associated with IA. For a 2-year period including 14-month renovation work, 91 acute leukaemia inpatients at the hematology department of University hospital in Sousse (Tunisia) were prospectively included. The incidence of probable IA (EORTC/MSG criteria) was 9.9%. Fifty-six Aspergillus were isolated from 53 (6.5%) of 811 sputa collected from 35 (38.5%) patients. Aspergillus spp. were isolated in 59.7% of 494 air samples and in 52.8% of 1579 surface samples taken in the patients' room. Aspergillus section Nigri (72.7%) was the most frequent. Aspergillus contamination peaked in autumn and winter on surface and in summer and autumn in air samples and was higher (P = 0.03) during the renovation work period. Multivariate analysis showed that for each Aspergillus section Nigri CFU airborne contamination IA risk increased by 1.05 (P = 0.04). In Tunisia, Aspergillus section Nigri and Flavi, but not Fumigati, are chiefly involved in IA. Our findings support swift implementation of airborne fungal contamination control measures in areas where immunocompromised patient are hospitalised. PMID- 25809009 TI - Template Electrosynthesis of High-Performance Graphene Microengines. AB - Template-prepared graphene/Pt and graphene/Au tubular microengines, with extremely high electrocatalytic activity and propulsion efficiency, are described. The new bubble-propelled graphene/metal micromotors are synthesized rapidly and inexpensively by the direct electrodeposition of graphene oxide (GO) within the conical pores of a polycarbonate template membrane followed by deposition of the inner metal layer. The presence of high number of edges and defects in the graphene layer results in highly reactive microporous Pt or Au catalytic structures. The high catalytic activity leads to an ultrafast bubble propulsion (as high as 170 body lengths/sec) and operation at extremely low levels (0.1%) of the peroxide fuel. The effect of such dramatically enhanced catalytic surface area on the bubble growth and motor speed has been theoretically modeled. The template-prepared graphene-based microengines display distinct moving trajectories, along with long microbubble tails. The fast catalytic locomotion and attractive performance of the new graphene/Pt micromotors hold considerable promise for diverse applications. PMID- 25809010 TI - Establishment of Four New Human Primary Cell Cultures from Chemo-Naive Italian Osteosarcoma Patients. AB - Osteosarcoma (OS) is a primary highly malignant tumor of bone, affecting predominately adolescents and young adults between 10 and 20 years of age. OS is characterized by an extremely aggressive clinical course, with a rapid development of metastasis to the lung and distant bones. PMID- 25809011 TI - Effects of Glucosinolates from Turnip (Brassica rapa L.) Root on Bone Formation by Human Osteoblast-Like MG-63 Cells and in Normal Young Rats. AB - Turnip (Brassica rapa L.) root ethanol extract (TRE) was prepared, and its chemical constituents were characterized by ultra-performance liquid chromatography and mass spectrometry. Thirteen glucosinolates (GSLs) were identified, comprising eight aliphatic, four indolic, and one aromatic compounds. The effects of these GSLs on bone formation were investigated in vitro by incubating human osteoblast-like MG-63 cells with TRE and then analyzing their viability, alkaline phosphatase (ALP) activity, collagen content, and mineralization and in vivo by administering TRE orally to normal young rats (500 mg/kg/day) and assessing subsequent changes in serum osteocalcin and bone microstructure in these animals. No TRE-related toxicity was found, and the levels of cell viability, ALP activity, collagen synthesis, and mineralization were significantly increased relative to the negative control. In particular, stimulatory effects on the differentiation of MG-63 cells were strongly enhanced as compared with a positive control (daidzein). Serum osteocalcin was also significantly increased, and some important bone microstructural parameters were improved in TRE-administered rats compared with their saline-administered counterparts. GSLs therefore appear to have a stimulatory effect on bone formation in both MG-63 cells and normal young rats. This is the first report on the usefulness of turnip root and its GSL compounds for bone formation. PMID- 25809012 TI - The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post-first and post-second hematopoietic stem cell transplant. AB - The reported incidence of post-allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T-cell depletion, and chronic GvHD are significantly associated with post-transplant AIHA. During an 11 yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post-first and post-second transplants. Demographic, transplant, and post-transplant-related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post-first and post-second HSCT, respectively. Post-first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post-second transplant AIHA. The incidence of AIHA post-first and post-second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post transplant AIHA. PMID- 25809014 TI - Implications and considerations of thermal effects when applying irreversible electroporation tissue ablation therapy. AB - Irreversible electroporation (IRE) describes a cellular response to electric field exposure, resulting in the formation of nanoscale defects that can lead to cell death. While this behavior occurs independently of thermally-induced processes, therapeutic ablation of targeted tissues with IRE uses a series of brief electric pulses, whose parameters result in secondary Joule heating of the tissue. Where contemporary clinical pulse protocols use aggressive energy regimes, additional evidence is supplementing original studies that assert care must be taken in clinical ablation protocols to ensure the cumulative thermal effects do not induce damage that will alter outcomes for therapies using the IRE non-thermal cell death process for tissue ablation. In this letter, we seek to clarify the nomenclature regarding IRE as a non-thermal ablation technique, as well as identify existing literature that uses experimental, clinical, and numerical results to discretely address and evaluate the thermal considerations relevant when applying IRE in clinical scenarios, including several approaches for reducing these effects. Existing evidence in the literature describes cell response to electric fields, suggesting cell death from IRE is a unique process, independent from traditional thermal damage. Numerical simulations, as well as preclinical and clinical findings demonstrate the ability to deliver therapeutic IRE ablation without occurrence of morbidity associated with thermal therapies. Clinical IRE therapy generates thermal effects, which may moderate the non thermal aspects of IRE ablation. Appropriate protocol development, utilization, and pulse delivery devices may be implemented to restrain these effects and maintain IRE as the vastly predominant tissue death modality, reducing therapy mitigating thermal damage. Clinical applications of IRE should consider thermal effects and employ protocols to ensure safe and effective therapy delivery. PMID- 25809013 TI - Circulating anti-retinal antibodies in response to anti-angiogenic therapy in exudative age-related macular degeneration - reply. PMID- 25809015 TI - Donor liver histology--a valuable tool in graft selection. AB - BACKGROUND: Due to a tremendous organ shortage, livers from donors with extended criteria are increasingly considered for transplantation. Pathologists are more and more requested to evaluate these livers histopathologically using frozen sections at high urgency for acceptability. METHODS: This article reviews the current knowledge on pre-transplant histology in liver transplantation. Prerequisites and conditions for proper pre-transplant evaluation of donor liver tissue are discussed as well as frozen section evaluation and reporting. Data sources include the relevant medical literature, web sites specialized in organ transplantation, and the authors' experiences in liver transplant centers. CONCLUSIONS: Pre-transplant histopathological evaluation is a time-effective, accurate, and reliable tool to assess liver quality from candidate deceased donors. Pre-transplant biopsies are of value in the selection of donor livers for transplantation, especially in case of extended criteria donors, and should be performed more frequently in order to avoid unnecessary loss of organs suitable for transplantation and transplantation of inappropriate organs. Correlation of histopathological findings with clinical conditions is essential and requires excellent communication between pathologists, surgeons, and the other members of the transplant team. PMID- 25809016 TI - Population genetics of freeze tolerance among natural populations of Populus balsamifera across the growing season. AB - Protection against freeze damage during the growing season influences the northern range limits of plants. Freeze tolerance and freeze avoidance are the two major freeze resistance strategies. Winter survival strategies have been extensively studied in perennials, but few have addressed them and their genetic basis during the growing season. We examined intraspecific phenotypic variation in freeze resistance of Populus balsamifera across latitude and the growing season. To investigate the molecular basis of this variation, we surveyed nucleotide diversity and examined patterns of gene expression in the poplar C repeat binding factor (CBF) gene family. Foliar freeze tolerance exhibited latitudinal and seasonal variation indicative of natural genotypic variation. CBF6 showed signatures of recent selective sweep. Of the 46 SNPs surveyed across the six CBF homologs, only CBF2_619 exhibited latitudinal differences consistent with increased freeze tolerance in the north. All six CBF genes were cold inducible, but showed varying patterns of expression across the growing season. Some Poplar CBF homologs exhibited patterns consistent with historical selection and clinal variation in freeze tolerance documented here. However, the CBF genes accounted for only a small amount of the variation, indicating that other genes in this and other molecular pathways likely play significant roles in nature. PMID- 25809018 TI - Infection of farmed pigs with porcine kobuviruses in Italy. AB - Two-hundred eight swine fecal samples from six Italian farms were tested using a kobuvirus-specific RT-PCR with primers that amplify a region within the 3D gene. All farms were kobuvirus positive, with prevalence rates ranging between 24 % and 84 %. Overall, 57.5 % of asymptomatic pigs and 49.7 % of animals with diarrhea were positive for kobuvirus. Sequence analysis showed a different predominant strain circulating on each farm and indicated that the strains detected were related to both European and Asiatic strains. A possible pathogenic role of kobuvirus should be investigated further, since infections with this virus occur frequently in pigs of different ages. PMID- 25809017 TI - Behavior of POP-calcium carbonate hydrogel as bone substitute with controlled release capability: a study in rat. AB - Gypsum or calcium sulfate (CS) or plaster of Paris (POP) is considered as a fast degradable material that usually resorbs before the bone defect area is completely filled by new bone. In this study, the incorporation of CaCO3 hydrogel into POP in different compositions was proposed to enhance the bone biological activity of POP and to decrease its degradability. The mechanical and degradation properties of the various materials were characterized by in vitro analysis. Subsequently, the materials were inserted into cylindrically sized bone defects as created into the femoral condyle of rats and left in situ for 1, 4, and 8 weeks. Histological analysis of the retrieved specimens indicated that the addition of CaCO3 hydrogel into POP increased bone formation, angiogenesis and collagen density and resulted into faster bone formation and maturation. It was also confirmed that the degradation rate of the POP decreased by the addition of CaCO3 hydrogel. The in vivo findings did corroborate with the in vitro analysis. In conclusion, the incorporation of CaCO3 hydrogel provides a promising technology to improve the properties of POP, the oldest biomaterial used for bone grafting. PMID- 25809019 TI - Genetic variability of blueberry scorch virus isolates from highbush blueberry in New York State. AB - The genetic variability of blueberry scorch virus (BlScV) isolates from New York was determined within a portion of the RNA-dependent RNA polymerase gene and the triple gene block and coat protein (CP) genes. Phylogenetic analysis of 19 New York isolates and other isolates for which sequence information is available in GenBank revealed two distinct clades, regardless of the coding region analyzed, and limited variability within (0.029 +/- 0.007) and between (0.183 +/- 0.032) phylogroups. Recombination events were identified in the CP gene of three New York isolates, and codons of the five BlScV genes characterized were found to be under neutral or negative selective pressure. PMID- 25809020 TI - Staying alive: rethinking deterritorialization in a post-feminist era. AB - In recent years, the concept 'post-feminism' and its links to neoliberal economic structures and to the extreme reinforcement of individualization as raison d'etre of Western civilization have been discussed at length by numerous distinguished scholars in feminist cultural studies and feminist philosophy. This article takes its point of departure in this discussion. Drawing on Wendy Brown, Elizabeth Grosz, Angela McRobbie, Wendy Larner, and others, the text is examining the discourse of post-feminism and neoliberalism, and its effects on overarching political scenarios, as well as on everyday life: What happens to feminist politics when the collective, both as figuration and as virtual political platform, is deemed to be something situated in the discursive outskirts? By drawing on examples form the contemporary cultural imaginaries, from popular culture, economic structures, and public debate, and by pointing out the links between the micro-perspective of our everyday living and overarching political structures, this article aims at bringing to the fore and critically discuss these issues, and the ways in which they intersect with contemporary Western feminism. The article ends with a discussion of possible points of exit or paths to follow in order to find alternatives. PMID- 25809022 TI - Synthesizing Econometric Evidence: The Case of Demand Elasticity Estimates. AB - Econometric estimates of the responsiveness of health-related consumer demand to higher prices are often key ingredients for risk policy analysis. We review the potential advantages and challenges of synthesizing econometric evidence on the price-responsiveness of consumer demand. We draw on examples of research on consumer demand for health-related goods, especially cigarettes. We argue that the overarching goal of research synthesis in this context is to provide policy relevant evidence for broad-brush conclusions. We propose three main criteria to select among research synthesis methods. We discuss how in principle and in current practice synthesis of research on the price-elasticity of smoking meets our proposed criteria. Our analysis of current practice also contributes to academic research on the specific policy question of the effectiveness of higher cigarette prices to reduce smoking. Although we point out challenges and limitations, we believe more work on research synthesis in this area will be productive and important. PMID- 25809021 TI - Rosuvastatin Enhances the Catabolism of LDL apoB-100 in Subjects with Combined Hyperlipidemia in a Dose Dependent Manner. AB - Dose-associated effects of rosuvastatin on the metabolism of apolipoprotein (apo) B-100 in triacylglycerol rich lipoprotein (TRL, d < 1.019 g/ml) and low density lipoprotein (LDL) and of apoA-I in high density lipoprotein (HDL) were assessed in subjects with combined hyperlipidemia. Our primary hypothesis was that maximal dose rosuvastatin would decrease the apoB-100 production rate (PR), as well as increase apoB-100 fractional catabolic rate (FCR). Eight subjects received placebo, rosuvastatin 5 mg/day, and rosuvastatin 40 mg/day for 8 weeks each in sequential order. The kinetics of apoB-100 in TRL and LDL and apoA-I in HDL were determined at the end of each phase using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Rosuvastatin at 5 and 40 mg/day decreased LDL cholesterol by 44 and 54% (both P < 0.0001), triacylglycerol by 14% (ns) and 35% (P < 0.01), apoB by 30 and 36% (both P < 0.0001), respectively, and had no significant effects on HDL cholesterol or apoA I levels. Significant decreases in plasma markers of cholesterol synthesis and increases in cholesterol absorption markers were observed. Rosuvastatin 5 and 40 mg/day increased TRL apoB-100 FCR by 36 and 46% (both ns) and LDL apoB-100 by 63 and 102% (both P < 0.05), respectively. HDL apoA-I PR increased with low dose rosuvastatin (12%, P < 0.05) but not with maximal dose rosuvastatin. Neither rosuvastatin dose altered apoB-100 PR or HDL apoA-I FCR. Our data indicate that maximal dose rosuvastatin treatment in subjects with combined hyperlipidemia resulted in significant increases in the catabolism of LDL apoB-100, with no significant effects on apoB-100 production or HDL apoA-I kinetics. PMID- 25809023 TI - Cutaneous infections caused by rapidly growing mycobacteria: case reports and review of clinical and laboratory aspects. AB - Skin and soft tissue infections caused by rapidly growing non-tuberculous mycobacteria (RG-NTM) have become a growing clinical concern over the past decades. These RG-NTM are ubiquitous environmental organisms and most are resistant to traditional antituberculous agents. In this report, we describe 3 cutaneous infections caused by RG-NTM, namely, Mycobacterium abscessus, M. chelonae, and M. conceptionense, and present the clinical and laboratory characteristics of these infections. PMID- 25809025 TI - The Cryptophlebia leucotreta granulovirus-10 years of commercial field use. AB - In the last 15 years, extensive work on the Cryptophlebia leucotreta granulovirus (CrleGV) has been conducted in South Africa, initially in the laboratory, but subsequently also in the field. This culminated in the registration of the first CrleGV-based biopesticide in 2004 (hence, the 10 years of commercial use in the field) and the second one three years later. Since 2000, more than 50 field trials have been conducted with CrleGV against the false codling moth, Thaumatotibia leucotreta, on citrus in South Africa. In a representative sample of 13 field trials reported over this period, efficacy (measured by reduction in larval infestation of fruit) ranged between 30% and 92%. Efficacy was shown to persist at a level of 70% for up to 17 weeks after application of CrleGV. This only occurred where the virus was applied in blocks rather than to single trees. The addition of molasses substantially and sometimes significantly enhanced efficacy. It was also established that CrleGV should not be applied at less than ~2 * 1013 OBs per ha in order to avoid compromised efficacy. As CrleGV-based products were shown to be at least as effective as chemical alternatives, persistent and compatible with natural enemies, their use is recommended within an integrated program for control of T. leucotreta on citrus and other crops. PMID- 25809026 TI - Time trends in lifetime incidence rates of first-time diagnosed anorexia nervosa and bulimia nervosa across 16 years in a Danish nationwide psychiatric registry study. AB - OBJECTIVE: To study recent time trends in the incidence of diagnosed anorexia nervosa (AN) and bulimia nervosa (BN) based on nationwide psychiatric register data. METHOD: The Danish Psychiatric Central Research Registry was used to identify the incidence of diagnosed cases with AN and BN at the ages of 4-65 years from 1995 to 2010. Age- and sex-adjusted incidence rates per 100,000 person years were calculated and were adjusted for time trends in the total number of people diagnosed in psychiatry. Time trends were analyzed using JoinPoint regression analysis. RESULTS: A total of N = 5,902 persons had a first-time incidence of AN, and a total of N = 5,113 had first-time incidence of BN. Incidence rates increased for AN from 6.4 to 12.6 per 100,000 person-years, and for BN from 6.3 to 7.2 per 100,000 person-years. In 2010, the male-to-female ratio was 1:8 for AN, and 1:20 for BN. There was an earlier onset for AN than for BN, and age at incidence decreased during the observation period for AN but not for BN. A sizeable part of the increasing incidence rates for AN and in particular, the younger AN age groups, could be attributed to an increase in the total number of N = 249,607 persons with first-time diagnoses in psychiatry. DISCUSSION: Incidence rates had increased slightly for AN, but were stable for BN across 16 years in this nationwide study and to a large extent were reflective of a general increase in diagnosed mental disorders. PMID- 25809028 TI - TRPs revisited. PMID- 25809027 TI - Lu/BCAM-mediated cell adhesion as biological marker of JAK2V617F activity in erythrocytes of polycythemia vera patients. PMID- 25809029 TI - Revival of an old standard. PMID- 25809030 TI - Nurse-led eye clinic opens to meet demand in Wales. PMID- 25809033 TI - Cuddly 'seal pup' robot helps patients with dementia to relax. PMID- 25809031 TI - 'Vanguards' to test ideas for radical redesign of NHS. PMID- 25809034 TI - Guidance on covert filming in care homes issued by watchdog. PMID- 25809035 TI - Nursing students need general grounding before they specialise. PMID- 25809036 TI - Poor pay and conditions threaten homecare market. PMID- 25809037 TI - Hospice staff given stress-busting advice as complexity of role grows. PMID- 25809041 TI - A smoother pathway. PMID- 25809047 TI - Practice question. Extending the scope of practice. PMID- 25809048 TI - Risk factors for and assessment of constipation. AB - Constipation commonly occurs in older people, particularly in hospital or residential care settings, and leads to decreased quality of life and increased healthcare costs. Despite its frequency, however, nurses often overlook the condition. One possible reason for this may be the lack of appropriate tools or scales for nurses to assess risk factors for developing constipation. This article identifies, from the academic literature, 14 risk factors for developing constipation in older people. These factors are then considered in light of four common constipation assessment charts. The article concludes by arguing the need for more comprehensive assessment tools to, firstly, identify risk factors; and, secondly, support the implementation of appropriate preventative strategies that will enable better health outcomes for older people. PMID- 25809049 TI - The role of the named nurse in long-term settings. AB - The term 'named nursing' was introduced in the UK more than 25 years ago but it has re-emerged recently in the light of recommendations made in the Francis report on the poor standards of care at Mid-Staffordshire NHS Foundation Trust. The original definition of named nurse by the Department of Health was someone that a patient could identify as responsible for their care from hospital admission to discharge. It was largely practised in the UK exclusively but there are now various accounts of its use throughout Europe, particularly Scandinavia, and North America. This article provides an overview of the named nursing concept. It provides recommendations for implementation of a named nursing system in nursing home settings, because most previous recommendations have referred to acute hospitals. PMID- 25809050 TI - Effect of time of day on language in healthy ageing and Alzheimer's disease. AB - AIM: To investigate whether narrative discourse followed a diurnal pattern across one ten-hour day in healthy ageing people and those with mild to moderate Alzheimer's disease (AD). METHOD: Ten healthy ageing people and ten clinically labelled with probable AD were recruited. Measurements of language and cognition were collected across one day at 9am, 12pm, 3pm and 6pm. Language samples were evaluated for quantity (total utterances and words per minute) and quality: mazes or fillers, repetitions and revisions, abandoned utterances and type token ratio or percentage of different words to total words. RESULTS: The healthy ageing group performed significantly better on cognitive measures across the day than the AD group. At all times the healthy ageing group produced significantly longer narrative samples that were significantly less aborted and revised than the AD group. Additionally, both groups demonstrated declining narrative performance as the day progressed. CONCLUSION: Based on these results, time of day may be an additional factor that moderates narrative performance. This change in narrative ability may have an effect on making a proper diagnosis, therapeutic effectiveness and patient interactions, therefore affecting quality of care. PMID- 25809051 TI - The art of listening. PMID- 25809053 TI - Human fetal osteoblast behavior on zirconia dental implants and zirconia disks with microstructured surfaces. An experimental in vitro study. AB - OBJECTIVES: To measure the lateral surface area of microgrooved zirconia implants, to evaluate the cell geometry and cell density of human fetal osteoblasts seeded on zirconia microgrooved implants, to describe the surface roughness and chemistry, and to evaluate the activity of human fetal osteoblasts seeded on zirconia microgrooved disks. MATERIALS AND METHODS: This experimental in vitro study used 62 zirconia implants and 130 zirconia disks. Two experimental groups were created for the implants: 31 non-microgrooved implants (Control) and 31 microgrooved implants (Test); two experimental groups were created for the disks: 65 non-microgrooved disks (Control) and 65 microgrooved disks (Test). The following evaluations of the implants were made: lateral surface area (LSA), cell morphology, and density of human fetal osteoblasts seeded on implant surfaces. On the disks, surface parameters (roughness and chemistry) and cell activity (alkaline phosphatase - ALP and alizarin red - ALZ) were evaluated at 7 and 15 days. RESULTS: LSA was lower for control implants (62.8 mm) compared with test implants (128.74 mm) (P < 0.05). Cell bodies on control surfaces were flattened and disorganized, while in the test group, they were aligned inside the microgrooves. Control group cells showed few lamellipodia, which were attached mainly inside topographical accidents (surface cracks, valleys, and pits). Test group implants presented cells rich in lamellipodia prolongations, attached to the inner walls or to the borders of the microgrooves and in the flat areas between the microgrooves. Cell density was higher in the test group compared with controls (P < 0.05) Surface roughness and oxygen content increased in test disks samples compared with controls (P < 0.05). Carbon and aluminum were reduced in disks test samples compared with controls (P < 0.05), and ALP and ALZ levels were significantly increased on test surfaces (P < 0.05) at both study times. CONCLUSIONS: Within the limitations of this experimental study, it may be concluded that (i) Roughness is increased and chemical composition enhanced on the surface of zirconia implants with microgrooves. (ii) The LSA of microgrooved zirconia implants is greater and provides more available surface compared with implants of the same dimensions without microgrooves. (iii) Microgrooves on zirconia implants modify the morphology and guide the size and alignment of human fetal osteoblasts. (iv) Zirconia surfaces with microgrooves of 30 MUm width and 70 MUm separation between grooves enhance ALP and ALZ expression by human fetal osteoblasts. PMID- 25809052 TI - Early life stress is associated with default system integrity and emotionality during infancy. AB - BACKGROUND: Extensive animal research has demonstrated the vulnerability of the brain to early life stress (ELS) with consequences for emotional development and mental health. However, the influence of moderate and common forms of stress on early human brain development is less well-understood and precisely characterized. To date, most work has focused on severe forms of stress, and/or on brain functioning years after stress exposure. METHODS: In this report we focused on conflict between parents (interparental conflict), a common and relatively moderate form of ELS that is highly relevant for children's mental health outcomes. We used resting state functional connectivity MRI to examine the coordinated functioning of the infant brain (N = 23; 6-12-months-of-age) in the context of interparental conflict. We focused on the default mode network (DMN) due to its well-characterized developmental trajectory and implications for mental health. We further examined DMN strength as a mediator between conflict and infants' negative emotionality. RESULTS: Higher interparental conflict since birth was associated with infants showing stronger connectivity between two core DMN regions, the posterior cingulate cortex (PCC) and the anterior medial prefrontal cortex (aMPFC). PCC to amygdala connectivity was also increased. Stronger PCC-aMPFC connectivity mediated between higher conflict and higher negative infant emotionality. CONCLUSIONS: The developing DMN may be an important marker for effects of ELS with relevance for emotional development and subsequent mental health. Increasing understanding of the associations between common forms of family stress and emerging functional brain networks has potential to inform intervention efforts to improve mental health outcomes. PMID- 25809055 TI - Relationship between the FAS gene A-670G polymorphism and Alzheimer's disease: a meta-analysis. AB - BACKGROUNDS AND AIMS: The pathogenetic mechanism of Alzheimer's disease (AD) is still unknown; however, gene polymorphism may play a critical role in the pathogenesis of AD. The aim of this meta-analysis was to evaluate the association between FAS gene A-670G polymorphism and AD. METHODS: We searched all related subjects in PubMed, Embase, Cochrane Library, SinoMed, and the China Knowledge Resource Integrated Database and identified seven studies reporting a relationship between the A-670G polymorphism in the FAS gene and AD. RESULTS: A total of 1512 cases and 1707 controls were included in the seven studies. The meta-analyses results suggested no significant association between the A-670G polymorphism and AD in any genetic models. When a subgroup analysis was conducted by ethnicity, the A-670G polymorphism was also not relevant to AD. However, when stratified by age, the GG genotype increased the risk of early-onset AD. We also found that the A-670G polymorphism was related to patients with AD who carried the apolipoprotein-E epsilon4 allele in three genetic models. CONCLUSIONS: To sum up, our data suggested that the FAS gene A-670G polymorphism may not be associated with AD. When a subgroup analysis was conducted by ethnicity, the A 670G polymorphism was also not related with AD in Asian and Caucasian population. However, the FAS-670 GG genotype may increase the risk of AD in the younger population (age, <=65 years). Furthermore, we found that the A-670G polymorphism was related to patients with AD who carried the APOE4 allele in dominant, allele and homozygous models. PMID- 25809056 TI - Efficacy and spatial distribution of ultrasound-mediated clot lysis in the absence of thrombolytics. AB - Ultrasound and microbubble (MB) contrast agents accelerate clot lysis, yet clinical trials have been performed without defining optimal acoustic conditions. Our aim was to assess the effect of acoustic pressure and frequency on the extent and spatial location of clot lysis. Clots from porcine blood were created with a 2-mm central lumen for infusion of lipid-shelled perfluorocarbon MBs (1*10(7) ml( 1)) or saline. Therapeutic ultrasound at 0.04, 0.25, 1.05, or 2.00 MHz was delivered at a wide range of peak rarefactional acoustic pressure amplitudes (PRAPAs). Ultrasound was administered over 20 minutes grouped on-off cycles to allow replenishment of MBs. The region of lysis was quantified using contrast enhanced ultrasound imaging. In the absence of MBs, sonothrombolysis did not occur at any frequency. Sonothrombolysis was also absent in the presence of MBs despite their destruction at 0.04 and 2.00 MHz. It occurred at 0.25 and 1.05 MHz in the presence of MBs for PRAPAs > 1.2 MPa and increased with PRAPA. At 0.25 MHz the clot lysis was located in the far wall. At 1.05 MHz, however, there was a transition from far to near wall as PRAPA was increased. The area of clot lysis measured by ultrasound imaging correlated with that by micro-CT and quantification of debris in the effluent. In conclusion, sonothrombolysis with MBs was most efficient at 0.25 MHz. The spatial location of sonothrombolysis varies with pressure and frequency indicating that the geometric relation between therapeutic probe and vascular thrombosis is an important variable for successful lysis clinically. PMID- 25809054 TI - The Report-AGE project: a permanent epidemiological observatory to identify clinical and biological markers of health outcomes in elderly hospitalized patients in Italy. AB - BACKGROUND: Italy is expected to experience the largest growth in persons >=65 years (>20% by 2020). This demographic shift allows for geriatric research on predictive clinical and biological markers of outcomes related to frailty, re hospitalization and mortality. AIMS: To describe rationale and methods of the Report-AGE study project of acute care patients in Italian National Research Center on Aging (INRCA) research hospitals. METHODS: Report-AGE study is a large observational study on health conditions and outcomes of hospitalized elderly patients (>=65 years). The primary objective of the study is to create a high level data resource of demographics, comprehensive geriatric assessments, clinical and diagnostic information, as well as biological and molecular markers in all older patients admitted to INRCA Hospitals. Assessments in physical and nutritional parameters, co-morbid health conditions, and associations with frailty parameters are ongoing in older hospitalized adults following an acute event. Study collection began in September 2011. RESULTS: Up to date, there are 3479 patients >=65 years (mean age: 85 +/- 7years) with 1543 men and 1936 women enrolled. Data have been recorded regarding functional and clinical parameters before, during hospital admission and at discharge. Data collection for primary outcome analyses related to re-hospitalization and mortality is estimated for September 2016. DISCUSSION: This study aims at collecting precise clinical data, comprehensive geriatric assessment, risk factors, and biological data from acute care patients. Data will also be used to identify mechanisms underlying frailty in this specific population. CONCLUSION: This study provides a descriptive epidemiological collection of the health conditions of older in-patients. PMID- 25809057 TI - Codeine should not be prescribed for breastfeeding mothers or children under the age of 12. AB - Medical regulatory authorities, including the Food and Drug Administration and European Medicine Agency, have published restrictions regarding the use of codeine in paediatric patients and breastfeeding mothers. This review explored the various parameters that are involved in the metabolism and toxicology of codeine in these two populations. CONCLUSION: The growing volume of data on potential serious adverse events and questionable efficacy indicates that codeine should not be prescribed for children under 12 years of age and breastfeeding mothers. PMID- 25809059 TI - The Implementation of the Bethesda System for Reporting Thyroid Cytopathology Improves Malignancy Detection Despite Lower Rate of Thyroidectomy in Indeterminate Nodules. AB - BACKGROUND: The Bethesda system for reporting thyroid cytopathology (TBSRTC) was developed in 2009 to standardize the terminology for interpreting fine-needle aspiration (FNA) specimens. METHODS: A historical prospective case series design was employed. The study group included patients with a thyroid nodule classified as TBSRTC AUS/FLUS (B3) or FN/SFN (B4) in 2011-2012 in a tertiary university affiliated medical center. Rates of surgery and malignancy detection were compared to our pre-TBSRTC (1999-2000) study. RESULTS: Of 3927 nodules aspirated, 575 (14.6%) were categorized as B3/B4. Complete data were available for 322. Thyroidectomy was performed in 123 (38.2%) cases: 66/250 (26.4%) B3 and 57/72 (79.2%) B4. Differentiated thyroid cancer was found in 66 (53.7%) patients: 30/66 (45.5%) B3 and 36/57 (63.2%) B4 (p=0.075). Operated patients were younger than the non-operated (B3: 52.4+/-16 vs. 59.7+/-13 years, p=0.009; B4: 51.7+/-15 vs. 60.5+/-14 years, p=0.042), and operated B3 nodules were larger than the non operated (27.2 vs. 22.2 mm, p=0.014). Additional FNA was done in 160 patients (49.7%): 137/250 (54.8%) B3 and 23/72 (31.9%) B4 (p=0.002). The additional B3 nodules aspirations yielded a diagnosis of B2 in 84 patients (61.3%), B3 in 48 (35%), and B4 in 5 (3.6%). Of the 23 repeated B4 aspirations, B2 was reported in 5 (21.7%), B3 in 12 (52.2%), B4 in 4 (17.4%), and B6 in 2 (8.7%). The number of aspirated nodules was twice that reported in 1999-2000. The rate of indeterminate nodules increased from 6 to 14.6%, the surgery rate decreased from 52.3 to 38.2%, and the accuracy of malignancy diagnosis increased from 25.9 to 53.7%. CONCLUSIONS: The application of TBSRTC significantly improves diagnostic accuracy for indeterminate thyroid nodules, leading to higher rates of malignancy detection despite lower rates of thyroidectomies. PMID- 25809058 TI - Detection of Toxoplasma gondii DNA in horse meat from supermarkets in France and performance evaluation of two serological tests. AB - In France, some cases of severe toxoplasmosis have been linked to the consumption of horse meat that had been imported from the American continent where atypical strains of Toxoplasma gondii are more common than in Europe. Many seroprevalence studies are presented in the literature but risk assessment of T. gondii infection after horse meat consumption is not possible in the absence of validated serological tests and the unknown correlation between detection of antibodies against T. gondii and presence of tissue cysts. We performed magnetic capture polymerase chain reaction (MC-PCR) to detect T. gondii DNA in 231 horse meat samples purchased in supermarkets in France and evaluated the performance and level of agreement of the modified agglutination test (MAT) and enzyme-linked immunosorbent assay (ELISA) in the meat juices. The serological tests lacked sensitivity, specificity, and agreement between them, and there was no correlation with the presence of T. gondii DNA in horse meat, raising concerns about the reliability of T. gondii seroprevalence data in horses from the literature. T. gondii DNA was detected in 43% of horse meat samples but the absence of strain isolation in mice following inoculation of more than 100 horse meat samples suggests a low distribution of cysts in skeletal muscles and a low risk of T. gondii infection associated with horse meat consumption. However, to avoid any risk of toxoplasmosis, thorough cooking of horse meat is recommended. PMID- 25809061 TI - Changing Trends in Thyroid and Parathyroid Surgery Over the Decade: Is Same Day Discharge Feasible in the United Kingdom?: Reply. PMID- 25809060 TI - High False Positivity in Positron Emission Tomography is a Potential Diagnostic Pitfall in Patients with Suspected Adrenal Metastasis. AB - BACKGROUND: Although 18F-fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET/CT) is a potentially powerful, non invasive imaging tool in differentiating adrenal metastasis from benign disease, some adenomas also exhibit high FDG uptake, therefore mimicking metastasis (i.e., false positives). We aimed to evaluate the accuracy of FDG-PET/CT based exclusively on histology and to identify risk factors for adrenal metastasis. METHODS: Among the 289 consecutive patients who underwent adrenalectomy, 39 (78.0%) patients had suspected solitary adrenal metastasis and had a positive preoperative FDG-PET/CT. The FDG-PET/CT findings were correlated with the histology of the excised adrenal gland. To identify risk factors for adrenal metastasis, characteristics were compared between patients with histologically proven adrenal metastasis and those without. Youden's index was used to calculate the optimal cut-off value for predicting adrenal metastasis. RESULTS: Histology of the excised adrenal tumor confirmed adrenal metastasis in 28/39 (71.8%) patients while non-metastatic lesions comprised mostly benign adrenal cortical adenoma (n=10) and one non-functional pheochromocytoma. Therefore, the overall false-positive rate of FDG-PET/CT was 28.2%. History of primary lung malignancy [odds ratio (OR) (95% CI) 20.00 (1.01-333.3), p=0.049] and SUVmax>2.65 [OR (95% CI) 31.606 (2.46-405.71), p=0.008] were independent risk factors for adrenal metastasis. CONCLUSIONS: Single adrenal uptake on FDG-PET/CT in suspected solitary adrenal metastasis was associated with a high false-positive rate (28.2%). Risk factors associated with adrenal metastasis included a history of known primary lung malignancy and a SUVmax>2.65 at the adrenal lesion of interest on FDG-PET/CT. Based on these findings, a new algorithm was constructed. PMID- 25809062 TI - The Effect of beta-blockade on Survival After Isolated Severe Traumatic Brain Injury. AB - BACKGROUND: Several North American studies have observed survival benefit in patients exposed to beta-blockers following traumatic brain injury (TBI). The purpose of this study was to evaluate the effect of beta-blockade on mortality in a Swedish cohort of isolated severe TBI patients. METHODS: The trauma registry of an urban academic trauma center was queried to identify patients with an isolated severe TBI between 1/2007 and 12/2011. Isolated severe TBI was defined as an intracranial injury with an Abbreviated Injury Scale (AIS)>=3 excluding extra cranial injuries AIS>=3. Multivariable logistic regression analysis was used to determine the effect of beta-blocker exposure on mortality. Also, a subgroup analysis was performed to investigate the risk of mortality in patients on pre admission beta-blocker versus not and the effect of specific type of beta-blocker on the overall outcome. RESULTS: Overall, 874 patients met the study criteria. Of these, 33% (n=287) were exposed to beta-blockers during their hospital admission. The exposed patients were older (62+/-16 years vs. 49+/-21 years, p<0.001), and more severely injured based on their admission GCS, ISS, and head AIS scores (GCS<=8: 32% vs. 28%, p=0.007; ISS>=16: 71% vs. 59%, p=0.001; head AIS>=4: 60% vs. 45%, p<0.001). The crude mortality was higher in patients who did not receive beta-blockers (17% vs. 11%, p=0.007) during their admission. After adjustment for significant confounders, the patients not exposed to beta-blockers had a 5-fold increased risk of in-hospital mortality (AOR 5.0, CI 95% 2.7-8.5, p=0.001). No difference in survival was noted in regards to the type of beta-blocker used. Subgroup analysis revealed a higher risk of mortality in patients naive to beta blockers compared to those on pre-admission beta-blocker therapy (AOR 3.0 CI 95% 1.2-7.1, p=0.015). CONCLUSIONS: beta-blocker exposure after isolated severe traumatic brain injury is associated with significantly improved survival. We also noted decreased mortality in patients on pre-admission beta-blocker therapy compared to patients naive to such treatment. Further prospective studies are warranted. PMID- 25809063 TI - Comorbidity-Polypharmacy Score as Predictor of Outcomes in Older Trauma Patients: A Retrospective Validation Study. AB - INTRODUCTION: Traditional injury severity assessment is insufficient in estimating the morbidity and mortality risk for older (>=45 years) trauma patients. Commonly used tools involve complex calculations or tables, do not consider all comorbidities, and often rely on data that are not available early in the trauma patient's hospitalization. The comorbidity-polypharmacy score (CPS), a sum of all pre-injury medications and comorbidities, was found in previous studies to independently predict morbidity and mortality in this older patient population. However, these studies are limited by relatively small sample sizes. Consequently, we sought to validate previous research findings in a large, administrative dataset. METHODS: A retrospective study of patients ages>=45 years was performed using an administrative trauma database from St. Luke's University Hospital's Level I Trauma Center. The study period was from 1 January 2008 to 31 December 2013. Abstracted data included patient demographics, injury mechanism and severity [injury characteristics and severity score (ISS)], Glasgow coma scale (GCS), hospital and intensive care unit lengths of stay (HLOS and ILOS, respectively), morbidity, post-discharge destination, and in-hospital mortality. Univariate analyses were conducted with mortality, all-cause morbidity, and discharge destination as primary end-points. Variables reaching statistical significance (p<=0.20) were included in a multivariate logistic regression model. Data are presented as adjusted odds ratios (AORs), with p<0.05 denoting statistical significance. RESULTS: A total of 5863 patient records were analyzed. Average patient age was 68.5+/-15.3 years (52% male, 89% blunt mechanism, mean GCS 14.3). Mean HLOS and ILOS increased significantly with increasing CPS (p<0.01). Independent predictors of mortality included age (AOR 1.05, p<0.01), CPS (per-unit AOR 1.08, p<0.02), GCS (AOR 1.43 per-unit decrease, p<0.01), and ISS (per-unit 1.08, p<0.01). Independent predictors of all-cause morbidity included age (AOR 1.02, p<0.01), GCS (AOR per-unit decrease 1.08, p<0.01), ISS (per-unit AOR 1.09, p<0.01), and CPS (per-unit AOR 1.04, p<0.01). CPS did not independently predict need for discharge to a facility. CONCLUSIONS: This study confirms that CPS is an independent predictor of all-cause morbidity and mortality in older trauma patients. However, CPS was not independently associated with need for discharge to a facility. Prospective multicenter studies are needed to evaluate the use of CPS as a predictive and interventional tool, with special focus on correlations between specific pre-existing conditions, pharmacologic interactions, and morbidity/mortality patterns. PMID- 25809064 TI - Validation and Comparison of Nomograms in Predicting Disease-Specific Survival for Papillary Thyroid Carcinoma. AB - BACKGROUND: Nomogram could estimate individualized prognosis in papillary thyroid carcinoma (PTC). We aimed to create and validate a new nomogram and compare it with other published nomograms using a large patient cohort. METHODS: Eight hundred and forty-nine PTC patients with >=7 years follow-up were randomly assigned to the development (n=425) and validation (n=424) groups. The former was used for developing a nomogram for disease-specific survival (DSS), while the latter was for validating the nomogram by discrimination [or area under curve (AUC)]. AUC of the newly developed nomogram was compared to other published nomograms. RESULTS: The 5- and 10-year risk of dying from PTC were 1.4 and 3.3%, respectively, while dying from non-PTC-related causes were 2.3 and 5.1%, respectively. The new nomogram was developed from age, tumor size, multifocality, nodal status and distant metastases. The discrimination was excellent (AUC (95% CI) for 5- and 10-year DSS were 0.896 (0.683-0.971) and 0.919 (0.871-0.967), respectively). Its predictability was similar to other published nomograms (p>0.05). Based on the new nomogram, a total score of <28 meant 99.72% chance of surviving from PTC at 10 years while a score of >=28 meant 9.09% chance of dying from PTC at 10 years. CONCLUSIONS: Using variables from the current tumor node metastasis (TNM) staging system, a new nomogram was developed. It exhibited excellent discriminatory ability and accuracy in predicting 10-year DSS relative to other published nomograms. However, given the excellent prognosis of PTC, the new nomogram was better at ruling out than predicting PTC-related death. Further validation by an external cohort is required. PMID- 25809065 TI - Ultrasound Diagnosis of Pneumothorax in Blunt Trauma: Reply. PMID- 25809066 TI - Global Surgery in the Elderly must Focus on Education. PMID- 25809068 TI - Preoperative Sarcopenia Negatively Impacts Postoperative Outcomes Following Major Hepatectomy with Extrahepatic Bile Duct Resection. PMID- 25809067 TI - Implementation of an Enhanced Recovery Pathway After Pancreaticoduodenectomy in Patients with Low Drain Fluid Amylase. AB - INTRODUCTION: The safety and feasibility of an enhanced recovery pathway (ERP) after pancreatic surgery is largely unknown. Our aim was to prospectively evaluate a targeted ERP after pancreaticoduodenectomy (PD), using first postoperative day (POD) drain fluid amylase (DFA1) values to identify patients at low risk of pancreatic fistula (PF). PATIENTS AND METHODS: Non-randomized cohort study of 130 consecutive patients. Perioperative outcomes were compared before (pre-ERP; N=65) and after (post-ERP; N=65) implementation of an ERP. Patients in each group were stratified according to the risk of PF using DFA1<350 IU/l. Low risk patients in the post-ERP group were selected for early oral intake and early drain removal. RESULTS: 81/130 patients had a DFA1<350. Incidence of PF was significantly lower in low-risk patients (9 vs. 45%, P=0.0001). In low-risk patients, morbidity (43 vs. 36%) and mortality (2.7 vs. 4.5%) were similar for both pre- and post-ERP patients. Hospital stay (median 9 vs. 7 days, P=0.03) and 30-day readmissions (17 vs. 2%, P=0.04) were lower in low-risk patients in the post-ERP group. In high-risk patients, there was no difference in outcomes between pre- and post-ERP. CONCLUSION: Patients at low risk of PF after PD can be identified by first POD DFA1. Enhanced recovery after PD is safe and leads to improved short-term outcomes in low-risk patients. PMID- 25809069 TI - Relative Risk of Prolonged Operative Times From Inconsistent Surgical Teams: Reply. PMID- 25809070 TI - Effects of different maturity stages and growing locations on changes in chemical, biochemical and aroma volatile composition of 'Wonderful' pomegranate juice. AB - BACKGROUND: This study investigated the changes in chemical attributes of pomegranate fruit such as total soluble solids (TSS), titratable acidity (TA), TSS/TA ratio, pH, individual compounds (organic acids and sugars) and volatile composition as affected by fruit maturity status and growing location (Kakamas, Koedoeshoek and Worcester in South Africa). Headspace solid phase microextraction coupled with gas chromatography/mass spectrometry was used for volatile analysis. RESULTS: A significant increase in TSS from 14.7 +/- 0.6 to 17.5 +/- 0.6 degrees Brix was observed with advancement in fruit maturity, while TA decreased from 2.1 +/- 0.7 to 1.1 +/- 0.3 g citric acid per 100 mL across all agro-climatic locations investigated. Fruit TSS/TA ratio and pH increased from 7.8 +/- 2.6 to 16.6 +/- 2.8 and from 3.3 +/- 0.1 to 3.6 +/- 0.2 respectively during fruit maturation across all agro-climatic locations. Fructose and glucose concentrations increased continually with fruit maturity from 69.4 +/- 4.9 to 91.1 +/- 4.9 g kg(-1) and from 57.1 +/- 4.7 to 84.3 +/- 5.2 g kg(-1) respectively. A total of 13 volatile compounds were detected and identified, belonging to five chemical classes. The most abundant volatile in unripe and mid ripe fruit was 1-hexanol, while 3-hexen-1-ol was highest at commercial maturity. CONCLUSION: Knowledge on the impact of fruit maturity and agro-climatic locations (with different altitudes) on biochemical and aroma volatile attributes of pomegranate fruit provides a useful guide for selecting farm location towards improving fruit quality and the maturity stage best for juice processing. PMID- 25809072 TI - A comparison of occipital and temporal lobe epilepsies. AB - PURPOSE: Differentiating between occipital lobe epilepsy (OLE) and temporal lobe epilepsy (TLE) is often challenging. This retrospective case-control study compares OLE to TLE and explores markers that suggest the diagnosis of OLE. METHODS: We queried the Jefferson Epilepsy Center surgery database for patients who underwent a resection that involved the occipital lobe. For each patient with OLE, three sequential case-control patients with TLE were matched. Demographic characteristics, symptoms, electrophysiological findings, imaging findings, and surgical outcome were compared. RESULTS: Nineteen patients with OLE and 57 patients with TLE were included in the study. Visual symptoms were unique to patients with OLE (8/19) and were not reported by patients with TLE (P < 0.0001). Occipital interictal spikes (IIS) were found only in one-third of the patients with OLE (6/19) and in no patients with TLE (P < 0.0001). IIS in the posterior temporal lobe were found in five of 19 patients with OLE vs one of 57 patients with TLE (P = 0.003). IIS involved more than one lobe of the brain in most patients with OLE (11/19) but only in nine of 57 the TLE group. (P = 0.0003) Multilobar resection was needed in most patients with OLE (15/19), typically including the temporal lobe, but in only one of the patients with TLE (P < 0.0001). CONCLUSION: Occipital lobe epilepsy is difficult to identify and may masquerade as temporal lobe epilepsy. Visual symptoms and occipital findings in the EEG suggest the diagnosis of OLE, but absence of these features, does not exclude the diagnosis. When posterior temporal EEG findings or multilobar involvement occurs, the diagnosis of OLE should be considered. PMID- 25809071 TI - A case-control study of MC1R variants in Greek patients with basal cell carcinoma: increased risk independently of pigmentary characteristics. AB - Melanocortin 1 receptor (MC1R) gene variants are a major contributor to pigmentation characteristics and the modulation of sporadic basal cell carcinoma (BCC) risk. This is a hospital-based, case-control study to investigate the association of MC1R variants and pigmentary characteristics with the risk of BCC development in a Southern European population in Greece. In total, 141 patients with BCC and 166 controls were studied. Increased BCC risk was found for the presence of 2 or more MC1R variants (OR:3.07, 95% CI:1.13-8.34), or 2 or more variants of which at least 1 was major function (OR:7.15, 95% CI:1.37-5.52), after adjustment for the 'red hair colour' (RHC) phenotype. Increased BCC risk persisted in the presence of 2 or more MC1R variants (OR:4.15, 95% CI:1.35 12.72), after adjustment for potential confounding factors including skin color (P:0.237) and atypical nevi (OR:9.57, 95% CI:2.19-41.81, P:0.003). MC1R genotype is a risk factor for the development of BCC in Greek patients independently of pigmentary characteristics, and the combination of MC1R variants may modulate this risk. PMID- 25809073 TI - Oxidative damage of naphthenic acids on the Eisenia fetida earthworm. AB - Naphthenic acids (NAs) have been gaining recognition in recent years as potentially harmful environmental contaminants. Few studies have focused on the potential ecotoxicity of NAs to terrestrial environment. In this study, the responses of antioxidant system and lipid peroxidation and DNA damage were investigated after exposing Eisenia fetida to soil contaminated with NAs. The results indicated that NAs induced a significant increase (p < 0.05) in superoxide dismutase and catalase enzyme activities. The glutathione peroxidase enzyme activities were significantly inhibited (p < 0.05) in the medium and high dose treatments. An increase in malondialidehyde indicated that NAs could cause cellular lipid peroxidation in the tested earthworms. The percentage of DNA in the tail of comet assay of coelomocytes as an indication of DNA damage increased after treatment with different doses of NAs, and a dose-dependent DNA damage of coelomocytes was found. In conclusion, oxidative stress caused by NAs exposure induces physiological responses and genotoxicity on earthworms. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1337-1343, 2016. PMID- 25809074 TI - Resequencing at >=40-Fold Depth of the Parental Genomes of a Solanum lycopersicum * S. pimpinellifolium Recombinant Inbred Line Population and Characterization of Frame-Shift InDels That Are Highly Likely to Perturb Protein Function. AB - A recombinant in-bred line population derived from a cross between Solanum lycopersicum var. cerasiforme (E9) and S. pimpinellifolium (L5) has been used extensively to discover quantitative trait loci (QTL), including those that act via rootstock genotype, however, high-resolution single-nucleotide polymorphism genotyping data for this population are not yet publically available. Next generation resequencing of parental lines allows the vast majority of polymorphisms to be characterized and used to progress from QTL to causative gene. We sequenced E9 and L5 genomes to 40- and 44-fold depth, respectively, and reads were mapped to the reference Heinz 1706 genome. In L5 there were three clear regions on chromosome 1, chromosome 4, and chromosome 8 with increased rates of polymorphism. Two other regions were highly polymorphic when we compared Heinz 1706 with both E9 and L5 on chromosome 1 and chromosome 10, suggesting that the reference sequence contains a divergent introgression in these locations. We also identified a region on chromosome 4 consistent with an introgression from S. pimpinellifolium into Heinz 1706. A large dataset of polymorphisms for the use in fine-mapping QTL in a specific tomato recombinant in-bred line population was created, including a high density of InDels validated as simple size-based polymerase chain reaction markers. By careful filtering and interpreting the SnpEff prediction tool, we have created a list of genes that are predicted to have highly perturbed protein functions in the E9 and L5 parental lines. PMID- 25809075 TI - Comparative analysis of wolbachia genomes reveals streamlining and divergence of minimalist two-component systems. AB - Two-component regulatory systems are commonly used by bacteria to coordinate intracellular responses with environmental cues. These systems are composed of functional protein pairs consisting of a sensor histidine kinase and cognate response regulator. In contrast to the well-studied Caulobacter crescentus system, which carries dozens of these pairs, the streamlined bacterial endosymbiont Wolbachia pipientis encodes only two pairs: CckA/CtrA and PleC/PleD. Here, we used bioinformatic tools to compare characterized two-component system relays from C. crescentus, the related Anaplasmataceae species Anaplasma phagocytophilum and Ehrlichia chaffeensis, and 12 sequenced Wolbachia strains. We found the core protein pairs and a subset of interacting partners to be highly conserved within Wolbachia and these other Anaplasmataceae. Genes involved in two component signaling were positioned differently within the various Wolbachia genomes, whereas the local context of each gene was conserved. Unlike Anaplasma and Ehrlichia, Wolbachia two-component genes were more consistently found clustered with metabolic genes. The domain architecture and key functional residues standard for two-component system proteins were well-conserved in Wolbachia, although residues that specify cognate pairing diverged substantially from other Anaplasmataceae. These findings indicate that Wolbachia two-component signaling pairs share considerable functional overlap with other alpha proteobacterial systems, whereas their divergence suggests the potential for regulatory differences and cross-talk. PMID- 25809077 TI - A cross-sectional study of radiation oncology outpatients' concern about, preferences for, and perceived barriers to discussing anxiety and depression. AB - OBJECTIVE: Although elevated psychological distress is commonly reported among cancer patients, our understanding of patients' preferences for, and perceived barriers to, accessing psychological support from key cancer care providers is limited. The aim of this study was to assess cancer patients' level of concern about, and willingness to discuss, their anxiety and depression. METHODS: Radiation oncology outpatients completed a touchscreen computer survey with questions assessing their concern about and willingness to discuss anxiety and depression. RESULTS: Among consenting respondents (n = 145), 51% (95% CI: 43% 59%) were concerned about their levels of anxiety, and 34% (95% CI: 26%-42%) about their levels of depression. If experiencing anxiety or depression, 92% (95% CI: 87%-96%) would want to discuss this with their general practitioner (GP), and 60% (95% CI: 52%-68%) with their cancer doctor. Almost half of the 58 respondents who would not want to discuss anxiety or depression with their cancer doctor indicated that this was because there were more important things to talk about during their appointment. CONCLUSIONS: The majority of cancer patients undergoing radiotherapy would be willing to discuss anxiety and depression with their cancer doctor and GP. These findings provide additional support for service delivery models in which GPs and oncologists play key roles in initiating and coordinating discussions about cancer patients' psychosocial concerns. PMID- 25809076 TI - The effect of different training modes on skeletal muscle microvascular density and endothelial enzymes controlling NO availability. AB - It is becoming increasingly apparent that a high vasodilator response of the skeletal muscle microvasculature to insulin and exercise is of critical importance for adequate muscle perfusion and long-term microvascular and muscle metabolic health. Previous research has shown that a sedentary lifestyle, obesity and ageing lead to impairments in the vasodilator response, while a physically active lifestyle keeps both microvascular density and vasodilator response high. To investigate the molecular mechanisms behind these impairments and the benefits of exercise training interventions, our laboratory has recently developed quantitative immunofluorescence microscopy methods to measure protein content of eNOS and NAD(P)Hoxidase specifically in the endothelial layer of capillaries and arterioles of human skeletal muscle. As eNOS produces nitric oxide (NO) and NAD(P)Hoxidase produces superoxide anions (O2 (-) , quenching NO) we propose that the eNOS/NAD(P)Hoxidase protein ratio is a marker of vasodilator capacity. The novel methods show that endurance training (ET) and high intensity interval training (HIT), generally regarded as a time-efficient alternative to ET, increase eNOS protein content and the eNOS/NADP(H)oxidase protein ratio in previously sedentary lean and obese young men. Resistance exercise training had smaller but qualitatively similar effects. Western blot data of other laboratories suggest that endurance exercise training leads to similar changes in sedentary elderly men. Future research will be required to investigate the relative importance of other sources and tissues in the balance between NO and O2 (-) production seen by the vascular smooth muscle layer of terminal arterioles. PMID- 25809079 TI - Association study confirms the role of two OCA2 polymorphisms in normal skin pigmentation variation in East Asian populations. AB - OBJECTIVES: The main goal of the study was to test the association of 18 polymorphisms located within nine pigmentation candidate genes with quantitative skin pigmentation measures collected in a sample of individuals of East Asian ancestry living in Canada (N = 419). METHODS: The 18 polymorphisms are located within genes that show putative signatures of positive selection in East Asian populations. The genetic markers were selected for genotyping based on an annotation of common East Asian polymorphisms to predict potential functional effects. We restricted our attention to polymorphisms that have an allele frequency difference of at least 30% between East Asian populations and African and European populations, or have alleles that are present in East Asians, but are absent in Africans and Europeans. RESULTS: Two nonsynonymous variants selected within the OCA2 gene, rs1800414 (His615Arg) and rs74653330 (Ala481Thr), were significantly associated with melanin levels in the sample. Both single nucleotide polymorphisms (SNPs) are nonsynonymous polymorphisms located more than 30 kb apart on chromosome 15 and have very different frequencies in the East Asian sample. Additionally, both polymorphisms are predicted to have a deleterious effect on the protein. Linear regression analysis using an additive model indicate that each copy of the derived rs1800414 allele G decreases Melanin Index approximately 0.9 units and each copy of the derived rs74653330 allele A decreases Melanin Index approximately 1.9 units. CONCLUSIONS: Two nonsynonymous OCA2 polymorphisms (rs1800414 and rs74653330) are independently associated with normal skin pigmentation variation in East Asian populations and have very different frequency distributions in East Asia. PMID- 25809080 TI - Socio-contextual factors are linked to differences in the course of problem drinking in midlife: A discordant-twin study. AB - BACKGROUND: Course of alcohol use disorders (AUD) during midlife is understudied, and most research designs are unable to attribute an unambiguous environmental explanation to observed findings. OBJECTIVES & METHODS: Test whether socio contextual factors are linked to differences in the course of problem drinking during midlife. Participants were 163 monozygotic and dizygotic twin pairs concordant for a history of AUD but discordant on problem drinking in the past 10 years. RESULTS: Frequency of drinking with spouse, and peer and emotional problems were associated with discordance. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Socio-contextual factors are linked to differences in course of problem drinking in midlife and are not confounded by genetic effects. (Am J Addict 2015;24:193-196). PMID- 25809082 TI - Cardiovascular molecular imaging: Expanding the paradigms and parameters. PMID- 25809083 TI - Imaging moving heart structures with PET. PMID- 25809084 TI - Malaria in Sydney, Australia: Lessons learned from case management. AB - AIM: To evaluate the clinical presentation and profile of malaria cases diagnosed at a tertiary children's hospital in Australia METHODS: A retrospective file review of children diagnosed with malaria at the Children's Hospital Westmead from 1 January 2000 to 31 December 2010. RESULTS: During the 11-year study period, 40 children were diagnosed with malaria; 30 (75%) presented with fever; 14 (35%) complained of nausea, vomiting or abdominal pain; and eight (20%) were completely asymptomatic. The median time between arrival in Australia and malaria diagnosis was 32 (range 4-434) days. Sixteen (40%) were refugees from sub-Saharan Africa, six (15%) were immigrants from South-East Asia, and seven (18%) recently travelled to or visited friends and family in malaria-endemic areas. Most (68%) cases had Plasmodium falciparum; Plasmodium vivax was identified in four cases with exposures in India and Papua New Guinea; one had mixed P. falciparum and P. vivax infection. CONCLUSION: Malaria signs and symptoms were non-specific, with an absence of fever in a quarter of cases. Diagnostic vigilance is required in all children with potential malaria exposure in the preceding year. Asymptomatic parasitaemia should be considered in recent migrants from malaria-endemic areas. PMID- 25809081 TI - Dual Delivery of EPO and BMP2 from a Novel Modular Poly-E-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps. AB - Poly-E-caprolactone (PCL) is a biocompatible polymer that has mechanical properties suitable for bone tissue engineering; however, it must be integrated with biologics to stimulate bone formation. Bone morphogenetic protein-2 (BMP2) delivered from PCL produces bone when implanted subcutaneously, and erythropoietin (EPO) works synergistically with BMP2. In this study, EPO and BMP2 are adsorbed separately on two 3D-printed PCL scaffold modules that are assembled for codelivery on a single scaffold structure. This assembled modular PCL scaffold with dual BMP2 and EPO delivery was shown to increase bone growth in an ectopic location when compared with BMP2 delivery along a replicate scaffold structure. EPO (200 IU/mL) and BMP2 (65 MUg/mL) were adsorbed onto the outer and inner portions of a modular scaffold, respectively. Protein binding and release studies were first quantified. Subsequently, EPO+BMP2 and BMP2 scaffolds were implanted subcutaneously in mice for 4 and 8 weeks, and the regenerated bone was analyzed with microcomputed tomography and histology; 8.6+/-1.4 MUg BMP2 (22%) and 140+/-29 IU EPO (69.8%) bound to the scaffold and <1% BMP2 and 83% EPO was released in 7 days. Increased endothelial cell proliferation on EPO-adsorbed PCL discs indicated protein bioactivity. At 4 and 8 weeks, dual BMP2 and EPO delivery regenerated more bone (5.1+/-1.1 and 5.5+/-1.6 mm(3)) than BMP2 alone (3.8+/-1.1 and 4.3+/-1.7 mm(3)). BMP2 and EPO scaffolds had more ingrowth (1.4%+/-0.6%) in the outer module when compared with BMP2 (0.8%+/-0.3%) at 4 weeks. Dual delivery produced more dense cellular marrow, while BMP2 had more fatty marrow. Dual EPO and BMP2 delivery is a potential method to regenerate bone faster for prefabricated flaps. PMID- 25809085 TI - How important is the {103} plane of stable Ge2 Sb2 Te5 for phase-change memory? AB - Closely correlating with {200} plane of cubic phase, {103} plane of hexagonal phase of Ge(2)Sb(2)Te(5) plays a crucial role in achieving fast phase change process as well as formation of modulation structures, dislocations and twins in Ge(2)Sb(2)Te(5). The behaviors of {103} plane of hexagonal phase render the phase change memory process as a nanoscale shape memory. PMID- 25809086 TI - Patient safety in primary care: incident reporting and significant event reviews in British general practice. AB - Over the past 20 years, healthcare has adapted to the 'quality revolution' by moving away from direct provision and hierarchical control mechanisms. In their place, new structures based on contractual relationships are being developed coupled with attempts to create an organisational culture that shares learning and that scrutinises existing practice so that it can be improved. The issue here is that contractual arrangements require surveillance, monitoring, regulation and governance systems that can be perceived as antipathetic to the examination of practice and subsequent learning. Historically, reporting levels from general practice have remained low; little information is shared and consequently lessons are not shared across the general practice community. Given large-scale under engagement of general practitioners (GPs) in incident reporting systems, significant event analysis is advocated to encourage sharing of information about incidents to inform the patient safety agenda at a local and national level. Previous research has concentrated on the secondary care environment and little is known about the situation in primary care, where the majority of patient contacts with healthcare occur. To explore attitudes to incident reporting, the study adopted a qualitative approach to GPs working in a mixture of urban and rural practices reporting to a Welsh Local Health Board. The study found that GPs used significant event analysis methodology to report incidents within their practice, but acknowledged under-reporting. They were less enthusiastic about reporting externally. A number of barriers exist to reporting, including insufficient time to report, lack of feedback, fear of blame, and damage to reputations and patient confidence in a competitive environment. If incident reporting processes are perceived as supportive and formative, and where protected time is allocated to discuss incidents, then GPs are willing to participate. They also need to know how the information is used, and whether lessons are being learnt from errors. PMID- 25809087 TI - The potential long-term effect of previous schistosome infection reduces the risk of metabolic syndrome among Chinese men. AB - The association between potential long-term effects of previous schistosome infection (PSI) and the development of metabolic syndrome remains unknown. Therefore, we aimed to evaluate the association between them. Participants were from regions which were all reportedly heavily endemic for S. japonicum in China 40 years ago. One thousand five hundred and ninety-seven men were enrolled. Among these, 465 patients with PSI were selected as study subjects and 1132 subjects served as controls. We found PSI significantly correlated with lower prevalences of metabolic syndrome and its components, including central obesity, hypertriglyceridemia and low high-density lipoprotein cholesterol, which indicates that the potential long-term effects of PSI may reduce the risk of metabolic syndrome. However, further studies are needed to investigate the protective immune effects of PSI. PMID- 25809088 TI - Genomics in a changing arctic: critical questions await the molecular ecologist. AB - Molecular ecology is poised to tackle a host of interesting questions in the coming years. The Arctic provides a unique and rapidly changing environment with a suite of emerging research needs that can be addressed through genetics and genomics. Here we highlight recent research on boreal and tundra ecosystems and put forth a series of questions related to plant and microbial responses to climate change that can benefit from technologies and analytical approaches contained within the molecular ecologist's toolbox. These questions include understanding (i) the mechanisms of plant acquisition and uptake of N in cold soils, (ii) how these processes are mediated by root traits, (iii) the role played by the plant microbiome in cycling C and nutrients within high-latitude ecosystems and (iv) plant adaptation to extreme Arctic climates. We highlight how contributions can be made in these areas through studies that target model and nonmodel organisms and emphasize that the sequencing of the Populus and Salix genomes provides a valuable resource for scientific discoveries related to the plant microbiome and plant adaptation in the Arctic. Moreover, there exists an exciting role to play in model development, including incorporating genetic and evolutionary knowledge into ecosystem and Earth System Models. In this regard, the molecular ecologist provides a valuable perspective on plant genetics as a driver for community biodiversity, and how ecological and evolutionary forces govern community dynamics in a rapidly changing climate. PMID- 25809089 TI - Homocysteine plasma levels in psoriasis patients: our experience and review of the literature. AB - BACKGROUND: People with psoriasis are at higher cardiovascular risk. Plasma levels of homocysteine over the normal range have been recognized as marker of cardiovascular risk. Psoriasis patients express higher levels of plasma homocysteine than healthy people. OBJECTIVE: Our study aims to investigate the correlation between homocysteinaemia, severity and duration of psoriasis and psoriasis arthritis, and to evaluate the effect of a 12-week administration of a target therapy for psoriasis on homocysteinaemia. METHODS: Fifty-two psoriasis patients (study group) submitted to different kind of therapy for psoriasis (biological, systemic not biological and topical) and 24 healthy Italian subject (control group) were evaluated for their plasmatic homocysteine levels, both at baseline (T0) and 12 weeks after they a specific therapy for psoriasis. RESULTS: A significant difference between the homocysteinaemia of psoriasis patients (mean 19.71 +/- 11.16) and control group (13.90 +/- 11.18), P < 0.05 (Fig. 1), was found at baseline (T0). The mean plasma levels of homocysteine were directly correlated with disease severity (P = 0.0401), but not with disease duration (P = 0.6018) or presence of arthritis (P = 0.6221) at baseline. None among the treatments administered to psoriasis patients caused a significant reduction in homocysteinaemia after 12 weeks of treatment. CONCLUSION: Our results confirm that psoriasis patients with more severe disease, can have hyperhomocysteinaemia, without regard to disease duration or joint involvement. Hyperhomocysteinaemia is not influenced by a target therapy for psoriasis and it is as greater as psoriasis severity. However, limitation of our study is the relatively small number of cases. Homocysteine plasmatic levels should be advisable as a further independent risk factor for cardiovascular disease in psoriasis patients. PMID- 25809090 TI - Favorable response to composite treatment including infliximab in a case of granulomatous cheilitis with Crohn's disease. PMID- 25809091 TI - Erratum to: platinum-based chemotherapy in triple-negative advanced breast cancer. PMID- 25809093 TI - Weight Reduction Goal Achievement with High-Intensity MOVE!((r)) Treatment. AB - OBJECTIVE: The purpose of this study was to examine the effect of high-intensity treatment with the behavioral weight reduction program, MOVE!((r)), available at Veterans Administration Medical Centers, on achieving at least a 5% weight reduction 6 months after enrolling in the program. MOVE!((r)) is free to veterans but little is known about the recommended number of sessions. DESIGN AND SAMPLE: Using longitudinal clinical data from electronic health records of 216 MOVE!((r)) program participants, weight reduction was examined in this secondary data analysis. MEASURES: Based on the 2013 guidelines for overweight and obesity management, weights were evaluated at baseline and 6 months following enrollment in the program, and high-intensity MOVE!((r)) was determined by attending 14 or more sessions within the first 6 months following enrollment. RESULTS: High intensity MOVE!((r)) participants were five times as likely to achieve at least the 5% weight reduction goal at 6 months compared to those participants with low intensity, while controlling for age, gender, and race (OR = 4.74; CI: 1.3, 17.2; p < .02). CONCLUSION: This research supports the 2013 recommendations for high intensity lifestyle intervention as participants who completed 14 or more sessions were almost five times more likely to achieve a 5% weight reduction. PMID- 25809095 TI - A two-arm cluster randomized control trial to determine the effectiveness of a pressure ulcer prevention bundle for critically ill patients. AB - PURPOSE: This study tested the effectiveness of a pressure ulcer (PU) prevention bundle in reducing the incidence of PUs in critically ill patients in two Saudi intensive care units (ICUs). DESIGN: A two-arm cluster randomized experimental control trial. METHODS: Participants in the intervention group received the PU prevention bundle, while the control group received standard skin care as per the local ICU policies. Data collected included demographic variables (age, diagnosis, comorbidities, admission trajectory, length of stay) and clinical variables (Braden Scale score, severity of organ function score, mechanical ventilation, PU presence, and staging). All patients were followed every two days from admission through to discharge, death, or up to a maximum of 28 days. Data were analyzed with descriptive correlation statistics, Kaplan-Meier survival analysis, and Poisson regression. FINDINGS: The total number of participants recruited was 140: 70 control participants (with a total of 728 days of observation) and 70 intervention participants (784 days of observation). PU cumulative incidence was significantly lower in the intervention group (7.14%) compared to the control group (32.86%). Poisson regression revealed the likelihood of PU development was 70% lower in the intervention group. The intervention group had significantly less Stage I (p = .002) and Stage II PU development (p = .026). CONCLUSIONS: Significant improvements were observed in PU related outcomes with the implementation of the PU prevention bundle in the ICU; PU incidence, severity, and total number of PUs per patient were reduced. CLINICAL RELEVANCE: Utilizing a bundle approach and standardized nursing language through skin assessment and translation of the knowledge to practice has the potential to impact positively on the quality of care and patient outcome. PMID- 25809094 TI - A Novel Nonanchoring Technique for Implantation of Paddle Leads in the Cervical Spine Under Conscious Sedation. AB - OBJECTIVES: Spinal cord stimulation (SCS) revision surgery remains common, with a negative impact on cost-effectiveness and outcomes. The primary goal of this report was to retrospectively study the need for revision surgery in a cohort of complex regional pain syndrome type I (CRPS-1) patients with newly implanted cervical surgical paddle leads, focusing on a method of implantation to reduce the need for revision surgery. METHODS: Fifteen patients underwent implantation of paddle SCS leads in the cervical spine with cervical laminotomies under conscious sedation for CRPS-1 from 2008 to 2012. Electrodes were not anchored and 11 of the electrodes were three-column paddle leads. A disinterested third party performed initial chart reviews, supplemented by subsequent telephone interviews. The need for revision surgery was the endpoint. A single surgeon performed all implants with a consistent method. RESULTS: There were no paddle electrode lead revisions required for suboptimal lead placement, fracture, migration, or infection at a median follow-up period of 22 months. CONCLUSIONS: This study is the first to report on: 1) cervical electrode implantation with no anchoring; and 2) cervical paddle lead implantation (including three-column paddles) performed under conscious sedation. The specific method of nonanchoring of the paddle implants under conscious sedation may have contributed to low electrode lead revision rates. PMID- 25809092 TI - Obesity, body fat distribution, and risk of breast cancer subtypes in African American women participating in the AMBER Consortium. AB - African American (AA) women are more likely than white women to be obese and to be diagnosed with ER- and triple-negative (TN) breast cancer, but few studies have evaluated the impact of obesity and body fat distribution on breast cancer subtypes in AA women. We evaluated these associations in the AMBER Consortium by pooling data from four large studies. Cases were categorized according to hormone receptor status as ER+, ER-, and TN (ER-, PR-, and HER2-) based on pathology data. A total of 2104 ER+ cases, 1070 ER- cases (including 491 TN cases), and 12,060 controls were included. Odds ratios (OR) and 95 % confidence intervals (CI) were computed using logistic regression, taking into account breast cancer risk factors. In postmenopausal women, higher recent (most proximal value to diagnosis/index date) BMI was associated with increased risk of ER+ cancer (OR 1.31; 95 % CI 1.02-1.67 for BMI >= 35 vs. <25 kg/m(2)) and with decreased risk of TN tumors (OR 0.60; 95 % CI 0.39-0.93 for BMI >= 35 vs. <25). High young adult BMI was associated with decreased premenopausal ER+ cancer and all subtypes of postmenopausal cancer, and high recent waist-to-hip ratio with increased risk of premenopausal ER+ tumors (OR 1.35; 95 % CI 1.01-1.80) and all tumor subtypes combined in postmenopausal women (OR 1.26; 95 % CI 1.02-1.56). The impact of general and central obesity varies by menopausal status and hormone receptor subtype in AA women. Our findings imply different mechanisms for associations of adiposity with TN and ER+ breast cancers. PMID- 25809096 TI - An insecure base: Attachment style and orienting response to positive stimuli. AB - In adults as in infants, psychological attachment to close others provides a "secure base" for exploration and pursuit of opportunities. Insecure attachment is likely to interfere with this function. The present study examined the association of individual differences in adult attachment style with peripheral physiological measures of automatic orienting to several kinds of positive, rewarding stimuli. Attachment style was largely unrelated to extent of heart rate deceleration in response to the appearance of positive emotion-eliciting images. However, attachment avoidance was associated with reduced skin conductance responding to the onset of several kinds of positive stimuli. These findings suggest that working models of relationships with close others have complex implications for the early stages of responding to opportunities for reward presented by the environment. PMID- 25809100 TI - The challenge: real-world application of 'omics endpoints. PMID- 25809098 TI - Anthropometry in 5- to 9-Year-Old Greenlandic and Ukrainian Children in Relation to Prenatal Exposure to Perfluorinated Alkyl Substances. AB - BACKGROUND: In some animal studies, perfluorinated alkyl substances are suggested to induce weight gain. Human epidemiological studies investigating these associations are sparse. OBJECTIVE: We examined pregnancy serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and the prevalence of offspring overweight (> 1 SD) and waist-to-height ratio (WHtR) > 0.5 at 5-9 years of age. METHODS: Sera from 1,022 pregnant women enrolled in the INUENDO cohort (2002-2004) from Greenland and Kharkiv (Ukraine) were analyzed for PFOA and PFOS using liquid chromatography-tandem mass spectrometry. Relative risks (RR) of being overweight and having WHtR > 0.5 in relation to continuous and categorized (tertiles) PFOA and PFOS were calculated at follow-up (2010-2012) using generalized linear models. RESULTS: Pooled PFOA median (range) was 1.3 (0.2 5.1) and PFOS median (range) was 10.8 (0.8-73.0) ng/mL. For each natural logarithm-unit (ln-unit) increase of pregnancy PFOA, the adjusted RR of offspring overweight was 1.11 [95% confidence interval (CI): 0.82, 1.53] in Greenlandic children. In Ukrainian children, the adjusted RR of offspring overweight was 1.02 (95% CI: 0.72, 1.44) for each ln-unit increase of pregnancy PFOA. Prenatal exposure to PFOS was not associated with overweight in country-specific or pooled analysis. The adjusted RR of having WHtR > 0.5 for each ln-unit increase of prenatal exposure to PFOA was 1.30 (95% CI: 0.97, 1.74) in the pooled analysis. For 1-ln-unit increase of prenatal exposure to PFOS, the adjusted RR of having a WHtR > 0.5 was 1.38 (95% CI: 1.05, 1.82) in the pooled analysis. CONCLUSIONS: The results indicate that prenatal PFOA and PFOS exposures may be associated with child waist-to-height ratio > 0.5. Prenatal PFOA and PFOS exposures were not associated with overweight. PMID- 25809099 TI - Photochemical and microbial transformation of emerging flame retardants: cause for concern? AB - Among anthropogenic chemicals, flame retardants have attracted mounting environmental concerns. In recent years, an increasing number of studies have been conducted worldwide to investigate flame-retardant sources, environmental distribution, wildlife and human exposure, and toxicity. Data generated have demonstrated that some flame-retardant substances such as polybrominated diphenyl ethers (PBDE) are persistent, bioaccumulative, and toxic to exposed organisms. However, comparatively much less attention has been paid to the mechanisms and products of environmental transformation of flame retardants. This lack of information undermines our understanding of the environmental behavior and fate of flame retardants, as well as the associated risks to environmental and human health. Photochemical and microbial transformation of flame retardants in various matrices and environmental compartments can elevate the toxicological significance of flame retardant exposure, via the formation of, for example, lesser halogenated but more bioaccumulative degradation products and toxic radicals. Such pathways raise concerns related to the environmental safety of some alternative flame retardants that are presumably safe and used to replace PBDEs. To fully assess the environmental risks, more research is needed to investigate the environmental transformation potential of emerging flame retardants including polymeric flame retardants. Enhanced analytical efforts are needed to better characterize transformation products and transient radicals. Additional mesocosm and field studies are needed to elucidate transformation kinetics and consequences under environmentally relevant conditions. PMID- 25809101 TI - In response: integration of 'omics to larger-scale watershed assessments: a mixed government/academic perspective. PMID- 25809097 TI - Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl+ K562 and Jak2(V617F)+ HEL Leukemia Cells. AB - Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl+ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)+ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5. PMID- 25809102 TI - In response: embracing 'omic diversity: a mixed academic/government perspective. PMID- 25809103 TI - In response: ecotoxicogenomics addressing future needs: an industry perspective. PMID- 25809104 TI - In summary. PMID- 25809105 TI - Modeling and interpreting biological effects of mixtures in the environment: introduction to the metal mixture modeling evaluation project. AB - The fate and biological effects of chemical mixtures in the environment are receiving increased attention from the scientific and regulatory communities. Understanding the behavior and toxicity of metal mixtures poses unique challenges for incorporating metal-specific concepts and approaches, such as bioavailability and metal speciation, in multiple-metal exposures. To avoid the use of oversimplified approaches to assess the toxicity of metal mixtures, a collaborative 2-yr research project and multistakeholder group workshop were conducted to examine and evaluate available higher-tiered chemical speciation based metal mixtures modeling approaches. The Metal Mixture Modeling Evaluation project and workshop achieved 3 important objectives related to modeling and interpretation of biological effects of metal mixtures: 1) bioavailability models calibrated for single-metal exposures can be integrated to assess mixture scenarios; 2) the available modeling approaches perform consistently well for various metal combinations, organisms, and endpoints; and 3) several technical advancements have been identified that should be incorporated into speciation models and environmental risk assessments for metals. PMID- 25809107 TI - Eye lens dose in interventional cardiology. AB - The ICRP has recently recommended reducing the occupational exposure dose limit for the lens of the eye to 20 mSv y(-1), averaged over a period of 5 y, with no year exceeding 50 mSv, instead of the current 150 mSv y(-1). This reduction will have important implications for interventional cardiology and radiology (IC/IR) personnel. In this work, lens dose received by a staff working in IC is studied in order to determine whether eye lens dose monitoring or/and additional radiological protection measures are required. Eye lens dose exposure was monitored in 10 physicians and 6 nurses. The major IC procedures performed were coronary angiography and percutaneous transluminal coronary angioplasty. The personnel were provided with two thermoluminescent dosemeters (TLDs): one calibrated in terms of Hp(3) located close to the left ear of the operator and a whole-body dosemeter calibrated in terms of Hp(10) and Hp(0.07) positioned on the lead apron. The estimated annual eye lens dose for physicians ranged between 8 and 60 mSv, for a workload of 200 procedures y(-1). Lower doses were collected for nurses, with estimated annual Hp(3) between 2 and 4 mSv y(-1). It was observed that for nurses the Hp(0.07) measurement on the lead apron is a good estimate of eye lens dose. This is not the case for physicians, where the influence of both the position and use of protective devices such as the ceiling shield is very important and produces large differences among doses both at the eyes and on the thorax. For physicians, a good correlation between Hp(3) and dose area product is shown. PMID- 25809108 TI - Automatic patient dose registry and clinical audit on line for mammography. AB - The use of automatic registry systems for patient dose in digital mammography allows clinical audit and patient dose analysis of the whole sample of individual mammography exposures while fulfilling the requirements of the European Directives and other international recommendations. Further parameters associated with radiation exposure (tube voltage, X-ray tube output and HVL values for different kVp and target/filter combinations, breast compression, etc.) should be periodically verified and used to evaluate patient doses. This study presents an experience in routine clinical practice for mammography using automatic systems. PMID- 25809109 TI - Thyroid cancer radioiodine therapy: health service performance and radiation safety. AB - Greek Atomic Energy Commission collected data related to radioiodine I-131 therapy (RAIT) delivery to differentiated thyroid carcinoma patients, for the period 2003-13, corresponding to 100 % of hospitals at national level. Radiation safety and health service performance outcome indicators were assessed. The numbers of hospitals and nuclear medicine (NM) therapy wards, as well as RAIT annual frequencies, have increased. Geographical inhomogeneous distribution of existing infrastructure is recorded. In some cases, the observed inefficient use of NM therapy wards seems to be due to lack of human resources (e.g. nurses). Regular assessment of appropriate key indicators could serve as a useful tool for radiation safety monitoring and health service performance improvement. PMID- 25809110 TI - Dose surveys and DRLs: critical look and way forward. AB - The main purpose of dose surveys has been to detect and bring down wide variation in radiation doses for any particular radiological examination and to avoid doses that are on higher side. Diagnostic reference levels (DRLs) have been used for over two decades as an aid in this objective. With very limited success that has been achieved through DRL, the author has recently described a new term 'acceptable quality dose' (AQD) that is aimed at optimisation within the DRL, is facility initiated and takes into account all three important parameters-image quality, dose and patient's body build. It is hoped that AQD will be found easy to establish, will be a useful tool to achieve optimisation in the facilities and will serve as the standard dose. PMID- 25809111 TI - In vivo TLD dose measurements in catheter-based high-dose-rate brachytherapy. AB - Routine in vivo dosimetry is well established in external beam radiotherapy; however, it is restricted mainly to detection of gross errors in high-dose-rate (HDR) brachytherapy due to complicated measurements in the field of steep dose gradients in the vicinity of radioactive source and high uncertainties. The results of in vivo dose measurements using TLD 100 mini rods and TLD 'pin worms' in catheter-based HDR brachytherapy are provided in this paper alongside with their comparison with corresponding dose values obtained using calculation algorithm of the treatment planning system. Possibility to perform independent verification of treatment delivery in HDR brachytherapy using TLDs is discussed. PMID- 25809112 TI - Clean Transfer of Wafer-Scale Graphene via Liquid Phase Removal of Polycyclic Aromatic Hydrocarbons. AB - Pentacene (C22H14), a polycyclic aromatic hydrocarbon, was used as both supporting and sacrificing layers for the clean and doping-free graphene transfer. After successful transfer of graphene to a target substrate, the pentacene layer was physically removed from the graphene surface by using intercalating organic solvent. This solvent-mediated removal of pentacene from graphene surface was investigated by both theoretical calculation and experimental studies with various solvents. The uses of pentacene and appropriate intercalation solvent enabled graphene transfer without forming a residue from the supporting layer. Such residues tend to cause charged impurity scattering and unintentional graphene doping effects. As a result, this clean graphene exhibited extremely homogeneous surface potential profiles over a large area. A field effect transistor fabricated using this graphene displayed a high hole (electron) mobility of 8050 cm(2)/V.s (9940 cm(2)/V.s) with a nearly zero Dirac point voltage. PMID- 25809113 TI - Is it time to advance pediatric NAFLD diagnosis to the magnetic resonance imaging era? PMID- 25809114 TI - Is the evaluation of risk of bias in periodontology and implant dentistry comprehensive? A systematic review. AB - BACKGROUND/OBJECTIVE: The objective of this study was to assess how authors of systematic reviews (SRs) with meta-analyses published in periodontology and implant dentistry evaluate risk of bias (ROB) in primary studies included in these reviews. MATERIAL/METHODS: A literature search for SRs with meta-analyses was performed in PubMed and Cochrane library databases up to July 20th 2014. The reference lists of included articles were screened for further reviews. The standards of evaluating ROB in primary studies were evaluated by using a 14-item checklist based on the Cochrane approach for evaluating ROB. Standards in ROB evaluations in Cochrane and paper-based SRs were compared using the Fisher's exact test. All searches, data extraction and evaluations were performed independently and in duplicate. RESULTS: Seventy SRs were included (45 paper based and 25 Cochrane SRs, respectively). The median percentage of items addressed was 58% (interquartile range 4-100%). Cochrane SRs more frequently included ROB assessments than paper-based reviews in terms of examiner blinding (p = 0.0026), selective outcome reporting (p = 0.0207) and other bias (p = 0.0241). CONCLUSIONS: The ROB evaluation in primary studies currently included in SRs with meta-analyses in periodontology and implant dentistry is not sufficiently comprehensive. Cochrane SRs have more comprehensive ROB evaluation than paper-based reviews. PMID- 25809115 TI - Haploidentical stem cell transplantation in patients aged 50 yr and older with leukemia: similar outcomes compared to younger adults. AB - AIM: We aimed to analyze the complications and survival associated with myeloablative haploidentical SCT in patients aged >= 50 yr and compare these results with a younger group population. DESIGN AND METHODS: In this case-control study, enrolled patients with leukemia were identified from 1262 patients between May 2002 and May 2013 at a single institution. RESULTS: Thirty-one patients were aged >= 50 yr (the older group) and 165 patients were aged 18-49 yr (the younger group). Of the older group, 20 of 31 (64.5%) had a hematopoietic cell transplantation comorbidity index (HCT-CI) of 0 or 2. Statistical analysis showed no significant differences in the incidences of grades II to IV acute GVHD, extensive chronic GVHD, and non-relapse mortality (NRM), or probability of relapse between the two groups. Furthermore, the 3-yr overall survival (OS) and leukemia-free survival (LFS) were not significantly different between the older and younger groups: 67.0 +/- 9.3% vs. 75.3 +/- 3.4% (p = 0.406) and 60.5 +/- 9.6% vs. 72.5 +/- 3.5% (p = 0.183), respectively. CONCLUSION: Selected older patients aged >= 50 yr with low HCT-CI and good performance status could safely undergo haploidentical SCT. PMID- 25809116 TI - Acetaldehyde production by major oral microbes. AB - OBJECTIVES: To assess acetaldehyde (ACH) production by bacteria constituting the oral microbiota and the inhibitory effects of sugar alcohols on ACH production. MATERIALS AND METHODS: The predominant bacterial components of the salivary microbiota of 166 orally healthy subjects were determined by barcoded pyrosequencing analysis of the 16S rRNA gene. Bacterial ACH production from ethanol or glucose was measured using gas chromatography. In addition, inhibition by four sugars and five sugar alcohols of ACH production was assayed. RESULTS: Forty-one species from 16 genera were selected as predominant and prevalent bacteria based on the following criteria: identification in >=95% of the subjects, >=1% of mean relative abundance or >=5% of maximum relative abundance. All Neisseria species tested produced conspicuous amounts of ACH from ethanol, as did Rothia mucilaginosa, Streptococcus mitis and Prevotella histicola exhibited the ability to produce ACH. In addition, xylitol and sorbitol inhibited ACH production by Neisseria mucosa by more than 90%. CONCLUSIONS: The oral microbiota of orally healthy subjects comprises considerable amounts of bacteria possessing the ability to produce ACH, an oral carcinogen. Consumption of sugar alcohols may regulate ACH production by oral microbes. PMID- 25809118 TI - Meta-analysis of the correlation between IL-6 -174 G/C polymorphism and polycystic ovarian syndrome. AB - AIM: The correlation between interleukin-6 (IL-6) gene polymorphism and polycystic ovary syndrome (PCOS) has been reported, but the conclusions are controversial. The present study was aimed to evaluate the association between IL 6 -174 G/C polymorphism and susceptibility of PCOS by meta-analysis. MATERIAL AND METHODS: A systematic search on Medline, Embase, CNKI, Wanfang Data and VIP databases containing Chinese and English studies was conducted electronically using specific eligibility criteria. Meta-analysis was performed using Review Manager 5.2 software after Hardy-Weinberg equilibrium test. Effect sizes of odds ratio and 95% confidence interval (CI) were calculated and combined appropriately. To verify the reliability of the results, subgroup analyses and sensitivity analyses were performed. RESULTS: Four selected studies containing 351 cases and 464 control participants were included. The pooled odds ratio between IL-6 -174 G/C polymorphism and susceptibility of PCOS under allele (C/G), dominant (CC+GC/GG) and recessive (CC/GG+GC) models were 0.63 (95%CI, 0.41-0.96), 0.53 (95%CI, 0.26-1.08) and 0.67 (95%CI, 0.39-1.16), respectively. The result under allele model was unstable in sensitivity analysis. Subgroup analysis showed that the correlation between IL-6 -174 G/C polymorphism and susceptibility of PCOS was not statistically significant in the studies that conformed to the Hardy Weinberg equilibrium. CONCLUSION: IL-6 -174 G/C polymorphism may be not related to susceptibility of PCOS. Nevertheless, further studies with large samples and studies considering other single-nucleotide polymorphisms of the IL-6 gene are needed to confirm our findings. PMID- 25809119 TI - Urokinase receptor cleavage correlates with tumor volume in a transgenic mouse model of breast cancer. AB - The urokinase plasminogen activator system plays a key role in tissue degradation during cancer invasion. The linker region between domains I and II of the intact, three domain urokinase receptor uPAR(I-III) is highly susceptible to proteolytic cleavage and the resulting cleaved uPAR forms are strong prognostic biomarkers in several types of cancer, i.e., high levels of the cleaved uPAR forms indicate poor survival. To better understand the role of uPAR cleavage in cancer, we have designed immunoassays for specific quantification of intact mouse uPAR [muPAR(I III)] and mouse uPAR domain I [muPAR(I)]. The level of muPAR(I) is significantly increased in mammary tumor-bearing mice compared to controls and, notably, there is a strong correlation to tumor volume. In contrast, the tumor volume is only weakly correlated to the level of intact muPAR(I-III), indicating that cleavage of muPAR is a more specific marker for cancer than increased expression of muPAR per se. The levels of the muPAR forms are dramatically affected by in vivo challenge with a urokinase -blocking antibody, demonstrating a functional role of uPA in uPAR cleavage. The levels of the muPAR forms are, however, unaffected by uPA-deficiency, suggesting that redundant proteases maintains the task of cleaving uPAR(I-III) when uPA is absent. Our findings emphasize the significance of the cleaved uPAR forms as cancer biomarkers. The strong correlation between muPAR(I) and the tumor volume in our experimental setup may motivate investigations of human uPAR(I) as biomarker for response to oncological treatment. PMID- 25809120 TI - Proton pump inhibitor-induced subcutaneous lupus erythematosus in a patient with systemic lupus erythematosus. PMID- 25809117 TI - Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. AB - Neutrophil extracellular traps (NETs) composed of DNA decorated with histones and proteases trap and kill bacteria but also injure host tissue. Here we show that during a bloodstream infection with methicillin-resistant Staphylococcus aureus, the majority of bacteria are sequestered immediately by hepatic Kupffer cells, resulting in transient increases in liver enzymes, focal ischaemic areas and a robust neutrophil infiltration into the liver. The neutrophils release NETs into the liver vasculature, which remain anchored to the vascular wall via von Willebrand factor and reveal significant neutrophil elastase (NE) proteolytic activity. Importantly, DNase although very effective at DNA removal, and somewhat effective at inhibiting NE proteolytic activity, fails to remove the majority of histones from the vessel wall and only partly reduces injury. By contrast, inhibition of NET production as modelled by PAD4-deficiency, or prevention of NET formation and proteolytic activity as modelled in NE(-/-) mice prevent collateral host tissue damage. PMID- 25809122 TI - Cerebrospinal fluid proteomics in children during induction for acute lymphoblastic leukemia: A pilot study. AB - BACKGROUND: Thrombosis in patients with acute lymphocytic leukemia (ALL) can develop after treatment with L-asparaginase (asp) and is often localized to the central nervous system (CNS). We hypothesize that changes in the cerebrospinal fluid (CSF) proteome will occur after asp therapy and will anticipate CNS clots. METHODS: Five newly diagnosed patients, ages 1-11 years, with ALL (n = 4) or lymphoblastic lymphoma (LL) (n = 1) underwent serial lumbar punctures during induction. CSF was depleted of abundant plasma proteins and analyzed by gel-free, label-free quantitative proteomics. RESULTS: More than 600 proteins were quantified across all CSF samples. In four subjects, the expression of proteins involved in coagulation such as protein C Inhibitor (SERPINA5) and heparin cofactor II (SERPIND1) changed over the course of asp therapy. Antithrombin III (ATIII) and plasminogen (PLMN) levels were shown to have decreased expression over time in one child who developed a CNS thrombosis, compared to other subjects. CONCLUSIONS: CSF proteomics is feasible and reproducible in ALL and LL. CSF ATIII and PLMN should be further investigated as predictive markers of CNS thrombosis. PMID- 25809123 TI - Vanadium in asymmetric synthesis: emerging concepts in catalyst design and applications. AB - In recent years vanadium catalysis has been extended to a range of different and even complementary directions in asymmetric synthesis. Inspired by nature's way to activate both substrate and reagent in many cases, the design of efficient bifunctional and dinuclear vanadium catalysts has been achieved. Furthermore, vanadium catalysis has been an early field in which "hybrid catalysts" have been studied in detail by incorporation of oxovanadium complexes into proteins, thus giving artificial enzymes. In addition, a high compatibility of vanadium with proteins enabled the use of vanadium chemocatalysts for combinations with enzyme catalysis in one-pot, thus leading to dynamic kinetic resolutions. In this contribution, these three concepts of vanadium catalysis opening up new perspectives for asymmetric synthesis are reviewed. PMID- 25809124 TI - F-wave and motor-evoked potentials during motor imagery and observation in apraxia of Parkinson disease. AB - INTRODUCTION: The amplitudes of F-waves and motor-evoked potentials (MEPs) increase during imagination or active motor performance. The aim of this study was to investigate F-wave and MEP facilitation during assessment of apraxia. METHODS: Eight Parkinson disease (PD) patients with apraxia, 11 patients without apraxia, and 8 healthy volunteers were enrolled. F-waves and MEPs were recorded during 4 states (resting, imagination, observation, and active movement). RESULTS: The mean amplitude of the F-waves increased significantly during imagination and active movement as compared with at rest in healthy individuals (P = 0.028) and in the nonapraxia group (P = 0.005). PD patients with apraxia did not have similar facilitation. The mean amplitude of the MEPs also showed a similar loss of facilitation in PD with apraxia. CONCLUSIONS: Loss of facilitation during the preparation for movement is closely related to the "gold standard" clinical praxis battery. This study provides additional support and a potential electrophysiological assessment method for apraxia in PD. PMID- 25809121 TI - When to rely on maternal effects and when on phenotypic plasticity? AB - Existing insight suggests that maternal effects have a substantial impact on evolution, yet these predictions assume that maternal effects themselves are evolutionarily constant. Hence, it is poorly understood how natural selection shapes maternal effects in different ecological circumstances. To overcome this, the current study derives an evolutionary model of maternal effects in a quantitative genetics context. In constant environments, we show that maternal effects evolve to slight negative values that result in a reduction of the phenotypic variance (canalization). By contrast, in populations experiencing abrupt change, maternal effects transiently evolve to positive values for many generations, facilitating the transmission of beneficial maternal phenotypes to offspring. In periodically fluctuating environments, maternal effects evolve according to the autocorrelation between maternal and offspring environments, favoring positive maternal effects when change is slow, and negative maternal effects when change is rapid. Generally, the strongest maternal effects occur for traits that experience very strong selection and for which plasticity is severely constrained. By contrast, for traits experiencing weak selection, phenotypic plasticity enhances the evolutionary scope of maternal effects, although maternal effects attain much smaller values throughout. As weak selection is common, finding substantial maternal influences on offspring phenotypes may be more challenging than anticipated. PMID- 25809125 TI - Conditions, preventable deaths, procedures and validation of a countrywide survey of surgical care in Nepal. AB - BACKGROUND: To determine a true denominator of worldwide surgical need, it is imperative to include estimations at a population-based level, to capture those individuals unable to access surgical care. This study was designed to validate the Surgeons OverSeas Assessment of Surgical need (SOSAS) tool with the addition of a visual physical examination, and describe the prevalence of surgical conditions, deaths possibly averted with access to surgical care, and the number of surgical procedures performed annually, in Nepal. METHODS: The SOSAS tool, developed to measure the prevalence of surgical conditions at a population level and used in two African countries, was employed. Fifteen of the 75 districts of Nepal were chosen proportional to population. Responses were recorded for the head of the household for demographic information and recalled deaths, and two randomly selected household members underwent a verbal head-to-toe interview for surgical conditions and a visual physical examination by a trained physician. RESULTS: A total of 1350 households were surveyed (2695 respondents). Observed agreement between the verbal response and physical examination findings was 94.6 per cent. Some 10.0 (95 per cent c.i. 8.9 to 11.2) per cent of respondents had a current condition requiring surgical care and 23 per cent of deaths may have been averted with proper access to surgical care. An estimated 291.8 major operations per 100 000 population are performed annually in Nepal. CONCLUSION: The visual physical examination component validated the SOSAS tool, and justified the estimates of previous studies in Sierra Leone and Rwanda. These data provide insights into the health needs of Nepal and provide evidence to develop surgical programmes, assist with monitoring and evaluation, and help with advocacy for increased resources in Nepal. PMID- 25809126 TI - In vitro colonic metabolism of coffee and chlorogenic acid results in selective changes in human faecal microbiota growth. AB - Coffee is a relatively rich source of chlorogenic acids (CGA), which, as other polyphenols, have been postulated to exert preventive effects against CVD and type 2 diabetes. As a considerable proportion of ingested CGA reaches the large intestine, CGA may be capable of exerting beneficial effects in the large gut. Here, we utilise a stirred, anaerobic, pH-controlled, batch culture fermentation model of the distal region of the colon in order to investigate the impact of coffee and CGA on the growth of the human faecal microbiota. Incubation of coffee samples with the human faecal microbiota led to the rapid metabolism of CGA (4 h) and the production of dihydrocaffeic acid and dihydroferulic acid, while caffeine remained unmetabolised. The coffee with the highest levels of CGA (P<0.05, relative to the other coffees) induced a significant increase in the growth of Bifidobacterium spp. relative to the control vessel at 10 h after exposure (P<0.05). Similarly, an equivalent quantity of CGA (80.8 mg, matched with that in high-CGA coffee) induced a significant increase in the growth of Bifidobacterium spp. (P<0.05). CGA alone also induced a significant increase in the growth of the Clostridium coccoides-Eubacterium rectale group (P<0.05). This selective metabolism and subsequent amplification of specific bacterial populations could be beneficial to host health. PMID- 25809127 TI - Evaluation of rapid screening techniques for detection of Salmonella spp. from produce samples after pre-enrichment according to FDA BAM and a short secondary enrichment. AB - Conventional detection of Salmonella from foods involves enrichment and isolation on selective media which can significantly lengthen time to result. The objective of this study was to evaluate the utility of an accelerated plating procedure and the use of rapid screening devices for Salmonella detection. Fresh produce was inoculated with Salmonella at ~2.5, ~7.5 and ~25 CFU sample(-1) . After 24 h pre enrichment, subcultures were made into TT and RV broths and further incubated at 42 degrees C for an additional 7 and 24 h. Enrichments were streaked for isolation of Salmonella as well as tested by rapid screening methods. The 7-h accelerated plating procedure worked well from 4/6 to 6/6 in all produce samples inoculated at the lowest level. Both the RapidChek and Neogen Reveal tests worked as well as the VIDAS-SLM after 24 h secondary enrichment, but failed to detect the pathogen after 7 h selective enrichment in romaine lettuce and tomatoes, while fractional detection was observed in cilantro and jalapenos. Both devices detected Salmonella on cantaloupe at the lowest level of inoculation. An abbreviated selective enrichment procedure worked well to accelerate the isolation of colonies of Salmonella from contaminated samples providing isolates for further characterization 1 day earlier than standard analysis. SIGNIFICANCE AND IMPACT OF THE STUDY: In the event of a foodborne disease outbreak, rapid identification and characterization of the pathogen is essential to prevent the spread of disease and reduce the number of illnesses. This study reports the utility of an abbreviated secondary enrichment for the isolation of Salmonella in artificially contaminated fresh produce at very low levels. In addition, incorporation of rapid, easy-to-use lateral flow devices to screen enrichments can provide a low cost (equipment and highly trained personnel), high return (rapid identification of contaminated food) investment in the timely pathogen screening of fresh produce. PMID- 25809128 TI - Diguanylate cyclase DgcP is involved in plant and human Pseudomonas spp. infections. AB - The second messenger cyclic di-GMP (c-di-GMP) controls the transition between different lifestyles in bacterial pathogens. Here, we report the identification of DgcP (diguanylate cyclase conserved in Pseudomonads), whose activity in the olive tree pathogen Pseudomonas savastanoi pv. savastanoi is dependent on the integrity of its GGDEF domain. Furthermore, deletion of the dgcP gene revealed that DgcP negatively regulates motility and positively controls biofilm formation in both the olive tree pathogen P. savastanoi pv. savastanoi and the human opportunistic pathogen Pseudomonas aeruginosa. Overexpression of the dgcP gene in P. aeruginosa PAK led to increased exopolysaccharide production and upregulation of the type VI secretion system; in turn, it repressed the type III secretion system, which is a hallmark of chronic infections and persistence for P. aeruginosa. Deletion of the dgcP gene in P. savastanoi pv. savastanoi NCPPB 3335 and P. aeruginosa PAK reduced their virulence in olive plants and in a mouse acute lung injury model respectively. Our results show that diguanylate cyclase DgcP is a conserved Pseudomonas protein with a role in virulence, and confirm the existence of common c-di-GMP signalling pathways that are capable of regulating plant and human Pseudomonas spp. infections. PMID- 25809129 TI - Applying extender devices in patients with penile dysmorphophobia: assessment of tolerability, efficacy, and impact on erectile function. AB - INTRODUCTION: Most men seeking penile enhancement techniques have a normal penile size. They are either misinformed or suffer from penile dysmorphophobia and should be discouraged from undergoing invasive procedures. Less invasive techniques including penile extenders are not associated with major complications and may be beneficial from a psychological perspective. AIM: We conducted this study to assess the efficacy and safety of AndroPenis (Andromedical, Madrid, Spain) penile extender. METHODS: Between December 2010 and December 2013, 163 men presented to our institution complaining of small penile length and/or girth. All patients received structured psychosexual counseling. Fifty-four patients were willing to use the AndroPenis penile extender after counseling. Patients with major psychiatric disorders were excluded from enrollment. The patients were instructed to wear the device between 4 and 6 hours per day for 6 months. Penile dimensions including flaccid stretched and erected lengths were measured at baseline and after 1, 3, 6, and 9 months. Erectile function was assessed at baseline and 9 months after treatment using the simplified International Index of Erectile Function (IIEF-5). An institutional nonstandardized questionnaire was used to evaluate patient satisfaction at the end of study. MAIN OUTCOME MEASURES: Penile length and girth enhancement as well as satisfaction rate and improvement in erectile function were assessed during follow-up. RESULTS: At 6-month follow up, a mean gain of 1.7 +/- 0.8, 1.3 +/- 0.4, and 1.2 +/- 0.4 cm was noted for the flaccid, stretched, and erected penile lengths, respectively (all P values < 0.001). During the off treatment period, there were no significant changes in penile lengths. No effect on penile girth was observed. Patient satisfaction survey revealed modest satisfaction. From 13 patients with mild baseline erectile dysfunction, nine patients reported normal erectile function after 9 months. CONCLUSION: Penile extender as a minimally invasive technique is safe and provides modest benefits and patient satisfaction. PMID- 25809130 TI - Sibling Exposure and Risk of Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail. METHODS: We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case-hospital control sample (302 cases and 676 controls) from Victoria, Australia. RESULTS: We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28-0.74) (P = 0.001). The protective association appeared to increase with increasing number of siblings (e.g., for >=3 siblings, adjusted OR 0.25 [95% CI 0.13-0.48], P < 0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g., for >=3 years of exposure versus no exposure, adjusted OR 0.49 [95% CI 0.30-0.79], P = 0.003). We also compared cases to a second control sample (n = 341) collected from the community and weighted to represent the child population of Victoria. Data remained supportive of an association between sibling exposure and protection against JIA, particularly for exposure to younger siblings. CONCLUSION: Increased exposure to siblings is associated with a reduced risk of disease in our sample. This suggests that increased microbial exposure in childhood may confer protection against the development of JIA. PMID- 25809132 TI - Importance of Myc-related microRNAs in induced pluripotency. AB - Pluripotent stem cells (PSCs) have the capacity to differentiate into any cell type of the body. Therefore, induced pluripotent stem cells (iPSCs) are seen as a promising solution for patient-specific cell therapies. However, the safety is major issue for in vitro methods that are used in induction of pluripotency and also in differentiation of PSCs toward specific cell types. In pioneer studies of iPSC generation, the role of c-Myc has been highlighted as a possible master regulator of pluripotency, but direct c-Myc overexpression is known to prompt drawbacks, especially in human cells. In recent studies, the role of non-protein coding RNA molecules such as microRNAs (miRNAs) has been shown in enhanced reprogramming efficiency. In addition, new reprogramming methods have been ultimately improved by adding miRNAs, in the absence of previous factors. Cross interaction between miRNAs and c-Myc has been also found in differentiation of iPSCs, as well as in reprogramming and self-renewing the pluripotent state. Thence, miRNAs are promising solution for efficiency and safety of iPSC derivation and differentiation methods. The purpose of the present review is to evaluate interaction mechanisms of miRNAs with c-Myc and in iPSC technology. PMID- 25809131 TI - Pediatric intestinal transplant listing criteria - a call for a change in the new era of intestinal failure outcomes. AB - Current listing indications used for intestinal transplantation (IT) were proposed in 2001. We undertook the present single center study to see if these criteria are still valid. The 2001 criteria (advanced cholestasis, loss of >50% central venous catheter (CVC) sites, >=2 sepsis/year, ultrashort bowel) were compared in children with intestinal failure in old era-1998-2005 (N = 99) to current era-2006-2012 (N = 91) to predict the need for IT using sensitivity, specificity, NPV and PPV. Two 2001 criteria had poorer predictive value in the current era: Advanced cholestasis (PPV 64% old vs. 40% current era; sensitivity 84% vs. 65%, respectively) and ultrashort bowel (PPV 100% old vs. 9% current era; sensitivity 10% vs. 4%, respectively). Three newly proposed criteria had high predictive value: >=2 ICU admissions (p = 0.0001, OR 23.6, 95% CI 2.7-209.8), persistent bilirubin >75 mmol/L despite lipid strategies (p = 0.0005, OR 24.0, 95% CI 3.2-177.4), and loss of >=3 CVC sites (p = 0.0003, OR 33.3, 95% CI 18.8 54.0). There was 98% probability of needing IT when two of these new criteria were present. The 2001 IT criteria have limited predictive ability in the current era and should be revised. A multicenter study is required to validate the findings of this single center experience. PMID- 25809133 TI - Valbenazine granted breakthrough drug status for treating tardive dyskinesia. AB - The chronic use and high dosing of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics predispose patients to the onset of tardive syndromes. One particular subtype, tardive dyskinesia, is characterized by rapid, repetitive, stereotypic, involuntary movements of the face, limbs or trunk. The inhibition of the vesicular monoamine transporter system, using tetrabenazine therapy, improves the severity of tardive dyskinesia. But there are also drawbacks to tetrabenazine treatment, such as a fluctuating response and the need for frequent intake due to its rapid metabolism. Clinical research on the potentially more efficacious and easier to use tetrabenazine analogs is already under way. One of them is valbenazine, the purified parent drug of the (+)-alpha isomer of tetrabenazine. The FDA lowered approval hurdles for valbenazine due to a successful Phase II trial, which showed a distinctive improvement in tardive dyskinesia symptoms during valbenazine administration. This resurgence in the clinical research of tardive syndrome therapy is most welcome. This author notes that the putative long-term side effects of valbenazine should carefully be investigated in the future via naturalistic observational trials. Furthermore, valbenazine may also support the onset of symptoms, such as Parkinsonism and depression, with chronic administration, as it, to a certain extent, shares the mode of action of tetrabenazine. PMID- 25809134 TI - Origin of extraordinary stability of square-planar carbon atoms in surface carbides of cobalt and nickel. AB - Surface carbides of cobalt and nickel are exceptionally stable, having stabilities competitive with those of graphitic C on these surfaces. The unusual structure of these carbides has attracted much attention: C assumes a tetracoordinate square-planar arrangement, in-plane with the metal surface, and its binding favors a spontaneous p4g clock surface reconstruction. A chemical bonding model for these systems is presented and explains the unusual structure, special stability, and the reconstruction. C promotes local two-dimensional aromaticity on the surface and the aromatic arrangement is so powerful that the required number of electrons is taken from the void M4 squares, thus leading to Peierls instability. Moreover, this model predicts a series of new transition metal and main-group-element surface alloys: carbides, borides, and nitrides, which feature high stability, square-planar coordination, aromaticity, and a predictable degree of surface reconstruction. PMID- 25809136 TI - Effects of the dynein inhibitor ciliobrevin on the flagellar motility of sea urchin spermatozoa. AB - Ciliobrevin has recently been found to be a membrane-permeable inhibitor that is specific to AAA+ molecular motors such as cytoplasmic dyneins. In this study, we investigated how ciliobrevin inhibited the motility of sperm from sea urchins: Hemicentrotus pulcherrimus, Pseudocentrotus depressus, and Anthocidaris crassispina. After application of 100 MUM of ciliobrevin A to live spermatozoa, swimming speed decreased gradually and flagellar motion stopped almost completely within 5 to 10 min. This inhibition was reversible and the frequency of flagellar beating was reduced in a concentration-dependent manner. Ciliobrevin had similar inhibitory effects on the flagellar beating of demembranated and reactivated sperm and the sliding disintegration of trypsin-treated axonemes. We also analyzed the curvature and shear angle of the beating flagella and found that the proximal region of the sperm flagellum was less sensitive to ciliobrevin compared with more distal regions, where bending motions were blocked completely. Interestingly, the shear angle analysis of flagellar motility showed that ciliobrevin induced highly asymmetric bends in the proximal region of the flagellum. These results suggest that there is heterogeneity in the inhibitory thresholds of dynein motors, which depend on the regions along the flagellar shaft (proximal or distal) and on the sites of doublets in the flagellar cross section (doublet numbers). We expect that it will be possible to map the functional differences in dynein subtypes along and/or around the cross-sections of flagellar axonemes by analyzing the inhibitory effects of ciliobrevin. PMID- 25809135 TI - Hyperinsulinemia in newly diagnosed patients with multiple sclerosis. AB - There are limited data regarding glucose metabolism dysregulation in multiple sclerosis (MS). Present study investigates glucose and insulin response during oral glucose tolerance test (oGTT) in MS patients. We examined 19 MS patients and 19 age, sex and body mass index (BMI) matched healthy controls. MS patients were newly diagnosed, untreated and with low Expanded Disability Status Scale (EDSS) score (1.1 +/- 0.7). Plasma glucose, lactate, insulin and GLP-1 during oGTT, and fasting adipokines, lipid and inflammatory parameters were analyzed. Insulin sensitivity indices (ISI) were calculated. MS patients had comparable fasting (5.2 +/- 0.3 vs. 5.0 +/- 0.4 mmol/l, p = 0.05) and post-load glucose concentrations as controls. Insulin response to oral glucose load in MS was increased (p = 0.022). Insulin sensitivity was lower in MS compared to controls [ISI(Matsuda) 6.95 +/- 3.44 vs. 10.60 +/- 4.81, p = 0.011 and ISI(Cederholm) 49.9 +/- 15.3 vs. 61.3 +/- 16.3, p = 0.032]. We did not find any difference in lactate, GLP-1, total, HDL and LDL cholesterol, triglycerides, interleukin 6, tumor necrosis factor, C-reactive protein, resistin, leptin, adiponectin levels between groups. We found decreased insulin sensitivity with postprandial hyperinsulinemia in MS patients, which seems not to be related to chronic inflammation or physical inactivity. The role of hyperinsulinemia in CNS function impairment should be further investigated. PMID- 25809137 TI - Objective assessment of postural stability in Parkinson's disease using mobile technology. AB - BACKGROUND: A significant gap remains in the ability to effectively characterize postural instability in individuals with Parkinson's disease. Clinical evaluation of postural declines is largely subjective, whereas objective biomechanical approaches are expensive and time consuming, thus limiting clinical adoption. Recent advances in mobile devices present an opportunity to address the gap in the quantification of postural stability. The aim of this project was to determine whether kinematic data measured by hardware within a tablet device, a 3rd generation iPad, was of sufficient quantity and quality to characterize postural stability. METHODS: Seventeen patients and 17 age-matched controls completed six balance conditions under altered surface, stance, and vision. Simultaneous kinematic measurements were gathered from a three-dimensional motion capture system and tablet. RESULTS: The motion capture system and tablet provided similar measures of stability across groups. In particular, within the patient population, correlation between the two systems for peak-to-peak, normalized path length, root mean square, 95% volume, and total power values ranged from 0.66 to 1.00. Kinematic data from five balance conditions--double-leg stance with eyes open on a foam surface, double-leg stance with eyes closed on firm and foam surfaces, and tandem stance on firm and foam surfaces--were capable of discriminating patients from controls. CONCLUSIONS: The hardware within the tablet provides data of sufficient accuracy for the quantification of postural stability in patients with Parkinson's disease. The objectivity, portability, and ease of use of this device make it ideal for use in clinical environments lacking sophisticated biomechanical systems. PMID- 25809138 TI - Ruthenium-catalyzed C-C bond cleavage in lignin model substrates. AB - Ruthenium-triphos complexes exhibited unprecedented catalytic activity and selectivity in the redox-neutral C-C bond cleavage of the beta-O-4 lignin linkage of 1,3-dilignol model compounds. A mechanistic pathway involving a dehydrogenation-initiated retro-aldol reaction for the C-C bond cleavage was proposed in line with experimental data and DFT calculations. PMID- 25809139 TI - Mechanisms of plant cell division. AB - Plant cells are confined by a network of cellulosic walls that imposes rigid control over the selection of division plane orientations, crucial for morphogenesis and genetically regulated. While in animal cells and yeast, the actin cytoskeleton is instrumental in the execution of cytokinesis, in plant cells the microtubule cytoskeleton is taking the lead in spatially controlling and executing cytokinesis by the formation of two unique, plant-specific arrays, the preprophase band (PPB) and the phragmoplast. The formation of microtubule arrays in plant cells is contingent on acentrosomal microtubule nucleation. At the onset of mitosis, the PPB defines the plane of cell division where the partitioning cell wall is later constructed by the cytokinetic phragmoplast, imposing a spatio-temporal relationship between the two processes. Current research progress in the field of plant cell division focuses on identifying and tying the links between early and late events in spatial control of cytokinesis and how microtubule array formation is regulated in plant cells. PMID- 25809142 TI - In-capillary self-assembly study of quantum dots and protein using fluorescence coupled capillary electrophoresis. AB - As a vast number of novel materials in particular inorganic nanoparticles have been invented and introduced to all aspects of life, public concerns about how they might affect our ecosystem and human life continue to arise. Such incertitude roots at a fundamental question of how inorganic nanoparticles self assemble with biomolecules in solution. Various techniques have been developed to probe the interaction between particles and biomolecules, but very few if any can provide advantages of both rapid and convenient. Herein, we report a systematic investigation on quantum dots (QDs) and protein self-assembly inside a capillary. QDs and protein were injected to a capillary one after another. They were mixed inside the capillary when a high voltage was applied. Online separation and detection were then achieved. This new method can also be used to study the self assembly kinetics of QDs and protein using the Hill equation, the KD value for the self-assembly of QDs and protein was calculated to be 8.8 MUM. The obtained results were compared with the previous out of-capillary method and confirmed the effectiveness of the present method. PMID- 25809143 TI - Feeding-swallowing difficulties in children later diagnosed with language impairment. AB - AIM: The aim of this retrospective study was to assess the relationship between feeding-swallowing difficulties (FSDs) and later language impairments in children. METHOD: Retrospective analyses were carried out using the clinical files of 82 children with language impairments from a large urban rehabilitation center. Two subgroups of these children were established: children with motor impairments, referred to as the language impairment with motor impairment ('LI+MI') subgroup (n=23, mean age 4y 6mo, SD 8.7mo), and children without motor impairments, referred to as the language impairment without motor impairment ('LI MI') subgroup (n=59, mean age 5y, SD 8mo). The prevalence of food selectivity, difficulties in sucking, salivary control issues, and food transition difficulties was extracted. Data were compared with a general population estimate of FSDs. RESULTS: FSDs were documented in 62% of the clinical files; 87% of these files were from the LI+MI subgroup and 53% were from the LI-MI subgroup. Among each subgroup of children with language impairments, the prevalence of FSDs was significantly higher than the general population estimate of 20% (LI+MI:chi(2) =55.965, df=1, p<0.001; LI-MI: chi(2) =32.807, df=1, p<0.001). Furthermore, the prevalence of FSDs was significantly higher in children with language impairments and motor impairments than in those with language impairments but without motor impairments (chi(2) =6.936, df=1, p<0.01). Both food transition difficulties (chi(2) =14.99, df=1, p<0.001) and salivary control issues (chi(2) =5.02, df=1, p=0.02) were more frequent in the LI+MI subgroup than in the LI-MI subgroup. Combinations of two or more FSDs were also more frequent in the LI+MI subgroup than in the LI-MI subgroup (chi(2) =4.19, df=1, p=0.04). INTERPRETATIONS: These findings suggest that early FSDs may be used as a potential marker for language impairment. However, larger prospective studies are needed to confirm this. PMID- 25809144 TI - Immunological risks of minimization strategies. AB - During the past 10 years, minimization strategies have been legitimately initiated to decrease the many toxicities of calcineurin inhibitors, especially nephrotoxicity which was considered to be responsible for the majority of graft losses. Even though CNI-induced nephrotoxicity is undeniable, we have learned in the past 10 years that DSAs detected with solid-phase assays are excellent prognostic biomarkers in kidney transplantation (and in other organ transplantations as well) and that chronic antibody-mediated rejection has become the leading cause of graft loss. In this review, we will focus on the immunological risks linked to various strategies aiming at decreasing CNI doses either at time of transplantation or later in the course of follow-up. Some of these interventions are associated with an increase in acute cellular rejection rates but also with an improvement in renal function. The effects on antibody mediated rejection and occurrence of de novo donor-specific antibodies are still under-reported. We are currently missing long-term data to appreciate the influence of these minimization strategies on graft and patient survival. This then leads to a cautious attitude regarding reducing immunosuppression. PMID- 25809145 TI - Penicillium marneffei infection in a lung transplant recipient. AB - Penicillium marneffei is a thermally dimorphic fungus that can cause severe opportunistic infections in endemic regions of Southeast Asia, particularly in individuals infected with human immunodeficiency virus-1, but has rarely been reported in solid organ transplant recipients. Herein, we report the first case, to our knowledge, of P. marneffei infection in a lung transplant recipient, occurring in a 41-year-old woman 28 months post lung transplantation, after recent travel to Vietnam. We have reviewed the literature to derive some management principles for this rare infection in this clinical context. The number of P. marneffei infections in transplant recipients may increase, as a result of increasing rates of transplantation and travel to endemic areas. PMID- 25809146 TI - Charge-Transfer Supra-Amphiphiles Built by Water-Soluble Tetrathiafulvalenes and Viologen-Containing Amphiphiles: Supramolecular Nanoassemblies with Modifiable Dimensions. AB - In this study, multidimensional nanoassemblies with various morphologies such as nanosheets, nanorods, and nanofibers are developed via charge-transfer interaction and supra-amphiphile self-assembling in aqueous phase. The charge transfer interactions between tetrathiafulvalene derivatives (TTFs) and methyl viologen derivatives (MVs) have been confirmed by the characteristic charger transfer absorption. (1) H NMR and electrospray ionizsation mass spectrometry (ESI-MS) analyses also indicate supra-amphiphiles are formed by the combination of TTFs and MVs head group through charge-transfer interaction and Coulombic force. X-ray single crystal structural studies, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) reveal that both linkage pattern of TTFs in hydrophilic part and alkane chain structure in hydrophobic part have significant influence on nanoassemblies morphology and microstructure. Moreover, gold nanoparticles (AuNPs) are introduced in the above supramolecular nanoassemblies to construct a supra-amphiphile-driven organic-AuNPs assembly system. AuNPs could be assembled into 1D-3D structures by adding different amount of MVs. PMID- 25809147 TI - Castalagin Exerts Inhibitory Effects on Osteoclastogenesis Through Blocking a Broad Range of Signaling Pathways with Low Cytotoxicity. AB - Castalagin is a rare plant polyphenol that is classified as a hydrolyzable tannin. Although it has antioxidant, antitumorigenic, and leishmanicidal effects, the utility of castalagin against bone diseases remain to be elucidated. Here, we investigated the effects of castalagin on the differentiation of osteoclasts (OCLs), multinucleated bone-resorbing cells. After stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL), the formation of OCLs from bone marrow-derived macrophages was significantly inhibited by castalagin even at 1 MUM. However, castalagin displayed little cytotoxicity at a higher concentration of 50 MUM. The effects of castalagin on intracellular signaling during OCL differentiation showed that castalagin suppresses RANKL-stimulated phosphorylation of major signaling pathways including protein kinase B (Akt), extracellular signal-regulated kinase, Jun N-terminal kinase, p38 mitogen activated protein kinases, and inhibitor of nuclear factor kappa B alpha. Moreover, following castalagin treatment, the protein levels of nuclear factor of activated T-cells, cytoplasmic 1, a master regulator for OCL differentiation, and NF-kappaB were decreased. Thus, castalagin exerts inhibitory effects on osteoclastogenesis through blockage of a broad range of signaling pathways, but has low cytotoxicity. PMID- 25809148 TI - Molecular profiling of ETS and non-ETS aberrations in prostate cancer patients from northern India. AB - BACKGROUND: Molecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene-rearrangements, PTEN deletion, and SPINK1 over-expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over-expression, and PTEN deletion in this cohort. METHODS: In this multi-center study, formalin-fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA-ISH) and/or fluorescence in situ hybridization (FISH). RESULTS: ERG over-expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA-ISH, no alteration in ETV4 was observed. SPINK1 over expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG positive cases (P = 0.017) but in only one case with SPINK1 over-expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ~1% and ~4.5% of the PCa cases, respectively. CONCLUSIONS: This is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention. PMID- 25809149 TI - The activities of four constitutively expressed promoters in single-copy transgenic rice plants for two homozygous generations. AB - MAIN CONCLUSION: We have characterized four novel constitutive promoters ARP1, H3F3, HSP and H2BF3 that are active in all tissues/stages of transgenic plants and stable over two homozygous generations. Gene promoters that are active and stable over several generations in transgenic plants are valuable tools for plant research and biotechnology. In this study, we characterized four putative constitutive promoters (ARP1, H3F3, HSP and H2BF3) in transgenic rice plants. Promoter regions were fused to the green fluorescence protein (GFP) reporter gene and transformed into rice. Single-copy transgenic lines were then selected and promoter activity was analyzed in various organs and tissues of two successive homozygous generations. All four promoters showed a broad expression profile in most tissues and developmental stages, and indeed the expression of the ARP1 and H3F3 promoters was even greater than that of the PGD1 promoter, a previously described constitutive promoter that has been used in transgenic rice. This observation was based on expression levels in leaves, roots, dry seeds and flowers in both the T2 and T3 generations. Each promoter exhibited comparable levels of activity over two homozygous generations with no sign of transgene silencing, which is an important characteristic of promoters to be used in crop biotechnology applications. These promoters therefore have considerable potential value for the stable and constitutive expression of transgenes in monocotyledonous crops. PMID- 25809150 TI - Unique miRNome during anthesis in drought-tolerant indica rice var. Nagina 22. AB - MAIN CONCLUSION: Drought-tolerant rice variety, Nagina 22 (N22), has a unique spikelet miRNome during anthesis stage drought as well as transition from heading to anthesis. Molecular characterization of genetic diversity of rice is essential to understand the evolution and molecular basis of various agronomically important traits such as drought tolerance. miRNAs play an important role in regulating plant development as well as stress response such as drought. In this study, we characterized the yet unexplored dynamics of the spikelet miRNA population during developmental transition from 'heading' to 'anthesis' as well as anthesis stage drought stress in a drought-tolerant indica rice variety, N22. A significant proportion of miRNA population (~20 %) in N22 spikelets is modulated during transition from heading to anthesis indicating a unique miRNome at anthesis, a developmental stage highly sensitive to stress (drought/heat). Based on the analysis of degradome data, majority of differentially regulated miRNAs appear to regulate transcription factors, some of which are implicated in regulation of development and fertilization. Similarly, drought during anthesis leads to a global change in miRNA expression pattern including those which regulate ROS homeostasis. It was possible to identify several miRNAs that were not reported to be drought responsive in earlier studies. Interestingly, a significant proportion of the drought-regulated miRNAs co-localize within QTLs related to drought tolerance and associated traits. Comparison of the expression profiles between N22 and Pusa Basmati 1 (drought sensitive) identified miRNAs with variety-specific expression patterns during phase transition (miR164, miR396, miR812, and miR1881) as well as drought stress (miR1881) indicating an evolution of a distinct and variety-specific regulatory mechanism. The promoters of these miRNAs contain LREs (light-responsive elements) and are induced by dark treatment. It was also possible to identify 4 novel miRNAs including an intronic miRNA that was conserved in both rice varieties. PMID- 25809151 TI - Molecular approaches for improving desiccation tolerance: insights from the brine shrimp Artemia franciscana. AB - MAIN CONCLUSION: We have evaluated the endogenous expression and molecular properties of selected Group 3 LEA proteins from Artemia franciscana , and the capacity of selected Groups 1 and 3 proteins transfected into various desiccation sensitive cell lines to improve tolerance to drying. Organisms inhabiting both aquatic and terrestrial ecosystems frequently are confronted with the problem of water loss for multiple reasons--exposure to hypersalinity, evaporative water loss, and restriction of intracellular water due to freezing of extracellular fluids. Seasonal desiccation can become severe and lead to the production of tolerant propagules and entry into the state of anhydrobiosis at various stages of the life cycle. Such is the case for gastrula-stage embryos of the brine shrimp, Artemia franciscana. Physiological and biochemical responses to desiccation are central for survival and are multifaceted. This review will evaluate the impact of multiple late embryogenesis abundant proteins originating from A. franciscana, together with the non-reducing sugar trehalose, on prevention of desiccation damage at multiple levels of biological organization. Survivorship of desiccation-sensitive cells during water stress can be improved by use of the above protective agents, coupled to metabolic preconditioning and rapid cell drying. However, obtaining long-term stability of cells in the dried state at room temperature has not been accomplished and will require continued efforts on both the physicochemical and biological fronts. PMID- 25809154 TI - Peripapillary retinal vessel diameter correlates with mfERG alterations in retinitis pigmentosa. AB - PURPOSE: To investigate relationship between the peripapillary retinal vessel diameter and the residual retinal function, measured by mfERG, in patients with retinitis pigmentosa (RP). PATIENTS AND METHODS: A cross-sectional study based on 23 patients with RP (43 eyes) and 20 controls (40 eyes) was performed. Retinal vessel diameters were measured using a computer-based program of the retinal vessel analyser (RVA; IMEDOS Systems UG, Jena, Germany). We evaluated the mean diameter in all four major retinal arterioles (D-A) and venules (D-V) within 1.0 1.5 optic disc diameters from the disc margin. The data were compared with the N1 amplitudes (measured from the baseline to the trough of the first negative wave), with the N1P1 amplitudes (measured from the trough of the first negative wave to the peak of the first positive wave) of the mfERG overall response and with the mfERG responses averaged in zones [zone 1 (0 degrees -3 degrees ), zone 2 (3 degrees -8 degrees ), zone 3 (8 degrees -15 degrees ) and zone 4 (15 degrees -24 degrees )]. RESULTS: Mean (+/-SD) D-A and D-V were narrower in patients with RP [84.86 MUm (+/-13.37 MUm) and 103.35 MUm (+/-13.65 MUm), respectively] when compared to controls [92.81 MUm (+/-11.49 MUm) and 117.67 MUm (+/-11.93 MUm), respectively; the p-values between groups were p = 0.003 for D-A and p < 0.001 for D-V, linear mixed-effects model]. The RP group revealed clear differences compared to the controls: D-A and D-V became narrower with reduced mfERG responses. D-V correlated significantly with the overall mfERG N1 amplitudes (p = 0.013) and with N1P1 amplitudes (p = 0.016). D-V correlated with the mfERG amplitudes averaged in zones: (zone 2, 3 and 4; p <= 0.040) and N1P1 mfERG amplitudes (zones 1, 2, 3 and 4; p <= 0.013). CONCLUSIONS: Peripapillary retinal vessel diameter is reduced in RP proportionally to functional alterations. PMID- 25809155 TI - Power and practices: questions concerning the legislation of health professions in Brazil. AB - Developments in professional practice can be related to ongoing changes in relations of power among professionals, which often lead to changes in the boundaries of practices. The differing contexts of practices also influence these changing relations among health professionals. Legislation governing professional practice also differs from country to country. In Brazil, over the past 12 years, in a climate of deep disagreement, a new law to regulate medical practice has been discussed. It was sanctioned, or made into law, but with some notable changes, in July 2013. Of interest to us in this paper are the ways the proposed legislation, by setting out the boundaries and scope of medical practice, 'interfered' in the practices of other health professions, undermining many 'independent' practices that have developed over time. However, even taking into account the multiple routes through which practices are established and developed, the role of legislation that seems able to contradict and deny the historical realities of multiple, intersecting practices should be critically interrogated. In this paper, we use the theoretical resources of poststructuralist thinking to explore gaps, ambiguities, and power relations implicit in the discourses that constituted this law. We argue that although the new law can be understood as a social and political device that will interfere in the organization of other health professions' practices, such legislation is only part of what constitutes change in a consolidated professional practice. And while it is important to understand the effects of such legislation, healthcare practices are also realized or 'made real' through ongoing relations of knowledge and power, including, as we will see in this case, activities of resistance. The problem, then, is to understand the practical arrangements, including legislation, traditions and routines, values and knowledge that come to shape the practices of nursing in a particular context. PMID- 25809156 TI - Challenges in children's enrolment to psychosocial services. PMID- 25809152 TI - A gene co-expression network predicts functional genes controlling the re establishment of desiccation tolerance in germinated Arabidopsis thaliana seeds. AB - MAIN CONCLUSION: During re-establishment of desiccation tolerance (DT), early events promote initial protection and growth arrest, while late events promote stress adaptation and contribute to survival in the dry state. Mature seeds of Arabidopsis thaliana are desiccation tolerant, but they lose desiccation tolerance (DT) while progressing to germination. Yet, there is a small developmental window during which DT can be rescued by treatment with abscisic acid (ABA). To gain temporal resolution and identify relevant genes in this process, data from a time series of microarrays were used to build a gene co expression network. The network has two regions, namely early response (ER) and late response (LR). Genes in the ER region are related to biological processes, such as dormancy, acquisition of DT and drought, amplification of signals, growth arrest and induction of protection mechanisms (such as LEA proteins). Genes in the LR region lead to inhibition of photosynthesis and primary metabolism, promote adaptation to stress conditions and contribute to seed longevity. Phenotyping of 12 hubs in relation to re-establishment of DT with T-DNA insertion lines indicated a significant increase in the ability to re-establish DT compared with the wild-type in the lines cbsx4, at3g53040 and at4g25580, suggesting the operation of redundant and compensatory mechanisms. Moreover, we show that re establishment of DT by polyethylene glycol and ABA occurs through partially overlapping mechanisms. Our data confirm that co-expression network analysis is a valid approach to examine data from time series of transcriptome analysis, as it provides promising insights into biologically relevant relations that help to generate new information about the roles of certain genes for DT. PMID- 25809153 TI - A fungal transcription factor gene is expressed in plants from its own promoter and improves drought tolerance. AB - MAIN CONCLUSION: A fungal gene encoding a transcription factor is expressed from its own promoter in Arabidopsis phloem and improves drought tolerance by reducing transpiration and increasing osmotic potential. Horizontal gene transfer from unrelated organisms has occurred in the course of plant evolution, suggesting that some foreign genes may be useful to plants. The CtHSR1 gene, previously isolated from the halophytic yeast Candida tropicalis, encodes a heat-shock transcription factor-related protein. CtHSR1, with expression driven by its own promoter or by the Arabidopsis UBQ10 promoter, was introduced into the model plant Arabidopsis thaliana by Agrobacterium tumefaciens-mediated transformation and the resulting transgenic plants were more tolerant to drought than controls. Fusions of the CtHSR1 promoter with beta-glucuronidase reporter gene indicated that this fungal promoter drives expression to phloem tissues. A chimera of CtHSR1 and green fluorescence protein is localized at the cell nucleus. The physiological mechanism of drought tolerance in transgenic plants is based on reduced transpiration (which correlates with decreased opening of stomata and increased levels of jasmonic acid) and increased osmotic potential (which correlates with increased proline accumulation). Transcriptomic analysis indicates that the CtHSR1 transgenic plants overexpressed a hundred of genes, including many relevant to stress defense such as LOX4 (involved in jasmonic acid synthesis) and P5CS1 (involved in proline biosynthesis). The promoters of the induced genes were enriched in upstream activating sequences for water stress induction. These results demonstrate that genes from unrelated organisms can have functional expression in plants from its own promoter and expand the possibilities of useful transgenes for plant biotechnology. PMID- 25809157 TI - Oligonucleotide biofunctionalization enhances endothelial progenitor cell adhesion on cobalt/chromium stents. AB - As the endothelium still represents the ideal surface for cardiovascular devices, different endothelialization strategies have been attempted for biocompatibility and nonthrombogenicity enhancement. Since endothelial progenitor cells (EPCs) could accelerate endothelialization, preventing thrombosis and restenosis, the aim of this study was to use oligonucleotides (ONs) to biofunctionalize stents for EPC binding. In order to optimize the functionalization procedure before its application to cobalt-chromium (Co/Cr) stents, discs of the same material were preliminarily used. Surface aminosilanization was assessed by infrared spectroscopy and scanning electron microscopy. A fluorescent endothelial-specific ON was immobilized on aminosilanized surfaces and its presence was visualized by confocal microscopy. Fluorescent ON binding to porcine blood EPCs was assessed by flow cytometry. Viability assay was performed on EPCs cultured on unmodified, nontargeting ON or specific ON-coated discs; fluorescent staining of nuclei and F actin was then performed on EPCs cultured on unmodified or specific ON-coated discs and stents. Disc biofunctionalization significantly increased EPC viability as compared to both unmodified and nontargeting ON-coated surfaces; cell adhesion was also significantly increased. Stents were successfully functionalized with the specific ON, and EPC binding was confirmed by confocal microscopy. In conclusion, stent biofunctionalization for EPC binding was successfully achieved in vitro, suggesting its use to obtain in vivo endothelialization, exploiting the natural regenerative potential of the human body. PMID- 25809158 TI - Xylem development - from the cradle to the grave. AB - The development and growth of plants, as well as their successful adaptation to a variety of environments, is highly dependent on the conduction of water, nutrients and other important molecules throughout the plant body. Xylem is a specialized vascular tissue that serves as a conduit of water and minerals and provides mechanical support for upright growth. Wood, also known as secondary xylem, constitutes the major part of mature woody stems and roots. In the past two decades, a number of key factors including hormones, signal transducers and (post)transcriptional regulators have been shown to control xylem formation. We outline the main mechanisms shown to be essential for xylem development in various plant species, with an emphasis on Arabidopsis thaliana, as well as several tree species where xylem has a long history of investigation. We also summarize the processes which have been shown to be instrumental during xylem maturation. This includes mechanisms of cell wall formation and cell death which collectively complete xylem cell fate. PMID- 25809160 TI - Workers' Risk Tolerance and Occupational Injuries. AB - This study explores the relationship between individuals' risk tolerance and occupational injuries. We analyze data from a national representative survey of U.S. workers that includes information about injuries, risk tolerance, cognitive and noncognitive attributes, and risky behaviors. We measure risk tolerance through questions regarding individuals' willingness to gamble on their lifetime income. We estimate zero-inflated count models to assess the role played by such measures on workers' recurrent injuries. We discuss some implications of our results for future research and occupational safety policies. Our results highlight the concurrent and changing role played by individual, work, and environmental factors in explaining recurrent incidents. They show that risk tolerance affects recurrent injuries, although not in the direction that proponents of the concept of proneness would expect. Our measure of risk aversion shows that individuals who are somewhat more risk tolerant have fewer recurrent injuries than those who are risk averse. But the estimated relationship is U shaped, not monotonic and, therefore, not easy to predict. At the same time, we find that individuals' "revealed risk preferences"-specific risky behaviors-are related to higher injury probabilities. Demanding working conditions, measures of socioeconomic status, health, and safety problems experienced by workers during their youth remain among the most important factors explaining the phenomena of recurrent injuries. So our results contribute also to the important debate about the relationship between health and socioeconomic status. PMID- 25809159 TI - Active transportation in adult survivors of childhood cancer and neighborhood controls. AB - PURPOSE: Childhood cancer survivors (CCS) are at high risk of treatment-related late effects, including cardiovascular disease and diabetes, which can be exacerbated by inadequate physical activity (PA). Previous PA interventions targeting CCS have focused on the domain of leisure-time/recreational PA. Active transportation, another domain of PA, has not been described in CCS. Therefore, this study aimed to identify active transportation behaviors, barriers, and correlates in adult CCS. METHODS: We recruited 158 adult CCS and 153 controls matched on age, sex, and neighborhood for a survey regarding active transportation behaviors and perceptions. Linear and logistic regression models accounting for correlation among matched participants were used. RESULTS: Adult CCS engaged in similar levels of active transportation as controls (2.72 vs. 2.32 h/week, P = 0.40) despite perceiving greater health-related barriers (1.88 vs. 1.65 (measured on four-point Likert scale), P = 0.01). Marital/relationship status (odds ratio (OR) = 0.30, 95 % confidence interval (CI) = 0.11-0.81), planning/psychosocial barriers (OR = 0.15, 95 % CI = 0.04-0.53), and perceived neighborhood walkability (OR = 2.55, 95 % CI = 1.14-5.66) were correlates of active transportation among adult CCS, while objective neighborhood walkability (OR = 1.03, 95 % CI = 1.01-1.05) was a correlate among controls. CONCLUSIONS: Results suggest adult CCS and controls utilize active transportation at approximately equal levels. Factors other than health, including perceived neighborhood walkability, are related to active transportation behaviors to a greater degree in adult CCS. IMPLICATIONS FOR CANCER SURVIVORS: Interventions might consider promoting active transportation as a way to incorporate more PA into the daily lives of adult CCS. Such interventions will not be likely successful, however, without existing or improved neighborhood walkability/bikeability. PMID- 25809163 TI - [Effectiveness of one-stage microdiscectomy and radiofrequency denervation of intervertebral joints compared to microdiscectomy in patients with spinal disc herniation]. AB - The article analyzes of the early and long-term outcomes in 113 patients who underwent surgical treatment for lumbosacral disc herniations. The first group of patients (n=32) underwent microdiscectomy in a combination with radiofrequency destruction (RFD) of the facet nerves. The control group patients (n=81) underwent microdiscectomy. This study demonstrates the advantage of combining RFD with open surgery. In this case, regression of both nerve root and back pain is achieved, which greatly accelerates rehabilitation of patients, restoration of their work ability, and therefore their return to normal life. PMID- 25809164 TI - [A comparative analysis of the effectiveness and potential of endoscopic and microsurgical resection of disc herniations in the lumbosacral spine]. AB - The issue of advantage of endoscopic treatment of spinal disc herniations is debatable. Throughout the development, endoscopic technologies have been compared to microsurgical methods. The two-year experience of applying endoscopic methods was analyzed. The study included 183 patients. The effectiveness of the performed treatment was evaluated according to the MacNab scale of surgical treatment outcomes. Good and excellent results were obtained in 170 cases, which amounted to 92.9%. This cure rate was compared to the similar rate for good and excellent results of the microsurgical treatment method derived from the literature data. The article by American authors who conducted a multicenter study (Lumbar microdiscectomy: a historical perspective and current technical considerations. Koebbe C.J., Maroon J.C., Abla A., El-Kadi H., Bost J. Neurosurg Focus 2002 Aug 15; 13(2): E3) was used. On the basis of this study, the data on higher effectiveness of endoscopic discectomy compared to the microsurgical technique were obtained. The technical capabilities of the endoscopic method for removing spinal disc herniations in comparison to minimally invasive microsurgical techniques were carefully analyzed. It was noted that there were no significant instrumental limitations for using endoscopic techniques, while angled optics and excellent color rendition enable better visualization of the surgical wound structures and more efficient use of the approach space. Given that the technical characteristics and capabilities of this method are not inferior to those of the microsurgical technique, the former technology can be used instead of the standard technique for removing intervertebral disc herniations. Furthermore, the technical capabilities of the method allow performing wide decompression of the neural structures during surgery, which can be used to treat spinal stenoses. PMID- 25809161 TI - Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration. AB - Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of 2 weeks in vivo. We show that influenza induces DNA damage to both, when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via gammaH2AX foci). We show that DNA damage, as well as responses to DNA damage persist in vivo until long after virus has been cleared, at times when there are inflammation associated RONS (measured by xanthine oxidase activity and oxidative products). The frequency of lung epithelial and immune cells with increased gammaH2AX foci is elevated in vivo, especially for dividing cells (Ki-67-positive) exposed to oxidative stress during tissue regeneration. Additionally, we observed a significant increase in apoptotic cells as well as increased levels of DNA double strand break (DSB) repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA damage both in vitro and in vivo, and that DNA damage responses are activated, raising the possibility that DNA repair capacity may be a determining factor for tissue recovery and disease outcome. PMID- 25809165 TI - [Factors affecting the outcome of surgical management for extramedullary spinal cord tumors: a multicenter study]. AB - Extramedullary spinal cord tumors (ESCTs) are relatively rare neoplasms requiring surgical treatment. This paper presents a study of outcomes in patients with ESCTs treated at Irkutsk region hospitals with different facilities. AIM: To identify factors affecting the outcome of surgical treatment of ESCTs. MATERIAL AND METHODS: The disease stage before surgery was evaluated according to the I.Ya. Razdol'skiy and McCormick classifications. Features and extension of the approach, the extent of blood loss, surgery duration, and the equipment used were analyzed. Treatment outcomes were assessed according to the MacNub and McCormick neurological outcome scales. RESULTS: ESCTs were removed totally in 84 (95%) patients and subtotally in 4 (5%). Tumor recurrence was detected in 8 patients. No deaths were observed. No correlation was found between the treatment outcome, according to the McCormick scale, and factors such as gender, tumor location, histological type, tumor grade, disease duration, and type of a surgical approach and the equipment used. Factors having medium and high correlations with the disease outcome are a neurological disease phase and an initial neurological deficit: sensory deficit, r=0.32; motor deficit, r=0.33; pelvic disturbances, r=0.35; McCormick grade before surgery, r=0.74; disease phase r=0.41 (p<0.05). CONCLUSION: The disease phase is the most significant factor affecting the outcome of surgical treatment in patients with ESCTs. Despite this, important aspects of surgical treatment of ESCT include the approach that is adequate to the tumor size and localization, as well as combination of different surgical techniques. PMID- 25809162 TI - F-actin binding protein, anillin, regulates integrity of intercellular junctions in human epithelial cells. AB - Tight junctions (TJ) and adherens junctions (AJ) are key morphological features of differentiated epithelial cells that regulate the integrity and permeability of tissue barriers. Structure and remodeling of epithelial junctions depends on their association with the underlying actomyosin cytoskeleton. Anillin is a unique scaffolding protein interacting with different cytoskeletal components, including actin filaments and myosin motors. Its role in the regulation of mammalian epithelial junctions remains unexplored. Downregulation of anillin expression in human prostate, colonic, and lung epithelial cells triggered AJ and TJ disassembly without altering the expression of junctional proteins. This junctional disassembly was accompanied by dramatic disorganization of the perijunctional actomyosin belt; while the general architecture of the actin cytoskeleton, and activation status of non-muscle myosin II, remained unchanged. Furthermore, loss of anillin disrupted the adducin-spectrin membrane skeleton at the areas of cell-cell contact, selectively decreased gamma-adducin expression, and induced cytoplasmic aggregation of alphaII-spectrin. Anillin knockdown activated c-Jun N-terminal kinase (JNK), and JNK inhibition restored AJ and TJ integrity and cytoskeletal organization in anillin-depleted cells. These findings suggest a novel role for anillin in regulating intercellular adhesion in model human epithelia by mechanisms involving the suppression of JNK activity and controlling the assembly of the perijunctional cytoskeleton. PMID- 25809166 TI - [The use of minimally invasive approaches to resect intradural extramedullary spinal cord tumors]. AB - AIM: To conduct a comparative analysis of outcomes in patients with extramedullary tumors operated on using a minimally invasive approach and traditional laminectomy. MATERIAL AND METHODS: The study included 40 patients (13 males and 27 females) who underwent surgical treatment at the Department of Spinal Neurosurgery of the Burdenko Neurosurgical Institute. The mean age of patients was 47 years (range: 41-60 years). Tumors were located in the cervical, thoracic and lumbar spine. All patients were divided into two groups. In the control group, 20 patients underwent traditional laminectomy using a yard retractor or an Egorov-Freidin retractor. In the study group, 20 patients underwent hemilaminectomy using a retractor for minimally invasive surgery (Caspar and MAST Qudrant). The outcomes were evaluated 3, 6, and 12 months after surgery. The McCormik and VAS scales were used for the evaluation. MRI data were also evaluated. RESULTS: Total tumor resection was reached in all cases. The mean surgery duration was 247 min (range: 180-320 min) for the first group and 105.25 min (range: 60-190 min) for the second one. The volume of blood loss was 297 mL (range: 100-600 mL) for the first group and 210 mL (50 to 400 mL) for the second group. The histological nature of the tumors was as follows: neurinoma, meningioma, and ependymomas of the cauda equina. The evaluation of the pain syndrome in the early postoperative period revealed that the pain syndrome intensity according to VAS was reduced in patients of the second group compared to that in patients of the first group. The evaluation using the McCormik scale revealed no obvious difference in the results between the study and control groups. MRI studies performed in the postoperative period showed no tumor recurrence. CONCLUSION: Surgical treatment of patients with intradural extramedullary tumors can be safely and effectively performed using minimally invasive approaches. A potential reduction in surgery duration, intraoperative blood loss, the amount of anesthetic drugs and reduction in the pain syndrome in the early postoperative period allow us to conclude that, when performed by an experienced surgeon, the method of minimally invasive surgery may be an alternative to the traditional removal of an extramedullary tumor. PMID- 25809167 TI - [Epidemiology of pediatric intramedullary spinal cord tumors]. AB - Intramedullary spinal cord tumors (IMSCTs) are a rare neurosurgical disease. There are a lot of controversies in their epidemiology. Most references were published in the 80-90ss. The authors describe and analyze the largest contemporary clinical series of IMSCTs treated by one surgeon (YK). MATERIAL AND METHODS: 201 patients (aged 2 months - 18 years) with IMSCT operated on during the past 12 years. RESULTS: A slight predominance of male patients was discovered. Astrocytomas account for 74% of all pediatric IMSCTs. Classic ependymomas are rare (5,5%). Pediatric spinal cord hemangioblastomas (HABs) are highly suspicious for von Hippel-Lindau disease. CONCLUSION: Benign histological variants of astrocytomas are the most common type of pediatric IMCTs. No gender or age differences in the incidence of most tumors (except for HABs) have been observed. Patients with intramedullary HAB should be routinely screened for von Hippel-Lindau disease. There are still a lot of uncertainties in the published data on epidemiology of IMSCTs. PMID- 25809168 TI - [The use of intraoperative electrophysiological monitoring in patients with decompression of the ulnar nerve near the elbow joint]. AB - At the elbow, the ulnar nerve may be compressed either in the retrocondylar groove, in the cubital tunnel, or compressed by Osborne's band. Optimal surgical therapy should be directed at the specific site of involvement. It is more difficult to identify the level of ulnar nerve compression. Anatomical variations may make it difficult to identify the causes of ulnar neuropathy at the elbow. The data obtained by inspection, probing, or electroneurography do not allow one to reliably identify the compression level. Intraoperative electroneuromyography performed in conjunction with 14 ulnar nerve explorations helped localize the precise site of compression in 12 cases. Intraoperative studies helped identify compression by Osborne band in 8 patients. We conclude that intraoperative electroneuromyography identifies compression levels of ulnar neuropathy more accurately than the conventional examination methods do. PMID- 25809169 TI - [The use of botulinum toxin type a in the acute phase of facial nerve injury after neurosurgical surgery]. AB - AIM: To evaluate the role of botulinum toxin type A in the acute phase of facial nerve injury after neurosurgical surgery. MATERIALS AND METHODS: The study involved 55 patients with acute facial muscle paresis caused by facial nerve injury during surgery on the posterior cranial fossa and cerebello-pontine angle (CPA). The first group consisted of 35 patients (mean age, 48.14+/-1.26 years) who were administered botulinum toxin type A (xeomin) at a dose of 2-3 U per point in muscles of the intact side of the face. The control group included 20 patients (mean age, 49.85+/-1.4 years) who underwent standard rehabilitation treatment of this pathology. The treatment efficacy was evaluated using the House Brackmann Scale, the Yanagihara facial grading system, the Facial Disability Index (FDI), and the Sunnybrook Facial Grading (SFG) Scale. RESULTS: Before treatment, patients of both groups experienced severe dysfunction according to the House-Brackmann Scale. A month after the botulinium toxin type A therapy had been started, a significant improvement in the group of patients who received botulinum toxin was observed at all scales (p<0.05), whereas improvement in the facial nerve function in the second group was observed only by the 3rd month of rehabilitation treatment (p<0.05). The number of synkineses in the patients who did not receive botulinum toxin was 46% higher than that in the first group (p=0.019) one year after the surgery, and it was higher by 91% after 2 years (p<0.001). CONCLUSIONS: The use of botulinum toxin type A is reasonable in acute facial nerve injury and should be mandatory in combined therapy of these patients. PMID- 25809170 TI - [Intradural extramedullary myxoma at the L1 level]. AB - Myxoma of the peripheral nerve sheath is a rare benign tumor with predominant localization in the upper extremities, head, neck, and chest. In this study, we reported a clinical case of a patient with intradural myxoma at the L1 level. Much attention was given to histological characterization of the tumor and differential diagnosis of histological types of benign extramedullary tumors. A conclusion was drawn that patients with myxoma need further thorough examination as there is a risk of generalization of tumor process. PMID- 25809171 TI - [A protocol recommended for treating acute complicated and uncomplicated spinal injuries in adult patients (Association of Neurosurgeons of Russia). Part 1]. PMID- 25809172 TI - [Clinical thinking of a neurosurgeon]. PMID- 25809174 TI - An epidemic of opioid prescriptions. PMID- 25809173 TI - Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial. AB - In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated. PMID- 25809175 TI - Labor costs and economic impact of a primary care clinical pharmacy service on postfracture care in postmenopausal women. AB - STUDY OBJECTIVE: To compare costs associated with two osteoporosis management interventions and to quantify cost avoidance due to projected hip fracture prevention. DESIGN: Labor and cost analysis within a retrospective cohort study. SETTING: Integrated health care delivery system. PATIENTS OR PARTICIPANTS: Women aged 67 or older with a documented fracture between January 1 and December 31, 2007, managed by either a Clinical Pharmacy Osteoporosis Management Service (CPOMS) or comparator service using a registered nurse (RN). Recommendations included dual-energy x-ray absorptiometry (DEXA) scans and/or bisphosphonate therapy as appropriate. MEASUREMENT AND MAIN RESULTS: The primary end points were cost per patient reviewed, cost per patient achieving the quality end point of completing a DEXA scan or purchasing an antiosteoporosis medication, and cost avoidance due to projected hip fracture prevention. A total of 1129 women were managed by either CPOMS (n=827) or the comparator service (n=302). The cost of provider time for CPOMS and comparator group interventions was $25 ($21-$30) and $34 ($21-$53) per patient reviewed, respectively. The cost per patient achieving the quality end point was $92 ($77-$112) and $198 ($124-$307), respectively. If women in the CPOMS group persisted in receiving their bisphosphonate for 1 year, approximately two additional hip fractures would be avoided per 1000 patients reviewed. Based on this model, the projected annual cost of osteoporosis care for 1000 women was $619,736 (CPOMS) versus $726,887 (comparator service). CONCLUSIONS: The CPOMS resulted in comparable cost per patient reviewed but a lower cost per patient achieving quality end points. When including costs associated with projected hip fractures, CPOMS was less expensive than the comparator group because more patients initiated drug therapy, which resulted in fewer projected hip fractures. From the health care payer's perspective, the CPOMS intervention is associated with a lower cost per patient achieving treatment recommendations while providing future cost savings because of fewer hip fractures. PMID- 25809176 TI - Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study. AB - INTRODUCTION: Enteral clonidine represents a potentially less costly alternative to dexmedetomidine for sedation in intensive care unit (ICU) patients. This study describes our practice of transitioning selected adult ICU patients from dexmedetomidine to clonidine with a focus on efficacy, safety, and drug acquisition costs. METHODS: We conducted a single-center prospective observational pilot study from January through March 2014. Consecutive patients 18 years and older treated with dexmedetomidine and transitioned to clonidine were followed. The transition was assessed in five phases: dexmedetomidine maintenance, transition, clonidine maintenance, clonidine taper, and post clonidine. Efficacy data included any occurrence of significant pain, excessive agitation or oversedation, delirium, and need for ancillary psychoactive medications. Safety data included any occurrence of bradycardia, hypotension, new second- or third-degree atrioventricular node blockade, and clonidine withdrawal syndrome. Drug acquisition cost avoidances were estimated using average wholesale price. RESULTS: Twenty patients were evaluated. Fifteen (75%) were successfully transitioned from dexmedetomidine within 48 hours of starting clonidine. The initial and maintenance clonidine regimens were 0.3 mg every 6 hours. Clonidine was the sole alpha2A -receptor agonist administered for 45 hours while in the ICU and for 54 hours outside the ICU. Fentanyl requirements were lower when clonidine was administered as the sole alpha2A -receptor agonist as compared to dexmedetomidine alone (387 vs. 891 MUg/day, p = 0.03). Otherwise, there were no statistically significant differences in efficacy data during the dexmedetomidine and clonidine maintenance phases. No statistically significant differences in safety data were observed. Clonidine withdrawal syndrome criteria were met in one patient. The potential drug acquisition cost avoidance was $819-$2338 per patient during the 3-month study. CONCLUSIONS: Transitioning from dexmedetomidine to clonidine may be an efficacious, safe, and less costly method of maintaining alpha2A -receptor agonist therapy in critically ill adults; these results warrant confirmation in expanded studies. PMID- 25809177 TI - Relationship between antipsychotics and weight in patients with Prader-Willi syndrome. AB - BACKGROUND: Individuals with Prader-Willi Syndrome (PWS) are at increased risk for developing behavioral and psychiatric disorders, often requiring antipsychotics (APs). Contrary to significant AP-associated weight gain observed in the general population, existing literature suggests weight loss in patients with PWS. STUDY OBJECTIVE: To evaluate the relationship between AP use and body mass index (BMI) at admission, change in BMI during inpatient stay, and length of stay (LOS) in patients admitted to an inpatient PWS treatment program. DESIGN: Retrospective case-control study. SETTING: Hospital-based, inpatient PWS treatment program serving nationally and internationally referred children and adults with PWS. PATIENTS: Cases consisted of 52 pediatric patients with PWS who were taking APs at admission and during their stay, 97 adults with PWS who were taking APs at admission and during their stay, and 11 pediatric and adult patients with PWS who were AP naive at admission and subsequently started an AP during their stay; all cases were matched with patients with PWS who were AP naive at admission and during their stay by age (yrs), sex, and race-ethnicity (controls). MEASUREMENTS AND MAIN RESULTS: Between- and within-group differences in admission BMI, BMI change from admission to discharge, and LOS were analyzed. Admission BMI was lower (mean +/- SD 36.8 +/- 11.9 kg/m(2) vs 46.7 +/- 12.5 kg/m(2) , p<0.001) and LOS longer (mean +/- SD 75.9 +/- 38.5 days vs 57.8 +/- 23.2 days, p=0.005) for pediatric cases with AP exposure at admission and during their stay compared with matched controls. All groups experienced significant decreases in BMI from admission to discharge (p<=0.001 for all comparisons), except for pediatric cases with AP exposure at admission and during their stay. Cases that were AP naive at admission and subsequently started an AP during their inpatient stay experienced a significantly smaller decrease in BMI from admission to discharge than matched controls (-3.011 vs -7.288 kg/m(2) , p=0.027). No other comparisons between cases and controls were significantly different. CONCLUSION: On average, patients with PWS who were prescribed APs lost weight during their inpatient stay, but this varied with patient age and duration of AP use. PMID- 25809178 TI - Outcomes of rapid identification for gram-positive bacteremia in combination with antibiotic stewardship at a community-based hospital system. AB - BACKGROUND: Rapid diagnostics for bloodstream infections have been shown to improve outcomes. Most studies have focused on rapid diagnostics for a single pathogen and have been conducted in academic medical centers. The Verigene Gram Positive Blood Culture Test (BC-GP) identifies 12 gram-positive organisms and 3 genetic markers of antibiotic resistance from positive blood culture media in 2.5 hours. This study evaluates implementation of the Verigene BC-GP panel in combination with real-time support from the Antibiotic Stewardship Team (AST) in a community hospital system. METHODS: This multicenter, pre-post, quasi experimental study was conducted at the five hospitals that compose Scripps Healthcare. Rapid diagnostic testing was performed at a central laboratory from 7 a.m.-7 p.m. Pharmacists notified physicians of results and assisted with antibiotic modifications. The primary outcomes were average time to targeted antibiotic therapy and difference in antibiotic duration for contaminants. Secondary end points included hospital length of stay, mortality, pharmacy costs, and overall hospitalization costs. Adult patients with a gram-positive bacteremia admitted in 2011 (pre-rapid testing) were compared with those admitted in 2014 (post-rapid testing). RESULTS: There were 103 patients in the preintervention group and 64 patients in the intervention group. The optimized identification process, combined with AST intervention, improved mean time to targeted antibiotic therapy (61.1 vs 35.4 hrs, p<0.001) and decreased mean duration of antibiotic therapy for blood culture contaminants (42.3 vs 24.5 hrs, p=0.03). Median length of stay (9.1 vs 7.2 days, p=0.04) and overall median hospitalization costs ($17,530 vs $10,290, p=0.04) were lower in the intervention group. Mortality was similar between groups (9.1% vs 9.2%, p=0.98). CONCLUSION: Rapid identification of gram-positive blood cultures with AST intervention decreased time to targeted antibiotic therapy, length of unnecessary antibiotic therapy for blood culture contaminants, length of stay, and overall hospital costs. PMID- 25809179 TI - Inhaled technosphere insulin: a novel delivery system and formulation for the treatment of types 1 and 2 diabetes mellitus. AB - Complications from uncontrolled diabetes mellitus were reduced significantly with the introduction of insulin more than 90 years ago. Despite the proven benefits of normal glycemic levels, patients are deterred by the inconvenience and perceived pain related to multiple daily subcutaneous insulin injections. Inhaled insulin was first approved by the U.S. Food and Drug Administration (FDA) in 2006, but because profit margins did not achieve expectations, the drug manufacturer discontinued sales 2 years later. The second-generation inhaled insulin, developed with Technosphere technology, received FDA approval in 2014. The pharmacology, pharmacokinetics, drug interactions, clinical safety and efficacy, patient satisfaction, dosage and administration, warnings, precautions, contraindications, adverse effects, and place in therapy of inhaled Technosphere insulin are reviewed in this article. PMID- 25809180 TI - Efficacy of triclosan as an antimicrobial hand soap and its potential impact on antimicrobial resistance: a focused review. AB - Triclosan is a synthetic biocide found in many household products, including antimicrobial hand soap. Levels of triclosan have been found throughout the environment and in human urine, blood, and even breast milk. Increasing levels of exposure to triclosan have led to concerns over the development of resistance to triclosan and cross-resistance to other antimicrobials. We performed a literature search to assess whether the widespread use of triclosan displays a favorable benefit: risk ratio, defined by evaluation of triclosan's efficacy as an antimicrobial hand soap and its potential effect on the development of antimicrobial resistance. Data from laboratory-based studies regarding the efficacy of triclosan are conflicting, although well-designed studies suggest no significant difference in efficacy over nonantimicrobial soap. In addition, when triclosan was introduced in a community setting, no beneficial effects were observed on the reduction of infections over nonantimicrobial soap. Resistance to triclosan and cross-resistance to antimicrobials have been consistently demonstrated in laboratory settings, although overall resistance rates and cross resistance rates in the community setting are low. Based on the available evidence, the risk of potential antimicrobial resistance outweighs the benefit of widespread triclosan use in antimicrobial soaps. PMID- 25809181 TI - Breakthrough seizures after starting vilazodone for depression. AB - Vilazodone is a new selective serotonin reuptake inhibitor (SSRI) and serotonin 5 HT1a partial agonist that is approved by the United States Food and Drug Administration to treat major depression. SSRI-induced seizures are rare and are more likely to be associated with larger doses and severe symptoms such as those present in serotonin syndrome. Several case reports have implicated SSRIs, buspirone, or the combination of these agents as the cause of seizures, but these reports were confounded with either coingestions or doses that exceeded FDA recommendations. We describe a 22-year-old woman with a history of seizure disorder who had been seizure free for the previous 8 years and experienced two breakthrough seizures shortly after starting vilazodone. Her dose of vilazodone had recently been titrated to 40 mg/day when she experienced the first seizure. She was instructed to taper vilazodone over the next several days, then discontinue the drug, and then follow up with her neurologist. Based on the patient's history, physical examination, and recent dose increase, it was plausible that vilazodone was the cause of the seizures. Use of the Naranjo adverse drug reaction probability scale indicated a possible relationship (score of 4) between her development of seizures and vilazodone therapy. The pharmacodynamics of this particular class of SSRI has both proconvulsive and anticonvulsive mechanisms. This is of particular concern in patients with a history of seizure disorder who are starting antidepressive therapy. In persons with epilepsy who are taking vilazodone and experience breakthrough seizures, practitioners should consider this drug as a potential cause of these seizures. Thus, until future research and experience with vilazodone can provide a definitive answer, clinicians should be cautious when prescribing this medication to treat depression in patients with a history of seizure disorder. PMID- 25809182 TI - beta3 -AR and the vertebrate heart: a comparative view. AB - Recent cardiovascular research showed that, together with beta1- and beta2 adrenergic receptors (ARs), beta3-ARs contribute to the catecholamine (CA) dependent control of the heart. beta3-ARs structure, function and ligands were investigated in mammals because of their applicative potential in human cardiovascular diseases. Only recently, the concept of a beta3-AR-dependent cardiac modulation was extended to non-mammalian vertebrates, although information is still scarce and fragmentary. beta3-ARs were structurally described in fish, showing a closer relationship to mammalian beta1-AR than beta2 AR. Functional beta3-ARs are present in the cardiac tissue of teleosts and amphibians. As in mammals, activation of these receptors elicits a negative modulation of the inotropic performance through the involvement of the endothelium endocardium (EE), Gi/0 proteins and the nitric oxide (NO) signalling. This review aims to comparatively analyse data from literature on beta3-ARs in mammals, with those on teleosts and amphibians. The purpose is to highlight aspects of uniformity and diversity of beta3-ARs structure, ligands activity, function and signalling cascades throughout vertebrates. This may provide new perspectives aimed to clarify the biological relevance of beta3-ARs in the context of the nervous and humoral control of the heart and its functional plasticity. PMID- 25809184 TI - Infection by the cestode parasite Schistocephalus sp. and effects on diet, body condition and survival of sculpins Cottus aleuticus and Cottus cognatus. AB - Sampling in Iliamna Lake, Alaska, U.S.A. revealed that a greater proportion of coastrange sculpins Cottus aleuticus were infected by the cestode Schistocephalus solidus than slimy sculpins Cottus cognatus (52 v. 23%), and infected C. aleuticus contained more cestodes than did C. cognatus (2.1 v. 1.3 per fish). Consumption of sockeye salmon Oncorhynchus nerka eggs (the primary diet item) was lower in fishes with cestodes, and a model based on cestode prevalence and age composition estimated higher rates of infection and parasite-associated mortality in C. aleuticus compared with C. cognatus. PMID- 25809185 TI - Scientific evidence and reduced surgical treatment in acute ligament ruptures of the ankle. PMID- 25809186 TI - Exercise and oral health: implications of the exercise intensity on dental diseases. PMID- 25809183 TI - 2-year follow-up report on micromotion of a short tibia stem. A prospective, randomized RSA study of 59 patients. AB - BACKGROUND AND PURPOSE: A shortened tibial stem could influence the early prosthetic fixation. We therefore compared the short stem to the standard-length stem using radiostereometric analysis (RSA) as primary outcome measure. PATIENTS AND METHODS: 60 patients were randomized to receive a cemented Triathlon total knee arthroplasty (TKA) with a tibial tray of either standard or short stem length. The patients were blinded regarding treatment allocation. The micromotion of the tibial component was measured by RSA postoperatively, at 3 months, and after 1 and 2 years; clinical outcome was measured with the American Knee Society score (AKSS) and the knee osteoarthritis and injury outcome score (KOOS). RESULTS: The maximum total point motion (MTPM) for the standard stem was 0.36 (SD 0.16) mm at 3 months, 0.51 (SD 0.27) mm at 1 year, and 0.54 (SD 0.28) mm at 2 years. For the short stem, it was 0.42 (0.24) mm, 0.59 (0.43) mm, and 0.61 (0.39) mm. 4 short-stemmed components and 2 standard-stemmed components had more than 0.2 mm of migration between the first- and second-year follow-up, and were classified as continuously migrating. INTERPRETATION: The short-stemmed cemented tibial prosthesis showed an early prosthetic migratory pattern similar to that of the standard-stemmed cemented Triathlon knee prosthesis. The number of continuously migrating tibial plates in each group is predictive of a lower revision rate than 5% at 10 years. PMID- 25809187 TI - Comment on the editorial: hyperoxia and cerebral vasoconstriction in healthy newborns. PMID- 25809188 TI - Biochemical characterization of a D-psicose 3-epimerase from Treponema primitia ZAS-1 and its application on enzymatic production of D-psicose. AB - BACKGROUND: The rare sugar D-psicose is a hexoketose monosaccharide and a C-3 epimer of D-fructose. D-Psicose is a novel functional sweetener with 70% of the sweetness but only 0.3% of the energy content of sucrose. Generally, the industrial production of D-psicose involves a bioconversion from D-fructose induced by ketose 3-epimerases. RESULTS: The D-psicose 3-epimerase (DPEase) gene from Treponema primitia ZAS-1 (Trpr-DPEase) was cloned and overexpressed in Escherichia coli BL21 (DE3). The recombinant enzyme was purified with a molecular mass of 33 kDa. Trpr-DPEase exhibited optimal activity at pH 8.0 and 70 degrees C and was sensitive to temperature, with relative thermal stability below 50 degrees C. It was strictly metal-dependent and displayed maximum catalytic activity with 450 umol L(-1) Co(2+). The Km values of the enzyme for D-psicose and D-fructose were 209 and 279 mmol L(-1) respectively. The D-psicose/D-fructose equilibrium ratio of Trpr-DPEase was 28:72. CONCLUSION: A novel DPEase from T. primitia ZAS-1 was characterized that could catalyze the formation of D-psicose from D-fructose. D-Psicose was produced at a yield of 137.5 g L(-1) from 500 g L( 1) D-fructose, suggesting that Trpr-DPEase might be appropriate for the industrial production of D-psicose. PMID- 25809191 TI - Predictors of progression in patients presenting with minor subcortical stroke. AB - OBJECTIVES: Early neurological worsening is common in minor subcortical strokes (SS) and may lead to a poor outcome. We aimed to describe clinical and imaging features associated with progression. MATERIAL AND METHODS: Consecutive patients with SS were divided into progressive and non-progressive. Progression was defined as an increase of NIHSS motor score >= 1 point within 72 h from onset. Vascular risk factors and imaging features (vascular territory, size and number of slices in which the lesion was visible, the presence of leukoaraiosis) were compared in the two groups. We investigated potential independent determinants of progression using stepwise logistic regression. RESULTS: Thirty of 94 patients (31.9%) underwent progression. The distribution of vascular risk factors did not differ significantly between the two groups. Increasing number of risk factors was associated with a higher risk of progression (OR 2.2; 95% CI 1.1-4.5). Patients who progressed were more likely to have a lesion >= 15 mm in diameter (P = 0.004) or a lesion visible >= 3 slices (P = 0.007). After logistic regression stepwise adjustment for all the considered potential determinants, diameter >= 15 mm and severe leukoaraiosis proved to be independently associated with neurological worsening (OR = 6.3, 95% CI 2.0-19.6 and OR = 5.9, 95% CI 1.3-25.7, respectively). CONCLUSION: In a series of consecutive SS, early neurological worsening was associated with a high vascular risk profile, a larger infarct size and the presence of severe leukoaraiosis. Based on the knowledge that extensive microvascular changes are a feature of severe leukoaraiosis, we hypothesize that stroke progression could be promoted through an impaired compensatory flow in the penumbral area. PMID- 25809189 TI - NR4A receptors up-regulate the antiproteinase alpha-2 macroglobulin (A2M) and modulate MMP-2 and MMP-9 in vascular smooth muscle cells. AB - Matrix metalloproteinases (MMPs) are associated with tissue remodelling and repair. In non-vascular tissues, NR4A receptors have been involved in the regulation of MMPs by transcriptional repression mechanisms. Here, we analyse alternative mechanisms involving NR4A receptors in the modulation of MMP activity in vascular smooth muscle cells (VSMC). Lentiviral overexpression of NR4A receptors (NOR-1, Nurr1 and Nur77) in human VSMC strongly decreased MMP-2 and MMP 9 activities (analysed by zymography and DQ-gelatin assays) and protein levels. NR4A receptors also down-regulated MMP-2 mRNA levels. Real-time PCR analysis evidenced that alpha-2-macroglobulin (A2M), but not other MMP inhibitors (TIMP-1 and TIMP-2) were up-regulated in NR4A-transduced cells. Interestingly, A2M was expressed in human vascular tissues including the smooth muscle media layer. While NR4A receptors increased A2M expression and secretion in VSMC, NR4A knockdown significantly reduced basal A2M expression in these cells. The direct transcriptional regulation of the human A2M promoter by NR4A receptors was characterised in luciferase reporter assays, electrophoretic mobility shift assays and by chromatin immunoprecipitation, identifying a NGFI-B response element (NBRE-71/-64) essential for the NR4A-mediated induction. The blockade of A2M partially prevented the reduction of MMPs activity observed in NR4A transduced cells. Although mouse A2M promoter was unresponsive to NR4A receptors, vascular MMP expression was attenuated in transgenic mice over-expressing human NOR-1 in VSMC challenged with lipopolysaccharide. Our results show that the pan proteinase inhibitor A2M is expressed in the vasculature and that NR4A receptors modulate VSMC MMP activity by several mechanisms including the up-regulation of A2M. PMID- 25809190 TI - Inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5) is overexpressed in inflammatory skin diseases and affects epidermal morphology in constitutive knockout mice and murine 3D skin models. AB - Inter-alpha-trypsin inhibitors are protease inhibitors that are thought to be important regulators in various acute-phase processes. They are composed of one light chain (bikunin) and different heavy chains (ITIHs). The only function known so far of ITIHs is the covalent linkage to hyaluronan (HA). As there is virtually no knowledge on the distribution and function of ITIH proteins in skin tissue, we performed a systematic characterization of ITIH expression in healthy and diseased skin. Using GeneChip((r)) Human Exon 1.0 ST expression profiling, we found that ITIH5 represents the major ITIH family member expressed in human skin. Moreover, the use of quantitative reverse transcription PCR and a customized ITIH5-specific antibody indicated that ITIH5 is predominantly produced by dermal fibroblasts. Immunohistochemical analysis revealed a clearly detectable ITIH5 protein expression in normal skin. Interestingly, ITIH5 expression was significantly up-regulated in inflammatory skin diseases. Furthermore, 3D skin models employing murine Itih5(-/-) epidermal keratinocytes and dermal fibroblasts as well as skin specimens of Itih5(-/-) mice revealed a significantly altered epidermal structure compared to wild-type controls. Hence, we can strengthen the presumption that ITIH5 may constitute a novel regulatory molecule of the human skin that could play an important role in inflammation via its interaction with HA. PMID- 25809192 TI - Objective Assessment of the Rheological Muscle Property in the Treatment of Fibromyalgia. AB - Fibromyalgia (FM), clinical condition characterized by several signs and symptoms such as widespread pain, trigger point, morning stiffness and extreme tiredness for scarce hours of sleep, is linked to several changes in several brain neurotransmitters, particularly serotonin and norepinephrine. Consequently, the Neural Vegetative System works more and so it generates an exaggerated muscular contraction, sweating and constriction of blood vessels. The aim of our study was to treat a selected group of female patients suffering from FM with duloxetine with physiotherapy. We used two clinical scales (VAS and FIQ) and an objective evaluation such as myometric. The analysis of the data Myoton used during any inspection showed a statistically significant reduction in the values of muscle tone in each district analyzed. This finding was also confirmed by the patients themselves who have experienced a significant welfare and less muscle tension in different locations, as evidenced by data obtained from the clinical scales used by us. In addition, our patients were thought to be satisfied with the improvements not only subjective, but also with the objective witnessed myometry, making them a share of the study and feeling constantly monitored for treatment aimed at a real reduction in muscle stiffness. In conclusion, our study demonstrates combined treatment duloxetine- physiotherapy effectively reduces a symptom often disabling and particularly troublesome in patients with FM as the exaggerated muscle contraction. PMID- 25809193 TI - Beneficial Effects of Vildagliptin on Metabolic Parameters in Patients with Type 2 Diabetes. AB - Blood pressure and lipid profile are important determinants of cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). To identify the pleiotropic effects of vildagliptin other than blood glucose lowering effect, a retrospective study was conducted in 128 patients with T2DM treated with vildagliptin 50 mg twice daily. The patients were separated into two groups: patients who were initiated with vildagliptin as monotherapy or add-on therapy (add-on group, n = 66) and patients who were switched from sitagliptin 100 mg once daily to vildagliptin (switching group, n = 62). Hemoglobin A1c (HbA1c), body mass index (BMI), systolic/diastolic blood pressure, lipid profiles, and uric acid (UA) at 3, 6, and 12 months of vildagliptin therapy were compared with those at baseline in each group. At baseline, there were no significant differences in HbA1c, BMI, blood pressures, lipid profiles, and UA levels between the two groups. After vildagliptin initiation, HbA1c decreased significantly but BMI and blood pressure did not change in both groups. Only in the add-on group, total cholesterol and low density lipoprotein cholesterol decreased significantly from baseline to 3, 6, and 12 months. On the other hand, triglyceride and high density lipoprotein cholesterol did not change in both groups. Serum UA levels decreased only in the switching group from baseline to 3, 6, and 12 months. These results indicate that vildagliptin add-on treatment may have beneficial effects on lipid profiles, and switching from sitagliptin to vildagliptin reduces UA in patients with T2DM; these are important findings linked to the beneficial effects of vildagliptin on lipid and UA metabolisms in the treatment of T2DM. PMID- 25809194 TI - Cutaneous vascular and sweating responses to intradermal administration of ATP: a role for nitric oxide synthase and cyclooxygenase? AB - KEY POINTS: In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation along with whether and how ATP increases sweating remains uncertain. Recent work has implicated nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine in the modulation of cutaneous vasodilatation and sweat production during both local (i.e. localized heating) and whole-body heat stress (i.e. exercise-induced heat stress). We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via NOS, COX and/or adenosine. We show that in humans in vivo, intradermal administration of ATP induces pronounced vasodilatation which is partially mediated by NOS, but neither COX nor adenosine influences ATP-mediated vasodilatation, and ATP alone does not induce an increase in sweating. These findings advance our basic physiological knowledge regarding control of skin blood flow and sweating, and provide insight into the mechanisms governing thermoeffector activity, which has major implications for whole-body heat exchange and therefore core temperature regulation in humans during heat stress. ABSTRACT: In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation and whether and how ATP increases sweating remain uncertain. We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine-dependent mechanisms. Cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated at intradermal microdialysis forearm skin sites, each receiving pharmacological agents (two separate protocols). In Protocol 1 (n = 12), sites were perfused with: (1) lactated Ringer solution (Control), (2) 10 mm N(omega) -nitro-l arginine (l-NNA, a NOS inhibitor), (3) 10 mm ketorolac (Ketorolac, a COX inhibitor) or (4) a combination of 10 mm l-NNA + 10 mm ketorolac (l-NNA + Ketorolac). In Protocol 2 (n = 8), sites were perfused with: (1) lactated Ringer solution (Control) or (2) 4 mm theophylline (Theophylline, an adenosine receptor inhibitor). At all sites, ATP was simultaneously perfused at 0.12, 1.2, 12, 120 and 1200 nm min(-1) (each for 20 min). Relative to CVC at the Control site with ATP infused at 120 nm min(-1) (71 +/- 9% of max CVC), CVC at the Ketorolac site was comparable (64 +/- 13% of max CVC, P = 0.407), but lower at l-NNA (51 +/- 15% of max CVC, P = 0.040) and l-NNA + Ketorolac (51 +/- 13% of max CVC, P = 0.049) sites. Conversely, across the four skin sites at any other ATP infusion rate (all P > 0.174), no differences in CVC were observed. Theophylline did not influence CVC at any ATP infusion rate (all P > 0.234). Furthermore, no ATP infusion rate elicited an increase in sweating from baseline at any skin site (all P > 0.235). We show that NOS, but neither COX nor adenosine receptors, modulates ATP-mediated cutaneous vasodilatation, whereas ATP does not directly increase sweating. PMID- 25809195 TI - Associated bacteria of different life stages of Meloidogyne incognita using pyrosequencing-based analysis. AB - The root knot nematode (RKN), Meloidogyne incognita, belongs to the most damaging plant pathogens worldwide, and is able to infect almost all cultivated plants, like tomato. Recent research supports the hypothesis that bacteria often associated with plant-parasitic nematodes, function as nematode parasites, symbionts, or commensal organisms etc. In this study, we explored the bacterial consortia associated with M. incognita at different developmental stages, including egg mass, adult female and second-stage juvenile using the pyrosequencing approach. The results showed that Proteobacteria, with a proportion of 71-84%, is the most abundant phylum associated with M. incognita in infected tomato roots, followed by Actinobacteria, Bacteroidetes, Firmicutes etc. Egg mass, female and second-stage juvenile of M. incognita harbored a core microbiome with minor difference in communities and diversities. Several bacteria genera identified in M. incognita are recognized cellulosic microorganisms, pathogenic bacteria, nitrogen-fixing bacteria and antagonists to M. incognita. Some genera previously identified in other plant-parasitic nematodes were also found in tomato RKNs. The potential biological control microorganisms, including the known bacterial pathogens and nematode antagonists, such as Actinomycetes and Pseudomonas, showed the largest diversity and proportion in egg mass, and dramatically decreased in second-stage juvenile and female of M. incognita. This is the first comprehensive report of bacterial flora associated with the RKN identified by pyrosequencing-based analysis. The results provide valuable information for understanding nematode-microbiota interactions and may be helpful in the development of novel nematode-control strategies. PMID- 25809196 TI - Nanoporous Ru as a carbon- and binder-free cathode for Li-O2 batteries. AB - Porous carbon-free cathodes are critical to achieve a high discharge capacity and efficient cycling for rechargeable Li-O2 battery. Herein, we present a very simple method to directly grow nanoporous Ru (composed of polycrystalline particles of ~5 nm) on one side of a current collector of Ni foam via a galvanic replacement reaction. The resulting Ru@Ni can be employed as a carbon- and binder free cathode for Li-O2 batteries and delivers a specific capacity of 3720 mAh gRu (-1) at a current density of 200 mA gRu (-1) . 100 cycles of continuous discharge and charge are obtained at a very narrow terminal voltage window of 2.75~3.75 V with a limited capacity of 1000 mAh gRu (-1) . The good performance of the nanoporous Ru@Ni cathode can be mainly attributed to the effective suppression of the by-products related to carbon or binder, the good adhesion of the catalyst to the current collector, and the good permeation of O2 and electrolyte into the active sites of the nanoporous Ru with the open pore system. This new type electrode provides a snapshot toward developing high-performance carbon- and binder-free Li-O2 batteries. PMID- 25809197 TI - Breast cancer survivors' experiences of partner support and physical activity participation. AB - OBJECTIVE: To examine women's experiences of enablers and constraints to physical activity participation after being diagnosed with breast cancer while mothers of dependent children. METHODS: In-depth, semi-structured interviews were conducted with 36 Australian women diagnosed with breast cancer while mothers of dependent children. RESULTS: Social, structural and individual enablers and constraints to women's participation in physical activity included level of intimate partner support, daily household and childcare responsibilities, post-treatment pain and fatigue and level of priority for and pleasure derived from physical activity participation. CONCLUSIONS: The study concludes that social enablers and constraints, particularly partner support and gendered identity, were powerful in framing women's participation. Implications for those working in survivorship care include the need to consider ways to address women's gendered identities and their associated social roles, relationships and responsibilities when designing strategies to increase breast cancer survivors' physical activity participation. Further research is needed to understand the prevalence of the effects of perceived partner support on breast cancer survivors' physical activity participation. PMID- 25809199 TI - Prevalence of metabolic syndrome in rural elderly of Asian Indian origin. AB - OBJECTIVES: Virtually no studies have been undertaken to investigate the prevalence of metabolic syndrome (MS) among the rural elderly in India. The aim of the present study was to identify the effects of sex and age on body fat distribution, blood pressure (BP), and metabolic variables as well as to look at the prevalence of MS and related phenotypes by age-groups and sex. METHODS: A total of 312 participants aged >=55 years took part in the present cross sectional study. All the participants were grouped into: Group I (55-59 years); Group II (60-64 years); Group III (65-69 years); and Group IV (>=70 years). Anthropometric measures were collected using standard techniques. Metabolic profiles and blood pressure were also measured. RESULTS: MANOVA revealed significant sex and age group effects on percent body fat, trunk extremity ratio, and diastolic BP. Significant sex effects were evident for BMI, waist-hip ratio, waist-height ratio, total cholesterol, and HDL. The overall prevalence of MS was found to be 28.2% with a higher prevalence in females (36.9%) as compared to males (23.9%). CONCLUSION: It seems reasonable to argue that MS is considerably high in the rural elderly of Asian Indian origin and early intervention is warranted to avoid further escalation in cardiovascular disease. PMID- 25809198 TI - HIV-1 IN/Pol recruits LEDGF/p75 into viral particles. AB - BACKGROUND: The dynamic interaction between HIV and its host governs the replication of the virus and the study of the virus-host interplay is key to understand the viral lifecycle. The host factor lens epithelium-derived growth factor (LEDGF/p75) tethers the HIV preintegration complex to the chromatin through a direct interaction with integrase (IN). Small molecules that bind the LEDGF/p75 binding pocket of the HIV IN dimer (LEDGINs) block HIV replication through a multimodal mechanism impacting early and late stage replication including HIV maturation. Furthermore, LEDGF/p75 has been identified as a Pol interaction partner. This raised the question whether LEDGF/p75 besides acting as a molecular tether in the target cell, also affects late steps of HIV replication. RESULTS: LEDGF/p75 is recruited into HIV-1 particles through direct interaction with the viral IN (or Pol polyprotein) and is a substrate for HIV-1 protease. Incubation in the presence of HIV-1 protease inhibitors resulted in detection of full-length LEDGF/p75 in purified viral particles. We also demonstrate that inhibition of LEDGF/p75-IN interaction by specific mutants or LEDGINs precludes incorporation of LEDGF/p75 in virions, underscoring the specificity of the uptake. LEDGF/p75 depletion did however not result in altered LEDGIN potency. CONCLUSION: Together, these results provide evidence for an IN/Pol mediated uptake of LEDGF/p75 in viral particles and a specific cleavage by HIV protease. Understanding of the possible role of LEDGF/p75 or its cleavage fragments in the viral particle awaits further experimentation. PMID- 25809200 TI - Electronic cigarettes in adults in outpatient substance use treatment: Awareness, perceptions, use, and reasons for use. AB - BACKGROUND AND OBJECTIVES: Most studies on e-cigarettes have come from population based surveys. The current research aimed to provide initial data on e-cigarette awareness, perceptions, use, and reasons for use among adults seeking substance use treatment. METHODS: A survey was conducted among 198 participants >=18 years old in a community-based outpatient substance use treatment program. RESULTS: Of the 198 participants, 69% currently smoked cigarettes, 92% were aware of e cigarettes, and 58% had ever used e-cigarettes. The proportion of the number of participants who had ever used e-cigarettes to the number who currently smoked (89.7%) appeared higher than the corresponding proportion in the 2012-13 National Adult Tobacco Survey (78.3%). Almost half of the sample who reported ever using e cigarettes endorsed quitting or reducing smoking as a reason for use, and 32% endorsed reasons for use relating to curiosity/experimentation. A greater likelihood of e-cigarette ever-use was significantly associated with younger age (adjusted odds ratio [AOR] = 0.94, 95%confidence interval [CI] = 0.90, 0.98) and perceptions related to using e-cigarettes in public places where smoking cigarettes is not allowed (AOR = 2.96, 95%CI = 1.18, 7.42) but was not associated with primary drug of choice. DISCUSSION AND CONCLUSIONS: E-cigarette use in adults seeking substance use treatment appears higher than it is in the US general population of smokers. The high frequency of use may be due to curiosity/experimentation or attempts to quit or reduce smoking. SCIENTIFIC SIGNIFICANCE: Future research may consider how e-cigarettes interact with other substance use and affect high rates of nicotine and tobacco use in this population. PMID- 25809201 TI - Sucrose Diffusion in Decellularized Heart Valves for Freeze-Drying. AB - Decellularized heart valves can be used as starter matrix implants for heart valve replacement therapies in terms of guided tissue regeneration. Decellularized matrices ideally need to be long-term storable to assure off-the shelf availability. Freeze-drying is an attractive preservation method, allowing storage at room temperature in a dried state. However, the two inherent processing steps, freezing and drying, can cause severe damage to extracellular matrix (ECM) proteins and the overall tissue histoarchitecture and thus impair biomechanical characteristics of resulting matrices. Freeze-drying therefore requires a lyoprotective agent that stabilizes endogenous structural proteins during both substeps and that forms a protective glassy state at room temperature. To estimate incubation times needed to infiltrate decellularized heart valves with the lyoprotectant sucrose, temperature-dependent diffusion studies were done using Fourier transform infrared spectroscopy. Glycerol, a cryoprotective agent, was studied for comparison. Diffusion of both protectants was found to exhibit Arrhenius behavior. The activation energies of sucrose and glycerol diffusion were found to be 15.9 and 37.7 kJ.mol(-1), respectively. It was estimated that 4 h of incubation at 37 degrees C is sufficient to infiltrate heart valves with sucrose before freeze-drying. Application of a 5% sucrose solution was shown to stabilize acellular valve scaffolds during freeze-drying. Such freeze-dried tissues, however, displayed pores, which were attributed to ice crystal damage, whereas vacuum-dried scaffolds in comparison revealed no pores after drying and rehydration. Exposure to a hygroscopic sucrose solution (80%) before freeze-drying was shown to be an effective method to diminish pore formation in freeze-dried ECMs: matrix structures closely resembled those of control samples that were not freeze-dried. Heart valve matrices were shown to be in a glassy state after drying, suggesting that they can be stored at room temperature. PMID- 25809202 TI - Using factor analytic models to examine the association between attention deficit/hyperactivity disorder symptoms and health-related outcomes in a representative population survey. AB - The objective of the study was to examine the factor structure of attention deficit/hyperactivity disorder (ADHD) symptoms in a representative population survey of adults and the association of these factors with health outcomes. Hierarchical and correlated factor analysis models were compared, and regression analyses with these models were used to determine the associations with psychological distress and substance use problems. A total of 1449 adults 18-65 years of age participated in a cross-sectional survey over the phone. ADHD symptom data came from an ADHD screener (10 items), and health outcomes were assessed using a questionnaire measuring psychological distress and two measures of substance use problems. The hierarchical general factor models with specific factors best represented the structure of ADHD in this representative population survey. The general factor and residual inattention factor were significantly associated with psychological distress, and the general factor was associated with substance use problems. From the correlated factor models, the inattention factor was associated with psychological distress and the hyperactivity factor was related to substance use problems. The hierarchical and correlated factor models explained similar levels of variance in outcomes. The results replicate previous studies indicating that a model of ADHD symptoms with a unitary dimension and separable dimensions of residual inattention and hyperactivity/impulsivity demonstrates a better fit than correlated factor models. The ADHD general factor was consistently significantly related to outcomes. PMID- 25809203 TI - Ageing on Hammond Island: Is there cause for concern in the Torres Strait? PMID- 25809204 TI - Patient-professional partnerships and chronic back pain self-management: a qualitative systematic review and synthesis. AB - Chronic back pain is common, and its self-management may be a lifelong task for many patients. While health professionals can provide a service or support for pain, only patients can actually experience it. It is likely that optimum self management of chronic back pain may only be achieved when patients and professionals develop effective partnerships which integrate their complementary knowledge and skills. However, at present, there is no evidence to explain how such partnerships can influence patients' self-management ability. This review aimed to explore the influence of patient-professional partnerships on patients' ability to self-manage chronic back pain, and to identify key factors within these partnerships that may influence self-management. A systematic review was undertaken, aiming to retrieve relevant studies using any research method. Five databases were searched for papers published between 1980 and 2014, including Cochrane Library, CINAHL, Medline, EMBASE and PsycINFO. Eligible studies were those reporting on patients being supported by professionals to self-manage chronic back pain; patients being actively involved for self-managing chronic back pain; and the influence of patient-professional partnerships on self management of chronic back pain. Included studies were critically appraised for quality, and findings were extracted and analysed thematically. A total of 738 studies were screened, producing 10 studies for inclusion, all of which happened to use qualitative methods. Seven themes were identified: communication, mutual understanding, roles of health professionals, information delivery, patients' involvement, individualised care and healthcare service. These themes were developed into a model suggesting how factors within patient-professional partnerships influence self-management. Review findings suggest that a partnership between patients and professionals supports patients' self-management ability, and effective communication is a fundamental factor underpinning their partnerships in care. It also calls for the development of individualised healthcare services offering self-referral or telephone consultation to patients with chronic conditions. PMID- 25809205 TI - Plasma IgG autoantibody against actin-related protein 3 in liver fluke Opisthorchis viverrini infection. AB - Opisthorchiasis secondary to Opisthorchis viverrini infection leads to cholangiocellular carcinoma through chronic inflammation of the bile ducts and possibly inducing autoimmunity. It was hypothesized that plasma autoantibodies directed against self-proteins are biomarkers for opisthorchiasis. Plasma from patients with opisthorchiasis was tested using proteins derived from immortalized cholangiocyte cell lines, and spots reacting with plasma were excised and subjected to LC-MS/MS. Seven protein spots were recognized by IgG autoantibodies, and the highest matching scored protein was actin-related protein 3 (ARP3). The antibody against ARP3 was tested in plasma from 55 O. viverrini-infected patients, 24 patients with others endemic parasitic infections and 17 healthy controls using Western blot and ELISA. Immunoreactivity against recombinant ARP3 was significantly more prevalent in opisthorchiasis compared to healthy controls at Western blotting and ELISA (P < 0.05). Plasma ARP3 autoantibody titres were also higher in opisthorchiasis compared to healthy individuals (P < 0.01) and other parasitic infections including Strongyloides stercoralis (P < 0.001), echinostome (P < 0.05), hookworms (P < 0.001) and Taenia spp. (P < 0.05). It was further characterized in that the ARP3 autoantibody titre had a sensitivity of 78.18% and specificity of 100% for opisthorchiasis. In conclusion, it may be suggested that plasma anti-ARP3 might represent a new diagnostic antibody for opisthorchiasis. PMID- 25809206 TI - Rapid diversification associated with ecological specialization in Neotropical Adelpha butterflies. AB - Rapid diversification is often associated with morphological or ecological adaptations that allow organisms to radiate into novel niches. Neotropical Adelpha butterflies, which comprise over 200 species and subspecies, are characterized by extraordinary breadth in host plant use and wing colour patterns compared to their closest relatives. To examine the relationship between phenotypic and species diversification, we reconstructed the phylogenetic history of Adelpha and its temperate sister genus Limenitis using genomewide restriction site-associated DNA (RAD) sequencing. Despite a declining fraction of shared markers with increasing evolutionary distance, the RAD-Seq data consistently generated well-supported trees using a variety of phylogenetic methods. These well-resolved phylogenies allow the identification of an ecologically important relationship with a toxic host plant family, as well as the confirmation of widespread, convergent wing pattern mimicry throughout the genus. Taken together, our results support the hypothesis that evolutionary innovations in both larvae and adults have permitted the colonization of novel host plants and fuelled adaptive diversification within this large butterfly radiation. PMID- 25809207 TI - Familial hypochondroplasia and acanthosis nigricans with FGFR3 K650T mutation. PMID- 25809208 TI - Case of burn-associated bullous pemphigoid caused by anti-BP230 immunoglobulin G autoantibodies. PMID- 25809209 TI - Clinical outcomes of mammography in the National Breast and Cervical Cancer Early Detection Program, 2009-2012. AB - PURPOSE: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) enrolls asymptomatic women for cancer screening and symptomatic women for diagnostic services. This study describes the results of mammograms provided by the NBCCEDP, by examination indication (screening or diagnostic), and by age group. METHODS: For the first NBCCEDP-funded mammogram received during 2009-2012, we calculated age-specific percentages of abnormal findings, rates of follow-up testing, and invasive and in situ breast cancer diagnoses per 1,000 mammograms. Logistic regression was used to estimate the odds for each of these outcomes by examination indication. RESULTS: The NBCCEDP provided 941,649 screening, 175,310 diagnostic, and 30,434 unknown indication mammograms to 1,147,393 women. The percentage with abnormal mammograms was higher for diagnostic mammograms (40.1 %) than for screening mammograms (15.5 %). Compared with women aged 40-49 years, fewer women aged 50-64 years had abnormal results for screening (13.7 vs. 19.7 %) and diagnostic mammograms (37.7 vs. 42.7 %). Follow-up rates per 1,000 mammograms were lower among women aged 50-64 compared to those aged 40-49 (screening: 143.9 vs. 207.5; diagnostic: 645.3 vs. 760.9); biopsy rates exhibited a similar pattern (screening: 24.1 vs. 32.9; diagnostic: 167.7 vs. 169.7). For screening mammograms, older women had more cancers detected than younger women (invasive: 3.6 vs. 2.2; in situ: 2.3 vs. 2.0). Similarly, for diagnostic mammograms, cancer detection was higher for older women (invasive: 67.8 vs. 36.6; in situ: 17.4 vs. 11.1). CONCLUSIONS: Abnormal mammograms and diagnostic follow-up procedures were less frequent in women aged 50-64 years compared to women aged 40-49 years, while breast cancer detection was higher, regardless of indication for the mammogram. Some of these differences between age groups were greater for screening mammograms than for diagnostic mammograms. Cancer detection rates were higher for diagnostic mammograms compared with screening mammograms. These findings support the NBCCEDP's priority of serving women aged 50-64 years and providing both screening and diagnostic mammograms. PMID- 25809210 TI - Swiss cheese-like atrial septal defect detected by three-dimensional echocardiography. PMID- 25809212 TI - Introduction to competitive visual processing across space and time: attention, memory, and prediction. PMID- 25809211 TI - Improved Poly(3,4-Ethylenedioxythiophene) (PEDOT) for Neural Stimulation. AB - OBJECTIVE: This study compares the stability of three variations of the conductive polymer poly(3,4-ethylenedioxythiophene) or PEDOT for neural micro stimulation under both in vitro and in vivo conditions. We examined PEDOT films deposited with counter-ions tetrafluoroborate (TFB) and poly(styrenesulfonate) (PSS), and PEDOT: PSS combined with carbon nanotubes (CNTs). METHODS: For the in vitro stability evaluation, implantable micro-wires were coated with the polymers, placed in a vial containing phosphate buffered saline (PBS) under accelerated aging conditions (60 degrees C), and current pulses were applied. The resulting voltage profile was monitored over time. Following the same polymer deposition protocol, chronic neural micro-probes were modified and implanted in the motor cortex of two rats for the in vivo stability comparison. Similar stimulating current pulses were applied and the output voltage was examined. The electrochemical impedance spectroscopic (EIS) data were also recorded and fit to an equivalent circuit model that incorporates and quantifies the time-dependent polymer degradation and impedance associated with tissue surrounding each micro electrode site. RESULTS: Both in vitro and in vivo voltage output profiles show relatively stable behavior for the PEDOT: TFB modified micro-electrodes compared to the PEDOT: PSS and CNT: PEDOT: PSS modified ones. EIS modeling demonstrates that the time-dependent increase in the polymeric resistance is roughly similar to the rise in the respective voltage output in vivo and indicates that the polymeric stability and conductivity, rather than the impedance due to the tissue response, is the primary factor determining the output voltage profile. It was also noted that the number of electrodes showing unit activity post-surgery did not decay for PEDOT: TFB as was the case for PEDOT: PSS and CNT: PEDOT: PSS. CONCLUSIONS: PEDOT: TFB may be an enabling material for achieving long lasting micro-stimulation and recording. PMID- 25809213 TI - Plantaricin IIA-1A5 from Lactobacillus plantarum IIA-1A5 displays bactericidal activity against Staphylococcus aureus. AB - Plantaricin IIA-1A5 is a bacteriocin produced by Lactobacillus plantarum IIA-1A5 isolated from Indonesian beef. This research aimed to identify the genes involved in plantaricin IIA-1A5 production and examine its mode of action against Staphylococcus aureus. It has been reported that a bacteriocin structural gene, plnW, is present in genome of L. plantarum IIA-1A5. Here, we reported the presence of additional genes responsible for plantaricin precursor (plnA and plnEF) and a gene encoding the quorum sensor of histidine kinase (plnB). It indicates that genes involved in production of plantaricin IIA-1A5 are organized in at least two bacteriocin operons (plnABCD, plnEFI) and a structural plnW gene. Purified plantaricin IIA-1A5 yielded a single band in SDS-PAGE with apparent size of 6.4 kDa. Amino acid composition of purified plantaricin IIA-1A5 was mainly composed of cationic glutamic acid and cysteine that allowed the formation of disulphide bonds, suggesting plantaricin IIA-1A5 belongs to the pediocin-subclass of class II bacteriocins. Plantaricin IIA-1A5 displayed remarkable antibacterial activity against S. aureus, which was initiated by the adsorption of plantaricin IIA-1A5 onto the cell membrane of S. aureus. The adsorption is hypothesised to be facilitated by non-ionic interactions as it is reduced by the presence of organic solvents or detergents. This adsorption promoted leakage of cellular metabolites through the cell membrane of S. aureus, as indicated by the release of genetic and proteinaceous material of S. aureus observed at 260 and 280 nm, respectively. The leakage also promoted the release of divalent (Ca(2+), Mg(2+)) and monovalent (K(+)) cations. The release of these intracellular components might be due to pores formed in the cell membrane of S. aureus by plantaricin IIA-1A5 as shown by scanning electron microscopy. Altogether, the mode of action of plantaricin IIA 1A5 against S. aureus seems to be bactericidal as indicated by lysis of the cell membrane. PMID- 25809214 TI - Involvement of the ornithine decarboxylase gene in acid stress response in probiotic Lactobacillus delbrueckii UFV H2b20. AB - Amino acid decarboxylation is important for the maintenance of intracellular pH under acid stress. This study aims to carry out phylogenetic and expression analysis by real-time PCR of two genes that encode proteins involved in ornithine decarboxylation in Lactobacillus delbrueckii UFV H2b20 exposed to acid stress. Sequencing and phylogeny analysis of genes encoding ornithine decarboxylase and amino acid permease in L. delbrueckii UFV H2b20 showed their high sequence identity (99%) and grouping with those of L. delbrueckii subsp. bulgaricus ATCC 11842. Exposure of L. delbrueckii UFV H2b20 cells in MRS pH 3.5 for 30 and 60 min caused a significant increase in expression of the gene encoding ornithine decarboxylase (up to 8.1 times higher when compared to the control treatment). Increased expression of the ornithine decarboxylase gene demonstrates its involvement in acid stress response in L. delbrueckii UFV H2b20, evidencing that the protein encoded by that gene could be involved in intracellular pH regulation. The results obtained show ornithine decarboxylation as a possible mechanism of adaptation to an acidic environmental condition, a desirable and necessary characteristic for probiotic cultures and certainly important to the survival and persistence of the L. delbrueckii UFV H2b20 in the human gastrointestinal tract. PMID- 25809215 TI - Effect of Bifidobacterium breve B-3 on skin photoaging induced by chronic UV irradiation in mice. AB - Probiotics have been shown to have a preventative effect on skin photoaging induced by short term UV irradiation, however, the underlying mechanisms and the effect of probiotics on skin photoaging induced by chronic UV irradiation remain unclear. In this study, we investigated the effect of Bifidobacterium breve B-3 on skin photoaging induced by chronic UV irradiation in hairless mice. Mice were irradiated with UVB three times weekly and orally administered B. breve B-3 (2*10(9) cfu/mouse /day) for 7 weeks. Nonirradiated mice and UVB-irradiated mice without probiotic treatment were used as controls. B. breve B-3 significantly suppressed the changes of transepidermal water loss, skin hydration, epidermal thickening and attenuated the damage to the tight junction structure and basement membrane induced by chronic UVB irradiation. Administration of B. breve B-3 tended to suppress the UV-induced interleukin-1beta production in skin (P=0.09). These results suggest that B. breve B-3 could potentially be used to prevent photoaging induced by chronic UV irradiation. PMID- 25809216 TI - Effect of Lactobacillus johnsonii CRL1647 on different parameters of honeybee colonies and bacterial populations of the bee gut. AB - Lactobacillus johnsonii CRL1647, isolated from the intestinal tract of a worker bee in Salta, Argentina, was delivered to Apis mellifera L. honey bee colonies according to two different administration schedules: 1*10(5) cfu/ml every 15 days (2011) or monthly (2012). The effect of each treatment on the bee-colony performance was monitored by measuring honey production, and the prevalence of varroasis and nosemosis. Worker bees from each assay were randomly captured 3 days after administration and assayed for the following intestinal culturable and defined bacterial populations: total aerobic microorganisms, Bacillus spp. spores, Lactobacillus spp., Enterococcus spp. and enterobacteria. Interestingly, both treatments generated a similar increase in honey production in treated colonies compared to controls: 36.8% (every 15 days) and 36.3% (monthly). Nosema index always exhibited a reduction when lactobacilli were administered; in turn, Varroa incidence was lower when the lactobacilli were administered once a month. Moreover, the administration of L. johnsonii CRL1647 every 15 days produced an increase in the total number of aerobic microorganisms and in bacteria belonging to the genera Lactobacillus and Enterococcus; at the same time, a decrease was observed in the number of total spores at the end of the treatment. The number of enterobacteria was constant and remained below that of control hives at the end of the assay. On the other hand, the delivery of lactobacilli once a month only showed an increase in the number of bacteria belonging to the genus Lactobacillus; meanwhile, viable counts of the remaining microorganisms assayed were reduced. Even though it seems that both treatments were similar, those bee colonies that received L. johnsonii CRL1647 every 15 days became so strong that they swarmed. PMID- 25809217 TI - Safety of probiotics and synbiotics in children under 18 years of age. AB - This study aimed to systematically evaluate safety of probiotics and synbiotics in children ageing 0-18 years. This study is the third and final part in a safety trilogy and an update is provided using the most recent available clinical data (2008-2013) by means of the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 74 clinical studies indicated that probiotic and/or synbiotic administration in children is safe with regard to the specific evaluated strains, dosages and duration. The population of children include healthy, immune compromised and obese subjects, as well as subjects with intestinal disorders, infections and inflammatory disorders. This study revealed no major safety concerns, as the adverse events (AEs) were unrelated, or not suspected to be related, to the probiotic or synbiotic product. In general the study products were well tolerated. Overall, AEs occurred more frequent in the control arm compared to children receiving probiotics and/or synbiotics. Furthermore, the results indicate inadequate reporting and classification of AEs in the majority of the studies. In addition, generalizability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes. PMID- 25809219 TI - The science of caregiver health. PMID- 25809220 TI - Combination of flecainide and propranolol for congenital junctional ectopic tachycardia. AB - Congenital junctional ectopic tachycardia is a rare tachyarrhythmia with high mortality. A pharmacological approach in early infancy is regarded as the first line therapeutic option. Pharmacologically, amiodarone alone or in combination with other drugs is the most commonly reported effective agent for congenital junctional ectopic tachycardia, but it has many adverse effects. Here we report the case of a 40-day-old infant. The clinical course suggests that combined oral flecainide and propranolol is an effective alternative therapy for early infants. Esophageal lead electrocardiography may give a clear diagnosis of junctional ectopic tachycardia. PMID- 25809222 TI - Growth and Optical Properties of High-Quality Monolayer WS2 on Graphite. AB - Atomic-layer transition metal dichalcogenides (TMDCs) have attracted appreciable interest due to their tunable band gap, spin-valley physics, and potential device applications. However, the quality of TMDC samples available still poses serious problems, such as inhomogeneous lattice strain, charge doping, and structural defects. Here, we report on the growth of high-quality, monolayer WS2 onto exfoliated graphite by high-temperature chemical vapor deposition (CVD). Monolayer-grown WS2 single crystals present a uniform, single excitonic photoluminescence peak with a Lorentzian profile and a very small full-width at half-maximum of 21 meV at room temperature and 8 meV at 79 K. Furthermore, in these samples, no additional peaks are observed for charged and/or bound excitons, even at low temperature. These optical responses are completely different from the results of previously reported TMDCs obtained by mechanical exfoliation and CVD. Our findings indicate that the combination of high temperature CVD with a cleaved graphite surface is an ideal condition for the growth of high-quality TMDCs, and such samples will be essential for revealing intrinsic physical properties and for future applications. PMID- 25809221 TI - Whole cell kinetics of ureolysis by Sporosarcina pasteurii. AB - AIMS: Ureolysis drives microbially induced calcium carbonate precipitation (MICP). MICP models typically employ simplified urea hydrolysis kinetics that do not account for cell density, pH effect or product inhibition. Here, ureolysis rate studies with whole cells of Sporosarcina pasteurii aimed to determine the relationship between ureolysis rate and concentrations of (i) urea, (ii) cells, (iii) NH4+ and (iv) pH (H(+) activity). METHODS AND RESULTS: Batch ureolysis rate experiments were performed with suspended cells of S. pasteurii and one parameter was varied in each set of experiments. A Michaelis-Menten model for urea dependence was fitted to the rate data (R(2) = 0.95) using a nonlinear mixed effects statistical model. The resulting half-saturation coefficient, Km , was 305 mmol l(-1) and maximum rate constant, Vmax , was 200 mmol l(-1) h(-1) . However, a first-order model with k1 = 0.35 h(-1) fit the data better (R(2) = 0.99) for urea concentrations up to 330 mmol l(-1) . Cell concentrations in the range tested (1 * 10(7) -2 * 10(8) CFU ml(-1) ) were linearly correlated with ureolysis rate (cell dependent Vmax' = 6.4 * 10(-9) mmol CFU(-1) h(-1) ). CONCLUSIONS: Neither pH (6-9) nor ammonium concentrations up to 0.19 mol l(-1) had significant effects on the ureolysis rate and are not necessary in kinetic modelling of ureolysis. Thus, we conclude that first-order kinetics with respect to urea and cell concentrations are likely sufficient to describe urea hydrolysis rates at most relevant concentrations. SIGNIFICANCE AND IMPACT OF THE STUDY: These results can be used in simulations of ureolysis driven processes such as microbially induced mineral precipitation and they verify that under the stated conditions, a simplified first-order rate for ureolysis can be employed. The study shows that the kinetic models developed for enzyme kinetics of urease do not apply to whole cells of S. pasteurii. PMID- 25809223 TI - Systemic effects of Leucaena leucocephala ingestion on ringtailed lemurs (Lemur catta) at Berenty Reserve, Madagascar. AB - Leucaena (Leucaena leucocephala) is a leguminous tree that is nutritious forage for domestic livestock when ingested in limited amounts. Unfortunately, leucaena contains mimosine, a plant amino acid, that can be toxic when ingested at higher concentrations. Reported toxic effects include alopecia (fur loss), poor body condition, infertility, low birth weight, thyroid gland dysfunction, and organ toxicity. Originally native to Mexico and Central America, leucaena has been introduced throughout the tropics, including Berenty Reserve, Madagascar where it was planted as supplemental browse for livestock. In Berenty, a seasonal syndrome of alopecia in ringtailed lemurs (Lemur catta) is associated with eating leucaena. Although much is known about the toxic effects of leucaena and mimosine on domestic animals and humans, the systemic effects on wildlife had not been studied. In a comparison of lemurs that include leucaena in their diet and those that do not, we found that animals that ingest leucaena absorb mimosine but that ingestion does not affect body condition, cause kidney or liver toxicity, or affect the intestinal tract. Alopecia is due to mimosine's interference of the hair follicle cycle. Leucaena ingestion is associated with higher serum albumin, alpha-tocopherol, and thyroxine concentrations, suggesting that leucaena may provide some nutritional benefit and that lemurs can detoxify and convert mimosine to a thyroid stimulating metabolite. The primary conservation consequence of leucaena ingestion at Berenty may be increased infant mortality due to the infants' inability cling to their alopecic mothers. The widespread introduction of leucaena throughout the tropics and its rapid spread in secondary forest conditions mean that many other leaf-eating mammals may be including this tree in their diet. Thus, exposure to leucaena should be considered when wildlife health is being evaluated, and the potential effects on wildlife health should be considered when contemplating leucaena introduction into or near wildlife habitat. PMID- 25809225 TI - A megacomplex composed of both photosystem reaction centres in higher plants. AB - Throughout the history of oxygen evolution, two types of photosystem reaction centres (PSI and PSII) have worked in a coordinated manner. The oxygen evolving centre is an integral part of PSII, and extracts an electron from water. PSI accepts the electron, and accumulates reducing power. Traditionally, PSI and PSII are thought to be spatially dispersed. Here, we show that about half of PSIIs are physically connected to PSIs in Arabidopsis thaliana. In the PSI-PSII complex, excitation energy is transferred efficiently between the two closely interacting reaction centres. PSII diverts excitation energy to PSI when PSII becomes closed state in the PSI-PSII complex. The formation of PSI-PSII complexes is regulated by light conditions. Quenching of excess energy by PSI might be one of the physiological functions of PSI-PSII complexes. PMID- 25809226 TI - Down-regulation of microRNA-9 leads to activation of IL-6/Jak/STAT3 pathway through directly targeting IL-6 in HeLa cell. AB - MicroRNA-9 (miR-9) presents to exert distinct and even opposite functions in different kinds of tumors through targeting different cellular genes. However, its role in cervical adenocarcinoma remains uncertain. Here, we report that miR-9 is down-regulated in cervical adenocarcinoma due to its frequent promoter hypermethylation and exerts its tumor suppressor role through inhibiting several novel target genes, including interleukin-6 (IL-6). The promoters of miR-9 precursors (mir-9-1, -2, and -3) were hypermethylated in cervical adenocarcinoma tissues. Demethylation treatment of HeLa dramatically increased the expression of mature miR-9. Both in vitro and in vivo functional experiments confirmed that miR 9 can inhibit the proliferation, migration, and malignant transformation abilities of HeLa cells. Bioinformatics methods and array-based RNA expression profiles were used to screen the downstream target genes of miR-9. Dual luciferase reporting assay, real-time qPCR, and ELISA or Western blot confirmed four genes (CKAP2, HSPC159, IL-6, and TC10) to be novel direct target genes of miR-9. Pathway annotation analysis of the differently expressed genes (DEGs) induced by ectopic miR-9 expression revealed the enrichment in Jak/STAT3 pathway, which is one of the downstream pathways of IL-6. Ectopic expression of miR-9 in HeLa inhibited Jak/STAT3 signaling activity. Moreover, such effect could be partially reversed by the addition of exogenous IL-6. In conclusion, our results here present a tumor suppressor potential of miR-9 in cervical adenocarcinoma for the first time and suggest that miR-9 could repress tumorigenesis through inhibiting the activity of IL-6/Jak/STAT3 pathway. PMID- 25809227 TI - Recombinant activated factor VII in the management of acute fatty liver of pregnancy: A case report. AB - A 20-year-old woman, primigravida at 36(+4) weeks' gestation presented with malaise, vomiting for 1 week, yellowish discoloration of the eyes for 3 days and loss of fetal movements. A clinical diagnosis of acute fatty liver with intrauterine fetal demise was made. Labor was induced with prostaglandin E2 gel and delivered vaginally. The post-partum period was complicated by atonic post partum hemorrhage, an episode of seizure, recurrent hypoglycemic attack, hypokalemia and continuing coagulopathy. Supportive management in the intensive care unit using blood and blood products and injection recombinant activated factor VIIa to arrest the bleeding resulted in a successful outcome. PMID- 25809228 TI - Neurofibromas arising from Becker naevus. PMID- 25809224 TI - The INHANCE consortium: toward a better understanding of the causes and mechanisms of head and neck cancer. AB - The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects. PMID- 25809230 TI - Fitness costs in spatially structured environments. AB - The clustering of individuals that results from limited dispersal is a double edged sword: although it allows for local interactions to be mostly among related individuals, it also results in increased local competition. Here I show that, because they mitigate local competition, fitness costs such as reduced fecundity or reduced survival are less costly in spatially structured environments than in nonspatial settings. I first present a simple demographic example to illustrate how spatial structure weakens selection against fitness costs. Then, I illustrate the importance of disentangling the evolution of a trait from the evolution of potential associated costs, using an example taken from a recent study investigating the effect of spatial structure on the evolution of host defense. In this example indeed, the differences between spatial and nonspatial selection gradients are due to differences in the fitness costs, thereby undermining interpretations of the results made in terms of the trait only. This illustrates the need to consider fitness costs as proper traits in both theoretical and empirical studies. PMID- 25809231 TI - Current attitudes of parents and patients toward hematopoietic stem cell transplantation for sickle cell anemia. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available cure for sickle cell anemia (SCA). HSCT-associated risks are one of many barriers to its widespread use for SCA. The study objective was to assess parent and patient perceptions of HSCT in the era of more widespread knowledge about HSCT for SCA. PROCEDURE: We surveyed parents of children with SCA and adolescents with SCA using the standard reference gamble paradigm. Survey responses between Africans (A) and African Americans (AA) and between parents and adolescents were compared. RESULTS: Seventy-two percent (64/89) of the respondents were willing to accept >= 5% risk of mortality, while 57% said they would accept a risk of >= 10% of graft versus host disease (GVHD). Twenty-two percent were unwilling to accept any risk of mortality or GVHD. Risk averseness did not differ between A or AA respondents. Fifty-six percent of respondents were willing to accept infertility post-HSCT. CONCLUSIONS: These data suggest that the majority of parents and adolescents are willing to accept the current risks associated with matched sibling HSCT for SCA. However, there continue to be significant numbers of parents and adolescents who are unwilling to accept any risk of HSCT-associated mortality or GVHD. PMID- 25809229 TI - Design, synthesis, antiviral activity and mode of action of phenanthrene containing N-heterocyclic compounds inspired by the phenanthroindolizidine alkaloid antofine. AB - BACKGROUND: The phenanthroindolizidine alkaloid antofine and its analogues have excellent antiviral activity against tobacco mosaic virus (TMV). To simplify the structure and the synthesis of the phenanthroindolizidine alkaloid, a series of phenanthrene-containing N-heterocyclic compounds (compounds 1 to 33) were designed and synthesised, based on the intermolecular interaction of antofine and TMV RNA, and systematically evaluated for their anti-TMV activity. RESULT: Most of these compounds exhibited good to reasonable anti-TMV activity. The optimum compounds 5, 12 and 21 displayed higher activity than the lead compound antofine and commercial ribavirin. Compound 12 was chosen for field trials of antiviral efficacy against TMV, and was found to exhibit better activity than control plant virus inhibitors. Compounds 5 and 12 were chosen for mode of action studies. The changes in fluorescence intensity of compounds 5 and 12 on separated TMV RNA showed that these small molecules can also bind to TMV RNA, but the mode is very different from that of antofine. CONCLUSION: The compounds combining phenanthrene and an N-heterocyclic ring could maintain the anti-TMV activity of phenanthroindolizidines, but their modes of action are different from that of antofine. The present study lays a good foundation for us to find more efficient anti-plant virus reagents. PMID- 25809232 TI - Facile synthesis and versatile reactivity of an unusual cyclometalated rhodium(I) pincer complex. AB - The synthesis of the reactive PN(C(H) ) ligand 2-di(tert-butylphosphanomethyl)-6 phenylpyridine (1(H) ) and its versatile coordination to a Rh(I) center is described. Facile C-H activation occurs in the presence of a (internal) base, thus resulting in the new cyclometalated complex [Rh(I) (CO)(kappa(3) -P,N,C-1)] (3), which has been structurally characterized. The resulting tridentate ligand framework was experimentally and computationally shown to display dual-site proton-responsive reactivity, including reversible cyclometalation. This feature was probed by selective H/D exchange with [D1 ]formic acid. The addition of HBF4 to 3 leads to rapid net protonolysis of the Rh-C bond to produce [Rh(I) (CO)(kappa(3) -P,N,(C-H)-1)] (4). This species features a rare aryl C-H agostic interaction in the solid state, as shown by X-ray diffraction studies. The nature of this interaction was also studied computationally. Reaction of 3 with methyl iodide results in rapid and selective ortho-methylation of the phenyl ring, thus generating [Rh(I) (CO)(kappa(2) -P,N-1(Me) )] (5). Variable-temperature NMR spectroscopy indicates the involvement of a Rh(III) intermediate through formal oxidative addition to give trans-[Rh(III) (CH3 )(CO)(I)(kappa(3) -P,N,C-1)] prior to C-C reductive elimination. The Rh(III) -trans-diiodide complex [Rh(I) (CO)(I)2 (kappa(3) -P,N,C-1)] (6) has been structurally characterized as a model compound for this elusive intermediate. PMID- 25809234 TI - Child Development. In this issue. PMID- 25809233 TI - Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy. AB - INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene. METHODS: Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed. RESULTS: A known VMA21 mutation, c.163+4A>G, and a new mutation, c.163+3A>G, respectively, were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement. CONCLUSIONS: This study highlights a distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA, even before muscle biopsy or genetic analysis. PMID- 25809235 TI - Long-term psychological benefits of cognitive-behavioral stress management for women with breast cancer: 11-year follow-up of a randomized controlled trial. AB - BACKGROUND: Breast cancer survivors experience long-term physical and psychological sequelae after their primary treatment that negatively influence their quality of life (QOL) and increase depressive symptoms. Group-based cognitive-behavioral stress management (CBSM) delivered after surgery for early stage breast cancer was previously associated with better QOL over a 12-month follow-up and with fewer depressive symptoms up to 5 years after study enrollment. This 8- to 15-year follow-up (median, 11 years) of a previously conducted trial (NCT01422551) evaluated whether women in this cohort receiving CBSM had fewer depressive symptoms and better QOL than controls at an 8- to 15 year follow-up. METHODS: Women with stage 0 to IIIb breast cancer were initially recruited 2 to 10 weeks after surgery and randomized to a 10-week CBSM intervention or a 1-day psychoeducational control group. One hundred women (51 CBSM patients and 49 controls) were recontacted 8 to 15 years after study enrollment to participate in a follow-up assessment. The Center for Epidemiologic Studies-Depression (CES-D) scale and the Functional Assessment of Cancer Therapy Breast (FACT-B) were self-administered. Multiple regression was employed to evaluate group differences on the CES-D scale and FACT-B over and above effects of confounding variables. RESULTS: Participants assigned to CBSM reported significantly lower depressive symptoms (d, 0.63; 95% confidence interval [CI], 0.56-0.70) and better QOL (d, 0.58; 95% CI, 0.52-0.65) above the effects of the covariates. CONCLUSIONS: Women who received CBSM after surgery for early-stage breast cancer reported lower depressive symptoms and better QOL than the control group up to 15 years later. Early implementation of cognitive-behavioral interventions may influence long-term psychosocial functioning in breast cancer survivors. PMID- 25809237 TI - Review article: Alcohol and gut microbiota - the possible role of gut microbiota modulation in the treatment of alcoholic liver disease. AB - BACKGROUND: Alcohol abuse represents the most common cause of liver disease in the Western countries. Pre-clinical and clinical studies showed that alcohol consumption affects amount and composition of gut microbiota. Moreover, gut flora plays an important role in the pathogenesis of alcoholic liver injury. AIM: To review the relationship between alcohol administration and changes on gut microbiota, its involvement in the pathogenesis of alcoholic liver disease, and how gut microbiota modulation could be a target for the treatment of alcoholic liver disease. METHODS: Articles were identified using the PubMed database with the search terms 'Alcohol', 'Gut Microbiota', 'Alcoholic liver disease', 'Probiotic', 'Prebiotic', 'Symbiotic' and 'Antibiotic'. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. RESULTS: Alcohol abuse induces changes in the composition of gut microbiota, although the exact mechanism for this alteration is not well known. The translocation of bacterial products into the portal blood appears to play a key role in alcohol-induced liver damage. Several studies show that the modulation of gut microbiota seem to be a promising strategy to reduce alcohol-induced liver injury. CONCLUSIONS: Further studies are needed to better understand the relationship between alcohol administration and changes in gut microbiota, and its involvement in alcoholic liver disease. Moreover larger studies are needed to confirm the preliminary results on the therapeutic effects of gut microbiota modulation. PMID- 25809236 TI - Responses in gut hormones and hunger to diets with either high protein or a mixture of protein plus free amino acids supplied under weight-loss conditions. AB - High-protein diets are an effective means for weight loss (WL), but the mechanisms are unclear. One hypothesis relates to the release of gut hormones by either protein or amino acids (AA). The present study involved overweight and obese male volunteers (n 18, mean BMI 36.8 kg/m2) who consumed a maintenance diet for 7 d followed by fully randomised 10 d treatments with three iso-energetic WL diets, i.e. with either normal protein (NP, 15% of energy) or high protein (HP, 30%) or with a combination of protein and free AA, each 15% of energy (NPAA). Psychometric ratings of appetite were recorded hourly. On day 10, plasma samples were taken at 30 min intervals over two consecutive 5 h periods (covering post breakfast and post-lunch) and analysed for AA, glucose and hormones (insulin, total glucose-dependent insulinotropic peptide, active ghrelin and total peptide YY (PYY)) plus leucine kinetics (first 5 h only). Composite hunger was 16% lower for the HP diet than for the NP diet (P<0.01) in the 5 h period after both meals. Plasma essential AA concentrations were greatest within 60 min of each meal for the NPAA diet, but remained elevated for 3-5 h after the HP diet. The three WL diets showed no difference for either fasting concentrations or the postprandial net incremental AUC (net AUCi) for insulin, ghrelin or PYY. No strong correlations were observed between composite hunger scores and net AUCi for either AA or gut peptides. Regulation of hunger may involve subtle interactions, and a range of signals may need to be integrated to produce the overall response. PMID- 25809239 TI - Value of fetuin-A as a predictor of liver fibrosis in patients with nonalcoholic fatty liver disease. Author's reply. PMID- 25809238 TI - Biotic inactivation of the Pseudomonas aeruginosa quinolone signal molecule. AB - In Pseudomonas aeruginosa, quorum sensing (QS) regulates the production of secondary metabolites, many of which are antimicrobials that impact on polymicrobial community composition. Consequently, quenching QS modulates the environmental impact of P. aeruginosa. To identify bacteria capable of inactivating the QS signal molecule 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a minimal medium containing PQS as the sole carbon source was used to enrich a Malaysian rainforest soil sample. This yielded an Achromobacter xylosoxidans strain (Q19) that inactivated PQS, yielding a new fluorescent compound (I-PQS) confirmed as PQS-derived using deuterated PQS. The I-PQS structure was elucidated using mass spectrometry and nuclear magnetic resonance spectroscopy as 2-heptyl-2 hydroxy-1,2-dihydroquinoline-3,4-dione (HHQD). Achromobacter xylosoxidans Q19 oxidized PQS congeners with alkyl chains ranging from C1 to C5 and also N-methyl PQS, yielding the corresponding 2-hydroxy-1,2-dihydroquinoline-3,4-diones, but was unable to inactivate the PQS precursor HHQ. This indicates that the hydroxyl group at position 3 in PQS is essential and that A. xylosoxidans inactivates PQS via a pathway involving the incorporation of oxygen at C2 of the heterocyclic ring. The conversion of PQS to HHQD also occurred on incubation with 12/17 A. xylosoxidans strains recovered from cystic fibrosis patients, with P. aeruginosa and with Arthrobacter, suggesting that formation of hydroxylated PQS may be a common mechanism of inactivation. PMID- 25809240 TI - Successful Portal Vein Stent Placement in a Child with Cavernomatous Replacement of the Portal Vein After Partial Liver Transplantation: The Importance of a Recognizable Portal Vein Remnant. AB - Late portal vein thrombosis with cavernomatous replacement has been reported in 4.5% of pediatric patients who have undergone partial liver transplantation. In such cases, minimally invasive radiological treatments have a high failure rate. We report a successful case of percutaneous recanalization of the portal vein remnant, and subsequent stent placement, in a pediatric patient who underwent left lateral split liver transplantation with cavernomatous replacement of the portal vein. PMID- 25809241 TI - Pattern selection: the importance of "how you get there". PMID- 25809242 TI - Activation of HERG channels: opening new applications for the biophysics of antiarrhythmic therapy. PMID- 25809243 TI - TRPV4 channel cooperativity in the resistance vasculature. PMID- 25809244 TI - A new understanding of antibiotic action via solid-state NMR of cells with uniform isotopic labeling. PMID- 25809245 TI - Improving survival of disassociated human embryonic stem cells by mechanical stimulation using acoustic tweezing cytometry. AB - Dissociation-induced apoptosis of human embryonic stem cells (hESCs) hampers their large-scale culture. Herein we leveraged the mechanosensitivity of hESCs and employed, to our knowledge, a novel technique, acoustic tweezing cytometry (ATC), for subcellular mechanical stimulation of disassociated single hESCs to improve their survival. By acoustically actuating integrin-bound microbubbles (MBs) to live cells, ATC increased the survival rate and cloning efficiency of hESCs by threefold. A positive correlation was observed between the increased hESC survival rate and total accumulative displacement of integrin-anchored MBs during ATC stimulation. ATC may serve as a promising biocompatible tool to improve hESC culture. PMID- 25809247 TI - Structural, mechanical, and dynamical variability of the actin cortex in living cells. AB - In eukaryotic cells, an actin-based cortex lines the inner leaflet of the plasma membrane, endowing the cells with crucial mechanical and functional properties. Unfortunately, it has not been possible to study the structural dynamics of the actin cortex at high lateral resolution in living cells. Here, we performed atomic force microscopy time-lapse imaging and mechanical mapping of actin in the cortex of living cells at high lateral and temporal resolution. Cortical actin filaments adopted discernible arrangements, ranging from large parallel bundles with low connectivity to a tight meshwork of short filaments. Mixing of these architectures resulted in attuned cortex networks with specific connectivity, mechanical responses, and marked differences in their dynamic behavior. PMID- 25809246 TI - Synaptic activity regulates the abundance and binding of complexin. AB - Nervous system function relies on precise chemical communication between neurons at specialized junctions known as synapses. Complexin (CPX) is one of a small number of cytoplasmic proteins that are indispensable in controlling neurotransmitter release through SNARE and synaptic vesicle interactions. However, the mechanisms that recruit and stabilize CPX are poorly understood. The mobility of CPX tagged with photoactivatable green fluorescent protein (pGFP) was quantified in vivo using Caenorhabditis elegans. Although pGFP escaped the synapse within seconds, CPX-pGFP displayed both fast and slow decay components, requiring minutes for complete exchange of the synaptic pool. The longer synaptic residence time of CPX arose from both synaptic vesicle and SNARE interactions, and surprisingly, CPX mobility depended on synaptic activity. Moreover, mouse CPX GFP reversibly dispersed out of hippocampal presynaptic terminals during stimulation, and blockade of vesicle fusion prevented CPX dispersion. Hence, synaptic CPX can rapidly redistribute and this exchange is influenced by neuronal activity, potentially contributing to use-dependent plasticity. PMID- 25809248 TI - Mechanosensitivity of a rapid bioluminescence reporter system assessed by atomic force microscopy. AB - Cells are sophisticated integrators of mechanical stimuli that lead to physiological, biochemical, and genetic responses. The bioluminescence of dinoflagellates, alveolate protists that use light emission for predator defense, serves as a rapid noninvasive whole-cell reporter of mechanosensitivity. In this study, we used atomic force microscopy (AFM) to explore the relationship between cell mechanical properties and mechanosensitivity in live cells of the dinoflagellate Pyrocystis lunula. Cell stiffness was 0.56 MPa, consistent with cells possessing a cell wall. Cell response depended on both the magnitude and velocity of the applied force. At the maximum stimulation velocity of 390 MUm s( 1), the threshold response occurred at a force of 7.2 MUN, resulting in a contact time of 6.1 ms and indentation of 2.1 MUm. Cells did not respond to a low stimulation velocity of 20 MUm s(-1), indicating a velocity dependent response that, based on stress relaxation experiments, was explained by the cell viscoelastic properties. This study demonstrates the use of AFM to study mechanosensitivity in a cell system that responds at fast timescales, and provides insights into how viscoelastic properties affect mechanosensitivity. It also provides a comparison with previous studies using hydrodynamic stimulation, showing the discrepancy in cell response between direct compressive forces using AFM and those within flow fields based on average flow properties. PMID- 25809249 TI - Angle of inclination of tank-treading red cells: dependence on shear rate and suspending medium. AB - Red cells suspended in solutions much more viscous than blood plasma assume an almost steady-state orientation when sheared above a threshold value of shear rate. This orientation is a consequence of the motion of the membrane around the red cell called tank-treading. Observed along the undisturbed vorticity of the shear flow, tank-treading red cells appear as slender bodies. Their orientation can be quantified as an angle of inclination (theta) of the major axis with respect to the undisturbed flow direction. We measured theta using solution viscosities (eta0) and shear rates (gamma) covering one and three orders of magnitude, respectively. At the lower values of eta0, theta was almost independent of gamma. At the higher values of eta0, theta displayed a maximum at intermediate shear rates. The respective maximal values of theta increased by ~10 degrees from 10.7 to 104 mPas. After accounting for the absent membrane viscosity in models by using an increased cytoplasmic viscosity, their predictions of theta agree qualitatively with our data. Comparison of the observed variation of theta at constant gamma with model results suggests a change in the reference configuration of the shear stiffness of the membrane. PMID- 25809250 TI - A systematic comparison of mathematical models for inherent measurement of ciliary length: how a cell can measure length and volume. AB - Cells control organelle size with great precision and accuracy to maintain optimal physiology, but the mechanisms by which they do so are largely unknown. Cilia and flagella are simple organelles in which a single measurement, length, can represent size. Maintenance of flagellar length requires an active transport process known as intraflagellar transport, and previous measurements suggest that a length-dependent feedback regulates intraflagellar transport. But the question remains: how is a length-dependent signal produced to regulate intraflagellar transport appropriately? Several conceptual models have been suggested, but testing these models quantitatively requires that they be cast in mathematical form. Here, we derive a set of mathematical models that represent the main broad classes of hypothetical size-control mechanisms currently under consideration. We use these models to predict the relation between length and intraflagellar transport, and then compare the predicted relations for each model with experimental data. We find that three models-an initial bolus formation model, an ion current model, and a diffusion-based model-show particularly good agreement with available experimental data. The initial bolus and ion current models give mathematically equivalent predictions for length control, but fluorescence recovery after photobleaching experiments rule out the initial bolus model, suggesting that either the ion current model or a diffusion-based model is more likely correct. The general biophysical principles of the ion current and diffusion-based models presented here to measure cilia and flagellar length can be generalized to measure any membrane-bound organelle volume, such as the nucleus and endoplasmic reticulum. PMID- 25809252 TI - Properties of an inward-facing state of LeuT: conformational stability and substrate release. AB - The leucine transporter (LeuT) is a bacterial homolog of the human monoamine transporters, which are important pharmaceutical targets. There are no high resolution structures of the human transporters available; however, LeuT has been crystallized in several different conformational states. Recently, an inward facing conformation of LeuT was solved revealing an unexpectedly large movement of transmembrane helix 1a (TM1a). We have performed molecular dynamics simulations of the mutated and wild-type transporter, with and without the cocrystallized Fab antibody fragment, to investigate the properties of this inward-facing conformation in relation to transport by LeuT within the membrane environment. In all of the simulations, local conformational changes with respect to the crystal structure are consistently observed, especially in TM1a. Umbrella sampling revealed a soft potential for TM1a tilting. Furthermore, simulations of inward-facing LeuT with Na(+) ions and substrate bound suggest that one of the Na(+) ion binding sites is fully disrupted. Release of alanine and the second Na(+) ion is also observed, giving insight into the final stage of the translocation process in atomistic detail. PMID- 25809251 TI - Spectral snapshots of bacterial cell-wall composition and the influence of antibiotics by whole-cell NMR. AB - Gram-positive bacteria surround themselves with a thick cell wall that is essential to cell survival and is a major target of antibiotics. Quantifying alterations in cell-wall composition are crucial to evaluating drug modes of action, particularly important for human pathogens that are now resistant to multiple antibiotics such as Staphylococcus aureus. Macromolecular and whole-cell NMR spectroscopy allowed us to observe the full panel of carbon and nitrogen pools in S. aureus cell walls and intact whole cells. We discovered that one dimensional (13)C and (15)N NMR spectra, together with spectroscopic selections based on dipolar couplings as well as two-dimensional spin-diffusion measurements, revealed the dramatic compositional differences between intact cells and cell walls and allowed the identification of cell-wall signatures in whole-cell samples. Furthermore, the whole-cell NMR approach exhibited the sensitivity to detect distinct compositional changes due to treatment with the antibiotics fosfomycin (a cell-wall biosynthesis inhibitor) and chloramphenicol (a protein synthesis inhibitor). Whole cells treated with fosfomycin exhibited decreased peptidoglycan contributions while those treated with chloramphenicol contained a higher percentage of peptidoglycan as cytoplasmic protein content was reduced. Thus, general antibiotic modes of action can be identified by profiling the total carbon pools in intact whole cells. PMID- 25809253 TI - NS1643 interacts around L529 of hERG to alter voltage sensor movement on the path to activation. AB - Activators of hERG1 such as NS1643 are being developed for congenital/acquired long QT syndrome. Previous studies identify the neighborhood of L529 around the voltage-sensor as a putative interacting site for NS1643. With NS1643, the V1/2 of activation of L529I (-34 +/- 4 mV) is similar to wild-type (WT) (-37 +/- 3 mV; P > 0.05). WT and L529I showed no difference in the slope factor in the absence of NS1643 (8 +/- 0 vs. 9 +/- 0) but showed a difference in the presence of NS1643 (9 +/- 0.3 vs. 22 +/- 1; P < 0.01). Voltage-clamp-fluorimetry studies also indicated that in L529I, NS1643 reduces the voltage-sensitivity of S4 movement. To further assess mechanism of NS1643 action, mutations were made in this neighborhood. NS1643 shifts the V1/2 of activation of both K525C and K525C/L529I to hyperpolarized potentials (-131 +/- 4 mV for K525C and -120 +/- 21 mV for K525C/L529I). Both K525C and K525C/K529I had similar slope factors in the absence of NS1643 (18 +/- 2 vs. 34 +/- 5, respectively) but with NS1643, the slope factor of K525C/L529I increased from 34 +/- 5 to 71 +/- 10 (P < 0.01) whereas for K525C the slope factor did not change (18 +/- 2 at baseline and 16 +/- 2 for NS1643). At baseline, K525R had a slope factor similar to WT (9 vs. 8) but in the presence of NS1643, the slope factor of K525R was increased to 24 +/- 4 vs. 9 +/- 0 mV for WT (P < 0.01). Molecular modeling indicates that L529I induces a kink in the S4 voltage-sensor helix, altering a salt-bridge involving K525. Moreover, docking studies indicate that NS1643 binds to the kinked structure induced by the mutation with a higher affinity. Combining biophysical, computational, and electrophysiological evidence, a mechanistic principle governing the action of some activators of hERG1 channels is proposed. PMID- 25809254 TI - Kinetic model for NS1643 drug activation of WT and L529I variants of Kv11.1 (hERG1) potassium channel. AB - Congenital and acquired (drug-induced) forms of the human long-QT syndrome are associated with alterations in Kv11.1 (hERG) channel-controlled repolarizing IKr currents of cardiac action potentials. A mandatory drug screen implemented by many countries led to a discovery of a large group of small molecules that can activate hERG currents and thus may act as potent antiarrhythmic agents. Despite significant progress in identification of channel activators, little is known about their mechanism of action. A combination of electrophysiological studies with molecular and kinetic modeling was used to examine the mechanism of a model activator (NS1643) action on the hERG channel and its L529I mutant. The L529I mutant has gating dynamics similar to that of wild-type while its response to application of NS1643 is markedly different. We propose a mechanism compatible with experiments in which the model activator binds to the closed (C3) and open states (O). We suggest that NS1643 is affecting early gating transitions, probably during movements of the voltage sensor that precede the opening of the activation gate. PMID- 25809256 TI - Sequence of gating charge movement and pore gating in HERG activation and deactivation pathways. AB - KV11.1 voltage-gated K(+) channels are noted for unusually slow activation, fast inactivation, and slow deactivation kinetics, which tune channel activity to provide vital repolarizing current during later stages of the cardiac action potential. The bulk of charge movement in human ether-a-go-go-related gene (hERG) is slow, as is return of charge upon repolarization, suggesting that the rates of hERG channel opening and, critically, that of deactivation might be determined by slow voltage sensor movement, and also by a mode-shift after activation. To test these ideas, we compared the kinetics and voltage dependence of ionic activation and deactivation with gating charge movement. At 0 mV, gating charge moved ~threefold faster than ionic current, which suggests the presence of additional slow transitions downstream of charge movement in the physiological activation pathway. A significant voltage sensor mode-shift was apparent by 24 ms at +60 mV in gating currents, and return of charge closely tracked pore closure after pulses of 100 and 300 ms duration. A deletion of the N-terminus PAS domain, mutation R4AR5A or the LQT2-causing mutation R56Q gave faster-deactivating channels that displayed an attenuated mode-shift of charge. This indicates that charge movement is perturbed by N- and C-terminus interactions, and that these domain interactions stabilize the open state and limit the rate of charge return. We conclude that slow on-gating charge movement can only partly account for slow hERG ionic activation, and that the rate of pore closure has a limiting role in the slow return of gating charges. PMID- 25809257 TI - Modes of diffusion of cholera toxin bound to GM1 on live cell membrane by image mean square displacement analysis. AB - The image-mean square displacement technique applies the calculation of the mean square displacement commonly used in single-molecule tracking to images without resolving single particles. The image-mean square displacement plot obtained is similar to the mean square displacement plot obtained using the single-particle tracking technique. This plot is then used to reconstruct the protein diffusion law and to identify whether the labeled molecules are undergoing pure isotropic, restricted, corralled, transiently confined, or directed diffusion. In our study total internal reflection fluorescence microscopy images were taken of Cholera toxin subunit B (CtxB) membrane-labeled NIH 3T3 mouse fibroblasts and MDA 231 MB cells. We found a population of CTxB undergoing purely isotropic diffusion and one displaying restricted diffusion with corral sizes ranging from 150 to ~1800 nm. We show that the diffusion rate of CTxB bound to GM1 is independent of the size of the confinement, suggesting that the mechanism of confinement is different from the mechanism controlling the diffusion rate of CtxB. We highlight the potential effect of continuous illumination on the diffusion mode of CTxB. We also show that aggregation of CTxB/GM1 in large complexes occurs and that these aggregates tend to have slower diffusion rates. PMID- 25809255 TI - Capsaicin interaction with TRPV1 channels in a lipid bilayer: molecular dynamics simulation. AB - Transient receptor potential vanilloid subtype 1 (TRPV1) is a heat-sensitive ion channel also involved in pain sensation, and is the receptor for capsaicin, the active ingredient of hot chili peppers. The recent structures of TRPV1 revealed putative ligand density within the S1 to S4 voltage-sensor-like domain of the protein. However, questions remain regarding the dynamic role of the lipid bilayer in ligand binding to TRPV1. Molecular dynamics simulations were used to explore behavior of capsaicin in a 1-palmitoyl-2-oleoyl phosphatidylcholine bilayer and with the target S1-S4 transmembrane helices of TRPV1. Equilibrium simulations reveal a preferred interfacial localization for capsaicin. We also observed a capsaicin molecule flipping from the extracellular to the intracellular leaflet, and subsequently able to access the intracellular TRPV1 binding site. Calculation of the potential of mean force (i.e., free energy profile) of capsaicin along the bilayer normal confirms that it prefers an interfacial localization. The free energy profile indicates that there is a nontrivial but surmountable barrier to the flipping of capsaicin between opposing leaflets of the bilayer. Molecular dynamics of the S1-S4 transmembrane helices of the TRPV1 in a lipid bilayer confirm that Y511, known to be crucial to capsaicin binding, has a distribution along the bilayer normal similar to that of the aromatic group of capsaicin. Simulations were conducted of the TRPV1 S1-S4 transmembrane helices in the presence of capsaicin placed in the aqueous phase, in the lipid, or docked to the protein. No stable interaction between ligand and protein was seen for simulations initiated with capsaicin in the bilayer. However, interactions were seen between TRPV1 and capsaicin starting from the cytosolic aqueous phase, and capsaicin remained stable in the majority of simulations from the docked pose. We discuss the significance of capsaicin flipping from the extracellular to the intracellular leaflet and mechanisms of binding site access by capsaicin. PMID- 25809258 TI - Switch-like responses of two cholesterol sensors do not require protein oligomerization in membranes. AB - Many cellular processes are sensitive to levels of cholesterol in specific membranes and show a strongly sigmoidal dependence on membrane composition. The sigmoidal responses of the cholesterol sensors involved in these processes could arise from several mechanisms, including positive cooperativity (protein effects) and limited cholesterol accessibility (membrane effects). Here, we describe a sigmoidal response that arises primarily from membrane effects due to sharp changes in the chemical activity of cholesterol. Our models for eukaryotic membrane-bound cholesterol sensors are soluble bacterial toxins that show an identical switch-like specificity for endoplasmic reticulum membrane cholesterol. We show that truncated versions of these toxins fail to form oligomers but still show sigmoidal binding to cholesterol-containing membranes. The nonlinear response emerges because interactions between bilayer lipids control cholesterol accessibility to toxins in a threshold-like fashion. Around these thresholds, the affinity of toxins for membrane cholesterol varies by >100-fold, generating highly cooperative lipid-dependent responses independently of protein-protein interactions. Such lipid-driven cooperativity may control the sensitivity of many cholesterol-dependent processes. PMID- 25809260 TI - Cargo transport at microtubule crossings: evidence for prolonged tug-of-war between kinesin motors. AB - Intracellular transport of cargos along microtubules is often complicated by the topology of the underlying filament network. The fundamental building blocks for this complex arrangement are filament intersections. The navigation of cargos across microtubule intersections remains poorly understood. Here, we demonstrate that kinesin-driven cargos are engaged in a tug-of-war at microtubule intersections. Tug-of-war events result in long pauses that can last from a few seconds to several minutes. We demonstrate that the extent of the tug-of-war and the duration of pauses change with the number of motors on the cargo and can be regulated by ionic strength. We also show that dwell times at intersections depend on the angle between crossing microtubules. Our data suggest that local microtubule geometry can regulate microtubule-based transport. PMID- 25809259 TI - Two fundamental mechanisms govern the stiffening of cross-linked networks. AB - Biopolymer networks, such as those constituting the cytoskeleton of a cell or biological tissue, exhibit a nonlinear strain-stiffening behavior when subjected to large deformations. Interestingly, rheological experiments on various in vitro biopolymer networks have shown similar strain-stiffening trends regardless of the differences in their microstructure or constituents, suggesting a universal stiffening mechanism. In this article, we use computer simulations of a random network comprised of cross-linked biopolymer-like fibers to substantiate the notion that this universality lies in the existence of two fundamental stiffening mechanisms. After showing that the large strain response is accompanied by the development of a stress path, i.e., a percolating path of axially stressed fibers and cross-links, we demonstrate that the strain stiffening can be caused by two distinctly different mechanisms: 1) the pulling out of stress-path undulations; and 2) reorientation of the stress path. The former mechanism is bending dominated and can be recognized by a power-law dependence with exponent 3/2 of the shear modulus on stress, whereas the latter mechanism is stretching-dominated and characterized by a power-law exponent 1/2. We demonstrate how material properties of the constituents, as well as the network microstructure, can affect the transition between the two stiffening mechanisms and, as such, control the dominant power-law scaling behavior. PMID- 25809261 TI - LKB1/Mo25/STRAD uniquely impacts sarcomeric contractile function and posttranslational modification. AB - The myocardium undergoes extensive metabolic and energetic remodeling during the progression of cardiac disease. Central to remodeling are changes in the adenine nucleotide pool. Fluctuations in these pools can activate AMP-activated protein kinase (AMPK), the central regulator of cellular energetics. Binding of AMP to AMPK not only allosterically activates AMPK but also promotes phosphorylation of AMPK by an upstream kinase complex, LKB1/Mo25/STRAD (liver kinase B 1, mouse protein 25, STE-related adaptor protein). AMPK phosphorylation by the LKB1 complex results in a substantial increase in AMPK activity. Molecular targeting by the LKB1 complex depends on subcellular localization and transcriptional expression. Yet, little is known about the ability of the LKB1 complex to modulate targeting of AMPK after activation. Accordingly, we hypothesized that differing stoichiometric ratios of LKB1 activator complex to AMPK would uniquely impact myofilament function. Demembranated rat cardiac trabeculae were incubated with varying ratios of the LKB1 complex to AMPK or the LKB1 complex alone. After incubation, we measured the Ca(2+) sensitivity of tension, rate constant for tension redevelopment, maximum tension generation, length-dependent activation, cooperativity, and sarcomeric protein phosphorylation status. We found that the Ca(2+) sensitivity of tension and cross-bridge dynamics were dependent on the LKB1 complex/AMPK ratio. We also found that the LKB1 complex desensitizes and suppresses myofilament function independently of AMPK. A phospho-proteomic analysis of myofilament proteins revealed site-specific changes in cardiac Troponin I (cTnI) phosphorylation, as well as a unique distribution of cTnI phosphospecies that were dependent on the LKB1 complex/ AMPK ratio. Fibers treated with the LKB1 complex alone did not alter cTnI phosphorylation or phosphospecies distribution. However, LKB1 complex treatment independent of AMPK increased phosphorylation of myosin-binding protein C. Therefore, we conclude that the LKB1/AMPK signaling axis is able to alter muscle function through multiple mechanisms. PMID- 25809262 TI - Myosin S2 origins track evolution of strong binding on actin by azimuthal rolling of motor domain. AB - Myosin crystal structures have given rise to the swinging lever arm hypothesis, which predicts a large axial tilt of the lever arm domain during the actin attached working stroke. Previous work imaging the working stroke in actively contracting, fast-frozen Lethocerus muscle confirmed the axial tilt; but strongly bound myosin heads also showed an unexpected azimuthal slew of the lever arm around the thin filament axis, which was not predicted from known crystal structures. We hypothesized that an azimuthal reorientation of the myosin motor domain on actin during the weak-binding to strong-binding transition could explain the lever arm slew provided that myosin's alpha-helical coiled-coil subfragment 2 (S2) domain emerged from the thick filament backbone at a particular location. However, previous studies did not adequately resolve the S2 domain. Here we used electron tomography of rigor muscle swollen by low ionic strength to pull S2 clear of the thick filament backbone, thereby revealing the azimuth of its point of origin. The results show that the azimuth of S2 origins of those rigor myosin heads, bound to the actin target zone of actively contracting muscle, originate from a restricted region of the thick filament. This requires an azimuthal reorientation of the motor domain on actin during the weak to strong transition. PMID- 25809263 TI - Probing the structural and dynamical effects of the charged residues of the TZF domain of TIS11d. AB - A member of the TTP family of proteins, TIS11d binds RNA with high specificity using a pair of CCCH-type tandem zinc fingers separated by a 18 residue long linker. Our previous work showed that the formation of hydrogen bonds between the C-terminal residue E220 and the residues of the linker region stabilized a compact structure of TIS11d in the absence of RNA. To investigate the role of the C-terminal residues in the structure of unbound TIS11d, the E220A mutant and the truncation mutant lacking the last two residues (D219/E220) were studied using molecular dynamics, NMR spectroscopy, and biochemical methods. This study confirmed the importance of the charged residues D219 and E220 in maintaining structural stability in unbound TIS11d and elucidated the underlying physical mechanisms. We observed a greater structural heterogeneity for the residues of the linker in the molecular dynamics trajectories of both mutant proteins relative to the wild-type. This heterogeneity was more pronounced in the D219/E220 deletion mutant than in the E220A mutant, indicating that a greater reduction of the charge of the C-terminus results in greater flexibility. In agreement with the increased flexibility and the reduced number of negatively charged residues of the D219/E220 deletion mutant, we measured more unfavorable entropic and a more favorable enthalpic contribution to the free energy of RNA binding in the mutant than in the wild-type protein. The relative orientation of the zinc fingers was stabilized by the electrostatic interaction between E220 and positively charged residues of the linker in TIS11d. In the E220A mutant, the relative orientation of the zinc fingers was less constrained, whereas in the D219/E220 deletion mutant, little orientational preference was observed. We posit that favorable electrostatic interactions provide a mechanism to promote preferential orientation of separate domains without imposing structural rigidity. PMID- 25809265 TI - A well-balanced preexisting equilibrium governs electron flux efficiency of a multidomain diflavin reductase. AB - Diflavin reductases are bidomain electron transfer proteins in which structural reorientation is necessary to account for the various intramolecular and intermolecular electron transfer steps. Using small-angle x-ray scattering and nuclear magnetic resonance data, we describe the conformational free-energy landscape of the NADPH-cytochrome P450 reductase (CPR), a typical bidomain redox enzyme composed of two covalently-bound flavin domains, under various experimental conditions. The CPR enzyme exists in a salt- and pH-dependent rapid equilibrium between a previously described rigid, locked state and a newly characterized, highly flexible, unlocked state. We further establish that maximal electron flux through CPR is conditioned by adjustable stability of the locked state domain interface under resting conditions. This is rationalized by a kinetic scheme coupling rapid conformational sampling and slow chemical reaction rates. Regulated domain interface stability associated with fast stochastic domain contacts during the catalytic cycle thus provides, to our knowledge, a new paradigm for improving our understanding of multidomain enzyme function. PMID- 25809264 TI - Revisiting the interaction between the chaperone Skp and lipopolysaccharide. AB - The bacterial outer membrane comprises two main classes of components, lipids and membrane proteins. These nonsoluble compounds are conveyed across the aqueous periplasm along specific molecular transport routes: the lipid lipopolysaccharide (LPS) is shuttled by the Lpt system, whereas outer membrane proteins (Omps) are transported by chaperones, including the periplasmic Skp. In this study, we revisit the specificity of the chaperone-lipid interaction of Skp and LPS. High resolution NMR spectroscopy measurements indicate that LPS interacts with Skp nonspecifically, accompanied by destabilization of the Skp trimer and similar to denaturation by the nonnatural detergent lauryldimethylamine-N-oxide (LDAO). Bioinformatic analysis of amino acid conservation, structural analysis of LPS binding proteins, and MD simulations further confirm the absence of a specific LPS binding site on Skp, making a biological relevance of the interaction unlikely. Instead, our analysis reveals a highly conserved salt-bridge network, which likely has a role for Skp function. PMID- 25809266 TI - Controlling electron transfer between the two cofactor chains of photosystem I by the redox state of one of their components. AB - Two functional electron transfer (ET) chains, related by a pseudo-C2 symmetry, are present in the reaction center of photosystem I (PSI). Due to slight differences in the environment around the cofactors of the two branches, there are differences in both the kinetics of ET and the proportion of ET that occurs on the two branches. The strongest evidence that this is indeed the case relied on the observation that the oxidation rates of the reduced phylloquinone (PhQ) cofactor differ by an order of magnitude. Site-directed mutagenesis of residues involved in the respective PhQ-binding sites resulted in a specific alteration of the rates of semiquinone oxidation. Here, we show that the PsaA-F689N mutation results in an ~100-fold decrease in the observed rate of PhQA(-) oxidation. This is the largest change of PhQA(-) oxidation kinetics observed so far for a single point mutation, resulting in a lifetime that exceeds that of the terminal electron donor, P700(+). This situation allows a second photochemical charge separation event to be initiated before PhQA(-) has decayed, thereby mimicking in PSI a situation that occurs in type II reaction centers. The results indicate that the presence of PhQA(-) does not impact the overall quantum yield and leads to an almost complete redistribution of the fractional utilization of the two functional ET chains, in favor of the one that does not bear the charged species. The evolutionary implications of these results are also briefly discussed. PMID- 25809267 TI - Structural studies of truncated forms of the prion protein PrP. AB - Prions are proteins that adopt self-propagating aberrant folds. The self propagating properties of prions are a direct consequence of their distinct structures, making the understanding of these structures and their biophysical interactions fundamental to understanding prions and their related diseases. The insolubility and inherent disorder of prions have made their structures difficult to study, particularly in the case of the infectious form of the mammalian prion protein PrP. Many investigators have therefore preferred to work with peptide fragments of PrP, suggesting that these peptides might serve as structural and functional models for biologically active prions. We have used x-ray fiber diffraction to compare a series of different-sized fragments of PrP, to determine the structural commonalities among the fragments and the biologically active, self-propagating prions. Although all of the peptides studied adopted amyloid conformations, only the larger fragments demonstrated a degree of structural complexity approaching that of PrP. Even these larger fragments did not adopt the prion structure itself with detailed fidelity, and in some cases their structures were radically different from that of pathogenic PrP(Sc). PMID- 25809270 TI - Commentary on: Does Surgeon Subjective Nerve Sparing Score Predict Recovery Time of Erectile Function Following Robot-Assisted Radical Prostatectomy? PMID- 25809268 TI - Pattern selection by dynamical biochemical signals. AB - The development of multicellular organisms involves cells to decide their fate upon the action of biochemical signals. This decision is often spatiotemporally coordinated such that a spatial pattern arises. The dynamics that drive pattern formation usually involve genetic nonlinear interactions and positive feedback loops. These complex dynamics may enable multiple stable patterns for the same conditions. Under these circumstances, pattern formation in a developing tissue involves a selection process: why is a certain pattern formed and not another stable one? Herein we computationally address this issue in the context of the Notch signaling pathway. We characterize a dynamical mechanism for developmental selection of a specific pattern through spatiotemporal changes of the control parameters of the dynamics, in contrast to commonly studied situations in which initial conditions and noise determine which pattern is selected among multiple stable ones. This mechanism can be understood as a path along the parameter space driven by a sequence of biochemical signals. We characterize the selection process for three different scenarios of this dynamical mechanism that can take place during development: the signal either 1) acts in all the cells at the same time, 2) acts only within a cluster of cells, or 3) propagates along the tissue. We found that key elements for pattern selection are the destabilization of the initial pattern, the subsequent exploration of other patterns determined by the spatiotemporal symmetry of the parameter changes, and the speeds of the path compared to the timescales of the pattern formation process itself. Each scenario enables the selection of different types of patterns and creates these elements in distinct ways, resulting in different features. Our approach extends the concept of selection involved in cellular decision-making, usually applied to cell-autonomous decisions, to systems that collectively make decisions through cell-to-cell interactions. PMID- 25809269 TI - Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH. AB - We examined the endothelial transient receptor vanilloid 4 (TRPV4) channel's vasodilatory signaling using mathematical modeling. The model analyzes experimental data by Sonkusare and coworkers on TRPV4-induced endothelial Ca(2+) events (sparklets). A previously developed continuum model of an endothelial and a smooth muscle cell coupled through microprojections was extended to account for the activity of a TRPV4 channel cluster. Different stochastic descriptions for the TRPV4 channel flux were examined using finite-state Markov chains. The model also took into consideration recent evidence for the colocalization of intermediate-conductance calcium-activated potassium channels (IKCa) and TRPV4 channels near the microprojections. A single TRPV4 channel opening resulted in a stochastic localized Ca(2+) increase in a small region (i.e., few MUm(2) area) close to the channel. We predict micromolar Ca(2+) increases lasting for the open duration of the channel sufficient for the activation of low-affinity endothelial KCa channels. Simulations of a cluster of four TRPV4 channels incorporating burst and cooperative gating kinetics provided quantal Ca(2+) increases (i.e., steps of fixed amplitude), similar to the experimentally observed Ca(2+) sparklets. These localized Ca(2+) events result in endothelium-derived hyperpolarization (and SMC relaxation), with magnitude that depends on event frequency. The gating characteristics (bursting, cooperativity) of the TRPV4 cluster enhance Ca(2+) spread and the distance of KCa channel activation. This may amplify the EDH response by the additional recruitment of distant KCa channels. PMID- 25809271 TI - Hepatic Mass and Coagulopathy in a Ten-Year-Old Boy With Fever. PMID- 25809275 TI - Structures and Biosynthesis of Corvol Ethers--Sesquiterpenes from the Actinomycete Kitasatospora setae. AB - Here we present the functional characterization of a sesquiterpene cyclase from Kitasatospora setae. The enzyme converts the sesquiterpene precursor farnesyl diphosphate (FPP) into two previously unknown and unstable sesquiterpene ethers for which we propose the trivial names corvol ethers A and B. Both compounds were purified and their structures were determined by one- and two-dimensional NMR spectroscopy. A biosynthetic mechanism for the FPP cyclization by the corvol ether synthase was proposed. The results from the incubation experiments of the corvol ether synthase with isotopically labeled precursors were in line with this mechanism, while alternative mechanisms could clearly be ruled out. PMID- 25809272 TI - Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. AB - Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes. PMID- 25809273 TI - Estrogen-mediated signaling is differentially affected by the expression levels of Sfrp1 in mammary epithelial cells. AB - Estrogen has been implicated in breast cancer risk for a variety of reasons including its role in stimulating mammary cell division. Secreted frizzled related proteins (SFRPs) are a family of Wnt signaling antagonists. Loss of Sfrp1 in mice results in focal ductal epithelial hyperplasias and in humans, loss of SFRP1 is associated with early changes in premalignant breast lesions as well as poor overall survival in patients with early stage breast cancer. Considering that SFRP1 expression is further reduced in ER positive breast cancers when compared with ER negative breast cancers, we chose to determine whether loss of Sfrp1 alters ER signaling. Immunohistochemical analysis revealed that loss of Sfrp1 significantly increased the number of PR and BrdU positve cells in the mammary gland. We further demonstrate that down stream actions of ER-mediated signaling, including cellular proliferation and PR transcription, are elevated in estradiol treated explant cultures derived from Sfrp1(-/-) mice. Additionally, we show that Control explant cultures treated with estradiol exhibit an increase in the mRNA levels of Sfrp1. Finally, we establish that in human mammary epithelial cells with either SFRP1 knocked down (TERT-siSFRP1) and rescued SFRP1 expression (MCF7-SFRP1), estrogen signaling is augmented. Modulation of ER activity appears to be through a mechanism dependent upon Wnt/beta-catenin activity. Taken together, our data suggest an important control mechanism by which estrogen signaling is tempered in normal cells and indicates why loss of SFRP1 in early lesions might be a causal change leading to enhanced estrogen-mediated proliferation. PMID- 25809276 TI - Actin-myosin network influences morphological response of neuronal cells to altered osmolarity. AB - Acute osmotic fluctuations in the brain occur during a number of clinical conditions and can result in a variety of adverse neurological symptoms. Osmotic perturbation can cause changes in the volumes of intra- and extracellular fluid and, due to the rigidity of the skull, can alter intracranial pressure thus making it difficult to analyze purely osmotic effects in vivo. The present study aims to determine the effects of changes in osmolarity on SH-SY5Y human neuroblastoma cells in vitro, and the role of the actin-myosin network in regulating this response. Cells were exposed to hyper- or hypoosmotic media and morphological and cytoskeletal responses were recorded. Hyperosmotic shock resulted in a drop in cell body volume and planar area, a persisting shape deformation, and increases in cellular translocation. Hypoosmotic shock did not significantly alter planar area, but caused a transient increase in cell body volume and an increase in cellular translocation via the development of small protrusions rich in actin. Disruption of the actin-myosin network with latrunculin and blebbistatin resulted in changes to volume and shape regulation, and a decrease in cellular translocation. In both osmotic perturbations, no apparent disruptions to cytoskeletal integrity were observed by light microscopy. Overall, because osmotically induced changes persisted even after volume regulation occurred, it is possible that osmotic stress may play a larger role in neurological dysfunction than currently believed. PMID- 25809274 TI - Phase II clinical trials on investigational drugs for the treatment of pancreatic cancers. AB - INTRODUCTION: Despite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival > 1 year. As the penultimate step prior to Phase III studies involving hundreds of patients, Phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease. AREAS COVERED: This review covers the results of published Phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting Phase III success from Phase II trial results. EXPERT OPINION: Promising therapies remain elusive in pancreatic cancer based on recent Phase II clinical trial results. Optimization and standardization of clinical trial design in the Phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant Phase III evaluation. PMID- 25809277 TI - Rs6922269 marker at the MTHFD1L gene predict cardiovascular mortality in males after acute coronary syndrome. AB - Myocardial infarction (MI) is the leading cause of death in industrialized countries. All the traditional risk factors for MI are responsible for approximately 50% of cases of MI cases. Attention therefore has recently focused on genetic variants that are not associated with conventional risk factors. One of them is the marker rs6922269, which has been suggested as a risk factor for development of MI in Western populations. We analyzed the relationship between rs6922269 variant on MTHFD1L gene and (i) risk of the acute coronary syndrome (ACS) in the Czech population and (ii) mortality in 7 years follow up. Rs6922269 (G>A) variant was analyzed (CR 99.3% for patients and 98.0% for controls) by PCR RFLP in consecutively examined 1614 men and 503 women with ACS (age below 65 years) and in population-based controls--1191 men and 1368 women (aged up to 65 years). ANOVA and Chi square were used for statistical analysis. The genotype frequencies were almost identical (P=0.87) in the ACS patients and in controls and no differences were observed, if males (P=0.73) and females (P=0.93) were analysed separately. In addition, rs6922269 polymorphism was not associated with the classical risk factors (dyslipidemia, hypertension, obesity, smoking, diabetes) in control population. Cardiovascular mortality was significantly higher in males, carriers of the AA genotype (P<0.001, OR 2.52, 95% CI 1.40-4.55, for AA vs. +G). We conclude, that rs6922269 variant at MTHFD1L gene could be an important prognostic factor for cardiovascular mortality in patients after ACS. PMID- 25809278 TI - International validation of a behavioral scale in Parkinson's disease without dementia. AB - The "Ardouin Scale of Behavior in Parkinson's Disease" is a new instrument specifically designed for assessing mood and behavior with a view to quantifying changes related to Parkinson's disease, to dopaminergic medication, and to non motor fluctuations. This study was aimed at analyzing the psychometric attributes of this scale in patients with Parkinson's disease without dementia. In addition to this scale, the following measures were applied: the Unified Parkinson's Disease Rating Scale, the Montgomery and Asberg Depression Rating Scale, the Lille Apathy Rating Scale, the Bech and Rafaelsen Mania Scale, the Positive and Negative Syndrome Scale, the MacElroy Criteria, the Patrick Carnes criteria, the Hospital Anxiety and Depression Scale, and the Mini-International Neuropsychiatric Interview. Patients (n=260) were recruited at 13 centers across four countries (France, Spain, United Kingdom, and United States). Cronbach's alpha coefficient for domains ranged from 0.69 to 0.78. Regarding test-retest reliability, the kappa coefficient for items was higher than 0.4. For inter-rater reliability, the kappa values were 0.29 to 0.81. Furthermore, most of the items from the Ardouin Scale of Behavior in Parkinson's Disease correlated with the corresponding items of the other scales, depressed mood with the Montgomery and Asberg Depression Rating Scale (rho=0.82); anxiety with the Hospital Anxiety and Depression Scale-anxiety (rho=0.56); apathy with the Lille Apathy Rating Scale (rho=0.60). The Ardouin Scale of Behavior in Parkinson's disease is an acceptable, reproducible, valid, and precise assessment for evaluating changes in behavior in patients with Parkinson's disease without dementia. PMID- 25809280 TI - A Trigonal-Pyramidal Erbium(III) Single-Molecule Magnet. AB - Given the recent advent of mononuclear single-molecule magnets (SMMs), a rational approach based on lanthanides with axially elongated f-electron charge cloud (prolate) has only recently received attention. We report herein a new SMM, [Li(THF)4[Er{N(SiMe3)2}3Cl]?2 THF, which exhibits slow relaxation of the magnetization under zero dc field with an effective barrier to the reversal of magnetization (DeltaEeff/kB =63.3 K) and magnetic hysteresis up to 3 K at a magnetic field sweep rate of 34.6 Oe s(-1). This work questions the theory that oblate or prolate lanthanides must be stabilized with the appropriate ligand framework in order for SMM behavior to be favored. PMID- 25809281 TI - Platinum(II) as bifunctional linker in antibody-drug conjugate formation: coupling of a 4-nitrobenzo-2-oxa-1,3-diazole fluorophore to trastuzumab as a model. AB - The potential of platinum(II) as a bifunctional linker in the coordination of small molecules, such as imaging agents or (cytotoxic) drugs, to monoclonal antibodies (mAbs) was investigated with a 4-nitrobenzo-2-oxa-1,3-diazole (NBD) fluorophore and trastuzumab (HerceptinTM) as a model antibody. The effect of ligand and reaction conditions on conjugation efficiency was explored for [Pt(en)(L-NBD)Cl](NO3 ) (en=ethylenediamine), with L=N-heteroaromatic, N-alkyl amine, or thioether. Conjugation proceeded most efficiently at pH 8.0 in the presence of NaClO4 or Na2 SO4 in tricine or HEPES buffer. Reaction of N coordinated complexes (20 equiv) with trastuzumab at 37 degrees C for 2 h, followed by removal of weakly bound complexes with excess thiourea, afforded conjugates with an NBD/mAb ratio of 1.5-2.9 that were stable in phosphate buffered saline at room temperature for at least 48 h. In contrast, thioether coordinated complexes afforded unstable conjugates. Finally, surface plasmon resonance analysis showed no loss in binding affinity of trastuzumab after conjugation. PMID- 25809279 TI - Osteoporosis: the emperor has no clothes. AB - Current prevention strategies for low-trauma fractures amongst older persons depend on the notions that fractures are mainly caused by osteoporosis (pathophysiology), that patients at high risk can be identified (screening) and that the risk is amenable to bone-targeted pharmacotherapy (treatment). However, all these three notions can be disputed. PATHOPHYSIOLOGY: Most fracture patients have fallen, but actually do not have osteoporosis. A high likelihood of falling, in turn, is attributable to an ageing-related decline in physical functioning and general frailty. SCREENING: Currently available fracture risk prediction strategies including bone densitometry and multifactorial prediction tools are unable to identify a large proportion of patients who will sustain a fracture, whereas many of those with a high fracture risk score will not sustain a fracture. TREATMENT: The evidence for the viability of bone-targeted pharmacotherapy in preventing hip fracture and other clinical fragility fractures is mainly limited to women aged 65-80 years with osteoporosis, whereas the proof of hip fracture-preventing efficacy in women over 80 years of age and in men at all ages is meagre or absent. Further, the antihip fracture efficacy shown in clinical trials is absent in real-life studies. Many drugs for the treatment of osteoporosis have also been associated with increased risks of serious adverse events. There are also considerable uncertainties related to the efficacy of drug therapy in preventing clinical vertebral fractures, whereas the efficacy for preventing other fractures (relative risk reductions of 20-25%) remains moderate, particularly in terms of the low absolute risk reduction in fractures with this treatment. PMID- 25809284 TI - A g-factor metric for k-t SENSE and k-t PCA based parallel imaging. AB - PURPOSE: To propose and validate a g-factor formalism for k-t SENSE, k-t PCA and related k-t methods for assessing SNR and temporal fidelity. METHODS: An analytical gxf -factor formulation in the spatiotemporal frequency domain is derived, enabling assessment of noise and depiction fidelity in both the spatial and frequency domain. Using pseudoreplica analysis of cardiac cine data the gxf factor description is validated and example data are used to analyze the performance of k-t methods for various parameter settings. RESULTS: Analytical gxf -factor maps were found to agree well with pseudoreplica analysis for 3x, 5x, and 7x k-t SENSE and k-t PCA. While k-t SENSE resulted in lower average gxf values (gx (avg) ) in static regions when compared with k-t PCA, k-t PCA yielded lower gx (avg) values in dynamic regions. Temporal transfer was better preserved with k-t PCA for increasing undersampling factors. CONCLUSION: The proposed gxf factor and temporal transfer formalism allows assessing noise performance and temporal depiction fidelity of k-t methods including k-t SENSE and k-t PCA. The framework enables quantitative comparison of different k-t methods relative to frame-by-frame parallel imaging reconstruction. PMID- 25809285 TI - Solid-type RCC originating from native kidneys in renal transplant recipients should be monitored cautiously. AB - Incidental hemodialysis-related renal cell carcinoma (id-RCC) has been reported to have a good prognosis. However, we have observed rapid progression of id-RCC in some renal transplant patients. Operative indications for id-RCC detected via computed tomography (CT) immediately before renal transplantation (RTx) remain unclear. The purpose of this study was to examine the effects of immunosuppression on the progression of solid-type RCC (s-RCC) and cystic-type RCC (c-RCC). We divided 202 patients with id-RCC into four groups as follows: Group 1, s-RCC with RTx (n = 17); Group 2, c-RCC with RTx (n = 27); Group 3, s RCC without RTx (n = 53); and Group 4, c-RCC without RTx (n = 105). Five-year cancer specific survival (CSS) rates were significantly worse in Group 1 than Group 3 (79.6% and 100%, respectively, P = 0.012), as were non-recurrence rates (NRRs) (59.2 and 100%, respectively, P < 0.001). In contrast, 5-year CSS rates were similar in Group 2 and Group 4 (100% and 95.7%, respectively, P = 0.295) as were NRR (100% and 98.7%, respectively, P = 0.230). Solid-type RCC should be removed immediately after RTx, and more carefully monitored for recurrence during follow-up. PMID- 25809283 TI - Comparative glycoprofiling of HIV gp120 immunogens by capillary electrophoresis and MALDI mass spectrometry. AB - The human immunodeficiency virus (HIV) envelope glycoprotein (Env) is the primary antigenic feature on the surface of the virus and is of key importance in HIV vaccinology. Vaccine trials with the gp120 subunit of Env are ongoing, with the recent RV144 trial showing moderate efficacy. gp120 is densely covered with N linked glycans that are thought to help evade the host's humoral immune response. To assess how the global glycosylation patterns vary between gp120 constructs, the glycan profiles of several gp120s were examined by CE with LIF detection and MALDI-MS. The glycosylation profiles were found to be similar for chronic versus transmitter/founder isolates and only varied moderately between gp120s from different clades. This study revealed that the addition of specific tags, such as the herpes simplex virus glycoprotein D tag used in the RV144 trial, had significant effects on the overall glycosylation patterns. Such effects are likely to influence the immunogenicity of various Env immunogens and should be considered for future vaccine strategies, emphasizing the importance of the glycosylation analysis approach described in this paper. PMID- 25809282 TI - Proteomic analysis of the herpes simplex virus 1 virion protein 16 transactivator protein in infected cells. AB - The herpes simplex virus 1 virion protein 16 (VP16) tegument protein forms a transactivation complex with the cellular proteins host cell factor 1 (HCF-1) and octamer-binding transcription factor 1 (Oct-1) upon entry into the host cell. VP16 has also been shown to interact with a number of virion tegument proteins and viral glycoprotein H to promote viral assembly, but no comprehensive study of the VP16 proteome has been performed at early times postinfection. We therefore performed a proteomic analysis of VP16-interacting proteins at 3 h postinfection. We confirmed the interaction of VP16 with HCF-1 and a large number of cellular Mediator complex proteins, but most surprisingly, we found that the major viral protein associating with VP16 is the infected cell protein 4 (ICP4) immediate early (IE) transactivator protein. These results raise the potential for a new function for VP16 in associating with the IE ICP4 and playing a role in transactivation of early and late gene expression, in addition to its well documented function in transactivation of IE gene expression. PMID- 25809287 TI - Lithium treatment and hippocampal subfields and amygdala volumes in bipolar disorder. AB - OBJECTIVES: Results from magnetic resonance imaging (MRI) studies are heterogeneous with regard to hippocampal and amygdala volume alterations in bipolar disorder (BD). Lithium treatment may influence both structures. It is unknown if lithium treatment has distinct effects on hippocampal subfield volumes and if subfield volumes change over the course of illness in BD. METHODS: MRI scans were obtained for 34 lithium-treated patients with BD (Li+), 147 patients with BD who were not treated with lithium (Non-Li), and 300 healthy controls. Hippocampal total and subfield volumes and amygdala volumes were automatically estimated using Freesurfer. General linear models were used to investigate volume differences between groups and the effects of illness course and lithium treatment. RESULTS: The Non-Li BD group displayed significantly smaller bilateral cornu ammonis (CA) 2/3 and CA4/dentate gyrus (DG) subfields, total hippocampal volumes, right CA1 and right subiculum subfields, and left amygdala volume compared to healthy controls. There were no differences between the Li+ BD and either the Non-Li BD or the healthy control groups. In patients with numerous affective episodes, Non-Li BD patients had smaller left CA1 and CA2/3 volumes compared to Li+ BD patients and healthy controls. There were positive associations between lithium treatment duration and left amygdala volume. CONCLUSIONS: Hippocampal subfield and amygdala volumes were reduced in Non-Li BD patients compared to healthy controls, whereas the Li+ BD volumes were no different from those in Non-Li BD patients or healthy controls. Over the course of BD, lithium treatment might counteract reductions specifically in the left CA1 and CA2/3 hippocampal subfields and amygdala volumes, in accordance with the suggested neuroprotective effects of lithium. PMID- 25809286 TI - Beyond the CA1 subfield: Local hippocampal shape changes in MRI-negative temporal lobe epilepsy. AB - OBJECTIVE: Hippocampal atrophy in temporal lobe epilepsy (TLE) can indicate mesial temporal sclerosis and predict surgical success. Yet many patients with TLE do not have significant atrophy (magnetic resonance imaging (MRI) negative), which presents a diagnostic challenge. We used a new variant of high-dimensional large-deformation mapping to assess whether patients with apparently normal hippocampi have local shape changes that mirror those of patients with significant hippocampal atrophy. METHODS: Forty-seven patients with unilateral TLE and 32 controls underwent structural brain MRI. High-dimensional large deformation mapping provided hippocampal surface and volume estimates for each participant, dividing patients into low versus high hippocampal atrophy groups. A vertex-level generalized linear model compared local shape changes between groups. RESULTS: Patients with low-atrophy TLE (MRI negative) had significant local hippocampal shape changes compared to controls, similar to those in the contralateral hippocampus of high-atrophy patients. These changes primarily involved the subicular and hilar/dentate regions, instead of the classically affected CA1 region. Disease duration instead co-varied with lateral hippocampal atrophy, co-localizing with the CA1 subfield. SIGNIFICANCE: These findings show that patients with "MRI-negative" TLE have regions of hippocampal atrophy that cluster medially, sparing the lateral regions (CA1) involved in high-atrophy patients. This suggests an overall effect of temporal lobe seizures manifesting as bilateral medial hippocampal atrophy, and a more selective effect of hippocampal seizures leading to disease-proportional CA1 atrophy, potentially reflecting epileptogenesis. PMID- 25809289 TI - Delay from biopsy to radical prostatectomy influences the rate of adverse pathologic outcomes. AB - BACKGROUND: We sought to determine maximum wait times between biopsy diagnosis and surgery for localized prostate cancer, beyond which the rate of adverse pathologic outcomes is increased. METHODS: We retrospectively reviewed 4,610 patients undergoing radical prostatectomy between 1990 and 2011. Patients were stratified by biopsy Gleason score and PSA value. For each stratification, chi2 analysis was used to determine the smallest 15-day multiple of surgical delay (e.g., 15, 30, 45...180 days) for which adverse pathologic outcomes were significantly more likely after the time interval than before. Adverse outcomes were defined as positive surgical margins, upgrading from biopsy, upstaging, seminal vesicle invasion, or positive lymph nodes. RESULTS: Two thousand two hundred twelve patients met inclusion criteria. Median delay was 64 days (mean 76, SD 47). One thousand six hundred seventy-five (75.7%), 537 (24.3%), and 60 (2.7%) patients had delays of <=90, >90, and >180 days, respectively. Twenty-six percent were upgraded on final pathology and 23% were upstaged. The positive surgical margin rate was 24.2% and the positive lymph node rate was 1.1%. Significant increases in the proportion of adverse pathological outcomes were found beyond 75 days in the overall cohort (P = 0.03), 150 days for patients with Gleason <=6, and PSA 0-10 (P = 0.038), 60 days for patients with Gleason 7 and PSA >20 (P = 0.032), and 30 days for patients with Gleason 8-10 and PSA 11-20 (0.041). CONCLUSION: In low-risk disease, there is a considerable but not unlimited surgical delay which will not adversely impact the rate of adverse pathologic features found. In higher risk disease, this time period is considerably shorter. PMID- 25809290 TI - High-Performance Sb/Sb2 O3 Anode Materials Using a Polypyrrole Nanowire Network for Na-Ion Batteries. AB - Three-dimensional porous Sb/Sb2 O3 anode materials are successfully fabricated using a simple electrodeposition method with a polypyrrole nanowire network. The Sb/Sb2 O3 -PPy electrode exhibits excellent cycle performance and outstanding rate capabilities; the charge capacity is sustained at 512.01 mAh g(-1) over 100 cycles, and 56.7% of the charge capacity at a current density of 66 mA g(-1) is retained at 3300 mA g(-1) . The improved electrochemical performance of the Sb/Sb2 O3 -PPy electrode is attributed not only to the use of a highly porous polypyrrole nanowire network as a substrate but also to the buffer effects of the Sb2 O3 matrix on the volume expansion of Sb. Ex situ scanning electron microscopy observation confirms that the Sb/Sb2 O3 -PPy electrode sustains a strong bond between the nanodeposits and polypyrrole nanowires even after 100 cycles, which maintains good electrical contact of Sb/Sb2 O3 with the current collector without loss of the active materials. PMID- 25809288 TI - The Flavonoid 7,4'-Dihydroxyflavone Inhibits MUC5AC Gene Expression, Production, and Secretion via Regulation of NF-kappaB, STAT6, and HDAC2. AB - Mucus overproduction is a significant component of the pathophysiology of obstructive lung diseases. Currently, there are only a few medications available that inhibit mucus production. Previous studies showed that glycyrrhizin, a triterpenoid in Glycyrrhiza uralensis inhibits mucin 5AC (MUC5AC) mRNA and protein expression. Other potential mucus production inhibitory compounds contained within in G. uralensis have not been fully investigated. The aim of the present study was to determine if the G. uralensis flavonoid 7,4' dihydroxyflavone (7,4'-DHF) inhibits MUC5AC gene expression, mucus production, and secretion, and if so, to elucidate the mechanism of this inhibition. 7,4' Dihydroxyflavone significantly decreased phorbol 12-myristate 13-acetate stimulated NCI-H292 human airway epithelial cell MUC5AC gene expression and mucus production, at a 28-fold lower concentration than glycyrrhizin (The half maximal inhibitory concentration IC50 value of 1.4 MUM vs 38 MUM, respectively); 7,4'-DHF also inhibited MUC5AC mucus secretion. Inhibition was associated with the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB), signal transducer and activator of transcription 6 (STAT6) activation, and enhanced histone deacetylase 2 (HDAC2) expression. In a murine model of asthma, 7,4'-DHF-treated mice exhibited a marked reduction in MUC5AC secretion in the bronchoalveolar lavage fluid compared with control mice. These findings, together with previous findings linking NF-kappaB, STAT6, and HDAC2 modulation to the control of MUC5AC expression, demonstrate that 7,4'-DHF is a newly identified component of G. uralensis that regulates MUC5AC expression and secretion via regulation of NF-kappaB, STAT6, and HDAC2. PMID- 25809291 TI - Perceived burdensomeness and thwarted belongingness predict excessive reassurance seeking among clinical outpatients. AB - OBJECTIVE: The current study aimed to investigate whether perceived burdensomeness and thwarted belongingness (i.e., suicide risk factors) were associated with excessive reassurance seeking (a behavior linked to rejection). It was predicted that perceived burdensomeness and thwarted belongingness would predict higher levels of excessive reassurance seeking, controlling for depressive symptoms and global functioning. METHOD: A cross-sectional sample of 415 clinical outpatients (62% female; mean age = 28) was examined. RESULTS: Perceived burdensomeness and thwarted belongingness significantly predicted excessive reassurance seeking, controlling for depressive symptoms and global functioning. CONCLUSIONS: Perceived burdensomeness and thwarted belongingness predicted excessive reassurance seeking, suggesting that it would be beneficial for clinicians to assess for and target excessive reassurance seeking among individuals experiencing perceived burdensomeness and thwarted belongingness so that excessive reassurance seeking does not elicit interpersonal rejection. PMID- 25809292 TI - Morphological and molecular characteristics of HER2 amplified urothelial bladder cancer. AB - Several (pre-) clinical trials are currently investigating the benefit of HER2 targeted therapy in urothelial bladder cancer (UBC). Patients with HER2 amplified UBC could potentially profit from these therapies. However, little is known about histomorphology, HER2 protein expression patterns and occurrence of alterations in the HER2 gene in their tumors. Among 150 metastasizing primary UBC, 13 HER2 amplified tumors were identified. Their histopathological features were compared with 13 matched, non-amplified UBC. HER2 protein expression was determined by immunohistochemistry. The 26 tumors were screened for mutations in exons 19 and 20 of the HER2 gene. UBC with HER2 amplification presented with a broad variety of histological variants (median 2 vs. 1), frequently featured micropapillary tumor components (77 % vs. 8 %) and demonstrated a high amount of tumor associated inflammation. Immunohistochemically, 10 of 13 (77 %) HER2 amplified tumors were strongly HER2 protein positive. Three tumors (23 %) were scored as HER2 negative. One of the HER2 amplified tumors harbored a D769N mutation in exon 19 of the HER2 gene; all other tested tumors were wild type. In conclusion, HER2 amplified UBC feature specific morphological characteristics. They frequently express the HER2 protein diffusely and are, therefore, promising candidates for HER2 targeted therapies. The detection of mutations at the HER2 locus might add new aspects to molecular testing of UBC. PMID- 25809293 TI - Virus-induced gene silencing of Withania somnifera squalene synthase negatively regulates sterol and defence-related genes resulting in reduced withanolides and biotic stress tolerance. AB - Withania somnifera (L.) Dunal is an important Indian medicinal plant that produces withanolides, which are triterpenoid steroidal lactones having diverse biological activities. To enable fast and efficient functional characterization of genes in this slow-growing and difficult-to-transform plant, a virus-induced gene silencing (VIGS) was established by silencing phytoene desaturase (PDS) and squalene synthase (SQS). VIGS of the gene encoding SQS, which provides precursors for triterpenoids, resulted in significant reduction of squalene and withanolides, demonstrating its application in studying withanolides biosynthesis in W. somnifera leaves. A comprehensive analysis of gene expression and sterol pathway intermediates in WsSQS-vigs plants revealed transcriptional modulation with positive feedback regulation of mevalonate pathway genes, and negative feed forward regulation of downstream sterol pathway genes including DWF1 (delta-24 sterol reductase) and CYP710A1 (C-22-sterol desaturase), resulting in significant reduction of sitosterol, campesterol and stigmasterol. However, there was little effect of SQS silencing on cholesterol, indicating the contribution of sitosterol, campesterol and stigmasterol, but not of cholesterol, towards withanolides formation. Branch-point oxidosqualene synthases in WsSQS-vigs plants exhibited differential regulation with reduced CAS (cycloartenol synthase) and cycloartenol, and induced BAS (beta-amyrin synthase) and beta-amyrin. Moreover, SQS silencing also led to the down-regulation of brassinosteroid-6-oxidase-2 (BR6OX2), pathogenesis-related (PR) and nonexpressor of PR (NPR) genes, resulting in reduced tolerance to bacterial and fungal infection as well as to insect feeding. Taken together, SQS silencing negatively regulated sterol and defence related genes leading to reduced phytosterols, withanolides and biotic stress tolerance, thus implicating the application of VIGS for functional analysis of genes related to withanolides formation in W. somnifera leaves. PMID- 25809294 TI - Diversity and bioprospection of fungal community present in oligotrophic soil of continental Antarctica. AB - We surveyed the diversity and capability of producing bioactive compounds from a cultivable fungal community isolated from oligotrophic soil of continental Antarctica. A total of 115 fungal isolates were obtained and identified in 11 taxa of Aspergillus, Debaryomyces, Cladosporium, Pseudogymnoascus, Penicillium and Hypocreales. The fungal community showed low diversity and richness, and high dominance indices. The extracts of Aspergillus sydowii, Penicillium allii-sativi, Penicillium brevicompactum, Penicillium chrysogenum and Penicillium rubens possess antiviral, antibacterial, antifungal, antitumoral, herbicidal and antiprotozoal activities. Bioactive extracts were examined using (1)H NMR spectroscopy and detected the presence of secondary metabolites with chemical shifts. Our results show that the fungi present in cold-oligotrophic soil from Antarctica included few dominant species, which may have important implications for understanding eukaryotic survival in cold-arid oligotrophic soils. We hypothesize that detailed further investigations may provide a greater understanding of the evolution of Antarctic fungi and their relationships with other organisms described in that region. Additionally, different wild pristine bioactive fungal isolates found in continental Antarctic soil may represent a unique source to discover prototype molecules for use in drug and biopesticide discovery studies. PMID- 25809296 TI - Re: peripheral hypertrophic subepithelial corneal degeneration - clinical and histopathological features. PMID- 25809295 TI - Small-angle X-ray scattering analysis reveals the ATP-bound monomeric state of the ATPase domain from the homodimeric MutL endonuclease, a GHKL phosphotransferase superfamily protein. AB - DNA mismatch repair is an excision system that removes mismatched bases chiefly generated by replication errors. In this system, MutL endonucleases direct the excision reaction to the error-containing strand of the duplex by specifically incising the newly synthesized strand. Both bacterial homodimeric and eukaryotic heterodimeric MutL proteins belong to the GHKL ATPase/kinase superfamily that comprises the N-terminal ATPase and C-terminal dimerization regions. Generally, the GHKL proteins show large ATPase cycle-dependent conformational changes, including dimerization-coupled ATP binding of the N-terminal domain. Interestingly, the ATPase domain of human PMS2, a subunit of the MutL heterodimer, binds ATP without dimerization. The monomeric ATP-bound state of the domain has been thought to be characteristic of heterodimeric GHKL proteins. In this study, we characterized the ATP-bound state of the ATPase domain from the Aquifex aeolicus MutL endonuclease, which is a homodimeric GHKL protein unlike the eukaryotic MutL. Gel filtration, dynamic light scattering, and small-angle X ray scattering analyses clearly showed that the domain binds ATP in a monomeric form despite its homodimeric nature. This indicates that the uncoupling of dimerization and ATP binding is a common feature among bacterial and eukaryotic MutL endonucleases, which we suggest is closely related to the molecular mechanisms underlying mismatch repair. PMID- 25809297 TI - Peptide gel in a scaffold as a composite matrix for endothelial cells. AB - The performance of a composite environment with human umbilical vein endothelial cells (HUVECs) has been studied to provide an in vitro proof of concept of their potential of being easily vascularized. These cells were seeded in 1 mm thick scaffolds whose pores had been filled with a self-assembling peptide gel, seeking to improve cell adhesion, and viability of these very sensitive cells. The combination of the synthetic elastomer poly(ethyl acrylate), PEA, scaffold and the RAD16-I peptide gel provides cells with a friendly ECM-like environment inside a mechanically resistant structure. Immunocytochemistry, flow cytometry and scanning electron microscopy were used to evaluate the cell cultures. The presence of the self-assembling peptide filling the pores of the scaffolds resulted in a truly 3D nanoscale context mimicking the extracellular matrix environment, and led to increased cells survival, proliferation as well as developed cell-cell contacts. The combined system consisting of PEA scaffolds and RAD16-I, is a very interesting approach as seems to enhance endothelization, which is the first milestone to achieve vascularized constructs. PMID- 25809298 TI - Contrasting growth phenology of native and invasive forest shrubs mediated by genome size. AB - Examination of the significance of genome size to plant invasions has been largely restricted to its association with growth rate. We investigated the novel hypothesis that genome size is related to forest invasions through its association with growth phenology, as a result of the ability of large-genome species to grow more effectively through cell expansion at cool temperatures. We monitored the spring leaf phenology of 54 species of eastern USA deciduous forests, including native and invasive shrubs of six common genera. We used new measurements of genome size to evaluate its association with spring budbreak, cell size, summer leaf production rate, and photosynthetic capacity. In a phylogenetic hierarchical model that differentiated native and invasive species as a function of summer growth rate and spring budbreak timing, species with smaller genomes exhibited both faster growth and delayed budbreak compared with those with larger nuclear DNA content. Growth rate, but not budbreak timing, was associated with whether a species was native or invasive. Our results support genome size as a broad indicator of the growth behavior of woody species. Surprisingly, invaders of deciduous forests show the same small-genome tendencies of invaders of more open habitats, supporting genome size as a robust indicator of invasiveness. PMID- 25809299 TI - Neuronal Na+/K+ ATPase is an autoantibody target in paraneoplastic neurologic syndrome. AB - OBJECTIVES: To identify an autoreactivity in a 66-year-old woman who presented with combined brainstem and cerebellar syndrome including vertical gaze palsy, severe progressive ataxia, and spastic tetraparesis, an acute deterioration of vision, dysarthria, and dysphagia with concurrent diagnosis of a colon adenocarcinoma. METHODS: Patient's serum and CSF underwent comprehensive autoantibody screening by indirect immunofluorescence assay and immunoblot. For autoantigen purification, a histo-immunoprecipitation technique was developed followed by mass spectrometrical analysis. Recombinant candidate antigens were expressed in HEK293 and used to verify the identification. RESULTS: Indirect immunofluorescence assay screening revealed strong immunoglobulin G reactivity with neural tissues in serum and CSF, but not with a panel of 28 recombinantly expressed established neural autoantigens. The hitherto unknown target antigen was identified as the neuronal Na(+)/K(+) ATPase. Epitope mapping and competitive inhibition experiments showed that the autoantibodies were directed against the membrane-spanning alpha 3 subunit (ATP1A3) of the enzyme but did not bind to extracellular epitopes. Immunohistochemical analysis revealed overexpression of this subunit in the patient's tumor. CONCLUSIONS: We describe a case of an anti ATP1A3-associated neurologic disorder. Mutations in the gene encoding this neuronal surface protein have already been recognized as the cause of infantile alternating hemiplegia, rapid-onset dystonia parkinsonism, and CAPOS syndrome. Although the autoantibodies are unlikely to be pathogenic, they are likely to be rare biomarkers for the apparently paraneoplastic neurologic syndrome or for the tumor itself. PMID- 25809301 TI - Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease. AB - OBJECTIVE: We performed a real-life observation of patients with Parkinson disease (PD) who received duodenal levodopa infusion (DLI) to determine which adverse events caused treatment discontinuation and when such events occurred. METHODS: All consecutive patients with PD treated at the Carlo Besta Neurological Institute were included. The patients were evaluated at baseline and after DLI at regular intervals. Their motor condition was assessed and adverse events were recorded. RESULTS: Thirty-five patients with PD (15 men and 20 women) were included. They received DLI implants between October 2007 and September 2013. Four patients died of causes unrelated to the procedure. At the end of the study, 21 patients (60%) were still on treatment. DLI provided efficacious motor control in all patients. Discontinuation was most frequently caused by device- or infusion-related adverse events. Ten patients of the remaining 31 discontinued DLI. There were 2 main causes of withdrawal: stoma infection (4 patients), and worsening of dyskinesias not manageable with infusion reduction (3 patients). In most patients, discontinuations occurred during the first year after implant. Risk of discontinuation was related to age at implant, but no other demographic or clinical variables. CONCLUSIONS: We identified 2 main causes leading to DLI withdrawal during the first year postimplant and suggest adopting measures to prevent such occurrences. Elderly patients are at higher risk of treatment discontinuation. PMID- 25809300 TI - Factors influencing sweat gland innervation in diabetes. AB - BACKGROUND: Using a stereologic approach, the density of nerve fibers innervating sweat gland (SG) fragments in patients with diabetes mellitus (DM) and healthy controls using protein gene product (PGP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP) was measured to determine which marker best detected differences between the groups. Factors associated with SG nerve fiber (SGNF) innervation were assessed and the change in SG innervation over a 1-year time period was determined. METHODS: Ninety-two control subjects and 2 groups of subjects with DM totaling 97 were assessed in this cross-sectional study. Intraepidermal nerve fiber density and SG innervation were determined from leg skin biopsies that were immunohistochemically stained for ubiquitin hydrolase, VIP, and TH. Factors associated with SG innervation were assessed and 15 subjects were longitudinally followed for 1 year. RESULTS: SGNF innervation was reduced in subjects with DM compared with controls. Lower SG innervation values were associated with increasing glycated hemoglobin A1c, body mass index (BMI), men compared with women, and tobacco use, but not diabetes type or age. Sex, A1c, and BMI remained significant in multivariate modeling. SG innervation measured by VIP+ fibers is a more sensitive marker for neuropathy than either PGP or TH. Fifteen subjects with DM followed for 1 year showed a significant decrease in SGNF innervation but not intraepidermal nerve fiber density. CONCLUSIONS: Stereologic measurement of SG innervation is feasible to assess postganglionic autonomic nerve fiber densities. SG innervation was reduced in subjects with DM compared with control subjects and was associated with sex, A1c, and BMI in multivariate modeling. VIP+ SGNF is more severely reduced in DM than TH+ or PGP9.5+-based assessments. Progression of diabetic polyneuropathy was detected by SGNF over a 1-year time period. PMID- 25809302 TI - Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women. AB - OBJECTIVE: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women. METHODS: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels. RESULTS: We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p = 0.006 to 0.037; odds ratio = 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women. CONCLUSIONS: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families. PMID- 25809303 TI - Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts. AB - OBJECTIVE: To study remote effects distant from acute ischemic infarcts by measuring longitudinal changes of cortical thickness in connected brain regions as well as changes in microstructural integrity in connecting fiber tracts. METHODS: Thirty-two patients (mean age 71 years) underwent a standardized protocol including multimodal MRI and clinical assessment both at stroke onset and 6 months after the event. Cortex connected to acute infarcts was identified by probabilistic diffusion tensor tractography starting from the acute lesion. Changes of cortical thickness were measured using the longitudinal stream of FreeSurfer. Microstructural damage in white matter tracts was assessed by changes of mean diffusivity. RESULTS: We found focal cortical thinning specifically in areas connected to acute infarcts (p < 0.001). Thinning was more pronounced in regions showing a high probability of connectivity to infarcts. Microstructural damage in white matter tracts connecting acute infarcts with distant cortex significantly correlated with thickness changes in that region (rho = -0.39, p = 0.028). There was no indication of an influence of cavitation status or infarct etiology on the observed changes in cortex and white matter. CONCLUSIONS: These findings identify secondary degeneration of connected white matter tracts and remote cortex as key features of acute ischemic infarcts. Our observations may have implications for the understanding of structural and functional reorganization after stroke. PMID- 25809304 TI - Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: We assessed CSF levels of the light chain subunit of neurofilaments (NfL) at baseline and after fingolimod therapy or placebo in patients with relapsing-remitting multiple sclerosis (RRMS). Changes in NfL levels were also correlated with relapse and MRI outcomes. METHODS: CSF samples were available, at baseline and 12 months after treatment initiation, from a subset of 36 patients with RRMS (fingolimod 0.5 mg: n = 9; fingolimod 1.25 mg: n = 15; placebo: n = 12) participating in the 2-year, phase 3 Fingolimod (FTY720) Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. NfL levels were determined in a blinded fashion using a commercial ELISA kit. RESULTS: Median NfL levels did not differ between treatment groups at baseline (0.5 mg: 644 pg/mL; 1.25 mg: 659 pg/mL; pooled 0.5/1.25 mg: 652 pg/mL, placebo: 886 pg/mL; p value [fingolimod vs placebo] = 0.619, 0.495, and 0.481, respectively). Following 12 months of treatment, median changes from baseline in NfL levels were lower than zero in the fingolimod groups (0.5 mg: -346 pg/mL, p = 0.039; 1.25 mg: -313 pg/mL, p = 0.035) and pooled 0.5/1.25 mg fingolimod group (-326 pg/mL, 83.3% with reduction, p = 0.002) but not in the placebo group (-214 pg/mL, 66.7% with reduction, p = 0.388). Reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes. CONCLUSIONS: Our results suggest a beneficial effect of fingolimod on this marker of axonal injury and support the utility of NfL as a quantitative biomarker in multiple sclerosis. PMID- 25809306 TI - Epigenetic diagnostics for neuropsychiatric disorders: Above the genome. PMID- 25809305 TI - Will CSF biomarkers guide future therapeutic decisions in multiple sclerosis? PMID- 25809307 TI - Effect of Climate Change on the Concentration and Associated Risks of Vibrio Spp. in Dutch Recreational Waters. AB - Currently, the number of reported cases of recreational- water-related Vibrio illness in the Netherlands is low. However, a notable higher incidence of Vibrio infections has been observed in warm summers. In the future, such warm summers are expected to occur more often, resulting in enhanced water temperatures favoring Vibrio growth. Quantitative information on the increase in concentration of Vibrio spp. in recreational water under climate change scenarios is lacking. In this study, data on occurrence of Vibrio spp. at six different bathing sites in the Netherlands (2009-2012) were used to derive an empirical formula to predict the Vibrio concentration as a function of temperature, salinity, and pH. This formula was used to predict the effects of increased temperatures in climate change scenarios on Vibrio concentrations. For Vibrio parahaemolyticus, changes in illness risks associated with the changed concentrations were calculated as well. For an average temperature increase of 3.7 degrees C, these illness risks were calculated to be two to three times higher than in the current situation. Current illness risks were, varying per location, on average between 10(-4) and 10(-2) per person for an entire summer. In situations where water temperatures reached maximum values, illness risks are estimated to be up to 10(-2) and 10(-1) . If such extreme situations occur more often during future summers, increased numbers of ill bathers or bathing-water-related illness outbreaks may be expected. PMID- 25809309 TI - [Not Available]. PMID- 25809308 TI - [Indication and control of volume therapy. First things first]. AB - BACKGROUND: Fluid therapy is a core concept in the management of perioperative and critically ill patients for maintenance of intravascular volume and organ perfusion. The clinical determination of the intravascular volume can be extremely difficult. Indication and control for intravascular volume therapy are among the most difficult aspects of intensive care. MATERIALS AND METHODS: A literature review was performed. RESULTS: The goal of cardiovascular therapy is to enhance adequate blood flow and oxygen delivery to the tissues to meet the varying metabolic demands of the tissues without inducing untoward cardiorespiratory complications. A careful history and clinical examination are indispensable and allow evaluation of tissue and organ perfusion. Laboratory examinations, bedside ultrasonography as well as invasive hemodynamic monitoring complete the assessment and allow guidance of fluid therapy. CONCLUSIONS: Case history, clinical examinations, bedside ultrasonography, and invasive hemodynamic monitoring complete the assessment and allow clinicians to assess volume responsiveness. PMID- 25809311 TI - [Role of evidence-based medicine in intensive care]. AB - Evidence-based medicine (EBM) plays an important role in intensive care. Along with the individual expertise of the attending physician and the preferences of the respective patient, recent study evidence is an important decision criterion when choosing the appropriate diagnostic and therapeutic procedures. Both a target-orientated literature search and adequate evaluation of the risk of bias as well as interpretation of the depicted outcomes are necessary to be able to draw the right conclusions from study results. Furthermore, proper publication formats might facilitate the synopsis of the available evidence and support the implementation of this knowledge in routine clinical work. PMID- 25809310 TI - [Choice of crystalloids in interventions and surgery]. AB - BACKGROUND: Fluid therapy is daily routine in the perioperative setting; however, high quality guidelines are lacking. The S3-guideline Intravasal Fluid Therapy in the Adult Patient gives evidence- and consensus-based recommendations for the use of fluids in perioperative and critically ill patients. In addition to identifying hypovolemia and guiding volume replacement, the type of fluid that should be used is addressed. OBJECTIVES: The purpose of this article is to present and discuss the recommendations of the S3-guideline with respect to the choice of crystalloids in the perioperative setting. MATERIALS AND METHODS: A literature search within the scope of the guideline development was performed. RESULTS AND CONCLUSIONS: In this review the recommendations and their rationale in the perioperative setting are presented. Crystalloids are the basis of fluid therapy. Instead of isotonic saline, buffered solutions are recommended. Regarding the type of buffer (lactate, acetate, malate), no preferences based on outcome data can be made. PMID- 25809312 TI - Pitfalls in the diagnosis of heparin-Induced thrombocytopenia: A 6-year experience from a reference laboratory. AB - Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies against complexes of platelet factor 4 (PF4) and heparin. The diagnosis of HIT is contingent on accurate and timely laboratory testing. Recently, alternative anticoagulants for the treatment of HIT have been introduced along with algorithms for better HIT diagnosis. However, the increased reliance on immunoassays for the diagnosis of HIT may have harmful consequences due to the high rate of false positive results. To compare trends and implications of current HIT testing approaches, we analyzed results over a six year period from the McMaster University Platelet Immunology Reference Laboratory. From 2008 to 2013, 8,546 samples were investigated for HIT using both an in-house IgG-specific anti-PF4/heparin enzyme immunoassay (EIA) and the serotonin-release assay (SRA). Of 8,546 samples tested, 13.4% were true-positives (positive in both assays); 65.6% were true-negatives (negative in both assays); 20.9% were presumed false positive for HIT (EIA-positive/SRA-negative); and 0.2% were EIA-negative/SRA-positive. The frequency of EIA-positive/SRA-negative results increased over time (from 12.9% in 2008 to 22.9% in 2013). We found that the number of SRA-negative samples was reduced from referring centers that used an immunoassay as an initial screen; however, 41% of those samples tested negative in the immunoassay and in the SRA at the reference laboratory. The suspicion of HIT continues at a high rate and the agreement between the EIA and SRA test results remains problematic. PMID- 25809313 TI - A Bayesian framework to account for uncertainty due to missing binary outcome data in pairwise meta-analysis. AB - Missing outcome data are a common threat to the validity of the results from randomised controlled trials (RCTs), which, if not analysed appropriately, can lead to misleading treatment effect estimates. Studies with missing outcome data also threaten the validity of any meta-analysis that includes them. A conceptually simple Bayesian framework is proposed, to account for uncertainty due to missing binary outcome data in meta-analysis. A pattern-mixture model is fitted, which allows the incorporation of prior information on a parameter describing the missingness mechanism. We describe several alternative parameterisations, with the simplest being a prior on the probability of an event in the missing individuals. We describe a series of structural assumptions that can be made concerning the missingness parameters. We use some artificial data scenarios to demonstrate the ability of the model to produce a bias-adjusted estimate of treatment effect that accounts for uncertainty. A meta-analysis of haloperidol versus placebo for schizophrenia is used to illustrate the model. We end with a discussion of elicitation of priors, issues with poor reporting and potential extensions of the framework. Our framework allows one to make the best use of evidence produced from RCTs with missing outcome data in a meta-analysis, accounts for any uncertainty induced by missing data and fits easily into a wider evidence synthesis framework for medical decision making. PMID- 25809316 TI - Neuropsychological predictors of conversion to probable Alzheimer disease in elderly with mild cognitive impairment. AB - In the field of neuropsychology, it is essential to determine which neuropsychological tests predict Alzheimer's disease (AD) in people with mild cognitive impairment (MCI) and which cut-off points should be used to identify people at greater risk for converting to dementia. The aim of the present study was to analyse the predictive value of the cognitive tests included in a neuropsychological battery for conversion to AD among MCI participants and to analyse the influence of some sociodemographic variables - sex, age, schooling - and others, such as follow-up time and emotional state. A total of 105 participants were assessed with a neuropsychological battery at baseline and during a 3-year follow-up period. For the present study, the data were analysed at baseline. During the follow-up period, 24 participants (22.85%) converted to dementia (2.79 +/- 1.14 years) and 81 (77.14%) remained as MCI. The logistic regression analysis determined that the long delay cued recall and the performance time of the Rey figure test were the best predictive tests of conversion to dementia after an MCI diagnosis. Concerning the sociodemographic factors, sex had the highest predictive power. The results reveal the relevance of the neuropsychological data obtained in the first assessment. Specifically, the data obtained in the episodic verbal memory tests and tests that assess visuospatial and executive components may help to identify people with MCI who may develop AD in an interval not longer than 4 years, with the masculine gender being an added risk factor. PMID- 25809314 TI - Topical Steroid Therapy for the Treatment of Eosinophilic Esophagitis (EoE): A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Current guidelines recommend topical steroids as first-line treatment for patients with eosinophilic esophagitis (EoE). However, the evidence for this approach has been inconsistent in earlier reports. This meta-analysis aimed to clarify the efficacy of topical steroid treatment in active EoE using updated evidence. METHODS: CENTRAL, MEDLINE and EMBASE databases were searched for randomized controlled trials (RCTs) published up to May 2014 that compared topical steroids with control treatments for active EoE. Study bias was assessed using the Cochrane Collaboration Tool, and outcomes were pooled using random effects models. The primary outcome was the mean change in eosinophil counts. Secondary outcomes were symptom responses and adverse events. RESULTS: In total, seven RCTs (226 patients) were included. Topical steroids were associated with a significant reduction in esophageal mucosal eosinophil counts compared with control therapy although substantial heterogeneity between studies was observed (weighted mean difference (WMD) -27.2, 95% confidence interval (CI) -45.3 to 9.1, I(2)=56.2%). Subgroup analysis indicated the reduction in eosinophil counts was only present in studies where a proton pump inhibitor (PPI) trial was used to exclude other diagnoses (WMD -46.3, 95% CI -61.3 to -31.4, I(2)=0.0%). Subdivision of studies on the use of a PPI trial also accounted for the majority of heterogeneity among RCTs. No clear trends in symptom resolution were observed. Eleven out of 127 patients who received topical steroids developed asymptomatic esophageal candidiasis. CONCLUSIONS: These data provide updated high-quality evidence that support current guidelines for first-line EoE treatment with topical steroids after an initial PPI trial to exclude non-EoE pathologies (PROSPERO ID: CRD42014008828). PMID- 25809315 TI - Which patients do not recover from shoulder impingement syndrome, either with operative treatment or with nonoperative treatment? AB - BACKGROUND AND PURPOSE: Shoulder impingement syndrome is common, but treatment is controversial. Arthroscopic acromioplasty is popular even though its efficacy is unknown. In this study, we analyzed stage-II shoulder impingement patients in subgroups to identify those who would benefit from the operation. PATIENTS AND METHODS: In a previous randomized study, 140 patients were either treated with a supervised exercise program or with arthroscopic acromioplasty followed by a similar exercise program. The patients were followed up at 2 and 5 years after randomization. Self-reported pain was used as the primary outcome measure. RESULTS: Both treatment groups had less pain at 2 and 5 years, and this was similar in both groups. Duration of symptoms, marital status (single), long periods of sick leave, and lack of professional education appeared to increase the risk of persistent pain despite the treatment. Patients with impingement with radiological acromioclavicular (AC) joint degeneration also had more pain. The patients in the exercise group who later wanted operative treatment and had it did not get better after the operation. INTERPRETATION: The natural course probably plays a substantial role in the outcome. Based on our findings, it is difficult to recommend arthroscopic acromioplasty for any specific subgroup. Regarding operative treatment, however, a concomitant AC joint resection might be recommended if there are signs of AC joint degeneration. Even more challenging for the development of a treatment algorithm is the finding that patients who do not recover after nonoperative treatment should not be operated either. PMID- 25809317 TI - Morphological and morphometric aspects of early life stages of piabanha Brycon gouldingi (Characidae). AB - Adult specimens of piabanha Brycon gouldingi were collected from Rio das Mortes (Mato Grosso, Brazil), adapted to captivity and induced to spawn at Buriti Fisheries (Nova Mutum, MT, Brazil). The early developmental stages of B. gouldingi were then characterized. Samples were collected at pre-determined times from oocyte extrusion to total yolk absorption. Oocyte diameter, total larval length (LT ) and yolk-sac volume were measured. The mean +/- s.d. duration of embryo developmental of B. gouldingi was 13.90 +/- 0.06 h at 26.40 +/- 1.13 degrees C. The mean +/- s.d. oocyte diameter was 1.13 +/- 0.06 mm with 54% of oocytes ranging from 1.11 to 1.20 mm. Seven stages characterized the early developmental phase of this species: zygote, cleavage, morula, blastula, gastrula, histogenesis-organogenesis and hatching, with unique features related to each stage. At hatching, the larvae measured 3.40 +/- 0.07 mm, presented an elongated shape with yolk-sac volume of 0.46 +/- 0.08 ul, non-pigmented eyes and exhibited swimming ability. When the yolk was completely absorbed at 55 h post hatch, mean +/- larval LT was 6.68 +/- 0.65 mm, the eyes were highly pigmented and the teeth were visible. These are the first reported findings on the initial developmental stages of B. gouldingi and could be used to improve captive breeding management and conservation practices. PMID- 25809318 TI - [Radiological diagnosis of non-neoplastic bowel diseases]. AB - Intestinal non-neoplastic diseases, including inflammation, bleeding and trauma, are common and frequently-occurring diseases. With the development of diagnosis and the change of disease spectrum, more and more clinical attentions are paid to autoimmune intestinal colitis, Crohn's disease, irritable bowel syndrome, ischemic bowel disease, intestinal polyps and other non-neoplastic diseases. Radiological modalities and characteristics of non-neoplastic bowel diseases are summarized and evaluated in this article. We hope to provide useful information for clinicians to select radiologic methods correctly. PMID- 25809319 TI - [Imaging evaluation of gastrointestinal tumor lesions]. AB - Gastrointestinal tumors are always the most common diseases in China, which are also the focus of attention by radiologists. In recent years, more and more patients benefit from the advance in diagnosis and treatment technique. The outcomes have been improved. Radiology plays an important role in this area. The strategy for diagnosis and treatment of gastrointestinal cancer has developed from single mode to multiple and comprehensive modes. It requires multidisciplinary collaboration to provide best individualized therapy. Recent literatures on gastric and colorectal tumors are reviewed. According to clinical evidence and personal experience, the hot topics of gastrointestinal tumors on radiology are introduced in this article. Future development and challenges of this area are also discussed. PMID- 25809320 TI - [Staging and response evaluation of gastric cancer: requirements and resolutions by multidisciplinary treatment]. AB - The popularization of the multidisciplinary treatment has brought more demands to the radiological evaluation of the gastric cancer, which includes staging and response evaluation. Limited by the resolution, the present imaging modalities can not demonstrate tiny structures of the serosa, and the employment of the hyperattenuating serosa sign may improve the diagnostic performance of T4a. The spectral CT and diffusion weighted MRI may provide new potential methods for the staging of gastric cancer. Attention should be paid to the unresectable signs caused by the dispersed infiltration of adjacent fat space to the organs. The comprehensive evaluation of peritoneal metastasis should base on the sites and early signs. Diffusion weighted MRI may provide new indicator for the response evaluation of gastric cancer to neoadjuvant chemotherapy. PMID- 25809321 TI - [Imaging in the diagnosis of small bowel diseases]. AB - There are still many difficulties in the diagnosis of small bowel diseases. Until recently, diagnosis of small bowel diseases relies primarily on imaging techniques. The traditional gastrointestinal barium meal examination and endoscopy can observe the changing of mucous membrane, but can not demonstrate the intestinal wall and the extraluminal structure. With the development and modification of CT and MR software and hardware, CT enterography (CTE) and MR enterography (MRE) are being increasingly usded in clinical practice, facilitating discrimination of mucous membrane, wall, lumen and extraluminal structure. Dynamic contrast scanning can reflect the blood supply of intestinal lesions, and CTA and MRA can reveal the vascularity and abnormality. Comprehensive analysis of imaging can provide overall and objective information and improve diagnostic accuracy of small bowel diseases. Besides, imaging features can be used as criteria in assessing the activity of Crohn's disease, which provides effective method of treatment selection and efficacy evaluation. PMID- 25809322 TI - [Value of magnetic resonance imaging in assessing the efficacy of neoadjuvant chemoradiotherapy for locally advanced rectal cancer]. AB - Before and after neoadjuvant chemoradiotherapy, overall and accurate evaluation of locally advanced rectal cancer is associated with the selection of treatment schedule, while imaging diagnosis is the key point. Anatomical and functional MRI has been applied in the prediction and assessment of neoadjuvant chemoradiotherapy efficacy for locally advanced rectal cancer. Before neoadjuvant chemoradiotherapy, distance of <= 5 cm from the lower margin to anal verge and extramural venous invasion status assessed by high resolution MRI are independent predictors of tumor response to neoadjuvant chemoradiotherapy. After neoadjuvant chemoradiotherapy, MRI assessment of tumor regression grade (TRG) is a valuable imaging indicator to evaluate the response to neoadjuvant chemoradiotherapy. Furthermore, FDG PET, diffusion weighted imaging and dynamic contrast enhanced MRI can be used to evaluate the efficacy based on tumor cell metabolism, tumor cell density and tumor blood perfusion respectively, which provides helpful supplement for high resolution MRI based on anatomy. PMID- 25809323 TI - [Correlation of diffusion weighted MR imaging with the prognosis of local advanced gastric carcinoma after neoadjuvant chemotherapy]. AB - OBJECTIVE: To investigate the correlation of the apparent diffusion coefficient (ADC) on diffusion-weighted MRI (DWI) with the prognosis of locally advanced gastric carcinoma after neoadjuvant chemotherapy (NACT). METHODS: Patients with locally advanced gastric carcinoma undergoing NACT in our hospital from November 2010 to September 2011 were enrolled in this prospective study. MRI examinations were performed before and after NACT. ADCs of the whole lesion (ADCentire) and high signal area on DWI (ADCmin) were calculated, and the cancer thickness on T2 weighted images was measured. All the patients were divided into long-term survival group and poor prognosis group, according to the 3-year survival status. The pre-therapy baseline values and early percentage changes (%delta) of the above parameters were compared between the two groups. Receiver operating characteristics (ROC) curves were employed to compare the performance of the above parameters in the discrimination of different prognosis groups. RESULTS: A total of 24 patients were enrolled in the study. There were 14 patients of long term survival group and 10 patients of poor prognosis group. No statistical difference in baseline ADCmin and ADCentire was shown between long-term survival group and poor prognosis group [ADCmin: (1.17 +/- 0.23)*10-3 mm2/s vs. (1.23 +/- 0.27) * 10-3 mm2/s, P>0.05; ADCentire: (1.43 +/- 0.20) * 10-3 mm2/s vs. (1.50 +/- 0.24) * 10-3 mm2/s, P>0.05]. The % DeltaADCmin and % DeltaADCentire were both higher in long-term survival group than those in poor prognosis group (% DeltaADCmin: 21% vs. 5%, P=0.06; % DeltaADCentire: 23% vs. 1%, P=0.02). Through ROC curves, the AUCs for pre-therapy cancer thickness, ADCmin and ADCentire were 0.693, 0.543 and 0.600 respectively, and AUCs for % deltathickness, % DeltaADCmin and % DeltaADCentire were 0.532, 0.729 and 0.779 respectively, in the differentiation of prognosis. Using % DeltaADC>=15% to predict long-term survival, the positive predictive value (PPV) for % DeltaADCmin was 81.8% and % DeltaADCentire was 83.3%. Using % DeltaADC <= 10% to predict poor prognosis, the PPV for % DeltaADCmin was 63.6% and % DeltaADCentire was 70.0%. CONCLUSIONS: The change of ADC after NACT of gastric carcinoma is correlated with long-term prognosis. The significantly increased ADC is prone to signify long-term survival. ADCentire is better than ADCmin in the prognosis prediction. PMID- 25809324 TI - [Value of the preoperative TNM staging and the longest tumor diameter measurement of gastric cancer evaluated by MSCT]. AB - OBJECTIVE: To explore the value of MSCT in the preoperative TNM staging and the longest tumor diameter measurement (RESIST standard) of gastric cancer. METHODS: Clinical data of 153 consecutive patients with biopsy-confirmed gastric carcinoma who were preoperatively evaluated with enhanced MSCT scanning in our hospital from January 2012 to March 2013 were retrospectively analyzed. Consistency comparison was performed between preoperative TNM staging and the longest tumor diameter measurement and histopathological findings. RESULTS: T-staging consistency of Kappa value was 0.566, and accuracy was 71.2%. N-staging consistency of Kappa value was 0.284, and accuracy was 47.7%. The Kappa value of M-staging consistency was 0.893, and accuracy was 98.7%. The overall accuracy of TNM staging consistency was 66.7% (102/153) with a Kappa value of 0.573. Effective measurement of the longest cancer diameter was carried out in 53 patients. There was no significant difference between preoperative longest tumor diameter acquired by MSCT and postoperative tumor measurement [(68.8 +/- 40.6) mm vs. (64.2 +/- 36.2) mm, P=0.969]. CONCLUSION: MSCT is accurate in preoperative TNM staging and longest tumor diameter measurement of gastric cancer compared with postoperative pathological examination, and can provide reliable evidence for preoperative staging and neoadjuvant therapy evaluation of gastric cancer, but it is unfavorable to evaluate the lymph node metastasis. PMID- 25809325 TI - [Correlation of 18F-FDG PET-CT maximum standard uptake value and T/N ratio with the prognosis of postoperative colorectal cancer]. AB - OBJECTIVE: To assess the correlation of primary colorectal cancer (CRC) lesions' maximum standardized uptake value (SUVmax) and tumor to normal tissue SUVmax ratio (T/N ratio) detected by 18F-deoxyglucose positron emission computed tomography (18F-FDG PET-CT) imaging with the postoperative prognosis. METHODS: Clinicopathological data of 92 CRC patients who underwent curative resection after the PET-CT examination and received 18F-FDG PET-CT examination from January 2009 to December 2013 in the First Affiliated Hospital of Sun Yat-sen University were reviewed retrospectively. The correlation of SUVmax and T/N ratio in primary lesions with clinicopathological factors was analyzed. The optimal cutoff point of disease-free survival time of SUVmax, T/N ratio and the maximum tumor diameter were investigated by using ROC curve analysis. Association of clinicopathological factors and prognosis was examined and the Cox proportional hazard regression model was used in the multivariate analysis. RESULTS: Primary SUVmax was associated with tumor TNM staging, location, differentiation degree and the maximum tumor diameter, while T/N ratio was only associated with pathological type (all P<0.05). The optimal cutoff point of disease-free survival time of SUVmax, T/N ratio and the maximum tumor diameter were 12.2 (sensitivity 67.6%, specificity 63.6% ), 6.9 (sensitivity 51.4%, specificity 74.5%) and 4.3 cm (sensitivity 56.8%, specificity 80.0%) respectively. Univariate analysis showed that age, TNM staging, tumor location, differentiation degree, the maximum tumor diameter, T/N ratio and CA125 level were significant predictors of survival. Multivariate analysis demonstrated that TNM staging (P=0.000, OR=3.98, 95% CI:2.12-7.45), tumor location (P=0.009, OR=0.43, 95% CI:0.23-0.81), tumor differentiation degree (P=0.001, OR=7.52, 95% CI:2.12-25.9) and T/N ratio (P=0.008, OR=2.92, 95% CI:1.33-6.411) were independent predictors of survival. However, SUVmax was not independent predictor of disease-free survival. CONCLUSION: For postoperative prognosis of colorectal cancer patients, T/N ratio is more valuable than the of primary tumor SUVmax. PMID- 25809326 TI - [Diagnostic value of 18F-fluorodexyglucose positron emission tomography combined with contrast enhanced computed tomography in colorectal cancer liver metastasis]. AB - OBJECTIVE: To explore the preoperative diagnostic value of 18F-fluorodexyglucose positron emission tomography combined with contrast enhanced computed tomography (18F-FDG PET-ceCT) in patients with colorectal cancer liver metastasis. METHODS: Clinical and imaging data of 58 patients with suspicious colorectal cancer liver metastasis between April 2010 and March 2013 were retrospectively evaluated. All the patients underwent 18F-FDG PET-ceCT. On the basis of definitive diagnosis, the sensitivity, specificity, accuracy and consistency of routine PET-CT, ceCT and 18F-FDG PET-ceCT were calculated. RESULTS: A total of 147 suspicious lesions of colorectal cancer liver metastasis were found in 58 patients. Finally, 125 lesions were confinmed as malignant, of which 58 (46.4%) lesions were less than 1.0 cm. The other 22 lesions were confinmed as benign, of which 17 (77.3%) lesions were less than 1.0 cm. The diagnostic accuracy of routine PET-CT, ceCT and 18F-FDG PET-ceCT in colorectal cancer liver metastasis for the lesions more than 1.0 cm was 100%, 93.1%, 100% respectively, and the consistency with final diagnosis was perfect, moderate, and perfect respectively (Kappa value 01.00, 0.408, 1.00). For the lesions less than 1.0 cm, the accuracy was 42.7%, 78.7%, 94.7% respectively, and the consistency with definitive diagnosis was insignificance, fair, and almost perfect respectively (Kappa value -0.005, 0.305, 0.848). The area under curve(AUC) was 0.525 (95% CI: 0.407-0.462) for routine PET CT, 0.651(95% CI:0.532-0.757) for ceCT, and 0.924 (95% CI:0.839-0.972) for 18F FDG PET-ceCT respectively. The AUC of 18F-FDG PET-ceCT was significantly larger than that of routine PET-CT (Z=5.559, P<0.05) or ceCT (Z=4.183, P<0.05). CONCLUSION: (18)F-FDG PET-ceCT can improve the diagnostic accuracy for smaller lesions of colorectal cancer liver metastasis. PMID- 25809327 TI - [Application value of CT spectrum curve and iodine measurement in the early diagnosis of gastric cancer]. AB - OBJECTIVE: To explore the value of dual-source CT spectrum curve and iodine measurement in the early diagnosis of gastric cancer. METHODS: Imaging materials of 21 cases with early gastric cancer confirmed by gastroscope and pathology, and 38 cases with normal stomach in our department from November 2011 to June 2013 were retrospectively analyzed. All the cases underwent dual-energy scanning with SOMATOM Definition Flash CT. The iodine concentration of the lesion in arterial phase and venous phase was measured respectively. The iodine concentration of small curvature side and aorta of same level was also measured for the cases with normal stomach. Normalized iodine concentration (NIC) difference was studied between early gastric cancer lesions and normal gastric wall. Spectrum curve characteristics of gastric cancer lesions and normal gastric lesser curvature were analyzed. RESULTS: There were significant differences in NIC between early gastric cancer lesions and normal gastric wall (arterial phase, 0.21 vs. 0.09, P=0.000; venous phase, 0.72 vs. 0.26, P=0.000). Spectrum curves of normal gastric wall and early gastric cancer, both in arterial and venous phase, showed descending tendency. Spectrum curve of early gastric cancer located above that of normal gastric wall, and was more steep. Difference between these two curves became greater during 40 to 70 keV, and became smaller during 80 to 140 keV. CONCLUSION: NIC and spectrum curve tendency are helpful to identify the early gastric cancer and the normal gastric wall through the dual-energy model scan. PMID- 25809328 TI - [Demonstration ability of 64-multislice spiral computed tomography with three dimensional reconstruction for perigastric artery and its clinical significance]. AB - OBJECTIVE: To investigate the demonstration ability of 64-multislice spiral computed tomography angiography (MSCTA) with 3-D reconstruction image fusion for the anatomy of perigastric artery. METHODS: From November 2012 to December 2013 in the Nanfang Hospital, a total of 469 patients underwent abdominal 64-MSCTA. 3 D reconstruction technique computed tomography angiography (CTA) was used to reconstruct perigastric arteries. The origin and the course of perigastric arteries were observed. Branching pattern of the hepatic artery was classified by Michels standard, and branching pattern of the right gastric artery was classified into three types according to RGA ramification patterns. RESULTS: Five patients failed to demonstrate hepatic artery because of abnormal development. 3 D reconstruction clearly showed the perigastric arteries in other 464 patients (98.9%). The most common branching pattern of hepatic artery was Michels type I in 346 patients (74.6%). Hepatic artery variation was found in 118 patients (25.4%), including 9 patients of non-Micles type (7.6%). 3-D reconstruction clearly showed the branching pattern of the right gastric artery in 337 patients (72.6%), including 54(16.0%) of proximal pattern, 221 of distal pattern(65.6%), 56 of caudal pattern (16.6%), and 6 of other pattern (3 from splenic artery, 3 from superior mesenteric artery). CONCLUSION: 64-MSCTA with 3-D reconstruction can clearly reveal individual perigastric arteries, and can provide guidance for laparoscopic gastrectomy. PMID- 25809329 TI - [Value of endorectal ultasound in predicting the circumferential resection margin and maximum tumor thickness of T3 rectal cancer]. AB - OBJECTIVE: To evaluate the accuracy of endorectal ultrasound (ERUS) in predicting the circumferential resection margin (CRM) and maximum tumor thickness (MTT) of in T3 rectal cancer. METHODS: Clinicl data of 53 patients with pT3 rectal cancer admitted to the Department of General Surgery in the Peking Union Medical College Hospital from June 2011 to January 2014 were retrospectively analyzed. CRM and MTT measured by ERUS were compared with corresponding pathologic measurements to assess the accuracy of ERUS diagnosis. RESULTS: ERUS correctly predicted CRM status in 52 patients (98.1%, 52/53), whose sensitivity was 100%, specificity was 97.8%, positive predictive value was 85.7%, and negative predictive value was 100%. ERUS correctly predicted MTT status in 51 patients (96.2%, 51/53), whose sensitivity was 100%, specificity was 95.5%, positive predictive value was 66.6%, and negative predictive value was 100%. In the Bland and Altman plot, the agreement between ERUS and pathology was good. CONCLUSION: Endorectal ultrasonography can accurately diagnose CRM and MTT, which can satisfy the clinical need for preoperative staging of rectal cancer. PMID- 25809330 TI - [Value of diffusion-weighted MRI in the diagnosis of T staging for rectal cancer]. AB - OBJECTIVE: To investigate the value of diffusion-weighted imaging (DWI) in the diagnosis of T staging for rectal cancer. METHODS: Clinicopathologic data and MR images of 46 patients with rectal cancer in our hospital from July 2013 to September 2014 were retrospectively analyzed. The diagnostic sensitivity, specificity and accuracy of T2WI were compared with those of T2WI plus DWI in T staging for rectal cancer. The relationship of mean apparent diffusion coefficient (ADC) value with different T stages of rectal cancer was analyzed. RESULTS: There were no significant differences in the diagnostic sensitivity, specificity and accuracy between T2WI and T2WI plus DWI (all P>0.05). The mean ADC value of DWI performed in pathologic T2, T3a, T3b, T3c and T4 stage was (1.110 +/- 0.117) * 10-3 mm2/s, (1.035 +/- 0.121) * 10-3 mm2/s, (0.948 +/- 0.109) * 10-3 mm2/s, (0.932 +/- 0.122) * 10-3 mm2/s and (0.843 +/- 0.050) * 10-3 mm2/s, respectively (F=6.972, P=0.000). CONCLUSION: DWI can serve as a complement for T2WI in the diagnosis of T stage patients with rectal cancer, and its ADC value presents a downward trend with the advance of T stage. PMID- 25809331 TI - [Value of computed tomography colonography with low radiation dose combined with enhancement scanning in the diagnosis of colorectal tumor]. AB - OBJECTIVE: To explore the value of computed tomography colonography with low radiation dose combined with the enhanced scanning in the diagnosis of colorectal carcinoma. METHODS: A total of 120 patients with clinical suspected colorectal carcinoma undergoing CT colonography and enhanced scanning were randomly divided into routine dose group and low dose group. Conventional colonoscopy and/or surgical pathology were used as the gold standard. Sensitivity, specificity and Youden's index of colorectal cancer TNM staging accuracy were calculated in two groups. The radiation dose of two groups was compared. RESULTS: For conventional dose and low dose group, in the diagnosis of colorectal cancer (including cancer and adenoma), the sensitivity was 100% (45/45 and 44/44), specificity was 93.3%(14/15) and 87.5%(14/16), the Youden's index was 0.93 and 0.88. There were no significant differences between two groups in T, N and M staging accuracy preoperatively (P>0.05). The effective radiation dose of low dose group was significantly lower than that of conventional dose group [(15.9 +/- 4.3) mSv vs. (21.4 +/- 5.5) mSv, P<0.01]. CONCLUSION: Low dose CTC combined with enhanced scanning not only reduces the radiation dose of patients, but can possesses similar value of conventional dose CTC in the early diagnosis and preoperative pathological staging of colorectal cancer. PMID- 25809332 TI - [Efficacy of pectin in the treatment of diarrhea predominant irritable bowel syndrome]. AB - OBJECTIVE: To evaluate the efficacy of pectin, a kind of soluble dietary fiber, in diarrhea predominant irritable bowel syndrome(IBS-D). METHODS: A total of 87 patients with IBS-D were selected in the Jinling Hospital between July 2011 and December 2013. Using a randomized, controlled trial, the efficacy of pectin for IBS-D was prospectively evaluated. Subjects were randomly assigned to receive 24 g pectin powder/d (n=46) or a placebo (n=41). Before and after 6 weeks of treatment, colonic microflora was examined by real-time PCR and compared between groups. Changes in stool frequency and form (Bristol stool scale), composite score of symptoms (Likert scale) and QOL scores (IBS-QOL questionnaire) were also monitored. Peripheral blood sample from patients with IBS-D was obtained to estimate the cytokines level, which was compared with that obtained from a group of age- and sex-matched healthy volunteers (n=20). RESULTS: Those patients randomized to pectin experienced a greater reduction in composite symptom scores and Bristol stool scale scores, as well as significant improvement in QOL scores (P<0.05). The pectin acted as prebiotics and significantly enhanced faecal bifidobacteria and decreased total Clostridium sp (P<0.05). At baseline, patients with IBS-D demonstrated an abnormal IL-10/IL-12 ratio, which was normalized by pectin feeding alone (P<0.01). Placebo did not exert these effects on the aforementioned parameters after treatment. No significant adverse effects were reported during the study. CONCLUSIONS: Pectin acts as a prebiotic in specifically stimulating gut bifidobacteria in IBS-D patients and is effective in alleviating clinical symptoms, balancing colonic microflora and relieving systemic inflammation. In view of its ability to re-establish a healthy gut ecosystem, pectin has the potential of being a therapeutic agent in IBS-D. PMID- 25809333 TI - [Expression of vasohibin-1 in colorectal cancer tissue and its correlation with vascular endothelial growth factor A and microvessei density]. AB - OBJECTIVE: To explore the clinical significance of vasohibin-1 expression in colorectal cancer tissues and its correlation with vascular endothelial growth factor A(VEGF-A) and microvessel density (MVD). METHODS: Tumor tissues and paired adjacent normal tissue (distance to cancer >5 cm) from 60 colorectal cancer patients undergoing resection in the Second Hospital of Tianjin Medical University from June 2013 to November 2013 were included in this study. The protein expressions of vasohibin-1, VEGF-A and MVD were detected by immunohistochemical staining. The mRNA expressions of vasohibin-1 and VEGF-A were detected by RT-PCR. The protein expressions of vasohibin-1 and VEGF-A were observed by Western blot. Correlation among parameters was examined. RESULTS: Vasohibin-1 expression was mainly localized in the cytoplasm of tumor cells and endothelial cells. VEGF-A expression was mainly localized in the cytoplasm and membrane of tumor cells. The expressions of vasohibin-1, VEGF-A and MVD in colorectal tumor tissues were significantly higher than those in corresponding adjacent tissues [43.3% (26/60) vs. 16.7% (10/60), 51.7%(31/60) vs. 18.3% (11/60), (39.67 +/- 16.80)/mm2 vs. (17.85 +/- 6.43)/mm2, all P<0.05]. Higher vasohibin-1 expression was significantly associated with TNM stage and metastasis (P<0.05). Vasohibin-1 expression was positively correlated with VEGF-A and MVD (r=0.378, 0.628, all P<0.05). Vasohibin-1 and VEGF-A mRNA expressions and protein expressions in colorectal cancer tissues were significantly higher than those in corresponding adjacent tissues (all P<0.05). CONCLUSION: Vasohibin-1 expression in colorectal cancer tissues is significantly higher as compared to corresponding adjacent tissues. Vasohibin-1 expression is positively correlated to VEGF-A and MVD, and associated to TNM stage and metastasis. Positive vasohibin-1 expression indicates a poor prognosis of patients with colorectal cancer. PMID- 25809334 TI - [Expression of prostaglandin transporter in colorectal cancer tissues and its relationship with clinicopathological features]. AB - OBJECTIVE: To investigate the expression of prostaglandin transporter (PGT) in colorectal cancer (CRC) tissues and its relationship with clinicopathological features. METHODS: The mRNA and protein levels of PGT were determined by real time PCR, Western blot and immunohistochemical methods in cancer tissues and adjacent normal tissue from 80 patients with colorectal cancer and their relationship with clinicopathological features was analyzed. RESULTS: Compared with the adjacent normal tissue of colorectal cancer, the PGT mRNA relative expression (0.57 +/- 0.33 vs. 2.33 +/- 1.20) and the PGT protein expression in cancer tissues decreased significantly [PGT/GAPDH 0.45 +/- 0.16 vs. 0.78 +/- 0.23, integral A 718.7 +/- 359.4 vs. 10412.0 +/- 6423.3, average A 0.03 +/- 0.01 vs. 0.12 +/- 0.09, all P<0.01]. Lower mRNA and protein expressions of PGT in colorectal cancer were associated with depth of invasion T3 to T4 and TNM stage III( to IIII( (P<0.01), while not associated with gender, age, tumor location and differentiation degree (all P>0.05). CONCLUSION: Expression levels of PGT mRNA and protein in colorectal cancer tissue are significantly down-regulation. PGT expression is associated with invasion depth and late stages. PMID- 25809335 TI - [Current status of the study on hereditary diffuse gastric cancer]. AB - Hereditary diffuse gastric cancer was discovered 25 years ago. During the last 25 years, the diagnostic standards and molecular mechanism of this type of hereditary gastric cancer have been established. With a better understanding of this disease, germline CDH1 mutation has been linked to hereditary diffuse gastric cancer with autosomal-dominant inheritance pattern. Therefore, strategies on genetic screening and follow-up have been evolved for CDH1 mutation carriers. In China, the studies on hereditary diffuse gastric cancer are sparse. We hope this article will bring more awareness and attention of this peculiar disease to Chinese physicians. PMID- 25809336 TI - [Radioimmuno-tracing of metastatic lymph node for gastric cancer: status quo and progress]. AB - Lymph node metastasis is one of the factors associated with the prognosis of gastric cancer patients. While precise evaluation of nodal status can promote the personalized surgery and improve prognosis. Although with many unsolved problems and limitations, radioimmune technique can be used to trace gastric cancer and metastatic lymph nodes. With the constant development of monoclonal antibody, genetic engineering antibody, nuclide molecular functional imaging, the radioimmune technique may allow tumor targeting, preoperative imaging, and intraoperative tracing. Therefore, more accurate tumor staging and optimal therapeutic regimen may be possible. This review mainly focuses on the utility of radioimmuno-tracing technique in metastatic lymph node for gastric cancer. PMID- 25809338 TI - Image-guided endoscopic surgery: results of accuracy and performance in a multicenter clinical study using an electromagnetic tracking system. 1997. PMID- 25809337 TI - Defective macrophage handling of Escherichia coli in Crohn's disease. AB - BACKGROUND AND AIM: Escherichia coli can be isolated from lamina propria macrophages in Crohn's disease (CD), and their intramacrophage persistence may provide a stimulus for inflammation. To further determine the contributions of macrophage dysfunction and E. coli pathogenicity to this, we aimed to compare in vitro functioning of macrophages from patients with CD and healthy controls (HC) in response to infection with CD-derived adherent-invasive E. coli (AIEC) and less pathogenic E. coli strains. METHODS: Monocyte-derived macrophages were cultured from patients with CD and HC. Intramacrophage survival of E. coli strains (CD-derived adherent-invasive [AI] and non-AI strains and laboratory strain K-12) was compared. Macrophage cytokine release (tumor necrosis factor alpha [TNFalpha], interleukin [IL]-23, IL-8 and IL-10) and monocyte phagoctyosis and respiratory burst function were measured after E. coli infection. For CD patients, laboratory data were correlated with clinical phenotype, use of immunomodulation, and CD risk alleles (NOD2, IL-23R, ATG16L1 and IRGM). RESULTS: Attenuated TNFalpha and IL-23 release from CD macrophages was found after infection with all E. coli strains. There was prolonged survival of CD-derived AIEC, CD-derived non-AIEC and E. coli K-12 in macrophages from CD patients compared to within those from HC. No abnormality of monocyte phagocytosis or respiratory burst function was detected in CD. Macrophage dysfunction in CD was not influenced by phenotype, use of immunomodulation or genotype. CONCLUSIONS: CD macrophage responses to infection with E. coli are deficient, regardless of clinical phenotype, CD genotype or E. coli pathogenicity. This suggests host immunodeficiency is an important contributor to intramacrophage E. coli persistence in CD. PMID- 25809339 TI - Ball flight kinematics, release variability and in-season performance in elite baseball pitching. AB - The purpose of this study was to quantify ball flight kinematics (ball speed, spin rate, spin axis orientation, seam orientation) and release location variability in the four most common pitch types in baseball and relate them to in season pitching performance. Nine NCAA Division I pitchers threw four pitching variations (fastball, changeup, curveball, and slider) while a radar gun measured ball speed and a 600-Hz video camera recorded the ball trajectory. Marks on the ball were digitized to measure ball flight kinematics and release location. Ball speed was highest in the fastball, though spin rate was similar in the fastball and breaking pitches. Two distinct spin axis orientations were noted: one characterizing the fastball and changeup, and another, the curveball and slider. The horizontal release location was significantly more variable than the vertical release location. In-season pitching success was not correlated to any of the measured variables. These findings are instructive for inferring appropriate hand mechanics and spin types in each of the four pitches. Coaches should also be aware that ball flight kinematics might not directly relate to pitching success at the collegiate level. Therefore, talent identification and pitching evaluations should encompass other (e.g., cognitive, psychological, and physiological) factors. PMID- 25809340 TI - VTE primary prevention, including hospitalised medical and orthopaedic surgical patients. AB - Primary prevention is the key to managing a significant proportion of the burden of venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) or pulmonary embolism (PE). This is because VTE may lead to sudden death or are often misdiagnosed and therefore treatment is not feasible. Primary prevention usually commences in hospital as VTE following hospitalisation adds to the significant disease burden worldwide. Numerous medical, surgical and other risk factors have been recognised and studied as indications for prophylaxis. The risk of VTE continues following admission to hospital with a medical or surgical condition, usually long after discharge and therefore prolonged primary prophylaxis is often recommended. Clinical and observational studies in surgical patients show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. For the specific groups of patients at higher risk of developing VTE primary prevention, either pharmaceutical or mechanical, is recommended. The aim of this review is to describe the population at risk, the main related risk factors and the approach to thromboprophylaxis in different populations. PMID- 25809341 TI - Nocturnal blood pressure dipping in acute ischemic stroke. AB - OBJECTIVES: We aim to assess the impact of early nocturnal blood pressure (BP) variation in the functional outcome of patients after an acute ischemic stroke. MATERIALS AND METHODS: We included consecutive stroke patients treated with intravenous thrombolysis (IVrtPA) in a tertiary stroke center. BP measurements were performed at regular intervals throughout day and night during the first 48 h after stroke onset, and subjects were divided into four dipping categories (extreme dippers, dippers, non-dippers, and reverse dippers). Recanalization was assessed by transcranial color-coded Doppler and/or angiographic CT. Hemorrhagic transformation was evaluated at 24 h follow-up CT scan. Functional outcome was evaluated at 3 months after stroke using the modified Rankin Scale. RESULTS: A total of 304 patients were included, mean age 72.80 +/- 11.10 years. After 24 h of systolic BP monitoring, 30.59% were classified as reverse dippers, 39.14% as non-dippers, 19.10% as dippers, and 11.18% as extreme dippers. Multivariate analysis did not show an independent association of any dipping class with 3 month functional outcome. Hemorrhagic transformation was not uniform between dipping classes: 25.81% for reverse dippers, 14.29% for non-dippers, 15.52% for dippers, and 5.88% for extreme dippers, P = 0.033. CONCLUSIONS: Nocturnal BP dipping pattern is not associated with functional outcome at 3 months in acute stroke patients treated with IVrtPA. Hemorrhagic transformation was more frequent in reverse dippers. PMID- 25809343 TI - Labial frenum tear from instrumental delivery. PMID- 25809342 TI - Cardiovascular response to exercise training in the systemic right ventricle of adults with transposition of the great arteries. AB - KEY POINTS: Patients with transposition of the great arteries (TGA) and systemic right ventricles have premature congestive heart failure; there is also a growing concern that athletes who perform extraordinary endurance exercise may injure the right ventricle. Therefore we felt it essential to determine whether exercise training might injure a systemic right ventricle which is loaded with every heartbeat. Previous studies have shown that short term exercise training is feasible in TGA patients, but its effect on ventricular function is unclear. We demonstrate that systemic right ventricular function is preserved (and may be improved) in TGA patients with exercise training programmes that are typical of recreational and sports participation, with no evidence of injury on biomarker assessment. Stroke volume reserve during exercise correlates with exercise training response in our TGA patients, identifying this as a marker of a systemic right ventricle (SRV) that may most tolerate (and possibly even be improved by) exercise training. ABSTRACT: We aimed to assess the haemodynamic effects of exercise training in transposition of the great arteries (TGA) patients with systemic right ventricles (SRVs). TGA patients have limited exercise tolerance and early mortality due to systemic (right) ventricular failure. Whether exercise training enhances or injures the SRV is unclear. Fourteen asymptomatic patients (34 +/- 10 years) with TGA and SRV were enrolled in a 12 week exercise training programme (moderate and high-intensity workouts). Controls were matched on age, gender, BMI and physical activity. Exercise testing pre- and post- training included: (a) submaximal and peak; (b) prolonged (60 min) submaximal endurance and (c) high-intensity intervals. Oxygen uptake (VO2; Douglas bag technique), cardiac output (Qc, foreign-gas rebreathing), ventricular function (echocardiography and cardiac MRI) and serum biomarkers were assessed. TGA patients had lower peak VO2, Qc, and stroke volume (SV), a blunted Qc/VO2 slope, and diminished SV response to exercise (SV increase from rest: TGA = 15.2%, controls = 68.9%, P < 0.001) compared with controls. After training, TGA patients increased peak VO2 by 6 +/- 8.5%, similar to controls (interaction P = 0.24). The magnitude of SV reserve on initial testing correlated with Qc training response (r = 0.58, P = 0.047), though overall, no change in peak Qc was observed. High sensitivity troponin T (hs-TnT) and N-terminal prohormone of brain naturetic peptide (NT pro-BNP) were low and did not change with acute exercise or after training. Our data show that TGA patients with SRVs in this study safely participated in exercise training and improved peak VO2. Neither prolonged submaximal exercise, nor high-intensity intervals, nor short-term exercise training seem to injure the systemic right ventricle. PMID- 25809344 TI - Assessing the incidence of anti-NMDAR encephalitis. PMID- 25809345 TI - Probiotic supplementation in children with autism spectrum disorder. PMID- 25809346 TI - The value of microarray-based comparative genomic hybridisation (aCGH) testing in the paediatric clinic. PMID- 25809347 TI - Preventing peanut allergy. PMID- 25809348 TI - Orange-brown chromonychia in Kawasaki disease. PMID- 25809349 TI - The impact of stopping high-energy oral nutritional supplements on eating behaviour and weight gain. AB - BACKGROUND AND AIMS: Many children referred to a tertiary feeding clinic are already taking high-energy oral nutritional supplements (HEOS), but these often seem not clinically useful. We undertook a retrospective review of all children on HEOS at the time of referral to the clinic in order to describe their subsequent progress in terms of growth and feeding behaviour. RESULTS: A total of 48 children were on HEOS at referral and withdrawal of HEOS was attempted in 38 children, aged median 3.0 years (range 0.7-10 years) who were taking volumes equivalent to 2/3 of total daily energy requirements. The children tended to be very short and slim (median height SD score (SDS) -2.0 (range -5.7 to 1.9); body mass index -2.0 (-5.1 to 1.9)). Half had normal neurodevelopment (ND) but 4 (11%) had learning disability and 4 (11%) severe ND problems. By last follow-up after 0.86 (0-2.9) years, 30 (79%) had stopped all feeds. Those who stopped had a mean (SD) change in weight of 0.08 (0.6) SDS (range -0.88 to +1.59). Five children (17%) showed significant catch-up weight gain after stopping feeds, of whom three had been referred for weight faltering and possible tube feeding. Improvement in feeding behaviour was documented in 76% (29). CONCLUSIONS: The use of HEOS in children suppresses appetite for solid food due to energy compensation. In some cases, HEOS may perpetuate or even cause weight faltering. It should not be assumed that failure to respond to HEOS is an indication for tube feeding. PMID- 25809350 TI - Incorporation of a Metal Oxide Interlayer using a Virus-Templated Assembly for Synthesis of Graphene-Electrode-Based Organic Photovoltaics. AB - Transition metal oxide (TMO) thin films have been exploited as interlayers for charge extraction between electrodes and active layers in organic photovoltaic (OPV) devices. Additionally, graphene-electrode-based OPVs have received considerable attention as a means to enhance device stability. However, the film deposition process of a TMO thin-film layer onto the graphene electrode is highly restricted owing to the hydrophobic nature of the graphene surface; thus, the preparation of the device should rely on a vacuum process that is incompatible with solution processing. In this study, we present a novel means for creating a thin tungsten oxide (WO3 ) interlayer on a graphene electrode by employing an engineered biotemplate of M13 viruses, whereby nondestructive functionalization of the graphene and uniform synthesis of a WO3 thin interlayer are concurrently achieved. As a result, the incorporated virus-templated WO3 interlayer exhibited solar-conversion efficiency that was 20 % higher than that of conventional OPVs based on the use of a (3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) interlayer. Notably, bilayer-structured OPVs with synergistically integrated WO3 /PEDOT:PSS achieved >60 % enhancement in device performance. PMID- 25809351 TI - A couple-based complex intervention for Chinese spousal caregivers and their partners with advanced cancer: an intervention study. AB - BACKGROUND: Guided by the Preliminary Live with Love Conceptual Framework (P LLCF) for Cancer Couple Dyads, a Caring for Couples Coping with Cancer (4Cs) program was developed to support couples coping with cancer as a unit. This study examined the acceptability, feasibility, and the preliminary effect of the 4Cs program. METHODS: A pre- and post-intervention study design with no control group was conducted among Chinese cancer patients and their spousal caregivers. Among the 135 couples approached, a total of 117 dyads were successfully recruited at baseline, with 92 dyads successfully followed-up at 6 weeks. Outcome measures, including dyadic mediators (self-efficacy), dyadic appraisal (Cancer Related Communication Problem, CRCP), dyadic coping (Dyadic Coping Inventory, DCI), and dyadic outcomes (physical and mental health, negative and positive emotions, and marital satisfaction), were assessed at T0 (pre-intervention) and T1 (post intervention). Repeated measures analysis of variance was applied in testing the outcomes of the 4Cs program. RESULTS: The recruitment and retention rates were 86.7% and 78.6%, respectively. Significant improvements were seen in the couples' scores on overall (total) self-efficacy (P < 0.01), CRCP (P < 0.05), DCI (P < 0.05), the physical component summary (PCS) of SF-12 (P < 0.05), anxiety (P < 0.01), and benefit findings (P < 0.05) from T0 to T1. Spousal caregivers scored significantly higher on self-efficacy (P < 0.05), the PCS (P < 0.01), and anxiety (P < 0.05) than the patients. The overall effect sizes calculated in this study ranged from medium to small. CONCLUSIONS: This study provides evidence suggesting that the 4Cs program is acceptable, feasible, and improved outcomes in supporting Chinese couples coping with cancer as dyads. PMID- 25809352 TI - Initial clinical experience with the Zenith alpha stent-graft. AB - PURPOSE: To assess safety and short-term efficacy of endovascular repair of the thoracic aorta with the new Zenith Alpha stent-graft. METHODS: Between August 2010 and May 2014, 33 patients (21 men; mean age 73.2+/-9.0 years) were treated Zenith Alpha stent-graft (group ZA). Outcomes of this group were compared with those of 34 patients (25 men; mean age 70.3+/-8.5 years) treated contemporaneously with the Zenith TX-2 for the same pathologies (group TX). The primary outcome measure was technical success. Data on iliac tortuosity, minimum access vessel diameter, and previous unsuccessful treatment with other endografts was also recorded. RESULTS: Technical success was 93.9% in group ZA and 91.2% in group TX (p=0.67). There was no case of surgical death or conversion to open repair in either group. Two (6%) type I endoleaks occurred in group ZA and 3 (9%) in group TX (p=0.67). Three patients died within 30 days in group ZA vs. none in group TX (p=0.07). Mean minimum access vessel diameter was significantly smaller (5.07 vs. 6.65 mm, p=0.002) and iliac tortuosity indices significantly higher in group ZA (1.34 vs. 1.25, p=0.02). Access vessel complications occurred in 1 (3%) patient in group ZA and 4 (12%) patients in group TX (p=0.17). Significantly more patients in group ZA (6, 18%) were unsuccessfully treated previously with other endografts vs. none in group TX (p=0.01). CONCLUSION: The new Zenith Alpha appears to be equally as safe and efficacious as the Zenith TX-2 while being used in patients with demanding access vessel morphology. PMID- 25809353 TI - Commentary: new low-profile zenith alpha stent-graft for the treatment of thoracic aortic disease: a real breakthrough? PMID- 25809354 TI - Midterm outcome of EndoAnchors for the prevention of endoleak and stent-graft migration in patients with challenging proximal aortic neck anatomy. AB - PURPOSE: To explore the use of EndoAnchors as an adjunct to endovascular abdominal aortic aneurysm repair for prevention of proximal neck complications in patients with challenging neck anatomy. METHODS: Over a 28-month period, 208 patients (159 men; mean age 72+/-8 years) were enrolled in the ANCHOR prospective, multicenter registry (ClinicalTrials.gov; identifier NCT01534819) for prophylaxis against proximal neck complications. Patients were eligible when, in the opinion of the investigators, they were at increased risk for type Ia endoleak or migration owing to a hostile neck (length <10 mm, diameter >28 mm, angulation >60 degrees , mural thrombus or calcium >2 mm in thickness or >180 degrees in circumference, or conical shape). Overall, 123/157 (78.3%) patients met the criteria for a hostile neck according to core laboratory assessment of 157 adequate preoperative computed tomographic (CT) images. RESULTS: Implantation of EndoAnchors was technically successful in 204/208 (98.1%) patients. The frequency of fracture was 0.3% (3/1118); there were no clinical sequelae associated with the fractures. Over the mean 14-month follow-up, 95.2% of patients were alive, and no deaths were attributable to EndoAnchors. There were no ruptures, migrations, or open surgical conversions. Aneurysm-related reinterventions were performed in 8 (3.8%) patients. Among 130 patients with postprocedure contrast CT studies, core laboratory analysis identified 2 (1.5%) patients with type Ia endoleaks. Aneurysm sac diameter decreased >5 mm in 42.9% of patients with CT scans at or beyond 1 year; 1.6% of patients developed sac enlargement >5 mm. CONCLUSION: Prophylactic EndoAnchor use for challenging aortic neck anatomy was associated with satisfactory midterm results. PMID- 25809355 TI - Commentary: are EndoAnchors up to the challenge of a hostile proximal neck? PMID- 25809356 TI - Active proximal sealing in the endovascular repair of abdominal aortic aneurysms: early results with a new stent-graft. AB - PURPOSE: To investigate the performance of a new device that uses the STRATA polytetrafluoroethylene graft material and a mechanism that provides active proximal sealing in order to prevent type Ia endoleak during endovascular aneurysm repair (EVAR). METHODS: Between April 2013 and July 2014, 21 consecutive patients (all men; median age 71 years, range 60-84 years) with abdominal aortic aneurysm (median diameter 5.9 cm, range 4.9-7.8 cm) and suitable anatomy were offered elective EVAR using the AFX endograft. These patients had an irregular, conical, tapered, or bulging proximal neck, for which this specific device was considered appropriate. Aneurysm exclusion and incidence of type Ia endoleak were the primary outcomes; secondary outcomes included mortality, morbidity, migration, and other graft-related complications. RESULTS: Primary technical success was 90%; 2 intraoperative type Ia endoleaks due to low endograft deployment were treated with additional proximal cuffs. During a median follow-up of 10 months (range 2-15 months), no type I endoleak was observed. One type II endoleak was encountered, with no associated sac enlargement. There was no stent graft migration or any other device-related complication. One patient had a nonfatal myocardial infarction and another developed renal failure requiring transient dialysis. No deaths occurred. CONCLUSION: In this early experience, this newly available device appears to be safe and efficient in providing seal along irregularly shaped necks over the short term. PMID- 25809357 TI - Commentary: new-generation devices and adjunctive procedures are the key elements to expanding the indications for endovascular aneurysm repair. PMID- 25809358 TI - Sonographic appearance following endovascular aneurysm repair using the Nellix endovascular sealing system. PMID- 25809359 TI - Feasibility and safety of renal and visceral target vessel cannulation using robotically steerable catheters during complex endovascular aortic procedures. AB - PURPOSE: To evaluate the safety and success of target vessel cannulation in the visceral aortic segment using the Magellan robotic catheter system (RCS) during complex endovascular aortic procedures. METHODS: Robotic navigation was attempted for access to 37 target vessels in 15 patients (14 men; mean age 75+/-10 years) during 16 fenestrated and/or branched stent-grafting procedures and 1 endovascular repair requiring the chimney technique. For each target vessel, robotic navigation was attempted for a maximum of 15 minutes; if cannulation was unsuccessful in that time, manual catheters were employed. Safety was evaluated by recording intraoperative adverse events, intraoperative complications related to robotic navigation, and postoperative complications. Technical success of robotic cannulation, wire cannulation times, and times for inserting the leader over the wire in the target vessels were recorded to assess RCS performance. RESULTS: Successful robotic cannulation was achieved for 30 (81%) of the 37 target vessels, with a median wire cannulation time of 263 seconds (range 40-780) and a median 15 seconds (range 5-450) for inserting the leader over the wire. No intraoperative complications related to robotic navigation were observed. Seven of 27 arteries accessed via 7 fenestrations could not be cannulated within 15 minutes; all were cannulated successfully using conventional catheters (mean cannulation time 31+/-7 minutes). All 10 target vessels accessed via branches and chimney stents were successfully cannulated with the RCS. CONCLUSION: Cannulation of target vessels with the RCS during complex endovascular aortic procedures is feasible and safe. The robotic system was particularly effective for branched and chimney stents. PMID- 25809360 TI - Aortic hybrid sutureless anastomosis on porcelain aorta. AB - PURPOSE: To describe a hybrid sutureless anastomosis technique between a prosthetic graft, an endograft, and a circumferentially calcified infrarenal aorta. TECHNIQUE: The technique is demonstrated in a 65-year-old man with flush distal aortoiliac occlusion and patent infrarenal porcelain aorta (IPA). After laparotomy, the IPA was occluded below the renal arteries by inflating an aortic balloon introduced via an axillary access. The IPA was transected in its distal part and aortic thrombectomy performed. A Zenith iliac extension was modified on a back table by cutting the terminal tip; the device was then was inserted and deployed into the IPA in a standard fashion and the sheath removed. A Dacron bifurcated graft was sutured in an end-to-end anastomosis to the endograft and terminal aorta. The 12-month computed tomography scan showed patency of the graft. CONCLUSIONS: This sutureless anastomosis technique seems safe and feasible and represents a valid alternative to standard surgical approaches in cases of heavy and circumferentially calcified infrarenal aorta. PMID- 25809361 TI - Is the reevaluation of cardiac status and medical treatment mandatory for patients with coronary artery disease after endovascular aneurysm repair? PMID- 25809362 TI - Inflammatory response and renal function following endovascular repair of the descending thoracic aorta. AB - PURPOSE: To evaluate inflammatory response and renal function after thoracic endovascular aortic repair (TEVAR) of lesions in the descending thoracic aorta. METHODS: Thirty-two consecutive patients treated with TEVAR from January 2010 to August 2013 were enrolled in this prospective study. Two were excluded owing to dissecting thoracic aortic aneurysm (TAA) extending into the renal arteries with renal failure in one and a saccular TAA in which a multilayer flow-modulating stent was implanted in the other. This left 30 patients (28 men; mean age 68.8+/ 5.9 years) with 28 TAAs, an aortic dissection, and an aortic ulcer for the analysis. Temperature and serum levels of white blood cells (WBCs), C-reactive protein (CRP), interleukin-10 (IL-10), IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), creatinine, urea, and cystatin C were measured preoperatively and at 24 and 48 hours postoperatively. RESULTS: Statistically significant increases in temperature and serum levels of WBCs, CRP, IL-10, and IL-6 were observed 24 and 48 hours postoperatively compared to baseline (all p<0.05). The number of endografts and the coverage of the celiac or subclavian artery did not affect the magnitude of the inflammatory response. No significant differences were observed concerning serum levels of IL-8, TNF-alpha, creatinine, or cystatin C from baseline to 24 or 48 hours postoperatively. CONCLUSION: Endograft implantation in the thoracic aorta may propagate an inflammatory response during the early postoperative period. No clinical adverse events related to the increased inflammatory response were observed. Renal function does not seem to be deteriorated after TEVAR in the descending thoracic aorta. PMID- 25809363 TI - Fenestrated endografting after bare metal dissection stent implantation. AB - PURPOSE: To present a case that demonstrates the ability to deploy a 4 fenestrated endograft in an aorta previously treated with an endovascular graft and additional distal bare stents for acute type B dissection. CASE REPORT: Five years ago, a 61-year-old man had a Zenith TX2 endovascular graft and 2 distal bare metal stents deployed for acute type B dissection. In follow-up, a distal extension endograft was deployed below the bare stent for false lumen reperfusion and aortic growth. The ascending aorta and the arch were replaced surgically at 3 years, with the distal end of the graft sewn to the existing endograft. At the current admission, a Crawford type III thoracoabdominal aortic aneurysm was found and excluded with a 4-fenestration endograft. Using 3-dimensional fusion imaging, there was no major conflict with the struts of the bare dissection stent during catheterization and bridging stent placement. A distal bifurcated endograft was also implanted. The total procedure time was 240 minutes, the radiation dose was 8066 cGy.cm(2), and the contrast volume was 100 mL. The patient was discharged on the sixth postoperative day and continues to do well at 9 months. CONCLUSION: Prior dissection stent deployment within the thoracoabdominal segment does not preclude further fenestrated endograft placement. Intraoperative fusion imaging can be very helpful to the successful completion of these complex procedures. PMID- 25809364 TI - Drug-coated balloon dilation before carotid artery stenting of post-carotid endarterectomy restenosis. AB - PURPOSE: To investigate if drug-coated balloon (DCB) predilation may improve the efficacy of carotid artery stenting (CAS) for restenosis after carotid endarterectomy (CEA). METHODS: Eighteen consecutive patients (11 men; median age 75 years) with significant restenosis within 24 months of CEA were treated with a paclitaxel-coated DCB prior to CAS. Clinical outcomes and stent patency were systematically appraised. RESULTS: All patients were successfully treated according to this clinical protocol. The only complication occurred in a patient who had a transient ischemic attack during prolonged DCB inflation. At a median follow-up of 18 months, no >50% restenosis was observed on duplex ultrasound scans; however, moderate hyperplasia at the proximal stent edge was found in 4 patients. One patient died at 9 months from a myocardial infarction. CONCLUSION: Despite the small sample size and in keeping with the historically high risk of recurrent restenosis after CAS for CEA restenosis, this case series suggests that DCB dilation followed by CAS for postsurgical restenosis is feasible, safe, and may be associated with favorable clinical outcomes at midterm follow-up. PMID- 25809365 TI - Commentary: drug-coated balloon angioplasty to improve carotid stenting outcomes after postendarterectomy restenosis: fad or an answer to the problem of recurrent restenosis? PMID- 25809366 TI - Initial clinical experience with the micromesh Roadsaver carotid artery stent for the treatment of patients with symptomatic carotid artery disease. AB - PURPOSE: To assess the effectiveness, technical aspects, handling, and safety of the micromesh Roadsaver Carotid Artery Stent in the treatment of atherosclerotic carotid artery stenosis and tandem lesions in ischemic stroke patients. METHODS: Seven patients (5 men; mean age 75+/-11.4 years, range 53-86) suffering from symptomatic internal carotid artery (ICA) stenosis (mean 76% diameter reduction) were treated with the dual layer closed-cell stent without embolic protection. Postdilation was performed in 6 of 7 patients. Two patients were treated in the context of ischemic stroke and concurrent middle cerebral artery occlusion. Mean National Institutes of Health Stroke Scale score at admission was 12.8+/-5. RESULTS: All devices were deployed satisfactorily. One wall-adherent thromboembolus in a proximal ICA was covered with the Roadsaver stent in a tandem lesion setting. The modified Rankin Scale (mRS) declined from 3.7+/-0.7 to 2.4+/ 0.8 in hospital, showing an improvement in clinical symptoms. No complications were detected during or after the procedure. The 30-day mRS was 1.7+/-1.1. At 6 months, ultrasound examination demonstrated patency of stents and the external carotid arteries. CONCLUSION: The Roadsaver double layer micromesh stent seems to be safe and effective in the treatment of extracranial ICA stenosis and in the context of tandem lesions in ischemic stroke. Further studies with larger populations are warranted. PMID- 25809367 TI - Initial experience with the absorb bioresorbable vascular scaffold below the knee: six-month clinical and imaging outcomes. AB - PURPOSE: To investigate a new bioresorbable vascular scaffold for the treatment of focal tibial and distal popliteal lesions. METHODS: Tibial and distal popliteal angioplasty was performed in 15 limbs of 14 patients (9 men; median age 82 years) with critical limb ischemia (CLI, n=7) or severe claudication. The 18 lesions (mean length 22.2+/-14.0 mm) were implanted with 22 everolimus-eluting bioresorbable scaffolds (Absorb). Clinical and ultrasound follow-up was performed at 1, 3, 6, and 12 months to detect restenosis and evaluate safety, midterm restenosis rate, and clinical improvement. RESULTS: Immediate technical success was 100%, although a single limb suffered 2 scaffold thromboses on the first day; it was salvaged with repeat endovascular intervention. All patients were available for surveillance examinations during a follow-up of 6.1+/-3.9 months; no patient died. Of the 15 limbs in the analysis, clinical improvement was present in 12 (4 of 7 CLI patients); there was no amputation, bypass surgery, or evidence of binary restenosis on follow-up sonographic examination. CONCLUSION: Midterm follow-up for this small pilot sample demonstrates acceptable safety and patency results, together with freedom from all major adverse limb events, using the Absorb bioresorbable vascular scaffold below the knee. PMID- 25809369 TI - Commentary: which comes first, the phoenix or the flame? Reflections on the role of inflammation in patients undergoing lower limb revascularization for peripheral artery disease. PMID- 25809368 TI - C-reactive protein and endovascular treatment of lower limb peripheral artery disease: an independent prognostic factor. AB - PURPOSE: To determine if C-reactive protein (CRP) can predict the outcomes of lower extremity endovascular therapy (EVT) in patients with peripheral artery disease and to calculate a cutoff value that may be useful in identifying patients with a higher risk of EVT failure at 1 year. METHODS: In this prospective single-center study, 121 patients (94 men; mean age 67.7+/-9.8 years) undergoing EVT of lower limb lesions in an 18-month period were enrolled as a derivation set. In the subsequent 6 months, 53 patients (39 men; mean age 70.1+/ 10.0 years) were enrolled as the validation set. Blood samples were collected before EVT and at 1 month postintervention from both sets of patients to measure CRP levels. The cohorts were followed for 1 year, and data on reinterventions were recorded. A cutoff CRP value was calculated with the highest sensitivity and specificity for EVT failure based on receiver operator characteristic (ROC) curve analysis. The cutoff value was confirmed in the validation set. Cox proportional hazards analysis was performed to evaluate the independent contribution of CRP levels and other variables to the risk of reintervention; results are given as the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: The area under the ROC curve relating preprocedure CRP levels to 1-year reintervention was 0.77+/-0.05. The highest likelihood ratio corresponded to a pre-EVT CRP value of 9.8 mg/L (likelihood ratio test=133, df=1, p<0.001). Reintervention before the first year after EVT was related to preprocedure CRP levels (HR 1.1, 95% CI 1.05 to 1.2; p<0.001). These results were confirmed in the validation set (HR 1.1, 95% CI 1.02 to 1.18; p=0.008). CONCLUSION: CRP values can be used as an independent marker of EVT outcome. Baseline CRP levels >9.8 mg/L indicate increased risk of secondary interventions, which are often open surgical procedures. PMID- 25809370 TI - Runoff detected by magnetic resonance angiography as an indicator for better recanalization outcomes in below-the-knee chronic total occlusions in diabetic patients. AB - PURPOSE: To compare the feasibility and efficacy of recanalizing below-the-knee (BTK) chronic total occlusions (CTOs) between patients with good or poor distal runoff based on magnetic resonance angiography (MRA) scans. METHODS: Two hundred long-segment BTK CTOs in 171 limbs of 113 diabetic patients (58 men; mean age 69.8+/-1.9 years) were divided into good distal runoff (GDR: 119 lesions, 98 limbs) or poor distal runoff groups (PDR: 81 lesions, 73 limbs) based on baseline MRA findings. After angioplasty, modified thrombolysis in myocardial ischemia (mTIMI) grades and ankle-brachial index (ABI) were used to assess immediate outcomes. Regularly scheduled duplex or MRA imaging was performed in follow-up. The restenosis and limb salvage rates were compared. RESULTS: The success rates were 93.3% and 87.7% in the GDR and PDR groups, respectively (p=0.21); subintimal angioplasty was more common in the PDR group (93.0% vs. 63.1%, p<0.01). Completion angiography indicated an mTIMI grade 3 blood flow in 71.2% lesions in the GDR patients and in 52.1% in the PDR (p=0.01) group. Improvement in the ABI was greater in the GDR limbs (p<0.001 vs. PDR). Mean imaging follow-up was 10.8+/ 6.9 months in the GDR group and 11.1+/-6.6 months in the PDR group. Kaplan-Meier analysis showed a better restenosis-free rate in the GDR group (80.6% vs. 61.7%; p=0.02) at 12 months and for lesions with mTIMI grade 3 flow (p<0.01). At 24 months, Kaplan-Meier analysis revealed a better limb salvage rate in the GDR group (84.2% vs. 54.6%; p=0.02). CONCLUSION: Distal runoff detected using MRA could be a predictor for successful intraluminal recanalization, better distal tissue perfusion, improved long-term patency, and better limb salvage for patients with BTK CTOs. PMID- 25809371 TI - Commentary: intra-arterial digital subtraction angiography: what you see is not always what you get. PMID- 25809372 TI - Duplex ultrasound assessment of native stenoses in the superficial femoral and popliteal arteries: a comparative study examining the influence of multisegment lesions. AB - PURPOSE: To evaluate duplex ultrasonography (DUS) in the assessment of femoropopliteal stenoses comparing a single native stenosis (SNS) to multisegmental native stenoses (MNS). METHODS: Among the 1284 patients treated for atherosclerotic occlusive disease involving the femoropopliteal segment between November 2002 and November 2012, 139 patients (97 men; mean age 68+/-8 years) with 142 SNS or 143 MNS in 79 and 60 patients, respectively, were eligible for this retrospective analysis. The peak systolic velocity ratios with proximal (PSVRprox) and distal (PSVRdist) reference for the 285 lesions were compared with their respective angiographic stenosis grade as measured by 2 independent readers using quantitative vascular analysis to ensure objectivity. Receiver operating characteristic curve analysis was used to evaluate sensitivity, specificity, and the optimal thresholds of PSV and PSVR for detection of stenoses by grade (>50%, >70%, or >80% diameter stenosis). The area under the curve (AUC) values of dependent and independent receiver operating characteristic curves were compared. RESULTS: For SNS, correlation of PSVRprox to diameter stenosis (R=0.88) was higher (p<0.001) than the correlation for MNS (R=0.78). In the SNS group, the AUC for detecting a >50% (0.99+/-0.01), >70% (0.98+/-0.01), and >80% (0.96+/-0.01) stenosis with PSVRprox was significantly higher than in the MNS group [AUC50% 0.93+/-0.02 (p=0.01), AUC70% 0.92+/-0.02 (p=0.02), and AUC80% 0.87+/-0.03 (p=0.003)]. The optimal thresholds for detecting >50%, >70%, and >80% stenoses for SNS using PSVRprox were 2.6, 3.3, and 3.9, respectively. For MNS, the optimal thresholds of PSVRprox were 2.6, 3.4, and 3.9, respectively, with respective sensitivities of 87%, 81%, and 75%; respective specificities of 93%, 90%, and 82%; negative predictive values of 45%, 64%, and 74%; and positive predictive values of 99%, 95%, and 83%. CONCLUSION: DUS is an optimal tool for quantification of SNS. However, a multisegment setting has a significant negative impact on the quantification of femoropopliteal artery stenosis. PMID- 25809374 TI - Intravenous intravascular ultrasound using the AcuNav ultrasound catheter for guiding recanalization of aortoiliac chronic total occlusions. PMID- 25809375 TI - Re: "diagnostic value of peripheral fractional flow reserve in isolated iliac artery stenosis: a comparison with the post-exercise ankle-brachial index". PMID- 25809373 TI - A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention. AB - Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban. PMID- 25809379 TI - Resiliency as a factor protecting youths from risky behaviour: Moderating effects of gender and sport. AB - We hypothesised that resiliency may protect adolescents against risky behaviours, and that both the practicing of sports, and gender are moderating variables in relationships between resiliency and risky behaviours. The study included 18-year old pupils from a selection of secondary schools (n = 556). A total of 188 individuals practiced competitive sports and the remaining 368 participants were non-athletes. The participants were examined with the Resiliency Assessment Scale for Children and Adolescents (SPP-18) and with a survey containing questions and statements related to high-risk "experiments with adulthood". Adolescent athletes showed higher levels of resiliency than their peers. The power of the "Determination and Persistence in Action" effect on "Alcohol" scale differed significantly between male athletes and male non-athletes. Only in the athletes groups were higher scores on this scale reflected by lower values on the "Drugs" scale. Moreover, it is possible to observe differences in undertaking risky behaviour between male and female athletes. The analysis of risky sexual behaviour suggests that sport is a risk factor for men, and a protective factor for women. These data suggest that consistent prophylactic and psycho-educative activities, with a special attention to differences between genders, should be provided to all the adolescents, irrespective of their sport performance levels. PMID- 25809376 TI - The HIV-1 antisense protein (ASP) induces CD8 T cell responses during chronic infection. AB - BACKGROUND: CD8+ T cells recognize HIV-1 epitopes translated from a gene's primary reading frame (F1) and any one of its five alternative reading frames (ARFs) in the forward (F2, F3) or reverse (R1-3) directions. The 3' end of HIV 1's proviral coding strand contains a conserved sequence that is directly overlapping but antiparallel to the env gene (ARF R2) and encodes for a putative antisense HIV-1 protein called ASP. ASP expression has been demonstrated in vitro using HIV-transfected cell lines or infected cells. Although antibodies to ASP were previously detected in patient sera, T cell recognition of ASP-derived epitopes has not been evaluated. We therefore investigated the ex vivo and in vitro induction of ASP-specific T cell responses as a measure of immune recognition and protein expression during HIV-1 infection. RESULTS: A panel of overlapping peptides was initially designed from the full-length ASP sequence to perform a global assessment of T cell responses. Recognition of ASP-derived antigens was evaluated in an IFN-gammaELISpot assay using PBMCs from HIV-1 seropositive and seronegative individuals. Eight of 25 patients had positive responses to ASP antigens and none of the seronegative donors responded. As a complimentary approach, a second set of antigens was designed using HLA-I binding motifs and affinities. Two ASP-derived peptides with high predicted binding affinities for HLA-A*02 (ASP-YL9) and HLA-B*07 (ASP-TL10) were tested using PBMCs from HIV-1 seropositive and seronegative individuals who expressed the matching HLA-I-restricting allele. We found that HLA-I-restricted ASP peptides were only recognized by CD8+ T cells from patients with the relevant HLA-I and did not induce responses in any of the seronegative donors or patients who do not express the restrictive HLA alleles. Further, ASP-YL9-specific CD8+ T cells had functional profiles that were similar to a previously described HLA-A*02 restricted epitope (Gag-SL9). Specific recognition of ASP-YL9 by CD8+ T cells was also demonstrated by tetramer staining using cells from an HLA-A*02 HIV-infected patient. CONCLUSION: Our results provide the first description of CD8+ T cell mediated immune responses to ASP in HIV-1-infected patients, demonstrating that ASP is expressed during infection. Our identification of epitopes within ASP has implications for designing HIV vaccines. PMID- 25809381 TI - Risk factors for oxygen desaturation on arrival in the postanesthesia care unit. PMID- 25809378 TI - Prompted to treatment by the criminal justice system: Relationships with treatment retention and outcome among cocaine users. AB - BACKGROUND AND OBJECTIVES: A substantial portion of individuals entering treatment for substance use have been referred by the criminal justice system, yet there are conflicting reports regarding treatment engagement and outcome differences compared to those not referred. This study examined baseline characteristic and treatment outcome differences among cocaine-dependent individuals participating in cocaine treatment randomized trials. METHODS: This secondary analysis pooled samples across five completed randomized controlled trials, resulting in 434 participants. Of these, 67 (15%) were prompted to treatment by the criminal justice system. RESULTS: This subsample of criminal justice prompted (CJP) individuals did not differ from those not prompted by the criminal justice system in terms of gender, race/ethnicity, marital status, or age. However, the CJP group reported more years of regular cocaine use, more severe employment and legal problems, as well as less readiness to change prior to treatment. Treatment outcomes did not differ significantly from those without a criminal justice prompt, and on some measures the outcomes for CJP group were better (e.g., percentage of days cocaine abstinent, number of therapy sessions attended). DISCUSSION AND CONCLUSIONS: These findings suggest that being prompted to treatment by the criminal justice system may not lead to poorer treatment engagement or substance use outcomes for individuals participating in randomized controlled treatment trials. SCIENTIFIC SIGNIFICANCE: Despite some baseline indicators of poorer treatment prognosis, individuals who have been prompted to treatment by the criminal justice system have similar treatment outcomes as those presenting to treatment voluntarily. PMID- 25809380 TI - Increasing access to sexual health care for rural and regional young people: Similarities and differences in the views of young people and service providers. AB - OBJECTIVE: This study aims to describe the views of sexual health service providers on access issues for young people and consider them together with the views of young people themselves. DESIGN: A cross-sectional mixed-methods study design involving semi-structured interviews with health service providers and an electronic survey with young people. SETTING: Four towns in rural and regional Queensland, Australia. PARTICIPANTS: A total of 32 service providers: 9 sexual health nurses, 8 general practitioners, 6 school-based youth health nurses, 5 sexual health educators, 2 Australian Aboriginal health workers and 2 youth workers. There were 391 young people who participated in the Young People's Survey. MAIN OUTCOME MEASURES: Themes generated from interviews with service providers and quantitative data from young people addressing access to sexual and reproductive health (SRH) services for rural and regional young people. RESULTS: Service providers frequently identified structural barriers, confidentiality and lack of awareness of SRH services as barriers for young people seeking SRH care. Young people also reported that structural factors such as transport, cost and service operating hours were important; however, they placed greater value on personal attributes of service providers, particularly welcoming and non judgemental attitudes. CONCLUSION: Health service policy and training focused on attitudinal qualities of individual service providers may improve access to SRH services for young people. Selective staff recruitment and professional development are important to increase sensitivity to youth issues. Promotion of non-judgemental and confidential care may also improve access for youth. PMID- 25809383 TI - Long-term care use among old people in their last 2 years of life: variations across Finland. AB - Variations across Finland in the use of six different long-term care (LTC) services among old people in their last 2 years of life, and the effects of characteristics of municipalities on the variations were studied. We studied variations in the use of residential home, sheltered housing, regular home care and inpatient care in health centre wards by using national registers. We studied how the use of LTC was associated with characteristics of the individuals and in particular characteristics of the municipalities in which they lived. Analyses were conducted with multilevel binary logistic regression. Data included all individuals (34,753) who died in the year 2008 at the age of 70 or over. Of those, 58.3% used some kind of LTC during their last 2 years of life. We found considerable variations between municipalities in the use of different kinds of LTC. A portion of the variation was explained by municipality characteristics. The size and location of the municipality had the strongest association with the use of different kinds of LTC. The economic status of the municipality and morbidity at the population level were poorly associated with LTC use, whereas old-age dependency showed no association. When individual-level characteristics were added to the models, these associations did not alter. Results indicated that the delivery system characteristics had an important effect on the use of LTC services. The considerable variation in LTC services also poses questions with respect to equity in access and to quality of LTC across the country. PMID- 25809384 TI - Innovative Stride to Zero Hunger Beyond 2015 in Nigeria. AB - Overcoming food and nutritional insecurity among the elderly, pregnant women and children under five years, remains a big challenge to human and sustainable development in many resourse- poor communities in developing countries, where over 57% of the people go to bed hungry. Diversification of dietary habit to include derelict plant genetic resources which are cheap, readily available and affordable, could contribute to the daily dietary requirements of these resource poor people. This work was initiated to explore the nutritional values of some Neglected and Underutilized Species (NUS) from Nigeria, as an innovative approach of reducing food and nutrition insecurity in this country. Multidimensional Analysis (MDA) for decision making tool was used to pool the desirable nutrients in each of these species and rank them. These were then compared with Lactuca sativa var. longifolia L (exotic). Results from these analyses showed that these NUS are endowed with appreciable levels of nutrients. MDA showed that S. occidentalis ranked 1st with a WF of (4.16), followed by T. occidentals 2(nd) with WF of (3.75) when all desirable nutrient values of high moisture, carbohydrate, protein content, low fat and better energy calorie (kcal) nutrients were pooled together amongst these species. It implies that these NUS could contribute to the Acceptable Macronutrient Distribution Range (AMDR) for micronutrient as recommended US8053007B2 and could help in reducing malnutrition as entrenched in the Millennium Development Goal (MDGs). There is a need for expanded policy programmes for sustainable enlightenment on their nutritional benefits in order to promote their selection as part of cooked food, cultivation and green job creation. PMID- 25809382 TI - Highly specific gene silencing in a monocot species by artificial microRNAs derived from chimeric miRNA precursors. AB - Artificial microRNAs (amiRNAs) are used for selective gene silencing in plants. However, current methods to produce amiRNA constructs for silencing transcripts in monocot species are not suitable for simple, cost-effective and large-scale synthesis. Here, a series of expression vectors based on Oryza sativa MIR390 (OsMIR390) precursor was developed for high-throughput cloning and high expression of amiRNAs in monocots. Four different amiRNA sequences designed to target specifically endogenous genes and expressed from OsMIR390-based vectors were validated in transgenic Brachypodium distachyon plants. Surprisingly, amiRNAs accumulated to higher levels and were processed more accurately when expressed from chimeric OsMIR390-based precursors that include distal stem-loop sequences from Arabidopsis thaliana MIR390a (AtMIR390a). In all cases, transgenic plants displayed the predicted phenotypes induced by target gene repression, and accumulated high levels of amiRNAs and low levels of the corresponding target transcripts. Genome-wide transcriptome profiling combined with 5'-RLM-RACE analysis in transgenic plants confirmed that amiRNAs were highly specific. PMID- 25809385 TI - Kinship, inbreeding and fine-scale spatial structure influence gut microbiota in a hindgut-fermenting tortoise. AB - Herbivorous vertebrates rely on complex communities of mutualistic gut bacteria to facilitate the digestion of celluloses and hemicelluloses. Gut microbes are often convergent based on diet and gut morphology across a phylogenetically diverse group of mammals. However, little is known about microbial communities of herbivorous hindgut-fermenting reptiles. Here, we investigate how factors at the individual level might constrain the composition of gut microbes in an obligate herbivorous reptile. Using multiplexed 16S rRNA gene sequencing, we characterized the faecal microbial community of a population of gopher tortoises (Gopherus polyphemus) and examined how age, genetic diversity, spatial structure and kinship influence differences among individuals. We recovered phylotypes associated with known cellulolytic function, including candidate phylum Termite Group 3, suggesting their importance for gopher tortoise digestion. Although host genetic structure did not explain variation in microbial composition and community structure, we found that fine-scale spatial structure, inbreeding, degree of relatedness and possibly ontogeny shaped patterns of diversity in faecal microbiomes of gopher tortoises. Our findings corroborate widespread convergence of faecal-associated microbes based on gut morphology and diet and demonstrate the role of spatial and demographic structure in driving differentiation of gut microbiota in natural populations. PMID- 25809386 TI - Long-term remission of primary cutaneous neutrophil-rich CD30+ anaplastic large cell lymphoma treated with topical imiquimod. A case report. PMID- 25809388 TI - Loss of heterozygosity in a case of glomuvenous malformations. PMID- 25809389 TI - Dynamic LVOT Obstruction and Aortic Stenosis in the Same Patient: A Case of Challenging Doppler Hemodynamics. AB - We present a patient with both dynamic left ventricular outflow tract obstruction and valvular aortic stenosis. The aortic valve was calcified, and velocities and gradients measured by continuous-wave Doppler met standard criteria for severe aortic stenosis. The increased subvalvular velocities invalidated assumptions of the simplified Bernoulli equation; correction using the longer form of the Bernoulli equation suggested a lower but still significant gradient. The complex shape of the subvalvular spectral Doppler envelope indicated supranormal systolic function and dynamic left ventricular outflow obstruction. Left heart catheterization with an end-hole catheter was required to determine the subvalvular and valvular components of the obstruction. PMID- 25809391 TI - Clinical features and biomarkers of concussion and mild traumatic brain injury in pediatric patients. AB - There has been increasing awareness of the incidence and potential long-term consequences of mild traumatic brain injury (mTBI) in children and young adults. While parents, school systems, and athletic programs are clamoring for evidence based guidelines, the field remains primitive in understanding the factors resulting in a spectrum of individual outcomes, most of which are complete, but some of which are not. In this article, we discuss the definition, epidemiology, clinical presentation, course, and outcomes of mTBI, with a focus on the pediatric population as the context for reviewing the mechanisms and pathophysiology mediating, and biomarkers reflective of, more significant concussion-induced brain injury. Our goal is to present a general overview of the features of mTBI in the pediatric population in order to provide a conceptual model for pediatricians and pediatric subspecialists. This model emphasizes the importance of establishing actionable, noninvasive biomarkers that are reflective of brain injury and that may identify those pediatric patients who can benefit from earlier and more aggressive interventions. We will focus on the specific features of mTBI in pediatric patients; although given the relative lack of research in the pediatric population, we will also extrapolate from research on adults. PMID- 25809390 TI - Short-term outcomes of robotic radical esophagectomy for esophageal cancer by a nontransthoracic approach compared with conventional transthoracic surgery. AB - Transthoracic esophagectomy (TTE) is believed to have advantages for mediastinal lymphadenectomy in the treatment of resectable esophageal cancer despite its association with a greater incidence of pulmonary complications and postoperative mortality. Transhiatal esophagectomy is regarded as less invasive, though insufficient in terms of lymph node dissection. With the aim of achieving lymph dissection equivalent to that of TTE, we have developed a nontransthoracic esophagectomy (NTTE) procedure combining a video-assisted cervical approach for the upper mediastinum and a robot-assisted transhiatal approach for the middle and lower mediastinum. We prospectively studied 22 accumulated cases of NTTE and verified feasibility by analyzing perioperative and histopathological outcomes. We compared this group's short-term outcomes with outcomes of 139 equivalent esophageal cancer cases operated on at our institution by conventional TTE (TTE group). In the NTTE group, there were no procedure-related events and no midway conversions to the conventional surgery; the mean operation time was longer (median, 524 vs. 428 minutes); estimated blood loss did not differ significantly between the two groups (median, 385 mL vs. 490 mL); in the NTTE group, the postoperative hospital stay was shorter (median, 18 days vs. 24 days). No postoperative pneumonia occurred in the NTTE group. The frequencies of other major postoperative complications did not differ significantly, nor were there differences in the numbers of harvested mediastinal lymph nodes (median, 30 vs. 29) or in other histopathology findings. NTTE offers a new radical procedure for resection of esophageal cancer combining a cervical video-assisted approach and a transhiatal robotic approach. Although further accumulation of surgical cases is needed to corroborate these results, NTTE promises better prevention of pulmonary complications in the management of esophageal cancer. PMID- 25809387 TI - Multi-modality imaging for the assessment of myocardial perfusion with emphasis on stress perfusion CT and MR imaging. AB - High-quality and non-invasive diagnostic tools for assessing myocardial ischemia are necessary for therapeutic decisions regarding coronary artery disease. Myocardial perfusion has been studied using myocardial contrast echo perfusion, single-photon emission computed tomography, positron emission tomography, cardiovascular magnetic resonance, and, more recently, computed tomography. The addition of coronary computed tomography angiography to myocardial perfusion imaging improves the specificity and overall diagnostic accuracy of detecting the hemodynamic significance of coronary artery stenosis. This study reviews the benefits, limitations, and imaging findings of various imaging modalities for assessing myocardial perfusion, with particular emphasis on stress perfusion computed tomography and cardiovascular magnetic resonance imaging. PMID- 25809392 TI - High on-treatment platelet reactivity with ticagrelor versus prasugrel: a systematic review and meta-analysis. AB - BACKGROUND: Ticagrelor and prasugrel have shown superiority over clopidogrel. However, it remains unclear if one is superior to another regarding on-treatment platelet reactivity. OBJECTIVES: To compare the impact of ticagrelor and prasugrel on high on-treatment platelet reactivity (HTPR). METHODS: The PubMed and Cochrane databases were searched for eligible studies in December 2014. Studies were eligible if they compared ticagrelor and prasugrel regarding high on treatment platelet reactivity (HTPR). Pooled estimates were calculated by using a random-effects model with 95% confidence intervals. RESULTS: We included 14 studies and 1822 patients: 805 and 1017 in the ticagrelor and prasugrel groups, respectively. The rate of HTPR was significantly lower in the ticagrelor group: 1.5% vs. 9.8% (RR = 0.27 [0.14-0.50]). The pre-specified analysis focusing on randomized trials (n = 10) showed consistent results (RR = 0.27 [0.12-0.60]). CONCLUSION: Our results suggest that ticagrelor allows a higher platelet reactivity inhibition as compared with prasugrel and leads to a further decrease in the rate of HTPR. PMID- 25809393 TI - Aluminium, gallium, and molybdenum toxicity to the tropical marine microalga Isochrysis galbana. AB - There is a shortage of established chronic toxicity test methods for assessing the toxicity of contaminants to tropical marine organisms. The authors tested the suitability of the tropical microalga Isochrysis galbana for use in routine ecotoxicology and assessed the effects of 72-h exposures to copper (Cu, a reference toxicant), aluminium (Al), gallium (Ga), and molybdenum (Mo), key metals of alumina refinery discharge, on the growth of I. galbana at 3 temperatures: 24 degrees C, 28 degrees C, and 31 degrees C. The sensitivity of both I. galbana and the test method was validated by the response to Cu exposure, with 10% and 50% effect concentrations (EC10 and EC50) of 2.5 MUg/L and 18 MUg/L, respectively. The EC10 and EC50 values for total Al at 28 degrees C were 640 MUg/L and 3045 MUg/L, respectively. The toxicity of both Cu and Al at 24 degrees C and 31 degrees C was similar to that at 28 degrees C. There was no measurable toxicity from dissolved Ga exposures of up to 6000 MUg/L or exposures to dissolved Mo of up to 9500 MUg/L. Solubility limits at 28 degrees C for the dissolved fractions (<10 kDa) of Al, Ga, and Mo were approximately 650 MUg/L Al, >7000 MUg/L Ga, and >6000 MUg/L Mo. In test solutions containing >650 MUg/L total Al, dissolved and precipitated forms of Al were present, with precipitated Al becoming more dominant as total Al increased. The test method proved suitable for routine ecotoxicology, with I. galbana showing sensitivity to Cu but Al, Ga, and Mo exhibiting little to no toxicity to this species. PMID- 25809394 TI - Relationship between Small Animal Intern Rank and Performance at a University Teaching Hospital. AB - The purpose of this study was to determine if there is a relationship between selection committee rankings of internship applicants and the performance of small animal interns. The hypothesis was that there would be a relationship between selection committee rank order and intern performance; the more highly an application was ranked, the better the intern's performance scores would be. In 2007, the Department of Small Animal Medicine and Surgery instituted a standardized approach to its intern selection process both to streamline the process and to track its effectiveness. At the end of intern years 2010-2014, every faculty member in the department was provided an intern assessment form for that year's class. There was no relationship between an individual intern's final rank by the selection committee and his/her performance either as a percentile score or a Likert-type score (p=.25, R2=0.04; p=0.31, R2=0.03, respectively). Likewise, when interns were divided into the top and bottom quartile based on their final rank by the selection committee, there was no relationship between their rank and their performance as a percentile score (median rank 15 vs. 20; p=.14) or Likert-type score (median rank 14 vs. 19; p=.27). Institutions that use a similar intern selection method may need to reconsider the time and effort being expended for an outcome that does not predict performance. Alternatively, specific criteria more predictive of performance outcomes should be identified and employed in the internship selection process. PMID- 25809395 TI - Fibrodysplasia ossificans progressiva in a newborn with cardiac involvement. AB - Fibrodysplasia ossificans progressiva is a rare genetic disease that manifests in early life with malformed big toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. Mutation c.617G>A in the activin A receptor type I gene is reported in all patients with fibrodysplasia ossificans progressiva. No cases of cardiac involvement have been described in children. We report the case of a child with halluces valgi at birth, along with two tender, firm, immovable masses located on the right and left parietal-occipital region, a transitory subluxation of the right hip and an unusual ventricular septal hypertrophy. We hypothesize that the ventricular septal hypertrophy could be the result of a thickening of the fibrous portion of the septum, and a possible new element of the phenotype, probably resulting from the mechanical stimuli secondary to the significant hemodynamic changes occurring at birth. PMID- 25809396 TI - Modeling variation in early life mortality in the western lowland gorilla: Genetic, maternal and other effects. AB - Uncovering sources of variation in gorilla infant mortality informs conservation and life history research efforts. The international studbook for the western lowland gorilla provides information on a sample of captive gorillas large enough for which to analyze genetic, maternal, and various other effects on early life mortality in this critically endangered species. We assess the importance of variables such as sex, maternal parity, paternal age, and hand rearing with regard to infant survival. We also quantify the proportions of variation in mortality influenced by heritable variation and maternal effects from these pedigree and survival data using variance component estimation. Markov chain Monte Carlo simulations of generalized linear mixed models produce variance component distributions in an animal model framework that employs all pedigree information. Two models, one with a maternal identity component and one with both additive genetic and maternal identity components, estimate variance components for different age classes during the first 2 years of life. This is informative of the extent to which mortality risk factors change over time during gorilla infancy. Our results indicate that gorilla mortality is moderately heritable with the strongest genetic influence just after birth. Maternal effects are most important during the first 6 months of life. Interestingly, hand-reared infants have lower mortality for the first 6 months of life. Aside from hand rearing, we found other predictors commonly used in studies of primate infant mortality to have little influence in these gorilla data. PMID- 25809397 TI - The effective differentiation of Salmonella isolates using four PCR-based typing methods. AB - AIMS: Discrimination of Salmonella strains below the species level is very important to trace the source of outbreaks. To this end molecular typing methods can be successfully applied to routine analysis in nonspecialized laboratories due to their simplicity and speed. Here, the discriminatory ability of four molecular typing methods was investigated in 74 Salmonella enterica isolates. METHODS AND RESULTS: Salmonella strains isolated from human stool, blood, bone marrow, synovial fluid, ascites and urine sources in Iran during the years 2012 and 2013 were differentiated by random amplification of polymorphic DNA (RAPD), enterobacterial repetitive intergenic consensus (ERIC), repetitive extragenic palindromic (REP) and BOX repeat-based (BOXAIR) PCR methods. A total of 74 isolates were obtained, with 67 isolates belonging to eight serotypes/serogroups, while seven were nontypeable. The 74 strains produced 32 fingerprints with OPS-11 primers, 44 RAPD fingerprints using OPP-16 primers and 54 fingerprints with P1254 primers; their discriminatory index (DI) was 0.942, 0.978, and 0.984 respectively. BOXAIR fingerprinting produced 49 patterns (DI 0.985), while REP resulted in 55 patterns (DI 0.991) and ERIC in 48 fingerprints (DI 0.983). The discrimination of Salmonella isolates was improved when methods were combined. The combination of ERIC, REP and BOXAIR as well as the combination of BOXAIR with ERIC or REP could differentiate all 74 investigated Salmonella strains. CONCLUSIONS: The combined use of RAPD and ERIC fingerprinting offers an excellent means of differentiating Salmonella strains. SIGNIFICANCE AND IMPACT OF THE STUDY: The discrimination power of Salmonella molecular typing by combination of ERIC, REP and BOXAIR methods, or by combination of BOXAIR with ERIC or REP, is sufficient to determine genetic relationships for epidemiological purposes. PMID- 25809398 TI - Continuous measurement of intra-oral pH and temperature: development, validation of an appliance and a pilot study. AB - To describe a novel approach for continuous measurement of intra-oral pH and temperature in individuals carrying out normal daily activities over 24 h. We designed, validated and constructed a custom-made appliance fitted with a pH probe and a thermocouple. Six subjects wore the appliance over a 24-h period for two non-consecutive days, while the intra-oral pH and temperature were measured continuously and recorded. Intra-oral pH and temperature were very similar across different recording days, the difference being not statistically significant (P >= 0.14). There was a noticeable difference in the pattern of variation of pH between day and night. During the day, the mean pH was 7.3 (+/-0.4) and dropped markedly only after consumption of acidic food and drinks. The intra-oral pH decreased slowly during sleep with an average pH of 6.6 (+/-0.4) being recorded. The difference between day and night was statistically significant (P = 0.002). The mean intra-oral temperature was 33.9 degrees C (+/-0.9) during daytime and 35.9 degrees C (+/-0.5) during sleep (P = 0.013) with minor fluctuations occurring over 24 h. The continuous and simultaneous intra-oral pH and temperature measurement system described in this report is reliable, easy to construct, able to measure variables over a sustained period and may serve as a future diagnostic tool in a number of applications. PMID- 25809401 TI - Human oscillatory activity in near-miss events. AB - Near-miss events are situations in which an action yields a negative result but is very close to being successful. They are known to influence behavior, especially in gambling scenarios. Previous neuroimaging studies have described an 'anomalous' activity of brain reward areas following these events. The goal of the present research was to study electrophysiological correlates of near-misses in the expectation and outcome phases. Electroencephalography was recorded while participants were playing a simplified version of a slot machine. Four possible outcomes (gain, near-miss, loss and no-information) were presented in a pseudorandom order to ensure fixed proportions. Results from the time-frequency analysis for the theta (4-8 Hz), alpha (9-13 Hz), low beta (15-22 Hz) and beta gamma (25-35 Hz) frequency-bands presented larger power increases for wins and near-misses compared with losses. In the anticipation phase, power changes were lower than in the resolution phase. The current results are in agreement with previous studies showing that near-miss events recruit brain areas of the reward network. Likewise, the oscillatory activity in near-misses is very similar to the one elicited in the gain condition. In addition, present findings suggest that oscillatory activity in the expectation phase does not play a crucial role in near-miss events. PMID- 25809400 TI - Neural correlates of aberrant emotional salience predict psychotic symptoms and global functioning in high-risk and first-episode psychosis. AB - Neurobiological and behavioral findings suggest that psychosis is associated with corticolimbic hyperactivity during the processing of emotional salience. This has not been widely studied in the early stages of psychosis, and the impact of these abnormalities on psychotic symptoms and global functioning is unknown. We sought to address this issue in 18 patients with first-episode psychosis (FEP), 18 individuals at ultra high risk of psychosis (UHR) and 22 healthy controls (HCs). Corticolimbic response and subjective ratings to emotional and neutral scenes were measured using functional magnetic resonance imaging. The clinical and functional impact of corticolimbic abnormalities was assessed with regression analyses. The FEP and UHR groups reported increased subjective emotional arousal to neutral scenes compared with HCs. Across groups, emotional vs neutral scenes elicited activation in the dorsomedial prefrontal cortex, inferior frontal gyrus/anterior insula and amygdala. Although FEP and UHR participants showed reduced activation in these regions when viewing emotional scenes compared with controls, this was driven by increased activation to neutral scenes. Corticolimbic hyperactivity to neutral scenes predicted higher levels of positive symptoms and poorer levels of functioning. These results indicate that disruption of emotional brain systems may represent an important biological substrate for the pathophysiology of early psychosis and UHR states. PMID- 25809402 TI - Effects of personal space intrusion in affective contexts: an fMRI investigation with women suffering from borderline personality disorder. AB - The amygdala and the parietal cortex play a key role in the neural representation of personal space. Although the concept of personal space is clinically very relevant for borderline personality disorder (BPD), especially in affective contexts, it has not been investigated thus far with functional magnetic resonance imaging (fMRI). In this fMRI study, 25 female BPD patients and 25 healthy women were exposed to photos of angry, disgusted and neutral facial expressions. All stimuli were once shown as still photos, and once were zoomed-in in order to simulate intrusion into one's own personal space. Approaching faces generally provoked activation of the amygdala and the somatosensory cortex. BPD patients showed an increased activation within both regions, but only toward approaching disgusted faces. Their amygdala activation in this specific condition positively correlated with self-disgust scores. Moreover, the clinical group indicated an enhanced personal distance preference, which was associated with parietal activation. The present study revealed altered personal space processing of BPD patients, especially in situations that relate to social contexts involving disgust. Future studies should focus on the temporal stability of personal space processing during the natural course of BPD as well as during therapy. PMID- 25809403 TI - Age-related changes in intrinsic function of the superior temporal sulcus in autism spectrum disorders. AB - Currently, the developmental trajectories of neural circuits implicated in autism spectrum disorders (ASD) are largely unknown. Here, we specifically focused on age-related changes in the functional circuitry of the posterior superior temporal sulcus (pSTS), a key hub underlying social-cognitive processes known to be impaired in ASD. Using a cross-sectional approach, we analysed resting-state functional magnetic resonance imaging (fMRI) data collected from children, adolescents and adults available through the autism brain imaging data exchange repository [n = 106 with ASD and n = 109 typical controls (TC), ages 7-30 years]. The observed age-related changes of pSTS intrinsic functional connectivity (iFC) suggest that no single developmental pattern characterizes ASD. Instead, pSTS circuitry displayed a complex developmental picture, with some functional circuits showing patterns consistent with atypical development in ASD relative to TC (pSTS-iFC with fusiform gyrus and angular gyrus) and others showing delayed maturation (pSTS-iFC with regions of the action perception network). Distinct developmental trajectories in different functional circuits in ASD likely reflect differential age-related changes in the socio-cognitive processes they underlie. Increasing insight on these mechanisms is a critical step in the development of age-specific interventions in ASD. PMID- 25809406 TI - Room-Temperature Ba(Fe1-x Cox)2 As2 is not Tetragonal: Direct Observation of Magnetoelastic Interactions in Pnictide Superconductors. AB - Lattice distortions corresponding to Ba displacements with respect to the FeAs sublattice are revealed to break the room-temperature tetragonal symmetry in Ba(Fe1-x Cox)2 As2. The displacements yield twin domains of the size of ~10 nm. The domain size correlates with the magnitude of the local Fe magnetic moment and its non-monotonic dependence on Co concentration. PMID- 25809404 TI - Distinct contributions of Brodmann areas 1 and 2 to body ownership. AB - Although body ownership--i.e. the feeling that our bodies belong to us--modulates activity within the primary somatosensory cortex (S1), it is still unknown whether this modulation occurs within a somatotopically defined portion of S1. We induced an illusory feeling of ownership for another person's finger by asking participants to hold their palm against another person's palm and to stroke the two joined index fingers with the index and thumb of their other hand. This illusion (numbness illusion) does not occur if the stroking is performed asynchronously or by the other person. We combined this somatosensory paradigm with ultra-high field functional magnetic resonance imaging finger mapping to study whether illusory body ownership modulates activity within different finger specific areas of S1. The results revealed that the numbness illusion is associated with activity in Brodmann area (BA) 1 within the representation of the finger stroking the other person's finger and in BA 2 contralateral to the stroked finger. These results show that changes in bodily experience modulate the activity within certain subregions of S1, with a different finger-topographical selectivity between the representations of the stroking and of the stroked hand, and reveal that the high degree of somatosensory specialization in S1 extends to bodily self-consciousness. PMID- 25809408 TI - Necrobiotic xanthogranuloma with multiple myeloma. PMID- 25809407 TI - Perinatal morbidity and mortality for extremely low-birthweight infants: A population-based study of regionalized maternal and neonatal transport. AB - AIM: The aim of this study was to clarify the mortality and long-term outcomes of extremely low-birthweight infants according to the process of maternal or infant transport and indications for maternal transport. MATERIAL AND METHODS: We conducted a population-based study between 2005 and 2009. The collected data included the process and indications for maternal or neonatal transport, maternal and infant characteristics and the prognosis of extremely low-birthweight infants. Intergroup comparisons were made using the Mann-Whitney U-test, while multiple group comparisons were made using the Kruskal-Wallis test followed by the post-hoc paired t-test according to the Dunn procedure. Comparisons of the cumulative survival rates based on postnatal age according to the process of maternal or neonatal transport were performed using a Kaplan-Meier survival analysis and the log-rank test. RESULTS: The study subjects included 195 infants from 189 mothers following 50,632 deliveries during the study period. Overall, 32 (16.4%) infants died and 33 (20.2%) infants had neurological impairments. The rates of mortality and handicaps among the infants in the maternal transport group were 15.2% and 23.2%, respectively, compared to 25% and 44%, respectively, in the neonatal transport group. There were no differences in the prognoses of the infants according to the process of maternal transport, although more premature neonates were managed in the tertiary center. There were no differences in the cumulative survival rates based on the institution that managed the neonate. The incidence of a poor prognosis was significantly higher among the infants born from mothers transported to the tertiary center due to bulging membranes (P = 0.047). All mothers with placental abruption were transported to the nearest secondary center. CONCLUSION: The morbidity and mortality of extremely low-birthweight infants demonstrated a low incidence following the regionalization of high-risk pregnancies in our region. Further reductions in severe neonatal morbidities may depend on reducing the rate of neonatal transport. PMID- 25809405 TI - Fundamental origins and limits for scaling a maternal morphogen gradient. AB - Tissue expansion and patterning are integral to development; however, it is unknown quantitatively how a mother accumulates molecular resources to invest in the future of instructing robust embryonic patterning. Here we develop a model, Tissue Expansion-Modulated Maternal Morphogen Scaling (TEM(3)S), to study scaled anterior-posterior patterning in Drosophila embryos. Using both ovaries and embryos, we measure a core quantity of the model, the scaling power of the Bicoid (Bcd) morphogen gradient's amplitude nA. We also evaluate directly model-derived predictions about Bcd gradient and patterning properties. Our results show that scaling of the Bcd gradient in the embryo originates from, and is constrained fundamentally by, a dynamic relationship between maternal tissue expansion and bcd gene copy number expansion in the ovary. This delicate connection between the two transitioning stages of a life cycle, stemming from a finite value of nA~3, underscores a key feature of developmental systems depicted by TEM(3)S. PMID- 25809410 TI - Caregiver and health care provider preferences of nutritional support in a hematopoietic stem cell transplant unit. AB - BACKGROUND: Many pediatric oncology patients undergoing hematopoietic stem cell transplantation (HSCT) require nutritional support (NS) because of their inability to consume adequate caloric intake enough calories orally. Although NS can be provided either enteraly (EN) or parenteraly (PN), EN is the preferred method of NS as long as if the gastrointestinal tract is functioning. In this qualitative study, we determined the type of NS preferences and the reservations of caregivers of pediatric HSCT patients undergoing hematopoietic stem cell transplantation (HSCT) as well as those of health care (HC) providers working on the HSCT unit. PROCEDURES: A survey was developed and completed anonymously by HC providers and caregivers. The hypothesis was that HC providers and caregivers would prefer PN because it is convenient to use in patients who already have a central line in place. RESULTS: Most caregivers preferred PN to EN, while most HC providers preferred EN to PN. The barrier between EN initiation and caregivers' approval was the caregivers' perception that EN was invasive and painful, most common obstacle for initiation of EN among caregivers was that it hurts/is invasive, while the barrier with HC providers was vomiting and/abdominal pain associated with EN. CONCLUSIONS: If caregivers were better educated about NS and the advantages/disadvantages of the different forms of NS, their preferences may change. There have been policy changes at St. Jude have been implemented since this study, and an outpatient dietitian now provides education to caregivers about NS during the pre-evaluation for HSCT. PMID- 25809409 TI - Managing the evolution of herbicide resistance. AB - BACKGROUND: Understanding and managing the evolutionary responses of pests and pathogens to control efforts is essential to human health and survival. Herbicide resistant (HR) weeds undermine agricultural sustainability, productivity and profitability, yet the epidemiology of resistance evolution - particularly at landscape scales - is poorly understood. We studied glyphosate resistance in a major agricultural weed, Amaranthus tuberculatus (common waterhemp), using landscape, weed and management data from 105 central Illinois grain farms, including over 500 site-years of herbicide application records. RESULTS: Glyphosate-resistant (GR) A. tuberculatus occurrence was greatest in fields with frequent glyphosate applications, high annual rates of herbicide mechanism of action (MOA) turnover and few MOAs field(-1) year(-1) . Combining herbicide MOAs at the time of application by herbicide mixing reduced the likelihood of GR A. tuberculatus. CONCLUSIONS: These findings illustrate the importance of examining large-scale evolutionary processes at relevant spatial scales. Although measures such as herbicide mixing may delay GR or other HR weed traits, they are unlikely to prevent them. Long-term weed management will require truly diversified management practices that minimize selection for herbicide resistance traits. PMID- 25809412 TI - Theoretical Studies on the Asymmetric Baeyer-Villiger Oxidation Reaction of 4 Phenylcyclohexanone with m-Chloroperoxobenzoic Acid Catalyzed by Chiral Scandium(III)-N,N'-Dioxide Complexes. AB - The mechanism and enantioselectivity of the asymmetric Baeyer-Villiger oxidation reaction between 4-phenylcyclohexanone and m-chloroperoxobenzoic acid (m-CPBA) catalyzed by Sc(III) -N,N'-dioxide complexes were investigated theoretically. The calculations indicated that the first step, corresponding to the addition of m CPBA to the carbonyl group of 4-phenylcyclohexanone, is the rate-determining step (RDS) for all the pathways studied. The activation barrier of the RDS for the uncatalyzed reaction was predicted to be 189.8 kJ mol(-1) . The combination of an Sc(III) -N,N'-dioxide complex and the m-CBA molecule can construct a bifunctional catalyst in which the Lewis acidic Sc(III) center activates the carbonyl group of 4-phenylcyclohexanone while m-CBA transfers a proton, which lowers the activation barrier of the addition step (RDS) to 86.7 kJ mol(-1) . The repulsion between the m-chlorophenyl group of m-CPBA and the 2,4,6-iPr3 C6 H2 group of the N,N'-dioxide ligand, as well as the steric hindrance between the phenyl group of 4 phenylcyclohexanone and the amino acid skeleton of the N,N'-dioxide ligand, play important roles in the control of the enantioselectivity. PMID- 25809411 TI - Environmentally induced changes in correlated responses to selection reveal variable pleiotropy across a complex genetic network. AB - Selection in novel environments can lead to a coordinated evolutionary response across a suite of characters. Environmental conditions can also potentially induce changes in the genetic architecture of complex traits, which in turn could alter the pattern of the multivariate response to selection. We describe a factorial selection experiment using the nematode Caenorhabditis remanei in which two different stress-related phenotypes (heat and oxidative stress resistance) were selected under three different environmental conditions. The pattern of covariation in the evolutionary response between phenotypes or across environments differed depending on the environment in which selection occurred, including asymmetrical responses to selection in some cases. These results indicate that variation in pleiotropy across the stress response network is highly sensitive to the external environment. Our findings highlight the complexity of the interaction between genes and environment that influences the ability of organisms to acclimate to novel environments. They also make clear the need to identify the underlying genetic basis of genetic correlations in order understand how patterns of pleiotropy are distributed across complex genetic networks. PMID- 25809413 TI - Daily prednisone treatment in Duchenne muscular dystrophy in southwest China. AB - INTRODUCTION: In this study we aimed to determine the influence of daily prednisone treatment in Duchenne muscular dystrophy (DMD) by performing a prospective, randomized, placebo-controlled trial in southwestern China. METHODS: Sixty-six children with DMD (4-12 years of age) were divided randomly into prednisone and placebo groups. Efficacy and safety of daily prednisone at 0.75 mg/kg/day were evaluated over 12 months by muscle strength and function, quality of life (QoL), quantitative muscle ultrasound (QMUS), and side effects. RESULTS: Significant improvements in muscle strength and function, QoL, and QMUS were observed in the prednisone group compared with the placebo-treated group (P < 0.05). Changes in body weight, height, body mass index, and diastolic blood pressure were similar in both groups (P > 0.05). CONCLUSIONS: This pilot study in southwestern China found that daily prednisone at 0.75 mg/kg/day is suitable for children with DMD. It slowed disease progression and improved QoL and QMUS. Moderate side effects were generally well tolerated. PMID- 25809417 TI - Decreased stress resilience in young men significantly increases the risk of subsequent peptic ulcer disease - a prospective study of 233 093 men in Sweden. AB - BACKGROUND: Psychosocial stress may influence peptic ulcer disease (PUD) risk, but it can be difficult to identify reliably whether stressful exposures pre dated disease. The association of stress resilience (susceptibility to stress) with subsequent PUD risk has been incompletely investigated. AIM: To assess if stress resilience in adolescence is associated with subsequent PUD risk. METHODS: The participants comprised of 233 093 men resident in Sweden, born 1952-1956 and assessed for compulsory military conscription during 1969-1976, with data provided by national Swedish registers. Stress resilience was evaluated through semi-structured interviews by a certified psychologist. Cox regression assessed the association between stress resilience in adolescence and the risk of PUD from 1985 to 2009, between ages 28 and 57 years, with adjustment for parental socioeconomic index, household crowding and number of siblings in childhood, as well as cognitive function and erythrocyte sedimentation rate in adolescence. RESULTS: In total, 2259 first PUD diagnoses were identified. Lower stress resilience in adolescence is associated with a higher risk of PUD in subsequent adulthood: compared with high resilience, the adjusted hazard ratios (and 95% CI) are 1.84 (1.61-2.10) and 1.23 (1.09-1.38) for low and moderate stress resilience, respectively. CONCLUSION: Stress may be implicated in the aetiology of PUD and low stress resilience is a marker of risk. PMID- 25809414 TI - Dietary intake of fish, polyunsaturated fatty acids, and survival after breast cancer: A population-based follow-up study on Long Island, New York. AB - BACKGROUND: In laboratory experiments, omega-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from omega-6 PUFA metabolism via competitive inhibition, and the omega-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary omega-3 PUFA intake benefits survival after breast cancer are limited and inconsistent. METHODS: The authors used resources from a population-based follow up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire). Vital status was determined through 2011, yielding a median follow-up of 14.7 years and 485 deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression. RESULTS: All-cause mortality was reduced among women with breast cancer reporting the highest quartile of intake (compared with never) for tuna (HR, 0.71; 95% CI, 0.55-0.92), other baked/broiled fish (HR, 0.75; 95% CI, 0.58-0.97), and the dietary long-chain omega-3 PUFAs docosahexaenoic acid (HR, 0.71; 95% CI, 0.55-0.92) and eicosapentaenoic acid (HR, 0.75; 95% CI, 0.58-0.97). CONCLUSIONS: All-cause mortality was reduced by 16% to 34% among women with breast cancer who reported a high intake of fish and long chain omega-3 PUFAs. Long-chain omega-3 PUFA intake from fish and other dietary sources may provide a potential strategy to improve survival after breast cancer. PMID- 25809415 TI - Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up-regulating regulatory T cells. AB - Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-gamma expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL 17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORgammat). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy. PMID- 25809416 TI - Reciprocal crosses between two populations of Trissolcus vassilievi (Mayr) (Hymenoptera: Scelionidae) reveal maternal effects on thermal phenotypes. AB - The egg parasitoid Trissolcus vassilievi (Mayr) (Hymenoptera: Scelionidae) is a significant natural enemy of the sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae), the most important pest of wheat in Iran. This study examined the developmental time and egg-to-adult survival of two geographically separate populations of T. vassilievi on two corresponding host populations at five constant temperatures ranging from 15.0 to 35.0 +/- 1 degrees C. No wasps of either population emerged at 15.0 degrees C and the temperature threshold for development was similar between populations, ranging from 13.1 +/- 0.3 to 13.8 +/ 0.4 degrees C for males and 12.2 +/- 0.1 to 12.6 +/- 0.1 degrees C for females, but the thermal constant varied with gender and parasitoid population. Development of wasps from the colder Tabriz location was slower, with thermal constants for males and females of 172.6 +/- 3.1 and 204.1 +/- 1.2 degree-days, respectively, compared to Varamin wasps with 164.7 +/- 3.0 and 195.6 +/- 1.3 degree-days, respectively. Based on genetic inheritance patterns, reciprocal crosses between the two populations were expected to result in females with thermal phenotypes intermediate to their parental populations, and males that resembled their mothers. However, female progeny of crosses more closely resembled their maternal population, indicating a maternal effect on thermal phenotype. Furthermore, the magnitude of the maternal effect on the thermal constant was asymmetric and was more strongly expressed by Varmin than Tabriz females. These results suggest the possibility of using selective crosses between wasp populations, in combination with artificial selection in the laboratory, to tune the thermal phenotype of parasitoids to specific regions prior to augmentative releases. PMID- 25809418 TI - Field experimental evidence that stochastic processes predominate in the initial assembly of bacterial communities. AB - To assess the relative importance of environmental selection, dispersal and stochastic processes in structuring ecological communities, we conducted a bacterial community assembly experiment using microcosms filled with sterile liquid medium under field conditions in the Inner Mongolian grasslands. Multiple replicate microcosms containing different carbon substrates were placed at nine locations across three spatial scales (10, 300 and 10 000 m distance between locations) in such a way that the environment of microcosms varies independently of the geographical distance. The operational taxonomic units within the experimental communities were assessed via the terminal restriction fragment length polymorphism techniques on the 10th and 17th days after the onset of the experiment. We found no evidence of distance decay in community similarity, and communities within a given location were more similar to each other regardless of environment than communities at other locations within the same spatial scale. Variance partitioning indicated that location explained more compositional variation in microbial communities than environment, particularly on the 17th day, despite that environment and location in combination could only explain less than half of the total variation. These results suggest that bacterial dispersal is not limited by distance in this experiment, and community assembly in microcosms is not environmentally determined but governed by stochastic processes. PMID- 25809421 TI - Laparoscopic Transplantation Following Transvaginal Insertion of the Kidney: Description of Technique and Outcome. AB - Laparoscopic kidney transplantation (LKT) is well accepted modality of treatment for ESRD patients at our center. Usually, the kidney is inserted through small Pfannenstiel incision. With the permission of the Internal Review Board, we carried out LKT in eight female recipients following insertion of the kidney through the vagina. The kidney was procured by the retroperitoneoscopic approach. Antibiotic prophylaxis was given. All cases were carried out successfully with immediate graft function and 100% graft and patient survival at 1 year of follow up. Estimated glomerular filtration rate at 1 month and 1 year was similar to eight randomly selected female recipients who underwent open kidney transplantation (OKT). No analgesia was required in seven out of eight patients after the 3rd postoperative day. In summary, vaginal insertion of kidney and LKT is safe and feasible in a selected group of patients. It is associated with better analgesia and has similar allograft function as compare to OKT. PMID- 25809422 TI - Distribution of cytokine gene polymorphisms in five Malay subethnic groups in Peninsular Malaysia. AB - In this survey, we have successfully genotyped 22 single nucleotide polymorphisms in the 13 cytokine genes for five Malay subethnic groups (Kelantan, Acheh, Mandailing, Minangkabau and Patani Malays) using polymerase chain reaction sequence-specific primer cytokine genotyping kit (Invitrogen, Carlsbad, CA, USA). Most of the cytokine genes showed similar pattern of allelic spectra with wild type alleles (e.g. ILIa-889/C, ILIB+3962/C and IL6 nt565/G) that represent more than 80% in the studied Malay subethnic groups. These newly observed cytokine alleles and subsequent analyses clearly indicate genetic contribution from Asia in the studied Malay subethnic groups with evidence of admixture from neighbouring populations in Patani Malays. The cytokine data sets for the five Malay subethnic groups deposited in this report can also be used as reference standard for searching suitable donor for allograft transplant and diseases association study. This is particularly relevance as our analyses showed differences between the Malay subethnic groups and other populations screened for cytokine genes. PMID- 25809420 TI - International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. PMID- 25809423 TI - Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib. AB - INTRODUCTION: UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes responsible for the glucuronidation reaction. Many therapeutic classes of drugs used in solid tumors are UGT substrates, including cancer therapies. AREAS COVERED: This article describes the tyrosine kinase inhibitors (TKIs) undergoing hepatic glucuronidation; its effect on transport and tissue accumulation and the clinical consequences of this particular metabolism. A PubMed search concerning the pharmacokinetics of the TKIs was performed. All are extensively metabolized by CYP450. Two TKIs, sorafenib and regorafenib, also have a major UGT-mediated metabolism and were therefore studied. EXPERT OPINION: The prescription of the same dose of sorafenib and regorafenib for all patients may be inappropriate since at each enzymatic step of this multistep metabolism inter-individual fluctuations exist. Having a non-exclusive CYP-mediated route of metabolism may reduce the risk of variability in drug exposure when CYP3A4 substrates are concomitantly given. Several clinical consequences derive from this pharmacokinetic particularity of sorafenib and regorafenib. Since no clear difference distinguishes TKIs in efficacy in large randomized trials, the differences for the clinical management of their toxicity is a critical aspect. PMID- 25809419 TI - The value of serum aspartate aminotransferase and gamma-glutamyl transpetidase as biomarkers in hepatotoxicity. AB - BACKGROUND & AIMS: The current definition of the pattern of liver injury in hepatotoxicity (DILI) is given by the R (ratio) value, dividing alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in upper limits of normal at DILI onset. We aimed to explore the validity of using aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) as biomarkers of hepatocelullar and cholestatic damage, respectively, when calculating the R value. METHODS: Clinical, laboratory and histological data from 588 DILI episodes included in the Spanish DILI Registry were analyzed. Linear regression analysis was performed to establish the most appropriate cut-off points for hepatocellular and cholestatic patterns when calculating R with AST and GGT. RESULTS: The overall agreement between ALT/ALP and AST/ALP was 76%, with 96%, 61% and 41% agreement in the hepatocellular (R >= 5), cholestatic (R <= 2) and mixed groups respectively (P < 0.001). Classified by the causative drug, the agreement was higher (87-95%) among drug classes that mainly present with hepatocellular damage and lower (48-58%) for those in which cholestatic-mixed injury predominate (P < 0.001)). The overall agreement between ALT/ALP and ALT/GGT was weak (59%), except for in hepatocellular cases that showed a good agreement (94%) (P = 0.001). Pattern of injury according to liver histology demonstrated 65%, 68% and 47% agreement for ALT/ALP, AST/ALP and ALT/GGT ratios respectively. CONCLUSIONS: AST can reliably replace ALT when calculating pattern of liver injury in DILI, while GGT can only substitute ALP when the R value scores as hepatocellular. The biochemical signature of causative drugs does influence the validity of the ratios with AST or GGT. PMID- 25809424 TI - Pathway analysis of genome-wide association datasets of personality traits. AB - Although several genome-wide association (GWA) studies of human personality have been recently published, genetic variants that are highly associated with certain personality traits remain unknown, due to difficulty reproducing results. To further investigate these genetic variants, we assessed biological pathways using GWA datasets. Pathway analysis using GWA data was performed on 1089 Korean women whose personality traits were measured with the Revised NEO Personality Inventory for the 5-factor model of personality. A total of 1042 pathways containing 8297 genes were included in our study. Of these, 14 pathways were highly enriched with association signals that were validated in 1490 independent samples. These pathways include association of: Neuroticism with axon guidance [L1 cell adhesion molecule (L1CAM) interactions]; Extraversion with neuronal system and voltage gated potassium channels; Agreeableness with L1CAM interaction, neurotransmitter receptor binding and downstream transmission in postsynaptic cells; and Conscientiousness with the interferon-gamma and platelet-derived growth factor receptor beta polypeptide pathways. Several genes that contribute to top-ranked pathways in this study were previously identified in GWA studies or by pathway analysis in schizophrenia or other neuropsychiatric disorders. Here we report the first pathway analysis of all five personality traits. Importantly, our analysis identified novel pathways that contribute to understanding the etiology of personality traits. PMID- 25809425 TI - Thrilling strain! Donor-acceptor-substituted cyclobutanes for the synthesis of (hetero)cyclic compounds. AB - The analogy goes further: Following the often-studied donor-acceptor-substituted cyclopropanes, the corresponding cyclobutane derivatives were employed for the ring-strain-driven stereoselective syntheses of carbo- and heterocycles. PMID- 25809426 TI - Bilateral traumatic hip dislocation with sciatic nerve palsy. AB - Bilateral hip dislocation is a rare condition. We report a case of traumatic bilateral hip dislocation and unilateral sciatic nerve palsy in a young woman with known idiopathic scoliosis. With prompt reduction of the dislocated hips, there was reasonable neurological recovery. There was no avascular necrosis of the femoral head or post-traumatic arthritis up to 3-year follow-up. The gender difference in incidence, as well as the predisposition of hip dislocation in scoliosis is discussed. In our case, the decreased femoral anteversion was the culprit. PMID- 25809427 TI - Parotid epithelial-myoepithelial carcinoma: an unexpected intraoperative finding. AB - We present a case of a 72-year-old man with a parotid mass which was initially diagnosed as a pleomorphic adenoma. Intraoperatively, the tumour was found to be invading the facial nerve. It was later found to be an epithelial-myoepithelial carcinoma, a rare salivary gland tumour. Despite invasion of the facial nerve, function of the nerve remained intact. PMID- 25809428 TI - Sarcoidosis presented as retroperitoneal and lung mass. AB - Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology characterised pathologically by the presence of non-caseating granulomas in involved organs. Sarcoidosis most frequently involves the lungs followed by eye and skin. Presentation as retroperitoneal and lung mass is rare in sarcoidosis. We describe an unusual case of sarcoidosis where the patient presented with large retroperitoneal and lung masses, and was treated as tuberculosis. PMID- 25809429 TI - Management of the sodium hypochlorite accident: a rare but significant complication of root canal treatment. AB - A 66-year-old female patient presented to the accident and emergency department, 3 h following a dental appointment. Significant right-sided facial swelling, bruising and pain were present. The patient had been sent by her general dental practitioner with a covering letter explaining that a hypochlorite accident had occurred during root canal treatment of the upper right first premolar tooth. An iatrogenic perforation was suspected. The patient was admitted under the care of the maxillofacial team and intravenous antibiotics, analgesia and steroids were administered. The patient was prepared for the possibility of requiring surgical intervention under a general anaesthetic. No nerve injury was encountered and the periorbital tissues were spared. A full recovery was made by the patient with no surgical intervention required but significant bruising and swelling were present up to 4 weeks following the incident. PMID- 25809430 TI - Flucloxacillin and fusidic acid-associated neutropenia in a patient with periaortic abscess: rare side effects of commonly used antibiotics. AB - The use of long-term antibiotics for deep-seated infections is very common, and is associated with many clinically significant side effects. In this report we describe the history of a 48-year-old man who attended West Suffolk Hospital with nausea and vomiting, and was subsequently found to have a deep-seated infection following his repeat aortic valve replacement. He completed a 7-week course of intravenous flucloxacillin and oral fusidic acid, however, prior to finishing this course a random blood test revealed a neutrophil count of zero. He was re admitted to hospital with fever, and was treated accordingly as per the trust's neutropenic sepsis protocol with the addition of growth colony stimulating factor (GCSF). His neutrophil count recovered after 3 days and has remained within the normal range ever since. PMID- 25809431 TI - Mediastinal germ cell tumour causing superior vena cava tumour thrombosis. AB - We report a rare case of a 35-year-old man who presented with a 1-week history of retrosternal chest pain of moderate intensity. A positron emission tomography CT (PET-CT) showed a large fluorodeoxy-glucose (FDG)-avid heterogeneously enhancing necrotic mass in the anterosuperior mediastinum with a focal FDG-avid thrombosis of the superior vena cava (SVC) suggestive of tumour thrombus and vascular invasion. alpha-Fetoprotein levels were raised (5690 IU/L). Image guided biopsy of the mediastinal mass was suggestive of non-seminomatous germ cell tumour (NSGCT). The patient received four cycles of BEP (bleomycin, etoposide and cisplatin) along with therapeutic anticoagulation with low-molecular-weight heparin. Follow-up whole body PET-CT revealed complete resolution of mediastinal mass and SVC tumour thrombosis. The documentation of FDG-PET-avid tumour thrombus resolving with chemotherapy supports the concept of circulating tumour cells being important not only in common solid tumours such as breast and colon cancer but also in relatively less common tumours such as NSGCT. The detection of circulating tumour cells could help deploy aggressive regimens upfront. PMID- 25809432 TI - Severe hypercalcaemia and colon ischaemia: dehydration as an unusual cause? AB - Hypercalcaemia is an emergency with severe consequences. Dehydration can be an uncommon cause of hypercalcaemia, as seen in this case. A 63-year-old woman with type 2 diabetes mellitus, hypothyroidism and osteoporosis, was admitted to the emergency room with abdominal distension and vomiting for 24 h. Initial evaluation was Hg 18.5 g/dL, Htc 56.2%, creatinine 2 mg/dL, metabolic acidaemia, lactate 8.3 mmol/L, anion gap 19, total Ca(2+) 17.7 mg/dL and PO4+ 6.6 mg/dL. CT revealed colonic distension without obstruction or ischaemia. Renal replacement therapy and pamidronate were initiated. The patient's clinical condition deteriorated with septic shock in the context of toxic megacolon and she underwent an emergency subtotal colectomy (10 kg). Hypercalcaemia was corrected in 24 h with aggressive fluid replacement (8 L NaCl 0.9% first 12 h), with a reduction of total Ca(2+) to 8.2 mg/dL. Other causes of hypercalcaemia were excluded. 'Hypercalcaemic crisis' secondary to severe acute dehydration is not mentioned in the literature. PMID- 25809433 TI - A rare case of fatal stroke after ethylene glycol toxicity. AB - A 58-year-old man presented to the emergency department with acute left-sided weakness and left visual field defect. His examination was significant for confusion, acetone odour, tachycardia and tachypnoea. Further blood tests revealed an anion gap of 31 mEq/L, serum osmolal gap of 34 mOsm/kg, and creatinine 3.6 mg/dL. Brain MRI revealed acute infarctions scattered throughout the brain along with generalised oedema. The patient deteriorated rapidly and soon thereafter it was reported that a bottle of antifreeze was found near him at home. Haemodialysis was initiated and the patient received fomepizole and bicarbonate. Three days later the patient did not show any neurological improvement and expired later that day. Ethylene glycol toxicity can rarely present with stroke which can be life-threatening when not diagnosed and managed in a timely fashion. PMID- 25809434 TI - Complete recovery after severe myxoedema coma complicated by status epilepticus. AB - We report a case of life-threatening myxoedema presenting with hypothermia, hypotension, bradycardia, pericardial effusion and deep coma. The condition was complicated by prolonged status epilepticus. The optimal treatment strategy has been debated over the years and the literature is briefly reviewed. Treatment with l-thyroxine (LT4) monotherapy without initial loading dose and with no l triiodothyronine (LT3) treatment was successful with full recovery after hospitalisation for more than a month. Myxoedema coma is a rare, reversible condition with a high mortality and should be considered as a differential diagnosis in medical emergencies. PMID- 25809435 TI - i-gel: a new supraglottic device for effective resuscitation of a very low birthweight infant with Cornelia de Lange syndrome. AB - Laryngeal Mask Airway (LMA) has been indicated as an effective device for airway management when face-mask ventilation and intubation have both failed in infants weighing >2000 g or delivered >=34 weeks of gestation. All previous studies used a classic LMA. The current report describes the first case of a very low birthweight infant (1470 g, <3rd centile; 36(+3)gestational weeks) with micrognathia and palate cleft with Cornelia De Lange syndrome, resuscitated at birth with a new supraglottic airway device, i-gel size-1, positioned by a trainee paediatrician at first attempt. The procedure allowed reaching prompt effective ventilation and oxygenation of the patient, who was stabilised and intubated through i-gel. PMID- 25809436 TI - Conservative management of a post-traumatic pseudoaneurysm of the artery of cervical enlargement-anterior spinal artery junction. AB - A 22-year-old man suffered severe sudden onset head and neck pain after being pushed from behind during an assault. Physical examination was normal. Cervical MRI demonstrated an intradural hematoma, anterior to the cord, between C2-4. Subsequent contrast enhanced MR angiography and digital subtraction vertebral angiography confirmed that the cause of the hemorrhage was a fusiform (presumed dissecting) pseudoaneurysm of the artery of the cervical enlargement at its junction with the anterior spinal artery. The aneurysm was managed conservatively. Follow-up angiography demonstrated that the aneurysm had spontaneously thrombosed within 10 days and remained occluded at 2 months. The patient remained occluded at 6 months following the initial injury. Anterior spinal aneurysms represent a management dilemma and options are discussed. PMID- 25809438 TI - MLT1 links cytoskeletal asymmetry to organelle placement in chlamydomonas. AB - Asymmetric placement of the photosensory eyespot organelle in Chlamydomonas is patterned by mother-daughter differences between the two basal bodies, which template the anterior flagella. Each basal body is associated with two bundled microtubule rootlets, one with two microtubules and one with four, forming a cruciate pattern. In wild-type cells, the single eyespot is positioned at the equator in close proximity to the plus end of the daughter rootlet comprising four microtubules, the D4. Here we identify mutations in two linked loci, MLT1 and MLT2, which cause multiple eyespots. Antiserum raised against MLT1 localized the protein along the D4 rootlet microtubules, from the basal bodies to the eyespot. MLT1 associates immediately with the new D4 as it extends during cell division, before microtubule acetylation. MLT1 is a low-complexity protein of over 300,000 Daltons. The expression or stability of MLT1 is dependent on MLT2, predicted to encode a second large, low-complexity protein. MLT1 was not restricted to the D4 rootlet in cells with the vfl2-220 mutation in the gene encoding the basal body-associated protein centrin. The cumulative data highlight the role of mother-daughter basal body differences in establishing asymmetry in associated rootlets, and suggest that eyespot components are directed to the correct location by MLT1 on the D4 microtubules. PMID- 25809440 TI - A unique fluoride nanocontainer: porous molecular capsules can accommodate an unusually high number of "rather labile" fluoride anions. AB - The present work refers to the challenging issue of fluoride anion recognition/binding in water by taking advantage of the unique possibilities offered by the porous molecular nanocontainers of the {Mo132} Keplerate type allowing the study of a variety of new phenomena. Reaction of the highly reactive carbonate-type capsule with aqueous HF results in the release of carbon dioxide and integration of an unprecedentedly large number of fluoride anions--partly as coordinated ligands at both the pentagonal units and the linkers, partly as a disordered water/fluoride assembly inside the cavity. The internal assembly and some of the fluoride ligands are easily released, which provides interesting options for future studies regarding coordination chemistry and catalysis under confined conditions. PMID- 25809437 TI - Cognitive phenotype of psychotic symptoms in Alzheimer's disease: evidence for impaired visuoperceptual function in the misidentification subtype. AB - BACKGROUND: Establishing the cognitive phenotype of psychotic symptoms in Alzheimer's disease (AD) could localise discrete pathology and target symptomatic treatment. This study aimed to establish whether psychotic symptoms would be associated with poorer performance on neuropsychological tests known to correlate with striatal dopaminergic function and to investigate whether these differences would be attributed to the paranoid (persecutory delusions) or misidentification (misidentification phenomena +/- hallucinations) subtype. METHODS: Seventy patients with probable AD (34 psychotic and 36 nonpsychotic) were recruited to the study. Analysis of covariance was used to compare motor speed and the rapid visual processing test of sustained visual attention, after adjusting for potential confounding factors. Multivariate analyses were used to compare performance across other cognitive domains. Significant findings were explored by separating patients on the basis of subtype. RESULTS: Rapid visual processing performance accuracy was reduced in patients with psychotic symptoms (F1,58 = 5.94, p = 0.02) and differed significantly across subtypes (F2,51 = 3.94, p = 0.03), largely because of poorer performance in the misidentification compared with nonpsychotic group. Multivariate analyses (corrected for multiple comparisons) showed poorer performance on the incomplete letters task in psychotic patients (F1,63 = 8.77, p = 0.004) and across subtypes (F2,55 = 10.90, p < 0.001), similarly attributed to the misidentification subtype. CONCLUSIONS: These findings provide further support of the involvement of dopaminergic networks in the psychosis endophenotype in AD and, in addition, implicate the ventral (temporo-occipital) pathway in the misidentification subtype. Future studies should investigate the early trajectory of neuropathological change in vivo across psychosis subtypes. PMID- 25809441 TI - Investigation of structure-activity relationships of synthetic anti-gonadotropin releasing hormone vaccine candidates. AB - The immunoneutralization of gonadotropin-releasing hormone (GnRH) can be used for the treatment of human hormone-dependent male and female cancers or as immunocontraceptives in animals. Vaccine candidates 1 [Th(K-LP)GnRH], 2 [GnRH(K LP)Th], 3 [GnRH(K-Th)LP], and 4 [Th(K-GnRH)LP] (for which K=lysine, LP=lipopeptide Ser-Ser-C16 -C16 , and Th=T helper cell epitope influenza HA2), were synthesized by assembling a CD4(+) T helper cell epitope (Th), GnRH, and an adjuvanting lipid moiety (LP) in various spatial arrangements. All compounds were efficiently taken up by antigen-presenting cells with significant immunogenicity without an external adjuvant. Compounds 2, 3, and 4, in which GnRH is conjugated through its C terminus, produced higher GnRH-specific antibody responses than construct 1, in which the GnRH moiety is conjugated through its N terminus. All four constructs induced a significant antiproliferative effect (up to 55 %) on GnRH-receptor-positive LNCaP cells, but showed weaker activity in the GnRH receptor-negative SKOV-3 cell line. Marked degenerative changes were observed in morphology and follicular development in the ovaries of immunized mice, with approximately 30 % higher degenerative antral and atretic follicles. PMID- 25809439 TI - Agreement between questionnaire report of allergy-related outcomes in school-age children and objective measures of atopy: the Saskatchewan rural health study. AB - BACKGROUND AND OBJECTIVES: In population-based studies, questionnaires remain the most efficient tool to assess the presence of allergy and atopic conditions, but the quality of the information obtained needs to be validated. We sought to evaluate the agreement and predictive values of a questionnaire to assess atopy in rural children, an understudied population with regard to atopy and allergic disease. METHODS: A total of 480 schoolchildren (grades 1-8) from rural Saskatchewan completed a questionnaire report of allergy and atopic outcomes and participated in skin prick testing (SPT). SPT for 6 common allergens (local grasses, wheat dust, cat dander, house dust mite mixed, Alternaria, and Cladosporium) was completed. Subjects with at least one positive SPT (>= 3 mm) compared to the negative control were considered to be atopic. We considered per cent concordance, Kappa, sensitivity, specificity, and the positive predictive value and negative predictive value (NPV, PPV) of reported allergies or allergic conditions in comparison with SPT as the gold standard. RESULTS: We found that 25.0% of children reported a history of any allergy and 19.4% were atopic based on SPT. The agreement between questionnaire report of allergic triggers and atopy measured by SPT was high (83.0-89.5%). The agreement between atopy and report of allergic conditions ranged from 67.1% to 79.6%. Individual allergic conditions demonstrated high specificity but low sensitivity. The questionnaire report of any allergy had a low PPV in detecting atopy (47.3%) and high NPV (86.3%). The PPV of reported allergic conditions was low (24.8-43.9%), but the NPV was again high (82.0-82.9%). CONCLUSIONS: We found that the standardized questionnaire report of allergy and atopic conditions was shown not to efficiently and reliably predict atopy. However, given the good specificity and the NPV, the questionnaire may be an efficient tool for epidemiological studies that involve the differential inclusion of subjects without atopy. PMID- 25809443 TI - Metalless electrodes for capacitively coupled contactless conductivity detection on electrophoresis microchips. AB - This paper describes the use of ionic solutions as sensing electrodes for capacitively coupled contactless conductivity detection on electrophoresis microchips. Initially, two channels were engraved in a PMMA holder by using a CO2 laser system and sealed with a thin adhesive membrane. PDMS electrophoresis chips were fabricated by soft lithography and reversibly sealed against the polymer membrane. Different ionic solutions were investigated as metalless electrodes. The electrode channels were filled with KCl solutions prepared in conductivity values from approximately 10 to 40 S/m. The best analytical response was achieved using the KCl solution with 21.9 S/m conductivity (2 mol/L). Besides KCl, we also tested NaCl and LiCl solutions for actuating as detection electrodes. Taking into account the same electrolyte concentration (2 mol/L), the best response was recorded with KCl solution due to its higher ionic conductivity. The optimum operating frequency (400 kHz) and the best sensing electrode (2 mol/L KCl) were used to monitor electrophoretic separations of a mixture containing K(+) , Na(+) , and Li(+) . The use of liquid solutions as sensing electrodes for capacitively coupled contactless conductivity detection measurements has revealed great performance to monitor separations on chip-based devices, avoiding complicated fabrication schemes to include metal deposition and encapsulation of electrodes. The LOD values were estimated to be 28, 40, and 58 MUmol/L for K(+) , Na(+) , and Li(+) , respectively, what is comparable to that of conventional metal electrodes. When compared to the use metal electrodes, the proposed approach offers advantages regarding the easiness of fabrication, simplicity, and lower cost per device. PMID- 25809444 TI - Aerosol deposition in the lungs of spontaneously breathing rats using Gd-DOTA based contrast agents and ultra-short echo time MRI at 1.5 Tesla. AB - PURPOSE: Aerosol toxicology and drug delivery through the lungs, which depend on various parameters, require methods to quantify particle deposition. Intrapulmonary-administered MRI contrast agent combined with lung-specific imaging sequences has been proposed as a high performance technique for aerosol research. Here, aerosol deposition is assessed using ultra-short echo (UTE) sequences. METHODS: Before and after administration of Gd-DOTA-based aerosol delivered nose-only in free-breathing healthy rats, a T1 -weighted 3D UTE sequence was applied in a clinical 1.5 Tesla scanner. Administration lasted 14 min, and the experiment was performed on six rats. A contrast-enhanced quantitative analysis was done. RESULTS: Fifty percent signal enhancement was obtained in the lung parenchyma. Lung clearance of the contrast agent was evaluated to be 14% per h (corresponding to a characteristic clearance time of 3.6 h) and aerosol deposition was shown to be homogeneous throughout the lung in healthy rats. The total deposited dose was estimated to be 1.05 umol/kg body weight, and the concentration precision was 0.02 mM. CONCLUSION: The UTE protocol with nebulized Gd-DOTA is replicable to significantly enhance the lung parenchyma and to map aerosol deposition. This functional strategy, applied in a clinical system with a clinical nebulization setup and a low inhaled dose, suggests a feasible translation to human. PMID- 25809445 TI - Differences between high- and low-motility buffalo sperm identified by comparative proteomics. AB - This study was undertaken to investigate differences in protein expression between high- and low-motility sperm of swamp buffalo. The research used two dimensional gel electrophoresis (2DE) coupled to matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS) to analyse the different proteins. The results showed 18 different expression protein spots between high- and low-motility buffalo sperm; eight of these proteins were up-regulated in low-motility sperm, five were down-regulated, one deleted and four proteins specifically expressed. Finally, four proteins were successfully identified by MS as belonging to three unique proteins; they are outer dense fibre of sperm tails protein 2 (ODF2), ATP synthase subunit alpha (ATP5A1) and succinyl-CoA synthetase subunit beta (SUCLG2). In summary, these results help to develop an understanding of the molecular mechanisms associated with low-motility sperm and provide clues for finding molecular markers associated with sperm motility. PMID- 25809442 TI - Proteomic approaches to analyzing hepatitis C virus biology. AB - Hepatitis C virus (HCV) is a major cause of liver disease worldwide. Acute infection often progresses to chronicity resulting frequently in fibrosis, cirrhosis, and in rare cases, in the development of hepatocellular carcinoma. Although HCV has proven to be an arduous object of research and has raised important technical challenges, several experimental models have been developed all over the last two decades in order to improve our understanding of the virus life cycle, pathogenesis and virus-host interactions. The recent development of direct acting-agents, leading to considerable progress in treatment of patients, represents the direct outcomes of these achievements. Proteomic approaches have been of critical help to shed light on several aspect of the HCV biology such as virion composition, viral replication, and virus assembly and to unveil diagnostic or prognostic markers of HCV-induced liver disease. Here, we review how proteomic approaches have led to improve our understanding of HCV life cycle and liver disease, thus highlighting the relevance of these approaches for studying the complex interactions between other challenging human viral pathogens and their host. PMID- 25809446 TI - Comparing cortical auditory processing in children with typical and atypical benign epilepsy with centrotemporal spikes: Electrophysiologic evidence of the role of non-rapid eye movement sleep abnormalities. AB - OBJECTIVE: The mismatch negativity (MMN) is an objective measure of central auditory discrimination. MMN alterations have been shown in children with language and/or developmental disorders. In benign focal epilepsies, neuropsychological disorders are often reported and linked to interictal epileptic discharges (IEDs) during non-rapid eye movement (NREM) sleep. There are few studies reporting MMN in children with benign epilepsy with centrotemporal spikes (BECTS) and sleep IEDs. Moreover, no MMN recording has yet been reported in atypical BECTS children with continuous spike-and-wave during sleep (CSWS). We retrospectively compared MMN in typical and atypical BECTS children, particularly addressing the impact of NREM sleep IEDs on auditory discrimination. Moreover, we attempted a neuropsychological characterization of patients. METHODS: The MMN was recorded in 9 normal controls and 23 patients (14 typical BECTS and 9 atypical BECTS) in an oddball paradigm with syllable stimuli. MMN, sleep electroencephalography (EEG) and neuropsychological evaluation were realized in the same testing session. RESULTS: Measurable MMN responses to speech stimuli were identified in both the control and patient groups. A significant difference between control and atypical BECTS children was found with respect to amplitude (p = 0.0061). Atypical BECTS also showed a lower MMN amplitude with respect to typical BECTS, but this difference did not reach statistical significance (p = 0.0545). Statistical comparisons between groups revealed no differences in latency. Among the neuropsychological variables, academic difficulties were significantly more prominent in the patients with atypical BECTS (p = 0.04). SIGNIFICANCE: CSWS EEG pattern affects auditory discrimination and may have a long-lasting impact on academic skills acquisition, whereas in typical BECTS children with a lower degree of IED NREM sleep, plastic brain reorganization or the preservation of participating networks may prevent such difficulty. Early electrophysiologic identification of auditory discrimination deficits in epileptic children could be used in early rehabilitation, thereby reducing the risk of developing neuropsychological disorders. PMID- 25809447 TI - HDL particle subpopulations: Focus on biological function. AB - Low levels of high-density lipoprotein-cholesterol (HDL-C) constitute an independent biomarker of cardiovascular morbi-mortality. However, recent advances have drastically modified the classical and limited view of HDL as a carrier of 'good cholesterol', and have revealed unexpected levels of complexity in the circulating HDL particle pool. HDL particles are indeed highly heterogeneous in structure, intravascular metabolism and biological activity. This review describes recent progress in our understanding of HDL subpopulations and their biological activities, and focuses on relationships between the structural, compositional and functional heterogeneity of HDL particles. PMID- 25809449 TI - Actor-Partner Effects and the Differential Roles of Depression and Anxiety in Intimate Relationships: A Cross-Sectional and Longitudinal Analysis. AB - OBJECTIVE: The purpose of the present study was to investigate the differential roles of depression and anxiety in intimate relationship satisfaction, both cross sectionally and longitudinally. METHOD: The cross-sectional sample comprised 70 couples, of which 48 couples also participated at follow-up. All couples completed measures of relationship satisfaction and symptoms of depression and anxiety. RESULTS: Cross-sectionally, actor symptoms of depression were the only predictor of relationship satisfaction, after controlling for symptoms of anxiety. Conversely, depressive symptoms did not predict change in relationship satisfaction over time above and beyond the effects of anxiety. Instead, actor symptoms of anxiety at time 1 predicted a decline in relationship satisfaction from time 1 to time 2. For wives, their husbands' levels of anxiety at time 1 also predicted longitudinal change in relationship satisfaction. CONCLUSION: These results highlight the importance of studying the constructs of depression and anxiety simultaneously, and point to intriguing gender differences. PMID- 25809450 TI - Response to the comments on the paper by Horowitz et al. (2014). PMID- 25809451 TI - Fetal/neonatal alloimmune thrombocytopenia: more data favouring less invasive treatment. PMID- 25809452 TI - Effects on membrane lung gas exchange of an intermittent high gas flow recruitment maneuver: preliminary data in veno-venous ECMO patients. AB - Gas exchange capabilities of polymethylpentene membrane lungs (MLs) worsen over time. ML deterioration is related to protein deposit and clot formation. Condensation and trapping of water vapor inside ML hollow fibers might affect ML performances as well. Increasing sweep gas flow (GF) could remove such fluid. The purpose of this study was to evaluate the effects on ML gas exchange of a recruitment maneuver (RM) based on a brief increase in GF, during veno-venous ECMO support. Short-term (15 min) effects of 20 RMs were assessed. RM raised ML CO2 removal from 149 +/- 37 to 174 +/- 41 ml/min (p < 0.001). Conversely, RM did not improve ML O2 transfer (155 +/- 31 and 158 +/- 31 ml/min before and after RM, respectively). ML outlet pCO2 decreased after RM from 51.2 +/- 5.8 to 45.8 +/- 5.4 mmHg (p < 0.001), while ML outlet pO2 increased from 520 +/- 61 to 555 +/- 51 mmHg (p < 0.001). Both ML dead space and shunt fractions decreased from 47.8 +/- 15.3 to 29.6 +/- 14.7 % (p < 0.001) and from 8.8 +/- 4.2 to 7.0 +/- 3.8 % (p < 0.001), respectively. Furthermore, a subset of 5 RMs was evaluated on a 6-h time frame. The beneficial effects on ML performances due to the RM gradually diminished and waned over a 6-h interval after the RM. The RM improved ML CO2 removal substantially, albeit temporarily. ML oxygenation performance was marginally affected. PMID- 25809453 TI - Acute response test to adaptive servo-ventilation, a possible modality to assessing the reversibility of pulmonary vascular resistance. AB - Since pulmonary hypertension (PH) due to left-sided heart failure (HF) with elevated pulmonary vascular resistance (PVR) is contraindication for heart transplantation (HTx), correct evaluation of reversibility in PVR is essential for adequate therapeutic decision-making. However, guidelines or recommended protocols for pharmacological testing to evaluate the reversibility of PVR have not been established yet. In this report, we presented a 34-year-old male with advanced HF complicated by severe PH with high PVR [5.93 Wood units (WU)] who was deemed eligible for HTx. To evaluate his HTx candidacy, oxygen inhalation test was applied during right heart catheterization (RHC) and PVR was drastically decreased to 2.29 WU. At that time, acute response test to adaptive servo ventilation (ASV) was also applied and use of ASV temporarily but substantially decreased PVR to 2.15 WU. From the results of both oxygen inhalation test and acute response test to ASV, reversibility of PVR in this patient was confirmed, and the patient was approved as HTx candidate and received left ventricular assist device (LVAD) implantation for bridge to transplant. After LVAD implantation, PVR substantially and persistently decreased to 2.4 WU. These findings indicate that acute response test to ASV during RHC may be a possible modality to evaluate the reversibility of PVR in HF patients with PH complicated by elevated PVR. PMID- 25809454 TI - Characterizing patients with chronic heart failure in community care after hospitalization: a potential role for ivabradine. AB - AIMS: To identify the prevalence and characteristics of recently hospitalized chronic heart failure (CHF) patients in community care who meet the indication for ivabradine. METHODS: A retrospective clinical audit of CHF patients recently hospitalized with acute decompensated heart failure (ADHF) and subsequently referred to the Tayside Heart Failure Nurse Liaison Service (THFNLS), a Scottish nurse-led community heart failure liaison service. Inclusion criteria were previous hospitalization with ADHF, subsequent referral to the THFNLS, data for >= 2 nurse visits, and a recorded pulse. The main outcome measure was the proportion of patients who meet the indicated criteria for ivabradine. RESULTS: In the UK, ivabradine is indicated for CHF with systolic dysfunction in patients in sinus rhythm, with a heart rate >= 75 bpm, and NYHA class II-class IV. After up-titration of a beta-blocker, 19.0% of patients in the full dataset (158 of 830) met the indication for ivabradine at the last visit. Of these "ivabradine suitable" patients, 101 of 158 (63.9%) received bisoprolol "at any time" during the study period; 20 of 158 (12.7%) achieved the target dose (10 mg daily); 52 of 158 (32.9%) received 5 mg or 7.5 mg daily; and 93 of 158 (58.9%) received <5 mg daily. CONCLUSIONS: In this group of Scottish patients previously hospitalized with ADHF and under the care of a protocol-driven clinic, 19% met the indication for ivabradine and may benefit from the increased control of CHF that ivabradine can provide. Among these "ivabradine-suitable" patients, <15% achieved the target dose of beta-blockers, illustrating the substantial clinical need for a well tolerated and effective therapy such as ivabradine. PMID- 25809455 TI - Biocompatibility and osteogenesis of calcium phosphate composite scaffolds containing simvastatin-loaded PLGA microspheres for bone tissue engineering. AB - By utilizing a modified solid/oil/water (s/o/w) emulsion solvent evaporation technique, calcium phosphate composite scaffolds containing simvastatin-loaded PLGA microspheres (SIM-PLGA-CPC) were prepared in this study. We characterized the morphology, encapsulation efficiency and in vitro drug release of SIM-loaded PLGA microspheres as well as the macrostructure, pore size, porosity and mechanical strength of the scaffolds. Rabbit bone mesenchymal stem cells (BMSCs) were seeded onto SIM-PLGA-CPC scaffolds, and the proliferation, morphology, cell cycle and differentiation of BMSCs were investigated using the cell counting kit 8 (CCK-8) assay, scanning electron microscopy (SEM), flow cytometry, alkaline phosphatase (ALP) activity and alizarin red S staining, respectively. The results revealed that SIM-PLGA-CPC scaffolds were biocompatible and osteogenic in vitro. To determine the in vivo biocompatibility and osteogenesis of the scaffolds, both pure PLGA-CPC scaffolds and SIM-PLGA-CPC scaffolds were implanted in rabbit femoral condyles and microradiographically and histologically investigated. SIM PLGA-CPC scaffolds exhibited good biocompatibility and could improve the efficiency of new bone formation. All these results suggested that the SIM-PLGA CPC scaffolds fulfilled the basic requirements of bone tissue engineering scaffold and possessed application potentials in orthopedic surgery. PMID- 25809456 TI - Exploring the Scope of Consumer Participation in Mental Health Nursing Education: Perspectives From Nurses and Consumers. AB - PURPOSE: Exploration of the views and experiences of nurse academics and consumer academics and educators regarding the scope of consumer participation in mental health nursing education. DESIGN AND METHODS: A qualitative, exploratory inquiry into the description and views of mental health nurse academics and consumer educators about these roles FINDINGS: A significant variation in roles from guest speaker to substantive academic positions was evident, with most involvement brief and specifically teaching focused. Consumer participation in education was generally valued but noted to be limited in breadth and scope. Some concern was raised about the relevance of consumer academic roles, with a clear conceptualization of the consumer academic role necessary to facilitate their contribution to the education of health professionals. PRACTICE IMPLICATIONS: Mental health consumer involvement in the education of nurses has been shown to impact positively on the attitudes of health professionals to people with mental illness. Advocacy for increased, meaningful input from consumers into nursing education is therefore necessary to improve practice. PMID- 25809457 TI - Framing Effects in Narrative and Non-Narrative Risk Messages. AB - Narrative messages are increasingly popular in health and risk campaigns, yet gain/loss framing effects have never been tested with such messages. Three experiments examined framing in narrative messages. Experiment 1 found that only the character's decision, not framing, influenced judgments about characters in a narrative derived from a prospect theory context. Experiment 2 found that a framing effect that occurred when presented in a decision format did not occur when the same situation was presented as a narrative. Using a different story/decision context, Experiment 3 found no significant difference in preference for surgery over radiation therapy in a narrative presentation compared to a non-narrative presentation. The results suggest that health and risk campaigns cannot assume that framing effects will be the same in narrative messages and non-narrative messages. Potential reasons for these differences and suggestions for future research are discussed. PMID- 25809458 TI - Obesity and diabetes in Pacific Islanders: the current burden and the need for urgent action. AB - Non-communicable diseases (NCDs) now account for more than 36 million deaths each year; many of which are premature. Pacific Islanders are some of the worst afflicted by obesity and diabetes with prevalence of both diseases rising disproportionately faster in the Pacific region over the past three decades than in the rest of the world. A high burden of disease is also found among enclaves of Pacifican migrants in the USA, Australia, and New Zealand. Urgent action is needed to alleviate the high economic and personal costs now associated with NCDs in Pacific Islanders. In this article, we describe contributors to the temporal trends in obesity and diabetes, discuss the current burden of disease in the Pacific Islands and among migrant communities, and suggest priorities for future research in this area. Finally, we discuss challenges unique to intervention among Pacific Islanders and highlight promising opportunities to reduce the NCD burden. PMID- 25809460 TI - [Prof. Dr. Hans Merk on the occasion of his 65th birthday]. PMID- 25809459 TI - [Optical coherence tomography]. AB - Optical coherence tomography (OCT) was introduced in the 1990s in dermatology and is nowadays established as a noninvasive high-resolution technique for the in vivo evaluation of the skin. To date several studies have been successfully demonstrated the application of OCT for various dermatological questions. The main indication for OCT in the daily practice is the noninvasive diagnosis of nonmelanoma skin cancer such as actinic keratosis and basal cell carcinoma. OCT has also been shown to be a valuable tool in treatment monitoring and evaluation of therapeutic success of noninvasive treatment strategies like topical immune modulators or photodynamic treatment. Other potential applications for OCT include inflammatory diseases, microbial or parasitic infestations of the skin, e.g. scabies mites or onychomycosis. In recent years high-definition OCT devices have been developed that can potentially be used for the evaluation of melanocytic lesions and, due to the higher resolution, for the visualization of intrafollicular demodex mites. Furthermore different commercially available devices offer-in addition to the cross-sectional images-a fast-generated horizontal (en face) imaging mode. With respect to resolution and penetration depth the OCT technique is taking a middle position in comparison to other noninvasive imaging devices in dermatology such as sonography and reflectance confocal microscopy. PMID- 25809461 TI - Three-dimensional virtual histology of Silurian osteostracan scales revealed by synchrotron radiation microtomography. AB - We used propagation phase contrast X-ray synchrotron microtomography to study the three-dimensional (3D) histology of scales of two osteostracans, Tremataspis and Oeselaspis, members of a jawless vertebrate group often cited as the sister group of jawed vertebrates. 3D-models of the canal systems and other internal structures are assembled based on the virtual thin section datasets and compared with previous models based on real thin sections. The primary homology framework of the canal systems in the two taxa is revised and new histological details are revealed based on the results of this work. There is no separation of vascular canals and lower mesh canals in the Tremataspis scale, contrary to previous results. The secondary upper mesh canals have a limited distribution to the anterior region of the Tremataspis scale. The upper and lower mesh canal systems of Tremataspis have different geometries, inferred to reflect different developmental origins: we interpret the upper system as a probable epithelial invagination, the lower system as entirely vascular. Oeselaspis has no equivalent of the upper mesh canal system. The upper mesh canal system of Tremataspis may have been sensory in function. In Oeselaspis, numerous polyp-shaped structures opening from the canal system onto the surface of the scale resemble the innervation tracts for neuromast organs. The growth of the Oeselaspis scale proceeds by addition of small odontodes containing unmineralized lacunae, which may further mineralize and become more compact. Our results highlight that 3D histological investigation on scales and other dermal skeletons of osteostracans is necessary to fully appreciate the diversity of skeletal histologies in the group. Traditional 3D-models based on thin sections alone are not reliable and should no longer be used as the basis for homology assessments or functional hypotheses. PMID- 25809462 TI - Neither fixed nor random: weighted least squares meta-analysis. AB - This study challenges two core conventional meta-analysis methods: fixed effect and random effects. We show how and explain why an unrestricted weighted least squares estimator is superior to conventional random-effects meta-analysis when there is publication (or small-sample) bias and better than a fixed-effect weighted average if there is heterogeneity. Statistical theory and simulations of effect sizes, log odds ratios and regression coefficients demonstrate that this unrestricted weighted least squares estimator provides satisfactory estimates and confidence intervals that are comparable to random effects when there is no publication (or small-sample) bias and identical to fixed-effect meta-analysis when there is no heterogeneity. When there is publication selection bias, the unrestricted weighted least squares approach dominates random effects; when there is excess heterogeneity, it is clearly superior to fixed-effect meta-analysis. In practical applications, an unrestricted weighted least squares weighted average will often provide superior estimates to both conventional fixed and random effects. PMID- 25809463 TI - The role of transduced bone marrow cells overexpressing BMP-2 in healing critical sized defects in a mouse femur. AB - The role that transduced mouse bone marrow stromal cells (mBMSCs) engineered to overexpress human bone morphogenetic protein 2 (BMP-2) play in healing critical sized skeletal defects is largely unknown. We evaluated the interaction between host osteoprogenitor cells and donor mBMSCs transduced with either a lentiviral (LV) vector-expressing red fluorescent protein (RFP) with or without BMP-2 that were implanted into a critical-sized femoral defect. Radiographs taken at the time of killing were evaluated using a five-point scaled scoring system. Frozen histologic sections were analyzed to assess both the transduced cells' role in bone repair and the local osteoprogenitor response. There was complete radiographic bridging in 94% of group I (LV-RFPch-BMP-2-cmyc) and 100% of group III (recombinant human BMP-2) specimens. Radiographs demonstrated a lack of healing in group II (LV-RFPch). Mouse BMSCs transduced with an LV-RFPch-BMP-2 vector were able to induce host cells to differentiate down an osteoblastic lineage and heal a critical-sized defect. However, the donor cells appeared to be functioning as a delivery vehicle of BMP-2 rather than actually differentiating into osteoblasts capable of participating in bone repair as evidenced by a lack of colocalization of the transduced cells to the sites of skeletal repair where the host progenitor cells were found. PMID- 25809464 TI - Cochlear protection against cisplatin by viral transfection of X-linked inhibitor of apoptosis protein across round window membrane. AB - We have previously demonstrated that both age-related and noise-induced hearing loss are reduced in transgenic mice that ubiquitously overexpress X-linked inhibitor of apoptosis protein (XIAP). In view of the therapeutic implications of these findings, we have developed a minimally invasive surgical method to deliver adenoid-associated virus (AAV) across the round window membrane (RWM) of the cochlea, enabling efficient gene transfer to hair cells and sensory neurons in this enclosed structure. This RWM approach was used in the present study to evaluate the effectiveness of AAV-mediated XIAP overexpression in protecting against cisplatin-induced ototoxicity. Two weeks following surgery, AAV-derived XIAP was detected in the majority of inner and outer hair cells, resulting in a threefold elevation of this antiapoptotic protein in the cochlea. The protection of AAV-mediated XIAP overexpression was evaluated in animals treated with cisplatin at a dose of 4 mg kg(-1) per day for 4-7 consecutive days. The XIAP overexpression was found to attenuate cisplatin-induced hearing loss by ~22 dB. This was accompanied by a reduction of the loss of vulnerable hair cells and sensory neurons in the cochlea by 13%. PMID- 25809466 TI - The relation between depression and appreciation: The role of perceptions of emotional utility in an experimental test of causality. AB - The present research examined the potential role of perceived utility of appreciation in depressive symptoms. In a between-subjects design, participants were induced to increase their experience of appreciation or their perceived usefulness of appreciation. Self-reported perceptions of emotional utility, actual experience of emotion, as well as depression scores gathered from semi structured interviews, were obtained at baseline and post-induction. As predicted, although participants in both groups evidenced lower levels of depressive symptoms at post-induction than at baseline, there was a greater decrease among participants in the appreciation-utility condition than among those in the appreciation-experience condition. Further, perceived utility of appreciation was an important mediator in moderated mediation models. PMID- 25809467 TI - The long-term outcome of extremely preterm (<28 weeks' gestational age) infants with and without severe retinopathy of prematurity. AB - BACKGROUND: Severe retinopathy of prematurity (ROP) is associated with an increased risk for ophthalmologic morbidity, but the long-term impact in other domains is less clear. The aim of the current study was to determine whether severe ROP was related to poorer visual, cognitive, and educational outcomes in a representative sample of EP adolescents, and whether this persisted after adjusting for confounding neonatal risk factors. METHOD: One hundred and eighty extremely preterm (EP; <28 weeks) adolescents (17-18 years) were assessed on a range of neurodevelopmental measures, including visual processing, IQ, visual learning, visual-motor integration, and academic achievement. EP adolescents were grouped according to ROP status, (1) severe ROP (stage 3 or greater) in the worse eye; or (2) no or mild ROP and were compared on each outcome. Longitudinal data were compared at 2, 5, 8, and 17-18 years for general cognitive outcome. RESULTS: The severe ROP group performed more poorly and had more impairments than the non severe ROP group on measures of visual processing, visual-motor integration, visual learning, IQ, and some academic achievement tests at 17-18 years of age. Group differences diminished after controlling for perinatal risk factors (severe white matter injury, post-natal corticosteroid, and surgery in the neonatal period), and only visual acuity scores remained significantly different between the groups. IQ scores remained consistently lower in the severe ROP group over time, but the magnitude reduced after adjusting for perinatal risk factors. CONCLUSIONS: Extremely preterm children with severe ROP are at increased risk for ongoing visual processing difficulties and lower IQ compared with EP peers without severe ROP. While severe ROP is a predictor of long-term impairments, this association is largely mediated by other neonatal risk factors. PMID- 25809468 TI - Using biological variables and reproductive strategy of the undulate ray Raja undulata to evaluate productivity and susceptibility to exploitation. AB - The present work provides a detailed analysis of the reproductive strategy of the undulate ray Raja undulata in Portuguese mainland waters. The species was found mostly between 30 and 40 m deep on sandy bottoms. Egg-laying sites were observed in the north, centre and south-west regions, mainly at depths below 30 m. The peak of the reproductive season occurred from December to May. Asynchrony between reproductively active females and males appeared to occur, although most adult males were capable of reproducing throughout the year. The estimated length at 50% maturity was 86.2 cm (8.7 years) and 76.8 cm (7.6 years) total length for females and males, respectively. The maximum potential fecundity was estimated to be 69.8 follicles per female per reproductive season, which are released in 4.7 batches of 15 follicles. The life-history and demographic parameters of R. undulata are similar to those of other skate species, while the potential rate of population increase (0.49) is above the published values for other elasmobranch species. With these new findings, this study makes an important contribution to the understanding of the life history of R. undulata, and provides a first evaluation of the productivity and susceptibility of the species to exploitation. PMID- 25809465 TI - Optogenetic control of insulin secretion by pancreatic beta-cells in vitro and in vivo. AB - The present study assessed the ability of optogenetics techniques to provide a better understanding of the control of insulin secretion, particularly regarding pancreatic beta-cell function in homeostasis and pathological conditions such as diabetes mellitus (DM). We used optogenetics to investigate whether insulin secretion and blood glucose homeostasis could be controlled by regulating intracellular calcium ion concentrations ([Ca(2+)]i) in a mouse pancreatic beta cell line (MIN6) transfected with the optogenetic protein channelrhodopsin-2 (ChR2). The ChR2-transfected MIN6 (ChR2-MIN6) cells secreted insulin following irradiation with a laser (470 nm). The increase in [Ca(2+)]i was accompanied by elevated levels of messenger RNAs that encode calcium/calmodulin-dependent protein kinase II delta and adenylate cyclase 1. ChR2-MIN6 cells suspended in matrigel were inoculated into streptozotocin-induced diabetic mice that were then subjected to a glucose tolerance test. Laser irradiation of these mice caused a significant decrease in blood glucose, and the irradiated implanted cells expressed insulin. These findings demonstrate the power of optogenetics to precisely and efficiently controlled insulin secretion by pancreatic beta-cells 'on demand', in contrast to techniques using growth factors or chemical inducers. Optogenetic technology shows great promise for understanding the mechanisms of glucose homeostasis and for developing treatments for metabolic diseases such as DM. PMID- 25809469 TI - Effect of retinal defocus on basketball free throw shooting performance. AB - BACKGROUND: Vision plays a critical role in athletic performance; however, previous studies have demonstrated that a variety of simulated athletic sensorimotor tasks can be surprisingly resilient to retinal defocus (blurred vision). The purpose of the present study was to extend this work to determine the effect of retinal defocus on overall basketball free throw performance, as well as for the factors gender, refractive error and experience. METHODS: Forty four young adult participants of both genders were recruited. They had a range of refractive errors and basketball experience. Each performed 20 standard basketball free throws under five lens defocus conditions in a randomised manner: plano, +1.50 D, +3.00 D, +4.50 D and +10.00 D. RESULTS: Overall, free throw performance was significantly reduced under the +10.00 D lens defocus condition only. Previous experience, but neither refractive error nor gender, yielded a statistically significant difference in performance. CONCLUSION: Consistent with previous studies of complex sensorimotor tasks, basketball free throw performance was resilient to low and moderate levels of retinal defocus. Thus, for a relatively non-dynamic motor task at a fixed far distance, such as the basketball free throw, precise visual clarity was not critical. Other factors such as motor memory may be important. However, in the dynamic athletic competitive environment it is likely that visual clarity plays a more critical role in one's performance level, at least for specific task demands. PMID- 25809470 TI - The alterations in SATB1 and nuclear F-actin expression affect apoptotic response of the MCF-7 cells to geldanamycin. AB - INTRODUCTION: The function and localization of actin in the nucleus have not yet been fully described. However, actin seems to be a key protein in nuclear processes interacting with chromatin and matrix proteins. The aim of the study was to evaluate the effect of controlled expression of nuclear pool of F-actin and special AT-rich sequence-binding protein 1 (SATB1) on the in vitro induction of active cell death by geldanamycin (GA). MATERIAL AND METHODS: The expression of SATB1 was regulated by the transfection of non-aggressive breast cancer MCF-7 cells with siRNA against SATB1 or expression plasmid with cloned cDNA of SATB1. The altered expression of cofilin-1 in these cells was used to regulate the nuclear expression and localization of F-actin. The effect of GA was analyzed in the context of cell death induction and cell cycle alterations. RESULTS: Our studies revealed that the targeted regulation of SATB1 and cofilin-1 expression changed the apoptotic response of the MCF-7 cells to GA. The overexpression of these proteins potentiated GA-induced arrest of the cells in the G1 phase of cell cycle and increased the population of the hypodiploid cells. CONCLUSION: The alterations in the nuclear expression of SATB1 and F-actin in MCF-7 cells may affect their active cell death in response to GA. PMID- 25809471 TI - Expression of toll-like receptor genes in leukocytes of patients with sudden sensorineural hearing loss. AB - OBJECTIVES/HYPOTHESIS: Sudden sensorineural hearing loss (SNNHL) is a disease entity that could be caused by multiple etiologies in which the innate immunity status of the patients might be involved. The aim of this study is to investigate the expression of Toll-like receptor (TLR) genes in peripheral blood leukocytes of SNNHL patients. STUDY DESIGN: Basic research. METHODS: We examined the expression of six TLR genes in the peripheral blood leukocytes of SNNHL patients and normal controls using real-time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: We found significantly higher expression of TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 genes in SNNHL patients as compared with normal controls (P < 0.05). Higher expression of the TLR2 gene was found in patients with profound hearing loss compared with those with less severe hearing loss (P < 0.05). The result was validated by the positively stained leukocytes for TLR2 protein in SNNHL patients using the immunocytochemical study. In addition, the percentage of CD14(+) monocytes expressing TLR2 in SNNHL patients was higher than in normal controls assessed by flow cytometry and significantly correlated with the hearing thresholds of the affected ear (P < 0.05). CONCLUSION: Our study implies a role for TLRs in SNNHL. The expression of TLR2 in particular correlates with the severity of the disease. LEVEL OF EVIDENCE: N/A. PMID- 25809472 TI - Is repetition failure critical for the development of muscle hypertrophy and strength? AB - This investigation sought to determine the effect of resistance training to failure on functional, structural and neural elbow flexor muscle adaptation. Twenty-eight males completed a 4-week familiarization period and were then counterbalanced on the basis of responsiveness across; non-failure rapid shortening (RS; rapid concentric, 2 s eccentric), non-failure stretch-shortening (SSC; rapid concentric, rapid eccentric), and failure control (C, 2 s concentric, 2 s eccentric), for a 12-week unilateral elbow flexor resistance training regimen, 3 * week using 85% of one repetition maximum (1RM). 1RM, maximal voluntary contraction (MVC), muscle cross-sectional area (CSA), and muscle activation (EMG(RMS)) of the agonist, antagonist, and stabilizer muscles were assessed before and after the 12-week training period. The average number of repetitions per set was significantly lower in RS 4.2 [confidence interval (CI): 4.2, 4.3] and SSC 4.2 (CI: 4.2, 4.3) compared with C 6.1 (CI: 5.8, 6.4). A significant increase in 1RM (30.5%), MVC (13.3%), CSA (11.4%), and agonist EMG(RMS) (22.1%) was observed; however, no between-group differences were detected. In contrast, antagonist EMG(RMS) increased significantly in SSC (40.5%) and C (23.3%), but decreased in RS (13.5%). Similar adaptations across the three resistance training regimen suggest repetition failure is not critical to elicit significant neural and structural changes to skeletal muscle. PMID- 25809474 TI - Stiripentol for the treatment of super-refractory status epilepticus. AB - BACKGROUND: To determine whether stiripentol (STP) might be a treatment option in super-refractory status epilepticus (SRSE). METHODS: Medical records of patients treated due to a status epilepticus in Marburg between January 2013 and June 2014 were reviewed for administration of STP. Primary outcome measures were resolution of SE after initiation of STP. RESULTS: Five adult patients were started with STP due to SRSE. The median age was 78 years (interquartile range [IQR] 11 years), and four patients were female. The median duration of SRSE before initiation of STP was 39 days (IQR 16 days), and the median number of anticonvulsants used before was 6 (IQR 1). SRSE ceased in three patients within 2-4 days after the start of STP. In two patients, SRSE continued after administration of STP and further escalation of anticonvulsant regimen. Both were switched eventually to supportive care only. None serious side effects were observed while on STP. CONCLUSIONS: Based on our presented cases and previous experimental animal data, STP may prove useful in treating super-refractory SE. Prospective trials are warranted to examine the efficacy of the STP in adults with refractory SE and to examine whether earlier treatment leads to better control of SE. PMID- 25809475 TI - Metals in cosmetics: implications for human health. AB - Cosmetics, preparations repeatedly applied directly to the human skin, mucous membranes, hair and nails, should be safe for health, however, recently there has been increasing concern about their safety. Unfortunately, using these products in some cases is related to the occurrence of unfavourable effects resulting from intentional or the accidental presence of chemical substances, including toxic metals. Heavy metals such as lead, mercury, cadmium, arsenic and nickel, as well as aluminium, classified as a light metal, are detected in various types of cosmetics (colour cosmetics, face and body care products, hair cosmetics, herbal cosmetics, etc.). In addition, necessary, but harmful when they occur in excessive amounts, elements such as copper, iron, chromium and cobalt are also present in cosmetic products. Metals occurring in cosmetics may undergo retention and act directly in the skin or be absorbed through the skin into the blood, accumulate in the body and exert toxic effects in various organs. Some cases of topical (mainly allergic contact dermatitis) and systemic effects owing to exposure to metals present in cosmetics have been reported. Literature data show that in commercially available cosmetics toxic metals may be present in amounts creating a danger to human health. Thus, the present review article focused on the problems related to the presence of heavy metals and aluminium in cosmetics, including their sources, concentrations and law regulations as well as danger for the health of these products users. Owing to the growing usage of cosmetics it is necessary to pay special attention to these problems. PMID- 25809473 TI - Real-time supervised detection of pink areas in dermoscopic images of melanoma: importance of color shades, texture and location. AB - BACKGROUND/PURPOSE: Early detection of malignant melanoma is an important public health challenge. In the USA, dermatologists are seeing more melanomas at an early stage, before classic melanoma features have become apparent. Pink color is a feature of these early melanomas. If rapid and accurate automatic detection of pink color in these melanomas could be accomplished, there could be significant public health benefits. METHODS: Detection of three shades of pink (light pink, dark pink, and orange pink) was accomplished using color analysis techniques in five color planes (red, green, blue, hue, and saturation). Color shade analysis was performed using a logistic regression model trained with an image set of 60 dermoscopic images of melanoma that contained pink areas. Detected pink shade areas were further analyzed with regard to the location within the lesion, average color parameters over the detected areas, and histogram texture features. RESULTS: Logistic regression analysis of a separate set of 128 melanomas and 128 benign images resulted in up to 87.9% accuracy in discriminating melanoma from benign lesions measured using area under the receiver operating characteristic curve. The accuracy in this model decreased when parameters for individual shades, texture, or shade location within the lesion were omitted. CONCLUSION: Texture, color, and lesion location analysis applied to multiple shades of pink can assist in melanoma detection. When any of these three details: color location, shade analysis, or texture analysis were omitted from the model, accuracy in separating melanoma from benign lesions was lowered. Separation of colors into shades and further details that enhance the characterization of these color shades are needed for optimal discrimination of melanoma from benign lesions. PMID- 25809477 TI - The Non-catalytic B Subunit of Coagulation Factor XIII Accelerates Fibrin Cross linking. AB - Covalent cross-linking of fibrin chains is required for stable blood clot formation, which is catalyzed by coagulation factor XIII (FXIII), a proenzyme of plasma transglutaminase consisting of catalytic A (FXIII-A) and non-catalytic B subunits (FXIII-B). Herein, we demonstrate that FXIII-B accelerates fibrin cross linking. Depletion of FXIII-B from normal plasma supplemented with a physiological level of recombinant FXIII-A resulted in delayed fibrin cross linking, reduced incorporation of FXIII-A into fibrin clots, and impaired activation peptide cleavage by thrombin; the addition of recombinant FXIII-B restored normal fibrin cross-linking, FXIII-A incorporation into fibrin clots, and activation peptide cleavage by thrombin. Immunoprecipitation with an anti fibrinogen antibody revealed an interaction between the FXIII heterotetramer and fibrinogen mediated by FXIII-B and not FXIII-A. FXIII-B probably binds the gamma chain of fibrinogen with its D-domain, which is near the fibrin polymerization pockets, and dissociates from fibrin during or after cross-linking between gamma chains. Thus, FXIII-B plays important roles in the formation of a ternary complex between proenzyme FXIII, prosubstrate fibrinogen, and activator thrombin. Accordingly, congenital or acquired FXIII-B deficiency may result in increased bleeding tendency through impaired fibrin stabilization due to decreased FXIII-A activation by thrombin and secondary FXIII-A deficiency arising from enhanced circulatory clearance. PMID- 25809476 TI - Large Ca2+-dependent facilitation of Ca(V)2.1 channels revealed by Ca2+ photo uncaging. AB - KEY POINTS: CaV 2.1 channels constitute a dominant Ca(2+) entry pathway into brain neurons, triggering downstream Ca(2+) -dependent processes such as neurotransmitter release. CaV 2.1 is itself modulated by Ca(2+) , resulting in activity-dependent enhancement of channel opening termed Ca(2+) -dependent facilitation (CDF). Real-time Ca(2+) imaging and Ca(2+) uncaging here reveal that CDF turns out to be strikingly faster, more Ca(2+) sensitive, and larger than anticipated on previous grounds. Robust resolution of the quantitative profile of CDF enables deduction of a realistic biophysical model for this process. These results suggest that CaV 2.1 CDF would figure most prominently in short-term synaptic plasticity and cerebellar Purkinje cell rhythmicity. ABSTRACT: CaV 2.1 (P-type) voltage-gated Ca(2+) channels constitute a major source of neuronal Ca(2+) current, strongly influencing rhythmicity and triggering neurotransmitter release throughout the central nervous system. Fitting with such stature among Ca(2+) entry pathways, CaV 2.1 is itself feedback regulated by intracellular Ca(2+) , acting through calmodulin to facilitate channel opening. The precise neurophysiological role of this calcium-dependent facilitation (CDF) remains uncertain, however, in large measure because the very magnitude, Ca(2+) dependence and kinetics of CDF have resisted quantification by conventional means. Here, we utilize the photo-uncaging of Ca(2+) with CaV 2.1 channels fluxing Li(+) currents, so that voltage-dependent activation of channel gating is no longer conflated with Ca(2+) entry, and CDF is then driven solely by light induced increases in Ca(2+) . By using this strategy, we now find that CDF can be unexpectedly large, enhancing currents by as much as twofold at physiological voltages. CDF is steeply Ca(2+) dependent, with a Hill coefficient of approximately two, a half-maximal effect reached by nearly 500 nm Ca(2+) , and Ca(2+) on/off kinetics in the order of milliseconds to tens of milliseconds. These properties were established for both native P-type currents in cerebellar Purkinje neurons, as well as their recombinant channel counterparts under heterologous expression. Such features suggest that CDF of CaV 2.1 channels may substantially enhance the regularity of rhythmic firing in cerebellar Purkinje neurons, where regularity is believed crucial for motor coordination. In addition, this degree of extensive CDF would be poised to exert large order-of magnitude effects on short-term synaptic plasticity via rapid modulation of presynaptic Ca(2+) entry. PMID- 25809478 TI - Phosphorylation of Minichromosome Maintenance 3 (MCM3) by Checkpoint Kinase 1 (Chk1) Negatively Regulates DNA Replication and Checkpoint Activation. AB - Mechanisms controlling DNA replication and replication checkpoint are critical for the maintenance of genome stability and the prevention or treatment of human cancers. Checkpoint kinase 1 (Chk1) is a key effector protein kinase that regulates the DNA damage response and replication checkpoint. The heterohexameric minichromosome maintenance (MCM) complex is the core component of mammalian DNA helicase and has been implicated in replication checkpoint activation. Here we report that Chk1 phosphorylates the MCM3 subunit of the MCM complex at Ser-205 under normal growth conditions. Mutating the Ser-205 of MCM3 to Ala increased the length of DNA replication track and shortened the S phase duration, indicating that Ser-205 phosphorylation negatively controls normal DNA replication. Upon replicative stress treatment, the inhibitory phosphorylation of MCM3 at Ser-205 was reduced, and this reduction was accompanied with the generation of single strand DNA, the key platform for ataxia telangiectasia mutated and Rad3-related (ATR) activation. As a result, the replication checkpoint is activated. Together, these data provide significant insights into the regulation of both normal DNA replication and replication checkpoint activation through the novel phosphorylation of MCM3 by Chk1. PMID- 25809480 TI - Domain organization and conformational plasticity of the G protein effector, PDE6. AB - The cGMP phosphodiesterase of rod photoreceptor cells, PDE6, is the key effector enzyme in phototransduction. Two large catalytic subunits, PDE6alpha and -beta, each contain one catalytic domain and two non-catalytic GAF domains, whereas two small inhibitory PDE6gamma subunits allow tight regulation by the G protein transducin. The structure of holo-PDE6 in complex with the ROS-1 antibody Fab fragment was determined by cryo-electron microscopy. The ~11 A map revealed previously unseen features of PDE6, and each domain was readily fit with high resolution structures. A structure of PDE6 in complex with prenyl-binding protein (PrBP/delta) indicated the location of the PDE6 C-terminal prenylations. Reconstructions of complexes with Fab fragments bound to N or C termini of PDE6gamma revealed that PDE6gamma stretches from the catalytic domain at one end of the holoenzyme to the GAF-A domain at the other. Removal of PDE6gamma caused dramatic structural rearrangements, which were reversed upon its restoration. PMID- 25809479 TI - Interleukin-1beta-induced Reduction of CD44 Ser-325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes, Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats. AB - The proinflammatory cytokine interleukin-1beta (IL-1beta) attracts leukocytes to sites of inflammation. One of the recruitment mechanisms involves the formation of extended, hyaluronan-rich pericellular coats on local fibroblasts, endothelial cells, and epithelial cells. In the present work, we studied how IL-1beta turns on the monocyte adhesion of the hyaluronan coat on human keratinocytes. IL-1beta did not influence hyaluronan synthesis or increase the amount of pericellular hyaluronan in these cells. Instead, we found that the increase in the hyaluronan dependent monocyte binding was associated with the CD44 of the keratinocytes. Although IL-1beta caused a small increase in the total amount of CD44, a more marked impact was the decrease of CD44 phosphorylation at serine 325. At the same time, IL-1beta increased the association of CD44 with ezrin and complex formation of CD44 with itself. Treatment of keratinocyte cultures with KN93, an inhibitor of calmodulin kinase 2, known to phosphorylate Ser-325 in CD44, caused similar effects as IL-1beta (i.e. homomerization of CD44 and its association with ezrin) and resulted in increased monocyte binding to keratinocytes in a hyaluronan dependent way. Overexpression of wild type CD44 standard form, but not a corresponding CD44 mutant mimicking the Ser-325-phosphorylated form, was able to induce monocyte binding to keratinocytes. In conclusion, treatment of human keratinocytes with IL-1beta changes the structure of their hyaluronan coat by influencing the amount, post-translational modification, and cytoskeletal association of CD44, thus enhancing monocyte retention on keratinocytes. PMID- 25809481 TI - Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1. AB - The release of fatty acids from plasma triglycerides for tissue uptake is critically dependent on the enzyme lipoprotein lipase (LPL). Hydrolysis of plasma triglycerides by LPL can be disrupted by the protein angiopoietin-like 4 (ANGPTL4), and ANGPTL4 has been shown to inactivate LPL in vitro. However, in vivo LPL is often complexed to glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) on the surface of capillary endothelial cells. GPIHBP1 is responsible for trafficking LPL across capillary endothelial cells and anchors LPL to the capillary wall during lipolysis. How ANGPTL4 interacts with LPL in this context is not known. In this study, we investigated the interactions of ANGPTL4 with LPL-GPIHBP1 complexes on the surface of endothelial cells. We show that ANGPTL4 was capable of binding and inactivating LPL complexed to GPIHBP1 on the surface of endothelial cells. Once inactivated, LPL dissociated from GPIHBP1. We also show that ANGPTL4-inactivated LPL was incapable of binding GPIHBP1. ANGPTL4 was capable of binding, but not inactivating, LPL at 4 degrees C, suggesting that binding alone was not sufficient for ANGPTL4's inhibitory activity. We observed that although the N terminal coiled-coil domain of ANGPTL4 by itself and full-length ANGPTL4 both bound with similar affinities to LPL, the N-terminal fragment was more potent in inactivating both free and GPIHBP1-bound LPL. These results led us to conclude that ANGPTL4 can both bind and inactivate LPL complexed to GPIHBP1 and that inactivation of LPL by ANGPTL4 greatly reduces the affinity of LPL for GPIHBP1. PMID- 25809483 TI - The MDM2 RING domain and central acidic domain play distinct roles in MDM2 protein homodimerization and MDM2-MDMX protein heterodimerization. AB - The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that plays a prominent role in p53 suppression by promoting its polyubiquitination and proteasomal degradation. In its active form, MDM2 forms homodimers as well as heterodimers with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through their respective C-terminal RING (really interesting new gene) domains. In this study, using multiple MDM2 mutants, we show evidence suggesting that MDM2 homo- and heterodimerization occur through distinct mechanisms because MDM2 RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with WT MDM2. Intriguingly, deletion of a portion of the MDM2 central acidic domain selectively inhibits interaction with MDM2 while leaving intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an MDM2 C-terminal deletion mutant reveals that the C-terminal residues of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model in which MDM2 MDMX heterodimerization requires the extreme C terminus and proper RING domain structure of MDM2, whereas MDM2 homodimerization requires the extreme C terminus and the central acidic domain of MDM2, suggesting that MDM2 homo- and heterodimers utilize distinct MDM2 domains. Our study is the first to report mutations capable of separating MDM2 homo- and heterodimerization. PMID- 25809482 TI - Phosphorylation regulates the ubiquitin-independent degradation of yeast Pah1 phosphatidate phosphatase by the 20S proteasome. AB - Saccharomyces cerevisiae Pah1 phosphatidate phosphatase, which catalyzes the conversion of phosphatidate to diacylglycerol for triacylglycerol synthesis and simultaneously controls phosphatidate levels for phospholipid synthesis, is subject to the proteasome-mediated degradation in the stationary phase of growth. In this study, we examined the mechanism for its degradation using purified Pah1 and isolated proteasomes. Pah1 expressed in S. cerevisiae or Escherichia coli was not degraded by the 26S proteasome, but by its catalytic 20S core particle, indicating that its degradation is ubiquitin-independent. The degradation of Pah1 by the 20S proteasome was dependent on time and proteasome concentration at the pH optimum of 7.0. The 20S proteasomal degradation was conserved for human lipin 1 phosphatidate phosphatase. The degradation analysis using Pah1 truncations and its fusion with GFP indicated that proteolysis initiates at the N- and C-terminal unfolded regions. The folded region of Pah1, in particular the haloacid dehalogenase-like domain containing the DIDGT catalytic sequence, was resistant to the proteasomal degradation. The structural change of Pah1, as reflected by electrophoretic mobility shift, occurs through its phosphorylation by Pho85 Pho80, and the phosphorylation sites are located within its N- and C-terminal unfolded regions. Phosphorylation of Pah1 by Pho85-Pho80 inhibited its degradation, extending its half-life by ~2-fold. The dephosphorylation of endogenously phosphorylated Pah1 by the Nem1-Spo7 protein phosphatase, which is highly specific for the sites phosphorylated by Pho85-Pho80, stimulated the 20S proteasomal degradation and reduced its half-life by 2.6-fold. These results indicate that the proteolysis of Pah1 by the 20S proteasome is controlled by its phosphorylation state. PMID- 25809484 TI - The Active Form of Vitamin D Transcriptionally Represses Smad7 Signaling and Activates Extracellular Signal-regulated Kinase (ERK) to Inhibit the Differentiation of a Inflammatory T Helper Cell Subset and Suppress Experimental Autoimmune Encephalomyelitis. AB - The ability of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), to transcriptionally modulate Smads to inhibit Th17 differentiation and experimental autoimmune encephalomyelitis (EAE) has not been adequately studied. This study reports modulation of Smad signaling by the specific binding of the VDR along with its heterodimeric partner RXR to the negative vitamin D response element on the promoter of Smad7, which leads to Smad7 gene repression. The vitamin D receptor-mediated increase in Smad3 expression partially explains the IL10 augmentation seen in Th17 cells. Furthermore, the VDR axis also modulates non-Smad signaling by activating ERK during differentiation of Th17 cells, which inhibits the Th17-specific genes il17a, il17f, il22, and il23r. In vivo EAE experiments revealed that, 1,25(OH)2D3 suppression of EAE correlates with the Smad7 expression in the spleen and lymph nodes. Furthermore, Smad7 expression also correlates well with IL17 and IFNgamma expression in CNS infiltered inflammatory T cells. We also observed similar gene repression of Smad7 in in vitro differentiated Th1 cells when cultured in presence of 1,25(OH)2D3. The above canonical and non-canonical pathways in part address the ability of 1,25(OH)2D3-VDR to inhibit EAE. PMID- 25809485 TI - Pathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cycling. AB - Human CblC catalyzes the elimination of the upper axial ligand in cobalamin or B12 derivatives entering the cell from circulation. This processing step is critical for assimilation of dietary cobalamin into the active cofactor forms that support the B12-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase. Using a modified nitroreductase scaffold tailored to bind cobalamin and glutathione, CblC exhibits versatility in the mechanism by which it removes cyano versus alkyl ligands in cobalamin. In this study, we have characterized the effects of two pathogenic missense mutations at the same residue, R161G and R161Q, which are associated with early and late onset of the CblC disorder, respectively. We find that the R161Q and R161G CblC mutants display lower protein stability and decreased dealkylation but not decyanation activity, suggesting that cyanocobalamin might be therapeutically useful for patients carrying mutations at Arg-161. The mutant proteins also exhibit impaired glutathione binding. In the presence of physiologically relevant glutathione concentrations, stabilization of the cob(II)alamin derivative is observed, which occurs at the expense of increased oxidation of glutathione. Futile redox cycling, which is suppressed in wild-type human CblC, explains the reported increase in oxidative stress levels associated with the CblC disorder. PMID- 25809486 TI - Dynamic Sialylation in Transforming Growth Factor-beta (TGF-beta)-induced Epithelial to Mesenchymal Transition. AB - Epithelial-mesenchymal transition (EMT) is a fundamental process in embryonic development and organ formation. Aberrant regulation of EMT often leads to tumor progression. Changes in cell surface sialylation have recently been implicated in mediating EMT. Herein we report the visualization of dynamic changes of sialylation and glycoproteomic analysis of newly synthesized sialylated proteins in EMT by metabolic labeling of sialylated glycans with azides, followed by click labeling with fluorophores or affinity tags. We discovered that sialylation was down-regulated during EMT but then reverted and up-regulated in the mesenchymal state after EMT, accompanied by mRNA expression level changes of genes involved in the sialic acid biosynthesis. Quantitative proteomic analysis identified a list of sialylated proteins whose biosynthesis was dynamically regulated during EMT. Sialylation of cell surface adherent receptor integrin beta4 was found to be down-regulated, which may regulate integrin functions during EMT. Furthermore, a global sialylation inhibitor was used to probe the functional role of sialylation during EMT. We found that inhibition of sialylation promoted EMT. Taken together, our findings suggest the important role of sialylation in regulating EMT and imply its possible function in related pathophysiological events, such as cancer metastasis. PMID- 25809489 TI - Work-related stress and reward: an Australian study of multidisciplinary pediatric oncology healthcare providers. AB - OBJECTIVE: Managing staff stress and preventing long-term burnout in oncology staff are highly important for both staff and patient well-being. Research addressing work-related stress in adult oncology is well documented; however, less is known about this topic in the pediatric context. This study examined sources of work-related stress and reward specific to multidisciplinary staff working in pediatric oncology in Australia. METHOD: Participants were 107 pediatric oncology clinicians, including medical, nursing, and allied health staff from two Australian pediatric oncology centers. Participants completed an online survey using two newly developed measures: the work stressors scale pediatric oncology and the work rewards scale-pediatric oncology. RESULTS: The most commonly reported sources of both stress and reward are related to patient care and interactions with children. Results indicated that levels of work related stress and reward were similar between the professional disciplines and between the two hospitals. Regression analyses revealed no demographic or organizational factors that were associated with either stress or reward. CONCLUSIONS: Work-related stress and reward are not mutually exclusive; particular situations and events can be simultaneously stressful and rewarding for healthcare providers. Although patient care and interactions with children was found to be the most stressful aspect of working in this speciality, it was also the greatest source of reward. Results are discussed in relation to workplace approaches to staff well-being and stress reduction. PMID- 25809487 TI - Self-cleavage of the Pseudomonas aeruginosa Cell-surface Signaling Anti-sigma Factor FoxR Occurs through an N-O Acyl Rearrangement. AB - The Fox system of Pseudomonas aeruginosa is a cell-surface signaling (CSS) pathway employed by the bacterium to sense and respond to the presence of the heterologous siderophore ferrioxamine in the environment. This regulatory pathway controls the transcription of the foxA ferrioxamine receptor gene through the extracytoplasmic function sigma factor sigma(FoxI). In the absence of ferrioxamine, the activity of sigma(FoxI) is inhibited by the transmembrane anti sigma factor FoxR. Upon binding of ferrioxamine by the FoxA receptor, FoxR is processed by a complex proteolytic cascade leading to the release and activation of sigma(FoxI). Interestingly, we have recently shown that FoxR undergoes self cleavage between the periplasmic Gly-191 and Thr-192 residues independent of the perception of ferrioxamine. This autoproteolytic event, which is widespread among CSS anti-sigma factors, produces two distinct domains that interact and function together to transduce the presence of the signal. In this work, we provide evidence that the self-cleavage of FoxR is not an enzyme-dependent process but is induced by an N-O acyl rearrangement. Mutation analysis showed that the nucleophilic side chain of the Thr-192 residue at +1 of the cleavage site is required for an attack on the preceding Gly-191, after which the resulting ester bond is likely hydrolyzed. Because the cleavage site is well preserved and the hydrolysis of periplasmic CSS anti-sigma factors is widely observed, we hypothesize that cleavage via an N-O acyl rearrangement is a conserved feature of these proteins. PMID- 25809490 TI - Targeting FAK scaffold functions inhibits human renal cell carcinoma growth. AB - Human conventional renal cell carcinoma (CCC) remains resistant to current therapies. Focal Adhesion Kinase (FAK) is upregulated in many epithelial tumors and clearly implicated in nearly all facets of cancer. However, only few reports have assessed whether FAK may be associated with renal tumorigenesis. In this study, we investigated the potential role of FAK in the growth of human CCC using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as well as normal/tumoral renal tissue pairs. FAK was found constitutively expressed in human CCC both in culture cells and freshly harvested tumors obtained from patients. We showed that CCC cell growth was dramatically reduced in FAK-depleted cells or after FAK inhibition with various inhibitors and this effect was obtained through inhibition of cell proliferation and induction of cell apoptosis. Additionally, our results indicated that FAK knockdown decreased CCC cell migration and invasion. More importantly, depletion or pharmacological inhibition of FAK substantially inhibited tumor growth in vivo. Interestingly, investigations of the molecular mechanism revealed loss of FAK phosphorylation during renal tumorigenesis impacting multiple signaling pathways. Taken together, our findings reveal a previously uncharacterized role of FAK in CCC whereby FAK exerts oncogenic properties through a non canonical signaling pathway involving its scaffolding kinase-independent properties. Therefore, targeting the FAK scaffold may represent a promising approach for developing innovative and highly specific therapies in human CCC. PMID- 25809493 TI - The physiological cost of reproduction for rich and poor across 65 countries. AB - OBJECTIVES: One of the fundamental tradeoffs posited in life history theory is between storing energy for future reproduction versus spending that energy on current reproduction. However, past studies have shown variable and sometimes contradictory effects of reproduction on energy stores among women. METHODS: To examine how varying economic resources can account for these diverse findings, we applied mixed models to Demographic and Health Survey (DHS) data from 187,848 nulliparous and primiparous women of reproductive age (20-34 years) in 65 countries varying widely in economic resources. Using this approach, we tracked average trajectories of body mass through pregnancy and the post-partum period, and assessed how these trajectories varied by household wealth and breastfeeding. RESULTS: In all four wealth categories, sustained breastfeeding posed a substantial tradeoff with energy stores, reducing post-partum BMI by 0.5 to 1.0 kg m(-2) relative to non-breastfeeding women. However, among the wealthiest households (>6,400 USD per capita), this deficit was buffered substantially by greater pre-partum weight gain (+1.1 kg m(-2) compared to women from the poorest households). CONCLUSION: These findings show how the level of economic resources can systematically and profoundly shape a physiological tradeoff in reproduction, and can help account for past contradictory findings. More broadly, these results illustrate how integrating economic and energetic resources in a common framework can help clarify the apparently disparate weight-related outcomes of fertility in different countries. PMID- 25809496 TI - John MacMillan, M.D. (1959-2014): an inspiring example of a community clinical geneticist. PMID- 25809494 TI - Needs assessment survey of addictions training in general psychiatry residency. PMID- 25809495 TI - Effect of pH and molar ratio of pollutant to oxidant on a photochemical advanced oxidation process using hypochlorite. AB - Ultra violet (UV)-photolysis of hydrogen peroxide (H2O2) is a conventional advanced oxidation process (AOP) and is advantageous in its simplicity, although H2O2 is costly. Accordingly, we tried to substitute H2O2 by hypochlorite in the photochemical AOP, and discussed the effect of pH and the molar ratio of a pollutant to hypochlorite on the process using 1,4-dioxane as a model pollutant. The photochemical treatment of hypochlorite solutions at a wavelength of 254 nm under various pH values revealed that the UV-photolysis of hypochlorous acid (HOCl) species mainly contributed to hydroxyl radical (*OH) production. The reaction efficiency, as defined by the molar ratio of removed 1,4-dioxane to consumed hypochlorite, deteriorated under higher pH levels due to the stronger radical scavenging effect of hypochlorite ion (ClO(-)) as compared to that of HOCl. The optimal pH for the UV-photolysis of hypochlorite as an AOP was found to be in the range of 3-6. The reaction efficiency at a high molar ratio of initial 1,4-dioxane to initial hypochlorite exceeded 100%, which was caused by the regeneration of HOCl from photochemically generated chlorine radicals (*Cl). Finally, the overall reaction of the UV-photolysis of HOCl was proposed on the basis of the radical reactions that were related to chlorine species, which suggested that the UV-photolysis of 1 mmol of HOCl stoichiometrically produced 2 mmol of *OH. Since the use of liquid chlorine is more economical than that of H2O2, the substitution of HOCl for H2O2 in the photochemical AOP was concluded to be feasible from the viewpoints of both stoichiometry and chemical costs. PMID- 25809491 TI - Potent restriction of HIV-1 and SIVmac239 replication by African green monkey TRIM5alpha. AB - BACKGROUND: The TRIM5alpha protein is a principal restriction factor that contributes to an HIV-1 replication block in rhesus macaque CD4+ T cells by preventing reverse transcription. HIV-1 restriction is induced in human CD4+ T cells by expression of rhesus TRIM5alpha as well as those of other old world monkeys. While TRIM5alpha restriction has been extensively studied in single round infection assays, fewer studies have examined restriction after extended viral replication. RESULTS: To examine TRIM5alpha restriction of replication, we studied the ability of TRIM5alpha proteins from African green monkey (AgmTRIM5alpha) and gorilla (gorTRIM5alpha) to restrict HIV-1 and SIVmac239 replication. These xenogeneic TRIM5alpha genes were transduced into human Jurkat CCR5 cells (JR5), which were then exposed to HIV-1 or SIVmac239. In our single round infection assays, AgmTRIM5alpha showed a relatively modest 4- to 10-fold restriction of HIV-1 and SIVmac239, while gorTRIM5alpha produced a 2- and 3-fold restriction of HIV-1 and SIVmac239, respectively, consistent with the majority of previously published single-round studies. To assess the impact of these modest effects on infection, we tested restriction in replication systems initiated with either cell-free or cell-to-cell challenges. AgmTRIM5alpha powerfully restricted both HIV-1 and SIVmac239 replication 14 days after cell-free infection, with a >= 3-log effect. Moreover, expression of AgmTRIM5alpha restricted HIV-1 and SIVmac239 replication by 2-logs when co-cultured with infected JR5 cells for 12 days. In contrast, neither expression of gorTRIM5alpha nor rhesus TRIM5alpha induced significant resistance when co-cultured with infected cells. Follow up experiments showed that the observed differences between replication and infection were not due to assembly defects as xenogeneic TRIM5alpha expression had no effect on either virion production or specific infectivity. CONCLUSIONS: Our results indicate that AgmTRIM5alpha has a much greater effect on extended replication than on any single infection event, suggesting that AgmTRIM5alpha restriction acts cumulatively, building up over many rounds of replication. Furthermore, AgmTRIM5alpha was able to potently restrict both HIV-1 and SIV replication in a cell-to-cell infection challenge. Thus, AgmTRIM5alpha is unique among the TRIM5alpha species tested to date, being able to restrict even at the high multiplicities of infection presented by mixed culture with nonrestrictive infected cells. PMID- 25809498 TI - Partnership-based practice with young people: relational dimensions of partnership in a therapeutic setting. AB - The recent literature concerning partnership between professionals and young people reveals important developments regarding the nature of partnership: from short-term partnerships with young people's parents intended to improve decision making in the context of critical life decisions, to a growing interest in direct partnership between professionals and young people as a core principle of long term relationships. Although it is widely acknowledged among health and social service professionals that partnerships can have positive outcomes for young people, the concept and implementation of partnership remain vague. This article examines the meanings of partnership for people involved in a community youth centre for marginalised youth. Data were collected during the year 2011 using multiple-methods including focus groups (with eight youth workers), participant observations (in assembly meetings and 'partnership meetings') and semi structured interviews (with 10 principal stakeholders, including youth, youth workers and the Center's founders). Data were analysed using principles of grounded theory to articulate partnership as an ongoing experience, combining both structural-technical and content-experiential components. Our findings present partnership as existing simultaneously in the practice of decision-making and in the realm of self-experience and interpersonal relationships, and explore the relationship between both spheres. The findings also shed light on the importance of the specific characteristics of shared decision-making (atmosphere, content and duration) in the creation of partnership. We discuss our findings in the light of possibilities for partnership-based practice with marginalised youth. PMID- 25809497 TI - Identification of a Taraxacum brevicorniculatum rubber elongation factor protein that is localized on rubber particles and promotes rubber biosynthesis. AB - Two protein families required for rubber biosynthesis in Taraxacum brevicorniculatum have recently been characterized, namely the cis prenyltransferases (TbCPTs) and the small rubber particle proteins (TbSRPPs). The latter were shown to be the most abundant proteins on rubber particles, where rubber biosynthesis takes place. Here we identified a protein designated T. brevicorniculatum rubber elongation factor (TbREF) by using mass spectrometry to analyze rubber particle proteins. TbREF is homologous to the TbSRPPs but has a molecular mass that is atypical for the family. The promoter was shown to be active in laticifers, and the protein itself was localized on the rubber particle surface. In TbREF-silenced plants generated by RNA interference, the rubber content was significantly reduced, correlating with lower TbCPT protein levels and less TbCPT activity in the latex. However, the molecular mass of the rubber was not affected by TbREF silencing. The colloidal stability of rubber particles isolated from TbREF-silenced plants was also unchanged. This was not surprising because TbREF depletion did not affect the abundance of TbSRPPs, which are required for rubber particle stability. Our findings suggest that TbREF is an important component of the rubber biosynthesis machinery in T. brevicorniculatum, and may play a role in rubber particle biogenesis and influence rubber production. PMID- 25809499 TI - Genetic divergence between the sympatric queen morphs of the ant Myrmica rubra. AB - Pairs of obligate social parasites and their hosts, where some of the parasites have recently diverged from their host through intraspecific social parasitism, provide intriguing systems for studying the modes and processes of speciation. Such speciation, probably in sympatry, has also been propounded in the ant Myrmica rubra and its intraspecific social parasite. In this species, parasitism is associated with queen size dimorphism, and the small microgyne has become a social parasite of the large macrogyne. Here, we investigated the genetic divergence of the host and the parasite queen morphs in 11 localities in southern Finland, using nuclear and mitochondrial markers of queens and workers. We formulated and tested four speciation-related hypotheses that differed in the degree of genetic divergence between the morphs. The queen morphs were genetically distinct from each other with little hybridization. In the nuclear data, when localities were nested within queen morphs in the hierarchical amova, 39% of the genetic variation was explained by the queen morph (standardized F'CT = 0.63, uncorrected FCT = 0.39), whereas 18% was explained by the locality (F'SC = 0.39, FSC = 0.29). This result corroborated the hypothesis of advanced sympatric speciation. In contrast, the mitochondrial DNA could not settle between the hierarchical levels of locality and queen morph, thus substantiating equally the hypotheses of incipient and advanced sympatric speciation. Together, our results support the view that the microgynous parasite has genetically diverged from its macrogynous host to the level of a nascent species. PMID- 25809500 TI - A mild case of hyaline fibromatosis syndrome, presenting in an adult. PMID- 25809501 TI - Phlda3, a urine-detectable protein, causes p53 accumulation in renal tubular cells injured by cisplatin. AB - Measurable indicators of renal injury are required for the assessment of kidney function after toxicant challenge. In our previous study, pleckstrin homology like domain, family A, member 3 (Phlda3) was a most greatly up-regulated molecule downstream from p53, culminating with kidney tubular injury. This study investigated the positive feedforward effect of Phlda3 on p53 in an effort to explain the largest increase of Phlda3 in injured tubules and the potential of its urine excretion. qRT-PCR assays confirmed a rapid and substantial increase in Phlda3 messenger RNA (mRNA) in the kidney cortex of mice treated with a single dose of cisplatin. Cisplatin overexpression of Phlda3 was verified by gene set analyses of three different microarray databases. In the immunohistochemistry, Phlda3 staining intensities were augmented in the tubules as kidney injury worsened. Moreover, the urinary content of Phlda3 was increased after cisplatin treatment, as were those of other kidney injury markers (Kim-1 and Timp-1). By contrast, cisplatin failed to increase Phlda3 mRNA in the liver despite hepatocyte necrosis and ensuing increases in serum transaminase activities. In NRK52E tubular cells, siRNA knockdown of Phlda3 enhanced the ability of cisplatin to increase p-Mdm2 presumably via Akt, enforcing the interaction between Mdm2 and p53. Consistently, a deficiency in Phlda3 abrogated p53 increase by cisplatin, indicating that Phlda3 promotes p53 accumulation. Phlda3 overexpression had the opposite effect. In addition, treatment with cyclosporine A or CdCl2, other nephrotoxicants, increased Phlda3 mRNA and protein levels in NRK52E cells, as did cisplatin treatment. Overall, Phlda3 may cause p53 accumulation through a feedforward pathway, facilitating tubular injury and its urine excretion. PMID- 25809502 TI - Exploration of a standard treatment for Buruli ulcer through a comprehensive analysis of all cases diagnosed in Japan. AB - Buruli ulcer (BU) is a refractory skin ulcer caused by Mycobacterium ulcerans or M. ulcerans ssp. shinshuense, a subspecies thought to have originated in Japan or elsewhere in Asia. Although BU occurs most frequently in tropical and subtropical areas such as Africa and Australia, the occurrence in Japan has gradually increased in recent years. The World Health Organization recommends multidrug therapy consisting of a combination of oral rifampicin (RFP) and i.m. streptomycin (SM) for the treatment of BU. However, surgical interventions are often required when chemotherapy alone is ineffective. As a first step in developing a standardized regimen for BU treatment in Japan, we analyzed detailed records of treatments and prognoses in 40 of the 44 BU cases that have been diagnosed in Japan. We found that a combination of RFP (450 mg/day), levofloxacin (LVFX; 500 mg/day) and clarithromycin (CAM; at a dose of 800 mg/day instead of 400 mg/day) was superior to other chemotherapies performed in Japan. This simple treatment with oral medication increases the probability of patient adherence, and may often eliminate the need for surgery. PMID- 25809503 TI - Trileaflet Mitral Valve with Three Papillary Muscles Associated with Hypertrophic Cardiomyopathy: A Novel Case. AB - Congenital mitral valve (MV) malformations are uncommon, except for MV prolapse. Despite their infrequency, most of them are well-known and defined entities, such as congenital MV stenosis with two papillary muscles, parachute MV, supravalvular mitral ring, hypoplastic MV, isolated cleft in the anterior and/or posterior leaflets, and double-orifice MV. A trileaflet MV with three separate papillary muscles with concordant atrioventricular and ventricle-arterial connections is exceptionally rare. To the best of the authors' knowledge, it has been reported only once in association with subaortic valvular stenosis. We hereby describe a novel case associated with hypertrophic cardiomyopathy. PMID- 25809504 TI - Matrigel coatings for Parylene sheath neural probes. AB - The biologically derived hydrogel Matrigel (MG) was used to coat a Parylene-based sheath intracortical electrode to act as a mechanical and biological buffer as well as a matrix for delivering bioactive molecules to modulate the cellular response and improve recording quality. MG was loaded with dexamethasone to reduce the immune response together with nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) to maintain neuronal density and encourage neuronal ingrowth toward electrodes within the sheath. Coating the Parylene sheath electrode with the loaded MG significantly improved the signal-to-noise ratio for neural events recorded from the motor cortex in rat for more than 3 months. Electron microscopy showed even coverage of both the Parylene substrate and the platinum recording electrodes. Electrochemical impedance spectroscopy (EIS) of coated electrodes in 1* phosphate-buffered saline demonstrated low impedance required for recording neural signals. This result was confirmed by in vivo EIS data, showing significantly decreased impedance during the first week of recording. Dexamethasone, NGF, and BDNF loaded into MG were released within 1 day in 1* phosphate-buffered saline. Although previous studies showed that MG loaded with either the immunosuppressant or the neurotrophic factor cocktail provided modest improvement in recording quality in a 1-month in vivo study, the combination of these bioactive molecules did not improve the signal quality over coating probes with only MG in a 3-month in vivo study. The MG coating may further improve recording quality by optimizing the in vivo release profile for the bioactive molecules. PMID- 25809505 TI - Intestinal epithelial culture under an air-liquid interface: a tool for studying human and mouse esophagi. AB - This study investigated whether an intestinal epithelial culture method can be applied to mouse and human esophageal cultures. The esophagi harvested from 1-day old mice and adult humans were maintained in collagen gels. A commercially available culture medium for human embryonic stem cells was used for the human esophageal culture. We discovered that the intestinal epithelial culture method can be successfully applied to both mouse and human esophageal cultures. The long term cultured esophageal organoids were rod-like luminal structures lined with myofibroblasts. We discovered that regeneration of the esophageal mucosal surface can be almost completely achieved in vitro, and the advantage of this method is that organoid cultures may be generated using host-derived fibroblasts as a niche. This method is a promising tool for mouse and human research in intestinal biology, carcinogenesis, and regenerative medicine. PMID- 25809506 TI - Weekly trends in preschoolers' physical activity and sedentary time in childcare. AB - This study sought to examine how the physical activity levels and sedentary time of preschoolers attending center-based childcare varied across the week. Sex differences were also explored. Participants (n=101) wore ActicalTM accelerometers (15 s epoch) for five consecutive days during childcare hours only. A multivariate repeated measures analysis of variance was used to evaluate levels of sedentary, light, and moderate-to-vigorous (MVPA) physical activity across the five weekdays. Total physical activity (TPA) was analyzed separately in a univariate repeated measures ANOVA. Sex was entered as an additional between subjects factor. Levels of sedentary time, LPA, and TPA across the week were found to be statistically significant, and can best be described by quadratic effects. Participants' activity levels and sedentary time typically peaked mid week. Levels of physical activity and sedentary time were not found to significantly differ based on sex. Childcare centers may benefit from the introduction and/or modification of active play-based programming and curricula, particularly at the start and end of the week where preschoolers' activity levels tend to be lower. Additional investigations are required to confirm these findings. PMID- 25809507 TI - Physiological and psychological effects of forest therapy on middle-aged males with high-normal blood pressure. AB - Time spent walking and relaxing in a forest environment ("forest bathing" or "forest therapy") has well demonstrated anti-stress effects in healthy adults, but benefits for ill or at-risk populations have not been reported. The present study assessed the physiological and psychological effects of forest therapy (relaxation and stress management activity in the forest) on middle-aged males with high-normal blood pressure. Blood pressure and several physiological and psychological indices of stress were measured the day before and approximately 2 h following forest therapy. Both pre- and post-treatment measures were conducted at the same time of day to avoid circadian influences. Systolic and diastolic blood pressure (BP), urinary adrenaline, and serum cortisol were all significantly lower than baseline following forest therapy (p<0.05). Subjects reported feeling significantly more "relaxed" and "natural" according to the Semantic Differential (SD) method. Profile of Mood State (POMS) negative mood subscale scores for "tension-anxiety," "confusion," and "anger-hostility," as well as the Total Mood Disturbance (TMD) score were significantly lower following forest therapy. These results highlight that forest is a promising treatment strategy to reduce blood pressure into the optimal range and possibly prevent progression to clinical hypertension in middle-aged males with high-normal blood pressure. PMID- 25809508 TI - WWOSC 2014: research needs for better health resilience to weather hazards. AB - The first World Weather Open Science Conference (WWOSC, held from 17-21 August 2014 in Montreal, Quebec), provided an open forum where the experience and perspective of a variety of weather information providers and users was combined with the latest application advances in social sciences. A special session devoted to health focused on how best the most recent weather information and communication technologies (ICT) could improve the health emergency responses to disasters resulting from natural hazards. Speakers from a plenary presentation and its corresponding panel shared lessons learnt from different international multidisciplinary initiatives against weather-related epidemics, such as malaria, leptospirosis and meningitis and from public health responses to floods and heat waves such as in Ontario and Quebec, Canada. Participants could bear witness to recent progress made in the use of forecasting tools and in the application of increased spatiotemporal resolutions in the management of weather related health risks through anticipative interventions, early alert and warning and early responses especially by vulnerable groups. There was an agreement that resilience to weather hazards is best developed based on evidence of their health impact and when, at local level, there is a close interaction between health care providers, epidemiologists, climate services, public health authorities and communities. Using near real time health data (such as hospital admission, disease incidence monitoring...) combined with weather information has been recommended to appraise the relevance of decisions and the effectiveness of interventions and to make adjustments when needed. It also helps appraising how people may be more or less vulnerable to a particular hazard depending on the resilience infrastructures and services. This session was mainly attended by climate, environment and social scientists from North American and European countries. Producing a commentary appears to be an effective way to share this session's conclusions to research institutions and public health experts worldwide. It also advocates for better linking operational research and decision making and for appraising the impact of ICT and public health interventions on health. PMID- 25809509 TI - Comments on Lu et al. Association between self-reported global sleep status and prevalence of hypertension in Chinese adults: data from Kailuan community. Int. J. Environ. Res. Public Health 2015, 12, 488-503. PMID- 25809510 TI - Response to Huang et al. Comments on Lu et al. Association between self-reported global sleep status and prevalence of hypertension in Chinese adults: data from Kailuan Community. Int. J. Environ. Res. Public Health 2015, 12, 488-503. PMID- 25809511 TI - Decreasing health disparities for people with disabilities through improved communication strategies and awareness. AB - Factors influencing access to health care among people with disabilities (PWD) include: attitudes of health care providers and the public, physical barriers, miscommunication, income level, ethnic/minority status, insurance coverage, and lack of information tailored to PWD. Reducing health care disparities in a population with complex needs requires implementation at the primary, secondary and tertiary levels. This review article discusses common barriers to health care access from the patient and provider perspective, particularly focusing on communication barriers and how to address and ameliorate them. Articles utilized in this review were published from 2005 to present in MEDLINE and CINAHL and written in English that focused on people with disabilities. Topics searched for in the literature include: disparities and health outcomes, health care dissatisfaction, patient-provider communication and access issues. Ineffective communication has significant impacts for PWD. They frequently believe that providers are not interested in, or sensitive to their particular needs and are less likely to seek care or to follow up with recommendations. Various strategies for successful improvement of health outcomes for PWD were identified including changing the way health care professionals are educated regarding disabilities, improving access to health care services, and enhancing the capacity for patient centered care. PMID- 25809512 TI - Monoamine oxidase a promoter variable number of tandem repeats (MAOA-uVNTR) in alcoholics according to Lesch typology. AB - BACKGROUND: The aim of this study was to examine the association between the MAOA uVNTR gene polymorphism in a homogeneous subgroups of patients with alcohol dependence categorized according to Lesch's typology. METHODS: DNA was provided from alcohol dependent (AD) patients (n=370) and healthy control subjects (n=168) all of Polish descent. The history of alcoholism was obtained using the Polish version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Samples were genotyped using PCR methods. RESULTS: We found no association between alcohol dependence and MAOA gene polymorphism. CONCLUSIONS: Lesch typology is a clinical consequence of the disease and its phenotypic description is too complex for a simple genetic analysis. PMID- 25809513 TI - Can metabolic disorders in aging men contribute to prostatic hyperplasia eligible for transurethral resection of the prostate (TURP)? AB - PURPOSE: The aim of this study was to evaluate the incidence and severity of metabolic disorders occurring in the metabolic syndrome in patients with benign prostatic hyperplasia eligible for surgical treatment. METHODS: The study group consisted men with diagnosed benign prostatic hyperplasia. The control group consisted patients recruited from basic health care units. Abdominal circumference, body weight and blood serum metabolic parameters were determined in the experimental and control groups. The concentrations of glucose were determined, as well as total cholesterol (ChT), low-density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides (TAG), by spectrophotometric method using reagent kits. RESULTS: In the study group 91 (60.3%) cases of metabolic syndrome (MetS) were diagnosed, while in the control group 71 (46.1%) men met the diagnostic criteria for this syndrome (p=0.018). The analysis shows a relationship between MetS in patients with BPH and concentration glucose, ChT, LDL, HDL, systolic blood pressure and diastolic blood pressure. We found no significant statistical relationship between body weight, abdominal circumference and concentration TAG, hypertension in patients and controls. CONCLUSIONS: in the study presented in this article, statistically significant relationships between BPH and the diagnostic parameters of the metabolic syndrome were demonstrated. These results indicate to the necessity of the modification of the lifestyle, taking preventive measures in diabetes, and evaluation of lipid metabolism disorders. It is recommended to assess symptoms that may suggest BPH (as a manifestation of LUTS) in men over 50 years of age with diagnoses of metabolic disorders (including MetS), and provide them with specialist urological care in order to prevent surgical treatment of the prostate. PMID- 25809515 TI - Comments on Triassi et al. Environmental pollution from illegal waste disposal and health effects: a review on the "Triangle of Death". Int. J. Environ. Res. Public health 2015, 12, 1216-1236. PMID- 25809514 TI - Knowledge of the population about visceral leishmaniasis transmission in endemic areas near the banks of the Mossoro River in northeastern Brazil. AB - Visceral leishmaniasis (VL) is an anthropozoonosis with high prevalence and incidence in the Northeastern region of Brazil. This study aimed to determine whether people living near the Mossoro River in the city of Mossoro, Rio Grande do Norte, have knowledge of VL and to characterize the environmental properties of this region. Questionnaires were administered to 478 residents in three neighborhoods near the Mossoro River, addressing the population's knowledge about VL and environmental characteristics. Most survey participants were female, with ages between 18 and 40 years, 53.8% had completed primary education, and 61.5% owned pet dogs (p<0.05). The majority (95.9%) showed little knowledge about the characteristics inherent to sandflies, and 85.3% were unaware of the environments preferred by this vector (p<0.05). Sewage from the homes of respondents was mainly dumped into the river (44.6%), and 76.6% of the respondents complained about the accumulation of garbage in the streets (p<0.05). The association between education and knowledge about the transmission of VL and preferred vector locations was statistically significant (p<0.05). The lack of knowledge in the population about VL and the residential environment indicates a risk of maintaining sand fly habitats and hence disease transmission. PMID- 25809516 TI - Response to Bifulco. Comments on Triassi et al. Environmental pollution from illegal waste disposal and health effects: a reviewer on the "Triangle of Death". Int. J. Environ. Res. Public health 2015, 12, 1216-1236. PMID- 25809517 TI - Efficiency of a multi-soil-layering system on wastewater treatment using environment-friendly filter materials. AB - The multi-soil-layering (MSL) system primarily comprises two parts, specifically, the soil mixture layer (SML) and the permeable layer (PL). In Japan, zeolite is typically used as the permeable layer material. In the present study, zeolite was substituted with comparatively cheaper and more environmentally friendly materials, such as expanded clay aggregates, oyster shells, and already-used granular activated carbon collected from water purification plants. A series of indoor tests indicated that the suspended solid (SS) removal efficiency of granular activated carbon was between 76.2% and 94.6%; zeolite and expanded clay aggregates achieved similar efficiencies that were between 53.7% and 87.4%, and oyster shells presented the lowest efficiency that was between 29.8% and 61.8%. Further results show that the oyster shell system required an increase of wastewater retention time by 2 to 4 times that of the zeolite system to maintain similar chemical oxygen demand (COD) removal efficiency. Among the four MSL samples, the zeolite system and granular activated carbon system demonstrated a stable NH3-N removal performance at 92.3%-99.8%. The expanded clay aggregate system present lower removal performance because of its low adsorption capacity and excessively large pores, causing NO3--N to be leached away under high hydraulic loading rate conditions. The total phosphorous (TP) removal efficiency of the MSL systems demonstrated no direct correlation with the permeable layer material. Therefore, all MSL samples achieved a TP efficiency of between 92.1% and 99.2%. PMID- 25809518 TI - The interface of depression and cardiovascular disease: therapeutic implications. AB - Patients with major depression are at an increased risk for developing cardiovascular disease, respond more poorly to treatment, and exhibit worse outcomes, including increased morbidity and mortality. This article reviews the relationship between depression and heart disease, with an emphasis on epidemiology, biological substrates that likely underlie this relationship, and implications for treatment. PMID- 25809519 TI - Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. AB - BACKGROUND: Coagulopathy has a high prevalence in critically ill patients. An increased International Normalized Ratio (INR) is a common trigger to transfuse fresh frozen plasma (FFP), even in the absence of bleeding. Therefore, FFP is frequently administered to these patients. However, the efficacy of FFP in correcting hemostatic disorders in non-bleeding recipients has been questioned. OBJECTIVES: To assess whether INR prolongation parallels changes in the results of other tests investigating hemostasis, and to evaluate the coagulant effects of a fixed dose of FFP in non-bleeding critically ill patients with a coagulopathy. METHODS: Markers of coagulation, individual factor levels and levels of natural anticoagulants were measured. Also, thrombin generation and thromboelastometry (ROTEM) assays were performed before and after FFP transfusion (12 mL kg(-1) ) to 38 non-bleeding critically ill patients with an increased INR (1.5-3.0). RESULTS: At baseline, levels of factor II, FV, FVII, protein C, protein S and antithrombin were reduced, and thrombin generation was impaired. ROTEM variables were within reference ranges, except for a prolonged INTEM clot formation time. FFP transfusion increased the levels of coagulation factors (FII, 34% [interquartile range (IQR) 26-46] before vs. 44% [IQR 38-52] after; FV, 48% [IQR 28-76] before vs. 58% [IQR 44-90] after; and FVII, 25% [IQR 16-38] before vs. 37% [IQR 28-55] after), and the levels of anticoagulant proteins. Thrombin generation was unaffected by FFP transfusion (endogenous thrombin potential, 72% [IQR 51-88] before vs. 71% [IQR 42-89] after), whereas ROTEM EXTEM clotting time and maximum clot firmness slightly improved in response to FFP. CONCLUSION: In non-bleeding critically ill patients with a coagulopathy, FFP transfusion failed to induce a more procoagulant state. PMID- 25809520 TI - A fluorescence-based hydrolytic enzyme activity assay for quantifying toxic effects of Roundup(r) to Daphnia magna. AB - Daphnia magna is a widely used model organism for aquatic toxicity testing. In the present study, the authors investigated the hydrolytic enzyme activity of D. magna after exposure to toxicant stress. In vivo enzyme activity was quantified using 15 fluorogenic enzyme probes based on 4-methylumbelliferyl or 7-amino-4 methylcoumarin. Probing D. magna enzyme activity was evaluated using short-term exposure (24-48 h) to the reference chemical K2 Cr2 O7 or the herbicide formulation Roundup(r). Toxicant-induced changes in hydrolytic enzyme activity were compared with changes in mobility (International Organization for Standardization standard 6341). The results showed that hydrolytic enzyme activity was quantifiable as a combination of whole body fluorescence of D. magna and the fluorescence of the surrounding water. Exposure of D. magna to lethal and sublethal concentrations of Roundup resulted in loss of whole body enzyme activity and release of cell constituents, including enzymes and DNA. Roundup caused comparable inhibition of mobility and alkaline phosphatase activity with median effective concentration values at 20 degrees C of 8.7 mg active ingredient (a.i.)/L to 11.7 mg a.i./L. Inhibition of alkaline phosphatase activity by Roundup was lowest at 14 degrees C and greater at 20 degrees C and 26 degrees C. The results suggest that the fluorescence-based hydrolytic enzyme activity assay (FLEA assay) can be used as an index of D. magna stress. Combining enzyme activity with fluorescence measurements may be applied as a simple and quantitative supplement for toxicity testing with D. magna. PMID- 25809521 TI - Vaccine therapy update for pregnant, immunocompromised, and chronic diseases patients. AB - The use of vaccines in pregnant, immunocompromised or chronic diseases patients has been widely discussed in the literature recently. Vaccines continue to be a safe and effective method to induce or recall immune response to several infective agents or even induce an effective response in chronically infected patients. The general presumption of adverse events, lack of response and unwanted tolerance seem to be responsible for the decreased vaccination rate in these patients. In the present review, the use of rational vaccination schemes, new patents of use, along as new approaches and patents have been discussed with the scope to diminish the high morbidity and mortality often encountered in these patients. PMID- 25809522 TI - Suspected fetal onset of neonatal transient eosinophilic colitis and development of respiratory distress. AB - Neonatal transient eosinophilic colitis (NTEC) is a new disease concept within eosinophilic gastroenteritis, which was proposed by Ohtsuka et al. It causes hematochezia as a result of eosinophilia, in neonates who have not yet started to receive enteral nutrition, although the whole-body status of the infant is in fact relatively good. To date, there have been no reports of this disease in which abnormalities were noted during gestation, and the clinical phenomena surrounding it, along with any complications, are not yet clear. We encountered a suspected case of NTEC causing respiratory distress with aspiration of hematochezia, in which dilated bowel was noted during gestation. This case indicates that NTEC may occur at the fetal stage and be complicated by respiratory distress. PMID- 25809523 TI - Habitat use of bonobos (Pan paniscus) at Wamba: Selection of vegetation types for ranging, feeding, and night-sleeping. AB - Understanding the habitat requirements of great apes is essential for effective conservation strategies. We examined annual habitat use of a bonobo group in the Wamba field site within the Luo Scientific Reserve, Democratic Republic of the Congo. Using satellite imagery, we categorized the group's ranging area into three forest types: (1) primary and old secondary forest (P/OS), (2) young secondary forest and agriculture (YS/Ag), and (3) swamp forest (Sw). We tracked the group for 1 year (2007-2008) and compared usage of the three forest types for ranging, feeding, and night-sleeping. We also recorded what the bonobos ate and monitored monthly fruit availability in each forest type. The group ranged and fed more often in P/OS and less often in YS/Ag and Sw than expected based on habitat availability. Also, the group slept mostly in P/OS (94% of nights monitored), but also in YS/Ag (1%), and Sw (5%). Fruit availability in P/OS had no significant effect on habitat selection, but the group fed in YS/Ag most often during the two months when fruits in P/OS were least abundant. In June, when fruit of Uapaca spp. (selectively eaten by bonobos) was generally abundant in Sw, the group mostly ranged and slept there. The bonobos fed most often on herbaceous plants in all three forest types. In Sw, the bonobos frequently ate mushrooms. Our results show that semi-open forest with abundant herbaceous plants such as YS/Ag could be an important feeding habitat and may provide fallback food for bonobos when fruits are scarce. Furthermore, Sw can serve seasonally as a main habitat to complement P/OS if adequate food resources and tree nesting opportunities are available. We conclude that bonobos use diverse habitats depending on their needs and we highlight the importance of minor-use habitats for sustaining populations of target species in conservation planning. PMID- 25809524 TI - Antitumour and apoptotic effects of a novel Tris-peptide complex obtained after isolation of Raoultella ornithinolytica extracellular metabolites. AB - AIMS: The characterization of the antitumour activity and chemical identification of the compounds obtained after the isolation of extracellular metabolites of bacteria Raoultella ornithinolytica. METHODS AND RESULTS: The fraction with anticancer activity against the HeLa cell line, T47D and TOV-112D was obtained from the supernatants of R. ornithinolytica culture using ion-exchange chromatography, and separated by Sephadex G-50 medium gel filtration into two subfractions. The obtained compounds were analysed using Fourier Transform Infrared Spectroscopy, Raman spectroscopy and matrix-assisted laser desorption/ionization MS/MS spectrometry. The antitumour activity of the two subfractions was analysed using 5-bromo-2-deoxy-uridine kit. The subfraction with the highest activity against HeLa cells was identified as Tris-peptide complex. The amino acid sequence of the peptide from the complex was found to be TDAPSFSDIPN and molecular weight was estimated at 1430.6576 Da. Cytotoxic, cytopathic and apoptotic effects in HeLa cells treated with the active complex were observed; however, the cytotoxic effect against normal human skin fibroblasts was minimal. CONCLUSIONS: The Tris-peptide complex from R. ornithinolytica showed selective antitumour activity against the HeLa cell line. SIGNIFICANCE AND IMPACT OF THE STUDY: The Tris-peptide complex due to the high selectivity can be used in biomedicine, and its derivatives may contribute to the development of new anticancer compounds. PMID- 25809525 TI - Impact of social norms and social support on diet, physical activity and sedentary behaviour of adolescents: a scoping review. AB - The prevalence of non-communicable diseases (NCDs) in adulthood is rapidly increasing, and it is essential that risk factors for NCDs be addressed in adolescence, both for the health of individuals during adolescence and for their health in later life. These risk factors include diet, physical activity and sedentary behaviour. No literature has been published that comprehensively summarizes the impact of social norms and social support on these behaviours among adolescents. Therefore, a scoping review was conducted to determine the extent of recent (since 2000) literature available on this topic. A comprehensive search strategy was used to search PubMed and EMBASE for eligible reviews. Review papers (narrative reviews, systematic and non-systematic reviews) published in English in peer-reviewed journals from 2000 to February 2013 were included in the overview. Two of the authors screened the titles and abstracts of the search results independently. Thirty reviews were included in the scoping review. This scoping review has shown sufficient evidence for parental influences, and especially the positive impact of an authoritative parenting style, on healthy behaviours of adolescents, although the evidence is somewhat more compelling for diet than for physical activity and sedentary behaviour. More research is needed to investigate parental and family influences on physical activity and sedentary behaviour. And the effect of peer influences on diet, physical activity and sedentary behaviour of adolescents requires further investigation. The evidence presented affirms the consideration of social norms and social support in the development of interventions to address these behaviours in adolescents. The evidence regarding parenting style provides some concrete guidance for such interventions. PMID- 25809529 TI - A qualitative study of the relationship between the Scottish Medicines Consortium and their clinical experts. AB - RATIONALE, AIMS AND OBJECTIVES: Internationally, health technology assessments (HTAs) are ubiquitous drivers to health policy. Within Scotland, the Scottish Medicines Consortium undertakes the medicine review process. Input from clinical experts, involved in frontline care, is an integral component of the assessment process. This paper explores the relationship between the clinical experts and the HTA agency within Scotland to better understand what motivates expert clinicians to devote their time to the medicine review process with no remuneration. METHODS: Twenty-seven clinical experts from 16 different clinical specialties took part in one-to-one interviews at their place of work between October 2011 and March 2012. Data analysis was inductive and comprised the organization of data into a framework and a subsequent thematic analysis. RESULTS: Three distinct themes were identified: (1) recruitment, which identified two types of explanations for the experts' appointment: external justification (nominated by another) and internal justification (being recognized as an expert); (2) flexibility of the procedures, with experts able to determine their own response style and negotiate timelines; (3) health care systems, demonstrating that their affiliation to the health system underpinned the relationship and their motivation to be clinical experts. CONCLUSIONS: The findings of this study provide insight into the elements important to clinicians who voluntarily contribute to HTA processes. Examination of these elements in the context of the organizational citizenship behavior literature provides a foundation on which to improve understanding of this relationship and sustain and improve clinical expert participation in an increasingly intensified clinical environment and within cash-limited HTA systems. PMID- 25809528 TI - Amino-acid-based chiral nanoparticles for enantioselective crystallization. AB - Chiral polymer nanoparticles based on amino acids are prepared by miniemulsion polymerization and are demonstrated to serve as nucleating agents for the enantioselective crystallization of racemic mixtures of amino acids. The synthesized chiral nanoparticles are suited for the development of enantioselective processes and also contribute to a better understanding of chiral recognition on polymer surfaces. PMID- 25809530 TI - Progressive widespread asymptomatic telangiectases. PMID- 25809527 TI - The genome-wide effects of ionizing radiation on mutation induction in the mammalian germline. AB - The ability to predict the genetic consequences of human exposure to ionizing radiation has been a long-standing goal of human genetics in the past 50 years. Here we present the results of an unbiased, comprehensive genome-wide survey of the range of germline mutations induced in laboratory mice after parental exposure to ionizing radiation and show irradiation markedly alters the frequency and spectrum of de novo mutations. Here we show that the frequency of de novo copy number variants (CNVs) and insertion/deletion events (indels) is significantly elevated in offspring of exposed fathers. We also show that the spectrum of induced de novo single-nucleotide variants (SNVs) is strikingly different; with clustered mutations being significantly over-represented in the offspring of irradiated males. Our study highlights the specific classes of radiation-induced DNA lesions that evade repair and result in germline mutation and paves the way for similarly comprehensive characterizations of other germline mutagens. PMID- 25809531 TI - Comparative and synergistic activity of Rosmarinus officinalis L. essential oil constituents against the larvae and an ovarian cell line of the cabbage looper, Trichoplusia ni (Lepidoptera: Noctuidae). AB - BACKGROUND: Plant essential oils are usually complex mixtures, and many factors can affect their chemical composition. To identify relationships between the composition and bioactivity of the constituents, comparative and synergistic interactions of the major constituents of rosemary essential oil were evaluated against third-instar larvae and an ovarian cell line of the cabbage looper, Trichoplusia ni, via different methods of application. RESULTS: The major constituents of the rosemary oil we used were 1,8-cineole, (+/-)-camphor, (+) alpha-pinene and camphene. Via topical application to larvae, 1,8-cineole was identified as the major active compound, whereas via fumigation, 1,8-cineole and (+/-)-camphor, and in a cytotoxicity assay, (+)-alpha-pinene, were determined to be the major active principles. Several combinations of these constituents exhibited synergistic insecticidal activities when topically applied, particularly among combinations of three major constituents, (+/-)-camphor, (+) alpha-pinene and camphene. A binary mixture of 1,8-cineole and (+/-)-camphor showed enhanced activity, with a synergy ratio of 1.72. CONCLUSION: Based on our results, the insecticidal activity of rosemary oil appears to be a consequence of the synergistic interaction between 1,8-cineole and (+/-)-camphor, and (+/-) camphor should be considered a promising synergizing agent. PMID- 25809533 TI - Controllable Assembly and Separation of Colloidal Nanoparticles through a One Tube Synthesis Based on Density Gradient Centrifugation. AB - Self-assembly of gold nanoparticles into one-dimensional (1D) nanostructures with finite primary units was achieved by introducing a thin salt (NaCl) solution layer into density gradient before centrifugation. The electrostatic interactions between Au nanoparticles would be affected and cause 1D assembly upon passing through the salt layer. A negatively charged polymer such as poly(acrylic acid) was used as an encapsulation/stabilization layer to help the formation of 1D Au assemblies, which were subsequently sorted according to unit numbers at succeeding separation zones. A centrifugal field was introduced as the external field to overcome the random Brownian motion of NPs and benefit the assembly effect. Such a facile "one-tube synthesis" approach couples assembly and separation in one centrifuge tube by centrifuging once. The method can be tuned by changing the concentration of interference salt layer, encapsulation layer, and centrifugation rate. Furthermore, positively charged fluorescent polymers such as perylenediimide-poly(N,N-diethylaminoethyl methacrylate) could encapsulate the assemblies to give tunable fluorescence properties. PMID- 25809534 TI - Acute-onset chronic inflammatory demyelinating polyneuropathy: An electrodiagnostic study. AB - INTRODUCTION: Acute-onset chronic inflammatory demyelinating polyneuropathy (A CIDP) is an increasingly recognized CIDP subtype. Differentiating A-CIDP from Guillain-Barre syndrome (GBS) is challenging but important, because there are different treatment outcomes. METHODS: We report 3 patients with A-CIDP who were initially diagnosed with severe GBS but were later confirmed to have CIDP based on their clinical course and electrodiagnostic (EDx) studies. We also report on the long-term treatment of these patients and review the literature on EDx studies in this syndrome. RESULTS: Three patients were initially diagnosed with GBS and responded to treatment. However, all 3 had arrest in improvement or deterioration during their rehabilitation phases. EDx studies showed prominent demyelinating changes many months after the initial presentation. All responded very well to immunotherapy. CONCLUSION: Although several features may suggest the diagnosis of A-CIDP at initial presentation, close follow-up of GBS patients during the recovery phase is also needed for accurate diagnosis. EDx studies may distinguish patients with A-CIDP from GBS patients. PMID- 25809532 TI - Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane((r))) by the Pediatric Preclinical Testing Program (PPTP). AB - BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane((r))) is FDA approved for the treatment of several adult cancers. Antimitotic agents are essential components for curative therapy of pediatric solid tumors, although taxanes have shown limited activity. Because of the novel formulation, nab paclitaxel was evaluated against a limited series of Pediatric Preclinical Testing Program (PPTP) solid tumors. PROCEDURES: Nab-paclitaxel was tested against a limited subset of PPTP solid tumor xenograft models at a dose of 50 mg/kg using a q4d * 3 schedule intravenously. RESULTS: Nab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose. All 20 xenograft models tested were considered evaluable for efficacy. Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors. Objective responses were observed in 12 of 20 (60%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in 5 of 8 Ewing sarcoma models and 6 of 8 rhabdomyosarcomas. There were no objective regressions in either neuroblastoma (n = 2) or osteosarcoma (n = 2) xenograft panels. At the dose tested, systemic exposures of nab-paclitaxel in mice were somewhat greater than those tolerated in humans. CONCLUSIONS: The high level of activity observed against the rhabdomyosarcoma and Ewing sarcoma PPTP preclinical models makes nab paclitaxel an interesting agent to consider for pediatric evaluation. PMID- 25809536 TI - Health system delay and its effect on clinical stage of breast cancer: Multicenter study. AB - BACKGROUND: The objective of this study was to determine the correlation between health system delay and clinical disease stage in patients with breast cancer. METHODS: This was a cross-sectional study of 886 patients who were referred to 4 of the largest public cancer hospitals in Mexico City for the evaluation of a probable breast cancer. Data on time intervals, sociodemographic factors, and clinical stage at diagnosis were retrieved. A logistic regression model was used to estimate the average marginal effects of delay on the probability of being diagnosed with advanced breast cancer (stages III and IV). RESULTS: The median time between problem identification and the beginning of treatment was 7 months. The subinterval with the largest delay was that between the first medical consultation and diagnosis (median, 4 months). Only 15% of the patients who had cancer were diagnosed with stage 0 and I disease, and 48% were diagnosed with stage III and IV disease. Multivariate analyses confirmed independent correlations for the means of problem identification, patient delay, health system delay, and age with a higher probability that patients would begin cancer treatment in an advanced stage. CONCLUSIONS: In the sample studied, the majority of patients with breast cancer began treatment after a delay. Both patient delays and provider delays were associated with advanced disease. Research aimed at identifying specific access barriers to medical services is much needed to guide the design of tailored health policies that go beyond the promotion of breast care awareness and screening participation to include improvements in health services that facilitate access to timely diagnosis and treatment. PMID- 25809535 TI - The cost of phage resistance in a plant pathogenic bacterium is context dependent. AB - Parasites are ubiquitous features of living systems and many parasites severely reduce the fecundity or longevity of their hosts. This parasite-imposed selection on host populations should strongly favor the evolution of host resistance, but hosts typically face a trade-off between investment in reproductive fitness and investment in defense against parasites. The magnitude of such a trade-off is likely to be context-dependent, and accordingly costs that are key in shaping evolution in nature may not be easily observable in an artificial environment. We set out to assess the costs of phage resistance for a plant pathogenic bacterium in its natural plant host versus in a nutrient-rich, artificial medium. We demonstrate that mutants of Pseudomonas syringae that have evolved resistance via a single mutational step pay a substantial cost for this resistance when grown on their tomato plant hosts, but do not realize any measurable growth rate costs in nutrient-rich media. This work demonstrates that resistance to phage can significantly alter bacterial growth within plant hosts, and therefore that phage mediated selection in nature is likely to be an important component of bacterial pathogenicity. PMID- 25809537 TI - Blood coagulation and fibrinolysis in aortic valve stenosis: links with inflammation and calcification. AB - Aortic valve stenosis (AS) increasingly afflicts our aging population. However, the pathobiology of the disease is still poorly understood and there is no effective pharmacotherapy for treating those at risk for clinical progression. The progression of AS involves complex inflammatory and fibroproliferative processes that resemble to some extent atherosclerosis. Accumulating evidence indicates that several coagulation proteins and its inhibitors, including tissue factor, tissue factor pathway inhibitor, prothrombin, factor XIII, von Willebrand factor, display increased expression within aortic stenotic valves, predominantly on macrophages and myofibroblasts around calcified areas. Systemic impaired fibrinolysis, along with increased plasma and valvular expression of plasminogen activator inhibitor-1, has also been observed in patients with AS in association with the severity of the disease. There is an extensive cross-talk between inflammation and coagulation in stenotic valve tissue which contributes to the calcification and mineralisation of the aortic valve leaflets. This review summarises the available data on blood coagulation and fibrinolysis in AS with the emphasis on their interactions with inflammation and calcification. PMID- 25809539 TI - Host suitability analysis of the bark beetle Scolytus amygdali (Coleoptera: Curculionidae: Scolytinae). AB - Scolytus amygdali is a polyphagous insect pest that feeds on fruit trees and forest trees. Our study assessed the host preference and reproductive potential of S. amygdali on four tree species: almond (Prunus dulcis), apricot (Prunus armeniaca), peach (Prunus persica), and plum (Prunus domestica). Females of S. amygdali produced maternal galleries that were longer on peach than the other three trees, and female fecundity was highest on peach. Females with longer maternal galleries produced more eggs, indicating a positive correlation between maternal gallery length and female fertility. The under-bark development time of S. amygdali is significantly shorter on plum (45 days) and almond (56 days) than on apricot (65 days) and peach (64 days). Despite this longer development time on peach, our results still suggest that, of the four types of tree tested, peach is the most preferred host for S. amygdali. PMID- 25809538 TI - Neutrophil functions in morbidly obese subjects. AB - The present study aimed to determine different peripheral blood neutrophil functions in 18 morbidly obese subjects with body mass index (BMI) ranging between 35 and 69 kg/m(2) in parallel with age- and gender-matched lean controls. Peripheral blood neutrophil functions of obese subjects and matched lean controls were determined. Neutrophils of obese subjects showed significant elevation of the release of basal superoxides (P < 0.0001), formyl-methionyl-leucyl phenylalanine (fMLP)-stimulated superoxides (P < 0.0001) and opsonized zymosan (OZ)-stimulated superoxides (P < 0.045) compared with lean controls. Interestingly, there were no differences in phorbol myristate acetate (PMA) stimulated superoxide production by neutrophils of the obese subjects and controls. There was also a significant elevation of chemotactic (P < 0.0003) and random (P < 0.0001) migration of neutrophils from obese subjects compared with lean controls. Phagocytosis, CD11b surface expression and adherence of neutrophils from obese subjects were not significantly different from those of the lean controls. The elevated superoxide production and chemotactic activity, together with the normal phagocytosis and adherence, suggest that neutrophils from obese subjects are primed and have the capability to combat infections. However, neutrophils in the priming state may participate in the pathogenesis of obesity-related diseases. PMID- 25809540 TI - Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. AB - BACKGROUND: Clearance of hepatitis B surface antigen (HBsAg) indicates clinical control of hepatitis B virus (HBV) infection. However, little is known about the impact of viral genomic variations on HBsAg loss. METHODS: We explored the association between viral genomic factors and HBsAg loss in 2121HBeAg-negative patients. HBV pre-core stop codon (1896) and basal core promoter (BCP) (1762/1764) sequences were determined in patients with HBV DNA >=200 IU/mL (N = 1693). The effect of HBV genotype on HBsAg loss was further validated in the whole cohort of 3445 HBsAg carriers. RESULTS: The cumulative lifetime (age 28-75 years) incidence of HBsAg loss was 50.4% in 2121 HBeAg-negative patients. We found that genotype C, but not pre-core stop codon or BCP mutants, was associated with HBsAg loss. Compared to genotype B patients, genotype C patients had higher lifetime chance of HBsAg loss, with hazard ratio of 1.8 (95% confidence interval: 1.4-2.4). Multivariable analysis showed that male sex, elevated ALT levels, lower serum HBV DNA and HBsAg levels, and genotype C infection were associated with higher chance of HBsAg loss independently. We then performed sensitivity analysis, which re-included HBeAg-positive, cirrhotic and treatment-experienced patients, and confirmed the robustness of our results in 3445 HBsAg carriers. CONCLUSION: Genotype C infection, compared to genotype B, is associated with a higher lifetime chance of HBsAg loss in Asian HBV carriers. PMID- 25809541 TI - Extended survival of patients with persistently suppressed hepatitis B transplanted for hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has become a major cause of liver-related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. METHODS: We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/ml) and 90 (89%) were within Milan criteria (MC). All patients received post-transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. RESULTS: During 106 (range 3-165) months following LT, HCC recurred in 11 (11%) patients (nine beyond MC at explant, two with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, P = 0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, P < 0.0001) were the only independent pretransplant predictors of tumour recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared with 45% among those beyond MC at LT (P = 0.004). Overall, 18 patients (18%, nine HCC, nine non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89% respectively. CONCLUSIONS: Extended survival of HBV cirrhotics transplanted for HCC can be achieved by coupling MC at listing with persistent pharmacological suppression of HBV. PMID- 25809543 TI - Targeting the EWS-FLI1 transcription factor in Ewing sarcoma. AB - PURPOSE: Preclinical data indicate there is strong synergism of action against Ewing sarcoma in sequential treatment with trabectedin followed by irinotecan and it appears to be related to a selective blockade of the transcription factor EWS FLI1. This combination was evaluated in Ewing sarcoma patient who was progressing with standard therapies. METHODS: Trabectedin was given as a 24-h iv infusion on day 1 at the dose of 1 mg/sqm, and irinotecan 75 mg/sqm on day 2 and then on days 2 and 4, every 3 weeks from the seventh course. RESULTS: The therapy was well tolerated with transient hematological toxicity and transaminitis and induced stabilization of the disease lasting for 11 courses, with clinical improvement and marked reduction of the need for opioids. However, shortly before the 12th course, sudden death occurred, possibly due to cerebral stroke, presumably not related to the drug treatment. CONCLUSIONS: The encouraging clinical benefit observed with the combination and its good tolerability deserves further investigation in Ewing sarcoma. PMID- 25809544 TI - Development and implementation of intranasal naloxone opioid overdose response protocol at a homeless health clinic. AB - PURPOSE: To describe the development, implementation, and preliminary evaluation of Opioid Overdose Response Protocol using intranasal (IN) naloxone in a homeless shelter. DATA SOURCES: Opioid Overdose Response Protocol and training curriculum were developed using the Massachusetts Department of Public Health Opioid Overdose Education and Naloxone Distribution (OEND) flow chart, the American Heart Association (AHA) simplified adult basic life support algorithm, and resources through Harms Reduction Coalition. CONCLUSIONS: Intranasal naloxone offers a safe and effective method for opioid reversal. To combat the rising incidence of opioid overdose, IN naloxone should be made available at homeless shelters and other facilities with high frequency of opioid overdose, including the training of appropriate staff. This project has demonstrated the effective training and implementation of an Opioid Overdose Response Protocol, based on feedback received from cardiopulmonary resuscitation (CPR) trained nonhealthcare staff. Nurse practitioners (NPs), with our focus on patient care, prevention, and education, are well suited to the deployment of this life-saving protocol. IMPLICATIONS FOR PRACTICE: NPs are in critical positions to integrate opioid overdose prevention education and provide naloxone rescue kits in clinical practices. PMID- 25809542 TI - Three-dimensional structure and cyanobacterial activity within a desert biological soil crust. AB - Desert biological soil crusts (BSCs) are formed by adhesion of soil particles to polysaccharides excreted by filamentous cyanobacteria, the pioneers and main producers in this habitat. Biological soil crust destruction is a central factor leading to land degradation and desertification. We study the effect of BSC structure on cyanobacterial activity. Micro-scale structural analysis using X-ray microtomography revealed a vesiculated layer 1.5-2.5 mm beneath the surface in close proximity to the cyanobacterial location. Light profiles showed attenuation with depth of 1%-5% of surface light within 1 mm but also revealed the presence of 'light pockets', coinciding with the vesiculated layer, where the irradiance was 10-fold higher than adjacent crust parts at the same depth. Maximal photosynthetic activity, examined by O2 concentration profiles, was observed 1 mm beneath the surface and another peak in association with the 'light pockets'. Thus, photosynthetic activity may not be visible to currently used remote sensing techniques, suggesting that BSCs' contribution to terrestrial productivity is underestimated. Exposure to irradiance higher than 10% full sunlight diminished chlorophyll fluorescence, whereas O2 evolution and CO2 uptake rose, indicating that fluorescence did not reflect cyanobacterial photosynthetic activity. Our data also indicate that although resistant to high illumination, the BSC inhabiting cyanobacteria function as 'low-light adapted' organisms. PMID- 25809545 TI - National Healthcare Delivery Systems Influence Lung Transplant Outcomes for Cystic Fibrosis. AB - Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. Therefore, we conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom. Patients with CF who underwent lung or heart-lung transplantation in the United States or United Kingdom between January 1, 2000 and December 31, 2011 were included. The primary outcome was all cause mortality. Kaplan-Meier analysis and Cox proportional hazards regression evaluated the effect of healthcare system and insurance on mortality after LTx. 2,307 US LTx recipients and 451 individuals in the United Kingdom were included. 894 (38.8%) US LTx recipients had publically funded Medicare/Medicaid insurance. US private insurance and UK patients had improved median predicted survival compared with US Medicare/Medicaid recipients (p < 0.001). In multivariable Cox regression, US Medicare/Medicaid insurance was associated with worse survival after LTx (US private: HR0.78,0.68-0.90,p = 0.001 and UK: HR0.63,0.41-0.97, p = 0.03). This study in CF patients is the largest comparison of LTx in two unique health systems. Both the United States and United Kingdom have similar early survival outcomes, suggesting important dissemination of best practices internationally. However, the performance of US public insurance is significantly worse and may put patients at risk. PMID- 25809547 TI - Evaluation of Ignition and Burn Risk Associated with Contemporary Fiberoptic and Distal Sensor Endoscopic Technology. AB - PURPOSE: To evaluate the ignition and burn risk associated with contemporary fiberoptic and distal sensor endoscopic technologies. MATERIALS AND METHODS: We used new and used SCB Xenon 300 light sources to illuminate a 4.8 mm fiberoptic cable, 10 mm laparoscope, 5 mm laparoscope, rigid cystoscope, semirigid ureteroscope, flexible cystoscope, flexible fiberoptic ureteroscope, distal sensor cystoscope, and a distal sensor ureteroscope (Karl Storz, Inc., Tuttlingen, Germany). We measured peak temperatures at the distal end of each device. We then evaluated each device on a flat and folded surgical drape to establish ignition risk. Finally, we evaluated the effects of all devices on human cadaver skin covered by surgical drape. RESULTS: Peak temperatures recorded for each device ranged from 26.9 degrees C (flexible fiberoptic ureteroscope) to 194.5 degrees C (fiberoptic cable). Drape ignition was noted when the fiberoptic cable was placed against a fold of drape. Contact with the fiberoptic cable, 10 mm laparoscope, 5 mm laparoscope, and distal sensor cystoscope resulted in cadaver skin damage. Cadaver skin damage occurred despite little or no visible change to the surgical drape. Rigid and flexible fiberoptic cystoscopes and flexible fiberoptic ureteroscopes had no effect on surgical drapes or cadaver skin. CONCLUSIONS: Fiberoptic light cables and some endoscopic devices have the potential to cause thermal injury and drape ignition. Thermal injury may occur without visible damage to drapes. Surgeons should remain vigilant regarding the risks associated with these devices and take necessary safety precautions to prevent patient injury. PMID- 25809546 TI - Imputation of class I and II HLA loci using high-density SNPs from ImmunoChip and their associations with Kawasaki disease in family-based study. AB - Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States. The etiology of KD is not known; however, epidemiological and immunological data suggest infectious or immune-related factors in the manifestation of the disease. Further, KD has several hereditary features that strongly suggest a genetic component to disease pathogenesis. Human leucocyte antigen (HLA) loci have also been reported to be associated with KD, but results have been inconsistent, in part, because of small study samples and varying linkage disequilibrium (LD) patterns observed across different ethnic groups. To maximize the informativeness of single nucleotide polymorphism (SNP) genotypes in the major histocompatibility (MHC) region, we imputed classical HLA I (A, B, C) and HLA II (DRB1, DQA1, DQB1) alleles using SNP2HLA method from genotypes of 6700 SNPs within the extended MHC region contained in the ImmunoChip among 112 White patients with KD and their biological parents from North America and tested their association with KD susceptibility using the transmission disequilibrium test. Mendelian consistency in the trios suggested high accuracy and reliability of the imputed alleles (class I = 97.5%, class II = 96.6%). While several SNPs in the MHC region were individually associated with KD susceptibility, we report over-transmission of HLA-C*15 (z = +2.19, P = 0.03) and under-transmission of HLA-B*44 (z = -2.49, P = 0.01) alleles from parents to patients with KD. HLA-B*44 has been associated with KD in other smaller studies, and both HLA-C*15 and HLA-B*44 have biological mechanisms that could potentially be involved in KD pathogenesis. Overall, inferring HLA loci within the same ethnic group, using family-based information is a powerful approach. However, studies with larger sample sizes are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD. PMID- 25809550 TI - Quantitative structural constraints for organic powders at natural isotopic abundance using dynamic nuclear polarization solid-state NMR spectroscopy. AB - A straightforward method is reported to quantitatively relate structural constraints based on (13)C-(13)C double-quantum build-up curves obtained by dynamic nuclear polarization (DNP) solid-state NMR to the crystal structure of organic powders at natural isotopic abundance. This method relies on the significant gain in NMR sensitivity provided by DNP (approximately 50-fold, lowering the experimental time from a few years to a few days), and is sensitive to the molecular conformation and crystal packing of the studied powder sample (in this case theophylline). This method allows trial crystal structures to be rapidly and effectively discriminated, and paves the way to three-dimensional structure elucidation of powders through combination with powder X-ray diffraction, crystal-structure prediction, and density functional theory computation of NMR chemical shifts. PMID- 25809549 TI - Hybrid epicardial and endocardial ablation of atrial fibrillation: is ablation on two sides of the atrial wall better than one? PMID- 25809548 TI - Sequential hybrid procedure for persistent atrial fibrillation. AB - BACKGROUND: Catheter ablation of persistent atrial fibrillation yields an unsatisfactorily high number of failures. The hybrid approach has recently emerged as a technique that overcomes the limitations of both surgical and catheter procedures alone. METHODS AND RESULTS: We investigated the sequential (staged) hybrid method, which consists of a surgical thoracoscopic radiofrequency ablation procedure followed by radiofrequency catheter ablation 6 to 8 weeks later using the CARTO 3 mapping system. Fifty consecutive patients (mean age 62+/ 7 years, 32 males) with long-standing persistent atrial fibrillation (41+/-34 months) and a dilated left atrium (>45 mm) were included and prospectively followed in an unblinded registry. During the electrophysiological part of the study, all 4 pulmonary veins were found to be isolated in 36 (72%) patients and a complete box-lesion was confirmed in 14 (28%) patients. All gaps were successfully re-ablated. Twelve months after the completed hybrid ablation, 47 patients (94%) were in normal sinus rhythm (4 patients with paroxysmal atrial fibrillation required propafenone and 1 patient underwent a redo catheter procedure). The majority of arrhythmias recurred during the first 3 months. Beyond 12 months, there were no arrhythmia recurrences detected. The surgical part of the procedure was complicated by 7 (13.7%) major complications, while no serious adverse events were recorded during the radiofrequency catheter part of the procedure. CONCLUSIONS: The staged hybrid epicardial-endocardial treatment of long-standing persistent atrial fibrillation seems to be extremely effective in maintenance of normal sinus rhythm compared to radiofrequency catheter or surgical ablation alone. Epicardial ablation alone cannot guarantee durable transmural lesions. CLINICAL TRIAL REGISTRATION: URL: www.ablace.cz Unique identifier: cz-060520121617. PMID- 25809551 TI - A pilot study of an HbA1c chairside screening protocol for diabetes in patients with chronic periodontitis: the dental hygienist's role. AB - OBJECTIVE: To assess effectiveness, convenience and cost of point-of-care diabetes screenings performed by a dental hygienist for patients with periodontitis, using a diabetes risk questionnaire, periodontal findings and a glycosylated haemoglobin (HbA1c) analyser. METHODS: A purposive sample of 50 participants with periodontitis, never diagnosed with diabetes, reporting >=one diabetes risk factor, were administered an HbA1c test. Spearman's correlation measured relationships between HbA1c and diabetes risk test scores, numbers of missing teeth, percentage of deep pockets >=5 mm and percentage of bleeding sites (BOP). Cost and time were assessed. Analyses used 0.05 alpha levels. RESULTS: Thirty-two per cent (n = 16) of participants presented HbA1c values indicating prediabetes; one HbA1c value indicated type 2 diabetes, totalling 34% (N = 17). No relationships existed between HbA1c values and diabetes risk scores (rs = 0.153; P = 0.144), numbers of missing teeth (r = 0.190; P = 0.093), percentage of deep pockets (rs = -0.048; P = 0.370) or percentage of BOP sites (rs = 0.066, P = 0.324). Direct cost for each HbA1c was $9US, excluding follow-up medical diagnosis. Mean screening time including patient education was 14 min (SD = 6.2). Fifty-three per cent (n = 9 of 17) of participants with elevated HbA1c values contacted their primary healthcare provider within 2 weeks as recommended. CONCLUSION: Point-of-care HbA1c screenings by dental hygienists were effective and convenient for identifying undiagnosed prediabetes and provide opportunity for interprofessional patient care; cost or lack of dental insurance may inhibit implementation. Identification of patients at risk for diabetes requires further evaluation. PMID- 25809552 TI - Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment. AB - Bone marrow-derived mesenchymal stem cells (BMSC) modulate inflammatory/immune responses and promote motor functional recovery after spinal cord injury (SCI). However, the effects of BMSC transplantation on central neuropathic pain and neuronal hyperexcitability after SCI remain elusive. This is of importance because BMSC-based therapies have been proposed for clinical treatment. We investigated the effects of BMSC transplantation on pain hypersensitivity in green fluorescent protein (GFP)-positive bone marrow-chimeric mice subjected to a contusion SCI, and the mechanisms of such effects. BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. The pain improvements were mediated by suppression of protein kinase C-gamma and phosphocyclic AMP response element binding protein expression in dorsal horn neurons. BMSC transplants significantly reduced levels of p-p38 mitogen-activated protein kinase and extracellular signal regulated kinase (p-ERK1/2) in both hematogenous macrophages and resident microglia and significantly reduced the infiltration of CD11b and GFP double positive hematogenous macrophages without decreasing the CD11b-positive and GFP negative activated spinal-microglia population. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB), which was associated with decreased levels of (a) inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6); (b) mediators of early secondary vascular pathogenesis (matrix metallopeptidase 9); (c) macrophage recruiting factors (CCL2, CCL5, and CXCL10), but increased levels of a microglial stimulating factor (granulocyte-macrophage colony-stimulating factor). These findings support the use of BMSC transplants for SCI treatment. Furthermore, they suggest that BMSC reduce neuropathic pain through a variety of related mechanisms that include neuronal sparing and restoration of the disturbed BSCB, mediated through modulation of the activity of spinal-resident microglia and the activity and recruitment of hematogenous macrophages. PMID- 25809553 TI - Suicide in the oldest old: an observational study and cluster analysis. AB - OBJECTIVES: The older population are at a high risk for suicide. This study sought to learn more about the characteristics of suicide in the oldest-old and to use a cluster analysis to determine if oldest-old suicide victims assort into clinically meaningful subgroups. METHODS: Data were collected from a coroner's chart review of suicide victims in Toronto from 1998 to 2011. We compared two age groups (65-79 year olds, n = 335, and 80+ year olds, n = 191) and then conducted a hierarchical agglomerative cluster analysis using Ward's method to identify distinct clusters in the 80+ group. RESULTS: The younger and older age groups differed according to marital status, living circumstances and pattern of stressors. The cluster analysis identified three distinct clusters in the 80+ group. Cluster 1 was the largest (n = 124) and included people who were either married or widowed who had significantly more depression and somewhat more medical health stressors. In contrast, cluster 2 (n = 50) comprised people who were almost all single and living alone with significantly less identified depression and slightly fewer medical health stressors. All members of cluster 3 (n = 17) lived in a retirement residence or nursing home, and this group had the highest rates of depression, dementia, other mental illness and past suicide attempts. CONCLUSIONS: This is the first study to use the cluster analysis technique to identify meaningful subgroups among suicide victims in the oldest old. The results reveal different patterns of suicide in the older population that may be relevant for clinical care. PMID- 25809555 TI - Changing prevalence of wheeze, rhinitis and allergic sensitisation in late childhood: findings from 2 Isle of Wight birth cohorts 12 years apart. AB - BACKGROUND: While the prevalence of asthma in children is decreasing or remaining the same, time trends in the prevalence of rhinitis in children are not known. Understanding sensitisation trends may help inform about trends in asthma and rhinitis prevalence. OBJECTIVE: To assess time trends of wheeze, rhinitis and aero-allergen sensitisation prevalence at 10 years of age, we compared two birth cohorts established 12 years apart. To gain insight into differences in disease prevalence, we assessed association of family history, early life exposures and sensitisation with wheeze and rhinitis in each cohort. METHODS: The IoW (Isle of Wight) and FAIR (Food Allergy and Intolerance Research) unselected birth cohorts were established in 1989 and 2001 respectively in IoW. Identical ISAAC questionnaire and skin prick test data were collected and compared at 10 years of age. RESULTS: Over the 12-year period from 2001 to 2012, prevalence of lifetime wheeze, current wheeze and those ever treated for asthma decreased by 15.9% (45.5 vs. 29.6, P < 0.001), 3.9% (18.9 vs. 15, P = 0.020) and 8.2% (31.7 vs. 23.5, P = 0.001), respectively. Conversely, current rhinitis and lifetime rhinitis prevalence increased by 5.5% (22.6 vs. 28.1, P = 0.004) and 13% (18.6 vs. 31.7, P < 0.001), respectively. Atopic status remained stable; however, house dust mite (HDM) sensitisation decreased by 5.6% (19.2 vs. 13.6, P = 0.004) and grass sensitisation increased by 3.5% (12.9 vs. 16.4, P = 0.054). Male sex, parental history of asthma and HDM sensitisation were significantly associated with lifetime wheeze in both cohorts, while maternal smoking during pregnancy was a significant risk factor only in the earlier IoW cohort. Parental history of rhinitis and grass sensitisation was significantly associated with lifetime rhinitis in both cohorts, while HDM sensitisation was significant only for the IoW cohort. CONCLUSION: Contrasting changes were noted with falling wheeze and HDM sensitisation but rising rhinitis and grass sensitisation prevalence. Changing prevalence of aero-allergen sensitisations may explain the different time trends observed in these cohorts. PMID- 25809554 TI - Genetic and epigenetic modifications to the BBAA component of common wheat during its evolutionary history at the hexaploid level. AB - The formation and evolution of common wheat (Triticum aestivum L., genome BBAADD) involves allopolyploidization events at two ploidy levels. Whether the two ploidy levels (tetraploidy and hexaploidy) have impacted the BBAA subgenomes differentially remains largely unknown. We have reported recently that extensive and distinct modifications of transcriptome expression occurred to the BBAA component of common wheat relative to the evolution of gene expression at the tetraploid level in Triticum turgidum. As a step further, here we analyzed the genetic and cytosine DNA methylation differences between an extracted tetraploid wheat (ETW) harboring genome BBAA that is highly similar to the BBAA subgenomes of common wheat, and a set of diverse T. turgidum collections, including both wild and cultivated genotypes. We found that while ETW had no significantly altered karyotype from T. turgidum, it diverged substantially from the later at both the nucleotide sequence level and in DNA methylation based on molecular marker assay of randomly sampled loci across the genome. In particular, ETW is globally less cytosine-methylated than T. turgidum, consistent with earlier observations of a generally higher transcriptome expression level in ETW than in T. turgidum. Together, our results suggest that genome evolution at the allohexaploid level has caused extensive genetic and DNA methylation modifications to the BBAA subgenomes of common wheat, which are distinctive from those accumulated at the tetraploid level in both wild and cultivated T. turgidum genotypes. PMID- 25809556 TI - Intracellular modulation of excited-state dynamics in a chromophore dyad: differential enhancement of photocytotoxicity targeting cancer cells. AB - The photosensitized generation of reactive oxygen species, and particularly of singlet oxygen [O2 (a(1) Deltag )], is the essence of photodynamic action exploited in photodynamic therapy. The ability to switch singlet oxygen generation on/off would be highly valuable, especially when it is linked to a cancer-related cellular parameter. Building on recent findings related to intersystem crossing efficiency, we designed a dimeric BODIPY dye with reduced symmetry, which is ineffective as a photosensitizer unless it is activated by a reaction with intracellular glutathione (GSH). The reaction alters the properties of both the ground and excited states, consequently enabling the efficient generation of singlet oxygen. Remarkably, the designed photosensitizer can discriminate between different concentrations of GSH in normal and cancer cells and thus remains inefficient as a photosensitizer inside a normal cell while being transformed into a lethal singlet oxygen source in cancer cells. This is the first demonstration of such a difference in the intracellular activity of a photosensitizer. PMID- 25809557 TI - Time taken for superior osteotomy in primary powered endoscopic dacryocystorhinostomy: is there a difference between an ultrasonic aspirator and a mechanical burr? AB - BACKGROUND: The purpose of this study is to report the time taken for superior osteotomy and complications during this step in primary powered endoscopic dacryocystorhinostomy (PEnDCR) using the piezoelectric system and mechanical burr. METHODS: This prospective interventional comparative series was performed on all consecutive patients who underwent a primary PEnDCR over a 4-month period. The surgery was performed as per standard protocols and all patients were operated on by a single surgeon (M.J.A.). Parameters documented were demographic data, type of powered instrument used, time taken for superior osteotomy, exposure of the agger nasi, exposure of entire sac, and complications such as excess bleeding, soft tissue injury, or mucosal burns. Statistical analyses were performed using the linear mixed-effect model and 2-sample t tests. RESULTS: A total of 55 PEnDCRs were studied, 29 in the mechanical burr group and 26 in the piezoelectric or ultrasonic group. The mean time for superior osteotomy in the mechanical burr group was 3.71 minutes (range, 1.75 to 6.58 minutes); in the ultrasonic group it was 4.12 minutes (range, 1.33 to 6.25 minutes). There was no significant difference (p = 0.17) between the 2 groups. Subcategory analyses of time taken by age (p = 0.057) and sex (p = 0.56) did not show any difference between the groups. Two patients in the mechanical burr group had an insignificant superficial sac injury and 1 patient in the ultrasonic group suffered epithelial burns away from the site of osteotomy, which resolved spontaneously without any sequelae. There was no excess bleeding in any of the groups. CONCLUSION: The time taken by mechanical burr and piezoelectric system are comparable for superior osteotomy in PEnDCR. If anatomical boundaries are respected, their use appears to be safe without major complications. PMID- 25809558 TI - Benzo[b]tryptanthrin inhibits MDR1, topoisomerase activity, and reverses adriamycin resistance in breast cancer cells. AB - Tryptanthrin is an indoloquinazoline alkaloid isolated from indigo. Tryptanthrin and its benzo-annulated derivative, benzo[b]tryptanthrin, inhibit both topoisomerases I (topo I) and II (topo II) and cause cytotoxicity in several human cancer cell lines. From diverse assessment methods, including cleavage complex stabilization, comet, DNA unwinding/intercalation, topo II ATPase inhibition, ATP competition for topo II, and wound-healing assays, we determined that the mode of action of benzo[b]tryptanthrin is as a DNA non-intercalative and ATP-competitive topo I and II dual catalytic inhibitor. Benzo[b]tryptanthrin induced apoptosis through the cleavage of caspase-3 and PARP in HCT15 colon cancer cells. Additionally, benzo[b]tryptanthrin reversed adriamycin resistance by down-regulation of multidrug resistance protein 1 (MDR1) in adriamycin resistant MCF7 breast cancer cells (MCF7adr) with more potent inhibitory activity than tryptanthrin. Taken together, derivatization by benzo-annulation of tryptanthrin ameliorated the MDR-reversing effect of tryptanthrin and may pave the way to the discovery of a novel potent adjuvant agent for chemotherapy. PMID- 25809560 TI - In-line coupled single drop liquid-liquid-liquid microextraction with capillary electrophoresis for determining fluoroquinolones in water samples. AB - A simple in-line single drop liquid-liquid-liquid microextraction (SD-LLLME) coupled with CE for the determination of two fluoroquinolones was developed. The method is capable to quantify trace amount of analytes in water samples and to improve the sensitivity of CE detection. For the SD-LLLME, a thin layer of organic phase was used to separate a drop of 0.1 M NaOH hanging at the inlet of the capillary from the aqueous donor phase. By this way, the analytes were extracted to the acceptor phase through the organic layer based on their acidic/basic dissociation equilibrium. The drop was immersed into the organic phase during 10 min for extraction and then it is directly injected into the capillary for the analysis. Parameters such as type and volume of organic solvent phase, aqueous donor, and acceptor phases and extraction time and temperature were optimized. The enrichment factor was calculated, resulting 40-fold for enrofloxacin (ENR) and sixfold for ciprofloxacin (CIP). The linear range were 20 400 MUg/L for ENR and 60-400 MUg/L for CIP. The detection limits were 10.1 MUg/L and 55.3 MUg/L for ENR and CIP, respectively, and a good reproducibility was obtained (4.4% for ENR and 5.6% for CIP). Two real water samples were analysed applying the new method and the obtained results presented satisfactory recovery percentages (90-100.3%). PMID- 25809559 TI - Reducing sensitivity losses due to respiration and motion in accelerated echo planar imaging by reordering the autocalibration data acquisition. AB - PURPOSE: To reduce the sensitivity of echo-planar imaging (EPI) auto-calibration signal (ACS) data to patient respiration and motion to improve the image quality and temporal signal-to-noise ratio (tSNR) of accelerated EPI time-series data. METHODS: ACS data for accelerated EPI are generally acquired using segmented, multishot EPI to distortion-match the ACS and time-series data. The ACS data are, therefore, typically collected over multiple TR periods, leading to increased vulnerability to motion and dynamic B0 changes. The fast low-angle excitation echo-planar technique (FLEET) is adopted to reorder the ACS segments so that segments within any given slice are acquired consecutively in time, thereby acquiring ACS data for each slice as rapidly as possible. RESULTS: Subject breathhold and motion phantom experiments demonstrate that artifacts in the ACS data reduce tSNR and produce tSNR discontinuities across slices in the accelerated EPI time-series data. Accelerated EPI data reconstructed using FLEET ACS exhibit improved tSNR and increased tSNR continuity across slices. Additionally, image quality is improved dramatically when bulk motion occurs during the ACS acquisition. CONCLUSION: FLEET-ACS provides reduced respiration and motion sensitivity in accelerated EPI, which yields higher tSNR and image quality. Benefits are demonstrated in both conventional-resolution 3T and high resolution 7T EPI time-series data. PMID- 25809561 TI - Prostasomes of canine seminal plasma - zinc-binding ability and effects on motility characteristics and plasma membrane integrity of spermatozoa. AB - Prostasomes are small lipid membrane-confined vesicles that are involved in various fertilization-related processes. The aim of this study was to demonstrate canine seminal plasma prostasomes' ability to bind zinc ions, as well as examining their effects on sperm motility characteristics and plasma membrane integrity during cold storage. Ejaculates, collected from five cross-bred dogs (n = 50), were subjected to ultracentrifugation followed by gel filtration (GF) on a Superose 6 column. Prostasomes appeared as a single fraction in the elution profile. Transmission electron microscopy (TEM) analysis of canine prostasomes revealed the presence of membrane vesicles with diameters ranging from 20.3 to 301 nm. The zinc-affinity chromatography on a Chelating Sepharose Fast Flow - Zn(2 +) showed that from 93 to 100% of the prostasome proteins bind zinc ions (P(+) Zn). SDS-PAGE revealed that canine P(+) Zn comprised four protein bands, with low molecular weights (10.2-12 kDa). We have also shown a positive effect of prostasomes (p < 0.05), especially variant B (2% of total seminal plasma protein) on canine sperm motility parameters after 2 h storage at 5 degrees C (TMOT%, 44.75 +/- 5.18) and PMOT%, 12.42 +/- 1.59) and VAP, VSL, VCL, when compared with Control (TMOT%, 7.30 +/- 1.41 and PMOT%, 1.70 +/- 0.42). Higher percentage of spermatozoa with intact plasma membrane (SYBR/PI dual staining) and intact acrosome (Giemsa stained), after 2 h storage at 5 degrees C, was showed, in variant A (1.5% of total seminal plasma protein) and B, when compared with Control and variant C (2.5% of total seminal plasma protein). The prostasomes' effect on motility and plasma membrane integrity of canine cold-stored spermatozoa may be related to their ability to bind zinc ions and regulate their availability to the sperm. PMID- 25809562 TI - Effectiveness of cognitive rehabilitation following epilepsy surgery: Current state of knowledge. AB - OBJECTIVE: Cognitive rehabilitation (CR) is a well-researched therapeutic option for a variety of neurocognitive problems. Recently, CR has been proposed as an option for patients who experience cognitive difficulties following epilepsy surgery (ES). However, there is inconsistency in reporting the efficacy of CR in this population. We appraise existing evidence regarding CR approaches in patients undergoing resective ES and review effectiveness of specific CR strategies. METHODS: A comprehensive literature search using MEDLINE, Embase, CINAHL, PsycINFO, and EBM Reviews (including the Cochrane database) identified studies in English published before September 2014, without age restriction, related to CR in patients who underwent resective ES. We included studies focused on patients who underwent ES and who received at least one type of cognitive rehabilitation. RESULTS: Of 2,059 citations identified, four fulfilled eligibility criteria (n = 577), and all investigated the effectiveness of specific CR strategies in patients with either left or right temporal lobe resections. CR strategies used included internal compensatory strategies, external memory aids, psychoeducation, verbal and visual memory training, and exercises of attention and executive functions. None were randomized trials, and only one study involved standardized methods or described the procedures in detail. Evidence suggests that CR may contribute to improvements in aspects of verbal memory, with particular benefit of visual imagery techniques; CR aimed at verbal memory functions may be less effective for patients with hemispheric dominant resections, and figural memory may not be improved by CR. Furthermore, CR may improve functional and life outcomes, but its timing does not appear to influence its effectiveness. SIGNIFICANCE: We demonstrate that CR interventions are overwhelmingly under researched or underreported, and there is a need for a systematic evaluation of CR in this patient population. CR should be given greater attention after ES to determine its efficacy and role in the management of these patients. PMID- 25809563 TI - High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis. AB - AIMS: c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c Met immunostaining in this setting. METHODS AND RESULTS: c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: >= 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis. CONCLUSIONS: Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival. PMID- 25809565 TI - Randomized Controlled Trial of Home-Based Telehealth Versus In-Person Prolonged Exposure for Combat-Related PTSD in Veterans: Preliminary Results. AB - OBJECTIVES: Telehealth technology may reduce the effect of treatment barriers and improve participation in treatment for veterans with posttraumatic stress disorder (PTSD). The present study is an ongoing randomized controlled trial comparing the effectiveness of prolonged exposure (PE) delivered via in person or home-based video telehealth modalities. METHOD: A total of 52 veterans with combat-related PTSD were randomized to receive 8-12 weeks of PE through either home-based telehealth or standard in-person office-based care. RESULTS: Participants evinced significant reductions in symptoms of PTSD, depression, and anxiety from pre- to posttreatment across both conditions. Analyses conducted within a noninferiority framework suggested nonsignificant treatment outcome differences in clinician-reported PTSD and self-reported anxiety between the conditions. Results were inconclusive for self-reported PTSD and depression symptoms. Patient satisfaction ratings did not significantly differ between the two groups. CONCLUSIONS: Results suggest that PE can be delivered via home-based telehealth with outcomes and satisfaction ratings comparable to in-person practices for certain symptoms, however additional research is needed. This modality has the potential to address stigma- and geographic-related barriers to treatment, such as travel time and cost. PMID- 25809564 TI - U937 cell apoptosis induced by arsenite is prevented by low concentrations of mitochondrial ascorbic acid with hardly any effect mediated by the cytosolic fraction of the vitamin. AB - Arsenite directly triggers cytochrome c and Smac/DIABLO release in mitochondria isolated from U937 cells. These effects were not observed in mitochondria pre exposed for 15 min to 10 uM L-ascorbic acid (AA). In other experiments, intact cells treated for 24-72 h with arsenite were found to die by apoptosis through a mechanism involving mitochondrial permeability transition. Pre-exposure (15 min) to low micromolar concentrations of AA and dehydroascorbic acid (DHA), resulting in identical cytosolic levels of the vitamin, had a diverse impact on cell survival, as cytoprotection was only observed after treatment with AA. Also the mitochondrial accumulation of the vitamin was restricted to AA exposure. An additional indication linking cytoprotection to the mitochondrial fraction of the vitamin was obtained in experiments measuring susceptibility to arsenite in parallel with loss of mitochondrial and cytosolic AA at different times after vitamin exposure. Finally, we took advantage of our recent findings that DHA potently inhibits AA transport to demonstrate that DHA abolishes all the protective effects of AA, under the same conditions in which the mitochondrial accumulation of the vitamin is prevented without affecting the overall cellular accumulation of the vitamin. PMID- 25809567 TI - Evaluating effectiveness of small group information literacy instruction for Undergraduate Medical Education students using a pre- and post-survey study design. AB - BACKGROUND: The Undergraduate Medical Education (UME) programme at the University of Calgary is a three-year programme with a strong emphasis on small group learning. OBJECTIVE: The purpose of our study was to determine whether librarian led small group information literacy instruction, closely integrated with course content and faculty participation, but without a hands on component, was an effective means to convey EBM literacy skills. METHOD: Five 15-minute EBM information literacy sessions were delivered by three librarians to 12 practicing physician led small groups of 15 students. Students were asked to complete an online survey before and after the sessions. Data analysis was performed through simple descriptive statistics. RESULTS: A total of 144 of 160 students responded to the pre-survey, and 112 students answered the post-survey. Instruction in a small group environment without a mandatory hands on component had a positive impact on student's evidence-based information literacy skills. Students were more likely to consult a librarian and had increased confidence in their abilities to search and find relevant information. CONCLUSION: Our study demonstrates that student engagement and faculty involvement are effective tools for delivering information literacy skills when working with students in a small group setting outside of a computer classroom. PMID- 25809566 TI - The specific NK cell response in concert with perforin prevents CD8(+) T cell mediated immunopathology after mouse cytomegalovirus infection. AB - Natural killer (NK) and CD8(+) T cells play a crucial role in the control of mouse cytomegalovirus (MCMV) infection. These effector cells exert their functions by releasing antiviral cytokines and by cytolytic mechanisms including perforin activation. In addition to their role in virus control, NK cells play an immunoregulatory role since they shape the CD8(+) T cell response to MCMV. To investigate the role of perforin-dependent cytolytic mechanism in NK cell modulation of CD8(+) T cell response during acute MCMV infection, we have used perforin-deficient C57BL/6 mice (Prf1(-/-)) and have shown that virus control by CD8(+) T cells in Prf1(-/-) mice is more efficient if NK cells are activated by the engagement of the Ly49H receptor with the m157 MCMV protein. A lack of perforin results in severe liver inflammation after MCMV infection, which is characterized by immunopathological lesions that are more pronounced in Prf1(-/-) mice infected with virus unable to activate NK cells. This immunopathology is caused by an abundant infiltration of activated CD8(+) T cells. The depletion of CD8(+) T cells has markedly reduced pathohistological lesions in the liver and improved the survival of Prf1(-/-) mice in spite of an increased viral load. Altogether, the results of our study suggest that a lack of perforin and absence of the specific activation of NK cells during acute MCMV infection lead to an unleashed CD8(+) T cell response that is detrimental for the host. PMID- 25809568 TI - Cardioprotective Effect of MicroRNA-21 in Murine Myocardial Infarction. AB - INTRODUCTION: To investigate the cardioprotective effect of MicroRNA-21 (miR-21) in murine myocardial infarction (MI). METHODS: Forty C57BL/6 male mice were divided into sham group, MI group, LV-GFP group, and miR-21 group. Mice in the MI group, LV-GFP group, and miR-21 group were subjected to MI by left anterior descending artery (LAD) ligation, while chest was opened/closed without ligation in sham group. In MI group, expression of miR-21 in the MI area and its surrounding areas was detected at 1st, 2nd, and 4th week after experiment. Subsequently, lentivirus expressing miR-21 and lentivirus that did not express miR-21 were transfected into mice left ventricular cavity of miR-21 group and LV GFP group, respectively. Cardiac function, MI size, miR-21 expression, collagen I level, fibronectin content, number of alpha-SMA-positive cells, number of apoptotic cells, apoptosis-related factors were compared between the three groups. RESULTS: Compared with sham group, miR-21 levels in MI group were significantly decreased in the 1st week and 2nd week, but were almost the same in the 4th week. Left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) in the miR-21 group improved compared to the LV-GFP group. In miR-21 group, myocardial infarct size reduced by 36.9% in comparison with LV-GFP group. Compared to sham group, miR-21 expression in the miR-21 group and LV-GFP group decreased significantly. In the miR-21 group, collagen I level, fibronectin content and number of alpha-SMA-positive cells of miR-21 decreased significantly compared to the LV-GFP group. The number of apoptotic cells in the MI areas of the miR-21 group was significantly less than the LV-GFP group. Compared with the LV-GFP group, Bcl-2 level and the ratio of Bcl-2 to Bax were significantly increased, and the levels of Bax and Caspase-3 decreased. CONCLUSIONS: Our results suggest miR-21 is an important regulatory molecule in the pathophysiology of MI. PMID- 25809569 TI - Treatment with recombinant tissue plasminogen activator alters the microRNA expression profiles in mouse brain after acute ischemic stroke. AB - Thrombolysis with recombinant tissue plasminogen activator (rtPA) is the only FDA approved treatment for the brain ischemic stroke. MicroRNAs, non-coding RNA sequences that regulate gene expression, might play important roles in regulating the rtPA thrombolysis process. The present study investigated changes in the microRNA profiles in a middle cerebral artery occlusion (MCAo) mouse model after rtPA treatment. Using microarrays containing 1179 microRNAs, we compared microRNAs expression profiles of brain tissues from C57 BL/6J mice subjected to focal cerebral ischemia with and without rtPA thrombolysis. We found that rtPA treatment upregulated 31 microRNAs and downregulated 11 microRNAs. Expression alterations of selected microRNAs mmu-miR-125a-3p, -208a-5p, -709, -721 were confirmed by real-time PCR. Differentially expressed microRNAs were analyzed using Targetscan v6.2 and David v6.7. 2200 predicted genes were subjected to GO analysis and pathway analysis, which identified mediators involved in multiple signaling pathways during proliferation. These data demonstrated that rtPA treatment alters microRNAs expression after stroke, and provided new insight into understanding the biological process of rtPA thrombolysis. PMID- 25809570 TI - Season of birth and Parkinson's disease: possible relationship? AB - The amount of sun exposure in early life and consequent vitamin D3 level may influence the risk of developing Parkinson's disease (PD). Yet few studies have previously investigated birth trends in PD related to a possible seasonality and sun exposure. The aim of this study was to investigate a possible relationship between PD risk and sun exposure looking at seasonal birth variation of PD subjects in the homogenous geographic area of Naples, Italy. We selected 898 PD subjects and matched with 1796 controls. McNemar's test with Bonferroni correction and autocorrelation were used to test seasonality in birth trends. No difference was found for the month and season of birth between PD subjects and controls. We found a 3.3 % increase of PD female subjects born in September (3.3 %) and 4.1 % increase of PD male subjects born in spring comparing to controls but were not significant after Bonferroni correction. This study evaluated for the first time the seasonal birth trends in relation to PD risk in a Southern European population. We found no association between seasonal birth variations and risk of PD. PMID- 25809571 TI - Leptin upregulation in advanced multiple system atrophy with hypocholesterolemia and unexpected fat accumulation. AB - Advanced multiple system atrophy (MSA) patients exhibit malnutrition with hypocholesterolemia and hypoalbuminemia, similar to patients with other neurodegenerative disorders, but also display unexpected fat accumulation. To understand this paradox, we herein examined the relationship between fat accumulation, measured by triceps skinfold thickness (TSF), and plasma leptin in 29 MSA patients at three clinical stages: activities of daily living (ADL) 1: ambulatory with/without wheelchair; ADL2: bedridden/communicable; and ADL3: bedridden/non-communicable. TSF and leptin were higher while cholesterol and albumin were lower in advanced stage ADL3 than in ADL1 or ADL2. Although a correlation was observed between leptin and TSF, a stepwise regression analysis identified the first significant positive predictor of leptin as the duration of autonomic symptoms (p < 0.005) rather than TSF. Leptin/TSF strongly correlated with the duration of autonomic symptoms (p < 0.001). These results implicate leptin resistance through autonomic dysfunction in the paradoxical fat accumulation observed in patients with advanced MSA, but not to be seen in the cholesterol metabolism. PMID- 25809573 TI - Trait Predictors of Aggression and Crash-Related Behaviors Across Drivers from the United Kingdom and the Irish Republic. AB - Aggressive driving is acknowledged as a contributor to motor vehicle crashes. This study explored a theoretical model of aggressive expression and crash related outcomes using self-report data collected, using an online questionnaire, from drivers in the United Kingdom and the Republic of Ireland. The proposed model tested whether the personality traits of boredom proneness, sensation seeking, and impulsivity, coupled with trait driving anger, predicted aggressive driving; and whether aggressive driving predicted crash-related outcomes (loss of concentration and control, near misses, and moving violations). The structural model was confirmed, with aggressive expressions of anger being found to mediate the relationships driving anger and impulsivity had with the crash-related outcomes. Multigroup invariance analysis showed that the model remained invariant across drivers from the United Kingdom and Ireland, suggesting that the contributing factors for aggressive expression and crash involvement are similar across both countries. When self-reported crash-related conditions were compared between drivers in the United Kingdom and Ireland, drivers in the United Kingdom reported more aggressive driving, more minor crashes, more incidents of road rage, and more frequent losses of concentration and vehicle control. PMID- 25809572 TI - Nitric oxide-eluting scaffolds and their interaction with smooth muscle cells in vitro. AB - Fabrication of scaffolds loaded with nitric oxide (NO) donors (S nitrosoglutathione, GSNO, and isosorbide mononitrate, ISMN) with suitable cell compatibility and optimized properties for tissue-engineering applications is reported using "in situ" technique. Based on FDA-approved polymer, solvent and dosage forms, this gentle process allowed the incorporation of the GSNO labile drug into scaffolds made of either poly(lactide-co-glycolide) (PLGA) or PLGA/poly(E-caprolactone) (PCL) blend. During scaffolds manufacturing process including washing cycles, NO donors were leached from scaffolds. However, GSNO and ISMN concentrations in the last washing medium (10(-7) M and 10(-4) M, respectively) were in the range of cell suitability for tissue engineering. Further morphological analyses indicated that smoother surfaces with fewer but bigger pores (compatible with cell penetration and ingrowth) were obtained with PLGA in comparison with PLGA/PCL scaffolds. Among all tested matrices, only unloaded PLGA and GSNO-loaded PLGA/PCL exhibited intermediate cell anchorage, with mitochondrial activity close to the control and an increase in protein content, a prognostic for scaffold cell colonization, defining them as promising candidates. Deeper analyses of these two scaffolds looking at intracellular redox balance through reactive oxygen species production, glutathione, S-nitrosothiols, and nitrite ions content exhibited GSNO-loaded PLGA/PCL as the best of all tested 3D scaffolds for tissue engineering. PMID- 25809576 TI - A practical design for a dual-agent dose-escalation trial that incorporates pharmacokinetic data. AB - Traditionally, model-based dose-escalation trial designs recommend a dose for escalation based on an assumed dose-toxicity relationship. Pharmacokinetic data are often available but are currently only utilised by clinical teams in a subjective manner to aid decision making if the dose-toxicity model recommendation is felt to be too high. Formal incorporation of pharmacokinetic data in dose-escalation could therefore make the decision process more efficient and lead to an increase in the precision of the resulting recommended dose, as well as decreasing the subjectivity of its use. Such an approach is investigated in the dual-agent setting using a Bayesian design, where historical single-agent data are available to advise the use of pharmacokinetic data in the dual-agent setting. The dose-toxicity and dose-exposure relationships are modelled independently and the outputs combined in the escalation rules. Implementation of stopping rules highlight the practicality of the design. This is demonstrated through an example which is evaluated using simulation. PMID- 25809574 TI - Cutaneous manifestations of viral hepatitis. AB - There are several extrahepatic cutaneous manifestations associated with hepatitis B and hepatitis C virus infection. Serum sickness and polyarteritis nodosa are predominantly associated with hepatitis B infection, whereas mixed cryoglobulinemia associated vasculitis and porphyria cutanea tarda are more frequently seen in hepatitis C infection. The clinico-pathogenic associations of these skin conditions are not completely defined but appear to involve activation of the host immune system including the complement system. Management of the aforementioned cutaneous manifestations of viral hepatitis is often similar to that done in cases without viral hepatitis, with control of immune activation being a key strategy. In cases associated with hepatitis B and C, control of viral replication with specific antiviral therapy is also important and associated with improvement in most of the associated clinical manifestations. PMID- 25809577 TI - In vivo strains in the femur of the nine-banded armadillo (Dasypus novemcinctus). AB - The capacity of limb bones to resist the locomotor loads they encounter depends on both the pattern of those loads and the material properties of the skeletal elements. Among mammals, understanding of the interplay between these two factors has been based primarily on evidence from locomotor behaviors in upright placentals, which show limb bones that are loaded predominantly in anteroposterior bending with minimal amounts of torsion. However, loading patterns from the femora of opossums, marsupials using crouched limb posture, show appreciable torsion while the bone experiences mediolateral (ML) bending. These data indicated greater loading diversity in mammals than was previously recognized, and suggested the possibility that ancestral loading patterns found in sprawling lineages (e.g., reptilian sauropsids) might have been retained among basal mammals. To further test this hypothesis, we recorded in vivo locomotor strains from the femur of the nine-banded armadillo (Dasypus novemcinctus), a member of the basal xenarthran clade of placental mammals that also uses crouched limb posture. Orientations of principal strains and magnitudes of shear strains indicate that armadillo femora are exposed to only limited torsion; however, bending is essentially ML, placing the medial aspect of the femur in compression and the lateral aspect in tension. This orientation of bending is similar to that found in opossums, but planar strain analyses indicate much more of the armadillo femur experiences tension during bending, potentially due to muscles pulling on the large, laterally positioned third trochanter. Limb bone safety factors were estimated between 3.3 and 4.3 in bending, similar to other placental mammals, but lower than opossums and most sprawling taxa. Thus, femoral loading patterns in armadillos show a mixture of similarities to both opossums (ML bending) and other placentals (limited torsion and low safety factors), along with unique features (high axial tension) that likely relate to their distinctive hindlimb anatomy. PMID- 25809578 TI - Dynamic regulation of the angiotensinogen gene by DNA methylation, which is influenced by various stimuli experienced in daily life. AB - Angiotensinogen (AGT) has a central role in maintaining blood pressure and fluid balance. DNA methylation is an epigenomic modification maintaining a steady pattern in somatic cells. Herein we summarize the link between AGT regulation and DNA methylation. DNA methylation negatively regulates AGT expression and dynamically changes in response to continuous AGT promoter stimulation. High-salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT enhancer-binding protein-binding sites, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue. Salt-dependent hypertension may be partially affected by increased adipose AGT expression. Because angiotensin II is a well-established aldosterone-releasing hormone, stimulation of adipose AGT by aldosterone creates a positive feedback loop. This effect is pathologically associated with obesity-related hypertension, although it would be physiologically favorable for humans to efficiently retain their body fluid. The clear difference in DNA demethylation patterns between aldosterone and cortisol indicates a difference in the respective target DNA binding sites between mineralocorticoid and glucocorticoid receptors in the AGT promoter. Stimulation-induced interactions between transcription factors and target DNA-binding sites trigger DNA demethylation. Dynamic changes in DNA methylation occur in relaxed chromatin regions both where transcription factors actively interact and where transcription is initiated. In contrast to rapid histone modifications, DNA demethylation and remethylation will progress relatively slowly over days or years. A wide variety of stimuli in daily life will continue to slowly and dynamically change DNA methylation patterns throughout life. Wise choices of beneficial stimuli will improve health. PMID- 25809581 TI - Assessing collective affect recognition via the Emotional Aperture Measure. AB - Curiosity about collective affect is undergoing a revival in many fields. This literature, tracing back to Le Bon's seminal work on crowd psychology, has established the veracity of collective affect and demonstrated its influence on a wide range of group dynamics. More recently, an interest in the perception of collective affect has emerged, revealing a need for a methodological approach for assessing collective emotion recognition to complement measures of individual emotion recognition. This article addresses this need by introducing the Emotional Aperture Measure (EAM). Three studies provide evidence that collective affect recognition requires a processing style distinct from individual emotion recognition and establishes the validity and reliability of the EAM. A sample of working managers further shows how the EAM provides unique insights into how individuals interact with collectives. We discuss how the EAM can advance several lines of research on collective affect. PMID- 25809580 TI - Old-style epidemiology and epigeneticdemiology. PMID- 25809579 TI - Treatment-induced changes in ambulatory arterial stiffness index: one-year prospective study and meta-analysis of evidence. AB - The ambulatory arterial stiffness index (AASI) has been introduced as an index of arterial function, predicting cardiovascular events. However, treatment-induced changes in AASI are rather equivocal. This study aims to: (i) present the results of treatment-induced changes in AASI in untreated subjects with elevated blood pressure (BP), subjected to antihypertensive treatment for 1 year and (ii) perform a meta-analysis of studies reporting on treatment-induced change in AASI. A total of 104 subjects (mean age 51.4+/-10.3 years, 62% males, mean follow-up: 13.6+/-2.4 months) were analyzed. Despite significant reductions in 24-h ambulatory systolic/diastolic BP, pulse pressure and pulse wave velocity (mean change: -15.9+/-12/-10.4+/-7.6 mm Hg, -5.4+/-6.8 mm Hg, -0.7+/-1.9 m s(-1), respectively, all P<0.05), there was no significant change (Follow up-Baseline) in AASI values (mean change: 0.01+/-0.17, P=not significant). The treatment induced change in AASI was correlated with baseline AASI (r=-0.61), baseline 24-h pulse pressure (-0.26), treatment-induced change in 24-h pulse pressure (0.26) and in systolic/diastolic nocturnal dipping (-0.25/-0.40, respectively). Meta analysis of eight trials (n=990) revealed a marginal decrease in AASI with antihypertensive treatment (pooled change: -0.018 (95% confidence interval (CI): 0.033,-0.003)). When the analysis was restricted to data with renin-angiotensin system blockers (n=755, 76% of total), the results did not significantly change (pooled change -0.028 (95% CI -0.048, -0.007)). In conclusion, although AASI is an independent predictor of cardiovascular events, its response to antihypertensive treatment is only marginal and clinically uncertain, which may render its use as a therapeutic target in clinical practice questionable. PMID- 25809583 TI - Mucous contribution to gut nutrient content in American gizzard shad Dorosoma cepedianum. AB - This study developed and applied an approach to calculate the proportion of fish gut content composed of mucus secreted by the oropharyngeal cavity and gut. The amount of nitrogen in the contents of the foregut (oesophagus and gizzard) and the epibranchial organs of suspension-feeding American gizzard shad Dorosoma cepedianum was significantly higher than the nitrogen in the homogeneous food source. Using data collected from suspension-feeding experiments and the nitrogen content of D. cepedianum mucus, a series of equations illustrated that mucus constituted c. 10% of D. cepedianum foregut content and 12% of epibranchial organ content by dry mass. Future quantification of fish feeding selectivity and absorption efficiency can use this approach to take into account the contribution of fish mucus to the nutrients in the gut contents. This study supports the conclusion that suspension-feeding D. cepedianum in a heterogeneous environment selectively ingest nutrient-rich particles, even when gut nutrient content is adjusted to take into account the contribution of mucus. PMID- 25809584 TI - Suspension flow: do particles act as mixers? AB - Recently, Roht et al. [J. Contam. Hydrol., 2013, 145, 10-16] observed that the presence of suspended non-Brownian macroscopic particles decreased the dispersivity of a passive solute, for a pressure-driven flow in a narrow parallel plate channel at low Reynolds numbers. This result contradicts the idea that the streamline distortion caused by the random diffusive motion of the particles increases the dispersion and mixing of the solute. Therefore, to estimate the influence of this motion on the dispersivity of the solute, and investigate the origin of the reported decrease, we experimentally studied the probability density function (pdf) of the particle velocities, and spatio-temporal correlations, in the same experimental configuration. We observed that, as the mean suspension velocity exceeds a critical value, the pdf of the streamwise velocity of the particles markedly changes from a symmetric distribution to an asymmetric one strongly skewed to high velocities and with a peak of the most probable velocity close to the maximum velocity. The latter observations and the analysis of the suspension microstructure indicate that the observed decrease in the dispersivity of the solute is due to particle migration to the mid-plane of the channel, and consequent flattening of the velocity profile. Moreover, we estimated the contribution of particle diffusive motion to the solute dispersivity to be three orders of magnitude smaller than the reported decrease, and thus negligible. Solute dispersion is then much more affected by how particles modify the flow velocity profile across the channel than by their random diffusive motion. PMID- 25809582 TI - AWHONN Position Statement. Intimate partner violence. AB - The Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) opposes laws and other policies that require nurses to report the results of screening for intimate partner violence (IPV) to law enforcement or other regulatory agencies without the consent of the woman who experiences the IPV. Nurses and other health care professionals, however, should become familiar with laws on mandatory reporting in their states and comply as applicable. Women should be universally screened for IPV in private, safe settings where health care is provided. Nurses are ideally positioned to screen for IPV for the purpose of initiating a referral for services and support when applicable. To protect the woman's safety, AWHONN supports policies that require a woman's consent before reporting occurs. PMID- 25809585 TI - Efficacy of neurostimulation to treat symptoms of Mal de Debarquement Syndrome. A preliminary study using repetitive transcranial magnetic stimulation. AB - Mal de debarquement syndrome (MdDS) is a rare and poorly understood condition of perceived continual motion. Using a multiple-case design (n = 13; 8 f; 63.5 +/- 12.6 years), this study investigated the efficacy of eight 20-min sessions, over 4 weeks, of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral pre-frontal cortex. Compared to sham, rTMS demonstrated improvement in balance and confidence in daily living activities. rTMS shows promise for the treatment of MdDS. However, larger trials with longer intervention periods are required. PMID- 25809586 TI - Xylitol-containing products for preventing dental caries in children and adults. AB - BACKGROUND: Dental caries is a highly prevalent chronic disease which affects the majority of people. It has been postulated that the consumption of xylitol could help to prevent caries. The evidence on the effects of xylitol products is not clear and therefore it is important to summarise the available evidence to determine its effectiveness and safety. OBJECTIVES: To assess the effects of different xylitol-containing products for the prevention of dental caries in children and adults. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 14 August 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2014, Issue 7), MEDLINE via OVID (1946 to 14 August 2014), EMBASE via OVID (1980 to 14 August 2014), CINAHL via EBSCO (1980 to 14 August 2014), Web of Science Conference Proceedings (1990 to 14 August 2014), Proquest Dissertations and Theses (1861 to 14 August 2014). We searched the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of xylitol products on dental caries in children and adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the electronic searches, extracted data and assessed the risk of bias of the included studies. We attempted to contact study authors for missing data or clarification where feasible. For continuous outcomes, we used means and standard deviations to obtain the mean difference and 95% confidence interval (CI). We used the continuous data to calculate prevented fractions (PF) and 95% CIs to summarise the percentage reduction in caries. For dichotomous outcomes, we reported risk ratios (RR) and 95% CIs. As there were less than four studies included in the meta-analysis, we used a fixed-effect model. We planned to use a random-effects model in the event that there were four or more studies in a meta-analysis. MAIN RESULTS: We included 10 studies that analysed a total of 5903 participants. One study was assessed as being at low risk of bias, two were assessed as being at unclear risk of bias, with the remaining seven being at high risk of bias.The main finding of the review was that, over 2.5 to 3 years of use, a fluoride toothpaste containing 10% xylitol may reduce caries by 13% when compared to a fluoride-only toothpaste (PF -0.13, 95% CI -0.18 to -0.08, 4216 children analysed, low-quality evidence).The remaining evidence on children, from small single studies with risk of bias issues and great uncertainty associated with the effect estimates, was insufficient to determine a benefit from xylitol products. One study reported that xylitol syrup (8 g per day) reduced caries by 58% (95% CI 33% to 83%, 94 infants analysed, low quality evidence) when compared to a low dose xylitol syrup (2.67 g per day) consumed for 1 year.The following results had 95% CIs that were compatible with both a reduction and an increase in caries associated with xylitol: xylitol lozenges versus no treatment in children (very low quality body of evidence); xylitol sucking tablets versus no treatment in infants (very low quality body of evidence); xylitol tablets versus control (sorbitol) tablets in infants (very low quality body of evidence); xylitol wipes versus control wipes in infants (low quality body of evidence).There was only one study investigating the effects of xylitol lozenges, when compared to control lozenges, in adults (low quality body of evidence). The effect estimate had a 95% CI that was compatible with both a reduction and an increase in caries associated with xylitol.Four studies reported that there were no adverse effects from any of the interventions. Two studies reported similar rates of adverse effects between study arms. The remaining studies either mentioned adverse effects but did not report any usable data, or did not mention them at all. Adverse effects include sores in the mouth, cramps, bloating, constipation, flatulence, and loose stool or diarrhoea. AUTHORS' CONCLUSIONS: We found some low quality evidence to suggest that fluoride toothpaste containing xylitol may be more effective than fluoride only toothpaste for preventing caries in the permanent teeth of children, and that there are no associated adverse-effects from such toothpastes. The effect estimate should be interpreted with caution due to high risk of bias and the fact that it results from two studies that were carried out by the same authors in the same population. The remaining evidence we found is of low to very low quality and is insufficient to determine whether any other xylitol-containing products can prevent caries in infants, older children, or adults. PMID- 25809587 TI - Modulation of satellite cells activity and MyoD in rat thyroarytenoid muscle after reinnervation. AB - OBJECTIVES/HYPOTHESIS: To examine modulation of M-cadherin, a marker for satellite cells (SCs); and MyoD, which may indicate the myogenic activity following recurrent laryngeal nerve (RLN) denervation and immediate reinnervation; and to elucidate the correlation between their modulations and establishment of neuromuscular junctions (NMJs) in the reinnervated rat thyroarytenoid (TA) muscle. STUDY DESIGN: Quantitative real-time polymerase chain reaction qPCR and histologic assessment of the TA muscle following RLN transection and anastomosis. METHODS: Rats were divided into three groups: 1) denervation alone (DNV) (n = 60), 2) denervation with anastomosis (ANS) (n = 60), and 3) sham-operated controls (n = 12). Animals were sacrificed at 3 days and 1, 3, and 5 weeks after treatment. TA muscles harvested from 40 animals from each DNV and ANS group; all of sham group were subjected to qPCR for assessment of the modulation of M-cadherin and MyoD; and the remaining larynges of DNV and ANS group were used for histologic analysis. RESULTS: The expression levels of messenger RNAs (mRNAs) encoding M-cadherin and MyoD in the TA muscle of the DNV group were significantly higher (P < 0.05) than in the control throughout the study period. These mRNA levels in the ANS group were significantly higher (P < 0.05) at <= 1 week than in the controls but fell to control levels at >= 3 weeks. In the ANS group, recovery of muscle area and NMJs structure occurred by 3 weeks. CONCLUSION: These data suggested that NMJ formation following reinnervation might prompt recovery of M-cadherin and MyoD mRNA expression to the quiescent level of SCs. PMID- 25809588 TI - The validity and reliability of the functional rating index for evaluating low back pain in athletes. AB - The purpose of the present study was to determine the reliability and validity of the Functional Rating Index (FRI) for athletes with low back pain (LBP). In this cross-sectional and prospective cohort study, the validated Persian FRI (PFRI) was tested in 100 athletes with LBP and 50 healthy athletes. From the athletes with LBP, data were recollected among 50 athletes with a 7-day interval to examine test-retest reliability. The content validity was excellent, and the athletes with LBP responded to all items with no floor or ceiling effects. The discriminative validity was supported by a statistically significant difference in PFRI total scores between the athletes with LBP and healthy athletes. The concurrent criterion validity was good (rho = 0.72). The construct, convergent validity was good (r = 0.83). The internal consistency reliability estimate was high (Cronbach's alpha = 0.90). Factor analysis demonstrated a single-factor structure with an explained variance of 52.22%. The test-retest reliability was excellent, indicated by an ICC(agreement) of 0.97, and the agreement observed in the Bland and Altman plot demonstrated no systematic bias. It is concluded that the PFRI has excellent psychometric properties for assessing athletes with LBP. PMID- 25809589 TI - The trichotillometry: a technique for hair assessment. AB - BACKGROUND: There are many different non-invasive or invasive techniques for studying the hair state either in the normal or diseased conditions. OBJECTIVE: A technique is used to evaluate the current hair status through setting a normal standard value or range of the epilating force of different hair follicle types in normal individuals. METHODS: The trichotillometer is used to record in grams the force exerted to epilate a single hair in different locations of scalp. RESULTS: Of all the plucked hairs from all the volunteers, the epilating force, the diameter, and the follicular length were calculated. The shear strain needed for epilating different hair types is calculated. CONCLUSION: Using the trichotillometry technique to identify the normal range of the shear strain for different hair types is important as it may aid in diagnostic, prognostic, or even therapeutic decision making for many hair diseases. PMID- 25809590 TI - SCAI/AATS/ACC/STS operator and institutional requirements for transcatheter valve repair and replacement, Part III: Pulmonic valve. AB - With the evolution of transcatheter valve replacement, an important opportunity has arisen for cardiologists and surgeons to collaborate in identifying the criteria for performing these procedures. Therefore, The Society for Cardiovascular Angiography and Interventions (SCAI), American Association for Thoracic Surgery (AATS), American College of Cardiology (ACC), and The Society of Thoracic Surgeons (STS) have partnered to provide recommendations for institutions to assess their potential for instituting and/or maintaining a transcatheter valve program. This article concerns transcatheter pulmonic valve replacement (tPVR). tPVR procedures are in their infancy with few reports available on which to base an expert consensus statement. Therefore, many of these recommendations are based on expert consensus and the few reports available. As the procedures evolve, technology advances, experience grows, and more data accumulate, there will certainly be a need to update this consensus statement. The writing committee and participating societies believe that the recommendations in this report serve as appropriate requisites. In some ways, these recommendations apply to institutions more than to individuals. There is a strong consensus that these new valve therapies are best performed using a Heart Team approach; thus, these credentialing criteria should be applied at the institutional level. Partnering societies used the ACC's policy on relationships with industry (RWI) and other entities to author this document (http://www.acc.org/guidelines/about-guidelines-and-clinical-documents). To avoid actual, potential, or perceived conflicts of interest due to industry relationships or personal interests, all members of the writing committee, as well as peer reviewers of the document, were asked to disclose all current healthcare-related relationships including those existing 12 months before the initiation of the writing effort. A committee of interventional cardiologists and surgeons was formed to include a majority of members with no relevant RWI and to be led by an interventional cardiology cochair and a surgical cochair with no relevant RWI. Authors with relevant RWI were not permitted to draft or vote on text or recommendations pertaining to their RWI. RWI were reviewed on all conference calls and updated as changes occurred. Author and peer reviewer RWI pertinent to this document are disclosed in the Appendices. In addition, to ensure complete transparency, authors' comprehensive disclosure information (including RWI not pertinent to this document) is available in Appendix AII. The work of the writing committee was supported exclusively by the partnering societies without commercial support. SCAI, AATS, ACC, and STS believe that adherence to these recommendations will maximize the chances that these therapies will become a successful part of the armamentarium for treating valvular heart disease in the United States. In addition, these recommendations will hopefully facilitate optimum quality during the delivery of this therapy, which will be important to the development and successful implementation of future, less invasive approaches to structural heart disease. PMID- 25809591 TI - Comparative effects of sulfhydryl compounds on target organellae, nuclei and mitochondria, of hydroxylated fullerene-induced cytotoxicity in isolated rat hepatocytes. AB - DNA damage and cytotoxicity induced by a hydroxylated fullerene [C60 (OH)24 ], which is a spherical nanomaterial and/or a water-soluble fullerene derivative, and their protection by sulfhydryl compounds were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60 (OH)24 at a concentration of 50 MUM caused time (0 to 3 h)-dependent cell death accompanied by the formation of cell surface blebs, the loss of cellular levels of ATP and reduced glutathione, accumulation of glutathione disulfide, and induction of DNA fragmentation assayed using alkali single-cell agarose-gel electrophoresis. C60 (OH)24 -induced cytotoxicity was effectively prevented by pretreatment with sulfhydryl compounds. N-acetyl-L-cysteine (NAC), L-cysteine and L-methionine, at a concentration of 2.5 mM, ameliorated cell death, accompanied by a decrease in cellular ATP levels, formation of cell surface blebs, induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential caused by C60 (OH)24 . In addition, DNA fragmentation caused by C60 (OH)24 was also inhibited by NAC, whereas an antioxidant ascorbic acid did not affect C60 (OH)24 -induced cell death and DNA damage in rat hepatocytes. Taken collectively, these results indicate that incubation of rat hepatocytes with C60 (OH)24 elicits DNA damage, suggesting that nuclei as well as mitochondria are target sites of the hydroxylated fullerene; and induction of DNA damage and oxidative stress is ameliorated by an increase in cellular GSH levels, suggesting that the onset of toxic effects may be partially attributable to a thiol redox-state imbalance caused by C60 (OH)24 . PMID- 25809594 TI - Characterization of two neurogenin genes from the brook lamprey lampetra planeri and their expression in the lamprey nervous system. AB - CONCLUSIONS: Neurogenins are required for the specification of neuronal precursors and regulate the expression of basic Helix-Loop-Helix genes involved in neuronal differentiation. Jawed vertebrates possess three Neurogenin paralogy groups and their combined expression covers the entire nervous system, apart from the autonomic nervous system. RESULTS: Here we report the isolation of two Neurogenin genes, LpNgnA and LpNgnB, from the lamprey Lampetra planeri. Phylogenetic analyses show both genes have orthologues in other lamprey species and in a hagfish. Neither gene shows evidence of orthology to specific jawed vertebrate Neurogenin paralogues. LpNgnA is expressed in the ventricular zone of regions of the brain and spinal cord, with expression in the brain demarcating brain sub-compartments including the pallium, tegmentum, tectum, and dorsal thalamus. In the peripheral nervous system, LpNgnA is expressed in cranial sensory placodes and their derivatives, and in the dorsal root ganglia. LpNgnB is expressed transiently in placodal head ectoderm and throughout the central nervous system in early development, and in a small population cells that form part of the macula. CONCLUSIONS: Combined, LpNgnA and LpNgnB were detected in most cell populations marked by Neurogenin gene expression in jawed vertebrates, with the exception of the cerebellum, retina and the non-neural expression sites. Developmental Dynamics 244:1096-1108, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25809596 TI - Proteomic Analysis of Cerebellum in Common Marmoset Exposed to Methylmercury. AB - The cerebellum is known as the major target regions of methylmercury (MeHg) toxicity, but the mechanisms are still not fully understood. We studied the effects of MeHg exposure in the cerebellum of common marmoset (Callithrix jacchus) using a shotgun proteomic approach with liquid chromatography coupled to mass spectrometry. A total of 1000 common proteins were identified in all samples, and 102 proteins were significantly differentially expressed in the cerebellum of common marmoset with orally dosed MeHg (1.5 mg MeHg/kg body weight for 2 weeks) compared with those of the control group. Functional enrichment analysis and pathway predictions showed that the differentially expressed proteins were involved in carbohydrate derivative metabolic process, ion transport including synaptic transmission, cell development, and calcium signaling pathway. Cellular component enrichment analysis showed that they were mainly distributed in plasma membrane, excitatory synapse, and synaptic membrane. These results indicate that synaptic transmission and calcium signaling pathways are the core functions affected by MeHg. We found a total of 21 novel proteins affected by MeHg in synaptic transmission and calcium signaling pathways. DLG4: (PSD95) and MIR-19A/MIR-19B were found to be potential key targets leading to the multiple effects of MeHg neurotoxicity. These results show the global effects of MeHg on cellular functions and pathways leading to neurological deficits in common marmoset. PMID- 25809593 TI - Associations of intergenerational education with metabolic health in U.S. Latinos. AB - OBJECTIVE: The purpose of this study was to examine the association of intergenerational education and country of birth with waist circumference, metabolic syndrome, and type 2 diabetes among older adult Latinos in the United States. METHODS: We used cross-sectional data from the Sacramento Area Latino Study on Aging, a cohort of older adult Mexican-American Latinos (mean age = 70 years). At baseline, we measured waist circumference and assessed metabolic syndrome and diabetes according to established guidelines (N = 1,789). Participants were classified as US-born or foreign-born based on self-reported birth country. Participants reported their parents' education level (>=6 vs. <6 years) and their own educational attainment (>=12 vs. <12 years). RESULTS: US born participants who achieved high adult education, regardless of their parents' education, had 37% lower odds of type 2 diabetes compared to US-born participants with both low parental and personal education levels [e.g., multivariable adjusted OR (parental low/adult high) = 0.63; 95% CI = 0.40, 0.99]. Among the foreign-born, only those with both high parental and high personal education levels had 55% lower odds of large waist circumference (OR = 0.45; 95% CI = 0.23, 0.88) compared to foreign-born participants with both low parental and personal education levels. CONCLUSIONS: Intergenerational exposure to low education levels may increase central obesity and type 2 diabetes differentially among US-born and foreign-born Latinos. PMID- 25809597 TI - Authors' response to Letter to the Editor. PMID- 25809595 TI - Mitochondrial Toxicity of Cadmium Telluride Quantum Dot Nanoparticles in Mammalian Hepatocytes. AB - There are an increasing number of studies indicating that mitochondria are relevant targets in nanomaterial-induced toxicity. However, the underlying mechanisms by which nanoparticles (NPs) interact with these organelles and affect their functions are unknown. The aim of this study was to investigate the effects of cadmium telluride quantum dot (CdTe-QD) NPs on mitochondria in human hepatocellular carcinoma HepG2 cells. CdTe-QD treatment resulted in the enlargement of mitochondria as examined with transmission electron microscopy and confocal microscopy. CdTe-QDs appeared to associate with the isolated mitochondria as detected by their inherent fluorescence. Further analyses revealed that CdTe-QD caused disruption of mitochondrial membrane potential, increased intracellular calcium levels, impaired cellular respiration, and decreased adenosine triphosphate synthesis. The effects of CdTe-QDs on mitochondrial oxidative phosphorylation were evidenced by changes in levels and activities of the enzymes of the electron transport chain. Elevation of peroxisome proliferator-activated receptor-gamma coactivator levels after CdTe-QD treatment suggested the effects of CdTe-QDs on mitochondrial biogenesis. Our results also showed that the effects of CdTe-QDs were similar or greater to those of cadmium chloride at equivalent concentrations of cadmium, suggesting that the toxic effects of CdTe-QDs were not solely due to cadmium released from the NPs. Overall, the study demonstrated that CdTe-QDs induced multifarious toxicity by causing changes in mitochondrial morphology and structure, as well as impairing their function and stimulating their biogenesis. PMID- 25809592 TI - The regulation of neuronal mitochondrial metabolism by calcium. AB - Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca(2+) acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca(2+) stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca(2+) -regulated mitochondrial carriers, whereas an increase in matrix Ca(2+) stimulates the citric acid cycle and ATP synthase. The aspartate-glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate-aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca(2+) and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K(+) -depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca(2+) influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca(2+) ]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca(2+) signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca(2+) is increased and mitochondria fragmented. Thus, the fine tuning of Ca(2+) signals plays a key role in shaping mitochondrial bioenergetics. PMID- 25809598 TI - Being born after your brother is not a disadvantage: Reproductive success does not depend on the sex of the preceding sibling. AB - OBJECTIVES: The aim of the present study is to examine whether being born after a brother versus after a sister differentially impacts reproductive outcomes in a contemporary population. The sex of the preceding sibling may influence an individual's fitness, and, in fact, individuals born after a brother have been shown to have lower reproductive success in historical populations. Males, as the more expensive sex, constitute a drain on maternal resources and elicit an immune response during pregnancy, which may have negative consequences on subsequent siblings. METHODS: A questionnaire was used to collect data on reproductive health and family history from 951 women and 380 men between 20 and 92 years of age in villages throughout the Mogielica Human Ecology Study Site in southern Poland. Number of children, number of sons and daughters, age at menarche, age at marriage, age at menopause, and age at first and last reproduction were tested as components of reproductive success. RESULTS: The sex of one's preceding sibling had no statistically significant impact on any of the reproductive characteristics tested. CONCLUSIONS: Our results suggest that potential immunological and nutritional disadvantages experienced during prenatal life by individuals born after male siblings do not have long-lasting effects in modern, well-nourished populations. PMID- 25809599 TI - HIV-1 replicates in human osteoclasts and enhances their differentiation in vitro. AB - BACKGROUND: HIV-1 infected patients frequently have osteolytic bone disease, which is caused by the dysregulation of the bone remodeling system that involves the interaction between osteoblasts and osteoclasts, but the relationship between osteolytic disease and HIV-1 infection remains unclear. In this study we tested whether HIV-1 infection of osteoclasts affects their differentiation. RESULTS: We prepared human osteoclasts from CD14+ monocytes and examined them for their susceptibility to HIV-1. Furthermore, we investigated the effect of HIV-1 infection on osteoclast differentiation. CD14-derived osteoclasts were shown to express CD4, CCR5, and CXCR4 each at the similar level to that shown with macrophages. R5-tropic HIV-1 and X4-tropic HIV-1 were found to infect CD14 derived osteoclasts and replicate in them. Furthermore, HIV-1 infection induced formation of larger osteoclastst, enhanced the expression of mRNAs for three osteoclast specific marker molecules (tartrate-resistant acid phosphatase, cathepsin K, and the calcitonin receptor), and up-regulated osteoclast bone resorption activity. CONCLUSIONS: Our results suggest that osteoclasts serve as a novel target for HIV-1 infection, which may enhance the osteoclast differentiation contributing to the development of osteolytic disease in HIV-1 infected patients. PMID- 25809601 TI - Autoextraction of twelve permanent teeth in a child with autistic spectrum disorder. AB - BACKGROUND: This report discusses self-injurious behaviour; this is not unusual in people with autistic spectrum disorders but is not commonly experienced as autoextraction. CASE REPORT: This case concerns a 12 year old child who presented as a new patient with two teeth missing. He then went on to remove a further ten teeth over a relatively short space of time. CONCLUSION: The recognition of autoextraction by the dental team is important. its management involves a multidisciplinary team which includes professionals from education, health and social care who work together to prevent progressive self-injury. PMID- 25809600 TI - Physician perspectives on care of individuals with severe mobility impairments in primary care in Southwestern Ontario, Canada. AB - Despite the high health risks associated with severe mobility impairments, individuals with physical disabilities are less likely to receive the same level of primary care as able-bodied persons. This study explores family physicians' perspectives on primary care for individuals with mobility impairments to identify and better understand the challenges that prevent equitable service delivery to this group of patients. Semi-structured interviews were conducted in the autumn of 2012 with a purposeful sample of 20 family physicians practising in Southwestern Ontario to gather their perspectives of the personal and professional barriers to healthcare delivery for individuals with mobility impairments, including perceptions of challenges, contributing reasons and possible improvements. A thematic analysis was conducted on the transcripts generated from the interviews to identify perceptions of existing barriers and gaps in care, needs and existing opportunities for improving primary care for this patient population. Eight themes emerged from the interviews that contributed to understanding the perceived challenges of providing care to patients with mobility impairments: transportation barriers, knowledge gaps and practice constraints resulting in episodic care rather than preventive care, incongruence between perceived and actual accessibility to care, emergency departments used as centres for primary care, inattention to mobility issues among specialist and community services, lack of easily accessible practice tools, low patient volumes impact decision-making regarding building decreased motivation to expand clinical capacity due to low patient volume, and lastly, remuneration issues. Despite this patient population presenting with high healthcare needs and significant barriers and care gaps in primary care, low prevalence rates negatively impact the acquisition of necessary equipment and knowledge required to optimally care for these patients in typical primary care settings. Novel approaches to address inequitable healthcare practices for this vulnerable group are needed. PMID- 25809602 TI - Techno-economic evaluation of biodiesel production from waste cooking oil--a case study of Hong Kong. AB - Fossil fuel shortage is a major challenge worldwide. Therefore, research is currently underway to investigate potential renewable energy sources. Biodiesel is one of the major renewable energy sources that can be obtained from oils and fats by transesterification. However, biodiesel obtained from vegetable oils as feedstock is expensive. Thus, an alternative and inexpensive feedstock such as waste cooking oil (WCO) can be used as feedstock for biodiesel production. In this project, techno-economic analyses were performed on the biodiesel production in Hong Kong using WCO as a feedstock. Three different catalysts such as acid, base, and lipase were evaluated for the biodiesel production from WCO. These economic analyses were then compared to determine the most cost-effective method for the biodiesel production. The internal rate of return (IRR) sensitivity analyses on the WCO price and biodiesel price variation are performed. Acid was found to be the most cost-effective catalyst for the biodiesel production; whereas, lipase was the most expensive catalyst for biodiesel production. In the IRR sensitivity analyses, the acid catalyst can also acquire acceptable IRR despite the variation of the WCO and biodiesel prices. PMID- 25809604 TI - Thinopyrum ponticum chromatin-integrated wheat genome shows salt-tolerance at germination stage. AB - A wild wheatgrass, Thinopyrum ponticum (2n = 10x = 70), which exhibits substantially higher levels of salt tolerance than cultivated wheat, was employed to transfer its salt tolerance to common wheat by means of wide hybridization. A highly salt-tolerant wheat line S148 (2n = 42) was obtained from the BC3F2 progenies between Triticum aestivum (2n = 42) and Th. ponticum. In the cross of S148 * salt-sensitive wheat variety Chinese Spring, the BC4F2 seeds at germination stage segregated into a ratio of 3 salt tolerant to 1 salt sensitive, indicating that the salt tolerance was conferred by a dominant gene block. Genomic in situ hybridization analysis revealed that S148 had a single pair of Th. ponticum-T. aestivum translocated chromosomes bearing the salt-tolerance. This is an initial step of molecular breeding for salt-tolerant wheat. PMID- 25809603 TI - Cell membrane CD44v6 levels in squamous cell carcinoma of the lung: association with high cellular proliferation and high concentrations of EGFR and CD44v5. AB - Membranous CD44v6 levels in tumors and surrounding samples obtained from 94 patients with squamous cell lung carcinomas were studied and compared to clinical stage, cellular proliferation, membranous CD44v5 levels, epidermal growth factor receptor EGFR and cytoplasmatic concentrations of CYFRA 21.1. CD44v6 positive values were observed in 33/38 non-tumor samples and in 76/94 tumor samples, but there were not statistically significant differences between both subgroups. In CD44v6 positive tumor samples, CD44v6 was not associated with clinical stage, histological grade, ploidy and lymph node involvement, but significant association was found with high cellular proliferation. Likewise, CD44v6 positive tumors had significantly higher levels of EGFR and CD44v5. In patients with squamous cell lung carcinomas and clinical stage I, positive CD44v6 cases were associated with the same parameters. Furthermore, positive CD44v5 squamous tumors were associated significantly with histological grade III and lower levels of CYFRA21.1. Our findings support the value of CD44v6 as a possible indicator of poor outcome in patients with squamous lung carcinomas. PMID- 25809605 TI - Protease and hemicellulase assisted extraction of dietary fiber from wastes of Cynara cardunculus. AB - The action of protease and hemicellulase for the extraction of fractions enriched in soluble fiber from bracts and stems of Cynara cardunculus was evaluated. Using a two-factor simplex design comprising protease amounts of 0-200 MUL and hemicellulase amounts of 0-200 mg for 5 g of material, we explored the effect of a 5 h enzymatic treatment at 40 degrees C on the chemical composition and yield of the fractions isolated. The fractions contained inulin and pectin. In general, the protein, inulin, and polyphenol contents and also the yields were higher for fractions obtained from stems. The most marked effects were observed when enzymes were used at higher concentrations, especially for hemicellulase. The inclusion of a pre-heating step increased the yield and the inulin content for fractions isolated from bracts and stems and decreased the protein and polyphenol contents, and the galacturonic acid for bracts. These fractions, in general, contained the polyphenolic compounds monocaffeoylquinic acid, apigenin, and pinoresinol. PMID- 25809606 TI - Genotyping test with clinical factors: better management of acute postoperative pain? AB - Individualization of acute postoperative pain treatment on an evidence-based decision process is a major health concern. The aim of this study is to investigate the influence of genetic and non-genetic factors on the variability of response to morphine in acute postoperative pain. A group of nighty-five patients undergoing major surgery were included prospectively. At 24 h, a logistic regression model was carried out to determine the factors associated with morphine doses given by a Patient Controlled Analgesia device. The dose of morphine was associated with age (p = 0.011), patient weight (p = 0.025) and the duration of operation (p = 0.030). This dose decreased with patient's age and duration of operation and increased with patient's weight. OPRM1 and ABCB1 polymorphisms were significantly associated with administered dose of morphine (p = 0.038 and 0.012 respectively). Patients with at least one G allele for c.118A>G OPRM1 polymorphism (AG/GG) needed 4 times the dose of morphine of AA patients. Additionally, patients with ABCB1 CT and CC genotypes for c.3435C>T polymorphism were 5.6 to 7.1 times more prone to receive higher dose of morphine than TT patients. Our preliminary results support the evidence that OPRM1/ABCB1 genotypes along with age, weight and duration of operation have an impact on morphine consumption for acute postoperative pain treatment. PMID- 25809608 TI - Supramolecular cationic assemblies against multidrug-resistant microorganisms: activity and mechanism of action. AB - The growing challenge of antimicrobial resistance to antibiotics requires novel synthetic drugs or new formulations for old drugs. Here, cationic nanostructured particles (NPs) self-assembled from cationic bilayer fragments and polyelectrolytes are tested against four multidrug-resistant (MDR) strains of clinical importance. The non-hemolytic poly(diallyldimethylammonium) chloride (PDDA) polymer as the outer NP layer shows a remarkable activity against these organisms. The mechanism of cell death involves bacterial membrane lysis as determined from the leakage of inner phosphorylated compounds and possibly disassembly of the NP with the appearance of multilayered fibers made of the NP components and the biopolymers withdrawn from the cell wall. The NPs display broad-spectrum activity against MDR microorganisms, including Gram-negative and Gram-positive bacteria and yeast. PMID- 25809611 TI - Characterization and antihyperglycemic activity of a polysaccharide from Dioscorea opposita Thunb roots. AB - A polysaccharide DOTP-80 from Dioscorea opposita Thunb was obtained by using the method of acid water-extraction and ethanol-precipitation. After being purified by chromatography, the structure characteristics of DOTP-80 were established. Based on the calibration curve obtained with standard dextrans, the molecular weight of the polysaccharide fraction DOTP-80 was calculated to be 123 kDa. The results of Infrared spectrum (FT-IR) indicated that the polysaccharide contained the alpha-configuration of sugar units. GC-MS analysis revealed that DOTP-80 was mainly composed of mannose and glucose. Alloxan-induced diabetic rats and mice models were developed to evaluate the in vivo hypoglycemic activity of the polysaccharide. The results indicated that a high dose DOTP-80 (400 mg/kg) had strong hypoglycemic activity. Moreover, DOTP-80 could increase the level of antioxidant enzymes (SOD) activity in alloxan-induced diabetic mice and stimulate an increase in glucose disposal in diabetic rats. Therefore, the polysaccharide DOTP-80 should be evaluated as a candidate for future studies on diabetes mellitus. PMID- 25809607 TI - Mitochondria as key targets of cardioprotection in cardiac ischemic disease: role of thyroid hormone triiodothyronine. AB - Ischemic heart disease is the major cause of mortality and morbidity worldwide. Early reperfusion after acute myocardial ischemia has reduced short-term mortality, but it is also responsible for additional myocardial damage, which in the long run favors adverse cardiac remodeling and heart failure evolution. A growing body of experimental and clinical evidence show that the mitochondrion is an essential end effector of ischemia/ reperfusion injury and a major trigger of cell death in the acute ischemic phase (up to 48-72 h after the insult), the subacute phase (from 72 h to 7-10 days) and chronic stage (from 10-14 days to one month after the insult). As such, in recent years scientific efforts have focused on mitochondria as a target for cardioprotective strategies in ischemic heart disease and cardiomyopathy. The present review discusses recent advances in this field, with special emphasis on the emerging role of the biologically active thyroid hormone triiodothyronine (T3). PMID- 25809612 TI - Exploring the nature of silicon-noble gas bonds in H3SiNgNSi and HSiNgNSi compounds (Ng = Xe, Rn). AB - Ab initio and density functional theory-based computations are performed to investigate the structure and stability of H3SiNgNSi and HSiNgNSi compounds (Ng = Xe, Rn). They are thermochemically unstable with respect to the dissociation channel producing Ng and H3SiNSi or HSiNSi. However, they are kinetically stable with respect to this dissociation channel having activation free energy barriers of 19.3 and 23.3 kcal/mol for H3SiXeNSi and H3SiRnNSi, respectively, and 9.2 and 12.8 kcal/mol for HSiXeNSi and HSiRnNSi, respectively. The rest of the possible dissociation channels are endergonic in nature at room temperature for Rn analogues. However, one three-body dissociation channel for H3SiXeNSi and one two body and one three-body dissociation channels for HSiXeNSi are slightly exergonic in nature at room temperature. They become endergonic at slightly lower temperature. The nature of bonding between Ng and Si/N is analyzed by natural bond order, electron density and energy decomposition analyses. Natural population analysis indicates that they could be best represented as (H3SiNg)+(NSi)- and (HSiNg)+(NSi)-. Energy decomposition analysis further reveals that the contribution from the orbital term (DeltaEorb) is dominant (ca. 67%-75%) towards the total attraction energy associated with the Si-Ng bond, whereas the electrostatic term (DeltaEelstat) contributes the maximum (ca. 66%-68%) for the same in the Ng-N bond, implying the covalent nature of the former bond and the ionic nature of the latter. PMID- 25809610 TI - SOD2 activity is not impacted by hyperoxia in murine neonatal pulmonary artery smooth muscle cells and mice. AB - Pulmonary hypertension (PH) complicates bronchopulmonary dysplasia (BPD) in 25% of infants. Superoxide dismutase 2 (SOD2) is an endogenous mitochondrial antioxidant, and overexpression protects against acute lung injury in adult mice. Little is known about SOD2 in neonatal lung disease and PH. C57Bl/6 mice and isogenic SOD2+/+ and SOD2-/+ mice were placed in room air (control) or 75% O2 (chronic hyperoxia, CH) for 14 days. Right ventricular hypertrophy (RVH) was assessed by Fulton's index. Medial wall thickness (MWT) and alveolar area were assessed on formalin fixed lung sections. Pulmonary artery smooth muscle cells (PASMC) were placed in 21% or 95% O2 for 24 h. Lung and PASMC protein were analyzed for SOD2 expression and activity. Oxidative stress was measured with a mitochondrially-targeted sensor, mitoRoGFP. CH lungs have increased SOD2 expression, but unchanged activity. SOD2-/+ PASMC have decreased expression and activity at baseline, but increased SOD2 expression in hyperoxia. Hyperoxia increased mitochondrial ROS in SOD2+/+ and SOD2-/+ PASMC. SOD2+/+ and SOD2-/+ CH pups induced SOD2 expression, but not activity, and developed equivalent increases in RVH, MWT, and alveolar area. Since SOD2-/+ mice develop equivalent disease, this suggests other antioxidant systems may compensate for partial SOD2 expression and activity in the neonatal period during hyperoxia-induced oxidative stress. PMID- 25809613 TI - Host and parasite life history interplay to yield divergent population genetic structures in two ectoparasites living on the same bat species. AB - Host-parasite interactions are ubiquitous in nature. However, how parasite population genetic structure is shaped by the interaction between host and parasite life history remains understudied. Studies comparing multiple parasites infecting a single host can be used to investigate how different parasite life history traits interplay with host behaviour and life history. In this study, we used 10 newly developed microsatellite loci to investigate the genetic structure of a parasitic bat fly (Basilia nana). Its host, the Bechstein's bat (Myotis bechsteinii), has a social system and roosting behaviour that restrict opportunities for parasite transmission. We compared fly genetic structure to that of the host and another parasite, the wing-mite, Spinturnix bechsteini. We found little spatial or temporal genetic structure in B. nana, suggesting a large, stable population with frequent genetic exchange between fly populations from different bat colonies. This contrasts sharply with the genetic structure of the wing-mite, which is highly substructured between the same bat colonies as well as temporally unstable. Our results suggest that although host and parasite life history interact to yield similar transmission patterns in both parasite species, the level of gene flow and eventual spatiotemporal genetic stability is differentially affected. This can be explained by the differences in generation time and winter survival between the flies and wing-mites. Our study thus exemplifies that the population genetic structure of parasites on a single host can vary strongly as a result of how their individual life history characteristics interact with host behaviour and life history traits. PMID- 25809609 TI - The role of hypoxia-induced miR-210 in cancer progression. AB - Prolonged hypoxia, the event of insufficient oxygen, is known to upregulate tumor development and growth by promoting the formation of a neoplastic environment. The recent discovery that a subset of cellular microRNAs (miRs) are upregulated during hypoxia, where they function to promote tumor development, highlights the importance of hypoxia-induced miRs as targets for continued investigation. miRs are short, non-coding transcripts involved in gene expression and regulation. Under hypoxic conditions, miR-210 becomes highly upregulated in response to hypoxia inducing factors (HIFs). HIF-1alpha drives miR-210's overexpression and the resultant alteration of cellular processes, including cell cycle regulation, mitochondria function, apoptosis, angiogenesis and metastasis. Here we discuss hypoxia-induced dysregulation of miR-210 and the resultant changes in miR-210 protein targets that regulate cancer progression. Potential methods of targeting miR-210 as a therapeutic tool are also explored. PMID- 25809615 TI - The 40-Hz auditory steady-state response: a selective biomarker for cortical NMDA function. AB - When subjected to a phasic input, sensory cortical neurons display a remarkable ability to entrain faithfully to the driving stimuli. The entrainment to rhythmic sound stimuli is often referred to as the auditory steady-state response (ASSR) and can be captured using noninvasive techniques, such as scalp-recorded electroencephalography (EEG). An ASSR to a driving frequency of approximately 40 Hz is particularly interesting in that it shows, in relative terms, maximal power, synchrony, and synaptic activity. Moreover, the 40-Hz ASSR has been consistently found to be abnormal in schizophrenia patients across multiple studies. The nature of the reported abnormality has been less consistent; while most studies report a deficit in entrainment, several studies have reported increased signal power, particularly when there are concurrent positive symptoms, such as auditory hallucinations. However, the neuropharmacological basis for the 40-Hz ASSR, as well as its dysfunction in schizophrenia, has been unclear until recently. On the basis of several recent reports, it is argued that the 40-Hz ASSR represents a specific marker for cortical NMDA transmission. If confirmed, the 40-Hz ASSR may be a simple and easy-to-access pharmacodynamic biomarker for testing the integrity of cortical NMDA neurotransmission that is robustly translational across species. PMID- 25809614 TI - Anesthetic Propofol Attenuates Apoptosis, Abeta Accumulation, and Inflammation Induced by Sevoflurane Through NF-kappaB Pathway in Human Neuroglioma Cells. AB - Anesthetics have been reported to promote Alzheimer's disease neuropathogenesis by inducing amyloid beta (Abeta) protein accumulation and apoptosis. The aim of this study was to evaluate the effect of propofol on the apoptosis, Abeta accumulation, and inflammation induced by sevoflurane in human neuroglioma cells. Human neuroglioma cells were treated with or without sevoflurane and then co incubated with or without propofol. Cell apoptosis was evaluated by fluorescence activated cell sorting analysis (FACS) using AV-PI kits, and data showed that apoptosis induced by sevoflurane was significantly attenuated by propofol treatment. In addition, with the reactive oxygen species (ROS) production measured by FACS after staining with dichloro-dihydrofluorescein diacetate, propofol could significantly reduce the production of ROS as well as the accumulation of Abeta induced by sevoflurane assessed by enzyme-linked immuno sorbent assay (ELISA) analysis. On the other hand, the same treatment decreased the inflammation factor production of interleukin-6. Moreover, the level of nuclear factor-kappa B (NF-kappaB) was tested by Western blot and immunofluorescence assay. We found that the activation of NF-kappaB pathway was suppressed by propofol. The results suggest that propofol can effectively attenuate the apoptosis, Abeta accumulation, and inflammation induced by sevoflurane in human neuroglioma cells through NF-kappaB signal pathway. PMID- 25809616 TI - CCR4 is expressed on infiltrating cells in lesional skin of early mycosis fungoides and atopic dermatitis. AB - CCR4 is expressed on tumor cells of mycosis fungoides (MF) and Sezary syndrome (SS). In MF, most infiltrating cells in patches and plaques express CXCR3, while tumor cells express CCR4 in advanced stages. Poteligeo Test IHC (CCR4 staining kit) is a newly developed staining kit that can examine the presence of CCR4 expressed on tumor cells of adult T-cell leukemia/lymphoma, peripheral T-cell lymphoma and cutaneous T-cell lymphoma before treatment of anti-CCR4 antibody using paraffin-embedded samples. In this study, we analyzed CCR4 expression in lesional skin of MF, SS, atopic dermatitis (AD) and psoriasis with this new kit. CCR4 was expressed on infiltrating cells in lesional skin of patch, plaque, tumor MF and SS, and the number of positive cells increased as the disease progressed. Immunohistochemistry with frozen sections also showed some positive cells scattered in the dermis, although the quality was not high enough to quantify positive cells. There were significant positive correlations between CCR4(+) cells and serum lactate dehydrogenase levels. Interestingly, CCR4(+) cells were also detected in AD skin, whose number was larger than that in psoriatic skin. Previous studies showed only scattered CCR4(+) cells in skin samples by standard immunohistochemical staining. The new, sensitive CCR4 staining kit has revealed that CCR4 is expressed on infiltrating cells in lesional skin of early MF and AD as well as advanced MF and SS. These cells can be therapeutic targets for patients who are resistant to standard treatments. PMID- 25809617 TI - Conventional vs. daylight methyl aminolevulinate photodynamic therapy for actinic keratosis of the face and scalp: an intra-patient, prospective, comparison study in Italy. AB - INTRODUCTION: Daylight photodynamic therapy (DL-PDT) with methyl aminolevulinate (MAL) is a simplified PDT procedure that was recently shown in a few trials to be effective for grade I actinic keratosis (AK), with improved tolerability and reduced time of clinical attendance as compared to conventional PDT (c-PDT). OBJECTIVE: To evaluate the efficacy and tolerability of DL-PDT vs. c-PDT with MAL in the treatment of grade I AK on the face and scalp in Italy. METHODS: Thirty five patients with AKs on the face (n = 17) or scalp (n = 18) were prospectively enrolled in an intra-patient, left-right, prospective, comparison study between DL-PDT and c-PDT at a single centre between September and October 2013. Weather conditions and outdoor temperature during daylight exposure were recorded for each DL-PDT session. Pain was assessed after the PDT session and local adverse events 2 days after treatment. Lesion response rate was evaluated on both sides at 3 months. AKs with complete regression were followed until 6 months. Patient's preference for either treatment was recorded. RESULTS: There was no difference in complete response (CR) rate of AK I at 3 months between DL-PDT and c-PDT (87% vs. 91%; RR = 0.96; P = 0.16). A lower CR rate was observed with DL-PDT than with c PDT for AK II (36% vs. 61%; RR = 0.58, P = 0.06) and III (25% vs. 46%; RR = 0.50, P = 0.20). Recurrence rate at 6 months was slightly higher for cleared AK I after DL-PDT than after c-PDT (17% vs. 12%, RR = 1.50, P < 0.05). DL-PDT was associated with lower pain (DeltaVAS = -2.2, P < 0.01) and reduced severity of local adverse events (DeltaLSR = -1.4, P < 0.01) than c-PDT. Increasing outdoor temperature was associated with the efficacy of DL-PDT and the severity of adverse events. DL-PDT was preferred by 88% of the patients. CONCLUSION: MAL DL-PDT showed similar efficacy to c-PDT in the treatment of AK I of the face/scalp but was less effective than c-PDT for AKs II and III. DL-PDT was better tolerated being associated with lower pain and occurrence of fewer adverse events. Clinical response to DL-PDT was significantly moderated by outdoor temperature, increasing at higher temperatures. PMID- 25809618 TI - Novel in situ liquefying antimicrobial wrap for preventing tissue expander infections following breast reconstructive surgeries. AB - Breast reconstruction surgeries using tissue expanders (TEs) have highly reported infection rates. To decrease this, we developed a method for disinfecting TEs and surgical pockets, where an antimicrobial solution was applied as a solid film at implantation that subsequently liquefied in situ to provide extended prophylaxis. Silicone discs cut from TEs were covered with gelatin-based films containing minocycline (M) and rifampin (R). Discs and films soaked in saline were subsequently challenged with pathogen at days 1, 3, 7, and 10 and quantified for potential biofilm formation. Discs that were not harvested at each specific time points were refreshed with sterile saline. The discs were challenged with clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and multidrug-resistant Pseudomonas aeruginosa (MDR-PA). Recoveries of adherent organisms from uncovered silicone discs and gelatin-wrapped discs without added antimicrobial agents were >5 * 10(4) CFU/disc for each organism at each time point. Experimental 0.1%M/0.05%R gelatin films completely inhibited all challenge organisms from attaching to the silicone (p < 0.05) at each time point through day 10. Cytotoxicity was assessed by incubating films with HEK-293T human fibroblasts. There were no significant differences in HEK-293T cell survival between controls and any of the antimicrobial films. The in situ liquefying, bioabsorable, antimicrobial wrap prevented biofilm formation by microorganisms on silicone surfaces in vitro with minimal cytotoxicity. PMID- 25809619 TI - Aortic Arch Interruption and Persistent Fifth Aortic Arch in Phace Syndrome: Prenatal Diagnosis and Postnatal Course. AB - PHACE is a rare congenital neurocutaneous syndrome where posterior fossa malformations, hemangiomas, cerebrovascular anomalies, aortic arch anomalies, cardiac defects, and eye abnormalities are variably associated. We describe the prenatal detection and the postnatal course of a child with PHACE syndrome with a unique type of aortic arch anomaly consisting of proximal interruption of the aortic arch and persistence of the fifth aortic arch. The fifth aortic arch represented in this case a vital systemic-to-systemic connection between the ascending aorta and the transverse portion of the aortic arch allowing adequate forward flow through the aortic arch without surgical treatment. PMID- 25809621 TI - Candidiasis: a fungal infection--current challenges and progress in prevention and treatment. AB - Despite therapeutic advances candidiasis remains a common fungal infection most frequently caused by C. albicans and may occur as vulvovaginal candidiasis or thrush, a mucocutaneous candidiasis. Candidiasis frequently occurs in newborns, in immune-deficient people like AIDS patients, and in people being treated with broad spectrum antibiotics. It is mainly due to C. albicans while other species such as C. tropicalis, C. glabrata, C. parapsilosis and C. krusei are increasingly isolated. OTC antifungal dosage forms such as creams and gels can be used for effective treatment of local candidiasis. Whereas, for preventing spread of the disease to deeper vital organs, candidiasis antifungal chemotherapy is preferred. Use of probiotics and development of novel vaccines is an advanced approach for the prevention of candidiasis. Present review summarizes the diagnosis, current status and challenges in the treatment and prevention of candidiasis with prime focus on host defense against candidiasis, advancements in diagnosis, probiotics role and recent progress in the development of vaccines against candidiasis. PMID- 25809620 TI - Treatment choices and outcomes of patients with manometrically diagnosed achalasia. AB - This prospective population-based study was designed to evaluate treatment choices in patients with new manometrically diagnosed achalasia and their outcomes. Patients referred to the esophageal function laboratory were enrolled after a new manometric diagnosis of achalasia. Patients completed an initial achalasia symptom score validated questionnaire on their symptom severity, duration, treatment pre-diagnosis and Medical Outcomes Study 36-item Short-Form (SF-36) survey. Treatment decisions were made by the referring physician and the patient. Follow-up questionnaires were completed every 3 months for 1 year. Patients who chose not to undergo treatment at 1-year follow-up completed another questionnaire after 5 years. Between January 2004 and January 2005, 83 of 124 eligible patients were enrolled. Heller myotomy was performed on 31 patients, three patients received botulinum toxin injections, and 25 patients received 29 pneumatic balloon dilatations. Twenty-four patients chose to receive no treatment. Following treatment, patients treated with surgery, dilatation and botulinum toxin had an average improvement in achalasia symptom score of 23 +/- 12.2, 17 +/- 10.9, and 9 +/- 14, respectively. Patients receiving no treatment had worsening symptoms with a symptom score change of -3.5 +/- 11.4. Surgery and dilatation resulted in significant improvement (P < 0.01) relative to no treatment. In univariate logistic regression, symptom severity score (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.00 to 1.08), sphincter tone (OR 1.04, 95% CI 1.00 to 1.09), difficulty swallowing liquids (OR 3.21, 95% 1.15 to 8.99), waking from sleep (OR 2.75, 95% 1.00 to 7.61), and weight loss (OR 5.99, 95% CI 1.93 to 18.58) were all significant in predicting that patients would select treatment. In the multivariate analysis, older age (OR 1.05, 95% CI 1.01 to 1.09) and weight loss (OR 3.91, 95% CI 1.02 to 15.2) were statistically significant for undergoing treatment. At 5 years, five (21%) of those who had initially declined treatment at 1 year ultimately chose a treatment. Patients who finally chose Heller myotomy had lower mental component dimension scores on the SF-36 at 1 year than those who did not. This study shows that almost one third of patients with manometrically diagnosed achalasia choose not to undergo treatment within 1 year of their diagnosis. Patients who are more symptomatic appear to be more likely to undergo treatment by univariate analysis. In multivariate analysis, increasing age and weight loss are predictive of those who will undergo treatment, with weight loss having the greatest influence. Patients who choose not to undergo treatment make lifestyle changes to maintain their quality of life, and only a minority of them ultimately undergo treatment. PMID- 25809622 TI - Complications of serogroup B meningococcal disease in survivors: a review. AB - This systematic review evaluates the prevalence of long-term complications of serogroup B meningococcal disease (MD) in light of the recent licensure of a vaccine against meningococcal B disease. Twelve appropriate studies were identified by searching available databases from 1946 to July 2014. The average prevalence of hearing impairment was 4.2% among serogroup B MD survivors; 2.3% suffered amputation and 2.3% developed seizures. When compared with complications due to non-meningococcal B bacterial meningitis, physical impairment and seizures were more common in survivors of meningococcal B disease but hearing impairment had similar prevalence. Few studies quantified less frequent complications such as visual impairment and cognitive dysfunction. Better comprehensive reporting of the complications and costs of serogroup B MD in survivors and their families is needed to inform vaccination policy. PMID- 25809623 TI - Current perspectives on rabies postexposure prophylaxis. AB - Rabies is a zoonose affecting wild and domestic animals and transmitted to humans through bites or scratches, causing over 60,000 human deaths, annually. The disease results from the transmission of a neurotropic virus leading to invariably deadly encephalitis. The post-exposure prophylaxis consists of careful washing and disinfection of the wound, antibiotherapy and tetanus prophylaxis when needed. Furthermore, rabies vaccine and rabies immunoglobulin [RIG] administration should be applied according to the type of wound, and the animal involved, according to the WHO protocols that are regularly updated. Unfortunately it is sometimes difficult to obtain RIG in some countries due to their high cost, leading to suboptimal treatment and possible death. Also, observance can be weak, due to the number of repeated visits required with protocols [up to five visits over 28 days]. These limitations justify research on new vaccines which were not conclusive at the moment. New RIGs are under development, including a monoclonal antibody cocktail which is more promising in a near future. Finally, vaccination protocols are in the way of being shortened in given conditions. Further studies are needed to validate these new practices. PMID- 25809624 TI - Effective Strategies for Diagnosis of Systemic Inflammatory Response Syndrome (SIRS) due to Bacterial Infection in Surgical Patients. AB - Surgery associated with trauma and soft tissue injuries after surgery significantly activates the systemic immune response. If an infection after surgery occurs, the response is even stronger. Due to spontaneous activation of immune response and elevated biomarkers for sepsis and cytokines, posttraumatic complications such as new-coming postoperative infections are difficult to diagnose. Sepsis as systemic inflammatory response syndrome (SIRS) rapidly progresses through severe sepsis to septic shock and organ failure, and with no applied antibiotic treatment, the disease often ends at death of the patients. In the treatment of non-surgery patients, the biomarkers like white cell blood count, C-reactive protein (CRP) or procalcitonin (PCT) proved to be useful in sepsis recognition. However, diagnostics after surgeries are more complicated and these biomarkers are not ideal. The solution is a sepsis biomarker, which would have high sensitivity and specificity, that can improve diagnostic accuracy of sepsis, should also be measured easily by the patients, and should not be too expensive. We think more sensitive and specific biomarkers such as presepsin (sCD14-ST) or CD64 index on neutrophils could be useful. A diagnosis of sepsis should be based on clinical signs, and clinicians should use biomarker that is not only most sensitive and specific but also is cost effective. Furthermore, confirmation of the bacterial or fungal infection with blood cultures or with the use of broad range polymerase chain reaction (PCR), when culturing is impossible, should be performed. PMID- 25809626 TI - Medication Errors in Ambulatory Paediatric Patient Setting--How Close, or Far, are we from an Error Free Process? AB - The medication management pathway (MMP) outlines the medication journey from the decision to prescribe through to monitoring the outcomes. Medication errors (MEs) can occur at any point of the pathway. MEs in children may result in poor health outcomes; and as children are more vulnerable to dose calculation and administration errors especially in the ambulatory setting, this cohort may be at a higher risk of adverse outcomes. This review aimed to identify MEs in children and attribute them to the steps within the MMP for paediatric ambulatory patients. A systematic search of studies related to MEs in children was performed using MEDLINE, EMBASE and International Pharmaceutical Abstracts in the period from Jan 1991 to June 2011, using keywords pertaining to children, medication errors and ambulatory settings. Thirty articles met the review inclusion criteria and the findings of these studies were reported. Based on the MMP, 26 studies reported prescribing errors, 7 dispensing errors, and 12 administration errors. Twelve studies reported errors at more than one time point within the MMP; four studies at 2 stages and 8 studies at 3 stages. The most common types of the errors identified were dose errors which commonly occurred during prescribing, dispensing, or administration. Studies have highlighted that MEs occurring in children, with most of the errors reported at the prescribing stage. This could be a reflection of the studies' focus, and further work is needed to review errors occurring at other time points during the medication management cycle. Identifying where errors occur will contribute to the development of novel strategies to detect and prevent these errors in ambulatory settings. PMID- 25809625 TI - Lung cancer may increase serum procalcitonin level. AB - INTRODUCTION: Serum procalcitonin (PCT) is a biomarker used routinely to diagnose infections. Some malignancies are usual false positives for PCT. However, its value and behavior in the setting of lung cancers are poorly known. The objective of this study was to assess PCT positivity in a lung cancer cases series. METHOD: Between November 2011 and September 2012, all cases of newly diagnosed lung cancer with a pre-antineoplastic PCT assay and no patent signs of infection were included in the study. All PCT levels were assessed by immunofluorescent assay in a single laboratory. RESULTS: Eighty-nine patients were included (70.8% male; mean age 62; small-cell cancer 20.2%; stage IV cancer 60.7%). Overall, PCT was positive in 42%. A neuroendocrine component, having 2 or more metastatic sites, having a pleura or a liver metastasis, and being positive for CRP were all significantly associated with positive PCT in univariate analysis. In multivariate analysis, only the presence of a neuroendocrine component remained strongly associated with a positive PCT (AOR=7.24 [CI=95% 1.91-27.51]; P=0.004). Finally, baseline PCT levels <0.5 ug/l were found in 43% of NSCLC with a neuroendocrine component, vs. 9% of cancers with other histology (P=0.0001). CONCLUSION: Lung cancer may cause false positives for procalcitonin, particularly in cases of neuroendocrine cancers or in the presence of multiple metastases. These results should be taken into account for PCT-based decisional algorithms. PMID- 25809627 TI - Prevalence of influenza at Hajj: is it correlated with vaccine uptake? AB - Travellers attending mass gathering events like Hajj are at high risk of acquisition of respiratory viral infection, especially influenza. Following the official recommendation from the Saudi Ministry of Health in 2005, the coverage rate of influenza vaccine rose to 100% by the year 2009, and thereafter remained above 80% in pilgrims from resource-rich countries. In a meta-analysis of observational studies, influenza vaccine was found to be significantly effective against laboratory-confirmed influenza; therefore, it is interesting to determine whether there has been any change in the prevalence of influenza. Over the last few decades a score of studies have been undertaken to establish the prevalence of influenza among Hajj pilgrims. The studies varied greatly in their designs; most notably, two separate endpoints were used: 'point prevalence' and 'attack rate'. The attack rate of influenza among Hajj pilgrims has remained stable between 4% and 15%, as did its point prevalence between 1.3% and 10%. However, the prevalence of influenza-like illness (ILI) varied widely between 8% and 63%, depending on how ILI was defined. It is therefore sensible to assume that the prevalence of influenza at Hajj has not declined considerably, and vaccine and other preventive measures may have contributed to keep the epidemiology stable. More studies are needed to understand the epidemiology of influenza at Hajj, particularly by assessing the efficacy of influenza vaccine against laboratory proven influenza in pilgrims. PMID- 25809628 TI - Therapeutic value of black seed oil in methotrexate hepatotoxicity in Egyptian children with acute lymphoblastic leukemia. AB - BACKGROUND: 'Acute lymphoblastic leukemia is the most common childhood malignancy'. Adding methotrexate to treatment protocols increased survival rate in children with leukemia. Methotrexate efficacy is limited by its hepatotoxicity. AIM OF THE STUDY: To assess the therapeutic value of Black seed oil in 'methotrexate induced hepatotoxicity in Egyptian children with acute lymphoblastic leukemia'. SUBJECTS AND METHODS: This study was conducted on 40 children with acute lymphoblastic leukemia' including 20 patients under methotrexate therapy and Black seeds 80 mg/kg/day for one week after each methotrexate dose [Group II] and 20 patients under methotrexate therapy and placebo [Group III]. This study included also '20 healthy children of matched age and sex as a control group' [Group I]. All patients were subjected to complete blood picture, bone marrow aspiration and liver functions. RESULTS: No significant differences in liver functions between group II and III before therapy were observed. There were nonsignificant increase in total, direct and indirect serum bilirubin, serum ALT, AST, and alkaline phosphatase levels and prothrombin time in group II after methotrexate and Black seed oil therapy but there was significant increase in group III after treatment with methotrexate and placebo with 'significant differences between group II and III ' after therapy. There were significant differences in prognosis regarding remission, relapse, death and 'disease free survival but no significant difference in overall survival between group II and III'. CONCLUSION: Black cumin seeds decreased MTX hepatotoxicity and improved survival in children with ALL and can be recommended as adjuvant drug in patients with ALL under methotrexate therapy. PMID- 25809629 TI - Neuroimaging findings in a series of children with cerebral palsy and congenital cytomegalovirus infection. AB - Congenital cytomegalovirus (cCMV) is a contributing cause of neurodevelopmental disabilities including cerebral palsy (CP). In this case series we reviewed the neuroimaging findings of children with CP and cCMV infection in the context of the children's clinical profile. PARTICIPANTS: Children with CP and laboratory confirmed cCMV (n=12) reported to the Australian CP Register, born in South Australia and Victoria, 1993-2006, with magnetic resonance imaging (MRI) and/or computerized tomography (CT) report available. Clinical details and neuroimaging findings were tabulated and compared to published literature. Children in this series were mostly born at term (n=8), with symptoms or signs of cCMV (n=10) and had spastic quadriplegia (n=9), epilepsy (n=8), intellectual deficit (n=12), communication (n=10) and hearing impairments (n=9). All but one had abnormal neuroimaging findings reported on MRI or CT (n=11): most commonly brain malformations including disorders of neuronal migration (n=10), such as lissencephaly, pachygyria and polymicrogyria, and cerebellar hypoplasia (n=5). Other findings included ventricular dilatation (n=8), calcifications (n=7) and white matter abnormalities (n=6). This study suggests that brain malformations, calcifications, ventricular dilatation and cerebellar hypoplasia are common neuroimaging patterns in children with CP and cCMV infection. The presence of these findings should prompt investigations for congenital cytomegalovirus. PMID- 25809630 TI - Gammaretrovirus-specific antibodies in free-ranging and captive Namibian cheetahs. AB - The cheetah population in Namibia is the largest free-ranging population in the world and a key population for research regarding the health status of this species. We used serological methods and quantitative real-time PCR to test free ranging and captive Namibian cheetahs for the presence of feline leukemia virus (FeLV), a gammaretrovirus that can be highly aggressive in populations with low genetic diversity, such as cheetahs. We also assessed the presence of antibodies to other gammaretroviruses and the responses to a FeLV vaccine developed for domestic cats. Up to 19% of the free-ranging cheetahs, 27% of the captive nonvaccinated cheetahs, and 86% of the captive vaccinated cheetahs tested positive for FeLV antibodies. FeLV-antibody-positive free-ranging cheetahs also tested positive for Rauscher murine leukemia virus antibodies. Nevertheless, FeLV was not detectable by quantitative real-time PCR and no reverse transcriptase activity was detectable by product-enhanced reverse transcriptase assay in the plasma of cheetahs or the supernatants from cultures of peripheral blood mononuclear cells. The presence of antibodies to gammaretroviruses in clinically healthy specimens may be caused either by infection with a low-pathogenic retrovirus or by the expression of endogenous retroviral sequences. The strong humoral immune responses to FeLV vaccination demonstrate that cheetahs can respond to the vaccine and that vaccination against FeLV infection may be beneficial should FeLV infection ever become a threat, as was seen in Iberian lynx and Florida panthers. PMID- 25809631 TI - Induction of potent adaptive immunity by the novel polyion complex nanoparticles. AB - The development of effective and simple methods of vaccine preparation is desired for the prophylaxis and treatment of a variety of infectious diseases and cancers. We have created novel polyion complex (PIC) nanoparticles (NPs) composed of amphiphilic anionic biodegradable poly(gamma-glutamic acid) (gamma-PGA) and cationic polymers as a vaccine adjuvant. PIC NPs can be prepared by mixing gamma PGA-graft-l-phenylalanine ethylester (gamma-PGA-Phe) polymer with cationic polymer in phosphate-buffered saline. We examined the efficacy of PIC NPs for antigen delivery and immunostimulatory activity in vitro and in vivo. PIC NPs enhanced the uptake of ovalbumin (OVA) by dendritic cells (DCs) and subsequently induced DC maturation. The immunization of mice with OVA-carrying PIC NPs induced potent and antigen-specific cellular and humoral immunity. Since PIC NPs can be created with water-soluble anionic gamma-PGA-Phe and a cationic polymer by simple mixing in the absence of any organic solvents, PIC NPs may have potential as a novel candidate for an effective antigen carrier and vaccine adjuvant. PMID- 25809632 TI - Needle-Free Dermal Delivery of a Diphtheria Toxin CRM197 Mutant on Potassium Doped Hydroxyapatite Microparticles. AB - Injections with a hypodermic needle and syringe (HNS) are the current standard of care globally, but the use of needles is not without limitation. While a plethora of needle-free injection devices exist, vaccine reformulation is costly and presents a barrier to their widespread clinical application. To provide a simple, needle-free, and broad-spectrum protein antigen delivery platform, we developed novel potassium-doped hydroxyapatite (K-Hap) microparticles with improved protein loading capabilities that can provide sustained local antigen presentation and release. K-Hap showed increased protein adsorption over regular hydroxyapatite (P < 0.001), good structural retention of the model antigen (CRM197) with 1% decrease in alpha-helix content and no change in beta-sheet content upon adsorption, and sustained release in vitro. Needle-free intradermal powder inoculation with K-Hap-CRM197 induced significantly higher IgG1 geometric mean titers (GMTs) than IgG2a GMTs in a BALB/c mouse model (P < 0.001) and induced IgG titer levels that were not different from the current clinical standard (P > 0.05), namely, alum-adsorbed CRM197 by intramuscular (i.m.) delivery. The presented results suggest that K-Hap microparticles may be used as a novel needle free delivery vehicle for some protein antigens. PMID- 25809634 TI - Apathy in Neurodegenerative Diseases: Recommendations on the Design of Clinical Trials. AB - Apathy is a common feature of neurodegenerative disorders but is difficult to study in a clinical trial setting due to practical and conceptual barriers. Principal challenges include a paucity of data regarding apathy in these disorders, an absence of established diagnostic criteria, the presence of confounding factors (eg, coexisting depression), use of concomitant medications, and an absence of a gold-standard apathy assessment scale. Based on a literature search and ongoing collaboration among the authors, we present recommendations for the design of future clinical trials of apathy, suggesting Alzheimer disease and Parkinson disease as models with relevance across a wider array of neuropsychiatric disorders. Recommendations address clarification of the targeted study population (apathy diagnosis and severity at baseline), confounding factors (mood/cognition, behavior, and treatment), outcome measures, study duration, use of comparators and considerations around environment, and the role of the caregiver and patient assent. This review contributes to the search for an optimal approach to study treatment of apathy in neuropsychiatric disorders. PMID- 25809633 TI - Comparative Exoproteomics and Host Inflammatory Response in Staphylococcus aureus Skin and Soft Tissue Infections, Bacteremia, and Subclinical Colonization. AB - The exoproteome of Staphylococcus aureus contains enzymes and virulence factors that are important for host adaptation. We investigated the exoprotein profiles and cytokine/chemokine responses obtained in three different S. aureus-host interaction scenarios by using two-dimensional gel electrophoresis (2-DGE) and two-dimensional immunoblotting (2D-IB) combined with tandem mass spectrometry (MS/MS) and cytometric bead array techniques. The scenarios included S. aureus bacteremia, skin and soft tissue infections (SSTIs), and healthy carriage. By the 2-DGE approach, 12 exoproteins (the chaperone protein DnaK, a phosphoglycerate kinase [Pgk], the chaperone GroEL, a multisensor hybrid histidine kinase, a 3 methyl-2-oxobutanoate hydroxymethyltransferase [PanB], cysteine synthase A, an N acetyltransferase, four isoforms of elongation factor Tu [EF-Tu], and one signature protein spot that could not be reliably identified by MS/MS) were found to be consistently present in more than 50% of the bacteremia isolates, while none of the SSTI or healthy-carrier isolates showed any of these proteins. By the 2D-IB approach, we also identified five antigens (methionine aminopeptidase [MetAPs], exotoxin 15 [Set15], a peptidoglycan hydrolase [LytM], an alkyl hydroperoxide reductase [AhpC], and a haptoglobin-binding heme uptake protein [HarA]) specific for SSTI cases. Cytokine and chemokine production varied during the course of different infection types and carriage. Monokine induced by gamma interferon (MIG) was more highly stimulated in bacteremia patients than in SSTI patients and healthy carriers, especially during the acute phase of infection. MIG could therefore be further explored as a potential biomarker of bacteremia. In conclusion, 12 exoproteins from bacteremia isolates, MIG production, and five antigenic proteins identified during SSTIs should be further investigated for potential use as diagnostic markers. PMID- 25809636 TI - Cardiac mucosa: the heart of the problem. PMID- 25809637 TI - Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection. AB - Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by persistent infectious mononucleosis-like symptoms, can lead to cardiovascular complications including coronary artery aneurysm or myocarditis. Here, we present the case of an 11-year-old boy with pulmonary arterial hypertension (PAH) and junctional ectopic tachycardia associated with CAEBV. The patient did not have any major symptoms attributed to CAEBV, such as fever, lymphadenopathy or splenomegaly when the PAH developed. Mild liver dysfunction was found at the first examination, and it persisted. Two years after the PAH symptoms appeared, CAEBV was evident, based on deteriorated liver function, hepatosplenomegaly, and coronary artery aneurysms. CAEBV should be considered as a cause of secondary PAH, particularly when liver dysfunction coexists. PMID- 25809635 TI - PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. AB - During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid beta-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade. PMID- 25809640 TI - The Role of hsa-miR-548l Dysregulation as a Putative Modifier Factor for Glaucoma Associated FOXC1 Mutations. AB - Mutations of the FOXC1 transcription factor are involved in a variety of autosomal dominant ocular anterior segment defects, ranging from Axenfeld-Rieger malformations to isolated glaucoma in some patients. In this study we have evaluated the possible role of the c.*734A>T FOXC1 variant as a modifier factor of the activity of two FOXC1 mutations previously identified in families primarily affected by dominant glaucoma (haplotypes p.G447_G448insDG-c.*734A>T and p.I126S-c.*734A>T). Previous bioinformatic analyses indicated that the c.*734A>T variant is located in a potential target sequence for hsa-miR-548l. Co expression of this miRNA with a reporter cDNA construct in which the wild-type 3'UTR sequence of FOXC1 was fused to the 3'-end of the firefly luciferase coding region, led to approximately 20% decreased luciferase activity compared to the controls, confirming the presence of a target sequence for hsa-miR-548l. In contrast, this miRNA did not show any effect on the luciferase activity associated with the mutant 3'UTR FOXC1 sequence, showing that it resulted in a loss-of-function of the has-miR-548l target sequence. In addition, functional evaluation of the two glaucoma-associated haplotypes revealed increased protein levels and transactivation, compared to the corresponding individual coding mutations (approximately 1.2-fold on average). These data support the role of hsa miR-548l as a regulator of FOXC1 translation and provide evidence for the c.*734A>T variant as a modifier factor for the activity of coding glaucoma associated FOXC1 mutations. PMID- 25809638 TI - The Association of HIV Stigma and HIV/STD Knowledge With Sexual Risk Behaviors Among Adolescent and Adult Men Who Have Sex With Men in Ghana, West Africa. AB - Ghanaian men who have sex with men (MSM) have a high HIV seroprevalence, but despite a critical need to address this public health concern, research evidence has been extremely limited on influences on sexual risk behavior among MSM in Ghana. To investigate associations between HIV/STD knowledge, HIV stigma, and sexual behaviors in a sample of MSM in Ghana, we conducted a secondary data analysis of cross-sectional survey data from a non-probability sample of Ghanaian MSM (N = 137). Nearly all the men (93%) had more than one current sex partner (M = 5.11, SD = 7.4). Of those reported partners, the average number of current female sexual partners was 1.1 (SD = 2.6). Overall, knowledge levels about HIV and STDs were low, and HIV stigma was high. There was no age-related difference in HIV stigma. Younger MSM (<=25 years) used condoms less often for anal and vaginal sex than did those over 25. Relative frequency of condom use for oral sex was lower in younger men who had higher STD knowledge and also was lower in older men who reported high HIV stigma. Knowledge and stigma were not associated with condom use for anal or vaginal sex in either age group. These descriptive data highlight the need for the development of intervention programs that address HIV/STD prevention knowledge gaps and reduce HIV stigma in Ghanaian communities. Intervention research in Ghana should address age-group-specific HIV prevention needs of MSM youth. PMID- 25809639 TI - Safety and efficacy of blood exchange transfusion for priapism complicating sickle cell disease. AB - BACKGROUND: Priapism is unwanted painful penile erection that affects about 36% of boys and men with sickle cell disease (SCD) most of whom have sickle cell anemia. Clinically, priapism could be stuttering, minor, or major. The first two types are mild, last < 4 h, are usually treated at home, have good prognosis with normal sexual function. The major type of priapism lasts >4 h, associated with severe pain, requires hospitalization; often does not respond to medical treatment and may require shunt surgery. Untreated major priapism and surgical intervention often cause impotence. In this study, we report our 15-year experience in treating adult patients with SCD and major priapism with blood exchange transfusion after being refractory to other medical therapies. METHODS: Adult male African Americans patients with SCD and major priapism were enrolled in this study and followed for 15 years. A Haemonitics V-50 machine was initially used for whole blood exchange and was later replaced with Cobe Spectra machine for RBC exchange. RESULTS: We used 239 blood exchanges requiring 1,136 RBC units. We maintained a post-exchange hemoglobin level of about 10 g/dL and hemoglobin S level < 30%. None of the patients had any neurological complications such as headache, seizures, neurological deficits, or obtundation post-exchange. CONCLUSION: Together, the data indicate that blood exchange transfusion for the treatment of patients with SCD and major priapism is efficacious and safe. PMID- 25809641 TI - Many families may face sharply higher costs if public health insurance for their children is rolled back. AB - Millions of US children could lose access to public health care coverage if Congress does not renew federal funding for the Children's Health Insurance Program (CHIP), which is set to expire September 30, 2015-the end of the federal fiscal year. Additional cuts in public coverage for children in families with incomes above 133 percent of the federal poverty level are possible if the Affordable Care Act's "maintenance of effort" provisions regarding Medicaid and CHIP are allowed to expire as scheduled in 2019. The potential for a significant rollback of public coverage for children raises important policy questions regarding alternative pathways to affordable and high-quality coverage for low income children. For many children at risk of losing eligibility for public coverage, the primary alternative pathway to coverage would be through their parents' employer-sponsored insurance, yet relatively little is known about the cost and quality of that coverage. Our estimates, based on data from the Insurance Component of the 2012 and 2013 Medical Expenditure Panel Surveys, show that many families would face sharply higher costs of covering their children. In many cases, the only employer-sponsored coverage available would be a high deductible plan. PMID- 25809642 TI - White-cheeked macaque (Macaca leucogenys): A new macaque species from Medog, southeastern Tibet. AB - We describe a newly discovered Macaca species from the Medog, in southeastern Tibet, China, Macaca leucogenys sp. nov or the "white-cheeked macaque". Based on 738 photos taken during direct observations and captured by camera traps this new species appears to be distinct from the Macaca sinica species group. Moreover, the species is distinguished from all potential sympatric macaque species (M. mulatta, M. thibetana, M. assamensis, and M. munzala) in exhibiting a suite of pelage characteristics including relatively uniform dorsal hair pattern, hairy ventral pelage, relative hairless short tail, prominent pale to white side- and chin-whiskers creating a white cheek and round facial appearance, dark facial skin on the muzzle, long and thick hairs on its neck, and a round rather than arrow-shaped male genitalia. This new macaque species was found to exploit a diverse set of habitat types from tropical forest at 1395 m, to primary and secondary evergreen broad-leaved forest at 2000 m, as well as mixed broadleaf conifer forest at 2700 m. Its range may extend to neighboring counties in Tibet and the part of southeastern Tibet controlled by India. The white-cheeked macaque is threatened by illegal hunting and the construction of hydropower stations. Discovery of this new primate species further highlights the high value for biodiversity conservation of southeastern Tibet and calls for more intensive surveys, studies, and environmental protection in this area. PMID- 25809643 TI - Graphene single crystals: size and morphology engineering. AB - Recently developed chemical vapor deposition (CVD) is considered as an effective way to large-area and high-quality graphene preparation due to its ultra-low cost, high controllability, and high scalability. However, CVD-grown graphene film is polycrystalline, and composed of numerous grains separated by grain boundaries, which are detrimental to graphene-based electronics. Intensive investigations have been inspired on the controlled growth of graphene single crystals with the absence of intrinsic defects. As the two most concerned parameters, the size and morphology serve critical roles in affecting properties and understanding the growth mechanism of graphene crystals. Therefore, a precise tuning of the size and morphology will be of great significance in scale-up graphene production and wide applications. Here, recent advances in the synthesis of graphene single crystals on both metals and dielectric substrates by the CVD method are discussed. The review mainly covers the size and morphology engineering of graphene single crystals. Furthermore, recent progress in the growth mechanism and device applications of graphene single crystals are presented. Finally, the opportunities and challenges are discussed. PMID- 25809644 TI - Secondary Crystal Nucleation: Nuclei Breeding Factory Uncovered. AB - Secondary nucleation, wherein crystal seeds are used to induce crystallization, is widely employed in industrial crystallizations. Despite its significance, our understanding of the process, particularly at the molecular level, remains rudimentary. An outstanding question is why do a few seeds give rise to a many fold increase in new crystals? Using molecular simulation coupled with experiments we have uncovered the molecular processes that give rise to this autocatalytic behavior. The simulations reveal formation of molecular aggregates in solution, which on coming in contact with the surface of the seed undergo nucleation to form new crystallites. These crystallites are weakly bound to the crystal surface and can be readily sheared by fluid, making the seed surfaces available again to repeat the process. Further, the new crystallites on development can in turn serve as seeds. This mechanistic insight will enable better control in engineering crystalline products to design. PMID- 25809646 TI - Response to conspecific and heterospecific semiochemicals by Sesamia nonagrioides (L.) (Lepidoptera: Noctuidae) gravid females. AB - The Mediterranean corn borer, Sesamia nonagrioides, occurs sympatrically in the northeast of Spain with other lepidopteran pests such as Ostrinia nubilalis and Mythimna unipuncta. In this study, we evaluated the electrophysiological and behavioural response of mated and unmated females and males of S. nonagrioides to their own complete pheromone blend, to its own four components separately, and to the pheromone components of the sympatric species O. nubilalis and M. unipuncta. Results of the electroantennogram recordings revealed that females of S. nonagrioides can detect their own pheromone blend and its individual components. Moreover, our results show that unmated females and males of S. nonagrioides are more sensitive to the female pheromone, showing higher electrophysiological response than the mated females and males. Electroantennogram recordings showed that males and females can detect the major sexual pheromone component of O. nubilalis (Z)-11-tetradecenyl acetate and the minor component of the pheromone of M. unipuncta (Z)-9-hexadecenyl acetate. When the sex pheromone stimulus was presented in the dual-choice assays, gravid females of S. nonagrioides were attracted to both their own complete pheromone blend and one of their own minor pheromone components, (Z)-11-hexadecenal, but the major sexual pheromone component of O. nubilalis acts as a behavioural antagonist to the females. PMID- 25809647 TI - Impact of LPL gene rs283 polymorphism on exercise-induced changes in metabolism of obese adolescents and the regulatory mechanisms behind it. AB - NEW FINDINGS: What is the central question of this study? We investigated whether the LPL gene rs283 polymorphism affects exercise-induced changes in body composition and lipid and glucose metabolism in obese adolescents and whether it is functional. What is the main finding and its importance? Chinese obese adolescents of Han nationality with the GG genotype of the rs283 polymorphism were more sensitive to exercise-induced reduction of the body fat percentage, insulin resistance and plasma triglyceride levels. The G allele can significantly increase reporter gene expression level, which may be the molecular reason for the difference in exercise-induced parameter changes among obese adolescents. The aim of this investigation was to explore the association between the rs283 polymorphism located in the lipoprotein lipase (LPL) gene and exercise-induced changes in body composition and lipid and glucose metabolism in obese adolescents and to probe into the molecular regulatory mechanisms. Fifty-five obese adolescents of Han nationality underwent aerobic training for 4 weeks. Body composition and lipid and glucose metabolic parameters were tested before and after the training. The rs283 polymorphism was genotyped by PCR-restriction fragment length polymorphism, and association analysis with the weight-reducing effect was performed. The regulatory mechanisms of the rs283 polymorphism were explored through the dual-luciferase reporter assay. Exercise-induced change rates were as follows: the change in body fat percentage of GG genotype groups was 3.37 +/- 1.60, significantly higher than that of GA genotype groups (2.09 +/- 1.53, P < 0.01); the change in the homeostasis model assessment of insulin resistance was 0.52 +/- 0.13, obviously higher than that of GA genotype groups (0.44 +/- 0.10, P < 0.05); and the change in triglyceride was 51.91 +/- 6.56, much higher than that of GA genotype groups (47.06 +/- 5.36, P < 0.01). The relative luciferase activity of the reporter gene in recombinant vector carrying the G allele was 2.67 +/- 0.22, markedly higher than that in recombinant vector carrying the A allele (1.63 +/- 0.03, P < 0.01). Chinese obese adolescents of Han nationality with GG genotype of the rs283 polymorphism were more sensitive to exercise-induced parameter changes. The G allele can improve reporter gene expression level, indicating the effects of rs283 on gene expression. PMID- 25809648 TI - What health care system delays reveal about inequalities in breast cancer medicine and global health. PMID- 25809649 TI - Intravenous thrombolysis for stroke in patients taking non-VKA oral anticoagulants: an update. PMID- 25809651 TI - Development of a reliable, valid measure to assess parents' and teachers' understanding of postural care for children with physical disabilities: the (UKC PostCarD) questionnaire. AB - BACKGROUND: Previous research has highlighted lack of knowledge, understanding and confidence among parents and teachers responsible for the postural care of children with physical disability. Interventions designed to improve these qualities require a reliable and validated tool to assess pre- and post intervention levels. Currently, however, no validated measure of postural care confidence (i.e. self-efficacy) exists. Hence, the aim of this research was to develop a reliable and valid questionnaire to assess parents' and teachers' confidence, alongside knowledge and understanding of postural care - the Understanding Knowledge and Confidence in providing POSTural CARe for children with Disabilities (UKC PostCarD) questionnaire. METHODS: Items were developed by a multidisciplinary team and designed to map onto the content of 'An A-to-Z of Postural Care'. Parents, teachers and therapists assessed items for face validity. Scale reliability was then assessed using Cronbach's alpha and known group validity was assessed by comparing scores of an 'expert' group (physiotherapists and occupational therapists) with those of a 'non-expert' group (with no formal training in postural care). RESULTS: The total scale and all three subscales (understanding and knowledge, confidence and concerns) demonstrated adequate reliability (alpha > 0.83) and subscale correlations formed a logical pattern (understanding and knowledge correlated positively with confidence and negatively with concerns). Experts' (n = 111) scores were higher than non-experts' (n = 79) for the total scale and all subscales (P < 0.001). CONCLUSION: Findings support the reliability and validity of the UKC PostCarD questionnaire as a measure of understanding, knowledge and confidence in providing postural care for children with disabilities. PMID- 25809650 TI - Embedding the perceptions of people with dementia into quantitative research design. AB - PURPOSE: Patient perspectives about quality of life are often found in the results of qualitative research and could be applied to steer the direction of future research. The purpose of this paper was to describe how findings from a body of qualitative research on patient perspectives about quality of life were linked to a clinical administrative dataset and then used to design a subsequent quantitative study. METHODS: Themes from two systematic reviews of qualitative evidence (i.e., metasyntheses) identified what affects quality of life according to people with dementia. Selected themes and their sub-concepts were then mapped to an administrative dataset (the Resident Assessment Instrument 2.0) to determine the study focus, formulate nine hypotheses, and select a patient reported outcome. A literature review followed to confirm existence of a knowledge gap, identify adjustment variables, and support design decisions. RESULTS: A quantitative study to test the association between conflict and sadness for people with dementia in long-term care was derived from metasynthesis themes. Challenges included (1) mapping broad themes to the administrative dataset; (2) decisions associated with inclusion of variables not identified by people with dementia from the qualitative research; and (3) selecting a patient reported outcome, when the dataset lacked a valid subjective quality-of-life measure. CONCLUSIONS: Themes derived from a body of qualitative research capturing a target populations' perspective can be linked to administrative data and used to design a quantitative study. Using this approach, the quantitative findings will be meaningful with respect to the quality of life of the target population. PMID- 25809652 TI - Health promoting interactive technology: Finnish, Norwegian, Russian and Swedish students' reflections. AB - The aim of this study was to elucidate Finnish, Norwegian, Russian and Swedish students' reflections and ideas on how interactive technology can be used to promote health in school. The data were collected in the northern part of these four countries, and 630 students aged 13-15 filled out the World Health Organization's 'Health Behavior in School-Aged Children' self-completion questionnaire with one additional open question, which is analyzed in this article (n = 419). The phenomenological analysis resulted in four themes: A sense of control, Balancing enjoyable options, Sharing with others and Learning made easier. The students point out that interactive technology promotes empowerment and independence, reduces stress and makes learning easier. They argue for a healthy balance of Internet use for it to be health promoting. According to the students, good relationships increase well-being; and interactive technology can offer a way to socialize, provide a tool for meeting and making new friends, help when not feeling well and give support when encouraging classmates. We argue, based on the findings of the present study and previous research, that students need a combination of freedom and meaningful relationships with adults who have an empowered child perspective, to fully take advantage of the empowering effects of interactive technology. We suggest, as implications for practice, that teachers, school leaders and health care professionals find ways to act as partners using an appreciative process, asking questions on what works well, to make interactive technology an enabling technology to increase health literacy, thus improving health and well-being in students. PMID- 25809653 TI - Does the response to aspirin and clopidogrel vary over 6 months in patients with ischemic heart disease? AB - BACKGROUND: Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, mostly clopidogrel, is the default therapy in both acute coronary syndrome (ACS) and after intracoronary stents. It is well established that responses to antiplatelet therapy (APT), particularly clopidogrel, are subject to considerable interindividual variability. OBJECTIVES: We investigated whether responses to APT in individuals vary significantly over time. METHODS: Simultaneous assay with VerifyNow(TM) and short thrombelastography (s-TEG) was performed before and at four time points over 6 months after hospital discharge in 40 patients receiving DAPT. Serum thromboxane B2 levels were also measured. RESULTS: While aspirin response units (ARU) by VerifyNow(TM) and serum thromboxane B2 levels remained stable over time, arachidonic acid (AA)-mediated platelet aggregation with s-TEG (i.e. area under the curve at 15 min in AA channel, AUC15AA ) increased at 1 week compared with predischarge (P < 0.008). In addition, platelet reactivity units (PRU) by VerifyNow(TM) (P = 0.046) and adenosine diphosphate (ADP)-mediated platelet aggregation with s-TEG (i.e. AUC15ADP ) also increased at 1 week compared with predischarge (P = 0.026). There were no significant changes in either platelet reactivity or rates of high on-treatment platelet reactivity while receiving clopidogrel beyond 1 week. CONCLUSIONS: This study demonstrates important variability in responses to APT within individuals between predischarge and 1 week but not thereafter. The use of a single early (predischarge) platelet function assay as an indicator of future response may therefore be flawed. The design of future strategies to assess individual responses for tailored therapy needs to take this into account. PMID- 25809654 TI - [Diagnostic molecular pathology of lymphatic and myeloid neoplasms]. AB - Molecular pathology has been an integral part of the diagnostics of tumors of the hematopoietic system substantially longer than for solid neoplasms. In contrast to solid tumors, the primary objective of molecular pathology in hematopoietic neoplasms is not the prediction of drug efficacy but the diagnosis itself by excluding reactive proliferation and by using molecular features for tumor classification. In the case of malignant lymphomas, the most commonly applied molecular tests are those for gene rearrangements for immunoglobulin heavy chains and T-cell receptors. However, this article puts the focus on new and diagnostically relevant assays in hematopathology. Among these are mutations of MYD88 codon 265 in lymphoplasmacytic lymphomas, B-raf V600E in hairy cell leukemia and Stat3 exon 21 in indolent T-cell lymphomas. In myeloproliferative neoplasms, MPL W515, calreticulin exon 9 and the BCR-ABL and JAK2 V617F junctions are the most frequently analyzed differentiation series. In myelodysplastic and myeloproliferative neoplasms, SRSF2, SETBP1 and CSF3R mutations provide important differential diagnostic information. Genes mutated in myelodysplastic syndromes (MDS) are particularly diverse but their analysis significantly improves the differential diagnostics between reactive conditions and MDS. The most frequent changes in MDS include mutations of TET2 and various genes encoding splicing factors. PMID- 25809655 TI - Insecticide resistance alleles in wetland and residential populations of the West Nile virus vector Culex pipiens in New Jersey. AB - BACKGROUND: In spite of the extensive use of insecticides to control Culex pipiens in the aftermath of West Nile virus, knowledge of the spatial distribution and frequency of insecticide resistance in this species is poorly understood in the United States. This paper reports on the occurrence of upregulated esterases that detoxify organophosphates (OPs) and mutations conferring resistance to pyrethroid insecticides in natural and developed areas of New Jersey. RESULTS: We report the first observations of the OP resistance alleles Ester(B1) and Ester(2) and the classical knockdown resistance (kdr) mutation L1014F in New Jersey Cx. pipiens. Upregulated Ester(B1) peaked at 23% (mean +/- SE = 12 +/- 2.3%) and Ester(2) at 14% (8 +/- 1.8%), and both were widely distributed. L1014F, which confers strong resistance to pyrethroids when homozygous, was also widely distributed and ranged in frequency from 2 to 19% (5.1% heterozygous individuals and 1.4% homozygous). CONCLUSION: We have demonstrated that OP resistance is common and broadly distributed in New Jersey Cx. pipiens, and that homozygous individuals resistant to pyrethroids are present. Further, we have detected double mutants at Ester and kdr, a condition that may annul the purging effects of insecticide rotations. Our results therefore indicate the need for continued monitoring of insecticide resistance in order to achieve effective mosquito control. PMID- 25809656 TI - An overview of the metabolic functions of osteocalcin. AB - A recent unexpected development of bone biology is that bone is an endocrine organ regulating a growing number of physiological processes. One of the functions regulated by bone through the hormone osteocalcin is glucose homeostasis. In this overview, we will explain why we hypothesized that bone mass and energy metabolism should be subjected to a coordinated endocrine regulation. We will then review the experiments that revealed the endocrine function of osteocalcin and the cell biology events that allow osteocalcin to become a hormone. We will also illustrate the importance of this regulation to understand whole-body glucose homeostasis in the physiological state and in pathological conditions. Lastly, we will mention epidemiological and genetic evidence demonstrating that this function of osteocalcin is conserved in humans. PMID- 25809657 TI - PGSE, OGSE, and sensitivity to axon diameter in diffusion MRI: Insight from a simulation study. AB - PURPOSE: To identify optimal pulsed gradient spin-echo (PGSE) and oscillating gradient spin-echo (OGSE) sequence settings for maximizing sensitivity to axon diameter in idealized and practical conditions. METHODS: Simulations on a simple two-compartment white matter model (with nonpermeable cylinders) are used to investigate a wide space of clinically plausible PGSE and OGSE sequence parameters with trapezoidal diffusion gradient waveforms. Signal sensitivity is measured as a derivative of the signal with respect to axon diameter. Models of parallel and dispersed fibers are investigated separately to represent idealized and practical conditions. RESULTS: Simulations show that, for the simple case of gradients perfectly perpendicular to straight parallel fibers, PGSE always gives maximum sensitivity. However, in real-world scenarios where fibers have unknown and dispersed orientation, low-frequency OGSE provides higher sensitivity. Maximum sensitivity results show that on current clinical scanners (Gmax = 60 mT/m, signal to noise ratio (SNR) = 20) axon diameters below 6 um are indistinguishable from zero. Scanners with stronger gradient systems such as the Massachusetts General Hospital (MGH) Connectom scanner (Gmax = 300 mT/m) can extend this sensitivity limit down to 2-3 um, probing a much greater proportion of the underlying axon diameter distribution. CONCLUSION: Low-frequency OGSE provides additional sensitivity to PGSE in practical situations. OGSE is particularly advantageous for systems with high performance gradients. PMID- 25809660 TI - Palladium-catalyzed C-H activation of N-allyl imines: regioselective allylic alkylations to deliver substituted aza-1,3-dienes. AB - A new mode of activation of an imine via a rare aza-substituted pi-allyl complex is described. Palladium-catalyzed C(sp(3))-H activation of the N-allyl imine and the subsequent nucleophilic attack by the alpha-alkyl cyanoester produced the 1 aza-1,3-diene as the sole regioisomer. In contrast, nucleophilic attack by the alpha-aryl cyanoester exclusively delivered the 2-aza-1,3-diene, which was employed in an inverse-electron-demand Diels-Alder reaction for heterobiaryl synthesis. PMID- 25809659 TI - Production of arabitol by yeasts: current status and future prospects. AB - Arabitol belongs to the pentitol family and is used in the food industry as a sweetener and in the production of human therapeutics as an anticariogenic agent and an adipose tissue reducer. It can also be utilized as a substrate for chemical products such as arabinoic and xylonic acids, propylene, ethylene glycol, xylitol and others. It is included on the list of 12 building block C3-C6 compounds, designated for further biotechnological research. This polyol can be produced by yeasts in the processes of bioconversion or biotransformation of waste materials from agriculture, the forest industry (l-arabinose, glucose) and the biodiesel industry (glycerol). The present review discusses research on native yeasts from the genera Candida, Pichia, Debaryomyces and Zygosaccharomyces as well as genetically modified strains of Saccharomyces cerevisiae which are able to utilize biomass hydrolysates to effectively produce L- or D-arabitol. The metabolic pathways of these yeasts leading from sugars and glycerol to arabitol are presented. Although the number of reports concerning microbial production of arabitol is rather limited, the research on this topic has been growing for the last several years, with researchers looking for new micro-organisms, substrates and technologies. PMID- 25809658 TI - Body mass index (BMI) predicts percent body fat better than body adiposity index (BAI) in school children. AB - BACKGROUND/AIMS: Child obesity is associated with increased risk of adult obesity, and is considered as one important health risk factor. Appropriate indicators are required to identify potential risks of child adiposity. This study for the first time compares body mass index (BMI) and body adiposity index (BAI) for predicting percent body fat (PBF) in children. METHODS: We measured statures, weights, and hip circumferences of 527 children of Han ethnicity and calculated BMI and BAI. PBF was obtained by bioelectrical impedance analysis. We adopted Pearson correlation analysis, linear regression analysis, and receiver operating characteristic (ROC) analysis. RESULTS: For each sex, we found that: 1) BMI and BAI were significantly correlated with PBF; 2) the correlation coefficient between BMI and PBF was higher than that between BAI and PBF; 3) BMI better predicted PBF in the linear regression analysis; 4) the discriminatory capacity of the BMI is higher than the one of BAI in ROC analysis. CONCLUSION: Taken together, BMI is a more reliable PBF indicator predicting adiposity in children. This finding may aid future obesity monitoring and intervention in children. PMID- 25809661 TI - In Memoriam: John O. Corliss (1922-2014). PMID- 25809663 TI - Brain discriminative cognition on the perception of touching different fabric using fingers actively. AB - BACKGROUND/PURPOSE: Using touching movement of fingers, human subjects can discriminate various tactile perception of fabric. As a continuation of the previous study, we aim to further investigate the discriminative mechanisms of the brain cognition to tactile stimulation of different fabric. METHODS: We used functional magnetic resonance imaging to observe the brain responses when the subjects touched linen fabric, as well as revisited the data from the previous silk fabric. And all the subjects were asked to compare the perception of touching the two fabric. RESULTS: Combining the results of brain responses and perception comparison, we found that activation in the primary somatosensory cortex (SI) and the secondary somatosensory cortex (SII), especially parietal operculum 1 (OP1) in this region, could discriminate this two kinds of fabric distinctly. CONCLUSION: It is suggested that the functional regions involved in the macrogeometric properties of fabric (such as pliability) is in SI, and the perception of microgeometry of fabric surface (such as roughness and glutinousness) in SII, especially in the sub-region OP1 of the OP. Besides, activation in motor cortex can be a reference for the characterization of the brain cognition on the tactile stimulation of fabric. PMID- 25809662 TI - Coculture of dorsal root ganglion neurons and differentiated human corneal stromal stem cells on silk-based scaffolds. AB - Corneal tissue displays the highest peripheral nerve density in the human body. Engineering of biomaterials to promote interactions between neurons and corneal tissue could provide tissue models for nerve/cornea development, platforms for drug screening, as well as innovative opportunities to regenerate cornea tissue. The focus of this study was to develop a coculture system for differentiated human corneal stromal stem cells (dhCSSCs) and dorsal root ganglion neurons (DRG) to mimic the human cornea tissue interactions. Axon extension, connectivity, and neuron cell viability were studied. DRG neurons developed longer axons when cocultured with dhCSSCs in comparison to neuron cultures alone. To assess the mechanism involved in the coculture response, nerve growth factors (NGF) secreted by dhCSSCs including NGF, brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and neurotrophin-3 were characterized with greater focus on BDNF secretion. DhCSSCs also secreted collagen type I, an extracellular matrix molecule favorable for neuronal outgrowth. This coculture system provides a slowly degrading silk matrix to study neuronal responses in concert with hCSSCs related to innervation of corneal tissue with utility toward human corneal nerve regeneration and associated diseases. PMID- 25809664 TI - The 2011-2014 prevalence of eosinophilic oesophagitis in the elderly amongst 10 million patients in the United States. AB - BACKGROUND: Eosinophilic oesophagitis (EoE) is primarily diagnosed by clinicians. There are less than a handful of epidemiological studies in EoE that have included elderly patients (>65 years). AIM: To determine the prevalence of elderly subjects among EoE patients and compare their clinical presentation, associated conditions and treatment modalities with adult and paediatric EoE patients. METHODS: A large nationwide database (Explorys) between January 2011 and January 2014 was used. The term 'Eosinophilic Oesophagitis' was used in the Explorys search tool. The patient population was divided into three groups, Paediatric (<18 years), Adult (18-65 years) and Elderly (>65 years). RESULTS: We identified 4840 patients coded as EoE. The total estimated prevalence was 50.6 cases per 100 000 patients (0.05%). A total of 360 cases (7.44%) were elderly patients with an estimated prevalence rate of 18.6 cases per 100 000. Across all age groups, the majority of EoE patients were Caucasians and males. A significantly greater proportion of older patients had concomitant GERD. Dysphagia was the most common symptom among elderly EoE patients as compared with the paediatric EoE patients (P < 0.001). The proportion of elderly EoE patients with food allergies or asthma was significantly lower as compared with paediatric and adult EoE patients (P < 0.001). Oesophageal dilation and/or proton pump inhibitor treatment were the most commonly used therapeutic modalities in elderly EoE patients. CONCLUSION: Eosinophilic oesophagitis is uncommon in elderly subjects and the clinical presentation is markedly different as compared with adults or the paediatric population. PMID- 25809668 TI - Development of modifiable bidentate amino oxazoline directing group for pd catalyzed arylation of secondary C-H bonds. AB - A novel bidentate alpha-amino oxazolinyl directing group has been developed. Different from previous directing groups, this newly designed directing group was easily prepared from amino acids and modified in structure. This auxiliary preferentially effects functionalization at secondary C(sp(3) )-H bonds, rather than at aryl C(sp(2) )-H bonds. The diastereoselectivity of direct arylation between geminal secondary C(sp(3) )-H bonds in linear molecules has also been realized for the first time with a chiral directing group by remote chirality relay. Two diastereoisomers are produced with the same chiral source by changing the substituents of substrates and aryl halides. PMID- 25809666 TI - Pluripotency Versus Self-Renewal of ES Cells: Two Sides of the Same Coin or More? PMID- 25809667 TI - Statins use and the risk of all and subtype hematological malignancies: a meta analysis of observational studies. AB - In order to quantify the association between use of statins and the risk of all hematological malignancies and of subtypes, we performed a meta-analysis of observational studies. We achieved a MEDLINE/EMBASE comprehensive search for studies published up to August 2014 investigating the association between use of statins and the risk of hematological malignancies, including Hodgkin- and non Hodgkin lymphoma, leukemia, and myeloma. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR) based on adjusted study specific results. Between-study heterogeneity was assessed using the Q and I(2) statistics and the sources of heterogeneity were investigated using Deeks' test. Moreover, an influence analysis was performed. Finally, publication bias was evaluated using funnel plot and Egger's regression asymmetry test. Fourteen studies (10 case-control and four cohort studies) contributed to the analysis. Statin use, compared to nonuse of statins, was negatively associated with all hematological malignancies taken together (summary RR 0.86; 95% CI: 0.77-0.96), with leukemia (0.83; 0.74-0.92), and non-Hodgkin lymphoma (0.81; 0.68 to 0.96), but it was not related to the risk of myeloma (0.89; 0.53-1.51). Long-term users of statins showed a statistically significant reduction in the risk of all hematological malignancies taken together (0.78; 0.71-0.87). Statistically significant between-studies heterogeneity was observed for all outcome except for leukemia. Heterogeneity was caused by differences confounding-adjustment level of the included studies only for Myeloma. No significant evidence of publication bias was found. PMID- 25809669 TI - A Spatial Model of Insulin-Granule Dynamics in Pancreatic beta-Cells. AB - Insulin secretion from pancreatic beta-cells in response to sudden glucose stimulation is biphasic. Prolonged secretion in vivo requires synthesis, delivery to the plasma membrane (PM) and exocytosis of insulin secretory granules (SGs). Here, we provide the first agent-based space-resolved model for SG dynamics in pancreatic beta-cells. Using recent experimental data, we consider a single beta cell with identical SGs moving on a phenomenologically represented cytoskeleton network. A single exocytotic machinery mediates SG exocytosis on the PM. This novel model reproduces the measured spatial organization of SGs and insulin secretion patterns under different stimulation protocols. It proposes that the insulin potentiation effect and the rising second-phase secretion are mainly due to the increasing number of docking sites on the PM. Furthermore, it shows that 6 min after glucose stimulation, the 'newcomer' SGs are recruited from a region within less than 600 nm from the PM. PMID- 25809665 TI - Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing. AB - In order to pass through the nuclear pore complex, proteins larger than ~40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ~100-120 kDa proteins, consisting of one out of three different O2-labile alpha subunits (primarily HIF-1alpha) and a more constitutive 1beta subunit. In the presence of O2, the alpha subunits are hydroxylated by specific prolyl-4 hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1alpha and HIF-1beta is mainly mediated by importins alpha and beta (alpha/beta). HIF-1alpha can shuttle between nucleus and cytoplasm, while HIF-1beta is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin alpha/beta receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF 1alpha occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin alpha/beta receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases. PMID- 25809671 TI - A case of tuberculous lymphadenitis associated with subepidermal immunobullous disease. PMID- 25809670 TI - Evaluating the role of hnRNP-C and FMRP in the cAMP-induced APP metabolism. AB - Cyclic adenosine monophosphate (cAMP) modulates synaptic plasticity and memory and manipulation of the cAMP/protein kinase A/cAMP responsive element binding protein pathway significantly affects cognitive functions. Notably, cAMP can increase the expression of the amyloid precursor protein (APP), whose proteolytic processing gives rise to amyloid beta (Abeta) peptides. Despite playing a pathogenic role in Alzheimer's disease, physiological concentrations of Abeta are necessary for the cAMP-mediated regulation of long-term potentiation, supporting the existence of a novel cAMP/APP/Abeta cascade with a crucial role in memory formation. However, the molecular mechanisms by which cAMP stimulates APP expression and Abeta production remain unclear. Here, we investigated whether hnRNP-C and FMRP, two RNA-binding proteins largely involved in the expression of APP, are the cAMP effectors inducing the protein synthesis of APP. Using RNA immunoprecipitation and RNA-silencing approaches, we found that neither hnRNP-C nor FMRP is required for cAMP to stimulate APP and Abeta production. PMID- 25809672 TI - Written threat: Electrophysiological evidence for an attention bias to affective words in social anxiety disorder. AB - Social anxiety disorder (SAD) is associated with heightened sensitivity to threat cues, typically represented by emotional facial expressions. To examine if this bias can be transferred to a general hypersensitivity or whether it is specific to disorder relevant cues, we investigated electrophysiological correlates of emotional word processing (alpha activity and event-related potentials) in 20 healthy participants and 20 participants with SAD. The experimental task was a silent reading of neutral, positive, physically threatening and socially threatening words (the latter were abusive swear words) while responding to a randomly presented dot. Subsequently, all participants were asked to recall as many words as possible during an unexpected recall test. Participants with SAD showed blunted sensory processing followed by a rapid processing of emotional words during early stages (early posterior negativity - EPN). At later stages, all participants showed enhanced processing of negative (physically and socially threatening) compared to neutral and positive words (N400). Moreover, at later processing stages alpha activity was increased specifically for negative words in participants with SAD but not in healthy controls. Recall of emotional words for all subjects was best for socially threatening words, followed by negative and positive words irrespective of social anxiety. The present findings indicate that SAD is associated with abnormalities in emotional word processing characterised by early hypervigilance to emotional cues followed by cognitive avoidance at later processing stages. Most importantly, the specificity of these attentional biases seems to change as a function of time with a general emotional bias at early and a more specific bias at later processing stages. PMID- 25809673 TI - Delayed graft function in laparoscopic kidney transplantation: the importance of prolonged cold and warm ischemia-response. PMID- 25809674 TI - Perspective for stroke and brain injury research: mechanisms and potential therapeutic targets. PMID- 25809675 TI - Validation of virtual-reality-based simulations for endoscopic sinus surgery. AB - BACKGROUND: Virtual reality (VR) simulators provide an alternative to real patients for practicing surgical skills but require validation to ensure accuracy. Here, we validate the use of a virtual reality sinus surgery simulator with haptic feedback for training in Otorhinolaryngology - Head & Neck Surgery (OHNS). METHODS: Participants were recruited from final-year medical students, interns, resident medical officers (RMOs), OHNS registrars and consultants. All participants completed an online questionnaire after performing four separate simulation tasks. These were then used to assess face, content and construct validity. anova with post hoc correlation was used for statistical analysis. RESULTS: The following groups were compared: (i) medical students/interns, (ii) RMOs, (iii) registrars and (iv) consultants. Face validity results had a statistically significant (P < 0.05) difference between the consultant group and others, while there was no significant difference between medical student/intern and RMOs. Variability within groups was not significant. Content validity results based on consultant scoring and comments indicated that the simulations need further development in several areas to be effective for registrar-level teaching. However, students, interns and RMOs indicated that the simulations provide a useful tool for learning OHNS-related anatomy and as an introduction to ENT-specific procedures. CONCLUSIONS: The VR simulations have been validated for teaching sinus anatomy and nasendoscopy to medical students, interns and RMOs. However, they require further development before they can be regarded as a valid tool for more advanced surgical training. PMID- 25809676 TI - A classification system for describing anthropogenic influence on nonhuman primate populations. AB - Many nonhuman primates live in proximity to humans, and all studied primate populations are influenced in some ways by human interaction. While the effects of human interference on primate behavior and ecology are an important area of research in contemporary primatology, to date there is no systematic way to report the types or level of anthropogenic influence for a primate study population. In this paper, I introduce a diagnostic classification system that will allow primate field researchers to clearly and consistently report anthropogenic conditions at their study sites. This system provides a way to identify population conditions for four major variables: landscape, human nonhuman primate interface, diet, and predation risk. The incredible diversity of the Order Primates necessitates a descriptive system that is applicable across a wide range of habitat types, social groupings, and ecological roles, so the proposed classification system has been specifically designed to avoid quantitative ranking. Instead, the system is intended to provide a standardized way to report a wealth of population and site information in a simple format. This will allow for meta-analysis of specific conditions across study sites, leading to a greater understanding of the effects of different forms of anthropogenic influence on primate behavior and ecology. PMID- 25809677 TI - Stimulating dissecting instruments during neuromonitoring of RLN in thyroid surgery. AB - OBJECTIVES/HYPOTHESIS: During intraoperative neuromonitoring (IONM) of recurrent laryngeal nerve (RLN) in thyroid surgery, the need for frequent shifting between the dissecting instruments and stimulating probe is troublesome and time consuming. Therefore, use of these two instruments in combination would be a noticeable future direction. This study aimed to investigate the feasibility and safety of using stimulating dissecting instruments (SDIs) that combine the function of surgical dissection and nerve stimulation during IONM. STUDY DESIGN: Prospective outcomes research. METHODS: One hundred consecutive patients with 168 RLNs at risk were enrolled. We developed prototypes of SDIs and applied them to early detect adverse EMG changes during the risky phase of RLN dissection. In the case of substantial EMG change (amplitude decrease > 50%) during dissection, the surgical maneuver was paused and thyroid traction was released immediately. RESULTS: The application of SDIs was feasible in all cases and did not result in any morbidity. Nineteen RLNs were detected with substantial EMG change that was caused by traction stress during dissection with SDIs and that featured progressive gradual EMG recovery after releasing thyroid traction. After thyroid resection, 10 RLNs had a weak point of nerve conduction detected at region of Berry's ligament, but only one nerve with 79% amplitude reduction developed postoperative temporary vocal palsy. CONCLUSION: The application of SDIs is a simple and effective way to monitor the nerve's function instantly during the risky phase of RLN injury in thyroid surgery. It provides surgeons with real-time feedback of EMG response and can be applied as a tool for the early detection of adverse EMG change caused by traction distress. LEVEL OF EVIDENCE: 4. PMID- 25809678 TI - Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial? AB - Childhood wheezing is common particularly in children under the age of 6 years and in this age group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is, however, considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side effects, in particular the reduction of growth velocity, have resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease, and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time consuming and difficult, and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review was to summarize the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze. PMID- 25809679 TI - Nurse practitioner faculty research: Results from the 2012 National Organization of Nurse Practitioner Faculties Survey. AB - PURPOSE: To better understand the research capacity and productivity of nurse practitioner (NP) faculty, a study was conducted to describe the types of research that have been and are being completed by National Organization of Nurse Practitioner Faculties (NONPF) members. DATA SOURCES: A web-based survey was developed with input from members of the NONPF Research Special Interest Group and the NONPF Board. This 23-question survey included demographic, academic degree, NP population focus, and research-related questions. Three e-mails were sent to NONPF members over a 10-week period of time (late December 2012 to early February 2013). CONCLUSIONS: Respondents (N = 344) in the sample were Advanced Practice Registered Nurses with either a Masters, Doctor of Nursing Practice, DNS or PhD as their highest academic degree. Study results demonstrated that current NP faculty research includes a wide breadth of clinical areas studied, types of methodologies used, variety of funding mechanisms, and successful publication records. IMPLICATIONS FOR PRACTICE: Because NP faculty conduct a wide array of research on clinically relevant topics, and demonstrate successful funding and publication track records, they are poised to continue to be leaders in healthcare research. PMID- 25809680 TI - Consuming Beef vs. Soy Protein Has Little Effect on Appetite, Satiety, and Food Intake in Healthy Adults. AB - BACKGROUND: Although protein-rich plant foods have recently been touted as an equivalent to animal products, limited data exist regarding the effects of animal vs. plant proteins on appetite, satiety, and subsequent food intake. OBJECTIVE: The objective was to determine whether a high-protein beef lunch alters the appetitive, hormonal, and neural signals controlling food intake regulation vs. a macronutrient and fiber-matched (MF) or serving size-matched (SS) soy lunch in healthy adults. METHODS: A randomized, double-blind, crossover design study was completed in 21 adults (aged 23 +/- 1 y; body mass index: 23.8 +/- 0.6 kg/m2; mean +/- SEM) to compare 400-kcal MF and SS lunches varying in protein quality. The MF lunches contained 24-g beef protein or 24-g soy protein, whereas the SS lunches contained 1 serving of beef (24-g protein/1-g fiber) or soy (14-g protein/5-g fiber). Pre- and postlunch appetite questionnaires and blood sampling were completed over an 8-h period until dinner was voluntarily requested. In addition, pre- and postlunch functional MRI brain scans were completed to assess neural activation in response to food stimuli. RESULTS: On average, dinner was requested at ~250 +/- 20 min postlunch with no differences between beef vs. soy within the MF and SS conditions. Furthermore, no differences in hunger, fullness, peptide YY, or glucagon-like peptide-1 responses were observed after the beef vs. soy lunches within the MF and SS conditions. The SS beef meal led to reductions in anterior cingulate activation (-22 +/- 6%) vs. soy (+7 +/- 9%; P < 0.01) and greater reductions in insular activation (-30 +/- 6%) vs. SS soy (-7 +/- 10%; P < 0.01). The participants consumed ~945 +/- 78 kcal after the MF meals and 910 +/- 74 kcal after the SS meals with no differences between beef vs. soy. CONCLUSIONS: When comparing 2 high-quality protein sources, such as beef and soy, the type of protein consumed within a mixed meal elicited very little effect on appetite, satiety, and food intake in healthy adults. PMID- 25809682 TI - Vitamin D Status Is Positively Associated with Calcium Absorption among Postmenopausal Thai Women with Low Calcium Intakes. AB - BACKGROUND: Few data exist on the ability of postmenopausal women to absorb calcium from diets habitually low in calcium. OBJECTIVE: The objective of this study was to evaluate fractional calcium absorption from a green leafy vegetable vs. milk in relation to vitamin D status. METHODS: We measured fractional calcium absorption from both a dairy- and plant-based source in 19 postmenopausal Thai women (aged 52-63 y) with low calcium consumption (350 +/- 207 mg/d) in relation to serum parathyroid hormone (PTH) and serum 25-hydroxyvitamin D [25(OH)D]. Fractional calcium absorption was measured using a triple stable calcium isotope method based on isotope recovery in a 28-h urine collection. Two extrinsically labeled test meals were ingested in random order: a green leafy vegetable (cassia) ingested along with 43Ca or a glass of milk containing 44Ca. Women received intravenous 42Ca with the first test meal. RESULTS: In 19 postmenopausal women studied (mean age, 56.9 +/- 3.4 y), ~95% were 25(OH)D sufficient (>=20 MUg/L). Serum 25(OH)D status was positively correlated with fractional absorption from both cassia (P = 0.05, R2 = 0.21) and milk (P = 0.03, R2 = 0.26). Fractional calcium absorption from cassia was significantly lower than that measured from milk (42.6% +/- 12.3% vs. 47.8% +/- 12.8%, P = 0.03), but true calcium absorption did not significantly differ (120 +/- 35 mg/d vs. 135 +/- 36 mg/d). Serum PTH was significantly inversely associated with serum 25(OH)D (P = 0.006, R2 = 0.37) even though PTH was not elevated (>65 pg/mL). CONCLUSIONS: These findings suggest that vitamin D status is an important determinant of calcium absorption among Thai women with low calcium intakes, and cassia may be a readily available source of calcium in this population. Furthermore, these data indicate that serum 25(OH)D concentrations may affect PTH elevation in postmenopausal women with low calcium intakes. PMID- 25809681 TI - Chronic Intake of Sucrose Accelerates Sarcopenia in Older Male Rats through Alterations in Insulin Sensitivity and Muscle Protein Synthesis. AB - BACKGROUND: Today, high chronic intake of added sugars is frequent, which leads to inflammation, oxidative stress, and insulin resistance. These 3 factors could reduce meal-induced stimulation of muscle protein synthesis and thus aggravate the age-related loss of muscle mass (sarcopenia). OBJECTIVES: Our aims were to determine if added sugars could accelerate sarcopenia and to assess the capacity of antioxidants and anti-inflammatory agents to prevent this. METHODS: For 5 mo, 16-mo-old male rats were starch fed (13% sucrose and 49% wheat starch diet) or sucrose fed (62% sucrose and 0% wheat starch diet) with or without rutin (5 g/kg diet), vitamin E (4 times), vitamin A (2 times), vitamin D (5 times), selenium (10 times), and zinc (+44%) (R) supplementation. We measured the evolution of body composition and inflammation, plasma insulin-like growth factor 1 (IGF-I) concentration and total antioxidant status, insulin sensitivity (oral-glucose tolerance test), muscle weight, superoxide dismutase activity, glutathione concentration, and in vivo protein synthesis rates. RESULTS: Sucrose-fed rats lost significantly more lean body mass (-8.1% vs. -5.4%, respectively) and retained more fat mass (+0.2% vs. -33%, respectively) than starch-fed rats. Final muscle mass was 11% higher in starch-fed rats than in sucrose-fed rats. Sucrose had little effect on inflammation, oxidative stress, and plasma IGF-I concentration but reduced the insulin sensitivity index (divided by 2). Meal induced stimulation of muscle protein synthesis was significantly lower in sucrose-fed rats (+7.3%) than in starch-fed rats (+22%). R supplementation slightly but significantly reduced oxidative stress and increased muscle protein concentration (+4%) but did not restore postprandial stimulation of muscle protein synthesis. CONCLUSIONS: High chronic sucrose intake accelerates sarcopenia in older male rats through an alteration of postprandial stimulation of muscle protein synthesis. This effect could be explained by a decrease of insulin sensitivity rather than by changes in plasma IGF-I, inflammation, and/or oxidative stress. PMID- 25809683 TI - Comparisons among Equations Used for Retinol Isotope Dilution in the Assessment of Total Body Stores and Total Liver Reserves. AB - Vitamin A plays an essential role in animal biology and has negative effects associated with both hypo- and hypervitaminosis A. Many notable interventions are being done globally to eliminate vitamin A deficiency, including supplementation, fortification, and biofortification. At the same time, it is important to monitor vitamin A status in nations where preformed vitamin A intake is high because of consumption of animal source foods (e.g., liver, dairy, eggs), fortified foods (e.g., milk, cereals, oil, sugar, margarine), or vitamin supplements (e.g., one-a day multivitamins) to ensure the population does not reach hypervitaminosis A. To accurately assess population status and evaluate interventions aimed at improving vitamin A status, accurate assessment methods are needed. The primary storage site of vitamin A is the liver; however, routinely obtaining liver samples from humans is impractical and unethical. Isotope dilution using deuterium- or (13)C labeled retinol is currently the most sensitive indirect biomarker of vitamin A status across a wide range of liver reserves. The major drawback to its application is the increased technicality in sample analysis and data calculations when compared to less sensitive methodology, such as serum retinol concentrations and dose response tests. Two main equations have emerged for calculating vitamin A body pool size or liver concentrations from isotope dilution data: the "Olson equation" and the "mass balance equation." Different applications of these equations can lead to confusion and lack of consistency if the underlying principles and assumptions used are not clarified. The purpose of this focused review is to describe the evolution of the equations used in retinol stable-isotope work and the assumptions appropriate to different applications of the test. Ultimately, the 2 main equations are shown to be fundamentally the same and differ only in assumptions made for each specific research application. PMID- 25809685 TI - Common Variants and Haplotypes in the TF, TNF-alpha, and TMPRSS6 Genes Are Associated with Iron Status in a Female Black South African Population. AB - BACKGROUND: It is unknown whether single nucleotide polymorphisms (SNPs), associated with iron status in European and Asian populations, have the same relation within the African population. OBJECTIVES: We investigated associations of reported SNPs with iron markers in a South African cohort. METHODS: Hemoglobin concentration, serum ferritin (SF) and soluble transferrin receptor (sTfR) concentrations, and body iron (BI) stores were measured in women (n = 686; range, 32-86 y) who were part of the Prospective Urban and Rural Epidemiology study. Thirty-two SNPs in 12 genes were selected based on existing genome-wide association study data. RESULTS: In the transferrin (TF) gene, SF and BI were significantly lower in the heterozygote genotype (AG) of reference SNP (rs) 1799852 (P = 0.01 and 0.03, respectively) and sTfR concentrations were significantly higher (P = 0.004) than the homozygote minor allele genotype (AA), whereas transferrin receptor and BI concentrations were significantly lower in the heterozygote genotype (AG) of rs3811647 (both P = 0.03) than the homozygote wild-type (AA) and minor allele groups (GG). The chromosome 6 allele combination (AAA) consisting of rs1799964 and rs1800629 both in tumor necrosis factor-alpha (TNF-alpha) and rs2071592 in nuclear factor kappaB inhibitor-like protein 1 (NFKBIL1) was associated with higher odds for low SF concentrations (SF < 15 MUg/L; OR: 1.86; 95% CI: 1.23, 2.79) than the allele combinations AGA, GGT, and AGT. The chromosome 22 allele combination (GG) consisting of rs228918 and rs228921 in the transmembrane protease serine 6 (TMPRSS6) gene was associated with lower odds for increased sTfR concentrations (sTfR > 8.3mg/L; OR: 0.79; 95% CI: 0.63, 0.98) than the allele combination AA. CONCLUSIONS: Various SNPs and allele combinations in the TF, TNF-alpha, and TMPRSS6 genes are associated with iron status in black South African women; however, these association patterns are different compared with European ancestry populations. This stresses the need for population-specific genomic data. PMID- 25809684 TI - Fathers that are born small program alterations in the next-generation preimplantation rat embryos. AB - BACKGROUND: Low birth weight is associated with increased risk of adult cardiovascular and metabolic disease development, with recent studies highlighting transmission to subsequent generations via both maternal and paternal lines. However, the timing of parent-specific programming of disease risk to the next generation remains to be characterized. OBJECTIVE: The aim of this study was to examine how paternal low birth weight affects the cellular and molecular physiology of the next-generation [second-generation (F2)] blastocysts, before uterine implantation. METHODS: Uteroplacental insufficiency was surgically induced in Wistar Kyoto pregnant rats in late gestation, giving rise to first generation restricted (born small) and sham-operated control (normal birth weight) male offspring, respectively. First-generation restricted and control male rats were naturally mated with normal females. RESULTS: Resultant F2 blastocysts derived from restricted males displayed reduced expression of growth regulatory genes of the mammalian target of rapamycin pathway compared with F2 control blastocysts (9-74%; P < 0.05). No differences were found in F2 restricted blastocyst structural characteristics, cell number, or carbohydrate utilization at the time of blastocyst retrieval or after 24 h of in vitro culture. However, histidine, methionine, pyruvate, serine, and tryosine consumption and aspartate and leucine production were greater in F2 restricted outgrowth than in controls (P < 0.05). CONCLUSIONS: The findings from this study clearly indicate that male rat offspring born small, arising from uteroplacental insufficiency, have physiologic alterations that manifest as modifications in gene expression levels and nutrient metabolism of F2 blastocysts, even in the absence of overt cellular growth differences. These data demonstrate that growth restriction and associated disease risk have the capacity to be transmitted to the next generation of offspring via the male germ line and is manifest as early as the blastocyst stage of development. PMID- 25809686 TI - Metal Bridging for Directing and Accelerating Electron Transfer as Exemplified by Harnessing the Reactivity of AIBN. AB - A new strategy for tuning the electron transfer between radicals and enolates has been developed. This method elicits the innate reactivity of AIBN with a copper catalyst and enables a cascade reaction with cinnamic acids. Electron paramagnetic resonance studies and control experiments indicate that the redox active copper species not only activates the radical by coordination, but also serves as a bridge to bring the radical and nucleophile within close proximity to facilitate electron transfer. By exploiting possible combinations of redox-active metals and radical entities with suitable coordinating functional groups, this strategy should contribute to the development of a broad range of radical-based reactions. PMID- 25809687 TI - Linking macrotrends and microrates: Re-evaluating microevolutionary support for Cope's rule. AB - Cope's rule, wherein a lineage increases in body size through time, was originally motivated by macroevolutionary patterns observed in the fossil record. More recently, some authors have argued that evidence exists for generally positive selection on individual body size in contemporary populations, providing a microevolutionary mechanism for Cope's rule. If larger body size confers individual fitness advantages as the selection estimates suggest, thereby explaining Cope's rule, then body size should increase over microevolutionary time scales. We test this corollary by assembling a large database of studies reporting changes in phenotypic body size through time in contemporary populations, as well as studies reporting average breeding values for body size through time. Trends in body size were quite variable with an absence of any general trend, and many populations trended toward smaller body sizes. Although selection estimates can be interpreted to support Cope's rule, our results suggest that actual rates of phenotypic change for body size cannot. We discuss potential reasons for this discrepancy and its implications for the understanding of Cope's rule. PMID- 25809688 TI - Night shift work, chronotype, and prostate cancer risk: Incentives for additional analyses and prevention. PMID- 25809689 TI - Tissue Engineering the Cornea: The Evolution of RAFT. AB - Corneal blindness affects over 10 million people worldwide and current treatment strategies often involve replacement of the defective layer with healthy tissue. Due to a worldwide donor cornea shortage and the absence of suitable biological scaffolds, recent research has focused on the development of tissue engineering techniques to create alternative therapies. This review will detail how we have refined the simple engineering technique of plastic compression of collagen to a process we now call Real Architecture for 3D Tissues (RAFT). The RAFT production process has been standardised, and steps have been taken to consider Good Manufacturing Practice compliance. The evolution of this process has allowed us to create biomimetic epithelial and endothelial tissue equivalents suitable for transplantation and ideal for studying cell-cell interactions in vitro. PMID- 25809691 TI - Bayesian regression discontinuity designs: incorporating clinical knowledge in the causal analysis of primary care data. AB - The regression discontinuity (RD) design is a quasi-experimental design that estimates the causal effects of a treatment by exploiting naturally occurring treatment rules. It can be applied in any context where a particular treatment or intervention is administered according to a pre-specified rule linked to a continuous variable. Such thresholds are common in primary care drug prescription where the RD design can be used to estimate the causal effect of medication in the general population. Such results can then be contrasted to those obtained from randomised controlled trials (RCTs) and inform prescription policy and guidelines based on a more realistic and less expensive context. In this paper, we focus on statins, a class of cholesterol-lowering drugs, however, the methodology can be applied to many other drugs provided these are prescribed in accordance to pre-determined guidelines. Current guidelines in the UK state that statins should be prescribed to patients with 10-year cardiovascular disease risk scores in excess of 20%. If we consider patients whose risk scores are close to the 20% risk score threshold, we find that there is an element of random variation in both the risk score itself and its measurement. We can therefore consider the threshold as a randomising device that assigns statin prescription to individuals just above the threshold and withholds it from those just below. Thus, we are effectively replicating the conditions of an RCT in the area around the threshold, removing or at least mitigating confounding. We frame the RD design in the language of conditional independence, which clarifies the assumptions necessary to apply an RD design to data, and which makes the links with instrumental variables clear. We also have context-specific knowledge about the expected sizes of the effects of statin prescription and are thus able to incorporate this into Bayesian models by formulating informative priors on our causal parameters. PMID- 25809690 TI - Genome-wide identification of auxin response factor (ARF) genes and its tissue specific prominent expression in Gossypium raimondii. AB - Auxin response factors (ARFs) are recently discovered transcription factors that bind with auxin response elements (AuxRE, TGTCTC) to regulate the expression of early auxin-responsive genes. To our knowledge, the ARF gene family has never been characterized in cotton, the most important fiber crop in the world. In this study, a total of 35 ARF genes, named as GrARFs, were identified in a diploid cotton species Gossypium raimondii. The 35 ARF genes were located in 12 of the 13 cotton chromosomes; the intron/exon distribution of the GrARF genes was similar among sister pairs, whereas the divergence of some GrARF genes suggests the possibility of functional diversification. Our results show that the middle domains of nine GrARF proteins rich in glutamine (Q) are activators, while 26 other GrARF proteins rich in proline (P), serine (S), and threonine (T) are repressors. Our results also show that the expression of GrARF genes is diverse in different tissues. The expression of GrARF1 was significantly higher in leaves, whereas GrARF2a had higher expression level in shoots, which implicates different roles in the tested tissues. The GrARF11 has a higher expression level in buds than that in leaves, while GrARF19.2 shows contrasting expression patterns, having higher expression in leaves than that in buds. This suggests that they play different roles in leaves and buds. During long-term evolution of G. raimondii, some ARF genes were lost and some arose. The identification and characterization of the ARF genes in G. raimondii elucidate its important role in cotton that ARF genes regulate the development of flower buds, sepals, shoots, and leaves. PMID- 25809692 TI - Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice. AB - In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug induced liver injury (DILI). In addition, a relatively small number of human leukocyte antigen (HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI. PMID- 25809696 TI - The last and next decades of the Asian core program on cutting-edge organic chemistry in Asia. PMID- 25809697 TI - Prognostic factors of oral mucosal melanoma: histopathological analysis in a retrospective cohort of 82 cases. AB - AIMS: To investigate the histopathological predictors of overall survival and metastatic failure of oral mucosal melanoma (OMM), of which the histopathological classification and microstaging has not been established. METHODS AND RESULTS: The pathological data, including cell type (CT), level of invasion, ulceration, mitotic rate, pigmentation, necrosis, tumour-infiltrating lymphocyte (TIL) and vascular invasion, of 82 OMM patients from April 2002 to April 2012 were reviewed and analysed retrospectively. CT, ulceration, mitotic rate, pigmentation, necrosis and vascular invasion were found to be of significance in predicting the overall survival of OMM patients. CT was an independent prognostic factor of overall survival in multivariate analysis. In patients with localized OMM, CT, level of invasion, mitotic rate, pigmentation and necrosis were associated with overall survival but none of them proved to be an independent prognostic factor. CT, mitotic rate and TIL were associated with the risk of distant metastasis. TIL was revealed to be an independent factor of distant metastases risk in multivariate analysis. CONCLUSIONS: CT was an independent prognostic factor of overall survival. Patients with epithelioid cell type OMM had a poor prognosis. Patients without TIL had a higher risk of distant metastasis. PMID- 25809693 TI - Antiviral gene expression in psoriasis. AB - BACKGROUND: Psoriasis patients have relatively infrequent cutaneous viral infections compared to atopic dermatitis patients. Increased expression of four antiviral proteins (MX1, BST2, ISG15 and OAS2) has been reported in psoriatic skin and genetic studies of psoriasis have identified susceptibility genes in antiviral pathways. OBJECTIVE: To determine if psoriasis is associated with pervasive expression of antiviral genes in skin and blood. METHODS: We performed RNA sequencing on skin samples of 18 subjects with chronic plaque psoriasis and 16 healthy controls. We examined the expression of a predefined set of 42 antiviral genes, each of which has been shown in previous studies to inhibit viral replication. In parallel, we examined antiviral gene expression in atopic dermatitis, non-lesional psoriatic skin and psoriatic blood. We performed HIV-1 infectivity assays in CD4+ peripheral blood T cells from psoriatic and healthy individuals. RESULTS: We observed significant overexpression of 16 antiviral genes in lesional psoriatic skin, with a greater than two-fold increase in ISG15, RSAD2, IRF7, MX2 and TRIM22 (P < 1E-07). None of these genes was overexpressed in atopic dermatitis skin (P < 0.0001) or non-lesional psoriatic skin. In contrast to the skin compartment, no differences in antiviral gene expression were detected in the peripheral blood of psoriasis cases compared to healthy controls. CD4+ T cells from both psoriatic and healthy patients supported HIV-1 infection at a similar rate. CONCLUSION: Our findings highlight psoriasis as an inflammatory disease with cutaneous but not systemic immune activation against viral pathogens. PMID- 25809699 TI - Hormonal and reproductive factors and risk of esophageal cancer in women: a meta analysis. AB - Currently published studies on the relationship between hormonal and reproductive factors and esophageal cancer (EC) risk in women have yielded contradictory findings. For a better understanding of this relationship, we first performed this meta-analysis by pooling all available publications. Sixteen independent studies were retrieved after a comprehensive search in PubMed and Embase databases. The pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were calculated. The pooled RRs implicated that hormone replacement therapy was negatively associated with the risk of EC (RR = 0.72, 95% CI 0.60-0.86, P < 0.001) and esophageal squamous cell carcinoma (RR = 0.68, 95% CI 0.48-0.97, P = 0.031). Menopausal women were at an increased risk of EC (RR = 1.47, 95% CI 1.07 2.03, P = 0.018), particularly esophageal squamous cell carcinoma (RR = 1.66, 95% CI 1.12-2.48, P = 0.012). Additionally, decreased risk of EC (RR = 0.79, 95% CI 0.68-0.92, P = 0.003) and esophageal adenocarcinoma (RR = 0.66, 95% CI 0.53-0.82, P < 0.001) was demonstrated among women with breast-feeding history. Moreover, such associations were more significant among Caucasians, but not Asians. Our study suggests that menopause is an independent risk factor for EC, while hormone replacement therapy and breast-feeding history play a protective role against EC, particularly among Caucasians. All results are consistent with the hypothesis that effects of estrogen may lower the risk of EC in women. PMID- 25809700 TI - Particle uptake efficiency is significantly affected by type of capping agent and cell line. AB - Surface-functionalized silver nanoparticles (AgNPs) are the most deployed engineered nanomaterials in consumer products because of their optical, antibacterial and electrical properties. Almost all engineered nanoparticles are coated with application-specific capping agents (i.e. organic/inorganic ligands on particle surface) to enhance their stability in suspension or increase their biocompatibility for biomedicine. The aim of this study was to investigate the contribution of the selected capping agents to their observed health impacts using realistic dose ranges. AgNPs capped with citrate, polyvinylpyrrolidone (PVP) and tannic acid were studied with human bronchoalveolar carcinoma (A549) and human colon adenocarcinoma (Caco-2) cell lines and compared against exposures to Ag ions. Cellular uptake and cytotoxicity were evaluated up to 24 h. Tannic acid capped AgNPs induced higher cellular uptake and rate in both cell lines. Citrate-capped and PVP-capped AgNPs behaved similarly over 24 h. All three of the capped AgNPs penetrated more into the A549 cells than Caco-2 cells. In contrast, the uptake rate of Ag ions in Caco-2 cells (0.11 +/- 0.0001 ug h(-1) ) was higher than A549 cells (0.025 +/- 0.00004 ug h(-1) ). The exposure concentration of 3 mg l(-1) is below the EC50 value for all of the AgNPs; therefore, little cytotoxicity was observed in any experiment conducted herein. Exposure of Ag ions, however, interrupted cell membrane integrity and cell proliferation (up to 70% lysed after 24 h). These findings indicate cellular uptake is dependent on capping agent, and when controlled to realistic exposure concentrations, cellular function is not significantly affected by AgNP exposure. PMID- 25809698 TI - Erectile dysfunction and phosphodiesterase type 5 inhibitor use: associations with sexual activities, function and satisfaction in a population sample of older men. AB - The objective of this study was to examine the association between sexual activities, problems and satisfaction, and ED and PDE5 inhibitor (PDE5i) use. A nationally representative sample of men (n=2612) aged 51-87 years from the English Longitudinal Study of Ageing completed an in-depth Sexual Relationships and Activities Questionnaire. Associations between ED and/or PDE5i use and sexual outcomes were explored using logistic regression models adjusted for age, health and lifestyle factors. PDE5i use in the preceding 3 months was reported by a total of 191 (7%) men, whereas 542 (21%) reported ED but no PDE5i use (untreated ED). Compared with men without ED, PDE5i users were more likely to be sexually active and report more frequent sexual intercourse. Men with untreated ED reported the lowest frequency of sexual activities. Compared with men without ED, both PDE5i users and those with untreated ED were more likely to report being concerned about their level of sexual desire, frequency of sexual activities, erectile function, waking erections and orgasmic experience. PDE5i users were also more concerned about and dissatisfied with their overall sex life than men without ED. This population-based study shows that while PDE5i use is associated with improved sexual functioning, this is not equally reflected in decreased levels of concern and dissatisfaction with their overall sexual health. Clinicians should be aware of this disparity between functional gains and continuing sexual concerns and dissatisfaction, and, where appropriate, offer psychosexual counselling as an adjunct to PDE5i medication. PMID- 25809701 TI - Total anomalous pulmonary venous connection with ccTGA and VSD: Can pulmonary artery banding avert pulmonary venous obstruction? AB - We describe a rare case of infracardiac total anomalous pulmonary venous connection (TAPVC), associated with congenitally corrected transposition of the great arteries (ccTGA) and ventricular septal defect, in which the patient had undergone pulmonary artery banding (PAB) at 16 days of age. She began to have episodes of severe cyanosis while crying, 2 weeks after PAB. Cardiac catheterization at 34 days of age showed severe pulmonary hypertension and a transhepatic pressure gradient of 7 mmHg. The infant underwent TAPVC repair and conventional repair for ccTGA at 35 days of age. Although PAB might have the provisional effect of delaying the manifestation of pulmonary venous obstruction (PVO), it is unable to prevent the development of PVO due to the high resistance of the hepatic sinusoids. Signs of PVO should be closely monitored so that TAPVC can be repaired in a timely fashion. PMID- 25809702 TI - Passive motion reduces vestibular balance and perceptual responses. AB - With the hypothesis that vestibular sensitivity is regulated to deal with a range of environmental motion conditions, we explored the effects of passive whole-body motion on vestibular perceptual and balance responses. In 10 subjects, vestibular responses were measured before and after a period of imposed passive motion. Vestibulospinal balance reflexes during standing evoked by galvanic vestibular stimulation (GVS) were measured as shear reaction forces. Perceptual tests measured thresholds for detecting angular motion, perceptions of suprathreshold rotation and perceptions of GVS-evoked illusory rotation. The imposed conditioning motion was 10 min of stochastic yaw rotation (0.5-2.5 Hz <= 300 deg s(-2) ) with subjects seated. This conditioning markedly reduced reflexive and perceptual responses. The medium latency galvanic reflex (300-350 ms) was halved in amplitude (48%; P = 0.011) but the short latency response was unaffected. Thresholds for detecting imposed rotation more than doubled (248%; P < 0.001) and remained elevated after 30 min. Over-estimation of whole-body rotation (30-180 deg every 5 s) before conditioning was significantly reduced (41.1 to 21.5%; P = 0.033). Conditioning reduced illusory vestibular sensations of rotation evoked by GVS (mean 113 deg for 10 s at 1 mA) by 44% (P < 0.01) and the effect persisted for at least 1 h (24% reduction; P < 0.05). We conclude that a system of vestibular sensory autoregulation exists and that this probably involves central and peripheral mechanisms, possibly through vestibular efferent regulation. We propose that failure of these regulatory mechanisms at different levels could lead to disorders of movement perception and balance control during standing. PMID- 25809703 TI - Diagnostic value of [18F] FDG-PET and PET/CT in urinary bladder cancer: a meta analysis. AB - An early diagnosis of urinary bladder cancer is crucial for early treatment and management. The objective of this systematic review was to assess the overall diagnostic accuracy of 18 F FDG-PET and PET/CT in urinary bladder cancer with meta-analysis. The PubMed and CNKI databases were searched for the eligible studies published up to June 01, 2014. The sensitivity, specificity, and other measures of accuracy of 18 F FDG-PET and PET/CT in the diagnosis of urinary bladder cancer were pooled along with 95 % confidence intervals (CI). Summary receiver operating characteristic (ROC) curves were used to summarize overall test performance. Ten studies met our inclusion criteria. The summary estimates for 18 F FDG-PET and PET/CT in the diagnosis of urinary bladder cancer in meta analysis were as follows: a pooled sensitivity, 0.82 (95 % confidence interval [CI], 0.75 to 0.88); a pooled specificity, 0.92 (95 % CI, 0.87 to 0.95); positive likelihood ratio, 6.80 (95 % CI, 4.31 to 10.74); negative likelihood ratio, 0.27 (95 % CI, 0.19 to 0.36); and diagnostic odds ratio, 25.18 (95 % CI, 17.58 to 70.4). The results indicate that 18 F FDG-PET and PET/CT are relatively high sensitive and specific for the diagnosis of urinary bladder cancer. PMID- 25809705 TI - Oncocers: ceRNA-mediated cross-talk by sponging miRNAs in oncogenic pathways. AB - Competing endogenous RNAs (ceRNAs) are RNA transcripts which can communicate with each other by decreasing targeting concentration of micro-RNA (miRNA) with the derepression of other messenger RNAs (mRNAs) having the common miRNA response elements (MREs). Oncocers are ceRNAs taking crucial roles in oncogenic pathways processed in many types of cancer, and this study analyzes oncocer-mediated cross talk by sponging microRNAs (miRNAs) in these pathways. While doing this, breast, liver, colon, prostate, gastric, lung, endometrium, thyroid and epithelial cancers and melanoma, rhabdomyosarcoma, glioblastoma, acute promyelocytic leukemia, retinoblastoma, and neuroblastoma were analyzed with respect to ceRNA based carcinogenesis. This study defines, firstly, oncocers in the literature and contains all oncocer-related findings found up to now. Therefore, it will help to increase our comprehension about oncocer-mediated mechanisms. Via this study, a novel perspective would be produced to make clear cancer mechanisms and suggest novel approaches to regulate ceRNA networks via miRNA competition for cancer therapeutics. Graphical Abstract Multiple RNA transcripts have common MREs for the similar miRNA in their 3'-untranslated regions (3'-UTRs). Upregulation of ceRNAs rises the abundance of specific MREs and shifts the miRNA pool distribution, as a result, leading to the increased expression of target mRNA. The depot of genomic mutations and epigenetic alterations changing gene function and expression causes cancers. Herewith, genome-based somatic base-pair mutations, DNA copy number alterations, chromosomal translocation, also transcript fusions, alternative splicing are usually seen in cancer situations. Consequently, such cases causing changed UTR expression in transcripts influence the levels of MRE or present new MREs into the cells. Alterations in MREs of ceRNAs affect the capability of a specific mRNA transcript to attach or titrate miRNAs. As a result, the disturbed ceRNA network can lead to diseases and cancers. As a new term in RNA world, oncocers-the name for ceRNAs taking crucial roles in oncogenic pathways-are processed in many types of cancer, and oncocer mediated cross-talk are analyzed by sponging miRNAs in these pathways. PMID- 25809704 TI - A study on oncogenic role of leptin and leptin receptor in oral squamous cell. AB - Leptin been mainly produced by adipose tissue and cancer cells is the most studied adipokine, amongst the several cytokines. Leptin is an antiapoptotic molecule and inducer of cancer stem cells as well as activates cell proliferation. Its oncogenic, mitogenic, proinflammatory and proangiogenic actions lead to its vital roles in tumourigenesis. Two common functional DNA polymorphisms in the genes of leptin G2548A (LEP) and leptin receptor A668G (LEPR) affect the amount of circulating cytokine-type hormone leptin with risk for development of oral squamous cell carcinoma (OSCC). The present study investigated whether these LEP and LEPR gene polymorphisms are affecting risk for OSCC by comparing the genotypes of patients with controls. A total of 306 OSCC and 228 controls participated in this study. We have determined the frequency of LEP (G2548A) and LEPR (A668G) gene polymorphisms in OSCC cases and controls by polymerase chain reaction and restriction fragment length polymorphism (PCR RFLP). The incidence of leptin gene G2548A homozygous mutant AA polymorphism was significantly increased in the OSCC patients (p = 0.002, odds ratio (OR) = 2.4, 95 % confidence interval (CI) = 1.37-4.22) when compared with controls, and leptin receptor A668G homozygous mutant GG polymorphism was significantly high in the OSCC patients as compared to controls (p = 0.000, OR = 3.8, 95 % CI = 1.98 7.62). The polymorphism of homozygous mutant allele A of leptin gene and G allele of leptin receptor may be associated with increased risk for OSCC. The observations showed regular increase of supporting role of leptin in OSCC. The present study showed an association of AA genotype and A allele of LEP G2548A as well as GG genotype and G allele of LEPR A668G polymorphisms with increased risk for OSCC in north Indian patients. Moreover, the combination of both the polymorphisms may be involved in susceptibility and progression of OSCC. PMID- 25809706 TI - The significant association of CCND1 genotypes with colorectal cancer in Taiwan. AB - Colorectal cancer, one million cases of diagnosis worldwide annually, is one of the most common malignant tumors and 20 % incidence caused by low penetrance susceptibility genes. Cyclin D1 (CCND1) regulating cell cycle transition may determine the susceptible individuals to genomic instability and carcinogenesis. The study aimed at examining the contribution of CCND1 genotypes to colorectal cancer risk in Taiwan. The genotypes of CCND1 A870G (rs9344) and G1722C (rs678653) were determined among 362 colorectal cancer patients and 362 age- and gender-matched cancer-free controls. Significant differences were observed between colorectal cancer and control groups in the distributions of genotypic (P = 9.71 * 10(-4)) and allelic (P = 0.0017) frequencies at CCND1 A870G. Additionally, individuals carried AG or GG genotype had 0.56- or 0.51-fold higher of odds ratios for developing colorectal cancer than the AA genotype (95 % confidence intervals = 0.40-0.78 and 0.32-0.81, respectively). Furthermore, G allele of CCND1 A870G performed a protective effects for nonsmokers and nonalcohol drinkers (P = 0.0012 and 0.0007, respectively) on colorectal cancer risk. These findings support the concept that the cell cycle regulation may play a role in colorectal cancer initiation and development and CCND1 A870G genotyping maybe a feasible technology for colorectal cancer early detection. PMID- 25809708 TI - Bengt Langstrom--a pioneer in carbon-11 radiochemistry. PMID- 25809709 TI - Bengt Langstrom--personal recollections of the gentle giant of short-lived radiotracers. PMID- 25809707 TI - Functional elucidation of miR-494 in the tumorigenesis of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma has very high incidence and high mortality worldwide. MiRNA is related to the tumorigenesis and metastasis of a variety of tumors. In the present study, we verify that the expression of miR-494 in NPC tissues and NPC-derived cells was down-regulated, respectively. The proliferation, colony formation, migration, and invasion of NPC-derived cells were suppressed, while the cell apoptosis was promoted, when miR-494 was over-expressed in these cells. GALNT7 and CDK16 were confirmed to be the direct targets of miR-494. These results suggested that miR-494 play an inhibitory role in the tumorigenesis of NPC. PMID- 25809710 TI - A three-step radiosynthesis of 6-[(18) F]fluoro-L-meta-tyrosine starting with [(18) F]fluoride. AB - The radiosynthesis of 6-[(18) F]fluoro-L-m-tyrosine has generally been performed by electrophilic radiofluorination, which exhibits several drawbacks. In the present work, a three-step radiochemical synthesis is described starting from [(18) F]fluoride. The synthetic sequence, including isotopic exchange, Baeyer Villiger oxidation, and hydrolysis, were examined comparing four fluorobenzophenone derivatives as labeling precursors. Of those, (2S,5S)-tert butyl 5-(5-acetyl-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1 carboxylate (1a) and (2S,5S)-tert-butyl 2-tert-butyl-5-(2-fluoro-5-(2,2,2 trifluoroacetyl)benzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1d) proved to be the most suitable ones. 6-[(18) F]Fluoro-L-m-tyrosine was obtained with overall radiochemical yields of 8-13% and an enantiomeric excess of up to 98%. PMID- 25809711 TI - No-carrier-added labeling of the neuroprotective Ebselen with selenium-73 and selenium-75. AB - Selenium-73 is a positron emitting non-standard radionuclide, which is suitable for positron emission tomography. A copper-catalyzed reaction allowed no-carrier added labeling of the anti-inflammatory seleno-organic compound Ebselen with (73) Se and (75) Se under addition of sulfur carrier in a one-step reaction. The new authentically labeled radioselenium molecule is thus available for preclinical evaluation and positron emission tomography studies. PMID- 25809713 TI - Integrating between-session interventions (homework) in therapy: the importance of the therapeutic relationship and cognitive case conceptualization. AB - Between-session interventions, or homework, are crucial to a range of psychological therapies, including cognitive behavior therapy (CBT). Therapeutic interventions often involve experiencing emotions and situations, or examining strongly held views about their problems, that clients can find distressing. Hence, the clinician faces a particular challenge in collaborating with the client to carry out these interventions between sessions. In this article, we convey how this process in CBT requires not only a consideration of the theoretically meaningful determinants of adherence behavior but also a sophisticated cognitive case conceptualization. Using case material, we illustrate the interplay between in-session design, planning, and review of between-session interventions and the conceptualization. We also include a distinction between generic elements of the therapeutic relationship and CBT specific elements. The case material also attends to the person of the therapist, and his or her own cognitive and emotional reactions occurring throughout the process of discussing between-session interventions. PMID- 25809715 TI - WITHDRAWN: Interventions for treating chronic pelvic pain in women. PMID- 25809714 TI - The impact of dental appearance and anxiety on self-esteem in adult orthodontic patients. AB - OBJECTIVES: To analyse the relationship between different dimensions of dental appearance impact and self-esteem in adult patients undergoing orthodontic treatment, with special attention to the possible mediating role of anxiety. SETTING AND SAMPLE POPULATION: A quasi-experimental design was used with a matched control group (without orthodontic treatment). In each group (experimental and control), there were 85 patients. MATERIAL AND METHODS: The impact of dental appearance was measured using the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ). State anxiety was assessed with the State Anxiety Inventory (STAI-S) and self-esteem with Rosenberg's self-esteem scale. RESULTS: In both groups (experimental and control), self-esteem correlates negatively, ranging between 0.26 and 0.43, with all dimensions of dental appearance impact (except for the positive dental self-confidence dimension, where all correlations were positive). Anxiety correlates positively, ranges between 0.35 and 0.44, with social impact, psychological impact and aesthetic concern, although it maintains no significant correlations with dental self confidence. Nevertheless, in patients undergoing orthodontic treatment, anxiety plays a mediating role between dental impact dimensions and self-esteem, whilst for the control group anxiety only plays a mediator role between psychological impact and self-esteem. CONCLUSION: Anxiety plays a fundamental role in the effect of perceived dental impact on self-esteem in adult patients undergoing orthodontic treatment. These results have important practical implications for the design of bio-psycho-social intervention programs that contemplate cognitive affective variables as an essential part of orthodontic treatment in adults. PMID- 25809716 TI - Support needs and survivorship concerns of thyroid cancer patients. AB - BACKGROUND: The number of thyroid cancer (TC) survivors is increasing exponentially worldwide. However, little research details the unmet information, support needs, and survivorship concerns of TC patients. METHODS: Two thousand TC survivors completed an online survey examining the importance of and recollection of receiving care addressing three areas at the time of diagnosis and treatment: medical/physical issues, practical matters, and emotional/psychological concerns. A summed score was generated of (1) the "important" responses for each category, and (2) if they remembered receiving that information/support. Regression analyses explored the relationship between each total score of importance and a patient's demographics, treatment, and recollection of receiving each domain of information/support. RESULTS: Respondents were generally female (88.6%), part white (91.1%), and had eventual total thyroidectomy (95.8%) and radioiodine (80.6%). Mean age at diagnosis was 42.1 years and average time from diagnosis 5.43 years. Less than 50% of patients recalled receiving information regarding long-term and health effects after treatment, or any practical matter or emotional/psychological concern. Multivariate linear modeling with forward stepwise regression revealed that age, sex, and survivorship time were important predictors for recollecting having received information and support for medical/physical issues, practical needs, and emotional/psychological concerns after controlling for treatment and other demographic factors (all 0.001 or <0.001). Similar modeling demonstrated that female sex and feeling that they received care in a given category (medical/physical issues, practical needs, or emotional/psychological concerns) predicted the importance placed on those specific needs when controlled for other variables (all 0.001 or <0.001). CONCLUSION: TC patients place high importance on most types of information and concerns. However, the majority of information and support needs are unmet, which varies based on demographic and treatment factors as well as the importance placed on each specific topic of information. Qualitative research is needed to further focus and refine these unmet needs that should be followed by targeted interventions. PMID- 25809717 TI - Comparison of apically extruded debris after root canal instrumentation using Reciproc((r)) instruments with various kinematics. AB - AIM: To assess the amount of apically extruded debris using Reciproc((r)) instruments with different kinematics (150 degrees counter clockwise [CCW]-30 degrees clockwise [CW], 270 degrees CCW-30 degrees CW, 360 degrees CCW-30 degrees CW and continuous rotation). METHODOLOGY: Forty-eight maxillary central incisors were selected and assigned to four root canal shaping groups as follows (n = 12): 150 degrees CCW-30 degrees CW, 270 degrees CCW-30 degrees CW, 360 degrees CCW-30 degrees CW and continuous rotation. Reciproc R25 and R50((r)) instruments were used in all groups. Apically extruded debris was collected and dried in preweighed Eppendorf tubes. The weight of extruded debris was assessed with an electronic balance. The data were analysed with one way analysis of variance and LSD post hoc tests (P = 0.05). RESULTS: The 150 degrees CCW-30 degrees CW and 270 degrees CCW-30 degrees CW reciprocating motions extruded significantly less debris than continuous rotation (P < 0.05). However, no significant differences were found between the 360 degrees CCW and 30 degrees CW reciprocating motion and the continuous rotation (P > 0.05). CONCLUSIONS: All instrument movements were associated with apically extruded debris. However, the 150 degrees CCW-30 degrees CW and 270 degrees CCW-30 degrees CW reciprocating motions were associated with less extrusion than continuous rotation. PMID- 25809719 TI - Antidepressant use in pregnancy: knowledge transfer and translation of research findings. AB - RATIONALE: Knowledge transfer and translation (KT) has become an important component in health care systems worldwide. Antidepressant use in pregnancy has become a controversial subject for a number of reasons, including differing interpretations of study results. METHODS: Selected key articles were indentified and retrieved from the literature. Relevant information was extracted and synthesized into themes, addressing each of the stated objectives. OBJECTIVES: (1) To determine how knowledge regarding the safety/risk of antidepressant use in pregnancy is created; (2) to describe different research models and statistical analyses that have been used, so as to critically evaluate the results; and (3) to identify how this information is currently disseminated. RESULTS: All of the methods used for examining the safety of antidepressants in pregnancy have some deficiencies in study design and analysis, thus reinforcing the need for accurate interpretations when discussing results. In addition, dissemination in both the scientific and lay press has been selective and therefore potentially biased. CONCLUSION: It is critical, starting with the creators of knowledge, through to the recipients that discrepancies are resolved, as lack of clarity may impede the transfer of unambiguous evidence-based information from health care providers to patients, thus impacting decision making. For example, by implementing improved (KT) strategies, a pregnant, depressed woman, will be empowered to make a rational evidence-based decision regarding whether or not she should take an antidepressant during pregnancy. PMID- 25809720 TI - Does adherence to epilepsy quality measures correlate with reduced epilepsy related adverse hospitalizations? A retrospective experience. AB - In 2011, the American Academy of Neurology (AAN) established eight epilepsy quality measures (EQMs) for chronic epilepsy treatment to address deficits in quality of care. This study assesses the relationship between adherence to these EQMs and epilepsy-related adverse hospitalizations (ERAHs). A retrospective chart review of 475 new epilepsy clinic patients with an ICD-9 code 345.1-9 between 2010 and 2012 was conducted. Patient demographics, adherence to AAN guidelines, and annual number of ERAHs were assessed. Fisher's exact test was used to assess the relationship between adherence to guidelines (as well as socioeconomic variables) and the presence of one or more ERAH per year. Of the eight measures, only documentation of seizure frequency, but not seizure type, correlated with ERAH (relative risk [RR] 0.343, 95% confidence interval [CI] 0.176-0.673, p = 0.010). Among patients in the intellectually disabled population (n = 70), only review/request of neuroimaging correlated with ERAH (RR 0.128, 95% CI 0.016 1.009, p = 0.004). ERAHs were more likely in African American patients (RR 2.451, 95% CI 1.377-4.348, p = 0.008), Hispanic/Latino patients (RR 4.016, 95% CI 1.721 9.346, p = 0.016), Medicaid patients (RR 2.217, 95% CI 1.258-3.712, p = 0.009), and uninsured patients (RR 2.667, 95% CI 1.332-5.348, p = 0.013). In this retrospective series, adherence to the eight AAN quality measures did not strongly correlate with annual ERAH. PMID- 25809722 TI - Two novel 5' promoter sequences of the MHC class I-related chain A gene. AB - In this study, we have characterized two novel polymorphism of the 5' promoter sequence of MICA gene, MICA-P13 and MICA-P14, by sequence-based typing and cloning. PMID- 25809721 TI - Effects of Silencing Heme Biosynthesis Enzymes on 5-Aminolevulinic Acid-mediated Protoporphyrin IX Fluorescence and Photodynamic Therapy. AB - Aminolevulinic acid (ALA)-mediated protoporphyrin IX (PpIX) production is being explored for tumor fluorescence imaging and photodynamic therapy (PDT). As a prodrug, ALA is converted in heme biosynthesis pathway to PpIX with fluorescent and photosensitizing properties. To better understand the role of heme biosynthesis enzymes in ALA-mediated PpIX fluorescence and PDT efficacy, we used lentiviral shRNA to silence the expression of porphobilinogen synthase (PBGS), porphobilinogen deaminase (PBGD) and ferrochelatase (FECH) in SkBr3 human breast cancer cells. PBGS and PBGD are the first two cytosolic enzymes involved in PpIX biosynthesis, and FECH is the enzyme responsible for converting PpIX to heme. PpIX fluorescence was examined by flow cytometry and confocal fluorescence microscopy. Cytotoxicity was assessed after ALA-mediated PDT. Silencing PBGS or PBGD significantly reduced ALA-stimulated PpIX fluorescence, whereas silencing FECH elevated basal and ALA-stimulated PpIX fluorescence. However, compared with vector control cells, the ratio of ALA-stimulated fluorescence to basal fluorescence without ALA was significantly reduced in all knockdown cell lines. PBGS or PBGD knockdown cells exhibited significant resistance to ALA-PDT, while increased sensitivity to ALA-PDT was found in FECH knockdown cells. These results demonstrate the importance of PBGS, PBGD and FECH in ALA-mediated PpIX fluorescence and PDT efficacy. PMID- 25809723 TI - Reduced field of view imaging using a static second-order gradient for functional MRI applications. AB - PURPOSE: Imaging using reduced FOV excitation allows higher resolution or signal to-noise ratio (SNR) per scan time but often requires long radiofrequency pulses. The goal of this study was to improve a recent reduced field of view (FOV) method that uses a second-order shim gradient to decrease pulse length and evaluate its use in functional MRI (fMRI) applications. THEORY AND METHODS: The method, which was initially limited to excite thin disc-shaped regions at the isocenter, was extended to excite thicker regions off the isocenter and produced accurate excitation profiles on a grid phantom. Visual stimulation fMRI scans were performed with full and reduced FOV. The resolution of the time series images and functional activation maps were assessed using the full-width half-maxima of the autocorrelation functions (FACFs) of the noise images and the activation map values, respectively. RESULTS: The resolution was higher in the reduced FOV time series images (4.1% +/- 3.7% FACF reduction, P < 0.02) and functional activation maps (3.1% +/- 3.4% FACF reduction, P < 0.01), but the SNR was lower (by 26.5% +/ 16.9%). However, for a few subjects, the targeted region could not be localized to the reduced FOV due to the low Z2 gradient strength. CONCLUSION: The results of this study suggest that the proposed method is feasible, though it would benefit from a stronger gradient coil. PMID- 25809724 TI - Lactones 46. Synthesis, antifeedant and antibacterial activity of gamma-lactones with a p-methoxyphenyl substituent. AB - BACKGROUND: Lactones are well known for their biological activity. Grosheimin and repin are potent deterrents against storage pests. The unsaturated lactones have exhibited a wide spectrum of antibacterial activity. In our study we focused on the synthesis and evaluation of the biological activity of anisaldehyde derivatives containing lactone function. RESULTS: Four new lactones were synthesized in one-step reductive dehalogenation or dehydrohalogenation reactions. These compounds, together with halolactones synthesized earlier, were tested for their antifeedant activity towards Sitophilus granaries, Trogoderma granarium and Tribolium confusum. The results of the tests showed that the highest activity, comparable with that of azadirachtin, towards all tested pests (total coefficient of deterrence 143.3-183.9) was observed for lactone with a vinyl substituent. The antibacterial activity of these compounds was also evaluated. The most potent lactone was active towards gram-positive bacteria strains. CONCLUSIONS: The results of biological tests showed that halogen atom removal significantly increased the antifeedant properties of gamma-lactones with a p-methoxyphenyl substituent. Unsaturated lactones are most promising in the context of their possible industrial application as crop protection agents. Further structural modifications of lactones with aromatic rings are needed to find important structural factors increasing the antibacterial activity. PMID- 25809725 TI - Current resources for evidence-based practice, May/June 2015. PMID- 25809726 TI - Feasibility of pig and human-derived aortic valve interstitial cells seeding on fixative-free decellularized animal pericardium. AB - Glutaraldehyde-fixed pericardium of animal origin is the elective material for the fabrication of bio-prosthetic valves for surgical replacement of insufficient/stenotic cardiac valves. However, the pericardial tissue employed to this aim undergoes severe calcification due to chronic inflammation resulting from a non-complete immunological compatibility of the animal-derived pericardial tissue resulting from failure to remove animal-derived xeno-antigens. In the mid/long-term, this leads to structural deterioration, mechanical failure, and prosthesis leaflets rupture, with consequent need for re-intervention. In the search for novel procedures to maximize biological compatibility of the pericardial tissue into immunocompetent background, we have recently devised a procedure to decellularize the human pericardium as an alternative to fixation with aldehydes. In the present contribution, we used this procedure to derive sheets of decellularized pig pericardium. The decellularized tissue was first tested for the presence of 1,3 alpha-galactose (alphaGal), one of the main xenoantigens involved in prosthetic valve rejection, as well as for mechanical tensile behavior and distensibility, and finally seeded with pig- and human derived aortic valve interstitial cells. We demonstrate that the decellularization procedure removed the alphaGAL antigen, maintained the mechanical characteristics of the native pig pericardium, and ensured an efficient surface colonization of the tissue by animal- and human-derived aortic valve interstitial cells. This establishes, for the first time, the feasibility of fixative-free pericardial tissue seeding with valve competent cells for derivation of tissue engineered heart valve leaflets. PMID- 25809727 TI - Impact of acute geriatric care in elderly patients according to the Screening Tool of Older Persons' Prescriptions/Screening Tool to Alert doctors to Right Treatment criteria in northern France. AB - INTRODUCTION: In France, over 20% of hospitalizations of elderly people are a result of adverse drug events, of which 50% are considered preventable. Tools have been developed to detect inappropriate prescriptions. The Screening Tool of Older Persons' Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) criteria are innovative and adapted to French prescriptions. This is one of the first French prospective studies to evaluate the impact of acute geriatric care on prescriptions at discharge in elderly patients using the STOPP/START criteria. METHOD: The evaluation of prescriptions according to STOPP/START was carried out on admission and at discharge of patients in acute geriatric units at three hospitals in the Nord-Pas de Calais region, France. A total of 202 elderly hospitalized patients were included during the 4.5 months of the study (1.5 months per center). RESULTS: The mean number of drugs was seven on admission and at discharge. Over half of the prescriptions at admission contained at least one potentially inappropriate medication or one potential prescription omission. The prescriptions at discharge contained significantly fewer potentially inappropriate medications than prescriptions on admission (P < 0.001). In contrast, there was no difference between prescriptions at discharge in terms of potential prescription omissions. CONCLUSION: Acute geriatric hospitalization in France improves prescriptions in terms of potentially inappropriate medication, but has no impact on potential prescription omissions. Further studies must be carried out to see if STOPP/START could be used as a tool in French prescription. PMID- 25809731 TI - Phase 1/1B trial of the heat shock protein 90 inhibitor NVP-AUY922 as monotherapy or in combination with bortezomib in patients with relapsed or refractory multiple myeloma. AB - BACKGROUND: NVP-AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP-AUY922 alone and with bortezomib in patients with relapsed or refractory MM. METHODS: Dose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP-AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP-AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP-AUY922. RESULTS: Twenty-four patients received NVP-AUY922 monotherapy at doses of 8 to 70 mg/m(2) . One dose-limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m(2) ); no MTD was reached. The recommended phase 2 dose was 70 mg/m(2) . The most frequent drug-related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (>=45 mg/m(2) ). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP-AUY922 (which was started at 50 mg/m(2) ) plus bortezomib (1.3 mg/m(2) ). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP-AUY922 plus bortezomib was not established. CONCLUSIONS: This study showed disease stabilization with NVP-AUY922 in patients with relapsed or refractory MM. The MTD for NVP-AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP-AUY922 was not tolerated. PMID- 25809732 TI - Neuropsychological and neuroimaging characteristics of amnestic mild cognitive impairment subtypes: a selective overview. AB - Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Amnestic mild cognitive impairment (aMCI) is considered to represent early AD. Various aMCI clinical subtypes have been identified as either single domain (SD) or multidomain (MD). The various subtypes represent heterogeneous syndrome, indicating the different probability of progression to AD. Understanding the heterogeneous concept of aMCI can help to construct potential biomarkers to monitor the progression of aMCI to AD. This review provides an overview of various neuroimaging measures for subtypes of aMCI. Focusing on neuropsychological, structural, and functional neuroimaging findings, we found that aMCI showed differences in clinical progression and the abnormalities in MD aMCI were distributed across temporal, frontal, and parietal cortices, which is similar to AD. This is also compatible with the notion that MD-aMCI is a transition stage between SD-aMCI and AD. Our review provided a framework for the diagnosis of clinical subtypes of aMCI and early detection and intervention of the progression from aMCI to AD. PMID- 25809733 TI - A bioinspired, reusable, paper-based system for high-performance large-scale evaporation. AB - A bioinspired, reusable, paper-based gold-nanoparticle film is fabricated by depositing an as-prepared gold-nanoparticle thin film on airlaid paper. This paper-based system with enhanced surface roughness and low thermal conductivity exhibits increased efficiency of evaporation, scale-up potential, and proven reusability. It is also demonstrated to be potentially useful in seawater desalination. PMID- 25809734 TI - Novel integration strategy coupling codon and fermentation optimization for efficiently enhancing sarcosine oxidase (SOX) production in recombinant Escherichia coli. AB - Sarcosine oxidase (SOX) was an important diagnostic enzyme in the renal function examination. An integrated strategy coupling codon and fermentation optimization was firstly proposed for improving SOX production from recombinant E. coli in 3-L fermentor. The expression suppression (gene phase) and poor balance between SOX expression and cell growth (fermentation phase) in the traditional SOX production were respectively improved by the multiple strategies. Based on the codon bias, the expression suppression was weakened via codon optimization and SOX activity reached 1,521 U/L. The induction toxicity was reduced with the optimal induction condition and SOX production increased to 4,015 U/L. Based on the kinetic analysis of MU x and MU p , a better balance between cell growth and expression was achieved by the two-stage pH-stat control strategy. The SOX activity was further improved to 8,490 U/L and fermentation cycle was also significantly shortened from 44 to 32 h. The substrate inhibition was weakened with a constant feeding fed-batch. With the assistance of integrated strategy, the activity and productivity reached 12,466 U/L and 389.6 U/(L h), respectively, or 3.1-fold and 4.3-fold of the uncontrolled fermentation. The strategy would be also useful in the industrial application of other similar enzymes. PMID- 25809735 TI - Incidence and risk factors of hepatocellular carcinoma in patients with hepatic venous outflow tract obstruction. AB - BACKGROUND: Frequency of hepatocellular carcinoma (HCC) in hepatic venous outflow tract obstruction (HVOTO) is unclear and risk factors in HVOTO associated with HCC are unknown. AIM: To assess the incidence of HCC and to identify risk factors for HCC in primary HVOTO. METHODS: In the consecutive primary HVOTO patients evaluated between 1989 to 2013, the incidence of HCC among HVOTO was assessed in a retrospective cohort study and identification of the risk factors for HCC in HVOTO patients done by a case-control study. RESULTS: Of the 421 HVOTO patients, 8 had HCC at presentation (prevalence 1.9%). Another 8 of the remaining 413 developed HCC during 2076.2 person-years follow-up (mean 5.03 + 4.65 years, range 0.08-20 years). The cumulative incidence of HCC was 3.5% (95% CI 1.28-9.2%) at 10 years. The case-control study included 16 HCC as cases and remaining 405 as controls. Controls were predominantly males (M:F - 230:175), mean age 29 +/- 10.3 years. Cases were predominantly females with an older age of 36.2 +/- 11.4 years (P < 0.01, OR = 1.06, CI 1.0-1.10%). Presence of cirrhosis (P < 0.001), combined inferior vena cava (IVC) and hepatic vein (HV) block (P < 0.03, OR = 5.58, CI 1.43-25.30%) and long-segment IVC block (P < 0.02, OR = 6.50, CI 1.32-32.0%) were significantly higher among cases than controls. CONCLUSIONS: Hepatic venous outflow tract obstruction is a risk factor for HCC. The cumulative incidence of HCC in HVOTO is low and progressively increases over time. Those with liver cirrhosis, combined IVC and HV block and long-segment IVC block are at risk to develop HCC and need active surveillance. PMID- 25809736 TI - Concise Review: Making Stem Cells Retinal: Methods for Deriving Retinal Pigment Epithelium and Implications for Patients With Ocular Disease. AB - Stem cells provide a potentially unlimited source of cells for treating a plethora of human diseases. Regenerative therapies for retinal degenerative diseases are at the forefront of translation to the clinic, with stem cell derived retinal pigment epithelium (RPE)-based treatments for age-related macular degeneration (AMD) already showing promise in human patients. Despite our expanding knowledge of stem cell biology, methods for deriving cells, including RPE have remained inefficient. Thus, there has been a push in recent years to develop more directed approaches to deriving cells for therapy. In this concise review, we summarize recent efforts that have been successful in improving RPE derivation efficiency by directing differentiation from human pluripotent stem cells using developmental cues important for normal RPE specification and maturation in vivo. In addition, potential obstacles for clinical translation are discussed. Finally, we review how derivation of RPE from human induced pluripotent stem cells (hiPSCs) provides in vitro models for studying mechanisms of retinal disease and discovering new avenues for treatment. PMID- 25809738 TI - Post-liver transplant hepatitis C therapy. AB - OPINION STATEMENT: Pharmacologic therapies to treat chronic hepatitis C virus (HCV) have rapidly evolved over the past few years and resulted in short courses of all oral multidrug cocktails of direct-acting antivirals (DAAs) that achieve sustained virologic response (SVR) rates consistently >90 % in low-risk patient populations. Of note, these same cocktails are now being used off-label with unprecedented success in patients post-liver transplantation (LT) revolutionizing how we think about treating HCV in patients who need and have a liver transplant. For patients who are already post-LT, the tolerability of therapy has improved affording most patients the opportunity to be treated and cured. In patients not on cyclosporine, sofosbuvir (SOF) and simeprevir with or without ribavirin (RBV) showed in a pooled analysis an SVR12 rate of 87-90 %. Paritaprevir, ritonavir, ombitasvir, dasabuvir, and ribavirin treatment has also been studied post-LT and demonstrated a 97 % SVR12 rate with 24 weeks of therapy in patients with early stage fibrosis. Ledipasvir + SOF + RBV for 12 or 24 weeks achieved SVR12 rates of >96 % in post-LT patients including those with compensated cirrhosis. We are fortunate to have truly entered a new era of HCV therapy, where non-decompensated post-LT patients are no longer disadvantaged and can enjoy SVR rates similar to non-transplant patients. These well-tolerated medications call into question the ideal time to cure HCV. Specifically, short courses of interferon-free medication may be able to be administered peri-transplant in order to spare the new graft all the potential complications of viral infection. At this time, the best tolerated and most cost-effective approach to this important new strategy is under active investigation. PMID- 25809739 TI - Contralateral cochlear implantation prior to vestibular nerve section for 'drop attacks' in the only hearing ear. AB - BACKGROUND: A dilemma occurs in the treatment of second-sided Meniere's disease in the only hearing ear, particularly in patients with severe symptoms such as 'drop attacks'. This paper describes a patient treated with contralateral cochlear implantation prior to vestibular nerve section of the symptomatic ear. CASE REPORT: A 53-year-old man, with second-sided Meniere's disease and drop attacks in the only serviceable right ear, underwent successful left cochlear implantation 30 years after hearing loss, followed by right vestibular nerve section. The patient achieved control of Meniere's attacks and improved hearing. Although the patient experienced oscillopsia post-operatively, he was satisfied with his improved everyday functioning. CONCLUSION: Patients with severe second sided Meniere's disease in the only hearing ear are a small but difficult treatment group. In those that are suitable for cochlear implantation in the non serviceable ear, it is suggested that this be employed prior to surgical treatment of the Meniere's symptoms, even if the implanted ear has had no auditory stimulation for many years. PMID- 25809737 TI - Influence of physical activity on the association between the FTO variant rs9939609 and adiposity in young adults. AB - OBJECTIVES: To investigate in a population sample of Portuguese young adults the association of the FTO variant rs9939609 with obesity, BMI, and body-fat and interaction with physical activity (PA) on obesity-susceptibility. METHODS: SNP rs9939609 A/T was genotyped in 550 subjects (231 males and 319 females; 18-36 years old; mean age 21 years old) by TaqMan assay. PA was assessed with a validated self-reported questionnaire of IPAQ. RESULTS: We replicated the association of rs9939609-A risk allele with BMI (P = 0.04) and fat-mass (P = 0.031), and with overweight (including obesity) under a recessive model (P = 0.034). Stratified analyses showed (i) a significant association with overweight/obesity in inactive individuals (P = 0.02) but not in a group reporting participation in sports (P = 0.97). Spearman's correlation test suggested that the impact of a successive increase in PA was a decrease in the body-fat percentage (r = -0.16; P = 0.0002), which is accentuated for homozygous AA (r = -0.34; P = 0.002), and an increase in BMI (r = 0.14; P = 0.001), with a statistically significant correlation for homozygous TT (r = 0.22; P = 0.002). CONCLUSIONS: This study reveals interactions between rs9939609 and PA on obesity indices in Portuguese young adults, suggesting a change in the different body components (lean and fat mass) depending on the FTO genotypes. PMID- 25809740 TI - Microenvironment-dependent respiration of T-47D cells cultured in alginate biostructures. AB - OBJECTIVES: The main objective of this paper was to investigate whether the oxygen consumption rate (OCR) of cells entrapped in alginate hydrogels depends on presence of soluble factors present in foetal bovine serum (FBS). MATERIALS AND METHODS: Pericellular oxygen concentrations were measured using a photochemical oxygen sensor inserted into bioconstructs made from different formulations of alginate, containing T-47D cells. Cell count was corrected for viability as determined by cell uptake and exclusion of standard live/dead fluorophores, in sections of freshly prepared biostructures. Based on concentration data, OCR of the embedded cells was calculated according to a simple algorithm. RESULTS: OCR was found to vary significantly between the different formulations investigated. Inclusion of high concentrations of FBS in the biostructure matrices elicited significantly higher OCRs, in guluronate-rich gels similar to those previously found in monolayer culture. Guluronate-rich gels also generally permitted highest OCR. Respiration also had a falling tendency with increasing alginate concentration and elastic modulus. CONCLUSIONS: Presence of FBS in biostructure matrices elicited higher OCR in T-47D cells. Formulation of biostructures must consider differential diffusion of macromolecular substances. PMID- 25809741 TI - International Society of Pediatric Oncology (SIOP): Developmental goals 2014 2016: Communication update. PMID- 25809742 TI - Ultrasound versus magnetic resonance imaging for Morton neuroma: systematic review and meta-analysis. AB - OBJECTIVES: To compare ultrasound (US) and magnetic resonance imaging (MRI) in the diagnosis of Morton's neuroma. METHODS: Studies that assessed the diagnostic accuracy of US and MRI for Morton's neuroma were retrieved from major medical libraries independently by two reviewers up to 1 April 2014. Predefined inclusion and exclusion criteria were adopted. RESULTS: 277 studies were initially found, and the meta-analysis was conducted on 14 studies. US sensitivity was studied in five studies, MRI sensitivity in three studies, and bothin six studies. All studies used surgery as the reference standard. A high sensitivity (SE) of diagnostic testing was observed for both US (SE (95 % CI) = 0.91 (0.83-0.96)) and MRI (SE (95 % CI) = 0.90 (0.82-0.96)) with no significant differences between the two modalities in diagnosis (Q test p = 0.88). For MRI, specificity of test was 1.00 with a pooled estimation of 1.00 (0.73-1.00), while the pooled specificity was 0.854 (95 % CI: 0.41-1.00) for US. No differences were observed between US and MRI in study design (p = 0.76). CONCLUSION: This meta-analysis shows that the SE of US (0.91) is equal to (p = 0.88) that of MRI (0.90) for identification of Morton's neuroma. KEY POINTS: * For Morton's neuroma, US sensitivity is equal to MRI. * US is as accurate as MRI in diagnosing Morton's neuroma. * US may be the most cost-effective imaging method for Morton's neuroma. PMID- 25809743 TI - Quantitative computed tomography assessment of graft-versus-host disease-related bronchiolitis obliterans in children: A pilot feasibility study. AB - OBJECTIVE: To suggest a simple method that can quantify air trapping from chest CT in children with graft-versus-host disease (GVHD)-related bronchiolitis obliterans (BO). METHODS: This institutional review board-approved retrospective study included eight GVHD-related BO patients (age, 6 - 17 years) who underwent both 31 CTs of variable settings and pulmonary function tests (PFT). The attenuation values of lung parenchyma in normal (An) and air trapping (Aa) areas were obtained. Individualized threshold [(An + Aa)/2] and fixed threshold of -950 HU were set for air trapping quantification. Spearman correlation analysis and generalized linear mixed models were used for statistical analysis. RESULTS: The mean value of individualized threshold was -830.2 +/- 48.3 HU. The mean air trapping lung volume percentage with individualized threshold and -950 HU were 45.4 +/- 18.9% and 1.4 +/- 1.9%, respectively. The air trapping lung volume percentage with individualized threshold showed a significant negative correlation with the PFT of FEV1/FVC% in all data (gamma = -0.795, P < .001) and in the correction of repetition (gamma = -0.837, P = .010). CONCLUSIONS: We suggest a simple and individualized threshold attenuation setting method for air trapping quantification insusceptible to CT imaging protocols or respiratory phase control in children with GVHD-related BO. KEY POINTS: * Simple and individualized threshold attenuation setting for air trapping quantification is possible. * Individualized threshold attenuation setting is insusceptible to CT imaging protocols or respiratory phase control. * CT air trapping quantification correlates with PFT of pulmonary obstruction. PMID- 25809744 TI - Perfusion volume correlates, percentage of involution, and clinical efficacy at diverse follow-up survey times after MR-guided focused ultrasound surgery in uterine fibroids: first report in a Mexican mestizo population. AB - OBJECTIVES: To evaluate the clinical efficacy of magnetic resonance-guided focused ultrasound surgery in a Mexican mestizo population. METHODS: This retrospective study included 159 women (mean age 37 +/- 6.4 years, range 22-53 years) from 2008 to 2010. Two hundred sixty-eight symptomatic uterine fibroids were treated using MR-guided focused ultrasound surgery. Parameters included initial perfused volume, final perfused volume, non-perfused volume (NPV), and treated volume ratio (TVR). Follow-up up to 15 months assessed treatment efficacy and symptomatic relief. Non-parametric statistics and the Kaplan-Meier method were performed. RESULTS: T2-weighted hypointense fibroids showed a frequency of 93.6%; isointense and hyperintense fibroids had frequencies of 5.60 and 1.1%. There was a negative correlation between NPV and age (r = -0.083, p = 0.307) and treatment time (r = -0.253, p = 0.001). Median TVR was 96.0% in small fibroids and 76.5% in large fibroids. Involution of 50% and 80% was achieved at months 6-7 and month 11, respectively. Relief of symptoms was significant (p < 0.05). CONCLUSIONS: Our data show that higher TVR attained immediately post-treatment of MRgFUS favours higher involution percentages at follow-up; however, careful patient selection and use of pretreatment imaging are important components for predicting success using MR-guided focused ultrasound surgery. KEY POINTS: * Type 1 fibroids were the most common (93.2%). * Age and treated volume were not correlated (r s = -0.215, p = 0.165). * Small fibroids achieved a higher treated volume than large (96.0% vs. 76.5%). * A 50% involution was achieved at 6 month follow-up for type-1 fibroid. * A decrease of 80% was reached at 11 months for type-1 fibroids. PMID- 25809745 TI - Prognostic CT and MR imaging features in patients with untreated extranodal non Hodgkin lymphoma of the head and neck region. AB - OBJECTIVE: To determine the prognostic CT and MR imaging features of extranodal non-Hodgkin lymphoma in the head and neck region. METHODS: The clinical data and CT and MR imaging features of 59 patients with histologically confirmed extranodal non-Hodgkin lymphoma in the head and neck region were retrospectively reviewed. Subjects included 27 male and 32 female patients between 13 and 81 years of age, with a mean age of 60.3 years. The clinical outcomes were categorized according to whether relapse or metastasis occurred within 2 years after therapy. The association between the clinical outcome and radiologic factors including tumour size, margin, shape, local tumour invasiveness, regional lymph node involvement, number of involvement sites, and contrast enhancement patterns was determined using univariate and multiple logistic regression analysis. RESULTS: Radiologic factors including tumour size, margin, shape, and local tumour invasiveness were associated with poor clinical outcomes, as determined by univariate analysis (P < 0.05). Only the lesion margin category (ill-defined) remained an independent risk factor for clinical outcome in multivariate logistic regression analysis, with an OR of 8.14 (P < 0.05). CONCLUSION: Ill-defined margin of the primary lesion was indicative of unfavourable survival outcome for patients with extranodal non-Hodgkin lymphoma of the head and neck region. KEY POINTS: * Tumour size, margin, shape and local tumour invasiveness were prognostically relevant. * Tumour margin was an independent risk factor for clinical outcome. * Ill-defined margin of primary lesion was indicative of unfavourable survival outcome. PMID- 25809746 TI - Tumor oncogene (KRAS) status and risk of venous thrombosis in patients with metastatic colorectal cancer. AB - BACKGROUND: Patients with metastatic colon cancer (mCRC) are at increased risk of venous thromboembolism (VTE). Limited preclinical data suggest that the oncogene (KRAS) mutational status of the tumor represents a plausible clinical link to systemic hypercoagulability in cancer patients. OBJECTIVES: To determine if a tumor genetic characteristic, KRAS mutational status, is associated with an increased risk of VTE in patients with mCRC. PATIENTS/METHODS: A retrospective cohort study of patients with mCRC and KRAS test results was conducted at multiple practice sites across New England in the United States. The primary outcome was a VTE event, defined as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), either 6 months before or at any time after the diagnosis of mCRC. KRAS status (mutated vs. wild type) and other relevant predictors of thrombosis were collected. RESULTS: Of 172 histologically confirmed patients with mCRC, 40 developed a VTE (23.3%). Sixty-five patients (37.8%) had a mutant KRAS status. The incidence of VTE and DVT among patients with mutated KRAS was 32.3 and 23.1%, respectively. The corresponding incidence among patients with wild-type KRAS was 17.8 and 9.4%. Odd ratios for the association were 2.21 (95% CI, 1.08-4.53) for VTE and 2.62 (95% CI, 1.12-6.12) for DVT, and remained significant despite adjustment for Khorana score and bevacizumab use. CONCLUSION: Tumor mutant KRAS status is associated with an increased risk of VTE in patients with mCRC. The tumor genetic profile may represent a novel and important risk factor for thrombosis in patients with cancer. PMID- 25809748 TI - Commemorating World Tuberculosis Day 2015. PMID- 25809747 TI - Quantitative single cell gene expression profiling in the avian embryo. AB - BACKGROUND: Single cell gene profiling has been successfully applied to cultured cells. However, isolation and preservation of a cell's native gene expression state from an intact embryo remain problematic. RESULTS: Here, we present a strategy for in vivo single cell profiling that optimizes cell identification, isolation and amplification of nucleic acids with nominal bias and sufficient material detection. We first tested several photoconvertible fluorescent proteins to selectively mark a cell(s) of interest in living chick embryos then accurately identify and isolate the same cell(s) in fixed tissue slices. We determined that the dual color mDendra2 provided the optimal signal/noise ratio for this purpose. We developed proper procedures to minimize cell death and preserve gene expression, and suggest nucleic acid amplification strategies for downstream analysis by microfluidic reverse transcriptase quantitative polymerase chain reaction or RNAseq. Lastly, we compared methods for single cell isolation and found that our fluorescence-activated cell sorting (FACS) protocol was able to preserve native transcripts and generate expression profiles with much higher efficiency than laser capture microdissection (LCM). CONCLUSIONS: Quantitative single cell gene expression profiling may be accurately applied to interrogate complex cell dynamics events during embryonic development by combining photoconversion cell labeling, FACS, proper handling of isolated cells, and amplification strategies. PMID- 25809749 TI - Tuberculosis vaccines--state of the art, and novel approaches to vaccine development. AB - The quest for a vaccine that could have a major impact in reducing the current global burden of TB disease in humans continues to be extremely challenging. Significant gaps in our knowledge and understanding of the pathogenesis and immunology of tuberculosis continue to undermine efforts to break new ground, and traditional approaches to vaccine development have thus far met with limited success. Existing and novel candidate vaccines are being assessed in the context of their ability to impact the various stages that culminate in disease transmission and an increase in the global burden of disease. Innovative methods of vaccine administration and delivery have provided a fresh stimulus to the search for the elusive vaccine. Here we discuss the current status of preclinical vaccine development, providing insights into alternative approaches to vaccine delivery and promising candidate vaccines. The state of the art of clinical development also is reviewed. PMID- 25809750 TI - Mycobacterium tuberculosis-specific and MHC class I-restricted CD8+ T-cells exhibit a stem cell precursor-like phenotype in patients with active pulmonary tuberculosis. AB - The nature and longevity of the T-cell response directed against Mycobacterium tuberculosis (MTB) are important for effective pathogen containment. We analyzed ex vivo the nature of MTB antigen-specific T-cell responses directed against the MTB secreted antigens Rv0288, Rv1886c, Rv3875, the antigens Rv2958c, Rv2957, and Rv0447c (intracellular, non-secreted enzymes) in blood from Korean patients with active tuberculosis (TB). MTB-specific T-cell function was defined by intracellular cytokine production (interleukin (IL)-2, interferon gamma, tumour necrosis factor alpha, and IL-17) and by multimer-guided (HLA-A*02:01 and HLA A*24:02) analysis of epitope-specific CD8+ T-cells, along with phenotypic markers (CD45RA and CCR7), CD107a, a marker for degranulation, and CD127 co-staining for T-cell differentiation and homing. Cytokine production analysis underestimated the frequencies of MTB antigen-specific T-cells defined by major histocompatibility complex (MHC) class I-peptide multimer analysis. We showed that MTB antigen-specific CD8+ T-cells exhibit a distinct marker profile associated with the nature of the MTB antigens, i.e., Rv0288, Rv1886c, and Rv3875 reactive T-cells clustered in the precursor T-cell compartment, whereas Rv2958c, Rv2957, and Rv0447c-reactive T-cells were associated with the terminally differentiated T-cell phenotype, in the patient cohort. Rv0288, Rv1886c, and Rv3875-specific CD8+ T-cells were significantly enriched for CD107a+ T-cells in HLA-A*02:01 (p<0.0001) and HLA-A*24:02 (p=0.0018) positive individuals, as compared to Rv2958c, Rv2957, and Rv0447c antigens. CD127 (IL-7 receptor) expressing T-cells were enriched in HLA-A*02:01-positive individuals for the Rv0288, Rv1886c, and Rv3875 specificities (p=0.03). A high proportion of antigen specific T-cells showed a precursor-like phenotype (CD45RA+CCR7+) and expressed the stem cell-associated markers CD95 and c-kit. These data show that MTB specific T-cells can express stem cell-like features; this is associated with the nature of the MTB antigen and the genetic background of the individual. PMID- 25809752 TI - Host-directed therapies for tuberculous pericarditis. AB - TB Pericarditis is associated with significant inflammatory and immune responses which can paradoxically cause injury to the pericardium and myocardium. Management with anti-TB therapy alone does not prevent complications or reduce mortality. Thus the prevailing view is that adjunct host-directed therapies such as use of glucocorticoid treatment could attenuate destructive inflammatory responses and improve morbidity and mortality rates. A recent trial showed no advantage of using adjunct corticosteroid treatment on the combined endpoint of death, cardiac tamponade or constriction. The current lack of effective medical treatment for reducing the significant morbidity and mortality associated with TB pericarditis, highlights the urgent need for newer approaches to treating the disease. Newer treatment options for pericarditis using adjunct host-directed therapies, including autologous bone-marrow-derived Mesenchymal Stromal Cells (MSCs) therapy, now require evaluation in randomized placebo-controlled controlled trials. PMID- 25809751 TI - Frequency of Mycobacterium tuberculosis-specific CD8+ T-cells in the course of anti-tuberculosis treatment. AB - Anti-tuberculosis drug treatment is known to affect the number, phenotype, and effector functionality of antigen-specific T-cells. In order to objectively gauge Mycobacterium tuberculosis (MTB)-specific CD8+ T-cells at the single-cell level, we developed soluble major histocompatibility complex (MHC) class I multimers/peptide multimers, which allow analysis of antigen-specific T-cells without ex vivo manipulation or functional tests. We constructed 38 MHC class I multimers covering some of the most frequent MHC class I alleles (HLA-A*02:01, A*24:02, A*30:01, A*30:02, A*68:01, B*58:01, and C*07:01) pertinent to a South African or Zambian population, and presenting the following MTB-derived peptides: the early expressed secreted antigens TB10.4 (Rv0288), Ag85B (Rv1886c), and ESAT 6 (Rv3875), as well as intracellular enzymes, i.e., glycosyltransferase 1 (Rv2957), glycosyltransferase 2 (Rv2958c), and cyclopropane fatty acid synthase (Rv0447c). Anti-TB treatment appeared to impact on the frequency of multimer positive CD8+ T-cells, with a general decrease after 6 months of therapy. Also, a reduction in the total central memory CD8+ T-cell frequencies, as well as the antigen-specific compartment in CD45RA-CCR7+ T-cells was observed. We discuss our findings on the basis of differential dynamics of MTB-specific T-cell frequencies, impact of MTB antigen load on T-cell phenotype, and antigen-specific T-cell responses in tuberculosis. PMID- 25809753 TI - Cellular therapy in tuberculosis. AB - Cellular therapy now offer promise of potential adjunct therapeutic options for treatment of drug-resistant tuberculosis (TB). We review here the role of Mesenchymal stromal cells, (MSCs), as well as other immune effector cells in the therapy of infectious diseases with a focus on TB. MSCs represent a population of tissue-resident non-hematopoietic adult progenitor cells which home into injured tissues increase the proliferative potential of broncho-alveolar stem cells and restore lung epithelium. MSCs have been shown to be immune-modulatory and anti inflammatory mediated via cell-cell contacts as well as soluble factors. We discuss the functional profile of MSCs and their potential use for adjunct cellular therapy of multi-drug resistant TB, with the aim of limiting tissue damage, and to convert unproductive inflammatory responses into effective anti pathogen directed immune responses. Adjunct cellular therapy could potentially offer salvage therapy options for patients with drug-resistant TB, increase clinically relevant anti-M.tuberculosis directed immune responses and possibly shorten the duration of anti-TB therapy. PMID- 25809754 TI - Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis. AB - The coalescence of the HIV-1 and tuberculosis (TB) epidemics in Sub-Saharan Africa has had a significant and negative impact on global health. The availability of effective antimicrobial treatment for both HIV-1 (in the form of highly active antiretroviral therapy (HAART)) and TB (with antimycobacterial agents) has the potential to mitigate the associated morbidity and mortality. However, the use of both HAART and antimycobacterial therapy is associated with the development of inflammatory paradoxical syndromes after commencement of therapy. These include paradoxical reactions (PR) and immune reconstitution inflammatory syndromes (IRIS), conditions that complicate mycobacterial disease in HIV seronegative and seropositive individuals. Here, we discuss case definitions for PR and IRIS, and explore how advances in identifying the risk factors and immunopathogenesis of these conditions informs our understanding of their shared underlying pathogenesis. We propose that both PR and IRIS are characterized by the triggering of exaggerated inflammation in a setting of immunocompromise and antigen loading, via the reversal of immunosuppression by HAART and/or antimycobacterials. Further understanding of the molecular basis of this pathogenesis may pave the way for effective immunotherapies for the treatment of PR and IRIS. PMID- 25809755 TI - Tackling the tuberculosis epidemic in sub-Saharan Africa--unique opportunities arising from the second European Developing Countries Clinical Trials Partnership (EDCTP) programme 2015-2024. AB - Tuberculosis (TB) today remains a global emergency affecting 9.0 million people globally. The African Region bears the highest global TB/HIV burden and over 50% of TB cases in SSA are co-infected with HIV. An estimated 1.5 million died from the TB globally in 2013. A large majority of the 360,000 HIV-positive TB cases who died were from sub-Saharan Africa. Research and development is an important pillar of the WHO post-2015 global TB strategy. Advances in development of diagnostics, drugs, host-directed therapies, and vaccines will require evaluation under field conditions through multi-centre clinical trials at different geographical locations. Thus it is critically important that these evaluations are fully supported by all African governments and the capacity, trained staff and infrastructure required to perform the research and evaluations is built and made available. This viewpoint article reviews the opportunities provided by recently launched second programme (2015-2024) of the European & Developing Countries Clinical Trials Partnership (EDCTP2) for tackling the TB epidemic in Africa through its magnanimous portfolio. The unique opportunities provided by EDCTP2 for leadership of scientific research in TB and other diseases fully devolving to Africa are also covered. PMID- 25809756 TI - Repurposing-a ray of hope in tackling extensively drug resistance in tuberculosis. AB - Tuberculosis (TB) remains a serious concern more than two decades on from when the World Health Organization declared it a global health emergency. The alarming rise of antibiotic resistance in Mycobacterium tuberculosis, the etiological agent of TB, has made it exceedingly difficult to control the disease with the existing portfolio of anti-TB chemotherapy. The development of effective drugs with novel mechanism(s) of action is thus of paramount importance to tackle drug resistance. The development of novel chemical entities requires more than 10 years of research, requiring high-risk investment to become commercially available. Repurposing pre-existing drugs offers a solution to circumvent this mammoth investment in time and funds. In this context, several drugs with known safety and toxicity profiles have been evaluated against the TB pathogen and found to be efficacious against its different physiological states. As the endogenous targets of these drugs in the TB bacillus are most likely to be novel, there is minimal chance of cross-resistance with front-line anti-TB drugs. Also, reports that some of these drugs may potentially have multiple targets means that the possibility of the development of resistance against them is minimal. Thus repurposing existing molecules offers immense promise to tackle extensively drug resistant TB infections. PMID- 25809757 TI - Access to new medications for the treatment of drug-resistant tuberculosis: patient, provider and community perspectives. AB - Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions. PMID- 25809758 TI - Surgical treatment of complications of pulmonary tuberculosis, including drug resistant tuberculosis. AB - Surgery for drug-resistant tuberculosis has been shown to be safe and effective, with similar level of mortalities associated with surgical intervention observed with that for lung cancer. While surgery has been an option to treat TB in the pre-antibiotic era, it is now increasingly used to treat complications of pulmonary TB, particularly in patients with drug-resistant TB who do not respond to medical treatment. The two most frequent indications for lung resection in drug- resistant TB, are i) failed medical treatment with persistent sputum positivity or ii) patients who have had medical treatment and are sputum negative, but with persistent localized cavitary disease or bronchiectasis. Massive hemoptysis is a potentially life-threatening complication of TB. Lung resection is potentially curative in patients with massive hemoptysis and cavitary or bronchiectatic disease. Bronchial artery embolization in these patients has a high success rate but bears also the risk of recurrence. Lung resection can be safely undertaken in selected patients with HIV co-infection and pulmonary complications of TB. Ambulatory drainage is a novel, safe, affordable and effective method of draining a chronic TB associated empyema thoracis. We review here the current surgical treatment of the complications of pulmonary TB and discuss the experience from the Durban Cardiothoracic Surgery Unit for the surgical treatment of patients with complicated pulmonary TB. PMID- 25809759 TI - Health status and quality of life in tuberculosis. AB - Tuberculosis (TB) is a leading cause of global morbidity, yet there is limited information regarding its impact on quality of life and health status. This is surprising given the implications for patient care, the evaluation of novel treatments or preventative strategies, and also health policy. Furthermore, there is no validated TB-specific instrument that measures health status, and thus a wide and non-standardized range of assessment tools have been employed. The studies to date have chosen a number of different comparator populations, and in many TB endemic areas there is a lack of normative data regarding the health status of the general population. Systematic evaluations of quality of life are urgently needed in specific groups, including those with extrapulmonary TB, drug resistant disease, HIV co-infection, and latent TB infection, and in children with TB; the assessment of post-treatment disability is also required. PMID- 25809760 TI - Understanding anti-tuberculosis drug efficacy: rethinking bacterial populations and how we model them. AB - Tuberculosis still remains a global health emergency, claiming 1.5 million lives in 2013. The bacterium responsible for this disease, Mycobacterium tuberculosis (M.tb), has successfully survived within hostile host environments, adapting to immune defence mechanisms, for centuries. This has resulted in a disease that is challenging to treat, requiring lengthy chemotherapy with multi-drug regimens. One explanation for this difficulty in eliminating M.tb bacilli in vivo is the disparate action of antimicrobials on heterogeneous populations of M.tb, where mycobacterial physiological state may influence drug efficacy. In order to develop improved drug combinations that effectively target diverse mycobacterial phenotypes, it is important to understand how such subpopulations of M.tb are formed during human infection. We review here the in vitro and in vivo systems used to model M.tb subpopulations that may persist during drug therapy, and offer aspirations for future research in this field. PMID- 25809761 TI - New tuberculosis diagnostics and rollout. AB - Early detection and effective treatment are crucial for tuberculosis control, but global case detection rates remain low. The diagnosis of paediatric and extrapulmonary disease is problematic and there are, as yet, no rapid screening tests to assist active case finding in the community. Progress has been made in clinic-based detection tools with the introduction of Xpert MTB/RIF, a nucleic acid amplification test that combines sample processing and analysis in a single instrument to provide a diagnostic result and detection of resistance to rifampicin in under 2h. Enthusiasm for Xpert MTB/RIF has been high and global rollout has been facilitated by donor agencies. However, concerns remain about access and sustainability due to the high cost and infrastructure requirements. Although more sensitive than smear microscopy, early studies suggest the impact of the new test on case detection rates and patient survival has been limited. Alternative technologies are being developed, including non-sputum-based tests to assist the detection of extrapulmonary disease. Evaluation studies are needed to provide evidence of the impact of the new technologies on patient outcomes. This will enable appropriate placement of new diagnostic products in the healthcare system to support the control and eventual eradication of tuberculosis disease. PMID- 25809762 TI - Imaging in tuberculosis. AB - Early diagnosis of tuberculosis (TB) is necessary for effective treatment. In primary pulmonary TB, chest radiography remains the mainstay for the diagnosis of parenchymal disease, while computed tomography (CT) is more sensitive in detecting lymphadenopathy. In post-primary pulmonary TB, CT is the method of choice to reveal early bronchogenic spread. Concerning characterization of the infection as active or not, CT is more sensitive than radiography, and (18)F fluorodeoxyglucose positron emission tomography/CT ((18)F-FDG PET/CT) has yielded promising results that need further confirmation. The diagnosis of extrapulmonary TB sometimes remains difficult. Magnetic resonance imaging (MRI) is the preferred modality in the diagnosis and assessment of tuberculous spondylitis, while (18)F FDG PET shows superior image resolution compared with single-photon-emitting tracers. MRI is considered superior to CT for the detection and assessment of central nervous system TB. Concerning abdominal TB, lymph nodes are best evaluated on CT, and there is no evidence that MRI offers added advantages in diagnosing hepatobiliary disease. As metabolic changes precede morphological ones, the application of (18)F-FDG PET/CT will likely play a major role in the assessment of the response to anti-TB treatment. PMID- 25809763 TI - The complex evolution of antibiotic resistance in Mycobacterium tuberculosis. AB - Multidrug-resistant and extensively drug-resistant tuberculosis (TB) represent a major threat to the control of the disease worldwide. The mechanisms and pathways that result in the emergence and subsequent fixation of resistant strains of Mycobacterium tuberculosis are not fully understood and recent studies suggest that they are much more complex than initially thought. In this review, we highlight the exciting new areas of research within TB resistance that are beginning to fill these gaps in our understanding, whilst also raising new questions and providing future directions. PMID- 25809764 TI - Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment. AB - In this article we describe the key role of tuberculosis (TB) treatment, the challenges (mainly the emergence of drug resistance), and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM) is discussed in detail. Treatment success in multidrug-resistant (MDR) TB cases is low (62%, with 7% failing or relapsing and 9% dying) and in extensively drug-resistant (XDR) TB cases is even lower (40%, with 22% failing or relapsing and 15% dying). The treatment of drug-resistant TB is also more expensive (exceeding ?50,000 for MDR-TB and ?160,000 for XDR-TB) and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The 'dried blood spot' technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world. PMID- 25809765 TI - The social context of tuberculosis treatment in urban risk groups in the United Kingdom: a qualitative interview study. AB - OBJECTIVES: There is scant qualitative research into the experiences of tuberculosis (TB) treatment in urban risk groups with complex health and social needs in the UK. This study aimed to describe the social context of adherence to treatment in marginalized groups attending a major TB centre in London. METHODS: A qualitative cross-sectional study was performed using semi-structured interviews with patients receiving treatment for TB. Analytical frameworks aimed to reflect the role of broader social structures in shaping individual health actions. RESULTS: There were 17 participants; the majority were homeless and had complex medical and social needs, including drug and alcohol use or immigration problems affecting entitlement to social welfare. Participants rarely actively chose not to take their medication, but described a number of social and institutional barriers to adherence and their need for practical support. Many struggled with the physical aspects of taking medication and the side effects. Participants receiving directly observed therapy (DOT) reported both positive and negative experiences, reflecting the type of DOT provider and culture of the organization. CONCLUSIONS: There is a need for integrated care across drug, alcohol, HIV, and homeless services in order to address the complex clinical co morbidities and social needs that impact on the patient's ability to sustain a course of treatment. PMID- 25809767 TI - Fluoroquinolone-resistant tuberculosis: implications in settings with weak healthcare systems. AB - Fluoroquinolones (FQ) play an essential role in the treatment and control of multidrug-resistant tuberculosis (MDR-TB). They are also being evaluated as part of newer regimens under development for drug-sensitive TB. As newer FQ-based regimens are explored, knowledge of FQ resistance data from high TB burden countries becomes essential. We examine available FQ resistance data from high TB burden countries and demonstrate the need for comprehensive surveys to evaluate FQ resistance in these countries. The factors driving FQ resistance in such conditions and the cost of such resistance to weak healthcare systems are discussed. The need for a comprehensive policy for addressing the issue of FQ resistance is highlighted. PMID- 25809766 TI - Tuberculosis control in prisons: current situation and research gaps. AB - BACKGROUND: Tuberculosis (TB) in penitentiary services (prisons) is a major challenge to TB control. This review article describes the challenges that prison systems encounter in TB control and provides solutions for the more efficient use of limited resources based on the three pillars of the post-2015 End TB Strategy. This paper also proposes research priorities for TB control in prisons based on current challenges. METHODS: Articles (published up to 2011) included in a recent systematic review on TB control in prisons were further reviewed. In addition, relevant articles in English (published 1990 to May 2014) were identified by searching keywords in PubMed and Google Scholar. Article bibliographies and conference abstracts were also hand-searched. RESULTS: Despite being a serious cause of morbidity and mortality among incarcerated populations, many prison systems encounter a variety of challenges that hinder TB control. These include, but are not limited to, insufficient laboratory capacity and diagnostic tools, interrupted supply of medicines, weak integration between civilian and prison TB services, inadequate infection control measures, and low policy priority for prison healthcare. CONCLUSIONS: Governmental commitment, partnerships, and sustained financing are needed in order to facilitate improvements in TB control in prisons, which will translate to the wider community. PMID- 25809768 TI - Perspectives on tuberculosis in pregnancy. AB - Tuberculosis (TB) has been recognized as an important cause of morbidity and mortality in pregnancy for nearly a century, but research and efforts to roll out comprehensive TB screening and treatment in high-risk populations such as those with a high prevalence of HIV or other diseases of poverty, have lagged behind similar efforts to address HIV infection in pregnancy and the prevention of mother-to-child-transmission. Immunological changes during pregnancy make the activation of latent TB infection or de novo infection more likely than among non pregnant women. TB treatment in pregnancy poses several problems that have been under-researched, such as contraindications to anti-TB and anti-HIV drugs and potential risks to the neonate, which are particularly important with respect to second-line TB treatment. Whilst congenital TB is thought to be rare, data from high HIV burden settings suggest this is not the case. There is a need for more studies screening for TB in neonates and observing outcomes, and testing preventative or curative actions. National tuberculosis control programmes (NTPs) should work with antenatal and national HIV programmes in high-burden populations to provide screening at antenatal clinics, or to establish functioning systems whereby pregnant women at high risk can drop in to routine NTP screening stations. PMID- 25809769 TI - Tuberculosis among older adults--time to take notice. AB - Knowledge that older people are vulnerable to develop tuberculosis is rarely considered in developing country settings. According to 2010 Global Burden of Disease estimates, the majority of tuberculosis-related deaths occurred among people older than 50; most in those aged 65 and above. Older people also contribute a large proportion of Disability-Adjusted Life Years (DALYs); 51% of tuberculosis DALYs occurred in patients aged 50 years and older in East Asia. Tuberculosis age distributions in Africa have been severely skewed by the human immunodeficiency virus (HIV) epidemic, but emerging data suggest increasing disease burdens among older people. Older adults are more likely to develop extra pulmonary and atypical forms of disease that are often harder to diagnose than conventional sputum smear-positive pulmonary tuberculosis. Their care is complicated by more frequent drug-related adverse events and increased co morbidity, which may prove difficult to manage in regions where health resources are already constrained. Health systems will have to confront the challenge of an ageing global population and the integrated services required to address their health needs. PMID- 25809770 TI - Tuberculosis and chronic respiratory disease: a systematic review. AB - BACKGROUND: Chronic respiratory disease causes substantial global morbidity and mortality. The contribution of pulmonary tuberculosis to the aetiology of chronic respiratory disease is rarely considered, but may be important in tuberculosis endemic areas. METHODS: We performed a systematic literature review to assess the association between a history of tuberculosis and the presence of chronic obstructive pulmonary disease (COPD) or chronic suppurative lung disease (bronchiectasis). Study quality was evaluated using the National Heart Lung and Blood Institute quality assessment tool. Meta-analysis was performed using the DerSimonian and Laird random effects model. RESULTS: We identified 9 eligible studies for COPD and 2 for bronchiectasis. Overall, there was a significant association between a history of tuberculosis and the presence of COPD in adults aged over 40 years (pooled odds ratio 3.05 (95% confidence interval 2.42, 3.85). Among individual COPD studies the strongest associations were found in countries with a high incidence of tuberculosis, as well as among never smokers and younger people. CONCLUSION: In tuberculosis endemic areas, tuberculosis is strongly associated with the presence of chronic respiratory disease in adults. Efforts to improve long-term lung health should be part of tuberculosis care. PMID- 25809772 TI - Tuberculosis elimination in the post Millennium Development Goals era. AB - The Millennium Development Goal for tuberculosis (TB) is to stop the increase in incidence and halve the mortality of TB between 1990 and 2015. This goal has now been reached on a global scale, although not in the most affected region of Africa. The new target is TB elimination, defined as one case of active TB per one million population per year, which is to be reached before 2050. This review will discuss the main tools in play, namely case-finding and new diagnostics, increased access and effectiveness of anti-TB therapy (directly observed therapy, short course (DOTS)), preventive therapy for latent infection, and vaccination. Each approach is discussed and a way forward in research and management is suggested. PMID- 25809771 TI - Why healthcare workers are sick of TB. AB - Dr Thato Mosidi never expected to be diagnosed with tuberculosis (TB), despite widely prevalent exposure and very limited infection control measures. The life threatening diagnosis of primary extensively drug-resistant TB (XDR-TB) came as an even greater shock. The inconvenient truth is that, rather than being protected, Dr Mosidi and thousands of her healthcare colleagues are at an increased risk of TB and especially drug-resistant TB. In this viewpoint paper we debunk the widely held false belief that healthcare workers are somehow immune to TB disease (TB-proof) and explore some of the key factors contributing to the pervasive stigmatization and subsequent non-disclosure of occupational TB. Our front-line workers are some of the first to suffer the consequences of a progressively more resistant and fatal TB epidemic, and urgent interventions are needed to ensure the safety and continued availability of these precious healthcare resources. These include the rapid development and scale-up of improved diagnostic and treatment options, strengthened infection control measures, and focused interventions to tackle stigma and discrimination in all its forms. We call our colleagues to action to protect themselves and those they care for. PMID- 25809773 TI - Supporting clinical management of the difficult-to-treat TB cases: the ERS-WHO TB Consilium. AB - Multi-drug and extensively drug-resistant tuberculosis (MDR/XDR-TB) are considered a serious threat for TB control and elimination. The outcome of these patients is still largely unsatisfactory as of today, with treatment success rates being consistently below 50% at global level. The World Health Organization (WHO) recommends that management of MDR-TB cases is supported by a specialized team, including complementary medical professionals able to cover several perspectives (clinical, both for adults and children; surgical; radiological; public health; psychological; nursing, among others). Implementation of such a body (known as Consilium in most of the former Soviet Union countries) is often a pre-requisite to apply for international TB control funding and concessionally priced medicines to treat M/XDR-TB cases. The primary objective of the ERS/WHO TB Consilium is to provide clinical consultation for drug-resistant TB and other difficult-to-treat TB cases, including co-infection with HIV and paediatric cases. Through technical guidance to clinicians managing complex TB cases, the main contribution and outcome of the initiative will be a public health response aimed at achieving correct treatment of affected patients and preventing further development of drug resistance. The Consilum's secondary objective is to ensure monitoring and evaluation of clinical practices on the ground (diagnosis, treatment and prevention). PMID- 25809774 TI - Western Pacific Regional Green Light Committee: progress and way forward. AB - The Western Pacific Regional Green Light Committee (rGLC WPR) was established in 2011 to promote the rational scale-up of programmatic management of drug resistant tuberculosis (PMDT). We reflect on its achievements, consider the challenges faced, and explore its potential future role. Achievements include the supervision and support of national PMDT action plans, increased local ownership, contextualized guidance, and a strong focus on regional capacity building, as well as a greater awareness of regional challenges. Future rGLC activities should include (1) advocacy for high-level political commitment; (2) monitoring, evaluation, and supervision; (3) technical support and contextualized guidance; and (4) training, capacity building, and operational research. Regional activities require close collaboration with both national and global efforts, and should be an important component of the new Global Drug-resistant TB Initiative. PMID- 25809775 TI - Regional initiatives to address the challenges of tuberculosis in children: perspectives from the Asia-Pacific region. AB - Increasing attention is being given to the challenges of management and prevention of tuberculosis in children and adolescents. There have been a number of recent important milestones achieved at the global level to address this previously neglected disease. There is now a need to increase activities and build partnerships at the regional and national levels in order to address the wide policy-practice gaps for implementation, and to take the key steps outlined in the Roadmap for Child Tuberculosis published in 2013. In this article, we provide the rationale and suggest strategies illustrated with examples to improve diagnosis, management, outcomes and prevention for children with tuberculosis in the Asia-Pacific region, with an emphasis on the need for greatly improved recording and reporting. Effective collaboration with community engagement between the child health sector, the National Tuberculosis control Programmes, community-based services and the communities themselves are essential. PMID- 25809776 TI - Tuberculosis and HIV co-infection-focus on the Asia-Pacific region. AB - Tuberculosis (TB) is the leading opportunistic disease and cause of death in patients with HIV infection. In 2013 there were 1.1 million new TB/HIV co infected cases globally, accounting for 12% of incident TB cases and 360,000 deaths. The Asia-Pacific region, which contributes more than a half of all TB cases worldwide, traditionally reports low TB/HIV co-infection rates. However, routine testing of TB patients for HIV infection is not universally implemented and the estimated prevalence of HIV in new TB cases increased to 6.3% in 2013. Although HIV infection rates have not seen the rapid rise observed in Sub-Saharan Africa, indications are that rates are increasing among specific high-risk groups. This paper reviews the risks of TB exposure and progression to disease, including the risk of TB recurrence, in this vulnerable population. There is urgency to scale up interventions such as intensified TB case-finding, isoniazid preventive therapy, and TB infection control, as well as HIV testing and improved access to antiretroviral treatment. Increased awareness and concerted action is required to reduce TB/HIV co-infection rates in the Asia-Pacific region and to improve the outcomes of people living with HIV. PMID- 25809777 TI - The history of tuberculosis management in Sweden. AB - We review the history of TB in Sweden beginning in 1800, when 25% of mortality in Sweden was associated with TB. The Royal Family was involved in establishing dedicated sanatoria in Sweden to offer better diagnostics and clinical care. TB has declined in Sweden steadily, with some recent increases due to local spread of TB and challenging international and national socio-economical structures. Improved research and clinical knowledge is needed to diagnose and manage drug susceptible as well as drug-resistant TB. PMID- 25809779 TI - Lessons for tuberculosis from scrutiny of HIV/AIDS and Malaria UK Parliamentary Questions. AB - OBJECTIVES: To identify whether parliamentary scrutiny, in the form of Written Parliamentary Questions (WPQs), has any significant impact on the UK government's stated aid priorities and whether, by refining the approach that MPs with an interest in TB take to scrutinising the government on its aid priorities, more resources could be secured for TB. METHODS: We downloaded 19,234 Written Parliamentary Questions directed at the Department for International Development posed by Members of Parliament between June 2001 and September 2014. We categorised questions by theme, party of questioner, geographical area, date and government. We then identified questions which specifically referenced HIV, TB and Malaria, or the Global Fund to Fight Aids, TB and Malaria. Analyses were conducted on each of these categorisations to identify trends which could account for differences in government funding between the three diseases. RESULTS: A significantly greater number of questions were posed on HIV than on TB and Malaria. These questions were more likely to reference a specific geographical area, and come from a wider group of MPs. A broadly equivalent number of questions were asked on TB and Malaria although there were differences between the parties of the MPs tabling questions. We also identified a significant fall in the number of WPQs tabled from the Labour government of 2005-2010 and the Coalition Government of the present day. CONCLUSION: High volumes of WPQs targeting specific policy areas or geographical locations can play a role in increasing political commitment within government towards a certain disease or condition, however other factors, including high-level MP champions and party policy, can play an equally significant role. Nonetheless, evidence suggests that a broad base of political support (as manifested through WPQs) is important to motivating a government response to a health issue and that the TB community should devote more effort to mobilising this wide political support. PMID- 25809778 TI - The economic burden of tuberculosis in Denmark 1998-2010. Cost analysis in patients and their spouses. AB - OBJECTIVE: To evaluate the economic burden of tuberculosis (TB) in Denmark, METHODS: 8,433 Danish TB-patients (1998-2010) were matched with 33,707 controls by age, gender, civil status and geography. Health-related costs (health system contacts and -procedures, medications) and socio-economic parameters (foregone earnings and social transfer expenses) were calculated on data from national databases. The same information was obtained for 3,485 spouses of TB-patients, and 17,403 controls. RESULTS: Health-related costs were higher for cases throughout the period. Before diagnosis, cases posed ? 1,180 more health costs per year than controls. Excess health costs in the 2 years around diagnosing and treating TB were ? 10,509. Cases received an average excess public transfer income of ? 3,345 before vs. ? 3,121 after diagnosis. Average employment income deficiency was ? 11,635 before vs. ? 13,885 after diagnosis, but the increasing difference showed a linear shape throughout the period. Spouses also had lower income, more social transfer, and posed higher health-related costs than matched controls. CONCLUSION: We estimate the direct costs per TB patient to be ?10,509. TB patients and their households are characterized by increasingly lower employment income, lower employment rate, and higher dependency on public transfer, but the socio/economic deterioration is rather a risk factor for TB than a direct consequence of the disease. PMID- 25809781 TI - Carl Djerassi (1923-2015). PMID- 25809783 TI - Stickler syndrome associated with epilepsy: report of three cases. AB - Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial abnormalities. Stickler syndrome type 1 typically presents ophthalmologic involvement and is due to heterozygous defects of the COL2A1 gene, that have been also identified as the molecular cause of a continuous spectrum of different disorders mainly affecting the cartilage and bone (i.e., Kniest dysplasia, achondrogenesis type II, Legg-Calve-Perthes disease). We report three Caucasian children with: (a) ocular, oral, facial, auditory, and musculoskeletal manifestations of Stickler syndrome type 1; (b) history of generalized and/or partial seizures coupled with abnormal electroencephalographic records; and (c) pathogenic heterozygous mutations of the COL2A1 gene. Epilepsy has been never reported so far in literature as a possible feature of Stickler syndrome, although neurological presentations, including epilepsy and brain abnormalities, have been occasionally described in other COL2A1-related phenotypes (e.g., Legg-Calve-Perthes disease). CONCLUSIONS: This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting the presence of a continuous neurological spectrum in some individuals harboring heterozygous mutations in COL2A1. WHAT IS KNOWN: * Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial anomalies. What is New: * Involvement of the nervous central system is not a typical feature of Stickler syndrome and the association with epilepsy has not been reported so far. * This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting a continuous neurological spectrum in some individuals affected by heterozygous mutations of COL2A1. PMID- 25809780 TI - An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations. AB - Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in beta-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH. PMID- 25809784 TI - Hypertriglyceridemic waist-to-height ratio phenotype: association with atherogenic lipid profile in Han adolescents. AB - Hypertriglyceridemic waist (HW) phenotype was associated with an atherogenic lipid profile in adolescents. But unlike adults, the cutoffs of waist circumference are age- and gender-specific standards and are less feasible for non-professional use. The present study tested the hypothesis that simple variables, such as waist-to-height ratio (WHtR) and serum triacylglycerol (TG) concentrations, could be used as screening tools for the identification of adolescents characterized by atherogenic lipid profile. In 2006, anthropometric and biochemical measurements were assessed in a cross-sectional population-based study of 3136 Han adolescents, aged 13-17 years. The hypertriglyceridemic waist to-height ratio (HWHtR) phenotype was defined as serum TG concentrations >=1.47 mmol/L and WHtR >=0.48 for boys and >=0.46 for girls. Hypercholesterolemia (total cholesterol >=5.18 mmol/L), high low-density lipoprotein cholesterol (LDL-C >=3.37 mmol/L), low high-density lipoprotein cholesterol (HDL-C <1.03 mmol/L), and high non-HDL-C (>=3.76 mmol/L) were considered as atherogenic lipid profiles. After control for age and sex, adolescents with the HWHtR phenotype were more likely to have hypercholesterolemia (odds ratio (OR) = 7.8, 95 % confidence interval (CI) = 3.5-17.3, P < 0.001), high LDL-C (OR = 9.4, 95 % CI = 2.8-31.2, P < 0.001), low HDL-C (OR = 10.8, 95 % CI = 6.9-17.0, P < 0.001), and high non-HDL C (OR = 22.9, 95 % CI = 10.0-52.2, P < 0.001) than those adolescents with normal WHtR and normal serum TG concentrations. CONCLUSION: The present study demonstrates that HWHtR phenotype is a simple marker for identifying adolescents with atherogenic lipid profile. Compared with HW phenotype, HWHtR phenotype is a non-age-dependent index with higher applicability to screen for cardiovascular risk factors in adolescents. WHAT IS KNOWN: * The hypertriglyceridemic waist phenotype is represented by the simultaneous presence of elevated serum triacylglycerol and increased waist circumference. Hypertriglyceridemic waist phenotype can identify adolescents with metabolic syndrome. But the cutoffs of waist circumference are age- and gender-specific standards and are less feasible for non-professional use. WHAT IS NEW: * The present study demonstrates that hypertriglyceridemic waist-to-height ratio phenotype is a simple marker for identifying adolescents with atherogenic lipid profile. Compared with hypertriglyceridemic waist phenotype, hypertriglyceridemic waist-to-height ratio phenotype is a non-age-dependent index with higher applicability to screen for cardiovascular risk factors in adolescents. PMID- 25809785 TI - Discrepancies in marginal and internal fits for different metal and alumina infrastructures cemented on implant abutments. AB - Cemented crowns are increasingly being used on dental implants instead of on screw-retained prostheses because of the reliability of internal Morse taper implant-abutment connections. However, there is a lack of information on the fit of metal ceramic and premachined alumina infrastructures. Therefore, the aim of this study was to evaluate the marginal and internal fits of different metal and alumina infrastructures cemented on universal post abutments. A total of 45 abutments (6 mm in height and 3.3 mm in diameter) were divided into five groups on the basis of their infrastructure material: cobalt-chromium (CoCr), nickel chromium (NiCr), nickel-chromium-molybdenum-titanium (NiCrMoTi), gold (Au), and premachined alumina. The alumina group showed marginal overextension, and the Au group showed the highest discrepancy in marginal fit among the metal alloys. The CoCr and alumina groups showed the lowest discrepancies in internal fit. In conclusion, the alumina cylinders exhibited the best internal fit, despite their horizontal overextension. Among the metal alloys, CoCr exhibited the best fit at critical regions, such as the cervical and occlusal areas. PMID- 25809786 TI - Nickel-catalyzed monofluoromethylation of aryl boronic acids. AB - Aryl boronic acids can be monofluoromethylated under nickel catalysis. The utility of this method is demonstrated by the monofluoromethylation of a borylated and acyl-protected derivative of the statin drug ezetimibe. Mechanistic investigations indicate that a fluoromethyl radical is involved in the Ni(I)/Ni(III) catalytic cycle. PMID- 25809787 TI - Caries-removal effectiveness of a papain-based chemo-mechanical agent: A quantitative micro-CT study. AB - The aim of this study was to access the effectiveness and specificity of a papain based chemo-mechanical caries-removal agent in providing minimum residual caries after cavity preparation. In order to do it, extracted carious molars were selected and scanned in a micro-CT before and after caries-removal procedures with the papain-based gel. Similar parameters for acquisition and reconstruction of the image stacks were used between the scans. After classification of the dentin substrate based on mineral density intervals and establishment of a carious tissue threshold, volumetric parameters related to effectiveness (mineral density of removed dentin volume and residual dentin tissue) and specificity (relation between carious dentin in removed volume and initial caries) of this caries-removal agent were obtained. In general, removed dentin volume was similar or higher than the initial carious volume, indicating that the method was able to effectively remove dentin tissue. Samples with an almost perfect accuracy in carious dentin removal also showed an increased removal of caries-affected tissue. On the contrary, less or no affected dentin was removed in samples where some carious tissue was left in residual dentin. Mineral density values in residual dentin were always higher or similar to the threshold for mineral density values in carious dentin. In conclusion, the papain-based gel was effective in removing carious dentin up to a conservative in vitro threshold. Lesion characteristics, such as activity and morphology of enamel lesion, may also influence caries-removal properties of the method. PMID- 25809788 TI - Soil microbiome responses to the short-term effects of Amazonian deforestation. AB - Slash-and-burn clearing of forest typically results in increase in soil nutrient availability. However, the impact of these nutrients on the soil microbiome is not known. Using next generation sequencing of 16S rRNA gene and shotgun metagenomic DNA, we compared the structure and the potential functions of bacterial community in forest soils to deforested soils in the Amazon region and related the differences to soil chemical factors. Deforestation decreased soil organic matter content and factors linked to soil acidity and raised soil pH, base saturation and exchangeable bases. Concomitant to expected changes in soil chemical factors, we observed an increase in the alpha diversity of the bacterial microbiota and relative abundances of putative copiotrophic bacteria such as Actinomycetales and a decrease in the relative abundances of bacterial taxa such as Chlamydiae, Planctomycetes and Verrucomicrobia in the deforested soils. We did not observe an increase in genes related to microbial nutrient metabolism in deforested soils. However, we did observe changes in community functions such as increases in DNA repair, protein processing, modification, degradation and folding functions, and these functions might reflect adaptation to changes in soil characteristics due to forest clear-cutting and burning. In addition, there were changes in the composition of the bacterial groups associated with metabolism-related functions. Co-occurrence microbial network analysis identified distinct phylogenetic patterns for forest and deforested soils and suggested relationships between Planctomycetes and aluminium content, and Actinobacteria and nitrogen sources in Amazon soils. The results support taxonomic and functional adaptations in the soil bacterial community following deforestation. We hypothesize that these microbial adaptations may serve as a buffer to drastic changes in soil fertility after slash-and-burning deforestation in the Amazon region. PMID- 25809782 TI - Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB. AB - BACKGROUND: The exact molecular mechanisms regarding HTLV-1 Tax-mediated viral gene expression and CD4 T-cell transformation have yet to be fully delineated. Herein, utilizing virus-infected primary CD4+ T cells and the virus-producing cell line, MT-2, we describe the involvement and regulation of Myocyte enhancer factor-2 (specifically MEF-2A) during the course of HTLV-1 infection and associated disease syndrome. RESULTS: Inhibition of MEF-2 expression by shRNA and its activity by HDAC9 led to reduced viral replication and T-cell transformation in correlation with a heightened expression of MEF-2 in ATL patients. Mechanistically, MEF-2 was recruited to the viral promoter (LTR, long terminal repeat) in the context of chromatin, and constituted Tax/CREB transcriptional complex via direct binding to the HTLV-1 LTR. Furthermore, an increase in MEF-2 expression was observed upon infection in an extent similar to CREB (known Tax interacting transcription factor), and HATs (p300, CBP, and p/CAF). Confocal imaging confirmed MEF-2 co-localization with Tax and these proteins were also shown to interact by co-immunoprecipitation. MEF-2 stabilization of Tax/CREB complex was confirmed by a novel promoter-binding assay that highlighted the involvement of NFAT (nuclear factor of activated T cells) in this process via Tax mediated activation of calcineurin (a calcium-dependent serine-threonine phosphatase). MEF-2-integrated signaling pathways (PI3K/Akt, NF-kappaB, MAPK, JAK/STAT, and TGF-beta) were also activated during HTLV-1 infection of primary CD4+ T cells, possibly regulating MEF-2 activity. CONCLUSIONS: We demonstrate the involvement of MEF-2 in Tax-mediated LTR activation, viral replication, and T cell transformation in correlation with its heightened expression in ATL patients through direct binding to DNA within the HTLV-1 LTR. PMID- 25809790 TI - We-Language and Sustained Reductions in Drinking in Couple-Based Treatment for Alcohol Use Disorders. AB - Couple-based treatments for alcohol use disorders (AUDs) produce higher rates of abstinence than individual-based treatments and posit that active involvement of both identified patients (IPs) and significant others (SOs) is partly responsible for these improvements. Separate research on couples' communication has suggested that pronoun usage can indicate a communal approach to coping with health-related problems. The present study tested whether communal coping, indicated by use of more first-person plural pronouns ("we" language), fewer second-person pronouns ("you" language), and fewer first-person singular pronouns ("I" language), predicted improvements in abstinence in couple-based AUD treatment. Pronoun use was measured in first- and mid-treatment sessions for 188 heterosexual couples in four clinical trials of alcohol behavioral couple therapy (ABCT). Percentages of days abstinent were assessed during treatment and over a 6-month follow-up period. Greater IP and SO "we" language during both sessions was correlated with greater improvement in abstinent days during treatment. Greater SO "we" language during first- and mid-treatment sessions was correlated with greater improvement in abstinence at follow-up. Greater use of IP and SO "you" and "I" language had mixed correlations with abstinence, typically being unrelated to or predicting less improvement in abstinence. When all pronoun variables were entered into regression models, only greater IP "we" langue and lower IP "you" language predicted improvements in abstinence during treatment, and only SO "we" language predicted improvements during follow-up. Most pronoun categories had little or no association with baseline relationship distress. Results suggest that communal coping predicts better abstinence outcomes in couple-based AUD treatment. PMID- 25809789 TI - Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments. AB - Treatments for major depressive disorder (MDD) act at different hierarchical levels of biological complexity, ranging from the individual synapse to the brain as a whole. Theories of antidepressant medication action traditionally have focused on the level of cell-to-cell interaction and synaptic neurotransmission. However, recent evidence suggests that modulation of synchronized electrical activity in neuronal networks is a common effect of antidepressant treatments, including not only medications, but also neuromodulatory treatments such as repetitive transcranial magnetic stimulation. Synchronization of oscillatory network activity in particular frequency bands has been proposed to underlie neurodevelopmental and learning processes, and also may be important in the mechanism of action of antidepressant treatments. Here, we review current research on the relationship between neuroplasticity and oscillatory synchrony, which suggests that oscillatory synchrony may help mediate neuroplastic changes related to neurodevelopment, learning, and memory, as well as medication and neuromodulatory treatment for MDD. We hypothesize that medication and neuromodulation treatments may have related effects on the rate and pattern of neuronal firing, and that these effects underlie antidepressant efficacy. Elucidating the mechanisms through which oscillatory synchrony may be related to neuroplasticity could lead to enhanced treatment strategies for MDD. PMID- 25809792 TI - Vascular Expression of Transient Receptor Potential Vanilloid 1 (TRPV1). PMID- 25809791 TI - Preferential Pathway Pacing within the Aortic Sinus of Valsalva: Strong Evidence for the Existence of Preferential Conduction with Different Exit Sites Traversing the Ventricular Septum. AB - A 57-year-old male who presented with frequent ventricular premature contraction (VPC) was referred for catheter ablation. Two different QRS morphologies (VPC1 and VPC2) were recorded. Pace mapping at the right ventricular outflow (RVOT) was identical to VPC1 without latency. During the mapping within the right sinus of Valsalva where the RF applications were successful for elimination of VPC, discrete prepotential was recorded and the pace mapping produced both VPC1 and VPC2 morphology with different latency. These electrophysiological findings were thought to prove the existence of preferential pathway traversing the ventricular outflow septum with different exit sites. PMID- 25809793 TI - CD133+ and Nestin+ Glioma Stem-Like Cells Reside Around CD31+ Arterioles in Niches that Express SDF-1alpha, CXCR4, Osteopontin and Cathepsin K. AB - Poor survival of high-grade glioma is at least partly caused by glioma stem-like cells (GSLCs) that are resistant to therapy. GSLCs reside in niches in close vicinity of endothelium. The aim of the present study was to characterize proteins that may be functional in the GSLC niche by performing immunohistochemistry on serial cryostat sections of human high-grade glioma samples. We have found nine niches in five out of five high-grade glioma samples that were all surrounding arterioles with CD31+ endothelial cells and containing cellular structures that were CD133+ and nestin+. All nine niches expressed stromal-derived factor-1alpha (SDF-1alpha), its receptor C-X-C chemokine receptor type 4 (CXCR4), osteopontin and cathepsin K. SDF-1alpha plays a role in homing of CXCR4+ stem cells and leukocytes, whereas osteopontin and cathepsin K promote migration of cancer cells and leukocytes. Leukocyte-related markers, such as CD68, macrophage matrix metalloprotease-9, CD177 and neutrophil elastase were often but not always detected in the niches. We suggest that SDF-1alpha is involved in homing of CXCR4+ GSLCs and leukocytes and that cathepsin K and osteopontin are involved in the migration of GSLCs out of the niches. PMID- 25809797 TI - Phototherapy in the elderly. AB - BACKGROUND: Elderly patients present with a unique spectrum of dermatoses that pose particular management opportunities and challenges, which will be increasingly encountered in dermatological practice. The skin of elderly patients differs from that of younger patients not only in appearance but also in structure, physiology and response to ultraviolet (UV) radiation. However, little is known about the safety and efficacy of phototherapy in elderly patients and how phototherapy is currently being utilized to treat them. AIM: To investigate the safety, efficacy and utilization of phototherapy in elderly patients. METHODS: In January 2014, we analysed all patients recently referred for, currently receiving or recently having completed a course of phototherapy at a university teaching hospital in England (UK). RESULTS: In total, 249 patients were identified; 37 (15%) were over the age of 65 years (the WHO definition of an elderly or older person). The dermatoses being treated were psoriasis (51%), eczema (11%), nodular prurigo (11%), pruritus (11%), Grover disease (5%) and others (11%). One patient with dementia was deemed not safe to embark on phototherapy, and five patients were yet to start. The remaining 31 elderly patients received 739 individual phototherapy treatments: 88% narrowband (NB)-UVB and 12% systemic, bath and hand/foot psoralen UVA (PUVA). The acute adverse event (AE) rate was 1.89%, all occurring in those receiving NB-UVB. No severe acute AEs occurred. Of those who completed their course of phototherapy, 80% achieved a clear/near clear or moderate response, while just two patients (8%) had minimal response and two (8%) had worsening of the disease during treatment. Of those receiving NB-UVB for psoriasis, 91% achieved a clear or near-clear response. CONCLUSIONS: In this small survey, the first of its kind to focus on elderly patients, phototherapy appears to be well-tolerated, safe and efficacious in the short term. Further thought and investigation should be given to delivering phototherapy to an ageing population. PMID- 25809798 TI - Affective expressions in groups and inferences about members' relational well being: The effects of socially engaging and disengaging emotions. AB - Our findings draw attention to the interpersonal communication function of a relatively unexplored dimension of emotions-the level of social engagement versus disengagement. In four experiments, regardless of valence and target group gender, observers infer greater relational well-being (more cohesiveness and less conflict) between group members from socially engaging (sadness and appreciation) versus disengaging (anger and pride) emotion expressions. Supporting our argument that social (dis)engagement is a critical dimension communicated by these emotions, we demonstrate (1) that inferences about group members' self-interest mediate the effect of socially engaging emotions on cohesiveness and (2) that the influence of socially disengaging emotion expressions on inferences of conflict is attenuated when groups have collectivistic norms (i.e., members value a high level of social engagement). Furthermore, we show an important downstream consequence of these inferences of relational well-being: Groups that seem less cohesive because of their members' proud (versus appreciative) expressions are also expected to have worse task performance. PMID- 25809796 TI - HPyV6, HPyV7 and TSPyV DNA sequences detection in skin disease patients and healthy subjects. AB - BACKGROUND: The discovery, from 2007, of eight new human polyomaviruses (HPyVs) has revived interest in the Polyomaviridae family and their association with human diseases and cancer. In particular, HPyV6 and HPyV7 were discovered in skin swabs of healthy donors and TSPyV was discovered in a heart transplant recipient affected by virus-associated Trichodysplasia Spinulosa (TS), a rare skin disease, exclusively found in immunocompromised patients. OBJECTIVE: The presence of HPyV6, HPyV7 and TSPyV DNA in skin biopsies from patients affected by different skin diseases (cancers and inflammatory disorders) has been evaluated to confirm their skin tropism and the possible pathological association. METHODS: DNA extracted was amplified with HPyV6, HPyV7 and TSPyV specific PCR real time on Taqman platform with standard profile. RESULTS: HPyV7 and TSPyV sequences were not found in any skin specimen analysed. HPyV6, on the other hand, was detected in 30% of samples from healthy subjects vs. 14.3% of skin cancer patients and 2.9% of inflammatory disorders. HPyV6 sequences have been detected in primary cutaneous T-cell lymphoma (CTCL) patients (in 18.6% out of Mycosis Fungoides (MF) patients and in 16.7% out of CTCL not MF/SS(Sezary syndrome) but have not been detected in primary cutaneous B-cell lymphoma (CBCL) patients. CONCLUSION: Our preliminary data suggest that these three novel human polyomaviruses seem not to play a significant role neither in the pathogenesis of cutaneous malignancies nor in that of inflammatory disorders but, according to literature, can inhabit the skin. On the basis of our data regarding the HPyV6 DNA presence with decreasing percentages in healthy subjects, skin cancer and inflammatory disorders patients, it could be an intriguing matter to study if the activated innate immune response in inflammatory disorders can suppress the virus. Further investigations are needed to better understand their relationship with the human host and its innate immune system. PMID- 25809794 TI - Inpatient burden of childhood functional GI disorders in the USA: an analysis of national trends in the USA from 1997 to 2009. AB - BACKGROUND: Functional gastrointestinal disorders (FGIDs) are among the most common outpatient diagnoses in pediatric primary care and gastroenterology. There is limited data on the inpatient burden of childhood FGIDs in the USA. The aim of this study was to evaluate the inpatient admission rate, length of stay (LoS), and associated costs related to FGIDs from 1997 to 2009. METHODS: We analyzed the Kids' Inpatient Sample Database (KID) for all subjects in which constipation (ICD 9 codes: 564.0-564.09), abdominal pain (ICD-9 codes: 789.0-789.09), irritable bowel syndrome (IBS) (ICD-9 code: 564.1), abdominal migraine (ICD-9 code: 346.80 and 346.81) dyspepsia (ICD-9 code: 536.8), or fecal incontinence (ICD-codes: 787.6-787.63) was the primary discharge diagnosis from 1997 to 2009. The KID is the largest publicly available all-payer inpatient database in the USA, containing data from 2 to 3 million pediatric hospital stays yearly. KEY RESULTS: From 1997 to 2009, the number of discharges with a FGID primary diagnosis increased slightly from 6,348,537 to 6,393,803. The total mean cost per discharge increased significantly from $6115 to $18,058 despite the LoS remaining relatively stable. Constipation and abdominal pain were the most common FGID discharge diagnoses. Abdominal pain and abdominal migraine discharges were most frequent in the 10-14 year age group. Constipation and fecal incontinence discharges were most frequent in the 5-9 year age group. IBS discharge was most common for the 15-17 year age group. CONCLUSIONS & INFERENCES: Hospitalizations and associated costs in childhood FGIDs have increased in number and cost in the USA from 1997 to 2009. Further studies to determine optimal methods to avoid unnecessary hospitalizations and potentially harmful diagnostic testing are indicated. PMID- 25809795 TI - High nevus counts confer a favorable prognosis in melanoma patients. AB - A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5- and 10-year melanoma specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21-0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08-0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi. PMID- 25809799 TI - The Genotype-Tissue Expression (GTEx) Project: Linking Clinical Data with Molecular Analysis to Advance Personalized Medicine. AB - Evaluation of how genetic mutations or variability can directly affect phenotypic outcomes, the development of disease, or determination of a tailored treatment protocol is fundamental to advancing personalized medicine. To understand how a genotype affects gene expression and specific phenotypic traits, as well as the correlative and causative associations between such, the Genotype-Tissue Expression (GTEx) Project was initiated The GTEx collection of biospecimens and associated clinical data links extensive clinical data with genotype and gene expression data to provide a wealth of data and resources to study the underlying genetics of normal physiology. These data will help inform personalized medicine through the identification of normal variation that does not contribute to disease. Additionally, these data can lead to insights into how gene variation affects pharmacodynamics and individualized responses to therapy. PMID- 25809800 TI - Living situations associated with poor dietary intake among healthy Japanese elderly: the Ohasama Study. AB - BACKGROUND: Rapid increases in life expectancy have led to concurrent increases in the number of elderly people living alone or those forced to change living situations. Previous studies have found that poor dietary intake was common in elderly people living alone. However, there have been few studies about the dietary intake in elderly people living in other situations, particularly those living with family other than a spouse (nonspouse family), which is common in Japan. OBJECTIVE: To examine the differences in dietary intake by different living situations in elderly Japanese people. We analyzed the data of 1542 healthy residents in the town of Ohasama aged 60 years and over who had completed self-administered questionnaires. METHODS: The dietary intake was measured using a validated 141-item food frequency questionnaire. Multiple regression models with robust (White-corrected) standard errors were individually fitted for nutrients and foods by living situation. RESULTS: In men, although the presence of other family was correlated with significantly lower intake of protein-related foods, e.g., legumes, fish and shellfish, and dairy products, these declines were more serious in men living with nonspouse family. Conversely, in men living alone the intake of fruits and vegetables was significantly lower. In women, lower intakes of fruit and protein-related foods were significantly more common in participants living with nonspouse family than those living with only a spouse. CONCLUSION: These findings revealed that elderly people living alone as well as those living with family other than a spouse had poor dietary intake, suggesting that strategies to improve food choices and skills for food preparation could promote of healthy eating in elderly Japanese people. PMID- 25809801 TI - The Mini Nutritional Assessment-Short Form and mortality in nursing home residents--results from the INCUR study. AB - OBJECTIVES: To examine whether the Mini Nutritional Assessment-Short Form (MNA SF) score and its individual items are predictors of mortality in a nursing home population. DESIGN: Prospective, secondary analysis from the Incidence of pNeumonia and related ConseqUences in nursing home Residents (INCUR) study with 1 year follow-up. PARTICIPANTS: A total of 773 older persons (women 74.4%) living in 13 French nursing homes. MEASUREMENTS: At baseline, nutritional status was assessed with the MNA-SF. Overall mortality rate was measured over a 12-month follow-up period after the baseline assessment visit. Cox proportional hazard models were performed to test the predictive capacity of the MNA-SF score and its single components for mortality. RESULTS: Mean age of participants was 86.2 (standard deviation, SD 7.5) years. Mean MNA-SF score was 9.8 (SD 2.4). Among participants, 198 (25.6%) presented a normal nutritional status (12-14 points), 454 (58.7%) were at risk of malnutrition (8-11 points), and 121 (15.7%) were malnourished. After one year of follow-up, 135 (17.5%) participants had died. Age, female gender, baseline weight, BMI and MNA-SF were significant predictors of mortality whereas no specific chronic disease was. The total MNA-SF score was a significant predictor of mortality (Hazard Ratio=0.83; 95% CI 0.75-0.91; p<0.001), even after adjustment for potential confounders. Four individual items: weight loss, decrease in food intake, recent stress and BMI were independent predictors of mortality. CONCLUSIONS: The MNA-SF appears to be an accurate predictor of one-year mortality in nursing home residents. Thus, this tool may be regarded not only as a nutritional screening tool, but also as an instrument for identifying the most-at-risk individuals in this population. PMID- 25809802 TI - Skeletal muscle ceramide species in men with abdominal obesity. AB - BACKGROUND: Obesity is a risk factor for diabetes and its consequences, including accelerated ageing and mortality. The underlying factor could be accumulation of certain lipid moieties, such as ceramides (CER) and diacylgycerol (DAG) within muscle tissue, which are known to promote insulin resistance (IR), induce inflammation and oxidative injury, ultimately altering muscle function. AIM: First, to study the relationship between body composition and age (independent variables) with skeletal muscle accumulation of lipid species, oxidative injury and strength. Second, to analyze the relationship between muscle tissue metabolites and insulin resistance, inflammation and lymphocyte telomere length, the latter as an indicator of ageing. METHODOLOGY: The sample included 56 healthy sedentary males, scheduled for inguinal hernia surgery, aged 27 to 80 y. Each individual was subject to anthropometric measurements, body composition assessment through radiologic densitometry (DEXA), measurement of handgrip and quadriceps strength, serum biochemical parameters (lipoproteins, creatinine, high sensitivity C reactive protein [hsCRP], fasting and post glucose insulin and glucose concentrations for calculation of IR through the Matsuda and HOMA-IR indexes), and extraction of peripheral leukocytes for measurement of telomere length. During the surgical procedure, a sample of muscle tissue was obtained (anterior abdominal oblique) in order to measure CER and DAG (and sub species according to chain length and saturation) by mass spectrometry, 4 hydroxy-2 nonenal adducts (4-HNE) using electron microscopy immunohistochemistry, and carboxymethyl-lisine (CML) by immunohistochemistry, the latter as indicators of oxidative stress (OS). RESULTS: Body mass index (BMI) of twenty six individuals was > 25 k/m2, while BMI of 7 was > 30 k/m2. Overweight/obese individuals, did not exhibit differences in skeletal muscle lipid metabolites, however total CER and specific long chain CER sub-species (20 and 22 carbon) increased significantly among individuals with a central fat distribution (n = 14) as well as in glucose intolerant subjects (n =23). A negative association was found between mononuclear leukocyte telomere length and 20 and 22 carbon CER (rho = - 0.4 and -0.5 0 p < 0.05). Muscle strength was not associated with any of the measured muscle metabolites or markers of OS. A multiple regression analysis accepted central abdominal fat and telomere length as significant predictors of CER (R2 = 0.28). CONCLUSIONS: An association was found between accumulation of specific ceramide species in muscle tissue and abdominal obesity, glucose intolerance and shortening of leukocyte telomeres, although not with muscle oxidative injury or dysfunction. PMID- 25809803 TI - Social and economic correlates of malnutrition in Polish elderly population: the results of PolSenior study. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence of malnutrition in Polish elderly population and analyse its social and economic correlates based on the data from the PolSenior project, the first large-scale study of a representative group of Polish seniors. DESIGN: A cross-sectional population based study. SETTING: All territorial provinces in Poland. PARTICIPANTS: 4482 community-dwelling respondents aged 65 years or above (women: n=2142, age=79.0+/ 8.4 years; men: n=2340, age= 78.3+/-8.6 years). MEASUREMENTS: The nutritional status of participants was assessed through the Mini Nutritional Assessment Short Form (the revised MNA-SF). Out of social and economic correlates we evaluated age, sex, level of education, marital status, place of residence, living conditions and economic status. Economic status of the respondents was determined on the basis of questions on how well they could manage their own budgets. Those who could afford only the cheapest food or clothes were considered the group of self-reported poverty. RESULTS: Frequency of malnutrition in the PolSenior population accounted for 7.5% (in 5.0% men and 9.0% women; p<0.001). The risk of malnutrition was present in 38.9% (33.3% men and 42.4% women; p<0.001). In our study female sex, older age, unmarried status, living in a rural area and self reported poverty were independent correlates of malnutrition. CONCLUSIONS: Our data showed high prevalence of malnutrition and the risk of its development among the community-dwelling elderly people in Poland. Screening with MNA-SF should focus in particular on unmarried, poorly educated individuals, in late old age, living in rural areas and self-reporting a poor financial state, especially women. PMID- 25809806 TI - Subjective sleep and cognitive complaints in 65 year old subjects: a significant association. The PROOF cohort. AB - OBJECTIVE: The prevalence of subjective sleep and cognitive complaints increases with age. The purpose of this study was to investigate the link between subjective cognitive and sleep complaints in a population aged 65. DESIGN AND SETTING: analysis of a cohort of 1011 subjects aged 65 years old at time of inclusion. METHODS: Older people underwent a cognitive tests battery and a nocturnal polygraphy recording. Subjective cognitive difficulties were scored on the McNair and Kahn Scale. Subjective sleep complaints were evaluated according to the St. Mary's Hospital Sleep Questionnaire and the Epworth Sleepiness Scale score. RESULTS: In a 65 years old population, an association between subjective cognitive difficulties and poor sleep quality was observed. This remained significant after adjustment on gender, depression score, anxiety, educational level, medication intake, Apnea/Hypopnea index, Body Mass Index and Mini-Mental State Examination (OR = 2.1; p = 0.0002). Similar significant association was demonstrated between subjective cognitive difficulties and daytime sleepiness (OR = 2.6; p = 0.0007). CONCLUSION: There was a significant association between subjective cognitive and sleep complaints, and daytime sleepiness in our population of older people. PMID- 25809804 TI - Adipokine pathways are altered in hippocampus of an experimental mouse model of Alzheimer's disease. AB - A growing body of evidence suggests that beta-amyloid peptides (Abeta) are unlikely to be the only factor involved in Alzheimer's disease (AD) aetiology. In fact, a strong correlation has been established between AD patients and patients with type 2 diabetes and/or cholesterol metabolism alterations. In addition, a link between adipose tissue metabolism, leptin signalling in particular, and AD has also been demonstrated. In the present study we analyzed the expression of molecules related to metabolism, with the main focus on leptin and prolactin signalling pathways in an APPswe/PS1dE9 (APP/PS1) transgenic mice model, at 3 and 6 months of age, compared to wild-type controls. We have chosen to study 3 months old APP/PS1 animals at an age when neither the cognitive deficits nor significant Abeta plaques in the brain are present, and to compare them to the 6 months-old mice, which exhibit elevated levels of Abeta in the hippocampus and memory loss. A significant reduction in both mRNA and protein levels of the prolactin receptor (PRL-R) was detected in the hippocampi of 3 months old APP/PS1 mice, with a decrease in the levels of the leptin receptor (OB-R) first becoming evident at 6 months of age. We proceeded to study the expression of the intracellular signalling molecules downstream of these receptors, including stat (1-5), sos1, kras and socs (1-3). Our data suggest a downregulation in some of these molecules such as stat-5b and socs (1-3), in 3 months-old APP/PS1 brains. Likewise, at the same age, we detected a significant reduction in mRNA levels of lrp1 and cyp46a1, both of which are involved in cholesterol homeostasis. Taken together, these results demonstrate a significative impairment in adipokine receptors signalling and cholesterol regulation pathways in the hippocampus of APP/PS1 mice at an early age, prior to the Abeta plaque formation. PMID- 25809805 TI - Nutrient patterns and brain biomarkers of Alzheimer's disease in cognitively normal individuals. AB - OBJECTIVES: Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease (AD) is rapidly increasing. However, there is little or no evidence for a direct association between dietary nutrients and brain biomarkers of AD. This study identifies nutrient patterns associated with major brain AD biomarkers in a cohort of clinically and cognitively normal (NL) individuals at risk for AD. DESIGN: Cross sectional study. SETTING: Manhattan (broader area). PARTICIPANTS: Fifty-two NL individuals (age 54+12 y, 70% women, Clinical Dementia Rating=0, MMSE>27, neuropsychological test performance within norms by age and education) with complete dietary information and cross-sectional, 3D T1-weighted Magnetic Resonance Imaging (MRI; gray matter volumes, GMV, a marker of brain atrophy), 11C Pittsburgh compound-B (PiB; a marker of fibrillar amyloid-beta, Abeta) and 18F fluorodeoxyglucose (FDG; a marker of glucose metabolism, METglc) Positron Emission Tomography (PET) scans were examined. MEASUREMENTS: Dietary intake of 35 nutrients associated with cognitive function and AD was assessed using the Harvard/Willet Food Frequency Questionnaire. Principal component analysis was used to generate nutrient patterns (NP) from the full nutrient panel. Statistical parametric mapping and voxel based morphometry were used to assess the associations of the identified NPs with AD biomarkers. RESULTS: None of the participants were diabetics, smokers, or met criteria for obesity. Five NPs were identified: NP1 was characterized by most B-vitamins and several minerals [VitB and Minerals]; NP2 by monounsaturated and polyunsaturated fats, including omega-3 and omega-6 PUFA, and vitamin E [VitE and PUFA]; NP3 by vitamin A, vitamin C, carotenoids and dietary fibers [Anti-oxidants and Fibers]; NP4 by vitamin B12, vitamin D and zinc [VitB12 and D]; NP5 by saturated, trans-saturated fats, cholesterol and sodium [Fats]. Voxel-based analysis showed that NP4 scores [VitB12 and D] were positively associated with METglc and GMV, and negatively associated with PiB retention in AD-vulnerable regions (p<0.001). In addition, both METglc and GMV were positively associated with NP2 scores [VitE and PUFA], and negatively associated with NP5 scores [Fats] (p<0.001), and METglc was positively associated with higher NP3 scores [Anti-oxidants and Fibers] (p<0.001). Adjusting for age, gender, ethnicity, education, caloric intake, BMI, alcohol consumption, family history and Apolipoprotein E (APOE) status did not attenuate these relationships. The identified 'AD-protective' nutrient combination was associated with higher intake of fresh fruit and vegetables, whole grains, fish and low-fat dairies, and lower intake of sweets, fried potatoes, high-fat dairies, processed meat and butter. CONCLUSION: Specific dietary NPs are associated with brain biomarkers of AD in NL individuals, suggesting that dietary interventions may play a role in the prevention of AD by modulating AD-risk through its effects on Abeta and associated neuronal impairment. PMID- 25809807 TI - Dietary patterns and incidence of depression in a cohort of community-dwelling older Canadians. AB - OBJECTIVES: To investigate the association of dietary patterns with a 3-year incidence of depression among healthy older adults. DESIGN: Multiple logistic regression models adjusted for age, sex, marital status, smoking, education, total energy intake, physical activity, body mass index, hypertension, functional autonomy, cognitive functioning, social activities, and stressful life events. Energy and macronutrient intakes were also analyzed as potential predictors of depression. SETTING: Cities of Montreal, Laval, and Sherbrooke in Quebec, CA. PARTICIPANTS: Community-dwelling older adults, free of depression at baseline (N=1,358, 67-84 y), followed for 3y in the Quebec Longitudinal Study on Nutrition and Aging (NuAge). MEASUREMENTS: Dietary patterns derived from principal components analysis of three 24 h-recalls at baseline, and depression incidence as measured by the 30-item Geriatric Depression Scale (>=11) and/or use of antidepressants at follow-up years. RESULTS: 170 people (63% women) became depressed over the 3 years. People in the highest tertile of adherence to the "varied diet" had lower risk of depression before adjustment (OR 0.58, 98% C.I. 0.38-0.86) but not significant once age and sex were controlled. No other dietary pattern was associated with the incidence of depression. The highest tertile of energy intake was associated with lower depression incidence after controlling for all confounders (OR 0.55, 95%CI 0.34-0.87). CONCLUSION: Among healthy older adults, dietary patterns do not appear to be related to depression. Those who eat less, however, possibly reflecting declining health, are at higher risk of becoming depressed. PMID- 25809808 TI - Effects of leucine-rich protein supplements on anthropometric parameter and muscle strength in the elderly: a systematic review and meta-analysis. AB - OBJECTIVE: The primary objective of the present systematic review and meta analysis was to synthesize the available literature relating to leucine supplementation in the elderly with respect to its effects on anthropometrical parameters and muscle strength. The secondary aim was to perform a selective subgroup analysis when possible differentiating between healthy and sarcopenic subjects. METHODS: Literature search was performed using the electronic databases MEDLINE, EMBASE, SportDiscus, and the Cochrane Central Register of trials with restrictions to randomized controlled trials or studies following a cross-over design. Parameters taken into account were body weight, body mass index, lean body mass, fat mass, percentage of body fat, hand grip strength, and knee extension strength. Moreover, biomarkers of glucose metabolism (fasting glucose, fasting insulin, albumin, and HOMA index) were extracted when possible. For each outcome measure of interest, a meta-analysis was performed in order to determine the pooled effect of the intervention in terms of weighted mean differences between the post-intervention (or differences in means) values of the leucine and the respective control groups. Data analysis was performed using the Review Manager 5.2.4. software. RESULTS: A total of 16 studies enrolling 999 subjects met the inclusion criteria. Compared with control groups, leucine supplementation significantly increased gain in body weight [mean differences 1.02 kg, 95%-CI (0.19, 1.85), p=0.02], lean body mass [mean differences 0.99 kg, 95%-CI (0.43, 1.55), p=0.0005], and body mass index [mean differences 0.33 kg/m2, 95%-CI (0.13, 0.53), p=0.001], when compared to the respective control groups. With respect to body weight and lean body mass, leucine supplementation turned out to be more effective in the subgroup of study participants with manifested sarcopenia. All other parameters under investigation were not affected by leucine supplementation in a fashion significantly different from controls. CONCLUSIONS: It is concluded that leucine supplementation was found to exert beneficial effects on body weight, body mass index, and lean body mass in older persons in those subjects already prone to sarcopenia, but not muscle strength. However, due to the heterogeneity between the trials included in this systematic review, further studies adopting a homogenous design with respect to participant characteristics duration as well as the kind and amount of daily supplement in use are required. PMID- 25809809 TI - Providing instrumental social support is more beneficial to reduce mortality risk among the elderly with low educational level in Taiwan: a 12-year follow-up national longitudinal study. AB - BACKGROUND: To evaluate whether the effects of providing or receiving social support are more beneficial to reduce mortality risk among the elderly with different educational levels. METHODS: In this long-term prospective cohort study, data were retrieved from the Taiwan Longitudinal Study on Aging. This study was initiated from 1996 until 2007. The complete data from 1492 males and 1177 females aged >=67 years were retrieved. Participants received financial, instrumental, and emotional support, and they actively provided instrumental and emotional support to others and involved in social engagement. Education attainment was divided into two levels: high and low. The low education level included illiterate and elementary school. The high education level included junior high school to senior high school and above college. Cox regression analysis was used to examine the association between providing or receiving social support on mortality with different educational levels. RESULTS: The average age of the participants in 1996 was 73.0 (IQR=8.0) years, and the median survival following years (1996-2007) of participants was 10.3 (IQR=6.7) years. Most participants were low educational level including illiterate (39.3%) and elementary school (41.2%). Participants with high educational level tend to be younger and more male significantly. On the contrary, participants with low educational level tend to have significant more poor income, more depression, more cognition impairment, more with IADL and ADL disability than high educational level. Most participants received instrumental support from others (95.5%) and also provided emotional support to others (97.7%). Providing instrumental support can reduce 17% of mortality risk among the elderly with a low level of education after adjusting several covariates [Hazard ratio (HR) = 0.83; 95% confidence interval (CI) = 0.70-0.99; p = 0.036]. CONCLUSIONS: Providing instrumental social support to others confer benefits to the giver and prolong life expectancy among the elderly with low educational levels. PMID- 25809810 TI - Tailored nutritional guidance for home-dwelling AD families: the Feasibility of and Elements Promoting Positive Changes in Diet (NuAD-Trial). AB - OBJECTIVES: To describe the process and feasibility of our randomised, controlled intervention study (NuAD trial) that positively affected the nutrition and quality of life, and prevented falls of home-dwelling persons with Alzheimer disease (AD). DESIGN, SETTING, PARTICIPANTS: This qualitative study comprised 40 persons with AD and spousal caregivers of our trial. Our intervention during one year involved tailored nutritional guidance for these couples. The nutritionist's field notes (about 100 pages) and the participant feedback questionnaires (N = 28) served to analyse the feasibility of intervention, factors promoting the application of intervention and challenges hindering it. Thematic content analysis served to analyse our data with the grounded theory approach. RESULTS: We identified several positive elements promoting better nutrition: positive attitudes on nutrition to participants including a participant-centred approach, positive feedback, findings of food diaries and practical suggestions. Home visits by the nutritionist were convenient and participants felt that someone cares. Group meetings which included protein-rich snacks strengthened the nutritional message by enabling discussions and socialising. The oral nutritional supplements (ONS) helped participants to regain their energy and to motivate them to exercise and make changes in their diets. Obstacles to making changes in diets included participants' false ideas about nutrition, especially with regard to weight gain. Health problems and functional limitations hampered food management, and some families had inveterate eating habits. The positive feedback from participants indicated the feasibility of our tailored nutritional guidance. CONCLUSIONS: Assessment-based, tailored nutritional guidance implemented with a personal and positive approach may inspire and empower AD families to make positive changes in their diets, leading them to improved nutrition and quality of life. PMID- 25809811 TI - Body mass index, Mini Nutritional Assessment, and their association with five year mortality in very old people. AB - OBJECTIVES: to investigate the prevalence of malnutrition and the association between Body Mass Index (BMI), Mini Nutritional Assessment (MNA) and five-year mortality in a representative population of very old (>85 years) people. DESIGN: A prospective cohort study. SETTING: A population-based study of very old people in northern Sweden and western Finland, living in institutional care or in the community. PARTICIPANTS: Out of 1195 potential participants, 832 were included (mean age 90.2+/-4.6 years). MEASUREMENTS: Nutritional status was assessed using BMI and MNA and the association of those two variables with five-year mortality was analyzed. RESULTS: The mean BMI value for the whole population was 25.1+/-4.5 kg/m2, with no difference between genders (P=0.938). The mean MNA score was 22.5+/-4.6 for the whole sample, and it was lower for women than for men (P<0.001). Thirteen percent were malnourished (MNA<17) and 40.3% at risk of malnutrition (MNA 17-23.5) according to MNA. Also, 34.8% of those with a MNA score <17 still had a BMI value >=22.2 kg/m2. A BMI value <22.2 kg/m2 and a MNA score<17 were associated with lower survival. The association with mortality seemed to be J-shaped for BMI, and linear for MNA. CONCLUSIONS: Malnutrition according to MNA was common, but a substantial portion of those with a low MNA score still had a high BMI value, and vice versa. The association with mortality appeared to be J-shaped for BMI, and linear for MNA. The MNA seems to be a good measurement of malnutrition in very old people, and BMI might be misleading and could underestimate the prevalence of malnutrition, especially in women. PMID- 25809812 TI - Walking and psychomotor speed in the elderly: concordance, correlates and prediction of death. AB - OBJECTIVES: To investigate the concordance between walking (WS) and psychomotor speed (PS), correlates of both tasks, and their capacity to predict mortality in the elderly. DESIGN, SETTING AND PARTICIPANTS: Seven-year cohort study of 1,365 community-dwelling subjects aged 65-95 years, participating in the Bordeaux sample of the Three City Study, a French prospective cohort designed to evaluate the risk of cognitive decline attributable to vascular risk factors. MEASUREMENTS: Participants completed a battery of cognitive assessments including time to complete Trail Making Test A used as a PS measure, and a measure of WS. Socio-demographic determinants, co-morbidities, functional and cognitive evaluation, and incident mortality were taken into account. RESULTS: Mean age was 75.7 (SD +/- 5.4) years. WS and TMT-A speed have very low concordance (kappa coefficient=.05). The correlates of each measure were different: mostly clinical co-morbidities for WS, and mostly cognition and function for TMT-A speed. However, TMT-A speed and WS are both independent predictors of death after seven years of follow-up. CONCLUSION: WS and TMT-A speed could be considered as two different dimensions of age-related slowness, but both performances were associated with higher risk of mortality. PMID- 25809813 TI - Comprehensive nutritional status in sarco-osteoporotic older fallers. AB - OBJECTIVES: In older persons, the combination of osteoporosis and sarcopenia has been proposed as a subset of frailer individuals at higher risk of falls and fractures. However, the particular nutritional status of the sarco-osteoporotic (SOP) patients remains unknown. The goal of this study was to obtain a comprehensive picture of nutritional status in SOP patients. DESIGN: Cross sectional study. SETTING: Falls and Fractures Clinic, Nepean Hospital (Penrith, Australia). PARTICIPANTS: 680 subjects (mean age=79, 65% female) assessed between 2008-2013. MEASUREMENTS: Assessment included medical history, mini-nutritional assessment, physical examination, bone densitometry and body composition by DXA, and blood tests for nutritional status (albumin, creatinine, hemoglobin, vitamin D, vitamin B-12, calcium, phosphate and folate). Patients were divided in 4 groups: 1) osteopenia/osteoporosis (BMD<-1.0 SD); 2) sarcopenia; 3) SOP; and 4) normal (no sarcopenia/no osteoporosis). Difference between groups was assessed with one-way ANOVA and chi square analysis. Multivariable linear regression evaluated the association between the groups and measures of nutritional parameters. RESULTS: Sarcopenia was present in 47.4% of those with osteopenia (167/352) and 62.7% in those with osteoporosis (91/145). Mean age of the SOP was 80.4+/-7 years. SOP patients showed significantly higher prevalence of falls and fractures. Univariate analyses showed that SOP were more likely than normal to have a BMI< 25 (OR 2.42 95%CI 1.45-4.041, p<0.001), a MNA score <12 (OR 2.0, 95%CI 1.15-3.49, p<0.05), serum folate <20 nmol/L (OR 4.0 95%CI 1.35-11.87, p<0.01) and hemoglobin <120g/L (OR 2.0 95%CI 1.28-3.30, p<0.01). Multivariate analysis showed that a MNA score <12 was independently associated with SOP compared to normal when adjusted for age and gender. Hemoglobin <120g/L, BMI <25, and GDS >6 remained independently associated with SOP after adjustment for all variables including inflammatory conditions. Hypoalbuminemia (<35 g/L) was associated with just osteopenia/osteoporosis (OR: 2.03, 95%CI 1.08-3.81, p<0.01) and just sarcopenia (OR: 1.77, 95%CI 1.0-3.0, p<0.01) compared to normal. No differences in vitamin D, glomerular filtration rate, albumin, corrected calcium, phosphate, red blood cells folate or vitamin B12 levels were found between the subgroups. CONCLUSIONS: In approaching SOP patients, early prevention protocols directed to optimize their nutritional status would be a key strategy to prevent poor outcomes such as falls and fractures in this high risk population. Therefore, nutritional assessment and early nutritional supplementation should be essential domains in this strategy. PMID- 25809814 TI - Prognostic factors of long-term survival in geriatric inpatients. Should we change the recommendations for the oldest people? AB - OBJECTIVES: Identification of optimal predictors of the 5.5-year survival in former geriatric inpatients.Investigation of the direction and shape of the relationship between mortality risk and its predictors. DESIGN: Retrospective survival analysis with the application of the Cox proportional hazards model. SETTING: Teaching geriatric unit. PARTICIPANTS: 478 inpatients (mean age 77.9; +6.8) discharged from geriatric ward during year 2008, without any exclusion criteria. MEASUREMENTS: Comprehensive geriatric assessment of numerous health variables, body mass index (BMI), clinical and biochemical findings, and outcomes of the final diagnosis. Records on the dates of deaths were obtained from the Provincial Office of Population Register. RESULTS: During the 5.5-year follow-up 209 (43.7%) patients died. In the multivariate setup, six risk factors with an independent impact on mortality were identified: age (p=0.036), cognitive functioning on the Blessed test (p=0.005), score on instrumental ADL (p<0.0001), score on Charlson comorbidity index (p<0.0001), cholesterol level (p<0.0001), BMI (p<0.0001), and hemoglobin level (p=0.02). The latter two predictors exhibited a significant inverted J-shaped association with mortality, i.e., considerably higher risk of death corresponds to the lower values of these variables in comparison to their higher levels. CONCLUSION: Older age, worse IADL and cognitive functioning, and higher comorbidity were recognized as endangering one's long-term survival. On the other hand, moderate obesity (BMI 36), higher cholesterol and the absence of anemia (hemoglobin 13.6 g/dL) are associated with longer survival. Therefore, irrespective of the individualized treatment and physical exercise, nutrient-dense food seems to be a key recommendation to prevent frailty or malnutrition in the oldest and comorbid population. PMID- 25809815 TI - Two-stage designs for cross-over bioequivalence trials. AB - The topic of applying two-stage designs in the field of bioequivalence studies has recently gained attention in the literature and in regulatory guidelines. While there exists some methodological research on the application of group sequential designs in bioequivalence studies, implementation of adaptive approaches has focused up to now on superiority and non-inferiority trials. Especially, no comparison of the features and performance characteristics of these designs has been performed, and therefore, the question of which design to employ in this setting remains open. In this paper, we discuss and compare 'classical' group sequential designs and three types of adaptive designs that offer the option of mid-course sample size recalculation. A comprehensive simulation study demonstrates that group sequential designs can be identified, which show power characteristics that are similar to those of the adaptive designs but require a lower average sample size. The methods are illustrated with a real bioequivalence study example. PMID- 25809816 TI - Prevalence and triage of first-contact complaints on pelvic floor dysfunctions in female patients at a Pelvic Care Centre. AB - AIMS: (i) To describe and analyse pelvic floor dysfunction symptoms in women referred to a Pelvic Care Centre (PCC). (ii) To describe the triage process of the same patients based on response to a first-contact interview. METHODS: Triage started with a telephone interview using previously constructed questions, asking for seven types of PF complaints during the preceding 6 months. If present, complaint severity was registered on a 0-10 scale. Next, these first-contact complaints were used to describe patient case mix profiles using cross-tabular analysis. Later on, at first PCC visit, an intake questionnaire containing questions on specific PF health problem(s) was filled out. This procedure contributed to a firm baseline characterization of the individual patient profile and a clinically valid allocation to structured, predefined assessment, and treatment. RESULTS: From 2005 to 2013, 4473 first-time patients (mean age 56.9 (SD 16.2) have been referred to the PCC. Most frequently mentioned complaints: voiding dysfunction (59.5%), urinary incontinence (46.6%), prolapse (41.1%), fecal incontinence (15.1%), constipation (12.6%), and sexual problems (4.6%). A first appointment to a single specialist was determined in 3.110 (69.5%) patients, in 1.192 (26.7%) consultation of >1 specialist. Data analysis revealed higher-order interactions between PF complaints, suggesting patient profile complexity and patient population heterogeneity. CONCLUSIONS: More than one out of four PCC patients showed multifactorial problems, needing >1 specialist. PF complaints either turned out to stand alone or cluster with others, or even to strengthen, weaken, nullify, or inverse relationships. Neurourol. Urodynam. 35:503-508, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25809817 TI - Repair of spinal cord injury by chitosan scaffold with glioma ECM and SB216763 implantation in adult rats. AB - The loss of spinal cord tissue and the cavity formation are major obstacles to the repair of spinal cord injury (SCI). In the study, the scaffold of chitosan+ECM+SB216763 was fabricated and used for the repair of injured spinal cord injury. First, the biocompatibility of the scaffold was analyzed and results showed that the scaffold had a good compatibility with the neural stem cells. Especially, the processes of differentiated neural stem cell embedded in the scaffold were found in the experiment. At the same time, we also investigated the effect of scaffold on the differentiation of neural stem cell. The results showed that the scaffold of chitosan+ECM+SB216763 could significantly promote the differentiation of neural stem cells into neurons, astrocytes, and oligodendrocytes relative to those in other groups. In order to probe the application of scaffold in vivo, the rat models of spinal cord hemisection were set up and scaffolds were implanted into transected gap. Then the electrophysiology and BBB score were evaluated and results showed that the amplitude, latency period and BBB score in chitosan+ECM+SB216763 group were dramatically better than those in other groups. In addition, the differentiation of neural stem cells into nerve cells was also assayed and the results revealed that the number of neural stem cells differentiating into neuron, astrocytes and oligodendrocytes in chitosan+ECM+SB216763 group was significantly bigger than those in other groups. All these data suggested that the scaffold of chitosan+ECM+SB216763 would be a promising medium for the repair of injured spinal cord. PMID- 25809818 TI - Cell size versus body size in geophilomorph centipedes. AB - Variation in animal body size is the result of a complex interplay between variation in cell number and cell size, but the latter has seldom been considered in wide-ranging comparative studies, although distinct patterns of variation have been described in the evolution of different lineages. We investigated the correlation between epidermal cell size and body size in a sample of 29 geophilomorph centipede species, representative of a wide range of body sizes, from 6 mm dwarf species to gigantic species more than 200 mm long, exploiting the marks of epidermal cells on the overlying cuticle in the form of micro-sculptures called scutes. We found conspicuous and significant variation in average scute area, both between suprageneric taxa and between genera, while the within-species range of variation is comparatively small. This supports the view that the average epidermal cell size is to some extent taxon specific. However, regression analyses show that neither body size nor the number of leg-bearing segments explain this variation, which suggests that cell size is not an usual target of change for body size evolution in this group of arthropods, although there is evidence of its correlation with other morphological variables, like cuticle thickness. Scute sizes of miniaturized geophilomorph species are well within the range of the lineage to which the species belong, suggesting recent evolutionary transitions to smaller body size. PMID- 25809819 TI - Structure and process quality as predictors of satisfaction with elderly care. AB - The structure versus process approach to quality of care presented by Donabedian is one of the most cited ever. However, there has been a paucity of research into the empirical validity of this framework, specifically concerning the relative effects of structure and process on satisfaction with elderly care as perceived by the older persons themselves. The current research presents findings from a national survey, including a wide range of quality indicators for elderly care services, conducted in 2012 at the request of the Swedish National Board of Health and Welfare in which responses from 95,000 elderly people living in 324 municipalities and districts were obtained. The results revealed that the only structural variable which significantly predicted quality of care was staffing, measured in terms of the number of caregivers per older resident. More interestingly, process variables (e.g. respect and access to information) explained 40% and 48% of the variance in satisfaction with care, over and above the structural variables, in home care and nursing homes respectively. The findings from this large nationwide sample examining Donabedian's model suggest that quality in elderly care is primarily determined by factors pertaining to process, that is, how caregivers behave towards the older persons. This encourages a continued quality improvement in elderly care with a particular focus on process variables. PMID- 25809820 TI - A review of the management of 84 cases of nasal polyposis in a Tertiary Otorhinolaryngology Centre: Our experience. PMID- 25809821 TI - Lymphomatous variant of hairy cell leukaemia: a distinctive presentation mimicking low-grade B-cell lymphoma. AB - AIMS: Hairy cell leukaemia (HCL) is an indolent B-cell neoplasm that primarily involves the peripheral blood, bone marrow, and spleen. Rarely, patients with HCL present with a lymphoma-like clinicopathological picture mimicking other types of low-grade B-cell lymphoma. Distinguishing HCL from other types of lymphoma is essential, given the different treatments and prognoses. We report two cases of the lymphomatous variant of HCL to draw attention to this unusual presentation. METHODS AND RESULTS: Two cases of HCL presented initially as salivary gland and soft tissue masses. Morphologically, the neoplastic cells showed a typical fried egg or monocytoid appearance with reniform nuclei, and were positive for CD11c, CD20, CD25, CD103, annexin A1, and cyclin D1. Both cases were positive for the BRAF V600E mutation, as shown by pyrosequencing and mutation-specific immunohistochemistry. The diagnosis was challenging in both patients, and one patient experienced 5 years of disease relapse and progression after treatment with multiple lymphoma-type regimens before the final diagnosis of HCL was established and complete remission was achieved following cladribine therapy. CONCLUSIONS: HCL can very rarely present as an extranodal mass. Being aware of this unusual presentation of HCL is essential to avoid diagnostic confusion with other types of low-grade B-cell lymphoma and to facilitate appropriate therapy. PMID- 25809822 TI - Fear of cancer is associated with cancer information seeking, scanning and avoiding: a cross-sectional study among cancer diagnosed and non-diagnosed individuals. AB - BACKGROUND: Nowadays, there is an abundance of health and cancer information in the mass media. Because of this high amount of information, it is possible for individuals to find or incidentally encounter cancer information, but it is also possible to be overloaded by this information and, consequently, to avoid it. Previous studies have indicated that fear of cancer could be both positively and negatively related to behaviours such as screening, help-seeking and information avoidance. OBJECTIVE: The aims of this study were (1) to assess the relationship between fear of cancer and cancer information acquisition and avoiding behaviour, (2) to examine whether this relationship was curvilinear, and (3) to determine whether this relationship was moderated by being diagnosed with cancer or not. METHOD: Six hundred and twenty-one cancer diagnosed and 1387 non-diagnosed individuals were recruited through a convenience sample in Flanders (Belgium) and filled in a standardised survey questionnaire. RESULTS: The results showed a positive linear association between fear of cancer and information seeking, scanning and avoiding. Being diagnosed with cancer or not did not moderate this relationship. CONCLUSION: Fear of cancer is positively associated with cancer information acquisition and avoiding behaviour. This suggests that fear of cancer predicts different behaviours in different individuals. PMID- 25809823 TI - Abnormalities in chromosome 6q24 as a cause of early-onset, non-obese, non autoimmune diabetes mellitus without history of neonatal diabetes. AB - AIMS: Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus (6q24-related transient neonatal diabetes). 6q24-Related transient neonatal diabetes is characterized by the patient being small-for-gestational age, diabetes mellitus at birth, spontaneous remission within the first few months and frequent recurrence of diabetes after childhood. However, it is not clear whether individuals with 6q24 abnormalities invariably develop transient neonatal diabetes. This study explored the possibility that 6q24 abnormalities might cause early-onset, non-autoimmune diabetes without transient neonatal diabetes. METHODS: The 6q24 imprinted locus was screened for abnormalities in 113 Japanese patients with early-onset, non obese, non-autoimmune diabetes mellitus who tested negative for mutations in the common maturation-onset diabetes of the young (MODY) genes and without a history of transient neonatal diabetes. Positive patients were further analysed by combined loss of heterozygosity / comparative genomic hybridization analysis and by microsatellite analysis. Detailed clinical data were collected through the medical records of the treating hospitals. RESULTS: Three patients with paternal uniparental isodisomy of chromosome 6q24 were identified. None presented with hyperglycaemia in the neonatal period. Characteristically, these patients were born small-for-gestational age, representing 27.2% of the 11 patients whose birth weight standard deviation score (SDS) for gestational age was below -2.0. CONCLUSIONS: Abnormalities in the imprinted locus on chromosome 6q24 do not necessarily cause transient neonatal diabetes. Non-penetrant 6q24-related diabetes could be an underestimated cause of early-onset, non-autoimmune diabetes in patients who are not obese and born small-for-gestational age. PMID- 25809825 TI - Bearded saki feeding strategies on an island in Lago Guri, Venezuela. AB - Free-ranging bearded sakis (Chiropotes spp.) live in relatively large social groups (22-65+), inhabit very large home ranges (200-1,000 ha), and travel long distances (1.8 to >7 km) each day. While these characteristics would seem to reduce their ability to occupy habitat fragments, several studies suggest otherwise. The key to their success may lie in their dietary adaptations. Bearded sakis are strongly frugivorous, but are primarily seed eaters, and are able to ingest both young and mature fruit. We examined feeding activities of a group of bearded sakis over a 19-month period on a 180 ha island in Lago Guri, Venezuela. Given their feeding adaptations, we predicted that they would minimize peaks and troughs in plant species used for food, limit seasonal variation in the mechanical properties of foods ingested, and balance ingestion of energy-rich foods (e.g. lipids, nonstructural carbohydrates (TNC), and/or free simple sugars). We found that bearded sakis on Danto Manchado had a diverse (plant based) diet, but two resources (Pradosia caracasana, Sapotaceae, and Oryctanthus alveolatus, Loranthaceae) provided a stable dietary base and were present in the diet almost every month. Second, we found little variation in the mechanical resistance properties of fruits opened seasonally. Third, they alternated months ingesting foods with high TNC content and months of high lipid content. This may be an attempt to balance energy intake from available foods. Finally, their social propensity to split up into subgroups may predispose them to reduce group sizes to accommodate smaller available areas. We suggest that bearded sakis use both ecological and behavioral mechanisms to survive in smaller-than-typical areas. Longer-term studies (beyond a few generations) of bearded sakis in habitat fragments would allow us to estimate minimum survival area and identify critical resources or resource combinations. PMID- 25809824 TI - Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer. AB - BACKGROUND: We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study. METHODS: Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m(2) we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response. RESULTS: In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35-4.63). CONCLUSIONS: In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583. PMID- 25809826 TI - In Obese Patients, the Distance Between Skin and Renal Collecting System Changes with the Position of the Patient from Supine to Prone. AB - PURPOSE: To investigate how prone and supine redistribution of a patient's adipose tissue affects the distance from skin to the renal collecting system. METHODS: There were 48 patients who underwent CT intravenous urography with both supine and prone scans. The distance between skin and the posterior lower pole calix was measured in both positions. The difference was calculated using paired t tests. Subgroup analyses were conducted for patients with a body mass index (BMI) >= 28 and BMI >= 30. RESULTS: In all patients, the mean distance between skin and the posterior lower pole calix was 9.9 +/- 0.3 cm and 8.7 +/- 0.3 cm for patients supine and prone, respectively (P < 0.01). Patients with a BMI >= 28 had a mean distance of 10.6 +/- 0.3 cm and 8.8 +/- 0.3 cm in supine and prone positions, respectively (P < 0.01), while patients with BMI >= 30 had a mean distance of 11.3 +/- 0.3 cm and 9.3 +/- 0.3 cm (P < 0.01). Three patients had a BMI > 39 and exhibited differences in skin to the posterior lower pole calix >= 3.2 cm between supine and prone positioning. Coefficient of determination analysis for supine minus prone tract length yielded R(2) = 0.70895. CONCLUSION: The distance between skin and the renal collecting system is decreased in the prone position when compared with the supine position. This difference increases with the patient's BMI and is further accentuated in morbidly obese patients. In these obese patients, the difference when lying prone can exceed >4 cm. PMID- 25809827 TI - A multinational examination of weight bias: predictors of anti-fat attitudes across four countries. AB - BACKGROUND/OBJECTIVES: As rates of obesity have increased throughout much of the world, so too have bias and prejudice toward people with higher body weight (that is, weight bias). Despite considerable evidence of weight bias in the United States, little work has examined its extent and antecedents across different nations. The present study conducted a multinational examination of weight bias in four Western countries with comparable prevalence rates of adult overweight and obesity. METHODS: Using comprehensive self-report measures with 2866 individuals in Canada, the United States, Iceland and Australia, the authors assessed (1) levels of explicit weight bias (using the Fat Phobia Scale and the Universal Measure of Bias) and multiple sociodemographic predictors (for example, sex, age, race/ethnicity and educational attainment) of weight-biased attitudes and (2) the extent to which weight-related variables, including participants' own body weight, personal experiences with weight bias and causal attributions of obesity, play a role in expressions of weight bias in different countries. RESULTS: The extent of weight bias was consistent across countries, and in each nation attributions of behavioral causes of obesity predicted stronger weight bias, as did beliefs that obesity is attributable to lack of willpower and personal responsibility. In addition, across all countries the magnitude of weight bias was stronger among men and among individuals without family or friends who had experienced this form of bias. CONCLUSIONS: These findings offer new insights and important implications regarding sociocultural factors that may fuel weight bias across different cultural contexts, and for targets of stigma reduction efforts in different countries. PMID- 25809828 TI - Urinary (1)H-NMR-based metabolic profiling of children with NAFLD undergoing VSL#3 treatment. AB - BACKGROUND: Nowadays, non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children. Our recent clinical trial demonstrated that dietary and VSL#3-based interventions may improve fatty liver by ultrasound and body mass index (BMI) after 4 months. OBJECTIVES: As in this short-term trial, as in others, it is impracticable to monitor response to therapy or treatment by liver biopsy, we aimed to identify a panel of potential non-invasive metabolic biomarkers by a urinary metabolic profiling. METHODS: Urine samples from a group of 31 pediatric NAFLD patients, enrolled in a VSL#3 clinical trial, were analyzed by high-resolution proton nuclear magnetic resonance spectroscopy in combination with analysis of variance-Simultaneous Component Analysis model and multivariate data analyses. Urinary metabolic profiles were interpreted in terms of clinical patient feature, treatment and chronology pattern correlations. RESULTS: VSL#3 treatment induced changes in NAFLD urinary metabolic phenotype mainly at level of host amino-acid metabolism (that is, valine, tyrosine, 3-amino-isobutyrate or beta-aminoisobutyric acid (BAIBA)), nucleic acid degradation (pseudouridine), creatinine metabolism (methylguanidine) and secondarily at the level of gut microbial amino-acid metabolism (that is, 2-hydroxyisobutyrate from valine degradation). Furthermore, some of these metabolites correlated with clinical primary and secondary trial end points after VSL#3 treatment: tyrosine and the organic acid U4 positively with alanine aminotransferase (R=0.399, P=0.026) and BMI (R=0.36, P=0.045); BAIBA and tyrosine negatively with active glucagon-like-peptide 1 (R=-0.51, P=0.003; R= 0.41, P=0.021, respectively). CONCLUSIONS: VSL#3 treatment-dependent urinary metabotypes of NAFLD children may be considered as non-invasive effective biomarkers to evaluate the response to treatment. PMID- 25809829 TI - Strong association of serum- and glucocorticoid-regulated kinase 1 with peripheral and adipose tissue inflammation in obesity. AB - OBJECTIVE: The serum- and glucocorticoid-regulated kinase 1 (SGK1) is an early transcriptional target of glucocorticoids and is activated via insulin. Here we investigate the regulation of SGK1 expression in human obesity, diet-induced murine obesity and human monocytic cell line THP-1 monocytes. SUBJECTS AND METHODS: SGK1 expression was studied in subcutaneous and omental adipose tissue (AT) of 20 morbidly obese and 20 age- and gender-matched non-obese controls in murine diet-induced obesity and the THP-1 cell line. The regulation of SGK1 by inflammatory signals was tested in THP-1 cells. RESULTS: Murine diet-induced obesity is associated with a significant upregulation of Sgk1 in gonadal AT. Sgk1 expression is highest in the macrophage-rich stromal vascular fraction and lower in adipocytes. In humans, AT SGK1 is predominantly expressed in CD14(+) macrophages and significantly upregulated in omental and subcutaneous AT of obese subjects. SGK1 mRNA expression in both omental and subcutaneous AT correlates with body mass index, circulating leptin and C-reactive protein, and the local expression of inflammatory markers including monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. The expression of SGK1 in THP-1 cells is upregulated by inflammatory signals, such as lipopolysaccharide and tumour necrosis factor-alpha, as well as during the induction of monocyte-to-macrophage maturation. CONCLUSIONS: Our data present the first link between SGK1 and obesity associated inflammation. SGK1 expression is stimulated in response to inflammatory signals and increased in AT macrophages. The characterisation of SGK1 functions in obesity and immunity may help identify potential therapeutic targets in the treatment of obesity. PMID- 25809830 TI - Allergic conjunctivitis: a cross-sectional study. AB - BACKGROUND: Ocular allergy is a common disease in daily practice. OBJECTIVES: A cross-sectional study was conducted to evaluate clinical aspects of and therapeutic approaches to ocular allergy in Italy. METHODS: Of the 3685 patients affected by ocular allergy and enrolled by 304 ophthalmologists nationally, 3545 were eligible to be included in the statistical analysis. A questionnaire was administered in office to record demographic data, comorbidities, trigger factors, number of conjunctivitis episodes, and past treatments. Signs and symptoms were graded according to their severity, frequency, and duration. RESULTS: Mean age of enrolled patients was 38 +/- 19 years. Seasonal allergic conjunctivitis (55% of patients) was equally distributed among the different age groups, while perennial allergic conjunctivitis (18%) increased with age and vernal keratoconjunctivitis (9%) was more frequent under the age of 18. Itching and redness were reported in 90% and 85%, respectively; lid skin involvement was observed in 22% of cases and keratitis in 11%. Pollen sensitivities were indicated as the most frequent triggers; however, exposure to non-specific environmental conditions, pollutants, and cigarette smoke was frequently reported. Only 35% of patients underwent a diagnostic evaluation of specific allergic sensitization, with positive allergy tests found in 82% of this subset. With regard to treatment, topical decongestants were used in 43% of patients, corticosteroids in 41%, antihistamines in 29%, systemic antihistamines in 27%, and mast cell stabilizers in 15%. CONCLUSION: This survey provided useful epidemiological information regarding the clinical characteristics and treatment options of a large cohort of patients affected by different forms of ocular allergy. CLINICAL RELEVANCE: An understanding of ocular allergic disease, its incidence, demographics, and treatment paradigms provides important information towards understanding its pharmacoeconomics and burden on the national health system. PMID- 25809834 TI - Mumps encephalitis with akinesia and mutism. AB - Measles-rubella-mumps vaccination is routine in many countries, but the mumps vaccine remains voluntary and is not covered by insurance in Japan. A 5-year-old Japanese boy who had not received the mumps vaccine was affected by mumps parotitis. Several days later, he presented with various neurological abnormalities, including akinesia, mutism, dysphagia, and uncontrolled respiratory disorder. Mumps encephalitis was diagnosed. Despite steroid pulse and immunoglobulin treatment, the disease progressed. Magnetic resonance imaging showed necrotic changes in bilateral basal ganglia, midbrain, and hypothalamus. At 1 year follow up, he was bedridden and required enteral feeding through a gastric fistula and tracheostomy. Mumps vaccination should be made routine as soon as possible in Japan, because mumps encephalitis carries the risk of severe sequelae. PMID- 25809835 TI - Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat. AB - This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the 'tonic' period immediately preceding locomotor-like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor-like episodes. Locomotion was identified by alternating flexor extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as 'idle' motoneurones. LDP and idle motoneurones during locomotion had hyperpolarized spike threshold (Vth ; LDP: 3.8 mV; idle: 5.8 mV), decreased rheobase and an increased discharge rate (LDP: 64%; idle: 41%) during triangular ramp current injection even though the frequency-current slope was reduced by 70% and 55%, respectively. Modulation began in the tonic period immediately preceding locomotion, with a hyperpolarized Vth and reduced rheobase. Spike frequency adaptation did not occur in spiking LDPs or firing generated from sinusoidal current injection, but occurred during a sustained current pulse during locomotion. Input conductance showed no change. Results suggest motoneurone modulation occurs across the pool and is not restricted to motoneurones engaged in locomotion. PMID- 25809837 TI - Relief of dysphagia during neoadjuvant treatment for cancer of the esophagus or gastroesophageal junction. AB - Dysphagia is the main symptom of cancer of the esophagus and gastroesophageal junction and causing nutritional problems and weight loss, often counteracted by insertion of self-expandable metal stents or nutrition via an enteral route. Clinical observations indicate that neoadjuvant therapy may effectively and promptly alleviate dysphagia, making such nutrition supportive interventions redundant before surgical resection. The objective of the current study was to carefully study the effects of induction neoadjuvant therapy on dysphagia and its subsequent course and thereby investigate the actual need for alimentary gateways for nutritional support. Thirty-five consecutive patients scheduled for neoadjuvant therapy were recruited and assessed regarding dysphagia and appetite at baseline, after the first cycle of preoperative treatment with either chemotherapy alone or with chemoradiotherapy and before surgery. Platinum-based therapy in combination with 5-fluorouracil was administered intravenously days 1 5 every 3 weeks and consisted of three treatments. Patients receiving combined chemoradiotherapy started radiotherapy on day one of second chemotherapy cycle. They received fractions of 2 Gy/day each up to a total dose of 40 Gy. Watson and Ogilvie dysphagia scores were used to assess dysphagia, while appetite was assessed by the Edmonton Assessment System Visual analogue scale-appetite questionnaire. Patients were evaluated at regular outpatient clinic visits or by telephone. The histological tumor response in the surgical specimen was assessed using the Chirieac scale. Ten patients scheduled for neoadjuvant chemotherapy and 25 patients scheduled for chemoradiotherapy were included in the analysis. There was a significant improvement in dysphagia in both treatment groups, according to both scales, already from baseline to the completion of the first chemotherapy cycle which remained to the end of the neoadjuvant treatment (P < 0.001). Appetite also improved after the first chemotherapy cycle (P = 0.03). Body weight did not change during any type of neoadjuvant therapy. We were unable to demonstrate any association between relief of dysphagia and the degree of histological response to neoadjuvant therapy in the surgical specimen. The present study shows that a platin - 5FU-based neoadjuvant chemotherapy, with or without concomitant radiotherapy, effectively and promptly relieves dysphagia in patients presenting with cancers of the esophagus or gastroesophageal junction already after the first cycle. PMID- 25809836 TI - Human rights of children with intellectual disabilities: comparing self-ratings and proxy ratings. AB - BACKGROUND: A child rights-based approach to research articulates well with Article 12 of the United Nations Convention on the Rights of the Child (CRC) and highlights the importance and value of including children's own views about aspects that concern them. The aim of this study is to compare children with intellectual disability's own ratings (as self-raters) to those of their primary caregivers (as proxy raters) regarding human rights of children. The study also aims to establish whether there is an inter-rater agreement between the self raters and proxy raters concerning Maslow's hierarchy of needs. METHOD: This study is nested in a larger study examining the human rights of children with intellectual disability in South Africa. In total, 162 children with intellectual disability from 11 schools across three provinces and their primary caregivers participated by answering parts of a Children's Rights Questionnaire (CRQ) developed by the researchers based on the United Nation's CRC. We compared the answers for six questions in the questionnaire that were addressed to self-raters (children) and proxy raters (primary caregivers) in the same way. RESULTS: Questions regarding basic needs, such as access to clean water or whether the child had food to eat at home, were answered similarly by self-raters and proxy raters. Larger differences were found when self-raters and proxy raters were asked about whether the child had things or friends to play with at home. Socio economic variables seemed to affect whether self-raters and proxy raters answered similarly. CONCLUSION: The results underscore the importance of promoting children's rights to express themselves by considering the opinions of both the children as self-raters and their primary caregivers as proxy raters - not only the latter. The results indicate that it is especially important to include children's own voices when more complex needs are surveyed. Agreement between self- and proxy ratings could be affected by socio-economic circumstances. PMID- 25809838 TI - Visible implant elastomer (VIE) tagging and simulated predation risk elicit similar physiological stress responses in three-spined stickleback Gasterosteus aculeatus. AB - The effect of visible implant elastomer (VIE) tagging on the immediate physiological stress response was tested in female three-spined stickleback Gasterosteus aculeatus, using non-invasive waterborne cortisol analysis. Post tagging cortisol levels were significantly higher compared with pretreatment baseline concentrations; however, when comparing post-tagging cortisol levels with cortisol levels after exposure to a simulated aerial predator, no significant differences were found. This study indicates that VIE tagging elicits a physiological stress response similar to those occurring in the everyday lives of this important biological model organism. PMID- 25809839 TI - Exploring End-of-Life Care in Veterans Affairs Community Living Centers. AB - OBJECTIVES: To compare quality of end-of-life (EOL) care indicators and family evaluation of care in community living centers (CLCs) with that of EOL care in acute, intensive, and hospice and palliative care units. DESIGN: Retrospective chart review and survey with next of kin of recently deceased inpatients. SETTING: Inpatient Veterans Affairs (VA) Medical Centers (N = 145), including 132 CLCs, across the United States. PARTICIPANTS: The chart review included all individuals who died in VA inpatient units (n = 57,397). Family survey results included data for 33,497 veterans. MEASUREMENTS: Indicators of optimal EOL care: palliative consultation in the last 90 days of life, contact with a chaplain, family contact with a chaplain, and emotional support given to family after death. The main outcome was a single Bereaved Family Survey item in which respondents provided a global evaluation of quality of EOL care (excellent to very good, good, fair to poor). RESULTS: Family evaluations of overall EOL care and quality of EOL care indicators for veterans who died in CLCs were better than those of veterans dying in acute or intensive care units but worse than those dying in hospice or palliative care units. CONCLUSION: Care in CLCs can be enhanced through the integration of palliative care practices. Future research should identify critical elements of enhancing EOL care in nursing homes. PMID- 25809840 TI - Effects of Salivary Secretion Stimulation on the Treatment of Chronic Radioactive Iodine-Induced Sialadenitis. AB - BACKGROUND: The aim of this prospective study was to investigate the effect of salivary stimulation therapy using pilocarpine (a cholinergic agent) on chronic radioactive iodine (RAI)-induced sialadenitis. METHODS: Sixty-one patients with a diagnosis of chronic RAI-induced sialadenitis after thyroidectomy and RAI therapy were enrolled in this prospective study. Patients received salivary stimulation therapy with pilocarpine (5 mg, 3 times daily) over a 3-month period. Subjective symptom scores were assessed using self-reported questionnaires. Salivary flow rates (SFRs) were measured and salivary gland scintigraphy (SGS) was performed to evaluate objective salivary gland functions. RESULTS: After salivary stimulation therapy, subjective symptom scores were significantly improved (p=0.002), but posttreatment unstimulated and stimulated SFRs did not differ significantly from pretreatment values. SGS parameters, that is, uptake ratio (UR), maximum accumulation (MA), Tmin, and maximum secretion (MS) of parotid and submandibular glands were nonsignificantly different after salivary stimulation therapy. CONCLUSION: The study shows that salivary stimulation therapy may reduce the subjective symptoms of RAI-induced chronic sialadenitis but does not significantly induce functional restoration. PMID- 25809841 TI - Delayed graft function in laparoscopic kidney transplantation: the importance of prolonged cold and warm ischemia. PMID- 25809843 TI - Mesial temporal lobe epilepsy with hippocampal sclerosis is a network disorder with altered cortical hubs. AB - OBJECTIVE: Electrophysiologic hubs within the large-scale functional networks in mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis (HS) have not been investigated. We hypothesized that mTLE with HS has different resting-state network hubs in their large-scale functional networks compared to the hubs in healthy controls (HC). We also hypothesized that the hippocampus would be a functional hub in mTLE patients with HS. METHODS: Resting-state functional networks, identified by using magnetoencephalography (MEG) signals in the theta, alpha, beta, and gamma frequency bands, were evaluated. Networks in 44 mTLE patients with HS (left mTLE = 22; right mTLE = 22) were compared with those in 46 age-matched HC. We investigated betweenness centrality at the source-level MEG network. RESULTS: The main network hubs were at the pole of the left superior temporal gyrus in the beta band, the pole of the left middle temporal gyrus in the beta and gamma bands, left hippocampus in the theta and alpha bands, and right posterior cingulate gyrus in all four frequency bands in mTLE patients; all of which were different from the main network hubs in HC. Only patients with left mTLE showed profound differences from HC at the left hippocampus in the alpha band. SIGNIFICANCE: Our analysis of resting-state MEG signals shows that altered electrophysiologic functional hubs in mTLE patients reflect pathophysiologic brain network reorganization. Because we detected network hubs in both hippocampal and extrahippocampal areas, it is probable that mTLE is a large-scale network disorder rather than a focal disorder. The hippocampus was a network hub in left mTLE but not in right mTLE patients, which may be due to intrinsic functional and structural asymmetries between left and right mTLE patients. The evaluation of cortical hubs, even in the spike-free resting-state, could be a clinical diagnostic marker of mTLE with HS. PMID- 25809844 TI - Photo and Chemical Reduction of Copper onto Anatase-Type TiO2 Nanoparticles with Enhanced Surface Hydroxyl Groups as Efficient Visible Light Photocatalysts. AB - In this study, the photocatalytic efficiency of anatase-type TiO2 nanoparticles synthesized using the sol-gel low-temperature method, were enhanced by a combined process of copper reduction and surface hydroxyl groups enhancement. UV-light assisted photo and NaBH4 -assisted chemical reduction methods were used for deposition of copper onto TiO2. The surface hydroxyl groups of TiO2 were enhanced with the assistance of NaOH modification. The prepared catalysts were immobilized on glass plates and used as the fixed-bed systems for the removal of phenazopyridine as a model drug contaminant under visible light irradiation. NaOH modified Cu/TiO2 nanoparticles demonstrated higher photocatalytic efficiency than that of pure TiO2 due to the extending of the charge carriers lifetime and enhancement of the adsorption capacity of TiO2 toward phenazopyridine. The relationship of structure and performance of prepared nanoparticles has been established by using various techniques, such as XRD, XPS, TEM, EDX, XRF, TGA, DRS and PL. The effects of preparation variables, including copper content, reducing agents rate (NaBH4 concentration and UV light intensity) and NaOH concentration were investigated on the photocatalytic efficiency of NaOH-modified Cu/TiO2 nanoparticles. PMID- 25809845 TI - Development of genome-wide insertion/deletion markers in rice based on graphic pipeline platform. AB - DNA markers play important roles in plant breeding and genetics. The Insertion/Deletion (InDel) marker is one kind of co-dominant DNA markers widely used due to its low cost and high precision. However, the canonical way of searching for InDel markers is time-consuming and labor-intensive. We developed an end-to-end computational solution (InDel Markers Development Platform, IMDP) to identify genome-wide InDel markers under a graphic pipeline environment. IMDP constitutes assembled genome sequences alignment pipeline (AGA-pipe) and next generation re-sequencing data mapping pipeline (NGS-pipe). With AGA-pipe we are able to identify 12,944 markers between the genome of rice cultivars Nipponbare and 93-11. Using NGS-pipe, we reported 34,794 InDels from re-sequencing data of rice cultivars Wu-Yun-Geng7 and Guang-Lu-Ai4. Combining AGA-pipe and NGS-pipe, we developed 205,659 InDels in eight japonica and nine indica cultivars and 2,681 InDels showed a subgroup-specific pattern. Polymerase chain reaction (PCR) analysis of subgroup-specific markers indicated that the precision reached 90% (86 of 95). Finally, to make them available to the public, we have integrated the InDels/markers information into a website (Rice InDel Marker Database, RIMD, http://202.120.45.71/). The application of IMDP in rice will facilitate efficiency for development of genome-wide InDel markers, in addition it can be used in other species with reference genome sequences and NGS data. PMID- 25809846 TI - Wild boars from Sweden, Austria, the Czech Republic and Japan possess intact mannose-binding lectin 2 (MBL2) genes. AB - The two-nucleotide deletion recently detected in the mannose-binding lectin 2 gene in purebred and crossbred domestic pigs was not found among 68 wild boars representing 4 populations from Europe and Asia. This suggests that the deletion is a result of breeding and/or genetic drift/bottle necks. PMID- 25809848 TI - When votes depend on who's listening: Voters' intragroup status and voting procedure predict representative endorsement in intergroup contexts. AB - Three experiments investigated whether the selection of a representative in intergroup interdependence settings can reflect group members' strategic behaviour. We tested the impact of an individual's intragroup status (normative vs. pro-out-group deviant, Experiments 1-3) and of voting procedure (Experiments 2 and 3) on the choice of an in-group representative. Experiment 1 shows that normative members prefer normative representatives, whereas pro-out-group deviant members equally like normative and pro-out-group deviant representatives. Experiment 2 extends these results and shows that voting procedure (private vs. in-group audience) moderates this effect. Pro-out-group deviant members' preferences and behaviours appear more strategic and context-sensitive than normative ones. Specifically, pro-out-group deviants vote more for normative representatives than for pro-out-group deviants when facing an in-group audience, whereas the reverse pattern emerges in private. Experiment 3 shows that this moderation effect is specific to in-group audiences compared to out-group ones, reinforcing the idea that normative members 'stick to their guns'. Implications of these findings for leader endorsement and intergroup relations are discussed. PMID- 25809847 TI - XD-GRASP: Golden-angle radial MRI with reconstruction of extra motion-state dimensions using compressed sensing. AB - PURPOSE: To develop a novel framework for free-breathing MRI called XD-GRASP, which sorts dynamic data into extra motion-state dimensions using the self navigation properties of radial imaging and reconstructs the multidimensional dataset using compressed sensing. METHODS: Radial k-space data are continuously acquired using the golden-angle sampling scheme and sorted into multiple motion states based on respiratory and/or cardiac motion signals derived directly from the data. The resulting undersampled multidimensional dataset is reconstructed using a compressed sensing approach that exploits sparsity along the new dynamic dimensions. The performance of XD-GRASP is demonstrated for free-breathing three dimensional (3D) abdominal imaging, two-dimensional (2D) cardiac cine imaging and 3D dynamic contrast-enhanced (DCE) MRI of the liver, comparing against reconstructions without motion sorting in both healthy volunteers and patients. RESULTS: XD-GRASP separates respiratory motion from cardiac motion in cardiac imaging, and respiratory motion from contrast enhancement in liver DCE-MRI, which improves image quality and reduces motion-blurring artifacts. CONCLUSION: XD GRASP represents a new use of sparsity for motion compensation and a novel way to handle motions in the context of a continuous acquisition paradigm. Instead of removing or correcting motion, extra motion-state dimensions are reconstructed, which improves image quality and also offers new physiological information of potential clinical value. PMID- 25809850 TI - Medical management of patients on clozapine: A guide for internists. AB - Clozapine was approved by the US Food and Drug Administration in 1989 for the management of treatment-resistant schizophrenia, and has since proven to reduce symptom burden and suicide risk, increase quality of life, and reduce substance use in individuals with psychotic disorders. Nevertheless, clozapine's psychiatric benefits have been matched by its adverse effect profile. Because they are likely to encounter medical complications of clozapine during admissions or consultations for other services, hospitalists are compelled to maintain an appreciation for these iatrogenic conditions. The authors outline common (eg, constipation, sialorrhea, weight gain) and serious (eg, agranulocytosis, seizures, myocarditis) medical complications of clozapine treatment, with internist-targeted recommendations for management, including indications for clozapine discontinuation. PMID- 25809849 TI - A Cre-inducible fluorescent reporter for observing apical membrane dynamics. AB - The ability to image living tissues with fluorescent proteins has revolutionized the fields of cell and developmental biology. Fusions between fluorescent proteins and various polypeptides are allowing scientists to image tissues with sub-cellular resolution. Here, we describe the generation and activity of a genetically engineered mouse line expressing a fusion between the green fluorescent protein (GFP) and the apically localized protein Crumbs3 (Crb3). This reporter drives Cre-inducible expression of Crb3-GFP under control of the EF1a regulatory domains. The fusion protein is broadly expressed in embryonic and adult tissues and shows apical restriction in the majority of epithelial cell types. It displays a variably penetrant gain of function activity in the neural tube. However, in several cell types, over-expression of Crb3 does not appear to have any effect on normal development or maintenance. Detailed analysis of kidneys expressing this reporter indicates normal morphology and function highlighting the utility for live imaging. Thus, the EF1a(Crb3-GFP) mouse line will be of broad use for studying membrane and/or tissue dynamics in living tissues. PMID- 25809851 TI - Recommendations for reporting whole-grain intake in observational and intervention studies. AB - The finding that people who eat the most whole grains have a lower risk of cardiovascular disease and diabetes, compared with those who eat the least, is one of the most consistent findings in nutritional epidemiology. However, criteria for reporting whole-grain intake have varied widely, making it difficult to precisely explore the relation of whole grains and grain components with health outcomes. To enable better understanding of the health benefits of whole grain-rich diets, we propose that both observational and intervention studies should as far as possible be required to report as follows when describing whole grains: 1) quantify the amount of whole grain in the food or product in grams on a dry-weight basis, 2) describe the whole-grain definition used, 3) report and separate the different types of grains used, 4) if possible, report the structure of the grains (intact, crushed, partially milled) in foods, and 5) describe the main types of products used and processes used to make them. Added bran and germ should be reported distinctly from whole grains. In addition, we strongly recommend the incorporation of biomarkers of whole-grain intake to check compliance to intervention diets and help attenuate for errors in dietary recall of whole-grain intake. Of these measures, reporting whole-grain intake in grams is essential for future research work in the area. Improving reporting and estimation of whole-grain intake will enable easier comparison between different studies and lead to stronger meta-analyses in the future. PMID- 25809852 TI - Are active video games useful to combat obesity? PMID- 25809853 TI - The effect of a low-fat spread with added plant sterols on vascular function markers: results of the Investigating Vascular Function Effects of Plant Sterols (INVEST) study. AB - BACKGROUND: Plant sterols (PSs) lower LDL cholesterol, an established risk factor for coronary artery disease (CAD). No direct evidence is available supporting a reduced risk of CAD for foods with added PSs. Endothelial dysfunction is seen as an early indicator of atherosclerotic damage. OBJECTIVES: This study was primarily designed to investigate the effect of a low-fat spread with added PSs on brachial artery endothelial function as measured by flow-mediated dilation (FMD). Second, effects on arterial stiffness, blood pressure, serum lipids, and plasma PS concentrations were investigated. We hypothesized that PSs would not worsen FMD but would rather modestly improve FMD. DESIGN: This study had a double blind, randomized, placebo-controlled, parallel design. After a 4-wk run-in period, 240 hypercholesterolemic but otherwise healthy men and women consumed 20 g/d of low-fat spread without (control) or with added PSs (3 g/d) during 12 wk. Pre- and postintervention, vascular function measurements and blood sampling were performed. RESULTS: In total, 232 participants completed the study period. For the primary endpoint FMD, 199 participants were included in the statistical analysis. PS intake did not affect FMD (+0.01 percentage points; 95% CI: -0.73, 0.75) compared with control. Measures of arterial stiffness (pulse wave velocity and augmentation index) and blood pressure were also not significantly changed compared with control. After PS intervention, LDL cholesterol significantly decreased on average by 0.26 mmol/L (95% CI: -0.40, -0.12) or 6.7% compared with control. Plasma sitosterol and campesterol concentrations significantly increased in the PS group up to on average 11.5 MUmol/L and 13.9 MUmol/L (expressed as geometric means), respectively. CONCLUSIONS: The intake of a low-fat spread with added PSs neither improved nor worsened FMD or other vascular function markers in hypercholesterolemic men and women. As expected, serum LDL cholesterol decreased, whereas plasma PSs increased after PS intake. This study was registered at clinicaltrials.gov as NCT01803178. PMID- 25809854 TI - Red meat, dairy, and insulin sensitivity: a randomized crossover intervention study. AB - BACKGROUND: Epidemiologic studies have linked high consumption of red and processed meat with risk of developing type 2 diabetes, whereas high dairy consumption has been associated with decreased risk, but interventions have been limited. OBJECTIVE: We compared the effects on insulin sensitivity of consuming a diet high in lean red meat with minimal dairy, a diet high in primarily low-fat dairy (from milk, yogurt, or custard) with no red meat, and a control diet that contained neither red meat nor dairy. DESIGN: A randomized crossover study was undertaken with 47 overweight and obese men and women divided into 2 groups as follows: those with normal glucose tolerance and those with impaired fasting glucose or impaired glucose tolerance. Participants followed the 3 weight-stable dietary interventions for 4 wk with glucose, insulin, and C-peptide measured by using oral-glucose-tolerance tests at the end of each diet. RESULTS: Fasting insulin was significantly higher after the dairy diet than after the red meat diet (P < 0.01) with no change in fasting glucose resulting in a decrease in insulin sensitivity after the high-dairy diet (P < 0.05) as assessed by homeostasis model assessment of insulin resistance (HOMA-IR). A significant interaction between diet and sex was observed such that, in women alone, HOMA-IR was significantly lower after the red meat diet than after the dairy diet (1.33 +/- 0.8 compared with 1.71 +/- 0.8, respectively; P < 0.01). Insulin sensitivity calculated by using the Matsuda method was 14.7% lower in women after the dairy diet than after the red meat diet (P < 0.01) with no difference between diets in men. C-peptide was not different between diets. CONCLUSION: In contrast to some epidemiologic findings, these results suggest that high consumption of dairy reduces insulin sensitivity compared with a diet high in lean red meat in overweight and obese subjects, some of whom had glucose intolerance. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12613000441718. PMID- 25809856 TI - Theoretical comparative studies on transport properties of pentacene, pentathienoacene, and 6,13-dichloropentacene. AB - Pentacene derivative 6,13-dichloropentacene (DCP) is one of the latest additions to the family of organic semiconductors with a great potential for use in transistors. We carry out a detailed theoretical calculation for DCP, with systematical comparison to pentacene, pentathienoacene (PTA, the thiophene equivalent of pentacene), to gain insights in the theoretical design of organic transport materials. The charge transport parameters and carrier mobilities are investigated from the first-principles calculations, based on the widely used Marcus electron transfer theory and quantum nuclear tunneling model, coupled with random walk simulation. Molecular structure and the crystal packing type are essential to understand the differences in their transport behaviors. With the effect of molecule modification, significant one-dimensional pi-stacks are found within the molecular layer in PTA and DCP crystals. The charge transport along the a-axis plays a dominant role for the carrier mobilities in the DCP crystal due to the strong transfer integrals within the a-axis. Pentacene shows a relatively large 3D mobility. This is attributed to the relatively uniform electronic couplings, which thus provides more transport pathways. PTA has a much smaller 3D mobility than pentacene and DCP for the obvious increase of the reorganization energy with the introduction of thiophene. It is found that PTA and DCP exhibit lower HOMO (highest occupied molecular orbital) levels and better environmental stability, indicating the potential applications in organic electronics. PMID- 25809857 TI - Development and testing of a scale for assessing the quality of home nursing. AB - AIM: To develop a home nursing quality scale and to evaluate its psychometric properties. METHOD: This was a 3-year study. In the first year, 19 focus group interviews with caregivers of people using home nursing services were carried out in northern, central and southern Taiwan. Content analysis was carried out and a pool of questionnaire items compiled. In the second year (2007), study was carried out on a stratified random sample selected from home nursing organizations covered by the national health insurance scheme in southern Taiwan. The study population was the co-resident primary caregivers of home care nursing service users. Item analysis and exploratory factor analysis were carried out on data from 365 self-administered questionnaires collected from 13 selected home care organizations. In the third year (2008), a random sample of participants was selected from 206 hospital-based home care nursing organizations throughout Taiwan, resulting in completion of 294 questionnaires from 27 organizations. Confirmatory factor analysis was then carried out on the scale, and the validity and reliability of the scale assessed. RESULTS: The present study developed a reliable and valid home nursing quality scale from the perspective of users of home nursing services. The scale comprised three factors: dependability, communication skills and service usefulness. This scale is of practical value for the promotion of long-term community care aging in local policies. CONCLUSION: The scale is ready to be used to assess the quality of services provided by home care nursing organizations. PMID- 25809855 TI - The effect of tree nut, peanut, and soy nut consumption on blood pressure: a systematic review and meta-analysis of randomized controlled clinical trials. AB - BACKGROUND: Although several studies have assessed the effects of nut consumption (tree nuts, peanuts, and soy nuts) on blood pressure (BP), the results are conflicting. OBJECTIVE: The aim was to conduct a systematic review and meta analysis of published randomized controlled trials (RCTs) to estimate the effect of nut consumption on BP. DESIGN: The databases MEDLINE, SCOPUS, ISI Web of Science, and Google Scholar were searched for RCTs carried out between 1958 and October 2013 that reported the effect of consuming single or mixed nuts (including walnuts, almonds, pistachios, cashews, hazelnuts, macadamia nuts, pecans, peanuts, and soy nuts) on systolic BP (SBP) or diastolic BP (DBP) as primary or secondary outcomes in adult populations aged >=18 y. Relevant articles were identified by screening the abstracts and titles and the full text. Studies that evaluated the effects for <2 wk or in which the control group ingested different healthy oils were excluded. Mean +/- SD changes in SBP and DBP in each treatment group were recorded for meta-analysis. RESULTS: Twenty-one RCTs met the inclusion criteria. Our findings suggest that nut consumption leads to a significant reduction in SBP in participants without type 2 diabetes [mean difference (MD): -1.29; 95% CI: -2.35, -0.22; P = 0.02] but not in the total population. Subgroup analyses of different nut types suggest that pistachios, but not other nuts, significantly reduce SBP (MD: -1.82; 95% CI: -2.97, -0.67; P = 0.002). Our study suggests that pistachios (MD: -0.80; 95% CI: -1.43, -0.17; P = 0.01) and mixed nuts (MD: -1.19; 95% CI: -2.35, -0.03; P = 0.04) have a significant reducing effect on DBP. We found no significant changes in DBP after the consumption of other nuts. CONCLUSIONS: Total nut consumption lowered SBP in participants without type 2 diabetes. Pistachios seemed to have the strongest effect on reducing SBP and DBP. Mixed nuts also reduced DBP. PMID- 25809858 TI - Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. AB - RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors. PMID- 25809859 TI - A novel in chemico method to detect skin sensitizers in highly diluted reaction conditions. AB - The direct peptide reactivity assay (DPRA) is a simple and versatile alternative method for the evaluation of skin sensitization that involves the reaction of test chemicals with two peptides. However, this method requires concentrated solutions of test chemicals, and hydrophobic substances may not dissolve at the concentrations required. Furthermore, hydrophobic test chemicals may precipitate when added to the reaction solution. We previously established a high-sensitivity method, the amino acid derivative reactivity assay (ADRA). This method uses novel cysteine (NAC) and novel lysine derivatives (NAL), which were synthesized by introducing a naphthalene ring to the amine group of cysteine and lysine residues. In this study, we modified the ADRA method by reducing the concentration of the test chemicals 100-fold. We investigated the accuracy of skin sensitization predictions made using the modified method, which was designated the ADRA-dilutional method (ADRA-DM). The predictive accuracy of the ADRA-DM for skin sensitization was 90% for 82 test chemicals which were also evaluated via the ADRA, and the predictive accuracy in the ADRA-DM was higher than that in the ADRA and DPRA. Furthermore, no precipitation of test compounds was observed at the initiation of the ADRA-DM reaction. These results show that the ADRA-DM allowed the use of test chemicals at concentrations two orders of magnitude lower than that possible with the ADRA. In addition, ADRA-DM does not have the restrictions on test compound solubility that were a major problem with the DPRA. Therefore, the ADRA-DM is a versatile and useful method. PMID- 25809860 TI - Obesity, perceived weight discrimination, and psychological well-being in older adults in England. AB - OBJECTIVE: To examine whether the adverse effect of obesity on psychological well being can be explained by weight discrimination. METHODS: The study sample included 5056 older (>=50 y) men and women living in England and participating in the English Longitudinal Study of Ageing. Participants reported experiences of weight discrimination in everyday life and completed measures of quality of life (CASP-19 scale), life satisfaction (Satisfaction With Life Scale), and depressive symptoms (eight-item CES-D scale). Height and weight were objectively measured, with obesity defined as BMI >=30 kg/m2 . Mediation analyses were used to test the role of perceived weight discrimination in the relationship between obesity and each psychological factor. RESULTS: Obesity, weight discrimination, and psychological well-being were all significantly inter-related. Mediation models revealed significant indirect effects of obesity through perceived weight discrimination on quality of life (beta = -0.072, SE = 0.008), life satisfaction (beta = -0.038, SE = 0.008), and depressive symptoms (beta = 0.057, SE = 0.008), with perceived weight discrimination explaining approximately 40% (range: 39.5 44.1%) of the total association between obesity and psychological well-being. CONCLUSIONS: Perceived weight discrimination explains a substantial proportion of the association between obesity and psychological well-being in English older adults. Efforts to reduce weight stigma in society could help to reduce the psychological burden of obesity. PMID- 25809862 TI - Method for time-resolved monitoring of a solid state biological film using photothermal infrared nanoscopy on the example of poly-L-lysine. AB - We report time-resolved photothermal infrared nanoscopy measurements across a spectral range of more than 100 cm(-1) (1565 cm(-1) to 1729 cm(-1)) at nanoscale spatial resolution. This is achieved through a custom-built system using broadly tunable external cavity quantum cascade lasers in combination with a commercially available atomic force microscope. The new system is applied to the analysis of conformational changes of a polypeptide (poly-l-lysine) film upon temperature induced changes of the humidity in the film. Changes of the secondary structure from beta-sheet to alpha-helix could be monitored at a time resolution of 15 s per spectrum. The time-resolved spectra are well comparable to reference measurements acquired with conventional Fourier transform infrared microscopy. PMID- 25809861 TI - Long-term impact of androgen-deprivation therapy on physical function and quality of life. AB - BACKGROUND: This study examined the impact of androgen-deprivation therapy (ADT) on physical function and quality of life (QOL) over 36 months. METHODS: Eighty seven men with nonmetastatic prostate cancer (PC) who were starting continuous ADT and 2 control groups (86 PC controls without ADT and 86 healthy controls), matched by age and education, were enrolled. Physical function was assessed with the 6-minute walk test (6MWT), grip strength, and Timed Up and Go (TUG) test. QOL was measured with the 36-Item Short Form Health Survey of the Medical Outcomes Study. Subjects were assessed at the baseline and at 3, 6, 12, 18, 24, 30, and 36 months. Mixed effects regression models were fitted with adjustments for baseline covariates. RESULTS: The 6MWT distance improved initially and then stabilized in both control groups but remained unchanged for ADT users (P = .0030). Grip strength remained stable in control groups but declined sharply in the ADT group by 3 months and then remained stable to 36 months (P = .0041). TUG scores declined gradually in the ADT group over 36 months but were unchanged in control groups (P = .0008). Aggregate physical QOL declined in ADT users over time but remained stable in control groups (P = .0001). Aggregate mental QOL was stable in all groups. Declines seen in the first year of ADT use generally persisted over 36 months and were independent of age. CONCLUSIONS: Previously noted physical side effects over the first 12 months of ADT persisted or continued to worsen over an additional 2 years with no evidence of recovery. Exercise interventions to counteract these declines may be warranted. PMID- 25809863 TI - Oral human papillomavirus is common in individuals with Fanconi anemia. AB - BACKGROUND: Fanconi anemia is a rare genetic disorder resulting in a loss of function of the Fanconi anemia-related DNA repair pathway. Individuals with Fanconi anemia are predisposed to some cancers, including oropharyngeal and gynecologic cancers, with known associations with human papillomavirus (HPV) in the general population. As individuals with Fanconi anemia respond poorly to chemotherapy and radiation, prevention of cancer is critical. METHODS: To determine whether individuals with Fanconi anemia are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with Fanconi anemia and 162 unaffected first-degree family members for 37 HPV types. RESULTS: Fourteen individuals (11.1%) with Fanconi anemia tested positive, significantly more (P = 0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with Fanconi anemia (17.7% vs. 2.4% in family; P = 0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in Fanconi anemia vs. 2.9% in siblings). Indeed, having Fanconi anemia increased HPV positivity 4.9-fold (95% CI, 1.6-15.4) considering age and sexual experience, but did not differ by other potential risk factors. CONCLUSION: Our studies suggest that oral HPV is more common in individuals with Fanconi anemia. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time. IMPACT: HPV vaccination should be emphasized in those with Fanconi anemia as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine whether the level of protection it offers in this population is adequate. PMID- 25809864 TI - Folate pathway gene polymorphisms and risk of childhood brain tumors: results from an Australian case-control study. AB - BACKGROUND: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk. METHODS: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case-control study in Australia (2005 2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, MTR 5049C>A, and CBS 2199 T>C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case-parent trio analyses were also undertaken. RESULTS: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48-1.07]; 0.54 (95% CI, 0.34-0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively). CONCLUSIONS: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication. IMPACT: The possible interaction between folic acid supplementation and MTRR 66A>G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT. PMID- 25809866 TI - Replication and heritability of prostate cancer risk variants: impact of population-specific factors. AB - BACKGROUND: Prostate cancer incidence and mortality rates vary across populations, with African American men exhibiting the highest rates. To date, genome-wide association studies have identified 104 SNPs independently associated with prostate cancer in men of European ancestry. METHODS: We investigated whether the ability to replicate findings for these 104 SNPs in African American, Asian, and Latino populations depends on variation in risk allele frequencies (RAF), strength of associations, and/or patterns of linkage disequilibrium (LD) at the associated loci. We extracted estimates of effect from the literature, and determined RAF and LD information across the populations from the 1000 Genomes Project. RESULTS: Risk variants were largely replicated across populations. Relative to Europeans, 83% had smaller effect sizes among African Americans and 73% demonstrated smaller effect sizes among Latinos. Among Asians, however, 56% showed larger effect sizes than among Europeans. The largest difference in RAFs was observed between European and African ancestry populations, but this difference did not impact our ability to replicate. The extent of LD within 250 kb of risk loci in Asian ancestry populations was suggestively lower for variants that did not replicate (P = 0.013). CONCLUSIONS: Despite substantial overlap in prostate cancer risk SNPs across populations, the variation in prostate cancer incidence among different populations may still in part reflect unique underlying genetic architectures. IMPACT: Studying different ancestral populations is crucial for deciphering the genetic basis of prostate cancer. PMID- 25809867 TI - Oppositely charged polyelectrolytes form tough, self-healing, and rebuildable hydrogels. AB - A series of tough polyion complex hydrogels is synthesized by sequential homopolymerization of cationic and anionic monomers. Owing to the reversible interpolymer ionic bonding, the materials are self-healable under ambient conditions with the aid of saline solution. Furthermore, self-glued bulk hydrogels can be built from their microgels, which is promising for 3D/4D printing and the additive manufacturing of hydrogels. PMID- 25809865 TI - Racial variation in breast tumor promoter methylation in the Carolina Breast Cancer Study. AB - BACKGROUND: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes. METHODS: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS). RESULTS: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor-negative (HR(-)) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII 52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific. CONCLUSIONS: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases. IMPACT: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. PMID- 25809868 TI - Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome. AB - The aim of this study is to investigate the role of the purinergic receptor P2X3 in the peripheral and central nervous systems during acupuncture treatment for the visceral pain of irritable bowel syndrome (IBS). A total of 24 8-day-old Sprague-Dawley (SD) neonatal male rats (SPF grade) were stimulated using colorectal distention (CRD) when the rats were awake. The modeling lasted for 2 weeks with one stimulation per day. After 6 weeks, the rats were randomly divided into three groups of eight each: (1) the normal group (NG, n = 8); (2) the model group (MG, n = 8); and (3) the model + electroacupuncture group (EA, n = 8) that received electroacupuncture at a needling depth of 5 mm at the Shangjuxu (ST37, bilateral) and Tianshu (ST25, bilateral) acupoints. The parameters of the Han's acupoint nerve stimulator (HANS) were as follows: sparse-dense wave with a frequency of 2/100 Hz, current of 2 mA, 20 min/stimulation, and one stimulation per day; the treatment was provided for seven consecutive days. At the sixth week after the treatment, the abdominal withdrawal reflex (AWR) score was determined; immunofluorescence and immunohistochemistry were used to measure the expression of the P2X3 receptor in myenteric plexus neurons, prefrontal cortex, and anterior cingulate cortex; and, a real-time PCR assay was performed to measure the expression of P2X3 messenger RNA (mRNA) in the dorsal root ganglion (DRG) and spinal cord. After stimulation with CRD, the expression levels of the P2X3 receptor in the inter-colonic myenteric plexus, DRG, spinal cord, prefrontal cortex, and anterior cingulate cortex were upregulated, and the sensitivity of the rats to IBS visceral pain was increased. Electroacupuncture (EA) could downregulate the expression of the P2X3 receptor and ease the sensitivity to visceral pain. The P2X3 receptor plays an important role in IBS visceral pain. The different levels of P2X3 in the peripheral enteric nervous system and central nervous system mediate the effects of the EA treatment of the visceral hyperalgesia of IBS. PMID- 25809870 TI - Pluripotency Activity of Nanog Requires Biochemical Stabilization by Variant Histone Protein H2A.Z. AB - The variant histone protein H2A.Z plays a critical role in early development. Likewise, Nanog, a master regulator of embryonic stem cells (ESCs), is essential for proper development in early embryogenesis. In this study, we establish that these two factors work together to maintain pluripotency. It is shown that H2A.Z influences the protein level of Nanog through the ubiquitin-proteasome pathway. Knockdown of H2A.Z causes differentiation of mouse ESCs and disrupts the reprogramming of somatic cells, which can be partially rescued by overexpression of Nanog. We conclude that the H2A.Z-Nanog partnership is involved in ESC pluripotency and reprogramming of somatic cells. Stem Cells 2015;33:2126-2134. PMID- 25809869 TI - Review article: applying pharmacokinetics to optimise dosing of anti-TNF biologics in acute severe ulcerative colitis. AB - BACKGROUND: Acute severe ulcerative colitis (ASUC), the most aggressive presentation of ulcerative colitis (UC), occurs in 15% of adults and children with UC. First line therapy with intravenous corticosteroids is ineffective in half of adults and one-third of children. Therapeutic monoclonal antibodies against TNF (anti-TNF therapy) are emerging as a common treatment for ASUC due to their similar efficacy to calcineurin inhibitors and more favourable adverse effect profile. AIM: To comprehensively review the evidence for anti-TNF therapy for ASUC in children and adults with regard to outcomes and pharmacokinetics. METHODS: PubMed and recent conference proceedings were searched using the terms 'ulcerative colitis', 'acute severe ulcerative colitis', 'anti-TNF', 'pharmacokinetics' and the generic names of specific anti-TNF agents. RESULTS: Outcomes after anti-TNF therapy for ASUC remain suboptimal with about one half of children and adults undergoing colectomy. While several randomised controlled trials have demonstrated the efficacy of anti-TNF therapy for ambulatory patients with moderate to severely active UC, patients in these studies were less ill than those with ASUC. Patients with ASUC may exhibit more rapid clearance of anti-TNF biologics due to pharmacokinetic mechanisms influenced by disease severity. CONCLUSIONS: Conventional weight-based dosing effective in patients with moderately to severely active UC, may not be equally effective in those with acute severe ulcerative colitis. Personalised anti-TNF dosing strategies, which integrate patient factors and early measures of pharmacokinetics and response, hold promise for ensuring sustained drug exposure and maximising early mucosal healing in patients with acute severe ulcerative colitis. PMID- 25809871 TI - Involvement of endothelins in deoxycorticosterone acetate-salt hypertension through the modulation of noradrenergic transmission in the rat posterior hypothalamus. AB - NEW FINDINGS: What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA-salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA-salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA-salt rats, but ETB receptors showed no changes. These results show that ET-1 and ET-3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA-salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model. PMID- 25809872 TI - Cachexia: clinical features when inflammation drives malnutrition. AB - Cachexia is a clinically relevant syndrome which impacts on quality of life, morbidity and mortality of patients suffering from acute and chronic diseases. The hallmark of cachexia is muscle loss, which is triggered by disease-associated inflammatory response. Cachexia is a continuum and therefore a staging system is needed. Initially, a three-stage system (i.e. pre-cachexia, cachexia and refractory cachexia) was proposed. More recent evidence supports the use of a five-stage classification system, based on patient's BMI and severity of weight loss, to better predict clinical outcome. Also, large clinical trials in cancer patients demonstrated that cachexia emerging during chemotherapy has greater influence on survival than weight loss at baseline. Therefore, becoming widely accepted is the importance of routinely monitoring patients' nutritional status to detect early changes and diagnose cachexia in its early phases. Although cachexia is associated with the presence of anabolic resistance, it has been shown that sustained yet physiological hyperaminoacidaemia, as well as the use of specific nutrients, is able to overcome impaired protein synthesis and revert catabolism. More importantly, clinical evidence demonstrates that preservation of nutritional status during chemotherapy or improvement of body weight after weight loss is associated with longer survival in cancer patients. PMID- 25809873 TI - Nedd4 E3 ubiquitin ligase promotes cell proliferation and autophagy. AB - OBJECTIVES: Nedd4 (neural precursor cell expressed developmentally down-regulated protein 4) is a member of the HECT E3 ubiquitin ligases, and is elevated in prostate, bladder and colorectal cancers, and promotes colonic cell population expansion. Up to now, molecular mechanisms of how Nedd4 functions, have not been well understood. MATERIALS AND METHODS: In this study, shRNA was used to reduce expression of Nedd4 in the human prostate carcinoma cell line DU145. To analyse effects of Nedd4 on cell proliferation, MTT and colony formation assays were performed. DAPI staining and FACS analysis were used to investigate outcomes of Nedd4 activity, on apoptosis. Results of Nedd4 expression on lysosomal membrane permeabilization and autophagy were further investigated using acridine orange (AO) staining, immunofluorescence and western blot analysis. RESULTS: We found that in HeLa cells, expression of Nedd4 promoted cell proliferation, whereas its knockdown inhibited colony formation and induced apoptosis in DU145 cells. Furthermore, down-regulation of Nedd4 in DU145 cells promoted lysosomal membrane permeabilization. We also found that down-regulation of Nedd4 inhibited autophagy in both DU145 and A549 cells. Investigation into mechanisms involved revealed that knockdown of endogenous Nedd4 expression notably increased activated mTOR (p mTOR) levels, which suggests that mTOR signalling was involved in the Nedd4 mediated autophagy. CONCLUSIONS: Our results indicate that expression of Nedd4 promoted cell proliferation and colony formation but prevented apoptosis. Moreover, Nedd4 promoted autophagy and was associated with the mTOR signalling pathway. PMID- 25809874 TI - Orthopaedic Surgery Residents and Program Directors Agree on How Time Is Currently Spent in Training and Targets for Improvement. AB - BACKGROUND: Although much attention has been paid to the role of deliberate practice as a means of achieving expert levels of performance in other medical specialties, little has been published regarding its role in maximizing orthopaedic surgery resident potential. As an initial step in this process, this study seeks to determine how residents and program directors (PDs) feel current time spent in training is allocated compared with a theoretical ideal distribution of time. QUESTIONS/PURPOSES: According to residents and PDs, (1) how do resident responsibilities change by level of training as perceived and idealized by residents and PDs? (2) How do resident and PD perceptions of current and ideal time distributions compare with one another? (3) Do the current training structures described by residents and PDs differ from what they feel represents an ideal time allocation construct that maximizes the educational value of residency training? METHODS: A survey was sent to orthopaedic surgery resident and PD members of the Midwest Orthopedic Surgical Skills Consortium asking how they felt residents' time spent in training was distributed across 10 domains and four operating room (OR) roles and what they felt would be an ideal distribution of that time. Responses were compared between residents and PDs and between current schedules and ideal schedules. RESULTS: Both residents and PDs agreed that time currently spent in training differs by postgraduate year with senior-level residents spending more time in the OR (33.7% +/- 8.3% versus 17.9% +/- 6.2% [interns] and 27.4% +/- 10.2% [juniors] according to residents, p < 0.001; and 38.6% +/- 8.1% versus 11.8% +/- 6.4% [interns] and 26.1% +/- 5.7% [juniors] according to PD, p < 0.001). The same holds true for their theoretical ideals. Residents and PDs agree on current resident time allocation across the 10 domains; however, they disagree on multiple components of the ideal program with residents desiring more time spent in the OR than what PDs prefer (residents 40.3% +/- 10.3% versus PD 32.6% +/- 14.6% [mean difference {MD}, 7.7; 95% confidence interval {CI}, 4.4, 11.0], p < 0.001). Residents would also prefer to have more time spent deliberately practicing surgical skills outside of the OR (current 1.8% +/- 2.1% versus ideal 3.7% +/- 3.2% [MD, -1.9; 95% CI, -.2.4 to 1.4], p < 0.001). Both residents and PDs want residents to spend less time completing paperwork (current 4.4% +/- 4.1% versus ideal 0.8% +/- 1.6% [MD, 3.6; 95% CI, 3.0-4.2], p < 0.001 for residents; and current 3.6% +/- 4.1% versus ideal 1.5% +/- 1.9% [MD, 2.1; 95% CI, 0.9-3.3], p < 0.001 for PDs). CONCLUSIONS: Residents and PDs seem to agree on how time is currently spent in residency training. Some differences of opinions continue to exist regarding how an ideal program should be structured; however, this work identifies a few potential targets for improvement that are agreed on by both residents and PDs. These areas include increasing OR time, finding opportunities for deliberate practice of surgical skills outside of the OR, and decreased clerical burden. This study may serve as a template to allow programs to continue to refine their educational models in an effort to achieve curricula that meet the desired goals of both learners and educators. Additionally, it is an initial step toward more objective identification of the optimal educational structure of an orthopaedic residency program. PMID- 25809875 TI - CORR Insights(r): Higher Preoperative Patient Activation Associated With Better Patient-reported Outcomes After Total Joint Arthroplasty. PMID- 25809876 TI - Comparison of clinical outcomes between upgraded pathologic Gleason score 3 + 4 and non-upgraded 3 + 4 prostate cancer among patients who are candidates for active surveillance. AB - PURPOSE: To clarify differences patients with pathological GS (pGS) 3 + 4 according to biopsy Gleason score (bGS) after radical prostatectomy (RP) among candidates for active surveillance. METHODS: Between January 2006 and June 2014, 619 patients who met Royal Marsden criteria and had a pGS 3 + 4 after RP were identified. Patients were stratified into two groups according to bGS: Group A (n = 430) with bGS (3 + 3) and Group B (n = 189) with bGS 7 (3 + 4). Pathological outcomes were compared between the two groups, and the impact of bGS on adverse pathological outcomes was analyzed by logistic regression and biochemical recurrence (BCR)-free survival compared by log-rank test and the Cox proportional hazards model. RESULTS: The patients in Group B had a higher rate of extracapsular extension (ECE), seminal vesicle invasion and positive surgical margins than those in Group A (p < 0.001, p = 0.005, p = 0.046, respectively). In univariate and multivariate, bGS was significantly associated with ECE [odds ratio (OR) 2.615, p < 0.001; OR 1.769, p < 0.001]. In Kaplan-Meier analysis, BCR free survival rate was higher in Group A than in Group B (log rank, p = 0.037). In multivariable Cox regression, maximum percentage of core involvement were strongly associated with BCR [hazard ratio (HR) 1.773 (1.248-2.519), p = 0.001]. CONCLUSIONS: pGS 3 + 4 was associated with heterogeneous pathologic and biochemical outcomes according to bGS. Patients with pGS 3 + 4 upgraded from bGS 3 + 3 had more favorable pathological outcomes and biochemical survival outcomes than those with bGS 3 + 4. PMID- 25809878 TI - Second malignant neoplasms among children, adolescents and young adults with Wilms tumor. AB - BACKGROUND: The goal of this study was to describe the incidence, characteristics, and outcomes of secondary malignant neoplasms (SMN) in survivors of Wilms tumor. PROCEDURES: Patients who were 0-20 years of age at time of primary diagnosis with Wilms tumor and reported to the Surveillance, Epidemiology, and End Results [SEER] program between 1973 and 2011 were eligible for inclusion in the cohort. We used competing risks methods to estimate the cumulative incidence of SMNs and assess contributing factors for developing SMN. We estimated standardized incidence ratios (SIR), absolute excess risk and overall survival after SMN using standard methods. RESULTS: Within the SEER database, 2,851 patients were diagnosed with Wilms tumor as their first malignancy. Of these, 34 patients were reported to have a SMN. Cumulative incidence of for a secondary malignancy was 0.6% (95% confidence interval [95% CI] 0.3-1.0%) at 10 years, 1.6% (95% CI 1.0-2.3%) at 20 years, and 3.8% (95% CI 2.4-5.9%) at 30 years. Median time from primary diagnosis to SMN diagnosis was 12.5 years. SIR for SMN for survivors of Wilms tumor was 3.4 (95% CI 2.2-4.9) with an absolute excess risk of 7.6 per 10,000 persons per year. Exposure to radiation did not significantly increase risk for development of second malignancy. Overall survival for patients with SMN was 64.5% at 5 years. CONCLUSION: Survivors of Wilms tumor are at an increased risk of SMN compared to the general population, but the added risk is relatively small compared to other pediatric cancers. PMID- 25809877 TI - A critical assessment of the effects of tamsulosin and solifenacin as monotherapies and as a combination therapy for the treatment of ureteral stent related symptoms: a 2 * 2 factorial randomized trial. AB - OBJECTIVE: To assess the efficacy of tamsulosin, solifenacin, and combination therapy of both agents for the treatment of ureteral stent-related symptoms (SRSs). METHODS: An open-label, randomized controlled trial was conducted with 112 patients who underwent unilateral ureteral stent insertion following ureteroscopic stone surgery. Patients were randomized with a 2 * 2 factorial design to one of four groups, i.e., A (control), B (tamsulosin 0.2 mg once daily), C (solifenacin 5 mg once daily), and D (both active treatments). Patients were evaluated at week 2 by the ureteral stent symptom questionnaire (USSQ). The primary efficacy outcome was the urinary symptom score of the USSQ, and the secondary efficacy outcomes were the scores in the other five USSQ domains, the Euro-QOL score, and oral analgesic requirements during the 2 weeks. Efficacy outcomes were primarily analyzed for the per-protocol set population. RESULTS: The four groups were generally well balanced in terms of baseline characteristics. Eighty-one patients (72.3 %) completed the study protocol. Comparison of the six USSQ domain scores at week 2 showed no differences between the four groups. Similarly, comparison of the domain scores stratified by tamsulosin or solifenacin medication showed no differences for either medication. The other secondary outcomes were also similar in the group comparisons. CONCLUSIONS: Neither tamsulosin nor solifenacin medications provide beneficial effects for relieving various SRSs. In addition, the combination therapy did not have beneficial effects. Further studies are warranted to determine the benefit of medical therapy for the treatment of SRSs and to determine the optimal management strategy for SRSs. PMID- 25809879 TI - Nonpharmacological therapy for the management of neuropsychiatric symptoms of Alzheimer's disease: linking evidence to practice. AB - BACKGROUND: Behavioral and psychiatric symptoms of dementia affect up to 90% of all patients at some point during their dementing illness. Today, many of these symptoms are treated with pharmacological therapy alone, incongruent with clinical recommendations. Barriers to the use of nonpharmacological interventions with dementia include a lack of education among caregivers on available options, shortage of time for implementation, lack of education on effects of nonpharmacological therapy, poor staff to resident ratios, and unmodifiable physical environments. AIMS: The purpose of this paper is to explore current literature regarding the implementation of nonpharmacological therapy as an adjunct treatment to manage agitation in dementia, to identify practice discrepancies seen commonly among formal and informal caregivers, and to make recommendations for implementing evidence into practice. METHODS: A systematic review of the literature published between 2009 and 2014 was conducted. Four databases were searched including CINAHL, Pubmed, the Cochrane Library, and PsycInfo. FINDINGS: The most prevalent and substantial conclusion among the 10 studies evaluated is that nonpharmacological therapy is safe and effective. Although not every study was able to show statistically significant outcomes when compared to controls, all studies demonstrated a positive trend toward decreasing agitation without any adverse side effects. LINKING EVIDENCE TO ACTION: A multicomponent caregiver education program focused on evidence-based nonpharmacological strategies for addressing agitation in persons with Alzheimer's disease has the potential to decrease agitation, improve patient outcomes, and increase caregiver satisfaction. PMID- 25809881 TI - Case of clear cell sarcoma in the left buttock in which serum neuron-specific enolase was a useful marker for monitoring disease progression. AB - We report a case of clear cell sarcoma (CCS) in the left buttock in which serum neuron-specific enolase (NSE) was useful as a biomarker of CCS progression. A 40 year-old man had a subcutaneous tumor, 1.7 cm in diameter, in the left buttock. Histopathology revealed that the tumor consisted of nests of polygonal or spindle shaped cells with abundant clear cytoplasm delineated by fibrous septa in the subcutaneous tissue. There was cellular atypia but no melanin deposits. Immunohistochemically, the tumor cells were positive for HMB-45, Melan-A, S-100 protein and NSE. Reverse transcription polymerase chain reaction demonstrated Ewing's sarcoma oncogene-activating transcription factor 1 fusion transcripts in the tumor cells. CCS was diagnosed. There was no metastasis to the lymph nodes and viscera, and the patient was treated by surgical wide resection. The serum NSE levels increased before detection of distant metastasis and further increased in parallel with the expansion of metastasis. The present case suggests that serum NSE could be used as a biochemical marker in the clinical follow up of patients with CCS. PMID- 25809883 TI - Vinylic MIDA Boronates: New Building Blocks for the Synthesis of Aza Heterocycles. AB - A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a "metal free" nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex "drug-like" molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic beta-aminophosphonate motif. PMID- 25809882 TI - Deinococcus as new chassis for industrial biotechnology: biology, physiology and tools. AB - Deinococcus spp are among the most radiation-resistant micro-organisms that have been discovered. They show remarkable resistance to a range of damage caused by ionizing radiation, desiccation, UV radiation and oxidizing agents. Traditionally, Escherichia coli and Saccharomyces cerevisiae have been the two platforms of choice for engineering micro-organisms for biotechnological applications, because they are well understood and easy to work with. However, in recent years, researchers have begun using Deinococcus spp in biotechnologies and bioremediation due to their specific ability to grow and express novel engineered functions. More recently, the sequencing of several Deinococcus spp and comparative genomic analysis have provided new insight into the potential of this genus. Features such as the accumulation of genes encoding cell cleaning systems that eliminate organic and inorganic cell toxic components are widespread among Deinococcus spp. Other features such as the ability to degrade and metabolize sugars and polymeric sugars make Deinococcus spp. an attractive alternative for use in industrial biotechnology. PMID- 25809885 TI - Comprehensive approach to better malaria control. PMID- 25809880 TI - Wnt8a and Wnt3a cooperate in the axial stem cell niche to promote mammalian body axis extension. AB - BACKGROUND: Vertebrate body axis extension occurs in a head-to-tail direction from a caudal progenitor zone that responds to interacting signals. Wnt/beta catenin signaling is critical for generation of paraxial mesoderm, somite formation, and maintenance of the axial stem cell pool. Body axis extension requires Wnt8a in lower vertebrates, but in mammals Wnt3a is required, although the anterior trunk develops in the absence of Wnt3a. RESULTS: We examined mouse Wnt8a(-/-) and Wnt3a(-/-) single and double mutants to explore whether mammalian Wnt8a contributes to body axis extension and to determine whether a posterior growth function for Wnt8a is conserved throughout the vertebrate lineage. We find that caudal Wnt8a is expressed only during early somite stages and is required for normal development of the anterior trunk in the absence of Wnt3a. During this time, we show that Wnt8a and Wnt3a cooperate to maintain Fgf8 expression and prevent premature Sox2 up-regulation in the axial stem cell niche, critical for posterior growth. Similar to Fgf8, Wnt8a requires retinoic acid (RA) signaling to restrict its caudal expression boundary and possesses an upstream RA response element that binds RA receptors. CONCLUSIONS: These findings provide new insight into interaction of caudal Wnt-FGF-RA signals required for body axis extension. PMID- 25809884 TI - Family history of cancer and childhood rhabdomyosarcoma: a report from the Children's Oncology Group and the Utah Population Database. AB - Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case-control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children's Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (OR(s) ) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (OR(s) = 1.39, 95% CI: 0.97-1.98). Notably, this association was stronger among those with embryonal RMS (OR(s) = 2.44, 95% CI: 1.54-3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (<30 years) was associated with a greater risk of RMS (OR(s) = 2.37, 95% CI: 1.34 4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at <30 years of age. PMID- 25809886 TI - A closer inspection of tedizolid. PMID- 25809887 TI - A closer inspection of tedizolid. PMID- 25809888 TI - A closer inspection of tedizolid - authors' reply. PMID- 25809889 TI - Investment in antibiotics against pneumonia. PMID- 25809890 TI - Investment in antibiotics against pneumonia. PMID- 25809891 TI - Overconsumption of antibiotics. PMID- 25809892 TI - Overconsumption of antibiotics. PMID- 25809893 TI - Probiotics to prevent early-life infection. PMID- 25809894 TI - Filovirus epidemic in 1956 in Bili, DRC. PMID- 25809895 TI - India tackles lymphatic filariasis. AB - The Indian Government has instigated an ambitious plan to tackle this disabling disease with a combination of a high-profile campaign and mass drug administration. Sanjeet Bagcchi reports. PMID- 25809896 TI - The health of nations. AB - Prevention of infectious diseases and other global health threats will rely on tackling poverty, a senior researcher argues. Peter Ranscombe reports. PMID- 25809897 TI - HIV-hepatitis C co-infection. PMID- 25809898 TI - Assessing a broader user base for new HCV drug. PMID- 25809901 TI - Emphysematous osteomyelitis. PMID- 25809902 TI - Structure, Activity and Stereoselectivity of NADPH-Dependent Oxidoreductases Catalysing the S-Selective Reduction of the Imine Substrate 2-Methylpyrroline. AB - Oxidoreductases from Streptomyces sp. GF3546 [3546-IRED], Bacillus cereus BAG3X2 (BcIRED) and Nocardiopsis halophila (NhIRED) each reduce prochiral 2 methylpyrroline (2MPN) to (S)-2-methylpyrrolidine with >95 % ee and also a number of other imine substrates with good selectivity. Structures of BcIRED and NhIRED have helped to identify conserved active site residues within this subgroup of imine reductases that have S selectivity towards 2MPN, including a tyrosine residue that has a possible role in catalysis and superimposes with an aspartate in related enzymes that display R selectivity towards the same substrate. Mutation of this tyrosine residue-Tyr169-in 3546-IRED to Phe resulted in a mutant of negligible activity. The data together provide structural evidence for the location and significance of the Tyr residue in this group of imine reductases, and permit a comparison of the active sites of enzymes that reduce 2MPN with either R or S selectivity. PMID- 25809904 TI - Interindividual variation, correlations, and sex-related differences in the salivary biochemistry of young healthy adults. AB - A cross-sectional observational study was conducted to evaluate interindividual biochemical variation in unstimulated whole saliva in a population of 268 systemically healthy young students, 18-30 yr of age, with no apparent caries lesions or periodontal disease. Salivary flow rate, protein content, pH, buffering capacity, mucins MUC5B and MUC7, albumin, secretory IgA, cystatin S, lactoferrin, chitinase, amylase, lysozyme, and proteases were measured using ELISAs and enzymatic activity assays. Significant differences were found between male and female subjects. Salivary pH, buffering capacity, protein content, MUC5B, secretory IgA, and chitinase activity were all lower in female subjects compared with male subjects, whereas MUC7 and lysozyme activity were higher in female subjects. There was no significant difference between sexes in salivary flow rate, albumin, cystatin S, amylase, and protease activity. Principal component analysis (PCA) and spectral clustering (SC) were used to assess intervariable relationships within the data set and to identify subgroups. Spectral clustering identified two clusters of participants, which were subsequently described. This study provides a comprehensive overview of the distribution and inter-relations of a set of important salivary biochemical variables in a systemically healthy young adult population, free of apparent caries lesions and periodontal disease. It highlights significant gender differences in salivary biochemistry. PMID- 25809906 TI - Better communication of the work of the Scientific Committee on Consumer Safety (SCCS). PMID- 25809903 TI - HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages. AB - BACKGROUND: Non-mac-tropic HIV-1 R5 viruses are predominantly transmitted and persist in immune tissue even in AIDS patients who carry highly mac-tropic variants in the brain. Non-mac-tropic R5 envelopes (Envs) require high CD4 levels for infection contrasting with highly mac-tropic Envs, which interact more efficiently with CD4 and mediate infection of macrophages that express low CD4. Non-mac-tropic R5 Envs predominantly target T-cells during transmission and in immune tissue where they must outcompete mac-tropic variants. Here, we investigated whether Env+ pseudoviruses bearing transmitted/founder (T/F), early and late disease non-mac-tropic R5 envelopes mediated more efficient infection of CD4+ T-cells compared to those with highly mac-tropic Envs. RESULTS: Highly mac tropic Envs mediated highest infectivity for primary T-cells, Jurkat/CCR5 cells, myeloid dendritic cells, macrophages, and HeLa TZM-bl cells, although this was most dramatic on macrophages. Infection of primary T-cells mediated by all Envs was low. However, infection of T-cells was greatly enhanced by increasing virus attachment with DEAE dextran and spinoculation, which enhanced the three Env+ virus groups to similar extents. Dendritic cell capture of viruses and trans infection also greatly enhanced infection of primary T-cells. In trans-infection assays, non-mac-tropic R5 Envs were preferentially enhanced and those from late disease mediated levels of T-cell infection that were equivalent to those mediated by mac-tropic Envs. CONCLUSIONS: Our results demonstrate that T/F, early or late disease non-mac-tropic R5 Envs do not preferentially mediate infection of primary CD4+ T-cells compared to highly mac-tropic Envs from brain tissue. We conclude that non-macrophage-tropism of HIV-1 R5 Envs in vitro is determined predominantly by a reduced capacity to target myeloid cells via low CD4 rather than a specific adaptation for T-cells entry that precludes macrophage infection. PMID- 25809908 TI - Activation of Water in Titanium Dioxide Photocatalysis by Formation of Surface Hydrogen Bonds: An In Situ IR Spectroscopy Study. AB - The hole-driving oxidation of titanium-coordinated water molecules on the surface of TiO2 is both thermodynamically and kinetically unfavorable. By avoiding the direct coordinative adsorption of water molecules to the surface Ti sites, the water can be activated to realize its oxidation. When TiO2 surface is covered by the H-bonding acceptor F, the first-layer water adsorption mode is switched from Ti coordination to a dual H-bonding adsorption on adjacent surface F sites. Detailed in situ IR spectroscopy and isotope-labeling studies reveal that the adsorbed water molecules by dual H-bonding can be oxidized to O2 even in the absence of any electron scavengers. Combined with theoretical calculations, it is proposed that the formation of the dual H-bonding structure can not only enable the hole transfer to the water molecules thermodynamically, but also facilitate kinetically the cleavage of O-H bonds by proton-coupled electron transfer process during water oxidation. PMID- 25809905 TI - Evaluation of the prognostic value and functional roles of CD44v6 in gastric cancer. AB - PURPOSE: Tumor stem cell surface marker CD44v6, a member of the CD44 protein family, is causally involved in the metastasis of cancer. Little is known about the functions of CD44v6 in gastric cancer. The aim of this study was to evaluate the prognostic value of CD44v6 and investigate its functional roles. METHODS: The expression of CD44v6 in 208 primary gastric adenocarcinoma patient samples was examined using immunohistochemistry and its correlation with clinicopathological parameters, and 5-year patient survival was assessed. Two pairs of MGC-803 stable cells with either CD44v6 overexpression or knockdown were created. The effect of CD44v6 on cell proliferation, colony formation, migration and apoptosis was investigated using these two pairs of cells. RESULTS: Overexpression of CD44v6 was observed in all cancer cell lines. The 5-year survival rate of patients with positive CD44v6 expression is significantly worse compared to those with negative expression (38.8 vs. 73.6 %). CD44v6 and TNM stage are two independent prognostic factors of primary gastric adenocarcinoma. The risk factors for the positive CD44v6 expression are location of tumor, depth of invasion, lymph node metastasis, Lauren classification and TNM stage. In MGC-803 cells, CD44 stimulated proliferation and colony formation, antagonized oxaliplatin-induced apoptosis, but did not affect migration. CONCLUSION: CD44v6 is an important prognosis marker in gastric cancer. Tissue specificity may affect the functions of CD44v6, and further work is needed to elucidate its regulation. PMID- 25809909 TI - The impact of Quaternary climate oscillations on divergence times and historical population sizes in Thylamys opossums from the Andes. AB - Climate oscillations during the Quaternary altered the distributions of terrestrial animals at a global scale. In mountainous regions, temperature fluctuations may have led to shifts in range size and population size as species tracked their shifting habitats upslope or downslope. This creates the potential for both allopatric speciation and population size fluctuations, as species are either constrained to smaller patches of habitat at higher elevations or able to expand into broader areas at higher latitudes. We considered the impact of climate oscillations on three pairs of marsupial species from the Andes (Thylamys opossums) by inferring divergence times and demographic changes. We compare four different divergence dating approaches, using anywhere from one to 26 loci. Each pair comprises a northern (tropical) lineage and a southern (subtropical to temperate) lineage. We predicted that divergences would have occurred during the last interglacial (LIG) period approximately 125 000 years ago and that population sizes for northern and southern lineages would either contract or expand, respectively. Our results suggest that all three north-south pairs diverged in the late Pleistocene during or slightly after the LIG. The three northern lineages showed no signs of population expansion, whereas two southern lineages exhibited dramatic, recent expansions. We attribute the difference in responses between tropical and subtropical lineages to the availability of 'montane-like' habitats at lower elevations in regions at higher latitudes. We conclude that climate oscillations of the late Quaternary had a powerful impact on the evolutionary history of some of these species, both promoting speciation and leading to significant population size shifts. PMID- 25809910 TI - Left Atrial Appendage Conduction Jump for Real-Time Evaluation of Conduction Block Over the Anterior Mitral Annulus Line. AB - INTRODUCTION: Evaluation of conduction over a linear ablation lesion at the anterior mitral annulus can be time-consuming and difficult during ongoing radiofrequency application. The purpose of this study was to validate conduction time from the beginning of the p wave and from the coronary sinus ostium to the left atrial appendage (LAA) as a new method of conduction block surveillance. METHODS: Conduction across the anterior mitral annulus line was evaluated using a total of 55 patients. We verified completeness of conduction block by standard techniques including differential pacing, double potential mapping and activation mapping. Those methods were compared to the new method of observing an abrupt prolongation of conduction time into the LAA as well as a conduction sequence change on a circular multipolar mapping catheter placed inside the LAA during sinus rhythm. RESULTS: Bidirectional conduction block across the ablated line was achieved in 51 (92.7%) of the patients. Prior to ablation, mean conduction time across the line was 59 +/- 21 milliseconds. This value increased to 163 +/- 43 milliseconds after a successful ablation. An abrupt prolongation of conduction time into the LAA of at least 50 milliseconds was observed in all patients at the moment when a complete conduction block was achieved. Additionally, a change of conduction sequence recorded with the multi-electrode catheter placed in the LAA was observed in all of these patients. CONCLUSIONS: A sudden jump of p wave and coronary sinus ostium to LAA conduction time together with a change of conduction sequence recorded with a multi-electrode catheter placed inside the LAA during sinus rhythm is a simple and reliable approach for beat-to-beat surveillance of conduction block across the anterior mitral annulus during radiofrequency ablation. PMID- 25809911 TI - If We Build It, They Will Come: Exploring Policy and Practice Implications of Public Support for Couple and Relationship Education for Lower Income and Relationally Distressed Couples. AB - Over the past decade, public funding for Couple and Relationship Education programs has expanded. As program administrators have been able to extend their reach to low-income individuals and couples using this support, it has become apparent that greater numbers of relationally distressed couples are attending classes than previously anticipated. Because psychoeducational programs for couples have traditionally served less distressed couples, this dynamic highlights the need to examine the policy and practice implications of more distressed couples accessing these services. This paper reviews some of the most immediate issues, including screening for domestic violence and couple needs, pedagogical considerations, and the potential integration of therapy and education services. We also make suggestions for future research that can inform policy and practice efforts. PMID- 25809912 TI - Transforming growth factor type-beta inhibits Mas receptor expression in fibroblasts but not in myoblasts or differentiated myotubes; Relevance to fibrosis associated to muscular dystrophies. AB - Duchenne muscular dystrophy is a genetic disorder characterized by myofiber degeneration, muscle weakness, and increased fibrosis. Transforming growth factor type-beta (TGF-beta), a central mediator of fibrosis, is upregulated in fibrotic diseases. Angiotensin-(1-7) [Ang-(1-7)] is a peptide with actions that oppose those of angiotensin-II (Ang II). Ang-(1-7) effects are mediated by the Mas receptor. Treatment with Ang-(1-7) produce positive effects in the mdx mouse, normalizing skeletal muscle architecture, decreasing local fibrosis, and fibroblasts, and improving muscle function. Mdx mice deficient for the Mas receptor showed the opposite effects. To identify the cell type(s) responsible for Mas receptor expression, and to characterize whether profibrotic effectors had any effect on its expression, we determined the effect of profibrotic agents on Mas expression. TGF-beta, but not connective tissue growth factor or Ang-II, reduced the expression of Mas receptor in fibroblasts isolated from skeletal muscle cells and fibroblasts from two established cell lines. In contrast, no effects were observed in myoblasts and differentiated myotubes. This inhibition was mediated by the Smad-dependent (canonical) and the PI3K and MEK1/2 (noncanonical) TGF-beta signaling pathways. When both canonical and noncanonical inhibitors of the TGF-beta-dependent pathways were added together, the inhibitory effect of TGF-beta on Mas expression was lost. The decrease in Mas receptor induced by TGF-beta in fibroblasts reduced the Ang-(1-7) mediated stimulation of phosphorylation of AKT pathway proteins. These results suggest that reduction of Mas receptor in fibroblasts, by TGF-beta, could increase the fibrotic phenotype observed in dystrophic skeletal muscle decreasing the beneficial effect of Ang-(1 7). PMID- 25809913 TI - Efficacy of combination therapy with probiotics and mosapride in patients with IBS without diarrhea: a randomized, double-blind, placebo-controlled, multicenter, phase II trial. AB - BACKGROUND: Probiotics can be beneficial in irritable bowel syndrome (IBS). Mosapride citrate, a selective 5-HT4 receptor agonist, stimulates gastrointestinal motility. We investigated the efficacy of combination therapy with probiotics and mosapride for non-diarrheal-type IBS. METHODS: Two hundred and eighty-five IBS patients were randomly assigned to either a combination of probiotics (Bacillus subtilis and Streptococcus faecium) and mosapride at one of four different doses or a placebo for 4 weeks. The primary outcome was the proportion of patients experiencing adequate relief (AR) of global IBS symptoms at week 4. The secondary outcomes included subject's global assessment (SGA) of IBS symptom relief, individual symptoms, stool parameters, and IBS-quality of life. KEY RESULTS: The proportion of AR at week 4 was significantly higher in all treatment groups compared to the placebo group (53.7% in group 1, 55.0% in group 2, 55.2% in group 3, 53.6% in group 4 [the highest dose], and 35.1% in placebo group, respectively, p < 0.05). The proportion of patients reporting 'completely or considerably relieved' in the SGA was higher in the treatment groups than in the placebo group. The abdominal pain/discomfort score in the treatment group 4 was more prominently improved compared with that of the placebo group. In patients with constipation-predominant IBS, the improvements in stool frequency and consistency were significantly higher in the treatment groups 4 and 1, respectively, than those in the placebo group. CONCLUSIONS & INFERENCES: Combination therapy with probiotics and mosapride is effective for relief of symptoms in patients with non-diarrheal-type IBS. The study has been registered in the US National Library of Medicine (http://www.clinicaltrials.gov, NCT01505777). PMID- 25809914 TI - Bombyx mori nucleopolyhedrovirus actin rearrangement-inducing factor 1 enhances systemic infection in B. mori larvae. AB - The actin rearrangement-inducing factor 1 (arif-1) gene is a baculoviral early gene conserved in most alphabaculoviruses. Previous studies reported that Autographa californica nucleopolyhedrovirus ARIF-1 protein induces filamentous actin concentration on the plasma membrane during the early stage of infection in Trichoplusia ni TN-368 cells, but its role in larval infection remains unknown. In this study, we performed behavioural screening using Bombyx mori larvae infected with Bombyx mori nucleopolyhedrovirus (BmNPV) mutants and found that larvae infected with arif-1-mutated BmNPVs did not show locomotor hyperactivity that was normally observed in BmNPV-infected larvae. arif-1-deficient BmNPVs also showed reduced pathogenicity and total viral propagation in B. mori larvae, whereas viral propagation of arif-1-deficient viruses was comparable with that of control viruses in B. mori cultured cells. An arif-1-defective BmNPV expressing the GFP gene (gfp) was used to monitor the progression of infection in B. mori larvae. GFP expression and quantitative reverse transcription-PCR analyses revealed that infection by the arif-1-disrupted virus was significantly delayed in trachea, fat body, suboesophageal ganglion and brain. These results indicated that BmNPV ARIF-1 enhanced systemic infection in B. mori larvae. PMID- 25809916 TI - Structural and Qualitative Bone Remodeling Around Repetitive Loaded Implants in Rabbits. AB - BACKGROUND: Bone mechanical function is regulated by bone quality and bone mineral density (BMD) that reflect bone strength. The preferential alignment of biological apatite (BAp) c-axis/collagen fibers and osteocytes is a determinant factor of bone quality. However, the effect of mechanical loading on bone quality around dental implants is unclear. PURPOSE: The aim of this study was to clarify the effects of mechanical loading on osseointegration, bone volume BMD, and bone quality around dental implants. MATERIALS AND METHODS: Twenty anodized Ti-6Al-4V alloy implants (KYOCERA Co., Kyoto, Japan) were placed in the proximal tibial metaphysis of 10 rabbits. Twelve weeks after surgery, mechanical loading was applied along the long axis of the implant (50 N, 3 Hz, 1,800 cycles, 2 days/week) for 8 weeks. Osseointegration, bone volume, BMD, and bone quality were evaluated using light microscopy, microcomputed tomography, polarized light microscopy, and microbeam X-ray diffractometer. RESULTS: Mechanical loading increased osseointegration, bone volume, and BMD. Bone quality around dental implant was altered with increased osteocyte numbers and the preferential alignment direction and degree of BAp c-axis/collagen fibers. CONCLUSIONS: These findings suggest that mechanical loading effectively induces bone anabolic responses around dental implants. Altered bone quality may upregulate bone strength, contributing to long-term implant stability. PMID- 25809915 TI - The N-terminal domain of Npro of classical swine fever virus determines its stability and regulates type I IFN production. AB - The viral protein Npro is unique to the genus Pestivirus within the family Flaviviridae. After autocatalytic cleavage from the nascent polyprotein, Npro suppresses type I IFN (IFN-alpha/beta) induction by mediating proteasomal degradation of IFN regulatory factor 3 (IRF-3). Previous studies found that the Npro-mediated IRF-3 degradation was dependent of a TRASH domain in the C-terminal half of Npro coordinating zinc by means of the amino acid residues C112, C134, D136 and C138. Interestingly, four classical swine fever virus (CSFV) isolates obtained from diseased pigs in Thailand in 1993 and 1998 did not suppress IFN alpha/beta induction despite the presence of an intact TRASH domain. Through systematic analyses, it was found that an amino acid mutation at position 40 or mutations at positions 17 and 61 in the N-terminal half of Npro of these four isolates were related to the lack of IRF-3-degrading activity. Restoring a histidine at position 40 or both a proline at position 17 and a lysine at position 61 based on the sequence of a functional Npro contributed to higher stability of the reconstructed Npro compared with the Npro from the Thai isolate. This led to enhanced interaction of Npro with IRF-3 along with its degradation by the proteasome. The results of the present study revealed that amino acid residues in the N-terminal domain of Npro are involved in the stability of Npro, in interaction of Npro with IRF-3 and subsequent degradation of IRF-3, leading to downregulation of IFN-alpha/beta production. PMID- 25809917 TI - Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer. AB - Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR) = 4.93, 95% CI = 2.72-8.92, p < 0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p < 0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR = 2.15, 95% CI = 1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR = 3.68, 95%CI = 1.12 12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target. PMID- 25809918 TI - A novel KRT86 mutation in a Turkish family with monilethrix, and identification of maternal mosaicism. AB - BACKGROUND: Monilethrix is a rare monogenic dystrophic hair loss disorder with high levels of intrafamilial and interfamilial variability. It is characterized by diffuse occipital or temporal alopecia, hair fragility and follicular hyperkeratosis of the occipital region. Mutations in the keratin genes KRT81, KRT83 and KRT86 lead to autosomal dominant monilethrix, whereas mutations in the desmoglein 4 gene (DSG4) cause an autosomal recessive form. AIM: To identify the mutation in a consanguineous Turkish family with three affected children and apparently unaffected parents. METHODS: Sequencing analysis of the genes DSG4 and KRT86 was performed. SNaPshot analysis was conducted to quantify the proportion of cells carrying the KRT86 mutation and to confirm maternal mosaicism of KRT86. RESULTS: No pathogenic mutation was found by sequencing analysis of DSG4; however, analysis of KRT86 revealed a novel mutation, c.1231G>T;p.Glu411*, in exon 7 in the three affected children and their mother. The mutation signal was weaker in the mother than in the three siblings, and SNaPshot analysis revealed substantial mutation-level variation between the children and their mother. CONCLUSIONS: Our results extend the spectrum of KRT86 mutations and indicate KRT86 mosaicism in the family examined. This study is the first, to our knowledge, to describe mosaicism for a monogenic hair loss disorder, and suggests that mosaicism leads to a mild manifestation of monilethrix. PMID- 25809920 TI - The time course of attentional modulation on emotional conflict processing. AB - Cognitive conflict resolution is critical to human survival in a rapidly changing environment. However, emotional conflict processing seems to be particularly important for human interactions. This study examined whether the time course of attentional modulation on emotional conflict processing was different from cognitive conflict processing during a flanker task. Results showed that emotional N200 and P300 effects, similar to colour conflict processing, appeared only during the relevant task. However, the emotional N200 effect preceded the colour N200 effect, indicating that emotional conflict can be identified earlier than cognitive conflict. Additionally, a significant emotional N100 effect revealed that emotional valence differences could be perceived during early processing based on rough aspects of input. The present data suggest that emotional conflict processing is modulated by top-down attention, similar to cognitive conflict processing (reflected by N200 and P300 effects). However, emotional conflict processing seems to have more time advantages during two different processing stages. PMID- 25809921 TI - Complete characterization of the mutation landscape reveals the effect on amylin stability and amyloidogenicity. AB - Type-II diabetes is believed to be partially aggravated by the emergence of toxic amylin protein deposits in the extracellular space of the pancreas beta-cells. Amylin, the regulatory hormone that is co-secreted with insulin, has been observed to misfold into toxic structures. Pramlintide, an FDA approved injectable amylin analog mutated at positions 25, 28, and 29 was therefore developed to create a more stable, soluble, less-aggregating, and equipotent peptide that is used as an adjunctive therapy for diabetes. However, because Pramlintide is not ideal, researchers have been exploring other amylin analogs as therapeutic replacements. In this work, we assist the finding of optimal analogs by computationally revealing the mutational landscape of amylin. We computed the structure energies of all possible single-point mutations and studied the effect they have on amylin stability and amyloidogenicity. Each of the 37 amylin residues was mutated in silico into the 19 canonical amino acids and an energy function computing the Lennard-Jones, Coulomb and solvation energy was used to analyze changes in stability. The mutation landscape identified amylin's conserved stable regions, residues that can be tweaked to further stabilize structure, regions that are susceptible to mutations, and mutations that are amyloidogenic. We used the single-point mutational landscape data to generate estimations for higher-order multiple-point mutational landscapes and discovered millions of three-point mutations that are more stable and less amyloidogenic than Pramlintide. The landscapes provided an explanation for the effect of the S20G and Q10R mutations on the onset of diabetes of the Chinese and Maori populations, respectively. PMID- 25809919 TI - Phenotypical characterization of circulating cell subsets in pyoderma gangrenosum patients: the experience of the Italian immuno-pathology group. AB - BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+). PMID- 25809922 TI - Relationship Between Speech Intelligibility and Speech Comprehension in Babble Noise. AB - PURPOSE: The authors investigated the relationship between the intelligibility and comprehension of speech presented in babble noise. METHOD: Forty participants listened to French imperative sentences (commands for moving objects) in a multitalker babble background for which intensity was experimentally controlled. Participants were instructed to transcribe what they heard and obey the commands in an interactive environment set up for this purpose. The former test provided intelligibility scores and the latter provided comprehension scores. RESULTS: Collected data revealed a globally weak correlation between intelligibility and comprehension scores (r = .35, p < .001). The discrepancy tended to grow as noise level increased. An analysis of standard deviations showed that variability in comprehension scores increased linearly with noise level, whereas higher variability in intelligibility scores was found for moderate noise level conditions. CONCLUSION: These results support the hypothesis that intelligibility scores are poor predictors of listeners' comprehension in real communication situations. Intelligibility and comprehension scores appear to provide different insights, the first measure being centered on speech signal transfer and the second on communicative performance. Both theoretical and practical implications for the use of speech intelligibility tests as indicators of speakers' performances are discussed. PMID- 25809923 TI - Measures used to assess chronic pelvic pain in randomized controlled clinical trials: a systematic review. AB - RATIONALE: Many types of pain assessment are available to researchers carrying out clinical trials in chronic pelvic pain (CPP), ranging from a single-item scale to multidimensional inventories. AIM: Our objective was to investigate which assessments of pain are more commonly used in clinical trials on CPP. METHOD: We have reviewed articles published between 1991 and 2014. A total of 74 studies out of 1299 original research articles reviewed met the selection criteria by containing at least one method of pain assessment. The selected studies were classified according to the dimensions of pain evaluated, the type of scale and the descriptors used. RESULTS: The instruments most frequently used were single-item VAS and Biberoglu and Behrman pain score, while multidimensional inventories were used in few studies. The results of clinical studies in CPP are more frequently based on one-dimensional measurements. Valuable results from clinical studies in CPP might have been omitted because of incomplete outcome measurements. CONCLUSION: We believe the authors of clinical studies should report their results in a comprehensive way including in the outcomes of the measurement of one-dimensional and multidimensional pain characteristics. PMID- 25809926 TI - Development of an Interspecies Nested Dose-Response Model for Mycobacterium avium subspecies paratuberculosis. AB - Mycobacterium avium subspecies paratuberculosis (MAP) causes chronic inflammation of the intestines in humans, ruminants, and other species. It is the causative agent of Johne's disease in cattle, and has been implicated as the causative agent of Crohn's disease in humans. To date, no quantitative microbial risk assessment (QMRA) for MAP utilizing a dose-response function exists. The objective of this study is to develop a nested dose-response model for infection from oral exposure to MAP utilizing data from the peer-reviewed literature. Four studies amenable to dose-response modeling were identified in the literature search and optimized to the one-parameter exponential or two-parameter beta Poisson dose-response models. A nesting analysis was performed on all permutations of the candidate data sets to determine the acceptability of pooling data sets across host species. Three of four data sets exhibited goodness of fit to at least one model. All three data sets exhibited good fit to the beta-Poisson model, and one data set exhibited goodness of fit, and best fit, to the exponential model. Two data sets were successfully nested using the beta-Poisson model with parameters alpha = 0.0978 and N50 = 2.70 * 10(2) CFU. These data sets were derived from sheep and red deer host species, indicating successful interspecies nesting, and demonstrate the highly infective nature of MAP. The nested dose-response model described should be used for future QMRA research regarding oral exposure to MAP. PMID- 25809924 TI - Hypothesis testing for two-stage designs with over or under enrollment. AB - Simon's two-stage designs are widely used in cancer phase II clinical trials for assessing the efficacy of a new treatment. However in practice, the actual sample size for the second stage is often different from the planned sample size, and the original inference procedure is no longer valid. Previous work on this problem has certain limitations in computation. In this paper, we attempt to maximize the unconditional power while controlling for the type I error for the modified second stage sample size. A normal approximation is used for computing the power, and the numerical results show that the approximation is accurate even under small sample sizes. The corresponding confidence intervals for the response rate are constructed by inverting the hypothesis test, and they have reasonable coverage while preserving the type I error. PMID- 25809925 TI - Is pilates as effective as conventional pelvic floor muscle exercises in the conservative treatment of post-prostatectomy urinary incontinence? A randomised controlled trial. AB - AIMS: To verify the efficacy of a Pilates exercise program compared to conventional pelvic floor muscle exercise (PFME) protocol in the conservative treatment of post-prostatectomy urinary incontinence (PPUI). METHODS: Baseline assessment was performed four weeks postoperatively and included 24 hr pad test, bladder diary, and the ICIQ-SF. Patients were randomised into three groups: Pilates (G1), PFME combined with anal electrical stimulation (G2), and a control group (G3). Both treatment groups had to perform 10 weekly treatment sessions. Primary outcomes were mean reduction of daily pads and mean reduction of ICIQ-SF score four months after surgery. The significance level was set at P < 0.05. RESULTS: 85 patients completed the study. Differences between treatment groups (G1 and G2) in terms of mean reduction in daily pad usage, 24 hr pad test, and ICIQ-SF scores were not statistically significant (P > 0.05). The control group differed from G1 in daily pad usage (P = 0.01) and ICIQ-SF score (P = 0.0073). Intergroup comparisons revealed that 57.7% of the volunteers in G1 and 50% of the individuals from G2 no longer used pads by the end of the treatment period (P = 0.57). In the control group, 22.6% were not using pads four months after surgery, with statistical difference compared to G1 (P < 0.05). CONCLUSIONS: The Pilates exercise program proved to be as effective as conventional PFME to speed up continence recovery in PPUI. It also achieved a higher rate of fully continent patients when compared to the control group in the short-term. Neurourol. Urodynam. 35:615-621, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25809928 TI - Problems with measuring satisfaction with social care. AB - The measurement of customer satisfaction has become widespread in both healthcare and social care services, and is informative for performance monitoring and service development. Satisfaction with social care services is routinely measured with a single question on overall satisfaction with care, comprising part of the Adult Social Care Survey. The measurement of satisfaction has been problematised, and existing satisfaction measures are known to be under-theorised. In this article, the process of making an evaluation of satisfaction with social care services is first informed by a literature review of the theoretical background, and second examined through qualitative interviews conducted in 2012-2013 with 82 service users and family carers in Hampshire, Portsmouth and Southampton. Participants in this study were from white British and South Asian backgrounds, and the influence of ethnicity in the process of satisfaction evaluation is discussed. The findings show that the majority of participants selected a positive satisfaction rating even though both positive and negative experiences with services were described in their narratives. It is recommended that surveys provide opportunity for service users and family carers to elaborate on their satisfaction ratings. This addition will provide more scope for services to review their strengths and weaknesses. PMID- 25809927 TI - [Diagnostic accuracy of dual energy CT angiography in patients with diabetes mellitus]. AB - OBJECTIVES: Peripheral arterial disease (PAD) represents a major and highly prevalent complication in patients with diabetes mellitus. The diagnostic, non invasive work-up by computed tomography angiography (CTA) is limited in the presence of extensive calcification. The aim of the study was to determine the diagnostic accuracy of dual energy CTA (DE-CTA) for the detection and characterization of PAD in patients with diabetes mellitus. MATERIAL AND METHODS: In this study 30 diabetic patients with suspected or known PAD were retrospectively included in the analysis. All subjects underwent DE-CTA (Somatom Definition Flash, Siemens Healthcare, Erlangen, Germany) prior to invasive angiography, which served as the reference standard. Blinded analysis included assessment of the presence and degree of peripheral stenosis on curved multiplanar reformatting (MPR) and maximum intensity projections (MIP). Conventional measures of diagnostic accuracy were derived. RESULTS: Among the 30 subjects included in the analysis (83% male, mean age 70.0 +/- 10.5 years, 83% diabetes type 2), the prevalence of critical stenosis in 331 evaluated vessel segments was high (30%). Dual energy CT identified critical stenoses with a high sensitivity and good specificity using curved MPR (100% and 93.1%, respectively) and MIP images (99% and 91.8%, respectively). In stratified analysis, the diagnostic accuracy was higher for stenosis pertaining to the pelvic and thigh vessels as compared with the lower extremities (curved MPR accuracy 97.1% vs. 99.2 vs. 90.9%; respectively, p < 0.001). CONCLUSION: The use of DE-CTA allows reliable detection and characterization of peripheral arterial stenosis in patients with diabetes mellitus with higher accuracy in vessels in the pelvic and thigh regions compared with the vessels in the lower legs. PMID- 25809929 TI - Reducing the follow-up rates over three consecutive specialist registrar trainees placements. PMID- 25809930 TI - Overexpression of Ras-GTPase-activating protein SH3 domain-binding protein 1 correlates with poor prognosis in gastric cancer patients. AB - AIMS: Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a downstream effector of Ras signalling, and is overexpressed in several types of human malignancy. However, its role in gastric cancer remains unclear. The aim of this study was to investigate the prognostic significance of G3BP1 in gastric cancer. METHODS AND RESULTS: G3BP1 mRNA and protein levels in paired frozen tumour samples were detected by real-time polymerase chain reaction and western blotting, respectively. Paraffin-embedded tumour samples were used for immunohistochemistry. Gastric cancer cells were used to detect the tumorigenic role of G3BP1 in vitro. We found that G3BP1 protein expression was markedly increased in gastric cancer tissues as compared with corresponding non-malignant mucosa, whereas corresponding changes in mRNA levels were not observed. G3BP1 staining was positively correlated with tumour size, vascular invasion, T classification, lymph node metastasis, TNM stage, and reduced overall survival. Further analysis identified G3BP1 as an independent prognostic factor for poor prognosis, and combining G3BP1 with TNM stage generated a better predictive model for patient outcomes. G3BP1 also promoted proliferation, migration/invasion and extracellular signal-related kinase and AKT activation in gastric cancer cells. CONCLUSIONS: Our data define G3BP1 as a novel independent prognostic factor that is correlated with gastric cancer progression. PMID- 25809932 TI - Role of geometrical shape in like-charge attraction of DNA. AB - While the phenomenon of like-charge attraction of DNA is clearly observed experimentally and in simulations, mean-field theories fail to predict it. Kornyshev et al. argued that like-charge attraction is due to DNA's helical geometry and hydration forces. Strong-coupling (SC) theory shows that attraction of like-charged rods is possible through ion correlations alone at large coupling parameters, usually by multivalent counterions. However for SC theory to be applicable, counterion-counterion correlations perpendicular to the DNA strands need to be sufficiently small, which is not a priori the case for DNA even with trivalent counterions. We study a system containing infinitely long DNA strands and trivalent counterions by computer simulations employing varying degrees of coarse-graining. Our results show that there is always attraction between the strands, but its magnitude is indeed highly dependent on the specific shape of the strand. While discreteness of the charge distribution has little influence on the attractive forces, the role of the helical charge distribution is considerable: charged rods maintain a finite distance in equilibrium, while helices collapse to close contact with a phase shift of pi, in full agreement with SC predictions. The SC limit is applicable because counterions strongly bind to the charged sites of the helices, so that helix-counterion interactions dominate over counterion-counterion interactions. Thus DNA's helical geometry is not crucial for like-charge DNA attraction, but strongly enhances it, and electrostatic interactions in the strong-coupling limit are sufficient to explain this attraction. PMID- 25809931 TI - Carbonate fabrics in the modern microbialites of Pavilion Lake: two suites of microfabrics that reflect variation in microbial community morphology, growth habit, and lithification. AB - Modern microbialites in Pavilion Lake, BC, provide an analog for ancient non stromatolitic microbialites that formed from in situ mineralization. Because Pavilion microbialites are mineralizing under the influence of microbial communities, they provide insights into how biological processes influence microbialite microfabrics and mesostructures. Hemispherical nodules and micrite microbial crusts are two mesostructures within Pavilion microbialites that are directly associated with photosynthetic communities. Both filamentous cyanobacteria in hemispherical nodules and branching filamentous green algae in micrite-microbial crusts were associated with calcite precipitation at microbialite surfaces and with characteristic microfabrics in the lithified microbialite. Hemispherical nodules formed at microbialite surfaces when calcite precipitated around filamentous cyanobacteria with a radial growth habit. The radial filament pattern was preserved within the microbialite to varying degrees. Some subsurface nodules contained well-defined filaments, whereas others contained only dispersed organic inclusions. Variation in filament preservation is interpreted to reflect differences in timing and amount of carbonate precipitation relative to heterotrophic decay, with more defined filaments reflecting greater lithification prior to degradation than more diffuse filaments. Micrite-microbial crusts produce the second suite of microfabrics and form in association with filamentous green algae oriented perpendicular to the microbialite surface. Some crusts include calcified filaments, whereas others contained voids that reflect the filamentous community in shape, size, and distribution. Pavilion microbialites demonstrate that microfabric variation can reflect differences in lithification processes and microbial metabolisms as well as microbial community morphology and organization. Even when the morphology of individual filaments or cells is not well preserved, the microbial growth habit can be captured in mesoscale microbialite structures. These results suggest that when petrographic preservation is extremely good, ancient microbialite growth structures and microfabrics can be interpreted in the context of variation in community organization, community composition, and lithification history. Even in the absence of distinct microbial microfabrics, mesostructures can capture microbial community morphology. PMID- 25809933 TI - Chemical investigation of metabolites produced by an endophytic Aspergillus sp. isolated from Limonia acidissima. AB - Endophytic fungi are considered as a good source to produce important secondary metabolites with interesting bioactivities. In a continuation of our studies towards the search for environmentally friendly bioactive compounds from Sri Lankan flora, we investigated the secondary metabolites produced by the endophytic fungi Aspergillus sp. isolated from the seeds of the popular edible fruit Limonia acidissima L. of the family Rutaceae. The pure culture of the Aspergillus sp. was grown on potato dextrose broth media. After 4 weeks fermentation, fungal media were extracted with organic solvents. Chromatographic separation of the fungal extracts over silica gel, Sephadex LH-20 and RP-HPLC furnished flavasperone (1), rubrofusarin B (2), aurasperone A (3), fonsecinone D (4) and aurasperone B (5). Compounds 1-4 showed moderate activities in brine shrimp toxicity assay. This is the first report of the (13)C NMR data of compounds 4 and 5. PMID- 25809934 TI - Quality and overlap of individual core areas are related to group tenure in female spider monkeys. AB - In species with a high degree of fission-fusion dynamics group members may differ in the use of the group home range to reduce food competition. Such differential use may result in distinct individual core areas. We studied core area quality and overlap among 21 female spider monkeys belonging to the same group over a period of 4 years. Core areas ranged between 62 and 161 ha with a mean overlap of 56% between any given two females. Only a small portion (mean = 3 ha) of each individual core area was used exclusively. No single part of the home range was used as core area by all females, and only an area of less than 1 ha was used as part of the core area by 20 of the 21 females. The time a female spent in the group (i.e., group tenure) was associated with characteristics of the core areas: the longer the group tenure, the better the quality of her core area. In addition, the longer the time two females spent together in the same group, the larger the overlap between their individual core areas. As this result was obtained while controlling for the time two females spent together in the same subgroup, females may reduce direct competition by using the same resource at different times. In sum, spider monkey females' group tenure plays a central role in the quality and overlapping patterns of their individual core areas. PMID- 25809935 TI - Riboflavin-induced photo-crosslinking of collagen hydrogel and its application in meniscus tissue engineering. AB - A meniscus tear is a common knee injury, but its regeneration remains a clinical challenge. Recently, collagen-based scaffolds have been applied in meniscus tissue engineering. Despite its prevalence, application of natural collagen scaffold in clinical setting is limited due to its extremely low stiffness and rapid degradation. The purpose of the present study was to increase the mechanical properties and delay degradation rate of a collagen-based scaffold by photo-crosslinking using riboflavin (RF) and UV exposure. RF is a biocompatible vitamin B2 that showed minimal cytotoxicity compared to conventionally utilized photo-initiator. Furthermore, collagen photo-crosslinking with RF improved mechanical properties and delayed enzyme-triggered degradation of collagen scaffolds. RF-induced photo-crosslinked collagen scaffolds encapsulated with fibrochondrocytes resulted in reduced scaffold contraction and enhanced gene expression levels for the collagen II and aggrecan. Additionally, hyaluronic acid (HA) incorporation into photo-crosslinked collagen scaffold showed an increase in its retention. Based on these results, we demonstrate that photo-crosslinked collagen-HA hydrogels can be potentially applied in the scaffold-based meniscus tissue engineering. PMID- 25809936 TI - Supercritical synthesis of poly (2-dimethylaminoethyl methacrylate)/ferrite nanocomposites for real-time monitoring of protein release. AB - A supercritical carbon dioxide (SCC)-assisted process was developed to synthesize protein-supported poly (2-dimethylaminoethyl methacrylate)/ferrite nanocomposites (PNCs). The process involve 2,2-azobisisobutyronitrile-initiated in situ polymerization of 2-dimethylaminoethyl methacrylate in presence of ferrite nanoparticles and bisacrylamide at 90 +/- 1 degrees C, 1200 psi over 6 h in SCC. This was followed by subsequent loading of bovine serum albumin (BSA) as a model protein over PNCs in phosphate buffer (PBS, pH 7.4) at 1200 psi, 35 +/- 1 degrees C over additional 2 h in SCC. The formation of PNCs was ascertained through ultraviolet-visible, Fourier transform-infrared, X-ray diffraction spectra, transmission electron, atomic force microscopy and magnetometry. The developed process extends large scale production of nanomagnetic PNCs suitable as carrier for protein release applications with optimal release properties. The release of protein from PNCs under in vitro in PBS down to nanomolar range with high temporal resolution, speed and reproducibility was quantified through square wave voltammetry. PMID- 25809937 TI - A novel mutation of EYA4 in a large Chinese family with autosomal dominant middle frequency sensorineural hearing loss by targeted exome sequencing. AB - The middle-frequency sensorineural hearing loss (MFSNHL) is rare among hereditary non-syndromic hearing loss. To date, only three genes are reported to be associated with MFSNHL, including TECTA, EYA4 and COL11A2. In this report, we analyzed and explored the clinical audiological characteristics and the causative gene of a Chinese family named HG-Z087 with non-syndromic autosomal dominant inherited MFSNHL. Clinical audiological characteristics and inheritance pattern of a family were evaluated, and pedigree was drawn based on medical history investigation. Our results showed that the Chinese family was characterized by late onset, progressive, non-sydromic autosomal dominant MFSNHL. Targeted exome sequencing, conducted using DNA samples of an affected member in this family, revealed a novel heterozygous missense mutation c.1643C>G in exon 18 of EYA4, causing amino-acid (aa) substitution Arg for Thr at a conserved position aa-548. The p.T548R mutation related to hearing loss in the selected Chinese family was validated by Sanger sequencing. However, the mutation was absent in control group containing 100 DNA samples from normal Chinese families. In conclusion, we identified the pathogenic gene and found that the novel missense mutation c.1643C>G (p.T548R) in EYA4 might have caused autosomal dominant non-syndromic hearing impairment in the selected Chinese family. PMID- 25809938 TI - A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype. AB - Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and post-natal growth retardation, dysmorphic facial features and body asymmetry. About 50% of the patients carry (epi)genetic alterations involving chromosomes 7 or 11.The high proportion of patients with unidentified molecular etiology suggests the involvement of other genes. Interestingly, SRS patients share clinical features with the 12q14 microdeletion syndrome, characterized by several deletions with a 2.6 Mb region of overlap. Among the genes present in this interval, high mobility AT-hook 2 (HMGA2) appears to be the most likely cause of the growth deficiency, due to its described growth control function. To define the role of HMGA2 in SRS, we looked for 12q14 chromosome imbalances and HMGA2 mutations in a cohort of 45 patients with growth retardation and SRS-like phenotype but no 11p15 (epi)mutations or maternal uniparental disomy of chromosome 7 (matUPD7). We identified a novel 7 bp intronic deletion in HMGA2 present in heterozygosity in the proband and her mother both displaying the typical features of SRS. We demonstrated that the deletion affected normal splicing, indicating that it is a likely cause of HMGA2 deficiency. This study provides the first evidence that a loss-of-function mutation of HMGA2 can be associated with a familial form of SRS. We suggest that HMGA2 mutations leading to haploinsufficiency should be investigated in the SRS patients negative for the typical 11p15 (epi)mutations and matUPD7. PMID- 25809940 TI - Cytological diagnosis of desmoplastic malignant melanoma of the great toe. PMID- 25809939 TI - A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings. AB - Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5'-UTR of the RARS2 gene in the homozygous state. This variant was identified through next generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6. PMID- 25809941 TI - An Oligonucleotide Transfection Vector Based on HSA and PDMAEMA Conjugation: Effect of Polymer Molecular Weight on Cell Proliferation and on Multicellular Tumor Spheroids. AB - A novel gene transfection vector was fabricated based on the conjugation of human serum albumin (HSA) and maleimide end functionalized poly[(N,N-dimethylamino) ethyl methacrylate] (PDMAEMA). The bioconjugation was achieved in a site-specific manner to yield well-defined polymer-protein conjugates. The biohybrid was able to bind DNA with high affinity resulting in nanoparticles with a HSA shell. This paper mainly focuses on the influence of polymeric chain length on the particle properties and their drug-carrying ability to deliver oligonucleotides into breast cancer cells. The cytotoxic agent of interest, ISIS5132, is an oligonucleotide which disrupts DNA function within the cell. There was no evidence that the polymeric chain length had any effects on the conjugation efficiency and the subsequent condensation ability of the conjugates to oligonucleotide. However, the polymeric chain length had an obvious effect on the size of the complex micelles. Low molecular weights only led to loosely compacted complexes with the oligonucleotide, while large molecular weight led to well defined nanoparticle structures. More importantly, it was found that the variation in the length of the PDMAEMA block resulted in a change in cytotoxicity of the drug loaded complex micelle. That is, the concentration of 50% inhibition (IC50 ) of the complex micelle on MDA-MB-231 and MCF-7 cells reached the lowest value at a chain length of around 21 000 g mol(-1) . The IC50 value increased when the polymeric chain length was shorter (8000 g mol(-1) and 10 000 g mol(-1) ) while it increased again when PDMAMEA of M-n = 47 000 g mol(-1) , probably due to insufficient release of the drug. These result were reflected when investigating the performance of the polyplex using MCF-7 multicellular tumor spheroids, where again the medium PDMAEMA chain length led to the best delivery vehicle for ISIS5132. PMID- 25809943 TI - The ventral portion of the anterior pretectal nucleus controls descending mechanisms that initiate neuropathic pain in rats. AB - Stimulating the dorsal anterior pretectal nucleus (dAPtN) in rats is more effective than stimulating the ventral APtN (vAPtN) at reducing tail-flick latency, whereas stimulation of the vAPtN is more effective at reducing postoperative pain behaviour. This study examines whether a cell lesion caused by injecting N-methyl-D-aspartate into the dAPtN or vAPtN changes the withdrawal threshold of a rat hind paw during different phases of the tactile hypersensitivity induced by a chronic constriction injury (CCI) of the contralateral sciatic nerve. The number of Fos immunoreactive cells in the APtN was also evaluated. The rats whose vAPtN was lesioned 2 days before CCI had more intense tactile hypersensitivity 2 days after CCI than that of the control group, but the groups were not different 7 days after the CCI. The rats whose vAPtN was lesioned 5 days after CCI had withdrawal thresholds that did not differ significantly 7 days after the CCI. The tactile hypersensitivity of the rats whose dAPtN was lesioned 2 days before or 5 days after CCI was not different from that of the control on the second and seventh days after the CCI. The number of Fos immunoreactive cells in the vAPtN and dAPtN increased 2 days after CCI, but did not differ from that in the control 7 days after CCI. We conclude that vAPtN and dAPtN cells are activated by nerve injury; the vAPtN exerts inhibitory control of the initial phase of neuropathic pain whereas the dAPtN does not appear to exert an inhibitory effect in neuropathic processing. PMID- 25809942 TI - Contractile properties and sarcoplasmic reticulum calcium content in type I and type II skeletal muscle fibres in active aged humans. AB - KEY POINTS: Muscle weakness in old age is due in large part to an overall loss of skeletal muscle tissue, but it remains uncertain how much also stems from alterations in the properties of the individual muscle fibres. This study examined the contractile properties and amount of stored intracellular calcium in single muscle fibres of Old (70 +/- 4 years) and Young (22 +/- 3 years) adults. The maximum level of force production (per unit cross-sectional area) in fast twitch fibres in Old subjects was lower than in Young subjects, and the fibres were also less sensitive to activation by calcium. The amount of calcium stored inside muscle fibres and available to trigger contraction was also lower in both fast- and slow-twitch muscle fibres in the Old subjects. These findings indicate that muscle weakness in old age stems in part from an impaired capacity for force production in the individual muscle fibres. ABSTRACT: This study examined the contractile properties and sarcoplasmic reticulum (SR) Ca(2+) content in mechanically skinned vastus lateralis muscle fibres of Old (70 +/- 4 years) and Young (22 +/- 3 years) humans to investigate whether changes in muscle fibre properties contribute to muscle weakness in old age. In type II fibres of Old subjects, specific force was reduced by ~17% and Ca(2+) sensitivity was also reduced (pCa50 decreased ~0.05 pCa units) relative to that in Young. S Glutathionylation of fast troponin I (TnIf ) markedly increased Ca(2+) sensitivity in type II fibres, but the increase was significantly smaller in Old versus Young (+0.136 and +0.164 pCa unit increases, respectively). Endogenous and maximal SR Ca(2+) content were significantly smaller in both type I and type II fibres in Old subjects. In fibres of Young, the SR could be nearly fully depleted of Ca(2+) by a combined caffeine and low Mg(2+) stimulus, whereas in fibres of Old the amount of non-releasable Ca(2+) was significantly increased (by > 12% of endogenous Ca(2+) content). Western blotting showed an increased proportion of type I fibres in Old subjects, and increased amounts of calsequestrin-2 and calsequestrin-like protein. The findings suggest that muscle weakness in old age is probably attributable in part to (i) an increased proportion of type I fibres, (ii) a reduction in both maximum specific force and Ca(2+) sensitivity in type II fibres, and also a decreased ability of S-glutathionylation of TnIf to counter the fatiguing effects of metabolites on Ca(2+) sensitivity, and (iii) a reduction in the amount of releasable SR Ca(2+) in both fibre types. PMID- 25809944 TI - Loss of the Atypical Kinases ABC1K7 and ABC1K8 Changes the Lipid Composition of the Chloroplast Membrane. AB - The activity of bc1 complex kinase (ABC1K) family is a large group of atypical protein kinases found in prokaryotes and eukaryotes. In bacteria and mitochondria, ABC1K kinases are necessary for the synthesis of coenzyme Q and are therefore involved in the respiratory pathway. In chloroplasts, they are involved in prenylquinone synthesis and stress responses, but their functional role remains unclear. Plants can respond to biotic and abiotic stress by modifying membrane fluidity in order to create a suitable environment for the activity of integral membrane proteins. Therefore, this work was focused on the analysis of the effect of ABC1K7 and ABC1K8 on the production of polar lipids and their accumulation in Arabidopsis thaliana leaves. A comparison of abc1k7 and abc1k8 single mutants and the abc1k7/abc1k8 double mutant with wild-type plants and transgenic lines overexpressing ABC1K7 and ABC1K8 was performed using untargeted lipidomic analysis based on liquid chromatography coupled to mass spectrometry. Multivariate data analysis identified sets of chloroplast lipids representing the different genotypes. The abc1k7 and abc1k8 single mutants produced lower levels of the highly unsaturated lipid digalactosyldiacylglycerol (DGDG) than wild-type plants and also different forms of monogalactosyldiacylglycerol (MGDG) and kaempferol. The abc1k8 mutant also produced higher levels of oxylipin-conjugated DGDG and sinapates. The double mutant produced even higher levels of oxylipin conjugated MGDG and DGDG. These results show that ABC1K7 and ABC1K8 influence chloroplast lipid synthesis or accumulation and modulate chloroplast membrane composition in response to stress. PMID- 25809945 TI - High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy. AB - Eosinophilic esophagitis (EoE) is an antigen/allergy-mediated chronic inflammatory condition. The rapid rise in the number of cases of EoE suggests an as-yet undiscovered environmental trigger. This study tested the hypothesis that immunoglobulin E (IgE) to galactose-alpha-1,3-galactose (alpha-gal), a newly recognized sensitization induced by a tick bite that causes mammalian meat allergy, is a risk factor for EoE. We conducted a case-control study using prospectively collected and stored samples in the University of North Carolina EoE Patient Registry and Biobank. Serum from 50 subjects with a new diagnosis of EoE and 50 non-EoE subjects (either with gastroesophageal reflux disease or dysphagia from non-EoE etiologies) was tested for alpha-gal-specific IgE using an ImmunoCAP-based method. Specific IgE > 0.35 kUA /L was considered a positive result. Subjects with EoE were a mean of 35 years old, 68% were male, and 94% were white. Non-EoE controls were a mean of 42 years, 50% were male, and 78% were white. A total of 22 (22%) subjects overall had alpha-gal-specific IgE > 0.35 kUA /L. Of the EoE cases, 12 (24%) were positive, and of the non-EoE controls, 10 (20%) were positive (p=0.63). Neither the proportion sensitized nor the absolute values differed between EoE and non-EoE subjects. We found a similar but high rate of alpha-gal sensitization in patients with EoE as found in non-EoE controls who were undergoing endoscopy. While our data do not support alpha-gal sensitization as a risk factor for EoE, the high rates of sensitization observed in patients undergoing upper endoscopy for symptoms of esophageal dysfunction is a new finding. PMID- 25809946 TI - Ovarian nests in cultured Russian sturgeon Acipenser gueldenstaedtii and North American paddlefish Polyodon spathula comprised of previtellogenic oocytes. AB - Ovarian nests in the ovaries of sexually maturing Russian sturgeon Acipenser gueldenstaedtii and North American paddlefish Polyodon spathula were investigated. They comprised early previtellogenic, diplotene stage oocytes and somatic cells. In the nucleoplasm, these oocytes contained chromatin in the form of grains, threads and lampbrush chromosomes, primary nucleoli and multiple nucleoli. Two stages of oocytes in nests were distinguished by differences in the distribution of mitochondria with distorted cristae and lipid droplets in the ooplasm. These stages were as follows: pre-early stage 1 (PE 1) and early stage 1 (EP 1) previtellogenic oocytes. In PE 1 oocytes few mitochondria with distorted cristae and lipid droplets were distributed randomly. The ooplasm of PE 1 oocytes was not differentiated into homogeneous and granular compartments. In EP 1 oocytes, mitochondria with distorted cristae were more numerous and grouped in the vicinity of the nucleus, lipid droplets accumulated near these mitochondria. In the nucleoplasm of EP 1 oocytes several low electron-dense spherical bodies, possibly Cajal bodies, were present. PMID- 25809947 TI - Disease mongering of age-associated declines in testosterone and growth hormone levels. PMID- 25809948 TI - United in death-related by blood? Genetic and archeometric analyses of skeletal remains from the neolithic earthwork Bruchsal-Aue. AB - OBJECTIVES: Straight next to a segment of the outer ditch of the Late Neolithic Michelsberg Culture earthwork of Bruchsal-Aue in SW-Germany (ca. 4250-3650 calBC), a multiple burial of eight individuals (two male adults and six children) plus a subsequent child burial was excavated. In this study, we applied a multidisciplinary approach to elucidate interpersonal relationships and life histories within this collective. MATERIALS AND METHODS: To determine the identity of this collective, we performed aDNA analyses in addition to osteological examination using HVR I plus Y-chromosomal and autosomal STR profiling to find evidence for kinship relations. Strontium isotopic analyses were used to reconsider migrational behavior. To find evidence for a specific social affiliation, the individual diet was reconstructed by performing nitrogen and carbon isotopic analyses. Furthermore, radiocarbon-dating was carried out to integrate the burial context into an absolute timeframe. Two nearby single burials were included in the analyses for comparison. RESULTS: Because of a shared HVR I haplotype, three pairs of individuals were most likely linked by kinship, and statistical testing on autosomal STR profiles shows a high probability for the pair of two men being brothers. Although it cannot be excluded, isotopic data gave no clear proof for migration. A rather poor health status is indicated by skeletal stress markers even though the isotope data attest to a diet rich in meat and fish. DISCUSSION: Although clear kinship relations among the infants remain unconfirmed, a relationship could also be indicated by the positioning of the bodies in the burial pit. Whereas a common cause of death might have been the presupposition for their special treatment, interpersonal relationships were likely the decisive factor for the multiple burial. PMID- 25809950 TI - APOL1 genotyping of African American deceased organ donors: not just yet. PMID- 25809949 TI - Using diffusion-weighted MRI to predict aggressive histological features in papillary thyroid carcinoma: a novel tool for pre-operative risk stratification in thyroid cancer. AB - BACKGROUND: Initial management recommendations of papillary thyroid carcinoma (PTC) are very dependent on preoperative studies designed to evaluate the presence of PTC with aggressive features. The purpose of this study was to evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) before surgery can be used as a tool to stratify tumor aggressiveness in patients with PTC. METHODS: In this prospective study, 28 patients with PTC underwent DW-MRI studies on a three Tesla MR scanner prior to thyroidectomy. Due to image quality, 21 patients were finally suitable for further analysis. Apparent diffusion coefficients (ADCs) of normal thyroid tissues and PTCs for 21 patients were calculated. Tumor aggressiveness was defined by surgical histopathology. The Mann Whitney U test was used to compare the difference in ADCs among groups of normal thyroid tissues and PTCs with and without features of tumor aggressiveness. Receiver operating characteristic (ROC) analysis was performed to assess the discriminative specificity, sensitivity, and accuracy of and determine the cutoff value for the ADC in stratifying PTCs with tumor aggressiveness. RESULTS: There was no significant difference in ADC values between normal thyroid tissues and PTCs. However, ADC values of PTCs with extrathyroidal extension (ETE; 1.53+/ 0.25*10(-3) mm2/s) were significantly lower than corresponding values from PTCs without ETE (2.37+/-0.67*10(-3) mm2/s; p<0.005). ADC values identified 3 papillary carcinoma patients with extrathyroidal extension that would have otherwise been candidates for observation based on ultrasound evaluations. The cutoff value of ADC to discriminate PTCs with and without ETE was determined at 1.85*10(-3) mm2/s with a sensitivity of 85%, specificity of 85%, and ROC curve area of 0.85. CONCLUSION: ADC value derived from DW-MRI before surgery has the potential to stratify ETE in patients with PTCs. PMID- 25809951 TI - Getting order in mesostructured thin films, from pore organization to crystalline walls, the case of 3-glycidoxypropyltrimethoxysilane. AB - A new type of mesostructured hybrid organic-inorganic film has been synthesised by evaporation-induced self-assembly using 3-glycidoxypropyltrimethoxysilane as the precursor and a tri-block copolymer, Pluronic F127, as the template. The chemistry has been tuned to form bridged polysilsesquioxanes that self-organise into ordered lamellar structures. Controlled aging under highly basic conditions, which has been monitored by Raman and infrared spectroscopy, has been used to obtain the layered ordered hybrid structures in the precursor sol. The pH of the sol has been adjusted to form the micelles that act as templates during solvent evaporation. The self-assembly of the system has been studied in situ by small and wide angle X-ray scattering using a synchrotron light source, which has confirmed both the formation of hybrid layered structures and the long-range organization of the mesophase in the hybrid films. The present approach allows ordering the hybrid film on two different length scales; at the end of film processing, hybrid crystals are incorporated into the pore walls and the micelles are arranged within the films with long range order. PMID- 25809952 TI - Early and chronic gray matter volume changes in limbic encephalitis revealed by voxel-based morphometry. AB - OBJECTIVE: Antibody-associated limbic encephalitis (LE) is an increasingly recognized cause of mostly adult-onset temporal lobe epilepsy. Magnetic resonance imaging (MRI) typically shows volume and signal changes of the mesiotemporal structures. However, recent studies indicate that imaging characteristics depend on the type of the associated antibody. The aim of the present study was to investigate early and chronic gray matter (GM) volume changes in LE by means of voxel-based morphometry (VBM). METHODS: Optimized VBM analysis was applied to altogether 73 MRI volumes of 55 patients with antibody-associated LE. Based on the time point of MRI acquisition, patients were split into two separate groups to enable the evaluation of early (<=2 years after LE onset) and chronic (>2 years after LE onset) GM volume changes. In addition, separate analyses for the two most common LE subtypes in our study cohort, that is, glutamic acid decarboxylase (GAD)-associated LE and voltage-gated potassium channel (VGKC) complex-associated LE were performed. Age- and gender-matched healthy subjects served as controls. RESULTS: Referring to the entire LE group, VBM revealed bi amygdalar GM volume increase in the early disease stage. In the chronic disease stage, amygdala enlargement had resolved and we found GM volume reduction in the right cerebellar hemisphere. In the subgroup analysis, VBM showed corresponding bi-amygdalar GM volume increase in VGKC-complex-associated LE on early MRI, whereas no changes were found in GAD-associated LE. In the chronic disease stage, VBM revealed left frontal GM volume increase in VGKC-complex-associated LE and right frontoparietal GM volume reduction in GAD-associated LE. SIGNIFICANCE: The present study provides further evidence of a predominant affection of the amygdala in the early disease stage of LE, which resolves during the later course of the disease. Furthermore, our results show that LE features distinct imaging characteristics depending on the associated antibody and thus may contribute to a better pathophysiologic understanding of this disease. PMID- 25809953 TI - Functional diversification of the dehydrin gene family in apple and its contribution to cold acclimation during dormancy. AB - Dehydrins (DHN) are proteins involved in plant adaptive responses to abiotic stresses, mainly dehydration. Several studies in perennial crops have linked bud dormancy progression, a process characterized by the inability to initiate growth from meristems under favorable conditions, with DHN gene expression. However, an in-depth characterization of DHNs during bud dormancy progression is still missing. An extensive in silico characterization of the apple DHN gene family was performed. Additionally, we used five different experiments that generated samples with different dormancy status, including genotypes with contrasting dormancy traits, to analyze how DHN genes are being regulated during bud dormancy progression in apple by real-time quantitative polymerase chain reaction (RT qPCR). Duplication events took place in the diversification of apple DHN family. Additionally, MdDHN genes presented tissue- and bud dormant-specific expression patterns. Our results indicate that MdDHN genes are highly divergent in function, with overlapping levels, and that their expressions are fine-tuned by the environment during the dormancy process in apple. PMID- 25809954 TI - Validating the absolute reliability of a fat free mass estimate equation in hemodialysis patients using near-infrared spectroscopy. AB - The assessment of nutritional states using fat free mass (FFM) measured with near infrared spectroscopy (NIRS) is clinically useful. This measurement should incorporate the patient's post-dialysis weight ("dry weight"), in order to exclude the effects of any change in water mass. We therefore used NIRS to investigate the regression, independent variables, and absolute reliability of FFM in dry weight. The study included 47 outpatients from the hemodialysis unit. Body weight was measured before dialysis, and FFM was measured using NIRS before and after dialysis treatment. Multiple regression analysis was used to estimate the FFM in dry weight as the dependent variable. The measured FFM before dialysis treatment (Mw-FFM), and the difference between measured and dry weight (Mw-Dw) were independent variables. We performed Bland-Altman analysis to detect errors between the statistically estimated FFM and the measured FFM after dialysis treatment. The multiple regression equation to estimate the FFM in dry weight was: Dw-FFM = 0.038 + (0.984 * Mw-FFM) + (-0.571 * [Mw-Dw]); R(2) = 0.99). There was no systematic bias between the estimated and the measured values of FFM in dry weight. Using NIRS, FFM in dry weight can be calculated by an equation including FFM in measured weight and the difference between the measured weight and the dry weight. PMID- 25809956 TI - Effect of Slip Time in Forming Neo-Esophageal Stenosis After Replacement of a Thoracic Esophagus With Nitinol Artificial Esophagus. AB - Attempts have been made to investigate the effect of slip time of nitinol artificial esophagus for forming neo-esophageal stenosis after replacement of a thoracic esophagus with nitinol artificial esophagus in 20 experimental pigs. The pigs whose slip time was less than 90 days postoperatively had severe dysphagia (Bown's III) immediately after they were fed, and the dysphagia aggravated gradually later on (Bown's III-IV). The pigs whose slip time was more than 90 days postoperatively had mild/moderate dysphagia (Bown's I-II) immediately after they were fed, and the dysphagia relieved gradually later on (Bown's II-I-0). The ratios between the diameter of neo-esophagus in different slip time and normal esophagus were 25% (at 2 months postoperatively), 58% (at 4 months postoperatively), and 93% (at 6 months postoperatively), respectively. The relationship between nitinol artificial esophagus slip time and neo-esophageal stenosis showed a positive correlation. After replacement of a thoracic esophagus with nitinol artificial esophagus, the artificial esophageal slip time not only affected the original diameter of the neo-esophagus immediately, but also affected the neo-esophageal scar stricture forming process later on. The narrowing of neo-esophagus is caused by overgrowth of scar tissue. But there is the positive correlation between artificial esophagus slip time and neo esophageal stenosis, so this can be a way of overcoming neo-esophageal stenosis by delaying slip time of artificial esophagus. PMID- 25809958 TI - A multifaceted hospitalist quality improvement intervention: Decreased frequency of common labs. AB - PURPOSE: Common labs such as a daily complete blood count or a daily basic metabolic panel represent possible waste and have been targeted by professional societies and the Choosing Wisely campaign for critical evaluation. We undertook a multifaceted quality-improvement (QI) intervention in a large community hospitalist group to decrease unnecessary common labs. METHODS: The QI intervention was composed of academic detailing, audit and feedback, and transparent reporting of the frequency with which common labs were ordered as daily within the hospitalist group. We performed a pre-post analysis, comparing a cohort of patients during the 10-month baseline period before the QI intervention and the 7-month intervention period. Demographic and clinical data were collected from the electronic medical record. The primary endpoint was number of common labs ordered per patient-day as estimated by a clustered multivariable linear regression model clustering by ordering hospitalist. Secondary endpoints included length of stay, hospital mortality, 30-day readmission, blood transfusion, amount of blood transfused, and laboratory cost per patient. RESULTS: The baseline (n = 7824) and intervention (n = 5759) cohorts were similar in their demographics, though the distribution of primary discharge diagnosis-related groups differed. At baseline, a mean of 2.06 (standard deviation 1.40) common labs were ordered per patient-day. Adjusting for age, sex, and principle discharge diagnosis, the number of common labs ordered per patient-day decreased by 0.22 (10.7%) during the intervention period compared to baseline (95% confidence interval [CI], 0.34 to 0.11; P < 0.01). There were nonsignificant reductions in hospital mortality in the intervention period compared to baseline (2.2% vs 1.8%, P = 0.1) as well as volume of blood transfused in patients who received a transfusion (127.2 mL decrease; 95% CI, -257.9 to 3.6; P = 0.06). No effect was seen on length of stay or readmission rate. The intervention decreased hospital direct costs by an estimated $16.19 per admission or $151,682 annualized (95% CI, $119,746 to $187,618). CONCLUSION: Implementation of a multifaceted QI intervention within a community-based hospitalist group was associated with a significant, but modest, decrease in the number of ordered lab tests and hospital costs. No effect was seen on hospital length of stay, mortality, or readmission rate. This intervention suggests that a community-based hospitalist QI intervention focused on daily labs can be effective in safely reducing healthcare waste without compromising quality of care. PMID- 25809959 TI - Solvents effects on the mechanism of cellulose hydrolysis: A QM/MM study. AB - This article reports a combined quantum mechanics/molecular mechanics (QM/MM) investigation on the acid hydrolysis of cellulose in water using two different models, cellobiose and a 40-unit cellulose chain. The explicitly treated solvent molecules strongly influence the conformations, intramolecular hydrogen bonds, and exoanomeric effects in these models. As these features are largely responsible for the barrier to cellulose hydrolysis, the present QM/MM results for the pathways and reaction intermediates in water are expected to be more realistic than those from a former density functional theory (DFT) study with implicit solvent (CPCM). However, in a qualitative sense, there is reasonable agreement between the DFT/CPCM and QM/MM predictions for the reaction mechanism. Differences arise mainly from specific solute-solvent hydrogen bonds that are only captured by QM/MM and not by DFT/CPCM. PMID- 25809955 TI - Pleiotropy analysis of quantitative traits at gene level by multivariate functional linear models. AB - In genetics, pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. A common approach is to analyze the phenotypic traits separately using univariate analyses and combine the test results through multiple comparisons. This approach may lead to low power. Multivariate functional linear models are developed to connect genetic variant data to multiple quantitative traits adjusting for covariates for a unified analysis. Three types of approximate F-distribution tests based on Pillai-Bartlett trace, Hotelling-Lawley trace, and Wilks's Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants in one genetic region. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and optimal sequence kernel association test (SKAT-O). Extensive simulations were performed to evaluate the false positive rates and power performance of the proposed models and tests. We show that the approximate F-distribution tests control the type I error rates very well. Overall, simultaneous analysis of multiple traits can increase power performance compared to an individual test of each trait. The proposed methods were applied to analyze (1) four lipid traits in eight European cohorts, and (2) three biochemical traits in the Trinity Students Study. The approximate F distribution tests provide much more significant results than those of F-tests of univariate analysis and SKAT-O for the three biochemical traits. The approximate F-distribution tests of the proposed functional linear models are more sensitive than those of the traditional multivariate linear models that in turn are more sensitive than SKAT-O in the univariate case. The analysis of the four lipid traits and the three biochemical traits detects more association than SKAT-O in the univariate case. PMID- 25809957 TI - Derivation of chondrocyte and osteoblast reporter mouse embryonic stem cell lines. AB - With the establishment of methods that provide evidence for the generation of chondrocyte and osteoblast cell types from ESCs, there is a need for reagents that will enable their further characterization. Here we report on the derivation of chondrocyte and osteoblast reporter ESCs from previously generated and characterized transgenic mouse lines, Collagen type 2 alpha 1(Col2a1)-ECFP, Bone Sialoprotein (BSP)-Topaz, and BSP-Topaz/Dentin Matrix Protein 1 (DMP1)-Cherry dual reporter mice. Col2a1-ECFP is highly expressed in chondrocytes, while BSP Topaz and DMP1-Cherry are highly expressed in osteoblasts and osteocytes, respectively. These new skeletal reporter mouse ESC lines will serve as valuable reagents to investigate the functionality of ESC derived chondrocyte and osteoblast cell types. PMID- 25809960 TI - Prevalence and burden of vertebral fractures in older men and women with hip fracture: A cross-sectional study. AB - AIM: To investigate the prevalence and burden (combination of number and severity) of vertebral fractures in men and women with hip fracture. METHODS: We investigated 458 of 490 hip-fracture patients admitted consecutively to a rehabilitation hospital. Lateral radiographs of the spine were taken 19.2 +/- 5.5 days (mean +/- SD) after hip-fracture occurrence. To obtain a summary measure of vertebral fracture burden, we calculated the spinal deformity index (SDI) by summing the fracture grades assessed using Genant's method of all vertebrae (T4 to L4). RESULTS: The median SDI score was 2 in both the 411 women and the 47 men (interquartile range 0-4 in both groups), and no significant between-sex differences were found (P = 0.52). A total of 69% of the women (95% CI 65-74%), and 60% of the men (95% CI 45-74%) had at least one mild vertebral fracture (SDI score >=1), 41% of the women (95% CI 36-46%) and 38% of the men (95% CI 24-53%) had a SDI score >=3, whereas 16% of the women (95% CI 12% 19%) and 17% of the men (95%CI 6-28%) had at least one severe vertebral fracture. Sex was not significantly associated with a SDI score >=1, or >=3 or with the presence of at least one severe vertebral fracture after adjustment for age, hip-fracture type, cognitive impairment, pressure ulcers, neurological impairment, comorbidities, number of medications in use and Barthel index scores. CONCLUSIONS: The prevalence of vertebral fractures was high after hip fracture in both men and women. We found no significant between-sex differences in the prevalence and burden of vertebral fractures. PMID- 25809961 TI - Human health risk assessment related to contaminated land: state of the art. AB - Exposure of humans to contaminants from contaminated land may result in many types of health damage ranging from relatively innocent symptoms such as skin eruption or nausea, on up to cancer or even death. Human health protection is generally considered as a major protection target. State-of-the-art possibilities and limitations of human health risk assessment tools are described in this paper. Human health risk assessment includes two different activities, i.e. the exposure assessment and the hazard assessment. The combination of these is called the risk characterization, which results in an appraisal of the contaminated land. Exposure assessment covers a smart combination of calculations, using exposure models, and measurements in contact media and body liquids and tissue (biomonitoring). Regarding the time frame represented by exposure estimates, biomonitoring generally relates to exposure history, measurements in contact media to actual exposures, while exposure calculations enable a focus on exposure in future situations. The hazard assessment, which is different for contaminants with or without a threshold for effects, results in a critical exposure value. Good human health risk assessment practice accounts for tiered approaches and multiple lines of evidence. Specific attention is given here to phenomena such as the time factor in human health risk assessment, suitability for the local situation, background exposure, combined exposure and harmonization of human health risk assessment tools. PMID- 25809962 TI - Functional Characterization of the FNT Family Nitrite Transporter of Marine Picocyanobacteria. AB - Many of the cyanobacterial species found in marine and saline environments have a gene encoding a putative nitrite transporter of the formate/nitrite transporter (FNT) family. The presumed function of the gene (designated nitM) was confirmed by functional expression of the gene from the coastal marine species Synechococcus sp. strain PCC7002 in the nitrite-transport-less mutant (NA4) of the freshwater cyanobacterium Synechococcus elongatus strain PCC7942. The NitM mediated nitrite uptake showed an apparent Km (NO2-) of about 8 MUM and was not inhibited by nitrate, cyanate or formate. Of the nitM orthologs from the three oceanic cyanobacterial species, which are classified as alpha-cyanobacteria on the basis of the occurrence of Type 1a RuBisCO, the one from Synechococcus sp. strain CC9605 conferred nitrite uptake activity on NA4, but those from Synechococcus sp. strain CC9311 and Prochlorococcus marinus strain MIT9313 did not. A strongly conserved hydrophilic amino acid sequence was found at the C termini of the deduced NitM sequences from alpha-cyanobacteria, with a notable exception of the Synechococcus sp. strain CC9605 NitM protein, which entirely lacked the C-terminal amino acids. The C-terminal sequence was not conserved in the NitM proteins from beta-cyanobacteria carrying the Type 1b RuBisCO, including the one from Synechococcus sp. strain PCC7002. Expression of the truncated nitM genes from Synechococcus sp. strain CC9311 and Prochlorococcus marinus strain MIT9313, encoding the proteins lacking the conserved C-terminal region, conferred nitrite uptake activity on the NA4 mutant, indicating that the C-terminal region of alpha-cyanobacterial NitM proteins inhibits the activity of the transporter. PMID- 25809963 TI - Protocells: at the interface of life and non-life. AB - The cellular form, manifesting as a membrane-bounded system (comprising various functional molecules), is essential to life. The ultimate reason for this is that, typically, one functional molecule can only adopt one "correct" structure to perform one special function (e.g., an enzyme), and thus molecular cooperation is inevitable. While this is particularly true for advanced life with complex functions, it should have already been true for life at its outset with only limited functions, which entailed some sort of primitive cellular form "protocells". At the very beginning, the protocells may have even been unable to intervene in the growth of their own membrane, which can be called "pseudo protocells". Then, the ability to synthesize membrane components (amphiphiles) may have emerged under selective pressure, leading to "true-protocells". The emergence of a "chromosome" (with genes linked together)-thus avoiding "gene loss" during the protocell division, was another key event in the evolution of protocells. Such "unitary-protocells", containing a central genetic molecule, may have appeared as a milestone-in principle, since then life could evolve endlessly, "gaining" more and more functions by introducing new genes. To synthesize in laboratory these different types of protocells, which stand at the interface between life and non-life, would greatly enhance our understanding on the essence of life. PMID- 25809964 TI - Does DNA exert an active role in generating cell-sized spheres in an aqueous solution with a crowding binary polymer? AB - We report the spontaneous generation of a cell-like morphology in an environment crowded with the polymers dextran and polyethylene glycol (PEG) in the presence of DNA. DNA molecules were selectively located in the interior of dextran-rich micro-droplets, when the composition of an aqueous two-phase system (ATPS) was near the critical condition of phase-segregation. The resulting micro-droplets could be controlled by the use of optical tweezers. As an example of laser manipulation, the dynamic fusion of two droplets is reported, which resembles the process of cell division in time-reverse. A hypothetical scenario for the emergence of a primitive cell with DNA is briefly discussed. PMID- 25809965 TI - Modes of Fatty Acid desaturation in cyanobacteria: an update. AB - Fatty acid composition of individual species of cyanobacteria is conserved and it may be used as a phylogenetic marker. The previously proposed classification system was based solely on biochemical data. Today, new genomic data are available, which support a need to update a previously postulated FA-based classification of cyanobacteria. These changes are necessary in order to adjust and synchronize biochemical, physiological and genomic data, which may help to establish an adequate comprehensive taxonomic system for cyanobacteria in the future. Here, we propose an update to the classification system of cyanobacteria based on their fatty acid composition. PMID- 25809966 TI - Effect of novel curcumin-encapsulated chitosan-bioglass drug on bone and skin repair after gamma radiation: experimental study on a Wistar rat model. AB - Radiation therapy contributes to a significant increase in bone osteoporosis and skin loss. Various natural health products might be beneficial to reduce bone and skin alterations. Curcumin (CUR) medicines derived from natural plants have played an important role in health care. This study aims at synthesizing and evaluating the performance therapy of CUR-encapsulated bioglass-chitosan (CUR-BG CH). In vitro, the antioxidant assay was evaluated by using 1,1-diphenyl-2 picrylhydrazyl free-radical (DPPH) scavenging and the nitroblue tetrazolium reduction. The CUR-BG-CH antimicrobial effects were tested in liquid media. In vivo, after rat (60) Co gamma-radiation, the tissue wound-healing process was studied by grafting CUR and CUR-BG-CH in femoral condyle and dorsal skin rat tissue. The antioxidant studies indicated that CUR-BG-CH quenches free radicals more efficiently than unmodified CUR and had effective DPPH (91%) and superoxide anion (51%) radical scavenging activities. The CUR-BG-CH biomaterial exhibited an important antimicrobial activity against Staphylococcus aureus. The histomorphometric parameters showed amelioration in CUR-BG-CH-treated rats. An improved mechanical property was noticed (33.16 +/- 5.0 HV) when compared with that of unmodified CUR group (23.15 +/- 4.9 HV). A significant decrease in tumour necrosis factor-alpha cytokine production was noted in the CUR-BG-CH rats (90 pg/ml) as compared with that of unmodified CUR group (240 pg/ml). The total amount of hydroxyproline was significantly enhanced (33.5%) in CUR-BG-CH group as compared with that of control. Our findings suggested that CUR-BG-CH might have promising potential applications for wound healing. PMID- 25809968 TI - Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. AB - BACKGROUND: The treatment of older adults with acute myeloid leukemia (AML) using standard intensive chemotherapy has been associated with poor outcomes. Effective, less toxic therapies are needed to achieve and maintain durable remissions. METHODS: One hundred eighteen patients with newly diagnosed AML (median age, 68 years; range, 60-81 years) were treated with a regimen of clofarabine and low-dose cytarabine (LDAC) alternating with decitabine (DAC). The induction consisted of intravenous clofarabine at 20 mg/m(2) on days 1 to 5 combined with subcutaneous LDAC at 20 mg twice daily on days 1 to 10. Responding patients were then treated with a prolonged consolidation/maintenance regimen consisting of cycles of clofarabine plus LDAC alternating with cycles of DAC. RESULTS: The overall response rate was 68%. The complete remission (CR) rate was 60% overall, 71% for patients with a diploid karyotype, and 50% for patients with an adverse karyotype. The median overall survival (OS) was 11.1 months for all patients and 18.5 months for those achieving a CR/complete remission with incomplete platelet recovery (CRp). The median relapse-free survival for patients achieving a CR/CRp was 14.1 months. According to a multivariate analysis, only adverse cytogenetics and a white blood cell count >= 10 * 10(9)/L predicted worse OS. The regimen was well tolerated with 4- and 8-week mortality rates of 3% and 7%, respectively. The most common nonhematologic adverse events were nausea, elevated liver enzymes, and rash. CONCLUSIONS: The lower intensity, prolonged therapy program of clofarabine and LDAC alternating with DAC is well tolerated and highly effective in older patients with AML. PMID- 25809969 TI - Evaluation of Level of Agreement in Bordetella Species Identification in Three U.S. Laboratories during a Period of Increased Pertussis. AB - While PCR is the most common method used for detecting Bordetella pertussis in the United States, most laboratories use insertion sequence 481 (IS481), which is not specific for B. pertussis; therefore, the relative contribution of other Bordetella species is not understood. The objectives of this study were to evaluate the proportion of other Bordetella species misidentified as B. pertussis during a period of increased pertussis incidence, determine the level of agreement in Bordetella species detection between U.S. commercial laboratories and the CDC, and assess the relative diagnostic sensitivity of CDC's PCR assay when using a different PCR master mix. Specimens collected between May 2012 and May 2013 were tested at two U.S. commercial laboratories for B. pertussis and B. parapertussis detection. Every fifth specimen positive for IS481 and/or IS1001 with cycle threshold (CT) values of <=35 was sent to CDC for PCR testing that identifies Bordetella species. Specimens with indeterminate or negative results in the CDC PCR were tested using an alternate PCR master mix. Of 755 specimens, there was agreement in species identification for 83.4% (n = 630). Of the specimens with different identifications (n = 125), 79.2% (n = 99) were identified as indeterminate B. pertussis at CDC. Overall, 0.66% (n = 5) of the specimens were identified as B. holmesii or B. bronchiseptica at CDC. Of 115 specimens with indeterminate or negative results, 46.1% (n = 53) were B. pertussis positive when tested by an alternate master mix, suggesting a possible increase in assay sensitivity. This study demonstrates good agreement between the two U.S. commercial laboratories and CDC and little misidentification of Bordetella species during the 2012 U.S. epidemic. PMID- 25809970 TI - Multidrug-Resistant Candida auris Misidentified as Candida haemulonii: Characterization by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and DNA Sequencing and Its Antifungal Susceptibility Profile Variability by Vitek 2, CLSI Broth Microdilution, and Etest Method. AB - Candida auris is a multidrug-resistant yeast that causes a wide spectrum of infections, especially in intensive care settings. We investigated C. auris prevalence among 102 clinical isolates previously identified as Candida haemulonii or Candida famata by the Vitek 2 system. Internal transcribed spacer region (ITS) sequencing confirmed 88.2% of the isolates as C. auris, and matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) easily separated all related species, viz., C. auris (n = 90), C. haemulonii (n = 6), C. haemulonii var. vulnera (n = 1), and Candida duobushaemulonii (n = 5). The in vitro antifungal susceptibility was determined using CLSI broth microdilution (CLSI-BMD), the Vitek 2 antifungal susceptibility test, and the Etest method. C. auris isolates revealed uniformly elevated fluconazole MICs (MIC50, 64 MUg/ml), and an alarming percentage of isolates (37%) exhibited elevated caspofungin MICs by CLSI-BMD. Notably, 34% of C. auris isolates had coexisting elevated MICs (>=2 MUg/ml) for both fluconazole and voriconazole, and 10% of the isolates had elevated coexisting MICs (>=2 MUg/ml) to two additional azoles, i.e., posaconazole and isavuconazole. In contrast to reduced amphotericin B MICs by CLSI-BMD (MIC50, 1 MUg/ml) for C. auris, elevated MICs were noted by Vitek 2 (MIC50, 8 MUg/ml), which were statistically significant. Candida auris remains an unnoticed pathogen in routine microbiology laboratories, as 90% of the isolates characterized by commercial identification systems are misidentified as C. haemulonii. MALDI-TOF MS proved to be a more robust diagnostic technique for rapid identification of C. auris. Considering that misleading elevated MICs of amphotericin B by the Vitek AST-YS07 card may lead to the selection of inappropriate therapy, a cautionary approach is recommended for laboratories relying on commercial systems for identification and antifungal susceptibility testing of rare yeasts. PMID- 25809971 TI - Evaluation of the Blue-Carba test for rapid detection of carbapenemases in gram negative bacilli. PMID- 25809972 TI - Evaluation of a Method Using Three Genomic Guided Escherichia coli Markers for Phylogenetic Typing of E. coli Isolates of Various Genetic Backgrounds. AB - Genotyping and characterization of bacterial isolates are essential steps in the identification and control of antibiotic-resistant bacterial infections. Recently, one novel genotyping method using three genomic guided Escherichia coli markers (GIG-EM), dinG, tonB, and dipeptide permease (DPP), was reported. Because GIG-EM has not been fully evaluated using clinical isolates, we assessed this typing method with 72 E. coli collection of reference (ECOR) environmental E. coli reference strains and 63 E. coli isolates of various genetic backgrounds. In this study, we designated 768 bp of dinG, 745 bp of tonB, and 655 bp of DPP target sequences for use in the typing method. Concatenations of the processed marker sequences were used to draw GIG-EM phylogenetic trees. E. coli isolates with identical sequence types as identified by the conventional multilocus sequence typing (MLST) method were localized to the same branch of the GIG-EM phylogenetic tree. Sixteen clinical E. coli isolates were utilized as test isolates without prior characterization by conventional MLST and phylogenetic grouping before GIG-EM typing. Of these, 14 clinical isolates were assigned to a branch including only isolates of a pandemic clone, E. coli B2-ST131-O25b, and these results were confirmed by conventional typing methods. Our results suggested that the GIG-EM typing method and its application to phylogenetic trees might be useful tools for the molecular characterization and determination of the genetic relationships among E. coli isolates. PMID- 25809973 TI - First Probable Case of Subcutaneous Infection Due to Truncatella angustata: a New Fungal Pathogen of Humans? AB - Truncatella angustata is a coelomycetous fungus, typically associated with vascular plants as either an endophyte or a pathogen. This organism has not previously been implicated in human disease. This report describes a case of T. angustata subcutaneous infection in an immunocompetent patient. A conclusive diagnosis was achieved through partial sequencing of ribosomal DNA (rDNA) cluster. The patient was successfully treated with voriconazole followed by itraconazole. PMID- 25809974 TI - Bacteremia Caused by Kerstersia gyiorum. AB - Kerstersia spp. are an unusual cause of human infections. We report the first known case of bacteremia and sepsis due to Kerstersia gyiorum, in a patient with chronic lower-extremity ulcers, and we review the literature on this uncommon pathogen. PMID- 25809975 TI - What Is the Origin of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Clonal Complex 398 Isolates from Humans without Livestock Contact? An Epidemiological and Genetic Analysis. AB - Fifteen percent of all methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 398 (CC398) human carriers detected in The Netherlands had not been in direct contact with pigs or veal calves. To ensure low MRSA prevalence, it is important to investigate the likely origin of this MRSA of unknown origin (MUO). Recently, it was shown that CC398 strains originating from humans and animals differ in the presence of specific mobile genetic elements (MGEs). We hypothesized that determining these specific MGEs in MUO isolates and comparing them with a set of CC398 isolates of various known origin might provide clues to their origin. MUO CC398 isolates were compared to MRSA CC398 isolates obtained from humans with known risk factors, a MRSA CC398 outbreak isolate, livestock associated (LA) MRSA CC398 isolates from pigs, horses, chickens, and veal calves, and five methicillin-susceptible Staphylococcus aureus (MSSA) CC398 isolates of known human origin. All strains were spa typed, and the presence or absence of, scn, chp, phi3 int, phi6 int, phi7 int, rep7, rep27, and cadDX was determined by PCRs. The MRSA CC398 in humans, MUO, or MRSA of known origin (MKO) resembled MRSA CC398 as found in pigs and not MSSA CC398 as found in humans. The distinct human MSSA CC398 spa type, t571, was not present among our MRSA CC398 strains; MRSA CC398 was tetracycline resistant and carried no phi3 bacteriophage with scn and chp. We showed by simple PCR means that human MUO CC398 carriers carried MRSA from livestock origin, suggestive of indirect transmission. Although the exact transmission route remains unknown, direct human-to-human transmission remains a possibility as well. PMID- 25809976 TI - Ground steel target plates in combination with direct transfer of clinical Candida isolates improves frequencies of species-level identification by matrix assisted laser desorption ionization-time of flight mass spectrometry in comparison with polished steel target plates. PMID- 25809977 TI - Evaluation of the Qiagen artus C. difficile QS-RGQ Kit for Detection of Clostridium difficile Toxins A and B in Clinical Stool Specimens. AB - We compared the Qiagen artus C. difficile QS-RGQ kit, a new nucleic acid amplification test for the detection of Clostridium difficile toxins in stool specimens, with the Cepheid Xpert C. difficile test. The sensitivity, specificity, positive predictive value, and negative predictive value for the Qiagen artus C. difficile QS-RGQ test were 100%, 89.5%, 60.9%, and 100%, and those for the Cepheid Xpert C. difficile test were 100%, 90%, 62.2%, and 100%, respectively. PMID- 25809978 TI - Mycobacterium lepromatosis Infections in Nuevo Leon, Mexico. AB - The frequency of infection caused by the recently described pathogen Mycobacterium lepromatosis is unknown. Here, we describe the demographics, clinical characteristics, and therapeutic outcomes of five lepromatous leprosy patients suffering from M. lepromatosis infection in Nuevo Leon, Mexico. Diagnosis was facilitated by a new highly specific PCR procedure. PMID- 25809980 TI - Through-bond energy transfer-based ratiometric two-photon probe for fluorescent imaging of Pd(2+) ions in living cells and tissues. AB - Palladium can cause severe skin and eye irritation once it enters the human body. Ratiometric two-photon fluorescent probes can both eliminate interference from environmental factors and realize deep-tissue imaging with improved spatial localization. To quantitatively track Pd(2+) in biosystems, we report here a colorimetric and two-photon ratiometric fluorescent probe, termed Np-Rh-Pd, which consists of a two-photon fluorophore (naphthalene derivative with a D-pi-A structure) and a rhodamine B dye. The two fluorophores are directly linked to form a two-photon ratiometric fluorescent probe for Pd(2+) based on a through bond energy transfer (TBET) strategy. It exhibits highly efficient energy transfer (90%) with two well-resolved emission peaks (wavelength difference of 100 nm), which could efficiently diminish the cross talk between channels and is especially favorable for ratiometric bioimaging applications. A signal-to background ratio of 31.2 was observed for the probe, which affords a high sensitivity for Pd(2+) with a detection limit of 2.3 * 10(-7) M. It was also found that acidity does not affect the fluorescent response of the probe to Pd(2+), which is favorable for its applications in practical samples. The probe was further used for fluorescence imaging of Pd(2+) ions in live cells and tissue slices under two-photon excitation, which showed significant tissue-imaging depths (90-270 MUm) and a high resolution for ratiometric imaging. PMID- 25809979 TI - Predominant Mycobacterium tuberculosis Families and High Rates of Recent Transmission among New Cases Are Not Associated with Primary Multidrug Resistance in Lima, Peru. AB - Sputum samples from new tuberculosis (TB) cases were collected over 2 years as part of a prospective study in the northeastern part of Lima, Peru. To measure the contribution of recent transmission to the high rates of multidrug resistance (MDR) in this area, Mycobacterium tuberculosis complex (MTBc) isolates were tested for drug susceptibility to first-line drugs and were genotyped by spoligotyping and 15-locus mycobacterial interspersed repetitive-unit (MIRU-15) variable-number tandem repeat (VNTR) analysis. MDR was found in 6.8% of 844 isolates, of which 593 (70.3%) were identified as belonging to a known MTBc lineage, whereas 198 isolates (23.5%) could not be assigned to these lineages and 12 (1.4%) represented mixed infections. Lineage 4 accounted for 54.9% (n = 463) of the isolates, most of which belonged to the Haarlem family (n = 279). MIRU-15 analysis grouped 551/791 isolates (69.7%) in 102 clusters, with sizes ranging from 2 to 46 strains. The overall high clustering rate suggests a high level of recent transmission in this population, especially among younger patients (odds ratio [OR], 1.6; P = 0.01). Haarlem strains were more prone to cluster, compared to the other families taken together (OR, 2.0; P < 0.0001), while Beijing (OR, 0.6; P = 0.006) and LAM (OR, 0.7; P = 0.07) strains clustered less. Whereas streptomycin-resistant strains were more commonly found in clusters (OR, 1.8; P = 0.03), clustering rates did not differ between MDR and non-MDR strains (OR, 1.8; P = 0.1). Furthermore, only 16/51 MDR strains clustered with other MDR strains, suggesting that patients with primary MDR infections acquired the infections mostly from index cases outside the study population, such as retreated cases. PMID- 25809982 TI - Rationally Designed Energy Transfer in Upconverting Nanoparticles. AB - Significant advances in the analysis and theoretical modeling of upconverting nanoparticles (UCNPs) are beginning to reveal the complex details of their energy transfer (ET) pathways. UCNPs combine multiple NIR photons to emit at higher energies in the NIR or visible, and are an ideal system for the rational design and precise engineering of optical processes. The ET pathways that drive photon upconversion can be tuned by varying the combination of lanthanide co-dopants, their concentrations, and their spatial distribution within the nanocrystal. Here, recent work is reviewed on the development of complex UCNP architectures that segregate lanthanides across multiple domains in a heterostructure or within the unit cell of the host lattice. These designs direct ET in UCNPs to enhance their brightness, to maximize desired emission wavelengths, to suppress undesirable electronic transitions, and to sensitize absorption of light at different wavelengths. The development of holistic computational models for ET in UCNPs is yielding novel nanocrystal designs with unexpected properties, such as UCNPs with exceptional brightness at single molecule imaging powers. These rational approaches for engineering ET will accelerate the development of UCNPs tailored to specific nanophotonic applications that require the efficient and directed flow of energy. PMID- 25809981 TI - Laparoscopic hysterectomy in large uteri: Experience from a tertiary care hospital in Bangladesh. AB - INTRODUCTION: The purpose of this study was to examine the safety and feasibility of laparoscopically assisted vaginal hysterectomy for uteri weighing more than 500 g as compared to uteri weighing less than 500 g in benign gynecological diseases. METHODS: This was a retrospective study. Patients were admitted through the outpatient department. They were divided into two groups: uterine weight >=500 g (group 1) and uterine weight >500 g (group 2). There were no exclusion criteria based on the size, number, or location of leiomyomas. The patient characteristics for the two groups were compared in terms of demographic and socioeconomic details, operating time, amount of blood loss, requirement of blood transfusion, need for analgesia, and length of hospital stay. RESULTS: The characteristics age and BMI were well balanced between the two groups. Uterine weight was 267.2 +/- 97.6 g in group 1 and 740.0 +/- 371.4 g in group 2 (P < 0.001). Length of operation and amount of blood loss were greater in group 2 than in group 1 (operation: 89.1 +/- 26.7 vs 73.3 +/- 24.6 min, P < 0.01; blood loss: 570.5 +/- 503.6 vs 262.5 +/- 270.0 mL, P < 0.001). However, there was no significant difference in hospital stay or incidence of operative complications between the two groups. No patients were switched from laparoscopy to laparotomy during operation. The rate of blood transfusion was lower in group1 than in group 2 (4.9% vs 32.6%; P < 0.001). CONCLUSION: This study demonstrated that despite the increased operating time and blood loss, laparoscopy should be considered instead of laparotomy in cases of large uteri. Laparoscopically assisted vaginal hysterectomy can be performed safely for a large uterus. PMID- 25809983 TI - Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells. AB - The purpose of this study was to clarify the expression of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) and its contribution to the supply of biotin and pantothenic acid to the human brain via the blood-brain barrier. DNA microarray and immunohistochemical analyses confirmed that SLC5A6 is expressed in microvessels of human brain. The absolute expression levels of SLC5A6 protein in isolated human and monkey brain microvessels were 1.19 and 0.597 fmol/MUg protein, respectively, as determined by a quantitative targeted absolute proteomics technique. Using an antibody-free method established by Kubo et al. (2015), we found that SLC5A6 was preferentially localized at the luminal membrane of brain capillary endothelium. Knock-down analysis using SLC5A6 siRNA showed that SLC5A6 accounts for 88.7% and 98.6% of total [(3) H]biotin and [(3) H]pantothenic acid uptakes, respectively, by human cerebral microvascular endothelial cell line hCMEC/D3. SLC5A6-mediated transport in hCMEC/D3 was markedly inhibited not only by biotin and pantothenic acid, but also by prostaglandin E2, lipoic acid, docosahexaenoic acid, indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen. This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier. In humans, it was unclear (not concluded) about what transport system at the blood-brain barrier (BBB) is responsible for the brain uptakes of two vitamins, biotin and pantothenic acid, which are necessary for brain proper function. This study clarified for the first time that the solute carrier 5A6/Na(+) -dependent multivitamin transporter SLC5A6/SMVT is responsible for the supplies of biotin and pantothenic acid into brain across the BBB in humans. DHA, docosahexaenoic acid; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2. PMID- 25809984 TI - TNF-alpha antagonist may not be suitable for severe rituximab-induced interstitial lung disease. AB - WHAT IS KNOWN AND OBJECTIVE: Rituximab-induced interstitial lung disease (R-ILD) has aroused more concern in recent years. Anti-TNF-alpha treatment has been suggested for the treatment of severe R-ILD, due to the plausible suggestion that its pathogenesis is related to TNF-alpha. This commentary aimed to comment on the role of TNF-alpha antagonists in R-ILD. COMMENT: Although most R-ILD patients respond well to glucocorticoids, other treatment options are needed for patients who are refractory to conventional treatment. Contrary to expectations, the TNF alpha antagonist etanercept brought no benefit in R-ILD. Moreover, TNF-alpha targeted therapies were reported to induce or exacerbate interstitial lung disease. WHAT IS NEW AND CONCLUSION: The role of TNF-alpha in the pathogenesis of R-ILD is still unclear due to limited studies on its aetiology. Use of TNF-alpha antagonists in R-ILD is still speculative, as clinical trials do not support its efficacy. What's more, TNF-alpha antagonists may themselves induce interstitial lung disease with poor prognosis. PMID- 25809985 TI - Exploring emotion recognition in adults and adolescents with anorexia nervosa using a body motion paradigm. AB - OBJECTIVE: There is consistent evidence of difficulties in social cognition in adults with anorexia nervosa (AN), but less is known about adolescents. The aim of this study was to investigate the ability to recognise emotion expressed in body movement in adults and adolescents with AN. METHOD: One hundred and ninety three females participated in the study (AN = 97: 61 adults and 36 adolescents). The performance of participants with AN on a body emotion recognition task was compared to age-matched healthy controls (HC = 96). RESULTS: AN participants were significantly worse than HC recognising sadness, with adolescent AN participants showing worse performance overall. There were no difficulties in the recognition of other emotions. DISCUSSION: The results partially support previous studies and the literature on facial emotion recognition, showing poorer recognition of sadness in AN. The results also suggest that difficulties in emotion recognition through body movements may be more subtle than other socio-emotional difficulties observed in AN. PMID- 25809986 TI - Prenatal diagnosis of extrahepatic umbilicosystemic shunt: a new variant? PMID- 25809987 TI - Transoral robotic-assisted surgical excision of a retropharyngeal parathyroid adenoma: a case report. AB - BACKGROUND: Transoral robotic surgery has been used with increasing frequency for oropharyngeal malignancies. We present the first known case of a transoral robotic-assisted parathyroidectomy. METHODS/RESULTS: A 77-year-old woman with primary hyperparathyroidism was suspected of having a parathyroid adenoma. After several nonlocalizing single photon emission CT/CT sestamibi scans, a neck ultrasound revealed a suspicious low level 6 nodule. Surgical excision of this nodule proved to be a reactive lymph node. She then had a dynamic parathyroid protocol MRI and CT, which revealed a small retropharyngeal adenoma candidate. A transoral robotic-assisted surgical approach was utilized to bluntly dissect the retropharyngeal space just above the arytenoids to excise the nodule. After excision, the intraoperative parathyroid hormone (PTH) normalized and surgical pathology confirmed parathyroid adenoma. CONCLUSION: Transoral robotic-assisted surgery is a novel technique that can be utilized for resection of a parathyroid adenoma in the retropharyngeal space. PMID- 25809988 TI - Raman spectroscopy for medical diagnostics--From in-vitro biofluid assays to in vivo cancer detection. AB - Raman spectroscopy is an optical technique based on inelastic scattering of light by vibrating molecules and can provide chemical fingerprints of cells, tissues or biofluids. The high chemical specificity, minimal or lack of sample preparation and the ability to use advanced optical technologies in the visible or near infrared spectral range (lasers, microscopes, fibre-optics) have recently led to an increase in medical diagnostic applications of Raman spectroscopy. The key hypothesis underpinning this field is that molecular changes in cells, tissues or biofluids, that are either the cause or the effect of diseases, can be detected and quantified by Raman spectroscopy. Furthermore, multivariate calibration and classification models based on Raman spectra can be developed on large "training" datasets and used subsequently on samples from new patients to obtain quantitative and objective diagnosis. Historically, spontaneous Raman spectroscopy has been known as a low signal technique requiring relatively long acquisition times. Nevertheless, new strategies have been developed recently to overcome these issues: non-linear optical effects and metallic nanoparticles can be used to enhance the Raman signals, optimised fibre-optic Raman probes can be used for real-time in-vivo single-point measurements, while multimodal integration with other optical techniques can guide the Raman measurements to increase the acquisition speed and spatial accuracy of diagnosis. These recent efforts have advanced Raman spectroscopy to the point where the diagnostic accuracy and speed are compatible with clinical use. This paper reviews the main Raman spectroscopy techniques used in medical diagnostics and provides an overview of various applications. PMID- 25809990 TI - Apoptin as a potential viral gene oncotherapeutic agent. AB - The use of viruses for treatment of cancer overcomes the bottlenecks of chemotherapy and radiotherapy. Several viruses and their proteins have been evaluated for oncolytic effect. The VP3 protein (apoptin) of chicken anemia virus is one such protein with an inherent ability to lyse cancer and transformed cells while leaving normal cells unharmed. In the present study, the apoptosis inducing potential of VP3 protein of CAV was evaluated in human cervical cancer cell line (HeLa). It was found that in VP3-induced apoptosis, caspase-dependent intrinsic pathway plays an important role with the cleavage of poly (ADP-ribose) polymerase (PARP) and there was no evidence of involvement of death receptor-mediated extrinsic pathway. The results of this study provide intuitive information and strengthen the candidacy of apoptin as a viral oncotherapeutic agent. PMID- 25809989 TI - Is surviving enough? Coping and impact on activities of daily living among melanoma patients with lymphoedema. AB - We assessed the impact of lymphoedema (defined as >= 10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb volume was measured prospectively, pre operatively and every 3-6 months for 18 months post-operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping [odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30-13.47] and performance of ADLs (OR: 7.46, CI: 3.38-16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35-6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29-4.97). Patient education about lymphoedema at the time of surgical consent may improve self efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs. PMID- 25809991 TI - Cheese production using kefir culture entrapped in milk proteins. AB - The aim of the present study was to evaluate the use of kefir culture entrapped in casein and in whey protein as starter cultures for the production of Feta-type cheese. Microbiological analysis showed that counts of enterobacteria, coliforms, and staphylococci were significantly reduced due to kefir culture. In addition, the effect of kefir culture on the formation of volatile compounds, such as esters, organic acids, alcohols, carbonyl compounds, and lactones, was also investigated using the SPME GC/MS technique. Cheese samples produced with kefir culture entrapped in milk proteins presented improved profile of aroma-related compounds. Principal component analysis of the results indicated that the volatile composition of the different cheese types was dependent on the nature of the starter culture. Finally, the sensory evaluation showed that the products produced with kefir culture had a soft, fine taste, and were of improved quality. PMID- 25809992 TI - Potato Patatin Generates Short-Chain Fatty Acids from Milk Fat that Contribute to Flavour Development in Cheese Ripening. AB - The potato lipase, patatin, has long been thought of as essentially inactive towards triacylglycerols. Recently, technology has been developed to isolate potato proteins in native form as food ingredients at industrial scale. Characterisation of native patatin obtained in this way revealed that this enzyme activity towards triacylglycerols has been underestimated. This enables the application of patatin in cheese ripening, which is described in this study. When patatin is added to milk during cheese making, the lipase preferentially releases short-chain fatty acids that contribute to cheese flavour in a dose-dependent manner. Fortuitously, the lipase activity is found mainly in the curd. The release of the short-chain fatty acids matches the activity profile of patatin towards homotriacylglycerols of defined chain length. Residual patatin in the whey fraction can be inactivated effectively by heat treatment that follows Arrhenius kinetics. The results are discussed in terms of cheese making, patatin substrate preference and implications for the use of patatin more generally in food emulsions. PMID- 25809993 TI - Lipase-Catalyzed Production of 6-O-cinnamoyl-sorbitol from D-sorbitol and Cinnamic Acid Esters. AB - To overcome the poor properties of solubility and stability of cinnamic acid, cinnamate derivatives with sugar alcohols were produced using the immobilized Candida antarctica lipase with vinyl cinnamate and D-sorbitol as substrate at 45 degrees C. Immobilized C. antarctica lipase was found to synthesize 6-O-cinnamoyl sorbitol and confirmed by HPLC and (1)H-NMR and had a preference for vinyl cinnamate over other esters such as allyl-, ethyl-, and isobutyl cinnamate as co substrate with D-sorbitol. Contrary to D-sorbitol, vinyl cinnamate, and cinnamic acid, the final product 6-O-cinnamoyl-sorbitol was found to have radical scavenging activity. This would be the first report on the biosynthesis of 6-O cinnamoyl-sorbitol with immobilized enzyme from C. antarctica. PMID- 25809995 TI - Effect of Light Wavelengths and Coherence on Growth, Enzymes Activity, and Melanin Accumulation of Liquid-Cultured Inonotus obliquus (Ach.:Pers.) Pilat. AB - To investigate effects of light wavelengths and coherence on growth of liquid cultured Inonotus obliquus mycelia, melanin accumulation and enzymes activity, culture condition as light of different wavelengths and coherence were studied. Short-term exposure of the vegetative mycelium by low-intensity coherent blue light was optimal for stimulation of growth, melanin synthesis, and increase in extracellular and intracellular activities of tyrosinase and polyphenoloxidase and extracellular catalase. Red coherent light, in the same mode, can effectively be used to stimulate the growth of mycelium and to increase intracellular and extracellular activity of polyphenoloxidase, extracellular catalase and tyrosinase, and intracellular peroxidase. Low-coherent light had less stimulating effect on the biosynthetic activity of I. obliquus. It should be used in the cultivation directed at the obtaining endomelanin, polyphenoloxidase, and extracellular tyrosinase. PMID- 25809994 TI - New chemiluminescent substrates of paraoxonase 1 with improved specificity: synthesis and properties. AB - Paraoxonase 1 (PON1) is an important hydrolase, and the enzyme activity decreases in patients with liver disease, diabetes, coronary heart disease, etc. Phenyl acetate and organophosphates are usually employed as substrates for serum PON1 activity assay. However, phenyl acetate for arylesterase activity assay exhibits disadvantage of high background. According to properties of PON1, four new chemiluminescent acridinium esters were designed, prepared through three steps, and characterized with (1)H NMR and mass spectrometry (MS) data, and their properties as PON1 substrates were investigated. The hydrolyses of the four compounds catalyzed by recombinant human PON1 (rhPON1) (or serum) followed first order kinetics within 22 min. The PON1 activator (NaCl, 0.10 mol L(-1)) could boost the rhPON1-mediated and serum-mediated hydrolyses of the acridinium esters to 2.01 ~ 2.26 folds, but 1.0 mol L(-1) NaCl decreased the serum arylesterase activity. RhPON1 showed selectivity over other serum esterases such as lipase, acetylcholinesterase, and esterase D more than 300 folds. By using ethylene diamine tetraacetic acid (EDTA) inhibitor, the specificities of the four substrates toward serum PON1 were determined as 78.3 ~ 92.9%, which is improved than that of the model compound 9-(4-chloro-phenoxycarbonyl)-10-methylacridinium ester triflate. Due to low toxicity, high specificity, and sensitivity of the substrates, they are useful for serum PON1 activity assay. PMID- 25809996 TI - Urease immobilized fluorescent gold nanoparticles for urea sensing. AB - We report a surfactant-free synthesis of monodispersed gold nanoparticles (AuNPs) with average size of 15 nm. An approach for visual and fluorescent sensing of urea in aqueous solution based on shift in surface plasmon band (SPB) maxima as well as quench in fluorescence intensity. To enable the urea detection, we functionalized the thiol-capped gold nanoparticles with urease, the enzyme specific to urea using carbodiimide chemistry. The visible color changed of the gold colloidal solution from red to blue (or purple); this was evident from quenching in absorbance and fluorescence intensity, is the principle applied here for the sensing of urea. The solution turns blue when the urea concentration exceeds 8 mg/dL which reveals visual lower detection limit. The lower detection limits governed by the fluorescence quenching were found 5 mg/dL (R(2) = 0.99) which is highly sensitive and selective compared to shift in SPB maxima. The approach depicted here seems to be important in clinical diagnosis. PMID- 25809998 TI - Microfluidic Precolumn Derivatization of Environmental Phenols with Coumarin-6 Sulfonyl Chloride and HPLC Separation. AB - A simple, fast, sensitive and versatile method for the analysis of phenols in water is proposed using microfluidic precolumn derivatization with the fluorogenic label coumarin-6-sulfonyl chloride (C6SCl) and HPLC separation on monolithic columns. Phenols react with C6SCl within 3.0 min in the microreactor at ambient temperature to produce phenol-coumarin sulphonamides derivatives which were separated in reversed phase high-performance liquid chromatography followed by postcolumn ring-opening and fluorescence detection at lambdaexc = 360 nm and lambdaem = 460 nm. The optimum conditions for the derivatization, separation and ring-opening reaction have been established. The calibration curves were linear for the studied phenols in the range of 0.75-12.5 mg L(-1). The application of the method to environmental samples was demonstrated by analyzing tap and fountain water samples spiked with the phenolic compounds. PMID- 25809997 TI - Chronic myelomonocytic leukemia with nucleophosmin (NPM1) mutation. AB - Nucleophosmin (NPM1) mutations in chronic myelomonocytic leukemia (CMML) are extremely uncommon, and the clinicopathologic features of these neoplasms are poorly characterized. Over a 10-yr interval, NPM1 mutation analysis was performed in 152 CMML at our institution. NPM1 mutations were identified in 8 (5.3%) patients, five men and three women, with a median age of 72 yr (range, 27-87). In all patients, the bone marrow was hypercellular with multilineage dysplasia, monocytosis, and retained maturation supporting a diagnosis of CMML. NPM1 mutation allele burden was <5% in two patients and >10% in six patients. Four (50%) patients, all with >10% NPM1, progressed AML with a median interval of 11 months (range, 1-21). Compared with 144 CMML without NPM1 mutations, CMML patients with NPM1 mutation presented with more severe anemia (P = 0.053), higher BM monocyte percentage (P = 0.033), and an increased tendency for AML progression (P = 0.088) and an inferior overall survival (P = 0.076). Mutations involving NRAS/KRAS (2/7), TET2(2/5), ASXL1(1/5,) and FLT3(0/8) were not significantly different between these two groups. In summary, CMML with NPM1 mutation shows histopathological features of CMML, but patients appear to have a high probability for AML progression and may require aggressive clinical intervention, especially in patients with a high mutation burden. PMID- 25810000 TI - Implementing the new essential evidence-based practice competencies in real-world clinical and academic settings: moving from evidence to action in improving healthcare quality and patient outcomes. PMID- 25809999 TI - Warming up and shipping out: arousal and emergence timing in hibernating little brown bats (Myotis lucifugus). AB - Phenology refers to the timing of events in the annual cycle of organisms. For temperate-zone mammals, hibernation is one such event, but little is known about its phenology. Hibernation consists of energy-saving torpor bouts interspersed with energetically expensive arousals to normothermic Tb, and hibernators should benefit from mechanisms which reduce arousal costs and help them time arousals to coincide with foraging opportunities. In a previous study, we showed that, in contrast to hibernating bats from warmer climates, little brown bats (Myotis lucifugus) from central Canada abandon a circadian pattern to arousal in the middle of winter when there is no chance of feeding. Here, we used temperature telemetry to test whether they would re-synchronize arousals with normal foraging time (i.e. sunset) during late winter as the chance of foraging or emergence opportunities improves, and whether they would synchronize arousals with conspecifics, possibly to exploit social thermoregulation. We also used passive transponders to test whether energy reserves and/or sex differences in reproductive timing influence phenology and the sensitivity of emergence timing to environmental cues. In contrast to patterns in mid-winter, after 7 April 2013, bats synchronized arousals with sunset and with conspecifics. Females emerged earlier than males, and females in the best condition emerged first while body condition had no influence on male emergence timing. Both male and female bats appeared to time emergence with falling barometric pressure, a cue that predicts favourable foraging conditions for bats but which, unlike outside temperature, would have been readily detectable by bats inside the hibernaculum. Our results highlight hibernation traits associated with extreme winter energy limitation for insect-eating bats in cold climates and illustrate the influence of reproductive timing and environmental conditions on hibernation energetics and phenology. PMID- 25810001 TI - Refractory case of adrenergic urticaria successfully treated with clotiazepam. AB - Adrenergic urticaria (AU) is a rare type of stress-induced physical urticaria characterized by widespread pruritic urticarial papules. Diagnosis can be made by i.d. injection of adrenaline or noradrenaline, which produces the characteristic rash. Although the lesions of AU typically respond to beta-blockers such as propranolol, the therapeutic options for AU are limited. Here, we report a case of AU that was resistant to beta-blockers and successfully treated with clotiazepam. The clinical picture of AU resembles that of cholinergic urticaria (CU), however, positive noradrenaline test and negative acetylcholine skin test were useful for the differential diagnosis of AU and CU. Although his symptoms were resistant to several therapeutic methods including olopatadine (H1 antagonist), lafutidine (H2 antagonist) and propranolol, the severity and frequency of his attacks and his subjective symptoms were reduced by oral clotiazepam, an anxiolytic benzodiazepine. Dermatologists should be aware that anxiolytic benzodiazepines may be a therapeutic option in AU. PMID- 25810002 TI - Suspected early onset of congenital Langerhans cell histiocytosis involving ectopic cervical thymus and mediastinal thymus, simultaneously. PMID- 25810003 TI - Copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols. AB - An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni's reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which beta-H elimination is prohibited, CF3 containing oxetanes are isolated as the sole product. PMID- 25810004 TI - Characterization of a novel bacteriophage, Phda1, infecting the histamine producing Photobacterium damselae subsp. damselae. AB - AIMS: Photobacterium damselae subsp. damselae is a potent histamine-producing micro-organism. The aim of this study was to isolate and characterize a bacteriophage Phda1 that infected P. damselae subsp. damselae to inhibit its growth and histamine accumulation. METHODS AND RESULTS: Phda1 was isolated from a raw oyster, and the host range, morphology and the bacteriophage genome size were analysed. Phda1 formed a clear plaque only against P. damselae subsp. damselae JCM8969 among five Gram-positive and 32 Gram-negative bacterial strains tested. Phda1 belongs to the family Myoviridae, and its genome size was estimated as 35.2 39.5 kb. According to the one-step growth curve analysis, the latent period, rise period and burst size of Phda1 were 60 min, 50 min and 19 plaque-forming units per infected cell, respectively. Divalent cations, especially Ca(2+) and Mg(2+) , strongly improved Phda1 adsorption to the host cells and its propagation. Phda1 treatment delayed the growth and histamine production of P. damselae subsp. damselae in an in vitro challenge test. CONCLUSIONS: The bacteriophage Phda1 might serve as a potential antimicrobial agent to inhibit the histamine poisoning caused by P. damselae subsp. damselae. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first description of a bacteriophage specifically infecting P. damselae subsp. damselae and its potential applications. Bacteriophage therapy could prove useful in the prevention of histamine poisoning. PMID- 25810005 TI - Assessing patients' risk of febrile neutropenia: is there a correlation between physician-assessed risk and model-predicted risk? AB - This study evaluated the correlation between the risk of febrile neutropenia (FN) estimated by physicians and the risk of severe neutropenia or FN predicted by a validated multivariate model in patients with nonmyeloid malignancies receiving chemotherapy. Before patient enrollment, physician and site characteristics were recorded, and physicians self-reported the FN risk at which they would typically consider granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (FN risk intervention threshold). For each patient, physicians electronically recorded their estimated FN risk, orders for G-CSF primary prophylaxis (yes/no), and patient characteristics for model predictions. Correlations between physician assessed FN risk and model-predicted risk (primary endpoints) and between physician-assessed FN risk and G-CSF orders were calculated. Overall, 124 community-based oncologists registered; 944 patients initiating chemotherapy with intermediate FN risk enrolled. Median physician-assessed FN risk over all chemotherapy cycles was 20.0%, and median model-predicted risk was 17.9%; the correlation was 0.249 (95% CI, 0.179-0.316). The correlation between physician assessed FN risk and subsequent orders for G-CSF primary prophylaxis (n = 634) was 0.313 (95% CI, 0.135-0.472). Among patients with a physician-assessed FN risk >= 20%, 14% did not receive G-CSF orders. G-CSF was not ordered for 16% of patients at or above their physician's self-reported FN risk intervention threshold (median, 20.0%) and was ordered for 21% below the threshold. Physician assessed FN risk and model-predicted risk correlated weakly; however, there was moderate correlation between physician-assessed FN risk and orders for G-CSF primary prophylaxis. Further research and education on FN risk factors and appropriate G-CSF use are needed. PMID- 25810007 TI - Central blood pressure physiology: a (more) critical analysis. PMID- 25810008 TI - Response to "Central blood pressure physiology" a (more) critical review (Schultz et al.). PMID- 25810006 TI - Elevated expression of LAG-3, but not PD-1, is associated with impaired iNKT cytokine production during chronic HIV-1 infection and treatment. AB - BACKGROUND: LAG-3 is a potent negative regulator of the immune response but its impact in HIV infection in poorly understood. Unlike exhaustion markers such as PD-1, Tim-3, 2B4 and CD160, LAG-3 is poorly expressed on bulk and antigen specific T cells during chronic HIV infection and its expression on innate lymphocyte subsets is not well understood. The aim of this study was to assess LAG-3 expression and association with cellular dysfunction on T cells, NK cells and iNKT cells among a cohort of healthy and HIV-infected female sex workers in Nairobi, Kenya. RESULTS: Ex vivo LAG-3 expression was measured by multiparametric flow cytometry, and plasma cytokine/chemokine concentrations measured by bead array. Although LAG-3 expression on bulk T cells was significantly increased among HIV-infected women, the proportion of cells expressing the marker was extremely low. In contrast, LAG-3 was more highly expressed on NK and iNKT cells and was not reduced among women treated with ART. To assess the functional impact of LAG-3 on iNKT cells, iNKT cytokine production was measured in response to lipid (alphaGalCer) and PMA/Io stimulation by both flow cytometry and cytokine bead array. iNKT cytokine production is profoundly altered by both HIV infection and treatment, and LAG-3, but not PD-1, expression is associated with a reduction in iNKT IFNgamma production. CONCLUSIONS: LAG-3 does not appear to mediate T cell exhaustion in this African population, but is instead expressed on innate lymphocyte subsets including iNKT cells. HIV infection alters iNKT cytokine production patterns and LAG-3 expression is uniquely associated with iNKT dysfunction. The continued expression of LAG-3 during treatment suggests it may contribute to the lack of innate immune reconstitution commonly observed during ART. PMID- 25810010 TI - JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth. AB - Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) 3 has been implicated in cell proliferation and survival of many cancers including head and neck squamous cell carcinoma (HNSCC). AZD1480, an orally active pharmacologic inhibitor of JAK1/JAK2, has been tested in several cancer models. In the present study, the in vitro and in vivo effects of AZD1480 were evaluated in HNSCC preclinical models to test the potential use of JAK kinase inhibition for HNSCC therapy. AZD1480 treatment decreased HNSCC proliferation in HNSCC cell lines with half maximal effective concentration (EC50) values ranging from 0.9 to 4 MUM in conjunction with reduction of pSTAT3(Tyr705) expression. In vivo antitumor efficacy of AZD1480 was demonstrated in patient-derived xenograft (PDX) models derived from two independent HNSCC tumors. Oral administration of AZD1480 reduced tumor growth in conjunction with decreased pSTAT3(Tyr705) expression that was observed in both PDX models. These findings suggest that the JAK1/2 inhibitors abrogate STAT3 signaling and may be effective in HNSCC treatment approaches. PMID- 25810011 TI - ABCG2 localizes to the nucleus and modulates CDH1 expression in lung cancer cells. AB - Breast cancer resistance protein [BCRP/ATP-binding cassette subfamily G member 2 (ABCG2)] is a member of the ATP-binding cassette transporter family. The presence of ABCG2 on the plasma membrane in many kinds of human cancer cells contributes to multidrug resistance during chemotherapy, and it has been used as the side population marker for identifying cancer stem cells in lung cancers. We report here that, in addition to the membranous form, ABCG2 proteins are also found inside the nucleus, where they bind to the E-box of CDH1 (E-cadherin) promoter and regulate transcription of this gene. Increased expression of ABCG2 causes an increase of E-cadherin and attenuates cell migration, whereas knockdown of ABCG2 downregulates E-cadherin and enhances cell motility. In mice, xenografted A549 cells that have less ABCG2 are more likely to metastasize from the subcutaneous inoculation site to the internal organs. However, for the cancer cells that have already entered the blood circulation, an increased level of ABCG2, and correspondingly increased E-cadherin, may facilitate circulating cancer cells to colonize at a distant site and form a metastatic tumor. We propose a novel role for nuclear ABCG2 that functions as a transcription regulator and participates in modulation of cancer metastasis. PMID- 25810009 TI - The challenges and the promise of molecular targeted therapy in malignant gliomas. AB - Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy. PMID- 25810012 TI - Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subanalyses from BOLERO-2. AB - Hormone receptor-positive breast cancer is typically managed with endocrine therapies. However, resistance to endocrine therapy results in disease progression in a large proportion of breast cancers. Through the understanding of the mechanisms of endocrine resistance, identification of implicated pathways and targets has led to the development of novel agents targeting these pathways. Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway aberrations are common in breast cancer, with increased PI3K/AKT/mTOR signaling associated with resistance to endocrine and human epidermal growth factor receptor 2 (HER2)-targeted therapies. The mTOR inhibitor everolimus, in combination with exemestane, has been approved for patients with advanced hormone receptor-positive/HER2-negative breast cancer who progress on prior nonsteroidal aromatase inhibitor therapy based on results reported in the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study. This review will summarize the overall findings from BOLERO-2 and will consider available subanalyses by age, Asian origin, visceral or bone metastases, and prior therapy, with the aim of identifying populations most likely to benefit from everolimus therapy. The review will also summarize safety findings and their management and the effects of everolimus on quality of life. PMID- 25810013 TI - Targeting the pro-survival protein MET with tivantinib (ARQ 197) inhibits growth of multiple myeloma cells. AB - The hepatocyte growth factor (HGF)/MNNG HOS transforming gene (MET) pathway regulates cell growth, survival, and migration. MET is mutated or amplified in several malignancies. In myeloma, MET is not mutated, but patients have high plasma concentrations of HGF, high levels of MET expression, and gene copy number, which are associated with poor prognosis and advanced disease. Our previous studies demonstrated that MET is critical for myeloma cell survival and its knockdown induces apoptosis. In our current study, we tested tivantinib (ARQ 197), a small-molecule pharmacological MET inhibitor. At clinically achievable concentrations, tivantinib induced apoptosis by >50% in all 12 human myeloma cell lines tested. This biologic response was associated with down-regulation of MET signaling and inhibition of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, which are downstream of the HGF/MET axis. Tivantinib was equally effective in inducing apoptosis in myeloma cell lines resistant to standard chemotherapy (melphalan, dexamethasone, bortezomib, and lenalidomide) as well as in cells that were co-cultured with a protective bone marrow microenvironment or with exogenous cytokines. Tivantinib induced apoptosis in CD138+ plasma cells from patients and demonstrated efficacy in a myeloma xenograft mouse model. On the basis of these data, we initiated a clinical trial for relapsed/refractory multiple myeloma (MM). In conclusion, MET inhibitors may be an attractive target-based strategy for the treatment of MM. PMID- 25810014 TI - Basosquamous carcinoma of the head and neck: clinical and histologic characteristics and their impact on disease progression. AB - OBJECTIVES: Basosquamous carcinoma (BSC) is a rare tumor entity, and the most common onset is in the head and neck region (BSC-HN). The data on diagnosis, treatment, and especially risk assessment concerning disease course and outcome are deficient or inconsistent. This study aimed to evaluate risk factors for local relapse (LR) and lymph node metastasis (LNM) and their impact on progression-free survival (PFS). MATERIALS AND METHODS: In a retrospective monocentric study, patients with BSC-HN treated between 1999 and 2011 were analyzed regarding clinical and histologic characteristics. Prognostic parameters for LR, LNM, and PFS were evaluated. In total, 89 patients (55 male, 34 female, mean age of 71.8 years) with a mean follow-up time of 47.7 months (range 12-112) were included. RESULTS: LR occurred in four patients (4.5%), LNM occurred in five patients (5.6%). Patients with LNM had a significantly shorter PFS time (16.1 months) compared with patients without LNM (154.2 months; P < .001). Tumor depth and size (T classification), incomplete resection, localization at the ear, deep maximal vertical infiltration, muscle and vessel invasion all showed significant (P < .05) associations with LR, LNM, and shorter PFS time. BSC showed more histologic features of basal cell carcinoma (BCC), especially with regard to BerEP4 expression. CONCLUSION: While histology shows some typical characteristics of BCC, the biologic behavior and aggressiveness of BSC are similar to those of cutaneous squamous cell carcinoma. This is the first study to show that LR and, especially, LNM indicate a higher risk of an unfavorable outcome. PMID- 25810015 TI - Characterizing the prevalence of chromosome instability in interval colorectal cancer. AB - A substantial proportion of colorectal cancers (CRCs) are interval CRCs (I-CRCs; i.e., CRCs diagnosed soon after a colonoscopy). Chromosomal instability (CIN) is defined as an increase in the rate of which whole chromosomes/large chromosomal fragments are gained or lost and is observed in 85% of non-hereditary CRCs. The contribution of CIN to the etiology of I-CRCs remains unknown. We established a fluorescence in situ hybridization (FISH) approach to characterize CIN by enumerating specific chromosomes and determined the prevalence of numerical CIN in a population-based cohort of I-CRCs and control (sporadic) CRCs. Using the population-based Manitoba Health administrative databases and Manitoba Cancer Registry, we identified an age, sex, and colonic site of CRC matched cohort of I CRCs and controls and retrieved their archived paraffin-embedded tumor samples. FISH chromosome enumeration probes specifically recognizing the pericentric regions of chromosomes 8, 11, and 17 were first used on cell lines and then CRC tissue microarrays to detect aneusomy, which was then used to calculate a CIN score (CS). The 15th percentile CS for control CRC was used to define CIN phenotype. Mean CSs were similar in the control CRCs and I-CRCs; 82% of I-CRCs exhibited a CIN phenotype, which was similar to that in the control CRCs. This study suggests that CIN is the most prevalent contributor to genomic instability in I-CRCs. Further studies should evaluate CIN and microsatellite instability (MSI) in the same cohort of I-CRCs to corroborate our findings and to further assess concomitant contribution of CIN and MSI to I-CRCs. PMID- 25810017 TI - Occupational hazards in diagnosing pigmented lesions: nickel release from hand held tools. PMID- 25810018 TI - Prospective Evaluation of Bilateral Diaphragmatic Electromyograms During Cryoballoon Ablation of Atrial Fibrillation. AB - BACKGROUND: Left phrenic nerve injury (PNI) can occur during cryoballoon ablation of the left pulmonary veins (PVs). This study aimed to evaluate the feasibility of monitoring the bilateral phrenic nerve function during cryoballoon ablation of atrial fibrillation (AF). METHODS: Fifty consecutive paroxysmal AF patients undergoing cryoballoon ablation using one 28-mm second-generation balloon were prospectively enrolled. Bilateral diaphragmatic compound motor action potentials (CMAPs) were obtained from modified surface electrodes by pacing from the bilateral subclavian veins, and monitored during 3-minute cryoballoon applications at the ipsilateral PVs. RESULTS: One hundred ninety of 202 PVs were successfully isolated exclusively using 28-mm cryoballoons. CMAPs could be obtained in all except 3 cases with catheter inaccessibility in the left subclavian vein. The left and right CMAP amplitudes were similar at baseline (1.04 +/- 0.41 mV vs. 1.01 +/- 0.43 mV, P = 0.49). Among 105 left and 132 right PV applications while monitoring CMAPs, 2 (1.9%) and 13 (9.8%) applications were interrupted for a decreased CMAP amplitude (P = 0.01). Among them, CMAPs decreased due to right PNI in 4 applications/patients and to catheter dislodgement in the remaining applications. PNI remained in 1 and recovered in the remaining 3 patients one day after the procedure. Applications without requiring interruptions exhibited no significant CMAP amplitude changes throughout the applications, and the time-course pattern was similar between the bilateral CMAPs (P = 0.292). CONCLUSIONS: A stable bilateral diaphragmatic CMAP could be similarly obtained during cryoballoon applications in the vast majority of patients. Monitoring CMAPs might be useful to anticipate not only right but also left PNI during cryoballoon ablation. PMID- 25810019 TI - Obstructive sleep apnea and risk of Parkinson's disease: a population-based cohort study. AB - Sleep disorders could be associated with neurodegenerative diseases. This study aimed to determine the risk of Parkinson's disease in patients with obstructive sleep apnea. The incident cases of newly diagnosed obstructive sleep apnea were identified between 2000 and 2009 from the medical claims database of National Health Institute of Taiwan. The risk of Parkinson's disease onset at least 1 year after the diagnosis of obstructive sleep apnea was measured during and up to 11 years of period, compared to that of age- and gender-matched controls estimated in the same period. A total of 5864 patients with newly diagnosed obstructive sleep apnea and 23,269 subjects without obstructive sleep apnea were identified for data analysis. The study reported that the incidence of Parkinson's disease in the obstructive sleep apnea cohort was approximately two times higher than that in the control cohort (2.57 versus 1.32 per 1000 person-years), with an adjusted hazard ratio of 1.84. Furthermore, the risk of Parkinson's disease was particularly greater for the obstructive sleep apnea with insomnia subgroup (adjusted hazard ratio = 1.97, 95% confidence interval = 1.44-2.69) than for the control cohort. The sex-age-specific analysis further discovered that the most elevated risk of Parkinson's disease onset was noted in female obstructive sleep apnea patients aged 50-69 years (adjusted hazard ratio = 2.82). This population based study indicated that patients with obstructive sleep apnea, especially those who suffered from insomnia, are at an increased risk of Parkinson's disease onset. PMID- 25810016 TI - Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression. AB - Transforming growth factor-beta (TGF-beta) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-beta acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain-containing mTOR-interacting protein (Deptor), in coupling TGF-beta to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor alpha-negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli. PMID- 25810020 TI - The Embodied Attunement of Therapists and a Couple within Dialogical Psychotherapy: An Introduction to the Relational Mind Research Project. AB - In dialogical practice, therapists seek to respond to the utterances of clients by including in their own response what the client said. No research so far exists on how, in dialogs, therapists and clients attune themselves to each other with their entire bodies. The research program The Relational Mind is the first to look at dialog in terms of both the outer and the inner dialogs of participants (clients and therapists), observed in parallel with autonomic nervous system (ANS) measurements. In the ANS, the response occurs immediately, even before conscious thought, making it possible to follow how participants in a multiactor dialog synchronize their reactions and attune themselves to each other. The couple therapy case presented in this article demonstrates how attunement is often not a simple "all at the same time" phenomenon, but rather a complex, dyadic or triadic phenomenon which changes over time. In the case presented, there was strong synchrony between one therapist and one client in terms of their arousal level throughout the therapy session. It was also observed that high stress could occur when someone else was talking about something related to the participant, or if that person mirrored the participant's words. Overall, it seems that in evaluating the rhythmic attunement between therapists and clients it is not enough to look at single variables; instead, integrated information from several channels is needed when one is seeking to make sense of the embodiment. PMID- 25810021 TI - Expression, characterization and crystal structure of thioredoxin from Schistosoma japonicum. AB - Schistosoma japonicum, a human blood fluke, causes a parasitic disease affecting millions of people in Asia. Thioredoxin-glutathione system of S. japonicum plays a critical role in maintaining the redox balance in parasite, which is a potential target for development of novel antischistosomal agents. Here we cloned the gene of S. japonicum thioredoxin (SjTrx), expressed and purified the recombinant SjTrx in Escherichia coli. Functional assay shows that SjTrx catalyses the dithiothreitol (DTT) reduction of insulin disulphide bonds. The coupling assay of SjTrx with its endogenous reductase, thioredoxin glutathione reductase from S. japonicum (SjTGR), supports its biological function to maintain the redox homeostasis in the cell. Furthermore, the crystal structure of SjTrx in the oxidized state was determined at 2.0 A resolution, revealing a typical architecture of thioredoxin fold. The structural information of SjTrx provides us important clues for understanding the maintenance function of redox homeostasis in S. japonicum and pathogenesis of this chronic disease. PMID- 25810023 TI - The effects of morphine and methylnaltrexone on gastrointestinal pain in healthy male participants. AB - BACKGROUND: Opioid antagonists are increasingly used to abolish the gastrointestinal side effects of opioids. However, they can potentially interfere with local analgesia exerted via opioid receptors in the gut. Thus, in the current study we aimed to explore the effect of rectal morphine before and after blocking opioid receptors outside the central nervous system with methylnaltrexone (MNTX). METHODS: In this randomized, placebo controlled, cross over study 15 healthy male participants received the following drugs at three separate sessions: (i) placebo, (ii) 30 mg morphine administered per rectum, or (iii) 12 mg MNTX given subcutaneously before 30 mg rectal morphine. At baseline and after drug administration peripheral and central effects of the drugs were assessed by experimental pain to the skin, muscle, rectum and pupillometry. KEY RESULTS: Compared to placebo there was no local effect of morphine on mechanical rectal distension. In contrast, an increase in tolerated volume was seen following MNTX/morphine administration (p < 0.001), starting 7 min after dosing. Both morphine and MNTX/morphine had a central effect manifested as an increase in mechanical muscle pressure thresholds (both p < 0.001) and a decrease in pupil diameter (both p < 0.001). These effects occurred 30 min after dosing. CONCLUSIONS & INFERENCES: No peripheral analgesic effect of morphine was found. Methodological shortcomings may have contributed to the lack of peripheral analgesia and thus, a peripheral morphine effect on rectal pain cannot be excluded. On the other hand, the combination of MNTX and morphine exerted a local effect on rectal distensions and seems to improve analgesia. PMID- 25810022 TI - Retinol binding protein-4 predicts incident diabetes in Asian Indian men with prediabetes. AB - The association of retinol binding protein-4 (RBP4) with incident type 2 diabetes (T2DM) in Asian Indian middle-aged men with impaired glucose tolerance (IGT) was studied. This was an ancillary analysis of a subsample from a cohort of participants with IGT in a 2 year prospective diabetes prevention program in India. For this analysis, 71 incident T2DM and 76 non-diabetic cases (non progressors) based on the final glycemic outcome were selected. Baseline serum RBP4 was measured using competitive enzyme immunoassay. Correlations of RBP4 with relevant anthropometric and biochemical variables and also its association with diabetes were assessed using appropriate statistical analyses. Participants who developed T2DM had higher levels of serum RBP4 (21.3 [IQR: 17.7-24.9] ug/mL) compared with non-progressors (17.3 [IQR: 13.1-21.0] ug/mL; P = 0.001). Levels of RBP4 were lower than in Caucasians. Stepwise linear regression analysis showed that body mass index (BMI), systolic blood pressure, triglycerides, and HbA1c had independent associations with RBP4 levels. Multiple logistic regression analyses showed that RBP4 was independently associated with incident diabetes (odds ratio [OR] [95%confidence interval (CI)]: 1.69 [1.18-2.41]; P = 0.004). Adjustment for study group, age, BMI, waist circumference, 2 H plasma glucose, triglycerides, gamma glutamyl transferase, and insulin resistance weakened the significance of its association (OR [95%CI]: 1.65 [1.03-2.66]; P = 0.038).The results of this preliminary analyses showed that baseline serum RBP4 levels were independently associated with incident diabetes in Asian Indian men with IGT. It may be used as an additional predictor of future diabetes. PMID- 25810024 TI - Local review of treatment of hand enchondroma (artificial bone substitute versus autologous bone graft) in a tertiary referral centre: 13 years' experience. AB - OBJECTIVE: To evaluate the treatment outcomes of enchondroma of the hand with artificial bone substitute versus autologous (iliac) bone graft. DESIGN: Historical cohort study. SETTING: Tertiary referral centre, Hong Kong. PATIENTS: A total of 24 patients with hand enchondroma from January 2001 to December 2013 who underwent operation at the Prince of Wales Hospital and Alice Ho Miu Ling Nethersole Hospital in Hong Kong were reviewed. Thorough curettage of the tumour was performed in all patients, followed by either autologous bone graft impaction under general anaesthesia in 13 patients, or artificial bone substitute in 11 patients (10 procedures were performed under local or regional anaesthesia and 1 was done under general anaesthesia). The functional outcomes and bone incorporation were measured by QuickDASH (shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire) scores and radiological appearance, respectively. The mean follow-up period was 59 months. RESULTS: There were eight men and 16 women, with a mean age of 40 years. Overall, 17 cases involved phalangeal bones and seven involved metacarpal bones. Among both groups of patients, most of the affected digits had good range of motion and function after surgery. One patient in each study group had complications of local soft tissue inflammation. One patient in the artificial bone substitute group was suspected to have recurrence 8 years after operation. Among the autologous bone graft group, four patients had persistent donor site morbidity at the last follow-up. In all patients, radiographs showed satisfactory bone incorporation. CONCLUSIONS: Artificial bone substitute is a safe and effective treatment option for hand enchondroma, with satisfactory functional and radiographic outcomes. Artificial bone substitute offers the additional benefits of enabling the procedure to be done under local anaesthesia on a day-case basis with minimal complications. PMID- 25810026 TI - Associations of Resonance Frequency Analysis with Dynamic Mechanical Analysis of Dental Implant Systems. AB - BACKGROUND: Resonance frequency analysis (RFA) has been introduced as a noninvasive method to clinically estimate the stability of dental implant systems. PURPOSE: The objective of this study was to examine whether implant stability quotient (ISQ) values of RFA can account for mechanical stability of the dental implant system, which is assessed using dynamic mechanical analysis (DMA). MATERIALS AND METHODS: Fifty-seven screw-type titanium dental implants were placed in artificial polyurethane foams with seven different thicknesses (3.5 to 12 mm) and eight edentulous mandibles of human cadavers (four men and four women, 79.11 +/- 13.48 years). After the ISQ values, insertion torque, and static stiffness of each implant system were measured, the DMA was performed to assess dynamic stiffness and viscoelastic tan delta. RESULTS: The ISQ value had strong positive correlations with thickness, insertion torque, static and dynamic stiffness, and a negative correlation with tan delta of implant systems in artificial bone blocks (r = 0.769 to 0.992, p < .043). However, the ISQ value was correlated with only the insertion torque of implant systems in human mandibles (p < .049). CONCLUSION: The ISQ values could reflect mechanical stability of the dental implant system under the controlled condition of homogeneous density in simple dimensions. PMID- 25810025 TI - Unprecedented Quassinoids with Promising Biological Activity from Harrisonia perforata. AB - Perforalactone A (1), a new 20S quassinoid with a unique cagelike 2,4 dioxaadamantane ring system and a migrated side chain, was isolated from the plant Harrisonia perforata together with two biosynthetically related new quassinoids. The structures of these natural products were elucidated by NMR spectroscopy, X-ray diffraction analysis, computational modeling, and the CD excitation chirality method. The compounds exhibited notable biological properties, including insecticidal activity against Aphis medicaginis Koch and antagonist activity at the nicotinic acetylcholine receptor of Drosophila melanogaster. The structural features of these compounds may be related to their promising biological characteristics. Their biosynthesis and an alternative origin of quassinoid-type natural products are also discussed. PMID- 25810027 TI - Sialidase NEU3 contributes neoplastic potential on colon cancer cells as a key modulator of gangliosides by regulating Wnt signaling. AB - The plasma membrane-associated sialidase NEU3 is a key enzyme for ganglioside degradation. We previously demonstrated remarkable up-regulation of NEU3 in various human cancers, with augmented malignant properties. Here, we provide evidence of a close link between NEU3 expression and Wnt/beta-catenin signaling in colon cancer cells by analyzing tumorigenic potential and cancer stem-like characteristics. NEU3 silencing in HT-29 and HCT116 colon cancer cells resulted in significant decrease in clonogenicity on soft agar and in vivo tumor growth, along with down-regulation of stemness and Wnt-related genes. Analyses further revealed that NEU3 enhanced phosphorylation of the Wnt receptor LRP6 and consequently beta-catenin activation by accelerating complex formation with LRP6 and recruitment of GSK3beta and Axin, whereas its silencing exerted the opposite effects. NEU3 activity-null mutants failed to demonstrate the activation, indicating the requirement of ganglioside modulation by the sialidase for the effects. Under sphere-forming conditions, when stemness genes are up-regulated, endogenous NEU3 expression was found to be significantly increased, whereas NEU3 silencing suppressed sphere-formation and in vivo tumor incidence in NOD-SCID mice. Increased ability of clonogenicity on soft agar and sphere formation by Wnt stimulation was abrogated by NEU3 silencing. Furthermore, NEU3 was found to regulate phosphorylation of ERK and Akt via EGF receptor and Ras cascades, thought to be additionally required for tumor progression. The results indicate an essential contribution of NEU3 to tumorigenic potential through maintenance of stem-like characteristics of colon cancer cells by regulating Wnt signaling at the receptor level, in addition to tumor progression via Ras/MAPK signaling. PMID- 25810028 TI - DaPeCa-1: diagnostic accuracy of sentinel lymph node biopsy in 222 patients with penile cancer at four tertiary referral centres - a national study from Denmark. AB - OBJECTIVES: To estimate the diagnostic accuracy of sentinel lymph node biopsy (SNB) in patients with penile cancer and assess SNB complications in a national multicentre setting. PATIENTS AND METHODS: Retrospectively data were collected from records in four university centres by one medical doctor covering all SNBs performed in Denmark between 1 January 2000 and 31 December 2010. Patients had either impalpable lymph nodes (LNs) in one or both groins, or had a palpable inguinal mass from which aspiration cytology failed to reveal malignancy. Patients were injected with nanocolloid technetium and had a scintigram recorded before the SNB. The primary endpoint was LN recurrence on follow-up. The secondary endpoint was complications after SNB. Diagnostic accuracy was computed. RESULTS: In all, 409 groins in 222 patients were examined by SNB. The median (interquartile range) follow-up of patients who survived was 6.6 (5-10) years. Of 343 negative groins, eight were false negatives. The sensitivity was 89.2% (95% confidence interval 79.8-95.2%) per groin. Interestingly, four of 67 T1G1 patients had a positive SNB. In all, 28 of 222 (13%) patients had complications of Clavien-Dindo grade I-IIIa. CONCLUSION: Penile cancer SNB with a close follow up stages LN involvement reliably and has few complications in a national multicentre setting. Inguinal LN dissection was avoided in 76% of patients. PMID- 25810029 TI - Comet flap for the repair of large surgical defects of the face and scalp. PMID- 25810031 TI - Crystal structure of the human odorant binding protein, OBPIIa. AB - Human odorant-binding protein, OBPIIa , is expressed by nasal epithelia to facilitate transport of hydrophobic odorant molecules across the aqueous mucus. Here, we report its crystallographic analysis at 2.6 A resolution. OBPIIa is a monomeric protein that exhibits the classical lipocalin fold with a conserved eight-stranded beta-barrel harboring a remarkably large hydrophobic pocket. Basic residues within the four loops that shape the entrance to this ligand-binding site evoke a positive electrostatic potential. Human OBPIIa shows distinct features compared with other mammalian OBPs, including a potentially reactive Cys side chain within its pocket similar to human tear lipocalin. PMID- 25810030 TI - Will you touch a dirty diaper? Attitudes towards disgust and behaviour. AB - Individuals differ in their willingness to engage with disgusting stimuli (e.g., dirty diapers). We propose that such differences are associated with attitudes towards disgust. Specifically, we predicted that people with less negative attitudes towards disgust (i.e., those who evaluate disgust less negatively) would be more willing to engage with disgusting stimuli. We asked participants to engage with disgusting stimuli in the laboratory and used two measures that assess behavioural and affective or cognitive components of attitudes towards disgust. As predicted, less negative attitudes towards disgust were associated with greater engagement with disgusting stimuli, above and beyond the current experience of disgust and the tendency to experience disgust. These findings stress the importance of attitudes towards emotions in understanding emotion relevant behaviour. PMID- 25810033 TI - Bridging barriers to health promotion: a feasibility pilot study of the 'Promoting Aging Migrants' Capabilities study'. AB - RATIONALE, AIMS AND OBJECTIVES: Improving the possibilities for ageing persons to take control over their health is an increasingly important public health issue. Health promotion has previously been visualized to succeed with this goal, but research has primarily focused on ageing persons who are native-born, leaving the generalizability to persons who are foreign-born unexplored. Therefore, as part of the development of a larger health promotion initiative for ageing persons who have experienced migration, this study aimed to assess the feasibility of an adapted protocol. The specific feasibility objectives were to assess recruitment procedure, retention rates, study questionnaire administration and variability of collected data. METHOD: Forty persons who were >=70 years, and who had migrated from Finland, Bosnia and Herzegovina, Croatia, Montenegro or Serbia to Sweden were randomly allocated to a health promotion programme or a control group. The programme was linguistically adapted with regard to translated information material, bilingual health professionals and evaluators, and a person-centred approach was applied to both programme development and provision. The data analysis was explorative and descriptive. RESULTS: The results visualized structural and linguistic barriers to recruitment and study questionnaire administration, and describe strategies for how to bridge them. Retention rates and data variability were satisfying. CONCLUSIONS: Calling for iterative and pragmatic programme design, the findings describe how to move towards a more inclusive health care environment. Person-centred and bilingual approaches with attention to the possibilities for building authentic relationships between participants and providers are emphasized, and a structured methodology for developing study questionnaires is suggested. PMID- 25810032 TI - Aging Affects Identification of Vocal Emotions in Semantically Neutral Sentences. AB - PURPOSE: The authors determined the accuracy of younger and older adults in identifying vocal emotions using the Toronto Emotional Speech Set (TESS; Dupuis & Pichora-Fuller, 2010a) and investigated the possible contributions of auditory acuity and suprathreshold processing to emotion identification accuracy. METHOD: In 2 experiments, younger and older adults with normal hearing listened to and identified vocal emotions in the TESS stimuli. The TESS consists of phrases with controlled syntactic, lexical, and phonological properties spoken by an older female talker and a younger female talker to convey 7 emotion conditions (anger, disgust, fear, sadness, neutral, happiness, and pleasant surprise). Participants in both experiments completed audiometric testing; participants in Experiment 2 also completed 3 tests of suprathreshold auditory processing. RESULTS: Identification by both age groups was above chance for all emotions. Accuracy was lower for older adults in both experiments. The pattern of results was similar across age groups and experiments. Auditory acuity did not predict identification accuracy for either age group in either experiment, nor did performance on tests of auditory processing in Experiment 2. CONCLUSIONS: These results replicate and extend previous findings concerning age-related differences in ability to identify vocal emotions and suggest that older adults' auditory abilities do not explain their difficulties in identifying vocal emotions. PMID- 25810034 TI - Point and interval estimation of baseline risk and treatment effect based on logistic model for observational studies. AB - In observational studies with dichotomous outcome of a population, researchers usually report treatment effect alone, although both baseline risk and treatment effect are needed to evaluate the significance of the treatment effect to the population. In this article, we study point and interval estimates including confidence region of baseline risk and treatment effect based on logistic model, where baseline risk is the risk of outcome of the population under control treatment while treatment effect is measured by the risk difference between outcomes of the population under active versus control treatments. Using approximate normal distribution of the maximum-likelihood (ML) estimate of the model parameters, we obtain an approximate joint distribution of the ML estimate of the baseline risk and the treatment effect. Using the approximate joint distribution, we obtain point estimate and confidence region of the baseline risk and the treatment effect as well as point estimate and confidence interval of the treatment effect when the ML estimate of the baseline risk falls into specified range. These interval estimates reflect nonnormality of the joint distribution of the ML estimate of the baseline risk and the treatment effect. The method can be easily implemented by using any software that generates normal distribution. The method can also be used to obtain point and interval estimates of baseline risk and any other measure of treatment effect such as risk ratio and the number needed to treat. The method can also be extended from logistic model to other models such as log-linear model. PMID- 25810035 TI - A guideline for the management of bladder dysfunction in Parkinson's disease and other gait disorders. AB - Parkinson's disease (PD) is a common neurodegenerative disorder, and lower urinary tract (LUT) dysfunction is one of the most common autonomic disorders with an estimated incidence rate of 27-80%. Studies have shown that bladder dysfunction significantly influences quality-of-life (QOL) measures, early institutionalisation, and health economics. We review the pathophysiology of bladder dysfunction in PD, lower urinary tract symptoms (LUTS), objective assessment, and treatment options. In patients with PD, disruption of the dopamine D1-GABAergic direct pathway may lead to LUTS. Overactive bladder (OAB) is the most common LUT symptom in PD patients, and an objective assessment using urodynamics commonly shows detrusor overactivity (DO) in these patients. The post void residual (PVR) volume is minimal in PD, which differs significantly from multiple system atrophy (MSA) patients who have a more progressive disease that leads to urinary retention. However, subclinical detrusor weakness during voiding may also occur in PD. Regarding bladder management, there are no large, double blind, prospective studies in this area. It is well recognised that dopaminergic drugs can improve or worsen LUTS in PD patients. Therefore, an add-on therapy with anticholinergics is required. Beta-3 adrenergic agonists are a potential treatment option because there are little to no central cognitive events. Newer interventions, such as deep brain stimulation (DBS), are expected to improve bladder dysfunction in PD. Botulinum toxin injections can be used to treat intractable urinary incontinence in PD. Transurethral resection of the prostate gland (TURP) for comorbid BPH in PD is now recognised to be not contraindicated if MSA is excluded. Collaboration of urologists with neurologists is highly recommended to maximise a patients' bladder-associated QOL. Neurourol. Urodynam. 35:551-563, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25810036 TI - Toward ecosystem-based sediment quality guidelines for polychlorinated biphenyls (PCBs). AB - To investigate whether Sediment Quality Guidelines (SQGs) for polychlorinated biphenyls (PCBs) in Canada and British Columbia achieve their objective of protecting ecosystems, we measured and compiled concentrations of PCB congeners in sediments, bivalves, crustaceans, fish, and marine mammals from 3 areas off the Pacific coast of British Columbia, Canada. The concentration data showed that whereas PCB concentrations in sediments were predominantly below the SQG of 20 ug/kg dry weight, large fractions of the PCB concentrations in fish and shellfish species exceeded the tissue residue guideline for the consumption of fish and shellfish by wildlife (i.e., 50 ug/kg wet weight [ww]) but were below the tissue residue guideline for the consumption of fish and shellfish by human populations (i.e., 2000 ug/kg ww). Also, PCB concentrations in marine mammals exceeded toxicity reference concentrations. The concentration data were used to develop species- and location-specific Biota-Sediment Accumulation Factors (BSAF = Cbiota /Csediment ), that were used to estimate PCB concentrations in wildlife species that may exist if the PCB concentration in sediments are equal to the SQGs. The results show that if the PCB concentration is equal to the SQGs, then PCB concentrations in most wildlife species can be expected to exceed the tissue residue guideline for the consumption of fish and shellfish by wildlife species and by humans, as well as toxicity reference concentrations for marine mammals. A methodology for developing SQGs for PCBs that are protective of the health of different wildlife species and human consumers of fish and shellfish from general Canadian and coastal First Nations populations was developed and applied. The proposed guidelines may provide useful guidance to establish SQGs for PCBs that can account for the ecological diversity in coastal environments and that better achieve the intent of the guidelines to protect ecosystems. The proposed methodology for guideline development may also be useful in the development of SQGs for other bioaccumulative substances. PMID- 25810037 TI - Islet transplantation from a nationally funded UK centre reaches socially deprived groups and improves metabolic outcomes. AB - AIMS/HYPOTHESIS: Type 1 diabetes complicated by hypoglycaemia is prevalent in socioeconomically deprived populations. Islet transplantation is of proven efficacy in type 1 diabetes complicated by hypoglycaemia, but it is not known if nationally funded programmes reach the socioeconomically deprived. Our aim was to determine: (1) socioeconomic indices in participants referred to our nationally funded programme; and (2) if metabolic outcomes in our transplant recipients were improved. METHODS: Participants referred (n = 106) and receiving transplants (n = 18; 32 infusions) were examined with respect to socioeconomic status (deprivation category score) and their ability to work and drive. In participants followed for >=12 months after transplantation, metabolic and anthropometric measurements (n = 14) were recorded pre- and post-transplant (assessed ~1, ~3, ~6 and ~12 months with mixed-meal tolerance tests and 6 day continuous glucose monitoring assessments). Donor data was also examined. RESULTS: There was a greater prevalence of socioeconomic deprivation in referred and transplant recipients than the general population (p < 0.05). Of the transplant recipients, 73% were socioeconomically deprived, 88% did not hold a driver's license and 94% had reduced ability to work (all p < 0.01 vs referred participants). Donors were predominantly obese and included circulatory death donors. At 12 months, 93% of participants who had received transplants had graft function, diminished frequency of hypoglycaemia (10 [4-11] vs 0 [0-2] hypoglycaemic episodes/week), improved awareness of hypoglycaemia (Gold score 7 [5-7] vs 1 [1-2]) and glycaemic control (HbA1c: 7.9% [7.2-8.5%]; 63 [55-69] mmol/mol vs 7.2% [6.8-7.5%]; 55 [51 58] mmol/mol), diminished glycaemic lability and decreased central adiposity (all p < 0.05). CONCLUSIONS/INTERPRETATION: A nationally funded islet transplant programme reaches the socioeconomically deprived and outcomes are significantly improved in this group. PMID- 25810038 TI - The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells. AB - AIMS/HYPOTHESIS: The role of the redox adaptor protein p66(Shc) as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. METHODS: The effects of the FA palmitate on p66(Shc) expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66(Shc) expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66(Shc) was investigated using pancreatic islets from p66 (Shc-/-) mice and in INS-1E cells with knockdown of p66(Shc) or overexpression of wild-type and phosphorylation-defective p66(Shc). Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. RESULTS: Palmitate induced a selective increase in p66(Shc) protein expression and phosphorylation on Ser(36) and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66(Shc) expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 (Shc /-) mice and following p66 (Shc) knockdown in INS-1E cells; by contrast, overexpression of p66(Shc), but not that of the phosphorylation-defective p66(Shc) mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66(Shc) were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser(36) and associated with generation of ROS. p66(Shc) protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors. CONCLUSIONS/INTERPRETATION: p53 dependent augmentation of p66(Shc) expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity. PMID- 25810040 TI - Tuning to the right signal. AB - Pancreatic beta cells are clustered in islets of Langerhans together with alpha cells in an arrangement that facilitates the tight coordination of insulin and glucagon secretion at the source of their release. Other secretory cells, including somatostatin-secreting delta cells and pancreatic polypeptide cells, co localise with alpha and beta cells in the islet and serve to modulate islet endocrine output. A multitude of non-secretory cell types, including endothelial cells, pericytes, stromal cells, glial cells and macrophages, complete the cellular make up of the islet, which is further enhanced by (para)sympathetic nerve terminals that impinge on the islets via neurotransmitters released in the islet microenvironment. While this islet architecture is relatively simple compared with the vast complexity of the central nervous system, the constellation of cell types united in the islet nevertheless provides a rich substrate for local paracrine and autocrine interactions that affect diverse aspects of islet physiology, ranging from the modulation of hormone secretion to the regulation of islet cell mass via proliferation and death. In this issue of Diabetologia (DOI: 10.1007/s00125-015-3552-5 ), Yang et al take the notion of rich crosstalk within the islet as their point of departure for a systematic evaluation of the beta cell-protective properties of an extensive panel of over 200 factors, with some surprising and highly interesting results, as discussed in this commentary. PMID- 25810039 TI - Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation. AB - AIMS/HYPOTHESIS: Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy 2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator activated receptor-delta (PPARdelta), which in turn augmented glucose-stimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability. METHODS: INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 MUmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly. RESULTS: PA was incorporated into membrane phospholipids in a concentration- and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARdelta in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death. CONCLUSIONS/INTERPRETATION: These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells. PMID- 25810041 TI - Within-class differences of the sulfonylureas should be accounted for. Reply to Schrijnders D, Kleefstra N and Landman GWD [letter]. PMID- 25810043 TI - The use of gentamicin-impregnated collagen sponges (Garacol(r)/Duracoll(r)) in cochlear implant infections: our experience in four cases. PMID- 25810044 TI - Nurses' perceptions of climate and environmental issues: a qualitative study. AB - AIM: The aim of this study was to explore nurses' perceptions of climate and environmental issues and examine how nurses perceive their role in contributing to the process of sustainable development. BACKGROUND: Climate change and its implications for human health represent an increasingly important issue for the healthcare sector. According to the International Council of Nurses Code of Ethics, nurses have a responsibility to be involved and support climate change mitigation and adaptation to protect human health. DESIGN: This is a descriptive, explorative qualitative study. METHODS: Nurses (n = 18) were recruited from hospitals, primary care and emergency medical services; eight participated in semi-structured, in-depth individual interviews and 10 participated in two focus groups. Data were collected from April-October 2013 in Sweden; interviews were transcribed verbatim and analysed using content analysis. RESULTS: Two main themes were identified from the interviews: (i) an incongruence between climate and environmental issues and nurses' daily work; and (ii) public health work is regarded as a health co-benefit of climate change mitigation. While being green is not the primary task in a lifesaving, hectic and economically challenging context, nurses' perceived their profession as entailing responsibility, opportunities and a sense of individual commitment to influence the environment in a positive direction. CONCLUSIONS: This study argues there is a need for increased awareness of issues and methods that are crucial for the healthcare sector to respond to climate change. Efforts to develop interventions should explore how nurses should be able to contribute to the healthcare sector's preparedness for and contributions to sustainable development. PMID- 25810042 TI - Hospice volunteers: bridging the gap to the community? AB - Current demographic, policy and management changes are a challenge to hospices to develop their volunteering practices. The study upon which this paper is based aimed to explore good practice in volunteer involvement and identify ways of improving care through developing volunteering. The project consisted of a narrative literature review; a survey of volunteer managers; and organisational case studies selected through purposive diversity sampling criteria. A total of 205 staff, volunteers, patients and relatives were interviewed across 11 sites in England in 2012. This article focuses on one of the findings - the place that volunteers occupy between the hospice and the community beyond its walls. External changes and pressures in society were impacting on volunteer management, but were viewed as requiring a careful balancing act to retain the 'spirit' of the hospice philosophy. Honouring the developmental history of the hospice was vital to many respondents, but viewed less positively by those who wished to modernise. Hospices tend to be somewhat secluded organisations in Britain, and external links and networks were mostly within the end-of-life care arena, with few referring to the wider volunteering and community fields. Volunteers were seen as an informal and symbolic 'link' to the local community, both in terms of their 'normalising' roles in the hospice and as providing a two-way flow of information with the external environment where knowledge of hospice activities remains poor. The diversity of the community is not fully represented among hospice volunteers. A few hospices had deliberately tried to forge stronger interfaces with their localities, but these ventures were often controversial. The evidence suggests that there is substantial scope for hospices to develop the strategic aspects of volunteering through greater community engagement and involvement and by increasing diversity and exploiting volunteers' 'boundary' position more systematically to educate, recruit and raise awareness. PMID- 25810045 TI - Intralesional botulinum toxin type A equally effective and better tolerated than intralesional steroid in the treatment of keloids: a randomized controlled trial. AB - Intralesional (IL) corticosteroid therapy is a treatment for keloids. IL botulinum toxin type A (BTA) has been postulated in such an indication with controversial reports. To compare efficacy and safety of IL BTA to the IL corticosteroid therapy in treatment of keloids. Twenty-four patients with keloids were randomly divided into two equal groups: receiving IL steroid repeated every 4 weeks for six sessions (group A) and IL BTA 5 IU/cm(3) repeated every 8 weeks for three sessions (group B). Objective parameters (hardness, elevation, and redness), subjective complaints (itching, pain, and tenderness), patient satisfaction, and side effects were evaluated. There was a significant decrease in the volume of the lesions after treatment (P < 0.01), with a volume reduction of 82.7% and 79.2%, respectively, in both groups. A significant softening of lesions vs. baseline was observed (P < 0.01), with statistically significant improvement in softening in group A (P < 0.01). There was a significant decrease in height of lesions and in redness score compared with baseline (P < 0.01) with no significant difference in between both groups. All patients mentioned a significant reduction of their subjective complaints (P < 0.01) that were more significant in group B. Skin atrophy and telangiectasia were evident in three patients of group A. The efficacy and safety of the IL BTA were clearly evident in the current work from the rapid significant amelioration of the subjective complaints and the comparable significant improvement of the objective parameters as well as the volume of the keloids in comparison with the IL corticosteroids. PMID- 25810046 TI - Supramolecular Polyelectrolyte Complexes of Bone Morphogenetic Protein-2 with Sulfonated Polyrotaxanes to Induce Enhanced Osteogenic Differentiation. AB - Although bone morphogenetic protein-2 (BMP-2) has received considerable attention because of its strong osteoinductivity, the clinical application of BMP-2 is limited due to its degradation and deactivation under physiological conditions. Negatively charged heparin is known to form polyelectrolyte complexes with BMP-2 to prevent deactivation and enhance the osteoinduction capability of BMP-2. Herein, we report the sulfonated polyrotaxanes (S-PRX) composed of alpha cyclodextrin threaded onto a linear polymer for the protection of BMP-2 through the polyelectrolyte complex formation. When MC3T3-E1 osteoprogenitor cells were treated with the S-PRX/BMP-2 complexes, significantly high alkaline phosphatase production and mineralized matrix deposition were observed compared with that of free BMP-2 and heparin/BMP-2 complexes. Note that the S-PRXs showed negligible anticoagulant activity and cytotoxicity, whereas heparin showed strong anticoagulant activity. Accordingly, the S-PRXs are promising candidates for enhanced osteoinduction ability of BMP-2 without toxicity and anticoagulant activity and could contribute to clinical bone regeneration. PMID- 25810048 TI - Metabolites profiling of Chrysanthemum pacificum Nakai parts using UPLC-PDA-MS coupled to chemometrics. AB - Methanol-soluble constituents from the flowers, non-flowering aerial parts and roots of Chrysanthemum pacificum Nakai were analysed via high resolution UPLC-PDA qTOF-MS followed by chemometrics. Forty-seven chromatographic peaks belonging to various metabolite classes were detected. Most metabolite classes showed qualitative and quantitative differences across parts, with luteolin conjugates being mostly enriched in flowers whereas non-flowering aerial parts contained mostly quercetin and methoxylated flavone conjugates. Root sample ranked the lowest for all flavones and dicaffeoylquinic acids. In contrast, 1,5-di caffeoylquinic acid levels were found at high levels in flowers and aerial parts reaching 3145 and 1390 MUg/g, respectively, suggesting that C. pacificum could serve as a natural resource of this well-recognised anti-hepatotoxic phenolic. Principal component analysis was further used for organs classification in an untargeted manner. This study provides the first map of secondary metabolites distribution in C. pacificum Nakai organs. PMID- 25810053 TI - Integration and development in schizotypy research: an introduction to the special supplement. AB - In its fifth decade of existence, the construct of schizotypy is recapturing the early scientific interest it attracted when Paul E. Meehl (1920-2003), who coined the term, pioneered the field of schizotypy research. The International Lemanic Workshop on Schizotypy, hosted at the University of Geneva in December 2013, recently offered an opportunity to address some of the fundamental questions in contemporary schizotypy research and situate the construct in the greater scheme of future scientific projects on schizophrenia and psychological health research. What kind of knowledge has schizotypy research provided in furthering our understanding of schizophrenia? What types of questions can schizotypy research tackle, and which are the conceptual and methodological frameworks to address them? How will schizotypy research contribute to future scientific endeavors? The International Lemanic Workshop brought together leading experts in the field around the tasks of articulating the essential findings in schizotypy research, as well as providing some key insights and guidance to face scientific challenges of the future. The current supplement contains 8 position articles, 4 research articles, and 1 invited commentary that outline the state of the art in schizotypy research today. PMID- 25810054 TI - The assessment of schizotypy and its clinical relevance. AB - This article reviews several approaches to assessing schizotypal traits using a wide variety of self-report and interview measures. It makes a distinction between clinical approaches largely based on syndrome and symptom definitions, and psychometric approaches to measuring personality traits. The review presents a brief description of the content and psychometric properties of both sets of measures; these cover both the broad rubric of schizotypy often, but not exclusively based on DSM conceptions, as well as measures with a more specific focus. Measurement of schizotypy has taken place within clinical and nonclinical research utilizing a range of designs and methodologies. Several of these are elucidated with respect to the assessment choices open to researchers, and the implications of the measures chosen. These paradigms include the case-control study, "high risk"/"ultra-high risk" groups, a variety of nonclinical groups and other groups of interest, large scale epidemiology and "in vivo" designs. Evidence from a wide variety of designs continues to provide evidence of the validity of both clinical and personality approaches to schizotypal assessment. PMID- 25810055 TI - The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders. AB - Schizotypy provides a useful construct for understanding the development of schizophrenia spectrum disorders. As research on the epidemiology of psychotic symptoms and clinical risk for psychosis has expanded, conceptual challenges have emerged to comprehend the nature and borders of the space comprised between personality variation and psychosis. Schizotypy is considered in light of these more recent constructs. It is suggested that rather than being superseded by them due to their higher specificity and predictive power for transition to psychosis, schizotypy integrates them as it constitutes a dynamic continuum ranging from personality to psychosis. The advantages of schizotypy for studying schizophrenia etiology are discussed (eg, it facilitates a developmental approach and the identification of causal, resilience, and compensating factors and offers a multidimensional structure that captures etiological heterogeneity). An overview of putative genetic, biological, and psychosocial risk factors is presented, focusing on communalities and differences between schizotypy and schizophrenia spectrum disorders. The found notable overlap supports etiological continuity, and, simultaneously, differential findings appear that are critical to understanding resilience to schizophrenia. For example, discrepant findings in genetic studies might be interpreted as suggestive of sets of independent genetic factors playing a differential role in schizotypy and schizophrenia: some would influence variation specifically on schizotypy dimensions (ie, high vs low schizotypy, thereby increasing proneness to psychosis), some would confer unspecific liability to disease by impacting neural properties and susceptibility to environmental factors (ie, high vs low resilience to disorder) and some might contribute to disease-specific characteristics. Finally, schizotypy's promise for studying gene-environment interactions is considered. PMID- 25810058 TI - Schizotypy--do not worry, it is not all worrisome. AB - A long-standing tradition in personality research in psychology, and nowadays increasingly in psychiatry, is that psychotic and psychotic-like thoughts are considered common experiences in the general population. Given their widespread occurrence, such experiences cannot merely reflect pathological functioning. Moreover, reflecting the multi-dimensionality of schizotypy, some dimensions might be informative for healthy functioning while others less so. Here, we explored these possibilities by reviewing research that links schizotypy to favorable functioning such as subjective wellbeing, cognitive functioning (major focus on creativity), and personality correlates. This research highlights the existence of healthy people with psychotic-like traits who mainly experience positive schizotypy (but also affective features mapping onto bipolar disorder). These individuals seem to benefit from a healthy way to organize their thoughts and experiences, that is, they employ an adaptive cognitive framework to explain and integrate their unusual experiences. We conclude that, instead of focusing only on the pathological, future studies should explore the behavioral, genetic, imaging, and psychopharmacological correlates that define the healthy expression of psychotic-like traits. Such studies would inform on protective or compensatory mechanisms of psychosis-risk and could usefully inform us on the evolutionary advantages of the psychosis dimension. PMID- 25810059 TI - Dimensionality vs taxonicity of schizotypy: some new data and challenges ahead. AB - Heterogeneity in the expression of schizotypy may arise from underlying dimensional processes or a taxonic population structure. In a 2-phase study, we tested the taxonicity of self-reported schizotypy within a general psychiatric sample (n = 109) and examined taxon validity by testing its association with clinical schizotaxia in follow-up subsamples. Taxometric analyses indicated a taxonic structure (schizotypy prevalence = 38.8%) provided the best description of the underlying population distribution. After a year, schizotypal (n = 14) and nonschizotypal (n = 14) subsamples returned for diagnosis of clinical schizotaxia by assessment of executive functioning, attention, memory, and negative symptoms. Seven patients met diagnostic criteria, all members of the schizotypy class. Schizotypy was associated with impaired attention and memory, more negative symptoms, poorer global functioning, and more extensive psychiatric histories. We reconcile inconsistencies in the literature by discussing threats to the validity of this and similar research on Meehl's taxonomic model of schizotypy, including conceptual limitations of the lexical hypothesis and conventions of factor analysis. Scrutiny of Meehl's model should involve disambiguation and better measurement of the schizotaxia-schizotypy phenotype. PMID- 25810047 TI - Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. AB - INTRODUCTION: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. METHODS: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. RESULTS: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. CONCLUSIONS: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice. PMID- 25810057 TI - Schizotypy as an organizing framework for social and affective sciences. AB - Schizotypy, defined in terms of commonly occurring personality traits related to the schizophrenia spectrum, has been an important construct for understanding the neurodevelopment and stress-diathesis of schizophrenia. However, as schizotypy nears its sixth decade of application, it is important to acknowledge its impressively rich literature accumulating outside of schizophrenia research. In this article, we make the case that schizotypy has considerable potential as a conceptual framework for understanding individual differences in affective and social functions beyond those directly involved in schizophrenia spectrum pathology. This case is predicated on (a) a burgeoning literature noting anomalies in a wide range of social functioning, affiliative, positive and negative emotional, expressive, and social cognitive systems, (b) practical and methodological features associated with schizotypy research that help facilitate empirical investigation, and (c) close ties to theoretical constructs of central importance to affective and social science (eg, stress diathesis, neural compensation). We highlight recent schizotypy research, ie providing insight into the nature of affective and social systems more generally. This includes current efforts to clarify the neurodevelopmental, neurobiological, and psychological underpinnings of affiliative drives, hedonic capacity, social cognition, and stress responsivity systems. Additionally, we discuss neural compensatory and resilience factors that may mitigate the expression of stress-diathesis and functional outcome, and highlight schizotypy's potential role for understanding cultural determinants of social and affective functions. PMID- 25810061 TI - Thinking clearly about schizotypy: hewing to the schizophrenia liability core, considering interesting tangents, and avoiding conceptual quicksand. AB - The concept of schizotypy represents a rich and complex psychopathology construct. Furthermore, the construct implies a theoretical model that has considerable utility as an organizing framework for the study of schizophrenia, schizophrenia-related psychopathology (eg, delusional disorder, psychosis-NOS (not otherwise specified), schizotypal, and paranoid personality disorder), and putative schizophrenia endophenotypes as suggested by Rado, Meehl, Gottesman, Lenzenweger, and others. The understanding (and misunderstanding) of the schizophrenia-related schizotypy model, particularly as regards clinical illness, as well as an alternative approach to the construct require vigilance in order to ensure the methodological approach continues to yield the fruit that it can in illuminating the pathogenesis of schizophrenia-related psychopathology. The articles in the Special Section in this issue of Schizophrenia Bulletin highlight methodological and theoretical issues that should be examined carefully. PMID- 25810060 TI - Strange-face-in-the-mirror illusion and schizotypy during adolescence. AB - Patients with schizophrenia can sometimes report strange face illusions when staring at themselves in the mirror; such experiences have been conceptualized as anomalous self-experiences that can be experienced with a varying degree of depersonalization. During adolescence, anomalous self-experiences can also be indicative of increased risk to develop schizophrenia-spectrum disorders. To date however, the Mirror-Gazing test (MGT), an experimentally validated experiment to evaluate the propensity of strange face illusions in nonclinical and clinical adults, has yet to be investigated in an adolescent sample. The first goal of the present study was to examine experimentally induced self-face illusions in a nonclinical sample of adolescents, using the MGT. The second goal was to investigate whether dimensions of adolescent trait schizotypy were differentially related to phenomena arising during the MGT. One hundred and ten community adolescents (59 male) aged from 12 to 19 years (mean age = 16.31, SD age = 1.77) completed the MGT and Schizotypal Personality Questionnaire. The results yielded 4 types of strange face illusions; 2 types of illusions (slight change of light/color [20%] and own face deformation [45.5%]) lacked depersonalization-like phenomena (no identity change), while 2 other types (vision of other identity [27.3%], and vision of non-human identity [7.3%]) contained clear depersonalization-like phenomena. Furthermore, the disorganization dimension of schizotypy associated negatively with time of first illusion (first press), and positively with frequency of illusions during the MGT. Statistically significant differences on positive and disorganized schizotypy were found when comparing groups on the basis of degree of depersonalization-like phenomena (from slight color changes to non-human visions). Similarly to experimentally induced self face illusions in patients with schizophrenia, such illusions in a group of nonclinical adolescents present significant associations to schizotypy dimensions. PMID- 25810062 TI - Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis. AB - The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into beta state oligomers. Herein, we demonstrate that beta-state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP-induced neurotoxicity. We have characterized protein misfolding cyclic amplification induced monomer-to-oligomer conversion of PrP from three species using western blotting, circular dichroism, size-exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting beta oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3 in both wild-type and PrP( /-) cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain. We found that beta-state oligomeric PrPs can be generated through protein misfolding cyclic amplification (PMCA) from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP. beta-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, while the corresponding monomeric PrPs were not toxic. This toxicity is the result of oligomers-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3. These results may contribute to our understanding of prion transformation within the brain. PMID- 25810056 TI - Cognition and brain function in schizotypy: a selective review. AB - Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. While the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning, and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable interindividual differences that covary with performance on a wide range of perceptual, cognitive, and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterization of a personality constellation known to be associated with real life impairments, but also in generating hypotheses concerning the aetiology of schizophrenia. PMID- 25810063 TI - Preclinical Models for Translational Investigations of Left Ventricular Assist Device-Associated von Willebrand Factor Degradation. AB - Evidence suggests a major role for von Willebrand factor (vWF) in left ventricular assist device (LVAD)-associated bleeding. However, the mechanisms of vWF degradation during LVAD support are not well understood. We developed: (i) a simple and inexpensive vortexer model; and (ii) a translational LVAD mock circulatory loop to perform preclinical investigations of LVAD-associated vWF degradation. Whole blood was obtained from LVAD patients (n = 8) and normal humans (n = 15). Experimental groups included: (i) blood from continuous-flow LVAD patients (baseline vs. post-LVAD, n = 8); (ii) blood from normal humans (baseline vs. 4 h in vitro laboratory vortexer, ~ 2400 rpm, shear stress ~175 dyne/cm(2) , n = 8); and (iii) blood from normal humans (baseline vs. 12 h HeartMate II mock circulatory loop, 10 000 rpm, n = 7). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting. Blood from LVAD patients, blood exposed to in vitro supraphysiologic shear stress, and blood circulated through an LVAD mock circulatory loop demonstrated a similar profile of decreased large vWF multimers and increased vWF degradation fragments. A laboratory vortexer and an LVAD mock circulatory loop reproduced the pathologic degradation of vWF that occurs during LVAD support. Both models are appropriate for preclinical studies of LVAD-associated vWF degradation. PMID- 25810065 TI - Severity of obesity and management of hypertension, hypercholesterolaemia and smoking in primary care: population-based cohort study. AB - Obesity and obesity-associated cardiovascular risk are increasing worldwide. This study aimed to determine how different levels of obesity are associated with the management of smoking, hypertension and hypercholesterolaemia in primary care. We conducted a cohort study of adults aged 30-100 years in England, sampled from the primary care electronic health records in the Clinical Practice Research Datalink. Prevalence, treatment and control were estimated for each risk factor by body mass index (BMI) category. Adjusted odds ratios (AOR) were estimated, allowing for age, gender, comorbidity and socioeconomic status, with normal weight as reference category. Data were analysed for 247,653 patients including 153,308 (62%) with BMI recorded, of whom 46,149 (30%) were obese. Participants were classified into simple (29,257), severe (11,059) and morbid obesity (5833) categories. Smoking declined with the increasing BMI category, but smoking cessation treatment increased. Age-standardised hypertension prevalence was twice as high in morbid obesity (men 78.6%; women 66.0%) compared with normal weight (men 37.3%; women 29.4%). Hypertension treatment was more frequent (AOR 1.75, 1.59-1.92) but hypertension control less frequent (AOR 0.63, 0.59-0.69) in morbid obesity, with similar findings for severe obesity. Hypercholesterolaemia was more frequent in morbid obesity (men 48.2%; women 36.3%) than normal weight (men 25.0%; women 20.0%). Lipid lowering therapy was more frequent in morbid obesity (AOR 1.83, 1.61-2.07) as was cholesterol control (AOR 1.19, 1.06-1.34). Increasing obesity category is associated with elevated risks from hypertension and hypercholesterolaemia. Inadequate hypertension control in obesity emerges as an important target for future interventions. PMID- 25810064 TI - Vitamin D status, hypertension and ischemic stroke: a clinical perspective. AB - The relationship between vitamin D deficiency and stroke was cross-sectionally evaluated in the high-risk Asian Indian population. Age- and gender-matched, 239 ischemic stroke patients and 241 control subjects were recruited. Vitamin D status was estimated by measuring serum 25-hydroxyvitamin D (25(OH)D) levels. After multivariate adjustment for a range of potential covariates in a logistic regression model, an inverse association was found between serum 25(OH)D concentration and risk of ischemic stroke: subjects with severely low 25(OH)D levels (?9.33 ng ml(-1)) were found to be at 3.13-fold (95% confidence interval (CI), (1.22-8.07)) increased risk of ischemic stroke as compared with those with high levels. Adjustment for systolic blood pressure levels was found to abrogate this association (odds ratio (OR)=2.00, 95% CI=0.61-6.50). On stratification, a pronounced association was found between low 25(OH)D and risk of ischemic stroke in hypertensives, OR=13.54, 95% CI=1.94-94.43 as compared with no association in non-hypertensives, (Pinteraction=0.04). We conclude that high blood pressure partly explains the association between 25(OH)D levels and ischemic stroke. Presence of hypertension amply aggravates the risk of ischemic stroke associated with low vitamin D levels. Meticulous management of hypertension, regular monitoring of serum 25(OH)D levels and treatment of severe vitamin D deficiency, particularly in hypertensive subjects, could help in effective prevention of stroke. PMID- 25810066 TI - The role of sustained release isosorbide mononitrate on corticosteroid-induced hypertension in healthy human subjects. AB - There is evidence implicating abnormalities in the nitric oxide (NO) pathway in the development of glucocorticoid-induced hypertension (GC-HT). In humans, a reduction in NO availability during cortisol treatment has been observed. This study examined whether the NO donation may reverse the elevated blood pressure (BP) observed with cortisol treatment. A randomised double-blind, placebo controlled, crossover study was undertaken in eight healthy men to address the effect of co-administration of isosorbide mononitrate (ISMN, 60 mg single dose, day 5) with cortisol (200 mg per day, days 1-6) and then compared with placebo (single dose, day 5) with cortisol. After a 2-week washout period, subjects crossed over to the alternate treatment. BP measurements were obtained using a mercury sphygmomanometer. Tonometry was used to estimate central pressures. There was a significant rise in mean arterial pressure with cortisol: 80 +/- 3 vs 89 +/ 3 mm Hg (day 1 vs day 5, cortisol+ISMN phase, P < 0.001) and 81 +/- 3 vs 89 +/- 3 mm Hg (day 1 vs day 5, cortisol+placebo phase, P < 0.01). ISMN significantly decreased aortic augmentation index: -17.3 +/- 3.2 vs 1.8 +/- 3.5%, (differences calculated from day 5-day 1, cortisol/ISMN vs cortisol+placebo, P < 0.001). These results demonstrated that GC-HT can be modified by co-administration of exogenous NO donors, consistent with the hypothesis that GC-HT is accompanied by reduced NO activity in humans. PMID- 25810067 TI - Association of gene polymorphisms in RANKL/RANK/OPG system with hypertension and blood pressure in Chinese women. AB - Recent studies have revealed that the receptor activator of nuclear factor-kappa B ligand/RANK/osteoprotegerin (RANKL/RANK/OPG) system has an important role in vascular calcification, which is contributory to various cardiovascular diseases and intimately linked to the regulation of blood pressure. Therefore, we performed a case-control study to investigate the associations of 21 single nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A and TNFRSF11B genes in the RANKL/RANK/OPG system with hypertension and blood pressure in post-menopausal Chinese women. In this study, 503 hypertensive patients and 509 normal controls were recruited. Genotyping was performed using the high-throughput Sequenom genotyping platform. The results showed that two SNPs (rs6567270 and rs4603673) in the TNFRSF11A were associated with hypertension (P=0.010 and P=0.013, respectively) and systolic blood pressure (P=0.024 and P=0.023, respectively). One SNP (rs9646629) in the TNFRSF11A showed significant association with diastolic blood pressure (P=0.031). The results of this study suggest that TNFRSF11A but not TNFSF11 and TNFRSF11B genetic variation is associated with hypertension and blood pressure in Chinese women. The findings provide additional support for the genetic role of RANKL/RANK/OPG system in hypertension and blood pressure regulation. PMID- 25810068 TI - Pulse pressure is not an independent predictor of outcome in type 2 diabetes patients with chronic kidney disease and anemia--the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT). AB - Pulse pressure (PP) remains an elusive cardiovascular risk factor with inconsistent findings. We clarified the prognostic value in patients with type 2 diabetes, chronic kidney disease (CKD) and anemia in the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin alfa) Therapy. In 4038 type 2 diabetes patients, darbepoetin alfa treatment did not affect the primary outcome. Risk related to PP at randomization was evaluated in a multivariable model including age, gender, kidney function, cardiovascular disease (CVD) and other conventional risk factors. End points were myocardial infarction (MI), stroke, end stage renal disease (ESRD) and the composite of cardiovascular death, MI or hospitalization for myocardial ischemia, heart failure or stroke (CVD composite). Median (interquartile range) age, gender, eGFR and PP was 68 (60-75) years, 57.3% women, 33 (27-42) ml min(-1) per 1.73 m2 and 60 (50-74) mm Hg. During 29.1 months (median) follow-up, the number of events for composite CVD, MI, stroke and ESRD was 1010, 253, 154 and 668. In unadjusted analyses, higher quartiles of PP were associated with higher rates per 100 years of follow-up of all end points (P?0.04), except stroke (P=0.52). Adjusted hazard ratios (95% confidence interval) per one quartile increase in PP were 1.06 (0.99-1.26) for MI, 0.96 (0.83-1.11) for stroke, 1.01 (0.94-1.09) for ESRD and 1.01 (0.96-1.07) for CVD composite. Results were similar in continuous analyses of PP (per 10 mm Hg). In patients with type 2 diabetes, CKD and anemia, PP did not independently predict cardiovascular events or ESRD. This may reflect confounding by aggressive antihypertensive treatment, or PP may be too rough a risk marker in these high risk patients. PMID- 25810071 TI - Binding characteristics and protective capacity of cyanidin-3-glucoside and its aglycon to calf thymus DNA. AB - The binding characteristics and protective capacity of cyanidin (Cy) and cyanidin 3-glucoside (C3G) to calf thymus DNA were explored for the first time. The Cy and C3G gave a bathochromic shift to the ultraviolet-visible spectra of the DNA, indicating the formation of the DNA-Cy and DNA-C3G complexes. The complexes were formed by an intercalative binding mode based on the results of the fluorescence spectra and competitive binding analysis. Meanwhile, the Cy and C3G protected the DNA from the damage induced by the hydroxyl radical. The binding capacity and protective capacity of the C3G were stronger than that of the Cy. Furthermore, the formation of the DNA-anthocyanin complexes was spontaneous when the hydrogen bond and hydrophobic force played a key role. Hence, the Cy and C3G could protect the DNA automatically from the damage induced by the hydroxyl radical. PMID- 25810069 TI - In silico system analysis of physiological traits determining grain yield and protein concentration for wheat as influenced by climate and crop management. AB - Genetic improvement of grain yield (GY) and grain protein concentration (GPC) is impeded by large genotype*environment*management interactions and by compensatory effects between traits. Here global uncertainty and sensitivity analyses of the process-based wheat model SiriusQuality2 were conducted with the aim of identifying candidate traits to increase GY and GPC. Three contrasted European sites were selected and simulations were performed using long-term weather data and two nitrogen (N) treatments in order to quantify the effect of parameter uncertainty on GY and GPC under variable environments. The overall influence of all 75 plant parameters of SiriusQuality2 was first analysed using the Morris method. Forty-one influential parameters were identified and their individual (first-order) and total effects on the model outputs were investigated using the extended Fourier amplitude sensitivity test. The overall effect of the parameters was dominated by their interactions with other parameters. Under high N supply, a few influential parameters with respect to GY were identified (e.g. radiation use efficiency, potential duration of grain filling, and phyllochron). However, under low N, >10 parameters showed similar effects on GY and GPC. All parameters had opposite effects on GY and GPC, but leaf and stem N storage capacity appeared as good candidate traits to change the intercept of the negative relationship between GY and GPC. This study provides a system analysis of traits determining GY and GPC under variable environments and delivers valuable information to prioritize model development and experimental work. PMID- 25810072 TI - Prevalence and etiology of epilepsy in a Norwegian county-A population based study. AB - OBJECTIVE: Epilepsy represents a substantial personal and social burden worldwide. When addressing the multifaceted issues of epilepsy care, updated epidemiologic studies using recent guidelines are essential. The aim of this study was to find the prevalence and causes of epilepsy in a representative Norwegian county, implementing the new guidelines and terminology suggested by the International League Against Epilepsy (ILAE). METHODS: Included in the study were all patients from Buskerud County in Norway with a diagnosis of epilepsy at Drammen Hospital and the National Center for Epilepsy at Oslo University Hospital. The study period was 1999-2014. Patients with active epilepsy were identified through a systematic review of medical records, containing information about case history, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), genetic tests, blood samples, treatment, and other investigations. Epilepsies were classified according to the revised terminology suggested by the ILAE in 2010. RESULTS: In a population of 272,228 inhabitants, 1,771 persons had active epilepsy. Point prevalence on January 1, 2014 was 0.65%. Of the subjects registered with a diagnostic code of epilepsy, 20% did not fulfill the ILAE criteria of the diagnosis. Epilepsy etiology was structural-metabolic in 43%, genetic/presumed genetic in 20%, and unknown in 32%. Due to lack of information, etiology could not be determined in 4%. SIGNIFICANCE: Epilepsy is a common disorder, affecting 0.65% of the subjects in this cohort. Every fifth subject registered with a diagnosis of epilepsy was misdiagnosed. In those with a reliable epilepsy diagnosis, every third patient had an unknown etiology. Future advances in genetic research will probably lead to an increased identification of genetic and hopefully treatable causes of epilepsy. PMID- 25810073 TI - Investigating secondary-distinctiveness-based effects in aging and Alzheimer's disease patients. AB - The aim of the present study was 2-fold. First, two experiments were devised to further investigate secondary distinctiveness-based effects in relation to aging. By using a repeated study-test procedure, it aimed at restoring the bizarreness effect (Experiment 1) or at amplifying the orthographic distinctiveness (OD) effect in older adults (Experiment 2). Second, by including Alzheimer's disease patients (AD patients) in both experiments, it also aimed at instigating research on secondary distinctiveness-based effects in relation to Alzheimer disease. The results of Experiment 1 revealed that a repeated study-test procedure may to some extent facilitate the free recalling of bizarre images in older adults. However, the benefit of such procedure does not seem to be durable in older adults (no bizarreness effect for the last study-test cycle) and is inefficient in AD patients. Surprisingly, for both older adults and AD patients, results of Experiment 2 revealed a similar OD effect across all study-test cycles. The findings of both experiments were related to previous work suggesting that the bizarreness effect and the OD effect are mediated by different processing. PMID- 25810074 TI - Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. AB - Population structure inference with genetic data has been motivated by a variety of applications in population genetics and genetic association studies. Several approaches have been proposed for the identification of genetic ancestry differences in samples where study participants are assumed to be unrelated, including principal components analysis (PCA), multidimensional scaling (MDS), and model-based methods for proportional ancestry estimation. Many genetic studies, however, include individuals with some degree of relatedness, and existing methods for inferring genetic ancestry fail in related samples. We present a method, PC-AiR, for robust population structure inference in the presence of known or cryptic relatedness. PC-AiR utilizes genome-screen data and an efficient algorithm to identify a diverse subset of unrelated individuals that is representative of all ancestries in the sample. The PC-AiR method directly performs PCA on the identified ancestry representative subset and then predicts components of variation for all remaining individuals based on genetic similarities. In simulation studies and in applications to real data from Phase III of the HapMap Project, we demonstrate that PC-AiR provides a substantial improvement over existing approaches for population structure inference in related samples. We also demonstrate significant efficiency gains, where a single axis of variation from PC-AiR provides better prediction of ancestry in a variety of structure settings than using 10 (or more) components of variation from widely used PCA and MDS approaches. Finally, we illustrate that PC-AiR can provide improved population stratification correction over existing methods in genetic association studies with population structure and relatedness. PMID- 25810075 TI - Formation of a(1) ions directly from oxazolone b(2) ions: an energy-resolved and computational study. AB - It is well-known that oxazolone b2 ions fragment extensively by elimination of CO to form a2 ions, which often fragment further to form a1 ions. Less well-known is that some oxazolone b2 ions may fragment directly to form a1 ions. The present study uses energy-resolved collision-induced dissociation experiments to explore the occurrence of the direct b2->a1 fragmentation reaction. The experimental results show that the direct b2->a1 reaction is generally observed when Gly is the C-terminal residue of the oxazolone. When the C-terminal residue is more complex, it is able to provide increased stability of the a2 product in the b2 >a2 fragmentation pathway. Our computational studies of the relative critical reaction energies for the b2->a2 reaction compared with those for the b2->a1 reaction provide support that the critical reaction energies are similar for the two pathways when the C-terminal residue of the oxazolone is Gly. By contrast, when the nitrogen of the oxazolone ring in the b2 ion does not bear a hydrogen, as in the Ala-Sar and Tyr-Sar (Sar = N-methylglycine) oxazolone b2 ions, a1 ions are not formed but rather neutral imine elimination from the N-terminus of the b2 ion becomes a dominant fragmentation reaction. The M06-2X/6-31+G(d,p) density functional theory calculations are in general agreement with the experimental data for both types of reaction. In contrast, the B3LYP/6-31+G(d,p) model systematically underestimates the barriers of these SN2-like b2->a1 reaction. The difference between the two methods of barrier calculation are highly significant (P < 0.001) for the b2->a1 reaction, but only marginally significant (P = 0.05) for the b2->a2 reaction. The computations provide further evidence of the limitations of the B3LYP functional when describing SN2-like reactions. PMID- 25810077 TI - Sex differences in kin bias at maturation: Male rhesus macaques prefer paternal kin prior to natal dispersal. AB - Dispersal and mating patterns are known to affect the availability of both maternal and paternal kin within social groups, with important effects on the evolution of sociality. It is generally assumed that the philopatric sex forms stronger social bonds than the dispersing sex, possibly as a result of reduced kin availability for the dispersing sex after departure. However, few primate studies have directly compared whether sex differences in association patterns, particular with kin, are already present prior to dispersal when kin availability should be the same for both sexes. Here, we compared affiliative and aggressive interactions in a female philopatric species, the rhesus macaque (Macaca mulatta), to test whether sex differences in kin bias already occur around the age of maturation, when both sexes still live together with kin in their natal group. Our data confirmed that kin availability was the same for both sexes prior to male dispersal. Similar kin availability was partially reflected by comparable association patterns, as both females and males preferentially interacted with maternal kin. However, females had stronger affiliative bonds with maternal kin than males of the same age, indicating that kin associations not only depended upon kin availability, but were also sex-specific. Similarly, males were significantly more likely to affiliate with paternal kin than non-kin, as compared to females, suggesting that males discriminated paternal kin from non kin earlier in life than females. Males might have a stronger need than females to affiliate with paternal kin due to a reduced integration in the matrilineal family prior to dispersal and the high availability of paternally related age peers, with whom males could potentially migrate. Females, in contrast, form stronger affiliations with maternal kin, which may enhance their offspring's survival. More comparative studies are needed to understand the impact of different dispersal regimes on patterns of kin associations. PMID- 25810076 TI - The modulation of nicotinic acetylcholine receptors on the neuronal network oscillations in rat hippocampal CA3 area. AB - gamma oscillations are associated with higher brain functions such as memory, perception and consciousness. Disruption of gamma oscillations occur in various neuro-psychological disorders such as schizophrenia. Nicotinic acetylcholine receptors (nAChR) are highly expressed in the hippocampus, however, little is known about the role on hippocampal persistent gamma oscillation. This study examined the effects of nicotine and selective nAChR agonists and antagonists on kainate-induced persistent gamma oscillation in rat hippocampal slices. Nicotine enhanced gamma oscillation at concentrations of 0.1-10 MUM, but reduced it at a higher concentration of 100 MUM. The enhancement on gamma oscillation can be best mimicked by co-application of alpha4beta2- and alpha7-nAChR agonist and reduced by a combination of nAChR antagonists, DhbetaE and MLA. However, these nAChR antagonists failed to block the suppressing role of nicotine on gamma. Furthermore, we found that the NMDA receptor antagonist D-AP5 completely blocked the effect of nicotine. These results demonstrate that nicotine modulates gamma oscillations via alpha7 and alpha4beta2 nAChR as well as NMDA activation, suggesting that nAChR activation may have a therapeutic role for the clinical disorder such as schizophrenia, which is known to have impaired gamma oscillation and hypo-NMDA receptor function. PMID- 25810082 TI - Contemporary approaches to sarcoma. PMID- 25810078 TI - The repressor Rgt1 and the cAMP-dependent protein kinases control the expression of the SUC2 gene in Saccharomyces cerevisiae. AB - BACKGROUND: A low level of glucose is required for maximal transcription of the SUC2 gene in Saccharomyces cerevisiae. Although the repressor Rgt1 binds the SUC2 promoter in gel-shift assays, it has been reported that Rgt1 has only minimal effects on SUC2 expression. Rgt1 acts together with Mth1 to repress the HXT genes encoding glucose transporters, and the release of Rgt1 from some HXT promoters requires cAMP-dependent protein kinase (PKA) activity. METHODS: The genes RGT1 and MTH1 have been disrupted and the SUC2 promoter modified in several S. cerevisiae backgrounds. Yeast cells were grown in different carbon sources in the presence or absence of 0.1 or 2% glucose, and invertase was assayed in whole cells. RESULTS: Galactose, glycerol or ethanol hindered invertase induction by low glucose, but lactate did not. During growth in lactate, deletion of RGT1 or MTH1 caused a marked increase in invertase levels, and elimination of the Rgt1 binding site in the SUC2 promoter caused also invertase induction. PKA activity decreased invertase levels in cells growing in lactate, and increased them during growth in lactate+0.1% glucose. CONCLUSIONS: The low level of expression of SUC2 in the absence of glucose is mainly due to repression by the Rgt1-Mth1 complex. Repression is dependent on PKA activity, but not on any specific Tpk isoenzyme. GENERAL SIGNIFICANCE: The results show that previously overlooked regulatory elements, such as Rgt1 and Tpks, participate in the control of SUC2 expression in S.cerevisiae. PMID- 25810080 TI - Diode laser assisted minimal invasive sphenoidotomy for endoscopic transphenoidal pituitary surgery: our technique and results. AB - BACKGROUND AND OBJECTIVE: During endoscopic sinus surgery (ESS), intra-operative bleeding can significantly compromise visualization of the surgical field. The diode laser that provides good hemostatic and vaporization effects and excellent photocoagulation has been successfully applied in endoscopic surgery with several advantages. The current retrospective study demonstrates the feasibility of diode laser-combined endoscopic sinus surgery on sphenoidotomy. STUDY DESIGN/MATERIALS AND METHODS: The patients who went through endoscopic transphenoidal pituitary surgery were enrolled. During the operation, the quality of the surgical field was assessed and graded by the operating surgeon using the scale proposed by Boezaart. RESULTS: The mean operation time was 37.80 +/- 10.90 minutes. The mean score on the quality of surgical field was 1.95. A positive correlation between the lower surgical field quality score and the shorter surgical time was found with statistical significance (P < 0.0001). No infections, hemorrhages, or other complications occurred intra- or post-operatively. CONCLUSION: The diode laser assisted sphenoidotomy is a reliable and safe approach of pituitary gland surgery with minimal invasiveness. It is found that application of diode laser significantly improved quality of surgical field and shortened operation time. PMID- 25810083 TI - Ratosa playa lake in southern Spain. Karst pan or compound sink? AB - In Andalusia (Spain), there are more than 45 semiarid playa lakes protected as natural reserves and related to karstic outcrops. Some of them are located over regional karstic aquifers and have internal drainage networks with sporadic surface outlets, such as sinkholes (compound sinks), but the majority of such playas have no internal drainage systems, so the only water output is evaporation (karst pans). Karst pans are perched and disconnected from the groundwater system. The fact that the Ratosa playa lake is partially located over a karstic Sierra, as well as other hydromorphological observations, it is suggested that the system could be of a compound type, but a detailed hydrogeological analysis showed that the playa is disconnected from the aquifer, so it is in fact a karst pan. Once the hydrological functioning had been established, a monthly water balance for a 10-year period (1998-2008), enabled us to reproduce the evolution of the water level of the playa lake. Estimations of runoff were carried out by a soil water estimate for a water holding capacity in the soil of 191 mm. Results show a good correlation (>90%) after calibration with the time series of water level in the lake for the same period confirming geological observations. Our results highlight that this water body is extremely vulnerable to hydrological alterations of its watershed caused by human activities, particularly those related to land-use change for agriculture. For this reason, we propose a new protection zone, based on hydrological knowledge, instead of the present Peripheral Area of Protection. PMID- 25810084 TI - How climate change might influence the potential distribution of weed, bushmint (Hyptis suaveolens)? AB - Invasive species and climate change are considered as the most serious global environmental threats. In this study, we investigated the influence of projected global climate change on the potential distribution of one of the world's most successful invader weed, bushmint (Hyptis suaveolens (L.) Poit.). We used spatial data on 20 environmental variables at a grid resolution of 5 km, and 564 presence records of bushmint from its native and introduced range. The climatic profiles of the native and invaded sites were analyzed in a multi-variate space in order to examine the differences in the position of climatic niches. Maximum Entropy (MaxEnt) model was used to predict the potential distribution of bushmint using presence records from entire range (invaded and native) along with 14 eco physiologically relevant predictor variables. Subsequently, the trained MaxEnt model was fed with Hadley Centre Coupled Model (HadCM3) climate projections to predict potential distribution of bushmint by the year 2050 under A2a and B2a emission scenarios. MaxEnt predictions were very accurate with an Area Under Curve (AUC) value of 0.95. The results of Principal Component Analysis (PCA) indicated that climatic niche of bushmint on the invaded sites is not entirely similar to its climatic niche in the native range. A vast area spread between 34 degrees 02' north and 28 degrees 18' south latitudes in tropics was predicted climatically suitable for bushmint. West and middle Africa, tropical southeast Asia, and northern Australia were predicted at high invasion risk. Study indicates enlargement, retreat, or shift across bushmint's invasion range under the influence of climate change. Globally, bushmint's potential distribution might shrink in future with more shrinkage for A2a scenario than B2a. The study outcome has immense potential for undertaking effective preventive/control measures and long-term management strategies for regions/countries, which are at higher risk of bushmint's invasion. PMID- 25810085 TI - Fast scanning of illegal oil discharges for forensic identification: a case study of Turkish coasts. AB - Increasing marine traffic, over 55,000 ships visit per year, through the Turkish Straits System and the Sea of Marmara, produces a yearly average of 12 illegal oil discharges. This paper documents the comparison of chemical fingerprints of spilled oil with suspected sources of oils for identifying the source of illegal pollution in Turkey's seas. Fingerprinting is initiated by comparison of the synchronous fluorescence spectra (Delta=20 or 15 nm) of fugitive and suspected source oils. Potential matches of the spectra/chromatogram are confirmed or rejected by subsequent comparison of Fourier transform infrared spectrometry (FTIR), high-pressure liquid chromatography (HPLC) and gas chromatography with a flame ionisation detector (GC-FID) analysis results. In this study, 39 clean sea waters, 41 polluted sea waters and 111 suspected samples were analysed. According to the comparison of the suspected source sample and polluted sea water sample spectra by using spectrofluorometric analysis, 76 suspected source samples were categorised as non-match whilst 35 suspected samples were classified as match or probable match. Then, match and probable match samples were analysed by using further selected chromatographic methods. Finally, 28 suspected source samples were confirmed as a match, enabling legal proceedings to be initiated. PMID- 25810087 TI - Complete form of pachydermoperiostosis with SLCO2A1 gene mutation in a Korean family. PMID- 25810086 TI - Nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients. AB - BACKGROUND: While several analgesia and sedation guidelines and protocols have been developed and implemented for adults, there is still little evidence of clinical use of analgesia and sedation protocols and the impact on withdrawal symptoms in critically ill children. OBJECTIVE: The aim of this study was to evaluate the effects of a nurse-driven goal-directed analgesia and sedation protocol for mechanically ventilated pediatric patients (pASP) on duration of mechanical ventilation, pediatric intensive care unit (PICU) length of stay, total doses of opioids and benzodiazepines, and occurrence of withdrawal symptoms. PATIENTS AND METHODS: This is a before and after protocol implementation study in a 14-bed medical-surgical-cardiac pediatric intensive care unit at a university children's hospital. A total of 337 medical pediatric patients requiring mechanical ventilation with PICU length of stay for at least 24 h were included. Prior to implementation of the protocol, analgesia and sedation was managed by the attending physician's order. Afterwards, postimplementation, nurses managed analgesia and sedation following a pASP, including COMFORT 'behavioral' Scale, Nurse Interpretation Sedation Scale, and Sophia Observation Withdrawal Symptoms Scale. RESULTS: One hundred and sixty-five patients were included in the 15-month period before and 172 patients were included in the 15-month period after implementation of the pASP. Median duration of mechanical ventilation was 2.02 (0.96-25.0) days in the group preceding protocol implementation and 1.71 (0.96-66.0) days afterwards (P = 0.23). Median PICU length of stay was 5.8 (1-37.75) days in the preimplementation and 5.0 (1 120) days in the postimplementation group (P = 0.14). Total doses of opioids and benzodiazepines were 3.9 mg.kg(-1) .day(-1) (0.1-70) vs 3.1 mg.kg(-1) .day(-1) (0.05-56); P = 0.38 and 5.9 mg.kg(-1) .day(-1) (0-82.0) vs 4.2 mg.kg(-1) .day(-1) (0-66); P = 0.009 after implementation. Incidence of withdrawal was significantly lower over the postimplementation period (12.8% vs 23.6%; P = 0.005). CONCLUSION: Implementation of a nurse-driven pASP reduced the total dose of benzodiazepines and the occurrence of withdrawal symptoms significantly. PMID- 25810088 TI - Effects of Antitumor Drug Sorafenib on Chick Embryo Development. AB - Sorafenib has been used as an oral anti-cancer drug because of its ability to inhibit tumor growth. However, the pharmacological effect of sorafenib is still the lack of in vivo experimental evidence. Tumor and embryonic cells share some similar features, so we investigated the effects of sorafenib on the development of gastrulating chick embryos. We found that sorafenib exposure was markedly attributed to the number of embryonic cell in proliferation and apoptosis. We also detected sorafenib significantly interfered with epithelial-mesenchymal transition (EMT). Furthermore, sorafenib treatment impaired the production and migration of neural crest cells. PMID- 25810089 TI - 5,5'-Methylenedisalicylic Acid (MDSA) Modulates SarA/MgrA Phosphorylation by Targeting Ser/Thr Phosphatase Stp1. AB - SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC50 =9.68 +/- 0.52 MUM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1. PMID- 25810091 TI - Examining the Correlates of Women's Use of Sexual Coercion: Proposing an Explanatory Model. AB - Research in the last few years has begun to examine the prevalence of female sexual offending as well as attempting to understand the predictors of sexually coercive behavior among women. Although women engage in sexual coercion significantly less often than men, more research on female sexual coercion is warranted. The current study provides an exploratory examination of the relationship between several attitudinal, experiential, and situational factors, and the use of various sexual coercion tactics among a sample of 582 sexually active, female undergraduate students, as well as proposing an explanatory model of female sexual coercion. Results indicate that several variables that are significant predictors of sexual aggression for men are also predictive for women. However, these variables seem to work differently in predicting sexually coercive behavior for women. Implications for theory and further study are discussed. PMID- 25810092 TI - Exposure to Spousal Violence in the Family, Attitudes and Dating Violence Perpetration Among High School Students in Port-au-Prince. AB - This study examined the associations of exposure to spousal violence in the family and personal and peer attitudes with dating violence (DV) perpetration among high school students in Port-au-Prince, Haiti. Participants were 342 high school students in Grades 10 to 12 who stated that they had ever been on a date. Multiple linear regression methods were used to examine correlates of the scale of DV perpetration. Findings showed that personal acceptance of DV mediated the association between exposure to wife-perpetrated and husband-perpetrated spousal violence in the family and DV perpetration for girls. Boys who were exposed to husband-perpetrated spousal violence in the family had significantly higher levels of psychological DV perpetration than those who were not. Contrary to expectations, exposure to wife-perpetrated spousal violence in the family was negatively associated with psychological and physical/sexual DV perpetration by boys, after controlling for other factors. Overall, perceived peer tolerance of DV was more strongly associated with DV perpetration than personal tolerance of DV, and was the only significant correlate of psychological DV perpetration for girls. Perceived peer attitudes also moderated the association between boys' exposure to spousal violence in the family and DV perpetration. Implications for future research and policy are discussed. PMID- 25810090 TI - prdm1a functions upstream of itga5 in zebrafish craniofacial development. AB - Cranial neural crest cells are specified and migrate into the pharyngeal arches where they subsequently interact with the surrounding environment. Signaling and transcription factors, such as prdm1a regulate this interaction, but it remains unclear which specific factors are required for posterior pharyngeal arch development. Previous analysis suggests that prdm1a is required for posterior ceratobranchial cartilages in zebrafish and microarray analysis between wildtype and prdm1a mutants at 25 h post fertilization demonstrated that integrin alpha5 (itga5) is differentially expressed in prdm1a mutants. Here, we further investigate the interaction between prdm1a and itga5 in zebrafish craniofacial development. In situ hybridization for itga5 demonstrates that expression of itga5 is decreased in prdm1a mutants between 18 and 31 h post fertilization and itga5 expression overlaps with prdm1a in the posterior arches, suggesting a temporal window for interaction. Double mutants for prdm1a;itga5 have an additive viscerocranium phenotype more similar to prdm1a mutants, suggesting that prdm1a acts upstream of itga5. Consistent with this, loss of posterior pharyngeal arch expression of dlx2a, ceratobranchial cartilages 2-5, and cell proliferation in prdm1a mutants can be rescued with itga5 mRNA injection. Taken together, these data suggest that prdm1a acts upstream of itga5 and are both necessary for posterior pharyngeal arch development in zebrafish. PMID- 25810093 TI - Parental age affects somatic mutation rates in the progeny of flowering plants. AB - In humans, it is well known that the parental reproductive age has a strong influence on mutations transmitted to their progeny. Meiotic nondisjunction is known to increase in older mothers, and base substitutions tend to go up with paternal reproductive age. Hence, it is clear that the germinal mutation rates are a function of both maternal and paternal ages in humans. In contrast, it is unknown whether the parental reproductive age has an effect on somatic mutation rates in the progeny, because these are rare and difficult to detect. To address this question, we took advantage of the plant model system Arabidopsis (Arabidopsis thaliana), where mutation detector lines allow for an easy quantitation of somatic mutations, to test the effect of parental age on somatic mutation rates in the progeny. Although we found no significant effect of parental age on base substitutions, we found that frameshift mutations and transposition events increased in the progeny of older parents, an effect that is stronger through the maternal line. In contrast, intrachromosomal recombination events in the progeny decrease with the age of the parents in a parent-of-origin dependent manner. Our results clearly show that parental reproductive age affects somatic mutation rates in the progeny and, thus, that some form of age-dependent information, which affects the frequency of double-strand breaks and possibly other processes involved in maintaining genome integrity, is transmitted through the gametes. PMID- 25810094 TI - Interaction between glucose and brassinosteroid during the regulation of lateral root development in Arabidopsis. AB - Glucose (Glc) plays a fundamental role in regulating lateral root (LR) development as well as LR emergence. In this study, we show that brassinosteroid (BR) signaling works downstream of Glc in controlling LR production/emergence in Arabidopsis (Arabidopsis thaliana) seedlings. Glc and BR can promote LR emergence at lower concentrations, while at higher concentrations, both have an inhibitory effect. The BR biosynthesis and perception mutants showed highly reduced numbers of emerged LRs at all the Glc concentrations tested. BR signaling works downstream of Glc signaling in regulating LR production, as in the glucose insensitive2-1brassinosteroid insensitive1 double mutant, Glc-induced LR production/emergence was severely reduced. Differential auxin distribution via the influx carriers AUXIN RESISTANT1/LIKE AUXIN RESISTANT1-3 and the efflux carrier PIN-FORMED2 plays a central role in controlling LR production in response to Glc and BR. Auxin signaling components AUXIN RESISTANT2,3 and SOLITARY ROOT act downstream of Glc and BR. AUXIN RESPONSE FACTOR7/19 work farther downstream and control LR production by regulating the expression of LATERAL ORGAN BOUNDARIES-DOMAIN29 and EXPANSIN17 genes. Increasing light flux could also mimic the Glc effect on LR production/emergence. However, increased light flux could not affect LR production in those BR and auxin signaling mutants that were defective for Glc-induced LR production. Altogether, our study suggests that, under natural environmental conditions, modulation of endogenous sugar levels can manipulate root architecture for optimized development by altering its nutrient/water uptake as well as its anchorage capacity. PMID- 25810098 TI - The postdisaster prevalence of major depression relative to PTSD in survivors of the 9/11 attacks on the World Trade Center selected from affected workplaces. AB - BACKGROUND: Studies of survivors of the September 11, 2001 attacks on the World Trade Center in New York City suggest that postdisaster depressive disorders may be at least as prevalent, or even more prevalent, than posttraumatic stress disorder (PTSD), unlike findings from most other disaster studies. The relative prevalence and incidence of major depressive disorder (MDD) and PTSD were examined after the 9/11 attacks relative to trauma exposures. METHODS: This study used full diagnostic assessment methods and careful categorization of exposure groups based on DSM-IV-TR criteria for PTSD to examine 373 employees of 9/11 affected New York City workplaces. RESULTS: Postdisaster new MDD episode (26%) in the entire sample was significantly more prevalent (p<.001) than 9/11-related PTSD (14%). Limiting the comparison to participants with 9/11 trauma exposures, the prevalence of postdisaster new MDD episode and 9/11-related PTSD did not differ (p=.446). The only 9/11 trauma exposure group with a significant difference in relative prevalence of MDD and PTSD were those with a 9/11 trauma exposed close associate, for whom postdisaster new MDD episode (45%) was more prevalent (p=.046) than 9/11-related PTSD (31%). CONCLUSIONS: Because of the conditional definition of PTSD requiring trauma exposure that is not part of MDD criteria, prevalence comparisons of these two disorders must be limited to groups with qualifying trauma exposures to be meaningful. Findings from this study suggest distinct mechanisms underlying these two disorders that differentially relate to direct exposure to trauma vs. the magnitude of the disaster and personal connectedness to disaster and community-wide effects. PMID- 25810099 TI - Cytopathologists can reliably perform ultrasound-guided thyroid fine needle aspiration: a 1-year audit on 3715 consecutive cases. AB - OBJECTIVE: In our Pathology Department, fine needle aspiration (FNA) of palpable thyroid nodules is performed by cytopathologists who ensure correct sample management and rapid on-site evaluation (ROSE). Conversely, ultrasound (US) guided FNAs have traditionally been carried out by endocrinologists and radiologists in outside clinics, where the presence of a cytopathologist is not always feasible. To overcome this limitation, cytopathologists have started to perform US-guided FNAs themselves. This study retrospectively evaluates 1 year of this novel practice. METHODS: A total of 2225 US-guided FNAs were performed in our clinic by cytopathologists, whereas 1490 aspirates were taken by a group of non-cytopathologists. Among these, 756 FNAs were taken by a single experienced endocrinologist. The distribution of the Bethesda classification categories was evaluated in each of these groups. RESULTS: FNAs performed by cytopathologists were more often diagnostic and better prepared than those taken by non cytopathologists, including those taken by the experienced endocrinologist (P < 0.01). The latter operator yielded a higher rate of suspicious and malignant FNAs, reflecting a more appropriate clinical triage of worrisome nodules. CONCLUSION: Although the endocrinologist's evaluation is crucial to select clinically relevant thyroid nodules, cytopathologists can reliably perform US guidance in addition to their traditional expertise in sampling, specimen preparation and ROSE. PMID- 25810096 TI - Quantifying protein synthesis and degradation in Arabidopsis by dynamic 13CO2 labeling and analysis of enrichment in individual amino acids in their free pools and in protein. AB - Protein synthesis and degradation represent substantial costs during plant growth. To obtain a quantitative measure of the rate of protein synthesis and degradation, we supplied (13)CO2 to intact Arabidopsis (Arabidopsis thaliana) Columbia-0 plants and analyzed enrichment in free amino acids and in amino acid residues in protein during a 24-h pulse and 4-d chase. While many free amino acids labeled slowly and incompletely, alanine showed a rapid rise in enrichment in the pulse and a decrease in the chase. Enrichment in free alanine was used to correct enrichment in alanine residues in protein and calculate the rate of protein synthesis. The latter was compared with the relative growth rate to estimate the rate of protein degradation. The relative growth rate was estimated from sequential determination of fresh weight, sequential images of rosette area, and labeling of glucose in the cell wall. In an 8-h photoperiod, protein synthesis and cell wall synthesis were 3-fold faster in the day than at night, protein degradation was slow (3%-4% d(-1)), and flux to growth and degradation resulted in a protein half-life of 3.5 d. In the starchless phosphoglucomutase mutant at night, protein synthesis was further decreased and protein degradation increased, while cell wall synthesis was totally inhibited, quantitatively accounting for the inhibition of growth in this mutant. We also investigated the rates of protein synthesis and degradation during leaf development, during growth at high temperature, and compared synthesis rates of Rubisco large and small subunits of in the light and dark. PMID- 25810095 TI - The conserved endoribonuclease YbeY is required for chloroplast ribosomal RNA processing in Arabidopsis. AB - Maturation of chloroplast ribosomal RNAs (rRNAs) comprises several endoribonucleolytic and exoribonucleolytic processing steps. However, little is known about the specific enzymes involved and the cleavage steps they catalyze. Here, we report the functional characterization of the single Arabidopsis (Arabidopsis thaliana) gene encoding a putative YbeY endoribonuclease. AtYbeY null mutants are seedling lethal, indicating that AtYbeY function is essential for plant growth. Knockdown plants display slow growth and show pale-green leaves. Physiological and ultrastructural analyses of atybeY mutants revealed impaired photosynthesis and defective chloroplast development. Fluorescent microcopy analysis showed that, when fused with the green fluorescence protein, AtYbeY is localized in chloroplasts. Immunoblot and RNA gel-blot assays revealed that the levels of chloroplast-encoded subunits of photosynthetic complexes are reduced in atybeY mutants, but the corresponding transcripts accumulate normally. In addition, atybeY mutants display defective maturation of both the 5' and 3' ends of 16S, 23S, and 4.5S rRNAs as well as decreased accumulation of mature transcripts from the transfer RNA genes contained in the chloroplast rRNA operon. Consequently, mutant plants show a severe deficiency in ribosome biogenesis, which, in turn, results in impaired plastid translational activity. Furthermore, biochemical assays show that recombinant AtYbeY is able to cleave chloroplast rRNAs as well as messenger RNAs and transfer RNAs in vitro. Taken together, our findings indicate that AtYbeY is a chloroplast-localized endoribonuclease that is required for chloroplast rRNA processing and thus for normal growth and development. PMID- 25810100 TI - An unusual side effect of azathioprine. PMID- 25810102 TI - GC/MS analysis of triclosan and its degradation by-products in wastewater and sludge samples from different treatments. AB - A gas chromatography/mass spectrometry (GC/MS)-based method was developed for simultaneous determination of triclosan (TCS) and its degradation products including 2,4-dichlorophenol (2,4-DCP), 2,8-dichlorodibenzo-p-dioxin (2,8-DCDD), and methyl triclosan (MTCS) in wastewater and sludge samples. The method provides satisfactory detection limit, accuracy, precision and recovery especially for samples with complicated matrix such as sewage sludge. Liquid-liquid extraction and accelerated solvent extraction (ASE) methods were applied for the extraction, and column chromatography was employed for the sample cleanup. Analysis was performed by GC/MS in the selected ion monitoring (SIM) mode. The method was successfully applied to wastewater and sludge samples from three different municipal wastewater treatment plants (WWTPs). Satisfactory mean recoveries were obtained as 91(+/-4)-106(+/-7)%, 82(+/-3)-87(+/-4)%, 86(+/-6)-87(+/-8)%, and 88(+/-4)-105(+/-3)% in wastewater and 88(+/-5)-96(+/-8)%, 84(+/-2)-87(+/-3)%, 84(+/-7)-89(+/-4)%, and 88(+/-3)-97(+/-5)% in sludge samples for TCS, 2,4-DCP, 2,8-DCDD, and MTCS, respectively. TCS degradation products were detected based on the type of the wastewater and sludge treatment. 2,8-DCDD was detected in the plant utilizing UV disinfection at the mean level of 20.3(+/-4.8) ng/L. 2,4-DCP was identified in chemically enhanced primary treatment (CEPT) applying chlorine disinfection at the mean level of 16.8(+/-4.5) ng/L). Besides, methyl triclosan (MTCS) was detected in the wastewater collected after biological treatment (10.7 +/- 3.3 ng/L) as well as in sludge samples that have undergone aerobic digestion at the mean level of 129.3(+/-17.2) ng/g dry weight (dw). PMID- 25810097 TI - S-sulfhydration: a cysteine posttranslational modification in plant systems. AB - Hydrogen sulfide is a highly reactive molecule that is currently accepted as a signaling compound. This molecule is as important as carbon monoxide in mammals and hydrogen peroxide in plants, as well as nitric oxide in both eukaryotic systems. Although many studies have been conducted on the physiological effects of hydrogen sulfide, the underlying mechanisms are poorly understood. One of the proposed mechanisms involves the posttranslational modification of protein cysteine residues, a process called S-sulfhydration. In this work, a modified biotin switch method was used for the detection of Arabidopsis (Arabidopsis thaliana) proteins modified by S-sulfhydration under physiological conditions. The presence of an S-sulfhydration-modified cysteine residue on cytosolic ascorbate peroxidase was demonstrated using liquid chromatography-tandem mass spectrometry analysis, and a total of 106 S-sulfhydrated proteins were identified. Immunoblot and enzyme activity analyses of some of these proteins showed that the sulfide added through S-sulfhydration reversibly regulates the functions of plant proteins in a manner similar to that described in mammalian systems. PMID- 25810105 TI - Phosphonate appended porphyrins as versatile chemosensors for selective detection of trinitrotoluene. AB - Fluorescent molecular probes based on phosphonate-functionalized porphyrin derivatives have been designed for selective detection of nitroaromatics. It is shown that molecular recognition is based on cooperative hydrogen bonding and pi pi stacking interactions with electron-deficient molecules (nitroaromatic compounds, NACs), displaying superior detection toward trinitrotoluene (TNT). The P?O functional groups decrease the lowest unoccupied molecular orbital (LUMO) energy level of the porphyrins and, consequently, facilitate the electron inoculation to TNT through a photoinduced electron transfer (PET) process. The hydroxyl groups of the phosphonates and pyrrole -NH protons are further engaged in donor-acceptor interactions with TNT by strong intermolecular hydrogen bonding interactions (as evidenced by single crystal X-ray, NMR, and density functional theory (DFT)) showing turn off fluorescence behavior. The nonplanarity of the porphyrins induced by protonation at the central core of the porphyrin H4TPPA(2+) undergoes additional interactions, furnishing an anomalous increase in the selectivity of TNT at nanomolar levels in solution (limit of detection, LOD ~ 5 nM). Porphyrin-doped hybrid PMMA [poly(methyl methacrylate)] polymer films demonstrate the reversibility of the fluorescence behavior and exhibit high photostability. The formation of discrete molecular aggregates on the surface of hybrid films and efficient diffusion of TNT vapors (10 ppb) displayed high selectivity in the solid state. The hybrid films are further used to demonstrate the detection of NACs in the aqueous medium, ultimately providing a platform for a practical strategy and implementation for the detection of toxic NACs. PMID- 25810103 TI - Photolytic and thin TiO2 film assisted photocatalytic degradation of sulfamethazine in aqueous solution. AB - This paper deals with the photolytic and the photocatalytic degradation of sulfonamide antibiotic sulfamethazine (SMT) dissolved in Milli-Q water and in synthetic wastewater. Besides the direct photolysis, oxidation processes including UV/H2O2, UV/TiO2, and UV/TiO2/H2O2 using UV-A and UV-C radiation were investigated. Pseudo-first-order kinetics was observed for the degradation of SMT in all investigated processes. Additions of an electron acceptor (H2O2) and a catalyst (TiO2 film) accelerated the photolytic degradation of SMT for both the UV-A- and the UV-C-based processes. The most efficient process was UV-C/TiO2/H2O2 with complete degradation of SMT obtained in 10 min. The UV-A-based processes have been less efficient in terms of irradiation time required to totally degrade SMT than the UV-C-based processes. It was also confirmed that different wastewater components can significantly reduce the degradation rate of SMT. An almost ninefold reduction in the rate constant of SMT was observed for the specific synthetic wastewater. Although UV-A radiation experiments need more time and energy (2.7 times more electrical energy was consumed per gram of demineralized SMT) than UV-C experiments, they have a potential for practical use since natural UV-A solar radiation could be used here, which lowers the overall cost of the treatment. Five degradation products were detected during the degradation processes, and their structural formulae are presented. The structural formulae were elucidated based on mass spectra fragmentation pattern obtained using the tandem mass spectrometry (MS/MS) and NMR analysis. PMID- 25810104 TI - Application of hydrodynamic cavitation in ballast water treatment. AB - Ballast water is, together with hull fouling and aquaculture, considered the most important factor of the worldwide transfer of invasive non-indigenous organisms in aquatic ecosystems and the most important factor in European Union. With the aim of preventing and halting the spread of the transfer of invasive organisms in aquatic ecosystems and also in accordance with IMO's International Convention for the Control and Management of Ships Ballast Water and Sediments, the systems for ballast water treatment, whose work includes, e.g. chemical treatment, ozonation and filtration, are used. Although hydrodynamic cavitation (HC) is used in many different areas, such as science and engineering, implied acoustics, biomedicine, botany, chemistry and hydraulics, the application of HC in ballast water treatment area remains insufficiently researched. This paper presents the first literature review that studies lab- and large-scale setups for ballast water treatment together with the type-approved systems currently available on the market that use HC as a step in their operation. This paper deals with the possible advantages and disadvantages of such systems, as well as their influence on the crew and marine environment. It also analyses perspectives on the further development and application of HC in ballast water treatment. PMID- 25810106 TI - Prevalence and characteristics associated with default of treatment and follow-up in patients with cancer. AB - Defaulting is an important issue across all medical specialties, but much more so in cancer as delayed or incomplete treatment has been shown to result in worse clinical outcomes such as treatment resistance, disease progression as well as lower survival. Our objective was to identify psychosocial variables and characteristics associated with default among cancer patients. A total of 467 consecutive adult cancer patients attending the oncology clinic at a single academic medical centre completed the Hospital Anxiety and Depression Scale and reported their preference for psychological support at baseline, 4-6 weeks and 12 18 months follow-up. Default was defined as refusal, delay or discontinuation of treatment or visit, despite the ability to do so. A total of 159 of 467 (34.0%) cancer patients were defaulters. Of these 159 defaulters, 89 (56.0%) desired psychological support, compared to only 13 (4.2%) of 308 non-defaulters. Using a logistic regression, patients who were defaulters had 52 times higher odds (P = 0.001; 95% confidence interval 20.61-134.47) of desiring psychological support than non-defaulters after adjusting for covariates. These findings suggest that defaulters should be offered psychological support which may increase cancer treatment acceptance rates and improve survival. PMID- 25810108 TI - A randomised controlled comparison between stimulating and standard catheters for lumbar plexus block. AB - The aim of this randomised, prospective, blinded study was to evaluate if stimulating catheters can decrease the minimum effective anaesthetic volume in 50% of patients during lumbar plexus block using mepivacaine 1.5% compared with standard catheters. Fifty-eight patients of ASA physical status 1-3 were randomly allocated to receive a lumbar plexus block via a stimulating or standard catheter, with 29 in each group. The first dose was 30 ml and subsequent doses were determined using the up-and-down staircase method. The minimum effective anaesthetic volume50 was 12.2 ml (95% CI 7.3-17.1 ml) using the stimulating catheter and 24.8 ml (95% CI 23.2-27.5 ml) with the standard catheter (p < 0.0001). Complete lumbar plexus block was achieved with the initial dose of mepivacaine in 29 (100%) patients in the stimulating catheter group and 20 (69%) patients in the standard catheter group (p = 0.002). This study showed that use of a stimulating catheter halves the minimum effective anaesthetic volume50 of mepivacaine 1.5% while increasing the success rate in patients receiving continuous lumbar plexus block. PMID- 25810107 TI - Mutant p53 expression in fallopian tube epithelium drives cell migration. AB - Ovarian cancer is the fifth leading cause of cancer death among US women. Evidence supports the hypothesis that high-grade serous ovarian cancers (HGSC) may originate in the distal end of the fallopian tube. Although a heterogeneous disease, 96% of HGSC contain mutations in p53. In addition, the "p53 signature," or overexpression of p53 protein (usually associated with mutation), is a potential precursor lesion of fallopian tube derived HGSC suggesting an essential role for p53 mutation in early serous tumorigenesis. To further clarify p53 mutation dependent effects on cells, murine oviductal epithelial cells (MOE) were stably transfected with a construct encoding for the R273H DNA binding domain mutation in p53, the most common mutation in HGSC. Mutation in p53 was not sufficient to transform MOE cells but did significantly increase cell migration. A similar p53 mutation in murine ovarian surface epithelium (MOSE), another potential progenitor cell for serous cancer, was not sufficient to transform the cells nor change migration suggesting tissue specific effects of p53 mutation. Microarray data confirmed expression changes of pro-migratory genes in p53(R273H) MOE compared to parental cells, which could be reversed by suppressing Slug expression. Combining p53(R273H) with KRAS(G12V) activation caused transformation of MOE into high-grade sarcomatoid carcinoma when xenografted into nude mice. Elucidating the specific role of p53(R273H) in the fallopian tube will improve understanding of changes at the earliest stage of transformation. This information can help develop chemopreventative strategies to prevent the accumulation of additional mutations and reverse progression of the "p53 signature" thereby, improving survival rates. PMID- 25810112 TI - A 66-year-old woman with prolonged chest pain. PMID- 25810109 TI - Chitin and chitosan as direct compression excipients in pharmaceutical applications. AB - Despite the numerous uses of chitin and chitosan as new functional materials of high potential in various fields, they are still behind several directly compressible excipients already dominating pharmaceutical applications. There are, however, new attempts to exploit chitin and chitosan in co-processing techniques that provide a product with potential to act as a direct compression (DC) excipient. This review outlines the compression properties of chitin and chitosan in the context of DC pharmaceutical applications. PMID- 25810114 TI - Nomogram for Predicting Time to Death After Withdrawal of Life-Sustaining Treatment in Patients With Devastating Neurological Injury. AB - Reliable prediction of time of death after withdrawal of life-sustaining treatment in patients with devastating neurological injury is crucial to successful donation after cardiac death. Herein, we conducted a study of 419 neurocritical patients who underwent life support withdrawal at four neurosurgical centers in China. Based on a retrospective cohort, we used multivariate Cox regression analysis to identify prognostic factors for patient death, which were then integrated into a nomogram. The model was calibrated and validated using data from an external retrospective cohort and a prospective cohort. We identified 10 variables that were incorporated into a nomogram. The C indexes for predicting the 60-min death probability in the training, external validation and prospective validation cohorts were 0.96 (0.93-0.98), 0.94 (0.91 0.97), and 0.99 (0.97-1.00), respectively. The calibration plots after WLST showed an optimal agreement between the prediction of time to death by the nomogram and the actual observation for all cohorts. Then we identified 22, 26 and 37 as cut-points for risk stratification into four groups. Kaplan-Meier curves indicated distinct prognoses between patients in the different risk groups (p < 0.001). In conclusion, we have developed and validated a nomogram to accurately identify potential cardiac death donors in neurocritical patients in a Chinese population. PMID- 25810115 TI - Highly Efficient Hybrid Photovoltaics Based on Hyperbranched Three-Dimensional TiO2 Electron Transporting Materials. PMID- 25810113 TI - Metabolic syndrome showed significant relationship with carotid atherosclerosis. AB - Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease. We assessed the associations between MetS and the indicators of carotid atherosclerosis as assessed by ultrasonography taking into consideration of confounders in the general population. A total of 1281 subjects (856 males, 425 females) were included in the present study. The total plaque score and maximum intima-media thickness (IMT) of the carotid arteries were measured as indicators of atherosclerosis. Cardiovascular risk factors were several metabolic components, serum uric acid, serum C-reactive protein (CRP), and lifestyle factors. MetS was defined according to the criteria of the National Cholesterol Education Program. The prevalences of an elevated total plaque score (>=5) and elevated IMT (>1 mm) of the carotid arteries were significantly higher in subjects with MetS as compared to subjects without MetS. Furthermore, a trend was observed towards higher prevalences of these indicators of atherosclerosis as the number of components of MetS increased. Logistic regression analysis revealed a significant association between elevated plaque score and MetS even after adjustments for age, serum uric acid, serum CRP and lifestyle factors in the males. Among the indicators of atherosclerosis assessed by carotid ultrasonography, a significant independent association was observed between the total plaque score and MetS in males in the general population. PMID- 25810110 TI - "...Rewritten in the skin": clues to skin biology and aging from inherited disease. AB - The growing diversity of heritable skin diseases, a practical challenge to clinicians and dermato-nosologists alike, has nonetheless served as a rich source of insight into skin biology and disease mechanisms. I summarize below some key insights from the recent gene-driven phase of research on Werner syndrome, a heritable adult progeroid syndrome with prominent dermatologic features, constitutional genomic instability, and an elevated risk of cancer. I also indicate how new insights into skin biology, disease, and aging may come from unexpected sources. PMID- 25810116 TI - Exploring the health visiting service from the view of South Asian clients in England: a grounded theory study. AB - The fact that health inequalities disproportionately affect the minority ethnic population is not new and projections are that the minority ethnic population will continue to increase. The importance of early intervention and the key role that health visitors can play in attempting to reduce health inequalities is well documented as is the requirement for health providers to establish culturally sensitive services. To date, much of the research has focused on the perspectives of healthcare professionals caring for minority ethnic clients in hospital-based settings and little is known about the perspectives of minority ethnic clients regarding the health visiting service (HVS). The aim of this study was to explore the perspectives of South Asians regarding their experiences with the HVS. The study was conducted in a small town in the South of England between March and June 2013. A qualitative study using a grounded theory approach was used to capture the perspectives of this group regarding their interactions with the HVS. The sample consisted of 15 participants and data were collected through audio recorded semi-structured interviews and analysed using constant comparative approach. Three key categories were identified: 'understanding the health visitor's role', 'sensitivity of services' and 'the significance of family'. While clients valued one-to-one support from health visitors, there was some evidence of poor communication and ethnocentric tendencies within the service. It was found that South Asian clients distinguish between health and parenting advice, being more likely to accept health advice from their health visitor and more likely to accept parenting advice from their family. The findings, although limited in their generalisability, offer important insights into how South Asians perceive the service and will equip health visitors with a better understanding of how best to improve the experience of South Asian clients accessing the health visiting. PMID- 25810117 TI - Cytomegalovirus reactivation in patients with multiple myeloma. AB - The introduction of novel antimyeloma agents has improved the outcome of multiple myeloma (MM) dramatically. However, it has also led to an increasing incidence of Herpesviridae family virus infections, including a high incidence of post transplant cytomegalovirus (CMV) reactivation after treatment with novel agents. We herein retrospectively assessed the CMV reactivation in all 120 newly diagnosed patients with MM consecutively seen and treated at our hospital. CMV antigenemia tests were ordered in 58 patients depending on the clinical context, and the incidence of CMV reactivation and proven/suspected CMV disease requiring antiviral therapy was 20% (24 of 120) and 11% (13 of 120) respectively, including those without stem cell transplantation (SCT). The clinical and laboratory characteristics of these patients were compared with those in 34 CMV antigenemia negative (CMV-negative) patients. Patients with extramedullary disease or a low absolute lymphocyte count (ALC) had a higher risk of developing CMV reactivation. In addition, the median duration from the time of MM diagnosis to CMV reactivation was 5.0 months. These results suggest that, regardless of whether or not undergoing SCT, elderly patients with MM receiving novel agents should be monitored for CMV reactivation to allow for the timely diagnosis and treatment, especially for those with extramedullary disease. PMID- 25810118 TI - In vitro activity of bioactive extracts from rare actinomycetes against multi drug resistant Streptococcus pneumoniae. AB - AIMS: In this study, we investigated the in vitro potential of the bioactive extracts from five putatively novel species of actinomycetes isolated from the Indian hot desert against multi-drug resistant (MDR) Streptococcus pneumoniae. METHODS AND RESULTS: The antimicrobial activity of 10 different extracts was evaluated against S. pneumoniae strains with, erm(B) and mef(E) genes as well as fluoroquinolone-resistant (FQ(R) ) strains using the micro-broth dilution method. Of these 10 extracts, four exhibited good to excellent anti-S. pneumoniae activity with minimum inhibitory concentrations (MICs) ranging from 0.125 to 8 MUg ml(-1) . The time-kill kinetics study showed that these extracts killed the pathogens in 2-8 h. In vitro cell-free transcription/translation of luciferase gene using S30 bacterial extract and TNT mammalian ribosome indicated that they inhibited bacterial ribosomes at much lower concentrations than those required to inhibit the mammalian ribosomes. CONCLUSIONS: This study demonstrates that these are potent concentration-dependent bactericidal metabolites with 16-fold higher in vitro activity than levofloxacin against MDR S. pneumoniae. SIGNIFICANCE AND IMPACT OF THE STUDY: Metabolites from actinomycetes can be excellent inhibitors of MDR S. pneumoniae. Considering the in vitro efficacy of these crude extracts against S. pneumoniae MDR spp., once purified these can be used against streptococcal pathogens causing community-acquired pneumonia. PMID- 25810119 TI - Bartonellae are Prevalent and Diverse in Costa Rican Bats and Bat Flies. AB - Species in the bacterial genus, Bartonella, can cause disease in both humans and animals. Previous reports of Bartonella in bats and ectoparasitic bat flies suggest that bats could serve as mammalian hosts and bat flies as arthropod vectors. We compared the prevalence and genetic similarity of bartonellae in individual Costa Rican bats and their bat flies using molecular and sequencing methods targeting the citrate synthase gene (gltA). Bartonellae were more prevalent in bat flies than in bats, and genetic variants were sometimes, but not always, shared between bats and their bat flies. The detected bartonellae genetic variants were diverse, and some were similar to species known to cause disease in humans and other mammals. The high prevalence and sharing of bartonellae in bat flies and bats support a role for bat flies as a potential vector for Bartonella, while the genetic diversity and similarity to known species suggest that bartonellae could spill over into humans and animals sharing the landscape. PMID- 25810122 TI - Ultrasound-guided percutaneous aspiration of hyperreactio luteinalis avoids laparoscopic untwisting of ovarian torsion. AB - Hyperreactio luteinalis (HL) is characterized by multicystic bilateral enlargement of the ovaries and is a self-limiting benign condition associated with pregnancy or trophoblastic disease. Since HL regresses spontaneously over time, it should be managed conservatively as long as the patient's condition permits; torsion of the enlarged ovaries is believed to be the only exception that mandates surgical intervention. Here, we describe a case of HL complicated by ovarian torsion that was treated successfully without surgical intervention. A 33-year-old woman was admitted to our hospital owing to acute abdomen. Nine days previously, she had had a stillbirth caused by hydrops fetalis at 24 weeks' gestation. The characteristic findings observed on magnetic resonance imaging (MRI) led to the diagnosis of HL complicated by torsion of the enlarged left ovary. Emergency laparoscopic detorsion of the ischemic left ovary was planned. Aiming to reduce the risk of cystic injury and bleeding at the trocar insertion site, volume reduction of the left ovarian cyst was performed by percutaneous aspiration. The patient's pain diminished rapidly and laparoscopic surgery was deferred. Subsequent MRI revealed that gadolinium enhancement of the left ovarian tumor had been restored, indicating spontaneous detorsion of the left ovary. The patient remained asymptomatic and was discharged from the hospital 12 days after aspiration of the cyst. From this experience, we propose that, in cases of ovarian torsion occurring in large functional cysts, including HL, volume reduction by percutaneous cyst aspiration should be considered before performing emergency laparoscopic surgery. PMID- 25810120 TI - Development of Microsatellite Markers in the Deep-Sea Cup Coral Desmophyllum dianthus by 454 Sequencing and Cross-Species Amplifications in Scleractinia Order. AB - Microsatellite loci were isolated for the first time for the deep-sea coral Desmophyllum dianthus, using 454 GS-FLX Titanium pyrosequencing. We developed conditions for amplifying 24 markers in 10 multiplex reactions. Three to 16 alleles per locus were detected across 25 samples analyzed from Santa Maria di Leuca coral province (Mediterranean Sea). For the 24 polymorphic loci, observed and expected heterozygosities ranged from 0.211 to 0.880 and 0.383 to 0.910, respectively; 3 loci deviated from Hardy-Weinberg equilibrium, after null allele and sequential Holm-Bonferroni corrections. These newly isolated microsatellites are very useful genetic markers that provide data for future conservation strategies. Cross-amplification of these microsatellites, tested in 46 coral species, representing 40 genera, and 10 families of the phylum Cnidaria, produced informative allelic profiles for 1 to 24 loci. The utility of extending analyses to cross-species amplifications is also discussed. PMID- 25810121 TI - Genetic Subdivision and Variation in Selfing Rates Among Central American Populations of the Mangrove Rivulus, Kryptolebias marmoratus. AB - We used 32 polymorphic microsatellite loci to investigate how a mixed-mating system affects population genetic structure in Central American populations (N = 243 individuals) of the killifish Kryptolebias marmoratus (mangrove rivulus), 1 of 2 of the world's only known self-fertilizing vertebrates. Results were also compared with previous microsatellite surveys of Floridian populations of this species. For several populations in Belize and Honduras, population structure and genetic differentiation were pronounced and higher than in Florida, even though the opposite trend was expected because populations in the latter region were presumably smaller and highly selfing. The deduced frequency of selfing (s) ranged from s = 0.39-0.99 across geographic locales in Central America. This heterogeneity in selfing rates was in stark contrast to Florida, where s > 0.9. The frequency of outcrossing in a population (t = 1 - s) was tenuously correlated with local frequencies of males, suggesting that males are one of many factors influencing outcrossing. Observed distributions of individual heterozygosity showed good agreement with expected distributions under an equilibrium mixed mating model, indicating that rates of selfing remained relatively constant over many generations. Overall, our results demonstrate the profound consequences of a mixed-mating system for the genetic architecture of a hermaphroditic vertebrate. PMID- 25810123 TI - Glucose-Lowering Effect of Sevelamer Hydrochloride in Hemodialysis Patients. PMID- 25810124 TI - TRAIL and TRAIL receptors in patients with laryngeal cancer. AB - BACKGROUND: Tumor necrosis factor-related associated-inducing ligand (TRAIL) is a death ligand currently under clinical trials for laryngeal carcinoma. METHODS: Paraffin-embedded tissues from 40 patients with laryngeal carcinoma and 20 patients with benign laryngeal pathologies were retrospectively analyzed using immunohistochemistry in terms of distribution and intensity, and for final analysis of immunoreactivity of receptors, H-score was used. The study group was assessed in terms of localization, lymph node staging, tumor stage, overall survival, disease-free survival, locoregional control, perineural invasion, and vascular invasion. RESULTS: The H-score of decoy-R2 (DcR2) staining were increased significantly in tumor tissue (p = .04). A significantly greater increase in terms of H-score of DR5 receptor staining (p = .06) was detected in tumor tissue. CONCLUSION: TRAIL-mediated gene therapy may not be effective. Indeed, the findings may indicate treatment resistance. TRAIL and TRAIL receptor levels were not associated with prognosis (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E535-E541, 2016. PMID- 25810126 TI - Cryptosporidium parvum infections in a cohort of veterinary students in Sweden- CORRIGENDUM. PMID- 25810125 TI - PD-1/PD-L1 expression on CD(4+) T cells and myeloid DCs correlates with the immune pathogenesis of atrial fibrillation. AB - Although immuno-inflammatory response contributes to pathogenesis of AF, molecular and cellular mechanism in this process remains poorly understood. Recently, increasing evidence suggests that Programmed death-1 (PD-1)/PD-1 ligand (PD-L) pathway may be a potential pathway participating in AF pathogenesis. In this study, we detected the PD-1 and PD-L1, 2 expression on peripheral blood function cells by flow cytometry in 91 atrial fibrillation (AF) patients and 35 healthy volunteers. The expression of PD-1 on CD(4+) T cells and PD-L1 on myeloid dendritic cells (mDCs) in AF patients is significantly down-regulated compared with healthy volunteers. In addition, the extent of PD-1/PD-L1 down-regulation is closely related with AF burden. More importantly, Allogeneic mixed leukocyte reactions (MLR) shows that the mDCs PD-L1 down-regulation is associated with increased T cell (CD(4+) and CD(8+)) proliferation, increased type 1 effector cytokines (IL-2 and IFN-gamma) secretion, and decreased type 2 effector cytokine (IL-10) secretion. Then, PD-L1 up-regulation by the stimulation of IFN-alpha can significantly convert this representation. Collectively, our report suggest that T(CD(4+))/mDCs-associated PD-1/PD-L1 pathway plays a key role in AF immune regulation. PD-1/PD-L1 down-regulation in AF patients promotes T cells function and may contribute to AF pathogenesis. PMID- 25810127 TI - Pharmaceutical interventions in antiretroviral therapy: systematic review and meta-analysis of randomized clinical trials. AB - WHAT IS KNOWN AND OBJECTIVE: High levels of adherence to antiretroviral therapy (ART) are needed to achieve the desired results. Because pharmaceutical care might contribute to improved adherence to treatment, the aim of this study was to assess the impact of pharmaceutical interventions on ART via a systematic review of randomized clinical trials (RCT). METHODS: Study selection, data extraction and risk-of-bias assessment were performed independently by two reviewers. RESULTS AND DISCUSSION: A total of 681 studies were located; only four of these met the inclusion criteria and were analysed. The summary measure corresponding to the outcome adherence to treatment was 1.47 (95% confidence interval [CI]: 0.81-2.65), and the measure corresponding to the outcome virologic suppression was 1.95 (95% CI: 0.61-6.25). WHAT IS NEW AND CONCLUSION: The results suggest that pharmaceutical interventions might contribute to improved adherence to ART and the achievement of virologic suppression, although the differences between the intervention and control groups were not statistically significant. Pharmaceutical interventions might be more efficacious in populations with low adherence to treatment and greater vulnerability. PMID- 25810129 TI - Practical neuroanatomy teaching in the 21st century. PMID- 25810128 TI - The evolving role of adjuvant radiotherapy for elderly women with early-stage breast cancer. AB - BACKGROUND: Elderly patients with early-stage breast cancer (ESBC) derive a local control benefit from radiotherapy (RT) after lumpectomy, without any apparent effect on overall survival. Therefore, the use of RT is controversial. In the current study, the authors characterized updated trends in RT for elderly patients with estrogen receptor (ER)-positive ESBC. METHODS: Patients aged >=70 years with ER-positive ESBC measuring <=2 cm after lumpectomy with negative resection margins and known RT details were identified in the National Cancer Data Base. Patients were classified by year of diagnosis and segregated into 3 groups relative to the initial publication and updated presentation of the Cancer and Leukemia Group B (CALGB) 9343 trial. RT use overall, prescription of hypofractionated RT, and use of boost RT were compared between groups using logistic regression analysis, and the influence of clinicopathologic covariates was determined with multivariable logistic regression analysis. RESULTS: A total of 122,796 elderly patients with ER-positive ESBC who were diagnosed between 1998 and 2011 were identified. Overall, 84,649 patients (68.9%) received adjuvant RT, with a decline observed between successive cohorts (71.3% in the pre-initial publication cohort, 69.5% in the pre-update cohort, and 64.7% in the post-update cohort; P <.001). Hypofractionated RT use increased among treated patients over time (P<.001). Boost RT was used in 67.5% of patients, with a decline noted between the pre-update and post-update cohorts (68.7% vs 57.7%; P<.001). Overall RT use as well as use of boost RT were found to be lower among older patients and those with lower-grade or smaller tumors (P<.001), whereas hypofractionated RT was used more commonly in these groups (P<.001). CONCLUSIONS: RT use appears to have declined in elderly patients with ER-positive ESBC, a finding that is reflective of evidence-based practice integrating mature trial data. Further research is needed to develop tools to aid in the decision-making process regarding the delivery or avoidance of RT in this setting. PMID- 25810130 TI - Estradiol alters the chemosensitive cardiac afferent reflex in female rats by augmenting sympathoinhibition and attenuating sympathoexcitation. AB - The chemosensitive cardiac vagal and sympathetic afferent reflexes are implicated in driving pathophysiological changes in sympathetic nerve activity (SNA) in cardiovascular disease states. This study investigated the impact of sex and ovarian hormones on the chemosensitive cardiac afferent reflex. Experiments were performed in anaesthetized, sinoaortic baroreceptor denervated male, female and ovariectomized female (OVX) Wistar rats with either intact cardiac innervation or bilateral vagotomy. To investigate the chemosensitive cardiac afferent reflexes renal SNA, heart rate (HR) and arterial pressure (AP) were recorded before and following application of capsaicin onto the epicardial surface of the left ventricle. Compared to males, ovary-intact females displayed similar cardiac afferent reflex mediated changes in renal SNA albeit with a reduced maximum sympathetic reflex driven increase in renal SNA. In females, ovariectomy significantly attenuated the cardiac vagal afferent reflex mediated inhibition of renal SNA (renal SNA decreased 2 +/- 17% in OVX versus -50 +/- 4% in ovary-intact females, P < 0.05) and augmented cardiac sympathetic afferent reflex mediated sympathoexcitation (renal SNA increased 91 +/- 11% in OVX vs 62 +/- 9% in ovary intact females, P < 0.05) so that overall increases in reflex driven sympathoexcitation were significantly enhanced. Chronic estradiol replacement, but not progesterone replacement, begun at time of ovariectomy restored cardiac afferent reflex responses to be similar as ovary-intact females. Vagal denervation eliminated all group differences. The current findings show ovariectomy in female rats, mimicking menopause in women, results in greater chemosensitive cardiac afferent reflex driven sympathoexcitation and does so, at least partly, via the loss of estradiols actions on the cardiac vagal afferent reflex pathway. PMID- 25810131 TI - Reverse attenuation in interaction terms due to covariate measurement error. AB - Covariate measurement error may cause biases in parameters of regression coefficients in generalized linear models. The influence of measurement error on interaction parameters has, however, only rarely been investigated in depth, and if so, attenuation effects were reported. In this paper, we show that also reverse attenuation of interaction effects may emerge, namely when heteroscedastic measurement error or sampling variances of a mismeasured covariate are present, which are not unrealistic scenarios in practice. Theoretical findings are illustrated with simulations. A Bayesian approach employing integrated nested Laplace approximations is suggested to model the heteroscedastic measurement error and covariate variances, and an application shows that the method is able to reveal approximately correct parameter estimates. PMID- 25810133 TI - Late complications of mixed chimerism following allogeneic bone marrow transplantation for thalassemia major. PMID- 25810132 TI - Methylchloroisothiazolinone and methylisothiazolinone contact allergy: an occupational perspective. AB - BACKGROUND: Sensitivity to either methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) or MI has increased, with a reported frequency of up to 11.1% among dermatitis patients, the main context being allergic contact dermatitis caused by MCI or MCI/MI in personal care products. Case reports have described occupational allergic contact dermatitis caused by MI in paints and within the beauty industry. PATIENTS/MATERIALS/METHODS: This study identified incident cases of occupational allergic contact dermatitis caused by MCI/MI and or MI reported from 1996 to 2012 to a UK-wide surveillance scheme (EPIDERM), with the aim of identifying changes in incidence over the study period. RESULTS: The data show an increase in occupational allergic contact dermatitis caused by MCI/MI and or MI from 1996 to 2012 of 4.1% [95% confidence interval (CI) 1.6-6.9] per annum. Analysis by industry showed a 3.8% (95% CI: -0.3 to 8.0) per annum increase in those exposed to personal care products in the workplace as a primary exposure [healthcare workers, 8.1% (95% CI: 2.1-14.4) per annum; beauty workers, 6.6% (95% CI: -2.2 to 16.2) per annum; hairdressers, 1.5% (95% CI: -4.7 to 8.1) per annum]. There was a 6.3% (95% CI: 1.8-10.9) per annum increase for manufacturing workers. A statistically significant rise in the frequency of occupational allergic contact dermatitis was shown to be attributable to MCI/MI and or MI between 1996 and 2012. CONCLUSION: The findings support recommendations for a review of the regulations relating to MCI/MI and/or MI in cosmetic and personal care products and in industrial settings. PMID- 25810134 TI - Efficient molecular subtype classification of high-grade serous ovarian cancer. AB - High-grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost effective and high-throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman-based (low-density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin-fixed, paraffin-embedded samples. All platforms achieved > 90% classification accuracy with RNA from fresh frozen samples. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from individual chemo-naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian sample was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials. PMID- 25810136 TI - Acute cholecystitis in elderly patients after hip fracture: Incidence and epidemiology. AB - AIM: Acute cholecystitis is a medical complication that can develop in the postoperative period after hip surgery. However, few studies have examined this complication in elderly patients. Our aim was therefore to evaluate the incidence and clinical manifestations of acute cholecystitis after hip fracture in elderly patients. METHODS: Medical records and radiological studies of patients aged older than 65 years who underwent hip surgery for femoral neck or intertrochanteric fractures at a single hospital from April 2003 to March 2013 were reviewed retrospectively. We analyzed the type of cholecystitis (acalculous or calculous), clinical manifestations, fracture type (neck or trochanteric fracture), age, sex, body mass index, type of surgery, time to surgery, time from surgery to onset of acute cholecystitis and the timing of ambulation in acute cholecystitis cases. RESULTS: There were nine confirmed acute cholecystitis cases among 1211 hip fractures; thus, the incidence of acute cholecystitis within 2 months after hip fracture surgery was 0.74%. CONCLUSIONS: The incidence of acute cholecystitis was higher than we expected, and this condition can lead to more serious problems if overlooked. Acute cholecystitis as a medical complication after hip fracture was underestimated in previous studies. Furthermore, acute cholecystitis should be considered as a complication of hip fracture, not hip surgery, in the elderly. The present study does not imply that hip fracture causes acute cholecystitis, although elderly hip fracture patients are in an extremely debilitated state and are prone to developing acute cholecystitis. PMID- 25810137 TI - A Single Counterexample Leads to Moral Belief Revision. AB - What kind of evidence will lead people to revise their moral beliefs? Moral beliefs are often strongly held convictions, and existing research has shown that morality is rooted in emotion and socialization rather than deliberative reasoning. In addition, more general issues-such as confirmation bias-further impede coherent belief revision. Here, we explored a unique means for inducing belief revision. In two experiments, participants considered a moral dilemma in which an overwhelming majority of people judged that it was inappropriate to take action to maximize utility. Their judgments contradicted a utilitarian principle they otherwise strongly endorsed. Exposure to this scenario led participants to revise their belief in the utilitarian principle, and this revision persisted over several hours. This method provides a new avenue for inducing belief revision. PMID- 25810135 TI - Total chemical synthesis of human interferon alpha-2b via native chemical ligation. AB - Interferon-alpha (IFNalpha) is a cytokine that orchestrates innate and adaptive immune responses and potently inhibits proliferation of normal and tumor cells. These properties have warranted the use of IFNalpha in clinical practice for the treatment of several viral infections and malignancies. However, overexpression of IFNalpha leads to immunopathology observed in the context of chronic viral infections and autoimmune conditions. Thus, it is desirable to develop therapeutic approaches that aim at suppressing excessive IFNalpha production. To that end, artificial evolution of peptides from phage display libraries represents a strategy that seeks to disrupt the interaction between IFNalpha and its cell surface receptor and thus inhibit the ensuing biological effects. Mirror image phage display that screens peptide libraries against the D-enantiomer is particularly attractive because it allows for identification of proteolysis resistant D-peptide inhibitors. This approach, however, relies on the availability of chemically synthesized D-IFNalpha composed entirely of D-amino acids. Here, we describe the synthesis and biological properties of IFNalpha2b of 165 amino acid residues produced by native chemical ligation, which represents an important first step toward the discovery of D-peptide antagonists with potential therapeutic applications. PMID- 25810141 TI - Radical treatment of localised prostate cancer in the elderly. AB - Elderly men are more likely to be diagnosed with aggressive cancer, but are often inappropriately denied curative treatment. Biological rather than chronological age should be used to decide if a patient will profit from radical treatment. Therefore, every man aged >70 years should undergo a health assessment using a validated tool before making treatment decisions. Fit elderly men with intermediate- or high-risk disease should be offered standard curative local treatment in keeping with guidelines for younger men. Vulnerable and frail elderly men warrant geriatric intervention before treatment. In the case of vulnerable patients, this intervention may render them suitable for standard care. When considering radical prostatectomy outcomes a 'bifecta' of oncological control and continence is appropriate, as erectile dysfunction (although prevalent) has a much smaller impact on quality of life than in younger patients. Radiotherapy is an alternative to radical prostatectomy in men with a life expectancy of <10 years. Primary androgen-deprivation therapy is not associated with improved survival in localised prostate cancer and should only be used for symptom palliation. Further elderly-specific research is needed to guide prostate cancer care. PMID- 25810142 TI - Metal-Organic Framework/PVDF Composite Membranes with High H2 Permselectivity Synthesized by Ammoniation. AB - Herein we report a new ammoniation-based chemical modification strategy for synthesis of continuous and uniform metal-organic framework (MOF)/polyvinylidene fluoride (PVDF) membranes with attractive performance. Ammoniation can promote the support PVDF membrane to produce amino groups, form a nanoparticle structure, and be well cross-linked; therefore, the high-density heterogeneous nucleation sites for MOFs growth were provided and the thermal stability and chemical resistance of composite membranes can be greatly improved. The high-quality layers of representative Cu-BTC and ZIF-8 were synthesized on the chemically modified PVDF membranes. By ammoniation, ZIF-7 can even be grown under harsh synthetic conditions such as in DMF precursor solutions at 403 K. The fabricated MOF/PVDF composite membranes with excellent hollow fiber structures and enhanced structural stability exhibited high H2 permselectivities for H2 /CO2 and H2 /N2 . PMID- 25810140 TI - Proteomic profiling of white muscle from freshwater catfish Rita rita. AB - Muscle tissues contribute 34-48 % of the total body mass in fish. Proteomic analysis enables better understanding of the skeletal muscle physiology and metabolism. A proteome map reflects the general fingerprinting of the fish species and has the potential to identify novel proteins which could serve as biomarkers for many aspects of aquaculture including fish physiology and growth, flesh quality, food safety and aquatic environmental monitoring. The freshwater catfish Rita rita of the family Bagridae inhabiting the tropical rivers and estuaries is an important food fish with high nutritive value and is also considered a species of choice in riverine pollution monitoring. Omics information that could enhance utility of this species in molecular research is meager. Therefore, in the present study, proteomic analysis of Rita rita muscle has been carried out and functional genomics data have been generated. A reference muscle proteome has been developed, and 23 protein spots, representing 18 proteins, have been identified by MALDI-TOF/TOF-MS and LC-MS/MS. Besides, transcript information on a battery of heat shock proteins (Hsps) has been generated. The functional genomics information generated could act as the baseline data for further molecular research on this species. PMID- 25810138 TI - Comparative impact of diverse regulatory loci on Staphylococcus aureus biofilm formation. AB - The relative impact of 23 mutations on biofilm formation was evaluated in the USA300, methicillin-resistant strain LAC. Mutation of sarA, atl, codY, rsbU, and sigB limited biofilm formation in comparison to the parent strain, but the limitation imposed by mutation of sarA was greater than that imposed by mutation of any of these other genes. The reduced biofilm formation of all mutants other than the atl mutant was correlated with increased levels of extracellular proteases. Mutation of fur- and mgrA-enhanced biofilm formation but in LAC had no impact on protease activity, nuclease activity, or accumulation of the polysaccharide intercellular adhesin (PIA). The increased capacity of these mutants to form a biofilm was reversed by mutation of sarA, and this was correlated with increased protease production. Mutation of sarA, mgrA, and sigB had the same phenotypic effect in the methicillin-sensitive strain UAMS-1, but mutation of codY increased rather than decreased biofilm formation. As with the UAMS-1 mgrA mutant, this was correlated with increased production of PIA. Examination of four additional clinical isolates suggests that the differential impact of codY on biofilm formation may be a conserved characteristic of methicillin-resistant versus methicillin-sensitive strains. PMID- 25810143 TI - The Relationship Between Cardiac Vulnerability and Restitution Properties of the Ventricular Activation Recovery Interval. AB - INTRODUCTION: The restitution of the action potential duration (APD) is an important contributor to ventricular fibrillation (VF) initiation by a single critically timed ectopic beat. We hypothesized that a steep slope of the activation recovery interval restitution curve was related to the upper limit of vulnerability (ULV). METHODS AND RESULTS: Fifty-four consecutive patients with implantable cardioverter defibrillators (ICDs) implanted between April 2012 and July 2013 were included. At the implantation, pacing from the right ventricular (RV) coil to an indifferent electrode inserted in the ICD pocket was performed, and the unipolar electrograms from the RV coil were simultaneously recorded. We assessed the standard restitution by introducing extra-stimuli, while measuring the activation recovery interval (ARI). Our protocol for the vulnerability test consisted of delivering three 15 J shocks on the T-peak and within +/-20 milliseconds of it. If VF was not induced by that procedure, a ULV of <=15 J was defined. The relationship between the ULV and maximum slope of the restitution curve was analyzed. A restitution curve could finally be obtained in a total of 40 patients. The background characteristics were similar between the two groups. The maximum slope of the restitution curve was steeper in the ULV > 15 J group than ULV <= 15 J group (1.55 +/- 0.45 vs. 0.91 +/- 0.64, P < 0.05). A maximum slope exceeding 1.0 was the optimal point for discriminating patients with a ULV > 15 J from a ULV <= 15 J (sensitivity 61.5% and specificity 96.3%). CONCLUSION: The maximum slope of the restitution curve was significantly related to the ULV. High defibrillation threshold patients could be detected by the ARI dynamics. PMID- 25810144 TI - Emergence of reconfigurable wires and spinners via dynamic self-assembly. AB - Dissipative colloidal materials use energy to generate and maintain structural complexity. The energy injection rate, and properties of the environment are important control parameters that influence the outcome of dynamic self-assembly. Here we demonstrate that dispersions of magnetic microparticles confined at the air-liquid interface, and energized by a uniaxial in-plane alternating magnetic field, self-assemble into a variety of structures that range from pulsating clusters and single-particle-thick wires to dynamic arrays of spinners (self assembled short chains) rotating in either direction. The spinners emerge via spontaneous breaking of the uniaxial symmetry of the energizing magnetic field. Demonstration of the formation and disaggregation of particle assemblies suggests strategies to form new meso-scale structures with the potential to perform functions such as mixing and sensing. PMID- 25810147 TI - Left Ventricular Assist Device Implantation With Dor Procedure via Bilateral Limited Thoracotomy. PMID- 25810145 TI - Blood and immune cell engineering: Cytoskeletal contractility and nuclear rheology impact cell lineage and localization: Biophysical regulation of hematopoietic differentiation and trafficking. AB - Clinical success with human hematopoietic stem cell (HSC) transplantation establishes a paradigm for regenerative therapies with other types of stem cells. However, it remains generally challenging to therapeutically treat tissues after engineering of stem cells in vitro. Recent studies suggest that stem and progenitor cells sense physical features of their niches. Here, we review biophysical contributions to lineage decisions, maturation, and trafficking of blood and immune cells. Polarized cellular contractility and nuclear rheology are separately shown to be functional markers of a hematopoietic hierarchy that predict the ability of a lineage to traffic in and out of the bone marrow niche. These biophysical determinants are regulated by a set of structural molecules, including cytoplasmic myosin-II and nuclear lamins, which themselves are modulated by a diverse range of transcriptional and post-translational mechanisms. Small molecules that target these mechanobiological circuits, along with novel bioengineering methods, could prove broadly useful in programming blood and immune cells for therapies ranging from blood transfusions to immune attack of tumors. PMID- 25810148 TI - Morphological changes in the salivary acini after in vivo cholinergic stimulation. AB - AIMS: Overactive bladder syndrome treated by muscarinic receptor antagonists may be complicated by reduced salivation. Cholinergic agonists may reverse this effect. The aim of the present study was to determine the antagonizing effect of a cholinergic agonist (carbachol) on a muscarinic receptor antagonist (oxybutynin) in the submandibular acini in a rat model. METHODS: Forty male Sprague Dawley rats were divided into three groups: Group I (control), Group II (vehicle), and Group III (treatment). Group III was subdivided so Group IIIa was treated with a muscarinic receptor antagonist (oxybutynin) for 1 week, Group IIIb was treated with oxybutynin for 3 weeks, and Group IIIc was treated with oxybutynin for 1 week and oxybutynin and a cholinergic agonist (carbachol) for 2 weeks. Histological and ultrastructural studies were performed on submandibular glands. RESULTS: Group IIIa showed moderate atrophic changes in the serous acini and ducts. Group IIIb showed serous acini with distorted wall, widening of the inter-lobar space, and deposition of mononuclear cells in the connective tissue. Group IIIc had serous acini similar to Group I, with mildly dilated inter-lobar ducts, but some serous acini revealed double nuclei and the inter-lobar duct showed luminal vacuolations. Ultrastructural studies confirmed histological results. CONCLUSIONS: Muscarinic receptor antagonist administration led to changes in the submandibular gland of rats, while concomitant administration of cholinergic agonists seemed to counteract these atrophic changes. Additional studies should assess carbachol as a cholinergic agonist in treating dry mouth in patients with overactive bladder syndrome who are taking the muscarinic receptor. Neurourol. Urodynam. 35:574-581, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25810146 TI - Simultaneous imaging of 13C metabolism and 1H structure: technical considerations and potential applications. AB - Real-time imaging of (13)C metabolism in vivo has been enabled by recent advances in hyperpolarization. As a result of the inherently low natural abundance of endogenous (13)C nuclei, hyperpolarized (13)C images lack structural information that could be used to aid in motion detection and anatomical registration. Motion before or during the (13)C acquisition can therefore result in artifacts and misregistration that may obscure measures of metabolism. In this work, we demonstrate a method to simultaneously image both (1)H and (13)C nuclei using a dual-nucleus spectral-spatial radiofrequency excitation and a fully coincident readout for rapid multinuclear spectroscopic imaging. With the appropriate multinuclear hardware, and the means to simultaneously excite and receive on both channels, this technique is straightforward to implement requiring little to no increase in scan time. Phantom and in vivo experiments were performed with both Cartesian and spiral trajectories to validate and illustrate the utility of simultaneous acquisitions. Motion compensation of dynamic metabolic measurements acquired during free breathing was demonstrated using motion tracking derived from (1)H data. Simultaneous multinuclear imaging provides structural (1)H and metabolic (13)C images that are correlated both spatially and temporally, and are therefore amenable to joint (1)H and (13)C analysis and correction of structure function images. PMID- 25810149 TI - NMR Logging to Estimate Hydraulic Conductivity in Unconsolidated Aquifers. AB - Nuclear magnetic resonance (NMR) logging provides a new means of estimating the hydraulic conductivity (K) of unconsolidated aquifers. The estimation of K from the measured NMR parameters can be performed using the Schlumberger-Doll Research (SDR) equation, which is based on the Kozeny-Carman equation and initially developed for obtaining permeability from NMR logging in petroleum reservoirs. The SDR equation includes empirically determined constants. Decades of research for petroleum applications have resulted in standard values for these constants that can provide accurate estimates of permeability in consolidated formations. The question we asked: Can standard values for the constants be defined for hydrogeologic applications that would yield accurate estimates of K in unconsolidated aquifers? Working at 10 locations at three field sites in Kansas and Washington, USA, we acquired NMR and K data using direct-push methods over a 10- to 20-m depth interval in the shallow subsurface. Analysis of pairs of NMR and K data revealed that we could dramatically improve K estimates by replacing the standard petroleum constants with new constants, optimal for estimating K in the unconsolidated materials at the field sites. Most significant was the finding that there was little change in the SDR constants between sites. This suggests that we can define a new set of constants that can be used to obtain high resolution, cost-effective estimates of K from NMR logging in unconsolidated aquifers. This significant result has the potential to change dramatically the approach to determining K for hydrogeologic applications. PMID- 25810150 TI - Oil refinery experience with the assessment of refinery effluents and receiving waters using biologically based methods. AB - The trend in discharges of petroleum-related substances from refineries in Europe shows a consistent picture of declining emissions, since first measured in 1969. This decline coincides with enhanced internal capture or recycling procedures and increasing use of physical and biological treatments. At the same time, and partly in response to legislative drivers, there has been an increase in the use of chronic (long-term) toxicity tests and alternative methods for assessing the quality of effluent discharges. The Whole Effluent Assessment (WEA) approach has also driven the increased conduct of studies addressing the fate of effluent constituents. Such studies have included the use of biodegradation and solid phase micro-extraction-biomimetic extraction (SPME-BE) methods to address potentially bioaccumulative substances (PBS). In this way, it is then possible to address the persistence and toxicity of these PBS constituents of an effluent. The data collected in various case studies highlights the advantages and pitfalls of using biologically-based methods to assess the potential for refinery effluents to cause environmental impacts. PMID- 25810151 TI - Theory and practice: bulk synthesis of C3B and its H2- and Li-storage capacity. AB - Previous theoretical studies of C3B have suggested that boron-doped graphite is a promising H2- and Li-storage material, with large maximum capacities. These characteristics could lead to exciting applications as a lightweight H2-storage material for automotive engines and as an anode in a new generation of batteries. However, for these applications to be realized a synthetic route to bulk C3B must be developed. Here we show the thermolysis of a single-source precursor (1,3 (BBr2)2C6H4) to produce graphitic C3B, thus allowing the characteristics of this elusive material to be tested for the first time. C3B was found to be compositionally uniform but turbostratically disordered. Contrary to theoretical expectations, the H2- and Li-storage capacities are lower than anticipated, results that can partially be explained by the disordered nature of the material. This work suggests that to model the properties of graphitic materials more realistically, the possibility of disorder must be considered. PMID- 25810152 TI - Show them the money? The role of pay, managerial need support, and justice in a self-determination theory model of intrinsic work motivation. AB - The link between money and motivation has been a debated topic for decades, especially in work organizations. However, field studies investigating the amount of pay in relation to employee motivation is lacking and there have been calls for empirical studies addressing compensation systems and motivation in the work domain. The purpose of this study was to examine outcomes associated with the amount of pay, and perceived distributive and procedural justice regarding pay in relation to those for perceived managerial need support. Participants were 166 bank employees who also reported on their basic psychological need satisfaction and intrinsic work motivation. SEM-analyses tested a self-determination theory (SDT) model, with satisfaction of the competence and autonomy needs as an intervening variable. The primary findings were that amount of pay and employees' perceived distributive justice regarding their pay were unrelated to employees' need satisfaction and intrinsic work motivation, but procedural justice regarding pay did affect these variables. However, managerial need support was the most important factor for promoting need satisfaction and intrinsic work motivation both directly, indirectly, and as a moderator in the model. Hence, the results of the present organizational field study support earlier laboratory experiments within the SDT framework showing that monetary rewards did not enhance intrinsic motivation. This seems to have profound implications for organizations concerned about motivating their employees. PMID- 25810153 TI - Notch signaling regulates venous arterialization during zebrafish fin regeneration. AB - To protect against blood pressure, a mature artery is supported by mural cells which include vascular smooth muscle cells and pericytes. To regenerate a functional vascular system, arteries should be properly reconstructed with mural cells although the mechanisms underlying artery reconstruction remain unclear. In this study, we examined the process of artery reconstruction during regeneration of the zebrafish caudal fin as a model to study arterial formation in an adult setting. During fin regeneration, the arteries and veins form a net-like vasculature called the vascular plexus, and this plexus undergoes remodeling to form a new artery and two flanking veins. We found that the new vascular plexus originates mainly from venous cells in the stump but very rarely from the arterial cells. Interestingly, these vein-derived cells contributed to the reconstructed arteries. This arterialization was dependent on Notch signaling, and further analysis showed that Notch signaling was required for the initiation of arterial gene expression. In contrast, venous remodeling did not require Notch signaling. These results provide new insights toward understanding mechanisms of vascular regeneration and illustrate the utility of the adult zebrafish fin to study this process. PMID- 25810154 TI - Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. AB - BACKGROUND: The purpose of this report was to present the results of accelerated radiotherapy (RT) with concomitant weekly cisplatin in head and neck cancer. METHODS: One hundred six patients received concomitant cisplatin 40 mg/m(2) weekly with accelerated RT up to a dose of 68 Gy over 5.5 weeks. RESULTS: Ninety nine percent of the patients received planned RT and 90% received >=5 cycles of cisplatin. Moist desquamation of skin developed in 45% and confluent mucositis in 82%. Feeding tubes were required in 79% of the patients, and after 12 months in 4%. One patient developed nephrotoxicity. Three-year locoregional control, disease-free survival (DFS), and overall survival (OS) were 72%, 54%, and 61%, respectively. Human papillomavirus (HPV) status was positive on polymerase chain reaction (PCR) and p16 in 11 of 50 patients with oropharyngeal carcinoma. Three year OS was 81% and 66% in HPV-positive versus HPV-negative patients with oropharyngeal carcinoma. CONCLUSION: Concomitant weekly cisplatin 40 mg/m(2) with accelerated RT was well tolerated and treatment compliance was high. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E559-E565, 2016. PMID- 25810155 TI - Late outcomes in adults with coarctation of the aorta. AB - AIMS: Previous cohort studies of patients with coarctation of the aorta (CoA) demonstrate reduced long-term survival. Improved surgical outcomes in children and evolution of adult congenital heart disease (ACHD) services have resulted in improved survival in patients with other CHDs. We hypothesise that for young adult patients with CoA long-term outcomes have improved in the contemporary era. METHODS: 151 patients (58% men) with simple CoA followed up at a tertiary ACHD service in Sydney, Australia, from 1993 to 2013 were included. We documented mortality and major morbidity such as the need for re-intervention for re coarctation or aneurysms. RESULTS: 140 patients (mean age 35+/-15 years) underwent CoA repair at median age of 5 (IQR 0-10) years. Initial surgical strategy included end-to-end repair in 43, subclavian flap aortoplasty in 28 and patch aortoplasty in 31 patients (and was not documented in 28 cases). 6 patients had endovascular repair, 4 had interposition tube grafts and 11 were unrepaired. There were a total of seven deaths at a median age of 60 years. Actuarial survival was 98% at 40, 98% at 50 and 89% at 60 years of age. Re-coarctation occurred in 34% and descending aortic aneurysms were noted in 18%. Patients with end-to-end repair had lower rates of significant re-coarctation or descending aortic aneurysms (p=0.026 and <0.001, respectively). 66% had bicuspid aortic valve and 44% were hypertensive. CONCLUSIONS: Patients with CoA who reach adolescence demonstrate very good long-term survival up to age 60 years. Long term morbidity is common, however, related largely to aortic complications and late hypertension. PMID- 25810156 TI - Therapy for secondary mitral regurgitation: time to 'cut the chord'? PMID- 25810157 TI - A link between individual differences in multisensory speech perception and eye movements. AB - The McGurk effect is an illusion in which visual speech information dramatically alters the perception of auditory speech. However, there is a high degree of individual variability in how frequently the illusion is perceived: some individuals almost always perceive the McGurk effect, while others rarely do. Another axis of individual variability is the pattern of eye movements make while viewing a talking face: some individuals often fixate the mouth of the talker, while others rarely do. Since the talker's mouth carries the visual speech necessary information to induce the McGurk effect, we hypothesized that individuals who frequently perceive the McGurk effect should spend more time fixating the talker's mouth. We used infrared eye tracking to study eye movements as 40 participants viewed audiovisual speech. Frequent perceivers of the McGurk effect were more likely to fixate the mouth of the talker, and there was a significant correlation between McGurk frequency and mouth looking time. The noisy encoding of disparity model of McGurk perception showed that individuals who frequently fixated the mouth had lower sensory noise and higher disparity thresholds than those who rarely fixated the mouth. Differences in eye movements when viewing the talker's face may be an important contributor to interindividual differences in multisensory speech perception. PMID- 25810158 TI - Observation of time-dependent psychophysical functions and accounting for threshold drifts. AB - Methods to obtain estimates of psychophysical functions are used in numerous fields, such as audiology, vision, and pain. Neurophysiological and psychological processes underlying this function are assumed to remain stationary throughout a psychophysical experiment. However, violation of this assumption (e.g., due to habituation or changing decisional factors) likely affects the estimates of psychophysical parameters. We used computer simulations to study how non stationary processes, resulting in a time-dependent psychophysical function, affect threshold and slope estimates. Moreover, we propose methods to improve the estimation quality when stationarity is violated. A psychophysical detection experiment was modeled as a stochastic process ruled by a logistic psychophysical function. The threshold was modeled to drift over time and was defined as either a linear or nonlinear function. Threshold and slope estimates were obtained by using three estimation procedures: a static procedure assuming stationarity, a relaxed procedure accounting for linear effects of time, and a threshold tracking paradigm. For illustrative purposes, data acquired from two human subjects were used to estimate their thresholds and slopes using all estimation procedures. Threshold estimates obtained by all estimations procedures were similar to the mean true threshold. However, due to threshold drift, the slope was underestimated by the static procedure. The relaxed procedure only underestimated the slope when the threshold drifted nonlinearly over time. The tracking paradigm performed best and therefore, we recommend using the tracking paradigm in human psychophysical detection experiments to obtain estimates of the threshold and slope and to identify the mode of non-stationarity. PMID- 25810159 TI - Involuntary attentional capture by task-irrelevant objects that match the search template for category detection in natural scenes. AB - Theories of visual search postulate that the selection of targets amongst distractors involves matching visual input to a top-down attentional template. Previous work has provided evidence that feature-based attentional templates affect visual processing globally across the visual field. In the present study, we asked whether more naturalistic, category-level attentional templates also modulate visual processing in a spatially global and obligatory way. Subjects were cued to detect people or cars in a diverse set of photographs of real-world scenes. On a subset of trials, silhouettes of people and cars appeared in search irrelevant locations that subjects were instructed to ignore, and subjects were required to respond to the location of a subsequent dot probe. In three experiments, results showed a consistency effect on dot-probe trials: dot probes were detected faster when they appeared in the location of the cued category compared with the non-cued category, indicating attentional capture by template matching stimuli. Experiments 1 and 2 showed that this capture was involuntary: consistency effects persisted under conditions in which attending to silhouettes of the cued category was detrimental to performance. Experiment 3 tested whether these effects could be attributed to non-attentional effects related to the processing of the category cues. Results showed a consistency effect when subjects searched for category exemplars but not when they searched for objects semantically related to the cued category. Together, these results indicate that attentional templates for familiar object categories affect visual processing across the visual field, leading to involuntary attentional capture by template matching stimuli. PMID- 25810162 TI - Are processing limitations of visual attention and response selection subject to the same bottleneck in dual-tasks? AB - Visual attention and response selection are processes that are limited by capacity. The present study focuses on whether visual attention is subject to the response selection bottleneck. This was investigated by conducting 2 dual-task experiments of the psychological refractory period (PRP) type. A visual conjunction search task was chosen as Task 2 in these experiments. Conjunction search requires the binding of the stimulus' defining features. This binding is performed in a serial search process in displays of different amounts of stimuli until the presence or absence of the target is correctly indicated. In Experiment 1, the conjunction search was combined with a 2-choice tone discrimination Task 1, and in Experiment 2 with a 2-choice color discrimination Task 1. Detailed reaction time (RT) analyses revealed concurrent performance of visual search to both tone and color in Task 1's response selection. In conclusion, visual attention is not subject to the response selection bottleneck. PMID- 25810161 TI - Transfer of attunement in length perception by dynamic touch. AB - Earlier studies have revealed that the calibration of an action sometimes transfers in a functionally specific way-the calibration of one action transfers to other actions that serve the same goal, even when they are performed with different anatomical structures. In the present study, we tested whether attunement (the process by which perceivers learn to detect a more useful, specifying, informational pattern) follows such a functional organization. Participants were trained to perceive the length of rods by dynamic touch with one of their effectors. It was found that training the right hand resulted in an attunement to a specifying variable with both hands, but not with the feet. Training the other limbs did not result in attunement. However, substantial individual differences were found. The implications of the results are explored for theories on the organization of perceptual learning and discussions on individual differences in perception. PMID- 25810160 TI - The capacity limitations of orientation summary statistics. AB - The simultaneous-sequential method was used to test the processing capacity of establishing mean orientation summaries. Four clusters of oriented Gabor patches were presented in the peripheral visual field. One of the clusters had a mean orientation that was tilted either left or right, whereas the mean orientations of the other three clusters were roughly vertical. All four clusters were presented at the same time in the simultaneous condition, whereas the clusters appeared in temporal subsets of two in the sequential condition. Performance was lower when the means of all four clusters had to be processed concurrently than when only two had to be processed in the same amount of time. The advantage for establishing fewer summaries at a given time indicates that the processing of mean orientation engages limited-capacity processes (Exp. 1). This limitation cannot be attributed to crowding, low target-distractor discriminability, or a limited-capacity comparison process (Exps. 2 and 3). In contrast to the limitations of establishing multiple summary representations, establishing a single summary representation unfolds without interference (Exp. 4). When interpreted in the context of recent work on the capacity of summary statistics, these findings encourage a reevaluation of the view that early visual perception consists of creating summary statistic representations that unfold independently across multiple areas of the visual field. PMID- 25810164 TI - Successful Treatment Toward Gastrointestinal Stromal Tumors with Aggressive Behavior. PMID- 25810163 TI - Impact of gender on use of revascularization in acute coronary syndromes: the national observational study of diagnostic and interventional cardiac catheterization (ONACI). AB - OBJECTIVES: To assess the impact of gender on myocardial revascularization using data collected in a French nationwide registry: the national observational study of diagnostic and interventional cardiac catheterization (ONACI). BACKGROUND: Gender differences in management of patients with acute coronary syndromes (ACS) have been reported. METHODS: We analysed data from a nationwide French prospective multicentre registry including 64,932 suspected ACS patients recruited in 99 centres from 2004 to 2008. RESULTS: Overall, women were older (70.7 +/- 12.7 vs. 63.8 +/- 12.9 years), had a higher cardiovascular risk profile, and were more frequently admitted with non ST-elevation myocardial infarction or unstable angina (NSTEMI/UA) compared to men (73% vs. 68%). Women had significantly more angiographically normal coronary arteries or non significant coronary artery disease (CAD) in both STEMI (6% vs. 3%) and NSTEMI/UA (21% vs. 11%) while men had more severe CAD. After adjusting for age, cardiovascular risk factors, and extent of disease, myocardial revascularization (defined as the use of percutaneous coronary intervention (PCI) or coronary artery bypass grafting) was less frequently used in women (adjusted OR = 0.78; 95% CI: 0.77-0.83). For those receiving PCI, in-hospital mortality within 24 hr of intervention was higher in women (3.6% vs. 1.2%; adjusted OR = 1.51; 95% CI: 1.22-1.87). CONCLUSIONS: In the present study, despite having a higher cardiovascular risk profile, women more frequently had normal vessel/non significant angiographic coronary artery disease. In patients with significant coronary artery disease, myocardial revascularization was less frequently used in women whatever the type of ACS. PMID- 25810166 TI - Results after sacral nerve stimulation for chronic constipation. AB - BACKGROUND: Sacral nerve stimulation is an established treatment for fecal incontinence and initial reports describe successful results also in subjects with chronic constipation. METHODS: Consecutive patients with slow transit or outlet obstruction type constipation were offered external stimulation through a test electrode inserted in a sacral foramen during a 3-week period. The symptomatic evaluation was based on the number of bowel movements and a validated obstructed defecation score (ODS). A permanent implant was performed provided an overall 50% decrease in symptoms was observed. KEY RESULTS: In total, 44 patients with chronic constipation were treated with a 3-week test stimulation. Fifteen experienced a 50% reduction of symptoms and received a permanent implant. Four of the 15 with permanent implants were explanted during the course of the study. Five subjects (11% of original group) reported sustained symptom relief at final follow-up after a mean of 24 months (range 4-81). Mean ODS score did not change during the treatment. Patients with predominantly slow transit constipation or outlet obstruction did not differ concerning success rate. CONCLUSIONS & INFERENCES: Sacral nerve stimulation has limited efficacy in unselected patients with chronic constipation and cannot be recommended for treatment on routine basis. PMID- 25810165 TI - Concomitant chemoradiotherapy with Cisplatin plus 5-Fluorouracil for anal squamous cell carcinoma. AB - OBJECTIVE: The objective of this study was to evaluate the results of combined chemoradiotherapy using 5-fluorouracil and cisplatin with radiation in treatment of anal squamous cell carcinoma in terms of local control, survival, and toxicity. PATIENTS AND METHODS: This study included 32 patients with histologically confirmed locally advanced anal squamous cell carcinoma (T1-4 with any N). They received chemotherapy consisted of 5-fluorouracil 1000 mg/m(2)/day on the first 5 and last 5 days of RT, cisplatin 75 mg/m(2) on days 2 and 30. External beam RT consisted of 45Gy/f/25 sessions/5 sessions per week. A boost of 9Gy/5 sessions was given to those who developed complete or partial response. RESULTS: Median age was 55 years with female to male ratio 2.2:1. Fifty-six percent of them had ECOGPS of 1; moderately differentiated pathology was the most common one (53 %). Thirteen patients (40.6 %) presented with N0 and 56 % presented with T2. None of the patients died of acute complications and none developed grade 4 toxicity. Non-hematological complications were more common than hematological ones. Dermatitis was the most common toxicity (59.3 %) than diarrhea and neurologic one (40.7 %). Anemia was the most frequent hematological adverse event (37.5 %). Complete response was reported in 81.2 %. After median follow-up of 25 months, local recurrence was observed in five patients (15.6 %) as the following: three in the anal canal and two in the inguinal lymph nodes. Three patients (9.4 %) developed distant metastasis (two in the liver and one in the lung), while one patient (3 %) had both local and distant metastases. Three year overall survival rate (OS) was 81.3 %, while 3-year progression-free survival (PFS) rate was 72 %, and colostomy-free survival was 90 %. CONCLUSION: Concomitant chemoradiotherapy of 5-fluorouracil and cisplatin with radiotherapy is a highly effective and well-tolerated treatment of anal cancer. But further studies with larger number of patients are needed to support the indication to treat anal cancer using this regimen. PMID- 25810167 TI - Rethinking the brain. PMID- 25810169 TI - About time. PMID- 25810168 TI - Applied prestige. PMID- 25810182 TI - Inside the first pig biobank. PMID- 25810170 TI - Intelligent robots must uphold human rights. PMID- 25810183 TI - Climate modellers take tropical approach. PMID- 25810184 TI - Cloud cover protects gene data. PMID- 25810185 TI - Bright spots hint at active ice on Ceres. PMID- 25810186 TI - Biotech boot camp. PMID- 25810187 TI - Sustainability: Five steps for managing Europe's forests. PMID- 25810189 TI - Don't edit the human germ line. PMID- 25810192 TI - Typhoons: Storm-surge models helped for Hagupit. PMID- 25810194 TI - Support staff: Build reward system for ace technicians. PMID- 25810193 TI - Research management: Leadership training for African scientists. PMID- 25810195 TI - Corresponding authors: Is there fame bias in editorial choice? PMID- 25810196 TI - Data protection: Big data held to privacy laws, too. PMID- 25810197 TI - Correction. PMID- 25810198 TI - Physical chemistry: Square ice in a graphene sandwich. PMID- 25810199 TI - Molecular biology: DNA replication reconstructed. PMID- 25810200 TI - Developmental biology: Earn your wings. PMID- 25810201 TI - Quantum physics: Atomic doughnuts from single photons. PMID- 25810203 TI - Galaxy formation: When the wind blows. PMID- 25810204 TI - Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy. AB - Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 * 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows). PMID- 25810205 TI - Entanglement with negative Wigner function of almost 3,000 atoms heralded by one photon. AB - Quantum-mechanically correlated (entangled) states of many particles are of interest in quantum information, quantum computing and quantum metrology. Metrologically useful entangled states of large atomic ensembles have been experimentally realized, but these states display Gaussian spin distribution functions with a non-negative Wigner quasiprobability distribution function. Non Gaussian entangled states have been produced in small ensembles of ions, and very recently in large atomic ensembles. Here we generate entanglement in a large atomic ensemble via an interaction with a very weak laser pulse; remarkably, the detection of a single photon prepares several thousand atoms in an entangled state. We reconstruct a negative-valued Wigner function--an important hallmark of non-classicality--and verify an entanglement depth (the minimum number of mutually entangled atoms) of 2,910 +/- 190 out of 3,100 atoms. Attaining such a negative Wigner function and the mutual entanglement of virtually all atoms is unprecedented for an ensemble containing more than a few particles. Although the achieved purity of the state is slightly below the threshold for entanglement induced metrological gain, further technical improvement should allow the generation of states that surpass this threshold, and of more complex Schrodinger cat states for quantum metrology and information processing. More generally, our results demonstrate the power of heralded methods for entanglement generation, and illustrate how the information contained in a single photon can drastically alter the quantum state of a large system. PMID- 25810206 TI - Square ice in graphene nanocapillaries. AB - Bulk water exists in many forms, including liquid, vapour and numerous crystalline and amorphous phases of ice, with hexagonal ice being responsible for the fascinating variety of snowflakes. Much less noticeable but equally ubiquitous is water adsorbed at interfaces and confined in microscopic pores. Such low-dimensional water determines aspects of various phenomena in materials science, geology, biology, tribology and nanotechnology. Theory suggests many possible phases for adsorbed and confined water, but it has proved challenging to assess its crystal structure experimentally. Here we report high-resolution electron microscopy imaging of water locked between two graphene sheets, an archetypal example of hydrophobic confinement. The observations show that the nanoconfined water at room temperature forms 'square ice'--a phase having symmetry qualitatively different from the conventional tetrahedral geometry of hydrogen bonding between water molecules. Square ice has a high packing density with a lattice constant of 2.83 A and can assemble in bilayer and trilayer crystallites. Molecular dynamics simulations indicate that square ice should be present inside hydrophobic nanochannels independently of their exact atomic nature. PMID- 25810207 TI - Increases in tropical rainfall driven by changes in frequency of organized deep convection. AB - Increasing global precipitation has been associated with a warming climate resulting from a strengthening of the hydrological cycle. This increase, however, is not spatially uniform. Observations and models have found that changes in rainfall show patterns characterized as 'wet-gets-wetter' and 'warmer-gets wetter'. These changes in precipitation are largely located in the tropics and hence are probably associated with convection. However, the underlying physical processes for the observed changes are not entirely clear. Here we show from observations that most of the regional increase in tropical precipitation is associated with changes in the frequency of organized deep convection. By assessing the contributions of various convective regimes to precipitation, we find that the spatial patterns of change in the frequency of organized deep convection are strongly correlated with observed change in rainfall, both positive and negative (correlation of 0.69), and can explain most of the patterns of increase in rainfall. In contrast, changes in less organized forms of deep convection or changes in precipitation within organized deep convection contribute less to changes in precipitation. Our results identify organized deep convection as the link between changes in rainfall and in the dynamics of the tropical atmosphere, thus providing a framework for obtaining a better understanding of changes in rainfall. Given the lack of a distinction between the different degrees of organization of convection in climate models, our results highlight an area of priority for future climate model development in order to achieve accurate rainfall projections in a warming climate. PMID- 25810209 TI - Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations. AB - Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail. PMID- 25810211 TI - Voice outcomes following endolaryngeal surgery; are we achieving our aims? AB - OBJECTIVE: To determine voice outcomes in endolaryngeal surgery. METHODS: Prospective assessment of patients undergoing endolaryngeal surgery in one head and neck team in North Glasgow from 2007 to 2014. Each patient completed a VoiSS (the Voice Symptom Scale) questionnaire at pre-assessment and post-endolaryngeal surgery. Per-operatively, the aim of the procedure was recorded from a choice of seven options in addition to the clinical conditions and the procedure. RESULTS: One thousand and sixty-six patient episodes were recorded. Thirty-two had incomplete data at pre-assessment and were excluded. Of the remainder, 703 (68%) had complete paired data sets. 'To improve voice' (n = 169, 24%) and 'to achieve a biopsy with no deterioration in voice' (n = 185, 26%) categories had significant outcomes in keeping with the operative aims. CONCLUSION: This study demonstrated that it is possible to assess patient reported voice outcomes in universal heterogeneous endolaryngeal surgery cohort over a prolonged period. The voice outcomes were in keeping with the stated aims of the endolaryngeal surgical procedures. PMID- 25810210 TI - The Human Embryoid Body Cystic Core Exhibits Architectural Complexity Revealed by use of High Throughput Polymer Microarrays. AB - In pluripotent stem cell differentiation, embryoid bodies (EBs) provide a three dimensional [3D] multicellular precursor in lineage specification. The internal structure of EBs is not well characterized yet is predicted to be an important parameter to differentiation. Here, we use custom SU-8 molds to generate transparent lithography-templated arrays of polydimethylsiloxane (LTA-PDMS) for high throughput analysis of human embryonic stem cell (hESC) EB formation and internal architecture. EBs formed in 200 and 500 MUm diameter microarray wells by use of single cells, 2D clusters, or 3D early aggregates were compared. We observe that 200 MUm EBs are monocystic versus 500 MUm multicystic EBs that contain macro, meso and microsized cysts. In adherent differentiation of 500 MUm EBs, the multicystic character impairs the 3D to 2D transition creating non uniform monolayers. Our findings reveal that EB core structure has a size dependent character that influences its architecture and cell population uniformity during early differentiation. PMID- 25810213 TI - Effects of noninvasive ventilation on heart rate variability after coronary bypass grafting: comparison between ventilators. PMID- 25810212 TI - Understanding preload reserve using functional hemodynamic monitoring. PMID- 25810215 TI - Evaluation of autoimmune thyroid disease in melasma. AB - Melasma is one of the most frequently acquired hyperpigmentation disorders clinically characterized by symmetrical brown patches on sun-exposed areas. To date, few studies have been conducted about the relationship between thyroid autoimmun-ity and melasma. To evaluate the thyroid dysfunction and autoimmunity in nonpregnant women with melasma. A total of 70 women with melasma and 70 age matched healthy women with no history of melasma were enrolled in the study. We studied the thyroid hormone profile in both groups. The statistical analysis was performed using SPSS software. Patients with melasma had 18.5% frequency of thyroid disorders, and 15.7% had positive anti-TPO, while subjects from the control group had a 4.3% frequency of thyroid abnormalities, and only 5.7% had positive anti-TPO. There was a significantly higher prevalence of thyroid dysfunction in women with melasma compared with control group (P = 0.008). This study suggests that there is a relationship between thyroid autoimmunity and melasma. However, to make recommendations on screening for thyroid disease in patients with melasma, future research of good methodological quality is needed. PMID- 25810214 TI - Year in review in Intensive Care Medicine 2014: III. Severe infections, septic shock, healthcare-associated infections, highly resistant bacteria, invasive fungal infections, severe viral infections, Ebola virus disease and paediatrics. PMID- 25810216 TI - Clinical characteristics of rotavirus gastroenteritis with urinary crystals. AB - BACKGROUND: Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. In addition, some patients with acute obstructive uropathy due to ammonium acid urate stones, developing approximately 6-7 days after the onset of rotavirus gastroenteritis, have been reported, mainly in Japan. The pathophysiological mechanism responsible for stone formation has not been clarified. In the present study, we investigated the clinical characteristics of these patients, and analyzed the pathophysiology underlying the formation of urinary stones. METHODS: A total of 164 patients were enrolled. All had acute gastroenteritis due to rotavirus infection and were treated at Osaka Medical College Hospital and affiliated hospitals between January 2009 and May 2011. All were younger than 15 years of age, and their laboratory data, including urinalysis, were available. RESULTS: Among the enrolled patients, 30 (20 boys and 10 girls aged 0.2-10 years; median, 1.5 years; interquartile range, 1-3 years) had crystals in their urine. Most of the patients were admitted approximately 2 days after onset of gastroenteritis and had hyperuricemia and aciduria. The crystals consisted mainly of uric acid, and rarely of ammonium acid urate. CONCLUSION: In order for ammonium acid urate stones to form in patients with acute obstructive uropathy associated with rotavirus gastroenteritis, prolonged continuous acidosis with hyperuricemia, might be necessary. Therefore, normalization of metabolic acidosis is important in order to prevent the onset of obstructive uropathy associated with rotavirus gastroenteritis. PMID- 25810217 TI - Enhanced power generation in annular single-chamber microbial fuel cell via optimization of electrode spacing using chocolate industry wastewater. AB - Development and practical application of microbial fuel cell (MFC) is restricted because of the limitations such as low power output. To overcome low power limitation, the optimization of specific parameters including electrode materials and surface area, electrode spacing, and MFC's cell shape was investigated. To the best of our knowledge, no investigation has been reported in the literature to implement an annular single-chamber microbial fuel cell (ASCMFC) using chocolate industry wastewater. ASCMFC was fabricated via optimization of the stated parameters. The aspects of ASCMFC were comprehensively examined. In this study, the optimization of electrode spacing and its impact on performance of the ASCMFC were conducted. Reduction of electrode spacing by 46.15% (1.3-0.7 cm) resulted in a decrease in internal resistance from 100 to 50 Omega, which enhanced the power density and current output to 22.898 W/m(3) and 6.42 mA, respectively. An optimum electrode spacing of 0.7 cm was determined. Through this paper, the effects of these parameters and the performance of ASCMFC are also evaluated. PMID- 25810218 TI - Comparison of anthropometric measures as predictors of cancer incidence: A pooled collaborative analysis of 11 Australian cohorts. AB - Obesity is a risk factor for cancer. However, it is not known if general adiposity, as measured by body mass index (BMI) or central adiposity [e.g., waist circumference (WC)] have stronger associations with cancer, or which anthropometric measure best predicts cancer risk. We included 79,458 men and women from the Australian and New Zealand Diabetes and Cancer Collaboration with complete data on anthropometry [BMI, WC, Hip Circumference (HC), WHR, waist to height ratio (WtHR), A Body Shape Index (ABSI)], linked to the Australian Cancer Database. Cox proportional hazards models assessed the association between each anthropometric marker, per standard deviation and the risk of overall, colorectal, post-menopausal (PM) breast, prostate and obesity-related cancers. We assessed the discriminative ability of models using Harrell's c-statistic. All anthropometric markers were associated with overall, colorectal and obesity related cancers. BMI, WC and HC were associated with PM breast cancer and no significant associations were seen for prostate cancer. Strongest associations were observed for WC across all outcomes, excluding PM breast cancer for which HC was strongest. WC had greater discrimination compared to BMI for overall and colorectal cancer in men and women with c-statistics ranging from 0.70 to 0.71. We show all anthropometric measures are associated with the overall, colorectal, PM breast and obesity-related cancer in men and women, but not prostate cancer. WC discriminated marginally better than BMI. However, all anthropometric measures were similarly moderately predictive of cancer risk. We do not recommend one anthropometric marker over another for assessing an individuals' risk of cancer. PMID- 25810221 TI - Erratum to: the WHO ultrasonography protocol for assessing morbidity due to Schistosoma haematobium. Acceptance and evolution over 14 years. Systematic review. PMID- 25810220 TI - Anisakis infection in allis shad, Alosa alosa (Linnaeus, 1758), and twaite shad, Alosa fallax (Lacepede, 1803), from Western Iberian Peninsula Rivers: zoonotic and ecological implications. AB - Spawning individuals of allis shad, Alosa alosa (Linnaeus, 1758), and twaite shad, Alosa fallax (Lacepede, 1803), were sampled from three rivers on the Atlantic coast of the Iberian Peninsula (Ulla, Minho, Mondego) during 2008 to 2013 to assess the presence of the zoonotic marine parasite Anisakis spp. larvae. The results revealed that both shad species were infected by third-larval stage Anisakis simplex s.s. and Anisakis pegreffii. The latter is reported in mixed infections in both shad species of Western Iberian Peninsula for the first time. In A. alosa, the prevalence of Anisakis infection can reach 100%, while in A. fallax, prevalence was up to 83%. Infected individuals of the former species also often contain much higher number of parasites in theirs internal organs and flesh: from 1 to 1138 Anisakis spp. larvae as compared to 1 to 121 larvae, respectively. In general, numbers of A. pegreffii were higher than those of A. simplex s.s. Our results suggest that in the marine environment of the Western Iberian Peninsula, both anadromous shad species act as paratenic hosts for A. simplex s.s. and A. pegreffii, thus widening the distribution of the infective nematode larvae from the marine to the freshwater ecosystem. This finding is of great epidemiological relevance for wildlife managers and consumers, considering the zoonotic and gastroallergic threats posed of these parasites. PMID- 25810219 TI - Anti-skin ageing activity of napthoquinones from Arnebia nobilis Reichb.f. AB - The present isolation and identification of napthoquinones from roots of Arnebia nobilis Reichb.f. can lead to the discovery of new anti-skin ageing ingredient in colour cosmetics. Four compounds have been isolated and purified by rigorous column chromatography. The compounds are identified as beta, beta-dimethylacryl alkannin (AN-I), acetoxyisovaleryl alkannin (AAN-II), acetyl alkannin (AN-III) and alkannin (AN-IV) by interpretation of spectroscopic data. This study is the first to report the isolation of Acetoxyisovaleryl alkannin (AAN-II) from A. nobilis. The IC50 values of the compounds, determined in human skin cells (human dermal fibroblasts and human keratinocytes) and mouse embryonic fibroblasts (NIH3T3) varied significantly among the four alkannins. Among the four compounds, beta-acetoxyisovaleryl alkannin (AAN-II) significantly inhibited hydrogen peroxide (H2O2)-induced red blood corpuscle haemolysis and cellular senescence in human dermal fibroblasts. Collagen-I, elastin and involucrin syntheses in human dermal fibroblasts or keratinocytes were up regulated by AAN-II. These results support the potential utility of alkannins as novel anti-ageing ingredients. PMID- 25810223 TI - Cloning and expression of anthocyanin biosynthetic genes in red and white pomegranate. AB - Exterior fruit color is an important trait for the evaluation of pomegranate fruit quality, but the molecular mechanism underlying the variation in color between red- and white-fruited pomegranate is poorly understood. In this study, full-length cDNA clones encoding enzymes involved in anthocyanin biosynthesis such as chalcone synthase, chalcone isomerase, flavanone 3-hydoxylase, dihydroflavonol 4-reductase, anthocyanidin synthase (ANS), UDP-glucose-flavonoid 3-O-glucosyltransferase, and the R2R3 MYB transcription factor PgMYB-were isolated from fruit peels. In addition, transcript levels of anthocyanin biosynthetic genes were quantitatively measured by real-time PCR in red and white fruits. In both cultivars, two expression peaks for structural genes were detected during fruit development, whereas only one peak was observed-during early development-for PgMYB. While PgMYB is important for flavonoid biosynthesis, other transcription factors appear to also be necessary for the regulation of anthocyanin biosynthesis. No anthocyanins were detected in the white cultivar. Peels of white fruits contained transcripts of all identified genes except for PgANS, suggesting that the lack of PgANS expression may be the main factor responsible for the absence of anthocyanins in white pomegranate. PgANS may be the key gene involved in anthocyanin biosynthesis in pomegranate fruit. PMID- 25810224 TI - Synthesis and Structure-Property Relationships of Phosphole-Based pi Systems and Their Applications in Organic Solar Cells. AB - Phosphole is a chemically tunable heterole, and its pi-conjugated derivatives are potential candidates for optoelectronic materials. This account describes recent developments in the synthesis and structure-property relationships of pi conjugated phosphole derivatives made by my research group. Thiophene-phosphole styrene, phosphole-acetylene-arene, oligophosphole, polyphosphole, areno[c]phosphole, and phosphole-heterole pi systems are synthesized using titanacycle-mediated metathesis and palladium-catalyzed cross-coupling reactions. The structural, optical, and electrochemical properties of selected compounds are discussed. Initial results on some applications of thiophene-phosphole copolymers, acenaphtho[c]phospholes, and amine-terthiophene-phosphole donor-pi acceptor dyes in organic solar cells are described. These results give valuable information and guidelines for designing new phosphorus-containing organic materials for molecular electronics. PMID- 25810222 TI - WIND1-based acquisition of regeneration competency in Arabidopsis and rapeseed. AB - Callus formation and de novo organogenesis often occur in the wounded tissues of plants. Although this regenerative capacity of plant cells has been utilized for many years, molecular basis for the wound-induced acquisition of regeneration competency is yet to be elucidated. Here we find that wounding treatment is essential for shoot regeneration from roots in the conventional tissue culture of Arabidopsis thaliana. Furthermore, we show that an AP2/ERF transcription factor WOUND INDUCED DEDIFFERENTIATION1 (WIND1) plays a pivotal role for the acquisition of regeneration competency in the culture system. Ectopic expression of WIND1 can bypass both wounding and auxin pre-treatment and increase de novo shoot regeneration from root explants cultured on shoot-regeneration promoting media. In Brassica napus, activation of Arabidopsis WIND1 also greatly enhances de novo shoot regeneration, further corroborating the role of WIND1 in conferring cellular regenerative capacity. Our data also show that sequential activation of WIND1 and an embryonic regulator LEAFY COTYLEDON2 enhances generation of embryonic callus, suggesting that combining WIND1 with other transcription factors promote efficient and organ-specific regeneration. Our findings in the model plant and crop plant point to a possible way to efficiently induce callus formation and regeneration by utilizing transcription factors as a molecular switch. PMID- 25810225 TI - Thai transplant registry: an important resource for the Asia Pacific region. PMID- 25810226 TI - Basal glucosuria is ubiquitous in critically ill patients. AB - The 'renal threshold for glucose' has never been evaluated in critically ill patients. Therefore, we aimed to investigate the renal glucose threshold in this patient group using high-sensitivity urine glucose assays. In this retrospective analysis of prospectively collected data, we analysed 100 consecutive critically ill patients from a medical intensive care unit (ICU). Arterial blood glucose and spot urine glucose were simultaneously quantified daily during the first week after ICU admission. Three hundred seventy-three pairs of blood/urine glucose were plotted in five pre-defined categories of blood glucose (<80, 80-109, 110 139, 140-179 and >=180 mg/dL). Urine glucose values of the five categories were compared using the Kruskal-Wallis test to assess the relation with blood glucose. Urine glucose was detected in virtually all of the urine samples. Urine glucose showed a positive nonlinear correlation with blood glucose and was significantly elevated at blood glucose levels of 140-179 and >=180 mg/dL compared with lower blood glucose ranges. Basal glucosuria is ubiquitous in critically ill patients. A 'soft' renal threshold for glucose is present at blood glucose levels in the range of 140-179 mg/dL. PMID- 25810227 TI - Dangers of broth after transplantation. AB - Serum creatinine is routinely used to monitor renal function in transplant recipients. External factors including diet, exercise and hydration status can also influence serum creatinine concentration on a day-to-day basis. We describe a case of a patient whose serum creatinine increased from 128 to 171 MUmol/L after ingestion of creatinine-rich (3098 MUmol/L) soup. A renal biopsy was performed but revealed no cause for the rise in creatinine and by the next day, serum creatinine had returned to baseline. We conducted two experiments to examine the effect of soup ingestion by healthy volunteers. We measured the creatinine concentration of various store-bought stock preparations and found creatinine concentrations less than one-quarter of that contained in our patient's homemade soup. A creatinine-rich soup (4334 MUmol/L) was ingested by six healthy volunteers age 33 (+/- 6.5) years with baseline normal serum creatinine 68 (+/- 14) MUmol/L. Mean (standard deviation) serum creatinine increased to 77 (+/- 11) MUmol/L 4 hours after soup ingestion (P = 0.0015, paired t-test). Mean (standard deviation) creatinine clearance, extrapolated from the 4 hour urine collection following soup ingestion, was high (267 +/- 198 mL/min) exhibiting a supra-normal creatinine clearance. The rate of serum creatinine rise was lower in volunteers compared with the transplant patient, consistent with the concept of renal functional reserve. Our case highlights the importance of taking dietary changes into account when interpreting serum creatinine as a measure of allograft function. PMID- 25810228 TI - Statins for chronic kidney disease not requiring dialysis. PMID- 25810229 TI - Statins for end-stage kidney disease treated with dialysis. PMID- 25810230 TI - Statins for kidney transplant recipients. PMID- 25810231 TI - Anuric renal failure in a patient with Waldenstrom's macroglobulinaemia. PMID- 25810232 TI - Ultra-low dose heparin locks perform well on non-tunnelled temporary haemodialysis catheters. PMID- 25810233 TI - Cost-effectiveness of becaplermin gel on wound healing of diabetic foot ulcers. AB - We sought to determine the long-term cost effectiveness (payer's perspective) of becaplermin gel plus good wound care (BGWC) vs. good wound care (GWC) alone in terms of wound healing and risk of amputation in patients with diabetic foot ulcers (DFUs). Outcomes data were derived from a propensity score-matched cohort from the Curative Health Services database between 1998 and 2004, which was followed for 20 weeks. A four-state Markov model was used to predict costs and outcomes of wound healing and risk of amputation for BGWC vs. GWC alone over 1 year in patients with DFU. The primary outcome was closed-wound weeks. Transition probabilities for healing and amputation were derived from the aforementioned propensity score-matched cohorts. Ulcer recurrence was estimated from the medical literature. Utilization for becaplermin was calculated using the dosing algorithm in the product labeling. Of 24,898 eligible patients, 9.6% received BGWC. Based on the model, patients treated with BGWC had substantially more closed-wound weeks compared with GWC (16.1 vs. 12.5 weeks, respectively). More patients receiving BGWC had healed wounds at 1 year compared with those receiving GWC (48.1% vs. 38.3%). Risk of amputation was lower in the BGWC cohort (6.8% vs. 9.8%). Expected annual direct costs for DFU were $21,920 for BGWC and $24,640 for GWC. BGWC was economically dominant over GWC, providing better outcomes at a lower cost in patients with DFU. Compared with GWC alone, BGWC is more effective in healing wounds and lowering amputation risk, thereby decreasing long-term costs for DFU. PMID- 25810234 TI - The Predictability from Skull Morphology of Temporalis and Masseter Muscle Cross Sectional Areas in Humans. AB - To carry out functional simulations of the masticatory system that aim to predict strain magnitudes it is important to apply appropriate jaw-elevator muscle forces. Force magnitude estimation from directly measured muscle physiological cross-sectional area or anatomical cross-sectional area (CSA) is not possible for fossils and skeletal material from museum collections. In these cases, muscle CSAs are often estimated from bony features. This approach has been shown to be inaccurate in a prior study based on direct measurements from cadavers. Postmortem alterations as well as age changes in muscle form might explain this discrepancy. As such, the present study uses CT images from 20 living individuals to directly measure temporalis and masseter muscle CSAs and estimated cross sectional areas (ECSAs) from bony features. The relationships between CSAs and ECSAs were assessed by comparing mean values and by examining correlations. ECSAs are up to 100% greater than CSA and the means of these variables for each muscle differ significantly. Further, ECSA is significantly correlated with CSA for temporalis but not masseter. Cranial centroid size is only significantly associated with CSA for temporalis. These findings indicate that ECSAs should be employed with caution in simulations of human masticatory system functioning; they do not reflect CSAs and it is plausible that this also applies to studies of closely related living and fossil taxa. When ECSAs are used, sensitivity analyses are required to determine the impact of potential errors. PMID- 25810235 TI - Imatinib-induced agranulocytosis in patients with gastrointestinal stromal tumors. AB - Agranulocytosis is a rare but serious side effect of imatinib in gastrointestinal stromal tumor (GIST) patients. Imatinib is an inhibitor of the proto-oncogene tyrosine kinase (c-kit) and the first-line agent in patients with locally advanced and metastatic GIST. Little evidence is available on the management of this adverse event, and consensus-based guidelines are lacking. In this article, we describe 4 patients with agranulocytosis after starting imatinib. In addition, an overview of the available literature concerning the underlying mechanisms is given, and therapeutic strategies for overcoming this adverse event are discussed. In our experience it appears safe to restart imatinib after normalization of neutrophil count. In case of relapse of agranulocytosis, reintroduction combined with prednisolone, with treatment with granulocyte colony stimulating factor or dose reduction can be considered. PMID- 25810237 TI - Long-term Survival of Straumann Dental Implants with TPS Surfaces: A Retrospective Study with a Follow-up of 12 to 23 Years. AB - PURPOSE: The aim of this study was to evaluate the long-term dental implant survival rates of Straumann dental implants in a university hospital environment over 12 to 23 years. MATERIALS AND METHODS: A total of 388 Straumann dental implants with titanium-sprayed surfaces (TPS) were inserted in 92 patients between 1988 and 1999 in the Department of Oral and Maxillofacial Surgery of the University Hospital Schleswig-Holstein in Kiel, and they were reevaluated with standardized clinical and radiological exams. Kaplan-Meier analyses were performed for individual factors. Cox proportional hazard regression analysis was used to detect the factors influencing long-term implant failure. RESULTS: The long-term implant survival rate was 88.03% after an observation time of 12.2 to 23.5 years. Cox regression revealed statistically significant influences of the International Team for Implantology (ITI) implantation type (p = .00354) and tobacco smoking (p = .01264) on implant failure. A proportion 82.8% of the patients with implant losses had a medical history of periodontitis. Peri implantitis was diagnosed in 9.7% of the remaining implants in the long-term survey. CONCLUSIONS: This study emphasized the long-term rehabilitation capabilities of Straumann dental implants in complex cases. The survival rates after several years constitute important information for patients, as well as for clinicians, in deciding about different concepts of tooth replacement. Patient related and technical factors - determined before implant placement - could help to predict the risk of implant loss. PMID- 25810236 TI - Trichoscopic findings of androgenetic alopecia and their association with disease severity. AB - Trichoscopy is a novel tool for the diagnosis of hair loss disorders such as androgenetic alopecia (AGA), but there are still few reports on the association between trichoscopic findings and disease severity, especially in the Chinese population. A case-control observational study was conducted to observe the trichoscopic findings of AGA and to evaluate their relationship with disease severity. Trichoscopic examination was performed with a handheld dermoscope on 750 Chinese male AGA (MAGA) and 200 female AGA (FAGA) patients, along with 100 male and 50 female normal controls. Trichoscopically, AGA was featured by hair shaft thickness heterogeneity (HSTH), brown peripilar sign (BPPS), white peripilar sign (WPPS), yellow dots, pinpoint white dots, focal atrichia and scalp pigmentation. No significant difference in the occipital area was found between AGA and controls (P > 0.05). HSTH of more than 20% was demonstrated in all MAGA patients, and HSTH of more than 10% was seen in all FAGA patients. WPPS, yellow dots, pinpoint white dots, focal atrichia and scalp pigmentation were positively related to severity of disease (P < 0.05), while BPPS was the contrary (P < 0.05). HSTH is an essential criterion for diagnosing AGA. BPPS was more common in early AGA. However, WPPS, yellow dots, pinpoint white dots, focal atrichia and scalp pigmentation are positively correlated with advanced AGA. PMID- 25810238 TI - Engineering of a linear inactive analog of human beta-defensin 4 to generate peptides with potent antimicrobial activity. AB - Human beta-defensins (HBDs) are cationic antimicrobial peptides constrained by three disulfide bridges. They have diverse range of functions in the innate immune response. It is of interest to investigate whether linear analogs of defensins can be generated, which possess antimicrobial activity. In this study, we have designed linear peptides with potent antimicrobial activity from an inactive peptide spanning the N-terminus of HBD4. Our results show that l arginine to d-arginine substitution imparts considerable antimicrobial activity against both bacteria and Candida albicans. Increase in hydrophobicity by fatty acylation of the peptides with myristic acid further enhances their potency. In the presence of high concentrations of salt, antimicrobial activity of the myristoylated peptide with l-arginine is attenuated relatively to a lesser extent as compared with the linear active peptide with d-arginine. Substitution of cysteine with the hydrophobic helix-promoting amino acid alpha-aminoisobutyric acid favors candidacidal activity but not antibacterial activity. The mechanism of killing by d-arginine substituted unacylated analog involves transient interaction with the bacterial membrane followed by translocation into the cytoplasm without membrane permeabilization. Accumulation of peptides in the cytoplasm can affect various cellular processes that lead to cell death. However, the peptide causes membrane permeabilization in case of C. albicans. Myristoylation results in greater interaction of the peptide chain with the microbial cell surface and causes membrane permeabilization. Results described in the study demonstrate that it is possible to generate highly active linear analogs of defensins by selective introduction of d-amino acids and fatty acids, which could be attractive candidates for development as therapeutic agents. PMID- 25810239 TI - Analyzing paired diagnostic studies by estimating the expected benefit. AB - When the efficacy of a new medical drug is compared against that of an established competitor in a randomized controlled trial, the difference in patient-relevant outcomes, such as mortality, is usually measured directly. In diagnostic research, however, the impact of diagnostic procedures is of an indirect nature as test results do influence downstream clinical decisions, but test performance (as characterized by sensitivity, specificity, and the predictive values of a procedure) is, at best, only a surrogate endpoint for patient outcome and does not necessarily translate into it. Not many randomized controlled trials have been conducted so far in diagnostic research, and, hence, we need alternative approaches to close the gap between test characteristics and patient outcomes. Several informal approaches have been suggested in order to close this gap, and decision modeling has been advocated as a means of obtaining formal approaches. Recently, the expected benefit has been proposed as a quantity that allows a simple formal approach, and we take up this suggestion in this paper. We regard the expected benefit as an estimation problem and consider two approaches to statistical inference. Moreover, using data from a previously published study, we illustrate the possible insights to be gained from the application of formal inference techniques to determine the expected benefit. PMID- 25810241 TI - American society for laser medicine and surgery abstracts: american society for laser medicine and surgery abstracts. PMID- 25810240 TI - Liver inflammation abrogates immunological tolerance induced by Kupffer cells. AB - The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy-based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte-derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T-cell arrest, expansion of naturally occurring Foxp3(+) CD25(+) interleukin-10-producing antigen-specific regulatory T cells (Tregs) and tolerogenic immunity. Particle-associated tolerance induction in the liver protected mice from kidney inflammation in T-cell-mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune-mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen-specific CD4 T cells. In injured liver, infiltrating monocyte-derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype. CONCLUSIONS: Hepatic induction of tissue-protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases. PMID- 25810242 TI - Taking the aggravation out of data aggregation: A conceptual guide to dealing with statistical issues related to the pooling of individual-level observational data. AB - Field data often include multiple observations taken from the same individual. In order to avoid pseudoreplication, it is commonplace to aggregate data, generating a mean score per individual, and then using these aggregated data in subsequent analyses. Aggregation, however, can generate problems of its own. Not only does it lead to a loss of information, it can also leave analyses vulnerable to the "ecological fallacy": the drawing of false inferences about individual behavior on the basis of population level ("ecological") data. It can also result in Simpson's paradox, where relationships seen at the individual level can be completely reversed when analyzed at the aggregate level. These phenomena have been documented widely in the medical and social sciences but tend to go unremarked in primatological studies that rely on observational data from the field. Here, we provide a conceptual guide that explains how and why aggregate data are vulnerable to the ecological fallacy and Simpson's paradox, illustrating these points using data on baboons. We then discuss one particular analytical approach, namely multi-level modeling, that can potentially eliminate these problems. By highlighting the issue of the ecological fallacy, and increasing awareness of how datasets are often organized into a number of different levels, we also highlight the manner in which researchers can more positively exploit the structure of their datasets, without any information loss. These analytical approaches may thus provide greater insight into behavior by permitting more thorough investigation of interactions and cross-level effects. PMID- 25810243 TI - Control of human and plant fungal pathogens using pentaene macrolide 32, 33 didehydroroflamycoin. AB - AIMS: The aim of this study was to address the toxicity of recently described polyene macrolide 32, 33-didehydroroflamycoin (DDHR) on a wide range of fungal pathogens and its potential to control plant fungal diseases. METHODS AND RESULTS: The antifungal activity of DDHR in vitro was examined against common human and plant pathogenic fungi using a broth microdilution assay and a disk diffusion assay. Minimum inhibitory concentrations ranged from 12.5 to 35 MUg ml( 1) . A radial growth inhibition assay showed that DDHR inhibited mycelia growth, inducing mycelial necrosis and affecting sporulation. During the in vivo assay on apple fruits administration of DDHR 1 h before fungal inoculation inhibited spreading of the infection. Importantly, DDHR exhibited no phytotoxic effects on the model plant, Capsicum annum, verified by the plant growth rate and chlorophyll content. CONCLUSIONS: DDHR inhibits growth of various plant pathogens in vitro with the strongest activity against Alternaria alternata, Colletotrichum acutatum and Penicillium expansum, and protects apple fruits from decay. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of the inhibitory effect of DDHR on important pathogenic fungal isolates. DDHR could be a good scaffold for developing new antifungal agents for fruit and vegetable protection. PMID- 25810244 TI - Immunocytochemical analysis of p63 and 34betaE12 in fine needle aspiration cytology specimens for breast lesions: a potentially useful discriminatory marker between intraductal papilloma and ductal carcinoma in situ. AB - OBJECTIVE: We applied immunocytochemistry to fine needle aspiration (FNA) breast lesion slides in an attempt to enhance their objectivity and specificity. METHODS: We analysed 56 FNA specimens from patients with histologically confirmed breast lesions, using 34betaE12 and p63 antibodies. Immunostained slides were examined in terms of both solitary positive cells (within clusters and non clusters) and positive clusters within a slide. RESULTS: Positive scores (>=2) for p63(+) cells and percentages of p63(+) clusters differed significantly (P < 0.001) between malignant (3 of 34; 9%) and benign (11 of 22; 50%) cases and varied between benign and malignant groups: intraductal papilloma (IDP) (2 of 8), other benign lesions (9 of 14), ductal carcinoma in situ (DCIS) (1 of 11) and invasive carcinoma (IC) (2 of 23). Similarly, 34betaE12 scores were higher in benign cases (IDP, 8 of 8; other benign, 9 of 14) than in malignant cases (DCIS, 1 of 11; IC, 3 of 23). As well as a significant difference between benign and malignant cases (17 of 22, 77% versus 4 of 34, 12%; P < 0.001), the percentage of 34betaE12(+) clusters was significantly higher in IDP compared with DCIS (P = 0.001). CONCLUSIONS: The immunostaining of FNA breast specimens for p63 and 34betaE12 may help in difficult diagnoses. PMID- 25810245 TI - Influence of CYP2C19 loss-of-function variants on the metabolism of clopidogrel in patients from north-western China. AB - WHAT IS KNOWN AND OBJECTIVE: Variation of the cytochrome P450 2C19 gene coding for the CYP2C19 enzyme has been reported to be associated with clopidogrel response variability. The activity of the CYP2C19 enzyme is genetically influenced by polymorphisms of its gene. METHODS: This study was conducted to assess the impact of CYP2C19 polymorphism on the clopidogrel metabolism, indirectly selecting the plasma concentration ratios of clopidogrel to its inactive metabolite SR26334 as an evaluation index. Genotyping and plasma concentration results of 366 patients on clopidogrel maintenance therapy (75 mg daily dose) were analysed in this study. CYP2C19 genotypes were determined by PCR restriction fragment length polymorphism method. RESULTS AND DISCUSSION: As for CYP2C19, patients were classified into three metabolism genotype groups: EM (44.3%), IM (43.4%) and PM (12.3%). The mean plasma concentration ratio of clopidogrel to its inactive metabolite SR26334 for the entire sample was 0.507. The plasma concentration ratios of the 3 metabolism groups were significantly different (P < 0.001). The lowest plasma concentration ratio value was observed for PM patients. WHAT IS NEW AND CONCLUSION: Polymorphism of CYP2C19 was significantly associated with plasma concentration ratios of clopidogrel to its inactive metabolite SR26334. Clopidogrel metabolism was regulated by CYP2C19. The *2 and *3 allele carriage were independently associated with the antiplatelet effect of chronic clopidogrel therapy. PMID- 25810246 TI - The Signature Program: Bringing the Protocol to the Patient. AB - Early-phase clinical development in oncology has evolved dramatically with the deciphering of the human genome in 2004. Genomic analysis and the tools identifying genetically disrupted pathways within a patient's tumor have been a driving force for personalized medicine and for the development of highly targeted novel therapies. Tumors are often genetically heterogeneous, with multiple concurrent genetic abnormalities. On the other hand, tumors arising from different tissues may share identical molecular drivers. PMID- 25810247 TI - Clinical Implications of Basic Science Discoveries: Immune Homeostasis and the Microbiome-Dietary and Therapeutic Modulation and Implications for Transplantation. AB - Links between the human microbiome and the innate and adaptive immune systems and their impact on autoimmune and inflammatory diseases are only beginning to be recognized. Characterization of the complex human microbial community is facilitated by culture-independent nucleic acid sequencing tools and bioinformatics systems. Specific organisms and microbial antigens are linked with initiation of innate immune responses that, depending on the context, may be associated with tolerogenic or effector immune responses. Further complexity is introduced by preclinical data that demonstrate the impacts of dietary manipulation on the prevention of genetically determined, systemic autoimmune disorders and on gastrointestinal microbiota. Investigation of interactions of complex microbial populations with the human immune system may provide new targets for clinical management in allotransplantation. PMID- 25810248 TI - Effect of On-Line Hemodiafiltration on P-Wave Dispersion in Children. AB - P-wave dispersion (PWD) (difference between the maximum and minimum P-wave duration), has been proposed as a useful predictor of paroxysmal atrial fibrillation (AF). The consequences of hemodialysis (HD) on PWD and P-wave duration have not been unequivocally documented and understood, and may be complex. We aimed in this work to demonstrate the effects of online hemodiafiltration (OL-HDF) on the risk of developing AF through assessment of PWD. Thirty-three pediatric patients (14 males and 19 females with mean age of 11.66 +/- 2.93 years) on conventional HD for at least 6 months underwent echocardiography, 12-lead electrocardiogram and PWD calculation. Then they were switched to OL-HDF for another 6 months and same parameters were reassessed. Thirty sex- and aged-matched healthy children, served as controls. PWD significantly decreased upon switching to OL-HDF (P < 0.001) and fractional shortening significantly improved (P < 0.001). Mean PWD of controls (24 +/- 6 ms) was significantly less than PWD before and after OL-HDF (P < 0.001 and <0.001, respectively). Online HDF significantly decreased PWD and hence also the potential of AF development, which may invite a higher consideration of this renal replacement modality in a pediatric population. PMID- 25810249 TI - Primary cutaneous mucormycosis caused by Mucor irregularis. AB - We describe a case of primary cutaneous mucormycosis in a 44-year-old man with an 18-month history of infiltrative erythematous plaques and haemorrhagic crusting on the dorsum of his left hand. The isolate was identified as Mucor irregularis (formerly Rhizomucor variabilis) based on the fungus morphology and DNA sequencing results. Improvement was observed after a 6-month treatment course of itraconazole. No recrudescence was seen during a follow-up of 23 months after treatment. PMID- 25810250 TI - Gremlin regulates renal inflammation via the vascular endothelial growth factor receptor 2 pathway. AB - Inflammation is a main feature of progressive kidney disease. Gremlin binds to bone morphogenetic proteins (BMPs), acting as an antagonist and regulating nephrogenesis and fibrosis among other processes. Gremlin also binds to vascular endothelial growth factor receptor-2 (VEGFR2) in endothelial cells to induce angiogenesis. In renal cells, gremlin regulates proliferation and fibrosis, but there are no data about inflammatory-related events. We have investigated the direct effects of gremlin in the kidney, evaluating whether VEGFR2 is a functional gremlin receptor. Administration of recombinant gremlin to murine kidneys induced rapid and sustained activation of VEGFR2 signalling, located in proximal tubular epithelial cells. Gremlin bound to VEGFR2 in these cells in vitro, activating this signalling pathway independently of its action as an antagonist of BMPs. In vivo, gremlin caused early renal damage, characterized by activation of the nuclear factor (NF)-kappaB pathway linked to up-regulation of pro-inflammatory factors and infiltration of immune inflammatory cells. VEGFR2 blockade diminished gremlin-induced renal inflammatory responses. The link between gremlin/VEGFR2 and NF-kappaB/inflammation was confirmed in vitro. Gremlin overexpression was associated with VEGFR2 activation in human renal disease and in the unilateral ureteral obstruction experimental model, where VEGFR2 kinase inhibition diminished renal inflammation. Our data show that a gremlin/VEGFR2 axis participates in renal inflammation and could be a novel target for kidney disease. PMID- 25810251 TI - Chronic lithium treatment diminishes the female advantage in lifespan in Drosophila melanogaster. AB - Two studies have concluded that lithium exposure extends the lifespan of Caenorhabditis elegans. However, the effect of lithium on another widely used model organism, Drosophila melanogaster, remains unclear. Here, we demonstrate that chronic treatment with a low to moderate dose of lithium chloride does not extend lifespan in D. melanogaster and that the drug abolishes the female lifespan advantage in flies. PMID- 25810253 TI - Hemoglobin betaCys93 is essential for cardiovascular function and integrated response to hypoxia. AB - Oxygen delivery by Hb is essential for vertebrate life. Three amino acids in Hb are strictly conserved in all mammals and birds, but only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the beta-chain (betaCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO bioactivity by Hb redefines the respiratory cycle as a triune system (NO/O2/CO2). However, the physiological ramifications of RBC mediated vasodilation are unknown, and the apparently essential nature of betaCys93 remains unclear. Here we report that mice with a betaCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia. In addition, betaCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, betaCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia. PMID- 25810254 TI - RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin alpha-subunit gene. AB - Since the discovery that many transcriptional enhancers are transcribed into long noncoding RNAs termed "enhancer RNAs" (eRNAs), their putative role in enhancer function has been debated. Very recent evidence has indicted that some eRNAs play a role in initiating or activating transcription, possibly by helping recruit and/or stabilize binding of the general transcription machinery to the proximal promoter of their target genes. The distal enhancer of the gonadotropin hormone alpha-subunit gene, chorionic gonadotropin alpha (Cga), is responsible for Cga cell-specific expression in gonadotropes and thyrotropes, and we show here that it encodes two bidirectional nonpolyadenylated RNAs whose levels are increased somewhat by exposure to gonadotropin-releasing hormone but are not necessarily linked to Cga transcriptional activity. Knockdown of the more distal eRNA led to a drop in Cga mRNA levels, initially without effect on the forward eRNA levels. With time, however, the repression on the Cga increased, and the forward eRNA levels were suppressed also. We demonstrate that the interaction of the enhancer with the promoter is lost after eRNA knockdown. Dramatic changes also were seen in the chromatin, with an increase in total histone H3 occupancy throughout this region and a virtual loss of histone H3 Lys 4 trimethylation at the promoter following the eRNA knockdown. Moreover, histone H3 Lys 27 (H3K27) acetylation, which was found at both enhancer and promoter in wild-type cells, appeared to have been replaced by H3K27 trimethylation at the enhancer. Thus, the Cga eRNA mediates the physical interaction between these genomic regions and determines the chromatin structure of the proximal promoter to allow gene expression. PMID- 25810252 TI - RNA virus replication depends on enrichment of phosphatidylethanolamine at replication sites in subcellular membranes. AB - Intracellular membranes are critical for replication of positive-strand RNA viruses. To dissect the roles of various lipids, we have developed an artificial phosphatidylethanolamine (PE) vesicle-based Tomato bushy stunt virus (TBSV) replication assay. We demonstrate that the in vitro assembled viral replicase complexes (VRCs) in artificial PE vesicles can support a complete cycle of replication and asymmetrical RNA synthesis, which is a hallmark of (+)-strand RNA viruses. Vesicles containing ~85% PE and ~15% additional phospholipids are the most efficient, suggesting that TBSV replicates within membrane microdomains enriched for PE. Accordingly, lipidomics analyses show increased PE levels in yeast surrogate host and plant leaves replicating TBSV. In addition, efficient redistribution of PE leads to enrichment of PE at viral replication sites. Expression of the tombusvirus p33 replication protein in the absence of other viral compounds is sufficient to promote intracellular redistribution of PE. Increased PE level due to deletion of PE methyltransferase in yeast enhances replication of TBSV and other viruses, suggesting that abundant PE in subcellular membranes has a proviral function. In summary, various (+)RNA viruses might subvert PE to build membrane-bound VRCs for robust replication in PE-enriched membrane microdomains. PMID- 25810255 TI - Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases. AB - Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibalpha (GPIbalpha) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbalpha in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbalpha to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor-ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule kon (s(-1)) to bulk phase kon (s(-1)M(-1)) and the kon and koff values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements. PMID- 25810258 TI - Definitively, my cup of tea. Focus on "Caffeine inhibits glucose transport by binding at the GLUT1 nucleotide-binding site". PMID- 25810256 TI - Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function. AB - In older adults, we examined the effect of chronic muscle disuse on skeletal muscle structure at the tissue, cellular, organellar, and molecular levels and its relationship to muscle function. Volunteers with advanced-stage knee osteoarthritis (OA, n = 16) were recruited to reflect the effects of chronic lower extremity muscle disuse and compared with recreationally active controls (n = 15) without knee OA but similar in age, sex, and health status. In the OA group, quadriceps muscle and single-fiber cross-sectional area were reduced, with the largest reduction in myosin heavy chain IIA fibers. Myosin heavy chain IIAX fibers were more prevalent in the OA group, and their atrophy was sex-specific: men showed a reduction in cross-sectional area, and women showed no differences. Myofibrillar ultrastructure, myonuclear content, and mitochondrial content and morphology generally did not differ between groups, with the exception of sex specific adaptations in subsarcolemmal (SS) mitochondria, which were driven by lower values in OA women. SS mitochondrial content was also differently related to cellular and molecular functional parameters by sex: greater SS mitochondrial content was associated with improved contractility in women but reduced function in men. Collectively, these results demonstrate sex-specific structural phenotypes at the cellular and organellar levels with chronic disuse in older adults, with novel associations between energetic and contractile systems. PMID- 25810257 TI - Creatine kinase B is necessary to limit myoblast fusion during myogenesis. AB - Myoblast fusion is critical for proper muscle growth and regeneration. During myoblast fusion, the localization of some molecules is spatially restricted; however, the exact reason for such localization is unknown. Creatine kinase B (CKB), which replenishes local ATP pools, localizes near the ends of cultured primary mouse myotubes. To gain insights into the function of CKB, we performed a yeast two-hybrid screen to identify CKB-interacting proteins. We identified molecules with a broad diversity of roles, including actin polymerization, intracellular protein trafficking, and alternative splicing, as well as sarcomeric components. In-depth studies of alpha-skeletal actin and alpha-cardiac actin, two predominant muscle actin isoforms, demonstrated their biochemical interaction and partial colocalization with CKB near the ends of myotubes in vitro. In contrast to other cell types, specific knockdown of CKB did not grossly affect actin polymerization in myotubes, suggesting other muscle-specific roles for CKB. Interestingly, knockdown of CKB resulted in significantly increased myoblast fusion and myotube size in vitro, whereas knockdown of creatine kinase M had no effect on these myogenic parameters. Our results suggest that localized CKB plays a key role in myotube formation by limiting myoblast fusion during myogenesis. PMID- 25810259 TI - Cellular redox status determines sensitivity to BNIP3-mediated cell death in cardiac myocytes. AB - The atypical BH3-only protein Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is an important regulator of hypoxia-mediated cell death. Interestingly, the susceptibility to BNIP3-mediated cell death differs between cells. In this study we examined whether there are mechanistic differences in BNIP3-mediated cell death between neonatal and adult cardiac myocytes. We discovered that BNIP3 is a potent inducer of cell death in neonatal myocytes, whereas adult myocytes are remarkably resistant to BNIP3. When exploring the potential underlying basis for the resistance, we discovered that adult myocytes express significantly higher levels of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD) than neonatal myocytes. Overexpression of MnSOD confers resistance to BNIP3-mediated cell death in neonatal myocytes. In contrast, the presence of a pharmacological MnSOD inhibitor, 2-methoxyestradiol, results in increased sensitivity to BNIP3-mediated cell death in adult myocytes. Cotreatment with the mitochondria-targeted antioxidant MitoTEMPO or the MnSOD mimetic manganese (III) tetrakis (4-benzoic acid) porphyrin chloride abrogates the increased cell death by 2-methoxyestradiol. Moreover, increased oxidative stress also restores the ability of BNIP3 to induce cell death in adult myocytes. Taken together, these data indicate that redox status determines cell susceptibility to BNIP3-mediated cell death. These findings are clinically relevant, given that pediatric hearts are known to be more vulnerable than the adult heart to ischemic injury. Our studies provide important insight into why pediatric hearts are more sensitive to ischemic injury and may help in the clinical management of childhood heart disease. PMID- 25810260 TI - PPARalpha inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth. AB - Kidney cancer [renal cell carcinoma (RCC)] is the sixth-most-common cancer in the United States, and its incidence is increasing. The current progression-free survival for patients with advanced RCC rarely extends beyond 1-2 yr due to the development of therapeutic resistance. We previously identified peroxisome proliferator-activating receptor-alpha (PPARalpha) as a potential therapeutic target for this disease and showed that a specific PPARalpha antagonist, GW6471, induced apoptosis and cell cycle arrest at G0/G1 in RCC cell lines associated with attenuation of cell cycle regulatory proteins. We now extend that work and show that PPARalpha inhibition attenuates components of RCC metabolic reprogramming, capitalizing on the Warburg effect. The specific PPARalpha inhibitor GW6471, as well as a siRNA specific to PPARalpha, attenuates the enhanced fatty acid oxidation and oxidative phosphorylation associated with glycolysis inhibition, and PPARalpha antagonism also blocks the enhanced glycolysis that has been observed in RCC cells; this effect did not occur in normal human kidney epithelial cells. Such cell type-specific inhibition of glycolysis corresponds with changes in protein levels of the oncogene c-Myc and has promising clinical implications. Furthermore, we show that treatment with GW6471 results in RCC tumor growth attenuation in a xenograft mouse model, with minimal obvious toxicity, a finding associated with the expected on-target effects on c-Myc. These studies demonstrate that several pivotal cancer-relevant metabolic pathways are inhibited by PPARalpha antagonism. Our data support the concept that targeting PPARalpha, with or without concurrent inhibition of glycolysis, is a potential novel and effective therapeutic approach for RCC that targets metabolic reprogramming in this tumor. PMID- 25810262 TI - Intracranial hemorrhage following surgery for occult spinal dysraphism: a case based update. AB - BACKGROUND: Intracranial cerebrospinal fluid (CSF) volume depletion causes diverse clinical syndromes most of them constituting the manifestations of decreased intracranial pressure. Subdural collections or chronic subdural hematomas are the best-known consequences of persistent CSF leaks, especially in overshunted hydrocephalus. Continuous CSF escape also occurs after lumbar puncture, spinal anesthesia, and diverse spinal surgeries. CASE DESCRIPTION: A 6 year-old boy submitted to reoperation of spinal cord compression due to partial sacral agenesis complained of postoperative orthostatic headaches and vomiting initially attributed to CSF hypotension. There were neither subcutaneous fluid accumulations nor CSF leakage from the wound. The child was treated with strict bed rest and intravenous hydration for 5 days. On reassuming orthostatism, the patient had syncope but did not hit his head. A cranial computerized tomography scan showed an acute subdural hematoma that was managed conservatively with total recovery. DISCUSSION AND CONCLUSION: A review of current literature showed scanty reports of acute intracranial bleeding occurring after CSF depletion following spinal surgical procedures. To our knowledge, our reported patient represents the second case of this occurrence following surgery for closed spinal dysraphism in a child. The authors briefly review documented instances of acute subdural hematoma following spinal procedures, advise about its diagnosis, and suggest preventive measures. PMID- 25810261 TI - Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent intercellular signaling molecule involved in multiple homeostatic functions. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, making them a unique system to establish mechanisms underlying PACAP modulation of neuronal function. Calcium influx is required for the PACAP-increased cardiac neuron excitability, although the pathway is unknown. This study tested whether PACAP enhancement of calcium influx through either T type or R-type channels contributed to the modulation of excitability. Real-time quantitative polymerase chain reaction analyses indicated transcripts for Cav3.1, Cav3.2, and Cav3.3 T-type isoforms and R-type Cav2.3 in cardiac neurons. These neurons often exhibit a hyperpolarization-induced rebound depolarization that remains when cesium is present to block hyperpolarization-activated nonselective cationic currents (Ih). The T-type calcium channel inhibitors, nickel (Ni(2+)) or mibefradil, suppressed the rebound depolarization, and treatment with both drugs hyperpolarized cardiac neurons by 2-4 mV. Together, these results are consistent with the presence of functional T-type channels, potentially along with R-type channels, in these cardiac neurons. Fifty micromolar Ni(2+), a concentration that suppresses currents in both T-type and R-type channels, blunted the PACAP initiated increase in excitability. Ni(2+) also blunted PACAP enhancement of the hyperpolarization-induced rebound depolarization and reversed the PACAP-mediated increase in excitability, after being initiated, in a subset of cells. Lastly, low voltage-activated currents, measured under perforated patch whole cell recording conditions and potentially flowing through T-type or R-type channels, were enhanced by PACAP. Together, our results suggest that a PACAP-enhanced, Ni(2+)-sensitive current contributes to PACAP-induced modulation of neuronal excitability. PMID- 25810264 TI - Preconcentration modeling for the optimization of a micro gas preconcentrator applied to environmental monitoring. AB - This paper presents the optimization of a micro gas preconcentrator (MU-GP) system applied to atmospheric pollution monitoring, with the help of a complete modeling of the preconcentration cycle. Two different approaches based on kinetic equations are used to illustrate the behavior of the micro gas preconcentrator for given experimental conditions. The need for high adsorption flow and heating rate and for low desorption flow and detection volume is demonstrated in this paper. Preliminary to this optimization, the preconcentration factor is discussed and a definition is proposed. PMID- 25810265 TI - Growing well-beings: The positive experience of care farms. AB - OBJECTIVES: Care farms enable people who are in some way vulnerable to engage with agricultural places and farming activities. This study investigates how this impacts on the health and well-being of service users and explores associated processes and outcomes. DESIGN: A mixed methods design was adopted that allowed for the integration of quantitative measurements of change with qualitative descriptions of this change. A pragmatic approach provided sufficient flexibility to support the investigation of complex contexts. METHODS: A total of 216 service users completed an initial questionnaire, and 137 (63%) of this number provided comparative data in a follow-up questionnaire. Questionnaires contained multiple choice and open-ended questions alongside standardized health and well-being measures requiring Likert-format responses. Semi-structured interviews with 33 service users allowed personal experiences to be detailed. RESULTS: Statistical analysis of well-being measure scores identified significant positive relationships with the length of time people had been attending the care farm. Questionnaire and interview data presented health benefits as being enabled by the farm environment, the positive experience as supporting personal development, and associated social interactions as becoming increasingly influential as time progressed. CONCLUSIONS: The health and well-being outcomes that result from participating at a care farm influence multiple elements of the human condition and apply amongst vulnerable people with a wide range of personal needs. Care farms have access to a potentially unique range of resources that can support many service users in becoming happier and healthier individuals. Statement of contribution What is already known on this subject? Care farming is increasingly practised and is suggested to support the health and well-being of people who are in some way vulnerable. Care farms utilize agricultural spaces and activities to provide benefits that are presented as having relevance to public health and social inclusion agendas. What does this study add? This is the first longitudinal study to include participants with such differing personal needs. Associated outcomes are explored to provide an understanding of how they impact on health. People and place are found to be mutually supportive in facilitating positive change. PMID- 25810266 TI - Crucial role of posttranslational modifications of integrin alpha3 in interstitial lung disease and nephrotic syndrome. AB - Interstitial lung disease, nephrotic syndrome and junctional epidermolysis bullosa is an autosomal recessive multiorgan disorder caused by mutations in the gene for the integrin alpha3 subunit (ITGA3). The full spectrum of manifestations and genotype-phenotype correlations is still poorly characterized. Here, we uncovered the disease-causing role and the molecular mechanisms underlying a homozygous ITGA3 mutation leading to the single amino acid substitution, p.R463W. The patient suffered from respiratory distress and episodes of cyanosis with onset in the first week of life and had a nephrotic syndrome. Although there was no clinical evidence for cutaneous fragility, the analysis of a skin sample and of skin epithelial cells enabled the direct assessment of the authentic mutant protein. We show that the mutation altered the conformation of the extracellular beta-propeller domain of the integrin alpha3 subunit preventing correct processing of N-linked oligosaccharides, heterodimerization with beta1 integrin and maturation through cleavage into heavy and light chains in the Golgi. Confocal microscopy demonstrated that the mutant protein accumulated intracellularly, but it was not present in focal adhesions or on the cell membrane as shown by flow cytometry. These findings highlight that single amino acid changes in the integrin alpha3 subunit may crucially alter the structure and complex processing of this integrin, completely preventing its functionality. The present report also underscores that ITGA3 mutations may account for atypical cases solely with early onset respiratory and renal involvement. PMID- 25810263 TI - SIOP-PODC adapted risk stratification and treatment guidelines: Recommendations for neuroblastoma in low- and middle-income settings. AB - Neuroblastoma is the most common extracranial solid tumor in childhood in high income countries (HIC), where consistent treatment approaches based on clinical and tumor biological risk stratification have steadily improved outcomes. However, in low- and middle- income countries (LMIC), suboptimal diagnosis, risk stratification, and treatment may occur due to limited resources and unavailable infrastructure. The clinical practice guidelines outlined in this manuscript are based on current published evidence and expert opinions. Standard risk stratification and treatment explicitly adapted to graduated resource settings can improve outcomes for children with neuroblastoma by reducing preventable toxic death and relapse. PMID- 25810267 TI - Adapting Scott and Bruce's General Decision-Making Style Inventory to Patient Decision Making in Provider Choice. AB - OBJECTIVE: Research testing the concept of decision-making styles in specific contexts such as health care-related choices is missing. Therefore, we examine the contextuality of Scott and Bruce's (1995) General Decision-Making Style Inventory with respect to patient choice situations. METHODS: Scott and Bruce's scale was adapted for use as a patient decision-making style inventory. In total, 388 German patients who underwent elective joint surgery responded to a questionnaire about their provider choice. Confirmatory factor analyses within 2 independent samples assessed factorial structure, reliability, and validity of the scale. RESULTS: The final 4-dimensional, 13-item patient decision-making style inventory showed satisfactory psychometric properties. Data analyses supported reliability and construct validity. Besides the intuitive, dependent, and avoidant style, a new subdimension, called "comparative" decision-making style, emerged that originated from the rational dimension of the general model. CONCLUSIONS: This research provides evidence for the contextuality of decision making style to specific choice situations. Using a limited set of indicators, this report proposes the patient decision-making style inventory as valid and feasible tool to assess patients' decision propensities. PMID- 25810270 TI - Detection of complete molar pregnancy by single-nucleotide polymorphism-based non invasive prenatal testing. PMID- 25810268 TI - "I don't know" my cancer risk: exploring deficits in cancer knowledge and information-seeking skills to explain an often-overlooked participant response. AB - BACKGROUND: Perceived risk is a central theoretical construct in health behavior research. Participants' "don't know" responses to perceived-risk items (DKPR) are usually excluded from analyses. Yet those who provide such responses may have unique cancer information needs. OBJECTIVE: The hypotheses that DKPR responding may be due to cancer knowledge deficits or behavioral, skill, and attitudinal antecedents to knowledge deficits (information seeking, numeracy, and self efficacy, respectively) were explored. METHODS: Data from the 2005 Health Information National Trends Survey (HINTS; N = 1789), a US population-based survey, and an urban, minority, primary care clinic survey (N = 590) were analyzed. Multivariable logistic regressions were conducted to examine knowledge deficit explanations for responding DKPR to colon cancer risk perception questions (adjusting for demographics and family colorectal cancer history). MEASURES: Comparative (HINTS) and absolute verbal perceived risk of colon cancer (HINTS, clinic survey), knowledge of colon cancer risks and screening, cancer/health information-seeking behavior and self-efficacy (HINTS), and numeracy (clinic survey). RESULTS: Greater knowledge of colon cancer prevention and screening, cancer and health information seeking, and numeracy were each associated with lower odds of providing a DKPR response. LIMITATIONS: The study was cross-sectional, which limits the ability to infer causal direction. The use of existing data sets limited our variable choices. Other plausible hypotheses may also explain DKPR responding. CONCLUSIONS: People who report that they don't know their colon cancer risk may have low cancer knowledge and reduced knowledge acquisition behaviors and skills. Health behavior research could benefit from including data concerning DKPR responses to risk perception questions, because individuals who respond in this way may require interventions to address potential cancer risk knowledge deficits. PMID- 25810269 TI - Estimating the Expected Value of Sample Information Using the Probabilistic Sensitivity Analysis Sample: A Fast, Nonparametric Regression-Based Method. AB - Health economic decision-analytic models are used to estimate the expected net benefits of competing decision options. The true values of the input parameters of such models are rarely known with certainty, and it is often useful to quantify the value to the decision maker of reducing uncertainty through collecting new data. In the context of a particular decision problem, the value of a proposed research design can be quantified by its expected value of sample information (EVSI). EVSI is commonly estimated via a 2-level Monte Carlo procedure in which plausible data sets are generated in an outer loop, and then, conditional on these, the parameters of the decision model are updated via Bayes rule and sampled in an inner loop. At each iteration of the inner loop, the decision model is evaluated. This is computationally demanding and may be difficult if the posterior distribution of the model parameters conditional on sampled data is hard to sample from. We describe a fast nonparametric regression based method for estimating per-patient EVSI that requires only the probabilistic sensitivity analysis sample (i.e., the set of samples drawn from the joint distribution of the parameters and the corresponding net benefits). The method avoids the need to sample from the posterior distributions of the parameters and avoids the need to rerun the model. The only requirement is that sample data sets can be generated. The method is applicable with a model of any complexity and with any specification of model parameter distribution. We demonstrate in a case study the superior efficiency of the regression method over the 2-level Monte Carlo method. PMID- 25810271 TI - Non-elective cardiac surgery in octogenarians: Do these patients benefit in terms of clinical outcomes and quality of life? AB - AIM: The general assumption that non-elective cardiac procedures in octogenarians are related to poor postoperative outcomes and quality of life (QOL) might lead to a non-justified exclusion of elderly patients from surgical treatment. The aim of the present study was to assess survival, functional outcome and quality of life of octogenarians undergoing non-elective cardiac surgery. METHODS: Between 2009 and 2011, 62 consecutive octogenarians (mean age 83.5 +/- 3.5 years) underwent urgent (n = 33) or emergency (n = 29) cardiac surgery. In 69% of patients, coronary artery bypass grafting was carried out, and 24% of patients underwent coronary artery bypass grafting plus valve surgery. Preoperative risk, as well as the postoperative course, was analyzed. All discharged patients were contacted to gain information about survival, functional capacity and QOL using the Barthel Mobility Index and the Short Form 12 Health Survey questionnaire. Results were compared with age-adjusted population data. RESULTS: In-hospital mortality was 32.3% overall, 9.3% in urgent cases and 56.7% in emergency cases. After a mean follow-up period of 447 +/- 359 days, survival of the discharged patients was 93.1% (urgent) and 76.9% (emergency), respectively. QOL measures of the survivors were equivalent to those of the general elderly population. Functional capacity, calculated with Barthel Index, was high in both groups (86 +/- 13 and 81 +/- 21). A total of 92% of the patients were living at home. CONCLUSIONS: Although non-elective cardiac surgery in the elderly is related to high in-hospital mortality, physical and psychological recovery of the survivors is encouraging. QOL equals that of the general elderly population, and good functional status offers a highly independent life. Therefore, age per se should not disqualify patients from urgent or emergency cardiac surgery. PMID- 25810272 TI - Improved fabrication of melt electrospun tissue engineering scaffolds using direct writing and advanced electric field control. AB - Direct writing melt electrospinning is an additive manufacturing technique capable of the layer-by-layer fabrication of highly ordered 3d tissue engineering scaffolds from micron-diameter fibers. The utility of these scaffolds, however, is limited by the maximum achievable height of controlled fiber deposition, beyond which the structure becomes increasingly disordered. A source of this disorder is charge build-up on the deposited polymer producing unwanted coulombic forces. In this study, the authors introduce a novel melt electrospinning platform with dual voltage power supplies to reduce undesirable charge effects and improve fiber deposition control. The authors produced and characterized several 90 degrees cross-hatched fiber scaffolds using a range of needle/collector plate voltages. Fiber thickness was found to be sensitive only to overall potential and invariant to specific tip/collector voltage. The authors also produced ordered scaffolds up to 200 layers thick (fiber spacing 1 mm and diameter 40 MUm) and characterized structure in terms of three distinct zones: ordered, semiordered, and disordered. Our in vitro analysis indicates successful cell attachment and distribution throughout the scaffolds, with little evidence of cell death after seven days. This study demonstrates the importance of electrostatic control for reducing destabilizing polymer charge effects and enabling the fabrication of morphologically suitable scaffolds for tissue engineering. PMID- 25810273 TI - Studies of air, water, and ethanol vapor atmospheric pressure plasmas for antimicrobial applications. AB - The generation of air-based plasmas under atmospheric plasma conditions was studied to assess their antimicrobial efficacy against commonly found pathogenic bacteria. The mixture of initial gases supplied to the plasma was found to be critical for the formation of bactericidal actives. The optimal gas ratio for bactericidal effect was determined to be 99% nitrogen and 1% oxygen, which led to a 99.999% reduction of a pathogenic strain of Escherichia coli on stainless steel surfaces. The experimental substrate, soil load on the substrate, flow rate of the gases, and addition of ethanol vapor all were found to affect antimicrobial efficacy of studied plasmas. Optical emission spectroscopy was used to identify the species that were present in the plasma bulk phase for multiple concentrations of nitrogen and oxygen ratios. The collected spectra indicate a unique series of bands present in the ultraviolet region of the electromagnetic spectrum that can be attributed to nitric oxide species known to be highly antimicrobial. This intense spectral profile dramatically changes as the concentration of nitrogen decreases. PMID- 25810276 TI - Call for submissions. PMID- 25810274 TI - Mouse brain magnetic resonance microscopy: Applications in Alzheimer disease. AB - Over the past two decades, various Alzheimer's disease (AD) trangenetic mice models harboring genes with mutation known to cause familial AD have been created. Today, high-resolution magnetic resonance microscopy (MRM) technology is being widely used in the study of AD mouse models. It has greatly facilitated and advanced our knowledge of AD. In this review, most of the attention is paid to fundamental of MRM, the construction of standard mouse MRM brain template and atlas, the detection of amyloid plaques, following up on brain atrophy and the future applications of MRM in transgenic AD mice. It is believed that future testing of potential drugs in mouse models with MRM will greatly improve the predictability of drug effect in preclinical trials. PMID- 25810278 TI - The authors' reply: Too early to dismiss the block & replace regime for Graves' disease. PMID- 25810279 TI - Bridgehead Substitution via Putative Norborn-1-en-3-ones: Application in the Synthesis of Complex Molecules. AB - The base-mediated formation of a bridgehead double bond in a bicyclo[2.2.1]heptane system (anit-Bredt molecules) is described. The synthesis of exocyclic norbornyl enones by Wittig reaction of alpha-diketones is reported. These enones and their Michael adducts are used as substrates for the generation of transient bridgehead enones and their trapping with MeOH and H2 O. Bridgehead alcohols are easily synthesized from norbornyl enones and are exploited for the diversity oriented synthesis of frameworks of natural and unnatural products. PMID- 25810277 TI - Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia-like conditions: key roles of the transcription factors GATA2, Sp1 and TBP. AB - Monoamine oxidase A (MAOA) plays important roles in the pathogenesis of several neurological and cardiovascular disorders. The mechanism of transcriptional regulation of MAOA under basal and pathological conditions, however, remains incompletely understood. Here, we report systematic identification and characterization of cis elements and transcription factors that govern the expression of MAOA gene. Extensive computational analysis of MAOA promoter, followed by 5'-promoter deletion/reporter assays, revealed that the -71/-40 bp domain was sufficient for its basal transcription. Gel-shift and chromatin immunoprecipitation assays provided evidence of interactions of the transcription factors GATA-binding protein 2 (GATA2), Sp1 and TATA-binding protein (TBP) with this proximal promoter region. Consistently, over-expression of GATA2, Sp1 and TBP augmented MAOA promoter activity in a coordinated manner. In corroboration, siRNA-mediated down-regulation of GATA2/Sp1/TBP repressed the endogenous MAOA expression as well as transfected MAOA promoter activity. Tumor necrosis factor alpha and forskolin activated MAOA transcription that was reversed by Sp1 siRNA; in support, tumor necrosis factor-alpha- and forskolin-induced activities were enhanced by ectopic over-expression of Sp1. On the other hand, MAOA transcription was diminished upon exposure of neuroblasts or cardiac myoblasts to ischemia-like conditions because of reduced binding of GATA2/Sp1/TBP with MAOA promoter. In conclusion, this study revealed previously unknown roles of GATA2, Sp1 and TBP in modulating MAOA expression under basal as well as pathophysiological conditions such as inflammation and ischemia, thus providing new insights into the molecular basis of aberrant MAOA expression in neuronal/cardiovascular disease states. Dysregulation of monoamine oxidase A (MAOA) have been implicated in several behavioral and neuronal disease states. Here, we identified three crucial transcription factors (GATA2, Sp1 and TBP) that regulate MAOA gene expression in a coordinated manner. Aberrant MAOA expression under pathophysiological conditions including inflammation and ischemia is mediated by altered binding of GATA2/Sp1/TBP with MAOA proximal promoter. Thus, these findings provide new insights into pathogenesis of several common diseases. GATA2, GATA-binding protein 2; Sp1, specificity protein 1; TBP, TATA-binding protein. PMID- 25810280 TI - The regulation of positive and negative social feedback: A psychophysiological study. AB - Everyday social evaluations are psychologically potent and trigger self reflective thoughts and feelings. The present study sought to examine the psychophysiological impact of such evaluations using eye tracking, pupillometry, and heart-rate variability. Fifty-nine healthy adult volunteers received rigged social feedback (criticism and praise) based on their photograph. Gaze data were collected to investigate processes of attentional deployment/allocation toward the self or the evaluator expressing criticism or praise. Whereas voluntary attention was directed to evaluators who expressed praise, attention was drawn to one's own picture after criticism. Pupil dilation and heart-rate variability were larger in response to criticism as compared to praise, suggesting a flexible and adaptive emotion regulatory effort in response to social information that triggers an affective response. Altogether, healthy individuals recruited more regulatory resources to cope with negative (as compared to positive) social feedback, and this processing of social feedback was associated with adjustments in self-focused attention. PMID- 25810282 TI - Reply to Eisenhut. PMID- 25810281 TI - Epidemiological and biological determinants of Staphylococcus aureus clinical infection in New York State maximum security prisons. AB - BACKGROUND: Large outbreaks of Staphylococcus aureus (SA) infections have occurred in correctional facilities across the country. We aimed to define the epidemiological and microbiological determinants of SA infection in prisons to facilitate development of prevention strategies for this underserved population. METHODS: We conducted a case-control study of SA infection at 2 New York State maximum security prisons. SA-infected inmates were matched with 3 uninfected controls. Subjects had cultures taken from sites of infection and colonization (nose and throat) and were interviewed via structured questionnaire. SA isolates were characterized by spa typing. Bivariate and multivariable analyses were conducted using conditional logistic regression. RESULTS: Between March 2011 and January 2013, 82 cases were enrolled and matched with 246 controls. On bivariate analysis, the use of oral and topical antibiotics over the preceding 6 months was strongly associated with clinical infection (OR, 2.52; P < .001 and 4.38, P < .001, respectively). Inmates with clinical infection had 3.16 times the odds of being diabetic compared with inmates who did not have clinical infection (P < .001). Concurrent nasal and/or oropharyngeal colonization was also associated with an increased odds of infection (OR, 1.46; P = .002). Among colonized inmates, cases were significantly more likely to carry the SA clone spa t008 (usually representing the epidemic strain USA300) compared to controls (OR, 2.52; P = .01). CONCLUSIONS: Several inmate characteristics were strongly associated with SA infection in the prison setting. Although many of these factors were likely present prior to incarceration, they may help medical staff identify prisoners for targeted prevention strategies. PMID- 25810283 TI - Editorial Commentary: Transesophageal Echocardiography in Staphylococcus aureus Bloodstream Infection--Always Needed? PMID- 25810285 TI - Potential for a Significant Interaction Between Clopidogrel and Dasabuvir. PMID- 25810286 TI - Features of Myocarditis in Infants With Human Parechovirus Infection. PMID- 25810287 TI - Reply to Daskapan et al. PMID- 25810284 TI - Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT): Scoring System to Guide Use of Echocardiography in the Management of Staphylococcus aureus Bacteremia. AB - BACKGROUND: Infective endocarditis (IE) is a serious complication of Staphylococcus aureus bacteremia (SAB). There is limited clinical evidence to guide use of echocardiography in the management of SAB cases. METHODS: Baseline and 12-week follow-up data of all adults hospitalized at our institution with SAB from 2006 to 2011 were reviewed. Clinical predictors of IE were identified using multivariable logistic regression analysis. RESULTS: Of the 757 patients screened, 678 individuals with SAB (24% community acquired, 56% healthcare associated, and 20% nosocomial) met study criteria. Eighty-five patients (13%) were diagnosed with definite IE within the 12 weeks of initial presentation based on modified Duke criteria. The proportion of patients with IE was 22% (36/166) in community-acquired SAB, 11% (40/378) in community-onset healthcare-associated SAB, and 7% (9/136) in nosocomial SAB. Community-acquired SAB, presence of cardiac device, and prolonged bacteremia (>= 72 hours) were identified as independent predictors of IE in multivariable analysis. Two scoring systems, day 1 (SAB diagnosis day) and day 5 (when day 3 culture results are known), were derived based on the presence of these risk factors, weighted in magnitude by the corresponding regression coefficients. A score of >= 4 for day 1 model had a specificity of 96% and sensitivity of 21%, whereas a score of <2 for day 5 model had a sensitivity of 98.8% and negative predictive value of 98.5%. CONCLUSIONS: We propose 2 novel scoring systems to guide use of echocardiography in SAB cases. Larger prospective studies are needed to validate the classification performance of these scoring systems. PMID- 25810289 TI - The Never Ending Struggle Against Development of Drug Resistance. PMID- 25810288 TI - An evaluation of a novel dual treponemal/nontreponemal point-of-care test for syphilis as a tool to distinguish active from past treated infection. AB - BACKGROUND: Most syphilis point-of-care (POC) tests detect treponemal antibodies, which persist after successful treatment. Subsequent POC tests are positive, despite no active infection, and can lead to unnecessary treatment. We evaluated a new POC test, incorporating a nontreponemal component, to distinguish active from past infection. METHODS: Sera stored at 2 Australian laboratories were tested with DPP Screen and Confirm Assay. Treponemal and nontreponemal test lines were compared to corresponding conventional treponemal and nontreponemal reference test results: immunoassays and rapid plasma reagin (RPR), respectively, with RPR quantification by endpoint titration. POC test outcome concordance with conventional test results was assessed according to serological and clinical categories. RESULTS: Among 1005 serum samples tested, DPP treponemal line sensitivity was 89.8% (95% confidence interval [CI], 87.3%-91.9%) and specificity was 99.3% (95% CI, 97.0%-99.9%). DPP nontreponemal line sensitivity was 94.2% (95% CI, 91.8%-96.0%) and specificity was 62.2% (95% CI, 57.5%-66.6%). DPP test outcome (pair of test lines) was concordant with both reference test results for 94.3% of 404 high-titer infections, 90.1% of 121 low-titer infections, 27.5% of 211 past/treated infections, and 78.1% of 242 infections classified as not syphilis. Among 211 past/treated infections, 49.8% were incorrectly identified as active infection and a further 22.8% as not syphilis. CONCLUSIONS: DPP test use would result in identification of >93% of active syphilis infections, whereas just over half of past infections would be diagnosed as past or not syphilis, avoiding unnecessary treatment compared with other POC tests. This may be at the expense of missing some active infections; thus, its potential benefits will depend on the prevalence of past vs active infection in a population. PMID- 25810290 TI - Effective and rapid sealing of coronary, aortic and atrial suture lines ?. AB - OBJECTIVES: Cardiac surgical procedures carry a high risk of perioperative bleeding. Surgical sealants are often used to prevent suture line bleeding. PreveLeakTM is a surgical sealant composed of bovine serum albumin, a polyaldehyde cross-linker, and other components that forms a soft, flexible, water-tight, mechanical seal that is biocompatible and bioresorbable. METHODS: A prospective, multicentre study evaluated PreveLeak use in 44 subjects undergoing 63 cardiac procedures, primarily coronary artery bypass grafting (n = 23/63, 36.5%) and aortic valve replacement (n = 19/63, 30.2%). PreveLeak was applied to 127 suture lines and the time to sealing evaluated upon clamp release. The primary safety endpoint was the incidence of significant bleeding, infections, neurological deficits and immune/inflammatory allergic responses within 6 weeks post-treatment; subjects were followed for 3 months. RESULTS: Immediate sealing was achieved at all sites in 42 of 44 subjects (95.5%) and 125 of 127 treatment sites (98.4%). There were nine primary safety events: eight infections and one transient neurological deficit. Most adverse events were mild (n = 46/71, 64.8%) or moderate (n = 18/71, 25.4%) in severity. One adverse event (transient vasospasm) was considered possibly sealant-related. One death occurred due to a cardiac arrest. CONCLUSIONS: PreveLeak prevented bleeding at 98.4% of treated sites and was well tolerated; adverse events were consistent with those commonly observed in subjects undergoing surgical procedures. These results compared favourably with published studies of other sealants. The observed prevention of bleeding is clinically important in cardiac surgical patients. A randomized, comparative study is justified to further evaluate PreveLeak and confirm the findings from this study. PMID- 25810291 TI - Bronchus anastomosis after sleeve resection for lung cancer: does the suture technique have an impact on postoperative complication rate? AB - OBJECTIVES: Bronchoplastic resections emerged as an alternative to pneumonectomy for patients with impaired pulmonary function and have gained popularity due to a marked decrease in morbidity and at least similar oncological outcome. Actual guidelines recommend sleeve resections whenever technically feasible, even in cases with adequate pulmonary reserve for pneumonectomy, in order to maximally preserve functional lung parenchyma. Various suture techniques were described; the existing evidence, however, is insufficient to recommend one of them as standard. The aim of this study was to compare two suture techniques for bronchus repair after sleeve resection. METHODS: Two groups of patients from two separate institutions were retrospectively analysed. In Group A (n = 20), the anastomosis was performed with a running suture at the membranous part and an interrupted suture for the rest of the circumference. In Group B (n = 40), a telescoping continuous suture was used. Intra- and postoperative findings directly related to the anastomosis were compared. The parameters were assessed as absolute numbers and percentages; the statistical significance was determined using Pearson's chi(2) test for categorical variables and Student's t-test for continuous data (P < 0.05 considered as significant). RESULTS: Other than tumour location and resection type (predominance of the right upper lobe for Group B), the groups were comparable regarding patient characteristics. The intraoperative anastomotic assessment revealed: patency 100% in both groups, initial air tightness (100 vs 82.5%; P = 0.047) and buttressing 85 vs 5%. No suture revision was necessary in both groups. The analysis of anastomosis-related morbidity revealed no significant difference: atelectasis (1 in Group A and 2 in Group B; P = 1), reversible anastomotic changes (0 vs 2; P = 0.309), early stenosis (0 vs 0), bronchopleural fistula (1 vs 0; P = 0.154), bronchovascular fistula (0 vs 0), late stenosis (1 vs 0; P = 0.119) and reoperations (15 vs 5%; P = 0.186). The operative mortality rate was similar (2 vs 3; P = 0.741) without intraoperative deaths. CONCLUSIONS: Sleeve resections are technically challenging, especially concerning the tension in the suture and size mismatch. In our series, there was no significant difference between the two groups regarding parameters directly related to the anastomosis. The interrupted suture without telescoping is the most cited technique, can be performed in several variations and can universally be used with good ability to compensate size mismatch. The telescoping continuous anastomosis is less time- and material-consuming and is especially valuable for large-calibre bronchi and relevant size mismatch. PMID- 25810293 TI - Human genetics of atherothrombotic disease and its risk factors. PMID- 25810292 TI - Is minimally invasive mitral valve repair with artificial chords reproducible and applicable in routine surgery? AB - OBJECTIVES: Traditional resectional techniques and chordal transfer are difficult to apply in video-assisted mitral valve repair. Using artificial chords appears easier in this setting. The purpose of this study was to review the effectiveness and reproducibility of neochordal repair as a routine approach to minimally invasive mitral repair, and to assess the stability of neochord implantation using the figure-of-eight suture without pledgets in this setting. METHODS: This is a retrospective review of all patients who underwent minimally invasive video assisted mitral valve repair from 2008 to 2013. The primary endpoints were recurrent mitral regurgitation and reoperation. RESULTS: A total of 426 consecutive patients were included during the study period, with a mean age of 55 +/- 18 years. Neochords were used in all patients, and in association with leaflet resection in 47 patients. One patient was not repairable and underwent valve replacement (repair rate, 99.8%). Fifteen patients had Grade I (3.5%) regurgitation, whereas the remainder had none. Patients were fast-tracked, with 25% extubated in the operation theatre and the remainder within 6 h. There were 5 deaths within 30 days (1.2%). Follow-up ranged 3-60 months, during which all of the patients remained with no or trace mitral regurgitation. No de-insertion or rupture of any neochords was found, and no patients required a reoperation. CONCLUSIONS: Minimally invasive mitral valve repair using neochords provided a high rate of repair, reproducible results in a routine cardiac surgery setting and stable repair during follow-up. This has become our preferred technique for mitral valve surgery. PMID- 25810294 TI - SREBF2-embedded mir33 links the nuclear bile acid receptor FXR to cholesterol and lipoprotein metabolism. PMID- 25810296 TI - Many faces of matrix metalloproteinases in aortic aneurysms. PMID- 25810295 TI - Coronary heart disease risk factors take a disproportional toll on women. PMID- 25810297 TI - Endothelial glucocorticoid receptor suppresses atherogenesis--brief report. AB - OBJECTIVE: The purpose of this study was to determine the role of the endothelial glucocorticoid receptor in the pathogenesis of atherosclerosis. APPROACH AND RESULTS: Control mice and mice lacking the endothelial glucocorticoid receptor were bred onto an Apoe knockout background and subjected to high-fat diet feeding for 12 weeks. Assessment of body weight and total cholesterol and triglycerides before and after the diet revealed no differences between the 2 groups of mice. However, mice lacking the endothelial glucocorticoid receptor developed more severe atherosclerotic lesions in the aorta, brachiocephalic artery, and aortic sinus, as well as a heightened inflammatory milieu as evidenced by increased macrophage recruitment in the lesions. CONCLUSIONS: These data suggest that the endothelial glucocorticoid receptor is important for tonic inhibition of inflammation and limitation of atherosclerosis progression in this model. PMID- 25810298 TI - Regulation of Csf1r and Bcl6 in macrophages mediates the stage-specific effects of microRNA-155 on atherosclerosis. AB - OBJECTIVE: The function of microRNAs is highly context and cell type dependent because of their highly dynamic expression pattern and the regulation of multiple mRNA targets. MicroRNA-155 (miR-155) plays an important role in the innate immune response by regulating macrophage function; however, the effects of miR-155 in macrophages on atherosclerosis are controversial. We hypothesized that the stage dependent target selection of miR-155 in macrophages determines its effects on atherosclerosis. APPROACH AND RESULTS: The expression of miR-155 increased in lesional macrophages of apolipoprotein E-deficient mice between 12 and 24 weeks of a high-cholesterol diet. Mir155 knockout in apolipoprotein E-deficient mice enhanced lesion formation, increased the lesional macrophage content, and promoted macrophage proliferation after 12 weeks of the high-cholesterol diet. In vitro, miR-155 inhibited macrophage proliferation by suppressing colony stimulating factor-1 receptor, which was upregulated in lesional macrophages of Mir155(-/-) apolipoprotein E-deficient mice. By contrast, Mir155 deficiency reduced necrotic core formation and the deposition of apoptotic cell debris, thereby preventing the progression of atherosclerosis between 12 and 24 weeks of the high-cholesterol diet. miR-155 inhibited efferocytosis in vitro by targeting B-cell leukemia/lymphoma 6 and thus activating RhoA (ras homolog gene family, member A). Accordingly, B-cell leukemia/lymphoma 6 was upregulated in lesional macrophages of Mir155(-/-) apolipoprotein E-deficient mice after 24 weeks, but not after 12 weeks of the high-cholesterol diet. CONCLUSIONS: Our findings demonstrate a stage-specific role of miR-155 in lesion formation. miR-155 suppressed macrophage proliferation by targeting colony-stimulating factor-1 receptor in early and impaired efferocytosis by downregulating B-cell leukemia/lymphoma 6 in advanced atherosclerosis. Therefore, targeting the interaction between miR-155 and B-cell leukemia/lymphoma 6 may be a promising approach to inhibit the progression of atherosclerosis. PMID- 25810299 TI - Inhibition of ERK1/2 and activation of LXR synergistically reduce atherosclerotic lesions in ApoE-deficient mice. AB - OBJECTIVE: Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions. APPROACH AND RESULTS: Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317 induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways. CONCLUSIONS: Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects. PMID- 25810301 TI - Correction. PMID- 25810300 TI - Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: We aimed to examine associations of lipoprotein(a) (Lp(a)) concentrations with coronary heart disease (CHD) and determine whether current Lp(a) clinical laboratory cut points identify risk of disease incidence in 4 races/ethnicities of the Multi-Ethnic Study of Atherosclerosis (MESA). APPROACH AND RESULTS: A subcohort of 1323 black, 1677 white, 548 Chinese American, and 1044 Hispanic MESA participants were followed up during a mean 8.5-year period in which 235 incident CHD events were recorded. Lp(a) mass concentrations were measured using a turbidimetric immunoassay. Cox regression analysis determined associations of Lp(a) with CHD risk with adjustments for lipid and nonlipid variables. Lp(a) concentrations were continuously associated with risk of CHD incidence in black (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.09 2.04] and white participants (HR, 1.22; 95% CI, 1.02-1.45). Examining Lp(a) risk by the 50 mg/dL cut point revealed higher risks of incident CHD in all races except Chinese Americans: blacks (HR, 1.69; 95% CI, 1.03-2.76), whites (HR, 1.82; 95% CI, 1.15-2.88); Hispanics (HR, 2.37; 95% CI, 1.17-4.78). The lower Lp(a) cut point of 30 mg/dL identified higher risk of CHD in black participants alone (HR, 1.87; 95% CI, 1.08-3.21). CONCLUSIONS: Our findings suggest that the 30 mg/dL cutoff for Lp(a) is not appropriate in white and Hispanic individuals, and the higher 50 mg/dL cutoff should be considered. In contrast, the 30 mg/dL cutoff remains suitable in black individuals. Further research is necessary to develop the most clinically useful Lp(a) cutoff values in individual races/ethnicities. PMID- 25810303 TI - Envisioning an IDEAL future for urological innovation. PMID- 25810302 TI - A Signal-Passing DNA-Strand-Exchange Mechanism for Active Self-Assembly of DNA Nanostructures. AB - DNA nanostructured tiles play an active role in their own self-assembly in the system described herein whereby they initiate a binding event that produces a cascading assembly process. We present DNA tiles that have a simple but powerful property: they respond to a binding event at one end of the tile by passing a signal across the tile to activate a binding site at the other end. This action allows sequential, virtually irreversible self-assembly of tiles and enables local communication during the self-assembly process. This localized signal passing mechanism provides a new element of control for autonomous self-assembly of DNA nanostructures. PMID- 25810304 TI - Masked polycythaemia vera: presenting features, response to treatment and clinical outcomes. AB - Masked polycythaemia vera (PV) has been proposed as a new entity with poorer outcome than overt PV. In this study, the initial clinical and laboratory characteristics, response to treatment and outcome of masked and overt PV were compared using red cell mass and haemoglobin or haematocrit levels for the distinction between both entities. Sixty-eight of 151 PV patients (45%) were classified as masked PV according to World Health Organisation diagnostic criteria, whereas 16 (11%) were classified as masked PV using the British Committee for Standards in Haematology (BCSH). In comparison with overt PV, a higher platelet count and a lower JAK2V617F allele burden at diagnosis were observed in masked PV. Patients with masked PV needed lower phlebotomies and responded faster to hydroxcarbamide than those with overt PV. Complete haematological response was more frequently achieved in masked than in overt PV (79% vs. 58%, P = 0.001). There were no significant differences in the duration of haematological response, the rate of resistance or intolerance to hydroxycarbamide and the probability of molecular response according to type of PV (masked vs. overt). Overall survival, rate of thrombosis and major bleeding, and probability of transformation was superimposable among patients with masked and overt PV. PMID- 25810306 TI - Celebrate orthopedic research. PMID- 25810305 TI - Isolation and characterization of collagen from the body wall of sea cucumber Stichopus monotuberculatus. AB - To exploit a new collagen resource from the body wall of tropical sea cucumber, pepsin-solubilized collagen of Stichopus monotuberculatus (PSC-Sm) was isolated and characterized with UV-vis spectra, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), amino acid composition, enzyme-digested peptide maps, Fourier transform infrared spectroscopy (FTIR), maximum transition temperature (Tm ), and solubilities. The maximum absorbance of PSC-Sm was exhibited at 218 nm in UV-vis spectra. The triple helical structure and activity of PSC-Sm could be indicated by FTIR. SDS-PAGE showed that the triple helix of PSC-Sm was formed as (alpha1 )3 by 3 alpha1 chain homologous with molecular weight of 137 kDa. The Tm of PSC-Sm and calf skin collagen (CSC) were 30.2 and 35.0 oC, respectively, which consistent with the result of FTIR that CSC contained more stable triple-helix than PSC-Sm. Peptide maps were different between PSC-Sm and CSC, indicating the differences in their amino acid compositions and sequences. The maximum and minimum solubilities of PSC-Sm were observed at pH 2.0 and 4.0, respectively. A sharp decrease in solubility appeared when NaCl concentration was between 3% and 5%. These results showed that collagen from S. monotuberculatus had the type I collagen characteristics and good thermal stability, and therefore, it could be used as an alternative resource of collagen. PMID- 25810307 TI - Multiscale modelling in immunology: a review. AB - One of the greatest challenges in biomedicine is to get a unified view of observations made from the molecular up to the organism scale. Towards this goal, multiscale models have been highly instrumental in contexts such as the cardiovascular field, angiogenesis, neurosciences and tumour biology. More recently, such models are becoming an increasingly important resource to address immunological questions as well. Systematic mining of the literature in multiscale modelling led us to identify three main fields of immunological applications: host-virus interactions, inflammatory diseases and their treatment and development of multiscale simulation platforms for immunological research and for educational purposes. Here, we review the current developments in these directions, which illustrate that multiscale models can consistently integrate immunological data generated at several scales, and can be used to describe and optimize therapeutic treatments of complex immune diseases. PMID- 25810308 TI - Immunotherapy: making the case for precision medicine. PMID- 25810309 TI - Therapeutics to block autoantibody initiation and propagation in systemic lupus erythematosus and rheumatoid arthritis. AB - Most current therapies for the autoimmune diseases systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), as well as many of the drugs in the therapeutic pipeline, reduce the autoimmune inflammatory process but lead to a general immunosuppression. The goal of the next generation of therapies should be to reduce autoimmunity while at the same time better maintain immunocompetence. We propose three approaches for accomplishing this goal: (i) modulate antigen presentation to the adaptive immune system, (ii) alter B cell selection in the germinal center, and (iii) use decoy antigens to prevent the formation of proinflammatory immune complexes. These approaches are based on recent advances in the field: We now appreciate the role of dendritic cell function in autoimmune disease and the importance of citrullinated proteins as neoantigens in RA. There is also new recognition that most pathogenic autoantibodies are produced by B cells that have matured within the germinal center and that immune complexes in both diseases contain ligands for Toll-like receptors. We propose that treatments that target these newly revealed aspects of RA and SLE will decrease systemic inflammation with less immunocompromise. PMID- 25810310 TI - Advances in allergen immunotherapy: aiming for complete tolerance to allergens. AB - Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms, including regulating T and B cell responses, changing antibody isotypes, and decreasing mediator release and migration of eosinophils, basophils, and mast cells to affected tissues. Despite the relative success of AIT, attempts are being made to improve this therapy in order to overcome problems in standardization, efficacy, safety, long duration of treatment, and costs. These have led to the development of biotechnological products with successful clinical results. PMID- 25810311 TI - Adoptive cellular therapy: a race to the finish line. AB - Adoptive T cell transfer for cancer, chronic infection, and autoimmunity is an emerging field that shows promise in recent trials. Using the principles of synthetic biology, advances in cell culture and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities compared with the natural immune system. The prospects for widespread availability of engineered T cells have changed dramatically, given the recent entry of the pharmaceutical industry to this arena. Here, we discuss some of the challenges--such as regulatory, cost, and manufacturing--and opportunities, including personalized gene-modified T cells, that face the field of adoptive cellular therapy. PMID- 25810313 TI - On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. AB - The recent approvals of two drugs that block the function of the immune checkpoint programmed cell death 1 (PD-1) have firmly planted tumor immunotherapy in the mainstream of clinical oncology. We provide a historical and immunologic context for these recent advances and discuss translational studies that provide insight into the efficacy of cancer immunotherapy at the individual patient level. PMID- 25810315 TI - Leave Her out of It: Person-Presentation of Strategies is Harmful for Transfer. AB - A common practice in textbooks is to introduce concepts or strategies in association with specific people. This practice aligns with research suggesting that using "real-world" contexts in textbooks increases students' motivation and engagement. However, other research suggests this practice may interfere with transfer by distracting students or leading them to tie new knowledge too closely to the original learning context. The current study investigates the effects on learning and transfer of connecting mathematics strategies to specific people. A total of 180 college students were presented with an example of a problem-solving strategy that was either linked with a specific person (e.g., "Juan's strategy") or presented without a person. Students who saw the example without a person were more likely to correctly transfer the novel strategy to new problems than students who saw the example presented with a person. These findings are the first evidence that using people to present new strategies is harmful for learning and transfer. PMID- 25810314 TI - Protein tyrosine phosphatase 1B (PTP1B) inhibitory constituents from the aerial parts of Tradescantia spathacea Sw. AB - Inhibitors of protein tyrosine phosphatase 1B (PTP1B) are promising agents for the treatment of type 2 diabetes and obesity. The bioactivity-guided isolation led to the separation of two new compounds, (+/-)-tradescantin (13) and tradescantoside (16), along with fourteen known compounds (1-12, 14, and 15) from the aerial parts of Tradescantia spathacea Sw. (Commelinaceae). Their chemical structures were elucidated by spectroscopic methods as well as by comparing with those reported in the literature. The isolated compounds (1-16) were then examined for their inhibitory activity toward PTP1B. The results indicated that compounds 2, 6, 8, and 12 possessed potent inhibition with IC50 values of 7.82+/ 0.79, 6.80+/-0.89, 4.55+/-0.92, and 6.38+/-0.14 MUM, respectively. Kinetic study of compounds 2, 6, 8, 12, 13, and 16 was conducted and the structure-activity relationships of the isolated compounds (1-16) were also discussed herein. To the best of our knowledge, all the isolates were separated for the first time from this plant. PMID- 25810312 TI - Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation. AB - Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome. PMID- 25810317 TI - Analyzing Medical Image Search Behavior: Semantics and Prediction of Query Results. AB - Log files of information retrieval systems that record user behavior have been used to improve the outcomes of retrieval systems, understand user behavior, and predict events. In this article, a log file of the ARRS GoldMiner search engine containing 222,005 consecutive queries is analyzed. Time stamps are available for each query, as well as masked IP addresses, which enables to identify queries from the same person. This article describes the ways in which physicians (or Internet searchers interested in medical images) search and proposes potential improvements by suggesting query modifications. For example, many queries contain only few terms and therefore are not specific; others contain spelling mistakes or non-medical terms that likely lead to poor or empty results. One of the goals of this report is to predict the number of results a query will have since such a model allows search engines to automatically propose query modifications in order to avoid result lists that are empty or too large. This prediction is made based on characteristics of the query terms themselves. Prediction of empty results has an accuracy above 88%, and thus can be used to automatically modify the query to avoid empty result sets for a user. The semantic analysis and data of reformulations done by users in the past can aid the development of better search systems, particularly to improve results for novice users. Therefore, this paper gives important ideas to better understand how people search and how to use this knowledge to improve the performance of specialized medical search engines. PMID- 25810316 TI - Cutaneous embolism of an atrial myxoma. AB - Cardiac myxoma often presents with heterogeneous symptoms and signs and represents a challenging diagnosis. The cutaneous manifestations, if present, are often transient and non-specific and the clinician must possess a high degree of suspicion to secure the diagnosis. We present the case of a 36-year-old woman with a 6-month history of intermittent, painful, violaceous, non-blanching macules on the thumb and fingertips of the left hand and right ankle. A cutaneous embolic phenomenon was suspected and an urgent echocardiogram demonstrated an atrial mass, with subsequent histopathology confirming the clinical suspicion of atrial myxoma. Early diagnosis and excision of the tumour avoided serious complications. PMID- 25810318 TI - Inhibition of retinoic acid catabolism by minocycline: evidence for a novel mode of action? AB - Retinoic acid (RA) represents an essential and highly potent endogenous retinoid with pronounced anti-inflammatory properties and potent anti-acne activity, and has recently been suggested to share a common anti-inflammatory mode of action with tetracycline antibiotics. We hypothesized that tetracyclines may directly interfere with RA homeostasis via inhibition of its local cytochrome P450 (CYP450)-mediated degradation, an essential component of tightly regulated skin RA homeostasis. To test this hypothesis, we performed controlled in vitro RA metabolism assays using rat skin microsomes and measured RA levels in a RA synthesizing human keratinocyte cell line, both in the presence and in the absence of minocycline, a tetracycline popular in acne treatment. Interestingly, minocycline potently blocked RA degradation in rat skin microsomes, and strikingly enhanced RA levels in RA-synthesizing cell cultures, in a dose dependent manner. These findings indicate a potential role for CYP-450-mediated RA metabolism in minocycline's pleiotropic mode of action and anti-acne efficacy and could account for the overlap between minocycline and RA-induced effects at the level of their molecular mode of action, but also clinically at the level of the rare side effect of pseudotumor cerebri, which is observed for both, RA and minocycline treatment. PMID- 25810319 TI - Aggressive Treatment at End of Life. PMID- 25810320 TI - Soma-to-germline feedback is implied by the extreme polymorphism at IGHV relative to MHC: The manifest polymorphism of the MHC appears greatly exceeded at Immunoglobulin loci, suggesting antigen-selected somatic V mutants penetrate Weismann's Barrier. AB - Soma-to-germline feedback is forbidden under the neo-Darwinian paradigm. Nevertheless, there is a growing realization it occurs frequently in immunoglobulin (Ig) variable (V) region genes. This is a surprising development. It arises from a most unlikely source in light of the exposure of co-author EJS to the haplotype data of RL Dawkins and others on the polymorphism of the Major Histocompatibility Complex, which is generally assumed to be the most polymorphic region in the genome (spanning ~4 Mb). The comparison between the magnitude of MHC polymorphism with estimates for the human heavy chain immunoglobulin V locus (spanning ~1 Mb), suggests IGHV could be many orders of magnitude more polymorphic than the MHC. This conclusion needs airing in the literature as it implies generational churn and soma-to-germline gene feedback. Pedigree-based experimental strategies to resolve the IGHV issue are outlined. PMID- 25810322 TI - Comparative study on efficacy and safety of 1550 nm Er:Glass fractional laser and fractional radiofrequency microneedle device for facial atrophic acne scar. AB - BACKGROUND: The 1550 nm Er:Glass fractional laser is widely used for the treatment of atrophic acne scar. A novel fractional radiofrequency microneedle device has recently emerged as an alternative for treating acne scars. OBJECTIVES: To evaluate the clinical efficacy and safety of a Er:Glass fractional laser and fractional radiofrequency microneedle device in the treatment of facial atrophic acne scars and to assess the difference between the treatment modalities depending on facial compartment. METHODS: A total of 40 patients were equally randomized into two groups. Each group of 20 patients received three treatments at 4-week interval using Er:Glass fractional laser or fractional radiofrequency microneedle device. RESULTS: Scar severity scores (ECCA grading scale) improved by a mean of 25.0% and 18.6% in groups A and B, respectively (both P < 0.01). The difference in the degree of improvement was not statistically significant between the groups after three sessions of treatment. There were no significant side effects. CONCLUSION: Atrophic acne scars improved in both groups without significant side effects. Additionally, the fractional laser was a more effective treatment option for acne scars, but the fractional radiofrequency microneedle device offered good adherence and short downtime. PMID- 25810323 TI - Identification and expression analysis of the SQUAMOSA promoter-binding protein (SBP)-box gene family in Prunus mume. AB - SQUAMOSA promoter-binding protein (SBP)-box family genes encode plant-specific transcription factors that play crucial roles in plant development, especially flower and fruit development. However, little information on this gene family is available for Prunus mume, an ornamental and fruit tree widely cultivated in East Asia. To explore the evolution of SBP-box genes in Prunus and explore their functions in flower and fruit development, we performed a genome-wide analysis of the SBP-box gene family in P. mume. Fifteen SBP-box genes were identified, and 11 of them contained an miR156 target site. Phylogenetic and comprehensive bioinformatics analyses revealed that different groups of SBP-box genes have undergone different evolutionary processes and varied in their length, structure, and motif composition. Purifying selection has been the main selective constraint on both paralogous and orthologous SBP-box genes. In addition, the sequences of orthologous SBP-box genes did not diverge widely after the split of P. mume and Prunus persica. Expression analysis of P. mume SBP-box genes revealed their diverse spatiotemporal expression patterns. Three duplicated SBP-box genes may have undergone subfunctionalization in Prunus. Most of the SBP-box genes showed high transcript levels in flower buds and young fruit. The four miR156 nontargeted genes were upregulated during fruit ripening. Together, these results provide information about the evolution of SBP-box genes in Prunus. The expression analysis lays the foundation for further research on the functions of SBP-box genes in P. mume and other Prunus species, especially during flower and fruit development. PMID- 25810325 TI - Evaluation of cartilage repair and osteoarthritis with sodium MRI. AB - The growing need for early diagnosis and higher specificity than that which can be achieved with morphological MRI is a driving force in the application of methods capable of probing the biochemical composition of cartilage tissue, such as sodium imaging. Unlike morphological imaging, sodium MRI is sensitive to even small changes in cartilage glycosaminoglycan content, which plays a key role in cartilage homeostasis. Recent advances in high- and ultrahigh-field MR systems, gradient technology, phase-array radiofrequency coils, parallel imaging approaches, MRI acquisition strategies and post-processing developments have resulted in many clinical in vivo sodium MRI studies of cartilage, even at 3 T. Sodium MRI has great promise as a non-invasive tool for cartilage evaluation. However, further hardware and software improvements are necessary to complete the translation of sodium MRI into a clinically feasible method for 3-T systems. This review is divided into three parts: (i) cartilage composition, pathology and treatment; (ii) sodium MRI; and (iii) clinical sodium MRI studies of cartilage with a focus on the evaluation of cartilage repair tissue and osteoarthritis. PMID- 25810324 TI - Postgastrectomy pharmacokinetic changes of S-1 in patients with localized advanced gastric cancer. AB - S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4 dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5 fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5 fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication. PMID- 25810328 TI - Social workers' role in tempering inequality in healthcare in hospitals and clinics: a study in Israel. AB - The paper presents an empirical examination of the role social workers play in tempering inequality in medical care. Data were collected in 2011 through face-to face, semi-structured, in-depth interviews with 60 social workers employed in hospitals and clinics in Israel and selected through purposive sampling. The interviews probed the social workers' perceptions of the scope, causes and manifestations of inequality in health and healthcare and the actions they took to ameliorate it. The interviews were analysed using grounded theory. The findings show that all the social workers were acutely aware of the inequalities in their places of work, regarded reducing the inequalities as a major part of their role and made efforts to do so. They facilitated communication between doctors and patients of low socioeconomic status and advocated for such patients with medical staff and administration, as well as with the country's medical and social welfare bureaucracies. The paper details the means they used and the challenges they faced. The study highlights the important role that social workers play in reducing inequality in healthcare. PMID- 25810327 TI - 13-valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6-17 years of age with sickle cell disease previously vaccinated with 23 valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study. AB - BACKGROUND: A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23-valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13-valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. PROCEDURE: Children with SCD 6-17 years of age previously vaccinated with PPSV23 at least 6 months before study enrollment received two doses of PCV13 6 months apart. Anti pneumococcal polysaccharide immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured before, 1 month after each administration, and 1 year after the second administration. RESULTS: Following each PCV13 administration, IgG GMCs and OPA GMTs significantly increased, and antibody levels after doses 1 and 2 were generally comparable. Antibody levels declined over the year following dose 2. At 1 year after the second administration, OPA GMTs for all and IgG GMCs for most serotypes remained above pre-vaccination levels. Most adverse events were due to vaso-occlusive crises, a characteristic of the underlying condition of SCD. CONCLUSIONS: Children with SCD who were previously vaccinated with PPSV23 responded well to 1 PCV13 dose, and a second dose did not increase antibody response. PCV13 antibodies persisted above pre-vaccination levels for all serotypes 1 year after dose 2. Children with SCD may benefit from at least one dose of PCV13. PMID- 25810332 TI - Airway complications after single-stage unifocalization for pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries. AB - OBJECTIVE: We analyze the incidence of postoperative severe airflow limitation after single-stage unifocalization in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries (PA/VSD/MAPCAs) and comment on the treatment performed. METHODS: From 1994 until 2014, 118 patients with diagnosis of PA, VSD, MAPCAs underwent surgical treatment. Four patients (3.4%) developed severe airflow complications postoperatively. Chromosome 22q11 deletion was present in three of them. Median age at the time of unifocalization was 6.2 months (range 21 days to 11 months). RESULTS: The first patient developed malacia and compression of the left bronchus from the distal RV-PA conduit and was treated with external bronchial stenting with two incomplete costal cartilage rings. The second patient developed recurrent esophagus-left bronchus fistula treated with multiple surgical esophageal and bronchus reconstructions. The third child presented with bilateral bronchial malacia treated with bilateral stenting followed by surgical elongation of the neo-left pulmonary artery to avoid external compression. The last patient developed bilateral bronchomalacia treated with bilateral bronchial stenting followed by RV-PA conduit replacement and endobronchial stenting calibration. CONCLUSION: Particular categories of patients with PA, VSD, MAPCAs (22q11 chromosome deletion, neonates/infants, patients with dominant/exclusive collaterals) may be more predisposed to develop airway compromise. The treatment of the lesion should be individualized according to the pathogenic mechanism. We suggest endoluminal treatment in absence of compression by vascular structures while surgery was used in case of extrinsic compression. PMID- 25810331 TI - Sensory perception, nutritional role, and challenges of flavored milk for children and adults. AB - Milk and milk products provide essential nutrients for both adults and children. However, overall milk consumption of both adults and children does not meet the recommendations from Dietary Guidelines for Americans. Flavored milk can increase milk consumption for children and adolescents, but the added sugar content raises concern. Since the removal or reduction of flavored milk decreases milk consumption for children, it is important to understand all aspects of flavored milk in order to increase milk consumption while minimizing sugar intake. This review will address adult and children perception of flavored milk as well as its nutrition, regulations in school meal programs, and challenges. Understanding the sensory perception of both adults and children for flavored milk can help food developers and manufacturers to address attractive attributes while reducing the sugar content to meet the needs of a healthy diet. PMID- 25810326 TI - Estradiol modulates visceral hyperalgesia by increasing thoracolumbar spinal GluN2B subunit activity in female rats. AB - BACKGROUND: We previously reported estrogen modulates spinal N-methyl-d-aspartate (NMDA) receptor processing of colorectal pain through changes in spinal GluN1 subunit phosphorylation/expression. The purpose of this study was to investigate whether spinal GluN2B containing NMDA receptors are involved in estrogen modulation of visceral pain processing. METHODS: Behavioral, molecular, and immunocytochemical techniques were used to determine spinal GluN2B expression/phosphorylation and function 48 h following subcutaneous injection of estradiol (E2) or vehicle (safflower oil, Saff oil) in ovariectomized rats in the absence or presence of colonic inflammation induced by mustard oil. KEY RESULTS: E2 increased the magnitude of the visceromotor response (VMR) to colorectal distention compared to Saff oil in non-inflamed rats. Intrathecal injection of the GluN2B subunit antagonist, Ro 25-6981, had no effect on the VMR in non inflamed E2 or Saff oil rats. Colonic inflammation induced visceral hyperalgesia in E2, but not Saff oil rats. Visceral hyperalgesia in E2 rats was blocked by intrathecal GluN2B subunit selective antagonists. In inflamed rats, E2 increased GluN2B protein and gene expression in the thoracolumbar (TL), but not lumbosacral (LS), dorsal spinal cord. Immunocytochemical labeling showed a significant increase in GluN2B subunit in the superficial dorsal horn of E2 rats compared to Saff oil rats. CONCLUSIONS & INFERENCES: These data support the hypothesis that estrogen increases spinal processing of colonic inflammation-induced visceral hyperalgesia by increasing NMDA receptor activity. Specifically, an increase in the activity of GluN2B containing NMDA receptors in the TL spinal cord by estrogen underlies visceral hypersensitivity in the presence of colonic inflammation. PMID- 25810333 TI - Practical Use of Computationally Frugal Model Analysis Methods. AB - Three challenges compromise the utility of mathematical models of groundwater and other environmental systems: (1) a dizzying array of model analysis methods and metrics make it difficult to compare evaluations of model adequacy, sensitivity, and uncertainty; (2) the high computational demands of many popular model analysis methods (requiring 1000's, 10,000 s, or more model runs) make them difficult to apply to complex models; and (3) many models are plagued by unrealistic nonlinearities arising from the numerical model formulation and implementation. This study proposes a strategy to address these challenges through a careful combination of model analysis and implementation methods. In this strategy, computationally frugal model analysis methods (often requiring a few dozen parallelizable model runs) play a major role, and computationally demanding methods are used for problems where (relatively) inexpensive diagnostics suggest the frugal methods are unreliable. We also argue in favor of detecting and, where possible, eliminating unrealistic model nonlinearities-this increases the realism of the model itself and facilitates the application of frugal methods. Literature examples are used to demonstrate the use of frugal methods and associated diagnostics. We suggest that the strategy proposed in this paper would allow the environmental sciences community to achieve greater transparency and falsifiability of environmental models, and obtain greater scientific insight from ongoing and future modeling efforts. PMID- 25810335 TI - Stroke and anticoagulation in heart failure without atrial fibrillation: from risk to opportunity. PMID- 25810334 TI - Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials. AB - BACKGROUND: Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). METHODS AND RESULTS: We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by chi(2) value): age (hazard ratio, 1.34; 95% confidence interval, 1.18-1.63 per 10 years), New York Heart Association class (1.60, 1.21-2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22-2.88), body mass index (0.74, 0.60-0.91 per 5 kg/m(2) up to 30), and previous stroke (1.81, 1.19-2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11-1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. CONCLUSIONS: A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke. PMID- 25810336 TI - Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients. AB - BACKGROUND: Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined. METHODS AND RESULTS: Using noninvasive ECG imaging, we studied 25 BrS patients to characterize the electrophysiological substrate and 6 patients with right bundle-branch block for comparison. Seven healthy subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract with the following properties (in comparison with healthy controls; P<0.005): (1) ST-segment elevation and inverted T wave of unipolar electrograms (2.21+/-0.67 versus 0 mV); (2) delayed right ventricular outflow tract activation (82+/-18 versus 37+/-11 ms); (3) low-amplitude (0.47+/-0.16 versus 3.74+/-1.60 mV) and fractionated electrograms, suggesting slow discontinuous conduction; (4) prolonged recovery time (381+/-30 versus 311+/-34 ms) and activation-recovery intervals (318+/-32 versus 241+/-27 ms), indicating delayed repolarization; (5) steep repolarization gradients (Deltarecovery time/Deltax=96+/-28 versus 7+/-6 ms/cm, Deltaactivation recovery interval/Deltax=105+/-24 versus 7+/-5 ms/cm) at right ventricular outflow tract borders. With increased heart rate in 6 BrS patients, reduced ST segment elevation and increased fractionation were observed. Unlike BrS, right bundle-branch block had delayed activation in the entire right ventricle, without ST-segment elevation, fractionation, or repolarization abnormalities on electrograms. CONCLUSIONS: The results indicate that both slow discontinuous conduction and steep dispersion of repolarization are present in the right ventricular outflow tract of BrS patients. ECG imaging could differentiate between BrS and right bundle-branch block. PMID- 25810337 TI - Expanding Saga of the Renin-Angiotensin System: The Angiotensin II Counter Regulatory AT2 Receptor Pathway. PMID- 25810338 TI - Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor. AB - BACKGROUND: The renin-angiotensin system and especially the angiotensin peptides play a central role in blood pressure regulation. Here, we hypothesize that an as yet unknown peptide is involved in the action of angiotensin II modulating the vasoregulatory effects as a cofactor. METHODS AND RESULTS: The peptide with vasodilatory properties was isolated from adrenal glands chromatographically. The effects of this peptide were evaluated in vitro and in vivo, and the receptor affinity was analyzed. The plasma concentration in humans was quantified in patients with chronic kidney disease, patients with heart failure, and healthy control subjects. The amino acid sequence of the peptide from bovine adrenal glands was HSSYEDELSEVL EKPNDQAE PKEVTEEVSSKDAAE, which is a degradation product of chromogranin A. The sequence of the peptide isolated from human plasma was HSGFEDELSEVLENQSSQAELKEAVEEPSSKDVME. Both peptides diminished significantly the vasoconstrictive effect of angiotensin II in vitro. Therefore, we named the peptide vasoconstriction-inhibiting factor (VIF). The vasoregulatory effects of VIF are mediated by the angiotensin II type 2 receptor. VIF impairs angiotensin II-induced phosphorylation of the p38 mitogen-activated protein kinase pathway but not of extracellular-regulated kinase 1/2. The vasodilatory effects were confirmed in vivo. The plasma concentration was significantly increased in renal patients and patients with heart failure. CONCLUSIONS: VIF is a vasoregulatory peptide that modulates the vasoconstrictive effects of angiotensin II by acting on the angiotensin II type 2 receptor. It is likely that the increase in VIF may serve as a counterregulatory effect to defend against hypertension. The identification of this target may help us to understand the pathophysiology of renal and heart failure and may form a basis for the development of new strategies for the prevention and treatment of cardiovascular disease. PMID- 25810339 TI - p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer. AB - OBJECTIVE: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). STUDY DESIGN: Historical cohort study. SETTING: Tertiary medical center. METHODS: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. RESULTS: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). CONCLUSIONS: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy. PMID- 25810341 TI - Occupational health hazards of interventional cardiologists in the current decade: Results of the 2014 SCAI membership survey. AB - BACKGROUND: Interventional cardiologists and staff are subject to unique physical demands that predispose them to distinct occupational health hazards not seen in other medical disciplines. METHODS: To characterize the prevalence of these occupational health problems, The Society for Cardiovascular Angiography and Interventions (SCAI) surveyed its members by email. Inquiries included age, years of invasive practice, and diagnostic and interventional cases per year. Questions focused on orthopedic (spine, hips, knees, and ankles) and radiation-associated problems (cataracts and cancers). RESULTS: There were 314 responses. Responders were on average busy and experienced, performing a mean of 380+/-249 diagnostic and 200+/-129 interventional cases annually. Of the responders, 6.9% of operators have had to limit their caseload because of radiation exposure and 9.3% have had a health-related period of absence. Furthermore, 153 (49.4%) operators reported at least one orthopedic injury: 24.7% cervical spine disease, 34.4% lumbar spine problems, and 19.6% hip, knee or ankle joint problems. Age was most significantly correlated with orthopedic illnesses: cervical injuries (chi2=150.7, P<0.0001); hip/knee or ankle injuries (chi2=80.9, P<0.0001); lumbar injuries (chi2=147.0, P<0.0001); and any orthopedic illness (chi2= 241.2, P<0.0001). Annual total caseload was also associated: the estimated change in the odds of orthopedic illness for each additional total caseload quintile is 1.0013 (1.0001, 1.0026). There is a small but substantial incidence of cancer. CONCLUSIONS: These findings are consistent with, and extend the findings, of a prior 2004 SCAI survey, in documenting a substantial prevalence of orthopedic complications among active interventional cardiologists, which persists despite increased awareness. PMID- 25810340 TI - Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses. AB - Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ) mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, alpha-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFbeta1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFbeta1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFbeta1 to induce the expression of profibrotic genes and tubular apoptosis. PMID- 25810342 TI - Experimental designs for detecting synergy and antagonism between two drugs in a pre-clinical study. AB - The identification of synergistic interactions between combinations of drugs is an important area within drug discovery and development. Pre-clinically, large numbers of screening studies to identify synergistic pairs of compounds can often be ran, necessitating efficient and robust experimental designs. We consider experimental designs for detecting interaction between two drugs in a pre clinical in vitro assay in the presence of uncertainty of the monotherapy response. The monotherapies are assumed to follow the Hill equation with common lower and upper asymptotes, and a common variance. The optimality criterion used is the variance of the interaction parameter. We focus on ray designs and investigate two algorithms for selecting the optimum set of dose combinations. The first is a forward algorithm in which design points are added sequentially. This is found to give useful solutions in simple cases but can lack robustness when knowledge about the monotherapy parameters is insufficient. The second algorithm is a more pragmatic approach where the design points are constrained to be distributed log-normally along the rays and monotherapy doses. We find that the pragmatic algorithm is more stable than the forward algorithm, and even when the forward algorithm has converged, the pragmatic algorithm can still out perform it. Practically, we find that good designs for detecting an interaction have equal numbers of points on monotherapies and combination therapies, with those points typically placed in positions where a 50% response is expected. More uncertainty in monotherapy parameters leads to an optimal design with design points that are more spread out. PMID- 25810344 TI - Simultaneous reactivation of cytomegalovirus in an adult patient with varicella. PMID- 25810345 TI - Synthesis and characterization of biphenylene-containing diazaacenes. AB - We describe the efficient synthesis of substituted benzo[3,4]cyclobuta[1,2 b]phenazine, benzo[3,4]cyclobuta[1,2]benzo[1,2-i]phenazine, and benzo[3,4]cyclobuta[1,2-b]naphtho[2,3-i]phenazine by a condensation reaction of aromatic diamines with the stable biphenylene-2,3-dione. PMID- 25810343 TI - Performance of the 2-hour accelerated diagnostic protocol within the American College of Radiology Imaging Network PA 4005 cohort. AB - OBJECTIVES: The 2-hour accelerated diagnostic protocol (ADAPT) is a decision rule designed to identify emergency department (ED) patients with chest pain for early discharge. Previous studies in the Asia-Pacific region demonstrated high sensitivity (97.9% to 99.7%) for major adverse cardiac events (MACE) at 30 days. The objective of this study was to determine the validity of ADAPT for risk stratification in a cohort of U.S. ED patients with suspected acute coronary syndrome (ACS). METHODS: A secondary analysis of participants enrolled in the American College of Radiology Imaging Network (ACRIN) PA 4005 trial was conducted. This trial enrolled 1,369 patients at least 30 years old with symptoms suggestive of ACS. All data elements were collected prospectively at the time of enrollment. Each patient was classified as low risk or at risk by ADAPT. Early discharge rate and sensitivity for MACE, defined as cardiac death, myocardial infarction (MI), or coronary revascularization at 30 days, were calculated. RESULTS: Of 1,140 patients with complete biomarker data, MACE occurred in 31 patients (2.7%). Among 551 of the 1,140 (48.3%, 95% confidence interval [CI] = 45.4% to 51.3%), ADAPT identified for early discharge; five of the 551 (0.9%, 95% CI = 0.3% to 2.1%) had MACE at 30 days. ADAPT was 83.9% (95% CI = 66.3% to 94.5%) sensitive, identifying 26 of 31 patients with MACE. Of the five patients identified for early discharge by ADAPT with MACE, there were no deaths, one patient with MI, and five with revascularizations. CONCLUSIONS: In this first North American application of the ADAPT strategy, sensitivity for MACE within 30 days was 83.9%. One missed adverse event was a MI, with the remainder representing coronary revascularizations. The effect of missing revascularization events needs further investigation. PMID- 25810347 TI - The transmission of attachment across generations: The state of art and new theoretical perspectives. AB - The paper reviews the body of research testing the intergenerational transmission of attachment and the theoretical shift from the linear or mediation model (van IJzendoorn, 1995), according to which parental sensitivity is the main factor responsible for the correspondence between maternal and infant's attachment, to the ecological model of the transmission of attachment (van IJzendoorn & Bakermans-Kranenburg, 1997). This latter model has prompted researchers, over time, to identify potential mediators, other than caregiver's sensitivity, of the established association between parental representations regarding attachment and infant's attachment, as well as the potential moderators of the transmission process. Each of these two research domains will be carefully explored; lastly new perspectives on the intergenerational transmission of attachment and relevant areas of research needing more investigation are highlighted. PMID- 25810348 TI - Maxillary Four Implant-retained Overdentures via Locator(r) Attachment: Intermediate-term Results from a Retrospective Study. AB - BACKGROUND: Maxillary overdentures have been utilized to restore oral function in scenarios where limited bone structure represents a drawback for financial issues and for cases where oral hygiene is uncertain. PURPOSE: The aim of this study was to evaluate the intermediate-term clinical outcome of four locator attachment retaining maxillary overdentures and to test their reliability. MATERIALS AND METHODS: A retrospective study was conducted from January 2007 to October 2013. After the placement of four maxillary dental implants and a healing period of approximately 3 months, all the implants were restored with locator-retained overdentures with partial palatal coverage. Subjects and implant characteristics, implant position (anterior vs posterior maxilla), bone quality, and opposing dentition were recorded. Peri-implant clinical parameters and marginal bone loss (MBL) were evaluated after delivery of the final prosthesis and annually thereafter. The performance of locator components and the prosthetic restoration were also recorded at follow-up. RESULTS: A total of 104 implants were placed in 26 subjects (11 women, 15 men; mean age, 64 years; age range, 55-76 years). One implant failed before loading. One subject dropped out of the study during a mean follow-up period of 46 months (range: 7-73 months), achieving an overall survival rate of 95.2%. Clinical parameters revealed healthy tissues around most of the implants, with low scores of plaque and bleeding indices. At the last follow-up evaluation, the mean MBL was 1.7 +/- 1.1 mm (0.4-2.6 mm). Regression model analysis indicated that MBL for implants in the posterior maxilla was significantly higher than that for implants in the anterior maxilla (p = .0487). Overall, 26 technical and prosthetic complications were reported. CONCLUSION: Within the limitations of this study, maxillary four implant-retained overdentures via Locator attachment seem to be a predictable alternative for oral rehabilitation. PMID- 25810349 TI - Hyoid Bone Development: An Assessment Of Optimal CT Scanner Parameters and Three Dimensional Volume Rendering Techniques. AB - The hyoid bone anchors and supports the vocal tract. Its complex shape is best studied in three dimensions, but it is difficult to capture on computed tomography (CT) images and three-dimensional volume renderings. The goal of this study was to determine the optimal CT scanning and rendering parameters to accurately measure the growth and developmental anatomy of the hyoid and to determine whether it is feasible and necessary to use these parameters in the measurement of hyoids from in vivo CT scans. Direct linear and volumetric measurements of skeletonized hyoid bone specimens were compared with corresponding CT images to determine the most accurate scanning parameters and three-dimensional rendering techniques. A pilot study was undertaken using in vivo scans from a retrospective CT database to determine feasibility of quantifying hyoid growth. Scanning parameters and rendering technique affected accuracy of measurements. Most linear CT measurements were within 10% of direct measurements; however, volume was overestimated when CT scans were acquired with a slice thickness greater than 1.25 mm. Slice-by-slice thresholding of hyoid images decreased volume overestimation. The pilot study revealed that the linear measurements tested correlate with age. A fine-tuned rendering approach applied to small slice thickness CT scans produces the most accurate measurements of hyoid bones. However, linear measurements can be accurately assessed from in vivo CT scans at a larger slice thickness. Such findings imply that investigation into the growth and development of the hyoid bone, and the vocal tract as a whole, can now be performed using these techniques. PMID- 25810352 TI - Prediction of small-for-gestational-age neonates: screening by uterine artery Doppler and mean arterial pressure at 19-24 weeks. AB - OBJECTIVE: To investigate the potential value of uterine artery (UtA) pulsatility index (PI) and mean arterial pressure (MAP) at 19-24 weeks' gestation, in combination with maternal characteristics and medical history and fetal biometry in the prediction of delivery of small-for-gestational-age (SGA) neonates in the absence of pre-eclampsia (PE) and to examine the potential value of such assessment in deciding whether the third-trimester scan should be performed at 32 and/or 36 weeks' gestation. METHODS: This was a screening study in 63 975 singleton pregnancies, including 3702 (5.8%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ) in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal head circumference (HC), abdominal circumference (AC), femur length (FL), UtA-PI and MAP had significant contribution in predicting SGA neonates. A model was developed to select gestational age for the third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. RESULTS: The detection rates (DRs) of combined screening by maternal factors, fetal biometry and UtA-PI at 19-24 weeks were 90%, 68% and 44% for SGA < 5(th) delivering < 32, 32-36 and >= 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The performance of screening was not improved by the addition of MAP. The DR of SGA < 5(th) delivering at 32-36 weeks improved from 68% to 90% with screening at 32 rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering >= 37 weeks improved from 44% with screening at 19-24 weeks to 59% and 76% when screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 17% of the population at the 19 24-week assessment to be reassessed at 32 weeks and 38% to be reassessed at 36 weeks; 62% would not require a third-trimester scan. CONCLUSION: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks. PMID- 25810350 TI - Craniofacial abnormalities and developmental delay in two families with overlapping 22q12.1 microdeletions involving the MN1 gene. AB - Deletions spanning the MN1 gene (22q12.1) have recently been proposed as playing a role in craniofacial abnormalities that include cleft palate, as mouse studies have demonstrated that Mn1 haploinsufficiency results in skull abnormalities and secondary cleft palate. We report on four patients (two families) with craniofacial abnormalities and intellectual disability with overlapping microdeletions that span the MN1 gene. Comparative genomic hybridization microarray analysis revealed a 2.76 Mb deletion in the 22q12.1 region, in three family members (Family 1), that contains the MN1 gene. In addition, a complex 22q12 rearrangement, including a 1.61 Mb deletion containing the MN1 gene and a 2.28 Mb deletion encompassing the NF2 gene, has been identified in another unrelated patient (Family 2). Based upon genotype-phenotype correlation among our patients and those previously reported with overlapping 22q12 deletions, we identified a 560 kb critical region containing the MN1 gene that is implicated in human cleft palate formation. Importantly, NF2 was also found within the 22q12 deletion region in several patients which enabled specific clinical management for neurofibromatosis 2. PMID- 25810351 TI - Prediction of Development of Critical Limb Ischemia in Hemodialysis Patients. AB - Hemodialysis (HD) patients with critical limb ischemia (CLI) suffer chronic inflammation and repeated infection, require intervention, and may have a protracted hospital stay. Therefore, early prediction is particularly important for management of CLI in patients with suspected peripheral artery disease. The purpose of this study is to develop a simple score for predicting the incidence of CLI in HD patients with suspected peripheral artery disease. The subjects were 139 asymptomatic patients receiving maintenance HD and with ABI <1.0. Multivariate logistic regression analysis was used to identify factors associated with development of CLI. These factors were subsequently weighted and integrated into a scoring system for the prediction of onset of CLI. Twenty-five patients had onset of CLI. Five factors selected from the multivariate model were weighted proportionally using their respective odds ratio (OR) for incidence of CLI (history of cerebral vascular disease, OR 6.42 [3 points]; diabetes, OR 3.92 [2 points]; hypoesthesia, OR 4.21 [2 points]; left ventricular ejection fraction <50%, OR 3.89 [2 points]; serum albumin <3.5 g/dL, OR 4.39 [2 points]). Three strata of risk were defined (low risk, 0 to 3 points; intermediate risk, 4 to 6 points; and high risk 7 to 11 points) with excellent prognostic accuracy for progression to CLI using the Kaplan-Meier method. Five factors were identified that increased the risk of progression to CLI in HD patients with suspected peripheral artery disease. A combination of those factors permitted establishment of three risk strata for accurate prediction of onset of CLI. PMID- 25810353 TI - Correlative scanning electron and confocal microscopy imaging of labeled cells coated by indium-tin-oxide. AB - Confocal microscopy imaging of cells allows to visualize the presence of specific antigens by using fluorescent tags or fluorescent proteins, with resolution of few hundreds of nanometers, providing their localization in a large field-of-view and the understanding of their cellular function. Conversely, in scanning electron microscopy (SEM), the surface morphology of cells is imaged down to nanometer scale using secondary electrons. Combining both imaging techniques have brought to the correlative light and electron microscopy, contributing to investigate the existing relationships between biological surface structures and functions. Furthermore, in SEM, backscattered electrons (BSE) can image local compositional differences, like those due to nanosized gold particles labeling cellular surface antigens. To perform SEM imaging of cells, they could be grown on conducting substrates, but obtaining images of limited quality. Alternatively, they could be rendered electrically conductive, coating them with a thin metal layer. However, when BSE are collected to detect gold-labeled surface antigens, heavy metals cannot be used as coating material, as they would mask the BSE signal produced by the markers. Cell surface could be then coated with a thin layer of chromium, but this results in a loss of conductivity due to the fast chromium oxidation, if the samples come in contact with air. In order to overcome these major limitations, a thin layer of indium-tin-oxide was deposited by ion sputtering on gold-decorated HeLa cells and neurons. Indium-tin-oxide was able to provide stable electrical conductivity and preservation of the BSE signal coming from the gold-conjugated markers. PMID- 25810354 TI - Comparison of throat swab and nasopharyngeal aspirate specimens for rapid detection of adenovirus. AB - Nasopharyngeal aspirate (NPA) and throat swab (TS) specimens from individual patients were compared with regard to usefulness for adenovirus detection. In 153 adenovirus-infected patients, rapid test sensitivities with NPAs (90.8%) were nearly equivalent to those with TSs (91.5%) based on real-time polymerase chain reaction standards, indicating that NPAs are equally useful. PMID- 25810355 TI - Plant essential oils against Aeromonas hydrophila: in vitro activity and their use in experimentally infected fish. AB - AIMS: The aims of this study were to investigate the in vitro antibacterial activity of the essential oils (EOs) of Hesperozygis ringens (HREO), popularly known as 'espanta-pulga' and two different species of basil, Ocimum gratissimum (OGEO) and Ocimum americanum (OAEO), as well as, the potential of these products to be used in silver catfish (Rhamdia quelen) infected with Aeromonas hydrophila. METHODS AND RESULTS: OGEO and HREO showed better antibacterial activity in vitro. Subinhibitory concentrations of all EOs inhibited haemolysis caused by Aer. hydrophila in fish erythrocytes (100% reduction for OAEO at 100 MUg ml(-1) and more than 90% for HREO and OGEO at 150 MUg ml(-1) ). However, OAEO and HREO showed the best survival results (75 and 70% respectively) after their use as treatment (therapeutic baths-1 h daily/5 days) in silver catfish experimentally infected with Aer. hydrophila. A second in vivo assay using healthy fish was conducted to verify the potential of the EOs (preventive baths-1 h daily/5 days) to promote fish survival. Fish exposed to HREO and OAEO and their diluent (ethanol) showed significant lower haematocrit values and higher complement system activity compared to control. Plasma cortisol level was significantly higher in the groups exposed to both EOs. There was no significant difference in survival of silver catfish challenged with Aer. hydrophila after preventive baths with HREO, OAEO and control group. CONCLUSIONS: All tested EOs showed in vitro antibacterial properties against Aer. hydrophila and HREO and OAEO showed potential to be used in the treatment of infected fish. SIGNIFICANCE AND IMPACT OF THE STUDY: These products can be used in aquaculture as therapeutic and prophylactic agents against fish pathogens, with antimicrobial and/or immunostimulant properties. PMID- 25810357 TI - Incorporating Stream Features into Groundwater Contouring Tools Within GIS. AB - Hydrogeologists often are called upon to estimate surfaces from discrete, sparse data points. This estimation is often accomplished by manually drawing contours on maps using interpolation methods between points of known value while accounting for features known to influence the water table's surface. By contrast, geographic information systems (GIS) are good at creating smooth continuous surfaces from limited data points and allowing the user to represent the resulting surface resulting with contours, but these automated methods often fail to meet the expectations of many hydrogeologists because they do not include knowledge of other influences on the water table. In this study, we seek to fill this gap in the GIS-based methodology for hydrogeologists through an interactive tool that shapes an interpolated surface based on additional knowledge of the water table inferred from gaining or losing streams. The modified surface is reflected in water table contours that, for example, "V" upstream for gaining streams, and can be interactively adjusted to fit the user's expectations. By modifying not only the contours but also the associated interpolated surface, additional contours will follow the same trend, and the modified surface can be used for other analyses like calculating average gradients and flow paths. The tool leverages Esri's ArcGIS Desktop software, building upon a robust suite of mapping tools. We see this as a prototype for other tools that could be developed for hydrogeologists to account for variations in the water table inferred from local topographic trends, pumping or injection wells, and other hydrogeologic features. PMID- 25810356 TI - Hypocalcemia-induced seizure: demystifying the calcium paradox. AB - Calcium is essential for both neurotransmitter release and muscle contraction. Given these important physiological processes, it seems reasonable to assume that hypocalcemia may lead to reduced neuromuscular excitability. Counterintuitively, however, clinical observation has frequently documented hypocalcemia's role in induction of seizures and general excitability processes such as tetany, Chvostek's sign, and bronchospasm. The mechanism of this calcium paradox remains elusive, and very few pathophysiological studies have addressed this conundrum. Nevertheless, several studies primarily addressing other biophysical issues have provided some clues. In this review, we analyze the data of these studies and propose an integrative model to explain this hypocalcemic paradox. PMID- 25810358 TI - Health related quality of life and perception of stigmatisation in adolescents living with sickle cell disease in Nigeria: A cross sectional study. AB - BACKGROUND: Sickle cell disease impacts the physical, emotional and psychological aspects of life of the affected persons, often times exposing them to disease associated stigma from the society and alters the health related quality of life (HRQoL). This study compared the HRQoL of adolescents with sickle cell disease with their healthy peers, identified socio-demographic and clinical factors impacting HRQoL, and determined the extent and effects of SCD related stigma on quality of life. PROCEDURE: We conducted a cross-sectional survey among 160 adolescents, 80 with SCD and 80 adolescents without SCD. Socio-demographic and clinical data were collected using a pre-tested questionnaire. HRQoL was investigated using the Short Form (SF-36v2) Health Survey. SCD perceived stigma was measured using an adaptation of a perceived stigma questionnaire. RESULTS: Adolescents with SCD have significantly worse HRQoL than their peers in all of the most important dimensions of HRQoL (physical functioning, physical roles limitation, emotional roles limitation, social functioning, bodily pain, vitality and general health perception) except mental health. Recent hospital admission and SCD related complication further lowered HRQoL scores. Over seventy percent of adolescents with SCD have moderate to high level of perception of stigmatisation. Hospitalisation, SCD complication, SCD stigma were inversely, and significantly associated with HRQoL. CONCLUSIONS: Adolescents living with SCD in Nigeria have lower health related quality of life compared to their healthy peers. They also experience stigma that impacts their HRQoL. Complications of SCD and hospital admissions contribute significantly to this impairment. PMID- 25810359 TI - Pharmacists' and general practitioners' pharmacology knowledge and pharmacotherapy skills. AB - Understanding differences in the pharmacology knowledge and pharmacotherapy skills of pharmacists and physicians is vital to optimizing interprofessional collaboration and education. This study investigated these differences and the potential influence of work experience. The pharmacology knowledge and pharmacotherapy skills of pharmacists, general practitioners (GPs), and trainees were compared, using a written assessment; 294 participants were included. Overall scores (mean +/- SD) ranged from 69.3% +/- 6.5% to 76.5% +/- 9.5% for basic knowledge, 70.3% +/- 10.8% to 79.7% +/- 8.4% for applied knowledge, and 66.3% +/- 21.1% to 84.7% +/- 20.7% for pharmacotherapy skills (analysis of variance all P < .05). The pharmacists had the highest scores for all domains (P < .05), with the exception of pharmacist trainees, who had comparable scores for basic knowledge and pharmacotherapy skills (both P > .05). The GPs scored the lowest for pharmacotherapy skills (P < .05). More work experience was associated with better knowledge of applied pharmacology among pharmacists (by 2% per 10 work-years), but with poorer pharmacotherapy skills among pharmacists and GPs (by 3% and 4% per 10 work-years, respectively). In conclusion, pharmacists and GPs differ in their knowledge and skills, and these differences become more pronounced with more work experience. In general, pharmacists outperform pharmacist trainees, whereas GP trainees outperform GPs. These differences could be important for interdisciplinary collaboration and education. PMID- 25810361 TI - Melatonin-induced changes in kiss/gnrh gene expression patterns in the brain of male sea bass during spermatogenesis. AB - Evidence exists that melatonin may drive the seasonal changes in kisspeptin expressing cells and GnRH/gonadotropin secretion in mammals, thus modulating their reproductive activity. This study established the influence of long-term melatonin administration (as an implant) on growth performance and reproduction of adult male sea bass. Melatonin reduced the fish weight and condition factor, thus affecting the performance of fish. Melatonin also affected gonadogenesis, as shown by a decrease in the gonadosomatic index after 150 days of treatment and the lower percentage of running males during the spermatogenesis and full spermiation stages of this species. Exogenous melatonin also resulted in lower plasma androgen levels during the reproductive period, and showed a significant decrease in serum Lh and Fsh concentration after 30 and 60 days of treatment, respectively. Thus, melatonin elicited seasonal changes in key reproductive hormones that affected testicular maturity. The hypothalamic expression of kiss1 was significantly higher in melatonin-treated fish than in controls after 30 days of treatment, while a significant increase in kiss2 expression was detected on day 90 of treatment. By contrast, melatonin showed a significant decrease in kisspeptin expression in the dorsal brain on day 150 of treatment and also affected the expression of gnrh-1 and gnrh-3 and gnrhr-II-1a and 2b and the fshbeta gene in the pituitary. These results suggest that in this species, melatonin evokes changes in the mRNA levels of kisspeptin and gnrh system genes that appear to mirror disturbances in spermatogenesis. PMID- 25810360 TI - 4D MRI of polycystic kidneys from rapamycin-treated Glis3-deficient mice. AB - Polycystic kidney disease (PKD) is a life-threatening disease that leads to a grotesque enlargement of the kidney and significant loss of function. Several imaging studies with MRI have demonstrated that cyst size in polycystic kidneys can determine disease severity and progression. In the present study, we found that, although kidney volume and cyst volume decreased with drug treatment, renal function did not improve with treatment. Here, we applied dynamic contrast enhanced MRI to study PKD in a Glis3 (GLI-similar 3)-deficient mouse model. Cysts from this model have a wide range of sizes and develop at an early age. To capture this crucial stage and assess cysts in detail, we imaged during early development (3-17 weeks) and applied high spatiotemporal resolution MRI (125 * 125 * 125 cubic microns every 7.7 s). A drug treatment with rapamycin (also known as sirolimus) was applied to determine whether disease progression could be halted. The effect and synergy (interaction) of aging and treatment were evaluated using an analysis of variance (ANOVA). Structural measurements, including kidney volume, cyst volume and cyst-to-kidney volume ratio, changed significantly with age. Drug treatment significantly decreased these metrics. Functional measurements of time-to-peak (TTP) mean and TTP variance were determined. TTP mean did not change with age, whereas TTP variance increased with age. Treatment with rapamycin generally did not affect these functional metrics. Synergistic effects of treatment and age were not found for any measurements. Together, the size and volume ratio of cysts decreased with drug treatment, whereas renal function remained the same. The quantification of renal structure and function with MRI can comprehensively assess the pathophysiology of PKD and response to treatment. PMID- 25810362 TI - Serotonin effects in the crab Neohelice granulata: Possible involvement of two types of receptors in peripheral tissues. AB - In crustaceans, serotonin (5-HT) controls various physiological processes, such as hormonal secretion, color changes, reproduction, and metabolism. Since 5-HT injections cause hyperglycemia, this study was designed to further investigate this action of 5-HT in the crab Neohelice granulate, fed with a high-carbohydrate (HC) or a high-protein (HP) diet. The effects of pre-treatment with mammalian 5 HT receptor antagonists, cyproheptadine and methiothepin, were also investigated. A series of in vivo experiments with (3)H-5-HT was carried out in order to investigate the presence of putative receptors in peripheral tissues. Since gills were the tissue with the highest labeling in in vivo experiments, in vitro studies with isolated anterior and posterior gills were also conducted. Cyproheptadine blocked the hyperglycemic effect of 5-HT in HP-fed crabs. Methiothepin reduced glycogen levels in the anterior gills of HP crabs and partially blocked the 5-HT-like posture. The injection of (3)H-5-HT identified specific binding sites in all the tissues studied and revealed that the binding can be influenced by the type of diet administered to the crabs. Incubation of the anterior and posterior gills with (3)H-5-HT and 5-HT confirmed the specificity of the binding sites. Both antagonists inhibited (3)H-5-HT binding. In conclusion, this study highlights the importance of serotonin in the control of glucose homeostasis in crustaceans and provides evidences of at least two types of 5-HT binding sites in peripheral tissues. Further studies are necessary to identify the structure of these receptors and their signaling pathways. PMID- 25810363 TI - Odorant-binding proteins display high affinities for behavioral attractants and repellents in the natural predator Chrysopa pallens. AB - Chrysopa pallens is an important natural predator of various pests in many different cropping systems. Understanding the sophisticated olfactory system of insect antennae is crucial for studying the physiological bases of olfaction and could also help enhance the effectiveness of C. pallens in biological control. However, functional studies of the olfactory genes in C. pallens are still lacking. In this study, we cloned five odorant-binding protein (OBP) genes from C. pallens (CpalOBPs). Quantitative RT-PCR results indicated that the five CpalOBPs had different tissue expression profiles. Ligand-binding assays showed that farnesol, farnesene, cis-3-hexenyl hexanoate, geranylacetone, beta-ionone, octyl aldehyde, decanal, nerolidol (Ki<20 MUM), and especially 2-pentadecanone (Ki=1.19 MUM) and 2-hexyl-1-decanol (Ki=0.37 MUM) strongly bound to CpalOBP2. CpalOBP15 exhibited high binding affinities for beta-ionone, 2-tridecanone, trans nerolidol, and dodecyl aldehyde. Behavioral trials using the 14 compounds exhibiting high binding affinities for the CpalOBPs revealed that nine were able to elicit significant behavioral responses from C. pallens. Among them, farnesene and its corresponding alcohol, farnesol, elicited remarkable repellent behavioral responses from C. pallens. Our study provides several compounds that could be selected to develop slow-release agents that attract/repel C. pallens and to improve the search for strategies to eliminate insect pests. PMID- 25810366 TI - Cochlear efferents in developing adult and pathological conditions. AB - Cochlear activity is regulated by the olivo-cochlear bundle, which originates from the brainstem and projects onto the hair cells and auditory nerve fibers. Two efferent components can be distinguished: the medial and lateral olivo cochlear efferent originating from the medial, and the lateral nuclei of the superior olivary complex. The input of the efferent systems on hair cells occurs during development and persists in the adult cochlea. Recent studies have shown that the efferent innervations are required to set the activity pattern in developing hair cells and auditory nerve fibers and to protect the synaptic structures in adult cochlea. In addition, efferent innervations undergo plasticity during pathological conditions such as noise-trauma or aging. This review discusses the mechanisms underlying the control of the hair cells and afferent fibers excitability by efferent neurons and their putative role in developing adult and pathological conditions. PMID- 25810364 TI - Influence of the complex of retinol-vitamin C on skin surface lipids. AB - BACKGROUND: Retinol is used to reduce symptoms of skin aging. It affects surface lipids and increases skin regeneration ability. AIM: The aim of our study was to investigate the effect of retinol peel on the face and neck skin lipids in women, aged 50-69. MATERIAL AND METHODS: The level of secreted sebum was measured using Sebumeter SM15 (Courage & Khazaka, Germany) on the forehead, cheeks, nose, chin, and neck. The measurements were carried out before each of the 3 retinol peel treatments applied at 3-week interval and 3 weeks after the last treatment. RESULTS: A statistically significant increase of lipid film in both U-zone and T zone and on the neck was observed in the study group. CONCLUSION: Retinol peel treatments can help to increase the amount of skin surface lipids in women during menopause. PMID- 25810365 TI - Clinical and Radiological Long-Term Outcome of a Tapered Implant System with Special Emphasis on the Influence of Augmentation Procedures. AB - BACKGROUND AND PURPOSE: Tapered implant designs aim to improve primary stability and implant survival in soft bone. However, respective clinical long-term data are scarce. Therefore, a clinical and radiological evaluation of the long-term success of a transgingival-supracrestal inserted tapered implant system with special emphasis on the influence of augmentation procedures was conducted. MATERIAL AND METHODS: In a retrospective study design, all in the Department of Oral and Maxillofacial Surgery of the University Medical Centre, Mainz, Germany, between May 2002 and March 2012, placed tapered implants (Straumann TE(r), Basel, Switzerland) were analyzed. In this time period, a total of one hundred ninety seven tapered implants were inserted in 90 patients. For patients available for clinical recall, success criteria according to Albrektsson and Buser were evaluated. RESULTS: The in situ rate was 96.3% after an average time in situ of 62 +/- 31 months. In one hundred twenty-seven sites, bone augmentation procedures were performed. Hereof, 96 sites were sinus augmentation procedures and 31 sites were alveolar ridge augmentations. For patients with sinus augmentation procedures, implant survival was 97.9% and for patients with alveolar ridge augmentations, implant survival was 93.5% after 5 years, indicating a higher implant survival for sinus augmentation, however not statistically different (p = .194). Implant diameter and timing of implant placement had no significant impact on implant survival (p > .05). Mean marginal bone loss was -0.50 +/- 1.54 mm for patients receiving maxillary sinus augmentation and -1.16 +/- 1.13 mm for patients with alveolar ridge augmentations, indicating a lower marginal bone loss in patients receiving maxillary sinus augmentation (p = .046). Implant success rates ranged between 88% and 92% after a mean follow-up of 6 years. CONCLUSIONS: Within the limits of the retrospective character of this study, the tapered soft tissue level implant showed especially in maxillary sinus augmentation promising long-term survival and success rates and a low peri-implant bone resorption compared with the literature. PMID- 25810367 TI - Developmental expression patterns of chemokines CXCL11, CXCL12 and their receptor CXCR7 in testes of common marmoset and human. AB - The chemokine receptor CXCR7 interacts with the chemokines CXCL11 and CXCL12. During development, this ligand receptor system (C-X-C) provokes cell-type specific responses in terms of migration, adhesion or ligand sequestration. It is active in zebrafish and rodents but no data are available for its presence or function in primate testes. Real-time quantitative polymerase chain reaction was performed in monkeys to detect CXCL11, CXCL12 and CXCR7. At the protein level, CXCL12 and CXCR7 were localized in the testes of the marmoset (Callitrix jacchus) whereas CXCR7 patterns were determined for various stages in human testes. Morphometry and flow cytometry were applied to quantify CXCR7-positive cells in monkeys. Transcript levels and protein expression of CXCR7 were detectable throughout testicular development. In both species, CXCR7 protein expression was restricted to premeiotic germ cells. In immature marmoset testes, 69.9% +/- 9% of the total germ cell population were labelled for CXCR7, whereas in the adult, 4.7% +/- 2.7% were positive for CXCR7. CXCL12 mRNA was detectable in all developmental stages in marmosets. The CXCL12 protein was exclusively localized to Sertoli cells. This pattern of CXCL12/CXCR7 indicates their involvement in regulatory processes that possibly orchestrate the interaction between undifferentiated germ cells and Sertoli cells. PMID- 25810370 TI - Experiences of autism diagnosis: A survey of over 1000 parents in the United Kingdom. AB - A sample of 1047 parents completed an online survey about their experiences and opinions regarding the process of attaining a diagnosis of autism spectrum disorder for their children. The results revealed that parents usually waited a year from when they first had concerns about their child's development before they sought professional help. On average, there was a delay of around 3.5 years from the point at which parents first approached a health professional with their concerns to the confirmation of an autism spectrum disorder diagnosis. Just over half of the parents surveyed were dissatisfied with the diagnostic process as a whole. Several factors predicted parents' overall levels of satisfaction with the diagnostic process, including the time taken to receive a diagnosis, satisfaction with the information provided at diagnosis, the manner of the diagnosing professional, the stress associated with the diagnostic process and satisfaction with post-diagnostic support. Post-diagnosis, the support (if any) that was provided to parents was deemed unsatisfactory, and this was highlighted as an area of particular concern among parents. PMID- 25810371 TI - Infrared and visible emissions of rare-earth-doped CeO2 phosphor. AB - This paper reports the synthesis and characterization of Er(3+)-doped CeO2 phosphor with variable concentrations of erbium. The sample was synthesized using a solid-state reaction method, which is useful for the large-scale production of phosphors and is also eco-friendly. The prepared sample was characterized using an X-ray diffraction (XRD) technique. The XRD pattern confirmed that sample has the pure cubic fluorite crystal structure of CeO2. The crystallite size of the prepared phosphor was determined by Scherer's formula and the crystallite size giving an intense XRD peak is 40.06 nm. The surface morphology of the phosphor was determined by field emission gun scanning electron microscopy (FEGSEM). From the FEGSEM image, good surface morphology with some agglomerates was found. The functional group in the prepared sample was analysed by Fourier transform infrared (FTIR) spectroscopy. All samples prepared with variable concentrations of Er(3+) (0.1-2 mol%) were studied by photoluminescence analysis and it was found that the excitation spectra of the prepared phosphor shows broad excitation centred at 251 nm. Emission spectra at different concentrations of Er(3+) show strong peaks at 413 and 470 nm and a weaker peak at 594 nm. The dominant peaks at 413 and 470 nm are caused by the allowed electronic transition (4)S3/2 -> (4)I15/2 and the weaker transition at 594 nm is due to the transition (4)F9/2 -> (4)I15/2. Spectrophotometric determinations of peaks were evaluated using the Commission Internationale de I'Eclairage (CIE) technique. The emission spectra were also observed using an infrared (IR) laser 980 nm source, and three distinct peaks were found in the IR region at 848, 870 and 980 nm. The prepared phosphor has utility for application in display devices. PMID- 25810372 TI - De Novo interstitial deletion 13q33.3q34 in a male patient with double outlet right ventricle, microcephaly, dysmorphic craniofacial findings, and motor and developmental delay. AB - We describe a 6-year-old male, diagnosed at birth with double outlet right ventricle (DORV), anterior aorta, multiple ventricular septal defects, pulmonary stenosis, microcephaly and mildly dysmorphic craniofacial findings. Chromosomal analysis showed a normal male karyotype but on subsequent array comparative genomic hybridization (array CGH) analysis a de novo 2.5 Mb loss in chromosome 13q at 13q33.3q34, together with an inherited gain at 4p12, were detected. The propositus underwent placement of a Blalock Taussig shunt and subsequently a Glenn and Fontan operation was performed. In this report we propose that COL4A1 and COL4A2 may be candidate genes for congenital heart disease (CHD) in individuals with a deletion in 13q within the 6Mb critical region for cardiac development proposed by Huang et al., [2012]. PMID- 25810373 TI - Molecular Pathways: GLI1-Induced Drug Glucuronidation in Resistant Cancer Cells. AB - Drug resistance remains a major impediment in the development of durable cancer therapies. Studies in acute myelogenous leukemia (AML) patients revealed a new form of multidrug resistance. Here, increased glioma-associated protein GLI1 leads to elevation of the UDP-glucuronosyl transferase (UGT) enzymes. UGTs add glucuronic acid to xenobiotics and metabolites. Traditionally, the loss of these enzymes is thought to contribute to cancer as a result of impaired clearance of environmental carcinogens. However, we demonstrate that overexpression of UGTs can contribute to oncogenesis by promoting drug resistance. Indeed, UGT levels in AML patients treated with ribavirin and/or cytarabine were elevated at relapse relative to diagnosis. This was reversed by GLI1 inhibition, suggesting a clinically relevant strategy to overcome drug resistance. Further, overexpression of UGTs can also lead to drug resistance in other cancers, such as certain Hsp90 inhibitors and vorinostat in colorectal and chronic lymphoblastic leukemia, respectively. Not all drugs are targets of glucuronidation, suggesting that UGT status could be relevant to treatment choice. Here, we describe several facets of UGT biology and how these could be exploited clinically. These studies demonstrate how drugs in cancer cells can be metabolized differentially than their normal counterparts. In summary, we describe a new form of drug resistance relevant to a variety of cancer contexts. PMID- 25810374 TI - The miR-30 Family Inhibits Pulmonary Vascular Hyperpermeability in the Premetastatic Phase by Direct Targeting of Skp2. AB - PURPOSE: Before metastasis, primary tumor can create a premetastatic niche in distant organ to facilitate the dissemination of tumor cells. In the premetastatic phase, the permeability of pulmonary vasculatures is increased to accelerate the extravasation of circulating tumor cells. However, it is not clear whether local miRNAs contribute to the vascular hyperpermeability of the premetastatic niche. EXPERIMENTAL DESIGN: The expression of total miRNAs was determined using microarray in series of premetastatic lungs from tumor-bearing mice. Significantly differentially expressed miRNAs were identified and validated with qRT-PCR. Vascular permeability assays, vascular mimic systems, and orthotopic tumor models were used to investigate roles of selected miRNAs and target genes in premetastatic hyperpermeability. RESULTS: We identified a miRNA signature in premetastatic lungs. Among these miRNAs, miR-30a, b, c, d, and e were significantly attenuated. Subsequent investigations elucidated that lung fibroblast-derived miR-30s stabilized pulmonary vessels. Overexpression of miR 30s in lungs postponed metastasis and extended overall survival of B16 tumor bearing mice. Following studies uncovered that Skp2 was directly targeted by miR 30s. Overexpression of Skp2 could disrupt pulmonary vessels, promote lung metastasis, and decrease overall survival of B16 tumor-bearing mice. CONCLUSIONS: These findings illuminate a novel mechanism for the modulation of premetastatic niches by miR-30s, which suggest that miR-30s represent not only promising targets for antimetastasis therapy but also indicators for metastasis. PMID- 25810376 TI - Value of surgical resection in children with high-risk neuroblastoma. AB - BACKGROUND: The value of gross total resection (GTR) for children with high-risk neuroblastoma (NB) is controversial. We hypothesized that patients undergoing GTR would demonstrate improved overall survival (OS) compared those having 90% resection compared to <90% resection (P = 0.008). Multivariable Cox models confirmed these findings with improved survival in children undergoing >90% vs. <90% resection but no difference in GTR vs. 90% resection is associated with improved OS compared to less than 90% resection. PMID- 25810375 TI - CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma. AB - PURPOSE: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3- or PAX7-FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13-q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion positive RMS. EXPERIMENTAL DESIGN: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts. RESULTS: Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distribution, proliferation, or transformation were not observed in RMS cells overexpressing CDK4. Treatment with LEE011 phenocopied CDK4 knockdown, decreasing viability, RB phosphorylation, and E2F-responsive gene expression and inducing G1-phase cell cycle arrest. Although all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition, there was diminished sensitivity associated with CDK4 amplification and overexpression. This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and nonamplified fusion positive RMS. CONCLUSIONS: Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB-E2F-mediated G1-phase cell-cycle progression, proliferation, and transformation in fusion-positive RMS. Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition. PMID- 25810379 TI - Beauty in Simplicity: Abnormal Neutrophil to Lymphocyte Ratio in Resistant Hypertension. PMID- 25810377 TI - Adiponectin and interleukin-6, but not adipose tissue, are associated with worse neurocognitive function in HIV-infected men. AB - BACKGROUND: Generalized obesity has been associated with cognitive decline, a process potentially mediated by adipocytokines. The effects of regional adipose tissue (AT) on cognition, however, are not well understood. We explored cross sectional relationships between regional AT, adipocytokines, inflammatory markers and neuropsychological (NP) test scores among HIV+ and HIV- men enrolled in the Multicenter AIDS Cohort Study. METHODS: Visceral, subcutaneous abdominal and subcutaneous thigh AT areas were quantified by computed tomography (CT). NP tests (Trail Making Test parts A and B, and Symbol-Digit Modalities) obtained within 2 years of CT screened for psychomotor speed and executive function. Adiponectin, leptin, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were measured. RESULTS: Of 509 HIV+ and 271 HIV- participants, HIV+ men (98% on antiretroviral therapy, 81% HIV-1 RNA<50 copies/ml) had lower median subcutaneous AT and adiponectin levels and higher hs-CRP levels, but visceral AT, body mass index, IL-6 and NP scores did not vary by HIV serostatus. In multivariable analysis, older age, <= high school education and African American race, but not AT area or site, were associated with worse NP test scores among all participants. In HIV+ only, higher adiponectin and IL-6 were associated with worse cognitive function independent of AT area. No HIV-specific factors were associated with NP test scores. CONCLUSIONS: Demographic factors were associated with NP test performance, but regional adiposity was not. In HIV+ only, higher adiponectin and IL-6 were associated with worse NP test scores, supporting a role for chronic inflammation and adipocytokine imbalance in neurocognitive decline in HIV+ persons. PMID- 25810378 TI - Aged garlic extract ameliorates the oxidative stress, histomorphological, and ultrastructural changes of cisplatin-induced nephrotoxicity in adult male rats. AB - AIM: Aged garlic extract (AGE) is a natural dietary substance having different antioxidant free-radical-scavenger compounds that ameliorates the toxicity of the oxidative stress. This study aimed to investigate the effect of AGE on cisplatin (CP)-induced nephrotoxicity in rats. MATERIALS AND METHODS: Twenty-four, adult male Wistar albino rats were randomly divided into four groups namely control, AGE-treated (a single oral dose of 250 mg/kg/day for 21 days), CP-treated (a single intraperitoneal dose of 7.5 mg/kg on Day 16), and AGE + CP-treated (AGE at a dose of 250 mg/kg/once daily for 21 days and a single dose of CP of 7.5 mg/kg intraperitoneally on Day 16). Body weight and absolute and relative kidney weights of each rat were calculated. Serum creatinine, uric acid, and urea levels were determined. Level of malondialdehyde and reduced glutathione and activity of superoxide dismutase and catalase of renal tissues were measured. Renal specimens from each rat were prepared for both light and electron microscopic examinations. RESULTS: Interstitial cell infiltration, hemorrhage, glomerular atrophy, necrosis, and tubular degeneration were observed after CP treatment. Superoxide dismutase and catalase activities and glutathione level were significantly decreased and malondialdehyde level was significantly increased in CP-treated rats compared with AGE + CP-treated animals. A remarkable improvement in the histopathological and ultrastructural changes induced by CP in renal tissues was observed in AGE + CP-treated rats. CONCLUSION: AGE exhibited antioxidant effect that could ameliorate the nephrotoxic effects of CP. PMID- 25810380 TI - Simultaneous determination of three banned psychiatric drugs in pig feed and tissue using solid-phase reactor on-line oxidizing and HPLC-fluorescence detection. AB - The banned addition of psychiatric drugs such as phenothiazines to animal feed and foodstuffs increases the risk of human organ lesion. Phenothiazines usually exhibit weak native fluorescence and can be oxidized to strongly fluorescent compounds. In this study, a novel, sensitive and convenient method of HPLC fluorescence detection based on post-column on-line oxidizing with lead dioxide solid-phase reactor has been developed for simultaneous determination of three banned psychotropic drugs, promethazine, chlorpromazine and thioridazine. Three compounds were successfully separated on an Agilent TC-C18 column with mobile phase of acetonitrile (A) and water (B), both containing 0.5% (v/v) formic acid. A gradient elution was programmed and fluorimetric detection was performed at lambdaex /lambdaem of 332/373 nm for promethazine, 340/380 nm for chlorpromazine and 352/432 nm for thioridazine. The calibration graphs gave good linearity over the concentration ranges of 30.0-4976.4 ug/L for promethazine, 2.0-2153.2 ug/L for chlorpromazine, and 15.0-3088.0 ug/L for thioridazine, and correlation coefficients (r) were >=0.995. The method was applied to the determination of phenothiazines in pig feed and pig tissue, and the average spiked recoveries were in the range 69.1-115.4%. PMID- 25810381 TI - Psychological flexibility and mindfulness explain intuitive eating in overweight adults. AB - The current study investigated whether mindfulness and psychological flexibility, independently and together, explain intuitive eating. The participants were overweight or obese persons (N = 306) reporting symptoms of perceived stress and enrolled in a psychological lifestyle intervention study. Participants completed self-report measures of psychological flexibility; mindfulness including the subscales observe, describe, act with awareness, non-react, and non-judgment; and intuitive eating including the subscales unconditional permission to eat, eating for physical reasons, and reliance on hunger/satiety cues. Psychological flexibility and mindfulness were positively associated with intuitive eating factors. The results suggest that mindfulness and psychological flexibility are related constructs that not only account for some of the same variance in intuitive eating, but they also account for significant unique variances in intuitive eating. The present results indicate that non-judgment can explain the relationship between general psychological flexibility and unconditional permission to eat as well as eating for physical reasons. However, mindfulness skills-acting with awareness, observing, and non-reacting-explained reliance on hunger/satiety cues independently from general psychological flexibility. These findings suggest that mindfulness and psychological flexibility are interrelated but not redundant constructs and that both may be important for understanding regulation processes underlying eating behavior. PMID- 25810382 TI - ANG II modulation of cardiac growth and remodeling in immature fetal sheep. AB - ANG II increases fetal blood pressure and stimulates fetal heart growth; however, little is known regarding its direct effects on cardiomyocytes in vivo. We sought to determine whether ANG II stimulates heart growth and cardiomyocyte hypertrophy and/or hyperplasia in utero in the immature fetal heart independent of the effects on cardiac afterload. In twin gestation, fetal sheep at ~100 days gestation (term 145 days), one fetus received a chronic (6 days) infusion of ANG II alone (50 MUg.kg(-1).min(-1)) or ANG II plus nitroprusside (NTP) to attenuate the increase in blood pressure; noninstrumented twins served as controls. ANG II alone, but not ANG II + NTP resulted in a significant increase in heart mass (left and right ventricle + septum, corrected for body weight) compared with controls. ANG II, but not ANG II+NTP, also significantly increased cardiomyocyte area compared with control and increased the percentage of binucleated myocytes. ANG II with or without concomitant infusion of NTP increased cardiac PCNA expression, a marker of proliferation. Steady-state protein expression of terminal mitogen-activated protein kinases, cyclin B1, cyclin E1, and p21 were similar among groups. We conclude that in vivo, ANG II increases fetal cardiac mass via cardiomyocyte hypertrophy, differentiation, and to a lesser extent hyperplasia. The effects of ANG II on hypertrophy appear dependent upon the increase in blood pressure (mechanical load), whereas effects on proliferation are load-independent. PMID- 25810384 TI - Pregnant rats treated with a high-fat/prooxidant Western diet with ANG II and TNF alpha are resistant to elevations in blood pressure and renal oxidative stress. AB - Oxidative stress and inflammation are risk factors for hypertension in pregnancy. Here, we examined the 24-h mean arterial pressure (MAP) via telemetry and the nitric oxide (NO) and redox systems in the kidney cortex, medulla, and aorta of virgin and pregnant rats treated with a high-fat/prooxidant Western diet (HFD), ANG II, and TNF-alpha. Female Sprague-Dawley rats were given a normal diet (ND) or a HFD for 8 wk before mating. Day 6 of pregnancy and age-matched virgins were implanted with minipumps infusing saline or ANG II (150 ng.kg(-1).min(-1)) + TNF alpha (75 ng/day) for 14 days. Groups consisted of Virgin + ND + Saline (V+ND) (n = 7), Virgin + HFD +ANG II and TNF-alpha (V+HFD) (n = 7), Pregnant + ND + Saline (P+ND) (n = 6), and Pregnant + HFD + ANG II and TNF-alpha (P+HFD) (n = 8). After day 6 of minipump implantation, V+HFD rats displayed an increase in MAP on days 7, 8, and 10-15 vs. V+ND rats. P+HFD rats, after day 6 of minipump implantation, showed an increase in MAP only on day 7 vs. P+ND rats. P+HFD rats had a normal fall in 24-h MAP, hematocrit, plasma protein concentration, and osmolality at late pregnancy. No change in kidney cortex, medulla, or aortic oxidative stress in P+HFD rats. P+HFD rats displayed a decrease in nNOSbeta abundance, but no change in kidney cortex NOx content vs. P+ND rats. Pregnant rats subjected to a chronic HFD and prooxidant and proinflammatory insults have a blunted increase in 24-h MAP and renal oxidative stress. Our data suggest renal NO bioavailability is not altered in pregnant rats treated with a HFD, ANG II, and TNF-alpha. PMID- 25810383 TI - Vasopressin: the missing link for preeclampsia? AB - Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5-7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a "tissue rejection" type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein by product of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Furthermore, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal, and vascular systems in the nonpregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established midpregnancy dysfunctions that cause preeclampsia. PMID- 25810385 TI - Reduced muscle lengthening during eccentric contractions as a mechanism underpinning the repeated-bout effect. AB - This study investigated biceps brachii distal myotendinous junction (MTJ) displacement during maximal eccentric elbow flexor contractions to test the hypothesis that muscle length change would be smaller (less MTJ displacement) during the second than the first exercise bout. Ten untrained men performed two eccentric exercise bouts (ECC1 and ECC2) with the same arm consisting of 10 sets of six maximal isokinetic (60 degrees /s) eccentric elbow flexor contractions separated by 4 wk. Biceps brachii distal MTJ displacement was assessed using B mode ultrasonography, and changes in the displacement (muscle length change) from the start to the end of each contraction during each set and over 10 sets were compared between bouts by two-way repeated-measures ANOVA. Several indirect muscle damage markers were also measured and compared between bouts by two-way repeated-measures ANOVA. The magnitude of MTJ displacement (average of six contractions) increased from set 1 (8.2 +/- 4.7 mm) to set 10 (16.4 +/- 4.7 mm) during ECC1 (P < 0.05), but no significant changes over sets were evident during ECC2 (set 1: 8.5 +/- 4.0 mm; set 10: 9.3 +/- 3.1 mm). Changes in maximal voluntary isometric contraction strength, range of motion, muscle thickness, ultrasound echo intensity, serum creatine kinase activity, and muscle soreness (visual analog scale) were smaller (P < 0.05) following ECC2 than ECC1, showing less damage in the repeated bout. These results indicate that the magnitude of muscle lengthening was less during the second than the first eccentric exercise bout, which appears to be a mechanism underpinning the repeated-bout effect. PMID- 25810386 TI - End tidal-to-arterial CO2 and O2 gas gradients at low- and high-altitude during dynamic end-tidal forcing. AB - We sought to characterize and quantify the performance of a portable dynamic end tidal forcing (DEF) system in controlling the partial pressure of arterial CO2 (Pa(CO2)) and O2 (Pa(O2)) at low (LA; 344 m) and high altitude (HA; 5,050 m) during an isooxic CO2 test and an isocapnic O2 test, which is commonly used to measure ventilatory and vascular reactivity in humans (n = 9). The isooxic CO2 tests involved step changes in the partial pressure of end-tidal CO2 (PET(CO2)) of -10, -5, 0, +5, and +10 mmHg from baseline. The isocapnic O2 test consisted of a 10-min hypoxic step (PET(O2) = 47 mmHg) from baseline at LA and a 5-min euoxic step (PET(O2) = 100 mmHg) from baseline at HA. At both altitudes, PET(O2) and PET(CO2) were controlled within narrow limits (<1 mmHg from target) during each protocol. During the isooxic CO2 test at LA, PET(CO2) consistently overestimated Pa(CO2) (P < 0.01) at both baseline (2.1 +/- 0.5 mmHg) and hypercapnia (+5 mmHg: 2.1 +/- 0.7 mmHg; +10 mmHg: 1.9 +/- 0.5 mmHg). This P(a)-PET(CO2) gradient was approximately twofold greater at HA (P < 0.05). At baseline at both altitudes, PET(O2) overestimated Pa(O2) by a similar extent (LA: 6.9 +/- 2.1 mmHg; HA: 4.5 +/- 0.9 mmHg; both P < 0.001). This overestimation persisted during isocapnic hypoxia at LA (6.9 +/- 0.6 mmHg) and during isocapnic euoxia at HA (3.8 +/- 1.2 mmHg). Step-wise multiple regression analysis, on the basis of the collected data, revealed that it may be possible to predict an individual's arterial blood gases during DEF. Future research is needed to validate these prediction algorithms and determine the implications of end-tidal-to-arterial gradients in the assessment of ventilatory and/or vascular reactivity. PMID- 25810388 TI - High affinity and temperature sensitivity of blood oxygen binding in Pangasianodon hypophthalmus due to lack of chloride-hemoglobin allosteric interaction. AB - Air-breathing fishes represent interesting organisms in terms of understanding the physiological changes associated with the terrestrialization of vertebrates, and, further, are of great socio-economic importance for aquaculture in Southeast Asia. To understand how environmental factors, such as high temperature, affect O2 transport in air-breathing fishes, this study assessed the effects of temperature on O2 binding of blood and Hb in the economically important air breathing fish Pangasianodon hypophthalmus. To determine blood O2 binding properties, blood was drawn from resting cannulated fishes and O2 binding curves made at 25 degrees C and 35 degrees C. To determine the allosteric regulation and thermodynamics of Hb O2 binding, Hb was purified, and O2 equilibria were recorded at five temperatures in the absence and presence of ATP and Cl(-). Whole blood had a high O2 affinity (O2 tension at half saturation P50 = 4.6 mmHg at extracellular pH 7.6 and 25 degrees C), a high temperature sensitivity of O2 binding (apparent heat of oxygenation DeltaH(app) = -28.3 kcal/mol), and lacked a Root effect. Further, the data on Hb revealed weak ATP binding and a complete lack of Cl(-) binding to Hb, which, in part, explains the high O2 affinity and high temperature sensitivity of blood O2 binding. This study demonstrates how a potent mechanism for increasing O2 affinity is linked to increased temperature sensitivity of O2 transport and provides a basic framework for a better understanding of how hypoxia-adapted species will react to increasing temperatures. PMID- 25810387 TI - Triacylglyceride physiology in the short-finned eel, Anguilla australis-changes throughout early oogenesis. AB - During certain stages in an animal's life cycle, energy requirements may exceed energy intake from the diet. The spawning migration of temperate eels is a textbook example of negative energy balance, forcing these fish to rely on stored fats (triacylglycerides) to provide their muscles with energy for swimming and their growing oocytes with the nutrients needed to develop and support healthy offspring. We predicted broad implications of this great need for endogenous triacylglycerides in terms of their packaging, transport, and ovarian uptake. To test this, serum lipid concentrations and transcript abundances of intestinal and hepatic triacylglyceride packagers and ovarian triacylglyceride modifiers and receivers were investigated throughout previtellogenesis (feeding phase) and into early vitellogenesis (fasting phase) in short-finned eels. A switch from exogenous to endogenous triacylglyceride packaging was seen as the liver upregulated transcript levels of apolipoprotein B and microsomal triacylglyceride transport protein and downregulated those of apolipoprotein E and lipoprotein lipase. In the intestine, the reverse response was observed. Furthermore, ovarian transcript abundances of triacylglyceride modifiers and receivers increased (apolipoprotein E, lipoprotein lipase, and vitellogenin receptor), indicative of increased triacylglyceride uptake during previtellogenesis. We propose that increased hepatic apolipoprotein B production is a conserved vertebrate response to prolonged periods of negative energy balance. PMID- 25810389 TI - Effects of tempol on baroreflex neural arc versus peripheral arc in normotensive and spontaneously hypertensive rats. AB - Although oxidative redox signaling affects arterial pressure (AP) regulation via modulation of vascular tone and sympathetic nerve activity (SNA), it remains unknown which effect plays a dominant role in the determination of AP in vivo. Open-loop systems analysis of the carotid sinus baroreflex was conducted to separately quantify characteristics of the neural arc from baroreceptor pressure input to SNA and the peripheral arc from SNA to AP in normotensive Wistar-Kyoto (WKY; n = 8) and spontaneously hypertensive rats (SHR; n = 8). Responses in SNA and AP to a staircase-wise increase in carotid sinus pressure were examined before and during intravenous administration of the membrane-permeable superoxide dismutase mimetic tempol (30 mg/kg bolus followed by 30 mg.kg(-1).h(-1)). Two-way ANOVA indicated that tempol significantly decreased the response range of SNA (from 89.1 +/- 2.4% to 60.7 +/- 2.5% in WKY and from 77.5 +/- 3.2% to 56.9 +/- 7.3% in SHR, P < 0.001) without affecting the lower plateau of SNA (from 12.5 +/- 2.4% to 9.5 +/- 2.5% in WKY, and from 28.8 +/- 2.8% to 30.4 +/- 5.7% in SHR, P = 0.800) in the neural arc. While tempol did not affect the peripheral arc characteristics in WKY, it yielded a downward change in the regression line of AP vs. SNA in SHR. In conclusion, oxidative redox signaling plays an important role, not only in the pathological AP elevation, but also in the baroreflex-mediated physiological AP regulation. The effect of modulating oxidative redox signaling on the peripheral arc contributed to the determination of AP in SHR but not in WKY. PMID- 25810390 TI - Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses. AB - Successfully fighting infection requires a properly tuned immune system. Recent epidemiological studies link exposure to pollutants that bind the aryl hydrocarbon receptor (AHR) during development with poorer immune responses later in life. Yet, how developmental triggering of AHR durably alters immune cell function remains unknown. Using a mouse model, we show that developmental activation of AHR leads to long-lasting reduction in the response of CD8(+) T cells during influenza virus infection, cells critical for resolving primary infection. Combining genome-wide approaches, we demonstrate that developmental activation alters DNA methylation and gene expression patterns in isolated CD8(+) T cells prior to and during infection. Altered transcriptional profiles in CD8(+) T cells from developmentally exposed mice reflect changes in pathways involved in proliferation and immunoregulation, with an overall pattern that bears hallmarks of T cell exhaustion. Developmental exposure also changed DNA methylation across the genome, but differences were most pronounced following infection, where we observed inverse correlation between promoter methylation and gene expression. This points to altered regulation of DNA methylation as one mechanism by which AHR causes durable changes in T cell function. Discovering that distinct gene sets and pathways were differentially changed in developmentally exposed mice prior to and after infection further reveals that the process of CD8(+) T cell activation is rendered fundamentally different by early life AHR signaling. These findings reveal a novel role for AHR in the developing immune system: regulating DNA methylation and gene expression as T cells respond to infection later in life. PMID- 25810391 TI - NF-kappaB regulates PD-1 expression in macrophages. AB - Programmed cell death-1 (PD-1) is responsible for T cell exhaustion during chronic viral infections and is expressed on a variety of immune cells following activation. Despite its importance, the mechanisms that regulate PD-1 in cell types other than CD8 T cells are poorly defined. In this study, the molecular mechanisms for inducing PD-1 expression in CD4 T cells, macrophages, and B cells were explored. In CD4 T cells, PD-1 induction following TCR stimulation required NFAT, as the calcineurin/NFAT pathway inhibitor cyclosporin A was able to block PD-1 induction in a manner similar to that seen in CD8 T cells. In contrast, LPS but not PMA and ionomycin stimulation was able to induce PD-1 expression in macrophages in a manner insensitive to cyclosporin A-mediated inhibition. B cells could use both pathways, although the levels of PD-1 expression were highest with PMA and ionomycin. An NF-kappaB binding site located upstream of the gene in conserved region C was required for NF-kappaB-dependent PD-1 gene activation in macrophages. Chromatin immunoprecipitation showed NF-kappaB p65 binding to this region following stimulation of macrophages with LPS. PD-1 induction was associated with histone modifications characteristic of accessible chromatin; however, in contrast to CD8 T cells, conserved region B in macrophages did not lose CpG methylation upon stimulation and PD-1 expression. The linkage of TLR/NF kappaB signaling to the induction of PD-1 suggests the possibility of an opportunistic advantage to microbial infections in manipulating immune inhibitory responses. PMID- 25810393 TI - KIR and HLA genotypes predictive of low-affinity interactions are associated with lower relapse in autologous hematopoietic cell transplantation for acute myeloid leukemia. AB - Killer cell Ig-like receptors (KIRs) bind cognate HLA class I ligands with distinct affinities, affecting NK cell licensing and inhibition. We hypothesized that differences in KIR and HLA class I genotypes predictive of varying degrees of receptor-ligand binding affinities influence clinical outcomes in autologous hematopoietic cell transplantation (AHCT) for acute myeloid leukemia (AML). Using genomic DNA from a homogeneous cohort of 125 AML patients treated with AHCT, we performed KIR and HLA class I genotyping and found that patients with a compound KIR3DL1(+) and HLA-Bw4-80Thr(+), HLA-Bw4-80Ile(-) genotype, predictive of low affinity interactions, had a low incidence of relapse, compared with patients with a KIR3DL1(+) and HLA-Bw4-80Ile(+) genotype, predictive of high-affinity interactions (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06-0.78; p = 0.02). This effect was influenced by HLA-Bw4 copy number, such that relapse progressively increased with one copy of HLA-Bw4-80Ile (HR, 1.6; 95% CI, 0.84 3.1; p = 0.15) to two to three copies (HR, 3.0; 95% CI, 1.4-6.5; p = 0.005) and progressively decreased with one to two copies of HLA-Bw4-80Thr (p = 0.13). Among KIR3DL1(+) and HLA-Bw4-80Ile(+) patients, a predicted low-affinity KIR2DL2/3(+) and HLA-C1/C1 genotype was associated with lower relapse than a predicted high affinity KIR2DL1(+) and HLA-C2/C2 genotype (HR, 0.25; 95% CI, 0.09-0.73; p = 0.01). Similarly, a KIR3DL1(+) and HLA-Bw4-80Thr(+), HLA-Bw4-80Ile(-) genotype, or lack of KIR3DL1(+) and HLA-Bw4-80Ile(+) genotype, rescued KIR2DL1(+) and HLA C2/C2 patients from high relapse (p = 0.007). These findings support a role for NK cell graft-versus-leukemia activity modulated by NK cell receptor-ligand affinities in AHCT for AML. PMID- 25810392 TI - A ceramide analogue stimulates dendritic cells to promote T cell responses upon virus infections. AB - The ceramide family of lipids plays important roles in both cell structure and signaling in a diverse array of cell types, including immune cells. However, very little is known regarding how ceramide affects the activation of dendritic cells (DCs) in response to viral infection. In this study, we demonstrate that a synthetic ceramide analog (C8) stimulates DCs to increase the expansion of virus specific T cells upon virus infection. Exogenously supplied C8 ceramide elevated the expression of DC maturation markers such as MHC class I and costimulatory molecules following infection with the clone 13 strain of lymphocytic choriomeningitis virus (LCMV) or influenza virus. Importantly, ceramide conditioned, LCMV-infected DCs displayed an increased ability to promote expansion of virus-specific CD8(+) T cells when compared with virus-infected DCs. Furthermore, a locally instilled ceramide analog significantly increased virus reactive T cell responses in vivo to both LCMV and influenza virus infections. Collectively, these findings provide new insights into ceramide-mediated regulation of DC responses against virus infection and help us establish a foundation for novel immune-stimulatory therapeutics. PMID- 25810394 TI - Regulatory T cells prevent inducible BALT formation by dampening neutrophilic inflammation. AB - Inducible BALT (iBALT) can amplify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts. PMID- 25810395 TI - Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection. AB - By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF)3 axis in mediating IFN-alphabeta induction and defense mechanisms. In contrast, viruses have evolved with diverse immune evasion/interference mechanisms to undermine innate receptor signaling and IFN response. In this regard, approaches enabling host to overcome such immune evasion/interference mechanisms are urgently needed to combat infections by epidemic/pandemic viruses. In this study, we report that protein kinase CK2 serves as a key component controlling TBK1 and IRF3 activation in IFN-inducing TLR, RIG-I-like receptors, and cGAS/STING signaling pathways. Accordingly, knocking down of CK2 expression or genetic ablation of its kinase activity resulted in elevated IFN-alphabeta response in response to infection by DNA and RNA viruses. Moreover, PP2A was identified as one of the intermediate phosphatases responsible for CK2-regulated IFN response, suggesting that CK2 may regulate TBK1 and IRF3 activation indirectly. Importantly, blockade of CK2 activity by small molecule inhibitor was able to activate TBK1, whereby eliciting effective host defense mechanisms against hepatitis C virus infection. Taken together, our results identify CK2 as a novel regulator of TBK1 and IRF3 and suggest that targeting CK2 by small molecular inhibitor may be a viable approach to prevent and treat viral infections. PMID- 25810397 TI - Vibsanin B preferentially targets HSP90beta, inhibits interstitial leukocyte migration, and ameliorates experimental autoimmune encephalomyelitis. AB - Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz-enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90beta. At the molecular level, inactivation of HSP90 can mimic vibsanin B's effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90beta and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases. PMID- 25810396 TI - The adaptor 3BP2 is required for KIT receptor expression and human mast cell survival. AB - SH3-binding protein 2 (3BP2) is a cytoplasmic adaptor protein that acts as a positive regulator in mast cell FcepsilonRI-dependent signaling. The KIT receptor whose ligand is the stem cell factor is necessary for mast cell development, proliferation, and survival as well as for optimal IgE-dependent signal. Activating mutations in KIT have been associated with several diseases including mastocytosis. In the present work, we found that 3BP2 silencing impairs KIT signaling pathways, thus affecting phosphoinositide 3-kinase and MAPK pathways in human mast cells (huMCs) from HMC-1, LAD2 (huMC lines), and CD34(+)-derived mast cells. Unexpectedly, silencing of 3BP2 reduces KIT expression in normal huMCs as well as in HMC-1 cells where KIT is mutated, thus increasing cellular apoptosis and caspase-3/7 activity. 3BP2 silencing reduces KIT transcription expression levels. Interestingly, 3BP2 silencing decreased microphthalmia-associated transcription factor (MITF) expression, a transcription factor involved in KIT expression. Reconstitution of 3BP2 in knockdown cells leads to reversal of KIT expression as well as survival phenotype. Accordingly MITF reconstitution enhances KIT expression levels in 3BP2-silenced cells. Moreover, downregulation of KIT expression by miRNA-221 overexpression or the proteasome inhibitor bortezomib also reduced 3BP2 and MITF expression. Furthermore, KIT tyrosine activity inhibition reduced 3BP2 and MITF expression, demonstrating again a tight and reciprocal relationship between these molecules. Taken together, our results show that 3BP2 regulates huMC survival and participates in KIT-mediated signal transduction by directly controlling KIT receptor expression, suggesting its potential as a therapeutic target in mast cell-mediated inflammatory diseases and deregulated KIT disorders. PMID- 25810398 TI - Impact of natural gas extraction on PAH levels in ambient air. AB - Natural gas extraction, often referred to as "fracking," has increased rapidly in the U.S. in recent years. To address potential health impacts, passive air samplers were deployed in a rural community heavily affected by the natural gas boom. Samplers were analyzed for 62 polycyclic aromatic hydrocarbons (PAHs). Results were grouped based on distance from each sampler to the nearest active well. PAH levels were highest when samplers were closest to active wells. Additionally, PAH levels closest to natural gas activity were an order of magnitude higher than levels previously reported in rural areas. Sourcing ratios indicate that PAHs were predominantly petrogenic, suggesting that elevated PAH levels were influenced by direct releases from the earth. Quantitative human health risk assessment estimated the excess lifetime cancer risks associated with exposure to the measured PAHs. Closest to active wells, the risk estimated for maximum residential exposure was 2.9 in 10 000, which is above the U.S. EPA's acceptable risk level. Overall, risk estimates decreased 30% when comparing results from samplers closest to active wells to those farthest. This work suggests that natural gas extraction may be contributing significantly to PAHs in air, at levels that are relevant to human health. PMID- 25810399 TI - Detection of alphaS2-casein variants in Chinese yak (Bos grunniens) by PCR-SSCP. PMID- 25810401 TI - Molecular characterization of rainbow trout, Oncorhynchus mykiss (Walbaum, 1972) stocks in India. PMID- 25810400 TI - Isolation and screening of microsatellite markers from the pearl oyster, Pinctada fucata using FIASCO method. PMID- 25810402 TI - Utility of ITS1 as a molecular tool for reliable identification of Henosepilachna pusillanima and H. septima (Coleoptera: Coccinellidae). PMID- 25810403 TI - Genetic variation and geographical differentiation revealed using ISSR markers in tung tree, Vernicia fordii. PMID- 25810404 TI - Further Data on Sesamoid Identity from Two Anuran Species. AB - Considering that the identification of equivalent entities is the basis for any comparative analysis, we compare the histology, histochemistry, shape and dimensions of epiphyses, carpal and sesamoids in two anuran frogs. Our goal was to explore the morphological correspondence among these three skeletal elements in order to clarify the sesamoid identity. We studied the skeletogenesis, contour geometric morphometry and dimensions of forelimb elements of juveniles of two anurans species Leptodactylus bufonius and Rhinella arenarum. Skeletogenesis in anurans present a common trait between carpals and sesamoids: both elements exhibit endochondral ossification. A difference between these elements is the presence of fibrocartilage in the development of sesamoids. The geometric morphometry does not allow us to establish a shape pattern that can be compared either between sesamoids and epiphyses or carpals. With regard to dimensions, our data indicate that bones categorization based on these aspects is ambiguous and therefore is useless to classify of skeletal bones. The data about tissue differentiation of sesamoids provide evidence that support the idea that these elements should be considered part of the typical endowment of the vertebrate skeleton. PMID- 25810405 TI - Temporal-spatial changes in viabilities and electrochemical properties of anode biofilms. AB - Sustained current generation by anodic biofilms is a key element for the longevity and success of bioelectrochemical systems. Over time, however, inactive or dead cells can accumulate within the anode biofilm, which can be particularly detrimental to current generation. Mixed and pure culture (Geobacter anodireducens) biofilms were examined here relative to changes in electrochemical properties over time. An analysis of the three-dimensional metabolic structure of the biofilms over time showed that both types of biofilms developed a live outer layer that covered a dead inner-core. This two-layer structure appeared to be mostly a result of relatively low anodic current densities compared to other studies. During biofilm development, the live layer reached a constant thickness, whereas dead cells continued to accumulate near the electrode surface. This result indicated that only the live outer-layer of biofilm was responsible for current generation and suggested that the dead inner-layer continued to function as an electrically conductive matrix. Analysis of the electrochemical properties and biofilm thickness revealed that the diffusion resistance measured using electrochemical impedance spectroscopy might not be due to acetate or proton diffusion limitations to the live layer, but rather electron-mediator diffusion. PMID- 25810406 TI - Duck gait: Relationship to hip angle, bone ash, bone density, and morphology. AB - The rapid growth meat birds, including ducks, undergo requires skeletal integrity; however, fast growth may not be conducive to adequate bone structure. A relationship likely exists between skeletal changes and duck mobility. Reduced mobility in meat ducks may have impacts on welfare and production. This study examined the relationships among gait score, bone parameters, and hip angle. Commercial Pekin ducks, ages 14 d (n = 100), 21 d (n = 100), and 32 d (n = 100) were weighed and gait scored with a 3-point gait score system by an observer as they walked over a Tekscan gait analysis system. Gait was scored as GS0, GS1, or GS2 with a score of GS0 defined as good walking ability and a score of GS2 as poorest walking ability. Ducks were humanely euthanized, full body scanned using quantitative computed tomography (QCT), and the right femur and tibia were extracted. Leg bones were cleaned, measured, fat extracted, and ashed. QCT scans were rendered to create computerized 3D models where pelvic hip angles and bone density were measured. Statistical analysis was conducted using PROC MIXED with age and gait score in the model. Body weight increased with age, but within an age, body weight decreased as walking ability became worse (P < 0.01). As expected, linear increases in tibia and femur bone width and length were observed as the ducks aged (P < 0.01). Right and left hip angle increased with duck age (P < 0.01). Additionally, ducks with a GS2 had wider hip angles opposed to ducks with a GS0 (P < 0.01). Bone density increased linearly with both age and gait score (P < 0.05). Femur ash content was lowest in 32-day-old ducks and ducks with GS1 and GS2 (P < 0.0001). Tibia ash content increased with age, but decreased as gait score increased (P < 0.001). The observation that right hip angle changed with gait scores merits further investigation into the relationship between duck mobility and skeletal changes during growth. PMID- 25810407 TI - The fatty acid, amino acid, and mineral composition of Egyptian goose meat as affected by season, gender, and portion. AB - With the current absence of scientific information on the nutritive aspects it is essential to investigate the fatty acid, mineral, and amino acid composition of Egyptian geese as well as the factors of influence. The forage vs. grain based diets of Egyptian geese during certain periods of the yr leads to variation in the content of the key fatty acids such as oleic acid, linoleic acid, and alpha linolenic acid. The differences in these fatty acids results in variation between the n-6/n-3 ratios of the seasons; the portions from winter (July) are within the recommendations (ratio <5) and those from summer (November) not. This study indicates that Egyptian goose meat does not only vary in nutritional composition but season may also have a substantial effect on the flavor profile and ultimate uniformity of the meat. The season and portion effects were, however, interlinked but the general tendency shows that the portions, especially the breast and thigh do differ concerning the major fatty acids. No substantial differences were found in the mineral composition of the breast portion on account of season and gender; however there were some variation in certain amino acids such as lysine and arginine due to season/diet. This research provides essential information that should be considered not only regarding the everyday consumption of Egyptian goose meat but the potential utilization and ultimate consistency of this meat product. PMID- 25810408 TI - Interactions between supplemented mineral phosphorus and phytase on phytate hydrolysis and inositol phosphates in the small intestine of broilers1,2. AB - Phytate breakdown in the digestive tract of broilers is affected by supplements of mineral phosphorus (P) and phytase with unknown interactions between the 2 factors. It was the objective to study phytate hydrolysis and the presence of inositol phosphate isomers (InsPs) as affected by supplements of mineral P and phytase in the small intestine of broilers. Fifteen-day old broilers were assigned to 48 pens of 20 broilers each (n = 8 pens/treatment). Two low-P corn soybean meal-based diets without (BD-; 4.4 g P/kg dry matter) or with monocalcium phosphate (MCP; BD+; 5.2 g P/kg dry matter) were supplied without or with added phytase at 500 or 12,500 FTU/kg. On d 24, digesta from the duodenum/jejunum and lower ileum was pooled per segment on a by-pen basis, freeze-dried, and analyzed for P, InsPs, and the marker TiO2. Another 180 broilers (n = 6 pens/treatment, 10 birds each) were fed the 3 BD+ diets from d 1 to 21 to assess the influence of supplemented phytase on tibia mineralization and strength. Significant interactions between MCP and phytase supplements on myo-inositol 1,2,3,4,5,6 hexakis (dihydrogen phosphate) (InsP6) hydrolysis (duodenum/jejunum: P <= 0.001; ileum: P = 0.004) and level of specific lower InsPs were detected. Supplementation with 12,500 FTU/kg phytase resulted in 92% InsP6 hydrolysis and strong degradation of InsP5. This treatment resulted in higher P net absorption, affirmed by higher BW gain, tibia strength, and mineralization compared to treatments without or with 500 FTU/kg phytase (P <= 0.05). MCP supplementation reduced the degradation of InsP6 and specific lower InsPs in birds fed diets without or with 500 FTU/kg of phytase (P <= 0.05), but did not reduce InsP6 hydrolysis or degradation of InsP5 at the high phytase dose. Effects of added MCP on phytase efficacy depend on the dose of supplemented phytase. Differences in the concentrations of lower InsPs indicated that the initial step of InsP6 hydrolysis is not the only catabolic step that is influenced by MCP or phytase levels. PMID- 25810409 TI - An assessment of the impact of pulsed electric fields processing factors on oxidation, color, texture, and sensory attributes of turkey breast meat. AB - Pulsed electric fields (PEF) is a novel nonthermal technology that has the potential to cause physical disruption to muscle tissue which in turn could alter the sensorial aspects of meat in both a positive (e.g., enhanced tenderization) and a negative way (e.g., off-flavor development). If there is a risk of off flavor development it should be identified prior to embarking on an extensive investigation on PEF in meat tenderization and turkey meat was chosen for this purpose as it is particularly prone to oxidation. The objective of this study was to investigate the effect of various PEF treatments on the quality attributes of turkey breast meat. Turkey breast meat obtained 1 d postslaughter was treated in a batch PEF chamber with increasing electric field strength up to 3 kV/cm and analyzed for lipid oxidation by thiobarbituric acid reactive substances assay (TBARS) with up to 5 d storage at 4 degrees C in aerobic conditions. In a separate experiment, turkey breast meat samples were exposed to PEF under various combinations of pulse number, frequency, and voltage. Following PEF treatments weight loss, cook loss, lipid oxidation, texture, and color were assessed by instrumental methods. A sensory analysis was also performed to determine consumer acceptability for color, texture, and odor of the samples. Lipid oxidation in all PEF-treated samples progressed at the same rate with storage as the untreated samples and was not found to be significantly different to the control. Under the conditions examined PEF treatments did not induce differences in instrumentally measured weight loss, cook loss, lipid oxidation, texture, and color (raw and cooked) either on fresh or frozen samples. However, the sensory evaluation suggested that panelists could detect slight differences between the PEF-treated samples and the controls in terms of texture and odor. PMID- 25810410 TI - Atypical velogenic Newcastle disease in a commercial layer flock in Japan. AB - In 2002, a commercial layer flock in Japan was initially diagnosed as being infected with infectious bronchitis (IB) based on clinical signs, virus isolation, and serological analysis but was later found to be atypically infected with velogenic Newcastle disease virus (NDV) following molecular diagnosis. The flock had slightly decreased egg production and an increased occurrence of soft shelled eggs without significant mortality. IB-like viruses were isolated, which caused dwarfing and curling in 12-day-old chicken embryos. Ten years after this case, retrospective genetic analyses showed that apart from IB virus (IBV), the flock was also infected with NDV. Mean death time (MDT), intracerebral pathogenicity index (ICPI), and deduced amino acid sequence of the cleavage site of the fusion (F)-protein gene revealed that the NDV isolate was velogenic ((112)RRQKR(116)). These results indicate that poultry clinicians should look out for atypical velogenic ND, especially in vaccinated commercial chicken flocks, which may harbor hidden NDV infection. PMID- 25810411 TI - Vitamin C prevents the effects of high rearing temperatures on the quality of broiler thigh meat1. AB - We investigated the effects of incubation temperatures and vitamin C injections into eggs (treatments: 37.5oC, 39oC, 39oC+vitamin C) on resultant chick pectoralis major and sartorius muscle fiber hypertrophy, as well as their effects on the quality of breast and over-thigh meat of broilers reared under cold, control, or hot temperatures. Incubation at 39oC increased the shear force and reduced meat redness in breast meat (P < 0.05). Vitamin C prevented these high temperature incubation effects [shear force (kgf cm(-2)): 37.5oC = 2.34, 39oC = 2.79, 39oC+vitamin C = 2.44; redness: 37.5oC = 2.64, 39oC = 1.90, 39oC+vitamin C = 2.30], but reduced water content (37.5oC = 74.81%, 39oC = 74.53%, 39oC+vitamin C = 69.39%) (P < 0.05). Cold rearing temperatures increased breast meat redness (a*: cold = 2.78, control = 2.12, hot = 1.98), while hot rearing temperatures reduced the muscle fiber area (cold = 5.413 MUm(2), control = 5.612 MUm(2), hot = 4.448 MUm(2)) (P < 0.05) without altering meat quality (P > 0.05). Hot rearing temperatures increased the cooking loss (cold = 30.10%, control = 33.66%, hot = 37.01%), shear force (cold = 3.05 kgf cm(-2), control = 3.43 kgf cm(-2), hot = 4.29 kgf cm(-2)) and redness (a*: cold = 4.63, control = 3.55, hot = 3.20) in the over-thigh meat of broilers from eggs incubated at 37.5oC, increasing the area of muscle fibers, while cold rearing temperatures diminished cooking loss and shear force, reducing the muscle fiber area (P < 0.05). Incubation at 39oC and 39oC+vitamin C prevented the effects of hot and cold rearing temperatures, by diminishing and increasing the muscle fiber area, respectively. PMID- 25810412 TI - Effects of dietary protein levels during rearing and dietary energy levels during lay on body composition and reproduction in broiler breeder females. AB - A study with a 2 * 3 * 2 factorial arrangement was conducted to determine the effects of 2 dietary protein levels (high = CPh and low = CPl) during rearing, 3 dietary energy levels (3,000, MEh1; 2,800, MEs1; and 2,600, MEl1, kcal/kg AMEn, respectively) during the first phase of lay, and 2 dietary energy levels (2,800, MEs2; and 3,000, MEh2, kcal/kg AMEn, respectively) during the second phase of lay on body composition and reproduction in broiler breeders. No meaningful interactions for energy and protein treatments within the different phases of the study were found and, therefore, this paper focusses on the main effects. Pullets fed the CPl diet had a 12.8% higher feed intake, 14% lower breast muscle, and 97% higher abdominal fat pad portion at 22 wk age. The increased abdominal fat pad and decreased breast muscle of the CPl compared to the CPh birds increased hatchability during the first phase of lay, due to a decreased embryonic mortality between d 10 to 21 of incubation, and increased egg production during the second phase of lay. Feeding birds the MEh1 and MEl1 diets slightly decreased egg production compared to the MEs1 birds. Birds fed the MEh1 diet showed a higher mortality compared to the birds fed the MEs1 and MEl1 diets. Feeding birds the MEh2 diet did not affect egg production, increased hatchability of fertile eggs, decreased embryonic mortality between d 3 to 21 of incubation, and increased the number of first-grade chicks. It was concluded that a low-protein diet during rearing changed body composition with positive effects on incubation traits during the first phase of lay and improved egg production during the second phase of lay in broiler breeders. A high-energy or low-energy diet compared to a standard diet during the first phase of lay slightly decreased total and settable egg numbers while a high-energy diet during the second phase of lay increased hatchability and number of saleable chicks. PMID- 25810414 TI - Semantic information influences race categorization from faces. AB - It is well established that low-level visual features affect person categorization in a bottom-up fashion. Few studies have examined top-down influences, however, and have largely focused on how information recalled from memory or from motivation influences categorization. Here, we investigated how race categorizations are affected by the context in which targets are perceived by manipulating semantic information associated with the faces being categorized. We found that presenting faces that systematically varied in racial ambiguity with race-congruent (vs. incongruent) semantic labels shifted the threshold at which perceivers distinguished between racial groups. The semantic information offered by the labels therefore appeared to influence the categorization of race. These findings suggest that semantic information creates a context for the interpretation of perceptual cues during social categorization, highlighting an active role of top-down information in race perception. PMID- 25810413 TI - The prosocial versus proself power holder: how power influences sacrifice in romantic relationships. AB - Romantic partners often have to sacrifice their interests to benefit their partner or to maintain the relationship. In the present work, we investigated whether relative power within the relationship plays an important role in determining the extent to which partners are likely to sacrifice. Drawing from both classic theories and recent research on power, we tested two competing predictions on the relationship between power and sacrifice in romantic relationships. We tested whether (a) power is negatively related to sacrifice and (b) power is positively related to sacrifice. Furthermore, we also explored whether the association between power and sacrifice is moderated by commitment and inclusion of the other in the self. To test our hypotheses, we used different methodologies, including questionnaires, diary studies, and videotaped interactions. Results across the five studies (N = 1,088) consistently supported the hypothesis that power is negatively related to tendencies to sacrifice in close relationships. PMID- 25810416 TI - A critical review of adolescent mindfulness-based programmes. AB - OBJECTIVES: Previous research has demonstrated that mindfulness-based programmes improve psychological functioning in a myriad of adult domains. These include health care, marketing and sports industries. The efficacy of mindfulness-based programmes in the adult population is well established. Indeed, compared to adult empirical literature, mindfulness programmes for adolescents are relatively developmental and less articulated until now. It may be argued that mindfulness based programmes could and should begin early and be applicable to young people at a time that is critical in their development. Hence, this article analyses the characteristics, objectives and outcomes of mindfulness interventions for adolescents, focusing on the mindfulness programme adjustments and adaptations made to the content for this target group. METHOD: A critique of the literature that included published articles of mindfulness-based interventions (both clinical and universal programmes) for adolescents were sourced and reviewed. Conference papers and unpublished dissertations were excluded. RESULTS: The review indicated that a majority of these were longitudinal and feasibility studies, with only one clinical randomised controlled trial study. CONCLUSION: Preliminary evidence for the use of mindfulness-based with adolescents continues to be nascent, with many of the studies using inappropriate or no mindfulness process measures at all. In addition, a majority of the studies did not provide specific details of the mindfulness programmes for adolescents, nor discuss what modifications were undertaken--all of which makes comparison difficult. However, with the availability of recent and age-appropriate mindfulness measures for adolescents, more rigorous and robust research looks promising. PMID- 25810415 TI - How to study improvement interventions: a brief overview of possible study types. AB - Improvement (defined broadly as purposive efforts to secure positive change) has become an increasingly important activity and field of inquiry within healthcare. This article offers an overview of possible methods for the study of improvement interventions. The choice of available designs is wide, but debates continue about how far improvement efforts can be simultaneously practical (aimed at producing change) and scientific (aimed at producing new knowledge), and whether the distinction between the practical and the scientific is a real and useful one. Quality improvement projects tend to be applied and, in some senses, self evaluating. They are not necessarily directed at generating new knowledge, but reports of such projects if well conducted and cautious in their inferences may be of considerable value. They can be distinguished heuristically from research studies, which are motivated by and set out explicitly to test a hypothesis, or otherwise generate new knowledge, and from formal evaluations of improvement projects. We discuss variants of trial designs, quasi-experimental designs, systematic reviews, programme evaluations, process evaluations, qualitative studies, and economic evaluations. We note that designs that are better suited to the evaluation of clearly defined and static interventions may be adopted without giving sufficient attention to the challenges associated with the dynamic nature of improvement interventions and their interactions with contextual factors. Reconciling pragmatism and research rigour is highly desirable in the study of improvement. Trade-offs need to be made wisely, taking into account the objectives involved and inferences to be made. PMID- 25810417 TI - Horses for courses? A qualitative exploration of goals formulated in mental health settings by young people, parents, and clinicians. AB - INTRODUCTION: This research sought to explore and categorise goals set by children and young people, parents/caregivers and jointly by a combination of children/young people, parents/caregivers and/or clinicians within mental health settings across the United Kingdom. METHOD: Using a dataset of 441 goals formed at the outset of 180 treatment episodes (2007-2010) from UK child mental health services using the Goal-Based Outcomes tool, a grounded theory approach was taken, which built on previous research into child-rated goals to develop frameworks for parent and joint goal data which were then compared with the child goal data. RESULTS: A total of 19 subthemes and four overarching themes were identified for parent goals. A total of 19 subthemes in five overarching themes were identified for joint goals. These were compared with 25 subthemes and three overarching themes for child goals. A comparison of subthemes between parent, child and joint goals demonstrated many consistencies, but also differences. Most commonly rated goals from children focused on coping with specific difficulties, personal growth and independence. Parent goals focused mainly on managing specific difficulties, parent-specific goals and improving self or life. Jointly negotiated goals focused on parent-specific goals, self-confidence and understanding, hopes for the future and managing specific problems. CONCLUSION: The results suggest that goals may capture areas not captured by other normed outcome measures. In particular, goals may capture higher order, underlying factors, such as confidence, resilience, coping, and parenting factors that may not be explored by other measures. The differences across perspectives also link to existing literature suggesting a different focus on treatment based on perspectives and highlights the potential importance when jointly agreeing goals of ensuring the voice of the child/young person is heard and included in goal setting. PMID- 25810420 TI - Prognosis of Pregnant Women with One Abnormal Value on 75g OGTT. AB - The aim of this study was to identify risk factors to allow us to detect patients at high risk of requiring insulin therapy, among Japanese pregnant women with one abnormal value (OAV) on a 75-g oral glucose tolerance test (75-g OGTT). A total of 118 pregnant women with OAV on a previous 75-g OGTT between 1997 and 2010 were studied. We identified the factors which can predict patients at high risk of requiring insulin therapy among Japanese pregnant women with OAV, by comparing severe abnormal glucose tolerance (insulin treatment; n=17) with mild glucose tolerance patients (diet only; n=101). The following factors were examined; plasma level of glucose (PG) and immunoreactive insulin (IRI) at fasting, 0.5, 1 and 2 hours after loading glucose, insulinogenic index, homeostasis model assessment insulin resistance (HOMA-IR), insulin sensitivity index-composite (ISI composite), and HbA1c at the time of the 75-g OGTT. Univariate analysis showed a positive correlation between insulin therapy and 2-h PG value, 0.5-h and 1-h IRI values, AUC-IRI and insulinogenic index (p<0.05). Multivariate analysis showed that the PG 2-h value and insulinogenic index were independent predictive factors of insulin therapy. A 2-h PG >=153 mg / dl and an insulinogenic index of <0.42 had a sensitivity of 81.8%, a specificity of 83.8%, a positive predictive value of 60.0% and a negative predictive value of 93.9% for the prediction of patients who required insulin therapy among pregnant women with OAV. These results suggest that a level of 2-h PG >=153 mg/dl and an insulinogenic index of <0.42 on 75-g OGTT are predictive factors for insulin therapy in Japanese pregnant women with OAV. PMID- 25810421 TI - The Impact of Body Mass Index on Perioperative Outcomes After Laparoscopic Colorectal Surgery. AB - Laparoscopic colorectal surgery has gained increasing attention during the past 20 years. Surgeons today are more often confronted with obese patients. Therefore, it is timely to investigate the feasibility and safety of laparoscopic surgery for colorectal disease in obese patients. This study included 65 patients with colorectal disease who underwent laparoscopic surgery, between January 2009 and January 2014, at Kurume University Hospital. We divided the patients in this study into two groups based on their body mass index (BMI): <25 kg/m(2) (non obese group) and >= 25 kg/m(2) (obese group). We assessed baseline characteristics and surgical outcomes, and these were compared between the non obese group and the obese group. There were 53 patients in the non-obese group, and 12 patients in the obese group. There was no significant difference between the two groups of patients with regard to age, sex, co-morbidity, tumor location, tumor node metastasis (TNM) stage, tumor size and serum carcinoembryonic antigen (CEA) level. The duration of the operation was longer (by about 49 mins) for obese patients than non-obese patients. The conversion rate, amount of blood loss, number of lymph nodes resected, and duration of postoperative hospital insertion were each similar between the two groups. There was no significant difference between the two groups with regard to the overall incidence of postoperative complications; however, the incidence of incisional hernia tended to be more frequent in obese patients. There was no mortality in the two groups. Laparoscopic colorectal surgery is technically feasible and safe for obese patients. However, obesity is associated with longer duration and with higher risk of incisional hernia. Our findings suggest that BMI may not be an accurate estimate of visceral fat, and further studies may be useful for understanding the impact of obesity. PMID- 25810422 TI - Regular Tooth Brushing is Associated with a Decreased Risk of Metabolic Syndrome According to a Medical Check-Up Database. AB - Associations have been reported between periodontal disease and increased cardiovascular disease risk, as well as between healthy self-reported tooth brushing behavior and reduced cardiovascular disease risk. We examined the association between self-reported tooth brushing behavior and the risk of metabolic syndrome (MetS) using a large medical check-up database. A total of 12,548 medical checkup records from a medical screening center in a city in southwest Japan were assessed. Subjects were aged 30 to 59 years. As lifestyle is associated with both tooth brushing and MetS, many lifestyle variables were considered as potential confounders. Logistic regression model were employed with a list of 127 lifestyle variables. Twenty variables associated with both tooth brushing and MetS were selected for both males and females. Furthermore, final confounding variables were selected by principal component analysis to avoid collinearity problems. The association of tooth brushing and MetS was evaluated for males and females separately by calculating adjusted odds ratios (ORs) with selected confounders plus age. The association between daily tooth brushing frequency and MetS risk for both genders was significant after adjusting for confounders, with the risk of MetS decreasing with increased frequency of daily tooth brushing (adjusted OR = 0.57 (95%Cl:0.48-0.81), 0.50 (95%Cl:0.35-0.71), 0.42 (95%Cl: 0.29-0.61) for males and adjusted OR = 0.65 (95%Cl:0.48-0.87), 0.44 (95%Cl:0.32-0.62) for females). Therefore, oral hygiene, including the frequency of tooth brushing as a significant component, may be an important factor in preventing MetS. PMID- 25810423 TI - Add-on treatment with mitiglinide improves residual postprandial hyperglycemia in type 2 diabetic patients receiving the combination therapy with insulin glargine and sitagliptin. AB - The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-acting insulin analogue is widely used in clinical practice. However, some patients fail to achieve lower postprandial hyperglycemia. Mitiglinide, a short-acting insulinotropic sulfonylurea receptor ligand, is effective for postprandial hyperglycemia. Recently, it has been reported that the combination therapy of mitiglinide with a DPP-4 inhibitor could improve glycemic control. However, the efficacy of those under long-acting insulin analogue therapy remains to be investigated. Thus, we conducted a prospective single-center study of eight Japanese patients with type 2 diabetes mellitus receiving mitiglinide added to the combination therapy of sitagliptin and insulin glargine, and evaluated its efficacy and safety by continuous glucose monitoring (CGM). Participants' (four men and four women) mean age was 70.3 +/- 10.6 years. Their mean body mass index, HbA1c level, and urinary C-peptide level were 22.0 +/- 2.8 kg/m(2), 9.2 +/- 1.2%, and 50.0 +/- 31.4 MUg/day, respectively. CGM showed that as compared with the combination of only sitagliptin and insulin glargine, mitiglinide in combination with sitagliptin and insulin glargine significantly reduced glycemic fluctuation indices, total area for the range of 24-h glycemic fluctuations (p = 0.04), mean amplitude of glycemic excursions (p = 0.03), and the proportion of time in hyperglycemia (p = 0.02) without significant difference in the proportion of time in hypoglycemia (p = 0.18). Hence, we have demonstrated the efficacy and safety of the add-on treatment with mitiglinide in type 2 diabetic patients, receiving the combination therapy of sitagliptin and insulin glargine. PMID- 25810419 TI - A microbiological revolution meets an ancient disease: improving the management of tuberculosis with genomics. AB - Tuberculosis (TB) is an ancient disease with an enormous global impact. Despite declining global incidence, the diagnosis, phenotyping, and epidemiological investigation of TB require significant clinical microbiology laboratory resources. Current methods for the detection and characterization of Mycobacterium tuberculosis consist of a series of laboratory tests varying in speed and performance, each of which yields incremental information about the disease. Since the sequencing of the first M. tuberculosis genome in 1998, genomic tools have aided in the diagnosis, treatment, and control of TB. Here we summarize genomics-based methods that are positioned to be introduced in the modern clinical TB laboratory, and we highlight how recent advances in genomics will improve the detection of antibiotic resistance-conferring mutations and the understanding of M. tuberculosis transmission dynamics and epidemiology. We imagine the future TB clinic as one that relies heavily on genomic interrogation of the M. tuberculosis isolate, allowing for more rapid diagnosis of TB and real time monitoring of outbreak emergence. PMID- 25810425 TI - Inspiratory muscle training improves aerobic capacity and pulmonary function in patients with ankylosing spondylitis: a randomized controlled study. AB - OBJECTIVE: To evaluate the impact of inspiratory muscle training on aerobic capacity and pulmonary function in patients with ankylosing spondylitis. DESIGN: Randomized controlled study. SETTING: Rheumatic Rehabilitation Centre. SUBJECTS: A total of 54 ankylosing spondylitis patients, all males, were randomized to a conventional exercise training associated with an inspiratory muscle training group, or to a conventional exercise training group. INTERVENTIONS: Group 1 (27 patients) performed eight weeks of conventional exercise training (supervised weekly group sessions followed by a home-based exercise programme) associated with inspiratory muscle training sessions. Group 2 (27 patients) received eight weeks of conventional exercise training only. MAIN MEASURES: Resting pulmonary function (forced vital capacity - FVC, forced expiratory volume in one second - FEV1); effort ventilatory efficiency (lowest ventilatory equivalent ratio for oxygen and carbon dioxide - VE/VO2 and VE/VCO2) and aerobic capacity (peak oxygen uptake - VO2peak) were assessed at baseline and after eight weeks of exercise based intervention. RESULTS: After eight weeks follow-up, patients in Group 1 had a significant increased chest expansion and VO2peak compared with Group 2 (3.6 +/ 0.8 cm vs. 3.2 +/-0.5 cm, P = 0.032; 2.0 +/-0.5 l/min vs. 1.8 +/-0.3 l/min, P = 0.033). There were no significant differences of spirometric measurements, except FVC which significantly improved in patients who performed inspiratory muscle training (82.7 +/-5.1% vs. 79.5 +/-3.5%, P = 0.014). VE/VCO2 also improved significantly in Group 1 (26.6 +/-3.6 vs. 29.2 +/-4.7, P = 0.040). CONCLUSIONS: Ankylosing spondylitis patients who performed eight weeks of inspiratory muscle training associated to conventional exercise training had an increased chest expansion, a better aerobic capacity, resting pulmonary function and ventilatory efficiency than those who performed conventional exercise training only. PMID- 25810424 TI - A rare case of IgG4-related disease involving the uterus. PMID- 25810427 TI - ASBench: benchmarking sets for allosteric discovery. AB - Allostery allows for the fine-tuning of protein function. Targeting allosteric sites is gaining increasing recognition as a novel strategy in drug design. The key challenge in the discovery of allosteric sites has strongly motivated the development of computational methods and thus high-quality, publicly accessible standard data have become indispensable. Here, we report benchmarking data for experimentally determined allosteric sites through a complex process, including a 'Core set' with 235 unique allosteric sites and a 'Core-Diversity set' with 147 structurally diverse allosteric sites. These benchmarking sets can be exploited to develop efficient computational methods to predict unknown allosteric sites in proteins and reveal unique allosteric ligand-protein interactions to guide allosteric drug design. PMID- 25810418 TI - Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. AB - The source of the severe acute respiratory syndrome (SARS) epidemic was traced to wildlife market civets and ultimately to bats. Subsequent hunting for novel coronaviruses (CoVs) led to the discovery of two additional human and over 40 animal CoVs, including the prototype lineage C betacoronaviruses, Tylonycteris bat CoV HKU4 and Pipistrellus bat CoV HKU5; these are phylogenetically closely related to the Middle East respiratory syndrome (MERS) CoV, which has affected more than 1,000 patients with over 35% fatality since its emergence in 2012. All primary cases of MERS are epidemiologically linked to the Middle East. Some of these patients had contacted camels which shed virus and/or had positive serology. Most secondary cases are related to health care-associated clusters. The disease is especially severe in elderly men with comorbidities. Clinical severity may be related to MERS-CoV's ability to infect a broad range of cells with DPP4 expression, evade the host innate immune response, and induce cytokine dysregulation. Reverse transcription-PCR on respiratory and/or extrapulmonary specimens rapidly establishes diagnosis. Supportive treatment with extracorporeal membrane oxygenation and dialysis is often required in patients with organ failure. Antivirals with potent in vitro activities include neutralizing monoclonal antibodies, antiviral peptides, interferons, mycophenolic acid, and lopinavir. They should be evaluated in suitable animal models before clinical trials. Developing an effective camel MERS-CoV vaccine and implementing appropriate infection control measures may control the continuing epidemic. PMID- 25810428 TI - PRROC: computing and visualizing precision-recall and receiver operating characteristic curves in R. AB - Precision-recall (PR) and receiver operating characteristic (ROC) curves are valuable measures of classifier performance. Here, we present the R-package PRROC, which allows for computing and visualizing both PR and ROC curves. In contrast to available R-packages, PRROC allows for computing PR and ROC curves and areas under these curves for soft-labeled data using a continuous interpolation between the points of PR curves. In addition, PRROC provides a generic plot function for generating publication-quality graphics of PR and ROC curves. PMID- 25810426 TI - Concordance and discordance between measured and perceived balance and the effect on gait speed and falls following stroke. AB - OBJECTIVE: To ascertain the existence of discordance between perceived and measured balance in persons with stroke and to examine the impact on walking speed and falls. DESIGN: A secondary analysis of a phase three, multicentered randomized controlled trial examining walking recovery following stroke. SUBJECTS: A total of 352 participants from the Locomotor Experience Applied Post Stroke (LEAPS) trial. METHODS: Participants were categorized into four groups: two concordant and two discordant groups in relation to measured and perceived balance. Number and percentage of individuals with concordance and discordance were evaluated at two and 12 months. Walking speed and fall incidence between groups were examined. MAIN MEASURES: Perceived balance was measured by the Activities-Specific Balance Confidence scale, measured balance was determined by the Berg Balance Scale and gait speed was measured by the 10-meter walk test. RESULTS: Discordance was present for 35.8% of participants at two months post stroke with no statistically significant change in proportion at 12 months. Discordant participants with high perceived balance and low measured balance walked 0.09 m/s faster at two months than participants with concordant low perceived and measured balance (p < 0.05). Discordant participants with low perceived balance and high measured balance walked 0.15 m/s slower than those that were concordant with high perceived and measured balance (p ? 0.0001) at 12 months. Concordant participants with high perceived and measured balance walked fastest and had fewer falls. CONCLUSIONS: Discordance existed between perceived and measured balance in one-third of individuals at two and 12 months post stroke. Perceived balance impacted gait speed but not fall incidence. PMID- 25810430 TI - Learning chromatin states with factorized information criteria. AB - MOTIVATION: Recent studies have suggested that both the genome and the genome with epigenetic modifications, the so-called epigenome, play important roles in various biological functions, such as transcription and DNA replication, repair, and recombination. It is well known that specific combinations of histone modifications (e.g. methylations and acetylations) of nucleosomes induce chromatin states that correspond to specific functions of chromatin. Although the advent of next-generation sequencing (NGS) technologies enables measurement of epigenetic information for entire genomes at high-resolution, the variety of chromatin states has not been completely characterized. RESULTS: In this study, we propose a method to estimate the chromatin states indicated by genome-wide chromatin marks identified by NGS technologies. The proposed method automatically estimates the number of chromatin states and characterize each state on the basis of a hidden Markov model (HMM) in combination with a recently proposed model selection technique, factorized information criteria. The method is expected to provide an unbiased model because it relies on only two adjustable parameters and avoids heuristic procedures as much as possible. Computational experiments with simulated datasets show that our method automatically learns an appropriate model, even in cases where methods that rely on Bayesian information criteria fail to learn the model structures. In addition, we comprehensively compare our method to ChromHMM on three real datasets and show that our method estimates more chromatin states than ChromHMM for those datasets. PMID- 25810429 TI - DISSCO: direct imputation of summary statistics allowing covariates. AB - BACKGROUND: Imputation of individual level genotypes at untyped markers using an external reference panel of genotyped or sequenced individuals has become standard practice in genetic association studies. Direct imputation of summary statistics can also be valuable, for example in meta-analyses where individual level genotype data are not available. Two methods (DIST and ImpG-Summary/LD), that assume a multivariate Gaussian distribution for the association summary statistics, have been proposed for imputing association summary statistics. However, both methods assume that the correlations between association summary statistics are the same as the correlations between the corresponding genotypes. This assumption can be violated in the presence of confounding covariates. METHODS: We analytically show that in the absence of covariates, correlation among association summary statistics is indeed the same as that among the corresponding genotypes, thus serving as a theoretical justification for the recently proposed methods. We continue to prove that in the presence of covariates, correlation among association summary statistics becomes the partial correlation of the corresponding genotypes controlling for covariates. We therefore develop direct imputation of summary statistics allowing covariates (DISSCO). RESULTS: We consider two real-life scenarios where the correlation and partial correlation likely make practical difference: (i) association studies in admixed populations; (ii) association studies in presence of other confounding covariate(s). Application of DISSCO to real datasets under both scenarios shows at least comparable, if not better, performance compared with existing correlation-based methods, particularly for lower frequency variants. For example, DISSCO can reduce the absolute deviation from the truth by 3.9-15.2% for variants with minor allele frequency <5%. PMID- 25810431 TI - Proper evaluation of alignment-free network comparison methods. AB - MOTIVATION: Network comparison is a computationally intractable problem with important applications in systems biology and other domains. A key challenge is to properly quantify similarity between wiring patterns of two networks in an alignment-free fashion. Also, alignment-based methods exist that aim to identify an actual node mapping between networks and as such serve a different purpose. Various alignment-free methods that use different global network properties (e.g. degree distribution) have been proposed. Methods based on small local subgraphs called graphlets perform the best in the alignment-free network comparison task, due to high level of topological detail that graphlets can capture. Among different graphlet-based methods, Graphlet Correlation Distance (GCD) was shown to be the most accurate for comparing networks. Recently, a new graphlet-based method called NetDis was proposed, which was claimed to be superior. We argue against this, as the performance of NetDis was not properly evaluated to position it correctly among the other alignment-free methods. RESULTS: We evaluate the performance of available alignment-free network comparison methods, including GCD and NetDis. We do this by measuring accuracy of each method (in a systematic precision-recall framework) in terms of how well the method can group (cluster) topologically similar networks. By testing this on both synthetic and real-world networks from different domains, we show that GCD remains the most accurate, noise-tolerant and computationally efficient alignment-free method. That is, we show that NetDis does not outperform the other methods, as originally claimed, while it is also computationally more expensive. Furthermore, since NetDis is dependent on the choice of a network null model (unlike the other graphlet-based methods), we show that its performance is highly sensitive to the choice of this parameter. Finally, we find that its performance is not independent on network sizes and densities, as originally claimed. CONTACT: natasha@imperial.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25810432 TI - Integration of somatic mutation, expression and functional data reveals potential driver genes predictive of breast cancer survival. AB - MOTIVATION: Genome and transcriptome analyses can be used to explore cancers comprehensively, and it is increasingly common to have multiple omics data measured from each individual. Furthermore, there are rich functional data such as predicted impact of mutations on protein coding and gene/protein networks. However, integration of the complex information across the different omics and functional data is still challenging. Clinical validation, particularly based on patient outcomes such as survival, is important for assessing the relevance of the integrated information and for comparing different procedures. RESULTS: An analysis pipeline is built for integrating genomic and transcriptomic alterations from whole-exome and RNA sequence data and functional data from protein function prediction and gene interaction networks. The method accumulates evidence for the functional implications of mutated potential driver genes found within and across patients. A driver-gene score (DGscore) is developed to capture the cumulative effect of such genes. To contribute to the score, a gene has to be frequently mutated, with high or moderate mutational impact at protein level, exhibiting an extreme expression and functionally linked to many differentially expressed neighbors in the functional gene network. The pipeline is applied to 60 matched tumor and normal samples of the same patient from The Cancer Genome Atlas breast cancer project. In clinical validation, patients with high DGscores have worse survival than those with low scores (P = 0.001). Furthermore, the DGscore outperforms the established expression-based signatures MammaPrint and PAM50 in predicting patient survival. In conclusion, integration of mutation, expression and functional data allows identification of clinically relevant potential driver genes in cancer. AVAILABILITY AND IMPLEMENTATION: The documented pipeline including annotated sample scripts can be found in http://fafner.meb.ki.se/biostatwiki/driver-genes/. CONTACT: yudi.pawitan@ki.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25810433 TI - Computational modeling of the expansion of human cord blood CD133+ hematopoietic stem/progenitor cells with different cytokine combinations. AB - MOTIVATION: Many important problems in cell biology require dense non-linear interactions between functional modules to be considered. The importance of computer simulation in understanding cellular processes is now widely accepted, and a variety of simulation algorithms useful for studying certain subsystems have been designed. Expansion of hematopoietic stem and progenitor cells (HSC/HPC) in ex vivo culture with cytokines and small molecules is a method to increase the restricted numbers of stem cells found in umbilical cord blood (CB), while also enhancing the content of early engrafting neutrophil and platelet precursors. The efficacy of the expanded product depends on the composition of the cocktail of cytokines and small molecules used for culture. Testing the influence of a cytokine or small molecule on the expansion of HSC/HPC is a laborious and expensive process. We therefore developed a computational model based on cellular signaling interactions that predict the influence of a cytokine on the survival, duplication and differentiation of the CD133(+) HSC/HPC subset from human umbilical CB. RESULTS: We have used results from in vitro expansion cultures with different combinations of one or more cytokines to develop an ordinary differential equation model that includes the effect of cytokines on survival, duplication and differentiation of the CD133(+) HSC/HPC. Comparing the results of in vitro and in silico experiments, we show that the model can predict the effect of a cytokine on the fold expansion and differentiation of CB CD133(+) HSC/HPC after 8-day culture on a 3D scaffold. Supplementary data are available at Bioinformatics online. PMID- 25810434 TI - A statistical physics perspective on alignment-independent protein sequence comparison. AB - MOTIVATION: Within bioinformatics, the textual alignment of amino acid sequences has long dominated the determination of similarity between proteins, with all that implies for shared structure, function and evolutionary descent. Despite the relative success of modern-day sequence alignment algorithms, so-called alignment free approaches offer a complementary means of determining and expressing similarity, with potential benefits in certain key applications, such as regression analysis of protein structure-function studies, where alignment-base similarity has performed poorly. RESULTS: Here, we offer a fresh, statistical physics-based perspective focusing on the question of alignment-free comparison, in the process adapting results from 'first passage probability distribution' to summarize statistics of ensemble averaged amino acid propensity values. In this article, we introduce and elaborate this approach. PMID- 25810435 TI - MeDuSa: a multi-draft based scaffolder. AB - MOTIVATION: Completing the genome sequence of an organism is an important task in comparative, functional and structural genomics. However, this remains a challenging issue from both a computational and an experimental viewpoint. Genome scaffolding (i.e. the process of ordering and orientating contigs) of de novo assemblies usually represents the first step in most genome finishing pipelines. RESULTS: In this article we present MeDuSa (Multi-Draft based Scaffolder), an algorithm for genome scaffolding. MeDuSa exploits information obtained from a set of (draft or closed) genomes from related organisms to determine the correct order and orientation of the contigs. MeDuSa formalizes the scaffolding problem by means of a combinatorial optimization formulation on graphs and implements an efficient constant factor approximation algorithm to solve it. In contrast to currently used scaffolders, it does not require either prior knowledge on the microrganisms dataset under analysis (e.g. their phylogenetic relationships) or the availability of paired end read libraries. This makes usability and running time two additional important features of our method. Moreover, benchmarks and tests on real bacterial datasets showed that MeDuSa is highly accurate and, in most cases, outperforms traditional scaffolders. The possibility to use MeDuSa on eukaryotic datasets has also been evaluated, leading to interesting results. PMID- 25810436 TI - ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3. AB - The mutations in the CLCNKB gene encoding the ClC-Kb chloride channel are responsible for Bartter syndrome type 3, one of the four variants of Bartter syndrome in the genetically based nomenclature. All forms of Bartter syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism, but Bartter syndrome type 3 has the most heterogeneous presentation, extending from severe to very mild. A relatively large number of CLCNKB mutations have been reported, including gene deletions and nonsense or missense mutations. However, only 20 CLCNKB mutations have been functionally analyzed, due to technical difficulties regarding ClC-Kb functional expression in heterologous systems. This review provides an overview of recent progress in the functional consequences of CLCNKB mutations on ClC-Kb chloride channel activity. It has been observed that 1) all ClC-Kb mutants have an impaired expression at the membrane; and 2) a minority of the mutants combines reduced membrane expression with altered pH-dependent channel gating. Although further investigation is needed to fully characterize disease pathogenesis, Bartter syndrome type 3 probably belongs to the large family of conformational diseases, in which the mutations destabilize channel structure, inducing ClC-Kb retention in the endoplasmic reticulum and accelerated channel degradation. PMID- 25810437 TI - Quercetin attenuates cyclooxygenase-2 expression in response to acute ureteral obstruction. AB - Unilateral ureteral obstruction (UUO) is associated with increased hydrostatic pressure, inflammation, and oxidative stress in the renal parenchyma. Previous studies have demonstrated marked cyclooxygenase (COX)-2 induction in renal medullary interstitial cells (RMICs) in response to UUO. The aim of the present study was to evaluate the effect of quercetin, a naturally occurring antioxidant, on COX-2 induction in vivo and in vitro. Rats subjected to 24 h of UUO were treated intraperitoneally with quercetin (50 mg.kg(-1).day(-1)). Quercetin partly prevented COX-2 induction in the renal inner medulla in response to UUO. Moreover, RMICs exposed to conditions associated with obstruction, inflammation (produced by IL-1beta), oxidative stress (produced by H2O2), and mechanical stress (produced by stretch) showed increased COX-2 expression. Interestingly, quercetin reduced COX-2 induction in RMICs subjected to stretched. Similarly, PGE2 production was markedly increased in RMICs exposed to stretch and was reversed to control levels by quercetin treatment. Furthermore, stretch-induced phosphorylation of ERK1/2 was blocked by quercetin, and inhibition of ERK1/2 attenuated stretch-induced COX-2 induction in RMICs. These results indicate that quercetin attenuated the induction of COX-2 expression and activity in RMICs exposed to mechanical stress as a consequence of acute UUO and that the MAPK ERK1/2 pathway might be involved in this quercetin-mediated reduction in COX-2. PMID- 25810439 TI - Translating genetic findings in hereditary nephrotic syndrome: the missing loops. AB - Nephrotic syndrome (NS) is a clinicopathological entity characterized by proteinuria, hypoalbuminemia, peripheral edema, and hyperlipidemia. It is the most common cause of glomerular disease in children and adults. Although the molecular pathogenesis of NS is not completely understood, data from the study of familial NS suggest that it is a "podocytopathy." Virtually all of the genes mutated in hereditary NS localize to the podocyte or its secreted products and the slit diaphragm. Since the completion of human genome sequence and the advent of next generation sequencing, at least 29 causes of single-gene NS have been identified. However, these findings have not been matched by therapeutic advances owing to suboptimal in vitro and in vivo models for the study of human glomerular disease and podocyte injury phenotypes. Multidisciplinary collaboration between clinicians, geneticists, cell biologists, and molecular physiologists has the potential to overcome this barrier and thereby speed up the translation of genetic findings into improved patient care. PMID- 25810438 TI - Harvest and primary culture of the murine aldosterone-sensitive distal nephron. AB - The aldosterone-sensitive distal nephron (ASDN) exhibits axial heterogeneity in structure and function from the distal convoluted tubule to the medullary collecting duct. Ion and water transport is primarily divided between the cortex and medulla of the ASDN, respectively. Transcellular transport in this segment is highly regulated in health and disease and is integrated across different cell types. We currently lack an inexpensive, high-yield, and tractable technique to harvest and culture cells for the study of gene expression and physiological properties of mouse cortical ASDN. To address this need, we harvested tubules bound to Dolichos biflorus agglutinin lectin-coated magnetic beads from the kidney cortex and characterized these cell preparations. We determined that these cells are enriched for markers of distal convoluted tubule, connecting tubule, and cortical collecting duct, including principal and intercalated cells. In primary culture, these cells develop polarized monolayers with high resistance (1,000-1,500 Omega * cm(2)) and maintain expression and activity of key channels. These cells demonstrate an amiloride-sensitive short-circuit current that can be enhanced with aldosterone and maintain measurable potassium and anion secretion. Our method can be easily adopted to study the biology of the ASDN and to investigate phenotypic differences between wild-type and transgenic mouse models. PMID- 25810440 TI - An Improved Reverse Genetics System to Overcome Cell-Type-Dependent Ebola Virus Genome Plasticity. AB - Reverse genetics systems represent a key technique for studying replication and pathogenesis of viruses, including Ebola virus (EBOV). During the rescue of recombinant EBOV from Vero cells, a high frequency of mutations was observed throughout the genomes of rescued viruses, including at the RNA editing site of the glycoprotein gene. The influence that such genomic instability could have on downstream uses of rescued virus may be detrimental, and we therefore sought to improve the rescue system. Here we report an improved EBOV rescue system with higher efficiency and genome stability, using a modified full-length EBOV clone in Huh7 cells. Moreover, by evaluating a variety of cells lines, we revealed that EBOV genome instability is cell-type dependent, a fact that has significant implications for the preparation of standard virus stocks. Thus, our improved rescue system will have an impact on both basic and translational research in the filovirus field. PMID- 25810441 TI - Analysis of Breath Specimens for Biomarkers of Plasmodium falciparum Infection. AB - Currently, the majority of diagnoses of malaria rely on a combination of the patient's clinical presentation and the visualization of parasites on a stained blood film. Breath offers an attractive alternative to blood as the basis for simple, noninvasive diagnosis of infectious diseases. In this study, breath samples were collected from individuals during controlled malaria to determine whether specific malaria-associated volatiles could be detected in breath. We identified 9 compounds whose concentrations varied significantly over the course of malaria: carbon dioxide, isoprene, acetone, benzene, cyclohexanone, and 4 thioethers. The latter group, consisting of allyl methyl sulfide, 1-methylthio propane, (Z)-1-methylthio-1-propene, and (E)-1-methylthio-1-propene, had not previously been associated with any disease or condition. Before the availability of antimalarial drug treatment, there was evidence of concurrent 48-hour cyclical changes in the levels of both thioethers and parasitemia. When thioether concentrations were subjected to a phase shift of 24 hours, a direct correlation between the parasitemia and volatile levels was revealed. Volatile levels declined monotonically approximately 6.5 hours after initial drug treatment, correlating with clearance of parasitemia. No thioethers were detected in in vitro cultures of Plasmodium falciparum. The metabolic origin of the thioethers is not known, but results suggest that interplay between host and parasite metabolic pathways is involved in the production of these thioethers. PMID- 25810442 TI - Identification of Aspergillus fumigatus Surface Components That Mediate Interaction of Conidia and Hyphae With Human Platelets. AB - BACKGROUND: Platelets were recently identified as a part of innate immunity. They are activated by contact with Aspergillus fumigatus; putative consequences include antifungal defense but also thrombosis, excessive inflammation, and thrombocytopenia. We aimed to identify those fungal surface structures that mediate interaction with platelets. METHODS: Human platelets were incubated with Aspergillus conidia and hyphae, isolated wall components, or fungal surface mutants. Interaction was visualized microscopically; activation was quantified by flow cytometry of specific markers. RESULTS: The capacity of A. fumigatus conidia to activate platelets is at least partly due to melanin, because this effect can be mimicked with "melanin ghosts"; a mutant lacking melanin showed reduced platelet stimulating potency. In contrast, conidial hydrophobin masks relevant structures, because an A. fumigatus mutant lacking the hydrophobin protein induced stronger platelet activation than wild-type conidia. A. fumigatus hyphae also contain surface structures that interact with platelets. Wall proteins, galactomannan, chitin, and beta-glucan are not the relevant hyphal components; instead, the recently identified fungal polysaccharide galactosaminogalactan potently triggered platelet activation. CONCLUSIONS: Conidial melanin and hydrophobin as well as hyphal galactosaminogalactan represent important pathogenicity factors that modulate platelet activity and thus might influence immune responses, inflammation, and thrombosis in infected patients. PMID- 25810443 TI - Relationships (II) of International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases with ventilatory functions indices for parenchymal abnormalities. AB - The International Classification of High-Resolution Computed Tomography (HRCT) for Occupational and Environmental Respiratory Diseases (ICOERD) is used to screen and diagnose respiratory illnesses. Using univariate and multivariate analysis, we investigated the relationship between subject characteristics and parenchymal abnormalities according to ICOERD, and the results of ventilatory function tests (VFT). Thirty-five patients with and 27 controls without mineral dust exposure underwent VFT and HRCT. We recorded all subjects' occupational history for mineral dust exposure and smoking history. Experts independently assessed HRCT using the ICOERD parenchymal abnormalities (Items) grades for well defined rounded opacities (RO), linear and/or irregular opacities (IR), and emphysema (EM). High-resolution computed tomography showed that 11 patients had RO; 15 patients, IR; and 19 patients, EM. According to the multiple regression model, age and height had significant associations with many indices ventilatory functions such as vital capacity, forced vital capacity, and forced expiratory volume in 1 s (FEV1). The EM summed grades on the upper, middle, and lower zones of the right and left lungs also had significant associations with FEV1 and the maximum mid-expiratory flow rate. The results suggest the ICOERD notation is adequate based on the good and significant multiple regression modeling of ventilatory function with the EM summed grades. PMID- 25810444 TI - Relationships (I) of International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases with the ILO International Classification of Radiographs of Pneumoconioses for parenchymal abnormalities. AB - The International Classification of High-resolution Computed Tomography (HRCT) for Occupational and Environmental Respiratory Diseases (ICOERD) has been developed for the screening, diagnosis, and epidemiological reporting of respiratory diseases caused by occupational hazards. This study aimed to establish a correlation between readings of HRCT (according to the ICOERD) and those of chest radiography (CXR) pneumoconiotic parenchymal opacities (according to the International Labor Organization Classification/International Classification of Radiographs of Pneumoconioses [ILO/ICRP]). Forty-six patients with and 28 controls without mineral dust exposure underwent posterior-anterior CXR and HRCT. We recorded all subjects' exposure and smoking history. Experts independently read CXRs (using ILO/ICRP). Experts independently assessed HRCT using the ICOERD parenchymal abnormalities grades for well-defined rounded opacities (RO), linear and/or irregular opacities (IR), and emphysema (EM). The correlation between the ICOERD summed grades and ILO/ICRP profusions was evaluated using Spearman's rank-order correlation. Twenty-three patients had small opacities on CXR. HRCT showed that 21 patients had RO; 20 patients, IR opacities; and 23 patients, EM. The correlation between ILO/ICRP profusions and the ICOERD grades was 0.844 for rounded opacities (p<0.01). ICOERD readings from HRCT scans correlated well with previously validated ILO/ICRP criteria. The ICOERD adequately detects pneumoconiotic micronodules and can be used for the interpretation of pneumoconiosis. PMID- 25810445 TI - Flow characteristics of an inclined air-curtain range hood in a draft. AB - The inclined air-curtain technology was applied to build an inclined air-curtain range hood. A draft generator was applied to affect the inclined air-curtain range hood in three directions: lateral (theta=0 degrees ), oblique (theta=45 degrees ), and front (theta=90 degrees ). The three suction flow rates provided by the inclined air-curtain range hood were 10.1, 10.9, and 12.6 m(3)/min. The laser-assisted flow visualization technique and the tracer-gas test method were used to investigate the performance of the range hood under the influence of a draft. The results show that the inclined air-curtain range hood has a strong ability to resist the negative effect of a front draft until the draft velocity is greater than 0.5 m/s. The oblique draft affected the containment ability of the inclined air-curtain range hood when the draft velocity was larger than 0.3 m/s. When the lateral draft effect was applied, the capture efficiency of the inclined air-curtain range hood decreased quickly in the draft velocity from 0.2 m/s to 0.3 m/s. However, the capture efficiencies of the inclined air-curtain range hood under the influence of the front draft were higher than those under the influence of the oblique draft from 0.3 m/s to 0.5 m/s. PMID- 25810446 TI - Stakeholders' perception of the possible implications of "green jobs" for health and safety at work in Italy. AB - Despite all the emphasis laid today on the green economy, occupational health and safety (OHS) issues have still been talked only limitedly, as already noted in previous studies and literature reviews. The Department of Occupational and Environmental Medicine, Epidemiology and Hygiene of the Italian Workers' Compensation Authority (INAIL) has conducted a survey among some Italian stakeholders, social partners, institutions and "green" businesses to gather their perceptions of the potential effects of green jobs on OHS, particularly in the renewable energy sector. The survey involved a sample of 61 stakeholders in the following categories: institutions (11), trade unions (11), employers' organizations (13), businesses (11), research (15). Participation in this survey of national stakeholders who have a central role in the development and management of policies on renewable energy and OHS, allowed to analyze in depth the fundamental aspects for a fair transition towards green economy. Also, the good agreement among respondents brought to light quite clearly the main critical points as regards the OHS implications of green work in Italy, and pointed to the principal policies to be adopted to safeguard workers' health and safety. PMID- 25810447 TI - Musculoskeletal disorders in the teaching profession: an emerging workplace hazard with significant repercussions for developing countries. PMID- 25810448 TI - Can a self-administered questionnaire identify workers with chronic or recurring low back pain? AB - To verify if the Nordic Musculoskeletal Questionnaire (NMQ), Visual Analogue Scale (VAS), Roland-Morris Disability Questionnaire (RDQ) and physical examination of the lumbar spine can identify workers with chronic or recurring low back pain, using health history for reference. Fifty office workers of both sexes, aged between 19 and 55 yr, were evaluated using a standardized physical examination and the NMQ, VAS and RDQ. Discriminant analysis was performed to determine the discriminant properties of these instruments. A higher success rate (94%) was observed in the model including only the NMQ and in the model including the NMQ and the physical examination. The lowest success rate (82%) was observed in the model including the NMQ, RDQ and VAS. The NMQ was able to detect subjects with chronic or recurring low back pain with 100% sensitivity and 88% specificity. The NMQ appears to be the best instrument for identifying subjects with chronic or recurring low back pain. Thus, this self-reported questionnaire is suitable for screening workers for chronic or recurring low back pain in occupational settings. PMID- 25810449 TI - Design of a cluster-randomized trial of electronic health record-based tools to address overweight and obesity in primary care. AB - BACKGROUND: Primary care providers often fail to identify patients who are overweight or obese or discuss weight management with them. Electronic health record-based tools may help providers with the assessment and management of overweight and obesity. PURPOSE: We describe the design of a trial to examine the effectiveness of electronic health record-based tools for the assessment and management of overweight and obesity among adult primary care patients, as well as the challenges we encountered. METHODS: We developed several new features within the electronic health record used by primary care practices affiliated with Brigham and Women's Hospital in Boston, MA. These features included (1) reminders to measure height and weight, (2) an alert asking providers to add overweight or obesity to the problem list, (3) reminders with tailored management recommendations, and (4) a Weight Management screen. We then conducted a pragmatic, cluster-randomized controlled trial in 12 primary care practices. RESULTS: We randomized 23 clinical teams ("clinics") within the practices to the intervention group (n = 11) or the control group (n = 12). The new features were activated only for clinics in the intervention group. The intervention was implemented in two phases: the height and weight reminders went live on 15 December 2011 (Phase 1), and all of the other features went live on 11 June 2012 (Phase 2). Study enrollment went from December 2011 through December 2012, and follow-up ended in December 2013. The primary outcomes were 6-month and 12-month weight change among adult patients with body mass index >=25 who had a visit at one of the primary care clinics during Phase 2. Secondary outcome measures included the proportion of patients with a recorded body mass index in the electronic health record, the proportion of patients with body mass index >=25 who had a diagnosis of overweight or obesity on the electronic health record problem list, and the proportion of patients with body mass index >=25 who had a follow-up appointment about their weight or were prescribed weight loss medication. LESSONS LEARNED: We encountered challenges in our development of an intervention within the existing structure of an electronic health record. For example, although we decided to randomize clinics within primary care practices, this decision may have introduced contamination and led to some imbalance of patient characteristics between the intervention and control practices. Using the electronic health record as the primary data source reduced the cost of the study, but not all desired data were recorded for every participant. CONCLUSION: Despite the challenges, this study should provide valuable information about the effectiveness of electronic health record-based tools for addressing overweight and obesity in primary care. PMID- 25810450 TI - Understanding the Role of Context-Specific Drinking in Neglectful Parenting Behaviors. AB - AIMS: Child neglect is the most common form of child maltreatment, yet little is known about how drinking context may be related to particular subtypes of child neglect. This study examines the relationship between parental drinking in multiple contexts and the use of supervisory and physical neglectful. METHODS: A sample of 2152 parents of children 12 years or younger in 50 cities in California was obtained using a computer-assisted telephone interview. Past-year prevalence of child neglect was measured using the Multidimensional Neglectful Behavior Scale. Information was collected on past month or past-year frequency of having at least one drink in five contexts, continued drinking measures (e.g. number of drinks after the first drink) and sociodemographics. Data were analyzed using multilevel random effects logit models. RESULTS: Frequency of drinking in various contexts was related to different neglect subtypes. Specifically, frequency of drinking with friends was positively related leaving a child home alone when an adult should be present. Parents who drank more frequently with family were less likely to leave their child home alone in the past year yet more likely to unsafely monitor their child in the past year. Drinking at parties more often was related to being more likely to leave a child alone in a car sometime during the past year. CONCLUSIONS: That no single drinking context is universally problematic for supervisory and physical neglect suggests that different social mechanisms may underlie the relationships observed between different drinking contexts and neglect subtypes. PMID- 25810451 TI - EphB2 and EphB3 play an important role in the lymphoid seeding of murine adult thymus. AB - Adult thymuses lacking either ephrin type B receptor 2 (EphB2) or EphB3, or expressing a truncated form of EphB2, the forward signal-deficient EphB2LacZ, have low numbers of early thymic progenitors (ETPs) and are colonized in vivo by reduced numbers of injected bone marrow (BM) lineage-negative (Lin(-)) cells. Hematopoietic progenitors from these EphB mutants showed decreased capacities to colonize wild type (WT) thymuses compared with WT precursors, with EphB2(-/-) cells exhibiting the greatest reduction. WT BM Lin(-) cells also showed decreased colonizing capacity into mutant thymuses. The reduction was also more severe in EphB2(-/-) host thymuses, with a less severe phenotype in the EphB2LacZ thymus. These results suggest a major function for forward signaling through EphB2 and, to a lesser extent, EphB3, in either colonizing progenitor cells or thymic stromal cells, for in vivo adult thymus recruitment. Furthermore, the altered expression of the molecules involved in thymic colonization that occurs in the mutant thymus correlates with the observed colonizing capacities of different mutant mice. Reduced production of CCL21 and CCL25 occurred in the thymus of the 3 EphB-deficient mice, but their expression, similar to that of P-selectin, on blood vessels, the method of entry of progenitor cells into the vascular thymus, only showed a significant reduction in EphB2(-/-) and EphB3(-/-) thymuses. Decreased migration into the EphB2(-/-) thymuses correlated also with reduced expression of both ephrinB1 and ephrinB2, without changes in the EphB2LacZ thymuses. In the EphB3(-/-) thymuses, only ephrinB1 expression appeared significantly diminished, confirming the relevance of forward signals mediated by the EphB2-ephrinB1 pair in cell recruitment into the adult thymus. PMID- 25810452 TI - Assessing the robustness of power posing: no effect on hormones and risk tolerance in a large sample of men and women. PMID- 25810453 TI - Social influence on risk perception during adolescence. AB - Adolescence is a period of life in which peer relationships become increasingly important. Adolescents have a greater likelihood of taking risks when they are with peers rather than alone. In this study, we investigated the development of social influence on risk perception from late childhood through adulthood. Five hundred and sixty-three participants rated the riskiness of everyday situations and were then informed about the ratings of a social-influence group (teenagers or adults) before rating each situation again. All age groups showed a significant social-influence effect, changing their risk ratings in the direction of the provided ratings; this social-influence effect decreased with age. Most age groups adjusted their ratings more to conform to the ratings of the adult social-influence group than to the ratings of the teenager social-influence group. Only young adolescents were more strongly influenced by the teenager social-influence group than they were by the adult social-influence group, which suggests that to early adolescents, the opinions of other teenagers about risk matter more than the opinions of adults. PMID- 25810454 TI - Effects of Hydroxy Groups in the A-Ring on the Anti-proteasome Activity of Flavone. AB - The ubiquitin-proteasome pathway plays an important role in regulating apoptosis and the cell cycle. Recently, proteasome inhibitors have been shown to have antitumor effects and have been used in anticancer therapy for several cancers such as multiple myeloma. Although some flavones, such as apigenin, chrysin and luteolin, have a specific role in the inhibition of proteasome activity and induced apoptosis in some reports, these findings did not address all flavone types. To further investigate the proteasome-inhibitory mechanism of flavonoids, we examined the inhibitory activity of 5,6,7-trihydroxyflavone, baicalein and 5,6,7,4'-tetrahydroxyflavone, scutellarein on extracted proteasomes from mice and cancer cells. Unlike the other flavones, baicalein and scutellarein did not inhibit proteasome activity or accumulate levels of ubiquitinated proteins. These results indicate that flavones with hydroxy groups at positions 5, 6 and 7 of the A-ring lack the anti-proteasome function. PMID- 25810456 TI - Lifetime risk: childhood obesity and cardiovascular risk. AB - In a recent report, the worldwide prevalence of childhood obesity was estimated to have increased by 47% between 1980 and 2013. As a result, substantial concerns have been raised about the future burden of cardiovascular (CV) disease that could ensue. The purpose of this review is to summarize and interpret (i) the evidence linking early life obesity with adverse changes in CV structure and function in childhood, (ii) the lifetime risk for CV disease resulting from obesity in childhood, and (iii) the potential effects of lifestyle interventions in childhood to ameliorate these risks. PMID- 25810455 TI - Phenotype-driven chemical screening in zebrafish for compounds that inhibit collective cell migration identifies multiple pathways potentially involved in metastatic invasion. AB - In the last decade, high-throughput chemical screening has become the dominant approach for discovering novel compounds with therapeutic properties. Automated screening using in vitro or cultured cell assays have yielded thousands of candidate drugs for a variety of biological targets, but these approaches have not resulted in an increase in drug discovery despite major increases in expenditures. In contrast, phenotype-driven screens have shown a much stronger success rate, which is why we developed an in vivo assay using transgenic zebrafish with a GFP-marked migrating posterior lateral line primordium (PLLp) to identify compounds that influence collective cell migration. We then conducted a high-throughput screen using a compound library of 2160 annotated bioactive synthetic compounds and 800 natural products to identify molecules that block normal PLLp migration. We identified 165 compounds that interfere with primordium migration without overt toxicity in vivo. Selected compounds were confirmed in their migration-blocking activity by using additional assays for cell migration. We then proved the screen to be successful in identifying anti-metastatic compounds active in vivo by performing orthotopic tumor implantation assays in mice. We demonstrated that the Src inhibitor SU6656, identified in our screen, can be used to suppress the metastatic capacity of a highly aggressive mammary tumor cell line. Finally, we used CRISPR/Cas9-targeted mutagenesis in zebrafish to genetically validate predicted targets of compounds. This approach demonstrates that the migrating PLLp in zebrafish can be used for large-scale, high-throughput screening for compounds that inhibit collective cell migration and, potentially, anti-metastatic compounds. PMID- 25810458 TI - Epidemiology's continuing contribution to public health: The power of "Then and Now". AB - The 47th annual meeting of the Society for Epidemiologic Research hosted 17 invited speakers charged by the Executive Committee with presenting some of the many ways that epidemiologists have improved the health of the general population. There were 9 "Then and Now" sessions that were structured to focus on how early epidemiologists overcame research hurdles and advanced health through innovative strategies. For most topics, a longstanding expert was paired with an excellent contemporary epidemiologist working in the area, and both were given the freedom to deliver an integrated story about epidemiology's temporal role in protecting and promoting public health. Epidemiologic discoveries in cardiovascular, cancer, and perinatal epidemiology were discussed on day 1, followed by discussions of accomplishments in reducing exposures that adversely impact health (nutrition, environment/occupation, and tobacco use) on day 2. Topics with relevancy for many aspects of epidemiology were presented on day 3, including infectious diseases, social forces, and causal thinking in epidemiologic research. Given the large number of outstanding senior and junior epidemiologists that attended the meeting, choosing speakers was a unique challenge. What became evident from all sessions was the passion that epidemiologists have for population health, tempered with concerns for remaining true to epidemiologic principles, the timely adoption of innovative methods, and the responsible interpretation of research findings. PMID- 25810457 TI - Overweight and Obesity in Midlife and Brain Structure and Dementia 26 Years Later: The AGES-Reykjavik Study. AB - High adiposity in midlife might increase risk for late-life brain pathology, including dementia. Using data from the prospective Age, Gene/Environment Susceptibility-Reykjavik Study of men and women (born 1907-1935), we studied the associations of overweight and obesity at midlife (mean age, 50 (standard deviation, 4.7) years) with 1.5-T brain magnetic resonance imaging measures of infarct-like brain lesions, cerebral microbleeds, total brain volume, and white matter lesions volume, as well as dementia, in late life (mean age, 76 (standard deviation, 5.2) years). We used linear and Poisson models to estimate associations in 3,864 persons after adjustment for sociodemographic, health, and lifestyle characteristics. In midlife, the prevalence of overweight was 39% and that of obesity was 8%. After a mean follow-up of 26.2 (standard deviation, 4.9) years, midlife overweight and obesity were not associated with infarct-like brain lesions (relative risk (RR) = 0.82, 95% confidence interval (CI): 0.61, 1.10), cerebral microbleeds (RR = 0.69, 95% CI: 0.37, 1.32), total brain volume (beta = 0.05, 95% CI: -0.34, 0.45), white matter lesions volume (beta = -0.10, 95% CI: 0.20, 0.01), or dementia (RR = 0.91, 95% CI: 0.49, 1.72) compared with normal weight. These findings do not support the hypothesis that high body mass index in midlife modulates the risk for dementia. PMID- 25810459 TI - Resection Arthroplasty for Resistant Ulcers Underlying the Hallux in Insensate Diabetics. AB - BACKGROUND: Foot ulcers carry considerable morbidity in patients with peripheral neuropathy and frequently lead to foot amputation. The purpose of this study was to present our experience treating recalcitrant ulcers underlying the hallux interphalangeal joint in patients with diabetes mellitus (DM)-related neuropathy with a first metatarsophalangeal (MTPJ1) resection arthroplasty. METHODS: We retrospectively reviewed the computerized medical files of patients with diabetic neuropathy treated with a MTPJ1 resection arthroplasty. We performed 28 arthroplasties on 20 patients with a mean age of 59 years. The patients had a diagnosis of DM for a mean of 10.7 years. Of the ulcers, 26 were grade 1A ulcers, and 2 were grade 2A ulcers (University of Texas score); the ulcer's mean age was 5.4 months. The mean dorsiflexion of the hallux before surgery was 46 degrees. RESULTS: The primary ulcer recovered in a mean of 3.1 weeks. Major complications (wound dehiscence and infection) occurred in 6 of 28 operations. Patients returned to normal activity 4 weeks after all procedures except in the 6 patients with dehiscence. In a subgroup of patients with follow-up longer than a year, the ulcer recurred after 4 of 18 arthroplasties (22%) between 3 and 12 months due to postoperative hallux rigidus. In the remaining 14 of 18 arthroplasties (78%), there was no recurrence during a mean follow-up of 26 months. CONCLUSION: MTPJ1 resection arthroplasty may be considered in a patient with resistant plantar hallux ulcerations, even in the absence of hallux rigidus. As with all operations on neuropathic feet in patients with DM, the surgeon and the patient should be aware that there is a significant likelihood of complications, but most are treatable. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25810460 TI - Nonunion Risk Assessment in Foot and Ankle Surgery: Proposing a Predictive Risk Assessment Model. AB - BACKGROUND: Nonunion risk factor identification and modification are subjective. We describe and validate a predictive nonunion risk factor model to identify foot and ankle operative patients at risk for nonunion. MATERIALS AND METHODS: One hundred international experts in foot and ankle surgery were surveyed. Nineteen nonunion risk factors were stratified into 3 categories: more significant than, as significant as, and less significant than smoking 1 pack per day. A nonunion risk assessment model was developed by assigning a weighted score to each risk factor, based on its mean score from the survey. A total nonunion risk (TNR) score was calculated for individual patients. It was retrospectively validated in 2 patient cohorts from a single center's prospectively collected end-stage ankle arthritis patient database: 22 cases of ankle and/or hindfoot fusion nonunion and 40 sex- and procedure-matched controls with bony fusion. Analyses included descriptive statistics, logistic regression, and univariate and multivariate linear regression models. RESULTS: The mean TNR score was 6.6 +/- 5.6 in controls and 13.5 +/- 8.2 in the nonunion group (P < .001). Data showed excellent intraobserver and interobserver correlation coefficients. In a logistic regression model, the risk of nonunion exceeded 9% with a TNR score greater than or equal to 10. Multivariate linear regression analysis, adjusted for age and sex, suggested that lack of fusion site stability and obesity (body mass index greater than 30) were significantly predictive of nonunion. CONCLUSION: The nonunion risk assessment model provides a reliable, sensitive, and specific method for predicting nonunion based on objective patient assessment. Orthopaedic patients at risk for nonunion could benefit from targeted intervention. LEVEL OF EVIDENCE: Level IV, retrospective observational study. PMID- 25810461 TI - Radiographic Outcomes Following Lateral Column Lengthening With a Porous Titanium Wedge. AB - BACKGROUND: Lateral column lengthening (LCL) is commonly utilized in treating stage II posterior tibialis tendon dysfunction. This study aimed to analyze the outcomes of LCL with porous titanium wedges compared to historic controls of iliac crest autograft and allograft. We hypothesized that the use of a porous titanium wedge would have radiographic improvement and union rates similar to those with the use of autograft and allograft in LCL. METHODS: Between May 2009 and May 2014, 28 feet in 26 patients were treated with LCL using a porous titanium wedge. Of the 26 patients, 9 were males (34.6%). The average age for males was 43 years (range, 17.9-58.7), 48.7 years (range, 21-72.3) for females. Mean follow-up was 14.6 months. Radiographs were examined for correction of the flatfoot deformity and forefoot abduction. All complications were noted. RESULTS: Radiographically, the patients had a significant deformity correction in the anteroposterior talo-first metatarsal angle, talonavicular coverage angle, lateral talo-first metatarsal angle, and calcaneal pitch. All but 1 patient (96%) had bony incorporation of the porous titanium wedge. The average preoperative visual analog scale pain score was 5; all patients but 3 (12%) had improvements in their pain score, with a mean change of 3.4. CONCLUSION: LCL with porous titanium had low nonunion rates, improved radiographic correction, and pain relief. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25810462 TI - Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the Hypopituitary Control and Complications Study. AB - OBJECTIVE: Speculation remains that GH treatment is associated with increased neoplasia risk. Studies in GH-treated childhood cancer survivors suggested higher rates of second neoplasms, while cancer risk data for GH-treated and untreated hypopituitary adults have been variable. We present primary cancer risk data from the Hypopituitary Control and Complications Study (HypoCCS) with a focus on specific cancers, and assessment of recurrence rates for pituitary adenomas (PA) and craniopharyngiomas (CP). DESIGN: Incident neoplasms during HypoCCS were evaluated in 8418 GH-treated vs 1268 untreated patients for primary malignancies, 3668 GH-treated vs 720 untreated patients with PA history, and 956 GH-treated vs 102 untreated patients with CP history. METHODS: Using population cancer rates, standardised incidence ratios (SIRs) were calculated for all primary cancers, breast, prostate, and colorectal cancers. Neoplasm rates in GH-treated vs untreated patients were analysed after propensity score adjustment of baseline treatment group imbalances. RESULTS: During mean follow-up of 4.8 years, 225 primary cancers were identified in GH-treated patients, with SIR of 0.82 (95% CI 0.71-0.93). SIRs (95% CI) for GH-treated patients were 0.59 (0.36-0.90) for breast, 0.80 (0.57-1.10) for prostate, and 0.62 (0.38-0.96) for colorectal cancers. Cancer risk was not statistically different between GH-treated and untreated patients (relative risk (RR)=1.00 (95% CI 0.70-1.41), P=0.98). Adjusted RR for recurrence was 0.91 (0.68-1.22), P=0.53 for PA and 1.32 (0.53-3.31), P=0.55 for CP. CONCLUSIONS: There was no increased risk for all-site cancers: breast, prostate or colorectal primary cancers in GH-treated patients during HypoCCS. GH treatment did not increase the risk of PA and CP recurrences. PMID- 25810464 TI - Between My Body and My "Dead Body": Narratives of Coma. AB - This article is based on narrative research that focuses on corporeal experience during coma and during the rehabilitation process. Seventeen participants from different areas of Israel who had been in various kinds of coma states reveal what the corporeal experience of coma is. The participants are divided into three types of narrative protagonists--"dead-alive," "rational," and "emissaries." Each of the participants redefined the boundaries of the body, especially in cases when they spoke of experiences they did not understand as corporeal, for example, out-of-body experiences, near-death experiences, or experiences of being between the earthly and unearthly. Their struggle to find suitable words to tell their coma stories emphasizes these boundaries between experiencing and telling, which crossed the normative discursive border of the medical establishment and illustrates the ambiguous nature of human existence. PMID- 25810465 TI - Shame and Gender Differences in Paths to Youth Suicide: Parents' Perspective. AB - Risk factors, suicidal behavior, and help-seeking patterns differ between young women and men. We constructed a generic conceptual model of the processes underlying youth suicide, grounded in 78 interviews with parents in 52 consecutive cases of suicide (19 women, 33 men) identified at forensic medical autopsy and compared by sex. We found different forms of shame hidden behind gender-specific masks, as well as gender differences in their paths to suicide. Several interacting factors formed negative feedback loops. Finding no way out, the young persons looked for an "emergency exit." Signs and preparations could be observed at different times but recognized only in retrospect. Typically, the young persons and their parents asked for professional help but did not receive the help they needed. We discuss parents' experiences from the theoretical perspective on gender identity and developmental breakdown. Giving voice to the parents' tacit knowledge can contribute to better prevention and treatment. PMID- 25810466 TI - Maximizing Theoretical Contributions of Participant Observation While Managing Challenges. AB - Participant observation (PO) is an important method of data collection used in a variety of research methodologies. PO can inform theory development by providing understanding of participants' behaviors and the contexts that influence their behaviors. Because theory development is important in grounded theory studies, we emphasize theoretical contributions of PO while interrogating the challenges of using PO, in particular, attending to informed consent. We use the exemplar of a mid-range theory about nursing practice with hospitalized older adults to highlight contributions of PO to category development. While acknowledging theoretical contributions, we explore challenges entailed in observations where consenting participants interact with vulnerable patients and a changing cast of health care professionals in dynamic contexts. Reflexivity about interactions with vulnerable individuals, as well as other actions to avoid compromising voluntary consent, enhances contributions of PO. PMID- 25810463 TI - Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient-derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1-related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7-10 mouse-to-mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor-orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well-characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine. PMID- 25810467 TI - Health as Submission and Social Responsibilities: Embodied Experiences of Javanese Women With Type II Diabetes. AB - By examining women's experiences with type II diabetes, we explore how illness can provide resources to construct meanings of everyday life in Javanese culture. We conducted in-depth interviews with 30 female participants in Central Java, Indonesia, and adopted grounded theory for data analysis. We identified four themes that diabetes serves as resources for women in Indonesia to (a) normalize suffering, (b) resist social control, (c) accept fate, and (d) validate faith. We concluded by noting three unique aspects of Javanese women's illness management. First, through the performance of submission, our participants demonstrated spirituality and religiosity as essential elements of health. Second, diabetes empowers individuals in everyday suffering through two divergent processes: embracing submission and resisting control. Finally, diabetes provides opportunities for individuals within a social network to (re)negotiate social responsibilities. In summary, diabetes provides unique resources to empower our participants to obtain voices that they otherwise would not have had. PMID- 25810468 TI - Alexithymia, emotional dysregulation, and recovery from alcoholism: therapeutic response to assessment of mood. AB - This study is a secondary analysis of a randomized controlled trial that tested the effects of a gratitude intervention on well-being in a sample of individuals in outpatient treatment for alcohol use disorder (AUD). Follow-up qualitative interviews unexpectedly revealed that participants found the Positive and Negative Affect Schedule (PANAS) to be helpful to their recovery in the ways that it asked them to identify and rate their emotions. Participant statements were purposively sampled and analyzed using grounded theory methods to produce a conceptual framework illustrating the process of mood identification and its sequelae. Evidence of existing alexithymia and emotional dysregulation, dominance of negative mood, and increasing ability to identify, accept, and regulate mood as part of recovery was found. Findings suggest that emotion regulation is a compelling topic for those in recovery from AUD, and may deserve a more prominent role in treatment. PMID- 25810469 TI - A Process Evaluation of an Efficacious Family-Based Intervention to Promote Healthy Eating: The Entre Familia: Reflejos de Salud Study. AB - Entre Familia: Reflejos de Salud was a successful family-based randomized controlled trial designed to improve dietary behaviors and intake among U.S. Latino families, specifically fruit and vegetable intake. The novel intervention design merged a community health worker (promotora) model with an entertainment education component. This process evaluation examined intervention implementation and assessed relationships between implementation factors and dietary change. Participants included 180 mothers randomized to an intervention condition. Process evaluation measures were obtained from participant interviews and promotora notes and included fidelity, dose delivered (i.e., minutes of promotora in-person contact with families, number of promotora home visits), and dose received (i.e., participant use of and satisfaction with intervention materials). Outcome variables included changes in vegetable intake and the use of behavioral strategies to increase dietary fiber and decrease dietary fat intake. Participant satisfaction was high, and fidelity was achieved; 87.5% of families received the planned number of promotora home visits. In the multivariable model, satisfaction with intervention materials predicted more frequent use of strategies to increase dietary fiber (p <= .01). Trends suggested that keeping families in the prescribed intervention timeline and obtaining support from other social network members through sharing of program materials may improve changes. Study findings elucidate the relationship between specific intervention processes and dietary changes. PMID- 25810470 TI - The Collective Impact Model and Its Potential for Health Promotion: Overview and Case Study of a Healthy Retail Initiative in San Francisco. AB - As resources for health promotion become more constricted, it is increasingly important to collaborate across sectors, including the private sector. Although many excellent models for cross-sector collaboration have shown promise in the health field, collective impact (CI), an emerging model for creating larger scale change, has yet to receive much study. Complementing earlier collaboration approaches, CI has five core tenets: a shared agenda, shared measurement systems, mutually reinforcing activities, continuous communication, and a central infrastructure. In this article, we describe the CI model and its key dimensions and constructs. We briefly compare CI to community coalition action theory and discuss our use of the latter to provide needed detail as we apply CI in a critical case study analysis of the Tenderloin Healthy Corner Store Coalition in San Francisco, California. Using Yin's multimethod approach, we illustrate how CI strategies, augmented by the community coalition action theory, are being used, and with what successes or challenges, to help affect community- and policy-level change to reduce tobacco and alcohol advertising and sales, while improving healthy, affordable, and sustainable food access. We discuss the strengths and weaknesses of CI as a framework for health promotion, as well as the benefits, challenges, and initial outcomes of the healthy retail project and its opportunities for scale-up. Implications for health promotion practice and research also are discussed. PMID- 25810473 TI - Diagnosing spermatogonial stemness. PMID- 25810472 TI - Protein arginine methyltransferase 5 (Prmt5) is required for germ cell survival during mouse embryonic development. AB - In mammals, germ cells undergo massive epigenetic remodeling during fetal development. However, the physiological functions of epigenetic modification in germ cell development remain unclear. In this study, we found that protein arginine methyltransferase 5 (Prmt5) was abundantly expressed in the germ cells of both male and female gonads. Deletion of Prmt5 by crossing with Tnap-Cre mice resulted in germ cell depletion in adult mice. Germ cell loss was first observed between Embryonic Days 12.5 and 13.5 (E12.5 and E13.5), and very few of these cells remained at birth. Oct4, Sox2, and Nanog were abundantly expressed in Prmt5 deficient germ cells at E13.5 and E15.5, whereas the expression of these genes was dramatically decreased in control germ cells. Interestingly, the expression of meiosis-associated genes was virtually absent in Prmt5-deficient female germ cells at E13.5, whereas the expression of other germ cell-specific genes was not changed. Further study revealed that H4R3me2s was completely absent after Prmt5 inactivation, whereas the level of H3R2me2s was not changed in Prmt5-deficient germ cells. Collectively, this study demonstrated that Prmt5 plays critical roles in germ cell development that are required for germ cell survival during embryonic stages. PMID- 25810475 TI - Retinoid acid: the trigger for the cycle of the seminiferous epithelium in the adult testis? PMID- 25810471 TI - Early life exposure to undernutrition induces ER stress, apoptosis, and reduced vascularization in ovaries of adult rat offspring. AB - Maternal nutritional restriction has been shown to induce impairments in a number of organ systems including the ovary. We have previously shown that maternal undernutrition induces fetal growth restriction and low birth weight, and results in an offspring ovarian phenotype characteristic of premature ovarian aging with reduced ovarian reserve. In the present study, we set out to investigate the underlying mechanisms that lead offspring of undernourished mothers to premature ovarian aging. Pregnant dams were randomized to 1) a standard diet throughout pregnancy and lactation (control), 2) a calorie-restricted (50% of control) diet during pregnancy, 3) a calorie-restricted (50% of control) diet during pregnancy and lactation, or 4) a calorie-restricted (50% of control) diet during lactation alone. The present study shows that early life undernutrition-induced reduction of adult ovarian follicles may be mediated by increased ovarian endoplasmic reticulum stress in a manner that increased follicular apoptosis but not autophagy. These changes were associated with a loss of ovarian vessel density and are consistent with an accelerated ovarian aging phenotype. Whether these changes are mediated specifically by a reduction in the local antioxidant environment is unclear, although our data suggest the possibility that ovarian melatonin may play a part in early life nutritional undernutrition and impaired offspring folliculogenesis. PMID- 25810476 TI - Activation of Mouse Cumulus-Oocyte Complex Maturation In Vitro Through EGF-Like Activity of Versican. AB - In vitro maturation of oocytes is suboptimal to in vivo maturation with altered gene expression and compromised oocyte quality. The large proteoglycan versican is abundant in mouse cumulus-oocyte complexes (COCs) matured in vivo but is absent in cultured COCs. Versican is also positively correlated with human oocyte quality. Versican contains an epidermal growth factor (EGF) motif, and based on EGF-like activities in other systems we hypothesized that versican acts as an EGF like signaling factor during COC maturation. Here, we purified recombinant versican and compared its function with that of EGF during in vitro maturation (IVM). Versican significantly increased cumulus expansion and induced cumulus specific genes Ptgs2, Tnfaip6, and Has2, which was blocked by EGF receptor antagonist. Microarray analysis revealed that versican has overlapping function with EGF; however, a subset of genes was uniquely altered following 6 h of IVM with either treatment. Following 6 h of IVM, both Areg and Ereg were significantly increased by both treatments, whereas Egln3, Nr4a1, Nr4a2, Nr4a3, and Adamts5 were significantly higher following versican treatment compared with EGF. In contrast, Sprr1a and Aqp3 were increased after 6 h of EGF but not versican treatment. To determine whether there were temporal differences, COCs were cultured with EGF or versican for 0-12 h. Versican-induced expression occurred later but remained elevated for longer compared with EGF for Ptgs2, Ereg, and Nr4a3. The unique expression profiles of Aqp3 and Nr4a3 during IVM were similarly regulated in vivo. These data indicate that versican has EGF-like effects on COC gene expression, but with distinct temporal characteristics. PMID- 25810474 TI - Challenges and Potential for Ovarian Preservation with SERMs. AB - Tamoxifen (TAM) is a selective estrogen receptor modulator with tissue-specific effects on estrogen signaling used predominantly for treatment and chemoprevention of breast cancers. Recent studies have shown that TAM prevents infertility and decreases follicular loss from common cancer chemotherapy and radiation therapy in preclinical models. Here we review current and novel uses of selective estrogen receptor modulator s and advantages and challenges for translation of TAM for human fertility preservation. PMID- 25810478 TI - What Sexual Recidivism Rates Are Associated With Static-99R and Static-2002R Scores? AB - Empirical actuarial risk tools are routinely used to assess the recidivism risk of adult sexual offenders. Compared with other forms of risk assessment, one advantage of actuarial risk tools is that they provide recidivism rate estimates. Previous research, however, suggests that there is considerable variability in the recidivism rates associated with the most commonly used sexual offender risk assessment tools (Static-99/R, Static-2002/R). The current study examined the extent to which the variability in the recidivism rates across 21 Static-99R studies (N = 8,805) corresponded to the normative groups proposed by the STATIC development group (routine, treatment, high risk/high need). We found strong evidence that routine (i.e., complete) samples were, on average, less likely to reoffend with a sexual offense than offenders in the high-risk/high-need samples (i.e., those explicitly preselected on risk-relevant variables external to STATIC scales). The differences between routine/complete and high-risk/high-need samples, however, were only consistently observed for offenders with low or moderate scores; for offenders with high STATIC scores, the 5-year sexual recidivism rates for these two groups were not meaningfully different. There was only limited evidence to support treatment samples as a distinct sample type; consequently, the use of separate normative tables for treatment samples is not recommended. The current results reinforce the value of regularly updating the norms for empirical actuarial risk tools. Options are discussed on how STATIC scores could be used to inform recidivism rates estimates in applied assessments. PMID- 25810479 TI - Early glucose variability in cardiogenic shock following acute myocardial infarction: a pilot study. AB - BACKGROUND: No data are so far available on the association between glycaemic variability and outcomes in patients with cardiogenic shock (CS) following ST elevation myocardial infarction (STEMI). METHODS: We assessed the relationship between glycaemic variability and mortality, both short term and long term, in 67 consecutive patients with cardiogenic shock following STEMI admitted to our Intensive Cardiac Care Unit. Glycaemic variability was measured in the first 48 h by means of standard deviation (SD) of glucose values and the mean absolute glucose change per hour (MAGC) defined as the sum of all absolute glucose change divided by the time in hours. RESULTS: Lower glycaemic variability was observed in survivors when compared with nonsurvivors, as indicated by lower values of SD and MAGC, respectively. In Cox regression analysis, MAGC and SD were independent predictors of death (MAGC: adjusted hazard ratio [HR]: 8.60, 95% confidence interval [CI]: 2.21-33.41, p = 0.002; SD: adjusted HR: 6.64, 95% CI: 1.92-22.99, p = 0.003), as well as peak glycaemia (adjusted HR: 1.95, 95% CI: 1.20-3.15, p = 0.007). CONCLUSIONS: According to our results, in patients with CS following acute myocardial infarction, early glycaemic variability is an independent predictor of mortality. Further studies are needed to confirm our results in larger cohorts and eventually to assess the effect of strategies specifically targeting glucose variability reduction on mortality. PMID- 25810477 TI - Mono(2-ethylhexyl) phthalate accelerates early folliculogenesis and inhibits steroidogenesis in cultured mouse whole ovaries and antral follicles. AB - Humans are ubiquitously exposed to di(2-ethylhexyl) phthalate (DEHP), which is an environmental toxicant present in common consumer products. DEHP potentially targets the ovary through its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, the direct effects of MEHP on ovarian folliculogenesis and steroidogenesis, two processes essential for reproductive and nonreproductive health, are unknown. The present study tested the hypotheses that MEHP directly accelerates early folliculogenesis via overactivation of phosphatidylinositol 3 kinase (PI3K) signaling, a pathway that regulates primordial follicle quiescence and activation, and inhibits the synthesis of steroid hormones by decreasing steroidogenic enzyme levels. Neonatal ovaries from CD-1 mice were cultured for 6 days with vehicle control, DEHP, or MEHP (0.2-20 MUg/ml) to assess the direct effects on folliculogenesis and PI3K signaling. Further, antral follicles from adult CD-1 mice were cultured with vehicle control or MEHP (0.1-10 MUg/ml) for 24 96 h to establish the temporal effects of MEHP on steroid hormones and steroidogenic enzymes. In the neonatal ovaries, MEHP, but not DEHP, decreased phosphatase and tensin homolog levels and increased phosphorylated protein kinase B levels, leading to a decrease in the percentage of germ cells and an increase in the percentage of primary follicles. In the antral follicles, MEHP decreased the mRNA levels of 17alpha-hydroxylase-17,20-desmolase, 17beta-hydroxysteroid dehydrogenase, and aromatase leading to a decrease in testosterone, estrone, and estradiol levels. Collectively, MEHP mediates the effect of DEHP on accelerated folliculogenesis via overactivating PI3K signaling and inhibits steroidogenesis by decreasing steroidogenic enzyme levels. PMID- 25810480 TI - Contrasting effects of strabismic amblyopia on metabolic activity in superficial and deep layers of striate cortex. AB - To probe the mechanism of visual suppression, we have raised macaques with strabismus by disinserting the medial rectus muscle in each eye at 1 mo of age. Typically, this operation produces a comitant, alternating exotropia with normal acuity in each eye. Here we describe an unusual occurrence: the development of severe amblyopia in one eye of a monkey after induction of exotropia. Shortly after surgery, the animal demonstrated a strong fixation preference for the left eye, with apparent suppression of the right eye. Later, behavioral testing showed inability to track or to saccade to targets with the right eye. With the left eye occluded, the animal demonstrated no visually guided behavior. Optokinetic nystagmus was absent in the right eye. Metabolic activity in striate cortex was assessed by processing the tissue for cytochrome oxidase (CO). Amblyopia caused loss of CO in one eye's rows of patches, presumably those serving the blind eye. Layers 4A and 4B showed columns of reduced CO, in register with pale rows of patches in layer 2/3. Layers 4C, 5, and 6 also showed columns of CO activity, but remarkably, comparison with more superficial layers showed a reversal in contrast. In other words, pale CO staining in layers 2/3, 4A, and 4B was aligned with dark CO staining in layers 4C, 5, and 6. No experimental intervention or deprivation paradigm has been reported previously to produce opposite effects on metabolic activity in layers 2/3, 4A, and 4B vs. layers 4C, 5, and 6 within a given eye's columns. PMID- 25810481 TI - Freshly dissociated mature hippocampal astrocytes exhibit passive membrane conductance and low membrane resistance similarly to syncytial coupled astrocytes. AB - Mature astrocytes exhibit a linear current-to-voltage K(+) membrane conductance (passive conductance) and an extremely low membrane resistance (Rm) in situ. The combination of these electrophysiological characteristics establishes a highly negative and stable membrane potential that is essential for basic functions, such as K(+) spatial buffering and neurotransmitter uptake. However, astrocytes are coupled extensively in situ. It remains to be determined whether the observed passive behavior and low Rm are attributable to the intrinsic properties of membrane ion channels or to gap junction coupling in functionally mature astrocytes. In the present study, freshly dissociated hippocampal tissues were used as a new model to examine this basic question in young adult animals. The morphologically intact single astrocytes could be reliably dissociated from animals postnatal day 21 and older. At this animal age, dissociated single astrocytes exhibit passive conductance and resting membrane potential similar to those exhibited by astrocytes in situ. To precisely measure the Rm from single astrocytes, dual-patch single-astrocyte recording was performed. We show that dissociated single astrocytes exhibit a low Rm similarly to syncytial coupled astrocytes. Functionally, the symmetric expression of high-K(+) conductance enabled rapid change in the intracellular K(+) concentrations in response to changing K(+) drive force. Altogether, we demonstrate that freshly dissociated tissue preparation is a highly useful model for study of the functional expression and regulation of ion channels, receptors, and transporters in astrocytes and that passive behavior and low Rm are the intrinsic properties of mature astrocytes. PMID- 25810482 TI - Brain-wide analysis of electrophysiological diversity yields novel categorization of mammalian neuron types. AB - For decades, neurophysiologists have characterized the biophysical properties of a rich diversity of neuron types. However, identifying common features and computational roles shared across neuron types is made more difficult by inconsistent conventions for collecting and reporting biophysical data. Here, we leverage NeuroElectro, a literature-based database of electrophysiological properties (www.neuroelectro.org), to better understand neuronal diversity, both within and across neuron types, and the confounding influences of methodological variability. We show that experimental conditions (e.g., electrode types, recording temperatures, or animal age) can explain a substantial degree of the literature-reported biophysical variability observed within a neuron type. Critically, accounting for experimental metadata enables massive cross-study data normalization and reveals that electrophysiological data are far more reproducible across laboratories than previously appreciated. Using this normalized dataset, we find that neuron types throughout the brain cluster by biophysical properties into six to nine superclasses. These classes include intuitive clusters, such as fast-spiking basket cells, as well as previously unrecognized clusters, including a novel class of cortical and olfactory bulb interneurons that exhibit persistent activity at theta-band frequencies. PMID- 25810483 TI - Direct mapping rather than motor prediction subserves modulation of corticospinal excitability during observation of actions in real time. AB - Motor facilitation refers to the specific increment in corticospinal excitability (CSE) elicited by the observation of actions performed by others. To date, the precise nature of the mechanism at the basis of this phenomenon is unknown. One possibility is that motor facilitation is driven by a predictive process reminiscent of the role of forward models in motor control. Alternatively, motor facilitation may result from a model-free mechanism by which the basic elements of the observed action are directly mapped onto their cortical representations. Our study was designed to discern these alternatives. To this aim, we recorded the time course of CSE for the first dorsal interosseous (FDI) and the abductor digiti minimi (ADM) during observation of three grasping actions in real time, two of which strongly diverged in kinematics from their natural (invariant) form. Although artificially slow movements used in most action observation studies might enhance the observer's discrimination performance, the use of videos in real time is crucial to maintain the time course of CSE within the physiological range of daily actions. CSE was measured at 4 time points within a 240-ms window that best captured the kinematic divergence from the invariant form. Our results show that CSE of the FDI, not the ADM, closely follows the functional role of the muscle despite the mismatch between the natural and the divergent kinematics. We propose that motor facilitation during observation of actions performed in real time reflects the model-free coding of perceived movement following a direct mapping mechanism. PMID- 25810485 TI - Difference in perceptual and oculomotor responses revealed by apparent motion stimuli presented with an interstimulus interval. AB - To understand the mechanisms underlying visual motion analyses for perceptual and oculomotor responses and their similarities/differences, we analyzed eye movement responses to two-frame animations of dual-grating 3f5f stimuli while subjects performed direction discrimination tasks. The 3f5f stimulus was composed of two sinusoids with a spatial frequency ratio of 3:5 (3f and 5f), creating a pattern with fundamental frequency f. When this stimulus was shifted by 1/4 of the wavelength, the two components shifted 1/4 of their wavelengths and had opposite directions: the 5f forward and the 3f backward. By presenting the 3f5f stimulus with various interstimulus intervals (ISIs), two visual-motion-analysis mechanisms, low-level energy-based and high-level feature-based, could be effectively distinguished. This is because response direction depends on the relative contrast between the components when the energy-based mechanism operates, but not when the feature-based mechanism works. We found that when the 3f5f stimuli were presented with shorter ISIs (<100 ms), and 3f component had higher contrast, both perceptual and ocular responses were in the direction of the pattern shift, whereas the responses were reversed when the 5f had higher contrast, suggesting operation of the energy-based mechanism. On the other hand, the ocular responses were almost negligible with longer ISIs (>100 ms), whereas perceived directions were biased toward the direction of pattern shift. These results suggest that the energy-based mechanism is dominant in oculomotor responses throughout ISIs; however, there is a transition from energy-based to feature-tracking mechanisms when we perceive visual motion. PMID- 25810484 TI - Brain oscillatory signatures of motor tasks. AB - Noninvasive brain-computer-interfaces (BCI) coupled with prosthetic devices were recently introduced in the rehabilitation of chronic stroke and other disorders of the motor system. These BCI systems and motor rehabilitation in general involve several motor tasks for training. This study investigates the neurophysiological bases of an EEG-oscillation-driven BCI combined with a neuroprosthetic device to define the specific oscillatory signature of the BCI task. Controlling movements of a hand robotic orthosis with motor imagery of the same movement generates sensorimotor rhythm oscillation changes and involves three elements of tasks also used in stroke motor rehabilitation: passive and active movement, motor imagery, and motor intention. We recorded EEG while nine healthy participants performed five different motor tasks consisting of closing and opening of the hand as follows: 1) motor imagery without any external feedback and without overt hand movement, 2) motor imagery that moves the orthosis proportional to the produced brain oscillation change with online proprioceptive and visual feedback of the hand moving through a neuroprosthetic device (BCI condition), 3) passive and 4) active movement of the hand with feedback (seeing and feeling the hand moving), and 5) rest. During the BCI condition, participants received contingent online feedback of the decrease of power of the sensorimotor rhythm, which induced orthosis movement and therefore proprioceptive and visual information from the moving hand. We analyzed brain activity during the five conditions using time-frequency domain bootstrap-based statistical comparisons and Morlet transforms. Activity during rest was used as a reference. Significant contralateral and ipsilateral event-related desynchronization of sensorimotor rhythm was present during all motor tasks, largest in contralateral-postcentral, medio-central, and ipsilateral-precentral areas identifying the ipsilateral precentral cortex as an integral part of motor regulation. Changes in task-specific frequency power compared with rest were similar between motor tasks, and only significant differences in the time course and some narrow specific frequency bands were observed between motor tasks. We identified EEG features representing active and passive proprioception (with and without muscle contraction) and active intention and passive involvement (with and without voluntary effort) differentiating brain oscillations during motor tasks that could substantially support the design of novel motor BCI-based rehabilitation therapies. The BCI task induced significantly different brain activity compared with the other motor tasks, indicating neural processes unique to the use of body actuators control in a BCI context. PMID- 25810487 TI - Structural constraints on learning in the neural network. AB - Recent research suggests the brain can learn almost any brain-computer interface (BCI) configuration; however, contrasting behavioral evidence from structural learning theory argues that previous experience facilitates, or impedes, future learning. A study by Sadtler and colleagues (Nature 512: 423-426, 2014) used BCI to demonstrate that neural network structural characteristics constrain learning, a finding that might also provide insight into how the brain responds to and recovers after injury. PMID- 25810488 TI - Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). AB - Data on the clinical course of lupus anticoagulant (LA)-positive individuals with or without thrombotic manifestations or pregnancy complications are limited. To investigate mortality rates and factors that might influence mortality, we conducted a prospective observational study of LA-positive individuals. In total, 151 patients (82% female) were followed for a median of 8.2 years; 30 of the patients (20%) developed 32 thromboembolic events (15 arterial and 17 venous events) and 20 patients (13%) died. In univariable analysis, new onset of thrombosis (hazard ratio [HR] = 8.76; 95% confidence interval [CI], 3.46-22.16) was associated with adverse survival. Thrombosis remained a strong adverse prognostic factor after multivariable adjustment for age and hypertension (HR = 5.95; 95% CI, 2.43-14.95). Concomitant autoimmune diseases, anticoagulant treatment at baseline, or positivity for anticardiolipin- or anti-beta2 glycoprotein I antibodies were not associated with mortality. In a relative survival analysis, our cohort of LA positives showed a persistently worse survival in comparison with an age-, sex-, and study-inclusion-year-matched Austrian reference population. The cumulative relative survival was 95.0% (95% CI, 88.5-98.8) after 5 years and 87.7% (95% CI, 76.3-95.6) after 10 years. We conclude that occurrence of a thrombotic event is associated with higher mortality in patients with LA. Consequently, the prevention of thromboembolic events in LA positives might improve survival. PMID- 25810486 TI - Activity-dependent regulation of prestin expression in mouse outer hair cells. AB - Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used Tecta(C1509G) mice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied Tecta(C1509G) mice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment. PMID- 25810489 TI - How I treat priapism. AB - Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic variant, is often associated with devastating complications, notably erectile dysfunction. Because priapism demonstrates high prevalence in patients with hematologic disorders, most commonly sickle cell disease (SCD), there is significant concern for its sequelae in this affected population. Thus, timely diagnosis and management are critical for the prevention or at least reduction of cavernosal tissue ischemia and potential damage consequent to each episode. Current guidelines and management strategies focus primarily on reactive treatments. However, an increasing understanding of the molecular pathophysiology of SCD-associated priapism has led to the identification of new potential therapeutic targets. Future agents are being developed and explored for use in the prevention of priapism. PMID- 25810491 TI - Transcription Factor AP2epsilon: A Potential Predictor of Chemoresistance in Patients With Gastric Cancer. AB - Chemotherapy is a mainstay of therapy for advanced gastric cancer (GC); however, owing to drug resistances, the effectiveness of chemotherapy is not satisfactory for some patients with GC. Therefore, identification of a marker that predicts treatment response is beneficial to patients. Hypermethylation of transcription factor activating enhancer-binding protein 2? (TFAP2E) has been implicated in chemotherapy resistance to fluorouracil-based chemotherapy in patients with colorectal cancer, but its role in GC is still unknown. In this study, we investigated TFAP2E as a predictor of treatment response in GC. We used methylation-sensitive high-resolution melting analysis to study the methylation of TFAP2E in 141 GC tissue specimens and 45 adjacent nontumor tissue specimens. In vitro experiments, we analyzed the expression and methylation of TFAP2E and to examine the sensitivity of GC cell lines to 5-fluorouracil (5-FU). The TFAP2E methylation occurred at a significantly higher incidence rate in tumor tissues compared to adjacent nontumor tissues (chi-square [chi2] = 38.919, P < .001). Hypermethylation of TFAP2E occurred more frequently in tumors with lower differentiation grades (P < .001) and was significantly associated with nonresponse to fluorouracil-based chemotherapy (P = .010). Hypermethylation was also associated with decreased expression of TFAP2E (P < .01) and nonresponse to 5-FU exposure in vitro (P < .001). Hypermethylation of TFAP2E was associated with lack of response to fluorouracil-based chemotherapy, indicating that it might be a potential predictor of treatment response in patients with GC. PMID- 25810490 TI - IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. AB - Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. PMID- 25810493 TI - Colorectal cancer prevention and fishful thinking. PMID- 25810492 TI - Marine omega-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability. AB - BACKGROUND: Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine omega-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive. METHODS: We investigated whether the association between marine omega-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses' Health Study and Health Professionals Follow-up Study. We documented and classified 1125 CRC cases into either MSI-high tumors, in which 30% or more of the 10 microsatellite markers demonstrated instability, or microsatellite-stable (MSS) tumors. Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MSS tumors and MSI-high tumors in relation to marine omega-3 PUFA intake. All statistical tests were two-sided. RESULTS: Marine omega-3 PUFA intake was not associated with overall incidence of CRC. However, a statistically significant difference was detected by MSI status (P heterogeneity = .02): High marine omega-3 PUFA intake was associated with a lower risk of MSI-high tumors (comparing >=0.30g/d with <0.10g/d: multivariable HR = 0.54, 95% CI = 0.35 to 0.83, P linearity = .03) but not MSS tumors (HR = 0.97, 95% CI = 0.78 to 1.20, P linearity = .28). This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status. CONCLUSIONS: High marine omega-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors, suggesting a potential role of omega-3 PUFAs in protection against CRC through DNA mismatch repair. Further research is needed to confirm our findings and elucidate potential underlying mechanisms. PMID- 25810497 TI - UK alcohol industry's "billion units pledge": interim evaluation flawed. PMID- 25810498 TI - Brain damage in American Football. PMID- 25810494 TI - Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression. AB - The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI. PMID- 25810495 TI - The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study. AB - OBJECTIVE: To determine whether higher past exposure to particulate air pollution is associated with prevalent high symptoms of anxiety. DESIGN: Observational cohort study. SETTING: Nurses' Health Study. PARTICIPANTS: 71,271 women enrolled in the Nurses' Health Study residing throughout the contiguous United States who had valid estimates on exposure to particulate matter for at least one exposure period of interest and data on anxiety symptoms. MAIN OUTCOME MEASURES: Meaningfully high symptoms of anxiety, defined as a score of 6 points or greater on the phobic anxiety subscale of the Crown-Crisp index, administered in 2004. RESULTS: The 71,271 eligible women were aged between 57 and 85 years (mean 70 years) at the time of assessment of anxiety symptoms, with a prevalence of high anxiety symptoms of 15%. Exposure to particulate matter was characterized using estimated average exposure to particulate matter <2.5 MUm in diameter (PM2.5) and 2.5 to 10 MUm in diameter (PM2.5-10) in the one month, three months, six months, one year, and 15 years prior to assessment of anxiety symptoms, and residential distance to the nearest major road two years prior to assessment. Significantly increased odds of high anxiety symptoms were observed with higher exposure to PM2.5 for multiple averaging periods (for example, odds ratio per 10 ug/m(3) increase in prior one month average PM2.5: 1.12, 95% confidence interval 1.06 to 1.19; in prior 12 month average PM2.5: 1.15, 1.06 to 1.26). Models including multiple exposure windows suggested short term averaging periods were more relevant than long term averaging periods. There was no association between anxiety and exposure to PM2.5-10. Residential proximity to major roads was not related to anxiety symptoms in a dose dependent manner. CONCLUSIONS: Exposure to fine particulate matter (PM2.5) was associated with high symptoms of anxiety, with more recent exposures potentially more relevant than more distant exposures. Research evaluating whether reductions in exposure to ambient PM2.5 would reduce the population level burden of clinically relevant symptoms of anxiety is warranted. PMID- 25810499 TI - Risks of the unregulated market in human breast milk. PMID- 25810501 TI - Hormesis: umbrella mechanism only for agents present in the environment. PMID- 25810500 TI - Air pollution, stroke, and anxiety. PMID- 25810502 TI - GPs should urge patients to focus on physical activity rather than obesity, say MPs. PMID- 25810503 TI - Stenting increases stroke risk in patients with intracranial stenosis, study shows. PMID- 25810505 TI - Alastair Henderson: Charming theatre enthusiast. PMID- 25810504 TI - Doctors call for long term solutions to pressure on emergency departments. PMID- 25810496 TI - Short term exposure to air pollution and stroke: systematic review and meta analysis. AB - OBJECTIVE: To review the evidence for the short term association between air pollution and stroke. DESIGN: Systematic review and meta-analysis of observational studies DATA SOURCES: Medline, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science searched to January 2014 with no language restrictions. ELIGIBILITY CRITERIA: Studies investigating the short term associations (up to lag of seven days) between daily increases in gaseous pollutants (carbon monoxide, sulphur dioxide, nitrogen dioxide, ozone) and particulate matter (<2.5 um or <10 um diameter (PM2.5 and PM10)), and admission to hospital for stroke or mortality. MAIN OUTCOME MEASURES: Admission to hospital and mortality from stroke. RESULTS: From 2748 articles, 238 were reviewed in depth with 103 satisfying our inclusion criteria and 94 contributing to our meta-estimates. This provided a total of 6.2 million events across 28 countries. Admission to hospital for stroke or mortality from stroke was associated with an increase in concentrations of carbon monoxide (relative risk 1.015 per 1 ppm, 95% confidence interval 1.004 to 1.026), sulphur dioxide (1.019 per 10 ppb, 1.011 to 1.027), and nitrogen dioxide (1.014 per 10 ppb, 1.009 to 1.019). Increases in PM2.5 and PM10 concentration were also associated with admission and mortality (1.011 per 10 MUg/m(3) (1.011 to 1.012) and 1.003 per 10 ug/m(3) (1.002 to 1.004), respectively). The weakest association was seen with ozone (1.001 per 10 ppb, 1.000 to 1.002). Strongest associations were observed on the day of exposure with more persistent effects observed for PM(2.5). CONCLUSION: Gaseous and particulate air pollutants have a marked and close temporal association with admissions to hospital for stroke or mortality from stroke. Public and environmental health policies to reduce air pollution could reduce the burden of stroke. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009225. PMID- 25810506 TI - Axial T2 weighted magnetic resonance image at the level of the lateral ventricles. PMID- 25810507 TI - Target for GPs to diagnose two thirds of dementia cases by April 2015 is likely to be missed. PMID- 25810508 TI - GMC is given power to appeal judgments against doctors that it considers too lenient. PMID- 25810509 TI - Towards an empirically grounded predictive coding account of action understanding. PMID- 25810510 TI - Deep brain stimulation of different pedunculopontine targets in a novel rodent model of parkinsonism. AB - The pedunculopontine tegmental nucleus (PPTg) has been proposed as a target for deep brain stimulation (DBS) in parkinsonian patients, particularly for symptoms such as gait and postural difficulties refractory to dopaminergic treatments. Several patients have had electrodes implanted aimed at the PPTg, but outcomes have been disappointing, with little evidence that gait and posture are improved. The PPTg is a heterogeneous structure. Consequently, exact target sites in PPTg, possible DBS mechanisms, and potential benefits still need systematic investigation in good animal models. We have investigated the role of PPTg in gait, developed a refined model of parkinsonism including partial loss of the PPTg with bilateral destruction of nigrostriatal dopamine neurons that mimics human pathophysiology, and investigated the effect of DBS at different PPTg locations on gait and posture using a wireless device that lets rats move freely while receiving stimulation. Neither partial nor complete lesions of PPTg caused gait deficits, underlining questions raised previously about the status of PPTg as a motor control structure. The effect of DBS in the refined and standard model of parkinsonism were very different despite minimal behavioral differences in nonstimulation control conditions. Anterior PPTg DBS caused severe episodes of freezing and worsened gait, whereas specific gait parameters were mildly improved by stimulation of posterior PPTg. These results emphasize the critical importance of intra-PPTg DBS location and highlight the need to take PPTg degeneration into consideration when modeling parkinsonian symptoms. They also further implicate a role for PPTg in the pathophysiology of parkinsonism. PMID- 25810511 TI - Tau phosphorylation at serine 396 residue is required for hippocampal LTD. AB - Tau is required for the induction of long-term depression (LTD) of synaptic transmission in the hippocampus. Here we probe the role of tau in LTD, finding that an AMPA receptor internalization mechanism is impaired in tau KO mice, and that LTD causes specific phosphorylation at the serine 396 and 404 residues of tau. Surprisingly, we find that phosphorylation at serine 396, specifically, is critical for LTD but has no role in LTP. Finally, we show that tau KO mice exhibit deficits in spatial reversal learning. These findings underscore the physiological role for tau at the synapse and identify a behavioral correlate of its role in LTD. PMID- 25810512 TI - Effects of rTMS of pre-supplementary motor area on fronto basal ganglia network activity during stop-signal task. AB - Stop-signal task (SST) has been a key paradigm for probing human brain mechanisms underlying response inhibition, and the inhibition observed in SST is now considered to largely depend on a fronto basal ganglia network consisting mainly of right inferior frontal cortex, pre-supplementary motor area (pre-SMA), and basal ganglia, including subthalamic nucleus, striatum (STR), and globus pallidus pars interna (GPi). However, causal relationships between these frontal regions and basal ganglia are not fully understood in humans. Here, we partly examined these causal links by measuring human fMRI activity during SST before and after excitatory/inhibitory repetitive transcranial magnetic stimulation (rTMS) of pre SMA. We first confirmed that the behavioral performance of SST was improved by excitatory rTMS and impaired by inhibitory rTMS. Afterward, we found that these behavioral changes were well predicted by rTMS-induced modulation of brain activity in pre-SMA, STR, and GPi during SST. Moreover, by examining the effects of the rTMS on resting-state functional connectivity between these three regions, we showed that the magnetic stimulation of pre-SMA significantly affected intrinsic connectivity between pre-SMA and STR, and between STR and GPi. Furthermore, the magnitudes of changes in resting-state connectivity were also correlated with the behavioral changes seen in SST. These results suggest a causal relationship between pre-SMA and GPi via STR during response inhibition, and add direct evidence that the fronto basal ganglia network for response inhibition consists of multiple top-down regulation pathways in humans. PMID- 25810513 TI - Visual fixation in human newborns correlates with extensive white matter networks and predicts long-term neurocognitive development. AB - Infants are well known to seek eye contact, and they prefer to fixate on developmentally meaningful objects, such as the human face. It is also known, that visual abilities are important for the developmental cascades of cognition from later infancy to childhood. It is less understood, however, whether newborn visual abilities relate to later cognitive development, and whether newborn ability for visual fixation can be assigned to early microstructural maturation. Here, we investigate relationship between newborn visual fixation (VF) and gaze behavior (GB) to performance in visuomotor and visual reasoning tasks in two cohorts with cognitive follow-up at 2 (n = 57) and 5 (n = 1410) years of age. We also analyzed brain microstructural correlates to VF (n = 45) by voxel-based analysis of fractional anisotropy (FA) in newborn diffusion tensor imaging. Our results show that newborn VF is significantly related to visual-motor performance at both 2 and 5 years, as well as to visual reasoning at 5 years of age. Moreover, good newborn VF relates to widely increased FA levels across the white matter. Comparison to motor performance indicated that early VF is preferentially related to visuocognitive development, and that early motor performance relates neither to white matter integrity nor to visuocognitive development. The present findings suggest that newborn VF is supported by brainwide subcortical networks and it represents an early building block for the developmental cascades of cognition. PMID- 25810514 TI - Clathrin-independent trafficking of AMPA receptors. AB - Membrane trafficking of AMPA receptors (AMPARs) is critical for neuronal function and plasticity. Although rapid forms of AMPAR internalization during long-term depression (LTD) require clathrin and dynamin, the mechanisms governing constitutive AMPAR turnover and internalization of AMPARs during slow homeostatic forms of synaptic plasticity remain unexplored. Here, we show that, in contrast to LTD, constitutive AMPAR internalization and homeostatic AMPAR downscaling in rat neurons do not require dynamin or clathrin function. Instead, constitutive AMPAR trafficking is blocked by a Rac1 inhibitor and is regulated by a dynamic nonstructural pool of F-actin. Our findings reveal a novel role for neuronal clathrin-independent endocytosis controlled by actin dynamics and suggest that the interplay between different modes of receptor endocytosis provides for segregation between distinct modes of neuronal plasticity. PMID- 25810515 TI - Cross-recognition of a myelin peptide by CD8+ T cells in the CNS is not sufficient to promote neuronal damage. AB - Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8(+) T cells are frequently found in multiple sclerosis lesions, their distinct role remains controversial because direct signs of cytotoxicity have not been confirmed in vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8(+) T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40-54 (MOG40-54) both in vitro and in vivo. The aim of this study was to investigate whether such cross-recognizing CD8(+) T cells are capable of inducing CNS damage in vivo. Using intravital two-photon microscopy in the mouse model of multiple sclerosis, we detected antigen recognition motility of the OT-1 CD8(+) T cells within the CNS leading to a selective enrichment in inflammatory lesions. However, this cross-reactivity of OT-1 CD8(+) T cells with MOG peptide in the CNS did not result in clinically or subclinically significant damage, which is different from myelin-specific CD4(+) Th17-mediated autoimmune pathology. Therefore, intravital imaging demonstrates that local myelin recognition by autoreactive CD8(+) T cells in inflammatory CNS lesions alone is not sufficient to induce disability or increase axonal injury. PMID- 25810516 TI - Neural mechanisms for discounting head-roll-induced retinal motion. AB - An extensive series of physiological studies in macaques shows the existence of neurons in three multisensory cortical regions, dorsal medial superior temporal area (MSTd), ventral intraparietal area (VIP), and visual posterior sylvian area (VPS), that are tuned for direction of self-motion in both visual and vestibular modalities. Some neurons have congruent direction preferences, suggesting integration of signals for optimum encoding of self-motion trajectory; others have opposite preferences and could be used for discounting retinal motion that arises from perceptually irrelevant head motion. Whether such a system exists in humans is unknown. Here, artificial vestibular stimulation was administered to human participants during fMRI scanning in conjunction with carefully calibrated visual stimulation that emulated either congruent or opposite stimulation conditions. Direction and speed varied sinusoidally, such that the two conditions contained identical vestibular stimulation and identical retinal stimulation, differing only in the relative phase of the two components. In human MST and putative VIP, multivoxel pattern analysis permitted classification of stimulus phase based on fMRI time-series data, consistent with the existence of separate neuron populations responsive to congruent and opposite cue combinations. Decoding was also possible in the vicinity of parieto-insular vestibular cortex, possibly in a homolog of macaque VPS. PMID- 25810517 TI - Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model. AB - In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid beta protein (Abeta). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, Abeta*56 levels decreased, suggesting a link between tau and Abeta oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of Abeta pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD. PMID- 25810518 TI - Reward-based decision signals in parietal cortex are partially embodied. AB - Recordings in the lateral intraparietal area (LIP) reveal that parietal cortex encodes variables related to spatial decision-making, the selection of desirable targets in space. It has been unclear whether parietal cortex is involved in spatial decision-making in general, or whether specific parietal compartments subserve decisions made using specific actions. To test this, we engaged monkeys (Macaca mulatta) in a reward-based decision task in which they selected a target based on its desirability. The animals' choice behavior in this task followed the molar matching law, and in each trial was governed by the desirability of the choice targets. Critically, animals were instructed to make the choice using one of two actions: eye movements (saccades) and arm movements (reaches). We recorded the discharge activity of neurons in area LIP and the parietal reach region (PRR) of the parietal cortex. In line with previous studies, we found that both LIP and PRR encode a reward-based decision variable, the target desirability. Crucially, the target desirability was encoded in LIP at least twice as strongly when choices were made using saccades compared with reaches. In contrast, PRR encoded target desirability only for reaches and not for saccades. These data suggest that decisions can evolve in dedicated parietal circuits in the context of specific actions. This finding supports the hypothesis of an intentional representation of developing decisions in parietal cortex. Furthermore, the close link between the cognitive (decision-related) and bodily (action-related) processes presents a neural contribution to the theories of embodied cognition. PMID- 25810519 TI - Distinct influence of hand posture on cortical activity during human grasping. AB - We recently showed that subcortical circuits contribute to control the gain of motor cortical inputs to spinal motoneurons during precision grip of a small object. Here, we examine whether the involvement of the motor cortex could be revealed by grasping with different hand postures. Using noninvasive cortical, cervicomedullary, and peripheral nerve stimulation we examined in humans motor evoked potentials (MEPs) and the activity in intracortical circuits (suppression of voluntary electromyography) and spinal motoneurons (F-waves) in intrinsic hand muscles when grasping a 6 mm cylinder with the index finger and thumb while the hand was held in the neutral position or during full pronation and supination. We demonstrate that the size of cortically evoked MEPs in the first dorsal interosseous, but not in the abductor pollicis brevis and abductor digit minimi muscles, was reduced to a similar extent during grasping with the hand pronated or supinated compared with the neutral position. Notably, the suppression of MEPs was present from the MEP onset, suggesting that indirect corticospinal pathways were less likely to be involved than direct connections. There was less intracortical inhibition targeting the first dorsal interosseous during hand pronation and supination compared with neutral and this negatively correlated with changes in MEP size. In contrast, cervicomedullary MEPs and F-waves remained unchanged across conditions, as did MEPs evoked during unopposed weak flexion of the index finger. Our findings reveal a distinct influence of the posture of the hand on the activity of cortical pathways controlling different hand muscles during grasping. PMID- 25810520 TI - Dissociation between the experience-dependent development of hippocampal theta sequences and single-trial phase precession. AB - Theta sequences are circuit-level activity patterns produced when groups of hippocampal place cells fire in sequences that reflect a compressed behavioral order of place fields within each theta cycle. The high temporal coordination between place cells exhibited in theta sequences is compatible with the induction of synaptic plasticity and has been proposed as one of the mechanisms underlying the encoding of episodic memory of recently acquired experience. Yet how theta sequences develop with experience has not been directly addressed. Here we simultaneously recorded large numbers of cells in the dorsal hippocampal CA1 area from rats exploring on a novel linear track. Although place cell firing activities accurately represented the animal's current location, distinct theta sequences were absent on the first lap but emerged immediately thereafter and remained stable once established. The absence of theta sequences on the first lap was not due to place field instability, decreased overall excitability of place cells, behavior variables, or the absence of individual neuronal phase precession. We observed strong single-lap phase precession in a significant percentage of place fields on the first lap and throughout the recording. Individual neuronal phase precession was stable from the first lap to subsequent laps but, across neurons, phase precession became more synchronized after experience, suggesting a novel mechanism for the generation of theta sequences. These results suggest that experience-independent temporal coding in individual neurons is combined with rapid plasticity of hippocampal neural networks during experience to acquire predictive representations of the immediate future. PMID- 25810522 TI - Neural substrates of intention--consequence integration and its impact on reactive punishment in interpersonal transgression. AB - When evaluating interpersonal transgressions, people take into account both the consequential damage and the intention of the agent. The intention and consequence, however, do not always match, as is the case with accidents and failed attempts. We combined an interactive game and functional MRI to investigate the neural substrates underlying the processing of intention and consequence, and its bearing on reactive punishment. The participant interacted with anonymous partners, who decided to deliver pain stimulation either to himself/herself or to the participant to earn a monetary reward. In some cases, the decision was reversed by the computer. After pain delivery, the partner's intention was revealed. Unbeknownst to the partner, the participant was then allowed to punish the partner by reducing his/her monetary reward. Behaviorally, the punishment was lower in the accidental condition (unintended harm relative to intended harm) but higher in the failed-attempt condition (unintended no-harm relative to intended no-harm). Neurally, the left amygdala/hippocampus was activated in the conditions with blameworthy intention (i.e., intentional harm and failed attempt). The accidental (relative to intentional) harm activated the right temporoparietal junction (TPJ) and the anterior inferior frontal gyrus (IFG), while the failed attempt (relative to genuine no-harm) activated the anterior insula (AI) and the posterior IFG. Effective connectivity analysis revealed that in the unintentional conditions (i.e., accidental and failed attempt) the IFG received input from the TPJ and AI, and sent regulatory signals to the amygdala. These findings demonstrate that the processing of intention may gate the emotional responses to transgression and regulate subsequent reactive punishment. PMID- 25810525 TI - Ventral pallidal projections to mediodorsal thalamus and ventral tegmental area play distinct roles in outcome-specific Pavlovian-instrumental transfer. AB - Outcome-specific Pavlovian-instrumental transfer (PIT) demonstrates the way that reward-related cues influence choice between instrumental actions. The nucleus accumbens shell (NAc-S) contributes critically to this effect, particularly through its output to the rostral medial ventral pallidum (VP-m). Using rats, we investigated in two experiments the role in the PIT effect of the two major outputs of this VP-m region innervated by the NAc-S, the mediodorsal thalamus (MD) and the ventral tegmental area (VTA). First, two retrograde tracers were injected into the MD and VTA to compare the neuronal activity of the two populations of projection neurons in the VP-m during PIT relative to controls. Second, the functional role of the connection between the VP-m and the MD or VTA was assessed using asymmetrical pharmacological manipulations before a PIT test. It was found that, whereas neurons in the VP-m projecting to the MD showed significantly more neuronal activation during PIT than those projecting to the VTA, neuronal activation of these latter neurons correlated with the size of the PIT effect. Disconnection of the two pathways during PIT also revealed different deficits in performance: disrupting the VP-m to MD pathway removed the response biasing effects of reward-related cues, whereas disrupting the VP-m to VTA pathway preserved the response bias but altered the overall rate of responding. The current results therefore suggest that the VP-m exerts distinct effects on the VTA and MD and that these latter structures mediate the motivational and cognitive components of specific PIT, respectively. PMID- 25810523 TI - MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance. AB - The muscle-specific kinase MuSK is one of the key molecules orchestrating neuromuscular junction (NMJ) formation. MuSK interacts with the Wnt morphogens, through its Frizzled-like domain (cysteine-rich domain [CRD]). Dysfunction of MuSK CRD in patients has been recently associated with the onset of myasthenia, common neuromuscular disorders mainly characterized by fatigable muscle weakness. However, the physiological role of Wnt-MuSK interaction in NMJ formation and function remains to be elucidated. Here, we demonstrate that the CRD deletion of MuSK in mice caused profound defects of both muscle prepatterning, the first step of NMJ formation, and synapse differentiation associated with a drastic deficit in AChR clusters and excessive growth of motor axons that bypass AChR clusters. Moreover, adult MuSKDeltaCRD mice developed signs of congenital myasthenia, including severe NMJs dismantlement, muscle weakness, and fatigability. We also report, for the first time, the beneficial effects of lithium chloride, a reversible inhibitor of the glycogen synthase kinase-3, that rescued NMJ defects in MuSKDeltaCRD mice and therefore constitutes a novel therapeutic reagent for the treatment of neuromuscular disorders linked to Wnt-MuSK signaling pathway deficiency. Together, our data reveal that MuSK CRD is critical for NMJ formation and plays an unsuspected role in NMJ maintenance in adulthood. PMID- 25810521 TI - Spatially heterogeneous choroid plexus transcriptomes encode positional identity and contribute to regional CSF production. AB - A sheet of choroid plexus epithelial cells extends into each cerebral ventricle and secretes signaling factors into the CSF. To evaluate whether differences in the CSF proteome across ventricles arise, in part, from regional differences in choroid plexus gene expression, we defined the transcriptome of lateral ventricle (telencephalic) versus fourth ventricle (hindbrain) choroid plexus. We find that positional identities of mouse, macaque, and human choroid plexi derive from gene expression domains that parallel their axial tissues of origin. We then show that molecular heterogeneity between telencephalic and hindbrain choroid plexi contributes to region-specific, age-dependent protein secretion in vitro. Transcriptome analysis of FACS-purified choroid plexus epithelial cells also predicts their cell-type-specific secretome. Spatial domains with distinct protein expression profiles were observed within each choroid plexus. We propose that regional differences between choroid plexi contribute to dynamic signaling gradients across the mammalian cerebroventricular system. PMID- 25810524 TI - Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. AB - Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6 trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor alpha in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients. PMID- 25810526 TI - Adding words to the brain's visual dictionary: novel word learning selectively sharpens orthographic representations in the VWFA. AB - The nature of orthographic representations in the human brain is still subject of much debate. Recent reports have claimed that the visual word form area (VWFA) in left occipitotemporal cortex contains an orthographic lexicon based on neuronal representations highly selective for individual written real words (RWs). This theory predicts that learning novel words should selectively increase neural specificity for these words in the VWFA. We trained subjects to recognize novel pseudowords (PWs) and used fMRI rapid adaptation to compare neural selectivity with RWs, untrained PWs (UTPWs), and trained PWs (TPWs). Before training, PWs elicited broadly tuned responses, whereas responses to RWs indicated tight tuning. After training, TPW responses resembled those of RWs, whereas UTPWs continued to show broad tuning. This change in selectivity was specific to the VWFA. Therefore, word learning appears to selectively increase neuronal specificity for the new words in the VWFA, thereby adding these words to the brain's visual dictionary. PMID- 25810527 TI - Input-gain control produces feature-specific surround suppression. AB - In primary visual cortex (V1), neuronal responses are sensitive to context. For example, responses to stimuli presented within the receptive field (RF) center are often suppressed by stimuli within the RF surround, and this suppression tends to be strongest when the center and surround stimuli match. We sought to identify the mechanism that gives rise to these properties of surround modulation. To do so, we exploited the stability of implanted multielectrode arrays to record from neurons in V1 of alert monkeys with multiple stimulus sets that more exhaustively probed center-surround interactions. We first replicated previous results concerning center-surround similarity using gratings representing all combinations of center and surround orientation. With this stimulus set, the surround simply scaled population responses to the center, such that the overall population tuning curve had the same shape and peak response. However, when the center contained two superimposed gratings (i.e., a visual "plaid"), one component of which always matched the surround orientation, suppression selectively affected the portion of the response driven by the matching center component, thereby producing shifts in the peak of the population orientation tuning curve. In effect, the surround caused neurons to respond predominantly to the component grating of the center plaid that was unmatched to the surround grating, as if by reducing the effective strength of whichever stimulus attributes were matched to the surround. These results provide key physiological support for theoretical models that propose feature-specific, input gain control as the mechanism underlying surround suppression. PMID- 25810530 TI - The Wnt effector transcription factor 7-like 2 positively regulates oligodendrocyte differentiation in a manner independent of Wnt/beta-catenin signaling. AB - Genetic or pharmacological activation of canonical Wnt/beta-catenin signaling inhibits oligodendrocyte differentiation. Transcription factor 7-like 2 (TCF7l2), also known as TCF4, is a Wnt effector induced transiently in the oligodendroglial lineage. A well accepted dogma is that TCF7l2 inhibits oligodendrocyte differentiation through activation of Wnt/beta-catenin signaling. We report that TCF7l2 is upregulated transiently in postmitotic, newly differentiated oligodendrocytes. Using in vivo gene conditional ablation, we found surprisingly that TCF7l2 positively regulates neonatal and postnatal mouse oligodendrocyte differentiation during developmental myelination and remyelination in a manner independent of the Wnt/beta-catenin signaling pathway. We also reveal a novel role of TCF7l2 in repressing a bone morphogenetic protein signaling pathway that is known to inhibit oligodendrocyte differentiation. Thus, our study provides novel data justifying therapeutic attempts to enhance, rather than inhibit, TCF7l2 signaling to overcome arrested oligodendroglial differentiation in multiple sclerosis and other demyelinating diseases. PMID- 25810531 TI - Time flies when we intend to act: temporal distortion in a go/no-go task. AB - Although many of our actions are triggered by sensory events, almost nothing is known about our perception of the timing of those sensory events. Here we show that, when people react to a sudden visual stimulus that triggers an action, that stimulus is perceived to occur later than an identical stimulus that does not trigger an action. In our experiments, participants fixated the center of a clock face with a rotating second hand. When the clock changed color, they were required to make a motor response and then to report the position of the second hand at the moment the clock changed color. In Experiment 1, in which participants made a target-directed saccade, the color change was perceived to occur 59 ms later than when they maintained fixation. In Experiment 2, in which we used a go/no-go paradigm, this temporal distortion was observed even when participants were required to cancel a prepared saccade. Finally, in Experiment 3, the same distortion in perceived time was observed for both go and no-go trials in a manual task in which no eye movements were required. These results suggest that, when a visual stimulus triggers an action, it is perceived to occur significantly later than an identical stimulus unrelated to action. Moreover, this temporal distortion appears to be related not to the execution of the action (or its effect) but rather to the programming of the action. In short, there seems to be a temporal binding between a triggering event and the triggered action. PMID- 25810529 TI - mGlu5 acts as a switch for opposing forms of synaptic plasticity at mossy fiber CA3 and commissural associational-CA3 synapses. AB - Within the hippocampus, different kinds of spatial experience determine the direction of change of synaptic weights. Synaptic plasticity resulting from such experience may enable memory encoding. The CA3 region is very striking in this regard: due to the distinct molecular properties of the mossy fiber (MF) and associational-commissural (AC) synapses, it is believed that they enable working memory and pattern completion. The question arises, however, as to how information reaching these synapses results in differentiated encoding. Given its crucial role in enabling persistent synaptic plasticity in other hippocampal subfields, we speculated that the metabotropic glutamate receptor mGlu5 may regulate information encoding at MF and AC synapses. Here, we show that antagonism of mGlu5 inhibits LTP, but not LTD at MF synapses of freely behaving adult rats. Conversely, mGlu5 antagonism prevents LTD but not LTP at AC-CA3 synapses. This suggests that, under conditions in which mGlu5 is activated, LTP may be preferentially induced at MF synapses, whereas LTD is favored at AC synapses. To assess this possibility, we applied 50 Hz stimulation that should generate postsynaptic activity that corresponds to thetam, the activation threshold that lies between LTP and LTD. MGlu5 activation had no effect on AC responses but potentiated MF synapses. These data suggest that mGlu5 serves as a switch that alters signal-to-noise ratios during information encoding in the CA3 region. This mechanism supports highly tuned and differentiated information storage in CA3 synapses. PMID- 25810528 TI - The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. AB - In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/beta-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/beta-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts. PMID- 25810533 TI - Blockade of glutamatergic transmission in perirhinal cortex impairs object recognition memory in macaques. AB - The perirhinal cortex (PRc) is essential for visual recognition memory, as shown by electrophysiological recordings and lesion studies in a variety of species. However, relatively little is known about the functional contributions of perirhinal subregions. Here we used a systematic mapping approach to identify the critical subregions of PRc through transient, focal blockade of glutamate receptors by intracerebral infusion of kynurenic acid. Nine macaques were tested for visual recognition memory using the delayed nonmatch-to-sample task. We found that inactivation of medial PRc (consisting of Area 35 together with the medial portion of Area 36), but not lateral PRc (the lateral portion of Area 36), resulted in a significant delay-dependent impairment. Significant impairment was observed with 30 and 60 s delays but not with 10 s delays. The magnitude of impairment fell within the range previously reported after PRc lesions. Furthermore, we identified a restricted area located within the most anterior part of medial PRc as critical for this effect. Moreover, we found that focal blockade of either NMDA receptors by the receptor-specific antagonist AP-7 or AMPA receptors by the receptor-specific antagonist NBQX was sufficient to disrupt object recognition memory. The present study expands the knowledge of the role of PRc in recognition memory by identifying a subregion within this area that is critical for this function. Our results also indicate that, like in the rodent, both NMDA and AMPA-mediated transmission contributes to object recognition memory. PMID- 25810535 TI - Characterizing KIF16B in neurons reveals a novel intramolecular "stalk inhibition" mechanism that regulates its capacity to potentiate the selective somatodendritic localization of early endosomes. AB - An organelle's subcellular localization is closely related to its function. Early endosomes require localization to somatodendritic regions in neurons to enable neuronal morphogenesis, polarized sorting, and signal transduction. However, it is not known how the somatodendritic localization of early endosomes is achieved. Here, we show that the kinesin superfamily protein 16B (KIF16B) is essential for the correct localization of early endosomes in mouse hippocampal neurons. Loss of KIF16B induced the aggregation of early endosomes and perturbed the trafficking and functioning of receptors, including the AMPA and NGF receptors. This defect was rescued by KIF16B, emphasizing the critical functional role of the protein in early endosome and receptor transport. Interestingly, in neurons expressing a KIF16B deletion mutant lacking the second and third coiled-coils of the stalk domain, the early endosomes were mistransported to the axons. Additionally, the binding of the motor domain of KIF16B to microtubules was inhibited by the second and third coiled-coils (inhibitory domain) in an ATP-dependent manner. This suggests that the intramolecular binding we find between the inhibitory domain and motor domain of KIF16B may serve as a switch to control the binding of the motor to microtubules, thereby regulating KIF16B activity. We propose that this novel autoregulatory "stalk inhibition" mechanism underlies the ability of KIF16B to potentiate the selective somatodendritic localization of early endosomes. PMID- 25810534 TI - Preparing the periphery for a subsequent behavior: motor neuronal activity during biting generates little force but prepares a retractor muscle to generate larger forces during swallowing in Aplysia. AB - Some behaviors occur in obligatory sequence, such as reaching before grasping an object. Can the earlier behavior serve to prepare the musculature for the later behavior? If it does, what is the underlying neural mechanism of the preparation? To address this question, we examined two feeding behaviors in the marine mollusk Aplysia californica, one of which must precede the second: biting and swallowing. Biting is an attempt to grasp food. When that attempt is successful, the animal immediately switches to swallowing to ingest food. The main muscle responsible for pulling food into the buccal cavity during swallowing is the I3 muscle, whose motor neurons B6, B9, and B3 have been previously identified. By performing recordings from these neurons in vivo in intact, behaving animals or in vitro in a suspended buccal mass preparation, we demonstrated that the frequencies and durations of these motor neurons increased from biting to swallowing. Using the physiological patterns of activation to drive these neurons intracellularly, we further demonstrated that activating them using biting-like frequencies and durations, either alone or in combination, generated little or no force in the I3 muscle. When biting-like patterns preceded swallowing-like patterns, however, the forces during the subsequent swallowing-like patterns were significantly enhanced. Sequences of swallowing-like patterns, either with these neurons alone or in combination, further enhanced forces in the I3 muscle. These results suggest a novel mechanism for enhancing force production in a muscle, and may be relevant to understanding motor control in vertebrates. PMID- 25810532 TI - The attentional field revealed by single-voxel modeling of fMRI time courses. AB - The spatial topography of visual attention is a distinguishing and critical feature of many theoretical models of visuospatial attention. Previous fMRI-based measurements of the topography of attention have typically been too crude to adequately test the predictions of different competing models. This study demonstrates a new technique to make detailed measurements of the topography of visuospatial attention from single-voxel, fMRI time courses. Briefly, this technique involves first estimating a voxel's population receptive field (pRF) and then "drifting" attention through the pRF such that the modulation of the voxel's fMRI time course reflects the spatial topography of attention. The topography of the attentional field (AF) is then estimated using a time-course modeling procedure. Notably, we are able to make these measurements in many visual areas including smaller, higher order areas, thus enabling a more comprehensive comparison of attentional mechanisms throughout the full hierarchy of human visual cortex. Using this technique, we show that the AF scales with eccentricity and varies across visual areas. We also show that voxels in multiple visual areas exhibit suppressive attentional effects that are well modeled by an AF having an enhancing Gaussian center with a suppressive surround. These findings provide extensive, quantitative neurophysiological data for use in modeling the psychological effects of visuospatial attention. PMID- 25810536 TI - The Role of Self-Objectification in the Mental Health of Early Adolescent Girls: Predictors and Consequences. AB - OBJECTIVES: The overall aim of the study was to investigate the applicability of Objectification Theory to the mental health of early adolescent girls, in particular, their dieting behaviors and depressive symptoms. Both predictors and consequences of self-objectification were examined. METHODS: A sample of 204 girls with a mean age of 11.6 years completed questionnaire measures of media consumption, time spent on sports and hobbies, appearance conversations, self objectification, body shame, dieting, and depressive symptoms. RESULTS: Structural equation modeling showed that magazine and Internet exposure and appearance conversations with friends predicted self-objectification. Self objectification itself predicted body shame, which in turn predicted both dieting and depressive symptoms, in accord with the pathways postulated by Objectification Theory. CONCLUSIONS: The results confirm that, as is the case with adult women, self-objectification plays a significant role in the mental health of early adolescent girls. PMID- 25810539 TI - Asymptomatic Middle East respiratory syndrome coronavirus infection in rabbits. AB - The ability of Middle East respiratory syndrome coronavirus (MERS-CoV) to infect small animal species may be restricted given the fact that mice, ferrets, and hamsters were shown to resist MERS-CoV infection. We inoculated rabbits with MERS CoV. Although virus was detected in the lungs, neither significant histopathological changes nor clinical symptoms were observed. Infectious virus, however, was excreted from the upper respiratory tract, indicating a potential route of MERS-CoV transmission in some animal species. PMID- 25810540 TI - Pandemic Swine H1N1 Influenza Viruses with Almost Undetectable Neuraminidase Activity Are Not Transmitted via Aerosols in Ferrets and Are Inhibited by Human Mucus but Not Swine Mucus. AB - A balance between the functions of the influenza virus surface proteins hemagglutinin (HA) and neuraminidase (NA) is thought to be important for the transmission of viruses between humans. Here we describe two pandemic H1N1 viruses, A/swine/Virginia/1814-1/2012 and A/swine/Virginia/1814-2/2012 (pH1N1low 1 and -2, respectively), that were isolated from swine symptomatic for influenza. The enzymatic activity of the NA of these viruses was almost undetectable, while the HA binding affinity for alpha2,6 sialic acids was greater than that of the highly homologous pH1N1 viruses A/swine/Pennsylvania/2436/2012 and A/swine/Minnesota/2499/2012 (pH1N1-1 and -2), which exhibited better-balanced HA and NA activities. The in vitro growth kinetics of pH1N1low and pH1N1 viruses were similar, but aerosol transmission of pH1N1low-1 was abrogated and transmission via direct contact in ferrets was significantly impaired compared to pH1N1-1, which transmitted by direct and aerosol contact. In normal human bronchial epithelial cells, pH1N1low-1 was significantly inhibited by mucus but pH1N1-1 was not. In Madin-Darby canine kidney cell cultures overlaid with human or swine mucus, human mucus inhibited pH1N1low-1 but swine mucus did not. These data show that the interaction between viruses and mucus may be an important factor in viral transmissibility and could be a barrier for interspecies transmission between humans and swine for influenza viruses. IMPORTANCE: A balance between the functions of the influenza virus surface proteins hemagglutinin (HA) and neuraminidase (NA) is thought to be important for transmission of viruses from swine to humans. Here we show that a swine virus with extremely functionally mismatched HA and NAs (pH1N1low-1) cannot transmit via aerosol in ferrets, while another highly homologous virus with HA and NAs that are better matched functionally (pH1N1-1) can transmit via aerosol. These viruses show similar growth kinetics in Madin-Darby canine kidney (MDCK) cells, but pH1N1low-1 is significantly inhibited by mucus in normal human bronchial epithelial cells whereas pH1N1-1 is not. Further, human mucus could inhibit these viruses, but swine mucus could not. These data show that the interaction between viruses and mucus may be an important factor in viral transmissibility and could be a species barrier between humans and swine for influenza viruses. PMID- 25810541 TI - The 5' untranslated region of a novel infectious molecular clone of the dicistrovirus cricket paralysis virus modulates infection. AB - Dicistroviridae are a family of RNA viruses that possesses a single-stranded positive-sense RNA genome containing two distinct open reading frames (ORFs), each preceded by an internal ribosome entry site that drives translation of the viral structural and nonstructural proteins, respectively. The type species, Cricket paralysis virus (CrPV), has served as a model for studying host-virus interactions; however, investigations into the molecular mechanisms of CrPV and other dicistroviruses have been limited as an established infectious clone was elusive. Here, we report the construction of an infectious molecular clone of CrPV. Transfection of in vitro-transcribed RNA from the CrPV clone into Drosophila Schneider line 2 (S2) cells resulted in cytopathic effects, viral RNA accumulation, detection of negative-sense viral RNA, and expression of viral proteins. Transmission electron microscopy, viral titers, and immunofluorescence coupled transwell assays demonstrated that infectious viral particles are released from transfected cells. In contrast, mutant clones containing stop codons in either ORF decreased virus infectivity. Injection of adult Drosophila flies with virus derived from CrPV clones but not UV-inactivated clones resulted in mortality. Molecular analysis of the CrPV clone revealed a 196-nucleotide duplication within its 5' untranslated region (UTR) that stimulated translation of reporter constructs. In cells infected with the CrPV clone, the duplication inhibited viral infectivity yet did not affect viral translation or RNA accumulation, suggesting an effect on viral packaging or entry. The generation of the CrPV infectious clone provides a powerful tool for investigating the viral life cycle and pathogenesis of dicistroviruses and may further understanding of fundamental host-virus interactions in insect cells. IMPORTANCE: Dicistroviridae, which are RNA viruses that infect arthropods, have served as a model to gain insights into fundamental host-virus interactions in insect cells. Further insights into the viral molecular mechanisms are hampered due to a lack of an established infectious clone. We report the construction of the first infectious clone of the dicistrovirus, cricket paralysis virus (CrPV). We show that transfection of the CrPV clone RNA into Drosophila cells led to production of infectious particles that resemble natural CrPV virions and result in cytopathic effects and expression of CrPV proteins and RNA in infected cells. The CrPV clone should provide insights into the dicistrovirus life cycle and host-virus interactions in insect cells. Using this clone, we find that a 196-nucleotide duplication within the 5' untranslated region of the CrPV clone increased viral translation in reporter constructs but decreased virus infectivity, thus revealing a balance that interplays between viral translation and replication. PMID- 25810538 TI - Early Kinetics of the HLA Class I-Associated Peptidome of MVA.HIVconsv-Infected Cells. AB - Cytotoxic T cells substantially contribute to the control of intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). Here, we evaluated the immunopeptidome of Jurkat cells infected with the vaccine candidate MVA.HIVconsv, which delivers HIV-1 conserved antigenic regions by using modified vaccinia virus Ankara (MVA). We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify 6,358 unique peptides associated with the class I human leukocyte antigen (HLA), of which 98 peptides were derived from the MVA vector and 7 were derived from the HIVconsv immunogen. Human vaccine recipients responded to the peptide sequences identified by LC-MS/MS. Peptides derived from the conserved HIV-1 regions were readily detected as early as 1.5 h after MVA.HIVconsv infection. Four of the seven conserved peptides were monitored between 0 and 3.5 h of infection by using quantitative mass spectrometry (Q-MS), and their abundance in HLA class I associations reflected levels of the whole HIVconsv protein in the cell. While immunopeptides delivered by the incoming MVA vector proteins could be detected, all early HIVconsv-derived immunopeptides were likely synthesized de novo. MVA.HIVconsv infection generally altered the composition of HLA class I-associated human (self) peptides, but these changes corresponded only partially to changes in the whole cell host protein abundance. IMPORTANCE: The vast changes in cellular antigen presentation after infection of cells with a vectored vaccine, as shown here for MVA.HIVconsv, highlight the complexity of factors that need to be considered for efficient antigen delivery and presentation. Identification and quantitation of HLA class I-associated peptides by Q-MS will not only find broad application in T-cell epitope discovery but also inform vaccine design and allow evaluation of efficient epitope presentation using different delivery strategies. PMID- 25810537 TI - What Do Chaotrope-Based Avidity Assays for Antibodies to HIV-1 Envelope Glycoproteins Measure? AB - When HIV-1 vaccine candidates that include soluble envelope glycoproteins (Env) are tested in humans and other species, the resulting antibody responses to Env are sifted for correlates of protection or risk. One frequently used assay measures the reduction in antibody binding to Env antigens by an added chaotrope (such as thiocyanate). Based on that assay, an avidity index was devised for assessing the affinity maturation of antibodies of unknown concentration in polyclonal sera. Since a high avidity index was linked to protection in animal models of HIV-1 infection, it has become a criterion for evaluating antibody responses to vaccine candidates. But what does the assay measure and what does an avidity index mean? Here, we have used a panel of monoclonal antibodies to well defined epitopes on Env (gp120, gp41, and SOSIP.664 trimers) to explore how the chaotrope acts. We conclude that the chaotrope sensitivity of antibody binding to Env depends on several properties of the epitopes (continuity versus tertiary- and quaternary-structural dependence) and that the avidity index has no simple relationship to antibody affinity for functional Env spikes on virions. We show that the binding of broadly neutralizing antibodies against quaternary-structural epitopes is particularly sensitive to chaotrope treatment, whereas antibody binding to epitopes in variable loops and to nonneutralization epitopes in gp41 is generally resistant. As a result of such biases, the avidity index may at best be a mere surrogate for undefined antibody or other immune responses that correlate weakly with protection. IMPORTANCE: An effective HIV-1 vaccine is an important goal. Such a vaccine will probably need to induce antibodies that neutralize typically transmitted variants of HIV-1, preventing them from infecting target cells. Vaccine candidates have so far failed to induce such antibody responses, although some do protect weakly against infection in animals and, possibly, humans. In the search for responses associated with protection, an avidity assay based on chemical disruption is often used to measure the strength of antibody binding. We have analyzed this assay mechanistically and found that the epitope specificity of an antibody has a greater influence on the outcome than does its affinity. As a result, the avidity assay is biased toward the detection of some antibody specificities while disfavoring others. We conclude that the assay may yield merely indirect correlations with weak protection, specifically when Env vaccination has failed to induce broad neutralizing responses. PMID- 25810543 TI - Structure of Serotype 1 Reovirus Attachment Protein sigma1 in Complex with Junctional Adhesion Molecule A Reveals a Conserved Serotype-Independent Binding Epitope. AB - Mammalian orthoreoviruses use glycans and junctional adhesion molecule A (JAM-A) as attachment receptors. We determined the structure of serotype 1 reovirus attachment protein sigma1 alone and in complex with JAM-A. Comparison with the structure of serotype 3 reovirus sigma1 bound to JAM-A reveals that both sigma1 proteins engage JAM-A with similar affinities and via conserved binding epitopes. Thus, sigma1-JAM-A interactions are unlikely to explain the differences in pathogenesis displayed by these reovirus serotypes. PMID- 25810542 TI - Influenza virus-induced caspase-dependent enlargement of nuclear pores promotes nuclear export of viral ribonucleoprotein complexes. AB - Influenza A viruses (IAV) replicate their segmented RNA genome in the nucleus of infected cells and utilize caspase-dependent nucleocytoplasmic export mechanisms to transport newly formed ribonucleoprotein complexes (RNPs) to the site of infectious virion release at the plasma membrane. In this study, we obtained evidence that apoptotic caspase activation in IAV-infected cells is associated with the degradation of the nucleoporin Nup153, an integral subunit of the nuclear pore complex. Transmission electron microscopy studies revealed a distinct enlargement of nuclear pores in IAV-infected cells. Transient expression and subcellular accumulation studies of multimeric marker proteins in virus infected cells provided additional evidence for increased nuclear pore diameters facilitating the translocation of large protein complexes across the nuclear membrane. Furthermore, caspase 3/7 inhibition data obtained in this study suggest that active, Crm1-dependent IAV RNP export mechanisms are increasingly complemented by passive, caspase-induced export mechanisms at later stages of infection. IMPORTANCE: In contrast to the process seen with most other RNA viruses, influenza virus genome replication occurs in the nucleus (rather than the cytoplasm) of infected cells. Therefore, completion of the viral replication cycle critically depends on intracellular transport mechanisms that ensure the translocation of viral ribonucleoprotein (RNP) complexes across the nuclear membrane. Here, we demonstrate that virus-induced cellular caspase activities cause a widening of nuclear pores, thereby facilitating nucleocytoplasmic translocation processes and, possibly, promoting nuclear export of newly synthesized RNPs. These passive transport mechanisms are suggested to complement Crm1-dependent RNP export mechanisms known to occur at early stages of the replication cycle and may contribute to highly efficient production of infectious virus progeny at late stages of the viral replication cycle. The report provides an intriguing example of how influenza virus exploits cellular structures and regulatory pathways, including intracellular transport mechanisms, to complete its replication cycle and maximize the production of infectious virus progeny. PMID- 25810544 TI - CpG Oligodeoxynucleotides Facilitate Delivery of Whole Inactivated H9N2 Influenza Virus via Transepithelial Dendrites of Dendritic Cells in Nasal Mucosa. AB - The spread of the low-pathogenicity avian H9N2 influenza virus has seriously increased the risk of a new influenza pandemic. Although whole inactivated virus (WIV) vaccine via intranasal pathway is the effective method of blocking virus transmission, the mucosal barrier seems to be a major factor hampering its development. CpG oligodeoxynucleotides, a known adjuvant, can target downstream dendritic cells (DCs) and effectively enhance the mucosal and systemic immune responses. However, the ability of CpGs to assist H9N2 WIV in transepithelial transport remains unknown. Here, in vitro and in vivo, we showed that CpGs provided assistance for H9N2 WIV in recruiting DCs to the nasal epithelial cells (ECs) and forming transepithelial dendrites (TEDs) to capture luminal viruses. CD103(+) DCs participated in this process. Chemokine CCL20 from nasal ECs played a key role in driving DC recruitment and TED formation. Virus-loaded DCs quickly migrated into the draining cervical lymph nodes (CLNs) for antigen presentation. In addition, the competence of CpGs was independent of direct epithelial transport via the transcellular or paracellular pathway. Taken together, our data demonstrated that CpGs enhanced the transport of H9N2 WIV via TEDs of nasal DCs, which might be a novel mechanism for optimal adaptive immune responses. IMPORTANCE: This paper demonstrates by both an in vivo and an in vitro coculture model that CpG oligodeoxynucleotides, known as an adjuvant generally targeting downstream immune responses, also are crucial for the transport of H9N2 WIV across nasal epithelial cells (ECs) via the uptake of transepithelial dendrites (TEDs). Our results prove for the first time to our knowledge that the immune potentiating mechanism of CpGs is based on strengthening the transepithelial uptake of H9N2 WIV in nasal mucosa. These findings provide a fresh perspective for further improvement of intranasal influenza vaccines, which are urgently needed in the face of the potential threat of H9N2 influenza. PMID- 25810545 TI - Function of the Herpes Simplex Virus 1 Small Capsid Protein VP26 Is Regulated by Phosphorylation at a Specific Site. AB - Replacement of the herpes simplex virus 1 small capsid protein VP26 phosphorylation site Thr-111 with alanine reduced viral replication and neurovirulence to levels observed with the VP26 null mutation. This mutation reduced VP26 expression and mislocalized VP26 and its binding partner, the major capsid protein VP5, in the nucleus. VP5 mislocalization was also observed with the VP26 null mutation. Thus, we postulate that phosphorylation of VP26 at Thr 111 regulates VP26 function in vitro and in vivo. PMID- 25810546 TI - The glycoprotein precursor gene of Junin virus determines the virulence of the Romero strain and the attenuation of the Candid #1 strain in a representative animal model of Argentine hemorrhagic fever. AB - The New World arenavirus Junin virus (JUNV) is the causative agent of Argentine hemorrhagic fever (AHF), a potentially deadly disease endemic to central regions of Argentina. The live-attenuated Candid #1 (Can) strain of JUNV is currently used to vaccinate the human population at risk. However, the mechanism of attenuation of this strain is still largely unknown. Therefore, the identification and functional characterization of viral genetic determinants dictating JUNV virulence or attenuation would significantly improve the understanding of the mechanisms underlying AHF and facilitate the development of novel, more effective, and safer vaccines. Here, we utilized a reverse genetics approach to generate recombinant JUNV (rJUNV) strains encoding different gene combinations of the pathogenic Romero (Rom) and attenuated Can strains of JUNV. All strains of rJUNV exhibited in vitro growth kinetics similar to those of their parental counterparts. Analysis of virulence of the rJUNV in a guinea pig model of lethal infection that closely reproduces the features of AHF identified the envelope glycoproteins (GPs) as the major determinants of pathogenesis and attenuation of JUNV. Accordingly, rJUNV strains expressing the full-length GPs of Rom and Can exhibited virulent and attenuated phenotypes, respectively, in guinea pigs. Mutation F427I in the transmembrane region of JUNV envelope glycoprotein GP2 has been shown to attenuate the neurovirulence of JUNV in suckling mice. We document that in the guinea pig model of AHF, mutation F427I in GP2 is also highly attenuating but insufficient to prevent virus dissemination and development of mild clinical and pathological symptoms, indicating that complete attenuation of JUNV requires additional mutations present in Can glycoprotein precursor (GPC). IMPORTANCE: Development of antiviral strategies against viral hemorrhagic fevers, including AHF, is one of the top priorities within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Live-attenuated Candid #1 strain, derived from the 44th mouse brain passage of the prototype XJ strain of JUNV, has been demonstrated to be safe, immunogenic, and highly protective and is currently licensed for human use in Argentina. However, the bases for the attenuated phenotype of Candid #1 have not been established. Therefore, the identification and functional characterization of viral genetic factors implicated in JUNV pathogenesis and attenuation would significantly improve the understanding of the molecular mechanisms underlying AHF and facilitate the development of novel antiviral strategies. PMID- 25810547 TI - Decoding viral infection by ribosome profiling. AB - Ribosome profiling is an emerging technique that uses deep sequencing to monitor translation in live cells. Studies using ribosome profiling have already provided novel insights into the identities and amounts of the proteins being produced in cells, as well as novel insights into the mechanism of protein synthesis and translation regulation. Application of ribosome profiling to cells infected with human cytomegalovirus and Kaposi's sarcoma-associated herpesvirus revealed unanticipated complexity in the coding capacity of herpesviruses. Here, I discuss these results and how the application of ribosome profiling to cells infected with other viruses can reveal novel insights into the process of infection. PMID- 25810548 TI - Increased infectivity of anchorless mouse scrapie prions in transgenic mice overexpressing human prion protein. AB - Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previous in vivo studies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16 fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal. IMPORTANCE: Prion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection. PMID- 25810549 TI - Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cdelta Pathway. AB - Epstein-Barr virus (EBV), an oncogenic herpesvirus, has the potential to immortalize primary B cells into lymphoblastoid cell lines (LCLs) in vitro. During immortalization, several EBV products induce cytokines or chemokines, and most of these are required for the proliferation of LCLs. Interleukin-32 (IL-32), a recently discovered proinflammatory cytokine, is upregulated after EBV infection, and this upregulation is detectable in all LCLs tested. EBV latent membrane protein 1 (LMP1) is responsible for inducing IL-32 expression at the mRNA and protein levels. Mechanistically, we showed that this LMP1 induction is provided by the p65 subunit of NF-kappaB, which binds to and activates the IL-32 promoter. Furthermore, the short hairpin RNA (shRNA)-mediated depletion of endogenous LMP1 and p65 in LCLs suppressed IL-32 expression, further suggesting that LMP1 is the key factor that stimulates IL-32 in LCLs via the NF-kappaB p65 pathway. Functionally, knockdown of IL-32 in LCLs elicits viral reactivation and affects cytokine expression, but it has no impact on cell proliferation and apoptosis. Of note, we reveal the mechanism whereby IL-32 is involved in the maintenance of EBV viral latency by inactivation of Zta promoter activity. This atypical cytoplasmic IL-32 hijacks the Zta activator protein kinase Cdelta (PKCdelta) and inhibits its translocation from the cytoplasm to the nucleus, where PKCdelta binds to the Zta promoter and activates lytic cycle progression. These novel findings reveal that IL-32 is involved in the maintenance of EBV latency in LCLs. This finding may provide new information to explain how EBV maintains latency, in addition to viral chromatin structure and epigenetic modification. IMPORTANCE: EBV persists in two states, latency and lytic replication, which is a unique characteristic of human infections. So far, little is known about how herpesviruses maintain latency in particular tissues or cell types. EBV is an excellent model to study this question because more than 90% of people are latently infected. EBV can immortalize primary B cells into lymphoblastoid cell lines in vitro. Expression of IL-32, a novel atypical cytoplasmic proinflammatory cytokine, increased after infection. The expression of IL-32 was controlled by LMP1. In investigating the regulatory mechanism, we demonstrated that the p65 subunit of NF-kappaB is required for this upregulation. Of note, the important biological activity of IL-32 was to trap protein kinase Cdelta in the cytoplasm and prevent it from binding to the Zta promoter, which is the key event for EBV reaction. So, the expression of LMP1-induced IL-32 plays a role in the maintenance of EBV latency. PMID- 25810550 TI - A virus-like particle system identifies the endonuclease domain of Crimean-Congo hemorrhagic fever virus. AB - Crimean-Congo hemorrhagic fever virus (CCHFV; genus Nairovirus) is an extremely pathogenic member of the Bunyaviridae family. Since handling of the virus requires a biosafety level 4 (BSL-4) facility, little is known about pathomechanisms and host interactions. Here, we describe the establishment of a transcriptionally competent virus-like particle (tc-VLP) system for CCHFV. Recombinant polymerase (L), nucleocapsid protein (N) and a reporter minigenome expressed in human HuH-7 cells resulted in formation of transcriptionally active nucleocapsids that could be packaged by coexpressed CCHFV glycoproteins into tc VLPs. The tc-VLPs resembled authentic virus particles in their protein composition and neutralization sensitivity to anti-CCHFV antibodies and could recapitulate all steps of the viral replication cycle. Particle attachment, entry, and primary transcription were modeled by infection of naive cells. The subsequent steps of genome replication, secondary transcription, and particle assembly and release can be obtained upon passaging the tc-VLPs on cells expressing CCHFV structural proteins. The utility of the VLP system was demonstrated by showing that the endonuclease domain of L is located around amino acid D693, as was predicted in silico by B. Morin et al. (PLoS Pathog 6:e1001038, 2010, http://dx.doi.org/10.1371/journal.ppat.1001038). The tc-VLP system will greatly facilitate studies and diagnostics of CCHFV under non-BSL-4 conditions. IMPORTANCE: Crimean-Congo hemorrhagic fever virus (CCHFV) is an extremely virulent pathogen of humans. Since the virus can be handled only at the highest biosafety level, research is restricted to a few specialized laboratories. We developed a plasmid-based system to produce virus-like particles with the ability to infect cells and transcribe a reporter genome. Due to the absence of viral genes, the virus-like particles are unable to spread or cause disease, thus allowing study of aspects of CCHFV biology under relaxed biosafety conditions. PMID- 25810551 TI - Association of Kaposi's Sarcoma-Associated Herpesvirus ORF31 with ORF34 and ORF24 Is Critical for Late Gene Expression. AB - Transcription of herpesvirus late genes depends on several virus-encoded proteins whose function is not completely understood. Here, we identify a viral trimeric complex of Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 31 (ORF31), ORF24, and ORF34 that is required for late gene expression but not viral DNA replication. We found that (i) ORF34 bridges the interaction between ORF31 and ORF24, (ii) the amino-terminal cysteine-rich and carboxyl-terminal basic domains of ORF31 mediate the ORF31-ORF34 interaction required for late gene expression, and (iii) a complex consisting of ORF24, ORF31, and ORF34 specifically binds to the K8.1 late promoter. Together, our results support the model that a subset of lytic viral proteins assembles into a transcriptional activator complex to induce expression of late genes. PMID- 25810552 TI - Dissection of amino-terminal functional domains of murine coronavirus nonstructural protein 3. AB - Coronaviruses, the largest RNA viruses, have a complex program of RNA synthesis that entails genome replication and transcription of subgenomic mRNAs. RNA synthesis by the prototype coronavirus mouse hepatitis virus (MHV) is carried out by a replicase-transcriptase composed of 16 nonstructural protein (nsp) subunits. Among these, nsp3 is the largest and the first to be inserted into the endoplasmic reticulum. nsp3 comprises multiple structural domains, including two papain-like proteases (PLPs) and a highly conserved ADP-ribose-1"-phosphatase (ADRP) macrodomain. We have previously shown that the ubiquitin-like domain at the amino terminus of nsp3 is essential and participates in a critical interaction with the viral nucleocapsid protein early in infection. In the current study, we exploited atypical expression schemes to uncouple PLP1 from the processing of nsp1 and nsp2 in order to investigate the requirements of nsp3 domains for viral RNA synthesis. In the first strategy, a mutant was created in which replicase polyprotein translation initiated with nsp3, thereby establishing that complete elimination of nsp1 and nsp2 does not abolish MHV viability. In the second strategy, a picornavirus autoprocessing element was used to separate a truncated nsp1 from nsp3. This provided a platform for further dissection of amino-terminal domains of nsp3. From this, we found that catalytic mutation of PLP1 or complete deletion of PLP1 and the adjacent ADRP domain was tolerated by the virus. These results showed that neither the PLP1 domain nor the ADRP domain of nsp3 provides integral activities essential for coronavirus genomic or subgenomic RNA synthesis. IMPORTANCE: The largest component of the coronavirus replicase-transcriptase complex, nsp3, contains multiple modules, many of which do not have clearly defined functions in genome replication or transcription. These domains may play direct roles in RNA synthesis, or they may have evolved for other purposes, such as to combat host innate immunity. We initiated a dissection of MHV nsp3 aimed at identifying those activities or structures in this huge molecule that are essential to replicase activity. We found that both PLP1 and ADRP could be entirely deleted, provided that the requirement for proteolytic processing by PLP1 was offset by an alternative mechanism. This demonstrated that neither PLP1 nor ADRP plays an essential role in coronavirus RNA synthesis. PMID- 25810553 TI - African Swine Fever Virus Georgia Isolate Harboring Deletions of MGF360 and MGF505 Genes Is Attenuated in Swine and Confers Protection against Challenge with Virulent Parental Virus. AB - African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal disease of domestic pigs that has significant economic consequences for the swine industry. The control of African swine fever (ASF) has been hampered by the unavailability of vaccines. Experimental vaccines have been developed using genetically modified live attenuated ASFVs where viral genes involved in virus virulence were removed from the genome. Multigene family 360 (MGF360) and MGF505 represent a group of genes sharing partial sequence and structural identities that have been connected with ASFV host range specificity, blocking of the host innate response, and virus virulence. Here we report the construction of a recombinant virus (ASFV-G-DeltaMGF) derived from the highly virulent ASFV Georgia 2007 isolate (ASFV-G) by specifically deleting six genes belonging to MGF360 or MGF505: MGF505-1R, MGF360-12L, MGF360-13L, MGF360-14L, MGF505-2R, and MGF505-3R. ASFV-G-DeltaMGF replicates as efficiently in primary swine macrophage cell cultures as the parental virus. In vivo, ASFV-G-DeltaMGF is completely attenuated in swine, since pigs inoculated intramuscularly (i.m.) with either 10(2) or 10(4) 50% hemadsorbing doses (HAD50) remained healthy, without signs of the disease. Importantly, when these animals were subsequently exposed to highly virulent parental ASFV-G, no signs of the disease were observed, although a proportion of these animals harbored the challenge virus. This is the first report demonstrating the role of MGF genes acting as independent determinants of ASFV virulence. Additionally, ASFV-G-DeltaMGF is the first experimental vaccine reported to induce protection in pigs challenged with highly virulent and epidemiologically relevant ASFV-G. IMPORTANCE: The main problem for controlling ASF is the lack of vaccines. Studies focusing on understanding ASFV virulence led to the production of genetically modified recombinant viruses that, while attenuated, are able to confer protection in pigs challenged with homologous viruses. Here we have produced an attenuated recombinant ASFV derived from highly virulent ASFV strain Georgia (ASFV-G) lacking only six of the multigene family 360 (MGF360) and MGF505 genes (ASFV-G-DeltaMGF). It is demonstrated, by first time, that deleting specific MGF genes alone can completely attenuate a highly virulent field ASFV isolate. Recombinant virus ASFV G-DeltaMGF effectively confers protection in pigs against challenge with ASFV-G when delivered once via the intramuscular (i.m.) route. The protection against ASFV-G is highly effective by 28 days postvaccination. This is the first report of an experimental vaccine that induces solid protection against virulent ASFV-G. PMID- 25810555 TI - Deep sequencing and phylogenetic analysis of variants resistant to interferon based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus. AB - Because of recent advances in deep sequencing technology, detailed analysis of hepatitis C virus (HCV) quasispecies and their dynamic changes in response to direct antiviral agents (DAAs) became possible, although the role of quasispecies is not fully understood. In this study, to clarify the evolution of viral quasispecies and the origin of drug-resistant mutations induced by interferon (IFN)-based protease inhibitor therapy, the nonstructural-3 (NS3) region of genotype 1b HCV in 34 chronic hepatitis patients treated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) was subjected to a deep sequencing study coupled with phylogenetic analysis. Twenty-six patients (76.5%) achieved a sustained viral response (SVR), while 8 patients did not (non-SVR; 23.5%). When the complexity of the quasispecies was expressed as the mutation frequency or Shannon entropy value, a significant decrease in the IFNL3 (rs8099917) TT group and a marginal decrease in the SVR group were found soon (12 h) after the introduction of treatment, whereas there was no decrease in the non SVR group and no significant decrease in mutation frequency in the IFNL3 TG/GG group. In the analysis of viral quasispecies composition in non-SVR patients, major populations greatly changed, accompanied by the appearance of resistance, and the compositions were unlikely to return to the pretreatment composition even after the end of therapy. Clinically TVR-resistant variants were observed in 5 non-SVR patients (5/8, 62.5%), all of which were suspected to have acquired resistance by mutations through phylogenetic analysis. In conclusion, results of the study have important implications for treatment response and outcome in interferon-based protease inhibitor therapy. IMPORTANCE: In the host, hepatitis C virus (HCV) consists of a variety of populations (quasispecies), and it is supposed that dynamic changes in quasispecies are closely related to pathogenesis, although this is poorly understood. In this study, recently developed deep sequencing technology was introduced, and changes in quasispecies associated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) triple therapy and their clinical significance were investigated extensively by phylogenetic tree analysis. Through this study, the associations among treatment response, changes in viral quasispecies complexity in the early stage of treatment, changes in the quasispecies composition, and origin of TVR-resistant variant HCV were elucidated. PMID- 25810556 TI - Murine norovirus replication induces G0/G1 cell cycle arrest in asynchronously growing cells. AB - Many viruses replicate most efficiently in specific phases of the cell cycle, establishing or exploiting favorable conditions for viral replication, although little is known about the relationship between caliciviruses and the cell cycle. Microarray and Western blot analysis of murine norovirus 1 (MNV-1)-infected cells showed changes in cyclin transcript and protein levels indicative of a G1 phase arrest. Cell cycle analysis confirmed that MNV-1 infection caused a prolonging of the G1 phase and an accumulation of cells in the G0/G1 phase. The accumulation in G0/G1 phase was caused by a reduction in cell cycle progression through the G1/S restriction point, with MNV-1-infected cells released from a G1 arrest showing reduced cell cycle progression compared to mock-infected cells. MNV-1 replication was compared in populations of cells synchronized into specific cell cycle phases and in asynchronously growing cells. Cells actively progressing through the G1 phase had a 2-fold or higher increase in virus progeny and capsid protein expression over cells in other phases of the cell cycle or in unsynchronized populations. These findings suggest that MNV-1 infection leads to prolonging of the G1 phase and a reduction in S phase entry in host cells, establishing favorable conditions for viral protein production and viral replication. There is limited information on the interactions between noroviruses and the cell cycle, and this observation of increased replication in the G1 phase may be representative of other members of the Caliciviridae. IMPORTANCE: Noroviruses have proven recalcitrant to growth in cell culture, limiting our understanding of the interaction between these viruses and the infected cell. In this study, we used the cell-culturable MNV-1 to show that infection of murine macrophages affects the G1/S cell cycle phase transition, leading to an arrest in cell cycle progression and an accumulation of cells in the G0/G1 phase. Furthermore, we show that MNV replication is enhanced in the G1 phase compared to other stages of the cell cycle. Manipulating the cell cycle or adapting to cell cycle responses of the host cell is a mechanism to enhance virus replication. To the best of our knowledge, this is the first report of a norovirus interacting with the host cell cycle and exploiting the favorable conditions of the G0/G1 phase for RNA virus replication. PMID- 25810558 TI - Plugging PDS Pilferage: A Study of an SMS-based Monitoring Project. AB - The targeted public distribution system is fraught with leakages. With the Food Security Act in place now, policymakers face a greater challenge in curtailing leakages and improving delivery on a much larger scale. This article studies a project in Uttar Pradesh which uses mobile phone SMS to monitor PDS supplies and finds an enthusiastic response from the users, even if the project itself has not worked well. PMID- 25810554 TI - Borna disease virus phosphoprotein modulates epigenetic signaling in neurons to control viral replication. AB - Understanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which viral origin is suspected. Borna disease virus (BDV) represents an ideal model to analyze the molecular mechanisms of viral persistence in neurons and its consequences for neuronal homeostasis. It is now established that BDV ensures its long-term maintenance in infected cells through a stable interaction of viral components with the host cell chromatin, in particular, with core histones. This has led to our hypothesis that such an interaction may trigger epigenetic changes in the host cell. Here, we focused on histone acetylation, which plays key roles in epigenetic regulation of gene expression, notably for neurons. We performed a comparative analysis of histone acetylation patterns of neurons infected or not infected by BDV, which revealed that infection decreases histone acetylation on selected lysine residues. We showed that the BDV phosphoprotein (P) is responsible for these perturbations, even when it is expressed alone independently of the viral context, and that this action depends on its phosphorylation by protein kinase C. We also demonstrated that BDV P inhibits cellular histone acetyltransferase activities. Finally, by pharmacologically manipulating cellular acetylation levels, we observed that inhibiting cellular acetyl transferases reduces viral replication in cell culture. Our findings reveal that manipulation of cellular epigenetics by BDV could be a means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction. IMPORTANCE: Persistent DNA viruses often subvert the mechanisms that regulate cellular chromatin dynamics, thereby benefitting from the resulting epigenetic changes to create a favorable milieu for their latent and persistent states. Here, we reasoned that Borna disease virus (BDV), the only RNA virus known to durably persist in the nucleus of infected cells, notably neurons, might employ a similar mechanism. In this study, we uncovered a novel modality of virus-cell interaction in which BDV phosphoprotein inhibits cellular histone acetylation by interfering with histone acetyltransferase activities. Manipulation of cellular histone acetylation is accompanied by a modulation of viral replication, revealing a perfect adaptation of this "ancient" virus to its host that may favor neuronal persistence and limit cellular damage. PMID- 25810557 TI - Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction. AB - Retinoic acid-inducible gene I (RIG-I) is an important innate immune sensor that recognizes viral RNA in the cytoplasm. Its nonself recognition largely depends on the unique RNA structures imposed by viral RNA. The panhandle structure residing in the influenza A virus (IAV) genome, whose primary function is to serve as the viral promoter for transcription and replication, has been proposed to be a RIG-I agonist. However, this has never been proved experimentally. Here, we employed multiple approaches to determine if the IAV panhandle structure is directly involved in RIG-I activation and type I interferon (IFN) induction. First, in porcine alveolar macrophages, we demonstrated that the viral genomic coding region is dispensable for RIG-I-dependent IFN induction. Second, using in vitro synthesized hairpin RNA, we showed that the IAV panhandle structure could directly bind to RIG-I and stimulate IFN production. Furthermore, we investigated the contributions of the wobble base pairs, mismatch, and unpaired nucleotides within the wild-type panhandle structure to RIG-I activation. Elimination of these destabilizing elements within the panhandle structure promoted RIG-I activation and IFN induction. Given the function of the panhandle structure as the viral promoter, we further monitored the promoter activity of these panhandle variants and found that viral replication was moderately affected, whereas viral transcription was impaired dramatically. In all, our results indicate that the IAV panhandle promoter region adopts a nucleotide composition that is optimal for balanced viral RNA synthesis and suboptimal for RIG-I activation. IMPORTANCE: The IAV genomic panhandle structure has been proposed to be an RIG-I agonist due to its partial complementarity; however, this has not been experimentally confirmed. Here, we provide direct evidence that the IAV panhandle structure is competent in, and sufficient for, RIG-I activation and IFN induction. By constructing panhandle variants with increased complementarity, we demonstrated that the wild type panhandle structure could be modified to enhance RIG-I activation and IFN induction. These panhandle variants posed moderate influence on viral replication but dramatic impairment of viral transcription. These results indicate that the IAV panhandle promoter region adopts a nucleotide composition to achieve optimal balance of viral RNA synthesis and suboptimal RIG-I activation. Our results highlight the multifunctional role of the IAV panhandle promoter region in the virus life cycle and offer novel insights into the development of antiviral agents aiming to boost RIG-I signaling or virus attenuation by manipulating this conserved region. PMID- 25810559 TI - Unusual phenolic compounds contribute to ecophysiological performance in the purple-colored green alga zygogonium ericetorum (zygnematophyceae, streptophyta) from a high-alpine habitat. AB - The filamentous green alga Zygogonium ericetorum (Zygnematophyceae, Streptophyta) was collected in a high-alpine rivulet in Tyrol, Austria. Two different morphotypes of this alga were found: a purple morph with a visible purple vacuolar content and a green morph lacking this coloration. These morphotypes were compared with respect to their secondary metabolites, ultrastructure, and ecophysiological properties. Colorimetric tests with aqueous extracts of the purple morph indicated the presence of soluble compounds such as phenolics and hydrolyzable tannins. High-performance liquid chromatography-screening showed that Z. ericetorum contained several large phenolic peaks with absorption maxima at ~280 nm and sometimes with minor maxima at ~380 nm. Such compounds are uncommon for freshwater green microalgae, and could contribute to protect the organism against increased UV and visible (VIS) irradiation. The purple Z. ericetorum contained larger amounts (per dry weight) of the putative phenolic substances than the green morph; exposure to irradiation may be a key factor for accumulation of these phenolic compounds. Transmission electron microscopy of the purple morph showed massive vacuolization with homogenous medium electron-dense content in the cell periphery, which possibly contains the secondary compounds. In contrast, the green morph had smaller, electron-translucent vacuoles. The ecophysiological data on photosynthesis and desiccation tolerance indicated that increasing photon fluence densities led to much higher relative electron transport rates (rETR) in the purple than in the green morph. These data suggest that the secondary metabolites in the purple morph are important for light acclimation in high-alpine habitats. However, the green morph recovered better after 4 d of rehydration following desiccation stress. PMID- 25810560 TI - Phylogenetic position of Zygogonium ericetorum (zygnematophyceae, charophyta) from a high alpine habitat and ultrastructural characterization of unusual aplanospores. AB - Characeae (Charophyceae, Charophyta) contains two tribes with six genera: tribe Chareae with four genera and tribe Nitelleae, which includes Tolypella and Nitella. This paper uses molecular and morphological data to elucidate the phylogeny of Tolypella species in North America. In the most comprehensive taxonomic treatment of Characeae, 16 Tolypella species worldwide were subsumed into two species, T. intricata and T. nidifica, in two sections, Rothia and Tolypella respectively. It was further suggested that Tolypella might be a derived group within Nitella. In this investigation into species diversity and relationships in North American Tolypella, sequence data from the plastid genes atpB, psbC, and rbcL were assembled for a broad range of charophycean and land plant taxa. Molecular data were used in conjunction with morphology to test monophyly of the genus and species within it. Phylogenetic analyses of the sequence data showed that Characeae is monophyletic but that Nitelleae is paraphyletic with Tolypella sister to a monophyletic Nitella + Chareae. The results also supported the monophyly of Tolypella and the sections Rothia and Tolypella. Morphologically defined species were supported as clades with little or no DNA sequence differences. In addition, molecular data revealed several lineages and a new species (T. ramosissima sp. nov.), which suggests greater species diversity in Tolypella than previously recognized. PMID- 25810561 TI - Dehydration, temperature, and light tolerance in members of the aeroterrestrial green algal genus interfilum (streptophyta) from biogeographically different temperate soils. AB - Unicellular green algae of the genus Interfilum (Klebsormidiales, Streptophyta) are typical components of biological soil crusts. Four different aeroterrestrial Interfilum strains that have previously been molecular-taxonomically characterized and isolated from temperate soils in Belgium, Czech Republic, New Zealand, and Ukraine were investigated. Photosynthetic performance was evaluated under different controlled abiotic conditions, including dehydration, as well as under a light and temperature gradient. For standardized desiccation experiments, a new methodological approach with silica gel filled polystyrol boxes and effective quantum yield measurements from the outside were successfully applied. All Interfilum isolates showed a decrease and inhibition of the effective quantum yield under this treatment, however with different kinetics. While the single cell strains exhibited relatively fast inhibition, the cell packet forming isolates dried slower. Most strains fully recovered effective quantum yield after rehydration. All Interfilum isolates exhibited optimum photosynthesis at low photon fluence rates, but with no indication of photoinhibition under high light conditions suggesting flexible acclimation mechanisms of the photosynthetic machinery. Photosynthesis under lower temperatures was generally more active than respiration, while the opposite was true for higher temperatures. The presented data provide an explanation for the regular occurrence of Interfilum species in soil habitats where environmental factors can be particularly harsh. PMID- 25810562 TI - Linking carbon and nitrogen metabolism to depth distribution of submersed macrophytes using high ammonium dosing tests and a lake survey. AB - Strategies of carbon (C) and nitrogen (N) utilisation are among the factors determining plant distribution. It has been argued that submersed macrophytes adapted to lower light environments are more efficient in maintaining C metabolic homeostasis due to their conservative C strategy and ability to balance C shortage. We studied how depth distributions of 12 submersed macrophytes in Lake Erhai, China, were linked to their C-N metabolic strategies when facing acute [Formula: see text] dosing.[Formula: see text] dosing changed C-N metabolism significantly by decreasing the soluble carbohydrate (SC) content and increasing the [Formula: see text]-N and free amino acid (FAA) content of plant tissues.The proportional changes in SC contents in the leaves and FAA contents in the stems induced by [Formula: see text] dosing were closely correlated (positive for SC and negative for FAA) with the colonising water depths of the plants in Lake Erhai, the plants adapted to lower light regimes being more efficient in maintaining SC and FAA homeostasis.These results indicate that conservative carbohydrate metabolism of submersed macrophytes allowed the plants to colonise greater water depths in eutrophic lakes, where low light availability in the water column diminishes carbohydrate production by the plants. PMID- 25810563 TI - Polymorphisms rs12998 and rs5780218 in KiSS1 suppressor metastasis gene in Mexican patients with breast cancer. AB - AIMS: KiSS1 is a metastasis suppressor gene associated with inhibition of cellular chemotaxis and invasion attenuating the metastasis in melanoma and breast cancer cell lines. Along the KiSS-1 gene at least 294 SNPs have been described; however the association of these polymorphisms as genetic markers for metastasis in breast cancer studies has not been investigated. Here we describe two simple PCR-RFLPs protocols to identify the rs5780218 (9DelT) and the rs12998 (E20K) KiSS1 polymorphisms and the allelic, genotypic, and haplotypic frequencies in Mexican general population (GP) and patients with benign breast disease (BBD) or breast cancer (BC). RESULTS: The rs5780218 polymorphism was individually associated with breast cancer (P = 0.0332) and the rs12998 polymorphism shows statistically significant differences when GP versus case (BC and BBD) groups were compared (P < 0.0001). The H1 Haplotype (G/-) occurred more frequently in BC group (0.4256) whereas H2 haplotype (G/T) was the most prevalent in BBD group (0.4674). CONCLUSIONS: Our data indicated that the rs5780218 polymorphism individually confers susceptibility for development of breast cancer in Mexican population and a possible role as a genetic marker in breast cancer metastasis for H1 haplotype (Wt/variant) in KiSS1 gene must be analyzed in other populations. PMID- 25810564 TI - Circulating microRNA-223 serum levels do not predict sepsis or survival in patients with critical illness. AB - BACKGROUND AND AIMS: Dysregulation of miR-223 was recently linked to various diseases associated with systemic inflammatory responses such as type 2 diabetes, cancer, and bacterial infections. However, contradictory results are available on potential alterations of miR-223 serum levels during sepsis. We thus aimed to evaluate the diagnostic and prognostic value of miR-223 serum concentrations in patients with critical illness and sepsis. METHODS: We used i.v. injection of lipopolysaccharide (LPS) as well as cecal pole ligation and puncture (CLP) for induction of polymicrobial sepsis in mice and measured alterations in serum levels of miR-223. These results from mice were translated into a large and well characterized cohort of critically ill patients admitted to the medical intensive care unit (ICU). Finally, results from analysis in patients were correlated with clinical data and extensive sets of routine and experimental biomarkers. RESULTS: Although LPS injection induced moderately elevated serum miR-223 levels in mice, no significant alterations in miR-223 serum levels were found in mice after CLP induced sepsis. In accordance with these results from animal models, serum miR 223 levels did not differ between critically ill patients and healthy controls. However, ICU patients with more severe disease (APACHE-II score) showed moderately reduced circulating miR-223. Strikingly, no differences in miR-223 levels were found in critically ill patients with or without sepsis, and serum levels of miR-223 did not correlate with classical markers of inflammation or bacterial infection. Finally, low miR-223 serum levels were moderately associated with an unfavorable prognosis of patients during the ICU treatment but did not predict long-term mortality. CONCLUSION: Recent reports on alterations in miR-223 serum levels during sepsis revealed contradictory results, preventing a potential use of this miRNA in clinical routine. We clearly show that miR-223 serum levels do not reflect the presence of sepsis neither in mouse models nor in a large cohort of ICU patients and do not indicate clinical outcome of critically ill patients. Thus miR-223 serum levels should not be used as a biomarker in this setting. PMID- 25810565 TI - VEGF overexpression is a valuable prognostic factor for non-Hodgkin's lymphoma evidence from a systemic meta-analysis. AB - Vascular endothelial growth factor (VEGF) plays a vital role in the progression of Non-Hodgkin's lymphoma (NHL). Although multiple studies have investigated the relationship between VEGF expression and prognosis of NHL, these studies have yielded conflicting results. Therefore, we performed a meta-analysis to evaluate the role of VEGF in the prognosis of NHL patients. We systematically searched eligible studies from databases and determined that there was a significant correlation between VEGF overexpression and overall survival (HR (hazard ratio) = 1.66, 95% CI: 1.25-2.22, P = 0.001). Based on subgroup analysis by study location, number of patients, the source of VEGF expression, and study design, we found that VEGF overexpression in surgically resected tissue (HR = 1.95, 95% CI: 1.41-2.69, P = 0.000), but not in serum (HR = 1.37, 95% CI: 0.96-1.95, P = 0.087), was associated with poorer prognosis. Additionally, VEGF overexpression did not correlate with performance status, LDH level, IPI score, tumor staging, B symptoms, or NHL relapse. In summary, overexpression of VEGF in lymphoma tissue represents a promising potential prognostic factor in NHL. PMID- 25810566 TI - Coenzyme Q10, alpha-tocopherol, and oxidative stress could be important metabolic biomarkers of male infertility. AB - Oxidative stress, decreased antioxidant capacity, and impaired sperm mitochondrial function are the main factors contributing to male infertility. The goal of the present study was to assess the effect of the per os treatment with Carni-Q-Nol (440 mg L-carnitine fumarate + 30 mg ubiquinol + 75 IU vitamin E + 12 mg vitamin C in each softsule) in infertile men on sperm parameters, concentration of antioxidants (coenzyme Q10, CoQ(10-TOTAL), gamma, and alpha tocopherols), and oxidative stress in blood plasma and seminal fluid. Forty infertile men were supplemented daily with two or three Carni-Q-Nol softsules. After 3 and 6 months of treatment, improved sperm density was observed (by 48.9% and 80.9%, resp.) and after 3-month treatment the sperm pathology decreased by 25.8%. Concentrations of CoQ(10-TOTAL) (ubiquinone + ubiquinol) and alpha tocopherol were significantly increased and the oxidative stress was decreased. In conclusion, the effect of supplementary therapy with Carni-Q-Nol showed benefits on sperm function in men, resulting in 45% pregnancies of their women. We assume that assessment of oxidative stress, CoQ(10-TOTAL), and alpha tocopherol in blood plasma and seminal fluid could be important metabolic biomarkers in both diagnosis and treatment of male infertility. PMID- 25810568 TI - Biobanking in the era of precision oncology. PMID- 25810567 TI - Effect of TLR4/MyD88 signaling pathway on expression of IL-1beta and TNF-alpha in synovial fibroblasts from temporomandibular joint exposed to lipopolysaccharide. AB - Accumulating evidence from previous studies suggested that interleukin-1 (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha) play an important role in pathogenesis of temporomandibular disorders (TMD). However, the cell surface receptors and the intracellular signal pathways leading to these cytokines expression are not fully understood. In the current study, we investigated the roles of Toll-like receptor 4 (TLR4) and its adaptor myeloid differentiation factor 88 (MyD88) in the expression of IL-1beta and TNF-alpha in synovial fibroblasts (SFs) separated from rat temporomandibular joint (TMJ) with lipopolysaccharide (LPS) stimulation. The results showed that treatment with LPS could increase TLR4, MyD88, IL-1beta, and TNF-alpha expression at both mRNA and protein levels. In addition, increased expression of IL-1beta and TNF-alpha could be blocked by treatment with TAK-242, a blocker of TLR4 signaling, and also by MyD88 inhibitory peptide (MIP). These findings suggested that maybe TLR4/MyD88 signal transduction pathway participates in enhanced expression of IL-1 and TNF alpha in patients with TMD. The activation of TLR4/MyD88 signal transduction pathway which results in production of proinflammatory factors may play a role in the pathogenesis of TMD. PMID- 25810570 TI - Impacts of a biobank: Bridging the gap in translational cancer medicine. AB - The prevalence of people affected by cancer has been steadily increasing. More and more people are being offered the chance of increased longevity. This has been possible due to advances not only in medicines and techniques but also because of the gain in understanding of cancer biology through Translational Cancer Medicine. A significant step towards obtaining this success was the establishment of successful biobanking practise. In this review we discuss about the importance of a Biobank and the various impacts that a biobank can have not only in the field of cancer but also on many other aspects. Later we discuss a method of quantitative evaluation of these impacts of a biobank. PMID- 25810569 TI - Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia. AB - According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia.Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years.The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India.This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India. PMID- 25810572 TI - Tobacco-related knowledge, attitudes, and practices among urban low socioeconomic women in Mumbai, India. AB - CONTEXT: Tobacco use is an important health issue globally. It is responsible for a large number of diseases and deaths in India. Female tobacco users have additional health risks. AIMS: The aim was to assess changes in pre and post intervention tobacco-related knowledge, attitudes, and practices among women from urban low socioeconomic strata, after three rounds of interventions. SUBJECTS AND METHODS: A structured questionnaire was used to interview women living in low socioeconomic housing clusters in Mumbai, regarding their tobacco consumption, attitudes, and practices, by Medical Social Workers. These data were entered into IBM SPSS Statistics, version 20 and analysed. Interventions for tobacco cessation were provided 3 times over a span of 9 months, comprising of health education and counseling. Post-intervention questionnaire was introduced at 12 months. RESULTS: There was statistically significant improvement in the knowledge of women, following the interventions, with particular reference to poor oral hygiene and tobacco use being main cause of oral cancer (P = 0.007), knowledge of ill effects of second hand smoke (P = 0.0001), knowledge about possibility of early detection of oral cancer (P = 0.0001), perception of pictorial and written warnings on tobacco products (P = 0.0001), and availability of help for quitting tobacco (P = 0.024). CONCLUSION: The prevalence of smokeless tobacco use is very high among urban women from lower socioeconomic strata. Therefore, tobacco awareness programs and tobacco cessation services tailor made for this group of women must be planned and implemented. PMID- 25810571 TI - Harmful effects of nicotine. AB - With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies which show otherwise. We undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel. PMID- 25810573 TI - Neoadjuvant chemotherapy in advanced epithelial ovarian cancer: A survival study. AB - CONTEXT: Patients with advanced ovarian cancer have a poor prognosis in spite of the best possible care. Primary debulking surgery has been the standard of care in advanced ovarian cancer; however, it is associated with high mortality and morbidity rates as shown in various studies. Several studies have discussed the benefit of neoadjuvant chemotherapy in patients with advanced ovarian cancer. AIMS: This study aims to evaluate the survival statistics of the patients who have been managed with interval debulking surgery (IDS) from January 2007 to December 2009. MATERIALS AND METHODS: During the period from January 2007 to December 2009, a retrospective analysis of 104 patients who underwent IDS for stage IIIC or IV advanced epithelial ovarian cancer at our institute were selected for the study. IDS was attempted after three to five courses of chemotherapy with paclitaxal (175 mg/m(2) ) and carboplatin (5-6 of area under curve). Overall survival (OS) and progression free survival (PFS) were compared with results of primary debulking study from existing literature. OS and PFS rates were estimated by means of the Kaplan-Meier method. Results were statistically analyzed by IBM SPSS Statistics 19. RESULTS: The median OS was 26 months and the median PFS was 18 months. In multivariate analysis it was found that both OS and PFS was affected by the stage, and extent of debulking. CONCLUSIONS: Neoadjuvant chemotherapy, followed by surgical cytoreduction is a promising treatment strategy for the management of advanced epithelial ovarian cancers. PMID- 25810575 TI - Role of CTCF poly(ADP-Ribosyl)ation in the regulation of apoptosis in breast cancer cells. AB - INTRODUCTION: CTCF is a candidate tumor suppressor gene encoding a multifunctional transcription factor. CTCF function is controlled by posttranslational modification and interaction with other proteins. Research findings suggested that CTCF function can be regulated by poly(ADP-ribosyl)ation (PARlation) and has specific anti-apoptotic function in breast cancer cells. The aim of this study is to assess the effect of CTCF-wild type (WT) and CTCF complete mutant, which is deficient of PARlation in regulating apoptosis in breast cancer cells. MATERIALS AND METHODS: The effect of CTCF-WT and CTCF complete mutant was expressed in breast cancer cell-lines by DNA-mediated transfection technique monitored by enhanced green fluorescent protein fluorescence. Evaluation of apoptotic cell death was carried out with immunohistochemical staining using 4'-6'-diamino-2 phenylindole and scoring by fluorescent microscopy. RESULTS: CTCF-WT supports survival of breast cancer cells and was observed that CTCF complete mutant interferes with the functions of the CTCF-WT and there was a considerable apoptotic cell death in the breast cancer cell lines such as MDA-MB-435, CAMA-1 and MCF-7. CONCLUSION: The study enlighten CTCF as a Biological Marker for breast cancer and the role of CTCF PARlation may be involved in breast carcinogenesis. PMID- 25810574 TI - Immunomodulated anterior chemotherapy followed by concurrent chemoradiotherapy in locally advanced tongue cancer: An Institutional experience. AB - CONTEXT: Sequential induction chemotherapy with cisplatin and 5-fluorouracil (PF) along with interferon-alpha2b and concurrent chemoradiation offers superior loco regional control for locally advanced carcinoma of oral tongue. AIMS: The study was designed to evaluate the beneficial role of induction PF chemotherapy and interferon-alpha2b followed by chemoradiation over definitive chemoradiation only for patients with locally advanced carcinoma of oral tongue. SETTINGS AND DESIGN: Phase II randomized, prospective, open-labeled, single-institutional study. METHODS AND MATERIAL: Fifty patients were randomized into 2 arms. Arm A patients were treated with induction chemotherapy with PF regimen for 3 cycles and interferon alpha 2b, 3MU biweekly for 6 such followed by chemoradiation with cisplatin 30 mg/ m(2)/ week and external radiotherapy. Arm B patients received chemoradiation only, in the same dose schedule as in Arm A. STATISTICAL ANALYSIS USED: Chi-square test was done to find out the statistical correlation between the two arms. For plotting the disease-free survival (DFS) and overall survival (OS) for the two arms, Kaplan-Meier method was used. RESULTS: The loco-regional response rate of patients treated with interferon containing induction chemotherapy followed by concurrent chemoradiation was superior to concurrent chemoradiation only. However the toxicities and treatment interruption were more in patients treated with induction chemotherapy. CONCLUSIONS: In locally advanced carcinoma of oral tongue, induction chemotherapy with cisplatin and 5 fluorouracil (PF) along with interferon alpha 2b followed by concurrent chemoradiation may produce superior loco-regional control with manageable toxicities that needs to be validated by more randomized trials with adequate number of patients. PMID- 25810577 TI - Delivering palliative care the CanSupport way. PMID- 25810578 TI - Severe skin toxicity due to weekly paclitaxel administration. PMID- 25810576 TI - Time from last chemotherapy to death and its correlation with the end of life care in a referral hospital. AB - BACKGROUND: A substantial number of cancer patients receive chemotherapy until the end of life (EoL). Various factors have been shown to be associated with receipt of chemotherapy until near death. In this study, we determine our average time from last chemotherapy to death (TLCD) and explore different factors that may be associated with decreased TLCD. MATERIALS AND METHODS: A retrospective review of medical records of adult cancer patients who received chemotherapy during their illness and died in our hospital between January 2010 and January 2012 was conducted. Chi-square test and t-test were used to examine the correlation between selected factors and use of chemotherapy within 60 days of death. Multivariate analysis was used to test independent significance of factors testing positive in univariate analysis. Kaplan-Meier method was used to perform survival analysis. RESULTS: Of the 115 cancer patients who died in the hospital, 41 (35.6%) had TLCD of 60 days or less. Patients with better performance status and those dying under medical oncology service were more likely to be in this group of patients. Univariate analysis showed that these patients were less likely to have palliative care involvement, were more likely to die of treatment related causes, and more likely to have died in the Intensive Care Unit. Multivariate analysis confirmed lack of palliative care involvement and better performance status as independent factors for TLCD less than 60 days. Survival analyses showed that patients with palliative care involvement and those dying under palliative care service were likely to have significantly longer TLCD. CONCLUSIONS: Cancer patients who have no involvement of palliative care team in their management tend to receive chemotherapy near the EoL, have more aggressive EoL care, and have higher risk of dying die from treatment related complications. Palliative care should be involved early in the care of cancer patients. PMID- 25810579 TI - Commentary on 19(th) annual scientific meeting of the Society for Neuro-Oncology. AB - The Society for Neuro-Oncology (SNO) is the premier organization dedicated to the cause of central nervous system (CNS) tumors. Although it is primarily located in North America, it attracts considerable memberships from all over the world with truly multi-disciplinary representations from not only neuro-oncology, neurosurgery, radiation oncology, medical oncology and basic scientists, but also in recent years from imaging, psychology, epidemiology, public health and industry, etc. SNO annual meetings are very much looked forward to with presentations of the latest cutting edge data as well as several educational sessions for trainees and updates for senior members too. The meeting is unique in the way that almost the entire scientific agenda is based on submitted abstracts with very few invited lectures. PMID- 25810580 TI - Updates from the 2014 San antonio breast cancer symposium. AB - The san antonio breast cancer syposium (SABCS 2014) was an exciting one this year. Data from the SOFT trial was presented that had potential implications on the treatment of pre menapausal women with hormone receptor positive breast cancer. In a phase II trial fulvestrant was found to significantly improve progression free and overall survival compared to anastrazole in the first line treatment of women with hormone receptor positive metastatic breast cancer. We saw a number of intersting abstracts looking at trying to refine the role of platinums and exploring the role of blocking PD-1 among women with triple receptor negative breast cancer. We also saw the results of a number of trials trying to refine standard chemotherapeutic regimens. Here we will review some fon the most interesting abstracts presented this year at SABCS 2014. PMID- 25810581 TI - Outcome of neoadjuvant chemotherapy in locally advanced breast cancer: A tertiary care centre experience: Retraction. AB - [This retracts the article on p. 215 in vol. 35, PMID: 25336793.]. PMID- 25810582 TI - 2015 - My resolution: A broom in every adult's hand AND a toothbrush in every child's hand! What's yours? PMID- 25810583 TI - Soaring high! PMID- 25810584 TI - Evaluation of usage of interdental aids among dentists as a preventive measure. PMID- 25810585 TI - Computerized implant-dentistry: Advances toward automation. AB - Advancements in the field of implantology such as three-dimensional imaging, implant-planning software, computer-aided-design/computer-aided-manufacturing (CAD/CAM) technology, computer-guided, and navigated implant surgery have led to the computerization of implant-dentistry. This three-dimensional computer generated implant-planning and surgery has not only enabled accurate preoperative evaluation of the anatomic limitations but has also facilitated preoperative planning of implant positions along with virtual implant placement and subsequently transferring the virtual treatment plans onto the surgical phase via static (guided) or dynamic (navigated) systems aided by CAD/CAM technology. Computerized-implant-dentistry being highly predictable and minimally invasive in nature has also allowed implant placement in patients with medical comorbidities (e.g. radiation therapy, blood dyscrasias), in patients with complex problems following a significant alteration of the bony anatomy as a result of benign or malignant pathology of the jaws or trauma and in patients with other physical and emotional problems. With significant achievements accomplished in the field of computerized implant-dentistry, attempts are now been made toward complete automation of implant-dentistry. PMID- 25810586 TI - Sclerostin and occlusion: A brief review. AB - In its pursuit of understanding the wonders of human body, mankind has stumbled upon yet another discovery which not only is a key to chest of unanswered queries but also opens a plethora of new possibilities. Till recently the osteocytes were considered latent cells merely entrapped in the matrix of bone. With the discovery of beta-catenin pathway and sclerostin molecule, these cells are now being recognized to perform a multitude of physiological functions which are important to bone function and turnover. Mechanosensor function of osteocytes via sclerostin molecule offers new possibilities in alveolar bone preservation. Sclerostin and its inhibitors have potential in prosthetic, regenerative and preventive therapy in dentistry. Osteocytic pathway of sclerostin release and mechanism of its interaction with occlusion is discussed in this article. PMID- 25810587 TI - Interleukin-17 and interleukin-18 levels in different stages of inflammatory periodontal disease. AB - CONTEXT: Chronic periodontitis is an inflammatory condition of the tooth supporting structures. There is increasing evidence that the cytokines interleukin-17 (IL-17) and interleukin-18 (IL-18) play a role in progression of chronic periodontitis. AIM: The objective of this study was to compare the levels of the cytokines IL-17 and IL-18 in gingival tissue extracts from individuals with healthy gingiva, chronic gingivitis, and mild chronic periodontitis. SETTINGS AND DESIGN: The study was performed in a hospital-based population with an experimental design. MATERIALS AND METHODS: A total of 69 individuals (n = 23 per group) were recruited for the study. Group 1 included 23 individuals with healthy gingiva and Group 2 included 23 chronic gingivitis patients and Group 3 included 23 patients with mild chronic periodontitis. Gingival tissues were collected during surgical procedures and levels of IL-17 and IL-18 were determined using enzyme-linked immunosorbent assay. STATISTICAL ANALYSIS: Intergroup comparison was done by posthoc Tukey's test. RESULTS: The gingival tissue concentration of IL-17 was found to be highest in Group 2 (415.19 +/- 76.84 pg/mg) followed by Group 3 (193.77 +/- 37.32 pg/mg) and Group 1 (20.49 +/- 6.05 pg/mg). Concentrations of IL-18 were significantly higher (P < 0.01) in Group 2 (1479.42 +/- 330.33 pg/mg) when compared with Group 1 (385.18 +/- 71.26 pg/mg) and Group 3 (330.24 +/- 48.56 pg/mg). CONCLUSION: There appears to be considerable variation of IL-17 and IL-18 levels in gingival tissue during periodontal health and disease. PMID- 25810590 TI - In vitro evaluation of mechanical properties of platelet-rich fibrin membrane and scanning electron microscopic examination of its surface characteristics. AB - BACKGROUND: The aim of this study was to evaluate the mechanical properties of the platelet-rich fibrin (PRF) membrane and to compare these properties with that of commercially available collagen membranes used for guided tissue regeneration (GTR) procedures. Scanning electron microscopic (SEM) examination of PRF membrane was also performed to determine the cell distribution pattern within the different regions of the membrane. MATERIALS AND METHODS: Modulus of elasticity and hardness of (i) PRF membrane (ii) bovine collagen membrane and (iii) fish collagen membrane were assessed by performing surface indentation test using T1 950 Triboindenter. The in vitro degradation tests were conducted by placing the (i) PRF membrane (ii) bovine collagen membrane and (iii) fish collagen membrane of equal sizes (10 mm * 5 mm) in 5 ml of pH 7.4 phosphate buffer solution on a shaker set at 40 rpm for 1-week. The degradation profiles were expressed as the accumulated weight losses of the membrane. SEM evaluation of the PRF membrane was done under both low and high magnification. RESULTS: Young's Modulus of elasticity was found to be 0.35 GPa for PRF membrane, 2.74 GPa for bovine collagen membrane and 1.92 GPa for fish collagen. The hardness was 10.67 MPa for PRF membrane, 110.7 MPa for bovine collagen membrane and 90.5 MPa for fish collagen membrane. PRF membrane degraded by about 36% of initial weight after a 1 week in vitro shaking test. Fish collagen membrane degraded by about 8% of initial weight, bovine collagen membrane degraded by about 3% of initial weight. Dense clusters of platelets formed due to extensive aggregation, and few leukocytes were observed in buffy coat area. CONCLUSIONS: The preliminary findings from the assessment of the mechanical properties of PRF membrane showed that it was lacking in several desired properties when compared to commercially available collagen membranes. Lack of rigidity and faster degradation may limit its application in GTR procedures. PMID- 25810588 TI - Efficacy versus health risks: An in vitro evaluation of power-driven scalers. AB - BACKGROUND: Power-driven instrumentation of root surfaces during supportive periodontal therapy is an alternative to hand instrumentation. The purpose of this pilot in vitro study was to investigate the efficacy of sub- and supragingival plaque removal with a sonic (AIR: Synea, W and H, Burmoos, Austria) and two ultrasonic devices (TIG: Tigon+, W and H, Burmoos, Austria; VEC: Vector, Durr, Bietigheim-Bissingen, Germany) as well as the health-risk for dental professionals during treatment. MATERIALS AND METHODS: The power-driven devices were utilized to remove plaque from model teeth in dummy heads. The percentage of residual artificial plaque after 2 min of supra- or subgingival instrumentation was calculated by means of image-processing techniques at four sites (n = 576) of each tooth. The Health-Risk-Index (HRI: spatter/residual plaque quotient) with the different power-driven devices was assessed during treatment. RESULTS: The smallest amounts of residual plaque were found for the sonic device AIR (8.89% +/ 10.92%) and the ultrasonic scaler TIG (8.72% +/- 12.02%) (P = 0.707). Significantly more plaque was remained after the use of the ultrasonic scaler VEC (18.76% +/- 18.07%) (P < 0.001). Irrespectively of the scaler, efficacy was similar sub- (10.7% +/- 11.6%) and supragingivally (13.5% +/- 17.2%) (P = 0.901). AIR/TIG demonstrated equal residual amounts of plaque sub- (P = 0.831) as well as supragingivally (P = 0.510). However, AIR/VEC and TIG/VEC were significantly in favor of AIR and TIG (P < 0.001). In contrast, the lowest HRI was found after using VEC (0.0043) and differed considerably for AIR (0.2812) and TIG (0.0287). CONCLUSION: Sonic devices are as effective as ultrasonic devices in the removal of biofilm but bear a higher risk to the dental professional's health concerning the formation of spatter. PMID- 25810589 TI - Modulatory effects by neodymium-doped yttrium aluminum garnet laser on fibroblast attachment to single rooted tooth surfaces following ultrasonic scaling and root planning: An in vitro study. AB - CONTEXT: One of the most important goals of periodontal therapy is connective tissue reattachment to previously diseased root surfaces. In the recent years, laser therapy has been considered as an important tool in improving the treatment of periodontal disease. AIMS: To evaluate the neodymium-doped yttrium aluminum garnet (Nd: YAG) lasers effects on root surfaces affected by periodontal disease and compare this treatment with scaling and root planning (SRP) in terms of fibroblast attachment. MATERIALS AND METHODS: A sample of 30 single-rooted human teeth extracted because of advanced periodontal disease was used in this study. Sixty specimens obtained by longitudinal sectioning were randomly divided in three groups. Group A control (untreated); Group B SRP; Group C laser (Nd: YAG) and ultrasonic scaling. All specimens were incubated with fibroblast suspension and then fixed and observed under scanning electron microscope. RESULTS: With a median of 8, the control group (Group A) exhibited the least number of total fibroblasts among all the three groups. The laser and scaling - treated group (Group C) showed the highest number of fibroblasts (median = 49, mean +/- standard deviation [SD] = 48.28 +/- 17.18), followed by SRP only (Group B, median = 22, mean +/- SD = 22.24 +/- 8.67). CONCLUSIONS: Nd: YAG laser irradiation at specific energy densities can be used as a useful tool to condition the root surfaces, enhancing fibroblast attachment. Hence aiding in re-establishment of the connective tissue attachment to the root surfaces of previously diseased teeth. PMID- 25810591 TI - Local delivery of hyaluronan 0.8% as an adjunct to scaling and root planing in the treatment of chronic periodontitis: A clinical and microbiological study. AB - BACKGROUND: The purpose of this study was to assess the clinical and microbiological effects of the local and sub-gingival application of a hyaluronan gel on scaling and root planing (SRP) in the treatment of moderate generalized chronic periodontitis. MATERIALS AND METHODS: In this split mouth study, 72 teeth in 18 patients with generalized chronic periodontitis with moderate severity were chosen for the study. Plaque samples were obtained by paper points at required intervals. Contra-lateral pairs of premolars and canine teeth in the maxilla or the mandible were selected to receive test treatment or serve as controls. Experimental jaw quadrants received sub-gingival administration of 0.2-ml 0.8% hyaluronan gel into selected sites following SRP and 1-week later. Clinical parameters were assessed at baseline, 1(st), 4(th), and 12(th) week. Colony forming units (CFU) per milliliter were assessed at baseline, after SRP and after 2 weeks of drug insertion Student t-test and repeated measure ANOVA (RMANOVA) were used in this study. RMANOVA was used to find the significance in bleeding on probing (BOP) and plaque index (PI) and t-test for probing pocket depth (PPD) and clinical attachment level (CAL). RESULTS: The results revealed that there was a significant reduction in BOP (P < 0.001) PI (P < 0.001), PPD (P < 0.001) and CAL (P < 0.001) were also observed in experimental jaw quadrant following SRP and insertion of 0.8% hyaluronan when compared with the control group. A statistically significant reduction of CFUs was also found (P < 0.001) in the experimental site when compared with the control site. CONCLUSION: Sub-gingival placement of 0.2-ml of 0.8% hyaluronan along with SRP resulted in a significant improvement in both clinical and microbiological parameters when compared with the control site. PMID- 25810592 TI - Evaluation of the use of a 940 nm diode laser as an adjunct in flap surgery for treatment of chronic periodontitis. AB - BACKGROUND: Lasers have several potential benefits such as antibacterial effect and stimulation of wound healing. In addition, hemostasis and delaying epithelial migration may facilitate the outcome of flap surgery. There is a minimal research and evidence currently available for the optimum method of use of a diode laser in flap surgery and its benefit and safety. Hence, this study aimed to investigate the adjunctive effect of diode laser irradiation in open flap debridement (OFD), while treating chronic periodontitis. MATERIALS AND METHODS: A total of 30 patients with generalized chronic moderate to severe periodontitis with pocket probing depth (PD) >=5 mm post - Phase I therapy were selected for a split-mouth study. Flap surgery with adjunctive diode laser irradiation was performed in the test quadrant while routine OFD was done in the control quadrant. Clinical parameters including PD, clinical attachment level, gingival recession, plaque index, gingival index and tooth mobility were recorded at baseline, 3 months and 6 months following treatment. In addition, patients' rating of procedural pain as well as the development of complications postoperatively was assessed. RESULTS: All clinical parameters significantly improved after therapy without any statistically significant difference between the two groups for any of the parameters. The exception was a significantly greater reduction in gingival inflammation in the laser treated group. The laser treatment was acceptable to the patient and did not cause any complications. CONCLUSION: The diode laser can be safely and effectively used as an adjunct to the treatment of chronic periodontitis with the advantage of decreased gingival inflammation. PMID- 25810593 TI - Evaluation of pain on use of electrosurgery and diode lasers in the management of gingival hyperpigmentation: A comparative study. AB - BACKGROUND: Gingival depigmentation is a periodontal plastic surgical procedure whereby the gingival hyperpigmentation is removed by various techniques such as electrosurgery, cryosurgery, abrasion with diamond bur and lasers. The aim of this study was to determine the pain levels during the gingival depigmentation procedure using electrosurgery and lasers. MATERIALS AND METHODS: Twenty patients, both male and female, between the ages of 20 and 40 years were randomly allocated into two groups of 10 patients each: Those undergoing depigmentation with electrosurgery (Group I) and those by diode lasers (Group II). Patients of both groups were asked to define the level of pain and discomfort by using the Visual Analog Scale (VAS) intraoperatively, 24 h post-operatively and 1 week post operatively. RESULTS: Both the groups showed a decrease in the pain levels, which was statistically highly significant 1 week post-operatively when compared 24 h post-operatively. There was a statistically highly significant difference in the pain levels between the electrosurgery and the lasers groups after 24 h (P < 0.001), with the lasers group demonstrating lesser pain and discomfort. Although there was no significant difference between the two groups intraoperatively and 1 week post-operatively on comparison, lesser mean scores were observed for the lasers group. CONCLUSION: The growing concern for esthetic requires the removal of hyperpigmentated gingival areas to create a confident and pleasant smile, which could be easily attained by using either electrosurgery or lasers. This study concluded that lasers produce lesser pain and discomfort compared with electrosurgery during gingival depigmentation. PMID- 25810594 TI - Comparative evaluation of platelet-rich fibrin with demineralized freeze-dried bone allograft in periodontal infrabony defects: A randomized controlled clinical study. AB - INTRODUCTION: Several bone graft materials have been used in the treatment of infrabony defects. Demineralized freeze-dried bone allograft (DFDBA) has been histologically proven to be the material of choice for regeneration. However, platelet-rich fibrin (PRF) has been said to have several properties that aid in healing and regeneration. Hence, this study focuses on the regenerative capacity of PRF when compared with DFDBA. MATERIALS AND METHODS: A total of 40 sites with intrabony defects were selected and were assigned to the test group (open flap debridement [OFD] and PRF, n = 20) and the control group (OFD + DFDBA, n = 20). At the test sites, two PRF plugs were placed in the intrabony defect after debridement of the site and flap was sutured in place. The parameters measured were probing depth (PD), relative attachment level (RAL), and gingival marginal level (GML). These parameters were measured just before surgery (baseline) and at 6 months postsurgery. The changes in PD, RAL, and GML were analyzed at baseline and postsurgically after 6 months in each group with paired t-test and between the two groups with unpaired t-test. RESULTS: The mean reduction in PD after 6 months in the test PRF group is 3.67 +/- 1.48 mm where in control DFDBA group is 3.70 +/- 1.78 mm. Gain in RAL in the test PRF group is 2.97 +/- 1.42 mm where in control DFDBA group, it is 2.97 +/- 1.54 mm. Gingival margin migrated apically in the test PRF group by 0.43 +/- 1.31 mm where in control DFDBA group by 0.72 +/- 2.3 mm. It was seen that the differences in terms of PD (P = 0.96), RAL (P = 1.00) and GML (P = 0.62) were not significant. CONCLUSION: Platelet-rich fibrin has shown significant results after 6 months, which is comparable to DFDBA for periodontal regeneration in terms of clinical parameters. Hence, it can be used in the treatment of intrabony defects. PMID- 25810596 TI - Comparative clinical evaluation of coronally advanced flap with or without platelet rich fibrin membrane in the treatment of isolated gingival recession. AB - AIM: The aim of this study was to determine whether the addition of an autologous platelet rich fibrin (PRF) membrane to a coronally advanced flap (CAF) would improve the clinical outcome in terms of root coverage, in the treatment of isolated gingival recession. MATERIALS AND METHODS: Systemically healthy 20 subjects each with single Miller's class I or II buccal recession defect were randomly assigned to control (CAF) or test (CAF + PRF) group. Clinical outcome was determined by measuring the following clinical parameters such as recession depth (RD), recession width (RW), probing depth (PD), clinical attachment level (CAL), width of keratinized tissue (WKT), gingival thickness (GTH), plaque index (PI), and gingival index (GI) at baseline, 3(rd), and 6(th) month postsurgery. RESULTS: The root coverage was 65.00 +/- 44.47% in the control group and 74.16 +/ 28.98% in the test group at 6(th) month, with no statistically significant difference between them. Similarly, CAL, PD, and WKT between the groups were not statistically significant. Conversely, there was statistically significant increase in GTH in the test group. CONCLUSION: CAF is a predictable treatment for isolated Miller's class I and II recession defects. The addition of PRF to CAF provided no added advantage in terms of root coverage except for an increase in GTH. PMID- 25810595 TI - Clinical and radiographic evaluation of nanocrystalline hydroxyapatite with or without platelet-rich fibrin membrane in the treatment of periodontal intrabony defects. AB - BACKGROUND: Nano-sized ceramics may represent a promising class of bone graft substitutes due to their improved osseointegrative properties. Nanocrystalline hydroxyapatite (NcHA) binds to bone and stimulate bone healing by stimulation of osteoblast activity. Platelet-rich fibrin (PRF), an intimate assembly of cytokines, glycan chains, and structural glycoproteins enmeshed within a slowly polymerized fibrin network, has the potential to accelerate soft and hard tissue healing. The present study aims to explore the clinical and radiographical outcome of NcHA bone graft with or without PRF, in the treatment of intrabony periodontal defects. MATERIALS AND METHODS: In a split-mouth study design, 20 patients having two almost identical intrabony defects with clinical probing depth of at least 6 mm were selected for the study. Selected sites were randomly divided into two groups. In Group I, mucoperiosteal flap elevation followed by the placement of NcHA was done. In Group II, mucoperiosteal flap elevation, followed by the placement of NcHA with PRF was done. Clinical and radiographic parameters were recorded at baseline and at 6-month postoperatively. RESULTS: Both treatment groups showed a significant probing pocket depth (PPD) reduction, clinical attachment gain, increase bone density 6-month after surgery compared with baseline. However, there was a significantly greater PPD reduction and clinical attachment gain when PRF was added to NcHA. CONCLUSION: The NcHA bone graft in combination with PRF demonstrated clinical advantages beyond that achieved by the NcHA alone. PMID- 25810597 TI - Vascularized interpositional periosteal connective tissue flap: A modern approach to augment soft tissue. AB - CONTEXT: Nowadays esthetics plays an important role in dentistry along with function of the prosthesis. Various soft tissue augmentation procedures are available to correct the ridge defects in the anterior region. The newer technique, vascularized interpositional periosteal connective tissue (VIP-CT) flap has been introduced, which has the potential to augment predictable amount of tissue and has many benefits when compared to other techniques. AIM: The study was designed to determine the efficacy of the VIP-CT flap in augmenting the ridge defect. MATERIALS AND METHODS: Ten patients with Class III (Seibert's) ridge defects were treated with VIP-CT flap technique before fabricating fixed partial denture. Height and width of the ridge defects were measured before and after the procedure. Subsequent follow-up was done every 3 months for 1-year. STATISTICAL ANALYSIS USED: Paired t-test was performed to detect the significance of the procedure. RESULTS: The surgical site healed uneventfully. The predictable amount of soft tissue augmentation had been achieved with the procedure. The increase in height and width of the ridge was statistically highly significant. CONCLUSION: The VIP-CT flap technique was effective in augmenting the soft tissue in esthetic area that remained stable over a long period. PMID- 25810598 TI - Comparison of oral health status between children with cerebral palsy and normal children in India: A case-control study. AB - BACKGROUND: The aim of the present research was to describe and compare the oral health of children with cerebral palsy (CP) with the normal children in India. MATERIALS AND METHODS: Fifty children with CP of the age range 7-17 years and fifty normal children were selected for the study. An oral examination was carried out and decayed, missing, and filled teeth (dmft/DMFT) index, oral hygiene index-simplified (OHI-S) index, Angles malocclusion were charted along with other significant dental findings. Data were analyzed using Student's t-test and Kruskal-Wallis one-way ANOVA test. RESULTS: The mean dmft/DMFT of the CP group was 4.11 +/- 2.62, while that of controls was 2.95 +/- 2.75, which showed higher caries prevalence in the CP group. There was a significant association between the dmft/DMFT (P = 0.03), OHI-S (P = 0.001), and Angles Class 2 malocclusion and CP. CONCLUSIONS: Cerebral palsy group had higher caries, poor oral hygiene and Class 2 malocclusion when compared to controls primarily because of their compromised general health condition and also less dental awareness. Effort should be made for better organization of preventive dental care and promoting dental health of this challenged population. PMID- 25810599 TI - Peripheral ossifying fibroma: A clinicopathologic study of 27 cases and review of the literature with emphasis on histomorphologic features. AB - The peripheral ossifying fibroma (POF) is a relatively uncommon, reactive gingival overgrowth usually composed of cellular fibroblastic tissue containing one or more mineralized tissues, namely bone, cementum-like material, or dystrophic calcification. The aetiology and pathogenesis of POF are yet not clear, but some authors have hypothesized a reaction originating from the periodontal ligament, as a result of irritating agents such as dental calculus, plaque, orthodontic appliances, and ill-fitting restorations. The aim of our study was to report the clinicopathologic features of a case series of POF from a single Italian institution. A total of 27 cases were collected over an 18-year period. Detailed relevant medical history, clinical and histological information were recorded for each patient. The age range of patients (m = 6; f = 21) was 17.2-80.1 years with a mean of 42.9 +/- 18.1 years. Occurrence of the lesion in the mandibular and maxillary arches was similar, and 67.0% occurred in the incisor-cuspid region. The lesions ranged in size from 0.3 to 5.0 cm (mean, 1.3 cm +/- 1.1 cm). All the different types of mineralization were present, with higher prevalence of lamellar bone. The lesions were treated by surgical excision and four lesions in three patients recurred after surgery. Surgeons should consider the high recurrence rate of POF and remove the lesion down to the bone involving also the adjacent periosteum and the periodontal ligament. Professional prophylaxis should precede any surgical procedure, and periodical dental hygiene recalls are important in order to remove any possible irritating factor. PMID- 25810600 TI - Isolated cleft lip with generalized aggressive periodontitis: A rare entity. AB - Oro-facial clefts are one of the most common birth defects and may be associated with other genetic anomalies. Aggressive periodontitis is a rare condition that progresses rapidly, but affects only a small percentage of the population. Most of the cases of aggressive periodontitis are familial. Even though, literature has documented the association of various genetic disorders with aggressive periodontitis, the aggressive periodontitis in patients with isolated cleft lip (CL) have never been addressed. Here, we report a rare case of isolated CL with generalized aggressive periodontitis. The concomitant presentation of isolated CL with aggressive periodontitis in an individual has clinical significance for multi-disciplinary care. PMID- 25810602 TI - An interdisciplinary management of severely resorbed maxillary anterior ridge complicated by traumatic bite using a ridge splitting technique. AB - Injury to the teeth and alveolar ridge of the maxillary anterior region due to trauma can cause severe alveolar ridge deficiency. Ridge augmentation is a valuable periodontal plastic surgical method for the correction of ridge defects for esthetic purpose. Although ridge augmentation can help to restore the ridge volume, the grafting procedures can significantly increase the patient morbidity, treatment time, and the cost. Among the ridge augmentation techniques, the ridge split procedure demonstrates many benefits such as no need for donor site, the rare risk of damage to underlying anatomical structures, less pain, and swelling. This case report presents a vertical split technique for increasing the bone volume. There was a remarkable healing and significant increase in bone volume. We have followed the case for 6 months. PMID- 25810601 TI - Recurrent idiopathic gingival fibromatosis with generalized aggressive periodontitis: A rare case report. AB - Gingival fibromatosis is an enlargement of the gingival tissue, which may be localized or generalized, characterized by hypertrophy and proliferation of the connective tissue, predominantly Type I collagen, with occasional presence of an increased number of cells, supposedly fibroblasts. Gingival fibromatosis occurs more commonly as a side- effect of systemic drugs, such as phenytoin, cyclosporine, nifedipine, or due to hereditary factors. However, in some cases, it is idiopathic. We report one such case in 30 -year- old - female who presented with a complaint of swelling of gums since 2 months. This case appears to be of special interest because of the recurrent nature of gingival enlargement along with excessive osseous destruction. PMID- 25810603 TI - Periosteal pedicle graft: A novel root coverage approach. AB - Gingival recession along with reduced width of attached gingiva and inadequate vestibular depth is a very common finding. Many techniques have been adopted in order to treat such defects and obtain predictable root coverage. Several graft procedures are used to obtain the coverage, but they have not been able to deliver predictable and satisfactory results (except connective tissue graft). Some of them also resulted in the secondary surgical site that was very uncomfortable for the patients. There was an intense need for a technique that provides not only good and predictable root coverage, but also reduces the need for secondary surgical site. Hence, this paper describes a single stage technique for increasing the width of attached gingiva and root coverage by using the periosteal pedicle graft. PMID- 25810604 TI - Modified Whale's tail technique for the management of bone-defect in anterior teeth. AB - The purpose of this case report is to describe the efficacy of a modified Whale's tail technique to achieve primary closure and thereby aid in regeneration of an interdental osseous defect between maxillary central incisors complicated by an aberrant frenal attachment. A healthy 32-year-old female patient reported with the complaint of spacing between her upper front teeth. Clinical examination revealed an aberrant frenum extending into the interdental papilla in relation to the central incisors. There was a 6 mm periodontal pocket in relation to the mesiopalatal aspect of maxillary left central incisor. Intraoral periapical radiograph showed vertical bone loss in relation to mesial aspect of maxillary left central incisor. A modified Whale's tail flap was employed to access the area. The defect was filled with an alloplastic graft. Six months postoperative review showed complete elimination of the pocket along with radiographic bone fill of the defect. PMID- 25810605 TI - End-of-life care in the Pediatric Intensive Care Units: Challenges and ethical principles. PMID- 25810606 TI - Can we consider procalcitonin as a consolidated biomarker in sepsis management? PMID- 25810607 TI - Candida glabrata candidemia. PMID- 25810608 TI - Procalcitonin kinetics as a prognostic marker in severe sepsis/septic shock. AB - BACKGROUND AND AIMS: To evaluate the prognostic value of change (fall) in serum procalcitonin level (PCT) in critically ill adults with severe sepsis/septic shock. METHODS: This was a prospective observational study in a general purpose Intensive Care Unit of a teaching Institute. PCT was measured at admission (D0) and after 72-96 h (D4) by electrochemi-luminescence immunoassay (BRAHMS PCT kit) in adults (>18 years) admitted with severe sepsis or septic shock. Change in procalcitonin values from D0 to D4 was correlated with the primary outcome, that is, 28 days mortality. All results are reported as median (interquartile range). RESULTS: A total of 171 (100 males) of 181 patients were included. The median age was 46 years (range 19-79). 137 patients were in septic shock and 34 in severe sepsis. The sequential organ failure assessment (SOFA) score in all patients was 11 (9-14).91 (53.2%) patients survived at 28 days (survivors). The baseline procalcitonin was similar in two groups (3.48 [1.04-15.85] vs. 5.27 [1.81-23.57] ng/ml in survivors and nonsurvivors [NS] respectively). The procalcitonin change was 1.58 (0.20-8.52) in survivors and 0.28 (-1.38-6.17) in NS (P = 0.01). The C statistic of percentage change in procalcitonin from D0 to D4 to predict survival was 0.73 (95% confidence interval [CI]: 0.65-0.82) when compared to 0.78 (95% CI: 0.71-0.86) for change of SOFA score. For an absolute fall in procalcitonin of >1 ng/ml, a 70% fall predicted survival with 75% sensitivity and 64% specificity. CONCLUSIONS: In critically ill-patients with severe sepsis/septic shock, change (fall) in procalcitonin is associated with good outcome. PMID- 25810609 TI - Mortality patterns among critically ill children in a Pediatric Intensive Care Unit of a developing country. AB - BACKGROUND AND AIM: Advances in biomedical technology have made medical treatment to be continued beyond a point, at which it does not confer an advantage but may increase the suffering of patients. In such cases, continuation of care may not always be useful, and this has given rise to the concept of limitation of life sustaining treatment. Our aim was to study mortality patterns over a 6-year period in a Pediatric Intensive Care Unit (PICU) in a developing country and to compare the results with published data from other countries. MATERIALS AND METHODS: Retrospective cohort study was conducted in a PICU of a tertiary care hospital in Pakistan. Data were drawn from the medical records of children aged 1 month - 16 years of age who died in PICU, from January 2007 to December 2012. RESULTS: A total of 248 (from an admitted number of 1919) patients died over a period of 6 years with a mortality rate 12.9%. The median age of children who died was 2.8 years, of which 60.5% (n = 150) were males. The most common source of admission was from the emergency room (57.5%, n = 143). The most common cause of death was limitation of life-sustaining treatment (63.7%, n = 158) followed by failed cardiopulmonary resuscitation (28.2%, n = 70) and brain death (8.1%, n = 20). We also found an increasing trend of limitation of life-sustaining treatment do-not-resuscitate (DNR) over the 6-year reporting period. CONCLUSION: We found limitation of life support treatment (DNR + Withdrawal of Life support Treatment) to be the most common cause of death, and parents were always involved in the end of-life care decision-making. PMID- 25810610 TI - Candida glabrata candidemia: An emerging threat in critically ill patients. AB - BACKGROUND: Candidemia is an important nosocomial blood stream infection in critically ill patients. Although several studies have addressed candidemia, very few have reviewed the impact of Candida glabrata candidemia in Intensive Care Unit (ICU) patients. MATERIALS AND METHODS: The medical records of ICU patients between 2006 and 2010 were reviewed retrospectively. The epidemiology, clinical features and mortality related risk factors among our adult ICU patients were seen. RESULTS: Among 144 episodes of candidemia, C. glabrata (n = 26; 18.05%) was the third most common species isolated. The incidence of C. glabrata candidemia was 0.21/1000 ICU admissions. The most common risk factors were prior exposure to broad spectrum antibiotics (100%), central venous catheter (100%), mechanical ventilation (76.9%), diabetes mellitus (50%), age >65 years (46.15%). Urine (23%) was the most common source of C. glabrata candidemia. Overall in hospital 30 days mortality rate due to C. glabrata fungemia was 53.8%. Patients who were treated with fluconazole showed better outcome than patients treated with amphotericin B. Renal failure requiring hemodialysis was the significantly associated with mortality in our study. CONCLUSION: Candida glabrata was the 3(rd) most common Candida causing candidemia in our ICUs with a incidence of 0.21/1000 ICU admissions. The outcome of ICU acquired C. glabrata candidemia was poor with 30 days mortality rate of 53.8%. Renal failure requiring hemodialysis was the only risk factor associated with mortality. Further studies are required to identify the other risk factors associated with mortality in C. glabrata candidemia. PMID- 25810611 TI - Age influences the predictive value of Acute Physiology and Chronic Health Evaluation II and Intensive Care National Audit and Research Centre scoring models in patients admitted to Intensive Care Units after in-hospital cardiac arrest. AB - INTRODUCTION: Outcomes following in-hospital cardiac arrest (IHCA) are generally poor though different patient populations may benefit to different degrees from admission to Intensive Care Units (ICUs). Risk stratification algorithms may be useful in identifying patients who are most likely to benefit from ICU admission and so may aid allocation of this scarce resource. We aimed to compare the performance of the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Intensive Care National Audit and Research Centre (ICNARC) scoring systems in predicting outcome following ICU admission after IHCA in younger (<=69 years) and older (>=70 years) patients. MATERIALS AND METHODS: We performed a retrospective observational study in two adult ICUs from January 2006 to February 2010 inclusive. Patients were divided into younger (<=69 years) and older (>=70 years) patients. The primary outcome measures were acute hospital mortality and area under the curve (AUC) calculation for receiver operating characteristic (ROC) analysis. RESULTS: Two hundred and sixty-one adult consecutive adult patients admitted following IHCA. Hospital mortality was 58.6%. ROC analysis demonstrated that ICNARC was more accurate than APACHE II in predicting acute hospital outcomes in the adult population (AUC 0.734 vs. 0.706). Both scoring systems performed weaker when predicting outcomes in younger patients compared to older patients (ICNARC AUC 0.655 vs. 0.810; APACHE II AUC 0.660 vs. 0.759). DISCUSSION: Both APACHE II and ICNARC predict outcome well in older patients. In younger patients, their value is less clear, and so they must be used with caution. PMID- 25810613 TI - Osmotic demyelination syndrome in Intensive Care Unit. AB - Dyselectrolytemia, especially hyponatremia is a common occurrence in hospitalized patients, and a number of dreaded complications arise out of the disorder itself and its treatment. Osmotic demyelination syndrome develops secondary to rapid correction of hyponatremia. As the disease is rare and available literature from Intensive Care Units are limited, we report our retrospective observation over 5 years. Overall incidence was 2.5% with altered sensorium and hypokalemia as most common symptom and associated factor respectively. Isolated pontine involvement was in 41% and combined pontine, and extra-pontine lesions were found in 23% of cases. All patients received supportive therapy; out of which 2 died and complete neurological recovery was seen in 24% of patients. Our findings suggest that a well organized supportive therapy and multidisciplinary approach is of more concern than many available therapeutic modalities which are still to be proved. PMID- 25810614 TI - Laryngeal air column width ratio in predicting post extubation stridor. AB - AIM: Correlation of upper air column width ratio in postextubation stridor patients. MATERIALS AND METHODS: A prospective observational study was conducted in a tertiary hospital between January and December 2013. Patients who were admitted in Intensive Care Unit and intubated for >24 h were included (72 patients). The upper airway air column width ratio (air column width before extubation/air column width after intubation) was calculated and compared in patient with or without postextubation stridor. RESULTS: The incidence of stridor was 6.9% (5/72). The duration of mechanical ventilation was 5.60 +/- 1.14 days and 3.91 +/- 1.45 days in stridor and nonstridor group respectively. In all 5 patients who had stridor, the upper airway air column width ratio was 0.8 or less. CONCLUSION: Air column width ratio of 0.8 or less may be helpful in predicting postextubation stridor, which should be confirmed by large observational studies. PMID- 25810612 TI - Could a protocol based on early goal-directed therapy improve outcomes in patients with severe sepsis and septic shock in the Intensive Care Unit setting? AB - CONTEXT: Sepsis is a disease with high incidence and mortality. Among the interventions of the resuscitation bundle, the early goal-directed therapy (EGDT) is recommended. AIMS: The aim was to evaluate outcomes in patients with severe sepsis and septic shock using EGDT in real life compared with patients who did not undergo it in the Intensive Care Unit (ICU) setting. SETTINGS AND DESIGN: retrospective and observational cohort study at tertiary hospital. SUBJECTS AND METHODS: All the patients admitted to ICU were screened for severe sepsis or septic shock and included in a registry and followed. The patients were allocated in two groups according to submission or not to EGDT. RESULTS: A total of 268 adult patients with severe sepsis or septic shock were included. EGDT was employed in 97/268 patients. The general mortality was higher in no early goal directed therapy (no-EGDT) then in EGDT groups (49.7% vs. 37.1% [P = 0.04] in hospital and 40.4% vs. 29.9% [P = 0.08] in the ICU, respectively. The general length of stay [LOS] in the no-EGDT and EGDT groups was 45.0 +/- 59.8 vs. 29.1 +/ 30.1 days [P = 0.002] in hospital and 17.4 +/- 19.4 vs. 9.1 +/- 9.8 days [P < 0.001] in the ICU, respectively). CONCLUSIONS: Our study shows reduced mortality and LOS in patients submitted to EGDT in the ICU setting. A simplified EGDT without central venous oxygen saturation is an important tool for sepsis management. PMID- 25810615 TI - A rare case of leptospirosis with isolated lung involvement. AB - Leptospirosis is a zoonosis caused by a pathogenic spirochete "leptospira interrogans." Severe form of leprospira infection is usually associated with jaundice and renal involvement, leading to major hemorrhagic complications. Lung involvement can vary from subtle clinical features to deadly pulmonary hemorrhage and acute respiratory distress syndrome (ARDS). We recently managed a case of leptospirosis with isolated lung involvement as alveolar hemorrhage and ARDS. Our patient had acute febrile illness with respiratory symptoms associated with radiological picture of pulmonary hemorrhage. Patient was managed with noninvasive ventilation with high flow oxygen, antibiotic and pulse steroids therapy. In conclusion, leptospirosis can present with predominant pulmonary involvement, instead of the classical triad of Weil disease. High index of suspicion should be kept in acute febrile illness patients with respiratory symptoms and alveolar hemorrhage. Early diagnosis and management with oxygenation, antibiotics and immunosuppresents can prevent complications and mortality. PMID- 25810616 TI - Fatal lactic acidosis possibly related to ganciclovir therapy in a renal transplant patient? AB - Ganciclovir is widely prescribed in renal transplant patients for the prevention or treatment of herpes and cytomegalovirus (CMV) infections. Side-effects are usually represented by hematological disorders, and particularly leucopenia. We report a case of severe and fatal lactic acidosis developing in a 76-year-old renal transplant woman, a few days after ganciclovir has been introduced to treat CMV pneumonia. Usual etiologies of lactic acidosis were ruled out. A high lactate/pyruvate molecular ratio was suggestive of a respiratory chain dysfunction. With the analogy to nucleoside analogues-related lactic acidosis, we suggest that ganciclovir may exceptionally be responsible for respiratory chain dysfunction and subsequent lactic acidosis, and we discuss potential risk factors in our patient. PMID- 25810617 TI - Near fatal spontaneous intraperitoneal bleeding: A rare manifestation in a congenital factor X deficiency carrier. AB - Congenital factor X (FX) deficiency is a rare coagulation disorder of autosomal recessive inheritance, characterized by bleeding of variable severity. Bleeding severity generally correlates with the level of FX functional activity and severe bleeding usually occurs in moderate and severe deficiency, when FX coagulant activity is <5%. FX activity above 10% is infrequently associated with severe bleeding. Here we report the rare occurrence of life-threatening massive spontaneous intraperitoneal bleeding with hypovolemic shock, resulting from spontaneous rupture of an ovarian luteal cyst in a 25-year-old FX deficiency carrier woman, with a FX activity of 26%. She was managed successfully conservatively, with fresh frozen plasma and packed red blood cell transfusions and she showed gradual improvement. The case is being reported to discuss the diagnosis and management of this rare inherited coagulation disorder. PMID- 25810619 TI - Pharmaceutical companies as the funding sources for continuing medical education. PMID- 25810618 TI - Methylmalonic acidemia mimicking diabetic ketoacidosis and septic shock in infants. AB - Methylmalonic acidemia (MMA) is most common inherited type of organic acidemia. It has diverse presentation in older infants without any initial apparent symptoms. MMA sometimes present with sudden metabolic decompensation, which may mimics common emergencies like septic shock and diabetic ketoacidosis (DKA) without early recognition can be fatal. In born error of metabolism especially organic acidemia should be suspected in any infant presented with severe high anion gap metabolic acidosis. We report two cases of MMA in infants presented acutely mimicking DKA and septic shock. PMID- 25810620 TI - Methyl alcohol poisoning causing putamen necrosis. PMID- 25810621 TI - Mobilization in Indian intensive care units: Where do we stand? PMID- 25810622 TI - Hyponatremia management in critically ill: Food (protein) for thought. PMID- 25810623 TI - Rhabdomyolysis in lumbar spinal surgery: Early detection is crucial. PMID- 25810624 TI - Geriatric critical care in India. PMID- 25810625 TI - Need for evidence-based practice at grass root level to improve child health and development. PMID- 25810626 TI - Prevalence of acute respiratory infection among under-five children in urban and rural areas of puducherry, India. AB - INTRODUCTION: The incidence of Acute respiratory infections (ARI) is high among under-five children, especially in developing countries. However, the data on ARI from rural and urban areas in India are scarce. OBJECTIVE: To estimate the prevalence of ARI and selected associated factors among under-five children. MATERIALS AND METHODS: A community-based cross-sectional study was conducted in urban and rural areas of Puducherry, India. Data were collected from 509 parents of under-five children regarding ARI incidence along with socio-demographic and selected associated factors. RESULTS: Overall prevalence of ARI was observed to be 59.1%, with prevalence in urban and rural areas being 63.7% and 53.7%, respectively. Bivariate analysis indicated that overcrowding, place of residence, and mother's education were significantly associated with ARI. Multiple logistic regression analysis suggested that presence of overcrowding (adjusted odds ratio [AOR] = 1.492), urban residence (AOR = 2.329), and second birth order (AOR = 0.371) were significant predictors of ARI. CONCLUSION: The prevalence of ARI is high, particularly in urban areas. Improvement of living conditions may help in reduction of burden of ARI in the community. PMID- 25810627 TI - Discrimination against differently abled children among rural communities in India: Need for action. AB - BACKGROUND: Persons with disabilities comprise at least 4 to 8 percent of the Indian population. Children with disabilities in India are subject to multiple deprivations and limited opportunities in several dimensions of their lives. Their families and caregivers also go through lot of stress and challenges in having a person with disability at home which ultimately leads to grave discriminatory practices towards these children. MATERIALS AND METHODS: The article attempts to analyze and describe the common discriminatory grounds that children with disabilities commonly face from their immediate families and from the larger community through analyzing the filed visit reports of the Basic Needs India Staff providing on job training (handholding support) for the community based rehabilitation workers. RESULTS: The case studies describes the various ugly forms of the discriminatory practices seen in the community towards differently abled children, same been categorized as denial of disability, physical restraints, social boycott, denial of property rights, decreased marital life prospects due to disabled member in family, implications on sexuality of people with disability, women with disability, discrepancies in state welfare programs, and problems in measuring disabilities. CONCLUSION: During the last two decades, there has been a growing realization that institutional care for the disabled is not entirely suitable for their individual needs, dignity and independence. A movement towards community based rehabilitation has picked up pace and contribute toward greater independence and self sustainability of the disabled. PMID- 25810628 TI - Prevention of childhood obesity in India: Way forward. AB - Childhood obesity is a burden in developed and developing countries. Overweight and obesity are caused by numerous social and environmental factors that influence people's food habit and physical activity. Role of primary or secondary prevention is the mainstay plan for controlling this epidemic. Various adaptable best practice models are available in the developed nations. However, further research needs to be done to examine the most effective strategies of intervention, prevention, and treatment of obesity in our setting. Through this paper, we would like to highlight best practices and potential interventions to reduce the burden of obesity in India. PMID- 25810629 TI - Malnutrition among under-five children in India and strategies for control. AB - Malnutrition among under-five children is an important concern for the health authorities in India. The aim of the present review was to assess the burden of under-nutrition and over-nutrition, its determinants and strategies required to tackle malnutrition among under-five children in India. Recent data were collected from Google search, Medline, and others. The information retrieved was reviewed and analyzed for discrepancies. Existing evidence shows that the prevalence of under-nutrition among under-five children was high and varied widely (under-weight: 39-75%, stunting: 15.4-74%, wasting: 10.6-42.3%) depending on the assessment methodology adopted. Studies on assessment of over-nutrition status among under-five children were limited. Distribution of various types of risk factors and its influence on nutrition status of children in a given set up should be analyzed for planning the control measures. Strengthening public health interventions for mild malnutrition cases and vulnerable groups, effective implementation and evaluation of the strategies at regional level, research on overweight, obesity and its etiological factors and steps for improving socioeconomic development are the prerequisites for tackling malnutrition among under-five children in India. PMID- 25810630 TI - Diarrheal diseases among children in India: Current scenario and future perspectives. AB - Diarrhea is the third leading cause of childhood mortality in India, and is responsible for 13% of all deaths/year in children under 5 years of age. Information on diarrheal diseases, its determinants and preventive and control strategies need to be reviewed for better planning and organization of health services. This study reviewed literature on diarrheal disease control among under five children in India from literature published in PubMed, Google search engine and other databases on the internet. Data were described in terms of disease burden in India, determinants, management and intervention strategies, preventive strategies, and role of public health and scope for future action. This review calls for a comprehensive diarrheal disease control strategy, through improved case management, addressing social determinants of health and research in the field of cost-effective interventions to reduce the burden of diarrhea among children in India. With < almost one year left to reach the 2015 Millennium Development Goal on reducing child mortality, progress on control of diarrheal diseases must be accelerated. PMID- 25810631 TI - Current overview on dental stem cells applications in regenerative dentistry. AB - Teeth are the most natural, noninvasive source of stem cells. Dental stem cells, which are easy, convenient, and affordable to collect, hold promise for a range of very potential therapeutic applications. We have reviewed the ever-growing literature on dental stem cells archived in Medline using the following key words: Regenerative dentistry, dental stem cells, dental stem cells banking, and stem cells from human exfoliated deciduous teeth. Relevant articles covering topics related to dental stem cells were shortlisted and the facts are compiled. The objective of this review article is to discuss the history of stem cells, different stem cells relevant for dentistry, their isolation approaches, collection, and preservation of dental stem cells along with the current status of dental and medical applications. PMID- 25810632 TI - Mast cells and oral pathologies: A Review. AB - Mast cells (MCs) are resident cells of several types of tissues and contain many granules rich in histamine and heparin. They are distributed preferentially about the micro-vascular endothelial cells in the oral mucosa. These cells play a key role in the inflammatory process and thus their number has been found to be altered in various oral pathological conditions such as oral pyogenic granuloma, oral lichen planus, leukoplakia, oral squamous cell carcinoma, periapical cysts etc. The present review article is aimed to describe the alteration in the number of MCs along with their probable roles in these pathological conditions. PMID- 25810634 TI - The clinical efficacy of using autologous platelet rich plasma in hip arthroplasty: A retrospective comparative study. AB - BACKGROUND: Platelet rich plasma (PRP) is a blood derivative concentrate of platelets, fibrin and growth factors obtained through withdrawal and centrifugation of autologous blood and use for its inherent hemostatic and adhesive properties to promote wound healing. Hip arthroplasty is often associated with significant perioperative complications including blood loss necessitating blood transfusions, which can lead to multiple adverse reactions, infection transmission, and longer hospital stay. MATERIALS AND METHODS: We conducted this retrospective comparative study to determine whether the use of PRP can reduce the bleeding complications in hip replacement surgeries and therefore decrease analgesic requirements and shorten the hospital stay. RESULTS: Sixty patients had consecutive hip replacement surgeries. The study group (n=23) received PRP applications while the control group (n=37) were operated without PRP applications. Postoperative drop of hemoglobin, number of red blood cell (RBC) transfusions, analgesic requirements, and duration of hospital stay were recorded. There was no significant difference in the drop of hemoglobin preoperatively and postoperatively comparing study and control groups (P=0.75). There was no difference in transfusion requirements between the two groups (P=0.16) but there was trend toward less transfusion in the PRP-treated group. There were also no statistical differences in analgesic use (P=0.83) and lengths of hospitalization (P=0.68) between the two groups. CONCLUSION: We concluded that there is no clinical efficacy in using PRP in hip replacement surgeries. We recommend a larger prospective study be conducted to determine its clinical utility as an optimization strategy to improve outcome after hip arthroplasty. PMID- 25810633 TI - Laparoscopic ovarian drilling: An alternative but not the ultimate in the management of polycystic ovary syndrome. AB - Since its introduction in 1984, laparoscopic ovarian drilling has evolved into a safe and effective surgical treatment for anovulatory, infertile women with polycystic ovary syndrome (PCOS), unresponsive to clomiphene citrate. It is as effective as gonadotropins in terms of pregnancy and live birth rates, but without the risks of ovarian hyperstimulation syndrome and multiple pregnancies. It improves ovarian responsiveness to successive ovulation induction agents. Its favorable reproductive and endocrinal effects are sustained long. Despite its advantages, its use in unselected cases of PCOS or for non-fertility indications is not prudent owing to the potential risks of iatrogenic adhesions and ovarian insufficiency. PMID- 25810635 TI - Evaluation of antidiabetic, hypolipedimic and antioxidant activity of hydroalcoholic extract of leaves and fruit peel of Punica granatum in male Wistar albino rats. AB - BACKGROUND: We investigated anti-diabetic, hypolipedimic and antioxidant activity of hydroalcoholic extract from leaves and fruit peel of Punica granatum. MATERIALS AND METHODS: Streptozotocin induced diabetic Wister rats were used in this study consisting of seven groups of six animals each. Groups (1) normal control, (2) diabetic control, (3) leaves extract 100 mg/kg b.w. of P. granatum, (4) leaves extract 200 mg/kg b.w. of P. granatum, (5) fruit peel extract 100 mg/kg b.w. of P. granatum, (6) peel extract 200 mg/kg b.w. of P. granatum and (7) glibenclamide respectively. Fasting blood sugar was recorded on 1(st), 7(th), 14(th), 21(st) and 28(th) day. At the end of the experiment Lipid profile and levels of antioxidants were determined. Safety profile of both extracts was evaluated using acute and chronic toxicity studies. RESULTS: Higher dose of fruit peel extract of P. granatum (PEPG) and glibenclamide significantly lowered blood glucose level from 7(th) day onwards however glibenclamide was found to be more effective. Leaves extract at higher dose and fruit extract at lower dose also significantly lowered blood glucose level from 14(th) day onwards. Leaves extract at lower dose also significantly lowered blood glucose level from 21(st) day onwards. Glibenclamide and higher dose of fruit PEPG extract significantly reduced the total cholesterol, triglyceride levels and significantly increased the high density lipoprotein cholesterol level. Glibenclamide followed by higher dose was found more effective in reducing plasma thiobarbituric acid reactive substances and increasing levels of antioxidant enzymes (superoxide dismutase and catalase). No toxicity was observed even when both extracts were administered at 10 times of higher dose used in this study and no significant changes were seen when it were used chronically. CONCLUSION: Leaves and fruit PEPG possesses significant anti-diabetic, hypolipedimic and antioxidant properties. This study supports the traditional use of P. granatum in diabetes. Fruit peel which is normally thrown by many while eating pomegranate fruit is having anti-diabetic, hypolipedimic and Antioxidant activity. Furthermore high therapeutic index is safe for chronic use. PMID- 25810636 TI - Gender disparities in retreatment patients of tuberculosis: A north Indian study. AB - BACKGROUND: 'Retreatment' for tuberculosis (TB) has long been a neglected area in global TB control India. However India disproportionately accounts for nearly half of retreatment TB cases notified globally. Sex differences vary in different age groups and in different parts of the world. The present study focuses on whether gender-based differences are present in notification rates, clinical presentation, and treatment outcomes of different subcategories of patients registered under category II of Revised National TB Control Programme (RNTCP) Chandigarh. MATERIALS AND METHODS: A longitudinal study was designed and the patients registered under RNTCP category II from June 2010 to December 2011. Out of total 607 patients registered during this period under category II of RNTCP in Chandigarh, 545 consented to participate in the study. These were followed-up to September 2012 till the completion of treatment. All 545 recruited cases were stratified into males and females and the results analyzed. The Z test for proportion (for comparing differences in proportions) and Student's t-test (for comparing mean) were performed for statistical analysis. RESULTS: From the cohort of 545 patients, 348 (63.9%) were males and 197 (36.1%) were female patients with overall male to female ratio 1.8:1. The proportion of male patients notified was significantly higher than females (Z = 5.93, P < 0.001). The proportion of extrapulmonary cases was higher in the females (28.4%) as compared with males (17%) (P < 0.001). Males outnumbered females in all the unfavorable outcomes death, default, and failure. The default in males was significant as compared to the females (Z = 5.21, P < 0.001). CONCLUSIONS: The findings of this study suggest a sex difference in the notification rate of retreatment cases of TB. Reasons for a better outcome and low notification rate for TB in females are more due to epidemiological factors than a differential access of the health care. Integrated research is required to outline the relative roles played by epidemiology. PMID- 25810637 TI - Natural sweeteners as fixatives in histopathology: A longitudinal study. AB - BACKGROUND: Fixation is the essential step in histopathological processing of tissues. Since formalin is a corroborated biohazard, its routine use as a fixative is a major health and safety concern and hence the quest for safer alternatives is envisaged. Natural sweeteners like jaggery and honey have proved to be effective tissue preservatives over 24 h. This pioneer eco-idea needs further research to expand its application. AIM: (1) To evaluate the fixative property of jaggery and honey over 6 months and ascertaining the results using hematoxylin and eosin stain (H and E). (2) To evaluate the compatibility of jaggery and honey fixed tissues for special stains - Periodic acid Schiff (PAS) and Masson-Trichrome (MT). MATERIALS AND METHODS: Equal bits of commercially available animal mucosae were preserved in 30% jaggery, 20% honey, and 10% buffered formalin (control) over 6 months at intervals. Following which, tissues were subjected to routine H and E, special stains - PAS and MT using standard operating procedures established in our group. RESULTS: Formalin, jaggery, and honey yielded satisfactory results post 6 months for H and E and special stains, jaggery was comparable to formalin in tissue preservation. CONCLUSION: We propose the use of eco-friendly jaggery and honey as alternatives to formalin for long term tissue preservation. PMID- 25810638 TI - Clinicopathological study and management of liver abscess in a tertiary care center. AB - BACKGROUND: Liver abscess is a burning problem in tropical nations, with often lethal consequences and diagnostic/therapeutic challenges. We have determined etiopathology, clinical, radiological, and bacteriological characteristics of this condition and review its management strategies. MATERIALS AND METHODS: During the period of the month from May 2007 to September 2009, a prospective study was performed involving 125 patients admitted to the in-patient ward of the Department of General Surgery of N.R.S Medical College their diagnosis was made on the basis of clinical features (such as right upper abdomen pain, and fever), laboratory investigations and radiological evidence of liver abscess. RESULTS: Amoebic liver abscess was the most common (88%) type of liver abscess among the study groups. There was a strong correlation with the occurrence of liver abscesses and addiction to alcohol, history of diabetes mellitus and low socioeconomic status. The most common etiology of pyogenic liver abscess was Escherichia coli. Ultrasonography (USG) of the abdomen was accurate and cost effective in diagnosis of liver abscesses. Percutaneous catheter drainage was the most effective method of treatment (with a 100% success rate). CONCLUSION: Most patients in our study had liver abscess of amoebic origin and had temporal relationship with diabetes, alcoholism, and staggering socioeconomic status. We suggest early recognition of clinical features and prompt abdominal USG as cost effective means for treatment initiation and reducing complications. PMID- 25810639 TI - Health, safety and environment conditions in primary schools of Northern Iran. AB - BACKGROUND: People spend a considerable part of their childhood time in the schools, a phase that coincides with their physical and mental growth. A healthy educational environment is vital to student's health and wellbeing. MATERIALS AND METHODS: This study is a descriptive study conducted in 100 primary schools (both state and nonprofit schools) from Sari's Districts 1 and 2 in Iran. Sampling was performed by census and data were collected using the standard questionnaire by direct interview. Data were analyzed by Excel and SPSS software (Version 20.0. IBM Corp, Armonk), NY: IBM Corp using independent numerical T2 testing. RESULTS: Significant relationship was observed between the kind of schools (P = 0.045) and their locations (P = 0.024), however the health, safety and environment (HSE) ratings among boys only versus girls only schools were similar (P = 0.159). Interestingly private and nongovernment schools and primary schools from Sari's districts one had consistently higher HSE ratings. CONCLUSION: The differential and higher HSE ratings in primary schools run by Private organizations and primary schools from Sari's districts one could be due to manager's awareness and implementation of recommended HSE standards, schools neglecting and overlooking these standards had lower HSE ratings. It is necessary that schools with lower HSE ratings are made aware of the guidelines and necessary infrastructures allocated to improve their HSE ratings. PMID- 25810640 TI - Evaluation of DNA damage in Type 2 diabetes mellitus patients with and without peripheral neuropathy: A study in South Indian population. AB - BACKGROUND: The increasing incidence of Type 2 diabetes mellitus globally has collaterally increased the incidence of diabetes-associated complications such as neuropathy. Oxidative stress induced DNA damage is one of the mechanisms implicated in the pathogenesis of diabetic complications. Here we aimed to evaluate the extent of DNA damage in diabetes patients with and without clinical neuropathy using the Cytokinesis Block Micronucleus Cytome assay, in a group of South Indian population. MATERIALS AND METHODS: The Cytokinesis Block Micronucleus Cytome assay was performed in lymphocyte cultures of 42 type 2 diabetes patients (22 with neuropathy and 20 without neuropathy) and 42 age and sex matched controls. Nuclear aberrations like Nuclear Buds, Nucleoplasmic Bridges and Micronuclei were analyzed. RESULTS: The frequency of nuclear aberrations in diabetes patients with neuropathy was higher than compared to diabetes patients without neuropathy. The mean frequencies of nuclear aberrations per cell in diabetes patients with neuropathy and without neuropathy were 0.02 +/ 0.02 and 0.01 +/- 0.01, respectively. This was significantly higher than in the controls (0.002 +/- 0.002) (P < 0.0001). An increasing trend of nuclear aberrations in correlation with the duration of diabetes was observed. CONCLUSION: This study highlights the use of the Cytokinesis Block Micronucleus Cytome assay as a potent tool for the identification of DNA damage, which may prove to be useful biomarker to assess the severity diabetes-associated complications such as neuropathy. Implementation of this technique at the clinical level would potentially enhance the quality of management of patients with diabetes and its complications like neuropathy. PMID- 25810641 TI - Retrospective magnetic resonance imaging evaluation of fatty filum terminale in Kuwaiti population. AB - OBJECTIVE: Thickened fatty filum terminale (FFT) can cause tethered cord syndrome (TCS) and can be easily diagnosed on magnetic resonance (MR) imaging. We aimed to assess a) the incidence, distribution and clinical significance of the incidentally detected FFT in Kuwaiti population and b) the relationship between degenerative disk disease (DDD) and thickness of the FFT. MATERIALS AND METHODS: A retrospective study was planned at Jaber Al Ahmad Armed Forces Hospital, Kuwait involving 1111 patients. A 1.5T GE machine was used for MR imaging to acquire multiplanar MR sequences. MR images of lumbar spine in 1111 subjects were reviewed and location, size, tightness of FFT, the DDD and clinical details were evaluated. RESULTS: FFT was observed in 43 out of 1111 (3.9%) subjects based on MRI, out of which 11 were females and 32 were males. The mean distance between the tip of conus medullaris and the FFT was 41 mm. The mean diameter of the FFT was 1.74 mm. 40 of 43 patients had DDD of varying severity on MR images and no significant or appreciable slackness of FFT was observed in these cases. There were no clinical symptoms related to FFT associated with degenerated disks. CONCLUSION: FFT is frequently observed in Kuwaiti male population. No significant slackness of FFT was observed in cases with varying severity of DDD. There were no clinical symptoms related to FFT with or without degenerated disks. PMID- 25810642 TI - Relationship between postprandial endotoxemia in nonobese postmenopausal women and diabetic nonobese postmenopausal women. AB - BACKGROUND: We hypothesised that nonobese postmenopausal women (NoPoW) and diabetic NoPoW (DNoPoW) may be independently associated with postprandial endotoxemia. MATERIALS AND METHODS: NoPoW and DNoPoW were evaluated for weight, eating habits, physical activity, body circumferences, fasting plasma glucose level, postprandial plasma glucose level, and insulin level. The lipopolysaccharide (LPS) levels and circulating LPS-binding protein (LBP) were determined in serum at fasting, 1 h, 2 h, 3 h, and 4 h after meal intake and their levels were co-related in 80 NoPoW and 80 DNoPoW. RESULTS: Both DNoPoW group and NoPoW group showed a significant increase (P < 0.05) in LPS levels and circulating LBP in plasma after the meal intake, interestingly the increase was higher in the DNoPoW group. CONCLUSIONS: Elevated LPS and circulating LBP were associated significantly with DNoPoW group and NoPoW, especially after a meal intake. These findings suggested a role of LPS and LBP in postprandial systemic inflammation in DNoPoW group. Prospective studies are needed to confirm these results. PMID- 25810643 TI - Does a single loading dose of tranexamic acid reduce perioperative blood loss and transfusion requirements after total knee replacement surgery? A randomized, controlled trial. AB - BACKGROUND: Total knee replacement (TKR) is associated with high-perioperative blood loss, which often requires allogenic blood transfusion. Among the many strategies to decrease the need for allogenic transfusion, tranexamic acid (TA) is used systemically in perioperative setting with promising outcome. Here we evaluated the efficacy of single preoperative bolus dose of TA on reduction in blood loss and red blood cell transfusion in patients undergoing unilateral TKR. MATERIALS AND METHODS: 70, American Society of Anesthesiologists I-II patients scheduled for unilateral TKR were included. Patients were randomly allocated into two groups to receive either TA (Group-TA; 20 mg/kg diluted to 25 cc with normal saline) or an equivalent volume of normal saline (Group P). Hemoglobin concentration, packed cell volume, platelet count, fibrinogen level, D-dimer level was measured preoperatively and at 6(th) and 24(th) h postoperative period. RESULTS: In Group P more blood, colloid and crystalloid solutions were used to replace the blood loss. 27 patients in Group TA did not require transfusion of any blood products compared to 6 patients in Group P (P < 0.0001) and only 3 units of blood was transfused in Group TA where as a total of 32 units of blood was transfused in Group P. Despite the more numerous transfusions, Hb% after 6 h and 24 h in Group P were considerably low in comparison with Group TA (P < 0.0001). CONCLUSION: Tranexamic acid while significantly reducing blood loss caused by TKR surgery collaterally reduced the need for postoperative blood transfusion. PMID- 25810645 TI - A study of blood utilization in a tertiary care hospital in South India. AB - BACKGROUND: Monitoring blood utilization helps in effective management of blood stock to meet present and future demands in a hospital. Hence, we analyzed the age, gender and frequency distribution of each blood product used in different diseases conditions. MATERIALS AND METHODS: We included all blood products utilized from January 2008 to December 2012 in our tertiary care hospital in South India. The primary and secondary discharge diagnoses (International Classification of Diseases [ICD-10]) were matched with clinical information provided in the request forms. The most relevant indication requiring blood transfusion was selected for each recipient and grouped into broad diagnostic categories according to the headings of ICD-10. The utilization of stored whole blood, packed red blood cells (RBCs), fresh frozen plasma (FFP) and platelets was stratified according to age, gender and diagnosis. RESULTS: Our results indicated decline in usage of whole blood and an increase in use of FFP and platelets over the years. While packed RBCs were frequently used for treating injury and poisoning conditions, platelets and FFP were preferred for infectious and parasitic diseases. Various blood products were used less frequently in patients aged over 60 years and the overall usage of blood products was higher in males. CONCLUSION: The patterns of blood products utilization is in contrast to the Western nations, which may be due to difference in age structure among Indian population and higher prevalence of infectious diseases such as Dengue in our region. Nevertheless, this study highlights the importance of understanding the epidemiology of blood transfusion locally to improve usage of blood and blood products. PMID- 25810644 TI - Effects of passive smoking on students at College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh. AB - BACKGROUND: Despite the recent campaigns to eliminate smoking, the rates are still increasing world-wide. Exposure to passive smoking (PS) is associated with morbidity and mortality from awful diseases. Although many college students smoke, little is known about their exposure to PS, common places and sources of exposures in Saudi Arabia. AIM: The aim of the following study is to identify prevalence and magnitude of PS among college students, exposure time, locations, sources of exposure, investigate the effects and make recommendations. MATERIALS AND METHODS: A cross-sectional study was performed to identify factors associated with PS exposure among students of College of Applied Medical Sciences, Riyadh. RESULTS: Out of 61 students included in the study, 91.8% were found exposed to PS. Exposure in Hospitality venues (Estirah) was the most common followed by other areas. Among the sources of exposure, the highest was among friends and the least were parents and guests. The frequency of highest exposure per month was >15 times and the lowest was 10-15 times. Levels of annoyance varied between 18% and 37.7%, respectively. Since the values obtained for different markers in the pulmonary function test are more than the predicted values, the observed spirometry is normal. The percent oxygen saturation in hemoglobin and blood pressure of PS were in normal range. CONCLUSION: Since the properties of mainstream smoke and environmental tobacco smoke are quite different, risk extrapolation from active to PS is uncertain, especially during a short period. Nevertheless, it can be deteriorating during a longer duration, hence; the administrators, policy makers and tobacco control advocates may endorse policies to restrict smoking in shared areas, particularly working environment. PMID- 25810646 TI - Periodontal health status and treatment needs of the rural population of India: A cross-sectional study. AB - BACKGROUND: Periodontal disease is of public health concern and hence data on its prevalence rate are necessary. We have documented the prevalence pattern of periodontal disease in a rural population of Belgaum district, India, and identify the optimal treatment needs (TNs). MATERIALS AND METHODS: A cross sectional study was carried on 1680 dentate adult subjects, examined from 12 villages in Belgaum district, Karnataka, India for prevalence of periodontal status and their TNs (using Community Periodontal Index for Treatment Needs [CPITN]). RESULTS: Increase in CPITN score positively correlated with age. Only 4.3% (13) of subjects in the age-group of 20-29 had a CPITN score of 4 indicative of pockets of 6 mm or more when compared to 26% (91) of subjects in the age-group of 45-60 years. 92% (569) of the subjects in the age-group of 30-44 were having a TN score 2 whereas only 5.3% (33) of subjects were having a TN score 0 in the same age-group. Significantly higher need for treatment was observed in males, smokers and subjects using finger and tooth powder. Surprisingly diet of the subjects did not influence TNs. CONCLUSION: Increased prevalence of periodontal diseases and TNs was observed. There is a need for initiating adequate awareness regarding oral hygiene, specifically primary prevention could help in reducing the prevalence of periodontal disease. PMID- 25810648 TI - Comparison of obstetric outcome in pregnant women with and without microalbuminuria. AB - BACKGROUND: Maternal and neonatal outcome is an index of quality of health and life in human society. To predict serious outcomes in pregnancy various parameters are being researched so that pregnant women who are at risk are identified early and measures taken to ensure a good outcome of pregnancy. Studies have shown an association between microalbuminuria and adverse pregnancy outcome. This study was undertaken to compare obstetric outcome in pregnant women with and without microalbuminuria. MATERIALS AND METHODS: A prospective cohort study was performed on 69 pregnant women between 20 and 28 weeks of gestation. Urine tests for albuminuria and creatinine measurements were performed in all women and the albumin to creatinine ratio was calculated. The women with microalbuminuria and those without microalbuminuria were monitored until the end of their pregnancy and compared for pregnancy outcome. RESULTS: The age distribution in the two groups was found to be similar and comparable. Preterm labor was strongly associated with microalbuminuria group (P = 0.001**)strongly significant. Incidence of maternal complications were more with microalbuminuria group (P < 0.001**). Fetal complications were significantly more in terms of intrauterine growth restriction, prematurity, low birth weight, low Apgar score and more incidence of neonatal intensive care unit admission with microalbuminuria group (P = 0.010*)moderately significant. CONCLUSION: It was found that fetal complications were more associated with babies of pregnant women with microalbuminuria. Though maternal complications were more associated with microalbuminuria group, individual events like premature rupture of membrane, preterm premature rupture of membrane had no statistically significant association with microalbuminuria except preterm labor. However, occurrence of pre-eclampsia was more with microalbuminuria, though it didn't carry any statistical significance. PMID- 25810647 TI - Awareness and practice concerning oral cancer among Ayurveda and Homeopathy practitioners in Davangere District: A speciality-wise analysis. AB - CONTEXT: In India, oral cancer accounts for one-third of all cancers. Early detection and immediate intervention can lead to marked reduction in the morbidity and mortality. In India, Ayurveda and homeopathy practitioners are distributed widely in rural and urban areas and are easily accessible. Until date, no assessment on their oral cancer knowledge and practice has been done. AIMS: The present study was undertaken to evaluate the knowledge, awareness, and practice concerning oral cancer. SUBJECTS AND METHODS: Questionnaire comprising 15 questions was distributed to 42 Ayurveda and 38 homeopathy doctors in Davangere District, Karnataka, India, assessing their oral examination habits, knowledge on the risk factors, patient education, clinical signs of the disease and its treatment. STATISTICAL ANALYSIS USED: The results were analyzed using Chi square test. RESULTS: Lesser number of the practitioners routinely examined oral mucosa (16.7% and 5.3%, respectively). Fewer advised their patients about the risk factors (2.4% and 2.6%). Less positive response was obtained for the correct method for confirmation of diagnosis (28.6% and 15.8%). Many doctors agreed that they had not undergone training in cancer institute (P = 0.29). Twenty-three (54.8%) Ayurveda and 28 (73.7%) homeopathy doctors opined that they did not have sufficient knowledge regarding early detection and prevention of oral cancer and many were desirous of receiving further information (97.6% and 84.2% respectively). CONCLUSIONS: This study attempts to highlight the need for improving the oral cancer knowledge and awareness among practicing Ayurveda and homeopathy doctors. PMID- 25810649 TI - Reliability of Beta angle in assessing true anteroposterior apical base discrepancy in different growth patterns. AB - INTRODUCTION: Beta angle as a skeletal anteroposterior dysplasia indicator is known to be useful in evaluating normodivergent growth patterns. Hence, we compared and verified the accuracy of Beta angle in predicting sagittal jaw discrepancy among subjects with hyperdivergent, hypodivergent and normodivergent growth patterns. MATERIALS AND METHODS: Lateral cephalometric radiographs of 179 patients belonging to skeletal Classes I, II, and III were further divided into normodivergent, hyperdivergent, and hypodivergent groups based on their vertical growth patterns. Sagittal dysplasia indicators - angle ANB, Wits appraisal, and Beta angle values were measured and tabulated. The perpendicular point of intersection on line CB (Condylion-Point B) in Beta angle was designated as 'X' and linear dimension XB was evaluated. RESULTS: Statistically significant increase was observed in the mean values of Beta angle and XB distance in the vertical growth pattern groups of both skeletal Class I and Class II patients thus pushing them toward Class III and Class I, respectively. CONCLUSIONS: Beta angle is a reliable indicator of sagittal dysplasia in normal and horizontal patterns of growth. However, vertical growth patterns significantly increased Beta angle values, thus affecting their reliability as a sagittal discrepancy assessment tool. Hence, Beta angle may not be a valid tool for assessment of sagittal jaw discrepancy in patients exhibiting vertical growth patterns with skeletal Class I and Class II malocclusions. Nevertheless, Class III malocclusions having the highest Beta angle values were unaffected. PMID- 25810650 TI - Diagnostic role of magnetic resonance cholangiopancreatography in evaluation of obstructive biliopathies and correlating it with final diagnosis and clinical profile of patients. AB - AIMS AND OBJECTIVE: We assessed the utility of magnetic resonance cholangiopancreatography (MRCP) as a noninvasive diagnostic tool in patients with obstructive biliopathies. MATERIALS AND METHODS: A prospective study was conducted on 54 patients with clinically suspected biliary obstruction. MRCP in these patients was compared and correlated with final diagnosis and their clinical profile. STATISTICAL ANALYSIS: Sample profile was described in terms of sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy. Pearson's Chi-square statistics was used to assess the strength of association between diagnostic accuracy of MRCP and final diagnosis. RESULTS: Out of the 54 patients, 50 had biliary obstruction. The cause of biliary obstruction was finally identified on the basis of direct cholangiography/surgery/histopathology. In 52 of the 54 patients, MRCP agreed with final diagnosis in identifying the level of block. MRCP agreed with final diagnosis in identifying the cause of obstruction in 48 of the 54 patients (89%). Sensitivity of MRCP in identifying the level of obstruction in comparison with final diagnosis was 100%, while diagnostic accuracy of MRCP in identifying the level of obstruction in comparison with final diagnosis was 96.29%. The correlation between MRCP and final diagnosis in diagnosing cause of obstruction was 0.95 (Pearson's correlation coefficient, P = 0.017). CONCLUSION: MRCP is a safe ionizing radiation and iodinated contrast free modality which has the ability to display the biliary tree by combining the advantages of projectional and cross-sectional imaging. PMID- 25810652 TI - Comparison of relationship between salivary electrolyte levels and dental caries in children with Down syndrome. AB - AIM: The aim of this study was to relate the salivary electrolyte levels with dental caries in children with Down syndrome and to compare salivary electrolyte levels and dental caries of these children with their siblings. MATERIALS AND METHODS: Study population consisted of 30 Down syndrome children (study group) and their 30 healthy siblings (control group). Caries status was determined by dental caries indices in deciduous and permanent dentitions. Un-stimulated saliva from both groups was collected for salivary electrolyte examination. RESULTS: In the study group, mean caries experience in primary dentition was 1.00 +/- 0.79 and in the control group it was 2.33 +/- 1.42, the difference being statistically significant. Mean caries experience in the permanent dentition of the study group (0. 97 +/- 0.76) was significantly lower than the control group (2.47 +/- 1.25). Salivary electrolyte levels in the study group were significantly higher than the control group. CONCLUSION: There was a significant decrease in dental caries in primary as well as permanent dentition of Down syndrome patients with increase in their salivary electrolyte levels. PMID- 25810651 TI - Conventional versus digital approach for measuring dentin translucency in forensic age estimation. AB - BACKGROUND: Root dentine translucency remains the method of choice providing the most accurate results for age estimation. Conventionally, translucency is measured using calipers. In recent times, computer-based methods are proposed, which require the use of custom-built software programs. AIMS AND OBJECTIVES: The aim was to use a digital method to measure dentinal translucency on sectioned teeth and to compare digital measurements to conventionally obtained translucency measurements. MATERIALS AND METHODS: A total of 200 extracted permanent teeth were collected and were sectioned to a thickness of 250 MUm. Translucency measurements were obtained using the digital method and compared with those obtained using a caliper. RESULTS: Correlation coefficients of translucency measurements to age were statistically significant for both methods (P < 0.001), although marginally higher correlation was observed for the conventional method (r = 0.612). Application of derived linear regression equations on an independent sample (n = 25) suggested that conventional approach is marginally better in estimating age to within 5 years of the actual age, both the methods are similar in assessing age within 5-10 years of the actual age, and digital approach is marginally better in estimating age beyond 10 years of actual age. CONCLUSION: The translucency measurements obtained by the two methods were identical, with no clear superiority of one method over the other. PMID- 25810653 TI - Survey on utility of yoga as an alternative therapy for occupational hazards among dental practioners. AB - BACKGROUND: The therapeutic potential of yoga are often considered complementary to various forms of medical practice. Very few studies have evaluated the effects of yoga in the treatment of occupational hazards among dentists. Hence, this cross-sectional study was designed to evaluate the adoption of yoga techinques as an alternative therapy in treatment of physical and psychological occupational hazards among dental general practitioners in Chennai, India. MATERIALS AND METHODS: A validated closed-ended questionnaire was circulated to 500 dental general practitioners in Chennai, India and we received 394 completed questionnaires. The questionnaire documented demographic data, occupational hazards and the type of treatment taken for the hazards. RESULTS: Musculoskeletal pain with stress (47%) was the most common occupational hazard reported, followed by only stress (27.4%), and only musculoskeletal pain (25.6%). Only 9.6% of practitioners adopted yoga as an alternative treatment for these occupational hazards. Interestingly, majority (46.4%) of them did exercise, gym, massage, walking and heard music. Surprisingly, 43.9% did not take any measures to treat these occupational hazards. However 53.3% of the dentists who did not consider yoga as an alternative therapy, stated lack of time as a reason for not practicing yoga while 17.6% of them don't believe yoga as a therapy. CONCLUSION: Despite musculoskeletal pain and stress being the most common occupational hazard prevalent among dentists, over 50% of the subjects surveyed didn't seek any measure to treat these occupational hazards and only 10% of them practiced yoga as the alternative therapy. PMID- 25810654 TI - A Prospective, double-blinded randomized controlled study comparing two different Trendelenburg tilts in laparoscopically assisted vaginal hysterectomy positioning. AB - BACKGROUND: Bispectral index (BIS) used for intra-operative depth assessment under general anesthesia (GA) can be altered by different factors. This study was designed to detect the alteration in BIS reading with two different Trendelenburg (TBG) tilt in laparoscopically assisted vaginal hysterectomy (LAVH) procedure. MATERIALS AND METHODS: A prospective, double-blinded, randomized controlled study was designed involving 40 American Society of Anesthesiologists Grade I and II female patients, aged 35-60 years, scheduled to undergo LAVH under GA. Patients were divided into two groups with TBG >30 degrees and TBG <30 degrees . BIS readings; systolic and diastolic blood pressure, heart rate were recorded in supine position. Patients were then shifted to desired TBG position either (>30 degrees ) or (<30 degrees ) as per group allotment. Data were recorded at 30 min intervals and all the patients were followed upto 24 h postoperatively for any recall. RESULTS: A rise in BIS value was noticed, when position was changed from supine to head down in both groups. During comparison between two groups with different angulations, TBG >30 degrees showed a higher BIS value than TBG <30 degrees . This statistically significant (P < 0.05) trend was observed at all the 30, 60, 90, and 120(th) min interval. Interestingly, BIS values returned to preoperative levels following adopting final supine position. No incidence of awareness was reported in both the series throughout the study. CONCLUSION: Though awareness remains unaltered BIS value gets increased with higher angle of inclination in TBG position during LAVH operation. PMID- 25810655 TI - Isolation and identification of Acinetobacter species with special reference to antibiotic resistance. AB - BACKGROUND: Acinetobacter is clinically important pathogen with widespread resistance to various antibiotics. We assessed the incidence of Acinetobacter infection at a tertiary care hospital, analyze their resistance pattern and identify the production of extended spectrum beta-lactamases (ESBLs) and metallo beta-lactamases (MBLs). MATERIALS AND METHODS: The study was conducted in tertiary care hospital, India over a period of 2 years. Acinetobacter species were isolated from various clinical samples received in Department of Microbiology. After identification, Acinetobacter isolates were speciated and antibiotic susceptibility was determined by the standard disc diffusion method. ESBL and MBL production was detected by the double disc synergy test and combined disc diffusion test respectively. RESULTS: Of 3298 infected samples, 111 (3.36%) were found to be Acinetobacter. The most predominant species was Acinetobacter calcoaceticus-A. baumannii (Acb) complex (72%). High incidence of resistance was recorded for piperacillin (55%), followed by ceftriaxone (46%) and ceftazidime (46%). Isolation rate and antibiotic resistance was higher in the Intensive Care Units (ICUs) of the hospital. ESBL and MBL production was detected in 31.5% and 14.4% of the isolates respectively. DISCUSSION AND CONCLUSION: A high level of antibiotic resistance was observed in our study and maximum isolation rate of Acinetobacter was in the ICUs. Acb complex was the most predominant and most resistant species. The analysis of susceptibility pattern will be useful in understanding the epidemiology of this organism in our hospital setup, which will help in treating individual cases and controlling the spread of resistant isolates to other individuals. PMID- 25810656 TI - Association of atherosclerosis with dyslipidemia and co-morbid conditions: A descriptive study. AB - BACKGROUND: Dyslipidemia (Dys), the commonest cause of cardiovascular diseases, leads to lipid deposits on the arterial wall, thereby aggravating the process of atherosclerosis. To assess the impact of Dys and other co-morbid conditions on atherosclerosis (i.e., increased intimo medial thickness (IMT) or plaques) in the common carotid arteries (CCAs) we studied the incidence and association of plaques and increased IMT in dyslipidemic patients from North Indian population (south-west of Punjab, India). MATERIALS AND METHODS: A cross-sectional study consisting of 88 (male-39 and female-49) dyslipidemic patients (age group 30-80 years); was designed. Blood pressure, waist circumference (WC), hip circumference (HC) were measured and fasting lipid profile, renal function, and liver function tests were performed. B-mode sonography, for CCA, was performed to assess IMT. RESULTS: Average value (mg/dl) of total cholesterol, triglyceride, low density lipoprotein and high density lipoprotein in males and females was 220.30 versus 231.93, 240.3 versus 242.14, 125.29 versus 133.62 and 44.33 versus 46.09 respectively (P > 0.05, all), while WC, HC, systolic blood pressure and diastolic blood pressure were 101.8 versus 96.53 cm, 98.23 versus 99.53 cm, 143.23 versus 138.98 mmHg and 91.53 versus 88.97 mmHg respectively. Increased IMT and atherosclerotic plaques were observed in 36.36% cases (n = 32, male - 14 and female - 18) and 29.54% cases (n = 26, male 14, female 12) respectively. Odd ratio (OR) for plaques was more for Dys with coronary artery disease (CAD; 11.43) and Dys with CAD (Dys-CAD) + hypertension (HT) (24) respectively vs isolated Dys. CONCLUSION: Dyslipidemia patients have higher waist and HCs than normal subjects. Incidence and OR of plaques is higher in Dys-CAD or Dys-CAD + HT when compared to isolated Dys or Dys with HT. Hence, treatment of dyslipidemic patients' needs to be intensified if more than one risk factor(s) is present simultaneously. PMID- 25810657 TI - Contribution and citation Impact of CSIR, India publications during 2007-11. AB - INTRODUCTION: The paper analysis the performance of CSIR at the overall level as well as laboratory level in terms of various indicators during 2007-11. It identifies the strength and weakness of CSIR at the overall level as well as under laboratory level under 13 broad subjects. MATERIALS AND METHODS: The paper uses Scopes database for analyzing publications on CSIR and its 37 laboratories during 2007-11. RESULTS: The largest contribution of CSIR has been in the area of chemistry, followed by biochemistry, genetics and molecular biology, materials science, chemical engineering, physics, engineering, pharmacology, toxicology and pharmaceutics, agricultural and biological sciences, environmental science, medicine, earth and planetary sciences and energy. PMID- 25810658 TI - Antioxidant and protective effects of Phytocee(TM) against carbon tetrachloride induced oxidative stress. AB - BACKGROUND: This study evaluated the antioxidant potential of a polyherbal formulation (Phytocee(TM)) in the rodent model. MATERIALS AND METHODS: Four groups of rats (n = 6) were pretreated with Vitamin C (20 mg/kg) or Phytocee(TM) (20, 100, and 200 mg/kg), respectively for 10 days. Oxidative stress in rat liver was induced by administration of carbon tetrachloride (CCl4) at 2 ml/kg as a single dose orally to all groups except the vehicle control group. After 24 h of administration of CCl4, hepatic levels of malondialdehyde (MDA), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels were evaluated. RESULTS: Phytocee(TM) administered groups at all the dose levels significantly reduced the hepatic MDA, serum ALT and AST levels with a marked increase in hepatic SOD and catalase as compared with CCl4 treated group. CONCLUSION: The findings suggest that Phytocee(TM) markedly reversed the effects of CCl4 induced oxidative stress and can be used as an antioxidant feed supplement. PMID- 25810659 TI - Effect of dielectric interface on charge aggregation in the voltage-gated K(+) ion channel. AB - BACKGROUND: There is experimental evidence of many cases of stable macromolecular conformations with charged amino-acids facing lipid, an arrangement thought to be energetically unfavourable. METHODS AND OBJECTIVES: Employing classical electrostatics, we show that, this is not necessarily the case and studied the physical basis of the specific role of proximity of charges to the dielectric interface between two different environments. We illustrate how self and induced energies due to the dielectric medium polarization, on either side of the interface, contribute differentially to the stability of a pair of charges and hence the mutual conformation of the S3b-S4 alpha-helix pair of the voltage-gated K(+) channel. RESULTS AND CONCLUSION: We show that (1) a pair of opposite charges on either side of lipid-protein interface confers significant stability; (2) hydrophobic media has an important role in holding together two similar repelling charges; (3) dielectric interface has stabilizing effect on a pair of charges, when an ion is closer to its interface than its neighboring charge; (4) in spite of the presence of dielectric interface, there is a nonexistence of any dielectric effect, when an ion is equidistant from its image and neighboring charge. We also demonstrate that, variation in dielectric media of the surrounding environment confers new mutual conformations to S3b-S4 alpha-helices of voltage sensor domain at zero potential, especially lipid environment on the helix side, which improved stability to the configuration by lowering the potential energy. Our results provide an answer to the long standing question of why charges face hydrophobic lipid membranes in the stable conformation of a protein. PMID- 25810660 TI - Antibiotic susceptibility pattern of Enterobacteriaceae and non-fermenter Gram negative clinical isolates of microbial resource orchid. AB - BACKGROUND: Microbial resource orchid is a collection of Gram-positive and Gram negative clinical isolates sourced from different hospitals and diagnostic laboratories in India. We determined the antibiotic susceptibility of a set of Gram-negative Enterobacteriaceae and non-fermenter clinical isolates from microbial resource orchid, collected during the period of 2002-2012 against commonly used antibiotics. MATERIALS AND METHODS: A total of 247 Gram negative strains consisting of 142 Enterobacteriaceae and 105 non-fermenters from microbial resource orchid were selected for determining minimum inhibitory concentration against beta-lactams, aminoglycosides, quinolone, and tetracycline by agar dilution method as per clinical and laboratory standards institute guidelines. RESULTS: All the isolates had high resistance to ampicillin, piperacillin, ceftazidime, gentamicin, tetracycline, and ciprofloxacin. Pseudomonas aeruginosa showed moderate resistance to carbapenems. CONCLUSION: This study demonstrated the high level of antibiotic resistance among the strains collected under microbial resource orchid and further, such data and the strains can be used in new chemical entities profiling. PMID- 25810661 TI - Better theoretical models and protein design experiments can help to understand protein folding. AB - In our study, we have concluded that two proteins with 88% homology choose different energetically favorable pathways in the very early stage of the folding process to attain their native folds. Subsequent reports from other investigators by performing folding and unfolding kinetics experiments concur with our findings. We herewith discuss the key papers revealing computational and experimental analysis of two designed proteins with similar sequence distant folds. Further we suggest that the theoretical/computational analysis of protein sequences and structures along with the relevant experiments provide a better understanding of the relationship between protein sequence, folding, and structure. PMID- 25810662 TI - Tooth fragment reattachment: An esthetic, biological restoration. AB - Coronal fractures of the anterior teeth are a common form of dental trauma. If the original tooth fragment is retained following fracture, reattachment of the fractured fragment to the remaining tooth can provide better and long lasting esthetics, improved function, a positive psychological response, and is a faster and less complicated procedure. This paper reports on coronal tooth fracture case that was successfully treated using adhesive reattachment of fractured fragment and post placement. PMID- 25810663 TI - Enterogenous cyst of the small bowel causing intussusception in an adult: Case report and review of literature. AB - Small bowel intussusception is a rare congenital disease entity, mostly manifesting before the age of two with abdominal pain and acute intestinal obstruction. In adults, colon intussusception is a rare event causing approximately 1% of all acute intestinal obstructions and they can occur idiopathically in adults or due to an intraluminal tumor mass. We report a case of an enterogenous cyst causing intussusception and iron deficiency anemia in an adult treated by surgical excision and resection of the small bowel. PMID- 25810664 TI - Primary adenocarcinoma of rete testis with distinct biphasic pattern: An extremely rare entity and diagnostic challenge. AB - Primary adenocarcinoma of rete testis is one of the rarest intrascrotal tumors. Very few cases have been reported in the literature. In addition, presence of biphasic component creates difficulty in the diagnosis. We present here a unique third case of rete testis adenocarcinoma having distinct cytologically malignant spindle cell component in a young male who presented with recurrent hydrocele. PMID- 25810665 TI - Urinothorax: A path, less travelled: Case report and review of literature. AB - Urinothorax is a very rare occurrence of urine in the pleural space. Urinothorax can occur as a consequence to percutaneous nephrolithotomy (PCNL), ureterorenoscopic lithotripsy (URSL) or shock wave lithotripsy (SWL). We herewith report a rare case of Urinothorax in a 35 years old male patient and discuss its current knowhow and clinical management. PMID- 25810666 TI - Transanal impalement of double J steel bar with colonic and jejunal injury: A unique pediatric case report. AB - Pediatric transanal impalement injuries are relatively uncommon and most are attributed to accidental fall on offending objects, sexual assault or blunt trauma. There may be difficulty in recognizing or properly treating such injuries because their severity may not be reflected externally. Evaluation of suspected rectal impalement injury involves careful history and physical examination and proper investigation. There are very few reports on pediatric perianal impalement with associated visceral injuries. We report a case of assault transanal impalement injury associated with mesenteric tear and jejunal perforation leading to devitalization of proximal jejunum in a 2 year male child and relevant literatures were reviewed. To the best of our knowledge, such dual proximal and distal gastrointestinal injury in such a small child has not been reported in any of the English literature so far. PMID- 25810667 TI - Corporate social responsibility in public health: A case-study on HIV/AIDS epidemic by Johnson & Johnson company in Africa. AB - HIV/AIDS has claimed millions of lives in the global workforce and continues to remain a threat to many businesses. An estimated 36.5 million of working people are living with HIV; the global workforce has lost 28 million people from AIDS since the beginning of the epidemic. In the absence of access to treatment, this number could grow to 74 million by 2015. The epidemic continues to affect the working population through absenteeism, sickness and death. Corporate Social Responsibility (CSR) is an obligation that corporates have toward their employees, community and society. A review and documentation of one such CSR by Johnson & Johnson (a multinational company) for HIV/AIDS in Africa is presented here. Johnson & Johnson Company is involved in numerous projects around the world to combat the HIV/AIDS epidemic. The company is working to fight the spread of the disease and improve the quality of life for those living with the illness through various donations of its products and sponsorship of local programs. This case study also highlights different categories of CSR activities such as Cause Promotion, Cause related Marketing, Corporate Philanthropy, Corporate Social Marketing, Corporate Volunteering and Socially responsible business practices, which are discussed with specific examples from different countries in Africa. CONCLUSIONS: CSR of any business encompasses the economic, legal, ethical & discretionary expectation placed on the organization by society at a given point of time. CSR is therefore the obligation that corporations have toward their stakeholders and society in general which horizons beyond what is prescribed by law or union contracts. Johnson & Johnson has a proved history of being committed to caring for people and a good example of a company with a long history of citizenship and sustainability. PMID- 25810668 TI - Autologus Platelet Rich Fibrin aided Revascularization of an immature, non-vital permanent tooth with apical periodontitis: A case report. AB - Caries or trauma induced non-vital immature permanent tooth with blunderbuss, thin root which are very common among childrens are corrected using regenerative endodontic (revascularization) procedures. In the presented case, a 16-year-old boy reported with chief complaint of pain in maxillary left central incisor (Tooth #21). Tooth #21 showed grade III mobility, draining labial sinus, and short blunderbuss root with diffuse periapical radiolucency. Patient was explained the treatment plan and written informed consent was taken. Platelet rich fibrin (PRF) was prepared according to standard protocol. Autologous PRF was carried to the apical portion of the root canal after inducing revascularization. Access opening was double sealed with MTA and resin modified glass ionomer cement (RMGI). Baseline, 12 month and 18 month follow-up intraoral radiographs were taken. Clinically case was asymptomatic with complete resolution of intraoral sinus. Periapical healing, apical closure, root lengthening and dentinal wall thickening were uneventful. Thus PRF supplementation hastens the predictability and rate of revascularization in non-vital immature permanent teeth. PMID- 25810669 TI - Facial nerve paralysis: A case report of rare complication in uncontrolled diabetic patient with mucormycosis. AB - Mucormycosis is a rare opportunistic aggressive and fatal infection caused by mucor fungus. Seven types of mucormycosis are identified based on the extension and involvement of the lesion, of which the rhino orbital mucormycosis is most common in the head and neck region. Although it is widely spread in nature, clinical cases are rare and observed only in immunocompromised patients and patients with uncontrolled diabetes mellitus. Early symptoms include fever, nasal ulceration or necrosis, periorbital edema or facial swelling, paresthesia and reduced vision. Involvement of cranial nerves although not common, facial nerve palsy is a rare finding. The infection may spread through cribriform plate to the brain resulting in extensive cerebellar infarctions. Timely diagnosis and early recognition of the signs and symptoms, correction of underlying medical disorders, and aggressive medical and surgical intervention are necessary for successful therapeutic outcome. PMID- 25810670 TI - Floral double mesiodentes: A rare case report. AB - Mesiodens is the most commonly erupting supernumerary in the midline between two maxillary central incisors. Mesiodentes is a rare condition when mesiodens erupt in multiples, which may present as either labial or palatal to permanent central incisors. We report a rare case of double mesiodentes (non-syndromic mesiodentes) with floret like appearance. The presence of mesiodens has functional and esthetic implications. Careful radiographic evaluation should be done to prevent complications during their extraction. PMID- 25810671 TI - A rare case of cleidocranial dysplasia presenting with failure to thrive. AB - Cleidocranial dysplasia (CCD) is a rare (1:1,000,000) congenital condition secondary to spontaneous mutation (40%) or autosomal dominant inheritance (60%) affecting skeletal and dental systems. Hypomineralization of the hypoplastic clavicles and/or cranium is the major feature observed by prenatal ultrasound. Radiologically clavicles are hypoplastic or absent in chest X-ray. Delayed closure of the fontanelle and the skull sutures in pediatric and adolescent population and increased mobility of shoulders in all age groups (exhibited by the ability to bring shoulders close to each other) are prominent clinical diagnostic features of CCD. The diagnosis of CCD is often missed or significantly delayed. The management of CCD involves a multidisciplinary approach and its early diagnosis is essential to select an optimum plan and therapeutic benefit. We present here a case of CCD in a 17-month-old girl referred to us for investigation of below average weight and height gain; we stress on the usefulness of early diagnosis in the management of CCD and discuss current management concepts. PMID- 25810672 TI - Computed tomography and magnetic resonance imaging features of a rare case of a primary epidermoid tumor of the jugular foramen. AB - We present computed tomography (CT) and magnetic resonance imaging (MRI) features of a very rare case of a primary epidermoid tumor of the jugular foramen (JF). A 45-year-old male patient presented with gradually progressive vertigo and tinnitus. CT and MRI scans revealed a 3.5 cm right-sided JF tumor with characteristic bright signal (restricted diffusion) on diffusion-weighted MRI (DWI). DWI may be useful in accurately differentiating the lesion from other cystic neoplasms of the JF. We describe the imaging features of intracranial epidermoid and JF tumors and discuss its differential diagnosis. PMID- 25810673 TI - Multiple hepatocellular adenomas presenting in a male 8 years post pancreaticoduodenectomy for islet cell tumor of the pancreas. AB - We report the case of a 29-year-old male who presented with vague right upper quadrant pain, 8 years following a pancreaticoduodenectomy for a symptomatic pancreatic islet cell tumor. Subsequent imaging revealed multiple lesions in the right lobe of the liver. A diagnosis of metastatic disease could not be out ruled and hence a formal resection was performed. A formal retrospective review of case notes, preoperative imaging, operative notes, subsequent histology as well as a review of the current literature using the Medline, CINAHL, and EMBASE databases was performed. Histologic analysis showed these lesions to be hepatocellular adenomas. We highlight in this case the importance of preoperative imaging and workup, discuss hepatocellular adenomas in males and hypothesize as to the underlying pathophysiology in this particular case based on the available evidence. PMID- 25810674 TI - Rhinosporidiosis presenting as an oropharyngeal mass: A clinical predicament? AB - Rhinosporidiosis, is a chronic granulomatous disease presenting as a polypoidal mass in the nasal cavity and nasopharynx caused by Rhinosporidium seeberi and is endemic in India and Sri Lanka. Diagnosis is mainly by clinical observations and is confirmed by histopathology. We report a case of atypical rhinosporidiosis that presented as an oropharyngeal mass and mimicked chronic tonsillitis. Hence possibility of this atypical rhinosporidiosis should be included in the clinical differential diagnosis of any posterior oral or oropharyngeal mass, particularly when managing patients from rural endemic areas. PMID- 25810675 TI - A rare case of clear cell variant of oral squamous cell carcinoma. AB - Oral squamous cell carcinoma with prominent clear cell differentiation is a rare occurrence. A 35-year-old female patient presented with a nonhealing ulcer persistent for 1-month involving the left lateral border of the tongue and lingual vestibule. Lobules of malignant squamous epithelial cells with abundant cytoplasm and vesicular nuclei in the connective tissue were observed following histopathology. Neoplastic cells constituting majority of lobules exhibited clear cell changes. Periodic acid-Schiff and mucicarmine stains showed negative reaction. Immunohistochemical study using antibody for cytokeratin, revealed diffuse and intense positivity. The neoplastic cells showed complete negative reaction with antibodies for vimentin, smooth muscle actin and homatropine bromide-45 antigens. PMID- 25810676 TI - Wilson's disease: A Clinical autopsy case report with review of literature. AB - Wilson's disease is an autosomal recessive disease resulting in defective copper metabolism, which is usually seen in young adults, predominantly affecting liver and brain. Although it is not uncommon in India, variation in epidemiology, clinical presentation and course are reported. However, community-based incidence and prevalence rates are not available in India and incidences are limited to hospital based reports. Most often, the diagnosis is delayed. We present a clinical autopsy case in a 39 year-old female who had presented with clinical symptoms at 18 years of age. The duration of illness was 21 years. Patient's parent had consanguineous marriage and the younger sibling had died at 5 years of age with similar complaints. PMID- 25810677 TI - Hemisection: A conservative management of periodontally involved molar tooth in a young patient. AB - Hemisection is sectioning of multi-rooted teeth with its crown portion, with the loss of periodontal attachment and is performed to retain the original tooth structure and attain the fixed prosthodontic prosthesis. We describe hemisection of a mandibular molar tooth followed by adequate restoration in a young patient. PMID- 25810678 TI - Prune Belly syndrome: A rare case report. AB - Prune Belly syndrome (PBS) is a rare congenital anomaly of uncertain etiology almost exclusive to males. We report a case of term male baby born to a 39-year old grand multipara with previous four normal vaginal births. There was no history of genetic or congenital anomaly in her family. Examination of the baby revealed hypotonia, deficient abdominal muscle, cryptorchidism, palpable kidney, and bladder. Ultrasound examination of the abdomen revealed bilateral gross hydronephrosis and megaureter. Provisional diagnosis of PBS was made and the baby was admitted in neonatal intensive care units for further management. Routine antenatal care with ultrasonography will help in detecting renal anomalies, which can be followed postnatally. Early diagnosis of this syndrome and determining its optimal treatment are very important in helping to avoid its fatal course. PMID- 25810679 TI - Cervical ectopic pregnancy. AB - Cervical pregnancy is a rare type of ectopic pregnancy and it represents <1% of all ectopic pregnancies. Early diagnosis and medical management with systemic or local administration of methotrexate is the treatment of choice. If the pregnancy is disturbed, it may lead to massive hemorrhage, which may require hysterectomy to save the patient. We report three cases of cervical pregnancy managed successfully with different approaches of management. Our first case, 28 years old G3P2L2 with previous two lower segment cesarean sections, presented with bleeding per vaginum following 6 weeks of amenorrhea. Clinical examination followed by transvaginal ultrasound confirmed the diagnosis of cervical pregnancy. Total abdominal hysterectomy was done in view of intractable bleeding to save the patient. The second case, a 26-year-old second gravida with previous normal vaginal delivery presented with pain abdomen and single episode of spotting per vaginum following 7 weeks of amenorrhea. Transvaginal ultrasound revealed empty endometrial cavity, closed internal os with gestational sac containing live fetus of 7 weeks gestational age in cervical canal and she was treated with intra-amniotic potassium chloride followed by systemic methotrexate. Follow up with serum beta human chorionic gonadotropin level revealed successful outcome. Our third case, a 27-year-old primigravida with history of infertility treatment admitted with complaints of bleeding per vaginum for 1 day following 8 weeks amenorrhea. She was diagnosed as cervical pregnancy by clinical examination, confirmed by transvaginal ultrasonography and subsequently managed by dilation and curettage with intracervical Foleys' ballon tamponade. PMID- 25810680 TI - An unusual oral manifestation of type 1 neurofibromatosis: A case report and review of literature. AB - Neurofibroma is a benign peripheral nerve sheath tumor and is the most frequent tumor of neural origin. Its presence is one of the clinical criteria for the diagnosis of neurofibromatosis type 1 (NF1; a common hereditary disease occurring in one out of every 3000 births). The diagnosis can sometimes be made at birth, while in others the diagnosis is made later in life after the appearance of additional clinical criteria. Majority of the solitary neurofibromas are sporadic, while a few are associated with NF1 syndrome. Oral hard and soft tissue are affected by the tumor; however, the tongue is the most affected site. Gingival neurofibroma is an uncommon oral manifestation of NF. Here, we report a rare case of gingival neurofibroma in NF1 patient. One of the most feared complications of NF1 is its transformation into neurofibrosarcoma, which bears a very poor prognosis. Treatment of neurofibroma is surgical resection. PMID- 25810681 TI - Sirenomelia: The mermaid syndrome: Report of two cases. AB - Sirenomelia (mermaid syndrome) is a rare congenital fetal anomaly with characteristic feature of complete or partial fusion of lower limbs. Although, this syndrome is incompatible with life due to the association of several congenital visceral abnormalities; however, there are few reports of surviving infants. Our first case was a live born, normally delivered at term by a 27-year old third gravida of lower socioeconomic status with history of tobacco use. Examination of the baby revealed caudal dysgenesis having fusion of lower limbs, single leg with 1 foot and 5 toes. There was no identifiable external genitalia and anus. The second case was a 34 week, 1.6 kg preterm infant of unidentified sex born to a 28-year-old primigravida mother with overt diabetes mellitus. Incidentally, both the infants died few hours after birth and we report these cases due to their rarity and term live birth. PMID- 25810682 TI - Infra-orbital nerve schwannoma: Report and review. AB - Extra-cranial schwannomas although common in head and neck region are very rarely seen originating from the infra-orbital nerve. We report a case of schwannoma arising from infra-orbital nerve in a 40-year-old male patient. The case presented as an isolated, asymptomatic, slow growing sub-cutaneous nodular swelling over left side of mid-face. On ultrasonography, a localized lesion within the sub-cutaneous tissue of cheek was observed, without involvement of orbital, maxillary sinus or underlying bone. Aspiration biopsy of the lesion showed spindle shaped cells predominantly arranged in Antoni A pattern around verocay bodies, with less organized Antoni B tissue in few places. Diagnosis of schwannoma, probably arising from terminal branch of infra-orbital nerve was established. The tumor was approached through skin incision. At the time of exploration, the lesion was found to emanate from the nerve trunk of peripheral branch of infra-orbital nerve, which was dissected and preserved. We correlate our experience with previously reported cases of infra-orbital nerve schwannoma. PMID- 25810683 TI - A rare case of thyrotoxic periodic paralysis precipitated by hydrocortisone. AB - Thyrotoxic periodic paralysis (TPP) is a rare, but serious condition characterized by acute paralytic attacks and hypokalemia in association with thyrotoxicosis. Although carbohydrate rich meals, strenuous exercise, alcohol, emotional stress are known precipitants of TPP, steroid treatment has rarely been reported to induce TPP. We report a case in which a patient with previously untreated Grave's disease developed TPP following administration of Intravenous hydrocortisone for control of severe anaphylaxis, which to best of our knowledge is very rare. PMID- 25810684 TI - Rehabilitation of amputed thumb with a silicone prosthesis. AB - Creating prosthesis, having realistic skin surface and seamless visual integration with the surrounding tissues, requires both artistic and technical skill. Anatomical design, thin margins, lifelike fingernails and realistic color/contours are essential for patient satisfaction. Prosthesis is especially useful in case of lost body parts, as reconstructive surgery cannot fully restore aesthetics. This case report describes a simple technique for fabricating silicon finger prosthesis for a patient. PMID- 25810685 TI - Reaching the limits of reform: medical education and the Hellenic academic institutions facing the euro-crisis. PMID- 25810686 TI - Tissue antinuclear antibodies in renal biopsies of patients with systemic connective tissue disorders. PMID- 25810689 TI - Fluorescence In Situ Hybridization for MDM2 Amplification as a Routine Ancillary Diagnostic Tool for Suspected Well-Differentiated and Dedifferentiated Liposarcomas: Experience at a Tertiary Center. AB - Background. The assessment of MDM2 gene amplification by fluorescence in situ hybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute. Methods. All routine histology samples in which MDM2 amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings. Results. 365 samples from 347 patients had FISH for MDM2 gene amplification. 170 were positive (i.e., showed MDM2 gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in "classical" (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in "classical" sites but again more frequently core biopsies. Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory. PMID- 25810687 TI - Influenza and pregnancy: a review of the literature from India. AB - Maternal influenza infection is known to cause substantial morbidity and mortality among pregnant women and young children. Many professional healthcare bodies including the World Health Organization (WHO) have identified pregnant women as a priority risk group for receipt of inactivated seasonal influenza vaccination. However influenza prevention in this group is not yet a public health priority in India. This literature review was undertaken to examine the Indian studies of influenza among pregnant women. Eight Indian studies describing influenza burden and/or outcomes among pregnant women with influenza were identified. In most studies, influenza A (pH1N1) was associated with increased maternal mortality (25-75%), greater disease severity, and adverse fetal outcomes as compared to nonpregnant women. Surveillance for seasonal influenza infections along with higher quality prospective studies among pregnant women is needed to quantify disease burden, improve awareness among antenatal care providers, and formulate antenatal influenza vaccine policies. PMID- 25810690 TI - Growing better brains? Pregnancy and neuroscience discourses in English social and welfare policies. AB - In recent years, English welfare and health policy has started to include pregnancy within the foundation stage of child development. The foetus is also increasingly designated as 'at risk' from pregnant women. In this article, we draw on an analysis of a purposive sample of English social and welfare policies and closely related advocacy documents to trace the emergence of neuroscientific claims-making in relation to the family. In this article, we show that a specific deterministic understanding of the developing brain that only has a loose relationship with current scientific evidence is an important component in these changes. We examine the ways in which pregnancy is situated in these debates. In these debates, maternal stress is identified as a risk to the foetus; however, the selective concern with women living in disadvantage undermines biological claims. The policy claim of neurological 'critical windows' also seems to be influenced by social concerns. Hence, these emerging concerns over the foetus' developing brain seem to be situated within the gendered history of policing women's pregnant bodies rather than acting on new insights from scientific discoveries. By situating these developments within the broader framework of risk consciousness, we can link these changes to wider understandings of the 'at risk' child and intensified surveillance over family life. PMID- 25810692 TI - Length of prostate biopsies is not necessarily compromised by pooling multiple cores in one paraffin block: an observational study. AB - BACKGROUND: Individually submitted prostatic needle biopsies are recommended by most guidelines because of their potential advantage in terms of core quality. However, unspecified bilateral biopsies are commonly submitted in many centers. The length of the core is the key quality indicator of prostate biopsies. Because there are few recent publications comparing the quality of 12 site-designated biopsies versus pooled biopsies, we compared the lengths of the biopsies obtained by both methods. METHODS: The material was obtained from 471 consecutive subjects who underwent prostatic needle biopsy in the Tampere University Hospital district between January and June 2013. Biopsies from 344 subjects fulfilled the inclusion criteria. The total number of cores obtained was 4047. The core lengths were measured on microscope slides. Extraprostatic tissue was subtracted from the core length. RESULTS: The aggregate lengths observed were 129.5 +/- 21.8 mm (mean +/- SD) for site-designated cores and 136.9 +/- 26.4 mm for pooled cores (p = 0.09). The length of the core was 10.8 +/- 1.8 mm for site-designated cores and 11.4 +/- 2.2 mm for pooled cores (p = 0.87). The median length for pooled cores was 11 mm (range 5 mm - 18 mm). For individual site-designated cores, the median length was 11 mm (range 7 mm -15 mm). The core length was not correlated with the number of cores embedded into one paraffin block (r = 0.015). There was no significant difference in cancer detection rate (p = 0.62). CONCLUSIONS: Our results suggest that unspecified bilateral biopsies do not automatically lead to reduced core length. We conclude that carefully embedded multiple (three to nine) cores per block may yield cores of equal quality in a more cost-efficient way and that current guidelines favoring individually submitted cores may be too strict. PMID- 25810691 TI - Palliative sedation for terminally ill cancer patients in a tertiary cancer center in Shanghai, China. AB - BACKGROUND: There are a number of studies dedicated to characteristics of sedation, but these studies are mostly bound to western country practices. The aim of this study is to describe the characteristics of patients who suffered from cancer and who had been sedated until their death in Shanghai, China. METHODS: Retrospective medical data of 244 terminally ill cancer patients including 82 sedated patients were collected. Data collected included demographic characteristics, disease-related characteristics and details of the sedation. RESULTS: In sedated cases, patients and/or caregivers gave the consent to start palliative sedation due to unmanageable symptoms. On average, sedation was performed 24.65(+/-1.78)hours before death. Agitated delirium and dyspnea were the most frequent indications for palliative sedation. There was no significant difference in survival time from admission till death between sedated and non sedated patients (p > 0.05). CONCLUSIONS: Palliative sedation is effective for reducing terminally ill cancer patients' suffering without hastening death. Prospective research is needed to determine the optimal conditions for Chinese patients including indications, decision making process, informed consent, cultural and ethical issues, type of sedation and drugs. PMID- 25810694 TI - Synthesis of silver abietate as an antibacterial agent for textile applications. AB - This study explored the potential use of new silver abietate obtained from abietic acid as an antibacterial agent for textile applications. Synthesis, structure, and antibacterial studies of silver abietate compound are reported. Silver complex was obtained reacting abietic acid with silver. The new compounds were characterized by (1)H NMR, (13)C NMR, DEPT, IR, UV, and ESI-MS techniques which support the proposed structures. The new Ag abietate complex has no environmental hazard, its antibacterial activities were evaluated after being applied to cotton fabric by padding process according to the JIS L 1902-2008 agar diffusion test method and against three Gram-negative and three Gram-positive bacteria, respectively. Stability of antibacterial effect after repeated washings (3, 5, 10, and 20) was also tested which indicated that the synthesized silver abietate compound could be used as a new antibacterial agent in textile industry. In this way, the compound has been synthesized the first time in the literature and the applications have been investigated. PMID- 25810693 TI - Implementing Yoga Therapy Adapted for Older Veterans Who Are Cancer Survivors. AB - OBJECTIVES: This goal of this paper is to describe the reach, application, and effectiveness of an 8-week yoga therapy protocol with older cancer survivors within a Veterans Health Administration setting. METHODS: To document the reach of this intervention, recruitment efforts, attendance, and practice rates were tracked. To explore the application of the protocol to this population, physical therapy pre-assessment and observations by the yoga therapist were recorded to ascertain necessary pose modifications. Effectiveness was measured through pre- and post-course structured interviews, tracking self-reported symptoms of combat related posttraumatic stress disorder, depression, anxiety, fatigue, insomnia, and pain. RESULTS: Regarding reach, 15% of eligible veterans (n = 14) enrolled, participated in 3-16 classes (M+/-SD = 11.64+/-3.39), and practiced at home for 0 56 days (M+/-SD = 26.36+/-17.87). Participants were primarily Caucasian (n = 13), male (n = 13), ranged in age from 55 to 78 years (M+/-SD = 65.64+/-5.15), and had multiple medical problems. During application, substantial individualized modifications to the yoga therapy protocol were necessary. Effectiveness of the intervention was mixed. During post-course interviews, participants reported a variety of qualitative benefits. Notably, the majority of participants reported that breathing and relaxation techniques were the most useful to learn. Group comparisons of mean pre- and post-course scores on standardized measures showed no significant differences. CONCLUSIONS: A minority of older veterans express an interest in yoga, but those who do have high rates of class attendance and home practice. Careful physical pre-assessment and attentive therapists are required to undertake the adaptations required by participants with multiple comorbidities. The effectiveness of yoga in this setting requires additional study. PMID- 25810696 TI - Clinical value of whole-body magnetic resonance imaging in health screening of general adult population. AB - BACKGROUND: Whole-body magnetic resonance imaging (WB-MRI) and angiography (WB MRA) has become increasingly popular in population-based research. We evaluated retrospectively the frequency of potentially relevant incidental findings throughout the body. MATERIALS AND METHODS: 22 highly health-conscious managers (18 men, mean age 47+/-9 years) underwent WB-MRI and WB-MRA between March 2012 and September 2013 on a Discovery MR750w wide bore 3 Tesla device (GE Healthcare) using T1 weighted, short tau inversion recovery (STIR) and diffusion weighted imaging (DWI) acquisitions according to a standardized protocol. RESULTS: A suspicious (pararectal) malignancy was detected in one patient which was confirmed by an endorectal sonography. Incidental findings were described in 20 subjects, including hydrocele (11 patients), benign bony lesion (7 patients) and non-specific lymph nodes (5 patients). Further investigations were recommended in 68% (ultrasound: 36%, computed tomography: 28%, mammography: 9%, additional MRI: 9%). WB-MRA were negative in 16 subjects. Vascular normal variations were reported in 23%, and a 40% left proximal common carotid artery stenosis were described in one subject. CONCLUSIONS: WB-MRI and MRA lead to the detection of clinically relevant diseases and unexpected findings in a cohort of healthy adults that require further imaging or surveillance in 68%. WB-MR imaging may play a paramount role in health screening, especially in the future generation of (epi)genetic based screening of malignant and atherosclerotic disorders. Our study is the first which involved a highly selected patient group using a high field 3-T wide bore magnet system with T1, STIR, MRA and whole-body DWI acquisitions as well. PMID- 25810695 TI - The role of PET-CT in radiotherapy planning of solid tumours. AB - BACKGROUND: PET-CT is becoming more and more important in various aspects of oncology. Until recently it was used mainly as part of diagnostic procedures and for evaluation of treatment results. With development of personalized radiotherapy, volumetric and radiobiological characteristics of individual tumour have become integrated in the multistep radiotherapy (RT) planning process. Standard anatomical imaging used to select and delineate RT target volumes can be enriched by the information on tumour biology gained by PET-CT. In this review we explore the current and possible future role of PET-CT in radiotherapy treatment planning. After general explanation, we assess its role in radiotherapy of those solid tumours for which PET-CT is being used most. CONCLUSIONS: In the nearby future PET-CT will be an integral part of the most radiotherapy treatment planning procedures in an every-day clinical practice. Apart from a clear role in radiation planning of lung cancer, with forthcoming clinical trials, we will get more evidence of the optimal use of PET-CT in radiotherapy planning of other solid tumours. PMID- 25810697 TI - Dynamic contrast-enhanced computed tomography to assess early activity of cetuximab in squamous cell carcinoma of the head and neck. AB - BACKGROUND: Cetuximab, a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), has demonstrated activity in various tumor types. Using dynamic contrast-enhanced computed tomography (DCE-CT), we investigated the early activity of cetuximab monotherapy in previously untreated patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Treatment-naive patients with SCCHN received cetuximab for 2 weeks before curative surgery. Treatment activity was evaluated by DCE-CT at baseline and before surgery. Tumor vascular and interstitial characteristics were evaluated using the Brix two-compartment kinetic model. Modifications of the perfusion parameters (blood flow Fp, extravascular space ve, vascular space vp, and transfer constant PS) were assessed between both time points. DCE data were compared to FDG-PET and histopathological examination obtained simultaneously. Plasmatic vascular markers were investigated at different time points. RESULTS: Fourteen patients had evaluable DCE-CT parameters at both time points. A significant increase in the extravascular extracellular space ve accessible to the tracer was observed but no significant differences were found for the other kinetic parameters (Fp, vp or PS). Significant correlations were found between DCE parameters and the other two modalities. Plasmatic VEGF, PDGF-BB and IL-8 decreased as early as 2 hours after cetuximab infusion. CONCLUSIONS: Early activity of cetuximab on tumor interstitial characteristics was detected by DCE-CT. Modifications of plasmatic vascular markers are not sufficient to confirm anti-angiogenic cetuximab activity in vivo. Further investigation is warranted to determine to what extent DCE-CT parameters are modified and to evaluate whether they are able to predict treatment outcome. PMID- 25810698 TI - Appearance of Hurthle cell carcinoma soon after surgical extirpation of Hurthle cell adenoma and follicular adenoma of the thyroid gland. AB - BACKGROUND: Hurthle cell neoplasms could be benign (Hurthle cell adenoma) or malignant (Hurthle cell carcinoma). Hurthle cell carcinoma is a rare tumour, representing 5% of all differentiated thyroid carcinomas. The cytological evaluation of Hurthle cell neoplasms by fine needle aspiration biopsy (FNAB) is complicated because of the presence of Hurthle cells in both Hurthle cell adenoma and Hurthle cell carcinoma. Thus, the preoperative distinction between these two entities is very difficult and possible only with pathohistological findings of the removed tumour. CASE REPORT: A 57-year old female patient was admitted at our Department, for investigation of nodular thyroid gland. She was euthyroid and FNAB of the nodules in both thyroid lobes were consistent of Hurthle cell adenoma with cellular atypias. After thyroidectomy the histopathology revealed Hurthle cell adenoma with high cellular content and discrete cellular atypias in the left lobe and follicular thyroid adenoma without cellular atypias in the right lobe. One year after substitution therapy, a palpable tumour on the left side of the remnant tissue was found, significantly growing with time, presented as hot nodule on (99m)Tc-sestamibi scan and conclusive with Hurthle cell adenoma with marked cellularity on FNAB. Tumorectomy was performed and well-differentiated Hurthle cell carcinoma detected. The patient received ablative dose of 100 mCi (131)I. No signs of metastatic disease are present up to date. CONCLUSIONS: The differences between Hurthle cell adenomas and Hurthle cell carcinomas could be clearly made only by histopathological evaluation. Patients with cytological diagnosis of Hurthle cell neoplasms should proceed to total thyroidectomy, especially if tumour size is > 1cm, FNAB findings comprise cellular atypias and/or multiple bilateral nodules are detected in the thyroid gland. PMID- 25810699 TI - Adjuvant TNF-alpha therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectiveness. AB - BACKGROUND: Electrochemotherapy is a tumour ablation modality, based on electroporation of the cell membrane, allowing non-permeant anticancer drugs to enter the cell, thus augmenting their cytotoxicity by orders of magnitude. In preclinical studies, bleomycin and cisplatin proved to be the most suitable for clinical use. Intravenous administration of cisplatin for electrochemotherapy is still not widely accepted in the clinics, presumably due to its lower antitumor effectiveness, but adjuvant therapy by immunomodulatory or vascular-targeting agents could provide a way for its potentiation. Hence, the aim of the present study was to explore the possibility of adjuvant tumour necrosis factor alpha (TNF-alpha) therapy to potentiate antitumor effectiveness of electrochemotherapy with intravenous cisplatin administration in murine sarcoma. MATERIALS AND METHODS: In vivo study was designed to evaluate the effect of TNF-alpha applied before or after the electrochemotherapy and to evaluate the effect of adjuvant TNF-alpha on electrochemotherapy with different cisplatin doses. RESULTS: A synergistic interaction between TNF-alpha and electrochemotherapy was observed. Administration of TNF-alpha before the electrochemotherapy resulted in longer tumour growth delay and increased tumour curability, and was significantly more effective than TNF-alpha administration after the electrochemotherapy. Tumour analysis revealed increased platinum content in tumours, TNF-alpha induced blood vessel damage and increased tumour necrosis after combination of TNF-alpha and electrochemotherapy, indicating an anti-vascular action of TNF-alpha. In addition, immunomodulatory effect might have contributed to curability rate of the tumours. CONCLUSION: Adjuvant intratumoural TNF-alpha therapy synergistically contributes to electrochemotherapy with intravenous cisplatin administration. Due to its potentiation at all doses of cisplatin, the combined treatment is predicted to be effective also in tumours, where the drug concentration is suboptimal or in bigger tumours, where electrochemotherapy with intravenous cisplatin is not expected to be sufficiently effective. PMID- 25810700 TI - Mild hyperthermia influence on Herceptin((r)) properties. AB - BACKGROUND: Mild hyperthermia (mHT) increases the tumor perfusion and vascular permeability, and reduces the interstitial fluid pressure, resulting in better intra-tumoral bioavailability of low molecular weight drugs. This approach is potentially also attractive for delivery of therapeutic macromolecules, such as antibodies. Here, we investigated the effects of mHT on the stability, immunological and pharmacological properties of Herceptin((r)), a clinically approved antibody, targeting the human epidermal growth factor receptor 2 (HER-2) overexpressed in breast cancer. RESULTS: Herceptin((r)) was heated to 37 degrees C (control) and 42 degrees C (mHT) for 1 hour. Formation of Herceptin((r)) aggregates was measured using Nile Red assay. mHT did not result in additional Herceptin((r)) aggregates compared to 37 degrees C, showing the Herceptin((r)) stability is unchanged. Immunological and pharmacological properties of Herceptin((r)) were evaluated following mHT using HER-2 positive breast cancer cells (BT-474). Exposure of Herceptin((r)) to mHT preserved recognition and binding affinity of Herceptin((r)) to HER-2. Western-blot and cell proliferation assays on BT-474 cells showed that mHT left the inhibitory activities of Herceptin((r)) unchanged. CONCLUSIONS: The stability, and the immunological and pharmacological properties of Herceptin((r)) are not negatively affected by mHT. Further in-vivo studies are required to evaluate the influence of mHT on intra tumoral bioavailability and therapeutic effectiveness of Herceptin((r)). PMID- 25810702 TI - Higher levels of total pepsin and bile acids in the saliva as a possible risk factor for early laryngeal cancer. AB - BACKGROUND: Gastroesophageal reflux is suspected to be an etiological factor in laryngeal and pharyngeal cancer. The aim of this study was to establish, using a non-invasive method, whether laryngopharyngeal reflux (LPR) appears more often in patients with early laryngeal cancer than in a control group. PATIENTS AND METHODS: We compared the pH, the level of bile acids, the total pepsin and the pepsin enzymatic activity in saliva in a group of 30 patients with T1 laryngeal carcinoma and a group of 34 healthy volunteers. RESULTS: The groups differed significantly in terms of levels of total pepsin and bile acids in the saliva sample. Higher levels of total pepsin and bile acids were detected in the group of cancer patients. No significant impact of other known factors influencing laryngeal mucosa (e.g. smoking, alcohol consumption, and the presence of irritating substances in the workplace) on the results of saliva analysis was found. CONCLUSIONS: A higher level of typical components of LPR in the saliva of patients with early laryngeal cancer than in the controls suggests the possibility that LPR, especially biliary reflux, has a role in the development of laryngeal carcinoma. PMID- 25810701 TI - EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides. AB - BACKGROUND: There is limited effect of tyrosine kinase inhibitors or "naked" antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder cancer and these methods are therefore not routinely used. Targeting radio nuclides to the extracellular domain of the receptors is potentially a better possibility. METHODS: EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose. RESULTS: EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients. CONCLUSIONS: At least one of the EGFR- or HER2-receptors was present in most cases and co expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention. PMID- 25810703 TI - Hypodontia phenotype in patients with epithelial ovarian cancer. AB - BACKGROUND: Ovarian cancer is usually diagnosed in an advanced stage and the present clinical and diagnostic molecular markers for early OC screening are insufficient. The aim of this study was to identify potential relationship between the hypodontia and epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A retrospective study was conducted on 120 patients with EOC treated at the Department of Gynaecologic and Breast Oncology at the University Clinical Centre and 120 gynaecological healthy women (control group) of the same mean age. Women in both groups were reviewed for the presence of hypodontia and the patients with EOC also for clinicopathological characteristics of EOC according to hypodontia phenotype. RESULTS: Hypodontia was diagnosed in 23 (19.2%) of patients with EOC and 8 (6.7%) controls (p = 0.004; odds ratio [OR] = 3.32; confidence interval [CI], 1.42-7.76). There was no statistically significant difference in patients with EOC with or without hypodontia regarding histological subtype (p = 0.220); they differed in regard to FIGO stage (p = 0.014; OR =3.26; CI, 1.23-8.64) and tumour differentiation grade (p = 0.042; OR = 3.1; CI, 1.01-9.53). Also, bilateral occurrence of EOC was more common than unilateral occurrence in women with hypodontia (p = 0.021; OR = 2.9; CI, 1.15-7.36). We also found statistically significant difference between the ovarian cancer group and control group in presence of other malignant tumours in subjects (p < 0.001). CONCLUSIONS: The results of the study suggest a statistical association between EOC and hypodontia phenotype. Hypodontia might serve as a risk factor for EOC detection. PMID- 25810705 TI - Treatment of tongue cavernous haemangioma with direct puncture and sclerotization with ethanol. AB - BACKGROUND: Haemangiomas of tongue are rare type of malformations. They can be treated mostly conservatively but in some cases they need more aggressive treatment with preoperative intra arterial embolization and surgical resection. Lesions of tongue that are localized superficially can also be treated with direct puncture and injection of sclerosing agent (absolute ethanol). CASE REPORT: We present a case of a 48 years old female patient, where we performed embolization of cavernous haemangioma with mixture of absolute ethanol and oil contrast. After the procedure the patient received analgetics and antioedematous therapy. After the sclerotization the planed surgery was abandoned. Control MRI examinations 6 and 12 months after the procedure showed only a small remnant of haemangioma and no signs of a larger relapse. CONCLUSIONS: In our case the direct puncture of haemangioma and sclerotherapy with ethanol proved to be a safe and effective method to achieve preoperative devascularization of the lesion. Direct puncture of the lesion is not limited by the anatomy of the vessels or vasospasm, which can occur during the intra-arterial approach. PMID- 25810704 TI - Consolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenib. AB - BACKGROUND: Small molecules that inhibit V600 mutated BRAF protein, such as vemurafenib and dabrafenib, are effective in treatment of metastatic melanoma. CASE REPORT: We here describe the clinical course of a V600E BRAF mutated metastatic melanoma patient with systemic disease, who developed tumor progression on superficial soft-tissue metastases during treatment with dabrafenib. Bleomycin electrochemotherapy during dabrafenib treatment was administered to control the soft-tissue progressing metastases and ensured sustained local control without significant toxicity. CONCLUSIONS: The new combined approach maintained the patient quality of life and allowed for the prosecution of the target therapy, which proved to be still effective on systemic disease, up to 17 months. PMID- 25810707 TI - A new instrument for estimating the survival of patients with metastatic epidural spinal cord compression from esophageal cancer. AB - BACKGROUND: This study was initiated to create a predictive instrument for estimating the survival of patients with metastatic epidural spinal cord compression (MESCC) from esophageal cancer. METHODS: In 27 patients irradiated for MESCC from esophageal cancer, the following nine characteristics were evaluated for potential impact on survival: age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of involved vertebrae, ambulatory status before irradiation, further bone metastases, visceral metastases, and dynamic of developing motor deficits before irradiation. In addition, the impact of the radiation regimen was investigated. According to Bonferroni correction, p-values of < 0.006 were significant representing an alpha level of < 0.05. RESULTS: ECOG performance score (p < 0.001), number of involved vertebrae (p = 0.005), and visceral metastases (p = 0.004) had a significant impact on survival and were included in the predictive instrument. Scoring points for each characteristic were calculated by dividing the 6-months survival rates (in %) by 10. The prognostic score for each patient was obtained by adding the scoring points of the three characteristics. The prognostic scores were 4, 9, 10, 14 or 20 points. Three prognostic groups were formed, 4 points (n = 11), 9-14 points (n = 12) and 20 points (n = 4). The corresponding 6-months survival rates were 0%, 33% and 100%, respectively (p < 0.001). Median survival times were 1 month, 5 months and 16.5 months, respectively. CONCLUSIONS: This new instrument allows the physician estimate the 6-months survival probability of an individual patient presenting with MESCC from esophageal cancer. This is important to know for optimally personalizing the treatment of these patients. PMID- 25810706 TI - Bevacizumab and irinotecan in recurrent malignant glioma, a single institution experience. AB - BACKGROUND: Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. PATIENTS AND METHODS: The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) or 125 mg/m(2)) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0-2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3-8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6-8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1-2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed. CONCLUSIONS: In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity. PMID- 25810709 TI - Estimated collective effective dose to the population from radiological examinations in Slovenia. AB - BACKGROUND: The aim of the study was to systematically evaluate population exposure from diagnostic and interventional radiological procedures in Slovenia. METHODS: The study was conducted in scope of the "Dose Datamed 2" project. A standard methodology based on 20 selected radiological procedures was adopted. Frequencies of the procedures were determined via questionnaires that were sent to all providers of radiological procedures while data about patient exposure per procedure were collected from existing databases. Collective effective dose to the population and effective dose per capita were estimated from the collected data (DLP for CT, MGD for mammography and DAP for other procedures) using dose conversion factors. RESULTS: The total collective effective dose to the population from radiological in 2011 was estimated to 1300 manSv and an effective dose per capita to 0.6 mSv of which approximately 2/3 are due to CT procedures. CONCLUSIONS: The first systematic study of population exposure to ionising radiation from radiological procedures in Slovenia was performed. The results show that the exposure in Slovenia is under the European average. It confirmed large contributions of computed tomography and interventional procedures, identifying them as the areas that deserve special attention when it comes to justification and optimisation. PMID- 25810708 TI - Dosimetric comparison for volumetric modulated arc therapy and intensity modulated radiotherapy on the left-sided chest wall and internal mammary nodes irradiation in treating post-mastectomy breast cancer. AB - BACKGROUND: The aim of the study was to evaluate the dosimetric benefit of applying volumetric modulated arc therapy (VMAT) on the post-mastectomy left sided breast cancer patients, with the involvement of internal mammary nodes (IMN). PATIENTS AND METHODS: The prescription dose was 50 Gy delivered in 25 fractions, and the clinical target volume included the left chest wall (CW) and IMN. VMAT plans were created and compared with intensity-modulated radiotherapy (IMRT) plans on Pinnacle treatment planning system. Comparative endpoints were dose homogeneity within planning target volume (PTV), target dose coverage, doses to the critical structures including heart, lungs and the contralateral breast, number of monitor units and treatment delivery time. RESULTS: VMAT and IMRT plans showed similar PTV dose homogeneity, but, VMAT provided a better dose coverage for IMN than IMRT (p = 0.017). The mean dose (Gy), V30 (%) and V10 (%) for the heart were 13.5 +/- 5.0 Gy, 9.9% +/- 5.9% and 50.2% +/- 29.0% by VMAT, and 14.0 +/- 5.4 Gy, 10.6% +/- 5.8% and 55.7% +/- 29.6% by IMRT, respectively. The left lung mean dose (Gy), V20 (%), V10 (%) and the right lung V5 (%) were significantly reduced from 14.1 +/- 2.3 Gy, 24.2% +/- 5.9%, 42.4% +/- 11.9% and 41.2% +/- 12.3% with IMRT to 12.8 +/- 1.9 Gy, 21.0% +/- 3.8%, 37.1% +/- 8.4% and 32.1% +/- 18.2% with VMAT, respectively. The mean dose to the contralateral breast was 1.7 +/- 1.2 Gy with VMAT and 2.3 +/- 1.6 Gy with IMRT. Finally, VMAT reduced the number of monitor units by 24% and the treatment time by 53%, as compared to IMRT. CONCLUSIONS: Compared to 5-be am step-and-shot IMRT, VMAT achieves similar or superior target coverage and a better normal tissue sparing, with fewer monitor units and shorter delivery time. PMID- 25810711 TI - Feeding habits of mosquitoes (Diptera: Culicidae) in an area of sylvatic transmission of yellow fever in the state of Sao Paulo, Brazil. AB - BACKGROUND: The reintroduction of sylvatic yellow fever in the state of Sao Paulo after about six decades was confirmed in the Northwestern region in 2000, where in 2008 there also occurred an important epizootic. The purpose of this study was to investigate the feeding habits of culicids potentially involved in the sylvatic transmission of the virus in this region. METHODS: Specimens were collected in 24 forested localities at ground level with hand nets and mouth aspirators. Collections were made quarterly between October 2006 and July 2008 during daylight hours. Blood-meal identification was carried out in mosquitoes of the tribes Aedini, Mansoniini and Sabethini. The biotin/avidin sandwich ELISA was employed to determine six source types: bird, bovine, equine, rat, human and monkey. RESULTS: A total of 24,879 females of the three tribes were obtained, 245 (0.98%) of which were engorged. The presence of three different blood sources per engorged female was the predominant situation, and included 35.10% of the total of samples processed. Samples with two or four different sources were represented by 25.31% and 25.71%, of the specimens, respectively, while just 9.39% had only one type and 1.22%, five different sources. Aedes scapularis, Ae. serratus (Group), Psorophora albigenu and Ps. ferox were the most abundant species and accounted for about 95% of the engorged specimens. Of the principal vector species, Haemagogus janthinomys/capricornii was found with bird, bovine and primate blood. These sources were predominant and alternated top ranking as the most frequent source according to the mosquito species and collection site. In general, primate blood was the most prevalent source. CONCLUSIONS: The human population of the region visits this ecotone frequently, which indicates the need for the periodical assessment of vaccination coverage against yellow fever. The frequency of non-human primate blood source in mosquito species that show minor vector importance in yellow fever virus transmission deserves attention. The eclectic feeding habits and some aspects of the interactions between potential vectors and reservoirs of yellow fever may be associated with the habitat fragmentation characteristic of the region. We recommend that further studies on the capacity and vector competence be performed on secondary vectors in extra Amazonian region. PMID- 25810713 TI - The intelligence of dual simplex method to solve linear fractional fuzzy transportation problem. AB - An approach is presented to solve a fuzzy transportation problem with linear fractional fuzzy objective function. In this proposed approach the fractional fuzzy transportation problem is decomposed into two linear fuzzy transportation problems. The optimal solution of the two linear fuzzy transportations is solved by dual simplex method and the optimal solution of the fractional fuzzy transportation problem is obtained. The proposed method is explained in detail with an example. PMID- 25810712 TI - Report of 15 injuries caused by lionfish (pterois volitans) in aquarists in Brazil: a critical assessment of the severity of envenomations. AB - Lionfish are venomous fish that belong to the Scorpaenidae family. Individuals of this family and those of the Synanceiidae family comprise most of the existing venomous fish in the world. Lionfish are originally found in the Indo-Pacific, but they have received special attention in the last years for their dissemination in the Atlantic Ocean, with the emergence of large populations in the USA, Caribbean and South America. Because of its beauty, this fish has always been present in private and commercial aquariums around the world. Herein, we describe 15 envenomations in aquarists registered in a period of eighteen years (1997-2014). The stings caused excruciating pain and marked inflammation, with local erythema, edema, heat, paleness and cyanosis. In one case, it was possible to observe vesicles and blisters. There were no skin necroses or marked systemic manifestations. We discuss the possible coming of the fish to South America and the circumstances and clinical impact of the envenomations. PMID- 25810710 TI - Interface Immobilization Chemistry of cRGD-based Peptides Regulates Integrin Mediated Cell Adhesion. AB - The interaction of specific surface receptors of the integrin family with different extracellular matrix-based ligands is of utmost importance for the cellular adhesion process. A ligand consists of an integrin-binding group, here cyclic RGDfX, a spacer molecule that lifts the integrin-binding group from the surface and a surface anchoring group. c(-RGDfX-) peptides are bound to gold nanoparticle structured surfaces via polyproline, polyethylene glycol or aminohexanoic acid containing spacers of different lengths. Although keeping the integrin-binding c(-RGDfX-) peptides constant for all compounds, changes of the ligand's spacer chemistry and length reveal significant differences in cell adhesion activation and focal adhesion formation. Polyproline-based peptides demonstrate improved cell adhesion kinetics and focal adhesion formation compared with common aminohexanoic acid or polyethylene glycol spacers. Binding activity can additionally be improved by applying ligands with two head groups, inducing a multimeric effect. This study gives insights into spacer-based differences in integrin-driven cell adhesion processes and remarkably highlights the polyproline based spacers as suitable ligand-presenting templates for surface functionalization. PMID- 25810714 TI - Association between Portal Vein Thrombosis and Survival in Non-Liver-Transplant Patients with Liver Cirrhosis: A Systematic Review of the Literature. AB - A systematic review of the literature was performed to analyze the association between portal vein thrombosis (PVT) and survival in non-liver-transplant patients with liver cirrhosis. PubMed, EMBASE, and Cochrane Library databases were searched for all relevant papers which evaluated the prognostic value of PVT in predicting the survival of liver cirrhosis. Meta-analyses were not conducted because the ways of data expression and lengths of follow-up were heterogeneous among studies. Overall, 13 papers were included. The 5-day, 6-week, and 1-year mortality were investigated in 1, 3, and 1 studies, respectively; and all of them were not significantly different between cirrhotic patient with and without PVT. By comparison, the 3-year mortality was reported in 1 study; and it was significantly increased by the presence of PVT. The overall mortality was analyzed in 5 studies; and the association with overall mortality and PVT was significant in 4 studies, but not in another one. However, as for the cirrhotic patients undergoing surgical or interventional shunts, the overall mortality was not significantly associated with the presence of PVT in 4 studies. In conclusion, the presence of PVT might be associated with the long-term mortality in non-liver-transplant patients with liver cirrhosis, but not with the short term mortality. PMID- 25810715 TI - Feasibility of endoscopic resection for sessile nonampullary duodenal tumors: a multicenter retrospective study. AB - Objectives. Sessile nonampullary duodenal tumors (SNADTs) are relatively rare and endoscopic resection of these lesions is considered more challenging than in other parts of the gastrointestinal tract. The aim of this study was to evaluate the feasibility of endoscopic resection for SNADT. Methods. Medical records including endoscopic resection for SNADT from July 2002 to July 2013 from 5 centers affiliated to The Catholic University of Korea were reviewed retrospectively. Demographic features and clinical outcomes such as complete resection and complications were analyzed. Results. A total of 56 lesions from 54 patients were enrolled in this study. Forty-five lesions were resected by endoscopic mucosal resection (EMR), 6 lesions by endoscopic submucosal dissection (ESD), and 5 lesions by simple polypectomy. Histologic examination after endoscopic resection revealed adenocarcinoma in 2, low grade adenoma in 25, high grade adenoma in 11, and carcinoid tumor in 18 lesions. En bloc resection rates and histological complete resection rates were 78.6% (44/56) and 80.0% (28/35), respectively. Bleeding which required additional endoscopic intervention occurred in 1.8% (1/56) and perforation in 7.1% (4/56). There was no procedure-related mortality. Conclusions. Endoscopic resection techniques including ESD might be safe and effective modalities for the management of SNADT. PMID- 25810716 TI - Early laparoscopic cholecystectomy with continuous pressurized irrigation and dissection in acute cholecystitis. AB - Background. The aim of this study was to evaluate the preliminary results of a new dissection technique in acute cholecystitis. Material and Method. One hundred and forty-nine consecutive patients with acute cholecystitis were operated on with continuous pressurized irrigation and dissection technique. The diagnosis of acute cholecystitis was based on clinical, laboratory, and radiological evidences. Age, gender, time from symptom onset to hospital admission, operative risk according to the American Society of Anesthesiologists (ASA) score, white blood cell count, C-reactive protein test levels, positive findings of radiologic evaluation of the patients, operation time, perioperative complications, mortality, and conversion to open surgery were prospectively recorded. Results. Of the 149 patients, 87 (58,4%) were female and 62 (41,6%) were male. The mean age was 46.3 +/- 6.7 years. The median time from symptom onset to hospital admission 3.2 days (range, 1-6). There were no major complications such as bile leak, common bile duct injury or bleeding. Subhepatic liquid collection occurred in 3 of the patients which was managed by percutaneous drainage. Conversion to open surgery was required in four (2,69%) patients. There was no mortality in the study group. Conclusion. Laparoscopic cholecystectomy with continuous pressurized irrigation and dissection technique in acute cholecystitis seems to be an effective and reliable procedure with low complication and conversion rates. PMID- 25810717 TI - Teleultrasound: historical perspective and clinical application. AB - The health care of patients in rural or isolated areas is challenged by the scarcity of local resources, limited patient access to doctors and hospitals, and the lack of specialized professionals. This has led to a new concept in telemedicine: teleultrasonography (or teleultrasound), which permits ultrasonographic diagnoses to be performed remotely. Telemedicine and teleultrasonography are effective in providing diagnostic imaging services to these populations and reduce health care costs by decreasing the number and duration of hospitalizations and reducing unnecessary surgical procedures. This is a narrative review to present the potential clinical applications of teleultrasonography in clinical practice. The results indicate that although barriers persist for implementing teleultrasonography in a more universal and routine way, advances in telecommunications, Internet bandwidth, and the high resolution currently available for portable ultrasonography suggest teleultrasonography applications will continue to expand. Teleultrasound appears to be a valuable addition to remote medical care for isolated populations with limited access to tertiary healthcare facilities and also a useful tool for education and training. PMID- 25810718 TI - Polymorphism in LEP and LEPR May Modify Leptin Levels and Represent Risk Factors for Thyroid Cancer. AB - Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 +/- 0.98 ng/mL) than those with AG genotype (10.07 +/- 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 +/- 0.59 ng/mL) than the subjects with GG genotype (9.52 +/- 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516-90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161-12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426-20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness. PMID- 25810719 TI - Evidence for the adverse effect of starvation on bone quality: a review of the literature. AB - Malnutrition and starvation's possible adverse impacts on bone health and bone quality first came into the spotlight after the horrors of the Holocaust and the ghettos of World War II. Famine and food restrictions led to a mean caloric intake of 200-800 calories a day in the ghettos and concentration camps, resulting in catabolysis and starvation of the inhabitants and prisoners. Severely increased risks of fracture, poor bone mineral density, and decreased cortical strength were noted in several case series and descriptive reports addressing the medical issues of these individuals. A severe effect of severely diminished food intake and frequently concomitant calcium- and Vitamin D deficiencies was subsequently proven in both animal models and the most common cause of starvation in developed countries is anorexia nervosa. This review attempts to summarize the literature available on the impact of the metabolic response to Starvation on overall bone health and bone quality. PMID- 25810720 TI - One-year clinical evaluation of the bonding effectiveness of a one-step, self etch adhesive in noncarious cervical lesion therapy. AB - This study evaluated the one-year clinical performance of a one-step, self-etch adhesive (Optibond All-in-One, Kerr, CA, USA) combined with a composite (Herculite XRV Ultra, Kerr Hawe, CA, USA) to restore NCCLs with or without prior acid etching. Restorations performed by the same practitioner were evaluated at baseline and after 3, 6, and 12 months using modified USPHS criteria. At 6 months, the recall rate was 100%. The retention rate was 84.2% for restorations with prior acid etching, but statistically significant differences were observed between baseline and 6 months. Without acid etching, the retention rate was 77%, and no statistically significant difference was noted between 3 and 6 months. Marginal integrity (93.7% with and 87.7% without acid etching) and discoloration (95.3% with and 92.9% without acid etching) were scored as Alpha or Bravo, with better results after acid etching. After one year, the recall rate was 58.06%. Loss of pulp vitality, postoperative sensitivity, or secondary caries were not observed. After one year retention rate was of 90.6% and 76.9% with and without acid conditioning. Optibond All-in-One performs at a satisfactory clinical performance level for restoration of NCCLs after 12 months especially after acid etching. PMID- 25810721 TI - Impaired fibrinolysis in angiographically documented coronary artery disease. AB - Impaired fibrinolysis may predispose to coronary artery disease (CAD). Hypofibrinolysis due to high levels of plasminogen activator inhibitor-1 (PAI-1) has been reported in CAD. A novel regulator of fibrinolytic activity, thrombin activatable fibrinolysis inhibitor (TAFI), has attracted attention in recent years. It acts by blocking the formation of a ternary complex of plasminogen, fibrin, and tissue plasminogen activator (t-PA). Previously ambiguous results regarding TAFI levels have been reported in CAD. We measured plasma levels of PAI 1 and TAFI antigen in 123 patients with age ranging from 40 to 65 years who had been submitted to coronary angiography and assessed the association of these markers with the extent of stenosis in three groups: angiographically normal artery (NAn), mild to moderate atheromatosis (MA), and severe atheromatosis (SA). Plasma levels of PAI-1 were increased in patients with severe atheromatosis compared to mild/moderate atheromatosis or to normal patients (66.60, 40.50, and 34.90 ng/mL, resp.; P < 0.001). For TAFI no difference was found between different groups. When patients were grouped in only two groups based on clinical cut-off point for intervention (stenosis less than or above 70%) we found increased plasma levels for PAI-1 (37.55 and 66.60 ng/mL, resp.; P < 0.001) and decreased plasma levels for TAFI (5.20 and 4.53 MUg/mL, resp.; P = 0.04) in patients with stenosis above 70%. No difference was found in PAI-1 or TAFI levels comparing the number of affected vessels. Conclusion. As evidenced by a raised level of PAI-1 antigen, one can suggest an impaired fibrinolysis in stable CAD, although no correlation with the number of affected vessels was found. Curiously, a decreased plasma level of total TAFI levels was observed in patients with stenosis above 70%. Further studies measuring functional TAFI are required in order to elucidate its association with the extent of degree of atheromatosis. PMID- 25810722 TI - A case of sarcoidosis of the central nervous system and orbita. AB - Sarcoidosis is a multisystemic disease characterized by granulomatous inflammation. Lung or lymph node involvement is common. We present a rare case of sarcoidosis that began with orbital involvement, and a month later, due to insufficient treatment, it involved the central nervous system. A 49-year-old female patient began suffering from swelling in her right eye, redness, ptosis, and limited eye movements two months ago. Gadolinium-enhanced orbital magnetic resonance imaging showed thickening of the lacrimal gland and the right medial rectus muscle. After three weeks of local antibiotic and steroid treatments, her symptoms were resolved. One month ago, the patient reported sudden weakness in her right arm and leg. After laboratory tests and imaging studies, the patient was diagnosed with probable neurosarcoidosis using the Zajicek criteria and treated with prednisone (1 mg/kg/day). Although sarcoidosis frequently presents with lung and lymph node involvement, it is rarely accompanied by orbital involvement. Patients with orbital symptoms may receive a late diagnosis and insufficient central nervous system treatment. Involvement of the central nervous system in sarcoidosis leads to high morbidity and mortality rates. Therefore, early diagnosis and treatment are very important. PMID- 25810723 TI - Chin necrosis as a consequence of prone positioning in the intensive care unit. AB - Pressure necrosis of the skin is a rarely reported avoidable complication of prone positioning that can be minimised by active collaboration between care teams. We report a case of pressure necrosis of the chin after prone ventilation in the intensive care setting. Such injuries pose a risk of infection, possible need for surgical intervention, and increased costs to the health care system. Pressure necrosis injuries should be diligently guarded against by the careful selection of support devices, frequent turning, and rigorous skin care to minimise extended external compression, particularly on the face and bony prominences. PMID- 25810724 TI - Bone Marrow-Derived Mesenchymal Stem Cells Repair Necrotic Pancreatic Tissue and Promote Angiogenesis by Secreting Cellular Growth Factors Involved in the SDF-1 alpha /CXCR4 Axis in Rats. AB - Acute pancreatitis (AP), a common acute abdominal disease, 10%-20% of which can evolve into severe acute pancreatitis (SAP), is of significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to have a potential therapeutic role on SAP, but the specific mechanism is unclear. Therefore, we conducted this experiment to shed light on the probable mechanism. We validated that SDF-1alpha significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-beta, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100. The capacities of proliferation, migration, and repair of human umbilical vein endothelial cells were enhanced by BMSCs supernatant. Meanwhile, BMSCs supernatant could also promote angiogenesis, especially after the stimulation with SDF-1alpha. In vivo, the migration of BMSCs was regulated by SDF-1alpha/CXCR4 axis. Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-alpha?, IL-1beta?, IL-6?, IL-4?, IL 10?, and TGF-beta?), and promote tissue repair and angiogenesis (VEGF?, ANG-1?, HGF?, TGF-beta?, and CD31?), compared with the SAP and anti-CXCR4 groups. Taken together, the results showed that BMSCs ameliorated SAP and the SDF-1alpha/CXCR4 axis was involved in the repair and regeneration process. PMID- 25810725 TI - Neuroprotective and antiapoptotic activity of lineage-negative bone marrow cells after intravitreal injection in a mouse model of acute retinal injury. AB - We investigated effects of bone marrow-derived, lineage-negative cell (Lin(-)BMC) transplantation in acute retinal injury. Lin(-)BMCs were intravitreally injected into murine eyes at 24 h after NaIO3-induced injury. Morphology, function, and expression of apoptosis-related genes, including brain-derived neurotrophic factor (BDNF) and its receptor, were assessed in retinas at 7 days, 28 days, and 3 months after transplantation. Moreover, global gene expression at day 7 was analyzed by RNA arrays. We observed that Lin(-)BMCs integrated into outer retinal layers improving morphological retinal structure and induced molecular changes such as downregulation of proapoptotic caspase-3 gene, a decrease in BAX/BCL-2 gene ratio, and significant elevation of BDNF expression. Furthermore, transplanted Lin(-)BMCs differentiated locally into cells with a macrophage-like phenotype. Finally, Lin(-)BMCs treatment was associated with generation of two distinct transcriptomic patterns. The first relates to downregulated genes associated with regulation of neuron cell death and apoptosis, response to oxidative stress/hypoxia and external stimuli, and negative regulation of cell proliferation. The second relates to upregulated genes associated with neurological system processes and sensory perception. Collectively, our data demonstrate that transplanted Lin(-)BMCs exert neuroprotective function against acute retinal injury and this effect may be associated with their antiapoptotic properties and ability to express neurotrophic factors. PMID- 25810727 TI - Allergy to cooked, but not raw, peas: a case series and review. AB - Allergic reactions to legumes are common.Food allergy to cooked, but not raw, pea has been rarely reported in the literature. This case series describes five children who had various IgE-mediated symptoms upon consumption of cooked pea, but tolerated raw pea. Skin testing then confirmed positive responses to cooked, but not raw, peas. It is important to consider allergy to cooked legumes, even in the context of raw legume tolerance. PMID- 25810726 TI - Diversity of epithelial stem cell types in adult lung. AB - Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays, in vitro and/or ex vivo models, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer. PMID- 25810728 TI - Practical application of coronary imaging devices in cardiovascular intervention. AB - The significant morbidity and mortality associated with coronary artery disease has spurred the development of intravascular imaging devices to optimize the detection and assessment of coronary lesions and percutaneous coronary interventions. Intravascular ultrasound (IVUS) uses reflected ultrasound waves to quantitatively and qualitatively assess lesions; integrated backscatter and virtual histology IVUS more precisely characterizes plaque composition; angioscopy directly visualize thrombus and plaque; optical coherence tomography using near-infrared (NIR) light with very high spatial resolution provides more accurate images; and the recently introduced NIR spectroscopy identifies chemical components in coronary artery plaques based on differential light absorption in the NIR spectrum. This article reviews usefulness of these devices and hybrids thereof. PMID- 25810731 TI - Distribution of blood cholesterol profile in untreated korean population. PMID- 25810730 TI - Subclinical hypothyroidism or thyroid autoimmunity and variant angina: by chance? Or with a chance? PMID- 25810729 TI - Management of organic mitral regurgitation: guideline recommendations and controversies. AB - Mitral regurgitation (MR) represents the second most frequent valvular heart disease. The appropriate management of organic MR remains unclear in many aspects, especially in several specific clinical scenarios. This review aims to discuss the current guideline recommendations regarding the management of organic MR, while highlighting the controversial aspects encountered in daily clinical practice. The role of imaging is essential in establishing the most appropriate type of surgical treatment (repair or replace), which is based on morphological mitral valve (MV) characteristics (reparability of the valve) and local surgical expertise in valve repair. The potential advantages of 3-dimensional echocardiography in assessing the MV are discussed. Other modern imaging techniques (tissue Doppler and speckle tracking) may provide additional useful information in borderline cases. Exercise echocardiography (evaluating MR severity, pulmonary pressure, or right ventricular function) may have an important role in the management of difficult cases. Finally, the moment when surgery is no longer an option and alternative solutions should be sought is also discussed. Although in everyday clinical practice the timing of surgery is not always straightforward, some newer clinical and echocardiographic indicators can guide this decision and help improve the outcome of these patients. PMID- 25810732 TI - Effect of pretreatment of ezetimibe/simvastatin on arterial healing and endothelialization after drug-eluting stent implantation in a porcine coronary restenosis model. AB - BACKGROUND AND OBJECTIVES: We sought to evaluate the effect of the early use of ezetimibe/simvastatin (Vytorin(r)) on arterial healing and endothelialization after the implantation of a drug-eluting stent (DES) in a porcine model of coronary restenosis. MATERIALS AND METHODS: A total of 20 pigs (40 coronary arteries) were randomly allocated to a pretreatment or no treatment group. The pretreatment group (n=20) received oral ezetimibe/simvastatin (10/20 mg) daily for 7 days before stenting and the no pretreatment group (n=20) did not. All pigs were treated with ezetimibe/simvastatin (10/20 mg) daily after stenting for 4 weeks. Stenting was performed using a bare-metal stent (BMS, n=10) and three types of DES: biolimus A9-eluting stent (BES, n=10), zotarolimus-eluting stent (ZES, n=10), and everolimus-eluting stents (EES, n=10). Four weeks later, pigs underwent a follow-up coronary angiography and were sacrificed for histopathologic analysis. RESULTS: There were no significant differences between the pretreatment and no pretreatment groups in the internal elastic lamina area, lumen area, neointima area, stenotic area, injury score, fibrin score, and inflammation score. In both groups, the fibrin score was higher in pigs with DES than in BMS, particularly in ZES and EES. The inflammatory score was not different between DES and BMS. CONCLUSION: In a porcine model of coronary restenosis, pretreatment with ezetimibe/simvastatin before DES implantation failed to improve arterial healing and endothelialization compared to treatment after stenting. PMID- 25810733 TI - Poor health-related quality of life and proactive primary control strategy may act as risk factors for acute coronary syndrome. AB - BACKGROUND AND OBJECTIVES: Increasing evidence supports that psychological factors may be related to development of coronary artery disease (CAD). Although psychological well-being, ill-being, and control strategy factors may play a significant role in CAD, rarely have these factors been simultaneously examined previously. We assessed comprehensive psychological factors in patients with acute coronary syndrome (ACS). SUBJECTS AND METHODS: A total of 85 ACS patients (56 unstable angina, 29 acute myocardial infarction; 52.6+/-10.2 years; M/F=68/17) and 63 healthy controls (48.7+/-6.7 years, M/F=43/20) were included. Socio-demographic information, levels of psychological maladjustment, such as anxiety, hostility, and job stress, health-related quality of life (HRQoL), and primary and secondary control strategy use were collected through self-report questionnaires. RESULTS: There was no significant difference between the ACS group and control group in levels of anxiety, hostility, and job stress. However, ACS patients had significantly lower scores on the general health perception and bodily pain subscales of HRQoL than the control group. The ACS group, as compared with the controls, tended to use primary control strategies more, although not reaching statistical significance by univariate analysis. Multivariate logistic regression analysis after adjusting age and gender identified the physical domain of HRQoL {odds ratio (OR)=0.40}, primary control strategy (OR=1.92), and secondary control strategy (OR=0.53) as independent predictors of ACS. CONCLUSION: Poor HRQoL and primary control strategy, proactive behaviors in achieving ones' goal, may act as risk factors for ACS, while secondary control strategy to conform to current situation may act as a protective factor for ACS. PMID- 25810734 TI - The Impact of Subclinical Hypothyroidism or Thyroid Autoimmunity on Coronary Vasospasm in Patients without Associated Cardiovascular Risk Factors. AB - BACKGROUND AND OBJECTIVES: Subclinical hypothyroidism is associated with endothelial dysfunction and impaired coronary flow reserve. However, the effect of subclinical hypothyroidism or thyroid autoimmunity on variant angina has yet to be determined. SUBJECTS AND METHODS: Among 385 consecutive patients without associated cardiovascular risk factors who underwent coronary angiography with the ergonovine provocation test (EPT), 165 had a positive EPT {EPT(+)} and 220 had a negative EPT {EPT(-)}. The relationship between coronary artery spasm and the presence of subclinical thyroid dysfunction as well as serum thyroid peroxidase autoantibody (TPO Ab) was evaluated. RESULTS: The proportion of patients with subclinical hypothyroidism among those who were EPT(+) was significantly higher than that in those who were EPT(-) (18% vs. 11%, p=0.001). However, there was no significant difference in the proportion of patients with subclinical hyperthyroidism between the groups. Moreover, EPT(+) patients showed significantly more positive TPO Ab (33% vs. 14%, p<0.001) than those with EPT(-). There was a positive correlation between EPT(+) and TPO positivity (r=0.226, p<0.001), subclinical hypothyroidism (r=0.112, p=0.033), and body mass index (r=0.123, p=0.018). Binary logistic regression analysis revealed that the significant predictors of EPT(+) were body mass index {adjusted odds ratio (OR)=1.042, 95% confidence interval (CI)=1.005-1.080}, presence of subclinical hypothyroidism (OR=3.047, 95% CI=1.083-8.572), TPO Ab titer (OR=1.028, 95% CI=1.015-1.041), and the presence of TPO Ab (OR=4.904, 95% CI=1.544-15.567). CONCLUSION: Subclinical hypothyroidism and the presence of TPO Ab are significantly associated with coronary vasospasm in patients without cardiovascular risk factors. PMID- 25810735 TI - Normal left ventricular torsion mechanics in healthy children: age related changes of torsion parameters are closely related to changes in heart rate. AB - BACKGROUND AND OBJECTIVES: This study was aimed at assessing left ventricular torsion (LVtor) mechanics using speckle tracking echocardiography (STE), establishing normal reference values of principal LVtor parameters, and analyzing the age-related changes in normal children. SUBJECTS AND METHODS: Eighty children (aged 3 months to 15 years) with normal cardiac function and rhythm were recruited. LVtor parameters including rotations, twist and untwist, torsion, and their rate indices were measured using STE. Age and heart rate related changes of the parameters were analyzed. RESULTS: Speckle tracking echocardiography analyses for LVtor parameters had excellent reliability in 64 of 80 subjects (80%) (intraclass correlation coefficients; 0.93-0.97). Early systolic twist (EST) motions (-8.4--0.1 degrees ) were observed in all subjects during an early 20+/ 7% of systolic time intervals. The peak systolic twist and torsion were 17.0+/ 6.5 degrees and 2.9+/-1.3 degrees /cm, respectively. The peak twist velocity was recorded at 51+/-13% of systolic time and the peak untwist velocity at 13.8+/ 11.5% of diastolic time intervals. Multivariate analysis showed that heart rate change was an independent predictor of changes in torsion parameters; significantly decreasing LV length-normalized apical and basal rotation, torsion, and twist and untwist rate with increasing age. Isovolumetric recoil rate was independent of change in age and heart rate. CONCLUSION: Left ventricle showed unique torsion mechanics in children with EST, torsion, and untwists. Heart rate was an independent predictor of the change in torsion parameters with aging. PMID- 25810736 TI - Effects of age, sex, and menopausal status on blood cholesterol profile in the korean population. AB - BACKGROUND AND OBJECTIVES: To investigate age-specific and sex-specific distributions of blood cholesterol in the general Korean population. SUBJECTS AND METHODS: We analyzed data for 8284 men and 9246 women aged >=10 years who participated in the fifth (2010-2012) Korea National Health and Nutrition Examination Survey. Age-specific means, medians, and selected percentiles were calculated for men, premenopausal women, and postmenopausal women. RESULTS: Median total cholesterol (TC) level increased with age across all age groups, from 147 to 196 mg/dL in males and from 159 to 210 mg/dL in females. Triglyceride (TG) levels increased with age in females; however, in males, TG levels rapidly increased during young adulthood, peaked at 50-54 years, and then decreased. High density lipoprotein-cholesterol (HDL-C) levels were higher in females than in males and decreased with increasing age in both males and females. Low density lipoprotein-cholesterol (LDL-C) levels increased with age across all age groups, from 89 to 127 mg/dL in males and from 82 to 113 mg/dL in females. Lipoprotein cholesterol fraction (TC/HDL-C, LDL-C/HDL-C, TG/HDL-C, non-HDL-C) levels increased with age in females, but increased more rapidly in males during young adulthood and decreased after middle age. CONCLUSION: Blood cholesterol levels and lipoprotein-cholesterol fractions present different distributions by age, sex, and menopausal status. PMID- 25810738 TI - Simultaneous thrombosis of the left anterior descending artery and the right coronary artery in a 34-year-old crystal methamphetamine abuser. AB - This case report underscores that crystal methamphetamine abuse is an important cause of multivessel coronary thrombosis and raises doubts about the therapeutic options. The patient was a 34-year-old smoker and crystal methamphetamine abuser with no significant medical history, who presented with retrosternal chest pain associated with cold sweats. Twelve-lead electrocardiogram revealed diffuse ST segment elevation in I, II, AVL, AVF, and V 2-6 leads. He underwent urgent coronary angiography and it showed Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in coronary arteries and presence of a thrombus in the left anterior descending artery (LAD) and the right coronary artery (RCA). The patient underwent medical therapy with antiplatelet agents and anticoagulants. Repeat coronary angiography after three months of dual therapy with warfarin and aspirin did not show any thrombus or any significant lesion in the RCA and the LAD having TIMI grade 3 flow. PMID- 25810737 TI - Cervical vagal nerve stimulation activates the stellate ganglion in ambulatory dogs. AB - BACKGROUND AND OBJECTIVES: Recent studies showed that, in addition to parasympathetic nerves, cervical vagal nerves contained significant sympathetic nerves. We hypothesized that cervical vagal nerve stimulation (VNS) may capture the sympathetic nerves within the vagal nerve and activate the stellate ganglion. MATERIALS AND METHODS: We recorded left stellate ganglion nerve activity (SGNA), left thoracic vagal nerve activity (VNA), and subcutaneous electrocardiogram in seven dogs during left cervical VNS with 30 seconds on-time and 30 seconds off time. We then compared the SGNA between VNS on and off times. RESULTS: Cervical VNS at moderate (0.75 mA) output induced large SGNA, elevated heart rate (HR), and reduced HR variability, suggesting sympathetic activation. Further increase of the VNS output to >1.5 mA increased SGNA but did not significantly increase the HR, suggesting simultaneous sympathetic and parasympathetic activation. The differences of integrated SGNA and integrated VNA between VNS on and off times (DeltaSGNA) increased progressively from 5.2 mV-s {95% confidence interval (CI): 1.25-9.06, p=0.018, n=7} at 1.0 mA to 13.7 mV-s (CI: 5.97-21.43, p=0.005, n=7) at 1.5 mA. The difference in HR (DeltaHR, bpm) between on and off times was 5.8 bpm (CI: 0.28-11.29, p=0.042, n=7) at 1.0 mA and 5.3 bpm (CI 1.92 to 12.61, p=0.122, n=7) at 1.5 mA. CONCLUSION: Intermittent cervical VNS may selectively capture the sympathetic components of the vagal nerve and excite the stellate ganglion at moderate output. Increasing the output may result in simultaneously sympathetic and parasympathetic capture. PMID- 25810740 TI - Intracardiac echocardiography to guide biopsy for two cases of intracardiac masses. AB - Pathologic diagnosis of a cardiac mass is vital in determining the proper treatment modality. Open heart surgery or transesophageal echocardiography guided biopsy can be feasible methods to confirm the pathology. However, the former is highly invasive and both methods require general anesthesia. The introduction of intracardiac echocardiography (ICE) can provide good anatomic information of heart and does not require general anesthesia. In this report, we present two cases of cardiac tumors which were confirmed by percutaneous biopsy under the guidance of an ICE. The patients underwent cardiac biopsy without any complications. PMID- 25810739 TI - A Case of Constrictive Pericarditis due to Immunoglobulin G4-Related Disease. AB - Immunoglobulin G4-related disease (IgG4-RD) can involve any organ. The majority of reported cases involve IgG4-RD of the biliary tract or pancreas, while only two cases of pericarditis have been reported. A 58-year-old man visited the outpatient clinic of our institution with a seven-day history of progressive dyspnea. Based on his transthoracic echocardiogram and transesophageal echocardiogram, he was diagnosed with constrictive pericarditis. The histopathology of his pericardiectomy revealed the cause of constrictive pericarditis to be IgG4-RD. Prednisolone (40 mg) was initiated after the pericardiectomy. As the patient's symptoms resolved, he was discharged and followed-up on an outpatient basis. This is the first case report of constrictive pericarditis caused by IgG4-RD in Korea. PMID- 25810741 TI - Transcatheter treatment of atrial septal defect presenting with platypnea orthodeoxia syndrome. AB - A 29-year-old woman was referred to our institute for symptomatic hypoxemia. Her dyspnea was aggravated while sitting or standing and relieved while in supine position. She did not have any pulmonary disease. Transthoracic echocardiography and heart computed tomography revealed an underestimated small atrial septal defect (ASD) with a left-to-right shunt. A cardiac catheterization was performed to evaluate pulmonary hypertension. It revealed a normal pulmonary artery pressure and a large ASD with bidirectional shunt during Valsalva maneuver by intracardiac echocardiogram. Her arterial oxygen saturation decreased from 93% while supine to 79% while at a 15 degrees sitting position. Thus, the patient was diagnosed with platypnea-orthodeoxia syndrome. The ASD was successfully closed with Amplatzer(r) (St. Jude Medical) septal occluder and both platypnea and orthodeoxia were resolved immediately after the procedure. PMID- 25810743 TI - Electroacupuncture Suppressed Neuronal Apoptosis and Improved Cognitive Impairment in the AD Model Rats Possibly via Downregulation of Notch Signaling Pathway. AB - Acupuncture is a potential strategy for the treatment of Alzheimer's disease (AD) and the possible mechanisms worth to be explored. In this study, we proposed and tested the hypothesis that whether Notch signaling pathway is involved in the effect of electroacupuncture (EA) treatment. Rats that received EA treatment on the acupoints of Baihui (Du 20) and Shenshu (BL 23) had shorter latency and remained in the original platform quadrant longer and crossed the former platform contained quadrant more frequently compared to the Abeta injection rats without EA treatment. EA obviously alleviated the cell apoptosis resulted by Abeta infusion in hippocampus CA1 regions through upregulating the expression of Bcl-2 and downregulating the expression of Bax. EA could further obviously promote the expression of synapsin-1 and synaptophysin in hippocampus. Abeta injection significantly increased the expression of Notch1, Jag1, and Hes1 mRNA, while EA treatment downregulated the level of Notch1 and Hes1 mRNA in hippocampus, but not Jag1 mRNA. Our data suggested that EA treatment improved learning and memory function in the AD rat model partially through downregulating Notch signaling pathway. PMID- 25810742 TI - Herb-Partitioned Moxibustion and the miRNAs Related to Crohn's Disease: A Study Based on Rat Models. AB - Crohn's disease (CD) is a major subtype of inflammatory bowel disease (IBD). Herb partitioned moxibustion (HPM) has been proven to be effective in treating CD by a large amount of clinical and experimental researches. MiRNAs (microRNAs) are increasingly recognized as important posttranscriptional regulators of inflammatory genes. In this study, we established experimental CD rat models and investigated the miRNAs associated with the onset of experimental CD; then, we further identified CD-related miRNAs that were regulated by HPM and explored the relationship between CD and the potential target genes of involved miRNAs. We found that miR-147 and miR-205 were significantly downregulated in colons of experimental CD rats and may be closely associated with the onset of experimental CD. HPM may extenuate inflammatory responses in colons and ameliorate colonic damages in CD via upregulating the expression of miR-147 and miR-205 and then further downregulating the expression of inflammation-related mRNAs, negatively regulating inflammatory signal pathways, and reducing the production of downstream inflammatory cytokines. PMID- 25810744 TI - In Vitro and In Vivo Anticancer Activity of Root Extracts of Sansevieria liberica Gerome and Labroy (Agavaceae). AB - Introduction. Sansevieria liberica Gerome and Labroy (Agavaceae) is a perennial plant widely distributed in tropical Africa. Preparations of the plant are commonly used across Nigeria for the treatment of inflammatory conditions. Based on the fact that herbal medicine is a strong component of integrative medicine, this study was conducted to evaluate the anticancer activity of root extracts of Sansevieria liberica. Methods. Sulforhodamine B (SRB) in vitro cytotoxicity assay, Sarcoma-180 (S-180) ascites and solid tumor, and L1210 lymphoid leukemia in vivo models were used in this study. Results. SL-A002 (IC50 23 ug/mL with HeLa), SL-A003 (IC50 22 ug/mL with HCT-116), and SL-A004 (IC50 23 and 18 ug/mL with A549 and THP-1, resp.) demonstrated significant activity in the SRB cytotoxicity assay. Potency was highest with the following pairs of extract : cancer cell line: SL-A002 : HeLa (IC50 23 ug/mL), SL-A003 : HCT-116 (IC50 22 ug/mL), and SL-A004 : THP-1 (IC50 18 ug/mL). SL-A002 demonstrated significant dose-dependent antitumor activity in the Sarcoma-180 (S-180) ascites model with peak effect produced at the dose of 120 mg/kg (i.p.) with inhibition of 89.36% compared to 97.96% for 5-FU (20 mg/kg i.p.). The inhibition of tumor growth by SL A002 in the S-180 solid tumor model was 47.40% compared to a value of 50.18% for 5-FU. SL-A002 was also significantly active in the L1210 lymphoid leukemia model with 158.33% increase in mean survival time, the same value for 5-FU. Conclusions. The hydroethanolic extract of Sansevieria liberica, SL-A002, possesses significant anticancer activity to warrant further extensive study to identify, isolate, and characterize the specific bioactive molecules responsible for the observed antitumor activity and the precise mechanism(s) of action. PMID- 25810745 TI - Orostachys japonicus Inhibits Expression of the TLR4, NOD2, iNOS, and COX-2 Genes in LPS-Stimulated Human PMA-Differentiated THP-1 Cells by Inhibiting NF-kappaB and MAPK Activation. AB - Orostachys japonicus is traditionally used as an inflammatory agent. In this report, we investigated the effects of O. japonicus extract on the expression of genes encoding pathogen-recognition receptors (TLR2, TLR4, NOD1, and NOD2) and proinflammatory factors (iNOS, COX-2, and cytokines) in LPS-stimulated PMA differentiated THP-1 cells and the NF-kappaB and MAPK pathways. O. japonicus induced toxicity at high concentrations but had no effect at concentrations lower than 25 MUg/mL. O. japonicus inhibited LPS-induced TLR4 and NOD2 mRNA levels, suppressed LPS-induced iNOS and COX-2 transcription and translocation, and downregulated LPS-induced proinflammatory cytokine (IL-1beta, IL-6, IL-8, and TNF alpha) mRNA levels. In addition, O. japonicus inhibited LPS-induced NF-kappaB activation and IkappaBalpha degradation and suppressed LPS-induced JNK, p38 MAPK, and ERK phosphorylation. Overall, our results demonstrate that the anti inflammatory effects of O. japonicus are mediated by suppression of NF-kappaB and MAPK signaling, resulting in reduced TLR4, NOD2, iNOS, and COX-2 expression and inhibition of inflammatory cytokine expression. PMID- 25810746 TI - Evaluation of a topical herbal agent for the promotion of bone healing. AB - A topically used Chinese herbal paste, namely, CDNR, was designed to facilitate fracture healing which is usually not addressed in general hospital care. From our in vitro studies, CDNR significantly inhibited the release of nitric oxide from RAW264.7 cells by 51 to 77%. This indicated its anti-inflammatory effect. CDNR also promoted the growth of bone cells by stimulating the proliferation of UMR106 cells up to 18%. It also increased the biomechanical strength of the healing bone in a drill-hole defect rat model by 16.5% significantly. This result revealed its in vivo efficacy on facilitation of bone healing. Furthermore, the detection of the chemical markers of CDNR in the skin and muscle of the treatment area demonstrated its transdermal properties. However, CDNR did not affect the bone turnover markers in serum of the rats. With its anti-inflammatory and bone formation properties, CDNR is found effective in promoting bone healing. PMID- 25810747 TI - Saliva secretion disorder in a schizophrenic patient - a problem in dental and psychiatric treatment: a case report. AB - OBJECTIVE: Saliva secretion disorder may appear in patients at any age and represents a serious problem in interdisciplinary treatment. It is manifested by hyposecretion or hypersecretion of saliva. One of the major groups of patients who have been diagnosed with saliva secretion disorder includes those treated with neuroleptics. Among patients taking neuroleptics, schizophrenic patients represent the least cooperative group in terms of doctor-patient relationship. Schizophrenia is a mental disorder exacerbated by uncontrolled neuroleptic dose reduction or regardless of applied pharmacotherapy. METHOD: This paper presents a clinical case of a 30-year-old schizophrenic patient with saliva secretion problems. RESULTS: In schizophrenia, thought disorders (TD) and social functioning impairment have a negative impact on patients' somatic health care. Saliva hyposecretion and its health consequences, such as parodontitis and caries, are the reasons why the patients decide to have a dental appointment. CONCLUSION: This paper contains important information for dentists, psychiatrists, and psychologists, as it raises an issue of a proper interdisciplinary care approach provided to schizophrenic patients. It emphasises the importance of psychoeducation and draws attention to social functioning of mentally ill patients. PMID- 25810749 TI - Automatic detection of blood vessels in retinal images for diabetic retinopathy diagnosis. AB - Diabetic retinopathy (DR) is a leading cause of vision loss in diabetic patients. DR is mainly caused due to the damage of retinal blood vessels in the diabetic patients. It is essential to detect and segment the retinal blood vessels for DR detection and diagnosis, which prevents earlier vision loss in diabetic patients. The computer aided automatic detection and segmentation of blood vessels through the elimination of optic disc (OD) region in retina are proposed in this paper. The OD region is segmented using anisotropic diffusion filter and subsequentially the retinal blood vessels are detected using mathematical binary morphological operations. The proposed methodology is tested on two different publicly available datasets and achieved 93.99% sensitivity, 98.37% specificity, 98.08% accuracy in DRIVE dataset and 93.6% sensitivity, 98.96% specificity, and 95.94% accuracy in STARE dataset, respectively. PMID- 25810748 TI - Genetic programming based ensemble system for microarray data classification. AB - Recently, more and more machine learning techniques have been applied to microarray data analysis. The aim of this study is to propose a genetic programming (GP) based new ensemble system (named GPES), which can be used to effectively classify different types of cancers. Decision trees are deployed as base classifiers in this ensemble framework with three operators: Min, Max, and Average. Each individual of the GP is an ensemble system, and they become more and more accurate in the evolutionary process. The feature selection technique and balanced subsampling technique are applied to increase the diversity in each ensemble system. The final ensemble committee is selected by a forward search algorithm, which is shown to be capable of fitting data automatically. The performance of GPES is evaluated using five binary class and six multiclass microarray datasets, and results show that the algorithm can achieve better results in most cases compared with some other ensemble systems. By using elaborate base classifiers or applying other sampling techniques, the performance of GPES may be further improved. PMID- 25810750 TI - Computer-aided assessment of tumor grade for breast cancer in ultrasound images. AB - This study involved developing a computer-aided diagnosis (CAD) system for discriminating the grades of breast cancer tumors in ultrasound (US) images. Histological tumor grades of breast cancer lesions are standard prognostic indicators. Tumor grade information enables physicians to determine appropriate treatments for their patients. US imaging is a noninvasive approach to breast cancer examination. In this study, 148 3-dimensional US images of malignant breast tumors were obtained. Textural, morphological, ellipsoid fitting, and posterior acoustic features were quantified to characterize the tumor masses. A support vector machine was developed to classify breast tumor grades as either low or high. The proposed CAD system achieved an accuracy of 85.14% (126/148), a sensitivity of 79.31% (23/29), a specificity of 86.55% (103/119), and an A Z of 0.7940. PMID- 25810752 TI - Flexible growing rods: a pilot study to determine if polymer rod constructs may provide stability to skeletally immature spines. AB - BACKGROUND: Surgical treatments for early onset scoliosis (EOS), including growing rod constructs, involve many complications. Some are due to biomechanical factors. A construct that is more flexible than current instrumentation systems may reduce complications. The purpose of this preliminary study was to determine spine range of motion (ROM) after implantation of simulated growing rod constructs with a range of clinically relevant structural properties. The hypothesis was that ROM of spines instrumented with polyetheretherketone (PEEK) rods would be greater than metal rods and lower than noninstrumented controls. Further, adjacent segment motion was expected to be lower with polymer rods compared to conventional systems. METHODS: Biomechanical tests were conducted on 6 skeletally immature porcine thoracic spines (domestic swine, 35-40 kg). Spines were harvested after death from swine that had been utilized for other studies (IACUC approved) which had not involved the spine. Paired pedicle screws were used as anchors at proximal and distal levels. Specimens were tested under the following conditions: control, then dual rods of PEEK (6.25 mm), titanium (4 mm), and CoCr (5 mm) alloy. Lateral bending (LB) and flexion-extension (FE) moments of +/-5 Nm were applied. Vertebral rotations were measured using video. Differences were determined by two-tailed t-tests and Bonferroni correction with four primary comparisons: PEEK vs control and PEEK vs CoCr, in LB and FE (alpha=0.05/4). RESULTS: In LB, ROM of specimens with PEEK rods was lower than control at each instrumented level. ROM was greater for PEEK rods than both Ti and CoCr at every instrumented level. Mean ROM at proximal and distal noninstrumented levels was lower for PEEK than for Ti and CoCr. In FE, mean ROM at proximal and distal noninstrumented levels was lower for PEEK than for metal. Combining treated levels, in LB, ROM for PEEK rods was 35% of control (p<0.0001) and 270% of CoCr rods (p<0.01). In FE, ROM with PEEK was 27% of control (p<0.001) and 180% of CoCr (p<0.01). CONCLUSIONS: PEEK rods decreased flexibility versus noninstumented controls, and increased flexibility versus metal rods. Smaller increases in ROM at proximal and distal adjacent motion segments occurred with PEEK compared to metal rods, which may help decrease junctional kyphosis. Flexible growing rods may eventually help improve treatment options for young patients with severe deformity. PMID- 25810751 TI - Factors affecting intradiscal pressure measurement during in vitro biomechanical tests. AB - OBJECTIVES: To assess the reliability of intradiscal pressure measurement during in vitro biomechanical testing. In particular, the variability of measurements will be assessed for repeated measures by considering the effect of specimens and of freezing/thawing cycles. METHODS: Thirty-six functional units from 8 porcine spines (S1: T7-T8, S2: T9-T10, S3: T12-T11, S4: T14-T13, S5: L1-L2 and S6: L3-L4) have been used. The intervertebral discs were measured to obtain the frontal and sagittal dimensions. These measurements helped locate the center of the disc where a modified catheter was positioned. A fiber optic pressure sensor (measuring range: -0.1 to 17 bar) (360HP, SAMBA Sensors, Sweden) was then inserted into the catheter. The specimens were divided into 3 groups: 1) fresh (F), 2) after one freeze/thaw cycle (C1) and 3) after 2 freeze/thaw cycles (C2). These groups were divided in two, depending on whether specimens were subjected to 400 N axial loading or not. Ten measurements (insertion of the sensor for a period of one minute, then removal) were taken for each case. Statistical analyses evaluated the influence of porcine specimen and the vertebral level using a MANOVA. The effect of repeated measurements was evaluated with ANOVA. The difference between freeze/thaw cycles were analysed with U Mann-Whitney test (P<=0.05). RESULTS: Without axial loading, the F group showed 365 mbar intradiscal pressure, 473 mbar for the C1 group, and 391 mbar for the C2 group. With 400N axial load, the F group showed intradiscal pressure of 10610 mbar, the C1 group 10132 mbar, the C2 group 12074 mbar. The statistical analysis shows a significant influence of the porcine specimen (p<0.001), with or without axial loading and of the vertebral level with (p=0.048) and without load (p<0.001). The results were also significantly different between the freeze/thaw cycles, with (p<0.001) and without load (p=0.033). Repeated measurement (without load p = 0.82 and with p = 0.56) did not show significant influence. CONCLUSIONS: The results tend to support that freezing/thawing cycles can affect intradiscal pressure measurement with significant inter-specimen variability. The use of the same specimen as its own control during in vitro biomechanical testing could be recommended. PMID- 25810753 TI - HRQoL assessment by SRS-30 for Chinese patients with surgery for Adolescent Idiopathic Scoliosis (AIS). AB - INTRODUCTION: Health-related quality of life (HRQoL) outcome questionnaire, Scoliosis Research Society (SRS)-30, had been well received since its establishment in 2003. Literatures from Asia on the use of SRS-30 mainly focused on the translation process and validation process, but not on measuring outcomes, particularly in the Chinese community. We carried out a prospective cohort study to evaluate the HRQoL of Chinese AIS adolescents with severe scoliosis after surgery. METHODS: One hundred and four Chinese AIS patients with severe scoliosis undergoing posterior spinal fusion between 2009 and 2013 were recruited in this study. They completed SRS-30 questions before surgery, before hospital discharge, and at follow-up. Mean scores and percentages of individual scores in different domains, and composite scores in terms of subtotal and total scores were calculated referring to the scoring system. Gender-specific and period-specific descriptive analyses were described. Correlation of mean domain scores at the three time points were explored to look for any time-specific relationship. Linear regression analysis looking for potential risk factors on domain scores at different time points by gender were also carried out. RESULTS: Mean age was 16.28 at surgery, and 83.6% were female. Significant correlations between pre-op scores and scores after surgery were observed in function/activity domain (p=0.05) in males, and pain (p=0.04) and satisfaction with management (p=0.04) domains in females. No gender difference in all 5 domain scores at the 3 time points was found. Pre-op maximum Cobb angle and corrected angle were found to be risk factors on self-image, as well as satisfaction with management, in male and female patients. CONCLUSIONS: This is the first report on the evaluation of the clinical HRQoL outcomes of Chinese AIS patients with severe scoliosis after surgery. Medical professionals should pay attention to take care of the difference in personal perceptions of feelings between boys and girls. Special care should also be allocated to AIS patients, and try to arrange earlier surgical intervention. PMID- 25810754 TI - Scoliosis corrective force estimation from the implanted rod deformation using 3D FEM analysis. AB - BACKGROUND: Improvement of material property in spinal instrumentation has brought better deformity correction in scoliosis surgery in recent years. The increase of mechanical strength in instruments directly means the increase of force, which acts on bone-implant interface during scoliosis surgery. However, the actual correction force during the correction maneuver and safety margin of pull out force on each screw were not well known. In the present study, estimated corrective forces and pull out forces were analyzed using a novel method based on Finite Element Analysis (FEA). METHODS: Twenty adolescent idiopathic scoliosis patients (1 boy and 19 girls) who underwent reconstructive scoliosis surgery between June 2009 and Jun 2011 were included in this study. Scoliosis correction was performed with 6mm diameter titanium rod (Ti6Al7Nb) using the simultaneous double rod rotation technique (SDRRT) in all cases. The pre-maneuver and post maneuver rod geometry was collected from intraoperative tracing and postoperative 3D-CT images, and 3D-FEA was performed with ANSYS. Cobb angle of major curve, correction rate and thoracic kyphosis were measured on X-ray images. RESULTS: Average age at surgery was 14.8, and average fusion length was 8.9 segments. Major curve was corrected from 63.1 to 18.1 degrees in average and correction rate was 71.4%. Rod geometry showed significant change on the concave side. Curvature of the rod on concave and convex sides decreased from 33.6 to 17.8 degrees, and from 25.9 to 23.8 degrees, respectively. Estimated pull out forces at apical vertebrae were 160.0N in the concave side screw and 35.6N in the convex side screw. Estimated push in force at LIV and UIV were 305.1N in the concave side screw and 86.4N in the convex side screw. CONCLUSIONS: Corrective force during scoliosis surgery was demonstrated to be about four times greater in the concave side than in convex side. Averaged pull out and push in force fell below previously reported safety margin. Therefore, the SDRRT maneuver was safe for correcting moderate magnitude curves. To prevent implant breakage or pedicle fracture during the maneuver in a severe curve correction, mobilization of spinal segment by releasing soft tissue or facet joint could be more important than using a stronger correction maneuver with a rigid implant. PMID- 25810755 TI - Are the mediolateral joint forces in the lower limbs different between scoliotic and healthy subjects during gait? AB - INTRODUCTION: The quantification of internal joint efforts could be essential in the development of rehabilitation tools for patients with musculo-skeletal pathologies, such as scoliosis. In this context, the aim of this study was to compare the hips joint mediolateral forces during gait, between healthy subjects and adolescents with left lumbar or thoracolumbar scoliosis (AIS), categorized by their Cobb angle (CA). MATERIAL AND METHODS: Twelve healthy subjects, 12 AIS with CA between 20 degrees and 40 degrees and 16 AIS in pre-operative condition (CA : > 40 degrees ) walked at 4 km/h on an instrumented treadmill. The experimental set-up include six infrared cameras allow the computation of the tridimensional (3D) angular displacement and strain gauges located under the motor-driven treadmill allow the computation of ground reaction forces (GRF). The hips joint mediolateral forces were calculated using a 3D inverse dynamic of human body. One way ANOVA was performed for the maximum, the minimum and the range of medio lateral forces at each joint of the lower limbs. When appropriate, a Tukey's post hoc was performed to determine the differences. RESULTS: The mediolateral forces were significantly lower at the right hip for AIS with CA between 20 degrees and 40 degrees compared to healthy subject. CONCLUSION: The spinal deformation leads to a reduced medio-lateral force at the right hip, which could gradually change the scheme of postural adjustments for AIS during gait. Further research on the quantification of the joint lower limb efforts should include the knee and ankle joints to evaluate the impact of spinal deformation on the lower limb dynamic behaviour in AIS patients. PMID- 25810756 TI - The impact of the leg-lengthening total hip arthroplasty on the coronal alignment of the spine. AB - BACKGROUND: Coronal imbalance of the pelvis is recognized to lead to the development of degenerative lumbar scoliosis. We hypothesized that an abrupt change of pelvic obliquity may show a reproducible trend of coronal compensation in the lumbosacral spine. The aim of the study was to classify the change of coronal alignment of spine after THA. METHODS: This is a retrospective study based on the radiological analysis of 195 patients who underwent THA between 2009 and 2010. The mean age at surgery was 61.5 years old, and minimum follow up period was 24 months. Pelvic obliquity (POb) and Cobb's angle of lumbar scoliosis (LS) in coronal plane were measured. Over 3.5 degrees of change in POb was regarded as DeltaPOb(+) and over 10 degrees of lumbar scoliosis was regarded as LS(+). The change of LS were classified into 3 subtypes; DeltaLS(+), over 5 degrees of progress in LS, DeltaLS(-), over 5 degrees of improvement in LS, and DeltaLS(n), changes in LS within 5 degrees. RESULTS: Over 3.5 degrees of change in POb was significantly correlated with the change in LS. Among195 patients, 120 patients improved their pelvic obliquity (DeltaPOb(+)), and 75 patients did not have an improved pelvic obliquity (DeltaPOb(-)). 99 patients out of 120 DeltaPOb(+) patients did not show changes (54, DeltaLS(n)) or improvement in scoliosis (45, DeltaLS(-)).The remaining 21 patients showed progress or development of de novo scoliosis. Patients who failed to compensate for the POb change at lumbosacral area developed de novo lumbar scoliosis (7 cases), showed progression in lumbar scoliosis (7 cases) or developed coronal trunk shift over 20mm (7 cases). CONCLUSIONS: The patterns of compensation in lumbar or lumbosacral spine in coronal plane after leg lengthening THA were classified with regards to pelvic obliquity and Cobb's angle. 89.2% of 195 patients showed acceptable compensation in lumbar spine, 21 patients developed coronal imbalance. THA therefore is considered to be safe, as regards to spinal balance in coronal plane. However we have to keep in mind that preoperative rigid scoliosis could have a risk in progress for spinal imbalance. PMID- 25810757 TI - The rib index is not practically affected by the distance between the radiation source and the examined child. AB - BACKGROUND: All lateral spinal radiographs in idiopathic scoliosis (IS) show a Double Rib Contour Sign (DRCS) of the thoracic cage, a radiographic expression of the rib hump. The outline of the convex overlies the contour of the concave ribs. The rib index (RI) method was extracted from the DRCS to evaluate rib hump deformity in IS patients. The RI was calculated by the ratio of spine distances d1/d2 where d1 is the distance between the most extended point of the most extending rib contour and the posterior margin of the corresponding vertebra on the lateral scoliosis films, while d2 is the distance from the least projection rib contour and the posterior margin of the same vertebra, (Grivas et al 2002). In a symmetric thorax the "rib index" is 1. This report is the validity study of DRCS, ie how the rib index is affected by the distance between the radiation source and the irradiated child. METHODS: The American College of Radiology's (2009) guidelines for obtaining radiographs for scoliosis in children recommends for the scoliotic - films distance to be 1,80 meters. Normal values used for the transverse diameter of the ribcage in children aged 6-12 years were those reported by Grivas in 1988. RESULTS: Using the Euclidean geometry, it is shown that in a normal 12-year old child d1/d2 = 1.073 provided that the distance DeltaZ ~ 12cm (11,84) and EA = 180cm, with transverse ribcage diameter of the child 22 cm. CONCLUSIONS: This validity study demonstrates that the DRCS is substantially true and the RI is not practically affected by the distance between the radiation source and the irradiated child. The RI is valid and may be used to evaluate the effect of surgical or conservative treatment on the rib cage deformity (hump) in children with IS. It is noted that RI is a simple method and a safe reproducible way to assess the rib hump deformity based on lateral radiographs, without the need for any other special radiographs and exposure to additional radiation. PMID- 25810758 TI - Rib hump deformity assessment using the rib index in adolescent idiopathic scoliotics treated with full screw or hybrid constructs: aetiological implications. AB - BACKGROUND: Review of literature reveals that in Idiopathic Scoliosis (IS) children, the post-operative rib hump (RH) correction using full transpedicular screw construct has never been compared to hybrid constructs, applying the Rib Index (RI) method. Therefore the aim of this report is to study which of the above two constructs offers better postoperative Rib Hump Deformity (RHD) correction. METHODS: Twenty five patients with Adolescent Idiopathic Scoliosis (AIS) were operated using full pedicle screw construct or hybrid construct. Sixteen underwent full screw instrumentation (group A) and nine an hybrid one (group B). The median age for group A was 15 years and for group B 17.2 years. The RHD was assessed on the lateral spinal radiographs using the RI. The RI was calculated by the ratio of spine distances d1/d2, where d1 is the distance between the most extended point of the most extending rib contour and the posterior margin of the corresponding vertebra on the lateral scoliosis films and d2 is the distance from the least projected rib contour and the posterior margin of the same vertebra. Moreover the amount of RI correction was calculated by subtracting the post-operative RI from the pre-operative RI. RESULTS: Although within group A the RI correction was statistical significant (the pre-op RI was 1.93 and the post-op 1.37; p<0.001) and similarly in group B (the mean pre-op RI was 2.06 while the mean post-op 1.51; p=0.008), between group A and B the post operative RI correction mean values were found to be no statistically significant, (p=0.803). CONCLUSION: Although the pre- and post-operative RI correction was statistically significant within each group, this did not happen post-operatively between the two groups. It appears that the RHD correction is not different, no matter what the spinal construct type was used. Provided that the full screw construct is powerful, the post-operative derotation and RHD correction was expected to be better than when an hybrid construct is applied, which is not the case in this study. It is therefore implied that the RHD results more likely from the asymmetric rib growth rather than from vertebral rotation, as it has been widely believed up to now. In 2013 Lykissas et al, reported that costoplasty combined with pedicle screws and vertebral derotation significantly improved RH deformity as opposed to pedicle screws and vertebral derotation alone. Another interesting implication is that the spinal deformity is the result of the thoracic asymmetry, implication in line with the late Prof. John Sevastikoglou's (Sevastik's) thoracospinal concept. PMID- 25810759 TI - IL-10, IL-15, IL-17, and GMCSF levels in cervical cancer tissue of Tanzanian women infected with HPV16/18 vs. non-HPV16/18 genotypes. AB - BACKGROUND: Despite comparable screening rates for precancerous lesions, higher incidence and mortality related to cervical cancer in minority women persists. Recent evidence suggests that minority women with precancerous cervical lesions harbor a wider range of human papillomavirus (HPV) genotypes, many of these distinct from HPV16/18, those most commonly found in Caucasian women. The goal of the analysis was to determine if inflammatory cytokines and chemokines varied by HPV 16/18 versus other genotypes in cervical cancer tissues from Tanzanian women. METHODS: HPV genotypes and concentrations of chemokines and cytokines were measured from homogenized fresh tumor tissue of thirty-one women with invasive cervical cancer (ICC). Risk factors for cervical cancer including age, parity, hormonal contraceptive use and cigarette smoking were obtained by questionnaire. Generalized linear models were used to evaluate differences between chemokines/cytokine levels in women infected with HPV16/18 and those infected with other HPV genotypes. RESULTS: After adjusting for age, parity and hormonal contraceptives, IL-17 was found significantly more frequently in invasive cervical cancer samples of women infected with HPV16/18 compared to women infected with other HPV genotypes (p = 0.033). In contrast, higher levels for granular macrophage colony-stimulating factor (p = 0.004), IL-10 (p = 0.037), and IL-15 (p = 0.041) were found in ICC tissues of women infected with genotypes other than HPV16/18 when compared to those of women infected with HPV16/18. CONCLUSIONS: While the small sample size limits inference, our data suggest that infection with different HPV genotypes is associated with distinct pro inflammatory cytokine expression profiles; whether this explains some of the racial differences observed in cervical cancer is still unclear. Future studies are needed to confirm these findings. PMID- 25810760 TI - Ligustrazinyl amides: a novel class of ligustrazine-phenolic acid derivatives with neuroprotective effects. AB - BACKGROUND: Ligustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system. Previous study in our laboratory reported that ligustrazine-benzoic acid derivatives have been shown to exhibit beneficial effect against CoCl2-induced neurotoxicity in differentiated PC12 cells. To further improve ligustrazine's neuroprotection, we integrated the ligustrazine and phenolic acid fragments into one molecule via an amide bond based on structural combination. RESULTS: In this study, 12 novel ligustrazine-phenolic acid derivatives were synthesized and nine others were prepared by improved methods. Furthermore, these compounds were evaluated for their protective effects against CoCl2-induced neurotoxicity in differentiated PC12 cells. The amides conjunctional derivatives exhibited promising neuroprotective activities in comparison with ligustrazine. In addition, the most active congener (E)-3-(2,3,4-trimethoxyphenyl)-N-((3,5,6 trimethylpyrazin-2-yl)methyl)acrylamide (L10, EC50 = 25 MUM), which is 2 times higher than that of ligustrazine, may be a potential candidate for intervention in neurological diseases. Structure-activity relationship was discussed briefly. CONCLUSIONS: Results of series of ligustrazinyl amides enrich the study of ligustrazine derivatives with neuroprotective effects. Our completed work supports that the attempt to apply structure combination to discover more efficient neuroprotection lead compounds is viable. Graphical AbstractLigustrazinyl Amides L1-L21 with Neuroprotective Effects. PMID- 25810761 TI - Incidence and potential causative factors associated with chronic benign neutropenia in the Kingdom of Saudi Arabia. AB - BACKGROUND: Benign neutropenia often presents in certain populations without any genotype nor phenotype. Middle East countries are among the regions where endemic cases of chronic benign neutropenia are reported in the general population with an incidence of approximately between 10-15%. Not many studies have been performed to ascertain the cause or burden associated with this condition. The objective of the current study was to identify the frequency and characterize the consequences of chronic benign neutropenia in the country of Saudi Arabia. RESULTS: Benign neutropenia was found to be high in the Saudi Arabia general population (up to 20%), with an average neutrophil count of 1.48 (range 0.99 - 1.95 * 10(9)cells/L), with Saudis having a higher incidence of chronic benign neutropenia compared to non-Saudis (p = <0.05). Complete blood count analyses showed significant difference in the total white cell count of neutrophils (p < 0.0001), WBC (p < 0.0001), lymphocytes (p < 0.001), monocytes (p < 0.001), eosinophils (p = 0.013) as well as the CD19 B cells (p = 0.008). CONCLUSIONS: Our study is the first to carefully quantitate benign neutropenia in Saudi Arabia. We identified that this condition is prevalent in the middle aged population (18 years to 55 years). These individuals not only had lower neutrophil counts, but also reduced peripheral blood cells types, especially the B-lymphocyte population (CD19 subset). As B-lymphocytes are involved in antibody production and antigen recognition, a decrease might easily predispose the individuals to infectious agents. As such more mechanistic studies need to be undertaken to understand the cause and potential long-term consequences of benign neutropenia. PMID- 25810764 TI - No luck replicating the immune response in twins. AB - Recent twin studies highlight the astonishing impact of non-heritable contributions to our immune health and wellbeing. Immunologists, long familiar with heterogeneity generated from within cells, must now grapple with heterogeneity between and within individuals which is present to an extraordinary degree. The capacity to interpret and find patterns in the face of such immune system diversity may be limited when sampling is restricted to blood, necessitating the development of new approaches. PMID- 25810762 TI - History and evolution of cytogenetics. AB - The events that have led to the development of cytogenetics as a specialty within the life sciences are described, with special attention to the early history of human cytogenetics. Improvements in the resolution of chromosome analysis has followed closely the introduction of innovative technology. The review provides a brief account of the structure of somatic and meiotic chromosomes, stressing the high conservation of structure in plants and animals, with emphasis on aspects that require further research. The future of molecular cytogenetics is likely to depend on a better knowledge of chromosome structure and function. PMID- 25810763 TI - Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma. AB - BACKGROUND: Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors. METHODS: We perform genome wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs. RESULTS: We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis. CONCLUSIONS: Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC. PMID- 25810765 TI - Climate trends in the Arctic as observed from space. AB - The Arctic is a region in transformation. Warming in the region has been amplified, as expected from ice-albedo feedback effects, with the rate of warming observed to be ~0.60 +/- 0.07 degrees C/decade in the Arctic (>64 degrees N) compared to ~0.17 degrees C/decade globally during the last three decades. This increase in surface temperature is manifested in all components of the cryosphere. In particular, the sea ice extent has been declining at the rate of ~3.8%/decade, whereas the perennial ice (represented by summer ice minimum) is declining at a much greater rate of ~11.5%/decade. Spring snow cover has also been observed to be declining by -2.12%/decade for the period 1967-2012. The Greenland ice sheet has been losing mass at the rate of ~34.0 Gt/year (sea level equivalence of 0.09 mm/year) during the period from 1992 to 2011, but for the period 2002-2011, a higher rate of mass loss of ~215 Gt/year has been observed. Also, the mass of glaciers worldwide declined at the rate of 226 Gt/year from 1971 to 2009 and 275 Gt/year from 1993 to 2009. Increases in permafrost temperature have also been measured in many parts of the Northern Hemisphere while a thickening of the active layer that overlies permafrost and a thinning of seasonally frozen ground has also been reported. To gain insight into these changes, comparative analysis with trends in clouds, albedo, and the Arctic Oscillation is also presented. How to cite this article:WIREs Clim Change 2014, 5:389?409. doi: 10.1002/wcc.277. PMID- 25810766 TI - CHEMDNER: The drugs and chemical names extraction challenge. AB - Natural language processing (NLP) and text mining technologies for the chemical domain (ChemNLP or chemical text mining) are key to improve the access and integration of information from unstructured data such as patents or the scientific literature. Therefore, the BioCreative organizers posed the CHEMDNER (chemical compound and drug name recognition) community challenge, which promoted the development of novel, competitive and accessible chemical text mining systems. This task allowed a comparative assessment of the performance of various methodologies using a carefully prepared collection of manually labeled text prepared by specially trained chemists as Gold Standard data. We evaluated two important aspects: one covered the indexing of documents with chemicals (chemical document indexing - CDI task), and the other was concerned with finding the exact mentions of chemicals in text (chemical entity mention recognition - CEM task). 27 teams (23 academic and 4 commercial, a total of 87 researchers) returned results for the CHEMDNER tasks: 26 teams for CEM and 23 for the CDI task. Top scoring teams obtained an F-score of 87.39% for the CEM task and 88.20% for the CDI task, a very promising result when compared to the agreement between human annotators (91%). The strategies used to detect chemicals included machine learning methods (e.g. conditional random fields) using a variety of features, chemistry and drug lexica, and domain-specific rules. We expect that the tools and resources resulting from this effort will have an impact in future developments of chemical text mining applications and will form the basis to find related chemical information for the detected entities, such as toxicological or pharmacogenomic properties. PMID- 25810767 TI - Recognition of chemical entities: combining dictionary-based and grammar-based approaches. AB - BACKGROUND: The past decade has seen an upsurge in the number of publications in chemistry. The ever-swelling volume of available documents makes it increasingly hard to extract relevant new information from such unstructured texts. The BioCreative CHEMDNER challenge invites the development of systems for the automatic recognition of chemicals in text (CEM task) and for ranking the recognized compounds at the document level (CDI task). We investigated an ensemble approach where dictionary-based named entity recognition is used along with grammar-based recognizers to extract compounds from text. We assessed the performance of ten different commercial and publicly available lexical resources using an open source indexing system (Peregrine), in combination with three different chemical compound recognizers and a set of regular expressions to recognize chemical database identifiers. The effect of different stop-word lists, case-sensitivity matching, and use of chunking information was also investigated. We focused on lexical resources that provide chemical structure information. To rank the different compounds found in a text, we used a term confidence score based on the normalized ratio of the term frequencies in chemical and non chemical journals. RESULTS: The use of stop-word lists greatly improved the performance of the dictionary-based recognition, but there was no additional benefit from using chunking information. A combination of ChEBI and HMDB as lexical resources, the LeadMine tool for grammar-based recognition, and the regular expressions, outperformed any of the individual systems. On the test set, the F-scores were 77.8% (recall 71.2%, precision 85.8%) for the CEM task and 77.6% (recall 71.7%, precision 84.6%) for the CDI task. Missed terms were mainly due to tokenization issues, poor recognition of formulas, and term conjunctions. CONCLUSIONS: We developed an ensemble system that combines dictionary-based and grammar-based approaches for chemical named entity recognition, outperforming any of the individual systems that we considered. The system is able to provide structure information for most of the compounds that are found. Improved tokenization and better recognition of specific entity types is likely to further improve system performance. PMID- 25810769 TI - Chemical entity extraction using CRF and an ensemble of extractors. AB - BACKGROUND: As we are witnessing a great interest in identifying and extracting chemical entities in academic articles, many approaches have been proposed to solve this problem. In this work we describe a probabilistic framework that allows for the output of multiple information extraction systems to be combined in a systematic way. The identified entities are assigned a probability score that reflects the extractors' confidence, without the need for each individual extractor to generate a probability score. We quantitively compared the performance of multiple chemical tokenizers to measure the effect of tokenization on extraction accuracy. Later, a single Conditional Random Fields (CRF) extractor that utilizes the best performing tokenizer is built using a unique collection of features such as word embeddings and Soundex codes, which, to the best of our knowledge, has not been explored in this context before. RESULTS: The ensemble of multiple extractors outperforms each extractor's individual performance during the CHEMDNER challenge. When the runs were optimized to favor recall, the ensemble approach achieved the second highest recall on unseen entities. As for the single CRF model with novel features, the extractor achieves an F1 score of 83.3% on the test set, without any post processing or abbreviation matching. CONCLUSIONS: Ensemble information extraction is effective when multiple stand alone extractors are to be used, and produces higher performance than individual off the shelf extractors. The novel features introduced in the single CRF model are sufficient to achieve very competitive F1 score using a simple standalone extractor. PMID- 25810768 TI - A CRF-based system for recognizing chemical entity mentions (CEMs) in biomedical literature. AB - BACKGROUND: In order to improve information access on chemical compounds and drugs (chemical entities) described in text repositories, it is very crucial to be able to identify chemical entity mentions (CEMs) automatically within text. The CHEMDNER challenge in BioCreative IV was specially designed to promote the implementation of corresponding systems that are able to detect mentions of chemical compounds and drugs, which has two subtasks: CDI (Chemical Document Indexing) and CEM. RESULTS: Our system processing pipeline consists of three major components: pre-processing (sentence detection, tokenization), recognition (CRF-based approach), and post-processing (rule-based approach and format conversion). In our post-challenge system, the cost parameter in CRF model was optimized by 10-fold cross validation with grid search, and word representations feature induced by Brown clustering method was introduced. For the CEM subtask, our official runs were ranked in top position by obtaining maximum 88.79% precision, 69.08% recall and 77.70% balanced F-measure, which were improved further to 88.43% precision, 76.48% recall and 82.02% balanced F-measure in our post-challenge system. CONCLUSIONS: In our system, instead of extracting a CEM as a whole, we regarded it as a sequence labeling problem. Though our current system has much room for improvement, our system is valuable in showing that the performance in term of balanced F-measure can be improved largely by utilizing large amounts of relatively inexpensive un-annotated PubMed abstracts and optimizing the cost parameter in CRF model. From our practice and lessons, if one directly utilizes some open-source natural language processing (NLP) toolkits, such as OpenNLP, Standford CoreNLP, false positive (FP) rate may be very high. It is better to develop some additional rules to minimize the FP rate if one does not want to re-train the related models. Our CEM recognition system is available at: http://www.SciTeMiner.org/XuShuo/Demo/CEM. PMID- 25810770 TI - Improving chemical entity recognition through h-index based semantic similarity. AB - BACKGROUND: Our approach to the BioCreative IV challenge of recognition and classification of drug names (CHEMDNER task) aimed at achieving high levels of precision by applying semantic similarity validation techniques to Chemical Entities of Biological Interest (ChEBI) mappings. Our assumption is that the chemical entities mentioned in the same fragment of text should share some semantic relation. This validation method was further improved by adapting the semantic similarity measure to take into account the h-index of each ancestor. We applied this method in two measures, simUI and simGIC, and validated the results obtained for the competition, comparing each adapted measure to its original version. RESULTS: For the competition, we trained a Random Forest classifier that uses various scores provided by our system, including semantic similarity, which improved the F-measure obtained with the Conditional Random Fields classifiers by 4.6%. Using a notion of concept relevance based on the h-index measure, we were able to enhance our validation process so that for a fixed recall, we increased precision by excluding from the results a higher amount of false positives. We plotted precision and recall values for a range of validation thresholds using different similarity measures, obtaining higher precision values for the same recall with the measures based on the h-index. CONCLUSIONS: The semantic similarity measure we introduced was more efficient at validating text mining results from machine learning classifiers than other measures. We improved the results we obtained for the CHEMDNER task by maintaining high precision values while improving the recall and F-measure. PMID- 25810771 TI - Enhancing of chemical compound and drug name recognition using representative tag scheme and fine-grained tokenization. AB - BACKGROUND: The functions of chemical compounds and drugs that affect biological processes and their particular effect on the onset and treatment of diseases have attracted increasing interest with the advancement of research in the life sciences. To extract knowledge from the extensive literatures on such compounds and drugs, the organizers of BioCreative IV administered the CHEMical Compound and Drug Named Entity Recognition (CHEMDNER) task to establish a standard dataset for evaluating state-of-the-art chemical entity recognition methods. METHODS: This study introduces the approach of our CHEMDNER system. Instead of emphasizing the development of novel feature sets for machine learning, this study investigates the effect of various tag schemes on the recognition of the names of chemicals and drugs by using conditional random fields. Experiments were conducted using combinations of different tokenization strategies and tag schemes to investigate the effects of tag set selection and tokenization method on the CHEMDNER task. RESULTS: This study presents the performance of CHEMDNER of three more representative tag schemes-IOBE, IOBES, and IOB12E-when applied to a widely utilized IOB tag set and combined with the coarse-/fine-grained tokenization methods. The experimental results thus reveal that the fine-grained tokenization strategy performance best in terms of precision, recall and F-scores when the IOBES tag set was utilized. The IOBES model with fine-grained tokenization yielded the best-F-scores in the six chemical entity categories other than the "Multiple" entity category. Nonetheless, no significant improvement was observed when a more representative tag schemes was used with the coarse or fine-grained tokenization rules. The best F-scores that were achieved using the developed system on the test dataset of the CHEMDNER task were 0.833 and 0.815 for the chemical documents indexing and the chemical entity mention recognition tasks, respectively. CONCLUSIONS: The results herein highlight the importance of tag set selection and the use of different tokenization strategies. Fine-grained tokenization combined with the tag set IOBES most effectively recognizes chemical and drug names. To the best of the authors' knowledge, this investigation is the first comprehensive investigation use of various tag set schemes combined with different tokenization strategies for the recognition of chemical entities. PMID- 25810772 TI - CheNER: a tool for the identification of chemical entities and their classes in biomedical literature. AB - BACKGROUND: Small chemical molecules regulate biological processes at the molecular level. Those molecules are often involved in causing or treating pathological states. Automatically identifying such molecules in biomedical text is difficult due to both, the diverse morphology of chemical names and the alternative types of nomenclature that are simultaneously used to describe them. To address these issues, the last BioCreAtIvE challenge proposed a CHEMDNER task, which is a Named Entity Recognition (NER) challenge that aims at labelling different types of chemical names in biomedical text. METHODS: To address this challenge we tested various approaches to recognizing chemical entities in biomedical documents. These approaches range from linear Conditional Random Fields (CRFs) to a combination of CRFs with regular expression and dictionary matching, followed by a post-processing step to tag those chemical names in a corpus of Medline abstracts. We named our best performing systems CheNER. RESULTS: We evaluate the performance of the various approaches using the F-score statistics. Higher F-scores indicate better performance. The highest F-score we obtain in identifying unique chemical entities is 72.88%. The highest F-score we obtain in identifying all chemical entities is 73.07%. We also evaluate the F Score of combining our system with ChemSpot, and find an increase from 72.88% to 73.83%. CONCLUSIONS: CheNER presents a valid alternative for automated annotation of chemical entities in biomedical documents. In addition, CheNER may be used to derive new features to train newer methods for tagging chemical entities. CheNER can be downloaded from http://metres.udl.cat and included in text annotation pipelines. PMID- 25810774 TI - tmChem: a high performance approach for chemical named entity recognition and normalization. AB - Chemical compounds and drugs are an important class of entities in biomedical research with great potential in a wide range of applications, including clinical medicine. Locating chemical named entities in the literature is a useful step in chemical text mining pipelines for identifying the chemical mentions, their properties, and their relationships as discussed in the literature. We introduce the tmChem system, a chemical named entity recognizer created by combining two independent machine learning models in an ensemble. We use the corpus released as part of the recent CHEMDNER task to develop and evaluate tmChem, achieving a micro-averaged f-measure of 0.8739 on the CEM subtask (mention-level evaluation) and 0.8745 f-measure on the CDI subtask (abstract-level evaluation). We also report a high-recall combination (0.9212 for CEM and 0.9224 for CDI). tmChem achieved the highest f-measure reported in the CHEMDNER task for the CEM subtask, and the high recall variant achieved the highest recall on both the CEM and CDI tasks. We report that tmChem is a state-of-the-art tool for chemical named entity recognition and that performance for chemical named entity recognition has now tied (or exceeded) the performance previously reported for genes and diseases. Future research should focus on tighter integration between the named entity recognition and normalization steps for improved performance. The source code and a trained model for both models of tmChem is available at: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/tmChem. The results of running tmChem (Model 2) on PubMed are available in PubTator: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/PubTator. PMID- 25810775 TI - CHEMDNER system with mixed conditional random fields and multi-scale word clustering. AB - BACKGROUND: The chemical compound and drug name recognition plays an important role in chemical text mining, and it is the basis for automatic relation extraction and event identification in chemical information processing. So a high performance named entity recognition system for chemical compound and drug names is necessary. METHODS: We developed a CHEMDNER system based on mixed conditional random fields (CRF) with word clustering for chemical compound and drug name recognition. For the word clustering, we used Brown's hierarchical algorithm and Skip-gram model based on deep learning with massive PubMed articles including titles and abstracts. RESULTS: This system achieved the highest F-score of 88.20% for the CDI task and the second highest F-score of 87.11% for the CEM task in BioCreative IV. The performance was further improved by multi-scale clustering based on deep learning, achieving the F-score of 88.71% for CDI and 88.06% for CEM. CONCLUSIONS: The mixed CRF model represents both the internal complexity and external contexts of the entities, and the model is integrated with word clustering to capture domain knowledge with PubMed articles including titles and abstracts. The domain knowledge helps to ensure the performance of the entity recognition, even without fine-grained linguistic features and manually designed rules. PMID- 25810776 TI - LeadMine: a grammar and dictionary driven approach to entity recognition. AB - BACKGROUND: Chemical entity recognition has traditionally been performed by machine learning approaches. Here we describe an approach using grammars and dictionaries. This approach has the advantage that the entities found can be directly related to a given grammar or dictionary, which allows the type of an entity to be known and, if an entity is misannotated, indicates which resource should be corrected. As recognition is driven by what is expected, if spelling errors occur, they can be corrected. Correcting such errors is highly useful when attempting to lookup an entity in a database or, in the case of chemical names, converting them to structures. RESULTS: Our system uses a mixture of expertly curated grammars and dictionaries, as well as dictionaries automatically derived from public resources. We show that the heuristics developed to filter our dictionary of trivial chemical names (from PubChem) yields a better performing dictionary than the previously published Jochem dictionary. Our final system performs post-processing steps to modify the boundaries of entities and to detect abbreviations. These steps are shown to significantly improve performance (2.6% and 4.0% F1-score respectively). Our complete system, with incremental post BioCreative workshop improvements, achieves 89.9% precision and 85.4% recall (87.6% F1-score) on the CHEMDNER test set. CONCLUSIONS: Grammar and dictionary approaches can produce results at least as good as the current state of the art in machine learning approaches. While machine learning approaches are commonly thought of as "black box" systems, our approach directly links the output entities to the input dictionaries and grammars. Our approach also allows correction of errors in detected entities, which can assist with entity resolution. PMID- 25810773 TI - The CHEMDNER corpus of chemicals and drugs and its annotation principles. AB - The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/. PMID- 25810778 TI - A document processing pipeline for annotating chemical entities in scientific documents. AB - BACKGROUND: The recognition of drugs and chemical entities in text is a very important task within the field of biomedical information extraction, given the rapid growth in the amount of published texts (scientific papers, patents, patient records) and the relevance of these and other related concepts. If done effectively, this could allow exploiting such textual resources to automatically extract or infer relevant information, such as drug profiles, relations and similarities between drugs, or associations between drugs and potential drug targets. The objective of this work was to develop and validate a document processing and information extraction pipeline for the identification of chemical entity mentions in text. RESULTS: We used the BioCreative IV CHEMDNER task data to train and evaluate a machine-learning based entity recognition system. Using a combination of two conditional random field models, a selected set of features, and a post-processing stage, we achieved F-measure results of 87.48% in the chemical entity mention recognition task and 87.75% in the chemical document indexing task. CONCLUSIONS: We present a machine learning-based solution for automatic recognition of chemical and drug names in scientific documents. The proposed approach applies a rich feature set, including linguistic, orthographic, morphological, dictionary matching and local context features. Post-processing modules are also integrated, performing parentheses correction, abbreviation resolution and filtering erroneous mentions using an exclusion list derived from the training data. The developed methods were implemented as a document annotation tool and web service, freely available at http://bioinformatics.ua.pt/becas-chemicals/. PMID- 25810777 TI - Optimising chemical named entity recognition with pre-processing analytics, knowledge-rich features and heuristics. AB - BACKGROUND: The development of robust methods for chemical named entity recognition, a challenging natural language processing task, was previously hindered by the lack of publicly available, large-scale, gold standard corpora. The recent public release of a large chemical entity-annotated corpus as a resource for the CHEMDNER track of the Fourth BioCreative Challenge Evaluation (BioCreative IV) workshop greatly alleviated this problem and allowed us to develop a conditional random fields-based chemical entity recogniser. In order to optimise its performance, we introduced customisations in various aspects of our solution. These include the selection of specialised pre-processing analytics, the incorporation of chemistry knowledge-rich features in the training and application of the statistical model, and the addition of post-processing rules. RESULTS: Our evaluation shows that optimal performance is obtained when our customisations are integrated into the chemical entity recogniser. When its performance is compared with that of state-of-the-art methods, under comparable experimental settings, our solution achieves competitive advantage. We also show that our recogniser that uses a model trained on the CHEMDNER corpus is suitable for recognising names in a wide range of corpora, consistently outperforming two popular chemical NER tools. CONCLUSION: The contributions resulting from this work are two-fold. Firstly, we present the details of a chemical entity recognition methodology that has demonstrated performance at a competitive, if not superior, level as that of state-of-the-art methods. Secondly, the developed suite of solutions has been made publicly available as a configurable workflow in the interoperable text mining workbench Argo. This allows interested users to conveniently apply and evaluate our solutions in the context of other chemical text mining tasks. PMID- 25810779 TI - A comparison of conditional random fields and structured support vector machines for chemical entity recognition in biomedical literature. AB - BACKGROUND: Chemical compounds and drugs (together called chemical entities) embedded in scientific articles are crucial for many information extraction tasks in the biomedical domain. However, only a very limited number of chemical entity recognition systems are publically available, probably due to the lack of large manually annotated corpora. To accelerate the development of chemical entity recognition systems, the Spanish National Cancer Research Center (CNIO) and The University of Navarra organized a challenge on Chemical and Drug Named Entity Recognition (CHEMDNER). The CHEMDNER challenge contains two individual subtasks: 1) Chemical Entity Mention recognition (CEM); and 2) Chemical Document Indexing (CDI). Our study proposes machine learning-based systems for the CEM task. METHODS: The 2013 CHEMDNER challenge organizers provided a manually annotated 10,000 UTF8-encoded PubMed abstracts according to a predefined annotation guideline: a training set of 3,500 abstracts, a development set of 3,500 abstracts and a test set of 3,000 abstracts. We developed machine learning-based systems, based on conditional random fields (CRF) and structured support vector machines (SSVM) respectively, for the CEM task for this data set. The effects of three types of word representation (WR) features, generated by Brown clustering, random indexing and skip-gram, on both two machine learning-based systems were also investigated. The performance of our system was evaluated on the test set using scripts provided by the CHEMDNER challenge organizers. Primary evaluation measures were micro Precision, Recall, and F-measure. RESULTS: Our best system was among the top ranked systems with an official micro F-measure of 85.05%. Fixing a bug caused by inconsistent features marginally improved the performance (micro F-measure of 85.20%) of the system. CONCLUSIONS: The SSVM-based CEM systems outperformed the CRF-based CEM systems when using the same features. Each type of the WR feature was beneficial to the CEM task. Both the CRF-based and SSVM-based systems using the all three types of WR features showed better performance than the systems using only one type of the WR feature. PMID- 25810780 TI - Incorporating domain knowledge in chemical and biomedical named entity recognition with word representations. AB - BACKGROUND: Chemical and biomedical Named Entity Recognition (NER) is an essential prerequisite task before effective text mining can begin for biochemical-text data. Exploiting unlabeled text data to leverage system performance has been an active and challenging research topic in text mining due to the recent growth in the amount of biomedical literature. We present a semi supervised learning method that efficiently exploits unlabeled data in order to incorporate domain knowledge into a named entity recognition model and to leverage system performance. The proposed method includes Natural Language Processing (NLP) tasks for text preprocessing, learning word representation features from a large amount of text data for feature extraction, and conditional random fields for token classification. Other than the free text in the domain, the proposed method does not rely on any lexicon nor any dictionary in order to keep the system applicable to other NER tasks in bio-text data. RESULTS: We extended BANNER, a biomedical NER system, with the proposed method. This yields an integrated system that can be applied to chemical and drug NER or biomedical NER. We call our branch of the BANNER system BANNER-CHEMDNER, which is scalable over millions of documents, processing about 530 documents per minute, is configurable via XML, and can be plugged into other systems by using the BANNER Unstructured Information Management Architecture (UIMA) interface. BANNER CHEMDNER achieved an 85.68% and an 86.47% F-measure on the testing sets of CHEMDNER Chemical Entity Mention (CEM) and Chemical Document Indexing (CDI) subtasks, respectively, and achieved an 87.04% F-measure on the official testing set of the BioCreative II gene mention task, showing remarkable performance in both chemical and biomedical NER. BANNER-CHEMDNER system is available at: https://bitbucket.org/tsendeemts/banner-chemdner. PMID- 25810781 TI - Oxidative DNA damage in diabetic and mild gestational hyperglycemic pregnant women. AB - BACKGROUND: Pregnant women with mild gestational hyperglycemia present high risk for hypertension, obesity and hyperglycemia, and appeared to reproduce the model of metabolic syndrome in pregnancy, with hyperinsulinemia and insulin resistance. Our clinical studies showed that mild gestational hyperglycemia or gestational diabetes are related to similar adverse maternal and perinatal outcomes. Hyperglycemia and other factors associated with diabetes generate reactive oxygen species that increase DNA damage levels. The aim of this study was to evaluate oxidative DNA damage in lymphocytes of pregnant women with diabetes or mild gestational hyperglycemia. METHODS: The study included 111 pregnant women distributed into three groups based on oral glucose tolerance test (OGTT) and glycemic profiles (GP), as follows: Normal OGTT and GP (control group); Normal OGTT and abnormal GP (mild gestational hyperglycemia group); Abnormal OGTT and GP (diabetic group). Maternal blood samples (5-10 mL) were collected and processed for determination of oxidative DNA damage by the comet assay, using Fpg and Endo III enzymes. Urine samples were also collected for determination of 8-OHdG concentrations by ELISA. RESULTS: Subjects in the diabetes group presented increased amount of oxidized purines, while mild gestational hyperglycemia women presented with increased oxidized pyrimidines, compared to the control group. CONCLUSION: Gestational, overt diabetes and mild gestational hyperglycemia, were all related to increased oxidative DNA damage. Diabetic pregnant women showed increased level of oxidative DNA damage, perhaps mainly due to hyperglycemia. On the other hand, oxidative DNA damage detected in women with mild gestational hyperglycemia might be associated with repercussions from obesity, hypertension and/or insulin resistance. Interestingly, the type of DNA base affected seemed to be dependent on the glycemic profile or oxidative stress. PMID- 25810782 TI - Inverse association between central obesity and arterial stiffness in Korean subjects with metabolic syndrome: a cross-sectional cohort study. AB - BACKGROUND: Metabolic syndrome (MetS) is associated with increased risks of diabetes and atherosclerotic cardiovascular disease. Whether central obesity (CeO) is a prerequisite for the diagnosis of MetS in the International Diabetes Federation (IDF) definition is a substantial issue because it may influence the clinical value of MetS for predicting subclinical atherosclerosis. METHODS: We investigated the relation between MetS, as defined by the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) III criteria, and arterial stiffness according to CeO status in 2,560 healthy Korean subjects who participated in a community-based cohort study. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV). RESULTS: The prevalence of MetS was 37%; 84% of MetS subjects had CeO. The prevalence of diabetes was significantly higher in MetS subjects than in non-MetS subjects (30 vs. 8%, p <0.001). The number of MetS components was significantly correlated with baPWV (r = 0.311, p <0.001). In a subgroup analysis of MetS subjects, the prevalence of diabetes was not significantly different in MetS subjects with and without CeO. MetS subjects without CeO had significantly higher baPWV than those with CeO (1654 +/- 315 vs. 1578 +/- 270 cm/s, p = 0.002). Multiple regression models revealed that waist circumference was independently associated with decreased baPWV in MetS subjects. CONCLUSIONS: Despite the significant correlation between the number of MetS components and arterial stiffness, there appeared to be an inverse association between CeO and arterial stiffness in MetS subjects. In contrast to the IDF definition, our findings suggest that CeO is not crucial for the diagnosis of MetS in otherwise healthy Koreans having multiple metabolic risk factors with respect to subclinical atherosclerosis reflected in arterial stiffness. PMID- 25810785 TI - Serum vitamin D and parathyroid hormone profiles in patients with various stages of renal disease. AB - BACKGROUND: The prevalence of vitamin D deficiency among Saudi population has increased recently. The social and pathological factors, including kidney disease that may have influenced the vitamin status have not been investigated in the Hail population. AIMS: The present study aims to: (1) investigate changes in the serum vitamin D, parathyroid hormone, serum calcium, and phosphate levels in Saudi patients with kidney disease; and (2) elucidate the other possible physiological factors that may have influence on the vitamin status. METHODS: A cross-sectional study was carried out in King Khalid Hospital in Hail, Saudi Arabia. The database of kidney disease patients that attended the Kidney Unit between September 2012 and June 2013 was searched and data classified according to the estimated glomerular filtration rate into stages 1-4. Beside the kidney function parameters, serum calcium, phosphorus, vitamin D, and parathyroid hormone were measured. RESULTS: Out of the 167 patients who visited the kidney unit, the data of 96 patients was included in the study. The results exhibited significant reductions in serum vitamin D level in stage 4 patients by 52.05 per cent with significant increase in the serum PTH level amounting to 3.5-fold. Kidney impairment at stage 4 caused significant increase in the serum phosphate level by 15.74 per cent and the serum calcium by 8.17 per cent. Significant correlations were observed between serum creatinine and Log PTH (r=0.704, p<0.0001) and a negative correlation between creatinine and log vitamin D (r= 0.373, p=0.001). CONCLUSION: The results exhibited depletion of serum vitamin D concentration accompanied with the development of severe secondary hyperparathyroidism with the progression in kidney disease. The vitamin D deficiency was more prominent in females, older ages, and advanced kidney disease. PMID- 25810786 TI - Prevalence and patterns of hearing loss among chronic kidney disease patients undergoing haemodialysis. AB - BACKGROUND: The prevalence, degree, and patterns of hearing loss associated with chronic kidney disease (CKD) reported by various studies differ significantly. The effects of haemodialysis and duration of disease on hearing loss remain unclear. AIMS: The aim of this study was to determine the prevalence and degree of hearing loss in CKD patients on haemodialysis. METHODS: This study included 120 CKD patients on haemodialysis. Information regarding age, gender, duration of disease, subjective hearing loss, exposure to ototoxic drugs, comorbidities like diabetes, hypertension, and hypothyroidism, renal functions, electrolytes and number of haemodialysis sessions received were obtained. An equal number of age and sex matched controls were used to determine prevalence of hearing loss in CKD patients after subjecting both groups to pure tone audiometry. We compared CKD patients with and without hearing loss for association of hearing loss with disease duration, number of haemodialysis, and blood parameters. RESULTS: Hearing loss was present in 41.7 per cent of CKD patients, significantly higher than controls (p=0.001), and was mild in the majority of patients. Impairment was noted across high and low frequencies of audiometric testing. Median duration of disease was the same (18 months) among CKD patients with and without hearing loss (p=0.62). CKD patients with hearing loss received 72 haemodialysis compared to 122 sessions by those without hearing loss (p=0.04). CONCLUSION: Mild sensorineural hearing loss is common in CKD. Hearing loss has no specific pattern as it prevails at high and low frequencies. Hearing loss may be inversely associated with the number of haemodialysis sessions but not with duration of disease. PMID- 25810787 TI - Infant mortality rates and decentralisation in Uganda. AB - BACKGROUND: Many countries in the developing world have embarked on the path of decentralisation over the last three decades to improve the provision of public goods such as healthcare services. It is hypothesised that devolving power to local governments would improve efficiency as well as equity and thereby health outcomes by bringing decision makers closer to the people, and by enhancing the participation of the community in the decision-making and implementation processes. AIMS: This paper aims to assess the impact of decentralisation on infant mortality rates in Uganda. METHODS: The intervention model was used to analyse national representative data from Uganda Demographic Health Surveys (1988/89, 1995, 2001, 2006). RESULTS: Results indicate that infant mortality rates deteriorated during the decentralisation period in three out of four regions in Uganda, but not overall when analysed for the whole country. CONCLUSION: Decentralisation was supposed to lead to a decrease in infant mortality rates, however, the opposite effect was seen with rates increasing in individual regions. There is need for further detailed studies to understand why infant mortality rates increased during the period of decentralisation in Uganda. PMID- 25810783 TI - What we can learn from animal models about cerebral multi-morbidity. AB - Late-onset diseases such as Alzheimer's disease, Parkinson's disease, or frontotemporal lobar degeneration are considered to be protein-folding disorders, with the accumulation of protein deposits causing a gain-of-toxic function. Alzheimer's disease is characterized by two histological hallmark lesions: amyloid-beta-containing plaques and tau-containing neurofibrillary tangles. However, signature proteins, including alpha-synuclein, which are found in an aggregated fibrillar form in the Lewy bodies of Parkinson's disease brains, are also frequently found in Alzheimer's disease. This highlights the fact that, although specific aggregates form the basis for diagnosis, there is a high prevalence of clinical overlap between neuropathological lesions linked to different diseases, a finding known as cerebral co- or multi-morbidity. Furthermore, the proteins forming these lesions interact, and this interaction accelerates an ongoing degenerative process. Here, we review the contribution that transgenic animal models have made to a better mechanistic understanding of the causes and consequences of co- or multi-morbidity. We discuss selected vertebrate and invertebrate models as well as the insight gained from non transgenic senescence-accelerated mouse-prone mice. This article is part of a series on 'Cerebral multi-morbidity of the aging brain'. PMID- 25810788 TI - The potential role for a pharmacist in a multidisciplinary general practitioner super clinic. AB - BACKGROUND: The Australian government's General Practitioner (GP) super clinics programme aims to provide well-integrated, multidisciplinary, patient-centred care for people with chronic disease. However, there is no research into the current role of pharmacists in this setting. AIMS: To explore the perspectives of GP super clinic staff on current and potential (future) pharmacist-led services provided in this setting. METHODS: Individual interviews (facilitated using a semi-structured interview guide and thematically analysed) were conducted with purposively sampled staff of a GP super clinic in a semirural location in the state of New South Wales, until theme saturation. Participating staff included (n=9): three GPs, one pharmacist, one nurse, one business manager, and three reception staff. RESULTS: Three themes emerged conveying perspectives on: working relationships between staff; a pharmacist's current role; and potential future roles for a pharmacist. All clinic staff actively engaged the pharmacist in their "team approach". Currently established roles for home medicines reviews (HMRs) and drug information were well supported, but needed to be expanded, for example, with formalised case conferences between GPs, pharmacists, and other staff. New roles needed be explored in auditing medication use, optimising medication records, specialised drug information, dispensing, and prescribing. Although GPs had differing views about opportunities for pharmacists' prescribing in this setting, they saw several benefits to this service, such as reducing the time pressure on GPs to enable more effective consultations. CONCLUSION: Results suggest a pharmacist's services can potentially be better used within the multidisciplinary super clinic model of care to address current gaps within the semi-rural practice setting. Any future role for the pharmacist could be addressed as part of a formalised, strategic approach to creating an integrated healthcare team, with attention to funding and government legislation. PMID- 25810789 TI - Neonatal sepsis caused by Shewanella algae: A case report. AB - Sepsis remains a leading cause of mortality among neonates, especially in developing countries. Most cases of neonatal sepsis are attributed to Escherichia coli and other members of the Enterobacteriaceae family. Shewanella algae (S. algae) is a gram-negative saprophytic bacillus, commonly associated with the marine environment, which has been isolated from humans. Early onset neonatal sepsis caused by S. algae is uncommon. We report a case of S. algae blood stream infection in a newborn with early onset neonatal sepsis. PMID- 25810790 TI - Impact of assessment of medical students in India on assuring quality primary care. PMID- 25810791 TI - Cryptic diversity of caddisflies in the Balkans: the curious case of Ecclisopteryx species (Trichoptera: Limnephilidae). AB - Adults and larvae of two new cryptic, endemic caddisflies, Ecclisopteryx keroveci sp.n. and Ecclisopteryx ivkae sp.n., are described and illustrated from the Western Balkans. Phylogenetic analysis (Bayesian MCMCMC) and association of different life history stages in both cryptic species were achieved through comparison of morphological characters and mitochondrial (mtCOI and mtLSU) and nuclear (nuWG) gene sequence data. The new species form a sister clade to the widely distributed E. dalecarlica and E. guttulata, with which they were formerly misidentified. Adults differ from each other and other species in the genus by the uniquely shaped inferior appendages in males and segment X in females. The larvae differ from each other and their congeners in the shape of the pronotum, and presence and constitution of additional spines on the parietalia. Larvae of both species are grazers and prefer stony substrate. Ecclisopteryx keroveci sp.n. has a wide distribution in the Western Balkans, while E. ivkae sp.n. is endemic to Dalmatia. Our findings demonstrate the significance of the Western Balkans as a freshwater biodiversity hotspot, and accentuate the importance of research focused on freshwater biodiversity and biogeography in southern Europe. PMID- 25810792 TI - Investigations of cell morphology and reproduction in Macrochloris radiosa Ettl & Gartner (Stephano-sphaerinia, Chlorophyta) by light- and WUDQVPLVVLRQ electron microscopy. AB - Cell division and reproduction of a cultivated strain of Macrochloris radiosa (Stephanosphaerinia clade) were studied by light- and transmission electron microscopy. Multinucleate cells were frequently observed allowing description of the cell structure and details of the reproduction process. Nuclear staining revealed the position of the multiple polymorphic nuclei between the chloroplast lobes. Ultrastructure of coenocytic cells showed no signs of cleavage of the protoplast in the cytoplasm, although basal bodies were already present within the multinucleate cells. In the further course of the reproduction, biflagellate zoospores were developed that retained their flagella during sporulation. Zoospores were subsequently released from the sporangia. PMID- 25810793 TI - Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities. AB - BACKGROUND: Relative to other aspects of Down syndrome, remarkably little is known about the psychiatric problems experienced by youth and young adults with this syndrome and if these problems differ from others with intellectual disabilities. Yet adolescence and young adulthood are particularly vulnerable time periods, as they involve multiple life transitions in educational, medical, and other service systems. METHODS: This study compared the psychiatric diagnoses of 49 adolescent and young adult patients with Down syndrome to 70 patients with other intellectual disabilities (IDs). The groups were similar in age, gender, and level of intellectual impairment. The 119 participants, aged 13 to 29 years (M = 21) were evaluated in one of two specialized psychiatric clinics. RESULTS: In contrast to previous literature, those with Down syndrome versus other IDs had significantly higher rates of psychosis NOS or depression with psychotic features (43% versus 13%). Unlike the ID group, psychosis was predominantly seen in females with Down syndrome. Marked motoric slowing in performing routine daily activities or in expressive language was manifested in 17% of patients with Down syndrome. No group differences were found in anxiety or depressive disorders, and the ID group had significantly higher rates of bipolar and impulse control disorders. CONCLUSIONS: These preliminary observations warrant further studies on genetic, neurological, and psychosocial factors that place some young people with Down syndrome or other IDs at high risk for severe psychiatric illness. PMID- 25810795 TI - [Conservative treatment of breast cancer: experience of a Tunisian team]. PMID- 25810797 TI - [Congenital nevi associated with melanoma: about a case]. PMID- 25810794 TI - Role of Glutamine in Protection of Intestinal Epithelial Tight Junctions. PMID- 25810796 TI - [Cutaneous leishmaniasis by Leishmania major and Leishmania tropica in Morocco: comparative epidemioclinical aspects of 268 cases]. PMID- 25810798 TI - Microscopic examination and smear negative pulmonary tuberculosis in Ethiopia. AB - INTRODUCTION: Tuberculosis causes illness among millions of people each year and ranks as the second leading cause of death from infectious disease worldwide. The aim of this study was to investigate the detection rate of microscopic examination and estimate risk of transmission of TB by smear negative pulmonary TB patients. METHODS: A cross-sectional study and retrospective data analysis on TB were undertaken in Northwest Shewa, Ethiopia. Microscopic examination, bacterial culture and PCR were performed. The statistical analysis was made by using STATA software version 10. RESULTS: A total of 92 suspected TB cases was included in the study. Of these, 27.17% (25/92) were positive for microscopic examination and 51% (47/92) for culture. The sensitivity and specificity of microscopic examination with 95% CI were 48.94% (34.08% to 63.93%) and 95.56% (84.82 to 99.33%), respectively. The positive and negative predictive values were 92% (73.93% to 98.78%) and 64.18% (51.53% to 75.53%), respectively. Of 8150 pulmonary TB cases in the retrospective study, 58.9% was smear negative. The proportion of TB-HIV co-infection was 28.66% (96/335). CONCLUSION: The sensitivity of microscopic examination was 48.94% which was very low. The poor sensitivity of this test together with the advent of HIV/AIDS elevated the prevalence of smear negative pulmonary TB. This in turn increased the risk of TB transmission. PMID- 25810800 TI - Congenital hypertrophy of the retinal pigment epithelium in Gardner's syndrome. PMID- 25810799 TI - Clinical presentation, treatment and outcome of paraphenylene-diamine induced acute kidney injury following hair dye poisoning: a cohort study. AB - INTRODUCTION: In Africa and Asia hair dye is applied together with henna to decorate the hands and feet. Paraphenylene-diamine (PPD), a highly toxic constituent of hair dye can lead to acute kidney injury (AKI). METHODS: A cohort study was conducted during the period from April 2012 to March 2013 in Khartoum Teaching Hospital, Sudan. It targeted adults presenting acutely with an evident history and clinical features of hair dye poisoning, together with AKI as per the RIFLE criteria. Analysis of data was done using SPSS. RESULTS: 30 adults were included, their mean age was 25.6 +/- 4.2 years, 93.3% were females. Exposure to PPD was suicidal in 86.7%. The mean duration to onset of renal symptoms was 34.8 +/- 7.6 hours, maximum median serum creatinine was 8.6 +/- 2.3 mg/dl, 86.7% had loss of kidney function as per the RIFLE classification and required dialysis. Initial renal recovery was seen after a mean duration of 9.8 +/- 2.2 days. One patient died, 3.3%; all others, 96.7%, recovered normal kidney function. The amount of ingested PPD correlated significantly to the severity of symptoms, number of dialysis sessions required and time for renal recovery with P values < 0.05. CONCLUSION: Hair dye poisoning was associated with prolonged hospital stay, requirement of dialysis and increased morbidity. The severity of symptoms directly correlates to the dose of PPD ingested, with the kidney damage being reversible in almost all survivors. PMID- 25810801 TI - [Naso-sinusal chondrosarcoma: report of two cases and review of the literature]. PMID- 25810802 TI - [DRESS syndrome: report of three cases]. PMID- 25810803 TI - [Massive postpartum vulvar hematoma: about one case at Yaounde Central Hospital (Cameroon)]. PMID- 25810804 TI - An association of vertebral breast cancer metastasis and multiple myeloma, revealed by a spinal cord compression. AB - Authors describe the case of a patient with breast cancer and multiple myeloma as the second metachronous disease responsible for spinal cord compression. Synchronous occurrence of bone marrow breast cancer disease and multiple myeloma has not been described in the literature, as in this case. By presenting this case, we point to possible association between both diseases and the possible factors involved in the development of second malignant disease. PMID- 25810806 TI - When treatment success is not as black and white as a radiograph: the bio/psycho/social impact of chronic osteomyelitis. AB - This case report is from Malawi Beit CURE international Hospital (BCIH), a center of excellence for the management of chronic osteomyelitis (COM) in children. Currently minimal evidence based data exists on the long term outcomes for treatment of bone defects following COM. Few studies evaluating outcomes are based solely on clinical parameters. This case study highlights the often debilitating outcome after treatment and hence the need for further research to find the most effective treatment to create treatment guidelines. It particularly demonstrates the importance of the bio/psycho/social impact of long-term morbidity and disability, which must be considered alongside clinical outcomes in evaluation. PMID- 25810805 TI - [Mortality risk factors in newborns transferred to the neonatal unit of the Hospital Jason Sendwe Lubumbashi, DR Congo]. PMID- 25810807 TI - [Genu varum osteoarthritis: treatment with tibial valgus osteotomy]. PMID- 25810808 TI - CO2 pneumoperitoneum preserves beta-arrestin 2 content and reduces high mobility group box-1 (HMGB-1) expression in an animal model of peritonitis. AB - Laparoscopy (LS) has been shown to decrease the inflammatory sequelae of endotoxemia. beta-arrestin 2 plays an important function in signal transduction pathway of TLR4. High mobility group box-1 (HMGB-1) is involved in the delayed systemic inflammatory response. We investigated the effects of CO2 insufflation on liver, lung, and kidney expression of both beta-arrestin 2 and HMGB-1 during sepsis. Cecal ligation and puncture (CLP) was performed in male rats and 6 h later the animals were randomly assigned to receive a CO2 pneumoperitoneum or laparotomy. Animals were euthanized; liver, lung, and kidney were removed for the evaluation of beta-arrestin 2 and HMGB-1 expression. Immunohistochemical detection of myeloperoxidase (MPO) was investigated in lung and liver and bacterial load was determined in the peritoneal fluid. CO2 pneumoperitoneum reduced peritoneal bacterial load, increased the expression of beta-arrestin 2, and blunted the expression of the potent proinflammatory HMGB-1 in liver, lung, and kidney compared with laparotomy. Liver and lung MPO was markedly reduced in rats subjected to LS compared with laparotomy. We believe that CO2 exerts an early protective effect by reducing bacterial load and likely toll-like receptor activation which in turn leads to a preserved beta-arrestin 2 expression and a reduced HMGB-1 expression. PMID- 25810810 TI - Catheter ablation of persistent atrial fibrillation: The importance of substrate modification. AB - Accumulating data have shown that elimination of atrial fibrillation (AF) sources should be the goal in persistent AF ablation. Pulmonary vein isolation, linear lesions and complex fractionated atrial electrograms (CFAEs) ablation have shown limited efficacy in patients with persistent AF. A combined approach using voltage, CFAEs and dominant frequency (DF) mapping may be helpful for the identification of AF sources and subsequent focal substrate modification. The fibrillatory activity is maintained by intramural reentry centered on fibrotic patches. Voltage mapping may assist in the identification of fibrotic areas. Stable rotors display the higher DF and possibly drive AF. Furthermore, the single rotor is usually consistent with organized AF electrograms without fractionation. It is therefore quite possible that rotors are located at relatively "healthy islands" within the patchy fibrosis. This is supported by the fact that high DF sites have been negatively correlated to the amount of fibrosis. CFAEs are located in areas adjacent to high DF. In conclusion, patchy fibrotic areas displaying the maximum DF along with high organization index and the lower fractionation index are potential targets of ablation. Prospective studies are required to validate the efficacy of substrate modification in left atrial ablation outcomes. PMID- 25810809 TI - Protective effects of the flavonoid chrysin against methylmercury-induced genotoxicity and alterations of antioxidant status, in vivo. AB - The use of phytochemicals has been widely used as inexpensive approach for prevention of diseases related to oxidative damage due to its antioxidant properties. One of dietary flavonoids is chrysin (CR), found mainly in passion fruit, honey, and propolis. Methylmercury (MeHg) is a toxic metal whose main toxic mechanism is oxidative damage. Thus, the study aimed to evaluate the antioxidant effects of CR against oxidative damage induced by MeHg in Wistar rats. Animals were treated with MeHg (30 ug/kg/bw) in presence and absence of CR (0.10, 1.0, and 10 mg/kg/bw) by gavage for 45 days. Glutathione (GSH) in blood was quantified spectrophotometrically and for monitoring of DNA damage, comet assay was used in leukocytes and hepatocytes. MeHg led to a significant increase in the formation of comets; when the animals were exposed to the metal in the presence of CR, higher concentrations of CR showed protective effects. Moreover, exposure to MeHg decreased the levels of GSH and GSH levels were restored in the animals that received CR plus MeHg. Taken together the findings of the present work indicate that consumption of flavonoids such as CR may protect humans against the adverse health effects caused by MeHg. PMID- 25810811 TI - Coronary artery disease in type 2 diabetes mellitus: Recent treatment strategies and future perspectives. AB - Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of developing coronary artery disease (CAD) than are non-T2DM patients. Moreover, the clinical outcomes in CAD with T2DM are poor despite improvements in medications and other interventions. Coronary artery bypass grafting is superior to percutaneous coronary intervention in treating multivessel coronary artery disease in diabetic patients. However, selecting a revascularization strategy depends not only on the lesion complexity but also on the patient's medical history and comorbidities. Additionally, comprehensive risk management with medical and non-pharmacological therapies is important, as is confirmation regarding whether the risk-management strategies are being appropriately achieved. Furthermore, non-pharmacological interventions using exercise and diet during the earlier stages of glucose metabolism abnormalities, such as impaired glucose tolerance, might be beneficial in preventing the development or progression of T2DM and in reducing the occurrence of cardiovascular events. PMID- 25810812 TI - Making cardiomyocytes with your chemistry set: Small molecule-induced cardiogenesis in somatic cells. AB - Cell transplantation is an attractive potential therapy for heart diseases. For example, myocardial infarction (MI) is a leading cause of mortality in many countries. Numerous medical interventions have been developed to stabilize patients with MI and, although this has increased survival rates, there is currently no clinically approved method to reverse the loss of cardiac muscle cells (cardiomyocytes) that accompanies this disease. Cell transplantation has been proposed as a method to replace cardiomyocytes, but a safe and reliable source of cardiogenic cells is required. An ideal source would be the patients' own somatic tissue cells, which could be converted into cardiogenic cells and transplanted into the site of MI. However, these are difficult to produce in large quantities and standardized protocols to produce cardiac cells would be advantageous for the research community. To achieve these research goals, small molecules represent attractive tools to control cell behavior. In this editorial, we introduce the use of small molecules in stem cell research and summarize their application to the induction of cardiogenesis in non-cardiac cells. Exciting new developments in this field are discussed, which we hope will encourage cardiac stem cell biologists to further consider employing small molecules in their culture protocols. PMID- 25810815 TI - Percutaneous closure of secundum type atrial septal defects: More than 5-year follow-up. AB - AIM: To investigate long-term efficacy of two different devices more than five years after percutaneous atrial septal defect (ASD) closure in adults. METHODS: All patients who underwent percutaneous closure of an ASD in the St. Antonius Hospital, Nieuwegein, The Netherlands, between February 1998 and December 2006 were included. Percutaneous closure took place under general anaesthesia and transesophageal echocardiographic monitoring. Transthoracic echocardiography (TTE) was performed 24 h post-procedure to visualize the device position and to look for residual shunting using color Doppler. All complications were registered. All patients were invited for an outpatient visit and contrast TTE more than 5-years after closure. Efficacy was based on the presence of a residual right-to-left shunt (RLS), graded as minimal, moderate or severe. The presence of a residual left-to-right shunt (LRS) was diagnosed using color Doppler, and was not graded. Descriptive statistics were used for patients' characteristics. Univariate analysis was used to identify predictors for residual shunting. RESULTS: In total, 104 patients (mean age 45.5 +/- 17.1 years) underwent percutaneous ASD closure using an Amplatzer device (ASO) in 76 patients and a Cardioseal/Starflex device (CS/SF) in 28 patients. The mean follow-up was 6.4 +/- 3.4 years. Device migration occurred in 4 patients of whom two cases occurred during the index hospitalization (1 ASO, 1 CS/SF). The other 2 cases of device migration occurred during the first 6 mo of follow-up (2 CS/SF). The recurrent thrombo-embolic event rate was similar in both groups: 0.4% per follow-up year. More than 12 mo post-ASD closure and latest follow-up, new-onset supraventricular tachyarrhythmia's occurred in 3.9% and 0% for the ASO and CS/SF group, respectively. The RLS rate at latest follow-up was 17.4% (minimal 10.9%, moderate 2.2%, severe 4.3%) and 45.5% (minimal 27.3%, moderate 18.2%, severe 0%) for the ASO- and CS/SF groups, respectively. There was no residual LRS in both groups. CONCLUSION: Percutaneous ASD closure has good long-term safety and efficacy profiles. The residual RLS rate seems to be high more than 5 years after closure, especially in the CS/SF. Residual LRS was not observed. PMID- 25810814 TI - Palm oil and the heart: A review. AB - Palm oil consumption and its effects on serum lipid levels and cardiovascular disease in humans is still a subject of debate. Advocacy groups with varying agenda fuel the controversy. This update intends to identify evidence-based evaluations of the influence of palm oil on serum lipid profile and cardiovascular disease. Furthermore, it suggests a direction for future research. The sources of information were based on a PubMed, Google Scholar, African Journal online and Medline search using key words including: palm oil, palmitic acid, saturated fatty acids and heart disease. Published animal and human experiments on the association of palm oil and its constituents on the serum lipid profile and cardiovascular disease were also explored for relevant information. These papers are reviewed and the available evidence is discussed. Most of the information in mainstream literature is targeted at consumers and food companies with a view to discourage the consumption of palm oil. The main argument against the use of palm oil as an edible oil is the fact that it contains palmitic acid, which is a saturated fatty acid and by extrapolation should give rise to elevated total cholesterol and low-density lipoprotein cholesterol levels. However, there are many scientific studies, both in animals and humans that clearly show that palm oil consumption does not give rise to elevated serum cholesterol levels and that palm oil is not atherogenic. Apart from palmitic acid, palm oil consists of oleic and linoleic acids which are monounsaturated and polyunsaturated respectively. Palm oil also consists of vitamins A and E, which are powerful antioxidants. Palm oil has been scientifically shown to protect the heart and blood vessels from plaques and ischemic injuries. Palm oil consumed as a dietary fat as a part of a healthy balanced diet does not have incremental risk for cardiovascular disease. Little or no additional benefit will be obtained by replacing it with other oils rich in mono or polyunsaturated fatty acids. PMID- 25810813 TI - Role of Helicobacter pylori infection in pathogenesis of atherosclerosis. AB - Though a century old hypothesis, infection as a cause for atherosclerosis is still a debatable issue. Epidemiological and clinical studies had shown a possible association but inhomogeneity in the study population and study methods along with potential confounders have yielded conflicting results. Infection triggers a chronic inflammatory state which along with other mechanisms such as dyslipidemia, hyper-homocysteinemia, hypercoagulability, impaired glucose metabolism and endothelial dysfunction, contribute in pathogenesis of atherosclerosis. Studies have shown a positive relations between Cytotoxic associated gene-A positive strains of Helicobacter pylori and vascular diseases such as coronary artery disease and stroke. Infection mediated genetic modulation is a new emerging theory in this regard. Further large scale studies on infection and atherosclerosis focusing on multiple pathogenetic mechanisms may help in refining our knowledge in this aspect. PMID- 25810816 TI - 9.1 cm abdominal aortic aneurysm in a 69-year-old male patient. AB - We are presenting a case of one of the largest un-ruptured abdominal aortic aneurysm ever reported. Presented here is a rare case of a 69-year-old active smoker male with history of hypertension and incidental diagnosis of abdominal aortic aneurysm of 6.2 cm in 2003, who refused surgical intervention at the time of diagnosis with continued smoking habit and was managed medically. Patient was subsequently admitted in 2012 to the hospital due to unresponsiveness secondary to hypoglycemia along with diagnosis of massive symptomatic pulmonary embolism and non-ST elevation myocardial infarction. With the further inpatient workup along with known history of abdominal aortic aneurysm, subsequent computed tomography scan of abdomen pelvis revealed increased in size of infrarenal abdominal aortic aneurysm to 9.1 cm of without any signs of rupture. Patient was unable to undergo any surgical intervention this time because of his medical instability and was eventually passed away under hospice care. PMID- 25810817 TI - Trauma and syncope-evidence for further sleep study? A case report. AB - We report on an 83-year-old male with traumatic brain injury after syncope with a fall in the morning. He had a history of seizures, coronary artery disease and paroxysmal atrial fibrillation (AF). No medical cause for seizures and syncope was determined. During rehabilitation, the patient still complained of seizures, and also reported sleepiness and snoring. Sleep apnea diagnostics revealed obstructive sleep apnea (SA) with an apnea-hypopnoea index of 35/h, and sudden onset of tachycardia with variations of heart rate based on paroxysmal atrial fibrillation. Additional tests showed nocturnal AF which spontaneously converted to sinus rhythm mid-morning with an arrest of 5 s (sick sinus syndrome) and seizures. A DDD-pacer was implanted and no further seizures occurred. SA therapy with nasal continuous positive airway pressure was refused by the patient. Our findings suggests that screening for SA may offer the possibility to reveal causes of syncope and may introduce additional therapeutic options as arrhythmia and SA often occur together which in turn might be responsible for trauma due to syncope episodes. PMID- 25810819 TI - Tooth size discrepancy in a Libyan population, a cross-sectional study in schoolchildren. AB - Objetives: The aim of this cross-sectional study was to investigate the tooth size discrepancy (TSD) in a group of Libyan schoolchildren, and to compare TSD between sexes. MATERIAL AND METHODS: The sample comprised 333 Libyan schoolchildren (162 males with a mean (SD) age of 14.4 (1.1) years, and 171 females with a mean age of 14.1 (1.1) years). Anterior and overall TSD ratios were computed using descriptive statistics. Sex differences were statistically assessed using an independent t-test (P<0.05). RESULTS: Males showed significantly wider MD tooth width compared to females (P<0.05), except for the maxillary first premolars and mandibular central incisors. There were significant differences (P<0.05) between the paired (right and left sides) tooth measurements except for the maxillary and mandibular central and lateral incisors as well as mandibular canines. The mean (SD) for overall and anterior TSD ratios were 91.3% (2.1) and 78.2% (2.6), respectively, with no significant sex differences for both variables (P> 0.05). The percentages of participants showing more than 2 SD variation for the anterior and overall ratios comprised 3% and 4.2% of the total sample, respectively. CONCLUSIONS: The anterior and overall TSD ratios for the examined subjects were established and showed no significant sexual dimorphism. Key words:Tooth size discrepancy, Libyan, schoolchildren. PMID- 25810818 TI - Tumour associated tissue eosinophilia as a predictor of locoregional recurrence in oral squamous cell carcinoma. AB - OBJECTIVES: The increasing global burden of oral cancer has driven much of the focus of research to the determination of reliable prognostic markers which may have significant effects on survival and the control of post-treatment morbidity. This study was undertaken to evaluate tumour associated tissue eosinophilia (TATE) quantitatively in oral cancer specimens and observe for its possible association with tumour stage, patterns of locoregional recurrence and overall prognosis. STUDY DESIGN: 14 patients undergoing surgical resection for primary oral squamous cell carcinoma (OSCC) were subjected to grey scale ultrasonography (USG) to assess tumour dimensions. The findings were compared with the cTNM stage initially documented. TATE was evaluated along the invasive tumour front (ITF) using H & E stained sections of histopathological specimens for 10 continuous high power fields (HPF) and graded as mild, moderate or intense. Patients were followed up over 5 years and observed for patterns of recurrence. RESULTS: Loco regional recurrence was significantly associated with intense degree of TATE. (p<0.001) cTNM stage as well as USG stage did not correlate with the degree of TATE with p=0.419 and 0.772 respectively. None of the patients with mild/ moderate dysplasia developed locoregional recurrence within the period of follow up. CONCLUSIONS: Analysis of TATE in OSCC patients may provide an early indication of future locoregional recurrence. Identification of an appropriate biopsy site representing the ITF where TATE analysis can be performed may be a simple, inexpensive method of obtaining valuable prognostic information at the time of diagnosis. Key words:Tumour associated tissue eosinophilia, oral cancer, prognosis. PMID- 25810820 TI - Children's oral health-related quality of life and associated factors: Mid-term changes after dental treatment under general anesthesia. AB - OBJECTIVES: This study aimed to document the mid-term effects of comprehensive dental treatment under general anesthesia (DTGA) on parent-assessed children's oral health-related quality of life (COHRQoL). A second aim was to examine some epidemiological factors associated with COHRQoL and treatment outcome. STUDY DESIGN: A pretest-posttest design was followed in which parents were surveyed using the Child Oral Health Quality of Life Questionnaire before and 6-9 months after their children (age ranges 3-10 years) underwent DTGA. Some clinical conditions and epidemiological factors were examined to assess their association with COHRQoL and changes resulting from treatment. RESULTS: The clinical sample consisted of 80 children-parent dyads. The effect sizes of change following DTGA were large for both the child impact section and family impact section of the COHRQoL. COHRQoL scores after treatment were comparable or lower than those of a cross-matched group of children with no complaints related to oral health. Child's age, pain and number of teeth with pulpal involvement showed significant association with both pretreatment scores and change scores. CONCLUSIONS: Children's OHRQoL improved after DTGA as assessed by parents 6-9 months postoperatively. Child's age, pain and number of pulpally-involved teeth can be used as predictors for COHRQoL and change scores. Key words:Quality of life, children, oral health, reliability. PMID- 25810821 TI - Correlation between dental caries experience and mutans streptococci counts using saliva and plaque as microbial risk indicators in 3-8 year old children. A cross Sectional study. AB - OBJECTIVES: Determination of the relative amounts of mutans streptococcus in both saliva and plaque and to study its correlation with dental caries in children. STUDY DESIGN: The study comprised of 60 children aged 3-8 years divided into 2 groups (30 children in each): Group A- Children with more than 4 carious teeth and Group B- Children without caries. Saliva and plaque was collected from children of both the groups with the help of Dentocult SM strip test kit (Orion Diagnostic). Following incubation, mutans streptococcus scores (from 0 to 3) in each individual was evaluated and compared between both the groups. RESULTS: On comparing the two groups, mean +/- SD of saliva score and plaque score was 2.40 +/- 0.675 and 2.40 +/- 0.621 respectively in group A, whereas it was 0.60 +/- 0.498 and 0.83 +/- 0.531 in children of group B showing a significant correlation (p = < 0.001) between mutans streptococci scores in both saliva and plaque and dental caries experience. CONCLUSIONS: There is a direct and strong co-relation between the salivary and plaque mutans streptococcus counts and caries activity in children aged 3-8 years. Key words:Mutans streptococci, dentocult, dental caries. PMID- 25810822 TI - An in vitro evaluation of the effect of sandblasting and laser surface treatment on the shear bond strength of a composite resin to the facial surface of primary anterior stainless steel crowns. AB - OBJECTIVES: The present study was conducted to evaluate the optimal method of enhancing the bond strength of a composite resin to the facial surface of the primary anterior stainless steel crowns using various surface treatments namely Nd: YAG laser surface treatment, sandblasting , alloy primer application and no surface treatment. STUDY DESIGN: The study sample consisted of 60 primary anterior stainless steel crowns (UnitekTM size R 4), with 15 samples randomly divided into the 4 study groups, embedded in acrylic blocks. The facial surface of these surface treated crowns was utilized as the bonding surface to which 2.5mm diameter composite resin cylinders were bonded for the evaluation of the shear bond strength. Shear bond strength measurements were made using a universal testing machine utilizing a shearing blade (jig).The mode of failure at composite metal interface was determined using a Stereomicroscope at 10 X magnification. RESULTS: The mean bond strength values obtained for surface treatment of Nd: YAG laser surface treated, Sandblasting ,Alloy Primer and No surface treatments were 17.01+/-.92 , 13.18 +/- .73, 7.46 +/- .70 and 7.33 +/- .77 MPa respectively. The obtained bond strength values were subjected to a one way ANOVA and a Scheffe's post-hoc comparison test. The results of the present study indicated that Laser surface treatment of the facial surface of the crowns enhanced the bond strength of the composite resin significantly compared to the other groups. CONCLUSIONS: Nd: YAG laser surface treatment produced an excellent surface roughness and obtained the highest shear bond strength values suggestive for recommendation as an optimal surface treatment to be used to enhance the resin-metal bond at the interface of the composite resin and the facial surface of primary anterior stainless steel crowns for the purpose of chairside veneering. Key words:Nd: YAG laser treatment, Sandblasting, Primary anterior stainless steel crown, Chairside veneering, Enhancing Resin-Metal Bond, Early childhood caries, Shear bond strength (SBS). PMID- 25810823 TI - The intraoral device of overlaid disk-holding splints as a new in situ oral biofilm model. AB - OBJECTIVES: To design a device that allows the formation of in situ oral biofilm with similar characteristics to those from the dental plaque, overcoming the limitations of previous devices. STUDY DESIGN: The Intraoral Device of Overlaid Disk-holding Splints (IDODS) was designed and manufactured. To test its validity, five healthy adult volunteers wore them for two and four days allowing the biofilm to grow without any type of distortion. After each period, the thickness, vitality and structure of the formed biofilm were measured with a Confocal Laser Scanning Microscope (CLSM) in combination with a dual fluorescence solution. All volunteers filled out a Likert-type questionnaire to evaluate the device. RESULTS: Mean bacterial vitality in the 2- and 4-day biofilms was 71% and 63%, respectively. Mean thicknesses were 21 um and 28 um, respectively. There was predominance in the open and heterogeneous structure whose complexity was ascending as the biofilm matured. The results obtained from the questionnaire were 2/5 in the influence in aesthetics, 3.4/5 in comfort, and 5/5 in ease of maintaining oral hygiene and withdrawal from the oral cavity. CONCLUSIONS: A biofilm with optimum characteristics was obtained by IDODS. Its use is associated with good aesthetic and comfort results and is absent of functional limitations, allowing optimal oral hygiene without altering the structure of the in situ oral biofilm. Key words:Confocal Laser Scanning Microscope, fluorochromes, in situ, intraoral device, oral biofilm. PMID- 25810824 TI - Evaluation of the effect of transcutaneous electrical nerve stimulation (TENS) on whole salivary flow rate. AB - BACKGROUND: Saliva plays a critical role in maintaining oral homeostasis; it modulates the ecosystem through lubrication of the alimentary bolus, protection against microorganisms, buffer and repair of the oral mucosa, and helps in dental re-mineralization. Various local and systemic factors such as medications, radiation therapy, systemic conditions, etc. can lead to reduction in salivary flow. A decrease in salivary function, known as Xerostomia, increases a patient's risk for caries and other oral infections. Palliative management of Xerostomia includes wetting agents such as ice chips, drugs and saliva substitutes. Systemic agents stimulate salivary flow but often have unfavorable side effects. Newer modalities like transcutaneous electrical nerve stimulation (TENS), which has fewer side effects, have been used to stimulate salivary flow. The aim of the present study was to assess and evaluate the effect of TENS on whole salivary flow rates in healthy adult subjects. STUDY DESIGN: A total of 80 healthy adult subjects were enrolled in the study. Unstimulated and stimulated saliva (using TENS) was collected for 5 minutes and the mean salivary flow rates were calculated. Data obtained was analyzed using the SPSS (Statistical package for social sciences) version 15. Students 't' test was employed for comparative analysis. RESULTS: Sixty-five of the 80 subjects demonstrated an increase in the salivary flow rate on application of TENS. Twelve subjects demonstrated a mild reduction in the salivary flow rates. Seven subjects experienced transient mild twitching of facial musculature as side effects. CONCLUSION: Significant increase in salivary flow rates was observed on application of TENS with minimal or no side effects. Key words:Stimulated saliva, whole salivary flow, TENS. PMID- 25810825 TI - Ectopic third molar in the mandibular sigmoid notch: Report of a case and literature review. AB - PURPOSE: To evaluate the etiopathogenesis, clinical features and surgical approaches for removal of ectopic third molars in the mandible. METHODS: We report a case of an impacted mandibular third molar dislocated on mandibular sigmoid notch. 20 cases of ectopic mandibular third molars reported in the English-language literature, identified from Pubmed and Medline databases are also reviewed. RESULTS: Among the 20 article reported in the presented study, ectopic third molars were generally located in the condylar region. The common symptoms of the clinical examination were pain, trismus, swelling, temporomandibular joint syndroms or no symptoms. CONCLUSIONS: Ectopic third molar may be asymptomatic initially with clinical manifestations, later on as adjacent structures are affected. The surgical approach must be carefully planned for the aim of choosing the more conservative technique that produces the minimum trauma to patients. Key words:Ectopic third molar, sigmoid notch, cyst. PMID- 25810826 TI - Graft-versus-host disease affecting oral cavity. A review. AB - Graft versus host disease (GVHD) is one of the most frequent and serious complications of hematopoietic stem cell transplantation, and is regarded as the leading cause of late mortality unrelated to the underlying malignant disease. GVHD is an autoimmune and alloimmune disorder that usually affects multiple organs and tissues, and exhibits a variable clinical course. It can manifest in either acute or chronic form. The acute presentation of GVHD is potentially fatal and typically affects the skin, gastrointestinal tract and liver. The chronic form is characterized by the involvement of a number of organs, including the oral cavity. Indeed, the oral cavity may be the only affected location in chronic GVHD. The clinical manifestations of chronic oral GVHD comprise lichenoid lesions, hyperkeratotic plaques and limited oral aperture secondary to sclerosis. The oral condition is usually mild, though moderate to severe erosive and ulcerated lesions may also be seen. The diagnosis is established from the clinical characteristics, though confirmation through biopsy study is sometimes needed. Local corticosteroids are the treatment of choice, offering overall response rates of close to 50%. Extracorporeal photopheresis and systemic corticosteroids in turn constitute second line treatment. Oral chronic GVHD is not considered a determinant factor for patient survival, which is close to 52% five years after diagnosis of the condition. Key words:Chronic graft-versus-host disease, oral chronic graft-versus-host disease, pathogenics, management, survival. PMID- 25810827 TI - Flapless implant surgery: A review of the literature and 3 case reports. AB - Since the 1970s, modern Implantology is based on a concept of surgery with flap elevation. Gradually, several clinical trials demonstrated that a mid-crestal incision gives similar success rates compared to those obtained using the classical protocol. However, over the past decade in medicine it has been established the concept of minimally invasive surgery, consisting in taking advantage of advancements experienced in diagnostic techniques and specific surgical instruments, to perform surgical procedures infringing as less damage as possible to the patient The present work aims to produce a thorough review of the literature published on the field of Implantology with flapless surgery, to determine the current scientific evidence of the technique, along with illustrating the results with different clinical cases. After presenting the clinical cases, and the review of literature, we can say that flapless surgeries should be restricted to well-selected cases in which a proper clinical and radiological planning has been made. Patients treated with anticoagulant drugs or medically compromised equally can get benefitted by this minimal invasion technique. Key words:Flapless, minimally invasive surgery, dental implant. PMID- 25810829 TI - Closure of oroantral communication with buccal fat pad after removing bilateral failed zygomatic implants: A case report and 6-month follow-up. AB - The aim of this study was to assess the use of buccal fat pad (BFP) technique as an option to close oroantral communications (OAC) after removing failed zygomatic implants in a patient with a severely resorbed maxilla, and to determine the degree of patient satisfaction. A 64-year-old woman presented recurrent sinusitis and permanent oroantral communication caused by bilateral failed zygomatic implants, 3 years after prosthetic loading. Zygomatic implants were removed previous antibiotic treatment and the BFP flap technique was used to treat the OAC and maxillary defect. The degree of patient satisfaction after treatment was assessed through a visual analogue scale (VAS). At 6-months follow-up, patient showed complete healing and good function and the results in terms of phonetics, aesthetics and chewing were highly rated by the patient. Key words:Bichat fat pad, buccal fat pad, zygomatic implants, oroantral communication. PMID- 25810828 TI - A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients. AB - Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric. PMID- 25810830 TI - Clear cell variant of calcifying epithelial odontogenic tumor: Case report with immunohistochemical findings. AB - Calcifying epithelial odontogenic tumor (CEOT) is a rare benign odontogenic neoplasm, locally aggressive, characterized by sheets and nests of polyhedral epithelial cells exhibiting eosinophilic cytoplasm or less often clear cytoplasm. Additional features include nuclear pleomorphism without mitotic activity, concentric calcifications, and deposits of amyloid. Herein, we present an additional example of clear cell variant of CEOT occurring in a 25-year-old female. Microscopically, the tumor consisted on proliferation of epithelial cells with eosinophilic, clear vacuolated cytoplasm interspersed with focal areas of amyloid deposition. Tumor cells were immunopositive for AE1/AE3, CK14, CK19, beta catenin, CD138, and p63. Key words:Calcifying epithelial odontogenic tumor, clear cell, histopathology, immunohistochemistry. PMID- 25810831 TI - Mirror imaging of impacted and supernumerary teeth in dizygotic twins: A case report. AB - BACKGROUND: Mesiodens is the most common type of supernumerary tooth found in the premaxilla. It might be discovered by the clinical examination by chance on a radiograph or as the cause of an unerupted maxillary central incisor. The genetic transmission of supernumerary and impacted teeth is poorly understood. Mirror imaging in twins has been reported frequently in relation to several unilateral dental anomalies including mesiodens. This phenomenon is the appearance of an asymmetrical feature or anomaly occurring on the right side of one twin but on the left side of the other twin. The event of mesiodens mirror imaging in monozygotic twins has been described in literature. RESULTS: This is the first reported case of mesiodens mirror images in dizygotic twins. The de-scribed mesiodens caused the eruption failure of maxillary permanent incisors. The super numerary teeth were removed to facilitate the spontaneous eruption of the impacted perma-nent maxillary incisors. CLINICAL IMPLICATIONS: Studies related to supernumerary teeth can be useful to clinicians in the early diagnosis of this anomaly. Clinical and radiographic examinations provide a correct therapeutic approach. Key words:Supernumerary teeth, twins, dental development. PMID- 25810832 TI - Minimally invasive prosthetic procedures in the rehabilitation of a bulimic patient affected by dental erosion. AB - The population affected by dental erosion due to bulimia is generally very young. This population group has a high aesthetic requirement; the dentition in these patients is severely damaged, especially in the anterior maxillary quadrant. In terms of treatment, it is still controversial whether an adhesive rehabilitation is preferable to a longer-lasting but more aggressive conventional treatment, such as full-crown coverage of the majority of teeth. This case report describes the prosthetic rehabilitation of a young female patient previously affected by bulimia nervosa and presenting erosion of the maxillary teeth. The prosthetic rehabilitation was performed through indirect adhesive restorations of the anterior teeth and direct restorations of the posterior teeth. A clinical follow up after 4 years showed that the occlusion remained satisfactorily restored. Posterior direct composite resin restorations and anterior indirect adhesive composite restorations proved to be an effective time and money-saving procedure to rehabilitate patients affected by dental erosion. Adhesive rehabilitation provides a functional and good aesthetic result while preserving tooth structure. Key words:Bulimia, dental erosion, composite resin, veneers. PMID- 25810833 TI - Immediate placement of single implant simultaneously with immediate loading in a fresh socket associated to periapical infection: A clinical case report. AB - Early restoration of the masticatory function, phonatory and aesthetics is some of the current goals of the therapy based on endosseous implants. Facing the classic protocols of implant insertion, which recommend a period of several months between extraction and implant placement, alternatives have been developed that demonstrate that immediate implant placement after tooth extraction permits adequate osseointegration, even in those cases where there is a periapical disease. The immediate restoration of implants after placement is a possibility where aesthetic requirements are high. This article presents a case with immediate implant placement and immediate loading of a first upper premolar with prior periapical pathology due to a vertical fracture. The immediate prosthetic was performed using the extracted crown, which is adapted to be attached to a titanium temporary abutment using a resin cement. After a 4 month healing period work began on the final prosthetic crown. The screw crown was made of zirconium oxide with a covering feldspathic ceramic. At the 12-month follow-up, there were no mechanical or biological complications. The patient gave high satisfaction marks for the overall treatment, giving visual analogue scale score of nine. Immediate post-extraction implants have arisen as an alternative to traditional implants on completely healed bone. Their main aim is to reduce treatment time and number of surgical procedures, along with other objectives such as reduced bone re-absorption and improved aesthetics. Key words:Post-extraction implants, immediate loading prosthetic, implant-retained prosthesis, periapical disease, vertical fracture. PMID- 25810836 TI - Rotational panoramic radiographs-unusual triple images. AB - Currently clinicians advice rotational panoramic radiography (RPR) for preliminary investigation. Despite few inherent limitations, rotational panoramic radiography still remains the diagnostic tool of choice. Abnormal structures such as a supernumerary tooth or a device falling within the certain central regions in conventional RPR images may mislead the clinicians towards an inaccurate diagnosis by producing multiple ghost images. Such cases must be treated with circumspect, and apart from RPR, additional imaging modalities need be employed to provide a judicious interpretation of the clinical situation. Thus this manuscript, we present a case where a paramedian supernumerary tooth which exhibited double ghost images on a conventional RPR. This prompted us to elicit the use of a CBCT and 3 dimensional images to determine the true nature of the problem. We outline the working of the diamond principle behind a conventional RPR which cause the appearance of multiple ghost images. The discerning clinician must be cognizant of the possible positional and analytical errors which may be prevalent in a conventional RPR when viewing structures lying in the palatal region, specifically in the midline while making diagnosis. Key words:CBCT, double image, midline supernumerary, OPG. PMID- 25810834 TI - Relationship between perception of malocclusion and the psychological impact of dental aesthetics in university students. AB - INTRODUCTION AND OBJECTIVES: The objectives were to assess the relationship between perceived smile aesthetics and perceived psychological impact as measured by the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ), and their own perception of it using the Aesthetic Component of the Index of Orthodontic Treatment Need (IOTN-AC) and a Visual Analog Scale (VAS); relate the IOTN-AC and VAS to the PIDAQ; and study the predictive capacity of the scales for psychological impact. MATERIAL AND METHODS: A cross-sectional study was conducted in 447 college students in Spain and Portugal (average age 20.4 years, 33.1% men and 66.9% women). The online self-completed surveys used the recently-validated Spanish and Portuguese versions of the PIDAQ to assess the self-reported psychological impact of the students' dental aesthetics and IOTN-AC and an ad hoc 100 mm VAS for their perception of their dental aesthetics. RESULTS: PIDAQ was linearly correlated with IOTN AC and VAS. Pearson's coefficient was 0.55 for PIDAQ and IOTN-AC (CI 95% 0.48-0.61) and -0.72 for PIDAQ and VAS (CI 95% -0.66 - 0.76). VAS and IOTN-AC were predictive variables in a linear regression model of the total PIDAQ score. The VAS diagnosed individuals whose dental aesthetics had a self-perceived psychological impact (area under the curve 0.827, CI 95% 0.787 0.868) more precisely than the IOTN-AC (area under the curve 0.742, CI 95% 0. 696 0.788). CONCLUSIONS: In adults patients, there is a significant linear relationship between perceived smile aesthetics and self-perceived psychological impact. Key words:Visual Analog Scale, Index of Orthodontic Treatment Need, malocclusion, psychological, aesthetics. PMID- 25810835 TI - Oral non-Hodgkin's lymphoma in a patient with rheumatoid arthritis treated with etanercept and methotrexate. AB - Oral non-Hodgkin's lymphomas (O-NHLs) are a rare group of diverse lymphoid tissue malignancies and represent less than 5% of the oral cavity malignancies and 2% of all extra-nodal NHLs. Oral-NHLs affect the Waldeyer's-ring, the salivary glands, the bone of the jaws and the oral mucosa, their clinical appearance is very heterogeneous. Among the risk factors for NHLs are immunosuppression (primary or secondary), autoimmunity and inflammation. O-NHLs share the same risk factors. This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis. To our knowledge this is probably among the first cases of O-NHL with possible relation to the use of a Tumor Necrosis Factor (TNF) antagonist biological agent (etanercept). This case could contribute to the sensitization of the dentists for the signs and symptoms of this rare malignancy. It also underlines the need for thorough medical history and medication recording for all the dental patients. Key words:Lymphoma (oral) methotrexate, etanercept. PMID- 25810837 TI - Clinical pain evaluation with intraoral vibration device during local anesthetic injections. AB - OBJECTIVES: To evaluate the clinical pain during local anesthetic injection using such intra-oral device. STUDY DESIGN: A comparative split-mouth clinical study to evaluate clinical pain was conducted among the subjects who required bilateral local anesthetic intra-oral injections. RESULTS: A total of 99 subjects participated in the study out of which 39 were female. A total of 256 local anesthetic injections were administered to all the subjects with at least one pair of similar local anesthetic injections. Comparison of mean VAS score for anticipated pain in without vibration group was significantly higher in all types of nerve blocks when compared to that of with vibration. Similarly, the comparison of mean VAS score for actual pain in without vibration group was significantly higher in all types of nerve blocks when compared to that of with vibration. No significant difference in the mean VAS score was seen between anticipated and actual pain in without vibration group with respect to inferior alveolar (p=0.673), infra-orbital (p=0.175) and palatal (p=0.343) local anesthetic injections. The mean VAS score was significantly lower for actual pain when compared to anticipated pain in vibration group with respect to inferior alveolar (p<0.001) and infra-orbital (p=0.002) local anesthetic injections. CONCLUSIONS: There was significant reduction in the pain encountered during local anesthetic injection with the use of intra-oral vibration device. Key words:Pain, vibration, visual analogue scale, local anesthesia. PMID- 25810838 TI - Closure of oroantral communications with Bichat's buccal fat pad. Level of patient satisfaction. AB - PURPOSE: To report the closure of oroantral communications with the pedicled buccal fat pad in a series of patients, and to determine the level of patient satisfaction after the surgery. STUDY DESIGN: A prospective study of patients diagnosed of unilateral or bilateral oroantral communication (OAC) closed using the buccal fat pad between May 2012 and January 2013 was performed. Data analysis extended to: age, sex, and cause, location and size of oroantral communication. Complications and success related to buccal fat pad surgery were evaluated. Also, patient satisfaction was assessed after six months of surgery. RESULTS: Nine patients (3 men and 6 women) with a mean age of 50.5 years and 11 OAC treated with buccal fat pads were included. The most common cause of oroantral communication was the extraction of molars. The average widest diameter of the oroantral communication was 7.1 mm. One week after the surgeries no complications were found. One month after surgery, one patient presented persistence of the oroantral communication; in this patient, the buccal fat pad technique was considered a failure, and a second intervention was performed using a buccal mucoperiosteal flap to achieve primary closure of soft tissues. After six months, patient showed closure of the communication and complete healing. All the other communications had been solved with Bichat's ball technique, yielding a success rate of 90.9%. Mean patient overall satisfaction was 9.1 out of 10; patients were satisfied with phonetics (9.4), aesthetics (9) and chewing (9). CONCLUSIONS: The buccal fat pad technique was successful in closing 10 out of 11 oroantral communications and few complications were found. Patients were highly satisfied in overall with the treatment and with phonetics, aesthetics and chewing. Key words:Bichat's fat pad, buccal fat pad, oroantral communication. PMID- 25810839 TI - Diagnosis of simulated condylar bone defects using panoramic radiography, spiral tomography and cone-beam computed tomography: A comparison study. AB - OBJECTIVES: Radiographic examination is one of the most important parts of the clinical assessment routine for temporomandibular disorders. The aim of this study was to compare the diagnostic accuracy of cone-beam computed tomography(CBCT) with panoramic radiography and spiral computed tomography for the detection of the simulated mandibular condyle bone lesions. STUDY DESIGN: The sample consisted of 10 TMJs from 5 dried human skulls. Simulated erosive and osteophytic lesions were created in 3 different sizes using round diamond bur and bone chips, respectively. Panoramic radiography, spiral tomography and cone-beam computed tomography were used in defect detection. Data were statistically analyzed with the Mann-Whitney test. The reliability and degrees of agreement between two observers were also determined by the mean of Cohen's Kappa analysis. RESULTS: CBCT had a statistically significant superiority than other studied techniques in detection of both erosive and osteophytic lesions with different sizes. There were significant differences between tomography and panoramic in correct detection of both erosive and osteophytic lesions with 1mm and 1.5 mm in size. However, there were no significant differences between Tomography and Panoramic in correct detection of both erosive and osteophytic lesions with 0.5 mm in size. CONCLUSIONS: CBCT images provide a greater diagnostic accuracy than spiral tomography and panoramic radiography in the detection of condylar bone erosions and osteophytes. Key words:Bone defect, Condyle, CBCT, Panoramic, radiography. PMID- 25810840 TI - A retrospective study of 72 cases diagnosed with idiopathic trigeminal neuralgia in indian populace. AB - CONTEXT: Trigeminal neuralgia is as a chronic, debilitating condition, which can have a major impact on quality of life. There are few reports of trigeminal neuralgia in oriental populations. OBJECTIVES: To evaluate the retrospective data of the patients diagnosed with idiopathic trigeminal neuralgia and to understanding the disorder in the Indian populace. METHODS: The retrospective data of 72 patients with typical idiopathic trigeminal neuralgia regarding age of onset, gender, site of involvement, clinical presentations and treatment received during three years of the follow up was collected and analyzed. RESULTS: In the present retrospective study, the mean age was 54.9 years; female to male ratio was 2.13:1; rural to urban ratio 1.76:1 with 62.5% suffered trigeminal neuralgic pain on the right side. Carbamazepine was found to be highly effective in 60.8% of the cases on long-term basis with maintenance doses. Other treatment modalities were employed in more refractory cases including add-on of gabapentin, which relieved the symptoms for an additional duration of 13+/-3months. The neurolytic alcohol bloc was given in 30% of patients who stopped responding to combination of carbamazepine and gabapentin and relieved pain for a mean duration of 17.25+/-2.95 months. Twenty three percent of the patients (23%) required peripheral neurectomy. CONCLUSIONS: Carbamazepine was found to be highly effective in trigeminal neuralgia. Other treatment modality includes add-on of gabapentin, neurolytic alcohol blocs and peripheral surgical intervention in more refractory cases. Only limited cases needed further neurological consideration. Key words:Trigeminal neuralgia, carbamazepine, gabapentin, alcohol bloc, peripheral neurectomy. PMID- 25810841 TI - Prevalence of xerostomia in patients attending Shorish dental speciality in Sulaimani city. AB - OBJECTIVES: The aim of this study was to investigate the prevalence of xerostomia among dental patients and explore the possible risk factors and symptoms associated with this condition. PATIENT AND METHODS: The prevalence of xerostomia and its associations were investigated among patients (n=1132) who were visiting the department of oral medicine at shorish dental speciality in sulaimani city. The age range was between 10-79 years. 512 (45.2%) of participants were males and 620 (54.8%) were females. The data collected were age, sex, systemic diseases, medications and habit of smoking. Logistic regression models to estimate odds ratios and 95% confidence intervals were used to investigate the association of xerostomia with age, systemic diseases and medications and Chi Square test was also used to analyze the data. RESULTS: Prevalence of xerostomia was 16.07%. Prevalence of xerostomia was significantly higher among females (19.51%) than males (11.91%) (P=0.001). The most common diseases with the highest prevalence of xerostomia were psychological disorders (57.14%) followed by diabetes mellitus (53.84%), neurological disorders (40%), thyroid disorders (37.5%) and hypertension (36.48%). The most common medication with the highest prevalence of xerostomia was antihistamine (66.66%) followed by psychotherapeutic medications (60%), pain medications (55.88%), endocrinologic agents (51.21%), antidyslipidic agents (50%) and antihypertensive medication (38.98%). Xerostomia was significantly associated with ageing (OR: 1.02, P=0.000), systemic diseases (OR: 2.80, P=0.000) and medications (OR: 5.17, P=0.000). There was a high prevalence of reported symptoms of xerostomia and these symptoms were more prevalent among females, Prevalence of xerostomia was higher in heavy smoker patients (19.48%) than non smoker patients but not significantly (16.14%) (p= 0.44). CONCLUSIONS: There was a high prevalence of xerostomia among dental patients; xerostomia was significantly more prevalent among females and significantly associated with age, systemic diseases and medications; xerostomia adversely affects oral functions; dentist must be familial with sign and symptoms of xerostomia and can have an active role in the management of xerostomia and preventing or treating complications. Key words:Ageing, medications, xerostomia, prevalence. PMID- 25810842 TI - Indirect composite restorations luted with two different procedures: A ten years follow up clinical trial. AB - OBJECTIVES: The aim of this clinical trial was to evaluate posterior indirect composite resin restoration ten years after placement luted with two different procedures. STUDY DESIGN: In 23 patients 22 inlays/onlays (Group A) were luted using a dual-cured resin composite cement and 26 inlays/onlays (Group B) were luted using a light cured resin composite for a total of 48 Class I and Class II indirect composite resin inlays and onlays. The restorations were evaluated at 2 time points: 1) one week after placement (baseline evaluation) and 2) ten years after placement using the modified USPHS criteria. The Mann-Whitney and the Wilcoxon tests were used to examine the difference between the results of the baseline and 10 years evaluation for each criteria. RESULTS: Numerical but not statistically significant differences were noted on any of the recorded clinical parameters (p>0.05) between the inlay/onlays of Group A and Group B. 91% and 94 % of Group A and B respectively were rated as clinically acceptable in all the evaluated criteria ten years after clinical function. CONCLUSIONS: Within the limits of the study the results showed after ten years of function a comparable clinical performance of indirect composite resin inlays/onlays placed with a light cure or dual cure luting procedures. Key words:Light curing composite, dual curing composite, indirect composite restoration, inlays/onlays, clinical trial. PMID- 25810843 TI - Cleaning and retreatment protocol for a debonded ceramic restoration. AB - OBJECTIVES: The aim of this article is to propose a resin cement cleaning protocol for use before recementing a debonded restoration. STUDY DESIGN: Ceramic samples were fabricated from IPS d.sign(r) and IPS e.max Press(r) and were treated with hydrofluoric acid etching (HF), or HF+silane (S), or HF+S+adhesive or HF+S+A+resin cement. All samples were placed in a furnace at 650o for one minute in order to attempt to pyrolyze the composite. Each step was examined under scanning electron microscopy (SEM). RESULTS: When the cleaning protocol had been performed, it left a clean and retentive surface. CONCLUSIONS: If the restoration is placed in a furnace at 650o for one minute, the composite cement will burn or pyrolyze and disappear, allowing conventional retreatment of the ceramic before rebonding. Key words:Ceramic, debond, surface treatment. PMID- 25810845 TI - The effect of passive ultrasonic activation of 2% chlorhexidine or 3% sodium hypochlorite in canal wall cleaning. AB - OBJECTIVES: the purpose of this study was to compare debris removal and open tubules effectiveness of sodium hypochlorite (NaOCl) and chlorhexidine (CHX) applied as final irrigation in different protocols Study Design: sixty extracted premolars were divided into six groups according to the final irrigation technique: A and B 3 % NaOCl or 2 % CHX with the Miraject needle and no agitation; C and D, passive ultrasonic irrigation (PUI) with Irrisafe 20 tips and 3 % NaOCl or 2 % CHX; E and F, PUI with Irrisafe 25 tips and 3 % NaOCl or 2% CHX. The remaining dentine debris and opened tubules were evaluated by SEM at three root levels by two blinded investigators. The Kruskal Wallis and the Mann-Whitney U test was used to compare groups and levels, with a significance of p<0.05. RESULTS: Debris elimination was significantly higher in PUI groups (p<0.05). PUI groups showed a higher capability to open tubules, compared to groups A and B. In the coronal third, groups D to F eliminated more debris and opened more tubules than conventional irrigation (p<0.05). In medium third, group E eliminated significantly more debris (1.60) than group A (2.60). No differences were obtained among groups in apical third. Both NaOCl and CHX applied with PUI showed no differences in debris elimination or opened tubules. CONCLUSIONS: Final PUI with Irrisafe tips was the most effective procedure for eliminating the debris and opening up dentinal tubules, independent of the irrigant solution or Irrisafe type size. Key words:Ultrasonic irrigation, PUI, sodium hypochlorite, chlorhexidine. PMID- 25810844 TI - Analgesic and physiological effects in conscious sedation with different nitrous oxide concentrations. AB - OBJECTIVES: to study the physiological changes, as well as the psychosedative and analgesic effects of nitrous oxide, in experimental conditions. STUDY DESIGN: 101 dental students volunteers participated in a single nitrous oxide sedation session without dental treatment. Signs and symptoms were registered during and after the procedure. Pulse rate and hemoglobin oxygen saturation were monitored at: 100 per cent O2, 30 per cent N2O, 50 per cent N2O and 5 minutes after 100 per cent O2. A Likert scale was used to evaluate pain perception. The analgesic effects of nitrous oxide were evaluated at: 30 per cent N2O, 50 per cent N2O, and five minutes postoperatively. RESULTS: Pulse rate and hemoglobin oxygen saturation decreased significantly through all the procedure and after recovery. However, oxygen saturation recovered after the final oxygenation. Only 8.2% of subjects reported the pain stimulus as being quite annoying when they inhaled 30 per cent N2O, while this percentage was of 15.8 % when inhaling 50 per cent N2O, and of 32.7 % during the recovery period. The most common effects of nitrous oxide sedation were bright eyes (99%), voice change (98%) and smiling (91%). Most of the subjects reported tingling (98%) and relax (91.1%) CONCLUSIONS: nitrous oxide causes a significant decrease in heart rate and oxygen saturation, but always within safety limits. Maintaining an appropriate level of consciousness was confirmed as a feature in 50 per cent dose in this study. The analgesic effect of nitrous oxide was confirmed but a dose dependency could not be established. Key words:Nitrous oxide, conscious sedation, anxiolysis, safety, physiogical parameters, signs, symptoms, analgesia. PMID- 25810847 TI - Perceived barriers to the provision of preventive care among dentists of Udaipur, India. AB - AIM: To investigate the practice-, patient- and dentist related barriers to the provision of preventive dental care as perceived by dentists of Udaipur city, Rajasthan, India. SETTINGS AND DESIGN: - A cross sectional descriptive survey was conducted among 120 dentists of Udaipur city, Rajasthan. MATERIAL AND METHODS: Mean Content Validity Ratio (CVR) was calculated as 0.87 based on the opinions expressed by a panel of total six academicians. Cronbach's coefficient was found to be 0.88, which showed a high internal reliability of the questionnaire. The questionnaire consisted of demographic questions and 12 specific research questions. STATISTICAL ANALYSIS USED: - Student's t-test and ANOVA test were applied for the statistical evaluation of means. Level of significance was set at 0.05. RESULTS: The barriers correlated strongly with each other (0.60 to 0.85). A significant gender difference was observed in mean sums of scores of practice and patient related barriers. Practice, dentist and patient related barriers for very much hindrance were reported by 8 to 13%, 5 to19% and 0 to 29% of the dentists respectively. A significant difference was observed among mean of sum scores of practice and patient related barriers with age and experience. Qualification was significantly related to practice related barriers. CONCLUSIONS: Perception of dentists showed that patient related barriers were found to be the foremost to the provision of preventive care. Also, dentist's attitude towards health promotion and disease prevention needs a radical transformation. Key words:Dental care, dentists, patients, perception. PMID- 25810848 TI - Influence of surface preparation on fracture load of resin composite-based repairs. AB - The purpose of the present study is to evaluate the fracture load of composite based repairs to fractured zirconium oxide (Z) crowns and to ceramic-fused-to metal (CM) crowns, comparing different mechanical surface preparation methods. A total of 75 crowns were repaired; samples then underwent dynamic loading and thermocycling. Final fracture load values for failure of the repaired crowns were measured and the type of fracture registered. Group I: CM: Surface preparation with a diamond bur + 9.5% Hydrofluoric Acid (HF) etching; Group II): CM: air particle (Al2O3) + 9.5% HF; Group III: CM: Silica coating (SiO2); Group IV): Z: air-particle (Al2O3) + HF 9.5%; Group V) Z: Silica coating (SiO2). Of the three CM groups, Group I (CM-diamond bur) showed the highest mean failure value, with significant difference in comparison with Group III (CM-silica coating). For the zirconia groups, the highest value was obtained by Group V (silica coating). Key words:Crown, ceramic-fused-to-metal, zirconia, resin-composite, ceramic covering. PMID- 25810846 TI - Prevalence of oral lichen planus among a sample of the Egyptian population. AB - OBJECTIVES: To report on the prevalence of oral lichen planus among a sample of the Egyptian population. STUDY DESIGN: 4470 Egyptian patients, aged 15-75 years, were seen at the outpatient clinic at the Faculty of Oral and Dental Medicine, Cairo University, Egypt. 31.25 % of these patients were males and 68.75% were females. Oral mucosal lesions consistent with oral lichen planus (OLP) were identified both clinically and confirmed histologically (in atypical cases) so that the prevalence of oral lichen planus in this study is 1.43%. RESULTS: 64 patients were diagnosed with OLP (20 males and 44 females). The average age of the affected group was 48.07 years. Associated skin lesions were detected in 15/64 patients (23.44%) and tobacco habits was observed in 20/64 patients (31.25%). The average period of follow-up of the affected cases was 1-2 years, during which two cases developed squamous cell carcinoma of the oral lesion. CONCLUSIONS: Within the limitations of this study it revealed the prevalence of OLP among middle-aged women. Atrophic lesions were most frequent, followed by the erosive forms. Anti-HCV circulating antibodies were more common in patients with OLP and, notably, OLP was associated with Diabetes mellitus in 15.63% of patients. Key words:Prevalence, oral lichen planus, Egypt. PMID- 25810849 TI - A prospective randomized clinical trial compared the effect of various types of local anesthetics cartridges on hypertensive patients during dental extraction. AB - OBJECTIVES: To evaluate hemodynamic changes of blood pressure and heart rate on hypertensive patients undergoing tooth extraction using various types of local anesthesia (LA). STUDY DESIGN: A prospective randomized clinical trial was conducted on 45 hypertensive patients who were divided equally into 3 parallel groups according to LA received. Group 1: Lidociane 2% with epinephrine 1: 80,000. Group 2: Prilocaine 3% with Felypressin 0.03 IU/ml. Group 3: Mepivacaine 3% plain. INCLUSION CRITERIA: hypertensive patients, under medical management with blood pressure <= 159/99. EXCLUSION CRITERIA: Blood pressure >=160 /100 and patients receiving beta blockers. Negative aspiration was mandatory before the injection of 2 cartridges of LA. Blood pressure and heart rate were evaluated by Electronic Sphygmomanometer and Pulse Oximeters in 3 different time-points; 3 minutes before LA, three minutes after LA and three minutes after extraction. RESULTS: The mean of systolic blood pressure (SBP) had increased after LA injection, and then decreased after extraction in the 3 groups of patients. Increase of SBP after extraction with (Mepivacaine plain) was higher than (Lidociane with Epinephrine) and the difference was statistically significant using ANOVA (p=0.037). The differences in the mean heart rates and mean diastolic blood pressures in the 3 groups were not significant. CONCLUSIONS: The increase of blood pressure with Epinephrine and Felypressin is negligible. Therefore, it is safe to use 2 cartridges of Lidociane 2% with Epinephrine 1:80,000 or Prilocaine 3% with Felypressin 0.03 IU/ml for hypertensive patients whose blood pressure <= 159/99 provided negative aspiration is verified before injection. Key words:Local anesthesia, tooth extraction, hypertensive patients, vasoconstrictors, epinephrine, Felypressin. PMID- 25810850 TI - Cemented and screw-retained implant-supported single-tooth restorations in the molar mandibular region: A retrospective comparison study after an observation period of 1 to 4 years. AB - OBJECTIVES: The aim of this study was to evaluate the survival and compare the appearance of different mechanical and biological complications, in screw retained and cemented-retained single-tooth implant-supported restorations localized in the molar mandibular region, over a period of 1 to 4 years. MATERIAL AND METHODS: A retrospective study was carried out with a total of eighty implant supported restorations, which were placed in eighty patients for prosthetic rehabilitation of a mandibular molar. Forty patients were rehabilitated with a cemented-retained restoration and the other forty with a screw-retained restoration. The presence of the following complications was recorded for both types of prostheses: Fractures of the ceramic veneering, loosening screws, mucositis and peri-implantitis. Debonding of the restoration was analyzed in the cemented-retained restoration group. The clinical survival of crowns was analyzed with a Kaplan-Meier test and the clinical complications were compared, using a Student t test and Log-rank test. RESULTS: 27 patients registered some complication. The average rate of complications was 37,5% for cemented-retained restorations and 30% for screw-retained restorations. The complications more common in the cemented-retained restoration were the presence of mucositis (14,87%), while in the screw-retained restorations was the loosening screw (20%). Student t test and Log-Rank test found significant differences (p=0,001) between the screw loosening and presence of mucositis. CONCLUSIONS: The cemented-retained restorations seem to prevent screw loosening, but the presence of cement seem to increase the complications around the soft tissues, however in the screw-retained restorations the presence of mucositis and peri-implantitis are lower than cemented-retained restorations. The incidence of fracture of ceramic veneering was similar in both groups. Key words:Screw-retained restorations, cemented retained restorations, screw loosening, peri-implant diseases and fracture ceramic veneering. PMID- 25810851 TI - Oral mucosal diseases in anxiety and depression patients: Hospital based observational study from south India. AB - OBJECTIVES: The objective of this study was to evaluate the prevalence of different Oral Mucosal diseases in Anxiety and Depression patients. MATERIAL AND METHODS: A hospital based observational Study was conducted in the department of Psychiatry and department of Oral Medicine and Radiology. Patients who were diagnosed with Anxiety or Depression by the psychiatrists using Hamilton Anxiety and Depression scale were subjected to complete oral examination to check for oral diseases like Oral Lichen Planus (OLP), Recurrent Aphthous Stomatitis (RAS), and Burning Mouth Syndrome (BMS). Equal number of control group subjects were also included. RESULTS: In this study statistically significant increase in the oral diseases in patients with anxiety and depression than the control group was recorded. Oral diseases were significantly higher in anxiety patients (20.86%) than in depression (9.04%) and control group patients (5.17%). In anxiety patients, the prevalence of RAS was 12%, OLP was 5.7%, and BMS was 2.87%. In depression patients, the prevalence of RAS was 4.02%, OLP was 2.01% and BMS was 3.01%. In control group the prevalence was 2.2%, 1.33% and 1.62% in RAS, OLP and BMS respectively. RAS and OLP were significantly higher in the younger age group (18-49) and BMS was seen between the age group of 50-77 years in both study and control groups. CONCLUSIONS: The results of the present study showed a positive association between psychological alterations and changes in the oral mucosa, particularly conditions like OLP, RAS and BMS. Thus psychogenic factors like anxiety and depression may act as a risk factor that could influence the initiation and development of oral mucosal diseases. Hence psychological management should be taken into consideration when treating patients with these oral diseases. Key words:Lichen planus, anxiety, depression, burning mouth syndrome, recurrent aphthous stomatitis. PMID- 25810853 TI - Fully Implantable Deep Brain Stimulation System with Wireless Power Transmission for Long-term Use in Rodent Models of Parkinson's Disease. AB - OBJECTIVE: The purpose of this study to develop new deep-brain stimulation system for long-term use in animals, in order to develop a variety of neural prostheses. METHODS: Our system has two distinguished features, which are the fully implanted system having wearable wireless power transfer and ability to change the parameter of stimulus parameter. It is useful for obtaining a variety of data from a long-term experiment. RESULTS: To validate our system, we performed pre clinical test in Parkinson's disease-rat models for 4 weeks. Through the in vivo test, we observed the possibility of not only long-term implantation and stability, but also free movement of animals. We confirmed that the electrical stimulation neither caused any side effect nor damaged the electrodes. CONCLUSION: We proved possibility of our system to conduct the long-term pre clinical test in variety of parameter, which is available for development of neural prostheses. PMID- 25810852 TI - Comparison of the Effects of 13-cis Retinoic Acid and Melatonin on the Viabilities of SH-SY5Y Neuroblastoma Cell Line. AB - OBJECTIVE: Neuroblastoma is one of common childhood tumors. Although its mortality is very high, there is no effective treatment yet. The aim of this project is to evaluate cytotoxic effects of melatonin (MLT) an endogen hormone and 13-cis retinoic acid (13-cis-RA) also named as isotretinoin an analogue of vitamin A on neuroblastoma SH-SY5Y cell line. METHODS: In this study, SH-SY5Y cell line was used. After cell culture, the cells were exposed to different doses of MLT and 13-cis-RA. 24 and 48 hours later. While the viabilities was estimated with MTT cell viability assay test, apoptotic indexes were calculated after staining with TUNEL based apoptosis kit. RESULTS: It was observed that MLT has very effective cytotoxic potential than 13-cis-RA on neuroblastoma cell line. At the same time, when MLT and 13-cis-RA were combined, this effect was potentiated. On the other hand, it was found that the effect of 13-cis-RA individually on neuroblastoma cells was very slight. CONCLUSION: We suggest that in the treatment of patient with neuroblastoma, MLT is very effective and also this effect can be augmented by combination with 13-cis-RA. PMID- 25810854 TI - Endovascular Treatment of 429 Anterior Communicating Artery Aneurysms Using Bare Platinum Coils : Clinical and Radiologic Outcomes at the Long-term Follow-up. AB - OBJECTIVE: We reviewed the feasibility, safety and efficacy as well as the clinical outcome and long-term angiographic results of endovascular treatment (EVT) of the anterior communicating artery (ACoA) aneurysms. METHODS: A total of 429 ACoA aneurysms in 426 patients were treated using coil embolization between March 1996 and October 2010 in a single institution. Pretreatment aneurysmal features were checked using angiogram. We had usually used tailored steam shaped microcatheter according to individual angiographic architectures. Immediate postembolization outcomes were evaluated using an angiographic outcome scale and clinical evaluation was performed using the Glasgow Outcome Scale (GOS). RESULTS: Postembolization angiograms demonstrated total occlusion of aneurysm in 290 of 429 (67.6%) aneurysms, neck remnant in 80 (18.6%) and body filling in 59 (13.8%). Dome direction and aneurysm angle was not associated with initial angiographic outcomes. The procedure-related morbidity rate was 0.9% (4 of 429). Clinical and imaging follow-up more than 6 months were available in 382 (89.0%) patients with a mean of 26.2 months. Overall rate of major recanalization was 7.9% (30 of 382) and all of them were retreated without complications. At the last follow-up, 233 (99.2%) of 235 patients had GOS of 5 in unruptured group, and 152 (79.5%) of 191 patients showed good clinical outcomes (GOS of 4 or 5) in ruptured group. CONCLUSION: Tailored steam shaping of the microcatheter is vital to achieve good angiographic outcomes regardless of aneurysmal direction. EVT is feasible and safe for most ACoA aneurysms with acceptable immediate and long-term outcomes. PMID- 25810855 TI - The effectiveness of lumbar cerebrospinal fluid drainage to reduce the cerebral vasospasm after surgical clipping for aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Removal of blood from subarachnoid space with a lumbar drainage (LD) may decrease development of cerebral vasospasm. We evaluated the effectiveness of a LD for a clinical vasospasm and outcomes after clipping of aneurysmal subarachnoid hemorrhage (SAH). METHODS: Between July 2008 and July 2013, 234 patients were included in this study. The LD group consisted of 126 patients, 108 patients in the non LD group. We investigated outcomes as follow : 1) clinical vasospasm, 2) angioplasty, 3) cerebral infarction, 4) Glasgow outcome scale (GOS) score at discharge, 5) GOS score at 6-month follow-up, and 6) mortality. RESULTS: Clinical vasospasm occurred in 19% of the LD group and 42% of the non LD group (p<0.001). Angioplasty was performed in 17% of the LD group and 38% of the non LD group (p=0.001). Cerebral infarctions were detected in 29% and 54% of each group respectively (p<0.001). The proportion of GOS score 5 at 6 month follow-up in the LD group was 69%, and it was 58% in the non LD group (p=0.001). Mortality rate showed 5% and 10% in each group respectively. But, there was no difference in shunt between the two groups. CONCLUSION: LD after aneurysmal SAH shows marked reduction of clinical vasospasm and need for angioplasty. With this technique we have shown favorable GOS score at 6 month follow-up. PMID- 25810856 TI - Applicability of thoracolumbar injury classification and severity score to criteria of korean health insurance review and assessment service in treatment decision of thoracolumbar injury. AB - OBJECTIVE: For improving the drawbacks of previous thoracolumbar spine trauma classification, the Spine Trauma Study Group was developed new classification, Thoracolumbar Injury Classification and Severity Score (TLICS). The simplicity of this scoring system makes it useful clinical application. However, considering criteria of Korean Health Insurance Review and Assessment Service (HIRA), the usefulness of TLICS system is still controversial in the treatment decision of thoracolumbar spine injury. METHODS: Total 100 patients, who admitted to our hospital due to acute traumatic thoracolumbar injury, were enrolled. In 45, surgical treatment was performed and surgical treatment was decided following the criteria of HIRA in all patients. With assessing of TLICS score and Denis's classification, the treatment guidelines of TLICS and Denis's classification were applied to the criteria of Korean HIRA. RESULTS: According to the Denis's three column spine system, numbers of patients with 2 or 3 column injuries were 94. Only 45 of 94 patients (47.9%) with middle column injury fulfilled the criteria of HIRA. According to TLICS system, operation required fractures (score>4) were 31 and all patients except one fulfilled the criteria of HIRA. Conservative treatment required fractures (score<4) were 52 and borderline fracture (score=4) were 17. CONCLUSION: The TLICS system is very useful system for decision of surgical indication in acute traumatic thoracolumbar injury. However, the decision of treatment in TLICS score 4 should be carefully considered. Furthermore, definite criteria of posterior ligamentous complex (PLC) injury may be necessary because the differentiation of PLC injury between TLICS score 2 and 3 is very difficult. PMID- 25810857 TI - Retrolisthesis as a compensatory mechanism in degenerative lumbar spine. AB - OBJECTIVE: Posterior vertebral translation as a type of spondylolisthesis, retrolisthesis is observed commonly in patients with degenerative spinal problems. Nevertheless, there is insufficient literature on retrolisthesis compared to anterolisthesis. The purpose of this study is to clarify the clinical features of retrolisthesis, and its developmental mechanism associated with a compensatory role in sagittal imbalance of the lumbar spine. METHODS: From 2003 to 2012, 230 Korean patients who underwent spinal surgery in our department under the impression of degenerative lumbar spinal disease were enrolled. All participants were divided into four groups : 35 patients with retrolisthesis (group R), 32 patients with simultaneous retrolisthesis and anterolisthesis (group R+A), 76 patients with anterolisthesis (group A), and 87 patients with non translation (group N). The clinical features and the sagittal parameters related to retrolisthesis were retrospectively analyzed based on the patients' medical records. RESULTS: There were different clinical features and developmental mechanisms between retrolisthesis and anterolisthesis. The location of retrolisthesis was affected by the presence of simultaneous anterolisthesis, even though it predominantly manifest in L3. The relative lower pelvic incidence, pelvic tilt, and lumbar lordosis compared to anterolisthesis were related to the generation of retrolisthesis, with the opposite observations of patients with anterolisthesis. CONCLUSION: Retrolisthesis acts as a compensatory mechanism for moving the gravity axis posteriorly for sagittal imbalance in the lumbar spine under low pelvic incidence and insufficient intra-spinal compensation. PMID- 25810858 TI - Quantification of pediatric cervical growth: anatomical changes in the sub-axial spine. AB - OBJECTIVE: In order to provide normal values of the pediatric sub-axial cervical spinal canal and vertebral body growth pattern using computed tomographic scans, a total of 318 patients less than 10 years old were included. METHODS: The growth of the vertebral body and canal space was investigated using four different age groups. The Torg ratio (TR) was calculated and all patients were classified into a low TR group and a high TR group according to a cutoff value of 1.0. To account for spinal curvature, the C3-7 angle was measured. RESULTS: Very little axial expansion and growth in height were observed (2.9 mm and 3.4 mm, respectively), and the spinal canal increments (1.8 mm) were much smaller than the dimensions of the vertebral body. The mean TR values were 1.03+/-0.14 at the C3 vertebral level, 1.02+/-0.13 at C4, 1.05+/-0.13 at C5, 1.04+/-0.13 at C6, and 1.02+/-0.12 at C7 in all patients. The mean sub-axial angle (C3-7) was 7.9+/-10.6 degrees (range: -17-47 degrees ). CONCLUSION: The upper sub-axial spinal canal continuously increased in size compared to the lower sub-axial spine after 8 years of age. Considerable decrements in the TR was found after late childhood compared to younger ages. Generally, there were no significant differences between boys and girls in vertical length of the cervical vertebrae. However, the axial dimension of the vertebral body and the spinal canal space varied according to gender. PMID- 25810860 TI - The effects of propofol and thiopental continuous infusion on serum potassium disturbances in neurosurgical patients. AB - OBJECTIVE: The potassium disturbance associated with thiopental continuous infusion in neurosurgical patients is well known. However, the effect of propofol continuous infusion on serum potassium levels has not been investigated extensively. METHODS: We reviewed the medical records of 60 consecutive patients who received coma therapy or deep sedation for intracranial pressure control using either thiopental or propofol between January 2010 and January 2012. RESULTS: The overall incidence of hypokalemia (K<3.5 mmol/L) was comparable between thiopental and propofol groups (89.2% vs. 82.6%). But, the incidence of moderate to severe hypokalemia (K<3.0 mmol/L) was significantly higher in thiopental group (51.4% vs. 13.0%, p=0.003). The lowest potassium level (2.9 mmol/L vs. 3.2 mmol/L, p=0.020) was lower in thiopental group. The patients in the thiopental group required greater potassium replacement than the propofol group patients (0.08 mmol/kg/h vs. 0.02 mmol/kg/h, p<0.001). On multivariate analysis, thiopental [odds ratio, 95% confidence interval, 7.31 (1.78-27.81); p=0.005] was associated with moderate to severe hypokalemia during continuous infusion. The incidence of rebound hyperkalemia (K>5.0 mmol/L, 32.4% vs. 4.3%, p=0.010) and the peak potassium concentration (4.8 mmol/L vs. 4.2 mmol/L, p=0.037) after the cessation of therapy were higher in thiopental group. On multivariate analysis, thiopental [8.82 (1.00-77.81); p=0.049] and duration of continuous infusion [1.02 (1.00-1.04); p=0.016] were associated with rebound hyperkalemia once therapy was discontinued. CONCLUSION: Propofol was less frequently associated with moderate to severe hypokalemia after induction and rebound hyperkalemia following the cessation of continuous infusion than thiopental. PMID- 25810859 TI - Outcome of gamma knife thalamotomy in patients with an intractable tremor. AB - OBJECTIVE: Tremor is a common movement disorder that interferes with daily living. Since the medication for tremor has some limitations, surgical intervention is needed in many patients. In certain patients who cannot undergo aggressive surgical intervention, Gamma Knife thalamotomy (GKT) is a safe and effective alternative. METHODS: From June 2012 to August 2013, 7 patients with an intractable tremor underwent GKT. Four of these 7 patients had medical comorbidities, and 3 patients refused to undergo traditional surgery. Each patient was evaluated with the modified Fahn-Tolosa-Marin tremor rating scale (TRS) along with analysis of handwriting samples. All of the patients underwent GKT with a maximal dose of 130 Gy to the left ventralis intermedius (VIM) nucleus of the thalamus. Follow-up brain MRI was performed after 3 to 8 months of GKT, and evaluation with the TRS was also performed. RESULTS: Six patients showed objective improvement in the TRS score. Excluding one patient who demonstrated tremor progression, there was 28.9% improvement in the TRS score. However, five patients showed subjective improvement in their symptoms. On comparing the TRS scores between follow-up periods of more and less than 4 months, the follow-up TRS score at more than 4 months of GKT was significantly improved compared to that at less than 4 months of GKT. Follow-up MRI showed radiosurgical changes in 5 patients. CONCLUSION: GKT with a maximal dose of 130 Gy to the VIM is a safe procedure that can replace other surgical procedures. PMID- 25810861 TI - A case of dural arteriovenous fistula of superior sagittal sinus after tamoxifen treatment for breast cancer. AB - We are reporting an unusual case of dural arteriovenous fistula (AVF) of the superior sagittal sinus (SSS) after tamoxifen treatment for breast cancer. A 30 year-old female arrived at the emergency room with a sudden headache and left sided weakness and sensory loss. In her past medical history, she was diagnosed with breast cancer 1 year prior, and subsequently underwent a breast conserving mastectomy with whole breast radiation and adjuvant chemotherapy with tamoxifen. At the time of admission, computed tomography showed a small acute intracerebral hemorrhage at the right parietal cortex, and magnetic resonance imaging showed that a dural AVF at the SSS with a prominent and tortuous venous enhancement along the centrum semiovale was present. Cerebral angiography showed that the dural AVF at the mid-portion of the SSS with meningeal arterial feeding vessels entering the wall of the SSS, then draining through the dilated cortical veins. Our patient had no signs of active malignancy or any abnormalities in her coagulation profile, so it can be concluded that the tamoxifen was the likely cause of the SSS thrombosis and dural AVF. The dural AVF was treated by an endovascular coil embolization for the arterialized segment of the SSS. The patient dramatically recovered favorably from left side motor and sensory deficit. The best clinical approach is to screen potential patients of tamoxifen hormonal therapy and educate them on the sign and symptoms of life threatening thromboembolic events while taking tamoxifen. PMID- 25810862 TI - Sixth cranial nerve palsy caused by gastric adenocarcinoma metastasis to the clivus. AB - Tumors of the clivus and metastases to the clivus are very rare. Metastasis involving the clivus has previously been described in only two case reports. In skull metastasis, the breast and prostate are the most common primary foci, while metastasis from gastric carcinoma is extremely rare. A review of the English literature revealed only one published case of clivus metastases from gastric adenocarcinoma. There is no literature thoroughly explaining the differential diagnosis between chordoma and metastasis. Here we report a rare case of metastasis to the clivus from a gastric adenocarcinoma in a 42-year-old female patient with sudden blurry vision, presenting as bilateral cranial nerve VI palsy. PMID- 25810863 TI - A malignant transformation of a spinal epidural mass from ganglioneuroblastoma to neuroblastoma. AB - Ganglioneuromas are benign tumors. Surgical excision is the treatment of choice with very good prognosis. However, neuroblastomatous malignant transformation of ganglioneuromas was previously reported. We report a patient with spinal neuroblastoma recurrent from a ganglioneuroblastoma after disease free survival of 13 years. This is one of the rare examples of spinal neuroblastoma and to our knowledge the second case report with malignant transformation from a ganglioneuroblastoma or a ganglioneuroma. The present case is the only report in the literature with further genetic investigations. PMID- 25810864 TI - Delayed diagnosis of probable radiation induced spinal cord vascular disorders. AB - Occasionally, unexpected neurological deficits occur after lumbar spinal surgery. We report a case of monoparesis after lumbar decompressive surgery. A 63-year-old man, who had undergone decompression of L4-5 for spinal stenosis 4 days previously in the other hospital, visted the emergency department with progressive weakness in the left leg and hypoesthesia below sensory level T7 on the right side. He had been cured of lung cancer with chemotherapy and radiation therapy 10 years previously, but detailed information of radiotherapy was not available. Whole spine magnetic resonance (MR) imaging showed fatty marrow change from T1 to T8, most likely due to previous irradiation. The T2-weighted MR image showed a high-signal T4-5 spinal cord lesion surrounded by a low signal rim, and the T1-weighted MR image showed focal high signal intensity with focal enhancement. The radiological diagnosis was vascular disorders with suspicious bleeding. Surgical removal was refused by the patient. With rehabilitation, the patient could walk independently without assistance 2 months later. Considering radiation induced change at thoracic vertebrae, vascular disorders may be induced by irradiation. If the spinal cord was previously irradiated, radiation induced vascular disorders needs to be considered. PMID- 25810865 TI - Anatomic variation of the common palmar digital nerves and arteries. AB - Variations in the course and distribution of common palmar digital nerves and arteries are rare. A classic common palmar digital nerves and arteries are defined as concomitant. During routine dissection classes to undergraduate medical students we observed formation of each common palmar digital nerve divided into 2 or 3 branches and formed a ring enclosing the corresponding common palmar digital artery. Knowledge of the anatomical variations of the common palmar digital nerves and arteries is crucial for safe and successful hand surgery. PMID- 25810866 TI - A case of hemifacial spasm caused by an artery passing through the facial nerve. AB - Hemifacial spasm (HFS) is a clinical syndrome characterized by unilateral facial nerve dysfunction. The usual cause involves vascular compression of the seventh cranial nerve, but compression by an artery passing through the facial nerve is very unusual. A 20-year-old man presented with left facial spasm that had persisted for 4 years. Compression of the left facial nerve root exit zone by the anterior inferior cerebellar artery (AICA) was revealed on magnetic resonance angiography. During microvascular decompression surgery, penetration of the distal portion of the facial nerve root exit zone by the AICA was observed. At the penetrating site, the artery was found to have compressed the facial nerve and to be immobilized. The penetrated seventh cranial nerve was longitudinally split about 2 mm. The compressing artery was moved away from the penetrating site and the decompression was secured by inserting Teflon at the operative site. Although the facial spasm disappeared in the immediate postoperative period, the patient continued to show moderate facial weakness. At postoperative 12 months, the facial weakness had improved to a mild degree. Prior to performing microvascular decompression of HFS, surgeons should be aware of a possibility for rare complex anatomy, such as compression by an artery passing through the facial nerve, which cannot be observed by modern imaging techniques. PMID- 25810867 TI - Catastrophic intramedullary abscess caused by a missed congenital dermal sinus. AB - Congenital dermal sinus (CDS) is a type of occult spinal dysraphism characterized by a midline skin dimple. A 12-month-old girl presented with fever and ascending quadriparesis. She had a midline skin dimple in the upper sacral area that had been discovered in her neonatal period. Imaging studies revealed a holocord intramedullary abscess and CDS. Overlooking CDS or misdiagnosing it as benign sacrococcygeal dimple may lead to catastrophic infection and cause serious neurological deficits. Therefore, further imaging work-up or consultation with a pediatric neurosurgeon is recommended following discovery of any atypical-looking dimples in the midline. PMID- 25810868 TI - Iranian journal of basic medical sciences: 2014 in profile. PMID- 25810869 TI - Helicobacter pylori in Iran: A systematic review on the antibiotic resistance. AB - OBJECTIVES: Helicobacter pylori (H. pylori) is a pathogenic bacterium that colonizes the stomachs of approximately 50% of the world's population. Resistance of H. pylori to antibiotics is considered as the main reason for the failure to eradicate this bacterium. The aim of this study was to determine the rate of resistant H. pylori strains to various antimicrobial agents in different areas of Iran. MATERIALS AND METHODS: A systematic review of literatures on H. pylori antibiotic resistance in Iran was performed within the time span of 1997 to 2013. Data obtained from various studies were tabulated as following, 1) year of research and number strains tested, 2) number of H. pylori positive patients, 3) study place, 4) resistance of H. pylori to various antibiotics as percentage, and 5) methods used for evaluation of antibiotic resistance. RESULTS: Over the period, a total of 21 studies on H. pylori antibiotic resistance have been conducted in different parts of Iran. In these studies, H. pylori resistance to various antibiotics, including metronidazole, clarithromycin, amoxicillin, tetracycline, ciprofloxacin, levofloxacin and furazolidone were 61.6%, 22.4%, 16.0%, 12.2%, 21.0%, 5.3% and 21.6%, respectively. We found no study on H. pylori resistance to rifabutin in Iran. CONCLUSION: Compared to the global average, we noted that the prevalence of H. pylori resistance to metronidazole, clarithromycin, amoxicillin, and tetracycline has been rapidly growing in Iran. This study showed that in order to determine an appropriate drug regimen against H. pylori, information on antibiotic susceptibility of the bacterium within different geographical areas of Iran is required. PMID- 25810870 TI - Apoptotic and proliferative activity of mouse gastric mucosa following oral administration of fumonisin B1. AB - OBJECTIVES: Fumonisins are a group of toxic and carcinogenic mycotoxins, which contaminate the grains and their products. The aim of this study was to examine the apoptotic and proliferative activity of mouse gastric mucosa following administration of fumonisin B1 (FB1). MATERIALS AND METHODS: Twenty-nine female mice divided into treatment (n=15) and control (n=14) groups. The treatment group received FB1 (150 mg/kg diet) for 16 weeks. The gastric atrophy was allocated using grading criteria modeled on the updated Sydney System. Immunohistochemistry studies were performed for evaluation of apoptosis and proliferative activity in gastric mucosa. RESULTS: Mild to moderate gastric atrophy were observed in microscopic findings of the gastric mucosa in treated animals (P<0.05). Number of parietal cells significantly decreased in the treatment group in comparison with the control (P<0.05). Treatment with FB1 for 16 weeks significantly reduced both gastric mucosa height and mitotic index in the gastric glands (P<0.05). TUNEL- and Bax-labeled positive cell numbers significantly increased in the FB1-treated group compared to the control (P<0.05). In addition, proliferative activity of gastric glands in the treated group was significantly lower than the control (P<0.05). CONCLUSION: Oral administration of FB1 caused atrophy in gastric mucosa both via increasing of apoptosis and suppressing the mitotic activity of these cells. PMID- 25810871 TI - Role of morphine preconditioning and nitric oxide following brain ischemia reperfusion injury in mice. AB - OBJECTIVES: Morphine dependence (MD) potently protects heart against ischemia reperfusion (IR) injury through specific signaling mechanisms, which are different from the pathways involved in acute morphine treatment or classical preconditioning. Since opioid receptor density changes post cerebral ischemia strongly correlated with brain histological damage, in the present study, we tried to elucidate the possible role of opioid receptors in IR injury among morphine-dependent mice. MATERIALS AND METHODS: Accordingly, incremental doses (10 mg/kg/day to 30 mg/kg/day) of morphine sulphate were subcutaneously administered for 5 days before global brain ischemia induction through bilateral common carotid artery occlusion. Animals were received naloxone (5 mg/kg) or L NAME (20 mg/kg) 30 min after the last morphine dose. Twenty four hr after the ischemia induction, Retention trial of passive avoidance test and western blot analysis were done. histological analysis (TUNEL and NISSL staining) performed 72 hr after ischemia. RESULTS: MD improved post ischemia memory performance (P<0.01) and neuronal survival (P<0.001) and decreased apoptosis (P<0.05) in region I of hippocampus (CA1 region) in mouse. Treatment with naloxone or L-NAME abolished all MD aforementioned effects. CONCLUSION: Results of the present study suggested that opioid receptors activation in the early hr post ischemia is crucial for MD induced hippocampus tolerance against IR injury. Opioid receptor-dependent balance of NO production was another key factor in MD-induced protection. Further studies are required to determine the effect of MD on opioid receptor changes after ischemia and its correlation with MD-induced protection. PMID- 25810872 TI - Human Wharton's jelly-derived mesenchymal stem cells express oocyte developmental genes during co-culture with placental cells. AB - OBJECTIVES: The present day challenge is how to obtain germ cells from stem cells to treat patients with cancer and infertility. Much more efforts have been made to develop a procedure for attaining germ cells in vitro. Recently, human umbilical cord-derived mesenchymal stem cells (HUMSCs) have been introduced with higher efficacy for differentiation. In this work, we tried to explore the efficacy of HUMSCs and some effective products of placental cells such as transforming growth factors. This study is aimed to optimize a co-culture condition for HUMSCs with placental cells to obtain primordial germ cells (PGCs) and reach into oocyte-like cells in vitro. MATERIALS AND METHODS: In this experimental study, HUMSCs and placental cells were co-cultured for 14 days without any external inducer in vitro. Then HUMSCs were assessed for expression of PGC markers; Octamer-binding transcription factor 4(OCT4), Tyrosine-protein kinase Kit (CKIT), Stage specific embryonic antigen 4 (SSEA4), DEAD (Asp-Glu-Ala Asp) box polypeptide 4(DDX4) and oocyte specific markers; Growth differentiation factor-9(GDF9), Zona pellucida glycoprotein 3(ZP3). The pertinent markers were assessed by immunocytochemistry and Q-PCR. RESULTS: Co-cultured HUMSCs with placental cells (including amniotic and chorionic cells) presented Oct4 and DDX4, primordial germ cells specific markers significantly, but increment in expression of oocyte-like cell specific markers, GDF9 and ZP3 did not reach to statistically significant threshold. CONCLUSION: Placental cell supplements Transforming growth factor (TGF alpha, beta) and basic fibroblast growth factor (bFGF) in a co culture model can provide proper environment for induction of HUMSCs into PGCs and expression of oocyte-like markers. PMID- 25810873 TI - The congruence between matrilineal genetic (mtDNA) and geographic diversity of Iranians and the territorial populations. AB - OBJECTIVES: From the ancient era, emergence of Agriculture in the connecting region of Mesopotamia and the Iranian plateau at the foothills of the Zagros Mountains, made Iranian gene pool as an important source of populating the region. It has differentiated the population spread and different language groups. In order to trace the maternal genetic affinity between Iranians and other populations of the area and to establish the place of Iranians in a broad framework of ethnically and linguistically diverse groups of Middle Eastern and South Asian populations, a comparative study of territorial groups was designed and used in the population statistical analysis. MATERIALS AND METHODS: Mix of 616 samples was sequenced for complete mtDNA or hyper variable regions in this study. A published dataset of neighboring populations was used as a comparison in the Iranian matrilineal lineage study based on mtDNA haplogroups. RESULTS: Statistical analyses data, demonstrate a close genetic structure of all Iranian populations, thus suggesting their origin from a common maternal ancestral gene pool and show that the diverse maternal genetic structure does not reflect population differentiation in the region in their language. CONCLUSION: In the aggregate of the eastward spreads of proto-Elamo-Dravidian language from the Southwest region of Iran, the Elam province, a reasonable degree of homogeneity has been observed among Iranians in this study. The approach will facilitate our perception of the more detailed relationship of the ethnic groups living in Iran with the other ancient peoples of the area, testing linguistic hypothesis and population movements. PMID- 25810874 TI - Ellagic acid improves hyperalgesia and cognitive deficiency in 6-hydroxidopamine induced rat model of Parkinson's disease. AB - OBJECTIVES: Parkinson's disease (PD) is known for motor impairments. But often, there are non-motor symptoms such as cognitive deficiency and pain misperception, owing to possible role of nigrostriatal pathway. Antioxidants have protective effect on free radical-induced neuronal damage in PD. To further address, we examined the effects of ellagic acid (EA) in a rat model of PD induced by 6 hydroxidopamine (6-OHDA). MATERIALS AND METHODS: Right medial forebrain bundle (MFB) was lesioned by injecting 6-OHDA (16 ug/2 ul), in PD-animals. Sham operated animals received vehicle instead of 6-OHDA. PD was approved by apomorphine induced contralateral rotation. EA (50 mg/kg/2 ml, PO, for 10 days) was administered to PD-EA group. Some PD-animals received pramipexole (PPX; 2 mg/kg/2 ml, PO) as a positive control group. Analgesia was measured by tail-flick and hot plate tests. Passive avoidance task was measured by shuttle box apparatus to record the initial and step-through latency. Spatial cognition task was evaluated by Morris water maze test, measuring the escape latency time, path length, swimming speed and time spent in target quadrant. RESULTS: MFB-lesioned rats showed hyperalgesic responses to the stimulus in tail-flick and hot-plate tests. Also they showed memory and learning deficit in cognitive tests. These effects reversed by EA treatment. CONCLUSION: 6-OHDA can induce oxidative stress and can disrupt the neural mechanisms underlying proper integration of painful stimuli and cognitive processes in MFB-lesioned rats. Consequently, nigrostriatal pathway can play possible role in nociception and cognition. EA, a natural antioxidant, has neuroprotective effect on this pathway and can ameliorate this defect and be considered in PD management. PMID- 25810875 TI - In silico and in vitro studies of cytotoxic activity of different peptides derived from vesicular stomatitis virus G protein. AB - OBJECTIVES: This study aims at exploring cytotoxic activity of different peptides derived from VSVG protein against MCF-7 and MDA-MB-231 breast cancer cell lines and human embryonic kidney normal cell (HEK 293). MATERIALS AND METHODS: The ANTICP web server was used to predict anticancer peptides. The cytotoxic activity of peptides with high score (P26, P7) and low score (P19) was examined by MTT and DNA fragmentation assays. RESULTS: The results obtained from ANTICP web server demonstrated that 4 out of 48 peptides (P26, P7, P10, and P16) had anticancer activity. P26 and P7 peptides of these 4 peptides were detected to have high cytotoxic activity against MCF-7 cells with CC50 values of 98,280 ug/ml and MDA MB231 cells with CC50 100,550 ug/ml, respectively. In addition, the results showed that amino acid residues of these 4 peptides were located near fusion domain. CONCLUSION: The results confirmed that P26 and P7 peptides might induce membrane damage and initiate apoptosis. The present study suggested that P26 and P7 peptides could be appropriate candidates for further studies as cytotoxic agents and modifications in the residue at positions 70-280 might potentially produce a more efficient VSVG protein in gene therapy. PMID- 25810877 TI - Safranal-loaded solid lipid nanoparticles: evaluation of sunscreen and moisturizing potential for topical applications. AB - OBJECTIVES: In the current study, sunscreen and moisturizing properties of solid lipid nanoparticle (SLN)-safranal formulations were evaluated. MATERIALS AND METHODS: Series of SLN were prepared using glyceryl monostearate, Tween 80 and different amounts of safranal by high shear homogenization, and ultrasound and high-pressure homogenization (HPH) methods. SLN formulations were characterized for size, zeta potential, morphology, thermal properties, and encapsulation efficacy. The Sun Protection Factor (SPF) of the products was determined in vitro using transpore tape. The moisturizing activity of the products was also evaluated by corneometer. RESULTS: The SPF of SLN-safranal formulations was increased when the amount of safranal increased. Mean particle size for all formulas was approximately 106 nm by probe sonication and 233 nm using HPH method. The encapsulation efficiency of safranal was around 70% for all SLN safranal formulations. CONCLUSION: The results conclude that SLN-safranal formulations were found to be effective for topical delivery of safranal and succeeded in providing appropriate sunscreen properties. PMID- 25810876 TI - MEFV mutations in Northwest of Iran: a cross sectional study. AB - OBJECTIVES: Familial Mediterranean Fever (FMF) is an autosomal recessive disorder characterized by recurrent episodes of fever accompanied by peritonitis, pleurisy, and arthritis. FMF affects mainly Mediterranean populations and is caused by mutations in the familial Mediterranean fever (MEFV) gene. The aim of this study was to identify the frequency and distribution of MEFV mutations in Iranian Azerbaijanis with FMF. MATERIALS AND METHODS: Medical records of 1330 Iranian Azerbaijanis who were diagnosed with FMF according to Tel-Hashomer criteria from May 2006 to April 2013 were reviewed and 10 MEFV mutations were found in affected individuals. RESULTS: 243 patients (18.27%) were homozygous, 370 (27.82%) were compound heterozygous and 717 (53.91%) were identified as heterozygous for one of the studied mutations. Of the studied mutations, M694V, E148Q, V726A, M680I, and M694I accounted for 42%, 21%, 19%, 14% and 2% of mutations respectively. CONCLUSION: In our study, M694V was found to be the most prevalent mutation. M694I, the most common mutation among Arabs, is rare in this cohort. Allele frequencies of the common mutations in our studied population have some similarities to those of the Turkish population reported previously. However, M680I is less common in our cohort. PMID- 25810878 TI - Experimental therapeutic studies of Solanum aculeastrum Dunal. on Leishmania major infection in BALB/c mice. AB - OBJECTIVES: Solanum acueastrum Dunal. has been shown to have some chemotherapeutic value. Leaf and berry water and methanol compounds of S. acueastrum were evaluated for possible antileishmanial activity In vivo on BALB/c mice and in vitro against Leishmania major promastigotes, amastigotes and vero cells. MATERIALS AND METHODS: Dry S. aculeastrum berry and leaf material were extracted in methanol and water. L. major parasites were exposed to different concentrations of S. aculeastrum fruit and leaf compounds and the IC50 on the promastigotes, percentage of infection rate of macrophages by amastigotes and the toxicological effect on vero cells were determined. BALB/c mice were infected subcutaneously with 1*10(6) promastigotes and kept for four weeks to allow for disease establishment. Infected mice were treated with fruit and leaf methanolic and water compounds, amphotericin B (AmB), and sterile phosphate buffered saline (PBS). RESULTS: Fruit methanol compound was most effective in inhibiting the growth of promastigotes with IC5078.62 MUg/ml. Fruit water compound showed the best activity in inhibiting infection of macrophages by amastigotes. Fruit methanol compound was more toxic at Ld50=8.06 mg/ml to vero cells than amphotericin B. Analysis of variance computation indicated statistically significant difference in lesion sizes between experimental and control mice groups (P=0.0001). Splenic impression smears ANOVA indicated a highly significant difference in parasitic numbers between the experimental and the control groups (P=0.0001). CONCLUSION: The results demonstrate that compounds from S. aculeastrum have potential anti-leishmanial activities and the medicinal use of the plant poses considerable toxicity against dividing vero cells. PMID- 25810879 TI - Microinjection of calcitonin in midbrain periaqueductal gray attenuates hyperalgesia in a chronic constriction injury rat model. AB - OBJECTIVES: As heat, pain is one of the most common clinical symptoms. Generally, calcitonin (CT) is prescribed as an analgesic agent for the treatment of pain, especially for the pain caused by osteoporosis or primary and metastatic bone tumor. However, the detailed mechanism remains unknown. MATERIALS AND METHODS: In this study, chronic constriction injury (CCI) rat model was created, and hot plate test and von frey filaments test were employed to evaluate thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT), respectively. Immunohistochemistry staining and western blot analyses were used to assess the distribution and expression of calcitonin receptor (CT-R) in the midbrain periaqueductal gray (PAG), which was a pivotal site in the modulatory system for the endogenous pain. RESULTS: The TWL and MWT before the surgery (19.6+/-1.19 sec) were significantly longer than that at day 2 (12.5+/-1.60 sec), and day 14 (7.75+/-0.89 sec) (P< 0.01; P< 0.01), respectively. The TWL and MWT at day 14 were significantly increased compared to that at day 7 after microinjection of salmon calcitonin (sCT) with different doses. Interestingly, the expression of CT R was up-regulated in neuropathic pain. Furthermore, the expression of CT-R was significantly up-regulated and algesia was remarkably relieved when CT was microinjected into PAG. CONCLUSION: These results suggested that an increased CT R might be associated with hyperalgesia in CCI rat, and CT had a potent antinociceptive effect by the up-regulation of CT-R in the PAG. Thus, it might provide a potential approach for the treatment of bone pain. PMID- 25810882 TI - Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats. AB - OBJECTIVES: Therapies with high levels of oxygen are commonly used in the management of critical care. However, prolonged exposure to hyperoxia can cause acute lung injury. Although oxidative stress and inflammation are purported to play an important role in the pathogenesis of acute lung injury, the exact mechanisms are still less known in the hyperoxic acute lung injury (HALI). MATERIALS AND METHODS: In this study, we investigated the time course changes of oxidative stress and inflammation in lung tissues of rats exposed to >95% oxygen for 12-60 hr. RESULTS: We found that at 12 hr after hyperoxia challenge, the activities of superoxide dismutase and glutathione peroxidase were significantly reduced with remarkably increased lipid peroxidation. At 12 hr, NF-kappaB p65 expression was also upregulated, but Ikappa-Balpha expression showed a remarkable decline. Significant production of inflammatory mediators, e.g, interleukin 1beta, occurred 24 hr after hyperoxia exposure. In addition, the expression of intracellular adhesion molecule 1 expression and the activity of myeloperoxidase were significantly increased at 24 hr with a peak at 48 hr. CONCLUSION: Our data support that hyperoxia-induced oxidative damage and NF-kappaB pathway activation implicate in the early phase of HALI pathogenesis. PMID- 25810880 TI - Liver ischemia preconditions the heart against ischemia-reperfusion arrhythmias. AB - OBJECTIVES: This study aimed to examine the hypothesis that an antiarrhythmic effect might be obtained by ischemic preconditioning of the liver, and also to characterize the potential underlying mechanisms. MATERIALS AND METHODS: Male Wistar rats were anesthetized by thiopental sodium (50 mg/kg, IP) followed by IV injection of heparin (250 IU). Remote ischemic preconditioning (RIPC) was induced by 3 cycles of 5 min liver ischemia followed by 5 min of reperfusion. The hearts were excised within 5 min after the final cycle of preconditioning and perfused using Langendorff's system. The isolated perfused hearts were subjected to 30 min global ischemia followed by 90 min reperfusion. The myocardial arrhythmias induced by ischemia- reperfusion (I/R) were determined in accordance with the guidelines of Lambeth Conventions. The potential role of KATP channels on RIPC was assessed by injection of glibenclamide (nonselective KATP blocker) or 5 hydroxydecanoate (mitochondrial KATP blocker) on rats 30 and 15 min before induction of RIPC in the liver, respectively. RESULTS: Hepatic remote preconditioning of the heart significantly (P<0.0001) prevented the incidence of myocardial arrhythmias induced by I/R in the perfused hearts (5.33+/-1.54 vs. 32.33+/-6.44,). However, the protective effects of remote preconditioning was significantly (P<0.01) abolished by the KATP blocker, glibenclamide (25.5+/-4.9 vs. 5.33+/-1.54,). CONCLUSION: Hepatic RIPC may prevent the arrhythmias induced by I/R in the isolated perfused hearts via KATP channels. PMID- 25810881 TI - In vitro differentiation of rat mesenchymal stem cells to hepatocyte lineage. AB - OBJECTIVES: Mesenchyme is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm. Recently, mesenchymal stem cells (MSCs), as adult stem cells (ASCs) able to divide into a variety of different cells, are of utmost importance for stem cell research. In this research, ability of the liver extract to induce differentiation of rat derived omentum tissue mesenchymal stem cells (rOT-MSCs) into hepatocyte cells (HCs) was investigated. MATERIALS AND METHODS: After isolation and confirmation of rOT-MSCs they were co-cultured with liver extract and hepatogenic differentiation was monitored. Expressions of mesenchymal stem cell markers were also analyzed via flow cytometry. Moreover, expressions of octamer-binding transcription factor-4 (Oct-4), Wilm's tumor suppressor gene-1 (WT-1), albumin (ALB), alpha fetoprotein (AFP), cytokeratin-18 (CK-18), and mRNAs were analyzed using RT-PCR on days 16, 18 and 21. ALB production was analyzed by immunocytochemistry and western blot. Furthermore, glycogen and urea production were determined via periodic acid-Schiff (PAS) staining and colorimetric assays respectively. RESULTS: The phenotypic characterization revealed the positive expressions of CD90, CD44 and negative expression of CD45 in rOT-MSCs. These cells also expressed mRNA of Oct-4 and WT-1 as markers of omentum tissue. Differentiated rOT-MSCs in presence of 6 ug/ml liver extract expressed ALB, AFP, CK-18, glycogen and urea as specific markers of HCs. CONCLUSION: These observations suggest that liver extract is potentially able to induce differentiation of MSCs into hepatocyte lineage and can be considered an available source for imposing tissue healing on the damaged liver. PMID- 25810884 TI - Comparison of inducible nitric oxide synthase activity in pancreatic islets of young and aged rats. AB - OBJECTIVES: Some pathologic situations such as diabetes and metabolic syndrome are associated with alternation in nitric oxide level. Incidence of these condition increases with aging. On the other hand, insulin secretion is modulated by nitric oxide, and nitric oxide synthase (NOS) activity is also altered in diabetes. In this study, modification in the enzyme activity associated with aging and also optimized procedure for islet NOS assay was investigated. MATERIALS AND METHODS: Male Wistar rats were randomly divided in two experimental groups: A: adult rats; were 4 month old and B: old rats; were 12 month old. In all groups, plasma glucose, insulin and NOX (nitrite + nitrate = NOX) were measured, and also insulin secretion in isolated pancreatic islet with or without L-NAME was investigated. Furthermore, the inducible NOS activity with L citrulline measurement in islets was measured. RESULTS: L-citrulline was quantified using one step HPLC column. Aging induced hyperglycemia (P<0.05) and excess plasma NOX (17.74 +/- 1.664 and 26.25 +/- 2.166 MUmol/l in A and B groups respectively, P<0.05) with unaltered plasma insulin. Islet insulin secretion was significantly reduced in aging rats. L-NAME induced islet insulin secretion especially in aging rats (P=0.003). Inducible NOS activity in islets of aging rats was significantly higher than adult rats (1.082 +/- 0.084 and 6.277 +/- 0.475 pmol/min per mg protein in adult and aging rats, respectively, P<0.001). CONCLUSION: These findings show that decreased in islet insulin secretion may be related to increase in iNOS activity in islets, which follows impaired carbohydrate metabolism in aging. PMID- 25810883 TI - MicroRNAs that target RGS5. AB - OBJECTIVES: An earlier meta-analysis on gene expression data derived from four microarray, two cDNA library, and one SAGE experiment had identified RGS5 as one of only ten non-housekeeping genes that were reported to be expressed in human trabecular meshwork (TM) cells by all studies. RGS5 encodes regulator of G protein signaling-5. The TM tissue is the route of aqueous fluid outflow, and is relevant to the pathology of glaucoma. MicroRNAs constitute the most recently identified components of the cellular machinery for gene regulation in eukaryotic cells. Given our long standing interest in glaucoma, we aimed to identify miRNAs that may target RGS5. MATERIALS AND METHODS: Eight miRNAs were selected for study using bioinformatics tools and available data on miRNAs expressed in the eye. Their effects were assessed using the dual luciferase assay. 3'-UTR segments of RGS5 mRNA were cloned downstream of a luciferase coding gene in psiCHECK2 vectors, and these were co-transfected with each of the miRNAs into HEK293 cells. RESULTS: The outcomes evidenced that one or more of the segments are in fact targeted by miR-7, miR-9, miR-96, miR-23a, miR-23b, miR-204, and miR-211. Down regulations by the miRNAs were statistically significant. The effect of miR-204 is considered particularly important as this miRNA is well known to regulate eye development and to affect multiple ocular functions. CONCLUSION: Our results justify further studies on regulation of RGS5 expression and RGS5 downstream functions by these miRNAs. PMID- 25810885 TI - Characterization of inhibitory effects of the potential therapeutic inhibitors, benzoic acid and pyridine derivatives, on the monophenolase and diphenolase activities of tyrosinase. AB - OBJECTIVES: Involvement of tyrosinase in the synthesis of melanin and cell signaling pathway has made it an attractive target in the search for therapeutic inhibitors for treatment of different skin hyperpigmentation disorders and melanoma cancers. MATERIALS AND METHODS: In the present study, we conducted a comprehensive kinetic analysis to understand the mechanisms of inhibition imposed by 2-amino benzoic acid, 4-amino benzoic acid, nicotinic acid, and picolinic acid on the monophenolase and diphenolase activities of the mushroom tyrosinase, and then MTT assay was exploited to evaluate their toxicity on the melanoma cells. RESULTS: Kinetic analysis revealed that nicotinic acid and picolinic acid competitively restricted the monophenolase activity with inhibition constants (Ki) of 1.21 mM and 1.97 mM and the diphenolase activity with Kis of 2.4 mM and 2.93 mM, respectively. 2-aminobenzoic acid and 4-aminobenzoic acid inhibited the monophenolase activity in a non-competitive fashion with Kis of 5.15 uM and 3.8 uM and the diphenolase activity with Kis of 4.72 uM and 20 uM, respectively. CONCLUSION: Our cell-based data revealed that only the pyridine derivatives imposed cytotoxicity in melanoma cells. Importantly, the concentrations of the inhibitors leading to 50% decrease in the cell density (IC50) were comparable to those causing 50% drop in the enzyme activity, implying that the observed cytotoxicity is highly likely due to the tyrosinase inhibition. Moreover, our cell-based data exhibited that the pyridine derivatives acted as anti proliferative agents, perhaps inducing cytotoxicity in the melanoma cells through inhibition of the tyrosinase activities. PMID- 25810886 TI - Intra-CA1 administration of FK-506 (tacrolimus) in rat impairs learning and memory in an inhibitory avoidance paradigm. AB - OBJECTIVES: Calcineurin (CN) is a main phosphatase and a critical regulator of cellular pathways for learning, memory, and plasticity. The FK-506 (tacrolimus), a phosphatase inhibitor, is a fungal-derived agent and a common immune suppressant extensively used for tissue transplantation. To further clarify the role of CN in different stages of learning and memory the main aim of this study was to evaluate the role of FK-506 in an inhibitory avoidance model. MATERIALS AND METHODS: Using different doses of FK-506 (0.5, 5, and 50 nM) in the CA1 of hippocampus at different times (before, after the training and also before the test), the effect of drug was evaluated in a step-through inhibitory avoidance paradigm. The latency of entering to the dark compartment was considered as a criterion for memory. RESULTS: The pre-training intra-CA1 injections of FK-506 impaired inhibitory avoidance (IA) learning acquisition. In addition, the post training intra-CA1 injections of FK-506 at 1, 2, and 3 hr relative to training impaired memory consolidation. Moreover, the pre-test intra-CA1 injections of FK 506 impaired memory retrieval. CONCLUSION: These findings suggest that the FK-506 selectively interferes with acquisition, retention, and retrieval of information processing in CA1 of hippocampus. Given the crucial role of CN in common signaling pathway of higher functions such as memory performance and cognition, in future it would be a probable therapeutic target in the treatment of a wide verity of neurological conditions involving memory. PMID- 25810887 TI - Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors alpha and beta following traumatic brain injury. AB - OBJECTIVES: Estrogen (E2) has neuroprotective effects on blood-brain-barrier (BBB) after traumatic brain injury (TBI). In order to investigate the roles of estrogen receptors (ERs) in these effects, ER-alpha antagonist (MPP) and, ER-beta antagonist (PHTPP), or non-selective estrogen receptors antagonist (ICI 182780) were administered. MATERIALS AND METHODS: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 ug/Kg) or oil were administered 30 min after TBI. 1 dose (150 ug/Kg) of each of MPP, PHTPP, and (4 mg/kg) ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content) and brain edema (brain water content) evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. RESULTS: The results showed that E2 reduced brain edema after TBI compared to vehicle (P<0.01). The brain edema in the MPP+E2 and PHTPP+E2 groups decreased compared to the vehicle (P<0.001). There was no significant difference in MPP+PHTPP+E2 and ICI+E2 compared to TBI. This parameter in MPP was similar to vehicle. Evans blue content in E2 group was lower than vehicle (P<0.05). The inhibitory effect of E2 on Evans blue was not reduced by MPP+E2 and PHTPP+E2 groups, but decreased by treatment with MPP+PHTPP or ICI. MPP had no effect on Evans blue content. CONCLUSION: A combined administration of MPP and PHTPP or ICI inhibited the E2-induced decrease in brain edema and BBB disruption; this may suggest that these effects were mediated via both receptors. PMID- 25810888 TI - Optimization of multi-epitopic HIV-1 recombinant protein expression in prokaryote system and conjugation to mouse DEC-205 monoclonal antibody: implication for in vivo targeted delivery of dendritic cells. AB - OBJECTIVES: Multi-epitopic protein vaccines and direction of vaccine delivery to dendritic cells (DCs) are promising approaches for enhancing immune responses against mutable pathogens. Escherichia coli is current host for expression of recombinant proteins, and it is important to optimize expression condition. The aim of this study was the optimization of multi-epitopic HIV-1 tat/pol/gag/env recombinant protein (HIVtop4) expression by E. coli and conjugation of purified protein to anti DEC-205 monoclonal antibody as candidate vaccine. MATERIALS AND METHODS: In this study, expression was induced in BL21 (DE3) E. coli cells by optimization of induction condition, post induction incubation time, temperature and culture medium formula. Some culture mediums were used for cell culture, and isopropyl-beta-D-thiogalactopyranoside was used for induction of expression. Protein was purified by Ni-NTA column chromatography and confirmed against anti His antibody in western-blotting. To exploit DCs properties for immunization purposes, recombinant protein chemically coupled to alphaDEC-205 monoclonal antibody and confirmed against anti-His antibody in western-blotting. RESULTS: The optimum condition for expression was 1 mM IPTG during 4 hr cultures in 2XYT medium, and final protein produced in soluble form. Conjugation of purified protein to alphaDEC-205 antibody resulted in smears of protein: antibodies conjugate in different molecular weights. CONCLUSION: The best cultivation condition for production of HIVtop4 protein is induction by 1 mM IPTG during 4 hr in 2XYT medium. The final concentration of purified protein was 500 ug/ml. PMID- 25810889 TI - Antihypertensive effect of auraptene, a monoterpene coumarin from the genus Citrus, upon chronic administration. AB - OBJECTIVES: Auraptene, a monoterpene coumarin from Citrus species, exhibits cardioprotective effects. In this study, the effects of auraptene administration were investigated on blood pressure of normotensive and desoxycorticosterone acetate (DOCA) salt induced hypertensive rats. MATERIALS AND METHODS: Five weeks administration of auraptene (2, 4, 8 and 16 mg/kg/day) and nifedipine (0.25, 0.5, 1, 2 and 4 mg/kg/day) in different groups of normotensive and hypertensive rats (at the end of 3 weeks treatment by DOCA salt) was carried out and their effects on mean systolic blood pressure (MSBP) and mean heart rate (MHR) were evaluated using tail cuff method. RESULTS: Our results indicated that chronic administration of auraptene (2, 4, 8 and 16 mg/kg/day) significantly reduced the MSBP in DOCA salt treated rats in a dose and time dependent manner. The percent of decreases in MSBP levels by the highest dose of auraptene (16 mg/kg) at the end of 4 (th) to 8 (th) weeks, were 7.00%, 10.78%, 16.07%, 21.28% and 27.54% respectively (P<0.001). Moreover the antihypertensive effect of auraptene was less than nifedipine (ED50 value of nifedipine = 0.7 mg/kg at 8(th) week and ED50 value of auraptene = 5.64 mg/kg at 8 week). CONCLUSION: Auraptene considerably reduced MSBP in hypertensive rats, but not in normotensive (normal saline treated) rats. The results of MHR measurement showed that the increase in MHR was not significant in comparison with DOCA treated rats. PMID- 25810890 TI - Cloning and expression of NS3 helicase fragment of hepatitis C virus and the study of its immunoreactivity in HCV infected patients. AB - OBJECTIVES: Hepatitis C is a major cause of liver failure worldwide. Current therapies applied for this disease are not fully effective and produce side effects in most cases. Non-structural protein 3 helicase (NS3) of HCV is one of the key enzymes in viral replication and infection. Therefore, this region is a promising target to design new drugs and therapies against HCV infection. The aim of this study was cloning and expression of HCV NS3 helicase fragment in Escherichia coli BL21 (DE3) using pET102/D-TOPO expression vector and studying immunoreactivity of the expressed antigen in Iranian infected with hepatitis C. MATERIALS AND METHODS: The viral RNA was extracted from the serum of HCV infected patient. The NS3 helicase region was amplified by RT-PCR. The PCR product was directionally cloned into the expression vector pET102/D-TOPO and transformed into the BL21 strain of E. coli (DE3). The transformed bacteria were then induced by adding 1mM isopropyl-beta-D-thiogalactopyranoside (IPTG) into the culture medium to enhance the protein expression. SDS-PAGE and western blotting were carried out to identify the protein under investigation, and finally purified recombinant fusion protein was used as the antigen for ELISA method. RESULTS: The insertion of the DNA fragment of the NS3 region into the expression vector was further confirmed by PCR and sequencing. SDS-PAGE analysis showed the successful expression of the recombinant protein of interest. Furthermore, immunoreactivity of fusion NS3 helicase was confirmed by ELISA and western blotting. CONCLUSION: It seems that this recombinant protein could be a useful source of antigen for future studies on HCV diagnosis and therapy. PMID- 25810891 TI - Phenolic contents and bioactivities of pericarp and seeds of Pleiogynium solandri (Benth.) Engl. (Anacardiaceae). AB - OBJECTIVES: This study aimed to develop drugs from natural sources to overcome the side effects of many of synthetic drugs. Methanol extracts of both pericarp and seeds of Pleiogynium solandri were used to investigate antioxidant, hepatoprotective, and renal function protective, analgesic, and anti-inflammatory effects and to determine the chemical composition of the extract responsible for bioactivity. MATERIALS AND METHODS: Methanol (70%) extracts of the seeds and pericarps of P. solandri were prepared. Hot plate method was used to test analgesic activity, carrageenan-induced paw inflammation method was used to test anti-inflammatory activity, and colorimetric methods were used to test antioxidant, hepatoprotective (by determination of serum alanine and aspartate aminotransferase activities), and renal function protective effects (by measuring uric acid and creatinine levels). Chromatographic methods and means of (1)H-NMR, (13)C -NMR, and UV spectra were used for isolation and identification of the responsible compounds. RESULTS: In this study for the first time, four phenolic compounds were isolated from the pericarp of P. solandri which were identified as catechin, quercetin, quercetrin and rutin. Methanolic extract of both seeds and pericarp of P. solandri showed strong antioxidant effect, hepatoprotective, renal function protective, analgesic, and anti-inflammatory effects. However, seed extract had lower effect than pericarp in a dose dependent manner. CONCLUSION: This study showed that methanol extract of pericarp of P. solandri is more powerful than that of the seed regarding its antioxidant, hepato-protective; renal function protective, analgesic, and anti-inflammatory effects. The phenolic compounds isolated from the methanol extract of pericarp were responsible for bioactivity. PMID- 25810892 TI - Gestational hypothyroidism-induced changes in L-type calcium channels of rat aorta smooth muscle and their impact on the responses to vasoconstrictors. AB - OBJECTIVES: Thyroid hormones play an essential role in fetal growth and maternal hypo-thyroidism which leads to cardiovascular deficiency in their offspring. Considering this, we intended to investigate the impact of gestational hypothyroidism on offspring vascular contractibility and possible underlying mechanisms. MATERIALS AND METHODS: Hypothyroidism was induced in female rats by administration of 6-n-propyl-2-thiouracil in drinking water (0.02%) till delivery. The offspring aorta smooth muscle (without endothelium) contractile response to KCl (10-100 mM), KCl in the presence of nifedipine (10(-4)-10(-1) uM), phenylephrine (10(-9)-10(-6) M) and finally, phenylephrine and caffeine 100 mM in Ca(2+)-free Krebs were measured. RESULTS: KCl and phenylephrine-induced contractions were considerably lower in gestational hypothyroid (GH) than euthyroid offspring. GH responded to nifedipine with less sensitivity than control. The GH and control groups produced almost equal contraction in respond to phenylephrine and caffeine in Ca(2+)-free Krebs. CONCLUSION: This study suggests that in hypothyroid offspring L-type Ca(2+) channels are less functional, while intracellular Ca(2+) handling systems are less modified by low levels of maternal thyroid hormones. PMID- 25810893 TI - Putative mechanism for apoptosis-inducing properties of crude saponin isolated from sea cucumber (Holothuria leucospilota) as an antioxidant compound. AB - OBJECTIVES: Marine organisms are known as a potential source of natural products, which contain bioactive substances with therapeutic properties. Sea cucumbers are prominent among marine organisms because of their dietary and therapeutic applications. In addition, they have capacity of synthesizing saponins molecules and other metabolites with therapeutic properties such as antitumor, antimicrobial, anti-inflammatory and antioxidant activities. The aim of this study was to evaluate the antioxidant and pro-apoptotic effects of sea cucumber saponins (SCS) isolated from Holothuria leucospilota species. MATERIALS AND METHODS: Evaluation of antioxidant activity of SCS was carried out by DPPH (1, 1 diphenyl-2-picrylhydrazyl), ABTS (azino-bis-3-ethylbenzothiazoline-6-sulfonic acid), power reducing and total antioxidant assays. The anti-proliferative effect was studied by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. Mechanisms leading to apoptosis were also evaluated by fluorescence microscopy, flow cytometry and real time PCR. RESULTS: The results showed that the DPPH and ABTS activities increased in a dose dependent manner. The reducing capacity enhanced with increasing concentration of the saponin extract (0 to 2 mg/ml). The SCS exhibited moderate total antioxidant activity. Evaluation of anti-proliferative effect revealed that SCS with IC50 of about 6 MUg/ml, can display a good cytotoxic activity in a dose dependent manner. Further apoptosis induction was confirmed by fluorescence microscopy and flow cytometry. Sea cucumber saponin was also found to exert a pro-apoptotic effect by increasing the expression of Bax and decreasing the expression of Bcl2. CONCLUSION: These results indicate that the SCS may act as a natural antioxidant and antitumor agent. PMID- 25810894 TI - The effects of ATP-dependent potassium channel opener; pinacidil, and blocker; glibenclamide, on the ischemia induced arrhythmia in partial and complete ligation of coronary artery in rats. AB - OBJECTIVES: Electrical inhomogeneity between ischemic and non ischemic myocardium is the basis of arrhythmia which occurs following coronary artery occlusion. The leakage of potassium from the ischemic region to the non ischemic region is very effective in the generation of these arrhythmias. The aim of this study is to research the effect of ATP-dependent potassium (KATP) channel blocker (glibenclamide) and opener (pinacidil) on ischemia induced arrhythmia in the presence of small and large infarct sizes. MATERIALS AND METHODS: In this study Sprague-Dawley male rats of 8-9 months of age were used. Ischemia was produced by the partial ligation of left coronary artery ramus descending (PL) for smaller infarct and complete ligation of this artery (CL) for larger infarct for 30 min. The arrhythmia score which was calculated from the duration and type of arrhythmia was significantly higher in animals which had a larger infarct area than the animals which had a smaller infarct. RESULTS: Glibenclamide increased the rate of arrhythmia in animals having smaller infarct but not in animals having larger infarct. Pinacidil did not affect the occurrence of arrhythmia in either group. There was a significant difference in the infarct size and risk of infarct zone between animals which had small and large infarct sizes. The effect of glibenclamide and pinacidil on the arrhythmias differed depend on decrease of infarct size. CONCLUSION: Glibenclamide is not effective to decrease ischemia induced arrhythmia in the presence of small and pinacidil in large ischemic zone. PMID- 25810895 TI - Effects of mild hypothermia therapy on the levels of glutathione in rabbit blood and cerebrospinal fluid after cardiopulmonary resuscitation. AB - OBJECTIVES: The aim of this study was to investigate the effects of mild hypothermia therapy on oxidative stress injury of rabbit brain tissue after cardiopulmonary resuscitation (CPR). MATERIALS AND METHODS: Rabbit models of cardiac arrest were established. After the restoration of spontaneous circulation, 50 rabbits were randomly divided into normothermia and hypothermia groups. The following five time points were selected: before CPR, immediately after CPR, 2 hr after CPR (hypothermia group reached the target temperature), 14 hr after CPR (hypothermia group before rewarming), and 24 hr after CPR (hypothermia group recovered to normal temperature). Glutathione (GSH) concentrations in both the blood and cerebrospinal fluid of the normothermia and hypothermia groups were measured. RESULTS: At 2, 14, and 24 hr after CPR, the GSH concentrations in both the blood and cerebrospinal fluid were significantly higher in the hypothermia group than in the nomorthermia group. CONCLUSION: Mild hypothermia therapy may increase GSH concentrations in rabbit blood and cerebrospinal fluid after CPR as well as promote the recovery of cerebral function. PMID- 25810896 TI - Extension of Nakagawa & Schielzeth's R2GLMM to random slopes models. AB - Nakagawa & Schielzeth extended the widely used goodness-of-fit statistic R2 to apply to generalized linear mixed models (GLMMs). However, their R2GLMM method is restricted to models with the simplest random effects structure, known as random intercepts models. It is not applicable to another common random effects structure, random slopes models.I show that R2GLMM can be extended to random slopes models using a simple formula that is straightforward to implement in statistical software. This extension substantially widens the potential application of R2GLMM. PMID- 25810897 TI - Gene expression patterns that support novel developmental stress buffering in embryos of the annual killifish Austrofundulus limnaeus. AB - BACKGROUND: The cellular signaling mechanisms and morphogenic movements involved in axis formation and gastrulation are well conserved between vertebrates. In nearly all described fish, gastrulation and the initial patterning of the embryonic axis occur concurrently with epiboly. However, annual killifish may be an exception to this norm. Annual killifish inhabit ephemeral ponds in South America and Africa and permanent populations persist by the production of stress tolerant eggs. Early development of annual killifish is unique among vertebrates because their embryonic blastomeres disperse randomly across the yolk during epiboly and reaggregate several days later to form the embryo proper. In addition, annual killifish are able to arrest embryonic development in one to three stages, known as diapause I, II, and III. Little is known about how the highly conserved developmental signaling mechanisms associated with early vertebrate development may have shifted in order to promote the annual killifish phenotype. One of the most well-characterized and conserved transcription factors, oct4 (Pou5f1), may have a role in maintaining pluripotency. In contrast, BMP-antagonists such as chordin, noggin, and follistatin, have been previously shown to establish dorsal-ventral asymmetry during axis formation. Transcription factors from the SOXB1 group, such as sox2 and sox3, likely work to induce neural specification. Here, we determine the temporal expression of these developmental factors during embryonic development in the annual killifish Austrofundulus limnaeus using quantitative PCR and compare these patterns to other vertebrates. RESULTS: Partial transcript sequences to oct4, sox2, sox3, chordin, noggin-1, noggin-2, and follistatin were cloned, sequenced, and identified in A. limnaeus. We found oct4, sox3, chordin, and noggin-1 transcripts to likely be maternally inherited. Expression of sox2, follistatin, and noggin-2 transcripts were highest in stages following a visible embryonic axis. CONCLUSIONS: Our data suggest that embryonic cells acquire their germ layer identity following embryonic blastomere reaggregation in A. limnaeus. This process of cellular differentiation and axis formation may involve similar conserved signaling mechanisms to other vertebrates. We propose that the undifferentiated state is prolonged during blastomere dispersal, thus functioning as a developmental stress buffer prior to the establishment of embryonic asymmetry and positional identity among the embryonic cells. PMID- 25810898 TI - Hormonal treatments in metastatic endometrial stromal sarcomas: the 10-year experience of the sarcoma unit of Royal Marsden Hospital. AB - BACKGROUND: Hormonal manipulation is sometimes recommended in the treatment of metastatic endometrial stromal sarcoma, but there are few data assessing the efficacy of endocrine therapies in this subtype of uterine sarcomas. METHODS: We performed a retrospective electronic medical record review of patients with metastatic ESS treated with a hormonal agent at Royal Marsden Hospital between 1999 and 2011. We assessed progression-free survival (PFS), objective response and toxicity profile among patients with measurable disease. RESULTS: Thirteen patients with metastatic ESS were treated with hormonal therapies. Hormone receptor status (estrogen and progesterone receptors) was assessed in 9 out of 13 patients and in all of them it was moderately to strongly positive. Aromatase inhibitors (AIs) were prescribed as first endocrine line in 11/13 patients and progestins in the remainder, while in 2(nd) line treatment AIs were prescribed in 7/10 patients, followed by progestins and GnRH analogues. Median PFS for 1(st)line was 4.0 years (95% CI: 2.4 - 5.5 years) with 5-year progression-free rate of 30.8% (95% CI: 5.7 - 55.9%), both of which reflect the indolent natural history of ESS. Best objective response was partial response (PR) in 6/13 patients (46.2%; 95% CI: 19.2 - 74.9) and clinical benefit rate (defined as complete response + PR + stable disease >=6 months) was 92.4% (95% CI: 64.0 - 99.8%; 12/13 patients). Median PFS for 2(nd) line was 3.0 years (95% CI: 2.0 - 4.1 years) with 2-year progression-free rate of 88.9% (95% CI: 68.3 - 100.0). CONCLUSIONS: In this cohort of metastatic ESS patients, 1st line endocrine treatment achieved objective response in 46.2% of them and clinical benefit in 92.4%. Tamoxifen and hormone replacement therapy should not be prescribed in patients with ESS due to their detrimental effects. Until more solid data are available, a reasonable recommendation would be that 1(st) line treatment with an endocrine treatment, preferably with an AI. Moreover, in view of the positive outcomes of our patients that received 2(nd)/3(rd)line endocrine treatments, all available hormonal options should be used in sequence in the management of ESS. PMID- 25810899 TI - Development of a mouse monoclonal antibody for the detection of asymmetric dimethylarginine of Translocated in LipoSarcoma/FUsed in Sarcoma and its application in analyzing methylated TLS. AB - BACKGROUND: RNA-binding protein Translocated in LipoSarcoma/FUsed Sarcoma (TLS/FUS) is one of causative genes for familial amyotrophic lateral sclerosis (ALS). We previously identified that TLS was associated with protein arginine methyltransferase 1 (PRMT1), and four arginine residues within TLS (R216, R218, R242 and R394) were consistently dimethylated. Protein arginine methylation is involved in various cellular events such as signal transduction, transcriptional regulation and protein-protein interactions. RESULTS: To understand the biological role of arginine methylation of RNA-binding protein, we prepared and characterized a mouse monoclonal antibody against asymmetric dimethylarginine of TLS. By cloning and screening, one stable hybridoma cell clone (2B12) producing anti-asymmetric dimethylated TLS on R216 and R218 antibody was established. The monoclonal antibody 2B12 is specific for the asymmetrically dimethylated arginine peptide and does not react with the same peptide sequence containing unmodified and symmetrically dimethylated arginine residues by dot-blot analysis. 2B12 was also validated GST tagged TLS with PRMT1 by in vitro arginine methylation assays. Since methylated TLS in HeLa cells and mouse and human brain protein extracts was immunoprecipitated with 2B12, we performed RNA-binding protein immunoprecipitation assays using HeLa cell lysate and this antibody. We demonstrated that the long noncoding RNA (lncRNA) transcribed from cyclin D1 promoter binds methylated TLS. CONCLUSIONS: A monoclonal antibody that is capable of detecting the methylarginine status of TLS will facilitate the molecular and cellular analysis of transcriptional regulation by lncRNA through methylated TLS, and can be used as a favorable tool for clinical diagnosis of ALS caused by TLS dysregulation. PMID- 25810901 TI - Epigenetics and transgenerational inheritance in domesticated farm animals. AB - Epigenetics provides a molecular mechanism of inheritance that is not solely dependent on DNA sequence and that can account for non-Mendelian inheritance patterns. Epigenetic changes underlie many normal developmental processes, and can lead to disease development as well. While epigenetic effects have been studied in well-characterized rodent models, less research has been done using agriculturally important domestic animal species. This review will present the results of current epigenetic research using farm animal models (cattle, pigs, sheep and chickens). Much of the work has focused on the epigenetic effects that environmental exposures to toxicants, nutrients and infectious agents has on either the exposed animals themselves or on their direct offspring. Only one porcine study examined epigenetic transgenerational effects; namely the effect diet micronutrients fed to male pigs has on liver DNA methylation and muscle mass in grand-offspring (F2 generation). Healthy viable offspring are very important in the farm and husbandry industry and epigenetic differences can be associated with production traits. Therefore further epigenetic research into domestic animal health and how exposure to toxicants or nutritional changes affects future generations is imperative. PMID- 25810900 TI - Connectomics and new approaches for analyzing human brain functional connectivity. AB - Estimating the functional interactions between brain regions and mapping those connections to corresponding inter-individual differences in cognitive, behavioral and psychiatric domains are central pursuits for understanding the human connectome. The number and complexity of functional interactions within the connectome and the large amounts of data required to study them position functional connectivity research as a "big data" problem. Maximizing the degree to which knowledge about human brain function can be extracted from the connectome will require developing a new generation of neuroimaging analysis algorithms and tools. This review describes several outstanding problems in brain functional connectomics with the goal of engaging researchers from a broad spectrum of data sciences to help solve these problems. Additionally it provides information about open science resources consisting of raw and preprocessed data to help interested researchers get started. PMID- 25810902 TI - The effect of dietary tryptophan levels on oxidative stress of liver induced by diquat in weaned piglets. AB - Oxidative stress can induce abnormal tryptophan metabolism. The present study was mainly conducted to determine the effect of dietary tryptophan levels on oxidative stress in the liver of weaned pigs challenged by diquat. A total of 36 PIC piglets weaned at 21 days of age were randomly allotted to 1 of 3 diets containing dietary tryptophan levels of 0.18, 0.30, and 0.45% for 14 d. On day 8, the piglets were injected intraperitoneally with sterile 0.9% NaCl solution or diquat (10 mg/kg body weight). During the first 7 d of trial, increasing dietary tryptophan levels enhanced average daily gain (P = 0.09) and average daily feed intake (P = 0.08), and decreased the feed efficiency (P < 0.05) of piglets. The growth performance was decreased by diquat injection (P < 0.05). Diquat injection also decreased the activities of the superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma and liver (P < 0.05), increased plasma malondialdehyde (MDA) (P < 0.05) and urea nitrogen (P < 0.05) concentrations, and enhanced MDA concentration (P = 0.09) and tryptophan 2,3-dioxygenase (TDO) activity (P = 0.07) in liver of piglets. Increasing dietary tryptophan levels could attenuate the effects of diquat injection on the MDA (P = 0.06) concentration and the activities of SOD (P = 0.09) and GPx (P = 0.05) of the liver, and plasma urea nitrogen (P = 0.06) concentration in the piglet. There was a synergistic role for increasing TDO activity in the liver between dietary tryptophan levels and diquat injection (P < 0.05). These results suggest that increasing dietary tryptophan levels could attenuate the oxidative stress of the liver in weaned piglets intraperitoneally injected with diquat via enhancing the antioxidant capacity. PMID- 25810903 TI - Identification and quantitative mRNA analysis of a novel splice variant of GPIHBP1 in dairy cattle. AB - BACKGROUND: Identification of functional genes affecting milk production traits is very crucial for improving breeding efficiency in dairy cattle. Many potential candidate genes have been identified through our previous genome wide association study (GWAS). Of these, GPIHBP1 is an important novel candidate gene for milk production traits. However, the mRNA structure of the bovine GPIHBP1 gene is not fully determined up to now. RESULTS: In this study, we identified a novel alternatively splice transcript variant (X5) which leads to a 31 bp insertion in exon 3 and also confirmed the other four existed transcripts (X1, X2, X3 and X4) of the bovine GPIHBP1 gene. We showed that transcript X5 with a 31 bp insertion and transcript X1 with an 8 bp deletion might have tremendous effect on the protein function and structure of GPIHBP1, respectively. With semi-quantitative PCR and quantitative real-time RT-PCR, we found that the mRNA expression of GPIHBP1, GPIHBP1-X1 and GPIHBP1-X5 in mammary gland of lactating cows were much higher than that in other tissues. CONCLUSIONS: Our study reports a novel alternative splicing of GPIHBP1 in bovine for the first time and provide useful information for the further functional analyses of GPIHBP1 in dairy cattle. PMID- 25810905 TI - Improving beef hamburger quality and fatty acid profiles through dietary manipulation and exploitation of fat depot heterogeneity. AB - BACKGROUND: Hamburger is the most consumed beef product in North America, but lacks in nutritional appeal due to its high fat content and high proportion of saturated fatty acids (SFA). Objectives of the present study were to improve the FA profiles of hamburgers made with perirenal fat (PRF) and subcutaneous fat (SCF) when feeding steers different diets along with examining differences in sensory attributes and oxidative stability. Diets included a control diet containing 70:30 red clover silage: barley based concentrate, a diet containing sunflower-seed (SS) substituted for barley, and diets containing SS with 15% wheat dried distillers' grain with solubles (DDGS-15) or 30% DDGS (DDGS-30). Hamburgers were made from triceps brachii and either PRF or SCF (80:20 w/w). RESULTS: Perirenal fat versus SCF hamburgers FA had 14.3% more (P <0.05) 18:0, 11.8% less cis (c)9-18:1 (P <0.05), and 1.82% more total trans (t)-18:1 mainly in the form of t11-18:1. During sensory evaluation, PRF versus SCF hamburgers had greater (P <0.05) mouth coating, but the difference was less than one panel unit. Examining effects of steer diet within PRF hamburgers, feeding the SS compared to the control diet increased (P <0.05) t-18:1 by 2.89% mainly in the form of t11 18:1, feeding DGGS-15 diet led to no further changes (P >0.05), but feeding DDGS 30 diet reduced the proportions of (P <0.05) of t-18:1 chiefly t11-18:1. Feeding SS and DDGS diets had small but significant (P <0.05) effects on hamburger sensory attributes and oxidative stability. CONCLUSIONS: Feeding high-forage diets including SS and 15% DDGS, and taking advantage of the FA heterogeneity between fat depots offers an opportunity to differentially enhance beef hamburgers with 18:2n-6 biohydrogenation products (i.e., t11-18:1) with potential human health benefits without compromising their sensory attributes and oxidative stability during retail display. PMID- 25810906 TI - Bacterial diversity and Clostridia abundance decrease with increasing severity of necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating neonatal gastrointestinal disease that primarily affects premature infants. It is characterized by bowel inflammation and necrosis. In spite of extensive research, there has been little progress in decreasing the incidence or mortality of NEC over the past three decades. The exact etiology of NEC has not been identified. However, it is believed to result from an inappropriate immune response to gut microbiota. Using 454-pyrosequencing analyses of 16S rRNA genes that were PCR amplified from stool DNA specimens, we compared the gut microbiota of infants with NEC to matched controls without NEC. The infants with NEC were then categorized into three subgroups based on severity: mild, severe, and lethal. We compared the microbiota among these subgroups and between each severity group and appropriate controls. RESULTS: Bacterial diversity and the relative abundance of Actinobacteria and Clostridia were significantly lower in NEC specimens compared to controls. The absence of Clostridia was significantly associated with NEC. Microbial diversity and Clostridia abundance and prevalence decreased with increasing severity of NEC. CONCLUSIONS: Low bacterial diversity in stool specimens may be indicative of NEC and the severity of NEC. The low bacterial diversity, and the lack of Clostridia in lethal specimens, could indicate that the presence of a diverse bacterial population in the gut as well as the presence of taxa such as Clostridia may play a role in attenuating inflammation leading to NEC. PMID- 25810904 TI - Conceptus elongation in ruminants: roles of progesterone, prostaglandin, interferon tau and cortisol. AB - The majority of pregnancy loss in ruminants occurs during the first three weeks after conception, particularly during the period of conceptus elongation that occurs prior to pregnancy recognition and implantation. This review integrates established and new information on the biological role of ovarian progesterone (P4), prostaglandins (PGs), interferon tau (IFNT) and cortisol in endometrial function and conceptus elongation. Progesterone is secreted by the ovarian corpus luteum (CL) and is the unequivocal hormone of pregnancy. Prostaglandins (PGs) and cortisol are produced by both the epithelial cells of the endometrium and the trophectoderm of the elongating conceptus. In contrast, IFNT is produced solely by the conceptus trophectoderm and is the maternal recognition of pregnancy signal that inhibits production of luteolytic pulses of PGF2alpha by the endometrium to maintain the CL and thus production of P4. Available results in sheep support the idea that the individual, interactive, and coordinated actions of P4, PGs, IFNT and cortisol regulate conceptus elongation and implantation by controlling expression of genes in the endometrium and/or trophectoderm. An increased knowledge of conceptus-endometrial interactions during early pregnancy in ruminants is necessary to understand and elucidate the causes of infertility and recurrent early pregnancy loss and provide new strategies to improve fertility and thus reproductive efficiency. PMID- 25810908 TI - Metaprop: a Stata command to perform meta-analysis of binomial data. AB - BACKGROUND: Meta-analyses have become an essential tool in synthesizing evidence on clinical and epidemiological questions derived from a multitude of similar studies assessing the particular issue. Appropriate and accessible statistical software is needed to produce the summary statistic of interest. METHODS: Metaprop is a statistical program implemented to perform meta-analyses of proportions in Stata. It builds further on the existing Stata procedure metan which is typically used to pool effects (risk ratios, odds ratios, differences of risks or means) but which is also used to pool proportions. Metaprop implements procedures which are specific to binomial data and allows computation of exact binomial and score test-based confidence intervals. It provides appropriate methods for dealing with proportions close to or at the margins where the normal approximation procedures often break down, by use of the binomial distribution to model the within-study variability or by allowing Freeman-Tukey double arcsine transformation to stabilize the variances. Metaprop was applied on two published meta-analyses: 1) prevalence of HPV-infection in women with a Pap smear showing ASC-US; 2) cure rate after treatment for cervical precancer using cold coagulation. RESULTS: The first meta-analysis showed a pooled HPV-prevalence of 43% (95% CI: 38%-48%). In the second meta-analysis, the pooled percentage of cured women was 94% (95% CI: 86%-97%). CONCLUSION: By using metaprop, no studies with 0% or 100% proportions were excluded from the meta-analysis. Furthermore, study specific and pooled confidence intervals always were within admissible values, contrary to the original publication, where metan was used. PMID- 25810909 TI - A frame-critical policy analysis of Canada's response to the World Food Summit 1998-2008. AB - BACKGROUND: The 2012 visit to Canada of Olivier De Schutter, the United Nations Special Rapporteur on the Right to Food, led to a public rebuff by Canadian governmental officials. This paper adapts the frame-critical policy analysis of Schon and Rein (1994), to explore the rhetorical basis for this conflict. This examination is offered as an illustrative example of how food insecurity is framed as a public policy problem in a high-income nation and how this framing has changed over time. METHODS: We analyze Canada's decade of sequential responses to the 1996 World Food Summit, spanning 1998-2008, in the form of Canada's Action Plan on Food Security, and its subsequent Progress Reports. We conducted a qualitative policy analysis, adapting the frame-critical approach first delineated by Schon and Rein (1994). This analysis uses a social constructionist approach to map out the relationships between tacit understanding of policy by particular actors, explicit rhetoric in the public domain, and action in this policy area over time. RESULTS: We identify three key ways in which competing rhetorical frames arise over time: frame shifts (e.g., a shift away from language highlighting the right to food and health); frame blending (e.g., discussion about poverty becomes obscured by complexity discourse); and within-frame incongruence (e.g., monitoring for health indicators that are unrelated to policy solutions). Together, these frames illustrate how the conflict embodied in the UN Special Rapporteur's visit has been deeply woven into the policy discourse on food insecurity in Canada over time. CONCLUSION: Frame critical analysis is instructive for exposing and also predicting tensions that impede forward progress on difficult policy issues. Accordingly, such analyses may be helpful in not only dissecting how policy can become 'stuck' in the process of change but in active reframing towards new policy solutions. PMID- 25810910 TI - Determinant of factors associated with child health outcomes and service utilization in Ghana: multiple indicator cluster survey conducted in 2011. AB - BACKGROUND: The effects of National Health Insurance Scheme in Ghana and its impact on child health outcome and service utilization cannot be underestimated. Despite the tremendous improvement in child health care in Ghana, there are still some challenges in relation to how National health insurance membership, socioeconomic status and other demographic factors impacts on child health outcomes. The study seeks to determine the association between NHIS membership, socio-economic status, geographic location and other relevant background factors, on child health service utilization and outcomes. METHODS: Secondary data from the Multiple Indicator Cluster Survey conducted in 2011 was used. Multivariate analysis based on Binary Logistic Regression Models and Multiple linear regression techniques was applied to determine factors associated with child health outcomes and service utilization. Collection of best models was based on Hosmer-Lemeshow Goodness-Of-Fit as one criterion of fit and the Akaike Information Criterion. RESULTS: Controlling for confounding effect of socioeconomic status, age of the child, mothers education level and geographic location, the odds of a child developing anemia for children with National Health Insurance Scheme Membership is 65.2% [95% CI: 52.9-80.2] times less than children without National Health Insurance Scheme Membership. The odds of being fully immunized against common childhood illnesses for children with NHIS membership is 2.3[95% CI: 1.4-3.7] times higher than children without National Health Insurance Scheme Membership. There was no association between National Health Insurance Scheme Membership and stunted growth in children. CONCLUSIONS: National Health Insurance Scheme Membership was found to be related to child health service utilization (full immunization) of children under five a child's anemia status. Children with NHIS are more likely to be fully immunized against common childhood diseases and are less likely to develop anemia. Stunted growth of children was not associated with National Health Insurance Scheme Membership. Health Education on the registration and the use of the National Health Insurance should be made a national priority to enable the Ministry of Health achieve routine Immunization targets and to reduce to the bearers minimum prevalence of anemia. PMID- 25810907 TI - Mitophagy and cancer. AB - Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here. PMID- 25810911 TI - Lessons learned from a textbook outbreak: EHEC-O157:H7 infections associated with the consumption of raw meat products, June 2012, Limburg, Belgium. AB - BACKGROUND: On 5 June 2012 several enterohemorrhagic Escherichia coli, EHEC, O157:H7 infections were reported to the public health authorities of Limburg. METHODS: We performed a case-control study, a trace back/forward investigation and compared strains isolated from human cases and food samples. A case was defined as anyone with a laboratory-confirmed E. coli O157:H7-infection in North East Limburg from May 30 2012 till July 15 2012. Family members with bloody diarrhea were also included as cases. E. coli O157 was isolated by culture and the presence of the virulence genes was verified using (q)PCR. Isolates were genotyped and compared by Pulsed Field Gel Electrophoresis (PFGE) and insertion sequence 629-printing (IS629-printing). RESULTS: The outbreak involved 24 cases, of which 17 were laboratory-confirmed. Five cases developed Hemolytic Uremic Syndrome (HUS) and fifteen were hospitalized. Cases reported a significantly higher consumption of "steak tartare", a raw meat product (OR 48.12; 95% CI; 5.62 416.01). Cases were also more likely to buy meat-products at certain butcheries (OR 11.67; 95% CI; 1.41 - 96.49). PFGE and IS629-printing demonstrated that the vtx1a vtx2a eae ehxA positive EHEC O157:H7 strains isolated from three meat products and all seventeen human stool samples were identical. In a slaughterhouse, identified by the trace-back investigation, a carcass infected with a different EHEC strain was found and confiscated. CONCLUSION: We present a well described and effectively investigated foodborne outbreak associated with meat products. Our main recommendations are the facilitation and acceleration of the outbreak detection and the development of a communication plan to reaches all persons at risk. MESH: Foodborne diseases, Shiga-toxigenic Escherichia coli, Enterohemorrhagic Escherichia coli, Meat products, Case control studies, Electrophoresis, Gel, Pulsed-Field. PMID- 25810913 TI - Mode differences in a mixed-mode health interview survey among adults. AB - BACKGROUND: Health interview surveys are important data sources for empirical research in public health. However, the diversity of methods applied, such as in the mode of data collection, make it difficult to compare results across surveys, time, or countries. The aim of this study was to explore whether the prevalence rates of health-related indicators amongst adults differ when self-administered paper mail questionnaires (SAQ-Paper), self-administered web surveys (SAQ-Web), and computer-assisted telephone interviews (CATI) are used for data collection in a health survey. METHODS: Data were obtained from a population-based mixed-mode health interview survey of adults in Germany carried out within the 'German Health Update' (GEDA) study. Data were collected either by SAQ-Paper (n = 746), SAQ-Web (n = 414), or CATI (n = 411). Predictive margins from logistic regression models were used to estimate the prevalence rates of chronic conditions, subjective health, mental health, psychosocial factors, and health behaviours, adjusted for the socio-demographic characteristics of each mode group. RESULTS: Socio-demographic characteristics were found to differ significantly between study participants who responded by SAQ-Paper, SAQ-Web, and CATI. Crude prevalence rates for health-related indicators also showed significant variation across all three survey modes. After adjusting for socio-demographic factors though, significant differences in prevalence rates between the two self administered modes (SAQ-Paper and SAQ-Web) were found in only 2 out of the 19 health-related indicators studied. The differences between CATI and the two self administered modes remained significant however, especially for indicators of mental and psychosocial health and self-reported sporting activity. CONCLUSIONS: The findings of this study indicate that prevalence rates obtained from health interview surveys can vary with the mode of data collection, primarily between interviewer and self-administered modes. Hence, the type of survey mode used should be considered when comparing results from different health surveys. Mixing self-administered modes, such as paper-based questionnaires and web surveys, may be a combination to minimize mode differences in mixed-mode health interview surveys. PMID- 25810912 TI - Sarcopenia: burden and challenges for public health. AB - Sarcopenia, operationally defined as the loss of muscle mass and muscle function, is a major health condition associated with ageing, and contributes to many components of public health at both the patient and the societal levels. Currently, no consensual definition of sarcopenia exists and therefore it is still a challenge to establish the actual prevalence of sarcopenia or to establish the direct and indirect impacts of sarcopenia on public health. Anyway, this geriatric syndrome represents a huge potential public health issue because of its multiple clinical and societal consequences. Moreover, all these aspects have an impact on healthcare costs both for the patient and the society. Therefore, the implementation of effective and broadly applicable preventive and therapeutic interventions has become a medical and societal challenge for the growing number of older persons affected by sarcopenia and its disabling complications. PMID- 25810914 TI - Legionnaires' disease: overview of the situation concerning notification in Wallonia (Belgium) in 2012, a retrospective descriptive study based on a capture recapture method. AB - BACKGROUND: Legionnaires' disease is a severe form of pneumonia, and although public health medical inspectors must be notified, it is often under-reported. The objectives of this study were to determine the completeness rate of notification of Legionnaires' disease and to estimate the incidence of this disease in Wallonia, the southern part of Belgium, in 2012. METHOD: This retrospective, transversal descriptive study was based on a capture-recapture method using two sources. An estimation of the total number of Legionnaires' disease cases was calculated using Chapman and Seber's estimators for small numbers, thereby allowing us to estimate the real incidence of this disease in Wallonia as well as the completeness rate of notification. RESULTS: The total number of estimated Legionella cases for 2012 was 45 (IC 95%:41-48) and the completeness rate was 65% (IC 95%:61-70%). The estimated incidence of Legionnaires' disease in Wallonia was 1.27/100,000 inhabitants. CONCLUSIONS: The notification rate of Legionella must be improved in Wallonia. Doctors should be made aware of the importance of diagnosing and reporting Legionnaires' disease. PMID- 25810915 TI - Sleep hygiene awareness: its relation to sleep quality and diurnal preference. AB - BACKGROUND: Sleep hygiene is a core component for psychological treatments of insomnia and essential for maintaining a satisfactory sleep. Our study aimed to measure the sleep hygiene awareness and the self-reported quality of sleep among three age groups (young adults, adults and middle-aged adults) and to determine their relation. We also measured their relation with diurnal preference. METHODS: Using an online questionnaire, we surveyed six hundred fifty two participants, recruited nationwide from the community and from the students in three main cities in Romania. RESULTS: Sleep hygiene awareness was moderate on the whole and significantly worse in young adults (compared to the other age groups) and in those complaining of poor sleep (compared to those with good sleep). Sleep quality was average and linked positively with diurnal preference (the more evening oriented, the poorer the sleep). Diurnal preference was not found to play a role regarding sleep hygiene awareness. CONCLUSIONS: Our results suggest that better sleep hygiene awareness does not necessarily guarantee better sleep quality and that it may actually be an indicator of dissatisfaction with the obtained sleep. PMID- 25810917 TI - Symptomatic empty sella syndrome: an unusual manifestation of Erdheim-Chester disease. AB - Erdheim-Chester disease (ECD) is a potentially fatal condition characterized by infiltration of multiple organs by non-Langerhans histiocytes. Although endocrine dysfunction has been reported in association with ECD, to date, there have been no previous reports of empty sella syndrome (ESS) associated with it. We report the case of a patient with ECD who had symptomatic ESS. A 55-year-old man of Chinese ethnicity initially presented with symptoms of heart failure, fatigue and knee joint pain. Physical examination revealed xanthelasma, gynaecomastia, lung crepitations, hepatomegaly and diminished testicular volumes. He had laboratory evidence of hypogonadotrophic hypogonadism, secondary hypoadrenalism and GH deficiency. Imaging studies showed diffuse osteosclerosis of the long bones on X ray, a mass in the right atrium and thickening of the pleura and of the thoracic aorta on fusion positron emission tomography-computed tomography. Magnetic resonance imaging (MRI) of the brain showed an empty sella. The diagnosis of ECD was confirmed by bone biopsy. LEARNING POINTS: ECD is a multisystemic disease that can affect the pituitary and other organs. The diagnosis of ECD is based on clinical and radiological features and histology, showing lipid-laden CD68(+) CD1a(-) S100(-) histiocytes surrounded by fibrosis.The finding of xanthelasmas especially in the presence of normal lipid levels in the presence of a multisystem infiltrative disorder should raise the suspicion of ECD.Systemic perturbation of autoimmunity may play a role in the pathogenesis of ECD and is an area that merits further research. PMID- 25810918 TI - A Nationwide Assessment of the Burden of Urinary Tract Infection among Renal Transplant Recipients. AB - Objective. Evaluate the prevalence and outcomes of urinary tract infection (UTI) among renal transplant recipients. Methods. A secondary analysis of the Nationwide Inpatient Sample 2009-2011 was conducted. Survey-weighted multivariable regression analyses were used to examine the impact of UTI on transplant complications, total charges, and length of stay. Results. A total of 1,044 renal transplant recipients, representing a population estimate of 49,862, were included in the study. UTI was most common in transplant recipients with hypertension (53%) and prevalence was noted to be 28.2 and 65.9 cases per 1,000 for men and women, respectively. UTI increased the likelihood of transplant complications (182% for men, 169% for women). Total charges were 28% higher among men as compared to 22% among women with UTI. Such infection also increased the length of stay by 87% among men and 74% among women. Discussion. UTI in renal transplant recipients was associated with prolonged length of stay, total charges, and increased odds of transplant complications. Interventions to prevent UTI among such patients should be a priority area for future research and practice. PMID- 25810916 TI - Thrombocytopenia in adult patients with sepsis: incidence, risk factors, and its association with clinical outcome. AB - BACKGROUND: Sepsis is a major risk factor for the development of thrombocytopenia, but few studies have specifically evaluated prognostic importance of thrombocytopenia in patients with sepsis. We investigated the incidence, risk factors, and prognostic importance of thrombocytopenia in adult patients admitted to the intensive care unit (ICU) with sepsis. METHODS: A retrospective analysis of patients admitted with severe sepsis/septic shock from December 2007 to January 2009 to a 24-bed medical ICU was done. RESULTS: A total of 304 patients were included in the study. The patients' mean (+/-SD) age was 68.8 (+/-15.8) years. The majority (93.7%) had septic shock, and pneumonia was the most common infection (38.8%). Thrombocytopenia developed in 145 patients (47.6%): 77 (25.3%) at ICU admission and 68 (22.3%) during their hospital course. The median (IQR) duration of thrombocytopenia was 4.4 (1.9-6.9) days. Patients who developed thrombocytopenia had more episodes of major bleeding (14.4% vs. 3.7%, P < 0.01) and received more transfusions. Patients with thrombocytopenia had a higher incidence of acute kidney injury (44.1% vs. 29.5%, P < 0.01), prolonged vasopressor support (median (IQR): 37 (17-76) vs. 23 (13-46) h, P < 0.01), and longer ICU stay (median (IQR): 3.1 (1.6-7.8) vs. 2.1 (1.2-4.4) days, P < 0.01). The 28-day mortality was similar between patients with and without thrombocytopenia (32.4% vs. 24.5%, P = 0.12). However, while 15 of 86 patients (17.4%) who resolved their thrombocytopenia died, 32 of 59 patients (54.2%) whose thrombocytopenia did not resolve died (P < 0.01). The association between non resolution of thrombocytopenia and mortality remained significant after adjusting for age, APACHE III score and compliance with a sepsis resuscitation bundle (P < 0.01). CONCLUSIONS: Thrombocytopenia is common in patients who are admitted to the ICU with severe sepsis and septic shock. Patients with thrombocytopenia had more episodes of major bleeding, increased incidence of acute kidney injury, and prolonged ICU stay. Non-resolution of thrombocytopenia, but not thrombocytopenia itself, was associated with increased 28-day mortality. PMID- 25810919 TI - Precision of corneal thickness measurements obtained using the scheimpflug placido imaging and agreement with ultrasound pachymetry. AB - Purpose. To assess the reliability and comparability of measuring central corneal thickness (CCT) and thinnest corneal thickness (TCT) using a new Scheimpflug Placido analyzer (TMS-5, Japan) and ultrasound (US) pachymetry. Methods. Seventy six healthy subjects were prospectively measured 3 times by 1 operator using the TMS-5, 3 additional consecutive scans were performed by a second operator, and ultrasound (US) pachymetry measurements were taken. The test-retest repeatability (TRT), coefficient of variation (CoV), and intraclass correlation coefficient (ICC) were calculated to evaluate intraoperator repeatability and interoperator reproducibility. Agreement among the devices was assessed using Bland-Altman plots and 95% limits of agreement (LoA). Results. The intraoperators TRT and CoV were <19 MUm and 2.0%, respectively. The interoperators TRT and CoV were <12 MUm and 1.0%, respectively, and ICC was >0.90. The mean CCT and TCT measurements using the TMS-5 were 15.97 MUm (95% LoA from -26.42 to -5.52 MUm) and 20.32 MUm (95% LoA from -30.67 to -9.97 MUm) smaller, respectively, than those using US pachymetry. Conclusions. The TMS-5 shows good repeatability and reproducibility for measuring CCT and TCT in normal subjects but only moderate agreement with US pachymetry results. Caution is warranted before using these techniques interchangeably. PMID- 25810920 TI - The long-term financial and clinical impact of an electronic health record on an academic ophthalmology practice. AB - Purpose. To examine financial and clinical work productivity outcomes associated with the use of the electronic health record (EHR). Methods. 191,360 billable clinical encounters were analyzed for 12 clinical providers over a 9-year study period during which an EHR was implemented. Main outcome measures were clinical revenues collected per provider and secondary outcomes were charge capture, patient visit coding levels, transcription costs, patient visit volume per provider, digital drawing, and digital imaging volume. Results. The difference in inflation adjusted net clinical revenue per provider per year did not change significantly in the period after EHR implementation (mean = $404,198; SD = $17,912) than before (mean = $411,420; SD = $39,366) (P = 0.746). Charge capture, the proportion of higher- and lower-level visit codes for new and established patients, and patient visits per provider remained stable. A total savings of $188,951 in transcription costs occurred over a 4-year time period post-EHR implementation. The rate of drawing the ophthalmic exam in the EHR was low (mean = 2.28%; SD = 0.05%) for all providers. Conclusions. This study did not show a clear financial gain after EHR implementation in an academic ophthalmology practice. Ophthalmologists do not rely on drawings to document the ophthalmic exam; instead, the ophthalmic exam becomes text-driven in a paperless world. PMID- 25810921 TI - Twelve-Year Outcomes of Pterygium Excision with Conjunctival Autograft versus Intraoperative Mitomycin C in Double-Head Pterygium Surgery. AB - Purpose. The study aims to compare the long-term outcome of conjunctival autograft (CAU) and mitomycin C (MMC) in double-head pterygium surgery. Methods. This is a follow-up study of a comparative interventional trial. Thirty-nine eyes of the 36 patients with double-head pterygium excision in the original study 12 years ago were recruited for clinical assessment. Seven out of the 36 patients were lost. In the original study, each eye with double-head pterygium was randomized to have pterygium excision with CAU on one "head" (temporal or nasal) and MMC on the other "head." All patients were invited for clinical assessment for conjunctival bed status and the presence of pterygium recurrence in the current study. Results. There was no significant difference between the size, morphology, and type of pterygium among the two treatment groups. The recurrence rate of CAU group and MMC group 12 years after excision was 6.3% and 28.1%, respectively (P = 0.020). Among eyes without recurrence, the conjunctival bed was graded higher in the MMC group than the CAU group (P = 0.024). Conclusion. The use of conjunctival autograft has a significantly lower long-term recurrence rate than mitomycin C in double-head pterygium surgery. PMID- 25810922 TI - A Peer Health Educator Program for Breast Cancer Screening Promotion: Arabic, Chinese, South Asian, and Vietnamese Immigrant Women's Perspectives. AB - This study explored Arabic, Chinese, South Asian, and Vietnamese immigrant women's experiences with a peer health educator program, a public health program that facilitated access to breast health information and mammography screening. Framed within critical social theory, this participatory action research project took place from July 2009 to January 2011. Ten focus groups and 14 individual interviews were conducted with 82 immigrant women 40 years of age and older. Qualitative methods were utilized. Thematic content analysis derived from grounded theory and other qualitative literature was employed to analyze data. Four dominant themes emerged: Breast Cancer Prevention focused on learning within the program, Social Support provided by the peer health educator and other women, Screening Services Access for Women centered on service provision, and Program Enhancements related to specific modifications required to meet the needs of immigrant women accessing the program. The findings provide insights into strategies used to promote breast health, mammography screening, and the improvement of public health programming. Perceived barriers that continue to persist are structural barriers, such as the provision of information on breast cancer and screening by family physicians. A future goal is to improve collaborations between public health and primary care to minimize this barrier. PMID- 25810923 TI - Adherence to methotrexate in rheumatoid arthritis: a danish nationwide cohort study. AB - Objectives. To study adherence to methotrexate (MTX) and factors of importance thereof in patients with rheumatoid arthritis (RA). Methods. Patients with a hospital diagnosis of RA (ICD10 codes M05.X or M06.X) after January 1, 1997, and aged >=18 years at the date of first diagnosis/contact, with at least one prescription of MTX (L04AX03), were included. Results. A total of 18,703 (47.6%) patients had ever used MTX among 39,286 with a diagnosis of RA; among the MTX users, 16,503 (88.2%) had filed more than one MTX prescription. The median time from diagnosis to first MTX prescription was 0.66 (IQR 0.26-1.80) years. In those who filed more than one MTX prescription, the mean adherence time for >=7.5 mg MTX per week was 1,925 (IQR 467-3,056) days for patients treated in private practice versus 1,892 (IQR 452-3,316) days for patients treated in hospital. The main determinants of nonadherence were female gender, younger age, and time from diagnosis to initiation of MTX. Conclusions. Treatment at hospital or in private practice did not influence the adherence to MTX. Nonmodifiable factors of importance were gender and age, while adherence to MTX therapy decreased with time lapse between diagnosis and prescription. PMID- 25810924 TI - Formulation development and evaluation of fast disintegrating tablets of salbutamol sulphate, cetirizine hydrochloride in combined pharmaceutical dosage form: a new era in novel drug delivery for pediatrics and geriatrics. AB - The objective of the present study was to prepare the fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form for respiratory disorders such as bronchitis, asthma, and coughing for pediatrics and geriatrics. The tablets were prepared by direct compression technique. Superdisintegrant such as Sodium Starch Glycolate was optimized as 4% on the basis of least disintegration time. Different binders such as MCC and PVP K-30 were optimized along with optimized superdisintegrant concentration. 1% MCC was selected as optimum binder concentration on the basis of least disintegration time. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and drug content uniformity. Optimized formulation was further evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. Percent weight variation and content uniformity were within the acceptable limit. The friability was less than 1%. The wetting time and disintegration time were practically good for all formulations. FTIR studies and accelerated stability study showed that there was no interaction between the drug and excipients. It was concluded that, by employing commonly available pharmaceutical excipients such as superdisintegrants, hydrophilic and swellable excipients and proper filler, a fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form, were formulated successfully with desired characteristics. PMID- 25810925 TI - The surgical treatment of pelvic bone metastases. AB - Pelvic bone metastases are a growing concern in the field of orthopedic surgery. Patients with pelvic metastasis are individually different with different needs of treatment in order to attain the best possible quality of life despite the advanced stage of disease. A holistic collaboration among the oncologist, radiation therapist, and orthopedic surgeon is mandatory. Special attention has to be directed to osteolytic lesions in the periacetabular region as they can provoke pathological fractures and subsequent functional impairment. Different reconstruction techniques for the pelvis are available; the choice depends on the patient's prognosis, size of the bone defect, and response of the tumor to adjuvant treatment. If all the conservative treatments are exhausted and the patient is not eligible for surgery, one of the various percutaneous ablation procedures can be considered. We propose a pelvic analogue to the treatment algorithm in long bone metastasis and a scoring system in pelvic metastasis. This algorithm aims to simplify the teamwork and to avoid under- or overtreatment of pelvic bone metastases. PMID- 25810928 TI - Delayed replantation of avulsed teeth: two case reports. AB - This case report presents two cases of delayed replantation of avulsed maxillary central incisors after an extended dry extra-alveolar period. Eight-year-old boy and 10-year-old boy presented with avulsed maxillary central incisors due to trauma occurring 27 and 7 hours earlier, respectively. Treatment guidelines for avulsed mature/immature permanent teeth with prolonged extra-oral time were carried out for the teeth and the extra-oral endodontic treatment was completed. After having been repositioned, the teeth were stabilized for 4 weeks and prophylactic antibiotic was prescribed. Clinical and radiographic controls were done after 18 months for Case I and 12 months for Case II. During the follow-up periods the teeth reported in these cases have remained in a stable, functional position but revealed clinical initial replacement resorption and ankylosis. PMID- 25810929 TI - Severe impaction of the primary mandibular second molar accompanied by displacement of the permanent second premolar. AB - Tooth impaction is defined as any tooth that fails to erupt into a normal functional position and remains unerupted beyond the time at which it should normally erupt. Reports of impaction and eruption failure in primary teeth are relatively rare compared to permanent teeth. We report 2 rare cases where the second premolar was located on the occlusal side of the impacted mandibular second primary molar. In the first case, the succedaneous permanent tooth erupted after extraction of the primary tooth, fenestration, and traction. In the second case, the succedaneous permanent tooth erupted without fenestration or traction. Although the etiology of the tooth displacement was unknown in both cases, inhibition of the eruptive movement of the primary molar may have been associated with displacement of the succedaneous permanent premolar. PMID- 25810930 TI - Ectopic compound odontoma in the buccal mucosa: report of a rare case. AB - Eruption of tooth into extraosseous locations is an extremely rare condition. We report a case of a six-year-old girl child with tooth-like structure erupting from the right buccal mucosa. Clinical, radiographic, and histopathologic examination suggested the diagnosis of compound odontoma. Very few cases have been reported so far, where tooth has been located completely in the soft tissue and a variety of names have been used for that condition. A brief review of the literature and the ambiguity in naming the situation is discussed. PMID- 25810931 TI - Severe Bradycardia Possibly due to a Local Anesthetic Oral Mucosal Injection during General Anesthesia. AB - Local anesthesia may induce systemic complications leading to parasympathetic activity leading to bradycardia and hypotension. We report a case of a 50-year old man undergoing dental surgery under general anesthesia who experienced severe bradycardia and hypotension after local anesthesia infiltration. Concerns regarding the utilization of a relatively large lumen injection needle for local anesthesia during general anesthesia are discussed. PMID- 25810932 TI - Methimazole associated neutropenia in a preterm neonate treated for hyperthyroidism. AB - Maternal Graves' disease is relatively uncommon with an estimated incidence of 0.4%-1% of all pregnancies, but only 1-5% of newborns delivered to mothers with Graves' disease develop overt clinical signs and symptoms of hyperthyroidism. Here, we describe a case of a 1380-gram female neonate who was born at 30-week gestation to a mother with Graves' disease. Our patient presented with hyperthyroidism followed by transient hypothyroidism requiring treatment with levothyroxine. While hyperthyroid, she was treated with methimazole, iodine, and a beta-blocker. 20 days after the initiation of methimazole, she developed neutropenia. The neutrophil counts started to improve immediately after the initiation of the weaning of methimazole. To the best of our knowledge, this is the first case reported in the literature of methimazole induced neutropenia in a preterm infant being treated for neonatal Graves' disease. PMID- 25810927 TI - Combined cognitive-psychological-physical intervention induces reorganization of intrinsic functional brain architecture in older adults. AB - Mounting evidence suggests that enriched mental, physical, and socially stimulating activities are beneficial for counteracting age-related decreases in brain function and cognition in older adults. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate the functional plasticity of brain activity in response to a combined cognitive-psychological-physical intervention and investigated the contribution of the intervention-related brain changes to individual performance in healthy older adults. The intervention was composed of a 6-week program of combined activities including cognitive training, Tai Chi exercise, and group counseling. The results showed improved cognitive performance and reorganized regional homogeneity of spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signals in the superior and middle temporal gyri, and the posterior lobe of the cerebellum, in the participants who attended the intervention. Intriguingly, the intervention-induced changes in the coherence of local spontaneous activity correlated with the improvements in individual cognitive performance. Taken together with our previous findings of enhanced resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe regions following a combined intervention program in older adults, we conclude that the functional plasticity of the aging brain is a rather complex process, and an effective cognitive-psychological-physical intervention is helpful for maintaining a healthy brain and comprehensive cognition during old age. PMID- 25810933 TI - A Case of Apoplexy of Rathke's Cleft Cyst Followed by Cerebral Infarction. AB - Rathke's cleft cyst (RCC) apoplexy is a rare clinical entity. We report a case of apoplexy of an RCC followed by cerebral infarction. A 67-year-old woman was found lying on the street unconscious. She had fallen from her motorbike. On referral to our hospital she gradually regained consciousness and presented with no neurological deficits. CT showed a round and slightly hyperdense area in the suprasellar region. However, the attending physician did not find this abnormal finding on CT and the patient was discharged the same day. Thirteen days after the first emergency visit she developed left hemiparesis and dysarthria. CT showed a round hypodense area in the suprasellar region. The change of the density in the suprasellar region on CT suggested the pituitary apoplexy. CT also showed a low density area in the territory of the right middle cerebral artery, which indicated the cerebral infarction. MR angiography revealed poor visibility and stenotic changes of right middle cerebral arteries. Transsphenoidal surgery was performed. Histopathological findings confirmed a hemorrhagic RCC. Postoperative MR angiography showed that the visibility and stenosis of right middle cerebral arteries were recovered. This is the rare case of apoplexy of an RCC followed by cerebral infarction. PMID- 25810935 TI - Drug-Induced Thrombocytopenia following a Transvaginal Oocyte Retrieval for In Vitro Fertilization. AB - Drug-induced immune thrombocytopenia has been associated with hundreds of medications and can lead to devastating consequences for the patient. We present a case of a healthy 33-year-old female undergoing in vitro fertilization who developed a severe drug-induced thrombocytopenia, petechiae, and a large hemoperitoneum after receiving Cefazolin antibiotic prophylaxis for a transvaginal oocyte retrieval. The patient was admitted to the intensive care unit for resuscitation with blood products. The presence of drug-dependent platelet antibodies to Cefazolin was confirmed serologically. PMID- 25810934 TI - Intrasplenic Arterial Aneurysms during Pregnancy. AB - Splenic artery aneurysms account for about 60% of all visceral aneurysms. Pregnancy is a risk factor for splenic artery aneurysms rupture with high maternal mortality and fetal loss. Intrasplenic arterial aneurysms are extremely rare and have not been reported to be associated with pregnancy. This report presents a 34-year-old woman during the second trimester, admitted with severe left upper quadrant and left shoulder pain. She had two uncomplicated intrasplenic aneurysms. Splenectomy was done. She delivered a full term healthy girl. This is the first report of acute abdomen during pregnancy caused by intrasplenic artery aneurysms with maternal and fetal survival. PMID- 25810936 TI - Superior vena cava syndrome and colon carcinoma: a report of a multifactorial association. AB - Introduction. Superior vena cava (SVC) syndrome results from the obstruction of blood flow through the SVC, having distinct pathophysiological underlying mechanisms. Cancer is associated with an increased risk of thromboembolism that varies according to patient-, tumor-, and treatment-related factors. An individualized clinical approach is important to pursue the accurate diagnosis of the underlying pathology causing thromboembolism in cancer patients. Case Presentation. The authors present a case of a 58-year-old male with an infrequent presentation of an unknown colon carcinoma, who has never had any symptom until he was hospitalized with the diagnosis of superior vena cava syndrome and pulmonary thromboembolism. The patient had an advanced disease by the time of diagnosis and molecular alterations contributing to abnormal hemostasis. He presented venous and arterial thromboembolism and developed disseminated intravascular coagulopathy after surgery, anticoagulant and transfusion therapy, dying 40 days after the hospitalization. Conclusion. The authors discuss thromboembolic disease and tumor metastasis roles in a cancer patient with SVC syndrome. Thromboembolism in a malignancy context is a challenging clinical entity. A multifactorial perspective of the thrombotic disease is warranted to approach thromboembolism risk and stratify patients suitable to receive adequate anticoagulant prophylaxis and targeted therapies, aiming to improve clinical prognosis. PMID- 25810926 TI - Neuroplasticity underlying the comorbidity of pain and depression. AB - Acute pain induces depressed mood, and chronic pain is known to cause depression. Depression, meanwhile, can also adversely affect pain behaviors ranging from symptomology to treatment response. Pain and depression independently induce long term plasticity in the central nervous system (CNS). Comorbid conditions, however, have distinct patterns of neural activation. We performed a review of the changes in neural circuitry and molecular signaling pathways that may underlie this complex relationship between pain and depression. We also discussed some of the current and future therapies that are based on this understanding of the CNS plasticity that occurs with pain and depression. PMID- 25810938 TI - Cicatricial ectropion secondary to psoriatic arthritis. AB - Ectropion is characterized by the eversion of the eyelid margin and the consequent exposure of the conjunctiva and cornea. The shortening of the anterior lamella of the lid causes cicatricial ectropion. We described a case of skin pathology causing cicatricial ectropion. The case is about a 68-year-old woman with a 2-year history of psoriatic arthritis. She complained of eyelid tearing and redness for two years. Due to the psoriasis, she presented a very dry skin, also in the periocular region, resulting in cicatricial ectropion. A skin graft was indicated to correct the eyelid malposition. Careful investigation should be performed in patients who have a skin disease that can lead to cicatricial ectropion. PMID- 25810937 TI - Metastatic extrapulmonary small cell carcinoma to the cerebellopontine angle: a case report and review of the literature. AB - Extrapulmonary small cell carcinomas (EPSCC) are rare malignancies with poor patient prognoses. We present the case of a 63-year-old male who underwent surgical resection of a poorly differentiated small cell carcinoma, likely from a small intestinal primary tumor that metastasized to the cerebellopontine angle (CPA). A 63-year-old male presented with mild left facial paralysis, hearing loss, and balance instability. MRI revealed a 15 mm mass in the left CPA involving the internal auditory canal consistent with a vestibular schwannoma. Preoperative MRI eight weeks later demonstrated marked enlargement to 35 mm. The patient underwent a suboccipital craniectomy and the mass was grossly different visually and in consistency from a standard vestibular schwannoma. The final pathology revealed a poorly differentiated small cell carcinoma. Postoperative PET scan identified avid uptake in the small intestine suggestive of either a small intestinal primary tumor or additional metastatic disease. The patient underwent whole brain radiation therapy and chemotherapy and at last follow-up demonstrated improvement in his symptoms. Surgical resection and radiotherapy are potential treatment options to improve survival in patients diagnosed with NET brain metastases. We present the first documented case of skull base metastasis of a poorly differentiated small cell carcinoma involving the CPA. PMID- 25810939 TI - Parathyroid adenoma with prominent lymphocytic infiltrate. AB - Only very few previously reported cases of pronounced lymphocytic infiltration in parathyroid adenoma can be found in the English medical literature. The objective of this report is to present such a rare case and to investigate to a certain extent the immunohistochemical profile of this rare histologic observation. The lymphoid cell population within the tumour was composed of nodule-forming B-cells and different subsets of infiltrating T-cells and caused minimal destruction of neoplastic tissue. PMID- 25810940 TI - Self-inflicted needle injuries to the eye: a curing pain. AB - There are few reports of severe self-injury to eyes in patients with schizophrenia. We report on a 41-year-old woman, primarily visiting for symptoms of endophthalmitis resulting from self-inflicted needles. Further evaluations established the diagnosis of schizophrenia because of arguing and commenting on auditory hallucinations and negative symptoms including social isolation, decreased self-care, blunt affect, and a monotone voice. The patient had been suffering from auditory hallucinations for several years and found relief in bodily pain caused by needles. The patient received 6 mg of risperidone. Hallucinations were resolved and self-injury behaviour was not repeated. PMID- 25810941 TI - A Rare Cause of Cavitary Lesion in the Lung: Richter's Transformation. AB - Richter's transformation (RT) refers to the development of aggressive lymphoma during the course of CLL. Clinically, patients with RT present with an aggressive disease course with rapidly enlarging lymph nodes, hepatosplenomegaly, and elevated serum lactate dehydrogenase levels. But rarely it presents with extra nodal organ involvement at the beginning. Common sites of extra nodal involvement are the gastrointestinal tract, eye, central nervous system, lung, and kidney. We are reporting this case that was presented with RT in the lung involvement diagnosed while researching cavitary lesion etiology. PMID- 25810942 TI - Laparoscopic excision of coexisting left tubal and right pseudotubal pregnancy after conservative management of previous ectopic pregnancy with methotrexate: an unusual clinical entity. AB - Tubal pregnancy concerns 97% of all ectopic pregnancies. Treatment can be either surgical (salpingostomy or salpingectomy) or medical (methotrexate administration). We present a case of a pseudotubal pregnancy after methotrexate treatment of a previous ectopic pregnancy. A37-year-old woman was diagnosed with ectopic pregnancy in the left Fallopian tube. A year ago, she had an ectopic pregnancy in the right tube, which was successfully treated with intramuscular methotrexate. During laparoscopy, two tubal masses were revealed, one in each Fallopian tube, and bilateral salpingectomy was performed. Histological analysis confirmed tubal pregnancy in the left Fallopian tube and presence of endosalpingitis in the right tube with no signs of chorionic villi. The optimal management of such cases has not yet been clarified. However, evaluation of tubal patency after a medically treated ectopic pregnancy would permit proper counsel of the patient on her fertility options, in order to choose the appropriate method of conception to achieve and accomplish a future pregnancy. PMID- 25810943 TI - 28-Year Survival following Several Metastasectomies, Going through 8th Line Systemic Therapy in a Case of mRCC. AB - Metastatic renal cell carcinoma (mRCC) has been one of the most treatment resistant cancers because of its unpredictable clinical course, resistance to chemo- and radiotherapy, and the limited response to immunotherapy and targeted agents. We present a case of long-term survival, that is, 28 years, after primary diagnosis (longest survival in the literature up to our knowledge) with mRCC after several metastasectomies (from local site recurrence, liver, and lung) and eight lines of systemic targeted therapy. This case report shows how crucial is the regular follow-up of patients with RCC after primary management and positive impact of early metastasectomy and systemic targeted therapy in case of mRCC on patients' condition and overall survival. PMID- 25810944 TI - Upper limb ischemic gangrene as a complication of hemodialysis access. AB - Upper limb ischemia is a well-recognized complication of dialysis access creation but progression to gangrene is uncommon. We report a case of upper limb ischemic gangrene and discuss the lessons learned during the management of this case. Clinicians must be vigilant for this complication and they should be reminded that it requires urgent management to prevent tissue loss. PMID- 25810945 TI - Evolution of Metabolic Abnormalities in Alcoholic Patients during Withdrawal. AB - Chronic alcohol intoxication is accompanied by metabolic abnormalities. Evolution during the early withdrawal period has been poorly investigated. The aim of this study was to determine the evolution of metabolic parameters during alcohol withdrawal. Patients and Methods. Thirty-three patients admitted in our department for alcohol withdrawal were prospectively included. Results. Baseline hypophosphatemia was found in 24% of cases. FEPO4 was reduced from 14.2 +/- 9% at baseline to 7.3 +/- 4.2% at day 3 (P < 0.01). FEPO4 inversely correlated with albuminemia (rs = -0.41, P = 0.01). CPK level was 124 +/- 104 IU/L in men and 145 +/- 85 IU/L in women (nl < 308 and <192 IU/L, resp.), 7% and 28% of patients having a CPK level >nl, respectively. No correlation was found between the sodium and CPK levels (P = 0.75) nor between the CPK level and the amount of alcohol ingested (rs = 0.084, P = 0.097). Baseline urate level was elevated and returned to normal after three days. Baseline magnesium concentration was normal and stable over time. Conclusion. Chronic alcohol intoxication was accompanied by phosphaturia, rapidly reversible after alcohol withdrawal and inversely correlated with albuminemia, slight hyponatremia, low levels of 25 hydroxy vitamin D, elevated CPK level in about 30% of women, and hyperuricemia with rapid normalization. PMID- 25810946 TI - Neighborhood characteristics associated with the availability of alcohol outlets in quebec, Canada. AB - Objectives. The objectives of this study were to examine the spatial accessibility to alcohol outlets in Quebec and to assess the association between neighborhood level characteristics and availability of alcohol outlets. Methods. The Tobit Model was used to assess the association between neighborhood level characteristics and the availability of alcohol outlets within 500, 1000, 2000, and 3000 metres, respectively. Results. Alcohol outlets were found to be most available in the two largest metropolitan areas of the province of Quebec (Montreal and Quebec City). Within 1000 metres, alcohol outlets are more available in neighbourhoods with the following characteristics: highest concentration of men, least materially deprived highest concentration of persons aged 20 years or more, and location either in a metropolitan area or in a small town. Finally, the number of bars with video lottery terminals increases with the level of social and material deprivation. Conclusion. In Quebec, there is no rule governing the location of alcohol outlets. Thus, there is an abundant literature indicating that the regulation of alcohol outlet density could be an effective means of controlling risk attributable to alcohol consumption. PMID- 25810947 TI - Beneficial Effects of Teucrium polium and Metformin on Diabetes-Induced Memory Impairments and Brain Tissue Oxidative Damage in Rats. AB - Objective. The effects of hydroalcoholic extract of Teucrium polium and metformin on diabetes-induced memory impairment and brain tissues oxidative damage were investigated. Methods. The rats were divided into: (1) Control, (2) Diabetic, (3) Diabetic-Extract 100 (Dia-Ext 100), (4) Diabetic-Extract 200 (Dia-Ext 200), (5) Diabetic-Extract 400 (Dia-Ext 400), and (6) Diabetic-Metformin (Dia-Met). Groups 3-6 were treated by 100, 200, and 400 mg/kg of the extract or metformin, respectively, for 6 weeks (orally). Results. In passive avoidance test, the latency to enter the dark compartment in Diabetic group was lower than that of Control group (P < 0.01). In Dia-Ext 100, Dia-Ext 200, and Dia-Ext 400 and Metformin groups, the latencies were higher than those of Diabetic group (P < 0.01). Lipid peroxides levels (reported as malondialdehyde, MDA, concentration) in the brain of Diabetic group were higher than Control (P < 0.001). Treatment by all doses of the extract and metformin decreased the MDA concentration (P < 0.01). Conclusions. The results of present study showed that metformin and the hydroalcoholic extract of Teucrium polium prevent diabetes-induced memory deficits in rats. Protection against brain tissues oxidative damage might have a role in the beneficial effects of the extract and metformin. PMID- 25810951 TI - A verification strategy for web services composition using enhanced stacked automata model. AB - Currently, Service-Oriented Architecture (SOA) is becoming the most popular software architecture of contemporary enterprise applications, and one crucial technique of its implementation is web services. Individual service offered by some service providers may symbolize limited business functionality; however, by composing individual services from different service providers, a composite service describing the intact business process of an enterprise can be made. Many new standards have been defined to decipher web service composition problem namely Business Process Execution Language (BPEL). BPEL provides an initial work for forming an Extended Markup Language (XML) specification language for defining and implementing business practice workflows for web services. The problems with most realistic approaches to service composition are the verification of composed web services. It has to depend on formal verification method to ensure the correctness of composed services. A few research works has been carried out in the literature survey for verification of web services for deterministic system. Moreover the existing models did not address the verification properties like dead transition, deadlock, reachability and safetyness. In this paper, a new model to verify the composed web services using Enhanced Stacked Automata Model (ESAM) has been proposed. The correctness properties of the non-deterministic system have been evaluated based on the properties like dead transition, deadlock, safetyness, liveness and reachability. Initially web services are composed using Business Process Execution Language for Web Service (BPEL4WS) and it is converted into ESAM (combination of Muller Automata (MA) and Push Down Automata (PDA)) and it is transformed into Promela language, an input language for Simple ProMeLa Interpreter (SPIN) tool. The model is verified using SPIN tool and the results revealed better recital in terms of finding dead transition and deadlock in contrast to the existing models. PMID- 25810949 TI - Inhibition of Pasteurella multocida Adhesion to Rabbit Respiratory Epithelium Using Lectins. AB - This study aimed to evaluate the ability of a panel of lectins to inhibit the ability of Pasteurella multocida to adhere to and affect the rabbit respiratory epithelium. Nasal septa from rabbit fetuses were cultured with various lectins before the addition of P. multocida. The percentage of bacteria adhering to the epithelium was evaluated semiquantitatively by indirect immunoperoxidase (IIP) staining. The goblet cells (GCs) were counted in semithin sections stained with toluidine blue and served as the main morphological criterion to evaluate the inhibitory effect of the lectins. The lectins PNA, WGA, RCA120, and DBA significantly inhibited the adhesion of P. multocida to the ciliated epithelium (P < 0.05) and prevented the pathogen-induced increase in the number of GCs (P < 0.05) compared with those of positive control tissues. In addition, VVA, SJA, UEA I, DSL, SBA, and ECL significantly inhibited the increase in GCs compared with that of the control tissues. The results suggest that less aggressive therapeutic strategies, such as treatment with lectins, may represent alternative approaches to control bacterial respiratory infections. PMID- 25810950 TI - Unprotected left main percutaneous coronary intervention in acute coronary syndromes with extracorporeal life support backup. AB - Background. Left main PCI is superior to coronary bypass surgery in selected patients. Registry data, however, suggest significant early adverse event rates associated with unprotected left main PCI. We aimed to evaluate safety of an extracorporeal life support (ECLS) as backup system during PCI. Methods. We report a registry study of 16 high-risk patients presenting with acute coronary syndromes undergoing unprotected left main PCI with an ECLS backup. Results. Seven patients (43.8%) presented with an acute myocardial infarction while 9 patients (56.3%) had unstable angina. Unprotected left main PCI could be successfully performed in all 16 patients. Mortality or thromboembolic event rates were zero within the index hospital stay. General anesthesia was necessary only in 5 patients (31.3%). Access site bleeding requiring transfusion was encountered in 4 patients (25.0%). Three patients (18.8%) developed access site complications requiring surgical intervention. All patients were ECLS-free after 96 hours. Conclusions. Unprotected left main PCI could be safely and effectively performed after ECLS implantation as backup in acute coronary syndromes in our patient collectively. Vascular access site complications however need to be considered when applying ECLS as backup system. PMID- 25810953 TI - Exact solutions of unsteady Korteweg-de Vries and time regularized long wave equations. AB - In this paper, we implement the exp(-Phi(xi))-expansion method to construct the exact traveling wave solutions for nonlinear evolution equations (NLEEs). Here we consider two model equations, namely the Korteweg-de Vries (KdV) equation and the time regularized long wave (TRLW) equation. These equations play significant role in nonlinear sciences. We obtained four types of explicit function solutions, namely hyperbolic, trigonometric, exponential and rational function solutions of the variables in the considered equations. It has shown that the applied method is quite efficient and is practically well suited for the aforementioned problems and so for the other NLEEs those arise in mathematical physics and engineering fields. PACS numbers: 02.30.Jr, 02.70.Wz, 05.45.Yv, 94.05.Fq. PMID- 25810952 TI - Daily consumption of milk fat globule membrane plus habitual exercise improves physical performance in healthy middle-aged adults. AB - Our recent studies demonstrated that habitual exercise plus dietary supplementation with milk fat globule membrane (MFGM) improved endurance capacity and muscle function by stimulating neuromuscular development in mice. The aim of this study was to investigate the efficacy of dietary MFGM supplementation plus habitual exercise on the physical performance of middle-aged Japanese adults in a pilot randomized, double-blind, placebo-controlled trial. Forty-four subjects (men, n = 22; women, n = 22) were randomly assigned into two groups: one received placebo tablets (placebo group, n = 22 [men, n = 11; women, n = 11]), while the other received MFGM tablets (MFGM group, n = 22 [men, n = 11; women, n = 11]). The subjects ingested either MFGM (1 g/day) or placebo (1 g/day of whole milk powder) tablets every day for the 10-week study period and engaged in an exercise training program twice per week. A physical function test was performed at baseline and at 5 and 10 weeks. A significant group-by-time interaction was found for the side step test, muscle cross-sectional area (CSA), and muscle fiber conduction velocity (MFCV). In the placebo group, there were no significant intragroup differences. In the MFGM group, side step score and muscle CSA were significantly greater at 10 weeks compared to the baseline, and MFCV was significantly higher than that in the placebo group at 10 weeks. The changes in percentage of the side step score, muscle CSA, and MFCV in the MFGM group were significantly higher than in the placebo group at 10 weeks. These results suggest that daily MFGM ingestion combined with regular exercise might enhance physical performance such as agility in middle-aged adults. PMID- 25810954 TI - Direct Observation of Reversible Biomolecule Switching Controlled By Electrical Stimulus. PMID- 25810956 TI - What is new in critical illness and injury science? Acetazolamide in decompensated respiratory failure! PMID- 25810955 TI - The epidermal growth factor receptor (EGRF) in lung cancer. AB - In the last decade, important advances have been made in understanding of cancer biology, particularly non-small-cell lung cancer (NSCLC) with the discovery of oncogenic drivers of the disease. The epidermal growth factor receptor (EGFR) gene and its pathways was the first oncogenic driver discovered to be mutated and treatable in lung cancer. Treatment with EGFR tyrosine kinase inhibitors (TKIs) is the standard of care for molecularly selected EGFR-mutant patients, while its role in unselected lung cancer patients is nowadays controversial. This review will provide an overview of the EGFR pathway and options for its treatment of lung cancer. PMID- 25810957 TI - Impact of acetazolamide use in severe exacerbation of chronic obstructive pulmonary disease requiring invasive mechanical ventilation. AB - PURPOSE: To analyse the impact of acetazolamide (ACET) use in severe acute decompensation of chronic obstructive pulmonary disease requiring mechanical ventilation and intensive care unit (ICU) admission. PATIENTS AND METHODS: Retrospective pair-wise, case-control study with 1:1 matching. Patients were defined as cases when they had received acetazolamide (500 mg per day) and as controls when they did not received it. Patients were matched according to age, severity on admission (pH, PaO2/FiO2 ratio) and SAPSII score. Our primary endpoint was the effect of ACET (500 mg per day) on the duration of mechanical ventilation. Our secondary endpoints were the effect of ACET on arterial blood gas parameters, ICU length of stay (LOS) and ICU mortality. RESULTS: Seventy-two patients were included and equally distributed between the two studied groups. There were 66 males (92%). The mean age (+/- SD) was 69.7 +/- 7.4 years ranging from 53 to 81 years. There were no differences between baseline characteristics of the two groups. Concomitant drugs used were also not significantly different between two groups. Mean duration of mechanical ventilation was not significantly different between ACET(+) and ACET(-) patients (10.6+/-7.8 days and 9.6+/-7.6 days, respectively; P = 0.61). Cases had a significantly decreased serum bicarbonate, arterial blood pH, and PaCO2 levels. We did not found any significant difference between the two studied groups in terms of ICU LOS. ICU mortality was also comparable between ACET(+) and ACET(-) groups (38% and 52%, respectively; P = 0.23). CONCLUSION: Although our study some limitations, it suggests that the use of insufficient acetazolamide dosage (500 mg/d) ACET (500 mg per day) has no significant effect on the duration of mechanical ventilation in critically ill COPD patients requiring invasive mechanical ventilation. Our results should be confirmed or infirmed by further studies. PMID- 25810959 TI - Mid-gestational serum uric acid concentration effect on neonate birth weight and insulin resistance in pregnant women. AB - OBJECTIVE: To investigate the relationship between mid-gestational serum uric acid and birth weight in diabetic pregnant women with or without insulin resistance. METHODS: In a prospective cohort study, fasting uric acid, blood glucose, and serum insulin were measured in 247 pregnant women between 20-22 weeks of gestational period. Insulin resistance was estimated using the homeostasis model assessment-insulin resistance (HOMA-IR). Stratification analysis and independent t-test was used to assess the association between uric acid and birth weights regarding to insulin resistance. RESULTS: The means of the mid-gestational serum uric acid concentrations were not significantly different in women with and without insulin resistance. But stratification analysis showed that there was a significant difference between uric acid concentration and macrosomic birth in diabetic women without insulin resistance. CONCLUSIONS: Higher mid - gestation serum uric acid concentration, even if it does not exceed the normal range, is accompanied by lower birth weight only in non-insulin resistance women. Insulin resistance could have a negative confounding effect on hyperuriemia and birth weight. PMID- 25810958 TI - The assessment of an in-vitro model for evaluating the role of PARP in ethanol mediated hepatotoxicity. AB - This investigation aims to assess whether the hepatocellular carcinoma cell line, HepG2, is an appropriate model to assess the role of poly (ADP-ribose) polymerase (PARP) during acute ethanol toxicosis. HepG2 cells were dosed with graded concentrations of ethanol, ranging from 100 mM to 800 mM, for 6 hours to assess PARP activity induction, while another parallel experiment examined cellular damage via medium aspartate aminotransferase activity and cellular viability via MTT reduction. Aspartate aminotransferase activity was significantly elevated at 600 mM ethanol (FOLD; P < 0.01), with further increases at the 800 mM dose (1.43 fold; P < 0.001), compared to controls. Cellular viability was not significantly decreased compared to controls among all dose groups. PARP activity measured in total cell lysates showed a significant decreasing trend with respect to ethanol dose, reaching statistical significance at the 100 mM dose group (P < 0.05). Paradoxically, exposure to 50 MUM etoposide (Positive apoptosis-inducing control) did not demonstrate significant PARP activity ablation. When analyzing PARP activity observation temporally, a significant correlation (R(2) =0.5314) was observed between activity and assay sequence. Overall, a clear HepG2 insensitivity to ethanol was observed. PMID- 25810960 TI - Analysis of pediatric trauma data from a hospital based trauma registry in Qatar. AB - BACKGROUND: Trauma is the leading killer in the young age children, but data about the injury burden on pediatric population are lacking. The aim of this study is to describe the epidemiology and outcome of the traumatic injuries among children in Qatar. MATERIALS AND METHODS: This is a retrospective analysis of a trauma registry database, which reviewed all cases of serious traumatic injury (ISS >= 9) to children aged 0-18 years who were admitted to the national pediatric Level I trauma center at the Hamad General Hospital (HGH), over a period of one year. Data included demographics, day of injuries, location, time, type and mechanism of injuries, co-morbidity, safety equipment use, pre-hospital intubation, mode of pre-hospital transport, Glasgow Coma Scale (GCS), Injury Severity Score (ISS), emergency department (ED) intervention, hospital length of stay and mortality outcome. RESULTS: The incidence of severe pediatric trauma was 163 per 280,000 children who visited the ED of HGH in 2011. Out of them, 83% were male, mean age was 9.6 +/- 5.9 years and mortality rate was 1.8%. On presentation to the ED, the mean ISS was 13.9 +/- 6.6 and GCS was 13.4 +/- 3.8. Over half of the patients needed ICU admission. For the ages 0-4 years, injuries most frequently occurred at home; for 5-9 years (59%) and 15-18 years (68%), the street; and for 10-14 years (50%), sports and recreational sites. The most common mechanisms of injury for the age groups were falls for 0-4 years, motor vehicle collision (MVC) or pedestrian injury for 5-9 years, all-terrain vehicle (ATV)/bicycle injuries for 10-14 years, and MVC injuries for 15-18 years. Head (34%) and long bone (18%) injuries were the most common, with 18% suffering from polytrauma. None of the patients were using safety equipment when injured. CONCLUSION: Traumatic injuries to children have an age- and mechanism-specific pattern in Qatar. This has important implications for the formulation of focused injury prevention programs for the children of Qatar. PMID- 25810961 TI - A comparative evaluation of magnesium sulphate and nitroglycerine as potential adjuncts to lidocaine in intravenous regional anaesthesia. AB - INTRODUCTION: This randomized control trial was carried out to evaluate and compare the efficacy of magnesium sulphate and nitroglycerine (NTG) as adjuncts to lidocaine in intravenous regional anesthesia (IVRA). MATERIALS AND METHODS: Seventy-five, ASA grade I and II patients, aged between 20-50 years, scheduled for hand and forearm surgery were selected and entered randomly into three study groups. Patients in group C received 3 mg/kg of preservative free lidocaine 2% diluted with saline to a total volume of 40 ml. Patients in group M received 3 mg/kg of preservative free lidocaine 2% mixed with 6 ml of 25% magnesium sulphate (1.5 g) diluted with saline to a total volume of 40 ml. Patients in group N received 3 mg/kg of preservative free lidocaine 2% mixed with 200 MUg of nitroglycerine diluted with saline to a total volume of 40 ml. Sensory and motor block onset and recovery time, tourniquet pain onset time, intraoperative fentanyl requirement, the total number of patients requiring rescue analgesia and the time to first analgesia requirement, intra-operative and postoperative degree of analgesia were evaluated. RESULTS: The sensory and motor block onset times were shorter in group M and N as compared to group C (P- = 0.004, 0.0036 for sensory block, 0.021, 0.038 for motor block. The mean time of onset of sensory block was earliest in group M and the mean time of onset of motor block was earliest in group N. Mean time of onset of tourniquet pain in the three groups was similar in groups M and N. The sensory and motor block recovery time were significantly prolonged in M and N group as compared to group C (P < 0.001). Intraoperative fentanyl requirement (P value- = 0.041), the total number of patients requiring rescue analgesia (P value = 0.009) and the time to first analgesia requirement (P value = 0.038) were lower in group M. CONCLUSION: The addition of both magnesium suphate and nitroglycerin (NTG) to lidocaine for intravenous regional anesthesia (IVRA) leads to early onset of sensory block and prolonged postoperative analgesia, with no side effects. PMID- 25810962 TI - Diagnosing bacterial peritonitis made easy by use of leukocyte esterase dipsticks. AB - INTRODUCTION: Spontaneous bacterial peritonitis (SBP) requires rapid diagnosis for the initiation of antibiotics. Its diagnosis is usually based on manual examination of ascitic fluid (AF) having long reporting time. AF infection is diagnosed when the fluid polymorphonuclear leukocyte (PMNL) concentration >=250 cells/mm(3). AIMS AND OBJECTIVES: Aim was to evaluate the diagnostic utility of leukocyte esterase (LE) reagent strip for rapid diagnosis of SBP in patients who underwent abdominal paracentesis and to calculate the sensitivity, specificity, positive, and negative predictive values. MATERIALS AND METHODS: The study was carried out on 103 patients with ascites. Cell count of AF as determined by colorimetric scale of Multistix 10 SG reagent strip was compared with counting chamber method (PMNL count >=250 cells/mm(3) was considered positive). RESULTS AND OBSERVATIONS: Of the 103 patients SBP was diagnosed in 20 patients, 83 patients were negative for SBP by manual cell count. The sensitivity and specificity of the LE test for detecting neutrocytic SBP taking grade 2 as cut off were 95% and 96.4% respectively, with a positive predictive value of 86.4% and a negative predictive value of 98.8%. Diagnostic accuracy of LE test was 96.1%. DISCUSSION: There was a good correlation between the reagent strip result and PMNL count. The LE strip test is based on the esterase activity of activated granulocytes which reacts with an ester-releasing hydroxyphenylpyrrole causing a colour change in the azo dye of reagent strip. It is a very sensitive and specific method for the prompt detection of elevated PMNL count, and represents a convenient, inexpensive, simple, and bedside method for diagnosis of SBP. A negative LE test result excludes SBP with a high degree of certainty. PMID- 25810963 TI - Clinical conundrums and challenges during geriatric orthopedic emergency surgeries. AB - Despite so many advancements and innovations in anesthetic techniques, expectations and challenges have also grown in plenty. Cardiac, pediatric, obstetric and neuro-anesthesia have perfectly developed to fulfill the desired needs of respective patient population. However, geriatric anesthesia has been shown a lesser interest in teaching and clinical practices over the years as compared with other anesthetic sub-specialties. The large growing geriatric population globally is also associated with an increase number of elderly patients presenting for orthopedic emergency surgeries. Orthopedic emergency surgery in geriatric population is not only a daunting clinical challenge but also has numerous socio-behavioral and economic ramifications. Decision making in anesthesia is largely influenced by the presence of co-morbidities, neuro cognitive functions and the current socio-behavioral status. Pre-anesthetic evaluation and optimization are extremely important for a better surgical outcome but is limited by time constraints during emergency surgery. The current review aims to highlight comprehensively the various clinical, social, behavioral and psychological aspects during pre-anesthetic evaluation associated with emergency orthopedic surgery in geriatric population. PMID- 25810964 TI - Seatbelt versus seatbelt and airbag injuries in a single motor vehicle crash. AB - Seatbelt restraints are important for occupant safety which substantially reduces morbidity and mortality in severe motor vehicle crashes (MVC). Though, it has been established that the air bag and seatbelt use reduce injury severity and mortality but still there is limited information on the pattern of injury by restraint type. Herein, we presented two case reports which describe the injury pattern of two patients (both were restrained but only driver had airbag) involved in a single MVC. Both of them had severe traumatic injuries, however, the restrained passenger without airbag, sustained more severe injuries of intestine, kidney and spinal cord. In addition to seatbelt, airbag provides considerable protection against severe blunt abdominal trauma. Therefore, installation of airbags especially for front seat passenger is imperative for minimizing the risk of significant traumatic injuries. PMID- 25810965 TI - An uncommon pulmonary embolism. AB - OBJECTIVES: To report an unusual case of suicide attempt secondary complicated of pulmonary and systemic embolisms. DATA SOURCE: A 49-year-old-woman, with a factor V Leiden mutation and a notion of chronic depression, admitted to our intensive care unit for a suicide attempt by ingestion ofmepronizine and lormetazepam. DATA EXTRACTION: We report the rare evolution of this patient with a persistent alteration of consciousness associating a respiratory degradation. Despite the drug intoxication and possibility of aspiration, we performed a computed tomography (CT) angiography which confirmed the presence of a bilateral, proximal, pulmonary embolism suspected on transthoracic echocardiography. A cerebral CT showed left sylvian and cerebellar infarctions complicated of perilesional edema. Association of stroke and pulmonary embolism led us to suspect a patent foramen ovale (PFO). There was also a context of genetical perturbation of hemostasis. Transesophageal echocardiography confirmed the presence of a PFO undiagnosed by transthoracic echography. The PFO was complicated by an entrapped thrombus. The thrombotic complications were treated by unfractionated heparin. DATA SYNTHESIS: Neurological and respiratory degradation following voluntary drug intoxication led to the discovery of both a pulmonary and cerebral embolism secondary to a PFO entrapped thrombus. CONCLUSIONS: An entrapped thrombus in a PFO is a rare and dangerous situation, associated with many complications. Association of systemic and pulmonary embolisms should lead to PFO detection to guide therapeutic interventions. PMID- 25810967 TI - Massive intracardiac thrombosis during coronary artery bypass grafting surgery. AB - Thrombosis is a potential life-threatening complication in patients undergoing cardiac surgery. Various clinical and heritable conditions, like cancer, trauma, immobilization, the presence of factor V Leiden or prothrombin 20210A, deficiency of or resistance to the inhibitor proteins C, S, or antithrombin, elevated levels of coagulation proteins, antiphospholipid antibody syndrome, pregnancy, and the use of exogenous hormones, may contribute to catastrophic thrombosis. Massive thrombi with cerebrovascular and cardiovascular events develop in patients with polycythemia vera (PV). However, thrombus formation in the cardiac chambers is extremely rare. We report a case of massive intracardiac thrombosis in a patient undergoing coronary artery bypass grafting. PMID- 25810968 TI - Cerebral venous sinus thrombosis with nontraumatic subdural hematoma. PMID- 25810966 TI - Metastatic transitional cell carcinoma presenting with skin metastasis. AB - Transitional cell carcinomas (TCC) of upper urinary system account for 5% of all TCCs. The incidence of such metastases ranges from 0.18% to 2%. Experimental studies reported a general unsatisfactory survival time following skin metastasis. We report in this paper a case of metastatic urinary system TCC, which had become evident with a skin lesion in the right hypogastric region. A 60 year-old female patient with a history of being operated upon due to renal pelvic TCC was admitted to our outpatient clinic with complaints of red skin lesion in the near vicinity of the operational incision scar for 3 months. Her medical history revealed nothing but nephroureterectomy operation on the upper urinary system; moreover, it was learned that she had been ignoring what was recommended to her for routine controls. Thoraco-abdominal computed tomographic (CT) examination performed on the basis of aforementioned findings depicted a mass lesion of 24*20 mm dimension with high contrast uptake detected within the subcutaneous fat tissue in the right abdominal wall. The skin lesion depicted in CT was surgically excised. The pathological examination of the excised material was reported to be compatible with TCC. The patient was referred due to abdominal lesion to medical oncology after the operation. Followed up under chemotherapy protocol, the patient died 3 months after the metastasectomy operation. Skin metastasis of upper urinary system TCCs, especially renal pelvic TCCs, are quite rare conditions. Among the likely skin sites of metastasis for genitourinary system TCCs are head, face, extremities, suprapubic region and abdomen. Taking into consideration the low survival rates, the importance of early diagnosis of recurrences and/or distant metastases should be better appreciated. These patients die soon after the skin metastasis even with the administration of aggressive therapy. Similarly, our patient died 90 days after the diagnosis of skin metastasis despite the oncologic therapy. PMID- 25810969 TI - Severe hemophagocytic lymphohistiocytosis as a complication of drug-induced hypersensitivity syndrome. PMID- 25810970 TI - A letter in response to "Thoracostomy tubes: A comprehensive review of complications and related topics". PMID- 25810971 TI - Predictors of mortality in poisonous snake bite. PMID- 25810972 TI - Guillain-Barre syndrome presenting as Bell's palsy with crossed hemiparesis. PMID- 25810973 TI - Partial optic atrophy and homonymous quadrantanopia in a patient with occipital encephalomalacia. PMID- 25810974 TI - Child-witnessed domestic violence: An epidemic in the shadows. PMID- 25810975 TI - A crying shame: Battered baby. PMID- 25810976 TI - New year's eve pediatric celebratory gunshot wound. PMID- 25810948 TI - Monoamine reuptake inhibitors in Parkinson's disease. AB - The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4 dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia. PMID- 25810977 TI - Concomittant chronic lymphocytic leukemia and colon cancer a patient presenting with ileus. PMID- 25810978 TI - Prevalence of derangement of coagulation profile in surgical patients and its outcome in India. PMID- 25810979 TI - Lack of social or political demand for good health care in India: impact on unfolding universal health coverage. PMID- 25810980 TI - Evaluation of teaching and learning in family medicine by students: a sri lankan experience. AB - BACKGROUND: Family Medicine occupies a prominent place in the undergraduate curriculum of the Faculty of Medicine, University of Kelaniya, Sri Lanka. The one month clinical attachment during the fourth year utilizes a variety of teaching methods. This study evaluates teaching learning methods and learning environment of this attachment. METHODOLOGY: A descriptive cross sectional study was carried out among consenting students over a period of six months on completion of the clinical attachment using a pretested self administered questionnaire. RESULTS: Completed questionnaires were returned by 114(99%) students. 90.2% were satisfied with the teaching methods in general while direct observation and feed back from teachers was the most popular(95.1%) followed by learning from patients(91.2%), debate(87.6%), seminar(87.5%) and small group discussions(71.9%). They were highly satisfied with the opportunity they had to develop communication skills (95.5%) and presentation skills (92.9%). Lesser learning opportunity was experienced for history taking (89.9%), problem solving (78.8%) and clinical examination (59.8%) skills. Student satisfaction regarding space within consultation rooms was 80% while space for history taking and examination (62%) and availability of clinical equipment (53%) were less. 90% thought the programme was well organized and adequate understanding on family medicine concepts and practice organization gained by 94% and 95% of the students respectively. CONCLUSIONS: Overall student satisfaction was high. Students prefer learning methods which actively involve them. It is important to provide adequate infra structure facilities for student activities to make it a positive learning experience for them. PMID- 25810981 TI - Four new vaccines for routine immunization in India: what about hemophilus influenza B and pneumococcal vaccine? AB - Immunization is the process whereby a person is made immune or resistant to an infectious disease, typically by the administration of a vaccine. The Expanded Program on Immunization (EPI) was flagged off in India in 1978. According to the recommendation of National technical advisory group of India (NATGI), Government of India is going to include four new vaccines in the UIP for whole India. The four new vaccines are Inactivated Poliomyelitis Vaccine (IPV) for polio, rota viral vaccine, vaccine against rubella, and Japanese encephalitis vaccine (179 districts in India). Here, authors have tried to show a comparative descriptive analysis of the hemophilus influenza and pneumococcal pneumonia with rota virus, so that in near future Government of India can also consider their inclusion in the national UIP. In India, 39.2% of all diarrheal death are due to rota virus, whereas 0.72 million deaths are due to hemophilus influenza B and 1.3 million are due to pneumococcal pneumonia in <5 years age-group. India's indigenous developed rota viral vaccine's (Rotavac) efficacy is 56% in 1(st) year compared to H influenza B (Hib) efficacy 95% and PCV13 vaccine "3 + 1" dose efficacy 100% (South Africa). Rotarix incremental cost-effectiveness ratio is US $21.4 to US $34 per disability-adjusted life years (DALYs) compared to Hib US $ 819 per DALYs in India. In case of pneumococcal vaccine, India needs more trails on the serotype specificity, efficacy, and cost-effectiveness but there is enough evidence that hemophilus influenza burden is high in India and the present Hib vaccine is safe and highly effective. In future with the help of donor agencies, India should include the hemophilus influenza B and pneumococcal pneumonia vaccine in national UIP which will save millions of poor children's life. PMID- 25810983 TI - Making a case for melanoma screening: look, listen and feel. PMID- 25810982 TI - Primary care in dentistry - an untapped potential. AB - Dentistry is neither an allied health profession nor a paramedical profession. It is the only anatomically focused health care profession that is university-based and for which primary care responsibility is maintained by the profession. Dentists must have a reliable knowledge of basic clinical medicine for safely and effectively treating individuals with chronic and other diseases, which make them biologically and pharmacologically compromised. With changes in the life expectancy of people and lifestyles, as well as rapid advancement in biomedical sciences, dentists should have similar knowledge like a physician in any other fields of medicine. There are number of primary care activities that can be conducted in the dental office like screening of diabetics, managing hypertension etc., The present review was conducted after doing extensive literature search of peer-reviewed journals. The review throws a spotlight on these activities and also suggests some the measures that can be adopted to modify dental education to turn dentists to oral physicians. PMID- 25810984 TI - Psychological Co-morbidity in Children with Specific Learning Disorders. AB - Children under 19 years of age constitute over 40% of India's population and information about their mental health needs is a national imperative. Children with specific learning disorders (SLDs) exhibit academic difficulties disproportionate to their intellectual capacities. Prevalence of SLD ranges from 2% to 10%. Dyslexia (developmental reading disorder) is the most common type, affecting 80% of all SLD. About 30% of learning disabled children have behavioral and emotional problems, which range from attention deficit hyperactivity disorder (most common) to depression, anxiety, suicide etc., to substance abuse (least common). Co-occurrence of such problems with SLD further adds to the academic difficulty. In such instances, diagnosis is difficult and tricky; improvement in academics demands comprehensive holistic treatment approach. SLD remains a large public health problem because of under-recognition, inadequate treatment and therefore merits greater effort to understand the co-morbidities, especially in the Indian population. As the literature is scarce regarding co-morbid conditions in learning disability in Indian scenario, the present study has tried to focus on Indian population. The educational concessions (recent most) given to such children by Central Board of Secondary Education, New Delhi are referred to. The issues to be addressed by the family physicians are: Low level of awareness among families and teachers, improper dissemination of accurate information about psychological problems, available help seeking avenues, need to develop service delivery models in rural and urban areas and focus on the integration of mental health and primary care keeping such co-morbidity in mind. PMID- 25810985 TI - Posterior tibial tendon dysfunction: an overlooked cause of foot deformity. AB - Posterior tibial tendon dysfunction is the most common cause of adult acquired flatfoot. Degenerative changes in this tendon, lead to pain and weakness and if not identified and treated will progress to deformity of the foot and degenerative changes in the surrounding joints. Patients will complain of medial foot pain, weakness, and a slowly progressive foot deformity. A "too many toes" sign may be present and patients will be unable to perform a single heal raise test. Investigations such X-ray, ultrasound and magnetic resonance imaging will help stage the disease and decide on management. The optimal manage may change based on the progression of deformity and stage of disease. Early identification and prompt initiation of treatment can halt progression of the disease. The purpose of this article is to examine the causes, signs, symptoms, examinations, investigations and treatment options for posterior tibial tendon dysfunction. PMID- 25810986 TI - Assessment of Depression in a Primary Care Setting in Nigeria using the PHQ-9. AB - CONTEXT: Mental disorders are major contributors to the burden of diseases all over the world. In general practice, which provides essentially primary care, depression is the most common mental disorder seen and often goes unrecognized. AIMS: The aims of the study were to determine the prevalence of depression, the variables associated with depression, and the degree of recognition by the Physician in family medicine unit. SETTING AND DESIGN: A cross-sectional descriptive survey of consecutive patients who presented at the general medical out-patient unit of the State University Teaching Hospital, Ado-Ekiti, Nigeria was done. MATERIALS AND METHODS: Data were collected using a questionnaire incorporating sociodemographic variables and primary diagnosis made by attending Physician. Depression was assessed with the PHQ-9. RESULTS: Two hundred and seventy two patients were interviewed during the period of the study. Participants were mostly of 45 years or older (51.2%), female (59.9%), married (68.4%), and educated (85.7%). One hundred and thirty (47.8%) of the respondents had significant depressive symptoms with majority (49.2%) being classified as mild. Statistical analysis revealed significant association between depression and age, gender, marital status, and clinical diagnoses (P < 0.05). Over a quarter (28.7%) were presented with infectious diseases, other diagnoses made included cardiovascular disorders (15.8%), endocrine disorders (8.8%), psychiatric disorders other than depression (2.9%) and none had depression as primary diagnosis. CONCLUSIONS: The prevalence of depression among patients attending the general medical out-patient clinics is high and highly under recognised. PMID- 25810987 TI - Education-related Inequity in Access and Utilization of Oral Health Care in Iran. AB - BACKGROUND: Oral health affects peoples' lives physically and psychologically and is related to general health, quality of life, and feelings of social well-being. As the educational level is an important predictor of healthy life and can affect healthcare utilization, this study aims to estimate the inequity related to the educational level of parents on the access and utilization of oral health care (OHC) in Qom, Iran. STUDY DESIGN: An analytical, cross-sectional study. MATERIALS AND METHODS: Overall 281 children, six to seven years of age, were given a self administrated questionnaire to fill. The sex, access to utilization of OHC, and educational level of the children's parents were questioned. The concentration (C) index was used as the inequity measure and statistical inference was conducted by chi square and the confidence interval of C. STATISTICS: The mean age of the children was 6.48 +/- 0.5 years. There was not statistically significant difference in the access and utilization rate of OHC between the two sexes (P > 0.05). There was an increasing trend in the utilization rate of OHC, because of the increased educational level of the parents. The C for access and utilization rate, for different levels of fathers' education was 0.055(-0.095 to 0.205) and 0.097(-0.068 to 0.261) and for mothers' educational level was 0.086( 0.068 to 0.241) and 0.091(-0.81 to 0.263), respectively. CONCLUSION: Our results did not show evidence of sex disparity in the access and utilization of OHC in Iranian children. Also the inequity related to the educational level in access and utilization of OHC was low and not considerable. PMID- 25810988 TI - The Prevalence and Sociodemographic Risk Factors of Enuresis Nocturna among Elementary School-age Children. AB - INTRODUCTION AND AIM: Many etiological reasons are blamed for enuresis nocturna (EN). The aim of this study was to research prevalence and severity of EN among elementary school-age children and sociodemographic risk factors related to it. MATERIALS AND METHODS: The study was performed in three elementary schools in Ankara, Turkey between January and May 2011. It was planned to have 2500 students of 6-14 ages in the study. The questionnaire, which consisted of questions, aiming to evaluate the EN condition of participants and their characteristics, were distributed to the parents. It was observed that 2314 participants' questionnaires (92.56%) were in accordance with evaluation criteria. STATISTICAL ANALYSIS: The relation between EN and the sociodemographic factors was evaluated through Chi-square test and logistic regression analysis. RESULTS: The mean age of 2314 participants was 9.21 +/- 2.08. 48.5% (n = 1123) of the students were male and 51.5% (n = 1191) were female. While the general EN prevalence was 9.9% (n = 230); 10.7% (n = 120) for males, as 9.2% (n = 110) for females. Statistical significant difference was determined between the two groups, with EN and without EN, regarding age groups (P < 0.001), education level of parents (P < 0.001, P < 0.001), and the number of sibling (P = 0.002), income level (P < 0.001), and positive family history (P < 0.001). However, logistic regression analysis revealed that there was a significant difference only between EN and age groups (odds ratio [OR] =4.42, P < 0.001), education level of mother (OR = 2.13, P = 0.017) and family history (OR = 0.12, P < 0.001). CONCLUSIONS: As a consequence, such factors as age groups, education level of parents, positive family history could be accepted as a risk of concerning EN. It is important to perform a detailed evaluation on population, carrying risk of having EN. PMID- 25810990 TI - Patient Perceptions and Expectations From Primary Health-care Providers in India. AB - INTRODUCTION: The study of patient satisfaction at the primary care level has been mostly neglected in India. AIM: This objective of this study was to assess indices of Patient Satisfaction at the level of the family physician which is usually the first point of contact between the patient and the health-care system. MATERIALS AND METHODS: This study was carried out at a Private Primary Health-Care Center in a semirural area in New Delhi, by exit interviews in the form of a questionnaire from patients randomly selected from people visiting the center during the study period. STATISTICAL ANALYSIS: Descriptive statistical analysis was carried out on the data collected. RESULTS: The findings revealed that 83.58% of the patients were satisfied with the general experience and the behavior of the health-care provider and 85.9% were satisfied with the treatment and care provided, only 65.5% were satisfied with the physical environment of the clinic. However, the percentage of patients who would recommend the facility to their friends was overwhelming (94.6%). CONCLUSION: These results show that private health-care providers are still the first choice for any form of medical care. However, there was definitely a gap between the increasing expectations of the patients for more information, better Patient-Provider interaction, more control over the treatment process and better amenities even at the Primary Care level. It is this gap, which needs to be fulfilled to facilitate better utilization of Primary Health-Care Services in the community and reduce pressure on tertiary care services in order to ensure Universal Health Coverage. This study would also help us understand the challenges for Primary Care service providers, private and public, in a low socioeconomic urban setting. PMID- 25810991 TI - A study of the prevalence of serum vitamin B12 and folic Acid deficiency in Western maharashtra. AB - CONTEXT: This study summarizes the prevalence of vitamin B12 and folic acid deficiency in the population coming to tertiary care center in Western Maharashtra along with the main presenting symptom routinely misinterpreted in daily practice. AIMS AND OBJECTIVES: 1. To study the prevalence of vitamin B12 and folic acid deficiency in the population of western Maharashtra. 2. To correlate the symptoms with serum vitamin B12 and folic acid levels. MATERIALS AND METHODS: The present study is a cross-sectional observation study carried out on patients from western Maharashtra seeking medical attention on outpatient and inpatient basis in the medicine department of a teaching institute in Karad. One hundred patients were selected on basis of below mentioned symptoms viz. tingling and numbness in extremities, dizziness, unsteady gait, early tiredness, forgetfulness, proximal weakness, distal weakness, chronic headache, less interest in work, chronic loose stools, strict vegetarians, alcoholics, intake of medications like anti-tubercular treatment, surgery involving terminal ileum. Serum vitamin B12 and folic acid levels of these patients were observed. Deficiency of vitamin B12 and folic acid was studied in 4 groups: (a) Absolute vitamin B12 deficiency; (b) Absolute folic acid deficiency; (c) Borderline vitamin B12 deficiency; (d) Combined vitamin B12 and folic acid deficiency. RESULTS: Of the 100 cases, 33% patients were vegetarian. Folic acid deficiency formed the major chunk of deficiency group. Six percent patients had neuropsychiatric manifestations. Depressive illness in 1% patients, dementia in 0% patients, forgetfulness in 1% patients, mania/hallucination in 0% patients each, and chronic headache in 1% patients. Neuropathy in form of loss of reflexes, decreased touch sensation was present in 9% patients. Posterior column involvement viz. Loss of joint position, vibration, positive Romberg's sign were present in 34% patients of vitamin B12 and folic acid deficiency. CONCLUSION: In a small study, it was found that megaloblastic anemia may have symptoms and signs referable to several systems including hematology, dermatology, gastrointestinal, neurology, and neuropsychiatry. PMID- 25810989 TI - Nonalcoholic Fatty liver disease and risk of diabetes and cardiovascular disease: what is important for primary care physicians? AB - Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver condition in Western World and across the globe. NAFLD prevalence is estimated to be around one-third of the total population. There are no published data that project the future prevalence of NAFLD, but with an increase in epidemic of diabetes and obesity, it is possible to suggest an increase in a number of individuals with NAFLD. NAFLD is associated with insulin resistance and occurs with an increase in cluster of features of metabolic syndrome and type 2 diabetes. Therefore, it is important to exclude the possibility of diabetes in those individuals with evidence of fatty liver. The global diabetes epidemic continues to grow, and it is estimated that the number of people with diabetes will double by year 2030. NAFLD is also a risk factor for an increase in cardiovascular incidence independent of age, sex, low-density lipoprotein cholesterol, smoking, and cluster of metabolic syndromes. It is expected that NAFLD will be an important challenge for health providers in the near future. Taking all these factors into consideration, we believe that increasing awareness of metabolic and cardiovascular impact of NAFLD among general practitioners and health authorities may decrease the serious consequences of late diagnosis of NAFLD. Importantly, the collaboration between medical specialties is vital in decreasing the impact of the epidemic of NAFLD. The focus of this review is in the role of primary care physician in diagnosis, treatment and prevention of NAFLD and patients education. PMID- 25810992 TI - Quality of Life among Persons with Physical Disability in Udupi Taluk: A Cross Sectional Study. AB - BACKGROUND: Disability is not just a health problem or attribute of individuals, but it reflects the problems individuals experience in their interaction with society and physical movements. Disabled persons remain neglected part of society and they also experience various barriers due to restriction of participation. OBJECTIVES: The aim was to assess the quality of life (QOL) of physically disabled persons, the impact of physical disability on activities of daily living (ADL) and to study the awareness about laws and facilities available for disabled persons. MATERIALS AND METHODS: A cross-sectional community based study was conducted among 130 physical disabled persons who were selected using convenience sampling technique. The WHO BREF scale was used to assess QOL, while assessment of ADL was done using Barthel Index. Socio-demographic assessment was done using Udai Pareek scale. SPSS version 15.0 was used to analyze data. Categorical variables were expressed as frequencies and percentages. As per guidelines physical, psychological, social, and environmental domain scores for WHO BREF scale were calculated. RESULTS: Among the study participants, 36.2% had a disability from birth that is, congenital. The second common cause of disability was found to be postpolio residual paralysis as it was found among 26.2% respondents. Other causes found were stroke/paralysis and accidents, in 19.2% and 18.5% respondents, respectively. Activities such as transfer, mobility, and stair climbing showed greater impact of physical disability. It was found that 11.5% respondents required help in one of the ADL. QOL score was found to be low under the psychological domain reflecting on negative feelings, bodily image, appearance, spirituality, and self-esteem of respondents. CONCLUSION: Physical disability had affected social participation as well as marriage of the respondents. However, it was found that very few of them are aware about facilities provided under persons with disability act. PMID- 25810993 TI - Association of systemic diseases with cutaneous dermatosis in elderly population: preliminary observation at a rural tertiary care centre. AB - INTRODUCTION: Aging population is susceptible to many cutaneous and systemic diseases, simultaneously leading to impairment of quality of life in them. AIM: To know the association of dermatosis and systemic diseases in geriatric age group. MATERIALS AND METHODS: A retrospective study was carried on patients above 60 years of age who visited the Dermatology OPD at rural tertiary care centre from June 2009 to May 2010. Patients were assessed on a prescribed 30 point proforma. RESULTS: Total 457 geriatric patients with dermatosis were registered under the study, of these 203 patients had one or more systemic diseases. Hypertension (70.9%) was the commonest disease, followed by diabetes (32.5%). Eczema was commonest dermatosis in patients with hypertension and generalized pruritus in diabetes. CONCLUSION: Skin diseases cause considerable morbidity in elderly, particularly if associated with other comorbid conditions, so health promotion and education can do much to reduce the risk. PMID- 25810994 TI - Efficacy of supplementation in filipino children. AB - INTRODUCTION: At present, in the absence of an anemia prevention and screening program in Barangay Vasra, this will aid in the formation of programs that would teach about this health related issue, with an intervention that could be used efficiently by the health workers at the non-government organization run center. OBJECTIVE: The aim of the following study is to establish the efficacy of iron supplementation alone versus iron and ascorbic acid supplementation in improving the hemoglobin (Hgb), hematocrit (Hct), reticulocyte count and red cell indices of anemic undernourished children 5-10 years of age at Lingap Center, Barangay Vasra, Quezon City. METHODOLOGY: Anemic undernourished male and female children 5 10 years of age enrolled in the Supplementary Feeding Program of Lingap Center, Barangay Vasra, Quezon City. STUDY DESIGN: Prospective, experimental trial comparing two interventions-iron supplementation alone versus iron and ascorbic acid supplementation. RESULTS: A total of 25 children participated in this study, with a majority being female at 52% (13/25) of the total. Those who received iron supplementation alone for 6 months, while there were 50% (6/12) of either sex, whereas subjects who took iron and ascorbic acid supplementation for 6 months were predominantly female at 53.85% (7/13). Data obtained before and after iron supplementation alone revealed that there was an increase among the levels of Hgb, Hct, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and reticulocyte count, with the rise statistically significant. Hematological values gained before and after iron and ascorbic acid supplementation uncovered that there was an augmentation among the levels of Hct, MCV, MCH, MCHC and reticulocyte count, with the improvement statistically significant. Encompassing both interventions, the differences in findings were statistically significant in red blood cell (RBC) count, with the level progression statistically significant. CONCLUSION: Overall, the results were statistically significant in terms of RBC count alone. Therefore, this study demonstrated that compliance with intake of supplementation is a factor in improving the hematological parameters of these subjects. To address iron deficiency anemia, a similar endeavor may establish a system of support in Lingap Center to ensure the screening and therapeutic management of this population. PMID- 25810995 TI - Correlates of overweight and obesity among urban adolescents in bihar, India. AB - BACKGROUND: For better perception of adolescent overweight and obesity as a global public health problem, systematic collection of baseline data is urgently needed in India. OBJECTIVE: A community-based study was undertaken for better perception of the prevalence and correlates of obesity in an adolescent urban community in Katihar, Bihar. MATERIALS AND METHODS: A cross-sectional study was conducted among urban adolescents in the eastern part of India to find out prevalence of overweight and obesity and sociodemographic correlates by interview technique followed by clinical examination with ethical consideration. RESULTS: Out of 400 adolescent study participants, 21% were overweight or obese. The study showed that there was a significant association between less consumption of vegetable foods, fruits, meals cooked outside the home, alcohol consumption, yoga practice, socioeconomic status, and the occurrence of overweight/obesity in the adolescents. CONCLUSIONS: We attempted to find out the prevalence and risk correlates of overweight and obesity among adolescents and found it quite alarming compared to developed countries. The urban underserved population in India has difficulty to access quality healthcare and not conscious enough to seek healthcare until critically ill. Community-based studies are required to highlight the problem of obesity among urban adolescents by a comprehensive approach. PMID- 25810996 TI - The prevalence and burden of psychiatric disorders in primary health care visits in qatar: too little time? AB - BACKGROUND: Psychiatric disorders including anxiety, depression, somatization, obsessive compulsive, and bipolar disorders are recognized as causing the biggest burden of disease worldwide. AIM: In this study, we aimed to assess the prevalence and burden of common mental disorders at Primary Health Care Centers (PHCC) using the World Health Organization Composite International Diagnostic Interview (WHO-CIDI) in the Qatari population, aged 18-65 who attended Primary Health Care (PHC) settings. DESIGN: A prospective cross-sectional study conducted during November 2011 to October 2012. SETTING: Primary Health Care Centers of the Supreme Council of Health, Qatar. SUBJECTS: A total of 2,000 Qatari subjects aged 18-65 years were approached; 1475 (73.3%) agreed to participate. METHODS: Prevalence and severity of International Classification of Disease-10 disorders were assessed with the WHO-CIDI (Version 3.0). RESULTS: Of the 1475 participants, 830 (56.3%) were females and 645 (43.7%) was males. One-third were aged 35-49 years 558 (37.8%). The three most common disorders were major depression disorders (18.31%), any anxiety disorders (17.3%), any mood disorders (16.95%), followed by separation anxiety disorders (15.25%), personality disorder (14.1%). In the present study, prevalence in women was significantly higher than men for the most common psychiatric disorders, specifically generalized anxiety disorder, panic disorder, social phobia, specific phobias, obsessive compulsive disorders, posttraumatic disorder, somatization, major depressive disorder, bipolar disorder, dysthymia, and oppositional defiant disorder. Of the total 20% had only one psychiatric diagnosis and 12% had two disorders, 9.7% respondents with three diagnoses, and finally 4.3% of respondents had four or more diagnoses. CONCLUSION: One-fifth of all adults who attended the PHCC (20%) had at least one psychiatric diagnosis. The CIDI is a useful instrument for psychiatric diagnosis in community settings such as PHC clinics, clinical research and intervention studies. There is an urgent need to not only assess prevalence, but also risk factors, burden, treatment gaps and outcomes to obtain evidence for policy making. PMID- 25810997 TI - Seasonality of hepatitis: a review update. AB - BACKGROUND: Viral hepatitis is an infection that has been reported to be present throughout the year, but some particular months are associated with higher incidences. The primary objective was to review and report on the current knowledge and evidence that existed on seasonality of different type of acute viral hepatitis worldwide in order to develop recommendations for future research, prevention and control. MATERIALS AND METHODS: A systematic literature review was performed to identify all the primary reports and studies published during 1970-2013 on acute hepatitis A, B, C and E (AHA, AHB, AHC and AHE) in human subjects by searching PubMed, reference lists of major articles and correspondence with scientific experts. For each report or study included, the following information was extracted (as applicable to study): Location (country and setting), study population (number of cases, patients), seasonal or monthly rate and study duration. RESULTS: There is no definite and consistent seasonal pattern has been observed on AHA; AHB; AHE and AHC, although evidence points towards spring and summer peak for hepatitis A, B, C and E. Multiple source of transmission such as; summer travel to an endemic area, swimming habits of the population in hot months, increase sexual contact, tattoo, poor hygiene and environmental sanitation and food habits (feco-oral transmission of viral hepatitis) probably exists and should be further investigated through analytical and epidemiological. PMID- 25810998 TI - Prediction of ease of laryngoscopy and intubation-role of upper lip bite test, modified mallampati classification, and thyromental distance in various combination. AB - BACKGROUND: The incidence of difficult intubation in patients undergoing general anaesthesia is estimated to be approximately 1-18% whereas that of failure to intubate is 0.05-0.35%.1,2,3 Various methods have been used for prediction of difficult laryngoscopy. Although, upper lip bite has been shown to be a promising test in its introductory article, repeated validation in various populations is required for any test to be accepted as a routine test. We have compared upper lip bite test (ULBT), modified Mallampati test (MMC) and thyromental distance (TMD) individually and in various combinations to verify which of these predictor tests are significantly associated with difficult glottic exposure. METHODS: After obtaining institutional ethics committee approval, 402 ASA I and II adult patients undergoing elective surgical procedures requiring endotracheal intubation were included. All the three test were performed in all the patients preoperatively and their glottic exposure was recorded by Cormack-Lehane classification during intubation. Sensitivity, specificity, positive predictive value and negative predictive value were used for comparison. RESULTS: In our study, the incidence of difficult laryngoscopy was 11.4% and failure to intubate 0.49%. None of the three are a suitable predictive test when used alone. Combination of tests added incremental diagnostic value. CONCLUSION: We conclude that all three screening tests for difficult intubation have only poor to moderate discriminative power when used alone. Combinations of individual tests add some incremental diagnostic value. PMID- 25810999 TI - Epidemiology and Outcome of Chemical Burn Patients Admitted in Burn Unit of JNMC Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India: A 5-year Experience. AB - AIMS AND OBJECTIVE: The objectives of this study were to evaluate the epidemiology, clinical variable of chemical burns, and their outcomes to prevent or reduce the frequency and morbidity of such injuries. MATERIALS AND METHODS: A retrospective analysis was performed on all the patients with chemical burns admitted at author's center between November 2008 and December 2013. All the patients were evaluated in terms of age, sex, total body surface area, etiology, treatment given, morbidity, mortality, final outcome, and then educated regarding specific preventive measures. RESULTS: A total of 96 patients (2.4% of total burn admissions) (42 males and 54 females) were admitted to our hospital with chemical burn injuries. Most of the patients were in the age group of 16-30 years. Incidence in females was slightly higher than in males. Acid was found to be the most common cause of injury. We found 55% patients admitted had <10% total body surface area (TBSA) involvement, 35% had burns involving between 11 and 20% TBSA, and 4% had burns involving 21-30% TBSA, and 6% had burns in >30% TBSA. Morbidity was noticed in the form of skin defect in 80% of cases, soft tissue defect with exposed tendon, bone, or vessels in 16% of cases, and 4% of patients developed contracture and hypertrophic scar. Eighty-six percent of patients required operative intervention. A total of three deaths (3%) were recorded. CONCLUSION: It was found that chemical burns, though not very common, are deeper burns and can be accidental or non-accidental, and the high-risk age group is 16-25 years. Chemical burns are largely preventable and if properly managed have a good outcome. PMID- 25811000 TI - Profile of Diseases Prevalent in a Tribal Locality in Jharkhand, India: A Family Medicine Practitioner's Perspective. AB - BACKGROUND: Majority of Indian population is dependent on general practitioners (GPs) for medical services at primary care level in India. They are most preferred and considered to be first contact person for medical services at primary care level. But advances in medical science has put more emphasis on specialist culture and average Bachelor of Medicine and Bachelor of Surgery (MBBS) graduates who are working as general physician are gradually feeling themselves less competent because they are less exposed to latest advances in treatment of diseases. Amidst such scenario, Christian Medical College (CMC) has come up with an idea: "The refer less and resolve more initiative". It has started a decentralized 2-year family medicine distance diploma course (Postgraduate Diploma in Family Medicine (PGDFM)) now accredited by Dr. MGR Medical University, Chennai, Tamil Nadu, that trains the GPs to become family medicine specialist. MATERIALS AND METHODS: As component of PGDFM course, this study was conducted to provide better understanding of prevalent ailments and common treatment provided by the GPs in the community at present giving key insight of current practice in rural area by a registered family medicine practitioner. RESULTS: As part of study, among 500 patients evaluated, three most common diagnosis were upper respiratory infections (URIs; 18%), acute gastroenteritis including water-borne diseases (15.8%), and anemia (10.4%). Treatment given to these patients comprised of mostly of antipyretic, analgesic, and antimicrobial agents. Most common drug prescribed was paracetamol for fever. Other common drugs prescribed were amoxicillin/clavulanic acid, chloroquine, artemisin derivative, doxycycline, co-trimoxazole, miltefosine, cephalexin, ceftriaxone sodium, cefixime, oral rehydration salts, ranitidine, omeprazole, pantoprazole, metronidazole, albendazole, ondansetron, diclofenac sodium, piroxicam, ibuprofen, diphenhydramine, codeine-sulfate, amlodipine, ramipril, hydrochlorothiazide, atenolol, salbutamol, etophyline, metformin, glimepiride, fluoxetine, flavoxate, tamsulosin, iron-folic acid, etc. The fact that three or more drugs are given in most of the prescriptions, can be justified due to multiple morbidity and the severity of disease than to irresponsible prescribing. PMID- 25811001 TI - Concurrent multiple outbreaks of varicella, rubeola, german measles in unvaccinated children of co-educational mount carmel senior secondary school, thakurdwara palampur of northern himachal, India. AB - BACKGROUND: In April, 2009, in a co-education school, we investigated suspected triple outbreak; varicella first and then with chance detection of rubeola and rubella. The aim was to confirm diagnosis and recommend remedial measures to prevent further outbreaks. MATERIALS AND METHODS: We defined a case of varicella with maculopapulovesicular rash without other apparent cause in students or staff of the school and residents of neighboring villages of Khalet and Roady since 23(rd) March to 14(th) October, 2009. We line listed case patients and collected information on age, sex, residence, date of onset, symptoms, signs, traveling, treatment history, and vaccination status. The outbreak was described by time, place, and person characteristics. Diagnosis was confirmed epidemiologically and serologically; first to chickenpox, measles, and german measles viruses. RESULTS: We identified 505 case patients from mixed outbreaks of varicella, measles, and german measles (30/505 clinically, 467/505 epidemiologically linked and 8/505 laboratory confirmed case patients from a study population of 3280. We investigated the suspected outbreak with case definition of varicella but measles 20/3280 (0.60%) and rubella 34/3280 (1.03%) cases were also observed. The overall attack rate (AR) was 15% while in school; it was 22% but highest (56%) in Nursery up to 4(th) standard with index case in first standard. Sex-specific AR was (23%) more in boys. Triple concurrent infection caused 05% complications but no death was reported. Severity of the symptoms was more in 5(th) standard onwards with 49 249 lesions and severer in poor villages Roady and Khalet (P < 0.05). Only 4% were immunized against varicella/german measles privately. Seventeen percent of the cases went for traditional treatment vs modern medicine (P < 0.001). 5/10 samples for IgM antibodies for chickenpox and 2/10 samples were positive for rubella. CONCLUSIONS: Triple infection of varicella, measles, and rubella was confirmed epidemiologically and serologically. We recommended local authorities for MMRV in the school and near villages with aggressive IEC activities in affected areas. PMID- 25811002 TI - Tonsillar tuberculosis: a forgotten clinical entity. AB - Tuberculosis of tonsils is an extremely rare variety of extra-pulmonary tuberculosis which frequently simulates the tonsillar malignancy, especially in elderly individuals. Secondary form is more common than primary one, and in present day, contact with the infected sputum or saliva in a case of sputum smear positive pulmonary tuberculosis is the main source of the disease. Chronic or recurrent tonsillitis with enlarged tonsils and sore throat is the main clinical presentation. As it is very difficult to differentiate it from tonsillar malignancy on clinical ground, histopathological examination of the tissue is must for the diagnosis of tonsillar TB. Antitubercular therapy is adequate for its successful resolution. Here, we report a primary form of tonsillar tuberculosis in a 76-year-old male, in whom, no pulmonary tuberculosis was documented. PMID- 25811004 TI - Purple urine bag syndrome: time for awareness. AB - Purple urine bag syndrome occurs commonly in long-term catheterized patients causing significant stress for patients, care takers, and health care providers. This may lead to unwarranted investigation as well as treatment when not identified early. Demographic changes in Indian population with increasing geriatric care make it a case to increase awareness of this condition among health care providers in primary and secondary care settings. PMID- 25811003 TI - Eosinophilia induced by clozapine: a report of two cases and review of the literature. AB - Clozapine, an atypical antipsychotic, has been used in the treatment of schizophrenia and other psychotic disorders. Although it has good therapeutic effect but many a time it use is overridden by the associated adverse effects which range from minor to severe life-threatening events. There has been extensive literature for severe side effects like leukocytosis but limited data are available for transient eosinophilia. Here, we present two cases of benign transient eosinophilia and discuss the importance of recognizing eosinophilia while using clozapine. PMID- 25811006 TI - Infantile hemangioma in a v2 distribution: treatment with nadolol. AB - Infantile hemangiomas are common benign tumours of infancy affecting up to 10% of children. They are typically not present at birth but undergo a rapid proliferation stage and then plateau in growth before resolving spontaneously. Recently, beta-blockers have been favoured over systemic corticosteroids for treatment of disfiguring or life-threatening infantile hemangiomas. We present a case of an 11-week-old female with a 7 week history of an evolving hemangioma along a facial V2 distribution. Physical exam revealed a well-defined bright red plaque over the right zygoma and lower eyelid. MRI, echocardiograph, and liver ultrasound were normal. Patient was treated with nadolol and had a rapid and substantial regression of the hemangioma. Nadolol is an effective treatment option for disfiguring facial infantile hemangioma. The use of beta-blockers as treatment offers clues into the pathogenesis of infantile hemangioma, which is not yet completely understood. PMID- 25811005 TI - Bloody tears: a rare presentation of munchausen syndrome case report and review. AB - We report a 16-year-old Jordanian female who presented with bleeding from both eyes of sudden onset. Her physical examination was remarkable for blood pouring from both eyes, and normal otherwise examination including eye and nose examination. During hospital stay, it was noted that "bleeding" occurred only when alone in the room. She later was seen to prick her finger tips of the left hand with her right hand using a hair clip. She denied any psychological problems, and later did not show for follow-up. Munchausen syndrome as a cause of bleeding is discussed. PMID- 25811007 TI - Acute toxic neuropathy mimicking guillain barre syndrome. AB - CASE: A 30 year old male presented with numbness of palms and soles followed by weakness of upper limbs and lower limbs of 5 days duration, which was ascending and progressive. Three months back he was treated for oral and genital ulcers with oral steroids. His ulcers improved and shifted to indigenous medication. His clinical examination showed polyneuropathy. CSF study did not show albuminocytological dissociation. Nerve conduction study showed demyelinating polyneuropathy. His blood samples and the ayurvedic drug samples were sent for toxicological analysis. INFERENCE: Acute toxic neuropathy - Arsenic. PMID- 25811008 TI - Isolated native Tricuspid Valve Endocarditis Presenting as PUO in a Young Adult Male Without Any Risk Factors. AB - A 28-year-old male presented to our hospital with high-grade fever and weight loss for 4 months. Clinical examination was non-contributory and there was no history of any high-risk behavior or prolonged skin or dental infections. Native tricuspid-valve endocarditis may rarely present in these settings and high index of suspicion is essential for early diagnosis. PMID- 25811009 TI - An unusual cause of headache in a medical tourist. AB - With booming medical tourism, Indian doctors are seeing a lot of patients from other countries for varied medical conditions. A citizen of Nairobi presented for treatment of his complaints consisting of severe episodic headache, with abdominal pain, spermatorrhea, decreased libido, constipation, and impotence. On detailed evaluation, he was found to have developed dependence to khat chewing; a social habit in his native country and his symptoms were attributed to effects of khat withdrawal. He improved after treatment with topiramate and escitalopram and lifestyle modification. Physicians need to be aware about various cultural habits of addiction in different parts of the world and their common presentations in view of globalization of health care. PMID- 25811010 TI - Vitamin B12 and vitamin d deficiencies: an unusual cause of Fever, severe hemolytic anemia and thrombocytopenia. AB - The array of diagnostic workup for pyrexia of unknown origin (PUO) generally revolves in searching for infections, inflammatory/autoimmune, and endocrine etiologies. A differential diagnosis of fever, hemolytic anemia, and thrombocytopenia can have etiologies varying from infections like malaria, dengue, cytomegalovirus, Ebstein barr virus, Parvovirus, infective endocarditis, to autoimmune disorder (systemic lupus erythromatosis), vasculitis, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia/Evan's syndrome, paroxysmal nocturnal hemoglobinuri (PNH), or drugs. Nutritional deficiencies (especially vitamin B12 deficiency) as a cause of fever, hemolytic anemia, and thrombocytopenia are very rare and therefore rarely thought of. Severe vitamin B12 deficiency may cause fever and if accompanied by concurrent hyper-homocysteinemia and hypophosphatemia can sometimes lead to severe hemolysis mimicking the above-mentioned conditions. We present a case that highlights vitamin B12 and vitamin D deficiency as an easily treatable cause of PUO, hemolytic anemia, and thrombocytopenia, which should be actively looked for and treated before proceeding with more complicated and expensive investigation or starting empiric treatments. PMID- 25811011 TI - Pica and psychosis - clinical attributes and correlations: a case report. PMID- 25811012 TI - 'Hookah Smoking - An Age-old Modern Trend'. PMID- 25811013 TI - Video Directly Observed Treatment: How Effective Will it be in Indian Setting? PMID- 25811014 TI - Dengue and rectus sheath hematoma. PMID- 25811015 TI - Hyperkalemia and rhabdomyolyssis. PMID- 25811017 TI - Graduate Diploma in Dermatology, a Distant-learning Experience. PMID- 25811016 TI - Use of socioeconomic status scales in medicine and public health. PMID- 25811019 TI - First genomic analysis of dendritic cells from lung and draining lymph nodes in murine asthma. AB - Asthma is the consequence of allergic inflammation in the lung compartments and lung-draining lymph nodes. Dendritic cells initiate and promote T cell response and drive it to immunity or allergy. However, their modes of action during asthma are poorly understood. In this study, an allergic inflammation with ovalbumin was induced in 38 mice versus 42 control animals. After ovalbumin aerosol challenge, conventional dendritic cells (CD11c/MHCII/CD8) were isolated from the lungs and the draining lymph nodes by means of magnetic cell sorting followed by fluorescence-activated cell sorting. A comparative transcriptional analysis was performed using gene arrays. In general, many transcripts are up- and downregulated in the CD8(-) dendritic cells of the allergic inflamed lung tissue, whereas few genes are regulated in CD8(+) dendritic cells. The dendritic cells of the lymph nodes also showed minor transcriptional changes. The data support the relevance of the CD8(-) conventional dendritic cells but do not exclude distinct functions of the small population of CD8(+) dendritic cells, such as cross presentation of external antigen. So far, this is the first approach performing gene arrays in dendritic cells obtained from lung tissue and lung-draining lymph nodes of asthmatic-like mice. PMID- 25811018 TI - Adaptive clinical trial designs in oncology. AB - Adaptive designs have become popular in clinical trial and drug development. Unlike traditional trial designs, adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial. As a result, adaptive designs provide a flexible and effective way to conduct clinical trials. The designs have potential advantages of improving the study power, reducing sample size and total cost, treating more patients with more effective treatments, identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, and shortening the time for drug development. In this article, we review adaptive designs commonly used in clinical trials and investigate several aspects of the designs, including the dose-finding scheme, interim analysis, adaptive randomization, biomarker-guided randomization, and seamless designs. For illustration, we provide examples of real trials conducted with adaptive designs. We also discuss practical issues from the perspective of using adaptive designs in oncology trials. PMID- 25811020 TI - Aqueous cytokines as predictors of macular edema in patients with diabetes following uncomplicated phacoemulsification cataract surgery. AB - This study aims to ascertain whether cytokines in the aqueous humor can predict macular edema (ME) in diabetic patients following uncomplicated phacoemulsification cataract surgery. Undiluted aqueous humor samples were obtained from 136 consecutive type 2 diabetic patients who underwent cataract surgery. The concentrations of 27 cytokines were measured in aqueous humor using the multiplex bead immunoassay. At the final follow-up examination, 116 patients completed 4 weeks of follow-up, and the incidence of macular edema was 29.31% (34 patients) 4 weeks after cataract surgery. Compared to the ME (-) patients, the concentrations of interleukin-1beta (IL-1beta) (P < 0.001), IL-6 (P < 0.001), IL 8 (P < 0.001), interferon-induced protein-10 (IP-10) (P = 0.003), monocyte chemotactic protein-1 (MCP-1) (P < 0.001), and vascular endothelial growth factor (VEGF) (P < 0.001) in the ME (+) patients were significantly higher. In addition, the aqueous levels of IL-1beta (r = 0.288), IL-6 (r = 0.345), IL-8 (r = 0.256), IP-10 (r = 0.377), MCP-1 (r = 0.423), and VEGF (r = 0.279) were positively correlated with the postoperative foveal center point thickness (FCPT). However, the aqueous levels of IL-10 (P = 0.003) and IL-12 (P = 0.017) were significantly lower in patients with ME. These results suggest IL-1beta, IL-6, IL-8, IL-10, IL 12, IP-10, MCP-1, and VEGF may be potential predictors of postoperative macular thickness in patients with diabetes following uncomplicated phacoemulsification cataract surgery. PMID- 25811021 TI - Oxymatrine downregulates HPV16E7 expression and inhibits cell proliferation in laryngeal squamous cell carcinoma Hep-2 cells in vitro. AB - OBJECTIVE: To investigate the possible mechanisms of oxymatrine's role in anti laryngeal squamous cell carcinoma. METHODS: We examined the effects of oxymatrine on the proliferation, cell cycle phase distribution, apoptosis, and the protein and mRNA expression levels of HPV16E7 gene in laryngeal carcinoma Hep-2 cells in vitro. The HPV16E7 siRNA inhibition was also done to confirm the effect of downregulating HPV16E7 on the proliferation in Hep-2 cells. RESULTS: Oxymatrine significantly inhibited the growth and proliferation of Hep-2 cells in a dose dependence and time-dependence manner. Oxymatrine blocked Hep-2 cells in G0/G1 phase, resulting in an obvious accumulation of G0/G1 phase cells while decreasing S phase cells. Oxymatrine induced apoptosis of Hep-2 cells, whose apoptotic rate amounted to about 42% after treatment with 7 mg/mL oxymatrine for 72 h. Oxymatrine also downregulated the expression of HPV16E7 gene, as determined by the western blotting and reverse transcription-polymerase chain reaction analysis. Knockdown of HPV16E7 effectively inhibited the proliferation of Hep-2 cells. CONCLUSIONS: Oxymatrine inhibits the proliferation and induces apoptosis of laryngeal carcinoma Hep-2 cells, which might be mediated by a significant cell cycle arrest in G0/G1 phase and downregulation of HPV16E7 gene. Oxymatrine is considered to be a likely preventive and curative candidate for laryngeal cancer. PMID- 25811022 TI - Development of monoclonal antibodies in China: overview and prospects. AB - Monoclonal antibodies (mAbs) have become increasingly important as human therapeutic agents. Yet, current research concentrates on technology itself and pays attention to developed countries. This paper aims to provide a comprehensive review of mAbs development in China through systematic analysis of drug registry, patent applications, clinical trials, academic publication, and ongoing R&D projects. The trends in therapeutic areas and industrialization process are also highlighted. Development and research trends of mAbs are analyzed to provide a future perspective of mAbs as therapeutic agents in China. PMID- 25811023 TI - Establishment of hairy root cultures of Rhaponticum carthamoides (Willd.) Iljin for the production of biomass and caffeic acid derivatives. AB - The aim of the study was to obtain transformed roots of Rhaponticum carthamoides and evaluate their phytochemical profile. Hairy roots were induced from leaf explants by the transformation of Agrobacterium rhizogenes strains A4 and ATCC 15834. The best response (43%) was achieved by infection with A4 strain. The effects of different liquid media (WPM, B5, SH) with full and half-strength concentrations of macro- and micronutrients on biomass accumulation of the best grown hairy root line (RC3) at two different lighting conditions (light or dark) were investigated. The highest biomass (93 g L(-1) of the fresh weight after 35 days) was obtained in WPM medium under periodic light. UPLC-PDA-ESI-MS(3) and HPLC-PDA analyses of 80% aqueous methanol extracts from the obtained hairy roots revealed the presence of eleven caffeoylquinic acids and their derivatives and five flavonoid glycosides. The production of caffeoylquinic acids and their derivatives was elevated in hairy roots grown in the light. Only light-grown hairy roots demonstrated the capability for the biosynthesis of such flavonoid glycosides as quercetagetin, quercetin, luteolin, and patuletin hexosides. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid and a tentatively identified tricaffeoylquinic acid derivative were detected as the major compounds present in the transformed roots. PMID- 25811024 TI - Direct effects of (-)-epicatechin and procyanidin B2 on the respiration of rat heart mitochondria. AB - Flavonol (-)-epicatechin and its derived dimer procyanidin B2, present in high amounts in cocoa products, have been shown to exert beneficial effects on the heart and cardiovascular system; however, their mechanism of action has not been fully elucidated. We studied effects of (-)-epicatechin and procyanidin B2 on the oxidative phosphorylation of isolated rat heart mitochondria. (-)-Epicatechin and procyanidin B2 had stimulating effect (up to 30% compared to control) on substrate-driven (State 2) mitochondrial respiration. Their effect was dependent on the respiratory substrates used. (-)-Epicatechin at higher concentrations (from 0.27 ug/mL) significantly decreased (up to 15%) substrate- and ADP-driven (State 3) mitochondrial respiration in case of pyruvate and malate oxidation only. Procyanidin B2 (0.7-17.9 ng/mL) inhibited State 3 respiration rate up to 19%, the most profound effect being expressed with succinate as the substrate. ( )-Epicatechin at concentrations of 0.23 ug/mL and 0.46 ug/mL prevented loss of the cytochrome c from mitochondria when substrate was succinate, supporting the evidence of membrane stabilizing properties of this flavonol. Thus, both (-) epicatechin and procyanidin B2 directly influenced mitochondrial functions and the observed effects could help to explain cardiometabolic risk reduction ascribed to the consumption of modest amounts of cocoa products. PMID- 25811026 TI - ProGeRF: proteome and genome repeat finder utilizing a fast parallel hash function. AB - Repetitive element sequences are adjacent, repeating patterns, also called motifs, and can be of different lengths; repetitions can involve their exact or approximate copies. They have been widely used as molecular markers in population biology. Given the sizes of sequenced genomes, various bioinformatics tools have been developed for the extraction of repetitive elements from DNA sequences. However, currently available tools do not provide options for identifying repetitive elements in the genome or proteome, displaying a user-friendly web interface, and performing-exhaustive searches. ProGeRF is a web site for extracting repetitive regions from genome and proteome sequences. It was designed to be efficient, fast, and accurate and primarily user-friendly web tool allowing many ways to view and analyse the results. ProGeRF (Proteome and Genome Repeat Finder) is freely available as a stand-alone program, from which the users can download the source code, and as a web tool. It was developed using the hash table approach to extract perfect and imperfect repetitive regions in a (multi)FASTA file, while allowing a linear time complexity. PMID- 25811025 TI - The influence of electromagnetic pollution on living organisms: historical trends and forecasting changes. AB - Current technologies have become a source of omnipresent electromagnetic pollution from generated electromagnetic fields and resulting electromagnetic radiation. In many cases this pollution is much stronger than any natural sources of electromagnetic fields or radiation. The harm caused by this pollution is still open to question since there is no clear and definitive evidence of its negative influence on humans. This is despite the fact that extremely low frequency electromagnetic fields were classified as potentially carcinogenic. For these reasons, in recent decades a significant growth can be observed in scientific research in order to understand the influence of electromagnetic radiation on living organisms. However, for this type of research the appropriate selection of relevant model organisms is of great importance. It should be noted here that the great majority of scientific research papers published in this field concerned various tests performed on mammals, practically neglecting lower organisms. In that context the objective of this paper is to systematise our knowledge in this area, in which the influence of electromagnetic radiation on lower organisms was investigated, including bacteria, E. coli and B. subtilis, nematode, Caenorhabditis elegans, land snail, Helix pomatia, common fruit fly, Drosophila melanogaster, and clawed frog, Xenopus laevis. PMID- 25811027 TI - Predicting psychotic-like experiences during sensory deprivation. AB - AIMS: This study aimed to establish the contribution of hallucination proneness, anxiety, suggestibility, and fantasy proneness to psychotic-like experiences (PLEs) reported during brief sensory deprivation. METHOD: Twenty-four high and 22 low hallucination-prone participants reported on PLEs occurring during brief sensory deprivation and at baseline. State/trait anxiety, suggestibility, and fantasy proneness were also measured. RESULTS: Both groups experienced a significant increase in PLEs in sensory deprivation. The high hallucination prone group reported more PLEs both at baseline and in sensory deprivation. They also scored significantly higher on measures of state/trait anxiety, suggestibility, and fantasy proneness, though these did not explain the effects of group or condition. Regression analysis found hallucination proneness to be the best predictor of the increase in PLEs, with state anxiety also being a significant predictor. Fantasy proneness and suggestibility were not significant predictors. CONCLUSION: This study suggests the increase in PLEs reported during sensory deprivation reflects a genuine aberration in perceptual experience, as opposed to increased tendency to make false reports due to suggestibility of fantasy proneness. The study provides further support for the use of sensory deprivation as a safe and effective nonpharmacological model of psychosis. PMID- 25811029 TI - Trigger points: an anatomical substratum. AB - This study aimed to bring the trapezius muscle knowledge of the locations where the accessory nerve branches enter the muscle belly to reach the motor endplates and find myofascial trigger points (MTrPs). Although anatomoclinical correlations represent a major feature of MTrP, no previous reports describing the distribution of the accessory nerve branches and their anatomical relationship with MTrP are found in the literature. Both trapezius muscles from twelve adult cadavers were carefully dissected by the authors (anatomy professors and medical graduate students) to observe the exact point where the branches of the spinal accessory nerve entered the muscle belly. Dissection was performed through stratigraphic layers to preserve the motor innervation of the trapezius muscle, which is located deep in the muscle. Seven points are described, four of which are motor points: in all cases, these locations corresponded to clinically described MTrPs. The four points were common in these twelve cadavers. This type of clinical correlation between spinal accessory nerve branching and MTrP is useful to achieve a better understanding of the anatomical correlation of MTrP and the physiopathology of these disorders and may provide a scientific basis for their treatment, rendering useful additional information to therapists to achieve better diagnoses and improve therapeutic approaches. PMID- 25811028 TI - Probing the surface of human carbonic anhydrase for clues towards the design of isoform specific inhibitors. AB - The alpha carbonic anhydrases (alpha-CAs) are a group of structurally related zinc metalloenzymes that catalyze the reversible hydration of CO2 to HCO3(-). Humans have 15 different alpha-CAs with numerous physiological roles and expression patterns. Of these, 12 are catalytically active, and abnormal expression and activities are linked with various diseases, including glaucoma and cancer. Hence there is a need for CA isoform specific inhibitors to avoid off target CA inhibition, but due to the high amino acid conservation of the active site and surrounding regions between each enzyme, this has proven difficult. However, residues towards the exit of the active site are variable and can be exploited to design isoform selective inhibitors. Here we discuss and characterize this region of "selective drug targetability" and how these observations can be utilized to develop isoform selective CA inhibitors. PMID- 25811030 TI - Investigating the pretreatment miRNA expression patterns of advanced hepatocellular carcinoma patients in association with response to TACE treatment. AB - Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis and limited treatment options. Transarterial chemoembolization (TACE) using chemotherapy agents-doxorubicin and cisplatin-is an accepted treatment option for locally advanced hepatocellular carcinoma. In the current study, we analyzed the expression pattern of a selected panel of 94 miRNAs in archival samples that were collected prior to treatment from 15 Egyptian patients diagnosed with advanced hepatocelleular carcinoma. We observed an overall increase in miRNA expression in HCC samples compared with normal subjects. Out of 94 examined miRNAs, 53 were significantly upregulated while 3 miRNAs were downregulated in HCC samples compared to normal liver samples. Comparing the pretreatment miRNA expression profiles in HCC patients and the patients response to TACE treatment resulted in the identification of a set of 12 miRNAs that are significantly upregulated in nonresponders group. This miRNA panel includes miR-10a-1, miR-23a-1, miR-24, miR 26a, miR-27a, miR-30c, miR-30e, miR-106b, miR-133b, miR-199a, miR-199-3p, and miR 200b. Furthermore, we observed that a panel of 10 miRNAs was significantly associated with patients' survival status at 1 year. These results highlight the potential implications of pretreatment miRNAs expression profiling in prediction of the patients' response to TACE treatment in liver cancer. PMID- 25811031 TI - Associations of LIG4 and HSPB1 genetic polymorphisms with risk of radiation induced lung injury in lung cancer patients treated with radiotherapy. AB - OBJECTIVE: This study aims to explore the correlations of genetic polymorphisms in LIG4 and HSPB1 genes with the radiation-induced lung injury (RILI), especially radiation pneumonitis (RP), in lung cancer patients. METHODS: A total of 160 lung cancer patients, who were diagnosed with inoperable lung cancer and received radiotherapy, were included in the present study from September 2009 to December 2011. TaqMan Real-Time PCR (RT-PCR) was used to verify the SNPs of LIG4 and HSPB1 genes. Chi-square criterion was used to compare the differences in demographic characteristics, exposure to risk factors, and SNPs genotypes. Crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated by logistic regression analysis. All statistical analyses were conducted in SPSS 18.0. RESULTS: A total of 32 (20.0%) lung cancer patients had RP after receiving radiotherapy. Of the 32 cases, 4 cases were of grade 2, 24 cases were of grade 3, and 4 cases were of grade 4. However, our results indicated that the general condition and treatment of all patients had no significant difference with RP risk (P > 0.05). Meanwhile, our results revealed that there was no significant association between the frequencies of LIG4 rs1805388 and HSPB1 rs2868371 genotype distribution and the risk of RP (P > 0.05). CONCLUSION: In conclusion, we demonstrated that the genetic polymorphisms in LIG4 rs1805388 and HSPB1 rs2868371 were not obviously correlated with the risk of RP and RILI of lung cancer. PMID- 25811032 TI - Quantitative analysis of lung ultrasonography for the detection of community acquired pneumonia: a pilot study. AB - BACKGROUND AND OBJECTIVE: Chest X-ray is recommended for routine use in patients with suspected pneumonia, but its use in emergency settings is limited. In this study, the diagnostic performance of a new method for quantitative analysis of lung ultrasonography was compared with bedside chest X-ray and visual lung ultrasonography for detection of community-acquired pneumonia, using thoracic computed tomography as a gold standard. METHODS: Thirty-two spontaneously breathing patients with suspected community-acquired pneumonia, undergoing computed tomography examination, were consecutively enrolled. Each hemithorax was evaluated for the presence or absence of abnormalities by chest X-ray and quantitative or visual ultrasonography. RESULTS: Quantitative ultrasonography showed higher sensitivity (93%), specificity (95%), and diagnostic accuracy (94%) than chest X-ray (64%, 80%, and 69%, resp.), visual ultrasonography (68%, 95%, and 77%, resp.), or their combination (77%, 75%, and 77%, resp.). CONCLUSIONS: Quantitative lung ultrasonography was considerably more accurate than either chest X-ray or visual ultrasonography in the diagnosis of community-acquired pneumonia and it may represent a useful first-line approach for confirmation of clinical diagnosis in emergency settings. PMID- 25811033 TI - Prediction of outcome for transabdominal cerclage in women with cervical insufficiency. AB - We investigated pregnancy outcome following transabdominal cerclage (TAC) in women with cervical insufficiency (CI) and explored parameters for predicting pregnancy outcomes following TAC. In this retrospective cohort study, we included 161 women with TAC. We considered demographic, obstetric, and gynecologic histories, pre- and postoperative cervical length (CL), and CL at 20-24 weeks as parameters for predicting outcomes following TAC. Univariate and multivariate analyses were used to identify risk factors for predicting delivery before 34 weeks after TAC. 182 pregnancies occurred after TAC, and 290 pregnancies prior to TAC were identified. The rate of delivery <34 weeks significantly decreased following TAC (5% versus 82%, P < 0.001). Univariate analysis demonstrated that a short CL (<25 mm) at 20-24 weeks and adenomyosis were associated with delivery at <34 weeks' gestation following TAC (P = 0.015 and P = 0.005, resp.). However, multivariate analysis demonstrated that only a short CL (<25 mm) at 20-24 weeks was a significant predictor (P = 0.005). TAC is an efficacious procedure that prolongs pregnancy in women with CI. A short CL at 20-24 weeks may predict the delivery at <34 weeks' gestation following TAC. PMID- 25811034 TI - Impact of kefir derived Lactobacillus kefiri on the mucosal immune response and gut microbiota. AB - The evaluation of the impact of probiotics on host health could help to understand how they can be used in the prevention of diseases. On the basis of our previous studies and in vitro assays on PBMC and Caco-2 ccl20:luc reporter system presented in this work, the strain Lactobacillus kefiri CIDCA 8348 was selected and administrated to healthy Swiss mice daily for 21 days. The probiotic treatment increased IgA in feces and reduced expression of proinflammatory mediators in Peyer Patches and mesenteric lymph nodes, where it also increased IL 10. In ileum IL-10, CXCL-1 and mucin 6 genes were upregulated; meanwhile in colon mucin 4 was induced whereas IFN-gamma, GM-CSF, and IL-1beta genes were downregulated. Moreover, ileum and colon explants showed the anti-inflammatory effect of L. kefiri since the LPS-induced increment of IL-6 and GM-CSF levels in control mice was significantly attenuated in L. kefiri treated mice. Regarding fecal microbiota, DGGE profiles allowed differentiation of experimental groups in two separated clusters. Quantitative PCR analysis of different bacterial groups revealed only significant changes in Lactobacillus population. In conclusion, L. kefiri is a good candidate to be used in gut inflammatory disorders. PMID- 25811035 TI - Correlation between genetic variations and serum level of interleukin 28B with virus genotypes and disease progression in chronic hepatitis C virus infection. AB - Recent studies have demonstrated that polymorphisms near the interleukin-28B (IL 28B) gene could predict the response to Peg-IFN-a/RBV combination therapy in HCV infected patients. The aim of the study was to correlate the serum level of IL28B in HCV-infected patients with virus genotype/subgenotype and disease progression. IL28B serum level was detected and variations at five single nucleotide polymorphisms (SNPs) in IL28B gene region were genotyped and analyzed. The variation of IL28B genetic polymorphisms was found to be strongly associated with HCV infection when healthy control group was compared to HCV-infected patients with all P values <0.0001. Functional analysis revealed that subjects carrying rs8099917-GG genotype had higher serum level of IL28B than those with GT or TT genotypes (P = 0.04). Also, patients who were presented with cirrhosis (Cirr) only or with cirrhosis plus hepatocellular carcinoma (Cirr+HCC) had higher levels of serum IL28B when compared to chronic HCV-infected patients (P = 0.005 and 0.003, resp.). No significant association was found when serum levels of IL28B were compared to virus genotypes/subgenotypes. This study indicates that variation at SNP rs8099917 could predict the serum levels of IL28B in HCV infected patients. Furthermore, IL28B serum level may serve as a useful marker for the development of HCV-associated sequelae. PMID- 25811036 TI - Information and communication needs of Chinese American breast cancer patients: perspectives on survivorship care planning. AB - BACKGROUND: The existing knowledge on the survivorship experiences of Chinese American breast cancer survivors (CABCS) has arisen largely from aggregated data across multiethnic or multicancer studies that have focused on quality of life. Little is known about Chinese American perspectives and preferences for survivorship care. OBJECTIVE: To examine the experiences of CABCS to better understand their information and communication needs and their preferences for survivorship care plans (SCPs). METHODS: 16 CABCS, aged 37-72 years, were recruited through community-based organizations in the Northeast United States to participate in one-on-one telephone interviews about their breast cancer survivorship experience. The semistructured interviews were conducted in Mandarin, Cantonese, or English. Two investigators transcribed and translated the audio recordings into English and analyzed the interview transcripts using established methods of qualitative content analysis. RESULTS: Three main themes were identified through analysis of interview transcripts: the need for evidence based and culturally and linguistically appropriate health information; the role of language or communication barriers and culture in accessing care and communicating with providers; and preferences for SCP elements and format. LIMITATIONS: The sample may not be representative of the entire population of CABCS. CONCLUSIONS: The findings provide insight into the information and communication needs and SCP preferences of CABCS. Understanding the cultural nuances that underlie these needs and preferences is critical for improving CABCS's quality of life after treatment for cancer. SCPs that incorporate Chinese language resources and address the unique cultural needs of this population should be developed and they should include information about diet and nutrition as well as traditional Chinese medicine. PMID- 25811037 TI - Practice gaps and barriers to optimal care of hematologic malignancies in the United States. AB - BACKGROUND: Treating patients with hematologic malignancies can be challenging for physicians because of the rapidly evolving standards of care and relatively low incidence of these diseases. OBJECTIVE: To identify clinical challenges among hematologists and medical oncologists regarding the provision of care to patients with chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), or B cell lymphomas. Methods Hematologists and medical oncologists in active practice in the United States and who have a case load of >= 1 patient a year with CML, ALL, or B-cell lymphoma were recruited. The initial qualitative phase consisted of an online case-based survey followed by an interview exploring the contextual and behavioral factors that influence treatment decisions (n = 27). The analysis of qualitative data then informed a quantitative phase, in which 121 participants completed an online survey composed of case vignettes, multiple choice, and semantic differential rating scale questions. The respondents' answers were compared with recommendations from treatment guidelines and faculty experts. RESULTS: A higher frequency of bone marrow biopsies was reported compared with expert faculty recommendations by 74% of oncologists. Many respondents failed to recognize the clinical relevance of BCR-ABL mutations other than T315I. Respondents reported perceiving difficulties in individualizing treatment and interpreting response to treatment in patients with ALL and B-cell lymphomas. Fewer than 30% of respondents recognized the mechanisms of action of 5 of the 9 promising investigational agents presented. LIMITATIONS: Participant self selection bias is a possibility because participation was voluntary. Practice gaps are not based on clinical data, but hypothetical case situations and self report. CONCLUSIONS: Findings from this study can guide education to address the identified challenges in caring for patients with hematologic malignancies and improving patient care. FUNDING: This needs assessment was financially supported with an educational research grant from Pfizer Medical Education Group to the Annenberg Center for Health Sciences at Eisenhower. PMID- 25811038 TI - An incremental high-utility mining algorithm with transaction insertion. AB - Association-rule mining is commonly used to discover useful and meaningful patterns from a very large database. It only considers the occurrence frequencies of items to reveal the relationships among itemsets. Traditional association-rule mining is, however, not suitable in real-world applications since the purchased items from a customer may have various factors, such as profit or quantity. High utility mining was designed to solve the limitations of association-rule mining by considering both the quantity and profit measures. Most algorithms of high utility mining are designed to handle the static database. Fewer researches handle the dynamic high-utility mining with transaction insertion, thus requiring the computations of database rescan and combination explosion of pattern-growth mechanism. In this paper, an efficient incremental algorithm with transaction insertion is designed to reduce computations without candidate generation based on the utility-list structures. The enumeration tree and the relationships between 2-itemsets are also adopted in the proposed algorithm to speed up the computations. Several experiments are conducted to show the performance of the proposed algorithm in terms of runtime, memory consumption, and number of generated patterns. PMID- 25811039 TI - Calibration and algorithm development for estimation of nitrogen in wheat crop using tractor mounted N-sensor. AB - The experiment was planned to investigate the tractor mounted N-sensor (Make Yara International) to predict nitrogen (N) for wheat crop under different nitrogen levels. It was observed that, for tractor mounted N-sensor, spectrometers can scan about 32% of total area of crop under consideration. An algorithm was developed using a linear relationship between sensor sufficiency index (SIsensor) and SISPAD to calculate the N app as a function of SISPAD. There was a strong correlation among sensor attributes (sensor value, sensor biomass, and sensor NDVI) and different N-levels. It was concluded that tillering stage is most prominent stage to predict crop yield as compared to the other stages by using sensor attributes. The algorithms developed for tillering and booting stages are useful for the prediction of N-application rates for wheat crop. N-application rates predicted by algorithm developed and sensor value were almost the same for plots with different levels of N applied. PMID- 25811040 TI - Detection of pathogenic Escherichia coli and Staphylococcus aureus from cattle and pigs slaughtered in abattoirs in Vhembe District, South Africa. AB - Pathogenic food-borne bacteria have been associated with severe morbidity and mortality in humans and animals. This study was aimed at determining the prevalence of Staphylococcus aureus, Salmonella spp., and Escherichia coli present in cattle and pigs slaughtered in selected abattoirs in Vhembe District and at determining the susceptibility of the isolates to antibiotics. A total of 176 swab samples (28 cattle and 16 pigs) of the rump, flank, brisket, and neck of the animals were analyzed using standard microbiological methods. E. coli isolates were genotyped to detect pathogenic strains. Of the 176 samples, 104 (67.5%) were positive for E. coli and 50 (32.5%) for S. aureus. There was no statistically significant difference (P > 0.05) in the isolation rate from the different animal parts or abattoirs. Overall, 14/104 (13.46%) of the E. coli isolates were pathogenic strains which included enteropathogenic E. coli (EPEC) (bfpA) 1.9%, enterotoxigenic E. coli (ETEC) (LT) 3.8%, and enteroaggregative E. coli (EAEC) (aaiC) 7.6%. E. coli isolates were resistant (100%) to vancomycin and bacitracin. S. aureus (100%) were resistant to oxacillin and nalidixic acid. The presence of resistant strains of these bacteria in food of animal origin could serve as important vehicles transmitting these bacteria to humans. This finding is of epidemiological significance. PMID- 25811041 TI - PCR and ELISA vis-a-vis microscopy for detection of bovine anaplasmosis: a study on associated risk of an upcoming problem in North India. AB - This investigation demonstrates the status of bovine anaplasmosis caused by A. marginale in bovines from Submountain and Undulating Zone of Punjab. Out of 184 suspected animals, 25 (19.51%), 47 (31.71%), and 78 (68.75%) were positive by microscopy, indirect ELISA, and PCR assay, respectively. The microscopy showed 29% sensitivity and 99% specificity, while ELISA showed 32% sensitivity and 79% specificity in concordance with PCR assay. Five false negative samples by msp1beta PCR were reconfirmed for Anaplasma spp. targeting 16S rRNA gene. The sequence analysis showed the presence for A. marginale specific restriction site, indicating variation in the local strains of the organism resulting in no amplification with msp1beta gene primers. Of 82 samples positive by PCR, 57 were negative by ELISA indicating lower efficacy of ELISA to detect early anaplasmosis. The assessment of risk factor with results of PCR technique indicated that cattle (Odds ratio = 2.884), particularly those of age > 1 years (Odds ratio = 2.204) of district Pathankot (Odds ratio = 3.182) of Submountain Zone (Odds ratio = 2.086), were at high risk of anaplasmosis. All three districts of Submountain Zone are at higher risk indicating the impact of biotic and abiotic factors on the incidence of disease. PMID- 25811043 TI - Prevalence of musculoskeletal pain in construction workers in Saudi Arabia. AB - The objective of this study was to find out the prevalence, characteristics, and distribution of musculoskeletal pain among construction workers in Saudi Arabia. A questionnaire about musculoskeletal pain in different parts of the body was completed by 165 construction workers from the construction industries in Dammam and Riyadh cities. The descriptive data were analyzed using chi-square test. The level of statistical significance was set at P < 0.05. Eighty (48.5%) of the responding workers had pain in neck, shoulders, lower back, hand, knee, or ankle. The majority of respondents had low back pain (50%) followed by knee pain (20%). The average intensity of pain at all sites during activity and rest was 6.65 and 3.59, respectively. Thirty-four (42.5%) respondents had dull aching pain and 24 (30%) had cramping pain. There was an association between years of experience, duration of break during work, and use of protective equipment with the prevalence of musculoskeletal pain in construction workers (P < 0.05). Most of the workers complaining of pain got medical treatment (62.5%) and only 25% received physical therapy. It can be concluded from this study that the prevalence of musculoskeletal pain among construction workers in Saudi Arabia is high. PMID- 25811042 TI - Hypotensive anesthesia versus normotensive anesthesia during major maxillofacial surgery: a review of the literature. AB - Steady blood pressure within normal limits during surgery is one of the markers of the ideal and skillful anesthesia. Yet, reduced blood pressure is advantageous in some settings because it can contribute to a reduction in overall blood loss and improve the surgical field conditions. Controlled hypotension during anesthesia or hypotensive anesthesia is often used in major maxillofacial operations. Since hypotensive anesthesia carries the risk of hypoperfusion to important organs and tissues, mainly the brain, heart, and kidneys, it cannot be applied safely in all patients. In this paper we review the medical literature regarding hypotensive anesthesia during major maxillofacial surgery, the means to achieve it, and the risks and benefits of this technique, in comparison to normotensive anesthesia. PMID- 25811044 TI - Diarrheagenic Escherichia coli phylogroups are associated with antibiotic resistance and duration of diarrheal episode. AB - Conventionally, in Escherichia coli, phylogenetic groups A and B1 are associated with commensal strains while B2 and D are associated with extraintestinal strains. The aim of this study was to evaluate diarrheagenic (DEC) and commensal E. coli phylogeny and its association with antibiotic resistance and clinical characteristics of the diarrheal episode. Phylogenetic groups and antibiotic resistance of 369 E. coli strains (commensal strains and DEC from children with or without diarrhea) isolated from Peruvian children <1 year of age were determined by a Clermont triplex PCR and Kirby-Bauer method, respectively. The distribution of the 369 E. coli strains among the 4 phylogenetic groups was A (40%), D (31%), B1 (21%), and B2 (8%). DEC-control strains were more associated with group A while DEC-diarrhea strains were more associated with group D (P < 0.05). There was a tendency (P = 0.06) for higher proportion of persistent diarrhea (>= 14 days) among severe groups (B2 and D) in comparison with nonsevere groups (A and B1). Strains belonging to group D presented significantly higher percentages of multidrug resistance than the rest of the groups (P > 0.01). In summary, DEC-diarrhea strains were more associated with group D than strains from healthy controls. PMID- 25811045 TI - Bone morphology in 46 BXD recombinant inbred strains and femur-tibia correlation. AB - We examined the bone properties of BXD recombinant inbred (RI) mice by analyzing femur and tibia and compared their phenotypes of different compartments. 46 BXD RI mouse strains were analyzed including progenitor C57BL/6J (n = 16) and DBA/2J (n = 15) and two first filial generations (D2B6F1 and B6D2F1). Strain differences were observed in bone quality and structural properties (P < 0.05) in each bone profile (whole bone, cortical bone, or trabecular bone). It is well known that skeletal phenotypes are largely affected by genetic determinants and genders, such as bone mineral density (BMD). While genetics and gender appear expectedly as the major determinants of bone mass and structure, significant correlations were also observed between femur and tibia. More importantly, positive and negative femur-tibia associations indicated that genetic makeup had an influence on skeletal integrity. We conclude that (a) femur-tibia association in bone morphological properties significantly varies from strain to strain, which may be caused by genetic differences among strains, and (b) strainwise variations were seen in bone mass, bone morphology, and bone microarchitecture along with bone structural property. PMID- 25811047 TI - Energetics of atomic scale structure changes in graphene. AB - The presence of defects in graphene has an essential influence on its physical and chemical properties. The formation, behaviour and healing of defects are determined by energetic characteristics of atomic scale structure changes. In this article, we review recent studies devoted to atomic scale reactions during thermally activated and irradiation-induced processes in graphene. The formation energies of vacancies, adatoms and topological defects are discussed. Defect formation, healing and migration are quantified in terms of activation energies (barriers) for thermally activated processes and by threshold energies for processes occurring under electron irradiation. The energetics of defects in the graphene interior and at the edge is analysed. The effects of applied strain and a close proximity of the edge on the energetics of atomic scale reactions are overviewed. Particular attention is given to problems where further studies are required. PMID- 25811048 TI - [Surgery of the ear: superiority of perioperative only antibiotic]. PMID- 25811049 TI - [Tinnitus: Ringing in the ears often associated with depression, anxiety and stress]. PMID- 25811051 TI - Response to Dr Walsh. PMID- 25811046 TI - Renal and Gastrointestinal Considerations in Joint Replacement Surgery. AB - Renal and gastrointestinal diseases affect a significant portion of the general population. The process of decision making regarding surgical clearance and pre operative management of the various complexities and medical conditions associated with these diseases hence becomes crucial. To optimize postoperative outcomes, the considerations for the care of this patient population revolve around effective management of hemostasis and electrolyte status. This subset of conditions is uniquely important with regard to the negative impact of improper administration of medications and perioperative care on patients' prognoses. A thorough understanding and knowledge of standards of care and treatment guidelines for patients with renal dysfunction and gastrointestinal disease assures comprehensive preoperative planning and surgical clearance. This may ultimately lead to improvement of surgical outcomes and potential decrease in postoperative morbidity and mortality. PMID- 25811052 TI - Retraction notice to: The noncoding RNA mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. PMID- 25811050 TI - Quality improvement study of effectiveness of cue-based feeding in infants with bronchopulmonary dysplasia in the neonatal intensive care unit. AB - The effectiveness and safety of experimental cue-based versus health care provider-driven (baseline) feeding strategies were evaluated in infants with bronchopulmonary dysplasia. The experimental group (n = 55) and the control group(n = 60) included infants who had been previously diagnosed with varying levels of severity of bronchopulmonary dysplasia and were identified retrospectively. Previous research was used to derive an Oral Feeding Readiness Scale as well as an Oral Feeding Quality Scale. Results validated both scales as well as the cue-based feeding strategy. PMID- 25811053 TI - [Should we deliver radiotherapy after mastectomy and axillary surgery in the women with one to three positive lymph nodes?]. PMID- 25811054 TI - [Involvement of the cytomegalovirus in mucoepidermoid carcinomas of the salivary glands?]. PMID- 25811055 TI - Lou Underwood: in memoriam. PMID- 25811056 TI - Preface. Bacterial transcriptional control. PMID- 25811058 TI - Executive summary of the position paper of the German Cardiac Society on quality criteria for the implementation of transcatheter aortic valve implantation (TAVI. PMID- 25811057 TI - The future of heart valve replacement. PMID- 25811059 TI - Computing in Cardiology (CinC). PMID- 25811060 TI - Materialism and life satisfaction: the role of religion. AB - This study examines the role of religion and religiosity in the relationship between materialism and life satisfaction. The findings suggests that religion may be a key factor in understanding differences in findings of previous studies regarding the inverserelationship found in the vast majority of previous studies. Based on a large-scale study in Malaysia-a country comprised of several religious subcultures (mainly Muslims, Buddhists, and Hindus), the findings suggest that the influence of religiosity on materialism and life satisfaction is stronger among Malays than among Chinese and Indians, and life satisfaction partially mediates the relationship between religiosity and materialism. The paper discusses implications for theory development and further research. PMID- 25811061 TI - Nicholas A. Vick, MD (1939-2014). PMID- 25811062 TI - Arabella Leet, MD (1965-2013). PMID- 25811063 TI - Reflections: neurology and the humanities. Advice to my younger self while making evening rounds. PMID- 25811064 TI - Author response. PMID- 25811065 TI - Author response. PMID- 25811066 TI - Common sense and sociological explanations. AB - Sociologists have long advocated a sociological approach to explanation by contrasting it with common sense. The argument of this article, however, is that sociologists rely on common sense more than they realize. Moreover, this unacknowledged reliance causes serious problems for their explanations of social action, that is, for why people do what they do. Many such explanations, it is argued, conflate understandability with causality in ways that are not valid by the standards of scientific explanation. It follows that if sociologists want their explanations to be scientifically valid, they must evaluate them specifically on those grounds--in particular, by forcing them to make predictions. In becoming more scientific, however, it is predicted that sociologists' explanations will also become less satisfying from an intuitive, sense-making perspective. Even as novel sources of data and improved methods open exciting new directions for sociological research, therefore, sociologists will increasingly have to choose between unsatisfying scientific explanations and satisfying but unscientific stories. PMID- 25811067 TI - Race in California's prison fire camps for men: prison politics, space, and the racialization of everyday life. AB - The vast majority of social scientists agree that race is "socially constructed." Yet many scholars of punishment and prisons still treat race as static, self evident categories. One result is that not enough is known about the production, meanings, and consequences of race as experienced by prisoners and those who guard and manage them. The author's research on California's prison fire camps uncovers the micro-level ways in which race is performed and imbued with meaning; he reveals how racial understandings color people and settings. One puzzle is that prisoners in California's fire camps will fight natural disasters side by side, sharing water and provisions, but separate into racial groups when in the camp itself. In part to answer this (and in part to develop better understandings of race and prisons more generally), the author unpacks the variegated nature of punishment and the spatialization of race and advocates for research that is faithful to the constructivist framework. PMID- 25811068 TI - Class advantage and the gender divide: flexibility on the job and at home. AB - Using a survey, interviews, and observations, the authors examine inequality in temporal flexibility at home and at work. They focus on four occupations to show that class advantage is deployed in the service of gendered notions of temporal flexibility while class disadvantage makes it difficult to obtain such flexibility. The class advantage of female nurses and male doctors enables them to obtain flexibility in their work hours; they use that flexibility in gendered ways: nurses to prioritize family and physicians to prioritize careers. Female nursing assistants and male emergency medical technicians can obtain little employee-based flexibility and, as a result, have more difficulty meeting conventional gendered expectations. Advantaged occupations "do gender" in conventional ways while disadvantaged occupations "undo gender." These processes operate through organizational rules and cultural schemas that sustain one another but may undermine the gender and class neutrality of family-friendly policies. PMID- 25811069 TI - Beyond strong and weak: rethinking postdictatorship civil societies. AB - What is the impact of dictatorships on postdictatorial civil societies? Bottom-up theories suggest that totalitarian dictatorships destroy civil society while authoritarian ones allow for its development. Top-down theories of civil society suggest that totalitarianism can create civil societies while authoritarianism is unlikely to. This article argues that both these perspectives suffer from a one dimensional understanding of civil society that conflates strength and autonomy. Accordingly we distinguish these two dimensions and argue that totalitarian dictatorships tend to create organizationally strong but heteronomous civil societies, while authoritarian ones tend to create relatively autonomous but organizationally weak civil societies. We then test this conceptualization by closely examining the historical connection between dictatorship and civil society development in Italy (a posttotalitarian case) and Spain (a postauthoritarian one). Our article concludes by reflecting on the implications of our argument for democratic theory, civil society theory, and theories of regime variation. PMID- 25811070 TI - The denigration of heroes? How the status attainment process shapes attributions of considerateness and authenticity. AB - This article develops and tests a theory to explain the common tendency to "denigrate heroes," whereby high-status actors are suspected of being inconsiderate and inauthentic relative to low-status counterparts. This tendency is argued to reflect two conditions typical of status attainment processes: (a) assertions of superiority over others and (b) the presence of incentives to pursue status. The latter is key since awareness of such incentives breeds suspicions of inauthenticity, which in turn undermine perceptions of prosocial intentions. This theory is validated in a series of online experiments, in which categorical status hierarchies emerge either via deference on a coordinated task or via competitive interactions. Results show that high-status actors may also be "celebrated" as authentic and considerate when the observable incentive structure is such that assertions of superiority appear as unintended by-products of prosocial action. Implications are drawn regarding the sources of instability and insecurity in status hierarchies. PMID- 25811073 TI - Erratum. PMID- 25811071 TI - When politics froze fashion: the effect of the Cultural Revolution on naming in Beijing. AB - The authors examine the popularity of boys' given names in Beijing before and after the onset of the Cultural Revolution to clarify how exogenous and endogenous factors interact to shape fashion. Whereas recent work in the sociology of culture emphasizes the importance of endogenous processes in explaining fashion, their analysis demonstrates two ways in which politics shaped cultural expression during the Cultural Revolution: by promoting forms of expression reflecting prevailing political ideology and by limiting individuals' willingness to act differently. As argued by Lieberson and developed further in this article, the second condition is important because endogenous fashion cycles require a critical mass of individuals who seek to differentiate themselves from common practice. Exogenous factors can influence the operation of the endogenous factors. The authors discuss the implications of their study for understanding the nature of conformity under authoritarian regimes and social conditions supporting individual expression. PMID- 25811074 TI - Experimental evidence of large changes in terrestrial chlorine cycling following altered tree species composition. AB - Organochlorine molecules (Clorg) are surprisingly abundant in soils and frequently exceed chloride (Cl(-)) levels. Despite the widespread abundance of Clorg and the common ability of microorganisms to produce Clorg, we lack fundamental knowledge about how overall chlorine cycling is regulated in forested ecosystems. Here we present data from a long-term reforestation experiment where native forest was cleared and replaced with five different tree species. Our results show that the abundance and residence times of Cl(-) and Clorg after 30 years were highly dependent on which tree species were planted on the nearby plots. Average Cl(-) and Clorg content in soil humus were higher, at experimental plots with coniferous trees than in those with deciduous trees. Plots with Norway spruce had the highest net accumulation of Cl(-) and Clorg over the experiment period, and showed a 10 and 4 times higher Cl(-) and Clorg storage (kg ha(-1)) in the biomass, respectively, and 7 and 9 times higher storage of Cl(-) and Clorg in the soil humus layer, compared to plots with oak. The results can explain why local soil chlorine levels are frequently independent of atmospheric deposition, and provide opportunities for improved modeling of chlorine distribution and cycling in terrestrial ecosystems. PMID- 25811075 TI - Hydration Status and Sodium Balance of Endurance Runners Consuming Postexercise Supplements of Varying Nutrient Content. AB - Postexercise protein and sodium supplementation may aid recovery and rehydration. Preserved beef provides protein and contains high quantities of sodium that may alter performance related variables in runners. The purpose of this study was to determine the effects of consuming a commercial beef product postexercise on sodium and water balance. A secondary objective was to characterize effects of the supplementation protocols on hydration, blood pressure, body mass, and running economy. Eight trained males (age = 22 +/- 3 y, VO2max = 66.4 +/- 4.2 ml.kg-1.min-1) completed three identical weeks of run training (6 run.wk-1, 45 +/ 6 min.run-1, 74 +/- 5% HRR). After exercise, subjects consumed either, a beef nutritional supplement (beef jerky; [B]), a standard recovery drink (SRD), or SRD+B in a randomized counterbalanced design. Hydration status was assessed via urinary biomarkers and body mass. No main effects of treatment were observed for 24 hr urine volume (SRD, 1.7 +/- 0.5; B, 1.8 +/- 0.6; SRD+B, 1.4 +/- 0.4 L.d-1), urine specific gravity (1.016 +/- 0.005, 1.018 +/- 0.006, 1.017 +/- 0.006) or body mass (68.4 +/- 8.2, 68.3 +/- 7.7, 68.2 +/- 8.1 kg). No main effect of treatment existed for sodium intake-loss (-713 +/- 1486; -973 +/- 1123; -980 +/- 1220 mg.d-1). Mean arterial pressure (81.0 +/- 4.6, 81.1 +/- 7.3, 83.8 +/- 5.4 mm Hg) and average exercise running economy (VO2: SRD, 47.9 +/- 3.2; B, 47.2 +/- 2.6; SRD+B, 46.2 +/- 3.4 ml.kg-1.min-1) was not affected. Urinary sodium excretion accounted for the daily sodium intake due to the beef nutritional supplement. Findings suggest the commercial beef snack is a viable recovery supplement following endurance exercise without concern for hydration status, performance decrements, or cardiovascular consequences. PMID- 25811078 TI - Study of curcumin behavior in two different lipid bilayer models of liposomal curcumin using molecular dynamics simulation. AB - Liposomal formulation of curcumin is an important therapeutic agent for the treatment of various cancers. Despite extensive studies on the biological effects of this formulation in cancer treatment, much remains unknown about curcumin liposome interactions. Understanding how different lipid bilayers respond to curcumin molecule may help us to design more effective liposomal curcumin. Here, we used molecular dynamics simulation method to investigate the behavior of curcumin in two lipid bilayers commonly used in preparation of liposomal curcumin, namely dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylglycerol (DMPG). First, the free energy barriers for translocation of one curcumin molecule from water to the lipid bilayer were determined by using the potential of mean force (PMF). The computed free energy profile exhibits a global minimum at the solvent-headgroup interface (LH region) for both lipid membranes. We also evaluated the free energy difference between the equilibrium position of curcumin in the lipid bilayer and bulk water as the excess chemical potential. Our results show that curcumin has the higher affinity in DMPG compared to DPPC lipid bilayer (-8.39 vs. -1.69 kBT) and this is related to more hydrogen bond possibility for curcumin in DMPG lipid membrane. Next, using an unconstrained molecular dynamic simulation with curcumin initially positioned at the center of lipid bilayer, we studied various properties of each lipid bilayer system in the presence of curcumin molecule that was in full agreement with PMF and experimental data. The results of these simulation studies suggest that membrane composition could have a large effect on interaction of curcumin-lipid bilayer. PMID- 25811079 TI - Transformation of Ag nanowires into semiconducting AgFeS2 nanowires. AB - We report on the synthesis of semiconducting AgFeS2 nanowires, obtained from the conversion of Ag nanowires. The study of the conversion process shows that the formation of Ag2S nanowires, as an intermediate step, precedes the conversion into AgFeS2 nanowires. The chemical properties of AgFeS2 nanowires were characterized by X-ray diffraction, scanning electron microscopy, and energy dispersive X-ray spectroscopy at intermediate steps of the conversion process and show that the temperature at which the reaction takes place is critical to obtaining nanowires as opposed to nanotubes. Optical measurements on nanowire ensembles confirm the semiconducting nature of AgFeS2, with a direct band gap of 0.88 eV. PMID- 25811077 TI - miR-134 functions as a tumor suppressor in cell proliferation and epithelial-to mesenchymal Transition by targeting KRAS in renal cell carcinoma cells. AB - Aberrant microRNAs (miRNAs) are reported to contribute to the pathogenesis of most human malignancies. The miRNA, miR-134, has been found to be downregulated in renal cell carcinoma (RCC), but its function in the disease is unknown. The aims of this study were to detect the expression of miR-134 in human RCC samples and explore its function in RCC cell lines. Real-time qualitative polymerase chain reaction (qPCR) was used to quantify miR-134 in human RCC samples. Assays for cell cycle, viability, migration, and invasion were performed to assess the phenotypic changes in RCC cells. A luciferase reporter assay was carried out to confirm whether KRAS (Kirsten rat sarcoma viral oncogene homolog) is a direct target of miR-134. Western blot was used to identify the potential signaling pathways that had an impact on RCC cell growth and alterations of markers for epithelial-mesenchymal transition (EMT), which affected metastasis by miR-134. miR-134 was found to be downregulated in RCC samples (p<0.05), while overexpression of miR-134 suppressed proliferation (p<0.05) by triggering G1/G0 cell cycle arrest (p<0.05). Forced expression of miR-134 could also inhibit migration (p<0.05) and invasion (p<0.05) by blocking EMT in RCC cell lines. KRAS was identified as a target of miR-134, and miR-134 may act as a tumor suppressor through the KRAS-related MAPK/ERK pathway other than PI3K/AKT signaling. Thus, miR-134 may function as a tumor suppressor in cell proliferation and EMT by targeting KRAS in RCC cells. PMID- 25811080 TI - Electrochemical Generation of a Hydrogen Bubble at a Recessed Platinum Nanopore Electrode. AB - We report the electrochemical generation of a single hydrogen bubble within the cavity of a recessed Pt nanopore electrode. The recessed Pt electrode is a conical pore in glass that contains a micrometer-scale Pt disk (1-10 MUm radius) at the nanopore base and a nanometer-scale orifice (10-100 nm radius) that restricts diffusion of electroactive molecules and dissolved gas between the nanopore cavity and bulk solution. The formation of a H2 bubble at the Pt disk electrode in voltammetric experiments results from the reduction of H(+) in a 0.25 M H2SO4 solution; the liquid-to-gas phase transformation is indicated in the voltammetric response by a precipitous decrease in the cathodic current due to rapid bubble nucleation and growth within the nanopore cavity. Finite element simulations of the concentration distribution of dissolved H2 within the nanopore cavity, as a function of the H(+) reduction current, indicate that H2 bubble nucleation at the recessed Pt electrode surface occurs at a critical supersaturation concentration of ~0.22 M, in agreement with the value previously obtained at (nonrecessed) Pt disk electrodes (~0.25 M). Because the nanopore orifice limits the diffusion of H2 out of the nanopore cavity, an anodic peak corresponding to the oxidation of gaseous and dissolved H2 trapped in the recessed cavity is readily observed on the reverse voltammetric scan. Integration of the charge associated with the H2 oxidation peak is found to approach that of the H(+) reduction peak at high scan rates, confirming the assignment of the anodic peak to H2 oxidation. Preliminary results for the electrochemical generation of O2 bubbles from water oxidation at a recessed nanopore electrode are consistent with the electrogeneration of H2 bubbles. PMID- 25811081 TI - Color patterns of closely related bird species are more divergent at intermediate levels of breeding-range sympatry. AB - Closely related species of birds often differ markedly in their color patterns. Here we examine the influence of breeding-range overlap (breeding sympatry) on the evolution of color pattern differences in a sample of closely related bird species. We used a sister-lineage method to analyze 73 phylogenetically independent comparisons among 246 species and 39 families of birds worldwide. We found that divergence of color patterns among closely related species was greater between sympatric than between allopatric lineages, but only at intermediate levels of sympatry (50%-80% breeding-range overlap). This pattern suggests that closely related species incur costs at intermediate levels of sympatry if they exhibit similar color patterns-costs that could include hybridization, interspecific aggression, competition for signaling space, or ecological interactions that secondarily influence color patterns. The decline in color pattern divergence with further increase in sympatry suggests either the relaxation of divergent selection, increased impediment of gene flow, or an increased role for counteracting selection at higher levels of sympatry. We also found that the differences in color pattern between sympatric and allopatric sister species were greatest at lower latitudes. The global scale and broad taxonomic coverage in our study suggest that the divergence of color patterns between sympatrically breeding closely related species is widespread in birds. PMID- 25811076 TI - Animal-associated exposure to rabies virus among travelers, 1997-2012. AB - Among travelers, rabies cases are rare, but animal bites are relatively common. To determine which travelers are at highest risk for rabies, we studied 2,697 travelers receiving care for animal-related exposures and requiring rabies postexposure prophylaxis at GeoSentinel clinics during 1997-2012. No specific demographic characteristics differentiated these travelers from other travelers seeking medical care, making it challenging to identify travelers who might benefit from reinforced pretravel rabies prevention counseling. Median travel duration was short for these travelers: 15 days for those seeking care after completion of travel and 20 days for those seeking care during travel. This finding contradicts the view that preexposure rabies vaccine recommendations should be partly based on longer travel durations. Over half of exposures occurred in Thailand, Indonesia, Nepal, China, and India. International travelers to rabies-endemic regions, particularly Asia, should be informed about potential rabies exposure and benefits of pretravel vaccination, regardless of demographics or length of stay. PMID- 25811082 TI - Variable environmental effects on a multicomponent sexually selected trait. AB - Multicomponent signals are made up of interacting elements that generate a functional signaling unit. The interactions between signal components and their effects on individual fitness are not well understood, and the effect of environment is even less so. It is usually assumed that color patterns appear the same in all light environments and that the effects of each color are additive. Using guppies, Poecilia reticulata, we investigated the effect of water color on the interactions between components of sexually selected male coloration. Through behavioral mate choice trials in four different water colors, we estimated the attractiveness of male color patterns, using multivariate fitness estimates and overall signal contrast. Our results show that females exhibit preferences that favor groups of colors rather than individual colors independently and that each environment favors different color combinations. We found that these effects are consistent with female guppies selecting entire color patterns on the basis of overall visual contrast. This suggests that both individuals and populations inhabiting different light environments will be subject to divergent, multivariate selection. Although the appearance of color patterns changes with light environment, achromatic components change little, suggesting that these could function in species recognition or other aspects of communication that must work across environments. Consequently, we predict different phylogenetic patterns between chromatic and achromatic signals within the same clades. PMID- 25811083 TI - Alternative Reproductive Tactics Arising from a Continuous Behavioral Trait: Callers versus Satellites in Field Crickets. AB - Alternative reproductive tactics may arise when natural enemies use sexual signals to locate the signaler. In field crickets, elevated costs to male calling due to acoustically orienting parasitoid flies create opportunity for an alternative tactic, satellite behavior, where noncalling males intercept females attracted to callers. Although the caller-satellite system in crickets that risk detection by parasitoids resembles distinct behavioral phenotypes, a male's propensity to behave as caller or satellite can be a continuously variable trait over several temporal scales, and an individual may pursue alternate tactics at different times. We modeled a caller-satellite-parasitoid system as a spatially explicit interaction among male and female crickets using individual-based simulation. Males varied in their propensity to call versus behave as a satellite from one night to the next. We varied mortality, density, sex ratio, and female mating behavior, and recorded lifetime number of mates as a function of a male's probability of calling (vs. acting as a satellite) along a gradient in parasitism risk. Frequently, the optimal behavior switched abruptly from being pure caller (call every night) to pure satellite (never call) as parasitism rate increased. However, mixed strategies prevailed even with high parasitism risk under conditions of higher background mortality rate, decreasing density, increasing female-biased sex ratio, and increasing female choosiness. In natural populations, high parasitoid pressure alone would be unlikely to yield fixation of pure satellite behavior. PMID- 25811084 TI - Behavioral Isolation due to Cascade Reinforcement in Lucania Killifish. AB - Reinforcement occurs when behavioral isolation is strengthened between species due to selection against hybridization in sympatry. Mate preferences and their target traits may change in sympatry as a consequence of reinforcement. This can potentially generate further behavioral isolation within species if sympatric populations evolve extreme preferences or traits that cause them to reject individuals from foreign populations as mates or be rejected as mates. This process is known as cascade reinforcement. We measured behavioral isolation between sympatric and allopatric populations of Lucania killifish to determine whether isolation evolves due to reinforcement between species and whether reinforcement affects preferences within species, consistent with the cascade reinforcement hypothesis. We measured mate preferences in both sexes between species (Lucania parva vs. Lucania goodei) and within species (among populations of L. parva). Between species, both male and female preferences for conspecifics were highest in sympatric populations. Within species, L. parva females from sympatric populations preferred their own native males over foreign males. Allopatric L. parva females and all L. parva males showed no preferences within species. Within species, behavioral isolation showed no association with ecological variables, such as salinity. Thus, reinforcement is a primary factor generating behavioral isolation in Lucania killifish, creating strong preferences in both sexes among species and leading to cascade reinforcement of female mate preference within species. PMID- 25811085 TI - Exploring the Relationships between Mutation Rates, Life History, Genome Size, Environment, and Species Richness in Flowering Plants. AB - A new view is emerging of the interplay between mutation at the genomic level, substitution at the population level, and diversification at the lineage level. Many studies have suggested that rate of molecular evolution is linked to rate of diversification, but few have evaluated competing hypotheses. By analyzing sequences from 130 families of angiosperms, we show that variation in the synonymous substitution rate is correlated among genes from the mitochondrial, chloroplast, and nuclear genomes and linked to differences in traits among families (average height and genome size). Within each genome, synonymous rates are correlated to nonsynonymous substitution rates, suggesting that increasing the mutation rate results in a faster rate of genome evolution. Substitution rates are correlated with species richness in protein-coding sequences from the chloroplast and nuclear genomes. These data suggest that species traits contribute to lineage-specific differences in the mutation rate that drive both synonymous and nonsynonymous rates of change across all three genomes, which in turn contribute to greater rates of divergence between populations, generating higher rates of diversification. These observations link mutation in individuals to population-level processes and to patterns of lineage divergence. PMID- 25811086 TI - Functional Traits in Parallel Evolutionary Radiations and Trait-Environment Associations in the Cape Floristic Region of South Africa. AB - Evolutionary radiations with extreme levels of diversity present a unique opportunity to study the role of the environment in plant evolution. If environmental adaptation played an important role in such radiations, we expect to find associations between functional traits and key climatic variables. Similar trait-environment associations across clades may reflect common responses, while contradictory associations may suggest lineage-specific adaptations. Here, we explore trait-environment relationships in two evolutionary radiations in the fynbos biome of the highly biodiverse Cape Floristic Region (CFR) of South Africa. Protea and Pelargonium are morphologically and evolutionarily diverse genera that typify the CFR yet are substantially different in growth form and morphology. Our analytical approach employs a Bayesian multiple-response generalized linear mixed-effects model, taking into account covariation among traits and controlling for phylogenetic relationships. Of the pairwise trait-environment associations tested, 6 out of 24 were in the same direction and 2 out of 24 were in opposite directions, with the latter apparently reflecting alternative life-history strategies. These findings demonstrate that trait diversity within two plant lineages may reflect both parallel and idiosyncratic responses to the environment, rather than all taxa conforming to a global-scale pattern. Such insights are essential for understanding how trait environment associations arise and how they influence species diversification. PMID- 25811087 TI - The puzzle of partial resource use by a parasitoid wasp. AB - When there is conspicuous underexploitation of a limited resource, it is worth asking, what mechanisms allow presumably valuable resources to be left unused? Evolutionary biologists have generated a wide variety of hypotheses to explain this, ranging from interdemic group selection to selfishly prudent individual restraint. We consider a situation in which, despite high intraspecific competition, individuals leave most of a key resource unexploited. The parasitic wasp that does this finds virtually all host egg clusters in a landscape but parasitizes only about a third of the eggs in each and then leaves a deterrent mark around the cluster. We first test-and reject-a series of system-specific simple constraints that might limit full host exploitation, such as asynchronous maturation of host eggs. We then consider classical hypotheses for the evolution of restraint. Prudent predation and bet-hedging fail as explanations because the wasp lives as a large, well-mixed population. Additionally, we find no individual benefits to the parasitoid of developing in a sparsely parasitized host nest. However, an optimal foraging model, including empirically measured costs of superparasitism and hyperparasitism, can explain through individual selection both the consistently low rate of parasitism and deterrent marking. PMID- 25811088 TI - Inherent demographic stability in mutualist-resource-exploiter interactions. AB - Core principles of ecological theory predict that, in the absence of other factors, mutualisms should experience destabilizing positive feedback and should be vulnerable to extinction through competitive exclusion by exploiter species. Many effective stabilizing mechanisms address one issue or the other, and many turn upon additional features. Using an explicitly demographic approach, I show that indirect, demography-mediated interactions between mutualists and exploiters can enable mutualist-exploiter coexistence, which in turn can stabilize the abundances of mutualists, exploiters, and their shared resources. This occurs because of the distinct resource demographic responses that are inherent to interaction with mutualistic and exploitative partners and can occur in long lasting, exclusive interactions, such as protection mutualisms, as well as in apparently very different, short-lived mutualistic interactions, such as pollination. The key necessary factor-demographic response to interspecific interaction-is common in nature. Some demographic structure is also necessary and is generated through interspecific interaction in long-lasting associations; it is also very common in natural populations. Thus, the explicitly demographic and multispecies approach taken here constitutes a potentially promising single explanation for the apparent stability of mutualism in a wide range of natural systems. PMID- 25811089 TI - White Sharks Exploit the Sun during Predatory Approaches. AB - There is no conclusive evidence of any nonhuman animal using the sun as part of its predation strategy. Here, we show that the world's largest predatory fish-the white shark (Carcharodon carcharias)-exploits the sun when approaching baits by positioning the sun directly behind them. On sunny days, sharks reversed their direction of approach along an east-west axis from morning to afternoon but had uniformly distributed approach directions during overcast conditions. These results show that white sharks have sufficient behavioral flexibility to exploit fluctuating environmental features when predating. This sun-tracking predation strategy has a number of potential functional roles, including improvement of prey detection, avoidance of retinal overstimulation, and predator concealment. PMID- 25811090 TI - How memory-based movement leads to nonterritorial spatial segregation. AB - Home ranges (HRs) are a remarkably common form of animal space use, but we still lack an integrated view of the individual-level processes that can lead to their emergence and maintenance, particularly when individuals are in competition for resources. We built a spatially explicit mechanistic movement model to investigate how simple memory-based foraging rules may enable animals to establish HRs and to what extent this increases their foraging efficiency compared to individuals that do not base foraging decisions on memory. We showed that these simple rules enable individuals to perform better than individuals using the most efficient strategy that does not rely on memory and drive them to spatially segregate through avoidance of resource patches used by others. This striking result questions the common assumption that low HR overlaps are indicators of territorial behavior. Indeed, it appears that, by using an information-updating system, individuals can keep their environment relatively predictable without paying the cost of defending an exclusive space. However, memory-based foraging strategies leading to HR emergence seem unable to prevent the disruptive effects of the arrival of new individuals. This calls for further research on the mechanisms that can stabilize HR spatial organization in the long term. PMID- 25811091 TI - Expansion load and the evolutionary dynamics of a species range. AB - Expanding populations incur a mutation burden, the so-called expansion load. Using a mixture of individual-based simulations and analytical modeling, we study the expansion load process in models where population growth depends on the population's fitness (i.e., hard selection). We show that expansion load can severely slow down expansions and limit a species' range, even in the absence of environmental variation. We also study the effect of recombination on the dynamics of a species range and on the evolution of mean fitness on the wave front. If recombination is strong, mean fitness on front approaches an equilibrium value at which the effects of fixed mutations cancel each other out. The equilibrium rate at which new demes are colonized is similar to the rate at which beneficial mutations spread through the core. Without recombination, the dynamics is more complex, and beneficial mutations from the core of the range can invade the front of the expansion, which results in irregular and episodic expansion. Although the rate of adaptation is generally higher in recombining organisms, the mean fitness on the front may be larger in the absence of recombination because high-fitness individuals from the core have a higher chance to invade the front. Our findings have important consequences for the evolutionary dynamics of species ranges as well as on the role and the evolution of recombination during range expansions. PMID- 25811092 TI - Costs and benefits of thermoregulation revisited: both the heterogeneity and spatial structure of temperature drive energetic costs. AB - In recent years, ecologists have stepped up to address the challenges imposed by rapidly changing climates. Some researchers have developed niche-based methods to predict how species will shift their ranges. Such methods have evolved rapidly, resulting in models that incorporate physiological and behavioral mechanisms. Despite their sophistication, these models fail to account for environmental heterogeneity at the scale of an organism. We used an individual-based model to quantify the effects of operative environmental temperatures, as well as their heterogeneity and spatial structure, on the thermoregulation, movement, and energetics of ectotherms. Our simulations showed that the heterogeneity and spatial structure of a thermal landscape are as important as its mean temperature. In fact, temperature and heterogeneity interact to determine organismal performance. Consequently, the popular index of environmental quality (d(e)), which ignores variance and spatial structure, is inherently flawed as a descriptor of the thermal quality of an environment. Future efforts to model species' distributions should link thermoregulation and activity to environmental heterogeneity at fine scales. PMID- 25811093 TI - Label-free detection of tobramycin in serum by transmission-localized surface plasmon resonance. AB - In order to improve the efficacy and safety of treatments, drug dosage needs to be adjusted to the actual needs of each patient in a truly personalized medicine approach. Key for widespread dosage adjustment is the availability of point-of care devices able to measure plasma drug concentration in a simple, automated, and cost-effective fashion. In the present work, we introduce and test a portable, palm-sized transmission-localized surface plasmon resonance (T-LSPR) setup, comprised of off-the-shelf components and coupled with DNA-based aptamers specific to the antibiotic tobramycin (467 Da). The core of the T-LSPR setup are aptamer-functionalized gold nanoislands (NIs) deposited on a glass slide covered with fluorine-doped tin oxide (FTO), which acts as a biosensor. The gold NIs exhibit localized plasmon resonance in the visible range matching the sensitivity of the complementary metal oxide semiconductor (CMOS) image sensor employed as a light detector. The combination of gold NIs on the FTO substrate, causing NIs size and pattern irregularity, might reduce the overall sensitivity but confers extremely high stability in high-ionic solutions, allowing it to withstand numerous regeneration cycles without sensing losses. With this rather simple T LSPR setup, we show real-time label-free detection of tobramycin in buffer, measuring concentrations down to 0.5 MUM. We determined an affinity constant of the aptamer-tobramycin pair consistent with the value obtained using a commercial propagating-wave based SPR. Moreover, our label-free system can detect tobramycin in filtered undiluted blood serum, measuring concentrations down to 10 MUM with a theoretical detection limit of 3.4 MUM. While the association signal of tobramycin onto the aptamer is masked by the serum injection, the quantification of the captured tobramycin is possible during the dissociation phase and leads to a linear calibration curve for the concentrations over the tested range (10-80 MUM). The plasmon shift following surface binding is calculated in terms of both plasmon peak location and hue, with the latter allowing faster data elaboration and real-time display of the results. The presented T-LSPR system shows for the first time label-free direct detection and quantification of a small molecule in the complex matrix of filtered undiluted blood serum. Its uncomplicated construction and compact size, together with the remarkable performances, represent a leap forward toward effective point-of-care devices for therapeutic drug concentration monitoring. PMID- 25811094 TI - Impact of treatment planning with deformable image registration on dose distribution for carbon-ion beam lung treatment using a fixed irradiation port and rotating couch. AB - OBJECTIVE: When using a fixed irradiation port, treatment couch rotation is necessary to increase beam angle selection. We evaluated dose variations associated with positional morphological changes to organs. METHODS: We retrospectively chose the data sets of ten patients with lung cancer who underwent respiratory-gated CT at three different couch rotation angles (0 degrees , 20 degrees and -20 degrees ). The respective CT data sets are referred to as CT0, CT20 and CT-20. Three treatment plans were generated as follows: in Plan 1, all compensating bolus designs and dose distributions were calculated using CT0. To evaluate the rotation effect without considering morphology changes, in Plan 2, the compensating boli designed using CT0 were applied to the CT+/-20 images. Plan 3 involved compensating boli designed using the CT+/-20 images. The accumulated dose distributions were calculated using deformable image registration (DIR). RESULTS: A sufficient prescribed dose was calculated for the planning target volume (PTV) in Plan 1 [minimum dose received by a volume >=95% (D95) > 95.8%]. By contrast, Plan 2 showed degraded dose conformation to the PTV (D95 > 90%) owing to mismatch of the bolus design to the morphological positional changes in the respective CT. The dose assessment results of Plan 3 were very close to those of Plan 1. CONCLUSION: Dose distribution is significantly affected by whether or not positional organ morphology changes are factored into dose planning. ADVANCES IN KNOWLEDGE: In treatment planning using multiple CT scans with different couch positions, it is mandatory to calculate the accumulated dose using DIR. PMID- 25811095 TI - (223)Ra and other bone-targeting radiopharmaceuticals-the translation of radiation biology into clinical practice. AB - Osseous metastases are a source of significant morbidity for patients with a variety of cancers. Radiotherapy is well established as an effective means of palliating symptoms associated with such metastases. The role of external beam radiotherapy is limited where sites of metastases are numerous and widespread. Low linear energy transfer (LET) radionuclides have been utilized to allow targeted delivery of radiotherapy to disparate sites of disease, with evidence of palliative benefit. More recently, the bone targeting, high LET radionuclide (223)Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration-resistant prostate cancer with bone metastases. This article reviews the different radionuclide-based approaches for targeting bone metastases, with an emphasis on (223)Ra, and key elements of the underlying radiobiology of these that will impact their clinical effectiveness. Consideration is given to the remaining unknowns of both the basic radiobiological and applied clinical effects of (223)Ra as targets for future research. PMID- 25811098 TI - Influenza A(H10N7) virus in dead harbor seals, Denmark. AB - Since April 2014, an outbreak of influenza in harbor seals has been ongoing in northern Europe. In Denmark during June-August, 152 harbor seals on the island of Anholt were found dead from severe pneumonia. We detected influenza A(H10N7) virus in 2 of 4 seals examined. PMID- 25811096 TI - Reduction of radiation exposure by lead curtain shielding in dedicated extremity cone beam CT. AB - OBJECTIVE: A dedicated extremity cone beam CT (CBCT) was introduced recently, and is rapidly becoming an attractive modality for extremity imaging. This study aimed to evaluate the effectiveness of a curtain-shaped lead shielding in reducing the exposure of patients to scattered radiation in dedicated extremity CBCT. METHODS: A dedicated extremity CBCT scanner was used. The lead shielding curtain was 42 * 60 cm with 0.5-mm lead equivalent. Scattered radiation dose from CBCT was measured using thermoluminescence dosimetry chips at 20 points, at different distances and directions from the CT gantry. Two sets of scattered radiation dose measurements were performed before and after installation of curtain-shaped lead shield, and the percentage reduction in dose in air was calculated. RESULTS: Mean radiation exposure dose at measured points was 34.46 +/ 48.40 MUGy without curtains and 9.67 +/- 4.53 MUGy with curtains, exhibiting 71.94% reduction (p = 0.000). The use of lead shielding curtains significantly reduced scattered radiation at 0.5, 1.0 and 1.5 m from the CT gantry, with percent reductions of 84.8%, 58.0% and 35.5%, respectively (p = 0.000, 0.000 and 0.002). The percent reduction in the diagonal (+45 degrees , -45 degrees ) and vertical forward (0 degrees ) directions were 86.3%, 83.1% and 77.7%, respectively, and were statistically significant (p = 0.029, 0.020 and 0.041). CONCLUSION: Shielding with lead curtains suggests an easy and effective method for reducing patient exposure to radiation in extremity CBCT imaging. ADVANCES IN KNOWLEDGE: Lead shielding curtains are an effective technique to reduce scattered radiation dose in dedicated extremity CBCT, with higher dose reduction closer to the gantry opening. PMID- 25811099 TI - Stereochemical studies of the opening of chloro vinyl epoxides: cyclic chloronium ions as intermediates. AB - A systematic study of the opening of a collection of chlorinated vinyl epoxides is reported, which includes experiments that implicate both five- and four membered chloronium ions as plausible intermediates in this type of epoxide opening reaction. PMID- 25811100 TI - Conducting shrinkable nanocomposite based on au-nanoparticle implanted plastic sheet: tunable thermally induced surface wrinkling. AB - A thermally shrinkable and conductive nanocomposite material is prepared by supersonic cluster beam implantation (SCBI) of neutral Au nanoparticles (Au NPs) into a commercially available thermo-retractable polystyrene (PS) sheet. Micronanowrinkling is obtained during shrinking, which is studied by means of SEM, TEM and AFM imaging. Characteristic periodicity is determined and correlated with nanoparticle implantation dose, which permits us to tune the topographic pattern. Remarkable differences emerged with respect to the well-known case of wrinkling of bilayer metal-polymer. Wrinkled composite surfaces are characterized by a peculiar multiscale structuring that promises potential technological applications in the field of catalytic surfaces, sensors, biointerfaces, and optics, among others. PMID- 25811101 TI - Effect of Agave americana and Agave salmiana Ripeness on Saponin Content from Aguamiel (Agave Sap). AB - Steroidal saponins have shown beneficial health effects. Agave spp. leaves and rhizomes are sources of these compounds, but their presence has not been reported in the aguamiel. Aguamiel is the sweet edible sap from mature agave, and its quality is influenced by the plant ripening stage. The purpose of this research was to identify and quantitate saponins in aguamiel from Agave americana and Agave salmiana at two ripening stages. Saponins and sapogenins were identified with HPLC/ESI-MS/TOF and quantitated with HPLC/ELSD. Results proved the presence of saponins derived from kammogenin, manogenin, gentrogenin, and hecogenin. The saponin content in aguamiel from immature A. salmiana was 2-fold higher (478.3 protodioscin equivalents (PE) MUg/g aguamiel (DM)) compared with A. americana (179.0 PE MUg/g aguamiel (DM)). In both species, saponin content decreased when plants reached sexual maturity. This should be considered before evaluating the effects of Agave spp. as a source of bioactive saponins. PMID- 25811102 TI - Migrations of pentagon-heptagon defects in hexagonal boron nitride monolayer: the first-principles study. AB - The first-principles calculations are employed to study the migrations of pentagon-heptagon (5-7) defects in hexagonal boron nitride monolayer (h-BN). A type of grain boundaries, consisted of 5-7 defects, is constructed on the basis of experimental observations. With the absorption of a pair of atoms, one 5-7 defect in the grain boundary migrates apart by one unit cell and afterward migrates again through the bond rotation. It is also found that the two migrations could be replaced by one single step when the pair of absorbed atoms is located at another specific site in the same heptagon. Energy barriers and reaction paths for the migrations of 5-7 defects in h-BN by the bond rotation are theoretically investigated by the standard nudged elastic band method and the generalized solid-state nudged elastic band method. To elucidate the difference between the bond rotation process of the 5-7 defects with N-N bonds and those with B-B bonds, a couple of typical 21.7 degrees grain boundaries with either N N or B-B bonds are investigated. It is shown that the energy barrier of the migration of defects with N-N bonds is lower than that with B-B bonds in this type of grain boundaries. PMID- 25811103 TI - Couples' shared experiences of dementia: a meta-synthesis of the impact upon relationships and couplehood. AB - OBJECTIVES: There is a growing recognition of dementia as a condition that affects both members of a couple individually while also influencing the relational bond between them. This is an area which potentially has important service implications. Accordingly, the aim of this review was to elaborate the experience of dementia on partner/spousal relationships through a synthesis of pertinent qualitative literature. METHOD: A systematic literature search for qualitative research papers was undertaken in November 2013. Five databases (Academic Search Complete, CINAHL, MEDLINE, PsycARTICLES and PsycINFO) were searched using terms for dementia, partner and qualitative data analysis. Meta synthesis was conducted on the data within the found papers. RESULTS: A line-of argument synthesis of 10 studies yielded four overarching themes, which highlight couples' efforts to maintain their sense of togetherness; shifts in balance and power within their relationship which can impact upon both partners' sense of identity; the empathy and sensitive attunement between couples as they work to protect each other's sense of role and identity; and the resilience couples demonstrate in the face of great fear, uncertainty and hopelessness. CONCLUSION: Findings have important implications for both research and practice, particularly the need for services to support couples' efforts to enhance couplehood in spite of dementia. Ultimately, this review adds further weight to arguments to refocus dementia care on relationships in addition to individuals. PMID- 25811104 TI - Use of Antifibrotics to Prevent Ventriculoperitoneal Shunt Complications Due to Intra-abdominal Fibrosis: Experimental Study in a Rat Model. AB - BACKGROUND: Cerebrospinal fluid shunt operations have reduced the morbidity and mortality of hydrocephalus, but have potential complications. Ventriculoperitoneal (vp) shunt obstruction is one of the common complications of shunt surgery. The obstruction is caused by fibrosis and is usually located on the tip of the ventricular and/or peritoneal catheter. OBJECTIVE: In our study, we aimed to demonstrate the known antifibrotic effects of heparin, hyaluronate/carboxymethylcellulose, and icodextrin on peritoneal catheter obstruction in a vp shunt model in rats. METHODS: Thirty-two male Sprague-Dawley rats were used in this study. A shunt catheter was placed in the abdominal cavity. In the control group, isotonic solution, in the study groups, heparin, sodium hyaluronate/carboxymethylcellulose (HA/CMC), and icodextrin were intraperitoneally applied. The severity of adhesions and inflammation around the peritoneal catheter was evaluated after the rats were killed on day 30. RESULTS: One animal in the heparin group died due to intra-abdominal hemorrhage. We found the most adhesions in the control group. All three drugs (heparin, HA/CMC, icodextrin) were effective for adhesion prevention. HA/CMC was more effective than heparin, and icodextrin was most effective. There was a statistically significant difference between the icodextrin and the control group (p = 0.007). CONCLUSION: The intra-abdominal instillation of icodextrin, HA/CMC, and heparin, especially icodextrin, can decrease the rate of vp shunt dysfunction by preventing formation of intraperitoneal fibrosis. PMID- 25811105 TI - Norovirus GII.21 in children with Diarrhea, Bhutan. PMID- 25811106 TI - Efficient charge separation on 3D architectures of TiO2 mesocrystals packed with a chemically exfoliated MoS2 shell in synergetic hydrogen evolution. AB - Here we demonstrated that 3D architectures of TiO2 mesocrystals uniformly packed with a chemically exfoliated MoS2 shell exhibit promising reactive efficiency and good stability in synergetic hydrogen evolution. The efficient interfacial electron transfer from the excited TiO2 moieties to the decorated ultrathin MoS2 shell was effectively monitored. PMID- 25811107 TI - Co-infection with Avian (H7N9) and Pandemic (H1N1) 2009 Influenza Viruses, China. PMID- 25811110 TI - Complementary light scattering and synchrotron small-angle X-ray scattering studies of the micelle-to-unimer transition of polysulfobetaines. AB - AB and ABA di- and triblock copolymers where A is the hydrophilic poly(oligoethylene glycol methacrylate) (POEGMA) block and B is a thermo responsive sulfobetaine block [2-(methacryloyloxy) ethyl] dimethyl-(3 sulfopropyl) ammonium hydroxide (PDMAPS) were synthesised by aqueous RAFT polymerisation with narrow dispersity (DM <= 1.22), as judged by aqueous SEC analysis. The di- and triblock copolymers self-assembled in salt-free water to form micelles with a PDMAPS core and the self-assembly of these polymers was explored by SLS and TEM analysis. The micelles were shown, by DLS analysis, to undergo a micelle-to-unimer transition at a critical temperature, which was dependent upon the length of the POEGMA block. Increasing the length of the third, POEGMA, block decreased the temperature at which the micelle-to-unimer transition occurred as a result of the increased hydrophilicity of the polymer. The dissociation of the micelles was further studied by SLS and synchrotron SAXS. SAXS analysis revealed that the micelle dissociation began at temperatures below that indicated by DLS analysis and that both micelles and unimers coexist. This highlights the importance of using multiple complementary techniques in the analysis of self-assembled structures. In addition the micelle-to-unimer morphology transition was employed to encapsulate and release a hydrophobic dye, Nile Red, as shown by fluorescence spectroscopy. PMID- 25811108 TI - Fish consumption, long-chain omega-3 polyunsaturated fatty acid intake and risk of metabolic syndrome: a meta-analysis. AB - Fish and long-chain omega-3 polyunsaturated fatty acid (LComega3PUFA) intake in relation to the risk of cardiovascular diseases have been well studied. However, studies that directly link fish consumption or LComega3PUFA intake to the risk of metabolic syndrome (MetS) are sparse and the results are inconsistent. We reviewed literature through December 2014 and used random-effects or fixed effects models, as appropriate, to pool the associations of fish or LComega3PUFA intake with the risk of MetS. Nine independent cross-sectional samples (seven cross-sectional studies) and three independent prospective cohorts (two prospective cohort studies) were identified as eligible for this meta-analysis. By pooling data from the prospective cohorts (7860 participants and 1671 incident cases), a significant inverse association between fish consumption and incidence of MetS was found. The pooled RR (95% CI) was 0.71 (0.58, 0.87), comparing the highest to the lowest category of fish consumption, and 0.94 (0.90, 0.98) for one serving/week increment. Consistent results were found for LComega3PUFA intake. Non-significant inverse association of fish or LComega3PUFA intake with risk of MetS was found when pooling the cross-sectional studies. By quantitatively summarizing the literature, a modest inverse association between fish or LComega3PUFA intake and risk of MetS cannot be excluded. PMID- 25811109 TI - L-glutamine and whole protein restore first-phase insulin response and increase glucagon-like peptide-1 in type 2 diabetes patients. AB - L-glutamine triggers glucagon-like peptide-1 (GLP-1) release from L cells in vitro and when ingested pre-meal, decreases postprandial glycaemia and increases circulating insulin and GLP-1 in type 2 diabetes (T2D) patients. We aimed to evaluate the effect of oral L-glutamine, compared with whole protein low in glutamine, on insulin response in well-controlled T2D patients. In a randomized study with a crossover design, T2D patients (n = 10, 6 men) aged 65.1 +/- 5.8, with glycosylated hemoglobin (HbA1c) 6.6% +/- 0.7% (48 +/- 8 mmol/mol), received oral L-glutamine (25 g), protein (25 g) or water, followed by an intravenous glucose bolus (0.3 g/kg) and hyperglycemic glucose clamp for 2 h. Blood was frequently collected for analyses of glucose, serum insulin and plasma total and active GLP-1 and area under the curve of glucose, insulin, total and active GLP-1 excursions calculated. Treatments were tested 1-2 weeks apart. Both L-glutamine and protein increased first-phase insulin response (p <= 0.02). Protein (p = 0.05), but not L-glutamine (p = 0.2), increased second-phase insulin response. Total GLP-1 was increased by both L-glutamine and protein (p <= 0.02). We conclude that oral L-glutamine and whole protein are similarly effective in restoring first-phase insulin response in T2D patients. Larger studies are required to further investigate the utility of similar approaches in improving insulin response in diabetes. PMID- 25811111 TI - A Newly Developed Nested PCR Assay for the Detection of Helicobacter pylori in the Oral Cavity. AB - GOALS: To develop a new nested polymerase chain reaction (PCR) assay for identifying Helicobacter pylori DNA from dental plaque. BACKGROUND: H. pylori is one of the most common chronic bacterial pathogens in humans. The accurate detection of this organism is essential for proper patient management and for the eradication of the bacteria following treatment. STUDY: Forty-nine patients (24 males and 25 females; mean age: 51; range, 19 to 94 y) were investigated for the presence of H. pylori in dental plaque by single-step PCR and nested PCR and in the stomach by single-step PCR, nested PCR, and histologic examination. RESULTS: The newly developed nested PCR assay identified H. pylori DNA in gastric biopsies of 18 patients who were histologically classified as H. pylori-positive and 2 additional biopsies of patients who were H. pylori-negative by histologic examination (20/49; 40.8%). Dental plaque samples collected before and after endoscopy from the 49 patients revealed that single-step PCR did not detect H. pylori but nested PCR was able to detect H. pylori DNA in 40.8% (20/49) patients. Nested PCR gave a higher detection rate (40.8%, 20/49) than that of histology (36.7%, 18/49) and single-step PCR. When nested PCR results were compared with histology results there was no significant difference between the 2 methods. CONCLUSIONS: Our newly developed nested PCR assay is at least as sensitive as histology and may be useful for H. pylori detection in patients unfit for endoscopic examination. PMID- 25811112 TI - The Negative Prognostic Impact of a First Ever Episode of Spontaneous Bacterial Peritonitis in Cirrhosis and Ascites. AB - BACKGROUND: The prognostic impact of the first ever episode of spontaneous bacterial peritonitis (SBP) on patient outcomes is not well described. Our aim was to compare the clinical outcomes of cirrhotic patients with ascites, and with or without a first episode of SBP. METHODS: Consecutive patients with cirrhosis and ascites were prospectively enrolled. Demographics, liver and renal function, and hemodynamics were documented at baseline, at resolution of SBP, and thereafter at 4 monthly intervals for 12 months. Complications of cirrhosis and survival were noted. RESULTS: Twenty-nine cirrhotic patients with a first ever episode of SBP (group A) and 123 control patients slightly younger but similar in gender who never had SBP (group B) were enrolled. At SBP diagnosis, group A had worse liver and renal function (Model of End-Stage Liver Disease : 21.1+/-10.6 vs. 14.4+/-5.0), lower serum sodium concentrations, and a more hyperdynamic circulation compared with group B (all P<0.001). SBP resolution resulted in improvement in all measures to baseline levels. During follow-up, group A required more frequent hospital admissions than group B (58% vs. 43%), developed more cirrhotic complications, including further SBP (31% vs. 3%*), hyponatremia (12% vs. 0.8%*), acute kidney injury (50% vs. 23%*), hepatorenal syndrome type 1 (46% vs. 7%*), liver transplantation (62% vs. 30%*), and had a worse overall 1 year survival (38% vs. 70%*) (*P<0.05). CONCLUSIONS: A first SBP episode is commonly followed by multiple complications, and overall worse prognosis. Consideration should be given to assess cirrhotic patients for liver transplant after the first episode of SBP. PMID- 25811113 TI - Modern concepts in diverticular disease. AB - Over the last decade there has been a striking shift in our understanding of the epidemiology, pathology, and management of diverticular disease. Indeed, many of the guidelines published in the late nineties and early 2000s are now redundant. High-fiber diets, avoidance of nuts and seeds, antibiotic treatment for mild diverticulitis, elective resection after 2 attacks of diverticulitis, Hartmann's procedure (HP), and aggressive management of young patients are all open to question. The more we challenge our understanding of diverticulitis it becomes apparent how little we know about this disease entity. This review aims update the reader on current hypotheses and evidencebased modern management strategies in diverticular disease. PMID- 25811114 TI - Acute hepatitis induced by pure Garcinia cambogia. PMID- 25811115 TI - Confocal laser endomicroscopy for the detection of atrophic gastritis: a new application for confocal endomicroscopy? PMID- 25811116 TI - Cap-assisted Endoscopic Mucosal Resection is Highly Effective for Nonpedunculated Colorectal Lesions. AB - GOALS: To assess the safety and efficacy of cap-assisted endoscopic mucosal resection (C-EMR) for nonpedunculated colorectal lesions. BACKGROUND: There are little data supporting the safety and efficacy of C-EMR for colorectal polyps. STUDY: A retrospective review was conducted on the medical records of 97 consecutive patients who underwent C-EMR for nonpedunculated colorectal lesions in a tertiary center by a single gastroenterologist (L.H.J.). Reported outcomes were: overall eradication rate that included all attempted C-EMRs, endoscopist reported eradication rate that included C-EMRs reported as a success, and complications rate. RESULTS: A total of 134 C-EMRs were performed on 124 nonpedunculated colorectal lesions within a 55-month period, with a median follow up of 4.2 (1.6 to 46.8) months. Among the polyps with available follow-up, the overall eradication rate was 91% (81/89); the endoscopist-reported eradication rate was 98.8% (81/82). The complications rate was 10.2%: perforation (3.9%), intraprocedural bleeding (3.9%), and delayed bleeding (2.4%); all but 2 perforation cases that required surgical interventions (both occurring early in the time period in which procedures were performed), were treated endoscopically or conservatively with complete recovery. CONCLUSIONS: C-EMR is highly effective in treating nonpedunculated colorectal lesions, which can be learned and practiced in the appropriate setting. Decline in the complications rate was observed as the endoscopist gained experience. Although perforation remains a relatively high risk, this may be decreased by increasing the fluid cushion, and decreasing suction pressure. Immediate recognition and endoscopic management of perforation can be highly successful. C-EMR is our suggested method in approaching nonpedunculated colon polyps, especially flat polyps that are not easily accessible by other endoscopic techniques. PMID- 25811117 TI - Prophylaxis Versus Treatment Use of Laxative for Paralysis of Lower Gastrointestinal Tract in Critically Ill Patients. AB - GOALS: To evaluate the prevalence of lower gastrointestinal tract paralysis and to compare the success to achieve defecation between treatment and prophylaxis strategies. BACKGROUND: Laxatives use is commonly the first-level measure to achieve defecation in critically ill patients with lower gastrointestinal tract paralysis. Studies comparing prophylaxis versus treatment of lower gastrointestinal tract paralysis have not been performed yet. STUDY: We designed 3 sequential phases of 4 months each: observational phase, treatment phase, and prophylaxis phase. First-level measure was intermittent polyethylene glycol (PEG) 4000 by nasogastric tube. Second-level measures were enema, neostigmine, and continuous PEG. Primary endpoints were the prevalence of constipation for the observational phase and the number of patients that failed to achieve defecation with first-level measures for the treatment and prophylaxis phases. RESULTS: Paralysis of lower gastrointestinal tract in the observational phase was found in 57 of 63 patients (90.5%). Failure to achieve defecation with the first-level measure occurred in 16 of 64 patients (25%) in the treatment phase and in 6 of 70 patients (8.6%) in the prophylaxis phase (P=0.01). Eighteen measures of second level were applied in the treatment phase and 6 in the prophylaxis phase. CONCLUSIONS: Paralysis of the lower gastrointestinal tract in mechanically ventilated ICU patients is common. PEG given as prophylaxis on the first day after mechanical ventilation is associated with faster resolution of paralysis of gastrointestinal tract than PEG given as a treatment on day 4. PMID- 25811118 TI - Fecal Calprotectin as Predictor of Relapse in Patients With Inflammatory Bowel Disease Under Maintenance Infliximab Therapy. AB - BACKGROUND AND GOALS: Predicting relapse in Inflammatory Bowel Disease (IBD) could allow for early changes of treatment. Close monitoring of fecal calprotectin (FC) could be useful to predict relapse in IBD. Aim of the study was to evaluate the predictive value of a rapid FC test to predict flares in patients with IBD under maintenance therapy with Infliximab. STUDY: A prospective observational cohort study was designed. IBD patients in clinical remission under maintenance Infliximab therapy were included. FC was measured using a rapid test on a stool sample obtained within 24 hours before Infliximab infusion. Clinical examination was performed 2 months after that infusion. RESULTS: Fifty-three patients were included (52.8% female). Thirty-three patients (62.3%) had Crohn's disease and 20 (37.7%) had ulcerative colitis. All patients were in remission at inclusion. After 2 months, 41 patients (77.4%) remained in clinical remission and 12 (22.6%) presented a relapse. FC (mean+/-SD) in relapsing and not-relapsing disease was 332+/-168 and 110+/-163 ug/g, respectively (P<0.005). A FC concentration>160 ug/g had a sensitivity of 91.7%, and specificity of 82.9% to predict relapse. CONCLUSIONS: In IBD patients under Infliximab maintenance therapy, high FC levels allow predicting relapse within the following 2 months. Long-term remission is associated with low calprotectin levels. Further studies are required to confirm these results. PMID- 25811119 TI - Update on the Diagnosis and Management of Helicobacter pylori Infection in Adults. AB - Treatment of Helicobacter pylori infection is becoming increasingly challenging due largely to the rising rates of antimicrobial resistance and to the relative complexity of treatment regimens. If a reliable test to assess the antimicrobial sensitivity/resistance of H. pylori was readily available, treatment would be more focused and-presumably-more effective. However, antimicrobial sensitivity testing is difficult to obtain in most parts of the United States. Therefore, physicians have to rely on clinical judgment in selecting treatment regimens for their infected patients. The aims of this review are to summarize recent treatment recommendations and to examine available evidence for how we might improve on our current treatment selections. Information on this review is directed primarily toward physicians practicing in the United States. PMID- 25811120 TI - The nature of the bonding in symmetrical pincer palladacycles. AB - The accuracy of DFT-optimised geometries of the symmetrical pincer palladacycles PdNCN and PdSCS, [ClPd{2,6-(Me2NCH2)2C6H3}] and [ClPd{2,6-(MeSCH2)2C6H3}] respectively, has been evaluated by investigating the performance of eight commonly used density functionals with four combinations of basis set, in reproducing their X-ray crystal structures. It was found that whilst the omegaB97XD functional performed best over all, the PBE and TPSS functionals performed best when considering the palladium coordination geometry. The role of the donor atom in the stability and reactivity of the symmetric palladacycles, PdYCY, Y = N, S, or P, has been determined using Bader's Atoms in Molecules method to elucidate the nature of the bonding, and using a model formation reaction, which involves the C-H activation of the pincer ligand YCY by PdCl2. The calculations reveal distinct differences in the bond strength and nature of the interaction of Pd with the donor atoms Y, which support differences in the thermodynamic stability of the palladacycles. PMID- 25811121 TI - Hepatitis C and HIV Coinfection for Social Workers in Public Health, Medical and Substance Use Treatment Settings. AB - Hepatitis C virus (HCV) infection is a leading cause of liver disease and liver related deaths among those living with human immunodeficiency virus (HIV) infection. Due to recent pharmacologic advancements with direct acting antivirals, if detected and treated, HCV antiviral therapy can prevent liver disease progression and permanently cure coinfected patients of HCV. The objectives of this article are to inform public health social workers and social workers in medical and substance use treatment settings of the public health burden of HCV/HIV coinfection and to highlight state-of-the art pharmacologic advancements in HCV antiviral therapy. PMID- 25811122 TI - Very low amount of TiO2 on N-doped carbon nanotubes significantly improves oxygen reduction activity and stability of supported Pt nanoparticles. AB - Electrochemical corrosion is a major problem for carbon materials used in electrocatalysis. Highly dispersed TiO2 was deposited on O-functionalized and N doped carbon nanotubes by chemical vapour deposition to tackle the carbon corrosion problem. Very low Ti loadings of about 1 wt% were applied to minimize the negative influence of TiO2 as a semiconductor on the high conductivity of carbon materials. Both N doping and TiO2 coating facilitate strong metal-support interactions and favour the formation of small Pt particles. N doping improved the intrinsic catalytic activity of the carbon support and enhanced the conductivity due to the removal of surface oxygen groups, while the negative effect of TiO2 on conductivity is counterbalanced by its promoting effect on metal-support interactions leading to enhanced overall catalytic performance. Pt/TiO2/NCNTs showed the highest ORR activity, and significantly outperformed Pt/NCNTs in electrochemical stability tests. PMID- 25811123 TI - Changes in Obstetrics and Gynecologic Care Healthcare Triple Aims: Moving Women's Healthcare From Volume to Value. AB - Healthcare costs in the United States are over 17% of GDP and climbing. Yet compared with other countries in the developed world, the US healthcare system has the worst record for quality of care in relation to cost. This poor performance and lack of improvement in cost versus quality has led to the development of the Triple Aim framework spearheaded by the Institute for Healthcare Improvement. The focus of the Triple Aim is to improve value of care by improving access to care, systems of care delivery, and quality of care while reducing the overall expenditure. PMID- 25811124 TI - Vaginal birth after cesarean: an effective method to reduce cesarean. AB - Cesarean deliveries represent almost one third of US births. Given that repeat cesarean is the most common single indication for cesarean, trial of labor after cesarean (TOLAC) with subsequent vaginal birth after cesarean (VBAC) is an important mechanism to reduce the overall cesarean rate. The 2010 National Institutes of Health Conference found that one of the biggest barriers to VBAC is the lack of patient access to TOLAC. Many women who currently deliver by repeat cesarean would be candidates for a TOLAC. This manuscript will summarize the evidence on VBAC to help clinicians identify candidates, provide evidence-based counseling, and guide management of TOLAC. PMID- 25811125 TI - Management of fetal malpresentation. AB - Fetal malpresentation is an important cause of the high cesarean delivery rate in the United States and around the world. This includes breech, face, brow, and compound presentations as well as transverse lie. Risk factors include multiparity, previously affected pregnancy, polyhydramnios, and fetal and uterine anomalies. Appropriate management can reduce the need for cesarean delivery in some cases. This review discusses management options and focuses specifically on external cephalic version and vaginal breech delivery. PMID- 25811126 TI - Role of operative vaginal deliveries in prevention of cesarean deliveries. AB - Although the number of cesarean deliveries increased from 23% to 34.7% between 1996 and 2006, forceps and vacuum use declined, from 6.3% to 1.7% and 6.8% to 5.5%, respectively. When spontaneous vaginal delivery in the second stage of labor is not a possibility, operative vaginal delivery may be a safe, acceptable alternative to cesarean delivery. We explore indications for operative deliveries and the benefits and risks as compared with cesarean. In addition, we review the barriers to forceps and vacuum use and the importance of continued training to increase the number of providers who are able to safely perform these skills. PMID- 25811127 TI - Intrapartum fetal monitoring. AB - Intrapartum fetal monitoring to assess fetal well-being during the labor and delivery process has been a central component of intrapartum care for decades. Today, electronic fetal monitoring (EFM) is the most common method used to assess the fetus during labor without substantial evidence to suggest a benefit. A Cochrane review of 13 trials, which included over 37,000 women, found that continuous EFM provided no significant improvement in perinatal death rate [risk ratio (RR) 0.86; 95% confidence interval (CI), 0.59-1.23] or cerebral palsy rate (RR 1.75; 95% CI, 0.84-3.63) as compared with intermittent auscultation; however, there was a significant decrease in neonatal seizures (RR 0.50; 95% CI, 0.31 0.80). In addition, there was a significant increase in cesarean delivery (RR 1.63; 95% CI, 1.29-2.07) and operative vaginal delivery (RR 1.15; 95% CI, 1.01 1.33). Despite the lack of scientific support to suggest that EFM reduces adverse neonatal outcomes, its use is almost universal in the hospital setting and very likely has contributed to the rise in cesarean rate. PMID- 25811128 TI - Medicaid Consent to Sterilization forms: historical, practical, ethical, and advocacy considerations. AB - The US government developed a Medicaid Consent to Sterilization form in the mid 1970s to protect vulnerable populations from coerced sterilization. US health care practices have evolved significantly since that time. The form, however, has not changed, and may be preventing access to desired services for the same vulnerable populations it was originally created to protect. This paper discusses the relevant historical, practical use, ethical, and advocacy considerations of the Medicaid sterilization consent form and proposes changes to make the form more pertinent to today's medical environment. PMID- 25811129 TI - Preventing primary cesarean births: midwifery care. AB - The incidence of cesarean birth in the United States is alarmingly high and cesareans are associated with added morbidities for women and newborns. Thus strategies to prevent cesarean particularly for low-risk, nulliparous women at term with a singleton fetus are needed. This article addresses evidence-based practices that may be used during intrapartum to avoid primary cesarean, including patience with progress in labor, intermittent auscultation, continuous labor support, upright positions, and free mobility. Second-stage labor practices, such delayed pushing and manual rotation of the fetus, are also reviewed. This package of midwifery-style care practices can potentially lower primary cesarean rates. PMID- 25811132 TI - Manipulating Carbohydrate Availability Between Twice-Daily Sessions of High Intensity Interval Training Over 2 Weeks Improves Time-Trial Performance. AB - Commencing some training sessions with reduced carbohydrate (CHO) availability has been shown to enhance skeletal muscle adaptations, but the effect on exercise performance is less clear. We examined whether restricting CHO intake between twice daily sessions of high-intensity interval training (HIIT) augments improvements in exercise performance and mitochondrial content. Eighteen active but not highly trained subjects (peak oxygen uptake [VO2peak] = 44 +/- 9 ml/kg/min), matched for age, sex, and fitness, were randomly allocated to two groups. On each of 6 days over 2 weeks, subjects completed two training sessions, each consisting of 5 * 4-min cycling intervals (60% of peak power), interspersed by 2 min of recovery. Subjects ingested either 195 g of CHO (HI-HI group: ~2.3 g/kg) or 17 g of CHO (HI-LO group: ~0.3 g/kg) during the 3-hr period between sessions. The training-induced improvement in 250-kJ time trial performance was greater (p = .02) in the HI-LO group (211 +/- 66 W to 244 +/- 75 W) compared with the HI-HI group (203 +/- 53 W to 219 +/- 60 W); however, the increases in mitochondrial content was similar between groups, as reflected by similar increases in citrate synthase maximal activity, citrate synthase protein content and cytochrome c oxidase subunit IV protein content (p > .05 for interaction terms). This is the first study to show that a short-term "train low, compete high" intervention can improve whole-body exercise capacity. Further research is needed to determine whether this type of manipulation can also enhance performance in highly-trained subjects. PMID- 25811130 TI - CCAAT/enhancer-binding protein beta promotes receptor activator of nuclear factor kappa-B ligand (RANKL) expression and osteoclast formation in the synovium in rheumatoid arthritis. AB - INTRODUCTION: CCAAT/enhancer-binding protein beta (C/EBPbeta) is a transcription factor that is activated in the synovium in rheumatoid arthritis (RA) and promotes expression of various matrix metalloproteinases. In this study, we examined whether C/EBPbeta mediates the expression of receptor activator of nuclear factor-kappa-B ligand (RANKL) and drives osteoclast formation in primary fibroblast-like synoviocytes (FLS) from RA patients. The cooperation of C/EBPbeta and activation transcription factor-4 (ATF4) in the regulation of the RANKL promoter was also investigated. METHODS: Immunofluorescence staining was performed for C/EBPbeta, RANKL, and ATF4 in synovium from RA patients. Adenovirus expression vectors for two major isoforms, C/EBPbeta-liver-enriched activator protein (LAP) and - liver-enriched inhibitory protein (LIP), or small interfering RNA for C/EBPbeta, were used to manipulate C/EBPbeta expression in RA-FLS. RA-FLS over-expressing C/EBPbeta were co-cultured with peripheral blood mononuclear cells (PBMCs) to test osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. A promoter assay for RANKL, a chromatin immunoprecipitation (ChIP) assay and an immunoprecipitation (IP) assay were also performed. RESULTS: Immunofluorescence staining showed colocalization of C/EBPbeta, ATF4 and RANKL in RA synovium. Western blotting revealed the expression of C/EBPbeta-LAP and -LIP in RA-FLS. Over-expression of either C/EBPbeta-LAP or -LIP significantly increased the expression of RANKL mRNA, while C/EBPbeta-LIP down-regulated osteoprotegerin (OPG) mRNA. The RANKL/OPG mRNA ratio was significantly increased by C/EBPbeta-LIP over-expression. Knockdown of C/EBPbeta with siRNA decreased the expression of RANKL mRNA. The number of TRAP-positive multinucleated cells was increased in co-cultures of PBMCs and FLS over-expressing either C/EBPbeta-LAP or -LIP, but was more significant with LIP. C/EBPbeta-LIP does not have a transactivation domain. However, promoter assays showed that C/EBPbeta-LIP and ATF4 synergistically transactivate the RANKL promoter. ChIP and IP assays revealed the cooperative binding of C/EBPbeta and ATF4 on the RANKL promoter. CONCLUSIONS: We demonstrated that C/EBPbeta, especially C/EBPbeta-LIP in cooperation with ATF4, is involved in osteoclast formation by regulating RANKL expression in RA-FLS. These findings suggest that C/EBPbeta plays a crucial role in bone destruction in RA joints. PMID- 25811131 TI - La Crosse Virus in Aedes japonicus japonicus mosquitoes in the Appalachian Region, United States. AB - La Crosse virus (LACV), a leading cause of arboviral encephalitis in children in the United States, is emerging in Appalachia. For local arboviral surveillance, mosquitoes were tested. LACV RNA was detected and isolated from Aedes japonicus mosquitoes. These invasive mosquitoes may significantly affect LACV range expansion and dynamics. PMID- 25811133 TI - An update on civilian spinal gunshot wounds: treatment, neurological recovery, and complications. AB - STUDY DESIGN: Retrospective analysis of inpatient and outpatient data from a single academic trauma center. OBJECTIVE: To test the effectiveness of a conservative treatment algorithm for civilian spinal gunshot wounds (CSGSWs) by comprehensively evaluating neurological status and recovery, fracture type, concomitant injuries, indications for surgery, and complications. SUMMARY OF BACKGROUND DATA: Few large studies exist to guide treatment of CSGSWs, and none have been published in nearly 20 years. METHODS: A search of International Classification of Diseases, Ninth Revision (ICD-9) codes was performed for all hospital patients treated from 2003 to 2011 by either neurosurgery or orthopedic surgery to identify 159 consecutive patients who sustained CSGSWs. Mean follow-up was 13.6 months. American Spinal Injury Association grading was used to assess neurological injury. RESULTS: Fifty percent of patients had neurological deficits from CSGSW. Complete spinal injury was the most common injury grade; thoracic injuries had the most risk of complete injury (P < 0.001). Nearly 80% of patients had concomitant injuries to other organs. Operative treatment was more likely in patients with severe neurological injuries (P = 0.008) but was not associated with improved neurological outcomes (P = 1.00). Nonoperative treatment did not lead to any cases of late spinal instability or neurological deterioration. Overall, 31% of patients had an improvement of at least 1 American Spinal Injury Association grade by final follow-up. Nearly half of patients experienced at least 1 GSW-related complication; risk of complications was associated with neurological injury grade (P < 0.001) and operative treatment (P = 0.04). CONCLUSION: The vast majority of CSGSWs should be managed nonoperatively, regardless of neurological grade or number of spinal columns injured. Indications for surgery include spinal infection and persistent cerebrospinal fluid leaks. LEVEL OF EVIDENCE: 3. PMID- 25811135 TI - Point of view. PMID- 25811134 TI - Ossification of the posterior longitudinal ligament of the cervical spine in 3161 patients: a CT-based study. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: To examine the prevalence of ossification of the posterior longitudinal ligament (OPLL) and ossification of the nuchal ligament (ONL) of the cervical spine in the San Francisco area. SUMMARY OF BACKGROUND DATA: The prevalence of OPLL and ONL is unknown in the non Asian population. METHODS: This computed tomography-based cross-sectional study assessed the prevalence of OPLL and ONL within the cervical spine of patients treated at a level 1 trauma center between 2009 and 2012. The prevalence of both OPLL and ONL was compared between racial groups. RESULTS: Of the 3161 patients (mean age, 51.2 +/- 21.6 yr; 66.1% male), there were 1593 Caucasians (50.4%), 624 Asians (19.7%), 472 Hispanics (14.9%), 326 African Americans (10.3%), 62 Native Americans (2.0%), and 84 Others (2.7%). The prevalence of cervical OPLL was 2.2% (95% confidence interval [CI]: 1.7-2.8). The adjusted prevalence was 1.3% in Caucasian Americans (95% CI: 0.7-2.3), 4.8% in Asian Americans (95% CI: 2.8-8.1), 1.9% in Hispanic Americans (95% CI: 0.9-4.0), 2.1% in African Americans (95% CI: 0.9-4.8), and 3.2% in Native Americans (95% CI: 0.8-12.3). The prevalence of OPLL in Asian Americans was significantly higher than that in Caucasian Americans (P = 0.005). ONL was detected in 346 patients and the prevalence was 10.9% (95% CI: 10.0-12.0). The adjusted prevalence of ONL was 7.3% in Caucasian Americans (95% CI: 5.8-9.3), 26.4% in Asian Americans (95% CI: 21.9-31.5), 7.4% in Hispanic Americans (95% CI: 5.2-10.5), 2.5% in African Americans (95% CI: 1.2-4.9), and 25.8% in Native Americans (95% CI: 16.5-37.5). ONL was significantly more common in Asian Americans than in Caucasian Americans, Hispanic Americans, and African Americans (P = 0.001). CONCLUSION: This study also demonstrated that OPLL and ONL were significantly more common in Asian Americans than in Caucasian Americans. LEVEL OF EVIDENCE: 3. PMID- 25811137 TI - Incidence and mortality of sepsis, severe sepsis, and septic shock in intensive care unit patients with candidemia. AB - In this incidence study, of 16 074 patients admitted to the intensive care unit (ICU) from 1/1/2003 to 7/31/2011, 161 cases of candidemia were identified. The incidence of sepsis (27%), severe sepsis (31%), and septic shock (40%) was remarkably high in these cases of candidemia, as was the all-cause in-hospital mortality for sepsis (30%), severe sepsis (44%), and septic shock (65%). PMID- 25811139 TI - Comparative proteomic analysis of two distinct stem-cell populations from human amniotic fluid. AB - Human amniotic fluid (AF) contains a variety of stem cells of embryonic and extra embryonic origins. We characterized two distinct types of stem cells isolated from residual AF material derived from prenatal diagnostic amniocentesis. The two types of cells differed in their morphology and growth kinetics, showing fast (fast human amniotic stem cells; fHASCs) or slow (slow human amniotic stem cells; sHASCs) population-doubling times. Both fHASCs and sHASCs expressed pluripotent stem-cell markers, yet unlike sHASCs, clonogenic fHASCs would generate embryoid bodies and maintain their original phenotype during prolonged in vitro passaging. fHASCs - but not sHASCs - expressed the KLF4, SSEA-4 and CD117 markers. Differential proteomic analysis allowed us to identify the protein patterns specific for either cell type as potentially contributing to their distinct phenotypes. We found thirty-six proteins that were differentially expressed by the two cell types, and those proteins were classified according to their biological and molecular functions. Bioinformatic cluster analysis revealed differential occurrence of cytoskeletal proteins, such as vimentin, F-actin binding protein, and chloride intracellular channel protein 1. Selected proteins differentially expressed by fHASCs and sHASCs were further characterized by Western blot analysis and confocal microscopy. PMID- 25811140 TI - The effects of shell layer morphology and processing on the electrical and photovoltaic properties of silicon nanowire radial p+ - n+ junctions. AB - Single wire p(+)-n(+) radial junction nanowire solar cell devices were fabricated by low pressure chemical vapor deposition of n(+) silicon shell layers on p(+) silicon nanowires synthesized by vapor-liquid-solid growth. The n(+)-shell layers were deposited at two growth temperatures (650 degrees C and 950 degrees C) to study the impact of shell crystallinity on the device properties. The n-type Si shell layers deposited at 650 degrees C were polycrystalline and resulted in diodes that were not rectifying. A pre-coating anneal at 950 degrees C in H2 improved the structural quality of the shell layers and yielded diodes with a dark saturation current density of 3 * 10(-5) A cm(-2). Deposition of the n-type Si shell layer at 950 degrees C resulted in epitaxial growth on the nanowire core, which lowered the dark saturation current density to 3 * 10(-7) A cm(-2) and increased the solar energy conversion efficiency. Temperature-dependent current-voltage measurements demonstrated that the 950 degrees C coated devices were abrupt junction p(+)-n(+) diodes with band-to-band tunneling at high reverse bias voltage, while multi-step tunneling degraded the performance of devices fabricated with a 950 degrees C anneal and 650 degrees C coating. The higher trap density of the 950 degrees C annealed 650 degrees C coated devices is believed to arise from the polycrystalline nature of the shell layer coating, which results in an increased density of dangling bonds at the p(+)-n(+) junction interface. PMID- 25811138 TI - Overnight Polysomnographic Characteristics and Oxygen Saturation of Healthy Infants, 1 to 18 Months of Age, Born and Residing At High Altitude (2,640 Meters). AB - BACKGROUND: Approximately 8% of the world population resides above 1,600 m, with about 10 million people living above 2,500 m in Colombia. However, reference values for polysomnography (PSG) and oxygen saturation (Spo2) of children < 2 years old residing at high altitude are currently unavailable. METHODS: Healthy infants aged 1 to 18 months born and residing at high altitude (Bogota: 2,640 m) underwent overnight PSG. Four age groups were defined: group 1, < 45 days; group 2, 3 to 4 months; group 3, 6 to 7 months; and group 4, 10 to 18 months. Of 122 children enrolled, 50 had three consecutive PSG tests and were analyzed as a longitudinal subcohort. RESULTS: A total of 281 PSG tests were performed in 122 infants (56% girls): group 1, 106 PSG tests; group 2, 89 PSG tests; group 3, 61 PSG tests; and group 4, 25 PSG tests. Active sleep diminished and quiet sleep increased with maturation. Apnea-hypopnea indexes (total, central, and obstructive) were highest in group 1 (21.4, 12.4, and 6.8/h total sleep time, respectively) and diminished with age (P < .001). Mean Spo2 during waking and sleep increased with age (P < .001). Nadir Spo2 values during respiratory events were lower in younger infants. Longitudinal assessments of 50 infants confirmed the temporal trends described for the cross-sectional dataset. CONCLUSIONS: Healthy infants (<= 18 months old) born and residing at high altitude show preserved sleep architecture but higher apnea-hypopnea indexes and more prominent desaturation with respiratory events than do those living at low altitude. The current study findings can be used as reference values for infants at high altitude. PMID- 25811142 TI - Smarter medicine: do physicians need political pressure to eliminate useless interventions? AB - Echoing the "less is more" and "choosing wisely" campaigns in the USA, the "smarter medicine" campaign launched in 2014 by the Swiss Society of General Internal Medicine listed five tests or treatments that are often prescribed in ambulatory general internal medicine, but that may not provide any meaningful benefit and may carry the risk of generating harms and costs. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) supported the National Health Services in identifying "low value" activities that should be stopped. Political pressure and stringent regulatory measures for pharmaceuticals and medical technology triggered major controversy and opposition. NICE efforts now concentrate on editing guidelines based on consensus techniques, which integrate the evidence from systematic reviews with social values and patient preferences. To obtain significant changes and promote the paradigm of reducing unnecessary waste of medical resources, opinion leaders and leading scientific or academic institutions, as well as medical societies, can make a difference, together with consumer associations and the lay press. Politicians can undoubtedly contribute to the success of these strategies, but rather than putting physicians alone under pressure and setting up stringent regulatory measures, they should network with all stakeholders and put emphasis on a broader agenda, the one of improving healthcare quality and efficiency. PMID- 25811143 TI - Photodimerization behaviour of 1D-3D Zn(II) coordination polymers with tetrazolyl styrylpyridine. AB - The [2 + 2] photodimerization of tetrazolyl styrylpyridine leads to single crystal-to-single-crystal transformations of four Zn(II) coordination polymers with 1D-3D structures, exhibiting controllable reaction extent, luminescence decrease or blue shift, and a two-step reaction process with a phase transition point. PMID- 25811144 TI - Development of highly thermoresponsive fluorescent sensors consisting of plasmonic silver nanoprisms and poly(N-isopropylacrylamide)-fluorophore composites. AB - We developed a new hybrid consisting of Ag nanoprisms, poly(N isopropylacrylamide) (PNIPAm), and fluorophores via layer-by-layer assembly. The fluorescence intensity below the lower critical solution temperature (LCST) of PNIPAm was 6.4 times stronger than that above the LCST, meaning that the hybrids can function as nanosized highly thermoresponsive fluorescent sensors. PMID- 25811146 TI - Development of a customized radiation monitor for livestock screening. AB - The monitoring and decontamination of livestock has been an emerging topic in emergency response planning in recent years. Under the National Response Framework, the U.S. Department of Agriculture is tasked with providing support to the states during a radiological incident for the "assessment, control, and decontamination of contaminated animals, including companion animals, livestock, poultry, and wildlife." While there are currently no protocols in place on a national level for coordinated animal response, working groups have been developing a command structure and task force procedures, and some states have issued their own guidelines. A customized Bovine Screening Portal was manufactured and tested at Texas A&M University to investigate the operational capabilities in detecting, identifying, and localizing external contamination on livestock. An array of six sodium iodide detectors attached to power-over Ethernet Multi-Channel Analyzers was used to collect time-stamped count rates, and spectral data were collected as a heifer was led past the detector panel. A 1.85 * 10(5) Bq 137Cs source was placed in four locations on a heifer, which was led through a cattle chute adjacent to the detector panel. The trials were repeated walking the heifer through a walkway with detectors hung on cattle pens lining a walkway. The Bovine Screening Portal observed increased count rates (>10sigma) from the 1.85 * 10(5) Bq 137Cs source in live time. The identification capabilities with the intuitive software interface of the BSP are consistent with the requirements of a detection system for radiological emergency management of livestock. PMID- 25811147 TI - Myeloid leukemia risk assessment and dynamics of the granulocytopoietic system in acutely and continuously irradiated humans: modeling approach. AB - A dynamic modeling approach to the risk assessment of radiogenic myeloid leukemia is proposed. A basic tool of this approach is a biologically motivated mathematical model of the granulocytopoietic system, which is capable of predicting the dynamics of blood granulocytes and bone marrow granulocytopoietic cells in acutely and chronically irradiated humans. The performed modeling studies revealed that the dose dependence of the scaled maximal concentration of bone marrow granulocytopoietic cells with radiation-induced changes, which make a cell premalignant, and the dose dependence of the scaled integral of the concentration of these cells over the period of the response of the granulocytopoietic system to acute irradiation conform to the dose dependence of excess relative risk for myeloid leukemia among atomic bomb survivors in a wide range of doses and in a range of comparatively low doses, respectively. Additionally, the dose dependence of the scaled integral of the concentration of these cells over the period of the response of the granulocytopoietic system to continuous irradiation with the dose rate and durations, which were used in brachytherapy, conforms to the dose dependence of excess relative risk for leukemia among the respective groups of exposed patients. These modeling findings demonstrate the potential to use the proposed modeling approach for predicting the excess relative risk for myeloid leukemia among humans exposed to various radiation regimes. Obviously, this is especially important in the assessment of the risks for radiogenic myeloid leukemia among people residing in contaminated areas after an accident or explosion of a radiological device, among astronauts on long-term space missions, as well as among patients treated with radiotherapy. PMID- 25811148 TI - Twenty-five years of environmental radionuclide concentrations near a nuclear power plant. AB - The areas in and along a 262-km length of the Susquehanna River in Pennsylvania were monitored for the presence of radioactive materials. This study began two months after the 1979 Three Mile Island (TMI) partial reactor meltdown; it spanned the next 25 y. Monitoring points included stations at the PPL Susquehanna and TMI nuclear power plants. Monthly gamma measurements document concentrations of radionuclides from natural and anthropogenic sources. During this study, various series of gamma-emitting radionuclide concentration measurements were made in many general categories of animals, plants, and other inorganic matter. Sampling began in 1979 before the first start-up of the PPL Susquehanna power plant. Although all species were not continuously monitored for the entire period, an extensive database was compiled. In 1986, the ongoing measurements detected fallout from the Chernobyl nuclear accident. These data may be used in support of dose or environmental transport calculations. PMID- 25811149 TI - The high dose response and functional capability of the DT-702/Pd lithium fluoride thermoluminescent dosimeter. AB - The United States Navy monitors the dose its radiation workers receive using the DT-702/PD thermoluminescent dosimeter, which consists of the Harshaw 8840 holder and the four-element Harshaw 8841 card. There were two main objectives of this research. In the first objective, the dosimeters were exposed to 100 Gy using electron and x-ray beams and found to respond approximately 30-40% lower than the delivered dose. No significant effect on the under-response was found when dose rate, radiation type, dosimeter position on the phantom, and dosimeter material were varied or when the card was irradiated while enclosed in its holder. Since the current naval policy is to remove from occupational use any thermoluminescent dosimeter with an accumulated deep dose equivalent of 0.05 Sv or greater, the functionality of the dosimeter was also investigated at deep dose equivalents of 0.05, 0.15, and 0.25 Sv using 60Co and 137Cs sources as the second main objective. All dosimeters were annealed following exposure and then exposed to 5.0 mSv from a 90Sr source. In all cases, the dosimeters responded within 3% of the delivered dose, indicating that the dosimeters remained functional as defined by naval dosimetry requirements. However, the anneal time required to clear the thermoluminescent dosimeter's reading was found to increase approximately as the cube root with the delivered dose. PMID- 25811151 TI - Breath biomarkers of whole-body gamma irradiation in the Gottingen minipig. AB - There is widespread interest in the development of tools to estimate radiation exposures. Exhaled breath provides a novel matrix for assessing biomarkers that could be correlated with exposures. The use of exhaled breath for estimating radiation exposure is warranted, as studies have shown that external exposure to ionizing radiation causes oxidative stress that accelerates lipid peroxidation of polyunsaturated fatty acids, liberating alkanes and alkane metabolites that are excreted in the breath as volatile organic compounds (VOCs). As a proof of principle study, small groups (n = 4) of Gottingen minipigs were whole-body irradiated with gamma rays delivered by a 60Co source at absorbed doses of 0, 0.25, 0.5, 0.75, 1, 1.25, 2, and 4 Gy. Additional groups (n = 4) were treated with lipopolysaccharide (LPS) or granulocyte colony stimulating factor (G-CSF), with and without concurrent 60Co exposure, at an absorbed dose of 1 Gy. Breath and background air VOC samples were collected on days -3, -2, -1, 0 pre irradiation, then at 0.25, 24, 48, 72, and 168 h post-irradiation. VOCs were analyzed by automated thermal desorption with two-dimensional gas chromatography and time-of-flight mass spectrometry (ATD GCxGC TOF MS). The results show significant changes in 58 breath VOCs post-irradiation, mainly consisting of methylated and other derivatives of alkanes, alkenes, and benzene. Using a multivariate combination of these VOCs, a radiation response function was constructed, which was significantly elevated at 15 min post irradiation and remained elevated throughout the study (to 168 h post irradiation). As a binary test of radiation absorbed doses >= 0.25 Gy, the radiation response function distinguished irradiated animals from shams (0 Gy) with 83-84% accuracy. A randomly derived radiation response function was robust: When half of the biomarkers were removed, accuracy was 75%. An optimally derived function with two biomarkers was 82% accurate. As a binary test of radiation absorbed doses >= 0.5 Gy, the radiation response function identified irradiated animals with an accuracy of 87% at 15 min post irradiation and 75.5% at 168 h post irradiation. Treatment with LPS and G-CSF did not affect the radiation response function. This proof-of-principle study supports the hypothesis that breath VOCs may be used for estimating radiation exposures. Further studies will be required to validate the sensitivity and specificity of these potential biomarkers. PMID- 25811152 TI - Long-lived gamma emitting radionuclides in palm dates and estimates of annual effective doses. AB - An investigation of long-lived gamma emitting radionuclides in palm dates was performed. The palm date samples originated from eight countries, namely India, Iran, Jordan, Libya, Pakistan, Saudi Arabia, Tunisia, and the United Arab Emirates. Among the samples were the palm date types Sukari, Wanana, Umkhuber, Rashudiya, Libana, Madjool, Gumaizi, Anbar, Braim, Ajwa, Khadri, Munafee, Mabroom, Daglanoor, Sulag, and Khalas. Gamma spectrometry revealed activity concentrations of (AVG +/- STD) 0.983 +/- 0.457, 0.469 +/- 0.229, and 287.078 +/- 41.871 Bq kg(-1) dry weight for 226Ra, 228Ra, and 40K, respectively. Annual average effective dose was estimated to be 32 MUSv from the consumption of palm dates. Comparing these findings with values reported in the literature, it was concluded that consumption of palm dates is safe for the presence of the investigated radionuclides. PMID- 25811150 TI - Use of radiopharmaceuticals in diagnostic nuclear medicine in the United States: 1960-2010. AB - To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, the authors assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake; brain scan; brain blood flow; lung perfusion and ventilation; bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans; cardiac imaging procedures; tumor localization studies; localization of gastrointestinal bleeding; and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologists' cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations. PMID- 25811153 TI - A report from the 2013 international symposium: the evaluation of the effects of low-dose radiation exposure in the life span study of atomic bomb survivors and other similar studies. AB - The RERF International Low-Dose Symposium was held on 5-6 December 2013 at the RERF campus in Hiroshima, Japan, to discuss the issues facing the Life Span Study (LSS) and other low-dose studies. Topics included the current status of low-dose risk detection, strategies for low-dose epidemiological and statistical research, methods to improve communication between epidemiologists and biologists, and the current status of radiological studies and tools. Key points made by the participants included the necessity of pooling materials over multiple studies to gain greater insight where data from single studies are insufficient; generating models that reflect epidemiological, statistical, and biological principles simultaneously; understanding confounders and effect modifiers in the current data; and taking into consideration less studied factors such as the impact of dose rate. It is the hope of all participants that this symposium be used as a trigger for further studies, especially those using pooled data, in order to reach a greater understanding of the health effects of low-dose radiation. PMID- 25811154 TI - Comment on GEANT4 calibration of gamma spectrometry efficiency for measurements of airborne radioactivity on filter paper. PMID- 25811155 TI - Response to Comment on GEANT4 calibration of gamma spectrometry efficiency for measurements of airborne radioactivity on filter paper. PMID- 25811156 TI - Aircraft crewmember doses should be measured. PMID- 25811157 TI - Response to Bramlitt and Shonka. PMID- 25811158 TI - Health Physics Society. An affiliate of the International Radiation Protection Association (IRPA). Prospectus. PMID- 25811160 TI - PhI(OAc)2 mediated decarboxylative sulfonylation of beta-aryl-alpha,beta unsaturated carboxylic acids: a synthesis of (E)-vinyl sulfones. AB - A highly efficient metal-free decarboxylative sulfonylation protocol for the preparation of (E)-vinyl sulfones from of beta-aryl-alpha,beta-unsaturated carboxylic acids using sodium sulfinates and (diacetoxyiodo)benzene (PhI(OAc)2) was developed. This strategy offers a simple and expedient synthesis of (E)-vinyl sulfones bearing a wide variety of functional groups. A radical-based pathway has been proposed for this decarboxylative sulfonylation reaction. PMID- 25811161 TI - Subjective and Objective Measures in the Treatment of Hemifacial Spasm With OnabotulinumtoxinA. AB - PURPOSE: To evaluate the Sunnybrook Facial Grading System (SFGS) and Facial Clinimetric Evaluation (FaCE) Scale Instrument outcomes when treating hemifacial spasm (HFS) with onabotulinumtoxinA. METHODS: An Institutional Review Board approved retrospective review of records of 66 HFS patients treated with onabotulinumtoxinA. SFGS and FaCE surveys were completed prior to onabotulinumtoxinA therapy and at 1 month follow up. Surveys were analyzed for differences using paired Student t tests, with statistical significance set at p < 0.05. Correlations were determined using Spearman correlation (rs), with coefficients of >=0.40 or <=-0.40 considered significant. RESULTS: There were 22 complete data sets. SFGS composite score improved from mean, 56.9 (SD, 12.3) to 63.6 (SD, 12.3), p < 0.01. SFGS subdomain synkinesis score significantly improved (p < 0.01). The FaCE scale subdomain oral function significantly worsened (p = 0.05). The Delta pre-/post-SFGS composite score did not correlate with the Delta pre-/post-FaCE composite score (rs = 0.24). There was a significant positive correlation between SFGS composite score and FaCE social function score (rs = 0.462, p = 0.03) and between SFGS voluntary movement score and FaCE social function score (rs = 0.477, p = 0.03). Subgroup analysis of single FaCE questions demonstrated no statistical change in subjective dry eye (p = 0.30). CONCLUSIONS: There was an improvement in social functioning in treated HFS patients, which positively correlated with improvement in overall objective voluntary facial movement. There was no statistical difference in subjective dry eye symptoms. The overall SFGS composite score improved following treatment of HFS with botulinum toxin. This information can be used when counseling expected outcomes in HFS patients treated with onabotulinumtoxinA. PMID- 25811162 TI - A Survey of Current Blepharospasm Treatment Patterns Among Oculoplastic Surgeons. AB - PURPOSE: To determine the current practice pattern of ASOPRS members injecting onabotulinumtoxinA for Blepharospasm. METHODS: An invitation to participate in a web-based, anonymous survey was sent to current members of American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS) via e-mail. The survey consisted of 9 questions and used the Research Electronic Data Capture online application. Institutional Review board approval was obtained for this study. RESULTS: Forty-one percent of ASOPRS members invited responded to the survey. The mean initial dose of onabotulinumtoxinA used was 22.5 units per side and the most common number of injection sites was greater than 7 per side. Only 12 of the 247 responding surgeons who treat benign essential blepharospasm with onabotulinumtoxinA reported that their initial injection pattern is with 3 or fewer sites per side as per the Food and Drug Administration (FDA)-approved recommendations. CONCLUSIONS: Survey of current trends in the management of blepharospasm with onabotulinumtoxinA by ASOPRS members showed that the mean initial dose used to treat blepharospasm patients was 22.5 (standard deviation +/ 9.5 units, range 2.5 to 50 units per side). There is significant variation in the treatment doses. The majority of ASOPRS members do not follow the FDA approved recommendation for dosing. PMID- 25811163 TI - Reconstruction of Unilateral Incomplete Cryptophthalmos in Fraser Syndrome. AB - A full-term baby girl with Fraser syndrome was born with right incomplete cryptophthalmos. On examination, the globe was completely covered with skin with partially formed eyelids laterally. At 3 years of age, she underwent an evisceration with orbital implant and reconstruction of the eyelids and fornices using the pre-existing scleral remnant. Custom ocular prosthetic fitting was performed 5 weeks postoperatively. At 4 years follow up, she continued to successfully retain an ocular prosthesis. PMID- 25811164 TI - Engorgement of the Angular and Temporal Veins Following Periorbital Hyaluronic Acid Gel Injection. AB - PURPOSE: To study angular and temporal vein engorgement following periorbital hyaluronic acid gel (HAG) injection. METHODS: In this retrospective study, the authors reviewed the photographs of 805 patients who had periorbital HAG injection at Jules Stein Eye Institute Oculoplastic Clinic between January 2004 and January 2014. HAG injections were used to fill the orbital hollow, zygomatic hollow, septal confluence hollow, and cheek. The inclusion criteria were patients who had at least 1 pre-, immediate post-, and late postinjection photographs. Immediate postinjection photographs were taken right after HAG injection, and late postinjection photographs were taken at the following visit before any injection. The exclusion criteria were patients with any previous ocular surgery 6 months before filler injection, patients with orbital diseases, and patients who had HAG injections for functional purposes. The photographs were evaluated for the presence of angular and temporal vein engorgement at any of the injections during the follow-up visits. The photographs of eyes with vein engorgement were graded on a scale of 0 (no engorgement), 1 (mild engorgement), 2 (moderate engorgement), and 3 (severe engorgement). RESULTS: There were 78 eligible patients (156 orbits; 68 females and 10 males) with average age of 59.4 +/- 13.4 years. The authors found 18 orbits of 12 patients (15.4%; 6 unilateral and 6 bilateral) with angular vein engorgement at least 1 time after HAG injection during the follow-up visits. The frequency of temporal vein engorgement was 9.1%. The mean +/- SD of angular vein grading for engorgement increased from 0.72 +/- 0.51 on preinjection photographs to 1.45 +/- 0.88 on immediate postinjection photographs (p = 0.0001) and 0.89 +/- 0.50 on late postinjection photographs (p = 0.04). The mean +/- SD of angular vein grading for engorgement was 0.67 +/- 0.55 on the first preinjection photographs, which increased to 1.10 +/- 0.50 on the last late postinjection photographs. The difference was statistically significant (p = 0.001). CONCLUSIONS: Angular and temporal vein engorgement occurred following HAG injection in the periorbital region. The engorgement occurred immediately after injections and decreased considerably but not completely in the following visit. PMID- 25811165 TI - Evisceration With Implant Placement Posterior to Posterior Sclera. AB - PURPOSE: To describe the results and potential benefit of placement of a porous orbital implant (aluminum oxide) posterior to posterior sclera and compare the exposure rate with a former evisceration technique involving a posterior sclerotomy with placement of a porous implant partly within the scleral shell and partly within the intraconal space. METHODS: Single-center, retrospective, interventional case series. A chart review of 93 patients undergoing evisceration with placement of an aluminum oxide orbital implant in conjunction with 2 different posterior sclerotomy techniques between 1999 and 2013 was carried out. Seventy-one patients met the inclusion criteria having 1 of 2 posterior sclerotomy techniques with an aluminum oxide orbital implant, a normal or near normal size eye and at least 6 months follow-up. Retrospective data analysis included demographic profile and treatment outcomes of the different posterior sclerotomy techniques. This study was performed with Institutional Review Board Approval and in compliance with the Declaration of Helsinki. RESULTS: Thirty patients underwent the posterior radial sclerotomy technique, while 41 patients underwent implant placement posterior to posterior sclera technique. The average size implant used in the posterior radial sclerotomy technique was 18 mm versus 20 mm in the implant placement posterior to posterior sclera technique (p < 0.001) with the implant placed posterior to posterior sclera. The exposure rate with the posterior radial sclerotomy technique was 5 of the 30 patients (16.7%) and 0 of 41 (0%) for the implant placement posterior to posterior sclera technique (p = 0.006). CONCLUSION: Placement of an aluminum oxide orbital implant posterior to posterior sclera allowed the placement of larger implants which allowed enhancement of socket volume. In addition, it appeared to have a decreased risk of implant exposure during the study period. Porous implant placement posterior to posterior sclera is an alternate posterior sclerotomy technique that allows coverage of the implant surface with 3 layers of autogenous sclera. PMID- 25811166 TI - Anti-atherogenic properties of date vs. pomegranate polyphenols: the benefits of the combination. AB - Hydrolysable tannin polyphenols in pomegranate and phenolic acids in date fruit and seeds are potent antioxidants and anti-atherogenic agents, and thus, in the present study we investigated the possible benefits of combining them in vivo in atherosclerotic apolipoprotein E KO (E(0)) mice, compared with the individual fruit. In vitro studies revealed that the date seed extract contains more polyphenols than Amari or Hallawi date extracts, and possesses a most impressive free radical scavenging capacity. Similarly, pomegranate juice (PJ), punicalagin, punicalain, gallic acid, and urolithins A and B are very potent antioxidants. E(0) mice consumed 0.5 MUmol gallic acid equivalents (GAE) per mouse per day of PJ, Hallawi extract, date seed extract, or a combination for 3 weeks. Consumption of the combination was the most potent treatment, as it decreased serum cholesterol and triglyceride levels, and increased serum paraoxonase 1 (PON1) activity. Consumption of the combination also significantly reduced mouse peritoneal macrophage (MPM) oxidative stress, MPM cholesterol content, and MPM LDL uptake. Finally, the lipid peroxide content in the aortas of the mice significantly decreased, and the PON lactonase activity of the aortas increased after treatment with the combination. We thus conclude that consumption of pomegranate, together with date fruit and date seeds, has the most beneficial anti-atherogenic effects on E(0) mice serum, macrophages, and aortas, probably due to their unique and varied structures. PMID- 25811167 TI - Characteristics and prognostic factors of osteosarcoma of the jaws: a retrospective cohort study. AB - IMPORTANCE: Osteosarcoma of the jaws is rare and clinically distinct from osteosarcoma of the long bones of the body with different treatment and outcomes. The literature on these tumors is limited to case reports and small case series mostly from single institutions. We used data from the population-based national Surveillance, Epidemiology and End Results (SEER) cancer registry to determine the epidemiology and prognostic factors associated with osteosarcoma of the jaws. OBJECTIVE: To investigate the epidemiologic characteristics and prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, population-based cohort study of 541 patients in the SEER tumor registry diagnosed with osteosarcoma of the jaws from 1973 through 2011 were reviewed. EXPOSURES: Patients had been treated with surgery, radiation, both, or neither. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: A total of 541 patients diagnosed with osteosarcoma of the jaws were identified (49.9% male and 50.1% female, with a mean age of 41.3 years). Kaplan-Meier analysis demonstrated an overall survival (OS) and disease-specific survival (DSS) of 53% and 62%, respectively, at 5 years and 35% and 54%, respectively, at 10 years. Multivariate Cox regression analysis revealed that independent predictors of OS and DSS included age at diagnosis (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04 [P < .001] for OS; and HR, 1.03; 95% CI, 1.02-1.05 [P < .001] for DSS); stage at presentation (HR, 1.37; 95% CI, 1.10 1.71 [P = .006] for OS; and HR, 1.34; 95% CI, 1.01-1.76 [P = .04] for DSS); and surgical resection (HR, 0.31; 95% CI, 0.16-0.60 [P < .001] for OS; and HR, 0.22; 95% CI, 0.09-0.56 [P = .001] for DSS). Tumor size was not significant for OS (HR, 1.00; 95% CI, 1.00-1.01 [P = .11] but significant for DSS (HR, 1.01; 95% CI, 1.00 1.01 [P = .003]). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study to date investigating prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. Determinants of survival include age at diagnosis, stage at presentation, tumor size, and surgical therapy. Radiation therapy was not associated with improved survival, reflecting the controversy surrounding its use in clinical literature. PMID- 25811168 TI - Development of a web-based platform for studying lithiation reactions in silico. AB - A novel integrated web-based system which can compute, visualise and store systematised key parameters of a reaction has been developed from open-source components. As a proof of concept, it has been used to rationalise and predict the regioselectivity of lithiation reactions as well as relative reactivity of substrates. Excellent agreement between the in silico analysis and experimental data was obtained. PMID- 25811170 TI - Distribution of Hydroxyl Groups in Kukersite Shale Oil: Quantitative Determination Using Fourier Transform Infrared (FT-IR) Spectroscopy. AB - This article describes the use of Fourier transform infrared (FT-IR) spectroscopy to quantitatively measure the hydroxyl concentrations among narrow boiling shale oil cuts. Shale oil samples were from an industrial solid heat carrier retort. Reference values were measured by titration and were used to create a partial least squares regression model from FT-IR data. The model had a root mean squared error (RMSE) of 0.44 wt% OH. This method was then used to study the distribution of hydroxyl groups among more than 100 shale oil cuts, which showed that hydroxyl content increased with the average boiling point of the cut up to about 350 degrees C and then leveled off and decreased. PMID- 25811169 TI - The Effect of Intensified Language Exposure on Accommodating Talker Variability. AB - PURPOSE: This study systematically examined the role of intensified exposure to a second language on accommodating talker variability. METHOD: English native listeners (n = 37) were compared with Mandarin listeners who had either lived in the United States for an extended period of time (n = 33) or had lived only in China (n = 44). Listeners responded to target words in an English word-monitoring task in which sequences of words were randomized. Half of the sequences were spoken by a single talker and the other half by multiple talkers. RESULTS: Mandarin listeners living in China were slower and less accurate than both English listeners and Mandarin listeners living in the United States. Mandarin listeners living in the United States were less accurate than English natives only in the more cognitively demanding mixed-talker condition. CONCLUSIONS: Mixed talker speech affects processing in native and nonnative listeners alike, although the decrement is larger in nonnatives and further exaggerated in less proficient listeners. Language immersion improves listeners' ability to resolve talker variability, and this suggests that immersion may automatize nonnative processing, freeing cognitive resources that may play a crucial role in speech perception. These results lend support to the active control model of speech perception. PMID- 25811171 TI - Meta-analysis of the effect of mesenchymal stem cell transplantation on vascular remodeling after carotid balloon injury in animal models. AB - AIM: A meta-analysis was conducted to assess the efficacy of mesenchymal stem cell (MSC) transplantation in small animal coronary vessels after balloon injury, to provide data for the design of future pre-clinical experiments and human clinical trials. METHODS: The search strategy included the PubMed, EMBASE, Chinese Biomedical Literature (CBM), and China National Knowledge Infrastructure (CKNI) databases. The endpoint was the ratio of vascular neointima/media (I/M). Moreover, neointimal area, re-endothelialization, and proliferating cell nuclear antigen (PCNA) expression were analyzed. Pooled analyses were conducted using random effects models. Heterogeneity and publication bias were also explored. All data were analyzed using RevMan 5.2 and Stata 12.0. RESULTS: Fifteen studies were reviewed from 238 retrieved animal studies. Compared with controls, MSC transplantation resulted in greater I/M reduction (pooled difference, 0.39; 95% CI, 0.57-0.21; P < 0.0001), greater neointimal area reduction (pooled difference, 0.16; 95% CI, 0.22-0.10; P < 0.0001), decreased PCNA expression (pooled difference, 17.69; 95% CI, 28.94-6.44; P = 0.002), and enhanced re endothelialization (pooled difference, 3.37; 95% CI, 1.78-4.95; P < 0.0001). The multivariable meta-regression analysis showed that a higher number of transplanted cells (>106; P = 0.017) and later time point of I/M measurement (P = 0.022) were significantly associated with I/M reduction. Subgroup analysis demonstrated a trend for a greater reduction in the ratio of I/M with late MSC transplantation (>1 day), MSCs transplanted through intravenous injection, and atherosclerotic vessels. CONCLUSION: The meta-analysis results demonstrate that MSC transplantation might improve injured vascular remodeling. In addition to greater efficacy with a greater number of transplanted MSCs (>106), the long-term effect of MSC transplantation appears to be more significant. The findings of this meta-analysis may help to design future, effective MSC trials. PMID- 25811173 TI - Development of partial ontogenic resistance to powdery mildew in hop cones and its management implications. AB - Knowledge of processes leading to crop damage is central to devising rational approaches to disease management. Multiple experiments established that infection of hop cones by Podosphaera macularis was most severe if inoculation occurred within 15 to 21 days after bloom. This period of infection was associated with the most pronounced reductions in alpha acids, cone color, and accelerated maturation of cones. Susceptibility of cones to powdery mildew decreased progressively after the transition from bloom to cone development, although complete immunity to the disease failed to develop. Maturation of cone tissues was associated with multiple significant affects on the pathogen manifested as reduced germination of conidia, diminished frequency of penetration of bracts, lengthening of the latent period, and decreased sporulation. Cones challenged with P. macularis in juvenile developmental stages also led to greater frequency of colonization by a complex of saprophytic, secondary fungi. Since no developmental stage of cones was immune to powdery mildew, the incidence of powdery mildew continued to increase over time and exceeded 86% by late summer. In field experiments with a moderately susceptible cultivar, the incidence of cones with powdery mildew was statistically similar when fungicide applications were made season-long or targeted only to the juvenile stages of cone development. These studies establish that partial ontogenic resistance develops in hop cones and may influence multiple phases of the infection process and pathogen reproduction. The results further reinforce the concept that the efficacy of a fungicide program may depend largely on timing of a small number of sprays during a relatively brief period of cone development. However in practice, targeting fungicide and other management tactics to periods of enhanced juvenile susceptibility may be complicated by a high degree of asynchrony in cone development and other factors that are situation-dependent. PMID- 25811172 TI - Cordycepin and N6-(2-hydroxyethyl)-adenosine from Cordyceps pruinosa and their interaction with human serum albumin. AB - Cordyceps pruinosa (CP) is often used as Traditional Chinese Medicine, but the substance basis of its medicinal properties is unclear. In this study, two compounds were isolated from CP cultures by column chromatography, and identified as cordycepin and N6-(2-hydroxyethyl)-adenosine (HEA) by Nuclear Magnetic Resonance. In order to understand the efficacy of these two substances as potential therapeutic agents, it is necessary to explore their binding with proteins. The molecular mechanisms of interaction between cordycepin, HEA and human serum albumin (HSA) were studied using UV and fluorescence spectroscopy. The bingding constants between HSA and cordycepin were 4.227, 3.573 and 3.076 * 10(3).at 17, 27 and 37 degrees C respectively, and that of HSA and HEA were 27.102, 19.409 and 13.002 * 10(3).at the three tempretures respectively. Both cordycepin and HEA can quench the intrinsic fluorescence of HSA via static quenching, and they can bind with HSA to form complexes with a single binding site. The interaction forces between cordycepin and HSA were determined as electrostatic and hydrophobic, and those of HEA and HSA were hydrogen bonding and van der Waals forces. Using Foster's equation, the distance between fluorophores of cordycepin and HSA, and HEA and HSA are estimated to be 5.31 nm and 4.98 nm, respectively. In this study, cordycepin was isolated for the first time from CP, and will provide a new source of cordycepin and expand the use of this taxon. The interaction mechanisms between cordycepin and HSA was studied for the first time, which will provide a useful guide for the clinical application of cordycepin. The pharmacological importance of this study is to understand the interaction of HSA with cordycepin and HEA, which will be essential for the future designing of drugs based on the two compounds. PMID- 25811174 TI - Serum resistin and glomerular filtration rate in patients with type 2 diabetes. AB - BACKGROUND: High serum levels of the pro-inflammatory adipokine resistin have been associated with decreased renal function in the general population. The goal of this study was to investigate whether such association is also present among diabetic subjects, who are at increased risk of renal function loss. METHODS: The cross-sectional association between serum resistin levels and estimated glomerular filtration rate (eGFR) was investigated in 1,560 type 2 diabetic (T2D) patients of European ancestry comprised in two different cohorts: 762 patients from San Giovanni Rotondo (SGR; Italy) and 798 patients from Boston (US). RESULTS: Serum resistin was inversely associated with eGFR in SGR [beta (SE) for one SD of resistin increment = -1.01 (0.70) ml/min/1.73 m(2), p = 0.019] and in Boston [beta (SE) = -5.31 (0.74) ml/min/1.73 m(2), p < 0.001] samples, as well as in the two studies combined [beta (SE) = -3.42 (0.52) ml/min/1.73 m(2), p < 0.001]. The association was unaffected by adjustment for smoking habits, BMI, waist circumference, diabetes duration, HbA1c, insulin treatment, hypertension and lipid-lowering therapy: beta (SE) for one SD of resistin increment = -1.07 (0.70), p = 0.02; -5.50 (0.88), p < 0.001; and -2.81 (0.55) ml/min/1.73 m(2), p < .001, in SGR, Boston and the two studies combined, respectively. The association was significantly stronger in men than in women (p for resistin-by-gender interaction = 0.003). For each resistin SD increment, the odds of having eGFR < 0 ml/min/1.7 3m(2) increased by 22% (OR = 1.22; 95% CI 1.02-1.44; p = 0.025) in SGR sample, 69% (OR = 1.69; 95% CI 1.38-2.07; p < 0.001) in Boston sample, and 47% (OR = 1.47; 95% CI 1.29-1.68; p < 0.001) in the two studies considered together. Similar associations were observed in the adjusted model: OR 95% CI for each SD resistin increment being 1.23 (1.03-1.46), p = 0.021; 1.52 (1.20-1.92), p < 0.001; 1.33 (1.16-1.53), p < 0.001, in SGR, Boston and the two studies combined, respectively. CONCLUSIONS: This is the first report of an association between high serum resistin and low eGFR in patients with T2D of European ancestry. PMID- 25811177 TI - Analysis of world economic variables using multidimensional scaling. AB - Waves of globalization reflect the historical technical progress and modern economic growth. The dynamics of this process are here approached using the multidimensional scaling (MDS) methodology to analyze the evolution of GDP per capita, international trade openness, life expectancy, and education tertiary enrollment in 14 countries. MDS provides the appropriate theoretical concepts and the exact mathematical tools to describe the joint evolution of these indicators of economic growth, globalization, welfare and human development of the world economy from 1977 up to 2012. The polarization dance of countries enlightens the convergence paths, potential warfare and present-day rivalries in the global geopolitical scene. PMID- 25811175 TI - In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonist degarelix on human prostate cell growth. AB - Degarelix is a gonadrotropin-releasing hormone (GnRH) receptor (GnRHR) antagonist used in patients with prostate cancer who need androgen deprivation therapy. GnRHRs have been found in extra-pituitary tissues, including prostate, which may be affected by the GnRH and GnRH analogues used in therapy. The direct effect of degarelix on human prostate cell growth was evaluated. Normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH)-1 cells, androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells, as well as VCaP cells derived from a patient with castration resistant prostate cancer were used. Discriminatory protein and lipid fingerprints of normal, hyperplastic, and cancer cells were generated by matrix assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The investigated cell lines express GNRHR1 and GNRHR2 and their endogenous ligands. Degarelix treatment reduced cell viability in all prostate cell lines tested, with the exception of the PC-3 cells; this can be attributed to increased apoptosis, as indicated by increased caspase 3/7, 8 and 9 levels. WPE1-NA22, BPH 1, LNCaP, and VCaP cell viability was not affected by treatment with the GnRH agonists leuprolide and goserelin. Using MALDI MS, we detected changes in m/z signals that were robust enough to create a complete discriminatory profile induced by degarelix. Transcriptomic analysis of BPH-1 cells provided a global map of genes affected by degarelix and indicated that the biological processes affected were related to cell growth, G-coupled receptors, the mitogen-activated protein kinase (MAPK) pathway, angiogenesis and cell adhesion. Taken together, these data demonstrate that (i) the GnRH antagonist degarelix exerts a direct effect on prostate cell growth through apoptosis; (ii) MALDI MS analysis provided a basis to fingerprint degarelix-treated prostate cells; and (iii) the clusters of genes affected by degarelix suggest that this compound, in addition to its known use in the treatment of prostate cancer, may be efficacious in BPH. PMID- 25811176 TI - Evolution of ebola virus disease from exotic infection to global health priority, Liberia, mid-2014. AB - Over the span of a few weeks during July and August 2014, events in West Africa changed perceptions of Ebola virus disease (EVD) from an exotic tropical disease to a priority for global health security. We describe observations during that time of a field team from the Centers for Disease Control and Prevention and personnel of the Liberian Ministry of Health and Social Welfare. We outline the early epidemiology of EVD within Liberia, including the practical limitations on surveillance and the effect on the country's health care system, such as infections among health care workers. During this time, priorities included strengthening EVD surveillance; establishing safe settings for EVD patient care (and considering alternative isolation and care models when Ebola Treatment Units were overwhelmed); improving infection control practices; establishing an incident management system; and working with Liberian airport authorities to implement EVD screening of departing passengers. PMID- 25811178 TI - Comparing molecular dynamics force fields in the essential subspace. AB - The continued development and utility of molecular dynamics simulations requires improvements in both the physical models used (force fields) and in our ability to sample the Boltzmann distribution of these models. Recent developments in both areas have made available multi-microsecond simulations of two proteins, ubiquitin and Protein G, using a number of different force fields. Although these force fields mostly share a common mathematical form, they differ in their parameters and in the philosophy by which these were derived, and previous analyses showed varying levels of agreement with experimental NMR data. To complement the comparison to experiments, we have performed a structural analysis of and comparison between these simulations, thereby providing insight into the relationship between force-field parameterization, the resulting ensemble of conformations and the agreement with experiments. In particular, our results show that, at a coarse level, many of the motional properties are preserved across several, though not all, force fields. At a finer level of detail, however, there are distinct differences in both the structure and dynamics of the two proteins, which can, together with comparison with experimental data, help to select force fields for simulations of proteins. A noteworthy observation is that force fields that have been reparameterized and improved to provide a more accurate energetic description of the balance between helical and coil structures are difficult to distinguish from their "unbalanced" counterparts in these simulations. This observation implies that simulations of stable, folded proteins, even those reaching 10 microseconds in length, may provide relatively little information that can be used to modify torsion parameters to achieve an accurate balance between different secondary structural elements. PMID- 25811179 TI - From the ground up: global nitrous oxide sources are constrained by stable isotope values. AB - Rising concentrations of nitrous oxide (N2O) in the atmosphere are causing widespread concern because this trace gas plays a key role in the destruction of stratospheric ozone and it is a strong greenhouse gas. The successful mitigation of N2O emissions requires a solid understanding of the relative importance of all N2O sources and sinks. Stable isotope ratio measurements (delta15N-N2O and delta18O-N2O), including the intramolecular distribution of 15N (site preference), are one way to track different sources if they are isotopically distinct. 'Top-down' isotope mass-balance studies have had limited success balancing the global N2O budget thus far because the isotopic signatures of soil, freshwater, and marine sources are poorly constrained and a comprehensive analysis of global N2O stable isotope measurements has not been done. Here we used a robust analysis of all available in situ measurements to define key global N2O sources. We showed that the marine source is isotopically distinct from soil and freshwater N2O (the continental source). Further, the global average source (sum of all natural and anthropogenic sources) is largely controlled by soils and freshwaters. These findings substantiate past modelling studies that relied on several assumptions about the global N2O cycle. Finally, a two-box-model and a Bayesian isotope mixing model revealed marine and continental N2O sources have relative contributions of 24-26% and 74-76% to the total, respectively. Further, the Bayesian modeling exercise indicated the N2O flux from freshwaters may be much larger than currently thought. PMID- 25811180 TI - Modulators of hepatic lipoprotein metabolism identified in a search for small molecule inducers of tribbles pseudokinase 1 expression. AB - Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging. PMID- 25811183 TI - Correction: G-quadruplex structures and CpG methylation cause drop-out of the maternal allele in polymerase chain reaction amplification of the imprinted MEST gene promoter. PMID- 25811181 TI - Stereotypes possess heterogeneous directionality: a theoretical and empirical exploration of stereotype structure and content. AB - We advance a theory-driven approach to stereotype structure, informed by connectionist theories of cognition. Whereas traditional models define or tacitly assume that stereotypes possess inherently Group -> Attribute activation directionality (e.g., Black activates criminal), our model predicts heterogeneous stereotype directionality. Alongside the classically studied Group -> Attribute stereotypes, some stereotypes should be bidirectional (i.e., Group ? Attribute) and others should have Attribute -> Group unidirectionality (e.g., fashionable activates gay). We tested this prediction in several large-scale studies with human participants (NCombined = 4,817), assessing stereotypic inferences among various groups and attributes. Supporting predictions, we found heterogeneous directionality both among the stereotype links related to a given social group and also between the links of different social groups. These efforts yield rich datasets that map the networks of stereotype links related to several social groups. We make these datasets publicly available, enabling other researchers to explore a number of questions related to stereotypes and stereotyping. Stereotype directionality is an understudied feature of stereotypes and stereotyping with widespread implications for the development, measurement, maintenance, expression, and change of stereotypes, stereotyping, prejudice, and discrimination. PMID- 25811182 TI - A monoclonal antibody that tracks endospore formation in the microsporidium Nosema bombycis. AB - Nosema bombycis, the first identified microsporidium, is a destructive pathogen of the silkworm Bombyx mori and causes severe worldwide economic losses in sericulture. Major microsporidian structural proteins, such as the spore wall protein (SWP), are known to be involved in host invasion. In this study, the reactivity of the monoclonal antibody 2B10 was tested against an endospore protein of N. bombycis with a molecular weight size at 50-kDa, using Western blotting. The antigen was purified after immunoprecipitation and was further identified as EOB13320 according to MALDI-TOF MS assay. We found that EOB13320 locates to the surface of the different developmental stages of the parasite, mostly the sporoblast stage and the mature spore after immunoelectron microscopy examination. EOB13320 was also widely distributed in the developing endospore, especially at the sporoblast stage. This endospore protein also accumulated in the cytoplasm of both the merogony and sporoblast stages. These results imply that EOB13320 detected by monoclonal antibody 2B10 is expressed throughout the life cycle of the parasite, notably during the stage when the endospore is formed, and that this protein is important for spore-coat formation and parasite maintenance. Our study could be instrumental in the understanding of spore wall formation and will help to gain greater insight into the biology of this parasite. PMID- 25811185 TI - Higher prevalence of sexual transmitted diseases and correlates of genital warts among heterosexual males attending sexually transmitted infection clinics (MSCs) in Jiangmen, China: implication for the up-taking of STD related service. AB - BACKGROUND: Increasing burden of STDs is one of China's major public health concerns. However, only a limited number of studies have ever investigated the prevalence of these STDs, particular for genital warts and its correlates among heterosexual males attending STD clinics in China. In order to fill this gap, we conducted a cross-sectional study among MSCs in Jiangmen, China, between the years of 2009 and 2010. METHOD: The eligible participants were recruited from several STD-clinics in public hospitals. We collected demographic information and behaviors of the participants. After HIV and syphilis testing, we further checked whether the participants had genital warts and genital herpes. In addition, urine samples were collected from part of the participants for CT and NG testing. RESULTS: Of the 533 eligible participants, over three-fifths were aged 35 or below, nearly three quarters had no college degree, over three-fifths were residence of Jiangmen. The prevalence of HIV, syphilis, genital warts, genital herpes, CT and NG were 0.19%, 7.50%, 7.32%, 5.25%, 9.73% and 6.19%, respectively. Living with family members (versus living alone), no STD-related service in past year, experiencing STDs related symptoms in past year, and sex with FSWs in last three months were positively associated with genital warts, with adjusted ORs of 5.54 (95% CI 1.94-15.81), 2.26 (95% CI 1.08-4.74), 1.99 (95% CI 1.00-3.99) and 2.01 (95% CI 1.00-4.04), respectively. CONCLUSION: Our study indicates that the prevalence of STDs among MSCs in Jiangmen was high, which may further spread HIV among MSCs. Targeted interventions that focused on STDs related services uptake should be implemented urgently. PMID- 25811187 TI - Correction: Effectiveness of a worksite mindfulness-related multi-component health promotion intervention on work engagement and mental health: results of a randomized controlled trial. PMID- 25811184 TI - A RecA protein surface required for activation of DNA polymerase V. AB - DNA polymerase V (pol V) of Escherichia coli is a translesion DNA polymerase responsible for most of the mutagenesis observed during the SOS response. Pol V is activated by transfer of a RecA subunit from the 3'-proximal end of a RecA nucleoprotein filament to form a functional complex called DNA polymerase V Mutasome (pol V Mut). We identify a RecA surface, defined by residues 112-117, that either directly interacts with or is in very close proximity to amino acid residues on two distinct surfaces of the UmuC subunit of pol V. One of these surfaces is uniquely prominent in the active pol V Mut. Several conformational states are populated in the inactive and active complexes of RecA with pol V. The RecA D112R and RecA D112R N113R double mutant proteins exhibit successively reduced capacity for pol V activation. The double mutant RecA is specifically defective in the ATP binding step of the activation pathway. Unlike the classic non-mutable RecA S117F (recA1730), the RecA D112R N113R variant exhibits no defect in filament formation on DNA and promotes all other RecA activities efficiently. An important pol V activation surface of RecA protein is thus centered in a region encompassing amino acid residues 112, 113, and 117, a surface exposed at the 3'-proximal end of a RecA filament. The same RecA surface is not utilized in the RecA activation of the homologous and highly mutagenic RumA'2B polymerase encoded by the integrating-conjugative element (ICE) R391, indicating a lack of structural conservation between the two systems. The RecA D112R N113R protein represents a new separation of function mutant, proficient in all RecA functions except SOS mutagenesis. PMID- 25811186 TI - Diabetic foot syndrome and corneal subbasal nerve plexus changes in congolese patients with type 2 diabetes. AB - BACKGROUND: To study the severity of diabetic neuropathy, diabetic retinopathy and grades of diabetic foot syndrome for correlations with corneal subbasal nerve plexus (SBP) changes in Congolese patients with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-eight type 2 diabetes patients with diabetes-related foot ulceration were recruited in a diabetic care unit in Kinshasa, Democratic Republic of Congo. Corneal SBP was investigated by confocal laser-scanning microscopy to analyse nerve fibre density (NFD) [um/ um2], number of branches [n] and number of connectivity points [n]. Foot ulceration was graded using the Wagner ulcer classification. Corneal sensitivity (Cochet-Bonnet), Neuropathy Symptom Score (NSS), Neuropathy Disability Score (NDS), ankle-brachial index (ABI) and ophthalmological status were evaluated. Foot ulceration was ranked as mild (Wagner 0-1: 13 patients/46.4%), moderate (Wagner 2-3: 10 patients/35.7%) and severe (Wagner 4-5: 5 patients/17.9%). The correlation between Wagner Score and NFD (p=0.017, r = - 0,454), NDS and NFD (p=0,039, r = - 0.400) as well as Wagner Score and HbA1c (p=0,007, r = - 0.477) was stated. Significant differences in confocal SBP parameters were observed between Wagner 0 1 and Wagner 4 5 (number of branches (p=0.012), number of connectivity points (p=0.001), nerve fibre density (p=0.033)) and ABI (p=0.030), and between Wagner 2 3 and Wagner 4-5 (number of branches (p=0.003), number of connectivity points (p=0.005) and nerve fibre density (p=0.014)). Differences in NDS (p=0.001) and corneal sensation (p=0.032) were significant between Wagner 0-1 and Wagner 2-3. Patients with diabetic retinopathy had significantly longer diabetes duration (p=0.03) and higher NDS (p=0.01), but showed no differences in SBP morphology or corneal sensation. CONCLUSIONS/SIGNIFICANCE: While confirming the diabetic aetiology of foot ulceration due to medial arterial calcification, this study indicates that the grade of diabetic foot syndrome correlates with corneal SBP changes and corneal sensation in patients in sub-Saharan Africa. PMID- 25811189 TI - Correction: Effect of beta-blocker therapy on the risk of infections and death after acute stroke--a historical cohort study. PMID- 25811188 TI - Elevated NT-pro-brain natriuretic peptide level is independently associated with all-cause mortality in HIV-infected women in the early and recent HAART eras in the Women's Interagency HIV Study cohort. AB - BACKGROUND: HIV-infected individuals are at increased risk of right and left heart dysfunction. N-terminal-pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac ventricular strain and systolic dysfunction, may be associated with all-cause mortality in HIV-infected women. The aim of this study was to determine if elevated levels of NT-proBNP is associated with increased mortality in HIV infected women. DESIGN: Prospective cohort study. METHODS AND RESULTS: We measured NT-proBNP in 936 HIV-infected and 387 age-matched HIV-uninfected women early (10/11/94 to 7/17/97) and 1082 HIV-infected and 448 HIV-uninfected women late (4/1/08 to 10/7/08) in the highly active antiretroviral therapy (HAART) periods in the Women's Interagency HIV Study. An NT-proBNP >75th percentile was more likely in HIV-infected persons, but only statistically significant in the late period (27% vs. 21%, unadjusted p = 0.03). In HIV-infected participants, NT proBNP>75th percentile was independently associated with worse 5-year survival in the early HAART period (HR 1.8, 95% CI 1.3-2.4, p<0.001) and remained a predictor of mortality in the late HAART period (HR 2.8, 95% CI 1.4-5.5, p = 0.002) independent of other established risk covariates (age, race/ethnicity, body mass index, smoking, hepatitis C serostatus, hypertension, renal function, and hemoglobin). NT-proBNP level was not associated with mortality in HIV-uninfected women. CONCLUSION: NT-proBNP is a novel independent marker of mortality in HIV infected women both when HAART was first introduced and currently. As NT-proBNP is often associated with both pulmonary hypertension and left ventricular dysfunction, these findings suggest that these conditions may contribute significantly to adverse outcomes in this population, requiring further definition of causes and treatments of elevated NT-proBNP in HIV-infected women. PMID- 25811191 TI - Interaction between water and wind as a driver of passive dispersal in mangroves. AB - Although knowledge on dispersal patterns is essential for predicting long-term population dynamics, critical information on the modalities of passive dispersal and potential interactions between vectors is often missing. Here, we use mangrove propagules with a wide variety of morphologies to investigate the interaction between water and wind as a driver of passive dispersal. We imposed 16 combinations of wind and hydrodynamic conditions in a flume tank, using propagules of six important mangrove species (and genera), resulting in a set of dispersal morphologies that covers most variation present in mangrove propagules worldwide. Additionally, we discussed the broader implications of the outcome of this flume study on the potential of long distance dispersal for mangrove propagules in nature, applying a conceptual model to a natural mangrove system in Gazi Bay (Kenya). Overall, the effect of wind on dispersal depended on propagule density (g l(-1)). The low-density Heritiera littoralis propagules were most affected by wind, while the high-density vertically floating propagules of Ceriops tagal and Bruguiera gymnorrhiza were least affected. Avicennia marina, and horizontally floating Rhizophora mucronata and C. tagal propagules behaved similarly. Morphological propagule traits, such as the dorsal sail of H. littoralis, explained another part of the interspecific differences. Within species, differences in dispersal velocities can be explained by differences in density and for H. littoralis also by variations in the shape of the dorsal sail. Our conceptual model illustrates that different propagule types have a different likelihood of reaching the open ocean depending on prevailing water and wind currents. Results suggest that in open water, propagule traits (density, morphology, and floating orientation) appear to determine the effect of water and wind currents on dispersal dynamics. This has important implications for inter- and intraspecific variation in dispersal patterns and the likelihood of reaching suitable habitat patches within a propagule's viable period. PMID- 25811190 TI - Interaction of ATP with a small heat shock protein from Mycobacterium leprae: effect on its structure and function. AB - Adenosine-5'-triphosphate (ATP) is an important phosphate metabolite abundantly found in Mycobacterium leprae bacilli. This pathogen does not derive ATP from its host but has its own mechanism for the generation of ATP. Interestingly, this molecule as well as several antigenic proteins act as bio-markers for the detection of leprosy. One such bio-marker is the 18 kDa antigen. This 18 kDa antigen is a small heat shock protein (HSP18) whose molecular chaperone function is believed to help in the growth and survival of the pathogen. But, no evidences of interaction of ATP with HSP18 and its effect on the structure and chaperone function of HSP18 are available in the literature. Here, we report for the first time evidences of "HSP18-ATP" interaction and its consequences on the structure and chaperone function of HSP18. TNP-ATP binding experiment and surface plasmon resonance measurement showed that HSP18 interacts with ATP with a sub-micromolar binding affinity. Comparative sequence alignment between M. leprae HSP18 and alphaB-crystallin identified the sequence 49KADSLDIDIE58 of HSP18 as the Walker-B ATP binding motif. Molecular docking studies revealed that beta4-beta8 groove/strands as an ATP interactive region in M. leprae HSP18. ATP perturbs the tertiary structure of HSP18 mildly and makes it less susceptible towards tryptic cleavage. ATP triggers exposure of additional hydrophobic patches at the surface of HSP18 and induces more stability against chemical and thermal denaturation. In vitro aggregation and thermal inactivation assays clearly revealed that ATP enhances the chaperone function of HSP18. Our studies also revealed that the alteration in the chaperone function of HSP18 is reversible and is independent of ATP hydrolysis. As the availability and binding of ATP to HSP18 regulates its chaperone function, this functional inflection may play an important role in the survival of M. leprae in hosts. PMID- 25811192 TI - Structural models of zebrafish (Danio rerio) NOD1 and NOD2 NACHT domains suggest differential ATP binding orientations: insights from computational modeling, docking and molecular dynamics simulations. AB - Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2 are cytosolic pattern recognition receptors playing pivotal roles in innate immune signaling. NOD1 and NOD2 recognize bacterial peptidoglycan derivatives iE DAP and MDP, respectively and undergoes conformational alternation and ATP dependent self-oligomerization of NACHT domain followed by downstream signaling. Lack of structural adequacy of NACHT domain confines our understanding about the NOD-mediated signaling mechanism. Here, we predicted the structure of NACHT domain of both NOD1 and NOD2 from model organism zebrafish (Danio rerio) using computational methods. Our study highlighted the differential ATP binding modes in NOD1 and NOD2. In NOD1, gamma-phosphate of ATP faced toward the central nucleotide binding cavity like NLRC4, whereas in NOD2 the cavity was occupied by adenine moiety. The conserved 'Lysine' at Walker A formed hydrogen bonds (H bonds) and Aspartic acid (Walker B) formed electrostatic interaction with ATP. At Sensor 1, Arg328 of NOD1 exhibited an H-bond with ATP, whereas corresponding Arg404 of NOD2 did not. 'Proline' of GxP motif (Pro386 of NOD1 and Pro464 of NOD2) interacted with adenine moiety and His511 at Sensor 2 of NOD1 interacted with gamma-phosphate group of ATP. In contrast, His579 of NOD2 interacted with the adenine moiety having a relatively inverted orientation. Our findings are well supplemented with the molecular interaction of ATP with NLRC4, and consistent with mutagenesis data reported for human, which indicates evolutionary shared NOD signaling mechanism. Together, this study provides novel insights into ATP binding mechanism, and highlights the differential ATP binding modes in zebrafish NOD1 and NOD2. PMID- 25811193 TI - Removal of endotoxins from bacteriophage preparations by extraction with organic solvents. AB - Lipopolysaccharide (LPS, endotoxin, pyrogen) constitutes a very troubling contaminant of crude phage lysates produced in Gram-negative bacteria. Toxicity of LPS depends on the strong innate immunity response including the cytokines. Therefore, its removal is important for bacteriophage applications. In this paper, we present a procedure for extractive removal of endotoxin from bacteriophage preparations with water immiscible solvents (1-octanol or 1 butanol). During extraction most of the phage lytic activity is retained in the aqueous phase, while endotoxin accumulates in the organic solvent. The levels of endotoxin (expressed as endotoxin units, EU) in the aqueous bacteriophage containing fraction determined by limulus amebocyte lysate or EndoLISA assay were exceptionally low. While the initial endotoxin levels in the crude phage lysates ranged between 10(3) and 10(5) EU/ml the average level after organic extraction remaining in the aqueous fraction was 5.3 EU/ml. These values when related to phage titers decreased from 10(3)-10(5) EU/10(9) PFU (plaque forming units) down to an average of 2.8 EU/10(9) PFU. The purification procedure is scalable, efficient and applicable to all the bacteriophages tested: T4, HAP1 (E. coli) and F8 (P. aeruginosa). PMID- 25811195 TI - The health care cost of dying: a population-based retrospective cohort study of the last year of life in Ontario, Canada. AB - BACKGROUND: Coordinated and appropriate health care across sectors is an ongoing challenge, especially at the end-of-life. Population-level data on end-of-life health care use and cost, however, are seldom reported across a comprehensive array of sectors. Such data will identify the level of care being provided and areas where care can be optimized. METHODS: This retrospective cohort study identified all deaths in Ontario from April 1, 2010 to March 31, 2013. Using population-based health administrative databases, we examined health care use and cost in the last year of life. RESULTS: Among 264,755 decedents, the average health care cost in the last year of life was $53,661 (Quartile 1-Quartile 3: $19,568-$66,875). The total captured annual cost of $4.7 billion represents approximately 10% of all government-funded health care. Inpatient care, incurred by 75% of decedents, contributed 42.9% of total costs ($30,872 per user). Physician services, medications/devices, laboratories, and emergency rooms combined to less than 20% of total cost. About one-quarter used long-term-care and 60% used home care ($34,381 and $7,347 per user, respectively). Total cost did not vary by sex or neighborhood income quintile, but were less among rural residents. Costs rose sharply in the last 120 days prior to death, predominantly for inpatient care. INTERPRETATION: This analysis adds new information about the breadth of end-of-life health care, which consumes a large proportion of Ontario's health care budget. The cost of inpatient care and long-term care are substantial. Introducing interventions that reduce or delay institutional care will likely reduce costs incurred at the end of life. PMID- 25811194 TI - Macrophages modulate migration and invasion of human tongue squamous cell carcinoma. AB - Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity. PMID- 25811196 TI - Nutrient Intake by Ultramarathon Runners: Can They Meet Recommendations? AB - PURPOSE: The objective of this study was to investigate whether ultramarathon runners were able to meet nutrition recommendations during a training period and on a competition day. METHODS: In preparation for a 60 or 120 km ultramarathon covering a varied terrain, male and female ultramarathon runners (n = 68, age 46.5 +/- 7.1 y) reported habitual dietary intake during three independent days using a web-based 24-hr recall and questionnaires. The diet was assessed using probability of inadequacy or by qualitative evaluation using reference dietary intakes or sports nutrition recommendations. A small group of 120 km runners (n = 4) was observed continuously during the race. After the race, 60 km runners (n = 41) received a questionnaire to assess dietary intake and gastrointestinal (GI) distress on the race day. Spearman rank correlation coefficients (r) were applied to investigate the association between intake and general GI distress symptoms. RESULTS: In men and women, habitual mean carbohydrate (CHO) intake was lower than recommended, as was mean protein intake by women. CHO intake during the race was <60 g/h in 75% of the athletes. A large variation of nutrient and fluid intake was seen. GI distress during the race was reported in 82% of the runners; severe GI distress was low. In general, moderate, mostly negative, correlations with nutrient intake were seen for GI distress. CONCLUSION: Sports nutrition recommendations for the habitual diet were not achieved. During a competition day, a large variation was found in nutrient intake; this may be related to a high incidence of GI distress. PMID- 25811197 TI - Association patterns in saproxylic insect networks in three Iberian Mediterranean woodlands and their resistance to microhabitat loss. AB - The assessment of the relationship between species diversity, species interactions and environmental characteristics is indispensable for understanding network architecture and ecological distribution in complex networks. Saproxylic insect communities inhabiting tree hollow microhabitats within Mediterranean woodlands are highly dependent on woodland configuration and on microhabitat supply they harbor, so can be studied under the network analysis perspective. We assessed the differences in interacting patterns according to woodland site, and analysed the importance of functional species in modelling network architecture. We then evaluated their implications for saproxylic assemblages' persistence, through simulations of three possible scenarios of loss of tree hollow microhabitat. Tree hollow-saproxylic insect networks per woodland site presented a significant nested pattern. Those woodlands with higher complexity of tree individuals and tree hollow microhabitats also housed higher species/interactions diversity and complexity of saproxylic networks, and exhibited a higher degree of nestedness, suggesting that a higher woodland complexity positively influences saproxylic diversity and interaction complexity, thus determining higher degree of nestedness. Moreover, the number of insects acting as key interconnectors (nodes falling into the core region, using core/periphery tests) was similar among woodland sites, but the species identity varied on each. Such differences in insect core composition among woodland sites suggest the functional role they depict at woodland scale. Tree hollows acting as core corresponded with large tree hollows near the ground and simultaneously housing various breeding microsites, whereas core insects were species mediating relevant ecological interactions within saproxylic communities, e.g. predation, competitive or facilitation interactions. Differences in network patterns and tree hollow characteristics among woodland sites clearly defined different sensitivity to microhabitat loss, and higher saproxylic diversity and woodland complexity showed positive relation with robustness. These results highlight that woodland complexity goes hand in hand with biotic and ecological complexity of saproxylic networks, and together exhibited positive effects on network robustness. PMID- 25811198 TI - MicroRNAs as predictor markers for response to interferon treatment of chronic hepatitis C genotype-4 in Egyptian patients. AB - BACKGROUND: Hepatitis C virus genotype 4 (HCV-4) infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection. The aim of the present study was to assess serum miR-122, miR-221 and miR-21 expression profiles in HCV-4 patients prior to treatment with HCV-4 combination therapy (pegylated alpha interferon and ribavirin) and to determine whether the miRNAs were associated with the drug response. METHODS: RNA was extracted from pretreatment serum samples, and miR-122, miR-221 and miR-21 levels were measured by quantitative PCR. The results were compared among patients with sustained virological responses (SVR) and non-responders (NR). RESULTS: The expression levels of miR-21 and miR-122 were significantly different between the SVR and NR groups. Receiver operator characteristic (ROC) analysis revealed that the sensitivity, specificity and positive predictive values of miR-21 were 82.2%, 77.3% and 88.1%, respectively, with a cut-off value of 1.7. The sensitivity, specificity and positive predictive values of miR-122 were 68.9%, 59.1% and 77.5%, respectively, with a cut-off value of 3.5. CONCLUSION AND SIGNIFICANCE: miR-21 and miR-122 might be useful predictors for SVR in HCV-4 patients prior to the administration of combination therapy. A higher predictive response power was obtained for miR-21 than for miR-122. These results should reduce ineffective treatments. PMID- 25811201 TI - Association between Papio hamadryas populations and human gastrointestinal infectious diseases in southwestern Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Papio hamadryas baboons, known reservoirs of several infectious diseases, roam and deposit their excreta indiscriminately on footpaths, parks, and streets of the city peripheries of Taif, Baha, and Abha in southwestern Saudi Arabia. Nonetheless, city centers of these places are free of baboons. This study aims to determine the impact of baboons on human gastrointestinal health. DESIGN AND SETTINGS: This is a descriptive cross sectional analytical ecological study conducted in 3 cities located in southwestern Saudi Arabia between July 2011 and July 2012. MATERIALS AND METHODS: We investigated the impact of these baboons on the human health through a coprological survey of infectious agents of baboons and humans in these 3 cities using macroscopic and micro.scopic analyses, before and after parasite concentration, and culturing of bacteria on selective and differential media, which were then identified by 16S rDNA gene sequencing. Baboon fecal samples (n=823) were collected from city peripheries. Two groups of human fecal samples, each consisting of 795 samples were collected, one from city centers and the second from city peripheries where baboons intermingle with the human population. RESULTS: Baboon fecal samples were the most contaminated with infectious agents, except for Staphylococcus aureus, which was more commonly present in human fecal samples collected from city peripheries. Human fecal samples collected form city peripheries showed higher rates of most infective agents than those collected from city centers. CONCLUSION: This indicates that baboons are medically important reservoirs of infectious agents associated with higher human coproprevalence of gastrointestinal infectious agents. PMID- 25811202 TI - Effects of positive airway pressure therapy on exercise parameters in obstructive sleep apnea. AB - BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is common in adult population and may cause many adverse clinical results. We aimed to investigate possible changes in cardiopulmonary exercise capacity in OSA patients after positive airway pressure treatment. DESIGN AND SETTINGS: Patients who were admitted to Gaziantep University Pulmonary Diseases Sleep Center and diagnosed OSA were included. Studies carried out between May 2010 and July 2011. Sixty-five consecutive patients were included in this prospective study. PATIENTS AND METHODS: Sixty-five adult sleep clinic patients diagnosed with OSA by polysomnography and in whom continuous positive airway pressure (CPAP) ventilation therapy was indicated were included. Cardiopulmonary exercise capacity was assessed by bicycle ergometry during diagnostic workup and at least 4 weeks later. RESULTS: There were 57 (87.7%) males. The mean age was 45.29 (10.57) years, apnea-hypopnea index 38.02 (23.19 events/h, body mass index 31.72 (4.87) kg/m2. Patients were grouped with respect to compliance with CPAP. The peak oxygen consumption (VO2) did not change in the CPAP compliant group (n=33) (22.52 [6.62] mL/[min.kg] to 21.32 [5.26] mL/[min.kg]; P=.111), and decreased from 21.31 (5.66) mL/(min.kg) to 19.92 (5.40) mL/(min.kg) (P=.05) in the CPAP noncompliant group. Work rate increased from 84.0% to 85.0% in the CPAP compliant group and decreased from 79.6% to 77.1% in the noncompliant group (P=.041). In the group that used the device, ventilation (VE)/VCO2 at anaerobic threshold (AT) declined from 28.42 to 27.36; however, it increased from 27.41 to 27.81 in the group that did not use the device (P=.033). CONCLUSIONS: Decline in the exercise capacity was prevented in patients with OSA after 4 weeks of CPAP therapy. The changes in VE/VCO2 at AT suggest the reversal of pathophysiologic changes in OSA with the CPAP therapy that may improve cardiac function and cause more efficient ventilation. PMID- 25811200 TI - Burden of traumatic injuries in Saudi Arabia: lessons from a major trauma registry in Riyadh, Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: In Saudi Arabia (SA), injuries are the second leading cause of death; however, little is known about their frequencies and outcomes. Trauma registries play a major role in measuring the burden on population health. This study aims to describe the population of the only hospital-based trauma registry in the country and highlight challenges and potential opportunities to improve trauma data collection and research in SA. DESIGN AND SETTINGS: Using data between 2001 and 2010, this retrospective study included patients from a large trauma center in Riyadh, SA. PATIENTS AND METHODS: A staff nurse utilized a structured checklist to gather information on patients' demographic, physiologic, anatomic, and outcome variables. Basic descriptive statistics by age group ( 14 years) were calculated, and differences were assessed using student t and chi square tests. In addition, the mechanism of injury and the frequency of missing data were evaluated. RESULTS: 10 847 patients from the trauma registry were included. Over 9% of all patients died either before or after being treated at the hospital. Patients who were older than 14 years of age (more likely to be male) sustained traffic-related injuries and died in the hospital as compared to patients who were younger than or equal to years of age. Deceased patients were severely injured as measured by injury severity score and Glasgow Coma Scale (P < .001). Overall, the most frequent type of injury was related to traffic (52.0%), followed by falls (23.4%). Missing values were mostly prevalent in traffic related variables, such as seatbelt use (70.2%). CONCLUSION: This registry is a key step toward addressing the burden of injuries in SA. Improved injury classification using the International Classification of Disease-external cause codes may improve the quality of the registry and allow comparison with other populations. Most importantly, injury prevention in SA requires further investment in data collection and research to improve outcomes. PMID- 25811203 TI - Plasma level of hypoxanthine/xanthine as markers of oxidative stress with different stages of obstructive sleep apnea syndrome. AB - BACKGROUND AND OBJECTIVES: Tissue hypoxia due to repeated apneas among patients of obstructive sleep apnea syndrome (OSAS) leads to cumulative oxidative stress. It is established that an increased plasma level of hypoxanthine/xanthine may serve as a criterion of tissue hypoxia. We presumed that plasma levels of hypoxan.thine/xanthine might be high among patients of OSAS due to oxidative stress. Nobody studied this relationship earlier. The aim of this study was to estimate their plasma levels as markers of hypoxia. DESIGN AND SETTINGS: This case-control study was performed for a period of 1-year including patients re.ferred to a tertiary care hospital, New Delhi, India. MATERIALS AND METHODS: It was a case-control study. A total of 43 patients of OSAS, diagnosed by overnight polysomnography (PSG), were included in the study. Age- and sex-matched 43 subjects in whom the presence of OSAS was not confirmed by overnight PSG were enrolled as healthy controls. The severity of disease was classified on the basis of apnea-hypopnea index (AHI). Out of 43 patients, 9 were moderate and 14 were severe. None was with mild OSAS. The venous blood sample was collected in the morning after PSG. Hematological and biochemical assays were also performed. Plasma levels of hypoxanthine/xanthine were measured by fluorometric analysis (normal laboratory reference < 2.00 mmol/L). Data collected was analyzed statistically by SPSS version 14.0, student unpaired t test, chi-square test, Mann-Whitney U test, and Pearson correlation coefficient. RESULTS: The mean plasma level of hypoxanthine/xanthine in patients of OSAS was found to be 5.4 (5.1) mmol/L, and in controls it was 1.2 (0.4) mmol/L. A statistically significant (P=.000) difference was found be.tween both groups. Among patients, a positive correlation between hypoxanthine/xanthine levels with age, AHI, and serum triglyceride levels was observed. The joint explanatory power of these significant factors was found to be 59.6% (P < .001). CONCLUSION: Plasma levels of xanthine/hypoxanthine were significantly elevated in patients of OSAS, and these were positively correlated with age, serum triglyceride levels, AHI, and severity of the disease. PMID- 25811199 TI - Management of patients with hepatic metastases from neuroendocrine tumors. AB - Neuroendocrine tumors have a disposition toward metastasis to the liver. A range of treatment modalities for neuroendocrine liver metastases is available in the clinical arena, the indications for which depend on tumor characteristics such as patterns of metastasis, tumor grade, and anatomical origin. The complete surgical resection of liver deposits represents the only option with the intent to cure and is the gold standard approach, whereas cytoreductive resection (debulking) presents another surgical option aiming to ameliorate the symptoms and prolong survival. Liver transplantation is generally an accepted option for highly selected patients. For patients ineligible for radical surgery, liver-directed therapies-transarterial embolization/chemoembolization, selective internal radiotherapy, and local tumor ablation-present alternative strategies. Systemic therapies include peptide receptor radiotherapy, somatostatin analogues, cytotoxic chemotherapeutics, and novel molecularly targeted drugs. However, despite the variety of treatments available, there exists little evidence to guide optimal clinical practice with currently available data predominantly retrospective in nature. In this review, we discuss the diagnostic procedures that influence the trajectory of treatment of patients with neuroendocrine liver metastases before critically appraising the evidence pertaining to these therapeutic strategies. PMID- 25811204 TI - On-pump with beating heart or cardioplegic arrest for emergency conversion to cardiopulmonary bypass during off-pump coronary artery bypass. AB - BACKGROUND AND OBJECTIVES: Intraoperative conversion, especially under emergent circumstances during off-pump coronary artery bypass (OPCAB), is associated with a significantly higher rate of hospital mortality. This study compared the clinical early outcomes of patients emergently converting to cardiopulmonary bypass (CPB) with or without cardioplegic arrest and evaluated the efficacy of an on-pump beating heart technique for these critically ill patients. DESIGN AND SETTING: A retrospective study of patients treated at The First Affiliated Hospital of China Medical University over an 8-year period (2005 to 2013). PATIENTS AND METHODS: Between January 2005 and September 2013, 104 patients were emergently converted to CPB during OPCAB. In the first 55 patients (53%), the cardioplegic arrest was performed. In the most recent 49 patients (47%), the on pump beating heart procedure was used without cardioplegic arrest. RESULTS: There were no significant differences in their baseline clinical characteristics, number of anastomoses performed per patient, and reasons for conversions (P > .05). A significant reduction occurred in the observed mortality between the cardioplegic arrest group and the on-pump beating heart group (25.6% vs 6.1%, P=.008). A statistical difference was found between the cardioplegic arrest group and the on-pump beating heart group in the time of CPB, peak cardiac troponin I, duration of inotropic support, time to extubation, intensive care unit stay, postoperative hospital stay, incidence of new intra-aortic balloon pump support, and pulmonary complications (P < .05). The incidence of blood requirements, postoperative myocardial infarction, new-onset atrial fibrillation, hemodialysis, stroke, infective complications, and resurgery for bleeding were lower in on-pump beating heart group, but the difference did not reach statistical significance (P > .05). CONCLUSION: The on-pump beating heart technique is the preferred method of emergency conversion to CPB during OPCAB. It has lower postoperative mortality and morbidity than the cardioplegic arrest. PMID- 25811205 TI - Validation of the Arabic version of the client satisfaction with device module of the orthotics and prosthetics users survey. AB - BACKGROUND AND OBJECTIVES: Assessing patient satisfaction with orthosis (PSwO) is a key point for clinical practice to increase a patient's adherence to therapeutic programs and reduce orthotic-related costs. The Client Satisfaction with Device (CSD) module of the Orthotics and Prosthetics Users' Survey (OPUS) is one of the most widely-used questionnaires for assessing PSwO, but its validated version in the Arabic language is lacking. The objective of this study is to generate and psychometrically validate an Arabic version of the CSD (CSD-Ar). DESIGN AND SETTINGS: This is a cross-sectional study, conducted during February to June 2013 at 2 inpatient and outpatient rehabilitation departments in Riyadh, Saudi Arabia. PATIENTS AND METHODS: Translation of CSD-Ar was carried out according to the guideline recommendations of Linacre. A convenience sample of 100 orthotic-user patients with various conditions (59% men, mean age 36 years) completed the CSD-Ar. Data were analyzed using exploratory factor analysis followed by Rasch analysis. RESULTS: Factor analysis confirmed the unidimensionality of the CSD-Ar. Rasch criteria for the functioning of rating scale categories were fulfilled. All items showed an adequate fit to the Rasch model. The person separation reliability was .75 and Cronbach alpha .83. There was a borderline local dependency between items 1 ("My device fits well") and 3 ("My device is comfortable throughout the day"). CONCLUSION: The internal construct validity of the CSD-Ar in Arab patients with various types of orthotics has been confirmed. This study provides a useful starting point for the use of this outcome measure in Arabic-speaking countries. PMID- 25811206 TI - Cataract surgery under systemic infliximab therapy in patients with refractory uveitis associated with Behcet disease. AB - BACKGROUND AND OBJECTIVES: This study is to evaluate the outcome of cataract surgery in patients with refractory uveitis associated with Behcet disease (BD) treated with infliximab. DESIGN AND SETTINGS: A retrospective study in a university-based tertiary referral center in the period between July 2003 and November 2011. METHODS: This is a retrospective study of patients with refractory uveitis associated with BD who underwent phacoemulsification cataract surgery under systemic infliximab therapy between July 2003 and November 2011 at King Abdulaziz University Hospital, Riyadh, Saudi Arabia. RESULTS: Six patients (9 eyes), 5 of which were male and 1 female, were identified in this study. The mean (SD) age and follow-up period were 26.2 (6.6) years (range, 16-36 years) and 51.6 (28.8) months (range, 12.84 months), respectively. All the patients underwent phacoemulsification with intraocular lens implantation. Postoperatively, visual acuity improved in all eyes and was 20/40 or better in 7 eyes (77.8%). In the immediate postoperative period, anterior chamber inflammation ranged from 2+ to 3+ cells. None of the patients developed inflammation relapse postoperatively. The most common postoperative complication was posterior capsular opacification in 5 eyes (55%), 4 of which were managed with neodymium:yttrium-aluminum garnet laser capsulotomy. Three eyes had glaucoma, 2 of which underwent successful glaucoma surgery and one was managed with topical antiglaucoma medications. CONCLUSION: In patients with refractory uveitis associated with BD who are treated with infliximab, cataract surgery is safe and has a good prognosis. PMID- 25811207 TI - Polymorphisms in RETN gene and susceptibility to colon cancer in Saudi patients. AB - BACKGROUND AND OBJECTIVES: Resistin is an adipocytokine, which has been studied for its role in insulin resistance and recently in inflammation. Several single nucleotide polymorphisms (SNPs) have been identified in the human resistin gene (RETN). This study aims to investigate the association of RETN rs1862513 (C-420G) and rs3745367 (G+299A) SNPs with the colon cancer risk in Saudi patients. DESIGN AND SETTING: This is a case-control study conducted among Saudi adult colon cancer patients recruited from King Abdulaziz Hospital and Oncology Center in Jeddah, Saudi Arabia. SUBJECTS AND METHODS: In this study, 120 Saudi volunteers (60 colon cancer patients and 60 disease-free controls) were studied. The SNPs were determined by polymerase chain reaction (PCR) and genotyping using PCR- restriction fragment length polymorphism analysis. RESULTS: In comparing the result obtained for the patient group with that of the controls, colon cancer group displayed different genotype distribution of the RETN C-420G and G+299A SNPs. The study indicated that the SNP-420 heterozygous (CG) genotype (odds ratio [OR]=2.48, 95% CI 1.07-5.74, P=.03) and the SNP +299 heterozygous (GA) genotype (OR=6.5, 95% CI 1.77-24.18, P=.002) significantly increased the risk of colon cancer. A further analysis of the genotype combination of SNPs RETN C-420G and G+299A showed a larger increase in the colon cancer risk. CONCLUSION: These preliminary results suggested a potential role for RETN C-420G and G+299A polymorphisms in the genetic predisposition to colon cancer disease. PMID- 25811208 TI - Association of endothelial nitric oxide synthase Glu298Asp gene polymorphism in psoriasis cases with hypertension. AB - BACKGROUND AND OBJECTIVES: Psoriasis is a common autoimmune-mediated chronic, inflammatory skin disease. Although, the molecular mechanism is not completely understood, psoriasis is caused by genetic and non-genetic parameters. The current study aimed (1) to define genotype and allele frequency of endothelial nitric oxide synthase (eNOS Glu298Asp) gene polymorphism in hypertensive and/or non-hypertensive psoriatic patients (2) to investigate the possible relationship between the eNOS Glu298Asp polymorphism and the risk of hypertension among psoriatic patients in the Turkish population. DESIGN AND SETTINGS: This cross sectional, case-control study was performed between March 2010 and November 2012 at the University hospital in Canakkale, Turkey Patients and Methods: Gene profiles of 75 psoriatic patients (21 hypertensive and 54 normotensive pa.tients) and 55 healthy (normotensive and non-psoriatic) volunteers were compared. Peripheral blood-EDTA samples were used for total genomic DNA isolation and genotyping. Target eNOS gene was genotyped for patients and control groups by real-time PCR melting-curve analysis system (LightCycler 2.0,Roche, Germany, and results were compared statistically. RESULTS: An increased T allele frequency in eNOS Glu298Asp single-nucleotide polymorphism (SNP) was determined in psoriatic patients when compared with normotensive non-psoriatic healthy volunteers (OR 2.3, CI 1.14-3.99), (P=.017). The T allele frequency was also found to be increased in hypertensive psoriatic patients when compared with healthy volunteers (4.83-fold increased, 95% CI 1.62-14.43 ([P=.003]) and normotensive psoriatic patients (3.03-fold increased, 95% CI 1.03-8.94 [P=.041]), respectively. CONCLUSION: The current preliminary results suggested that there was a correlation between eNOS Glu298Asp polymorphism and hypertension among psoriatic patients in the Turkish population. The T allele frequency of eNOS Glu298Asp SNP was different in hypertensive psoriatic patients, and the difference was statistically significant when compared with the normotensive psoriatic patients and healthy controls. These results need to be confirmed by large-scale studies. PMID- 25811209 TI - Giant aneurysm of the right coronary artery and magnetic resonance coronary angiography. AB - Coronary artery aneurysm (CAA) is generally defined as coronary dilatation that exceeds the diameter of normal adjacent segments or the diameter of the patient's largest coronary vessel by 1.5 times. The prime cause of CAAs is atherosclerosis, and the most commonly affected artery is the right coronary artery. CAAs are quite commonly detected during X-ray coronary angiography. However, Coronary artery aneurysm (CAA) is generally defined as coronary dilatation that exceeds the diameter of normal adjacent segments or the diameter of the patient's largest coronary vessel by 1.5 times. The prime cause of CAAs is atherosclerosis, and the most commonly affected artery is the right coronary artery. CAAs are quite commonly detected during X-ray coronary angiography. However, giant CAAs, especially with the diameter exceeding 100 mm, are extremely rare. The treatment method of choice of giant CAAs is the excision of aneurysm with coronary artery bypass grafting. We present a case of a 41-year-old apparently healthy woman with a giant right CAA. This was detected by noninvasive methods, including magnetic resonance coronary angiography, and its maximum diameter exceeded 100 mm. In emergency, the aneurysmal sac was excised and the aortocoronary saphenous vein graft was performed. We also present a review of the published studies of giant CAAs with the diameter exceeding 100 mm. PMID- 25811210 TI - Morbihan disease and extrafacial lupus miliaris disseminatus faceie: a case report. AB - Lupus miliaris disseminatus faciei (LMDF) is characterized by discrete dome shaped papules on the bilateral face and neck. We report the first case of LMDF with a widespread distribution of extrafacial papules and concomitant bilateral eyelid edema. A unique case of a 30-year-old man presented with nonpruritic, painless, papular eruptions (3-5 mm in diameter) involving the bilateral trunk and upper extremities, along with bilateral eyelid edema. There was no facial eruption involved. The outbreak initially involved the back, and gradually spread to the chest and wrists. The histologic examination of the eyelids revealed histiocytic epitheloid cells, dermal intercellular edema, and an expanded vascular space, which led to the diagnosis of Morbihan disease. The immunohistochemical staining of the truncal eruption revealed nodular inflammatory changes involving the middle to lower dermis around the follicles, containing histiocytes, multinucleated giant cells, and small lymphocytes. This led to the diagnosis of LMDF. The truncal papular eruption ultimately improved with roxithromycin treatment, but the eyelid edema required surgical treatment. PMID- 25811211 TI - First fully laparoscopic donor hepatectomy for pediatric liver transplantation using the indocyanine green near-infrared fluorescence imaging in the Middle East: a case report. AB - Living donor liver transplantation (LDLT) is a well-established treatment modality for several pediatric end-stage liver diseases owning excellent long term results. Left lateral sectionectomy (LLS) through an open approach is a well standardized procedure. This technique has been modified for a fully laparoscopic approach and gaining more and more interest worldwide. We report herein the first fully laparoscopic LLS for pediatric LDLT in the Middle East with the use of indocyanine green dye and near-infrared fluorescence imaging to identify the biliary ducts intraoperatively. The recipient was a 2-year-old girl affected by glycogen storage disease type IV. The mother, aged 21 years, was her donor. The surgical technique, key-points of this procedure, and outcome are hereby discussed. PMID- 25811212 TI - An uncommon organism in ascitic fluid. PMID- 25811213 TI - Acute necrotizing encephalopathy secondary to sepsis. PMID- 25811214 TI - Comment on fasting among Muslim cancer patients during the holy month of Ramadan. PMID- 25811215 TI - Reply: To PMID 22588434. AB - We thank the reader for his inter.est in our published manuscript.1 We agree that there is paucity of research on such subject "fasting and cancer" and the need for more research and different designs. Definitely, the two suggested questions are very valid and would add value to our findings. However, they were not planned as part of our assessment. As the study was conducted in 2009, it would be dif.ficult to perform accurate follow on questions to report patients experience following the end of Ramadan that dates five years back. This is more confounded by the study populations who are cancer patients and some of them had metastatic or poor prognosis dis.ease with very limited survival. A recently published article by Tas et al in the Japanese Journal of Clinical Oncology, may be helpful in this regard.2 It reports the experience in a different setting and a different country; Turkey. The suggested questions deserve to be part of any future research on the topic of "Fasting among Cancer patients during Ramadan". PMID- 25811216 TI - Re: the obstacles facing scientific and medical publishing in Saudi Arabia. PMID- 25811217 TI - Reply: To PMID 25266178. PMID- 25811219 TI - High seroprevalence of antibodies against spotted fever and scrub typhus bacteria in patients with febrile Illness, Kenya. AB - Serum samples from patients in Kenya with febrile illnesses were screened for antibodies against bacteria that cause spotted fever, typhus, and scrub typhus. Seroprevalence was 10% for spotted fever group, <1% for typhus group, and 5% for scrub typhus group. Results should help clinicians expand their list of differential diagnoses for undifferentiated fevers. PMID- 25811220 TI - A Non-inferiority Pilot Study Comparing the Clinical Efficacy and Safety of Generic Wide-spectrum Antibiotic Use in Septic Oncology Patients. AB - The present study is a non-inferiority study based on a descriptive and comparative case series for comparison of generic vs. original intravenous antimicrobials in septic oncology patients at an oncology private ICU. 1906 cancer patients admitted to Arturo Lopez Perez Foundation, Chile, were included in this study. After recruitment, a first retrospective group of 206 septic cancer patients recorded from 1st January, 2008 until July 14th, 2010, treated with original antibiotics (cefoperazone-sulbactam, imipenem-cilastatin, piperacillin-tazobactam) were included for analyses and a second prospective group of 143 septic cancer patients recorded from July 15th, 2010 until January 02, 2013, treated with the same but generic antibiotics were also included for comparisons. The trial protocol was developed in accordance with Helsinki and Good Clinical Practices recommendations. The results of this study showed no significant differences between the 2 groups in days of treatment, rate of success and lab test determinations (white cell count, PCR and procalcitonin), with lower, but not significant, total bed days and CPU bed days for generic antibiotics. Therefore, we conclude that the safety and efficacy of the generic antibiotics cefactam(r), imipen(r) and Piperazam(r) are not inferior to original antibiotics for the treatment of severe sepsis in hospitalised patients at the Arturo Lopez Perez Foundation. PMID- 25811221 TI - Global avian influenza surveillance in wild birds: a strategy to capture viral diversity. AB - Wild birds play a major role in the evolution, maintenance, and spread of avian influenza viruses. However, surveillance for these viruses in wild birds is sporadic, geographically biased, and often limited to the last outbreak virus. To identify opportunities to optimize wild bird surveillance for understanding viral diversity, we reviewed responses to a World Organisation for Animal Health administered survey, government reports to this organization, articles on Web of Knowledge, and the Influenza Research Database. At least 119 countries conducted avian influenza virus surveillance in wild birds during 2008-2013, but coordination and standardization was lacking among surveillance efforts, and most focused on limited subsets of influenza viruses. Given high financial and public health burdens of recent avian influenza outbreaks, we call for sustained, cost effective investments in locations with high avian influenza diversity in wild birds and efforts to promote standardized sampling, testing, and reporting methods, including full-genome sequencing and sharing of isolates with the scientific community. PMID- 25811222 TI - Nairobi sheep disease virus RNA in ixodid ticks, China, 2013. PMID- 25811223 TI - A room temperature nitric oxide gas sensor based on a copper-ion-doped polyaniline/tungsten oxide nanocomposite. AB - The parts-per-billion-level nitric oxide (NO) gas sensing capability of a copper ion-doped polyaniline/tungsten oxide nanocomposite (Cu(2+)/PANI/WO3) film coated on a Rayleigh surface acoustic wave device was investigated. The sensor developed in this study was sensitive to NO gas at room temperature in dry nitrogen. The surface morphology, dopant distribution, and electric properties were characterized using scanning electron microscopy, energy-dispersive X-ray spectroscopy mapping, and Hall effect measurements, respectively. The Cu(2+)/PANI/WO3 film exhibited high NO gas sensitivity and selectivity as well as long-term stability. At 1 ppb of NO, a signal with a frequency shift of 4.3 ppm and a signal-to-noise ratio of 17 was observed. The sensor exhibited distinct selectivity toward NO gas with no substantial response to O2, NH3 and CO2 gases. PMID- 25811224 TI - A floor-map-aided WiFi/pseudo-odometry integration algorithm for an indoor positioning system. AB - This paper proposes a scheme for indoor positioning by fusing floor map, WiFi and smartphone sensor data to provide meter-level positioning without additional infrastructure. A topology-constrained K nearest neighbor (KNN) algorithm based on a floor map layout provides the coordinates required to integrate WiFi data with pseudo-odometry (P-O) measurements simulated using a pedestrian dead reckoning (PDR) approach. One method of further improving the positioning accuracy is to use a more effective multi-threshold step detection algorithm, as proposed by the authors. The "go and back" phenomenon caused by incorrect matching of the reference points (RPs) of a WiFi algorithm is eliminated using an adaptive fading-factor-based extended Kalman filter (EKF), taking WiFi positioning coordinates, P-O measurements and fused heading angles as observations. The "cross-wall" problem is solved based on the development of a floor-map-aided particle filter algorithm by weighting the particles, thereby also eliminating the gross-error effects originating from WiFi or P-O measurements. The performance observed in a field experiment performed on the fourth floor of the School of Environmental Science and Spatial Informatics (SESSI) building on the China University of Mining and Technology (CUMT) campus confirms that the proposed scheme can reliably achieve meter-level positioning. PMID- 25811225 TI - Thermodynamic modeling and analysis of an optical electric-field sensor. AB - The stability of the optical electric field sensor (OEFS) in actual operation is affected by environmental factors such as temperature and SF6 (sulfur hexafluoride). To analyze the operational environment parameters affecting the optical properties of crystals, a thermodynamic model of the OEFS in which the optical properties of the crystal are changed by the first-order effects and the second-order effects was established. The intensity parameters such as electric, stress and temperature fields were introduced. The theoretical analysis results show that under temperature, stress and electric field conditions, the optical properties of the sensing crystals are no longer changed only by the electro optic effect, but also by the temperature and the stress fields. Further synthesis suggests the expected optical property changes under the effect of the environment fields. OEFS tests show that the accuracy of OEFS is dependent on temperature with a ratio error of -0.8%~1.5% in the temperature range from -25 degrees C to +40 degrees C. PMID- 25811226 TI - Informational analysis for compressive sampling in radar imaging. AB - Compressive sampling or compressed sensing (CS) works on the assumption of the sparsity or compressibility of the underlying signal, relies on the trans informational capability of the measurement matrix employed and the resultant measurements, operates with optimization-based algorithms for signal reconstruction and is thus able to complete data compression, while acquiring data, leading to sub-Nyquist sampling strategies that promote efficiency in data acquisition, while ensuring certain accuracy criteria. Information theory provides a framework complementary to classic CS theory for analyzing information mechanisms and for determining the necessary number of measurements in a CS environment, such as CS-radar, a radar sensor conceptualized or designed with CS principles and techniques. Despite increasing awareness of information-theoretic perspectives on CS-radar, reported research has been rare. This paper seeks to bridge the gap in the interdisciplinary area of CS, radar and information theory by analyzing information flows in CS-radar from sparse scenes to measurements and determining sub-Nyquist sampling rates necessary for scene reconstruction within certain distortion thresholds, given differing scene sparsity and average per sample signal-to-noise ratios (SNRs). Simulated studies were performed to complement and validate the information-theoretic analysis. The combined strategy proposed in this paper is valuable for information-theoretic orientated CS-radar system analysis and performance evaluation. PMID- 25811227 TI - Detection of abnormal events via optical flow feature analysis. AB - In this paper, a novel algorithm is proposed to detect abnormal events in video streams. The algorithm is based on the histogram of the optical flow orientation descriptor and the classification method. The details of the histogram of the optical flow orientation descriptor are illustrated for describing movement information of the global video frame or foreground frame. By combining one-class support vector machine and kernel principal component analysis methods, the abnormal events in the current frame can be detected after a learning period characterizing normal behaviors. The difference abnormal detection results are analyzed and explained. The proposed detection method is tested on benchmark datasets, then the experimental results show the effectiveness of the algorithm. PMID- 25811228 TI - Goal-directed multimodal locomotion through coupling between mechanical and attractor selection dynamics. AB - One of the most significant challenges in bio-inspired robotics is how to realize and take advantage of multimodal locomotion, which may help robots perform a variety of tasks adaptively in different environments. In order to address the challenge properly, it is important to notice that locomotion dynamics are the result of interactions between a particular internal control structure, the mechanical dynamics and the environment. From this perspective, this paper presents an approach to enable a robot to take advantage of its multiple locomotion modes by coupling the mechanical dynamics of the robot with an internal control structure known as an attractor selection model. The robot used is a curved-beam hopping robot; this robot, despite its simple actuation method, possesses rich and complex mechanical dynamics that are dependent on its interactions with the environment. Through dynamical coupling, we will show how this robot performs goal-directed locomotion by gracefully shifting between different locomotion modes regulated by sensory input, the robot's mechanical dynamics and an internally generated perturbation. The efficacy of the approach is validated and discussed based on the simulation and on real-world experiments. PMID- 25811229 TI - Pathogenicity of 2 porcine deltacoronavirus strains in gnotobiotic pigs. AB - To verify whether porcine deltacoronavirus infection induces disease, we inoculated gnotobiotic pigs with 2 virus strains (OH-FD22 and OH-FD100) identified by 2 specific reverse transcription PCRs. At 21-120 h postinoculation, pigs exhibited severe diarrhea, vomiting, fecal shedding of virus, and severe atrophic enteritis. These findings confirm that these 2 strains are enteropathogenic in pigs. PMID- 25811231 TI - Implications of ammonia emissions from post-combustion carbon capture for airborne particulate matter. AB - Amine scrubbing, a mature post-combustion carbon capture and storage (CCS) technology, could increase ambient concentrations of fine particulate matter (PM2.5) due to its ammonia emissions. To capture 2.0 Gt CO2/year, for example, it could emit 32 Gg NH3/year in the United States given current design targets or 15 times higher (480 Gg NH3/year) at rates typical of current pilot plants. Employing a chemical transport model, we found that the latter emission rate would cause an increase of 2.0 MUg PM2.5/m(3) in nonattainment areas during wintertime, which would be troublesome for PM2.5-burdened areas, and much lower increases during other seasons. Wintertime PM2.5 increases in nonattainment areas were fairly linear at a rate of 3.4 MUg PM2.5/m(3) per 1 Tg NH3, allowing these results to be applied to other CCS emissions scenarios. The PM2.5 impacts are modestly uncertain (+/-20%) depending on future emissions of SO2, NOx, and NH3. The public health costs of CCS NH3 emissions were valued at $31-68 per tonne CO2 captured, comparable to the social cost of carbon itself. Because the costs of solvent loss to CCS operators are lower than the social costs of CCS ammonia, there is a regulatory interest to limit ammonia emissions from CCS. PMID- 25811230 TI - Rapid Weight Loss Elicits Harmful Biochemical and Hormonal Responses in Mixed Martial Arts Athletes. AB - The purpose of this study was to compare biochemical and hormonal responses between mixed martial arts (MMA) competitors with minimal prefight weight loss and those undergoing rapid weight loss (RWL). Blood samples were taken from 17 MMA athletes (Mean+/- SD; age: 27.4 +/-5.3yr; body mass: 76.2 +/- 12.4kg; height: 1.71 +/- 0.05m and training experience: 39.4 +/- 25 months) before and after each match, according to the official events rules. The no rapid weight loss (NWL, n = 12) group weighed in on the day of the event (~30 min prior fight) and athletes declared not having used RWL strategies, while the RWL group (n = 5) weighed in 24 hr before the event and the athletes claimed to have lost 7.4 +/- 1.1kg, approximately 10% of their body mass in the week preceding the event. Results showed significant (p < .05) increases following fights, regardless of group, in lactate, glucose, lactate dehydrogenase (LDH), creatinine, and cortisol for all athletes. With regard to group differences, NWL had significantly (p < .05) greater creatinine levels (Mean+/- SD; pre to post) (NWL= 101.6 +/- 15-142.3 +/- 22.9MUmol/L and RWL= 68.9 +/- 10.6-79.5 +/- 15.9MUmol/L), while RWL had higher LDH (median [interquartile range]; pre to post) (NWL= 211.5[183-236] to 231[203 258]U/L and RWL= 390[370.5-443.5] to 488[463.5-540.5]U/L) and AST (NWL= 30[22-37] to 32[22-41]U/L and 39[32.5-76.5] to 72[38.5-112.5] U/L) values (NWL versus RWL, p < .05). Post hoc analysis showed that AST significantly increased in only the RWL group, while creatinine increased in only the NWL group. The practice of rapid weight loss showed a negative impact on energy availability and increased both muscle damage markers and catabolic expression in MMA fighters. PMID- 25811232 TI - Fruit and vegetable intake and urinary levels of prostaglandin E2 metabolite in postmenopausal women. AB - Prostaglandin E2 (PGE2) is an inflammatory mediator that plays key roles in promoting tumor development and progression. Urinary concentration of a major PGE2 metabolite (PGE-M) has been recently proposed as a promising cancer biomarker. Using dietary intake data from 600 postmenopausal women aged 50-74 years, we examined cross-sectional relationships between fruit and vegetable intake and urinary levels of PGE-M, determined using liquid chromatography/tandem mass spectrometry. After multivariable adjustment, increasing consumption of fruits, but not vegetables, was associated with reduced levels of urinary PGE-M (P for linear trend = 0.02), with geometric means of 5.8 [95% confidence interval (CI): 5.2-6.6] in the lowest quintile versus 4.8 (95% CI: 4.3-5.4) in the highest quintile (Q5) of fruit consumption. A better quality diet, indicated by higher scores on the Healthy Eating Index, was also associated with decreased PGE-M (P for linear trend <0.01). The lack of association with vegetable intake may be related to variation in antioxidant capacities of the major dietary sources of fruits and vegetables for the study participants. Our findings suggest that urinary PGE-M may be modifiable by a healthy diet that follows current national dietary guideline. Further studies are warranted to assess potential utility of urinary PGE-M in assessing cancer prevention efficacy. PMID- 25811234 TI - The Impact of Continuous and Interval Cycle Exercise on Affect and Enjoyment. AB - Rates of physical activity remain low despite public health efforts. One form of physical activity that provides significant physiological benefit but has not been evaluated in terms of affective and enjoyment responses is interval exercise. PURPOSE: The purpose of this study was to compare affect and enjoyment assessed before, during, and after interval and continuous exercise sessions. METHOD: Twenty-four participants (12 men, 12 women; body mass index = 24 +/- 4, maximal oxygen consumption = 41 +/- 5 mL/kg/min) completed a maximal cycle ergometer test used to prescribe experimental trials: (a) moderate continuous, (b) heavy continuous, (c) heavy interval, and (d) severe interval. All trials were 20 min in length, and all intervals utilized 60-s segments and a 1:1 work-to rest ratio. RESULTS: Affective and enjoyment responses were significantly less positive for the heavy continuous trials in comparison with all other trials during exercise (p < .05; ES = .2-.8). Additionally, both severe and heavy interval exercise were more enjoyable than heavy continuous exercise (p > .05). CONCLUSION: Findings suggest that interval protocols produce affective and enjoyment responses that are equal to moderate continuous exercise and more positive than heavy continuous exercise. These results indicate that interval based exercise may be a viable alternative to continuous exercise in the promotion of health and fitness. PMID- 25811235 TI - Effect of broiler breeder feeding programme and feeder space change at photostimulation using maize- or wheat-based diets on broiler progeny growth performance and leg health. AB - 1. The aim of this study was to evaluate the effects of diet type, maternal feeding programme at 29 weeks of age and breeder feeder space change at photostimulation on broiler progeny performance and leg health at 6 weeks of age. 2. Fast-feathering Cobb 500 broiler breeders were fed on either maize- or wheat based diets that had been formulated to have similar nutrient composition during growing and layer phases. Two feeding programmes, fast or flow, were used from 14 to 29 weeks of age. At 22 weeks, 69 females from each pen were placed in a layer house where feeder space was either similar to that in rearing (6.3 to 6.5 cm/female) or was increased from 6.3 to 8.4 cm/female. Eggs produced at 32 and 44 weeks of age were collected and incubated for two broiler experiments. A total of 16 male and 16 female one-d-old chicks were placed in floor pens in two experiments, respectively, with 6 and 4 replicate pens. Broiler gait scores and leg problem prevalence were evaluated at 6 weeks of age. 3. Data were analysed as a 2 * 2 * 2 factorial design with diet type, feeding programme and feeder space change as main factors. 4. The wheat diet increased the probability of observing crooked toes in broiler progeny compared to the use of maize, but only when breeders were fed according to the fast feeding programme and given similar feeder space as during rearing. 5. Breeders given more feeder space in the laying period produced progeny with more locomotion problems compared with those provided similar feeder space, but only when maize was used and the slow feeding programme was applied to the breeders. 6. The maternal feeding programme interacted with other factors to influence progeny leg health, but it did not solely influence walking ability or leg problems of progeny. 7. In conclusion, an increased probability of observing walking impairment of broiler progeny was detected when breeders were given greater feeder space at photostimulation rather than no change and fed according to the slow feeding programme using maize diets in breeders and progeny. PMID- 25811233 TI - Evidence for an Important Role of Smad-7 in Intervertebral Disc Degeneration. AB - Smad-7 inhibited the transforming growth factor beta (TGF-beta)-induced proteoglycan synthesis in chondrocytes and completely antagonized the effect of TGF-beta on the proliferation of the cells. The aim of this study was to evaluate the contribution of Smad-7 to the pathophysiology of disc degeneration by determining the expression of Smad-7 in the degenerative intervertebral discs and its effect on the extracellular matrix metabolism of disc cells. Instability of the lumbar spine produced by imbalanced dynamic and static forces was used to induce intervertebral disc degeneration in rats. The expression of Smad-7 was assessed by the immunohistochemical method. Disc cell apoptosis was detected by in situ TUNEL staining. The effect of Smad-7 overexpression on the matrix metabolism of disc cells was analyzed in vitro by real-time polymerase chain reaction (PCR) and Western blotting. Finally, intradiscal injection of the Smad-7 overexpression lentivirus was performed to evaluate the in vivo effect of Smad-7 on disc degeneration. Radiographic and histomorphological examinations showed that lumbar disc degeneration became more and more severe in the rats with induced instability. Immunohistochemical observation demonstrated increasing protein expression of Smad-7 in the degenerative discs. A significantly positive correlation was found between Smad-7 expression and the degree of disc degeneration and between Smad-7 expression and disc cell apoptosis. Overexpression of Smad-7 in disc cells inhibited the expression of TGF-beta1, collagen type-I, collagen type-II, and aggrecan and promoted the expression of MMP-13, but did not change the expression of ADAMTS-5. The in vivo findings illustrated that intradiscal injection of lentivirus vector with Smad-7 overexpression accelerated the progress of disc degeneration. In conclusion, Smad 7 was highly expressed in the degenerative discs. Overexpression of Smad-7 weakened the protective role of TGF-beta and accelerated the progress of disc degeneration. Interference on Smad-7 might be a potential therapeutic method for the prevention and treatment of degenerative disc diseases. PMID- 25811236 TI - Determination of the Ergot Alkaloid Ergovaline in Tall Fescue Seed and Straw Using a QuEChERS Extraction Method with High-Performance Liquid Chromatography Fluorescence Detection. AB - Ergovaline is an ergot alkaloid produced by the symbiotic endophyte Epichloe coenophiala, which can colonize varieties of the cool-season grass tall fescue (Festuca arundinacea). It is the principle toxicant responsible for the vasoconstrictive and reproductive sequelae seen in "fescue toxicosis" in livestock which consume forage exceeding the threshold of toxicity established for this compound. A new method for extraction of ergovaline from tall fescue seed and straw was optimized and validated, on the basis of the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method, with high-performance liquid chromatography-fluorescence detection. Fourteen extraction solvents were tested; 2.1 mM ammonium carbonate/acetonitrile (50/50, v/v) had the highest and most consistent recovery (91-101%). Linearity, limit of detection, limit of quantitation, accuracy,and intra- and interday precisions for tall fescue seed and straw were 100-3500 MUg/kg, 37 and 30 MUg/kg, 100 MUg/kg, 98%, 3.0 and 1.6%, and 3.8 and 1.0%, respectively. When the currently used solid-phase extraction (SPE) and QuEChERS methods were applied to 17 tall fescue straw samples, there was good agreement (correlation coefficient 0.9978). The QuEChERS method achieved the goals of eliminating chlorinated solvents and developing a fast, efficient, reliable method for quantitating ergovaline in tall fescue forage that can be applied in a high-throughput food safety laboratory. PMID- 25811237 TI - TLR4 at the Crossroads of Nutrients, Gut Microbiota, and Metabolic Inflammation. AB - Obesity is accompanied by the activation of low-grade inflammatory activity in metabolically relevant tissues. Studies have shown that obesity-associated insulin resistance results from the inflammatory targeting and inhibition of key proteins of the insulin-signaling pathway. At least three apparently distinct mechanisms-endoplasmic reticulum stress, toll-like receptor (TLR) 4 activation, and changes in gut microbiota-have been identified as triggers of obesity associated metabolic inflammation; thus, they are expected to represent potential targets for the treatment of obesity and its comorbidities. Here, we review the data that place TLR4 in the center of the events that connect the consumption of dietary fats with metabolic inflammation and insulin resistance. Changes in the gut microbiota can lead to reduced integrity of the intestinal barrier, leading to increased leakage of lipopolysaccharides and fatty acids, which can act upon TLR4 to activate systemic inflammation. Fatty acids can also trigger endoplasmic reticulum stress, which can be further stimulated by cross talk with active TLR4. Thus, the current data support a connection among the three main triggers of metabolic inflammation, and TLR4 emerges as a link among all of these mechanisms. PMID- 25811238 TI - Recognizing Potential Buprenorphine Medication Misuse: Product Packaging Does Not Degrade With Laundering. AB - BACKGROUND: Expanded office-based buprenorphine opioid dependence treatment is associated with medication misuse and diversion consequences. Recurrent early refill requests may indicate misuse or diversion, although further research is needed on how to effectively recognize and address the issue in clinical practice. In the current study, patient report of damaged medication from laundering prompted evaluation of laundering on degradation of buprenorphine containing product packages and contents. METHODS: Four buprenorphine product packaging approaches were assessed: 3 buprenorphine/naloxone placebo demonstration products (Suboxone and Bunavail film in foil wrappers and Zubsolv tablet in a blister pack) and Rexam-manufactured Screw-Loc closure pill container filled with a chewable aspirin as a surrogate for generic buprenorphine and buprenorphine/naloxone products. Two experimental laundering conditions, wash machine alone (W) and washer/dryer (W+D), were compared with unlaundered control (C) condition. Standard laundering settings were based on patient presentation. Products from the 2 experimental conditions and the control condition were labeled A, B, or C with counterbalanced assignment prior to visual examination of packaging and contents by the investigator who was blinded to condition. RESULTS: Packaging and contents remained intact for all products across experimental conditions, with only minor cosmetic effects compared with control. The W+D Suboxone film had 1-2 mm curling of the wrapper corners. Zubsolv blister packs had slight paper label fading (W+D > W). Bunavail W+D foil had an indentation outlining the inner film. The W+D bottle tablet had a ~1 mm nick on one edge. No other differences were noted. After implementing more structured treatment and reviewing the results with the patient, he endorsed fabricating the laundering story to get additional medication. CONCLUSIONS: Laundering is an unlikely cause of damaged buprenorphine-containing medication packaged in foil wrappers (Suboxone, Bunavail), blister pack (Zubsolv), or prescription pill bottle (generic buprenorphine or buprenorphine/naloxone products). Patient reports of such may indicate medication misuse or diversion. PMID- 25811242 TI - Effect of Pore Structure on CO2 Adsorption Characteristics of Aminopolymer Impregnated MCM-36. AB - The CO2 adsorption characteristics of a pillared 2-dimensional porous silicate material impregnated with amine containing polymers have been investigated. It was determined that the introduction of amine polymer deteriorates the CO2 capture kinetics of the MCM-36 supported amine adsorbents compared to that of the bare material, due to the fact that with the addition of a higher loading of amine polymer the diffusion of CO2 through the 2-dimensional interlayer mesoporous channels of MCM-36 becomes greatly hindered. This pore blocking sets an upper limit to the CO2 capture performance of the polymer impregnated MCM-36 and greatly reduces the utility of using this sort of amine-solid adsorbent for carbon capture. Interestingly, these results suggest that for 2-D channel solid supports there is an optimal amine loading which is not likely to be equal to the maximum loading, and which can be determined and utilized to obtain the maximum improvement over the original materials. The study performed in this work for the MCM-36 material could therefore be applied to other porous supports to determine these optimum loadings and be used to more easily compare and contrast the alterations to capture characteristics which occur upon amine loading for a wide range of materials. It is believed this will make it more straightforward to determine which solid supports hold the promise for greatly improved capture characteristics upon amine loading and allow the field to more quickly determine avenues for fruitful development. These results also suggest the need for a new sort of support structure for amine loaded solids, one which can allow us to decouple amine loading from increasing diffusion resistance so that high amine efficiency can be maintained throughout the range of increased amine loadings. PMID- 25811241 TI - Phosphorylation and Alternative Splicing of 7B2 Reduce Prohormone Convertase 2 Activation. AB - FAM20C is a secretory kinase responsible for the phosphorylation of multiple secreted proteins in mammalian cells; it has been shown to phosphorylate serine residues within a variety of different bone proteins. In this work we demonstrate that FAM20C also phosphorylates threonines, specifically those within the N terminal domain of the neuroendocrine chaperone 7B2. Analysis of the primary sequence of 7B2 revealed that three threonine residues in its N-terminal domain are located within FAM20C consensus motifs: Thr73, Thr99, and Thr111. The individual substitution of Thr73 and Thr111 residues by neutral alanines caused a marked decrease in the total phosphorylation of 7B2. Furthermore, the phosphomimetic substitution of Thr111 by Glu clearly diminished the ability of 7B2 to activate pro-prohormone convertase 2 (PC2) in 7B2-lacking SK-N-MC neuroblastoma cells, suggesting that the phosphorylation of this residue critically impacts the 7B2-proPC2 interaction. However, the phosphomimetic mutation did not alter 7B2's ability to function as an antiaggregant for human islet amyloid polypeptide. FAM20C-mediated phosphorylation of a common alternatively spliced variant of human 7B2 that lacks Ala100 (thus eliminating the Thr99 phosphorylation consensus site) was similar to the Ala-containing protein, but this variant did not activate proPC2 as efficiently as the Ala containing protein. Although threonines within 7B2 were phosphorylated efficiently, FAM20C was incapable of performing the well-known regulatory threonine phosphorylation of the molecular chaperone binding immunoglobulin protein. Taken together, these results indicate that FAM20C plays a role in 7B2 mediated proPC2 activation by phosphorylating residue Thr111; and that 7B2 function is regulated by alternative splicing. PMID- 25811244 TI - Comparing the energetic and dynamic contributions of solvent to very low barrier isomerization using dynamic steady-state vibrational spectroscopy. AB - We report the solvent-dependent dynamics of carbonyl site exchange for Fe(CO)3(eta(4)-norbornadiene) (FeNBD) in a series of linear and nonlinear alkanes. The barrier to exchange is very low (~1.5 kcal/mol), and the resulting carbonyl dynamics are rapid enough to lead to a change in the vibrational spectra, which we use to extract the ultrafast rates of exchange from linear Raman spectra of FeNBD. The dynamics of the carbonyl exchange has a weak dependence upon the solvent, and we analyze this dependence in terms of energetic (reaction field) and dynamic (Kramers theory) models of solvent effects. We find that both models can reproduce the observed solvent dependence but that the dynamic model provides a more physically satisfying picture for the solvent effects than does the energetic model. Finally, we find that cyclohexane is more strongly coupled to the dynamics of FeNBD than are the noncyclic alkanes. PMID- 25811243 TI - Influence of Gadoxetate Disodium on Oxygen Saturation and Heart Rate during Dynamic Contrast-enhanced MR Imaging. AB - PURPOSE: To investigate whether gadoxetate disodium affects peripheral capillary oxygen saturation (SpO2) and/or heart rate (HR) during dynamic contrast material enhanced (DCE) magnetic resonance (MR) imaging in patients with liver diseases. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, who waived the requirement for informed consent. Four hundred fifty eight patients (171 women [mean age, 66.5 years; range, 23-87 years] and 287 men [mean age, 61.1 years; range, 25-89 years]) who underwent liver DCE MR imaging with gadoxetate disodium (0.025 mmol per kilogram of body weight) from October 28, 2013, to June 24, 2014, were included in this study. They were monitored for SpO2 and HR during DCE MR imaging. Motion artifact severity was graded by using a five-point scale, and transient severe motion (TSM) was defined by a score of at least 4. The association between TSM and baseline predictors was assessed, and HR and SpO2 at each postcontrast phase were compared with those at the precontrast phase in the TSM and non-TSM groups. RESULTS: Four hundred thirty-six patients were included in the non-TSM group, and 22 were included in the TSM group. Although the motion score was the worst at the arterial phase, the observed mean differences in SpO2 and HR between the precontrast phase and the arterial phase were less than 1% and 5 beats per minute, respectively (mean SpO2 +/- standard deviation for the non-TSM group, 96.7% +/- 1.8 vs 96.9% +/- 1.8 [P = .11]; SpO2 for the TSM group, 96.4% +/- 1.6 vs 96.1% +/- 1.6 [P > .99]) (HR for the non-TSM group, 68.9 beats per minute +/- 12.4 vs 70.9 beats per minute +/- 12.1 [P < .0001]; HR for the TSM group, 75.0 beats per minute +/- 11.8 vs 79.9 beats per minute +/- 10.2 [P < .0001]). CONCLUSION: Intravenous gadoxetate disodium (a weight-based dose) does not cause changes in SpO2 and HR that lead to image quality degradation. PMID- 25811245 TI - Vibratory stimulation increases interleukin-1 beta secretion during orthodontic tooth movement. AB - OBJECTIVES: To investigate the effects of application of vibratory stimuli on interleukin (IL)-1beta secretion during maxillary canine distalization. MATERIALS AND METHODS: Split-mouth design study in 15 subjects (mean age, 22.9 years; range 19-25 years) whose bilateral maxillary first premolars were extracted with subsequent canine distalization. On the experimental side, light force (60 g) was applied to the canine for 3 months in combination with vibratory stimuli provided using an electric toothbrush 15 minutes a day for 2 months; only orthodontic force was applied to the contralateral control canine. Gingival crevicular fluid (GCF) was collected from the mesial and distal sides of each canine at each monthly appointment. IL-1beta levels were analyzed using an enzyme-linked immunosorbent assay. Canine movement was measured monthly. RESULTS: Overall, enhanced IL-1beta secretion was observed at the pressure sites of experimental canines compared to control canines (mean, 0.64 +/- 0.33 pg/uL vs 0.10 +/- 0.11 pg/uL, respectively, P < .001). The accumulative amount of tooth movement was greater for the experimental canine than for the control canine (mean, 2.85 +/- 0.17 mm vs 1.77 +/- 0.11 mm, respectively, P < .001). CONCLUSIONS: This study demonstrates that, in combination with light orthodontic force, application of vibratory stimuli using an electric toothbrush enhanced the secretion of IL-1beta in GCF and accelerated orthodontic tooth movement. PMID- 25811240 TI - Intestinal pregnane X receptor links xenobiotic exposure and hypercholesterolemia. AB - Recent studies have associated endocrine-disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease in humans, but the underlying mechanisms responsible for these associations remain elusive. Many EDCs have been implicated in activation of the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Here we report an important role of intestinal PXR in linking xenobiotic exposure and hyperlipidemia. We identified tributyl citrate (TBC), one of a large group of Food and Drug Administration-approved plasticizers for pharmaceutical or food applications, as a potent and selective PXR agonist. TBC efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Interestingly, TBC activated intestinal PXR but did not affect hepatic PXR activity. Exposure to TBC increased plasma total cholesterol and atherogenic low density lipoprotein cholesterol levels in wild-type mice, but not in PXR deficient mice. TBC-mediated PXR activation stimulated the expression of an essential cholesterol transporter, Niemann-Pick C1-like 1 (NPC1L1), in the intestine. Promoter analysis revealed a DR-4 type of PXR response element in the human NPC1L1 promoter, and TBC promoted PXR recruitment onto the NPC1L1 promoter. Consistently, TBC treatment significantly increased lipid uptake by human and murine intestinal cells and deficiency of PXR inhibited TBC-elicited lipid uptake. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating the adverse effects of EDCs on cardiovascular disease risk in humans. PMID- 25811246 TI - A multicenter randomized controlled trial to compare a self-ligating bracket with a conventional bracket in a UK population: Part 2: Pain perception. AB - OBJECTIVE: To compare pain experience between self-ligating and conventional preadjusted edgewise appliance systems with a two-arm parallel trial. MATERIALS AND METHODS: A prospective multicenter randomized controlled clinical trial was conducted in three hospital orthodontic departments. Subjects were randomly allocated to receive treatment with either a self-ligating (3M SmartClipTM) or conventional (3M VictoryTM) bracket system with stratification for operator and center. Standardized protocol was followed for bracket bonding procedure and archwire sequence. Subject pain was recorded using a Verbal Rating Scale to assess discomfort felt on the teeth and soft tissues at the time of the appointment and 1, 3, and 5 days after each archwire change up to the working archwire. Multilevel modeling was used to analyze the data by blinded assessors. RESULTS: One hundred thirty-eight subjects (mean age 14 years 11 months) were enrolled in the study, of which 135 subjects (97.8%) completed the study and 113 (82%) returned the required data regarding pain/discomfort. Perceived pain was statistically higher with the SmartClipTM system compared to the VictoryTM system, but this difference was not deemed to be clinically significant. Discomfort was greatest after placement of the initial 0.014-inch nickel-titanium archwire, compared with subsequent wires, and was greatest on day 1, less on day 3, and much less on day 5 after each archwire change. Age and gender did not affect the level of discomfort experienced by subjects undergoing fixed appliance treatment. CONCLUSION: No clinically significant difference in pain experience was found between patients treated with a self-ligating bracket system compared to those treated with a conventional ligation system. PMID- 25811247 TI - Characterizing the catecholamine content of single mammalian vesicles by collision-adsorption events at an electrode. AB - We present the electrochemical response to single adrenal chromaffin vesicles filled with catecholamine hormones as they are adsorbed and rupture on a 33 MUm diameter disk-shaped carbon electrode. The vesicles adsorb onto the electrode surface and sequentially spread out over the electrode surface, trapping their contents against the electrode. These contents are then oxidized, and a current (or amperometric) peak results from each vesicle that bursts. A large number of current transients associated with rupture of single vesicles (86%) are observed under the experimental conditions used, allowing us to quantify the vesicular catecholamine content. PMID- 25811248 TI - Facile synthesis of pure 1,6,7,12-tetrachloroperylene-3,4,9,10-tetracarboxy bisanhydride and bisimide. AB - A robust and scalable procedure to obtain pure 1,6,7,12-tetrachloroperylene 3,4,9,10-tetracarboxy bisanhydride, a highly valuable synthon, has been developed via synthesis of a novel intermediate compound 1,6,7,12-perylene-3,4,9,10 tetracarboxy tetrabutylester. PMID- 25811249 TI - Increasing prehospital emergency medical service interventions for nursing home residents. AB - QUESTION: In the ageing European population, the proportion of interventions by the emergency medical services (EMS) for elderly patients is increasing, but little is known about the recent trend of EMS interventions in nursing homes. The aim of this analysis was to describe the evolution of the incidence of requests for prehospital EMS interventions for nursing home residents aged 65 years and over between 2004 and 2013. METHODS: A prospective population-based register of routinely collected data for each EMS intervention in the Canton of Vaud. Linear time trends of incidence of requests to the EMS in nursing homes were calculated and stratified by age categories. RESULTS: The number of ambulance interventions in nursing homes for people aged 65 years and over (65+) increased by 68.9% (1124 1898) between 2004 and 2013. A significant linear increase of the annual incidence of requests to EMS per 1,000 nursing home residents was found for people aged 65-79 (10.2, 95% confidence interval [CI] 6.2-14.2), 80-89 (16.5, 95% CI 14.0-19.0) and over 90 (12.1, 95% CI 5.8-18.4). EMS interventions in nursing home residents who required an emergency physician increased during the same period by 205.6% (from 106 to 324), representing an increase from 2% to 7% of all emergency physician interventions in the Canton. CONCLUSIONS: Our results confirmed an important increase in the incidence of EMS interventions in nursing homes during the last decade, far exceeding the actual increase of the nursing home population during the same period. This evolution represents an important opportunity to reconsider the EMS missions in the context of an ageing society. PMID- 25811250 TI - ORS interview with John Kwasniewski. PMID- 25811251 TI - Managing children during a radiological or nuclear emergency--Canadian perspectives. AB - Children have a higher chance of being contaminated by radioactive materials during a radiological or nuclear (RN) emergency. They are more sensitive to radiation health effects and suffer more significant psychosocial impacts than adults during emergency response. This paper presents a summary of recommendations on effective management of children during an RN emergency. These recommendations intend to be additional considerations for existing RN response protocols and procedures implemented at local, state/provincial, or national level. PMID- 25811252 TI - Normalization of energy-dependent gamma survey data. AB - Instruments and methods for normalization of energy-dependent gamma radiation survey data to a less energy-dependent basis of measurement are evaluated based on relevant field data collected at 15 different sites across the western United States along with a site in Mongolia. Normalization performance is assessed relative to measurements with a high-pressure ionization chamber (HPIC) due to its "flat" energy response and accurate measurement of the true exposure rate from both cosmic and terrestrial radiation. While analytically ideal for normalization applications, cost and practicality disadvantages have increased demand for alternatives to the HPIC. Regression analysis on paired measurements between energy-dependent sodium iodide (NaI) scintillation detectors (5-cm by 5 cm crystal dimensions) and the HPIC revealed highly consistent relationships among sites not previously impacted by radiological contamination (natural sites). A resulting generalized data normalization factor based on the average sensitivity of NaI detectors to naturally occurring terrestrial radiation (0.56 nGy hHPIC per nGy hNaI), combined with the calculated site-specific estimate of cosmic radiation, produced reasonably accurate predictions of HPIC readings at natural sites. Normalization against two to potential alternative instruments (a tissue-equivalent plastic scintillator and energy-compensated NaI detector) did not perform better than the sensitivity adjustment approach at natural sites. Each approach produced unreliable estimates of HPIC readings at radiologically impacted sites, though normalization against the plastic scintillator or energy compensated NaI detector can address incompatibilities between different energy dependent instruments with respect to estimation of soil radionuclide levels. The appropriate data normalization method depends on the nature of the site, expected duration of the project, survey objectives, and considerations of cost and practicality. PMID- 25811253 TI - Techniques to alleviate nuisance alarms observed by PCMs following 222Rn-progeny deposition on clothing. AB - This paper presents technically-based techniques to deal with nuisance personnel contamination monitor (PCM) alarms. The techniques derive from the fundamental physical characteristics of radon progeny. Some PCM alarms, although valid alarms and not actually "false," could be due to nuisance naturally-occurring radionuclides (i.e., radon progeny). Based on certain observed characteristics of the radon progeny, several prompt techniques are discussed that could either remediate or at least mitigate the problem of nuisance alarms. Examples are provided which demonstrate the effective use of the techniques. PMID- 25811254 TI - Shielding analysis of proton therapy accelerators: a demonstration using Monte Carlo-generated source terms and attenuation lengths. AB - Monte Carlo simulations are generally considered the most accurate method for complex accelerator shielding analysis. Simplified models based on point-source line-of-sight approximation are often preferable in practice because they are intuitive and easy to use. A set of shielding data, including source terms and attenuation lengths for several common targets (iron, graphite, tissue, and copper) and shielding materials (concrete, iron, and lead) were generated by performing Monte Carlo simulations for 100-300 MeV protons. Possible applications and a proper use of the data set were demonstrated through a practical case study, in which shielding analysis on a typical proton treatment room was conducted. A thorough and consistent comparison between the predictions of our point-source line-of-sight model and those obtained by Monte Carlo simulations for a 360 degrees dose distribution around the room perimeter showed that the data set can yield fairly accurate or conservative estimates for the transmitted doses, except for those near the maze exit. In addition, this study demonstrated that appropriate coupling between the generated source term and empirical formulae for radiation streaming can be used to predict a reasonable dose distribution along the maze. This case study proved the effectiveness and advantage of applying the data set to a quick shielding design and dose evaluation for proton therapy accelerators. PMID- 25811255 TI - Precision of measurements with arbitrary confidence levels when samples are counted equal to or longer than blanks by computer codes. AB - Past computer solutions for confidence intervals, both in paired counting and when the sample is counted an integer number of times more than the blank, are extended to computing the precision of the measurement. The blank count and the contribution of the sample to the gross count are assumed to be Poisson distributed. While the standard deviation and the probability density function of the net count are readily computed, the name and properties of the probability density function are unknown. Hence, the uncertainty of the net count is unknown. However, both the upper and lower confidence limits, at a given confidence level, can be computed. In general, the difference between the upper limit and the observed net count is greater than the difference between the observed net count and the lower confidence limit. So the bound on the uncertainty is taken to be the difference between the upper confidence limit and the observed net count. Then the precision can be taken to be the bound on the uncertainty divided by the observed net count (relative bound on the uncertainty). PMID- 25811256 TI - Ovarian hyperstimulation syndrome in the 21st century: the role of gonadotropin releasing hormone agonist trigger and kisspeptin. AB - PURPOSE OF REVIEW: Ovarian hyperstimulation syndrome (OHSS) complicates a considerable part of stimulated in-vitro fertilization (IVF) cycles and is a potential iatrogenic cause of death in otherwise healthy women undergoing fertility treatment. The triggering factor of OHSS is the widespread use of human chorionic gonadotropin (hCG) to induce final oocyte maturation. The aim of this review is to summarize different approaches available, using alternative triggering protocols such as gonadotropin-releasing hormone agonist (GnRHa) or kisspeptin for final oocyte maturation. RECENT FINDINGS: According to the latest European Society of Human Reproduction and Embryology report, the incidence of OHSS ranges from 0.18 to 1.40% in European countries. However, OHSS is still subject to substantial underreporting. New triggering protocols using GnRHa have shown to be similar to the gold standard hCG-trigger with regard to the reproductive outcome, but with a significant decrease in - and almost elimination of - OHSS. Lately, promising results have been reported for the use of kisspeptin to induce final oocyte maturation. Although until now no study has been performed in an OHSS risk population, theoretically, the risk of OHSS development might be even further reduced after kisspeptin trigger. SUMMARY: GnRHa trigger is currently the best tool we have to prevent OHSS and at the same time maintain good reproductive outcomes. Future research will explore the safety and efficacy of kisspeptin trigger. PMID- 25811257 TI - Significance of premature progesterone rise in IVF. AB - PURPOSE OF REVIEW: The current review will focus on the cause of premature progesterone and its impact on endometrial receptivity and endometrial gene expression. RECENT FINDINGS: Premature progesterone rise in stimulated IVF cycles seems to have a negative impact on the pregnancy rate. The current knowledge on the cause of a premature progesterone rise is still limited; however, it seems that overstimulating the ovaries during the end of the follicular phase will lead to a premature progesterone rise. The negative impact on the outcome is mainly due to reduced endometrial receptivity as can be seen in the altered endometrial gene expression. SUMMARY: Future studies should focus on how ovarian stimulation can be tailored according to individual requirements of the patients, aiming on preventing a possible progesterone rise during follicular phase of stimulated IVF cycles. PMID- 25811258 TI - Ovarian tissue freezing: current status. AB - PURPOSE OF REVIEW: This article aims to carefully evaluate a number of critical points related to ovarian tissue freezing and presents factual data in terms of live birth rates and risks. RECENT FINDINGS: Reimplantation of frozen-thawed ovarian tissue remains an experimental procedure according to the American Society for Reproductive Medicine, despite almost 40 live births reported in the literature. Recent literature on the topic has focused on the risk of reimplanting malignant cells, so the present review assesses the risks according to disease. SUMMARY: This manuscript emphasizes the crucial importance of not only preserving fertility in young women but also clearly explaining to patients the different available options and their respective success rates. Some previously published reviews have reported inaccurate reimplantation success rates. In this review, we report the true picture, with a live birth rate of 25%. Ovarian tissue freezing may be combined with pickup of immature oocytes (at the time of ovarian biopsy and tissue removal) or mature oocytes (if chemotherapy can be delayed). PMID- 25811259 TI - Infusion system carrier flow perturbations and dead-volume: large effects on drug delivery in vitro and hemodynamic responses in a swine model. AB - BACKGROUND: We have previously shown that, at constant carrier flow, drug infusion systems with large dead-volumes (V) slow the time to steady-state drug delivery in vitro and pharmacodynamic effect in vivo compared to those with smaller V. In this study, we tested whether clinically relevant alterations in carrier flow generate perturbations in drug delivery and pharmacodynamic effect, and how these might be magnified when V is large. METHODS: Drug delivery in vitro or mean arterial blood pressure (MAP) and ventricular contractility (max dP/dt) in a swine model were quantified during an infusion of norepinephrine (fixed rate 3 mL/h) with a crystalloid carrier (10 mL/h). The carrier flow was transiently halted for either 10 minutes or 20 minutes and then restarted. In separate experiments, a second drug infusion (50 mL over 10 minutes) was introduced into the same catheter lumen used by a steady-state norepinephrine infusion. The resulting perturbations in drug delivery and biologic effect were compared between drug infusion systems with large and small V. RESULTS: Halting carrier flow immediately decreased drug delivery in vitro, and MAP and max dP/dt. These returned to steady state before restarting carrier flow with the small, but not the large, V. Resuming carrier flow after 10 minutes resulted in a transient increase in drug delivery in vitro and max dP/dt in vivo, which were of longer duration and greater area under the curve (AUC) for larger V. MAP also increased for longer duration for larger V. Resuming the carrier flow after 20 minutes resulted in greater AUCs for drug delivery, MAP, and max dP/dt for the larger V. Adding a second infusion to a steady-state norepinephrine plus carrier flow initially resulted in a drug bolus in vitro and augmented contractility response in vivo, both greater with a larger V. Steady-state drug delivery resumed before the secondary infusion finished. After the end of the secondary infusion drug delivery, MAP and max dP/dt decreased over minutes. Drug delivery and max dP/dt returned to steady state more quickly with the small V. CONCLUSIONS: Stopping and resuming a carrier flow, or introducing a second medication infusion, impacts drug delivery in vitro and biologic response in vivo. Infusion systems with small dead-volumes minimize these perturbations and dampen the resulting hemodynamic instability. Alterations in carrier flow impact drug delivery, resulting in substantial effects on physiologic responses. Therefore, infusion systems for vasoactive drugs should be configured with small V when possible. PMID- 25811260 TI - What's New in Obstetric Anesthesia: The 2014 Gerard W. Ostheimer Lecture. PMID- 25811261 TI - Results of the 2014 SRS Survey on PJK/PJF: A Report on Variation of Select SRS Member Practice Patterns, Treatment Indications, and Opinions on Classification Development. AB - STUDY DESIGN: An electronic survey administered to Scoliosis Research Society membership. OBJECTIVE: To characterize surgeon views regarding proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) management providing the framework in which a PJK/PJF classification system and treatment guidelines could be established. SUMMARY OF BACKGROUND DATA: PJK/PJF are common complications of adult spinal deformity surgery. To date, there is no consensus on PJK/PJF definitions, classification, and indications for revision surgery. There is a paucity of data on deformity surgeon practice pattern variations and consensus opinion on treatment and prevention. METHODS: An electronic 19-question survey regarding PJK/PJF was administered to members of the Scoliosis Research Society who treat adult spinal deformity. Determinants included the surgeons' type of practice, number of years in practice, agreement with given PJK/PJF definitions, importance of key factors influencing prevention and revision, prevention methods currently used, and the importance of developing a classification system. RESULTS: A total of 226 surgeons responded (38.8% response rate). Both 44.4% of surgeons selected "extremely important" and 40.8% selected "very important" that PJK in adult spinal deformity surgery is a very important issue and that a Scoliosis Research Society PJK/PJF classification system and guidelines for detection and prevention of PJK/PJF is a "must have" (18.1%) and "very likely helpful" (31.9%). Both 86.2% and 90.7% of surgeons agreed with the provided definitions of PJK and PJF, respectively. Top 5 revision indications included neurological deficit, severe focal pain, translation or subluxation fracture, a change in kyphosis angle of greater than 30 degrees , chance fracture, spondylolisthesis greater than 6 mm, and instrumentation prominence. The majority of respondents use a PJK/PJF prevention strategy 60% of the time or more, the most common were terminal rod contour, preoperative bone mineral density testing, and frequent radiographical studies during first 3 months postoperative, preoperative bone mineral density medication for low bone mineral density. CONCLUSION: The results of this study provide insight from the practicing surgeons' perspective of the management of PJK and PJF that may aid in the validation of current definitions and consensus-based treatment decisions and prevention guidelines. LEVEL OF EVIDENCE: 5. PMID- 25811262 TI - Easy to Harm, Hard to Heal: Patient Views About the Back. AB - STUDY DESIGN: Qualitative interview study. OBJECTIVE: Explore attitudes, beliefs, and perceptions related to low back pain (LBP) and analyze how these might influence the perceived threat associated with back pain. SUMMARY OF BACKGROUND DATA: Psychological factors that contribute to the perceived threat associated with LBP play an important role in back pain development and the progression to persistent pain and disability. Improved understanding of underlying beliefs may assist clinicians to investigate and assess these factors. METHODS: Semistructured qualitative interviews were conducted with 12 participants with acute LBP (<6-wk duration) and 11 participants with chronic LBP (>3 mo duration). Data were analyzed thematically using the framework of Interpretive Description. RESULTS: The back was viewed as being vulnerable to injury due to its design, the way in which it is used, and personal physical traits or previous injury. Consequently, participants considered that they needed to protect their back by resting, being careful with or avoiding dangerous activities, and strengthening muscles or controlling posture. Participants considered LBP to be special in its nature and impact, and they thought it difficult to understand without personal experience. The prognosis of LBP was considered uncertain by those with acute pain and poor by those with chronic pain. These beliefs combined to create a negative (mis)representation of the back. CONCLUSION: Negative assumptions about the back made by those with LBP may affect information processing during an episode of pain. This may result in attentional bias toward information indicating that the spine is vulnerable, an injury is serious, or the outcome will be poor. Approaching consultations with this understanding may assist clinicians to have a positive influence on beliefs. LEVEL OF EVIDENCE: 3. PMID- 25811263 TI - A Novel Quality-of-Life Utility Index in Patients With Multilevel Cervical Degenerative Disc Disease: Comparison of Anterior Cervical Discectomy and Fusion With Total Disc Replacement. AB - STUDY DESIGN: Decision analysis from prior randomized controlled trial (RCT) data. OBJECTIVE: To describe the importance of developing baseline utility indices while identifying effective treatment options for cervical spine disease. SUMMARY OF BACKGROUND DATA: Cervical total disc replacement (CTDR) was developed to treat cervical spondylosis while preserving motion. Although anterior cervical discectomy and fusion (ACDF) has been the standard of care, a recent RCT suggested similar outcomes for 2-level disease. The quality-of-life benefit afforded by both CTDR and ACDF has never been fully elucidated. The purpose of our investigation was to better define the changes in utility and perceived value for patients undergoing these procedures. METHODS: Data were derived from LDR's RCT comparing CTDR and ACDF for 2-level cervical disc disease. Using linear regression, we constructed health states on the basis of the stratification of clinical outcomes used in the RCT, namely, neck disability index and visual analogue scale. Data from SF-12 questionnaires, completed preoperatively and at each follow-up visit, were transformed into utilities using the SF-6D mapping algorithm. SAS v.9.3 was used for the analyses. RESULTS: A strong correlation (R = 0.6864, P < 0.0001) was found between neck disability index and visual analogue scale. We constructed 5 distinct health states by projecting neck disability index intervals onto visual analogue scale. A poorer health state was associated with a lower mean utility value whereas a higher health state was associated with a higher mean utility value (P < 0.0001). The difference in preoperative utility between 2-level ACDF and CTDR was not significant (P = 0.1982), and yet, the difference in the postoperative utility between the cohorts was significant (P < 0.05) at every time point collected from 6 to 60 months. CONCLUSION: This is the first instance in which distinct utility values have been derived for validated health states related to cervical spine disease. There is substantial potential for these to become baseline future indices for cost-utility analyses in similar populations. LEVEL OF EVIDENCE: 1. PMID- 25811264 TI - Magnetic Resonance Neurography of the Lumbar Plexus at the L4-L5 Disc: Development of a Preoperative Surgical Planning Tool for Lateral Lumbar Transpsoas Interbody Fusion (LLIF). AB - STUDY DESIGN: Observational study. OBJECTIVE: To demonstrate use of magnetic resonance (MR) neurography to visualize the course of the lumbar plexus at the L4 L5 disc space. SUMMARY OF BACKGROUND DATA: Risk of injury to the lumbar plexus during lateral transpsoas approach for lumbar interbody fusion (LLIF) is significant. We describe a new technique for preoperative mapping using magnetic resonance neurography to directly visualize the course of the plexus relative to the L4-L5 disc space. METHODS: Consecutive lumbar plexus MR neurograms (n=35 patients, 70 sides) were studied. Scans were obtained on a Siemens 3-Tesla Skyra magnetic resonance imaging scanner. T1- and T2-color-coded fusion maps were generated along with 3-dimensional models of the lumbosacral plexus with attention to the L4-L5 interspace. The position of the plexus and the shape of the psoas muscle at the L4-L5 interspace were evaluated and recorded. RESULTS: Direct imaging of the lumbar plexus using MR neurography revealed a substantial variability in the position of the lumbar plexus relative to the L4-L5 disc space. The left-side plexus was identified in zone 2 (5.7%), zone 3 (54.3%), and zone 4 (40%) (P = 0.0014); on the right, zone 2 (8.6%), zone 3 (42.9%) or zone 4 (45.7%), and zone 5 (2.9%) (P = 0.01). Right-left symmetry was found in 18 of 35 subjects (51.4%) (P = 0.865). There was no association between the position of the plexus and the shape of the overlying psoas muscle identified. In patients with an elevated psoas (n = 12), the lumbar plexus was identified in zone 3 in 75% and 66% (left and right) compared with patients without psoas elevation (n = 23), 30.4% and 43.5% (left and right). CONCLUSION: The course of the lumbosacral plexus traversing the L4-L5 disc space may be more variable than has been suggested by previous studies. Magnetic resonance neurography may provide a more reliable means of preoperatively identifying the plexus when compared with current methods. LEVEL OF EVIDENCE: 3. PMID- 25811265 TI - Investigation of the 53 Markers in a DNA-Based Prognostic Test Revealing New Predisposition Genes for Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A genetic association study of 53 single nucleotide polymorphisms (SNPs) with adolescent idiopathic scoliosis (AIS). OBJECTIVE: To explore new predisposition genes of AIS in Chinese Han population SUMMARY OF BACKGROUND DATA.: A panel of 53 SNPs were reported to be associated with curve severity of AIS. However, there is still a lack of knowledge concerning the association of these SNPs with the susceptibility of AIS in the Chinese Han population. METHODS: A gene-based association study was conducted by genotyping the 53 SNPs of a prognostic test. DNA samples of 990 female patients with AIS and 1188 age-matched healthy controls were analyzed using the polymerase chain reaction-based Invader assay. The chi test was carried out to compare the differences of genotype and allele distributions between patients with AIS and healthy controls. RESULTS: A total of 4 SNPs were found to present significant differences in allele or genotype frequencies between the 2 groups. Compared with normal controls, patients were found to have significantly higher allele G of rs12618119 and allele A of rs9945359. Besides, patients were found to have significantly lower allele T of rs4661748 and allele C of rs4782809 than the normal controls. BIN1, CDH13, SETBP1, and SPATA21 genes could be associated with the susceptibility of AIS. CONCLUSION: Four new predisposition genes of AIS were identified on the basis of a large-scale case-control study. Putting all these findings together, it suggests that AIS is a multifactorial disease possibly involving different pathways such as development of central neural system and bone formation. Further studies exploring more predisposition gene are essential to illustrate the etiology of AIS and to guide the prevention or prognosis of the disease. LEVEL OF EVIDENCE: 3. PMID- 25811267 TI - Clinical discovery enhances clinical care. PMID- 25811266 TI - The Evaluation of Digital Rectal Examination for Assessment of Anal Tone in Suspected Cauda Equina Syndrome. AB - STUDY DESIGN: Seventy-five doctors completed a questionnaire documenting their grade, specialty, and experience in performing digital rectal examination (DRE). A model anus, using a pressure transducer surrounding an artificial canal, was assembled and calibrated. Participants performed 4 DREs on the model (with a break between attempts) and predicted tone as "reduced" or "normal" (35 and 60 mm Hg, respectively), followed by a "squeeze" test. Thirty health care assistants partook as a control group with no training in DRE. OBJECTIVE: Our main objective was to investigate the validity of digital rectal examination (DRE) for assessment of anal tone. SUMMARY OF BACKGROUND DATA: Cauda equina syndrome represents the constellation of symptoms and signs resulting from compression of lumbrosacral nerve routes. Combined with subjective neurological findings, a reduction in anal tone is an important sign, deeming further imaging necessary. DRE is an invasive procedure used to assess anal tone despite debated accuracy. METHODS: A total of 75 doctors from various specialties were asked to fill in a questionnaire detailing their grade, age, and area of expertise. In addition, information was gathered with regard to prior training in performing DRE to assess anal tone and the importance placed on any findings. Thirty hospital health care assistants (HCAs) were used as a control group. HCAs were selected as a control group because they receive no training on the technique and would never be required to perform it in their clinical practice. A model anus was assembled using a modified pediatric sphygmomanometer cuff to act as a sphincter. The cuff could be inflated to simulate a full range of anal tone. The cuff was incorporated into an artificial anal canal, which was, in turn, placed into a model buttock created from plaster of Paris. The apparatus was calibrated across a range of pressures. RESULTS: In each attempt, 60%, 61%, 63%, and 67% of doctors correctly identified the anal tone, respectively (average accuracy: 64%). HCAs had an identical average accuracy of 64%. All participants (100%) were able to correctly identify the squeeze test. For doctors, no correlation was found between confidence in assessing anal tone using DRE and a correct result. Seventy one percent had received previous training in DRE, with 64% of these taught how to assess anal tone. Forty-three percent of doctors thought that further training would be beneficial. CONCLUSION: The results demonstrate that accuracy in assessing anal tone using DRE is limited, with overall correctness of 64%. Poor correlation exists between perceived level of skill and study result. Doctors were not significantly more able than HCAs to detect correct tone. Therefore, DRE for the assessment of anal tone is not a wholly accurate tool. A squeeze test may be of greater value if interpreted correctly. LEVEL OF EVIDENCE: 4. PMID- 25811268 TI - Optic disc drusen associated with optic nerve tumors. AB - PURPOSE: To propose a theory based on clinical observation, namely, whether axonal distress induced by optic nerve tumors could be a triggering factor for optic disc drusen (ODD) formation. CASE REPORTS: A 28-year-old woman with ODD and optic disc melanocytoma, a 53-year-old woman with ODD and optic nerve meningioma, and a 29-year-old woman with ODD and optic nerve glioma underwent comprehensive ophthalmologic examinations including spectral-domain optical coherence tomography, swept-source optical coherence tomography, visual field tests, color vision tests, and complete neurologic examinations including brain magnetic resonance imaging. In two cases, unilateral ODD existed on the same side of optic nerve tumors. In the bilateral case, the nerve that contained the tumor had ODD that were located more deeply and on both nasal and temporal sides of the optic nerve compared with the contralateral eye. In two cases, optic disc edema (ODE) was also present, and ODD persisted after ODE resolved. CONCLUSIONS: Optic nerve tumors can trigger the formation of ODD, which suggests that ODD pathogenesis involves axonal flow distress in the optic nerve. The presence of asymmetric ODD and ODE may indicate the presence of an optic nerve tumor. PMID- 25811269 TI - Adopting an external focus of attention improves sprinting performance in low skilled sprinters. AB - For more than 10 years, researchers have investigated how the focusing of conscious attention influences motor skill execution. This line of investigation has consistently demonstrated that directing attention externally rather than internally improves motor skill learning and performance. The purpose of this study was to test the prediction that participants completing a 20-m sprint would run significantly faster when using an external focus of attention rather than an internal or no-focus of attention. Participants were college-aged volunteers (N = 84; 42 women, 42 men; mean age = 20.32, SD = 1.73 years) with no prior sprint training. This study used a counterbalanced within-participant design. Each participant completed 3 days of testing, with each day utilizing a different focus of attention (i.e. internal, external, or control). Running times were collected automatically using infrared timing gates. Data were analyzed using a 1 way repeated measures analysis of variance (ANOVA). The results of the ANOVA revealed a significant main effect for condition, F (1, 83) = 6565.3, p <= 0.001. Follow-up analysis indicated that the trials completed in the external focus condition (mean = 3.75 seconds, SD = 0.43) were significantly faster than trials completed in the internal (mean = 3.87 seconds, SD = 0.64) and control conditions (mean = 3.87 seconds, SD = 0.45). The analysis also indicated that the control and internal conditions were not significantly different. The results of this study extend the findings of previous research and demonstrate sprinting performance can be improved by using an external focus of attention. PMID- 25811270 TI - Religion-related factors and cervical cancer screening. PMID- 25811271 TI - Response to Yasri, "Associations between religion-related factors and cervical cancer screening among Muslims in Greater Chicago." J Low Genit Tract Dis. 2014 June 9. [E-pub ahead of print]. PMID- 25811272 TI - Letter to the editor regarding "Evaluation of a cervicography-based program to ensure quality of visual inspection of the cervix in HIV-infected women in Johannesburg, South Africa" by Firnhaber et al. PMID- 25811273 TI - Correspondence to "Evaluation of a cervicography-based program to ensure quality of visual inspection of the cervix in HIV-infected women in Johannesburg, South Africa". PMID- 25811274 TI - Reply to letter to the editor by Sue J. Goldie and Phil E. Castle regarding Evaluation of a cervicography-based program to ensure visual inspection of the cervix in HIV-infected women in Johannesburg, South Africa by Firnhaber et al. PMID- 25811275 TI - Reply to comment letter by Dr Jose Jeronimo and Dr Vivian Tsu, J Low Genit Tract Dis 10-1599. PMID- 25811276 TI - LAST terminology applied to the vulva: the challenge of VIN continues. PMID- 25811277 TI - Microscopic techniques and quantitative real-time PCR for the diagnosis of vaginal microflora alterations. PMID- 25811278 TI - Reply: letter to the editor on Sim's "Microscopic techniques and quantitative real-time PCR for the diagnosis of vaginal microflora alterations". PMID- 25811279 TI - Labioplasty specimens: when should pathological findings be considered as abnormal? PMID- 25811280 TI - Reply to Scurry et al.: vulvar lymphangiectasis, an indicator of lymph stasis, is an authentic sign of abnormal histopathology in labiaplasty specimens. PMID- 25811281 TI - Laser vaporization of VAIN. A word of caution. PMID- 25811282 TI - Reply to Dr. Jones's comment on "Use of CO2 laser vaporization for the treatment of high-grade vaginal intraepithelial neoplasia". PMID- 25811283 TI - Relative Intensity Correction of Raman Systems with National Institute of Standards and Technology Standard Reference Material 2242 in 90 degrees Scattering Geometry. AB - The U.S. National Institute of Standards and Technology (NIST) has certified a set of Standard Reference Materials (SRMs) that can be used to accurately determine the spectral sensitivity of Raman spectrometers. These solid-state reference sources offer benefits such as exact reproduction of Raman sampling geometry, simple implementation, and long-term stability. However, a serious drawback of these SRMs is that they are certified only in the backscattering (180 degrees ) configuration. In this study, we investigated if and how SRM 2242 (applicable for 532 nm) can be employed in a 90 degrees -scattering geometry Raman system. We found that the measurement procedure needs to be modified to comply with the certified uncertainty provided by NIST. This requires a change in the SRM illumination that is possible only if we polish the side surfaces. In addition, we need to account for the polarization configuration of the Raman system by choosing the appropriate polarization of the excitation beam. On top of that, the spatial inhomogeneity of the luminescence light needs to be taken into account, as well as its behavior while traveling through the SRM bulk. Finally, we show in a round-robin test that the resulting uncertainty for the quantification of Raman spectra using the modified technique is on the order of +/-1.5 percentage points. PMID- 25811284 TI - Population structure and antimicrobial resistance of invasive serotype IV group B Streptococcus, Toronto, Ontario, Canada. AB - We recently showed that 37/600 (6.2%) invasive infections with group B Streptococcus (GBS) in Toronto, Ontario, Canada, were caused by serotype IV strains. We report a relatively high level of genetic diversity in 37 invasive strains of this emerging GBS serotype. Multilocus sequence typing identified 6 sequence types (STs) that belonged to 3 clonal complexes. Most isolates were ST 459 (19/37, 51%) and ST-452 (11/37, 30%), but we also identified ST-291, ST-3, ST 196, and a novel ST-682. We detected further diversity by performing whole-genome single-nucleotide polymorphism analysis and found evidence of recombination events contributing to variation in some serotype IV GBS strains. We also evaluated antimicrobial drug resistance and found that ST-459 strains were resistant to clindamycin and erythromycin, whereas strains of other STs were, for the most part, susceptible to these antimicrobial drugs. PMID- 25811286 TI - Beneficial Physiological Effects With Blackcurrant Intake in Endurance Athletes. AB - Blackcurrant contains anthocyanins, known to influence vasorelaxation and peripheral blood flow. We examined the effects of 7 days intake of Sujon New Zealand blackcurrant powder (6g/day) on the lactate curve, maximum oxygen uptake, and cardiovascular responses at rest and during cycling. Thirteen trained triathletes with >3 yrs experience (8 men, age: 38 +/- 8 yrs, body mass: 71 +/- 9 kg, BF%: 19 +/- 5%, mean +/- SD) performed two incremental cycling protocols with recording of physiological and cardiovascular responses (Portapres Model 2). Cardiovascular function was also measured in rest. Experimental design was double blind, placebo-controlled, randomized and cross-over (wash-out 4 wks). Data were analyzed with two-tailed t tests and 2-way ANOVA and significance accepted at p < .05. Plasma lactate was lower at 40%, 50%, 60% and 70% of maximum power by 27%, 22%, 17% and 13%. Intensity at 4 mmol . La(-1) OBLA was 6% higher with blackcurrant without effect on heart rate and oxygen uptake. Maximum values of oxygen uptake, heart rate and power were not affected by blackcurrant, but obtained with 14% lower lactate. In rest, blackcurrant increased stroke volume and cardiac output by 25% and 26%, and decreased total peripheral resistance by 16%, with no changes in blood pressure and heart rate. Cardiovascular responses during exercise at 40%, 50%, 60%, 70% and 80% intensity were not affected. Sujon New Zealand blackcurrant powder affects lactate production and/or clearance during exercise. Sujon New Zealand blackcurrant powder affects physiological and cardiovascular responses in rest and during exercise that may have implications for exercise performance. PMID- 25811287 TI - A Randomized Trial of 1% vs 2% Lignocaine by the Spray-as-You-Go Technique for Topical Anesthesia During Flexible Bronchoscopy. AB - BACKGROUND: The optimal concentration of lignocaine to be used during flexible bronchoscopy (FB) remains unknown. This randomized controlled trial compared the efficacy and safety of 1% and 2% lignocaine solution for topical anesthesia during FB. METHODS: Consecutive patients were randomized to receive either 1% or 2% lignocaine solution through the bronchoscope by the "spray-as-you-go" technique. The primary outcome of the study was the assessment of cough by the operator and the patient using the visual analog scale (VAS) and pain assessment using the faces pain rating scale. The secondary outcomes included total lignocaine dose, oxygenation status, adverse reactions related to lignocaine, and others. RESULTS: Five hundred patients were randomized (median age, 51 years; 71% men) 1:1 to either group. The median operator VAS score for cough was significantly higher (25 vs 21, P = .015) in the 1% group; however, the patient VAS score was not significantly different (32 vs 27, P = .065). The pain rating was similar between the two groups. The median cumulative dose of lignocaine was significantly higher in the 2% group (397 mg vs 312 mg, P = .0001; 7.1 mg/kg vs 5.7 mg/kg, P = .0001). About 28% of patients in the 2% group exceeded the maximum recommended dose (> 8.2 mg/kg) of lignocaine. No adverse event related to lignocaine overdose was seen in either group. CONCLUSIONS: One percent lignocaine was found to be as effective as 2% solution for topical anesthesia during FB, albeit at a significantly lower dose as the latter. Thus, 1% lignocaine should be the preferred concentration for topical anesthesia during FB. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01955824; URL: www.clinicaltrials.gov. PMID- 25811288 TI - Analyses Comparing Visual Acuity Between Ranibizumab and Bevacizumab in the Comparison of Age-Related Macular Degeneration Treatments Trials. PMID- 25811289 TI - Using Direct Instruction: Teaching Preposition Use to Students With Intellectual Disability. AB - PURPOSE: Students with intellectual disability often struggle with significant language delays or impairments and can require explicit instruction in language skills. The purpose of this study was to investigate the effects of direct instruction on the use of and response to prepositions by 3 elementary school students with intellectual disability. METHOD: A multiple-baseline design across prepositions was used in this study with replication across students. RESULTS: Results of this study found that students were able to use and respond to prepositions consistently after receiving direct instruction on each of the 3 target prepositions. Furthermore, all 3 students demonstrated maintenance and generalization of the prepositions. CONCLUSION: These results have implications for practice that could influence preposition acquisition for students with intellectual disability, providing educators with a simple, efficient instructional approach. PMID- 25811290 TI - Hydroxyl-rich C-dots synthesized by a one-pot method and their application in the preparation of noble metal nanoparticles. AB - Hydroxyl-rich C-dots were used as both the reducing and stabilizing agent in the preparation of noble metal nanoparticles (AuNPs, AgNPs and Au@AgNPs) for the detection of glucose. PMID- 25811285 TI - Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach. AB - Bronchopulmonary dysplasia (BPD) is the most common respiratory consequence of premature birth and contributes to significant short- and long-term morbidity, mortality and resource utilization. Initially defined as a radiographic, clinical and histopathological entity, the chronic lung disease known as BPD has evolved as obstetrical and neonatal care have improved the survival of lower gestational age infants. Now, definitions based on the need for supplementary oxygen at 28 days and/or 36 weeks provide a useful reference point in the neonatal intensive care unit (NICU), but are no longer based on histopathological findings, and are neither designed to predict longer term respiratory consequences nor to study the evolution of a multifactorial disease. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. We found that the increasing use of respiratory support strategies that administer ambient air without supplementary oxygen confounds oxygen-based definitions of BPD. Furthermore, lack of reproducible, genetic, biochemical and physiological biomarkers limits the ability to identify an impending BPD for early intervention, quantify disease severity for standardized classification and approaches and reliably predict the long-term outcomes. More comprehensive, multidisciplinary approaches to overcome these challenges involve longitudinal observation of extremely preterm infants, not only those with BPD, using genetic, environmental, physiological and clinical data as well as large databases of patient samples. The Prematurity and Respiratory Outcomes Program (PROP) will provide such a framework to address these challenges through high resolution characterization of both NICU and post-NICU discharge outcomes. PMID- 25811291 TI - A bioaccessible fraction of parboiled germinated brown rice exhibits a higher anti-inflammatory activity than that of brown rice. AB - Parboiled germinated brown rice (PGBR) has been suggested as a functional food because it is relatively rich in a number of nutrients and health promoting compounds. Here we compared the bioaccessibility of several of the bioactive compounds in cooked PGBR and brown rice (BR) by simulating oral, gastric and small intestinal digestion. The uptake and retention of bioactive compounds from a bioaccessible fraction also was determined using Caco-2 human intestinal cells. The anti-inflammatory activity of the bioaccessible fraction from digested BR and PGBR was then assessed with Caco-2 cells that were activated with H2O2 + IL 1beta. PGBR had a higher content of GABA, gamma-oryzanol, gamma-tocotrienol, ferulic acid and p-coumaric acid than BR. The amounts of these compounds transferred to the aqueous fraction during digestion and the quantities accumulated by Caco-2 cells were proportional to those in cooked PGBR and BR. The anti-inflammatory activity of the bioaccessible fraction from digested BR and PGBR was then assessed for Caco-2 cells that were activated with H2O2 + IL-1beta. Pre-treatment of the cells with the bioaccessible fractions from PGBR and BR suppressed the secretion of IL-8 and MCP-1 and the ROS content in activated cells. Inhibitory activities were attenuated to a greater extent after cells had been pre-exposed to the bioaccessible fraction from digested PGBR compared to BR. These results suggest that digested PGBR contains and delivers greater amounts of compounds with anti-inflammatory activity to absorptive epithelial cells than digested BR. PMID- 25811292 TI - The effect of gamma-ray irradiation on the Mn(II) speciation in Deinococcus radiodurans and the potential role of Mn(II)-orthophosphates. AB - D. radiodurans accumulates large quantities of Mn(II), which is believed to form low molecular weight complexes with phosphate and metabolites that protect D. radiodurans from radiation damage. The concentration of Mn(II) species in D. radiodurans during the exponential and stationary phase was determined using high field EPR and biochemical techniques. In the exponential growth phase cells a large fraction of the manganese was in the form of Mn(II)-orthophosphate complexes. By contrast, the intracellular concentration of these compounds in stationary phase cells was less than 16 MUM, while that of Mn superoxide dismutase was 320 MUM and that of another, yet unidentified, Mn(II) protein was 250 MUM. Stationary cells were found to be equally resistant to irradiation as the exponential cells in spite of having significant lower Mn(II)-orthophosphate concentrations. Gamma irradiation induced no changes in the Mn(II) speciation. During stationary growth phase D. radiodurans favours the production of the two Mn-proteins over low molecular weight complexes suggesting that the latter were not essential for radio-resistance at this stage of growth. PMID- 25811294 TI - Rhodium-catalyzed asymmetric addition of arylboronic acids to cyclic N-sulfonyl ketimines towards the synthesis of alpha,alpha-diaryl-alpha-amino acid derivatives. AB - Rhodium/chiral diene complex-catalyzed asymmetric addition of arylboronic acids to cyclic ketimines having an ester group proceeded to give the corresponding alpha-amino acid derivatives in high yields with high enantioselectivity. The cyclic amino acid derivative was transformed into a linear alpha,alpha-diaryl substituted alpha-N-methylamino acid ester. PMID- 25811293 TI - Polyhydroxylated [60]fullerene binds specifically to functional recognition sites on a monomeric and a dimeric ubiquitin. AB - The use of nanoparticles (NPs) in biomedical applications requires an in-depth understanding of the mechanisms by which NPs interact with biomolecules. NPs associating with proteins may interfere with protein-protein interactions and affect cellular communication pathways, however the impact of NPs on biomolecular recognition remains poorly characterized. In this respect, particularly relevant is the study of NP-induced functional perturbations of proteins implicated in the regulation of key biochemical pathways. Ubiquitin (Ub) is a prototypical protein post-translational modifier playing a central role in numerous essential biological processes. To contribute to the understanding of the interactions between this universally distributed biomacromolecule and NPs, we investigated the adsorption of polyhydroxylated [60]fullerene on monomeric Ub and on a minimal polyubiquitin chain in vitro at atomic resolution. Site-resolved chemical shift and intensity perturbations of Ub's NMR signals, together with (15)N spin relaxation rate changes, exchange saturation transfer effects, and fluorescence quenching data were consistent with the reversible formation of soluble aggregates incorporating fullerenol clusters. The specific interaction epitopes were identified, coincident with functional recognition sites in a monomeric and lysine48-linked dimeric Ub. Fullerenol appeared to target the open state of the dynamic structure of a dimeric Ub according to a conformational selection mechanism. Importantly, the protein-NP association prevented the enzyme-catalyzed synthesis of polyubiquitin chains. Our findings provide an experiment-based insight into protein/fullerenol recognition, with implications in functional biomolecular communication, including regulatory protein turnover, and for the opportunity of therapeutic intervention in Ub-dependent cellular pathways. PMID- 25811295 TI - AMPED: a new platform for picolinate based luminescent lanthanide chelates. AB - The synthesis of a new nonacoordinating ligand based on an AMPED (6-amino-6 methylperhydro-1,4-diazepine) scaffold functionalized by three picolinate (6 carboxy-2-methylpyridine) arms is described. Coordination of lanthanide cations (Ln = Eu and Tb) was investigated by spectrophotometric titrations monitored by UV-Vis absorption and steady-state emission spectroscopy, showing the formation of [LnL] complexes in aqueous solutions. The corresponding Eu and Tb complexes were isolated and characterized, and their spectroscopic properties (luminescence quantum yields, excited state lifetimes) were determined in buffered water (TRIS/HCl, pH 7.4) and compared to the data reported in the literature for related systems. DFT modelling of the complexes showed the picolinate arms to be perfectly wrapped around the Ln(3+) cations, affording an excellent shielding of the metal as confirmed by the determination of the hydration number of q = 0 for both complexes. The high resolution emission spectrum was used to determine the radiative lifetime of Eu in the complex (taurad = 3.05 ms) and the metal-centred luminescence quantum yield (0.20). The modest 0.10 overall luminescence quantum yield of the Eu complex is a consequence of an energy transfer with medium efficiency (0.50) and a low metal centred luminescence efficiency attributed in part to the presence of numerous NH and CH bonds in close proximity to the metal centre. PMID- 25811297 TI - Improving Survival in Patients Treated for a Lung Cancer Using Self-Evaluated Symptoms Reported Through a Web Application. AB - OBJECTIVES: We retrospectively compared survivals in patients with a lung cancer history and followed by the so-called sentinel Web-application that allows early detection of relapse and early palliative care initiation versus a conventional follow-up in our center. METHODS: The survival in 98 consecutive patients with lung cancer was assessed. The first part of them (the control arm) was retrospectively recruited between March 2011 and August 2012. The second half of them (the experimental arm) was prospectively recruited between August 2012 and December 2013 to weekly fill a form of 11 self-assessed symptoms, then processed by the "sentinel" Web-application. Data were sent to this sentinel application in real-time between planned visits. An email alert was sent to the oncologist when self-scored symptoms matched some predefined criteria. Follow-up visit and imaging were then organized after a phone call for confirming the suspect symptoms. In the control arm (49 patients), a common follow-up was applied (visit and imaging every 2 to 6 mo according to stage of tumor and kind of treatment). RESULTS: Median follow-up duration was 12.3 months in the experimental arm and 16.7 months in the control arm (P=0.27). Survival was significantly better in the sentinel arm than in the control arm (P=0.0014). Median survival was 16.7 months in the control arm and 22.4 months in the experimental arm. One-year survival was 86.6% in the experimental arm and 59.1% in the control arm. CONCLUSIONS: Survival may be improved by early detection of relapse and early palliative care initiation by using sentinel-like Web-application. PMID- 25811296 TI - Potential Role of Single Nucleotide Polymorphisms of XRCC1, XRCC3, and RAD51 in Predicting Acute Toxicity in Rectal Cancer Patients Treated With Preoperative Radiochemotherapy. AB - OBJECTIVES: To investigate the association between polymorphisms of DNA repair genes and xenobiotic with acute adverse effects in locally advanced rectal cancer patients treated with neoadjuvant radiochemotherapy. METHODS: Sixty-seven patients were analyzed for the current study. Genotypes in DNA repair genes XRCC1 (G28152A), XRCC3 (A4541G), XRCC3 (C18067T), RAD51 (G315C), and GSTP1 (A313G) were determined by pyrosequencing technology. RESULTS: The observed grade >=3 acute toxicity rates were 23.8%. Chemotherapy and radiotherapy were interrupted for 46 and 14 days, respectively, due to critical complications. Four patients were hospitalized, 6 patients had been admitted to the ER, and 5 patients received invasive procedures (2 bladder catheters, 2 blood transfusions, and 1 growth factor therapy).RAD51 correlated with acute severe gastrointestinal toxicity in heterozygosity (Aa) and homozygosity (AA) (P=0.036). Grade >=3 abdominal/pelvis pain toxicity was higher in the Aa group (P=0.017) and in the Aa+AA group (P=0.027) compared with homozygous (aa) patients. Acute skin toxicity of any grade occurred in 55.6% of the mutated patients versus 22.8% in the wild-type group (P=0.04) for RAD51. XRCC1 correlated with skin toxicity of any grade in the Aa+AA group (P=0.03) and in the Aa group alone (P=0.044). Grade >=3 urinary frequency/urgency was significantly higher in patients with AA (P=0.01), Aa (P=0.022), and Aa+AA (P=0.031) for XRCC3 compared with aa group. CONCLUSIONS: Our study suggested that RAD51, XRCC1, and XRCC3 polymorphisms may be predictive factors for radiation-induced acute toxicity in rectal cancer patients treated with preoperative combined therapy. PMID- 25811299 TI - Functionalization of a GaSe monolayer by vacancy and chemical element doping. AB - Based on first-principles plane-wave calculations, functionalization of the two dimensional single-layered GaSe structure through vacancy and chemical element doping has been investigated. Our calculations show that the pristine GaSe monolayer, which is normally a non-magnetic, indirect-band-gap semiconductor, can induce net magnetic moments by introduction of Ga mono-vacancy, Ga di-vacancy, and GaSe3 and Ga2Se6 vacancy complexes. Magnetic moments can also be induced by selectively doping specific transition-metal atoms as well as A group atoms. The introduced donor or acceptor states are localized in the band gap, which expands the utilization of the single-layered GaSe in nanoelectronics and spintronics. In spite of the intrinsic p-type character of the two-dimensional GaSe material, substitution of Si for Ga and substitution of Cl for Se exhibit n-type character at relatively low dopant concentrations. These findings will provide useful supplements to the experimental studies on the newly synthesized two-dimensional layered metal monochalcogenides, which allows us to go beyond the current scope that is limited to applications within graphene, BN, and transition-metal dichalcogenide-based nanostructures. PMID- 25811298 TI - Exploring hydrogen peroxide responsive thiazolidinone-based prodrugs. AB - A novel approach for developing prodrugs based on masked carboxylic acids is described. Rather than using conventional esterase-based activation, thiazolidinone protecting groups have been identified that can reveal carboxylic acid groups upon activation by hydrogen peroxide. This may prove valuable in the continuing development of prodrug strategies that rely on reactive oxygen species (ROS) as a trigger. PMID- 25811300 TI - Enterovirus A71 subgenotype B5, France, 2013. PMID- 25811301 TI - Electrochemical performance and biosensor application of TiO2 nanotube arrays with mesoporous structures constructed by chemical etching. AB - Novel mesoporous TiO2 nanotube arrays (TiO2 NTAs) were synthesized by an anodization method combined with chemical etching in HF solution, and the electrochemical performance was studied. Glucose oxidase (GOx) was immobilized on the mesoporous TiO2 NTAs to achieve an efficient biosensor for amperometric detection of glucose. The morphology, structure, component and electrochemical performance of mesoporous TiO2 NTAs were characterized by scanning electron microscopy, high resolution transmission electron microscopy, X-ray diffractometry, X-ray photoelectron spectrometry and an electrochemical workstation, respectively. The influence of the mesoporous structure on the electrochemical performance is discussed in detail by comparing the cyclic voltammograms and electrochemical impedance spectrum of TiO2 and mesoporous TiO2 NTAs in different conditions. High electrochemical active surface area and electron transfer rate play key roles in enhancing the electrochemical performance of mesoporous TiO2 NTAs. When used as the basis of a biosensor, the amperometric response of glucose on a GOx/TiO2-0.5 NTAs electrode is linearly proportion to the glucose concentration in the range from 0.1 to 6 mM with a sensitivity of 0.954 MUA mM(-1) cm(-2), which is 14.3 times that of un-etched GOx/TiO2 NTAs. PMID- 25811302 TI - Prevalence of hepatitis E virus antibodies, Israel, 2009-2010. AB - We investigated prevalence of hepatitis E virus in a sample of the population of Israel. The overall seroprevalence of antibodies to the virus was 10.6% (95% CI 8.4%-13.0%); age-adjusted prevalence was 7.6%. Seropositivity was associated with age, Arab ethnicity, low socioeconomic status, and birth in Africa, Asia, or the former Soviet Union. PMID- 25811303 TI - Avian Influenza A(H10N7) virus-associated mass deaths among harbor seals. PMID- 25811305 TI - Applications of coherent Raman scattering microscopies to clinical and biological studies. AB - Coherent anti-Stokes Raman scattering (CARS) microscopy and stimulated Raman scattering (SRS) microscopy are two nonlinear optical imaging modalities that are at the frontier of label-free and chemical specific biological and clinical diagnostics. The applications of coherent Raman scattering (CRS) microscopies are multifold, ranging from investigation of basic aspects of cell biology to the label-free detection of pathologies. This review summarizes recent progress of biological and clinical applications of CRS between 2008 and 2014, covering applications such as lipid droplet research, single cell analysis, tissue imaging and multiphoton histopathology of atherosclerosis, myelin sheaths, skin, hair, pharmaceutics, and cancer and surgical margin detection. PMID- 25811304 TI - Contribution of organ vasculature in rat renal analysis for ochratoxin a: relevance to toxicology of nephrotoxins. AB - Assumptions surrounding the kidney as a target for accumulation of ochratoxin A (OTA) are addressed because the contribution of the toxin in blood seems invariably to have been ignored. Adult rats were maintained for several weeks on toxin-contaminated feed. Using standard perfusion techniques, animals were anaesthetised, a blood sample was taken, one kidney was ligated, and the other kidney perfused with physiological saline in situ under normal blood pressure. Comparative analysis of OTA in pairs of kidneys showed marked reduction in the perfused organ in the range 37%-98% (mean 75%), demonstrating the general efficiency of perfusion supported also by histology, and implying a major role of blood in the total OTA content of kidney. Translation of OTA values in plasma to whole blood, and its predicted contribution as a 25% vascular compartment in kidney gave values similar to those in non-perfused kidneys. Thus, apparent 'accumulation' of OTA in kidney is due to binding to plasma proteins and long half-life in plasma. Attention should be re-focused on whole animal pharmacokinetics during chronic OTA exposure. Similar principles may be applied to DNA-OTA adducts which are now recognised as occurring in blood; application could also extend to other nephrotoxins such as aristolochic acid. Thus, at least, quantitative reassessment in urological tissues seems necessary in attributing adducts specifically as markers of potentially-tumourigenic exposure. PMID- 25811306 TI - Butadiene from acetylene-ethylene cross-metathesis. AB - Acetylene to butadiene direct synthesis, via enyne cross-metathesis, is demonstrated with commercial ruthenium carbene catalysts. Using excess of ethylene, yields greater than 50% are obtained. High activity is observed in the first minute of the reaction (TOF > 800 h(-1) based on butadiene). Catalyst reusability and poisoning are discussed. PMID- 25811307 TI - Multidrug-resistant Salmonella enterica serotype Typhi, Gulf of Guinea Region, Africa. AB - We identified 3 lineages among multidrug-resistant (MDR) Salmonella enterica serotype Typhi isolates in the Gulf of Guinea region in Africa during the 2000s. However, the MDR H58 haplotype, which predominates in southern Asia and Kenya, was not identified. MDR quinolone-susceptible isolates contained a 190-kb incHI1 pST2 plasmid or a 50-kb incN pST3 plasmid. PMID- 25811308 TI - Postexercise Glycogen Recovery and Exercise Performance is Not Significantly Different Between Fast Food and Sport Supplements. AB - A variety of dietary choices are marketed to enhance glycogen recovery after physical activity. Past research informs recommendations regarding the timing, dose, and nutrient compositions to facilitate glycogen recovery. This study examined the effects of isoenergetic sport supplements (SS) vs. fast food (FF) on glycogen recovery and exercise performance. Eleven males completed two experimental trials in a randomized, counterbalanced order. Each trial included a 90-min glycogen depletion ride followed by a 4-hr recovery period. Absolute amounts of macronutrients (1.54 +/- 0.27 g.kg-1 carbohydrate, 0.24 +/- 0.04 g.kg fat-1, and 0.18 +/-0.03g.kg protein-1) as either SS or FF were provided at 0 and 2 hr. Muscle biopsies were collected from the vastus lateralis at 0 and 4 hr post exercise. Blood samples were analyzed at 0, 30, 60, 120, 150, 180, and 240 min post exercise for insulin and glucose, with blood lipids analyzed at 0 and 240 min. A 20k time-trial (TT) was completed following the final muscle biopsy. There were no differences in the blood glucose and insulin responses. Similarly, rates of glycogen recovery were not different across the diets (6.9 +/- 1.7 and 7.9 +/- 2.4 mmol.kg wet weight- 1.hr-1 for SS and FF, respectively). There was also no difference across the diets for TT performance (34.1 +/- 1.8 and 34.3 +/- 1.7 min for SS and FF, respectively. These data indicate that short-term food options to initiate glycogen resynthesis can include dietary options not typically marketed as sports nutrition products such as fast food menu items. PMID- 25811309 TI - Real-Time Analysis of Cellular Response to Small-Molecule Drugs within a Microfluidic Dielectrophoresis Device. AB - Quantitative detection of the biological properties of living cells is essential for a wide range of purposes, from the understanding of cellular characteristics to the development of novel drugs in nanomedicine. Here, we demonstrate that analysis of cell biological properties within a microfluidic dielectrophoresis device enables quantitative detection of cellular biological properties and simultaneously allows large-scale measurement in a noise-robust and probeless manner. Applying this technique, the static and dynamic biological responses of live B16F10 melanoma cells to the small-molecule drugs such as N-ethylmaleimide (NEM) and [(dihydronindenyl)oxy]alkanoic acid (DIOA) were quantitatively and statistically examined by investigating changes in movement of the cells. Measurement was achieved using subtle variations in dielectrophoresis (DEP) properties of the cells, which were attributed to activation or deactivation of K(+)/Cl(-) cotransporter channels on the cell membrane by the small-molecule drugs, in a microfluidic device. On the basis of quantitative analysis data, we also provide the first report of the shift of the complex permittivity of a cell induced by the small-molecule drugs. In addition, we demonstrate interesting quantifiable parameters including the drug effectiveness coefficient, antagonistic interaction coefficient, kinetic rate, and full width at half maximum, which corresponded to changes in biological properties of B16F10 cells over time when NEM and DIOA were introduced alone or in combination. Those demonstrated parameters represent very useful tools for evaluating the effect of small-molecule drugs on the biological properties of cells. PMID- 25811310 TI - Running up a wall: the role and challenges of dynamic climbing in enhancing multi modal legged systems. AB - Animals have demonstrated the ability to move through, across and over some of the most daunting environments on earth. This versatility and adaptability stems from their capacity to alter their locomotion dynamics and employ disparate locomotion modalities to suit the terrain at hand. As with modalities such as running, flying and swimming, dynamic climbing is commonly employed by legged animals, allowing for rapid and robust locomotion on vertical and near-vertical substrates. While recent robotic platforms have proven effective at anchoring reduced-order, dynamic climbing models, its adoption as a common modality for multi-modal, legged platforms remains nascent. In this work, we explore several of the open questions related to the physical implementation of dynamic climbing, including investigation of substrate inclinations for which dynamic climbing is suited, mitigation of destabilizing out-of-plane dynamics and improvement of attachment reliability in the presence of dynamic effects. The results from these inquiries provide several mechanisms and approaches for increasing the reliability and versatility of dynamic climbing as a dynamic legged modality. With these and other developments into legged locomotion modalities, future multi modal platforms will begin to approach the expertise of biological creatures at moving through a complex and challenging world. PMID- 25811311 TI - Measurements of the HO2 uptake coefficients onto single component organic aerosols. AB - Measurements of HO2 uptake coefficients (gamma) were made onto a variety of organic aerosols derived from glutaric acid, glyoxal, malonic acid, stearic acid, oleic acid, squalene, monoethanol amine sulfate, monomethyl amine sulfate, and two sources of humic acid, for an initial HO2 concentration of 1 * 10(9) molecules cm(-3), room temperature and at atmospheric pressure. Values in the range of gamma < 0.004 to gamma = 0.008 +/- 0.004 were measured for all of the aerosols apart from the aerosols from the two sources of humic acid. For humic acid aerosols, uptake coefficients in the range of gamma = 0.007 +/- 0.002 to gamma = 0.09 +/- 0.03 were measured. Elevated concentrations of copper (16 +/- 1 and 380 +/- 20 ppb) and iron (600 +/- 30 and 51 000 +/- 3000 ppb) ions were measured in the humic acid atomizer solutions compared to the other organics that can explain the higher uptake values measured. A strong dependence upon relative humidity was also observed for uptake onto humic acid, with larger uptake coefficients seen at higher humidities. Possible hypotheses for the humidity dependence include the changing liquid water content of the aerosol, a change in the mass accommodation coefficient or in the Henry's law constant. PMID- 25811312 TI - The impact of complementary and alternative medicines on cancer symptoms, treatment side effects, quality of life, and survival in women with breast cancer -a systematic review. AB - Breast cancer is the most common form of cancer amongst women. Women with breast cancer frequently consult dietitians for advice, and increasingly advice on complementary alternative medicines (CAM). The aim of this systematic review was to evaluate evidence of CAM administered orally on cancer-related outcomes. Databases were searched for studies recruiting women with a history of breast cancer reporting on the use of CAM administered orally as tablets, capsules, powders, and liquids for any 1 or more of the following: alleviation of cancer related symptoms and treatment side effects, improvement to quality of life, physical and emotional wellbeing, survival, and mortality. Twenty-two studies were identified as meeting the inclusion criteria. Ten CAM categories were established with no more than 4 articles published in each category. Although the evidence is of varying quality there is some data to support that guarana and Ganoderma lucidum may improve fatigue, whereas glutamine may also be effective in improving oral mucositis symptoms. Overall, the current available evidence is inconclusive to make definitive recommendations regarding the effectiveness for individuals' use of CAM in women with breast cancer. Further high-quality randomized controlled trials exploring safety, toxicity, and other potential adverse effects of CAM are required. PMID- 25811313 TI - Inter- and intra-tumoral relationships between vasculature characteristics, GLUT1 and budding in colorectal carcinoma. AB - Vascular characteristics, hypoxia and tumor budding are features that have been implied in the biology and prognosis of colorectal cancer. Internal relationships and the inter- and intra-tumoral variation of these tumor properties remain to be determined. In the current study we have characterized blood vessel status in different areas of CRC and in the peritumoral fibroblastic stroma. Analyses of these characteristics have been supplemented by characterization of budding and hypoxia. Analyses revealed significantly lower values of vessel perimeter (VP) and vessel lumen area (VL) at the invasive front and surrounding stroma as compared to the tumor center. Also, the number of vessels (VN) in the peritumoral stroma was higher than in the center. Thus, tumor center displays larger and fewer vessels as compared to the tumor periphery. GLUT1 expression was correlated directly with VN (r=0.351, p=0.028) and inversely with VL and VP (r=-0.432, p=0.006 and r=-0.484, p=0.002) at the invasive front. Moreover, GLUT1 expression, VP at the invasive front, and VN in the surrounding peritumoral stroma, were associated with budding score (r=0.574, p<0.000, r=-0.340, p=0,034 and r=-0.389, p=0.025 respectively). Furthermore, GLUT1, budding score, vessel number in peritumoral stroma, and vessel size in the invasive front, were significantly different in tumors with or without lymph node metastasis. This study reports previously unrecognized relationships between localization-specific vascular characteristics, hypoxia and tumor budding. The findings suggest potential functional relationships, which should be further explored, and also highlight the inter-tumoral variations in vasculature, which is highly relevant for ongoing efforts to identify vessel-based biomarkers. PMID- 25811314 TI - Serum Soluble CD14 in Egyptian Patients with Chronic Hepatitis C: Its Relationship to Disease Progression and Response to Treatment. AB - Hepatitis C virus (HCV) is a major public health problem. Soluble CD14 (sCD14) level was shown to be associated with HCV infection. In this study, we aimed to investigate the relationship between sCD14 concentration and disease progression, as well as the response to pegylated interferon/ribavirin (peg-IFN/RBV) therapy in Egyptian patients with chronic hepatitis C (CHC). The ELISA technique was used to test 80 patients with CHC and 20 healthy control persons for serum levels of sCD14 (pretreatment and after 12 weeks of treatment). CHC patients were 65 males and 15 females. Normal healthy controls included 20 age- and sex-matched volunteers. The mean age of the CHC patients was 39.94 years, while that of the controls was 39.2 years The serum sCD14 level was significantly higher in chronic HCV-infected patients (3.6+/-0.18 MUg/mL) compared to healthy control subjects (3.1+/-0.18 MUg/mL). The serum sCD14 level was significantly directly correlated with the hepatic fibrosis score (r=0.24, P=0.03), histological activity index (r=0.26, P=0.02), and serum aminotransferases [r=0.28, P=0.005 for alanine aminotransferase (ALT) and r=0.30, P=0.003 for aspartate aminotransferase (AST)]. The pretreatment sCD14 level was not significantly correlated to the treatment response, but it increased after 12 weeks of peg-IFN/RBV therapy and values were significantly higher in nonresponders (P=0.02). The pretreatment sCD14 level cannot predict the treatment response in chronic HCV patients receiving peg IFN/RBV therapy. However, the serum sCD14 level after 12 weeks of treatment can serve as a negative predictor of treatment response. PMID- 25811316 TI - Visual and Proprioceptive Adaptation of Arm Position in a Virtual Environment. AB - The authors examined the resolution of a discrepancy between visual and proprioceptive estimates of arm position in 10 participants. The participants fixed their right shoulder at 0 degrees , 30 degrees , or 60 degrees of transverse adduction while they viewed a video on a head-mounted display that showed their right arm extended in front of the trunk for 30 min. The perceived arm position more closely approached the seen arm position on the display as the difference between the actual and visually displayed arm positions increased. In the extreme case of a 90 degrees discrepancy, the seen arm position on the display was very gradually perceived as approaching the actual arm position. The magnitude of changes in sensory estimates was larger for proprioception (20%) than for vision (< 10%). PMID- 25811315 TI - Decreased Expression of miR-15b in Human Gliomas is Associated with Poor Prognosis. AB - MicroRNA-15b (miR-15b) has been demonstrated to suppress proliferation by arresting cell cycle progression and inducing apoptosis in glioma cells. However, the prognostic value of miR-15b expression in human gliomas remains unclear. In the present study, the authors examined the expression profile in glioma specimens and the prognostic value of miR-15b in patients with gliomas. Real-time polymerase chain reaction assay was employed to detect the expression levels of miR-15b in 92 glioma tissues categorized by World Health Organization (WHO) histopathological grades. However, the prognostic value of miR-15b in human glioma has not been evaluated yet. MiR-15b expression in human glioma tissues was distinctly lower than in normal brain tissues. Furthermore, the expression of miR 15b notably decreased with the ascending histopathological grade of gliomas. Additionally, Kaplan-Meier survival analysis showed that low miR-15b expression was associated with poor overall survival in patients with gliomas. Similarly, miR-15b reduction occurred with increasing frequency in glioma patients with lower Karnofsky performance scale (KPS) scores than in those with higher KPS scores. No significant difference was observed between miR-15b expression and gender, age, and tumor location. These findings revealed that a lower expression level of miR-15b was closely related to a shorter overall survival, suggesting that miR-15b could be an intrinsic factor that plays an important role in the malignant progression of gliomas. PMID- 25811318 TI - Severe insulin resistance alters metabolism in mesenchymal progenitor cells. AB - Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells (MPCs) from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male (control). INSR mRNA and protein were significantly reduced in DS MPC (for beta-subunit, 64% and 89% reduction, respectively, P < .05), but IGF1R mRNA and protein did not differ vs control. Insulin-stimulated phosphorylation of INSR or the downstream substrates insulin receptor substrate 1 and protein kinase B did not differ, but ERK phosphorylation tended to be reduced in DS (32% decrease, P = .07). By contrast, IGF-1 and insulin-stimulated insulin-like growth factor 1 (IGF-1) receptor phosphorylation were increased in DS (IGF-1, 8.5- vs 4.5-fold increase; INS, 11- vs 6-fold; P < .05). DS MPC tended to have higher oxygen consumption in both the basal state (87% higher, P =.09) and in response to the uncoupler carbonyl cyanide-p-triflouromethoxyphenylhydrazone (2-fold increase, P =.06). Although mitochondrial DNA or mass did not differ, oxidative phosphorylation protein complexes III and V were increased in DS (by 37% and 6%, respectively; P < .05). Extracellular acidification also tended to increase in DS (91% increase, P = .07), with parallel significant increases in lactate secretion (34% higher at 4 h, P < .05). In summary, DS MPC maintain signaling downstream of the INSR, suggesting that IGF-1R signaling may partly compensate for INSR mutations. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms. PMID- 25811317 TI - Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10 hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)-tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors. AB - The structure-activity relationships and hit-to-lead optimization of dual Top1 TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual Top1-TDP1 inhibition. The 9 hydroxy series exhibited potencies and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the Top1-mediated DNA cleavage assay. One member of this series was a more potent Top1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug-DNA-Top1 cleavage complex than CPT. PMID- 25811320 TI - Development of a strategy for the identification of surface proteins in the pathogenic microsporidian Nosema bombycis. AB - Parasite-host interactions mediated by cell surface proteins have been implicated as a critical step in infections caused by the microsporidian Nosema bombycis. Such cell surface proteins are considered as promising diagnostic markers and targets for drug development. However, little research has specifically addressed surface proteome identification in microsporidia due to technical barriers. Here, a combined strategy was developed to separate and identify the surface proteins of N. bombycis. Briefly, following (1) biotinylation of the spore surface, (2) extraction of total proteins with an optimized method and (3) streptavidin affinity purification of biotinylated proteins, 22 proteins were identified based on LC-MS/MS analysis. Among them, 5 proteins were confirmed to be localized on the surface of N. bombycis. A total of 8 proteins were identified as hypothetical extracellular proteins, whereas 7 other hypothetical proteins had no available function annotation. Furthermore, a protein with a molecular weight of 18.5 kDa was localized on the spore surface by western blotting and immunofluorescence analysis, even though it was predicted to be a nuclear protein by bioinformatics. Collectively, our work provides an effective strategy for isolating microsporidian surface protein components for both drug target identification and further diagnostic research on microsporidian disease control. PMID- 25811322 TI - Providing context for a medical school basic science curriculum: The importance of the humanities. AB - INTRODUCTION: To increase students' understanding of what it means to be a physician and engage in the everyday practice of medicine, a humanities program was implemented into the preclinical curriculum of the medical school curriculum. The purpose of our study was to determine how medical students' views of being a doctor evolved after participating in a required humanities course. METHODS: Medical students completing a 16-clock hour humanities course from 10 courses were asked to respond to an open-ended reflection question regarding changes, if any, of their views of being a doctor. The constant comparative method was used for coding; triangulation and a variety of techniques were used to provide evidence of validity of the analysis. RESULTS: A majority of first- and second year medical students (rr = 70%) replied, resulting in 100 pages of text. A meta theme of Contextualizing the Purpose of Medicine and three subthemes: the importance of Treating Patients Rather than a Disease, Understanding Observation Skills are Important, and Recognizing that Doctors are Fallible emerged from the data. CONCLUSIONS: Results suggest that requiring humanities as part of the required preclinical curriculum can have a positive influence on medical students and act as a bridge to contextualize the purpose of medicine. PMID- 25811323 TI - Supply of doctors to a rural region: Occupations of Tromso medical graduates 1979 2012. AB - BACKGROUND: The aim of establishing the medical school in Tromso in 1973 was to improve access to doctors and standards of health care for the previously underprivileged rural population of Northern Norway. In this study we examine how the aim of supplying doctors to the north has been achieved. MATERIAL AND METHODS: By utilising a cross-sectional design we have analysed 34 classes of Tromso medical graduates (1979-2012) with regard to occupations in 2013 by the year of graduation and by successive pools of cohorts. RESULTS: In 2013 altogether 822 of 1611 doctors (51%) were working in Northern Norway. The proportions working in the north for old, intermediate and young cohorts were 37%, 48% and 60%, respectively. Doctors graduating during recent years tended to start their careers in the north to a higher degree than doctors graduating in previous periods. Among doctors from the older classes a relatively large minority have their end-careers in Northern Norway, with a noticeable inclination for long term work in primary care. CONCLUSION: Our results support that the first rural oriented medical education model in Europe established in Tromso 40 years ago is sustainable, achieving its aims. PMID- 25811319 TI - A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing. AB - Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (~4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysosomal trafficking and iodo-Tg processing. The Ctns(-/-) thyroid is useful to study disease progression and evaluate novel therapies. PMID- 25811324 TI - Chemistry and release of gases from the surface ocean. PMID- 25811325 TI - PASylation of Murine Leptin Leads to Extended Plasma Half-Life and Enhanced in Vivo Efficacy. AB - Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong plasma half-life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to 600 residues, which adopt random coil conformation with expanded hydrodynamic volume in solution and, consequently, retard kidney filtration in a similar manner as polyethylene glycol (PEG). Relative to unmodified leptin, size exclusion chromatography and dynamic light scattering revealed an approximately 21-fold increase in apparent size and a much larger molecular diameter of around 18 nm for PAS(600)-leptin. High receptor-binding activity for all PASylated leptin versions was confirmed in BIAcore measurements and cell-based dual-luciferase assays. Pharmacokinetic studies in mice revealed a much extended plasma half-life after ip injection, from 26 min for the unmodified leptin to 19.6 h for the PAS(600) fusion. In vivo activity was investigated after single ip injection of equimolar doses of each leptin version. Strongly increased and prolonged hypothalamic STAT3 phosphorylation was detected for PAS(600)-leptin. Also, a reduction in daily food intake by up to 60% as well as loss in body weight of >10% lasting for >5 days was observed, whereas unmodified leptin was merely effective for 1 day. Notably, application of a PASylated superactive mouse leptin antagonist (SMLA) led to the opposite effects. Thus, PASylated leptin not only provides a promising reagent to study its physiological role in vivo but also may offer a superior drug candidate for clinical therapy. PMID- 25811327 TI - Infrared photodissociation spectroscopy of mass-selected silver and gold nitrosyl cation complexes. AB - The [M(NO)n](+) cation complexes (M = Au and Ag) are studied for exploring the coordination and bonding between nitric oxide and noble metal cations. These species are produced in a laser vaporization supersonic ion source and probed by infrared photodissociation spectroscopy in the NO stretching frequency region using a collinear tandem time-of-flight mass spectrometer. The geometric and electronic structures of these complexes are determined by comparison of the distinctive experimental spectra with simulated spectra derived from density functional theory calculations. All of these noble metal nitrosyl cation complexes are characterized to have bent NO ligands serving as one-electron donors. The spectrum of [Au(NO)2Ar](+) is consistent with 2-fold coordination with a near linear N-Au-N arrangement for this ion. The [Au(NO)n](+) (n = 3-4) cations are determined to be a mixture of 2-fold coordinated form and 3- or 4 fold coordinated form. In contrast, the spectra of [Ag(NO)n](+) (n = 3-6) provide evidence for the completion of the first coordination shell at n = 5. The high [Au(NO)n](+) and [Ag(NO)n](+) (n >= 3 for Au, n >= 4 for Ag) complexes each involve one or more (NO)2 dimer ligands, as observed in the copper nitrosyl cation complexes, indicating that ligand-ligand coupling plays an important role in the structure and bonding of noble metal nitrosyl cation complexes. PMID- 25811326 TI - Degradation of CT Low-Contrast Spatial Resolution Due to the Use of Iterative Reconstruction and Reduced Dose Levels. AB - PURPOSE: To determine the dose reduction that could be achieved without degrading low-contrast spatial resolution (LCR) performance for two commercial iterative reconstruction (IR) techniques, each evaluated at two strengths with many repeated scans. MATERIALS AND METHODS: Two scanner models were used to image the American College of Radiology (ACR) CT accreditation phantom LCR section at volume CT dose indexes of 8, 12, and 16 mGy. Images were reconstructed by using filtered back projection (FBP) and two manufacturers' IR techniques, each at two strengths (moderate and strong). Data acquisition and reconstruction were repeated 100 times for each, yielding 1800 images. Three diagnostic medical physicists reviewed the LCR images in a blinded fashion and graded the visibility of four 6-mm rods with a six-point scale. Noninferiority and inferiority superiority analyses were used to interpret the differences in LCR relative to FBP images acquired at 16 mGy. RESULTS: LCR decreased with decreasing dose for all reconstructions. Relative to FBP and full dose, 25%-50% dose reductions resulted in inferior LCR for vendors 1 and 2 for FBP and 25% dose reductions resulted in inferior and equivalent performance for vendor 1 and equivalent and superior performance for vendor 2 at moderate and strong IR settings, respectively. When dose was reduced by 50%, both IR techniques resulted in inferior LCR at both strength settings. CONCLUSION: For radiation dose reductions of 25% or more, the ability to resolve the four 6-mm rods in the ACR CT accreditation phantom can be lost. PMID- 25811328 TI - Continuous Positive Airway Pressure and the Burden of Care for Transient Tachypnea of the Neonate: Retrospective Cohort Study. AB - OBJECTIVES: Transient tachypnea of the neonate (TTN) is the commonest neonatal respiratory disorder. Given TTN physiopathology, continuous positive airway pressure (CPAP) could be indicated for its treatment, but no data are available. Our aim is to clarify if CPAP might reduce the TTN burden of care. DESIGN: Retrospective multicenter cohort study enrolling 42 full-term TTN babies treated with CPAP and 40 with oxygen supplementation. RESULTS: CPAP-treated infants show shorter intensive care unit stay (CPAP, 2.5 +/- 2 vs. Oxygen, 4.4 +/- 2.6 days; adjbeta, -2.1 [95% confidence interval (CI): -3.1; -1]); p < 0.001) and lower maximal oxygen fraction (adjbeta, -4.7 [95% CI: -7.7; -1.7]; p = 0.003). Air leak incidence was similar between the groups (adjOR, 0.36 [95% CI: 0.1; 1.1); p = 0.08). Patients' comfort as per EDIN score was also unchanged. Given the shorter length of intensive care, the use of CPAP for treating TTN would spare on average around 7,000 Euros/infant. CONCLUSION: CPAP seems a useful therapeutics for TTN, as it may reduce the burden of care without increasing air leaks or patients' discomfort. PMID- 25811329 TI - Analysis of SI models with multiple interacting populations using subpopulations. AB - Computing endemic equilibria and basic reproductive numbers for systems of differential equations describing epidemiological systems with multiple connections between subpopulations is often algebraically intractable. We present an alternative method which deconstructs the larger system into smaller subsystems and captures the interactions between the smaller systems as external forces using an approximate model. We bound the basic reproductive numbers of the full system in terms of the basic reproductive numbers of the smaller systems and use the alternate model to provide approximations for the endemic equilibrium. In addition to creating algebraically tractable reproductive numbers and endemic equilibria, we can demonstrate the influence of the interactions between subpopulations on the basic reproductive number of the full system. The focus of this paper is to provide analytical tools to help guide public health decisions with limited intervention resources. PMID- 25811330 TI - A double age-structured model of the co-infection of tuberculosis and HIV. AB - After decades on the decline, it is believed that the emergence of HIV is responsible for an increase in the tuberculosis prevalence. The leading infectious disease in the world, tuberculosis is also the leading cause of death among HIV-positive individuals. Each disease progresses through several stages. The current model suggests modeling these stages through a time-since-infection tracking transmission rate function, which, when considering co-infection, introduces a double-age structure in the PDE system. The basic and invasion reproduction numbers for each disease are calculated and the basic ones established as threshold for the disease progression. Numerical results confirm the calculations and a simple treatment scenario suggests the importance of time since-infection when introducing disease control and treatment in the model. PMID- 25811332 TI - Virus dynamics model with intracellular delays and immune response. AB - In this paper, we incorporate an extra logistic growth term for uninfected CD4+ T cells into an HIV-1 infection model with both intracellular delay and immune response delay which was studied by Pawelek et al. in [26]. First, we proved that if the basic reproduction number R0 < 1, then the infection-free steady state is globally asymptotically stable. Second, when R0 > 1, then the system is uniformly persistent, suggesting that the clearance or the uniform persistence of the virus is completely determined by R0. Furthermore, given both the two delays are zero, then the infected steady state is asymptotically stable when the intrinsic growth rate of the extra logistic term is sufficiently small. When the two delays are not zero, we showed that both the immune response delay and the intracellular delay may destabilize the infected steady state by leading to Hopf bifurcation and stable periodic oscillations, on which we analyzed the direction of the Hopf bifurcation as well as the stability of the bifurcating periodic orbits by normal form and center manifold theory introduced by Hassard et al. Third, we engaged numerical simulations to explore the rich dynamics like chaotic oscillations, complicated bifurcation diagram of viral load due to the logistic term of target cells and the two time delays. PMID- 25811331 TI - A singularly perturbed HIV model with treatment and antigenic variation. AB - We study the long term dynamics and the multiscale aspects of a within-host HIV model that takes into account both mutation and treatment with enzyme inhibitors. This model generalizes a number of other models that have been extensively used to describe the HIV dynamics. Since the free virus dynamics occur on a much faster time-scale than cell dynamics, the model has two intrinsic time scales and should be viewed as a singularly perturbed system. Using Tikhonov's theorem we prove that the model can be approximated by a lower dimensional nonlinear model. Furthermore, we show that this reduced system is globally asymptotically stable by using Lyapunov's stability theory. PMID- 25811333 TI - Travelling wave solutions of the reaction-diffusion mathematical model of glioblastoma growth: an Abel equation based approach. AB - We consider quasi-stationary (travelling wave type) solutions to a nonlinear reaction-diffusion equation with arbitrary, autonomous coefficients, describing the evolution of glioblastomas, aggressive primary brain tumors that are characterized by extensive infiltration into the brain and are highly resistant to treatment. The second order nonlinear equation describing the glioblastoma growth through travelling waves can be reduced to a first order Abel type equation. By using the integrability conditions for the Abel equation several classes of exact travelling wave solutions of the general reaction-diffusion equation that describes glioblastoma growth are obtained, corresponding to different forms of the product of the diffusion and reaction functions. The solutions are obtained by using the Chiellini lemma and the Lemke transformation, respectively, and the corresponding equations represent generalizations of the classical Fisher-Kolmogorov equation. The biological implications of two classes of solutions are also investigated by using both numerical and semi-analytical methods for realistic values of the biological parameters. PMID- 25811334 TI - Global dynamics of a general class of multi-group epidemic models with latency and relapse. AB - A multi-group model is proposed to describe a general relapse phenomenon of infectious diseases in heterogeneous populations. In each group, the population is divided into susceptible, exposed, infectious, and recovered subclasses. A general nonlinear incidence rate is used in the model. The results show that the global dynamics are completely determined by the basic reproduction number R0. In particular, a matrix-theoretic method is used to prove the global stability of the disease-free equilibrium when R0 <= 1, while a new combinatorial identity (Theorem 3.3 in Shuai and van den Driessche) in graph theory is applied to prove the global stability of the endemic equilibrium when R0 > 1. We would like to mention that by applying the new combinatorial identity, a graph of 3n (or 2n+m) vertices can be converted into a graph of n vertices in order to deal with the global stability of the endemic equilibrium in this paper. PMID- 25811335 TI - Construction of Lyapunov functions for some models of infectious diseases in vivo: from simple models to complex models. AB - We present a constructive method for Lyapunov functions for ordinary differential equation models of infectious diseases in vivo. We consider models derived from the Nowak-Bangham models. We construct Lyapunov functions for complex models using those of simpler models. Especially, we construct Lyapunov functions for models with an immune variable from those for models without an immune variable, a Lyapunov functions of a model with absorption effect from that for a model without absorption effect. We make the construction clear for Lyapunov functions proposed previously, and present new results with our method. PMID- 25811336 TI - On viable therapy strategy for a mathematical spatial cancer model describing the dynamics of malignant and healthy cells. AB - A mathematical spatial cancer model of the interaction between a drug and both malignant and healthy cells is considered. It is assumed that the drug influences negative malignant cells as well as healthy ones. The mathematical model considered consists of three nonlinear parabolic partial differential equations which describe spatial dynamics of malignant cells as well as healthy ones, and of the concentration of the drug. Additionally, we assume some phase constraints for the number of the malignant and the healthy cells and for the total dose of the drug during the whole treatment process. We search through all the courses of treatment switching between an application of the drug with the maximum intensity (intensive therapy phase) and discontinuing administering of the drug (relaxation phase) with the objective of achieving the maximum possible therapy (survival) time. We will call the therapy a viable treatment strategy. PMID- 25811337 TI - Aggregation and environmental transmission in Chronic Wasting Disease. AB - Disease transmission depends on the interplay between the infectious agent and the behavior of the host. Some diseases, such as Chronic Wasting Disease, can be transmitted directly between hosts as well as indirectly via the environment. The social behavior of hosts affects both of these pathways, and a successful intervention requires knowledge of the relative influence of the different etiological and behavioral aspects of the disease. We develop a strategic differential equation model for Chronic Wasting Disease and include direct and indirect transmission as well as host aggregation into our model. We calculate the basic reproduction number and perform a sensitivity analysis based on Latin hypercube sampling from published parameter values. We find conditions for the existence of an endemic equilibrium, and show that, under a certain mild assumption on parameters, the model does not exhibit a backward bifurcation or bistability. Hence, the basic reproduction number constitutes the disease elimination threshold. We find that the prevalence of the disease decreases with host aggregation and increases with the lifespan of the infectious agent in the environment. PMID- 25811338 TI - Dynamics of competitive systems with a single common limiting factor. AB - The concept of limiting factors (or regulating factors) succeeded in formulating the well-known principle of competitive exclusion. This paper shows that the concept of limiting factors is helpful not only to formulate the competitive exclusion principle, but also to obtain other ecological insights. To this end, by focusing on a specific community structure, we study the dynamics of Kolmogorov equations and show that it is possible to derive an ecologically insightful result only from the information about interactions between species and limiting factors. Furthermore, we find that the derived result is a generalization of the preceding work by Shigesada, Kawasaki, and Teramoto (1984), who examined a certain Lotka-Volterra equation in a different context. PMID- 25811339 TI - Delayed population models with Allee effects and exploitation. AB - Allee effects make populations more vulnerable to extinction, especially under severe harvesting or predation. Using a delay-differential equation modeling the evolution of a single-species population subject to constant effort harvesting, we show that the interplay between harvest strength and Allee effects leads not only to collapses due to overexploitation; large delays can interact with Allee effects to produce extinction at population densities that would survive for smaller time delays. In case of bistability, our estimations on the basins of attraction of the two coexisting attractors improve some recent results in this direction. Moreover, we show that the persistent attractor can exhibit bubbling: a stable equilibrium loses its stability as harvesting effort increases, giving rise to sustained oscillations, but higher mortality rates stabilize the equilibrium again. PMID- 25811342 TI - High-Dose Ribavirin Enhances Early Virological Response in Hepatitis C Genotype 1 Infected Patients. AB - BACKGROUND: The aim of the study was to investigate whether patients with a previous nonresponse to standard of care treatment with ribavirin dosed according to body weight would respond to a high individualized dose of concentration monitored ribavirin. METHODS: Previous nonresponders to standard of care treatment with peginterferon (peg-IFN) and ribavirin were included. Ribavirin was dosed aiming at a plasma concentration of >15 MUmol/L. The initial ribavirin dose was calculated from a formula based on renal function and body weight. Erythropoietin treatment was started 2 weeks before antiviral therapy. RESULTS: Twenty patients (16 men and 4 women) with a mean age of 52 years were included. Sixty percent had advanced fibrosis. Eighty percent of patients achieved an early viral response, and 60% were negative for hepatitis C virus ribonucleic acid (HCV RNA) at treatment week 24. High-dose ribavirin resulted in a significantly increased HCV RNA drop at week 12 (mean: 3.13 versus 2.05 IU/mL; P < 0.001). Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved sustained viral response. The final steady-state daily dose of ribavirin varied from 1400 to 4400 mg. Hemoglobin levels decreased during treatment, mean Hb 163, 134, and 110 g/L at week 0, 4, and 12, respectively. Two patients received blood transfusions. No other severe adverse events were recorded. CONCLUSIONS: An individualized high ribavirin dose resulted in a more pronounced early viral HCV RNA decline than a standard-dose ribavirin scheme. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given. PMID- 25811341 TI - Methodological Considerations for Hair Cortisol Measurements in Children. AB - BACKGROUND: Hair cortisol levels are used increasingly as a measure for chronic stress in young children. We propose modifications to the current methods used for hair cortisol analysis to more accurately determine reference ranges for hair cortisol across different populations and age groups. METHODS: The authors compared standard (finely cutting hair) versus milled methods for hair processing (n = 16), developed a 4-step extraction process for hair protein and cortisol (n = 16), and compared liquid chromatography-mass spectrometry (LC-MS) versus enzyme linked immunosorbent assays (ELISAs) for measuring hair cortisol (n = 28). The extraction process included sequential incubations in methanol and acetone, repeated twice. Hair protein was measured through spectrophotometric ratios at 260/280 nm to indicate the hair dissolution state using a BioTek plate reader and dedicated software. Hair cortisol was measured using an ELISA assay kit. Individual (n = 13), pooled hair samples (n = 12) with high, intermediate, and low cortisol values, and the ELISA assay internal standards (n = 3) were also evaluated by LC-MS. RESULTS: Milled and standard methods showed highly correlated hair cortisol (rs = 0.951, P < 0.0001) and protein values (rs = 0.902, P = 0.0002), although higher yields of cortisol and protein were obtained from the standard method in 13 of 16 and 14 of 16 samples, respectively (P < 0.05). Four sequential extractions yielded additional amounts of protein (36.5%, 27.5%, 30.5%, 3.1%) and cortisol (45.4%, 31.1%, 15.1%, 0.04%) from hair samples. Cortisol values measured by LC-MS and ELISA were correlated (rs = 0.737; P < 0.0001), although cortisol levels [median (interquartile range)] detected in the same samples by LC-MS [38.7 (14.4-136) ng/mL] were lower than that by ELISA [172.2 (67.9-1051) ng/mL]. LC-MS also detected cortisone, which comprised of 13.4% (3.7%-25.9%) of the steroids detected. CONCLUSIONS: Methodological studies suggest that finely cutting hair with sequential incubations in methanol and acetone, repeated twice, extracts greater yields of cortisol than does milled hair. Based on these findings, at least 3 incubations may be required to extract most of the cortisol in human hair samples. In addition, ELISA-based assays showed greater sensitivity for measuring hair cortisol levels than LC-MS-based assays. PMID- 25811343 TI - Proton therapy for head and neck cancer. AB - PURPOSE OF REVIEW: Proton therapy for head and neck cancer is an area of active research as technological advances are increasingly integrated into clinical practice, and also the subject of heightened scrutiny due to the significant associated cost. This article will highlight recent research into proton dosimetry, studies evaluating its clinical benefit relative to other advanced radiotherapy modalities, and key safety and cost considerations. RECENT FINDINGS: Recent dosimetric analyses have quantified the potential for the most sophisticated form of proton therapy, intensity-modulated proton therapy (IMPT), to reduce dose to key anatomic structures in the head and neck, and highlight the potential for dose uncertainty with IMPT if not implemented in a careful manner. Clinical contributions demonstrate the potential for protons to yield excellent local control and lower than expected morbidity for tumors adjacent to critical neurological structures. There are promising data in the reirradiation setting, and emerging data for IMPT in oropharyngeal cancer. SUMMARY: Proton therapy for head and neck cancer holds significant potential, and promising single institution experiences should be validated, wherever feasible, in prospective randomized clinical trials. In light of the significant associated cost, additional evidence is needed to guide the appropriate allocation of patients to IMPT versus intensity-modulated radiotherapy. PMID- 25811340 TI - The Affordable Care Act, Accountable Care Organizations, and Mental Health Care for Older Adults: Implications and Opportunities. AB - The Patient Protection and Affordable Care Act (ACA) represents the most significant legislative change in the United States health care system in nearly half a century. Key elements of the ACA include reforms aimed at addressing high cost, complex, vulnerable patient populations. Older adults with mental health disorders are a rapidly growing segment of the population and are among the most challenging subgroups within health care, and they account for a disproportionate amount of costs. What does the ACA mean for geriatric mental health? We address this question by highlighting opportunities for reaching older adults with mental health disorders by leveraging the diverse elements of the ACA. We describe nine relevant initiatives: (1) accountable care organizations, (2) patient-centered medical homes, (3) Medicaid-financed specialty health homes, (4) hospital readmission and health care transitions initiatives, (5) Medicare annual wellness visit, (6) quality standards and associated incentives, (7) support for health information technology and telehealth, (8) Independence at Home and 1915(i) State Plan Home and Community-Based Services program, and (9) Medicare-Medicaid Coordination Office, Center for Medicare and Medicaid Innovation, and the Patient Centered Outcomes Research Institute. We also consider potential challenges to full implementation of the ACA and discuss novel solutions for advancing geriatric mental health in the context of projected workforce shortages and the opportunities afforded by the ACA. PMID- 25811344 TI - Sequences and combinations of multifaceted therapy in advanced prostate cancer. AB - PURPOSE OF REVIEW: Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for use in advanced prostate cancer. The next wave of investigations is focused on the development of combinations and optimal sequences of the currently available agents. The focus of this article is to provide an update on clinical developments in advanced prostate cancer occurring within the past year and to highlight the ongoing investigations of promising novel targets and compounds. RECENT FINDINGS: The clinical use of enzalutamide prior to chemotherapy demonstrated improvement in progression-free survival and overall survival as compared with placebo in metastatic castrate resistant prostate cancer. This report of the Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (PREVAIL) trial led to the Food and Drug Administration approval of this agent. Novel agents such as cabozantinib and custirsen that had shown promising results in phase II trials revealed disappointing results in the phase III setting. The breakthrough report, of the ability of the androgen receptor splice variant mutation, detected in circulating tumor cells, to predict lack of response to abiraterone or enzalutamide, and the remarkable responses of poly(ADP-ribose) polymerase inhibitors in prostate cancer with breast cancer genes 1 and 2 (BRCA1/2) mutations, have elevated hopes of a bright future in the biomarker-driven therapeutic arena. SUMMARY: As the clinical application of the recently approved multifaceted therapies widens, trials addressing optimal sequences and combinations are gaining importance. In addition, exploring the utility of therapies in the hormone naive or nonmetastatic settings is an area of active investigation. Early use of available agents, optimal sequencing and aid of biomarkers to guide therapeutic choices will make the achievement of lifetime remissions in advanced prostate cancer a reachable goal. PMID- 25811346 TI - Emerging immunotherapies for bladder cancer. AB - PURPOSE OF REVIEW: Inhibition of immune escape mechanisms, such as the programed death-ligand 1 pathway, has demonstrated rapid, durable responses in multiple tumor types, including advanced urothelial carcinoma. This review discusses emerging immunotherapies for urothelial carcinoma in various stages of clinical development. RECENT FINDINGS: Urothelial carcinoma has a high mutational burden, which may increase the number of tumor antigens and potentially enhance the ability of the immune system to recognize tumor cells as foreign. However, urothelial carcinoma can evade the immune system by downregulating tumor-antigen presentation, upregulating various immune checkpoints, and inactivating cytotoxic T cells. Immunotherapies for urothelial carcinoma target each of these steps to restore immune-mediated cytotoxicity. Many of these agents are in clinical trials for urothelial carcinoma. SUMMARY: Immunotherapies are active in urothelial carcinoma, but only in a fraction of patients, implying the presence of persistent immune escape. Identifying the mechanisms of immune escape and developing rational combinatorial regimens may make the benefit of immunotherapy accessible to a broader population. PMID- 25811345 TI - Implications of ubiquitin ligases in castration-resistant prostate cancer. AB - PURPOSE OF REVIEW: Significant advances have been made in the study of ubiquitination-mediated regulation of androgen receptor (AR). This review will highlight the latest developments in the mechanisms by which E3 ubiquitin ligases control AR activity, with implications in castration-resistant prostate cancer (CRPC). RECENT FINDINGS: Several ubiquitin ligases have been identified to interact with and ubiquitinate AR, and consequently regulate the AR transcriptional programme. Different ubiquitin ligases can use distinct mechanisms to modulate the expression of AR target genes, including local turnover of AR chromatin complex, recruitment of AR coactivators and global AR stability. The expression or activity of ubiquitin ligases can be altered in prostate cancer and thus contribute to the growth of androgen-insensitive prostate cancer cells by modulating the AR transcriptional activity. SUMMARY: Understanding the regulation of AR transcriptional activity by ubiquitin ligases will contribute to the elucidation of mechanisms underlying AR reactivation that is believed to drive the development of CRPC. Ubiquitin ligases could potentially serve as promising targets for developing therapeutics in the treatment of advanced prostate cancers. PMID- 25811347 TI - What have we learned from exceptional tumour responses?: Review and perspectives. AB - PURPOSE OF REVIEW: Understanding the basis of exceptional responses may increase our knowledge of disease biology and the mechanism of action of targeted agents, and identify subpopulations of patients who derive important benefit from drugs that would otherwise not be developed due to lack of sufficient activity in the general population. We will discuss in this review the value of a systematic phenotype-to-genotype approach in these outlier responders to identify actionable therapeutic targets that can help to personalize the delivery of cancer treatment. RECENT FINDINGS: Genomic mapping of outlier responders by next generation sequencing is deciphering cancer biology at the individual level and providing insight in the somatic DNA alterations resulting in exceptional sensitivity to targeted agents in mono or combinational therapy. SUMMARY: In the era of targeted drugs, outlier or exceptional responders are frequently witnessed within early phase clinical trials. The genomic analysis of anecdotal 'exceptional responders' in trials that may otherwise not achieve prespecified efficacy endpoints may lead to the identification of predictive biomarkers for targeted therapies and revitalize or reposition the use of targeted agents in enriched populations. The era of unselected early clinical trials has passed with the advent of genomic-driven medicine and novel adaptive and biomarker-enrichment trials will accelerate drug approval, and overcome the challenges of testing targeted drugs against aberrations with low prevalence. PMID- 25811348 TI - Molecular pathways in renal cell carcinoma: recent advances in genetics and molecular biology. AB - PURPOSE OF REVIEW: Advanced renal cell carcinoma (RCC) remains a largely incurable disease with a grave prognosis despite the availability of a multiplicity of systemic therapies targeted against vascular endothelial growth factor, its receptors, and the mammalian target of rapamycin. Although immune 'checkpoint inhibitors' appear to have activity in clear cell RCC based on recent early phase trials, the true magnitude of the benefit conferred by these agents remains to be fully understood. Given the limitations of existing treatment paradigms, ongoing research into new targetable pathways is critical. This review will highlight some of the more promising avenues of investigation into the molecular biology of RCC. RECENT FINDINGS: The hypoxia-inducible factor and mammalian target of rapamycin pathways remain critical targets in clear cell RCC. In addition, genes involved in chromatin remodeling such as polybromo 1 (PBRM1), SET domain containing 2 (SETD2), and BRCA-1-associated protein-1 (BAP1) have been shown to influence tumor biology and predict survival. MET alterations and the Krebs cycle enzyme fumarate hydratase are associated with familial type 1 and type 2 papillary RCC (PRCC), respectively. Alterations in nuclear factor (erythroid-derived 2)-like 2, Kelch-like erythroid-derived cap-n-collar homology associated protein 1, and cullin 3, components of an oxidative stress response pathway, have been recently recognized in some sporadic papillary tumors as well as in fumarate hydratase-deficient tumor and may serve as additional therapeutic targets. In addition, whole-genome sequencing and integrated genomic analysis strategies are beginning to uncover unique molecular signatures associated with distinct subtypes of RCC, laying the foundation for a molecular classification of RCC and more precise, mechanism-based therapeutic intervention. SUMMARY: The complex molecular changes underlying individual RCC variants are yet to be fully elucidated and remain the subject of ongoing investigation. The findings summarized here further exemplify the diversity of RCC and the need to tailor our therapeutic approaches to the unique genetic alterations specific to individual subtypes of RCC. PMID- 25811349 TI - Prognostic Factors of Balance Quality After Transpetrosal Vestibular Schwannoma Microsurgery: An Instrumentally and DHI-based Prospective Cohort Study of 48 Patients. AB - OBJECTIVES: To evaluate short- and mid-term level of imbalance after vestibular schwannoma (VS) microsurgery by the transpetrosal approach, to search for factors predictive of vestibular compensation, and to determine which patient categories need a postoperative vestibular rehabilitation program. STUDY DESIGN: Prospective cohort study at a tertiary referral center. METHODS: Between 2010 and 2011, patients aged 18 to 75 operated on for VS by transpetrosal approaches were included. VS was characterized by its size (Koos classification) and the presence or not of a cystic component. Hearing was classified according to the Gardner Robertson grading. The preoperative workup included an audiogram, computerized video nystagmography (VNG) with caloric testing, gaze study, rotatory tests, click-evoked cervical vestibular evoked myogenic potential measurements (cVEMPs), and subjective visual vertical test. Patients were asked to complete a Dizziness Handicap Inventory (DHI). Postoperatively, patients were reevaluated on D7 (clinical status), D90 (VNG and DHI), and D180 (DHI). Timing and duration of vestibular rehabilitation were also recorded. RESULTS: Forty-eight patients were included. Preoperatively, 77% experienced mild instability problems with a mean DHI score of 14.1 (range 4-32). Postoperatively, 71% reported stable or even improved perceived stability. Mean DHI scores were 28.1 on D90 and 19.8 on D180. Serviceable hearing, cystic transformation, normal cVEMPs, diplopia, and vestibular syndrome on D7 were found to be predictive of worse equilibrium outcome than when absent. A preoperative caloric deficit greater than 75% seemed to be a good prognostic factor. Vestibular rehabilitation was conducted in 56% of patients. Starting it early (<1 mo) seemed to be beneficial for final equilibrium outcome. CONCLUSION: VS microsurgery provides good stability results. Some preoperative parameters may be predictive of worse or improved balance recovery, as is clinical status on D7. PMID- 25811350 TI - Real-World Verbal Communication Performance of Children Provided With Cochlear Implants or Hearing Aids. AB - OBJECTIVE: To compare the real-world verbal communication performance of children provided with cochlear implants (CIs) with their peers with hearing aids (HAs). STUDY DESIGN: Cross-sectional study in university tertiary referral centers and at hearing aid dispensers. METHODS: Verbal communication performance was assessed by the Functioning after Pediatric Cochlear Implantation (FAPCI) instrument. The FAPCI was administered to 38 parents of children using CIs and 62 parents of children with HAs. According to the WHO classification, children with HAs were categorized into three groups (mild-moderate-severe hearing loss). Analysis of variance (ANOVA) was performed on the FAPCI scores, with study group, hearing age (i.e., device experience), and age at hearing intervention as sources of variation. RESULTS: ANOVA showed that hearing age and study group significantly contribute to the FAPCI outcome. In all study groups except the children with mild hearing loss, FAPCI scores increased alongside growing experience with the devices. Children with mild hearing loss using HAs showed higher scores than those with severe hearing loss or implanted children. There were no significant differences between the children with CIs and the children with moderate or severe hearing loss using HAs. CONCLUSION: Real-world verbal communication abilities of children with CIs are similar to those of children with moderate-to severe hearing loss using amplification. Because hearing age significantly influences performance, children with moderate-to-severe hearing loss using HAs and implanted children catch up with children with mild hearing loss at a hearing age of approximately 3 years. PMID- 25811351 TI - A Retrospective Cohort Study on the Influence of Comorbidity on Soft Tissue Reactions, Revision Surgery, and Implant Loss in Bone-anchored Hearing Implants. AB - OBJECTIVE: To identify risk factors for complications after bone-anchored hearing implant (BAHI) surgery. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: All adult patients who received titanium bone anchored hearing implants at our clinic between September 1, 1988 and December 31, 2007 were approached to fill out a questionnaire on comorbidity factors. A total of 581 patients with 669 implants were included in the analysis. MAIN OUTCOME MEASURES: Implant loss, soft tissue reactions, and revision surgery after BAHI implantation. RESULTS: Skin disease and profound learning difficulties were risk factors for time to first soft tissue reaction, hazard rate ratio of 3.41 (95% CI 1.45-8.01) and 3.42 (1.03-11.39), respectively. Female gender showed a trend toward a negative risk for time to first soft tissue reaction, hazard rate ratio 0.60 (0.35-1.03). In multivariable analysis, skin disease and female gender were observed as independent associative factors, adjusted hazard ratio 3.08 (1.32-7.16) and 0.56 (0.33-0.94). For revision surgery, female gender and cardiovascular disease were identified as negative risk factors in univariable analysis, and smoking showed a trend toward a negative risk, with hazard ratios of 0.15 (0.07-0.32), 0.07 (0.03-0.20), and 0.51 (0.24-1.07), respectively. In multivariable analysis, smoking and female gender were observed as independent associative factors, adjusted hazard ratio 0.45 (0.22-0.95) and 0.14 (0.06-0.30). Smoking could be identified as a risk factor for implant loss with a hazard ratio of 3.32 (1.36-8.09). CONCLUSION: Retrospective analysis of comorbidity factors and clinical outcomes revealed risk factors for postoperative complications after BAHI surgery. PMID- 25811354 TI - Acute traumatic aortic injury: practical considerations for the diagnostic radiologist. AB - The diagnosis of acute traumatic aortic injury (ATAI) relies heavily on accurate and efficient imaging interpretation, thereby making the radiologist integral to the care of patients in whom these life-threatening lesions are suspected. Typically, this evaluation begins with the initial trauma radiograph, in which findings suggestive of mediastinal hematoma or ATAI can be detected. Definitive diagnosis of ATAI is made with the current gold standard, computed tomography, wherein indirect and direct signs of ATAI provide the means for sensitive and specific diagnosis. Although the diagnosis of ATAI on computed tomography can be straightforward, technical and anatomic pitfalls can complicate interpretation and must be understood. Once the diagnosis is made, the radiologist needs to provide a meaningful report that includes an appropriate description of the lesion location and characteristics. The purpose of this article is to review the key aspects of the imaging evaluation of ATAI with a focus on factors that affect the management of these patients. PMID- 25811352 TI - Influence of phthalates on cytokine production in monocytes and macrophages: a systematic review of experimental trials. AB - BACKGROUND: Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which could affect both pro- and anti-inflammatory abilities of these cells. STRATEGY AND RESULTS: A systematic search was performed in Medline, Embase and Toxline in June 2013, last updated 3rd of August 2014. Criteria used to select studies were described and published beforehand online on Prospero (http://www.crd.york.ac.uk/NIHR_PROSPERO, registration number CRD42013004236). In vivo, ex vivo and in vitro studies investigating the influence of phthalates on cytokine mRNA expression and cytokine secretion in animals and humans were included. A total of 11 reports, containing 12 studies, were found eligible for inclusion. In these, a total of four different phthalate diesters, six primary metabolites (phthalate monoesters) and seven different cytokines were investigated. Though all studies varied greatly in study design and species sources, four out of five studies that investigated di-2-ethylhexyl phthalate found an increased tumour necrosis factor alpha secretion/production from monocytes or macrophages. A summary of cytokine measurements was not possible since few studies were comparable in study design and due to insufficient reporting of raw data for most of the included studies. CONCLUSION: Results from this review have suggested that at least one phthalate (di-2-ethylhexyl phthalate) has the ability to enhance tumour necrosis factor alpha production/secretion from monocytes/macrophages in vitro, but also observed ex vivo. Influence of other phthalates on other cytokines has only been investigated in few studies. Thus, in vitro studies on primary human monocytes/macrophages as well as more in vivo studies are needed to confirm or dispute these findings. PMID- 25811355 TI - Diagnosing acute pulmonary embolism with computed tomography: imaging update. AB - Acute pulmonary embolism is recognized as a difficult diagnosis to make. It is potentially fatal if undiagnosed, yet increasing referral rates for imaging and falling diagnostic yields are topics which have attracted much attention. For patients in the emergency department with suspected pulmonary embolism, computed tomography pulmonary angiography (CTPA) is the test of choice for most physicians, and hence radiology has a key role to play in the patient pathway. This review will outline key aspects of the recent literature regarding the following issues: patient selection for imaging, the optimization of CTPA image quality and dose, preferred pathways for pregnant patients and other subgroups, and the role of CTPA beyond diagnosis. The role of newer techniques such as dual energy CT and single-photon emission-CT will also be discussed. PMID- 25811356 TI - Estimation of Pleural Fluid Volumes on Chest Radiography Using Computed Tomography Volumetric Analysis: An Update of the Visual Prediction Rule. AB - PURPOSE: The purpose of the study was to determine the volumes of pleural fluid (PF) required to produce visible menisci in the lateral and posterior costophrenic angles (CPA) and obscure the hemidiaphragms (HD) on upright frontal and lateral chest radiographs (CXRs), using volumetric analysis of chest computed tomography (CT). MATERIALS AND METHODS: A total of 98 patients with small pleural effusions on chest CT, in whom CXRs were obtained within a 24-hour interval, were selected for retrospective analysis. PF within each hemithorax was quantified using a semiautomatic method of image segmentation. A cardiothoracic radiologist scored each hemithorax on each CXR from 0 to 3 (0-normal CPA, 1--fluid meniscus below the HD, 2--fluid meniscus at the level of the HD, 3--fluid opacity obscures the HD). Each CXR category was correlated with CT-determined PF volumes. RESULTS: A mean of 20 mL of PF was present on CT without a visible correlate on CXR. A meniscus below the HD on CXR correlated with roughly 100 mL; a meniscus occurring at the HD correlated with roughly 250 mL; a meniscus obscuring the HD correlated with a mean of approximately 650 mL. There were large standard deviations for all PF volumes. CONCLUSIONS: We provide guidelines for estimating PF volumes on upright frontal and lateral CXRs. We also confirm that the lateral radiograph is more sensitive for detection of small pleural effusions, with blunting of the posterior CPA only correlating with a mean of 26 mL of PF. PMID- 25811353 TI - Mesoscale nanoparticles selectively target the renal proximal tubule epithelium. AB - We synthesized "mesoscale" nanoparticles, approximately 400 nm in diameter, which unexpectedly localized selectively in renal proximal tubules and up to 7 times more efficiently in the kidney than other organs. Although nanoparticles typically localize in the liver and spleen, modulating their size and opsonization potential allowed for stable targeting of the kidneys through a new proposed uptake mechanism. Applying this kidney targeting strategy, we anticipate use in the treatment of renal disease and the study of renal physiology. PMID- 25811357 TI - Correction: ENSO, nest predation risk, food abundance, and male status fail to explain annual variations in the apparent survival rate of a migratory songbird. PMID- 25811358 TI - Gender difference in ventricular response to aortic stenosis: insight from cardiovascular magnetic resonance. AB - BACKGROUND: Although left ventricular hypertrophy (LVH) and remodeling is associated with cardiac mortality and morbidity, little is known about the impact of gender on the ventricular response in aortic stenosis (AS) patients. This study aimed to analyze the differential effect of gender on ventricular remodeling in moderate to severe AS patients. METHODS AND RESULTS: A total of 118 consecutive patients (67+/-9 years; 63 males) with moderate or severe AS (severe 81.4%) underwent transthoracic echocardiography and cardiovascular magnetic resonance (CMR) within a 1-month period in this two-center prospective registry. The pattern of LV remodeling was assessed using the LV mass index (LVMI) and LV remodeling index (LVRI; LV mass/LV end-diastolic volume) by CMR. Although there were no differences in AS severity parameters nor baseline characteristics between genders, males showed a significantly higher LVMI (102.6+/-29.1 g/m2 vs. 86.1+/-29.2 g/m2, p=0.003) and LVRI (1.1+/-0.2 vs. 1.0+/-0.3, p=0.018), regardless of AS severity. The LVMI was significantly associated with aortic valve area (AVA) index and valvuloarterial impedance in females, whereas it was not in males, resulting in significant interaction between genders (PInteraction=0.007/0.014 for AVA index/valvuloarterial impedance, respectively). Similarly, the LVRI also showed a significantly different association between male and female subjects with the change in AS severity parameters (PInteraction=0.033/<0.001/0.029 for AVA index/transaortic mean pressure gradient/valvuloarterial impedance, respectively). CONCLUSION: Males are associated with greater degree of LVH and higher LVRI compared to females at moderate to severe AS. However, females showed a more exaggerated LV remodeling response, with increased severity of AS and hemodynamic loads, than males. PMID- 25811361 TI - CaMKII Phosphorylation in Primary Somatosensory Cortical Neurons is Involved in the Inhibition of Remifentanil-induced Hyperalgesia by Lidocaine in Male Sprague Dawley Rats. AB - BACKGROUND: Previous clinical studies have shown that lidocaine can alleviate severe postoperative pain after remifentanil-based anesthesia. Experimental studies have also demonstrated that lidocaine can inhibit remifentanil-induced hyperalgesia, yet the mechanism remains unknown. The present study explored the role of the primary somatosensory (S1) cortex in remifentanil-induced hyperalgesia as well as its inhibition by lidocaine through evaluation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation and protein expression levels in S1 cortical neurons. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly allocated to the following 3 groups: remifentanil only (R), lidocaine only (L), and remifentanil+lidocaine (RL). Experimentally naive animals were used as controls for immunoblotting and immunofluorescence evaluations. Via intravenous tail vein administration (24 G catheter), the animals received remifentanil at 2.4 MUg/kg/min, lidocaine at 200 MUg/kg/min, and remifentanil at 2.4 MUg/kg/min plus lidocaine at 200 MUg/kg/min for 2 hours. Paw withdrawal threshold (PWT) values for both mechanical and thermal hyperalgesia, along with immunoblotting and immunofluorescence, were used to measure remifentanil-induced hyperalgesia and changes in CaMKII phosphorylation (P-CaMKII) and total protein expression (T-CaMKII). RESULTS: There was a significant decrease in the PWT for mechanical stimulation at 0.5 and 2 hours after discontinuing infusion in groups R and RL (P<0.05, n=10 per group). However, there were no differences in thermal PWT in any group at any time period when compared with that of baseline. There was also a significant increase of P CaMKII (not T-CaMKII) in S1 cortical neurons of group R (not L and RL groups) at 0 to 2 hours after discontinuing infusion when compared with that of the corresponding control group (P<0.05, n=6 per group) as determined by immunoblotting and immunofluorescence microscopy. CONCLUSIONS: These results suggested that the phosphorylation of CaMKII in S1 cortical neurons increases significantly during the process of remifentanil-induced hyperalgesia. The increase of CaMKII phosphorylation could be inhibited by systemic application of lidocaine. This inhibition may play a role in the antihyperalgesia effects of lidocaine. PMID- 25811359 TI - HIF-1alpha contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling. AB - The aim of this study was to investigate the effects of hypoxia-inducible factor 1alpha (HIF-1alpha) on the proliferation, migration and invasion of neuroblastoma (NB) cells and the mechanisms involved. We here initially used the real-time polymerase chain reaction (real-time PCR), Western blotting and immunohistochemistry (IHC) to detect the expression of HIF-1alpha and components of the sonic hedgehog (SHH) signaling pathway in NB cells and human specimens. Subsequently, cell proliferation, migration and invasion were analyzed using the cell counting assay, wound healing assay and Transwell system in two types of human NB cell lines, SH-SY5Y and IMR32. In addition, the role of HIF-1alpha in NB cells growth was determined in a xenograft nude mouse model. We found that the level of HIF-1alpha was significantly upregulated during NB progression and was associated with the expression of two components of SHH signaling, SHH and GLI1. We next indicated that the proliferation, migration and invasiveness of SH-SY5Y and IMR32 cells were significantly inhibited by HIF-1alpha knockdown, which was mediated by small interfering RNAs (siRNAs) targeting against its mRNA. Furthermore, the growth of NB cells in vivo was also suppressed by HIF-1alpha inhibition. Finally, the pro-migration and proliferative effects of HIF-1alpha could be reversed by disrupting SHH signaling. In conclusion, our results demonstrated that upregulation of HIF-1alpha in NB promotes proliferation, migration and invasiveness via SHH signaling. PMID- 25811362 TI - Noninvasive Brain Physiology Monitoring for Extreme Environments: A Critical Review. AB - Our ability to monitor the brain physiology is advancing; however, most of the technology is bulky, expensive, and designed for traditional clinical settings. With long-duration space exploration, there is a need for developing medical technologies that are reliable, low energy, portable, and semiautonomous. Our aim was to review the state of the art for noninvasive technologies capable of monitoring brain physiology in diverse settings. A literature review of PubMed and the Texas Medical Center library sites was performed using prespecified search criteria to identify portable technologies for monitoring physiological aspects of the brain physiology. Most brain-monitoring technologies require a moderate to high degree of operator skill. Some are low energy, but many require a constant external power supply. Most of the technologies lack the accuracy seen in gold standard measures, due to the need for calibration, but may be useful for screening or monitoring relative changes in a parameter. Most of the technologies use ultrasound or electromagnetic radiation as energy sources. There is an important need for further development of portable technologies that can be operated in a variety of extreme environments to monitor brain health. PMID- 25811360 TI - Site-specific differences in T cell frequencies and phenotypes in the blood and gut of HIV-uninfected and ART-treated HIV+ adults. AB - Gastrointestinal T lymphocytes are critical for mucosal immunity and HIV pathogenesis, yet little is known about normal T cell numbers and phenotypes in different regions of the gut, or the degree to which ART can restore levels to those of HIV-uninfected individuals. To investigate these questions, we measured T cell frequencies and markers of memory, activation, anergy, and homing in the blood, ileum, and rectum of HIV- and ART-suppressed HIV+ adults. In HIV- individuals, T cell frequencies and phenotypes differed significantly between sites. Compared to HIV- adults, HIV+ adults had lower absolute CD4+T cell counts in the ileal lamina propria and lower relative CD4+T cell counts in the blood and ileum. In the gut, HIV+ adults had a higher proportion of CD38+ CD4+T cells, a lower proportion of terminally-differentiated effector cells, and, in the rectum, a higher proportion of CTLA-4+ CD4+T cells. In HIV+ individuals, relative CD4+T cell numbers in the ileum correlated with the proportion of CTLA-4+ CD4+T cells, whereas in the rectum, they tended to correlate with the proportion of circulating CD4+T cells expressing alpha4beta7 or CCR6. Mechanisms of T cell reconstitution may differ throughout the gut, with homing contributing more in the rectum while ileal reconstitution is associated with mucosal CD4+T cell anergy. PMID- 25811363 TI - The Potential Benefits of Awake Craniotomy for Brain Tumor Resection: An Anesthesiologist's Perspective. AB - Awake craniotomy for brain tumor resection is becoming a standard of care for lesions residing within or in close proximity to regions presumed to have language or sensorimotor function. Evidence shows an improved outcome including greater extent of resection, fewer late neurological deficits, shorter hospital stay, and longer survival after awake brain tumor resection compared with surgery under general anesthesia. The surgeon's ability to maximize tumor resection within the constraint of preserving neurological function by intraoperative stimulation mapping in an awake patient is credited for this advantageous result. It is possible that the care provided by anesthesiologists, especially the avoidance of certain components of general endotracheal anesthesia, may also be important in the outcome of awake brain tumor resection. We present our interpretation of the evidence that we believe substantiates this proposition. However, due to the lack of direct evidence based on randomized-controlled trials and the heterogeneity of anesthetic techniques used for awake craniotomy, our perspective is largely speculative and hypothesis generating that needs to be validated or refuted by future quality research. PMID- 25811364 TI - Signature wood modifications reveal decomposer community history. AB - Correlating plant litter decay rates with initial tissue traits (e.g. C, N contents) is common practice, but in woody litter, predictive relationships are often weak. Variability in predicting wood decomposition is partially due to territorial competition among fungal decomposers that, in turn, have a range of nutritional strategies (rot types) and consequences on residues. Given this biotic influence, researchers are increasingly using culture-independent tools in an attempt to link variability more directly to decomposer groups. Our goal was to complement these tools by using certain wood modifications as 'signatures' that provide more functional information about decomposer dominance than density loss. Specifically, we used dilute alkali solubility (DAS; higher for brown rot) and lignin:density loss (L:D; higher for white rot) to infer rot type (binary) and fungal nutritional mode (gradient), respectively. We first determined strength of pattern among 29 fungi of known rot type by correlating DAS and L:D with mass loss in birch and pine. Having shown robust relationships for both techniques above a density loss threshold, we then demonstrated and resolved two issues relevant to species consortia and field trials, 1) spatial patchiness creating gravimetric bias (density bias), and 2) brown rot imprints prior or subsequent to white rot replacement (legacy effects). Finally, we field-tested our methods in a New Zealand Pinus radiata plantation in a paired-plot comparison. Overall, results validate these low-cost techniques that measure the collective histories of decomposer dominance in wood. The L:D measure also showed clear potential in classifying 'rot type' along a spectrum rather than as a traditional binary type (brown versus white rot), as it places the nutritional strategies of wood-degrading fungi on a scale (L:D=0-5, in this case). These information-rich measures of consequence can provide insight into their biological causes, strengthening the links between traits, structure, and function during wood decomposition. PMID- 25811365 TI - Tertiary siRNAs mediate paramutation in C. elegans. AB - In the nematode Caenorhabditis elegans, different small RNA-dependent gene silencing mechanisms act in the germline to initiate transgenerational gene silencing. Piwi-interacting RNAs (piRNAs) can initiate transposon and gene silencing by acting upstream of endogenous short interfering RNAs (siRNAs), which engage a nuclear RNA interference (RNAi) pathway to trigger transcriptional gene silencing. Once gene silencing has been established, it can be stably maintained over multiple generations without the requirement of the initial trigger and is also referred to as RNAe or paramutation. This heritable silencing depends on the integrity of the nuclear RNAi pathway. However, the exact mechanism by which silencing is maintained across generations is not understood. Here we demonstrate that silencing of piRNA targets involves the production of two distinct classes of small RNAs with different genetic requirements. The first class, secondary siRNAs, are localized close to the direct target site for piRNAs. Nuclear import of the secondary siRNAs by the Argonaute HRDE-1 leads to the production of a distinct class of small RNAs that map throughout the transcript, which we term tertiary siRNAs. Both classes of small RNAs are necessary for full repression of the target gene and can be maintained independently of the initial piRNA trigger. Consistently, we observed a form of paramutation associated with tertiary siRNAs. Once paramutated, a tertiary siRNA generating allele confers dominant silencing in the progeny regardless of its own transmission, suggesting germline transmitted siRNAs are sufficient for multigenerational silencing. This work uncovers a multi-step siRNA amplification pathway that promotes germline integrity via epigenetic silencing of endogenous and invading genetic elements. In addition, the same pathway can be engaged in environmentally induced heritable gene silencing and could therefore promote the inheritance of acquired traits. PMID- 25811366 TI - Identification of multiple metabolic enzymes from mice cochleae tissue using a novel functional proteomics technology. AB - A new type of technology in proteomics was developed in order to separate a complex protein mixture and analyze protein functions systematically. The technology combines the ability of two-dimensional gel electrophoresis (2-DE) to separate proteins with a protein elution plate (PEP) to recover active proteins for functional analysis and mass spectrometry (MS)-based identification. In order to demonstrate the feasibility of this functional proteomics approach, NADH and NADPH-dependent oxidases, major redox enzyme families, were identified from mice cochlear tissue after a specific drug treatment. By comparing the enzymatic activity between mice that were treated with a drug and a control group significant changes were observed. Using MS, five NADH-dependent oxidases were identified that showed highly altered enzymatic activities due to the drug treatment. In essence, the PEP technology allows for a systematic analysis of a large enzyme family from a complex proteome, providing insights in understanding the mechanism of drug treatment. PMID- 25811368 TI - Norovirus genotype profiles associated with foodborne transmission, 1999-2012. AB - Worldwide, noroviruses are a leading cause of gastroenteritis. They can be transmitted from person to person directly or indirectly through contaminated food, water, or environments. To estimate the proportion of foodborne infections caused by noroviruses on a global scale, we used norovirus transmission and genotyping information from multiple international outbreak surveillance systems (Noronet, CaliciNet, EpiSurv) and from a systematic review of peer-reviewed literature. The proportion of outbreaks caused by food was determined by genotype and/or genogroup. Analysis resulted in the following final global profiles: foodborne transmission is attributed to 10% (range 9%%-11%) of all genotype GII.4 outbreaks, 27% (25%-30%) of outbreaks caused by all other single genotypes, and 37% (24%%-52%) of outbreaks caused by mixtures of GII.4 and other noroviruses. When these profiles are applied to global outbreak surveillance data, results indicate that ~14% of all norovirus outbreaks are attributed to food. PMID- 25811367 TI - Mitochondrial-derived reactive oxygen species play a vital role in the salicylic acid signaling pathway in Arabidopsis thaliana. AB - Plant mitochondria constitute a major source of ROS and are proposed to act as signaling organelles in the orchestration of defense response. At present, the signals generated and then integrated by mitochondria are still limited. Here, fluorescence techniques were used to monitor the events of mitochondria in vivo, as well as the induction of mitochondrial signaling by a natural defensive signal chemical salicylic acid (SA). An inhibition of respiration was observed in isolated mitochondria subjected to SA. The cytochrome reductase activity analysis in isolated mitochondria demonstrated that SA might act directly on the complex III in the respiration chain by inhibiting the activity. With this alteration, a quick burst of mitochondrial ROS (mtROS) was stimulated. SA-induced mtROS caused mitochondrial morphology transition in leaf tissue or protoplasts expressing mitochondria-GFP (43C5) and depolarization of membrane potential. However, the application of AsA, an H2O2 scavenger, significantly prevented both events, indicating that both of them are attributable to ROS accumulation. In parallel, SA-induced mtROS up-regulated AOX1a transcript abundance and this induction was correlated with the disease resistance, whereas AsA-pretreatment interdicted this effect. It is concluded that mitochondria play an essential role in the signaling pathway of SA-induced ROS generation, which possibly provided new insight into the SA-mediated biological processes, including plant defense response. PMID- 25811369 TI - The effect of symbiotic ant colonies on plant growth: a test using an Azteca Cecropia system. AB - In studies of ant-plant mutualisms, the role that ants play in increasing the growth rates of their plant partners is potentially a key beneficial service. In the field, we measured the growth of Cecropia glaziovii saplings and compared individuals that were naturally colonized by Azteca muelleri ants with uncolonized plants in different seasons (wet and dry). We also measured light availability as well as attributes that could be influenced by the presence of Azteca colonies, such as herbivory, leaf nutrients (total nitrogen and delta(15)N), and investments in defense (total phenolics and leaf mass per area). We found that colonized plants grew faster than uncolonized plants and experienced a lower level of herbivory in both the wet and dry seasons. Colonized plants had higher nitrogen content than uncolonized plants, although the delta(15)N, light environment, total phenolics and leaf mass per area, did not differ between colonized and uncolonized plants. Since colonized and uncolonized plants did not differ in the direct defenses that we evaluated, yet herbivory was lower in colonized plants, we conclude that biotic defenses were the most effective protection against herbivores in our system. This result supports the hypothesis that protection provided by ants is an important factor promoting plant growth. Since C. glaziovii is widely distributed among a variety of forests and ecotones, and since we demonstrated a strong relationship with their ant partners, this system can be useful for comparative studies of ant-plant interactions in different habitats. Also, given this study was carried out near the transition to the subtropics, these results help generalize the geographic distribution of this mutualism and may shed light on the persistence of the interactions in the face of climate change. PMID- 25811370 TI - Targeted deletion of the murine Lgr4 gene decreases lens epithelial cell resistance to oxidative stress and induces age-related cataract formation. AB - Oxidative stress contributes to the formation of cataracts. The leucine rich repeat containing G protein-coupled receptor 4 (LGR4, also known as GPR48), is important in many developmental processes. Since deletion of Lgr4 has previously been shown to lead to cataract formation in mice, we sought to determine the specific role that Lgr4 plays in the formation of cataracts. Initially, the lens opacities of Lgr4(-/-) mice at different ages without ocular anterior segment dysgenesis (ASD) were evaluated with slit-lamp biomicroscopy. Lenses from both Lgr4(-/-) and wild-type mice were subjected to oxidation induced protein denaturation to assess the ability of the lens to withstand oxidation. The expression of antioxidant enzymes was evaluated with real-time quantitative PCR. Phenotypically, Lgr4(-/-) mice showed earlier onset of lens opacification and higher incidence of cataract formation compared with wild-type mice of similar age. In addition, Lgr4(-/-) mice demonstrated increased sensitivity to environmental oxidative damage, as evidenced by altered protein expression. Real time quantitative PCR showed that two prominent antioxidant defense enzymes, catalase (CAT) and superoxidase dismutase-1 (SOD1), were significantly decreased in the lens epithelial cells of Lgr4(-/-) mice. Our results suggest that the deletion of Lgr4 can lead to premature cataract formation, as well as progressive deterioration with aging. Oxidative stress and altered expression of several antioxidant defense enzymes contribute to the formation of cataracts. PMID- 25811372 TI - Correction: logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production. AB - [This corrects the article DOI: 10.1371/journal.pone.0089864.]. PMID- 25811371 TI - Antithrombin III deficiency in Indian patients with deep vein thrombosis: identification of first India based AT variants including a novel point mutation (T280A) that leads to aggregation. AB - Antithrombin III (AT) is the main inhibitor of blood coagulation proteases like thrombin and factor Xa. In this study we report the identification and characterization of several variants of AT for the first time in Indian population. We screened 1950 deep vein thrombosis (DVT) patients for AT activity and antigen levels. DNA sequencing was further carried out in patients with low AT activity and/or antigen levels to identify variations in the AT gene. Two families, one with type I and the other with type II AT deficiency were identified. Three members of family I showed an increase in the coagulation rates and recurrent thrombosis in this family was solely attributed to the rs2227589 polymorphism. Four members of family II spanning two generations had normal antigen levels and decreased AT activity. A novel single nucleotide insertion, g.13362_13363insA in this family in addition to g.2603T>C (p.R47C) mutation were identified. AT purified from patient's plasma on hi-trap heparin column showed a marked decrease in heparin affinity and thrombin inhibition rates. Western blot analysis showed the presence of aggregated AT. We also report a novel point mutation at position g.7549 A>G (p.T280A), that is highly conserved in serpin family. Variant protein isolated from patient plasma indicated loss of regulatory function due to in-vivo polymerization. In conclusion this is the first report of AT mutations in SERPINC1 gene in Indo-Aryan population where a novel point mutation p.T280A and a novel single nucleotide insertion g.13362_13363insA are reported in addition to known variants like p.R47C, p.C4-X and polymorphisms of rs2227598, PstI and DdeI. PMID- 25811373 TI - Polyphenol extract from Phellinus igniarius protects against acrolein toxicity in vitro and provides protection in a mouse stroke model. AB - The basidiomycetous mushroom Phellinus igniarius (L.) Quel. has been used as traditional medicine in various Asian countries for many years. Although many reports exist on its anti-oxidative and anti-inflammatory activities and therapeutic effects against various diseases, our current knowledge of its effect on stroke is very limited. Stroke is a neurodegenerative disorder in which oxidative stress is a key hallmark. Following the 2005 discovery by Igarashi's group that acrolein produced from polyamines in vivo is a major cause of cell damage by oxidative stress, we now describe the effects of anti-oxidative extracts from P. igniarius on symptoms of experimentally induced stroke in mice. The toxicity of acrolein was compared with that of hydrogen peroxide in a mouse mammary carcinoma cell line (FM3A). We found that the complete inhibition of FM3A cell growth by 5 MUM acrolein could be prevented by crude ethanol extract of P. igniarius at 0.5 MUg/ml. Seven polyphenol compounds named 3,4 dihydroxybenzaldehyde, 4-(3,4-dihydroxyphenyl-3-buten-2one, inonoblin C, phelligridin D, inoscavin C, phelligridin C and interfungin B were identified from this ethanolic extract by LCMS and 1H NMR. Polyphenol-containing extracts of P. igniarius were then used to prevent acrolein toxicity in a mouse neuroblastoma (Neuro-2a) cell line. The results suggested that Neuro-2a cells were protected from acrolein toxicity at 2 and 5 MUM by this polyphenol extract at 0.5 and 2 MUg/ml, respectively. Furthermore, in mice with experimentally induced stroke, intraperitoneal treatment with P. igniarius polyphenol extract at 20 MUg/kg caused a reduction of the infarction volume by 62.2% compared to untreated mice. These observations suggest that the polyphenol extract of P. igniarius could serve to prevent ischemic stroke. PMID- 25811374 TI - How well does the World Health Organization definition of domestic violence work for India? AB - Domestic violence (DV) is reported by 40% of married women in India and associated with substantial morbidity. An operational research definition is therefore needed to enhance understanding of DV epidemiology in India and inform DV interventions and measures. To arrive at a culturally-tailored definition, we aimed to better understand how definitions provided by the World Health Organization and the 2005 India Protection of Women from Domestic Violence Act match the perceptions of behaviors constituting DV among the Indian community. Between September 2012 and January 2013, 16 key informant interviews with experts in DV and family counseling and 2 gender-concordant focus groups of lay community members were conducted in Pune, India to understand community perceptions of the definition of DV, perpetrators of DV, and examples of DV encountered by married women in Pune, India. Several key themes emerged regarding behaviors and acts constituting DV including 1) the exertion of control over a woman's reproductive decision-making, mobility, socializing with family and friends, finances, and access to food and nutrition, 2) the widespread acceptance of sexual abuse and the influences of affluence on sexual DV manifestations, 3) the shaping of physical abuse experiences by readily-available tools and the presence of witnesses, 4) psychological abuse for infertility, dowry, and girl-children, and 5) the perpetration of DV by the husband and other members of his family. Findings support the need for a culturally-tailored operational definition that expands on the WHO surveillance definition to inform the development of more effective DV intervention strategies and measures. PMID- 25811376 TI - Correction: Thermophysical properties of lignocellulose: a cell-scale study down to 41K. PMID- 25811375 TI - All Akt isoforms (Akt1, Akt2, Akt3) are involved in normal hearing, but only Akt2 and Akt3 are involved in auditory hair cell survival in the mammalian inner ear. AB - The kinase Akt is a key downstream mediator of the phosphoinositide-3-kinase signaling pathway and participates in a variety of cellular processes. Akt comprises three isoforms each encoded by a separate gene. There is evidence to indicate that Akt is involved in the survival and protection of auditory hair cells in vitro. However, little is known about the physiological role of Akt in the inner ear-especially in the intact animal. To elucidate this issue, we first analyzed the mRNA expression of the three Akt isoforms in the inner ear of C57/BL6 mice by real-time PCR. Next, we tested the susceptibility to gentamicin induced auditory hair cell loss in isoform-specific Akt knockout mice compared to wild-types (C57/BL6) in vitro. To analyze the effect of gene deletion in vivo, hearing and cochlear microanatomy were evaluated in Akt isoform knockout animals. In this study, we found that all three Akt isoforms are expressed in the cochlea. Our results further indicate that Akt2 and Akt3 enhance hair cell resistance to ototoxicity, while Akt1 does not. Finally, we determined that untreated Akt1 and Akt2/Akt3 double knockout mice display significant hearing loss, indicating a role for these isoforms in normal hearing. Taken together, our results indicate that each of the Akt isoforms plays a distinct role in the mammalian inner ear. PMID- 25811378 TI - A duplex PCR assay for the detection of Ralstonia solanacearum phylotype II strains in Musa spp. AB - Banana wilt outbreaks that are attributable to Moko disease-causing strains of the pathogen Ralstonia solanacearum (Rs) remain a social and economic burden for both multinational corporations and subsistence farmers. All known Moko strains belong to the phylotype II lineage, which has been previously recognized for its broad genetic basis. Moko strains are paraphyletic and are distributed among seven related but distinct phylogenetic clusters (sequevars) that are potentially major threats to Musaceae, Solanaceae, and ornamental crops in many countries. Although clustered within the Moko IIB-4 sequevar, strains of the epidemiologically variant IIB-4NPB do not cause wilt on Cavendish or plantain bananas; instead, they establish a latent infection in the vascular tissues of plantains and demonstrate an expanded host range and high aggressiveness toward Solanaceae and Cucurbitaceae. Although most molecular diagnostic methods focus on strains that wilt Solanaceae (particularly potato), no relevant protocol has been described that universally detects strains of the Musaceae-infecting Rs phylotype II. Thus, a duplex PCR assay targeting Moko and IIB-4NPB variant strains was developed, and its performance was assessed using an extensive collection of 111 strains representing the known diversity of Rs Moko-related strains and IIB-4NPB variant strains along with certain related strains and families. The proposed diagnostic protocol demonstrated both high accuracy (inclusivity and exclusivity) and high repeatability, detected targets on either pure culture or spiked plant extracts. Although they did not belong to the Moko clusters described at the time of the study, recently discovered banana-infecting strains from Brazil were also detected. According to our comprehensive evaluation, this duplex PCR assay appears suitable for both research and diagnostic laboratories and provides reliable detection of phylotype II Rs strains that infect Musaceae. PMID- 25811379 TI - Enhanced protection against malaria by indoor residual spraying in addition to insecticide treated nets: is it dependent on transmission intensity or net usage? AB - BACKGROUND: Insecticide treated nets (ITNs) and indoor residual spraying (IRS) are effective vector control tools that protect against malaria. There is conflicting evidence regarding whether using ITNs and IRS in combination provides additional benefit over using either of these methods alone. This study investigated factors that may modify the effect of the combined use of IRS and ITNs compared to using ITNs alone on malaria infection prevalence. METHODS: Secondary analysis was carried out on data from a cluster randomised trial in north-west Tanzania. 50 clusters received ITNs from a universal coverage campaign; of these 25 were randomly allocated to additionally receive two rounds of IRS in 2012. In cross-sectional household surveys children 0.5-14 years old were tested for Plasmodium falciparum infections (PfPR) two, six and ten months after the first IRS round. RESULTS: IRS protected those sleeping under nets (OR = 0.38, 95%CI 0.26-0.57) and those who did not (OR = 0.43, 95%CI 0.29-0.63). The protective effect of IRS was not modified by community level ITN use (ITN use<50%, OR = 0.39, 95%CI 0.26-0.59; ITN use> = 50%, OR = 0.46, 95%CI 0.28-0.74). The additional protection from IRS was similar in low (<10% PfPR, OR = 0.38, 95%CI 0.19-0.75) and high transmission areas (>=10% PfPR, OR = 0.34, 95%CI 0.18 0.67). ITN use was protective at the individual-level regardless of whether the village had been sprayed (OR = 0.83, 95%CI 0.70-0.98). Living in a sprayed village was protective regardless of whether the individual slept under an ITN last night (OR = 0.41, 95%CI 0.29-0.58). INTERPRETATION: Implementing IRS in addition to ITNs was beneficial for individuals from villages with a wide range of transmission intensities and net utilisation levels. Net users received additional protection from IRS. ITNs were providing some individual protection, even in this area with high levels of pyrethroid insecticide resistance. These results demonstrate that there is a supplementary benefit of IRS even when ITNs are effective. TRIAL REGISTRATION: ClinicalTrials.gov NCT01697852. PMID- 25811377 TI - Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta. AB - Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2alpha, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1alpha), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2alpha, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1alpha and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine exposure during pregnancy on placental health. PMID- 25811381 TI - Antimicrobial-induced DNA damage and genomic instability in microbial pathogens. PMID- 25811380 TI - Central melanocortins regulate the motivation for sucrose reward. AB - The role of the melanocortin (MC) system in feeding behavior is well established. Food intake is potently suppressed by central infusion of the MC 3/4 receptor agonist alpha-melanocyte stimulating hormone (alpha-MSH), whereas the MC 3/4 receptor inverse-agonist Agouti Related Peptide (AGRP) has the opposite effect. MC receptors are widely expressed in both hypothalamic and extra-hypothalamic brain regions, including nuclei involved in food reward and motivation, such as the nucleus accumbens (NAc) and the ventral tegmental area. This suggests that MCs modulate motivational aspects of food intake. To test this hypothesis, rats were injected intracerebroventricularly with alpha-MSH or AGRP and their motivation for sucrose was tested under a progressive ratio schedule of reinforcement. Food motivated behavior was dose-dependently decreased by alpha MSH. Conversely, AGRP increased responding for sucrose, an effect that was blocked by pretreatment with the dopamine receptor antagonist alpha-flupenthixol. In contrast to progressive ratio responding, free intake of sucrose remained unaltered upon alpha-MSH or AGRP infusion. In addition, we investigated whether the effects of alpha-MSH and AGRP on food motivation were mediated by the NAc shell. In situ hybridization of MC3 and MC4 receptor expression confirmed that the MC4 receptor was expressed throughout the NAc, and injection of alpha-MSH and AGRP into the NAc shell caused a decrease and an increase in motivation for sucrose, respectively. These data show that the motivation for palatable food is modulated by MC4 receptors in the NAc shell, and demonstrate cross-talk between the MC and dopamine system in the modulation of food motivation. PMID- 25811382 TI - The spectrum of kidney pathology in B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma: a 25-year multicenter experience. AB - BACKGROUND: Chronic lymphocytic leukemia and small lymphocytic lymphoma are 2 different presentations of the most common B-cell neoplasm in western countries (CLL/SLL). In this disease, kidney involvement is usually silent, and is rarely reported in the literature. This study provides a clinicopathological analysis of all-cause kidney disease in CLL/SLL patients. METHODS: Fifteen CLL/SLL patients with kidney biopsy were identified retrospectively. Demographic, clinical, pathological and laboratory data were assessed at biopsy, and during follow-up. RESULTS: At biopsy 11 patients presented impaired renal function, 7 patients nephrotic syndrome, 6 patients dysproteinemia, and 3 patients cryoglobulinemia. Kidney pathology revealed CLL/SLL-specific monoclonal infiltrate in 10 biopsies, glomerulopathy in 9 biopsies (5 membranoproliferative glomerulonephritis, 2 minimal change disease, 1 glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits, 1 AHL amyloidosis). Five patients presented interstitial granulomas attributed to CLL/SLL. After treatment of the hematological disease, improvement of renal function was observed in 7/11 patients, and remission of nephrotic syndrome in 5/7 patients. During follow-up, aggravation of the kidney disease systematically occurred in the absence of favorable response to hematological treatment. CONCLUSIONS: A broad spectrum of kidney diseases is associated with CLL/SLL. In this setting, kidney biopsy can provide important information for diagnosis and therapeutic guidance. PMID- 25811384 TI - Disagreeing on whether agreement is persuasive: perceptions of expert group decisions. AB - While expert groups often make recommendations on a range of non-controversial as well as controversial issues, little is known about how the level of expert consensus-the level of expert agreement-influences perceptions of the recommendations. This research illustrates that for non-controversial issues expert groups that exhibit high levels of agreement are more persuasive than expert groups that exhibit low levels of agreement. This effect is mediated by the perceived entitativity-the perceived cohesiveness or unification of the group of the expert group. But for controversial issues, this effect is moderated by the perceivers' implicit assumptions about the group composition. When perceivers are provided no information about a group supporting the Affordable Care Act-a highly controversial piece of U.S. legislation that is divided by political party throughout the country-higher levels of agreement are less persuasive than lower levels of agreement because participants assume there were more democrats and fewer republicans in the group. But when explicitly told that the group was half republicans and half democrats, higher levels of agreement are more persuasive. PMID- 25811383 TI - Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin. AB - Nephropathic cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene encoding cystine transporter cystinosin that results in accumulation of amino acid cystine in the lysosomes throughout the body and especially affects kidneys. Early manifestations of the disease include renal Fanconi syndrome, a generalized proximal tubular dysfunction. Current therapy of cystinosis is based on cystine-lowering drug cysteamine that postpones the disease progression but offers no cure for the Fanconi syndrome. We studied the mechanisms of impaired reabsorption in human proximal tubular epithelial cells (PTEC) deficient for cystinosin and investigated the endo-lysosomal compartments of cystinosin-deficient PTEC by means of light and electron microscopy. We demonstrate that cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. Treatment with cysteamine improved surface expression and lysosomal cargo processing but did not lead to a complete restoration and had no effect on the abnormal morphology of endo-lysosomal compartments. The obtained results improve our understanding of the mechanism of proximal tubular dysfunction in cystinosis and indicate that impaired protein reabsorption can, at least partially, be explained by abnormal trafficking of endosomal vesicles. PMID- 25811385 TI - Barriers to health and social services for street-involved youth in a Canadian setting. AB - Although street-involved youth contend with many health and social problems, the extent to which vulnerable youth engage with supportive services has not been well described. This study sought to examine the prevalence and correlates associated with having difficulty accessing health and social services among a prospective cohort of street-involved youth in Vancouver, Canada. Among 1019 street-involved youth, 650 (64 per cent) reported having difficulty accessing services during the study period. In a multivariate analysis, youth who reported having difficulty accessing services were significantly more likely to be socially and economically vulnerable. Specifically, they were more likely to report severe housing instability, high-intensity drug use, recent interactions with law enforcement, drug dealing, and histories of violence and physical abuse. Study findings point to opportunities to improve access to services among vulnerable youth through removal of blanket age restrictions for youth services, establishing youth-centric social housing, and supporting peer-driven, low threshold services. PMID- 25811386 TI - Consolidating HIV testing in a public health laboratory for efficient and sustainable early infant diagnosis (EID) in Uganda. AB - Uganda introduced an HIV Early Infant Diagnosis (EID) program in 2006, and then worked to improve the laboratory, transportation, and clinical elements. Reported here are the activities involved in setting up a prospective analysis in which the Ministry of Health, with its NGO partners, determined it would be more effective and efficient to consolidate the initial eight-laboratory system for EID testing of HIV dried blood samples offered by two nongovernmental partners operating research facilities into a single well-equipped and staffed laboratory within the Ministry. A retrospective analysis confirmed that redesign reduced overhead cost per PCR test of HIV dried blood samples from US$22.20 to an average of $5. Along with the revamped system of sample collection, transportation, and result communication, Uganda has been able to vastly increase the HIV diagnosis of babies and engagement of them and their mothers in clinical care, including antiretroviral therapy. Uganda reduced turnaround times for results reporting to clinicians from more than a month in 2006 to just 2 weeks by 2014, even as samples tested increased dramatically. The next challenge is overcoming loss of babies and mothers to follow up. PMID- 25811388 TI - Adding a dedicated public health approach to the international drug control regime. PMID- 25811387 TI - Middle East Respiratory Syndrome Corona Virus (MERS CoV): The next steps. AB - Developing countries are at risk of importing Middle East Respiratory Syndrome Corona Virus (MERS CoV) from the Middle East. Hospitals in the Middle East currently reporting the disease are staffed by immigrants. In the current hot spots for MERS CoV a sizeable portion of the population is from other countries, but many of these countries have yet to detect any importation of MERS CoV. To assess the disease transmission in these countries, supplemental surveillance strategies are urgently needed beyond the currently recommended measures. A few strategies to address the situation are: (i) improving preparedness with enhanced surveillance in particular regions; (ii) targeting certain sentinel groups for surveillance in hot spots; and (iii) limited use of serosurveillance. Recovered, immune patients can be employed to give patient care during outbreaks. PMID- 25811389 TI - Matrix Effects in Quantitative Assessment of Pharmaceutical Tablets Using Transmission Raman and Near-Infrared (NIR) Spectroscopy. AB - Raman spectroscopy can be an alternative to near-infrared spectroscopy (NIR) for nondestructive quantitative analysis of solid pharmaceutical formulations. Compared with NIR spectra, Raman spectra have much better selectivity, but subsampling was always an issue for quantitative assessment. Raman spectroscopy in transmission mode has reduced this issue, since a large volume of the sample is measured in transmission mode. The sample matrix, such as particle size of the drug substance in a tablet, may affect the Raman signal. In this work, matrix effects in transmission NIR and Raman spectroscopy were systematically investigated for a solid pharmaceutical formulation. Tablets were manufactured according to an experimental design, varying the factors particle size of the drug substance (DS), particle size of the filler, compression force, and content of drug substance. All factors were varied at two levels plus a center point, except the drug substance content, which was varied at five levels. Six tablets from each experimental point were measured with transmission NIR and Raman spectroscopy, and their concentration of DS was determined for a third of those tablets. Principal component analysis of NIR and Raman spectra showed that the drug substance content and particle size, the particle size of the filler, and the compression force affected both NIR and Raman spectra. For quantitative assessment, orthogonal partial least squares regression was applied. All factors varied in the experimental design influenced the prediction of the DS content to some extent, both for NIR and Raman spectroscopy, the particle size of the filler having the largest effect. When all matrix variations were included in the multivariate calibrations, however, good predictions of all types of tablets were obtained, both for NIR and Raman spectroscopy. The prediction error using transmission Raman spectroscopy was about 30% lower than that obtained with transmission NIR spectroscopy. PMID- 25811390 TI - Fluid Replacement Attenuates Physiological Strain Resulting From Mild Hypohydration Without Impacting Cognitive Performance. AB - PURPOSE: The impact of mild hypohydration on physiological responses and cognitive performance following exercise-heat stress (EHS) were examined compared with conditions when fluids were ingested ad libitum (AL) or replaced to match sweat losses (FR). METHODS: Twelve unacclimatized, recreationally-active men (22.2 +/- 2.4 y) completed 50 min cycling (60%VO2peak) in the heat (32 degrees C; 65% RH) under three conditions: no fluid (NF), AL, and FR. Before and after EHS, a cognitive battery was completed: Trail making, perceptual vigilance, pattern comparison, match-to-sample, and letter-digit recognition tests. RESULTS: Hypohydration during NF was greater compared with AL and FR (NF: -1.5 +/- 0.6; AL: -0.3 +/- 0.8; FR: -0.1 +/- 0.3% body mass loss) resulting in higher core temperature (by 0.4, 0.5 degrees C), heart rate (by 13 and 15 b.min-1), and physiological strain (by 1.3, 1.5) at the end of EHS compared with AL and FR, respectively. Cognitive performance (response time and accuracy) was not altered by fluid condition; however, mean response time improved (p < .05) for letter digit recognition (by 56.7 +/- 85.8 ms or 3.8%; p < .05) and pattern comparison (by 80.6 +/- 57.4 ms or 7.1%; p < .001), but mean accuracy decreased in trail making (by 1.2 +/- 1.4%; p = .01) after EHS (across all conditions). CONCLUSIONS: For recreational athletes, fluid intake effectively mitigated physiological strain induced by mild hypohydration; however, mild hypohydration resulting from EHS elicited no adverse changes in cognitive performance. PMID- 25811391 TI - Corneal Endothelial Cell Loss and Iritis Associated With a New Cosmetic Iris Implant. PMID- 25811393 TI - Roll-to-roll continuous patterning and transfer of graphene via dispersive adhesion. AB - We present a roll-to-roll, continuous patterning and transfer of graphene sheets capable of residue-free and fast patterning. The graphene sheet is supported with dispersive adhesion. Graphene is continuously patterned by the difference in adhesion forces with a pre-defined embossed roller. The patterned graphene sheet adheres to the polyethylene terephthalate (PET)/silicone with very low strength and can be easily transferred to various substrates without the aid of any heating mechanism. The width of the patterned film was 120 mm and a production rate of 15 m min(-1) for patterning was achieved. Large-area uniformity was confirmed by observing the optical images on 4 inch Si wafer and Raman mapping spectra for 50 * 50 mm(2). PMID- 25811394 TI - Increasing Physical Activity in Children: From Evidence to Action. AB - Daily physical activity has the potential to improve health and well-being, yet worldwide surveillance of physical activity levels indicate a growing number of children and adolescents do not meet current physical activity recommendations. The current symptom-reactive paradigm should be reconsidered, and preventive actions initiated, before inactive children become resistant to targeted interventions and require pharmacotherapy, and expensive medical procedures for treatment of preventable illnesses. A cascade of adverse events are associated with a sedentary lifestyle. Nurses are uniquely qualified to identify youth with exercise deficits and encourage daily participation in a variety of age-related physical activities that enhance both health- and skill-related components of physical fitness.Physical activity guidelines should support evidence-based activity recommendations by nurses working with children. New insights regarding the importance of improving muscular strength and motor skill performance early in life are valuable to nurses in formulating exercise recommendations for school age youth. Specific education in pediatric exercise science provides the foundation for prescribing age-related exercise interventions consistent with the needs, abilities, and interests of infants, toddlers, children, and adolescents. Given the critical importance of primary prevention, transformational change in the current system for identifying and treating youth with exercise deficits is warranted. PMID- 25811392 TI - Cytosolic 5'-nucleotidase II interacts with the leucin rich repeat of NLR family member Ipaf. AB - IMP/GMP preferring cytosolic 5'-nucleotidase II (cN-II) is a bifunctional enzyme whose activities and expression play crucial roles in nucleotide pool maintenance, nucleotide-dependent pathways and programmed cell death. Alignment of primary amino acid sequences of cN-II from human and other organisms show a strong conservation throughout the entire vertebrata taxon suggesting a fundamental role in eukaryotic cells. With the aim to investigate the potential role of this homology in protein-protein interactions, a two hybrid system screening of cN-II interactors was performed in S. cerevisiae. Among the X positive hits, the Leucin Rich Repeat (LRR) domain of Ipaf was found to interact with cN-II. Recombinant Ipaf isoform B (lacking the Nucleotide Binding Domain) was used in an in vitro affinity chromatography assay confirming the interaction obtained in the screening. Moreover, co-immunoprecipitation with proteins from wild type Human Embryonic Kidney 293 T cells demonstrated that endogenous cN-II co-immunoprecipitated both with wild type Ipaf and its LRR domain after transfection with corresponding expression vectors, but not with Ipaf lacking the LRR domain. These results suggest that the interaction takes place through the LRR domain of Ipaf. In addition, a proximity ligation assay was performed in A549 lung carcinoma cells and in MDA-MB-231 breast cancer cells and showed a positive cytosolic signal, confirming that this interaction occurs in human cells. This is the first report of a protein-protein interaction involving cN-II, suggesting either novel functions or an additional level of regulation of this complex enzyme. PMID- 25811397 TI - Utilisation of a lithium boryl as a reducing agent in low oxidation state group 15 chemistry: synthesis and characterisation of an amido-distibene and a boryl dibismuthene. AB - The first examples of an amido-distibene, L(?)Sb[double bond, length as m dash]SbL(?) (L(?) = -N(Ar(?))(SiPr(i)3), Ar(?) = C6H2{C(H)Ph2}2Pr(i)-2,6,4), and a boryl dibismuthene, {(DAB)B}Bi[double bond, length as m-dash]Bi{B(DAB)} (DAB = {(C6H3Pr(i)2-2,6)NCH}2, have been prepared by reaction of a lithium boryl complex, (THF)2LiB(DAB), with extremely bulky amido-group 15 dihalide precursor compounds. In these reactions, the lithium boryl acts as a boryl transfer reagent and/or a strong reducing agent. PMID- 25811396 TI - Risk Factors for TB in Patients With Early Gastric Cancer: Is Gastrectomy a Significant Risk Factor for TB? AB - BACKGROUND: Gastrectomy is known as one of the risk factors for TB. However, there is no study about the association between TB development and gastrectomy performed in patients with early gastric cancer (EGC). This study evaluated conventional risk factors, including gastrectomy, associated with TB development in patients with EGC. METHODS: A retrospective cohort study was performed using the database of the Center for Gastric Cancer of the National Cancer Center, Korea. The patients with EGC whose T1 lesions were pathologically confirmed by gastrectomy or endoscopic resection were included. RESULTS: A total of 1,935 patients constituted the EGC cohort. Of these, 1,495 patients were confirmed by gastrectomy and the remaining 440 by endoscopic resection. The median follow-up duration was 4.9 years, and during this period, 31 cases of TB developed (TB incidence, 334/100,000 person-years; 95% CI, 227-475). Multivariate Cox regression analysis showed that old TB lesion on chest radiograph and gastrectomy were significant risk factors (hazard ratio [HR], 5.01; 95% CI, 2.44-10.28; P < .001; and HR, 8.95; 95% CI, 1.22-65.78; P = .031; respectively). In the gastrectomy subgroup, old TB lesion and >= 15% reduction in weight and albumin level about 1 year after gastrectomy were significant risk factors (HR, 4.80; 95% CI, 2.26-10.18; P < .001; HR, 3.08; 95% CI, 1.47-6.48; P = .003; and HR, 5.02; 95% CI, 1.47-17.12; P = .010; respectively). CONCLUSIONS: Old TB lesion and gastrectomy were significant risk factors in the EGC cohort. In addition, old TB lesion and >= 15% postoperative reductions in weight and albumin level were significant risk factors in the gastrectomy subgroup. PMID- 25811398 TI - New nanoplatforms based on UCNPs linking with polyhedral oligomeric silsesquioxane (POSS) for multimodal bioimaging. AB - A new and facile method was used to transfer upconversion luminescent nanoparticles from hydrophobic to hydrophilic using polyhedral oligomeric silsesquioxane (POSS) linking on the surface of upconversion nanoparticles. In comparison with the unmodified upconversion nanoparticles, the POSS modified upconversion nanoplatforms [POSS-UCNPs(Er), POSS-UCNPs(Tm)] displayed good monodispersion in water and exhibited good water-solubility, while their particle size did not change substantially. Due to the low cytotoxicity and good biocompatibility as determined by methyl thiazolyl tetrazolium (MTT) assay and histology and hematology analysis, the POSS modified upconversion nanoplatforms were successfully applied to upconversion luminescence imaging of living cells in vitro and nude mouse in vivo (upon excitation at 980 nm). In addition, the doped Gd(3+) ion endows the POSS-UCNPs with effective T1 signal enhancement and the POSS-UCNPs were successfully applied to in vivo magnetic resonance imaging (MRI) for a Kunming mouse, which makes them potential MRI positive-contrast agents. More importantly, the corner organic groups of POSS can be easily modified, resulting in kinds of POSS-UCNPs with many potential applications. Therefore, the method and results may provide more exciting opportunities for multimodal bioimaging and multifunctional applications. PMID- 25811399 TI - Mobilizing evidence for impact: from CDIC to health promotion and chronic disease prevention. PMID- 25811395 TI - An Internet-Mediated Pedometer-Based Program Improves Health-Related Quality-of Life Domains and Daily Step Counts in COPD: A Randomized Controlled Trial. AB - BACKGROUND: Low levels of physical activity (PA) are associated with poor outcomes in people with COPD. Interventions to increase PA could improve outcomes. METHODS: We tested the efficacy of a novel Internet-mediated, pedometer based exercise intervention. Veterans with COPD (N = 239) were randomized in a 2:1 ratio to the (1) intervention group (Omron HJ-720 ITC pedometer and Internet mediated program) or (2) wait-list control group (pedometer). The primary outcome was health-related quality of life (HRQL), assessed by the St. George's Respiratory Questionnaire (SGRQ), at 4 months. We examined the SGRQ total score (SGRQ-TS) and three domain scores: Symptoms, Activities, and Impact. The secondary outcome was daily step counts. Linear regression models assessed the effect of intervention on outcomes. RESULTS: Participants had a mean age of 67 +/ 9 years, and 94% were men. There was no significant between-group difference in mean 4-month SGRQ-TS (2.3 units, P = .14). Nevertheless, a significantly greater proportion of intervention participants than control subjects had at least a 4 unit improvement in SGRQ-TS, the minimum clinically important difference (53% vs 39%, respectively, P = .05). For domain scores, the intervention group had a lower (reflecting better HRQL) mean than the control group by 4.6 units for Symptoms (P = .046) and by 3.3 units for Impact (P = .049). There was no significant difference in Activities score between the two groups. Compared with the control subjects, intervention participants walked 779 more steps per day at 4 months (P = .005). CONCLUSIONS: An Internet-mediated, pedometer-based walking program can improve domains of HRQL and daily step counts at 4 months in people with COPD. TRIAL REGISTRY: Clinical Trials.gov; No.: NCT01102777; URL: www.clinicaltrials.gov. PMID- 25811400 TI - Chronic fatigue syndrome and fibromyalgia in Canada: prevalence and associations with six health status indicators. AB - INTRODUCTION: Few studies have considered the factors independently associated with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) or considered the impact of these conditions on health status using population-based data. METHODS: We used data from the nationally representative 2010 Canadian Community Health Survey (n = 59 101) to describe self-reported health professional-diagnosed CFS and/or FM, and their associations with 6 health status indicators. RESULTS: In 2010, diagnosed CFS and FM are reported by 1.4% (95% confidence interval [CI]: 1.3%-1.6%) and 1.5% (1.4%-1.7%), respectively, of the Canadian household population aged 12 years and over, with comorbid CFS and FM affecting 0.3% (0.3% 0.4%) of that population. Prevalent CFS and/or FM were more common among women, adults aged 40 years and over, those with lowest income, and those with certain risk factors for chronic disease (i.e. obesity, physical inactivity and smoking). After controlling for differences between the groups, people with CFS and/or FM reported poorer health status than those with neither condition on 5 indicators of health status, but not on the measure of fair/poor mental health. Having both CFS and FM and having multiple comorbid conditions was associated with poorer health status. CONCLUSION: Co-occurrence of CFS and FM and having other chronic conditions were strongly related to poorer health status and accounted for much of the differences in health status. Understanding factors contributing to improved quality of life in people with CFS and/or FM, particularly in those with both conditions and other comorbidities, may be an important area for future research. PMID- 25811402 TI - Congenital anomalies in Canada 2013: a perinatal health surveillance report by the Public Health Agency of Canada's Canadian Perinatal Surveillance System. AB - Congenital Anomalies in Canada 2013: A Perinatal Health Surveillance Report is the second national surveillance report from the Public Health Agency of Canada dedicated to congenital anomalies. It provides comprehensive data on congenital anomalies in Canada, focussing on 6 categories of congenital anomalies: Down syndrome, neural tube defects, congenital heart defects, orofacial clefts, limb deficiency defects and gastroschisis. The report presents national-level birth prevalence data and temporal trends, provincial and territorial estimates, and international comparisons. Known risk factors, prevalence-related impacts of prenatal diagnosis and preventative measures are also discussed. PMID- 25811401 TI - A DASH dietary pattern and the risk of colorectal cancer in Canadian adults. AB - INTRODUCTION: Colorectal cancer (CRC) is a high incidence cancer affecting many Canadian adults each year. Diet is important in the etiology of CRC with many dietary components identified as potential risk factors. The Dietary Approaches to Stop Hypertension (DASH) diet is a well-established pattern to characterize overall eating. The purpose of this study was to characterize a DASH pattern within the Canadian context and to assess its relationship to the risk of CRC in Canadian adults. METHODS: Unconditional multiple logistic regression with control for confounding variables was performed using data from the National Enhanced Cancer Surveillance Study. Dietary intake was captured for this case-control study through a food frequency questionnaire (FFQ) and categorized into a DASH score ranging from 0 to 10 representing a poor to a strong DASH pattern respectively. RESULTS: Consuming a strong DASH pattern of eating (score >= 8) was not common in the 3161 cases and 3097 controls. Overall, only 10.8% of men and 13.6% of women had a strong DASH pattern. Multivariate analysis demonstrated a trend for decreasing risk of CRC in men with increasing DASH scores (p value for trend = .007). Men with a strong DASH score had a 33% reduction in risk of CRC compared to those with a low DASH score. There were no significant trends for women for CRC or for colon or rectal cancers separately. CONCLUSION: Our findings are similar to other researchers suggesting a benefit with a strong DASH pattern associated with a decreased risk of CRC, especially in men. Research should further investigate our gender-based differences. PMID- 25811403 TI - Perinatal health indicators 2013: a surveillance report by the Public Health Agency of Canada's Perinatal Surveillance System. AB - The Canadian Perinatal Surveillance System (CPSS) is a national health surveillance program of the Public Health Agency of Canada. The CPSS mandate is to monitor and report on key indicators of maternal, fetal and infant health. These indicators include both determinants and outcomes of perinatal health. Perinatal Health Indicators 2013 reports on 13 priority indicators using the most recent data from vital statistics, hospitalizations, the Canadian Community Health Survey and the National Longitudinal Survey of Children and Youth. PMID- 25811404 TI - Facile synthesis of a novel polymeric ionic liquid gel and its excellent performance for hexavalent chromium removal. AB - A novel polymeric ionic liquid gel (PIL gel) was simply synthesized by gamma radiation-induced polymerization of ionic liquid monomer 1-allyl-3 vinylimidazolium chloride and crosslinking at ambient temperature without any additives. By changing the radiation dose, the properties of the resulting gel including the gel fraction, crosslinking density and equilibrium degree of swelling were optimized. The resulting PIL gel exhibited a superior adsorption ability toward Cr(vi) in aqueous solutions with a broad pH range (1-7) through anion exchange. It was found that the adsorption kinetics followed the pseudo second-order model. The adsorption of Cr(vi) by the PIL gel obeyed the Langmuir isotherm equation with a theoretical maximum adsorption capacity of 283 mg g(-1), twice the highest value for ionic liquid-based adsorbents that have been reported. In addition, the PIL gel could be recovered using a NaCl solution or a NaOH solution without much decreasing the adsorption capacity. This work paves the way for the scale-up production of PIL gels using the radiation technique for potential application in heavy metal removal. PMID- 25811405 TI - Reaction dynamics of the UV-B photosensor UVR8. AB - UVR8 is a recently discovered ultraviolet-B (UV-B) photoreceptor protein identified in plants and algae. In the dark state, UVR8 exists as a homodimer, whereas UV-B irradiation induces UVR8 monomerization and initiation of signaling. Although the biological functions of UVR8 have been studied, the fundamental reaction mechanism and associated kinetics have not yet been fully elucidated. Here, we used the transient grating method to determine the reaction dynamics of UVR8 monomerization based on its diffusion coefficient. We found that the UVR8 photodissociation reaction proceeds in three stages: (i) photoexcitation of cross dimer tryptophan (Trp) pyramids; (ii) an initial conformational change with a time constant of 50 ms; and (iii) dimer dissociation with a time constant of 200 ms. We identified W285 as the key Trp residue responsible for initiating this photoreaction. Although the C-terminus of UVR8 is essential for biological interactions and signaling via downstream components such as COP1, no obvious differences were detected between the photoreactions of wild-type UVR8 (amino acids 1-440) and a mutant lacking the C-terminus (amino acids 1-383). This similarity indicates that the conformational change associated with stage ii cannot primarily be attributed to this region. A UV-B-driven conformational change with a time constant of 50 ms was also detected in the monomeric mutants of UVR8. Dimer recovery following monomerization, as measured by circular dichroism spectroscopy, was decreased under oxygen-purged conditions, suggesting that redox reactivity is a key factor contributing to the UVR8 oligomeric state. PMID- 25811407 TI - Advances in f-element cyanide chemistry. AB - This Dalton perspective gives an overview of the development of cyanide chemistry of 4f- and 5f-elements, a field which was poorly explored in contrast to the attention paid to the cyanide complexes of the d transition metals. The use of the cyanide ligand led to the discovery of mono- and polycyanide complexes which exhibit unprecedented and unexpected coordination geometries. A new type of linear metallocenes including [U(Cp*)2(CN)5](3-) (Cp* = C5Me5) and the first bent actinocenes [An(Cot)2(CN)](-) (An = Th, U; Cot = C8H8) were isolated. Thorocene was found to be much more reactive than uranocene since a series of sterically crowded cyanide complexes have been obtained only from [Th(Cot)2]. A series of cyanido-bridged dinuclear compounds and mononuclear mono-, bis- and tris(cyanide) complexes were prepared by addition of cyanide salts to [MN*3] (M = Ce, U) and [UN*3](+) [N* = N(SiMe3)2]. The Ce(III), U(III) and U(IV) ions were clearly differentiated in these reactions by cyanide linkage isomerism, as shown for example by the structures of the cyanide complex [U(III)N*3(CN)2](2-) and of the isocyanide derivatives [Ce(III)N*3(NC)2](2-) and [U(IV)N*3(NC)](-). While the U CN/NC coordination preference towards the U(III)/U(IV) pair is related to the subtle balance between steric, covalent and ionic factors, DFT computations and in particular the calculated total bonding energies between the metal and the cyanide ligand allowed the observed coordination mode to be predicted. The ability of the cyanide ligand to stabilize the high oxidation states was assessed with the synthesis of U(V) and U(VI) complexes in the inorganic and organometallic series. PMID- 25811406 TI - Ruthenium complex Lambda-WH0402 induces hepatocellular carcinoma LM6 (HCCLM6) cell death by triggering the Beclin-1-dependent autophagy pathway. AB - To evaluate the anticancer mechanism of the new ruthenium complex-Lambda-WH0402 at the cellular level, the in vitro cytotoxicity of Lambda-WH0402 was investigated on 10 human tumor cell lines. Lambda-WH0402 was found to have higher anticancer activity than cisplatin toward human liver cancer HCCLM6 cells that have high tumor metastatic characteristics. Meanwhile, Lambda-WH0402 showed an antimetastatic effect on HCCLM6 cells in vitro, mostly through its effect on cell adhesion, invasion and migration. In addition, Lambda-WH0402 significantly reduced tumor metastasis to the lungs in orthotopic mouse hepatocellular cancer (HCC) models induced by HCCLM6 cells. Furthermore, Lambda-WH0402 exerted an inhibitory effect on tumor cell growth and proliferation and induced dose dependent cell cycle arrest in the S phase in HCCLM6 cells. Immunoblotting analysis showed that Lambda-WH0402 not only decreased the expression of antiapoptotic protein Bcl-2 and nutrient-deprivation autophagy factor-1 (NAF-1), but also significantly increased the expression of Beclin-1 in HCCLM6 cells. More importantly, we identified that Lambda-WH0402 treatment reduced the interaction between Bcl-2 and Beclin-1, and increased the expression of autophagic activation marker LC3B-II in HCCLM6 cells. On the whole, our results suggested that the anitcancer activity of Lambda-WH0402 is mediated through promoting the Beclin-1 dependent autophagy pathway in HCCLM6 cells. PMID- 25811408 TI - A self-assembling magnetic resonance beacon for the detection of microRNA-1. AB - A self-assembling magnetic resonance beacon was used to visualize the microRNA-1 expression-dependent change in magnetic resonance signal intensity. PMID- 25811409 TI - How ABA block polymers activate cytochrome c in toluene: molecular dynamics simulation and experimental observation. AB - While the conjugation of enzymes with ABA copolymers has resulted in increased enzymatic activities in organic solvents, by several orders of magnitude, the underpinning mechanism has not been fully uncovered, particularly at the molecular level. In the present work, a coarse-grained molecular dynamics simulation of cytochrome c (Cyt c) conjugated with a PEO-PPO-PEO block copolymer (ABA) in toluene was simulated with Cyt c as a control. It is shown that the hydrophilic segments (PEO) of the conjugated block copolymer molecules tend to entangle around the hydrophilic patch of Cyt c, while the hydrophobic segments (PPO) extend into the toluene. At a lower temperature, the PEO tails tend to form a hairpin structure outside the conjugated protein, whereas the Cyt c-ABA conjugates tend to form larger aggregates. At a higher temperature, however, the PEO tails tend to adsorb onto the hydrophilic protein surface, thus improving the suspension of the Cyt c-ABA conjugates and, consequently, the contact with the substrate. Moreover, the temperature increase drives the conformational transition of the active site of Cyt c-ABA from an "inactive state" to an "activated state" and thus results in an enhanced activity. To validate the above simulations, Cyt c was conjugated to F127, an extensively used ABA copolymer. By elevating the temperature, a decrease in the average size of the Cyt c-F127 conjugates along with a great increase in the apparent activity in toluene was observed, as can be predicted from the molecular dynamics simulation. The above mentioned molecular simulations offer a molecular insight into the temperature responsive behaviour of protein-ABA copolymers, which is helpful for the design and application of enzyme-polymer conjugates for industrial biocatalysis. PMID- 25811410 TI - Zika virus infection, Philippines, 2012. PMID- 25811411 TI - Outbreak of severe zoonotic vaccinia virus infection, Southeastern Brazil. AB - In 2010, a vaccinia virus isolate caused an atypically severe outbreak that affected humans and cattle in Brazil. Of 26 rural workers affected, 12 were hospitalized. Our data raise questions about the risk factors related to the increasing number and severity of vaccinia virus infections. PMID- 25811412 TI - Preconditioning by cilostazol protects against cold hepatic ischemia-reperfusion injury. AB - BACKGROUND: In liver transplantation, prolonged cold storage and post-transplant reperfusion are associated with endothelial inflammation, organ dysfunction, and graft failure. We herein studied whether cilostazol, a phosphodiesterase-3 inhibitor, attenuates post-ischemic liver injury after prolonged cold storage. MATERIAL AND METHODS: Sprague-Dawley rats were assigned to 5 groups (n=6 each): sham animals (cold storage time (CST): 1 h), vehicle-treated (NaCl 0.9%) controls (CST: 24 h), and animals receiving 0.1, 1.0, or 10.0 mg/kg body weight (BW) cilostazol pre-treatment (CST: 24 h). After organ explantation, all livers were stored at 4 degrees C in HTK solution, followed by 60 min of reperfusion with 37 degrees C Krebs Henseleit buffer in a non-recirculating ex situ system. Bile flow was measured to evaluate liver function. To analyze inflammation and morphology, liver tissue samples were taken and histology, immunohistochemistry, and Western blotting were conducted. RESULTS: In vehicle-treated controls, prolonged cold storage and warm reperfusion induced inflammation, organ dysfunction, and cell death. This was indicated by an increase of hepatocellular vacuolization, endothelial ICAM-1 expression, and apoptotic cell death compared to sham animals. Cilostazol pre-treatment protected against cold hepatic ischemia-reperfusion injury by preventing hepatocellular disintegration, ICAM-1-associated endothelial inflammation, and apoptotic death. CONCLUSIONS: Inhibition of PDE3 reduces endothelial cell activation and hepatocellular injury in cold ischemia/reperfusion of the liver. PMID- 25811413 TI - Comparison of the methods for generating single-stranded DNA in SELEX. AB - The generation of single-stranded DNA (ssDNA) from double-stranded PCR products is an essential step in the selection of aptamers by systematic evolution of ligands by exponential enrichment (SELEX). Magnetic separation with streptavidin coated beads is always the most commonly used method. Recently, two size separation methods derived from unequal primers with chemical or structural modification were designed in SELEX. In this report, we made a comparison between magnetic separation and the two size separation methods for generation of ssDNA from double-stranded PCR products. Our results showed that all the methods produced ssDNA of good purity. Compared to the magnetic separation, size separation derived from unequal primers with chemical modification achieved an almost equivalent recovery rate of ssDNA, whereas size separation derived from unequal primers with structural modification showed a lower recovery rate of ssDNA. Considering the low cost, size separation derived from unequal primers with chemical modification could be a satisfactory alternative to the classic magnetic separation for the generation of ssDNA in SELEX. PMID- 25811414 TI - Candidate new rotavirus species in sheltered dogs, Hungary. AB - We identified unusual rotavirus strains in fecal specimens from sheltered dogs in Hungary by viral metagenomics. The novel rotavirus species displayed limited genome sequence homology to representatives of the 8 rotavirus species, A-H, and qualifies as a candidate new rotavirus species that we tentatively named Rotavirus I. PMID- 25811415 TI - Nutritional Supplement Habits of Athletes With an Impairment and Their Sources of Information. AB - The consumption of nutritional supplements (NS) is common among able-bodied (AB) athletes yet little is known about NS use by athletes with an impairment. This study examined the: (i) prevalence of NS use by athletes with an impairment; (ii) reasons for use/ nonuse; (iii) sources of information regarding NS; and (iv) whether age, gender, impairment, performance level and sport category influence NS use. The questionnaire was completed by 399 elite (n = 255) and nonelite (n = 144) athletes (296 M, 103 F) online or at a sporting event/training camp. Data were evaluated using chi-square analyses. Fifty-eight percent (n = 232) of athletes used NS in the previous 6-month period and 41% (n = 102) of these followed the instructions on the label to determine dose. Adherence to these AB recommendations may partly explain why 9% (n = 37) experienced negative effects from NS use. As expected, the most popular NS were: protein, sports drinks, multivitamins and carbohydrate supplements, which were obtained from health food/sport shops, internet and supermarkets (top 3) where evidence-based, impairment-specific advice is limited. The nutritionist/dietitian was the most used and trusted source of information, which is a promising finding. The most prevalent reasons for use were to support exercise recovery, support the immune system and provide energy. Elite athletes were more likely to use NS, which may reflect greater training hours and/or access to nutritionists. Fifty-two percent of athletes (n = 209) requested more information/ education regarding NS. NS use is prevalent in this population. Education on dosage and appropriate sources of information is required. PMID- 25811416 TI - Transition-metal-free cross-coupling of thioethers with aryl(cyano)iodonium triflates: a facile and efficient method for the one-pot synthesis of thiocyanates. AB - A novel transition-metal-free cross-coupling method for the one-step synthesis of thiocyanates via the C-S bond cleavage of readily available thioethers with aryl(cyano)-iodonium triflates as the cyanating agent is developed. This process features relatively broad substrate scopes, less-toxic hypervalent iodine reagents, mild operating conditions, excellent functional group compatibilities, and affords various thiocyanates in moderate to good yields. PMID- 25811417 TI - Performance analysis of jump-gliding locomotion for miniature robotics. AB - Recent work suggests that jumping locomotion in combination with a gliding phase can be used as an effective mobility principle in robotics. Compared to pure jumping without a gliding phase, the potential benefits of hybrid jump-gliding locomotion includes the ability to extend the distance travelled and reduce the potentially damaging impact forces upon landing. This publication evaluates the performance of jump-gliding locomotion and provides models for the analysis of the relevant dynamics of flight. It also defines a jump-gliding envelope that encompasses the range that can be achieved with jump-gliding robots and that can be used to evaluate the performance and improvement potential of jump-gliding robots. We present first a planar dynamic model and then a simplified closed form model, which allow for quantification of the distance travelled and the impact energy on landing. In order to validate the prediction of these models, we validate the model with experiments using a novel jump-gliding robot, named the 'EPFL jump-glider'. It has a mass of 16.5 g and is able to perform jumps from elevated positions, perform steered gliding flight, land safely and traverse on the ground by repetitive jumping. The experiments indicate that the developed jump-gliding model fits very well with the measured flight data using the EPFL jump-glider, confirming the benefits of jump-gliding locomotion to mobile robotics. The jump-glide envelope considerations indicate that the EPFL jump glider, when traversing from a 2 m height, reaches 74.3% of optimal jump-gliding distance compared to pure jumping without a gliding phase which only reaches 33.4% of the optimal jump-gliding distance. Methods of further improving flight performance based on the models and inspiration from biological systems are presented providing mechanical design pathways to future jump-gliding robot designs. PMID- 25811418 TI - Impacts of potential CO2-reduction policies on air quality in the United States. AB - Impacts of emissions changes from four potential U.S. CO2 emission reduction policies on 2050 air quality are analyzed using the community multiscale air quality model (CMAQ). Future meteorology was downscaled from the Goddard Institute for Space Studies (GISS) ModelE General Circulation Model (GCM) to the regional scale using the Weather Research Forecasting (WRF) model. We use emissions growth factors from the EPAUS9r MARKAL model to project emissions inventories for two climate tax scenarios, a combined transportation and energy scenario, a biomass energy scenario and a reference case. Implementation of a relatively aggressive carbon tax leads to improved PM2.5 air quality compared to the reference case as incentives increase for facilities to install flue-gas desulfurization (FGD) and carbon capture and sequestration (CCS) technologies. However, less capital is available to install NOX reduction technologies, resulting in an O3 increase. A policy aimed at reducing CO2 from the transportation sector and electricity production sectors leads to reduced emissions of mobile source NOX, thus reducing O3. Over most of the U.S., this scenario leads to reduced PM2.5 concentrations. However, increased primary PM2.5 emissions associated with fuel switching in the residential and industrial sectors leads to increased organic matter (OM) and PM2.5 in some cities. PMID- 25811421 TI - Freely Chosen Index Finger Tapping Frequency Is Increased in Repeated Bouts of Tapping. AB - Healthy individuals (n = 40) performed index finger tapping at freely chosen frequency during repeated bouts and before and after near-maximal muscle action consisting of 3 intense flexions of the index finger metacarpal phalangeal joint. One experiment showed, unexpectedly, that a bout of tapping increased the tapping frequency in the subsequent bout. Thus, a cumulating increase of 8.2 +/- 5.4% (p < .001) occurred across 4 bouts, which were all separated by 10 min rest periods. Follow-up experiments revealed that tapping frequency was still increased in consecutive bouts when rest periods were extended to 20 min. Besides, near maximal muscle activation, followed by 5 min rest, did not affect the tapping frequency. In conclusion, freely chosen tapping frequency was increased in repeated bouts of tapping, which were separated by 10-20 min rest periods. The observed phenomenon is suggested to be termed repeated bout rate enhancement. PMID- 25811419 TI - Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations. OBJECTIVES: To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014. SELECTION CRITERIA: Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta analyses were undertaken on outcomes at a number of time points. MAIN RESULTS: We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the DeltaF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the DeltaF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the DeltaF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the DeltaF508 participants.Significant reductions in sweat chloride concentration were reported in both G551D and DeltaF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference 49.03 mmol/L (95% CI -52.11 to -45.94); and from the DeltaF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20). AUTHORS' CONCLUSIONS: Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the DeltaF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing. PMID- 25811422 TI - Simple O2 plasma-processed V2O5 as an anode buffer layer for high-performance polymer solar cells. AB - A simple O2 plasma processing method for preparation of a vanadium oxide (V2O5) anode buffer layer on indium tin oxide (ITO)-coated glass for polymer solar cells (PSCs) is reported. The V2O5 layer with high transmittance and good electrical and interfacial properties was prepared by spin coating a vanadium(V) triisopropoxide oxide alcohol solution on ITO and then O2 plasma treatment for 10 min [V2O5 (O2 plasma)]. PSCs based on P3HT:PC61BM and PBDTTT-C:PC71BM using V2O5 (O2 plasma) as an anode buffer layer show high power conversion efficiencies (PCEs) of 4.47 and 7.54%, respectively, under the illumination of AM 1.5G (100 mW/cm(2)). Compared to that of the control device with PBDTTT-C:PC71BM as the active layer and PEDOT: PSS (PCE of 6.52%) and thermally annealed V2O5 (PCE of 6.27%) as the anode buffer layer, the PCE was improved by 15.6 and 20.2%, respectively, after the introduction of a V2O5 (O2 plasma) anode buffer layer. The improved PCE is ascribed to the greatly improved fill factor and enhanced short-circuit current density of the devices, which benefited from the change in the work function of V2O5, a surface with many dangling bonds for better interfacial contact, and the excellent charge transport property of the V2O5 (O2 plasma) layer. The results indicate that an O2 plasma-processed V2O5 film is an efficient and economical anode buffer layer for high-performance PSCs. It also provides an attractive choice for low-cost fabrication of organic electronics. PMID- 25811420 TI - Cyclooxygenase as a target in chemoprevention by probiotics during 1,2 dimethylhydrazine induced colon carcinogenesis in rats. AB - The present study was undertaken to assess the effects of potential probiotics in regulating the activity of cyclooxygenase-2 (COX-2) along with other morphological and histological analysis during 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in rats. The rats were divided into 6 groups viz., normal control, Lactobacillus plantarum (AdF10) treated, Lactobacillus rhamnosus GG (LGG) treated, DMH treated, AdF10 + DMH treated and LGG + DMH treated. Probiotics were supplemented to rats at dose levels of 2 * 10(10) cells per day for 6 days in a week. All the treatments were continued for a period of 16 wk. DMH treatment resulted in a statistically significant increase in the levels of total sialic acid (TSA). However, on supplementation with probiotics, a significant reduction in TSA was observed. DMH treatment brought about a significant increase in the expression of COX-2. But, supplementation of probiotics brought down the protein expression to moderate level. Further, supplementation with probiotics was also able to reduce tumor incidence, tumor multiplicity and average tumor size. Therefore, treatment with probiotics has the potential of providing protection against colon cancer by suppressing the COX-2 expression as one of the protective mechanisms. PMID- 25811423 TI - Contraception in perimenopause: when to discontinue. PMID- 25811424 TI - Simulated motion negatively affects motor task but not neuromuscular performance. AB - The effects of long duration simulated motion on motor task and neuromuscular performance along with time frames required to recover from these effects are relatively unknown. This study aimed to determine (1) how simulated motion affects motor task and neuromuscular performance over one hour of motion and (2) the time course of recovery from any decrements. The dependent variables that were measured included: reaction time; visuomotor accuracy tracking; maximal voluntary contractions; voluntary activation; evoked contractile properties and biceps brachii electromyography of the elbow flexors. Reaction times and error rates of the visuomotor accuracy tracking task were compromised in motion, but maximal force, voluntary activation, evoked contractile properties and rmsEMG responses of the biceps brachii were unaffected by motion. It is concluded that motion causes an increase in attention demands, which have a greater effect on motor task rather than neuromuscular performance. PRACTITIONER SUMMARY: Minor delays or mistakes can separate life and death at sea. The safety and productivity of most vessels rely on error-free performance of motor tasks. This study demonstrates that human ability to perform motor tasks is compromised by ship motions and may aid in developing training and safety guidelines for seafarers. PMID- 25811425 TI - Correction to disordered proteinaceous machines. PMID- 25811426 TI - Enantioselective syntheses of spiroketals via a tandem reaction of Cu(I) catalyzed cycloetherification and hydrogen-bond-induced [4 + 2] cyclization. AB - A tandem reaction consisting of a copper(I)-catalyzed cycloetherification and a hydrogen-bond-induced inverse-electron-demand oxa-Diels-Alder cycloaddition was performed from chiral propargyl alcohol, generating several kinds of optically pure [5, 6] spiroketals in excellent stereoselectivities and yields. The investigation on mechanism found that the cyclization prompted by a hydrogen bond not only improved the efficiency but also determined the diastereoselectivity. PMID- 25811428 TI - Reversible photochemical isomerization of N,N'-di(t-butoxycarbonyl)indigos. AB - We report on the photophysics of N,N'-di(t-butoxycarbonyl)indigos (tBOC indigos), finding that reversible photochemical trans-cis and cis-trans isomerization reactions proceed with high quantum yields (0.10-0.46). Absorption of wavelengths in the 500-600 nm region induces trans-cis isomerism, while blue light leads to the reverse cis-trans process. Like their parent indigos, trans-BOC indigos have low fluorescence yields (~1 * 10(-3)), while the cis isomers have no measurable emission. These compounds are the first examples of photoisomerizable indigoid dyes in which photochemical isomerism effectively outcompetes radiative decay processes. Though indigo dyes typically have poor solubility in organic solvents, tBOC indigos can be dissolved at concentrations up to 8 w% in common organic solvents like acetone. Furthermore, unlike other photoisomerizable indigoids, tBOC indigos are not sensitive to quenching by proton and electron donors. These features, combined with high quantum yields of reversible photoisomerism induced by relatively low-energy photons (~2 eV), make tBOC indigo derivatives potentially interesting for photochromic applications, such as photomechanically actuated materials. PMID- 25811427 TI - In Vivo Transfection and Detection of Gene Expression of Stem Cells Preloaded with DNA-carrying Microbubbles. AB - PURPOSE: To determine whether (a) stem cells loaded with DNA-carrying microbubbles (MBs) can be transfected in vivo, (b) the cells remain alive to express the gene, and (c) gene expression is sufficiently robust to be detected in vivo. MATERIALS AND METHODS: The study was approved by the Institutional Animal Care and Use Committee. Cationic MBs were prepared, characterized, and loaded with pLuciferase green fluorescent protein (GFP) plasmid. Loading was confirmed with SYBR Gold staining (Life Technologies, Carlsbad, Calif). C17.2 cells were loaded with the DNA-carrying MBs. Two hundred thousand cells suspended in 20 MUL phosphate-buffered saline were mixed with 200 MUL Matrigel (BD Biosciences, San Jose, Calif) and injected in both flanks of eight nude mice. One of the Matrigel (BD Biosciences) injections contained 50 000 cells pretransfected in vitro by using lipofectamine as a positive control. Nine flanks were exposed to 2.25-MHz ultrasonic pulses at 50% duty cycle for 1 minute at 1 W/cm(2) (n = 3) or 2 W/cm(2) (n = 6), and six flanks served as the negative control. Two days later, bioluminescent images were acquired in each mouse every 3 minutes for 1 hour after the intraperitoneal injection of d-luciferin (Perkin Elmer, Waltham, Mass). Differences between groups were assessed by using the nonparametric Kruskal-Wallis test with Wilcoxon rank sum tests for follow-up comparisons. Mice were then killed, plugs were explanted, and alternate sections were stained with hematoxylin-eosin or stained for GFP expression. RESULTS: Mean DNA-loaded MB diameter +/- standard deviation was 2.87 MUm +/- 1.69 with the DNA associated with the MB shell. C17.2 cells were associated with 2-4 MBs each, and more than 90% were viable. Peak background subtracted bioluminescent signal was fourfold higher when cells were exposed to 2 W/cm(2) pulses as compared with 1 W/cm(2) pulses (P = .02) and negative controls (P = .002). Histologic examination showed cells within the Matrigel (BD Biosciences) with robust GFP expression only after 2 W/cm(2) ultrasound exposure and lipofectamine transfection. CONCLUSION: Stem cells loaded with DNA-carrying MBs can be transfected in vivo with ultrasonic pulses and remain alive to demonstrate robust gene expression. PMID- 25811429 TI - Design and Function of Engineered Protein Nanocages as a Drug Delivery System for Targeting Pancreatic Cancer Cells via Neuropilin-1. AB - We describe the development of neuropilin 1-binding peptide (iRGD)-nanocages that specifically target human pancreatic cancer cells in which an iRGD is joined to the surface of naturally occurring heat shock protein (HSP) cages. Using a genetic engineering approach, the iRGD domain was joined to the C-terminal region of the HSP cage using flexible linker moieties. The characteristics of the interdomain linkages between the nanocage and the iRGD domain play an important role in the specificity and affinity of the iRGD-nanocages for their target cells. An engineered L30-iRGD-nanocage with 30 amino acid linkers, (GGS)10, showed greater binding affinity for pancreatic cancer cells relative to that of other linkers. Furthermore, a moderately hydrophobic anticancer drug, OSU03012, was successfully incorporated into the L30-iRGD-nanocage by heating the mixture. The OSU03012-loaded L30-iRGD-nanocage induced cell death of pancreatic cancer cells by activating the caspase cascade more effectively than the same concentrations of free OSU03012. The iRGD-nanocages show great potential as a novel nanocarrier for pancreatic cancer-targeted drug delivery. PMID- 25811430 TI - Letter to the editor. PMID- 25811431 TI - Responses from authors. PMID- 25811433 TI - Finite difference approximations for measure-valued solutions of a hierarchically size-structured population model. AB - We study a quasilinear hierarchically size-structured population model presented in [4]. In this model the growth, mortality and reproduction rates are assumed to depend on a function of the population density. In [4] we showed that solutions to this model can become singular (measure-valued) in finite time even if all the individual parameters are smooth. Therefore, in this paper we develop a first order finite difference scheme to compute these measure-valued solutions. Convergence analysis for this method is provided. We also develop a high resolution second order scheme to compute the measure-valued solution of the model and perform a comparative study between the two schemes. PMID- 25811432 TI - A review of the impact of biologics on surgical complications in Crohn's disease. AB - Anti-tumor necrosis factor therapy has revolutionized the treatment of Crohn's disease. Despite the increased use in the past decade and a half, a majority of patients with Crohn's disease with ultimately require operative management of their disease. No clear consensus has been made in the literature regarding the surgical outcomes in patients who have been exposed to anti-tumor necrosis factor therapy. This review highlights the most recent and relevant literature regarding the safety and effects of anti-tumor necrosis factor use in the perioperative period. PMID- 25811435 TI - A note on modelling with measures: two-features balance equations. AB - In this note we explain by an example what we understand by a balance situation and by a balance equation in terms of measures. The latter ones are an attempt to start modelling of (not only) diffusion-reaction or mass-conservation scenarios in terms of measures rather than by derivatives and other rates. By means of three examples this concept is extended to two-features (= two-traits-) balance situations, which, e.g., combine features like aging and physical motion in populations or physical motion and formation of polymers by means of a single model equation. PMID- 25811434 TI - Riemann problems with non--local point constraints and capacity drop. AB - In the present note we discuss in details the Riemann problem for a one dimensional hyperbolic conservation law subject to a point constraint. We investigate how the regularity of the constraint operator impacts the well- posedness of the problem, namely in the case, relevant for numerical applications, of a discretized exit capacity. We devote particular attention to the case in which the constraint is given by a non--local operator depending on the solution itself. We provide several explicit examples. We also give the detailed proof of some results announced in the paper [Andreianov, Donadello, Rosini, Crowd dynamics and conservation laws with nonlocal constraints and capacity drop], which is devoted to existence and stability for a more general class of Cauchy problems subject to Lipschitz continuous non--local point constraints. PMID- 25811436 TI - Basic stage structure measure valued evolutionary game model. AB - The ideas and techniques developed in [12,3] are extended to a basic stage structured model. Each strategy consists of two stages: a Juvenile (L for larvae), and Adult (A). A general model of this basic stage structure is formulated as a dynamical system on the state space of finite signed measures. Nonnegativity, well-posedness and uniform eventual boundedness are established under biologically natural conditions on the rates. Similar to [12] we also have the unifying of discrete and continuous systems and the containment of the classic nonlinearities. PMID- 25811437 TI - Parameter estimation of social forces in pedestrian dynamics models via a probabilistic method. AB - Focusing on a specific crowd dynamics situation, including real life experiments and measurements, our paper targets a twofold aim: (1) we present a Bayesian probabilistic method to estimate the value and the uncertainty (in the form of a probability density function) of parameters in crowd dynamic models from the experimental data; and (2) we introduce a fitness measure for the models to classify a couple of model structures (forces) according to their fitness to the experimental data, preparing the stage for a more general model-selection and validation strategy inspired by probabilistic data analysis. Finally, we review the essential aspects of our experimental setup and measurement technique. PMID- 25811438 TI - Modelling with measures: approximation of a mass-emitting object by a point source. AB - We consider a linear diffusion equation on Omega: = R(2) ? Omega[Symbol: see text], where Omega[Symbol: see text] is a bounded domain. The time-dependent flux on the boundary Gamma: = ? Omega[Symbol: see text] is prescribed. The aim of the paper is to approximate the dynamics by the solution of the diffusion equation on the whole of R(2) with a measure-valued point source in the origin and provide estimates for the quality of approximation. For all time t, we derive an L(2)([0,t];L2(Gamma))-bound on the difference in flux on the boundary. Moreover, we derive for all t > 0 an L(2)(Omega)-bound and an L2([0,t];H(1)(Omega))-bound for the difference of the solutions to the two models. PMID- 25811439 TI - Preface to '' Modeling with measures ''. AB - Different communities met in the research workshop ''Modeling with Measures" that took place at the Lorentz Center (Leiden, The Netherlands) during 26th--30th of August 2013. They were groups of researchers active in the following fields. PMID- 25811440 TI - Stability and optimization in structured population models on graphs. AB - We prove existence and uniqueness of solutions, continuous dependence from the initial datum and stability with respect to the boundary condition in a class of initial--boundary value problems for systems of balance laws. The particular choice of the boundary condition allows to comprehend models with very different structures. In particular, we consider a juvenile-adult model, the problem of the optimal mating ratio and a model for the optimal management of biological resources. The stability result obtained allows to tackle various optimal management/control problems, providing sufficient conditions for the existence of optimal choices/controls. PMID- 25811441 TI - A mixed system modeling two-directional pedestrian flows. AB - In this article, we present a simplified model to describe the dynamics of two groups of pedestrians moving in opposite directions in a corridor. The model consists of a 2 x 2 system of conservation laws of mixed hyperbolic-elliptic type. We study the basic properties of the system to understand why and how bounded oscillations in numerical simulations arise. We show that Lax-Friedrichs scheme ensures the invariance of the domain and we investigate the existence of measure-valued solutions as limit of a subsequence of approximate solutions. PMID- 25811442 TI - A hybrid model for traffic flow and crowd dynamics with random individual properties. AB - Based on an established mathematical model for the behavior of large crowds, a new model is derived that is able to take into account the statistical variation of individual maximum walking speeds. The same model is shown to be valid also in traffic flow situations, where for instance the statistical variation of preferred maximum speeds can be considered. The model involves explicit bounds on the state variables, such that a special Riemann solver is derived that is proved to respect the state constraints. Some care is devoted to a valid construction of random initial data, necessary for the use of the new model. The article also includes a numerical method that is shown to respect the bounds on the state variables and illustrative numerical examples, explaining the properties of the new model in comparison with established models. PMID- 25811443 TI - Desmoplastic Fibroma of the Temporal Bone. PMID- 25811444 TI - Multifunctional graphene optoelectronic devices capable of detecting and storing photonic signals. AB - The advantages of graphene photodetectors were utilized to design a new multifunctional graphene optoelectronic device. Organic semiconductors, gold nanoparticles (AuNPs), and graphene were combined to fabricate a photodetecting device with a nonvolatile memory function for storing photonic signals. A pentacene organic semiconductor acted as a light absorption layer in the device and provided a high hole photocurrent to the graphene channel. The AuNPs, positioned between the tunneling and blocking dielectric layers, acted as both a charge trap layer and a plasmonic light scatterer, which enable storing of the information about the incident light. The proposed pentacene-graphene-AuNP hybrid photodetector not only performed well as a photodetector in the visible light range, it also was able to store the photonic signal in the form of persistent current. The good photodetection performance resulted from the plasmonics-enabled enhancement of the optical absorption and from the photogating mechanisms in the pentacene. The device provided a photoresponse that depended on the wavelength of incident light; therefore, the signal information (both the wavelength and intensity) of the incident light was effectively committed to memory. The simple process of applying a negative pulse gate voltage could then erase the programmed information. The proposed photodetector with the capacity to store a photonic signal in memory represents a significant step toward the use of graphene in optoelectronic devices. PMID- 25811445 TI - FDG Uptake on Positron Emission Tomography Correlates with Survival and Time to Recurrence in Patients with Stage I Non-Small-Cell Lung Cancer. AB - INTRODUCTION: Patients with stage I non-small-cell lung cancer (NSCLC) have a wide variation in outcomes, most likely because there are undetected metastases at presentation. We retrospectively reviewed patients with early stage lung cancer to determine if FDG uptake of the primary tumor as measured on positron emission tomography (PET) at the time of diagnosis was associated with overall survival (OS) or time to recurrence (TTR). METHODS: We reviewed the Tumor Registry at our institution and identified 336 consecutive patients diagnosed with stage I NSCLC over a 5-year period who underwent an FDG-PET/computed tomography within 90 days before surgery. Kaplan-Meier curves were used to describe the survival and TTR experience within subgroups defined by PET maximum standardized uptake value (SUVmax). Cox proportional hazards model was used to assess the impact of PET SUVmax as a continuous variable on OS and TTR. Logistic regression was used to analyze the effect of SUVmax on dichotomized outcomes. RESULTS: Three hundred thirty-six consecutive patients (176 women and 160 men) with stage I NSCLC were retrospectively reviewed. Mean SUVmax was 9.2 +/- 6.9 (range 0.6-30.3). The hazard or risk of dying and recurrence increased significantly as SUVmax increased (p = 0.0008 and 0.024, respectively). CONCLUSIONS: Preoperative FDG uptake in the primary tumor in patients with stage I disease is associated with OS and TTR. This may be useful in identifying early stage patients who may benefit from more aggressive therapy after surgical resection. PMID- 25811446 TI - Enoxaparin-induced unilateral hemotympanum. AB - Hemotympanum is defined as the presence of blood in the middle ear cavity. It is commonly associated with skull fractures. Spontaneous hemotympanum secondary to anticoagulant therapy is extremely rare. Herein, we report the first case of a 51 year-old woman with right spontaneous hemotympanum related to the use of enoxaparin. Complete resolution of signs and symptoms was accomplished by conservative management. Close follow-up is important to assure resolution and reduce long-term sequelae. The use of anticoagulants should be considered in the differential diagnosis of hemotympanum. This is also a good case for clinicians to be mindful about hemorrhagic complications of anticoagulant treatment. PMID- 25811447 TI - Hemorrhagic risk due to platelet dysfunction in myelodysplastic patients, correlations with anemia severity and iron overload. AB - Platelet function is influenced by changes in membrane fluidity that has an important role in the expression of platelet receptors and in modulating the activity of proteins like phospholipase C or proteinkinase C. In freshly prepared platelets, membrane fluidity modifies the aggregation/agglutination function. Reactive oxygen species (ROS) represent another important parameter involved in platelet receptor activation. There is a certain association of high levels of ROS and iron overload. Patients with hemochromatosis have low platelet aggregation induced by thrombin; little is known about the anemia and effects of iron overload on platelet activation in myelodysplastic syndromes (MDS) patients. Study of platelet membrane fluidity and ROS production changes in patients with MDS and possible correlations with altered platelet function as reflected in aggregation curves and platelet receptor expression. To find out possible correlations of fluidity of platelet membrane and ROS level with hematologic parameters and iron levels. The prospective study included 34 patients with myelodysplastic syndromes classified according to French-American-British cooperative group proposals and 29 healthy volunteers. Platelet membrane fluidity was quantified by fluorescence anisotropy measurements using the marker 1-(4 trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate. ROS production was evaluated by fluorescence measurements using 2',7' dichlorodihydrofluorescein diacetate. Platelet function was analyzed by optical aggregometry using the agonists adenosine diphosphate, collagen, ristocetin and epinephrine. The expression of platelet receptors CD41/CD61, CD42a/CD42b and CD62P/CD63 was evaluated by flow cytometry. Platelet membrane fluidity in patients with MDS was similar to that of healthy volunteers and did not vary according to the risk category. Patients with MDS had increased platelet ROS production compared with the control group without statistical correlation with membrane fluidity. We found a negative correlation of ROS levels with the severity of anemia (R = -0.587, P = 0.017). Platelet response was reduced in patients with MDS compared with volunteers, for all reagents. The response was different according to the risk category only in case of ristocetin or collagen. Patients with anemia presented a decreased platelet aggregation induced by collagen or ristocetin (collagen: R = 0.395, P = 0.003; ristocetin: R = 0.420, P = 0.002). The membrane fluidity of platelets from MDS patients appeared unmodified, but the ROS production was increased in all risk categories of MDS. The levels of ROS were correlated with the degree of anemia, which, in turn, had a negative impact on the platelet aggregation function induced by collagen or ristocetin. PMID- 25811448 TI - Effect of von Willebrand factor on clot structure and lysis. AB - Von Willebrand Factor (vWF) is constitutively secreted by the endothelium and incorporated in the fibrin clots under slow clotting conditions. The aim of the present work was to study the effect of vWF on clot structure and lysis. Purified fibrinogen was mixed with vWF or Tris-buffered saline and clotted with thrombin - activated factor XIII. Fibrin polymerization was followed by turbidity at 350 nm during 2.5 h. After this time, plasmin was added on the top of the clots, and the optical density (OD) was read until baseline values. vWF effect on network[Combining Acute Accent]s porosity was evaluated by permeation using the same clotting conditions as for fibrin polymerization. Clot structure was visualized and analyzed by laser scanning confocal microscopy (LSCM). The rate of fibrin polymerization was 1.47 mOD/s in the presence of vWF and 0.5 mOD/s when vWF was not added (P < 0.05). The fibrin lysis rate was approximately four times faster when vWF was added to fibrinogen. The fibrin network porosity was (20.4 +/ 1.6) * 10 cm with vWF and (8.3 +/- 1.2) * 10 cm without external vWF (P < 0.05). The analysis of LSCM images showed that vWF increased fibrin fibers diameter and the networks[Combining Acute Accent] pores size. In conclusion, vWF covalently crosslinked to fibrin modify its structure (increases fibrin diameter and the pores filling space of the meshwork) that accelerates the fibrin lysis rate. PMID- 25811450 TI - Persistent global hypercoagulability in long-term survivors of acute pulmonary embolism. AB - Hypercoagulable and/or hypofibrinolytic states are risk factors for venous thromboembolism (VTE) including acute pulmonary embolism. Current screening for thrombophilia is targeted towards identifying a specific defect and guidelines recommend a population-based rather than individualized strategy for anticoagulation treatment. We investigated whether there is a global hypercoagulable state in long-term survivors of pulmonary embolism no longer receiving therapeutic anticoagulation utilizing the overall haemostatic potential (OHP) assay, which assesses overall coagulation potential (OCP), OHP and overall fibrinolytic potential (OFP). Long-term survivors of acute pulmonary embolism were identified from a local registry and OHP assays were performed and compared with age and sex-matched controls without pulmonary embolism. Time courses of fibrin formation and degradation were measured by spectrophotometry (absorption 405 nm) after addition of tissue factor and tissue plasminogen activator to plasma. OHP assays were performed in 67 long-term survivors of single pulmonary embolism (7.9 +/- 1.4 years after pulmonary embolism) and 20 age (61.7 +/- 11.2 vs 56.6 +/- 6.4 years, P = 0.06) and sex (P = 0.45)-matched controls. Survivors of pulmonary embolism were more hypercoagulable as reflected by significantly higher OCP (56.4 +/- 13.0 vs 49.9 +/- 6.9, P = 0.03) and had impaired fibrinolysis with higher OHP (12.6 +/- 7.0 vs 5.9 +/- 2.0, P < 0.001) and lower OFP (78.1 +/- 9.4 vs 88.2 +/- 2.9, P < 0.001) compared with controls. Importantly, these abnormalities in overall coagulation were independently predicted by levels of fibrinogen, platelet count, shortened activated partial thromboplastin time and inflammatory markers suggesting a multifactorial cause. Long-term survivors of pulmonary embolism demonstrate enhanced global coagulation and reduced fibrinolytic potential. Assessment of global coagulation may provide new insights into the aggregate effects of multiple prothombotic factors and long term risk of VTE recurrence. PMID- 25811449 TI - Baseline platelet indices and bleeding after transcatheter aortic valve implantation. AB - Bleeding complications are frequent and independently predict mortality after transcatheter aortic valve implantation (TAVI). It has been demonstrated that certain platelet parameters are indicative of platelet reactivity. We sought to determine the possible correlation between simple platelet indices and bleeding complications in patients undergoing TAVI. Platelet indices--platelet count, mean platelet volume (MPV), platelet distribution width and plateletcrit--were measured in 110 consecutive patients on the day preceding TAVI. In-hospital bleeding events after TAVI were assessed according to the Valve Academic Research Consortium-2 classification as any bleeding, major and life-threatening bleeding (MLTB) and need for transfusion. By receiver-operating characteristic analysis, only MPV was able to distinguish between patients with and without any bleeding [area under the curve (AUC) 0.629, 95% confidence interval (CI) 0.531-0.719, P = 0.0342], MLTB (AUC 0.730, 95% CI 0.637-0.811, P = 0.0004) and need for transfusion (AUC 0.660, 95% CI 0.563-0.747, P = 0.0045). By multivariate logistic regression, high MPV (>10.6) and low platelet distribution width (<14.8) were associated with increased risk of any bleeding [odds ratio (OR) 4.08, 95% CI 1.66 10.07, P = 0.0022; and OR 3.82, 95% CI 1.41-10.36, P = 0.0084, respectively] and MLTB (OR 10.76, 95% CI 3.05-38, P = 0.0002; and OR 8.46, 95% CI 1.69-42.17, P = 0.0092, respectively). Additionally, high MPV independently correlated with the need for transfusion (OR 4.11, 95% CI 1.71-9.86, P = 0.0016). Larger and less heterogenic platelets may be associated with increased risk of short-term bleeding complications after TAVI. PMID- 25811451 TI - Characterization of thrombin derived from human recombinant prothrombin. AB - Thrombin (FIIa) is the key enzyme in haemostasis and acts on several substrates involved in clot formation, platelet activation and feed-back regulation of its own formation. During activation of blood coagulation, FIIa is formed by proteolytic cleavage of prothrombin (FII). In the production of recombinant human FII (rhFII), a key question is whether the thrombin formed has the same properties as endogenous thrombin. We have investigated whether FIIa formed from rhFII and plasma-derived human FII (pdhFII) have the same enzymatic and haemostatic properties against a number of substrates and the same haemostatic capacity in plasma, whole blood and on platelets. Pure FIIa was isolated from rhFII and pdhFII cleaved by recombinant ecarin, and analytical methods were developed to compare the activity of FIIa against different substrates. FIIa derived from rhFII and pdhFII were found to have very similar properties in activating FVIII, FXIII, protein C, platelet aggregation and plasma or whole blood coagulation. Further, the same turnover for S-2366 was found with similar KM. However, activation of FV with rhFIIa was approximately 25% more effective than with pdhFIIa and heparin-enhanced inhibition of rhFIIa by antithrombin was significantly more efficient compared with pdhFIIa with 10% higher inhibition both at steady state and at initial rate conditions. Although differences between the two FIIa preparations using ecarin cleavage were observed, FIIa derived from rhFII administered to human would likely be very similar in activity and function as FIIa formed from endogenous FII. PMID- 25811452 TI - Successful treatment of immune tolerance induction with rituximab in a patient with severe hemophilia B and inhibitor. AB - Inhibitor development is one of the major problems in hemophilia patients. Whereas the inhibitor incidence in hemophilia A is estimated to be as high as 25 30%, it appears to be less frequent in hemophilia B, occurring in about 1-3% of hemophilia B patients. There are only a few case reports about immune tolerance induction (ITI) for hemophilia B patients. The present report describes ITI with rituximab in a patient with severe hemophilia B and inhibitor. The patient was diagnosed with severe hemophilia B at 9 months. He received prophylactic replacement therapy with plasma-derived factor IX (pd FIX). After 19 exposure days, inhibitor of factor IX was detected in his plasma, and replacement therapy was stopped. However, as he suffered from intracranial hemorrhage at the age of 1 year, he underwent first ITI at the age of 1 year. Unfortunately, this failed to reduce the level of the inhibitor, and this strategy was stopped after 2 years. Second ITI with pd FIX also failed. At the age of 14 years, ITI with rituximab was performed after obtaining informed consent. The patient received rituximab 375 mg/m once a week for four doses and received 40 u/kg of pd FIX every day. At 4 weeks after the start of ITI with rituximab, the level of the inhibitor of factor IX was diminished and was undetectable for 1 year after therapy. In this patient, ITI with rituximab was well tolerated and effective. This method should be considered for patients with hemophilia B and inhibitor. PMID- 25811454 TI - Disclosure of intimate partner violence in current marital/partner relationships among female university students and among women at an emergency department. AB - Detecting intimate partner violence (IPV) might empower women to start working on the impact that the abuse experience has had on their lives. Little, however, is known about disclosure of abuse in community and in clinical settings. The purpose of this study was to explore whether there was a difference in the disclosure of abuse experience among women who were attending the emergency department (ED) at Landspitali University Hospital or were located at a university site, that is, at the University Square at the University of Iceland. A cross-sectional research design was used. Data were collected at the same time in 2009 over a period of 9 months from N = 306 women ranging in age from 18 to 67 years (n = 166 at the University Square and n = 140 at the ED). A significantly higher proportion of the women at the ED reported that they were victims of IPV in their current marital/partner relationship and scored higher on the Women Abuse Screening Tool total scale than the women at the university site. This gave a clear indication that the women at the ED experienced significantly more frequent and more severe IPV in their current marital/partner relationship compared with the women at the university site. Identifying IPV in primary and clinical settings might, therefore, function as a protective factor if these women are offered appropriate first response and interventions. PMID- 25811453 TI - The relationship between fearfulness, GABA+, and fear-related BOLD responses in the insula. AB - The inhibitory neurotransmitter GABA plays a crucial role in anxiety and fear, but its relationship to brain activation during fear reactions is not clear. Previous studies suggest that GABA agonists lead to an attenuation of emotion processing related BOLD signals in the insula. The aim of this study was to investigate the relationship between GABA concentration and fear-related BOLD responses in this region. In 44 female participants with different levels of fearfulness, GABA concentration in the left insula was measured using a GABA+ MRS acquisition during rest; additionally, BOLD signals were obtained during performance of a fear provocation paradigm. Fearfulness was not associated with GABA+ in the left insula, but could predict fear-related BOLD responses in a cluster in the left anterior insula. The BOLD signal change in this cluster did not correlate with GABA+ concentration. However, we found a significant positive correlation between GABA+ concentration and fear-related BOLD responses in a different cluster that included parts of the left insula, amygdala and putamen. Our findings indicate that low insular GABA concentration is not a predisposition for fearfulness, and that several factors influence whether a correlation between GABA and BOLD can be found. PMID- 25811456 TI - The spatial distribution of Mustelidae in France. AB - We estimated the spatial distribution of 6 Mustelidae species in France using the data collected by the French national hunting and wildlife agency under the "small carnivorous species logbooks" program. The 1500 national wildlife protection officers working for this agency spend 80% of their working time traveling in the spatial area in which they have authority. During their travels, they occasionally detect dead or living small and medium size carnivorous animals. Between 2002 and 2005, each car operated by this agency was equipped with a logbook in which officers recorded information about the detected animals (species, location, dead or alive, date). Thus, more than 30000 dead or living animals were detected during the study period. Because a large number of detected animals in a region could have been the result of a high sampling pressure there, we modeled the number of detected animals as a function of the sampling effort to allow for unbiased estimation of the species density. For dead animals -- mostly roadkill -- we supposed that the effort in a given region was proportional to the distance traveled by the officers. For living animals, we had no way to measure the sampling effort. We demonstrated that it was possible to use the whole dataset (dead and living animals) to estimate the following: (i) the relative density -- i.e., the density multiplied by an unknown constant -- of each species of interest across the different French agricultural regions, (ii) the sampling effort for living animals for each region, and (iii) the relative detection probability for various species of interest. PMID- 25811455 TI - Deaths associated with respiratory syncytial and influenza viruses among persons >=5 years of age in HIV-prevalent area, South Africa, 1998-2009(1). AB - We estimated deaths attributable to influenza and respiratory syncytial virus (RSV) among persons >5 years of age in South Africa during 1998-2009 by applying regression models to monthly deaths and laboratory surveillance data. Rates were expressed per 100,000 person-years. The mean annual number of seasonal influenza associated deaths was 9,093 (rate 21.6). Persons >65 years of age and HIV positive persons accounted for 50% (n = 4,552) and 28% (n = 2,564) of overall seasonal influenza-associated deaths, respectively. In 2009, we estimated 4,113 (rate 9.2) influenza A(H1N1)pdm09-associated deaths. The mean of annual RSV associated deaths during the study period was 511 (rate 1.2); no RSV-associated deaths were estimated in persons >45 years of age. Our findings support the recommendation for influenza vaccination of older persons and HIV-positive persons. Surveillance for RSV should be strengthened to clarify the public health implications and severity of illness associated with RSV infection in South Africa. PMID- 25811457 TI - Introduction of soft X-ray spectromicroscopy as an advanced technique for plant biopolymers research. AB - Soft X-ray absorption spectroscopy coupled with nano-scale microscopy has been widely used in material science, environmental science, and physical sciences. In this work, the advantages of soft X-ray absorption spectromicroscopy for plant biopolymer research were demonstrated by determining the chemical sensitivity of the technique to identify common plant biopolymers and to map the distributions of biopolymers in plant samples. The chemical sensitivity of soft X-ray spectroscopy to study biopolymers was determined by recording the spectra of common plant biopolymers using soft X-ray and Fourier Transform mid Infrared (FT IR) spectroscopy techniques. The soft X-ray spectra of lignin, cellulose, and polygalacturonic acid have distinct spectral features. However, there were no distinct differences between cellulose and hemicellulose spectra. Mid infrared spectra of all biopolymers were unique and there were differences between the spectra of water soluble and insoluble xylans. The advantage of nano-scale spatial resolution exploited using soft X-ray spectromicroscopy for plant biopolymer research was demonstrated by mapping plant cell wall biopolymers in a lentil stem section and compared with the FT-IR spectromicroscopy data from the same sample. The soft X-ray spectromicroscopy enables mapping of biopolymers at the sub-cellular (~30 nm) resolution whereas, the limited spatial resolution in the micron scale range in the FT-IR spectromicroscopy made it difficult to identify the localized distribution of biopolymers. The advantages and limitations of soft X-ray and FT-IR spectromicroscopy techniques for biopolymer research are also discussed. PMID- 25811459 TI - Low RBM3 protein expression correlates with clinical stage, prognostic classification and increased risk of treatment failure in testicular non seminomatous germ cell cancer. AB - BACKGROUND: Expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate with favourable clinicopathological parameters and prognosis in several cancer diseases. The aim of this study was to examine the expression and prognostic ability of RBM3 in patients with testicular non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: Immunohistochemical RBM3 expression was analysed in tissue microarrays with tumours from 206 patients. Chi-square test was applied to analyze associations between RBM3 expression and clinicopathological parameters. Kaplan-Meier analysis was used to assess the impact of RBM3 expression on cancer-specific survival (CSS) and failure-free survival (FFS). Cox regression proportional hazards models were used to estimate the relative risk for failure. RESULTS: In the entire cohort, there was a significant association between clinical stage (p=0.044) and RBM3 expression. Weak RBM3 expression correlated with a significantly reduced FFS [79.3% versus 90.4% (p=0.019)] and CSS [87.5% versus 97.3% (p=0.047)]. For patients with metastatic disease (n = 88), significant associations were found between RBM3 expression and IGCCC group (p=0.007). The FFS was significantly inferior for patients with low tumour-specific RBM3 expression [59.3% versus 79.0% (p=0.013)], and this association remained significant in a multivariable model for patients with metastatic disease (HR=3.67; 95% CI 1.14, 11.89). CONCLUSION: Low RBM3 expression is an independent predictor of treatment failure in metastatic NSGCT, in relation to the prognostic factors included in the International Germ Cell Consensus Classification (IGCCC). These findings suggest that RBM3 may be a potential biomarker for treatment stratification in patients with metastatic non seminomatous germ cell tumours, and therefore merit further validation. PMID- 25811458 TI - Dual RNA sequencing reveals the expression of unique transcriptomic signatures in lipopolysaccharide-induced BV-2 microglial cells. AB - Microglial cells become rapidly activated through interactions with pathogens, and the persistent activation of these cells is associated with various neurodegenerative diseases. Previous studies have investigated the transcriptomic signatures in microglia or macrophages using microarray technologies. However, this method has numerous restrictions, such as spatial biases, uneven probe properties, low sensitivity, and dependency on the probes spotted. To overcome this limitation and identify novel transcribed genes in response to LPS, we used RNA Sequencing (RNA-Seq) to determine the novel transcriptomic signatures in BV-2 microglial cells. Sequencing assessment and quality evaluation showed that approximately 263 and 319 genes (>= 1.5 log2-fold), such as cytokines and chemokines, were strongly induced after 2 and 4 h, respectively, and the induction of several genes with unknown immunological functions was also observed. Importantly, we observed that previously unidentified transcription factors (TFs) (irf1, irf7, and irf9), histone demethylases (kdm4a) and DNA methyltransferases (dnmt3l) were significantly and selectively expressed in BV-2 microglial cells. The gene expression levels, transcription start sites (TSS), isoforms, and differential promoter usage revealed a complex pattern of transcriptional and post-transcriptional gene regulation upon infection with LPS. In addition, gene ontology, molecular networks and pathway analyses identified the top significantly regulated functional classification, canonical pathways and network functions at each activation status. Moreover, we further analyzed differentially expressed genes to identify transcription factor (TF) motifs (-950 to +50 bp of the 5' upstream promoters) and epigenetic mechanisms. Furthermore, we confirmed that the expressions of key inflammatory genes as well as pro inflammatory mediators in the supernatants were significantly induced in LPS treated primary microglial cells. This transcriptomic analysis is the first to show a comparison of the family-wide differential expression of most known immune genes and also reveal transcription evidence of multiple gene families in BV-2 microglial cells. Collectively, these findings reveal unique transcriptomic signatures in BV-2 microglial cells required for homeostasis and effective immune responses. PMID- 25811461 TI - Instability in the COPD diagnosis upon repeat testing vary with the definition of COPD. AB - BACKGROUND: A low FEV1/FVC from post-bronchodilator spirometry is required to diagnose COPD. Both the FEV1 and the FVC can vary over time; therefore, individuals can be given a diagnosis of mild COPD at one visit, but have normal spirometry during the next appointment, even without an intervention. METHODS: We analyzed two population-based surveys of adults with spirometry carried out for the same individuals 5-9 years after their baseline examination. We determined the factors associated with a change in the spirometry interpretation from one exam to the next utilizing different criteria commonly used to diagnose COPD. RESULTS: The rate of an inconsistent diagnosis of mild COPD was 11.7% using FEV1/FVC <0.70, 5.9% using FEV1/FEV6 = 30 kg/m(2)) before cancer diagnosis was associated with increased colorectal cancer-specific mortality (RR: 1.22, 95% CI: 1.003-1.35, p < 0.01) and all-cause mortality (RR: 1.25, 95% CI: 1.14-1.36, p < 0.01). On the other hand, being underweight (RR: 1.33, 95% CI: 1.20-1.47, p < 0.01), obese (RR: 1.08, 95% CI: 1.03-1.3, p < 0.01), and class II/III obese (BMI >= 35 kg/m(2); RR: 1.13, 95% CI: 1.04-1.23, p < 0.01) after diagnosis were associated with significantly increased all-cause mortality. Being obese prior to diagnosis of colorectal cancer was associated with increased colorectal cancer-specific mortality and all cause mortality, whereas being obese after diagnosis was associated with increased all-cause mortality. The associations with being underweight may reflect reverse causation. Maintaining a healthy body weight should be discussed with colorectal cancer survivors. PMID- 25811462 TI - Bayesian mapping of HIV infection among women of reproductive age in Rwanda. AB - HIV prevalence is rising and has been consistently higher among women in Rwanda whereas a decreasing national HIV prevalence rate in the adult population has stabilised since 2005. Factors explaining the increased vulnerability of women to HIV infection are not currently well understood. A statistical mapping at smaller geographic units and the identification of key HIV risk factors are crucial for pragmatic and more efficient interventions. The data used in this study were extracted from the 2010 Rwanda Demographic and Health Survey data for 6952 women. A full Bayesian geo-additive logistic regression model was fitted to data in order to assess the effect of key risk factors and map district-level spatial effects on the risk of HIV infection. The results showed that women who had STIs, concurrent sexual partners in the 12 months prior to the survey, a sex debut at earlier age than 19 years, were living in a woman-headed or high-economic status household were significantly associated with a higher risk of HIV infection. There was a protective effect of high HIV knowledge and perception. Women occupied in agriculture, and those residing in rural areas were also associated with lower risk of being infected. This study provides district-level maps of the variation of HIV infection among women of child-bearing age in Rwanda. The maps highlight areas where women are at a higher risk of infection; the aspect that proximate and distal factors alone could not uncover. There are distinctive geographic patterns, although statistically insignificant, of the risk of HIV infection suggesting potential effectiveness of district specific interventions. The results also suggest that changes in sexual behaviour can yield significant results in controlling HIV infection in Rwanda. PMID- 25811464 TI - Punishment as a means of competition: implications for strong reciprocity theory. AB - Strong negative reciprocity, that is, sanctions imposed on norm violators at the punisher's own expense, has powerful cooperation-enhancing effects in both real life and experimental game situations. However, it is plausible that punishment may obtain alternative roles depending on social context and the personality characteristics of participants. We examined the occurrence of punishing behavior among 80 subjects in a strongly competitive Public Goods game setting. Despite the punishment condition, the amount of the contributions decreased steadily during the game. The amount of contributions had no significant effect on received and imposed punishments. The results indicate that certain social contexts (in this case, intensive competition) exert modifying effects on the role that punishment takes on. Subjects punished each other in order to achieve a higher rank and a financially better outcome. Punishment primarily functioned as a means of rivalry, instead of as a way of second-order cooperation, as strong reciprocity suggests. These results indicate the need for the possible modification of the social conditions of punishment mechanisms described by the strong reciprocity theory as an evolutionary explanation of human cooperation. PMID- 25811463 TI - NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module. AB - MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) family member CIITA, which is recruited to SXY enhancers of MHCII promoters via a DNA-binding "enhanceosome" complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of NLRC5's target gene specificity and mechanism of action remained lacking. We performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-regulated genes. In addition to classical MHCI genes, we exclusively identified novel targets encoding non-classical MHCI molecules having important functions in immunity and tolerance. ChIP-sequencing performed with Rfx5(-/-) cells, which lack the pivotal enhanceosome factor RFX5, demonstrated its strict requirement for NLRC5 recruitment. Accordingly, Rfx5-knockout mice phenocopy Nlrc5 deficiency with respect to defective MHCI expression. Analysis of B cell lines lacking RFX5, RFXAP, or RFXANK further corroborated the importance of the enhanceosome for MHCI expression. Although recruited by common DNA-binding factors, CIITA and NLRC5 exhibit non-redundant functions, shown here using double deficient Nlrc5(-/-)CIIta(-/-) mice. These paradoxical findings were resolved by using a "de novo" motif-discovery approach showing that the SXY consensus sequence occupied by NLRC5 in vivo diverges significantly from that occupied by CIITA. These sequence differences were sufficient to determine preferential occupation and transactivation by NLRC5 or CIITA, respectively, and the S box was found to be the essential feature conferring NLRC5 specificity. These results broaden our knowledge on the transcriptional activities of NLRC5 and CIITA, revealing their dependence on shared enhanceosome factors but their recruitment to distinct enhancer motifs in vivo. Furthermore, we demonstrated selectivity of NLRC5 for genes encoding MHCI or related proteins, rendering it an attractive target for therapeutic intervention. NLRC5 and CIITA thus emerge as paradigms for a novel class of transcriptional regulators dedicated for transactivating extremely few, phylogenetically related genes. PMID- 25811465 TI - Markedly increased IP-10 production by blood-brain barrier in neuromyelitis optica. AB - OBJECTIVE: Severe damage to the blood-brain barrier (BBB) allows anti-aquaporin 4 (AQP4) antibodies to access the astrocytic endfeet in neuromyelitis optica (NMO). In the current study, we identified the pathogenic cytokines/chemokines that are responsible for the BBB malfunction induced by NMO sera. METHODS: We measured the levels of 27 cytokines/chemokines in human brain microvascular endothelial cells (BMECs) after exposure to sera obtained from patients with the acute and stable phases of anti-AQP4 antibody-positive NMO spectrum disorder (NMOSD), multiple sclerosis (MS) patients and healthy controls (HC) using a multiplexed fluorescent bead-based immunoassay system. RESULTS: The induced protein (IP)-10 level in the cells was markedly increased following exposure to acute phase NMOSD sera. Other cytokines/chemokines including interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 were also significantly increased in the acute NMOSD group compared to both the MS and HC groups. The up-regulation of the IP-10 levels in the cells after exposure to the acute-phase NMOSD sera was also observed using another specified ELISA, and this effect was significantly decreased during the remission phase in the individual NMOSD patients. Furthermore, the increase in the level of IP-10 after exposure to the sera was significantly correlated with the cerebrospinal fluid/serum albumin ratio. CONCLUSIONS: Sera from the acute phase of NMO markedly increased the autocrine secretion of IP-10 by BMECs. The over-production of IP-10 in BMECs may play an important role in the pathogenesis of NMO and may therefore help to mediate the trafficking of T cells expressing its receptor across the BBB. PMID- 25811466 TI - Genome-wide comparative analysis reveals similar types of NBS genes in hybrid Citrus sinensis genome and original Citrus clementine genome and provides new insights into non-TIR NBS genes. AB - In this study, we identified and compared nucleotide-binding site (NBS) domain containing genes from three Citrus genomes (C. clementina, C. sinensis from USA and C. sinensis from China). Phylogenetic analysis of all Citrus NBS genes across these three genomes revealed that there are three approximately evenly numbered groups: one group contains the Toll-Interleukin receptor (TIR) domain and two different Non-TIR groups in which most of proteins contain the Coiled Coil (CC) domain. Motif analysis confirmed that the two groups of CC-containing NBS genes are from different evolutionary origins. We partitioned NBS genes into clades using NBS domain sequence distances and found most clades include NBS genes from all three Citrus genomes. This suggests that three Citrus genomes have similar numbers and types of NBS genes. We also mapped the re-sequenced reads of three pomelo and three mandarin genomes onto the C. sinensis genome. We found that most NBS genes of the hybrid C. sinensis genome have corresponding homologous genes in both pomelo and mandarin genomes. The homologous NBS genes in pomelo and mandarin suggest that the parental species of C. sinensis may contain similar types of NBS genes. This explains why the hybrid C. sinensis and original C. clementina have similar types of NBS genes in this study. Furthermore, we found that sequence variation amongst Citrus NBS genes were shaped by multiple independent and shared accelerated mutation accumulation events among different groups of NBS genes and in different Citrus genomes. Our comparative analyses yield valuable insight into the structure, organization and evolution of NBS genes in Citrus genomes. Furthermore, our comprehensive analysis showed that the non-TIR NBS genes can be divided into two groups that come from different evolutionary origins. This provides new insights into non-TIR genes, which have not received much attention. PMID- 25811467 TI - Behavioural ecology and group cohesion of juvenile western lowland gorillas (Gorilla g. gorilla) during rehabilitation in the Bateke Plateaux National Park, Gabon. AB - Rehabilitation of animals followed by reintroduction into the wild can benefit conservation by supplementing depleted wild populations or reintroducing a species in an area where it has been extirpated or become extinct. The western lowland gorilla (WLG, Gorilla g. gorilla) is persistently poached; infants are often illegally traded and used as pets. Some are confiscated and rehabilitated, then kept in sanctuaries or reintroduced into the wild. Prior to reintroduction, the ability of the orphans to survive independently in their environment needs to be assessed. Here, we performed a multivariate analysis, including diet composition, activity-budget, and pattern of strata using of a group of five juvenile WLG in the process of rehabilitation and distinguished three sub-periods of ecological significance: the high furgivory period, the Dialium fruits consumption period, and the high folivory period. The consequences of these variations on their well-being (play behaviour) and the group cohesion (spatial proximity and social interactions) were examined. Like wild WLGs, diets shifted seasonally from frugivorous to folivorous, while the same staple foods were consumed and large amounts of Dialium fruits were seasonally gathered high in trees. When succulent fruit intake was the highest, thus providing high energy from sugar, juveniles spent less time feeding, more time playing and group cohesion was the highest. Conversely, the cohesion decreased with increasing folivory, individuals spent more time feeding and less time playing together. Nonetheless, the group cohesion also decreased after the death of one highly social, wild-born orphan. This may underscore the importance of skilled individuals in the cohesion and well-being of the entire group and, ultimately, to rehabilitation success. This study evaluates the rehabilitation success with regards to the methods used and highlights the need to consider a set of individual and environmental factors for enhancing rehabilitation while preserving the local biodiversity and individual well-being. PMID- 25811470 TI - [Genetic factors in pathogenesis, course and treatment of inflammatory bowel diseases]. AB - Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal disorders with alternating relapses and remissions. Two main types within IBD can be distinguished: Crohn's disease and ulcerative colitis. Considering the epidemiological, immunological and genetic data, it was concluded that IBD possess multifactorial etiology, where genetic and environmental factors form the immunological background for the disease. In this review we discuss the most important genes and their protein products in IBD etiology and their impact on IBD pharmacotherapy. PMID- 25811468 TI - Bladder uptake of liposomes after intravesical administration occurs by endocytosis. AB - Liposomes have been used therapeutically and as a local drug delivery system in the bladder. However, the exact mechanism for the uptake of liposomes by bladder cells is unclear. In the present study, we investigated the role of endocytosis in the uptake of liposomes by cultured human UROtsa cells of urothelium and rat bladder. UROtsa cells were incubated in serum-free media with liposomes containing colloidal gold particles for 2 h either at 37 degrees C or at 4 degrees C. Transmission Electron Microscopy (TEM) images of cells incubated at 37 degrees C found endocytic vesicles containing gold inside the cells. In contrast, only extracellular binding was noticed in cells incubated with liposomes at 4 degrees C. Absence of liposome internalization at 4 degrees C indicates the need of energy dependent endocytosis as the primary mechanism of entry of liposomes into the urothelium. Flow cytometry analysis revealed that the uptake of liposomes at 37 degrees C occurs via clathrin mediated endocytosis. Based on these observations, we propose that clathrin mediated endocytosis is the main route of entry for liposomes into the urothelial layer of the bladder and the findings here support the usefulness of liposomes in intravesical drug delivery. PMID- 25811469 TI - Combining paclitaxel with ABT-263 has a synergistic effect on paclitaxel resistant prostate cancer cells. AB - We assessed the capability of paclitaxel, one of the taxanes, to induce death in two prostate cancer lines, LNCaP and PC3. Paclitaxel drove an apoptotic pathway in LNCaP, but not in PC3 cells, in response to G2/M arrest. An examination of the levels of anti-apoptotic proteins revealed that Bcl-xl was much higher in PC3 cells than in LNCaP cells and Bcl2 could be detected only in PC3 cells, not in LNCaP cells. Knocking down Bcl-xl enhanced paclitaxel-induced apoptosis in LNCaP cells, while we were unable to knock down Bcl-xl efficiently in PC3 cells. Significantly, a comparison of ABT-263, a specific inhibitor of Bcl2 and Bcl-xl, with ABT-199, a Bcl2 selective inhibitor, disclosed that only ABT-263, not ABT 199, could induce apoptosis in LNCaP and PC3 cells. The results indicate that Bcl xl has a protective role against paclitaxel-induced apoptosis in LNCaP and PC3 cells, and its overexpression causes the paclitaxel resistance seen in PC3 cells. Interestingly, combined paclitaxel with ABT-263 to treat LNCaP and PC3 cells demonstrated synergistic apoptosis activation, indicating that ABT-263 could enhance paclitaxel-induced apoptosis in LNCaP cells and overcome Bcl-xl overexpression to trigger paclitaxel-induced apoptosis in PC3 cells. We also observed that the activation of apoptosis in LNCaP cells was more efficient than in PC3 cells in response to paclitaxel plus ABT-263 or to ABT-263 alone, suggesting that the apoptosis pathway in PC3 cells might have further differences from that in LNCaP cells even after Bcl-xl overexpression is accounted for. PMID- 25811471 TI - [Well-known and new variants of pathogenic Escherichia coli as a consequence of the plastic genome]. AB - E. coli is a diverse bacterial species encompassing commensal as well as intestinal and extraintestinal pathogenic strains. The ability to adapt to so many different niches in the host organism is determined by the extreme genomic plasticity of E. coli. The genetic diversity is due to a complex phylogenetic structure in which besides the well-known main groups A, B1, B2 and D, four new groups, C, E, F and Clad I, have been characterized recently. The mobile gene pool exchanged by horizontal gene transfer (HGT) is another important driving force in the evolution of E. coli. Pathogenicity of strains is conditioned by a specific repertoire of virulence factors located on the mobile genetic elements and transmitted by HGT. The environment changing constantly stimulates the formation of new virulence gene combinations that generate the formation, not observed so far, of new pathogenic clones of higher capacity for virulence and greater expansiveness. The presence of very similar virulence plasmids carrying conserved combinations of the virulence genes (CVP) among extraintestinal pathogenic strains in humans and birds has been observed. It indicates a real possibility of occurrence of common virulence factors. The increase in drug resistance among pathogenic E. coli is also reflected in the prevalence of highly expansive clones exhibiting both high virulence and resistance. The presented data indicate that further studies are required to determine the interdependencies of resistance and virulence at the genetic level to help improve our management of the infectious diseases caused by these bacteria. PMID- 25811472 TI - [Plants as an alternative source of therapeutic proteins]. AB - In recent years, there has been an increased interest of researchers in developing efficient plant heterologous expression systems of proteins for a wide range of applications. It represents an alternative to the traditional strategy utilizing bacterial, yeast, insect or mammalian cells. New techniques of identification and characterization and effective methods of plant genetic transformation allow the range of recombinant protein products to be expanded. Great expectations are associated with the use of plants as bioreactors for the production of specific proteins of therapeutic interest. This strategy offers a number of advantages, the most important being: the possibility of a significant reduction in production costs, the safety of the products obtained and full eukaryotic post-translational modifications of proteins. A group of proteins of special interest is pharmaceuticals, and a number of successful experiments have confirmed the possibility of obtaining heterogeneous proteins with therapeutic potential: monoclonal antibodies, vaccine antigens, and a variety of cytokines. This work is focused on selected recombinant proteins belonging to those groups expression of which was achieved in plant cells. These proteins may be used in the future for therapy or prevention of viral, bacterial or cancer diseases. PMID- 25811473 TI - [Use of organic acids in acne and skin discolorations therapy]. AB - Acne is one of the most frequent skin disorders that occurs in puberty, but often adults also have acne. The most important factors responsible for acne are elevated production of sebum by hyperactive sebaceous glands and blockage of the follicle because of hyperkeratosis [14]. The third etiopathogenic factor of acne is excessive microflora reproduction [8]. The most significant bacterium that is responsible for formation of skin lesions is Propionibacterium acnes, a rod shaped Gram-positive and aerotolerant anaerobic bacterium. It is estimated that P. acnes is responsible for acne in approximately 80% of people aged 11 to 30 [27,40]. Even healed skin lesions can often cause skin discolorations and scar formation [51]. Exfoliating chemical substances that are commonly used in dermatology and cosmetology are organic acids. Exfoliating treatment using organic acids is called "chemical peeling" and consists of controlled application of those substances on the skin [38]. The depth of exfoliation depends on organic acid concentration, type of substance and contact time with the skin [41]. Using exfoliating agents seems to be helpful in excessive keratinization - one of several factors responsible for acne. Moreover, epidermis exfoliation is a popular method of removing skin discoloration [22]. Considering chemical structure, exfoliating substances that are most often used in cosmetology contain alpha-hydroxyacids (glycolic acid, lactic acid, mandelic acid and citric acid), beta-hydroxyacids (salicylic acid) and other organic acids, such as trichloroacetic acid and pyruvic acid [47]. In this article, a literature review of use of organic acids in acne and skin discoloration therapy is presented. PMID- 25811474 TI - Sugar and Alzheimer's disease: a bittersweet truth. PMID- 25811475 TI - Cocaine shapes chromatin landscapes via Tet1. PMID- 25811476 TI - Carrot or stick in motor learning. PMID- 25811477 TI - The compass within. PMID- 25811478 TI - Forming artificial memories during sleep. PMID- 25811479 TI - Bullying as a risk for poor sleep quality among high school students in China. AB - OBJECTIVE: To determine whether involvement in bullying as a bully, victim, or bully-victim was associated with a higher risk of poor sleep quality among high school students in China. METHODS: A cross-sectional study was conducted. A total of 23,877 high school students were surveyed in six cities in Guangdong Province. All students were asked to complete the adolescent health status questionnaire, which included the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) and bullying involvement. Descriptive statistics were used to evaluate sleep quality and the prevalence of school bullying. Multi-level logistic regression analyses were conducted to examine the association between being victimized and bullying others with sleep quality. RESULTS: Among the 23,877 students, 6,127 (25.66%) reported having poor sleep quality, and 10.89% reported being involved in bullying behaviors. Of the respondents, 1,410 (5.91%) were pure victims of bullying, 401 (1.68%) were bullies and 784 (3.28%) were bully-victims. Frequently being involved in bullying behaviors (being bullied or bullying others) was related to increased risks of poor sleep quality compared with adolescents who were not involved in bullying behaviors. After adjusting for age, sex, and other confounding factors, the students who were being bullied (OR=2.05, 95%CI=1.81 2.32), bullied others (OR=2.30, 95%CI=1.85-2.86) or both (OR=2.58, 95%CI=2.20 3.03) were at a higher risk for poor sleep quality. CONCLUSIONS: Poor sleep quality among high school students is highly prevalent, and school bullying is prevalent among adolescents in China. The present results suggested that being involved in school bullying might be a risk factor for poor sleep quality among adolescents. PMID- 25811480 TI - Geographical analysis of aneurysmal subarachnoid hemorrhage in Japan utilizing publically-accessible DPC database. AB - Since the launch of the novel medical reimbursement system Diagnosis Procedure Combination (DPC) in 2003 in Japan, inpatient data has been accumulated over time as part of a Japanese governmental nationwide database. This is partially accessible by the public, and this study examined the adequacy of this database as epidemiological research material by extracting the data relating to aneurysmal subarachnoid hemorrhage (aSAH) with special attention given to the limitations that this involves. Datasets after 2010 are considered suitable for analysis because of the numbers of participating hospitals and the analysis term. Extracting the data by prefecture, those with a continuously high aSAH incidence were Aomori, Iwate, Akita, Yamagata, Kochi and Kumamoto Prefectures, and those with low aSAH incidence were Kanagawa, Shiga, Kyoto, Shimane and Ehime Prefectures. Although these obtained results are informative, a publically accessible DPC database has several limitations. Some limitations have been resolved: the analyzed term each year is now 12-months and the number of participating hospitals seems to have stabilized around 1700. However, other limitations such as masking the numbers in each hospital reporting less than 10 patients still exist, so careful and critical interpretation is necessary in utilizing a publically-accessible DPC database. Considering the potential of this database as material for epidemiological research, future analysis of the entire DPC database by qualified researchers is desirable. PMID- 25811481 TI - SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long chain acyl-CoA dehydrogenase. AB - SIRT3 and SIRT5 have been shown to regulate mitochondrial fatty acid oxidation but the molecular mechanisms behind the regulation are lacking. Here, we demonstrate that SIRT3 and SIRT5 both target human very long-chain acyl-CoA dehydrogenase (VLCAD), a key fatty acid oxidation enzyme. SIRT3 deacetylates and SIRT5 desuccinylates K299 which serves to stabilize the essential FAD cofactor in the active site. Further, we show that VLCAD binds strongly to cardiolipin and isolated mitochondrial membranes via a domain near the C-terminus containing lysines K482, K492, and K507. Acetylation or succinylation of these residues eliminates binding of VLCAD to cardiolipin. SIRT3 deacetylates K507 while SIRT5 desuccinylates K482, K492, and K507. Sirtuin deacylation of recombinant VLCAD rescues membrane binding. Endogenous VLCAD from SIRT3 and SIRT5 knockout mouse liver shows reduced binding to cardiolipin. Thus, SIRT3 and SIRT5 promote fatty acid oxidation by converging upon VLCAD to promote its activity and membrane localization. Regulation of cardiolipin binding by reversible lysine acylation is a novel mechanism that is predicted to extrapolate to other metabolic proteins that localize to the inner mitochondrial membrane. PMID- 25811483 TI - Effect of receptor dimerization on membrane lipid raft structure continuously quantified on single cells by camera based fluorescence correlation spectroscopy. AB - Membrane bound cell signaling is modulated by the membrane ultra-structure, which itself may be affected by signaling. However, measuring the interaction of membrane proteins with membrane structures in intact cells in real-time poses considerable challenges. In this paper we present a non-destructive fluorescence method that quantifies these interactions in single cells, and is able to monitor the same cell continuously to observe small changes. This approach combines total internal fluorescence microscopy with fluorescence correlation spectroscopy to measure the protein's diffusion and molecular concentration in different sized areas simultaneously. It correctly differentiates proteins interacting with membrane fences from proteins interacting with cholesterol-stabilized domains, or lipid rafts. This method detects small perturbations of the membrane ultra structure or of a protein's tendency to dimerize. Through continuous monitoring of single cells, we demonstrate how dimerization of GPI-anchored proteins increases their association with the structural domains. Using a dual-color approach we study the effect of dimerization of one GPI-anchored protein on another type of GPI-anchored protein expressed in the same cell. Scans over the cell surface reveal a correlation between cholesterol stabilized domains and membrane cytoskeleton. PMID- 25811482 TI - T-helper1/T-helper2 cytokine imbalance in the iris of patients with glaucoma. AB - The mechanistic study of glaucoma pathogenesis has shifted to seeking to understand the effects of immune responses on retinal ganglion cell damage and protection. Cytokines mediate the biological effects of the immune system, and our previous study revealed an imbalance of T-helper (Th) 1-derived and Th2 derived cytokines in the serum of patients with glaucoma. In this study, we collected irises from normal individuals and patients with primary open-angle closure (POAG) or chronic angle-closure glaucoma (CACG). We used real-time polymerase chain reaction (PCR) to measure the expression of Th1 (interleukin (IL)-2, interferon-gamma (IFN-gamma)), Th2 (IL-4, IL-6, IL-10), and Th3 (transforming growth factor-beta (TGF-beta)) cytokines. We then performed immunohistochemical staining to characterize the localization of the upregulated cytokines in iris cryosections. We observed an upward trend in the expression of IL-2 and IFN-gamma and a downward trend in IL-6 expression in the iris of POAG and CACG patients. Expression of TGF-beta also increased. Immunohistochemistry revealed that IL-2 expression in POAG and CACG patients was localized in the anterior surface of the blood vessel wall in the stroma of the iris, in the cytoplasm of some cells, in the anterior epithelium, and in the posterior pigment epithelium. These findings indicate that immune status differed between the iris tissues of POAG and CACG patients and those of normal individuals. A T-helper cytokine imbalance may modulate the immune microenvironment in glaucomatous eyes and thus influence optic neuropathy. PMID- 25811484 TI - Is scale-up of community mobilisation among sex workers really possible in complex urban environments? The case of Mumbai, India. AB - BACKGROUND: In the last decade, community mobilisation (CM) interventions targeting female sex workers (FSWs) have been scaled-up in India's national response to the HIV epidemic. This included the Bill and Melinda Gates Foundation's Avahan programme which adopted a business approach to plan and manage implementation at scale. With the focus of evaluation efforts on measuring effectiveness and health impacts there has been little analysis thus far of the interaction of the CM interventions with the sex work industry in complex urban environments. METHODS AND FINDINGS: Between March and July 2012 semi-structured, in-depth interviews and focus group discussions were conducted with 63 HIV intervention implementers, to explore challenges of HIV prevention among FSWs in Mumbai. A thematic analysis identified contextual factors that impact CM implementation. Large-scale interventions are not only impacted by, but were shown to shape the dynamic social context. Registration practices and programme monitoring were experienced as stigmatising, reflected in shifting client preferences towards women not disclosing as 'sex workers'. This combined with urban redevelopment and gentrification of traditional red light areas, forcing dispersal and more 'hidden' ways of solicitation, further challenging outreach and collectivisation. Participants reported that brothel owners and 'pimps' continued to restrict access to sex workers and the heterogeneous 'community' of FSWs remains fragmented with high levels of mobility. Stakeholder engagement was poor and mobilising around HIV prevention not compelling. Interventions largely failed to respond to community needs as strong target-orientation skewed activities towards those most easily measured and reported. CONCLUSION: Large scale interventions have been impacted by and contributed to an increasingly complex sex work environment in Mumbai, challenging outreach and mobilisation efforts. Sex workers remain a vulnerable and disempowered group needing continued support and more comprehensive services. PMID- 25811485 TI - Catch me if you can: the link between autophagy and viruses. PMID- 25811486 TI - Effects of a 3-year nurse-based case management in aged patients with acute myocardial infarction on rehospitalisation, mortality, risk factors, physical functioning and mental health. a secondary analysis of the randomized controlled KORINNA study. AB - BACKGROUND: Home-based secondary prevention programs led by nurses have been proposed to facilitate patients' adjustment to acute myocardial infarction (AMI). The objective of this study was to conduct secondary analyses of the three-year follow-up of a nurse-based case management for elderly patients discharged from hospital after an AMI. METHODS: In a single-centre randomized two-armed parallel group trial of hospitalized patients with AMI >=65 years, patients hospitalized between September 2008 and May 2010 in the Hospital of Augsburg, Germany, were randomly assigned to case management or usual care. The case-management intervention consisted of a nurse-based follow-up for three years including home visits and telephone calls. Study endpoints were time to first unplanned readmission or death, clinical parameters, functional status, depressive symptoms and malnutrition risk. Persons who assessed three-year outcomes and validated readmission data were blinded. The intention-to-treat approach was applied to the statistical analyses which included Cox Proportional Hazards models. RESULTS: Three hundred forty patients were allocated to receive case-management (n = 168) or usual care (n = 172). During three years, in the intervention group there were 80 first unplanned readmissions and 6 deaths, while the control group had 111first unplanned readmissions and 3 deaths. The intervention did not significantly affect time to first unplanned readmission or death (Hazard Ratio 0.89, 95% confidence interval (CI) 0.67-1.19; p = 0.439), blood pressure, cholesterol level, instrumental activities of daily life (IADL) (only for men), and depressive symptoms. However, patients in the intervention group had a significantly better functional status, as assessed by the HAQ Disability Index, IADL (only for women), and hand grip strength, and better SCREEN-II malnutrition risk scores than patients in the control group. CONCLUSIONS: A nurse-based management among elderly patients with AMI did not significantly affect time to unplanned readmissions or death during a three-year follow-up. However, the results indicate that functional status and malnutrition risk can be improved. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02893746. PMID- 25811488 TI - Google Glass for Recording Scleral Buckling Surgery. PMID- 25811487 TI - Impact of 'stretch' targets for cardiovascular disease management within a local pay-for-performance programme. AB - Pay-for-performance programs are often aimed to improve the management of chronic diseases. We evaluate the impact of a local pay for performance programme (QOF+), which rewarded financially more ambitious quality targets ('stretch targets') than those used nationally in the Quality and Outcomes Framework (QOF). We focus on targets for intermediate outcomes in patients with cardiovascular disease and diabetes. A difference-in-difference approach is used to compare practice level achievements before and after the introduction of the local pay for performance program. In addition, we analysed patient-level data on exception reporting and intermediate outcomes utilizing an interrupted time series analysis. The local pay for performance program led to significantly higher target achievements (hypertension: p-value <0.001, coronary heart disease: p-values <0.001, diabetes: p-values <0.061, stroke: p-values <0.003). However, the increase was driven by higher rates of exception reporting (hypertension: p-value <0.001, coronary heart disease: p-values <0.03, diabetes: p-values <0.05) in patients with all conditions except for stroke. Exception reporting allows practitioners to exclude patients from target calculations if certain criteria are met, e.g. informed dissent of the patient for treatment. There were no statistically significant improvements in mean blood pressure, cholesterol or HbA1c levels. Thus, achievement of higher payment thresholds in the local pay for performance scheme was mainly attributed to increased exception reporting by practices with no discernable improvements in overall clinical quality. Hence, active monitoring of exception reporting should be considered when setting more ambitious quality targets. More generally, the study suggests a trade-off between additional incentive for better care and monitoring costs. PMID- 25811489 TI - Can the Liebowitz Social Anxiety Scale - self-report version be used to differentiate clinical and non-clinical SAD groups among Brazilians? AB - BACKGROUND: The Liebowitz Social Anxiety Scale (LSAS) was the first evaluation instrument developed for screening for the signs and symptoms of Social Anxiety Disorder (SAD) and is currently still the most used worldwide. The aim of this study is to evaluate the ability of the LSAS - self-report version (LSAS-SR) to discriminate different Social Anxiety Disorder (SAD) clinical groups. METHOD: The sample was composed of Brazilians university students, allocated into three different groups, i.e., cases (C=118), non-cases (NC=95) and subclinical cases (SC=39). To achieve the aim, calculations of the ROC Curve and ANOVA were performed. RESULTS: The results found were excellent regardless of the technique used, highlighting the discriminatory capacity of the LSAS-SR. The score equal to or greater than 32 is suggested as a cutoff score for the Brazilian population, since this presented balance between the standards evaluated and the ability to differentiate both clinical and subclinical SAD cases from non-cases. CONCLUSION: Despite the specific sample used in this study being composed only of university students, the use of the LSAS-SR can be indicated, in the Brazilian setting, for SAD screening in both clinical and research contexts. PMID- 25811493 TI - Absorptive carbon nanotube electrodes: consequences of optical interference loss in thin film solar cells. AB - A current bottleneck in the thin film photovoltaic field is the fabrication of low cost electrodes. We demonstrate ultrasonically spray coated multiwalled carbon nanotube (CNT) layers as opaque and absorptive metal-free electrodes deposited at low temperatures and free of post-deposition treatment. The electrodes show sheet resistance as low as 3.4 Omega ?(-1), comparable to evaporated metallic contacts deposited in vacuum. Organic photovoltaic devices were optically simulated, showing comparable photocurrent generation between reflective metal and absorptive CNT electrodes for photoactive layer thickness larger than 600 nm when using archetypal poly(3-hexylthiophene) (P3HT) : (6,6) phenyl C61-butyric acid methyl ester (PCBM) cells. Fabricated devices clearly show that the absorptive CNT electrodes display comparable performance to solution processed and spray coated Ag nanoparticle devices. Additionally, other candidate absorber materials for thin film photovoltaics were simulated with absorptive contacts, elucidating device design in the absence of optical interference and reflection. PMID- 25811490 TI - Lipoprotein lipase SNPs rs13702 and rs301 correlate with clinical outcome in chronic lymphocytic leukemia patients. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and is characterized by a heterogeneous clinical course. This variability in clinical course has spiked the search for prognostic markers able to predict patient evolution at the moment of diagnosis. Markers demonstrated to be of value are the mutation status of the immunoglobulin heavy chain variable region genes (IGHV) and lipoprotein lipase (LPL) expression. High LPL mRNA expression has been associated with short treatment free (TFS) and decreased overall survival (OS) in CLL. The LPL SNPs rs301 (T100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo-pituitary-gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism. PMID- 25811531 TI - Multibody system dynamics for bio-inspired locomotion: from geometric structures to computational aspects. AB - This article presents a set of generic tools for multibody system dynamics devoted to the study of bio-inspired locomotion in robotics. First, archetypal examples from the field of bio-inspired robot locomotion are presented to prepare the ground for further discussion. The general problem of locomotion is then stated. In considering this problem, we progressively draw a unified geometric picture of locomotion dynamics. For that purpose, we start from the model of discrete mobile multibody systems (MMSs) that we progressively extend to the case of continuous and finally soft systems. Beyond these theoretical aspects, we address the practical problem of the efficient computation of these models by proposing a Newton-Euler-based approach to efficient locomotion dynamics with a few illustrations of creeping, swimming, and flying. PMID- 25811532 TI - Common Congenital Anomalies of the Central Airways in Adults. AB - The knowledge of airway anatomy is the most fundamental requirement of every bronchoscopist. There are numerous and frequent anatomic variations of the central airways making the examination unique for every individual. It is imperative for every bronchoscopist to be fully cognizant of the common congenital anomalies involving the central airways. Proper identification and reporting of these findings are a matter of the utmost importance, especially when surgical options in a patient with lung cancer or lung transplantation is under consideration. This article focuses on the congenital anomalies of central airway encountered among adults. Each of these anatomic variations has a characteristic appearance, yet requires bronchoscopic acumen for their identification. This review provides a comprehensive description of these anomalies and highlights their clinical implications. PMID- 25811533 TI - Ultrasensitive detection of nitroexplosive - picric acid via a conjugated polyelectrolyte in aqueous media and solid support. AB - Picric acid (PA) detection at parts per trillion (ppt) levels is achieved by a conjugated polyelectrolyte (PMI) in 100% aqueous media and on a solid platform using paper strips and chitosan (CS) films. The unprecedented selectivity is accomplished via combination of ground state charge transfer and resonance energy transfer (RET) facilitated by favorable electrostatic interactions. PMID- 25811534 TI - Chikungunya outbreak, French Polynesia, 2014. PMID- 25811536 TI - Covalent attachment of diphosphine ligands to glassy carbon electrodes via Cu catalyzed alkyne-azide cycloaddition. Metallation with Ni(II). AB - Covalent tethering of P(Ph)2N(C6H4C=CH)2 ligands (P(Ph)2N(C6H4C=CH)2 = 1,5-di-(4 ethynylphenyl)-3,7-diphenyl-1,5-diaza-3,7-diphosphacyclooctane) to planar, azide terminated glassy carbon electrode surfaces has been accomplished using a Cu(I) catalyzed alkyne-azide cycloaddition (CuAAC) coupling reaction, using a BH3<-P protection-deprotection strategy. Deprotected, surface-confined ligands were metallated using [Ni(II)(MeCN)6](BF4)2. X-ray photoelectron spectroscopic measurements demonstrate that metallation introduced 1.3 equivalents Ni(II) per diphosphine onto the electrode surface. Exposure of the surface to a second diphosphine ligand, P(Ph)2N(Ph)2, resulted in the removal of Ni from the surface. Protection, coupling, deprotection, and metallation conditions were optimized using solution-phase model systems, with benzyl azide as a model for the azide terminated carbon surface; these reactions generate a [Ni(II)(diphosphine)2](2+) complex. PMID- 25811535 TI - Glycerol-based contrast agents: a novel series of dendronized pentamethine dyes. AB - The synthesis of water-soluble dyes, which absorb and emit in the range between 650 and 950 nm and display high extinction coefficients (epsilon) as well as high fluorescence quantum yields (Phif), is still a demand for optical imaging. We now present a synthetic route for the preparation of a new group of glycerol substituted cyanine dyes from dendronized indole precursors that have been functionalized as N-hydroxysuccinimide (NHS) esters. High Phif values of up to 0.15 and extinction coefficients of up to 189 000 L mol(-1) cm(-1) were obtained for the pure dyes. Furthermore, conjugates of the new dendronized dyes with the antibody cetuximab (ctx) that were directed against the epidermal growth factor receptor (EGFR) of tumor cells could be prepared with dye to protein ratios between 0.3 and 2.2 to assess their potential as imaging probes. For the first time, ctx conjugates could be achieved without showing a decrease in Phif and with an increasing labeling degree that exceeded the value of the pure dye even at a labeling degree above 2. The incorporation of hydrophilically and sterically demanding dendrimers into cyanines prevented dimer formation after covalent conjugation to the antibody. The binding functionality of the resulting ctx conjugates to the EGFR was successfully demonstrated by cell microscopy studies using EGFR expressing cell lines. In summary, the combination of hydrophilic glycerol dendrons with reactive dye labels has been established for the first time and is a promising approach toward more powerful fluorescent labels with less dimerization. PMID- 25811537 TI - Use of solid-state nanopores for sensing co-translocational deformation of nano liposomes. AB - Membrane deformation of nano-vesicles is crucial in many cellular processes such as virus entry into the host cell, membrane fusion, and endo- and exocytosis; however, studying the deformation of sub-100 nm soft vesicles is very challenging using the conventional techniques. In this paper, we report detecting co translocational deformation of individual 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC) nano-liposomes using solid-state nanopores. Electrokinetic translocation through the nanopore caused the soft DOPC liposomes (85 nm diameter) to change their shape, which we attribute to the strong electric field strength and physical confinement inside the pore. The experiments were performed at varying transmembrane voltages and the deformation was observed to mount up with increasing applied voltage and followed an exponential trend. Numerical simulations were performed to simulate the concentrated electric field strength inside the nanopore and a field strength of 14 kV cm(-1) (at 600 mV applied voltage) was achieved at the pore center. The electric field strength inside the nanopore is much higher than the field strength known to cause deformation of 15 30 MUm giant membrane vesicles. As a control, we also performed experiments with rigid polystyrene beads that did not show any deformation during translocation events, which further established our hypothesis of co-translocational deformation of liposomes. Our technique presents an innovative and high throughput means for investigating deformation behavior of soft nano-vesicles. PMID- 25811538 TI - Composition and evolution of the solid-electrolyte interphase in Na2Ti3O7 electrodes for Na-ion batteries: XPS and Auger parameter analysis. AB - Na2Ti3O7 is considered a promising negative electrode for Na-ion batteries; however, poor capacity retention has been reported and the stability of the solid electrolyte interphase (SEI) could be one of the main actors of this underperformance. The composition and evolution of the SEI in Na2Ti3O7 electrodes is hereby studied by means of X-ray photoelectron spectroscopy (XPS). To overcome typical XPS limitations in the photoelectron energy assignments, the analysis of the Auger parameter is here proposed for the first time in battery materials characterization. We have found that the electrode/electrolyte interface formed upon discharge, mostly composed by carbonates and semicarbonates (Na2CO3, NaCO3R), fluorides (NaF), chlorides (NaCl) and poly(ethylene oxide)s, is unstable upon electrochemical cycling. Additionally, solid state nuclear magnetic resonance (NMR) studies prove the reaction of the polyvinylidene difluoride (PVdF) binder with sodium. The powerful approach used in this work, namely Auger parameter study, enables us to correctly determine the composition of the electrode surface layer without any interference from surface charging or absolute binding energy calibration effects. As a result, the suitability for Na ion batteries of binders and electrolytes widely used for Li-ion batteries is questioned here. PMID- 25811539 TI - Pyrene fused perylene diimides: synthesis, characterization and applications in organic field-effect transistors and optical limiting with high performance. AB - Three pyrene fused PDI derivatives have been obtained, in which totally different properties were observed when adopting different fusing types. For bilaterally benzannulated PDIs, through spin-coating, bottom-contact OFET devices exhibited a p-type mobility up to 1.13 cm(2) V(-1) s(-1), with an on/off ratio of 10(8) in air. PMID- 25811541 TI - Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious cutaneous adverse reactions. We mined the approved labels in Drugs@FDA, identified the SJS/TEN list of 259 small molecular drugs and biologics, and conducted systems pharmacological network analyses. Pharmacological network analysis revealed that drugs with treatment-related SJS and/or TEN are pharmacologically diverse and that the largest subnetwork is associated with antiepileptic drugs and their pharmacological targets. Our pharmacological network analysis identified CTNNB1 [catenin (cadherin-associated protein), beta 1, 88 kDa] as a significant intermediator. This protein is involved in maintaining the functional integrity of the epithelium through regulating cell growth and adhesion between cells in various organs, including the skin. Leveraging a publicly accessible genome-wide transcriptional expression database, we found that human leukocyte antigen-related (HLA) genes were significantly perturbed by various SJS/TEN-inducing drugs. Notably, carbamazepine (CBZ) perturbed several HLA genes, among which HLA-DQB1*0201 was reportedly shown to be associated with CBZ-induced SJS/TEN in caucasians. In short, systems analysis by leveraging a publicly accessible knowledge base and databases could produce meaningful results for further mechanistic investigation. Our study sheds light on the utility of systems pharmacology analysis for gaining insight into clinical drug toxicity. PMID- 25811542 TI - Colorless organometallic ionic liquids from cationic ruthenium sandwich complexes: thermal properties, liquid properties, and crystal structures of [Ru(eta(5)-C5H5)(eta(6)-C6H5R)][X] (X = N(SO2CF3)2, N(SO2F)2, PF6). AB - A series of ionic liquids containing cationic ruthenium complexes ([Ru(C5H5)(C6H5R)](+)) were prepared, and their thermal properties were investigated (R = C4H9 (1a), C8H17 (1b), OCH2OCH3 (2a), O(CH2CH2O)2CH3 (2b), O(CH2)3CN (3a), O(CH2)6CN (3b), CO(CH2)2CH3 (4a), CO(CH2)6CH3 (4b)). Bis(trifluoromethanesulfonyl)amide (TFSA) and bis(fluorosulfonyl)amide (FSA) were used as counter anions. These ionic liquids were colorless and stable toward air and light. These salts exhibited glass transitions upon cooling from the melt (Tg = -82 degrees C to -55 degrees C), and the glass transition temperatures of the salts increased as the polarity of the substituents increased (alkyl < ether < cyano < carbonyl). The decomposition temperatures decreased in the order of alkyl > cyano > carbonyl > ether. The viscosities, solvent polarities, and refractive indices of the salts of 1a and 2a were also evaluated. Hexafluorophosphate (PF6) salts were also prepared, which were solids with high melting points (Tm = 65-127 degrees C). X-ray crystal structure analyses of these salts revealed the importance of intermolecular contacts involving the ring hydrogens. The PF6 salt of 2a exhibited an order-disorder phase transition. PMID- 25811540 TI - Severity of influenza A(H1N1) illness and emergence of D225G variant, 2013-14 influenza season, Florida, USA. AB - Despite a regional decline in influenza A(H1N1)pdm09 virus infections during 2013 14, cases at a Florida hospital were more severe than those during 2009-10. Examined strains had a hemagglutinin polymorphism associated with enhanced binding to lower respiratory tract receptors. Genetic changes in this virus must be monitored to predict the effect of future pandemic viruses. PMID- 25811543 TI - Large electric-field-induced strain in centrosymmetric crystals of a dipolar ruthenium alkynyl complex. AB - Dipolar molecular crystals present different physical properties from traditionally strongly correlated ionic solid-state inorganic crystals due to the weak intermolecular bonding. Herein, centrosymmetric dipolar molecular crystals of the organoruthenium complex trans-[Ru(C=CC6H4-4-NO2)(C=CPh)(dppe)2] [dppe = 1,2-bis(diphenylphosphino)ethane] display a large electric-field-induced strain behaving differently from conventional piezoelectric materials that must, structurally, be noncentrosymmetric. Further studies of related systematically varied crystalline organoruthenium complexes reveal that the strong electromechanical coupling effect is not from classical ferroelectricity, electrostriction, flexoelectricity or electrochemical strain. It is, instead, attributed to the disorder in the molecular packing, which facilitates reorientation of the molecular dipoles under the action of an applied electric field. This provides a fresh insight into the design and development of new functional materials and a promising source of electromechanical coupling in organometallic, and more generally dipolar molecular, crystals. PMID- 25811544 TI - The Influence of Oral L-Glutamine Supplementation on Muscle Strength Recovery and Soreness Following Unilateral Knee Extension Eccentric Exercise. AB - The study aimed to examine the effects that L-glutamine supplementation has on quadriceps muscle strength and soreness ratings following eccentric exercise. It was hypothesized that glutamine ingestion would quicken the recovery rate of peak force production and decrease muscle soreness ratings over a 72-hr recovery period. Sixteen healthy participants (8?/8?; 22 +/- 4 years) volunteered in a double-blind, randomized, placebo-controlled crossover study. Supplement conditions consisted of isoenergetic placebo (maltodextrin, 0.6 g.kg-1.day-1) and L-glutamine (0.3 g.kg-1.day-1 + 0.3 g.kg-1.day-1 maltodextrin) ingestion once per day over 72 hr. Knee extensor peak torque at 0 degrees , 30 degrees , and 180 degrees per second and muscle soreness were measured before, immediately following, 24, 48, and 72 hr posteccentric exercise. Eccentric exercise consisted of 8 sets (10 repetitions/set) of unilateral knee extension at 125% maximum concentric force with 2-min rest intervals. L-glutamine resulted in greater relative peak torque at 180 degrees /sec both immediately after (71 +/- 8% vs. 66 +/- 9%), and 72 hr (91 +/- 8% vs. 86 +/- 7%) postexercise (all, p < .01). In men, L-glutamine produced greater (p < .01) peak torques at 30 degrees / sec postexercise. Men also produced greater normalized peak torques at 30 degrees /sec (Nm/kg) in the L-glutamine condition than women (all, p < .05). In the entire sample, L-glutamine resulted in lower soreness ratings at 24 (2.8 +/- 1.2 vs. 3.4 +/- 1.2), 48 (2.6 +/- 1.4 vs. 3.9 +/- 1.2), and 72 (1.7 +/- 1.2 vs. 2.9 +/- 1.3) hr postexercise (p < .01). The L-glutamine supplementation resulted in faster recovery of peak torque and diminished muscle soreness following eccentric exercise. The effect of L-glutamine on muscle force recovery may be greater in men than women. PMID- 25811545 TI - Repetitive infusion of levosimendan in patients with chronic heart failure: a meta-analysis. AB - BACKGROUND: Repetitive or intermittent levosimendan infusion is gradually becoming more commonly considered for patients with advanced chronic heart failure. However, previous randomized controlled studies (RCTs) reported conflicting results on the effects of levosimendan when administered repetitively. The aim of this meta-analysis was to generate up-to-date evidence to assess the effect of levosimendan in this group of patients. MATERIAL AND METHODS: A literature review identified 8 qualified studies. A meta-analysis was performed to assess mortality and left ventricular ejection fraction (LVEF). RESULTS: Use of levosimendan contributed to significantly reduced mortality at the end of mid-term follow-up. The mortality rates in levosimendan and control group were 23 of 226 (10.2%) and 53 of 198 (26.8%), respectively (RR: 0.40, 95%CI: 0.26-0.63, P<0.0001). The trend of significantly decreased mortality was observed in levosimendan vs. placebo subgroup (RR: 0.28, 95%CI: 0.15-0.54, P=0.0001, I2=0%) but not in levosimendan vs. dobutamine, PGE1, or furosemide subgroup (p=0.19, p=0.64 and p=0.25, respectively). Levosimendan also contributed to significantly improved LVEF improvement at the end of follow-up (mean difference: 3.69%, 95CI: 0.92-6.45%, p=0.009). CONCLUSIONS: Intermittent or repetitive levosimendan infusion might be a promising strategy to reduce mortality and improve LVEF in patients with advanced chronic, but not necessarily acutely decompensated, heart failure to maintain disease stability. PMID- 25811546 TI - Lack of middle East respiratory syndrome coronavirus transmission from infected camels. AB - To determine risk for Middle East respiratory syndrome coronavirus transmission from camels to humans, we tested serum from 191 persons with various levels of exposure to an infected dromedary herd. We found no serologic evidence of human infection, suggesting that zoonotic transmission of this virus from dromedaries is rare. PMID- 25811547 TI - An aggregate stochastic model incorporating individual dynamics for predation movements of Anelosimus studiosus. PMID- 25811548 TI - Threshold dynamics of a periodic SIR model with delay in an infected compartment. AB - Threshold dynamics of epidemic models in periodic environments attract more attention. But there are few papers which are concerned with the case where the infected compartments satisfy a delay differential equation. For this reason, we investigate the dynamical behavior of a periodic SIR model with delay in an infected compartment. We first introduce the basic reproduction number R0 for the model, and then show that it can act as a threshold parameter that determines the uniform persistence or extinction of the disease. Numerical simulations are performed to confirm the analytical results and illustrate the dependence of R0 on the seasonality and the latent period. PMID- 25811549 TI - A mathematical model of HTLV-I infection with two time delays. AB - In this paper, we include two time delays in a mathematical model for the CD8+ cytotoxic T lymphocytes (CTLs) response to the Human T-cell leukaemia virus type I (HTLV-I) infection, where one is the intracellular infection delay and the other is the immune delay to account for a series of immunological events leading to the CTL response. We show that the global dynamics of the model system are determined by two threshold values R0, the corresponding reproductive number of a viral infection, and R1, the corresponding reproductive number of a CTL response, respectively. If R0 < 1, the infection-free equilibrium is globally asymptotically stable, and the HTLV-I viruses are cleared. If R1<1140 mmHg) in the postanesthesia care unit (p = 0.045). Male sex was found to be a significant risk factor for the development of hematoma (p < 0.001). CONCLUSIONS: Meticulous perioperative blood pressure control significantly reduces the rate of postoperative hematoma formation. The use of a specific protocol developed by our senior author and primary anesthesia provider contributed to our very low hematoma rates. PMID- 25811572 TI - Elimination of reperfusion-induced microcirculatory alterations in vivo by adipose-derived stem cell supernatant without adipose-derived stem cells. AB - BACKGROUND: In the present study, the authors hypothesized that adipose-derived stem cells in cell culture may secrete multiple cytokines in the supernatant, which might have a significant impact in vivo on the reperfusion-induced microcirculatory alterations and endothelial dysfunction. METHODS: Fat tissue was surgically harvested from rat flanks and processed for adipose-derived stem cell isolation; cells (1 * 10(6)) were subcultured for 3, 6, 9, and 12 days without passage. The postcultivated medium was harvested with medium change every 3 days. After centrifugation, the supernatant was collected and stored at -20 degrees C. Supernatant collected on day 9 was analyzed for eight oxidative stress cytokines by an enzyme-linked immunosorbent assay strip. The effect of the supernatant on the reperfusion-induced microcirculatory alterations was examined in the vascular pedicle of isolated rat cremaster muscles subjected to 4 hours of ischemia followed by 2 hours of reperfusion. RESULTS: Enzyme-linked immunosorbent assay results demonstrated that adipose-derived stem cells produced several highly expressed cytokines in the supernatant. The average concentration of interleukin 6, in particular, was 5-fold higher compared with control. The reperfusion induced vasospasm, arteriole stagnation, and the capillary no-reflow that often appear in the early phase of reperfusion were eliminated by adipose-derived stem cell supernatant. CONCLUSIONS: Adipose-derived stem cells in cell culture display cytokine secretory properties that enable the cells to act through paracrine signaling. The supernatant even without cells could be used as a paracrine agent to interfere with the reperfusion-induced microcirculatory alterations and endothelial dysfunction. PMID- 25811573 TI - No efficacy for silicone gel sheeting in prevention of abnormal scar formation in children with cancer: a randomized controlled trial. AB - BACKGROUND: Placement of a totally implantable venous access device in children with cancer often leads to hypertrophic scars after its removal. This study investigates whether the use of silicone gel sheets has a beneficial effect on scar outcome in children with cancer. METHODS: In a three-arm randomized controlled trial, the effects of use of silicone gel sheets for 2 and 6 months were assessed and compared with no intervention in children with cancer after removal of the totally implantable venous access device. Silicone gel sheets were first administered 14 days after surgery. The 1-year follow-up included measurements at seven time points. Next to scar size assessment, the modified Vancouver Scar Scale was used to assess scar outcome. RESULTS: Thirty-six children participated. For hypertrophy, no significant differences were found between the two intervention groups and the control group. However, at 1-year follow-up, the 2-month application group showed significantly smaller scars compared with the group receiving silicone gel sheet treatment for 6 months (p = 0.04), but not when compared with the control group (p = 0.22). Longitudinal multilevel analyses could not confirm these findings and showed no significant intervention effects on both outcomes. CONCLUSIONS: This study provides no strong evidence to support the use of silicone gel sheets after totally implantable venous access device removal in children with cancer. There seems to be a small benefit for scar width with application for 2 months. However, for hypertrophy, the scar outcome shows no significant difference between the control group and the 2-month and 6-month treatment groups. PMID- 25811574 TI - Discussion: No efficacy for silicone gel sheeting in prevention of abnormal scar formation in children with cancer: a randomized controlled trial. PMID- 25811575 TI - Use of a Doppler signal to confirm migraine headache trigger sites. AB - BACKGROUND: The senior author (B.G.) has been able to use the Doppler as a tool for identifying the site of irritation of a nerve by an adjacent artery in different migraine trigger sites. The purpose of this study was to assess the correlation between the most intense pain site identified by the patients, presence of Doppler signal, and the intraoperative finding of an artery in the target site. METHODS: This was a retrospective review of the charts of patients who underwent surgical treatment of migraine headaches involving the auriculotemporal nerve. The target area was identified by asking patients to point to the most intense headache site and most tender area at the time of examination using the index finger tip. This site was marked and Doppler was used to identify the vascular signal. Doppler examination results, intraoperative presence of the superficial temporal artery or its branches, and the involved nerve were recorded and tabulated. RESULTS: A positive Doppler signal over the area of most intense temporal pain, identified by the patient preoperatively, correlated with intraoperative presence of the artery in 100 percent of the patients. Doppler signal was noted on 34 sites and arterectomy was carried out in all 34 sites. CONCLUSION: Doppler signal in the site of most intense pain can predictably document the presence of an artery in the most painful site and lead to precise location of the nerve irritation by a vessel and successful removal of the offending artery. PMID- 25811576 TI - The efficacy of postoperative antithrombotics in free flap surgery: a systematic review and meta-analysis. AB - BACKGROUND: Although the efficacy of postoperative antithrombotics in free flap survival is well demonstrated through animal studies, debate remains in the clinical literature. This review estimates the benefits and risks of each antithrombotic drug and evaluates whether antithrombotics can produce better outcomes than nonantithrombotic treatment. METHODS: English-language articles evaluating the efficacy of antithrombotics in free flap surgery through comparisons with control groups were analyzed. The outcome measures were total flap failure, pedicle thrombosis, and hematoma formation. RESULTS: Twelve articles representing 4984 cases were analyzed. None of the antithrombotics showed significant benefits for flap survival. Heparin reduced the risk of flap loss by 35 percent, but the difference was not significant (relative risk, 0.65; 95 percent CI, 0.25 to 1.69). Dextran and aspirin showed little protective effects on pedicle thrombosis and flap failure. All antithrombotics showed increased risks of hematoma, and aspirin raised the risk of hematoma significantly (relative risk, 1.91; 95 percent CI, 1.05 to 3.47). In an analysis combining six studies comparing outcomes between the antithrombotic group and the nonantithrombotic group, antithrombotic administration did not reduce the risk of total flap loss (relative risk, 0.99; 95 percent CI, 0.72 to 1.35) or thrombosis (relative risk, 1.00; 95 percent CI, 0.74 to 1.36) but significantly increased the risk of hematoma (relative risk, 1.78; 95 percent CI, 1.20 to 2.63). CONCLUSIONS: There is little evidence suggesting that the use of antithrombotics reduces the risk of thrombosis and total flap failure. Although randomized controlled studies would be required, the risks of routine administration of antithrombotics may outweigh the benefits. PMID- 25811577 TI - So is telehealth the future in medicine now? PMID- 25811579 TI - Tamoxifen (selective estrogen-receptor modulators) and aromatase inhibitors as potential perioperative thrombotic risk factors in free flap breast reconstruction. AB - BACKGROUND: Selective estrogen-receptor modulators and aromatase inhibitors have become ubiquitous in the treatment of breast cancer. However, hormone therapy is a well-established thromboembolic risk factor. The purpose of this study is two fold: (1) to further evaluate tamoxifen as a potential thrombotic risk factor and (2) to evaluate use of aromatase inhibitors as a potential novel risk factor. METHODS: Abdominally based free flaps were reviewed from January of 2008 to July of 2012. Preoperative records were used to identify patients receiving selective estrogen-receptor modulators (e.g., tamoxifen) or aromatase inhibitors before reconstruction. Patients were instructed to cease tamoxifen 2 weeks before surgery. Patients were not advised to cease their aromatase inhibitor regimen. Univariate statistical analyses included Fisher's exact test and the Mann-Whitney U test. A value of p < 0.05 denoted statistical significance. RESULTS: One thousand three hundred forty-seven flaps were performed on 858 patients. There were no statistically significant differences in thrombotic complications or flap failure in comparing those that did not receive preoperative hormone therapy versus those that did receive preoperative hormone therapy, nor were there significant differences specific to those receiving tamoxifen or aromatase inhibitors. A post hoc power analysis was performed with the supposition that hormone therapy exposure results in a two-fold increase in complication rate. The study power was found to be 0.863. CONCLUSIONS: Tamoxifen may have been previously overestimated as a microvascular thrombotic risk factor. At a minimum, these data suggest that withholding tamoxifen for 2 weeks before surgery can mitigate thrombotic risk. PMID- 25811580 TI - Preaponeurotic fat advancement in levator recession for treatment of upper eyelid retraction. AB - BACKGROUND: Postoperative cosmetic deformities can be encountered after surgical treatments for upper eyelid retraction. The authors described a preaponeurotic fat advancement technique and investigated the effectiveness in patients who underwent levator recession for upper lid retraction. METHODS: This retrospective comparative case series included 44 patients (57 eyelids) who underwent levator recession surgery with (flap group, n = 31) or without (no-flap group, n = 26) the preaponeurotic fat advancement flap procedure. Comparisons of the marginal reflex distance 1, palpebral fissure, upper palpebral fissure area, pretarsal show, eyelid asymmetry, and cosmetic complications were made between the two groups. Lid position outcomes (good, fair, and poor), which were grouped according to eyelid asymmetry, marginal reflex distance 1, and the position of upper eyelid margin, and cosmetic complications were assessed. RESULTS: In the flap group, lid position outcomes were graded as good in 16 patients (72.7 percent), fair in four patients (18.2 percent), and poor in two patients (9.1 percent). In the no-flap group, lid position outcomes were good in 15 patients (68.2 percent), fair in five patients (22.7 percent), and poor in two patients (9.1 percent). There were no differences between the two groups in achieving acceptable eyelid lowering and eyelid symmetry (90.9 percent in both groups). However, cosmetic outcomes demonstrated some differences. There were no multiple lid creases in the fat advancement group, compared with six eyes (23.1 percent) without fat advancement. CONCLUSION: Preaponeurotic fat advancement flap is an effective method with which to prevent unintended multiple lid creases and provide satisfactory cosmetic outcomes in levator recession. PMID- 25811581 TI - Natural evolution of seroma in abdominoplasty. AB - BACKGROUND: Abdominoplasty is one of the most performed aesthetic surgical procedures, and seroma is a common local complication. The aim of this study was to investigate the beginning of seroma formation after abdominoplasty and its progression. METHODS: Twenty-one female patients underwent standard abdominoplasty. To investigate seroma formation, abdominal ultrasound was performed in five regions of the abdominal wall (i.e., epigastric, umbilical, hypogastric, right iliac fossa, and left iliac fossa regions) at five different time points: postoperative days 4, 11, 18, 25, and 32. RESULTS: The incidence of seroma was 4.8 percent on postoperative day 4, 38.1 percent on postoperative day 11, 33.3 percent on postoperative day 18, 23.8 percent on postoperative day 25, and 19 percent on postoperative day 32. The left iliac fossa region had the highest relative volume of fluid collection on postoperative day 4, as did both the right iliac fossa and left iliac fossa regions on postoperative day 11. At other time points, the relative volume of fluid collection was significantly higher in the right iliac fossa region. CONCLUSION: The highest incidence of seroma occurred on postoperative day 11, and the iliac fossae were the most common locations of seroma. PMID- 25811582 TI - Cadaveric study of breast measurements during augmentation with implants. AB - BACKGROUND: The goal of this study was to compare immediate changes in breast shape and nipple position using different implant shapes and volumes, with variable release of the pectoralis major muscle in fresh cadavers. METHODS: Seventeen fresh cadaveric breasts were analyzed. Six different augmentation procedures were performed, including pocket dissection in the submuscular and subglandular planes, and partial and full release of the pectoralis major muscle insertion. Round and contoured implant volumes of 200, 300, 400, 500, and 600 ml were used, resulting in a total of 30 procedures per breast. RESULTS: Projection was greater when subjects received contoured implants versus round implants in all volumes both in submuscular and in subglandular pockets (p < 0.001). For implants larger than 200 ml, projection was greater when a subglandular pocket was chosen (p < 0.02), for both round and contoured implants. Nipple-to inframammary fold distance was increased with contoured implants compared with round implants in both subglandular and submuscular pockets for all implant volumes (p < 0.05). CONCLUSIONS: Implant shape, volume, and pocket location influence projection, causing it to increase in a linear fashion. Partial pectoralis major release seems to affect projection only for small volumes, but does not influence nipple position in the immediate setting. As projection increases with augmentation volume, cephalad movement of the nipple is produced by a relative increase in nipple-to-inframammary fold distance compared with the midclavicular point-to-nipple distance in our cadaveric sample. PMID- 25811583 TI - Evaluation of microvascular anastomosis using real-time, ultra-high-resolution, Fourier domain Doppler optical coherence tomography. AB - BACKGROUND: Evolution in microsurgical techniques and tools has paved the way for supermicrosurgical anastomoses, with vessel diameters often approaching below 0.8 mm in the clinical realm and even smaller (0.2 to 0.3 mm) in murine models. Several imaging and monitoring devices have been introduced for postoperative monitoring, but intraoperative guidance, assessment, and predictability have remained limited to binocular optical microscopy and the surgeon's experience. The authors present a high-resolution, real-time, three-dimensional imaging modality for intraoperative evaluation of luminal narrowing, thrombus formation, and flow alterations. METHODS: An imaging modality that provides immediate, in depth, high-resolution, three-dimensional structure view and flow information of the anastomosed site, called phase-resolved Doppler optical coherence tomography, was developed. Twenty-two mouse femoral artery anastomoses and 17 mouse venous anastomoses were performed and evaluated. Flow status, vessel inner lumen three dimensional structure, and early thrombus detection were analyzed based on imaging results. Predictions formed correlated with actual long-term surgical outcomes. Eventually, four cases of mouse orthotopic limb transplantation were carried out, and predicted long-term patency based on imaging results was confirmed by actual results. RESULTS: The assessments based on high-resolution three-dimensional visualization of the vessel flow status and inner lumen provided by phase-resolved Doppler optical coherence tomography show 92 percent sensitivity and 90 percent specificity for arterial anastomoses and 90 percent sensitivity and 86 percent specificity for venous anastomoses. CONCLUSIONS: Phase resolved Doppler optical coherence tomography is an effective evaluation tool for microvascular anastomosis. It can predict the long-term vessel patency with high sensitivity and specificity. PMID- 25811584 TI - Oxygen reduces tourniquet-associated pain: a double-blind, randomized, controlled trial for application in hand surgery. AB - BACKGROUND: Why do limb tourniquets cause pain? If ischemia is the mechanism, can supplemental oxygen reduce pain? The Reducing Tourniquet Associated Pain study investigated whether this simple treatment could extend tourniquet tolerance time to facilitate hand surgery under local or regional anesthesia. METHODS: The Reducing Tourniquet Associated Pain study was a double-blind, randomized, controlled trial of healthy volunteers. Participants received either 50% inhaled oxygen or air placebo via a face mask for 3 minutes before and up to 30 minutes after upper arm tourniquet inflation to 250 mmHg. Pain scores were recorded at 2 minute intervals using a validated 100-mm visual analogue scale. The primary outcomes were (1) difference in visual analogue scale score and (2) difference in time taken to reach visual analogue score of 40 mm or more in oxygen and air groups. RESULTS: Fifty participants enrolled and, after exclusion criteria were applied, 46 were analyzed (oxygen, n = 23; air, n = 23). Oxygen supplementation was associated with a 29 percent mean reduction in pain on visual analogue scoring compared with air placebo over the entire period of inhalation (p = 0.027). Oxygen also extended the time to visual analogue scale score of 40 mm or more by a mean of 61/2 minutes compared with air placebo (p = 0.008). CONCLUSIONS: Oxygen is a readily available, low-risk, low-cost treatment that significantly reduced tourniquet-associated pain in this study and significantly increased the time taken to reach visual analogue scale score of 40 or more. The authors recommend oxygen to facilitate hand surgery under a tourniquet and when a regional block fails to control tourniquet pain. PMID- 25811585 TI - Treatment of the syndromic midface: a long-term assessment at skeletal maturity. AB - BACKGROUND: Midfacial advancements improve function and normalize appearance in growing children with syndromic craniosynostosis yet carry substantial risks while often offering only transient benefits. The authors sought to evaluate outcomes and the number of advancements required, at skeletal maturity. METHODS: The authors performed a retrospective review of all children undergoing rigid external distraction Le Fort III advancement who had reached skeletal maturity, including examinations, photographic scoring, and cephalometric, anthropometric and polysomnography data. RESULTS: Over 15 years, 104 children underwent distraction and 32 met skeletal maturity criterion (mean age, 18.6 years). Thirty four percent had prior conventional Le Fort III advancement (mean age, 5.6 years), primarily by other surgeons. Primary distractions were performed on average at 9.1 years. Ten children presented with obstructive sleep apnea; eight normalized, two improved, but 30 percent subsequently developed recurrent apnea. Per anthropometry, no sagittal growth was noted after a Le Fort III. With a mean follow-up of 9.4 years, almost half (15 of 32) underwent two midfacial advancements; however, following primary distractions, only 25 percent required repeated advancements. Associated with repeated procedures were a greater degree of midfacial hypoplasia (-2.4 versus -1.6, p = 0.01), advancement at a younger age (7.1 versus 9.5 years, p = 0.04), and failure to overcorrect midfacial position (p = 0.03). CONCLUSIONS: These data suggest that sagittal midfacial growth ceases after advancement. Operation before 8 years old and failure to overadvance the midface were both associated with need for subsequent midfacial procedures. Although distraction effectively eliminated apnea, subsequent ventilatory degradation may occur, suggesting the need for continued surveillance. PMID- 25811586 TI - Classification of mandible defects and algorithm for microvascular reconstruction. AB - BACKGROUND: Composite mandibular tissue loss results in significant functional impairment and cosmetic deformity. This study classifies patterns of mandibular composite tissue loss and describes a microvascular treatment algorithm. METHODS: A retrospective review of microvascular composite mandibular reconstruction from July of 2005 to April of 2013 by the senior surgeon at the R Adams Cowley Shock Trauma Center and at The Johns Hopkins Hospital yielded 24 patients with a mean follow-up of 17.9 months. Causes of composite mandibular defects included tumors, osteoradionecrosis, trauma, infection, and congenital deformity. Patients with composite tissue loss were classified according to missing subunits. RESULTS: A treatment algorithm based on composite mandibular defects and microvascular reconstruction was developed and used to treat 24 patients. A type 1 defect is a unilateral dentoalveolar defect not crossing the midline and not extending into the angle of the mandible. A type 2 defect is a unilateral defect extending beyond the angle. A type 3 defect is a bilateral defect not involving the angles. A type 4 defect is a bilateral defect with extension into at least one angle. Type 2 defects were the predominant group. Patients had microvascular reconstruction using either fibula flaps (n = 19) or iliac crest flaps (n = 5). Complications included infection, partial necrosis, plate fracture, dehiscence, and microvascular thrombosis. CONCLUSION: This novel classification system and treatment algorithm allows for a consistent and reliable method of addressing composite mandibular defects and focuses on recipient vasculature and donor free flap characteristics. PMID- 25811587 TI - State of the art and science in postmastectomy breast reconstruction. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Examine clinicopathologic factors to determine the best timing for breast reconstruction. 2. Develop treatment plans for all patients for breast preserving reconstruction. 3. Determine the best approaches for partial and whole breast reconstruction. 4. Be familiar with advanced techniques in breast reconstruction. BACKGROUND: Often, the decision to perform a partial or total mastectomy hinges on reconstructive issues, not oncology-related considerations. METHODS: Innovative timing and reconstruction approaches are being implemented after partial mastectomy and breast reconstruction after mastectomy. RESULTS: Among patients undergoing repair of a partial mastectomy defect, immediate or delayed repair before radiation allows for use of remaining breast tissue for repair. Innovative approaches include breast remodeling, local rotation advancement, and concentric mastopexy and breast reduction techniques to recontour remaining breast tissue. Delayed repair after whole-breast radiation usually is not preferred and is performed with autologous fat grafting or a flap. However, partial breast radiation allows for safe delayed repair after irradiation using the same techniques used for preradiation repair. The optimal timing for breast reconstruction after mastectomy remains a topic of controversy. Adjunct techniques for implant-based postmastectomy reconstruction include the use of acellular dermal matrix and autologous fat grafting, especially in the setting of radiation therapy. Techniques also include a more focused use of flaps only in the setting of radiation therapy with increasing use of new perforator-based autologous tissue flap options. CONCLUSION: Innovative approaches to breast reconstruction have evolved to provide restorative healing for patients and hasten return to their modern, active lifestyles. PMID- 25811588 TI - Social problems in plastic surgery residents: a management perspective. AB - BACKGROUND: It is presumed that plastic surgery residents experience various social problems, just as do their peers in other specialty training programs and in the general public. These issues can occasionally disrupt the resident's personal training experience and sometimes the program as a whole. A survey was performed to assess the magnitude of the problem, and the issues revealed were assessed to assist the program director and the resident in reaching successful completion of the residency. METHODS: A survey was designed by the executive committee and staff of the American Council of Academic Plastic Surgeons and sent to all plastic surgery training programs in the United States. A response rate of 66 percent was achieved. The programs reported on the social issues occurring in their residents over the preceding 5 years. The results were presented at a business meeting of the Council. RESULTS: Thirty-seven percent of programs reported that at least one resident had left their program during the study period. Twenty percent reported that a resident had been asked to leave the program. The frequency of social problems resulting in disruption of the training program was tabulated in the following areas: divorce; pregnancy/parturition; financial, legal, or family issues; drug or alcohol abuse; illness/injury; and interpersonal conflicts. CONCLUSIONS: Plastic surgery residents experience social problems that can affect the timely completion of their training. Attention to these issues requires patience, creativity, sensitivity, and a commitment to the residents' ultimate success, and adherence to institutional, legal, and accreditation body mandates. PMID- 25811589 TI - From multidisciplinary to interdisciplinary to transdisciplinary care: an evolution in craniofacial surgery. PMID- 25811590 TI - Characterization of lipolytic inhibitor G(0)/G(1) switch gene-2 protein (G0S2) expression in male Sprague-Dawley rat skeletal muscle compared to relative content of adipose triglyceride lipase (ATGL) and comparitive gene identification 58 (CGI-58). AB - The rate-limiting enzyme in lipolysis, adipose triglyceride lipase (ATGL), is activated by comparative gene identification-58 (CGI-58) and inhibited by the G(0)/G(1) switch gene-2 (G0S2) protein. It is speculated that inhibition of ATGL is through a dose dependent manner of relative G0S2 protein content. There is little work examining G0S2 expression in lipolytic tissues, and the relative expression across oxidative tissues such as skeletal muscle has not yet been described. Three muscles, soleus (SOL), red gastrocnemius (RG), and white gastrocnemius (WG) were excised from 57-day old male Sprague-Dawley rats (n = 9). QRT-PCR was used for mRNA analysis, and western blotting was conducted to determine protein content. ATGL and G0S2 protein content were both greatest in the lipolytic SOL, with the least amount of both ATGL and G0S2 protein content found in the WG. CGI-58 protein content however did not mirror ATGL and G0S2 protein content, since the RG had the greatest CGI-58 protein content when compared to the SOL and WG. When comparing our tissues based on CGI-58-to-ATGL ratio and G0S2-to-ATGL ratio, it was discovered that contrary to oxidative demand, the glycolytic WG had the greatest activator CGI-58-to-ATGL ratio with the oxidative SOL having the least, and no differences in G0S2-to-ATGL across the three muscle types. These data suggest that the content of G0S2 relative to the lipase in skeletal muscle would not predict lipolytic potential. PMID- 25811591 TI - A near-infrared fluorescent probe for the detection of hydrogen polysulfides biosynthetic pathways in living cells and in vivo. AB - Hydrogen polysulfides (H2Sn, n > 1), derived from hydrogen sulfide (H2S), have been considered to be involved in cytoprotective processes and redox signaling. The emerging evidences imply that the actual signaling molecule is H2Sn rather than H2S. In this work, we present a near-infrared fluorescent probe BD-ss for the selective detection of H2Sn biosynthetic pathways in living cells and in vivo. The probe is constructed by equipping a bis-electrophilic H2Sn capture group p-nitrofluorobenzoate to a near-infrared fluorophore azo-BODIPY. BD-ss can provide a remarkable turn-on fluorescence response for assessing endogenous H2Sn formation ways in serum, in living cells and in vivo. PMID- 25811592 TI - Daily low-dose Cisplatin-based concurrent chemoradiotherapy for the treatment of cervical cancer in patients 70 years or older. AB - OBJECTIVES: It has been established that concurrent chemoradiotherapy (CCRT) is efficacious for cervical cancer, but adherence is unsatisfactory among elderly patients. To improve adherence, we have developed and initiated a daily low-dose cisplatin-based CCRT regimen. Here, we retrospectively evaluated the use of CCRT, especially for elderly patients. METHODS: The study included a total of 53 patients who were 70 years or older, had stage IB-IVA cervical cancer, and were initially treated with daily CCRT. The daily CCRT comprised pelvic external beam radiotherapy (2 Gy/d * 25) with daily low-dose cisplatin (8.0 mg/m(2) per day) and either low- or high-dose-rate intracavitary brachytherapy. RESULTS: The median age was 72 years (range, 70-85 years). The median follow-up duration was 32 months (range, 2-104 months). The 3-year overall survival rate was 79.0%. Daily cisplatin chemotherapy was successfully completed in 32 (60.4%) of the 53 patients. Grade 3 or 4 neutropenia was observed in 19 patients (36%). A late complication of grade 3 rectal hemorrhage occurred in 3 patients who received high-dose-rate brachytherapy. All primary tumors responded to daily CCRT; complete response was observed in 43 patients (91.5%) and partial response was observed in 4 patients (8.5%). CONCLUSIONS: Daily CCRT in patients 70 years and older had acceptable compliance and safety. Daily CCRT is suggested to be a good treatment option for elderly patients who have advanced cervical cancer and require concurrent cisplatin. PMID- 25811593 TI - Leptin Inhibits the Apoptosis of Endometrial Carcinoma Cells Through Activation of the Nuclear Factor kappaB-inducing Kinase/IkappaB Kinase Pathway. AB - OBJECTIVES: Leptin has recently been shown to affect cancer proliferation and invasion through multiple pathways. In the current study, we investigated the role of leptin in endometrial carcinoma (EC) apoptosis and the underlying mechanisms of action. METHODS: Immunoprecipitation was used to characterize leptin receptor expression in EC lines. The levels of nuclear factor kappaB inducing kinase (NIK)/IkappaB kinase (IKK) signaling proteins were analyzed using Western blot. In addition, Western blot and immunohistochemical analyses were used to detect the hierarchy of these proteins in EC tissues. Quantitative cancer cell apoptosis assay was performed using flow cytometry after incubation of cells with Annexin-V/fluorescein/propidium iodide, 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolcarbocyanine iodide or staining of cancer cell DNA fragments with propidium iodide. RESULTS: Leptin induced a decrease in apoptosis in Ishikawa and HEC-1A EC cells, partly through nuclear factor kappaB activation via phosphorylation in the IKK/NIK pathway. Inhibition of IKK or NIK partly neutralized this suppression of apoptosis. Expression levels of leptin receptors (Ob-Rs) and IKK/NIK signaling proteins were higher in poorly and moderately differentiated than in well-differentiated EC tissues, and higher Ob-Rs expression was observed in clinical stages II and III, compared with stage I EC (P = 0.012). High serum leptin concentration displayed mild correlation (r = 0.23, P = 0.035) with degree of EC differentiation. CONCLUSIONS: Leptin inhibits EC apoptosis partly through activation of the NIK/IKK pathway in vitro. Ob-Rb overexpression seems to facilitate EC progression. PMID- 25811594 TI - Adoption and use of digital technologies among general dental practitioners in the Netherlands. AB - OBJECTIVES: To investigate (1) the degree of digital technology adoption among general dental practitioners, and to assess (2) which personal and practice factors are associated with technology use. METHODS: A questionnaire was distributed among a stratified sample of 1000 general dental practitioners in the Netherlands, to measure the use of fifteen administrative, communicative, clinical and diagnostic technologies, as well as personal factors and dental practice characteristics. RESULTS: The response rate was 31.3%; 65.1% replied to the questionnaire on paper and 34.9% online. Each specific digital technology was used by between 93.2% and 6.8% of the dentists. Administrative technologies were generally used by more dentists than clinical technologies. Dentists had adopted an average number of 6.3 +/- 2.3 technologies. 22.5% were low technology users (0 to 4 technologies), 46.2% were intermediate technology users (5 to 7 technologies) and 31.3% were high technology users (8 to 12 technologies). High technology users more frequently had a specialization (p<0.001), were younger on average (p=0.024), and worked more hours per week (p=0.003) than low technology users, and invested more hours per year in professional activities (p=0.026) than intermediate technology users. High technology use was also more common for dentists working in practices with a higher average number of patients per year (p<0.001), with more dentists working in the practice (p<0.001) and with more staff (p<0.001). CONCLUSION: With few exceptions, all dentists use some or a substantial number of digital technologies. Technology use is associated with various patterns of person-specific factors, and is higher when working in larger dental practices. The findings provide insight into the current state of digital technology adoption in dental practices. Further exploration why some dentists are more reluctant to adopt technologies than others is valuable for the dental profession's agility in adjusting to technological developments. PMID- 25811597 TI - Barcoding of ancient lake ostracods (crustacea) reveals cryptic speciation with extremely low distances. AB - Ostracods are drastically reduced crustaceans, with never more than eight appendages enclosed between two valves, leaving only a limited number of morphological characters for species delineation. Conservative morphology of characters used to define genera, along with high variability of characters used to define species are creating problems in applying a morphospecies concept. A high intraspecific variability in a Lake Biwa (Japan) endemic, Physocypria biwaensis (Okubo, 1990), has been observed previously but was never studied in detail. Two sympatric forms, differing in pigmentation and size, suggest a presence of reproductive isolation. The aim of this study is to employ molecular and morphometric tools to aid in species delineation within P. biwaensis complex and reconstruct their phylogenetic relationships. A fragment of the mtCOI gene was amplified from 30 specimens, and an additional 37 specimens were studied for morphological characters. Resulting phylogenies showed that each morphologically distinct form is associated with a distinct phylogenetic group based on mtDNA. The average pairwise distance is very low (5%), indicating a recent divergence time. I speculate that there is a possibility that one of them originated in the lake, while the other probably colonized it afterwards. This seems to be supported with an apparent niche partitioning at different depths. In spite of the fact that traditionally used sexual characters are highly variable in these two species, the morphometric analysis of shell and soft part related characters clearly delineates them and suggests that such characters may be useful for future detection of seemingly cryptic ostracod species. PMID- 25811596 TI - Bactericidal activity of curcumin I is associated with damaging of bacterial membrane. AB - Curcumin, an important constituent of turmeric, is known for various biological activities, primarily due to its antioxidant mechanism. The present study focused on the antibacterial activity of curcumin I, a significant component of commercial curcumin, against four genera of bacteria, including those that are Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa). These represent prominent human pathogens, particularly in hospital settings. Our study shows the strong antibacterial potential of curcumin I against all the tested bacteria from Gram positive as well as Gram-negative groups. The integrity of the bacterial membrane was checked using two differential permeabilization indicating fluorescent probes, namely, propidium iodide and calcein. Both the membrane permeabilization assays confirmed membrane leakage in Gram-negative and Gram-positive bacteria on exposure to curcumin I. In addition, scanning electron microscopy and fluorescence microscopy were employed to confirm the membrane damages in bacterial cells on exposure to curcumin I. The present study confirms the broad spectrum antibacterial nature of curcumin I, and its membrane damaging property. Findings from this study could provide impetus for further research on curcumin I regarding its antibiotic potential against rapidly emerging bacterial pathogens. PMID- 25811595 TI - Oxidized low-density lipoprotein contributes to atherogenesis via co-activation of macrophages and mast cells. AB - Oxidized low-density lipoprotein (OxLDL) is a risk factor for atherosclerosis, due to its role in endothelial dysfunction and foam cell formation. Tissue resident cells such as macrophages and mast cells release inflammatory mediators upon activation that in turn cause endothelial activation and monocyte adhesion. Two of these mediators are tumor necrosis factor (TNF)-alpha, produced by macrophages, and histamine, produced by mast cells. Static and microfluidic flow experiments were conducted to determine the number of adherent monocytes on vascular endothelium activated by supernatants of oxLDL-treated macrophages and mast cells or directly by oxLDL. The expression of adhesion molecules on activated endothelial cells and the concentration of TNF-alpha and histamine in the supernatants were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. A low dose of oxLDL (8 MUg/ml), below the threshold for the clinical presentation of coronary artery disease, was sufficient to activate both macrophages and mast cells and synergistically increase monocyte-endothelium adhesion via released TNF-alpha and histamine. The direct exposure of endothelial cells to a much higher dose of oxLDL (80 MUg/ml) had less effect on monocyte adhesion than the indirect activation via oxLDL-treated macrophages and mast cells. The results of this work indicate that the co-activation of macrophages and mast cells by oxLDL is an important mechanism for the endothelial dysfunction and atherogenesis. The observed synergistic effect suggests that both macrophages and mast cells play a significant role in early stages of atherosclerosis. Allergic patients with a lipid-rich diet may be at high risk for cardiovascular events due to high concentration of low-density lipoprotein and histamine in arterial vessel walls. PMID- 25811600 TI - Correction: A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia. AB - [This corrects the article DOI: 10.1371/journal.pone.0060634.]. PMID- 25811598 TI - Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1. AB - Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML). Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Forster resonance energy transfer (TR-FRET) -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS) of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC50 values below 10 MUM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function. PMID- 25811599 TI - Thyroid Disease Is Prevalent and Predicts Survival in Patients With Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: A significant minority of patients with idiopathic pulmonary fibrosis (IPF) display features of autoimmunity without meeting the criteria for overt connective tissue disease. A link between IPF and other immune-mediated processes, such as hypothyroidism (HT), has not been reported. In this investigation, we aimed to determine whether HT is associated with IPF and if outcomes differ between patients with IPF with and without HT. METHODS: A retrospective case-control analysis was conducted. Of 311 patients referred to the University of Chicago Interstitial Lung Disease Center with an initial diagnosis of IPF, 196 met the inclusion criteria and were included in the final analysis. Each case was matched 1:1 by age, sex, and race to a control subject with COPD. RESULTS: HT was identified in 16.8% of cases and 7.1% of control subjects (OR, 2.7; 95% CI, 1.31-5.54; P = .01). Among patients with IPF, HT was associated with reduced survival time (P < .001) and was found to be an independent predictor of mortality in multivariable Cox regression analysis (hazard ratio, 2.12; 95% CI, 1.31-3.43; P = .002). A secondary analysis of two IPF clinical trial datasets supports these findings. CONCLUSIONS: HT is common among patients with IPF, with a higher prevalence than in those with COPD and the general population. The presence of HT also predicts mortality in IPF, a finding that may improve future prognostication models. More research is needed to determine the biologic link between IPF and HT and how the presence of thyroid disease may influence disease progression. PMID- 25811601 TI - Light absorption properties and radiative effects of primary organic aerosol emissions. AB - Organic aerosols (OAs) in the atmosphere affect Earth's energy budget by not only scattering but also absorbing solar radiation due to the presence of the so called "brown carbon" (BrC) component. However, the absorptivities of OAs are not represented or are poorly represented in current climate and chemical transport models. In this study, we provide a method to constrain the BrC absorptivity at the emission inventory level using recent laboratory and field observations. We review available measurements of the light-absorbing primary OA (POA), and quantify the wavelength-dependent imaginary refractive indices (kOA, the fundamental optical parameter determining the particle's absorptivity) and their uncertainties for the bulk POA emitted from biomass/biofuel, lignite, propane, and oil combustion sources. In particular, we parametrize the kOA of biomass/biofuel combustion sources as a function of the black carbon (BC)-to-OA ratio, indicating that the absorptive properties of POA depend strongly on burning conditions. The derived fuel-type-based kOA profiles are incorporated into a global carbonaceous aerosol emission inventory, and the integrated kOA values of sectoral and total POA emissions are presented. Results of a simple radiative transfer model show that the POA absorptivity warms the atmosphere significantly and leads to ~27% reduction in the amount of the net global average POA cooling compared to results from the nonabsorbing assumption. PMID- 25811602 TI - Is chronic suppurative otitis media a neglected tropical disease? PMID- 25811603 TI - Multigene assessment of the species boundaries and sexual status of the basidiomycetous yeasts Cryptococcus flavescens and C. terrestris (Tremellales). AB - Cryptococcus flavescens and C. terrestris are phenotypically indistinguishable sister species that belong to the order Tremellales (Tremellomycetes, Basidiomycota) and which may be mistaken for C. laurentii based on phenotype. Phylogenetic separation between C. flavescens and C. terrestris was based on rDNA sequence analyses, but very little is known on their intraspecific genetic variability or propensity for sexual reproduction. We studied 59 strains from different substrates and geographic locations, and used a multilocus sequencing (MLS) approach complemented with the sequencing of mating type (MAT) genes to assess genetic variation and reexamine the boundaries of the two species, as well as their sexual status. The following five loci were chosen for MLS: the rDNA ITS LSU region, the rDNA IGS1 spacer, and fragments of the genes encoding the largest subunit of RNA polymerase II (RPB1), the translation elongation factor 1 alpha (TEF1) and the p21-activated protein kinase (STE20). Phylogenetic network analyses confirmed the genetic separation of the two species and revealed two additional cryptic species, for which the names Cryptococcus baii and C. ruineniae are proposed. Further analyses of the data revealed a high degree of genetic heterogeneity within C. flavescens as well as evidence for recombination between lineages detected for this species. Strains of C. terrestris displayed higher levels of similarity in all analysed genes and appear to make up a single recombining group. The two MAT genes (STE3 and SXI1/SXI2) sequenced for C. flavescens strains confirmed the potential for sexual reproduction and suggest the presence of a tetrapolar mating system with a biallelic pheromone/receptor locus and a multiallelic HD locus. In C. terrestris we could only sequence STE3, which revealed a biallelic P/R locus. In spite of the strong evidence for sexual recombination in the two species, attempts at mating compatible strains of both species on culture media were unsuccessful. PMID- 25811605 TI - Highly effective fibrinolysis by a sequential synergistic combination of mini dose tPA plus low-dose mutant proUK. AB - Results of thrombolysis by monotherapy with either tPA or proUK have not lived up to expectations. Since these natural activators are inherently complementary, this property can be utilized to a synergistic advantage; and yet, this has undergone little evaluation. ProUK is no longer available because at pharmacological concentrations it converts to UK in plasma. Therefore, a single site proUK mutant, M5, was developed to address this problem and was used in this study. Fibrinolysis was measured using preformed fluoresceinated 24 h old clots in a plasma milieu rather than by the standard automated method, because proUK/M5 is sensitive to inactivation by thrombin and activation by plasmin. The shortest 50% clot lysis time that could be achieved by tPA or M5 alone was determined: mean times were 55 and 48 minutes respectively. These bench marks were matched by 6% of the tPA monotherapy dose combined with 40% that of M5: mean lysis time 47 minutes with less associated fibrinogenolysis. Results showed that the tPA effect was limited to initiating fibrinolysis which was completed by M5 and then tcM5. Plasma C1-inhibitor inhibited fibrinogenolysis by M5, providing protection from side effects not available for proUK. In conclusion, by utilizing the complementary properties and sequential modes of action of each activator, more efficient fibrinolysis with less non-specific effects can be achieved than with traditional monotherapy. In vivo validation is needed, but in a previous clinical trial using a similar combination of tPA and proUK (5% and 50% monotherapy doses) very promising results have already been obtained. PMID- 25811604 TI - CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)3Cl(glycinate)] Actions on a Heme-Deficient Mutant of Escherichia coli. AB - AIMS: Carbon monoxide-releasing molecules (CORMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically, including applications in antimicrobial therapy. Hemes are generally considered the prime targets of CO and CORMs, so we tested this hypothesis using heme deficient bacteria, applying cellular, transcriptomic, and biochemical tools. RESULTS: CORM-3 [Ru(CO)3Cl(glycinate)] readily penetrated Escherichia coli hemA bacteria and was inhibitory to these and Lactococcus lactis, even though they lack all detectable hemes. Transcriptomic analyses, coupled with mathematical modeling of transcription factor activities, revealed that the response to CORM-3 in hemA bacteria is multifaceted but characterized by markedly elevated expression of iron acquisition and utilization mechanisms, global stress responses, and zinc management processes. Cell membranes are disturbed by CORM-3. INNOVATION: This work has demonstrated for the first time that CORM-3 (and to a lesser extent its inactivated counterpart) has multiple cellular targets other than hemes. A full understanding of the actions of CORMs is vital to understand their toxic effects. CONCLUSION: This work has furthered our understanding of the key targets of CORM-3 in bacteria and raises the possibility that the widely reported antimicrobial effects cannot be attributed to classical biochemical targets of CO. This is a vital step in exploiting the potential, already demonstrated, for using optimized CORMs in antimicrobial therapy. PMID- 25811606 TI - Evolutionarily conserved 5'-3' exoribonuclease Xrn1 accumulates at plasma membrane-associated eisosomes in post-diauxic yeast. AB - Regulation of gene expression on the level of translation and mRNA turnover is widely conserved evolutionarily. We have found that the main mRNA decay enzyme, exoribonuclease Xrn1, accumulates at the plasma membrane-associated eisosomes after glucose exhaustion in a culture of the yeast S. cerevisiae. Eisosomal localization of Xrn1 is not achieved in cells lacking the main component of eisosomes, Pil1, or Sur7, the protein accumulating at the membrane compartment of Can1 (MCC) - the eisosome-organized plasma membrane microdomain. In contrast to the conditions of diauxic shift, when Xrn1 accumulates in processing bodies (P bodies), or acute heat stress, in which these cytosolic accumulations of Xrn1 associate with eIF3a/Rpg1-containing stress granules, Xrn1 is not accompanied by other mRNA-decay machinery components when it accumulates at eisosomes in post diauxic cells. It is important that Xrn1 is released from eisosomes after addition of fermentable substrate. We suggest that this spatial segregation of Xrn1 from the rest of the mRNA-decay machinery reflects a general regulatory mechanism, in which the key enzyme is kept separate from the rest of mRNA decay factors in resting cells but ready for immediate use when fermentable nutrients emerge and appropriate metabolism reprogramming is required. In particular, the localization of Xrn1 to the eisosome, together with previously published data, accents the relevance of this plasma membrane-associated compartment as a multipotent regulatory site. PMID- 25811608 TI - Phosphonamide pyrabactin analogues as abscisic acid agonists. AB - A four step synthesis towards novel phosphonic pyrabactin analogues is presented. Via a stomatal closure and germination assay, the ability of the analogues to selectively induce the ABA-signaling pathway was demonstrated. PMID- 25811609 TI - STAT1-mediated down-regulation of Bcl-2 expression is involved in IFN-gamma/TNF alpha-induced apoptosis in NIT-1 cells. AB - Tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma are the major pro inflammatory cytokines involved in beta-cell destruction. The fate of islet beta cells in the cytokine-induced intrinsic mitochondrial apoptotic pathway is determined by the interaction between members of the Bcl-2 family. However, the mechanism through which beta-cell apoptosis is regulated remains unclear. In this study, we treated the murine beta-cell line NIT-1 with TNF-alpha and IFN-gamma and then investigated the regulation of signal transducer and activator of transcription-1 (STAT-1) and expression of the members of the Bcl-2 family in this apoptotic pathway. Results showed that TNF-alpha and IFN-gamma synergistically reduced NIT-1 cell viability. In addition, the decrease in cell growth was due to apoptosis as shown by apoptotic body formation, detected by confocal laser microscope, and a significant increase in Annexin-Vup(+) cell percentage, detected by flow cytometry. Combination treatment with TNF-alpha and IFN-gamma caused a remarkable increase in the release of cytochrome c, and in the activation of caspase-9 and caspase-3, as well as, an obvious enhancement in STAT 1 phosphorylation; the treatment, however, resulted in the down-regulation in Bcl 2 expression. The enhancement in STAT-1 activity and a down-regulation in Bcl-2 expression was also observed in MIN6 cells, another murine beta-cell derived line, after cells exposure to the combination of TNF-alpha and IFN-gamma treatment. Knockdown of STAT-1 gene expression by siRNA or inhibition of STAT-1 activation with fludarabine reversed Bcl-2 down-expression and led to a significant decrease in apoptosis in TNF-alpha- and IFN-gamma-treated NIT-1 cells. Taken together, our results suggest that STAT1-mediated down-regulation of Bcl-2 is involved in NIT-1 cell apoptosis induced by combination treatment with TNF-alpha and IFN-gamma. PMID- 25811607 TI - Plastidic phosphoglucose isomerase is an important determinant of starch accumulation in mesophyll cells, growth, photosynthetic capacity, and biosynthesis of plastidic cytokinins in Arabidopsis. AB - Phosphoglucose isomerase (PGI) catalyzes the reversible isomerization of glucose 6-phosphate and fructose-6-phosphate. It is involved in glycolysis and in the regeneration of glucose-6-P molecules in the oxidative pentose phosphate pathway (OPPP). In chloroplasts of illuminated mesophyll cells PGI also connects the Calvin-Benson cycle with the starch biosynthetic pathway. In this work we isolated pgi1-3, a mutant totally lacking pPGI activity as a consequence of aberrant intron splicing of the pPGI encoding gene, PGI1. Starch content in pgi1 3 source leaves was ca. 10-15% of that of wild type (WT) leaves, which was similar to that of leaves of pgi1-2, a T-DNA insertion pPGI null mutant. Starch deficiency of pgi1 leaves could be reverted by the introduction of a sex1 null mutation impeding beta-amylolytic starch breakdown. Although previous studies showed that starch granules of pgi1-2 leaves are restricted to both bundle sheath cells adjacent to the mesophyll and stomata guard cells, microscopy analyses carried out in this work revealed the presence of starch granules in the chloroplasts of pgi1-2 and pgi1-3 mesophyll cells. RT-PCR analyses showed high expression levels of plastidic and extra-plastidic beta-amylase encoding genes in pgi1 leaves, which was accompanied by increased beta-amylase activity. Both pgi1 2 and pgi1-3 mutants displayed slow growth and reduced photosynthetic capacity phenotypes even under continuous light conditions. Metabolic analyses revealed that the adenylate energy charge and the NAD(P)H/NAD(P) ratios in pgi1 leaves were lower than those of WT leaves. These analyses also revealed that the content of plastidic 2-C-methyl-D-erythritol 4-phosphate (MEP)-pathway derived cytokinins (CKs) in pgi1 leaves were exceedingly lower than in WT leaves. Noteworthy, exogenous application of CKs largely reverted the low starch content phenotype of pgi1 leaves. The overall data show that pPGI is an important determinant of photosynthesis, energy status, growth and starch accumulation in mesophyll cells likely as a consequence of its involvement in the production of OPPP/glycolysis intermediates necessary for the synthesis of plastidic MEP-pathway derived hormones such as CKs. PMID- 25811610 TI - Dopamine and the development of executive dysfunction in autism spectrum disorders. AB - Persons with autism regularly exhibit executive dysfunction (ED), including problems with deliberate goal-directed behavior, planning, and flexible responding in changing environments. Indeed, this array of deficits is sufficiently prominent to have prompted a theory that executive dysfunction is at the heart of these disorders. A more detailed examination of these behaviors reveals, however, that some aspects of executive function remain developmentaly appropriate. In particular, while people with autism often have difficulty with tasks requiring cognitive flexibility, their fundamental cognitive control capabilities, such as those involved in inhibiting an inappropriate but relatively automatic response, show no significant impairment on many tasks. In this article, an existing computational model of the prefrontal cortex and its role in executive control is shown to explain this dichotomous pattern of behavior by positing abnormalities in the dopamine-based modulation of frontal systems in individuals with autism. This model offers excellent qualitative and quantitative fits to performance on standard tests of cognitive control and cognitive flexibility in this clinical population. By simulating the development of the prefrontal cortex, the computational model also offers a potential explanation for an observed lack of executive dysfunction early in life. PMID- 25811612 TI - Inhibition of type VI secretion by an anti-TssM llama nanobody. AB - The type VI secretion system (T6SS) is a secretion pathway widespread in Gram negative bacteria that targets toxins in both prokaryotic and eukaryotic cells. Although most T6SSs identified so far are involved in inter-bacterial competition, a few are directly required for full virulence of pathogens. The T6SS comprises 13 core proteins that assemble a large complex structurally and functionally similar to a phage contractile tail structure anchored to the cell envelope by a trans-membrane spanning stator. The central part of this stator, TssM, is a 1129-amino-acid protein anchored in the inner membrane that binds to the TssJ outer membrane lipoprotein. In this study, we have raised camelid antibodies against the purified TssM periplasmic domain. We report the crystal structure of two specific nanobodies that bind to TssM in the nanomolar range. Interestingly, the most potent nanobody, nb25, competes with the TssJ lipoprotein for TssM binding in vitro suggesting that TssJ and the nb25 CDR3 loop share the same TssM binding site or causes a steric hindrance preventing TssM-TssJ complex formation. Indeed, periplasmic production of the nanobodies displacing the TssM TssJ interaction inhibits the T6SS function in vivo. This study illustrates the power of nanobodies to specifically target and inhibit bacterial secretion systems. PMID- 25811614 TI - Association between Parenchymal Enhancement of the Contralateral Breast in Dynamic Contrast-enhanced MR Imaging and Outcome of Patients with Unilateral Invasive Breast Cancer. AB - PURPOSE: To retrospectively investigate whether parenchymal enhancement in dynamic contrast material-enhanced magnetic resonance (MR) imaging of the contralateral breast in patients with unilateral invasive breast cancer is associated with therapy outcome. MATERIALS AND METHODS: After obtaining approval of the institutional review board and patients' written informed consent, 531 women with unilateral invasive breast cancer underwent dynamic contrast-enhanced MR imaging between 2000 and 2008. The contralateral parenchyma was segmented automatically, in which the mean of the top 10% late enhancement was calculated. Cox regression was used to test associations between parenchymal enhancement, patient and tumor characteristics, and overall survival and invasive disease-free survival. Subset analyses were performed and stratified according to immunohistochemical subtypes and type of adjuvant treatment received. RESULTS: Median follow-up was 86 months. Age (P < .001) and immunohistochemical subtype (P = .042) retained significance in multivariate analysis for overall survival. In patients with estrogen receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer (n = 398), age (P < .001), largest diameter on MR images (P = .049), and parenchymal enhancement (P = .011) were significant. In patients who underwent endocrine therapy (n = 174), parenchymal enhancement was the only significant covariate for overall survival and invasive disease-free survival (P < .001). CONCLUSION: Results suggest that parenchymal enhancement in the contralateral breast of patients with invasive unilateral breast cancer is significantly associated with long-term outcome, particularly in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Lower value of the mean top 10% enhancement of the parenchyma shows potential as a predictive biomarker for relatively poor outcome in patients who undergo endocrine therapy. These results should, however, be validated in a larger study. PMID- 25811611 TI - Demonstration of the presence of the "deleted" MIR122 gene in HepG2 cells. AB - MicroRNA 122 (miR-122) is highly expressed in the liver where it influences diverse biological processes and pathways, including hepatitis C virus replication and metabolism of iron and cholesterol. It is processed from a long non-coding primary transcript (~7.5 kb) and the gene has two evolutionarily conserved regions containing the pri-mir-122 promoter and pre-mir-122 hairpin region. Several groups reported that the widely-used hepatocytic cell line HepG2 had deficient expression of miR-122, previously ascribed to deletion of the pre mir-122 stem-loop region. We aimed to characterise this deletion by direct sequencing of 6078 bp containing the pri-mir-122 promoter and pre-mir-122 stem loop region in HepG2 and Huh-7, a control hepatocytic cell line reported to express miR-122, supported by sequence analysis of cloned genomic DNA. In contrast to previous findings, the entire sequence was present in both cell lines. Ten SNPs were heterozygous in HepG2 indicating that DNA was present in two copies. Three validation isolates of HepG2 were sequenced, showing identical genotype to the original in two, whereas the third was different. Investigation of promoter chromatin status by FAIRE showed that Huh-7 cells had 6.2 +/- 0.19- and 2.7 +/- 0.01- fold more accessible chromatin at the proximal (HNF4alpha binding) and distal DR1 transcription factor sites, compared to HepG2 cells (p=0.03 and 0.001, respectively). This was substantiated by ENCODE genome annotations, which showed a DNAse I hypersensitive site in the pri-mir-122 promoter in Huh-7 that was absent in HepG2 cells. While the origin of the reported deletion is unclear, cell lines should be obtained from a reputable source and used at low passage number to avoid discrepant results. Deficiency of miR-122 expression in HepG2 cells may be related to a relative deficiency of accessible promoter chromatin in HepG2 versus Huh-7 cells. PMID- 25811613 TI - Bionano interactions of mcf-7 breast tumor cells with a transferrin receptor targeted nanoparticle. AB - Although transferrin receptor (TfR) is widely accepted as a target for cancer therapy, few studies have elaborated on delivery efficiency of TfR upon interactions with TfR-targeted nanomedicine. Here, a micellar system employing TfR-specific 7peptide (histidine-alanine-isoleucine-tyrosine- proline-arginine histidine, HAIYPRH, 7pep) as the targeting moiety was constructed; and its endocytosis, intracellular trafficking as well as influence on TfR expression and in vivo tumor targeting were explored in the MCF-7 tumor model. In contrast to unmodified micelles, 7pep modification enhanced the cellular uptake of micelles without altering endocytic pathways, and slowed down the trafficking of micelles to lysosomes without changing the final intracellular colocalization. Interestingly, cellular TfR level was increased by 7pep-modified micelles. Furthermore, receptor saturation and recovery was observed in vivo. In conclusion, this study comprehensively investigated the bionano interaction between TfR positive tumors and 7pep-modified micelles, and provided scientific information for cancer therapy with receptor-mediated nanomedicines. PMID- 25811615 TI - Surgical data and early postoperative outcomes after minimally invasive lumbar interbody fusion: results of a prospective, multicenter, observational data monitored study. AB - Minimally invasive lumbar interbody fusion (MILIF) offers potential for reduced operative morbidity and earlier recovery compared with open procedures for patients with degenerative lumbar disorders (DLD). Firm conclusions about advantages of MILIF over open procedures cannot be made because of limited number of large studies of MILIF in a real-world setting. Clinical effectiveness of MILIF in a large, unselected real-world patient population was assessed in this Prospective, monitored, international, multicenter, observational study. OBJECTIVE: To observe and document short-term recovery after minimally invasive interbody fusion for DLD. MATERIALS AND METHODS: In a predefined 4-week analysis from this study, experienced surgeons (>= 30 MILIF surgeries pre-study) treated patients with DLD by one- or two-level MILIF. The primary study objective was to document patients' short-term post-interventional recovery (primary objective) including back/leg pain (visual analog scale [VAS]), disability (Oswestry Disability Index [ODI]), health status (EQ-5D) and Patient satisfaction. RESULTS: At 4 weeks, 249 of 252 patients were remaining in the study; the majority received one-level MILIF (83%) and TLIF was the preferred approach (94.8%). For one-level (and two-level) procedures, surgery duration was 128 (182) min, fluoroscopy time 115 (154) sec, and blood-loss 164 (233) mL. Time to first ambulation was 1.3 days and time to study-defined surgery recovery was 3.2 days. Patients reported significantly (P < 0.0001) reduced back pain (VAS: 2.9 vs 6.2), leg pain (VAS: 2.5 vs 5.9), and disability (ODI: 34.5% vs 45.5%), and a significantly (P < 0.0001) improved health status (EQ-5D index: 0.61 vs 0.34; EQ VAS: 65.4 vs 52.9) 4 weeks postoperatively. One adverse event was classified as related to the minimally invasive surgical approach. No deep site infections or deaths were reported. CONCLUSIONS: For experienced surgeons, MILIF for DLD demonstrated early benefits (short time to first ambulation, early recovery, high patient satisfaction and improved patient-reported outcomes) and low major perioperative morbidity at 4 weeks postoperatively. PMID- 25811616 TI - Distinct mutations led to inactivation of type 1 fimbriae expression in Shigella spp. AB - Shigella spp. are responsible for bacillary dysentery in humans. The acquisition or the modification of the virulence plasmid encoding factors promoting entry of bacteria into and dissemination within epithelial cells was a critical step in the evolution of these bacteria from their Escherichia coli ancestor(s). Incorporation of genomic islands (GI) and gene inactivation also shaped interactions between these pathogens and their human host. Sequence analysis of the GI inserted next to the leuX tRNA gene in S. boydii, S. dysenteriae, S. flexneri, S. sonnei and enteroinvasive E. coli (EIEC) suggests that this region initially carried the fec, yjhATS and fim gene clusters. The fim cluster encoding type I fimbriae is systematically inactivated in both reference strains and clinical isolates and distinct mutations are responsible for this inactivation in at least three phylogenetic groups. To investigate consequences of the presence of fimbriae on the outcome of the interaction of Shigella with host cells, we used a S. flexneri strain harboring a plasmid encoding the E. coli fim operon. Production of fimbriae by this recombinant strain increased the ability of bacteria to adhere to and enter into epithelial cells and had no effect on their ability to disseminate from cell to cell. The observations that production of type I fimbriae increases invasion of epithelial cells and that independent mutations abolish fimbriae production in Shigella suggest that these mutations correspond to pathoadaptive events. PMID- 25811617 TI - TOX acts an oncological role in mycosis fungoides. AB - Mycosis fungoides (MF) is a low-grade lymphoma characterized by clonal expansion of atypical CD4+ skin-homing T lymphocytes. Herein, we examined the role of thymocytes selection associated HMG-box (TOX), a gene previously found to be unregulated in MF skin biopsies, in MF pathogenesis. TOX encodes a high-mobility group family (HMG) domain DNA binding nuclear protein, which regulates the differentiation of developing T-cells. First, we confirmed that TOX expression levels in MF were increased compared with those in benign inflammatory dermatitis (BID) and normal skin. In addition, TOX level increased with the progression MF from patch stage to tumor stage. Overexpression of TOX accelerated the proliferation and migration of MF cell lines in vitro, which were blocked by AKT inhibitors. In conclusion, our study confirmed that TOX was highly expressed in MF lesions and accelerates the proliferation and migration of MF. TOX is a diagnostic marker for MF and may play a pathogenic role in disease progression. PMID- 25811619 TI - Magnetic field assisted assembly of highly ordered percolated nanostructures and their application for transparent conductive thin films. AB - Magnetic field assisted assembly is used to fabricate aligned single nanowire mesh-like nanostructured films. Inhomogeneous magnetic field is applied to translocate high aspect ratio silver nanowires from suspensions to the surface of solid supports. The tangential component of the magnetic field vector is rotated in two consecutive steps to arrange the rectangular mesh-like structure of orthogonally oriented nanowires with minimal fractions of loops and bent structures. This work demonstrates highly ordered nanowire films with superior properties to randomly deposited structures- specifically one order of magnitude greater conductivity and more than ten percent higher transparency. This method is simple, scalable and can be used for the directed assembly of magnetic and nonmagnetic highly ordered, percolated structures. PMID- 25811621 TI - The Effect of Fish Oil, Vitamin D and Protein on URTI Incidence in Young Active People. PMID- 25811618 TI - Acquired alterations of hypothalamic gene expression of insulin and leptin receptors and glucose transporters in prenatally high-glucose exposed three-week old chickens do not coincide with aberrant promoter DNA methylation. AB - BACKGROUND: Prenatal exposures may have a distinct impact for long-term health, one example being exposure to maternal 'diabesity' during pregnancy increasing offspring 'diabesity' risk. Malprogramming of the central nervous regulation of body weight, food intake and metabolism has been identified as a critical mechanism. While concrete disrupting factors still remain unclear, growing focus on acquired epigenomic alterations have been proposed. Due to the independent development from the mother, the chicken embryo provides a valuable model to distinctively establish causal factors and mechanisms. AIM: The aim of this study was to determine the effects of prenatal hyperglycemia on postnatal hypothalamic gene expression and promoter DNA methylation in the chicken. METHODS AND FINDINGS: To temporarily induce high-glucose exposure in chicken embryos, 0.5 ml glucose solution (30 mmol/l) were administered daily via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. At three weeks of postnatal age, body weight, total body fat, blood glucose, mRNA expression (INSR, LEPR, GLUT1, GLUT3) as well as corresponding promoter DNA methylation were determined in mediobasal hypothalamic brain slices (Nucleus infundibuli hypothalami). Although no significant changes in morphometric and metabolic parameters were detected, strongly decreased mRNA expression occurred in all candidate genes. Surprisingly, however, no relevant alterations were observed in respective promoter methylation. CONCLUSION: Prenatal hyperglycemia induces strong changes in later hypothalamic expression of INSR, LEPR, GLUT1, and GLUT3 mRNA. While the chicken provides an interesting approach for developmental malprogramming, the classical expression regulation via promoter methylation was not observed here. This may be due to alternative/interacting brain mechanisms or the thus far under-explored bird epigenome. PMID- 25811622 TI - Understanding the Meaning of Lactate Threshold in Resistance Exercises. PMID- 25811623 TI - Activity Profiles of Successful and Less-successful Semi-elite Rugby League Teams. PMID- 25811620 TI - Parallel epigenomic and transcriptomic responses to viral infection in honey bees (Apis mellifera). AB - Populations of honey bees are declining throughout the world, with US beekeepers losing 30% of their colonies each winter. Though multiple factors are driving these colony losses, it is increasingly clear that viruses play a major role. However, information about the molecular mechanisms mediating antiviral immunity in honey bees is surprisingly limited. Here, we examined the transcriptional and epigenetic (DNA methylation) responses to viral infection in honey bee workers. One-day old worker honey bees were fed solutions containing Israeli Acute Paralysis Virus (IAPV), a virus which causes muscle paralysis and death and has previously been associated with colony loss. Uninfected control and infected, symptomatic bees were collected within 20-24 hours after infection. Worker fat bodies, the primary tissue involved in metabolism, detoxification and immune responses, were collected for analysis. We performed transcriptome- and bisulfite sequencing of the worker fat bodies to identify genome-wide gene expression and DNA methylation patterns associated with viral infection. There were 753 differentially expressed genes (FDR<0.05) in infected versus control bees, including several genes involved in epigenetic and antiviral pathways. DNA methylation status of 156 genes (FDR<0.1) changed significantly as a result of the infection, including those involved in antiviral responses in humans. There was no significant overlap between the significantly differentially expressed and significantly differentially methylated genes, and indeed, the genomic characteristics of these sets of genes were quite distinct. Our results indicate that honey bees have two distinct molecular pathways, mediated by transcription and methylation, that modulate protein levels and/or function in response to viral infections. PMID- 25811624 TI - Higher Insulin-sensitizing Response after Sprint Interval Compared to Continuous Exercise. PMID- 25811625 TI - Biochanin a gastroprotective effects in ethanol-induced gastric mucosal ulceration in rats. AB - BACKGROUND: Biochanin A notable bioactive compound which is found in so many traditional medicinal plant. In vivo study was conducted to assess the protective effect of biochanin A on the gastric wall of Spraguedawley rats' stomachs. METHODOLOGY: The experimental set included different animal groups. Specifically, four groups with gastric mucosal lesions were receiving either a) Ulcer control group treated with absolute ethanol (5 ml/kg), b) 20 mg/kg of omeprazole as reference group, c) 25 of biochanin A, d) 50 mg/kg of biochanin A. Histopathological sectioning followed by immunohistochemistry staining were undertaken to evaluate the influence of the different treatments on gastric wall mucosal layer. The gastric secretions were collected in the form of homogenate and exposed to superoxide dismutase (SOD) and nitric oxide enzyme (NO) and the level of malondialdehyde (MDA) and protein content were measured. Ulceration and patchy haemorrhage were clearly observed by light microscopy. The morphology of the gastric wall as confirmed by immunohistochemistry and fluorescent microscopic observations, exhibited sever deformity with notable thickness, oedematous and complete loss of the mucosal coverage however the biochanin-pretreated animals, similar to the omeprazole-pretreated animals, showed less damage compared to the ulcer control group. Moreover, up-regulation of Hsp70 protein and down-regulation of Bax protein were detected in the biochanin A pre-treated groups and the gastric glandular mucosa was positively stained with Periodic Acid Schiff (PAS) staining and the Leucocytes infiltration was commonly seen. Biochanin A displayed a great increase in SOD and NO levels and decreased the release of MDA. CONCLUSIONS: This gastroprotective effect of biochanin A could be attributed to the enhancement of cellular metabolic cycles perceived as an increase in the SOD, NO activity, and decrease in the level of MDA, and also decrease in level of Bax expression and increase the Hsp70 expression level. PMID- 25811626 TI - Grating-based phase-contrast imaging of tumor angiogenesis in lung metastases. AB - PURPOSE: To assess the feasibility of the grating-based phase-contrast imaging (GPI) technique for studying tumor angiogenesis in nude BALB/c mice, without contrast agents. METHODS: We established lung metastatic models of human gastric cancer by injecting the moderately differentiated SGC-7901 gastric cancer cell line into the tail vein of nude mice. Samples were embedded in a 10% formalin suspension and dried before imaging. Grating-based X-ray phase-contrast images were obtained at the BL13W beamline of the Shanghai Synchrotron Radiation Facility (SSRF) and compared with histological sections. RESULTS: Without contrast agents, grating-based X-ray phase-contrast imaging still differentiated angiogenesis within metastatic tumors with high spatial resolution. Vessels, down to tens of microns, showed gray values that were distinctive from those of the surrounding tumors, which made them easily identifiable. The vessels depicted in the imaging study were similar to those identified on histopathology, both in size and shape. CONCLUSIONS: Our preliminary study demonstrates that grating based X-ray phase-contrast imaging has the potential to depict angiogenesis in lung metastases. PMID- 25811629 TI - Commentary on "Do Written Disclosures of Serious Events Increase Risk of Malpractice Claims?: One Healthcare System's Experience" by Painter LM, Kidwell KM, Kidwell RP, et al. PMID- 25811627 TI - Delayed response and biosonar perception explain movement coordination in trawling bats. AB - Animal coordinated movement interactions are commonly explained by assuming unspecified social forces of attraction, repulsion and alignment with parameters drawn from observed movement data. Here we propose and test a biologically realistic and quantifiable biosonar movement interaction mechanism for echolocating bats based on spatial perceptual bias, i.e. actual sound field, a reaction delay, and observed motor constraints in speed and acceleration. We found that foraging pairs of bats flying over a water surface swapped leader follower roles and performed chases or coordinated manoeuvres by copying the heading a nearby individual has had up to 500 ms earlier. Our proposed mechanism based on the interplay between sensory-motor constraints and delayed alignment was able to recreate the observed spatial actor-reactor patterns. Remarkably, when we varied model parameters (response delay, hearing threshold and echolocation directionality) beyond those observed in nature, the spatio-temporal interaction patterns created by the model only recreated the observed interactions, i.e. chases, and best matched the observed spatial patterns for just those response delays, hearing thresholds and echolocation directionalities found to be used by bats. This supports the validity of our sensory ecology approach of movement coordination, where interacting bats localise each other by active echolocation rather than eavesdropping. PMID- 25811630 TI - Propensity score matching to measure the effect of survey mode on reports of racial and ethnic discrimination in health care. AB - OBJECTIVE: To examine the effect of survey mode (mail vs. telephone) on the likelihood of reporting health care-related discrimination based on race, ethnicity, or nationality. METHODS: We use data from a mixed-mode, mail and telephone survey of public health care program enrollees (N=2807), including Somali, Hmong, African American, American Indian, and Latino populations. Self reported discrimination was measured as the experience of unfair treatment by health care providers due to race, ethnicity, or nationality. We use propensity score matching to create exchangeable groups of phone and mail respondents based on the probability of completing the survey by phone. RESULTS: Overall, 33.1% of respondents reported having experienced discrimination in health care, but only 23.6% of telephone respondents reported discrimination compared with 36.8% of mail respondents. After matching phone and mail respondents based on probability of responding by telephone, all observable significant differences between respondents that were brought about by differential self-selection into mode were erased, allowing us to estimate the effect of survey mode on report of discrimination. Even after matching, the mode effect remains, where report of health care discrimination for telephone respondents would have been 12.6 percentage points higher had they responded by mail (22.6% vs. 35.2%). CONCLUSIONS: Survey mode has a significant effect on report of discrimination. Respondents may be more willing to disclose experiences of discrimination in a mail survey than to a telephone interviewer. Findings have substantial policy and clinical significance as variation in report of discrimination based on mode may lead to underestimation of the extent of the problem. PMID- 25811628 TI - The vascular effects of sodium tanshinone IIA sulphonate in rodent and human pregnancy. AB - Danshen, in particular its derivative tanshinone IIA (TS), is a promising compound in the treatment of cardiovascular diseases and has been used for many years in traditional Chinese medicine. Although many actions of TS have been researched, its vasodilator effects in pregnancy remain unknown. There have been a few studies that have shown the ability of TS to reduce blood pressure in women with hypertensive pregnancies; however, there are no studies which have examined the vascular effects of TS in the pregnant state in either normal or complicated pregnancies. Our aim was to determine the vasoactive role of TS in multiple arteries during pregnancy including: rat resistance (mesenteric and uterine) and conduit (carotid) arteries. Further, we aimed to assess the ability of TS to improve uterine blood flow in a rodent model of intrauterine growth restriction. Wire myography was used to assess vascular responses to the water-soluble derivative, sodium tanshinone IIA sulphonate (STS) or to the endothelium dependent vasodilator, methylcholine. At mid-pregnancy, STS caused direct vasodilation of rat resistance (pEC50 mesenteric: 4.47+/-0.05 and uterine: 3.65+/ 0.10) but not conduit (carotid) arteries. In late pregnancy, human myometrial arteries responded with a similar sensitivity to STS (pEC50 myometrial: 3.26+/ 0.13). STS treatment for the last third of pregnancy in eNOS-/- mice increased uterine artery responses to methylcholine (Emax eNOS-/-: 55.2+/-9.2% vs. eNOS-/- treated: 75.7+/-8.9%, p<0.0001). The promising vascular effects, however, did not lead to improved uterine or umbilical blood flow in vivo, nor to improved fetal biometrics; body weight and crown-rump length. Further, STS treatment increased the uterine artery resistance index and decreased offspring body weight in control mice. Further research would be required to determine the safety and efficacy of use of STS in pregnancy. PMID- 25811631 TI - Impact of the medical home model on the quality of primary care: the Belgian experience. AB - BACKGROUND: The Belgium medical home (MH) model, which has been garnering support of late, resembles its US counterpart in that it aims at improving the quality of health care while containing costs. OBJECTIVES: To compare the quality of care offered by MHs with that offered by traditional individual practices (IPs) in Belgium in terms of the extent of their adherence to clinical practice guidelines in antibiotherapy, cervical-cancer screening, influenza vaccination, and the management of diabetes. RESEARCH DESIGN: This is a retrospective study using public insurance claims data. Data consisted of a random sample of patients using the services of MHs and IPs who were previously matched according to sex, age category, location, disability, and socioeconomic status. We applied the McNemar test, the t test, or the Wilcoxon test, depending on the type of variable being compared. SUBJECTS: The final sample comprised 43,678 patients in the year 2004. MEASURES: On the basis of a review of the literature, we selected 4 themes, corresponding to 25 indicators: antibiotherapy, cervical-cancer screening, influenza vaccination, and the management of diabetes. RESULTS: MHs were more likely than IPs to adhere to evidence-based clinical practice guidelines. They prescribed less and more appropriate antibiotherapy, provided wider influenza vaccination coverage for target groups, and provided a better follow-up for diabetics than did IPs. In regard to cervical-cancer screening, no significant differences were found. CONCLUSIONS: MHs, as they combine a greater adherence to guidelines and savings in secondary care, are a cost-effective alternative to traditional IPs and therefore should be encouraged. PMID- 25811633 TI - When Legitimizing a Request Increases Compliance: The Legitimizing Object Technique. AB - Earlier research reported that using pictures in a fundraising request increases donations by legitimizing the solicitation. The present study tested the effectiveness of a solicitation for money made in the street when an object that legitimated the request was present or not. Male confederates asked passersby for money to buy a stamp while either holding or not holding an envelope in one hand. With a high effect-size, it was reported that the presence of the envelope increased compliance with the request. The legitimation of the request associated with the presence of the envelope is used to explain the results. PMID- 25811632 TI - Latinos with diabetes and food insecurity in an agricultural community. AB - BACKGROUND: Latinos from agricultural communities have a high prevalence of food insecurity and are at increased risk of obesity and diabetes, yet little is known about the associations between food insecurity and diabetes outcomes. OBJECTIVE: To examine the associations between food insecurity and diabetes outcomes among rural Latinos. METHODS: Cross-sectional survey with medical chart abstraction of 250 Latinos with diabetes. Primary outcomes are the control of 3 intermediate diabetes outcomes (hemoglobin A1C <=8.0%, LDL-cholesterol <=100 mg/dL, and blood pressure <=140/90 mm Hg), a composite of control of the 3, and receipt of 6 processes of care. Secondary outcomes are cost-related medication underuse and participation in self-care activities. RESULTS: Fifty-two percent of patients reported food insecurity and 1-in-4 reported cost-related medication underuse. Patients with food insecurity were more likely to report cost-related medication underuse [adjusted odds ratio (AOR)=2.49; 95% confidence intervals (CI), 1.30, 4.98; P=0.003], less likely to meet the composite measure for control of the 3 intermediate outcomes (AOR=0.24; 95% CI, 0.07, 0.84; P<0.05), and less likely to receive a dilated eye examination (AOR=0.37; 95% CI, 0.18, 0.77; P<0.05) and annual foot examinations (AOR=0.42; 95% CI, 0.20, 0.84; P<0.05) compared with those who were food secure. CONCLUSIONS: Among this rural Latino population, food insecurity was independently associated with not having control of the intermediate diabetes outcomes captured in the composite measure, not receiving dilated eye and foot examinations, and with self-reporting cost-related medication underuse. PMID- 25811634 TI - Persistence of pathological distribution of NK cells in HIV-infected patients with prolonged use of HAART and a sustained immune response. AB - OBJECTIVE: A prospective analysis of the distribution of NK subsets and natural cytotoxicity receptors (NKp30/NKp46) in HIV patients with long-term HAART use and sustained virological and immunological response. METHODS: The main inclusion criteria were: at least 3 years' receipt of HAART; current CD4+ count >= 500 cells/mm3; undetectable viral load for at least 24 months; no hepatotropic virus co-infection. Percentages of CD56dim, CD56bright NK cells and CD56neg CD16+ cells were obtained. Expression of the NCRs, NKp30 and NKp46 was analysed in CD56+ cells. Thirty-nine infected patients and sixteen healthy donors were included in the study. RESULTS: The percentages of total CD56+ and CD56dim NK cells were significantly lower in HIV-infected patients than in healthy donors (70.4 vs. 50.3 and 80.9 vs. 66.1 respectively). The percentage of total CD56+ NK cells expressing NCR receptors was lower in HIV patients than in healthy donors (NKp30: 25.20 vs. 58.63; NKp46: 24.8 vs. 50.59). This was also observed for CD56dim and CD56bright NK cells. Length of time with undetectable HIV viral load was identified as an independent factor associated with higher expression of NKp30 and NKp46. CONCLUSION: Despite the prolonged and effective use of HAART, HIV infected patients do not fully reconstitute the distribution of NK cells. Length of time with an undetectable viral load was related to greater recovery of NKp30/NKp46 receptors. PMID- 25811635 TI - Improving the hyperpolarization of (31)P nuclei by synthetic design. AB - Traditional (31)P NMR or MRI measurements suffer from low sensitivity relative to (1)H detection and consequently require longer scan times. We show here that hyperpolarization of (31)P nuclei through reversible interactions with parahydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold (31)P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan (31)P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal to-noise ratio of just 11.4. (31)P-hyperpolarized images are also reported from a 7 T preclinical scanner. PMID- 25811636 TI - High efficiency solar-to-hydrogen conversion on a monolithically integrated InGaN/GaN/Si adaptive tunnel junction photocathode. AB - H2 generation under sunlight offers great potential for a sustainable fuel production system. To achieve high efficiency solar-to-hydrogen conversion, multijunction photoelectrodes have been commonly employed to absorb a large portion of the solar spectrum and to provide energetic charge carriers for water splitting. However, the design and performance of such tandem devices has been fundamentally limited by the current matching between various absorbing layers. Here, by exploiting the lateral carrier extraction scheme of one-dimensional nanowire structures, we have demonstrated that a dual absorber photocathode, consisting of p-InGaN/tunnel junction/n-GaN nanowire arrays and a Si solar cell wafer, can operate efficiently without the strict current matching requirement. The monolithically integrated photocathode exhibits an applied bias photon-to current efficiency of 8.7% at a potential of 0.33 V versus normal hydrogen electrode and nearly unity Faradaic efficiency for H2 generation. Such an adaptive multijunction architecture can surpass the design and performance restrictions of conventional tandem photoelectrodes. PMID- 25811638 TI - Modulation of group I ribozyme activity by cationic porphyrins. AB - The effects of cationic porphyrins on the catalytic activities of four group I ribozymes were investigated. A cationic porphyrin possessing four pyridinium moieties (pPyP) inhibited two group IC3 ribozymes (Syn Rz and Azo Rz) and a group IC1 ribozyme (Tet Rz). In the case of a group IA2 ribozyme (Td Rz), however, pPyP served not only as an inhibitor but also as an activator, and the effects of pPyP were dependent on its concentration. To analyze the structural and electronic factors determining the effects of pPyP on group I ribozymes, three cationic porphyrins (pPyNCP, pPyF4P, and TMPyP) were also examined. As interactions between small organic molecules and nucleic acids are attractive and important issues in biochemistry and biotechnology, this study contributes to the development of porphyrin-based molecules that can modulate functions of structured RNA molecules. PMID- 25811639 TI - A multi-functional tubulovesicular network as the ancestral eukaryotic endomembrane system. AB - The origin of the eukaryotic endomembrane system is still the subject of much speculation. We argue that the combination of two recent hypotheses addressing the eukaryotic endomembrane's early evolution supports the possibility that the ancestral membranes were organised as a multi-functional tubulovesicular network. One of the potential selective advantages provided by this organisation was the capacity to perform endocytosis. This possibility is illustrated by membrane organisations observed in current organisms in the three domains of life. Based on this, we propose a coherent model of autogenous eukaryotic endomembrane system evolution in which mitochondria are involved at a late stage. PMID- 25811642 TI - Progressing towards tuberculosis elimination in the European Union and European Economic Area. PMID- 25811640 TI - NPPD: A Protein-Protein Docking Scoring Function Based on Dyadic Differences in Networks of Hydrophobic and Hydrophilic Amino Acid Residues. AB - Protein-protein docking (PPD) predictions usually rely on the use of a scoring function to rank docking models generated by exhaustive sampling. To rank good models higher than bad ones, a large number of scoring functions have been developed and evaluated, but the methods used for the computation of PPD predictions remain largely unsatisfactory. Here, we report a network-based PPD scoring function, the NPPD, in which the network consists of two types of network nodes, one for hydrophobic and the other for hydrophilic amino acid residues, and the nodes are connected when the residues they represent are within a certain contact distance. We showed that network parameters that compute dyadic interactions and those that compute heterophilic interactions of the amino acid networks thus constructed allowed NPPD to perform well in a benchmark evaluation of 115 PPD scoring functions, most of which, unlike NPPD, are based on some sort of protein-protein interaction energy. We also showed that NPPD was highly complementary to these energy-based scoring functions, suggesting that the combined use of conventional scoring functions and NPPD might significantly improve the accuracy of current PPD predictions. PMID- 25811641 TI - Variability of Tear Osmolarity in Patients With Dry Eye. AB - IMPORTANCE: Knowledge about the variability of measurements using the TearLab Osmolarity System is necessary when evaluating the clinical utility of readings. OBJECTIVE: To examine the variability of tear osmolarity measured by the TearLab Osmolarity System in patients with Sjogren syndrome (SS), patients with blepharitis, and control participants. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional study at a tertiary care academic center from June 13, 2012, to March 21, 2013. Participants included 74 eyes of 37 patients from a volunteer sample (18 patients with SS, 11 patients with blepharitis, and 8 control participants) who were evaluated using the TearLab Osmolarity System, with 3 consecutive osmolarity measurements taken at 1-minute intervals in a session; 15 of these patients had the same measurements taken by the same examiner in 2 additional sessions on the same day (9 AM-10 AM, 12 PM-1 PM, or 3 PM-4 PM). Most patients with SS and patients with blepharitis were taking systemic or topical dry eye medications at the time of enrollment. MAIN OUTCOMES AND MEASURES: Mean osmolarity and its variability calculated from a linear mixed model for each disease group that accounts for the variations attributable to different patients, eyes, and sessions and measurement error specific to each disease group. RESULTS: Mean tear osmolarity was 307 mOsm/L, 304 mOsm/L, and 301 mOsm/L in the SS, blepharitis, and control groups, respectively (P = .46). The error associated with repeated measurements within a session in the patients without dry eye (10.5 mOsm/L [95% CI, 9.0-12.4]) was significantly lower than in the patients with blepharitis (14.6 mOsm/L [95% CI, 12.5-17.5]; P = .006) and patients with SS (15.8 mOsm/L [95% CI, 14.2-17.8]; P < .001) but a difference in the error of repeated measurements between patients with blepharitis and patients with SS was not identified (P = .46). CONCLUSIONS AND RELEVANCE: There was increased variability attributable to error in repeated measurements in patients with SS and patients with blepharitis compared with control participants. The high variability of TearLab osmolarity readings in all groups makes the clinical interpretation of measurements unclear. PMID- 25811644 TI - Risk factors for TB and HIV coinfection in Scotland, 2001 to 2010. AB - The number of patients with tuberculosis (TB) increased steadily in Scotland between 2005 and 2010. Human immunodeficiency virus (HIV) infection has been a contributory factor to increases in TB in a number of comparable industrialised countries. This study investigated the extent of, and risk factors for, TB and HIV coinfection in Scotland from 2001 to 2010. Patients with TB in the national TB database were linked to those in the national HIV database using probabilistic data linkage. Patient records were anonymised to maintain confidentiality. From 2001 to 2010, 106/4, 097 (2.6%, 95% CI: 2.1 to 3.1) TB patients matched with HIV patients, equating to a 10-year incidence of 2.1 cases per million population. Patients with both TB and HIV were more often born outside the United Kingdom,were of black African ethnicity, had refugee status and had extra thoracic lymph node involvement or cryptic/disseminated TB disease. Individuals with TB and HIV coinfection were younger and symptomatic for a shorter time before their diagnosis of TB, compared with TB patients without HIV. TB and HIV coinfection was relatively uncommon in Scotland in the study period. Clinicians should recognise the potential for HIV infection among TB patients and the importance of offering an HIV test to all TB patients. PMID- 25811643 TI - Excess mortality among the elderly in European countries, December 2014 to February 2015. AB - Since December 2014 and up to February 2015, the weekly number of excess deaths from all-causes among individuals >= 65 years of age in 14 European countries have been significantly higher than in the four previous winter seasons. The rise in unspecified excess mortality coincides with increased proportion of influenza detection in the European influenza surveillance schemes with a main predominance of influenza A (H3N2) viruses seen throughout Europe in the current season, though cold snaps and other respiratory infections may also have had an effect. PMID- 25811645 TI - Impact of the BCG vaccination policy on tuberculous meningitis in children under 6 years in metropolitan France between 2000 and 2011. AB - In France, Bacillus Calmette-Guerin (BCG) vaccination by multipuncture device was withdrawn in 2006. In 2007, universal mandatory BCG vaccination was replaced by vaccination of high-risk children. To evaluate the impact of these changes on tuberculous meningitis (TBM) epidemiology, data on culture-positive and culture negative (or unknown microbiological result) TBM in <=5 years olds were collected from 2000-2011. Ten culture-positive and 17 culture-negative TBM cases were identified, with an annual incidence rate ranging from 0.16 to 0.66 cases per 10 million inhabitants. The average annual numbers of TBM cases were 2.7 and 1.8 from 2000-2005 and 2006-2011, respectively. In Ile-de-France where all children are considered at risk, the overall incidence rates were 1.14 and 0.29 per million for the two periods. In other regions where only at-risk children are vaccinated since 2007, rates were 0.30 and 0.47, respectively. None of these differences were significant. Annual incidence rates for each one year age group cohort were comparable before and after changes. Childhood TBM remains rare in France. No increase in incidence was observed after changes in BCG vaccination strategy. Ongoing surveillance should be maintained, as a slight increase in TBM in the coming years remains possible, in the context of suboptimal vaccination coverage of high-risk children. PMID- 25811646 TI - Self-sampling for analysis of respiratory viruses in a large-scale epidemiological study in Sweden. AB - Viral diagnosis of respiratory tract infections has so far required sampling by health professionals,hampering large-scale epidemiological studies of virus specific disease outcomes. As part of a population-based, prospective study of work-related risk factors for transmission of viral infections (SWEDE-I), we developed a scheme for self-sampling with nasal swabs. Random selection from the gainfully employed population of a medium-sized town in central Sweden resulted in a study cohort of 2,237 men and women aged 25 to 63 years. From September 2011 through May 2012, the cohort reported all instances of respiratory tract infection or gastroenteritis and participants concomitantly sent self-sampled nasal swabs for analysis using regular mail. Diagnosis of 14 viruses was performed. A total of 1,843 samples were received. The week-wise average delay between disease on set and arrival of the specimens at the laboratory varied between four and six days, and the corresponding median delay was between 3.5 and six days. In line with previous community-based studies, picorna- and coronaviruses dominated in specimens obtained from the self-sampling scheme. The results of self-sampling were contrasted to those from contemporaneous routine clinical sampling, on the same age group, in the adjacent Stockholm county. Although higher proportions of positive samples for respiratory syncytial virus and influenza were observed in the clinical sampling scheme, estimations of seasonality for influenza A and picornaviruses derived from both schemes were similar. Our findings show that nasal self-sampling is feasible in large-scale surveillance of respiratory infections and opens new prospects for population based,virologically verified research on virus spread,burden of disease, and effects of environmental factors or interventions. PMID- 25811647 TI - High-performance flexible photodetectors based on GaTe nanosheets. AB - 2D layered GaTe materials have attracted a great deal of attention for optoelectronic applications due to their direct band structure, whether in bulk or as a single layer. In this paper, for the first time, we have synthesized high quality, single crystalline GaTe nanosheets by employing a facile CVD method. The size of the GaTe nanosheets reached several tens of micrometers, and some of them even exceeded 100 MUm. In particular, planar GaTe nanosheets were achieved on a mica substrate following a van der Waals epitaxial growth mechanism. Further, through a systematic comparison of the performances under various conditions, we found that adsorbates on the GaTe surface under ambient conditions strongly deteriorated the GaTe photodetector device performance. After removing the adsorbates in a ~ 7 * 10(-5) torr vacuum, a flexible, fast response GaTe photodetector with a high photoresponse, high mechanical stability and an excellent linear input-output relationship was obtained. The results presented in this study suggest that the GaTe nanosheets grown by a CVD method are promising candidates for optoelectronic applications in the future. PMID- 25811648 TI - Annual costs of chronic obstructive pulmonary disease in Finland during 1996-2006 and a prediction model for 2007-2030. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major burden for the health care system, but the exact costs are difficult to estimate and there are insufficient data available on past and future time trends of COPD-related costs. AIMS: The aim of the study was to calculate COPD-related costs in Finland during the years 1996-2006 and estimate future costs for the years 2007-2030. METHODS: COPD-related direct and indirect costs in the public health care sector of the whole of Finland during the years 1996-2006 were retrieved from national registers. In addition, we made a mathematical prediction model on COPD costs for the years 2007-2030 on the basis of population projection and changes in smoking habits. RESULTS: The total annual COPD-related costs amounted to about 100-110 million Euros in 1996-2006, with no obvious change, but there was a slight decrease in direct costs and an increase in indirect costs during these years. The estimation model predicted a 60% increase up to 166 million Euros in COPD related annual costs by the year 2030. This is caused almost entirely by an increase in direct health care costs that reflect the predicted ageing of the Finnish population, as older age is a significant factor that increases the need for hospitalisation. CONCLUSIONS: The total annual COPD-related costs in Finland have been stable during the years 1996-2006, but if management strategies are not changed a significant increase in direct costs is expected by the year 2030 due to ageing of the population. PMID- 25811649 TI - Hepatorenal Disorders. AB - Renal dysfunction is common in patients with end-stage liver disease (ESLD); it takes on many forms from acute to chronic renal injury and may involve a variety of mechanisms. Hepatorenal syndrome (HRS) is a specific type of hepatorenal disorder (HRD) with a unique pathophysiology. HRS is characterized by splanchnic arterial vasodilatation and decreased effective intravascular volume that leads to renal vasoconstriction and decreased renal blood flow. The incidence of HRS in relation to other forms of HRD is unknown; however, it is estimated that 35% to 40% patients with ESLD and ascites eventually develop the condition. Two subtypes of HRS have been described. Type 1 HRS is rapidly progressive, whereas the renal function in type 2 HRS deteriorates slowly over weeks or months. Type 1 HRS may be precipitated by sepsis or acute alcoholic hepatitis and occasionally develops in patients who already have type 2 HRS. The diagnosis of HRS is based on the exclusion of other causes of renal dysfunction because no specific test is available. The definitive treatment of HRS is liver transplant. As a bridge to liver transplant, medical management with volume expansion and the use of vasoconstrictors is often implemented. A transjugular intrahepatic portosystemic shunt has been attempted in treating HRS, although there is little evidence of its efficacy compared with standard therapy. Renal replacement therapy is often used if the patient is a liver transplant candidate. Artificial liver assist devices are in the research phase. PMID- 25811650 TI - BRAF V600E mutation: A treatable driver mutation in pleomorphic xanthoastrocytoma (PXA). PMID- 25811651 TI - Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents. AB - Many nitrogen-moiety containing alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 h of noscapine exposure at 20 MUM elucidated chromosomal abnormalities and the inability of chromosomes to complete congression to the equatorial plane for proper mitotic separation ( Proc. Natl. Acad. Sci. U. S. A. 1998 , 95 , 1601 - 1606 ). A number of noscapine analogues possessing various modifications have been described within the literature and have shown significantly improved antiprolific profiles for a large variety of cancer cell lines. Several semisynthetic antimitotic alkaloids are emerging as possible candidates as novel anticancer therapies. This perspective discusses the advancing understanding of noscapine and related analogues in the fight against malignant disease. PMID- 25811652 TI - Eat now or later: self-control as an overlapping cognitive mechanism of depression and obesity. AB - While overlapping neurobiological mechanisms are known, relatively little is known about how "self-control" and cognitive affective processing of rewards may also influence the bi-directional risk between obesity and depression. The objective of this study was to identify the extent to which "self-control," measured using a delay discounting task is co-related to BMI and Depression diagnostic thresholds. A within-subjects counterbalanced design was used in which 92 participants (Mean +/- SD: BMI = 27.9 +/- 3.5, HAMD = 14.7 +/- 7.7) completed a series of clinical diagnostic, survey, and demographic questionnaires in a behavioral health laboratory setting. For the delay discounting task, participants chose between one large delayed reward and one successively smaller immediate reward for four food types (dessert, fried food, fruit, and vegetable). Results showed that delay discounting scores were predictive of BMI and depression with lower delay discounting scores associated with higher BMI and HAMD for the dessert (HAMD scores (beta = -.197, p = .013), BMI (beta = -.239, p < .001)) and fried food (HAMD scores (beta = -.328, p = .001), BMI (beta = -.166, p = .027)). Clinical significance was further evident when HAMD and BMI scores were converted to diagnostic thresholds. Only depression and/or atypical depressive symptoms were related to delay discounting scores with the fruit and vegetable. Thus, reduced cognitive affective self-control for impulsive food choices-particularly for "comfort foods" high in fat and sugar-appears to be a shared cognitive mechanism for both conditions perhaps contributing to the high prevalence of co-morbid mood disorders and weight gain. PMID- 25811653 TI - Effects of ocular hypertension in the visual system of pigmented mice. AB - To study the effects of ocular hypertension (OHT) on the visual system of C57BL/6 pigmented mice, the limbal and episcleral veins of the left eye were laser photocoagulated (LP). LP increased the intraocular pressure during the first five days (d), reaching basal values at 7d. To investigate the effect of OHT on the retinal ganglion cell (RGC) retrograde axonal transport, hydroxistilbamidine methanesulfonate (OHSt) was applied to both superior colliculi (SCi) and the retinas were dissected 2 or 4 weeks after LP. To determine RGC survival, these same retinas were immunoreacted against Brn3a (general RGC population) and melanopsin (intrinsically photosensitive RGCs, m+RGCs). To study whether OHT affected non-RGC neurons in the ganglion cell layer (GCL), RGCs were immunodetected with Brn3a and all GCL nuclei counterstained with DAPI in a group of animals examined 4 weeks post-LP. Innervation of the SCi was examined at 10 days, 8 or 14 weeks after LP with the orthogradely transported cholera toxin subunit-B. OHT resulted in diffuse and sectorial loss of OHSt+RGCs (50% at 2 weeks and 62% at 4 weeks) and in a comparable loss of Brn3a+RGCs at the same time intervals. m+RGCs decreased to 59% at 2 weeks and to 46% at 4 weeks, such loss was diffuse, did not parallel the sectorial loss of the general RGC population and was more severe in the superior-temporal retina. In the GCL, cell loss is selective for RGCs and does not affect other non-RGC neurons. The retinotectal innervation appeared significantly reduced at 10 days (55.7%) and did not progress further up to 14 weeks (46.6%). Thus, LP-induced OHT results in retrograde degeneration of RGCs and m+RGCs, as well as in the loss of CTB labelled retinotectal terminals. PMID- 25811654 TI - Prior population immunity reduces the expected impact of CTL-inducing vaccines for pandemic influenza control. AB - Vaccines that trigger an influenza-specific cytotoxic T cell (CTL) response may aid pandemic control by limiting the transmission of novel influenza A viruses (IAV). We consider interventions with hypothetical CTL-inducing vaccines in a range of epidemiologically plausible pandemic scenarios. We estimate the achievable reduction in the attack rate, and, by adopting a model linking epidemic progression to the emergence of IAV variants, the opportunity for antigenic drift. We demonstrate that CTL-inducing vaccines have limited utility for modifying population-level outcomes if influenza-specific T cells found widely in adults already suppress transmission and prove difficult to enhance. Administration of CTL-inducing vaccines that are efficacious in "influenza experienced" and "influenza-naive" hosts can likely slow transmission sufficiently to mitigate a moderate IAV pandemic. However if neutralising cross reactive antibody to an emerging IAV are common in influenza-experienced hosts, as for the swine-variant H3N2v, boosting CTL immunity may be ineffective at reducing population spread, indicating that CTL-inducing vaccines are best used against novel subtypes such as H7N9. Unless vaccines cannot readily suppress transmission from infected hosts with naive T cell pools, targeting influenza naive hosts is preferable. Such strategies are of enhanced benefit if naive hosts are typically intensively mixing children and when a subset of experienced hosts have pre-existing neutralising cross-reactive antibody. We show that CTL-inducing vaccination campaigns may have greater power to suppress antigenic drift than previously suggested, and targeting adults may be the optimal strategy to achieve this when the vaccination campaign does not have the power to curtail the attack rate. Our results highlight the need to design interventions based on pre existing cellular immunity and knowledge of the host determinants of vaccine efficacy, and provide a framework for assessing the performance requirements of high-impact CTL-inducing vaccines. PMID- 25811655 TI - Novel stably transfected human reporter cell line AIZ-AR as a tool for an assessment of human androgen receptor transcriptional activity. AB - Androgen receptor plays multiple physiological and pathological roles in human organism. In the current paper, we describe construction and characterization of a novel stably transfected human reporter cell line AIZ-AR for assessment of transcriptional activity of human androgen receptor. Cell line AIZ-AR is derived from human prostate carcinoma epithelial cell line 22Rv1 that was transfected with reporter plasmid containing 3 copies of androgen response regions (ARRs) followed by a single copy of androgen response element (ARE) from the promoter region of human prostate specific antigen (PSA) gene. AIZ-AR cells remained fully functional for more than 60 days and over 25 passages in the culture and even after cryopreservation. Time-course analyses showed that AIZ-AR cells allow detection of AR ligands as soon as after 8 hours of the treatment. We performed dose-response analyses with 23 steroids in 96-well plate format. We observed activation of AR by androgens, but not by estrogens and mineralocorticoids. Some glucocorticoids and progesterone also induced luciferase, but their potencies were 2-3 orders of magnitude weaker as compared to androgens. Taken together, we have developed a rapid, sensitive, selective, high-throughput and reproducible tool for detection of human AR ligands, with potential use in pharmacological and environmental applications. PMID- 25811656 TI - Psychological well-being and the human conserved transcriptional response to adversity. AB - Research in human social genomics has identified a conserved transcriptional response to adversity (CTRA) characterized by up-regulated expression of pro inflammatory genes and down-regulated expression of Type I interferon- and antibody-related genes. This report seeks to identify the specific aspects of positive psychological well-being that oppose such effects and predict reduced CTRA gene expression. In a new confirmation study of 122 healthy adults that replicated the approach of a previously reported discovery study, mixed effect linear model analyses identified a significant inverse association between expression of CTRA indicator genes and a summary measure of eudaimonic well-being from the Mental Health Continuum - Short Form. Analyses of a 2- representation of eudaimonia converged in finding correlated psychological and social subdomains of eudaimonic well-being to be the primary carriers of CTRA associations. Hedonic well-being showed no consistent CTRA association independent of eudaimonic well being, and summary measures integrating hedonic and eudaimonic well-being showed less stable CTRA associations than did focal measures of eudaimonia (psychological and social well-being). Similar results emerged from analyses of pooled discovery and confirmation samples (n = 198). Similar results also emerged from analyses of a second new generalization study of 107 healthy adults that included the more detailed Ryff Scales of Psychological Well-being and found this more robust measure of eudaimonic well-being to also associate with reduced CTRA gene expression. Five of the 6 major sub-domains of psychological well-being predicted reduced CTRA gene expression when analyzed separately, and 3 remained distinctively prognostic in mutually adjusted analyses. All associations were independent of demographic characteristics, health-related confounders, and RNA indicators of leukocyte subset distribution. These results identify specific sub dimensions of eudaimonic well-being as promising targets for future interventions to mitigate CTRA gene expression, and provide no support for any independent favorable contribution from hedonic well-being. PMID- 25811658 TI - Correction: Reference genes selection and normalization of oxidative stress responsive genes upon different temperature stress conditions in Hypericum perforatum L. AB - [This corrects the article DOI: 10.1371/journal.pone.0115206.]. PMID- 25811659 TI - Complex epidemiology of a zoonotic disease in a culturally diverse region: phylogeography of rabies virus in the Middle East. AB - The Middle East is a culturally and politically diverse region at the gateway between Europe, Africa and Asia. Spatial dynamics of the fatal zoonotic disease rabies among countries of the Middle East and surrounding regions is poorly understood. An improved understanding of virus distribution is necessary to direct control methods. Previous studies have suggested regular trans-boundary movement, but have been unable to infer direction. Here we address these issues, by investigating the evolution of 183 rabies virus isolates collected from over 20 countries between 1972 and 2014. We have undertaken a discrete phylogeographic analysis on a subset of 139 samples to infer where and when movements of rabies have occurred. We provide evidence for four genetically distinct clades with separate origins currently circulating in the Middle East and surrounding countries. Introductions of these viruses have been followed by regular and multidirectional trans-boundary movements in some parts of the region, but relative isolation in others. There is evidence for minimal regular incursion of rabies from Central and Eastern Asia. These data support current initiatives for regional collaboration that are essential for rabies elimination. PMID- 25811660 TI - Towards a comprehensive insight into efficient hydrogen production by self assembled Ru(bpy)3(2+)-polymer-Pt artificial photosystems. AB - The role of polymers in artificial photosystems has been studied in detail. The photosystems were composed of tris(2,2'-bipyridyl) ruthenium(II) chloride as a photosensitizer (PS), colloidal Pt stabilized by polymer as a hydrogen-evolving catalyst and sodium ascorbate as an electron donor, without the addition of a traditional molecular electron mediator. Comprehensive insights into the production of hydrogen on irradiation with visible light were achieved. Several polymers, including neutral polyvinyl pyrrolidone, anionic poly(sodium 4-styrene sulfonate) and poly(acrylic acid) not only stabilized the nanoparticles, but were also effective in the production of hydrogen. Under the optimum conditions, an outstanding apparent quantum efficiency of 12.8% for the evolution of hydrogen was achieved. The formation of self-assembled and spatially separated donor acceptor complexes via the non-covalent intermolecular interaction between PS and the polymer-Pt was pivotal in the efficient conversion of solar energy to hydrogen fuel. Important details of the photo-induced electron and energy transfer processes in the self-assembled artificial photosystems were determined by nanosecond transient absorption spectrometry and time-resolved fluorescence spectrometry. The initial step in the photo-catalytic production of hydrogen was a reductive quenching of the triplet excited state of the PS by sodium ascorbate, leading to a reduced form of PS, which could then be quickly quenched by the polymer. The rate-determining step was the electron transfer from PS to the catalyst via the polymer bridge. PMID- 25811663 TI - Structural and defect chemistry guidelines for Sr(V,Nb)O3-based SOFC anode materials. AB - Structural and defect chemistry guidelines were used for Nb-substituted SrVO3 delta materials, designed to meet SOFC anode requirements, with emphasis on redox tolerance, thermochemical compatibility with other SOFC materials, electrical conductivity and adjustable changes in oxygen stoichiometry for their prospective impact on electrocatalytic performance. SrV1-xNbxO3-delta (x = 0-0.30) ceramics were prepared by solid-state synthesis and sintered at 1773 K in a reducing atmosphere. XRD and SEM/EDS showed that under these conditions a single-phase cubic perovskite structure appears up to x ~ 0.25. Electrical conductivity is metallic-like and nearly p(O2)-independent. Although substitution by niobium decreases the conductivity, which still exceeds 100 S cm(-1) for x <= 0.20 at temperatures below 1273 K, it also expands the stability domain of the cubic perovskite phase and suppresses partly high thermochemical expansion characteristic of parent SrVO3-delta. The upper p(O2) limit of phase stability was found to shift from ~2 * 10(-15) atm for the undoped material to ~2 * 10(-12) atm for x = 0.30, whereas the average thermal expansion coefficient at 773-1223 K decreased from 22.7 * 10(-6) to 13.3 * 10(-6) K(-1). SrV1-xNbxO3-delta perovskites undergo oxidative decomposition in air, which causes dimensional and microstructural changes. However, sluggish kinetics of oxidation under inert gas conditions results in nearly reversible behavior in relatively short-term redox cycles between reducing and inert atmospheres. Subtle structural changes and a close correlation with point defect chemistry clarify these sluggish changes and provide guidelines to retain the metastability. PMID- 25811662 TI - Dual drug conjugated nanoparticle for simultaneous targeting of mitochondria and nucleus in cancer cells. AB - Effective targeting of mitochondria has emerged as an alternative strategy in cancer chemotherapy. However, considering mitochondria's crucial role in cellular energetics, metabolism and signaling, targeting mitochondria with small molecules would lead to severe side effects in cancer patients. Moreover, mitochondrial functions are highly dependent on other cellular organelles like nucleus. Hence, simultaneous targeting of mitochondria and nucleus could lead to more effective anticancer strategy. To achieve this goal, we have developed sub 200 nm particles from dual drug conjugates derived from direct tethering of mitochondria damaging drug (alpha- tocopheryl succinate) and nucleus damaging drugs (cisplatin, doxorubicin and paclitaxel). These dual drug conjugated nanoparticles were internalized into the acidic lysosomal compartments of the HeLa cervical cancer cells through endocytosis and induced apoptosis through cell cycle arrest. These nanoparticles damaged mitochondrial morphology and triggered the release of cytochrome c. Furthermore, these nanoparticles target nucleus to induce DNA damage, fragment the nuclear morphology and damage the cytoskeletal protein tubulin. Therefore, these dual drug conjugated nanoparticles can be successfully used as a platform technology for simultaneous targeting of multiple subcellular organelles in cancer cells to improve the therapeutic efficacy of the free drugs. PMID- 25811661 TI - A C-type lectin from Bothrops jararacussu venom disrupts Staphylococcal biofilms. AB - Bovine mastitis is a major threat to animal health and the dairy industry. Staphylococcus aureus is a contagious pathogen that is usually associated with persistent intramammary infections, and biofilm formation is a relevant aspect of the outcome of these infections. Several biological activities have been described for snake venoms, which led us to screen secretions of Bothrops jararacussu for antibiofilm activity against S. aureus NRS155. Crude venom was fractionated by size-exclusion chromatography, and the fractions were tested against S. aureus. Biofilm growth, but not bacterial growth, was affected by several fractions. Two fractions (15 and 16) showed the best activities and were also assayed against S. epidermidis NRS101. Fraction 15 was identified by TripleTOF mass spectrometry as a galactose-binding C-type lectin with a molecular weight of 15 kDa. The lectin was purified from the crude venom by D-galactose affinity chromatography, and only one peak was observed. This pure lectin was able to inhibit 75% and 80% of S. aureus and S. epidermidis biofilms, respectively, without affecting bacterial cell viability. The lectin also exhibited a dose-dependent inhibitory effect on both bacterial biofilms. The antibiofilm activity was confirmed using scanning electron microscopy. A pre formed S. epidermidis biofilm was significantly disrupted by the C-type lectin in a time-dependent manner. Additionally, the lectin demonstrated the ability to inhibit biofilm formation by several mastitis pathogens, including different field strains of S. aureus, S. hyicus, S. chromogenes, Streptococcus agalactiae, and Escherichia coli. These findings reveal a new activity for C-type lectins. Studies are underway to evaluate the biological activity of these lectins in a mouse mastitis model. PMID- 25811664 TI - Controlling the buckling instability of drying droplets of suspensions through colloidal interactions. AB - The present study focuses on the drying of droplets of colloidal suspensions using the Leidenfrost effect. At the end of drying, grains show different morphologies: cups or spheres depending on the ionic strength or zeta potential of the initial suspension. High ionic strengths and low absolute zeta potential values lead to spherical morphologies. A model based on the calculations of DLVO potentials has been implemented to extract a critical pressure, which provides a quantitative criterion for buckling whatever the initial formulation is. Particularly, the buckling time is quantitatively predicted from the interparticle interactions and shows an excellent agreement with experimental values. PMID- 25811657 TI - Clinical outcome and genetic differences within a monophyletic Dengue virus type 2 population. AB - The exact mechanisms of interplay between host and viral factors leading to severe dengue are yet to be fully understood. Even though previous studies have implicated specific genetic differences of Dengue virus (DENV) in clinical severity and virus attenuation, similar studies with large-scale, whole genome screening of monophyletic virus populations are limited. Therefore, in the present study, we compared 89 whole genomes of DENV-2 cosmopolitan clade III isolates obtained from patients diagnosed with dengue fever (DF, n = 58), dengue hemorrhagic fever (DHF, n = 30) and dengue shock syndrome (DSS, n = 1) in Singapore between July 2010 and January 2013, in order to determine the correlation of observed viral genetic differences with clinical outcomes. Our findings showed no significant difference between the number of primary and secondary infections that progressed to DHF and DSS (p>0.05) in our study cohort. Despite being highly homogenous, study isolates possessed 39 amino acid substitutions of which 10 substitutions were fixed in three main groups of virus isolates. None of those substitutions were specifically associated with DHF and DSS. Notably, two evolutionarily unique virus groups possessing C-P43T+NS1 S103T+NS2A-V83I+NS3-R337K+ NS3-I600T+ NS5-P136S and NS2A-T119N mutations were exclusively found in patients with DF, the benign form of DENV infections. Those mutants were significantly associated with mild disease outcome. These observations indicated that disease progression into DHF and DSS within our patient population was more likely to be due to host than virus factors. We hypothesize that selection for potentially less virulent groups of DENV-2 in our study cohort may be an evolutionary adaptation of viral strains to extend their survival in the human-mosquito transmission cycle. PMID- 25811665 TI - Effect of homopterocarpin, an isoflavonoid from Pterocarpus erinaceus, on indices of liver injury and oxidative stress in acetaminophen-provoked hepatotoxicity. AB - BACKGROUND: Novel hepatoprotectives are needed to address the increasing cases of liver problems worldwide. Pterocarpus erinaceus Poir (Fabaceae) ethanol stem bark extract (PE) and its constituent flavonoid, homopterocarpin (HP), were investigated for their protective property in acetaminophen-induced oxidative stress and liver damage. METHODS: Adult male albino rats were divided into nine groups. Seven groups were pretreated with PE (50-, 100-, and 150 mg/kg), HP (25-, 50-, and 75 mg/kg) or silymarin (25 mg/kg), respectively, once daily for 5 consecutive days and then administered acetaminophen (2 g/kg) on the 5th day. The control and acetaminophen-intoxicated groups received normal saline throughout the experimental period, with the latter group additionally receiving 2 g/kg acetaminophen on the 5th day. Administrations were performed po. RESULTS: In the acetaminophen-intoxicated group, there were significant increases (p<0.05) in serum activities of alanine aminotransferase (31.72+/-3.3 vs. 22.1+/-1.2 U/I), aspartate aminotransferase (185.1+/-10.1 vs. 103.83+/-13.3 U/I), bilirubin level and hepatic malondialdehyde (2.32+/-0.3 vs. 1.42+/-0.1 units/mg protein), accompanied with significant decreases (p<0.05) in hepatic reduced glutathione level (0.10+/-0.01 vs. 0.23+/-0.03 units/mg protein) and glutathione peroxidase activity (2.51+/-0.2 vs. 3.25+/-0.2 MUmol H2O2 consumed/min/mg protein) compared with the control. CONCLUSIONS: PE and HP ameliorated most of the observed biochemical alterations with HP appearing to show more potency. The results suggest that the flavonoid, homopterocarpin contributes to the hepatoprotective and antioxidant potentials of P. erinaceus extract. PMID- 25811666 TI - Novel association of FCGR2A polymorphism with age-related macular degeneration (AMD) and development of a novel CFH real-time genotyping method. AB - BACKGROUND: Age-related macular degeneration (AMD) is a degenerative ocular disease, which may lead to loss of central vision. In Caucasian populations, a strong correlation has been established with polymorphism Y402H (rs1061170) in the complement factor H gene (CFH). The H131R polymorphism (rs1801274) in the FCGR2A gene has been associated with many inflammatory diseases, but has not been investigated in relation to AMD. The goal of our study was the development of a novel method for Y402H (g.43097C>T) genotyping, the confirmation of its association with AMD in the Greek population and the investigation of the H131R polymorphism in AMD. METHODS: DNAs were extracted from blood samples of 120 patients with the severe wet form of AMD and 103 age- and sex-matched controls, all of whom were clinically evaluated. A real-time PCR and melting curve analysis method for Y402H genotyping was developed in the LightCycler platform, after in silico design of appropriate primers and probes. Genotyping for H131R was performed using a real-time PCR method previously described by our group. RESULTS: The novel genotyping method for Y402H in the CFH gene is fast, reproducible (Efficiency=1.79, reproducibility CVCq=3.33%, Tm C allele 53.36 degrees C and T allele 61.91 degrees C, DeltaTm=8.55) and accurate as results were confirmed with the gold standard DNA Sequencing method. CONCLUSIONS: The present study confirmed the association between CFH Y402H SNP and wet AMD in the Greek population (OR=1.77, p=0.002). FCGR2A H131R polymorphism was investigated for the first time in this present study for possible correlation with wet AMD and a statistically significant association was detected (OR=1.74, p=0.006), that awaits further confirmation in a larger set of samples. PMID- 25811667 TI - Uncertainty in measurement for 43 biochemistry, immunoassay, and hemostasis routine analytes evaluated by a method using only external quality assessment data. AB - BACKGROUND: International organizations require from medical laboratories a quantitative statement of the uncertainty in measurement (UM) to help interpret patient results. The French accreditation body (COFRAC) recommends an approach (SH GTA 14 IQC/EQA method) using both internal quality control (IQC) and external quality assessment (EQA) data. The aim of this work was to validate an alternative way to quantify UM using only EQA results without any need for IQC data. This simple and practical method, which has already been described as the long-term evaluation of the UM (LTUM), is based on linear regression between data obtained by participants in EQA schemes and target values. We used it for 43 routine analytes covering biochemistry, immunoassay, and hemostasis fields. METHODS: Data from 50 laboratories participating in ProBioQual (PBQ) EQA schemes over 25 months were used to obtain estimates of the median and 90th percentile LTUM and to compare them to the usual analytical goals. Then, the two UM estimation methods were compared using data from 20 laboratories participating in both IQC and EQA schemes. RESULTS: Median LTUMs ranged from 2.9% (sodium) to 16.3% (bicarbonates) for biochemistry analytes, from 12.6% (prothrombin time) to 18.4% (factor V) for hemostasis analytes when using the mean of all participants, and were around 10% for immunoassays when using the peer-group mean. Median LTUMs were, in most cases, slightly lower than those obtained with the SH GTA 14 method, whatever the concentration level. CONCLUSIONS: LTUM is a simple and convenient method that gives UM estimates that are reliable and comparable to those of recommended methods. Therefore, proficiency testing (PT) organizers are allowed to provide participants with an additional UM estimate using only EQA data and which could be updated at the end of each survey. PMID- 25811668 TI - Determination of 21-hydroxylase autoantibodies: inter-laboratory concordance in the Euradrenal International Serum Exchange Program. AB - BACKGROUND: 21-Hydroxylase autoantibodies (21OHAb) are markers of an adrenal autoimmune process that identifies individuals with autoimmune Addison's disease (AAD). Quality and inter-laboratory agreement of various 21OHAb tests are incompletely known. The objective of the study was to determine inter-laboratory concordance for 21OHAb determinations. METHODS: Sixty-nine sera from 51 patients with AAD and 51 sera from 51 healthy subjects were blindly coded by a randomization center and distributed to 14 laboratories that determined 21OHAb, either by an "in-house" assay (n=9) using in vitro-translated (35)S-21OH or luciferase-labeled 21OH or a commercial kit with (125)I-21OH (n=5). Main outcome measures were diagnostic accuracy of each participating laboratory and inter laboratory agreement of 21OHAb assays. RESULTS: Intra-assay coefficient of variation ranged from 2.6% to 5.3% for laboratories using the commercial kit and from 5.1% to 23% for laboratories using "in-house" assays. Diagnostic accuracy, expressed as area under ROC curve (AUC), varied from 0.625 to 0.947 with the commercial kit and from 0.562 to 0.978 with "in-house" methods. Cohen's kappa of inter-rater agreement was 0.603 among all 14 laboratories, 0.691 among "in-house" laboratories, and 0.502 among commercial kit users. Optimized cutoff levels, calculated on the basis of AUCs, increased the diagnostic accuracy of every laboratory (AUC >0.9 for 11/14 laboratories) and increased the Cohen's kappa of inter-rater agreement. Discrepancies in quantitation of 21OHAb levels among different laboratories increased with increasing autoantibody levels. CONCLUSIONS: The quality of 21OHAb analytical procedures is mainly influenced by selection of cutoff value and correct handling of assay materials. A standardization program is needed to identify common standard sera and common measuring units. PMID- 25811670 TI - Lack of major genome instability in tumors of p53 null rats. AB - Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT) activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions. PMID- 25811669 TI - Filament condition-specific response elements control the expression of NRG1 and UME6, key transcriptional regulators of morphology and virulence in Candida albicans. AB - Candida albicans is the most frequently isolated human fungal pathogen and can cause a range of mucosal and systemic infections in immunocompromised individuals. Morphogenesis, the ability to undergo a reversible transition from budding yeast to elongated filaments, is an essential virulence trait. The yeast to-filament transition is associated with expression of genes specifically important for filamentation as well as other virulence-related processes, and is controlled, in part, by the key transcriptional regulators Nrg1 and Ume6. Both of these regulators are themselves controlled at the transcriptional level by filament-inducing environmental cues, although little is known about how this process occurs. In order to address this question and determine whether environmental signals regulate transcription of UME6 and NRG1 via distinct and/or common promoter elements, we performed promoter deletion analyses. Strains bearing promoter deletion constructs were induced to form filaments in YEPD plus 10% serum at 37 degrees C, Spider medium (nitrogen and carbon starvation) and/or Lee's medium pH 6.8 (neutral pH) and reporter gene expression was measured. In the NRG1 promoter we identified several distinct condition-specific response elements for YEPD plus 10% serum at 37 degrees C and Spider medium. In the UME6 promoter we also identified response elements for YEPD plus 10% serum at 37 degrees C. While a few of these elements are distinct, others overlap with those which respond to Lee's pH 6.8 medium. Consistent with UME6 possessing a very long 5' UTR, many response elements in the UME6 promoter are located significantly upstream from the coding sequence. Our data indicate that certain distinct condition-specific elements can control expression of C. albicans UME6 and NRG1 in response to key filament-inducing environmental cues. Because C. albicans encounters a variety of host microenvironments during infection, our results suggest that UME6 and NRG1 expression can be differentially modulated by multiple signaling pathways to control filamentation and virulence in vivo. PMID- 25811673 TI - Probing organometallic reactions by time-resolved infrared spectroscopy in solution and in the solid state using quantum cascade lasers. AB - The photochemistry and photophysics of metal carbonyl compounds (W(CO)6, Cp*Rh(CO)2 (Cp* = eta(5)-C5Me5), and fac-[Re(CO)3(4,4'-bpy)2Br] [bpy = bipyridine]) have been examined on the nanosecond timescale using a time-resolved infrared spectrometer with an external cavity quantum cascade laser (QCL) as the infrared source. We show the photochemistry of W(CO)6 in alkane solution is easily monitored, and very sensitive measurements are possible with this approach, meaning it can monitor small transients with absorbance changes less than 10(-6) DeltaOD. The C-H activation of Cp*Rh(CO)(C6H12) to form Cp*Rh(CO)(C6H11)H occurs within the first few tens of nanoseconds following photolysis, and we demonstrate that kinetics obtained following deconvolution are in excellent agreement with those measured using an ultrafast laser-based spectrometer. We also show that the high flux and tunability of QCLs makes them suited for solid-state and time-resolved measurements. PMID- 25811672 TI - Influenza A and B Viruses but Not MERS-CoV in Hajj Pilgrims, Austria, 2014. PMID- 25811671 TI - Clinicopathologic predictors of survival in patients with desmoplastic melanoma. AB - BACKGROUND AND OBJECTIVES: Desmoplastic melanoma is a unique subtype of melanoma which typically affects older patients who often have comorbidities that can adversely affect survival. We sought to identify melanoma-specific factors influencing survival in patients with desmoplastic melanoma. METHODS: Retrospective review from 1993 to 2011 identified 316 patients with primary desmoplastic melanoma. Clinicopathologic characteristics were correlated with nodal status and outcome. RESULTS: Fifty-five patients (17.4%) had nodal disease: 33 had a positive sentinel lymph node biopsy and 22 developed nodal recurrences (no sentinel lymph node biopsy or false-negative sentinel lymph node biopsy). Nodal disease occurred more often in younger patients and in cases with mixed compared with pure histology (26.7% vs. 14.6%); both of these variables significantly predicted nodal status on multivariable analysis (p<0.05). After a median follow-up of 5.3 years, recurrence developed in 87 patients (27.5%), and 111 deaths occurred. The cause of death was known in 79 cases, with 47 deaths (59.5%) being melanoma-related. On multivariable analysis, Breslow thickness, mitotic rate >= 1/mm(2) and nodal status significantly predicted melanoma specific survival (p<0.05). CONCLUSIONS: Nodal status predicts melanoma-specific survival in patients with desmoplastic melanoma. However, since patients with desmoplastic melanoma represent an older population, and a considerable proportion of deaths are not melanoma-related (40.5%), comorbidities should be carefully considered in making staging and treatment decisions in this population. PMID- 25811674 TI - Acute Beetroot Juice Supplementation Does Not Improve Cycling Performance in Normoxia or Moderate Hypoxia. AB - Beetroot juice (BR) has been shown to lower the oxygen cost of exercise in normoxia and may have similar effects in hypoxia. We investigated the effect of BR on steady-state exercise economy and 10-km time trial (TT) performance in normoxia and moderate hypoxia (simulated altitude: ~2500 m). Eleven trained male cyclists (VO 2peak >= 60 ml . kg(-1) . min(-1)) completed four exercise trials. Two hours before exercise, subjects consumed 70 mL BR (~6 mmol nitrate) or placebo (nitrate-depleted BR) in a randomized, double-blind manner. Subjects then completed a 15-min self-selected cycling warm-up, a 15-min steady-state exercise bout at 50% maximum power output, and a 10-km time trial (TT) in either normoxia or hypoxia. Environmental conditions were randomized and single-blind. BR supplementation increased plasma nitrate concentration and fraction of exhaled nitric oxide relative to PL (p < .05 for both comparisons). Economy at 50% power output was similar in hypoxic and normoxic conditions (p > .05), but mean power output was greater in the normoxic TT relative to the hypoxic TT (p < .05). BR did not affect economy, steady-state SpO2, mean power output, or 10-km TT completion time relative to placebo in either normoxia or hypoxia (p > .05 in all comparisons). In conclusion, BR did not lower the oxygen cost of steady-state exercise or improve exercise performance in normoxia or hypoxia in a small sample of well-trained male cyclists. PMID- 25811675 TI - Two distinct molecular subtypes of chronic lymphocytic leukemia give new insights on the pathogenesis of the disease and identify novel therapeutic targets. AB - Biopsy samples of lymph nodes from 38 patients with CLL were analyzed. We found differential expression in 1092 genes in two different subgroups: 418 overexpressed in one subgroup and 674 in another. Molecular pathways identified in one subgroup appear to be characterized by greater dependence of signaling by cytokines and activation of the NFkB pathway, while in the other seem to depend on cell cycle. Despite having found a differential expression between both subgroups, none of these genes reached FDR < 0.25. We have not found significant association with survival or any prognostic factors. Analysis of the differences between normal lymph node and CLL in 253 genes with difference in the intensity of expression revealed upregulated genes different to BCR: CD40, TCL1, IL-7, and PAX5. Using large-scale molecular analysis, we may obtain information about molecular mechanisms of CLL pathogenesis and may contribute to the identification of new therapeutic targets. PMID- 25811676 TI - Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre "real-world" experience. AB - "Real life" data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3-164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML. PMID- 25811677 TI - Employment and activity limitations among adults with chronic obstructive pulmonary disease--United States, 2013. AB - Chronic obstructive pulmonary disease (COPD) is a group of progressive respiratory conditions, including emphysema and chronic bronchitis, characterized by airflow obstruction and symptoms such as shortness of breath, chronic cough, and sputum production. COPD is an important contributor to mortality and disability in the United States. Healthy People 2020 has several COPD-related objectives,* including to reduce activity limitations among adults with COPD. To assess the state-level prevalence of COPD and the association of COPD with various activity limitations among U.S. adults, CDC analyzed data from the 2013 Behavioral Risk Factor Surveillance System (BRFSS). Among U.S. adults in all 50 states, the District of Columbia (DC), and two U.S. territories, 6.4% (an estimated 15.7 million adults) had been told by a physician or other health professional that they have COPD. Adults who reported having COPD were more likely to report being unable to work (24.3% versus 5.3%), having an activity limitation caused by health problems (49.6% versus 16.9%), having difficulty walking or climbing stairs (38.4% versus 11.3%), or using special equipment to manage health problems (22.1% versus 6.7%), compared with adults without COPD. Smokers who have been diagnosed with COPD are encouraged to quit smoking, which can slow the progression of the disease and reduce mobility impairment. In addition, COPD patients should consider participation in a pulmonary rehabilitation program that combines patient education and exercise training to address barriers to physical activity, such as respiratory symptoms and muscle wasting. PMID- 25811678 TI - Mycoplasma pneumoniae outbreak in a long-term care facility--Nebraska, 2014. AB - On June 20, 2014, a Nebraska long-term care facility notified the East Central District Health Department (ECDHD) and Nebraska Department of Health and Human Services (NDHHS) of an outbreak of respiratory illness characterized by cough and fever in 22 residents and resulting in four deaths during the preceding 2 weeks. To determine the etiologic agent, identify additional cases, and implement control measures, Nebraska and CDC investigators evaluated the facility's infection prevention measures and collected nasopharyngeal (NP) and oropharyngeal (OP) swabs or autopsy specimens from patients for real-time polymerase chain reaction (PCR) testing at CDC. The facility was closed to new admissions until 1 month after the last case, droplet precautions were implemented, ill residents were isolated, and group activities were canceled. During the outbreak, a total of 55 persons experienced illnesses that met the case definition; 12 were hospitalized, and seven died. PCR detected Mycoplasma pneumoniae DNA in 40% of specimens. M. pneumoniae should be considered a possible cause of respiratory illness outbreaks in long-term care facilities. Morbidity and mortality from respiratory disease outbreaks at long-term care facilities might be minimized if facilities monitor for respiratory disease clusters, report outbreaks promptly, prioritize diagnostic testing in outbreak situations, and implement timely and strict infection control measures to halt transmission. PMID- 25811679 TI - Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. AB - During its February 2015 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended 9-valent human papillomavirus (HPV) vaccine (9vHPV) (Gardasil 9, Merck and Co., Inc.) as one of three HPV vaccines that can be used for routine vaccination. HPV vaccine is recommended for routine vaccination at age 11 or 12 years. ACIP also recommends vaccination for females aged 13 through 26 years and males aged 13 through 21 years not vaccinated previously. Vaccination is also recommended through age 26 years for men who have sex with men and for immunocompromised persons (including those with HIV infection) if not vaccinated previously. 9vHPV is a noninfectious, virus-like particle (VLP) vaccine. Similar to quadrivalent HPV vaccine (4vHPV), 9vHPV contains HPV 6, 11, 16, and 18 VLPs. In addition, 9vHPV contains HPV 31, 33, 45, 52, and 58 VLPs. 9vHPV was approved by the Food and Drug Administration (FDA) on December 10, 2014, for use in females aged 9 through 26 years and males aged 9 through 15 years. For these recommendations, ACIP reviewed additional data on 9vHPV in males aged 16 through 26 years. 9vHPV and 4vHPV are licensed for use in females and males. Bivalent HPV vaccine (2vHPV), which contains HPV 16, 18 VLPs, is licensed for use in females. This report summarizes evidence considered by ACIP in recommending 9vHPV as one of three HPV vaccines that can be used for vaccination and provides recommendations for vaccine use. PMID- 25811680 TI - Updated recommendations for the use of typhoid vaccine--Advisory Committee on Immunization Practices, United States, 2015. AB - These revised recommendations of the Advisory Committee on Immunization Practices update recommendations published in MMWR in 1994 and include updated information on the two currently available vaccines and on vaccine safety. They also include an update on the epidemiology of enteric fever in the United States, focusing on increasing drug resistance in Salmonella enterica serotype Typhi, the cause of typhoid fever, as well as the emergence of Salmonella serotype Paratyphi A, a cause of paratyphoid fever, against which typhoid vaccines offer little or no protection. PMID- 25811682 TI - Anti-Reflux Ureteral Stent with Polymeric Flap Valve Using Three-Dimensional Printing: An In Vitro Study. AB - PURPOSE: This article aims to describe the design of an anti-reflux ureteral stent with a polymeric flap valve and the fabrication methods using three dimensional (3D) printing. The stent effectively prevents backward flow with a negligible reduction in forward flow. Fabrication of miniaturized valves was easy with high precision and rapid prototyping. MATERIALS AND METHODS: The proposed stent comprised a 7F Double-J (DJ) stent and a polymeric flap valve. The valve was made of Tango Plus FLX980 and was fabricated using a 3D printer. Two types of stent were prepared for in vitro tests: DJ stents with (1) an uncoated valve (UCV) stent and (2) a parylene C coated valve (PCV) stent for enhanced biocompatibility. The flow characteristics of each stent were evaluated considering flow direction, parylene coating, and stent side holes, and were compared to the intact DJ stent. RESULTS: The forward flow rate for the distal portion of the UCV and PCV stents was 9.8 mL/min and 7.8 mL/min at applied pressure of 15 cm H2O (normal anterograde pressure in patients with stents), respectively. Backward flow rate for the distal portion of the UCV and PCV stents was decreased by 28 times and 8 times at applied pressure of 50 cm H2O (maximum bladder pressure), respectively, compared with the distal portion of the intact DJ stent. Forward flow rates of whole stents were 22.2 mL/min (UCV stent) and 20.0 mL/min (PCV stent) at applied pressure of 15 cm H2O, and backward flow rates of whole UCV and PCV stents were decreased by 8.3 times and 4.0 times at applied pressure of 50 cm H2O, respectively, compared with the intact DJ stent. CONCLUSIONS: The anti-reflux ureteral stent was successfully designed and fabricated using a 3D printer. In vitro studies showed that the stent effectively prevented backward flow while minimizing reduction in forward flow. PMID- 25811681 TI - Orthotopic transplantation of cryopreserved mouse ovaries and gonadotrophin releasing hormone analogues in the restoration of function following chemotherapy induced ovarian damage. AB - Therapy advances are constantly improving survival rates of cancer patients, however the toxic effects of chemotherapy drugs can seriously affect patients' quality of life. In women, fertility and premature ovarian endocrine dysfunction are of particular concern. It is urgently we find methods to preserve or reconstruct ovarian function for these women. This study compares GnRHa treatment with ovarian tissue cryopreservation and orthotopic transplantation in a chemotherapy-induced ovarian damage murine model. 56 inbred Lewis rats were divided into 4 treatment groups: Saline control (group I); cyclophosphamide only (group II); cyclophosphamide plus GnRHa (group III); cyclophosphamide and grafting of thawed cryopreserved ovaries (group IV). Body weight, estrous cycle recovery time, ovarian weight, morphology and follicle count, as well as breeding and fertility were compared among groups. Only group IV was able to restore to normal body weight by the end of the observation period and resumed normal estrous cycles in a shorter time compared to other treatment groups. There was a decrease in primordial follicles in all treatment groups, but group III had the greatest reduction. Although, there was no difference in pregnancy, only one animal littered normal pups in group II, none littered in group III and four littered in group IV. Thus, cryopreservation and orthotopic transplantation of ovarian tissue can restore the fertility of rats subjected to chemotherapy in a manner that is superior to GnRHa treatment. We also observed increased rates of hepatic, splenic and pulmonary haemorrhage in group III, suggesting there may be synergistic toxicity of GnRHa and cyclophosphamide. PMID- 25811683 TI - Close relationship of ruminant pestiviruses and classical Swine Fever virus. AB - To determine why serum from small ruminants infected with ruminant pestiviruses reacted positively to classical swine fever virus (CSFV)-specific diagnostic tests, we analyzed 2 pestiviruses from Turkey. They differed genetically and antigenically from known Pestivirus species and were closely related to CSFV. Cross-reactions would interfere with classical swine fever diagnosis in pigs. PMID- 25811685 TI - [The acedia and depression as care for the burial in the classic world and its contemporary echoes]. AB - This paper analyzes the concept of acedia as care for the burial of the dead in some Greek classic works from a philosophical point of view, pointing out the links between this care and the search for one's own identity, and the existential meaning of the human person. In addition to this view, the paper focalizes on the Jewish and Christian attitude toward the burial of the dead, in the Bible as well as in the writings of Patristic authors. Finally, this paper offers some psychoanalytic references on the subject echoing the assertions of the classics and proposes the relationship between acedia and depression. PMID- 25811684 TI - Andreas Vesalius (1514-1564) - an unfinished life. AB - The fame of Andreas Vesalius (1514-1564) rests on his anatomy text, De humani corporis fabrica, regarded as a seminal book in modern medicine. It was compiled while he taught anatomy at Padua, 1537-1543. Some of his findings challenged Galen's writings of the 2c AD, and caused De fabrica to be rejected immediately by classically trained anatomists. At age 29, Vesalius abandoned his studies and over the next two decades served as physician to Emperor Charles V of the Holy Roman Empire (HRE) and later to King Philip II of Spain in Madrid. In 1564, he sought to resume teaching anatomy in Padua, but release from royal service obliged him first to make a pilgrimage to Palestine. During the return voyage to Venice, he became ill and was put ashore alone on an Ionian island Zakynthos, where he died days later at age 50. PMID- 25811686 TI - Evolution of robots throughout history from Hephaestus to Da Vinci Robot. AB - Da Vinci robot is increasingly used for operations adding the advantages of robots to the favor of medicine. This is a historical article with the aim to present the evolution of robots in the medical area from the time of ancient myths to Renaissance and finally to the current revolutionary applications. We endeavored to collect several elegant narratives on the topic. The use of imagination could help the reader to find similarities. A trip from the Greek myths of Hephaestus through Aristotle and Leonardo Da Vinci to the robots of Karel Capek and Isaac Asimov and finally the invention of the medical robots is presented. PMID- 25811687 TI - [Smallpox vaccination in Koper district in 1830s]. AB - In the context of preventive measures against smallpox, this paper deals with some examples of vaccination which was carried out in the Koper district in the first half of the 19th century with special emphasis on general revaccination (1833) and vaccination of children (1835) which were promoted by the district physician Gian Andrea de Manzoni. In the time of his duty, the vaccination was regularly carried out in the town of Koper as well as in its surrounding, mostly rural localities within the district. Besides that, the revaccination of children and adults took place in case of the direct threat of the disease. With the analysis of existing nominative registers of the vaccinated, which are here discussed for the first time, a statistical research dealing with the vaccinated population structure by age and social status is being proposed, together with some starting points for reflection on the range and effect of these preventive measures. However, the author confronts some difficulties in the quantitative contextualization of the vaccinated within the present population of the area. Finally, some remaining questions regard also the mechanisms for persuading the population into the vaccination and the influence of the common attitude towards this practice on its actual range. PMID- 25811688 TI - [Analysis of civil hospitals in Pola (Pula) through a century of town history (1842-1947)]. AB - The purpose of this study is to present the history of civil hospitals present in Pula through the 19th and the first half of the 20th century. All circumstances which are related to their founding and development have been analysed, together with a number of complex events which had influenced them through several decades. Careful archival and bibliographic research has made it possible to present the above mentioned material which explains the most important aspects of hospital care in the Province of Istria in the processed period. The first communal sanatorium in Pula was founded in 1842, while the first city hospital was built in 1875. The extraordinary urban development of Pula in the last decade of the 19th century had led to an urgent need of building a bigger hospital complex which was built on the hill of St. Mihovil and solemnly opened 6th October, 1896. On the day of 3rd January, 1904 the complete medical institution became the property of the Province of Istria thus establishing the Provincial hospital of Pula. The reconstruction of the history of the civil hospitals in Pula has made it possible to identify the chronic difficulties through which the health care system in the province had gone through. The reasons for the explained status are mainly the result of financial and organisational problems that inevitably affected the quality of medical care available to the population. PMID- 25811689 TI - An incomplete fatal trepanation diagnosed on cremation remains (Rome, Italy, 2nd c. AD). AB - BACKGROUND: An original case of incomplete (and reasonably fatal) human trepanation is described in this short paper. The diagnosis was made on the cremated remains of a young adult individual who died in Rome, Italy during the 2nd century AD. CLINICAL PRESENTATION: The trepanation was incomplete, as death occurred quickly due to vascular lesions, according to the anatomic analysis of the bone piece. Comparable trepanation from Roman times are described and related to this case. CONCLUSION: Even if archaeological, this case highlights the possibility of such a diagnosis on post-fire fragmented bones. Very suggestive lesions of section are of great interest for the history of such a practice during classical Antiquity. Lastly, from a medical and forensic point of view, such a diagnosis may be of interest during any identification process and research for a cause of death during anthropological analyses. PMID- 25811690 TI - Liver abscess in ancient Greek and Greco-Roman texts. AB - OBJECTIVE: This paper presents liver abscesses, as studied in the ancient Greek and Greco-Roman bibliography. METHODS: Numerous references concerning this entity can be found in the writings of the Hippocratic doctors (5th cent. B.C.), Archigenes of Apamea (1st cent. A.D.), Galen (2nd cent. A.D.), Aretaeus of Cappadocia (2nd cent. A.D), Oribasius (4th cent. A.D.), Theophilus Protospatharius (7th cent. A.D.), and Paulus Nicaeensis (7th-10th cent. A.D.). RESULTS: In most cases the clinical manifestations, the prognosis and the method of treatment are presented. In all ancient writings we studied, the rupture of a liver abscess is also part of the main theme. In specific, the path that the fluid would follow after a rupture was considered to be a main prognostic factor, i.e. if the fluid "coursed into the stomach", the patient would definitely die. CONCLUSIONS: In this work, an attempt is also made to correlate the ancient descriptions to modern medical entities, such as amebic or pyogenic liver abscess. PMID- 25811691 TI - Mummification in the Ancient and New World. AB - In the Ancient and New World there was a custom to preserve the corpse in a natural and artificial way. Since Paleolithic man believed in an afterlife and even in Mesoamerica and the Andes cultures, care and ceremony were practiced to the burial of the dead in an ancestral cult. Mortuary rituals were developed in Pre-dynastic Egypt (4500-3100 BC) but apparently they had begun before in America, c. 5000 BC. Mummies served for assisting the soul to survive and for preventing the dead from frightening the livings. Incas arrived at a point of perfection in these practices after other Andean cultures but we should not forget their older predecessors, the Chinchorro culture on the arid coast of the Atacama Desert. Different steps in the technique can be distinguished in both worlds: natural desiccation covered by animal skins, methods to protect the body skin and flesh removal, replacement with clay; black, red or mud-coated corpses, evisceration, body cavity treatment, cleansing and anointing the interior, brain removal, mummified bodies, corpses covered with natron, before being washed and bandaged or wrapped. It will be necessary to carefully check dates, techniques and periods in the two zones to establish exactly the evolution of the methods applied. PMID- 25811692 TI - Cases of aphasia in a work on medicine from the 16th century. AB - The purpose of this paper is to bring to the attention of the international community the role in the history of aphasiology of the eminent Renaissance figure, the Extremaduran Francisco Arceo de Fregenal. To present the subject, after a brief biography of this surgeon, we will trace the development of the concept of aphasia up to the 16th century. In some ancient cultures we find that this disorder was described as a "cerebral accident", to be presented subsequently in the Middle Ages as a divine punishment, only for the original idea to be taken up again during the Renaissance. This return to the concept of the early civilisations was not to lead to the formal classification of this condition however, until the studies of Broca and Wernicke were published in the 19th century. The contribution of Arceo lies in the description of clinical cases included in his book De Recta cvrandorum, which are presented in their original written version in Latin accompanied by a translation in English. The first of these cases tells of spontaneous recovery from the disease, and the second of the evolution of a patient with aphasia secondary to traumatic brain injury following surgery. Despite the great value of Arceo's report, the historical context and his professional attitude did not allow for a localisationist interpretation of the concept of aphasia. PMID- 25811693 TI - From the "Art of cutting the umbilical cord" by Dr. J.B. Lalangue to the "Midwifery" by Prof.Dr. A. Lobmayer and Prof.Dr. F.Durst. AB - A short survey of midwifery and obstetrics development in the northwest part of Croatia is presented in this paper, from J.B. Lalangue's coming to VaraZdin, through the founding and work of Midwifery School and National Maternity in Zagreb to the persons without whom this would not be possible or it would be quite different. Lalangue, being an expert on obstetrics, noticed in a very short period of time, all misfortune caused by incompetent work of then's midwives, so he published the book "Brevis institutio de re obstetritia illiti kratek navuk od mestrie pupkorezne?", and started first midwifery courses for peasant women. Focus of this paper is on Prof. Dr Antun Lobmayer textbook analyses, and he was the first professor of midwifery, and the director of the "Royal Midwifery School" and the "National Maternity" in Zagreb. Textbooks for midwives named "Midwifery- Learning Book for Midwives', had six editions over 50 years and they represent the basis of Croatian midwifery textbook literature. Prof. Dr Franjo Durst, the assistant and successor of Prof. Lobmayer completed and partially revised the last two editions.Besides the biographies of the "rdquor;Midwifery School" professors, an analyssis and critical review on the mentioned textbooks is given from today' s medicine point of view. PMID- 25811694 TI - The loop of Henle as the milestone of mammalian kindey concentrating ability: a historical review. AB - The first description of the renal tubules is attributed to Lorenzo Bellini in 1662 and four years later Marcello Malpighi described the glomerulus. In 1842 Sir William Bowman described the capsule that surrounds the Malpighian body and its connection with the renal tubule and introduced the "excretory" hypothesis of urine formation. In the same year, Carl Ludwig introduced the "filtration reabsorption" hypothesis of urine formation. Bowman's hypothesis was accepted by the so-called "vitalists" and Ludwig's hypothesis by the so-called "mechanists". In the middle of this confliction, Jacob Henle described in 1862 the homonymous "U" shaped loop but his discovery has neglected. In 1942 Werner Kuhn, a physical chemist, proposed that the loop of Henle may be the natural analog of the hairpin countercurrent multiplication system which concentrates urine in mammalian kidneys. In 1951 Kuhn, Hargitay and Wirz showed experimentally that the loop of Henle was the most important part of the countercurrent multiplication system of urine-concentrating mechanism in mammalian kidneys. The new theory was accepted by English-speaking scientists later, in 1958, when Carl Gottschalk and Margaret Mylle published their experimental work and proved that Kuhn's theory was correct. Gottschalk summarized the evidence of the accumulated knowledge in 1962, three centuries after the first description of renal tubules and one century after description of Henle's loop. PMID- 25811695 TI - Synthesis of a 12R-type hexagonal perovskite solid solution Sr3NdNb(3-x)Ti(x)O(12 delta) and the influence of acceptor doping on electrical properties. AB - A solid solution forms for Sr3NdNb(3-x)Ti(x)O(12-delta) with approximate limits 0 <= x <= 0.06. The system crystallizes with a 12R-type hexagonal perovskite structure in the space group R3, as determined by neutron diffraction and selected area electron diffraction. The electrical properties of the end members have been investigated by impedance spectroscopy in the temperature range 550-800 degrees C under various gas atmospheres and as a function of oxygen and water vapour partial pressure. Proton transport dominates under wet oxidising conditions in the temperature range 550-700 degrees C, as confirmed by the H(+)/D(+) isotope effect. Acceptor doping considerably enhances proton conductivity with a value of 3.3 * 10(-6) S cm(-1) for the bulk response of x = 0.06 at 700 degrees C in moistened air. The presence of a -1/4 slope for both doped and undoped samples in the range 10(-19) <= pO2 <= 10(-8) atm at 900 degrees C indicates n-type transport under reducing conditions following the extrinsic model attributable to acceptor centres. The conductivity is essentially independent of pO2 at 600 degrees C under dry oxidising conditions, consistent with oxide-ion transport; a positive power-law dependence at higher temperature indicates extrinsic behaviour and a significant electron-hole contribution. The dielectric constant at RT of nominally stoichiometric Sr3NdNb3O12 is epsilonr ~ 37, with a moderately high quality factor of Q * f ~ 16,400 GHz at fr ~ 6.4 GHz. The temperature coefficient of resonant frequency of x = 0 is tauf ~ 12 ppm degrees C(-1), which lowers to -3 ppm degrees C(-1) for the Ti-doped phase x = 0.06. PMID- 25811696 TI - Anaplastic Large Cell Lymphoma Occurring in Women with Breast Implants: Analysis of 173 Cases, and Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Systematic Review. PMID- 25811697 TI - Reply: The Role of Estrogen in the Modulation of Autologous Fat Graft Outcomes. PMID- 25811698 TI - Reply: The Effects of Whole-Vault Cranioplasty versus Strip Craniectomy on Long Term Neuropsychological Outcomes in Sagittal Craniosynostosis. PMID- 25811699 TI - Modified Transconjunctival Lower Lid Approach for Orbital Fractures in East Asian Patients: The Lateral Paracanthal Incision Revisited. PMID- 25811700 TI - The Effects of Whole-Vault Cranioplasty versus Strip Craniectomy on Long-Term Neuropsychological Outcomes in Sagittal Craniosynostosis. PMID- 25811702 TI - On the role of gold nanoparticles in the selective photooxidation of 2-propanol over Au/TiO2. AB - The gas-phase photooxidation of 2-propanol over Au/TiO2 and TiO2 was studied by infrared spectroscopy and online mass spectrometry to gain insight into the mechanism and the role of gold. The presence of O2 was found to be essential for the formation of acetone under UV irradiation at room temperature. In the presence of gold nanoparticles the rate of acetone formation was increased compared to pure TiO2. Baseline bending in the ATR-IR spectra was used as a tool to monitor the accumulation of excess electrons. Electron accumulation was absent in the presence of gold and O2 suggesting that the gold nanoparticles act as co catalysts enhancing the rate of electron transfer from TiO2 to adsorbed O2 species. PMID- 25811701 TI - Mechanistic insights into the reactions of hydride transfer versus hydrogen atom transfer by a trans-dioxoruthenium(VI) complex. AB - A mononuclear high-valent trans-dioxoruthenium(VI) complex, trans [Ru(VI)(TMC)(O)2](2+) (TMC = 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane), was synthesized and characterized by various spectroscopic techniques and X-ray crystallography. The reactivity of the trans [Ru(VI)(TMC)(O)2](2+) complex was investigated in hydride transfer and hydrogen atom transfer reactions. The mechanism of hydride transfer from dihydronicotinamide adenine dinucleotide (NADH) analogues to trans [Ru(VI)(TMC)(O)2](2+), which proceeds via a proton-coupled electron transfer (PCET), followed by a rapid electron transfer (ET), has been proposed by the observation of a good linear correlation between the log rate constants of trans [Ru(VI)(TMC)(O)2](2+) and p-chloranil (Cl4Q) and a large kinetic isotope effect (KIE) value of 13(1). In the case of the oxidation of alkyl hydrocarbons by the trans-[Ru(VI)(TMC)(O)2](2+) complex, the second-order rate constants were dependent on the C-H bond dissociation energy (BDE) of the substrates, and a large KIE value of 26(2) was obtained in the oxidation of xanthene and deuterated xanthene-d2 by the trans-[Ru(VI)(TMC)(O)2](2+) complex, indicating that the C-H bond activation of alkyl hydrocarbons proceeds via an H-atom abstraction in the rate-determining step. PMID- 25811704 TI - Classical dynamics of H2O vibrational self-relaxation. AB - The vibrational self-relaxation rate constants of the (001), (100), (020), and (010) states of H2O from 295 to 2500 K are calculated, using ~1.6 * 10(6) classical trajectories with Gaussian binning for determining product vibrational quantum numbers. The calculations use a new H2O-H2O potential surface obtained by fitting 1.25 * 10(5) ab initio geometry points at the CCSD(T)//cc-pvtz level of theory. The resulting vibrational self-relaxation rate constants are generally within a factor of 2 of the measured data, which are large in magnitude and tend to increase with decreasing temperature. At lower temperatures, the calculations show long-lived (20 ps and longer) H2O-H2O collision complexes which accompany vibrational relaxation. Product rotational and translational energy distributions are investigated, and joint vibrational state and molecule-specific relaxation rate constants are presented. PMID- 25811703 TI - Graphene oxide-encoded Ag nanoshells with single-particle detection sensitivity towards cancer cell imaging based on SERRS. AB - Developing ultrasensitive Raman nanoprobes is one of the emerging interests in the field of biosensing and bioimaging. Herein, we constructed a new type of surface-enhanced resonance Raman scattering nanoprobe composed of an Ag nanoshell as a surface-enhanced Raman scattering-active nanostructure, which was encapsulated with 4,7,10-trioxa-1,13-tridecanediamine-functionalized graphene oxide as an ultrasensitive Raman reporter exhibiting strong resonance Raman scattering including distinct D and G modes. The designed nanoprobe was able to produce much more intense and simpler Raman signals even at a single particle level than the Ag nanoshell bearing a well-known Raman reporter, which is beneficial for the sensitive detection of a target in a complex biological system. Finally, this ultrasensitive nanoprobe successfully demonstrated its potential for bioimaging of cancer cells using Raman spectroscopy. PMID- 25811706 TI - Novel apical coring device for apicoaortic conduit insertion to treat off-pump aortic stenosis, coronary disease, and lung cancer. AB - The surgical treatment of concomitant cardiac disease and lung cancer represents a challenge. We report the case of a 66-year-old high-risk female patient with severe aortic stenosis as well as severely impaired left ventricular function associated with coronary artery disease involving the left anterior descending artery complicated from a severe functional mitral regurgitation in which an early-stage non-small cell carcinoma was incidentally discovered during workup. Because of the possibility of potential negative impact of cardiopulmonary bypass on the cancer prognosis and the severe impairment of systolic function of the left ventricle that impeded the treatment of lung cancer as the first step of such a complex treatment, we planned to treat all the diseases in a single-stage procedure. Using an automated delivering system composed of a ventricular connector (Correx AVB; Correx, Inc, Waltham, MA USA), we were able to perform an apicoaortic bypass as well as a left anterior descending revascularization using the left internal thoracic artery, both on a beating heart without the aid of cardiopulmonary bypass and a three-segmentectomy of the left upper lobe with the removal of paraaortic nodes. Six months postoperatively, she was asymptomatic with a noticeable increase of systolic function, a mild mitral incompetence, and no appearance of tumor recurrence. To the best of our knowledge, this is the first case described in the literature in which three major problems involving cardiac valves, coronary arteries, and the lung have been treated in one stage without cardiopulmonary bypass. PMID- 25811707 TI - Long-term outcomes after off-pump or conventional coronary artery bypass grafting within a veteran population. AB - OBJECTIVE: Recently published data indicate that outcomes for off-pump coronary artery bypass grafting (OPCABG) may be inferior to conventional CABG (cCABG) within the Veteran population, but this has been only partly addressed within high-volume off-pump centers. Here, we seek to examine the long-term outcomes for these patients within the Veteran population at a single institution well experienced with OPCABG. METHODS: With the use of a preexisting in-house database, all patients who had undergone isolated CABG from 2000 to 2011 (n = 1125) were identified. From these data, 18 demographic and risk factors were compared and used to create a propensity score, which was used for matching between groups (OPCABG vs cCABG). The primary end point examined was death. Survival was analyzed using the Kaplan-Meier method and the log-rank test. Groups were compared using a Student t test or Fisher exact test, where appropriate. RESULTS: Unmatched OPCABG and cCABG groups were found to have significant differences in risk factors, with the OPCABG being a higher-risk population by ejection fraction, chronic obstructive pulmonary disease status, age, and renal function, among others (all P < 0.05). Kaplan-Meier analysis of the unmatched groups demonstrated an increased mortality rate within the higher-risk OPCABG group (P = 0.0002). With the use of propensity score matching, 337 OPCABG patients were then matched to 337 cCABG controls. Comparison of demographic and risk factors between these matched groups did not demonstrate any statistically significant difference. When Kaplan-Meier analysis was performed for the matched groups, there was no statistically significant difference in survival. In addition, in the matched data set, OPCABG patients had a shorter average length of stay (8.2 vs 9.7 days, P = 0.022), shorter operative time (205 vs 270 minutes, P < 0.001), and lower rate of bleeding complications (0.9% vs 3.6%, P = 0.032). CONCLUSIONS: In this high-volume off-pump center, matched OPCABG survival is similar to cCABG. Although recent data indicate that OPCABG survival may be worse than that of cCABG within the entire Veteran population, in centers well experienced with OPCABG, this does not seem to hold true. In addition, the benefit of decreased length of stay and lower morbidity rates seems to be significant. Further study of the long-term outcomes of OPCABG in high-volume Veteran's centers is warranted. PMID- 25811708 TI - Cost-benefit analysis of robotic versus nonrobotic minimally invasive mitral valve surgery. AB - OBJECTIVE: To date, a direct comparison of minimally invasive mitral valve repair or replacement (mini-MVR) versus robotic MVR is lacking; therefore, the purpose of this study was to address this deficit and compare mini-MVR with robotic MVR from a cost-benefit perspective. METHODS: From a total of 759 literature citations, 21 studies were included for statistical comparisons of benefit outcomes, whereas 3 studies and our institutional experience were used to compare costs. RESULTS: The total cost per case exceeding that of conventional MVR is approximately $2063.90 for robotic MVR and $271 for mini-MVR. Mean 30-day mortality rates for mini-MVR and robotic MVR groups were 1.24% and 0.55%, respectively [106/8548 vs 6/1089; odds ratio (OR), 2.27; P = 0.052]. The conversion rate to conventional MVR was 0.77% in mini-MVR and 1.83% in robotic MVR (35/5092 vs 22/1046; OR, 0.32; P < 0.001). The rate of neurologic events was 1.32% in mini-MVR and 2.37% in robotic MVR (109/8257 vs 20/845; OR, 0.55; P = 0.02). Postoperative atrial fibrillation was seen in 11.42% of mini-MVR patients and in 19.67% of robotic MVR patients (371/3249 vs 203/1032; OR, 0.53, P < 0.001). Mean cardiopulmonary bypass time was longer in mini-MVR (137.4 vs 130.4 minutes), whereas cross-clamp time was shorter (82.2 vs 96.7 minutes). CONCLUSIONS: Our comparative analysis provides insights into the clinical benefits versus variable costs relationship related to mini-MVR and robotic MVR. PMID- 25811709 TI - Involvement of the TPJ area in processing of novel global forms. AB - The neuropsychological syndrome "simultanagnosia" is characterized by the inability to integrate local elements into a global entity. This deficit in Gestalt perception is mainly apparent for novel global structures administered in clinical tests or unfamiliar visual scenes. Recognition of familiar complex objects or well-known visual scenes is often unaffected. Recent neuroimaging studies and reports from simultanagnosia patients suggest a crucial involvement of temporoparietal brain areas in processing of hierarchically organized visual material. In this study, we investigated the specific role of the TPJ in Gestalt perception. On the basis of perceptual characteristics known from simultanagnosia, we hypothesized that TPJ is dominantly involved in processing of novel object arrangements. To answer this question, we performed a learning study with hierarchical stimuli and tested behavioral and neuronal characteristics of Gestalt perception pre- and posttraining. The study included 16 psychophysical training sessions and two neuroimaging sessions. Participants improved their behavioral performance for trained global stimuli and showed limited transfer to untrained global material. We found significant training dependent neuronal signal modulations in anterior right hemispheric TPJ regions. These activation changes were specific to trained global stimuli, whereas no systematic neuronal response changes were observed for recognition of untrained global stimuli, local elements and regular objects that served as control stimuli. In line with perceptual characteristics in simultanagnosia, the results argue for an involvement of TPJ in processing of novel global structures. We discuss the signal modulations in the context of a more efficient or different neuronal strategy to process familiar global stimuli. PMID- 25811711 TI - Basic level category structure emerges gradually across human ventral visual cortex. AB - Objects can be simultaneously categorized at multiple levels of specificity ranging from very broad ("natural object") to very distinct ("Mr. Woof"), with a mid-level of generality (basic level: "dog") often providing the most cognitively useful distinction between categories. It is unknown, however, how this hierarchical representation is achieved in the brain. Using multivoxel pattern analyses, we examined how well each taxonomic level (superordinate, basic, and subordinate) of real-world object categories is represented across occipitotemporal cortex. We found that, although in early visual cortex objects are best represented at the subordinate level (an effect mostly driven by low level feature overlap between objects in the same category), this advantage diminishes compared to the basic level as we move up the visual hierarchy, disappearing in object-selective regions of occipitotemporal cortex. This pattern stems from a combined increase in within-category similarity (category cohesion) and between-category dissimilarity (category distinctiveness) of neural activity patterns at the basic level, relative to both subordinate and superordinate levels, suggesting that successive visual areas may be optimizing basic level representations. PMID- 25811710 TI - The contribution of attentional lapses to individual differences in visual working memory capacity. AB - Attentional control and working memory capacity are important cognitive abilities that substantially vary between individuals. Although much is known about how attentional control and working memory capacity relate to each other and to constructs like fluid intelligence, little is known about how trial-by-trial fluctuations in attentional engagement impact trial-by-trial working memory performance. Here, we employ a novel whole-report memory task that allowed us to distinguish between varying levels of attentional engagement in humans performing a working memory task. By characterizing low-performance trials, we can distinguish between models in which working memory performance failures are caused by either (1) complete lapses of attention or (2) variations in attentional control. We found that performance failures increase with set-size and strongly predict working memory capacity. Performance variability was best modeled by an attentional control model of attention, not a lapse model. We examined neural signatures of performance failures by measuring EEG activity while participants performed the whole-report task. The number of items correctly recalled in the memory task was predicted by frontal theta power, with decreased frontal theta power associated with poor performance on the task. In addition, we found that poor performance was not explained by failures of sensory encoding; the P1/N1 response and ocular artifact rates were equivalent for high- and low performance trials. In all, we propose that attentional lapses alone cannot explain individual differences in working memory performance. Instead, we find that graded fluctuations in attentional control better explain the trial-by-trial differences in working memory that we observe. PMID- 25811713 TI - Suited versus unsuited analog astronaut performance using the Aouda.X space suit simulator: the DELTA experiment of MARS2013. AB - Space suit simulators are used for extravehicular activities (EVAs) during Mars analog missions. Flight planning and EVA productivity require accurate time estimates of activities to be performed with such simulators, such as experiment execution or traverse walking. We present a benchmarking methodology for the Aouda.X space suit simulator of the Austrian Space Forum. By measuring and comparing the times needed to perform a set of 10 test activities with and without Aouda.X, an average time delay was derived in the form of a multiplicative factor. This statistical value (a second-over-second time ratio) is 1.30 and shows that operations in Aouda.X take on average a third longer than the same operations without the suit. We also show that activities predominantly requiring fine motor skills are associated with larger time delays (between 1.17 and 1.59) than those requiring short-distance locomotion or short-term muscle strain (between 1.10 and 1.16). The results of the DELTA experiment performed during the MARS2013 field mission increase analog mission planning reliability and thus EVA efficiency and productivity when using Aouda.X. PMID- 25811712 TI - Sequence variability and geographic distribution of Lassa virus, Sierra Leone. AB - Lassa virus (LASV) is endemic to parts of West Africa and causes highly fatal hemorrhagic fever. The multimammate rat (Mastomys natalensis) is the only known reservoir of LASV. Most human infections result from zoonotic transmission. The very diverse LASV genome has 4 major lineages associated with different geographic locations. We used reverse transcription PCR and resequencing microarrays to detect LASV in 41 of 214 samples from rodents captured at 8 locations in Sierra Leone. Phylogenetic analysis of partial sequences of nucleoprotein (NP), glycoprotein precursor (GPC), and polymerase (L) genes showed 5 separate clades within lineage IV of LASV in this country. The sequence diversity was higher than previously observed; mean diversity was 7.01% for nucleoprotein gene at the nucleotide level. These results may have major implications for designing diagnostic tests and therapeutic agents for LASV infections in Sierra Leone. PMID- 25811714 TI - Spontaneous resolution upon crystallization of allenyl-bis-phosphine oxides. AB - The first example of 'spontaneous resolution by crystallization' in allene chemistry, by means of crystal structures and solid state CD spectra of the R and S enantiomers, is presented. These allenes are prepared by the simple reaction of Ph2PCl with o-nitro functionalized propargyl alcohols. PMID- 25811715 TI - Host APOBEC3G protein inhibits HCV replication through direct binding at NS3. AB - Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G's C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3's helicase and NTPase activity. Binding of hA3G to the C terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents. PMID- 25811717 TI - Correction: Integrated exon level expression analysis of driver genes explain their role in colorectal cancer. PMID- 25811716 TI - Type 2 Diabetes is a Delayed Late Effect of Whole-Body Irradiation in Nonhuman Primates. AB - One newly recognized consequence of radiation exposure may be the delayed development of diabetes and metabolic disease. We document the development of type 2 diabetes in a unique nonhuman primate cohort of monkeys that were whole body irradiated with high doses (6.5-8.4 Gy) 5-9 years earlier. We report here a higher prevalence of type 2 diabetes in irradiated monkeys compared to age matched nonirradiated monkeys. These irradiated diabetic primates demonstrate insulin resistance and hypertriglyceridemia, however, they lack the typical obese presentation of primate midlife diabetogenesis. Surprisingly, body composition analyses by computed tomography indicated that prior irradiation led to a specific loss of visceral fat mass. Prior irradiation led to reductions in insulin signaling effectiveness in skeletal muscle and higher monocyte chemoattractant protein 1 levels, indicative of increased inflammation. However, there was an absence of large defects in pancreatic function with radiation exposure, which has been documented previously in animal and human studies. Monkeys that remained healthy and did not become diabetic in the years after irradiation were significantly leaner and smaller, and were generally smaller and younger at the time of exposure. Irradiation also resulted in smaller stature in both diabetic and nondiabetic monkeys, compared to nonirradiated age-matched controls. Our study demonstrates that diabetogenesis postirradiation is not a consequence of disrupted adipose accumulation (generalized or in ectopic depots), nor generalized pancreatic failure, but suggests that peripheral tissues such as the musculature are impaired in their response to insulin exposure. Ongoing inflammation in these animals appears to be a consequence of radiation exposure and can interfere with insulin signaling. The reasons that some animals remain protected from diabetes as a late effect of irradiation are not clear, but may be related to body size. The translational relevance for these results suggest that muscle may be an important and underappreciated target organ for the delayed late effect of whole-body irradiation, leading to increased risk of insulin resistance and diabetes development. PMID- 25811718 TI - Treatment of corneal perforation with lenticules from small incision lenticule extraction surgery: a preliminary study of 6 patients. AB - PURPOSE: To evaluate the use of lenticules extracted using small incision lenticule extraction (SMILE) surgery as a surgical alternative for wound closure in corneal perforation. METHODS: Corneal lenticules obtained through SMILE surgery with central thickness >100 MUm were fixed over corneal perforation sites using 10-0 nylon interrupted stitches. Patients were monitored for a minimum of 1 year and were assessed using slit-lamp microscopy, fluorescein, digital tonometry, and best spectacle-corrected visual acuity (BSCVA) measurements. Postoperative complications throughout the study period were recorded. RESULTS: Corneal perforations were successfully sealed in all 6 patients; 3 patients (50%) exhibited improved postoperative BSCVA. Between 3 and 4 weeks after the operation, part of the lenticules became incorporated into the corneal stroma and complete reepithelialization was achieved. During the follow-up period of 12 months, no evidence of infection, relapse, or perforation was detected in any patient. CONCLUSIONS: These preliminary findings suggest that the use of corneal lenticules may be a safe and effective surgical alternative for corneal perforation closure, with potential clinical application as relatively simple and inexpensive temporary measures to improve the condition of the cornea for further definitive interventions. PMID- 25811719 TI - Prevention and treatment of corneal graft rejection: current practice patterns of the Cornea Society (2011). AB - PURPOSE: To analyze current practice patterns in the prevention and treatment of corneal graft rejection for both penetrating keratoplasty (PK) and endothelial keratoplasty (EK) and to compare these patterns with previously reported practices. METHODS: In 2011, an electronic survey was sent to 670 members of the Cornea Society worldwide addressing the routine postoperative management of corneal transplants at different time points, treatment of various manifestations of corneal graft rejection, and preferred surgical techniques. RESULTS: A total of 204 of 670 surveys (30%) were returned and evaluated. All respondents used topical corticosteroids for routine postoperative management and treatment of endothelial graft rejection. Prednisolone was the topical steroid of choice in all clinical scenarios, similar to previous surveys from 1989 to 2004. Use of subconjunctival and systemic steroids increased for many scenarios of probable and definite graft rejection. Routine use of prednisolone decreased by approximately 10% from previous surveys, whereas difluprednate was used in 13% of high-risk eyes during the first 6 months. Dexamethasone, fluorometholone, and loteprednol use remained stable. Adjunctive topical cyclosporine use increased significantly for PK and EK. EK was the preferred technique for endothelial dysfunction, whereas PK and deep anterior lamellar keratoplasty were both used for keratoconus and anterior scars. Most respondents (75%) felt that graft rejection occurs more frequently after PK than after EK. CONCLUSIONS: Prednisolone remains the treatment of choice for management and treatment of graft rejection; however, since the introduction of difluprednate, its use has declined slightly since the introduction of difluprednate. Despite perceived differences in rejection rates, there were no differences in prophylactic steroid treatment for PK and EK. PMID- 25811720 TI - Corneal Fine Needle Diathermy With Adjuvant Bevacizumab to Treat Corneal Neovascularization in Children. AB - PURPOSE: To report the outcomes of corneal fine needle diathermy (FND) with adjuvant intrastromal and subconjunctival bevacizumab injection for corneal neovascularization (CN) in children. METHODS: Medical records of all children who had undergone FND with adjuvant bevacizumab injection were reviewed retrospectively. Treatment efficacy was evaluated by changes in visual acuity, regression of CN, and clearing of lipid deposits with the aid of slit-lamp color images that were taken before surgical intervention and at last follow-up visit. Postoperative complications were recorded and served to assess the safety of the procedure. RESULTS: Nine eyes of 9 patients were included in the study. The mean age of the patients was 8.4 +/- 4.2 years (4-15 years) and the mean follow-up time was 18.7 +/- 12.2 months (5-35 months). Three eyes had a history of herpes simplex keratitis (HSK), 3 eyes had complete corneal anesthesia, 2 eyes had CN following suture tract infection after corneal transplant for HSK scar and limbal dermoid excision, and 1 eye had blepharokeratoconjunctivitis. After treatment, 8 eyes had complete CN resolution, and 1 eye with corneal anesthesia following brain tumor resection had partial regression in vessel distribution and size. Lipid deposition clearance lagged behind CN resolution. Mean duration of CN before treatment was 15.3 +/- 14.0 months (1-37 months). Mean corrected distance visual acuity before and after surgery was 0.66 +/- 0.31 and 0.50 +/- 0.37 logMAR, respectively (P = 0.02). CONCLUSIONS: Corneal FND with adjuvant bevacizumab injection is effective at treating sectorial corneal vessels in children. PMID- 25811721 TI - Corneal stromal demarcation line determined with anterior segment optical coherence tomography following a very high intensity corneal collagen cross linking protocol. AB - PURPOSE: To evaluate corneal stromal demarcation line depth after very high intensity (18 mW/cm) ultraviolet-A irradiation for a 5-minute corneal collagen cross-linking (CXL) protocol with the use of anterior segment optical coherence tomography. METHODS: This prospective interventional study enrolled 14 patients (18 eyes) with progressive keratoconus who underwent CXL with an ultraviolet-A irradiation intensity of 18 mW/cm for 5 minutes. One month postoperatively, corneal stromal demarcation line depth was measured with the use of anterior segment optical coherence tomography by 2 independent observers. The rate of reepithelialization and endothelial cell density at a 3-month follow-up period were also evaluated. RESULTS: No intraoperative or postoperative complications were observed in any of the patients. No statistically significant difference between the 2 observers' measurements was observed (P = 0.989). Mean corneal stromal demarcation line depth was 223 +/- 32 MUm (range, 159-265 MUm). The mean endothelial cell density decreased from 2714 +/- 174 preoperatively to 2671 +/- 192 at 3 months postoperatively; however, this decrease was not statistically significant (P = 0.221). CONCLUSIONS: Corneal stromal demarcation line depth after a very high intensity 5-minute CXL protocol seems to be shallower than the standard Dresden protocol. PMID- 25811723 TI - Ocular surface reconstruction with keratolimbal allograft for the treatment of severe or recurrent symblepharon. AB - PURPOSE: To describe an ocular surface reconstruction technique using keratolimbal allograft (KLAL) tissue to repair and treat severe or recurrent symblepharon. METHODS: Five eyes of 5 patients (age 23-71 years) with severe or recurrent symblepharon causing symptomatic restrictive diplopia in primary gaze have been treated. After meticulous symblepharon lysis and scar tissue removal, KLAL tissue was sutured onto the ocular surface and used as a spacer to prevent recurrent scar formation. Patients have been followed from 12 to 28 months. RESULTS: All eyes have been free of symblepharon recurrence in areas reconstructed with KLAL tissues. Mild recurrences of adhesions have occurred in areas posterior to the KLAL graft and none have recurred over the KLAL segments. Primary gaze diplopia has been resolved in all cases with only mild residual diplopia in extreme lateral gazes for 3 patients. CONCLUSIONS: Ocular surface reconstruction with KLAL tissue effectively achieves functional and anatomic success in fornix repair for patients with severe or recurrent symblepharon. Donor KLAL is a robust tissue alternative to traditional amniotic membrane or conjunctival autografts. PMID- 25811722 TI - Antibiotic Resistance in the Treatment of Staphylococcus aureus Keratitis: a 20 Year Review. AB - PURPOSE: We compared the resistance patterns of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) keratitis isolates with the common topically applied ophthalmic antimicrobials. METHODS: We reviewed the antibiotic susceptibility results of 122 MRSA and 276 MSSA keratitis isolates from January 1993 to November 2012. In vitro susceptibility testing of each Staphylococcus aureus (SA) isolate was performed using Kirby-Bauer disk diffusion based on modified serum interpretations for cefoxitin, bacitracin, cefazolin, ciprofloxacin, gatifloxacin, gentamicin, moxifloxacin, ofloxacin, polymyxin B, sulfamethoxazole, tobramycin, and trimethoprim. RESULTS: MRSA represented 30.7% (122 of 398) of the total SA isolates. All the SA isolates were susceptible to vancomycin, whereas they were less susceptible to the fluoroquinolones than to the non-fluoroquinolones. In comparison with MSSA, MRSA was significantly more resistant to all the antibiotics tested other than polymyxin B (both equally resistant) and vancomycin (both equally susceptible) (P < 0.001). Besides vancomycin, MRSA demonstrated the best susceptibilities to sulfamethoxazole (94.3%), bacitracin (89.3%), trimethoprim (88.5%), and gentamicin (86.1%). Additionally, MRSA was found to be significantly more resistant to the second-generation fluoroquinolones (ciprofloxacin and ofloxacin) than to the fourth-generation fluoroquinolones (moxifloxacin and gatifloxacin). An increase in resistance to the fourth generation fluoroquinolones was detected for both MRSA and MSSA over the study period. CONCLUSIONS: The in vitro susceptibilities of commonly used topical antibiotics differ for MRSA and MSSA isolates; thus, successful treatment of bacterial keratitis should be supported with laboratory studies. Vancomycin remains the treatment of choice for MRSA keratitis. The empiric use of second generation fluoroquinolones seems to be contraindicated in the treatment of MRSA keratitis. PMID- 25811724 TI - Trends in Microbiological and Antibiotic Sensitivity Patterns in Infectious Keratitis: 10-Year Experience in Mexico City. AB - PURPOSE: To report the distribution and trends in microbiological and antibiotic sensitivity patterns of infectious keratitis in a 10-year period at a reference center in Mexico City. METHODS: In this retrospective observational case series, samples were obtained from corneas with a diagnosis of infectious keratitis from January 2002 to December 2011 at the Institute of Ophthalmology "Conde de Valenciana" in Mexico City. Results of cultures, stains, and specific sensitivity/resistance antibiograms for each microorganism were analyzed. RESULTS: A total of 1638 consecutive corneal scrapings were analyzed. Pathogen was recovered in 616 samples (38%), with bacterial keratitis accounting for 544 of the positive cultures (88%). A nonsignificant increasing trend in gram negative isolates (P = 0.11) was observed. The most commonly isolated pathogen was Staphylococcus epidermidis, and the most common gram-negative isolated species was Pseudomonas aeruginosa. Methicillin-resistant Staphylococcus aureus (MRSA) was present in 45% of the S. aureus isolates; meanwhile, 53.7% coagulase negative Staphylococcus isolates were methicillin resistant (MRCNS). Pseudomonas aeruginosa resistance to ceftazidime increased from 15% in the first period to 74% for the last 5 years of the study (P = 0.01). The overall sensitivity for vancomycin of MRSA was 87.5%, whereas 99.6% of the MRCNS were sensitive. CONCLUSIONS: There was a nonsignificant increase in the recovered gram-positive and gram-negative microorganisms over time. We observed an increased resistance to methicillin in almost half of the MRSA and MRCNS isolates. PMID- 25811725 TI - Comparison of Corneal Layers and Anterior Sclera in Emmetropic and Myopic Eyes. AB - PURPOSE: The aim of this study was to compare the thickness of preocular tear film, corneal layers, and anterior sclera in patients with moderate to high myopia and emmetropia with anterior segment spectral domain optical coherence tomography. METHODS: This cross-sectional comparative study included 31 patients with high myopia and 31 emmetropic healthy controls. Patients with myopia had axial lengths ranging from 24 to 29 mm, whereas age-matched controls had axial lengths from 21 to 23.9 mm. Patients with myopia had refractive errors from -4.00 to -11.00 diopters spherical equivalent. Preocular tear film, corneal epithelium, Bowman layer, stroma, and Descemet membrane-endothelium complex were measured in the central cornea. Anterior scleral measurements were made at distances of 1, 3, and 5 mm from the limbus. Corneal-scleral thickness was measured with the anterior segment module of spectral domain optical coherence tomography. RESULTS: No statistically significant differences (P > 0.05) between patients with myopia and controls emerged regarding the thickness of preocular tear film, corneal epithelium, Bowman layer, corneal stroma, and Descemet membrane-endothelium complex. The anterior scleral thickness values of 1, 3, and 5 mm from the limbus were similar in both patients with myopia and control participants (P > 0.05). There were no significant correlations between central cornea stromal thickness and anterior scleral thickness in myopic participants (P > 0.05). CONCLUSIONS: The thickness of anterior wall structures and preocular tear film of patients with moderate to high myopia are not statistically different compared with those of healthy controls. PMID- 25811726 TI - Conjunctival extranodal natural killer/T-cell lymphoma, nasal type. AB - PURPOSE: To report a rare case of a patient with isolated primary conjunctival extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL) without nasal involvement. METHODS: The clinical course, magnetic resonance imaging, positron emission tomographic and immunohistopathological features of the patient were evaluated. RESULTS: A 57-year-old man presented with rapidly progressing swelling and redness in his right eye for 2 months. A salmon-colored mass was present under all parts of the bulbar conjunctiva. Magnetic resonance imaging demonstrated a mass anterior to the globe without any sinus involvement. Positron emission tomographic study did not show other disease sites. Immunohistopathological studies on incisional biopsy specimen demonstrated ENKTCL with positive CD2, CD7, CD56, bcl-2, and T cell-restricted intracellular antigen, and negative CD20, CD8, CD123, and terminal deoxynucleotidyl transferase staining. Epstein-Barr virus (EBV)-encoded mRNA was also diffusely positive. Ki 67 index was more than 90%. The patient received cyclophosphamide, vincristine, hydroxydaunorubicin, cisplatin, and prednisone chemotherapy with 4500 cGY radiotherapy in 25 fractions to the right orbit, resulting in total resolution of the conjunctival tumor. He developed intracranial and gastrointestinal tumors and died of cardiopulmonary failure 11 months later. CONCLUSIONS: Extranodal natural killer/T-cell lymphoma, nasal type may primarily arise in the conjunctiva without nasal or paranasal sinus involvement. Despite initial successful local tumor control by systemic chemotherapy and local irradiation, the overall prognosis is poor due to systemic dissemination. PMID- 25811727 TI - Ocular Surface Alterations and In Vivo Confocal Microscopic Features of Corneas in Patients With Newly Diagnosed Graves' Disease. AB - PURPOSE: To evaluate the ocular surface characteristics and corneal microstructure in patients with newly diagnosed Graves disease (GD) with no evidence of active thyroid eye disease (TED). METHODS: Eighty eyes of 40 patients with newly diagnosed GD and 40 age-matched control subjects were recruited in this cross-sectional study. All participants underwent ocular surface tests in the order of tear break-up time (BUT), lissamine green (LG) staining, Schirmer I test with anesthesia, and ocular surface disease index (OSDI) questionnaire. Basal epithelial cell, keratocyte, and endothelial cell densities and subbasal nerves were evaluated using in vivo confocal microscopy (IVCM). Independent sample t test, chi test, and Mann-Whitney U test were used for statistical analysis. RESULTS: Patients with GD had higher OSDI (5.9 +/- 6.6 vs. 1.7 +/- 2.4, respectively, P <= 0.001) and LG staining scores (0.5 +/- 0.6 vs. 0.2 +/- 0.4, respectively, P = 0.003), and lower BUT scores (7.3 +/- 2.5 vs. 9.9 +/- 1.7, respectively, P < 0.001) compared with those of control subjects. Patients with GD had lower mean basal epithelial cell density (3928 +/- 657 cells/mm2 vs. 4771 +/- 622 cells/mm2, respectively) and total subbasal nerve density (958 +/- 394 cells/mm2 vs. 1416 +/- 744 cells/mm2, respectively) and higher subbasal nerve tortuosity (2.7 +/- 0.8 vs. 1.6 +/- 0.6, respectively) compared with those of control subjects (P < 0.001). There was a statistically significant negative correlation between the duration of symptoms of hyperthyroidism and BUT (rho = 0.273, P = 0.014) and a positive correlation between LG staining scores (rho = 0.329, P = 0.003). A significant reduction in BUT (rho = -0.238, P = 0.003) and epithelial cell density (rho = -0.174, P = 0.029) and an increase in OSDI scores (rho = 0.328, P = 0.003) were found with increasing exophthalmometry measurements. CONCLUSIONS: Ocular surface alterations begin early in the course of Graves disease before the onset of overt TED. PMID- 25811730 TI - Phototherapeutic keratectomy with mitomycin C for recurrent granular corneal dystrophy under femtosecond-assisted anterior lamellar keratoplasty. PMID- 25811728 TI - Excessive Corneal Flattening and Thinning After Corneal Cross-linking: Single Case Report With 5-Year Follow-up. AB - PURPOSE: To present a case of significant progressive corneal flattening and thinning after corneal cross-linking (CXL), with 5 years of follow-up. METHODS: Case report. RESULTS: A 23-year-old woman presented with bilateral progressive keratoconus and received CXL treatment (Dresden protocol) for both eyes in March 2009. The patient has demonstrated gradual significant corneal thinning (from a preoperative value of 464 MUm to 243 MUm) and progressive flattening (+11.1 diopter change in spherical equivalent) in her right eye, over a 5-year period. The fellow eye remained stable during the same postoperative period. CONCLUSIONS: This is the first case report of significant progressive corneal flattening and thinning after undergoing CXL treatment for progressive keratoconus. PMID- 25811729 TI - Mutations in the Corneal Endothelial Dystrophy-Associated Gene SLC4A11 Render the Cells More Vulnerable to Oxidative Insults. AB - PURPOSE: To investigate the effect of mutations in SLC4A11 on cellular localization of the protein, mitochondrial function, and apoptosis due to oxidative stress. Mutations in SLC4A11 have been associated with 2 different forms of corneal endothelial dystrophy that lead to degeneration of the corneal endothelium, causing opacity of the cornea and gradual vision loss. METHODS: HEK 293 cells were transfected with wild-type SLC4A11 or mutants, Ser213Leu, Arg233Cys, Gly418Asp, and Thr584Lys, and exposed to oxidative stress. Cellular localization of the proteins was detected by confocal microscopy, whereas mitochondrial dysfunction, reactive oxygen species (ROS) generation, and apoptosis were analyzed by flow cytometry and a colorimetric assay. Expressions of antioxidant genes were quantitated by real-time polymerase chain reaction. RESULTS: Although wild-type SLC4A11 was localized on the cell membrane, mutant proteins were found diffused in the cytoplasm. Mutations in SLC4A11 caused an increase in generation of ROS and mitochondrial dysfunction due to oxidative stress. NRF2, HO-1, and NQO expression decreased significantly, and a higher rate of apoptosis was detected in cells with mutant proteins under oxidative stress. CONCLUSIONS: Our data suggest that mutations in SLC4A11 cause retention of the protein in the cytoplasm and generate increased reactive oxygen species. We found that cells containing mutant SLC4A11 are more vulnerable to oxidative and mitochondrial damage, less able to overcome oxidative stress through the expression of sufficient levels of antioxidant genes, and are more prone to apoptotic death. PMID- 25811731 TI - DemTect(r)--effective to asses MCI and dementia--validation study of the Polish language version. AB - OBJECTIVES: To validate DemTect(r), a highly sensitive psychometric screening tool--designed to identify patients with mild cognitive impairment (MCI) and patients with dementia (AD). METHOD: A prospective cohort/cross-sectional study was designed. The data were collected from a group of 224 subjects, including 85 patients with MCI, 109 with Alzheimer's disease (AD) and 30 healthy control (HC) subjects. All subjects underwent a detailed neuropsychological assessment including CT, the assessment of biological parameters and a psychometric examination using DemTect(r), MMSE, TYM, CDT and FAS. RESULTS: Subjects ranged in age from 55 to 94 years, with a mean age of 71.42 +/- 9.86 years. Classification rates of DemTect(r) were superior for both the MCI and AD groups compared with the MMSE, with high sensitivities of 90% (cut-off <=15) and 96.8% (cut-off < 10), respectively. The DemTect(r) Polish language version proved to be independent of age and education level. CONCLUSION: The Polish language version of the DemTect(r) scale is easy to administer. It may be seen as a superior cognitive screening tool in day-to-day practice as it achieves more accurate differentiation between HC/MCI/AD compared with MMSE. PMID- 25811732 TI - Semi-synthesis of thioamide containing proteins. AB - Our laboratory has shown that the thioamide, a single atom O-to-S substitution, can be a versatile fluorescence quenching probe that is minimally-perturbing when placed at many locations in a protein sequence. In order to make these and other thioamide experiments applicable to full-sized proteins, we have developed methods for incorporating thioamides by generating thiopeptide fragments through solid phase synthesis and ligating them to protein fragments expressed in E. coli. To install donor fluorophores, we have adapted unnatural amino acid mutagenesis methods, including the generation of new tRNA synthetases for the incorporation of small, intrinsically fluorescent amino acids. We have used a combination of these two methods, as well as chemoenzymatic protein modification, to efficiently install sidechain and backbone modifications to generate proteins labeled with fluorophore/thioamide pairs. PMID- 25811734 TI - The amphoteric properties of g-C3N4 nanosheets and fabrication of their relevant heterostructure photocatalysts by an electrostatic re-assembly route. AB - A stable colloid of g-C3N4 nanosheets was prepared on a large scale via a H2SO4 exfoliation route. The amphoteric nature due to the simultaneous presence of carboxyl and amino groups provided a strategy to fabricate heterostructures by an electrostatic re-assembly between g-C3N4 nanosheets and various charged guests in different pH systems. PMID- 25811733 TI - Antitubercular Nanocarrier Combination Therapy: Formulation Strategies and in Vitro Efficacy for Rifampicin and SQ641. AB - Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome the problems associated with dosing frequency, patient compliance, and drug resistance. To reduce side effects associated with systemic drug distribution and improve drug concentration at the target site, stable therapeutic nanocarriers (NCs) were prepared and evaluated for efficacy in vitro in Mycobacterium tuberculosis-infected macrophages. Rifampicin (RIF), a current, broad-spectrum antibiotic used in TB therapy, was conjugated by degradable ester bonds to form hydrophobic prodrugs. NCs encapsulating various ratios of nonconjugated RIF and the prodrugs showed the potential ability to rapidly deliver and knockdown intracellular M. tuberculosis by nonconjugated RIF and to obtain sustained release of RIF by hydrolysis of the RIF prodrug. NCs of the novel antibiotic SQ641 and a combination NC with cyclosporine A were formed by flash nanoprecipitation. Delivery of SQ641 in NC form resulted in significantly improved activity compared to that of the free drug against intracellular M. tuberculosis. A NC formulation with a three-compound combination of SQ641, cyclosporine A, and vitamin E inhibited intracellular replication of M. tuberculosis significantly better than SQ641 alone or isoniazid, a current first line anti-TB drug. PMID- 25811735 TI - Recombinant Human Thrombomodulin in Acute Exacerbation of Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) presents as episodes of acute respiratory worsening closely associated with endothelial damage and disordered coagulopathy. Recombinant human soluble thrombomodulin (rhTM) regulates the coagulation pathway mainly by reducing thrombin-mediated clotting and enhancing protein C activation. We investigated the efficacy of rhTM for the treatment of patients with AE-IPF. METHODS: This historical control study comprised 40 patients with AE-IPF. Twenty patients treated with rhTM (0.06 mg/kg/d) for about 6 days (rhTM group) and 20 patients treated without rhTM (control group) were evaluated. The predictors of 3-month mortality (logistic regression model) were evaluated. RESULTS: There was no difference in baseline characteristics between the control group and the rhTM group. Three-month mortality of the rhTM group and control group was 30.0% and 65.0%, respectively. In univariate analysis, C-reactive protein and rhTM therapy were significant determinants for 3-month survival. In multivariate analysis, rhTM therapy (OR, 0.219; 95% CI, 0.049-0.978; P = 0.047) was an independent significant determinant for 3-month survival. CONCLUSIONS: We found that rhTM therapy improved 3-month survival of AE-IPF. The results observed here warrant further investigation of rhTM in randomized control trials. PMID- 25811736 TI - Magnetic nanoparticle hyperthermia enhances radiation therapy: A study in mouse models of human prostate cancer. AB - PURPOSE: We aimed to characterise magnetic nanoparticle hyperthermia (mNPH) with radiation therapy (RT) for prostate cancer. METHODS: Human prostate cancer subcutaneous tumours, PC3 and LAPC-4, were grown in nude male mice. When tumours measured 150 mm3 magnetic iron oxide nanoparticles (MIONPs) were injected into tumours to a target dose of 5.5 mg Fe/cm3 tumour, and treated 24 h later by exposure to alternating magnetic field (AMF). Mice were randomly assigned to one of four cohorts to characterise (1) intratumour MIONP distribution, (2) effects of variable thermal dose mNPH (fixed AMF peak amplitude 24 kA/m at 160 +/- 5 kHz) with/without RT (5 Gy), (3) effects of RT (RT5: 5 Gy; RT8: 8 Gy), and (4) fixed thermal dose mNPH (43 degrees C for 20 min) with/without RT (5 Gy). MIONP concentration and distribution were assessed following sacrifice and tissue harvest using inductively coupled plasma mass spectrometry (ICP-MS) and Prussian blue staining, respectively. Tumour growth was monitored and compared among treated groups. RESULTS: LAPC-4 tumours retained higher MIONP concentration and more uniform distribution than did PC3 tumours. AMF power modulation provided similar thermal dose for mNPH and combination therapy groups (CEM43: LAPC-4: 33.6 +/- 3.4 versus 25.9 +/- 0.8, and PC3: 27.19 +/- 0.7 versus 27.50 +/- 0.6), thereby overcoming limitations of MIONP distribution and yielding statistically significant tumour growth delay. CONCLUSION: PC3 and LAPC-4 tumours represent two biological models that demonstrate different patterns of nanoparticle retention and distribution, offering a model to make comparisons of these effects for mNPH. Modulating power for mNPH offers potential to overcome limitations of MIONP distribution to enhance mNPH. PMID- 25811738 TI - Safety of recombinant VSV-Ebola virus vaccine vector in pigs. AB - The ongoing Ebola outbreak in West Africa has resulted in fast-track development of vaccine candidates. We tested a vesicular stomatitis virus vector expressing Ebola virus glycoprotein for safety in pigs. Inoculation did not cause disease and vaccine virus shedding was minimal, which indicated that the vaccine virus does not pose a risk of dissemination in pigs. PMID- 25811739 TI - Interactions of microorganisms with polymer nanocomposite surfaces containing oxidized carbon nanotubes. AB - In many environmental scenarios, the fate and impact of polymer nanocomposites (PNCs) that contain carbon nanotubes (CNT/PNCs) will be influenced by their interactions with microorganisms, with implications for antimicrobial properties and the long-term persistence of PNCs. Using oxidized single-wall (O-SWCNTs) and multi-wall CNTs (O-MWCNTs), we explored the influence that CNT loading (mass fraction<=0.1%-10%) and type have on the initial interactions of Pseudomonas aeruginosa with O-CNT/poly(vinyl alcohol) (PVOH) nanocomposites containing well dispersed O-CNTs. LIVE/DEAD staining revealed that, despite oxidation, the inclusion of O-SWCNTs or O-MWCNTs caused PNC surfaces to exhibit antimicrobial properties. The fraction of living cells deposited on both O-SWCNT and O MWCNT/PNC surfaces decreased exponentially with increasing CNT loading, with O SWCNTs being approximately three times more cytotoxic on a % w/w basis. Although not every contact event between attached microorganisms and CNTs led to cell death, the cytotoxicity of the CNT/PNC surfaces scaled with the total contact area that existed between the microorganisms and CNTs. However, because the antimicrobial properties of CNT/PNC surfaces require direct CNT-microbe contact, dead cells were able to shield living cells from the cytotoxic effects of CNTs, allowing biofilm formation to occur on CNT/PNCs exposed to Pseudomonas aeruginosa for longer time periods. PMID- 25811737 TI - Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival. AB - PURPOSE: We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers. METHODS: We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal. RESULTS: Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival. CONCLUSIONS: Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC. PMID- 25811740 TI - Logsum using Garbled Circuits. AB - Secure multiparty computation allows for a set of users to evaluate a particular function over their inputs without revealing the information they possess to each other. Theoretically, this can be achieved using fully homomorphic encryption systems, but so far they remain in the realm of computational impracticability. An alternative is to consider secure function evaluation using homomorphic public key cryptosystems or Garbled Circuits, the latter being a popular trend in recent times due to important breakthroughs. We propose a technique for computing the logsum operation using Garbled Circuits. This technique relies on replacing the logsum operation with an equivalent piecewise linear approximation, taking advantage of recent advances in efficient methods for both designing and implementing Garbled Circuits. We elaborate on how all the required blocks should be assembled in order to obtain small errors regarding the original logsum operation and very fast execution times. PMID- 25811741 TI - Critical Situations in Children, Adolescents and Young Adults with Terminal Cancer within the Home Setting. AB - BACKGROUND: Over the course of terminal cancer towards the end-of-life, children may experience symptoms that lead to distressing critical situations (CS) for the child and caregivers. METHODS: We analysed the records of 133 children cared for by our paediatric palliative care team (PPCT) from 01/98-12/09. A CS was defined as deterioration of a condition caused by a symptom, which was life-threatening or acutely scaring the patient (pt) or caregivers. RESULTS: The majority of pts who died sustained no CS. In 38 (28.6%) pts 45 CS occurred. These accumulated towards the end-of-life (62.2% within the last week). About two-thirds were anticipated. There was no clustering of CS during the night/weekend. Leading symptoms were neurological. In 4 CS a pre-hospital emergency physician was alerted. 5 pts were readmitted to hospital. Most CS (88.9%) could be controlled in the home setting. DISCUSSION: Despite anticipation, a relevant number of pts developed CS, which needed either additional medical intervention or other support by the PPCT. Considering the distressing and suffering character of status epilepticus and dyspnoea, it is important to thoroughly address these conditions in palliative care. CONCLUSION: Advanced planning, close contact, good communication, detailed parental information, and a 24-h on-call service can reduce CS in children with terminal cancer. CS are mainly manageable within the home setting. Treatment of CS should focus on the child's symptoms and wishes, and the needs of the whole family. PMID- 25811742 TI - [Correction of Acidosis in Neonatal Intensive-care Medicine: A National Survey]. AB - BACKGROUND: Metabolic acidosis is a common problem of patients on neonatal intensive care units. Only little data exists in literature and there are no clinical guidelines. The aim of this national survey was to assess criteria for correction of metabolic acidosis in neonatal patients and if there were effects to be observed. METHODS: We designed an online survey and sent it to 304 German children's hospitals. 101 questionnaires were included in our study. RESULTS: The question "How often do you buffer on your ward a week?" was answered 63 times with "zero". In perinatal asphyxia newborns with gestation age over 36+0 weeks 4% of the neonatologists would frequently perform a correction of acidosis, 74.3% would do it rarely and 21.8% never. In syndrome of persistent fetal circulation 28.4% would correct acidosis frequently, 42.0% would correct it rarely and 29.5% would never correct it. In case of sepsis 8.7% would correct acidosis frequently, 70.7% would do it rarely and 20.7% would never correct it. 75.2% of the participants distinguish in buffering a premature or a mature infant. 44.4% of neonatologists saw an improvement of the clinical status of the patient after buffering. 38.3% saw different effects, 16.0% saw no changes and 1.2% saw a worsening of the clinical status. 49.4% of those questioned saw side effects after using sodium bicarbonate as a buffer. CONCLUSION: Correction of acidosis with a buffer is rarely performed on German neonatology wards. The indication of buffering depends on the clinical picture and its underlying problem. Benefits from buffering were seen, as well as side effects. PMID- 25811743 TI - [Fear of progression in parents of children with cancer: adaptation of the Fear of Progression Questionnaire and correlates]. AB - BACKGROUND: Fear of Progression (FoP), the fear of further disease progression, is one of the most common psychological strains of chronically ill patients and can also be found in healthy partners of cancer patients. Parents of children with cancer are also at risk of developing distinct fears that may persist after medical treatment. This study aimed to assess FoP in parents of children with cancer and to investigate relationships between FoP in parents of children with cancer and disease- and treatment-related issues, the child's current medical condition and parents' quality of life. PATIENTS: In this study 76 parents (51 mothers, 25 fathers) whose children were in inpatient treatment or follow-up care were surveyed. METHOD: The short form of the FoP Questionnaire was adapted by rephrasing the items for the parental perspective (FoP-Q-SF/PR). RESULTS: The FoP Q-SF/PR is a short questionnaire with adequate psychometric properties (e. g. Cronbach's alpha=0.90) and satisfying results in terms of construct validity. Significant correlations with FoP are found for the child's current medical condition (r=0.35), time since diagnosis (r=- 0.30), parents' capacity to cope with disease-related fears (r=- 0.45) and parents' quality of life (r=- 0.55). A cut-off value of 46 points is recommended. CONCLUSION: The FoP-Q-SF/PR offers a feasible and sensitive battery to assess disease-related fears. For clinicians, evaluation of individual results can provide insight into specific problem areas for parents of children with cancer. The questionnaire is thus well suited for use in psychosocial care of families within the field of paediatric oncology. PMID- 25811745 TI - Correction: Foraging behaviour and landscape utilisation by the endangered golden crowned flying fox (Acerodon jubatus), The Philippines. AB - [This corrects the article DOI: 10.1371/journal.pone.0079665.]. PMID- 25811744 TI - [Adherence to Long-term Follow-up in Paediatric Oncology--Results of a Monocentric Analysis]. AB - BACKGROUND: Cured paediatric-oncology patients frequently present with health problems even years after treatment. Hence long-term follow-up (LTFU) is essential. This analysis tries to identify factors that influence regular LTFU attendance. STUDY POPULATION: Between 1991 and 2010, 2 153 children and adolescents were treated at Muenster University Department of Paediatric Hematology and Oncology (UKM). 1 708 patients with permanent residence in Germany and completed therapy have been included into this analysis. METHODS: Patients were reviewed for the duration and regularity of LTFU at UKM. Prospective analyses with postponed starting-points have been conducted as well as descriptive analyses to validate correlations. Prospective data were evaluated by Kaplan-Meier-Analyses, the analysis of multivariate correlations by Cox Proportional Hazard Model. RESULTS: 2 years after the end of therapy 83% of the patients were still in LTFU. After 5 and 10 years this percentage decreased to 67 and 42%. Patients diagnosed after the year 2000 and younger patients attended LTFU for a longer period (p<0,005). There were no significant gender differences. Statutory insured patients stayed longer in LTFU than private health insured (p<0,005). The multivariate examination showed only small differences between systemic diseases and solid tumours. The residential distance had no significant influence. CONCLUSIONS: Younger, more recently treated and statutory insured patients showed a significantly longer LTFU. PMID- 25811746 TI - The Face of the Chameleon: The Experience of Facial Mimicry for the Mimicker and the Mimickee. AB - This research addressed three questions concerning facial mimicry: (a) Does the relationship between mimicry and liking characterize all facial expressions, or is it limited to specific expressions? (b) Is the relationship between facial mimicry and liking symmetrical for the mimicker and the mimickee? (c) Does conscious mimicry have consequences for emotion recognition? A paradigm is introduced in which participants interact over a computer setup with a confederate whose prerecorded facial displays of emotion are synchronized with participants' behavior to create the illusion of social interaction. In Experiment 1, the confederate did or did not mimic participants' facial displays of various subsets of basic emotions. Mimicry promoted greater liking for the confederate regardless of which emotions were mimicked. Experiment 2 reversed these roles: participants were instructed to mimic or not to mimic the confederate's facial displays. Mimicry did not affect liking for the confederate but it did impair emotion recognition. PMID- 25811747 TI - Metal accumulation in the renal cortex of a pediatric patient with sickle cell disease: a case report and review of the literature. AB - BACKGROUND: Sickle cell disease (SCD) is a well-known multisystem illness characterized by vascular injury due to vasoocclusion and hemolysis, as well as infectious complications and iron overload, all of which contribute to high morbidity and mortality rates among children. In these patients, some authors have previously described iron cortical deposition in the kidney. We here report the first case in the literature of a girl affected by SCD showing an anomalous metal and rare element retention in the renal cortex. CASE PRESENTATION: A 10 year-old white girl affected by SCD underwent a routine magnetic resonance imaging investigation that evidenced a reduced signal intensity in the renal cortex, compatible with hemosiderin precipitation. Histologic and elemental analyses of the hepatic and the renal biotic samples, performed with inductively coupled plasma mass spectrometry, revealed that concomitant with the high iron deposition, toxic and potentially carcinogenic elements such as nickel, magnesium, rubidium, and gadolinuim were anomalously retained particularly in the kidney. CONCLUSIONS: The finding of rare and toxic elements in the kidney of SCD patients might be linked to the development of specific neoplastic transformations already described in this patient cohort. To be confirmed, our speculations need to be demonstrated in large sampling of patients. PMID- 25811748 TI - Cultural preferences and limited public resources influence the spectrum of thalassemia in Egypt. AB - BACKGROUND: Cultural beliefs of Egyptians with respect to the origin of thalassemia and its prevention, as well as national resources available for care, often differ from those of Western countries. OBJECTIVES: To assess the impact of cultural attitudes and the effect of limited medical and financial resources that could affect the management of Egyptian thalassemic patients. SUBJECTS: A cross sectional study included 205 Egyptians beta-thalassemia major (beta-TM) patients, with a mean age of 149+/-87.90 months and a male to female ratio of 94:111. METHODS: Demographic data stressing on order of birth, consanguineous marriage, and family history of beta-TM, transfusion, and chelation therapy, were reported. HCV-Ab, HBV-Ag, and complete blood count were recorded with calculation of mean pretransfusional hemoglobin. RESULTS: The age distribution was relatively nonhomogenous, with 39% of patients between 10 and 20 years of age and 16% were younger than 5. There were high family birth rates and 35% of patients were third or more in order of birth and a marked cultural preference for consanguineous marriage, representing 61% of all the parents' marriages, as well as a high rate (59.5%) of a positive family history of beta-TM. Patients transfused on low pretransfusion hemoglobin levels around 8 g/dL, and those receiving blood transfusion before the establishment of National Blood Transfusion Services showed a statistically significant higher rate of positive hepatitis B and C viral infections. Chelation therapy tended to start at late age, mean age was around 4 years. Before 2000, subcutaneous deferoxamine was the most widely used chelation, and since then a considerable number of patients (50%) had started to use oral iron chelators. CONCLUSIONS: The strong cultural preferences for consanguineous marriage and limited preventive programmes and resources have had a negative impact on the management of Egyptians thalassemic patients. PMID- 25811749 TI - 2 Genetically distinct Burkitt lymphomas (2 primaries rather than recurrent disease): consider X-linked lymphoproliferative disorder. PMID- 25811751 TI - Self-assembly of an unprecedented polyoxomolybdate anion [Mo20O66]12- in a giant peanut-like 62-core silver-thiolate nanocluster. AB - A polyoxometalate-templated silver thiolate nanocluster, [Ag62(S(t)Bu)40(Mo20O66)(Mo6O19)3(CH3CN)2].(CF3SO3)4 (1), has been isolated, in which a giant peanut-like silver(i)-thiolate cluster [Ag62(S(t)Bu)40](22+) encapsulates an unprecedented [Mo20O66](12-) polyoxoanion core. It opens a new approach for the synthesis of both elusive polyoxometalates and high-nuclearity silver(i)-thiolate nanoclusters. PMID- 25811750 TI - PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. AB - Neuroblastoma is the most common extracranial cancer in childhood. High-risk neuroblastoma continues to have a poor prognosis and there is an urgent need to design biologically based therapies that specifically target the pathways responsible for malignant transformation and progression. One such pathway is the PI3K/Akt/mTOR pathway. In this article we outline the evidence for aberrant activation of the PI3K/Akt/mTOR pathway in neuroblastoma and discuss the possible mechanisms which mediate it. We also discuss the development of treatments targeting this pathway in neuroblastoma and the challenges that must be overcome before such treatments can enter routine clinical practice. PMID- 25811753 TI - How Is Diffusion of Neutral and Charged Tracers Related to the Structure and Dynamics of a Room-Temperature Ionic Liquid? Large Deviations from Stokes Einstein Behavior Explained. AB - The deviations from Stokes-Einstein hydrodynamics of small solutes are more pronounced in ionic liquids than in conventional solvents (J. Phys. Chem. B 2013 117 (39), 11697). Small neutral solutes diffuse much faster than expected, whereas small charged solutes diffuse much slower. This article attempts to establish a link between the local friction experienced by tracer solutes and the polar/apolar structure of ionic liquids. We find that small neutral solutes probe locally "stiff" (mostly charged, high electrostriction) regions and locally "soft" (mostly apolar, low electrostriction) regions. These regions of high and low friction are associated with cage and jump regimes. Enhanced neutral tracer mobility in the low friction regions associated with the cationic apolar component has an important bearing on the large positive deviations from Stokes Einstein behavior. In contrast, diminished charged tracer mobility involves long caging dynamics separated by jump events often triggered by the loss and recovery of counterions. PMID- 25811752 TI - Control of middle ear inflammatory and ion homeostasis genes by transtympanic glucocorticoid and mineralocorticoid treatments. AB - HYPOTHESIS: Transtympanic steroid treatment will induce changes in ion homeostasis and inflammatory gene expression to decrease middle ear inflammation due to bacterial inoculation. BACKGROUND: Otitis media is common, but treatment options are limited to systemic antibiotic therapy or surgical intervention. Systemic glucocorticoid treatment of mice decreases inflammation and improves fluid clearance. However, transtympanic delivery of glucocorticoids or mineralocorticoid has not been explored to determine if direct steroid application is beneficial. METHODS: Balb/c mice received transtympanic inoculation of heat-killed Haemophilus influenzae (H flu), followed by transtympanic treatment with either prednisolone or aldosterone. Mice given PBS instead of steroid and untreated mice were used as controls. Four hours after steroid treatment, middle ears were harvested for mRNA extraction and 24 hours after inoculation middle ears were harvested and examined for measures of inflammation. RESULTS: H flu inoculation caused the increased expression of nearly all inflammatory cytokine genes and induced changes in expression of several genes related to cellular junctions and transport channels. Both steroids generally reversed the expression of inflammatory genes and caused ion and water regulatory genes to return to normal or near normal levels. Histologic evaluation of middle ears showed improved fluid and inflammatory cell clearance. CONCLUSION: Improvement in middle ear inflammation was noted with both the glucocorticoid prednisolone and the mineralocorticoid aldosterone. This was due to reversal of inflammation-induced changes in middle ear cytokine genes, as well as those involved in ion and water homeostasis. Because glucocorticoids bind to the mineralocorticoid receptor, but not the reverse, it is concluded that much of the reduction of fluid and other inflammation measures was due to these steroids impact on ion and water transport channels. Further research is necessary to determine if this alternative mineralocorticoid treatment for otitis media will be clinically effective with fewer side effects than glucocorticoids. PMID- 25811754 TI - Managing conflicts of interest in the UK National Institute for Health and Care Excellence (NICE) clinical guidelines programme: qualitative study. AB - BACKGROUND: There is international concern that conflicts of interest (COI) may bias clinical guideline development and render it untrustworthy. Guideline COI policies exist with the aim of reducing this bias but it is not known how such policies are interpreted and used by guideline producing organisations. This study sought to determine how conflicts of interest (COIs) are disclosed and managed by a national clinical guideline developer (NICE: the UK National Institute for Health and Care Excellence). METHODS: Qualitative study using semi structured telephone interviews with 14 key informants: 8 senior staff of NICE's guideline development centres and 6 chairs of guideline development groups (GDGs). We conducted a thematic analysis. RESULTS: Participants regard the NICE COI policy as comprehensive leading to transparent and independent guidance. The application of the NICE COI policy is, however, not straightforward and clarity could be improved. Disclosure of COI relies on self reporting and guideline developers have to take "on trust" the information they receive, certain types of COI (non-financial) are difficult to categorise and manage and disclosed COI can impact on the ability to recruit clinical experts to GDGs. Participants considered it both disruptive and stressful to exclude members from GDG meetings when required by the COI policy. Nonetheless the impact of this disruption can be minimised with good group chairing skills. CONCLUSIONS: We consider that the successful implementation of a COI policy in clinical guideline development requires clear policies and procedures, appropriate training of GDG chairs and an evaluation of how the policy is used in practice. PMID- 25811756 TI - Correction: nonequilibrium population dynamics of phenotype conversion of cancer cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0110714.]. PMID- 25811755 TI - Disordered sleep and myopia risk among Chinese children. AB - PURPOSE: Disordered sleep and myopia are increasingly prevalent among Chinese children. Similar pathways may be involved in regulation of both sleep cycles and eye growth. We therefore sought to examine the association between disordered sleep and myopia in this group. METHODS: Urban primary school children participating in a clinical trial on myopia and outdoor activity underwent automated cycloplegic refraction with subjective refinement. Parents answered questions about children's sleep duration, sleep disorders (Children's Sleep Habits Questionnaire [CSHQ]), near work and time spent outdoors. RESULTS: Among 1970 children, 1902 (96.5%, mean [standard deviation SD] age 9.80 [0.44] years, 53.1% boys) completed refraction and questionnaires. Myopia < = -0.50 Diopters was present in both eyes of 588 (30.9%) children (1329/3804 = 34.9% of eyes) and 1129 children (59.4%) had abnormal CSHQ scores (> 41). In logistic regression models by eye, odds of myopia < = -0.50D increased with worse CSHQ score (Odds Ratio [OR] 1.01 per point, 95% Confidence Interval [CI] [1.001, 1.02], P = 0.014) and more night-time sleep (OR 1.02, 95% CI [1.01, 1.04, P = 0.002], while male sex (OR 0.82, 95% CI [0.70, 0.95], P = 0.008) and time outdoors (OR = 0.97, 95% CI [0.95, 0.99], P = 0.011) were associated with less myopia. The association between sleep duration and myopia was not significant (p = 0.199) for total (night + midday) sleep. CONCLUSIONS: Myopia and disordered sleep were both common in this cohort, but we did not find consistent evidence for an association between the two. TRIAL REGISTRATION: clinicaltrials.gov NCT00848900. PMID- 25811757 TI - Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. AB - Compartmentalized HIV-1 replication within the central nervous system (CNS) likely provides a foundation for neurocognitive impairment and a potentially important tissue reservoir. The timing of emergence and character of this local CNS replication has not been defined in a population of subjects. We examined the frequency of elevated cerebrospinal fluid (CSF) HIV-1 RNA concentration, the nature of CSF viral populations compared to the blood, and the presence of a cellular inflammatory response (with the potential to bring infected cells into the CNS) using paired CSF and blood samples obtained over the first two years of infection from 72 ART-naive subjects. Using single genome amplification (SGA) and phylodynamics analysis of full-length env sequences, we compared CSF and blood viral populations in 33 of the 72 subjects. Independent HIV-1 replication in the CNS (compartmentalization) was detected in 20% of sample pairs analyzed by SGA, or 7% of all sample pairs, and was exclusively observed after four months of infection. In subjects with longitudinal sampling, 30% showed evidence of CNS viral replication or pleocytosis/inflammation in at least one time point, and in approximately 16% of subjects we observed evolving CSF/CNS compartmentalized viral replication and/or a marked CSF inflammatory response at multiple time points suggesting an ongoing or recurrent impact of the infection in the CNS. Two subjects had one of two transmitted lineages (or their recombinant) largely sequestered within the CNS shortly after transmission, indicating an additional mechanism for establishing early CNS replication. Transmitted variants were R5 T cell-tropic. Overall, examination of the relationships between CSF viral populations, blood and CSF HIV-1 RNA concentrations, and inflammatory responses suggested four distinct states of viral population dynamics, with associated mechanisms of local viral replication and the early influx of virus into the CNS. This study considerably enhances the generalizability of our results and greatly expands our knowledge of the early interactions of HIV-1 in the CNS. PMID- 25811758 TI - Characterization of resistance to rhabdovirus and retrovirus infection in a human myeloid cell line. AB - Viruses interact with various permissive and restrictive factors in host cells throughout their replication cycle. Cell lines that are non-permissive to viral infection have been particularly useful in discovering host cell proteins involved in viral life cycles. Here we describe the characterization of a human myeloid leukemia cell line, KG-1, that is resistant to infection by retroviruses and a Rhabdovirus. We show that KG-1 cells are resistant to infection by Vesicular Stomatits Virus as well as VSV Glycoprotein (VSVG) pseudotyped retroviruses due to a defect in binding. Moreover our results indicate that entry by xenotropic retroviral envelope glycoprotein RD114 is impaired in KG-1 cells. Finally we characterize a post- entry block in the early phase of the retroviral life cycle in KG-1 cells that renders the cell line refractory to infection. This cell line will have utility in discovering proteins involved in infection by VSV and HIV-1. PMID- 25811759 TI - Purification and characterization of a highly efficient calcium-independent alpha amylase from Talaromyces pinophilus 1-95. AB - Alpha-amylase is a very important enzyme in the starch conversion process. Most of the alpha-amylases are calcium-dependent and exhibit poor performance in the simultaneous saccharification and fermentation process of industrial bioethanol production that uses starch as feedstock. In this study, an extracellular amylolytic enzyme was purified from the culture broth of newly isolated Talaromyces pinophilus strain 1-95. The purified amylolytic enzyme, with an apparent molecular weight of 58 kDa on SDS-PAGE, hydrolyzed maltopentaose, maltohexaose, and maltoheptaose into mainly maltose and maltotriose and minor amount of glucose, confirming the endo-acting mode of the enzyme, and hence, was named Talaromyces pinophilus alpha-amylase (TpAA). TpAA was most active at pH 4.0 5.0 (with the temperature held at 37 degrees C) and 55 degrees C (at pH 5.0), and stable within the pH range of 5.0-9.5 (at 4 degrees C) and below 45 degrees C (at pH 5.0). Interestingly, the Ca2+ did not improve its enzymatic activity, optimal temperature, or thermostability of the enzyme, indicating that the TpAA was Ca2+ independent. TpAA displayed higher enzyme activity toward malto-oligosaccharides and dextrin than other previously reported alpha-amylases. This highly active Ca2+-independent alpha-amylase may have potential applications in starch-to ethanol conversion process. PMID- 25811760 TI - Plasma C-type natriuretic peptide as a predictor for therapeutic response to metoprolol in children with postural tachycardia syndrome. AB - POTS is a global public-health disease, but predictor for therapeutic response to metoprolol in children with POTS is lacking. This study was designed to investigate predictive value of plasma C-type natriuretic peptide (CNP) in the therapeutic efficacy of metoprolol on postural tachycardia syndrome (POTS) in children. Totally 34 children with POTS and 27 healthy children were included in the study. The head-up test or head-up tilt test was used to check heart rate and blood pressure from supine to upright in subjects. A double antibody (competitive) sandwich immunoluminometric assay was used to detect plasma CNP. Metoprolol was used to treat children with POTS. The difference in plasma concentrations of CNP between responders and non-responders was compared. An ROC curve was used to analyze plasma CNP to predict efficacy of metoprolol on POTS in children. Plasma CNP in children with POTS was significantly higher than that of healthy children [(51.9 +/- 31.4) vs. (25.1 +/- 19.1) pg/ml, P <0.001]. Plasma CNP in responders to metoprolol was significantly higher than non-responders [(59.1 +/- 33.5) vs. (34.8 +/- 16.7) pg/ml, P = 0.037] before treatment. The ROC curve showed that area under the curve was 0.821 (95% CI 0.642-0.999). The cut off value of plasma CNP > 32.55 pg/ml yielded a sensitivity of 95.8% and specificity of 70% in predicting therapeutic efficacy of metoprolol on POTS children. Plasma CNP might serve as a useful predictor for the therapeutic efficacy of metoprolol on POTS in children. PMID- 25811762 TI - Improving the capacity of sodium ion battery using a virus-templated nanostructured composite cathode. AB - In this work we investigated an energy-efficient biotemplated route to synthesize nanostructured FePO4 for sodium-based batteries. Self-assembled M13 viruses and single wall carbon nanotubes (SWCNTs) have been used as a template to grow amorphous FePO4 nanoparticles at room temperature (the active composite is denoted as Bio-FePO4-CNT) to enhance the electronic conductivity of the active material. Preliminary tests demonstrate a discharge capacity as high as 166 mAh/g at C/10 rate, corresponding to composition Na0.9FePO4, which along with higher C rate tests show this material to have the highest capacity and power performance reported for amorphous FePO4 electrodes to date. PMID- 25811763 TI - Patchy micelles based on coassembly of block copolymer chains and block copolymer brushes on silica particles. AB - Patchy particles are a type of colloidal particles with one or more well-defined patches on the surfaces. The patchy particles with multiple compositions and functionalities have found wide applications from the fundamental studies to practical uses. In this research patchy micelles with thiol groups in the patches were prepared based on coassembly of free block copolymer chains and block copolymer brushes on silica particles. Thiol-terminated and cyanoisopropyl-capped polystyrene-block-poly(N-isopropylacrylamide) block copolymers (PS-b-PNIPAM-SH and PS-b-PNIPAM-CIP) were synthesized by reversible addition-fragmentation chain transfer polymerization and chemical modifications. Pyridyl disulfide functionalized silica particles (SiO2-SS-Py) were prepared by four-step surface chemical reactions. PS-b-PNIPAM brushes on silica particles were prepared by thiol-disulfide exchange reaction between PS-b-PNIPAM-SH and SiO2-SS-Py. Surface micelles on silica particles were prepared by coassembly of PS-b-PNIPAM-CIP and block copolymer brushes. Upon cleavage of the surface micelles from silica particles, patchy micelles with thiol groups in the patches were obtained. Dynamic light scattering, transmission electron microscopy, and zeta-potential measurements demonstrate the preparation of patchy micelles. Gold nanoparticles can be anchored onto the patchy micelles through S-Au bonds, and asymmetric hybrid structures are formed. The thiol groups can be oxidized to disulfides, which results in directional assembly of the patchy micelles. The self-assembly behavior of the patchy micelles was studied experimentally and by computer simulation. PMID- 25811764 TI - Cleft and Craniofacial Coding in ICD-10. AB - OBJECTIVE: With the gradual replacement of the ICD-9 coding system by the newer ICD-10 system, there is a need to critically evaluate how the system improves-or fails to improve-the coding of specific cleft and craniofacial anomalies. The following review examines the new system and the key components for practitioners who treat patients with such anomalies. CONCLUSIONS: While seemingly beneficial in certain respects, the newer ICD-10 system remains far from ideal for cleft and craniofacial anomalies. With future iterations of the system, a more concerted effort to precisely code such anomalies is warranted, which will likely require input from key practitioners. PMID- 25811761 TI - Variations in the binding pocket of an inhibitor of the bacterial division protein FtsZ across genotypes and species. AB - The recent increase in antibiotic resistance in pathogenic bacteria calls for new approaches to drug-target selection and drug development. Targeting the mechanisms of action of proteins involved in bacterial cell division bypasses problems associated with increasingly ineffective variants of older antibiotics; to this end, the essential bacterial cytoskeletal protein FtsZ is a promising target. Recent work on its allosteric inhibitor, PC190723, revealed in vitro activity on Staphylococcus aureus FtsZ and in vivo antimicrobial activities. However, the mechanism of drug action and its effect on FtsZ in other bacterial species are unclear. Here, we examine the structural environment of the PC190723 binding pocket using PocketFEATURE, a statistical method that scores the similarity between pairs of small-molecule binding sites based on 3D structure information about the local microenvironment, and molecular dynamics (MD) simulations. We observed that species and nucleotide-binding state have significant impacts on the structural properties of the binding site, with substantially disparate microenvironments for bacterial species not from the Staphylococcus genus. Based on PocketFEATURE analysis of MD simulations of S. aureus FtsZ bound to GTP or with mutations that are known to confer PC190723 resistance, we predict that PC190723 strongly prefers to bind Staphylococcus FtsZ in the nucleotide-bound state. Furthermore, MD simulations of an FtsZ dimer indicated that polymerization may enhance PC190723 binding. Taken together, our results demonstrate that a drug-binding pocket can vary significantly across species, genetic perturbations, and in different polymerization states, yielding important information for the further development of FtsZ inhibitors. PMID- 25811765 TI - Fall risk factors in community-dwelling elderly depending on their physical function, cognitive status and symptoms of depression. AB - Falls are the leading cause of unintentional injuries and injury-related disability, morbidity and mortality in the geriatric population. Therefore, they may also lower quality of life. The aim of this study was to analyze the fall risk factors in the community-dwelling elderly depending on their physical function, cognitive status and symptoms of depression. The study involved 304 individuals aged 65-100 years with a mean age of 78.6 +/- 7.4. This survey-based study was conducted using the Geriatric Environmental Inquiry, the Barthel Scale (BS), the Abbreviated Mental Test Score (AMTS), the Geriatric Depression Scale (GDS) and the Tinetti Test (TT). There was a statistically significant correlation between the BS, the TT and the incidence of falls (p < 0.05). The number of falls correlated significantly with the results of the BS (R = -0.39), the GDS (R = 0.18), and the TT (R = -0.40). A statistically significant correlation was also noted between the TT results and the results of the BS (R = 0.77), the AMTS (R = 0.40) and the GDS (R = -0.37). The incidence of falls may significantly increase in people with a lower functional status, which may be related to cognitive process disturbances and lower affective functioning. A comprehensive geriatric assessment, related to all aspects of advanced-age patients' efficiency, is recommended. Fall prevention strategies should include actions undertaken to evaluate and treat depression and cognitive disturbances. PMID- 25811767 TI - Quit and smoking reduction rates in vape shop consumers: a prospective 12-month survey. AB - AIMS: Here, we present results from a prospective pilot study that was aimed at surveying changes in daily cigarette consumption in smokers making their first purchase at vape shops. Modifications in products purchase were also noted. DESIGN: Participants were instructed how to charge, fill, activate and use their e-cigarettes (e-cigs). Participants were encouraged to use these products in the anticipation of reducing the number of cig/day smoked. SETTINGS: Staff from LIAF contacted 10 vape shops in the province of the city of Catania (Italy) that acted as sponsors to the 2013 No Tobacco Day. PARTICIPANTS: 71 adult smokers (>=18 years old) making their first purchase at local participating vape shops were asked by professional retail staff to complete a form. MEASUREMENTS: Their cigarette consumption was followed-up prospectively at 6 and 12 months. Details of products purchase (i.e., e-cigs hardware, e-liquid nicotine strengths and flavours) were also noted. FINDINGS: Retention rate was elevated, with 69% of participants attending their final follow-up visit. At 12 month, 40.8% subjects could be classified as quitters, 25.4% as reducers and 33.8% as failures. Switching from standard refillables (initial choice) to more advanced devices (MODs) was observed in this study (from 8.5% at baseline to 18.4% at 12 month) as well as a trend in decreasing thee-liquid nicotine strength, with more participants adopting low nicotine strength (from 49.3% at baseline to 57.1% at 12 month). CONCLUSIONS: We have found that smokers purchasing e-cigarettes from vape shops with professional advice and support can achieve high success rates. PMID- 25811766 TI - Isolation and molecular characterization of free-living amoebae from different water sources in Italy. AB - Free-living amoebae (FLA) are protozoa ubiquitous in Nature, isolated from a variety of environments worldwide. In addition to their natural distribution, some species have been found to be pathogenic to humans. In the present study a survey was conducted in order to evaluate the presence and to characterize at molecular level the isolates of amoebic organisms collected from different water sources in Italy. A total of 160 water samples were analyzed by culture and microscopic examination. FLA were found in 46 (28.7%) of the investigated water samples. Groundwater, well waters, and ornamental fountain waters were the sources with higher prevalence rates (85.7%, 50.0%, and 45.9%, respectively). Identification of FLA species/genotypes, based on the 18S rDNA regions, allowed to identify 18 (39.1%) Acanthamoeba isolates (genotypes T4 and T15) and 21 (45.6%) Vermamoeba vermiformis isolates. Other FLA species, including Vahlkampfia sp. and Naegleria spp., previously reported in Italy, were not recovered. The occurrence of potentially pathogenic free-living amoebae in habitats related to human population, as reported in the present study, supports the relevance of FLA as a potential health threat to humans. PMID- 25811768 TI - Nicotine levels and presence of selected tobacco-derived toxins in tobacco flavoured electronic cigarette refill liquids. AB - BACKGROUND: Some electronic cigarette (EC) liquids of tobacco flavour contain extracts of cured tobacco leaves produced by a process of solvent extraction and steeping. These are commonly called Natural Extract of Tobacco (NET) liquids. The purpose of the study was to evaluate nicotine levels and the presence of tobacco derived toxins in tobacco-flavoured conventional and NET liquids. METHODS: Twenty one samples (10 conventional and 11 NET liquids) were obtained from the US and Greek market. Nicotine levels were measured and compared with labelled values. The levels of tobacco-derived chemicals were compared with literature data on tobacco products. RESULTS: Twelve samples had nicotine levels within 10% of the labelled value. Inconsistency ranged from -21% to 22.1%, with no difference observed between conventional and NET liquids. Tobacco-specific nitrosamines (TSNAs) were present in all samples at ng/mL levels. Nitrates were present almost exclusively in NET liquids. Acetaldehyde was present predominantly in conventional liquids while formaldehyde was detected in almost all EC liquids at trace levels. Phenols were present in trace amounts, mostly in NET liquids. Total TSNAs and nitrate, which are derived from the tobacco plant, were present at levels 200-300 times lower in 1 mL of NET liquids compared to 1 gram of tobacco products. CONCLUSIONS: NET liquids contained higher levels of phenols and nitrates, but lower levels of acetaldehyde compared to conventional EC liquids. The lower levels of tobacco-derived toxins found in NET liquids compared to tobacco products indicate that the extraction process used to make these products did not transfer a significant amount of toxins to the NET. Overall, all EC liquids contained far lower (by 2-3 orders of magnitude) levels of the tobacco derived toxins compared to tobacco products. PMID- 25811769 TI - A systematic review of community readiness tool applications: implications for reporting. AB - BACKGROUND: A systematic review characterised and synthesised applications of the Community Readiness Tool (CRT) and synthesised quantitative results for readiness applications at multiple time points. METHODS: Eleven databases in OvidSP and EBSCHOhost were searched to retrieve CRT applications. Information from primary studies was extracted independently by two researchers. RESULTS: Forty applications of the CRT met inclusion criteria focussing on 14 different health and social issues. The community of interest was most often defined solely on the basis of its geographical location (52.5%). Most studies used the CRT to plan (85%) and/or evaluate programs (40%). The CRT protocol was modified in 40% of studies. Six applications evaluated readiness at multiple time points, however limited reporting in primary studies precluded any synthesis of results. Applications identified methodological rigour, contextual information and community engagement as strengths, and time and resource costs as limitations. CONCLUSIONS: The CRT is well suited for planning and evaluating complex community health interventions given its flexibility to accommodate diverse definitions of community and issues. CRT applications would benefit from improved reporting; reporting recommendations for use of the CRT are outlined. PMID- 25811770 TI - Does an education seminar intervention improve the parents' knowledge on vaccination? Evidence from Yiwu, East China. AB - BACKGROUND: caregivers' knowledge on vaccination is an important impact factor for their children's vaccination status. The aims of this study were to evaluate the caregivers' knowledge of vaccination, and to assess effectiveness of a health education seminar for improving caregivers' knowledge on immunization. METHODS: pre- and post-assessment design was adopted for a single group to evaluate the effectiveness of the health education seminar on vaccination. The seminar consisted of a lecture using simple understandable language. Improvements in total knowledge score before and after the seminar were assessed using a validated questionnaire that included ten questions. Description analysis and non parametric tests were applied to evaluate and compare the vaccination knowledge level before and after the seminar. RESULTS: 378 caregivers participated in this study. The majority were mothers. Of the ten questions, the correct response rates had significantly increased for nine questions after the education seminar. The mean total score of the assessment before the seminar was 5.2 +/- 1.2 while that was 8.4 +/- 0.9 for the assessment after the seminar, with a significant increase of 3.18 points. CONCLUSION: a short education seminar designed for caregivers had a remarkable effect on their vaccination knowledge. Health education on vaccination targeting migrant caregivers, caregivers with lower education level or household income, and employed caregivers are needed in future. PMID- 25811771 TI - Impact of a patient-specific co-designed COPD care scorecard on COPD care quality: a quasi-experimental study. AB - BACKGROUND: The evidence that sharing mass care quality data with health service users improves care is weak. AIMS: We hypothesised that providing patients with individualised care quality data would drive improvements to the care received by those patients. METHODS: Together with patients who had chronic obstructive pulmonary disease (COPD), we co-designed a quality score card mapping indicators derived from National Institute for Clinical Excellence (NICE) quality standards against matched data taken from their general practice clinical records. All 640 COPD patients from 10 practices had improvements in these indicators before and 3 months after the intervention compared with 595 COPD patients in 10 control practices. RESULTS: Significant improvements in referral to pulmonary rehabilitation (P=0.03) and confirmation of diagnosis with spirometry (P=0.001) were seen in the intervention compared with the control practice population (P<0.001). Increases in the provision of self-management plans were seen in both the groups. No improvement was seen in other indicators. CONCLUSIONS: Although the study is not able to prove a direct cause and effect, there is sufficient evidence presented to warrant the larger-scale evaluation of co-designed, personalised, quality score cards for COPD patients used as a tool to enhance care quality. PMID- 25811773 TI - The unexpected non-monotonic inter-layer bonding dependence of the thermal conductivity of bilayered boron nitride. AB - Hexagonal boron nitride (BN) and its bilayer form are very fascinating two dimensional materials that have attracted tremendous interest recently. Their realistic applications in emerging nanoelectronics usually quest for manipulating the thermal transport properties in a precise manner. Using nonequilibrium molecular dynamics simulations, we herein studied the effect of inter-layer covalent bonding on the thermal conductivity of bilayered BN. We found that the in-plane thermal conductivity of bilayered BN, which can be largely tuned by introducing covalent bonding between the two BN layers, depends not only on the inter-layer bonding density, but also on the detailed topological configuration of the inter-layer bonds. For randomly distributed inter-layer bonding the thermal conductivity of bilayered BN decreases monotonically with inter-layer bonding density, the same behavior already found for bilayered graphene. However, for regularly arranged inter-layer bonding the thermal conductivity of bilayered BN surprisingly possesses a non-monotonic dependence on the inter-layer bonding density. This non-intuitive non-monotonic dependence is further explained by performing spectral energy density analysis, where the peak and valley values of the thermal conductivity are governed by different mechanisms. These results suggest the application of inter-layer covalent bonding in designing nanoscale devices with precisely tunable thermal conductivities. PMID- 25811774 TI - Patient Satisfaction: Why and How Patients Grade You and Your Pulmonary Practice. AB - Patient satisfaction is an important factor for consideration in pulmonary practice management. Although evidence regarding the correlation of patient satisfaction with care quality remains mixed, there is an increasing national emphasis on the importance of patient experience in physician reimbursement, credentialing, and public opinion. The introduction of the Affordable Care Act and value-based care purchasing has tied a portion of reimbursement to patient experience surveys and other metrics related to care quality rather than quantity. Through nationally recognized assessments such as the Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys and easily accessible websites such as RateMD and Yelp, patient opinion of care quality is more widely available and more important to pulmonary practice than ever before. Physician credentialing may also be impacted by the American Board of Internal Medicine's Maintenance of Certification program and potential future requirements for physicians to assess the patient experience to maintain certification. In the continually evolving health-care delivery, credentialing, and reimbursement climate, a thorough understanding of the increasing importance of patient satisfaction as well as strategies for successfully approaching this issue are essential to modern pulmonary inpatient and outpatient practice management. PMID- 25811775 TI - Factors associated with resilience of adult survivors five years after the 2008 Sichuan earthquake in China. AB - Given the paucity of quantitative empirical research on survivors' resilience and its predictors in the context of long-term recovery after disasters, we examined how resilience predictors differed by gender among adult survivors five years after the Sichuan earthquake. This was a cross-sectional survey study of adult survivors (N = 495; aged 18-60) living in reconstructed communities five years into the recovery process after the Wenchuan earthquake. The instruments we used included assessments of sociodemographic characteristics and earthquake exposure level, the Connor-Davidson Resilience Scale, and the Social Support Rating Scale. Support-seeking behaviors emerged as a significant predictor of male survivors' resilience, while subjective support and marital status were found to be predictors of female survivors' resilience. Annual household income and chronic disease were predictors for both male and female groups. The findings of this study can be used in devising methods to boost survivors' resilience by promoting their satisfaction with social support and their ability to obtain effective support. Additionally, the results suggest how to assist survivors who may have relatively poor resilience. PMID- 25811777 TI - Correction: Low message sensation health promotion videos are better remembered and activate areas of the brain associated with memory encoding. PMID- 25811772 TI - Validated System for Centralized Grading of Retinopathy of Prematurity: Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e ROP) Study. AB - IMPORTANCE: Measurable competence derived from comprehensive and advanced training in grading digital images is critical in studies using a reading center to evaluate retinal fundus images from infants at risk for retinopathy of prematurity (ROP). Details of certification for nonphysician trained readers (TRs) have not yet been described. OBJECTIVE: To describe a centralized system for grading ROP digital images by TRs in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study. DESIGN, SETTING, AND PARTICIPANTS: Multicenter observational cohort study conducted from July 1, 2010, to June 30, 2014. The TRs were trained by experienced ROP specialists and certified to detect ROP morphology in digital retinal images under supervision of an ophthalmologist reading center director. An ROP reading center was developed with standard hardware, secure Internet access, and customized image viewing software with an electronic grading form. A detailed protocol for grading was developed. Based on results of TR gradings, a computerized algorithm determined whether referral-warranted ROP (RW-ROP; defined as presence of plus disease, zone I ROP, and stage 3 or worse ROP) was present in digital images from infants with birth weight less than 1251 g enrolled from May 25, 2011, through October 31, 2013. Independent double grading was done by the TRs with adjudication of discrepant fields performed by the reading center director. EXPOSURE: Digital retinal images. MAIN OUTCOMES AND MEASURES: Intragrader and intergrader variability and monitoring for temporal drift. RESULTS: Four TRs underwent rigorous training and certification. A total of 5520 image sets were double graded, with 24.5% requiring adjudication for at least 1 component of RW-ROP. For individual RW-ROP components, the adjudication rate was 3.9% for plus disease, 12.4% for zone I ROP, and 16.9% for stage 3 or worse ROP. The weighted kappa for intergrader agreement (n = 80 image sets) was 0.72 (95% CI, 0.52-0.93) for RW ROP, 0.57 (95% CI, 0.37-0.77) for plus disease, 0.43 (95% CI, 0.24-0.63) for zone I ROP, and 0.67 (95% CI, 0.47-0.88) for stage 3 or worse ROP. The weighted kappa for grade-regrade agreement was 0.77 (95% CI, 0.57-0.97) for RW-ROP, 0.87 (95% CI, 0.67-1.00) for plus disease, 0.70 (95% CI, 0.51-0.90) for zone I ROP, and 0.77 (95% CI, 0.57-0.97) for stage 3 or worse ROP. CONCLUSIONS AND RELEVANCE: These data suggest that the e-ROP system for training and certifying nonphysicians to grade ROP images under the supervision of a reading center director reliably detects potentially serious ROP with good intragrader and intergrader consistency and minimal temporal drift. PMID- 25811776 TI - Role of Wnt/beta-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients. AB - BACKGROUND AND PURPOSE: Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/beta-catenin and RANKL/OPG pathways have a role in Charcot arthropathy. PATIENTS AND METHODS: 24 consecutive Charcot patients were treated by off loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand 1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference. RESULTS: Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study. INTERPRETATION: High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of particular clinical relevance considering the recent emergence of promising drugs that target this system. PMID- 25811778 TI - Cytokine, antibody and proliferative cellular responses elicited by Taenia solium calreticulin upon experimental infection in hamsters. AB - Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT) on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus). Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA) were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN) cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis. PMID- 25811779 TI - Partially overlapping primer-based PCR for genome walking. AB - Current genome walking methods are cumbersome to perform and can result in non specific products. Here, we demonstrate the use of partially overlapping primer based PCR (POP-PCR), a direct genome walking technique for the isolation of unknown flanking regions. This method exploits the partially overlapping characteristic at the 3' ends of a set of POP primers (walking primers), which guarantees that the POP primer only anneals to the POP site of the preceding PCR product at relatively low temperatures. POP primer adaptation priming at the genomic DNA/POP site occurs only once due to one low-/reduced-stringency cycle in each nested PCR, resulting in the synthesis of a pool of single-stranded DNA molecules. Of this pool, the target single-stranded DNA is replicated to the double-stranded form bound by the specific primer and the POP primer in the subsequent high-stringency cycle due to the presence of the specific primer binding site. The non-target single stranded DNA does not become double stranded due to the absence of a binding site for any of the primers. Therefore, the POP PCR enriches target DNA while suppressing non-target products. We successfully used POP-PCR to retrieve flanking regions bordering the gadA locus in Lactobacillus brevis NCL912, malQ in Pichia pastoris GS115, the human aldolase A gene, and hyg in rice. PMID- 25811780 TI - Exploring Twitter to analyze the public's reaction patterns to recently reported homicides in London. AB - Crime is an ubiquitous part of society. The way people express their concerns about crimes has been of particular interest to the scientific community. Over time, the numbers and kinds of available communication channels have increased. Today, social media services, such Twitter, present a convenient way to express opinions and concerns about crimes. The main objective of this study is to explore people's perception of homicides, specifically, how the characteristics and proximity of the event affect the public's concern about it. The analysis explores Twitter messages that refer to homicides that occurred in London in 2012. In particular, the dependence of tweeting propensity on the proximity, in space and time, of a crime incident and of people being concerned about that particular incident are examined. Furthermore, the crime characteristics of the homicides are analysed using logistic regression analysis. The results show that the proximity of the Twitter users' estimated home locations to the homicides' locations impacts on whether the associated crime news is spread or not and how quickly. More than half of the homicide related tweets are sent within the first week and the majority of them are sent within a month of the incident's occurrence. Certain crime characteristics, including the presence of a knife, a young victim, a British victim, or a homicide committed by a gang are predictors of the crime-tweets posting frequency. PMID- 25811781 TI - Development and validation of a cross-cultural knowledge, attitudes, and practices survey instrument for chronic kidney disease in a Swahili-speaking population. AB - INTRODUCTION: Non-communicable diseases are a growing global burden, and structured surveys can identify critical gaps to address this epidemic. In sub Saharan Africa, there are very few well-tested survey instruments measuring population attributes related to non-communicable diseases. To meet this need, we have developed and validated the first instrument evaluating knowledge, attitudes and practices pertaining to chronic kidney disease in a Swahili-speaking population. METHODS AND RESULTS: Between December 2013 and June 2014, we conducted a four-stage, mixed-methods study among adults from the general population of northern Tanzania. In stage 1, the survey instrument was constructed in English by a group of cross-cultural experts from multiple disciplines and through content analysis of focus group discussions to ensure local significance. Following translation, in stage 2, we piloted the survey through cognitive and structured interviews, and in stage 3, in order to obtain initial evidence of reliability and construct validity, we recruited and then administered the instrument to a random sample of 606 adults. In stage 4, we conducted analyses to establish test-retest reliability and known-groups validity which was informed by thematic analysis of the qualitative data in stages 1 and 2. The final version consisted of 25 items divided into three conceptual domains: knowledge, attitudes and practices. Each item demonstrated excellent test-retest reliability with established content and construct validity. CONCLUSIONS: We have developed a reliable and valid cross-cultural survey instrument designed to measure knowledge, attitudes and practices of chronic kidney disease in a Swahili speaking population of Northern Tanzania. This instrument may be valuable for addressing gaps in non-communicable diseases care by understanding preferences regarding healthcare, formulating educational initiatives, and directing development of chronic disease management programs that incorporate chronic kidney disease across sub-Saharan Africa. PMID- 25811782 TI - Childhood maltreatment and BMI trajectories to mid-adult life: follow-up to age 50 y in a British birth cohort. AB - BACKGROUND: Childhood maltreatment including abuse and neglect has been associated with adult obesity, but evidence on life-course development of obesity or BMI gain is unclear. We aim to establish whether childhood maltreatments are related to obesity or BMI at different life-stages 7 y-50 y and to identify possible explanations for associations. METHODS: Childhood physical, psychological and sexual abuse, neglect and BMI at seven ages were recorded in the 1958 birth cohort (n~15,000). Associations of child maltreatments with BMI at separate ages were tested using linear regression or logistic regression for obesity, and with rate of child-to-adult BMI gain using multilevel models. We adjusted for potential covariates. RESULTS: Abuse was reported in ~12% of the population. Abuse was not associated with elevated childhood BMI, but adult associations were observed: i.e. the abused had faster child-adult BMI gain than the non-abused; associations were independent of adult covariates. For physical abuse in both genders there was a positive linear association of ~0.006/y zBMI gain with age after adjustment for all covariates. Similarly, there was a linear association of physical abuse with obesity risk: e.g. among females from a low OR(adjusted) of 0.34 (0.16,0.71) at 7 y to 1.67 (1.25,2.24) at 50 y. In females faster zBMI gains with age of ~0.0034/y were observed for sexual abuse and increases in obesity risk were faster: from a low OR(adjusted) of 0.23 (0.06,0.84) at 7 y to 1.34 (0.86,2.10) at 50 y. Psychological abuse and neglect associations were less consistent. CONCLUSIONS: Childhood maltreatment associations with BMI or obesity varied across life: physical and, in females, sexual abuse were associated with faster lifetime BMI gains, which may have detrimental long-term health consequences. PMID- 25811784 TI - Correction: challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience. AB - [This corrects the article DOI: 10.1371/journal.pone.0108048.]. PMID- 25811783 TI - Intravenous therapy duration and outcomes in melioidosis: a new treatment paradigm. AB - BACKGROUND: International melioidosis treatment guidelines recommend a minimum 10 to 14 days' intravenous antibiotic therapy (intensive phase), followed by 3 to 6 months' oral therapy (eradication phase). This approach is associated with rates of relapse, defined as recurrence following the eradication phase, that can exceed 5%. Rates of recrudescence, defined as recurrence during the eradication phase, have not previously been reported. In response to low eradication phase completion rates in Australia, a local guideline has evolved over the last ten years recommending a longer minimum intensive phase duration for many cases of melioidosis. METHODOLOGY/ PRINCIPAL FINDINGS: This retrospective cohort study reviews antibiotic duration for the first episode of care for all patients diagnosed with melioidosis and surviving the intensive phase during a recent three year period in the tropical north of Australia's Northern Territory; we also review adherence to the current local guideline and treatment outcomes. Of 215 first episodes of melioidosis surviving the intensive phase, the median (interquartile range) intensive phase duration was 26 (14-34) days. One hundred and eight (50.2%) patients completed eradication therapy; 58 (27.0%) patients took no eradication therapy. At 28 months' follow-up, one (0.5%) relapse and eleven (5.1%) recrudescences had occurred. On exact logistic regression analysis, the only independent risk factors for recrudescence were self-discharge during the intensive phase (odds ratio 6.2 [95% confidence interval 1.2-30.0]) and septic shock (odds ratio 5.3 [95% confidence interval 1.1-25.7]). CONCLUSIONS/ SIGNIFICANCE: Relapsed melioidosis is rare in patients who receive a minimum intensive phase duration specified by our guideline and extended according to clinical progress. Recrudescence rates may improve with reductions in rates of self-discharge. Given the low relapse rate despite a high rate of eradication therapy non-adherence, the duration and necessity of eradication therapy for different patients after guideline-concordant intensive therapy should be evaluated further. PMID- 25811785 TI - Imaging quality evaluation of low tube voltage coronary CT angiography using low concentration contrast medium. AB - PURPOSE: To compare the image quality of prospectively ECG-gated low voltage coronary computed tomography angiography (CTA) with an administration of low concentration contrast medium. METHOD AND MATERIALS: A total of 101 patients, each with a heart rate below 65 beats per minute (BPM), underwent a prospectively ECG-gated axial scan in CT coronary angiography on a 64-slice CT scanner. All patients were allocated in three groups (group A: n=31, 80 kVp, 300 mgI/ml; group B: n=34, 100 kVp, 300 mgI/ml; group C: n=36, 120 kVp, 370 mgI/ml). The CT attenuation values of aortic root (AR), left main coronary artery (LMA), right main coronary artery (RMA) and chest subcutaneous fat tissue were measured. The contrast-to-noise ratio (CNR) of AR, LMA and RMA were calculated according to the formulas below. The values of computed tomography dose index (CTDI) and dose length product (DLP) were recorded. Image quality was assessed on a 5-point scale. The results were compared using the one-way ANOVA and rank sum tests. RESULTS: The values of CNR and SNR for vessels in group A and group B were not significantly different from group C (each p > 0.05). The effective radiation dose in group A (1.51 +/- 0.70 mSv) and group B (2.59 +/- 1.24 mSv) were both lower than group C (4.92 +/- 2.82 mSv) (each p < 0.05). There was no significant difference among the image quality scores of group A (4.10 +/- 0.41), group B (3.90 +/- 0.48) and group C (4.04 +/- 0.36) (each P > 0.05). CONCLUSION: Low tube voltage coronary CT angiography using low concentration contrast medium does not affect the imaging quality for assessing the coronary arteries compared with high voltage coronary CT angiography using high concentration contrast medium. Meanwhile low concentration contrast medium allowed 47-69% of radiation dose reduction. PMID- 25811786 TI - Automatic and integrated micro-enzyme assay (AIMUEA) platform for highly sensitive thrombin analysis via an engineered fluorescence protein-functionalized monolithic capillary column. AB - Nowadays, large-scale screening for enzyme discovery, engineering, and drug discovery processes require simple, fast, and sensitive enzyme activity assay platforms with high integration and potential for high-throughput detection. Herein, a novel automatic and integrated micro-enzyme assay (AIMUEA) platform was proposed based on a unique microreaction system fabricated by a engineered green fluorescence protein (GFP)-functionalized monolithic capillary column, with thrombin as an example. The recombinant GFP probe was rationally engineered to possess a His-tag and a substrate sequence of thrombin, which enable it to be immobilized on the monolith via metal affinity binding, and to be released after thrombin digestion. Combined with capillary electrophoresis-laser-induced fluorescence (CE-LIF), all the procedures, including thrombin injection, online enzymatic digestion in the microreaction system, and label-free detection of the released GFP, were integrated in a single electrophoretic process. By taking advantage of the ultrahigh loading capacity of the AIMUEA platform and the CE automatic programming setup, one microreaction column was sufficient for many times digestion without replacement. The novel microreaction system showed significantly enhanced catalytic efficiency, about 30 fold higher than that of the equivalent bulk reaction. Accordingly, the AIMUEA platform was highly sensitive with a limit of detection down to 1 pM of thrombin. Moreover, the AIMUEA platform was robust and reliable to detect thrombin in human serum samples and its inhibition by hirudin. Hence, this AIMUEA platform exhibits great potential for high-throughput analysis in future biological application, disease diagnostics, and drug screening. PMID- 25811790 TI - Drying with no concentration gradient in large microfluidic droplets. AB - In most situations, drying is accompanied by the development of strong concentration gradients. Here, we evidence theoretically and experimentally that there exist microfluidic geometries for which confined drying becomes homogeneous, i.e., with no concentration gradient regardless of the type of solute involved in the process; ions, molecules, and colloids do concentrate in the same way providing a limited set of assumptions concerning the microfluidic geometry. It thus makes possible the establishment of phase diagrams of multi component mixtures at the nanoliter scale. PMID- 25811788 TI - Toll-like receptor 4 promotes autonomic dysfunction, inflammation and microglia activation in the hypothalamic paraventricular nucleus: role of endoplasmic reticulum stress. AB - BACKGROUND & PURPOSE: Toll-like receptor 4 (TLR4) signaling induces tissue pro inflammatory cytokine release and endoplasmic reticulum (ER) stress. We examined the role of TLR4 in autonomic dysfunction and the contribution of ER stress. EXPERIMENTAL APPROACH: Our study included animals divided in 6 experimental groups: rats treated with saline (i.v., 0.9%), LPS (i.v., 10mg/kg), VIPER (i.v., 0.1 mg/kg), or 4-PBA (i.p., 10 mg/kg). Two other groups were pretreated either with VIPER (TLR4 viral inhibitory peptide) LPS + VIPER (i.v., 0.1 mg/kg) or 4 Phenyl butyric acid (4-PBA) LPS + PBA (i.p., 10 mg/kg). Arterial pressure (AP) and heart rate (HR) were measured in conscious Sprague-Dawley rats. AP, HR variability, as well as baroreflex sensitivity (BrS), was determined after LPS or saline treatment for 2 hours. Immunofluorescence staining for NeuN, Ib1a, TLR4 and GRP78 in the hypothalamic paraventricular nucleus (PVN) was performed. TNF alpha, TLR4 and GRP78 protein expression in the PVN were evaluated by western blot. Plasma norepinephrine levels were determined by ELISA. KEY RESULTS: Acute LPS treatment increased HR and plasma norepinephrine concentration. It also decreased HR variability and high frequency (HF) components of HR variability, as well BrS. Acute LPS treatment increased TLR4 and TNF-alpha protein expression in the PVN. These hemodynamic and molecular effects were partially abrogated with TLR4 blocker or ER stress inhibitor pretreatment. In addition, immunofluorescence study showed that TLR4 is co-localized with GRP78in the neurons. Further inhibition of TLR4 or ER stress was able to attenuate the LPS-induced microglia activation. CONCLUSIONS & IMPLICATIONS: TLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN. PMID- 25811789 TI - Protease activity of PprI facilitates DNA damage response: Mn2+-dependence and substrate sequence-specificity of the proteolytic reaction. AB - The extremophilic bacterium Deinococcus radiodurans exhibits an extraordinary resistance to ionizing radiation. Previous studies established that a protein named PprI, which exists only in the Deinococcus-Thermus family, acts as a general switch to orchestrate the expression of a number of DNA damage response (DDR) proteins involved in cellular radio-resistance. Here we show that the regulatory mechanism of PprI depends on its Mn(2+)-dependent protease activity toward DdrO, a transcription factor that suppresses DDR genes' expression. Recognition sequence-specificity around the PprI cleavage site is essential for DNA damage repair in vivo. PprI and DdrO mediate a novel DNA damage response pathway differing from the classic LexA-mediated SOS response system found in radiation-sensitive bacterium Escherichia coli. This PprI-mediated pathway in D. radiodurans is indispensable for its extreme radio-resistance and therefore its elucidation significantly advances our understanding of the DNA damage repair mechanism in this amazing organism. PMID- 25811791 TI - Inhibitory mechanisms of celastrol on human liver cytochrome P450 1A2, 2C19, 2D6, 2E1 and 3A4. AB - 1. The present study was conducted to examine the possibility of herb-drug interaction by celastrol, which is a main compound isolated from Tripterygium wilfordii Hook F. using human liver microsomes with cocktail methods. Focused on its inhibitory manner on the metabolism of model probe substrates of five cytochrome P450 isoenzymes (CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in vitro which are important with the metabolism of different xenobiotics. 2. The results showed that celastrol inhibited the five types of human cytochrome P450 isoforms, with the IC50 values of 2.65 MUM (CYP3A4), 5.99 MUM (CYP2C19), 6.27 MUM (CYP2D6), 7.66 MUM (CYP1A2) and 9.38 MUM (CYP2E1), respectively. The data indicated that celastrol acted in different manners as an inhibitor of human cytochrome P450 isoforms, which showed that celastrol not only un-competitively inhibited the CYP1A2 and 2E1 activities, but also competitively inhibited the CYP2C19 and 2D6 activities with Ki values of 1.41, 2.29, 5.27 and 4.21 MUM, respectively. Celastrol was also a mixed-type inhibitor of CYP3A4, with Ki and Kis values of 2.02 and 5.49 MUM, respectively. 3. Celastrol has the potential to inhibit cytochrome P450 activities and may cause the herb-drug interactions. Therefore, the use of celastrol and its preparations with conventional medicines should thus be taken in to account. PMID- 25811793 TI - Synthesis, Characterization, and Fluorescence Properties of Mixed Molecular Multilayer Films of BODIPY and Zn(II) Tetraphenylporphyrins. AB - A new azido functionalized 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) has been synthesized to achieve spectral complementarity to a Zn(II) tetraphenylethynyl porphyrin (ZnTPEP). Mixed multilayer films were assembled on glass and quartz up to 10 bilayers thick in a layer-by-layer (LbL) fabrication process using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to couple these two dyes together with a tris-azido linker. By varying the amount of BODIPY in the CuAAC reaction solutions for the azido linker layers, we achieve tunable doping of BODIPY within the porphyrin films. We are able to demonstrate linear film growth and determine thickness by X-ray reflectivity (XRR). XRR data indicated that lower BODIPY loading leads to higher porphyrin content and slightly thicker films. Fluorescence emission and excitation spectra of the mixed multilayer films show efficient quenching of the BODIPY singlet and enhanced ZnTPEP emission, suggesting efficient energy transfer (EnT). The ease of fabrication and tunability of these films may serve as potential light harvesting arrays for molecular-based solar cells. PMID- 25811792 TI - Discovery of Orally Available Runt-Related Transcription Factor 3 (RUNX3) Modulators for Anticancer Chemotherapy by Epigenetic Activation and Protein Stabilization. AB - Recently, we identified a novel strategy for anticancer chemotherapy by restoring runt-related transcription factor 3 (RUNX3) levels via lactam-based histone deacetylase (HDAC) inhibitors that stabilize RUNX3. Described here are the synthesis, biological evaluation, and pharmacokinetic evaluation of new synthetic small molecules based on pyridone-based HDAC inhibitors that specifically stabilize RUNX3 by acetylation and regulate its function. Many of the newly synthesized compounds showed favorable RUNX activities, HDAC inhibitory activities, and inhibitory activities on the growth of human cancer cell lines. Notably, one of these new derivatives, (E)-N-hydroxy-3-(2-oxo-1-(quinolin-2 ylmethyl)-1,2-dihydropyridin-3-yl)acrylamide (4l), significantly restored RUNX3 in a dose-dependent manner and showed high metabolic stability, a good pharmacokinetic profile with high oral bioavailability and long half-life, and strong antitumor activity. This study suggests that pyridone-based analogues modulate RUNX3 activity through epigenetic regulation as well as strong transcriptional and post-translational regulation of RUNX3 and could be potential clinical candidates as orally available RUNX3 modulators for the treatment of cancer. PMID- 25811795 TI - The efficacy of scale sampling for monitoring trace element concentrations and stable isotopes in commercially harvested walleye (Sander vitreus). AB - Commercial and sport fishes are subject to rigorous monitoring for concentrations of elements that could pose threats to human health, with numerous advisories issued by authorities annually for those fisheries with high mercury (Hg) concentrations. In Lake Winnipeg, Manitoba, Canada, the commercial walleye fishery is valued at more than $20 million/year, but has historically been subject to Hg advisories. We used an information theoretic approach to evaluate the utility of non-destructive fish-scale sampling to predict As, Mn and Hg concentrations, as well as stable isotope values in walleye muscle by analysing paired samples. Hg concentrations in scales were significantly related to those in muscle (r(2) = 0.75), but the relationships were weaker for As and Mn. The delta(15)N values in scales predicted delta(15)N in muscle reasonably well (r(2) = 0.72), whereas scale delta(13)C and delta(34)S had less predictive power for estimating their respective muscle stable isotope values. For all three isotope values, sex was a marginal predictor, with parameter confidence intervals bounding zero. Analytical constraints currently limit the utility of non destructively analysing scales for Hg, but hindcasting trophic changes using archived walleye scales may be useful in understanding shifts in nutrients and production, particularly in impacted lake systems. PMID- 25811794 TI - Relationships Among Adverse Events, Disease Characteristics, and Demographics in Treatment of Postherpetic Neuralgia With Gastroretentive Gabapentin. AB - OBJECTIVES: To characterize risk factors for occurrence of adverse events (AEs) and treatment discontinuations due to AEs for improving safety and tolerability of treatment of postherpetic neuralgia (PHN). METHODS: Patients with PHN (n=556) received 1800 mg once-daily gastroretentive gabapentin (G-GR) in 2 phase 3 and 1 phase 4 study. Safety assessments included the incidence and severity of AEs and analysis of discontinuations due to AEs. Multivariable, logistic regression analyses examined predictors of AE reporting and discontinuations due to AEs. RESULTS: In total, 53.2% of patients reported any AE, and 12.9% discontinued because of AEs. Both AE incidence and treatment discontinuations decreased rapidly during the 2-week titration to sustained, low levels. The probability to report any AE was 0.6 for females versus 0.4 for males, whereas there were no differences in probabilities for age (less than 75 vs. 75 y and older) and race (nonwhite vs. white). Consistent with this, only female sex was a significant (P=0.0006) predictor of AE reporting. Experiencing moderate (P<=0.0001) or severe (P=0.0006) AEs, but not patient demographics, was predictive of treatment discontinuations. The probability of discontinuation due to moderate AEs was 0.4 and 0.5 for severe AEs. DISCUSSION: The tolerability of G-GR was not affected by patient age, but was affected by AE severity. Although being female was predictive of reporting AEs, it did not influence treatment discontinuation. Given that PHN is a disease for which the risk and duration of PHN increases with age and with being female, G-GR appears to be a well-suited treatment option for PHN. PMID- 25811787 TI - Modulation of genetic associations with serum urate levels by body-mass-index in humans. AB - We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment. PMID- 25811796 TI - Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer. AB - Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease. PMID- 25811798 TI - Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model. AB - Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3(Tyr705), matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3 positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer. PMID- 25811797 TI - Determinants of Activity Levels in African Americans With Mild Cognitive Impairment. AB - Engaging in cognitive, social, and physical activities may prevent cognitive decline. In a sample of older African Americans with mild cognitive impairment (MCI; N=221), we investigated the cross-sectional relationships between activity levels and participants' demographic, clinical, and neuropsychological characteristics. The average age of participants was 75.4 years (SD, 7.0); 177 (80.1%) were women. Participation in cognitive/social activities was positively associated with education, depression, literacy, mobility, instrumental activities of daily living (IADL), verbal learning, and subcomponents of executive function. A linear regression identified IADLs, education, depression, and verbal learning as independent predictors. Participation in physical activities was positively associated with sex, depression, IADLs, and subcomponents of executive function. An ordinal regression identified executive function and depression as independent correlates. These data suggest that unique characteristics are associated with cognitive/social and physical activities in older African Americans with MCI. These characteristics, coupled with low activity levels, may increase the risk of progression from MCI to dementia. Culturally relevant behavioral interventions to reduce cognitive decline in this high-risk population are needed. PMID- 25811800 TI - Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression. AB - The high mortality in breast cancer is often associated with metastatic progression in patients. Previously we have demonstrated that testes-specific protease 50 (TSP50), an oncogene overexpressed in breast cancer samples, could promote cell proliferation and tumorigenesis. However, whether TSP50 also has a key role in cell invasion and cancer metastasis, and the mechanism underlying the process are still unclear. Here we found that TSP50 overexpression greatly promoted cell migration, invasion, adhesion and formation of the stellate structures in 3D culture system in vitro as well as lung metastasis in vivo. Conversely, TSP50 knockdown caused the opposite changes. Mechanistic studies revealed that NF-kappaB signaling pathway was required for TSP50-induced cell migration and metastasis, and further results indicated that TSP50 overexpression enhanced expression and secretion of MMP9, a target gene of NF-kappaB signaling. In addition, knockdown of MMP9 resulted in inhibition of cell migration and invasion in vitro and lung metastasis in vivo. Most importantly, immunohistochemical staining of human breast cancer samples strongly showed that the coexpression of TSP50 and p65 as well as TSP50 and MMP9 were correlated with increased metastasis and poor survival. Furthermore, we found that some breast cancer diagnosis-associated features such as tumor size, tumor grade, estrogen receptors (ER) and progesterone receptors (PR) levels, were correlated well with TSP50/p65 and TSP50/MMP9 expression status. Taken together, this work identified the TSP50 activation of MMP9 as a novel signaling mechanism underlying human breast cancer invasion and metastasis. PMID- 25811801 TI - D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH. AB - Somatic mutations in isocitrate dehydrogenase (IDH)-1 and -2 have recently been described in glioma. This mutation leads to a neomorphic enzymatic activity as the conversion of isocitrate to alpha ketoglutarate (alphaKG) is replaced by the conversion of alphaKG to D-2-hydroxyglutarate (D-2HG) with NADPH oxidation. It has been suggested that this oncometabolite D-2HG via inhibition of alphaKG dioxygenases is involved in multiple functions such as epigenetic modifications or hypoxia responses. The present study is aimed at deciphering how the mutant IDH can affect cancer pathogenesis, in particular with respect to its associated oncometabolite D-2HG. We show that the overexpression of mutant IDH in glioma cells or treatment with D-2HG triggered an increase in cell proliferation. However, although mutant IDH reduced cell sensitivity to the apoptotic inducer etoposide, D-2HG exhibited no effect on apoptosis. Instead, we found that the apoptotic effect was mediated through the mitochondrial NADH pool reduction and could be inhibited by oxamate. These data show that besides D-2HG production, mutant IDH affects other crucial metabolite pools. These observations lead to a better understanding of the biology of IDH mutations in gliomas and their response to therapy. PMID- 25811799 TI - Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia. AB - Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP 43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS. PMID- 25811802 TI - Loss of Drosophila pseudouridine synthase triggers apoptosis-induced proliferation and promotes cell-nonautonomous EMT. AB - Many developing tissues display regenerative capability that allows them to compensate cell loss and preserve tissue homeostasis. Because of their remarkable regenerative capability, Drosophila wing discs are extensively used for the study of regenerative phenomena. We thus used the developing wing to investigate the role played in tissue homeostasis by the evolutionarily conserved eukaryotic H/ACA small nucleolar ribonucleoprotein pseudouridine synthase. Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells. In fact, some cells undergo apoptosis, whereas those surrounding the apoptotic foci, although identically depleted, overproliferate. This overproliferation correlates with ectopic induction of the Wg and JAK-STAT (Janus kinase-signal transducer and activator of transcription) mitogenic pathways. Expression of a p35 transgene, which blocks the complete execution of the death program and generates the so called 'undead cells', amplifies the proliferative response. Pseudouridine synthase depletion also causes loss of apicobasal polarity, disruption of adherens cell junctions and ectopic induction of JNK (c-Jun N-terminal kinase) and Mmp1 (matrix metalloproteinase-1) activity, leading to a significant epithelial reorganization. Unexpectedly, cell-nonautonomous effects, such as epithelial mesenchymal transition in the contiguous unsilenced squamous epithelium, are also promoted. Collectively, these data point out that cell-cell communication and long-range signaling can take a relevant role in the response to pseudouridine synthase decline. Considering that all the affected pathways are highly conserved throughout evolution, it is plausible that the response to pseudouridine synthase depletion has been widely preserved. On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity. PMID- 25811805 TI - Rayleigh light scattering properties of atmospheric molecular clusters consisting of sulfuric acid and bases. AB - The Rayleigh light scattering properties of (H2SO4)a(NH3)b and (H2SO4)a((CH3)2NH)b atmospheric molecular clusters have been investigated using a response theory approach. Using density functional theory the molecular structures and stepwise formation free energies of clusters with a and b up to 4 have been re-investigated. The Rayleigh scattering intensities are calculated from the dipole polarizability tensor alpha using the CAM-B3LYP functional by applying linear response methods. The intrinsic scattering properties of (H2SO4)a(NH3)b and (H2SO4)a((CH3)2NH)b indicate that amine containing clusters scatter light significantly more efficiently then their ammonia containing counterparts. Using the Atmospheric Cluster Dynamics Code (ACDC) the steady state cluster concentrations are estimated and the effective scattering is calculated. The effective scattering is shown to be highly dependent on the estimated concentrations and indicates that there exist competitive pathways, such as nucleation and coagulation, which influence the cluster distributions. The frequency dependence of the scattering is found to depend on the cluster composition and show increased responses when clusters contain more bases than acid molecules. Based on structures obtained using semi-empirical molecular dynamics simulations the Rayleigh scattering properties of clusters with up to 20 acid-base pairs are evaluated. This study represents the first step towards gaining a fundamental understanding of the scattering properties of small atmospheric clusters in the ambient atmosphere. PMID- 25811803 TI - Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases. AB - Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(-/-) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70(-/-) mice. Here, we show that ku70(-/-) bax(+/-) and ku70(-/-) bax(-/-) mice have better survival, especially in females, than ku70(-/-) mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70-null background. Moreover, we found that ku70(-/-) mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70(-/ ) mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70(-/-) and Bax-deficient ku70(-/-) mice may be useful models to study these diseases. PMID- 25811806 TI - Enterovirus D68 infection, Chile, Spring 2014. PMID- 25811804 TI - Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice. AB - Fibroblast growth factor (FGF) 21 is an endocrine factor that normalizes glucose homeostasis and reduces insulin resistance in diabetes. Although the pancreas is an FGF21 target organ, its role in pancreatic islets remains obscure. This study aimed to elucidate the physiological role of FGF21 in pancreatic islets using FGF21-knockout (FGF21-KO) mice. Twenty-four-week-old male global FGF21-KO mice were used in this study. Glucose and insulin tolerance were assessed. Expression of genes and proteins related to islet function and underlying mechanisms were also examined. Islet morphology and insulin-secreting capacity were further evaluated. FGF21-KO mice exhibited insulin resistance while being normoglycemic, associated with increases in beta-cell proliferation and insulin synthesis, acting as compensatory responses. This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets. In addition, ex vivo FGF21 treatment in normal C57BL/6J mouse islets reduced GH signaling, probably via upregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPARgamma and CIS expression. FGF21 treatment also reversed GH induced insulin expression, beta-cell proliferation and GH-impaired glucose stimulated insulin secretion (GSIS) in islets. Furthermore, distorted islet morphology and impaired GSIS were observed in KO mice, suggestive of islet dysfunction, whereas the enhanced insulin expression and impaired GSIS in FGF21 KO mouse islets could be reversed by blockade of GH signaling. Our data indicate that FGF21 is important in the regulation of beta-cell proliferation and insulin synthesis, probably via modulation of GH signaling. These findings provide evidence that FGF21 is an obligatory metabolic regulator in pancreatic islets and shed new light onto the role of endogenous FGF21 in the pathogenesis of insulin resistance and islet dysfunction. PMID- 25811808 TI - Radical-induced, proton-transfer-driven fragmentations in [b(5)-H](+) ions derived from pentaalanyl tryptophan. AB - The collision-induced dissociation (CID) of [b5 - H](+) ions containing four alanine residues and one tryptophan give identical spectra regardless of the initial location of the tryptophan indicating that, as proposed for b5(+) ions, sequence scrambling occurs prior to dissociation. Cleavage occurs predominantly at the peptide bonds and at the N-Calpha bond of the alanine residue that is attached to the N-terminus of the tryptophan residue. The product of the latter pathway, an ion at m/z 240, is the base peak in all the mass spectra. With the exception of one minor channel giving a b3(+) ion, the product ions retain both the tryptophan residue and the radical. Experiments with one trideuterated alanine established the sequences of loss of alanine residues. Formation of identical products implies a common intermediate, a [b5 - H](+) ion that has a 'linear' structure in which the tryptophan residue is present as an alpha-radical located in the oxazolone ring, structure Ie. Density functional theory calculations show this structure to be at the global minimum, 14.6 kcal mol(-1) below the macrocyclic structure, ion II. Loss of CO from the [b5 - H](+) ions is inhibited by the presence of the radical centre in the oxazolone ring and migration of the proton from the oxazolone ring onto the peptide backbone induces cleavage of an N-Calpha or peptide bond. Three calculated structures for the ion at m/z 240 all have an oxazolone ring. Two of these structures may be formed from Ie, depending upon which proton migrates onto the peptide chain prior to the dissociation. The barrier to interconversion between these two structures requires a 1,3-hydrogen atom shift and is high (51.0 kcal mol(-1)), but both can convert into a third isomer that readily loses CO2 (barrier 38.7 kcal mol(-1)). The lowest barrier to the loss of CO, the usual fragmentation path observed for protonated oxazolones, is 47.0 kcal mol(-1). PMID- 25811809 TI - Open-system dynamics of entanglement: a key issues review. AB - One of the greatest challenges in the fields of quantum information processing and quantum technologies is the detailed coherent control over each and every constituent of quantum systems with an ever increasing number of particles. Within this endeavor, harnessing of many-body entanglement against the detrimental effects of the environment is a major pressing issue. Besides being an important concept from a fundamental standpoint, entanglement has been recognized as a crucial resource for quantum speed-ups or performance enhancements over classical methods. Understanding and controlling many-body entanglement in open systems may have strong implications in quantum computing, quantum simulations of many-body systems, secure quantum communication or cryptography, quantum metrology, our understanding of the quantum-to-classical transition, and other important questions of quantum foundations.In this paper we present an overview of recent theoretical and experimental efforts to underpin the dynamics of entanglement under the influence of noise. Entanglement is thus taken as a dynamic quantity on its own, and we survey how it evolves due to the unavoidable interaction of the entangled system with its surroundings. We analyze several scenarios, corresponding to different families of states and environments, which render a very rich diversity of dynamical behaviors.In contrast to single-particle quantities, like populations and coherences, which typically vanish only asymptotically in time, entanglement may disappear at a finite time. In addition, important classes of entanglement display an exponential decay with the number of particles when subject to local noise, which poses yet another threat to the already-challenging scaling of quantum technologies. Other classes, however, turn out to be extremely robust against local noise. Theoretical results and recent experiments regarding the difference between local and global decoherence are summarized. Control and robustness enhancement techniques, scaling laws, statistical and geometrical aspects of multipartite-entanglement decay are also reviewed; all in order to give a broad picture of entanglement dynamics in open quantum systems addressed to both theorists and experimentalists inside and outside the field of quantum information. PMID- 25811807 TI - The pcz1 gene, which encodes a Zn(II)2Cys6 protein, is involved in the control of growth, conidiation, and conidial germination in the filamentous fungus Penicillium roqueforti. AB - Proteins containing Zn(II)(2)Cys(6) domains are exclusively found in fungi and yeasts. Genes encoding this class of proteins are broadly distributed in fungi, but few of them have been functionally characterized. In this work, we have characterized a gene from the filamentous fungus Penicillium roqueforti that encodes a Zn(II)(2)Cys(6) protein, whose function to date remains unknown. We have named this gene pcz1. We showed that the expression of pcz1 is negatively regulated in a P. roqueforti strain containing a dominant active Galphai protein, suggesting that pcz1 encodes a downstream effector that is negatively controlled by Galphai. More interestingly, the silencing of pcz1 in P. roqueforti using RNAi silencing technology resulted in decreased apical growth, the promotion of conidial germination (even in the absence of a carbon source), and the strong repression of conidiation, concomitant with the downregulation of the genes of the central conidiation pathway brlA, abaA and wetA. A model for the participation of pcz1 in these physiological processes in P. roqueforti is proposed. PMID- 25811810 TI - Development of egg PC/cholesterol/alpha-tocopherol liposomes with ionic gradients to deliver ropivacaine. AB - CONTEXT: Ropivacaine (RVC) is an aminoamide local anesthetic widely used in surgical procedures. Studies with RVC encapsulated in liposomes and complexed in cyclodextrins have shown good results, but in order to use RVC for lengthy procedures and during the postoperative period, a still more prolonged anesthetic effect is required. OBJECTIVE: This study therefore aimed to provide extended RVC release and increased upload using modified liposomes. MATERIALS AND METHODS: Three types of vesicles were studied: (i) large multilamellar vesicle (LMV), (ii) large multivesicular vesicle (LMVV) and (iii) large unilamellar vesicle (LUV), prepared with egg phosphatidylcholine/cholesterol/alpha-tocopherol (4:3:0.07 mol%) at pH 7.4. Ionic gradient liposomes (inside: pH 5.5, pH 5.5 + (NH4)2SO4 and pH 7.4 + (NH4)2SO4) were prepared and showed improved RVC loading, compared to conventional liposomes (inside: pH 7.4). RESULTS AND DISCUSSION: An high performance liquid chromatography analytical method was validated for RVC quantification. The liposomes were characterized in terms of their size, zeta potential, polydispersion, morphology, RVC encapsulation efficiency (EE(%)) and in vitro RVC release. LMVV liposomes provided better performance than LMV or LUV. The best formulations were prepared using pH 5.5 (LMVV 5.5in) or pH 7.4 with 250 mM (NH4)2SO4 in the inner aqueous core (LMVV 7.4in + ammonium sulfate), enabling encapsulation of as much as 2% RVC, with high uptake (EE(%) ~70%) and sustained release (~25 h). CONCLUSION: The encapsulation of RVC in ionic gradient liposomes significantly extended the duration of release of the anesthetic, showing that this strategy could be a viable means of promoting longer-term anesthesia during surgical procedures and during the postoperative period. PMID- 25811812 TI - Impact of hydrostatic pressure on the crystal structure and photoluminescence properties of Mn4+-doped BaTiF6 red phosphor. AB - High-efficiency red phosphors with non-rare-earth activators are emerging as an alternative for next generation solid-state warm white LEDs. Their optical properties depend strongly on the local site symmetry and the crystal field strength. Herein we present the pressure tuning of structural and photoluminescence (PL) properties of Mn(4+)-doped BaTiF6 up to 40 GPa. In situ high pressure synchrotron X-ray diffraction, Raman and PL spectroscopy studies show that the crystal symmetry changes from trigonal at ambient pressure to monoclinic from 0.5 GPa and triclinic above 14 GPa, attributed to the distortion of (Ti/Mn)F6 octahedra. The red emission peaks shift monotonically to longer wavelengths due to the reinforced crystal field strength within MnF6 octahedra as pressure increases. A detailed comparison of emission shift rate, PL intensity and FWHM between Mn(4+)-doped BaTiF6 and ruby (Cr(3+)-doped Al2O3) was performed using neon pressure transmission medium. This demonstration provides not only an efficient way to artificially tune the emission properties of practically useful phosphors by means of hydrostatic pressure, but also alternative candidates as potential pressure gauges for high pressure techniques. PMID- 25811811 TI - Hydrophobized triphenyl phosphonium derivatives for the preparation of mitochondriotropic liposomes: choice of hydrophobic anchor influences cytotoxicity but not mitochondriotropic effect. AB - CONTEXT: Nanocarrier-based strategies to achieve delivery of bioactives specifically to the mitochondria are being increasingly explored due to the importance of mitochondria in critical cellular processes. OBJECTIVE: To test the ability of liposomes modified with newly synthesized triphenylphosphonium (TPP) phospholipid conjugates and to test their use in overcoming the cytotoxicity of stearyl triphenylphosphonium (STPP)-modified liposomes when used for delivery of therapeutic molecules to the mitochondria. METHODS: TPP-phospholipid conjugates with the dioleoyl, dimyristoyl or dipalmitoyl lipid moieties were synthesized and liposomes were prepared with these conjugates in a 1 mol% ratio. The subcellular distribution of the liposomes was tested by confocal microscopy. Furthermore, the liposomes were tested for their effect on cell viability using a MTS assay, on cell membrane integrity using a lactate dehydrogenase assay and on mitochondrial membrane integrity using a modified JC-1 assay. RESULTS: The liposomes modified with the new TPP-phospholipid conjugates exhibited similar mitochondriotropism as STPP-liposomes but they were more biocompatible as compared to the STPP liposomes. While the STPP-liposomes had a destabilizing effect on cell and mitochondrial membranes, the liposomes modified with the TPP-phospholipid conjugates did not demonstrate any such effect on biomembranes. CONCLUSIONS: Using phospholipid anchors in the synthesis of TPP-lipid conjugates can provide liposomes that exhibit the same mitochondrial targeting ability as STPP but with much higher biocompatibility. PMID- 25811813 TI - Acute Sodium Ingestion Before Exercise Increases Voluntary Water Consumption Resulting In Preexercise Hyperhydration and Improvement in Exercise Performance in the Heat. AB - Dehydration has been shown to hinder performance of sustained exercise in the heat. Consuming fluids before exercise can result in hyperhydration, delay the onset of dehydration during exercise and improve exercise performance. However, humans normally drink only in response to thirst, which does not result in hyperhydration. Thirst and voluntary fluid consumption have been shown to increase following oral ingestion or infusion of sodium into the bloodstream. We measured the effects of acute sodium ingestion on voluntary water consumption and retention during a 2-hr hydration period before exercise. Subjects then performed a 60-min submaximal dehydration ride (DR) followed immediately by a 200 kJ performance time trial (PTT) in a warm (30 degrees C) environment. Water consumption and retention during the hydration period was greater following sodium ingestion (1380 +/- 580 mL consumed, 821 +/- 367 ml retained) compared with placebo (815 +/- 483 ml consumed, 244 +/- 402 mL retained) and no treatment (782 +/- 454 ml consumed, 148 +/- 289 mL retained). Dehydration levels following the DR were significantly less after sodium ingestion (0.7 +/- 0.6%) compared with placebo (1.3 +/- 0.7%) and no treatment (1.6 +/- 0.4%). Time to complete the PTT was significantly less following sodium consumption (773 +/- 158 s) compared with placebo (851 +/- 156 s) and no treatment (872 +/- 190 s). These results suggest that voluntary hyperhydration can be induced by acute consumption of sodium and has a favorable effect on hydration status and performance during subsequent exercise in the heat. PMID- 25811814 TI - The value of health information technology: filling the knowledge gap. AB - Despite rapid growth in the rate of adoption of health information technology (HIT), and in the volume of evaluation studies, the existing knowledge base for the value of HIT is not advancing at a similar rate. Most evaluation articles are limited in that they use incomplete measures of value and fail to report the important contextual and implementation characteristics that would allow for an adequate understanding of how the study results were achieved. To address these deficiencies, we present a conceptual framework for measuring HIT value and we propose a checklist of characteristics that should be considered in HIT evaluation studies. The framework consists of 3 key principles: 1) value includes both costs and benefits; 2) value accrues over time; and 3) value depends on which stakeholder's perspective is used. Through examples, we show how these principles can be used to guide and improve HIT evaluation studies. The checklist includes a list of contextual and implementation characteristics that are important for interpretation of results. These improvements will make future studies more useful for policy makers and more relevant to the current needs of the healthcare system. PMID- 25811815 TI - Health information exchange and the frequency of repeat medical imaging. AB - OBJECTIVES: Medical imaging, which is expensive, is frequently repeated for the same patient within a relatively short period of time due to lack of access to previous images. Health information exchange (HIE) may reduce repeat imaging by facilitating provider access to prior images and reports. We sought to determine the effect of an HIE system on the occurrence of repeat imaging. STUDY DESIGN AND METHODS: We conducted a cohort study of adult patients who consented to participate in a community-based HIE system in an 11-county region in New York. Using data from 2009-2010, we linked log files of provider HIE usage to administrative claims data from 2 commercial health plans. Using generalized estimation equations, we measured the association between HIE system access and repeat imaging within 90 days. RESULTS: Of 196,314 patients in the cohort, 34,604 (18%) of patients had at least 1 imaging procedure, which was equivalent to a rate of 28.7 imaging procedures per 100 patients. Overall, 7.7% of images were repeated within 90 days. If the HIE system was accessed within the 90 days following an initial imaging procedure, imaging was significantly less likely to be repeated (5% repeated with HIE access vs 8% repeated without HIE access, P < .001). HIE system access reduced the adjusted odds of a repeat image by 25% (95% CI, 13%-35%). CONCLUSIONS: Use of the HIE system to access previous patient information was associated with a reduction in repeated imaging. PMID- 25811816 TI - Overcoming barriers to a research-ready national commercial claims database. AB - OBJECTIVES: Billions of dollars have been spent on the goal of making healthcare data available to clinicians and researchers in the hopes of improving healthcare and lowering costs. However, the problems of data governance, distribution, and accessibility remain challenges for the healthcare system to overcome. STUDY DESIGN: In this study, we discuss some of the issues around holding, reporting, and distributing data, including the newest "big data" challenge: making the data accessible to researchers and policy makers. METHODS: This article presents a case study in "big healthcare data" involving the Health Care Cost Institute (HCCI). HCCI is a nonprofit, nonpartisan, independent research institute that serves as a voluntary repository of national commercial healthcare claims data. RESULTS: Governance of large healthcare databases is complicated by the data holding model and further complicated by issues related to distribution to research teams. For multi-payer healthcare claims databases, the 2 most common models of data holding (mandatory and voluntary) have different data security requirements. Furthermore, data transport and accessibility may require technological investment. CONCLUSIONS: HCCI's efforts offer insights from which other data managers and healthcare leaders may benefit when contemplating a data collaborative. PMID- 25811817 TI - Electronic health record availability among advanced practice registered nurses and physicians. AB - OBJECTIVES: To characterize availability of electronic health records (EHRs) at the primary practice locations of certified nurse midwives (CNMs), nurse practitioners (NPs), and physicians in California prior to the implementation of the state's Medicaid EHR incentive program. STUDY DESIGN AND METHODS: Cross sectional mail surveys of samples of CNMs, NPs, and physicians who have active California licenses and reside in California. Descriptive statistics were calculated and multivariate regression analyses were estimated to identify characteristics associated with having an EHR. The following practice characteristics were included in the multivariate model: payer mix (% Medicaid), practice setting (hospital vs outpatient), and practice size. Variables for practitioner's age, sex, and practice location were also included. RESULTS: For both CNMs/NPs and physicians, practice size was the strongest predictor of EHR availability. Practicing in a large or mid-sized group was associated with higher odds of having a basic EHR or an advanced EHR. Having a high percentage of Medicaid patients was associated with lower odds of having an advanced EHR. Among physicians, but not CNMs/NPs, hospital-based practice was associated with higher odds of having an advanced EHR; being over age 45 years was associated with lower odds of having any EHR. CONCLUSIONS: The results suggest that prior to the launch of California's Medicaid EHR incentive program, similar characteristics predicted EHR availability among both CNMs/NPs and physicians, and that availability was concentrated among large practices with fewer Medicaid patients. Future studies should assess whether Medicaid and Medicare incentive payments attenuate these relationships. PMID- 25811818 TI - Information technology and hospital patient safety: a cross-sectional study of US acute care hospitals. AB - OBJECTIVES: To determine whether health information technology (IT) systems are associated with better patient safety in acute care settings. STUDY DESIGN: In a cross-sectional retrospective study, data on hospital patient safety performance for October 2008 to June 2010 were combined with 2007 information technology systems data. The sample included 3002 US non-federal acute care hospitals. Electronic health record (EHR) system was coded as a composite dichotomous variable based on the presence of 10 major clinical and administrative applications that (if in use) could potentially meet stage 1 "meaningful use" objectives. The surgical IT system was measured as a dichotomous variable if a hospital used at least 1 of the perioperative, preoperative, or postoperative information systems. Hospital patient safety performance was measured by risk standardized estimated rates per 1000 admissions. Statistical analyses were conducted using an estimated dependent variable methodology with gamma-log link based weighted generalized linear models, adjusting for hospital characteristics, historical composite process quality, and propensity for EHR adoption. RESULTS: We found that the use of surgical IT systems was associated with 7% to 26% lower rates for 7 of 8 patient safety indicators (incidence rate ratio [IRR] range from 0.74 to 0.93; all P values < .01). Further, stage 1 meaningful use-capable EHR systems were associated with 7% to 11% lower rates on 3 of 8 measures (IRR range from 0.89 to 0.93; all P values < .01). CONCLUSIONS: Our results suggest that the use of IT is associated with modestly lower rates of adverse events in hospitals. However, the cross-sectional design limits our ability to make causal conclusions. PMID- 25811820 TI - Trending health information technology adoption among New York nursing homes. AB - OBJECTIVES: Federal policies are incentivizing hospitals and providers to adopt and meaningfully use electronic health records (EHRs). Nursing homes are not eligible for incentives. However, understanding health information technology (HIT) adoption among nursing homes will be critical to developing HIT policies for this sector. Our objective was to assess the pace of EHR adoption, changes in computerized function adoption, and participation in health information exchange by New York state nursing homes over time. STUDY DESIGN: We used a repeated, cross-sectional study design. METHODS: We surveyed all New York state nursing homes between February and May 2013, comparing results to the same survey administered in 2012. RESULTS: We received responses from 472 of 630 nursing homes (74.9%). Rates of EHR adoption increased from 48.6% to 56.3% (P = .03). Participation in health information exchange remained unchanged (54.5% to 55.3%, P = .8). The top barriers to EHR adoption cited were: a) the initial cost of HIT investment (67.9%, n = 133), b) lack of technical IT staff (46.4%, n = 91), and c) lack of fiscal incentives (45.8%, n = 88). Comparing nursing homes with EHRs in 2012 to nursing homes with EHRs in 2013, the availability of many types of computerized functionalities significantly increased, although no gains were seen for order entry or clinical tools. CONCLUSIONS: While some gains are being made by nursing homes, HIT adoption generally lags behind that of other sectors. Public policy focusing on building HIT infrastructure is essential to ensure that nursing homes keep up with other healthcare segments. PMID- 25811819 TI - Automated detection of retinal disease. AB - Nearly 4 in 10 Americans with diabetes currently fail to undergo recommended annual retinal exams, resulting in tens of thousands of cases of blindness that could have been prevented. Advances in automated retinal disease detection could greatly reduce the burden of labor-intensive dilated retinal examinations by ophthalmologists and optometrists and deliver diagnostic services at lower cost. As the current availability of ophthalmologists and optometrists is inadequate to screen all patients at risk every year, automated screening systems deployed in primary care settings and even in patients' homes could fill the current gap in supply. Expanding screens to all patients at risk by switching to automated detection systems would in turn yield significantly higher rates of detecting and treating diabetic retinopathy per dilated retinal examination. Fewer diabetic patients would develop complications such as blindness, while ophthalmologists could focus on more complex cases. PMID- 25811821 TI - The effects of health information technology adoption and hospital-physician integration on hospital efficiency. AB - OBJECTIVES: To determine the impact of health information technology (HIT) adoption and hospital-physician integration on hospital efficiency. STUDY DESIGN: Using 2010 data from the American Hospital Association's (AHA) annual survey, the AHA IT survey, supplemented by the CMS Case Mix Index, and the US Census Bureau's small area income and poverty estimates, we examined how the adoption of HIT and employment of physicians affected hospital efficiency and whether they were substitutes or complements. METHODS: The sample included 2173 hospitals. We employed a 2-stage approach. In the first stage, data envelopment analysis was used to estimate technical efficiency of hospitals. In the second stage, we used instrumental variable approaches, notably 2-stage least squares and the generalized method of moments, to examine the effects of IT adoption and integration on hospital efficiency. RESULTS: We found that HIT adoption and hospital-physician integration, when considered separately, each have statistically significant positive impacts on hospital efficiency. Also, we found that hospitals that adopted HIT with employed physicians will achieve less efficiency compared with hospitals that adopted HIT without employed physicians. CONCLUSIONS: Although HIT adoption and hospital-physician integration both seem to be key parts of improving hospital efficiency when one or the other is utilized individually, they can hurt hospital efficiency when utilized together. PMID- 25811822 TI - The 3 key themes in health information technology. AB - This year's special issue on Health Information Technology (HIT) features an impressive body of new research that reflects progress in the field along an array of dimensions-new timely questions, emerging sources of data, and novel methodologies applied to HIT. PMID- 25811823 TI - Information retrieval pathways for health information exchange in multiple care settings. AB - OBJECTIVES: To determine which health information exchange (HIE) technologies and information retrieval pathways healthcare professionals relied on to meet their information needs in the context of laboratory test results, radiological images and reports, and medication histories. STUDY DESIGN: Primary data was collected over a 2-month period across 3 emergency departments, 7 primary care practices, and 2 public health clinics in New York state. METHODS: Qualitative research methods were used to collect and analyze data from semi-structured interviews and participant observation. RESULTS: The study reveals that healthcare professionals used a complex combination of information retrieval pathways for HIE to obtain clinical information from external organizations. The choice for each approach was setting- and information-specific, but was also highly dynamic across users and their information needs. CONCLUSIONS: Our findings about the complex nature of information sharing in healthcare provide insights for informatics professionals about the usage of information; indicate the need for managerial support within each organization; and suggest approaches to improve systems for organizations and agencies working to expand HIE adoption. PMID- 25811825 TI - Leveraging EHRs to improve hospital performance: the role of management. AB - OBJECTIVES: Recent studies fail to find a consistent relationship between adoption of electronic health records (EHRs) and improved hospital performance. We sought to examine whether the quality of hospital management modifies the association between EHR adoption and outcomes related to cost and quality. STUDY DESIGN: Retrospective study of a random sample of US acute care hospitals. METHODS: Management quality was assessed via phone interviews with clinical managers predominantly from cardiac units in a random sample of 325 hospitals using a validated scale of management practices in 4 areas: operations, performance monitoring, target setting, and talent management. American Hospital Association InformationTechnology Supplement data captured whether or not these hospitals had at least a basic EHR. Acute myocardial infarction (AMI) outcomes included risk-adjusted 30-day mortality, average length-of-stay, and average payment per discharge measured using MedPAR data. Ordinary least squares regressions assessed whether management quality modifies the relationship between EHR adoption and AMI outcomes. RESULTS: While we found no association between EHR adoption and our outcomes, management quality modified the relationship in the predicted direction. For length of stay, the coefficient on the interaction between EHR and management was -1.48 (P = .05) and for payment, it was -7786.74 (P = .014). We did not find strong evidence of effect modification for mortality (coefficient = -0.05; P = .37). CONCLUSIONS: Coupled with ongoing policy efforts to achieve nationwide EHR adoption is a growing unease that our national investment may not result in better, more efficient care. Our study is among the first to offer empirical evidence that management quality may help explain why some hospitals see substantial gains from EHR adoption while others do not. PMID- 25811824 TI - Improving adherence to cardiovascular disease medications with information technology. AB - OBJECTIVES: Evaluate the utility of 2 electronic medical record (EMR)-linked, automated phone reminder interventions for improving adherence to cardiovascular disease medications. STUDY DESIGN: A 1-year, parallel arm, pragmatic clinical trial in which 21,752 adults were randomized to receive either usual care (UC) or 1 of 2 interventions in the form of interactive voice recognition calls-regular (IVR) or enhanced (IVR+). The interventions used automated phone reminders to increase adherence to cardiovascular disease medications. The primary outcome was medication adherence; blood pressure and lipid levels were secondary outcomes. METHODS: The study took place in 3 large health maintenance organizations. We enrolled participants who were 40 years or older, had diabetes mellitus or atherosclerotic cardiovascular disease, and were suboptimally adherent. IVR participants received automated phone calls when they were due or overdue for a refill. IVR+ participants received these phone calls, plus personalized reminder letters, live outreach calls, EMR-based feedback to their primary care providers, and additional mailed materials. RESULTS: Both interventions significantly increased adherence to statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) compared with UC (1.6 to 3.7 percentage points). Adherence to ACEIs/ARBs was also significantly higher for IVR+ relative to IVR participants. These differences persisted across subgroups. Among statin users, IVR+ participants had significantly lower low-density lipoprotein (LDL) levels at follow-up compared with UC (Delta = -1.5; 95% CI, 2.7 to -0.2 mg/dL); this effect was seen mainly in those with baseline LDL levels >= 100 mg/dL (Delta = -3.6; 95% CI, -5.9 to -1.3 mg/dL). CONCLUSIONS: Technology based tools, in conjunction with an EMR, can improve adherence to chronic disease medications and measured cardiovascular disease risk factors. PMID- 25811826 TI - Electronic alerts and clinician turnover: the influence of user acceptance. AB - OBJECTIVES: Use of certain components of electronic health records (EHRs), such as EHR-based alerting systems (EASs), might reduce provider satisfaction, a strong precursor to turnover. We examined the impact of factors likely to influence providers' acceptance of an alerting system, designed to facilitate electronic communication in outpatient settings, on provider satisfaction, intentions to quit, and turnover. STUDY DESIGN AND METHODS: We conducted a cross sectional Web-based survey of EAS-related practices from a nationwide sample of primary care providers (PCPs) practicing at Department of Veterans Affairs (VA) medical facilities. Of 5001 invited VA PCPs, 2590 completed the survey. We relied on Venkatesh's Unified Theory of Acceptance and Use of Technology to create survey measures of 4 factors likely to impact user acceptance of EAS: supportive norms, monitoring/ feedback, training, and providers' perceptions of the value (PPOV) of EASs to provider effectiveness. Facility-level PCP turnover was measured via the VA's Service Support Center Human Resources Cube. Hypotheses were tested using structural equation modeling. RESULTS: After accounting for intercorrelations among predictors, monitoring/feedback regarding EASs significantly predicted intention to quit (b = 0.30, P < .01), and PPOV of EASs predicted both overall provider satisfaction (b = 0.58, P < .01) and facility level provider turnover levels (b = -0.19, P < .05), all without relying on any intervening mechanisms. CONCLUSIONS: Design, implementation, and use of EASs might impact provider satisfaction and retention. Institutions should consider strategies to help providers perceive greater value in these clinical tools. PMID- 25811827 TI - Cost implications of human and automated follow-up in ambulatory care. AB - OBJECTIVES: To compare the costs of human and automated follow-up processes in ambulatory care. STUDY DESIGN: Analysis of costs of nurse-initiated and interactive voice response (IVR) system follow-up interventions. METHODS: Using national cost data and data on follow-up processes and outcomes from a previous study, we examined the costs to the healthcare system and providers of developing a follow-up process using nurse-initiated telephone calls compared with calls made by an IVR. RESULTS: Whether using nurse-initiated telephone calls or IVR calls, costs over the first 2 years of follow-up for a practice assumed to have 4800 acute care patient visits per year are approximately the same. After 2 years, IVR follow-up is approximately $9000 per year less expensive than nurse follow-up. In addition, overall cost savings are greater with IVR. CONCLUSIONS: Follow-up of ambulatory care patients is a way to assess risks of future problems and associated costs and to improve quality of care. An automated follow-up process using IVR is more efficient than one based on nurse-initiated follow-up calls. PMID- 25811828 TI - Adoption of electronic prescribing for controlled substances among providers and pharmacies. AB - OBJECTIVES: Electronic prescribing for Schedule II through V controlled substances was legalized in the United States by the Drug Enforcement Administration in June 2010. However, little information exists about adoption and use of the electronic prescribing of controlled substances (EPCS) at the national level. Therefore, the objective of this study is to present the first information about national trends surrounding the adoption and use of the newly allowed EPCS by providers and pharmacies in the United States. STUDY DESIGN: Trends of EPCS adoption and use were examined for the number of EPCS, number of pharmacies enabled to accept EPCS, and the number of providers prescribing controlled substances electronically. METHODS: Using nationally representative transactional Surescripts data from July 2012 to December 2013, we examined EPCS trends. RESULTS: During the study period, the total number of EPCS increased from 1535 to 52,423, and the number and percentage of all pharmacies enabled for EPCS increased from 8768 (13%) to 20,498 pharmacies (30%). The proportion of all providers prescribing controlled substances electronically is currently 1%, but increasing steadily each month. CONCLUSIONS: There is a positive national growth for EPCS in pharmacy preparedness to accept EPCS, the number of EPCS prescriptions sent each month, and the number of providers with the ability to send EPCS. PMID- 25811829 TI - Primary care capacity as insurance coverage expands: examining the role of health information technology. AB - OBJECTIVES: Under the Affordable Care Act, many newly insured Americans have the challenge of establishing care with a primary care physician (PCP). We sought to examine whether health information technology (HIT) use in primary care practices was associated with anticipated capacity to accept new patients. STUDY DESIGN: Secondary analysis of a cross-sectional survey of Michigan PCPs from the specialties of pediatrics, internal medicine, and family medicine, conducted from October to December 2012. HIT use was considered independently for 8 types of HIT and in aggregate as a total count of HIT in use. Primary care capacity was assessed as self-reported capacity to accept new patients. RESULTS: Of 739 respondents, 83% reported they anticipated capacity to accept new patients. In multivariable analysis, we found that physiians using a greater number of HITs were significantly less likely to anticipate capacity to accept new patients (adjusted odds ratio [OR] = 0.86; 95% CI, 0.76-0.97). PCPs with higher HIT use were also less likely to accept patients with private insurance (adjusted OR 0.87; 95% CI, 0.77-0.97), but not with Medicaid (adjusted OR 0.94; 95% CI, 0.84 1.05) or Medicare (adjusted OR 0.91; 95% CI, 0.83-1.01). Among individual HITs, electronic health records (adjusted OR 0.54; 95% CI, 0.30-0.96) and electronic access to admitting hospital records (adjusted OR 0.46; 95% CI, 0.22-0.96) were the only HITs significantly associated with lower anticipated primary care capacity. CONCLUSIONS: ?PCPs using a greater number of HITs were less likely to anticipate capacity to accept new patients. Implementation of HIT and other practice innovations must be carefully coordinated to optimize capacity to care for the newly insured. PMID- 25811830 TI - Reassortant Avian Influenza A(H9N2) viruses in chickens in retail poultry shops, Pakistan, 2009-2010. AB - Phylogenetic analysis of influenza viruses collected during December 2009 February 2010 from chickens in live poultry retail shops in Lahore, Pakistan, showed influenza A(H9N2) lineage polymerase and nonstructural genes generate through inter- and intrasubtypic reassortments. Many amino acid signatures observed were characteristic of human isolates; hence, their circulation could enhance inter- or intrasubtypic reassortment. PMID- 25811832 TI - Simultaneous Multislice Echo Planar Imaging With Blipped Controlled Aliasing in Parallel Imaging Results in Higher Acceleration: A Promising Technique for Accelerated Diffusion Tensor Imaging of Skeletal Muscle. AB - OBJECTIVE: The aim of this study was to investigate the feasibility of accelerated diffusion tensor imaging (DTI) of skeletal muscle using echo planar imaging (EPI) applying simultaneous multislice excitation with a blipped controlled aliasing in parallel imaging results in higher acceleration unaliasing technique. MATERIALS AND METHODS: After federal ethics board approval, the lower leg muscles of 8 healthy volunteers (mean [SD] age, 29.4 [2.9] years) were examined in a clinical 3-T magnetic resonance scanner using a 15-channel knee coil. The EPI was performed at a b value of 500 s/mm2 without slice acceleration (conventional DTI) as well as with 2-fold and 3-fold acceleration. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in all 3 acquisitions. Fiber tracking performance was compared between the acquisitions regarding the number of tracks, average track length, and anatomical precision using multivariate analysis of variance and Mann-Whitney U tests. RESULTS: Acquisition time was 7:24 minutes for conventional DTI, 3:53 minutes for 2-fold acceleration, and 2:38 minutes for 3-fold acceleration. Overall FA and MD values ranged from 0.220 to 0.378 and 1.595 to 1.829 mm2/s, respectively. Two-fold acceleration yielded similar FA and MD values (P >= 0.901) and similar fiber tracking performance compared with conventional DTI. Three-fold acceleration resulted in comparable MD (P = 0.199) but higher FA values (P = 0.006) and significantly impaired fiber tracking in the soleus and tibialis anterior muscles (number of tracks, P < 0.001; anatomical precision, P <= 0.005). CONCLUSIONS: Simultaneous multislice EPI with blipped controlled aliasing in parallel imaging results in higher acceleration can remarkably reduce acquisition time in DTI of skeletal muscle with similar image quality and quantification accuracy of diffusion parameters. This may increase the clinical applicability of muscle anisotropy measurements. PMID- 25811831 TI - Does breastfeeding help to reduce the risk of childhood overweight and obesity? A propensity score analysis of data from the KiGGS study. AB - BACKGROUND: Current studies suggest that the beneficial effect of breastfeeding on overweight and obesity may have been largely overestimated. We examined the relationship between >4 months of full breastfeeding and overweight/obesity in children living in Germany. METHODS: We analyzed retrospectively collected data on breastfeeding from children aged 3-17 years who participated in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS baseline study) between 2003 and 2006 (n = 13163). To minimize confounding, we applied propensity score matching and multivariate logistic regression analyses to estimate the effect of breastfeeding on childhood overweight and obesity. RESULTS: Adjusted analyses of the matched dataset (n = 8034) indicated that children who were breastfed for >4 months had a significant reduction in the odds of overweight (OR 0.81 [95% CI 0.71-0.92]) and obesity (OR 0.75 [95% CI 0.61 0.92]) compared to children who were not breastfed or who were breastfed for a shorter duration [corrected].Further analyses stratified by age group showed that the association was strongest in children aged 7-10 years (OR 0.67 [95% CI 0.53 0.84] for overweight and OR 0.56 [95% CI 0.39-0.81] for obesity), while no significant effect could be seen in other age groups. DISCUSSION: Our findings support the hypothesis that breastfeeding does have a beneficial effect on childhood overweight and obesity, although the effect seems to be strongest in children of primary school age. PMID- 25811833 TI - Quantitative Computed Tomography Imaging Biomarkers in the Diagnosis and Management of Lung Cancer. AB - Tumor diameter has traditionally been used as a standard metric in terms of diagnosis and prognosis prediction of lung cancer. However, recent advances in imaging techniques and data analyses have enabled novel quantitative imaging biomarkers that can characterize disease status more comprehensively and/or predict tumor behavior more precisely. The most widely used imaging modality for lung tumor assessment is computed tomography. Therefore, we focused on computed tomography imaging biomarkers such as tumor volume and mass, ground-glass opacities, perfusion parameters, as well as texture features in this review. Herein, we first appraised the conventional 1- or 2-dimensional measurement with brief discussion on their limits and then introduced the potential imaging biomarkers with emphasis on the current understanding of their clinical usefulness with respect to the malignancy differentiation, treatment response monitoring, and patient outcome prediction. PMID- 25811834 TI - Assessing dietary quality of older Chinese people using the Chinese Diet Balance Index (DBI). AB - BACKGROUND/OBJECTIVES: Few studies have applied the Chinese Diet Balance Index (DBI) in evaluating dietary quality for Chinese people. The present cross sectional study assessed dietary quality based on DBI for older people, and the associated factors, in four socioeconomically distinct regions in China. METHODS: The China Health and Nutrition Survey (CHNS) involves 2745 older Chinese people, aged 60 or over, from four regions (Northeast, East Coast, Central and West) in 2009. Dietary data were obtained by interviews using 24 hour-recall over three consecutive days. Four indicators: Total Score (TS), Lower Bound Score (LBS), Higher Bound Score (HBS) and Diet Quality Distance (DQD) from DBI were calculated for assessing dietary quality in different aspects. RESULTS: 68.9% of older people had different levels of excessive cereals intake. More than 50% of older people had moderate or severe surplus of oil (64.9%) and salt (58.6%). Intake of vegetables and fruit, milk and soybeans, water, and dietary variety were insufficient, especially for milk and soybeans. 80.8% of people had moderate or severe unbalanced diet consumption. The largest differences of DQD scores have been found for people with different education levels and urbanicity levels. People with higher education levels have lower DQD scores (p<0.001), and people living in medium and low urbanicity areas had 2.8 and 8.9 higher DQD scores than their high urbanicity counterparts (p<0.001). Also, significant differences of DQD scores have been found according to gender, marital status, work status and regions (p<0.001). CONCLUSION: DBI can reveal problems of dietary quality for older Chinese people. Rectifying unbalanced diet intake may lead to prevention of non-communicable diseases (NCDs). Dieticians and health care professionals need to increase dissemination and uptake of nutrition education, with interventions targeted at regions of lower socioeconomic status. PMID- 25811835 TI - Iodine nutrition status in lactating mothers residing in countries with mandatory and voluntary iodine fortification programs: an updated systematic review. AB - BACKGROUND: The aim of this review is to assess data available on iodine nutrition status in lactating mothers residing in countries with mandatory and voluntary iodine fortification programs and/or iodine supplementation. SUMMARY: A systematic review was conducted by searching articles published between 1964 and 2013 in Pub Med, ISI Web, and Cochrane Library using iodine nutrition, lactation, iodine supplementation, and iodine fortification as keywords for titles and/or abstracts. Relevant articles were included if they reported urinary iodine concentration (UIC) in lactating mothers and, if determined, the type of iodine fortification program and/or iodine supplementation. Forty-two studies met the inclusion criteria. Among these, 21 studies assessed lactating mothers in countries with a mandatory iodine fortification program, 17 studies were from countries with voluntary and/or without iodine fortification programs, and four studies assessed iodine nutrition status in lactating mothers undergoing iodine supplementation. Among countries with mandatory iodine fortification programs, the range of salt iodization level in lactating mothers with a UIC <100 MUg/L was between 8 and 40 ppm, whereas among lactating mothers with UIC >100 MUg/L, it was between 15 and 60 ppm. Levels of UIC <100 MUg/L were observed among lactating women in India, Denmark, Mali, New Zealand, Australia, Slovakia, Sudan, and Turkey, whereas in countries such as Chile, Iran, Mongolia, New Guinea, and Nigeria, the median or mean of UIC was >100 MUg/L. There was a median or mean UIC <100 MUg/L in nearly all lactating mothers residing in countries where implementation of universal salt iodization program was voluntary, including Switzerland, Australia, New Zealand, Ireland, and Germany. However, in some countries with voluntary iodine fortification programs, such as the United States, Spain, and Japan, a mean or median UIC of >100 MUg/L has been reported. CONCLUSIONS: Although universal salt iodization is still the most feasible and cost-effective approach for iodine deficiency control in pregnant and lactating mothers, UIC in lactating mothers of most countries with voluntary programs and in areas with mandatory iodine fortification is still within the iodine deficiency range, indicating that iodine supplementation in daily prenatal vitamin/mineral supplements in lactating mothers is warranted. However, further investigations are still recommended in this regard. PMID- 25811836 TI - Weak sinusoidal electric fields entrain spontaneous Ca transients in the dendritic tufts of CA1 pyramidal cells in rat hippocampal slice preparations. AB - Neurons might interact via electric fields and this notion has been referred to as ephaptic interaction. It has been shown that various types of ion channels are distributed along the dendrites and are capable of supporting generation of dendritic spikes. We hypothesized that generation of dendritic spikes play important roles in the ephaptic interactions either by amplifying the impact of electric fields or by providing current source to generate electric fields. To test if dendritic activities can be modulated by electric fields, we developed a method to monitor local Ca-transients in the dendrites of a neuronal population in acute rat hippocampal slices by applying spinning-disk confocal microscopy and multi-cell dye loading technique. In a condition in which the dendrites of CA1 pyramidal neurons show spontaneous Ca-transients due to added 50 MUM 4 aminopyridine to the bathing medium and adjusted extracellular potassium concentration, we examined the impact of sinusoidal electric fields on the Ca transients. We have found that spontaneously occurring fast-Ca-transients in the tufts of the apical dendrites of CA1 pyramidal neurons can be blocked by applying 1 MUM tetrodotoxin, and that the timing of the transients become entrained to sub threshold 1-4 Hz electric fields with an intensity as weak as 0.84 mV/mm applied parallel to the somato-dendritic axis of the neurons. The extent of entrainment increases with intensity below 5 mV/mm, but does not increase further over the range of 5-20 mV/mm. These results suggest that population of pyramidal cells might be able to detect electric fields with biologically relevant intensity by modulating the timing of dendritic spikes. PMID- 25811837 TI - Chronic obstructive pulmonary disease and subsequent overall and lung cancer mortality in low-income adults. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a known risk factor for lung cancer and a leading cause of mortality in the U.S., but its impact may not be fully appreciated, especially among low-income populations in the southeast where COPD prevalence and lung cancer incidence are elevated. METHODS: We conducted a prospective study among 26,927 low-income adults age 40-79 in the Southern Community Cohort Study who had a Center for Medicare and Medicaid Services (CMS) encounter prior to enrollment and were followed for a median of over 6 years. Using a validated algorithm for assessing COPD from CMS claims data, we estimated COPD prevalence and potential misreporting. From Cox proportional hazard models, we computed overall and lung cancer-specific mortality according to COPD status. RESULTS: The overall prevalence of CMS diagnosed COPD was 16%, but was twice as high among whites as blacks. Only 35% of these individuals, however, self-reported having COPD, with underreporting significantly greater for blacks than whites. Smoking-adjusted all-cause mortality was increased by 1.7-fold and lung cancer mortality by 2.3-fold among those with a CMS COPD diagnosis, with similar patterns in blacks and whites, but no excess was found among those self-reporting COPD and without CMS confirmation. CONCLUSION: The prevalence of COPD in this low-income population may be greater than previously recognized and misreporting is common. COPD is associated with elevated lung cancer mortality, even among those not self-reporting the condition. PMID- 25811838 TI - Inertial measures of motion for clinical biomechanics: comparative assessment of accuracy under controlled conditions - changes in accuracy over time. AB - BACKGROUND: Interest in 3D inertial motion tracking devices (AHRS) has been growing rapidly among the biomechanical community. Although the convenience of such tracking devices seems to open a whole new world of possibilities for evaluation in clinical biomechanics, its limitations haven't been extensively documented. The objectives of this study are: 1) to assess the change in absolute and relative accuracy of multiple units of 3 commercially available AHRS over time; and 2) to identify different sources of errors affecting AHRS accuracy and to document how they may affect the measurements over time. METHODS: This study used an instrumented Gimbal table on which AHRS modules were carefully attached and put through a series of velocity-controlled sustained motions including 2 minutes motion trials (2MT) and 12 minutes multiple dynamic phases motion trials (12MDP). Absolute accuracy was assessed by comparison of the AHRS orientation measurements to those of an optical gold standard. Relative accuracy was evaluated using the variation in relative orientation between modules during the trials. FINDINGS: Both absolute and relative accuracy decreased over time during 2MT. 12MDP trials showed a significant decrease in accuracy over multiple phases, but accuracy could be enhanced significantly by resetting the reference point and/or compensating for initial Inertial frame estimation reference for each phase. INTERPRETATION: The variation in AHRS accuracy observed between the different systems and with time can be attributed in part to the dynamic estimation error, but also and foremost, to the ability of AHRS units to locate the same Inertial frame. CONCLUSIONS: Mean accuracies obtained under the Gimbal table sustained conditions of motion suggest that AHRS are promising tools for clinical mobility assessment under constrained conditions of use. However, improvement in magnetic compensation and alignment between AHRS modules are desirable in order for AHRS to reach their full potential in capturing clinical outcomes. PMID- 25811840 TI - Correction: antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. AB - [This corrects the article DOI: 10.1371/journal.pone.0021447.]. PMID- 25811839 TI - Influenza A(H7N9) virus transmission between finches and poultry. AB - Low pathogenicity avian influenza A(H7N9) virus has been detected in poultry since 2013, and the virus has caused >450 infections in humans. The mode of subtype H7N9 virus transmission between avian species remains largely unknown, but various wild birds have been implicated as a source of transmission. H7N9 virus was recently detected in a wild sparrow in Shanghai, China, and passerine birds, such as finches, which share space and resources with wild migratory birds, poultry, and humans, can be productively infected with the virus. We demonstrate that interspecies transmission of H7N9 virus occurs readily between society finches and bobwhite quail but only sporadically between finches and chickens. Inoculated finches are better able to infect naive poultry than the reverse. Transmission occurs through shared water but not through the airborne route. It is therefore conceivable that passerine birds may serve as vectors for dissemination of H7N9 virus to domestic poultry. PMID- 25811843 TI - Standoff detection of highly energetic materials using laser-induced thermal excitation of infrared emission. AB - A laser-mediated methodology for standoff infrared detection of threat chemicals is described in this article. Laser-induced thermal emissions (LITE) from vibrationally excited residue of highly energetic material (HEM) deposited on substrates were detected remotely. Telescope-based Fourier transform infrared (FT IR) spectroscopy measurements were carried out on substrates containing small amounts of HEM at surface concentrations of 5-200 MUg/cm(2). Target substrates of various thicknesses were heated remotely using a carbon dioxide laser, and their mid-infrared (mid-IR), thermally stimulated emission spectra were recorded after heating. The telescope was configured from reflective optical elements to minimize emission losses in the mid-IR frequencies. Spectral replicas were acquired at distances from 4 to 64 m using an FT-IR interferometer at 4 cm(-1) resolution. The laser power, laser exposure times, and acquisition time of the FT IR interferometer were adjusted to improve the detection and identification of samples. The advantages of increasing the thermal emission were easily observed in the results. The signal intensities were proportional to the thickness of the coated surface (a function of the surface concentration) as well as the laser power and laser exposure time. The limits of detection obtained for the HEM studied were 140-21 MUg/cm(2) at 4 m. Detection was achieved at 64 m for a surface concentration of 200 MUg/cm(2). PMID- 25811842 TI - Speeding up ecological and evolutionary computations in R; essentials of high performance computing for biologists. AB - Computation has become a critical component of research in biology. A risk has emerged that computational and programming challenges may limit research scope, depth, and quality. We review various solutions to common computational efficiency problems in ecological and evolutionary research. Our review pulls together material that is currently scattered across many sources and emphasizes those techniques that are especially effective for typical ecological and environmental problems. We demonstrate how straightforward it can be to write efficient code and implement techniques such as profiling or parallel computing. We supply a newly developed R package (aprof) that helps to identify computational bottlenecks in R code and determine whether optimization can be effective. Our review is complemented by a practical set of examples and detailed Supporting Information material (S1-S3 Texts) that demonstrate large improvements in computational speed (ranging from 10.5 times to 14,000 times faster). By improving computational efficiency, biologists can feasibly solve more complex tasks, ask more ambitious questions, and include more sophisticated analyses in their research. PMID- 25811841 TI - Signals of Ezh2, Src, and Akt Involve in myostatin-Pax7 pathways regulating the myogenic fate determination during the sheep myoblast proliferation and differentiation. AB - Myostatin and Pax7 have been well documented individually, however, the mechanism by which Myostatin regulates Pax7 is seldom reported. Here, based on muscle transcriptome analysis in Texel (Myostatin mutant) and Ujumqin (wild type) sheep across the five fetal stages, we constructed and examined the Myostatin-Pax7 pathways in muscle. Then we validated the signals by RNAi in the proliferating and differentiating sheep myoblasts in vitro at mRNA, protein, and cell morphological levels. We reveal that Myostatin signals to Pax7 at least through Ezh2, Src, and Akt during the sheep myoblast proliferation and differentiation. Other signals such as p38MAPK, mTOR, Erk1/2, Wnt, Bmp2, Smad, Tgfb1, and p21 are most probably involved in the Myostatin-affected myogenic events. Myostatin knockdown significantly reduces the counts of nucleus and myotube, but not the fusion index of myoblasts during cell differentiation. In addition, findings also indicate that Myostatin is required for normal myogenic differentiation of the sheep myoblasts, which is different from the C2C12 myoblasts. We expand the regulatory network of Myostatin-Pax7 pathways and first illustrate that Myostatin as a global regulator participates in the epigenetic events involved in myogenesis, which contributes to understand the molecular mechanism of Myostatin in regulation of myogenesis. PMID- 25811844 TI - Adaptations of the Shoulder to Overhead Throwing in Youth Athletes. AB - CONTEXT: The high number of repetitions and high forces associated with overhead throwing lead to anatomical adaptations, such as humeral retrotorsion and posterior-capsule thickness, in elite and professional baseball athletes. However, little is known about the origin and progression of these changes that may account for the increasing trend of chronic shoulder injuries in youth baseball and precipitate subsequent pathologic conditions throughout a young athlete's lifetime. OBJECTIVE: To investigate the relationship of age and upper extremity dominance on humeral retrotorsion, posterior-capsule thickness, and glenohumeral range of motion. DESIGN: Cross-sectional study. SETTING: Research laboratory, local baseball fields, and training facilities. PATIENTS OR OTHER PARTICIPANTS: Thirty-six boys (mean age = 10.94 +/- 1.34 years, height = 151.31 +/- 12.17 cm, mass = 42.51 +/- 10.32 kg) ranging in age from 8 to 12 years and involved in organized youth baseball. MAIN OUTCOME MEASURE(S): Diagnostic ultrasound was used to determine humeral retrotorsion and posterior-capsule thickness. Glenohumeral internal rotation and external rotation were measured using a handheld inclinometer. We used 2 * 2 mixed-model analyses of variance to compare the influence of limb dominance and age on the dependent variables of humeral retrotorsion, posterior-capsule thickness, internal rotation, and external rotation. RESULTS: The dominant shoulders of youth throwers exhibited less glenohumeral internal rotation but greater humeral retrotorsion, posterior capsule thickness, and glenohumeral external rotation than the nondominant shoulders. Dominant internal rotation was greater in the 8- to 10-year-old group than in the 11- to 12-year-old group, and results trended toward a difference (F1,33 = 4.12, P = .05). Correlations existed between humeral retrotorsion and range of motion (P < .05). CONCLUSIONS: The structural adaptations in the dominant shoulders of younger baseball players were similar to adaptations observed in older baseball athletes, indicating that more examination is needed in younger athletes. We are the first to demonstrate greater posterior-capsule thickness in the dominant shoulders of youth baseball athletes. PMID- 25811845 TI - Laboratory Measures of Postural Control During the Star Excursion Balance Test After Acute First-Time Lateral Ankle Sprain. AB - CONTEXT: No researchers, to our knowledge, have investigated the immediate postinjury-movement strategies associated with acute first-time lateral ankle sprain (LAS) as quantified by center of pressure (COP) and kinematic analyses during performance of the Star Excursion Balance Test (SEBT). OBJECTIVE: To analyze the kinematic and COP patterns of a group with acute first-time LAS and a noninjured control group during performance of the SEBT. DESIGN: Case-control study. SETTING: University biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 81 participants with acute first-time LAS (53 men, 28 women; age = 23.22 +/- 4.93 years, height = 1.73 +/- 0.09 m, mass = 75.72 +/- 13.86 kg) and 19 noninjured controls (15 men, 4 women; age = 22.53 +/- 1.68 years, height = 1.74 +/- 0.08 m, mass = 71.55 +/- 11.31 kg). INTERVENTION: Participants performed the anterior (ANT), posterolateral (PL), and posteromedial (PM) reach directions of the SEBT. MAIN OUTCOME MEASURE(S): We assessed 3 dimensional kinematics of the lower extremity joints and associated fractal dimension (FD) of the COP path during performance of the SEBT. RESULTS: The LAS group had decreased normalized reach distances in the ANT, PL, and PM directions when compared with the control group on their injured (ANT: 58.16% +/- 6.86% versus 64.86% +/- 5.99%; PL: 85.64% +/- 10.62% versus 101.14% +/- 8.39%; PM: 94.89% +/- 9.26% versus 107.29 +/- 6.02%) and noninjured (ANT: 60.98% +/- 6.74% versus 64.76% +/- 5.02%; PL: 88.95% +/- 11.45% versus 102.36% +/- 8.53%; PM: 97.13% +/- 8.76% versus 106.62% +/- 5.78%) limbs (P < .01). This observation was associated with altered temporal sagittal-plane kinematic profiles throughout each reach attempt and at the point of maximum reach (P < .05). This result was associated with a reduced FD of the COP path for each reach direction on the injured limb only (P < .05). CONCLUSIONS: Acute first-time LAS was associated with bilateral deficits in postural control, as evidenced by the bilateral reduction in angular displacement of the lower extremity joints and reduced reach distances and FD of the COP path on the injured limb during performance of the SEBT. PMID- 25811846 TI - The Landing Error Scoring System as a Screening Tool for an Anterior Cruciate Ligament Injury-Prevention Program in Elite-Youth Soccer Athletes. AB - CONTEXT: Identifying neuromuscular screening factors for anterior cruciate ligament (ACL) injury is a critical step toward large-scale deployment of effective ACL injury-prevention programs. The Landing Error Scoring System (LESS) is a valid and reliable clinical assessment of jump-landing biomechanics. OBJECTIVE: To investigate the ability of the LESS to identify individuals at risk for ACL injury in an elite-youth soccer population. DESIGN: Cohort study. SETTING: Field-based functional movement screening performed at soccer practice facilities. PATIENTS OR OTHER PARTICIPANTS: A total of 829 elite-youth soccer athletes (348 boys, 481 girls; age = 13.9 +/- 1.8 years, age range = 11 to 18 years), of whom 25% (n = 207) were less than 13 years of age. INTERVENTION(S): Baseline preseason testing for all participants consisted of a jump-landing task (3 trials). Participants were followed prospectively throughout their soccer seasons for diagnosis of ACL injuries (1217 athlete-seasons of follow-up). MAIN OUTCOME MEASURE(S): Landings were scored for "errors" in technique using the LESS. We used receiver operator characteristic curves to determine a cutpoint on the LESS. Sensitivity and specificity of the LESS in predicting ACL injury were assessed. RESULTS: Seven participants sustained ACL injuries during the follow-up period; the mechanism of injury was noncontact or indirect contact for all injuries. Uninjured participants had lower LESS scores (4.43 +/- 1.71) than injured participants (6.24 +/- 1.75; t1215 = -2.784, P = .005). The receiver operator characteristic curve analyses suggested that 5 was the optimal cutpoint for the LESS, generating a sensitivity of 86% and a specificity of 64%. CONCLUSIONS: Despite sample-size limitations, the LESS showed potential as a screening tool to determine ACL injury risk in elite-youth soccer athletes. PMID- 25811847 TI - Periodontal Therapy Effects on Nitrite Related to Oral Bacteria: A 6-Month Randomized Clinical Trial. AB - BACKGROUND: Nitrite is a biologic factor relevant to oral and systemic homeostasis. Through an oral bacteria reduction process, it was suggested that periodontal therapy and chlorhexidine (CHX) rinse could affect nitrite levels, leading to negative effects, such as an increase in blood pressure. This 6-month randomized clinical trial evaluated the effects of periodontal therapeutic protocols on salivary nitrite and its relation to subgingival bacteria. METHODS: One hundred patients with periodontitis were allocated randomly to debridement procedures in four weekly sections (quadrant scaling [QS]) or within 24 hours (full-mouth scaling [FMS]) in conjunction with a 60-day CHX (QS + CHX and FMS + CHX), placebo (QS + placebo and FMS + placebo), or no mouthrinse (QS + none and FMS + none) use. Real-time polymerase chain reaction determined total bacterial, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Streptococcus oralis, and Actinomyces naeslundii levels. Salivary nitrite concentration was determined with Griess reagent. Data were analyzed statistically at baseline and 3 and 6 months by analysis of variance, Kruskal-Wallis, Mann-Whitney U, and Spearman correlation tests (P <0.05). RESULTS: Nitrite concentrations did not tend to change over time. Regarding CHX use, there was a negative correlation between nitrite and total bacterial load at 6 months (FMS + CHX) and one positive correlation between P. gingivalis and nitrite at baseline (QS + CHX). Independently of rinse type, in the FMS group, nitrite correlated negatively with several microbial parameters and also with a higher percentage of deep periodontal pockets. CONCLUSIONS: The relationship between nitrite and bacterial levels appears weak. Short-term scaling exhibited a greater influence on nitrite concentrations then long-term CHX use. PMID- 25811848 TI - The Role of 6-Gingerol on Inhibiting Amyloid beta Protein-Induced Apoptosis in PC12 Cells. AB - Our previous study suggests that ginger root extract can reverse behavioral dysfunction and prevent Alzheimer's disease (AD)-like symptoms induced by the amyloid-beta protein (Abeta) in a rat model. 6-Gingerol is the major gingerol in ginger rhizomes, but its effect on the treatment of AD remains unclear. In this study, we aimed to determine if 6-gingerol had a protective effect on Abeta1-42 induced damage and apoptotic death in rat pheochromocytoma cells (PC12 cells) and to investigate the underlying mechanisms by which 6-gingerol may exert its neuroprotective effects. Our results indicated that pre-treatment with 6-gingerol significantly increased cell viability and reduced cell apoptosis in Abeta1-42 treated cells. Moreover, 6-gingerol pretreatment markedly reduced the level of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), the production of nitric oxide (NO), and the leakage of lactate dehydrogenase (LDH) and increased superoxide dismutase (SOD) activity compared with the Abeta1-42 treatment group. In addition, 6-gingerol pretreatment also significantly enhanced the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase 3beta (p-GSK-3beta). Overall, these results indicate that 6-gingerol exhibited protective effects on apoptosis induced by Abeta1-42 in cultured PC12 cells by reducing oxidative stress and inflammatory responses, suppressing the activation of GSK-3beta and enhancing the activation of Akt, thereby exerting neuroprotective effects. Therefore, 6-gingerol may be useful in the prevention and/or treatment of AD. PMID- 25811850 TI - The role of tryptophans in the UV-B absorption of a UVR8 photoreceptor--a computational study. AB - Arabidopsis thaliana UV RESISTANCE LOCUS8 (UVR8) has been identified as a photoreceptor for ultraviolet-B (UV-B). Tryptophan (Trp) residues have been shown to play a critical role in the response to UV-B irradiation in UVR8. In this work, we explore the spectroscopic behaviors of Trps in different protein environments of the UVR8 structure using the time-dependent density functional tight-binding (TD-DFTB) scheme. We show that W233 exhibits the longest absorption wavelength, highlighting its potential as a terminal Trp chromophore in the UV-B harvesting antenna. Our electronic and optical property analyses using various amino acid models support the important roles of W285 and W233 in sensing UV-B light at longer absorption wavelengths (~290 nm). We also provide evidence for the specific function of W94 in absorption at the longest wavelengths (305.8 nm in cluster II and 304.5 nm in cluster III). To these findings, we also add information about the influence of the arginine and aspartic acid residues surrounding the Trp pyramid on the particular absorption bands (280-300 nm) that are characteristic of the UV-B photoreceptor. PMID- 25811849 TI - Pregnancy prevention and condom use practices among HIV-infected women on antiretroviral therapy seeking family planning in Lilongwe, Malawi. AB - BACKGROUND: Programs for integration of family planning into HIV care must recognize current practices and desires among clients to appropriately target and tailor interventions. We sought to evaluate fertility intentions, unintended pregnancy, contraceptive and condom use among a cohort of HIV-infected women seeking family planning services within an antiretroviral therapy (ART) clinic. METHODS: 200 women completed an interviewer-administered questionnaire during enrollment into a prospective contraceptive study at the Lighthouse Clinic, an HIV/ART clinic in Lilongwe, Malawi, between August and December 2010. RESULTS: Most women (95%) did not desire future pregnancy. Prior reported unintended pregnancy rates were high (69% unplanned and 61% unhappy with timing of last pregnancy). Condom use was inconsistent, even among couples with discordant HIV status, with lack of use often attributed to partner's refusal. Higher education, older age, lower parity and having an HIV negative partner were factors associated with consistent condom usage. DISCUSSION: High rates of unintended pregnancy among these women underscore the need for integ rating family planning, sexually transmitted infection (STI) prevention, and HIV services. Contraceptive access and use, including condoms, must be improved with specific efforts to enlist partner support. Messages regarding the importance of condom usage in conjunction with more effective modern contraceptive methods for both infection and pregnancy prevention must continue to be reinforced over the course of ongoing ART treatment. PMID- 25811852 TI - Correction: The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease. PMID- 25811851 TI - Maternal depressive symptoms across early childhood and asthma in school children: findings from a Longitudinal Australian Population Based Study. AB - There is a growing body of evidence attesting to links between early life exposure to stress and childhood asthma. However, available evidence is largely based on small, genetically high risk samples. The aim of this study was to explore the associations between the course of maternal depressive symptoms across early childhood and childhood asthma in a nationally representative longitudinal cohort study of Australian children. Participants were 4164 children and their biological mothers from the Longitudinal Study of Australian Children. Latent class analysis identified three trajectories of maternal depressive symptoms across four biennial waves from the first postnatal year to when children were 6-7 years: minimal symptoms (74.6%), sub-clinical symptoms (20.8%), and persistent and increasing high symptoms (4.6%). Logistic regression analyses revealed that childhood asthma at age 6-7 years was associated with persistent and increasing high depressive symptoms after accounting for known risk factors including smoking during pregnancy and maternal history of asthma (adjusted OR 2.36, 95% CI 1.61-3.45), p.001). Our findings from a nationally representative sample of Australian children provide empirical support for a relationship between maternal depressive symptoms across the early childhood period and childhood asthma. The burden of disease from childhood asthma may be reduced by strengthening efforts to promote maternal mental health in the early years of parenting. PMID- 25811854 TI - Multiparametric flow cytometry using near-infrared fluorescent proteins engineered from bacterial phytochromes. AB - Engineering of fluorescent proteins (FPs) has followed a trend of achieving longer fluorescence wavelengths, with the ultimate goal of producing proteins with both excitation and emission in the near-infrared (NIR) region of the spectrum. Flow cytometers are now almost universally equipped with red lasers, and can now be equipped with NIR lasers as well. Most red-shifted FPs of the GFP like family are maximally excited by orange lasers (590 to 610 nm) not commonly found on cytometers. This has changed with the development of the iRFP series of NIR FPs from the protein family of bacterial phytochromes. The shortest wavelength variants of this series, iRFP670 and iRFP682 showed maximal excitation with visible red lasers. The longer wavelength variants iRFP702, iRFP713 and iRFP720 could be optimally excited by NIR lasers ranging from 685 to 730 nm. Pairs of iRFPs could be detected simultaneously by using red and NIR lasers. Moreover, a novel spectral cytometry technique, which relies on spectral deconvolution rather than optical filters, allowed spectra of all five iRFPs to be analyzed simultaneously with no spectral overlap. Together, the combination of iRFPs with the advanced flow cytometry will allow to first image tissues expressing iRFPs deep in live animals and then quantify individual cell intensities and sort out the distinct primary cell subpopulations ex vivo. PMID- 25811853 TI - New insights on the mechanism of the K(+-) independent activity of crenarchaeota pyruvate kinases. AB - Eukarya pyruvate kinases have glutamate at position 117 (numbered according to the rabbit muscle enzyme), whereas in Bacteria have either glutamate or lysine and in Archaea have other residues. Glutamate at this position makes pyruvate kinases K+-dependent, whereas lysine confers K+-independence because the positively charged residue substitutes for the monovalent cation charge. Interestingly, pyruvate kinases from two characterized Crenarchaeota exhibit K+ independent activity, despite having serine at the equivalent position. To better understand pyruvate kinase catalytic activity in the absence of K+ or an internal positive charge, the Thermofilum pendens pyruvate kinase (valine at the equivalent position) was characterized. The enzyme activity was K+-independent. The kinetic mechanism was random order with a rapid equilibrium, which is equal to the mechanism of the rabbit muscle enzyme in the presence of K+ or the mutant E117K in the absence of K+. Thus, the substrate binding order of the T. pendens enzyme was independent despite lacking an internal positive charge. Thermal stability studies of this enzyme showed two calorimetric transitions, one attributable to the A and C domains (Tm of 99.2 degrees C), and the other (Tm of 105.2 degrees C) associated with the B domain. In contrast, the rabbit muscle enzyme exhibits a single calorimetric transition (Tm of 65.2 degrees C). The calorimetric and kinetic data indicate that the B domain of this hyperthermophilic enzyme is more stable than the rest of the protein with a conformation that induces the catalytic readiness of the enzyme. B domain interactions of pyruvate kinases that have been determined in Pyrobaculum aerophilum and modeled in T. pendens were compared with those of the rabbit muscle enzyme. The results show that intra- and interdomain interactions of the Crenarchaeota enzymes may account for their higher B domain stability. Thus the structural arrangement of the T. pendens pyruvate kinase could allow charge independent catalysis. PMID- 25811855 TI - Tolerance and long-term MRI imaging of gadolinium-modified meshes used in soft organ repair. AB - BACKGROUND: Synthetic meshes are frequently used to reinforce soft tissues. The aim of this translational study is to evaluate tolerance and long-term MRI visibility of two recently developed Gadolinium-modified meshes in a rat animal model. MATERIALS AND METHODS: Gadolinium-poly-epsilon-caprolactone (Gd-PCL) and Gadolinium-polymethylacrylate (Gd-PMA) modified meshes were implanted in Wistar rats and their tolerance was assessed daily. Inflammation and biocompatibility of the implants were assessed by histology and immunohistochemistry after 30 days post implantation. Implants were visualised by 7T and 3T MRI at day 30 and at day 90. Diffusion of Gadolinium in the tissues of the implanted animals was assessed by Inductively Coupled Plasma Mass Spectrometry. RESULTS: Overall Gd-PMA coated implants were better tolerated as compared to those coated with Gd-PCL. In fact, Gd-PMA implants were characterised by a high ratio collagen I/III and good vascularisation of the integration tissues. High resolution images of the coated mesh were obtained in vivo with experimental 7T as well as 3T clinical MRI. Mass spectrometry analyses showed that levels of Gadolinium in animals implanted with coated mesh were similar to those of the control group. CONCLUSIONS: Meshes coated with Gd-PMA are better tolerated as compared to those coated with Gd-PCL as no signs of erosion or significant inflammation were detected at 30 days post implantation. Also, Gd-PMA coated meshes were clearly visualised with both 7T and 3T MRI devices. This new technique of mesh optimisation may represent a valuable tool in soft tissue repair and management. PMID- 25811858 TI - Numerical solution to generalized Burgers'-Fisher equation using Exp-function method hybridized with heuristic computation. AB - In this paper, a new heuristic scheme for the approximate solution of the generalized Burgers'-Fisher equation is proposed. The scheme is based on the hybridization of Exp-function method with nature inspired algorithm. The given nonlinear partial differential equation (NPDE) through substitution is converted into a nonlinear ordinary differential equation (NODE). The travelling wave solution is approximated by the Exp-function method with unknown parameters. The unknown parameters are estimated by transforming the NODE into an equivalent global error minimization problem by using a fitness function. The popular genetic algorithm (GA) is used to solve the minimization problem, and to achieve the unknown parameters. The proposed scheme is successfully implemented to solve the generalized Burgers'-Fisher equation. The comparison of numerical results with the exact solutions, and the solutions obtained using some traditional methods, including adomian decomposition method (ADM), homotopy perturbation method (HPM), and optimal homotopy asymptotic method (OHAM), show that the suggested scheme is fairly accurate and viable for solving such problems. PMID- 25811857 TI - Pharmacokinetics and Metabolism of 4R-Cembranoid. AB - 4R-cembranoid (4R) is a natural cyclic diterpenoid found in tobacco leaves that displays neuroprotective activity. 4R protects against NMDA, paraoxon (POX), and diisopropylfluorophosphate (DFP) damage in rat hippocampal slices and against DFP in rats in vivo. The purpose of this study was to examine the metabolism and pharmacokinetics of 4R as part of its preclinical development as a neuroprotective drug. 10 uM 4R was found to be very stable in plasma for up to 1 hr incubation. 4R metabolism in human microsomes was faster than in the rat. Ten metabolites of 4R were detected in the microsomal samples; 6 dihydroxy and 4 monohydroxy forms of 4R. Male rats received a single dose of 4R at 6 mg/kg i.v., i.m., or s.c. The i.v. group had the highest plasma concentration of 1017 ng/mL. The t1/2 was 36 min and reached the brain within 10 min. The brain peak concentration was 6516 ng/g. The peak plasma concentration in the i.m. group was 163 ng/mL compared to 138 ng/mL in the s.c. group. The t1/2 of 4R after i.m. and s.c. administration was approximately 1.5 hr. The brain peak concentration was 329 ng/g in the i.m. group and 323 ng/g for the s.c. group. The brain to plasma ratio in the i.v. group was 6.4, reached 10 min after dose, whereas in the i.m. and s.c. groups was 2.49 and 2.48, respectively, at 90 min after dose. Our data show that 4R crosses the BBB and concentrates in the brain where it exerts its neuroprotective effect. PMID- 25811856 TI - Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. AB - G protein-coupled receptors (GPCRs) constitute the largest family of proteins that transmit signal to regulate an array of fundamental biological processes. Viruses deploy diverse tactics to hijack and harness intracellular signaling events induced by GPCR. Herpesviruses encode multiple GPCR homologues that are implicated in viral pathogenesis. Cellular GPCRs are primarily regulated by their cognate ligands, while herpesviral GPCRs constitutively activate downstream signaling cascades, including the nuclear factor of activated T cells (NFAT) pathway. However, the roles of NFAT activation and mechanism thereof in viral GPCR tumorigenesis remain unknown. Here we report that GPCRs of human Kaposi's sarcoma-associated herpesvirus (kGPCR) and cytomegalovirus (US28) shortcut NFAT activation by inhibiting the sarcoplasmic reticulum calcium ATPase (SERCA), which is necessary for viral GPCR tumorigenesis. Biochemical approaches, entailing pharmacological inhibitors and protein purification, demonstrate that viral GPCRs target SERCA2 to increase cytosolic calcium concentration. As such, NFAT activation induced by vGPCRs was exceedingly sensitive to cyclosporine A that targets calcineurin, but resistant to inhibition upstream of ER calcium release. Gene expression profiling identified a signature of NFAT activation in endothelial cells expressing viral GPCRs. The expression of NFAT-dependent genes was up-regulated in tumors derived from tva-kGPCR mouse and human KS. Employing recombinant kGPCR-deficient KSHV, we showed that kGPCR was critical for NFAT dependent gene expression in KSHV lytic replication. Finally, cyclosporine A treatment diminished NFAT-dependent gene expression and tumor formation induced by viral GPCRs. These findings reveal essential roles of NFAT activation in viral GPCR tumorigenesis and a mechanism of "constitutive" NFAT activation by viral GPCRs. PMID- 25811861 TI - Preparation and characterization of 3,5-dinitro-1H-1,2,4-triazole. AB - Neat 3,5-dinitro-1H-1,2,4-triazole was obtained in quantitative yield from potassium 3,5-dinitro-1,2,4-triazolate and sulfuric acid. The compound was purified by sublimation in vacuo at 110 degrees C. Pure HDNT is a hygroscopic white solid that is impact and friction sensitive and decomposes explosively upon heating to 170 degrees C. However, the presence of impurities might lower the decomposition temperature and increase the sensitivity of the material. Potassium 3,5-dinitro-1,2,4-triazolate was prepared from commercially available 3,5-diamino 4H-1,2,4-triazole with sodium nitrite and sulfuric acid. The synthesis of HDNT from 2-cyanoguanidine and hydrazine hydrate without isolation and purification of the 3,5-diamino-4H-1,2,4-triazole intermediate can result in the formation of azidotriazole impurities. A triclinic and a monoclinic polymorph of 3,5-dinitro 1H-1,2,4-triazole were found by X-ray structure determination. In addition, the crystal structure of the hydrate (HDNT)3.4H2O, as well as those of several HDNT impurities and decomposition products were obtained. PMID- 25811860 TI - Geographic distribution and mortality risk factors during the cholera outbreak in a rural region of Haiti, 2010-2011. AB - BACKGROUND: In 2010 and 2011, Haiti was heavily affected by a large cholera outbreak that spread throughout the country. Although national health structure based cholera surveillance was rapidly initiated, a substantial number of community cases might have been missed, particularly in remote areas. We conducted a community-based survey in a large rural, mountainous area across four districts of the Nord department including areas with good versus poor accessibility by road, and rapid versus delayed response to the outbreak to document the true cholera burden and assess geographic distribution and risk factors for cholera mortality. METHODOLOGY/PRINCIPAL FINDINGS: A two-stage, household-based cluster survey was conducted in 138 clusters of 23 households in four districts of the Nord Department from April 22nd to May 13th 2011. A total of 3,187 households and 16,900 individuals were included in the survey, of whom 2,034 (12.0%) reported at least one episode of watery diarrhea since the beginning of the outbreak. The two more remote districts, Borgne and Pilate were most affected with attack rates up to 16.2%, and case fatality rates up to 15.2% as compared to the two more accessible districts. Care seeking was also less frequent in the more remote areas with as low as 61.6% of reported patients seeking care. Living in remote areas was found as a risk factor for mortality together with older age, greater severity of illness and not seeking care. CONCLUSIONS/SIGNIFICANCE: These results highlight important geographical disparities and demonstrate that the epidemic caused the highest burden both in terms of cases and deaths in the most remote areas, where up to 5% of the population may have died during the first months of the epidemic. Adapted strategies are needed to rapidly provide treatment as well as prevention measures in remote communities. PMID- 25811859 TI - Genome-guided analysis of physiological capacities of Tepidanaerobacter acetatoxydans provides insights into environmental adaptations and syntrophic acetate oxidation. AB - This paper describes the genome-based analysis of Tepidanaerobacter acetatoxydans strain Re1, a syntrophic acetate-oxidising bacterium (SAOB). Principal issues such as environmental adaptations, metabolic capacities, and energy conserving systems have been investigated and the potential consequences for syntrophic acetate oxidation discussed. Briefly, in pure culture, T. acetatoxydans grows with different organic compounds and produces acetate as the main product. In a syntrophic consortium with a hydrogenotrophic methanogen, it can also reverse its metabolism and instead convert acetate to formate/H2 and CO2. It can only proceed if the product formed is continuously removed. This process generates a very small amount of energy that is scarcely enough for growth, which makes this particular syntrophy of special interest. As a crucial member of the biogas producing community in ammonium-rich engineered AD processes, genomic features conferring ammonium resistance, bacterial defense, oxygen and temperature tolerance were found, as well as attributes related to biofilm formation and flocculation. It is likely that T. acetatoxydans can form an electrochemical gradient by putative electron-bifurcating Rnf complex and [Fe-Fe] hydrogenases, as observed in other acetogens. However, genomic deficiencies related to acetogenic metabolism and anaerobic respiration were discovered, such as the lack of formate dehydrogenase and F1F0 ATP synthase. This has potential consequences for the metabolic pathways used under SAO and non-SAO conditions. The two complete sets of bacteriophage genomes, which were found to be encoded in the genome, are also worthy of mention. PMID- 25811862 TI - Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. AB - INTRODUCTION: Elevated fibroblast growth factor-23 (FGF23) is an established marker of cardiovascular disease. The underlying reason(s) for the rise accompanying cardiovascular health decline are unclear. Prior studies have shown that FGF23 concentrations are associated with markers of inflammation and insulin resistance but they have been limited by a focus on persons with chronic kidney disease (CKD) and lack of race and sex diversity. The objective of this study was to examine the associations of FGF23 and markers of inflammation, insulin resistance, and anthropometrics in a large cohort of community-dwelling adults. METHODS: Associations of FGF23 with markers of inflammation [interleukin-6 (IL 6), IL-10, high sensitivity-CRP (hsCRP)], insulin utilization [resistin, adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR)] and anthropometrics [BMI and waist circumference (WC)] were examined cross sectionally in a 1,040 participants randomly selected from the Reason for Geographic and Racial Differences in Stroke (REGARDS) Study, a national study of black and white adults >=45 years. Effect modification by race and CKD status was tested, and stratified models were analyzed accordingly. RESULTS: Median FGF23 concentration was 69.6 RU/ml (IQR: 53.2, 102.7). Higher quartiles of FGF23 were associated with higher mean concentrations of IL-6, IL-10, hsCRP and resistin (Ptrend<0.001 for all). There were no significant differences in HOMA-IR, adiponectin concentrations, BMI, or WC across FGF23 quartiles in the crude analyses. CKD significantly modified the relationships between FGF23 and inflammatory markers, HOMA-IR, BMI and WC (P <= 0.01 for all). In linear regression models adjusted for sociodemographic and clinical variables, FGF23 was positively associated with IL-6, hsCRP, IL-10, HOMA-IR, BMI and WC in individuals without CKD, but not among individuals with CKD. Additionally, FGF23 was positively associated with resistin irrespective of CKD status. CONCLUSIONS: Elevated FGF23 concentrations may be considered a biomarker for decline in metabolic function among individuals with normal kidney function. PMID- 25811863 TI - Infection dynamic of symbiotic bacteria in the pea aphid Acyrthosiphon pisum gut and host immune response at the early steps in the infection process. AB - In addition to its obligatory symbiont Buchnera aphidicola, the pea aphid Acyrthosiphon pisum can harbor several facultative bacterial symbionts which can be mutualistic in the context of various ecological interactions. Belonging to a genus where many members have been described as pathogen in invertebrates, Serratia symbiotica is one of the most common facultative partners found in aphids. The recent discovery of strains able to grow outside their host allowed us to simulate environmental acquisition of symbiotic bacteria by aphids. Here, we performed an experiment to characterize the A. pisum response to the ingestion of the free-living S. symbiotica CWBI-2.3T in comparison to the ingestion of the pathogenic Serratia marcescens Db11 at the early steps in the infection process. We found that, while S. marcescens Db11 killed the aphids within a few days, S. symbiotica CWBI-2.3T did not affect host survival and colonized the whole digestive tract within a few days. Gene expression analysis of immune genes suggests that S. symbiotica CWBI-2.3T did not trigger an immune reaction, while S. marcescens Db11 did, and supports the hypothesis of a fine-tuning of the host immune response set-up for fighting pathogens while maintaining mutualistic partners. Our results also suggest that the lysosomal system and the JNK pathway are possibly involved in the regulation of invasive bacteria in aphids and that the activation of the JNK pathway is IMD-independent in the pea aphid. PMID- 25811864 TI - Characterization of the Xylella fastidiosa PD1671 gene encoding degenerate c-di GMP GGDEF/EAL domains, and its role in the development of Pierce's disease. AB - Xylella fastidiosa is an important phytopathogenic bacterium that causes many serious plant diseases including Pierce's disease of grapevines. X. fastidiosa is thought to induce disease by colonizing and clogging xylem vessels through the formation of cell aggregates and bacterial biofilms. Here we examine the role in X. fastidiosa virulence of an uncharacterized gene, PD1671, annotated as a two component response regulator with potential GGDEF and EAL domains. GGDEF domains are found in c-di-GMP diguanylate cyclases while EAL domains are found in phosphodiesterases, and these domains are for c-di-GMP production and turnover, respectively. Functional analysis of the PD1671 gene revealed that it affected multiple X. fastidiosa virulence-related phenotypes. A Tn5 PD1671 mutant had a hypervirulent phenotype in grapevines presumably due to enhanced expression of gum genes leading to increased exopolysaccharide levels that resulted in elevated biofilm formation. Interestingly, the PD1671 mutant also had decreased motility in vitro but did not show a reduced distribution in grapevines following inoculation. Given these responses, the putative PD1671 protein may be a negative regulator of X. fastidiosa virulence. PMID- 25811866 TI - In silico screening for novel inhibitors of DNA polymerase III alpha subunit of Mycobacterium tuberculosis (MtbDnaE2, H37Rv). AB - Tuberculosis, a pandemic disease is caused by Mycobacterium tuberculosis (Mtb). DNA polymerase III encoded by DnaE2 of Mtb is specifically required for its survival in vivo, and hence can be considered to be a potential drug target. Amino acid sequence analysis of the MtbDnaE2 and its human counterpart does not show any significant similarity. Therefore, a 3D model of the MtbDnaE2 was generated using Modeller 9v10 with the template structure of E. Coli DNA polymerase III alpha subunit (2HNH_A). The generated models were validated using a number of programmes such as RAMPAGE/PROCHECK, VERIFY_3D, and ProSA. MtbDnaE2 has few conserved residues and four conserved domains similar to that present in DNA polymerase III of E. coli. In silico screening was performed with bioactive anti-tuberculosis compounds and 6-AU (a known inhibitor of DNA polymerase III of Bacillus subtilis) and its analogues against the modeled MtbDnaE2 structure. Docking was performed using GOLD v5.2 software which resulted in the identification of top ten compounds with high GOLD fitness scores and binding affinity (X-Score). To further evaluate the efficacy of these compounds, in silico ADMET analysis was performed using MedChem Designer v3. Given their high binding affinity to the targeted MtbDnaE2, which is essential for DNA replication in the Mtb and good ADMET properties, these compounds are promising candidates for further evaluation and development as anti-tubercular agents. PMID- 25811865 TI - Structure-function dissection of Myxococcus xanthus CarD N-terminal domain, a defining member of the CarD_CdnL_TRCF family of RNA polymerase interacting proteins. AB - Two prototypes of the large CarD_CdnL_TRCF family of bacterial RNA polymerase (RNAP)-binding proteins, Myxococcus xanthus CarD and CdnL, have distinct functions whose molecular basis remain elusive. CarD, a global regulator linked to the action of several extracytoplasmic function (ECF) sigma-factors, binds to the RNAP beta subunit (RNAP-beta) and to protein CarG via an N-terminal domain, CarDNt, and to DNA via an intrinsically unfolded C-terminal domain resembling eukaryotic high-mobility-group A (HMGA) proteins. CdnL, a CarDNt-like protein that is essential for cell viability, is implicated in sigmaA-dependent rRNA promoter activation and interacts with RNAP-beta but not with CarG. While the HMGA-like domain of CarD by itself is inactive, we find that CarDNt has low but observable ability to activate ECF sigma-dependent promoters in vivo, indicating that the C-terminal DNA-binding domain is required to maximize activity. Our structure-function dissection of CarDNt reveals an N-terminal, five-stranded beta -sheet Tudor-like domain, CarD1-72, whose structure and contacts with RNAP-beta mimic those of CdnL. Intriguingly, and in marked contrast to CdnL, CarD mutations that disrupt its interaction with RNAP-beta did not annul activity. Our data suggest that the CarDNt C-terminal segment, CarD61-179, may be structurally distinct from its CdnL counterpart, and that it houses at least two distinct and crucial function determinants: (a) CarG-binding, which is specific to CarD; and (b) a basic residue stretch, which is also conserved and functionally required in CdnL. This study highlights the evolution of shared and divergent interactions in similar protein modules that enable the distinct activities of two related members of a functionally important and widespread bacterial protein family. PMID- 25811868 TI - Protein copy number distributions for a self-regulating gene in the presence of decoy binding sites. AB - A single transcription factor may interact with a multitude of targets on the genome, some of which are at gene promoters, others being part of DNA repeat elements. Being sequestered at binding sites, protein molecules can be prevented from partaking in other pathways, specifically, from regulating the expression of the very gene that encodes them. Acting as decoys at the expense of the autoregulatory loop, the binding sites can have a profound impact on protein abundance--on its mean as well as on its cell-to-cell variability. In order to quantify this impact, we study in this paper a mathematical model for pulsatile expression of a transcription factor that autoregulates its expression and interacts with decoys. We determine the exact stationary distribution for protein abundance at the single-cell level, showing that in the case of non-cooperative positive autoregulation, the distribution can be bimodal, possessing a basal expression mode and a distinct, up-regulated, mode. Bimodal protein distributions are more feasible if the rate of degradation is the same irrespective of whether protein is bound or not. Contrastingly, the presence of decoy binding sites which protect the protein from degradation reduces the availability of the bimodal scenario. PMID- 25811869 TI - Counseling patients for lifestyle change: making a 15-minute office visit work. AB - Lifestyle counseling is an intervention that can improve chronic disease management as well as patient and provider satisfaction. Patients and providers are often frustrated with difficulties faced in the implementation and maintenance of lifestyle change. Can we change this paradigm? Are there new strategies that work and can be implemented in a typical office visit? The medical literature confirms the effectiveness of lifestyle interventions and recommends that lifestyle counseling be considered as a cornerstone of care. Here we present a case study of a midlife woman to show how motivational interviewing can be used to help her identify and meet her health goals. PMID- 25811870 TI - Measuring engagement with music: development of an informant-report questionnaire. AB - OBJECTIVES: This study describes the development of the Music Engagement Questionnaire (MusEQ), a 35-item scale to measure engagement with music in daily life. Music has implications for well-being and for therapy, notably for individuals living with dementia. A number of excellent scales or questionnaires are now available to measure music engagement. Unlike these scales, the MusEQ may be completed by either the participant or an informant. METHOD: Study 1 drew on a community-based sample of 391 participants. Exploratory factor analysis revealed six interpretable factors, which formed the basis for construction of six subscales. Study 2 applied the MusEQ to a group of participants with Alzheimer's disease (AD; n = 16) as well as a group of neurotypical older adults (OA; n = 16). Informants completed the MusEQ, and the OA group also completed the self report version of the MusEQ. Both groups had an interview in which they described the place music had in their lives. These interviews were scored by three independent raters. RESULTS: The MusEQ showed excellent internal consistency. Five of the factor-derived subscales showed good or excellent internal consistency. MusEQ scores were moderately correlated with a global rating of 'musicality' and with music education. There was strong agreement between self report and informant-report data. MusEQ scores showed a significant positive relationship to independent ratings of music engagement. CONCLUSION: The MusEQ provides a meaningful and reliable option for measuring music engagement among participants who are unable to complete a self-report questionnaire. PMID- 25811867 TI - Mental health service use by young people: the role of caregiver characteristics. AB - AIMS: Many children and adolescents experiencing mental health problems do not receive appropriate care. Strategies to encourage appropriate access to services might be improved by a more detailed understanding of service use determinants within this group. In view of caregivers' key role in young people's pathways to care, this study aimed to advance understanding of caregiver-related characteristics that influence service use among young people. METHODS: We interviewed 407 primary caregivers of young people aged 9-18 years, recruited from a Greater London (United Kingdom) community sample. Caregivers reported on young people's service use in health care sector and/or education settings, and caregivers' intended stigmatising behaviours, help-seeking attitudes, and personal service use. Logistic regression analyses examined the relationship between these caregiver characteristics and young people's service use, controlling for young people's clinical and socio-demographic factors. RESULTS: Caregivers' intended stigmatising behaviours in particular exerted a strong influence on young people's service use within each service setting. The impact of this characteristic interacted with caregivers' service use in influencing young people's service use across health care and education settings and health care settings specifically. For young people's service use within education settings, caregivers' intended stigmatising behaviours score had a main effect. CONCLUSIONS: This study highlights the key role caregivers' attitudes and experiences hold in young people's service use. The findings indicate that strategies aiming to bridge the gap between young people's service needs and utilisation might be improved by targeting stigma amongst caregivers. PMID- 25811872 TI - Tales From the Wild West of US Drug Pricing: The Case of Intravenous Acetaminophen. AB - This article aims to discuss and provide insight into the effects of the increased use and price (from $12.43 to $35.40 in 2014) of intravenous acetaminophen, which has rapidly gained acceptance in the field of perioperative medicine. Overall use and characteristics are described for selected surgeries with absolute use particularly high in orthopedic surgeries associated with substantial costs (up to an additional $160,000 per year per hospital for just orthopedic use). The availability of large-scale data on costs and use of intravenous acetaminophen in the United States will greatly benefit the ongoing discussions on its place in current practice. PMID- 25811871 TI - Immune reaction and survivability of salmonella typhimurium and salmonella infantis after infection of primary avian macrophages. AB - Salmonella serovars are differentially able to infect chickens. The underlying causes are not yet fully understood. Aim of the present study was to elucidate the importance of Salmonella Pathogenicity Island 1 and 2 (SPI-1 and -2) for the virulence of two non-host-specific, but in-vivo differently invasive, Salmonella serovars in conjunction with the immune reaction of the host. Primary avian splenic macrophages were inoculated with Salmonella enterica sub-species enterica serovar (S.) Typhimurium and S. Infantis. The number and viability of intracellular bacteria and transcription of SPI-1 and -2 genes by the pathogens, as well as transcription of immune-related proteins, surface antigen expression and nitric oxide production by the macrophages, were compared at different times post inoculation. After infection, both of the Salmonella serovars were found inside the primary macrophages. Invasion-associated SPI-1 genes were significantly higher transcribed in S. Infantis- than S. Typhimurium-infected macrophages. The macrophages counteracted the S. Infantis and S. Typhimurium infection with elevated mRNA expression of inducible nitric oxide synthase (iNOS), interleukin (IL)-12, IL-18 and lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) as well as with an increased synthesis of nitric oxide. Despite these host cell attacks, S. Typhimurium was better able than S. Infantis to survive within the macrophages and transcribed higher rates of the SPI-2 genes spiC, ssaV, sifA, and sseA. The results showed similar immune reactions of primary macrophages after infection with both of the Salmonella strains. The more rapid and stronger transcription of SPI-2-related genes by intracellular S. Typhimurium compared to S. Infantis might be responsible for its better survival in avian primary macrophages. PMID- 25811874 TI - The facile synthesis of single crystalline palladium arrow-headed tripods and their application in formic acid electro-oxidation. AB - Single crystalline palladium arrow-headed tripods prepared via a simple one-pot strategy exhibit high electro-activity in formic acid oxidation, which could be a promising anodic catalyst for direct formic acid fuel cells. PMID- 25811873 TI - Genome-based identification of active prophage regions by next generation sequencing in Bacillus licheniformis DSM13. AB - Prophages are viruses, which have integrated their genomes into the genome of a bacterial host. The status of the prophage genome can vary from fully intact with the potential to form infective particles to a remnant state where only a few phage genes persist. Prophages have impact on the properties of their host and are therefore of great interest for genomic research and strain design. Here we present a genome- and next generation sequencing (NGS)-based approach for identification and activity evaluation of prophage regions. Seven prophage or prophage-like regions were identified in the genome of Bacillus licheniformis DSM13. Six of these regions show similarity to members of the Siphoviridae phage family. The remaining region encodes the B. licheniformis orthologue of the PBSX prophage from Bacillus subtilis. Analysis of isolated phage particles (induced by mitomycin C) from the wild-type strain and prophage deletion mutant strains revealed activity of the prophage regions BLi_Pp2 (PBSX-like), BLi_Pp3 and BLi_Pp6. In contrast to BLi_Pp2 and BLi_Pp3, neither phage DNA nor phage particles of BLi_Pp6 could be visualized. However, the ability of prophage BLi_Pp6 to generate particles could be confirmed by sequencing of particle protected DNA mapping to prophage locus BLi_Pp6. The introduced NGS-based approach allows the investigation of prophage regions and their ability to form particles. Our results show that this approach increases the sensitivity of prophage activity analysis and can complement more conventional approaches such as transmission electron microscopy (TEM). PMID- 25811875 TI - Expression of cellular components in granulomatous inflammatory response in Piaractus mesopotamicus model. AB - The present study aimed to describe and characterize the cellular components during the evolution of chronic granulomatous inflammation in the teleost fish pacus (P. mesopotamicus) induced by Bacillus Calmette-Guerin (BCG), using S-100, iNOS and cytokeratin antibodies. 50 fish (120+/-5.0 g) were anesthetized and 45 inoculated with 20 MUL (40 mg/mL) (2.0 x 10(6) CFU/mg) and five inoculated with saline (0,65%) into muscle tissue in the laterodorsal region. To evaluate the inflammatory process, nine fish inoculated with BCG and one control were sampled in five periods: 3rd, 7th, 14th, 21st and 33rd days post-inoculation (DPI). Immunohistochemical examination showed that the marking with anti-S-100 protein and anti-iNOS antibodies was weak, with a diffuse pattern, between the third and seventh DPI. From the 14th to the 33rd day, the marking became stronger and marked the cytoplasm of the macrophages. Positivity for cytokeratin was initially observed in the 14th DPI, and the stronger immunostaining in the 33rd day, period in which the epithelioid cells were more evident and the granuloma was fully formed. Also after the 14th day, a certain degree of cellular organization was observed, due to the arrangement of the macrophages around the inoculated material, with little evidence of edema. The arrangement of the macrophages around the inoculum, the fibroblasts, the lymphocytes and, in most cases, the presence of melanomacrophages formed the granuloma and kept the inoculum isolated in the 33rd DPI. The present study suggested that the granulomatous experimental model using teleost fish P. mesopotamicus presented a similar response to those observed in mammals, confirming its importance for studies of chronic inflammatory reaction. PMID- 25811876 TI - The novel tubulin polymerization inhibitor MHPT exhibits selective anti-tumor activity against rhabdomyosarcoma in vitro and in vivo. AB - The dose-limiting toxicity caused by standard chemotherapy has become a major roadblock to successful rhabdomyosarcoma chemotherapy. By screening a thiazolidinone library including 372 compounds, a novel synthetic compound, 2-((4 hydroxyphenyl)imino)-5-(3-methoxybenzylidene)thiazolidin-4-one (MHPT), was identified as a potent and selective anti-rhabdomyosarcoma agent. MHPT inhibited 50% of the growth of the rhabdomyosarcoma cell lines RD and SJ-RH30 at 0.44 MUM and 1.35 MUM, respectively, while displaying no obvious toxicity against normal human fibroblast cells at 100 MUM. Further investigation revealed that MHPT suppressed the polymerization of tubulin, leading to rhabdomyosarcoma cell growth arrest at the G2/M phase followed by apoptosis. In vivo, MHPT inhibited tumor growth by 48.6% relative to the vehicle control after 5 intraperitoneal injections of 40 mg/kg without appreciable toxicity to normal tissues and systems in an RD xenograft mouse model, while vincristine caused lethal toxicity when similar growth inhibition was achieved. As a moderate tubulin polymerization inhibitor compared with vincristine, MHPT requires a more dynamic tubulin to exert its cytotoxicity, which is a situation that only exists in cancer cells. This attribute may account for the low toxicity of MHPT in normal cells. Our data suggest that MHPT has the potential to be further developed into a selective anti rhabdomyosarcoma drug with low toxicity. PMID- 25811877 TI - Functional genomic analysis identifies indoxyl sulfate as a major, poorly dialyzable uremic toxin in end-stage renal disease. AB - BACKGROUND: Chronic renal failure is characterized by progressive renal scarring and accelerated arteriosclerotic cardiovascular disease despite what is considered to be adequate hemodialysis or peritoneal dialysis. In rodents with reduced renal mass, renal scarring has been attributed to poorly filtered, small protein-bound molecules. The best studied of these is indoxyl sulfate (IS). METHODS: We have attempted to establish whether there are uremic toxins that are not effectively removed by hemodialysis. We examined plasma from patients undergoing hemodialysis, employing global gene expression in normal human renal cortical cells incubated in pre- and post- dialysis plasma as a reporter system. Responses in cells incubated with pre- and post-dialysis uremic plasma (n = 10) were compared with responses elicited by plasma from control subjects (n = 5). The effects of adding IS to control plasma and of adding probenecid to uremic plasma were examined. Plasma concentrations of IS were measured by HPLC (high pressure liquid chromatography). RESULTS: Gene expression in our reporter system revealed dysregulation of 1912 genes in cells incubated with pre-dialysis uremic plasma. In cells incubated in post-dialysis plasma, the expression of 537 of those genes returned to baseline but the majority of them (1375) remained dysregulated. IS concentration was markedly elevated in pre- and post-dialysis plasma. Addition of IS to control plasma simulated more than 80% of the effects of uremic plasma on gene expression; the addition of probenecid, an organic anion transport (OAT) inhibitor, to uremic plasma reversed the changes in gene expression. CONCLUSION: These findings provide evidence that hemodialysis fails to effectively clear one or more solutes that effect gene expression, in our reporter system, from the plasma of patients with uremia. The finding that gene dysregulation was simulated by the addition of IS to control plasma and inhibited by addition of an OAT inhibitor to uremic plasma identifies IS as a major, poorly dialyzable, uremic toxin. The signaling pathways initiated by IS and possibly other solutes not effectively removed by dialysis may participate in the pathogenesis of renal scarring and uremic vasculopathy. PMID- 25811879 TI - A genomic portrait of haplotype diversity and signatures of selection in indigenous southern African populations. AB - We report a study of genome-wide, dense SNP (~ 900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region. PMID- 25811880 TI - Association between education level and prognosis after esophageal cancer surgery: a Swedish population-based cohort study. AB - BACKGROUND: An association between education level and survival after esophageal cancer has recently been indicated, but remains uncertain. We conducted a large study with long follow-up to address this issue. METHODS: This population-based cohort study included all patients operated for esophageal cancer in Sweden between 1987 and 2010 with follow-up until 2012. Level of education was categorized as compulsory (<=9 years), intermediate (10-12 years), or high (>=13 years). The main outcome measure was overall 5-year mortality after esophagectomy. Cox regression was used to estimate associations between education level and mortality, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), with adjustment for sex, age, co-morbidity, tumor stage, tumor histology, and assessing the impact of education level over time. RESULTS: Compared to patients with high education, the adjusted HR for mortality was 1.29 (95% CI 1.07-1.57) in the intermediate educated group and 1.42 (95% CI 1.17-1.71) in the compulsory educated group. The largest differences were found in early tumor stages (T-stage 0-1), with HRs of 1.73 (95% CI 1.00-2.99) and 2.58 (95% CI 1.51-4.42) for intermediate and compulsory educated patients respectively; and for squamous cell carcinoma, with corresponding HRs of 1.38 (95% CI 1.07-1.79) and 1.52 (95% CI 1.19-1.95) respectively. CONCLUSIONS: This Swedish population based study showed an association between higher education level and improved survival after esophageal cancer surgery, independent of established prognostic factors. The associations were stronger in patients of an early tumor stage and squamous cell carcinoma. PMID- 25811882 TI - Correction: De novo assembly of the common bean transcriptome using short reads for the discovery of drought-responsive genes. AB - [This corrects the article DOI: 10.1371/journal.pone.0109262.]. PMID- 25811878 TI - Intermittent hypoxia selects for genotypes and phenotypes that increase survival, invasion, and therapy resistance. AB - Hypoxia in tumors correlates with greater risk of metastases, increased invasiveness, and resistance to systemic and radiation therapy. The evolutionary dynamics that links specific adaptations to hypoxia with these observed tumor properties have not been well investigated. While some tumor populations may experience fixed hypoxia, cyclical and stochastic transitions from normoxia to hypoxia are commonly observed in vivo. Although some phenotypic adaptations to this cyclic hypoxia are likely reversible, we hypothesize that some adaptations may become fixed through mutations promoted by hypoxia-induced genomic instability. Here we seek to identify genetic alterations and corresponding stable phenotypes that emerge following cyclic hypoxia. Although these changes may originate as adaptations to this specific environmental stress, their fixation in the tumor genome may result in their observation in tumors from regions of normoxia, a condition known as pseudohypoxia. We exposed several epithelial cell lines to 50 cycles of hypoxia-normoxia, followed by culture in normoxia over a period of several months. Molecular analyses demonstrated permanent changes in expression of several oncogenes and tumor-suppressors, including p53, E-cadherin, and Hif-1alpha. These changes were associated with increased resistance to multiple cytotoxins, increased survival in hypoxia and increased anchorage-independent growth. These results suggest cycles of hypoxia encountered in early cancers can select for specific and stable genotypic and phenotypic properties that persist even in normoxic conditions, which may promote tumor progression and resistance to therapy. PMID- 25811881 TI - Do bird assemblages predict susceptibility by e-waste pollution? A comparative study based on species- and guild-dependent responses in China agroecosystems. AB - Indirect effects of electronic waste (e-waste) have been proposed as a causal factor in the decline of bird populations, but analyses of the severity impacts on community assembly are currently lacking. To explore how population abundance/species diversity are influenced, and which functional traits are important in determining e-waste susceptibility, here we surveyed breeding and overwintering birds with a hierarchically nested sampling design, and used linear mixed models to analyze changes in bird assemblages along an exposure gradient in South China. Total bird abundance and species diversity decreased with e-waste severity (exposed < surrounding < reference), reflecting the decreasing discharge and consequent side effects. Twenty-five breeding species exclusively used natural farmland, and nine species decreased significantly in relative abundance at e-waste polluted sites. A high pairwise similarity between exposed and surrounding sites indicates a diffuse effect of pollutants on the species assembly at local scale. We show that sensitivity to e-waste severity varies substantially across functional guild, with the prevalence of woodland insectivorous and grassland specialists declining, while some open farmland generalists such as arboreal frugivores, and terrestrial granivores were also rare. By contrast, the response of waterbirds, omnivorous and non-breeding visitors seem to be tolerable to a wide range of pollution so far. These findings underscore that improper e-waste dismantling results in a severe decline of bird diversity, and the different bird assemblages on polluted and natural farmlands imply species- and guild-dependent susceptibility with functional traits. Moreover, a better understanding of the impact of e-waste with different pollution levels, combined multiple pollutants, and in a food-web context on bird is required in future. PMID- 25811883 TI - Correction: Simultaneously uncovering the patterns of brain regions involved in different story reading subprocesses. PMID- 25811885 TI - Avian Influenza A(H7N9) virus antibodies in close contacts of infected persons, China, 2013-2014. PMID- 25811884 TI - Phenotypic profiling of Scedosporium aurantiacum, an opportunistic pathogen colonizing human lungs. AB - Genotyping studies of Australian Scedosporium isolates have revealed the strong prevalence of a recently described species: Scedosporium aurantiacum. In addition to occurring in the environment, this fungus is also known to colonise the respiratory tracts of cystic fibrosis (CF) patients. A high throughput Phenotype Microarray (PM) analysis using 94 assorted substrates (sugars, amino acids, hexose-acids and carboxylic acids) was carried out for four isolates exhibiting different levels of virulence, determined using a Galleria mellonella infection model. A significant difference was observed in the substrate utilisation patterns of strains displaying differential virulence. For example, certain sugars such as sucrose (saccharose) were utilised only by low virulence strains whereas some sugar derivatives such as D-turanose promoted respiration only in the more virulent strains. Strains with a higher level of virulence also displayed flexibility and metabolic adaptability at two different temperature conditions tested (28 and 37 degrees C). Phenotype microarray data were integrated with the whole-genome sequence data of S. aurantiacum to reconstruct a pathway map for the metabolism of selected substrates to further elucidate differences between the strains. PMID- 25811888 TI - Coordination-induced spin-state change in manganese(V) complexes: the electronic structure of manganese(V) nitrides. AB - This work illustrates that manganese(V) nitrido complexes are able to undergo a coordination-induced spin-state change by altering the ligand field from trigonal to tetragonal symmetry. For the reversible coordination of acetonitrile to trigonal [(TIMEN(xyl))Mn(N)](2+) (1; high-spin S = 1; with TIMEN(xyl) = tris[2-(3 xylylimidazol-2-ylidene)ethyl]-amine), a temperature-dependent coordination induced spin-state switch is established. Starting from the manganese(V) nitrido complex 1, the synthesis and characterization of a series of octahedral, low-spin (S = 0) manganese(V) nitrido complexes of the type [(TIMEN(xyl))Mn(N)(L)](n+) (L = MeCN (2), (t)BuNC (3), CN(-) (4), NCS(-) (5), F(-) (6), MU-{Ag(CN)2}(-) (7), with n = 1, 2) is described. These represent the first examples of d(2) transition metal complexes showing a coordination-induced spin-state change. Spectroscopic, as well as ligand-field theory and density functional theory studies suggest a transition from a 2 + 2 + 1 orbital splitting in the trigonal case to a 1 + 2 + 1 + 1 splitting in tetragonal symmetry as the origin of the coordination-induced spin-state change. PMID- 25811886 TI - Induction of interferon-stimulated genes by IRF3 promotes replication of Toxoplasma gondii. AB - Innate immunity is the first line of defense against microbial insult. The transcription factor, IRF3, is needed by mammalian cells to mount innate immune responses against many microbes, especially viruses. IRF3 remains inactive in the cytoplasm of uninfected cells; upon virus infection, it gets phosphorylated and then translocates to the nucleus, where it binds to the promoters of antiviral genes and induces their expression. Such genes include type I interferons (IFNs) as well as Interferon Stimulated Genes (ISGs). IRF3-/- cells support enhanced replication of many viruses and therefore, the corresponding mice are highly susceptible to viral pathogenesis. Here, we provide evidence for an unexpected pro-microbial role of IRF3: the replication of the protozoan parasite, Toxoplasma gondii, was significantly impaired in IRF3-/- cells. In exploring whether the transcriptional activity of IRF3 was important for its pro-parasitic function, we found that ISGs induced by parasite-activated IRF3 were indeed essential, whereas type I interferons were not important. To delineate the signaling pathway that activates IRF3 in response to parasite infection, we used genetically modified human and mouse cells. The pro-parasitic signaling pathway, which we termed PISA (Parasite-IRF3 Signaling Activation), activated IRF3 without any involvement of the Toll-like receptor or RIG-I-like receptor pathways, thereby ruling out a role of parasite-derived RNA species in activating PISA. Instead, PISA needed the presence of cGAS, STING, TBK1 and IRF3, indicating the necessity of DNA-triggered signaling. To evaluate the physiological significance of our in vitro findings, IRF3-/- mice were challenged with parasite infection and their morbidity and mortality were measured. Unlike WT mice, the IRF3-/- mice did not support replication of the parasite and were resistant to pathogenesis caused by it. Our results revealed a new paradigm in which the antiviral host factor, IRF3, plays a cell-intrinsic pro-parasitic role. PMID- 25811887 TI - Renal primordia activate kidney regenerative events in a rat model of progressive renal disease. AB - New intervention tools for severely damaged kidneys are in great demand to provide patients with a valid alternative to whole organ replacement. For repairing or replacing injured tissues, emerging approaches focus on using stem and progenitor cells. Embryonic kidneys represent an interesting option because, when transplanted to sites such as the renal capsule of healthy animals, they originate new renal structures. Here, we studied whether metanephroi possess developmental capacity when transplanted under the kidney capsule of MWF male rats, a model of spontaneous nephropathy. We found that six weeks post transplantation, renal primordia developed glomeruli and tubuli able to filter blood and to produce urine in cyst-like structures. Newly developed metanephroi were able to initiate a regenerative-like process in host renal tissues adjacent to the graft in MWF male rats as indicated by an increase in cell proliferation and vascular density, accompanied by mRNA and protein upregulation of VEGF, FGF2, HGF, IGF-1 and Pax-2. The expression of SMP30 and NCAM was induced in tubular cells. Oxidative stress and apoptosis markedly decreased. Our study shows that embryonic kidneys generate functional nephrons when transplanted into animals with severe renal disease and at the same time activate events at least partly mimicking those observed in kidney tissues during renal regeneration. PMID- 25811890 TI - [Frequencies of injuries and causes of accidents during ski touring on ski slopes - a pilot study]. PMID- 25811889 TI - Prognosis for Spontaneous Resolution of OSA in Children. AB - BACKGROUND: Adenotonsillectomy (AT) is commonly performed for childhood OSA syndrome (OSAS), but little is known about prognosis without treatment. METHODS: The Childhood Adenotonsillectomy Trial (CHAT) randomized 50% of eligible children with OSAS to a control arm (watchful waiting), with 7-month follow-up symptom inventories, physical examinations, and polysomnography. Polysomnographic and symptomatic resolution were defined respectively by an apnea/hypopnea index (AHI) <2 and obstructive apnea index (OAI) <1 and by an OSAS symptom score (Pediatric Sleep Questionnaire [PSQ]) < 0.33 with >= 25% improvement from baseline. RESULTS: After 194 children aged 5 to 9 years underwent 7 months of watchful waiting, 82 (42%) no longer met polysomnographic criteria for OSAS. Baseline predictors of resolution included lower AHI, better oxygen saturation, smaller waist circumference or percentile, higher-positioned soft palate, smaller neck circumference, and non-black race (each P < .05). Among these, the independent predictors were lower AHI and waist circumference percentile < 90%. Among 167 children with baseline PSQ scores >= 0.33, only 25 (15%) experienced symptomatic resolution. Baseline predictors were low PSQ and PSQ snoring subscale scores; absence of habitual snoring, loud snoring, observed apneas, or a household smoker; higher quality of life; fewer attention-deficit/hyperactivity disorder symptoms; and female sex. Only lower PSQ and snoring scores were independent predictors. CONCLUSIONS: Many candidates for AT no longer have OSAS on polysomnography after 7 months of watchful waiting, whereas meaningful improvement in symptoms is not common. In practice, a baseline low AHI and normal waist circumference, or low PSQ and snoring score, may help identify an opportunity to avoid AT. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00560859; URL: www.clinicaltrials.gov. PMID- 25811891 TI - The relation of ambulatory heart rate with all-cause mortality among middle-aged men: a prospective cohort study. AB - The aim of this study was to investigate the association between average 24-hour ambulatory heart rate and all-cause mortality, while adjusting for resting clinical heart rate, cardiorespiratory fitness, occupational and leisure time physical activity as well as classical risk factors. A group of 439 middle-aged male workers free of baseline coronary heart disease from the Belgian Physical Fitness Study was included in the analysis. Data were collected by questionnaires and clinical examinations from 1976 to 1978. All-cause mortality was collected from the national mortality registration with a mean follow-up period of 16.5 years, with a total of 48 events. After adjustment for all before mentioned confounders in a Cox proportional hazards regression analysis, a significant increased risk for all-cause mortality was found among the tertile of workers with highest average ambulatory heart rate compared to the tertile with lowest ambulatory heart rate (Hazard ratio = 3.21, 95% confidence interval: 1.22-8.44). No significant independent association was found between resting clinic heart rate and all-cause mortality. The study indicates that average 24-hour ambulatory heart rate is a strong predictor of all-cause mortality independent from resting clinic heart rate, cardiorespiratory fitness, occupational and leisure time physical activity and other classical risk factors among healthy middle-aged workers. PMID- 25811893 TI - Sarcocyst Development in Raccoons (Procyon lotor) Inoculated with Different Strains of Sarcocystis neurona Culture-Derived Merozoites. AB - Sarcocystis neurona is considered the major etiologic agent of equine protozoal myeloencephalitis (EPM), a neurological disease in horses. Raccoon ( Procyon lotor ) is considered the most important intermediate host in the life cycle of S. neurona in the United States; S. neurona sarcocysts do mature in raccoon muscles, and raccoons also develop clinical signs simulating EPM. The focus of this study was to determine if sarcocysts would develop in raccoons experimentally inoculated with different host-derived strains of in vitro cultivated S. neurona merozoites. Four raccoons were inoculated with strains derived from a raccoon, a sea otter, a cat, and a horse. Raccoon tissues were fed to laboratory-raised opossums ( Didelphis virginiana ), the definitive host of S. neurona . Intestinal scraping revealed sporocysts in opossums who received muscle tissue from raccoons inoculated with the raccoon-derived or the sea otter-derived isolates. These results demonstrate that sarcocysts can mature in raccoons inoculated with in vitro-derived S. neurona merozoites. In contrast, the horse and cat-derived isolates did not produce microscopically or biologically detected sarcocysts. Immunoblot analysis revealed both antigenic and antibody differences when testing the inoculated raccoons. Immunohistochemical staining indicated differences in staining between the merozoite and sarcocyst stages. The successful infections achieved in this study indicates that the life cycle can be manipulated in the laboratory without affecting subsequent stage development, thereby allowing further purification of strains and artificial maintenance of the life cycle. PMID- 25811892 TI - Compatibility of a novel thrombospondin-1 analog with fertility and pregnancy in a xenograft mouse model of endometriosis. AB - Endometriosis is a gynecological disease defined by the growth of endometrium outside of the uterus. Although endometriosis contributes to 50% of female infertility cases, medical treatments are incompatible with pregnancy. Angiogenesis, the growth of blood vessels from existing vasculature, plays a crucial role in endometriotic lesion growth and survival. Previously, we demonstrated the effectiveness of thrombospondin-1 analog, ABT-898 (Abbott Laboratories) to inhibit endometriotic lesion vascularization in mice. We have now evaluated the trans-generational implications of ABT-898 treatment before and during mouse pregnancy. We hypothesized that ABT-898 would target lesion vasculature without affecting pregnancy, offspring development, or ovarian and uterine vascularity in mice. Endometriosis was induced using human endometrium in beta-estradiol-primed BALB/c-Rag-2-/-Il2rgamma-/- mice receiving intraperitoneal injections of ABT-898 (25 mg/kg) or 5% dextrose control for 21 days. Ultrasound assessment of lesion vascularization revealed a reduction in blood flow supplying treated lesions. Excised ABT-898 treated lesions stained for CD31+ endothelial cells exhibited a decrease in microvessel density. Following confirmation of estrous cycling, mice were bred and treated with ABT-898 on gestation days 7, 9, 11, 13, 15, 17, and 19. ABT-898 did not affect estrous cycling or pregnancy parameters including litter size across generations and offspring weight gain. Quantification of angiogenic cytokine plasma levels revealed no significant differences between treatment groups. Vimentin staining of the uterus and ovary revealed no observable effects of ABT-898. Similarly, no obvious histological anomalies were observed in the kidney, liver, ovary, or uterus following ABT-898 treatment. These results suggest that ABT-898 effectively inhibit endometriotic lesion vascularization without affecting trans-generational pregnancy outcomes in mice. PMID- 25811894 TI - Understanding the roles of anionic redox and oxygen release during electrochemical cycling of lithium-rich layered Li4FeSbO6. AB - Li-rich oxides continue to be of immense interest as potential next generation Li ion battery positive electrodes, and yet the role of oxygen during cycling is still poorly understood. Here, the complex electrochemical behavior of Li4FeSbO6 materials is studied thoroughly with a variety of methods. Herein, we show that oxygen release occurs at a distinct voltage plateau from the peroxo/superoxo formation making this material ideal for revealing new aspects of oxygen redox processes in Li-rich oxides. Moreover, we directly demonstrate the limited reversibility of the oxygenated species (O2(n-); n = 1, 2, 3) for the first time. We also find that during charge to 4.2 V iron is oxidized from +3 to an unusual +4 state with the concomitant formation of oxygenated species. Upon further charge to 5.0 V, an oxygen release process associated with the reduction of iron +4 to +3 is present, indicative of the reductive coupling mechanism between oxygen and metals previously reported. Thus, in full state of charge, lithium removal is fully compensated by oxygen only, as the iron and antimony are both very close to their pristine states. Besides, this charging step results in complex phase transformations that are ultimately destructive to the crystallinity of the material. Such findings again demonstrate the vital importance of fully understanding the behavior of oxygen in such systems. The consequences of these new aspects of the electrochemical behavior of lithium-rich oxides are discussed in detail. PMID- 25811895 TI - Simultaneous measurement of genome-wide transcription elongation speeds and rates of RNA polymerase II transition into active elongation with 4sUDRB-seq. AB - 4sUDRB-seq separately measures, on a genomic scale, the distinct contributions of transcription elongation speed and rate of RNA polymerase II (Pol II) transition into active elongation (TAE) to the overall mRNA production rate. It uses reversible inhibition of transcription elongation with 5,6-dichloro-1-beta-D ribofuranosylbenzimidazole (DRB), combined with a pulse of 4-thiouridine (4sU), to tag newly transcribed RNA. After DRB removal, cells are collected at several time points, and tagged RNA is biotinylated, captured on streptavidin beads and sequenced. 4sUDRB-seq enables the comparison of elongation speeds between different developmental stages or different cell types, and it allows the impact of specific transcription factors on transcription elongation speed versus TAE to be studied. RNA preparation takes ~4 d to complete, with deep sequencing requiring an additional ~4-11 d plus 1-3 d for bioinformatics analysis. The experimental protocol requires basic molecular biology skills, whereas data analysis requires knowledge in bioinformatics, particularly MATLAB and the Linux environment. PMID- 25811896 TI - Multiplexed locus-specific analysis of DNA methylation in single cells. AB - This protocol details a method for measuring the DNA methylation state of multiple target sites in single cells, otherwise known as single-cell restriction analysis of methylation (SCRAM). The basic steps include isolating and lysing single cells, digesting genomic DNA with a methylation-sensitive restriction endonuclease (MSRE) and amplification of multiple targets by two rounds of PCR to determine the methylation status of target sites. The method can reliably and accurately detect the methylation status of multiple target sites in each single cell, and it can be completed in a relatively short time (<2 d) at low cost. Consequently, the method may be preferable over whole-genome methods in applications requiring highly reliable and cost-effective coverage of specific target sites in all cells from a sample and in cases when the DNA methylation states of single CpG sites are representative of the methylation status of corresponding regions of interest. PMID- 25811898 TI - Corrigendum: using TRIP for genome-wide position effect analysis in cultured cells. PMID- 25811897 TI - Quantitative prediction of charge mobilities of pi-stacked systems by first principles simulation. AB - This protocol is intended to provide chemists and physicists with a tool for predicting the charge carrier mobilities of pi-stacked systems such as organic semiconductors and the DNA double helix. An experimentally determined crystal structure is required as a starting point. The simulation involves the following operations: (i) searching the crystal structure; (ii) selecting molecular monomers and dimers from the crystal structure; (iii) using density function theory (DFT) calculations to determine electronic coupling for dimers; (iv) using DFT calculations to determine self-reorganization energy of monomers; and (v) using a numerical calculation to determine the charge carrier mobility. For a single crystal structure consisting of medium-sized molecules, this protocol can be completed in ~4 h. We have selected two case studies (a rubrene crystal and a DNA segment) as examples of how this procedure can be used. PMID- 25811899 TI - Corrigendum: solid-phase proximity ligation assays for individual or parallel protein analyses with readout via real-time PCR or sequencing. PMID- 25811900 TI - Corrigendum: a standardized protocol for repeated social defeat stress in mice. PMID- 25811901 TI - Erratum: antibody modeling using the Prediction of ImmunoGlobulin Structure (PIGS) web server. PMID- 25811902 TI - Corrigendum: functional genomics platform for pooled screening and generation of mammalian genetic interaction maps. PMID- 25811903 TI - GMI, an Immunomodulatory Protein from Ganoderma microsporum, Potentiates Cisplatin-Induced Apoptosis via Autophagy in Lung Cancer Cells. AB - Cisplatin-based therapy is common in the treatment of several types of cancers, including lung cancers. In our previous study, GMI, an immunomodulatory protein cloned from Ganoderma microsporum, induced a cytotoxic effect in lung cancer cells via autophagy. The aim of this study is to examine the role of GMI in enhancing cisplatin-mediated cell death. On the basis of MTT assay and Combination Index, GMI and cisplatin cotreatment induced a synergistic cytotoxic effect. GMI and cisplatin-induced apoptosis was determined by sub-G1, nuclear condensation, and annexin-V/propidium iodide analyses. On Western blot, expressions of gammaH2AX and cleaved forms of PARP, caspase-3, and caspase-7 were induced by combined treatment. Akt/mTOR pathway activity, LC3-II expression, and acidic vesicular organelle development demonstrated that cisplatin does not abolish GMI-mediated autophagy. Cyto-ID Green/hoechst 33342 double staining and time-dependent experiment indicated that GMI and cisplatin-treated A549 cells simultaneously express autophagosomes and apoptotic nuclei. To elucidate the role of autophagy in inducing apoptosis by GMI and cisplatin, chemical inhibitors and LC3 shRNA were used to inhibit autophagy. The results showed that 3-methyladenine decreases, while chloroquine increases GMI and cisplatin cotreatment-induced cleavage of caspase-7 and PARP. LC3 silencing abolished activation of apoptosis in A549 cells. Caspase inhibitors and caspase-7 silencing mitigated GMI and cisplatin-elicited cell viability inhibition and apoptosis. This is the first study to reveal the novel function of GMI in potentiating cisplatin-mediated apoptosis. GMI and cisplatin induce apoptosis via autophagy/caspase-7-dependent and survivin- and ERCC1-independent pathway. GMI may be a potential cisplatin adjuvant against lung cancer. PMID- 25811904 TI - Comparison of the four proposed Apgar scoring systems in the assessment of birth asphyxia and adverse early neurologic outcomes. AB - OBJECTIVES: To compare the Conventional, Specified, Expanded and Combined Apgar scoring systems in predicting birth asphyxia and the adverse early neurologic outcomes. METHODS: This prospective cohort study was conducted on 464 admitted neonates. In the delivery room, after delivery the umbilical cord was double clamped and a blood samples was obtained from the umbilical artery for blood gas analysis, meanwhile on the 1- , 5- and 10- minutes Conventional, Specified, Expanded, and Combined Apgar scores were recorded. Then the neonates were followed and intracranial ultrasound imaging was performed, and the following information were recorded: the occurrence of birth asphyxia, hypoxic Ischemic Encephalopathy (HIE), intraventricular hemorrhage (IVH), and neonatal seizure. RESULTS: The Combined-Apgar score had the highest sensitivity (97%) and specificity (99%) in predicting birth asphyxia, followed by the Specified-Apgar score that was also highly sensitive (95%) and specific (97%). The Expanded-Apgar score was highly specific (95%) but not sensitive (67%) and the Conventional Apgar score had the lowest sensitivity (81%) and low specificity (81%) in predicting birth asphyxia. When adjusted for gestational age, only the low 5 minute Combined-Apgar score was independently associated with the occurrence of HIE (B = 1.61, P = 0.02) and IVH (B = 2.8, P = 0.01). CONCLUSIONS: The newly proposed Combined-Apgar score is highly sensitive and specific in predicting birth asphyxia and also is a good predictor of the occurrence of HIE and IVH in asphyxiated neonates. PMID- 25811905 TI - Effect of Ni(2+) content on lithium/nickel disorder for Ni-rich cathode materials. AB - Li excess LiNi0.8Co0.1Mn0.1O2 was produced by sintering the Ni0.8Co0.1Mn0.1(OH)2 precursor with different amounts of a lithium source. X-ray photoelectron spectroscopy confirmed that a greater excess of Li(+) leads to an increase in the number of Ni(2+) ions. Interestingly, the level of Li(+)/Ni(2+) disordering decreases with an increase in Ni(2+) content determined by the I003/I104 ratio in the X-ray diffraction patterns. The electrochemical measurement shows that the cycling stability and rate capability improve with an increase in Ni(2+) content. After cycling, electrochemical impedance spectroscopy shows decreased charge transfer resistance, and the XRD patterns exhibit an increased I003/I104 ratio with an increase in Ni(2+) content, reflecting the decrease in the level of Li(+)/Ni(2+) disorder during cycling. PMID- 25811906 TI - Macrophage gene expression associated with remodeling of the prepartum rat cervix: microarray and pathway analyses. AB - As the critical gatekeeper for birth, prepartum remodeling of the cervix is associated with increased resident macrophages (Mphi), proinflammatory processes, and extracellular matrix degradation. This study tested the hypothesis that expression of genes unique to Mphis characterizes the prepartum from unremodeled nonpregnant cervix. Perfused cervix from prepartum day 21 postbreeding (D21) or nonpregnant (NP) rats, with or without Mphis, had RNA extracted and whole genome microarray analysis performed. By subtractive analyses, expression of 194 and 120 genes related to Mphis in the cervix from D21 rats were increased and decreased, respectively. In both D21 and NP groups, 158 and 57 Mphi genes were also more or less up- or down-regulated, respectively. Mphi gene expression patterns were most strongly correlated within groups and in 5 major clustering patterns. In the cervix from D21 rats, functional categories and canonical pathways of increased expression by Mphi gene related to extracellular matrix, cell proliferation, differentiation, as well as cell signaling. Pathways were characteristic of inflammation and wound healing, e.g., CD163, CD206, and CCR2. Signatures of only inflammation pathways, e.g., CSF1R, EMR1, and MMP12 were common to both D21 and NP groups. Thus, a novel and complex balance of Mphi genes and clusters differentiated the degraded extracellular matrix and cellular genomic activities in the cervix before birth from the unremodeled state. Predicted Mphi activities, pathways, and networks raise the possibility that expression patterns of specific genes characterize and promote prepartum remodeling of the cervix for parturition at term and with preterm labor. PMID- 25811907 TI - Hydrogen sulfide regulates the colonic motility by inhibiting both L-type calcium channels and BKCa channels in smooth muscle cells of rat colon. AB - OBJECTIVE: To examine the hypothesis that hydrogen sulfide (H2S) regulates the colonic motility by modulating both L-type voltage-dependent calcium channels and large conductance Ca2+-activated K+ (BKCa) channels. METHODS: Immunohistochemistry was performed on rat colonic samples to investigate the localization of the H2S-producing enzymes cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). The contractions of proximal colonic smooth muscle were studied in an organ bath system. The whole-cell patch-clamp technique was used to record both L-type calcium currents (ICa,L) and BKCa currents in colonic smooth muscle cells (SMCs) isolated from male Wistar rats. RESULTS: Immunohistochemistry revealed the presence of CBS and CSE in mucosa, smooth muscle cells and myenteric neurons. The H2S donor NaHS inhibited spontaneous contractions of the longitudinal muscle and circular muscle strips in a dose dependent manner, and the inhibitory effects were not blocked by tetrodotoxin. NaHS inhibited the peak ICa,L in colonic SMCs at a membrane potential of 0 mV. The current-voltage (I-V) relationship of L-type calcium channels was modified by NaHS, and the peak of the I-V curve was shifted to the right. NaHS (200 MUMU) evoked a significant rightward shift of the steady-state activation curve and inhibited the inactivation of L-type calcium channels. Furthermore, NaHS reversibly decreased the peak ICa,L in a dose-dependent manner. Likewise, BKCa channels were significantly inhibited by NaHS, and the addition of NaHS caused a time- and dose-dependent reduction in the BKCa current. CONCLUSION: The relaxant effect of H2S on colonic muscle strips may be associated with the direct inhibition of H2S on L-type calcium channels. H2S may be involved in the regulation of calcium homeostasis in colonic SMCs of rat colon. PMID- 25811908 TI - Anti-epidermal growth factor receptor conjugated mesoporous zinc oxide nanofibers for breast cancer diagnostics. AB - We report the fabrication of an efficient, label-free, selective and highly reproducible immunosensor with unprecedented sensitivity (femto-molar) to detect a breast cancer biomarker for early diagnostics. Mesoporous zinc oxide nanofibers (ZnOnFs) are synthesized by electrospinning technique with a fiber diameter in the range of 50-150 nm. Fragments of ZnOnFs are electrophoretically deposited on an indium tin oxide glass substrate and conjugated via covalent or electrostatic interactions with a biomarker (anti-ErbB2; epidermal growth factor receptor 2). Oxygen plasma treatment of the carbon doped ZnOnFs generates functional groups ( COOH, -OH, etc.) that are effective for the conjugation of anti-ErbB2. ZnOnFs without plasma treatment that conjugate via electrostatic interactions were also tested for comparison. Label-free detection of the breast cancer biomarker by this point-of-care device is achieved by an electrochemical impedance technique that has high sensitivity (7.76 kOmega MUM(-1)) and can detect 1 fM (4.34 * 10( 5) ng mL(-1)) concentration. The excellent impedimetric response of this immunosensor provides a fast detection (128 s) in a wide detection test range (1.0 fM-0.5 MUM). The oxy-plasma treated ZnOnF immunoelectrode shows a higher association constant (404.8 kM(-1) s(-1)) indicating a higher affinity towards the ErbB2 antigen compared to the untreated ZnOnF immunoelectrode (165.6 kM(-1) s(-1)). This sensor is about an order of magnitude more sensitive than the best demonstrated in the literature based on different nanomaterials and about three orders of magnitude better than the ELISA standard for breast cancer biomarker detection. This proposed point-of-care cancer diagnostic offers several advantages, such as higher stability, rapid monitoring, simplicity, cost effectiveness, etc., and should prove to be useful for the detection of other bio and cancer markers. PMID- 25811909 TI - The shear response of copper bicrystals with Sigma11 symmetric and asymmetric tilt grain boundaries by molecular dynamics simulation. AB - Grain boundaries (GBs) are important microstructure features and can significantly affect the properties of nanocrystalline materials. Molecular dynamics simulation was carried out in this study to investigate the shear response and deformation mechanisms of symmetric and asymmetric Sigma11<1 1 0> tilt GBs in copper bicrystals. Different deformation mechanisms were reported, depending on GB inclination angles and equilibrium GB structures, including GB migration coupled to shear deformation, GB sliding caused by local atomic shuffling, and dislocation nucleation from GB. The simulation showed that migrating Sigma11(1 1 3) GB under shear can be regarded as sliding of GB dislocations and their combination along the boundary plane. A non-planar structure with dissociated intrinsic stacking faults was prevalent in Sigma11 asymmetric GBs of Cu. This type of structure can significantly increase the ductility of bicrystal models under shear deformation. A grain boundary can be a source of dislocation and migrate itself at different stress levels. The intrinsic free volume involved in the grain boundary area was correlated with dislocation nucleation and GB sliding, while the dislocation nucleation mechanism can be different for a grain boundary due to its different equilibrium structures. PMID- 25811910 TI - Survey of physicians' perspectives and knowledge about diagnostic tests for bloodstream infections. AB - BACKGROUND: Physicians rely on blood culture to diagnose bloodstream infections (BSI) despite its limitations. As new technologies emerge for rapid BSI diagnosis, optimization of their application to patient care requires an understanding of clinicians' perspectives on BSI diagnosis and how a rapid test would influence medical decisions. METHODS: We administered a 26-question survey to practitioners in infectious diseases/microbiology, critical care, internal medicine, and hematology/oncology services in USA and Germany about current standards in diagnosing and treating BSI and a hypothetical rapid BSI test. RESULTS: Responses from 242 providers had roughly equal representation across specialties. For suspected BSI patients, 78% of practitioners would administer empiric broad spectrum antibiotics although they estimated, on average, that 31% of patients received incorrect antibiotics while awaiting blood culture results. The ability of blood culture to rule in or rule out infection was very/extremely acceptable in 67% and 36%, respectively. Given rapid test results, 60-87% of practitioners would narrow the spectrum of antimicrobial therapy depending on the microorganism detected, with significantly higher percentages when resistance determinants were also tested. Over half of respondents felt a rapid test would be very/extremely influential on clinical practice. CONCLUSIONS: Limitations of blood culture were perceived as a barrier to patient care. A rapid test to diagnose BSI would impact clinical practice, but the extent of impact may be limited by prevailing attitudes and practices. Opportunities exist for interventions to influence practitioners' behaviors in BSI management particularly with emergence of newer diagnostic tests. PMID- 25811911 TI - Bat coronavirus in Brazil related to appalachian ridge and porcine epidemic diarrhea viruses. PMID- 25811912 TI - Who needs bereavement support? A population based survey of bereavement risk and support need. AB - This study identifies and describes the profiles of bereavement risk and support needs of a community sample in Australia and tests the fit of the data with the three-tiered public health model for bereavement support. Family members who were bereaved 6-24 months prior to the survey and who were clients of four funeral providers participated (May-July 2013). A postal survey was used to collect information about bereaved people's experience of caring and perceived satisfaction with any bereavement support provided. The questionnaire included a validated risk assessment screening measure for Prolonged Grief Disorder (PG-13). A total of 678 bereaved people responded. The model predicted that 60% of the sample would be low risk, 30% moderate risk, and 10% high risk. Actual figures were very close at 58.4%, 35.2% and 6.4% respectively. The analysis of the demographic characteristics, experience and impact of caring and bereavement, and satisfaction with support received from a variety of sources revealed differential experiences and needs that align with the expectation of low, moderate, and high bereavement support need, as articulated in the public health model. This is the first empirical test of the public health model of bereavement support. As there is a lack of clear evidence to guide development and allocation of bereavement support programs, the findings have the potential to inform the ability of services, community organizations and informal networks to prioritize care according to each level of bereavement need. This is essential to achieve cost-effective and equitable resource allocation. PMID- 25811913 TI - Mechanistic studies of inactivation of inducible nitric oxide synthase by amidines. AB - Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L citrulline and nitric oxide. N(5)-(1-Iminoethyl)-L-ornithine (L-NIO), an amidine containing molecule, is a natural product known to be an inactivator of inducible NOS (iNOS). Because of the presence of the amidine methyl group in place of the guanidine amino group of substrate L-arginine, the active site heme peroxy intermediate sometimes cannot be protonated, thereby preventing its conversion to the heme oxo intermediate; instead, a heme oxygenase-type mechanism occurs, leading to conversion of the heme to biliverdin. This might be a new and general inactivation mechanism for heme-containing enzymes. In the studies described here, we attempted to provide support for amidines as substrates and inactivators of iNOS by the design and synthesis of amidine analogues of L-NIO having groups other than the amidine methyl group. No nitric oxide- or enzyme-catalyzed products could be detected by incubation of these amidines with iNOS. Although none of the L-NIO analogues acted as substrates, they all inhibited iNOS; increased inhibitory potency correlated with decreased substituent size. Computer modeling and molecular dynamics simulations were run on 10 and 11 to rationalize why these compounds do not act as substrates. Unlike the methyl amidine (L-NIO), the other alkyl groups block binding of O2 at the heme iron. Compounds 8, 9, and 11 were inactivators; however, no heme was lost, and no biliverdin was formed. No kinetic isotope effect on inactivation was observed with perdeuterated ethyl 8. A small amount of dimer disruption occurred with these inactivators, although the amount would not account for complete enzyme inactivation. The L-NIO analogues inactivate iNOS by a yet unknown mechanism; however, it is different from that of L-NIO, and the inactivation mechanism previously reported for L-NIO appears to be unique to methyl amidines. PMID- 25811914 TI - Ru(EDTA) mediated partial reduction of O2 by H2S. AB - An effective procedure for selective reduction of O2 to H2O2 exploring the use of hydrogen sulfide, an obnoxious industrial pollutant as reductant is reported herein. The reduction of [Ru(III)(EDTA)pz](-) (EDTA(4-) = ethylenediaminetetraacetate; pz = pyrazine) by hydrogen sulfide resulting in the formation of a red [Ru(II)(EDTA)pz](2-) complex (lambdamax = 462 nm) has been studied spectrophotometrically and kinetically using both rapid scan and stopped flow techniques. The time course of the reaction was followed as a function of [HS(-)]i, pH (5.5-8.5), and temperature. Alkali metal ions were found to have a positive influence (K(+) > Na(+) > Li(+)) on the reaction rate. Kinetic data and activation parameters are interpreted in terms of a mechanism (admittedly speculative) involving outer-sphere electron transfer between the reaction partners. Reaction of the red [Ru(II)(EDTA)pz](2-) complex with molecular oxygen regenerates the [Ru(III)(EDTA)pz](-) species in the reacting system along with the formation of H2O2, a partially reduced product of dioxygen (O2) reduction. A detailed reaction mechanism in agreement with the spectral and kinetic data is presented. PMID- 25811916 TI - Steric-dependent label-free and washing-free enzyme amplified protein detection with dual-functional synthetic probes. AB - Enzyme-catalyzed signal amplification with an antibody-enzyme conjugate is commonly employed in many bioanalytical methods to increase assay sensitivity. However, covalent labeling of the enzyme to the antibody, laborious operating procedures, and extensive washing steps are necessary for protein recognition and signal amplification. Herein, we describe a novel label-free and washing-free enzyme-amplified protein detection method by using dual-functional synthetic molecules to impose steric effects upon protein binding. In our approach, protein recognition and signal amplification are modulated by a simple dual-functional synthetic probe which consists of a protein ligand and an inhibitor. In the absence of the target protein, the inhibitor from the dual-functional probe would inhibit the enzyme activity. In contrast, binding of the target protein to the ligand perturbs this enzyme-inhibitor affinity due to the generation of steric effects caused by the close proximity between the target protein and the enzyme, thereby activating the enzyme to initiate signal amplification. With this strategy, the fluorescence signal can be amplified to as high as 70-fold. The generality and versatility of this strategy are demonstrated by the rapid, selective, and sensitive detection of four different proteins, avidin, O6 methylguanine DNA methyltransferase (MGMT), SNAP-tag, and lactoferrin, with four different probes. PMID- 25811918 TI - Intramolecular direct aldol reactions of sugar 2,7-diketones: syntheses of hydroxylated cycloalka(e)nones. AB - A regio- and stereoselective intramolecular direct aldol reaction of 2,7 diketones derived from carbohydrates has been developed to construct cycloalkanones , which were dehydrated to obtain heavily oxygenated cycloalkenones . PMID- 25811917 TI - Scotopic and Photopic Microperimetry in Patients With Reticular Drusen and Age Related Macular Degeneration. AB - IMPORTANCE: Clinical observations suggest that patients with age-related macular degeneration (AMD) have vision problems, particularly in dim light conditions. Previous studies on structural-functional analysis in patients with AMD with reticular drusen (RDR) have focused on photopic sensitivity testing but have not specifically assessed scotopic function. OBJECTIVE: To evaluate retinal function by scotopic and photopic microperimetry in patients with AMD and a well demarcated area of RDR. DESIGN, SETTING, AND PARTICIPANTS: Prospective case series in a referral center of 22 eyes from 18 patients (mean age, 74.7 years; range, 62-87 years). The study was conducted from June 1, 2014, to October 31, 2014. INTERVENTIONS: With the use of combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging, retinal areas with RDR (category 1) and no visible pathologic alterations (category 2) were identified in each eye. Scotopic and photopic microperimetry (MP-1S; Nidek Technologies) was performed using a grid with 56 stimulus points. MAIN OUTCOMES AND MEASURES: Comparison of mean threshold sensitivities for each category for scotopic and photopic microperimetry. RESULTS: In all eyes, areas of category 1 showed a relative and sharply demarcated reduction of scotopic threshold values compared with areas of category 2, but only less-pronounced differences were seen for photopic testing. Statistical analysis in the 18 eyes in which the 1.0-log unit neutral density filter was applied revealed a difference of scotopic threshold values in areas of category 1 (mean, 13.5 dB [95% CI, 12.1-15.0]) vs category 2 (mean, 18.3 dB; [95% CI, 17.4-19.3] (P <= .001). For photopic testing, the mean threshold values were 16.8 dB (95% CI, 15.5-18.2) in category 1 and 18.4 dB (95% CI, 17.1-19.6) in category 2 (P = .03). CONCLUSIONS AND RELEVANCE: The results of this study suggest that rod function is more severely affected than cone function in retinal areas with RDR. This differential structural-functional correlation underscores the functional relevance of RDR in patients with AMD. PMID- 25811919 TI - Wartime paediatric extremity injuries: experience from the Kabul International Airport Combat support hospital. AB - Since the beginning of Operation Enduring Freedom, management of Afghan military or civilian casualties including children is a priority of the battlefield medical support. The aim of this study is to describe the features of paediatric wartime extremities injuries and to analyse their management in the Kabul International Airport Combat Support Hospital. A retrospective review was carried out using the French surgical database OPEX (Service de Sante des Armees) from June 2009 to January 2013. Paediatric patients were defined as those younger than 16 years old. Of the 220 injured children operated on, 155 (70%) sustained an extremity injury and were included. The mean age of the children was 9.1 +/- 3.8 years. Among these children, 77 sustained combat-related injuries (CRIs) and 78 sustained noncombat-related injuries (NCRIs), with a total of 212 extremities injuries analysed. All CRIs were open injuries, whereas NCRIs were dominated by blunt injuries. Multiple extremities injuries and associated injuries were significantly more frequent in children with CRIs, whose median Injury Severity Score was higher than those with NCRIs. Debridement and irrigation was significantly predominant in the CRIs group, as well as internal fracture fixation in the NCRIs group. There were four deaths, yielding a global mortality rate of 2.6%. This study is the first to analyse specifically paediatric extremities trauma and their management at level 3 of battlefield medical facilities in recent conflicts. Except for severe burns and polytrauma, treatment of paediatric extremities injuries can be readily performed in Combat Support Hospitals by orthopaedic surgeons trained in paediatric trauma. PMID- 25811920 TI - Osteochondroma arising from a lumbar facet joint in a 16-year-old. AB - Osteochondromas are benign tumours of bony or cartilaginous origin, which may be solitary or multiple. They are rare in the axial skeleton and have previously been reported to arise from facet joints only in four cases in the English literature. We report the case of a 16-year-old girl who presented with a palpable bony lump and a short history of back pain. Imaging showed a bony lesion arising from a left-sided facet joint in the lumbar spine. Following excision biopsy, there was complete resolution of symptoms. The literature on the origin and management of spinal osteochondromas is discussed. PMID- 25811921 TI - Reply to 'Derotational osteotomies utilizing a trochanteric-start intramedullary nail'. PMID- 25811915 TI - Macrophages in vascular inflammation--From atherosclerosis to vasculitis. AB - The spectrum of vascular inflammatory disease ranges from atherosclerosis and hypertension, widespread conditions affecting large proportions of the population, to the vasculitides, rare syndromes leading to fast and irreversible organ failure. Atherosclerosis progresses over decades, inevitably proceeding through multiple phases of disease and causes its major complications when the vessel wall lesion ruptures, giving rise to lumen-occlusive atherothrombosis. Vasculitides of medium and large arteries progress rapidly, causing tissue ischemia through lumen-occlusive intimal hyperplasia. In both disease entities, macrophages play a decisive role in pathogenesis, but function in the context of other immune cells that direct their differentiation and their functional commitments. In atherosclerosis, macrophages are involved in the removal of lipids and tissue debris and make a critical contribution to tissue damage and wall remodeling. In several of the vasculitides, macrophages contribute to granuloma formation, a microstructural platform optimizing macrophage-T-cell interactions, antigen containment and inflammatory amplification. By virtue of their versatility and plasticity, macrophages are able to promote a series of pathogenic functions, ranging from the release of cytokines and enzymes, the production of reactive oxygen species, presentation of antigen and secretion of tissue remodeling factors. However, as short-lived cells that lack memory, macrophages are also amendable to reprogramming, making them promising targets for anti-inflammatory interventions. PMID- 25811922 TI - Isolated medial humeral epicondyle fracture. PMID- 25811923 TI - Liver resection for non-colorectal, non-carcinoid, non-sarcoma metastases: a multicenter study. AB - BACKGROUND: The role of liver resection for non-colorectal, non-neuroendocrine, non-sarcoma (NCNNNS) metastases is ill-defined. This study aimed to examine the oncologic outcomes of liver resection in such patients. METHODS: A retrospective analysis of liver resection for NCNNNS metastases was performed at two large centers. Liver resection was offered selectively in patients with stable disease. Oncologic outcomes were examined using the Kaplan-Meier method. RESULTS: Fifty two patients underwent liver resection for NCNNNS metastases. Overall 5-year survival was 58%. Five-year survival was 85% for breast metastases, 66% for ocular melanoma, 83% for other melanomas, 50% for gastro-esophageal metastases, and 0% for renal cell carcinoma metastases. A contemporary colorectal liver metastasis cohort had a survival of 63% (p=0.89). CONCLUSIONS: Liver resection is an effective option in the management of selected patients with NCNNNS metastases which have been deemed stable. Five-year survival rates were comparable to that of a contemporary cohort of patients with colorectal liver metastases in carefully selected patients. Further, larger studies are required to help identify potential prognostic variables and aid in decision-making in this heterogeneous population. PMID- 25811924 TI - Effect of Poly(ethylene oxide) Molecular Weight on the Pinning and Pillar Formation of Evaporating Sessile Droplets: The Role of the Interface. AB - We report on the drying process of sessile droplets of aqueous poly(ethylene oxide) (PEO) solutions studied by contact angle analysis. Liquid samples were prepared with the same initial concentration of four different molecular weights, Mw, of PEO. Droplets with initial volumes of between 1 and 5 MUL were left to evaporate while temperature, pressure, and relative humidity were kept constant. Residues were formed with either a disklike puddle or a distinctive tall conical pillar shape. The latter occurred following a four-stage deposition process: pinned drying, during which the contact line is stationary; pseudodewetting, where the receding contact line is induced by precipitation; bootstrap building, during which the liquid droplet is lifted on freshly precipitated solid; and late drying. Contact angle analysis allowed us to monitor all stages during drying and consider transitions between stages for different molecular weights. We illustrate the mechanisms taking place during the crucial stages of pinning and depinning, revealing the effect of adhesion and contact line friction for high molecular weights and its influence on the final morphology of the dried PEO solute. To this end, we performed PEO solution droplet evaporation on PEO and PTFE films demonstrating the importance of interfacial interaction phenomena. We show that the formation of disklike puddles for high molecular weights on glass is associated with continuous droplet contact line pinning. This results from the strong adhesion due to the interdigitation of the loops and tails of a polymer layer (adsorbed on glass during evaporation) with the polymer gel network inside the droplet that forms as water evaporates. PMID- 25811925 TI - ATR-FTIR spectroscopy for the assessment of biochemical changes in skin due to cutaneous squamous cell carcinoma. AB - Nonmelanoma skin cancers represent 95% of cutaneous neoplasms. Among them, squamous cell carcinoma (SCC) is the more aggressive form and shows a pattern of possible metastatic profile. In this work, we used Fourier transform infrared spectroscopy (FTIR) spectroscopy to assess the biochemical changes in normal skin caused by squamous cell carcinoma induced by multi-stage chemical carcinogenesis in mice. Changes in the absorption intensities and shifts were observed in the vibrational modes associated to proteins, indicating changes in secondary conformation in the neoplastic tissue. Hierarchical cluster analysis was performed to evaluate the potential of the technique to differentiate the spectra of neoplastic and normal skin tissue, so that the accuracy obtained for this classification was 86.4%. In this sense, attenuated total reflection (ATR)-FTIR spectroscopy provides a useful tool to complement histopathological analysis in the clinical routine for the diagnosis of cutaneous squamous cell carcinoma. PMID- 25811926 TI - A soluble pyrophosphatase is essential to oogenesis and is required for polyphosphate metabolism in the red flour beetle (Tribolium castaneum). AB - Polyphosphates have been found in all cell types examined to date and play diverse roles depending on the cell type. In eukaryotic organisms, polyphosphates have been mainly investigated in mammalian cells with few studies on insects. Some studies have demonstrated that a pyrophosphatase regulates polyphosphate metabolism, and most of them were performed on trypanosomatids. Here, we investigated the effects of sPPase gene knocked down in oogenesis and polyphosphate metabolism in the red flour beetle (Tribolium castaneum). A single sPPase gene was identified in insect genome and is maternally provided at the mRNA level and not restricted to any embryonic or extraembryonic region during embryogenesis. After injection of Tc-sPPase dsRNA, female survival was reduced to 15% of the control (dsNeo RNA), and egg laying was completely impaired. The morphological analysis by nuclear DAPI staining of the ovarioles in Tc-sPPase dsRNA-injected females showed that the ovariole number is diminished, degenerated oocytes can be observed, and germarium is reduced. The polyphosphate level was increased in cytoplasmic and nuclear fractions in Tc-sPPase RNAi; Concomitantly, the exopolyphosphatase activity decreased in both fractions. Altogether, these data suggest a role for sPPase in the regulation on polyphosphate metabolism in insects and provide evidence that Tc-sPPase is essential to oogenesis. PMID- 25811928 TI - Four novel p.N385K, p.V36A, c.1033-1034insT and c.1417-1418delCT mutations in the sphingomyelin Phosphodiesterase 1 (SMPD1) gene in patients with types A and B Niemann-Pick disease (NPD). AB - BACKGROUND: Types A and B Niemann-Pick disease (NPD) are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. METHODS: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis. RESULTS: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous) showed the p.V36A mutation. One patient was homozygous for the c.1033-1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417-1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM) protein stability, which might be evidence to suggest the pathogenicity of these mutations. CONCLUSION: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations. PMID- 25811930 TI - Adsorptive desulfurization with CPO-27/MOF-74: an experimental and computational investigation. AB - By combining experimental adsorption isotherms, microcalorimetric data, infrared spectroscopy and quantum chemical calculations the adsorption behaviour of the CPO-27/MOF-74 series (Ni, Co, Mg, Cu, and Zn) in the desulfurization of fuels is evaluated. The results show a clear influence of the metal ion on the adsorption capacity and affinity for S-heterocyclic compounds, with CPO-27(Ni) being the best performing material both in terms of capacity and affinity. The microcalorimetric data and infrared spectroscopy confirm the high affinity of CPO 27(Ni) for thiophene and similar compounds, while the computational data reveal that the origin of this outstanding adsorption performance is the strong sulfur metal interaction. PMID- 25811927 TI - Antitumor effects of vitamin D analogs on hamster and mouse melanoma cell lines in relation to melanin pigmentation. AB - Deregulated melanogenesis is involved in melanomagenesis and melanoma progression and resistance to therapy. Vitamin D analogs have anti-melanoma activity. While the hypercalcaemic effect of the active form of Vitamin D (1,25(OH)2D3) limits its therapeutic use, novel Vitamin D analogs with a modified side chain demonstrate low calcaemic activity. We therefore examined the effect of secosteroidal analogs, both classic (1,25(OH)2D3 and 25(OH)D3), and novel relatively non-calcemic ones (20(OH)D3, calcipotriol, 21(OH)pD, pD and 20(OH)pL), on proliferation, colony formation in monolayer and soft-agar, and mRNA and protein expression by melanoma cells. Murine B16-F10 and hamster Bomirski Ab cell lines were shown to be effective models to study how melanogenesis affects anti melanoma treatment. Novel Vitamin D analogs with a short side-chain and lumisterol-like 20(OH)pL efficiently inhibited rodent melanoma growth. Moderate pigmentation sensitized rodent melanoma cells towards Vitamin D analogs, and altered expression of key genes involved in Vitamin D signaling, which was opposite to the effect on heavily pigmented cells. Interestingly, melanogenesis inhibited ligand-induced Vitamin D receptor translocation and ligand-induced expression of VDR and CYP24A1 genes. These findings indicate that melanogenesis can affect the anti-melanoma activity of Vitamin D analogs in a complex manner. PMID- 25811931 TI - Evaluating Inhibition of Motoneuron Firing From Electromyogram Data to Assess Vestibular Output Using Vestibular Evoked Myogenic Potentials. AB - OBJECTIVES: Vestibular evoked myogenic potentials (VEMPs) are due to vestibular responses producing brief inhibitions of muscle contractions that are detectable in electromyographic (EMG) responses. VEMP amplitudes are traditionally measured by the peak to peak amplitude of the averaged EMG response (VEMPpp) or by a normalized VEMPpp (nVEMPpp). However, a brief EMG inhibition does not satisfy the statistical assumptions for the average to be the optimal processing strategy. Here, it is postulated that the inhibition depth of motoneuron firing is the desired metric for showing the influence of the vestibular system on the muscle system. The authors present a metric called "VEMPid" that estimates this inhibition depth from the EMG data obtained in a usual VEMP data acquisition. The goal of this article was to compare how well VEMPid, VEMPpp, and nVEMPpp track inhibition depth. DESIGN: To find a robust method to compare VEMPid, VEMPpp, and nVEMPpp, realistic physiological models for the inhibition of VEMP EMG signals were made using VEMP data from four measurement sessions on each of the five normal subjects. Each of the resulting 20 EMG-production models was adjusted to match the EMG autocorrelation of an individual subject and session. Simulated VEMP traces produced by these models were used to compare how well VEMPid, VEMPpp, and nVEMPpp tracked model inhibition depth. RESULTS: Applied to simulated and real VEMP data, VEMPid showed good test-retest consistency and greater sensitivity at low stimulus levels than VEMPpp or nVEMPpp. For large-amplitude responses, nVEMPpp and VEMPid were equivalent in their consistency across subjects and sessions, but for low-amplitude responses, VEMPid was superior. Unnormalized VEMPpp was always worse than nVEMPpp or VEMPid. CONCLUSIONS: VEMPid provides a more reliable measurement of vestibular function at low sound levels than the traditional nVEMPpp, without requiring a change in how VEMP tests are performed. The calculation method for VEMPid should be applicable whenever an ongoing muscle contraction is briefly inhibited by an external stimulus. PMID- 25811929 TI - Long noncoding RNA MALAT-1 enhances stem cell-like phenotypes in pancreatic cancer cells. AB - Cancer stem cells (CSCs) play a vital role in tumor initiation, progression, metastasis, chemoresistance, and recurrence. The mechanisms that maintain the stemness of these cells remain largely unknown. Our previous study indicated that MALAT-1 may serve as an oncogenic long noncoding RNA in pancreatic cancer by promoting epithelial-mesenchymal transition (EMT) and regulating CSCs markers expression. More significantly, there is emerging evidence that the EMT process may give rise to CSCs, or at least cells with stem cell-like properties. Therefore, we hypothesized that MALAT-1 might enhance stem cell-like phenotypes in pancreatic cancer cells. In this study, our data showed that MALAT-1 could increase the proportion of pancreatic CSCs, maintain self-renewing capacity, decrease the chemosensitivity to anticancer drugs, and accelerate tumor angiogenesis in vitro. In addition, subcutaneous nude mouse xenografts revealed that MALAT-1 could promote tumorigenicity of pancreatic cancer cells in vivo. The underlying mechanisms may involve in increased expression of self-renewal related factors Sox2. Collectively, we for the first time found the potential effects of MALAT-1 on the stem cell-like phenotypes in pancreatic cancer cells, suggesting a novel role of MALAT-1 in tumor stemness, which remains to be fully elucidated. PMID- 25811932 TI - Exploring the Effects of the Narrative Embodied in the Hearing Aid Fitting Process on Treatment Outcomes. AB - OBJECTIVES: There is strong evidence from other fields of health, and growing evidence in audiology, that characteristics of the process of intervention as perceived by the client (embodied narratives) can have significant effects on treatment outcomes, independent of the technical properties of the intervention itself. This phenomenon deserves examination because studies of technical interventions that fail to take account of it may reach erroneous conclusions and because clinical practice can put such effects to therapeutic use. The aim of this study was to test the idea that embodied narratives might affect outcomes in hearing aid fitting. This was achieved by carrying out experiments in which technical (acoustic) differences between alternative hearing aid fittings were absent, while providing test subjects with a strong contrast between the processes apparently applied to derive the fittings being compared. Thus, any effects of contrasting narratives could be observed, free of acoustical confounds. The hypothesis was that narrative effects would be observed. DESIGN: A balanced crossover design was used, in which subjects received and evaluated two bilateral hearing aid fittings in succession. Subjects were deceived as to the true identical content of the hearing aid fittings being compared, but encouraged to believe that one fitting process was "interactive" and the other was "diagnostic" in character. Two almost identical experiments were undertaken: one with 24 experienced adult hearing aid users and another with 16 adult first-time users. Each hearing aid fitting was worn at home for 2 weeks, after which self report outcome measures (Hearing Aid Performance Questionnaire, Hearing Handicap Inventory for the Elderly, and International Outcome Inventory for Hearing Aids) were administered. After the second test period, a short preference questionnaire was also completed. RESULTS: Twenty of the 24 experienced users showed a clear preference for one or the other fitting, and their self-report scores reflected these preferences. Effect sizes were comparable with those typically observed for true acoustical contrasts. No order effect was seen in this group. In contrast, 13 of the 16 first-time users preferred the second fitting. Trends in the self report measures were similar for this group but weaker than for the experienced users. In both groups, the reasons given for subjects' preference were predominantly related to sound, despite there being no acoustical differences. CONCLUSIONS: This study suggests that the narrative embodied in a given fitting process can have a substantial effect on the perceived benefit of the treatment, independent of any acoustical differences, at least for experienced users. For first-time users, acclimatization seems to overshadow the purely narrative effect of any fitting process. In the future, research study designs should include steps to avoid narrative effects when technical parameters of hearing aids are the intended object of study. In clinical practice, the narrative is part of the therapeutic context, and one may design it for maximum beneficial effect. PMID- 25811934 TI - Design and control of an active 1-DoF mechanism for knee rehabilitation. AB - A 1-DoF robot is designed and fabricated to be used for knee rehabilitation training. The mechanism (robot) is designed to perform specific set of exercises while the patient is sitting on a chair. The therapy process for patients has different stages; each stage consists of specific exercises to recover the knee to its condition before injury. The maximum torque of healthy joint during the extension/flexion exercise is evaluated by simulation and suitable actuator is selected based on the results. A prototype is then fabricated as a platform to evaluate the design and control concepts. The experiment procedure consisting of three stages of therapy indicates good tracking performance and safe operation of the system. Implication for Rehabilitation A 1-DoF mechanism for knee rehabilitation has been designed to perform three stages of therapy: passive, active assist and active resist. The assistive and resistive torque, during active assist and active resist stages, can be set according to the progress in therapy. The results of this study suggest the system has the potential to result in various benefits including reduction of physical workload of physiotherapists and improved repeatability. PMID- 25811933 TI - Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice. AB - NOD.H2(k) and NOD.H2(h4) mice carry the major histocompatibility complex (MHC) class II molecule I-A(k) associated with susceptibility to experimentally induced thyroiditis. Dietary iodine-enhanced spontaneous thyroid autoimmunity, well known in NOD.H2(h4) mice, has not been investigated in NOD.H2(k) mice. We compared NOD.H2(h4) and NOD.H2(k) strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2(h4) compared with NOD.H2(k) mice on NaI, and TPOAb developed in NOD.H2(h4) mice but not in NOD.H2(k) mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2(k) mice, and particularly NOD.H2(h4) mice, have substantial non-MHC parental DNA. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7, and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non MHC gene contributions. The exon 10 Tg haplotype, associated with experimentally induced thyroiditis, is absent in NOD.H2(h4) and NOD.H2(k) mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2(h4) and NOD.H2(k) mice in TgAb levels and, as in humans, autoantibody spreading to TPO. PMID- 25811935 TI - Peste des petits ruminants virus in Heilongjiang province, China, 2014. AB - During March 25-May 5, 2014, we investigated 11 outbreaks of peste des petits ruminants in Heilongjiang Province, China. We found that the most likely source of the outbreaks was animals from livestock markets in Shandong. Peste des petits ruminants viruses belonging to lineages II and IV were detected in sick animals. PMID- 25811936 TI - Limitations of AST/ALT ratio in paracetamol poisoning. PMID- 25811938 TI - Development and validation of a spontaneous smile assay. AB - IMPORTANCE: Smiling can be a voluntary or involuntary movement. Facial reanimation procedures differ in their ability to restore a spontaneous smile, and an assay designed to evoke and evaluate a spontaneous smile is not available. OBJECTIVE: To develop and validate an assay to assess the spontaneous smile of patients with facial paralysis. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory cohort study. A series of short video clips were administered to laypersons via an online survey service from January 1, 2014, to March 31, 2014. Respondents rated how funny each video was on a visual analog scale from 0 to 100. The 4 funniest videos were selected to generate a 11/2-minute spontaneous smile assay. The assay was then administered from July 1, 2014, to December 31, 2014, to 2 different study groups: the first was composed of 100 healthy individuals (control group) and the second was composed of 30 patients with facial paralysis. We analyzed the capability of this assay to provoke at least 1 spontaneous smile and calculated smile excursion in both groups. Statistical analysis was performed using analysis of variance. INTERVENTION: Spontaneous smile assay administered to both healthy and diseased groups. MAIN OUTCOMES AND MEASURES: Ability of the assay to elicit smiles, as defined by an oral commissure excursion greater than 3 mm, as well as difference in commissure excursion. RESULTS: Ninety-five (95.0%) participants in the control group and 29 (96.7%) patients with facial paralysis experienced at least 1 oral commissure excursion that appeared to be a spontaneous smile while viewing the assay. Mean oral commissure excursion with spontaneous smile was 9.08 mm (95% CI, 2.77-15.39) in controls, 6.72 mm (95% CI, 3.13-10.31) on the healthy side in patients with flaccid facial paralysis (P=.004 vs controls), and 9.64 mm (95% CI, 3.52-15.76) on the healthy side in patients with nonflaccid facial paralysis (P=.74). Among patients with flaccid facial paralysis, a statistically significant difference was found between smile excursion of the affected and the unaffected sides (P = .03). There was no statistically significant difference in the measurement between sides for the control group (P = .67). CONCLUSIONS AND RELEVANCE: Although humor is a challenging construct to universalize, our assay was able to elicit a smile in almost all individuals in the group with facial paralysis and the control group. The spontaneous smile assay will facilitate future research on the ability of facial reanimation procedures and other interventions to restore a spontaneous smile. LEVEL OF EVIDENCE: NA. PMID- 25811940 TI - Synthesis of the first completely spin-compatible N@C60 cyclopropane derivatives by carefully tuning the DBU base catalyst. AB - Two cyclopropane derivatives of N@C60 were synthesised by well-controlled Bingel reactions, in which 94% of the spin centres were retained, as confirmed by a series of quantitative electron spin paramagnetic resonance (EPR) measurements. Further study on the influence of the DBU catalyst base revealed a spin loss mechanism through a fullerene-DBU diradical. PMID- 25811939 TI - Regional nitrogen dynamics in the TERENO Bode River catchment, Germany, as constrained by stable isotope patterns. AB - Interactions between hydrological characteristics and microbial activities affect the isotopic composition of dissolved nitrate in surface water. Nitrogen and oxygen isotopic signatures of riverine nitrate in 133 sampling locations distributed over the Bode River catchment in the Harz Mountains, Germany, were used to identify nitrate sources and transformation processes. An annual monitoring programme consisting of seasonal sampling campaigns in spring, summer and autumn was conducted. delta(15)N and delta(18)O of nitrate and corresponding concentrations were measured as well as delta(2)H and delta(18)O of water to determine the deuterium excess. In addition, precipitation on 25 sampling stations was sampled and considered as a potential input factor. The Bode River catchment is strongly influenced by agricultural land use which is about 70 % of the overall size of the catchment. Different nitrogen sources such as ammonia (NH4) fertilizer, soil nitrogen, organic fertilizer or nitrate in precipitation show partly clear nitrate isotopic differences. Processes such as microbial denitrification result in fractionation and lead to an increase in delta(15)N of nitrate. We observed an evident regional and partly temporal variation of nitrate isotope signatures which are clearly different between main landscape types. Spring water sections within the high mountains contain nitrate in low concentrations with low delta(15)NNO3 values of -3 0/00 and high delta(18)ONO3 values up to 13 0/00. High mountain stream water sub-catchments dominated by nearly undisturbed forest and grassland contribute nitrate with delta(15)NNO3 and delta(18)ONO3 values of -1 and -3.5 0/00, respectively. In the further flow path, which is affected by an increasing agricultural land use and urban sewage, we recognized an increase in delta(15)NNO3 and delta(18)ONO3 up to 22 and 18 0/00, respectively, with high variations during the year. A correlation seems to exist between the percentage of agricultural land use area and the corresponding delta(15)NNO3 values for sub-catchments. A shift towards heavier isotope values in stream water samples taken in July 2012 is significant (p-value = 6 . 10(-6)) compared to samples from March and October 2012. We also see a season-depending impact of microbial denitrification. Denitrification, especially evident in the lowlands, predominantly takes place in the riverbeds. In addition, mixing processes of different nitrate sources and temperature-depending biological processes such as nitrification have to be taken into consideration. Constant tempered groundwater does not play a noticeable role in the processes of the stream water system. As constrained from oxygen isotope signatures, precipitation associated with low nitrate concentrations does not have an obvious impact on stream water nitrate in the high mountain region. PMID- 25811941 TI - Importance of interferon inducible trans-membrane proteins and retinoic acid inducible gene I for influenza virus replication: A review. AB - Understanding the interplay between Influenza viruses and host cells is key to elucidating the pathogenesis of these viruses. Several host factors have been identified that exert antiviral functions; however, influenza viruses continue to replicate utilizing host cell machinery. Herein, we review the mechanisms of action of two host-derived proteins on conferring cellular resistance to the influenza virus; (1) the interferon inducible trans-membrane proteins, 1, 2 and 3, a recently identified family of early restriction factors; and (2) retinoic acid inducible gene I, a key mediator of antiviral immunity. These data may contribute to the design of novel and efficient anti-influenza treatments. PMID- 25811943 TI - Energy decomposition analysis approaches and their evaluation on prototypical protein-drug interaction patterns. AB - The partitioning of the energy in ab initio quantum mechanical calculations into its chemical origins (e.g., electrostatics, exchange-repulsion, polarization, and charge transfer) is a relatively recent development; such concepts of isolating chemically meaningful energy components from the interaction energy have been demonstrated by variational and perturbation based energy decomposition analysis approaches. The variational methods are typically derived from the early energy decomposition analysis of Morokuma [Morokuma, J. Chem. Phys., 1971, 55, 1236], and the perturbation approaches from the popular symmetry-adapted perturbation theory scheme [Jeziorski et al., Methods and Techniques in Computational Chemistry: METECC-94, 1993, ch. 13, p. 79]. Since these early works, many developments have taken place aiming to overcome limitations of the original schemes and provide more chemical significance to the energy components, which are not uniquely defined. In this review, after a brief overview of the origins of these methods we examine the theory behind the currently popular variational and perturbation based methods from the point of view of biochemical applications. We also compare and discuss the chemical relevance of energy components produced by these methods on six test sets that comprise model systems that display interactions typical of biomolecules (such as hydrogen bonding and pi-pi stacking interactions) including various treatments of the dispersion energy. PMID- 25811942 TI - Highly pathogenic Avian Influenza A(H5N1) virus infection among workers at live bird markets, Bangladesh, 2009-2010. AB - The risk for influenza A(H5N1) virus infection is unclear among poultry workers in countries where the virus is endemic. To assess H5N1 seroprevalence and seroconversion among workers at live bird markets (LBMs) in Bangladesh, we followed a cohort of workers from 12 LBMs with existing avian influenza surveillance. Serum samples from workers were tested for H5N1 antibodies at the end of the study or when LBM samples first had H5N1 virus-positive test results. Of 404 workers, 9 (2%) were seropositive at baseline. Of 284 workers who completed the study and were seronegative at baseline, 6 (2%) seroconverted (7 cases/100 poultry worker-years). Workers who frequently fed poultry, cleaned feces from pens, cleaned food/water containers, and did not wash hands after touching sick poultry had a 7.6 times higher risk for infection compared with workers who infrequently performed these behaviors. Despite frequent exposure to H5N1 virus, LBM workers showed evidence of only sporadic infection. PMID- 25811944 TI - Expression of Leptin and Visfatin in Gingival Tissues of Chronic Periodontitis With and Without Type 2 Diabetes Mellitus: A Study Using Enzyme-Linked Immunosorbent Assay and Real-Time Polymerase Chain Reaction. AB - BACKGROUND: The aim of this study is to investigate the protein and gene expression of leptin and visfatin in gingival tissue from patients with chronic periodontitis (CP), patients with CP and type 2 diabetes mellitus (T2DM), and healthy individuals. METHODS: The study includes 50 individuals: 10 healthy individuals, 20 patients with CP, and 20 patients with CP and T2DM. Plaque index, gingival index, probing depth, and clinical attachment loss were measured, and gingival biopsies were obtained. Leptin and visfatin protein expression in gingival tissues was determined using enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was measured via real-time polymerase chain reaction. RESULTS: The highest leptin mRNA and protein expression was observed in the control group and was significantly (P <=0.05) different from the CP and CP+T2DM groups. Gingival tissues from patients with CP and T2DM had a significant increase in visfatin and a decrease in leptin gene and protein expression (P <0.05) compared with both controls and patients with CP. CONCLUSION: Expression of leptin and visfatin in the gingival tissues suggests a possible role for these adipokines in the pathogenesis of CP and T2DM. PMID- 25811945 TI - What We Talk About Matters: Content Moderates Cognitive Depletion in Interracial Interactions. AB - The antecedents and consequences of intergroup interactions have been well studied, but interaction content--what partners actually talk about--has not. In the experiment we report here, interaction content moderated well-documented self regulation effects (i.e., cognitive depletion) among White participants interacting with a Black partner. Specifically, White individuals participated in a video email interaction with an ostensible Black or White partner who broached topics systematically varying in intimacy. Greater cognitive depletion was evident after interacting with a Black partner relative to a White partner, but only after discussing more intimate topics. When conversation topics aligned with Whites' preferences to avoid intimacy in interracial interactions, depletion effects were reduced. Thus, interaction content, which has been largely ignored in intergroup interaction research, has important implications for intergroup interaction. PMID- 25811946 TI - Ingesting Isomaltulose Versus Fructose-Maltodextrin During Prolonged Moderate Heavy Exercise Increases Fat Oxidation but Impairs Gastrointestinal Comfort and Cycling Performance. AB - Certain commercial carbohydrate replacement products include slowly absorbed carbohydrates such as isomaltulose. Few studies have investigated the metabolic effects of ingesting isomaltulose during exercise and none have evaluated exercise performance and gastrointestinal comfort. Nine male cyclists participated postprandially during three trials of 2-h steady-state (S-S) exercise (60%Wmax) followed by a 16 km time trial (TT) while ingesting 63 g.h-1 of either, 0.8:1 fructose: maltodextrin (F:M) or isomaltulose (ISO) or placebo- flavored water (PL). Data were analyzed by magnitude-based inferences. During S-S exercise, ISO and PL similarly increased plasma nonesterified fatty acid (NEFA) concentration (mean change ISO versus F:M: 0.18, 90%CI +/-0.21 mmol.L-1, 88% likelihood) and fat oxidation (10, 90%CI +/-9 g, 89% likelihood) while decreasing carbohydrate oxidation (-36, 90%CI +/-30.2 g, 91% likelihood) compared with F:M, despite equal elevations in blood glucose concentration with ISO and F:M. Rating of stomach cramps and bloating increased progressively with ISO (rating: 0-90 min S-S, weak; 120 min S-S, moderate; TT, strong) compared with F:M and PL (0-120 min S-S and TT, very weak). TT performance was substantially slower with ISO (mean change: 1.5, 90%CI +/-1.4 min, 94% likely harmful) compared with F:M. The metabolic response of ISO ingestion during moderate exercise to increase NEFA availability and fat oxidation despite elevating blood glucose concentration is anomalous for a carbohydrate supplement. However, ingesting isomaltulose at a continuous high frequency to meet the recommended carbohydrate replacement dose, results in severe gastrointestinal symptoms during prolonged or high intensity exercise and negatively affects exercise performance compared with fructose maltodextrin supplementation. PMID- 25811947 TI - Inhomogeneous Quadriceps Femoris Hypertrophy in Response to Strength and Power Training. AB - INTRODUCTION: Previous studies have reported inhomogeneous changes in quadriceps femoris (QF) cross-sectional area (CSA) in response to strength training. It is assumed that these differential changes in muscle shape influence the muscle's functional capacity during high-force and high-power movements. The purpose of the current study was to compare intermuscular and intramuscular QF adaptations to high-load strength training and fast-speed power training. METHODS: Thirty-six non-strength-trained men were randomly assigned to four groups and completed 8 wk of parallel-depth heavy squat-lift training (HS-P), parallel-depth jump squat training (JS-P), volitional-depth jump squat training (JS-V), or no training (C). Quadriceps femoris, vastus lateralis (VL), intermedius (VI), medialis (VM), and rectus femoris (RF) CSA were measured in distal-, mid-, and proximal-thigh regions using extended field-of-view ultrasonography and compared using a 3 * 2 mixed-model MANOVA with Bonferroni post hoc tests (P < 0.05). RESULTS: Parallel depth heavy squat-lift training and JS-P elicited similar changes in mid-CSA(QF) as well as summed CSA of the QF, VL, VI, and VM. Cross-sectional area of the VL (CSA(VL)) and CSA(VI) increased in both HS-P and JS-P at mid-thigh, but only JS-P significantly increased CSA proximally, and only HS-P significantly increased CSA distally. Cross-sectional area of the VM (CSA(VM)) increased in HS-P and JS-P distally, but only HS-P increased at mid-thigh. No hypertrophy was observed in RF at any location and no significant differences were observed between JS-P and JS V. Parallel-depth heavy squat-lift training elicited greater proximal hypertrophy in each of the vasti muscles, whereas only JS-P elicited distal VL and VI hypertrophy. CONCLUSIONS: These observed inhomogeneous changes in CSA may alter the thigh's moment of inertia and moment arms of muscle "compartments," and the influence of elastic component force transmission on the muscular force expression. Such selective hypertrophy is speculated to be biomechanically beneficial to high-force or high-power movements used in training. PMID- 25811949 TI - Pearls and pitfalls in diagnosis and management of coats disease. AB - PURPOSE: To review current literature on Coats disease and provide a structured framework for differentiating challenging clinical features in Coats disease patients. METHODS: We critically reappraise historical and current literature and present clinical methods for developing a thorough differential diagnosis and management strategy for Coats disease. RESULTS: Coats disease is a sporadic, usually unilateral condition typically occurring in young males. When untreated, this disorder can lead to total exudative retinal detachment and secondary glaucoma. CONCLUSIONS: Anti-VEGF agents are currently a treatment option in combination with ablative therapy of telangiectatic vessels. Anti-VEGF agents appear particularly useful for patients with extensive areas of exudative retinal detachment, and are an effective treatment option for total retinal detachment. PMID- 25811948 TI - Addition of Exercise Increases Plasma Adiponectin and Release from Adipose Tissue. AB - INTRODUCTION: Adiponectin is an adipose tissue-derived anti-inflammatory protein that is down-regulated in obesity. The effects of caloric restriction and exercise-induced weight loss on adiponectin are not clear. PURPOSE: To determine whether addition of aerobic exercise training to caloric restriction has additive effects over caloric restriction alone on circulating adiponectin concentrations and adiponectin release from abdominal and gluteal adipose tissue. METHODS: Overweight or obese (body mass index, 25-40 kg.m(-2); waist >88 cm) postmenopausal women were randomized to 20-wk caloric restriction with and without aerobic exercise (CR + EX, n = 48; and CR, n = 22). Blood samples were collected for measuring plasma adiponectin concentration, and abdominal and gluteal subcutaneous adipose tissue biopsies were performed in a subgroup to determine in vitro adiponectin release, before and after the interventions. RESULTS: The interventions elicited similar amounts of weight loss (CR + EX, 11.3 +/- 4.6 kg; CR,-11.2 +/- 3.4 kg) and fat loss (CR + EX, -8.0 +/- 3.5 kg; CR, -7.4 +/- 2.7 kg). The two groups had differential changes in plasma adiponectin concentrations (for interaction, P = 0.014); CR + EX increased (6.9 +/- 3.9 to 8.5 +/- 4.9 MUg.mL(-1); P = 0.0001), whereas CR did not alter (6.4 +/- 4.4 to 6.5 +/- 4.5 MUg.mL(-1); P = 0.42) plasma adiponectin. Likewise, adiponectin release from abdominal and gluteal subcutaneous adipose tissue increased with CR + EX (P = 0.0076 and P = 0.089, respectively) but did not change with CR (P = 0.13 and P = 0.95, respectively). CONCLUSION: Despite similar reductions in body weight and fat mass, the addition of aerobic exercise to caloric restriction increased plasma adiponectin concentrations, which may be partly explained by increased adiponectin release from abdominal and gluteal subcutaneous adipose tissue. PMID- 25811950 TI - Choroidal degeneration in birdshot chorioretinopathy. AB - PURPOSE: The purpose of the study was to determine if progressive choroidal changes occur in birdshot chorioretinopathy (BSCR). METHODS: Retrospective chart review of all patients with BSCR who were seen over a 3-year period. Controls consisted of healthy age-matched and gender-matched patients. Choroidal thickness at baseline and final follow-up visit was measured with the use of optical coherence tomography. Results were analyzed using univariate and multivariable statistical models. RESULTS: A total of 11 patients (22 eyes) with BSCR were identified. The majority of BSCR eyes (86%) had clinically inactive disease. Follow-up ranged from 2 months to 27 months. Mean age was 55 years. Patients with BSCR had significantly thinner choroid compared with controls (P < 0.001). Furthermore, the rate of choroid thinning for patients diagnosed with BSCR (2.68 MUm per month) was significantly higher than that of controls (0.27 MUm per month) (P = 0.003). There was no statistically significant difference in the rate of choroidal thinning between the two eyes of patients with BSCR (P = 0.859), indicating that the choroidal thinning was symmetrical. CONCLUSION: Despite having clinically inactive uveitis, eyes with BSCR can develop progressive choroidal thinning. The clinical relevance of this choroidal thinning, or degeneration, remains to be fully elucidated. PMID- 25811952 TI - Correction: Systems analysis of the CO2 concentrating mechanism in cyanobacteria. PMID- 25811951 TI - Multi-Center Randomized Controlled Trial on the Effect of Triclosan-Coated Sutures on Surgical Site Infection after Colorectal Surgery. AB - BACKGROUND: Surgical site infection (SSI) remains the most frequent complication after colorectal resection. The role of sutures coated with antimicrobial agents such as triclosan in reducing SSI is controversial. METHODS: This was a multi center randomized controlled trial with patients and outcome assessors blinded to treatment. The study was performed in four university referral hospitals. Patient candidates for elective colorectal resection were assigned randomly to abdominal incision closure with polyglactin 910 triclosan-coated sutures (triclosan group) or with polyglactin 910 without triclosan (control group). The primary outcome was the rate of SSI within 30 d after hospital discharge. The secondary outcomes were the overall rate of incision complications and length of hospital stay (LOS). RESULTS: Two hundred eighty-one patients (triclosan group: 140; control group: 141) were analyzed after randomization. The rate of SSI was 12.9% (18/140) in the triclosan group versus 10.6% (15/141) in the control group (odds ratio: 1.24; 95% confidence interval: 0.60-2.57; p=0.564). Secondary outcome analysis showed an overall incision complication rate of 38.3% in the control group versus 45.7% in the triclosan group (odds ratio: 1.36; 95% confidence interval: 0.84 2.18; p=0.208). Median LOS was 11 d in both groups (p=0.55). CONCLUSIONS: Surgical sutures coated with triclosan do not appear to be effective in reducing the rate of SSI. PMID- 25811954 TI - Polypyrrole/silver coaxial nanowire aero-sponges for temperature-independent stress sensing and stress-triggered Joule heating. AB - To obtain ideal sensing materials with nearly zero temperature coefficient resistance (TCR) for self-temperature-compensated pressure sensors, we proposed an Incipient Network Conformal Growth (INCG) technology to prepare hybrid and elastic porous materials: the nanoparticles (NPs) are first dispersed in solvent to form an incipient network, another component is then introduced to coat the incipient network conformally via wet chemical route. The conformal coatings not only endow NPs with high stability but also offer them additional structural elasticity, meeting requirements for future generations of portable, compressive and flexible devices. The resultant polypyrrole/silver coaxial nanowire hybrid aero-sponges prepared via INCG technology have been processed into a piezoresistive sensor with highly sensing stability (low TCR 0.86 * 10(-3)/ degrees C), sensitivity (0.33 kPa(-1)), short response time (1 ms), minimum detectable pressure (4.93 Pa) after suffering repeated stimuli, temperature change and electric heating. Moreover, a stress-triggered Joule heater can be also fabricated mainly by the PPy-Ag NW hybrid aero-sponges with nearly zero temperature coefficient. PMID- 25811953 TI - The TyrR transcription factor regulates the divergent akr-ipdC operons of Enterobacter cloacae UW5. AB - The TyrR transcription factor regulates genes involved in the uptake and biosynthesis of aromatic amino acids in Enterobacteriaceae. Genes may be positively or negatively regulated depending on the presence or absence of each aromatic amino acid, all three of which function as cofactors for TyrR. In this report we detail the transcriptional control of two divergently transcribed genes, akr and ipdC, by TyrR, elucidated by promoter fusion expression assays and electrophoretic mobility shift assays to assess protein-DNA interactions. Expression of both genes was shown to be controlled by TyrR via interactions with two TyrR boxes located within the akr-ipdC intergenic region. Expression of ipdC required TyrR bound to the proximal strong box, and is strongly induced by phenylalanine, and to a lesser extent by tryptophan and tyrosine. Down-regulation of akr was reliant on interactions with the weak box, and may also require a second, as yet unidentified protein for further repression. Tyrosine enhanced repression of akr. Electrophoretic mobility shift assays demonstrated that TyrR interacts with both the strong and weak boxes, and that binding of the weak box in vitro requires an intact adjacent strong box. While the strong box shows a high degree of conservation with the TyrR binding site consensus sequence, the weak box has atypical spacing of the two half sites comprising the palindromic arms. Site-directed mutagenesis demonstrated sequence-specific interaction between TyrR and the weak box. This is the first report of TyrR-controlled expression of two divergent protein-coding genes, transcribed from independent promoters. Moreover, the identification of a predicted aldo-keto reductase as a member of the TyrR regulon further extends the function of the TyrR regulon. PMID- 25811955 TI - New organochalcogen multitarget drug: synthesis and antioxidant and antitumoral activities of chalcogenozidovudine derivatives. AB - In this article we present the synthesis, characterization, and in vitro biological and biochemical activities of new chalcogenozidovudine derivatives as antioxidant (inhibition of TBARS in brain membranes and thiol peroxidase-like activity) as well as antitumoral agents in bladder carcinoma 5637. A prominent response was obtained for the selected chalcogenonucleosides, showing effective antioxidant and antitumoral activities. PMID- 25811956 TI - Costs of using "tiny targets" to control Glossina fuscipes fuscipes, a vector of gambiense sleeping sickness in Arua District of Uganda. AB - INTRODUCTION: To evaluate the relative effectiveness of tsetse control methods, their costs need to be analysed alongside their impact on tsetse populations. Very little has been published on the costs of methods specifically targeting human African trypanosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: In northern Uganda, a 250 km2 field trial was undertaken using small (0.5 X 0.25 m) insecticide-treated targets ("tiny targets"). Detailed cost recording accompanied every phase of the work. Costs were calculated for this operation as if managed by the Ugandan vector control services: removing purely research components of the work and applying local salaries. This calculation assumed that all resources are fully used, with no spare capacity. The full cost of the operation was assessed at USD 85.4 per km2, of which USD 55.7 or 65.2% were field costs, made up of three component activities (target deployment: 34.5%, trap monitoring: 10.6% and target maintenance: 20.1%). The remaining USD 29.7 or 34.8% of the costs were for preliminary studies and administration (tsetse surveys: 6.0%, sensitisation of local populations: 18.6% and office support: 10.2%). Targets accounted for only 12.9% of the total cost, other important cost components were labour (24.1%) and transport (34.6%). DISCUSSION: Comparison with the updated cost of historical HAT vector control projects and recent estimates indicates that this work represents a major reduction in cost levels. This is attributed not just to the low unit cost of tiny targets but also to the organisation of delivery, using local labour with bicycles or motorcycles. Sensitivity analyses were undertaken, investigating key prices and assumptions. It is believed that these costs are generalizable to other HAT foci, although in more remote areas, with denser vegetation and fewer people, costs would increase, as would be the case for other tsetse control techniques. PMID- 25811957 TI - Antiproliferative effect of Dendrobium catenatum Lindley polypeptides against human liver, gastric and breast cancer cell lines. AB - Dendrobium catenatum Lindley is a precious plant with both dietary and medicinal applications. However, the antiproliferative activity of D. catenatum-derived peptides has not been investigated. In this study, the whole proteins of D. catenatum were extracted, hydrolysis with three proteases (alcalase 2.4L, alcalase 37017 and trypsin) was performed, and gel filtration chromatography was employed to obtain nine fractions. Fraction A3 possessed the best antiproliferative activity in vitro, with percentage inhibitions of 73.38%, 78.91% and 86.8% against HepG-2, SGC-7901 and MCF-7 cancer cells, respectively, and an inhibition of only 5.52% against L-O2 normal liver cells at 500 MUg mL( 1). Subsequently, mass spectrometry revealed the existence of 10 alcalase-derived peptides in fraction A3, and the sequences of the three most abundant peptides were determined by de novo sequencing as: RHPFDGPLLPPGD, RCGVNAFLPKSYLVHFGWKLLFHFD and KPEEVGGAGDRWTC. Moreover, these peptides were synthesized and their antiproliferative activities in vitro were also confirmed. This suggests that fraction A3 may be promising for use in food and pharmaceutical applications. PMID- 25811958 TI - Combination drug release of smart cyclodextrin-gated mesoporous silica nanovehicles. AB - An integrated gamma-cyclodextrin-gated mesoporous silica delivery system via dual dynamic covalent bonds was constructed with dual drug loading for simultaneous and cascade release in targeted combination drug therapy. PMID- 25811959 TI - Correction: Heat shock protein 90 positively regulates chikungunya virus replication by stabilizing viral non-structural protein nsP2 during infection. PMID- 25811960 TI - Stereodivergent hydrogermylations of alpha-trifluoromethylated alkynes and their applications in cross-coupling reactions. AB - The hydrometalation of alkynes with group 14 elements such as tin- or silyl hydrides is a classical transformation in organic synthesis. Strangely, among the group 14 elements, the use of germanium hydrides is rarely seen. Two efficient, stereodivergent, and broadly applicable routes to (Z)- and (E)-alpha-CF3 vinylgermanes by regio- and stereoselective hydrogermylation of alpha trifluoromethylated alkynes under radical or transition-metal-catalyzed conditions are reported. Furthermore, we demonstrate that the resulting stereodefined fluorinated building blocks are remarkable cross-coupling partners, provided that the vinylgermane is appropriately tuned electronically, as demonstrated by the synthesis of trisubstituted (Z)- and (E)-alpha trifluoromethylated alkenes. PMID- 25811961 TI - A hybrid platinum drug dichloroacetate-platinum(II) overcomes cisplatin drug resistance through dual organelle targeting. AB - A hybrid drug dichloroacetate-platinum(II) [DCA-Pt(II)] was found to overcome cisplatin drug resistance of ovarian cancer through a dual targeting mode, which is different from the mode of action of the present platinum (Pt) drugs used in clinics. DCA-Pt(II) exhibited remarkable cytotoxicity against both cisplatin sensitive (A2780) and cisplatin-resistant (A2780DDP) ovarian cancer cells. The Pt and Pt-DNA adduct content test showed that there was less Pt cellular uptake and fewer Pt-DNA adducts were present after DCA-Pt(II) treatment compared with treatment with cisplatin, carboplatin, and some other drugs. In the study, the effects of DCA-Pt(II) on the cell cycle and apoptosis were also investigated, which showed that DCA-Pt(II) induced G2/M phase arrest and mitochondria-mediated apoptosis in both sensitive and resistant cells lines. Interestingly, DCA-Pt(II) had much greater effects on mitochondria in A2780DDP cell lines than in A2780 cell lines. PMID- 25811963 TI - Three-weekly oxaliplatin combined with gemcitabine and capecitabine in the first line treatment of patients with advanced biliary tract cancer. AB - The primary objective of this study was to determine the activity and safety of 3 weekly oxaliplatin combined with gemcitabine and oral capecitabine in the first line treatment of advanced biliary tract cancer. Treatment consisted of intravenous oxaliplatin 100 mg/m every 3 weeks combined with intravenous gemcitabine 1000 mg/m on days 1 and 8 and oral capecitabine 1500 mg/m 14 days on 21 in two divided doses. Treatment was administered until progressive disease, unacceptable toxicity, or patient refusal. Thirty-seven patients were enrolled: eight patients had Eastern Cooperative Oncology Group 2 performance status at presentation. The overall response rate was 35.1% [95% confidence interval (CI): 20.2-52.5%] and the disease control rate was 72.9%. The median progression-free survival was 9.4 months (95% CI: 4.1-12.2 months) and the median overall survival was 13.8 months (95% CI: 7.7-17.1 months). There were no grade 4 toxicities. Grade 3 neutropenia occurred in 13.5% of patients and grade 3 thrombocytopenia in 10.8%. The present study suggests that 3-weekly oxaliplatin combined with gemcitabine and oral capecitabine is an active and well-tolerated chemotherapy regimen in the first-line treatment of metastatic biliary tract cancer. PMID- 25811962 TI - ERK-dependent phosphorylation of HSF1 mediates chemotherapeutic resistance to benzimidazole carbamates in colorectal cancer cells. AB - Drugs containing the benzimidazole carbamate scaffold include anthelmintic and antifungal agents, and they are now also recognized as having potential applications in the treatment of colorectal and other cancers. These agents act by binding to beta-tubulin, and in doing so they disrupt microtubules, arrest cell division, and promote apoptotic cell death in malignant cells. We have evaluated several commercially available benzimidazole carbamates for cytotoxic activity in colorectal cancer cells. In addition to cytotoxicity, we also observe activation of the transcription factor, heat shock factor-1 (HSF1). HSF1 is well known to mediate a cytoprotective response that promotes tumor cell survival and drug resistance. Here, we show that biochemical inhibition with the HSF1 inhibitor KRIBB11 or siRNA-based silencing of HSF1 results in a significant enhancement of drug potency, causing an approximately two-fold decrease in IC50 values of parbendazole and nocodazole. We also define a mechanism for drug induced HSF1 activation, which results from a phosphorylation event at Ser326 that is dependent on the activation of the extracellular regulated protein kinase 1/2 (ERK-1/2) mitogen-activated protein kinase pathway. Inhibition of the upstream kinase MEK-1/2 with U0126 attenuates the phosphorylation of both ERK-1/2 and HSF1, and significantly enhances drug cytotoxicity. From these data we propose a unique model whereby the ERK-1/2-dependent activation of HSF1 promotes chemotherapeutic resistance to benzimidazole carbamates. Therefore, targeting the ERK-1/2 signaling cascade is a potential strategy for HSF1 inhibition and a means of enhancing the cytotoxicity of these agents. PMID- 25811965 TI - Baicalein inhibits MMP-2 expression in human ovarian cancer cells by suppressing the p38 MAPK-dependent NF-kappaB signaling pathway. AB - Matrix metalloproteinases (MMPs) secreted by ovarian cancer play essential roles in tumor invasion and metastasis. In this study, we investigated the effect of baicalein, which is isolated from the traditional Chinese herbal medicine Scutellaria baicalensis Georgi, on human ovarian cancer cell lines by measuring MMP-2 expression, invasive potential, and the underlying molecular mechanisms. Analysis of MMP-2 was carried out by western blots and RT-PCR. The invasion ability of ovarian cancer cells was determined using a Transwell invasion assay. Nuclear factor-kappaB (NF-kappaB) and p38 MAPK activation was assessed by western blots. The results of the present study showed that baicalein reduced the expression of MMP-2 in a dose-dependent manner and the invasion of ovarian cancer cells was also significantly suppressed by baicalein. We also found that baicalein reduced the activation of NF-kappaB signaling molecules; in addition, the MMP-2 expression and invasion ability of ovarian cancer cells were abolished with the treatment of the NF-kappaB inhibitor, pyrrolidine dithiocarbamate. However, the addition of p38 MAPK inhibitor SB203580 significantly reduced the activation of NF-kappaB; meanwhile, baicalein was shown to exert an inhibitory effect on p38 activation. Furthermore, the MMP-2 expression and invasion ability of ovarian cancer cells were significantly inhibited by SB203580. In conclusion, baicalein inhibits the MMP-2 expression and invasion ability of ovarian cancer cells, possibly by the p38 MAPK-dependent NF-kappaB signaling pathway; these findings may provide insights into the potential of using baicalein as a therapeutic strategy against ovarian cancer. PMID- 25811964 TI - Derivatives containing both coumarin and benzimidazole potently induce caspase dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling. AB - Coumarins are a large family of compounds derived from a wide range of plants, fungi, and bacteria, and coumarin derivatives can have extremely variable structures and consequently diverse biological properties including antitumor activity. Compounds that bear a benzimidazole moiety are known to possess antitumor activity and a variety of other biological activities. High-throughput screening of a compound library identified a coumarin-containing and a benzimidazole-containing compound [#32, 7-(diethylamino)-3-(1-methyl-1H benzimidazol-2-yl)-2H-chromen-2-one] that has potent anticancer activity. Evaluation of 17 additional analogs further identified three compounds with anticancer activity in 14 different human cancer cell lines. Fluorescence activated cell sorting and western blotting analyses suggested that these compounds can induce caspase-dependent apoptosis. Real-time reverse transcriptase PCR analyses of 26 cancer-related genes revealed that seven genes (NPPB, ATF3, DDIT4, CDH10, TSPAN14, TXNIP, and AXL) were significantly upregulated and nine genes (PAGE4, LRP8, SNCAIP, IGFBP5, SLCO2A1, CLDN2, ESRRG, D2HGDH, and PDGFRA) were significantly downregulated. The most upregulated gene is natriuretic peptide precursor B (NPPB) or brain natriuretic peptide, which is increased by 7 , 27-, and 197-fold at 12, 24, and 48 h, respectively. The second most upregulated gene is ATF3, which is increased by 23-fold at the 48 h timepoint. PAGE4 and IGFBP5 are the two most downregulated genes, with a 17-fold reduction in both genes. The expression of several genes (DDIT4, PDGFRA, LRP8, IGFBP5) and western blotting data on key signaling proteins indicate that compound #32 significantly inhibits the PI3K-AKT-mTOR pathway, an intracellular signaling pathway critical in cell proliferation and apoptosis. PMID- 25811966 TI - Cytotoxic effect and mechanism inducing cell death of alpha-mangostin liposomes in various human carcinoma and normal cells. AB - The aims of this study were to develop alpha-mangostin liposomes as well as to evaluate their physicochemical properties and cytotoxic activity. alpha-Mangostin liposomes were prepared using the reverse-phase evaporation method with lipid composition of phosphatidylcholine to cholesterol at 7 : 3 molar ratios; their physicochemical properties and antiproliferative activity were assessed using an MTT assay in four human carcinoma cells [that is, human lung epithelial carcinoma (Calu-3), human colon carcinoma (HT-29), human breast carcinoma (MCF-7), and human colon carcinoma (Caco-2) cells], and two human normal cells [that is, human dermal fibroblasts (HDF) and human adult low-calcium elevated temperature (HaCaT) keratinocytes]. Determinations of morphological changes and oligonucleosomal DNA fragments were also carried out. The liposomal dispersions obtained were unilamellar vesicles as confirmed by cryotransmission and freeze-fracture electron microscopy with a particle size of 114 nm and a zeta potential of -2.56 mV. The P-NMR spectra showed that alpha-mangostin molecules orientated in the phospholipid bilayer membrane. The alpha-mangostin could appreciably be entrapped with an efficiency and loading of 81 and 4%, respectively. The antiproliferative activity of alpha-mangostin liposomes in various cancer and normal cells showed a dose-dependent inhibition in all treated cell lines. The antiproliferative effect of alpha-mangostin liposomes was found to be associated with apoptosis, with differences in sensitivity among the cell lines treated. PMID- 25811967 TI - Deep-Ultraviolet Raman Measurements Using a Spatial Heterodyne Raman Spectrometer (SHRS). AB - A deep-ultraviolet (UV) 244 nm excitation spatial heterodyne Raman spectrometer (SHRS) is demonstrated for the first time. The deep-UV SHRS has no moving parts, and even though it is small for a deep-UV Raman spectrometer, the spectral resolution is shown to be about 4 cm(-1). The deep-UV SHRS also has a large input aperture and acceptance angle, and the resulting large field of view is shown to be useful to avoid laser-induced sample degradation. In this feasibility study, Raman spectra of several compounds are measured to demonstrate the spectral resolution and range of the system. A photosensitive compound is also measured to demonstrate the use of a large laser spot to minimize UV-laser-induced sample degradation. PMID- 25811969 TI - Greenland ice sheet mass balance: a review. AB - Over the past quarter of a century the Arctic has warmed more than any other region on Earth, causing a profound impact on the Greenland ice sheet (GrIS) and its contribution to the rise in global sea level. The loss of ice can be partitioned into processes related to surface mass balance and to ice discharge, which are forced by internal or external (atmospheric/oceanic/basal) fluctuations. Regardless of the measurement method, observations over the last two decades show an increase in ice loss rate, associated with speeding up of glaciers and enhanced melting. However, both ice discharge and melt-induced mass losses exhibit rapid short-term fluctuations that, when extrapolated into the future, could yield erroneous long-term trends. In this paper we review the GrIS mass loss over more than a century by combining satellite altimetry, airborne altimetry, interferometry, aerial photographs and gravimetry data sets together with modelling studies. We revisit the mass loss of different sectors and show that they manifest quite different sensitivities to atmospheric and oceanic forcing. In addition, we discuss recent progress in constructing coupled ice ocean-atmosphere models required to project realistic future sea-level changes. PMID- 25811968 TI - Spanish validation of the Person-centered Care Assessment Tool (P-CAT). AB - OBJECTIVES: Person-centered Care (PCC) is an innovative approach which seeks to improve the quality of care services given to the care-dependent elderly. At present there are no Spanish language instruments for the evaluation of PCC delivered by elderly care services. The aim of this work is the adaptation and validation of the Person-centered Care Assessment Tool (P-CAT) for a Spanish population. METHOD: The P-CAT was translated and adapted into Spanish, then given to a sample of 1339 front-line care professionals from 56 residential elderly care homes. The reliability and validity of the P-CAT were analyzed, within the frameworks of Classical Test Theory and Item Response Theory models. RESULTS: The Spanish P-CAT demonstrated good reliability, with an alpha coefficient of .88 and a test-retest reliability coefficient of .79. The P-CAT information function indicates that the test measures with good precision for the majority of levels of the measured variables (theta values between -2 and +1). The factorial structure of the test is essentially one-dimensional and the item discrimination indices are high, with values between .26 and .61. In terms of predictive validity, the correlations which stand out are between the P-CAT and organizational climate (r = .689), and the burnout factors; personal accomplishment (r = .382), and emotional exhaustion (r = - .510). CONCLUSION: The Spanish version of the P-CAT demonstrates good psychometric properties for its use in the evaluation of elderly care homes both professionally and in research. PMID- 25811970 TI - Foam drainage placed on a porous substrate. AB - A model for drainage/imbibition of a foam placed on the top of a porous substrate is presented. The equation of liquid imbibition into the porous substrate is coupled with a foam drainage equation at the foam/porous substrate interface. The deduced dimensionless equations are solved using a finite element method. It was found that the kinetics of foam drainage/imbibition depends on three dimensionless numbers and the initial liquid volume fraction. The result shows that there are three different regimes of the process. Each regime starts after initial rapid decrease of a liquid volume fraction at the foam/porous substrate interface: (i) rapid imbibition: the liquid volume fraction inside the foam at the foam/porous substrate interface remains constant close to a final liquid volume fraction; (ii) intermediate imbibition: the liquid volume fraction at the interface with the porous substrate experiences a peak point and imbibition into the porous substrate is slower as compared with the drainage; (iii) slow imbibition: the liquid volume fraction at the foam/porous substrate interface increases to a maximum limiting value and a free liquid layer is formed between the foam and the porous substrate. However, the free liquid layer disappears after some time. The transition points between these three different drainage/imbibition regimes were delineated by introducing two dimensionless numbers. PMID- 25811971 TI - Nanoparticles of CoAPO-5: synthesis and comparison with microcrystalline samples. AB - The hydrothermal synthesis of a nanosized cobalt doped aluminum phosphate CoAPO-5 (CoAPO-5-N) in a water-surfactant-organic solvent mixture (emulsion method) is reported, along with its physico-chemical characterization and comparison with a sample obtained by conventional synthesis (CoAPO-5-C). Both XRD (X-ray Diffraction) peak widths and FESEM (Field Emission Scanning Electron Microscopy) pictures of CoAPO-5-N are in agreement with a nanoscale structure, although the aggregation of nanoparticles occurred. EDX analysis shows a more homogeneous distribution of cobalt in CoAPO-5-N, not attainable by conventional synthesis. The specific surface area, as measured by nitrogen adsorption at 77 K, shows a limited increase in CoAPO-5-N (242 m(2) g(-1)) with respect to CoAPO-5-C (216 m(2) g(-1)), whereas the external surface area is almost tripled. Such a definite increase in the outer surface of CoAPO-5-N is also evidenced by the fourfold increase in the rate of a reaction only involving the exterior surface of particles, the light-driven oxidation of water by persulfate anions, as activated by the bulky Ru(bipy)3(2+) complex, unable to enter CoAPO-5 micropores. Two new features were also noted, adding to the knowledge of CoAPO-5 systems: (i) tetrahedral Co(3+) species may coordinate ammonia molecules, assuming an octahedral configuration, as determined by UV-vis spectroscopy; (ii) Co(2+) species in trigonal coordination occur, able to coordinate either CO molecules at a low temperature or ammonia (or water) at room temperature, as evidenced by IR and UV-vis spectroscopy, respectively. PMID- 25811974 TI - Fano-like resonances in split concentric nanoshell dimers in designing negative index metamaterials for biological-chemical sensing and spectroscopic purposes. AB - In this study, we investigated numerically the plasmon response of a dimer configuration composed of a couple of split and concentric Au nanoshells in a complex orientation. We showed that an isolated composition of two concentric split nanoshells could be tailored to support strong plasmon resonant modes in the visible wavelengths. After determining the accurate geometric dimensions for the presented antisymmetric nanostructure, we designed a dimer array that shows complex behavior during exposure to different incident polarizations. We verified that the examined dimer was able to support destructive interference between dark and bright plasmon modes, which resulted in a pronounced Fano-like dip. Observation of a Fano minimum in such a simple molecular orientation of subwavelength particles opens new avenues for employing this structure in designing various practical plasmonic devices. Depositing the final dimer in a strong coupling condition on a semiconductor metasurface and measuring the effective refractive index at certain wavelengths, we demonstrate that each one of dimer units can be considered a meta-atom due to the high aspect ratio in the geometric parameters. Using this method, by extending the number of dimers periodically and illuminating the structure, we examined the isotropic, polarization-dependent, and transmission behavior of the metamaterial configuration. Using numerical methods and calculating the effective refractive indices, we computed and sketched corresponding figure of merit over the transmission window, where the maximum value obtained was 42.3 for Si and 54.6 for gallium phosphide (GaP) substrates. PMID- 25811973 TI - Thyrotropin versus age relation as an indicator of historical iodine intake. AB - BACKGROUND: In populations with mild iodine deficiency, the serum level of thyrotropin (TSH) is negatively and the serum free thyroxine (FT4) is positively associated with age. An ongoing decrease of TSH and increase of FT4 can be found after iodine supplementation. The aim of this study was to investigate whether there are current differences in the relation between thyroid function and age in relation to differences in iodine intake in the past. METHODS: Eight medical laboratories in several regions of The Netherlands, which are all iodine sufficient at present but with a difference in iodine status in the past, provided the results of all TSH and FT4 measurements performed from 2006 until 2011, resulting in 330,802 TSH and 103,940 FT4 measurements. RESULTS: The negative association between TSH and age in the elderly is only present in areas with a historical iodine deficiency (regression coefficients [RC] -0.008, 95% confidence interval [CI] -0.009; -0.007). In the historically iodine-sufficient population, TSH shows no obvious increase or decrease with age. In both the historically iodine-sufficient and iodine-deficient populations, FT4 levels were positively associated with age in the elderly (RC 0.009, 95% CI 0.008; 0.010 and RC 0.008, 95% CI 0.007; 0.010, respectively). CONCLUSIONS: There are differences in relation between thyroid function and age between populations with differences in iodine intake in the past, despite an adequate iodine status at present. This raises the question whether the present but also historical iodine status of a population should be taken into account when establishing the reference limits of TSH and FT4. PMID- 25811975 TI - Hepatitis E epidemic, Biratnagar, Nepal, 2014. PMID- 25811972 TI - Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells. AB - Cancer stem-like cell (CS-like cell) is considered to be responsible for recurrence and drug resistance events in breast cancer, which makes it a potential target for novel cancer therapeutic strategy. The FDA approved flubendazole, has been widely used in the treatment of intestinal parasites. Here, we demonstrated a novel effect of flubendazole on breast CS-like cells. Flubendazole inhibited breast cancer cells proliferation in dose- and time dependent manner and delayed tumor growth in xenograft models by intraperitoneal injection. Importantly, flubendazole reduced CD44high/CD24low subpopulation and suppressed the formation of mammosphere and the expression of self-renewal related genes including c-myc, oct4, sox2, nanog and cyclinD1. Moreover, we found that flubendazole induced cell differentiation and inhibited cell migration. Consistently, flubendazole reduced mesenchymal markers (beta-catenin, N-cadherin and Vimentin) expression and induced epithelial and differentiation marker (Keratin 18) expression in breast cancer cells. Mechanism study revealed that flubendazole arrested cell cycle at G2/M phase and induced monopolar spindle formation through inhibiting tubulin polymerization. Furthermore, flubendazole enhanced cytotoxic activity of conventional therapeutic drugs fluorouracil and doxorubicin against breast cancer cells. In conclusion, our findings uncovered a remarkable effect of flubendazole on suppressing breast CS-like cells, indicating a novel utilization of flubendazole in breast cancer therapy. PMID- 25811976 TI - Automatic segmentation of myocardium from black-blood MR images using entropy and local neighborhood information. AB - By using entropy and local neighborhood information, we present in this study a robust adaptive Gaussian regularizing Chan-Vese (CV) model to segment the myocardium from magnetic resonance images with intensity inhomogeneity. By utilizing the circular Hough transformation (CHT) our model is able to detect epicardial and endocardial contours of the left ventricle (LV) as circles automatically, and the circles are used as the initialization. In the cost functional of our model, the interior and exterior energies are weighted by the entropy to improve the robustness of the evolving curve. Local neighborhood information is used to evolve the level set function to reduce the impact of the heterogeneity inside the regions and to improve the segmentation accuracy. An adaptive window is utilized to reduce the sensitivity to initialization. The Gaussian kernel is used to regularize the level set function, which can not only ensure the smoothness and stability of the level set function, but also eliminate the traditional Euclidean length term and re-initialization. Extensive validation of the proposed method on patient data demonstrates its superior performance over other state-of-the-art methods. PMID- 25811977 TI - Quantifying short-term foraging movements in a marsupial pest to improve targeted lethal control and disease surveillance. AB - In New Zealand, the introduced marsupial brushtail possum (Trichosurus vulpecula) is a pest species subject to control measures, primarily to limit its ability to transmit bovine tuberculosis (TB) to livestock and for conservation protection. To better define parameters for targeted possum control and TB surveillance, we here applied a novel approach to analyzing GPS data obtained from 44 possums fitted with radio-tracking collars, producing estimates of the animals' short term nocturnal foraging patterns based on 1-, 3- or 5-nights' contiguous data. Studies were conducted within two semi-arid montane regions of New Zealand's South Island High Country: these regions support low-density possum populations (<2 possums/ha) in which the animals' home ranges are on average larger than in high-density populations in forested habitat. Possum foraging range width (FRW) estimates increased with increasing monitoring periods, from 150-200 m based on a single night's movement data to 300-400 m based on 5 nights' data. The largest average FRW estimates were recorded in winter and spring, and the smallest in summer. The results suggest that traps or poison-bait stations (for lethal control) or monitoring devices (for TB surveillance), set for > 3 consecutive nights at 150 m interval spacings, would likely place >95% of the possums in this type of habitat at risk of encountering these devices, year-round. Modelling control efficacy against operational expenditure, based on these estimations, identified the relative cost-effectiveness of various strategies that could be applied to a typical aerial poisoning operation, to reduce the ongoing TB vectorial risk that possums pose in the High Country regions. These habitat specific findings are likely to be more relevant than the conventional pest control and monitoring methodologies developed for possums in their more typical forested habitat. PMID- 25811978 TI - The synthesis and structural characterization of polycyclic derivatives of cobalt bis(dicarbollide)(1(-)). AB - The cobalt bis(dicarbollide) anion [(1,2-C2B9H11)2-3,3'-Co](-) (1(-)) is an increasingly important building block for the design of new biologically active compounds. Here we report the reactions of lithiated 1(-) with N-(omega bromoalkyl)phthalimides Br-(CH2)n-N(CO)2NC6H4 (where n = 1 to 3) that give a number of new compounds substituted at dicarbollide carbon atom positions. For n = 2 and 3, substitution of the cobalt bis(dicarbollide) anion is accompanied by cyclocondensation of the organic moieties to give polycyclic ring structures attached to the cage. Predominant products correspond to oxazolo[2,3-a]isoindol 5(9bH)-1,2,3-dihydro-9b-yl)-(1-cobalt(III) bis(1,2-dicarbollide)(1(-)) (2(-)) and 1-(2H-[1,3]-oxazino[2,3-a]isoindol-6(10bH)-1,3,4-dihydro-10b-yl)-(1-cobalt(III) bis(1,2-dicarbollide)(1(-)) (4(-)) ions with isoindolone functions containing either five- or six-membered lateral oxazine rings. Additionally, products (tetrahydro-2-benzo[4,5]furan-1(3H)-1-[3,3]-yl-)-1,1'-MU-cobalt(III) bis(1,2 dicarbollide)(1(-)) (3(-)) and (2-(azetidin-yl-carbonyl)benzoyl-)-1-cobalt(III) bis(1,2-dicarbollide)(1(-)) (5(-)) were isolated, which display unusual cyclic structures featuring a bicyclic benzofuranone ring attached in a bridging manner by a quarternary carbon to two skeletal carbon atoms and a ketobenzoic acid amide substituent with a side azetidine ring. However, in the case of n = 1, only the anticipated methylene amine derivative [(1-NH2CH2-1,2-C2B9H11)(1',2'-C2B9H11)2 3,3'-Co](-) (6(-)) was isolated in low yield after cleavage of the phthalimide intermediate species. The molecular structures of all isolated cyclic products 2( ) to 5(-) were confirmed by single-crystal X-ray diffraction studies, and the structure of cobalt bis(dicarbollide)-1-CH2NH2 6(-) was delineated using density functional theory applied at BP86/AE1 level in combination with NMR spectroscopy. Thus, the synthetic method described herein presents a facile route to new cobalt bis(dicarbollide) derivatives substituted by polycyclic structural motifs with potential biological activity. PMID- 25811980 TI - Soft perches in an aviary system reduce incidence of keel bone damage in laying hens. AB - Keel bone fractures and deviations are one of the major welfare and health issues in commercial laying hens. In non-cage housing systems like aviaries, falls and collisions with perches and other parts of the housing system are assumed to be one of the main causes for the high incidence of keel bone damage. The objectives of this study were to investigate the effectiveness of a soft perch material to reduce keel bone fractures and deviations in white (Dekalb White) and brown laying hens (ISA Brown) kept in an aviary system under commercial conditions. In half of 20 pens, all hard, metal perches were covered with a soft polyurethane material. Palpation of 20 hens per pen was conducted at 18, 21, 23, 30, 38, 44 and 64 weeks of age. Production data including egg laying rate, floor eggs, mortality and feed consumption were collected over the whole laying period. Feather condition and body mass was assessed twice per laying period. The results revealed that pens with soft perches had a reduced number of keel bone fractures and deviations. Also, an interaction between hybrid and age indicated that the ISA hybrid had more fractured keel bones and fewer non-damaged keel bones compared with the DW hybrid at 18 weeks of age, a response that was reversed at the end of the experiment. This is the first study providing evidence for the effectiveness of a soft perch material within a commercial setting. Due to its compressible material soft perches are likely to absorb kinetic energy occurring during collisions and increase the spread of pressure on the keel bone during perching, providing a mechanism to reduce keel bone fractures and deviations, respectively. In combination with genetic selection for more resilient bones and new housing design, perch material is a promising tool to reduce keel bone damage in commercial systems. PMID- 25811979 TI - YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation. AB - The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor suppressor pathway, functions as an oncoprotein in a variety of cancers. However, its contribution to breast cancer remains controversial. This study investigated the role of YAP in breast cancer cells under nutrient deprivation (ND). Here, we show that YAP knockdown sensitized MCF7 breast cancer cells to nutrient deprivation-induced apoptosis. Furthermore, in response to ND, YAP increased the autolysosome degradation, thereby enhancing the cellular autophagic flux in breast cancer cells. Of note, autophagy is crucial for YAP to protect MCF7 cells from apoptosis under ND conditions. In addition, the TEA domain (TEAD) family of growth-promoting transcription factors was indispensable for YAP-mediated regulation of autophagy. Collectively, our data reveal a role for YAP in promoting breast cancer cell survival upon ND stress and uncover an unappreciated function of YAP/TEAD in the regulation of autophagy. PMID- 25811982 TI - Testing for mechanistic interactions in long-term follow-up studies. AB - In follow-up studies, interactions are often assessed by including a cross product term in a (multiplicative) Cox model. However, epidemiologists/clinicians often misinterpret a significant multiplicative interaction as a genuine mechanistic interaction. Though indices specific to mechanistic interactions have been proposed, including the 'relative excess risk due to interaction' (RERI) and the 'peril ratio index of synergy based on multiplicativity' (PRISM), these indices assume no loss to follow up and no competing death in a study. In this paper, the authors propose a novel 'mechanistic interaction test' (MIT) for censored data. Monte-Carlo simulation shows that when the hazard curves are proportional to, non-proportional to, or even crossing over one another, the proposed MIT can maintain reasonably accurate type I error rates for censored data. It has far greater powers than the modified RERI and PRISM tests (modified for censored data scenarios). To test mechanistic interactions in censored data, we recommend using MIT in light of its desirable statistical properties. PMID- 25811981 TI - Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin. AB - BACKGROUND: Warfarin is a widely prescribed anticoagulant, and its effect depends on various patient factors including genotypes. Randomized controlled trials (RCTs) comparing genotype-guided dosing (GD) of warfarin with standard dosing have shown mixed efficacy and safety outcomes. We performed a meta-analysis of all published RCTs comparing GD vs standard dosing in adult patients with various indications of warfarin use. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and relevant references for English language RCTs (inception through March 2014). We performed the meta analysis using a random effects model. RESULTS: Ten RCTs with a total of 2,505 patients were included in the meta-analysis. GD compared with standard dosing resulted in a similar % time in therapeutic range (TTR) at <= 1 month follow-up (39.7% vs 40.2%; mean difference [MD], -0.52 [95% CI, -3.15 to 2.10]; P = .70) and higher % TTR (59.4% vs 53%; MD, 6.35 [95% CI, 1.76-10.95]; P = .007) at > 1 month follow-up, a trend toward lower risk of major bleeding (risk ratio, 0.46 [95% CI, 0.19-0.1.11]; P = .08) at <= 1 month follow-up and lower risks of major bleeding (0.34 [95% CI, 0.16-0.74], P = .006) at > 1-month follow-up, and shorter time to maintenance dose (TMD) (24.6 days vs 34.1 days; MD, -9.54 days [95% CI, 18.10 to -0.98]; P = .03) at follow-up but had no effects on international normalized ratio [INR] > 4.0, nonmajor bleeding, thrombotic outcomes, or overall mortality. CONCLUSIONS: In the first month of genotype-guided warfarin therapy, compared with standard dosing, there were no improvements in % TTR, INR > 4.0, major or minor bleeding, thromboembolism, or all-cause mortality. There was a shorter TMD, and, after 1 month, improved % TTR and major bleeding incidence, making this a cost-effective strategy in patients requiring longer anticoagulation therapy. PMID- 25811983 TI - Extended thymectomy including lung-sparing pleurectomy for the treatment of thymic malignancies with pleural spread. AB - OBJECTIVE: To investigate the outcome of extended thymectomy including lung sparing pleurectomy (extended surgery) in primary clinically advanced Masaoka Koga stage IVa thymic malignancies. PATIENTS AND METHODS: Thirteen patients diagnosed with thymic malignancies at primary clinically Masaoka-Koga stage IVa were retrospectively analyzed between January 2000 and December 2012 at the Department of Thoracic Surgery, Dr. Horst Schmidt Klinik, Wiesbaden. Chi-square tests, Kaplan-Meier analyses, log-rank tests, and Cox regression analyses were used to estimate survival and determine prognosticators of survival. RESULTS: World Health Organization (WHO) classification were type C (n = 6), type B3 (n = 5), and type AB (n = 2), respectively. Nine patients underwent extended surgery. Morbidity was observed in three patients (33%). Mortality occurred in one patient. Four patients (31%) were unresectable at the time of surgery and underwent chemoradiation. Despite the clinically staging, five patients had lymph node metastases and thus pathologic Masaoka-Koga stage IVb. Median survival (MS) for all patients was 49 months. Extended surgery (MS 89 months) was associated with prolonged survival compared with patients who underwent only chemoradiation (MS 5 months). Stage migration due to lymph node metastases, WHO-classification type C, and T3/4-status were associated with inferior survival in the univariate analysis. Extended surgery remained the only independent significant prognosticator in the multivariate analysis. CONCLUSION: Extended surgery within multimodality treatments might offer survival advantage for advanced thymic malignancies with pleural spread. Patients with lymph node metastases and WHO classification type C might be at high risk of unresectability. PMID- 25811985 TI - Famous face recognition, face matching, and extraversion. AB - It has been previously established that extraverts who are skilled at interpersonal interaction perform significantly better than introverts on a face specific recognition memory task. In our experiment we further investigate the relationship between extraversion and face recognition, focusing on famous face recognition and face matching. Results indicate that more extraverted individuals perform significantly better on an upright famous face recognition task and show significantly larger face inversion effects. However, our results did not find an effect of extraversion on face matching or inverted famous face recognition. PMID- 25811984 TI - S100A8/A9 stimulates keratinocyte proliferation in the development of squamous cell carcinoma of the skin via the receptor for advanced glycation-end products. AB - Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR. PMID- 25811987 TI - Cooperative coupling of cyanine and tictoid twisted pi-systems to amplify organic chromophore cubic nonlinearities. AB - We report a new class of hybrid pi-electron chromophores with a large, sign tunable third-order nonlinear optical (NLO) response, achieved via cooperative coupling of cyanine dye bond-length alternation effects with the rich density of states in zwitterionic twisted pi-system chromophores. A combined synthetic, linear/nonlinear spectroscopic, and quantum chemical study reveals exceptional third-order response exceeding the sum of the individual chromophore contributions. PMID- 25811986 TI - Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption. AB - Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficient osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10 deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, is thought to occur due to the inability of the osteoclasts to maintain normal calcium-phosphorus homeostasis. However, osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized. We conclude that tissue specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake. PMID- 25811988 TI - How many separable sources? Model selection in independent components analysis. AB - Unlike mixtures consisting solely of non-Gaussian sources, mixtures including two or more Gaussian components cannot be separated using standard independent components analysis methods that are based on higher order statistics and independent observations. The mixed Independent Components Analysis/Principal Components Analysis (mixed ICA/PCA) model described here accommodates one or more Gaussian components in the independent components analysis model and uses principal components analysis to characterize contributions from this inseparable Gaussian subspace. Information theory can then be used to select from among potential model categories with differing numbers of Gaussian components. Based on simulation studies, the assumptions and approximations underlying the Akaike Information Criterion do not hold in this setting, even with a very large number of observations. Cross-validation is a suitable, though computationally intensive alternative for model selection. Application of the algorithm is illustrated using Fisher's iris data set and Howells' craniometric data set. Mixed ICA/PCA is of potential interest in any field of scientific investigation where the authenticity of blindly separated non-Gaussian sources might otherwise be questionable. Failure of the Akaike Information Criterion in model selection also has relevance in traditional independent components analysis where all sources are assumed non-Gaussian. PMID- 25811989 TI - Gene-based association analysis identified novel genes associated with bone mineral density. AB - Genetic factors contribute to the variation of bone mineral density (BMD), which is a major risk factor of osteoporosis. The aim of this study was to identify more "novel" genes for BMD. Based on the publicly available SNP-based P values, we performed an initial gene-based analysis in a total of 32,961 individuals. Furthermore, we performed differential expression, pathway and protein-protein interaction analyses to find supplementary evidence to support the significance of the identified genes. About 21,695 genes for femoral neck (FN)-BMD and 21,683 genes for lumbar spine (LS)-BMD were analyzed using gene-based association analysis. A total of 35 FN-BMD associated genes and 53 LS-BMD associated genes were identified (P < 2.3*10(-6)) after Bonferroni correction. Among them, 64 genes have not been reported in previous SNP-based genome-wide association studies. Differential expression analysis further supported the significant associations of 14 genes with FN-BMD and 19 genes with LS-BMD. Especially, WNT3 and WNT9B in the Wnt signaling pathway for FN-BMD were further supported by pathway analysis and protein-protein interaction analysis. The present study took the advantage of gene-based association method to perform a supplementary analysis of the GWAS dataset and found some BMD-associated genes. The evidence taken together supported the importance of Wnt signaling pathway genes in determining osteoporosis. Our findings provided more insights into the genetic basis of osteoporosis. PMID- 25811990 TI - Genotype-phenotype correlation in Chinese patients with spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive motor neuron disease characterized by slowly progressive weakness and atrophy of proximal limbs and bulbar muscles. To assess the genotype-phenotype correlation in Chinese patients, we identified 155 patients with SBMA and retrospectively examined available data from laboratory tests and neurophysiological analyses. Correlations between genotype and phenotype were analyzed. There was an inverse correlation between the length of CAG repeats and age at first muscle weakness (p<0.0001). The serum creatine kinase level showed a significant inverse correlation with disease duration and the age at examination (p=0.019 and p=0.004, respectively). Unlike previous classification of motor- and sensory dominant phenotypes, all findings of nerve conduction, except the amplitudes of median nerve compound motor action potential, were positively correlated to the length of CAG repeats. A significant decline in sensory nerve action potential amplitudes may assist differential diagnosis of SBMA. PMID- 25811993 TI - Correction: CD4+CD25hiFOXP3+ cells in cord blood of neonates born from filaria infected mother are negatively associated with CD4+Tbet+ and CD4+RORgammat+ T cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0114630.]. PMID- 25811994 TI - Correction: Microbial stimulation and succession following a test well injection simulating CO2 leakage into a shallow Newark basin aquifer. PMID- 25811992 TI - Acetylbritannilactone Modulates MicroRNA-155-Mediated Inflammatory Response in Ischemic Cerebral Tissues. AB - Inflammatory responses play a critical role in ischemic brain injury. MicroRNA 155 (miR-155) induces the expression of inflammatory cytokines, and acetylbritannilactone (ABL) exerts potent antiinflammatory actions by inhibiting expression of inflammation-related genes. However, the functions of miR-155 and the actual relationship between ABL and miR-155 in ischemia-induced cerebral inflammation remain unclear. In this study, cerebral ischemia of wild-type (WT) and miR-155(-/-) mice was induced by permanent middle cerebral artery occlusion (MCAO). pAd-miR-155 was injected into the lateral cerebral ventricle 24 h before MCAO to induce miR-155 overexpression. MCAO mice and oxygen-glucose deprivation (OGD)-treated BV2 cells were used to examine the effects of ABL and miR-155 overexpression or deletion on the expression of proinflammatory cytokines. We demonstrated that ABL treatment significantly reduced neurological deficits and cerebral infarct volume by inhibiting tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) expression in ischemic cerebral tissue and OGD treated BV2 cells. Mechanistic studies suggested that the observed decrease in TNF-alpha and IL-1beta expression was attributable to the ABL-induced suppression of the expression of nuclear factor-kappa B (NF-kappaB) and Toll-like receptor 4 (TLR4). We further found that miR-155 promoted TNF-alpha and IL-1beta expression by upregulating TLR4 and downregulating the expression of suppressor of cytokine signaling 1 (SOCS1) and myeloid differentiation primary response gene 88 (MyD88), while ABL exerted an inhibitory effect on miR-155-mediated gene expression. In conclusion, miR-155 mediates inflammatory responses in ischemic cerebral tissue by modulating TLR4/MyD88 and SOCS1 expression, and ABL exerts its antiinflammatory action by suppressing miR-155 expression, suggesting a novel miR 155-based therapy for ischemic stroke. PMID- 25811991 TI - Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing. AB - Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression. PMID- 25811997 TI - Optimization of covalent immobilization of Trichoderma reesei cellulase onto modified ReliZyme HA403 and Sepabeads EC-EP supports for cellulose hydrolysis, in buffer and ionic liquids/buffer media. AB - The covalent immobilization of Trichoderma reesei cellulase onto modified ReliZyme HA403 and Sepabeads EC-EP supports were carried out. The optimal immobilization conditions were determined using response surface methodology. The hydrolysis of cellulose using the free and immobilized cellulase preparations in ionic liquids (IL) using cosolvents was investigated. The hydrolytic activities in buffer medium containing 25% (v/v) of 1-butyl-3-methylimidazolium hexafluorophosphate were around 2.6-, 1.6-, and 5.5-fold higher than the activities in buffer medium. The retained initial activities were 32% and 57%, respectively for cellulase preparations immobilized onto Sepabeads EC-EP support and onto modified ReliZyme HA403 support after 5 reuses. PMID- 25811996 TI - Wear testing of moderate activities of daily living using in vivo measured knee joint loading. AB - Resumption of daily living activities is a basic expectation for patients provided with total knee replacements. However, there is a lack of knowledge regarding the impact of different activities on the wear performance. In this study the wear performance under application of different daily activities has been analyzed. In vivo load data for walking, walking downstairs/upstairs, sitting down/standing up, and cycling (50 W & 120 W) has been standardized for wear testing. Wear testing of each activity was carried out on a knee wear simulator. Additionally, ISO walking was tested for reasons of comparison. Wear was assessed gravimetrically and wear particles were analyzed. In vivo walking produced the highest overall wear rates, which were determined to be three times higher than ISO walking. Moderate wear rates were determined for walking upstairs and downstairs. Low wear rates were determined for standing up/sitting down and cycling at power levels of 50 W and 120 W. The largest wear particles were observed for cycling. Walking based on in vivo data has been shown to be the most wear-relevant activity. Highly demanding activities (stair climbing) produced considerably less wear. Taking into account the expected number of loads, low impact activities like cycling may have a greater impact on articular wear than highly demanding activities. PMID- 25811995 TI - Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. AB - The present study evaluated the influence of hyperandrogenism on oocyte quality using a murine PCOS model induced by dehydroepiandrosterone (DHEA) and further explored the effect of metformin treatment. Female BALB/c mice were treated with a vehicle control or DHEA (6 mg /100 g body weight) or DHEA plus metformin (50 mg /100 g body weight) for 20 consecutive days. DHEA-induced mice resembled some characters of human PCOS, such as irregular sexual cycles and polycystic ovaries. After the model validation was completed, metaphase II (MII) oocytes were retrieved and subsequent analyses of oocyte quality were performed. DHEA-treated mice yielded fewer MII oocytes, which displayed decreased mtDNA copy number, ATP content, inner mitochondrial membrane potential, excessive oxidative stress and impaired embryo development competence compared with those in control mice. Metformin treatment partially attenuated those damages, as evidenced by the increased fertilization and blastocyst rate, ATP content, GSH concentration and GSH/GSSG ratio, and decreased reactive oxygen species levels. No significant difference in normal spindle assembly was observed among the three groups. During in vitro maturation (IVM), the periods of germinal vesicle breakdown (GVBD) and the first polar body (PB1) extrusion were extended and the maturation rate of GVBD oocytes was decreased in DHEA mice compared with controls. Metformin treatment decreased the time elapsed of GVBD while had no effect on PB1 extrusion. These results indicated that excessive androgen is detrimental to oocyte quality while metformin treatment is, directly or indirectly, beneficial for oocyte quality improvement. PMID- 25811998 TI - Artificial tissue sensitized with encapsulated methylene blue encapsulated by silica nanoparticles in photodynamic therapy. AB - BACKGROUND/AIMS: The synthesis of methylene blue (MB) encapsulated in silica nanoparticles (SiNPs) as an application for photodynamic therapy is reported in this study. Semi-rigid tissues with optical properties similar to that of human tissues were used as sample materials to determine the applicability of MB encapsulated in SiNPs. MATERIALS AND METHODS: The changes in optical properties of the tissue treated with encapsulated MB under light exposure (Intensity at 664 nm ~11.9 mW/cm(2)) were observed. The optimal exposure time required for naked MB and MB-SiNP to destroy red blood cells (RBCs) in the artificial tissue was also determined. RESULTS: The comparative analysis between the results of applying naked MB and MB encapsulated in SiNPs in the treatment of artificial tissue confirmed that the encapsulated MB is 62 percent higher in efficacy than naked MB. The results established the applicability of MB encapsulated in SiNP on artificial tissue and possible application on human tissue. PMID- 25811999 TI - Swelling, mechanical strength, and release properties of probucol microcapsules with and without a bile acid, and their potential oral delivery in diabetes. AB - We have demonstrated a permeation-enhancing effect of deoxycholic acid (DCA), the bile acid, in diabetic rats. In this study, we designed DCA-based microcapsules for the oral delivery of the antilipidemic drug probucol (PB), which has potential antidiabetic effects. We aimed to further characterize these microcapsules and examine their pH-dependent release properties, as well as the effects of DCA on their stability and mechanical strength at various pH and temperature values. Using the polymer sodium alginate (SA), we prepared PB-SA (control) and PB-DCA-SA (test) microcapsules. The microcapsules were examined for drug content, size, surface composition, release, Micro-CT cross-sectional imaging, stability, Zeta potential, mechanical strength, and swelling characteristics at different pH and temperature values. The microencapsulation efficiency and production yield were also examined. The addition of DCA resulted in microcapsules with a greater density and with reduced swelling at a pH of 7.8 and at temperatures of 25 degrees C and 37 degrees C (p < 0.01). The size, surface composition, production yield, and microencapsulation efficiency of the microcapsules remained similar after DCA addition. PB-SA microcapsules produced multiphasic PB release, while PB-DCA-SA microcapsules produced monophasic PB release, suggesting more controlled PB release in the presence of DCA. The PB-DCA SA microcapsules showed good stability and a pH-sensitive uniphasic release pattern, which may suggest potential applications in the oral delivery of PB in diabetes. PMID- 25812000 TI - Polymerized human placenta hemoglobin improves resuscitative efficacy of hydroxyethyl starch in a rat model of hemorrhagic shock. AB - This study was designed to investigate whether resuscitation with polymerized human placenta hemoglobin (PolyPHb) extended survival and the efficacy of hydroxyethyl starch (HES) in a rat model of hemorrhagic shock. After withdrawal of 39 ml of blood/kg, rats were randomly resuscitated with PolyPHb/HES or HES alone. Systemic, hemodynamic, and blood gas parameters, tissue oxygenation, and plasma erythropoietin (EPO) were evaluated. The results showed that resuscitation with PolyPHb/HES doubled the survival rate and maintained relatively high blood pressure and tissue oxygenation when compared with the results obtained using HES 130 alone. It is concluded that infusion of PolyPHb improves the resuscitative efficacy of HES in the present experimental conditions. PMID- 25812001 TI - Vascular endothelial growth factor 165-transfected adipose-derived mesenchymal stem cells promote vascularization-assisted fat transplantation. AB - OBJECTIVE: To investigate the effect of vascular endothelial growth factor 165 (VEGF165) and adipose-derived mesenchymal stem cells (ASCs) in promoting the survival of fat grafts, and to provide new methods and theoretical evidence for increasing the survival rate of autologous fat particle grafts. METHODS: The VEGF165 gene was recombined with the target fragment, and the recombinant gene was introduced into adenovirus pAdEasy-1 system; the virus was then packaged and the titer was detected. The control group received the same processing. ASCs were cultured and subcultured, and then identified with immunohistochemistry and adipogenic differentiation assay. The subsequent experiments were performed in three groups: the VEGF165 gene-virus group, blank virus group, and control group. After the viral solution was transfected into the ASCs, the viral transfection efficiency was detected using a tracing factor, EGFP. The expression of VEGF165 mRNA and protein in the transfected cells were determined. The proliferation of ASCs in each group was detected with the MTT assay. RESULTS: (1) Recombinant adenoviral vector was constructed successfully in the two groups and the packaging was identified. The viral titer was 2.0 * 10(8) pfu/ml and 1.9 * 10(8) pfu/ml, which was in line with the requirements of the subsequent transfection experiments. (2) Immunohistochemistry and adipogenic differentiation results showed that the culture of ASCs was successful, and the cultured cells could serve as seed cells in this experiment. (3) The RT-PCR analysis showed that the relative optical density of VEGF165 mRNA expression was 0.76 +/- 0.05 in the experimental group, and there were statistically significant differences compared with the values obtained for the other two groups (P < 0.05). (4) The western blot analysis showed that the relative optical density of VEGF165 protein expression in the experimental group was significantly higher than that in the other two groups (P < 0.05). (5) The proliferation of ASCs was significantly enhanced after transfection in the experimental group, relative to the other two groups (P < 0.05). This evidence indicated that VEGF165 significantly promoted the proliferation of ASCs. CONCLUSION: After transfection with the VEGF165 adenoviral vector, ASCs demonstrate sustained expression of the target protein and obviously promote the proliferation of ASCs, which lay the foundation for the in vitro experiments on transplantation of VEGF165 combined with ASCs, for the treatment of tissue defects. PMID- 25812003 TI - Response to "comment on 'structural determinants of drug partitioning in surrogates of phosphatidylcholine bilayer strata'". AB - We used the solvatochromic correlation to explain the influence of characteristics of studied compounds on the partition coefficients (P) measured using n-hexadecane (C16) and the novel headgroup surrogate (diacetyl phosphatidylcholine, DAcPC), and compared them with those in other systems, including the C16/water (W) system. The comment analyzes why our correlation for the C16/W system has the standard deviation (SD) higher than that published previously. The main reason is that in our, much smaller, data set the measured P values are complemented by the P values predicted by a reliable, unrelated method. We believe that this approach is acceptable for the aforementioned comparison. We did not use just experimental values, as suggested in the comment, because the solvatochromic correlation, although exhibiting 35% reduction in the SD, was accompanied by a sign change of one of the regression coefficients. The recommended use of special solvatochromic solute characteristics for a few compounds and replacement of a predicted PC16/W value by the experimental value resulted in improved correlations. The observed differences between our correlation and those published in the comment and in a previous article do not affect our main conclusions regarding the solvation of solutes in the surrogates (DAcPC and C16) of intrabilayer strata. PMID- 25812004 TI - Strongly stretched protein resistant poly(ethylene glycol) brushes prepared by grafting-to. AB - We present a new grafting-to method for resistant "non-fouling" poly(ethylene glycol) brushes, which is based on grafting of polymers with reactive end groups in 0.9 M Na2SO4 at room temperature. The grafting process, the resulting brushes, and the resistance toward biomolecular adsorption are investigated by surface plasmon resonance, quartz crystal microbalance, and atomic force microscopy. We determine both grafting density and thickness independently and use narrow molecular weight distributions which result in well-defined brushes. High density (e.g., 0.4 coils per nm(2) for 10 kDa) and thick (40 nm for 20 kDa) brushes are readily achieved that suppress adsorption from complete serum (10* dilution, exposure for 50 min) by up to 99% on gold (down to 4 ng/cm(2) protein coverage). The brushes outperform oligo(ethylene glycol) monolayers prepared on the same surfaces and analyzed in the same manner. The brush heights are in agreement with calculations based on a simple model similar to the de Gennes "strongly stretched" brush, where the height is proportional to molecular weight. This result has so far generally been considered to be possible only for brushes prepared by grafting-from. Our results are consistent with the theory that the brushes act as kinetic barriers rather than efficient prevention of adsorption at equilibrium. We suggest that the free energy barrier for passing the brush depends on both monomer concentration and thickness. The extraordinary simplicity of the method and good inert properties of the brushes should make our results widely applicable in biointerface science. PMID- 25812002 TI - Positive role of promyelocytic leukemia protein in type I interferon response and its regulation by human cytomegalovirus. AB - Promyelocytic leukemia protein (PML), a major component of PML nuclear bodies (also known as nuclear domain 10), is involved in diverse cellular processes such as cell proliferation, apoptosis, gene regulation, and DNA damage response. PML also acts as a restriction factor that suppresses incoming viral genomes, therefore playing an important role in intrinsic defense. Here, we show that PML positively regulates type I interferon response by promoting transcription of interferon-stimulated genes (ISGs) and that this regulation by PML is counteracted by human cytomegalovirus (HCMV) IE1 protein. Small hairpin RNA mediated PML knockdown in human fibroblasts reduced ISG induction by treatment of interferon-beta or infection with UV-inactivated HCMV. PML was required for accumulation of activated STAT1 and STAT2, interacted with them and HDAC1 and HDAC2, and was associated with ISG promoters after HCMV infection. During HCMV infection, viral IE1 protein interacted with PML, STAT1, STAT2, and HDACs. Analysis of IE1 mutant viruses revealed that, in addition to the STAT2-binding domain, the PML-binding domain of IE1 was necessary for suppression of interferon beta-mediated ISG transcription, and that IE1 inhibited ISG transcription by sequestering interferon-stimulated gene factor 3 (ISGF3) in a manner requiring its binding of PML and STAT2, but not of HDACs. In conclusion, our results demonstrate that PML participates in type I interferon-induced ISG expression by regulating ISGF3, and that this regulation by PML is counteracted by HCMV IE1, highlighting a widely shared viral strategy targeting PML to evade intrinsic and innate defense mechanisms. PMID- 25812006 TI - Transthoracic echocardiography in women with preeclampsia. AB - PURPOSE OF REVIEW: Recent literature on the role of transthoracic echocardiography in the management of women with preeclampsia is reviewed with emphasis on recommendations for its use in the life-threatening complications of acute pulmonary edema, chest pain, and hemorrhage. RECENT FINDINGS: The diagnostic criteria for preeclampsia are closer to reaching international consensus with most guidelines now removing the mandatory requirement for proteinuria. Hemodynamic findings using transthoracic echocardiography in women with untreated preeclampsia include normal or increased cardiac output, normal or increased contractility, a nondilated left ventricle, diastolic dysfunction, increased pericardial effusions, and increased left ventricular mass. Echocardiography is recommended as a diagnostic and monitoring tool for acute hemodynamic complications of preeclampsia, such as acute pulmonary edema, significant arterial hypertension, and chest pain. Despite this there has been limited uptake of transthoracic electrocardiography into routine clinical practice in women with preeclampsia. SUMMARY: The role of transthoracic echocardiography in the management of women with preeclampsia is emphasized by international groups. Research into the hemodynamics in preeclampsia, which demonstrates preserved ejection fraction, and diastolic dysfunction highlights its utility and acceptability by pregnant women with preeclampsia. Training of obstetric anesthesiologists in echocardiography is necessary to enable more widespread implementation of this important technology. PMID- 25812005 TI - Transfusion and coagulation management in major obstetric hemorrhage. AB - PURPOSE OF REVIEW: Major obstetric hemorrhage is a leading cause of maternal morbidity and mortality. We will review transfusion strategies and the value of monitoring the maternal coagulation profile during severe obstetric hemorrhage. RECENT FINDINGS: Epidemiologic studies indicate that rates of severe postpartum hemorrhage (PPH) in well resourced countries are increasing. Despite these increases, rates of transfusion in obstetrics are low (0.9-2.3%), and investigators have questioned whether a predelivery 'type and screen' is cost effective for all obstetric patients. Instead, blood ordering protocols specific to obstetric patients can reduce unnecessary antibody testing. When severe PPH occurs, a massive transfusion protocol has attracted interest as a key therapeutic resource by ensuring sustained availability of blood products to the labor and delivery unit. During early postpartum bleeding, recent studies have shown that hypofibrinogenemia is an important predictor for the later development of severe PPH. Point-of-care technologies, such as thromboelastography and rotational thromboelastometry, can identify decreased fibrin clot quality during PPH, which correlate with low fibrinogen levels. SUMMARY: A massive transfusion protocol provides a key resource in the management of severe PPH. However, future studies are needed to assess whether formula-driven vs. goal-directed transfusion therapy improves maternal outcomes in women with severe PPH. PMID- 25812007 TI - Computer-generated ovaries to assist follicle counting experiments. AB - Precise estimation of the number of follicles in ovaries is of key importance in the field of reproductive biology, both from a developmental point of view, where follicle numbers are determined at specific time points, as well as from a therapeutic perspective, determining the adverse effects of environmental toxins and cancer chemotherapeutics on the reproductive system. The two main factors affecting follicle number estimates are the sampling method and the variation in follicle numbers within animals of the same strain, due to biological variability. This study aims at assessing the effect of these two factors, when estimating ovarian follicle numbers of neonatal mice. We developed computer algorithms, which generate models of neonatal mouse ovaries (simulated ovaries), with characteristics derived from experimental measurements already available in the published literature. The simulated ovaries are used to reproduce in-silico counting experiments based on unbiased stereological techniques; the proposed approach provides the necessary number of ovaries and sampling frequency to be used in the experiments given a specific biological variability and a desirable degree of accuracy. The simulated ovary is a novel, versatile tool which can be used in the planning phase of experiments to estimate the expected number of animals and workload, ensuring appropriate statistical power of the resulting measurements. Moreover, the idea of the simulated ovary can be applied to other organs made up of large numbers of individual functional units. PMID- 25812010 TI - In situ fabrication of a perfect Pd/ZnO@ZIF-8 core-shell microsphere as an efficient catalyst by a ZnO support-induced ZIF-8 growth strategy. AB - Controllable encapsulation of nanoparticles with metal organic frameworks (MOFs) has been an efficient way to impart the unique chemical and physical properties of the nanoparticles to metal organic frameworks and create new types of multifunctional MOF core-shell materials with enhanced properties. Here, a novel ZnO support-induced encapsulation strategy is reported to efficiently fabricate a Pd/ZnO@ZIF-8 core-shell catalyst, with Pd/ZnO as the core and ZIF-8 as the shell. The novel synthesis procedure involves first loading Pd nanoparticles onto the surface of the ZnO microsphere to form a Pd/ZnO core and then coating the core with a layer of defect-free ZIF-8 shell via ZnO-induced in situ ZIF-8 growth to obtain the Pd/ZnO@ZIF-8 core-shell catalyst. It was crucial that the ZIF-8 was in situ formed from the ZnO core in an ethanol solution only containing 2 methylimidazole under mild conditions. This strategy allowed for the growth of ZIF-8 right on the surface of Pd/ZnO via the reaction between ZnO and the 2 methylimidazole ligands, and thus avoided the random deposition of ZIF-8 crystals on the Pd/ZnO core as in the case of the conventional ZIF-8 synthesis solution. Furthermore, use of ethanol as the solvent also favored achievement of the well defined Pd/ZnO@ZIF-8 structure, since the ethanol solution of 2-methylimidazole was able to keep the balance between ZnO dissolution and ZIF-8 formation. The as prepared Pd/ZnO@ZIF-8 core-shell microsphere as an efficient catalyst displayed excellent performance in terms of size-selectivity, stability and anti-poisoning in the liquid hydrogenations of alkenes. PMID- 25812008 TI - Serum biomarkers in patients with relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss). AB - INTRODUCTION: Previous studies suggest a role for eotaxin-3, TARC/CCL17 and IgG4 in newly-diagnosed patients with eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) with highly active disease. The role of these biomarkers in relapsing disease is unclear. METHODS: Serum levels of TARC/CCL17, eotaxin-3, IgG4, and IgG4/IgG ratio were determined in serum samples from a longitudinal cohort of patients with EGPA (105 visits of 25 patients). Epidemiological, clinical and laboratory data were available for all visits. RESULTS: At the first visit, 80% of patients were using glucocorticoids and 68% additional immunosuppressive drugs. Disease flares were seen at 18 visits. The median BVAS and BVAS/WG scores at time of relapse were 4 and 2, respectively. None of the biomarkers tested were useful to discriminate between active disease and remission. Patients treated with prednisone had lower eotaxin-3 and eosinophil levels compared to patients not taking glucocorticoids irrespective of disease activity. Use of immunosuppressive agents was not associated with biomarker levels. CONCLUSIONS: Serum levels of TARC/CCL17, eotaxin-3, IgG4, and IgG4/IgG ratio do not clearly differentiate active and inactive disease in established EGPA. Defining biomarkers in EGPA remains a challenge especially during times of glucocorticoid use. PMID- 25812011 TI - Construction of antibody-like nanoparticles for selective protein sequestration in living cells. AB - We demonstrate the successful construction of fluorescently labeled magnetic antibody-like nanoparticles (ANPs) via a facile one-step surface-initiated in situ molecular imprinting approach over silica coated magnetite (Fe3O4@SiO2) core shell nanocomposites. The as-prepared ANPs had a highly compact structure with an overall size of 83 +/- 5 nm in diameter and showed excellent aqueous dispersion stability. With the predetermined high specificity to the target protein and high biocompatibility, the ANPs enabled rapid, efficient, selective and optically trackable sequestration of target proteins within living cells. This work represents the first example of fully artificially engineered multifunctional ANPs for the intracellular protein-sequestration without disruption of the cells. The established approach may be further extended to generate ANPs for various proteins of interest and provide useful tools for related biological research and biomedical applications. PMID- 25812009 TI - The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes. AB - OBJECTIVE: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future. METHODS: All individuals are challenged with 5 mg glipizide * 1; twice daily 500 mg metformin * 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured. RESULTS: Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels. CONCLUSIONS: SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01762046. PMID- 25812013 TI - Comparative meta-analysis of tuberculosis contact investigation interventions in eleven high burden countries. AB - BACKGROUND: Screening of household contacts of tuberculosis (TB) patients is a recommended strategy to improve early case detection. While it has been widely implemented in low prevalence countries, the most optimal protocols for contact investigation in high prevalence, low resource settings is yet to be determined. This study evaluated contact investigation interventions in eleven lower and middle income countries and reviewed the association between context or program related factors and the yield of cases among contacts. METHODS: We reviewed data from nineteen first wave TB REACH funded projects piloting innovations to improve case detection. These nineteen had fulfilled the eligibility criteria: contact investigation implementation and complete data reporting. We performed a cross sectional analysis of the percentage yield and case notifications for each project. Implementation strategies were delineated and the association between independent variables and yield was analyzed by fitting a random effects logistic regression. FINDINGS: Overall, the nineteen interventions screened 139,052 household contacts, showing great heterogeneity in the percentage yield of microscopy confirmed cases (SS+), ranging from 0.1% to 6.2%). Compared to the most restrictive testing criteria (at least two weeks of cough) the aOR's for lesser (any TB related symptom) and least (all contacts) restrictive testing criteria were 1.71 (95%CI 0.94-3.13) and 6.90 (95% CI 3.42-13.93) respectively. The aOR for inclusion of SS- and extra-pulmonary TB was 0.31 (95% CI 0.15-0.62) compared to restricting index cases to SS+ TB. Contact investigation contributed between <1% and 14% to all SS+ cases diagnosed in the intervention areas. CONCLUSIONS: This study confirms that high numbers of active TB cases can be identified through contact investigation in a variety of contexts. However, design and program implementation factors appear to influence the yield of contact investigation and its concomitant contribution to TB case detection. PMID- 25812015 TI - Tandem repeat insertion in African swine fever virus, Russia, 2012. PMID- 25812012 TI - Vascular factors and multiple measures of early brain health: CARDIA brain MRI study. AB - OBJECTIVE: To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF). DESIGN: Cross-sectional brain Magnetic Resonance I (MRI) study. SETTING: Community based cohort in three U.S. sites. PARTICIPANTS: A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study. PRIMARY AND SECONDARY OUTCOMES: 3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function. RESULTS: Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01). CONCLUSION: In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia. PMID- 25812016 TI - Understanding thermosensitive transient receptor potential channels as versatile polymodal cellular sensors. AB - Transient receptor potential (TRP) ion channels are eukaryotic polymodal sensors that function as molecular cellular signal integrators. TRP family members sense and are modulated by a wide array of inputs, including temperature, pressure, pH, voltage, chemicals, lipids, and other proteins. These inputs induce signal transduction events mediated by nonselective cation passage through TRP channels. In this review, we focus on the thermosensitive TRP channels and highlight the emerging view that these channels play a variety of significant roles in physiology and pathophysiology in addition to sensory biology. We attempt to use this viewpoint as a framework to understand the complexity and controversy of TRP channel modulation and ultimately suggest that the complex functional behavior arises inherently because this class of protein is exquisitely sensitive to many diverse and distinct signal inputs. To illustrate this idea, we primarily focus on TRP channel thermosensing. We also offer a structural, biochemical, biophysical, and computational perspective that may help to bring more coherence and consensus in understanding the function of this important class of proteins. PMID- 25812017 TI - [Cu(N^N)(P^P)]+ complexes with 2,2':6',2''-terpyridine ligands as the N^N domain. AB - The first examples of [Cu(N^N)(POP)](+) complexes (POP = bis(2 (diphenylphosphino)phenyl)ether) in which the N^N domain is a 2,2':6',2'' terpyridine (tpy) ligand have been prepared and characterized; N^N = tpy, 5,5'' dimethyl-2,2':6',2''-terpyridine (1), 4'-(4-tolyl)-2,2':6',2''-terpyridine (2), 4'-(4-npropoxyphenyl)-2,2':6',2''-terpyridine (3) and 4'-(4-nbutoxyphenyl) 2,2':6',2''-terpyridine (4). In solution, the tpy domain in each [Cu(N^N)(POP)][PF6] complex is C2-symmetric, consistent with either tridentate coordination or a low energy dynamic process involving bidentate ligands; for [Cu(2)(POP)][PF6] and [Cu(4)(POP)][PF6], the (1)H NMR spectra showed negligible change between 295 and 210 K. The single crystal structures of [Cu(tpy)(POP)][PF6] and [Cu(4)(POP)][PF6] are presented. The asymmetric unit of [Cu(tpy)(POP)][PF6] contains two independent cations; in one the tpy ligand is tridentate and in the other, it is bidentate with the non-coordinated pyridine ring facing the Cu atom (Cu...N = 3.146(1) A). In contrast, the solid-state structure of [Cu(4)(POP)][PF6] features a [Cu(4)(POP)](+) cation containing a bidentate tpy-domain with the non-coordinated pyridine ring oriented with the N atom facing away from the Cu atom; this conformation may be associated with inter cation NHC non-classical hydrogen bonds. The photophysical properties of [Cu(N^N)(POP)][PF6] with N^N = tpy or 1-4 are described. In the solid state at room temperature, the compounds are poorly emissive. In solution, the emission behaviour is consistent with ligand dissociation. This is supported by (1)H and (31)P NMR spectroscopic data which show POP and [Cu(POP)2](+) in solutions of aged samples; mass spectrometric data are consistent with the formation of [Cu(N^N)2](2+) in these samples. PMID- 25812018 TI - Bilateral humeral fractures mimicking Todd's paralysis. PMID- 25812014 TI - Involvement of DNA-PKcs in the type I IFN response to CpG-ODNs in conventional dendritic cells in TLR9-dependent or -independent manners. AB - CpG-ODNs activate dendritic cells (DCs) to produce interferon alpha (IFNalpha) and beta (IFNbeta). Previous studies demonstrated that Toll-like receptor 9 (TLR9) deficient DCs exhibited a residual IFNalpha response to CpG-A, indicating that yet-unidentified molecules are also involved in induction of IFNalpha by CpG A. Here, we report that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) but not Ku70 deficient BMDCs showed defective IFNalpha and IFNbeta responses to CpG-A or CpG-B. Loss of both DNA-PKcs and TLR9 further reduced the IFNalpha response to CpG-A. These DNA-PKcs and TLR9 effects were mediated by their downstream Akt/mTORC1 pathway and downstream events IRAK1 and IKKalpha. Loss of DNA-PKcs, TLR9, MyD88 or IRAK4 impaired phosphorylation of Akt(S473), S6K, S6, IRAK1, or IKKalpha in BMDCs in response to CpG-ODNs. The residual IFNalpha and IFNbeta in DNA-PKcs-deficient BMDCs were partially responsible for the induction of IL-6 and IL-12 by CpG-ODNs and their stimulatory effect was blocked by IFNAR1 neutralizing antibodies. Further analysis indicated that CpG ODN associated with DNA-PKcs and Ku70, and induced DNA-PKcs's interaction with TRAF3. Intriguingly, DNA-PKcs but not Ku70 expression level was reduced in TLR9 deficient BMDCs. Taken together, our data suggest that DNA-PKcs is an important mediator in the type I IFN response to CpG-ODNs in TLR9-dependent or -independent fashions. PMID- 25812019 TI - Multiple intradural spinal metastases of esthesioneuroblastoma: A case report. AB - Spinal metastases from esthesioneuroblastoma (ENB) might have variable presentations. Discrete lesions, even when multiple, warrant radical excision, followed by radiotherapy. The authors present a case of anterior skull base ENB, metastasizing to spine at muliple levels. Clinical and radiological pictures are described with intraoperative findings. PMID- 25812020 TI - Bilateral flow changes after extracranial-intracranial bypass surgery in a complex setting of multiple brain-feeding arteries occlusion: The role of perfusion studies. AB - We report on a symptomatic case in which the whole intracranial blood supply was provided by a single vertebral artery as both internal carotid arteries were occluded and the contralateral vertebral artery was severely hypoplasic. The patient was treated by a flow-augmentation extracranial-intracranial bypass. Preoperative perfusion studies were essential in tailoring surgical strategy. Keypoints of the paper are contralateral perfusion changes after unilateral bypass surgery. The patient experienced a total recovery from symptoms and a bilateral improvement in brain perfusion, probably as consequence of post operative hemodynamic rearrangement. PMID- 25812021 TI - Long-term follow-up of bilateral subthalamic nucleus stimulation in Chinese Parkinson's disease patients. AB - BACKGROUND AND PURPOSE: The long-term benefits of deep bilateral brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with advanced Parkinson's disease (PD) are less well described, especially in Chinese cohorts. Here, we present a large group of Chinese PD patients treated with bilateral STN DBS. METHODS: Between 2003 and 2010, 195 consecutive PD patients received implants at the Xuanwu Hospital affiliated to the Capital Medical University in Beijing (China) for bilateral STN DBS. The mean age at implantation was 58.2 +/- 10.0 years, and they had a 5- to 15-year history of PD (mean: 6.8 years). Patients were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) at 1, 3, and 5 years, both on and off medication. RESULTS: Except for speech, patients' off-medication motor function scores at 5 years improved by 60.3% (P < 0.001) and those for activities of daily living improved by 54.2% (P < 0.001). With the exception of dyskinesia, on-medication motor function scores did not improve 1 year after surgery. On-medication akinesia, speech, postural stability, and freezing of gait worsened between years 1 and 5 (all P < 0.001). At 5 years, dopaminergic treatment dose and the duration and severity of levodopa-induced dyskinesia were reduced compared with baseline (all P < 0.001). There was one death associated with surgery to implant the STN DBS. CONCLUSIONS: PD patients who were treated with bilateral STN DBS exhibited marked motor function improvements over long-term follow-up while off medication and in dyskinesia while on medication. PMID- 25812022 TI - Intracranial extramedullary haematopoiesis: A case report. AB - Extramedullary haematopoiesis (EMH) is an ectopic production of blood cells to compensate for ineffective haematopoiesis. We report a rare symptomatic presentation of intracranial EMH and discuss its investigation and management. EMH should be considered a differential diagnosis in patients with haemoglobinopathies, haemolytic anaemias and myeloproliferative disorders, who present with symptoms of raised intracranial pressure. PMID- 25812023 TI - The diffusion-weighted imaging and 11-C-methionine positron emission tomography depiction of an endodermal cyst at the cervico-medullary junction. AB - A case of a 52-year-old male with left-sided neck pain, vertigo and gait instability is reported. A MRI scan revealed an intra-dural mass at the cervico medullary junction, further characterised by diffusion-weighted imaging and 11-C methionine positron emission tomography. Pathological diagnosis was endodermal cyst. The clinico-surgical relevance of the imaging findings is discussed. PMID- 25812025 TI - Need for studies to evaluate the role of endoscopic third ventriculostomy for post-operative hydrocephalus in Chiari I malformation. PMID- 25812024 TI - Acute and subacute effects of the ultrasonic blade and electrosurgery on nerve physiology. AB - Ultrasonic blades have been shown to cause less acute electrophysiological damage when applied near nerves than monopolar electrosurgery (ES). This study was performed to determine whether the acute nerve damage observed for ES, as well as the relative lack of damage observed for ultrasonic dissection, extends through a subacute timeframe. Muscle incisions were made in rat with the Harmonic((r)) Blade (HB) and ES at a distance of 2 mm from the sciatic nerve. Sham surgery was also performed which consisted of similar exposure of the sciatic nerve without use of an energized device. Electrophysiological function was assessed acutely over a 3-h period, and subacutely after a 7-day survival, by monitoring the sciatic nerve compound action potential (CAP), conduction velocity (CV), von Frey hair (VFH) stimulation force, leukocyte infiltration, and impaired axonal transport via beta-amyloid precursor protein (beta-APP) immunocytochemistry. During the acute period, ES produced significantly lower CAP and CV, and higher levels of leukocytes and beta-APP than sham, whereas the ultrasonic blade was not significantly different from sham, and had significantly lower VFH force than ES. After the subacute survival, ES continued to display significantly lower CAP and CV, and higher levels of leukocytes and beta-APP than sham, whereas ultrasonic blade had higher CAP and CV than sham, and lower VFH than ES. This study confirms that incisions made with an ultrasonic blade cause less acute nerve damage than monopolar ES, and are comparable to sham surgery at a distance of 2 mm from the sciatic nerve. The negative effects of electrosurgery extend through at least a 7 day survival period, whereas subacute recovery after application of the ultrasonic blade was comparable to that of sham surgery. For surgical procedures in the vicinity of vital nerves, use of the ultrasonic blade represents a lower risk than ES for both acute and subacute neural trauma. PMID- 25812026 TI - Change from the inside out: health care leaders taking the helm. PMID- 25812027 TI - Quantitative performance of internal standard platforms for absolute protein quantification using multiple reaction monitoring-mass spectrometry. AB - Stable-isotope-labeling mass spectrometry involves the addition of known quantities of stable-isotope labeled standards, which mimic native molecules, to biological samples. We evaluated three conventional internal standard platforms (synthetic peptides, QconCAT constructs, and recombinant proteins) for quantitative accuracy, precision, and inherent advantages and limitations. Internal standards for the absolute quantification of three human cytokine proteins (interferon gamma, interleukin-1 beta, and tumor necrosis factor alpha) were designed and verified. Multiple reaction monitoring assays, calibration curve construction, and regression analysis were used to assess quantitative performance of the internal standard platforms. We also investigated a strategy for methodological improvement to current platforms using natural flanking sequences. Data analysis revealed that full length protein standards have the broadest quantitative reliability with accuracy being peptide-dependent for QconCATs and synthetic peptides. Natural flanking sequences greatly improved the quantitative performance of both QconCAT and synthetic peptide standards. PMID- 25812028 TI - Triazolopyridopyrimidines: an emerging family of effective DNA photocleavers. DNA binding. Antileishmanial activity. AB - Triazolopyridopyrimidines 3-phenyl-6,8-di(2-pyridyl) [1,2,3]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine (1a), 6,8-di(pyridin-2-yl) [1,2,3]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (1b) and 3-methyl-6,8-di(2 pyridyl)-[1,2,3]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine (1c) were prepared and their electrochemical and luminescence properties were studied in depth. The DNA binding ability of this series of compounds has been investigated by means of UV vis absorption and fluorescence titrations, steady-state emission quenching with ferrocyanide as well as viscosity measurements. Results have shown that triazolopyridopyrimidine 1a interacts strongly at DNA grooves. This compound also displays preferential binding to GC-rich sequences and the ability to photooxidize guanine. Moreover, these studies have revealed the key role of the phenyl substituent at the triazole ring in the binding affinity of 1a-c. Compounds 1b and 1c did not show appreciable propensity for DNA binding, however these triazolopyridopyrimidines demonstrated to present photoinduced DNA cleavage activity, 1b being more active than 1c. DNA photocleavage mediated by these compounds takes place mainly through single strand scission events and, in a minor extent, through double strand cuts. Mechanistic investigations using radical scavengers showed that both 1b and 1c generate reactive oxygen species (singlet oxygen, superoxide and hydroxyl radicals) upon irradiation. Both type I and type II mechanisms are involved in the photocleavage process. Furthermore, compounds 1a-c were tested for their antiprotozoal activity against four different Leishmania spp. (L. infantum, L. braziliensis, L. guyanensis and L. amazonensis). Triazolopyridopyrimidines 1a and 1c resulted to be more active and selective than the reference drug (miltefosine) in vitro against L. infantum amastigotes. Compound 1a exhibited high leishmanicidal activity against L. infantum spleen forms in the in vivo test. PMID- 25812029 TI - Femoral head volume indicates the severity of developmental dysplasia of the hip by a method using three-dimensional magnetic resonance imaging. AB - The aims of this study were to quantify the femoral head volume (FHV) in developmental dysplasia of the hip (DDH) and to estimate its relation with the severity of the disease. Fifty-one patients (age range 2-11 months) with unilateral DDH were evaluated using three-dimensional MRI. The relation among FHV, age, severity, and displacement was investigated. The affected FHV gradually decreased according to severity. Cephalad displacement of the femoral head correlated negatively with FHV. This new approach showed severity-dependent growth disturbance of the femoral head. This quantification is a promising technique for understanding the pathology of DDH. PMID- 25812030 TI - Surgical treatment of active or aggressive aneurysmal bone cysts in children. AB - The aim of this study was to evaluate functional and radiological results, tumor control, and complications of the surgical treatment of aneurysmal bone cysts (ABCs) in children by extended curettage using a mechanical burr and cauterization, grafting, and internal fixation in specific locations. Sixty-four children [38 males, 26 females, median age=10 years (range, 5-18 years)] with active or aggressive ABCs of long and flat bones were subjected to a median follow-up of 66 months (range, 28-130 months) following surgical treatment. The pathological fracture rate was 72%. Surgical procedures included intralesional extended curettage (92%) or en-bloc resection (8%). Internal fixation was required in 53%. The pathological fractures healed successfully in 8-12 weeks. The median Musculoskeletal Tumor Society (MSTS) score at the last follow-up was 95% (range, 55-100%). Treatment failure (partial healing/recurrence) and complication rates following extended curettage were 7 and 5.2%, respectively. Statistically, the only parameter affecting partial healing and local recurrence was proximity of the lesion to the growth plate (P=0.011). Extended curettage using a mechanical burr and cauterization, grafting, and internal fixation in specific locations can promote healing in most cases of ABC, with low recurrence and complication rates. PMID- 25812031 TI - Closed reduction of slipped capital femoral epiphysis: high-risk factor for avascular necrosis. AB - How should we treat acute/unstable slipped capital femoral epiphysis (SCFE) without the development of avascular necrosis (AVN)? To answer this question, we investigated the risk factors of AVN development after SCFE. Seventy-six hips of 64 patients were classified using two kinds of classification systems, Loder's classification based on instability and the conventional classification based on the duration of symptom, because both classifications are related to AVN development. Of 21 unstable SCFEs, seven hips developed AVN. Of 35 hips defined as acute or acute on chronic, nine hips developed AVN. Two stable SCFEs of Loder's classification developed AVN, one was acute and the other was acute on chronic. No hips of chronic SCFE developed AVN. The factor that had influenced AVN development was only closed reduction, whether purposefully or inadvertently, in an acute or unstable SCFE. On the basis of the findings of this study, one should not embark on any modality of closed reduction for an unstable or acute form of SCFE, as there is a high risk for occurrence of AVN. For the same reason, a traction table should not be used for SCFE fixation, so as to avoid an inadvertent reduction or force that can lead to AVN. PMID- 25812032 TI - Correction: Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease. PMID- 25812035 TI - Unveiling the structure of polytetraruthenated nickel porphyrin by Raman spectroelectrochemistry. AB - The structure of polytetraruthenated nickel porphyrin was unveiled for the first time by electrochemistry, Raman spectroelectrochemistry, and a hydroxyl radical trapping assay. The electrocatalytic active material, precipitated on the electrode surface after successive cycling of [NiTPyP{Ru(bipy)2Cl}4](4+) species in strong aqueous alkaline solution (pH 13), was found to be a peroxo-bridged coordination polymer. The electropolymerization process involves hydroxyl radicals (as confirmed by the characteristic set of DMPO/(*)OH adduct EPR peaks) as reaction intermediates, electrocatalytically generated in the 0.80-1.10 V range, that induce the formation of Ni-O-O-Ni coordination polymers, as evidenced by Raman spectroelectrochemistry and molecular modeling studies. The film growth is halted above 1.10 V due to the formation of oxygen gas bubbles. PMID- 25812034 TI - Sulfated steroid-amino acid conjugates from the Irish marine sponge Polymastia boletiformis. AB - Antifungal bioactivity-guided fractionation of the organic extract of the sponge Polymastia boletiformis, collected from the west coast of Ireland, led to the isolation of two new sulfated steroid-amino acid conjugates (1 and 2). Extensive 1D and 2D NMR analyses in combination with quantum mechanical calculations of the electronic circular dichroism (ECD) spectra, optical rotation, and 13C chemical shifts were used to establish the chemical structures of 1 and 2. Both compounds exhibited moderate antifungal activity against Cladosporium cucumerinum, while compound 2 was also active against Candida albicans. Marine natural products containing steroidal and amino acid constituents are extremely rare in nature. PMID- 25812033 TI - Bioactive secondary metabolites from the Red Sea marine Verongid sponge Suberea species. AB - In a continuation of our efforts to identify bioactive compounds from Red Sea Verongid sponges, the organic extract of the sponge Suberea species afforded seven compounds including two new dibrominated alkaloids, subereamollines C and D (1 and 2), together with the known compounds aerothionin (3), homoaerothionin (4), aeroplysinin-1 (5), aeroplysinin-2 (6) and a revised subereaphenol C (7) as ethyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate. The structures of the isolated compounds were assigned by different spectral data including optical rotations, 1D (1H and 13C) and 2D (COSY, multiplicity-edited HSQC, and HMBC) NMR and high resolution mass spectroscopy. Aerothionin (3) and subereaphenol C (7) displayed potent cytotoxic activity against HeLa cell line with IC50 values of 29 and 13.3 uM, respectively. In addition, aeroplysinin-2 (6) showed potent antimigratory activity against the human breast cancer cell line MDA-MB-231 with IC50 of 18 uM. Subereamollines C and D are new congeners of the previously reported compounds subereamollines A and B with methyl ester functionalities on the side chain. These findings provide further insight into the biosynthetic capabilities of members of the genus Suberea and the chemical diversity as well as the biological activity of these compounds. PMID- 25812036 TI - Environmental applications of graphene-based nanomaterials. AB - Graphene-based materials are gaining heightened attention as novel materials for environmental applications. The unique physicochemical properties of graphene, notably its exceptionally high surface area, electron mobility, thermal conductivity, and mechanical strength, can lead to novel or improved technologies to address the pressing global environmental challenges. This critical review assesses the recent developments in the use of graphene-based materials as sorbent or photocatalytic materials for environmental decontamination, as building blocks for next generation water treatment and desalination membranes, and as electrode materials for contaminant monitoring or removal. The most promising areas of research are highlighted, with a discussion of the main challenges that we need to overcome in order to fully realize the exceptional properties of graphene in environmental applications. PMID- 25812037 TI - Genetic divergence in domesticated and non-domesticated gene regions of barley chromosomes. AB - Little is known about the genetic divergence in the chromosomal regions with domesticated and non-domesticated genes. The objective of our study is to examine the effect of natural selection on shaping genetic diversity of chromosome region with domesticated and non-domesticated genes in barley using 110 SSR markers. Comparison of the genetic diversity loss between wild and cultivated barley for each chromosome showed that chromosome 5H had the highest divergence of 35.29%, followed by 3H, 7H, 4H, 2H, 6H. Diversity ratio was calculated as (diversity of wild type - diversity of cultivated type)/diversity of wild type*100%. It was found that diversity ratios of the domesticated regions on 5H, 1H and 7H were higher than those of non-domesticated regions. Diversity ratio of the domesticated region on 2H and 4H is similar to that of non-domesticated region. However, diversity ratio of the domesticated region on 3H is lower than that of non-domesticated region. Averaged diversity among six chromosomes in domesticated region was 33.73% difference between wild and cultivated barley, and was 27.56% difference in the non-domesticated region. The outcome of this study advances our understanding of the evolution of crop chromosomes. PMID- 25812039 TI - Study of the synergistic effects of all-transretinoic acid and C-phycocyanin on the growth and apoptosis of A549 cells. AB - In the present study, we investigated the effects of the combination of all transretinoic acid (ATRA) and natural nontoxic C-phycocyanin (C-PC) on the growth of A549 lung cancer cells in vitro and in vivo. Furthermore, the anticancer mechanism of the drug combination was revealed. Results showed both C-PC and ATRA could inhibit the growth of A549 cells in vivo. The combination of ATRA+C-PC could yield a higher inhibition rate. C-PC exerted a major effect on the proliferation of human embryo lung cells, but ATRA at a high concentration exerted an inhibitory effect. In addition, ATRA+C-PC could decrease the CDK4 mRNA level, but upregulated caspase-3 protein expression and induced cell apoptosis. A mouse model with tumor was constructed by a subcutaneous injection to the left axilla of nu nude (NU/NU) mice. Compared with the control group, the tumor weight was decreased in the single-drug treatment group and was the lowest in the combination group. C-PC+ATRA could upregulate tumor necrosis factor levels and downregulate Bcl-2 expression and the cyclin D1 gene in the tumor. C-PC could promote T cells' activities and spleen weight, but a single use of ATRA exerted an opposite effect. The dosage of ATRA could be reduced when combined with C-PC to reduce the toxic side-effects. In summary, the antitumor effects of the C PC+ATRA combination were more significant than a single drug in vivo and in vitro. PMID- 25812038 TI - Cervical cancer screening in Belgium and overscreening of adolescents. AB - There has been a marked decrease in the incidence of cervical cancer thanks to cytological screening with the Pap smear test. In Belgium, this screening is rather opportunistic. Over 39% of Belgian women between 25 and 64 years of age are never or only rarely screened by cytological tests. Moreover, there is an excess use of Pap smears because of women who rely on their yearly cervical smear and because many Pap smears are obtained from women beyond the target age range of 25 to 64 years. Sexually active adolescents are increasingly being recognized as a population distinct from adult women. They are at a high risk of acquiring the human papillomavirus (HPV), but most infections and cervical intraepithelial lesions caused by HPV are efficiently cleared by the immune system. We present a description of cervical cancer screening in Belgium using the database of the National Health Insurance Institute (RIZIV/INAMI) and the Belgian Health Care Knowledge Centre (KCE). We describe why elimination of Pap testing in the adolescent population reduces costs and harms without increasing cervical cancer rates. Expectant management, education on the risk factors for cervical cancer and HPV persistence, and HPV vaccination are very important in adolescents and young adults. PMID- 25812040 TI - Single nucleotide polymorphisms in the DNA repair genes in HPV-positive cervical cancer. AB - Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to the risk of cancer. The human papillomavirus is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenesis. A hereditary component for this neoplasia has been reported. Evaluation of the association of six polymorphisms was carried out in the following DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), ERCC1 (Asp118Asp), ERCC2 (Lys751Gln), and ERCC4 (Arg415Gln). The cases (n=110) included 65 squamous cell carcinomas (SCCs) and 45 squamous intraepithelial lesions (SIL). Controls (n=68) were recruited from among women without cervical abnormalities. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. A positive association was observed between the polymorphisms of XRCC1 genes, that is, in codons 194 [P=0.001, odds ratio (OR)=20.1, 95% confidence interval (CI)=5.9-68.8], 280 (P=0.001, OR=5.4, 95% CI=2.3-12.6), and 399 (P=0.008, OR=4.2, 95% CI=1.5-12.1) and cervical cancer. SIL patients also showed a significant association with codon 194 (P=0.012, OR=3.8, 95% CI=1.3-10.6), but not with 280 (P=0.35) and 399 (P=0.81). A positive correlation was also found in ERCC4 Gln415Gln in both SCCs and SILs (P=0.001, OR=21.3, 95% CI=7.1-64.0 and P=0.001, OR=7.8, 95% CI=2.9-20.9, respectively). For ERCC2 Gln751Gln, the association was significant for both SCCs (P=0.001, OR=10.1, 95% CI=2.6-37.9) and SILs (P=0.001, OR=8.9, 95% CI=2.8-28.3). However, the risk of SCC did not appear to differ significantly among individuals with the ERCC1 Asp118Asp genotype (P=0.404). For SILs, it appeared to be a protective genotype (95% CI=0.1-0.7). This study indicates that variant types of DNA repair genes play an important role in modifying individual susceptibility to SCC. PMID- 25812041 TI - Difficulties in diagnosing Marfan syndrome using current FBN1 databases. AB - PURPOSE: The diagnostic criteria of Marfan syndrome (MFS) highlight the importance of a FBN1 mutation test in diagnosing MFS. As genetic sequencing becomes better, cheaper, and more accessible, the expected increase in the number of genetic tests will become evident, resulting in numerous genetic variants that need to be evaluated for disease-causing effects based on database information. The aim of this study was to evaluate genetic variants in four databases and review the relevant literature. METHODS: We assessed background data on 23 common variants registered in ESP6500 and classified as causing MFS in the Human Gene Mutation Database (HGMD). We evaluated data in four variant databases (HGMD, UMD FBN1, ClinVar, and UniProt) according to the diagnostic criteria for MFS and compared the results with the classification of each variant in the four databases. RESULTS: None of the 23 variants was clearly associated with MFS, even though all classifications in the databases stated otherwise. CONCLUSION: A genetic diagnosis of MFS cannot reliably be based on current variant databases because they contain incorrectly interpreted conclusions on variants. Variants must be evaluated by time-consuming review of the background material in the databases and by combining these data with expert knowledge on MFS. This is a major problem because we expect even more genetic test results in the near future as a result of the reduced cost and process time for next-generation sequencing.Genet Med 18 1, 98-102. PMID- 25812042 TI - Consumers report lower confidence in their genetics knowledge following direct-to consumer personal genomic testing. AB - PURPOSE: The aim of this study was to measure changes to genetics knowledge and self-efficacy following personal genomic testing (PGT). METHODS: New customers of 23andMe and Pathway Genomics completed a series of online surveys. We measured genetics knowledge (nine true/false items) and genetics self-efficacy (five Likert-scale items) before receipt of results and 6 months after results and used paired methods to evaluate change over time. Correlates of change (e.g., decision regret) were identified using linear regression. RESULTS: 998 PGT customers (59.9% female; 85.8% White; mean age 46.9 +/- 15.5 years) were included in our analyses. Mean genetics knowledge score was 8.15 +/- 0.95 (out of 9) at baseline and 8.25 +/- 0.92 at 6 months (P = 0.0024). Mean self-efficacy score was 29.06 +/ 5.59 (out of 35) at baseline and 27.7 +/- 5.46 at 6 months (P < 0.0001); on each item, 30-45% of participants reported lower self-efficacy following PGT. Change in self-efficacy was positively associated with health-care provider consultation (P = 0.0042), impact of PGT on perceived control over one's health (P < 0.0001), and perceived value of PGT (P < 0.0001) and was negatively associated with decision regret (P < 0.0001). CONCLUSION: Lowered genetics self-efficacy following PGT may reflect an appropriate reevaluation by consumers in response to receiving complex genetic information.Genet Med 18 1, 65-72. PMID- 25812043 TI - Speech audiometry in Estonia: Estonian words in noise (EWIN) test. AB - OBJECTIVE: Currently, there is no up-to-date speech perception test available in the Estonian language that may be used to diagnose hearing loss and quantify speech intelligibility. Therefore, based on the example of the Nederlandse Vereniging voor Audiologie (NVA)-lists ( Bosman, 1989 ; Wouters et al, 1994 ) an Estonian words in noise (EWIN) test has been developed. DESIGN: Two experimental steps were carried out: (1) selection and perceptual optimization of the monosyllables, and (2) construction of 14 lists and an evaluation in normal hearing (NH) subjects both in noise and in quiet. STUDY SAMPLE: Thirty-six normal hearing (NH) native speakers of Estonia (age range from 17 to 46 years). RESULTS: The reference psychometric curve for NH subjects was determined, with the slope and speech reception threshold being well in accordance with the respective values of the NVA lists. The 14 lists in noise yielded equivalent scores with high precision. CONCLUSION: The EWIN test is a reliable and valid speech intelligibility test, and is the first of its kind in the Estonian language. PMID- 25812045 TI - West Nile virus infection incidence based on donated blood samples and neuroinvasive disease reports, Northern Texas, USA, 2012. AB - During the 2012 outbreak of West Nile virus in the United States, approximately one third of the cases were in Texas. Of those, about half occurred in northern Texas. Models based on infected blood donors and persons with neuroinvasive disease showed, respectively, that ~0.72% and 1.98% of persons in northern Texas became infected. PMID- 25812044 TI - Oxalate Nephropathy After Continuous Infusion of High-Dose Vitamin C as an Adjunct to Burn Resuscitation. AB - Fluid resuscitation is the foundation of management in burn patients and is the topic of considerable research. One adjunct in burn resuscitation is continuous, high-dose vitamin C (ascorbic acid) infusion, which may reduce fluid requirements and thus decrease the risk for over resuscitation. Research in preclinical studies and clinical trials has shown continuous infusions of high-dose vitamin C to be beneficial with decrease in resuscitative volumes and limited adverse effects. However, high-dose and low-dose vitamin C supplementation has been shown to cause secondary calcium oxalate nephropathy, worsen acute kidney injury, and delay renal recovery in non-burn patients. To the best of our knowledge, the authors present the first case series in burn patients in whom calcium oxalate nephropathy has been identified after high-dose vitamin C therapy. PMID- 25812046 TI - Development and evaluation of a standardized method and atlas for contouring primary and permanent dentition. AB - OBJECTIVES: Radiation toxicity of the dentition may present significant treatment related morbidity in the paediatric head and neck cancer population. However, clear dose-effect relationships remain undetermined and must be predicated upon accurate structure delineation and dosimetry at the individual tooth level. Radiation oncologists generally have limited familiarity or experience with relevant dental anatomy. METHODS: We therefore developed a detailed CT atlas of permanent and primary dentition. After studying this atlas, five radiation oncology clinicians delineated all teeth for each of eight different cases (selected for breadth of dental maturity and anatomical variability). They were asked to record confidence in their contours on a per-tooth basis as well as the duration of time required per case. Contour accuracy and interclinician variability were assessed by Hausdorff distance and Dice similarity coefficient. All analyses were performed using R v. 3.1.1 and the RadOnc v. 1.0.9 package. RESULTS: Participating clinicians delineated teeth with varying degrees of completeness and accuracy, stratified primarily by the age of the subject. On a per-tooth basis, delineation of permanent dentition was feasible for incisors, canines, premolars and first molars among all subjects, even at the youngest ages. However, delineation of second and third molars was less consistent, commensurate with approximate timing of tooth development. Within each tooth contour, uncertainty was the greatest at the level of the dental roots. CONCLUSIONS: Delineation of individual teeth is feasible and serves as a necessary precursor for dental dose assessment and avoidance. Among the paediatric radiation oncology community in particular, this atlas may serve as a useful tool and reference. PMID- 25812048 TI - Incidental masticator space lesion in a teenager. PMID- 25812047 TI - The bidirectional relationship between quality of life and eating disorder symptoms: a 9-year community-based study of Australian women. AB - OBJECTIVE: Studies that have investigated quality of life (QoL) in eating disorders (EDs) have been focussed on the impact of the ED on QoL and little is known regarding the possible reciprocal impact of QoL on EDs. The aim of this study was to provide a first-time investigation of possible bidirectional relationships between EDs and both health-related QoL (HRQoL) and psychological distress (PD). METHOD: Structural equation modeling was applied to longitudinal data collected from a community sample of Australian women (N = 828) surveyed at baseline, five annual follow-ups, and again after nine years. Participants reported height and weight (from which body mass index, BMI, was calculated) and completed measures of ED symptoms (Eating Disorder Examination Questionnaire), HRQoL (12-item Medical Outcomes Study Short Form), and PD (Kessler Psychological Distress Scale). RESULTS: Overall, evidence was found for a bidirectional relationship, whereby ED symptoms predicted reduced HRQoL and greater PD over time, while lower levels of HRQoL and greater PD in turn predicted increased levels of ED symptoms. These relationships were stable, observable within 12 months, and remained observable over a time period of at least four years. However, also observed were some inconsistent findings where ED symptoms predicted a short term (one year) improvement in mental HRQoL. This short term boost was not sustained at longer follow-ups. CONCLUSIONS: Not only do ED symptoms impact on HRQoL and PD, but perceived poor HRQoL and PD also contribute to ED symptom development or exacerbation. This supports a movement away from symptom-centric approaches whereby HRQoL is conceptualized as a passive outcome expected to be rectified by addressing ED symptoms. Improvement in QoL and PD might rather be viewed as targets to be pursued in their own right under broader approaches in the treatment of EDs. PMID- 25812049 TI - A phase-transfer assisted solvo-thermal strategy for low-temperature synthesis of Na3(VO1-xPO4)2F1+2x cathodes for sodium-ion batteries. AB - We demonstrate that a series of high-performance cathode materials, sodium vanadium polyanionic compounds, Na3(VO1-xPO4)2F1+2x (x = 0, 0.5 and 1), can be synthesized by a phase-transfer assisted solvo-thermal strategy at a rather low temperature (80-140 degrees C) in one simple step, exhibiting a high Na storage capacity of ca. 120 mA h g(-1) and excellent cycling performance. This study makes a significant step to extend this strategy to the synthesis of functional materials from simple binary to complex multicomponent compounds. PMID- 25812050 TI - Preliminary study of genetic diversity and population structure of the Relict Gull Larus relictus (Charadriiformes Laridae) using mitochondrial and nuclear genes. AB - The genetic diversity and the population history of the Relict Gull (Larus relictus) were studied based on the sequences of two mitochondrial genes (Cyt b and ND2) and one nuclear gene (the third intron of the Z-linked muscle-specific kinase gene [MUSK]) from 47 individuals. The results showed that the population expresses very low genetic diversity while lacking large geographical population. Demographic history analysis suggested that population expansion might have been recent and that the average estimated expansion time of L. relictus is from 0.09 to 0.23 Ma BP. Whether the other three breeding subpopulations are involved in the Ordos breeding subpopulation, require further study with more effective molecular markers. The species is threatened by habitat loss and fragmentation, and actions to protect it are suggested to improve the population fragmentation of breeding. PMID- 25812051 TI - Mitochondrial tRNA mutations in patients with myelodysplastic syndromes. AB - Increasing evidence showed that mitochondria play an important role in the development of myelodysplastic syndromes (MDS). Mitochondrial dysfunctions caused by mitochondrial DNA mutations, especially mitochondrial tRNA mutations, were found to be associated with MDS in many studies. However, the link between a candidate mitochondrial tRNA mutation and MDS was not clear. In this study, we investigated the role of some mitochondrial tRNA mutations, and their deleterious roles were further discussed. PMID- 25812052 TI - The complete plastid genome sequence of Abies koreana (Pinaceae: Abietoideae). AB - The nucleotide sequence of the chloroplast genome from Abies koreana is the first to have complete genome sequence from genus Abies of family Pinaceae. The circular double-stranded DNA, which consists of 121,373 base pairs (bp), contains a pair of very short inverted repeat regions (IRa and IRb) of 264 bp each, which are separated by a small and large single-copy regions (SSC and LSC) of 54,197 and 66,648 bp, respectively. The genome contents of 114 genes (68 peptide encoding genes, 35 tRNA genes, four rRNA genes, six open reading frames and one pseudogene) are similar to the chloroplast DNA of other species of Abietoideae. Loss of ndh genes was also identified in the genome of A. koreana like other genomes in the family Pinaceae. Thirteen genes contain one (11 genes) or two (rps12 and ycf3 genes) introns. In phylogenetic analysis, the tree confirms that Abies, Keteleeria and Cedrus are strongly supported as monophyletic. Other inverted repeat sequences located in 42-kb inversion points (1186 bp) include trnS-psaM-ycf12- psitrnG genes. PMID- 25812053 TI - Identification of sequence polymorphisms in the D-loop region of mitochondrial DNA as risk biomarker for liposarcoma. AB - Single nucleotide polymorphisms (SNPs) in the Displacement-loop (D-loop) region of mitochondrial DNA have been reported to be associated with cancer risk in various types of cancer. To assess the frequency of D-loop SNPs in a large series of liposarcoma and establish correlations with cancer risk, we sequenced the D loop of 82 liposarcoma patients and analyzed their use as predictive biomarkers for liposarcoma risk. The minor alleles of nucleotides 73G, 523-524del, 16,290T, 16,319A, 16,356C were associated with an increased risk for liposarcoma patients, whereas the insertion of C at the site 315 (located within the D310) were associated with a decreased risk for liposarcoma patients. These results suggest that SNPs in the mitochondrial D-loop should be considered as a biomarker which may be useful for the early detection of liposarcoma in individuals at risk of this cancer. PMID- 25812054 TI - Sequencing and analysis of the complete mitochondrial genome of tundra shrew (Sorex tundrensis) from China. AB - The complete mitogenome sequence of tundra shrew (Sorex tundrensis) was determined using long PCR. The genome was 17,444 bp in length and contained 13 protein-coding genes, 2 ribosomal RNA genes, 23 transfer RNA genes, 1 origin of L strand replication and 1 control region. The overall base composition of the heavy strand is A (32.9%), C (24.8%), T (29.0%), and G (13.3%). The base compositions present clearly the A-T skew, which is most obviously in the control region and protein-coding genes. The extended termination-associated sequence domain, the central conserved domain and the conserved sequence block domain are defined in the mitochondrial genome control region of tundra shrew. Mitochondrial genome analyses based on MP, ML, NJ and Bayesian analyses yielded identical phylogenetic trees. The three Sorex species formed a monophyletic group with the high bootstrap value (100 %) in all examinations. PMID- 25812055 TI - Mitochondrial DNA-based genetic diversity of Anopheles nivipes in North East India. AB - Malaria is a major public health problem in north-east India mainly transmitted by Anopheles baimai and An. minimus while Anopheles nivipes plays an important supportive role. The genetic diversity of An. nivipes in north-east India was investigated by employing two mitochondrial DNA markers namely NADH dehydrogenase 5 (ND5) and cytochrome oxidase sub unit II (COII). High genetic diversity in An. nivipes was observed by the detection of 16 haplotypes among 30 sequences of ND5 gene and 29 haplotypes among 29 COII sequences. Anopheles nivipes of north-east India was significantly differentiated genetically with that of neighboring South east Asian An. nivipes as revealed by pairwise FST values of 0.127 (p < 0.01) and 0.044 (p < 0.001) for ND5 and COII genes, respectively, suggesting geographical barriers to gene flow in this species between the two geographical areas resulting in significant population structuring. PMID- 25812056 TI - DNA barcoding of true limpets (Order Patellogastropoda) along coast of China: a case study. AB - In this study, we applied a partial sequence of mitochondrial COI gene as DNA barcode to assess the viability of DNA barcoding for distinguishing Patellogastropoda. One-hundred thirty-five COI gene sequences were obtained from 13 species belonging to Nacellidae (Cellana) and Lottiidae (Lottia, Patelloida and Nipponacmea) along the coast of China. The alignment result of these sequences indicated the existence of insertions in mitochondrial COI gene of Patellogastropoda. The Kimura 2-parameter (K2P) distances within species and genera were 0.00-1.01% (average 0.07%) and 18.09-37.80% (average 24.07%), respectively, an obvious barcoding gap existed. All species in our study were clearly discriminated in all trees (neighbor-joining (NJ), Bayesian, and maximum likelihood (ML) tree) with a highly supported clade node. The character-based barcode method successfully identified 100% of the Patellogastropod species included, and performed well in discriminating Patellogastropod genera. The results of this study affirm that DNA barcoding based on the COI gene can identify species belonging to Patellogastropoda rapidly and accurately. PMID- 25812057 TI - The complete chloroplast genome of Cynara humilis. AB - The complete chloroplast genome of the wild thistle Cynara humilis L. (Asteraceae) is presented in this study. The genome is 152,585 bp in length and has a quadripartite structure composed by a large single-copy (LSC) of 83,622 bp, a small single-copy (SSC) of 18,651 bp and two inverted repeats (IRb/a) of 25,156 bp each. The GC content corresponds to 37.7%. The amount of unique genes is 114, in which 17 are duplicated in the IRs, for a total of 131 genes. A maximum parsimony phylogenetic analysis revealed that C. humilis chloroplast genome is closely related to that of the globe artichoke within the Carduoideae subfamily. PMID- 25812058 TI - A species-specific primer pair for distinguishing between Paramisgurnus dabryanus and Misgurnus anguillicaudatus based on mitochondrial DNA polymorphisms. AB - Paramisgurnus dabryanus and Misgurnus anguillicaudatus (family Cobitidae) are loaches with high morphological similarity. In this study, we designed primers to distinguish between Paramisgurnus dabryanus and Misgurnus anguillicaudatus based on the length differences in the mitochondrial COXII to tRNA(Lys) gene region. Samples of P. dabryanus and M. anguillicaudatus from different geographical locations were collected and amplified to verify primer specificity. The results of electrophoresis revealed the successful amplification of all P. dabryanus and M. anguillicaudatus DNA samples, which had distinct, specific-specific sizes (214 bp for P. dabryanus and 285 bp for M. anguillicaudatus). In conclusion, the new primers provide fast, reliable, and accurate identification between P. dabryanus and M. anguillicaudatus. PMID- 25812059 TI - The complete mitochondrial genome of the Synanceia verrucosa (Scorpaeniformes: Synanceiidae). AB - The complete mitochondrial genome of the Synanceia verrucosa has been sequenced. The mitochondrial genome is 16,506 bp in length, containing 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one control region. The gene order and the composition of S. verrucosa mitochondrial genome were similar to that of most other vertebrates. The overall nucleotides base composition of the heavy strand is A (31.01%), G (15.06%), C (25.60%), and T (28.34%). With the exception of the NADH dehydrogenase subunit 6 (ND6) and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. The tRNA-Ser2 gene lacked DHC arm and could not fold into a typical clover-leaf secondary structure. Seen from the phylogenetic tree, a stonefish (S. verrucosa), two lionfishes, and eight rockfishes from the same order (Scorpaeniformes) clustered into one branch. PMID- 25812060 TI - Depression and marital status determine the 10-year (2004-2014) prognosis in patients with acute coronary syndrome: the GREECS study. AB - BACKGROUND: The aim of the present work was to examine the association of depression and marital status, with the long-term prognosis of acute coronary syndrome (ACS), among a Greek sample of cardiac patients. METHODS: From October 2003 to September 2004, a sample of 2172 consecutive ACS patients from 6 hospitals was enrolled. In 2013-2014, the 10-year follow-up was performed in 1918 participants. Depressive symptoms were evaluated using the validated CES-D score (range 0-60), while marital status was classified as: single, married/cohabitants, divorced and widowed at the time of entry to the study. RESULTS: Patients in the upper tertile of CES-D (>20 score) had 41% (95%CI 14%, 75%) higher risk of ACS incidence as compared with those in the lowest (<7 score). In contrary, married patients had 29% lower risk (95%CI 6%, 46%) of ACS mortality compared with single, widowed or divorced. Multi-adjusted analysis revealed that among the 'not married' patients, 1-point increase in the CES-D score was associated with 2% (p = .02) and 4% (p = .001) higher risk of having non-fatal and fatal cardiac events, respectively. CONCLUSIONS: The present study highlights the important role of depression in the context of marital relationships among ACS patients. Secondary public health care intervention programmes are needed to improve patient outcomes and minimise disease burden in clinical and community setting. PMID- 25812062 TI - Synthesis and anticancer activity of silver(I)-N-heterocyclic carbene complexes derived from the natural xanthine products caffeine, theophylline and theobromine. AB - A new library of silver(I)-N-heterocyclic carbene complexes prepared from the natural products caffeine, theophylline and theobromine is reported. The complexes have been fully characterised using a combination of NMR spectroscopy, mass spectrometry, elemental analysis and X-ray diffraction analysis. Furthermore, the hydrophobicity of the complexes has been measured. The silver(I) N-heterocyclic carbenes have been evaluated for their antiproliferative properties against a range of cancer cell lines of different histological types, and compared to cisplatin. The data shows different profiles of response when compared to cisplatin in the same panel of cells, indicating a different mechanism of action. Furthermore, it appears that the steric effect of the ligand and the hydrophobicity of the complex both play a role in the chemosensitivity of these compounds, with greater steric bulk and greater hydrophilicity delivering higher cytotoxicity. PMID- 25812063 TI - Last medical wishes. PMID- 25812061 TI - Increased risk for group B Streptococcus sepsis in young infants exposed to HIV, Soweto, South Africa, 2004-2008(1). AB - Although group B Streptococcus (GBS) is a leading cause of severe invasive disease in young infants worldwide, epidemiologic data and knowledge about risk factors for the disease are lacking from low- to middle-income countries. To determine the epidemiology of invasive GBS disease among young infants in a setting with high maternal HIV infection, we conducted hospital-based surveillance during 2004-2008 in Soweto, South Africa. Overall GBS incidence was 2.72 cases/1,000 live births (1.50 and 1.22, respectively, among infants with early-onset disease [EOD] and late-onset [LOD] disease). Risk for EOD and LOD was higher for HIV-exposed than HIV-unexposed infants. GBS serotypes Ia and III accounted for 84.0% of cases, and 16.9% of infected infants died. We estimate that use of trivalent GBS vaccine (serotypes Ia, Ib, and III) could prevent 2,105 invasive GBS cases and 278 deaths annually among infants in South Africa; therefore, vaccination of all pregnant women in this country should be explored. PMID- 25812064 TI - New Zealand Blackcurrant Extract Improves High-Intensity Intermittent Running. AB - We examined the effect of New Zealand blackcurrant (NZBC) extract on high intensity intermittent running and postrunning lactate responses. Thirteen active males (age: 25 +/- 4 yrs, height: 1.82 +/- 0.07 m, body mass: 81 +/- 14 kg, VO2max: 56 +/- 4 ml.kg-1.min-1, vVO2max: 17.6 +/- 0.8 km.h-1) performed a treadmill running protocol to exhaustion, which consisted of stages with 6 * 19 s of sprints with 15 s of low-intensity running between sprints. Interstage rest time was 1 min and stages were repeated with increasing sprint speeds. Subjects consumed capsuled NZBC extract (300 mg.day-1 CurraNZ; containing 105 mg anthocyanin) or placebo for 7 days (double-blind, randomized, crossover design, wash-out at least 14 days). Blood lactate was collected for 30 min postexhaustion. NZBC increased total running distance by 10.6% (NZBC: 4282 +/- 833 m, placebo: 3871 +/- 622 m, p = .02), with the distance during sprints increased by 10.8% (p = .02). Heart rate, oxygen uptake, lactate and rating of perceived exertion were not different between conditions for the first 4 stages completed by all subjects. At exhaustion, blood lactate tended to be higher for NZBC (NZBC: 6.01 +/- 1.07 mmol.L-1, placebo: 5.22 +/- 1.52 mmol.L-1, p = .07). There was a trend for larger changes in lactate following 15 min (NZBC: -2.89 +/- 0.51 mmol.L-1, placebo: -2.46 +/- 0.39 mmol.L-1, p = .07) of passive recovery. New Zealand blackcurrant extract (CurraNZ) may enhance performance in sports characterized by high-intensity intermittent exercise as greater distances were covered with repeated sprints, there was higher lactate at exhaustion, and larger changes in lactate during early recovery after repeated sprints to exhaustion. PMID- 25812065 TI - Decreased Probability of Initial Pain Cessation in Classic Trigeminal Neuralgia Treated With Gamma Knife Surgery in Case of Previous Microvascular Decompression: A Prospective Series of 45 Patients With >1 Year of Follow-up. AB - BACKGROUND: Microvascular decompression (MVD) is the reference technique for pharmacoresistant trigeminal neuralgia (TN). OBJECTIVE: To establish whether the safety and efficacy of Gamma Knife surgery for recurrent TN are influenced by prior MVD. METHODS: Between July 1992 and November 2010, 54 of 737 patients (45 of 497 with >1 year of follow-up) had a history of MVD (approximately half also with previous ablative procedure) and were operated on with Gamma Knife surgery for TN in the Timone University Hospital. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range, 3.9-11.9 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range, 70-90 Gy) was delivered. RESULTS: The median follow-up time was 39.5 months (range, 14.1-144.6 months). Thirty-five patients (77.8%) were initially pain free in a median time of 14 days (range, 0-180 days), much lower compared with our global population of classic TN (P = .01). Their actuarial probabilities of remaining pain-free without medication at 3, 5, 7, and 10 years were 66.5%, 59.1%, 59.1%, and 44.3%. The hypoesthesia actuarial rate at 1 year was 9.1% and remained stable until 12 years (median, 8 months). CONCLUSION: Patients with previous MVD showed a significantly lower probability of initial pain cessation compared with our global population with classic TN (P = .01). The toxicity was low (only 9.1% hypoesthesia); furthermore, no patient reported bothersome hypoesthesia. However, the probability of maintaining pain relief without medication was 44.3% at 10 years, similar to our global series of classic TN (P = .85). PMID- 25812066 TI - Combination of Intraoperative Magnetic Resonance Imaging and Intraoperative Fluorescence to Enhance the Resection of Contrast Enhancing Gliomas. AB - BACKGROUND: Evidence suggests that extent of resection (EOR) is a prognostic factor for patients harboring gliomas. Recent studies have displayed the importance of intraoperative magnetic resonance imaging (iMRI) with 5 aminolevulinic acid (5-ALA) fluorescence-guidance in order to maximize EOR. OBJECTIVE: To compare iMRI and 5-ALA fluorescence-guidance and the impact on patient survival. METHODS: Thirty-two patients with contrast-enhancing gliomas undergoing intended gross total resection (GTR) were included in a prospective study. Surgeries were started under white-light conditions. When GTR was thought to be achieved, an iMRI scan was performed and a blue light turned on to search for unintentionally remaining tumor tissue. iMRI findings were compared with intraoperative fluorescence findings. Histological examination of tumor bulk and any additionally resected tissue was performed. All patients underwent early postoperative high-field MRI to determine EOR. RESULTS: In 13 patients (40.6%), iMRI and fluorescence unequivocally did not show residual tumor intraoperatively. In 19 patients (59.4%), resection was continued due to iMRI or fluorescence findings. In 9 of these (47.4%), iMRI and fluorescence findings were inconsistent regarding residual tumor. GTR according to postoperative MRI was achieved in all but 1 patient. Histological examination ruled out false positive findings in all additionally resected specimens. Sensitivity and specificity to detect residual tumor tissue were 75% and 100%, respectively, for iMRI and 70% and 100% for 5-ALA fluorescence. CONCLUSION: Use of iMRI as well as fluorescence-guidance are appropriate methods to improve the extent of resection in surgery of contrast enhancing gliomas. Best results can be achieved by complementary use of both modalities. PMID- 25812069 TI - A Survey of Chronic Pain Due to Spinal Dural Arteriovenous Fistulae. AB - BACKGROUND: Chronic pain due to spinal dural arteriovenous fistulae (SDAVF) during follow-up is a serious issue because it can affect patients' quality of life. The severity of posttreatment chronic leg pain in patients with SDAVF is unclear. OBJECTIVE: To investigate the prevalence, severity, and characteristics of chronic leg pain in patients with SDAVF and to examine the clinical factors associated with chronic pain. METHODS: We conducted a survey of their chronic posttreatment leg pain in 49 SDAVF patients. It consisted of a numeric rating scale and a neuropathic pain symptom inventory (NPSI). Of the 49 patients, 32 (65.3%) completed the questionnaire. There were 24 males and 8 females whose mean age was 69.1 years. The mean follow-up period was 86.3 months. RESULTS: Chronic leg pain was reported by 26 (81.3%) of 32 patients; 14 experienced pain before treatment and 12 had new-onset posttreatment pain. The pain was reported as moderate to severe by 21 (80.8%) of 26 patients; the mean numeric rating scale and NPSI scores were 6.0 +/- 2.3 and 17.4 +/- 10.3, respectively. The NPSI subscores were significantly higher for spontaneous pain and paresthesia/dysesthesia than for paroxysmal pain. We found no significant clinical factors related to chronic posttreatment pain; on magnetic resonance imaging scans we identified spinal cord atrophy in 8 patients with chronic pain. CONCLUSION: Most of our SDAVF patients reported moderate to severe chronic leg pain characterized by spontaneous pain and paresthesia/dysesthesia. Spinal cord atrophy on magnetic resonance imaging scans was a characteristic in patients with chronic pain. PMID- 25812067 TI - Imaging-Based Features of Headaches in Chiari Malformation Type I. AB - BACKGROUND: Suboccipital cough-induced headaches are considered a hallmark symptom of Chiari malformation type I (CMI). However, non--Valsalva-related suboccipital headaches and headaches in other locations are also common in CMI. The diagnostic significance and the underlying factors associated with these different headaches types are not well understood. OBJECTIVE: To compare cranial morphology and hydrodynamics in 3 types of headaches in CMI to better understand the pathophysiological basis for the different headache characteristics. METHODS: Twenty-two cranial physiological and morphological measures were obtained with specialized magnetic resonance imaging scans from 63 symptomatic pretreated CMI patients, 40 with suboccipital headaches induced by Valsalva maneuvers (34 women; age, 36 +/- 10 years), 15 with non--Valsalva-related suboccipital headaches (10 women; age, 33 +/- 9 years), 8 with nonsuboccipital non--Valsalva-induced headaches (8 women; age, 39 +/- 13 years), and 37 control subjects (24 women; age, 36 +/- 12 years). Group differences were identified with the use of the 2 tailed Student t test. RESULTS: Posterior cranial fossa markers of CMI were similar among the 3 headache subtypes. However, the Valsalva-related suboccipital headaches cohort demonstrated a significantly lower intracranial compliance index than the non--Valsalva-related suboccipital headaches cohort (7.5 +/- 3.4 vs 10.9 +/- 4.9), lower intracranial volume change during the cardiac cycle (0.48 +/- 0.19 vs 0.61 +/- 0.16 mL), and higher magnetic resonance imaging--derived intracranial pressure (11.1 +/- 4.3 vs 7.7 +/- 2.8 mm Hg; P = .02). The Valsalva related suboccipital headaches cohort had smaller intracranial and lateral ventricular volumes compared with the healthy cohort. The non--Valsalva-related suboccipital headaches cohort had reduced venous drainage through the jugular veins. CONCLUSION: Valsalva-induced worsening of occipital headaches appears to be related to a small intracranial volume rather than the smaller posterior cranial fossa. This explains the reduced intracranial compliance and corresponding higher pressure measured in CMI patients with headaches affected by Valsalva maneuvers. PMID- 25812070 TI - Three-dimensional computed tomography-based spinal navigation in minimally invasive lateral lumbar interbody fusion: feasibility, technique, and initial results. AB - BACKGROUND: As with most minimally invasive spine procedures, lateral lumbar interbody fusion (LLIF) requires the use of biplanar fluoroscopy for localization and safe interbody cage placement. Computed tomography (CT)-based intraoperative spinal navigation has been shown to be more effective than fluoroscopic guidance for posterior-based approaches such as pedicle screw instrumentation. However, the use of spinal navigation in LLIF has not been well studied. OBJECTIVE: To present the technique for using an intraoperative cone-beam CT and image-guided navigation system in LLIF and to provide a preliminary analysis of outcomes. METHODS: We retrospectively analyzed a prospectively acquired database and the electronic records of patients undergoing LLIF with spinal navigation. Eight patients were identified. Postoperative neurological deficits were recorded. All patients underwent postprocedural CT and x-ray imaging for analysis of accuracy of cage placement. Accuracy of cage placement was determined by location within the disk space. RESULTS: The mean age was 66 years, and 6 patients were women. A mean 2.8 levels were treated with a total of 22 lateral cages implanted via navigation. All cages were placed within quarters 1 to 2 or 2 to 3, signifying the anterior half or middle portions of the disk space. There were no sensory or motor deficits postoperatively. CONCLUSION: Use of an intraoperative cone-beam CT with an image-guided navigation system is feasible and safe and appears to be accurate, although a larger study is required to confirm these results. PMID- 25812068 TI - Contralateral Approach to Internal Carotid Artery Ophthalmic Segment Aneurysms: Angiographic Analysis and Surgical Results for 30 Patients. AB - BACKGROUND: Contralateral aneurysm clipping can be applied to bilateral intracranial aneurysms of the anterior circulation and to selected aneurysms on the medial wall of the internal carotid artery (ICA). OBJECTIVE: To identify anatomic and radiological parameters that would favor a contralateral microsurgical approach to ICA-ophthalmic segment (ICA-opht) aneurysms. METHODS: For the period January 1957 to December 2012, we retrospectively analyzed 268 patients with ICA-opht aneurysms treated in our institution. Of these patients, 30 underwent a contralateral approach; 15 patients (50%) had multiple intracranial aneurysms, and 15 patients had a single aneurysm on the contralateral side of the craniotomy. RESULTS: Thirty saccular aneurysms located on the contralateral ICA were treated. Six aneurysms (20%) were present in patients with a subarachnoid hemorrhage due to associated aneurysms, whereas 24 aneurysms (80%) had no history of bleeding. Contralateral aneurysms were smaller than 14 mm and showed no wall irregularities, calcifications, or secondary pouches. Projections of the aneurysms were superomedial (n = 23, 77%), medial (n = 4, 13%), and superior (n = 3, 10%). The median prechiasmatic distance was 5.7 mm (range, 3.4-8.7 mm), the median interoptic distance was 10.5 mm (range, 7.6 15.9 mm), and the median distance between both ICAs was 14.7 mm (range, 10.4-21.4 mm). CONCLUSION: The contralateral approach for ICA-opht aneurysms remains a treatment option for intracranial aneurysms. Its feasibility depends on specific anatomic parameters related to the aneurysm itself and to the prechiasmatic distance, interoptic distance, and relationship of the ICA with the anterior clinoid process. PMID- 25812071 TI - Intraoperative flow measurement by microflow probe during surgery for brain arteriovenous malformations. AB - BACKGROUND: Intraoperative quantitative flow measurement by a microvascular ultrasonic flow probe is an established methodology in aneurysm surgery. OBJECTIVE: To test the present flow measurement procedure in brain arteriovenous malformation (AVM) surgery. METHODS: Data from 25 patients with brain AVMs who consecutively underwent microsurgical resection with the assistance of flow measurement by a microflow probe were retrospectively analyzed. Flowmetry was performed on arterial feeders, potentially transit arteries, and venous drainage of AVM in different phases of resection. RESULTS: A quantitative flow measurement was performed 203 times on 92 vessels. Flowmetry was able to define the flow direction of AVM vessels in all cases, thereby discriminating between arterial feeders and venous drainages, both superficially and deeply located. During AVM dissection, flowmetry identified a transit artery in 12% of cases by detecting a flow drop between 2 points of the same vessel. At the final stage of resection, a residual nidus, potentially missed at surgical dissection, was detected when the flow value of venous drainage was greater than 4 mL/min (20% of patients). Pre resection microflow probe measurements were concordant with indocyanine green videoangiography data on AVM angioarchitecture in all cases. No microflow probe induced AVM vessel injury was reported. Complete AVM resection was achieved in all cases with a low morbidity (modified Rankin Scale score <= 1). CONCLUSION: Multistage intraoperative quantitative flow measurement proved to be a feasible, safe, repeatable, and reliable methodology to assist surgery in different phases of AVM resection. Further studies are needed to assess the impact of this approach on AVM patient outcomes.VA, indocyanine green videoangiographymRS, modified Rankin ScaleSM, Spetzler Martin. PMID- 25812072 TI - Severe Pediatric Head Injury During the Iraq and Afghanistan Conflicts. AB - BACKGROUND: Much has been written about injuries sustained by US and coalition soldiers during the Global War on Terrorism campaigns. However, injuries to civilians, including children, have been less well documented. OBJECTIVE: To describe the epidemiologic features and outcomes associated with isolated severe head injury in children during Operations Enduring Freedom and Iraqi Freedom (OEF and OIF). METHODS: A retrospective review of children (<18 years old) in the Joint Theater Trauma Registry with isolated head injury (defined as an Abbreviated Injury Score Severity Code >3) and treated at a US combat support hospital in Iraq or Afghanistan (2004-2012). The primary outcome was in-hospital mortality. RESULTS: We identified 647 children with severe isolated head injuries: 337 from OEF, 268 from OIF, and 42 nontheater specific. Most were boys (76%; median age = 8 years). Penetrating injuries were most common (60.6%). Overall, 330 (51%) children underwent a craniotomy/craniectomy; 156 (24.1%) succumbed to their injuries. Admission Glasgow Coma Score was predictive of survival among the entire cohort and each of the individual conflicts. Male sex also significantly increased the odds of survival for the entire group and OEF, but not for OIF. Closed-head injury improved the predictive ability of our model but did not reach statistical significance as an independent factor. CONCLUSION: This is the largest study of combat-related isolated head injuries in children. Admission Glasgow Coma Score and male sex were found to be predictive of survival. Assets to comprehensively care for the pediatric patient should be established early in future conflicts. PMID- 25812073 TI - Infected Prostheses after Lower-Extremity Bone Tumor Resection: Clinical Outcomes of 100 Patients. AB - BACKGROUND: Infection of megaprostheses after bone tumor resection is a major concern; management is challenging. This study evaluated the survivability from such infections, the microbial isolates, treatment tactics, and outcome of megaprosthesis reconstructions. MATERIALS AND METHODS: We studied 1,161 patients retrospectively who underwent megaprosthesis reconstruction for limb salvage after a sarcoma from 1983 to 2010. The mean followup was 9 y (range 3-20 y). We evaluated the overall survival of the megaprosthesis reconstructions in patients with infection and the survival with respect to the type of megaprosthesis, site of reconstruction, cemented or cementless fixation, type of tumor, adjuvant treatments, microbial isolate(s), treatment tactics, and outcome. RESULTS: The incidence of infection was 8.6%. The most common microbial isolate was Staphylococcus epidermidis (47%). Overall survival with definitive management of infection was 88% at 10 y and 84% at 20 y. Survival was higher for cementless reconstructions and not different with respect to the type of megaprosthesis, site of reconstruction, or adjuvant therapy. Infections resolved completely with one- or two-stage surgery in 75% of patients. The rate of amputation because of infection was 21%. CONCLUSIONS: Megaprosthesis reconstructions may be infected in 8.6% of cases. Infections more commonly occur late, caused usually by S. epidermidis. The survival rate is higher with cementless megaprosthesis reconstructions and no different with respect to the type of tumor or megaprosthesis or the adjuvant treatments. One-stage revision is effective for acute post-operative infections; however, two-stage revision surgery is necessary for early and late infections. The rate of amputation because of occurrence or persistence of megaprosthesis infection is 21%. PMID- 25812074 TI - Creativity and aggression as ornament and armament: intersexual and intrasexual selection on men's mating behaviors. AB - In three studies, we tested the hypothesis that men respond to intersexual and intrasexual selection by facultatively choosing between weapon-like and ornament like behaviors. In the first two studies, we manipulated intersexual and intrasexual selection by having male participants take part in a simulated dating game (Study 1) or imagine having a date (Study 2). In both studies, participants were told either that the target female would choose her date (intersexual) or that male suitors would nominate one another (intrasexual). Under the intersexual selection condition, men demonstrated increased creativity levels and decreased aggression levels, whereas the opposite pattern was observed under the intrasexual selection condition. Study 3 showed that individual differences in creativity and aggression as personality traits similarly predicted intrasexual and intersexual mating strategies, respectively. These extend existing evolutionary mating research by specifying the mechanism of intrasexual or intersexual selection in shaping men's weapon-like or ornament-like situational response and personality development. PMID- 25812076 TI - Water's tensile strength measured using an optofluidic chip. AB - In this paper, for the first time, the tensile strength of water is directly measured using an optofluidic chip based on the displacement of air-water interface deformation with homogeneous nucleation. When water in a microchannel is stretched dynamically via laser-induced shock reflection at the air-water interface, the shock pressures are determined by measuring the displacements of the deformed interface. Observation of the vapor bubbles is used as a probe to identify the cavitation threshold with a critical distance, and the tensile strength of water at 20 degrees C is measured to be -33.3 +/- 2.8 MPa. This method can be extended to investigate the tensile strength of other soft materials such as glycerol, which is measured to be -59.8 +/- 10.7 MPa at 20 degrees C. PMID- 25812075 TI - Modulating the Anticancer Activity of Ruthenium(II)-Arene Complexes. AB - Following the identification of [Ru(eta(6)-p-cymene)Cl2(1H,1H,2H,2H perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)-arene complex with a perfluoroalkyl-modified ligand that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity and migration assays) and in vivo (chicken chorioallantoic membrane) models and were found to exhibit potent antivascular effects. PMID- 25812077 TI - Metal-driven self-assembly: the case of redox-active discrete architectures. AB - The metal-driven self-assembly strategy is well-established for the construction of discrete architectures featuring a cavity. The resulting molecular rings and cages are potentially useful as hosts for complementary guests. Recent years have seen growing interest in the introduction of given functionalities, including redox properties which, among others, allow modulating the ionic charge of the cavity. Depending on which subunit is electroactive, various situations can be encountered, with a global redox activity which is ligand- and/or metal-centered and which involves or not electronic interactions between the constituting units. In this feature article, we propose to survey those different situations by exploring some recent examples of the growing family of redox-active self assembled rings and cages. PMID- 25812078 TI - Realized C-H functionalization of aryldiazo compounds via rhodium relay catalysis. AB - An unprecedented C-H functionalization of aryldiazo compounds without a preinstallation of directing group has been realized under mild conditions, which differs from former reports in its use of diazo compounds as coupling partners in directed C-H activations. This novel transformation has been realized by a rhodium self-relay catalysis, a tandem process of the in situ formation of a directing group and sequential C-H bond activation. PMID- 25812079 TI - Activation of Adenosine Triphosphate-regulated Potassium Channels during Reperfusion Restores Isoflurane Postconditioning-induced Cardiac Protection in Acutely Hyperglycemic Rabbits. AB - BACKGROUND: Hyperglycemia is known to inhibit myocardial anesthetic postconditioning. The authors tested whether activation of adenosine triphosphate regulated potassium (KATP) channels would restore anesthetic postconditioning during acute hyperglycemia. METHODS: Rabbits subjected to 40-min myocardial ischemia and 3-h reperfusion (ischemia-reperfusion [I/R]) were assigned to groups (n = 10 in each group) with or without isoflurane postconditioning (2.1% for 5 min) in the presence or absence of hyperglycemia and/or the KATP channel agonist diazoxide. Creatine kinase MB fraction and infarct size were measured. Phosphorylated protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) were assessed. Oxidative stress was evaluated by measuring malondialdehyde, and apoptosis was assessed by dUTP nick-end labeling and activated caspase-3. RESULTS: Postconditioning significantly reduced myocardial infarct size (26 +/- 4% in the isoflurane [ISO] group vs. 53 +/- 2% in the I/R group; P = 0.007); whereas, hyperglycemia inhibited this effect (infarct size: 47 +/- 2%, P = 0.02 vs. the ISO group). Phosphorylated and eNOS levels increased, whereas malondialdehyde and myocardial apoptosis were significantly lower after isoflurane postconditioning compared with I/R. These effects were inhibited by acute hyperglycemia. Diazoxide restored the protective effect of isoflurane in the hyperglycemic animals (infarct size: 29 +/- 2%; P = 0.01 vs. the I/R group), reduced malondialdehyde levels and myocardial apoptosis, but did not affect the expression of phosphorylated Akt or eNOS. CONCLUSIONS: KATP channel activation restored anesthetic postconditioning-induced myocardial protection under acute hyperglycemia. This effect occurred without increasing Akt or eNOS phosphorylation, suggesting that KATP channels are located downstream to Akt and eNOS in the pathway of isoflurane-induced myocardial postconditioning. PMID- 25812081 TI - Physico-chemical confinement of helical nanofilaments. AB - Helical nanofilaments (HNFs) have attracted much interest because of their unique optical properties, but there have been many hurdles to overcome in using them for the practical applications due to their structural complexity. Here we demonstrate that the molecular configuration and layer conformation of a modulated HNF (HNFs(mod)) can be studied using a physicochemical confinement system. The layer directions affected by the chemical affinity between the mesogen and surface were drastically controlled in surface-modified nanochannels. Furthermore, an in situ experiment using grazing-incidence X-ray diffraction (GIXD) was carried out to investigate in detail the structural evolution through thermal transitions. The results demonstrate that the HNF(mod) structure can be perfectly controlled for functional HNF device applications, and a combined system with chemical and physical confinement effects will be helpful to better understand the fundamentals of soft matter. PMID- 25812082 TI - A computational and conceptual DFT study on the mechanism of hydrogen activation by novel frustrated Lewis pairs. AB - A computational and conceptual density functional theory (DFT) study on the mechanism of molecular hydrogen activation by a set of three frustrated Lewis pairs (FLPs) was performed at the omegaB97X-D/6-311G(d,p) level of theory. A reduced model and other two prototypes derived from experimental data, based on the donor nitrogen and acceptor boron atoms, were used. Analysis based on the energy results, geometries and the global electron density transfer at the TSs made it possible to obtain some interesting conclusions: (i) despite the well known very low reactivity of molecular hydrogen, the catalytic effectiveness of the three FLPs produces reactions with almost unappreciable activation energies; (ii) the reactions, being exothermic, follow a one-step mechanism via polarised TSs; (iii) there are neither substituent effects on the kinetics nor on the thermodynamics of these reactions; (iv) the activation of molecular hydrogen seems to be attained when the N-B distance in the FLP derivatives is around 2.74 A; and (v) the proposed FLP model is consistent with the behaviour of the experimental prototypes. Finally, the ability of the three FLPs as efficient catalysts was evaluated studying the hydrogenation of acetylene to yield ethylene. PMID- 25812080 TI - Attachment-focused integrative reminiscence with older African Americans: a randomized controlled intervention study. AB - OBJECTIVES: Prior integrative reminiscence interventions have had a limited focus on attachment themes. The attachment-focused integrative reminiscence (AFIR) intervention differs from these in its central emphasis on attachment themes. The wide range of health benefits resulting from integrative reminiscence may be due in part to reminiscing about, mourning, and integrating unresolved attachment experiences. METHOD: Participants were randomized into treatment and wait-list control conditions, completed a pre-test, met for eight consecutive weekly two hour sessions of largely attachment-focused reminiscence, then completed post tests immediately following the intervention and again six months later. RESULTS: Results show treatment effects for depression (p = .01 and .05 at eight weeks and six months), perceived stress (p = .01 and .04), and emergency room (ER) visits at six months (p = .04), with the intervention group showing lower depression and stress and fewer ER visits. CONCLUSION: Integrative reminiscence interventions are cost effective, have rapid impact, and carry a certain appeal to older adults. Augmenting such interventions with a focus on attachment experiences may reduce perceived stress, an important health risk factor. Wider application of AFIRs may further reduce health disparities among US older adults. PMID- 25812083 TI - Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Dextran Sulfate Sodium-Induced Severe Colitis in Rats. AB - Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of human amnion-derived MSCs (AMSCs) in rats with severe colitis. Colitis was induced by the administration of 8% dextran sulfate sodium (DSS) from day 0 to day 5, and AMSCs (1 * 10(6) cells) were transplanted intravenously on day 1. Rats were sacrificed on day 5, and the colon length and histological colitis score were evaluated. The extent of inflammation was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The effect of AMSCs on the inflammatory signals was investigated in vitro. AMSC transplantation significantly ameliorated the disease activity index score, weight loss, colon shortening, and the histological colitis score. mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and migration inhibitory factor (MIF) were significantly decreased in the rectums of AMSC-treated rats. In addition, the infiltration of monocytes/macrophages was significantly decreased in AMSC-treated rats. In vitro experiments demonstrated that activation of proinflammatory signals induced by TNF-alpha or lipopolysaccharide (LPS) in immortalized murine macrophage cells (RAW264.7) was significantly attenuated by coculturing with AMSCs or by culturing with a conditioned medium obtained from AMSCs. Although the phosphorylation of IkappaB induced by TNF-alpha or LPS was not inhibited by the conditioned medium, nuclear translocation of NF-kappaB was significantly inhibited by the conditioned medium. Taken together, AMSC transplantation provided significant improvement in rats with severe colitis, possibly through the inhibition of monocyte/macrophage activity and through inhibition of NF kappaB activation. AMSCs could be considered as a new cell source for the treatment of severe colitis. PMID- 25812085 TI - Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) can lead to high frequencies and rates of hospitalization and mortality. Macrolides are a class of antibiotics that possess both antimicrobial and anti-inflammatory properties. Since the occurrence of AECOPDs is associated with aggravation of airway inflammation and bacterial infections, prophylactic macrolide treatment may be an effective approach towards the prevention of AECOPDs. METHODS: We systemically searched the PubMed, Embase and Cochrane Library databases to identify randomized controlled trials (RCTs) that evaluated the effect of prophylactic macrolide therapy on the prevention of AECOPDs. The primary outcomes were the total number of patients with one or more exacerbations as well as the rate of exacerbations per patient per year. RESULTS: Nine RCTs comprising 1666 patients met the inclusion criteria. Pooled evidence showed macrolides could reduce the frequency of exacerbations in patients with COPD by both unweighted (RR = 0.70; 95% CI: 0.56-0.87; P < 0.01) and weighted approaches (RR = 0.58, 95% CI: 0.43-0.78, P < 0.01). Subgroup analysis showed only 6-12 months of erythromycin or azithromycin therapy could be effective. Moreover, among studies with 6-12 months of azithromycin therapy, both the daily dosing regimen and the intermittent regimen significantly reduced exacerbation rates. The overall number of hospitalizations and the all-cause rate of death were not significantly different between the treatment and control groups. A tendency for more adverse events was found in the treatment groups (OR = 1.55, 95%CI: 1.003 2.39, P = 0.049). CONCLUSIONS: Our results suggest 6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in patients with COPD. However, Long-term treatment may bring increased adverse events and the emergence of macrolide-resistance. A recommendation for the prophylactic use of macrolide therapy should weigh both the advantages and disadvantages. PMID- 25812087 TI - Microbial fuel cell-based biosensors for environmental monitoring: a review. AB - The microbial fuel cell (MFC) is an innovative technology that was initially designed to harness energy from organic waste using microorganisms. It is striking how many promising applications beyond energy production have been explored in recent decades. In particular, MFC-based biosensors are considered to be the next generation biosensing technology for environmental monitoring. This review describes recent advances in this emerging technology of MFC-based biosensors, with a special emphasis on monitoring of biochemical oxygen demand and toxicity in the environment. The progress confirms that MFC-based biosensors could be used as self-powered portable biosensing devices with great potential in long-term and remote environmental monitoring. PMID- 25812088 TI - Chitosan use in chemical conditioning for dewatering municipal-activated sludge. AB - This work aims to evaluate the potential use of chitosan as an eco-friendly flocculant in chemical conditioning of municipal-activated sludge. Chitosan effectiveness was compared with synthetic cationic polyelectrolyte Sedipur CF802 (Sed CF802) and ferric chloride (FeCl3). In this context, raw sludge samples from Beni-Messous wastewater treatment plant (WWTP) were tested. The classic jar test method was used to condition sludge samples. Capillary suction time (CST), specific resistance to filtration (SRF), cakes dry solid content and filtrate turbidity were analyzed to determine filterability, dewatering capacity of conditioned sludge and the optimum dose of each conditioner. Data exhibit that chitosan, FeCl3and Sed CF802 improve sludge dewatering. Optimum dosages of chitosan, Sed CF802 and FeCl3allowing CST values of 6, 5 and 9 s, were found, respectively, between 2-3, 1.5-3 and 6 kg/t ds. Both polymers have shown faster water removal with more permeable sludge. SRF values were 0.634 * 1012, 0.932 * 1012 and 2 * 1012 m/kg for Sed CF802, chitosan and FeCl3respectively. A reduction of 94.68 and 87.85% of the filtrate turbidity was obtained with optimal dosage of chitosan and Sed CF802, respectively. In contrast, 54.18% of turbidity abatement has been obtained using optimal dosage of FeCl3. PMID- 25812086 TI - Co-endemicity of loiasis and onchocerciasis in rain forest communities in southwestern Nigeria. AB - BACKGROUND: Loiasis is currently receiving attention as a disease of public health importance because of the possibility of increased risk of developing neurologic serious adverse event following mass ivermectin treatment against onchocerciasis in individual co-infected with Onchocerca volvulus and Loa loa. METHODOLOGY/PRINCIPAL FINDINGS: Rapid assessment procedure for loiasis (RAPLOA) was conducted in 12 communities covering the 3 senatorial districts of Osun State, Nigeria. A total of 960 people were interviewed for history of eye worm using the WHO guidelines for rapid assessment. The survey confirmed the presence of loiasis in all the 12 communities with 4 in Osun East/Ife south senatorial district being at high risk with a prevalence of over 40%. Based on the RAPLOA results, communities within Osun East/Ife south senatorial district were selected for microfilaraemic assessment of L. loa and O. volvulus. A total of 1115 and 1091 individuals were screened for L. loa and O. volvulus microfilaria worms respectively. 160 (14.3%) had L. loa microfilaria detected in their blood with 8 (5.0%) individuals having L. loa loads above 8000 mf/ml. 166 (15.2%) subjects had O. volvulus microfilaria (range 4-504 mf/ml) detected in their skin snip. 30 (2.69%) subjects were co-infected with both L. loa and O. volvulus. There was a significant variation in the prevalence (2.1% to 33.3%) of onchocerciasis in the communities studied (p = 0.001). Five (41.7%) of the studied communities had a prevalence that is equal to or greater than 20%. CONCLUSIONS/SIGNIFICANCE: Low prevalence of onchocerciasis and loiasis co-infection in this study suggests that loiasis may not pose a serious epidemiological threat to the continuous distribution and sustainability of ivermectin for the treatment of onchocerciasis. Evaluation of the interruption of onchocerciasis transmissions in this region using all the indicators set forth by WHO is therefore suggested. PMID- 25812084 TI - Targeting AMPK for cancer prevention and treatment. AB - AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism. PMID- 25812089 TI - Ocean bacteria: performance on CODCr and NH4(+)-N removal in landfill leachate treatment. AB - An experiment was carried out to investigate the performance of mixed ocean bacteria, isolated from the ocean sediment, on landfill leachate treatment. In this treatment, ocean bacteria were the only constituent added to remove organics and NH(4)(+)-N. Given their considerable influence on wastewater purification, factors such as inoculum, initial pH, processing time and oxygen condition, were directly involved in this research. As indicated by laboratory test results, chemical oxygen demand (CODCr) and NH(4)(+)-N removal could reach 94.45% and 67.87%, respectively, after 3 days of treatment, in conditions of natural pH 6.3 and with the application of oxygen. The volt-ampere characteristics of the bacteria solution verified the redox-active ability of the bacteria in landfill leachate treatment. PMID- 25812090 TI - Optimization of operating parameters for efficient photocatalytic inactivation of Escherichia coli based on a statistical design of experiments. AB - In this work, the individual and interaction effects of three key operating parameters of the photocatalytic disinfection process were evaluated and optimized using response surface methodology (RSM) for the first time. The chosen operating parameters were: reaction temperature, initial pH of the reaction mixture and TiO2 P-25 photocatalyst loading. Escherichia coli concentration, after 90 minutes irradiation of UV-A light, was selected as the response. Twenty sets of photocatalytic disinfection experiments were conducted by adjusting operating parameters at five levels using the central composite design. Based on the experimental data, a semi-empirical expression was established and applied to predict the response. Analysis of variance revealed a strong correlation between predicted and experimental values of the response. The optimum values of the reaction temperature, initial pH of the reaction mixture and photocatalyst loading were found to be 40.3 degrees C, 5.9 g/L, and 1.0 g/L, respectively. Under the optimized conditions, E. coli concentration was observed to reduce from 10(7) to about 11 CFU/mL during the photocatalytic process. Moreover, all these results showed the great significance of the RSM in developing high performance processes for photocatalytic water disinfection. PMID- 25812091 TI - Granular activated algae for wastewater treatment. AB - The study used activated algae granules for low-strength wastewater treatment in sequential batch mode. Each treatment cycle was conducted within 24 h in a bioreactor exposed to 235 MUmol/m2/s light intensity. Wastewater treatment was performed mostly in aerobic conditions, oxygen being provided by microalgae. High removal efficiency of chemical oxygen demand (COD) was achieved (86-98%) in the first hours of the reaction phase, during which the indicator's removal rate was 17.4 +/- 3.9 mg O2/g h; NH(4)(+) was removed during organic matter degradation processes with a rate of 1.8 +/- 0.6 mg/g h. After almost complete COD removal, the (O+) remaining in the liquor was removed through nitrification processes promoted by the increase of the liquor's oxygen saturation (O2%), the transformation rate of NH4(+) into NO(3)(-) increasing from 0.14 +/- 0.05 to 1.5 +/- 0.4 mg NH4(+)/g h, along with an O2% increase. A wide removal efficiency was achieved in the case of PO(4)(3)(-) (11-85%), with the indicator's removal rate being 1.3 +/- 0.7 mg/g h. In the provided optimum conditions, the occurrence of the denitrifying activity was also noticed. A large pH variation was registered (5-8.5) during treatment cycles. The granular activated algae system proved to be a promising alternative for wastewater treatment as it also sustains cost efficient microalgae harvesting, with microalgae recovery efficiency ranging between 99.85 and 99.99% after granules settling with a velocity of 19 +/- 3.6 m/h. PMID- 25812092 TI - Model-based evaluation of mechanisms and benefits of mainstream shortcut nitrogen removal processes. AB - The main challenge in implementing shortcut nitrogen removal processes for mainstream wastewater treatment is the out-selection of nitrite oxidizing bacteria (NOB) to limit nitrate production. A model-based approach was utilized to simulate the impact of individual features of process control strategies to achieve NO(-)(2)-N shunt via NOB out-selection. Simulations were conducted using a two-step nitrogen removal model from the literature. Nitrogen shortcut removal processes from two case studies were modeled to illustrate the contribution of NOB out-selection mechanisms. The paper highlights a comparison between two control schemes; one was based on online measured ammonia and the other was based on a target ratio of 1 for ammonia vs. NOx (nitrate + nitrite) (AVN). Results indicated that the AVN controller possesses unique features to nitrify only that amount of nitrogen that can be denitrified, which promotes better management of incoming organics and bicarbonate for a more efficient NOB out-selection. Finally, the model was used in a scenario analysis, simulating hypothetical optimized performance of the pilot process. An estimated potential saving of 60% in carbon addition for nitrogen removal by implementing full-scale mainstream deammonification was predicted. PMID- 25812094 TI - Inhibitory mechanisms of Acacia mearnsii extracts on the growth of Microcystis aeruginosa. AB - Our previous work revealed that Acacia mearnsii extract can inhibit the growth of Microcystis aeruginosa, the common species forming toxic cyanobacterial blooms in eutrophic freshwater. In the present study, we demonstrated that this plant extract can significantly increase cell membrane permeability and Ca2+/Mg2+ ATPase activity on the membrane. Long-term exposure to concentrations of 20 ppm A. mearnsii extract led to algal cell membrane leakage or even lysis. Comparison of expression of three photosynthesis-related genes (rbcL, psaB and psbD) in M. aeruginosa with and without plant extract treatment revealed that their expression was remarkably reduced in the presence of the extract. Down-regulation of photosynthesis-related genes could indicate the inhibition of the photosynthetic process. Thus, our results suggested that both photosynthetic systems and membranes of M. aeruginosa are potentially damaged by A. mearnsii extract. PMID- 25812093 TI - Enhanced electrochemical oxidation of Acid Red 3R wastewater with iron phosphomolybdate supported catalyst. AB - Electrochemical oxidation of Acid Red 3R (AR3R) was investigated with the new catalyst of iron phosphomolybdate (FePMo12) supported on modified molecular sieves type 4 A (4A) as packing materials in the reactor. The results of the Fourier transform infrared spectroscopy and X-ray diffraction indicated that the heteropolyanion had a Keggin structure. The optimal conditions for decolorization of simulated AR3R wastewater were as follows: current density 35 mA/cm2, initial pH 4.0, airflow 0.08 m3/hour and inter-electrode distance 3.0 cm. With the addition of NaCl to the system, the decolorization efficiency increased. But Na2SO4had a negative effect on the decolorization efficiency, which was attributed to the negative salt effect. The degradation mechanisms of AR3R were also discussed in detail. PMID- 25812095 TI - Depression storage capacities of different ideal pavements as quantified by a terrestrial laser scanning-based method. AB - Rainfall partition on paved urban surfaces is governed to a great extent by depression storage. This is especially the case for small rainfall events, which are often ignored in urban hydrology. If storage, infiltration and evaporation (important for urban heat island mitigation), rather than storm water run-off, are of interest, high-resolution simulations with exact values for depression storage capacities are required. Terrestrial laser scanners deliver fast, high resolution surveys of pavement surface morphology. The depression storage capacity can be quantified from 3D points by generating digital elevation models and applying cut-and-fill algorithms in a geographic information system. The method was validated using a test model. It was possible to quantify depressions with a depth of at least 1.4 * 10(-3) m and a surface of at least 15 * 10(-6) m(2) with an uncertainty below 30%. Applying this method, the depression storage capacities for 11 ideal, typical pavement designs were found to vary from 0.07 to 1.4 mm. Realistic urban pavements must also be surveyed, as cracks and puddles from their use history can have a major impact on the depression storage capacities and thus on infiltration, evaporation and, finally, the annual run off. PMID- 25812096 TI - Effects of influent fractionation, kinetics, stoichiometry and mass transfer on CH4, H2 and CO2 production for (plant-wide) modeling of anaerobic digesters. AB - This paper examines the importance of influent fractionation, kinetic, stoichiometric and mass transfer parameter uncertainties when modeling biogas production in wastewater treatment plants. The anaerobic digestion model no. 1 implemented in the plant-wide context provided by the benchmark simulation model no. 2 is used to quantify the generation of CH4, H2and CO2. A comprehensive global sensitivity analysis based on (i) standardized regression coefficients (SRC) and (ii) Morris' screening's (MS's) elementary effects reveals the set of parameters that influence the biogas production uncertainty the most. This analysis is repeated for (i) different temperature regimes and (ii) different solids retention times (SRTs) in the anaerobic digester. Results show that both SRC and MS are good measures of sensitivity unless the anaerobic digester is operating at low SRT and mesophilic conditions. In the latter situation, and due to the intrinsic nonlinearities of the system, SRC fails in decomposing the variance of the model predictions (R2 < 0.7) making MS a more reliable method. At high SRT, influent fractionations are the most influential parameters for predictions of CH4and CO2emissions. Nevertheless, when the anaerobic digester volume is decreased (for the same load), the role of acetate degraders gains more importance under mesophilic conditions, while lipids and fatty acid metabolism is more influential under thermophilic conditions. The paper ends with a critical discussion of the results and their implications during model calibration and validation exercises. PMID- 25812097 TI - Optimized photocatalytic degradation of caffeic acid by sol-gel TiO2. AB - TiO2anatase powder was prepared by means of the sol-gel method with titanium(IV) butoxide as precursor. The formation of a tetragonal crystal structure of TiO2anatase at 500 degrees C was confirmed by X-ray powder diffraction. The characterization of the samples synthesized was complemented by scanning electron microscopy, diffuse reflectance infrared Fourier transform spectroscopy, nitrogen adsorption-desorption isotherms (Brunauer-Emmett-Teller) and diffuse reflectance spectroscopy. The photocatalytic activity of the TiO2anatase powder was evaluated in the degradation of caffeic acid in aqueous solution under ultraviolet radiation. A central composite circumscribed design was used to assess the weight of the experimental variables, pH and amount of catalyst in the percentage of caffeic acid degraded and the optimal conditions. The optimized conditions were found to be pH = 5.2 and a load of TiO2of 1.1 g L-1. Under these conditions more than 90% of caffeic acid degradation was achieved after 30 min of lamp irradiation. At this time the mineralization reached was almost 60%. PMID- 25812098 TI - Water use efficiency and productivity of habanero pepper (Capsicum chinense Jacq.) based on two transplanting dates. AB - Habanero pepper production was assessed with drip irrigation and plastic mulch, based on two transplanting dates. The objectives of the study were: (i) to evaluate the effect of two transplanting dates and the use of plastic mulch on water productivity and habanero pepper fruit yield under drip irrigation conditions; and (ii) to determine the profitability and economic viability of the product in the regional market. The work was conducted in the municipality of Huimanguillo, state of Tabasco, Mexico, in loam soils classified as Eutric Fluvisol. The Jaguar variety of habanero pepper, developed by INIFAP and possessing better genetic and productive characteristics, was used. Two transplanting dates were studied, (i) 30 January 2013 and (ii) 15 February 2013, with and without plastic mulch. The conclusions were: (i) application of irrigation depths based on crop evapotranspiration (ETc) and plastic mulch transplanted on 30 January increased the fruit yield of the crop and improved the benefit-cost ratio of the production system; and (ii) water use efficiency based on the 30 January transplanting date was 8.68 kg m-3 of water applied with plastic mulch, 6.51 kg m-3 without plastic mulch, and 3.65 kg m-3 for the 15 February transplanting date with plastic mulch. PMID- 25812099 TI - Struvite precipitation in raw and co-digested swine slurries for nutrients recovery in batch reactors. AB - The release of nitrogen (N) and phosphorus (P) from agro-industrial sources is a major environmental concern. Furthermore, the scarcity of mineable P and the growing demand for food worldwide necessitate that we find an alternative P source. This study applied struvite precipitation for N-P recovery to slurries with high levels of organics and ammonia to achieve environmental protection from excessive nutrients diffusion and to generate a sustainable P source. Batch tests were carried out on raw and co-digested swine slurries to study the feasibility of struvite precipitation and the effect of several parameters, including pH, reaction time, competing ions (Ca2+, K+), total solids (TS), and alkalinity. The batch assays with raw swine slurries showed high N-P removals (up to 80%), while the anaerobic liquor returned lower recovery efficiency due to the high solids and alkali content. Struvite crystallization was detected at pH values as low as 6, and the characteristics of the recovered struvite matched those of the theoretical. Slight co-precipitation of calcium-phosphates occurred and was dependent on the Ca2+/Mg2+ ratio rather than on varying pH values. Struvite precipitation was shown to be feasible in complex matrices as agro-industrial effluents, characterized by high NH(4)(+), alkalinity, solids and organic content, and interfering ions such as Ca2+ and K+. PMID- 25812100 TI - Modelling the impact of retention-detention units on sewer surcharge and peak and annual runoff reduction. AB - Stormwater management using water sensitive urban design is expected to be part of future drainage systems. This paper aims to model the combination of local retention units, such as soakaways, with subsurface detention units. Soakaways are employed to reduce (by storage and infiltration) peak and volume stormwater runoff; however, large retention volumes are required for a significant peak reduction. Peak runoff can therefore be handled by combining detention units with soakaways. This paper models the impact of retrofitting retention-detention units for an existing urbanized catchment in Denmark. The impact of retrofitting a retention-detention unit of 3.3 m3/100 m2 (volume/impervious area) was simulated for a small catchment in Copenhagen using MIKE URBAN. The retention-detention unit was shown to prevent flooding from the sewer for a 10-year rainfall event. Statistical analysis of continuous simulations covering 22 years showed that annual stormwater runoff was reduced by 68-87%, and that the retention volume was on average 53% full at the beginning of rain events. The effect of different retention-detention volume combinations was simulated, and results showed that allocating 20-40% of a soakaway volume to detention would significantly increase peak runoff reduction with a small reduction in the annual runoff. PMID- 25812101 TI - Characteristics of nitrogen and phosphorus removal by a surface-flow constructed wetland for polluted river water treatment. AB - The characteristics of nitrogen (N) and phosphorus (P) removal were studied during the 2-year operation of a free water surface flow wetland of 900 m2 with hydraulic loading of 0.1 m/d to evaluate its potential to treat water from an urban stream polluted with municipal and industrial wastewater. Attention was focused on the removal of dissolved N and P by harvesting plants (local Phragmites australis and Typha orientalis) at the end of each growing season. According to findings, the removals of N and P increased from 47.1% and 17.6%, respectively, in the 1st year to 52.3% and 32.4%, respectively, in the 2nd year. Increments of N and P removal were largely attributable to plant biomass, which increased from an average dry weight of 1.77 kg/m2 in the 1st year to 3.41 kg/m2 in the 2nd year. The amount of nutrients assimilated by plants in the 2nd year was almost double that of the 1st year. Increasing biomass in the 2nd year also improved redox conditions in the substrate layer, which contributed to increasing the efficiency of N removal. Compared with T. orientalis, P. australis was more competitive and adapted to conditions in the wetland better; it regenerated more vigorously and contributed more to nutrient removal. PMID- 25812102 TI - Submerged macrophyte Ceratophyllum demersum affects phosphorus exchange at the sediment-water interface. AB - Substantial research efforts were made to assess the effects of submerged macrophytes on water quality improvement, but information on the mechanism of submerged macrophytes relative to the exchange of phosphorus (P) at the sediment water interface is very limited. To help fill the void, a popular species, Ceratophyllum demersum L. was chosen to address the effects and mechanisms of submerged macrophyte growth on the processes of P exchange across the sediment- water interface. In treatment mesocosms (planted), equilibrium phosphorus concentration (EPC0) value falls from 68.4 to 36.0 ug/L, with a mean value of 52.5 ug/L. Conversely, the distribution coefficient (Kd) value has a predominantly increasing trend. But they are both significantly higher than an unplanted control (p < 0.05). Also, in the planted mesocosm, maximum phosphate sorption capacity (Qmax) was significantly reduced (4,721-3,845 mg/kg), and most of the linear correlations between different forms of phosphorus and sediment P adsorption parameters were affected (p < 0.05). The EPC0 Percentage Saturation percentages (EPCsat) in planted groups were 325% higher than that in control (p < 0.05). We conclude that C. demersum could promote the release of P from sediments, and soluble reactive phosphorus concentration in overlying water is probably the driving force for P exchange at the sediment-water interface. PMID- 25812103 TI - Anaerobic biodegradability of fish remains: experimental investigation and parameter estimation. AB - The generation of organic waste associated with aquaculture fish processing has increased significantly in recent decades. The objective of this study is to evaluate the anaerobic biodegradability of several fish processing fractions, as well as water treatment sludge, for tilapia and sturgeon species cultured in recirculated aquaculture systems. After substrate characterization, the ultimate biodegradability and the hydrolytic rate were estimated by fitting a first-order kinetic model with the biogas production profiles. In general, the first-order model was able to reproduce the biogas profiles properly with a high correlation coefficient. In the case of tilapia, the skin/fin, viscera, head and flesh presented a high level of biodegradability, above 310 mLCH4gCOD-1, whereas the head and bones showed a low hydrolytic rate. For sturgeon, the results for all fractions were quite similar in terms of both parameters, although viscera presented the lowest values. Both the substrate characterization and the kinetic analysis of the anaerobic degradation may be used as design criteria for implementing anaerobic digestion in a recirculating aquaculture system. PMID- 25812104 TI - Performance comparison between two equal stabilization ponds operating with and without sludge layer. AB - Stabilization ponds are a highly appropriate system for treating sewage in small to medium size communities. However, sludge accumulation at the pond bottom occurs with the passage of time, reducing the net pond volume, which, in principle, could affect its performance. The objective of this paper is to compare the behaviour of two equal ponds in parallel treating the same flow of municipal wastewater from an upflow anaerobic sludge blanket reactor in Brazil. Each pond treated a population equivalent of around 125 inhabitants. One pond had approximately 40% of its net volume occupied by sludge after 11 years of operation, while the other pond had previously undergone complete desludging. The study covers the removal of biochemical oxygen demand (BOD), chemical oxygen demand (COD), suspended solids (SS), nitrogen fractions and coliforms. Owing to the presence of a sludge layer, the theoretical hydraulic retention time (HRT) was lower in the pond without sludge. For BOD, COD, SS and Escherichia coli there were no significant differences (Wilcoxon matched-pairs test) between both ponds. The pond without sludge had significantly better removal efficiencies in terms of total Kjeldahl nitrogen and ammonia-N. The sludge layer probably allowed the occurrence of removal mechanisms that compensated for the reduction caused in the HRT. PMID- 25812105 TI - Vertical-flow constructed wetlands treating domestic wastewater contaminated by hydrocarbons. AB - The aim was to compare the impact of different design (aggregate size) and operational (contact time, empty time and chemical oxygen demand (COD) loading) variables on the long-term and seasonal performance of vertical-flow constructed wetland filters operated in tidal flow mode before and after a one-off spill of diesel. Ten different vertical-flow wetland systems were planted with Phragmites australis (Cav.) Trin. ex Steud. (common reed). Approximately 130 g of diesel fuel was poured into four wetland filters. Before the spill, compliance with secondary wastewater treatment standards was achieved by all wetlands regarding ammonia-nitrogen (NH4-N), nitrate-nitrogen (NO3-N) and suspended solids (SS), and non-compliance was recorded for biochemical oxygen demand and ortho-phosphate phosphorus (PO4-P). Higher COD inflow concentrations had a significantly positive impact on the treatment performance for COD, PO4-P and SS. The wetland with the largest aggregate size had the lowest mean NO3-N outflow concentration. However, the results were similar regardless of aggregate size and resting time for most variables. Clear seasonal outflow concentration trends were recorded for COD, NH4 N and NO3-N. No filter clogging was observed. The removal efficiencies dropped for those filters impacted by the diesel spill. The wetlands system shows a good performance regarding total petroleum hydrocarbon (TPH) removal. PMID- 25812106 TI - Characterization of modified PVDF membrane by gamma irradiation for non-potable water reuse. AB - Poly(vinylidene fluorine) (PVDF) membranes were grafted by gamma-ray irradiation and were sulfonated by sodium sulfite to modify the surface of the membranes. The characteristics of the modified PVDF membranes were evaluated by the data of Fourier transform infrared (FT-IR), X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscope (FE-SEM), the contact angle of the membrane surface and the water permeability. From the results of FT-IR, XPS and FE-SEM, it was shown that the modified membranes were successfully grafted by gamma-ray irradiation and were sulfonated. The content of oxygen and sulfur increased with the monomer concentration, while the content of fluorine sharply decreased. The pore size of the modified membranes decreased after gamma-ray irradiation. The contact angle and the water permeability showed that the hydrophilicity of the modified membranes played a role in determining the membrane performance. The feasibility study of the modified PVDF membranes for using non-potable water reuse were carried out using a laboratory-scale microfiltration system. Grey wastewater was used as the influent in the filtration unit, and permeate quality satisfied non-potable water reuse guidelines in the Republic of Korea. PMID- 25812107 TI - Corrigendum: Water Science and Technology 70 (10), 1663-1669: Adsorption and removal of triphenylmethane dyes from water by magnetic reduced graphene oxide, Jian-Zhong Sun, Zhi-Hong Liao, Rong-Wei Si, Gakai Peter Kingori, Fu-Xiang Chang, Lu Gao, Yu Shen, Xiang Xiao, Xiang-Yang Wu and Yang-Chun Yong. PMID- 25812110 TI - Correction: Piericidin A aggravates tau pathology in P301S transgenic mice. PMID- 25812111 TI - A Promising Raman Spectroscopy Technique for the Investigation of trans and cis Cholesteryl Ester Isomers in Biological Samples. AB - Lipid geometry is an important issue in biology and medicine. The cis-trans geometry conversion of double bonds in lipids is an endogenous process that can be mediated by sulfur-centered free radicals. Trans isomers of polyunsaturated fatty acids can be used as biological markers of free radical stress, and their presence in biological samples can be determined by synthesis and characterization of appropriate reference compounds. Fractions of plasma lipids, such as cholesteryl linoleate and arachidonate esters, are interesting targets because of their connection with membrane phospholipid turnover and their roles in cardiovascular health. In this context, Raman spectroscopy can provide a useful contribution, since Raman analysis can be performed directly on the lipid extracts without any derivatization reaction, is nondestructive, and can rapidly supply biochemical information. This study focused on the build up of Raman spectral libraries of different cis and trans isomers of cholesteryl esters to be used as references for the examination of complex biological samples and to facilitate isomer recognition. Unsaturated cholesteryl esters obtained by chemical synthesis and with different alkyl chain lengths, double bond numbers, or both, were analyzed. The potential of Raman analysis for trans isomer detection in biological samples was successfully tested on some cholesteryl ester lipid fractions from human serum. The data suggest promising applications of Raman spectroscopy in metabolomics and lipidomics. PMID- 25812108 TI - Viral etiology of community-acquired pneumonia among adolescents and adults with mild or moderate severity and its relation to age and severity. AB - BACKGROUND: Better knowledge of distribution of respiratory viruses (RVs) in adolescents and adults with community-acquired pneumonia (CAP) is needed. METHODS: To investigate the RVs etiology among adolescents and adults with CAP, according to age and pneumonia severity index (PSI), a multi-center, prospective study was conducted from November 2010 to April 2012. Fifteen RVs were tested by polymerase chain reaction (PCR). Bacteria were detected by urinary antigen, conventional culture and PCR. RESULTS: Mean (SD) age and median (IQR) PSI score of 954 patients enrolled was 45.2 (19.5) years (range 14-94) and 42 (36). RVs were found in 262 patients (27.5%): influenza virus A (IFV A, 9.9%) comprised of pandemic H1N1 (6.7%) and seasonal H3N2 (3.5%), human rhinovirus (4.3%), adenovirus (4.2%), human metapneumovirus (1.8%), parainfluenza virus 1, 3 and 2 (1.7%, 1.5% and 1.2%). Influenza virus B, enterovirus, respiratory syncytial virus, human coronavirus and parainfluenza virus 4 were rarely detected (<1%). Frequency of IFV A was highest among patients aged between 45-64 years (p < 0.001), while adenovirus among patients aged 14-17 years (p < 0.001), no differences was found in other RVs. The proportion of pandemic H1N1 increased with severity of pneumonia evaluated by PSI (P < 0.05). CONCLUSIONS: The proportion of RVs in CAP is higher than previously reported. IFV A pneumonia are usually found in patients older than 45 years, while, adenovirus pneumonia are common in adolescents and young adults. Pandemic H1N1 virus is still recognized by PSI as a high-severity pathogen. The findings contribute baseline data on viral CAP study in China. PMID- 25812109 TI - Human parvovirus 4 infection among mothers and children in South Africa. PMID- 25812112 TI - Stepwise construction of extra-large heterometallic calixarene-based cages. AB - Utilizing presynthesized large Na2Ni12Ln2 clusters (Ln = Dy and Tb) supported by calixarene as molecular building blocks (MBBs), we have obtained a series of cationic trigonal prismatic heterometallic organic nanocages (HMONCs) with tunable sizes through a stepwise method. Specially, in each structure of the HMONCs, three linear dicarboxylate linkers substitute the peripheral coordinated acetate ligands of two Na2Ni12Ln2 clusters to form an unprecedented Na4Ni24Ln4 HMONC through a M2L3 condensation. Moreover, magnetic study reveals that the Na2Ni12Dy2 core retains its slow magnetic relaxation behavior. Gas sorption behaviors of these HMONCs were also studied. To the best of our knowledge, these HMONCs built from large heterotrimetallic Na2Ni12Ln2 MBBs, which are based on smaller Ni4-calix ones, have not been reported in any other cages to date. In addition, this research also provides a new strategy for the design and construction of HMONCs with predictable structures and functional properties. PMID- 25812113 TI - Effect of Active Smoking on Comparative Efficacy of Antithrombotic Therapy in Patients With Atrial Fibrillation: The Loire Valley Atrial Fibrillation Project. AB - BACKGROUND: Active smoking is associated with elevated thrombotic risk. Smoking status has recently been incorporated into the SAMe-TT2R2 (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]) score that can help predict poor international normalized ratio control in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs). The clinical benefit of antiplatelet therapy (APT) has been seen primarily in smokers. We hypothesized that active smoking may differently influence the risks of stroke and bleeding in patients with AF treated with VKAs or with APT. METHODS: We examined the clinical course of 7,809 consecutive patients with AF seen between 2000 and 2010. Outcomes in patients who were active smokers were compared with those in other patients. RESULTS: Among 7,809 patients with AF, 1,034 (13%) were active smokers. APT was prescribed on an individual basis for 2,761 patients (35%) and VKAs for 4,534 (57%). After a follow-up of 929 +/- 1,082 days (median = 463 days, interquartile range = 1,564 days), smoking was not independently associated with a higher risk of stroke/thromboembolic event in patients with AF (hazard ratio [HR], 0.95; 95% CI, 0.78-1.22; P = .66). On multivariate analysis, smoking was independently associated with a worse prognosis for the risk of severe bleeding (HR, 1.23; 95% CI, 1.01-1.49; P = .04) and for the risk of major Bleeding Academic Research Consortium bleeding (HR, 1.40; 95% CI, 1.02-1.90; P = .03). Smoking was independently associated with a higher risk of bleeding in patients treated with VKAs (HR, 1.32; 95% CI, 1.04 1.67; P = .02), whereas the risk was nonsignificant in patients treated with APT (HR, 1.28; 95% CI, 0.94-1.74; P = .11). CONCLUSIONS: In AF, there was a higher risk of severe bleeding in smokers, mainly in those treated with VKAs. PMID- 25812114 TI - Progress in human embryonic stem cell research in the United States between 2001 and 2010. AB - On August 9th, 2001, the federal government of the United States announced a policy restricting federal funds available for research on human embryonic stem cell (hESCs) out of concern for the "vast ethical mine fields" associated with the creation of embryos for research purposes. Until the policy was repealed on March 9th, 2009, no U.S. federal funds were available for research on hESCs extracted after August 9, 2001, and only limited federal funds were available for research on a subset of hESC lines that had previously been extracted. This paper analyzes how the 2001 U.S. federal funding restrictions influenced the quantity and geography of peer-reviewed journal publications on hESC. The primary finding is that the 2001 policy did not have a significant aggregate effect on hESC research in the U.S. After a brief lag in early 2000s, U.S. hESC research maintained pace with other areas of stem cell and genetic research. The policy had several other consequences. First, it was tied to increased hESC research funding within the U.S. at the state level, leading to concentration of related activities in a relatively small number of states. Second, it stimulated increased collaborative research between US-based scientists and those in countries with flexible policies toward hESC research (including Canada, the U.K., Israel, China, Spain, and South Korea). Third, it encouraged independent hESC research in countries without restrictions. PMID- 25812115 TI - CEUS in hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma in 320 patients - early or late washout matters: a subanalysis of the DEGUM multicenter trial. AB - PURPOSE: The aim of the study was the comparison of tumor vascularization and contrast enhancement in contrast-enhanced ultrasound (CEUS) for the characterization of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC). We present data of the subpopulations HCC and ICC examined in the DEGUM multicenter trial for the characterization of focal liver lesions in clinical practice. MATERIALS AND METHODS: Based on the data of the DEGUM multicenter trial (1349 patients), all patients with histologically proven HCC (n = 278) and ICC (n = 42) were analyzed. The vascularity pattern and contrast enhancement pattern during the arterial, portal-venous and late phase were compared. RESULTS: An underlying liver cirrhosis was found in 214/278 patients with HCC (76.9 %) and 7/42 patients with ICC (16.7 %). In CEUS, HCC showed a global arterial hyperenhancement compared to ICC (HCC: tumor center: 60.3 %; tumor periphery: 75 %; ICC: tumor center: 16.7 %; tumor periphery: 40.5 %). ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC: 85.7 % vs. HCC: 61 %) followed by an early portal-venous contrast washout in the tumor center (ICC: 85.8 % vs. HCC: 49.8 %) and tumor periphery (ICC: 66.7 % vs. HCC: 32.6 %). HCC showed a delayed contrast washout (late phase hypoenhancement: HCC: 75 % vs. ICC: 92.9 %). CONCLUSION: ICCs are rare in cirrhotic livers. CEUS can demonstrate differences in the vascularization patterns between HCC and ICC. HCC showed an arterial global hyperenhancement and delayed contrast washout in the late phase. ICCs are characterized by an arterial contrast enhancement at the tumor periphery with early contrast washout of the vascularized parts of the lesions in the portal-venous and late phase. PMID- 25812116 TI - Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice. AB - Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg), to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition. PMID- 25812119 TI - Pd-catalyzed electrohydrogenation of carbon dioxide to formate: high mass activity at low overpotential and identification of the deactivation pathway. AB - Electrochemical reduction of CO2 to formate (HCO2(-)) powered by renewable electricity is a possible carbon-negative alternative to synthesizing formate from fossil fuels. This process is energetically inefficient because >1 V of overpotential is required for CO2 reduction to HCO2(-) on the metals currently used as cathodic catalysts. Pd reduces CO2 to HCO2(-) with no overpotential, but this activity has previously been limited to low synthesis rates and plagued by an unidentified deactivation pathway. Here we show that Pd nanoparticles dispersed on a carbon support reach high mass activities (50-80 mA HCO2(-) synthesis per mg Pd) when driven by less than 200 mV of overpotential in aqueous bicarbonate solutions. Electrokinetic measurements are consistent with a mechanism in which the rate-determining step is the addition of electrochemically generated surface adsorbed hydrogen to CO2 (i.e., electrohydrogenation). The electrodes deactivate over the course of several hours because of a minor pathway that forms CO. Activity is recovered, however, by removing CO with brief air exposure. PMID- 25812117 TI - Hospital admission of cancer patients: avoidable practice or necessary care? AB - BACKGROUND: Cancer patients are frequently admitted to hospital due to acute conditions or refractory symptoms. This occurs through the emergency departments and requires medical oncologists to take an active role. The use of acute-care hospital increases in the last months of life. PATIENTS AND METHODS: We aimed to describe the admissions to a medical oncology inpatient service within a 16-month period with respect to patients and tumor characteristics, and the outcome of the hospital stay. RESULTS: 672 admissions of 454 patients were analysed. The majority of admissions were urgent (74.1%), and were due to uncontrolled symptoms (79.6%). Among the chief complaints, dyspnoea occurred in 15.7%, pain in 15.2%, and neurological symptoms in 14.5%. The majority of the hospitalizations resulted in discharge to home (60.6%); in 26.5% the patient died and in 11.0% was transferred to a hospice. Admissions due to symptoms correlated with a longer hospital stay and a higher incidence of in-hospital death. CONCLUSION: We suggest that hospital use is not necessarily a sign of inappropriately aggressive care: inpatient care is probably an unavoidable step in the cancer trajectory. Optimization of inpatient supportive procedures should be a specific task of modern medical oncology. PMID- 25812118 TI - Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression. AB - Brown fat generates heat to protect against cold and obesity. Adrenergic stimulation activates the thermogenic program of brown adipocytes. Although the bioactivity of brown adipose tissue in adult humans had been assumed to very low, several studies using positron emission tomography-computed tomography (PET-CT) have detected bioactive brown adipose tissue in adult humans under cold exposure. In this study, we collected adipose tissues obtained from the perirenal regions of adult patients with pheochromocytoma (PHEO) or non-functioning adrenal tumors (NF). We demonstrated that perirenal brown adipocytes were activated in adult patients with PHEO. These cells had the molecular characteristics of classical brown fat rather than those of beige/brite fat. Expression of brown adipose tissue markers such as uncoupling protein 1 (UCP1) and cell death-inducing DFFA like effector A (CIDEA) was highly correlated with the amounts of PRD1-BF-1-RIZ1 homologous domain-containing protein-16 (PRDM16) - euchromatic histone-lysine N methyltransferase 1 (EHMT1) complex, the key transcriptional switch for brown fat development. These results provide novel insights into the reconstruction of human brown adipocytes and their therapeutic application against obesity and its complications such as type 2 diabetes. PMID- 25812120 TI - Hepatocyte-specific deletion of ARNT (aryl hydrocarbon Receptor Nuclear Translocator) results in altered fibrotic gene expression in the thioacetamide model of liver injury. AB - BACKGROUND & AIMS: Recent studies have shown that increased expression of liver hypoxia inducible factor 2-alpha (HIF-2alpha) leads to liver inflammation and a pro-fibrotic gene expression signature. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is required for HIF-2alpha transcriptional activity and has previously been shown to regulate hepatic metabolism in mice. In these studies we examined the role of hepatocyte ARNT in the thioacetamide (TAA)-induced model of liver fibrosis. METHODS: Hepatocyte-specific ARNT-null (LARNT) mice were created using an albumin promoter-driven Cre recombinase. LARNT and floxed control (FC) littermates were placed on chow diet and received twice weekly intraperitoneal injections of 0.15mg/g body weight of TAA for 13 weeks. RESULTS: TAA treated LARNT and FC mice had a similar pattern of fibrosis. Quantification of Sirius red histology staining and hydroxyproline content revealed mixed results in terms of collagen deposition in LARNT livers. There was no significant difference in hepatocyte apoptosis or proliferation, as assessed by cleaved Caspase-3 and Ki67 respectively. LARNT mice had decreased macrophage accumulation, and decreased liver mRNA expression of Col1A1, Col1A2, Col5A1, Tgfbeta1, Tgfbeta2, Timp1 and Timp2. CONCLUSIONS: Deletion of hepatocyte ARNT leads to altered expression of collagen associated mRNA and reduced macrophage infiltration in the TAA-induced model of liver fibrosis. It appears that hepatocyte ARNT is not a requirement for initiation of liver fibrogenesis, but does regulate pro-fibrotic gene expression and macrophage accumulation. PMID- 25812121 TI - Simple messages help set the record straight about scientific agreement on human caused climate change: the results of two experiments. AB - Human-caused climate change is happening; nearly all climate scientists are convinced of this basic fact according to surveys of experts and reviews of the peer-reviewed literature. Yet, among the American public, there is widespread misunderstanding of this scientific consensus. In this paper, we report results from two experiments, conducted with national samples of American adults, that tested messages designed to convey the high level of agreement in the climate science community about human-caused climate change. The first experiment tested hypotheses about providing numeric versus non-numeric assertions concerning the level of scientific agreement. We found that numeric statements resulted in higher estimates of the scientific agreement. The second experiment tested the effect of eliciting respondents' estimates of scientific agreement prior to presenting them with a statement about the level of scientific agreement. Participants who estimated the level of agreement prior to being shown the corrective statement gave higher estimates of the scientific consensus than respondents who were not asked to estimate in advance, indicating that incorporating an "estimation and reveal" technique into public communication about scientific consensus may be effective. The interaction of messages with political ideology was also tested, and demonstrated that messages were approximately equally effective among liberals and conservatives. Implications for theory and practice are discussed. PMID- 25812122 TI - Acceptance Mediates the Relationship Between Tinnitus-Related Cognitions and Anxiety Sensitivity. AB - PURPOSE: Negative cognitions related to tinnitus sensation have been previously shown to affect the level of emotional distress. Anxiety sensitivity is another psychological factor that influences individuals to more closely monitor their own bodily sensations, resulting in increased negative cognitions and negative emotional responses among tinnitus patients. However, increasing acceptance of tinnitus sensation may attenuate emotional distress. The goal of this research was to investigate the relationship between negative tinnitus-related cognitions, acceptance, and anxiety sensitivity. METHOD: Two hundred sixty-seven participants completed online measures of the Tinnitus Handicap Inventory (Newman, Jacobson, & Spitzer, 1996), Acceptance and Action Questionnaire (Hayes, Follette, & Linehan, 2004), and the Anxiety Sensitivity Index-3 (Taylor et al., 2007). RESULTS: Hierarchical regression analyses indicated that acceptance fully mediated the relationship between negative tinnitus-related cognitions and anxiety sensitivity. CONCLUSIONS: On the basis of these results, it is suggested that practitioners improve acceptance of tinnitus sensation, duration, and intensity. More research is warranted on the clinical techniques to improve acceptance. PMID- 25812123 TI - Phenobarbital and neonatal seizures affect cerebral oxygen metabolism: a near infrared spectroscopy study. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) measures oxygen metabolism and is increasingly used for monitoring critically ill neonates. The implications of NIRS-recorded data in this population are poorly understood. We evaluated NIRS monitoring for neonates with seizures. METHODS: In neonates monitored with video electroencephalography, NIRS-measured cerebral regional oxygen saturation (rSO2) and systemic O2 saturation were recorded every 5 s. Mean rSO2 was extracted for 1 h blocks before, during, and after phenobarbital doses. For each electrographic seizure, mean rSO2 was extracted for a period of three times the duration of the seizure before and after the ictal pattern, as well as during the seizure. Linear mixed models were developed to assess the impact of phenobarbital administration and of seizures on rSO2 and fractional tissue oxygen extraction. RESULTS: For 20 neonates (estimated gestational age: 39.6 +/- 1.5 wk), 61 phenobarbital doses and 40 seizures were analyzed. Cerebral rSO2 rose (P = 0.005), and fractional tissue oxygen extraction declined (P = 0.018) with increasing phenobarbital doses. rSO2 declined during seizures, compared with baseline and postictal phases (baseline 81.2 vs. ictal 77.7 vs. postictal 79.4; P = 0.004). Fractional tissue oxygen extraction was highest during seizures (P = 0.002). CONCLUSIONS: Cerebral oxygen metabolism decreases after phenobarbital administration and increases during seizures. These small, but clear, changes in cerebral oxygen metabolism merit assessment for potential clinical impact. PMID- 25812124 TI - Comparisons between the 35 mm quadrature surface resonator at 300 K and the 40 mm high-temperature superconducting surface resonator at 77 K in a 3T MRI imager. AB - This study attempts to compare the signal-to-noise ratio (SNR) of the 40 mm High Temperature Superconducting (HTS) surface resonator at 77 K and the 35 mm commercial quadrature (QD) surface resonator at 300 K in a 3 Tesla (T) MRI imager. To aquire images for the comparison, we implemented a phantom experiment using the 40 mm diameter Bi2Sr2Ca2Cu3Ox (Bi-2223) HTS surface resonator, the 35 mm commercial QD surface resonator and the 40 mm professionally-made copper surface resonator. The HTS surface resonator at 77 K provided a 1.43-fold SNR gain over the QD surface resonator at 300 K and provided a 3.84-fold SNR gain over the professionally-made copper surface resonator at 300 K on phantom images. The results agree with the predictions, and the difference between the predicted SNR gains and measured SNR gains is 1%. Although the geometry of the HTS surface resonator is different from the QD surface resonator, its SNR is still higher. The results demonstrate that a higher image quality can be obtained with the HTS surface resonator at 77 K. With the HTS surface resonator, the SNR can be improved, suggesting that the HTS surface resonator is a potentially helpful diagnostic tool for MRI imaging in various applications. PMID- 25812125 TI - Neurocognitive features distinguishing primary central nervous system lymphoma from other possible causes of rapidly progressive dementia. AB - OBJECTIVE: Define the neurocognitive features of primary central nervous system lymphoma (PCNSL) presenting with dementia, and compare with other causes of rapidly progressive dementia (RPD). BACKGROUND: PCNSL can present as an RPD. Differentiating PCNSL from other RPDs is critical because lymphomatous dementia may be reversible, and untreated PCNSL is fatal. METHODS: We performed a meta analysis of case reports of dementia from PCNSL (between 1950 and 2013); 20 patients (14 with lymphomatosis cerebri) met our criteria. We compared these patients to a case series of patients with RPD from Creutzfeldt-Jakob disease and other non-PCNSL etiologies (Sala et al, 2012. Alzheimer Dis Assoc Disord. 26:267 271). RESULTS: Median age was 66 years (range 41 to 81); 70% were men. Time from symptom onset to evaluation was <6 months in 65%. No patients had seizures; 5% had headaches; 45% had non-aphasic speech difficulty. There was significantly more memory impairment in patients with PCNSL than other RPDs and significantly less myoclonus and parkinsonism. Behavioral changes and cerebellar signs were not significantly different. Significantly more patients with PCNSL than other RPDs had white matter changes; significantly fewer had atrophy. Elevated CSF protein and pleocytosis were more frequent in PCNSL; patients with other RPDs tended to have normal CSF+/-14-3-3 protein. CONCLUSIONS: Unlike patients with RPD from other causes, those with PCNSL commonly present with impaired memory, apathy, and abnormal speech and gait, without headache, seizure, or myoclonus. White matter changes and CSF abnormalities predominate. Improved clinical awareness of PCNSL can prompt earlier diagnosis and treatment. PMID- 25812126 TI - Novelty seeking in patients with right- versus left-onset Parkinson disease. AB - OBJECTIVE AND BACKGROUND: In patients with Parkinson disease, the personality trait "novelty seeking" has been linked to higher-than-normal risk for impulse control disorders. We measured novelty seeking to test whether side of onset of Parkinson disease predicted patients' risk for impulsivity. METHODS: We evaluated 38 patients with Parkinson disease (19 right onset, 19 left onset) and 44 community-dwelling neurotypical controls. All participants completed demographic and mood measures and the Temperament and Character Inventory personality questionnaire. The right- and left-onset groups were nearly the same in background and clinical variables, including use of dopamine agonists. RESULTS: The patients with right-onset disease exhibited significantly higher levels of novelty seeking than the patients with left-onset disease. CONCLUSIONS: Our results suggest that patients with right-onset Parkinson disease who are taking dopamine agonists and who exhibit high novelty seeking are at greater risk for developing impulse control disorders than are patients with left onset who are also taking dopamine agonists. PMID- 25812128 TI - Diagnosis and quantification of cognitive fatigue in multiple sclerosis. AB - OBJECTIVE: To standardize a method to measure cognitive fatigue in patients with multiple sclerosis (MS). BACKGROUND: Many patients with MS complain of cognitive fatigue, defined as a decline in cognitive performance during a task requiring sustained activity. Until now there has not been a standardized way to detect cognitive fatigue or determine its severity. METHODS: We administered the Paced Auditory Serial Addition Test (PASAT) to 130 normal controls and 100 randomly selected patients with MS, and compared the number of correct responses between the first third and last third of the test. RESULTS: The controls averaged 2 more correct responses in the last third of the PASAT than in the first third. The patients with MS averaged 2 to 3 fewer correct responses in the last third than the first third. CONCLUSIONS: Our study showed that comparing responses between the first and last thirds of the PASAT is a reliable method to measure cognitive fatigue in patients with MS. We also present normative data to be used to determine whether patients with MS have cognitive fatigue. PMID- 25812129 TI - Articulation time does not affect speeded cognitive performance in multiple sclerosis. AB - OBJECTIVE AND BACKGROUND: Cognitive test performance by individuals with multiple sclerosis (MS) may be biased because of MS-related speech problems. The purpose of this study was to compare articulation and pause durations between individuals with MS and controls on cognitive tests requiring an oral response. METHOD: As part of a neuropsychological assessment, 41 patients with MS and 23 controls completed oral forms of 2 timed cognitive tests that are commonly used in MS. Acoustic analysis software segmented oral test responses into "articulation" and "pause" time durations. RESULTS: Overall cognitive test performance by the patients with MS was significantly associated with average pause duration, but not average articulation duration. Articulation time did not contribute to or confound the outcome of either test. CONCLUSIONS: Articulation time did not contribute to differences in test performance between patients with MS and controls; rather, the time spent in silence between responses (pause time) largely accounted for group differences. Future research could use the methods described here to study speech characteristics during cognitive tests that require oral responses for patients with known speech impairments and more progressive forms of MS. PMID- 25812127 TI - Impaired cognitive flexibility in amyotrophic lateral sclerosis. AB - BACKGROUND AND OBJECTIVE: Up to half of patients with amyotrophic lateral sclerosis (ALS) may have cognitive difficulty, but most cognitive measures are confounded by a motor component. Studies relating impaired cognition in ALS to disease in gray matter and white matter are rare. Our objective was to assess executive function in patients with ALS using a simple, untimed measure with minimal motor demands, and to relate performance to structural disease. METHODS: We gave the Visual-Verbal Test to 56 patients with ALS and 29 matched healthy controls. This brief, untimed measure of cognitive flexibility first assesses participants' ability to identify a feature shared by 3 of 4 simple geometric designs. The participants' cognitive flexibility is challenged when they are next asked to identify a different feature shared by another combination of 3 of the same 4 geometric designs. In a subset of 17 patients who underwent magnetic resonance imaging, regression analyses related test performance to gray matter atrophy and reduced white matter fractional anisotropy. RESULTS: The patients with ALS showed significant impairment in cognitive flexibility (P<0.01), with 48.2% making an error on the test. Regression analyses related impaired cognitive flexibility to gray matter atrophy in inferior frontal and insular regions, and to reduced fractional anisotropy in white matter projections in the inferior fronto-occipital and uncinate fasciculi and corpus callosum. CONCLUSIONS: Our patients with ALS had impaired cognitive flexibility on an untimed measure with minimal motor demands, a finding related in part to a large-scale frontal network that is degraded in ALS. PMID- 25812132 TI - Oxygen deficient ZnO 1-x nanosheets with high visible light photocatalytic activity. AB - Zinc oxide is one of the most important wide-band-gap (3.2 eV) materials with versatile properties, however, it can not be excited by visible light. In this work, we have developed an exquisite and simple way to prepare oxygen-deficient ZnO 1-x nanosheets with a gray-colored appearance and excellent visible light photocatalytic activity. Detailed analysis based on UV-Vis absorption spectra, X band electron paramagnetic resonance (EPR) spectra, and photoluminescence (PL) spectra confirms the existence of oxygen vacancies in ZnO 1-x. The incorporation of oxygen defects could effectively extend the light absorption of ZnO 1-x into the visible-light region due to the fact that the energy of the localized state is located in the forbidden gap. Thus, our obtained ZnO 1-x shows a higher photodegradation of methyl orange (MO) compared to defect-free ZnO under visible light illumination. Additionally, the high content of OH radicals with a strong photo-oxidation capability over the ZnO 1-x nanosheets significantly contributes to the improvement in the photocatalytic performance. Our oxygen deficient ZnO 1 x sample shows a very high photocatalytic activity for the degradation of MO even after 5 cycles without any obvious decline. The results demonstrate that defect engineering is a powerful tool to enhance the optoelectronic and photocatalytic performances of nanomaterials. PMID- 25812131 TI - Comparison of sequencing based CNV discovery methods using monozygotic twin quartets. AB - BACKGROUND: The advent of high throughput sequencing methods breeds an important amount of technical challenges. Among those is the one raised by the discovery of copy-number variations (CNVs) using whole-genome sequencing data. CNVs are genomic structural variations defined as a variation in the number of copies of a large genomic fragment, usually more than one kilobase. Here, we aim to compare different CNV calling methods in order to assess their ability to consistently identify CNVs by comparison of the calls in 9 quartets of identical twin pairs. The use of monozygotic twins provides a means of estimating the error rate of each algorithm by observing CNVs that are inconsistently called when considering the rules of Mendelian inheritance and the assumption of an identical genome between twins. The similarity between the calls from the different tools and the advantage of combining call sets were also considered. RESULTS: ERDS and CNVnator obtained the best performance when considering the inherited CNV rate with a mean of 0.74 and 0.70, respectively. Venn diagrams were generated to show the agreement between the different algorithms, before and after filtering out familial inconsistencies. This filtering revealed a high number of false positives for CNVer and Breakdancer. A low overall agreement between the methods suggested a high complementarity of the different tools when calling CNVs. The breakpoint sensitivity analysis indicated that CNVnator and ERDS achieved better resolution of CNV borders than the other tools. The highest inherited CNV rate was achieved through the intersection of these two tools (81%). CONCLUSIONS: This study showed that ERDS and CNVnator provide good performance on whole genome sequencing data with respect to CNV consistency across families, CNV breakpoint resolution and CNV call specificity. The intersection of the calls from the two tools would be valuable for CNV genotyping pipelines. PMID- 25812133 TI - N-heterocyclic carbene-palladium(II)-1-methylimidazole complex-catalyzed Suzuki Miyaura coupling of benzyl sulfonates with arylboronic acids. AB - The first example of palladium-catalyzed Suzuki-Miyaura coupling between benzyl sulfonates and arylboronic acids was reported in this paper. In the presence of a well-defined, air-stable and easily available NHC-Pd(II)-Im complex, all reactions worked well to give the desired products in good to almost quantitative yields under the optimal conditions. Electron-rich, -neutral, -poor and sterically-hindered substituents on both substrates are tolerated in such transformation, providing a convenient, efficient and alternative method for the synthesis of diarylmethanes. PMID- 25812130 TI - Wolbachia density and cytoplasmic incompatibility in Aedes albopictus: concerns with using artificial Wolbachia infection as a vector suppression tool. AB - The mosquito Aedes albopictusi is a competent vector of harmful human pathogens, including viruses causing dengue and chikungunya. Cytoplasmic incompatibility (CI) induced by endosymbiotic Wolbachia can be used to produce functionally sterile males that can be released in the field as a suppression tool against this mosquito. Because the available sexing methods are not efficient enough to avoid unintentional release of a few transinfected females, we assessed the CI pattern in crosses between wPip Wolbachia-transinfected (ARwP) females and wild type males of Ae. albopictus in this study. Quantitative polymerase chain reaction was used to monitor the titer of the Wolbachia strains that naturally infect Ae. albopictus, that is, wAlbA and wAlbB, in age-controlled males and females. Data were coupled with incompatibility level detected when the above mentioned males were crossed with ARwP females. Wolbachia infection titer was also monitored in samples of wild caught males. Incompatibility level was positively correlated only with wAlbA density. Crosses between wild-type males having very low wAlbA density (<0.001 wAlbA/actin copy numbers) and ARwP females were partially fertile (CIcorr = 68.06 +/- 6.20). Individuals with low wAlbA titer were frequently found among sampled wild males (30%-50% depending on the site and period). ARwP males can be as considered as a very promising tool for suppressing Ae. albopictus. However, crosses between wild males having low wAlbA density and ARwP females may be partially fertile. In the case of local establishment of the transinfected mosquito line, this occurrence may favor the replacement of the wild-type mosquitoes with the ARwP line, thus reducing the long-term efficacy of incompatible insect technique. Various alternative strategies have been discussed to prevent this risk and to exploit Wolbachia as a tool to control Ae. albopictus. PMID- 25812136 TI - Correction: Cost-effectiveness of procedures for treatment of ostium secundum atrial septal defects occlusion comparing conventional surgery and septal percutaneous implant. PMID- 25812135 TI - Comparison of the i-gel and the laryngeal mask airway proseal during general anesthesia: a systematic review and meta-analysis. AB - OBJECTIVES: Conflicting results have been reported for the i-gel and the laryngeal mask airway proseal (LMA-P) during general anesthesia. The objective of the current investigation was to compare the efficacy and safety of the i-gel vs. the LMA-P during general anesthesia. METHODS: Two authors performed searches of MEDLINE, EMBASE, CENTRAL, and Google Scholar to identify randomized clinical trials that compared the LMA-P with the i-gel during general anesthesia. A meta analysis was performed using both random and fixed-effect models. Publication bias was evaluated using Begg's funnel plot and Egger's linear regression test. RESULTS: Twelve randomized clinical trials met the eligibility criteria. There were no significant differences in insertion success rate at the first attempt (risk ratio [RR] 1.01, 95% confidence interval [CI] 0.97, 1.06), ease of insertion (RR 1.14, 95% CI 0.93, 1.39), oropharyngeal leak pressure (OLP) (MD 1.98, 95% CI -5.41, 1.45), quality of fiberoptic view (RR 1.00, 95% CI 0.91, 1.10) and success rate of gastric tube insertion (RR 1.07, 95% CI 0.98, 1.18) between the i-gel and the LMA-P, respectively. The i-gel had a shorter insertion time than the LMA-P (MD -3.99, 95% CI -7.13, -0.84) and a lower incidence of blood staining on the device (RR 0.26, 95% CI 0.14, 0.49), sore throat (RR 0.28, 95% CI 0.15, 0.50) and dysphagia (RR 0.27, 95% CI 0.10, 0.74). CONCLUSIONS: Both devices were comparable in ease of insertion to insert and both had sufficient OLP to provide a reliable airway. Only a few minor complications were reported. The i-gel was found to have fewer complications (blood staining, sore throat, dysphagia) than the LMA-P and offers certain advantages over the LMA-P in adults under general anesthesia. PMID- 25812138 TI - Meso enyne substituted BODIPYs: synthesis, structure and properties. AB - We report the synthesis of meso enyne substituted BODIPYs by the reaction of 8 chloro BODIPY with terminal alkynes under Sonogashira coupling conditions, and by Pd-Cu catalyzed hydroalkynylation reaction of terminal alkynes, across the C[triple bond, length as m-dash]C- bond of meso alkynylated BODIPYs. The scope of reaction was explored by reacting different meso alkynylated BODIPYs with various terminal alkynes, which results in meso enyne substituted BODIPYs with different substituents. The meso enyne substituted BODIPYs show blue shifted absorption and red shifted emission with large Stokes shift compared to meso alkynylated BODIPYs. The single crystal structures of BODIPYs , , and are reported. Their packing diagram exhibits extensive intermolecular C-Hpi, C-HF hydrogen bonding and pipi stacking interactions, leading to 1D supramolecular frameworks extending into the complex 3D structural frameworks. PMID- 25812134 TI - Topical application of lithium chloride on the pulp induces dentin regeneration. AB - We herein describe a novel procedure for dentin regeneration that mimics the biological processes of tooth development in nature. The canonical Wnt signaling pathway is an important regulator of the Dentin sialophosphoprotein (Dspp) expression. Our approach mimics the biological processes underlying tooth development in nature and focuses on the activation of canonical Wnt signaling to trigger the natural process of dentinogenesis. The coronal portion of the dentin and the underlying pulp was removed from the first molars. We applied lithium chloride (LiCl), an activator of canonical Wnt signaling, on the amputated pulp surface to achieve transdifferentiation toward odontoblasts from the surrounding pulpal cells. MicroCT and microscopic analyses demonstrated that the topical application of LiCl induced dentin repair, including the formation of a complete dentin bridge. LiCl-induced dentin is a tubular dentin in which the pulp cells are not embedded within the matrix, as in primary dentin. In contrast, a dentin bridge was not induced in the control group treated with pulp capping with material carriers alone, although osteodentin without tubular formation was induced at a comparatively deeper position from the pulp exposure site. We also evaluated the influence of LiCl on differentiation toward odontoblasts in vitro. In the mDP odontoblast cell line, LiCl activated the mRNA expression of Dspp, Axin2 and Kallikrein 4 (Klk4) and downregulated the Osteopontin (Osp) expression. These results provide a scientific basis for the biomimetic regeneration of dentin using LiCl as a new capping material to activate dentine regeneration. PMID- 25812139 TI - Changes in the perception of primary care practice during the medical curriculum in Geneva, Switzerland. PMID- 25812140 TI - Manganese(III)-mediated alkenyl C(sp2)-P bond formation from the reaction of beta nitrostyrenes with dialkyl phosphites. AB - Mn(OAc)3-mediated tandem phosphonyl radical addition to beta-nitrostyrenes followed by denitration to form (E)-2-alkenyl phosphonates in good yield is described. PMID- 25812137 TI - Intracellular growth is dependent on tyrosine catabolism in the dimorphic fungal pathogen Penicillium marneffei. AB - During infection, pathogens must utilise the available nutrient sources in order to grow while simultaneously evading or tolerating the host's defence systems. Amino acids are an important nutritional source for pathogenic fungi and can be assimilated from host proteins to provide both carbon and nitrogen. The hpdA gene of the dimorphic fungus Penicillium marneffei, which encodes an enzyme which catalyses the second step of tyrosine catabolism, was identified as up-regulated in pathogenic yeast cells. As well as enabling the fungus to acquire carbon and nitrogen, tyrosine is also a precursor in the formation of two types of protective melanin; DOPA melanin and pyomelanin. Chemical inhibition of HpdA in P. marneffei inhibits ex vivo yeast cell production suggesting that tyrosine is a key nutrient source during infectious growth. The genes required for tyrosine catabolism, including hpdA, are located in a gene cluster and the expression of these genes is induced in the presence of tyrosine. A gene (hmgR) encoding a Zn(II)2-Cys6 binuclear cluster transcription factor is present within the cluster and is required for tyrosine induced expression and repression in the presence of a preferred nitrogen source. AreA, the GATA-type transcription factor which regulates the global response to limiting nitrogen conditions negatively regulates expression of cluster genes in the absence of tyrosine and is required for nitrogen metabolite repression. Deletion of the tyrosine catabolic genes in the cluster affects growth on tyrosine as either a nitrogen or carbon source and affects pyomelanin, but not DOPA melanin, production. In contrast to other genes of the tyrosine catabolic cluster, deletion of hpdA results in no growth within macrophages. This suggests that the ability to catabolise tyrosine is not required for macrophage infection and that HpdA has an additional novel role to that of tyrosine catabolism and pyomelanin production during growth in host cells. PMID- 25812143 TI - Validity and Clinical Consequences of a Rotational Mechanism for Slipped Capital Femoral Epiphysis. AB - BACKGROUND: Recent anatomic data supports a mechanism for slipped capital femoral epiphysis (SCFE) where the metaphysis rotates on the epiphysis through the eccentrically located epiphyseal tubercle as a pivot. The validity of such a mechanism and its clinical consequences have not been well investigated. METHODS: This cadaveric study defined the normal location of the calcar ridge line in 100 paired femora and compared them with 11 SCFE specimens, and with 25 immature femora where the metaphysis was rotated 30, 60, and 90 degrees on the epiphysis to model progressive SCFE. Coronal, sagittal, and axial plane deformity were measured on the rotational model to define the characteristic deformity caused by rotation, and lateral epiphyseal foramina stretch was measured to quantify the protective effect of an eccentric pivot. RESULTS: The posterior displacement of the fovea with respect to the calcar ridge line was 1+/-5 mm for the controls, versus 23+/-10 mm for the SCFE specimens (P<0.0005), and posterior displacement increased with incremental rotation in the rotational model (P<0.0005). The rotational model found minimal varus deformity, but substantial extension and retroversion, with deformities of 0+/-5, -16+/-12, and -38+/-9 degrees, respectively, at 90 degrees of rotation. The eccentric pivot mitigated lateral epiphyseal vessel stretch by 55% to 70%. CONCLUSIONS: This study provides strong anatomic support for a rotational mechanism for stable SCFE. When the metaphysis is rotated on the epiphysis acutely, minimal varus deformity is created, while substantial retroversion occurs. As this rotation occurs the eccentric pivot protects the lateral epiphyseal vessels, and likely accounts for the low rate of avascular necrosis observed in stable SCFE. CLINICAL RELEVANCE: If SCFE is treated in an open manner then the presence of a chronic rotational deformity should be considered. When planning osteotomies for deformity after a stable SCFE, any suspected varus component should be carefully investigated as it may represent retroversion deformity brought into view by external rotation posturing of the leg. PMID- 25812141 TI - Identification of the neutralizing epitopes of Merkel cell polyomavirus major capsid protein within the BC and EF surface loops. AB - Merkel cell polyomavirus (MCPyV) is the first polyomavirus clearly associated with a human cancer, i.e. the Merkel cell carcinoma (MCC). Polyomaviruses are small naked DNA viruses that induce a robust polyclonal antibody response against the major capsid protein (VP1). However, the polyomavirus VP1 capsid protein epitopes have not been identified to date. The aim of this study was to identify the neutralizing epitopes of the MCPyV capsid. For this goal, four VP1 mutants were generated by insertional mutagenesis in the BC, DE, EF and HI loops between amino acids 88-89, 150-151, 189-190, and 296-297, respectively. The reactivity of these mutants and wild-type VLPs was then investigated with anti-VP1 monoclonal antibodies and anti-MCPyV positive human sera. The findings together suggest that immunodominant conformational neutralizing epitopes are present at the surface of the MCPyV VLPs and are clustered within BC and EF loops. PMID- 25812142 TI - The association between education and work stress: does the policy context matter? AB - OBJECTIVES: Several studies report socioeconomic differences in work stress, where people in lower socioeconomic positions (SEP) are more likely to experience this burden. In the current study, we analyse associations between education and work stress in a large sample of workers from 16 European countries. In addition we explore whether distinct national labour market policies are related to smaller inequalities in work stress according to educational attainment. METHODS: We use data collected in 2010/11 in two comparative studies ('Survey of Health, Ageing and Retirement in Europe' and the 'English Longitudinal Study of Ageing'; N = 13695), with samples of men and women aged 50 to 64 from 16 European countries. We measure highest educational degree according to the international standard classification of education (ISCED) and assess work stress in terms of the demand-control and the effort-reward imbalance model. National labour market policies are measured on the basis of policy indicators which are divided into (1) 'protective' policies offering financial compensation to those excluded from the labour market (e.g. replacement rate), and (2) 'integrative' policies supporting disadvantaged individuals on the labour market (e.g. investments into active labour market policies or possibilities for further qualification in later life). In addition to country-specific analyses, we estimate multilevel models and test for interactions between the indicators of national policies and individual education. RESULTS: Main findings demonstrate consistent associations between lower education and higher levels of work stress in all countries. The strength of this association, however, varies across countries and is comparatively small in countries offering pronounced 'integrative' policies, in terms of high investments into measures of an active labor market policy and high participation rates in lifelong learning activities. CONCLUSIONS: Our results point to different types of policies that may help to reduce educational differences in work stress, in particular policies supporting those who are disadvantaged on the labour market. PMID- 25812145 TI - Radial Neck Fractures in Children and Adolescents: An Examination of Operative and Nonoperative Treatment and Outcomes. AB - BACKGROUND: Although most pediatric radial neck fractures can be treated with either immobilization alone or closed reduction and immobilization, a small subset result in permanent loss of motion despite surgical management. We sought to characterize the most problematic fractures and correlate final outcomes with both presenting fracture characteristics and the reduction achieved through surgical intervention. METHODS: One hundred ninety-three consecutive children with a radial neck fracture, satisfactory initial treatment data, and follow-up range-of-motion (ROM) data presenting between 1999 and 2012 to our level 1 trauma center were evaluated. The O'Brien classification was used to evaluate angulation on radiographs. Final ROM outcomes were categorized into excellent, good, fair, and poor. ROM data were not used in the operative group if follow-up was <12 weeks (<6 wk in the nonoperative group) or if there was no follow-up after cast removal. RESULTS: Thirteen percent of all patients presenting with radial neck fractures required operative treatment (average age 9.1 y). Of patients treated operatively with adequate ROM data, 26.4% healed with fair or poor outcomes. Patients requiring open management were of older average age (average 10 y old, P=0.02) and had a significantly greater risk of a fair or poor ROM outcome than those treated with closed operative techniques (P=0.02). Patients treated nonoperatively were of a younger average age than those in the operative cohort (8.2 vs. 9.1 y, P=0.03). Patients treated operatively were more likely to develop complications (P=0.004); however, presence of a complication was not predictive of fair or poor outcomes in either the operative (P=0.117) or nonoperative (P=0.264) groups. CONCLUSIONS: Older children are more likely to have more severely displaced radial neck fractures requiring open surgical management, thus resulting in a greater risk of fair or poor outcomes. In the series as a whole, more complications were seen when operative management was required. Final outcomes were not shown to be significantly related to preoperative displacement, postoperative reduction, presence of associated injuries, energy of injury, or treatment complications. LEVELS OF EVIDENCE: Level III-therapeutic. PMID- 25812144 TI - Convex Instrumented Hemiepiphysiodesis With Concave Distraction: A Treatment Option for Long Sweeping Congenital Curves. AB - BACKGROUND: Convex hemiepiphysiodesis has been reported to have mixed results in the treatment of congenital spine deformities. Multiple modifications of the original technique were suggested to improve the results. The purpose of this study is to report the results and complications of an instrumented convex growth arrest procedure modified with concave distraction. METHODS: The records of 11 patients with long sweeping congenital curves (involving multiple anomalous vertebrae) who underwent convex instrumented hemiepiphysiodesis with concave distraction were evaluated. Mean age at index operation was 58 months (range, 29 to 101 mo). Lengthening of the concave distraction rod was done every 6 months. The magnitude of coronal/sagittal deformity and T1-T12 height were measured on the preoperative, postoperative, and latest follow-up radiographs. Average follow up was 44.9 months (range, 24 to 89 mo). RESULTS: In the coronal plane, the convex hemiepiphysiodesis segment was corrected from an average of 60.5 to 40.4 degrees postoperatively and further improved to 35.5 degrees at the latest follow up. The distracted segment was corrected from 33.4 to 15.2 degrees postoperatively and to 12.7 degrees at the latest follow-up. Sagittal plane alignment was minimally affected. The average T1-T12 height was 157.1 mm in the early postoperative period and 181.1 mm at last follow-up. During follow-up, we identified partial pull-out of screws on the distraction side in 5 of the 11 patients and rod breakages in 3 patients. These were revised during planned lengthenings. There were no unplanned surgeries, deep wound infections, nor neurological complications. CONCLUSIONS: Convex instrumented hemiepiphysiodesis with concave distraction resulted in good curve correction while maintaining the growth of thorax. The correction of the anomalous segment improved over time, proving the effectiveness of the hemiepiphysiodesis. Addition of a concave distraction construct appears to enhance spinal growth, thereby augmenting the hemiepiphysiodesis effect. PMID- 25812146 TI - A Comparative Analysis of International Knee Documentation Committee Scores for Common Pediatric and Adolescent Knee Injuries. AB - BACKGROUND: Several different etiologies cause knee pain in the pediatric and adolescent population, including anterior knee/patellofemoral pain, patellar instability, anterior cruciate ligament (ACL) tears, meniscal tears, osteochondritis dissecans (OCD) lesions, and discoid meniscus. The purpose of the current study was to determine the relative morbidity of different causes of knee pain in children and adolescents using the International Knee Documentation Committee (IKDC) score. METHODS: We performed a retrospective review of prospectively collected data of a cohort of pediatric and adolescent patients with knee pain who presented to a single surgeon. Each patient completed an IKDC questionnaire at the time of diagnosis and patients were grouped by diagnosis for analysis. Statistical analysis was performed to compare the IKDC scores of the 7 diagnostic groups, and a P-value <0.05 was considered significant. RESULTS: The IKDC mean score for all 242 patients was 50.3+/-18.3. The mean IKDC score for patients with isolated meniscal tears was 41.2+/-16.0, combined ACL and meniscal injuries was 50.2+/-13.9, and isolated ACL tears was 48.1+/-14.1. The mean IKDC score for patients with symptomatic discoid meniscus was 46.3+/-13.2, anterior knee pain/patellofemoral pain was 49.0+/-17.4, patellar instability was 49.2+/ 22.1, and OCD lesions was 62.2+/-19.5. CONCLUSIONS: The IKDC scores of most of the diagnostic groups were similar to the overall average score, with the notable exception of patients with OCD lesions exhibiting statistically significant less morbidity reflected by a higher IKDC score. Although symptoms in each individual clinical presentation may vary, knowledge of the relative morbidity of these diagnostic groups is valuable in counseling patients and their families regarding these common pediatric and adolescent sources of knee pain. LEVEL OF EVIDENCE: Level IV. PMID- 25812147 TI - Intracapsular Pressures After Stable Slipped Capital Femoral Epiphysis. AB - PURPOSE: Stable slipped capital femoral epiphysis (SCFE) has been shown to have a lower rate of avascular necrosis than unstable SCFE. A recent study found increased intracapsular hip pressures in the setting of unstable SCFE, thus increasing the risk of osteonecrosis. The purpose of this study was to measure the intracapsular pressure in stable SCFE and compare it to the intracapsular pressure in normal hips and in unstable SCFE. METHODS: Thirteen hips with stable SCFE and 15 hips with unstable SCFE were identified. Using a side-bored needle, intracapsular hip pressures were measured at the time of surgery. Within these 2 study groups, 11 unaffected (normal) hips were also measured. Diastolic blood pressure and mean arterial pressure at the time of measurement were also recorded. RESULTS: The average intracapsular hip pressure in the stable SCFE group was 27.0 mm Hg, whereas the average pressure in the unstable SCFE group was 48.2 mm Hg and the average pressure in the normal group was 21.8 mm Hg. There was no significant difference between the normal and stable SCFE groups. There was a statistically significant difference between the stable SCFE and unstable SCFE groups (P<0.001). We found similar trends when comparing the intracapsular hip pressure as a percentage of the mean arterial pressure as well as the difference between diastolic blood pressure and hip pressure. CONCLUSIONS: As expected, the intracapsular pressure in the setting of stable SCFE approaches that of normal hips. This may explain why the risk of AVN in stable SCFE is significantly lower than that of unstable SCFE. It also supports the idea that capsulotomy is indicated for unstable slips to decrease the elevated hip pressure but not in stable SCFE. PMID- 25812148 TI - Synthesis and biological properties of 5-(1H-1,2,3-triazol-4-yl)isoxazolidines: a new class of C-nucleosides. AB - A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases. An antiproliferative effect was observed for compounds 17a and 17b: the growth inhibitory effect reaches the 50% in HepG2 and HT-29 cells and increases up to 56% in the SH-SY5Y cell line after 72 h of incubation at a 100 uM concentration. PMID- 25812149 TI - Optimization of solid-supported Glaser-Hay reactions in the microwave. AB - The translation of organometallic reactions into a microwave reactor has numerous advantages. Herein, we describe the application of a previously developed solid supported Glaser-Hay reaction to microwave conditions. Overall, an array of diynes has been prepared demonstrating the ability to conduct chemoselective reactions in the microwave within 20 min compared to the 16 h thermal conditions. Moreover, non-microwave transparent alkynes have been found to react more quickly, preventing catalyst quenching, and resulting in higher yields. PMID- 25812153 TI - SEIRAS Studies of Water Structure in a Sodium Dodecyl Sulfate Film Adsorbed at a Gold Electrode Surface. AB - Surface-enhanced infrared reflection-absorption spectroscopy (SEIRAS) was used to investigate the structure of water that is incorporated within a film of sodium dodecyl sulfate (SDS) adsorbed at a thin gold nanoparticle film deposited onto a silicon substrate. Previous studies on a Au(111) electrode surface showed that SDS molecules form long-range ordered hemicylindrical hemimicelles (phase I) for potentials -0.2 <= E <= 0.45 V vs Ag/AgCl and a disordered bilayer (phase II) for potentials E >= 0.5 V vs Ag/AgCl. The SEIRA spectra demonstrated that the hemimicellar film is water-rich and contains both a network of hydrogen-bonded water and a disturbed network of hydrogen bonds consisting of monomeric and dimeric water in the hydrophobic region of the film. No network water was observed in phase II of the film. However, SEIRAS data showed that sulfate groups in the disordered bilayer are hydrated. The SEIRAS spectra of the film of SDS were compared to the previously measured spectra obtained using subtractively normalized interfacial Fourier transform IR spectroscopy (SNIFTIRS). The complementarity of the spectroscopic information obtained by these two techniques was demonstrated. PMID- 25812152 TI - Zinc complexes containing coumarin-derived anilido-aldimine ligands as catalysts for ring opening polymerization of L-lactide. AB - The coumarin-derived ligand precursors L(1)H-L(6)H have been prepared. Treatment of these ligand precursors with 1.2 equiv. of ZnEt2 in toluene affords zinc ethyl complexes (LZnEt) 1-6 (where L = coumarin-derived ligands bearing different functional groups). Reaction of ligand precursor L(3)H with 1.5 equiv. of Zn[N(SiMe3)2]2 in toluene affords the zinc amide complex, L(3)ZnN(SiMe3)2, 7. All these compounds were characterized by NMR spectroscopy and elemental analysis. The molecular structures are reported for 1 and 7. The catalytic activities of complexes 1-7 towards the ring opening polymerization of l-lactide in the presence of 9-AnOH have been investigated. PMID- 25812154 TI - Linking the future of anticancer metal-complexes to the therapy of tumour metastases. AB - Cancer chemotherapy is almost always applied to patients with one or more diagnosed metastases and is expected to impact these lesions, thus providing significant benefits to the patient. The outcome of metastasis is determined by the interplay between the specific subpopulation of metastatic cells and host homeostatic factors in specific microenvironments. In clinical practice, metal based drugs are represented by platinum compounds, which are constituents of a wide variety of chemotherapeutic regimens, and are only rarely active against tumour metastases unless they are combined with drugs that target specific pathways characterizing the malignancy of the tested tumour. On experimental grounds, a number of complexes based on ruthenium and other metals have been frequently studied in vitro using models and experimental conditions mimicking one or more steps of the metastatic process, such as invasion and migration. The ruthenium-based drug, NAMI-A, is the only one to have been subject to clinical testing for the treatment of metastatic tumours. The capacity of NAMI-A to modulate the relationship established between metastatic cells and their microenvironment suggests that metal-based drugs shall be viewed as an opportunity for the treatment of tumour metastases. PMID- 25812151 TI - In vivo efficacy and toxicity studies of a novel antibacterial agent: 14-o-[(2 amino-1,3,4-thiadiazol-5-yl)thioacetyl] mutilin. AB - A new pleuromutilin derivative with excellent antibacterial activity, 14-O-[(2 amino-1,3,4-thiadiazol-5-yl) thioacetyl] mutilin (ATTM), may serve as a possible lead compound for the development of antibacterial drugs. However, in vivo efficacy and toxicity evaluations of this compound have not been performed. In this study, we evaluated the efficacy of ATTM by measuring the survival of mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA), and the 50% effective dose (ED50) was 5.74 mg/kg by the intravenous route. In an oral single-dose toxicity study, ATTM was orally administered to mice at different doses and the 50% lethal dose (LD50) was calculated to be 2304.4 mg/kg by the Bliss method. The results of the subchronic oral toxicity study in rats showed no mortality, exterior signs of toxicity, or differences in the total weight gain or relative organ weights between the treated groups and control group after administration. The hematological and serum biochemical data showed no differences between the treated and control groups, except for the levels of alkaline phosphatase (ALP), creatinine (CR) and blood glucose (GLU), which were significantly different in the high-dose group. The differences in the histopathological findings between the treated groups and the control group were not considered to be treatment-related. Our results indicated that the no observed adverse effect level (NOAEL) for ATTM was 5 mg/kg in this study. PMID- 25812150 TI - Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities. AB - Bacterial resistance is a rapidly escalating threat to public health as our arsenal of effective antibiotics dwindles. Therefore, there is an urgent need for new antibiotics. Drug discovery has historically focused on bacteria growing in planktonic cultures. Many antibiotics were originally developed to target individual bacterial cells, being assessed in vitro against microorganisms in a planktonic mode of life. However, towards the end of the 20th century it became clear that many bacteria live as complex communities called biofilms in their natural habitat, and this includes habitats within a human host. The biofilm mode of life provides advantages to microorganisms, such as enhanced resistance towards environmental stresses, including antibiotic challenge. The community level resistance provided by biofilms is distinct from resistance mechanisms that operate at a cellular level, and cannot be overlooked in the development of novel strategies to combat infectious diseases. The review compares mechanisms of antibiotic resistance at cellular and community levels in the light of past and present antibiotic discovery efforts. Future perspectives on novel strategies for treatment of biofilm-related infectious diseases are explored. PMID- 25812155 TI - Getting cold feet?: Why health care mergers are abandoned. AB - BACKGROUND: Despite the frequent occurrence and sizeable consequences of merger abandonment in other sectors, there is no thorough understanding of merger abandonment in health care. PURPOSE: The purpose of this study is to improve the understanding of determinants of health care merger abandonment. APPROACH: On the basis of the literature on merger abandonment, we formulated a framework on potential determinants of health care merger abandonment. We then constructed a survey that was sent to 70% of all executives of Dutch health care organizations (response rate = 35%, n = 291). We provide descriptive overviews of open, multiple-response, and multiple-choice questions on merger abandonment and use chi-square tests and Fisher's exact tests to test whether abandoned and completed merger processes differ. FINDINGS: About 62% of the respondents were involved in at least one merger process during the period of 2005-2012. Thirty-eight percent of these respondents reported that their last merger case ended prematurely (n = 53). The most frequently mentioned determinants of merger abandonment are changing insights on the desirability and feasibility during merger processes, incompatibilities between executives, and insufficient support for the merger from internal stakeholders. We did not find significant relationships between merger abandonment and executives' previous merger experience, degree of organizational diversification, health care sector, size differences, or other organizational differences. DISCUSSION: Our findings partially confirm results from previous studies, especially with regard to the importance of changing insights and incompatibilities between the involved executives in merger abandonment. We also find that pressure from internal stakeholders, particularly nonexecutive directors, and distrust, fear, and animosity play an important role in merger abandonment. PRACTICE IMPLICATIONS: To minimize the organizational and societal costs of abandoned mergers, we advise executives who engage in mergers to construct backup plans with alternative strategies in case the merger is abandoned and to conduct a thorough analysis of pros and cons before the merger. PMID- 25812156 TI - Wheat aleurone fractions and plasma n-3 fatty acids in rats. AB - The main aim of this study was to compare the effects of two wheat aleurone (WA) fractions on circulating n-3 fatty acids in rats. We demonstrated that only the fraction able to induce the highest urinary excretion of polyphenol metabolites (>1umol) resulted in a significant increase in plasma level of Eicosapentanoic acid (+22%, p < 0.05). While other constituents of whole wheat can be involved in this response, our data suggest that cereals containing high levels of phenolic compounds can increase blood n-3 without affecting n-6 fatty acids. Further studies are required to confirm this hypothesis and explore the underlying biological mechanisms. PMID- 25812158 TI - Medialization laryngoplasty for odynophonia. AB - IMPORTANCE: Medialization laryngoplasty (ML) remains the gold standard for the long-term treatment of hoarseness related to glottal insufficiency. Odynophonia is a less common manifestation of glottal insufficiency related to vocal fold motion impairment (VFMI), and ML is hypothesized to relieve pain associated with this condition. OBJECTIVE: To evaluate whether patients with VFMI and a chief complaint of odynophonia may achieve pain relief with ML, regardless of the degree of vocal impairment. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of medical records for 8 patients with VFMI and a chief complaint of odynophonia who were treated at 2 tertiary care laryngology centers over a 2-year period. INTERVENTIONS: All patients underwent ML. MAIN OUTCOMES AND MEASURES: Patient-reported relief of pain, preoperative and postoperative Voice Handicap Index 10 (VHI-10) scores, and Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) scores were obtained. RESULTS: All eight patients (5 women and 3 men; mean age, 42 years) had durable relief of their discomfort postoperatively (average follow-up, 14 months). Mean VHI-10 scores improved significantly from 17.9 preoperatively to 6.3 postoperatively (P = .001), while perceptual voice parameters as measured by CAPE-V were unchanged. There were no complications. CONCLUSIONS AND RELEVANCE: In select cases of VFMI, ML can relieve pain related to voice use, even in the absence of significant hoarseness. PMID- 25812157 TI - Small RNA sequencing for profiling microRNAs in long-term preserved formalin fixed and paraffin-embedded non-small cell lung cancer tumor specimens. AB - BACKGROUND: The preservation of microRNAs in formalin-fixed and paraffin-embedded (FFPE) tissue makes them particularly useful for biomarker studies. The utility of small RNA sequencing for microRNA expression profiling of FFPE samples has yet to be determined. METHODS: Total RNA was extracted from de-paraffinized and proteinase K-treated FFPE specimens (15-20 years old) of 8 human lung adenocarcinoma tumors by affinity chromatography on silica columns. MicroRNAs in the RNA preparations were quantified by the Illumina HiSeq 2000 sequencing platform with sequencing libraries prepared with the TruSeq Small RNA Sample Preparation Kit (version 2.0) to obtain unpaired reads of 50 b for small RNA fragments. MicroRNAs were also quantified using Agilent Human miRNA (release 16.0) microarrays that can detect 1,205 mature microRNAs and by quantitative reverse transcription (RT)-PCR assays. RESULTS: Between 9.1-16.9 million reads were obtained by small RNA sequencing of extracted RNA samples. Of these, only 0.6-2.3% (mean = 1.5%) represented microRNAs. The sequencing method detected 454 625 microRNAs/sample (mean = 550) compared with 200-349 (mean = 286) microRNAs detected by microarray. In Spearman correlation analyses, the average correlation coefficient for the 126 microRNAs detected in all samples by both methods was 0.37, and >0.5 for 63 microRNAs. In correlation analyses of the sequencing- and RT-PCR-based measurements, the coefficients were 0.19-0.95 (mean = 0.73) and >0.7, respectively, for 7 of 9 examined microRNAs. The average inter-replicate Spearman correlation coefficient for the sequencing method was 0.81. CONCLUSIONS: Small RNA sequencing can be used to obtain microRNA profiles of FFPE tissue specimens with performance characteristics similar to those of microarrays, in spite of the fragmentation of ribosomal and messenger RNAs that reduces the method's informative capacity. The accuracy of the method can conceivably be improved by increasing sequencing depth and/or depleting FFPE tissue RNAs of ribosomal RNA fragments. PMID- 25812160 TI - Reversible and contrasting changes of the cloud point temperature of pillar[5]arenes with one quinone unit and tri(ethylene oxide) chains induced by redox chemistry and host-guest complexation. AB - A new water-soluble redox-active pillar[5]arene was synthesized by incorporation of one benzoquinone unit. The pillar[5]arene showed redox-responsive reversible lower critical solution temperature changes in aqueous solution. PMID- 25812159 TI - Kojak: efficient analysis of chemically cross-linked protein complexes. AB - Protein chemical cross-linking and mass spectrometry enable the analysis of protein-protein interactions and protein topologies; however, complicated cross linked peptide spectra require specialized algorithms to identify interacting sites. The Kojak cross-linking software application is a new, efficient approach to identify cross-linked peptides, enabling large-scale analysis of protein protein interactions by chemical cross-linking techniques. The algorithm integrates spectral processing and scoring schemes adopted from traditional database search algorithms and can identify cross-linked peptides using many different chemical cross-linkers with or without heavy isotope labels. Kojak was used to analyze both novel and existing data sets and was compared to existing cross-linking algorithms. The algorithm provided increased cross-link identifications over existing algorithms and, equally importantly, the results in a fraction of computational time. The Kojak algorithm is open-source, cross platform, and freely available. This software provides both existing and new cross-linking researchers alike an effective way to derive additional cross-link identifications from new or existing data sets. For new users, it provides a simple analytical resource resulting in more cross-link identifications than other methods. PMID- 25812162 TI - In situ controlled sputtering deposition of gold nanoparticles on MnO2 nanorods as surface-enhanced Raman scattering substrates for molecular detection. AB - Single-crystal tetragonal alpha-MnO2 nanorods with different amounts of gold nanoparticles (NPs) attached were successfully prepared by a facile sputtering deposition technique. Initially, the morphology and crystal structure of the bare alpha-MnO2 nanorods synthesized via a hydrothermal approach were investigated. Then, the amount of gold NPs at different sputtering times was analyzed. It was confirmed that the amount of the decorated gold NPs increased with the lengthening of the sputtering time until they completely covered the alpha-MnO2 nanorods. Theoretical calculation results indicated the advantages of the composite structure by showing the enhanced electromagnetic fields around both the bare alpha-MnO2 nanorods and the gold NP decorated ones. The surface-enhanced Raman scattering (SERS) efficiency of these nanocomposites was evaluated using methylene blue and 4-mercaptobenzoic acid as Raman probe molecules. It was found that the SERS intensity of the substrates strongly depended on the degree of aggregation of the gold NPs. Uniform SERS signals across the entire surface of these samples were obtained. Moreover, a typical chemical toxin, methyl parathion, was effectively detected over a broad concentration range from 1 * 10( 3) to 100 ppm using the gold NP decorated alpha-MnO2 nanorods, suggesting this hybrid structure is highly valuable for further applications on the rapid detection of organic environmental pollutants. PMID- 25812163 TI - Association between Traumatic Dental Injury, Obesity, and Socioeconomic Status in 6- and 13-Year-Old Schoolchildren. AB - Obesity and poverty are independent risk factors in trauma-related morbidity in children as well as adolescents. The main objective of this study was to investigate the association between traumatic dental injury, obesity, and socioeconomic status in 6- and 13-year-old schoolchildren in Davangere city, Karnataka, India. Data were obtained from 1,550 schoolchildren. Dental trauma was classified according to Andreasen's criteria. The medical evaluation assessed the Body Mass Index. Overjet was considered a risk factor when it presented values higher than 3 mm, whereas lip coverage was classified as adequate or inadequate. With appropriate sample weighting, relationships between traumatic dental injury and other variables were assessed using the chi-squared test and multivariable logistic regression. Overall prevalence of dental injuries was 10.52% (3.6% in 6 year-olds and 17.2% in 13-year-olds). Boys experienced more injuries than girls, 11.03% and 9.97%, respectively (p>.05). There was a statistically significant difference between traumatic dental injury and overjet (95% confidence interval [CI] [2.06, 4.78], p < 001) and between traumatic dental injury and inadequate lip coverage (95% CI [1.23, 4.65], p < .001). When adjusted for covariates, the logistic regression model showed that there was a significant association between obese children (p < .05) and dental trauma prevalence. Children from low socioeconomic status had an odds ratio 2.33 (95% CI [1.05, 3.97]) times higher likelihood of having dental trauma than children from medium and upper socioeconomic status. To conclude the results of this study support an association between traumatic dental injuries, obesity, and poverty. PMID- 25812164 TI - Asphaltene detection using surface enhanced Raman scattering (SERS). AB - Surface enhanced Raman spectroscopy using a gold substrate and excitation at 514 nm can detect sub parts per million quantities of asphaltene and thereby petroleum. This simple format and sensitivity make it transformative for applications including sample triage, flow assurance, environmental protection and analysis of unique one of a kind materials. PMID- 25812161 TI - Nevirapine, sodium concentration and HIV-1 RNA in breast milk and plasma among HIV-infected women receiving short-course antiretroviral prophylaxis. AB - INTRODUCTION: Risk factors for breast milk transmission of HIV-1 from mother to child include high plasma and breast milk viral load, low maternal CD4 count and breast pathology such as mastitis. OBJECTIVE: To determine the impact of nevirapine and subclinical mastitis on HIV-1 RNA in maternal plasma and breast milk after intrapartum single-dose nevirapine combined with either 1-week tail of Combivir (zidovudine/lamivudine) or single-dose Truvada (tenofovir/emtricitabine). METHODS: Maternal plasma and bilateral breast milk samples were collected between April 2008 and April 2011 at 1, 4 and 6 weeks postpartum from HIV-infected Tanzanian women. Moreover, plasma samples were collected at delivery from mother and infant. RESULTS: HIV-1 RNA was quantified in 1,212 breast milk samples from 273 women. At delivery, 96% of the women and 99% of the infants had detectable nevirapine in plasma with a median (interquartile range, IQR) of 1.5 MUg/mL (0.75-2.20 MUg/mL) and 1.04 MUg/mL (0.39 1.71 MUg/mL), respectively (P < 0.001). At 1 week postpartum, 93% and 98% of the women had detectable nevirapine in plasma and breast milk, with a median (IQR) of 0.13 MUg/mL (0.13-0.39 MUg/mL) and 0.22 MUg/mL (0.13-0.34 MUg/mL), respectively. Maternal plasma and breast milk HIV-1 RNA correlated at all visits (R = 0.48, R = 0.7, R = 0.59; all P = 0.01). Subclinical mastitis was detected in 67% of the women at some time during 6 weeks, and in 38% of the breast milk samples. Breast milk samples with subclinical mastitis had significantly higher HIV-1 RNA at 1, 4 and 6 weeks (all P < 0.05). CONCLUSION: After short-course antiretroviral prophylaxis, nevirapine was detectable in most infant cord blood samples and the concentration in maternal plasma and breast milk was high through week 1 accompanied by suppressed HIV-1 RNA in plasma and breast milk. PMID- 25812165 TI - Investigating the fluid dynamics of rapid processes within microfluidic devices using bright-field microscopy. AB - The widespread application of microfluidic devices in the biological and chemical sciences requires the implementation of complex designs and geometries, which in turn leads to atypical fluid dynamic phenomena. Accordingly, a complete understanding of fluid dynamics in such systems is key in the facile engineering of novel and efficient analytical tools. Herein, we present an accurate approach for studying the fluid dynamics of rapid processes within microfluidic devices using bright-field microscopy with white light illumination and a standard high speed camera. Specifically, we combine Ghost Particle Velocimetry and the detection of moving objects in automated video surveillance to track submicron size tracing particles via cross correlation between the speckle patterns of successive images. The efficacy of the presented technique is demonstrated by measuring the flow field over a square pillar (80 MUm * 80 MUm) in a 200 MUm wide microchannel at high volumetric flow rates. Experimental results are in excellent agreement with those obtained via computational fluid dynamics simulations. The method is subsequently used to study the dynamics of droplet generation at a flow focusing microfluidic geometry. A unique feature of the presented technique is the ability to perform velocimetry analysis of high-speed phenomena, which is not possible using micron-resolution particle image velocimetry (MUPIV) approaches based on confocal or fluorescence microscopy. PMID- 25812166 TI - Highly enantioselective hydrogenation of omicron-alkoxy tetrasubstituted enamides catalyzed by a Rh/(R,S)-JosiPhos catalyst. AB - Rh/(R,S)-JosiPhos complex-catalyzed asymmetric hydrogenation of o-alkoxy tetrasubstituted enamides has been achieved, and it furnished a set of beta-amino alcohol analogues in high yields and excellent enantiomeric excesses (>99% conversion, up to 99% ee).This method provides valuable chiral building blocks in chiral pharmaceuticals and useful motifs for catalysts. PMID- 25812167 TI - Are intramolecular frustrated Lewis pairs also intramolecular catalysts? A theoretical study on H2 activation. AB - We investigate computationally a series of intramolecular frustrated Lewis pairs (FLPs), with the general formula Mes2PCHRCH2B(C6F5)2, that are known from the literature to either activate molecular hydrogen (FLPs with R = H (1) or Me (4)), or remain inert (FLPs with R = Ph (2) or SiMe3 (3)). The prototypical system Mes2PCH2CH2B(C6F5)2 (1) has been described in the literature (Grimme et al., Angew. Chem., Int. Ed., 2010; Rokob et al., J. Am. Chem. Soc., 2013) as an intramolecular reactant that triggers the reaction with H2 in a bimolecular concerted fashion. In the current study, we show that the concept of intramolecular H2 activation by linked FLPs is not able to explain the inertness of the derivative compounds 2 and 3 towards H2. To cope with this, we propose an alternative intermolecular mechanism for the investigated reaction, assuming stacking of two open-chain FLP conformers, and formation of a dimeric reactant with two Lewis acid-base domains, that can split up to two hydrogen molecules. Using quantum-chemical methods, we compute the reaction profiles describing these alternative mechanisms, and compare the derived predictions with earlier reported experimental results. We show that only the concept of intermolecular H2 activation could explain both the activity of the FLPs having small substituents in the bridging molecular region, and the inertness of the FLPs with a bulkier substitution, in a consistent way. Importantly, the intermolecular H2 activation driven by intramolecular FLPs indicates the key role of steric factors and noncovalent interactions for the design of metal-free systems that can efficiently split H2, and possibly serve as metal-free hydrogenation catalysts. PMID- 25812168 TI - Self-assembly of luminescent N-annulated perylene tetraesters into fluid columnar phases. AB - A new class of N-annulated perylene tetraesters and their N-alkylated derivatives has been synthesized. N-Annulated perylene tetraesters stabilize a hexagonal columnar phase over a broad temperature range. The hexagonal columnar phase exhibited by these compounds shows good homeotropic alignment with few defects. Annulation in the bay region of the perylene tetraesters enhanced the width of the mesophase compared with the parent tetraesters. N-Alkylation of these compounds perturbed the self-assembly behaviour and the resulting compounds were non-mesomorphic. A bright green luminescence was visible under long wavelength UV light. These properties suggest that these materials may have promising applications in organic electronics. PMID- 25812169 TI - Cryopreserved Ex Vivo-Expanded Allogeneic Myeloid Progenitor Cell Product Protects Neutropenic Mice From a Lethal Fungal Infection. AB - Severe neutropenia induced by chemotherapy or conditioning for hematopoietic cell transplantation often results in morbidity and mortality due to infection by opportunistic pathogens. A system has been developed to generate ex vivo-expanded mouse myeloid progenitor cells (mMPCs) that produce functional neutrophils in vivo upon transplantation in a pathogen challenge model. It has previously been demonstrated that transplantation of large numbers of freshly isolated myeloid progenitors from a single donor provides survival benefit in radiation-induced neutropenic mice. In the present work, an ex vivo-expanded and cryopreserved mMPC product generated from an allogeneic donor pool retains protective activity in vivo in a lethal fungal infection model. Infusion of the allogeneic pooled mMPC product is effective in preventing death from invasive Aspergillus fumigatus in neutropenic animals, and protection is dose dependent. Cell progeny from the mMPC product is detected in the bone marrow, spleen, blood, and liver by flow cytometry 1 week postinfusion but is no longer evident in most animals 4 weeks posttransplant. In this model, the ex vivo-generated pooled allogeneic mMPC product (i) expands and differentiates in vivo; (ii) is functional and prevents death from invasive fungal infection; and (iii) does not permanently engraft or cause allosensitization. These data suggest that an analogous ex vivo-expanded human myeloid progenitor cell product may be an effective off-the-shelf bridging therapy for the infectious complications that develop during hematopoietic recovery following hematopoietic cell transplantation or intensive chemotherapy. PMID- 25812170 TI - Solution and Solid Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) Ultraviolet (UV) 229 nm Photochemistry. AB - We measured the 229 nm deep-ultraviolet resonance Raman (DUVRR) spectra of solution and solid-state hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). We also examined the photochemistry of RDX both in solution and solid states. RDX quickly photodegrades with a solution quantum yield of phi ~ 0.35 as measured by high performance liquid chromatography (HPLC). New spectral features form over time during the photolysis of RDX, indicating photoproduct formation. The photoproduct(s) show stable DUVRR spectra at later irradiation times that allow standoff detection. In the solution-state photolysis, nitrate is a photoproduct that can be used as a signature for detection of RDX even after photolysis. We used high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) and gas chromatography mass spectrometry (GCMS) to determine some of the major solution-state photoproducts. X-ray photoelectron spectroscopy (XPS) was also used to determine photoproducts formed during solid-state RDX photolysis. PMID- 25812171 TI - Patient Safety and Comparative Effectiveness of Anesthetic Technique in Open Lung Resections. AB - BACKGROUND: Despite literature suggesting benefits of using regional anesthesia, the impact of neuraxial anesthesia on perioperative outcomes in patients undergoing lung surgery remains unstudied. We studied the effect of combined neuraxial/general anesthesia (vs general anesthesia) on perioperative outcome in a large national sample of patients who underwent open lung resection. METHODS: We extracted data from the Premier Perspective database on patients who underwent open lung resection. The main effect of interest was anesthesia type: general and combined neuraxial/general anesthesia. Patient and health-care variables, complications, and resource use were compared between groups. Multivariable analyses assessed the independent impact of choice of anesthetic technique on outcomes. RESULTS: For 18,943 patients, anesthesia type was known: 79% (n = 14,912) were administered general anesthesia, and 21% (n = 4,031) received neuraxial/general anesthesia. Comparing general vs neuraxial/general anesthesia, unadjusted incidences for the latter were lower for acute myocardial infarction (1.09% vs 0.67%, P = .018), pulmonary complications (20.96% vs 18.98%, P = .006), blood transfusion (14.15% vs 9.80%, P < .0001), and mechanical ventilation (11.60% vs 8.81%, P < .0001). Neuraxial/general anesthesia was associated with lower adjusted odds of blood transfusion (OR, 0.82; 95% CI, 0.69-0.98) and mechanical ventilation (OR, 0.81; 95% CI , 0.67-0.98), while higher odds were seen for DVT (OR, 1.50; 95% CI, 1.01-2.23) and pulmonary embolism (OR, 1.56; 95% CI, 1.02-2.38). CONCLUSIONS: This study illustrates the association between adding neuraxial to general anesthesia in open lung resections among patients with cancer and perioperative outcomes. Neuraxial anesthesia use was associated with decreased risk for blood transfusion but increased thromboembolic risks. Additional studies are needed to elucidate mechanisms by which neuraxial anesthesia may affect these outcomes. PMID- 25812172 TI - Auditory Learning in Children With Cochlear Implants. AB - PURPOSE: The purpose of this study was to examine and characterize the training induced changes in speech-in-noise perception in children with congenital deafness who have cochlear implants (CIs). METHOD: Twenty-seven children with congenital deafness who have CIs were studied. Eleven children with CIs were trained on a speech-in-noise task, number recognition in white noise, at home for 5 weeks (total 40 hr). Speech recognition thresholds (SRTs) in the trained, partially trained (numbers in speech-shaped noise), and untrained (digit triplets in speech-shaped noise) conditions were measured before, immediately after, and 3 weeks after training completion. Data were also collected from children (n = 13) and adults (n = 5) with normal hearing for comparison. RESULTS: Analyses indicated that following training, the performance of children with CIs improved for all speech-in-noise tasks (?SRT was approximately 3 dB). Training-induced improvements in speech-in-noise performance were retained for 3 weeks following cessation of training. Untrained children with CIs showed no such improvements. The performance of children with CIs, even after intensive training, was significantly lower than children and adults with normal hearing. CONCLUSIONS: Training enhances speech-in-noise performance for children with congenital deafness who have CIs. Learning effects were stable and generalized to similar but untrained conditions. Current findings are encouraging for the consideration of home-based auditory training to be included in the pediatric CI habilitation programs. PMID- 25812174 TI - Photocatalytic overall water splitting on the perovskite-type transition metal oxynitride CaTaO2N under visible light irradiation. AB - Overall water splitting was achieved on a simple perovskite oxynitride photocatalyst, CaTaO2N, with an absorption edge at 510 nm. This photocatalyst, modified with a Rh-Cr bimetallic oxide cocatalyst, produced stoichiometric H2 and O2 steadily under UV and visible light irradiation after coating of the photocatalyst particles with amorphous Ti oxyhydroxide. PMID- 25812173 TI - Bonding and electronic states of boron in silicon nanowires characterized by an infrared synchrotron radiation beam. AB - The infrared synchrotron radiation (IR-SR) beamline of SPring-8 as an IR light source was applied to characterize boron (B) atoms in silicon nanowires (SiNWs). The use of an IR-SR beam with much higher brilliance than conventional IR light sources and a wide range of wavenumbers from visible to far IR regions made it possible to detect a local vibrational mode of B in SiNWs. The use of this technique has also made it possible to detect other IR peaks related to transitions of a bound hole from the ground state of a B acceptor atom to excited states, clarifying the electronic state of B acceptors in SiNWs. PMID- 25812176 TI - Limited Functional Effects of Subacute Syngeneic Bone Marrow Stromal Cell Transplantation After Rat Spinal Cord Contusion Injury. AB - Cell transplantation might be one means to improve motor, sensory, or autonomic recovery after traumatic spinal cord injury (SCI). Among the different cell types evaluated to date, bone marrow stromal cells (BMSCs) have received considerable interest due to their potential neuroprotective properties. However, uncertainty exists whether the efficacy of BMSCs after intraspinal transplantation justifies an invasive procedure. In the present study, we analyzed the effect of syngeneic BMSC transplantation following a moderate to severe rat spinal cord injury. Adult Fischer 344 rats underwent a T9 contusion injury (200 kDy) followed by grafting of GFP-expressing BMSCs 3 days postinjury. Animals receiving a contusion injury without cellular grafts or an injury followed by grafts of syngeneic GFP expressing fibroblasts served as control. Eight weeks posttransplantation, BMSC grafted animals showed only a minor effect in one measure of sensorimotor recovery, no significant differences in tissue sparing, and no changes in the recovery of bladder function compared to both control groups in urodynamic measurements. Both cell types survived in the lesion site with fibroblasts displaying a larger graft volume. Thus, contrary to some reports using allogeneic or xenogeneic transplants, subacute intraparenchymal grafting of syngeneic BMSCs has only a minor effect on functional recovery. PMID- 25812175 TI - The Influence of Reading on Vocabulary Growth: A Case for a Matthew Effect. AB - PURPOSE: Individual differences in vocabulary development may affect academic or social opportunities. It has been proposed that individual differences in word reading could affect the rate of vocabulary growth, mediated by the amount of reading experience, a process referred to as a Matthew effect (Stanovich, 1986). METHOD: In the current study, assessments of written word-reading skills in the 4th grade and oral vocabulary knowledge collected in kindergarten and in the 4th, 8th, and 10th grades from a large epidemiologically based sample (n = 485) allowed a test of the relationship of early word-reading skills and the subsequent rate of vocabulary growth. RESULTS: Consistent with the hypothesis, multilevel modeling revealed the rate of vocabulary growth after the 4th grade to be significantly related to 4th-grade word reading after controlling for kindergarten vocabulary level, that is, above average readers experienced a higher rate of vocabulary growth than did average readers. CONCLUSIONS: Vocabulary growth rate differences accumulated over time such that the effect on vocabulary size was large. PMID- 25812177 TI - Development of Morphosyntactic Accuracy and Grammatical Complexity in Dutch School-Age Children With SLI. AB - PURPOSE: The purpose of this study was to identify the development of morphosyntactic accuracy and grammatical complexity in Dutch school-age children with specific language impairment (SLI). METHOD: Morphosyntactic accuracy, the use of dummy auxiliaries, and complex syntax were assessed using a narrative task that was administered at three points in time (T1, T2, T3) with 12-month intervals during a 2-year period. Participants were 30 monolingual Dutch children with SLI, age 6;5 (years;months) at T1; 30 typically developing peers, age 6;6 at T1; and 30 typically developing language-matched children, age 4;7 at T1. RESULTS: On the morphosyntactic accuracy measures, the group with SLI performed more poorly than both control groups. Error rates in the group with SLI were much higher than expected on the basis of mean length of T-units and scores on standardized language tests. Percentages of dummy auxiliaries remained high over time. No group differences were found for grammatical complexity, except at T3, when the group with SLI used fewer relative clauses than the typically developing peer group. CONCLUSIONS: The narrative analysis demonstrates different developmental trajectories for morphosyntactic accuracy and grammatical complexity in children with SLI and typically developing peer and language matched children. In the group with SLI, grammatical skills continue to develop. PMID- 25812178 TI - The Aphasia Communication Outcome Measure (ACOM): Dimensionality, Item Bank Calibration, and Initial Validation. AB - PURPOSE: The purpose of this study is to investigate the structure and measurement properties of the Aphasia Communication Outcome Measure (ACOM), a patient-reported outcome measure of communicative functioning for persons with aphasia. METHOD: Three hundred twenty-nine participants with aphasia responded to 177 items asking about communicative functioning. The data were analyzed using a categorical item factor analysis approach. Validity of ACOM scores on the basis of their convergence with performance-based, clinician-reported, and surrogate reported assessments of communication was also assessed. RESULTS: Fifty-nine items that obtained adequate fit to a modified bifactor measurement model and functioned similarly across several demographic and clinical subgroupings were identified. The factor model estimates were transformed to item response theory graded response model parameters, and the resulting score estimates showed good precision and moderately strong convergence with other measures of communicative ability and functioning. A free software application for administration and scoring of the ACOM item bank is available from the first author. CONCLUSIONS: The ACOM provides reliable measurement of patient-reported communicative functioning in aphasia. The results supported the validity of ACOM scores insofar as (a) factor analyses provided support for a coherent measurement model, (b) items functioned similarly across demographic and clinical subgroups, and (c) scores showed good convergence with measures of related constructs. PMID- 25812179 TI - Effects of Lingual Effort on Swallow Pressures Following Radiation Treatment. AB - PURPOSE: This article investigated the effects of increased oral lingual pressure on pharyngeal pressures during swallowing in patients who have undergone radiotherapy for head and neck cancer. It was hypothesized that increased oral lingual pressure would result in increased pharyngeal pressures. METHOD: A within subject experimental design was used with 20 participants who were status post external beam radiotherapy for head and neck cancer. Participants completed typical swallows and swallows with increased lingual force during manofluoroscopic swallow studies. The swallow condition order was randomized across participants. RESULTS: Manometric data revealed significant differences in swallow pressure by condition at the base of tongue and upper esophageal sphincter sensor locations without significant pressure differences in the lower pharynx. The effortful lingual swallows resulted in higher mean pressures at all locations. CONCLUSIONS: The results of this study suggest that use of a maneuver designed to increase oral tongue effort can also increase pharyngeal tongue base pressure. Therefore, therapeutic activities used to generate greater pressure of the oral tongue may also alter pharyngeal response. Further research is needed to determine the direct clinical effect on swallow function for individuals with head and neck cancer. PMID- 25812180 TI - The sweetest troop. Members of the first Girl Scouts troop for kids with type 1 diabetes are going to sell you on their group. PMID- 25812181 TI - Two for one. New combination drugs may help people take their pills. PMID- 25812182 TI - The future is near. 14 diabetes products suggest big things to come. PMID- 25812183 TI - Why I use my diabetes devices. Learn about the features and benefits that matter to users. PMID- 25812184 TI - Meters: does your device measure up? PMID- 25812185 TI - Lancing devices. PMID- 25812186 TI - Continuous glucose monitors: in real time. PMID- 25812187 TI - Insulin pumps: closer to a pancreas. PMID- 25812188 TI - Infusion sets 101. PMID- 25812189 TI - Pens & needles. These devices make insulin dosing more convenient and portable. PMID- 25812190 TI - Injection helpers. PMID- 25812191 TI - Glucose products. Treat lows fast with these sources of sugar. PMID- 25812192 TI - Pump it up. PMID- 25812193 TI - Hint-of-summer chicken. PMID- 25812194 TI - Double tomato. PMID- 25812195 TI - [From archaeological discovery to pathology in the millennium of Abulcasis]. PMID- 25812196 TI - [Medical cartoon in the satirical magazine Cu-Cut! (1902-1912)]. PMID- 25812197 TI - The tools of Asclepius surgical instruments in Greek and Roman times. PMID- 25812198 TI - Cost-effectiveness analysis: adding value to assessment of animal health welfare and production. AB - Cost-effectiveness analysis (CEA) has been extensively used in economic assessments in fields related to animal health, namely in human health where it provides a decision-making framework for choices about the allocation of healthcare resources. Conversely, in animal health, cost-benefit analysis has been the preferred tool for economic analysis. In this paper, the use of CEA in related areas and the role of this technique in assessments of animal health, welfare and production are reviewed. Cost-effectiveness analysis can add further value to these assessments, particularly in programmes targeting animal welfare or animal diseases with an impact on human health, where outcomes are best valued in natural effects rather than in monetary units. Importantly, CEA can be performed during programme implementation stages to assess alternative courses of action in real time. PMID- 25812199 TI - The scientific rationale for the World Organisation for Animal Health standards and recommendations on avian influenza. AB - The World Organisation for Animal Health (OIE) prescribes standards for the diagnosis and control of avian influenza, as well as health measures for safe trade in birds and avian products, which are based on up-to-date scientific information and risk management principles, consistent with the role of the OIE as a reference standard-setting body for the World Trade Organization (WTO). These standards and recommendations continue to evolve, reflecting advances in technology and scientific understanding of this important zoonotic disease. The avian influenza viruses form part of the natural ecosystem by virtue of their ubiquitous presence in wild aquatic birds, a fact that human intervention cannot change. For the purposes of the Terrestrial Animal Health Code (Terrestrial Code), avian influenza is defined as an infection of poultry. However, the scope of the OIE standards and recommendations is not restricted to poultry, covering the diagnosis, early detection and management of avian influenza, including sanitary measures for trade in birds and avian products. The best way to manage avian influenza-associated risks to human and animal health is for countries to conduct surveillance using recommended methods, to report results in a consistent and transparent manner, and to applythe sanitary measures described in the Terrestrial Code. Surveillance for and timely reporting of avian influenza in accordance with OIE standards enable the distribution of relevant, up-to-date information to the global community. PMID- 25812200 TI - Animal health constraints to livestock exports from the Horn of Africa. AB - The Horn of Africa (Djibouti, Ethiopia, Somalia, Eritrea) is home to the largest population of livestock in Africa and is the historic centre of the livestock trade to the Middle East and northern Africa. The recent resumption of livestock exports from the region has resulted in the handling of over one million head of cattle, sheep, goats and camels at one quarantine facility during a single year. Several of the importing countries for which the facility operates have differing hygiene requirements for the same diseases. Most of the animals handled in the facility come from pastoralist areas, which lack state Veterinary Services. The pathological conditions encountered during one year of monitoring were recorded and the impacts of some of the endemic diseases are discussed, together with particular import-limiting hygiene requirements on this trade. PMID- 25812202 TI - Links between livestock production, the environment and sustainable development. AB - This study examines the prospects for strong growth in the supply and demand for animal products worldwide, especially in developing countries, where 80% of the world's population lives. Based on scientific publications, statistics and field observations, it reviews greenhouse gas emission levels from livestock, the ability of ruminant livestock systems to sequester carbon and the capacity of the livestock industry to meet the challenge of sustainable development and to share its benefits while minimising impacts to climate change. Special attention is paid to the situation of the 800 million livestock farmers in the world living at the extreme end of poverty. The study underlines the importance of improving livestock productivity and the interdependence of the economic, environmental and social components of sustainable development. It highlights how, in the least developed countries and most lower-middle-income countries, the pressure exerted by animal diseases hampers efforts to improve livestock productivity. Poor livestock farmers have not sufficiently benefited from development policies and need support to adopt technological advances to meet the challenges of sustainable development and poverty reduction. PMID- 25812201 TI - Improving animal health and livestock productivity to reduce poverty. AB - This study is based on scientific publications, statistics and field observations. It shows the importance of livestock in the economy and in the risk management strategies implemented by poor farming households. A comparison of livestock performance trends with the evolution of rural poverty in developing countries indicates that growth in livestock production alone is not enough to reduce rural poverty. To help reduce poverty, sustainable production should be based on productivity gains. Prerequisites for improving productivity include better public policies, enhanced research and the reduction of animal disease risk. The study draws attention to the economic, social and environmental consequences of inadequate support for animal health and production in the least developed countries, especially those of sub-Saharan Africa. PMID- 25812203 TI - Use of electronic leg tags for identification of small ruminants. AB - Few studies have evaluated the use of electronic leg tags for identification of small ruminants; thus the objectives of this study were i) to quantify the degree of development in the body region where the tags are placed, ii) to assess the effect of the farm management system on the suitability of the leg tags, and iii) to assess tag readability under dynamic conditions, i.e. as animals moved through a raceway. In three experiments, leg tags were applied as follows: 24ewe lambs and 24 kid goats (Experiment 1); 37 kid goats (Experiment 2); 1,519 goats and 248 sheep (Experiment 3). At 2.5 months of age, the metatarsal perimeter of ewe lambs and kid goats was 80% of the adult values; at 6 months of age, the metatarsal perimeter had reached 90% of the adult values but live weight had not exceeded 65% (Experiments 1 and 2). In Experiment 3, the retention rates of tags on farms where animals were housed indoors were between 99.2% and 100% after one year. On the farm where animals grazed natural pasture the retention and readability rates six months after tagging were 63% and 78.2%. Dynamic readings indicated 100% efficiency. In conclusion, the selection of the leg of replacement animals for attachment of these tags is appropriate because their normal development is not impeded. For different breeds, it might be necessary to identify the optimal age for tagging. Extensive rangeland grazing systems can reduce the retention of leg tags. The electronic tag evaluated in this study showed a high readability rate under dynamic conditions. PMID- 25812204 TI - Antiviral chemotherapy in veterinary medicine: current applications and perspectives. AB - The current situation in the use of antiviral drugs in veterinary medicine is characterised by a novel and optimistic approach.Viruses of veterinary importance are still used as animal models in the developmentof human therapeutics, but there is growing interest in many of these viruses in the identification of antiviral molecules for use in both livestock and companion animals. The use of antiviral drugs in livestock animals is envisaged for the treatment or control of disease on a large scale (mass treatment), whereas in companion animals an individual approach is favoured. An overview of the most recent examples of research in the use of antivirals in veterinary medicine is presented, with particular emphasis on their in vivo applications. PMID- 25812205 TI - Isolation of bluetongue virus serotype 1 from aborted goat fetuses. AB - Abortions and stillbirths were noticed in pregnant goats on a farm in the state of Gujarat, India. About 50% of the pregnant goats aborted or gave birth to dead kids. Bluetongue virus (BTV) antibody in the sera of affected goats was detected using a competitive enzyme-linked immunosorbent assay (ELISA). Viral antigen in the blood of these goats and in the aborted fetal spleens was detected using a sandwich ELISA. Two viruses (SKN-9, SKN-10) were isolated in cell culture from aborted fetal spleens and were confirmed as Orbivirus by demonstration of ten bands in RNA polyacrylamide gel electrophoresis and identified as BTV-1 by sequencing of the VP2 gene. Sequence analyses revealed thatthese isolates were very closely related to a BTV-1 (strain SKN-8) isolated from Culicoides vectors captured on the same farm one month after the occurrence of abortion. Isolation of BTV-1 from fetuses is probably evidence of transplacental transmission of the wild-type strain, because attenuated or laboratory-adapted BTV-1 strains have never been used in this region. This may have important implications in the epidemiology of bluetongue, considering the presence of many BTV serotypes in India. PMID- 25812206 TI - Animal trypanosomosis: making quality control of trypanocidal drugs possible. AB - African animal trypanosomosis is arguably the most important animal disease impairing livestock agricultural development in sub-Saharan Africa. In addition to vector control, the use oftrypanocidal drugs is important in controlling the impact of the disease on animal health and production in most sub-Saharan countries. However, there are no internationally agreed standards (pharmacopoeia type monographs or documented product specifications) for the quality control of these compounds. This means that it is impossible to establish independent quality control and quality assurance standards for these agents. An international alliance between the Food and Agriculture Organization of the United Nations, the International Federation for Animal Health, the Global Alliance for Livestock Veterinary Medicines, the University of Strathclyde and the International Atomic Energy Agency (with critical support from the World Organisation for Animal Health) was established to develop quality control and quality assurance standards for trypanocidal drugs, with the aim of transferring these methodologies to two control laboratories in sub-Saharan Africa that will serve as reference institutions for their respective regions. The work of the international alliance will allow development of control measures against sub standard or counterfeit trypanocidal drugs for treatment of trypanosome infection. Monographs on diminazene aceturate (synonym: diminazene diaceturate), isometamidium chloride hydrochloride, homidium chloride and bromide salts and their relevant veterinary formulations for these agents are given in the annex to this paper. However, the authors do not recommend use of homidium bromide and chloride, because of their proven mutagenic properties in some animal test models and their suspected carcinogenic properties. PMID- 25812207 TI - Development and evaluation of a live attenuated camelpox vaccine from a local field isolate of the virus. AB - A strain of camelpox virus (CMLV) isolated in the Sudan was attenuated by serial passage in Vero cell monolayers for use as a future vaccine strain. The safety and potency of passage 115 virus (designated Sudan CMLV/115) was tested. Camels inoculated with CMLV/115 showed no clinical disease or skin lesions, developed low-level antibodies and cell-mediated immune response and resisted challenge with virulent wild-type CMLV. Field testing of the candidate vaccine showed that the developed vaccine induces immune response and is safe for young and pregnant camels. PMID- 25812208 TI - Camelid brucellosis: a review. AB - Camel brucellosis has been diagnosed in all camel-rearing countries except Australia. In many countries the infection is on the rise in Old World camels (OWCs) due to the uncontrolled trade of live animals. Knowledge of camelid brucellosis has increased over the last decade through field investigations, experimental infection trials and comprehensive laboratory testing. Infection with Brucella melitensis is frequent in OWCs and rare with B. abortus. New World Camels rarely contract brucellosis. In East African countries the seroprevalence of brucellosis can reach 40% (herd level) and depends on the management system. The highest incidence is found when camels are kept together with infected small ruminants. Only a combination of serological methods can detect all serological reactors. Culturing the pathogen is still the preferred test method, although several assays based on polymerase chain reaction have been developed. PMID- 25812209 TI - Comparison of stabilisers for development of a lyophilised multiplex reverse transcription PCR mixture for rapid detection of foot and mouth disease virus serotypes. AB - Multiplex reverse-transcription polymerase chain reaction (mRT-PCR) assay is a sensitive and rapid method for the detection and serotyping of foot and mouth disease virus (FMDV). However, the method has not been used to its full potential, because of factors such as cost, a lack of infrastructure and the complexity of the reaction mixture. This study was undertaken to optimise and validate a thermostable, lyophilised, ready-to-use mRT-PCR kit for the rapid detection of FMDV in field laboratories in India. Trehalose, PEG-8000 and glycerol were evaluated for stabilisation of the PCR mixture at ambient temperatures. The lyophilised mRT-PCR kit was validated and found robust enough for use in field-level laboratories. The PCR reaction mixture in the ready-to-use kit has low complexity, so chances of cross-contamination during the preparation of the mixture are limited, but may easily be monitored by using lyophilised internal positive and negative controls. In addition, the requirement to maintain live FMDV isolates as internal positive controls at field-level regional laboratories is eliminated. PMID- 25812210 TI - Effect of incubation temperature on the diagnostic sensitivity of the glanders complement fixation test. AB - The complement fixation test (CFT) is the only serological test prescribed by the World Organisation for Animal Health (OIE) for the diagnosis of glanders in international trading of equids. However, false-positive reactions have caused financial losses to the animal owners in the past, and false-negative tests have resulted in the introduction of glanders into healthy equine populations in previously glanders-free areas. Both warm (incubation at 37 degrees C for 1 h) and cold (overnight incubation at 4 degrees C) procedures are recommended by the OIE for serodiagnosis of glanders. In a comparison of the sensitivity and specificity of the two techniques, using the United States Department of Agriculture antigen, warm CFT was found to be significantly less sensitive (56.8%; p < 0.0005) than the cold CFT (83.6%). Cold CFT thus increases the detection rate of glanders but a lower diagnostic specificity has to be accepted. The immunoblot was used as the gold standard. PMID- 25812211 TI - Lumpy skin disease in cattle in central Ethiopia: outbreak investigation and isolation and molecular detection of the virus. AB - The study was a combination of two investigations into active outbreaks of lumpy skin disease (LSD) in cattle in central Ethiopia and a retrospective analysis of outbreak reports between January 2007 and December 2011 covering the entire country. Active outbreaks were investigated in four districts of central Ethiopia: Adama, Wenji, Mojo and Welenchiti. A semi-structured questionnaire was used to acquire data at individual and herd levels, and tissue samples were collected for viral isolation and characterisation. The retrospective analyses showed that, during the five-year period, a total of 1,675 outbreaks were reported, with 62,176 cases and 4,372 deaths. The highest number of outbreaks was reported in Oromia (1,066), followed by Amhara (365) and the Southern Nations, Nationalities and People's Region (123). Outbreaks were more frequently observed between September and December and the highest number of outbreaks was reported in 2010. During the period studied, a total of 2,174 local zebu cattle were clinically examined and morbidity and mortality rates of 13.61% (296) and 4.97% (108) were recorded, respectively. Analysis of the active outbreaks revealed a relatively consistent morbidity rate, with the highest observed in Adama (15.38%), followed by Wenji (10.26%). The highest mortality rates were also observed in Adama (5.89%) and Wenji (3.42%). The LSD virus was isolated from 22 samples and all tested positive in polymerase chain reaction analysis. The disease was observed in the cattle regardless of previous vaccination with Kenyan sheep- and goat-pox vaccine; thus, vaccine efficacy was assessed under field conditions and the authors' findings, together with a possible remedy, are presented in this paper. PMID- 25812212 TI - The first recorded epidemic of leptospirosis in sheep in Egypt. AB - An outbreak of leptospirosis in sheep is recorded as the first epidemic of ovine leptospirosis in Egypt. The sick animals showed typical symptoms such as fever, jaundice, red urine and abortion, with a fatal course. Acute and convalescent sera were tested for demonstration of seroconversion using the microscopic agglutination testto confirm infection. Long-acting tetracycline was successfully used for treatment. PMID- 25812213 TI - Prevalence of Rift Valley fever in domestic ruminants in the central and northern regions of Burkina Faso. AB - The seroprevalence of Rift Valley fever was determined in cattle, sheep and goats in selected areas of northern and central Burkina Faso. A total of 520 serum samples were screened for anti-Rift Valley fever virus immunoglobulin G (IgG) antibodies using an inhibition enzyme-linked immunosorbent assay (ELISA). An average seroprevalence of 7.67% (range 5% to 20%) was found in ruminants in Seno and Soum provinces, and prevalences of 20% and 22.5% in cattle in Yatenga and Oubritenga provinces, respectively. The location, species and age of the animals were found to influence the seroprevalence. All the ELISA IgG-positive samples were tested for IgM in a competitive ELISA and were found negative, thus ruling out recent infections. The IgG-positive samples, including weak positives, were further tested in a serum neutralisation test for neutralising antibodies and 54.5% of these samples tested positive. The results show that the virus is in circulation in central and northern regions of Burkina Faso, suggesting the need for improved surveillance and control systems to prevent future outbreaks and the consequent economic impact of the disease in Burkina Faso livestock. PMID- 25812214 TI - Seroepidemiological survey on Rift Valley fever among small ruminants and their close human contacts in Makkah, Saudi Arabia, in 2011. AB - This study describes a seroepidemiological survey on Rift Valley fever (RVF) among small ruminants and their close human contacts in Makkah, Saudi Arabia. A total of 500 small ruminants (126 local, 374 imported) were randomly selected from the sacrifice livestock yards of Al-Kaakiah slaughterhouse, in the holy city of Makkah, during the pilgrimage season 1432 H (4-9 November 2011). In addition, blood samples were collected from 100 local workers in close contact with the animals at the slaughterhouse. An RVF competition multi-species enzyme-linked immunosorbent assay (ELISA) detecting anti-RVF virus immunoglobulin G (IgG)/ immunoglobulin M (IgM) antibodies and an RVF IgM-specific ELISA were used for serological investigations. In total, 84 (16.8%) of the 500 sacrificial sheep and goats tested seropositive in the competition ELISA but no IgM antibodies were detected in the IgM-specific assay. All seropositive samples, comprising 17.91% of the imported animals and 13.49% of the local ones, were therefore designated positive for anti-RVF virus IgG antibody. Among the local personnel working in close contact with the animals, 9% tested seropositive in the RVF competition ELISA. The study indicates that two factors may increase the likelihood of an RVF outbreak among sacrificial animals and pilgrims: i) the large-scale importation of small ruminants into Saudi Arabia from the Horn of Africa shortly before the pilgrimage season, and ii) the movement of animals within Saudi Arabia, from the RVF-endemic south-western area (Jizan region) to the Makkah region, particularly in the few weeks before the pilgrimage season. From these findings, it is recommended that i) all regulations concerning the import of animals into Saudi Arabia from Africa should be rigorously applied, particularly the RVF vaccination of all ruminants destined for export at least two weeks before exportation, and ii) the movement of animals from the RVF-endemic south-western area (Jizan region) of Saudi Arabia to the Makkah region should be strictly prohibited. PMID- 25812215 TI - Effectiveness of systematic foot and mouth disease mass vaccination campaigns in Argentina. AB - The objective of this paper is to evaluate the effectiveness of systematic mass vaccination campaigns against foot and mouth disease in Argentina. The analysis was based on an estimation of the proportion of protected animals and protected farms in vaccinated populations, as reflected by levels of antibodies measured in liquid-phase enzyme-linked immunosorbent assay. The analysis was carried out in 49 animal health districts in Buenos Aires province, using data collected from four cross-sectional studies, in 2004, 2007, 2008 and 2011. Cattle were assigned to one of two categories on the basis of correlation between serological titres and expected percentage protection: non-adequately protected (expected protection < 75%) and adequately protected (expected protection >= 75%). The proportions of adequately protected cattle and significantly non-adequately protected farms were estimated and compared among sampled locations. Protection was variable among the districts; cattle aged one to two years showed higher levels of protection than cattle six to 12 months old, and the proportion of protected cattle was higher in the more recent studies. The results of the analysis will allow the national animal health service to investigate in depth those districts where protection was lower than the regional background protection. The authors propose that this methodology could be used to evaluate the effectiveness of vaccination campaigns in other countries or zones where systematic foot and mouth disease mass vaccination campaigns are undertaken. PMID- 25812216 TI - Investigation of an outbreak of infectious pustular balanoposthitis in cattle breeding bulls at a frozen semen bank. AB - Infectious pustular balanoposthitis (IPB) is one of the reproductive disorders caused by bovine herpesvirus 1 (BoHV1) that can be transmitted through artificial insemination. A herd of 63 breeding bulls at a frozen semen bank in Odisha state in India experienced a suspected outbreak of IPB, with 11 bulls showing clinical signs of the infection. Clinical signs were noticed in two bulls initially and a few days after in the other nine animals. Serum samples from 53 bulls were examined for anti-BoHV1 antibodies using a virus neutralisation test (VNT) and a competitive enzyme-linked immunosorbent assay (cELISA); the remaining ten bulls were not included in the study because it was difficult to restrain them at that time. Paired serum samples were collected 21 days apart from ten clinically affected bulls (the eleventh clinically affected bull was not included in the study for the reason stated above). In the neutralisation test, the paired serum samples showed a two- to fourfold increase in anti-BoHV1 antibody titre; in the cELISA, the paired samples were also found positive for anti-BoHV1 antibodies. Serum samples from 43 in-contact bulls were collected about day 22 after the first observation of clinical infection in the herd. Among these serum samples, a total of 30 were found positive for anti-BoHV1 antibodies in the VNT and a total of 30 were found positive in cELISA. Ten samples were positive in one test but not the other and 25 tested positive in both tests. In all, 35 serum samples from in-contact bulls tested positive in either one or both of the two types of test. An overall agreement of 76.74% was found in detection of anti-BoHV1 antibodies in the two tests. Sensitivity was higher than specificity in detection of anti-BoHV1 antibodies in the serum samples. The glycoprotein C region of the genomic DNA of BoHV1 was amplified from semen samples by polymerase chain reaction. The findings from the outbreak indicate that continuous monitoring of breeding bulls at frozen semen banks is warranted to avoid the risks associated with artificial insemination. PMID- 25812218 TI - Development of a seroprevalence map for avian influenza in broiler chickens from Comunidad Valenciana, Spain. AB - The aim of this study was to design and implement a seroprevalence map based on business intelligence for low pathogenicity notifiable avian influenza (LPNAI) in broilerchickens in Comunidad Valenciana (Spain). The software mapping tool developed for this study consisted of three main phases: data collection, data analysis and data representation. To obtain the serological data, the authors analysed 8,520 serum samples from broiler farms over three years. The data were represented on a map of Comunidad Valenciana, including geographical information of flock locations to facilitate disease monitoring. No clinical signs of LPNAI were reported in the studied flocks. The data from this study showed no evidence of contact with LPNAI in broiler flocks and the novel software mapping tool proved a valuable method for easily monitoring on the serological response to avian influenza information, including geographical information. PMID- 25812217 TI - The equine arteritis virus isolate from the 2010 Argentinian outbreak. AB - A semen sample from a stallion infected during the 2010 equine arteritis virus (EAV) outbreak was received for viral isolation prior to castration of the animal. The virus was identified using a polyclonal antibody immunofluorescence test. Reverse-transcription polymerase chain reaction (RT-PCR) was used to amplify a region of the GP5 gene with primers GL105F and GL673R. The PCR products were purified and sequences of both strands were determined in a MegaBACETM1000 with inner primers CR2 and EAV32. A phylogenetic dataset was built with the previously reported sequences of five strains isolated in Argentina, together with a group of selected sequences obtained from GenBank. The unrooted neighbour joining tree was constructed using molecular evolutionary genetic analysis (MEGA) and bootstrap analyses were conducted using 1,000 replicate datasets. Evolutionary distances were computed using the maximum composite likelihood method. A NetNGlyc server analysis at the Technical University of Denmark (www.cbs.dtu.dk/services/NetNGlyc/) was used to predict N-glycosylation in GP5 sequences. The phylogenetic analysis revealed that the new strain GLD-LP-ARG), together with other strains previously isolated, belongs to the European group EU 1 but in a different branch. The new strain shows 99% nucleotide identity with strain Al1and 98.1% with the Belgian strain 08P178. Persistently infected stallions and their cryopreserved semen constitute a reservoir of EAV, which ensures its persistence in the horse population around the world. These findings reinforce the importance of careful monitoring of persistently infected stallions, as well as semen straws, by RT-PCR or test mating, in accordance with national regulations. PMID- 25812219 TI - Seroprevalence of brucellosis in sheep and isolation of Brucella abortus biovar 6 in Kassala State, Eastern Sudan. AB - Brucellosis is one of the important zoonotic diseases among livestock. This study was carried out to estimate the prevalence of brucellosis and isolate Brucella spp. in sheep in Kassala State in the east of Sudan. Two thousand and five serum samples were randomly collected from nine different localities. All serum samples were examined by the Rose Bengal plate test (RBPT) and the modified RBPT (mRBPT). Forty-three (2.15%, 95% confidence interval [CI]: 1.6,3.0) and 68 (3.4%, 95% CI: 2.6, 4.2) samples were positive with the RBPT and the mRBPT, respectively. According to a known diagnostic sensitivity of 86.6% and a known diagnostic specificity of 97.6% for the mRBPT, the true prevalence was estimated to be 1.2% (95% CI: 0.3, 2.2). Different tissue samples were collected from 41 mRBPT seropositive animals. Brucella abortus biovar 6 was isolated from a pyometra of a seropositive ewe. It is important to note that B. abortus biovar 6 cannot be differentiated from Brucella melitensis biovar 2 by routine bacteriology. Only phage typing performed in reference laboratories will allow accurate identification of the strain. The fact that B. abortus biovar 6 does not require CO2 for growth, combined with the fact that it has been isolated from a small ruminant in this study, could easily have led to misidentification (as B. melitensis biovar 2), to wrong epidemiological inferences and to the implementation of inappropriate control measures. The results presented here suggest that sheep are spillover hosts, as previously described for camels, and that the actual reservoir of B. abortus biovar 6 is cattle in Kassala State, Eastern Sudan. This study highlights the importance of isolating and identifying Brucella spp. in different livestock species in order to accurately decipher brucellosis epidemiology in sub-Saharan Africa. PMID- 25812220 TI - Prevalence of equine viral arteritis in Algeria. AB - In order to determine the prevalence of equine viral arteritis in Algeria, 268 sera from non-vaccinated horses were collected from the western and eastern regions. Serological analysis of the sera, which were collected from 2009 to 2011, was performed using the virus neutralisation test, as described by the World Organisation for Animal Health. Overall, 20 sera (7.46%) were seropositive, 152 (56.71%) were negative and 96 sera (35.82%) were cytotoxic. Equine arteritis virus (EAV) seroprevalence was significantly higher in the western region (Tiaret) than in the eastern region (Barika and El-Eulma). Interestingly, more than 20% of the tested horses over 16 years old were seropositive for EAV. However, EAV prevalence did not depend on either horse breed or horse gender. This study is the first to describe the circulation of EAV in the Algerian horse population. PMID- 25812221 TI - Antimicrobial residues in foods of animal origin in Africa: public health risks. AB - The authors report on the current status of work on residues of veterinary medicinal products and, in particular, antimicrobial residues in foods of animal origin. This review focuses on residues of veterinary antimicrobials, antimicrobials used in livestock production, the concept of residues, and antimicrobial residues in foods of animal origin. Only one antimicrobial substance has been approved in the West African Economic and Monetary Union, compared with 16 substances in Benin and 56 in the European Union. The issue of antimicrobial residues in foods of animal origin has rarely been a serious concern in developing countries, in contrast to the situation in Europe. However, while the prevalence of veterinary drug residues in foods of animal origin is less than 1% in Europe, in some African countries it can be as high as 94%. Antimicrobial residues in foods of animal origin can cause allergies, cancer, alterations in the intestinal flora, bacterial resistance and the inhibition of fermentation in the dairy industry. The harmonisation of regulations in Africa could reduce the circulation of prohibited antimicrobials and lead to the implementation of a plan for the control and surveillance of residues from veterinary medicinal products in foods of animal origin. PMID- 25812222 TI - Salmonella enterica serotypes isolated from squabs reveal multidrug resistance and a distinct pathogenicity gene repertoire. AB - The consumption of squab (young unfledged pigeons) as part of the cuisine of many countries, together with the observation that squabs are vectors of zoonotic agents, may make them a public health risk. This study was designed to determine the serotypes, distribution of 11 virulence genes (invA, avrA, ssaQ, mgtC, siiD, sopB, gipA, sodC1, sopE1, spvC, bcfC) and the antimicrobial resistance profiles of salmonellae recovered from squabs. Six isolates were identified from among 45 (13.3%) squabs sampled. Three serotypes were identified according to the Kauffmann-White serotyping scheme: Salmonella Typhimurium (4/6; 66.7%), S. Braenderup (1/6; 16.7%) and S. Lomita (1/6; 16.7%). Polymerase chain reaction analyses revealed the presence of invA, sopB and bcfC in all six isolates, whereas sopE1 and gipA were absent. All six isolates were resistant to lincomycin and streptomycin, but all were susceptible to ciprofloxacin, colistin sulphate and gentamicin. Among the S. Typhimurium isolates, seven resistance profiles were identified: penicillins,aminoglycosides,fluoroquinolones, lincosamides,phenicols, tetracyclines and sulphonamides; four resistance profiles were identified in the isolates of S. Braenderup and S. Lomita: aminoglycosides, fluoroquinolones, lincosamides and polymyxin. Thus, the distribution of resistance to the antibiotics was largely dependent on serotype identity. The presence of invA, avrA, ssaQ, mgtC, siiD, sopB and bcfC was associated with resistance to chloramphenicol; invA, sopB and bcfC with resistance to streptomycin and lincosamide; and invA and sodC1 with resistance to trimethoprim-sulfamethoxazole. The identification of serotypes S. Typhimurium, S. Braenderup and S. Lomita in the squab samples has important implications because these serotypes are significant causes of food poisoning and enteric fever in humans. PMID- 25812223 TI - Sales of veterinary antimicrobial agents for therapeutic use in food-producing animal species in Japan between 2005 and 2010. AB - The use of veterinary antimicrobial agents in animals can result in the emergence and selection of resistant bacteria in food-producing animals. This study elucidated the use of veterinary antimicrobial agents in Japan in terms of milligrams of active ingredient sold per kilogram of biomass between 2005 and 2010. Data on sales of antimicrobial agents and on the biomass of the target animal species were compiled from statistics published bythe Japanese Ministry of Agriculture, Forestry and Fisheries. The quantities of antimicrobials used varied between animal species: the highest usage was observed in pigs (392 to 423 mg/ kg), followed by beef cattle (45 to 67 mg/kg), broiler chickens (44 to 63 mg/kg) and dairy cattle (33 to 49 mg/kg). For the animal species combined, usage of third- and fourth-generation cefalosporins, fluoroquinolones and macrolides ranged from 0.10 to 0.14 mg/kg biomass, 1.1 to 1.3 mg/kg biomass and 7.8 to 10.6 mg/kg biomass, respectively. PMID- 25812224 TI - Salmonella enterica in imported and domestic day-old turkey poults in Egypt: repertoire of virulence genes and their antimicrobial resistance profiles. AB - Globalisation and international trade facilitate the rapid spread and transmission of foodborne pathogens. This study was designed to determine the serovars, distribution of virulence genes (invA, avrA, ssaQ, mgtC, siiD, sopB, gipA, sodC1, sopE1, spvC, bcfC) and antibiotic resistance profiles in salmonellae recovered from imported and domestic day-old turkey poults in Egypt. The prevalence of salmonellae in the imported poults was 4% (6/150): S. Enteritidis was the most frequent isolate (1.3%; 2/150), followed by Typhimurium, Virchow, Larochelle and a non-typeable strain, each with 0.7% (1/150) prevalence. The prevalence of salmonellae in the domestic poults was < 2% (2/150) and serotyping indicated a prevalence of 1.3% (1/150) for both Typhimurium and Altona. In polymerase chain reaction screening, the genes invA, sopB and bcfC were detected in all the Enteritidis, Typhimurium, Virchow, Larochelle, Altona and non-typeable isolates (100%); the gene gipA was absent from all isolates. Carriage of invA, sopB and bcfC among the Enteritidis, Typhimurium, Virchow, Larochelle, Altona and non-typeable isolates was associated with a core pattern of resistance to three antibiotics: streptomycin, nalidixic acid and chloramphenicol. The detection of S. Enteritidis, Typhimurium, Virchow, Larochelle, and Altona in turkey poults has important implications because these serovars are a significant cause of foodborne illness and enteric fever in humans. PMID- 25812226 TI - Be Share Aware. PMID- 25812227 TI - 2015 election: Burnham promises 'healthier start' for a generation. PMID- 25812225 TI - Contribution to the study of staphylococcus contamination of cows' milk on a number of farms in Algiers: its impact on human health. AB - The authors describe a survey and screening programme for staphylococcus. The study covers 14 dairy farms in the Algiers region, from which 203 samples of cows' milk were taken for bacteriological testing. The survey results show that poor husbandry conditions are the main cause of staphylococcus in cows' milk. Staphylococcus was found in the milk of 30% of the cows sampled. These results were influenced by a variety of factors, in that: the contamination rate rose with the number of pregnancies, age, and volume of milk output of the cow, as well as the bedding thickness; the milk contamination rate was greater when milking occurred outside a milking parlour and when it was performed by machine; higher rates of staphylococcus infection were found in the milk of cows at the end of lactation, in red and white breeds, and in those with cylindricalteats. Identification of the bacteria found (staphylococcus) showed that coagulase- negative staphylococci were present in 67.21% of samples, whereas coagulase- positive staphylococci were present in only 32.79%. The average count for the latter was equal to 0.54 x 10(4) colony-forming units per ml of Staphylococcus aureus. Seventy percent of the milk analysed was free from staphylococci and most of the bacteria identified were not pathogenic to consumers (coagulase- negative staphylococci); nevertheless, consuming fresh milk still presents a degree of risk. PMID- 25812228 TI - NMC issues updated Code for nurses and midwives. PMID- 25812229 TI - Relationships central to young person care. PMID- 25812231 TI - Inquiry into parenting support and social mobility launched. PMID- 25812230 TI - Children 'pester' for advertised junk food. PMID- 25812232 TI - Next government urged to make children's health a priority. PMID- 25812233 TI - Seven day working or seven day services? PMID- 25812234 TI - Core health visiting service specification updated. PMID- 25812235 TI - Role to play. PMID- 25812236 TI - Moving upstream. PMID- 25812237 TI - Author spotlight: Louise Perrin. PMID- 25812238 TI - How members can mobilise themselves for political change. PMID- 25812239 TI - The impact of infant crying on the parent-infant relationship. AB - Infant crying is distressing for parents, evoking a range of difficult feelings. Infants who cry often maybe perceived as difficult by their parents, with negative effects on bonding and attachment. Infant crying as a stimulus for child abuse is also highlighted, as parents' feelings of frustration may provoke harmful responses towards the child. A non-exhaustive literature review was conducted, exploring the impact of infant crying on parents, using CASP tools to support the analysis of twenty qualitative and quantitative studies, published between 2003 and 2013. This paper reports the findings of the review, with a specific focus on the effects of infant crying on the parent-infant relationship. The findings suggest parents may experience anxiety, depression, helplessness, anger and frustration in response to infant crying. Negative effects on bonding and parental perception of the baby are identified. Parents may also experience thoughts of harming their baby, and subsequent feelings of guilt and shame. Universal interventions to help parents prepare for parenthood, and to respond positively to crying are strongly recommended. Opportunities for parents to discuss their feelings towards their infant should be maximised, reducing the impact of infant crying on bonding and attachment. Parents should be empowered to develop strategies and sources of support to help them cope. Early identification of parents experiencing difficulties in coping with infant crying is essential, and risk in relation to potential abuse must be assessed. Health visitors have a key role in providing such support. PMID- 25812240 TI - Development and outcomes of a therapeutic group for women with postnatal depression. AB - Postnatal depression is a significant problem affecting approximately 14.5% of mothers and has the potential for negative long-term consequences for mothers and their children. Previous research suggests that group interventions using cognitive behavioural techniques can be helpful, providing mothers with strategies to address their problems as well as professional and peer support. This paper describes how a therapeutic group was developed by Health Visitors for mothers with postnatal depression in Oxfordshire. It was hypothesised that women who attended the group would feel better able to manage their mood, that their mood would improve and that attending the group would be a positive and supportive experience for them. Formal outcome measures as well as feedback questionnaires were used to evaluate the group and test these hypotheses as well as provide information to improve the service. An overview of the effectiveness of the group is given here, with the majority of women who attended showing improvement in their mood as well as high satisfaction with the content and processes of the course. The findings are discussed and plans for the future are presented. PMID- 25812241 TI - Independent prescribing supporting the delivery of the public health vaccination programme. AB - The parameters of non-medical prescribing have changed since its introduction in 1994. In July 2000 nurse independent prescribing was introduced, this opened up the opportunity for many practitioners to incorporate this into their practice. The national childhood immunisation programme is an area of practice that has not required the use of independent prescribers. Their skills can provide support to the effective and efficient delivery of the vaccination programme through enabling the work of a mixed skills team. Doncaster in South Yorkshire was one of the Public Health England pilot areas for the secondary school aged children in years seven and eight in 2014. This paper details the use of independent prescribing by a practitioner to sign patient specific directions for health care support workers to administer the nasal flu vaccine to children clearly identified in it. This process required the development and implementation of a clinical skills training package for health care support workers to administer the flu vaccination (FluenzTetra) nasal vaccine. Also governance arrangements needed to be in place to support this change in practice in the delivery of the childhood influenza immunisation programme. This enables nurses and health care support workers to practice safely and within acceptable and legal boundaries. PMID- 25812242 TI - Does mother know best? PMID- 25812243 TI - Foreign body ingestion in children. PMID- 25812244 TI - Letter to the editor: Adults asking adolescents to light cigarettes: parental prompting of adolescent smoking among Filipino Americans. PMID- 25812245 TI - Improved quality of care for cardiovascular disease for Latinos seen in high proportion Latino vs low proportion Latino clinics. AB - BACKGROUND: Primary care practices that concentrate linguistically and culturally appropriate services for Latinos may result in higher cardiology consultation rates and improved process measure performance for patients with coronary artery disease (CAD) and congestive heart failure (CHF). METHODS: Multivariable Cox proportional-hazards regression was used to assess differences in referral at high proportion (HP) vs low proportion (LP) practices. Multivariable Poisson regression was used to assess the frequency of follow-up consultation. RESULTS: Among the 9,761 patients, 9,168 had CAD, 4,444 had CHF, and 3,851 had both conditions. Latinos comprised 11% of the CAD cohort and 11% of the CHF cohort. Multivariable analyses showed higher consultation rates for Latinos at HP practices for CAD and CHF. Blacks and Whites at HP practices had no significant differences in rates of consultation compared to those in LP practices. Latinos at HP practices had 25% more consultations for CAD and 23% more consultations for CHF than Latinos at LP practices. Latinos at HP clinics had higher overall mean quality performance on clinical measures for both CAD and CHF. Latinos at an LP clinic had the largest improvement in quality performance with consultation. CONCLUSIONS: Among Latinos with CAD or CHF receiving care within a single large academic care network, Latino patients at HP practices have higher rates of cardiologist consultation and performance on CVD process measures compared to Latino patients at LP practices. Elucidating the essential components of individual practice environments that provide higher quality of care for Latinos will allow for well designed systems to reduce health care disparities. PMID- 25812247 TI - Association of Hispanic ethnicity with acute ischemic stroke care processes and outcomes. AB - BACKGROUND: Few studies have examined the actual hospital arrival mode, emergency department (ED) care processes, and early outcomes in Hispanic vs non-Hispanic acute ischemic stroke (AIS) patients. We evaluated processes and prognosis by Hispanic ethnicity among AIS patients encountered in urban setting. METHODS: We retrospectively reviewed prospectively-collected data on 1,117 AIS patients presenting within 12 hours of ictus to five hospitals in a tertiary-level stroke center network in San Diego, California. Variables of interest included pre hospital factors, ED care processes, and favorable outcome (day-90 modified Rankin Scale [mRS] score of 0-1); all of which were adjusted for pre-specified covariates in a multivariable logistic regression model. RESULTS: There were 192 Hispanic AIS patients (17.2% of cohort) encountered from June 2004 to March 2011. Hispanic patients were significantly more likely to be younger, female, and diabetic. Hispanic patients arrived by ambulance (vs other arrival modes) less frequently (adjusted OR .56; 95% CI: .38-.81), trended toward a longer time of stroke onset to treatment decision (351.6 vs. 320.02 minutes, P=.07), and experienced a favorable day-90 outcome less often (adjusted OR .52, CI: .28-.96). However, for the day-90 outcome, there was no interaction between ambulance arrival and Hispanic ethnicity (P=.5614). DISCUSSION: Hispanic AIS patients in this study were less likely to arrive at the hospital by ambulance, and experienced half the odds of a favorable outcome compared to others. Strategies to boost ambulance utilization among Hispanic AIS patients and identify contributors to this worrisome outcome disparity are needed. PMID- 25812246 TI - Residential ethnic segregation and stroke risk in Mexican Americans: the Brain Attack Surveillance in Corpus Christi project. AB - OBJECTIVE: Residential ethnic segregation may operate through multiple mechanisms to increase stroke risk. The current study evaluated if residential ethnic segregation was associated with stroke risk in a bi-ethnic population. DESIGN: Incident strokes were identified in Nueces County, Texas from 2000 to 2010. Residential ethnic segregation (range: 0-1) was derived for each census tract in the county (n=64) using 2000 US Census data, and categorized into: predominantly non-Hispanic White (NHW, <.3); ethnically mixed (.3-.7); predominantly Mexican American (MA, >.7). Multilevel Poisson regression models were fitted separately for NHWs and MAs to assess the association between residential ethnic segregation (predominantly NHW referent) and relative risk for stroke, adjusted for age category, sex and census tract-level median per capita income. Effect modification by age was also examined. RESULTS: In adjusted models, residential ethnic segregation was not associated with stroke risk in either ethnic group. Effect modification by age was significant in both groups. Young MAs and NHWs living in predominantly MA census tracts were at greater relative risk for stroke than those living in predominantly NHW census tracts, but this association was only significant for MAs (MAs: RR = 2.38 [95% CI: 1.31-4.31]; NHWs: RR = 1.53 [95% CI: .92-2.52]). CONCLUSION: Our findings demonstrate that residential ethnic segregation may influence downstream stroke risk in young MAs. Pathways between residential ethnic segregation and stroke in young MAs should be explored. PMID- 25812248 TI - John Henryism, socioeconomic position, and blood pressure in a multi-ethnic urban community. AB - OBJECTIVES: The John Henryism (JH) hypothesis suggests that, under adverse social and economic conditions, high-effort coping styles that reflect hard work and determination may contribute to elevated blood pressure. Results from tests of this hypothesis have been mixed, with variations by region, urban versus rural areas, race, gender, and age. The majority of studies reporting that socioeconomic position modifies associations between JH and blood pressure have been for non-Latino Blacks in rural communities. In contrast, most studies conducted in urban areas report little support for the JH hypothesis. Few studies have been conducted in samples that include Latinos. We extend previous research by testing the JH hypothesis in a multi-ethnic, low-to-moderate income urban community. DESIGN: We used multivariate linear regression to test the hypothesis that associations between JH and blood pressure were modified by income, education, or labor force status in a multi-ethnic (non-Latino Black, Latino, non Latino White) sample (N=703) in Detroit, Michigan. The outcome measures were systolic (SBP) and diastolic blood pressure (DBP). RESULTS: John Henryism was associated with higher SBP (beta=3.92, P=.05), but not DBP (beta=1.85, P=.13). These associations did not differ by income, education, or labor force status. Results did not differ by race or ethnicity. CONCLUSIONS: John Henryism is positively associated with SBP in this multi-ethnic, low-to-moderate income sample. This association did not differ by income, education, or labor force status. Results are consistent with studies conducted in urban communities, finding limited evidence that associations between JH and blood pressure vary by socioeconomic position. PMID- 25812251 TI - Race, socioeconomic status, and rurality influences on type 2 diabetes management among North Carolina adults. AB - PURPOSE: To examine the impact of race, socioeconomic status, and rurality on Type 2 diabetes education among adults in North Carolina. METHODS: Our study utilized data from the 2008 Behavioral Risk Factor Surveillance System (BRFSS) to conduct a retrospective study and secondary data analysis. To account for the multistage survey design of BRFSS, SAS/SUDAAN was used to calculate adjusted and unadjusted odds ratios and 95% confidence intervals (CIs). Univariate, bivariate, and multivariate analyses were performed to examine the association between race, socioeconomic status, and rurality and its effects on type 2 diabetes education among adults in North Carolina. MAIN FINDINGS: The majority of the participants (63%) did not have good diabetes education. Non-Whites had higher odds than Whites of good diabetes education (OR=1.56, 95%CI: 1.19, 2.03). Individuals who lived in rural North Carolina had lower odds of having good diabetes education than their urban counterparts, but the results remained insignificant (OR=.88, CI: .67, 1.15). Individuals who were of low socioeconomic status (SES) had poorer diabetes education than individuals who were identified as being high SES, but the results were insignificant (OR=.81, CI: .60, 1.09). PRINCIPAL CONCLUSIONS: Findings from the study indicate that non-White adults had higher odds than Whites of good type 2 diabetes education in North Carolina. The results of our study could be used for policies and recommendations for health organizations. Policy makers should make diabetes education mandatory for individuals who are diagnosed with this disease. Future studies should have a more accurate measurement of type 2 diabetes education. PMID- 25812252 TI - Asian American mothers' perception of their children's weight: a comparison with other racial/ethnic groups in Los Angeles. AB - OBJECTIVE: While mother's perception of child's weight is important for the success of early childhood obesity prevention programs, few studies have examined that of Asian Americans. Our study examined their perception and compared it to that of mothers of other racial/ethnic groups. DESIGN: Cross-sectional study of 2,051 randomly selected mothers of children aged 2-5 years living in Los Angeles County who were enrolled in the Special Supplemental Nutrition Program for Women Infants and Children (WIC). MAIN OUTCOME MEASURE: The primary outcome was mother's perception of child's weight. RESULTS: We found that Asian American mothers were 2.12 (95% CI: 1.27-3.54) times as likely as Hispanic mothers to accurately perceive their children's weight, adjusting for child's age, sex and birthweight, and mother's age and education. However, this relationship disappeared after adjusting for mother's BMI. We did not find differences in perception of child's weight among non-Hispanic White, non-Hispanic Black and Hispanic mothers. CONCLUSION: It appears that Asian American mothers' increased accurate perception of child's weight status can be partially explained by their lower prevalence of obesity. Our findings suggest that early childhood obesity prevention programs should consider the weight status of mothers. PMID- 25812250 TI - Sedentary behavior, body mass index, and weight loss maintenance among African American women. AB - OBJECTIVES: Relationships among sedentary behavior, weight gain, and weight loss and regain are understudied particularly for African Americans, a high risk group for obesity. The hypotheses were: sedentary behavior is positively associated with current body mass and % of weight loss maintained after initial weight loss; these associations differ by physical activity status. DESIGN: Cross-sectional. SETTING: National survey. PATIENTS OR PARTICIPANTS: 1,110 African American women. INTERVENTIONS: Observational study. MAIN OUTCOME MEASURES: A cross-sectional survey was administered to African Americans who had intentionally lost 10% of their body weight. Those who lost weight and maintained at least a 10% weight loss for a year were classified as weight loss maintainers; all others were classified as weight loss re-gainers. Participants were classified into one of four categories based on low and high levels of sedentary behavior and physical activity. The high physical activity, low sedentary behavior category was the reference group. Sociodemographic characteristics and health conditions were covariates. Data were collected in 2009 and analyzed in 2013. RESULTS: Each additional daily hour of sedentary time was associated with an increase in BMI (P<.001) and poorer weight loss maintenance (P<.01). Regardless of sedentary behavior, low physically active participants had BMIs that were greater (P<.001) compared to the reference group. Sedentary behavior had an independent effect on BMI and % of weight loss maintained for high but not low physically active participants. CONCLUSIONS: High levels of sedentary behavior were associated with poorer weight-loss maintenance among African American women even for those with high levels of physical activity. The implications of this study are that physical activity and sedentary behavior, independently and combined, are associated with BMI and weight-loss maintenance. PMID- 25812253 TI - Obesogenic behaviors among adolescents: the role of generation and time in the United States. AB - OBJECTIVES: To examine how obesogenic behaviors (consumption of sugary drinks, physical activity, and/or sedentary behaviors) differ among adolescents within and across generation. DESIGN: Data come from the 2008 Boston Youth Survey, a population-based sample of 9th-12th-graders in 22 public high schools in Boston, MA. We used self-reported information to calculate generation and obesogenic behaviors (i.e. physical activity in past 7 days, consumption of sugar-sweetened beverages in past 7 days, and TV/computer/video game use on an average school day). Multivariable models were conducted to estimate the association between generation and obesogenic behaviors, adjusting for race/ethnicity, sex, age, family structure, and school. RESULTS: Relative to first generation youth, 1.5 generation (RR=1.74, 95% CI=1.10, 2.77) and second generation (RR=1.45, 95% CI=1.02, 2.07) youth were more likely to consume soda. Second (RR=1.60, 95% CI=1.20, 2.14) and third generation (RR=2.29, 95% CI=1.43, 3.65) youth were significantly more likely to consume other sugary drinks. Only third generation youth were more likely to watch >=2 hours/day of TV when compared to first generation youth (RR=1.53, 95% CI=1.07, 2.18). No differences were seen by generation for levels of moderate-to-vigorous physical activity or computer/video games. CONCLUSIONS: Greater consumption of sugary drinks is seen across generation among adolescents. Sugary drinks, which are aggressively marketed to immigrant youth, may contribute to excess weight gain seen among foreign-born youth upon arrival in the United States. PMID- 25812249 TI - Uncovering physiological mechanisms for health disparities in type 2 diabetes. AB - Type 2 diabetes (T2D) prevalence in the United States is significantly higher in African Americans vs Whites. Yet, the physiological mechanisms contributing to this health disparity have been poorly described. To design effective strategies to reduce this disparity, there is a need to determine whether racial differences in diabetes prevalence are attributable to modifiable or non-modifiable factors. This review synthesizes and critically evaluates the potential physiological and genetic mechanisms that may contribute to the higher susceptibility of African Americans to T2D. These mechanisms include: 1) obesity and fat distribution; 2) metabolic flexibility; 3) muscle physiology; 4) energy expenditure and fitness; and 5) genetics. We focus on the clinical significance of findings and limitations of the recent literature. PMID- 25812254 TI - Association of UCP1 -3826A/G and UCP3 -55C/T gene polymorphisms with obesity and its related traits among multi-ethnic Malaysians. AB - OBJECTIVE: Our study investigated the association of UCP1 -3826A/G and UCP3 55C/T single nucleotide polymorphisms (SNPs) with obesity and its related traits among multi-ethnic Malaysians. PARTICIPANTS: A total of 447 (225 males; 46 Malays, 339 ethnic Chinese, 62 ethnic Indians; 111 obese) participated. METHODS: Demographic and anthropometric data were collected, and genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The minor allele frequencies (MAFs) for UCP1 according to Malay/Chinese/Indian ethnicities were .61/.55/.52 and .32/.55/.38, respectively. UCP3 genotype and allele distribution was significantly associated with ethnicity and waist-to-hip ratio (WHR), but among non-obese and Chinese participants only, respectively, after stratified analysis. Chinese participants with T allele had significantly lesser risk to be centrally obese [odds ratio =.69 (CI =.48, 1.00; P=.04)], and also had significantly lower WHR compared to those with C allele. The UCP1 or UCP3 SNPs were not associated with obesity/BMI and total body fat (TBF), but combinatory genotype analysis revealed that those having the AA and CC genotype for the former and latter SNPs had significantly highest BMI and TBF compared to other genotype combinations. CONCLUSIONS: UCP3 -55C/T SNP was associated with central obesity among Malaysian participants of Chinese descent. Combinatory genotype analysis showed that BMI and TBF were significantly different among UCPI -3826A/G and UCP3 -55C/T genotype combinations, suggesting the existence of a gene interaction between UCP1 and UCP3 in influencing obesity and adiposity. PMID- 25812256 TI - Stressors and coping mechanisms associated with perceived stress in Latinos. AB - OBJECTIVE: To evaluate the relationship between causes of perceived stress and the coping mechanisms used by Latino adults with perceived stress. DESIGN, SETTING, PARTICIPANTS: This cross-sectional survey was conducted on a convenience sample of 200 Latino adults (aged >=18 years). They were recruited from clinics, migrant camps, community events, and churches located in Charleston, S.C. This survey included questions regarding causes of perceived stress, perceived stress (Perceived Stress Scale 10), coping mechanisms (Brief COPE), and depression (Perceived Health Questionnaire 9). MEASURES: High perceived stress (PSS >=15) was the primary outcome measure. Coping mechanisms and stressors were secondary outcomes. RESULTS: Most (92%) of the sample was born outside the United States, and 66% reported high perceived stress. Stressors associated with high perceived stress included discrimination (P=.0010), lack of insurance (P=.0193), health problems (P=.0058), and lack of money (P=.0015). The most frequently utilized coping mechanisms were self-distraction (54.77%), active coping (69.85%), positive reframing (56.78%), planning (63.82%), acceptance (57.87%), and religion (57.79%). Latinos with higher perceived stress were more likely to report discrimination (OR: 3.401; 95%CI 1.285-9.004) and health problems (OR: 2.782; 95%CI 1.088-7.111) as stressors, and to use denial as a coping mechanism (OR: 2.904; 95%CI 1.280-6.589). CONCLUSION: An increased prevalence of perceived stress among the Latinos evaluated in this study was associated with using denial as a coping mechanism, and encountering discrimination and health problems as sources of perceived stress. Most individuals responded to stressors by utilizing a variety of both adaptive and maladaptive coping mechanisms. PMID- 25812255 TI - Recruitment and enrollment of African Americans and Caucasians in a health promotion trial for persons with serious mental illness. AB - African Americans with serious mental illness (SMI) continue to experience inadequate representation in clinical trials. Persons with SMI, regardless of race, have an increased burden of all cardiovascular disease (CVD) risk factors including obesity, hypertension, diabetes mellitus, dyslipidemia, metabolic syndrome and tobacco smoking. Having SMI and being African American, however, is each associated with an increased risk of CVD mortality compared to the general population. There is a critical need, therefore, to adapt health promotion interventions for African Americans with SMI. We sought to examine overall recruitment into a randomized clinical trial of CVD prevention among persons with SMI, and to examine racial differences in interest, enrollment, and potential barriers to participation. Although similar levels of interest in participation were seen between African Americans and Caucasians in signing screening consent, 9.6% fewer African Americans enrolled due to inability to complete initial data collection. Further work is needed to better understand the nature of the barriers encountered by African Americans with SMI who otherwise may be interested in participating within clinical trials. PMID- 25812257 TI - The association of depression with diabetes management among urban American Indians/Alaska Natives in the United States, 2011. AB - OBJECTIVE: To determine the relationship between depression and diabetes management among urban American Indians/Alaska Natives (AI/ANs). DESIGN: Retrospective, cross-sectional analysis of medical records. SETTING: 33 Urban Indian Health Organizations that participated in the Indian Health Service Diabetes Care and Outcomes Audit. PATIENTS: 3,741 AI/AN patient records. MAIN OUTCOME MEASURES: Diabetes management outcomes, including HbA1c, smoking, BMI, systolic blood pressure, creatinine, total cholesterol, and receipt of preventive services. RESULTS: Individuals with depression and diabetes were 1.5 times more likely to smoke than individuals with diabetes but without depression (OR=1.51; 95% Cl: 1.23, 1.86), controlling for age, sex, and facility. After adjustment, the geometric mean BMI in diabetes patients with depression was 3% higher than in patients without depression (beta=.034; 95% CI: .011, .057). CONCLUSIONS: Urban AI/ANs with diabetes and depression are more likely to smoke and have higher BMI than those with diabetes but without depression. These findings inform programmatic efforts to address the care of patients with both depression and diabetes. PMID- 25812258 TI - Racial differences in hospital mortality for medical and surgical admissions: variations by patient and hospital characteristics. AB - OBJECTIVE: To determine if there are disparities between White and Black inpatient mortality rates for specific medical and surgical conditions and whether disparities vary by patient and hospital subgroups. DESIGN, SETTING, PARTICIPANTS: All-payer discharge records in the 2009 Healthcare Cost and Utilization Project, State Inpatient Databases (SID) for 36 states that comprised about 80% of the Black and White populations in the United States were used to create a random, stratified sample of about 1,900 community hospitals (a 40% sample of US hospitals). All discharges in the hospitals were included and weighted for national estimates. MAIN OUTCOME MEASURES: Inpatient Quality Indicators, developed by the Agency for Healthcare Research and Quality, were used to measure risk-adjusted hospital mortality for six medical conditions and four surgeries. National estimates compared non-Hispanic Whites to Blacks by patient and hospital characteristics. RESULTS: Blacks had lower mortality for all medical conditions compared to Whites. However, they had higher mortality rates for two surgical procedures (coronary artery bypass graft and craniotomy) and lower mortality for one surgery (abdominal aortic anuerysm repair). These patterns held for most, though not all, patient and hospital subgroups for medical conditions, but disparities typically varied by subgroup for surgeries. CONCLUSIONS: Policymakers and researchers may use these findings in targeting interventions, designing quality reporting programs and designing studies on why the disparities exist and how to reduce them. PMID- 25812259 TI - A cross-sectional survey to evaluate knowledge, attitude and practice (KAP) regarding measles vaccination among ethnic minorities. AB - OBJECTIVE: Vaccines have prevented the spread of many diseases. However, lower vaccination rates have been found among the minority nationalities of China. We carried out this research to assess the knowledge, attitude and practice (KAP) in Xunhua Salar Automous County, of childhood immunization, particularly in regard to vaccination to prevent measles. METHODS: A close-ended questionnaire was designed to evaluate KAP among 240 primary caregivers sampled by using the probability proportional to size method. The chi-square test and the logistic regression were used for statistical analysis to explore the potential risk factors associated with childhood under- immunization. RESULTS: We found the majority of primary caregivers (80%) did not know their children could be immunized for free under the Expanded Program on Immunization (EPI) when they left the permanent resident areas. More than 95% of caregivers believed vaccines were effective. However, 34.6% of the children missed opportunities for vaccination or delayed vaccination. Our results showed that the potential risk factors associated with the increasing likelihood of a child missing or delaying immunization were: inadequate supplies of vaccine service; lacking information on immunization program; and lower educational level of caregivers. More than 70% of caregivers expected to acquire immunization information from village doctors or local religious leaders. CONCLUSIONS: To increase immunization rates among minority children, more immunization services are strongly suggested. Local religious leaders were encouraged to play a vital role in improving caregivers' awareness of the immunization program, especially for those without formal schooling. PMID- 25812260 TI - Racial differences in diabetes among Union Forces during the US Civil War. AB - Diabetes is the seventh leading cause of death in the United States and disproportionately affects ethnic minorities. While research examining health disparities is well-established, an historical understanding of how the disparities evolved over time may be warranted. This article examined racial differences in prevalence of diabetes and associated mortality in Blacks and Whites during the US Civil War. Data were extracted from the Medical and Surgical History of the War of Rebellion, 1861-1865, representing segregated White and Black Union Forces who served during the war. Data were collapsed by war theater (Atlantic, Central, Pacific). Results by race show that, from 1861 to 1866, the rates of Whites diagnosed with diabetes ranged overall from 0% to .11% and was distributed throughout the war theaters as: Atlantic 0.3% to .05%; Central 0.3% to .08%, and Pacific 0% to .11%. For Blacks, Atlantic ranged from .02% to .07% and Central .03% to .06%. None were reported for Pacific. Mortality was approximately .01% for both Blacks and Whites. These data suggest no racial differences in diabetes prevalence and mortality existed between Blacks and Whites during this time, implying that disparities may have evolved more recently. PMID- 25812261 TI - Bigger but not better: hospital mergers increase costs and do not improve quality. PMID- 25812262 TI - Why should we be politically active? PMID- 25812263 TI - Accountability: crossing the barriers. PMID- 25812264 TI - Breaking bad (news) death-telling in the emergency department. AB - Many physicians struggle with death-telling in sudden death. Families can be negatively impacted by suboptimal death-telling. Appropriate preparation and education can make death notification less stressful for the physician and may help decrease the development of pathologic grief in the surviving family members that can occur when death is unexpected. Although still controversial, there is a growing body of evidence that family witnessed resuscitation may be beneficial to the grieving process and desired by the public. A previously healthy 21-year-old male comes toyour community emergency department (ED) for a cough that started 4 days ago. He denies fever, shortness of breath, and chest pain. He does admit to a remote history of drug abuse. He states he is feeling "OK" and is only here because his family insisted he come because they were worried he might have pneumonia. His vital signs are normal and he appears well; therefore, he is triaged to the waiting room. About 30 minutes lates the patient complains of shortness of breath and he is brought back to an exam room. The patient is now hypotensive, tachycardic, and pulse oximetry is noted to be 87% on room air. A chest x-ray reveals severe pulmonary edema and an EKG shows ST segment elevation in multiple leads. The patient is taken to the cardiac catheterization lab by the interventional cardiologist, who makes the diagnosis of a ruptured aortic valve due to damage from endocarditis. The patient is returned to the ED to await emergent transfer to a tertiary facility; however, the patient rapidly decompensates and a Code Blue is called. Despite the absence of return of spontaneous circulation, resuscitation efforts are prolonged while the ED social worker attempts to contact the patient's family to come to the ED. Finally, the resuscitation is terminated and the patient is pronounced dead. Several hours later the patient's elderly mother arrives and asks you: "What's going on with Mikey?" PMID- 25812265 TI - Near-death experiences. The Mind-body debate & the nature of reality. PMID- 25812266 TI - The spirit of compassion: has it grown weak? PMID- 25812267 TI - Food and health challenges. PMID- 25812268 TI - Genetically modified organisms crops in agriculture? Food for thought. PMID- 25812269 TI - GMO author reponds to food for thought. PMID- 25812270 TI - The courts should not apply the seriously flawed learned intermediary doctrine. PMID- 25812271 TI - Why 'metrics' overload is bad medicine. PMID- 25812272 TI - How to improve data security in 2015. PMID- 25812273 TI - Health information technology advances health care delivery and enhances research. PMID- 25812274 TI - Effective implementation of electronic medical records and health information technologies. AB - Information technology (IT) capabilities are necessary for realizing the full promise of health information technologies in improving health care delivery process. In this study, three key IT capabilities for health care organizations are identified and their relationship with 30-day mortality rate from heart attack examined in a national sample of U.S. hospitals. The findings indicate that the negative relationship of IT capabilities with mortality rate from heart attack is mediated by effort/flexibility putforth by health care workers. PMID- 25812275 TI - Online electronic data capture and research data repository system for clinical and translational research. AB - Data is at the core of any clinical and translational research (CTR). In many studies, the electronic data capture (EDC) method has been found to be more efficient than standard paper-based data collection methods in many aspects, including accuracy, integrity, timeliness, and cost-effectiveness. The objective of this article is to present a secure, web-based EDC system for CTR that has been implemented by the Institute for Clinical and Translational Science (iCATS) at the University of Missouri School of Medicine. PMID- 25812276 TI - Ethical controversies about proper health informatics practices. PMID- 25812278 TI - Applying concept mapping to solving in-patient mental health recidivism. AB - Concept mapping is a powerful research tool using visual representation to expose the complementary impact and synergy of factors affecting a specific process. This article outlines an example, in the domain of mental health, of concept mapping applied to the specific issue of readmissions or recidivism of mental health patients. Concept mapping is used to unify the diverse perspectives found across the existing literature and in mental health care delivery so that patient input and engagement in the care process can be maximally applied to improvement in the delivery of local inpatient mental health care and, penultimately, to transformation of an inefficacious care delivery model. PMID- 25812277 TI - Systematically reviewing the literature: building the evidence for health care quality. AB - There are important research and non-research reasons to systematically review the literature. This article describes a step-by-step process to systematically review the literature along with links to key resources. An example of a graduate program using systematic literature reviews to link research and quality improvement practices is also provided. PMID- 25812279 TI - Physician-management interactions in the current 2015 environment. PMID- 25812280 TI - Health protection for nicotine addicts: a challenging goal. PMID- 25812281 TI - Carvedilol and spirulina may provide important health protection to smokers and other nicotine addicts: a call for pertinent research. AB - Nicotine and soluble semi-stable aldehydes and ketones in cigarette smoke are key mediators of the elevated risks for vascular disease, cancer, and chronic obstructive pulmonary disease observed in smokers. Nicotine, via sympathetic stimulation, increases risk for both vascular disease and cancer. Comprehensive suppression of sympathetic activity with the well-tolerated drug carvedilol, which inhibits betal 1, beta2 and alphal adrenergic receptors, may be protective to smokers and other nicotine addicts. The soluble aldehydes and ketones in tobacco smoke appear to exert their adverse effects through activation of NADPH oxidase complexes in vascular tissues and in the lungs. The phytochemical phycocyanobilin (PhyCB), richly supplied by the edible cyanobacterium spirulina, in studies on rodents and in human cell cultures has shown the ability to safely mimic intracellular bilirubin's physiological role as an inhibitor ofNADPH oxidase activity. It therefore may have potential for mitigating the pro oxidative effects of tobacco smoke aldehydes and ketones. Joint administration of carvedilol and spirulina merits exploration as a strategy for moderating the pathogenic impact of smoking in chronic tobacco users who either fail to quit or refuse to try cessation of tobacco. Carvedilol may be appropriate for those who manage a nicotine addiction in other ways (smokeless tobacco, e-cigarettes, nicotine gum). Further clinical studies to evaluate the impact of carvedilol on cardiovascular risk factors in nicotine addicts, and rodent studies to assess markers of lung inflammation in smoke- exposed rodents fed PhyCB, are recommended. PMID- 25812282 TI - Artificial vision: hope for the new millennium. PMID- 25812283 TI - Status of hepatitis B vaccination among surgeons practicing in Ethiopia: a cross sectional study. AB - BACKGROUND: Hepatitis B virus (HBV) is a well recognized but under emphasized occupational health hazard in Ethiopia. OBJECTIVES: To assess the vaccination status against Hepatitis B among surgeons practicing in Ethiopia and the reasons for poor adherence to vaccinations. METHODS: A structured questionnaire was developed using the Qualtrics Survey free software tool and sent to 131 surgeons and surgical residents practicing in 28 hospitals. 98 completed and submitted the online survey. The main outcome measures were vaccination status, recent occupational accidents and reasons for non-vaccination. RESULT: Ninety-four (95.9%) of the respondents were males, Only 24 (23.5%) were vaccinated against HBV, 18/24 (75%) of whom received the three recommended doses. The main reasons for non vaccination is lack of knowledge about the availability of the vaccine in the country, lack of time and mere negligence. Differences in age, sex, and duration of practice, field of specialty and respondent's institution between vaccinated and unvaccinated were not significant (P > 0.05). Ninety-two (93.9%) believe the vaccination is very useful for the surgeon. 86.4% of the respondents claim they wear double gloves in more than 50% of their operations while 76 (77.6%) had sustained sharp injury over the past one year. 13 (13.25%) of the respondents had taken ART prophylaxis in the past. CONCLUSION: Despite their strong belief that HBV vaccine is useful, most surgeons are still not vaccinated. As occupational injuries are very common, Hepatitis B vaccination should be a prerequisite for working in the theatre, hence putting the surgeons and surgical patients at reduced risk. PMID- 25812284 TI - Pattern of acute appendicitis in Mekelle, Ethiopia. AB - BACKGROUND: Acute appendicitis is one of the commonly encountered emergencies in the practice of general surgery but there are no much study regarding the magnitude and its pattern in Ethiopia and in Mekelle hospital in particular. OBJECTIVE: This study was aimed at assessing the magnitude, pattern and outcomes of acute appendicitis. METHODS: Between September 2008 to August 2010, 196 patients with acute appendicitis were admitted to Mekelle hospital. In this descriptive retrospective audit, case notes were obtained from medical records office and information entered included patient demographics, clinical symptoms, white blood cell count level and operative funding. Post-operative complications and operative outcomes were also recorded. Adequate records have been maintained in the hospital on patients undergoing appendectomy. RESULTS: There were 196 patients during the study period from all age groups with clinical suspicion of acute appendicitis who underwent appendectomy. The age ranged from 4 to 80 years (mean - 22 years). There were 143 (73%) males and females accounting for 53 (27%). The sex ratio was (M: F; 2.9:1). Majority of patients with acute appendicitis were between 20 - 29 years of age, accounting for 76 (38.7%), predominantly males affected than females. The other age group affected was between 10-19 years of age accounting for 56 (28.5%), again with male predominance. The frequent clinical presentation's of acute appendicitis were abdominal pain 196 (100.0%), vomiting 107 (54.6%) and anoxia 97 (49.5%). The duration of presentation ranged from 12 hours to 5 days (Mean- 3.5 days). CONCLUSION: This study has depicted that acute appendicitis is the commonest emergency surgical condition affecting the young in the study area. Early presentation, early diagnosis and prompt treatment have shown to attribute to lower rate of complications, likewise decreasing mortality. The other observed fact was the negative appendectomy which was more frequent in females in their reproductive age group. Additional modern imaging is fundamental to support diagnostic accuracy to significantly reduce or avoid negative explorations. PMID- 25812285 TI - Perception and predictors of quality of life among HIV patients attending art clinics in northwest Ethiopia: a prospective longitudinal study. AB - BACKGROUND: In treating HIV as a chronic disease, monitoring changes of quality of life of patient's overtime is important for clinicians and policy makers. However, to our knowledge little research attention has been directed towards examining the longitudinal change of quality of life overtime in sub-Saharan Africa. OBJECTIVE: To examine longitudinal changes in quality of life among patients initiated ART METHOD: A prospective longitudinal follow-up study was conducted from December 2009 to August 2011 to evaluate the changes in quality of life and how this relates with baseline socio-demographic and clinical characteristics among consecutive adult ART naive patients attending ART clinic. Quality of life was measured by WHOQOL-HIV BREF. RESULT: All quality of life domain scores improved significantly during 12 month follow-up in the ART program. At each follow-up visit, scores were significantly higher than baseline scores (p < 0.001). Predictors of improved quality of life were male gender, disclosure of HIV status, starting ART at higher CD4, > 200 cells/MUL, and good baseline overall quality of life, whereas predictors of poor quality of life were starting ART with advanced disease stage and tuberculosis co-infection. CONCLUSION: This study demonstrated that the quality of life improved overtime for HIV-infected individuals receiving ART which is consistent with previous studies. It also provided information regarding the predictive effects of baseline socio-demographic and clinical factors on the changes in quality of life at the 12-month follow-up time. The finding of the study has implications of starting ART at a higher CD4 and early stage of the disease for better quality of life outcomes. PMID- 25812286 TI - Medical students' choice of specialty and factors determining their choice: a cross-sectional survey at the Addis Ababa University, School oF Medicine, Ethiopia. AB - BACKGROUND: A consideration of the future specialization interests of undergraduate medical students might help in understanding the needs of higher medical education and future manpower availability for healthcare in a country. OBJECTIVE: This study assessed the career of choice made by medical students of the Addis Ababa University in the year 2012. METHOD: A cross-sectional study was conducted among 161 medical students of the Addis Ababa University, School of Medicine, Ethiopia in April 2012 using a self-administered questionnaire. Data were analyzed using computer based statistical software IBM SPSS data editor version 20.0. In addition to descriptive statistics difference in proportions was compared using Chi-square test RESULTS: Of the 161 students, 101 (62.7%) were male. The mean age of respondents was 24.1 years (SD 2.02, ranging from 21 to 35). Majority, 138 (85.7) wanted to pursue their specialty training in the near future, their first career of choice being surgery for, 50 (31.1%), followed by internal medicine for, 44 (27.3%) and Obstetrics and Gynaecology for, 29 (18.0%]), However 18 (11.2%) did not specify their career of choice. The basic science fields such as anesthesiology, and oncology were the least favored choices by the students. The main reasons that influenced the students' decisions to opt for a particular specialty were inspiration during their clinical practicein 67 (41.6%). Financial reward (24.2%), dedication to the field (19.2%) possession of competency needed for the speciality (18.6%) and Influence of teacher (16.1%) were also factors that influenced future choice of speciality of the students. CONCLUSION: The majority of medical students preferred to pursue their specialty training. As the number and interest in certain specialties is huge, training centers must be ready to cater for the interests shown by the students. The lack of interest towards certain specialists such as basic sciences, anesthesiology, and oncology requires a special attention by policy makers. PMID- 25812287 TI - Ethiopian patient with progression of Castleman's disease into non-Hodgkin's lymphoma. AB - A 35-year-old HIV-infected male patient diagnosed to have multicentric Castleman's disease at initial presentation, which later progressed to non Hodgkin's lymphoma. This case report reviewed the clinical and pathological features of Castleman's disease. PMID- 25812288 TI - A 60 year old Ethiopian farmer diagnosed with tick paralysis at Adera Medical Center. AB - A 60 year old farmer from west Shewa in Ethiopia presented on February 13 2014, with right arm flaccid monoplegia after bitten by a tick stuck to his right arm pit. The case was initially misdiagnosed as cellulitis. To our knowledge, tick paralysis has not been reported from Ethiopia. We report the case presentation with literature review. PMID- 25812289 TI - Community acquired multi drug resistant Staphylococcus aureus in a rural setting of North Western Ethiopia: a tough challenge. AB - Commnunity acquired Methicillin Resistant Staphylococcus aureus species are common causes of skin and soft tissue infections. Foot ulcer of former leprosy patients can be invaded by a multi-microbial infection. Cervicitis is usually caused by certain sexually transmitted agents. Here we report a series of cases of methicillin-resistant Staphylococcus aureus, isolated from two patients presenting with foot ulcer and cervicitis respectively, both in an outpatient or community setting (community onset) in rural North Western Ethiopia. The strains were resistant to all commonly available drugs such as trimethoprim sulfamethoxazole, ciprofloxacin, erythromycin, chloramphenicol and tetracycline but sensitive to clindamycin. This is the first report of CA-MRSA in the study area. PMID- 25812290 TI - Crash deconstruction. Something's not right behind a seemingly minor MVA. PMID- 25812291 TI - EMS response to the cancer patient. PMID- 25812292 TI - Naloxone's basic benefit. Why the overdose-reversal drug is worth expanding beyond just ALS providers. PMID- 25812293 TI - Management of less-lethal injuries. When called to assist police, EMS providers need to know how to treat injuries associated with less lethal weapons. PMID- 25812294 TI - Cardiac complications. Understanding restenosis following coronary angioplasty and stenting. PMID- 25812295 TI - How much? Keeping cost out of care decisions just isn't practical. PMID- 25812296 TI - Hands down. A snowblower accident mangles fingers--but what else is going on? PMID- 25812297 TI - What makes a good quality improvement program? The success of your department's QI efforts begins and ends with you. PMID- 25812299 TI - Goodness and light. Christmas is for the kids--we get the worry. PMID- 25812298 TI - Common STEMI imitators: Part 2. There are other causes of ST-segment elevation besides myocardial infarction. PMID- 25812300 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Editorial: For the special issue]. PMID- 25812301 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: I. Introduction; Statement on appraisal of skill and art on medical practice in current fee system for medical survices]. PMID- 25812302 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: II. Special column; the decision process of fee schedule]. PMID- 25812303 TI - [[Technical evaluation of medical practice--conversion from things to skill and art. Topics: III. The view of technical evaluation referenced foreign countries and other fields; 1. Stance of physician fee evaluation with reference to United States RBRVS]. PMID- 25812304 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: III. The view of technical evaluation referenced foreign countries and other fields; 2. The ttentative plan by Union of Social Security Committee of Surgical Associations for the assessment of surgical skills]. PMID- 25812305 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: III. The view of technical evaluation referenced foreign countries and other fields: 3. Measuring relative work values for nursing care]. PMID- 25812306 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: IV. Challenge to technical evaluation on medical practice: 1. A time study for doctors fee at Japanese outpatient clinic]. PMID- 25812307 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: IV. Challenge to technical evaluation on medical practice; 2. Doctor fee in the National Health Insurance of Japan for services of physician to inpatients of internal medicine]. PMID- 25812308 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice: 1. Specific medical examinations in internal medicine and Naihoren (Naihoren: Social Insurance Union of Societies related to internal medicine) Green Book ver.1]. PMID- 25812309 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice; 2. Degress of difficulty in diagnosis and treatment, and total work]. PMID- 25812310 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice; 3. Payment system for informed consent]. PMID- 25812311 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics; V. Toward establishment of technical evaluation on medical practice; 4. Informed consent under unusual conditions, 1) Medical fee for the decision making support of end of life]. PMID- 25812312 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice: 4. Informed consent under unusual conditions, 2) Genetic counseling and evaluation of medical treatment fee]. PMID- 25812313 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of Technical evaluation on medical practice: 5. Technical evaluation on medical practice in medication use--historical view and present issues. Appraisal of doctor's skill and art on medication use]. PMID- 25812314 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice; 5. Technical evaluation on medical practice in medication use--historical view and present issues. 1) Evaluation of remuneration for prescription in cancer chemotherapy]. PMID- 25812316 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice; 5. Technical evaluation on medical practice in medication use--historical view and present issues, 3) The evaluation of the medical reimburement system for the prescription in a fluid therapy]. PMID- 25812315 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice: 5. Technical evaluation on medical practice in medication use--historical view and present issues. 2) Evaluation for medical treatment fee of antimicrobial agents]. PMID- 25812317 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice: 6. Evaluation and issues related with laboratory and physical examination, 1) Value of clinical examination and its appropriate reimbursement--focusing on clinical test]. PMID- 25812318 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice: 6. Evaluation and Issues Related with laboratory and physical examination. 2) Focusing on exercise stress test]. PMID- 25812319 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: V. Toward establishment of technical evaluation on medical practice: 7. Joint efforts of the Social Insurance Union of Societies related to internal medicine and surgery for evaluation of endoscopic techniques]. PMID- 25812320 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: vi. Issues on fee for medical services in 20 internal medicine fields: 1. Laboratory Medicine Committee]. PMID- 25812321 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 2. Challenges on medical fees relating to radiation clinic]. PMID- 25812322 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 3. Rehabilitation Medicine Committee]. PMID- 25812323 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 4. Subject regarding the fee-for-medical service in the region of the digestive organ]. PMID- 25812325 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 6. Subjects of the medical payment system in the field of endocrinology]. PMID- 25812324 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 5. Impact of the revision of remunertion for medical care in 2014: summary from Angiocardiology Committee]. PMID- 25812326 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 7. Diabetes Committee]. PMID- 25812327 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 8. Nephrology and Blood Purification Committee]. PMID- 25812328 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 9. Hematology area]. PMID- 25812329 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 10. Respiratory Medicine Committee]. PMID- 25812330 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 11. Neurology Committee]. PMID- 25812331 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields: 12. Rheumatology and Collagen Disease Committee]. PMID- 25812332 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 13. Infectious Disease Committee]. PMID- 25812333 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 14. Medical Oncology Committee]. PMID- 25812334 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 15. Psychiatry Committee]. PMID- 25812335 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: IV. Issues on fee for medical services in 20 internal medicine fields; 16. Psychosomatic Medicine Committee]. PMID- 25812336 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 17. Pediatric Committee]. PMID- 25812337 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 18. Women's Medicine Committee]. PMID- 25812338 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics; VI. Issues on fee for medical services in 20 internal medicine fields; 19. Internal Medicine Clinic Committee]. PMID- 25812339 TI - [Technical evaluation of medical practice--conversion from things to skill and art. Topics: VI. Issues on fee for medical services in 20 internal medicine fields; 20. Home Care Medicine Committee]. PMID- 25812340 TI - [Discussion meeting on past steps and challenges today of the social insurance union of societies related to internal medicine]. PMID- 25812341 TI - [Case report: relapsing polychondritis in a young woman with delayed diagnosis due to the coverage by hair of painless red auricles]. PMID- 25812342 TI - [Case Report: Two cases of microscopic polyangiitis presenting with aortic wall thickening]. PMID- 25812343 TI - [Case report: A case of diabetic chorea associated hyperviscosity without abnormal findings of magnetic resonance imaging]. PMID- 25812344 TI - [The cutting-edge of medicine; current status and issues of home medical care]. PMID- 25812345 TI - [The cutting-edge of medicine; the cutting-edge of fatty liver disease and diabetes]. PMID- 25812346 TI - [How does the physician interpret the patient's narrative as it relates to the physical exam?; A case of intermittent fever accompanied with shaking chills]. PMID- 25812347 TI - [How does the physician interpret the patient's narrative as it relates to the physical exam?; Sudden abdominal pain with cold sweat]. PMID- 25812348 TI - Is Foxp3 a good marker for regulatory T cells? AB - To track the changes in the tested Treg markers especially Foxp3 following activation to determine whether data of human studies using Foxp3 in evaluation of Tregs are reliable or not. Four-colour flow cytometry analysis was carried out to calculate the percentages of Tregs before and after lymphocyte activation. Foxp3 expression by CD4(+)CD25(+)* and CD4(+)CD25(high) T cells increased after T cell activation. A moderate negative correlation was observed between the percentage of each of CD4(+)CD25(+)Foxp3(+)IL10(+) or CD4(+)CD25(high) Foxp3(+)IL10(+) T cells and the percentage of CD4(+)CD25(+) T cells "after activation" and a weak negative correlation was similarly observed between the percentage of CD4(+)CD25(-)Foxp3(+)IL10(+) T cells and the percentage of CD4(+)CD25(+) T cells "after activation". A moderate negative correlation was observed between the percentage of each of CD4(+)CD25(+)Foxp3(+)IL10(+), CD4(+)CD25(high)Foxp3(+)IL10(+) or CD4(+)CD25(-) Foxp3(+)lL10(+) T cells and the percentage of CD4(+)CD25(high) T cells "after activation". CD4(+)CD25(high) T cell subpopulation expressed a significantly higher level of intracellular Foxp3 compared with CD4(+)CD25(low) and CD4(+)CD25(-) T cells subpopulations. In conclusions, Foxp3 is a good marker of Tregs especially if panels of markers were used for their identification. CD4(+)CD25(high) Foxp3(+) T cell subpopulation mostly represents Tregs and thus should be the one targeted in Treg studies. PMID- 25812349 TI - Single nucleotide polymorphism T869C of transforming growth factor-beta 1 gene and systemic lupus erythematosus: association with disease susceptibility and lupus nephritis. AB - Transforming growth factor beta1 (TGF-beta1) has a large role in the control of autoimmunity. Single nucleotide polymorphisms (SNP) in the promoter of TGF-beta1 cytokine gene are known to alter the production of this important cytokine. Decreased levels of TGF-beta1 may contribute to systemic lupus erythematosus (SLE) susceptibility, activity and organ damage. Lupus nephritis (LN) occurs in more than one-third of patients with SLE. In this study we measured serum levels of TGF-beta1 and assessed TGF-beta1 single nucloetide polymorphism (SNP) at codon 10 (T869C) in Egyptian SLE population in order to verify whether there is a relationship between this polymorphism, serum level of TGF-beta1, SLE susceptibility, clinical manifestations and lupus nephritis. We studied 56 consecutive SLE female patients and 40 healthy female volunteers as control group. Serum levels of TGF-beta1 were measured by enzyme-linked immunosorbent assay (ELISA) and the polymorphism of the TGF-beta1 gene, T869C was analyzed using the method of amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). The genotype and allele frequencies of T869C of the TGF beta1 gene did not differ between SLE patients and healthy controls. Serum levels of TGF-beta1 were significantly reduced in patients with SLE as compared with levels in healthy controls (P < 0.001). The genotype and allele frequencies of T869C of the TGF-beta1 gene did not differ between SLE patients with lupus nephritis (LN) and SLE patients without LN. Lower levels of TGF-beta1 were found in patients with LN than in patients without LN. TGF-beta1 was significantly decreased in TT group than in CC and TC groups (P < 0.001). No significant correlation was found between serum TGF-beta1 level, SLEDAI scores and clinical manifestations. In conclusion, these results suggest that T869C polymorphism of the TGF-beta1 gene is not associated with SLE disease susceptibility and specific clinical manifestations. However, this polymorphism may lead to the production of low serum level of TGF-beta1 especially with TT genotype and consequently plays an important role in the development of renal damage. PMID- 25812350 TI - B-cell-attracting chemokine-1 (BCA-1/CXCL13) in systemic lupus erythematosus, its correlation to disease activity and renal involvement. AB - Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease in which cytokines such as B lymphocyte chemoattractant (BLC or CXCL13) may play important roles in pathogenesis. The aim of our study was to investigate the implications of CXCL13 in SLE diagnosis and its correlation with disease activity and renal involvement. The study included 50 adult female patients with SLE and 30 age-matched female healthy individuals serving as a control group. Patients' Group was further subdivided according to disease activity calculated by SLE Disease Activity Index (SLEDAI). All studied individuals were subjected to assessment of serum CXCL13 by ELISA. A highly significant stepwise progressive increase in CXCL 13 level was recorded through controls, inactive SLE and active disease (P < 0.01). Moreover, it correlated positively with SLEDAI and proteinuria (P < 0.01). At a cut- off level 80 pg/mL, CXCL13 could discriminate active SLE from inactive (AUC = 0.989, sensitivity 100% & specificity 96%). In conclusion, an increased level of CXCL13 is a distinctive feature in SLE. CXCL13 correlates with disease activity and renal involvement. PMID- 25812352 TI - Complement 1q (C1q) antibodies levels in sera of Egyptian patients with lupus nephritis. AB - Renal involvement is common in systemic lupus erythematosus (SLE). Anti-C1q antibodies are associated with SLE nephritis. This study attempted to correlate anti-C1q levels to different types of lupus nephritis (LN). Anti-C1q antibodies were assessed in two groups (15 subjects each) of SLE patients with and without LN. Ten apparently healthy volunteers served as controls. The sensitivity of anti C1q for diagnosis of lupus nephritis among SLE patients was 100.00% and the specificity reached 90.00%. The positive and negative predictive values for renal activity were 83.3% and 100.00%, with a predictive accuracy of 98.00%. The level of anti C1q was highest in patients with class IV lupus nephritis. We conclude that negative anti- C1q test results would exclude active nephritis in SLE. Our data support the hypothesis that anti-C1q antibodies may have pathogenic role in lupus nephritis. PMID- 25812351 TI - Th17/Treg imbalance in opioids and cannabinoids addiction: relationship to NF kappaB activation in CD4+ T cells. AB - Opioids are widely used for the treatment of severe pain. However, opioids, particularly morphine, is known to cause immunosuppression. This study investigated the impact of morphine and cannabinoids addiction on CD4+ T cell mediated immunity. We hypothesize that, accompanied immunosuppression is attributed to reduced T cell activation with an extent of affection to the cytoplasmic activity of the biologically active transcription factor nuclear factor-kappaB (NF-kappaB) which play crucial role in T-cell activation. A disturbance in cytokine balance, in particular, interleukin-17 (IL 17)/interleukin-10 (IL-10) production may also act as a mechanism of immunosuppression. Peripheral blood CD4+ T cells from 45 chronic morphine and cannabinoid addicts and 10 controls with no current or past history of drug abuse; were stimulated by anti-CD3 antibody plus phytoheamagglutinin (PHA). Activation of the NF-kappaB signaling pathway was examined by analyzing NF kappaBp65 in a solid phase sandwich ELISA. IL-17/IL-10 balance was assessed using quantitative ELISA on cultured CD4+ T cells supernatants. We found that, morphine and cannabinoids inhibited NF-kappaB signaling in activated T cells of addicts, whereas it enhanced activated T cell apoptosis as measured by quantitative in vitro determination of cytoplasmic histone-associated DNA fragmentation following induced cell death. These effects of morphine and cannabinoids T cell suppression were accompanied by elevation of IL-10 level and concomitant reduction in IL-17 secretion from cultured CD4+ T cells. We concluded that Th17/Treg imbalance may be attributed to inhibited NF-kappaB activity in CD4+ T cells under the effect of morphine and cannabinoids addiction. PMID- 25812353 TI - Apoptosis of T-cell subsets in colorectal cancer in vivo. AB - Dysfunction of the immune system in colorectal cancer (CRC) can be due to a number of reasons including apoptosis of tumour infiltrating lymphocytes (TILs). The aims of this study were to characterize, phenotypically, the apoptosis of TILs in CRC, and define the association of these findings with prognostic indicators. We used double immunohistochemistry to assess the apoptosis of T-cell subsets. Monoclonal antibodies to T lymphocytes, T helper cells, cytotoxic T cells (CTLs), natural killer cells (NK), CD45 and CD45RO were used. Antibodies against cleaved caspase-3 as a marker of apoptosis were used. Apoptosis of T-cell subsets was detected in the immune infiltrate in CRC. Apoptosis of T lymphocytes showed significant correlation with lymphatic metastasis (P = 0.01), Dukes' stage (P = 0.019). Apoptotic T helper cells showed significant correlation with metastasis (P = 0.04), lymphatic metastasis (P = 0.02), death (P = 0.04) and recurrence (P = 0.04). For apoptosis of CTLs, there was a significant correlation with histological classification (P = 0.02), lymphatic metastasis (P = 0.04), vascular metastasis (P = 0.03) and lymph node metastasis (P = 0.04). A significant association was found between the apoptosis of NK cells and the histological classification (P = 0.04). A significant association was found between the apoptosis of cd45RO cells and the histological classification (P = 0.04). In conclusion, apoptosis of lymphocytes provides theoretical foundation for metastasis and counterattack of colon cancer. PMID- 25812354 TI - Assessment of T cell response to novel Mycobacterium tuberculosis synthetic overlapping peptides mixtures (Rv2659 and Rv2660) and ESAT-6 in Egyptian patients. AB - Tuberculosis (TB) remains one of the major challenges to the global public health. The most powerful tools in any TB control program are prompt diagnosis and successful treatment of patients with active contagious disease. For almost 100 years the tuberculin skin test (TST) has been used to support the diagnosis of active and latent TB infection. The TST has a number of limitations, most notable low specificity in BCG vaccinated individuals due to cross-reactive components in PPD and the Mycobacterium bovis BCG vaccine strain and an intensive search for new and more specific diagnostic antigens has therefore been ongoing. The current diagnostic techniques utilize production of Interferon-gamma (IFN gamma) in response to novel M. tuberculosis (MTB) synthetic overlapping peptides mixtures to detect MTB infection. The aim of this study was to evaluate human immune responses to two novel Mycobacterium tuberculosis latency associated antigens Rv2659 Pepmix and Rv2660 Pepmix in comparison with ESAT-6 Pepmix. We compared the production of IFN-gamma by ELISA following overnight stimulation with the antigens among the different groups of our study, TST negative healthy subjects (n = 16), TST positive healthy subjects (n = 16) and active pulmonary TB patients (n = 30). Our results showed that in TB patients, a positive IFN-gamma response was observed to ESAT-6 by 73% of the donors, 47% responded to Rv2659 and 57% responded to Rv2660 when compared to TST negative controls. In conclusion, the ESAT-6 pepmix is recognized in a greater proportion of TB patients compared to Rv2659 and Rv2660, and levels of IFN-gamma in response to ESAT-6 are higher than the levels observed in response to Rv2659 and Rv2660. PMID- 25812355 TI - Vitamin D level among Egyptian patients with chronic spontaneous urticaria and its relation to severity of the disease. AB - Vitamin D has an important role in the immune system. Decreased serum vitamin D level is known to be associated with autoimmune and atopic diseases. This study aimed to assess vitamin D status in patients with chronic spontaneous urticaria (CSU) and its relation with severity of the disease. This case-control study was conducted on 22 patients and 20 age and sex matched controls. Patients were subjected to clinical assessment, routine laboratory examination: complete blood picture (CBC), erythrocyte sedimentation rate (ESR), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), anti-thyroid antibody, anti-nuclear antibody (ANA), total immunoglobulin E (IgE), vitamin D assay and stool analysis, and special investigations including: skin prick test (SPT), autologous serum skin test (ASST) and urticaria activity score (UAS). Patients' mean age was 32.8 +/- 13.17 years. The median and interquartile range of duration of illness was 2.5 (1-4) years and of Ig E was 79 (62-312) IU/ml. According to UAS; 14 (63.6%) had severe and 8 (36.4%) had moderate degree illness. The mean vitamin D level among the patients was 28.4 +/- 9.09 nmol/L. Vitamin D level was significantly lower among patients in comparison to controls (28.4 +/- 9.09 vs. 104.5 +/- 76.8, t = 4.4 P < 0.01). Vitamin D correlated negatively with IgE level (r = -0.45, P < 0.05), meanwhile it was insignificantly correlated with age and duration of illness (r = -0.117 and 0.34 respectively, P > 0.05). In conclusion; Low vitamin D level (r = 0.45) is associated with chronic spontaneous urticaria but has no relation with the severity of the disease. PMID- 25812356 TI - The Munsell Color System: a scientific compromise from the world of art. AB - Color systems make accurate color specification and matching possible in science, art, and industry by defining a coordinate system for all possible color perceptions. The Munsell Color System, developed by the artist Albert Henry Munsell in the early twentieth century, has influenced color science to this day. I trace the development of the Munsell Color System from its origins in the art world to its acceptance in the scientific community. Munsell's system was the first to accurately and quantitatively describe the psychological experience of color. By considering the problems that color posed for Munsell's art community and examining his diaries and published material, I conclude that Munsell arrived at his results by remaining agnostic as to the scientific definition of color, while retaining faith that color perceptions could be objectively quantified. I argue that Munsell was able to interest the scientific community in his work because color had become a controversial topic between physicists and psychologists. Parts of Munsell's system appealed to each field, making it a workable compromise. For contrast, I suggest that three contemporary scientists with whom Munsell had contact--Wilhelm Ostwald, Ogden Rood, and Edward Titchener- did not reach the same conclusions in their color systems because they started from scientific assumptions about the nature of color. PMID- 25812357 TI - On relativism and pluralism: response to Steven Bland. PMID- 25812358 TI - Clarifying interactional and contributory expertise. AB - This paper discusses the distinction between contributory expertise and interactional expertise developed by Harry Collins and Robert Evans over a series of publications. The distinction has been widely adopted and used to analyze the expertise of different groups.of people, such as scientists, journalists and color blind. While the distinction is a fruitful tool to begin thinking about expertise in a more structured way, one also finds substantial inconsistencies and unnecessary vagueness in Collins and Evans' writings. Clarifying these issues will make the distinction an even more useful tool for analyzing expertise in science. PMID- 25812359 TI - [Pharmacokinetics and pharmacodynamics of anti-diabetic drugs--from the viewpoints of drug transporters and metabolic enzymes]. PMID- 25812360 TI - [What is the natural history of type 2 diabetes mellitus]. AB - Type 2 diabetes mellitus (T2DM) is widely accepted as the progressive disease. It is natural to think, if the newly diagnosed patient does not change the life style habits and does not receive any medications, the state of T2DM will become more seriously. However, in this article, how to arrest the natural history of T2DM will be discussed by summarizing the recent findings on this topic. Those are; autophagy of pancreatic beta cell: a sweet process to diabetes, hyperglycemia-induced oxidative stress on beta cell function, zinc, insulin and the liver, and so on. In short, the important things are; people should know the reasons why minor abnormalities have happened, and the practitioners have to try hard to remove such causes triggering T2DM. PMID- 25812361 TI - [Transition and perspectives of antidiabetic agents]. AB - History of oral hypoglycemic agents (OHA) started in 1942 that was 20 years delayed to the discovery of insulin. The first two OHAs (sulfonylurea and biguanide) were discovered by chance. Ancient knowledge regarding antidiabetic agents present in nature is significant for the development of some drugs. For instance, principal components of biguanide, alpha-glucosidase inhibitors are contained in French lilac and mulberry leaves respectively, that are ancient diabetic medications. Thiazolidinediones, incretin related drugs, were discovered by a result of great effort paid to structural ingenuity and search of the compound. SGLT2 inhibitors are a new class of antidiabetic agents which has various potentials beyond lowering plasma glucose. In this review, we will discuss about transition and perspectives of antidiabetic agents. PMID- 25812362 TI - [Algorithm for selection of antidiabetic drugs based on the clinical guideline for diabetes care]. PMID- 25812363 TI - [Alpha-glucosidase inhibitor]. AB - Alpha-glucosidase inhibitors (alpha-GI) have abdominal signs which are generally regarded as side-reaction. The abdominal signs are caused by generation of intestinal gas which contains hydrogen gas. The hydrogen gas absorbed in the body eliminates oxidant stress and consequently the abdominal signs may have beneficial effects preventing onset and progression of arteriosclerosis. Recently, it has been reported that the combination therapy of dipeptidyl peptidase-4 inhibitors with a-GI enhances glucagon like peptide-1 (GLP- 1) secretion and increases active GLP-1 concentration. Therefore, alpha-GI is not only a matured and reliable oral anti-diabtic agent (OAD) but also a promising OAD which collaborates effectively with DPP-4 inhibitors or sodium-glucose cotransporter-2 inhibitors. PMID- 25812364 TI - [Biguanide]. AB - Metformin, a biguanide, is considered in EASD and ADA to be a first-line glucose lowering agent for patients with type 2 diabetes. The effectiveness of metformin as an anti-diabetic drug is explained by its ability to lower blood glucose by decreasing hepatic glucose production, stimulating glucose uptake in the muscle, and increasing fatty acid oxidation in adipose tissue. The exact mechanism of this effect has not been fully understood, but metformin is thought to activate hepatic AMP-activated protein kinase (AMPK), and it suppresses liver glucagon signal by increasing AMP due to inhibition of mitochondrial respiratory complex I. Caution is advised to avoid use of metformin in patients at risk for lactic acidosis (e.g., in patients with advanced renal and liver insufficiency, infection, dehydration, alcoholism, or in those using diuretics or SGLT2 inhibitor). PMID- 25812365 TI - [Thiazolidine, thiazolidinediones, TZD]. AB - In addition to a good efficacy to lower blood glucose without hypoglycemia, thiazolidinediones(TZDs) have been proved to have the effects to increase plasma adiponectin, and actually decrease the cardiovascular events in several randomized clinical trials, while some adverse effects have also been demonstrated such as increase of heart failure and born fracture, and fear of bladder cancer. Since TZDs could intervene the pathogenesis of adipocytes' hypertrophy and inflammation in adipose tissue, atherosclerotic lesions and liver by modulating PPARgamma of adipocytes and macrophages, TZDs are still considered at the special position among other diabetic drugs, and require further evidence for their efficacy and safety. PMID- 25812366 TI - [Sulfonylurea]. AB - SU drug promotes insulin secretion by acting on pancreatic beta cell. The hypoglycemic effect is the most powerful among oral diabetic drugs with high cost effectiveness. Particularly for the Japanese with type 2 diabetes caused by a decrease in insulin secretion as a main pathological condition, it was widely used until the present since 1957 and largely contributed for the sickness. On the other hand, it is true that a number of issues such as a prolonged hypoglycemic coma or obesity due to a neglect of proper usage, patient education, and a possibility of second failure have been discussed so far. After a structure of K(ATP) channel on pancreatic beta cell as playing an important role with insulin secretion is clarified recently and neonatal diabetes mellitus by the genetic defect is reported, a new possibility for SU drug receives attention. Furthermore, a receptor of SU drug on beta cell membrane was solely known as a target molecule for SU drug, but since a binding to Epac2 as a protein to detect a part of SU drug's cAMP signal within beta cell is determined, a relation with an enhancing mechanism of insulin secretion by incretin is being clarified at present. As understanding a new potential for SU drug, we consider a positioning and proper usage for SU drug again. PMID- 25812367 TI - [Prandial glucose regulator and insulin secretagogue; glinide and its combination therapy]. AB - The glinides are the therapeutic agents for indications for type 2 diabetic patients with postprandial hyperglycemia. These are a class of drug which have a similar response as sulfonylureas but act for a shorter time and are prescribed to be taken by patients with type 2 diabetes within 5-10 min before eating. As the drugs act for a shorter period than sulfonylureas, the side effects of hypoglycemia and weight gain have a smaller likelihood. Combination with glinides and DPP4 inhibitors is a good choice for type 2 diabetic patients in early stage. Also combination therapy with glinides and alpha-glucosidase inhibitors shows a good profile of daily blood glucose level in these patients. PMID- 25812368 TI - [DPP-4 inhibitor]. AB - Now seven compounds of DPP-4 inhibitor are available in Japan. They can be used in any stage of type 2 diabetes if the insulin secretion capacity is retained; first-line choice to third-line choice or combination with insulin therapy. There is no apparent difference in effect of each DPP-4 inhibitor on glycemic control; HbA1c levels are decreased by 0.6- 1.0% by monotherapy. Generally the drug is more effective for improving glycemic control in Japanese population compared to that in Western population. In addition, basal insulin therapy could be switched to the combination therapy with DPP-4 inhibitor and sulfonyl- urea in Japanese type 2 diabetes in cases where insulin secretion capacity is sufficiently preserved. Here we summarize the effect of DPP-4 inhibitor on glycemic control and algorithm for DPP-4 inhibitor treatment. PMID- 25812369 TI - [Glucagon-like peptide-1 receptor agonists]. AB - Recently, the number of diabetic patients with obesity has increased by changes in life-style including food and physical exercise. Appearance of incretin related drugs has given us more options for treating type 2 diabetes, and they are evaluated in regard to realizing appropriately controlled glycemic status. One of incretin-related drugs, glucagon-like peptide-1 receptor agonist (GLP 1RA), possesses pleiotropic actions to pancreatic beta/alpha cells and other targets, and is highly expected from the clinical aspect. Specifically, the long acting GLP-1RAs lower fasting glucose levels, and the short-acting GLP-1RAs lower post-prandial glucose levels. By optimally employing these drugs, better glycemic management should be enabled. PMID- 25812370 TI - [Mechanisms and efficacy of SGLT2 inhibitors]. AB - SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 <= eGFR <= 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors. PMID- 25812371 TI - [Current concept of insulin therapy intensification, and the role of human regular insulin and rapid-acting insulin analogs in insulin treatment]. AB - The evolution of insulin therapy from animal insulin to recombinant human regular insulin has improved diabetes treatment. Generating of rapid-acting insulin analogs, mimicking physiologic insulin action enables us to provide better control of post-prandial glucose level and lower incidence of hypoglycemia compared with human regular insulin. These rapid-acting insulin analogs show lower susceptibility of insulin precipitation and catheter occlusions, and are suitable for insulin pump therapy of continuous subcutaneous insulin infusion. Insulin lispro and insulin aspart are also applicable for diabetic patients with pregnancy, requiring excellent glycemic control. In some studies, stepwise addition of prandial insulin, as well as full basal-bolus regimen can improve glycemic control with less hypoglycemia. Treatment intensification with rapid acting insulin analogs may offer a proper method to reach glycemic goals. PMID- 25812373 TI - [Usefulness and limitations of basal insulin replacement in type 2 diabetes]. AB - In the earlier stage of type 2 diabetes, the disease can be managed by life-style modification with or without oral antidiabetic agents. However, as the disease progress, most patients eventually require insulin treatment to maintain good glycemic/control. Optimal insulin therapy should mimic the normal physiologic secretory pattern. As for ideal basal insulin, to maintain desirable pre-prandial glucose levels, duration of action should be long enough, profiles such as flat time-action and less day-to-day variation would be mandatory. This article discusses the usefulness and limitations of basal insulin therapy in type 2 diabetes comparing NPH insulin, insulin detemir, insulin glargin and insulin degludec. PMID- 25812372 TI - [Premixed insulin and intermediate-acting insulin]. AB - Intermediate-acting insulin and premixed insulin have a long history. They were widely used till the 1990s. However, due to the emergence of long-acting solubility insulin analogue and recent expanding EBM, premixed insulin became mainly used for type 2 patients who have stable lifestyles like elderly people. In the consensus algorithm for type 2 patients reached at ADA/EASD2012, premixed insulin is considered moderately complex but not so flexible. Instead, basal bolus therapy is recommended because it is more flexible than other regimens. Although not recommended strongly by the guideline, premixed insulin can be adopted after considering the condition, lifestyle and situation of patients. As for intermediate-acting insulin, the spread of long-acting insulin analogues has rendered its therapeutic role no longer significant today. PMID- 25812375 TI - [Drug adherence in type 2 diabetics]. AB - Long-term adherence and persistence with prescribed drug therapy are important factor of medication for diabetes. The causes of poor adherence are complex and include complicated drug regimens, older age, poor social support, cognitive problems, and depression. These commonly caused people to reduce or stop treatment. Physician must consider to reduce the number of drug to prescribe. Side effects of oral hypoglycemic drugs including hypoglycemia, leg swelling, gastrointestinal disorders, and urinary frequency were a widely reported reason for self adjusting or stopping drugs. Physicians may be able to improve medication adherence substantially by reducing the number of concomitant medications and by initiating diabetic medications together or close in time. PMID- 25812374 TI - [Fixed-dose combination]. AB - Many patients with type 2 diabetes mellitus(T2DM) do not achieve satisfactory glycemic control by monotherapy alone, and often require multiple oral hypoglycemic agents (OHAs). Combining OHAs with complementary mechanisms of action is fundamental to the management of T2DM. Fixed-dose combination therapy(FDC) offers a method of simplifying complex regimens. Efficacy and tolerability appear to be similar between FDC and treatment with individual agents. In addition, FDC can enhance adherence and improved adherence may result in improved glycemic control. Four FDC agents are available in Japan: pioglitazone-glimepiride, pioglitazone-metformin, pioglitazone-alogliptin, and voglibose-mitiglinide. In this review, the advantages and disadvantages of these four combinations are identified and discussed. PMID- 25812376 TI - [Consideration of the interaction of anti-diabetes agents]. AB - While taking anti-diabetes agents, in combination with drugs that attenuate the hypoglycemic action or drug, or that enhance the hypoglycemic action, it is necessary to pay attention to hypoglycemia and fluctuations in blood glucose levels. Furthermore, a coadministration of two or more anti-diabetes agents including newly coming drugs, especially used in combination with insulin formulations or insulin secretagogues should be closely monitored and may need to reduce the dose. PMID- 25812377 TI - [Diabetic macrovascular complications]. AB - Reactive derivatives from non-enzymatic glucose-protein condensation reactions, as well as lipids and nucleic acids exposed to reducing sugars, form a heterogeneous group of irreversible adducts called "advanced glycation end products(AGEs)". The formation and accumulation of AGEs have been known to progress at an accelerated rate under diabetes. There is accumulating evidence that AGEs and their receptor (RAGE) interaction elicits oxidative stress generation and subsequently evokes inflammatory and thrombogenic reactions, thereby being involved in vascular complications in diabetes. We, along with others, have recently found that pigment epithelium-derived factor(PEDF), a glycoprotein that belongs to the superfamily of serine protease inhibitors, has neuroprotective, anti-angiogenic, anti-oxidative, and anti-inflammatory properties both in cell culture and animal models. In this review, we discuss the role of AGE-RAGE axis in diabetic macroangiopathy and its therapeutic intervention by PEDF. PMID- 25812378 TI - [Pharmacological treatment for diabetic macular edema]. AB - Diabetic macular edema(DME) is a major cause of vision loss and has a remarkable impact on the quality of life of diabetic patients. New pharmacological approaches based on the use of intravitreal drugs, such as corticosteroids and anti-vascular endothelial growth factor, have recently been developed for the treatment of DME. Even though laser therapy has been the standard treatment for DME, the results of several clinical trials have shown the superiority of some of these new agents to laser therapy. The purpose of this review is to briefly summarize the currently available new pharmacological treatments for DME in Japan. PMID- 25812379 TI - [Diabetic nephropathy]. AB - Diabetic nephropathy is diagnosed by the appearance of microalbuminuria and progresses to macroalbuminuria and end-stage kidney disease. Thus, it is important to estimate the urinary albumin excretion and glomerular filtration rates. The main targets of the treatment of diabetic nephropathy include hyperglycemia and glomerular hypertension. The results of many randomized controlled trial indicate that strict glycemic control can reduce the risk for the development and progression of diabetic nephropathy. For the treatment of glomerular hypertension, the inhibitor of renin-angiotensin system is the first choice and the tight blood pressure control is also necessary. It is now possible to induce the remission of diabetic nephropathy by the intensified multifactorial treatment. PMID- 25812381 TI - [Metabolic homeostasis of glucose regulation in chronobiology]. PMID- 25812380 TI - [Diabetic neuropathy]. AB - Diabetic neuropathy is one of the major three diabetic complications, together with diabetic retinopathy and nephropathy. It develops early and with a high incidence after the onset of diabetes mellitus and influences the QOL and prognosis of patients with diabetes mellitus. Although the exact mechanism by which hyperglycemia causes nerve damage remains a subject of debate, metabolic and vascular disturbances due to hyperglycemia are assumed to cause nerve damage. The treatments of diabetic neuropathy aim at both the inhibition of its onset and progression (causative treatment) and the care for symptoms due to neuropathy such as pain(symptomatic treatment). In this paper, we describe the outlines of these two kinds of treatment for diabetic neuropathy. PMID- 25812382 TI - [Significance of glucagon control in the diabetes treatment]. AB - Among islet cell types, much less attention has been paid to alpha cells than to beta cells, but glucagon, the product of alpha cells, has been shown to play a major role in the development of hyperglycemia in T2DM. Recent clinical application of DPP4 inhibitor and GLP-1 receptor agonist gave attention to glucagon again. Furthermore, recently metformin has been also reported to suppress glucagon's function on hepatic glucose production. One of the critical issues in the glucagon research is the poor specificity of current assay systems. Our newly developed glucagon sandwich ELISA, having higher specificity than conventional systems, revealed that T2DM patients have more severe hyperglucagonemia than currently assumed. Thus, in the future diabetes treatment, we should pay more attention to plasma glucagon levels in diabetes patients. PMID- 25812383 TI - [Current status of clinical development of novel anti-diabetic drugs]. AB - Clinical development of novel antidiabetic drugs, such as GK activator, GPR40 agonist, GPR119 agonist, 11beta-HSD1 inhibitor and trelagliptin, has been progressing over the world. Especially, GK activator, GPR40 agonist, GPR119 agonist and 112-HSD1 inhibitor have unique action mechanism compared to existing drugs. GK activator potentiates glucose-stimulated insulin secretion from beta cells and stimulates glucose uptake into the liver. GPR40 agonists and GPR119 agonist stimulate glucose-dependent insulin secretion from beta cells. 11beta HSD1 inhibitor reduces the conversion of cortisone to cortisol. Trelagliptin is a long acting dipeptidyl peptidase-4(DPP-4) inhibitor and a once-weekly treatment by trelagliptin would improve the drug adherence of patients. This article focuses on these new and emerging diabetes agents. PMID- 25812384 TI - [Prostasin (PRSS8) as a new pathological factor]. AB - Serine proteases play pivotal roles in many biological processes including clotting, digestion, and immune system. A glycosylphosphatidylinositol-anchored serine protease prostasin(PRSS8) is ubiquitously expressed in many tissues such as kidney, prostate, skin, liver, lung, and colon. However, the physiological role for PRSS8 has not been fully understood. Recently, we have identified a novel role for PRSS8 in the regulation of glucose homeostasis via Toll-like receptor 4(TLR4)-mediated signaling in the liver and demonstrated new insight into the development of diabetes resulting from obesity-induced inflammation or metabolic endotoxemia. In this review, we provide an overview of current understanding of PRSS8 as a new pathological factor for human diseases. PMID- 25812386 TI - The influence of jet engine noise on hearing of technical staff. AB - BACKGROUND: Due to high sound pressure levels (SPLs), noise produced by jet planes may be harmful to hearing of people working in their proximity. The aim of this study was to assess the effects of exposure to jet engine noise on technical staff hearing. MATERIAL AND METHODS: The study comprised 60 men, aged 24-50 years, employed in army as technical staff and exposed to jet engine noise for 6 20 years. The control group were 50 non-noise exposed males, aged 25-51 years. Exposure to noise emitted by jet engines was evaluated. Pure-tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAE) were recorded in both groups. RESULTS: Jet engines emitted broadband noise with spectrum dominated by components in the frequency range 315-6300 Hz (1/3-octave bands). Maximum A weighted SPL during tests reached values of approx. 120-130 dB. Consequently, engine-servicing personnel (even in the case of a single engine test) was exposed to noise (at A-weighted daily noise exposure level above 95 dB) exceeding permissible levels. Averaged audiometric hearing threshold levels of technical staff were higher (<= 17 dB HL, p < 0.001) than in the control group. Similarly, the DPOAE amplitude was lower (<= 17 dB SPL, p < 0.01) in the noise-exposed subjects compared to the non-exposed ones. Significant reduction of DPOAE levels was mainly noted for high frequencies (3-6 kHz). CONCLUSIONS: Despite the usage of hearing protection devices, both PTA and DPOAE consistently showed poorer hearing in engine-servicing personnel vs. control group. PMID- 25812385 TI - Prevalence of tick-borne pathogens at various workplaces in forest exploitation environment. AB - BACKGROUND: The objective of the study was the evaluation of the infection of ticks with pathogenic microorganisms at various workplaces (timber acquisition, forest growing, forest cultivation, forest protection). MATERIAL AND METHODS: Eight hundred sixty one Ixodes ricinus ticks collected from 4 workplaces were examined for the presence of Borrelia burgdorferi, Anaplasma phagocytophilum and Babesia microti by polymerase chain reaction (PCR). Then, a comparative analysis of the relative density and infection of ticks at individual workplaces was done. In the statistical analysis, Chi2 test, and Pearson's test for correlation were applied. RESULTS: The differences in infection (15.9-50%) of ticks with B: burgdorferi between the examined workplaces were highly significant, with the highest percentage observed at forest growing. The percentages of infection of ticks with A. phagocytophilum at individual workplaces ranged from 1.1-3.7%, and differences were statistically insignificant. The percentages of infections of ticks with Babesia microti at individual workplaces fluctuated from 3.6-4.4% and differences were also insignificant. Co-infections of ticks with 2 or 3 pathogens were rare. CONCLUSIONS: Co-infections with B. burgdorferi and B. microti showed a significant relationship with the workplaces, while those with B. burgdorferi and A. phagocytophilum did not show such a dependence. No significant positive correlation was found between the relative density of ticks and the frequencies of infections with B. burgdorferi, A. phagocytophilum and B. microti. PMID- 25812387 TI - [Compliance with hygiene procedures among medical faculty students]. AB - BACKGROUND: Many of the healthcare associated infections (HCAIs) are transmitted by healthcare workers' hands, which actively contributes to transferring pathogens from patient to patient and within the healthcare environment. Hand hygiene is the easiest and cheapest method for preventing HCAIs. The article presents the compliance with hygiene procedures in a group of medical students of the Wroclaw Medical University. MATERIAL AND METHODS: The anonymous survey was conducted among 112 students. The survey included questions about the frequency of disinfection of hands and stethoscopes, changing clothes into clean ones, compliance with recommendations for healthcare workers, as well as subjective assessment of the availability of disinfectants in the hospital. RESULTS: The results of the survey revealed that 35.7% of students did not disinfect their hands before each patient's examination, 90% of them indicated limited access to disinfectants as the most important reason. The majority (93.8%) of respondents were trained in hand hygiene. In 34.82% the availability of disinfectants in hospitals was assesed as good, 62.5% of respondents drew attention to the fact that the dispensers were often empty. Compliance with recommendations for healthcare workers: 66.9% posessed white coat with short sleeves, 52.68% wore wristwatch or jewelery on their hands, 50% of students laundered white coat less frequently than once a week, 9.82% did not disinfect their stethoscope at all, 15.18% did that before each patient's examination. CONCLUSIONS: Students compliance with hand hygiene now and in their future work as doctors is the easiest method for preventing HCAIs. Providing easy access to disinfectants in the hospital environment and shaping hygiene habits during clinical activities play an essential role. PMID- 25812388 TI - [Polycyclic aromatic hydrocarbons in ultrafine particles of diesel exhaust fumes- the use of ultrafast liquid chromatography]. AB - BACKGROUND: The article presents the results of the determination of polycyclic aromatic hydrocarbons (PAHs) in the fine par ticles fraction emitted from 3 types of diesel fuels using ultra-high pressure liquid chromatography. MATERIAL AND METHODS: Samples of diesel Eco, Verwa and Bio exhaust combustion fumes were generated at the model station which consisted of a diesel engine from the 2007 Diesel TDI 2.0. Personal Cascade Sioutas Impactor (IPCSI) with Teflon filters was used to collect samples of exhaust fume ultrafine particles. PAHs adsorbed on particulate fractions were analyzed by ultra-high pressure liquid chromatography with fluorescence detection (UHPLC/FL). RESULTS: Phenanthrene, fluoranthene, pyrene and chrysene present the highest concentration in the particulate matter emitted by an engine. The total contents of fine particles collected during engine operation on fuels Eco, Verwa and Bio were 134.2 MUg/g, 183.8 MUg/g and 153.4 MUg/g, respectively, which makes 75%, 90% and 83% of the total PAHs, respectively. The highest content of benzo(a)pyrene determined in particles emitted during the combustion of fuels Eco and Bio was 1.5 MUg/g and 1 MUg/g, respectively. CONCLUSIONS: The study of the PAH concentration in the particles of fine fraction below 0.25 MUm emitted from different fuels designed for diesel engines indicate that the exhaust gas content of carcinogens, including PAHs deposited on particulates, is still significant, regardless of the fuel. Application of ultrahigh pressure liquid chromatography with fluorescence detection for the analysis ofPAHs in the particles emitted in the fine fraction of diesel exhaust allowed to shorten the analysis time from 35 min to 8 min. PMID- 25812389 TI - [Impact of wet work on epidermal barrier (tewl and stratum corneum hydration) and skin viscoelasticity in nurses]. AB - BACKGROUND: Nurses are prone to develop hand eczema due to occupational exposure to irritants, including wet work. The aim of the study was to evaluate the impact of wet work on selected skin properties, reflecting epidermal barrier function- transepidermal water loss (TEWL) and stratum corneum hydration--and additionally skin viscoelasticity, in nurses. MATERIAL AND METHODS: Study subjects included 90 nurses employed in hospital wards. Measurements were carried out within the dorsal aspect of the dominant hand, using a Cutometer MPA 580 equipped with Tewameter TM 300 and Corneometer CM 825 (Courage & Khazaka, Germany) probes. Examina- tions took place on hospital premises. Similar measurements were performed in the control group of females non-exposed to irritants. RESULTS: In the examined group of nurses, mean TEWL was 15.5 g/h/m2 and was higher than in the control group (12.99 g/h/m2). After rejecting the extreme results, the difference between the groups proved to be statistically significant (p < 0.05). The mean value of stratum corneum hydration was lower in the examined group (37.915) compared with the control group (40.05), but the difference was not sta tistically significant. Also results of viscoelasticity assessment showed no significant differences between studied groups. CONCLUSIONS: The results of the assessment of skin biophysical properties show that wet work exerts a moderately adverse impact on skin condition. A higher TEWL value and a lower stratum corneum hydration in workers exposed to irritants reflect an adverse impact of these factors on the epidermal barrier function. PMID- 25812390 TI - [The role of job satisfaction in the person-organization fit relationship in terms of goal pursuit strategies, and mental health]. AB - BACKGROUND: Person-organization (P-O) fit is a predictor of job satisfaction, and a misfit is a potential stressor. We aimed to examine the consequences of fit between a person and an organization in terms of goal pursuit strategies. We tested whether job satisfaction mediates the relationship between regulatory fit and mental health. MATERIAL AND METHODS: Research was conducted in a group of 169 employees. They were asked to fill in questionnaires assessing their chronic work regulatory focus, organiza tional regulatory focus and job satisfaction. To measure mental well-being we administered the General Health Questionnaire (GHQ 28). We conducted mediation analysis in regression. RESULTS: The results of the mediation analysis confirmed the me- diating role of job satisfaction in the relation between regulatory focus misfit and physical and mental symptoms of distress. CONCLUSIONS: The results of this study point to the fact that P-O fit can relate to goal pursuit strategies. It influences not only job satisfaction, but also employees' health.The conclusions can be applied in the human resources management practices, e.g., it may serve as a useful argument to motivate employers to shape goals and strategies individually by managers, according to employees preferences. The results should be interpreted with caution because of non-random sampling. PMID- 25812391 TI - [The rationale behind screening programs for early detection of hepatitis C virus]. AB - BACKGROUND: The objective of the study was to collect the data on undetected hepatitis C virus (HCV) in the frequently hospitalized residents of the Kujawsko Pomorskie Voivodeship. MATERIAL AND METHODS: The analysis focused on empirical data. The research was conducted in 2013 among 6332 citizens of the Kujawsko Pomorskie Voivodeship who had been hospitalized at least twice. The blood was tested for the presence of anti-HCV antibodies. The diagnostic survey with an anonymous questionnaire was developed and used for the purpose of the study. For the statistical analysis Statistica 10.0 was used. The hypothesis was verified using the Mann-Whitney U test and Chi2 test of independence. A level of statistical significance was assumed at alpha = 0.05. The results were considered to be statistically significant if the probability fulfilled the inequality of p < 0.05. RESULTS: Positive anti-HCV antigens were detected in 91 (1.44%) examined individuals. The relationship was found between blood transfusions provided before 1992, the use of intravenous narcotics and doping, and minor surgical procedures and the infection. CONCLUSIONS: Asymptomatic infection was detected in 91 citizens of the Kujawsko-Pomorskie Voivodeship. The highest risk of HCV infection occurs during small surgery and usage of intravenous narcotics and doping. The percentage of positive results is slightly higher in the group of people with cosmetic and beauty treatments. Planning screening programs special attention should be paid to this group of risk. Blood and blood products transfusions before 1992 were associated with a higher risk of HCV infection. People with above-mentioned interventions should become a particular group of screening program participants. Occupational medicine service plays an important role in prevention. PMID- 25812392 TI - [Influence of extremely low frequency magnetic field on total protein and -sh groups concentrations in liver homogenates]. AB - BACKGROUND: Free radicals are atoms, molecules or their fragments, whose excess leads to the development of oxidative stress, the cause of many neoplastic, neurodegenerative and inflammatory diseases, as well as aging of organisms. Industrial pollution, tobacco smoke, ionizing radiation, ultrasound and magnetic fields are the major exogenous sources of free radicals. The low frequency mag- netic field is commonly applied in physiotherapy. The aim of the present study was to evaluate the effect of extremely low frequency magnetic field (1L.F-MF) on the concentration ofsullhydryl groups (-SH) and proteins in liver tissues of experimental animals de- pending on the time of exposure to the field. MATERIAL AND METHODS: Twenty one Sprague-D)awley male rats, aged 3-4 months were randomly divided into 3 experimental groups (each containing 7 animals): controls (group I), the rats exposed to IEI.F-MF of 40 Hz, 7 mT (this kind of the ELF-MF is mostly used in magnetotherapy), 30 min/day for 2 weeks (group II) and the rats exposed to 40 Hz, 7 mT for 60 min/day for 2 weeks (group III). The concentrations of proteins and sulfhydryl groups in the liver tissues were determined after exposure to magnetic fields. RESULTS: Exposure to low magnetic field: 40 Hz, 7 mT for 30 min/day and 60 min/day for 2 weeks caused a significant increase in the concentration of-SH groups and total protein levels in the liver tissues. CONCLUSIONS: The study results suggest that exposure to magnetic fields leads to the development of adaptive mechanisms to maintain the balance in the body oxidation-reduction and in the case of the studied parameters does not depend on the time of exposure. PMID- 25812393 TI - [Patients' exposure to electromagnetic fields and radon in radon spas]. AB - BACKGROUND: Many patients of physiotherapeutic facilities using therapeutic radon are also referred to other treatments involving the use of electromagnetic field (EMF). However, in the light of the theory of EMF influence on free radicals, it is still an open question whether, application of EMF shortly after the radon treatment may alter the biological effects of radon or EMF. The aim of the study was to determine how large is the group of patients exposed to radon and EMF in Poland, and how high is the exposure of these patients to analyzed factors. The results of the study are to be used in the future assessment of the combined effects of radon and EMF in radon spas. MATERIAL AND METHODS: Based on the statistical data and interviews held in the major Polish radon spas, the analysis of treatment structure was performed and exposure to radon and EMF was assessed by measuring radon concentrations and characteristic values of exposure to EMF. RESULTS: More than 8000 people per year are subjected to combined exposure to radon and EMF. Significant differences were found between measured radon concentrations (they ranged from approximately 61 kBq/m3 for inhalations with inhaler to only 290 Bq/m3 for graduation towers, p = 0.049) and EMF intensities corresponded to those observed in hazardous and dangerous zones for occupational exposure. CONCLUSIONS: The results of the study showed significant differences between radon concentrations during various radon treatments. There is a need to develop clear and universal procedures for the application of radon or radon combined with EMF in radon spas. The effects of patients' exposure to radon, especially combined with EMF need to be further studied. PMID- 25812394 TI - [Titanium dioxide nanoparticles--biological effects]. AB - Titanium dioxide occurs as particles of various sizes. Particles of up to 100 nm, corresponding to nanoparticles, and in the size range of 0.1-3 mm are the most frequently used. Titanium dioxide in a bulk form is not classified as dangerous substance, nevertheless nanoparticles may cause adverse health effects. Inhalation exposure to nano-TiO2, causes pulmonary inflammation that may lead to fibrotic and proliferative changes in the lungs. Many studies confirm the genotoxic effect of TiO2, especially in the form of nanoparticles, on mammal and human cells. In rats exposed to TiO2-nanoparticles by inhalation the development of tumors has been observed. However, there is no evidence of additional lung cancer risk or mortality in workers exposed to TiO2 dust. There are some studies demonstrating the adverse effect of TiO2-nanoparticles on fetal development, as well as on reproduction of animals. TiO2 nanoparticles find a still wider application and thus the risk of occupational exposure to this substance increases as well. Considering such alarming data on the biological activity of TiO2 nanoparticles, more attention should be paid to occupational exposure and its health effects. Properties of the nanoparticles, due to their larger surface area and reactivity, differ significantly from the inhalable dust of TiO2, for which the hygiene standards are mandatory in Poland. PMID- 25812395 TI - [Cardiopulmonary exercise testing--its application in cardiology and occupational medicine]. AB - Cardiopulmonary exercise testing is a method used to assess the exercise capacity. It is used in cardiology to define the diagnostic and prognostic information, the treatment and its effectiveness. This method is also useful in sport medicine and in occupational medicine. The cardiopulmonary exercise test involves measuring of gas exchange during exercise testing. The article presents the main parameters assessed during the test and the indications and contraindications for conducting the test. It also reveals the results of recently published clinical trials on the use of cardiopulmonary exercise test in patients with cardiovascular disease and in the working population. The study included variability of respiratory parameters during the cardiopulmonary exercise test and after its completion, as well as their impact on the prognostic value. In addition, the results of a study involving an optimal choice of interval training on the basis of oxygen consumption at peak exercise are summarized. PMID- 25812397 TI - [Dangerous chemical substances--tools supporting occupational risk assessment]. AB - The assessment of risk associated with exposure to chemicals in the work environment is a task that still poses a lot of difficulties for the employers. At the same time the probability of adverse health effects faced by an employee as a result of such risks, and the related employer's material losses should motivate employers to seek effective solutions aimed at assessing the risks and controling them to an acceptable level by the application of appropriate preventive measures. The paper presents examples of tools to assist the employer in the risk assessment associated with the presence of chemical agents in the workplace. Examples of guides, manuals, checklists and various interactive tools, developed in Poland and other European Union (EU) countries, as well as in countries outside the EU and international organizations are described. These tools have been developed to meet the current requirements of the law and allow a rough estimation of chemical risk and based on these estimates take further steps to improve working con- ditions and safety. PMID- 25812396 TI - [Quaternary ammonium compounds--new occupational hazards]. AB - Quaternary ammonium compounds (QACs, quats) belong to organic ionic chemical agents which display unique properties of both surfactants and disinfectants. Their wide distribution in the work environment and also in private households brings about new occupational hazards. This paper reviews reports about the health effects of QACs. QACs could play a role of sensitizers and irritants to the skin and mucous membranes. It is suspected that particular QACs can display an immunologic cross-reactivity between each other and with other chemical compounds containing ammonium ion, such as muscle relaxants widely used in anesthesia. They may promote the development of airway allergy, however, the background mechanisms are still unclear and need to be further investigated. Until now, a few cases of occupational asthma induced by QACs have been described and their involvement in contact dermatitis has been documented. The possibility of anaphylaxis due to QACs cannot be excluded as well. PMID- 25812398 TI - [Work-related stress and burnout in physiotherapists--a literature review]. AB - Studies of some chronic conditions and some health risk factors in physiotherapists suggest that work-related stress and burn- out may have a significant but underestimated impact on their health status and productivity. This paper presents the author's attempt to review current knowledge of work related stress and burnout in physiotherapists. This review was aimed at explor- ing the relationship between causes, consequences and ways of prevention of work related stress and burnout in this occupa- tional group. Searching PubMed, PEDro and Health Source: Nursing/Academic Edition was conducted in July 2014, with no starting date limitation and with specified keywords. The literature on work related stress and burnout in physiotherapists has investigated their relationship with a large number of causes, consequences, and ways of prevention. Based on the research re- viewed, the conclusion can be drawn that further strategies to increase awareness among the management staff and health profes- sionals about the importance of prevention and stress management are required to decrease the prevalence of aforementioned pathologies. It was stressed that the majority of components of these strategies still require to be confirmed by future studies. PMID- 25812399 TI - [The "natural focal diseases" medical and geographical atlas of Russia as a tool to analyze their incidence in the population]. AB - The Faculty of Geography, M.V. Lomonosov Moscow State University, is creating a "Natural Focal Diseases" medical and geographical atlas of Russia. The paper considers the possibilities of the atlas to monitor and assess the epidemiological situation of a number of diseases. The atlas allows one to define a spectrum of the most epidemically significant natural focal diseases in Russia, to quantitatively characterize their incidence in the population, and to visualize it in a series of maps, to make a medical geographical analysis of the prevalence of the nosological entities of natural focal diseases in both individual subjects of the Russian Federation and in Russia as a whole. By using tick-borne encephalitis as an example, the authors consider approaches to analyzing the incidence of natural focal infections, by using different types of the maps given in the atlas. PMID- 25812400 TI - [Assessment of the risk of expansion of the habitats of the mosquitoes AEDES aegypti L. and Aedes albopictus Skus. in Russia]. AB - Based on climatic characteristics, the authors show that an invasive Aedes albopictus species is likely to emerge in new areas of the Russian Federation. PMID- 25812401 TI - [Change in the habitat of Yersinia pestis in the Gorno-Altaisk natural focus of plague]. AB - The paper analyzes the change that occurred in the habitat of the causative agent of plague in its Gorno-Altaisk natural focus in 1961 to 2012. Since 1961 when the plague microbe was found to come from the southern slopes of the Saylyugem mountain range, which are located in Mongolia, to the northern slopes situated in Russia, a gradual expansion of the habitat of Yersenia pestis subsp. altaica had commenced in South-Eastern Altai. During the considered period, the area where epizootic manifestations were registered showed an 11-fold increase. In most cases, the spread of the plague pathogen within the focus was natural and occurred in the successive and closely related settlements of Mongolian pikas (Ochotona pallasi). By now, the plague microbe has been widely distributed in three populations of this small animal, which inhabit the territory of South Eastern Altai. PMID- 25812403 TI - [Social bases for the functioning of nanophyetiasis foci in the Amur region]. AB - Parasitological examination of the population of the Amur Region has revealed that the nanophyetiasis foci affecting as high as 28.4% of the people are being preserved and functioning now; at the same time the highest rates of infection with the trematode Nanophyetus salmincola schikhobalowi are seen in the dwellers of the populated areas situated on the banks of the mountain Amur tributaries. It has been ascertained that the major season when the population is infected with Nanophyetus is summer and its highest incidence are noted in autumn (November) after the active fishing season is completed. It has been found that infection occurs in infants and the maximum incidence is in the age group of 21-30 years (45.5%) and remains virtually the same in a middle-aged population [31-50 years (37.0-42.2%)], by decreasing slightly in the older age groups (18.2-21.7%). According to the questionnaire survey data, fish (90% of its species are an intermediate host for Nanophyetus) is a staple food in the population of the highest incidence rural areas. The major causes of Nanophyetus infection are the wide consumption of raw and low-salt fish and a low population awareness of measures to prevent helminthiasis, the transmission factor of which is fish. PMID- 25812404 TI - [On the possibility of vertical transmission of Trichinella and the impact of its invasion]. AB - Whether experimentally infected female rats can transmit Trichinella in utero and its invasion may affect the immunity of their offspring has been investigated. There is evidence that maternal antibodies have a significant impact on the humoral immunity of the offspring and as a result on the number of Trichinella larvae accustomed in the muscles. Immune interlayer formation in the populations of carnivorous mammals in the endemic areas occurs due to reinvasions and passive transmission of maternal antibodies to the offspring. High-tension immunity in the population and animals contributes to a reduction in the onset of invasion and to a predominance of the subclinical course of the disease and asymptomatic carriage in a specific focus. Passive immunity transmitted from the Trichinella infected mother to its offspring is of importance in the development of epidemic and epizootic processes in the natural and synanthropic foci of trichinosis. PMID- 25812402 TI - [The distribution of the mosquitoes of the Anopheles maculipennis complex (Diptera, Culicidae, Anophelinae) in Central Asia]. AB - The polymerase chain reaction-restriction fragment length polymorphism method, cytogenetic analysis, and investigation of egg exochorion have indicated that three representatives of the Anopheles maculipennis complex (subgenus Anopheles): An artemievi Gordeev et al., An. messeae Falleroni, and An. marinius Shingarev. An. messeae is a European-Siberian species that has extended the southern border of its habitat and has been distributed in the south of Kazakhstan and in the north of Kyrgyzstan. In, Kyrgyzstan, An. messeae inhabiting the plains of Europe and Siberia is encountered rather high up in the mountains: the highest point where this species is found is at 1,879 m above sea level. An. artemievi is present in the highland and piedmont regions of Central Asia (Uzbekistan, Kyrgyzstan, southern Kazakhstan, and northern Tajikistan) and in the intermountain basins (Naryn and Fergana ones). The single finding of this species is in south-eastern Turkmenistan. On the contrary, An. martinius tends to be in the plains and occurs in north-eastern Turkmenistan, Karakalpakstan, and Kazakhstan (Kzyl-Orda). On the other hand, a population of this species is found in proximity to the foothills of the Gissar Range in the east of Uzbekistan. An.maculipennis s.str. is not seen in Central Asia. Early evidence for the presence of both An. maculipennis s.str. and An. martinius in Kopet Dag (Southern Turkmenistan) is rather questionable. It is not improbable that these data are appropriate for either the newly described species An.persiensis or the scientifically new representative of the An. maculipennis complex. PMID- 25812405 TI - [Determination of the concentration of platelet serotonin for the prediction of the two-wave course of tick-borne encephalitis]. AB - The paper gives the results of an investigation of platelet serotonin levels in patients with tick-borne encephalitis to determine a criterion for predicting the development of its to-wave course. Fifty-five patients were examined at the height of tick-borne encephalitis (in the first 2-4 days): Group 1 included 39 patients with a one-wave course of the disease; Group 2 consisted of 16 patients with its two-wave course. Platelet serotonin concentrations were determined by enzyme immunoassay. Analysis of platelet serotonin levels could establish its lower value in the two-wave course (115.6 +/- 36.2 ng/ml) than in the one-wave one (261.9 +/- 96.8 ng/ml; p < 0.001). The significant difference between these types of tick-borne encephalitis and the calculation of the optimal cutoff value could propose this indicator as a predictor to detect the second wave of the infection. PMID- 25812406 TI - [Characterization of contamination of hematology hospital environmental objects with micromycetes]. AB - The paper presents of laboratory studies of the environmental objects in the hematology unit of a multidisciplinary hospital for micromycetes. Its air was found to be highly contaminated with mold fungi (85.4 +/- 5.5%). The structure of micromycetes showed a preponderance of the fungi Aspergillus (47%), Rhizopus (36%), Penicillium, and other species (17%). The air contamination rate was 15.6 +/- 3.3 CFU/m3 and did not exceed the recommended thresholds. Yeast fungi were prevalent in washouts. The contamination rate of ward louvers was 12 and 4 times higher than that of bedside tables and door handles, respectively. The degree of micromycetes contamination of environmental objects in the hematology unit did not depend on the destination of rooms and the length of stay of hematology patients in them. PMID- 25812407 TI - [Assessment of the quality of laboratory diagnosis of intestinal parasitic diseases by the laboratories participating in the Federal System of External Quality Assessment of Clinical Laboratory Testing]. AB - In 2010-2013, the quality of microscopic detection of the causative agents ofparasitic diseases in the feces has been assessed by the specialists of the laboratories of the therapeutic-and-prophylactic institutions (TPIs) and Hygiene and Epidemiology Centers, Russian Inspectorate for the Protection of Consumer Rights and Human Welfare, which are participants of the Federal System of External Quality Assessment of Clinical Laboratory Testing. Thirty-two specimens containing 16 species of human helminths and 4 species of enteric protozoa in different combinations were examined. The findings suggest that the quality of microscopic detection of the causative agents of parasitic diseases is low in the laboratories of health care facilities and that the specialists of the laboratories of TPIs and Hygiene and Epidemiology Centers, Russian Inspectorate for the Protection of Consumer Rights and Human Welfare, do not not possess the knowledge and skills necessary to make a laboratory diagnosis of helminths and enteric protozoa. The average detection rates of helminths and protozoa were at a level of 64 and 36%, respectively. The correct results showed that the proportion of helminths and protozoa were 94.5 and 5.5%, respectively. According to the biological and epidemiological classification of helminths, there were higher detection rates for contact group parasites (Enterobius vermicularis and Hymenolepis nana) and geohelminths (Ascaris, Trichuris trichiura, and others). Biohelminths (Opisthorchis, tapeworms, and others) Were detectable slightly worse. PMID- 25812408 TI - [A novel bromine-containing salicylanilide (the compound MST-19). Preparation and anti-hymenolepic activity]. PMID- 25812409 TI - [The compound MST-16: the preparation and antihymenolepic activity]. PMID- 25812410 TI - [Efficacy of a new fenbendazole formulation produced by nanotechnology-based drug delivery system against nematodosis]. AB - The efficacy of a new fenbendazile formulation produced by nanotechnology-based drug delivery system was investigated in45 sheep naturally infected with gastrointestinal nematodes. The formulation showed 95.6% efficacy against Nematodes spp. at a dose of 1.0 mg/kg dw of its active ingredient and 100% efficacy against other species of gastrointestinal nematodes. Given at a dose of 10 mg/kg dw, the basic drug--fenbendazole (substance) displayed 96.39 and 100% efficacy, respectively. PMID- 25812411 TI - [Dengue fever in the Primorye Territory]. AB - Eighteen cases of dengue fever were imported to the Primorye Territory in 2012 2013. The cases were related to visits to Thailand, Indonesia, and Vietnam. Of the 18 patients, 17 and 1 had classic and hemorrhagic dengue fever, respectively. PMID- 25812412 TI - [Seasonal changes in the physiological age of Ixodes ricinus (Acari: Ixodidae) imagoes on the Stavropol Elevation]. AB - Ixodes ricinus imagoes were caught using a flannel flag in the April to October of 2011 to 2013. There were two seasons when these stages were numerous, namely: spring and autumn. The physiological age of 506 hungry I. ricinus imagoes was determined from their outward signs: the shape of their rear body, the surface of the cuticle, and visibility of the internals through the latter. The change in the age composition suggests that an autumn imago cohort consists of specimens that emerged from nymphs in summer. PMID- 25812413 TI - [Additional evidence for the species composition of mosquitoes (Diptera, Psichodidae, Phlebotominae) in the visceral leishmaniasis foci of Uzbekistan]. AB - The species composition of mosquitoes was studied in the foci of visceral leishmaniasis in the Navoiy and Samarkand Provinces of Uzbekistan. The human settlements where these observations were made were located at 1000-1200 m above sea level. Seven species: Phlebotomus sergenti, P. caucasicus, P. longiductus, P. papatasi, P. alexandri, Sergetomyia sumbarica, and S. grecovi were found. The predominant species was P. sergenti; P. longiductus was a vector for visceral leishmaniasis, which was present in all the collected samples. Bovine animal and small cattle yards were ascertained to be the hatching of mosquito eggs. PMID- 25812414 TI - [Analysis of a study of insecticides]. PMID- 25812415 TI - [A local case of acute opisthorchiasis in the Moscow Region]. AB - The paper describes a case of acute opisthorchiasis in a 31-year-old female patient after ingestion of dried fish of the family Cyprinidae caught in the Oka River basin on the border of the Moscow and Ryazan Regions. This case could convince of that there was a risk of human Opisthorchis infection despite the zoonotic pattern of circulation of the pathogen in European Russia. The dietary intake of unsterilized fish of the family Cyprinidae caught in the Moscow and neighboring regions may give rise to Opisthorchis invasion and, it a large infectious dose, to acute opisthorchiasis. PMID- 25812416 TI - [A case of Chikungunya fever in the Primorye Territory]. AB - The authors analyze a case of Chikungunya fever imported to Vladivostok. The disease was severe and resulted in disability in a female patient for more than 6 months. There were difficulties in its differential diagnosis with rheumatic diseases. PMID- 25812417 TI - [A case of imported mixed malaria in Kharkov]. PMID- 25812418 TI - [The development of exploratory competences in preventive medicine physicians on the basis of systemic biological background (in case of medical parasitologists)]. PMID- 25812419 TI - Identification and functional analysis of a novel IFN-like protein (CgIFNLP) in Crassostrea gigas. AB - Interferons (IFNs) belong to class II helical cytokines family with pleiotropic biological activities, which have been demonstrated to play crucial roles in innate and adaptive immunity in vertebrates. In the present study, a novel IFN like protein (designed CgIFNLP) was identified from oyster Crassostrea gigas, which contained an interferon domain from 14 to 97 amino acids showing low sequence similarities with vertebrates IFNs, but shared a similar three dimensional structure with class II helical cytokines. The mRNA transcripts of CgIFNLP was detected in all the tested tissues including gonad, adductor muscle, hemocytes, mantle, gills, and hepatopancreas, with the highest expression level in gills (39-fold, P < 0.05). Moreover, the expression level of CgIFNLP mRNA in hemocytes increased significantly at 12 h (8.35-fold, P < 0.01) and 24 h (4.95 fold, P < 0.01) after poly (I: C) stimulation. After the treatments by recombinant CgIFNLP protein (rCgIFNLP) at different concentrations, the apoptosis and phagocytosis rates of oyster hemocytes increased obviously. The proliferation rate of L929 did not change obviously after incubation with rCgIFNLP for 72 h, but the proliferation rate of A549 abated significantly at 36 h and 48 h after incubation with rCgIFNLP. The results collectively suggested that the IFN-like molecule existed in oyster and it tended to present conserved functions rather than conserved amino acid sequence in comparison with vertebrate IFNs. PMID- 25812420 TI - Enhancer-associated long noncoding RNAs: A novel frontier with new perception in cardiac regeneration. PMID- 25812422 TI - Health security for the time ahead. PMID- 25812421 TI - [Le Bulletin du Cancer. Editorial]. PMID- 25812423 TI - Federal funding in support of Ebola medical countermeasures R&D. PMID- 25812424 TI - Implementing the global health security agenda: lessons from global health and security programs. AB - The Global Health Security Agenda (GHSA) describes a vision for a world that is safe and secure from infectious disease threats; it underscores the importance of developing the international capacity to prevent, detect, and respond to pandemic agents. In February 2014, the United States committed to support the GHSA by expanding and intensifying ongoing efforts across the US government. Implementing these goals will require interagency coordination and harmonization of diverse health security elements. Lessons learned from the Global Health Initiative (GHI), the President's Emergency Program for AIDS Relief (PEPFAR), and the Cooperative Threat Reduction (CTR) program underscore that centralized political, technical, and fiscal authority will be key to developing robust, sustainable, and integrated global health security efforts across the US government. In this article, we review the strengths and challenges of GHI, PEPFAR, and CTR and develop recommendations for implementing a unified US global health security program. PMID- 25812425 TI - Potential biodefense model applications for portable chlorine dioxide gas production. AB - Development of decontamination methods and strategies to address potential infectious disease outbreaks and bioterrorism events are pertinent to this nation's biodefense strategies and general biosecurity. Chlorine dioxide (ClO2) gas has a history of use as a decontamination agent in response to an act of bioterrorism. However, the more widespread use of ClO2 gas to meet current and unforeseen decontamination needs has been hampered because the gas is too unstable for shipment and must be prepared at the application site. Newer technology allows for easy, onsite gas generation without the need for dedicated equipment, electricity, water, or personnel with advanced training. In a laboratory model system, 2 unique applications (personal protective equipment [PPE] and animal skin) were investigated in the context of potential development of decontamination protocols. Such protocols could serve to reduce human exposure to bacteria in a decontamination response effort. Chlorine dioxide gas was capable of reducing (2-7 logs of vegetative and spore-forming bacteria), and in some instances eliminating, culturable bacteria from difficult to clean areas on PPE facepieces. The gas was effective in eliminating naturally occurring bacteria on animal skin and also on skin inoculated with Bacillus spores. The culturable bacteria, including Bacillus spores, were eliminated in a time- and dose dependent manner. Results of these studies suggested portable, easily used ClO2 gas generation systems have excellent potential for protocol development to contribute to biodefense strategies and decontamination responses to infectious disease outbreaks or other biothreat events. PMID- 25812426 TI - US disaster planners' attitudes regarding preevent vaccine for first responders and point-of-dispensing workers. AB - Disaster planners' attitudes toward pre-event anthrax and smallpox vaccine for first responders and point-of-dispensing (POD) workers have not been examined. An online questionnaire was sent to US Cities Readiness Initiative (CRI) and non-CRI public health disaster planners in 2013. Multivariate logistic regressions were used to assess determinants of belief that first responders and POD workers should be offered the anthrax and/or smallpox vaccine before an event. A total of 301 disaster planners participated. Only half (50.6%, n=126) were aware of the ACIP recommendation that first responders could be offered pre-event anthrax vaccine. Many (66.0%, n=164) believed that pre-event anthrax vaccine should be offered to first responders. The oldest respondents were least likely to believe anthrax vaccine should be given (OR: 0.27, 0.12, 0.63, p<.001). Fewer disaster planners believed that pre-event anthrax vaccine should be offered to POD workers compared to first responders (55.0% vs 66.0%, X(2)=151, p<.001). Almost 20% (18.3%, n=47) reported having already received pre-event smallpox vaccine. Among the unvaccinated (n=210), half (52.0%, n=105) were willing to receive pre-event smallpox vaccine if it was offered free of charge. Half (53.4%, n=133) believed that POD workers should be offered smallpox vaccine before an event. Many disaster planners support pre-event anthrax vaccination for first responders and POD workers, and about half support pre-event smallpox vaccine for POD workers. Jurisdictions should consider partnering with first responder agencies to implement a pre-event anthrax vaccination program. PMID- 25812427 TI - Evaluation of an enzyme-linked immunosorbent assay (ELISA) kit for the detection of botulinum neurotoxins A, B, E, and F in selected food matrices. AB - The mouse bioassay (MBA) is the only accepted standard method for detection of botulinum neurotoxins (BoNTs) in foods. The ELISA method has several advantages over the MBA and is therefore widely used for in vitro detection of BoNTs. The US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) conducted a precollaborative study to evaluate the applicability of Botulinum Toxin ELISA kits for the detection of BoNT serotypes A, B, E, and F in a variety of food matrices. In this study, food samples (e.g., broccoli, salami, smoked salmon, green beans, orange juice, tomato juice, low-fat plain yogurt, whole milk, liquid infant formula milk, and liquid eggs) were spiked with high, medium, and low concentration BoNT serotypes A, B, E, and F. Samples (unspiked and spiked) were tested at both laboratories by the ELISA kits. All food samples were positive for BoNTs by ELISA in both laboratories at medium and high spiking levels; a positive ELISA result in low spiked samples was both serotype and laboratory dependent. Overall, the ELISA method appears to be an effective preliminary screening method for BoNT detection in food matrices. PMID- 25812428 TI - Applying crowd psychology to develop recommendations for the management of mass decontamination. AB - Mass decontamination is a public health intervention employed by emergency responders following a chemical, biological, or radiological release. It involves a crowd of people whose interactions with each other and with the emergency responders managing the incident are likely to affect the success of the decontamination process. The way in which members of the public collectively experience decontamination is likely to affect their behavior and hence is crucial to the success of the decontamination process. Consequently, responders and the responsible authorities need to understand crowd psychology during mass emergencies and disasters. Recently, the social identity approach to crowd psychology has been applied to explain public perceptions and behavior during mass emergencies. This approach emphasizes that crowd events are characteristically intergroup encounters, in which the behavior of one group can affect the perceptions and behavior of another. We summarize the results from a program of research in which the social identity approach was applied to develop and test recommendations for the management of mass decontamination. The findings from this program of research show that (1) responders' perceptions of crowd behavior matter; (2) participants value greater communication and this affects their compliance; and (3) social identity processes explain the relationship between effective responder communication and relevant outcome variables, such as public compliance, public cooperation, and public anxiety. Based on this program of research, we recommend 4 responder management strategies that focus on increasing public compliance, increasing orderly and cooperative behavior among members of the public, reducing public anxiety, and respecting public needs for privacy. PMID- 25812429 TI - The 49th hour: analysis of a follow-up medication and vaccine dispensing field test. AB - Anthrax response plans, exercises, and assessments over the past decade have focused almost exclusively on the first 48 hours of the public health response following a jurisdiction-wide exposure and provision of an initial 10-day supply of antibiotics from the Strategic National Stockpile (SNS). But mass dispensing of the subsequent 50-day course of antibiotics and administration of the 3-dose vaccine series have received considerably less attention, although these follow up activities may prove even more complex. In 2014, the Philadelphia Department of Public Health (PDPH) made its first foray into this next frontier of mass prophylaxis planning by: (1) researching patient safety and adherence considerations relevant to the antibiotics in the SNS; (2) designing a model for a second-visit antibiotic and vaccine point of dispensing (POD), including development of an enhanced screening protocol that assumes a higher level of medical responsibility; and (3) field testing this model during a real seasonal influenza vaccination clinic to assess throughput and accuracy and to evaluate the resources needed to operationalize this model. While the observations and data presented here provide some framework for local long-term mass prophylaxis planning efforts, many areas remain undefined, including the distribution of responsibilities among the public health and healthcare communities to ensure patient safety. In addition to presenting findings, the larger intent of this article is to initiate a dialogue with other stakeholders at the local, state, and federal levels to advance long-term mass prophylaxis planning. PMID- 25812431 TI - Poor functional performance following bidirectional dilatation of severe post radiation oesophageal stricture. AB - CONCLUSION: Bidirectional oesophageal dilatation for severe chemoradiation induced oesophageal strictures is efficacious in improving luminal patency but ineffective in relieving functional dysphagia. OBJECTIVE: To assess the efficacy of bidirectional oesophageal dilatation in the severely strictured oesophagus induced by radiation therapy following the treatment of head and neck malignancies. METHODS: The study design was a case series in the setting of a tertiary cancer centre. We carried out a retrospective analysis of patients who underwent bidirectional oesophageal dilatation for oesophageal stricture secondary to radiation therapy for head and neck malignancies over a 5-year period. The parameters of the primary tumour, evaluation of preoperative and postoperative oesophageal dysfunction and complications of the procedure were evaluated. RESULTS: There were nine episodes of bidirectional oesophageal dilatation among five patients with complete or severe oesophageal obstruction. Mean age was 63 years. The procedure was uneventful in all but one patient who was found to have postoperative mediastinitis, and healed completely. Four patients had persistent dysphagic symptoms despite post dilatation video fluoroscopy failing to reveal any significant narrowing of the oesophageal lumen. PMID- 25812430 TI - GcoGSA-BA: a global core genome SNP analysis for Bacillus anthracis. AB - As an issue of biosecurity, it is important to identify the origin of a suspected sample to distinguish whether it originated from the release of a bioterrorism agent or from environmental contamination with a virulent agent. Here we have developed an analytical pipeline that can infer the phylogenetic position of Bacillus cereus group species, including B. anthracis, from next-generation sequencing reads without extensive genomics skills. GcoGSA-BA can also detect the existence of anthrax plasmid pXO1 carrying 3 anthrax toxins (lethal factor, edema factor, and protective antigen). This pipeline can also be used to correctly infer the phylogenetic position and to detect the suspected isolate carrying anthrax toxins among B. cereus group. PMID- 25812433 TI - Osteoradionecrosis: an old toxicity in the IMRT era? PMID- 25812434 TI - Microbes in flow. AB - Microbes often live in moving fluids. Despite the multitude of implications that flow has on microbial ecology and environmental microbiology, only recently have experimental tools and conceptual frameworks from fluid physics been applied systematically to further our knowledge of the behavior of microbes in flow. This nascent research field, which truly straddles biology and physics, has already produced important contributions to our understanding of the physical interaction between microbes and flow, both in bulk fluid and close to surfaces, at the same time revealing the richness and complexity of the resulting dynamics. PMID- 25812432 TI - The perceived impact of the National Health Service on personalised nutrition service delivery among the UK public. AB - Personalised nutrition (PN) has the potential to reduce disease risk and optimise health and performance. Although previous research has shown good acceptance of the concept of PN in the UK, preferences regarding the delivery of a PN service (e.g. online v. face-to-face) are not fully understood. It is anticipated that the presence of a free at point of delivery healthcare system, the National Health Service (NHS), in the UK may have an impact on end-user preferences for deliverances. To determine this, supplementary analysis of qualitative data obtained from focus group discussions on PN service delivery, collected as part of the Food4Me project in the UK and Ireland, was undertaken. Irish data provided comparative analysis of a healthcare system that is not provided free of charge at the point of delivery to the entire population. Analyses were conducted using the 'framework approach' described by Rabiee (Focus-group interview and data analysis. Proc Nutr Soc 63, 655-660). There was a preference for services to be led by the government and delivered face-to-face, which was perceived to increase trust and transparency, and add value. Both countries associated paying for nutritional advice with increased commitment and motivation to follow guidelines. Contrary to Ireland, however, and despite the perceived benefit of paying, UK discussants still expected PN services to be delivered free of charge by the NHS. Consideration of this unique challenge of free healthcare that is embedded in the NHS culture will be crucial when introducing PN to the UK. PMID- 25812435 TI - Advancement in the chemical analysis and quality control of flavonoid in Ginkgo biloba. AB - Flavonoids are the main active constituents in Ginkgo biloba L., which have been suggested to have broad-spectrum free-radical scavenging activities. This review summarizes the recent advances in the chemical analysis of the flavonoids in G. biloba and its finished products (from 2009 to 2014), including chemical composition, sample preparation, separation, detection and different quality criteria. More than 70 kinds of flavonoids have been identified in this plant. In this review, various analytical approaches as well as their chromatographic conditions have been described, and their advantages/disadvantages are also compared. Quantitative analyses of Ginkgo flavonoids applied by most pharmacopeias start with an acidic hydrolysis followed by determination of the resulting aglycones using HPLC. But increasing direct assay of individual flavonol glycosides found that many adulterated products were still qualified by the present tests. To obtain an authentic and applicable analytical approach for quality evaluation of Ginkgo and its finished products, related suggestions and opinions in the recent publications are mainly discussed in this review. This discussion on chemical analyses of Ginkgo flavonoids will also be found as a significant guide for widely varied natural flavonoids. PMID- 25812436 TI - An overview of fecal sample preparation for global metabolic profiling. AB - The global metabolic profiling of feces represents a challenge for both analytical chemistry and biochemistry standpoints. As a specimen, feces is complex, not homogenous and rich in macromolecules and particulate, non-digested, matter that can present problems for analytical systems. Further to this, the composition of feces is highly dependent on short-term dietary factors whilst also representing the primary specimen where co-metabolism of the host organism and the gut-microbiota is expressed. Thus the presence and the content of metabolites can be a result of host metabolism, gut microbiota metabolism or co metabolism. Successful sample preparation and metabolite analysis require that the methodology applied for sample preparation is adequate to compensate for the highly variable nature of the sample in order to generate useful data and provide insight to ongoing biochemical processes, thereby generating hypotheses. The current practices for processing fecal samples for global metabolic profiling are described with emphasis on critical aspects in sample preparation: e.g., homogenization, filtration, centrifugation, solvent extraction and so forth and also conditions/parameter selection are discussed. The different methods applied for feces processing prior to metabolite analysis are summarized and illustrated using selected examples to highlight the effect of sample preparation on the metabolic profile obtained. PMID- 25812437 TI - Simple radiosensitizing of hypoxic tumor tissues by N2O/Br(-) mixture. AB - The radiosensitization model of hypoxic tumor tissues based on the N2O/Br(-) mixture is described. The well-documented radiolysis of water in the presence of N2O and Br(-) ions at a low concentration supports this model. An aqueous solution saturated with N2O gas during the radiolysis generates OH radicals in a large extent. In N2O/Br- media at pH<9, Br2 is formed. Br2 hydrolyzes in an aqueous solution to form a very reactive hypobromous (HOBr) acid. Such process is described by the following chemical reaction: H2O + Br(-) + N2O + ionizing radiation (IR) --> HOBr + OH(-). In vivo formed HOBr as a long-lived product with a high biological activity induces the hypoxic tumor cell damage via many unique mechanisms. A local application or inhalation of an N2O-O2 mixture before or during the radiotherapy to enhance the saturation of tissues with N2O is a key prerequisite. Since the extracellular concentration of Br(-) ions is very low (0.02-0.05 mM), an oral or local application of NaBr should be used to shift the extracellular concentration of Br(-) ions to the mM region. PMID- 25812438 TI - Molecular imaging of the human pulmonary vascular endothelium using an adrenomedullin receptor ligand. AB - This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N = 20) were included into escalating groups of 5 mCi (n = 5), 10 mCi (n = 5), or 15 mCi (n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% +/- 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension. PMID- 25812439 TI - Epitaxial LiCoO2 films as a model system for fundamental electrochemical studies of positive electrodes. AB - Epitaxial LiCoO2 (LCO) thin films of different orientations were fabricated by pulsed laser deposition (PLD) in order to model single-crystal behavior during electrochemical reaction. This paper demonstrates that deposition of conductive SrRuO3 between a SrTiO3 (STO) substrate and an LCO film allows (1) epitaxial growth of LCO with orientation determined by STO and (2) electrochemical measurements, such as cyclic voltammetry and impedance spectroscopy. Scanning transmission electron microscopy (S/TEM and SEM) has demonstrated an orientation relationship between LCO and STO of three orientations, (111), (110) and (100), and identified a LCO/electrolyte surface as consisting of two crystallographic facets of LCO, (001) and {104}. The difference in the orientation of LCO accounts for the difference in the exposed area of {104} planes to the electrolyte, where lithium ions have easy access to fast diffusion planes. The resistance for lithium ion transfer measured by electrochemical impedance spectroscopy had inverse correlation with exposed area of {104} plane measured by TEM. Chemical diffusivity of lithium ions in LCO was measured by fitting electrochemical impedance spectroscopy data to a modified Randles equivalent circuit and allowed us to determine its dependence on film orientation. PMID- 25812441 TI - Safety of a new protocol decreasing antibiotic utilization after laparoscopic appendectomy for perforated appendicitis in children: A prospective observational study. AB - INTRODUCTION: In a previous randomized trial, we found children with perforated appendicitis could be safely discharged prior to completion of a 5 day intravenous antibiotics course. To progress the protocol further, patients who met discharge criteria early were discharged without oral antibiotics if leukocyte counts were normal. METHODS: Children undergoing laparoscopic appendectomy for perforated appendicitis were prospectively observed after institution of a new antibiotic regimen consisting of daily intravenous dosing ceftriaxone/metronidazole while an inpatient. Patients discharged prior to 5 days were discharged home without oral amoxicillin-clavulanate if no leukocytosis at discharge. Outcomes were compared to the previous protocol of daily intravenous ceftriaxone/metronidazole with completion of a 7-day antibiotic course with amoxicillin-clavulanate of all patients discharged prior to 5 days. RESULTS: 540 patients (270 new protocol, 270 old protocol) were identified. There was no significant difference in patient demographics, admission leukocyte count, time to regular diet, or length of stay. Postoperative abscess occurred in 21.8% in the new protocol compared to 19.3% of the previous (P=0.5). There was a significant decrease in the number of patients discharged home on oral antibiotic therapy (P<0.001). CONCLUSIONS: Patients meeting discharge criteria with normal leukocyte count prior to completion of 5 days IV antibiotic therapy can be safely discharged home without oral antibiotics after laparoscopic appendectomy for perforated appendicitis. PMID- 25812440 TI - Repression of engrailed 2 inhibits the proliferation and invasion of human bladder cancer in vitro and in vivo. AB - Engrailed 2 (EN2) is a member of the homeobox gene family. Many studies suggest that overexpression of EN2 protein may be associated with tumor development, including bladder cancer (BC). However, to date, the mechanisms of how EN2 functions to promote BC progression remain elusive. The present study introduced RNAi to silence the expression of EN2 in BC cell lines. In vitro invasion and migration assays and in vivo experiments were carried out to examine the functions of EN2 in BC invasion and metastasis. The results of the present study indicated that EN2 was significantly expressed in BC cells. Ectopic expression of EN2 in normal urothelial cells significantly enhanced cellular proliferation and invasion, but inhibited cellular apoptosis. EN2 knockdown significantly promoted cell cycle arrest and apoptosis of BC cells with inhibition of proliferation and invasion in vitro as well as EN2 knockdown decreased the tumor growth of BC. The tumor growth was decreased by regulation of the cell cycle, apoptosis and epithelial-mesenchymal transition-related proteins, with inhibition of metastasis to the liver and lung in vivo. Furthermore, EN2 knockdown significantly decreased the levels of pAkt-473, pAkt-308 and phosphatidylinositol 3-kinase (PI3K), whereas EN2 knockdown increased the expression of PTEN in vitro. Taken together, EN2 may be a candidate oncogene in BC by activating the PI3K/Akt pathway and inhibiting PTEN, and may be a potential therapeutic target for the treatment of BC. PMID- 25812442 TI - Academic-community partnerships improve outcomes in pediatric trauma care. AB - BACKGROUND: To address the specialized needs of injured children, pediatric trauma centers (PTCs) were established at many large, academic hospitals. This study explores clinical outcomes observed for injured children treated at an academic-sponsored community facility. METHODS: In partnership with an academic medical center in a major metropolitan area, a not-for-profit community hospital became a designated Level II PTC in October 2010. Data for injured children <15 years old treated prior to PTC designation from January 2000 to September 2010 were prospectively collected using the Trauma and Emergency Medicine Information System and compared to data collected after PTC designation from January 2011 to December 2013. RESULTS: Overall, 681 injured children were treated at the community hospital from January 2011 to December 2013. Children treated after PTC designation were less likely to undergo computed tomography (CT) (50.9% vs. 81.3%, p<0.01), even when controlling for age, gender, injury type, injury severity, and year (OR 0.18, 95%CI 0.08-0.37). Specifically, fewer head (45.7% vs. 68.7%, p<0.01) and abdominal CTs (13.2% vs. 26.5%, p<0.01) were performed. Hospital length of stay was significantly shorter (2.8 +/- 3.7 days vs. 3.7 +/- 5.9 days, p<0.01). Mortality was low overall, but also decreased after PTC designation (0.4% vs. 2.0%, p=0.02). CONCLUSIONS: These results indicate that academic-community partnerships in pediatric trauma care are a feasible alternative and may lead to improved outcomes for injured children. PMID- 25812443 TI - Extraluminal distraction enterogenesis using shape-memory polymer. AB - PURPOSE: Although a few techniques for lengthening intestine by mechanical stretch have been described, they are relatively complex, and the majority involve placement of an intraluminal device. Ideally, techniques applicable to humans would be easy to perform and extraluminal to avoid the potential for mucosal injury. This study of distraction enterogenesis used an extraluminal, radially self-expanding shape-memory polymer cylinder and a simple operative approach to both elongate intestine and grow new tissue. METHODS: Young Sprague Dawley rats (250-350 g) underwent Roux-en-Y isolation of a small intestinal limb and were divided in three groups: no further manipulation (Control 1, C1); placement of a nonexpanding device (Control 2, C2); or placement of a radially expanding device by the limb (Experimental, Exp). For C2 and Exp animals, the blind end of the limb was wrapped around the radially expanding cylindrical device with the limb-end sutured back to the limb-side. Bowel length was measured at operation and at necropsy (14 days) both in-situ and ex-vivo under standard tension (6g weight). Change in length is shown as mean +/- standard deviation. A blinded gastrointestinal pathologist reviewed histology and recorded multiple measures of intestinal adaptation. The DNA to protein ratio was quantified as a surrogate for cellular proliferation. Changes in length, histologic measures, and DNA:protein were compared using analysis of variance, with significance set at P<0.05. RESULTS: The length of the Roux limb in situ increased significantly in Exp animals (n=8, 29.0 +/- 5.8mm) compared with C1 animals (n=5, -11.2 +/- 9.0mm, P<0.01). The length of the Roux limb ex vivo under standard tension increased in the Exp group (25.8 +/- 4.2mm) compared with the C2 group (n=6, -4.3 +/- 6.0, P<0.01). There were no differences in histologic measures of bowel adaptation between the groups, namely villous height and width, crypt depth, crypt density, and crypt fission rate (all P >= 0.08). Muscularis mucosal thickness was also not different (P=0.25). There was no difference in DNA:protein between groups (P=0.47). CONCLUSION: An extraluminally placed, radially expanding shape-memory polymer cylinder successfully lengthened intestine, without damaging mucosa. Lack of difference in muscularis thickness and a constant DNA:protein ratio suggests that this process may be related to actual growth rather than mere stretch. This study demonstrated a simple approach that warrants further study aiming at potential clinical applicability. PMID- 25812444 TI - Primary malignant pulmonary tumors in children: a review of the national cancer data base. AB - BACKGROUND: The purpose is to delineate the clinical and pathological characteristics of rare primary malignant pulmonary tumors in children. METHODS: Utilizing the National Cancer Data Base (NCDB), we analyzed all children (<= 18 years) with a primary malignant pulmonary tumor from 1998 to 2011 to identify factors associated with better survival. RESULTS: Of 211 children identified, the most common histology was carcinoid tumor (n=133, 63%) followed by mucoepidermoid carcinoma (MEC) (n=37, 18%), squamous cell carcinoma (SCC) (n=19, 9%), adenocarcinoma (n=16, 8%), bronchoalveolar carcinoma (BAC) (n=4, 2%), and small cell carcinoma (SCLC) (n=2, <1%). Factors that significantly affected survival include histology, race, tumor size, lymph node status, and extent of surgery. Patients with MEC and carcinoid tumors had a better overall survival compared to patients with other histologies (p<0.0001). The 5-year overall survival for MEC and carcinoid tumors was 100% and 95% (95% CI 87-98), respectively, versus 50% (95%CI 1-91) for BAC, 28% (95%CI 9-52) for SCC, and 26% (95%CI 5-55) for adenocarcinoma. CONCLUSION: The majority of pediatric patients with a primary malignant pulmonary tumor present with carcinoid tumor or MEC and have an excellent prognosis. Lung cancers which are common in adults, but rare in children, have a worse prognosis. PMID- 25812445 TI - Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children's Oncology Group. AB - PURPOSE: The purpose of this study was to determine prognostic factors correlating with outcome in boys with Stage I malignant testicular germ cell tumors (MTGCT) initially managed with surveillance after surgical resection. METHODS: Between November 2003 and July 2011, 80 boys 0-15 years with Stage I MTGCT were enrolled in Children's Oncology Group Study AGCT0132. Those with residual or recurrent disease were treated with chemotherapy. RESULTS: Characteristics include: age (65, 0-5 years and 15, 11+years), pure YST (93.9%, 0 5 years and 0%, 11+years); and lymphovascular invasion (LVI) (50.6% present vs. 49.4% absent). At median follow-up of 4.94 years, 19 had persistent or recurrent disease, all detected by elevated AFP at a median of 87 days after study enrollment. The outcome from enrollment was 4-year EFS 74% (95% CI: 63%-83%) and 4-year OS 100%. 4-year EFS was improved with younger age (<11 years, 80% vs. 11+years, 48%, p<0.01); pure YST vs. mixed histology (81% vs. 45%, p<0.01), and lack of LVI (84% vs. 62%, p=0.03). CONCLUSIONS: Boys with Stage I MTGCT have excellent overall survival when treated with surgery alone. Age greater than 10 years, mixed histology and presence of LVI are each associated with relapse and may allow identification of high risk boys at time of enrollment. PMID- 25812446 TI - Increased expression of activated pSTAT3 and PIM-1 in the pulmonary vasculature of experimental congenital diaphragmatic hernia. AB - PURPOSE: Signal transducer and activator of transcription (STAT) protein family (STAT1-6) regulates diverse cellular processes. Recently, the isoform STAT3 has been implicated to play a central role in the pathogenesis of pulmonary hypertension (PH). In human PH activated STAT3 (pSTAT3) was shown to directly trigger expression of the provirus integration site for Moloney murine leukemia virus (Pim-1), which promotes proliferation and resistance to apoptosis in SMCs. We designed this study to investigate the hypothesis that pSTAT3 and Pim-1 pulmonary vascular expression is increased in nitrofen-induced CDH. METHODS: Pregnant rats were exposed to nitrofen or vehicle on D9.5. Fetuses were sacrificed on D21 and divided into nitrofen (n=16) and control group (n=16). QRT PCR, western blotting, and confocal-immunofluorescence were performed to determine pulmonary gene and protein expression levels of pSTAT3 and Pim-1. RESULTS: Pulmonary Pim-1 gene expression was significantly increased in the CDH group compared to controls. Western blotting and confocal-microscopy confirmed increased pulmonary protein expression of Pim-1 and increased activation of pSTAT3 in CDH lungs compared to controls. CONCLUSION: Markedly increased gene and protein expression of Pim-1 and activated pSTAT3 in the pulmonary vasculature of nitrofen-induced CDH lungs suggest that pSTAT3 and Pim-1 are important mediators of PH in nitrofen-induced CDH. PMID- 25812447 TI - Analysis of submitted abstracts for the American Academy of Pediatrics, Section on Surgery, National Conference (AAP SoSU). AB - PURPOSE: In this study, we characterized the topics and type of research performed for abstracts submitted to the AAP SoSU national conferences from 2010 2013. METHODS: All abstracts submitted to the AAP SoSU Program Committee from 2010-2013 were analyzed. Abstracts were classified as basic science, clinical, domestic, international, as well as by disease processes, single, multicenter, retrospective, prospective, registry data, or other. RESULTS: From 2010-2013, 709 abstracts were submitted (2010 - 163, 2011 - 166, 2012 - 208, 2013 - 172), of which 349 were accepted (49% total acceptance rate (AR)). 17% represented basic science studies (74% AR), while 592 (84%) were clinical studies (44% AR). By disease state, CDH (57 abstracts, 70.2% AR), appendicitis (53 abstracts, 43% AR), and NEC (39 abstracts, 56% AR) were the most common. Most clinical abstracts (63%) were single-center retrospective reviews, 13% were large data registries, <5% were prospective studies, and only 5 abstracts were randomized controlled trials. CONCLUSIONS: The AAP SoSU abstract submission data demonstrate a wide variety of research studies spanning the entirety of our field. Basic science studies have a higher AR than clinical studies, and the topics of CDH, appendicitis, and NEC continue to be the most popular areas of study. PMID- 25812449 TI - Antimicrobial resistance in the 21st century. PMID- 25812448 TI - Secondary overtriage in pediatric trauma: can unnecessary patient transfers be avoided? AB - BACKGROUND: In an era of wide regionalization of pediatric trauma systems, interhospital patient transfer is common. Decisions regarding the location of definitive trauma care depend on prehospital destination criteria (primary triage) and interfacility transfers (secondary triage). Secondary overtriage can occur in any resource-limited setting but is not well characterized in pediatric trauma. METHODS: The National Trauma Data Bank from 2008 to 2011 was queried to identify patients 15 years or younger who were transferred to pediatric trauma centers. Secondary overtriage was defined as meeting all 4 of the following criteria: injury severity score (ISS) less than 9, no need for surgical procedure, no critical care admission, and length of stay of less than 24 hours. All other transfers were deemed appropriate triage. RESULTS: Our definition of secondary overtriage was met in 32,318 patients out of 144,420 transfers (22.4%). Within this group, 37.5% were discharged directly from the emergency department of the receiving hospital without hospital admission. Appropriately triaged patients required a therapeutic procedure in 43.5% of cases. Differences in age, sex, mechanism of injury, and payer status were modest. CONCLUSIONS: Secondary overtriage is prevalent in pediatric trauma systems nationwide and is not associated with any particular patient characteristics. Because clinical outcomes and healthcare spending are increasingly scrutinized, secondary overtriage may reflect unnecessary patient transfer and a source of potential cost savings. Development of better guidelines for secondary triage of pediatric trauma patients may enable timely assessment and treatment of children who require a higher level of care while also preventing inefficient use of available resources. PMID- 25812451 TI - Antibiotic resistance in hospitals. PMID- 25812450 TI - Next-generation sequencing of carbapenem-resistant Gram-negative microorganisms: a key tool for surveillance and infection control. PMID- 25812452 TI - Endolysins: redefining antibacterial therapy. AB - Bjorn Lars Herpers speaks to Natasha Leeson, Commissioning Editor: Bjorn Lars Herpers was born on 16 February 1974 in Schaesberg. In 1992 he graduated summa cum laude at Gymnasium Rolduc in Kerkrade (The Netherlands) and started to study medical biology at the University of Utrecht. After 3 years, he started to study medicine as well. He graduated cum laude in medical biology in 1999 and obtained his medical degree in 2001. After 1 year of residency in internal medicine at Gooi-Noord Hospital under supervision of DW Erkelens and P Niermeier, he switched to a residency in medical microbiology at the University Medical Center Utrecht and the St Antonius Hospital Nieuwegein under supervision of J Verhoef and B M de Jongh. During his residency, he started to work on his thesis on genetic polymorphisms in MBL and L-ficolin, two complement-activating pattern recognition receptors. In 2009 he became a medical microbiologist and joined the staff at the Regional Public Health Laboratory Kennemerland in Haarlem. Since 2012, he has been involved in clinical research on endolysin therapy in collaboration with Micreos in Bilthoven. PMID- 25812453 TI - Prospects of untreatable gonorrhea and ways forward. PMID- 25812454 TI - Screening methods for the detection of antimicrobial resistance genes present in bacterial isolates and the microbiota. PMID- 25812455 TI - 'The Chennai Declaration' and the attitude change in India. PMID- 25812456 TI - RfiA, a novel PAP2 domain-containing polytopic membrane protein that confers resistance to the FtsZ inhibitor PC190723. AB - BACKGROUND: As an essential protein for bacterial cell division, the tubulin-like FtsZ protein has been selected as a target for development of next generation antimicrobials. PC190723 is a fluoride-containing benzamide compound developed as a FtsZ inhibitor that selectively inhibits growth of multidrug resistant Gram positive bacteria. AIM: Our aim was to investigate the mechanism of resistance to PC109723 conferred by over-expression of a gene, rfiA, in an environmental bacterium Arthrobacter A3. MATERIALS & METHODS: The investigations included analysis of the effect of PC109723 on wild-type Arthrobacter A3 and a recombinant strain over-expressing rfiA, in vivo localization of RfiA, in vitro measurements of fluorine release from PC109723 by membrane extracts from the over-expression strain combined with mass spectrophotometric analysis of reaction products, and modelling of RfiA structure. RESULTS: We describe a novel protein, RfiA, from Arthrobacter A3 that confers PC190723 resistance. RfiA is a PAP2 domain containing polytopic transmembrane protein that can modify the fluoridated benzamide ring that is critical for high affinity binding of PC190723 with FtsZ. CONCLUSION: RfiA-mediated modification of PC190723 is the first reported instance of resistance to this antibiotic involving a change to its structure. We predict that adoption of PC190723 or related benzamides as antimicrobials in clinical practice will lead to the acquisition by resistant pathogens of a gene encoding this subfamily of proteins. PMID- 25812457 TI - The role of RND efflux pump and global regulators in tigecycline resistance in clinical Acinetobacter baumannii isolates. AB - AIM: To analyze the expression and regulation of resistance-nodulation-division (RND) efflux systems in clinical tigecycline-nonsusceptible (TNS) Acinetobacter baumannii. MATERIALS & METHODS: Comparisons of molecular and clinical characteristics were performed between 52 TNS and 53 tigecycline-susceptible isolates. Expression of RND efflux pumps and global regulators were analyzed by real-time RT-PCR. A complementation experiment was performed to evaluate the contribution of the adeRS mutations. RESULTS: Mechanical ventilation and prior use of carbapenems were more common among patients with TNS strains. The relative expression of adeB and adeJ was increased significantly in TNS isolates. Complementarity to the adeR or adeS mutations decreased tigecycline susceptibility by <=2-fold. Decreased expression of marR and soxR was detected in TNS isolates. CONCLUSION: A correlation between tigecycline MIC and expression level of adeB and adeJ was identified. The influence of adeRS mutation on adeB expression was limited. Global regulators marR and soxR may be involved in tigecycline resistance. PMID- 25812458 TI - Antimicrobial photodynamic activity of hypericin against methicillin-susceptible and resistant Staphylococcus aureus biofilms. AB - AIM: To evaluate the effectiveness of the photodynamic therapy using hypericin (HYP) against both planktonic and biofilm-forming Staphylococcus aureus. MATERIALS & METHODS: HYP photoactivity was evaluated against methicillin susceptible and resistant S. aureus. Bacterial suspension or biofilm were preincubated with HYP and subjected to LED illumination. Viable bacteria were determined by colony counting. RESULTS: Preincubation with HYP (5 min) plus light exposure (10 min) showed bactericidal effect against planktonic methicillin susceptible S. aureus and methicillin-resistant S. aureus. Longer preincubation times (24 h) and time light exposure (30 min) were required to reach HYP photoactivity against S. aureus biofilms. HYP-photoactivity was correlated to the biofilm production. CONCLUSION: HYP could be a potential photosensitizer for the inactivation of staphylococcal biofilms forming on the surfaces accessible to visible light. PMID- 25812459 TI - Antibiotic susceptibility of Gram-negatives isolated from bacteremia in children with cancer. Implications for empirical therapy of febrile neutropenia. AB - BACKGROUND: Monotherapy is recommended as the first choice for initial empirical therapy of febrile neutropenia, but local epidemiological and antibiotic susceptibility data are now considered pivotal to design a correct management strategy. AIM: To evaluate the proportion of Gram-negative rods isolated in bloodstream infections in children with cancer resistant to antibiotics recommended for this indication. MATERIALS & METHODS: The in vitro susceptibility to ceftazidime, piperacillin-tazobactam, meropenem and amikacin of Gram-negatives isolated in bacteremic episodes in children with cancer followed at the Istituto "Giannina Gaslini", Genoa, Italy in the period of 2001-2013 was retrospectively analyzed using the definitions recommended by EUCAST in 2014. Data were analyzed for any single drug and to the combination of amikacin with each beta-lactam. The combination was considered effective in absence of concomitant resistance to both drugs, and not evaluated by means of in vitro analysis of antibiotic combinations (e.g., checkerboard). RESULTS: A total of 263 strains were evaluated: 27% were resistant to piperacillin-tazobactam, 23% to ceftazidime, 12% to meropenem and 13% to amikacin. Concomitant resistance to beta-lactam and amikacin was detected in 6% of strains for piperacillin-tazobactam, 5% for ceftazidime and 5% for meropenem. During the study period there was a nonsignificant increase in the proportions of strains resistant to beta-lactams indicated for monotherapy, and also increase in the resistance to combined therapies. CONCLUSION: in an era of increasing resistance to antibiotics guideline-recommended monotherapy could be not appropriate for initial empirical therapy of febrile neutropenia. Strict local survey on etiology and antibiotic susceptibility is mandatory for a correct management of this complication in cancer patients. PMID- 25812460 TI - A multifaceted 'omics' approach for addressing the challenge of antimicrobial resistance. AB - The inappropriate use of antibiotics has severe global health and economic consequences, including the emergence of antibiotic-resistant bacteria. A major driver of antibiotic misuse is the inability to accurately distinguish between bacterial and viral infections based on currently available diagnostic solutions. A multifaceted 'omics' approach that integrates personalized patient data such as genetic predisposition to infections (genomics), natural microbiota composition and immune response to infection (proteomics and transcriptomics) together with comprehensive pathogen profiling has the potential to help physicians improve their antimicrobial prescribing practices. In this respect, the EU has funded a multidisciplinary project (TAILORED-Treatment) that will develop novel omics based personalized treatment schemes that have the potential to reduce antibiotic consumption, and help limiting the spread of antibiotic resistance. PMID- 25812461 TI - Breaking barriers: expansion of the use of endolysins as novel antibacterials against Gram-negative bacteria. AB - The emergence and spread of antibiotic-resistant bacteria drives the search for novel classes of antibiotics to replenish our armamentarium against bacterial infections. This is particularly critical for Gram-negative pathogens, which are intrinsically resistant to many existing classes of antibiotics due to the presence of a protective outer membrane. In addition, the antibiotics development pipeline is mainly oriented to Gram-positive pathogens such as methicillin resistant Staphylococcus aureus. A promising novel class of antibacterials is endolysins. These enzymes encoded by bacterial viruses hydrolyze the peptidoglycan layer with high efficiency, resulting in abrupt osmotic lysis and cell death. Their potential as novel antibacterials to treat Gram-positive bacteria has been extensively demonstrated; however, the Gram-negative outer membrane has presented a formidable barrier for the use of endolysins against Gram-negatives until recently. This review reports on the most recent advances in the development of endolysins to kill Gram-negative species with a special focus on endolysin-engineered Artilysins((r)). PMID- 25812462 TI - Fighting antibiotic resistance in the intensive care unit using antibiotics. AB - Antibiotic resistance is a global and increasing problem that is not counterbalanced by the development of new therapeutic agents. The prevalence of antibiotic resistance is especially high in intensive care units with frequently reported outbreaks of multidrug-resistant organisms. In addition to classical infection prevention protocols and surveillance programs, counterintuitive interventions, such as selective decontamination with antibiotics and antibiotic rotation have been applied and investigated to control the emergence of antibiotic resistance. This review provides an overview of selective oropharyngeal and digestive tract decontamination, decolonization of methicillin resistant Staphylococcus aureus and antibiotic rotation as strategies to modulate antibiotic resistance in the intensive care unit. PMID- 25812463 TI - Carbapenemase-producing Gram-negative bacteria: current epidemics, antimicrobial susceptibility and treatment options. AB - Carbapenemases, with versatile hydrolytic capacity against beta-lactams, are now an important cause of resistance of Gram-negative bacteria. The genes encoding for the acquired carbapenemases are associated with a high potential for dissemination. In addition, infections due to Gram-negative bacteria with acquired carbapenemase production would lead to high clinical mortality rates. Of the acquired carbapenemases, Klebsiella pneumoniae carbapenemase (Ambler class A), Verona integron-encoded metallo-beta-lactamase (Ambler class B), New Delhi metallo-beta-lactamase (Ambler class B) and many OXA enzymes (OXA-23-like, OXA-24 like, OXA-48-like, OXA-58-like, class D) are considered to be responsible for the worldwide resistance epidemics. As compared with monotherapy with colistin or tigecycline, combination therapy has been shown to effectively lower case fatality rates. However, development of new antibiotics is crucial in the present pandrug-resistant era. PMID- 25812464 TI - Emerging issues in antimicrobial resistance of bacteria from food-producing animals. AB - During the last decade, antimicrobial resistance in bacteria from food-producing animals has become a major research topic. In this review, different emerging resistance properties related to bacteria of food-producing animals are highlighted. These include: extended-spectrum beta-lactamase-producing Enterobacteriaceae; carbapenemase-producing bacteria; bovine respiratory tract pathogens, such as Pasteurella multocida and Mannheimia haemolytica, which harbor the multiresistance mediating integrative and conjugative element ICEPmu1; Gram positive and Gram-negative bacteria that carry the multiresistance gene cfr; and the occurrence of numerous novel antimicrobial resistance genes in livestock associated methicillin-resistant Staphylococcus aureus. The emergence of the aforementioned resistance properties is mainly based on the exchange of mobile genetic elements that carry the respective resistance genes. PMID- 25812465 TI - Impacting delayed pediatric influenza vaccination: a randomized controlled trial of text message reminders. AB - BACKGROUND: Influenza vaccination coverage is low, especially among low-income populations. Most doses are generally administered early in the influenza season, yet sustained vaccination efforts are crucial for achieving optimal coverage. The impact of text message influenza vaccination reminders was recently demonstrated in a low-income population. Little is known about their effect on children with delayed influenza vaccination or the most effective message type. PURPOSE: To determine the impact of educational plus interactive text message reminders on influenza vaccination of urban low-income children unvaccinated by late fall. DESIGN: Randomized controlled trial. SETTING/PARTICIPANTS: Parents of 5,462 children aged 6 months-17 years from four academically affiliated pediatric clinics who were unvaccinated by mid-November 2011. INTERVENTION: Eligible parents were stratified by their child's age and pediatric clinic site and randomized using a 1:1:1 allocation to educational plus interactive text message reminders, educational-only text message reminders, or usual care. Using an immunization registry-linked text messaging system, parents of intervention children received up to seven weekly text message reminders. One of the messages sent to parents in the educational plus interactive text message arm allowed selection of more information about influenza and influenza vaccination. MAIN OUTCOME MEASURES: Influenza vaccination by March 31, 2012. Data were collected and analyzed between 2012 and 2014. RESULTS: Most children were publicly insured and Spanish speaking. Baseline demographics were similar between groups. More children of parents in the educational plus interactive text message arm were vaccinated (38.5%) versus those in the educational-only text message (35.3%; difference=3.3%, 95% CI=0.02%, 6.5%; relative risk ratio (RRR)=1.09, 95% CI=1.002, 1.19) and usual care (34.8%; difference=3.8%, 95% CI=0.6%, 7.0%; RRR=1.11, 95% CI=1.02-1.21) arms. CONCLUSIONS: Text message reminders with embedded educational information and options for interactivity have a small positive effect on influenza vaccination of urban, low-income, minority children who remain unvaccinated by late fall. PMID- 25812466 TI - Determinants of physical and global functioning in adult HIV-positive heterosexual men. AB - Little is known about the psychosocial factors that might impact the functioning ability of heterosexual men living with HIV. We examined positive and negative coping, social support, and HIV stigma as predictors of physical and global functioning in a cross-sectional sample of 317 HIV-infected adult heterosexual male patients recruited from clinical and social service agencies in New York City. Study participants were primarily minority and low income. Sixty-four percent were African-American, 55% were single, and 90% were 40 years of age or older. The majority had long-term HIV (LTHIV), with an average duration of 15 years since diagnosis. After controlling for participant characteristics, structural equation modeling analyses revealed that positive coping and social support had a significant positive direct effect on global functioning, while stigma had a significant negative direct effect on global functioning. The physical functioning model revealed that negative coping and HIV stigma had significant negative direct effects, whereas social support had a significant positive indirect effect. Age and duration of HIV diagnosis were not associated with physical and global functioning. In conclusion, we found that heterosexual men living with LTHIV who have ineffective coping, less social support, and greater stigma have reduced functioning ability. Study findings have implications for developing interventions aimed at increasing and retaining functioning ability with the end goal of improving successful aging in this population. PMID- 25812468 TI - The influence of temperature variations on ultrasonic guided waves in anisotropic CFRP plates. AB - Carbon Fibre Reinforced Polymer (CFRP) materials are lightweight and corrosion resistant and therefore are increasingly used in aerospace, automotive and construction industries. In Structural Health Monitoring (SHM) applications of CFRP materials, ultrasonic guided waves potentially offer large area inspection or inspection from a remote location. This paper addresses the effect of temperature variation on guided wave propagation in highly anisotropic CFRP materials. Temperature variations cause changes in guided wave velocity that can in turn compromise the baseline subtraction procedures employed by many SHM systems for damage detection. A simple model that describes the dependence of elastic properties of the CFRP plates on temperature is presented in this paper. The model can be used to predict anisotropic velocity changes and baseline subtraction performance under varying thermal conditions. The results produced by the model for unidirectional and 0/90 CFRP plates are compared with experimental measurements. PMID- 25812467 TI - Cutting edge: FasL(+) immune cells promote resolution of fibrosis. AB - Immune cells, particularly those expressing the ligand of the Fas-death receptor (FasL), e.g. cytotoxic T cells, induce apoptosis in 'undesirable' self- and non self-cells, including lung fibroblasts, thus providing a means of immune surveillance. We aimed to validate this mechanism in resolution of lung fibrosis. In particular, we elucidated whether FasL(+) immune cells possess antifibrotic capabilities by induction of FasL-dependent myofibroblast apoptosis and whether antagonists of membrane (m) and soluble (s) FasL can inhibit these capabilities. Myofibroblast interaction with immune cells and its FasL-dependency, were investigated in vitro in coculture with T cells and in vivo, following transplantation into lungs of immune-deficient syngeneic Rag-/- as well as allogeneic SCID mice, and into lungs and air pouches of FasL-deficient (gld) mice, before and after reconstitution of the mice with wild-type (wt), FasL(+) immune cells. We found that myofibroblasts from lungs resolving fibrosis undergo FasL-dependent T cell-induced apoptosis in vitro and demonstrate susceptibility to in vivo immune surveillance in lungs of reconstituted, immune- and FasL deficient, mice. However, immune-deficient Rag-/- and SCID mice, and gld-mice with FasL-deficiency, endure the accumulation of transplanted myofibroblasts in their lungs with subsequent development of fibrosis. Concomitantly, gld mice, in contrast to chimeric FasL-deficient mice with wt immune cells, accumulated transplanted myofibroblasts in the air pouch model. In humans we found that myofibroblasts from fibrotic lungs secrete sFasL and resist T cell-induced apoptosis, whereas normal lung myofibroblasts are susceptible to apoptosis but acquire resistance upon addition of anti-s/mFasL to the coculture. Immune surveillance, particularly functional FasL(+) immune cells, may represent an important extrinsic component in myofibroblast apoptosis and serve as a barrier to fibrosis. Factors interfering with Fas/FasL-immune cell-myofibroblast interaction such as sFasL secreted by fibrotic-lung myofibroblasts, may abrogate immune surveillance during fibrosis. Annulling these factors may pave a new direction to control human lung fibrosis. PMID- 25812469 TI - A new nomogram for prediction of outcome of pediatric shock-wave lithotripsy. AB - INTRODUCTION: Despite the fact that shock-wave lithotripsy (SWL) remains a very good treatment option for smaller stones, it is being challenged by endourologic treatment modalities, which offer similar or even higher success rates in a shorter time, with minimal morbidity and invasiveness. The present study aimed to bring a new and practical insight in order to predict the outcomes of pediatric SWL and to provide objective information about pediatric SWL outcomes. OBJECTIVE: To design a nomogram for predicting the outcomes of pediatric shock-wave lithotripsy. STUDY DESIGN: The study was conducted with a retrospective design and included 402 renal units who underwent SWL between January 2009 and August 2013. Patients with known cystine stone disease and cystinuria, with internal or external urinary diversion, were excluded. Analysis was performed on 383 renal units. Postoperative imaging was performed by plain abdominal graphy and ultrasonography with 3-month intervals. Patients who were completely free of stones were considered to be a success and statistical analysis was done regardingly Multivariate analysis was conducted by logistic regression analysis and a nomogram was developed. RESULTS: The male/female distribution was 216/167, with a mean age of 48 +/- 40 months and a mean stone size of 9 +/- 3.5 mm. The overall stone-free rate was 70% (270/383) and efficacy quotient was 0.57. Mean follow-up was 11 +/- 11 months (3-54 months). The number of shock waves and amplitude of energy were higher in failed cases. Multivariate analysis showed that gender, stone size, number of stones, age, location of the stone, and history of previous intervention were found to be the independent prognostic factors for assessing the stone clearance rates. A nomogram was developed using these parameters. In this nomogram, the points achieved from each parameter are summed and total points correspond to the risk of failure in percent. DISCUSSION: A previous nomogram study by Onal et al. showed that younger age (<5 years), smaller stone burden (<1 cm), absence of previous stone treatment history, single stone, pelvis or upper ureter location (in girls) were favorable prognostic factors for successful outcome. As being the first pediatric study, it had some shortcomings. The study included 381 patients within a time period of 16 years. The present study included a similar number of cases within a 4-year period, which may reflect more homogeneity of data collection. Another issue is concern about the practical use of that nomogram. It constitutes two pages, which is a limiting factor for daily use. From a statistical point of view, they performed 200 bootstrapings with the aim of internal validation, which is less than the ideal number of 1000 bootstrapings, which was performed in the present nomogram. The presented nomogram is more practical, in that the pre-operative factors can be placed on the nomogram, the points can be added up and the parents can be given the approximate percentage of predicted stone-free rate after a single session. The expected treatment modality shown to the parents and patients ought to be the least minimally invasive, have the highest success rate, the least complication rate, and show the efficacy in one procedure at a time within the shortest period. However, SWL does not completely meet these criteria. The results gained from the present critical analysis of SWL in children, which was based on a strict definition of success, showed that outcome after a single session is not that good. Therefore, defining the patients who will benefit the most became one of the main issues. A more objective and skeptical look at SWL data enabled a nomogram to be developed that brings a new and practical insight in order to predict the outcomes of pediatric SWL. CONCLUSION: In most of the pediatric stone cases, SWL is the first-line treatment option. However, it is wise to define the patients who will benefit the most. Therefore, nomograms can be useful for this purpose. The nomogram in the present study revealed that gender, stone size, number of stones, age, location of the stone, and history of previous intervention were found to be the independent prognostic factors for assessing the stone clearance rates. This nomogram can practically be used to inform the parents, and for proper patient selection for SWL. PMID- 25812470 TI - Psychosocial screening at paediatric BEEC clinics: a pilot evaluation study. AB - INTRODUCTION: Bladder Exstrophy and Epispadias Complex (BEEC) is associated with an increased risk of impaired mental health, quality of life, and psychosocial functioning. Therefore, screening patients to help identify and evaluate potential psychosocial difficulty is arguably an important consideration for BEEC Services. OBJECTIVE: To screen paediatric BEEC patients for a range of general psychosocial difficulties in a multi-disciplinary out-patient clinic setting. STUDY DESIGN: This cross-sectional evaluation was conducted between April 2012 and July 2013. Families attending BEEC multi-disciplinary out-patient clinics were asked to complete a range of standardised psychosocial questionnaires, including the Paediatric Quality of Life Inventory (PedsQL 4.0 Generic Core and Family Impact Module), the Strengths and Difficulties Questionnaire (SDQ), the Paediatric Index of Emotional Distress (PI-ED), and the Hospital Anxiety and Depression Scale (HADS). 108 children attended clinic of which 80 (74.1%) patients and their parents/carers completed some or all of the questionnaires. The mean patient age was 8.41 years (SD = 4.46, range = 1-18 years). There were more boys (N = 50, 62.5%) and the majority had a diagnosis of classic bladder exstrophy (N = 51, 63.8%), followed by primary epispadias (N = 22, 27.5%) and cloacal exstrophy (N = 7, 8.7%). RESULTS: Mean total scores fell within the average/normal range on all questionnaires used (See table below). However, variation around these means was high. Age, gender and diagnosis were found to significantly influence certain questionnaire responses with older-age groups, males, and those with classic bladder exstrophy particularly at risk across some domains. The children/adolescents self-reported better health related quality of life (HRQoL) scores than published results for a range of paediatric chronic health conditions. Differences between parent and child responses on both the PedsQL and SDQ favoured a more positive response on the child self-report questionnaire but were not statistically significant. DISCUSSION: Mean scores on the measures used suggest a relatively optimistic picture of general psychosocial well-being, especially for HRQoL, in the BEEC population studied. Positive HRQoL outcomes have recently been reported for BEEC paediatric populations. Our results reflect this trend with better mean HRQoL scores than paediatric patients with a range of other chronic health conditions. However, this optimism is cautious given the limitations of this evaluation study and the high variation around the means. Limitations included the small sample size (especially for patients with cloacal exstrophy), the lack of a control group, the limited sensitivity of generic questionnaires in respect of BEEC-specific issues, and the low mean age of patients in the study. Future screening programmes may wish to consider measuring BEEC-specific variables (e.g. satisfaction with genital appearance/function); collecting information on medical aspects, such as continence, pubertal stage and frequency/timing of medical intervention; and asking both parents/carers (where possible) to complete the questionnaires. CONCLUSIONS: Screening questionnaire responses were used in conjunction with clinical psychology consultations to evaluate a range of psychosocial aspects in BEEC paediatric patients. Whilst mean scores on the measures used suggest a relatively optimistic picture, certain individual scores did fall within the clinical ranges, highlighting the potential need for further assessment. Developmentally tailored consultations with a clinical psychologist can provide detailed information around questionnaire responses and further assess BEEC specific aspects. PMID- 25812472 TI - Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice. AB - Understanding and effectively treating anxiety disorders are a challenge for both scientists and clinicians. Despite a variety of available therapies, the efficacy of current treatments is still not optimal and adverse side effects can result in non-compliance. Animal models have been useful for studying the underlying biology of anxiety and assessing the anxiolytic properties of potential therapeutics. The open field (OF) is a commonly used assay of anxiety-like behavior. The OF was developed and validated in rats and then transferred to use in the mouse with only limited validation. The present study tests the efficacy of prototypical benzodiazepine anxiolytics, chlordiazepoxide (CDP) and diazepam (DZ), for increasing center time in the OF in C57BL/6J (B6) mice. Multiple doses of CDP and DZ did not change time spent in the center of the OF. Increasing illumination in the OF did not alter these results. The non-benzodiazepine anxiolytic, buspirone (BUSP) also failed to increase center time in the OF while the anxiogenic meta-chlorophenylpiperazine (mCPP) increased center time. Additional inbred mouse strains, BALB/cJ (BALB) and DBA/2J (D2) did not show any change in center time in response to CDP. Moreover, evaluation of CDP in B6 mice in the elevated plus maze (EPM), elevated zero maze (EZM) and light dark assay (LD) did not reveal changes in anxiety-like behavior while stress-induced hyperthermia (SIH) was decreased by DZ. Pharmacokinetic (PK) studies suggest that adequate CDP is present to induce anxiolysis. We conclude that the measure of center time in the OF does not show predictive validity for anxiolysis in these inbred mouse strains. PMID- 25812474 TI - Association between Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in subgingival plaque and clinical parameters, in Argentine patients with aggressive periodontitis. AB - BACKGROUND: Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) have been associated with aggressive (AgP) and chronic periodontitis. OBJECTIVE: The aim of this study was to evaluate the levels of Aa and Pg in gingival crevicular fluid (GCF) of patients with AgP and its relation with clinical parameters. DESIGN: Sixteen females and fourteen males with clinical diagnosis of AgP aged 17-23 years and their match's controls, were included in this study. Clinical recording concerning probing pocket depth, clinical attachment level, plaque index and gingival bleeding index were performed at baseline, 30 and 60 days after baseline. After clinical examination GCF samples were analyzed for Aa and Pg with a real-time polymerase chain reaction technique. Patients group was treated with a combined of mechanical and oral antibiotic therapy (doxycycline 100 mg/day, during 21 days). A multivariate analysis was used to determine the relationship between Aa and Pg counts with clinical parameters. RESULTS: GCF from all subjects was positive for Aa and PG. In controls Pg concentration was higher than Aa (Pg: 42,420 +/- 3,034 copies/ml; Aa: 66.6 +/- 5.4 copies/ml p < 0.001) while in patients both microbes showed the same concentration (Aa: 559,878 +/- 39,698 Pg: 572,321 +/- 58,752). A significant and positive correlation was observed between counts of Aa and Pg (R square: 0.7965, p < 0.0001). Female showed more counts/ml. Aa might be closely associated with clinical parameters while Pg did not. At 30 and 60 days Aa counts in patients were similar to controls while Pg counts were equal to baseline. However, in spite of Pg presence a clinical improvement was observed in all patients. CONCLUSIONS: In our population the presence of Aa may be associated with AgP while Pg may be in GCF as an opportunistic pathogen which might caused disease when the ecological balance was favorable. PMID- 25812471 TI - Cocaine decreases saccharin preference without altering sweet taste sensitivity. AB - In rodents, saccharin consumption is suppressed when the sweet taste stimulus is paired with moderate doses of cocaine. Several hypotheses have been used to explain the seemingly contradictory effect of decreased consumption of a normally preferred substance following a highly rewarding drug. A common theme across these hypotheses is that saccharin is interpreted as less rewarding after cocaine pairing. We considered the alternative possibility that suppression is caused not by a change in reward circuitry, but rather by a change in taste detection, for instance by altering the afferent taste response and decreasing sensitivity to sweet taste stimuli. To evaluate this possibility, we measured saccharin taste sensitivity of mice before and after a standard cocaine-pairing paradigm. We measured taste sensitivity using a brief-access lickometer equipped with multiple concentrations of saccharin solution and established concentration-response curves before and after saccharin-cocaine pairing. Our results indicate that the EC50 for saccharin was unaltered following pairing. Instead, the avidity of licking saccharin, an indicator of motivation, was depressed. Latency to first lick, a negative indicator of motivation, was also dramatically increased. Thus, our findings are consistent with the interpretation that saccharin-cocaine pairing results in devaluing of the sweet taste reward. PMID- 25812475 TI - Radiology and mesenteric ischaemia. AB - This review focuses on the radiology of mesenteric ischaemia. Covering the acute and chronic presentations, both of which result from impaired vascularisation of the gastrointestinal tract, we evaluate the role of radiographs, ultrasound, CT, MRI, and catheter angiography in the diagnosis of these conditions. Looking to the future, we also assess some of the emerging imaging techniques. Across medicine and surgery there has been a significant shift towards minimally invasive interventions. Although percutaneous revascularisation of chronic mesenteric ischaemia has been performed for some time, there has been a developing trend for the use of such techniques in acute mesenteric ischaemia. We evaluate the available evidence for the use of these percutaneous interventions and assess how they compare with or in some instances compliment traditional surgical alternatives. PMID- 25812476 TI - Health care utilization by people with disabilities: A longitudinal analysis of the Korea Welfare Panel Study (KoWePS). AB - BACKGROUND: Health care is important for people with disabilities in terms of maintaining basic functional status and promoting health. However, empirical studies on health care utilization by this population in South Korea are rare. OBJECTIVE: The purpose of this study was to examine the characteristics of people with disabilities and to evaluate the relationship between the presence and severity of disabilities and health care utilization. METHODS: We analyzed the 2005-2011 Korea Welfare Panel Study data, and the final sample included 38,598 observations over seven years. Health care utilization was measured by health screening attendance, number of outpatient physician visits, and inpatient days. To examine the impact of disabilities on health care utilization, random-effects logistic regression and negative binomial regression models were adopted. RESULTS: About 3.3% of the sample had physical disabilities, as defined by the Korean disability registration system. In the sample, the prevalence of chronic diseases and percentage of poor self-rated health were higher in people with disabilities than in people without disabilities. The results of the regression analyses showed that people with severe disabilities had a lower probability of health screening attendance, and they also had significantly longer inpatient stays for health care services. CONCLUSIONS: These findings imply poor accessibility of preventive or outpatient health care services for people with severe disabilities in Korea, and suggest that barriers should be removed. Further studies are necessary for effective health care provision to meet the complex needs of people with disabilities. PMID- 25812473 TI - Point-of-care detection of Tannerella forsythia using an antigen-antibody assisted dielectrophoretic impedance measurement method. AB - The importance of periodontal treatment planning based on diagnosis with clinical detection of periodontal pathogens has been well recognized. However, reliable detection and quantification methods that can be conveniently used at chair-side have yet to be developed. This study aimed to evaluate the clinical use of a novel apparatus which uses an antigen-antibody reaction assisted dielectrophoretic impedance measurement (AA-DEPIM) for the detection of a prominent periodontal pathogen, Tannerella forsythia. A total of 15 patients with a clinical diagnosis of chronic periodontitis, three periodontally healthy volunteers and two with gingivitis were subjected to clinical and microbiological examinations. Saliva samples were analyzed for the presence of T. forsythia using AA-DEPIM, PCR-Invader and real-time PCR methods. The measurement values for total bacteria and T. forsythia using the prototype AA-DEPIM apparatus were significantly greater in periodontitis group than those in healthy/gingivitis group. Using the AA-DEPIM apparatus with tentative cut-off values, T. forsythia was detected for 14 (12 with periodontitis and 2 either healthy or with gingivitis) out of 20 individuals. The measurement for the detection of T. forsythia by the AA-DEPIM method showed a significant positive correlation with the detection by PCR-Invader (r = 0.541, p = 0.01) and the real-time PCR method (r = 0.834, p = 0.01). When the PCR-Invader method was used as a reference, the sensitivity and specificity of the AA-DEPIM method were 76.5% and 100%, respectively. The results suggested that the AA-DEPIM method has potential to be used for clinically evaluating salivary presence of T. forsythia at chair-side. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000012181. PMID- 25812477 TI - Metagenomics for the discovery of novel biosurfactants of environmental interest from marine ecosystems. AB - Research focused on the search for new biosurfactants aims to replace chemical surfactants, which while being cost-effective are ecologically undesirable. Metagenomics can lead to discovery of novel biosurfactants, tackling issues of low production yields. Recent successes include the heterologous production of biosurfactants. The dearth of biosurfactants discovered to date through metagenomics is puzzling given that good screening systems and heterologous host systems are available. PMID- 25812478 TI - Yeast toxicogenomics: lessons from a eukaryotic cell model and cell factory. AB - The yeast Saccharomyces cerevisiae remains a highly relevant experimental model in the field of toxicogenomics and is an important microbial cell factory for the production of added-value chemicals and biofuels. Its deep functional characterization coupled with the straightforward exploitation of Omic approaches and metabolic engineering, at the frontline of systems and synthetic biology, is instrumental to obtain mechanistic insights into the response to multiple toxicants and for the development of robust industrial strains. This critical review focuses on the current field, ranging from the identification of toxicological outcomes of exposure to environmental toxicants, with impact in risk assessment, bioremediation and plant biotechnology, to the improvement of biomass-based biorefinery processes, with applications in pharmacology and in the food and beverages industry. PMID- 25812479 TI - Who's who in the crew? Exploring participant involvement in the Active Living Coalition. AB - Health coalitions serve as an important "vehicle" to strengthen horizontal and vertical ties between organizations, community groups, and individuals whose intent and purpose is to improve wellness. Having a strong and diverse group of participants is essential for highly effective coalitions to carry out their mission in an organized and participatory manner. However, the extent that individuals become involved in coalition operations and activities remains ambiguous. A grounded theory approach was used to explore expressions of participant involvement of a local health coalition known as the Active Living Coalition (ALC). Open, axial, as well as domain and taxonomic coding were used to analyze transcripts from four focus groups (n = 37 participants) in order to develop a participant continuum that captured six network aggregates within the coalition. Findings suggest that participation, for the most part, was heterogeneous and ever-changing given the expectations of the level of partnership that best individuals' personal and professional interests. Differentiating the type of participants in health coalitions can help coalition leaders more successfully "manage" new and existing relationships. Findings imply that health coalitions can maximize coalition capacity by drawing upon the full range of potential human and material resources by further understanding the types of individuals that make up their network. PMID- 25812480 TI - Role of nociceptin/orphanin FQ in thermoregulation. AB - Nociceptin/Orphanin FQ (N/OFQ) is a 17-amino acid peptide that binds to the nociceptin receptor (NOP). N/OFQ and NOP receptors are expressed in numerous brain areas. The generation of specific agonists, antagonists and receptor deficient mice or rats has enabled progress in elucidating the biological functions of N/OFQ. These tools have been employed to identify the biological significance of the N/OFQ system and how it interacts with other endogenous systems to regulate several body functions. The present review focuses on the role of N/OFQ in the regulation of body temperature and its relationship with energy balance. Critical evaluation of the literature data suggests that N/OFQ, acting through the NOP receptor, may cause hypothermia by influencing the complex thermoregulatory system that operates as a federation of independent thermoeffector loops to control body temperature at the hypothalamic level. Furthermore, N/OFQ counteracts hyperthermia elicited by cannabinoids or u-opioid agonists. N/OFQ-induced hypothermia is prevented by omega-conotoxin GVIA, an N type calcium channel blocker. Hypothermia induced by N/OFQ is considered within the framework of the complex action that this neuropeptide exerts on energy balance. Energy stores are regulated through the complex neural controls exerted on both food intake and energy expenditure. In laboratory rodents, N/OFQ stimulates consummatory behavior and decreases energy expenditure. Taken together, these studies support the idea that N/OFQ contributes to the regulation of energy balance by acting as an "anabolic" neuropeptide as it elicits effects similar to those produced in the hypothalamus by other neuropeptides such as orexins and neuropeptide Y. PMID- 25812481 TI - Synthesis and evaluation of 1,2-trans alkyl galactofuranoside mimetics as mycobacteriostatic agents. AB - The simple octyl beta-D-galactofuranoside was previously described as a good bacteriostatic agent against Mycobacterium smegmatis, a non-pathogenic model of M. tuberculosis. In order to decipher its mechanism of action, STD NMR on whole M. smegmatis cells was implemented. It outlined the crucial role of the alkyl chain and the possibility of modulation on the furanosyl entity. Then, 16 new alkyl furanosides were synthesized in order to optimize the mycobacteriostatic activity. They all present the pending alkyl chain in a 1,2-trans configuration relative to the sugar ring. Three families were studied that differ by a substituent on the primary position of the galactofuranose ring, the series or the pending alkyl chain. Four of these neofuranosides showed growth inhibition inferior to the parent octyl beta-D-galactofuranoside. Double alkyl chains at C-1 and a polar substituent on the primary position of the furanoside significantly favored the activity. Finally, a mixed biantennary alkyl/aryl beta-D galactofuranoside exhibited the best growth inhibition concentration at 90 MUM. PMID- 25812483 TI - TELEmedicine for Patients with Inflammatory Bowel Disease (TELE-IBD): Design and implementation of randomized clinical trial. AB - BACKGROUND: Inflammatory bowel diseases (IBD), comprised of ulcerative colitis and Crohn's disease, are chronic disorders characterized by worsening of symptoms followed by symptom-free periods. Symptoms have a profound negative impact on quality of life and are associated with increased health care utilization. Despite effective treatments, outcomes are suboptimal secondary to nonadherence, medication intolerance, inconsistent monitoring, poor patient knowledge and limited access to care. OBJECTIVES: Compare disease activity and quality of life over 1 year in a randomized trial of IBD patients receiving standard care versus telemedicine. METHODS: Patients evaluated at 3 IBD referral centers with worsening symptoms within the last 2 years are eligible for randomization to one of two interventions or standard care. The interventions consist of either every other week or weekly assessment of symptoms, side effects, weight and delivery of medication prompts and education via texts to the participant's mobile phone. Individualized alerts and action plans are created on a secure portal. Participants in the standard care group undergo routine and urgent follow-up visits and telephone calls. The primary outcomes group comparisons of changes in disease activity and quality of life scores from baseline to 6 and 12 months. CONCLUSIONS: Methods such as telemedicine are needed to improve monitoring, adherence, self-efficacy, and patient knowledge in IBD. If effective, telemedicine should decrease symptoms, improve quality of life, and decrease health care utilization. The burden associated with use of telemedicine for patients and providers needs to be assessed. The trial is ongoing and will be completed in July 2016. PMID- 25812482 TI - The macular degeneration and aging study: Design and research protocol of a randomized trial for a psychosocial intervention with macular degeneration patients. AB - BACKGROUND: Age-related Macular Degeneration (AMD) is the leading cause of irreversible and predictable blindness among older adults with serious physical and mental health consequences. Visual impairment is associated with negative future outlook and depression and has serious consequences for older adults' quality of life and, by way of depression, on long-term survival. Psychosocial interventions have the potential to alleviate and prevent depression symptoms among older AMD patients. METHODS: We describe the protocol of the Macular Degeneration and Aging Study, a randomized clinical trial of a psychosocial Preventive Problem-Solving Intervention. The intervention is aimed at enhancing well-being and future planning among older adults with macular degeneration by increasing preparation for future care. RESULTS: Adequate randomization and therapeutic fidelity were achieved. Current retention rates were acceptable, given the vulnerability of the population. Acceptability (adherence and satisfaction) was high. CONCLUSION: Given the high public health significance and impact on quality of life among older adults with vision loss, this protocol contributes a valid test of a promising intervention for maintaining mental and physical health in this population. PMID- 25812484 TI - Resveratrol analogue (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline induces G2/M cell cycle arrest through the activation of ATM/ATR in human cervical carcinoma HeLa cells. AB - Styrylquinazolines are synthetic analogues of resveratrol and have been suggested to cause anti-inflammatory activity by modulating prostaglandin E2 (PGE2) production. In the present study, we evaluated cytotoxic effects of various styrylquinazoline derivatives and found that (E)-8-acetoxy-2-[2-(3,4 diacetoxyphenyl)ethenyl]-quinazoline (8-ADEQ) most potently inhibited the proliferation of the human cervical carcinoma HeLa cells. Exploring the growth inhibitory mechanisms of 8-ADEQ, we found that it causes a cell cycle arrest at the G2/M phase by DNA flow cytometric analysis, which was accompanied by upregulation of cyclin B1 expression and cyclin-dependent protein kinase 1 (Cdk1) phosphorylation. In addition, we observed that 8-ADEQ causes phosphorylation of the cell division cycle 25C (Cdc25C) protein through the activation of checkpoint kinases 1 (Chk1) and Chk2, which in turn were activated via ataxia telangiectasia mutated (ATM)/ataxia telangiectasia-Rad3-related (ATR) kinases in response to the DNA damage. Furthermore, ATM/ATR inhibitor caffeine, p53- or ATM/ATR-specific siRNA significantly attenuated 8-ADEQ-induced G2/M arrest. These results suggest that the 8-ADEQ inhibits the proliferation of human cervical cancer HeLa cells by DNA damage-mediated G2/M cell cycle arrest. 8-ADEQ-induced G2/M arrest is mediated by the activation of both Chk1/2-Cdc25 and p53-p21CIP1/WAF1 via ATM/ATR pathway, and indicates that 8-ADEQ appears to have potential in the treatment of cervical cancer. PMID- 25812486 TI - Correction of hypovolemia with crystalloid fluids: Individualizing infusion therapy. AB - Many situations in clinical practice involving patients with hypovolemia or acutely ill patients usually require the administration of intravenous fluids. Current evidence shows that the use of crystalloids should be considered, since most colloids and human albumin are usually associated with increased adverse effects and high cost, respectively. Among crystalloids, the use of normal saline is implicated with the development of hyperchloremic metabolic acidosis and renal vasoconstriction. These observations have led many authors to propose balanced solutions, mainly Lactated Ringer's, as the infusate of choice. However, although the restoration of volume status is the primary target in hypovolemic state, the correction of any associated acid-base or electrolyte disorders that frequently coexist is also of vital importance. This review presents specific situations that are common in daily clinical practice and require targeted infusate therapy in patients with reduced volume status. Furthermore, the review presents an algorithm aiming to help clinicians to make the best choice between normal or hypotonic saline and lactated Ringer's infusates. Lactated Ringer's infusate should not be given in patients with severe metabolic alkalosis, lactic acidosis with decreased lactate clearance, or severe hyperkalemia, and in patients with traumatic brain injury or at risk of increased intracranial pressure. The optimal choice of infusate should be guided by the cause of hypovolemia, the cardiovascular state of the patient, the renal function, as well as the serum osmolality and the coexisting acid-base and electrolyte disorders. Clinicians should be aware of any coexisting disorders in patients with hypovolemia and guide their choice of infusate treatment based on the overall picture of their patients. PMID- 25812485 TI - On the tear resistance of skin. AB - Tear resistance is of vital importance in the various functions of skin, especially protection from predatorial attack. Here, we mechanistically quantify the extreme tear resistance of skin and identify the underlying structural features, which lead to its sophisticated failure mechanisms. We explain why it is virtually impossible to propagate a tear in rabbit skin, chosen as a model material for the dermis of vertebrates. We express the deformation in terms of four mechanisms of collagen fibril activity in skin under tensile loading that virtually eliminate the possibility of tearing in pre-notched samples: fibril straightening, fibril reorientation towards the tensile direction, elastic stretching and interfibrillar sliding, all of which contribute to the redistribution of the stresses at the notch tip. PMID- 25812487 TI - History of hadron therapy accelerators. AB - In the last 60 years, hadron therapy has made great advances passing from a stage of pure research to a well-established treatment modality for solid tumours. In this paper the history of hadron therapy accelerators is reviewed, starting from the first cyclotrons used in the thirties for neutron therapy and passing to more modern and flexible machines used nowadays. The technical developments have been accompanied by clinical studies that allowed the selection of the tumours which are more sensitive to this type of radiotherapy. This paper aims at giving a review of the origin and the present status of hadron therapy accelerators, describing the technological basis and the continuous development of this application to medicine of instruments developed for fundamental science. At the end the present challenges are reviewed. PMID- 25812488 TI - How to monitor the brain in septic patients? AB - Brain injury is frequently observed after sepsis and may be primarily related to the direct effects of the septic insult on the brain (e.g., brain edema, ischemia, seizures) or to secondary/indirect injuries (e.g., hypotension, hypoxemia, hypocapnia, hyperglycemia). Management of brain injury in septic patients is first focused to exclude structural intracranial complications (e.g., ischemic/hemorrhagic stroke) and possible confounders (e.g., electrolyte alterations or metabolic disorders, such as dysglycemia). Sepsis-associated brain dysfunction is frequently a heterogeneous syndrome. Despite increasing understanding of main pathophysiologic determinants, therapy is essentially limited to protect the brain against further cerebral damage, by way of "simple" therapeutic manipulations of cerebral perfusion and oxygenation and by avoiding over-sedation. Non-invasive monitoring of cerebral perfusion and oxygenation with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) is feasible in septic patients. Electroencephalography (EEG) allows detection of sepsis-related seizures and holds promise also as sedation monitoring. Brain CT-scan detects intra-cerebral structural lesions, while magnetic resonance imaging (MRI) provides important insights into primary mechanisms of sepsis-related direct brain injury, (e.g., cytotoxic vs. vasogenic edema) and the development of posterior reversible encephalopathy. Together with EEG and evoked potentials (EP), MRI is also important for coma prognostication. Emerging clinical evidence suggests monitoring of the brain in septic patients can be implemented in the ICU. The objective of this review was to summarize recent clinical data about the role of brain monitoring - including TCD, NIRS, EEG, EP, CT, and MRI - in patients with sepsis and to illustrate its potential utility for the diagnosis, management and prognostication. PMID- 25812490 TI - Sound Heart: Spiritual Nursing Care Model from Religious Viewpoint. AB - Different methods of epistemology create different philosophical views. None of the nursing theories have employed the revelational epistemology and the philosophical views of Abrahamic religions. According to Abrahamic religions, the universe and human being have been created based on God's affection. Human being should deserve the position of God's representative on earth after achieving all ethical merits. Humans have willpower to shape their destiny by choosing manner of their relationship with God, people, themselves and the whole universe. They can adopt the right behavior by giving a divine color to their thoughts and intentions and thus attain peace and serenity in their heart. Health means having a sound heart (calm spirit with a sense of hope and love, security and happiness) that is achievable through faith and piety. Moral vices lead to diseases. Human beings are able to purge their inside (heart) through establishing a relationship with God and then take actions to reform the outside world. The worlds are run by God's will based on prudence and mercy. All events happen with God's authorization, and human beings have to respond to them. Nurses should try to recognize the patient's spiritual response to illness that can appear as symptoms of an unsound heart (fear, sadness, disappointment, anger, jealousy, cruelty, grudge, suspicion, etc.) due to the pains caused by illness and then alleviate the patient's suffering by appropriate approaches. Nurses help the patient to achieve the sound heart by hope in divine mercy and love, and they help the patient see good in any evil and relieve their fear and sadness by viewing their illness positively and then attain the status of calm, satisfaction, peace and serenity in their heart and being content with the divine fate. By invitation to religious morality, the model leads the patients to spiritual health. PMID- 25812489 TI - Immunosuppressive therapies after heart transplantation--The balance between under- and over-immunosuppression. AB - Since the first heart transplantation (HT) in 1967, survival has steadily improved. Issues related to over- and under-immunosuppression are, however, still common following HT. Whereas under-immunosuppression may result in rejection, over-immunosuppression may render other medical problems, including infections, malignancies and chronic kidney disease (CKD). As such complications constitute major limiting factors for long-term survival following HT, identifying improved diagnostic and preventive methods has been the focus of many studies. Notably, research on antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) has recently led to the development of nomenclatures that may aid in their diagnosis and treatment. Moreover, novel immunosuppressants (such as mammalian target of rapamycin [m-TOR] inhibitors) and strategies aimed at minimizing the use of calcineurin inhibitors (CNIs) and corticosteroids (CSs), have provided alternatives to the traditional combination maintenance immunosuppressive therapy of CSs, cyclosporine (CSA) or tacrolimus (TAC), and azathioprine (AZA) or mycophenolate mofetil (MMF). Research within this field of medicine is not only extensive, but also in constant progress. The purpose of the present review was therefore to summarize some major points regarding immunosuppressive therapies after HT and the balance between under- and over-immunosuppression. Transplant immunology, rejection, common medical problems related to over-immunosuppression, as well as induction and maintenance immunosuppressive drugs and therapies, are addressed. PMID- 25812491 TI - Do Self-efficacy Expectation and Spirituality Provide a Buffer Against Stress Associated Impairment of Health? A Comprehensive Analysis of the German Pastoral Ministry Study. AB - We aimed to analyse stress perception, psychosomatic health and life satisfaction in pastoral professionals, paying particular attention to their individual and shared resources. Enrolling 8574 German pastoral professionals (48% priests, 22% parish expert workers, 18% pastoral assistants, 12% deacons), we found that pastoral professionals' stress perception is associated with psychosomatic health impairment. General self-efficacy was a beneficial resource to protect against stress perceptions, while perception of the transcendent had a further yet weakly positive influence for stress-related impairment of health. External stressors (i.e. team size, duration of work per week and size of pastoral unit) were only of marginal independent relevance. PMID- 25812492 TI - [Recent advances in MR imaging for cancer diagnosis]. AB - The recent development in magnetic resonance(MR)hardware and techniques allows the acquisition of functional information, such as perfusion or metabolism, in addition to conventional anatomical information in of cancers.In this review article, various molecular imaging methods based on MR are introduced and their application and usefulness for diagnosis of cancer are discussed.Diffusion weighted image (DWI) is believed to correlate cell density and reflect malignancy of tumor. DWI has been widely used for the diagnosis and evaluation of responses to cancer treatment.Arterial spin labeling (ASL) allows acquisition of perfusion data without the use of any contrast agent and is expected to be an alternative or complementary method to dynamic contrast enhanced MR imaging.Amide proton transfer (APT) imaging reflects the amount of mobile peptide and proteins in cancer tissue, and could be a useful tool for assessing tumor malignancy or evaluating treatment responses.More specific measurement of cancer metabolites is available at the cost of spatial resolution by MR spectroscopy (MRS). Finally, the positron emission tomography (PET)/MR hybrid system enables simultaneous acquisition of functional/ anatomical information from MR imaging and molecular/metabolic information from PET imaging.Combining various molecular MR imaging methods with PET tracers may have a huge potential for clinical diagnosis of cancer. PMID- 25812493 TI - [Fertility preservation in patients with hematological malignancies]. AB - Antineoplastic chemotherapy and irradiation affect gonadal function and may lead to infertility. Recovery of gonadal function is frequently observed after conventional chemotherapy in young patients with hematological malignancies, but conditioning regimens before hematopoietic stem cell transplantation result in permanent gonadal failure. Cryopreservation of sperm is effective for male patients, but it becomes difficult even after a single cycle of chemotherapy and therefore should be accomplished before starting chemotherapy. Embryo freezing after in vitro fertilization of harvested oocytes is an established method to preserve fertility in female patients. In addition, harvesting and freezing of unfertilized oocytes is also being evaluated in a clinical study. However, collection of good oocytes after chemotherapy is difficult. In addition, oocyte harvesting is an invasive procedure and may be associated with hemorrhage or infectious complications. Ovarian shielding during total body irradiation allows ovary preservation in most female patients, but this cannot be performed in patients with active malignancies. Strategies for gonadal function preservation should be planned before starting treatment for hematological malignancies. PMID- 25812494 TI - [Fertility in testicular cancer patients]. AB - Testicular cancer(TC)is the most common and curable cancer affecting men of reproductive age. Successful treatment approaches have resulted in longer life expectancy in TC survivors. The most frequently used treatment for TC is a combination of inguinal orchiectomy, and either radiotherapy or cisplatin-based chemotherapy. In many TC patients, sperm quality is already abnormal and there may even be a lack of viable spermatozoa at the time of diagnosis. Therefore, the effect of cancer treatment on fertility is a potentially significant issue. Fertility preservation in these men has become essential and needs to be discussed prior to the start of cancer treatment. The only currently established fertility preservation method is the cryopreservation of sperm before therapy. For most patients seeking cryopreservation, the semen sample is collected via masturbation. If the patient is unable to ejaculate for any reason, other techniques such as vibratory stimulation and electroejaculation can be performed. In azoospermic or severely oligozoospermic patients, testicular sperm extraction at the time of the inguinal orchiectomy is a useful technique for obtaining spermatozoa before cytotoxic therapy. We herein present an overview of the current topics on fertility in TC patients, including the effects of surgery, chemotherapy, and radiation therapy. We also describe the strategy for fertility preservation in these patients. PMID- 25812495 TI - [Moving forward to overcome infertility after breast cancer treatment]. AB - An increase in the number of young women with breast cancer together with improved outcomes after breast cancer treatments have lead healthcare providers and society in general to become more aware of fertility preservation. The potential for infertility caused by cancer treatment is one of the most important quality-of-life issues for young women with cancer, and guidelines and decision aids to support those who wish to have children after cancer treatment have been developed. To move forward, a prospective database needs to be developed in order to overcome safety concerns, and to allow network building among breast oncologists and reproductive specialists. A multidisciplinary team is also urgently needed to address psychosocial and ethical issues. PMID- 25812496 TI - [Fertility-sparing treatment for gynecologic cancer]. AB - Japanese women bear children at a later age. Thus, fertility-sparing treatment for gynecologic cancer is very important. Per the Japanese treatment guidelines for cervical cancer, the uterus can be preserved by performing cervical conization alone in patients with stage I A1 disease. Radical trachelectomy (RT) is not yet recommended for patients with stage I A2 or I B 1 disease in Japan. Further, RT will not be popular in Japan because cervical cancer can be prevented with HPV vaccine. The efficacy of fertility-sparing treatment with a high-dose of medroxyprogesterone acetate for grade 1 endometrial cancer was proven in a Japan clinical oncology group (JCOG) phase II study. Japanese multi-institutional retrospective investigation data confirm that fertility-sparing surgery is safe for patients with stage I A disease with non-clear cell histology grade 1 or 2. These data suggest that patients with stage I A disease with clear cell histology and those with stage I C disease with non-clear cell histology grade 1 or 2 can be candidates for fertility sparing surgery followed by adjuvant chemotherapy. PMID- 25812497 TI - [Fertility problems in oncofertility treatment -- including ASCO guidelines]. AB - Owing to the progress in early detection and multidisciplinary treatment of cancer, the interest in better quality of life (QOL) among young cancer patients has increased in recent years. Previously, the top priority of these patients was cancer treatment; therefore, little focus was placed on various complications of cancer treatment. Consequently, some patients were forced to accept the prospect of fertility loss and not being able to bear children after cancer treatment. Young cancer patients face both the risk to their lives due to cancer and the risk of fertility loss, and the practice of fertility preservation with accurate information available at the appropriate time may become a great source of hope for these patients. However, whether this precise information relating to fertility is adequately provided to patients before cancer treatment is not known. Health care providers should have accurate knowledge of such issues and offer the best oncofertility treatment to young cancer patients. It is also necessary to emphasize to these patients that cancer treatment is the top priority, as well as to convey the limits of reproductive medicine, such as the fact that infertility treatment may have to be postponed or terminated because of the underlying disease situation. PMID- 25812498 TI - [The survey for anti-emetic guideline by using questioner]. AB - BACKGROUND: Japan Society of Clinical Oncology published a guideline for anti emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire. MATERIAL: Questionnaire analysis; From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff for the anti emetic guideline published by (JSCO). RESULTS: Questionnaire; 1,529 medical stuff responded to our questionnaire. 1,308 (85.5%) stuffs recognized JSCO guidelines, 586 (51%) had regard for guideline and 489 (42.6%) referred to the guideline. 899 (78.3%) changed their practice in clinic to recommended practice by the guideline. But 385 (33.5%) complained high medical cost of recommended anti emetic therapy. CONCLUSIONS: Degree of recognition and penetration of our guideline for anti-emetic therapy were very high in Japan. PMID- 25812499 TI - [A three-week regimen of S-1 monotherapy reduced gastrointestinal toxicity and maintained efficacy in patients with gemcitabine-refractory advanced pancreatic cancer]. AB - S-1 administration for 28 consecutive days followed by 14 days of rest (6-week cycle) is often chosen as second-line chemotherapy for advanced pancreatic cancer (PC), but it causes gastrointestinal toxicity. In comparison, in gastric cancer or head and neck cancer, S-1 administration for 14 consecutive days followed by a 7-day rest period (3-week cycle) reduced gastrointestinal toxicity. This study retrospectively evaluated the efficacy and safety of a 3-week S-1 schedule compared to a 6-week schedule in patients with gemcitabine (GEM)-refractory advanced PC. Fifty-seven patients were treated with the 6- week S-1 schedule and 68 patients were treated with the 3-week S-1 schedule. There were no statistical differences in overall survival (p=0.13) and progression-free survival (p=0.190). With regard to adverse events, the rates of nausea (p<0.01) and vomiting (p=0.04) were lower with the 3-week schedule than with the 6-week schedule. Thus, S-1 therapy with a 3- week schedule as second-line chemotherapy in patients with GEM refractory advanced PC was associated with reduced gastrointestinal toxicity and similar efficacy, when compared to a 6-week schedule. PMID- 25812500 TI - [The present status of CapeOX as adjuvant chemotherapy for colorectal cancer]. AB - We report on treatment with capecitabine plus oxaliplatin (CapeOX) as adjuvant therapy for patients with colorectal cancer. Twenty patients were treated. The mean age was 69 years; 15 patients were male and 5 were female. Thirteen patients with colon cancer and 7 patients with rectal cancer were enrolled after curative surgery. In total, 55% of patients completed the planned number of treatment cycles. Dose modifications were required for oxaliplatin in 60% of patients and for capecitabine in 67% of patients. The median relative dose intensities of oxaliplatin and capecitabine were 86% and 88%, respectively. Treatment-related Grade 3/4 neutropenia and Grade 3/4 thrombocytopenia were documented in 2 and 3 patients, respectively. Grade 3/4 hand-foot syndrome occurred in 1 patient. Treatment with CapeOX as adjuvant therapy for patients with colorectal cancer seems to be safe. PMID- 25812501 TI - [Methods of preventing phlebitis induced by infusion of fosaprepitant]. AB - At our hospital, we use aprepitant for nausea and vomiting when administering highly emetic anticancer agents, according to "Guidelines for the Appropriate Use of Antiemetic Agents" given by the Japan Society of Clinical Oncology. We initiated the intravenous administration of fosaprepitant for better compliance compared with aprepitant; however, we observed phlebitis after the infusion of fosaprepitant. Therefore, we investigated measures to reduce phlebitis associated with the infusion of fosaprepitant. For the first premedication, fosaprepitant (150 mg) was dissolved in 100 mL of saline and administered for 30 minutes; 1 of 2 patients showed grade 4 phlebitis. For the modified premedication, fosaprepitant, dexamethasone, and 5- HT(3) antagonist were dissolved in 100 mL of saline and administered for 30 minutes. The modified premedication was administered to a total of 27 patients; 5 patients developed mild phlebitis (grade 1), but infusion could be continued by treating their phlebitis with a hot pack. We used a combination of dexamethasone and 5-HT(3) antagonist with fosaprepitant as a modified premedication in order to avoid drug-induced vascular damage, which resulted in the pH decreasing to 6.20-7.55 (close to neutral) and a shorter infusion time. PMID- 25812502 TI - [Talking about home hospices with terminally ill cancer patients -- a multicenter survey of bereaved families]. AB - INTRODUCTION: Communicating with patients is clearly an integral part of physicians' practice, and introducing home hospice care is sometimes a difficult task for oncologists. The primary aims of this study were to clarify family reported degree of emotional distress and the necessity for improvement in communication when introducing home hospice care, and to identify factors contributing to distress levels. METHODS: A multicenter questionnaire survey was conducted involving 1,052 family members of cancer patients who died at home at 15 home-based hospice services throughout Japan. RESULTS: A total of 616 responses were analyzed(effective response rate of 60%). Fifty-nine percent of the bereaved family members reported that they were distressed or very distressed in receiving information about home hospice care, and 30% reported considerable or much improvement was necessary. There were 6 determinants of family-reported degree of emotional distress and the necessity for improvement: 1 ) Family distress was experienced when the physician stated that the disease progression defeated medicine and nothing could be done for the patient. 2 ) The physicians' explanation did not match with the state of family preparation. 3 ) There was no intimacy between hospital physician and home physician. 4 ) Physicians did not make the atmosphere relaxing enough to allow families to ask questions. 5 ) Nurses did not follow up to generate additional ideas to supplement the physician's statement. 6 ) Family members experienced pressure to make a rash decision. CONCLUSION: In receiving information about transition of home care, a considerable number of families experienced high levels of emotional distress and felt a need for improvement in the communication style. This study proposes 6 strategies to alleviate family distress. PMID- 25812503 TI - [Emetogenic potential of antineoplastic agents based on clinical trials in Japan]. AB - Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and distressing side effects of chemotherapy that decreases patients' quality of life and motivation for treatment. Therefore, prevention and treatment of CINV are essential for motivating patients to continue chemotherapy. International societies such as American Society of Clinical Oncology (ASCO), Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) have published guidelines for using antiemetics, and these guidelines were published in Japan in May 2010. However, both the Japananese and international guidelines do not provide sufficient clinical trial-based evidence for antiemetic use in the Japanese population. In this study, we attempted to evaluate and clarify the frequency of CINV in clinical trials in Japan. We found that thet guidelines specify different emetogenic potentials of some antineoplastic agents such as gemcitabine. Therefore, we believe that it is necessary to reevaluate the emetogenic risk of such antineoplastic agents and to develop a practical and standard antiemetic therapy so that in the future, patients do not hesitate to undergo chemotherapy because of side effects. PMID- 25812505 TI - [A case of stage IV breast cancer with improved cancer pain using bevacizumab and paclitaxel]. AB - A 65-year-old woman with a right breast tumor and right arm pain was seen in our hospital. She was diagnosed with scirrhous carcinoma (Stage IV, hormone receptor positive, and HER2-negative) with pleural effusion and metastasis to the lung, liver, bone, and multiple lymph nodes. Systemic chemotherapy with biweekly bevacizumab and weekly paclitaxel was administered, and an opioid (oxycodone 40 mg/day) was administered for pain control. At the end of the first course, the patient's pain was improved, and the opioid dose was reduced (oxycodone 20 mg/day). The patient had a partial response (PR) over 24 treatment courses (1 year 10 months), and good pain control was obtained. Bevacizumab and paclitaxel therapy successfully brought about a rapid and good response and improved the patient's quality of life as palliative chemo- therapy. PMID- 25812504 TI - [A case of stage IV breast cancer with long-term partial response treated with tri-weekly paclitaxel plus bevacizumab]. AB - Paclitaxel combined with bevacizumab yields significantly better progression-free survival (PFS) in patients with metastatic breast cancer than paclitaxel alone. Here, we report a case of stage IV breast cancer with multiple liver, lung, and bone metastases maintaining a long-term partial response (PR) with tri-weekly paclitaxel plus bevacizumab administration. A 46- year-old woman treated with endocrine therapy for 21 months for multiple metastases in her lungs and bones detected 4 years after surgery for left breast cancer was referred to our hospital. New metastases were discovered in her liver. She received paclitaxel (l 90 mg/m/(2)) on days 1, 8, and 15 combined with bevacizumab (10 mg/kg) on days 1 and 15 every 4 weeks. However, during the first 3 courses, the administration of paclitaxel on day 8 was postponed to 1 to 2 weeks because of severe neutropenia. We began tri-weekly administration of paclitaxel plus bevacizumab. She continued receiving the treatment for about 1 year, without severe side effects. The PR state with good performance status was maintained. We suggest that the tri-weekly administration of paclitaxel plus bevacizumab is an effective way to maintain long-term efficacy. PMID- 25812506 TI - [A recurrent gastric cancer with peritoneal metastasis 15 years after distal gastrectomy successfully treated with S-1 and weekly intravenous and intraperitoneal injections of Paclitaxel]. AB - Fifteen years after receiving a distal gastrectomy for advanced gastric cancer, a 70-year-old woman was admitted to our hospital because of abdominal fullness due to ascites. Although cytological examination showed adenocarcinoma cells in the fluid, no examination revealed the primary lesion. Peritoneal metastasis was detected via immunohistochemistry using the cell block technique. After chemotherapy failure (S-1 plus CDDP, weekly PTX, and S-1 plus DOC), the patient received S-1 and weekly intravenous and intraperitoneal injections of PTX. The ascites decreased, and she has been doing well. Our experience with this case suggests that S-1 and weekly intravenous and intraperitoneal injections of PTX is a promising means of treating gastric cancer with peritoneal metastasis. PMID- 25812507 TI - [A case of highly advanced gastric cancer with peritoneal dissemination -- a histological CR to S-1 and CDDP combination chemotherapy]. AB - A 64-year-old man with type 3 advanced gastric cancer was referred to our hospital. Abdominal computed tomography (CT)showed thickening of the gastric wall and lymph node metastasis near the stomach, and laparoscopy revealed peritoneal dissemination. After 6 courses of CDDP therapy, lymph node metastasis was no longer detectable on CT scans. A second laparoscopy showed no peritoneal dissemination; therefore, distal partial gastrectomy with D2 lymph node dissection was performed. Histological examination showed no tumor cells in the gastric primary lesion, no metastatic lymph nodes, and no disseminated peritoneal nodules, suggesting pathological complete remission. PMID- 25812509 TI - [Case report of disseminated carcinomatosis of the bone marrow originating from gastric cancer with cancer-related disseminated intravascular coagulation successfully treated with recombinant human soluble thrombomodulin]. AB - A 62-year-old man, who underwent distal gastrectomy due to gastric cancer, was diagnosed with disseminated carcinomatosis of the bone marrow 8 years later. Chemotherapy was administered following treatment with recombinant human soluble thrombomodulin (rTM), and as a result, he successfully recovered from his disseminated intravascular coagulation (DIC) status and experienced improvement of his severe cancer-related pain. The use of rTM may enable the safe continuation of chemotherapy, and rTM may also be a useful treatment for DIC associated with solid cancer, such as gastric cancer. PMID- 25812508 TI - [A case of HER2-positive advanced gastric cancer successfully treated via capecitabine, cisplatin, and trastuzumab combination chemotherapy]. AB - We report a case of human epidermal growth factor receptor 2 (HER2) -positive advanced gastric cancer effectively treated via capecitabine, cisplatin, and trastuzumab (XPT) chemotherapy followed by curative gastrectomy. The patient was a 66- year-old man with type 2 gastric cancer in the greater curvature of the gastric angle. Biopsy revealed that the tumor was a well or moderately differentiated adenocarcinoma, and immunohistochemistry showed positive expression of HER2(3+). Chest and abdominal computed tomography(CT)showed a liver tumor 21*9 mm in size in the caudate lobe and swollen lymph nodes in the paragastric, para-aortic, and left supraclavicular regions. After 4 courses of XPT, a clinical complete response was obtained. The patient received additional 13 courses of trastuzumab and capecitabine and underwent Billroth I distal gastrectomy with D2 lymph node dissection and resection of the para-aortic and left supraclavicular lymph nodes. Liver metastasis was not detected. No residual cancer cells were found in the stomach or lymph nodes except for the left supraclavicular lymph nodes. Pathological classification according to the Japanese Classification of Gastric Carcinoma, 14 th edition, was ypT0, ypN0, ypM1(LYM), Grade 2, ypStage IV. The patient developed a post-operative anastomotic leakage that required drainage via laparotomy, but was discharged 76 days after surgery in good condition. PMID- 25812510 TI - [A case of ampullary carcinoma progression-free for four years after treatment with TS-1]. AB - A 63-year old man was referred to our hospital because of fever, appetite loss, and increased biliary enzyme levels. Upper gastrointestinal endoscopy revealed a tumor in the duodenal papilla, diagnosed as an adenocarcinoma via biopsy, and computed tomography (CT) revealed multiple tumors in the liver. Chemotherapy with TS-1 was initiated based on a diagnosis of ampullary cancer with multiple liver metastases. After TS-1 treatment, the multiple tumors were no longer detectable, and the primary tumor did not increase in size for 4 years. At this time, however, the patient experienced fever, jaundice, and appetite loss. The hepatic mass was not detected via CT or MRI. The primary tumor was determined to be resectable; therefore, we performed subtotal stomach preserving pancreatoduodenectomy. The patient was discharged 55 days after surgery and is alive without recurrence 2 years after surgery. PMID- 25812511 TI - [A rare case of lymphangitis carcinomatosa of the lung due to primary pulmonary adenocarcinoma with intestinal differentiation successfully treated with chemotherapy]. AB - We report a rare case of lymphangitis carcinomatosa in a 66-year-old man with a relatively long survival of 18 months following chemotherapy.The patient initially presented with dyspnea and lower abdominal pain.Subsequent colonoscopy detected adenocarcinoma of the descending colon, and computed tomography (CT) demonstrated indications of lymphangitis carcinomatosa of the lung.Therefore, the patient was diagnosed with pulmonary metastasis due to colon cancer and administered chemotherapy.The performance status (PS) of patients with lymphangitis carcinomatosa is usually dismal.This patient's PS was also poor, but dyspnea markedly improved following chemotherapy, and a subsequent CT revealed disappearance of radiological findings of lymphangitis carcinomatosa.However, subsequent immunocytochemistry analysis using the cell transfer method in bronchoalveolar lavage fluid specimens revealed diffuse positivity for cytokeratin (CK) 7, while the colon carcinoma was negative for CK7.The difference in CK7 immunoreactivity between the bronchoalveolar lavage fluid and biopsy specimen of the colon indicated that the lymphangitis carcinomatosa in this patient could be reasonably postulated to be caused by a synchronous primary pulmonary adenocarcinoma with intestinal differentiation.However, an autopsy could not be performed to test this hypothesis. PMID- 25812512 TI - [Safe treatment of lung squamous cell carcinoma with nanoparticle albumin-bound Paclitaxel in a patient with a previous hypersensitivity reaction after docetaxel administration]. AB - A 61-year-old man was diagnosed with lung squamous cell carcinoma in the lower lobe of the right lung. He had received first-line chemotherapy consisting of cisplatin and docetaxel (DTX); however, an allergic/hypersensitivity reaction occurred shortly after administration of the second course of DTX. Thirty-nine months later, he received nanoparticle albumin-bound paclitaxel (nab-PTX) as sixth-line chemotherapy, which did not produce a hypersensitivity reaction. Hypersensitivity after DTX administration may have been due to the DTX vehicle. Therefore, nab-PTX administered under close supervision is a valid therapeutic option in similar cases. PMID- 25812513 TI - [Three cases of long-term control of non-small-cell lung cancer via S-1 monotherapy in elderly patients]. AB - We report 3 cases of long-term control achieved via S-1 monotherapy in elderly patients with advanced non-small-cell lung cancer. In case 1, a 75-year-old man clinically diagnosed with stage IIIA lung adenocarcinoma received S-1 as fourthline chemotherapy. PR was achieved, and PFS was 8 months. In case 2, a 78 year-old woman clinically diagnosed with stage IV lung squamous cell carcinoma received S-1 as third-line chemotherapy. A PR was achieved, and PFS was 14 months. In case 3, an 83-year-old man clinically diagnosed with stage IV lung squamous cell carcinoma received CBDCA plus PTX, followed by S-1 on alternate days. Although tumor size was not reduced, SD was maintained for 11 months. PMID- 25812514 TI - Dynamic study of methionine positron emission tomography in patients with glioblastoma with oligodendroglial components. AB - Anaplastic oligoastrocytoma (AOA) with necrosis is classified as glioblastoma (GBM) with oligodendroglioma component (GBMO), according to the 2007 World Health Organization classification. The prognosis of GBMO remains controversial because definitive diagnostic criteria regarding the percentage of the oligodendroglial components (OC) in the GBM do not exist. We previously reported dynamic methionine (MET) positron emission tomography (PET) in patients with these tumors. A significant decrease in the MET signal was seen in oligodendrocytic tumors, in contrast to a significant MET increase in GBMs. In this study, we analyzed the dynamic MET PET signal in four patients with primary (n = 2) and secondary (n = 2) GBMOs. Static PET scanning was performed in three consecutive phases. Both cases of primary GBMOs and one case of secondary GBMO presented with a gradual decrease in MET PET signal over the consecutive phases. In contrast, the remaining case of secondary GBMO presented with a pattern of slight increase. It is likely that the dynamic change of MET in patients with GBMO resemble those in patients with oligodendroglial tumor, however, further studies are needed to confirm them. We discuss the mechanisms from a viewpoint of pathological findings. PMID- 25812515 TI - The Arabidopsis NPR1 gene confers broad-spectrum disease resistance in strawberry. AB - Although strawberry is an economically important fruit crop worldwide, production of strawberry is limited by its susceptibility to a wide range of pathogens and the lack of major commercial cultivars with high levels of resistance to multiple pathogens. The objective of this study is to ectopically express the Arabidopsis thaliana NPR1 gene (AtNPR1) in the diploid strawberry Fragaria vesca L. and to test transgenic plants for disease resistance. AtNPR1 is a key positive regulator of the long-lasting broad-spectrum resistance known as systemic acquired resistance (SAR) and has been shown to confer resistance to a number of pathogens when overexpressed in Arabidopsis or ectopically expressed in several crop species. We show that ectopic expression of AtNPR1 in strawberry increases resistance to anthracnose, powdery mildew, and angular leaf spot, which are caused by different fungal or bacterial pathogens. The increased resistance is related to the relative expression levels of AtNPR1 in the transgenic plants. In contrast to Arabidopsis plants overexpressing AtNPR1, which grow normally and do not constitutively express defense genes, the strawberry transgenic plants are shorter than non-transformed controls, and most of them fail to produce runners and fruits. Consistently, most of the transgenic lines constitutively express the defense gene FvPR5, suggesting that the SAR activation mechanisms in strawberry and Arabidopsis are different. Nevertheless, our results indicate that overexpression of AtNPR1 holds the potential for generation of broad-spectrum disease resistance in strawberry. PMID- 25812517 TI - Asymmetric Suzuki-Miyaura cross-coupling of 1-bromo-2-naphthoates using the helically chiral polymer ligand PQXphos. AB - A single-handed helical polymer ligand PQXphos afforded axially chiral biaryl esters with high enantioselectivities in asymmetric Suzuki-Miyaura cross coupling. The use of naphthyl bromide bearing a 2,4-dimethyl-3-pentyl ester resulted in both high yields and high enantioselectivities. Either enantiomer could be synthesized selectively by using a single PQXphos through a solvent dependent switch of the helical chirality. PMID- 25812516 TI - Screening pigs for xenotransplantation: expression of porcine endogenous retroviruses in transgenic pig skin. AB - Pigs seem to be the answer to worldwide organ donor shortage. Porcine skin may also be applied as a dressing for severe burns. Genetic modifications of donor animals enable reduction of immune response, which prolongs xenograft survival as temporary biological dressing and allows achieving resistance against xenograft rejection. The risk posed by porcine endogenous retroviruses (PERVs) cannot be eliminated by breeding animals under specific-pathogen-free conditions and so all recipients of porcine graft will be exposed to PERVs. Therefore our study has been focused on the assessment of PERV DNA and mRNA level in skin samples of transgenic pigs generated for xenotransplantation. Porcine skin fragments were obtained from 3- to 6-month-old non-transgenic and transgenic Polish Landrace pigs. Transgenic pigs were produced by pronuclear DNA microinjection and were developed to express the human alpha-galactosidase and the human alpha-1,2 fucosyltransferase gene. The copy numbers of PERV DNA and RNA were evaluated using real-time Q-PCR and QRT-PCR. Comparative analysis of all PERV subtypes revealed that PERV-A is the main subtype of PERVs in analyzed skin samples. There was no significantly different copy number of PERV-A, PERV-B and PERV-C between non-transgenic pigs, pigs with the human alpha-galactosidase and pigs expressing the human alpha-1,2-fucosyltransferase gene, except of PERV-C DNA. It brings the conclusion, that transgenesis process exerts no influence on PERVs transinfection. That is another step forward in the development of pig skin xenografts as burn wounds dressing. PMID- 25812519 TI - Two paths to fat. AB - Excess caloric intake leads to both the growth of existing fat cells and the generation of new adipocytes. New findings show that PI3K-Akt2 signalling is involved in the differentiation of adult adipose precursor cells-a pathway not required for adipogenesis in the embryo. PMID- 25812518 TI - Role of urgent contrast-enhanced multidetector computed tomography for acute lower gastrointestinal bleeding in patients undergoing early colonoscopy. AB - BACKGROUND: The clinical significance of performing computed tomography (CT) for acute lower gastrointestinal bleeding (LGIB) remains unknown. This study aimed to evaluate the role of urgent CT in acute LGIB settings. METHODS: The cohort comprised 223 patients emergently hospitalized for LGIB who underwent early colonoscopy within 24 h of arriving at the hospital, including 126 who underwent CT within 3 h of arrival. We compared the bleeding source rate between two strategies: early colonoscopy following urgent CT or early colonoscopy alone. RESULTS: No significant differences in age, sex, comorbidities, vital signs, or laboratory data were observed between the strategies. The detection rate was higher with colonoscopy following CT for vascular lesions (35.7 vs. 20.6%, p = 0.01), leading to more endoscopic therapies (34.9 vs. 13.4%, p < 0.01). Of the 126 who underwent colonoscopy following CT, 26 (20.6%) had extravasation and 34 (27.0%) had nonvascular findings. The sensitivity and specificity of CT extravasation and nonvascular findings for predicting vascular lesions and inflammation or tumors were 37.8 and 88.9 and 81.3 and 80.9%, respectively. A high kappa agreement (0.83, p < 0.01) for active bleeding locations was found between CT and subsequent colonoscopy. There were no cases of contrast-induced nephropathy after 1 week of CT. CONCLUSIONS: Urgent CT before colonoscopy had about 15% additional value for detecting vascular lesion compared to colonoscopy alone and thus enabled subsequent endoscopic therapies. Contrast-enhanced CT in acute LGIB settings was safe and correctly identified the presence and location of active bleeding, as well as severe inflammation or tumor stenosis, facilitating decision making. PMID- 25812520 TI - Energy stress tames the Hippo pathway. AB - The kinase AMPK, a sensor of cellular energy stress, has been shown to oppose the growth-promoting activity of YAP, the transcriptional co-activator downstream of the Hippo signalling pathway. This finding may help to explain why the antidiabetic drug metformin, for which AMPK is a key effector, is linked to cancer-protective activity. PMID- 25812523 TI - Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels. PMID- 25812524 TI - Kinetochore-microtubule error correction is driven by differentially regulated interaction modes. PMID- 25812521 TI - Myosin-II-mediated cell shape changes and cell intercalation contribute to primitive streak formation. AB - Primitive streak formation in the chick embryo involves large-scale highly coordinated flows of more than 100,000 cells in the epiblast. These large-scale tissue flows and deformations can be correlated with specific anisotropic cell behaviours in the forming mesendoderm through a combination of light-sheet microscopy and computational analysis. Relevant behaviours include apical contraction, elongation along the apical-basal axis followed by ingression, and asynchronous directional cell intercalation of small groups of mesendoderm cells. Cell intercalation is associated with sequential, directional contraction of apical junctions, the onset, localization and direction of which correlate strongly with the appearance of active myosin II cables in aligned apical junctions in neighbouring cells. Use of class specific myosin inhibitors and gene specific knockdown shows that apical contraction and intercalation are myosin II dependent and also reveal critical roles for myosin I and myosin V family members in the assembly of junctional myosin II cables. PMID- 25812522 TI - Control of cell-cell forces and collective cell dynamics by the intercellular adhesome. AB - Dynamics of epithelial tissues determine key processes in development, tissue healing and cancer invasion. These processes are critically influenced by cell cell adhesion forces. However, the identity of the proteins that resist and transmit forces at cell-cell junctions remains unclear, and how these proteins control tissue dynamics is largely unknown. Here we provide a systematic study of the interplay between cell-cell adhesion proteins, intercellular forces and epithelial tissue dynamics. We show that collective cellular responses to selective perturbations of the intercellular adhesome conform to three mechanical phenotypes. These phenotypes are controlled by different molecular modules and characterized by distinct relationships between cellular kinematics and intercellular forces. We show that these forces and their rates can be predicted by the concentrations of cadherins and catenins. Unexpectedly, we identified different mechanical roles for P-cadherin and E-cadherin; whereas P-cadherin predicts levels of intercellular force, E-cadherin predicts the rate at which intercellular force builds up. PMID- 25812525 TI - Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation. PMID- 25812526 TI - RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2 mediated phosphorylation of BRCA2. PMID- 25812527 TI - Ascl1a regulates Muller glia dedifferentiation and retinal regeneration through a Lin-28-dependent, let-7 microRNA signalling pathway. PMID- 25812528 TI - Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. PMID- 25812529 TI - Multicenter Randomized Study of Obesity Treatment with Minimally Invasive Injection of Hyaluronic Acid Versus and Combined with Intragastric Balloon. AB - BACKGROUND: Research into minimally invasive techniques is worthwhile for greater acceptance in bariatric surgery, a useful first step being to evaluate the combination of these with current procedures. We suggest that intragastric balloon (IGB) can be performed with hyaluronic acid (HA) injections at the level of the gastroesophageal junction. METHODS: A submucosal restriction is created by circular injection of an absorbable material within a defined area based on endoscopic anatomy. We included 101 patients in a prospective multicenter randomized trial, with average body mass index (BMI) 33.4 (range 27-44), treated from April 2010 to April 2012 by IGB and/or HA injection, sequentially, and followed for two more years. Patients were divided into group 1 (IGB alone), group 2 (IGB followed by HA at IGB removal, at 6 months), and group 3 (HA and IGB at 6 months). RESULTS: BMI loss at 6 months was inferior in the HA group (32 patients) compared with the IGB groups (68 patients) (2.1 +/- 0.4 versus 3.4 +/- 0.3, p < 0.05). The efficacy of IGB alone compared with combined treatments (groups 2 and 3) was significantly inferior at 18 months only, but the impact of the treatment sequence (HA before or after IGB) on BMI loss was not statistically significant, although in favor of HA first. CONCLUSIONS: This study did not demonstrate the efficacy of HA injections as an obesity treatment. PMID- 25812530 TI - Perception of control over eating after bariatric surgery for super-obesity--a 2 year follow-up study. AB - BACKGROUND: Physiological and psychosocial factors might contribute to differences in weight loss, eating behaviour and health-related quality of life (HRQoL) after bariatric surgery. The aim of this study was to investigate how perceived control over eating changes after bariatric surgery and whether it affects outcome in super-obese patients. METHODS: In a retrospective analysis of a prospective study (n = 60), 49 patients were divided into two groups based on eating control 2 years after surgery, as assessed by the Three-Factor Eating Questionnaire-R21 (TFEQ-R21): 29 with good eating control (GC) and 20 patients with poor eating control (group PC). Eating behaviour and generic and condition specific HRQoL was assessed by questionnaires. RESULTS: There were significant differences in all TFEQ-R21 domains 2 years after surgery in favour of group GC; uncontrolled eating p < 0.001, emotional eating p < 0.001 and for cognitive restraint p = 0.04. The improvement in HRQoL 2 years after surgery was significantly less in group PC compared to group GC in 7 of 8 SF-36 domains (p < 0.05). Mean (SD) percentage of excess body mass index lost was similar between groups, 71.2 (17.8) in group GC versus 65.4 (17.4) in group PC 2 years after surgery (p = 0.27). However, group GC had a significant weight loss between first and second year after surgery (p < 0.001) compared to group PC (p = 0.15). CONCLUSIONS: In super-obese patients, perceived poor control over eating 2 years after bariatric surgery was associated with lower HRQoL and more emotional and cognitive restraint eating, than good control overeating. PMID- 25812531 TI - A Prospective Study to Evaluate Intravitreous Ranibizumab as Adjunctive Treatment for Trabeculectomy in Neovascular Glaucoma. AB - INTRODUCTION: The present study aimed to evaluate the effects of intravitreal ranibizumab (IVR) as adjunctive treatment for trabeculectomy with mitomycin C (TMC) in neovascular glaucoma (NVG). METHODS: This is a prospective study of 15 eyes from 14 consecutive patients with NVG carried out between December 2008 and December 2009. Each eye received IVR (0.5 mg/0.05 ml) 1 week before TMC. Trabeculectomy was performed with fornix-based conjunctival flap method. After TMC, additional panretinal photocoagulation (PRP), subconjunctival five fluorouracil injection, and bleb needling may be performed if indicated. The primary outcome measures were post-TMC intraocular pressure (IOP) and numbers of anti-glaucoma medication. The secondary outcome measures included of the recurrence of neovascularization at iris (NVI) and complications. RESULTS: Six eyes underwent adequate PRP before IVR but iris rubeosis still persisted. All eyes showed regression of NVI within 1 week after IVR. After TMC, mean IOP was significantly decreased from 37.9 mmHg preoperatively to 15.6 mmHg postoperatively (P < 0.001). Intraoperative hyphema was observed in four eyes. Thirteen eyes had controlled IOP (<21 mmHg) at last visit among which only one eye needed anti-glaucoma medication. Two eyes were considered as failure and needed further intervention. Visual acuity was maintained or improved in eight eyes. Recurrent NVI was not detected. All patients were symptom-free at last visit. Mean follow-up was 39 weeks. CONCLUSION: IVR is an effective treatment adjunctive to TMC for NVG. The occurrence of intraoperative complications was low and the short-term outcomes after trabeculectomy were favorable. PMID- 25812532 TI - High Reliability Organizations--Medication Safety. AB - High reliability organizations (HROs), such as the aviation industry, successfully engage in high-risk endeavors and have low incidence of adverse events. HROs have a preoccupation with failure and errors. They analyze each event to effect system wide change in an attempt to mitigate the occurrence of similar errors. The healthcare industry can adapt HRO practices, specifically with regard to teamwork and communication. Crew resource management concepts can be adapted to healthcare with the use of certain tools such as checklists and the sterile cockpit to reduce medication errors. HROs also use The Swiss Cheese Model to evaluate risk and look for vulnerabilities in multiple protective barriers, instead of focusing on one failure. This model can be used in medication safety to evaluate medication management in addition to using the teamwork and communication tools of HROs. PMID- 25812533 TI - Thermal Stability of Dopamine Transporters. AB - The thermal stabilities of the rat and mouse dopamine transporter (DAT) proteins were studied within the temperature range of 0-37 degrees C. The inactivation of the protein was followed by monitoring changes in radioligand-specific binding. We found that the process followed a rate equation with first-order kinetics and was characterized by having a single rate constant k inact. The activation energies (E a) that were calculated from the Arrhenius plots (ln k inact vs. 1/T) were 43 +/- 5 and 45 +/- 6 kJ/mol for the rat (rDAT) and mouse (mDAT) transporters, respectively, and 44 +/- 7 kJ/mol for rDAT from PC-6.3 cell line. These E a values were similar to the E a values of thermal inactivation of the muscarinic receptor from rat brain cortex and to the thermal inactivation of other transmembrane proteins. However, all of these activation energy values were significantly lower than the E a values for soluble single-subunit proteins of similar size. These results therefore suggest that the thermal stability of transmembrane proteins may be governed to a significant extent by cell membrane properties and by interactions between the membrane components and the protein. In contrast, the stability of soluble proteins seems to be mostly governed by protein structure and size, which determine the sum of the stabilizing intramolecular interactions within the protein molecule. It is therefore not surprising that cell membrane properties and composition may have significant effects on the functional properties of transmembrane proteins. PMID- 25812535 TI - Decreased semaphorin 3A expression is associated with a poor prognosis in patients with epithelial ovarian carcinoma. AB - Semaphorin 3A (SEMA3A) was initially identified to play an important role in axonal guidance. Recently, SEMA3A has also been considered as a candidate tumor suppressor, since it is often downregulated in numerous types of cancer, including prostate cancer, breast cancer and glioma. However, the biological role of SEMA3A in ovarian cancer is not clear. In the present study, the expression of SEMA3A in ovarian cancer and normal ovarian epithelial tissues was detected by immunofluorescence, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, and the associations between the expression of SEMA3A with the development of ovarian cancer, clinicopathological characteristics and survival were also analyzed. Results from immunofluorescence, RT-qPCR and western blotting showed that SEMA3A is significantly downregulated in epithelial ovarian carcinoma compared to normal ovarian epithelial specimens (P<0.05). The expression levels of SEMA3A were lower in the cancer tissues with III/IV stage [the International Federation of Gynecology and Obstetrics (FIGO) stage], poor histological grade, lymph node metastasis and distant metastasis compared to that in the cancer tissues with I/II stage (FIGO), well histological grade, or without lymph node metastasis and distant metastasis (P<0.05). A decreased expression of SEMA3A is associated with a poor prognosis (P<0.001). The present findings suggest that decreased SEMA3A expression may be associated with the development of epithelial ovarian carcinoma, and therefore, SEMA3A may be a valuable prognostic marker, as well as a potential molecular therapy target for ovarian cancer patients. PMID- 25812534 TI - Impact of FDG-PET findings on decisions regarding patient management strategies: a multicenter trial in patients with lung cancer and other types of cancer. AB - OBJECTIVE: To date, numerous studies have been conducted on the diagnostic capabilities of positron emission tomography using [(18)F]-fluorodeoxyglucose (FDG-PET). However, no studies designed to evaluate the influence of FDG-PET on the selection of patient management strategies within the Japanese healthcare system have been reported to date. The aim of the present study was to investigate prospectively the proportion of patients whose management strategies were modified based on FDG-PET findings (strategy modification rate). METHODS: The strategy modification rate was calculated by comparing the patient management strategy (test and treatment plans) after FDG-PET with the strategy before FDG PET for 560 cancer patients with nine types of cancer (lung cancer, breast cancer, colorectal cancer, head/neck cancer, brain tumor, pancreas cancer, malignant lymphoma, cancer of unknown origin, and melanoma). In addition, the details of the modifications to the patient management strategies were analyzed. RESULTS: The strategy modification rate for patients with lung cancer was 71.6% (149 of 208 patients, 95% confidence interval 65.0-77.7%), which was higher than previously reported strategy modification rates for lung cancer before and after FDG-PET (25.6%). The strategy modification rates for patients with cancers other than lung cancer were as follows: breast, 44.4% (56/126); colorectal, 75.6% (62/82); head and neck, 65.2% (15/23); malignant lymphoma, 70.0% (35/50); pancreas, 85.0% (17/20); and cancer of unknown origin, 78.0% (32/41). The mean modification rate (major and minor modifications) of the treatment plans after FDG-PET, relative to the plans before FDG-PET, was 55.4% (range 44.0-69.2%), with major modifications pertaining to the treatment plan made in 43.3-68.2% of the patients based on the objectives of the FDG-PET examination. CONCLUSIONS: The results from this study indicate that FDG-PET can contribute to the modification of management strategies (particularly treatment plans), especially for lung cancer patients but also for patients with other types of cancer. PMID- 25812536 TI - Are there racial disparities in utilization and outcomes after total elbow arthroplasty? AB - The aim of the study was to assess racial disparities in utilization rates and outcomes after primary total elbow arthroplasty (TEA). We used the National Inpatient Sample from 1998 to 2010, a US national database. Patient characteristics, comorbidity and outcomes after TEA were assessed over time and differences by race studied over the study period. Cochran-Armitage test was used for time trends and logistic regression for the comparison of outcomes by race. In 1998, TEA utilization rate was 0.38/100,000 in Whites and 0.24/100,000 in Blacks (p = 0.002); in 2010, it was 0.91 and 0.59/100,000, respectively (p < 0.0001). White-Black disparity in TEA utilization was significant across 13 years (p = 0.03). Compared with White patients, Black patients undergoing TEA were younger (61.9 vs. 52 years; p < 0.0001), less likely to be female (70.6 vs. 61.4 %; p = 0.0007) and more likely to have rheumatoid arthritis as the underlying diagnosis (13.0 vs. 17.2 %; p = 0.036). Mortality was rare, 0.26 % in Blacks and 0.32 % in Whites (p = 0.83). Discharge to an inpatient facility was higher in White versus Black patients in unadjusted analyses (16.8 vs. 10.4 %; p = 0.003), but in analyses adjusted for age, sex, Deyo-Charlson index and the underlying diagnosis, the differences were no longer significant (p = 0.79). The length of hospital stay greater than the median stay was noted in 29.8 % Whites versus 31.2 % Blacks, respectively (p = 0.61). There was no evidence of White-Black disparity in hospital length of stay in 1998-2000 (p = 0.66) or 2009-2010 (p = 0.59) periods. In this study, we found persisting racial disparities in TEA utilization rates. No White-Black disparities were noted in TEA outcomes, except slight differences in discharge disposition. PMID- 25812539 TI - Erratum: Interlayer water regulates the bio-nano interface of a beta-sheet protein stacking on graphene. PMID- 25812541 TI - Implications of epigenetic mechanisms in the development and treatment of personality disorders. AB - Epigenetics deals with the genic expression processes that do not involve modifications of the DNA sequence, that is, focuses on the different trajectories of a given genotype throughout the organism’s lifespan. These processes are involved in basic biological functions such as the cellular differentiation or sexual selection, in the development of complex diseases such as Rett’s syndrome and in psychiatric disorders such as schizophrenia and depression among others. Epigenetic studies are yielding evidence that environmental events and psychosocial factors can modify the epigenome. This work reviews studies analyzing the influence of environmental factors involved in the pathogenesis of behavioral features and phenotypic expression of personality disorder’s symptomatic domains, such as late onset affective symptoms related with early adverse events in childhood and dysfunction of stress modulation mechanisms. In addition, the knowledge of these epigenetic mechanisms may contribute to the identification of novel both psychotherapeutic and pharmacological therapeutic targets for the treatment of personality disorders. PMID- 25812540 TI - Detection of anti-streptococcal, antienolase, and anti-neural antibodies in subjects with early-onset psychiatric disorders. AB - INTRODUCTION: Infection with group A Streptococcus (StrepA) can cause post infectious sequelae, including a spectrum of childhood-onset obsessive-compulsive (OCD) and tic disorders with autoimmune origin (PANDAS, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). Until now, no single immunological test has been designed that unequivocally diagnoses these disorders. In this study, we assessed the detection of serum antibodies against human brain enolase (AE), neural tissue (AN) and Streptococcus (AS) as a laboratory tool for the diagnosis of early-onset psychiatric disorders. METHODOLOGY: Serum antibodies against human brain enolase, total brain proteins, and total proteins from StrepA were detected by ELISA in 37 patients with a presumptive diagnosis of PANDAS and in 12 healthy subjects from Mexico and Cuba. RESULTS: The antibody titers against human brain enolase (AE) and Streptococcal proteins (AS) were higher in patients than in control subjects (t-student, tAE= 2.17, P=0.035; tAS=-2.68, P=0.01, n=12 and 37/group, df=47, significance level 0.05), while the neural antibody titers did not differ between the two groups (P(t)=0.05). The number of subjects (titers> meancontrol + CI95) with simultaneous seropositivity to all three antibodies was higher in the patient group (51.4%) than in the control group (8.3%) group (X2=5.27, P=0.022, df=1, n=49). CONCLUSIONS: The simultaneous detection of all three of these antibodies could provide valuable information for the etiologic diagnosis of individuals with early-onset obsessive-compulsive disorders associated with streptococcal infection and, consequently, for prescribing suitable therapy. PMID- 25812537 TI - Epigenetics of osteoarticular diseases: recent developments. AB - A variety of osteoarticular conditions possess an underlying genetic aetiology. Large-scale genome-wide association studies have identified several genetic loci associated with osteoarticular conditions, but were unable to fully account for their estimated heritability. Epigenetic modifications including DNA methylation, histone modification, nucleosome positioning, and microRNA expression may help account for this incomplete heritability. This articles reviews insights from epigenetic studies in osteoarticular diseases, focusing on osteoarthritis, but also examines recent advances in rheumatoid arthritis, osteoporosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, and sarcoma. Genome-wide methylation studies are permitting identification of novel candidate genes and molecular pathways, and the pathogenic mechanisms with altered methylation status are beginning to be elucidated. These findings are gradually translating into improved understanding of disease pathogenesis and clinical applications. Functional studies in osteoarthritis, rheumatoid arthritis, and SLE are now identifying downstream molecular alterations that may confer disease susceptibility. Epigenetic markers are being validated as prognostic and therapeutic disease biomarkers in sarcoma, and clinical trials of hypomethylating agents as treatments for sarcoma are being conducted. In concert with advances in throughput and cost-efficiency of available technologies, future epigenetic research will enable greater characterisation and treatment for both common and rare osteoarticular diseases. PMID- 25812542 TI - Acute treatment of cycloid psychosis: study on a sample of naive hospitalized patients with first-episode psychosis (FEP). AB - INTRODUCTION: In spite of the historic, clinical and therapeutic importance of cycloid psychosis, no controlled studies have been performed as yet on its treatment. Electroconvulsive therapy has classically been the treatment of choice and the first generation antipsychotics have not been indicated. This study has aimed to analyze the acute treatment (and response to it) of cycloid psychoses. METHODOLOGY: In a sample of 75 hospitalized medication- naive patients treated for a First Psychotic Episode (FPE), possible cases of cycloid psychoses were detected using the Perris and Brockington operative diagnostic criteria. The sample was divided into “cycloids” and “non-cycloids” and both groups were compared based on clinical and therapeutic variables. RESULTS: All the patients were treated with second generation antipsychotics. No significant differences (p=0.17; t-1.39) were found in the antipsychotic dose prescribed (equivalents of chlorpromazine). However, significant differences were observed in the improvement on hospital discharge (clinical global impression severity: CGI-S), with better response in the “cycloid” group” (p=0.002; u=162). Significant differences were also observed in the dose of benzodiazepines, there being significantly greater improvement for the “cycloid” group (p>0.001; u=28). CONCLUSIONS: Without contradicting the classical idea of the treatment of cycloid psychoses, the present study contributes to the opening of a new therapeutic prospect. Thus, the use of second generation antipsychotics could have a particularly beneficial effect, especially if combined with high doses of benzodiazepines in the acute treatment of cycloid psychoses. However, controlled studies need to be carried out to confirm this. PMID- 25812544 TI - Paliperidone-induced rhabdomyolysis: a case report. PMID- 25812543 TI - Comorbid personality disorders in chronic fatigue syndrome patients: a marker of psychopathological severity. AB - INTRODUCTION: This study was designed to evaluate the presence of personality disorders (PDs) in Chronic Fatigue Syndrome (CFS) patients and to determine their influence on the severity of the associated psychopathology. METHODS: 132 CFS patients were assessed using SCID-I, Personality Diagnostic Questionnaire-4+ (PDQ 4+) with its Clinical Significance Scale, and Fatigue Impact Scale. The Beck Depression Inventory, Buss-Durkee Hostility Inventory and the State-Trait Anxiety Inventory were also administered. RESULTS: 48.5% patients presented PDs, being the most frequent the Obsessive-Compulsive and Avoidant ones. Patients with PDs had more depressive symptoms. Irritability, resentment, suspicion and guilt were the symptoms related with PDQ-4+ total score. CONCLUSIONS: According to these results, PDs may be frequent in CFS patients. This comorbidity is associated with a complex clinical profile, secondary to more severe psychiatric symptoms. PMID- 25812545 TI - [High-dose magnesium sulfate in the treatment of aconite poisoning]. AB - This article reports the case of a 62-year-old male patient who ingested the roots of Monkshood (Aconitum napellus) and white hellebore (Veratrum album) dissolved in alcohol with a suicidal intention and suffered cardiotoxic and neurotoxic symptoms. After contacting the Poison Information Centre ventricular arrhythmia was treated with high-dose magnesium sulphate as the only antiarrhythmic agent and subsequently a stable sinus rhythm could be established after approximately 3 h. Aconitum napellus is considered the most poisonous plant in Europe and it is found in gardens, the Alps and the Highlands. Poisoning is mainly caused by the alkaloid aconite that leads to persistent opening and activation of voltage-dependent sodium channels resulting in severe cardiac and neurological toxicity. As no specific antidote is known so far, poisoning is associated with a high mortality. The therapy with high-dose magnesium sulphate is based on in vitro and animal experiments as well as limited clinical case reports. PMID- 25812547 TI - Suicide Attempts and Associated Factors in Male and Female Korean Adolescents A Population-Based Cross-Sectional Survey. AB - Using data from the Korea Youth Risk Behavior Web-based Survey, this study seeks to investigate associations of suicide attempts with family, individual, and behavioral factors on the basis of gender. Among male adolescents, those who did not live with their parents, who had poor subjective academic achievement, depression, experiences of smoking and sexual coitus, drug abuse, suicidal ideation and plans were more likely to attempt suicide. Among the female adolescents, those who did not live with their parents, had depression, low self rated health, experiences of drug abuse and sexual coitus, and expressed unhappiness, suicidal ideation and suicide plans were more likely to attempt suicide. Thus, the development of a suicide prevention program for Korean adolescents requires different approaches for males and females. PMID- 25812549 TI - Kinesiophobia in relation to physical activity in chronic neck pain. AB - BACKGROUND: Little research is available concerning physical activity and its determinants in people with chronic neck pain. OBJECTIVE: To explore the relation between kinesiophobia and physical activity and gender effect on these relations in people with chronic neck pain. METHODS: Ninety-nine subjects (34 men and 65 women) with chronic neck pain were participated in the study. Pain intensity was assessed with Visual Analog Scale and kinesiophobia degree was determined by using Tampa Scale of Kinesiophobia. Level of physical activity was assessed with short form of the International Physical Activity Questionnaire. RESULTS: There was no statistically correlation between neck pain intensity and kinesiophobia degree (p= 0.246, r= 0.123) and physical activity level (p= 0.432, r= -0.083). It was also found that kinesiophobia degree was not correlated to physical activity level (p= 0.148, r= -0.153). There was a negative correlation between kinesiophobia degree and physical activity level only for women, not for men (p= 0.011, r= -0.318). CONCLUSIONS: Our results showed that although people with chronic neck pain reported higher pain intensity and fear of movement, pain intensity and kinesiophobia degree did not associate to their physical activity levels. It can be speculated that high kinesiophobia degrees cause low physical activity levels for women, but not for men. PMID- 25812546 TI - [Antibiotic dosing for renal function disorders and continuous renal replacement therapy]. AB - For patients with acute kidney injury (AKI) and continuous renal replacement therapy, it is essential that the dosing of antibiotics is adequately adjusted in order to achieve an effective drug level above the minimum inhibition concentration but avoiding toxic side effects. In the selection of substances, preference should be given to antibiotics with a broad therapeutic spectrum, low incidence of side effects and, as far as possible, extrarenal elimination. Determination of serum levels should always be carried out, when this is possible. In any case, a sufficiently high loading dose should be included. An accurate as possible estimation of residual renal function and calculation of the mechanical clearance allows determination of the necessary maintenance dosage, which is acceptably accurate for clinical needs. Recent studies have shown that under modern continuous renal replacement therapy, the extent of elimination of antibiotics is regularly underestimated so that nowadays, the risk of antibiotic underdosing is higher than toxicity due to overdosing. PMID- 25812548 TI - The effect of different exercise programs on cervical flexor muscles dimensions in patients with chronic neck pain. AB - OBJECTIVE: The effect of different exercise programs on cervical flexor muscles dimensions in patients with chronic neck pain is yet to be demonstrated. The purpose of this study was to assess the effect of two exercise programs; craniocervical flexion (CCF) and cervical flexion (CF), on flexor muscles dimensions in patients with chronic neck pain. METHODS: Following ethical approval, 60 patients were randomly assigned into either a CCF group or a CF group. Patients in the CCF group were given CCF exercises and those in the CF group received CF exercises. All patients received interventions for a period of ten weeks. Pain intensity and functional disability were assessed using numerical pain rate scale and neck disability index, respectively. Dimensions of longus colli (LC) and sternoclidomastoid (SCM) muscles were measured using ultrasonography (US). All measurements were taken before and after interventions. RESULTS: Following intervention, the CCF group demonstrated a significant increase in LC muscle dimensions including cross sectional area, width and thickness compared with the CF group. A statistically significant increase was found on SCM thickness in the CF group. Following intervention, SCM thickness measurement in the CCF group showed no significant changes. Statistically significant decrease on pain intensity and disability were also found in both groups. CONCLUSION: Present findings demonstrated that craniocervical flexion program which specifically recruiting deep cervical flexor muscles increased LC muscle dimension significantly and CF program as an endurance training program increased SCM thickness. PMID- 25812550 TI - Is the Sorensen test valid to assess muscle fatigue of the trunk extensor muscles? AB - BACKGROUND: Very few studies have quantified the degree of fatigue characterized by the decline in the maximal voluntary contraction (MVC) force of the trunk extensors induced by the widely used Sorensen test. OBJECTIVE: Measure the degree of fatigue of the trunk extensor muscles induced by the Sorensen test. METHODS: Eighty young healthy subjects were randomly divided into a control group (CG) and an experimental group (EG), each including 50% of the two genders. The EG performed an isometric MVC of the trunk extensors (pre-fatigue test) followed by the Sorensen test, the latter being immediately followed by another MVC (post fatigue test). The CG performed only the pre- and post-fatigue tests without any exertion in between. RESULTS: The comparison of the pre- and post-fatigue tests revealed a significant (P< 0.05) decrease in MVC force normalized by body mass ( 13%) in the EG, whereas a small increase occurred in the CG (+2.7%, P= 0.001). CONCLUSIONS: This study shows that the Sorensen test performed until failure in a young healthy population results in a reduced ability of the trunk extensor muscles to generate maximal force, and indicates that this test is valid for the assessment of fatigue in trunk extensor muscles. PMID- 25812551 TI - Raman scattering in La1-xSrxFeO3-delta thin films: annealing-induced reduction and phase transformation. AB - Raman scattering in thin film La0.2Sr0.8FeO3-delta on MgO(0 0 1) collected at 300 K after different stages of annealing at selected temperatures T (300 K < T < 543 K, to 10 h) and analysis reveal changes in spectral characteristics due to a loss of oxygen, onset of oxygen vacancy-induced disorder, and activation of Raman inactive modes that are attributed to symmetry lowering. The interpretation is further supported by carrier transport measurements under identical conditions showing orders of magnitude increase in the resistivity induced by oxygen loss. After prolonged annealing in air, evolution of the spectrum signals the appearance of a possible topotactic transformation of the crystal structure from that of the rhombohedral ABO3 perovskites to that of Brownmillerite-like structure consisting of octahedrally and tetrahedrally coordinated Fe atoms. PMID- 25812552 TI - Detection of human malaria using recombinant Plasmodium knowlesi merozoire surface protein-1 (MSP-119) expressed in Escherichia coli. AB - Malaria remains one of the world's most important infectious diseases and is responsible for enormous mortality and morbidity. Human infection with Plasmodium knowlesi is widely distributed in Southeast Asia. Merozoite surface protein-119 (MSP-119), which plays an important role in protective immunity against asexual blood stage malaria parasites, appears as a leading immunogenic antigen of Plasmodium sp. We evaluated the sensitivity and specificity of recombinant P. knowlesi MSP-119 (rMSP-119) for detection of malarial infection. rMSP-119 was expressed in Escherichia coli expression system and the purified rMSP-119 was evaluated with malaria, non-malaria and healthy human serum samples (n = 215) in immunoblots. The sensitivity of rMSP-119 for detection of P. knowlesi, Plasmodium falciparum, Plasmodium vivax and Plasmodium ovale infection was 95.5%, 75.0%, 85.7% and 100%, respectively. rMSP-119 did not react with all the non-malaria and healthy donor sera, which represents 100% specificity. The rMSP-119 could be used as a potential antigen in serodiagnosis of malarial infection in humans. PMID- 25812554 TI - Medical Education: Where are We Going? PMID- 25812555 TI - Historical perception of korean medical education. PMID- 25812553 TI - Vitreo-retinal relationship and post-operative outcome of macular hole repair in eyes with high myopia. AB - PURPOSE: To investigate the vitreoretinal relationship in eyes with full thickness macular hole (FTMH) without retinal schisis or detachment. Eyes with and without high myopia were compared using slit-lamp biomicroscopy, optical coherence tomography (OCT), and intraoperative observations. METHODS: Clinical records of 34 consecutive cases of FTMH without schisis or detachment in highly myopic eyes (refractive error larger than -6.0 diopters or axial length >26 mm) were retrospectively reviewed. All eyes underwent pars plana vitrectomy between 2006 and 2013. An additional 43 consecutive cases of FTMH in eyes without high myopia were also reviewed to serve as controls. All control patients underwent surgery during the same period. Ophthalmological, OCT, and intraoperative findings, and vitreoretinal interface features were documented in both groups. Anatomical closure rate and final best-corrected visual acuity (BCVA) were compared between groups. RESULTS: Premacular tissue was identified during surgery in 21 of 34 high myopia patients (61.8 %) and three of 43 control patients (7.0 %). The high myopia group showed two layers of premacular membranes. Two cases had a shiny, loose inner membrane, 13 cases had a tightly adherent outer membrane, and six cases had both. Only a tightly adherent membrane was found in controls. In the high myopia group, 11 of 21 eyes (52.4 %) did not have a preretinal membrane identified preoperatively. Anatomical closure was achieved in 91.2 and 95.3 % of high myopia and control patients respectively (p = 0.65). No significant intergroup difference in final BCVA was observed. CONCLUSION: Premacular tissue was found in 61.8 % of eyes with high myopia and FTMH without retinal schisis or detachment. Anatomically successful surgical closure in high myopia patients was achieved at a rate comparable to their idiopathic counterparts. PMID- 25812556 TI - The Relationships among Learning Behaviors, Major Satisfaction, and Study Skills of First-Year Medical Students. AB - PURPOSE: This study aims at increasing our understanding of first-year medical students' learning behaviors, major satisfaction, and study skills. We investigate different features of freshmen's behavior in relation to learning and explore the extent to which freshmen were satisfied with their major and perceived their study skills. METHODS: A total of 106 freshmen participated in this study. At midyear, first-year medical students were asked to complete a questionnaire that included the learning behaviors, major satisfaction, and study skills. The data collected from the survey were analyzed using t-test, ANOVA, chi square test, correlation analysis, and multiple regression analysis. RESULTS: The study reported that most of freshmen had a lot of difficulties in studying at medical school by lack of prior learning. Despite first-year students, they were studying hard their major. Freshmen spent studying an average of 1 hour or less than 2 hours every day. The study also indicated that of major satisfaction, the overall satisfaction of the department was the highest and the satisfaction in learning environment was the lowest. There were significant differences among the freshmen on the major satisfaction due to admission process, academic performance, and housing type. Of 11 study skills, while freshman highly perceived their teamwork, stress management, and reading skills, their weak study skills identified in this study were writing, note taking, time management, and test taking skills. There were significant differences among the freshmen on the study skills due to gender and academic performance. Finally, freshmen's learning behaviors and major satisfaction were significantly associated with some of study skills. CONCLUSION: This study may have implications for the academic adjustment and learning processes in the first year. We need to consider variables such as learning behaviors, major satisfaction, and study skills, when discussing about how to maximize the learning potential of medical students. It is also important that we develop education program so that all students acquire these necessary skills and continue to improve positive behaviors related to learning. PMID- 25812557 TI - The satisfaction of the freshman of graduate medical students to the new medical curriculum: one medical school. AB - PURPOSE: We changed a lot of the medical curricula to accept the freshman of graduate medical students in 2009. We surveyed the satisfaction of new medical curricula from graduate medical students. METHODS: We analysed the returned questionnaires from 118 freshmen of graduate medical students. RESULTS: The number of boys and girls was 56 (47.5%) and 62 (52.5%), respectively and of married students was 10 (8.5%). The graduate students thought that the future prospect was very positive and positive in 40.7%. The 77.1 percentages of medical students understood about 40~80% of the basic medicine. The satisfaction of medical curriculum was average 3.30 by Likert scale. The satisfaction of the professor who have enough information to the subjects was 4.00 and of integrated subjects which were organically related without repetition was 2.85 by Likert scale. Graduate students asked to strengthen clinical medicine lecture and practice. CONCLUSION: Generally, the satisfaction of the new medical curricula was positive in graduate students. But the satisfaction of the contents of the integrated subjects was lowest and so we have to check the organic relationship of integrated subjects. PMID- 25812559 TI - The effect of personal character on the results of clinical performance skill tests. AB - PURPOSE: Even though many studies have indicated that the personality of medical students affects learning style and academic achievement, the effect of personality types on the performance skill tests has not been well known in the medical field due to the rarity of published papers. Thus, the aim of this study was to reveal the effect of personal traits on clinical skill performance tests. METHODS: Fifty-seven fourth-grade medical students were enrolled in this study. They had all completed clinical performance tests. To assess personality types, we used the Korean version of the Myers-Briggs Type Indicator (MBTI). RESULTS: Fifty-five of 57 senior medical students responded completely to the MBTI questionnaire. The proportion of four paired MBTI dimensions was Introversion (I) Extroversion (E) (67.3% vs. 32.7%), Sensing (S)-Intuition (I) (76.4% vs. 23.6%), Thinking (T)-Feeling (F) (61.8% vs. 38.2%), and Judging (J)-Perception (P) (56.4% vs. 43.6%). The dominant personality types were ISTJ (23.6%), ESTJ (14.5%), and ISTP (10.9%). The first objective structured clinical examination (OSCE) test showed higher scores in Extraversion, Judging, and Sensing-Judging types compared to the counterparts (p<0.05), but this effect was not observed in the second OSCE test. On the clinical performance examination, Extraversion, Sensing, and Judging types had a higher score, as measured by standardized patients. CONCLUSION: Specific personal traits affect the test scores of the clinical performance skill examinations. So, personality measurement might be a useful tool for understanding a student who has difficulty in performance tests. We hope this study will give valuable information to examiners when they instruct and counsel students about clinical performance tests. PMID- 25812558 TI - Implementation of the medical research curriculum in graduate medical school. AB - PURPOSE: The purpose of this study was to analyze the effect of the medical research curriculum on the students' satisfaction and the research self-efficacy. METHODS: The curriculum was implemented to 79 graduate medical school students who entered in 2007 and 2008. This curriculum is implemented through 3 years consisting of 5 different sub-courses: Research design, Research ethics, Medical statistics, Writing medical paper, and Presentation. The effect of this program was measured with 2 self-administered surveys to students: the course satisfaction survey and the self-efficacy inventories. The Research Self-Efficacy Scale consisted of 18 items from 4 categories: Research design, Research ethics, Data analysis, and Result presentation. The descriptive statistics, paired t test, and analysis of covariance (ANCOVA) were implemented. RESULTS: The average point of satisfaction of the course was 2.74 out of 4, which told us that students generally satisfied with the course. The frequencies of tutoring for research course were 2 or 3 times on average and each session of tutorial lasted 1.5 to 2 hours. The research self-efficacy in three categories (Research design, Research ethics, and Result presentation) increased significantly (p<0.1). The self-efficacy of the male students was higher than females' one. The self efficacy was not significantly different by the experience of research paper writing at undergraduate level. CONCLUSION: The curriculum showed positive results in cultivating research self-efficacy of students. There is a need for improvement of the class of Statistical analysis as students reported that it was difficult. PMID- 25812560 TI - Analysis on teaching evaluation of clinical clerkship at korean medical schools. AB - PURPOSE: The purpose of this study was to investigate the teaching evaluation of clinical clerkship at Korean medical schools, and to suggest a desirable improvement for the clinical teaching evaluation in the future. METHODS: A questionnaire survey was conducted with a total of 9 multiple-choice questions and 1 essay-type question. The multiple-choice questions were analyzed by the frequency analysis using SPSS 17.0, and the essay-type question was coded by the content analysis. RESULTS: Survey results were as follows: First, clinical teaching evaluations via online (51.35%) were implemented once a year (94.59%) in most medical schools. Second, the self-made questionnaires by medical school (64.86%) rather than borrowing or adaptation (35.14%) were being used more often as teaching evaluation tool. Third, 37.84% medical schools used the specific form by class type, whereas 62.16% medical schools took the general form regardless of class type. Finally, evaluation tool (n=8), lack of concern and attention to teaching evaluation (n=4), formalities of evaluation (n=4), etc. were exposed as problems of clinical teaching evaluation. With regard to evaluation items, the development of specific questions was required. CONCLUSION: Teaching evaluation can be used as effective educational tools to improve the clinical clerkship program. To this end, clinical teaching evaluation tools reflecting the characteristics of clinical practice need to be developed. PMID- 25812561 TI - Clinical performance examination utilizing standardized patients in board examination: based on the board examination of korean neurological association for three years. AB - PURPOSE: Evaluation of clinical skills and attitude including development of dynamic patient-doctor relationship is important in board examination (BE). Korean Neurological Association (KNA) has introduced clinical performance examination (CPX) utilizing standardized patients (SP) to BE in 2007. In this study, the authors describe the 3-year experience of CPX in BE through 2009. METHODS: To implement CPX session in BE, KNA developed CPX workshop for BE attendees and members of grading committee. CPX sessions in BE consisted of two model scenarios mimicking neurological patients in clinical practice. The total score and itemized scores of CPX sessions were compared with other areas of BE, and scores from each year were also compared. RESULTS: Scores from CPX sessions were significantly correlated with BE step II. Among the itemized scores of CPX sessions, clinical items including history taking and physical examination were significantly correlated with scores from other areas of BE. However, scores from global assessment from SP were strongly associated with patient-doctor relationship, history taking, and patient education. CONCLUSION: Our experiences suggest that CPX utilizing SP is a useful tool to assess the clinical skills in BE. In order to produce clinically well qualified neurologists, more efforts should be made to develop cases and to improve assessment tools for CPX. PMID- 25812562 TI - How to teach open disclosure and saying "sorry". PMID- 25812564 TI - Percutaneous dilatational tracheostomy following total artificial heart implantation. AB - Coagulation disorders and an immune-altered state are common among total artificial heart patients. In this context, we sought to evaluate the safety of percutaneous dilatational tracheostomy in cases of prolonged need for mechanical ventilatory support. We retrospectively analysed the charts of 11 total artificial heart patients who received percutaneous dilatational tracheostomy. We focused on early and late complications. We observed no major complications and no procedure-related deaths. Early minor complications included venous oozing (45.4%) and one case of local infection. Late complications, including subglottic stenosis, stomal infection or infections of the lower respiratory tract, were not observed. In conclusion, percutaneous dilatational tracheostomy in total artificial heart patients is safe. Considering the well-known benefits of early tracheotomy over prolonged translaryngeal intubation, we advocate early timing of therapy in cases of prolonged mechanical ventilation. PMID- 25812566 TI - Dementia Team award. PMID- 25812565 TI - Toxic effects of ionic liquid 1-octyl-3-methylimidazolium bromide on the antioxidant defense system of freshwater planarian, Dugesia japonica. AB - The activities of antioxidant enzymes and the levels of glutathione (GSH) and malondialdehyde (MDA) were determined when freshwater planarian Dugesia japonica was exposed to different concentrations of 1-octyl-3-methylimidazolium bromide ([C8mim]Br) for one, three, and five days. The results showed that superoxide dismutase (SOD) activity began to increase in all treated groups after three days of exposure, while catalase (CAT) activity was inhibited after the first day, but increased notably on the fifth day except for the lowest concentration group. The activity of glutathione peroxidase (GPX) was induced from the first day of exposure and increased significantly after five days in all treated groups. During the experiment, the levels of intracellular GSH in all treated groups were higher than that of the control group. Changes in MDA suggest that [C8mim]Br is toxic to D japonica and may result in lipid peroxidation in planarian. Our results also indicate that GPX as well as GSH seem to be more sensitive biomarkers of oxidative stress compared with SOD and CAT. PMID- 25812567 TI - Use of Microarrays as a High-Throughput Platform for Label-Free Biosensing. AB - In recent years, various label-free biosensing technologies have been developed for studying the real-time kinetics of diverse biomolecular interactions. These biosensors partially take the place of fluorescence-based methods by providing a comparable sensitivity as well as retaining the conformational and functional integrality of biomolecules to be investigated. However, to completely eliminate the need of fluorescence, throughput is the next big consideration. Microarrays provide a high-throughput platform for screening tens of thousands of biomolecular interactions simultaneously, and many compatible fluorescent scanners have been commercially available. The combination of microarrays and label-free biosensors will be of great interest to researchers in related fields. Microarrays are fabricated by spotting, imprinting, or directly synthesizing biomolecules on solid supports such as glasses, silicon wafers, and other functionalized substrates, and they have been applied to detect DNAs, proteins, toxins, and so on in surface plasmon resonance (SPR) imaging systems and oblique incidence reflectivity difference (OI-RD) microscopes. Current challenges include increasing sensitivity, reducing sampling time, improving surface chemistry, identifying captured molecules, and minimizing reagent consumption. Future research directions are to improve the instruments themselves, modify the microarray surface for more efficient analyte capture, and combine the systems with mass spectrometry and microfluidics. PMID- 25812568 TI - Irbesartan attenuates atherosclerosis in Watanabe heritable hyperlipidemic rabbits: noninvasive imaging of inflammation by 18F-fluorodeoxyglucose positron emission tomography. AB - The purpose of this study was to assess the usefulness of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in evaluating the antiatherogenic effects of irbesartan, an angiotensin II type 1 receptor blocker. Watanabe heritable hyperlipidemic rabbits were divided into the irbesartan-treated group (75 mg/kg/d; n = 14) and the control group (n = 14). After a 9-month treatment, rabbits underwent 18F-FDG PET. Using the aortic lesions, autoradiography and histologic examinations were performed. PET imaging clearly visualized the thoracic lesions of control rabbits and showed a significant decrease in the 18F-FDG uptake level of irbesartan-treated rabbits (78.8% of controls; p < .05). Irbesartan treatment significantly reduced the plaque size (43.1% of controls) and intraplaque macrophage infiltration level (48.1% of controls). The 18F-FDG uptake level in plaques positively correlated with the plaque size (r = .65, p < .05) and macrophage infiltration level (r = .57, p < .05). Noninvasive imaging by 18F-FDG PET is useful for evaluating the therapeutic effects of irbesartan and reflects inflammation, a key factor involved in the therapeutic effects. PMID- 25812569 TI - Identification of potential targets for diallyl disulfide in human gastric cancer MGC-803 cells using proteomics approaches. AB - Diallyl disulfide (DADS) is characterized as an effective agent for the prevention and therapy of cancer, however, mechanisms regarding its anticancer effects are not fully clarified. In the present study, we compared the protein expression profile of gastric cancer MGC-803 cells subjected to DADS treatment with that of untreated control cells to explore potential molecules regulated by DADS. Using proteomic approaches, we identified 23 proteins showing statistically significant differences in expression, including 9 upregulated and 14 downregulated proteins. RT-PCR and western blot analysis confirmed that retinoid related orphan nuclear receptor alpha (RORalpha) and nM23 were increased by DADS, whereas LIM kinase-1 (LIMK1), urokinase-type plasminogen activator receptor (uPAR) and cyclin-dependent kinase-1 (CDK1) were decreased. DADS treatment and knockdown of uPAR caused suppression of ERK/Fra-1 pathway, downregulation of urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9) and vimentin, and upregulation of tissue inhibitor of metalloproteinase-3 (TIMP 3) and E-cadherin, concomitant with inhibition of cell migration and invasion. Moreover, knockdown of uPAR potentiated the effects of DADS on MGC-803 cells. These data demonstrate that downregulation of uPAR may partially be responsible for DADS-induced inhibition of ERK/Fra-1 pathway, as well as cell migration and invasion. Thus, the discovery of DADS-induced differential expression proteins is conducive to reveal unknown mechanisms of DADS anti-gastric cancer. PMID- 25812570 TI - In cross-sectional observations, dietary quality is not associated with CVD risk in women; in men the positive association is accounted for by BMI. AB - The role that BMI plays in the association between dietary quality and CVD risk is not known. We aimed to better understand this relationship using statistical methods which correct for sex-specific underreporting of dietary intake. Overall, dietary quality was assessed using the Healthy Eating Index (HEI) on data from 9797 non-pregnant adults (aged >20 years) who participated in the National Health and Nutrition Examination Survey from 2005 to 2010. CVD risk factors included blood pressure, fasting glucose and insulin, homeostatic models of insulin resistance (HOMA-IR), HDL- and LDL-cholesterol (HDL-C and LDL-C), TAG and C reactive protein (CRP). We controlled for demographic and lifestyle covariates, and we used the population ratio approach (which adjusts for the underreporting of intake) to compare mean HEI scores between the top and bottom quartiles of covariate-adjusted CVD risk factors. In women, the total HEI score was not associated with any CVD risk factors (all Q>0.11). In men, the total HEI score was associated with covariate-adjusted residuals for fasting insulin (Q<0.001), HOMA-IR (Q<0.001), HDL-C (Q=0.01) and CRP (Q<0.001). When we additionally adjusted for BMI, the association with total HEI score was not significant (all P>0.10). In the present analyses, dietary quality was associated with five CVD risk factors in a sex-specific manner. Moreover, the association of BMI with CVD risk attenuated the relationship between CVD risk and diet, which suggests that BMI is an important factor in heart disease prevention. PMID- 25812571 TI - Myocardial neuroendocrine tumour metastasis mimicking melanoma: multimodality imaging diagnosis. PMID- 25812574 TI - Is anybody listening? PMID- 25812572 TI - A quantitative high resolution voxel-wise assessment of myocardial blood flow from contrast-enhanced first-pass magnetic resonance perfusion imaging: microsphere validation in a magnetic resonance compatible free beating explanted pig heart model. AB - AIMS: To assess the feasibility of high-resolution quantitative cardiovascular magnetic resonance (CMR) voxel-wise perfusion imaging using clinical 1.5 and 3 T sequences and to validate it using fluorescently labelled microspheres in combination with a state of the art imaging cryomicrotome in a novel, isolated blood-perfused MR-compatible free beating pig heart model without respiratory motion. METHODS AND RESULTS: MR perfusion imaging was performed in pig hearts at 1.5 (n = 4) and 3 T (n = 4). Images were acquired at physiological flow ('rest'), reduced flow ('ischaemia'), and during adenosine-induced hyperaemia ('stress') in control and coronary occlusion conditions. Fluorescently labelled microspheres and known coronary myocardial blood flow represented the reference standards for quantitative perfusion validation. For the comparison with microspheres, the LV was divided into 48 segments based on a subdivision of the 16 AHA segments into subendocardial, midmyocardial, and subepicardial subsegments. Perfusion quantification of the time-signal intensity curves was performed using a Fermi function deconvolution. High-resolution quantitative voxel-wise perfusion assessment was able to distinguish between occluded and remote myocardium (P < 0.001) and between rest, ischaemia, and stress perfusion conditions at 1.5 T (P < 0.001) and at 3 T (P < 0.001). CMR-MBF estimates correlated well with the microspheres at the AHA segmental level at 1.5 T (r = 0.94, P < 0.001) and at 3 T (r = 0.96, P < 0.001) and at the subendocardial, midmyocardial, and subepicardial level at 1.5 T (r = 0.93, r = 0.9, r = 0.88, P < 0.001, respectively) and at 3 T (r = 0.91, r = 0.95, r = 0.84, P < 0.001, respectively). CONCLUSION: CMR-derived voxel-wise quantitative blood flow assessment is feasible and very accurate compared with microspheres. This technique is suitable for both clinically used field strengths and may provide the tools to assess extent and severity of myocardial ischaemia. PMID- 25812573 TI - Poorly cited articles in peer-reviewed cardiovascular journals from 1997 to 2007: analysis of 5-year citation rates. AB - BACKGROUND: The extent to which articles are cited is a surrogate of the impact and importance of the research conducted; poorly cited articles may identify research of limited use and potential wasted investments. We assessed trends in the rates of poorly cited articles and journals in the cardiovascular literature from 1997 to 2007. METHODS AND RESULTS: We identified original articles published in cardiovascular journals and indexed in the Scopus citation database from 1997 to 2007. We defined poorly cited articles as those with <=5 citations in the 5 years following publication and poorly cited journals as those with >75% of journal content poorly cited. We identified 164 377 articles in 222 cardiovascular journals from 1997 to 2007. From 1997 to 2007, the number of cardiovascular articles and journals increased by 56.9% and 75.2%, respectively. Of all the articles, 75 550 (46.0%) were poorly cited, of which 25 650 (15.6% overall) had no citations. From 1997 to 2007, the proportion of poorly cited articles declined slightly (52.1%-46.2%, trend P<0.001), although the absolute number of poorly cited articles increased by 2595 (trend P<0.001). At a journal level, 44% of cardiovascular journals had more than three-fourths of the journal's content poorly cited at 5 years. CONCLUSION: Nearly half of all peer reviewed articles published in cardiovascular journals are poorly cited 5 years after publication, and many are not cited at all. The cardiovascular literature and the number of poorly cited articles both increased substantially from 1997 to 2007. The high proportion of poorly cited articles and journals suggests inefficiencies in the cardiovascular research enterprise. PMID- 25812575 TI - Lentiviral vector-mediated doxycycline-inducible USP39 shRNA or cDNA expression in triple-negative breast cancer cells. AB - Triple-negative breast cancer (TNBC), characterized by distinct biological and clinicopathological features, has a poor prognosis due to lack of effective therapeutic targets. Our previous data revealed that high levels of USP39 were selectively present in TNBC samples compared with their normal breast tissue samples and USP39 was also expressed at different levels in cultured TNBC cells and normal breast cells. Yet, the underlying cellular and molecular mechanisms of USP39 remain unclear. In the present study, we describe a doxycycline (DOX) regulated lentiviral vector system expressing shRNA or cDNA of the USP39 gene in the TNBC cell line MDA-MB-231. USP39 expression was knocked down by the miR-30 based inducible lentiviral short hairpin RNA (shRNA) delivery system or overexpressed by the inducible cDNA system. The inducible shRNA-mediated downregulation of USP39 expression markedly reduced the proliferation and colony forming ability of MDA-MB-231 cells, while overexpression of USP39 by the inducible system did not promote cancer cell proliferation. The lentiviral vector mediated Tet-on system demonstrated efficient and inducible knockdown of USP39 or overexpression of USP39 in TNBC cells, facilitating a wide variety of applications for gene knockdown and overexpression experiments in gene functional studies in vitro and in vivo. PMID- 25812576 TI - The networks of care surrounding cancer palliative care patients. AB - OBJECTIVES: This paper explicates the nature and extent of the networks of care surrounding patients with cancer palliative care needs. METHOD: Twenty-four patients with 15 different types/sites of cancer were recruited in one city in England, UK. During one in-depth interview patients identified who was 'involved in their care' and any known pathways of communication between them. One hundred of these people (35 doctors, 32 nurses, 17 professions allied to medicine, 8 family members and 8 others) were also interviewed. Maps of people/teams and the connections between them for each patient were then reconstructed using social networking software (PAJEK). RESULTS: The 24 patients identified a total of 619 people or teams (mean 26, median 22, range 9-45 per patient) contributing to their care. Selected care network maps are displayed, illustrating the extent and nature of the care networks supporting palliative care patients. Common members of care networks for patients with palliative care needs are revealed, but their individual and unique nature is also apparent. CONCLUSIONS: The possible clinical utility and challenges of mapping care networks are discussed. Exploring the care networks surrounding individual patients can be useful for illuminating the extent and complexity of individual patient's care networks; clarifying who is involved and who they communicate with; providing opportunities to see interaction routes that may otherwise be hidden, revealing potentially missing or weak connections; and highlighting overlaps or gaps in provision. PMID- 25812577 TI - Palliative care in cardiopulmonary transplantation. AB - Cardiopulmonary transplantation is a life-prolonging therapy available to a select population of patients with cardiac or respiratory failure. Transplantation is associated with significant morbidity, mortality and unmet palliative care need. Despite recommendations that palliative care should be a core component of the heart and lung transplant process, collaboration within clinical practice is extremely rare. A key reason for this is the misperception among patients, their families and transplant clinicians, that palliative care is analogous with end of life care. Other challenges include prognostication, communication, and the balance of hope and reality. We suggest a change in clinical practice within cardiopulmonary transplantation, whereby palliative care takes place alongside active management. Greater partnership working will demonstrate clinical credibility and highlight the impact of palliative care interventions. Education is required to address current misperceptions and further research should explore the effect of initiatives to improve palliative care provision for this patient group. PMID- 25812578 TI - 'Quality End of Life Care for All' (QELCA): the national rollout of an end-of life workforce development initiative. AB - BACKGROUND: Most people in the UK die in National Health Service (NHS) hospitals and it is essential that NHS employees are equipped to provide high-quality end of-life care. Government policy encourages charities to work in partnership with the NHS and hospices have the necessary expertise to deliver education in end-of life care. INTERVENTION: This article describes the national rollout and evaluation of the 'Quality End of Life Care for All' (QELCA) programme funded by the NHS National End of Life Care Programme. QELCA enables health professionals from acute NHS trusts to experience hospice care and empowers them to improve end of-life care in their own practice settings. Seventeen acute NHS trusts took part with 21 hospices local to the trusts delivering the programme. Overall, 137 acute nurses participated in the programme, which involved 5 days at the hospice followed by 6 months of action-learning sets. OUTCOME: Participants gave concrete examples of improvements they made to end-of-life care and the majority of those who returned postcourse questionnaires believed that QELCA had changed their practice. Additional positive outcomes included better working relationships between acute trusts and hospices, and more appropriate referrals. DISCUSSION: Participants in QELCA progressed from passively identifying problems to actively problem solving and facilitating changes in practice. This attitudinal change has the potential to stimulate and sustain real change in end-of-life care in acute hospitals. QELCA is now being delivered to other members of the multidisciplinary team, including general practitioners. PMID- 25812581 TI - Prediction of the use of conventional hearing aids in Korean adults with unilateral hearing impairment. AB - OBJECTIVE: To determine the use of a hearing aid at six months post-fitting and to evaluate the predictors of its ongoing use in Korean adults with unilateral hearing impairment (HI). DESIGN: Retrospective study at a secondary referral hospital over a 15-year period. STUDY SAMPLE: This study analysed 119 adults with unilateral HI who had been recommended for hearing amplification (55 men and 64 women, mean age, 58.0 +/- 11.7 years). Six months after the fitting, all of the participants were surveyed regarding subsequent decisions and actions about obtaining hearing aids. RESULTS: General uptake rate for a hearing aid was 68.1% (58.0% of participants surveyed were successful users, and 10.1% were intermittent users). The most significant parameter associated with hearing-aid use was social and/or work activities (R(2) = 0.457), and the significant predictors for successful hearing-aid use were social and/or work activities and method of signal processing (discriminatory power = 56.3%). CONCLUSIONS: Six months post-fitting, 68.1% of Korean adults with unilateral HI who had agreed to try a hearing aid continued to use it regularly. The predictors for hearing-aid use six months post-fitting included social and/or work activities and digital signal processing. PMID- 25812580 TI - The audiological journey and early outcomes of twelve infants with auditory neuropathy spectrum disorder from birth to two years of age. AB - OBJECTIVE: To describe the audiological journey of a group of infants with auditory neuropathy spectrum disorder (ANSD) following the fitting of hearing aids, and to investigate the potential benefits of including cortical auditory evoked potentials (CAEPs) and a measure of functional auditory behaviour during early audiological management. DESIGN: Results from chart revision of estimated hearing threshold, early behavioural testing, parental observation, and functional auditory behaviour assessments were described, and compared to visual reinforcement audiometry (VRA) thresholds obtained at a mean corrected age of 10 months (SD 3). The relationship with CAEPs and functional performance was examined. STUDY SAMPLE: The study included 12 infants diagnosed with ANSD and fitted with amplification. RESULTS: The estimated 4FA at a mean corrected age of four months (SD5) was within +/- 10 dB of VRA results in 75% of infants when unaided and aided behavioural observation audiometry (BOA), together with unaided and aided parental observations was combined. Infants with a greater proportion of CAEPs present had higher PEACH scores. CONCLUSIONS: Delaying amplification until VRA results were available would have led to a significant period of auditory deprivation for infants in this study group. None of the assessments could accurately determine hearing thresholds when used in isolation, however when used in combination clinicians were able to obtain sufficient information to fit hearing aids early, and identify infants requiring closer monitoring. PMID- 25812579 TI - A systematic review and meta-analysis of meditative interventions for informal caregivers and health professionals. AB - BACKGROUND: Burnout, stress and anxiety have been identified as areas of concern for informal caregivers and health professionals, particularly in the palliative setting. Meditative interventions are gaining acceptance as tools to improve well being in a variety of clinical contexts, however, their effectiveness as an intervention for caregivers remains unknown. AIM: To explore the effect of meditative interventions on physical and emotional markers of well-being as well as job satisfaction and burnout among informal caregivers and health professionals. DESIGN: Systematic review of randomised clinical trials and pre post intervention studies with meditative interventions for caregivers. DATA SOURCES: PubMed, EMBASE, CINAHL and PsycINFO were searched up to November 2013. Of 1561 abstracts returned, 68 studies were examined in full text with 27 eligible for systematic review. RESULTS: Controlled trials of informal caregivers showed statistically significant improvement in depression (effect size 0.49 (95% CI 0.24 to 0.75)), anxiety (effect size 0.53 (95% CI 0.06 to 0.99)), stress (effect size 0.49 (95% CI 0.21 to 0.77)) and self-efficacy (effect size 0.86 (95% CI 0.5 to 1.23)), at an average of 8 weeks following intervention initiation. Controlled trials of health professionals showed improved emotional exhaustion (effect size 0.37 (95% CI 0.04 to 0.70)), personal accomplishment (effect size 1.18 (95% CI 0.10 to 2.25)) and life satisfaction (effect size 0.48 (95% CI 0.15 to 0.81)) at an average of 8 weeks following intervention initiation. CONCLUSIONS: Meditation provides a small to moderate benefit for informal caregivers and health professionals for stress reduction, but more research is required to establish effects on burnout and caregiver burden. PMID- 25812582 TI - Impact of frequency compression on music perception. AB - OBJECTIVE: To determine the effects of frequency compression on music perception, and the impact of previous music training and hearing status. It was hypothesized that lesser amounts of compression would be preferred, and that this pattern of preference would be more evident in the musically trained groups. DESIGN: A paired-comparison paradigm was used. Subjects listened to pairs of musical passages as processed by a hearing aid with different frequency-compression settings. Subjects indicated their preferred passage and the strength of their preference. STUDY SAMPLE: Fifty-seven subjects divided in four groups, according to hearing status (normal hearing, mild-to-moderate hearing loss), and previous music experience (trained, not trained). RESULTS: Subjects generally preferred the conditions with the lesser amount of compression. Listeners in the group with previous music training showed stronger preference for less compression than those without training, as did listeners with normal hearing when compared to subjects with hearing loss. CONCLUSIONS: Although less frequency compression was in general preferred, there was more variability in the comparisons involving the default settings for a 50-dB hearing loss (i.e. start frequency 4000 Hz, compression ratio 2.5:1) and no compression, suggesting that mild amounts of compression may not be detrimental to perceived sound quality. PMID- 25812583 TI - Significant aortic regurgitation after transfemoral aortic valve implantation: patients' gender as independent risk factor. AB - AIM: Significant aortic regurgitation (AR) has been reported in 20% of patients undergoing transfemoral aortic valve implantation (TAVI) and has been associated with increased mortality. Depending on the population included and the type of implanted prosthesis, several anatomical and procedural factors have been linked with increased risk of post-TAVI AR. While the impact of patients' gender on this complication, is still contradictory. We sought to assess the impact of patients' gender on the risk of significant AR after TAVI. METHODS: We included 323 consecutive patients (136 men) who underwent transfemoral implantation of either self-expandable or balloon-expandable prostheses for treatment of symptomatic aortic stenosis. RESULTS: After TAVI 52 patients (16.1%) had AR grade >= 2/4 as evaluated by angiography. They were more frequently male (59.6% vs. 40.4%, P = 0.005), received self-expandable (94.2% vs. 63.5%, P < 0.001) and bigger size prostheses (28 +/- 1.9 vs. 27.3 +/- 2.1 mm, P = 0.028) and had reduced left ventricular ejection fraction (45.3% +/- 14.2% vs. 51.2% +/- 13%, P = 0.003) compared to patients with AR grade < 2/4 (N. = 271). In multivariate analysis, men (OR 2.13 [95% CI, 1.08-4.18]) and prosthesis type (OR 13.17 [95% CI, 3.24 57.97]) were identified as independent predictors of AR grade >= 2/4. CONCLUSION: Alongside with the implantation of self-expandable aortic prosthesis, male gender independently increases the risk of significant AR in patients undergoing TAVI. The question if this finding is related to gender biology itself or to gender related aggregation of subtle anatomic characteristics needs further investigations. PMID- 25812584 TI - Caloric test as a predictor tool of postural control in CI users. AB - CONCLUSIONS: Balance was improved at 365 days after CI in all patients. Caloric test findings were important determinants of balance outcomes over a year after CI. Pre-operative vestibular assessment findings should be documented because postural recovery over time depends on this information. OBJECTIVE: To verify the importance of the caloric test as a pre-operative predictor tool of postural control after CI surgery. METHODS: Prospective observational study made with 24 post-lingual deafness patients who underwent unilateral CI surgery. Vestibular assessments: questionnaire assessing vertigo, caloric tests, rotary chair (RC) testing, and computerized dynamic posturography (CDP), were sequentially performed for all patients before and 60, 120, 180, and 365 days after CI. RESULTS: Thirteen patients (54.2%) reported dizziness before CI. At the end of the study, dizziness remained unchanged in one (7.7%) patient, ameliorated in 11 (84.6%), and worsened in one (7.7%). Baseline caloric tests identified 29.2% patients with normal reflexes, 33.3% with unilateral areflexia or hyporeflexia, 12.5% with bilateral hyporeflexia, and 25% with bilateral vestibular loss (BVL). Most patients exhibited objective improvements in postural stability. At 365 days, the CDP condition (particularly C5) and CS were higher for caloric tests responders at baseline than for those with BVL at baseline. PMID- 25812585 TI - Exploring oxidative modifications of tyrosine: an update on mechanisms of formation, advances in analysis and biological consequences. AB - Protein oxidation is increasingly recognised as an important modulator of biochemical pathways controlling both physiological and pathological processes. While much attention has focused on cysteine modifications in reversible redox signalling, there is increasing evidence that other protein residues are oxidised in vivo with impact on cellular homeostasis and redox signalling pathways. A notable example is tyrosine, which can undergo a number of oxidative post translational modifications to form 3-hydroxy-tyrosine, tyrosine crosslinks, 3 nitrotyrosine and halogenated tyrosine, with different effects on cellular functions. Tyrosine oxidation has been studied extensively in vitro, and this has generated detailed information about the molecular mechanisms that may occur in vivo. An important aspect of studying tyrosine oxidation both in vitro and in biological systems is the ability to monitor the formation of oxidised derivatives, which depends on a variety of analytical techniques. While antibody dependent techniques such as ELISAs are commonly used, these have limitations, and more specific assays based on spectroscopic or spectrometric techniques are required to provide information on the exact residues modified and the nature of the modification. These approaches have helped understanding of the consequences of tyrosine oxidation in biological systems, especially its effects on cell signalling and cell dysfunction, linking to roles in disease. There is mounting evidence that tyrosine oxidation processes are important in vivo and can contribute to cellular pathology. PMID- 25812587 TI - Oxidation of placental insulin and insulin-like growth factor receptors in mothers with diabetes mellitus or preeclampsia complicated with intrauterine growth restriction. AB - Placental insulin receptor (IR) and insulin-like growth factor receptors (IGFRs) are essential for fetal growth. We investigated structural changes of these receptors exposed to increased oxidative stress in mothers diagnosed with diabetes mellitus (DM) or preeclampsia (PE) complicated with intrauterine growth restriction. Increased amount of IR and decreased amounts of IGF1R and IGF2R were found in both pathologies, accompanied by significant elevation in protein carbonyls. When isolated receptors were examined, increased carbonylation of IR and IGF1R in PE placentas was detected, whereas the amounts of carbonylated IR and IGF1R were similar in DM and healthy placentas. Carbonylation status of IGF2R did not change due to pathology, confirming the detrimental role of primary structure and conformation in oxidative susceptibility. Ligand binding was similar in all three groups of samples and did not seem to be affected by receptor oxidation. Since babies delivered by mothers with PE were smaller than the referent population, increased carbonylation of receptors might have affected downstream receptor signaling post-ligand binding. PMID- 25812586 TI - Thiocyanate supplementation decreases atherosclerotic plaque in mice expressing human myeloperoxidase. AB - Elevated levels of the heme enzyme myeloperoxidase (MPO) are associated with adverse cardiovascular outcomes. MPO predominantly catalyzes formation of the oxidants hypochlorous acid (HOCl) from Cl(-), and hypothiocyanous acid (HOSCN) from SCN(-), with these anions acting as competitive substrates. HOSCN is a less powerful and more specific oxidant than HOCl, and selectively targets thiols; such damage is largely reversible, unlike much HOCl-induced damage. We hypothesized that increased plasma SCN(-), and hence HOSCN formation instead of HOCl, may decrease artery wall damage. This was examined using high-fat fed atherosclerosis-prone LDLR(-/-) mice transgenic for human MPO, with and without SCN(-) (10 mM) added to drinking water. Serum samples, collected fortnightly, were analyzed for cholesterol, triglycerides, thiols, MPO, and SCN(-); study-long exposure was calculated by area under the curve (AUC). Mean serum SCN(-) concentrations were elevated in the supplemented mice (200-320 MUM) relative to controls (< 120 MUM). Normalized aortic root plaque areas at sacrifice were 26% lower in the SCN(-)-supplemented mice compared with controls (P = 0.0417), but plaque morphology was not appreciably altered. Serum MPO levels steadily increased in mice on the high-fat diet, however, comparison of SCN(-) supplemented versus control mice showed no significant changes in MPO protein, cholesterol, or triglyceride levels; thiol levels were decreased in supplemented mice at one time-point. Plaque areas increased with higher cholesterol AUC (r = 0.4742; P = 0.0468), and decreased with increasing SCN(-) AUC (r = - 0.5693; P = 0.0134). These data suggest that increased serum SCN(-) levels, which can be achieved in humans by dietary manipulation, may decrease atherosclerosis burden. PMID- 25812589 TI - Unresolved issues in the analysis of F2-isoprostanes, F4-neuroprostanes, isofurans, neurofurans, and F2-dihomo-isoprostanes in body fluids and tissue using gas chromatography/negative-ion chemical-ionization mass spectrometry. AB - F2-isoprostanes (F2-IsoPs) generated from arachidonic acid (AA) have been recognized as the most reliable marker of nonenzymatic lipid peroxidation in vivo. F2-IsoPs are initially produced in esterified form on phospholipids, and then released into body fluids in free form. The same mechanism can lead to generation of F4-neuroprostanes (F4-NPs) and F2-dihomo-IsoPs from docosahexaenoic acid (DHA) and adrenic acid, respectively. In addition, isofurans (IsoFs) and neurofurans (NFs) may be preferentially produced from AA and DHA, respectively, under high oxygen tension. The detection of F2-IsoPs using gas chromatography/negative-ion chemical-ionization mass spectrometry (GC/NICI-MS) has been widely employed, which is important for human body fluids containing low quantity of free-form F2-IsoPs. F4-NPs have also been detected using GC/NICI-MS, but multiple peaks need to be quantified. In this paper, we summarize the basic workflow of the GC/NICI-MS method for analyzing F2-IsoPs and F4-NPs, and various formats of assays conducted by different groups. We then discuss the feasibility of simultaneous analysis of IsoFs, NFs, and F2-dihomo-IsoPs with F2-IsoPs or F4 NPs. Representative GC chromatograms for analyzing these markers in human body fluids and rat brain tissue are demonstrated. Furthermore, we discuss several factors that may affect the performance of the analysis, such as those related to the sample processing steps, interference from specimens, types of GC liners used, and the addition of electron multiplier voltage in the method setting for the MS detector. Finally, we question the appropriateness of measuring total (free plus esterified) levels of these markers in body fluids. PMID- 25812588 TI - Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-kappaB signaling pathways in murine splenocytes. AB - The adverse effects of ionizing radiation occur due to the generation of reactive oxygen species (ROS). The aim of this study was to identify the protective effects of naringin (NG), a citrus flavonoid, on ionizing radiation (IR)-induced differential stress response, with an exploration of the mechanisms involved in this process. Isolated murine splenocytes were incubated in the presence and in the absence of different concentrations of NG (50 and 100 MUM) for 1 h prior to 6 Gy gamma-irradiation, and the molecular mechanisms of action were determined through biochemical, immunoblot, flow cytometric, and immunofluorescence studies. Pretreatment with NG significantly prevented IR-induced intracellular ROS generation, thereby preventing the formation of cellular TBARS and the development of cellular nitrite. NG significantly reduced nuclear DNA damage with respect to the irradiated splenocytes, through the inhibition of DNA-PKcs and p gammaH2AX. The reduced cell viability as a result of irradiation was recovered by NG through modulation of the redox-regulated cell signaling system. NG pretreatment resulted in significant inhibition of IR-induced G1/S phase cell cycle arrest through the modulation of p53-dependent p21/WAF1, cyclin E, and CDK2 activation. The results also demonstrated that NG blocked the IR-induced p38 function and reversed IR-mediated differential stress response through inhibition of the NF-kappaB pathway. Thus, the p38/NF-kappaB pathway participated in the IR induced inflammatory development, leading to upregulation of CRP, MCP-1, and iNOS2 gene expression. However, NG pretreatment reversed the inflammatory development through downregulation of NF-kappaB, and regulated the expression of CRP, MCP-1, and iNOS2. The above results provide a theoretical basis for the preventive use of NG against radiation-induced multiple cellular anomalies. PMID- 25812590 TI - Measurement of oxidatively induced DNA damage and its repair, by mass spectrometric techniques. AB - Oxidatively induced damage caused by free radicals and other DNA-damaging agents generate a plethora of products in the DNA of living organisms. There is mounting evidence for the involvement of this type of damage in the etiology of numerous diseases including carcinogenesis. For a thorough understanding of the mechanisms, cellular repair, and biological consequences of DNA damage, accurate measurement of resulting products must be achieved. There are various analytical techniques, with their own advantages and drawbacks, which can be used for this purpose. Mass spectrometric techniques with isotope dilution, which include gas chromatography (GC) and liquid chromatography (LC), provide structural elucidation of products and ascertain accurate quantification, which are absolutely necessary for reliable measurement. Both gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS), in single or tandem versions, have been used for the measurement of numerous DNA products such as sugar and base lesions, 8,5'-cyclopurine-2'-deoxynucleosides, base-base tandem lesions, and DNA-protein crosslinks, in vitro and in vivo. This article reviews these techniques and their applications in the measurement of oxidatively induced DNA damage and its repair. PMID- 25812591 TI - Implications for your practice: Important changes in the 2014 guideline for the management of patients with atrial fibrillation. AB - Atrial fibrillation (AF) is an increasingly common cardiac arrhythmia, currently affecting more than 5 million Americans. Management of patients with AF can be complex, with key strategies including selecting rhythm control versus heart rate control and reducing the patient's risk of stroke or other systemic embolization. The American Heart Association, American College of Cardiology, and Heart Rhythm Society released 2014 Guideline for the Management of Patients with Atrial Fibrillation, which outlines several new recommendations with important clinical implications. Among these are a new recommendation to use the CHA2DS2-Vasc score for stroke risk assessment, rather than the previously advised CHADS2 score, expansion of anticoagulation options in selected patients, decreased emphasis on the role of aspirin, and an increased emphasis on the role of catheter ablation. PMID- 25812592 TI - [Clinical analysis of non-clear cell renal cell carcinoma]. AB - Clinicopathological features and prognosis of metastatic renal cell carcinoma (mRCC) vary by histopathological type. In this study, we analyzed these relationships with regard to non-clear cell RCC (nccRCC). We also analyzed the therapeutic trends for patients with mRCC. We initially identified 367 patients who were diagnosed with RCC and treated in our hospital between 2001 and 2013 ; 55 patients of whom were diagnosed with nccRCC. We reviewed their backgrounds, histopathological types and outcomes. Median age at diagnosis for patients with nccRCC was significantly younger (58.5 years) than for those with clear-cell RCC (66.3 years ; P=0.008) ; however, these histological types did not significantly differ by sex, affected side or rate of mRCC. Of the 55 nccRCC cases, 19 were mRCC, including 5 of the 8 cases of papillary type-2 RCC, and all patients who had either collecting duct carcinoma, sarcomatoid RCC or Xp11 translocation RCC. The most common metastatic site was lymph nodes. Although patients with papillary type-1 and Xp11 translocation RCC had relatively good prognoses, those with papillary type-2, collecting duct carcinoma and sarcomatoid RCC had poor prognoses. Among the 9 patients with nccRCC who received molecular targeted therapy, median survival was 13.3 months. Although existing therapeutic agents may be effective for some patients with nccRCC, identification of new target molecules and innovative drug development are needed in the future. PMID- 25812593 TI - [The significance of metastasectomy in patients with metastatic renal cell carcinoma]. AB - We conducted a retrospective study to clarify the clinical significance of metastasectomy in patients with metastatic renal cell carcinoma (mRCC). Of 83 mRCC patients who were treated at our hospital between 2005 and 2010, 19 patients who underwent metastasectomy during the treatment course were the subjects of the present study. By the purpose and timing of metastasectomy, we classified the 19 patients into three groups : (1) patients who immediately underwent metastasectomy at diagnosis of metastasis (primary group), (2) patients who underwent resection of clinically problematic metastatic lesions for the relief of their symptoms (palliative group), and (3) patients who underwent complete resection of all metastatic lesions after sufficient systemic therapies (consolidation group). In the primary group (n=5), four patients had lung metastasis and one had metastases to limbs and the adrenal gland. Overall survival at 3 years was 100%. In the palliative group (n=4), 3 patients underwent resection of brain metastasis and one underwent resection of skin metastasis. The symptoms associated with metastasis clearly improved. In the consolidation group (n=10), the metastasized organ was the lung in 5 patients, pancreas in 4, and liver in one. Preoperative systemic therapy included sunitinib or sorafenib in 5 patients, interferon-alpha in 4, and S-1 in one. After metastasectomy, systemic therapies were discontinued in 9 patients, 4 of whom did not experience RCC recurrence, with a median follow-up of 35 months. Overall survival at 3 years was 60%. Metastasectomy would be a good treatment option in patients with mRCC. PMID- 25812594 TI - [Investigation of incidence and risk factors of subcutaneous granulomas induced by injection of leuprorelin acetate]. AB - We investigated the incidence of granuloma and its related factors in 180 patients with prostate cancer who showed subcutaneous granuloma formation during androgen deprivation therapy with subcutaneously administered leuprorelin acetate. A granuloma was defined as a persistent induration over 30 mm in diameter in the injected portion. Small indurations which often developed and disappeared after every injection were excluded. The survey was performed using a questionnaire after receiving written informed consent. Among the 180 patients with prostate cancer, 21 (11.7%) developed a granuloma at the injection portion, and subsequently the injection of leuprorelin acetate had to be discontinued. Eighteen of the 21 patients alternatively received goserelin acetate. Three patients had high-grade granulomas with ulcer and abscess formation, and were successfully treated with oral antibiotics. The average duration between the first injection of leuprorelin acetate and granuloma formation was 20.2 months (range : 4 to 62 months). There was no association between granuloma formation and patient backgrounds, such as allergic predisposition and past history. Twenty one of the 180 prostatic cancer patients developed subcutaneous granuloma induced by the injection of leuprorelin acetate. The investigation showed an unexpectedly high incidence of granuloma formation. We must explain the risk of developing subcutaneous granuloma to the patients before introducing leuprorelin acetate. PMID- 25812596 TI - [Primary testicular malignant lymphoma in a hemodialysis patient : a case report]. AB - We report a case of testicular malignant lymphoma in a hemodialysis patient. A 65 year-old man who had been undergoing hemodialysis for 8 years and 10 months consulted our hospital with right testicular enlargement in August 2012. Under a diagnosis of testicular cancer from manipulation test and ultrasonography, high orchiectomy was performed. Computed tomography showed swelling of the retroperitoneal lymph nodes. Histopathological examination revealed diffuse, non Hodgkin B-cell lymphoma, CD20+. R-CHOP chemotherapy was initiated and retroperitoneal lymph node swelling completely disappeared after 1 cycle of chemotherapy. After completing 2 cycles of chemotherapy, the patient developed interstitial pneumonia, and thus radiotherapy to the retroperitoneal space including the left testis was performed. As of July 2014, the patient remains alive without recurrence. PMID- 25812597 TI - [Cyst of the tunica albuginea testis : a case report]. AB - This report concerns a case of cyst of the tunica albuginea testis in a 74-year old man, who presented with a painful swelling of right scrotal contents. Magnetic resonance imaging (MRI) and ultrasonography revealed a cystic mass on the surface of the right testicle. We performed resection of the cystic wall. The histological findings indicated cyst of the tunica albuginea testis. In this series, we collected 30 cases in the Japanese literature. PMID- 25812595 TI - [A case of extramammary Paget's disease with urethral invasion treated by construction of continent urinary diversion based on the Monti principle using the sigmoid colon]. AB - Extramammary Paget's disease occurring in the female vulva is occasionally associated with invasive disease to urethra and bladder mucosa. For such cases, ensuring adequate surgical margin is essential. Not only adequate removal of tumor, but also urinary diversion is important for patient's quality of life. A 77- year-old woman was treated with excision of vulvar tumor, urethra, vagina, rectum and anus. The determination of excision area was decided according to the result of mapping biopsy including urethra and bladder. Then she received reconstruction of vulva using the gracilis muscle skin flap. We applied a technique of channel formation for intermittent catheterization using the retubularized sigmoid colon based on the Monti principle. The tube was implanted submucosally into the bladder to prevent the reflux of urine. Fifteen days after operation, self-intermittent catheterization was started successfully. Surgical margins were negative in urethra, skin, vagina and rectum. There are no obvious recurrence or metastasis 1 year after surgery. PMID- 25812599 TI - Synthesis of linear piperazine/polyether functional polysiloxane and its modification of surface properties on cotton fabrics. AB - In this work, silicone softener (PTSO-PEG) was synthesized, with piperazine terminated polydimethylsiloxane (PTSO) and epoxy terminated polyethylene glycol (EPEG) as raw materials. Chemical structure of PTSO-PEG was characterized by (1)H NMR, FTIR, GPC, and TGA. Its application on cotton fabrics was studied. Morphologies of silicone modified surfaces on cotton fabrics and silicon wafers were investigated by SEM and AFM, respectively. The morphology images indicated that PTSO-PEG treated surface was macroscopically smooth and microscopically rough. Performance properties of silicone treated cotton fabrics, including hydrophilicity, whiteness, and softness, were tested. The results showed that PTSO-PEG treated cotton fabrics expressed better whiteness and hydrophilicity than traditional amino silicone treated sample. The piperazine and hydrophilic polyether groups on PTSO-PEG molecules disturbed the continuous and orderly arrangement of Si-CH3 groups, giving the cotton a hydrophilic and rough surface. This work provided a cost-effective and environmental method to synthesize and apply high performance silicone softener. PMID- 25812598 TI - ATP-sensitive potassium channels alleviate postoperative pain through JNK dependent MCP-1 expression in spinal cord. AB - Although adenosine triphosphate-sensitive potassium (KATP) channels have been proven to be involved in regulating postoperative pain, the underlying mechanism remains to be investigated. In this study, we aimed to determine the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat pain model, in which rats were subjected to skin/muscle incision and retraction (SMIR) surgery, as well as in LPS-stimulated astrocytes. The results showed that KATP channel subunits Kir6.1, SUR1 and SUR2 were normally expressed in the spinal cord and significantly downregulated after SMIR. SMIR caused a marked increase in monocyte chemoattractant protein-1 (MCP-1) mRNA expression and in the protein level of p-JNK in the spinal cord. Intrathecal administration of a KATP channel opener pinacidil (Pina) suppressed mechanical allodynia after SMIR and significantly downregulated the MCP-1 mRNA expression and the protein level of p JNK induced by SMIR. Inverted fluorescence microscopy showed that Kir6.1 was co localized with astrocytes only and SUR2 was co-localized primarily with neurons, in a small amount with astrocytes. Furthermore, in vitro studies showed that following incubation with LPS, the astrocytic MCP-1 mRNA expression and p-JNK content were markedly increased, whereas the mRNA levels of Kir6.1 and SUR2 were significantly downregulated in astrocytes. KATP channel opener pinacidil inhibited the LPS-triggered MCP-1 and p-JNK elevation in rat primary astrocytes. The results suggested that KATP channel opener treatment is an effective therapy for postoperative pain in animals, through the activation of the JNK/MCP-1 pathway in astrocytes. PMID- 25812600 TI - Sapropterin dihydrochloride for phenylketonuria. AB - BACKGROUND: Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with sapropterin dihydrochloride. We examined the evidence for the use of sapropterin dihydrochloride to treat phenylketonuria. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. SEARCH METHODS: We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 11 August 2014.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 4 September 2014We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. SELECTION CRITERIA: Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials and extracted outcome data. MAIN RESULTS: Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 MUmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference 51.90 MUmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. AUTHORS' CONCLUSIONS: There is evidence of short-term benefit from using sapropterin in some people with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria. PMID- 25812602 TI - Transversal Anderson localization of sound in acoustic waveguide arrays. AB - We present designs of one-dimensional acoustic waveguide arrays and investigate wave propagation inside. Under the condition of single identical waveguide mode and weak coupling, the acoustic wave motion in waveguide arrays can be modeled with a discrete mode-coupling theory. The coupling constants can be retrieved from simulations or experiments as the function of neighboring waveguide separations. Sound injected into periodic arrays gives rise to the discrete diffraction, exhibiting ballistic or extended transport in transversal direction. But sound injected into randomized waveguide arrays readily leads to Anderson localization transversally. The experimental results show good agreement with simulations and theoretical predictions. PMID- 25812601 TI - Enzyme replacement and substrate reduction therapy for Gaucher disease. AB - BACKGROUND: Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. OBJECTIVES: To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews.Date of last search: 07 August 2014. SELECTION CRITERIA: All randomized and quasi-randomized controlled studies (including open-label studies and cross over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. MAIN RESULTS: Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized.Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy.Treatment-naive participants had similar increases in haemoglobin when comparing those receiving imiglucerase or alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose.A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment.There are, as yet, no randomized trials of substrate reduction therapy in treatment-naive patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat.One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. AUTHORS' CONCLUSIONS: The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare diseases such as type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety - with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this chronic condition. PMID- 25812603 TI - Near-infrared fluorescent digital pathology for the automation of disease diagnosis and biomarker assessment. AB - Hematoxylin-eosin (H&E) staining of tissue has been the mainstay of pathology for more than a century. However, the learning curve for H&E tissue interpretation is long, whereas intra- and interobserver variability remain high. Computer-assisted image analysis of H&E sections holds promise for increased throughput and decreased variability but has yet to demonstrate significant improvement in diagnostic accuracy. Addition of biomarkers to H&E staining can improve diagnostic accuracy; however, coregistration of immunohistochemical staining with H&E is problematic as immunostaining is completed on slides that are at best 4 MUm apart. Simultaneous H&E and immunostaining would alleviate coregistration problems; however, current opaque pigments used for immunostaining obscure H&E. In this study, we demonstrate that diagnostic information provided by two or more independent wavelengths of near-infrared (NIR) fluorescence leave the H&E stain unchanged while enabling computer-assisted diagnosis and assessment of human disease. Using prostate cancer as a model system, we introduce NIR digital pathology and demonstrate its utility along the spectrum from prostate biopsy to whole mount analysis of H&E-stained tissue. PMID- 25812604 TI - High intake of heterocyclic amines from meat is associated with oxidative stress. AB - High meat intake has been related to chronic diseases such as cancer and CVD. One hypothesis is that heterocyclic amines (HCA), which are formed during the cooking process of meat, can generate reactive species. These compounds can cause oxidation of lipids, proteins and DNA, resulting in oxidative stress, cell damage and loss of biological function. This association has been seen in vitro; however, it remains unclear in vivo. The aim of the present study was to investigate the association between oxidative stress and HCA intake, and oxidative stress and meat intake. Data were from the Health Survey for Sao Paulo- ISA-Capital (561 adult and elderly). Food intake was estimated by one 24-h dietary recall (24HR) complemented by a detailed FFQ with preferences of cooking methods and level of doneness for meat. HCA intake was estimated linking the meat from the 24HR to a database of HCA. Oxidative stress was estimated by malondialdehyde (MDA) concentration in the plasma, after derivatisation with thiobarbituric acid and quantification by HPLC/diode array. Analyses were performed using multivariate logistic regressions adjusted for smoking, sex, age, BMI, skin colour, energy intake, fruit and vegetable intake, and physical activity. A positive association between HCA intake and MDA concentration (OR 1.17; 95% CI 1.01, 1.38) was observed, showing that HCA from meat may contribute to increase oxidative stress, and may consequently increase the risk of chronic diseases. PMID- 25812607 TI - Medical education - beyond the evaluation of intellectual competency. PMID- 25812605 TI - Tetramethylpyrazine inhibits the proliferation of acute lymphocytic leukemia cell lines via decrease in GSK-3beta. AB - Tetramethylpyrazine (TMP) has been proven to be an anticancer agent in many studies. However, its effectiveness in acute lymphoblastic leukemia (ALL) and its molecular mechanisms are still unclear. The present study aimed to evaluate the effect of TMP against Jurkat and SUP-B15 ALL cell lines and to investigate the possible detailed mechanism of action of TMP. A Cell Counting Kit-8 (CCK-8) assay was employed to examine the proliferation of Jurkat and SUP-B15 cells. Flow cytometric analysis was conducted to detect the cell cycle distribution and apoptotic rate. The expression of total glycogen synthase kinase-3beta (GSK 3beta), cox-2, survivin, bcl-2 and p27 RNA and protein levels was detected by quantitative real-time PCR and western blot assay, respectively. Additionally, western blot analysis was used to determine the whole-cell and nuclear protein levels of GSK-3beta downstream transcription factors, NF-kappaB (p65) and c-myc. TMP inhibited the proliferation of Jurkat and SUP-B15 cells in a dose- and time dependent manner, with IC50 values of 120 and 200 ug/ml, respectively at 48 h. TMP induced the apoptosis of Jurkat and SUP-B15 cells and synergistically blocked cell cycle progression at the G0/G1 phase. Cells treated with TMP exhibited significantly attenuated GSK-3beta, NF-kappaB (p65) and c-myc expression, followed by downregulation of bcl-2, cox-2 and survivin and an upregulation of p27. The results showed that TMP induced apoptosis and caused cell cycle arrest in Jurkat and SUP-B15 cells through the downregulation of GSK-3beta, which may have further prevented the induced translocation of NF-kappaB and c-myc from the cytoplasm to the nucleus. PMID- 25812606 TI - Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells. AB - Studies on stem cell differentiation led to the identification of paused genes, characterized by the contemporary presence of both activator and repressor epigenetic markers (bivalent marking). TXNIP is an oncosuppressor gene the expression of which was reduced in breast cancer. In the present study, we evaluated whether the concept of epigenetic bivalent marking can be applied to TXNIP gene in breast cancer cells. Using chromatin immunoprecipitation (ChIP), three histone modifications were investigated: two associated with transcriptional activation, lysines 9-14 acetylation of H3 histone (H3K9K14ac) and lysine 4 trimethylation of H3 histone (H3K4me3), and one associated with transcriptional silencing, lysine 27 trimethylation of H3 histone (H3K27me3). According to the bivalent marking model, TXNIP gene appears to be paused in MDA157 cells (markers of active and repressed transcription are present), but are definitively silenced in MDA468 cells (presence of only markers of transcription repression). This was proven by evaluating TXNIP mRNA and protein levels after the treatment of cell lines with a histone deacetylase inhibitor (SAHA) and a poly-ADP-ribose polymerases inhibitor (PJ34). In MDA157 cells, SAHA and PJ34 showed a synergistic effect: a large increment was observed in TXNIP mRNA and protein levels. By contrast, in MDA468 cells, synergy between the two compounds was not observed. Therefore, the pausing epigenetic signature was permissive for synergy between SAHA and PJ34 on TXNIP gene expression. The synergy between SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis. In MDA157 cells, but not in MDA468 cells, combined treatment of SAHA and PJ34 induced a decrease in cell viability and an increase of apoptosis. Thus, our data support the hypothesis that TXNIP is an effective target for the treatment of breast cancer. PMID- 25812608 TI - Effect of emotional intelligence on patient-physician interaction scores of clinical performance examination. AB - PURPOSE: The patient-physician interaction (PPI) is a critical part of the clinical encounter. Recent studies have emphasized the importance of the emotional intelligence (EI) of physician in the PPI. Despite emphasizing the EI, previous studies offer limited evidence regarding the effect of a student's EI on the PPI. The purpose of this study is to explore the differences in EI depending on the demographics of medical students and the correlation between EI and PPI scores. METHODS: The sample was 85 fourth-grade medical students. Prior to taking a 12-station clinical performance examination, the students completed questionnaires on their own perception of the EI, which included 5 domains and 50 items. The tool that was used to assess the level of EI was Moon's modified version of the EI test for adults. We investigated differences in EI depending on the demographics of medical students by ANOVA and noted a correlation between EI and PPI scores by stepwise multiple regression analysis. RESULTS: This study found that females or graduate entry students have higher EI scores and that 25 to 30-year-old students have higher EI scores than aged under 25 years. The PPI scores correlated positively with total EI scores (r=0.32) and 2 subdomains (perception and expression of emotion, r=0.26; empathy, r=0.33). Two subdomains were the best predictors of PPI score (R2=0.171). CONCLUSION: EI correlates significantly with PPI score and affects it. We conclude that EI is a key influence of the PPI. Further research is required to explore whether this is a consistent effect. PMID- 25812609 TI - The effects of attribution tendencies, academic stress, and coping efficacy on academic adjustment of medical students. AB - PURPOSE: This study investigated the relationship among types of attribution tendencies, academic stress, coping efficacy, and academic adjustment in medical students and identified the means by which the academic adjustment of medical students can improve. METHODS: Four hundred forty-two subjects from 2 medical schools in Korea were analyzed; 202 were male, 206 were female, and 34 did not identify their gender. We surveyed their academic adjustment, attribution tendencies, academic stress, and coping efficacy. The data were analyzed by descriptive statistics, t-test, and stepwise multiple regression analysis. RESULTS: The male group scored higher on academic adjustment, internal attribution tendency, and coping efficacy but lower on academic stress than the female group. Coping efficacy and internal attribution tendency affected the academic adjustment positively while academic stress influenced it negatively. CONCLUSION: The study indicates that students with higher scores on coping efficacy and internal attribution tendency and who have lower scores on academic stress tend to adjust better academically in medical school. Therefore, these findings may be helpful for medical schools in designing effective academic adjustment programs to improve coping efficacy and internal attribution tendency and reduce academic stress. Further, these findings have important implications for planning learning consultation programs, especially in Year 1. PMID- 25812610 TI - Analysis of medical students' enneagram personality types, stress, and developmental level. AB - PURPOSE: The purpose of this research was to examine the medical students' personality with stress and developmental level. The study explored three overarching topics: How are medical students' personality types reflected in an enneagram? Are there any differences between subtypes of stress points? How are the students' developmental levels by gender, academic level, and enneatypes? METHODS: The subjects were 414 medical students in three Korean medical schools. Enneagram Personality Types Inventory (Korean version) was used. These enneatypes were divided into four subtypes: centers of intelligence, hornevian triads, self consciousness, and harmonic group. Enneatypes and stress points were analyzed statistically by frequency and percentage of enneatypes, chi-square test, and ANOVA. RESULTS: Distribution of enneatypes; type 9 was the most frequent class (n=136, 32.9%). Types 1, 3, 4, and 9 had more disintegrated students than other types (chi2=59.2, p=0.000). Subtype analysis; in body-centered type more students were disintegrated than integrated or mediocre (chi2=25.8, p=0.000). In behavior patterns, aggressive and passive types showed more disintegration (chi2=25.2, p=0.000), and in self-consciousness groups only inner order types showed integration (chi2=19.3, p=0.001). In harmonic group, positive outlook types contained the most disintegrated students (chi2=20.5, p=0.000). Majority of medical students were in disintegrated developmental status. CONCLUSION: A program should be developed for students to know their ego-identity plainly and overcome their disintegration, based on their enneatypes. Such a program will help students improve their ways of thinking or their behavior and become more secure. PMID- 25812611 TI - The Development Study of a Medical Ethics Education Program by Using Simple ISD Model. AB - PURPOSE: Simple instructional systems design (ISD) model is based on a fast development, usability test, and continuos feedback, which are necessary for educational program development in medical school. This study aims to figure out the usability of Simple ISD model for a medical ethics education program by describing a developmental details of each phase and its evaluation results. METHODS: Research has been conducted in two steps. First, while researchers participated in the program development by using Simple ISD model, we collected empirical data of each development activities. Second, the developed program was evaluated by students' web-based usability test, a 8-students' focus group interview and 5 faculty members' individual interviews in 4 domains; learning contents, instructional methods and strategies, achievement evaluation, and self evaluation. RESULTS: Following the circular process of analysis, design, development, and usability test of Simple ISD model, a 10-week medical ethics program covering 9 instructional topics was developed. The average points of response on the developed medical ethics program in 2008 and 2009 are increased from 3.96 to 4.59 and 4.41, respectively. The prospects and limitations of the program are discussed. CONCLUSION: From a development study of the medical ethics program by using Simple ISD model, we could implement a more usable medical ethics program, and found 4 different usability of the Simple ISD model; the rapid development of educational program, program improvement by continuous feedback, faculty members' engagement in instructional design, and professional development of the faculty members. PMID- 25812612 TI - The Change of CPX Scores according to Repeated CPXs. AB - PURPOSE: Most medical schools have held clinical skills training programs recently. Despite these educational endeavors, few studies have attempted to address the effect of clinical skills assessments on clinical performance. This study investigated whether repeated experiences with the examination improved medical students' history-taking, physical exams, and patient-physician interactions (PPIs). METHODS: The subjects of the study were 101 4th-year medical students who participated in the clinical performance examination (CPX) 3 times. They completed their core clerkship before acquiring the first CPX scores; we tracked down the scores of three sets of CPX for 3 subdomains (history taking, physical exam, and patient-physician interaction) and investigated the changes in these scores. Additionally, we classified the research subjects into 3 groups by total CPX score-higher (upper 30%, n=30), intermediate (medium 40%, n=40), and lower (lower 30%, n=30)-and compared the curves for each group. RESULTS: Significant improvements were made on history taking and physical exam (F=130.786/237.358, p<0.01), while proficiency on the PPI declined (F=17.621, p<0.01). Additionally, scores in all levels improved continuously on history taking and physical exam, while students of the high and low levels experienced a sharp decline on the PPI (F=11.628, p<0.01). CONCLUSION: Improvement in the history-taking score reflects an accumulation of clinical knowledge and clinical exposure. Improvement on the physical exam score is affected by repeated practice on similar or identical cases and receipt of feedback. That PPI can deteriorate might be an effect of one's negative experience in a clinical clerkship. PMID- 25812613 TI - Analysis of first clinical skills examination in the korean medical licensing examination: focus on examinees' experience in a medical school. AB - PURPOSE: The purpose of this study was to investigate the experience of examinees who took the first clinical skill examination in Korea. METHODS: The data were collected by written survey, telephone, and face-to-face interviews with 46 examinees who took a clinical skills examination test at Jeju National University School of Medicine. Thirty-two questionnaires were valid for analysis. RESULTS: Examinees' self-evaluation scores with regard to the level of difficulty of the CPX was 2.83 on average (1 for very easy, 5 for very difficult), and the score on the degree of adequate time for the CPX was 2.69 on average (1 for enough, 5 for very short). Examinees' self-evaluation scores on the level of difficulty of the OSCE was 2.37 on average (1 for very easy, 5 for very difficult), and the score on the degree of adequate time for the OSCE was 2.56 on average (1 for enough, 5 for very short). CONCLUSION: We hope that our study provides useful information on practical questions in the development and review of exams and will be used to develop educational content and teaching methods in medical education. PMID- 25812615 TI - How to Write a Peer Reviewer's Opinion? PMID- 25812614 TI - Analysis of students' reflective essays on their first human dissection experience. AB - PURPOSE: Reflection is increasingly being used in higher education, but the criteria to assess the depth of reflection in student essays are difficult to define. This article tested the hypothesis that a good reflective essay contains more terms indicating mental processes. METHODS: The authors selected two essays written by first year medical students at The University of Hong Kong, after their first encounter with cadavers in their dissection class. The two essays were perceived by teachers as having different depths of reflection. The transitivity system in Systemic Functional Linguistics was adopted to compare the two essays in terms of percentage occurrence of different process types (mental, material, relational, verbal, behavioral, existential). RESULTS: The analysis showed that the essay with deeper reflection had a higher percentage occurrence of mental and relational processes and a low percentage occurrence of material processes. The other three processes accounted for only a low percentage of processes in both essays. CONCLUSION: From the transitivity analysis of the two reflective essays, the hypothesis that a good reflective essay contains more terms indicating mental processes is supported. The transitivity system in systemic functional linguistics can thus be used as an objective framework for assessing the depth of reflection in written essays. PMID- 25812616 TI - How to present at meetings. 2nd edition. PMID- 25812617 TI - Case of misconduct of publication ethics: fabrication of of manuscript submission proof. PMID- 25812618 TI - Correlation between treatment time, photobleaching, inflammation and pain after photodynamic therapy with methyl aminolevulinate on tape-stripped skin in healthy volunteers. AB - Photodynamic therapy (PDT) is an attractive treatment option for skin diseases such as actinic keratosis, since large skin areas can be treated with high response rates and good cosmetic outcomes. Nevertheless inflammation and pain are still major side effects. The aim of this study was to investigate the extent to which less time-consuming PDT treatment regimens using methyl aminolevulinate (MAL) decrease protoporphyrin IX (PpIX) photobleaching, inflammation and pain. Twenty-four healthy volunteers were treated with 4 different interventions on each forearm. All 8 fields were tape-stripped 10 times. On the right arm MAL was applied for 20, 40, 60 or 180 min, followed by further incubation after wiping off MAL until 180 min after start and then illuminating with red light 180 min after start. On the left arm MAL or vehicle was applied for 30, 60, or 90 min and illuminated immediately after MAL removal. PpIX fluorescence, photobleaching, objective and subjective erythema (as a measure for inflammation), pigmentation and pain were measured. The results showed a significant correlation between incubation time, time until illumination and photobleaching. Furthermore, there was a significant correlation between photobleaching and erythema and also between photobleaching and pain. In conclusion, shorter PDT regimens result in decreased photobleaching and also less inflammation and pain. We hypothesize that a shorter incubation time is important for the optimal specific subcellular distribution of PpIX and to avoid unspecific distribution. We propose a shorter PDT regimen, "Pulse PDT", comprising, for example 30 min incubation with MAL and illumination after 180 min, and we have planned a study of actinic keratosis and "Pulse PDT". PMID- 25812620 TI - Cutaneous Rosai-Dorfman disease. PMID- 25812619 TI - Effects of waste glass additions on quality of textile sludge-based bricks. AB - This research investigated the utilization of textile sludge as a substitute for clay in brick production. The addition of textile sludge to a brick specimen enhanced its pores, thus reducing the quality of the product. However, the addition of waste glass to brick production materials improved the quality of the brick in terms of both compressive strength and water absorption. Maximum compressive strength was observed with the following composition of waste materials: 30% textile sludge, 60% clay and 10% waste glass. The melting of waste glass clogged up pores on the brick, which improved water absorption performance and compressive strength. Moreover, a leaching test on a sludge-based brick to which 10% waste glass did not detect significant heavy metal compounds in leachates, with the product being in conformance with standard regulations. The recycling of textile sludge for brick production, when combined with waste glass additions, may thus be promising in terms of both product quality and environmental aspects. PMID- 25812621 TI - AuRu/AC as an effective catalyst for hydrogenation reactions. AB - AuRu bimetallic catalysts have been prepared by sequential deposition of Au on Ru or vice versa obtaining different nanostructures: when Ru has been deposited on Au, a Au(core)-Ru(shell) has been observed, whereas the deposition of Au on Ru leads to a bimetallic phase with Ru enrichment on the surface. In the latter case, the unexpected Ru enrichment could be attributed to the weak adhesion of Ru on the carbon support, thus allowing Ru particles to diffuse on Au particles. Both structures result very active in catalysing the liquid phase hydrogenolysis of glycerol and levulinic acid but the activity, the selectivity and the stability depend on the structure of the bimetallic nanoparticles. Ru@Au/AC core shell structure mostly behaved as the monometallic Ru, whereas the presence of bimetallic AuRu phase in Au@Ru/AC provides a great beneficial effect on both activity and stability. PMID- 25812622 TI - Outcomes of frontal mucoceles treated with conventional endoscopic sinus surgery. AB - CONCLUSION: Conventional endoscopic sinus surgery (CESS) is useful for frontal mucoceles. A patient with short anterior-posterior distance and bone thickening may need an axillary flap, Draf type IIb, or Draf type III procedure. OBJECTIVE: To present outcomes of frontal mucoceles treated with CESS and predict risk factors for poor outcomes to help define surgical indications. METHODS: A consecutive clinical series was reviewed retrospectively. The authors performed CESS without agger nasi resection (Draf type IIa) for 13 frontal sinus mucoceles in 12 patients between October 2011 and July 2013. Patient age, sex, blood eosinophil count, history of operation and co-existence of acute infection were compared. For the condition of the frontal sinus, anterior-posterior distance and width of frontal recess, bone thickening of the frontal recess, bone absorption due to continuous pressure by mucocele and anatomy of the frontal recess was noted. RESULTS: All operations were done without a navigation system. The post operative course was uneventful in all 12 patients, and all symptoms gradually receded. Among 13 mucoceles, one frontal sinus (7.7%) closed during follow-up. PMID- 25812623 TI - Ultrasonography in gastroenterology. AB - Ultrasonography (US) is a safe and available real-time, high-resolution imaging method, which during the last decades has been increasingly integrated as a clinical tool in gastroenterology. New US applications have emerged with enforced data software and new technical solutions, including strain evaluation, three dimensional imaging and use of ultrasound contrast agents. Specific gastroenterologic applications have been developed by combining US with other diagnostic or therapeutic methods, such as endoscopy, manometry, puncture needles, diathermy and stents. US provides detailed structural information about visceral organs without hazard to the patients and can play an important clinical role by reducing the need for invasive procedures. This paper presents different aspects of US in gastroenterology, with a special emphasis on the contribution from Nordic scientists in developing clinical applications. PMID- 25812625 TI - A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection. AB - Colchicine induces neurodegeneration, but the extent of neurodegeneration in different areas of the brain in relation to neuroinflammation remains unclear. Such information may be useful to allow for the development of a model to compare colchicine-induced neurodegeneration with other neurodegenerative diseases such as Alzheimer's Disease (AD). The present study was designed to investigate the extent of neurodegeneration along with neuroinflammation in different areas of the brain, e.g. frontal cortex, parietal cortex, occipital cortex, corpus striatum, amygdala and hippocampus, in rats along with memory impairment 21 days after a single intracerebroventricular (icv) injection of colchicine. Memory parameters were measured before and after icv colchicine injection in all test groups of rats (control, sham-operated, colchicine-injected [ICIR] rats). On Day 21 post-injection, rats from all groups were anesthesized and tissues from the various brain areas were collected for assessment of biomarkers of neuroinflammation (i.e. levels of ROS, nitrite and proinflammatory cytokines TNFalpha and IL-1beta) and neurodegeneration (assessed histologically). The single injection of colchicine resulted in impaired memory and neurodegeneration (significant presence of plaques, Nissl granule chromatolysis) in various brain areas (frontal cortex, amygdala, parietal cortex, corpus striatum), with maximum severity in the hippocampus. While IL-1beta, TNFalpha, ROS and nitrite levels were altered in different brain areas in the ICIR rats, these parameters had their greatest change in the hippocampus. This study showed that icv injection of colchicine caused strong neurodegeneration and neuroinflammation in the hippocampus of rats and the increases in neurodegeneration were corroborated with those of neuroinflammation at the site. The present study also showed that the extent of neurodegeneration and neuroinflammation in different brain areas of the colchicine-injected rats were AD-like and supported the fact that such rats might have the ability to serve as a sporadic model of AD. PMID- 25812626 TI - Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. AB - Inflammation is a crucial factor in the pathogenesis of numerous diseases. This study sought to evaluate the effects of thymol and carvacrol, the main components of Thymus vulgaris (thyme) essential oil, on transcription factors regulating inflammation. Lipopolysaccharide (LPS)-stimulated J774.1 mouse macrophages were examined by real time-PCR for interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha gene expression in the presence of these compounds. Levels of inducible phospho-nuclear factor-kappaB (pNF-kappaB) p65, activator protein-1 [AP 1(c-Fos/c-Jun)], and nuclear factors of activated T-cells (NFATs) were also measured using Western blots. Levels of phosphorylation of stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinase (SAPK/JNK), signal transducer, and activator of transcription (STAT-3), p38, IkappaBalpha, and NF-kappaB p65, as well as total levels of IL-1beta and TNFalpha were determined. The results indicated carvacrol significantly reduced both IL-1beta and TNFalpha at the protein and mRNA levels; thymol also significantly reduced IL-1beta expression. Western blot analyses of nuclear cell extracts revealed both agents caused significantly decreased expression of c-Fos, NFAT-1, and NFAT-2; decreased expression of c-Jun was only caused by carvacrol. Neither agent inhibited p-NF kappaB p65 expression. At the protein level, carvacrol and thymol each caused decreases in inducible phospho-SAPK/JNK and phospho-STAT3 levels, whereas only carvacrol resulted in increased p-p38 levels in the total cell extract. Despite the reduction of phospho-IkappaBalpha caused by both agents, p-NF-kappaB p65 still increased in the presence of carvacrol. Based on these findings, it is concluded that carvacrol and thymol could contribute to reduction of inflammatory responses through modulation of the expression of JNK, STAT-3, AP-1, and NFATs. PMID- 25812624 TI - Investigations of immunotoxicity and allergic potential induced by topical application of triclosan in mice. AB - Triclosan is an antimicrobial chemical commonly used occupationally and by the general public. Using select immune function assays, the purpose of these studies was to evaluate the immunotoxicity of triclosan following dermal exposure using a murine model. Triclosan was not identified to be a sensitizer in the murine local lymph node assay (LLNA) when tested at concentrations ranging from 0.75-3.0%. Following a 28-day exposure, triclosan produced a significant increase in liver weight at concentrations of >= 1.5%. Exposure to the high dose (3.0%) also produced a significant increase in spleen weights and number of platelets. The absolute number of B-cells, T-cells, dendritic cells and NK cells were significantly increased in the skin draining lymph node, but not the spleen. An increase in the frequency of dendritic cells was also observed in the lymph node following exposure to 3.0% triclosan. The IgM antibody response to sheep red blood cells (SRBC) was significantly increased at 0.75% - but not at the higher concentrations - in the spleen and serum. These results demonstrate that dermal exposure to triclosan induces stimulation of the immune system in a murine model and raise concerns about potential human exposure. PMID- 25812627 TI - Cord blood gene expression supports that prenatal exposure to perfluoroalkyl substances causes depressed immune functionality in early childhood. AB - Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds that have widespread use in consumer and industrial applications. PFAS are considered environmental pollutants that have various toxic properties, including effects on the immune system. Recent human studies indicate that prenatal exposure to PFAS leads to suppressed immune responses in early childhood. In this study, data from the Norwegian BraMat cohort was used to investigate transcriptomics profiles in neonatal cord blood and their association with maternal PFAS exposure, anti-rubella antibody levels at 3 years of age and the number of common cold episodes until 3 years. Genes associated with PFAS exposure showed enrichment for immunological and developmental functions. The analyses identified a toxicogenomics profile of 52 PFAS exposure-associated genes that were in common with genes associated with rubella titers and/or common cold episodes. This gene set contains several immunomodulatory genes (CYTL1, IL27) as well as other immune-associated genes (e.g. EMR4P, SHC4, ADORA2A). In addition, this study identified PPARD as a PFAS toxicogenomics marker. These markers can serve as the basis for further mechanistic or epidemiological studies. This study provides a transcriptomics connection between prenatal PFAS exposure and impaired immune function in early childhood and supports current views on PPAR- and NF kappaB-mediated modes of action. The findings add to the available evidence that PFAS exposure is immunotoxic in humans and support regulatory policies to phase out these substances. PMID- 25812628 TI - Deadly forecast. AB - Recent epidemiological studies from various countries point at the mounting incidence of cancer. This continuous increase in the number of cancer cases will keep its pace in the future. The lifetime risk of cancer for people born since 1960 is forecast to be more than 50%. Thus cancer becomes the major health problem, and policy-makers should plan ahead how to implement effective prevention programs, on the one hand, and optimize the strategy for better diagnosis, treatment and surveillance of cancer patients on the other hand. PMID- 25812630 TI - Temperature driven p-n-p type conduction switching materials: current trends and future directions. AB - Modern technological inventions have been going through a "renaissance" period. Development of new materials and understanding of fundamental structure-property correlations are the important steps to move further for advanced technologies. In modern technologies, inorganic semiconductors are the leading materials which are extensively used for different applications. In the current perspective, we present discussion on an important class of materials that show fascinating p-n-p type conduction switching, which can have potential applications in diodes or transistor devices that operate reversibly upon temperature or voltage change. We highlight the key concepts, present the current fundamental understanding and show the latest developments in the field of p-n-p type conduction switching. Finally, we point out the major challenges and opportunities in this field. PMID- 25812629 TI - Binder-free carbonized bacterial cellulose-supported ruthenium nanoparticles for Li-O2 batteries. AB - Network structured carbonized bacterial cellulose-supported Ru nanoparticles (CBC/Ru), which provide sufficient space for Li2O2 deposition without a significant volume effect and improve the transport of oxygen and electrons, were used as the binder-free oxygen electrode in a Li-O2 battery. The CBC/Ru exhibited high activities and good stability during discharge-recharge processes. PMID- 25812631 TI - Effects of androgen replacement therapy on cornea and tear function in men with idiopathic hypogonadotropic hypogonadism. AB - PURPOSE: Idiopathic hypogonadotropic hypogonadism (IHH) is an endocrine disorder defined with the presence of typical clinical signs and symptoms plus laboratory confirmation of serum testosterone (T) levels lower than 300 ng/dl. Androgen replacement therapy (ART) is the first-step treatment of male IHH. To date, no clinical trial, which investigates the changes on corneal structure and tear function, of systemic ART in men have been published. The objective of this study was to investigate the effects of ART on cornea and tear function in patients with IHH. MATERIALS AND METHODS: This prospective, interventional study was conducted at the Gulhane Military Medical Academy, Ankara, Turkey, a tertiary referral military hospital. Thirty-four eyes of 17 men with IHH patients were evaluated with Schirmer I test, ultrasound pachymeter, applanation tonometer and confocal microscopy. A Testosterone compound (Sustanon(r) 250 mg) was administered by intramuscular injection in the course of a 3-week period to induce puberty, and human chorionic gonadotropin (Pregnyl(r) 5000 IU) was administered twice weekly for 3 months to induce fertility. The patients were re evaluated at the third month of the treatment. Main Outcome Measures were Schirmer score, central corneal thickness (CCT), intraocular pressure (IOP), endothelial cell density, coefficient of variation and cell shape. RESULTS: Schirmer scores showed similar results after the treatment compared to pre treatment levels (p = 0.14). There was no statistically significant difference in CCT and IOP compared to baseline data (p = 0.96, p = 0.73, respectively), and no significant differences were found in corneal endothelial cell density, percentage of cell size variability or hexagonality (p = 0.83, p = 0.58, p = 0.64, respectively). CONCLUSIONS: This is the first study that investigates the effects of ART on corneal structure and tear function in men. ART seems to have no short-term effects on corneal structure and tear function. Further publications of larger, long-term and controlled studies are needed. PMID- 25812632 TI - Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (review). AB - Gingival overgrowth is an undesirable outcome of systemic medication and is evidenced by the accretion of collagenous components in gingival connective tissues along with diverse degrees of inflammation. Phenytoin therapy has been found to induce the most fibrotic lesions in gingiva, cyclosporine caused the least fibrotic lesions, and nifedipine induced intermediate fibrosis in drug induced gingival overgrowth. In drug-induced gingival overgrowth, efficient oral hygiene is compromised and has negative consequences for the systemic health of the patients. Toll-like receptors (TLRs) are involved in the effective recognition of microbial agents and play a vital role in innate immunity and inflammatory signaling responses. TLRs stimulate fibrosis and tissue repairs in several settings, although with evident differences between organs. In particular, TLRs exert a distinct effect on fibrosis in organs with greater exposure to TLR ligands, such as the gingiva. Cumulative evidence from diverse sources suggested that TLRs can affect gingival overgrowth in several ways. Numerous studies have demonstrated the expression of TLRs in gingival tissues and suggested its potential role in gingival inflammation, cell proliferation and synthesis of the extracellular matrix which is crucial to the development of gingival overgrowth. In the present review, we assessed the role of TLRs on individual cell populations in gingival tissues that contribute to the progression of gingival inflammation, and the involvement of TLRs in the development of gingival overgrowth. These observations suggest that TLRs provide new insight into the connection among infection, inflammation, drugs and gingival fibrosis, and are therefore efficient therapeutic target molecules. We hypothesize that TLRs are critical for the development and progression of gingival overgrowth, and thus blocking TLR expression may serve as a novel target for antifibrotic therapy. PMID- 25812633 TI - Self-Probing Spectroscopy of the SF6 Molecule: A Study of the Spectral Amplitude and Phase of the High Harmonic Emission. AB - We present characterizations of the attosecond pulse train produced in the high harmonic generation (HHG) from SF6 molecules irradiated by a strong pulsed laser field at 800 nm. At harmonic order 17, we observe a minimum in the amplitude of the emitted spectrum and a corresponding distortion in the phase. Our experimental results are compared to two models: a multicenter interference model focused on the effect of the structure of the SF6 molecule in HHG and a model focused on the interferences between multiple ionization channels in HHG. We find that the experimental results agree very well with the multiple ionization channels model, illustrating that HHG in molecules can be very complex and that it provides insights of the intramolecular electron dynamics during the interaction process. PMID- 25812634 TI - Quantum phase transitions in the Kondo-necklace model: perturbative continuous unitary transformation approach. AB - The Kondo-necklace model can describe magnetic low-energy limit of strongly correlated heavy fermion materials. There exist multiple energy scales in this model corresponding to each phase of the system. Here, we study quantum phase transition between the Kondo-singlet phase and the antiferromagnetic long-range ordered phase, and show the effect of anisotropies in terms of quantum information properties and vanishing energy gap. We employ the 'perturbative continuous unitary transformations' approach to calculate the energy gap and spin spin correlations for the model in the thermodynamic limit of one, two, and three spatial dimensions as well as for spin ladders. In particular, we show that the method, although being perturbative, can predict the expected quantum critical point, where the gap of low-energy spectrum vanishes, which is in good agreement with results of other numerical and Green's function analyses. In addition, we employ concurrence, a bipartite entanglement measure, to study the criticality of the model. Absence of singularities in the derivative of concurrence in two and three dimensions in the Kondo-necklace model shows that this model features multipartite entanglement. We also discuss crossover from the one-dimensional to the two-dimensional model via the ladder structure. PMID- 25812636 TI - The reply. PMID- 25812637 TI - Proton pump inhibition may promote Clostridium difficile recurrences. PMID- 25812635 TI - Different neuropeptides are expressed in different functional subsets of cholinergic excitatory motorneurons in the nematode Ascaris suum. AB - Neuropeptides are known to have dramatic effects on neurons and synapses; however, despite extensive studies of the motorneurons in the parasitic nematode Ascaris suum, their peptide content had not yet been described. We determined the peptide content of single excitatory motorneurons by mass spectrometry and tandem mass spectrometry. There are two subsets of ventral cord excitatory motorneurons, each with neuromuscular output either anterior or posterior to their cell body, mediating forward or backward locomotion, respectively. Strikingly, the two sets of neurons contain different neuropeptides, with AF9 and six novel peptides (As NLP-21.1-6) in anterior projectors, and the six afp-1 peptides in addition to AF2 in posterior projectors. In situ hybridization confirmed the expression of these peptides, validating the integrity of the dissection technique. This work identifies new components of the functional behavioral circuit, as well as potential targets for antiparasitic drug development. PMID- 25812638 TI - The reply. PMID- 25812639 TI - Infectious Diseases Society of America or American College of Gastroenterology guidelines for treatment of Clostridium difficile infection: which one to follow? PMID- 25812640 TI - The reply. PMID- 25812641 TI - Physicians should work more, not less. PMID- 25812642 TI - The reply. PMID- 25812643 TI - Is this right ventricular infarction or Brugada syndrome? PMID- 25812644 TI - The reply. PMID- 25812645 TI - Why not use a high-sensitivity troponin assay as an end point in clinical trials? PMID- 25812646 TI - Domestic violence may trigger Takotsubo. PMID- 25812647 TI - Serum microRNA-218 is a potential biomarker for esophageal cancer. AB - BACKGROUND: Several studies demonstrated that microRNAs are stably detectable in plasma/serum and are potential biomarkers for some diseases. The expression of microRNA-218 (miR-218) is downregulated in esophageal cancer as reported in previous research. OBJECTIVE: The purpose of this study is to investigate whether miR-218 can be served as a serum biomarker for esophageal cancer. METHODS: We tested the expression level of miR-218 in serum of 106 patients with esophageal cancer and 60 healthy volunteers by RT-PCR and analyzed the relationship between serum miR-218 expression and the clinical characteristics. RESULTS: The serum expression of miR-218 was significantly lower in patients with esophageal cancer than that in healthy individuals. The value of the area under the receiver operating characteristic (ROC) curve (AUC) was 0.833. Furthermore, the ROC curves to detect early esophageal cancer with Tis-T1 or Stage 0-I showed AUCs of 0.825 and 0.829, respectively. In the esophageal cancer group, the serum expression of miR-218 was found to be lower in esophageal cancer patients with poorer differentiation, later stage, and lymph node metastasis, highlighting that low serum expression of miR-218 may be related to tumor development and progression in esophageal cancer. CONCLUSIONS: The serum expression of miR-218 is downregulated in esophageal cancer patients and is correlated with tumor differentiation, stage, and lymph node metastasis. Serum miR-218 may be a potential biomarker for early detection and clinical evaluation in patient with esophageal cancer. PMID- 25812648 TI - Expression of ECM1 and MMP-2 in follicular thyroid lesions among Egyptians. AB - BACKGROUND: Thyroid nodules require pre-surgical cytological assessment for possible risk of malignancy. Many techniques were introduced to enhance differential diagnosis and to avoid unnecessary diagnostic surgery. OBJECTIVE: The study aims to investigate the potential use of ECM1 gene and MMP-2 protein as preoperative tumor markers in suspicious follicular thyroid lesions. METHODS: The study included 40 Egyptian cases with solitary thyroid nodules. They underwent preoperative FNAB followed by thyroidectomy. MMP-2 protein and ECM1 gene were detected using immunostaining and conventional semi-quantitative RT-PCR techniques; respectively. The diagnostic accuracy of FNAB, gene and protein expression level cutoffs was calculated by using ROC. RESULTS: Both MMP-2 protein and ECM1 gene expressions were significantly higher in malignant than benign group (P < 0.001). Both were significantly higher in higher tumor stages (PMMP-2= 0.002; PECM1 = 0.032) but only ECM1 significantly differed with tumor size (P < 0.006). The diagnostic performances of ECM1 expression scores was significantly better than that of FNAB (P = 0.049). A significant direct correlation was detected between ECM1 gene and MMP-2 protein expressions in cases of FVPC and of FC (P = 0.014). CONCLUSIONS: MMP-2 protein and ECM1 gene are useful preoperative markers for defining malignancy in suspicious thyroid nodules. PMID- 25812649 TI - miR-218 suppresses cardiac myxoma proliferation by targeting myocyte enhancer factor 2D. AB - Cardiac myxoma is the most common type of human heart tumor, yet the molecular mechanism is still poorly understood. In the present study, we found that the level of myocyte enhancer factor 2D (MEF2D), a key regulatory protein for cardiac development, was elevated in specimens of cardiac myxoma, and was positively associated with the proliferation of myxoma cells. MEF2D suppression reduced the proliferation of myxoma cells and its tumorigenicity. Cell cycle progression was also inhibited by MEF2D suppression. miR-218, which is downregulated in myxoma, suppressed MEF2D expression by targeting its mRNA 3'UTR. Altogether, we found that miR-218/MEF2D may be an effective target for myxoma treatment. PMID- 25812651 TI - TdT+ T-Lymphoblastic Proliferation in Castleman Disease. PMID- 25812650 TI - Antiproliferative effects of beta-blockers on human colorectal cancer cells. AB - Colon cancer is the fourth and third most common cancer, respectively in men and women worldwide and its incidence is on the increase. Stress response has been associated with the incidence and development of cancer. The catecholamines (CA), adrenaline (AD) and noradrenaline (NA), are crucial mediators of stress response, exerting their effects through interaction with alpha- and beta-adrenergic receptors (AR). Colon cancer cells express beta-AR, and their activation has been implicated in carcinogenesis and tumor progression. Interest concerning the efficacy of beta-AR blockers as possible additions to cancer treatment has increased. The aim of this study was to investigate the effect of several AR agonists and beta-blockers following cell proliferation of HT-29 cells, a human colon adenocarcinoma cell line. For this purpose, HT-29 cells were incubated in the absence (control) or in the presence of the AR-agonists, AD, NA and isoprenaline (ISO) (0.1-100 uM) for 12 or 24 h. The tested AR agonists revealed proliferative effects on HT-29 cells. In order to study the effect of several beta-blockers following proliferation induced by AR activation, the cells were treated with propranolol (PRO; 50 uM), carvedilol (CAR; 5 uM), atenolol (ATE; 50 uM), or ICI 118,551 (ICI; 5 uM) for 45 min prior, and simultaneously, to incubation with each of the AR agonists, AD and ISO, both at 1 and 10 uM. The results suggested that adrenergic activation plays an important role in colon cancer cell proliferation, most probably through beta-AR. The beta-blockers under study were able to reverse the proliferation induced by AD and ISO, and some of these blockers significantly decreased the proliferation of HT-29 cells. The elucidation of the intracellular pathways involved in CA-induced proliferation of colon cancer cells, and in the reversion of this effect by beta-blockers, may contribute to identifying promising strategies in cancer treatment. PMID- 25812652 TI - Molecular imaging in the era of personalized medicine. AB - Clinical imaging creates visual representations of the body interior for disease assessment. The role of clinical imaging significantly overlaps with that of pathology, and diagnostic workflows largely depend on both fields. The field of clinical imaging is presently undergoing a radical change through the emergence of a new field called molecular imaging. This new technology, which lies at the intersection between imaging and molecular biology, enables noninvasive visualization of biochemical processes at the molecular level within living bodies. Molecular imaging differs from traditional anatomical imaging in that biomarkers known as imaging probes are used to visualize target molecules-of interest. This ability opens up exciting new possibilities for applications in oncologic, neurological and cardiovascular diseases. Molecular imaging is expected to make major contributions to personalized medicine by allowing earlier diagnosis and predicting treatment response. The technique is also making a huge impact on pharmaceutical development by optimizing preclinical and clinical tests for new drug candidates. This review will describe the basic principles of molecular imaging and will briefly touch on three examples (from an immense list of new techniques) that may contribute to personalized medicine: receptor imaging, angiogenesis imaging, and apoptosis imaging. PMID- 25812654 TI - PHH3 as an Ancillary Mitotic Marker in Gastrointestinal Stromal Tumors. AB - BACKGROUND: Counting mitoses is subjective and time-consuming. The adjunctive diagnostic utility of a recently reported mitotic marker, phosphohistone H3 (PHH3), was investigated in gastrointestinal stromal tumors (GISTs). METHODS: We reviewed 77 GISTs for several proliferative indices. These included the mitotic count per 50 high power fields (HPFs), the immunohistochemical Ki- 67 labeling index and the immunohistochemical PHH3 mitotic index (MI). For comparison, Spearman's rank correlation and interclass correlation coefficient were used. RESULTS: Mitotic counts ranged from 0-138 (mean, 7.57+/-2.34) and the PHH3 MI ranged from 0-126 per 50 HPFs (mean, 9.61+/-2.27). We found a positive correlation between mitotic counts and PHH3 MI (r=0.810, p<.001). The inter observer correlation coefficient for three participants was 0.975 for mitotic counts and 0.940 for the PHH3 MI. When using the PHH3 MI instead of mitotic counts in the Armed Forces Institute of Pathology (AFIP) stratification criteria, 10 cases were reclassified. In one patient with a mitotic count of 2 and a PHH3 MI of 6 per 50 HPFs, distant metastasis occurred. CONCLUSIONS: In GISTs, the PHH3 MI correlated adequately with mitotic counts and can be used as a useful adjunctive to count mitotic figures efficiently. PMID- 25812653 TI - Genomic landscapes of pancreatic neoplasia. AB - Pancreatic cancer is a deadly disease with a dismal prognosis. However, recent advances in sequencing and bioinformatic technology have led to the systematic characterization of the genomes of all major tumor types in the pancreas. This characterization has revealed the unique genomic landscape of each tumor type. This knowledge will pave the way for improved diagnostic and therapeutic approaches to pancreatic tumors that take advantage of the genetic alterations in these neoplasms. PMID- 25812655 TI - Clinical and Prognostic Significances of Cytokeratin 19 and KIT Expression in Surgically Resectable Pancreatic Neuroendocrine Tumors. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are malignant endocrine neoplasms that present diverse clinical behaviors. Therefore, identification of biomarkers of PanNETs is important for stratification of the prognosis of PanNET patients. Recently, cytokeratin 19 (CK19) and KIT expression were reported to have prognostic significance in PanNET patients. METHODS: To identify their prognostic significance, CK19 and KIT protein expression were assessed in 182 surgically resected PanNETs and compared with clinicopathologic factors. RESULTS: Of 182 PanNETs cases, CK19 and KIT expression was noted in 97 (53.3%) and 16 (8.8%) cases, respectively. PanNET patients with CK19 expression had larger tumors (p=.006), higher World Health Organization (WHO) grade (p=.002) and pT classification (p<.001), increased distant metastasis (p=.004), and lymphovascular (p=.012) and perineural (p=.019) invasion. Similarly, those with KIT expression had larger tumors (p=.030), higher WHO grade (p=.001), advanced pT classification (p<.001), distant metastasis (p=.001), and lymphovascular invasion (p=.014). The 5-year survival rate for PanNET patients with KIT expression was significantly lower (62%) than that of patients without KIT expression (77%, p=.011), as determined by univariate but not by multivariate analyses. CONCLUSIONS: CK19 and KIT expression correlate with higher metastatic potential and advanced disease stage, and KIT expression is associated with worse survival in PanNET patients. PMID- 25812656 TI - Transglutaminase 2 expression and its prognostic significance in clear cell renal cell carcinoma. AB - BACKGROUND: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinicopathologic significance in a large number of human clear cell RCCs (CCRCCs). METHODS: We analyzed 638 CCRCC patients who underwent partial or radical nephrectomy between 1995 and 2005. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). RESULTS: TG2 staining intensity was negative in 8.5% of CCRCC (n=54), 1+ in 32.6% (n=208), 2+ in 50.5% (n=322), and 3+ in 8.5% (n=54). Strong TG2 expression was correlated with high Fuhrman nuclear grade (p=.011), high T category (p=.049), metastasis (p=.043) and male sex (p<.001) but not with N category.The survival analysis showed a significant association between strong TG2 expression and worse overall and cancer-specific survival (p=.027 and p=.010, respectively). On multivariate analysis, strong TG2 expression was a marginally significant prognostic indicator for Fuhrman nuclear grade and TNM staging (p=.054). CONCLUSIONS: Our study is the first to demonstrate the clinicopathologic significance of TG2 expression in a large number of human CCRCC samples. Strong TG2 expression was associated with high nuclear grade and poor prognosis. PMID- 25812657 TI - Expression of c-MET in Invasive Meningioma. AB - BACKGROUND: Meningiomas show high recurrence rates even after curative tumor removal. The invasiveness of meningiomas may contribute to their high recurrence rates. Recently, c-MET and hepatocyte growth factor (HGF) have been reported to be involved in cancer invasion. METHODS: We examined the immunohistochemical expression of c-MET and HGF in 100 cases of patients with meningiomas who have undergone complete tumor removal. RESULTS: c-MET(-High) and HGFHigh were found in 17% and 13% of meningiomas, respectively. Brain invasion was observed in 17.6% of c-MET(-High) meningiomas, but in only 2.4% of c-MET(-Low) meningiomas (p=.033). Bone/soft tissue invasion was observed in 23.5% of c-MET(-High) meningiomas and in 9.6% of c-MET(-Low) meningiomas (p=.119). HGF(-High) did not show statistical association with brain invasion or bone/soft tissue invasion. c-MET(-High) demonstrated shorter recurrence-free survival (RFS, 93.5+/-8.2 months vs 96.1+/ 1.9 months); however, this difference was not statistically significant (p=.139). There was no association of HGF(-High) with RFS. CONCLUSIONS: This study demonstrates that c- MET(-High) is associated with brain invasion of meningiomas, and that c-MET expression may be a useful predictive marker for meningioma recurrence. Patients with invasive meningiomas with high expressions of c-MET may be good candidates for targeted therapy using c-MET inhibitors. PMID- 25812658 TI - Diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration cytology of pancreatic lesions. AB - BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration cytology (EUS FNAC) is currently the most commonly used procedure for obtaining cytologic specimens of the pancreas. It is accurate, minimally invasive, safe and cost effective. However, there is discrepancy between cytological and surgical diagnoses. This study was aimed at evaluating the diagnostic accuracy of EUS-FNAC of the pancreas. METHODS: We performed a retrospective review of 191 cases of pancreatic lesions initially diagnosed by EUS-FNAC with subsequent histological diagnosis between 2010 and 2012 in the Department of Pathology, Seoul National University Hospital. Cytologic and surgical diagnoses were categorized into five groups: negative, benign, atypical, malignant, and insufficient for diagnosis. Subsequently, 167 cases with satisfactory yield in both surgical and cytology specimens were statistically analyzed to determine correlations with diagnosis. RESULTS: In comparison to surgical diagnoses, cytologic diagnoses were true positive in 103 cases (61.7%), true-negative in 28 cases (16.8%), false-positive in 9 cases (5.4%), and false-negative in 27 cases (16.1%). The diagnostic accuracy was 78.4%, sensitivity was 79.2%, and specificity was 75.7%. The positive predictive value was 92.0%, and negative predictive value was 50.9%. CONCLUSIONS: EUS-FNAC has high accuracy, sensitivity, specificity and positive predictive value. Overcoming the limitations of EUS-FNAC will make it a useful and reliable diagnostic tool for accurate evaluation of pancreatic lesions. PMID- 25812659 TI - Mixed carcinoid-mucinous adenocarcinoma arising in mature teratoma of mesentery. PMID- 25812660 TI - Ewing's Sarcoma/Primitive Neuroectodermal Tumor of the Uterine Corpus. PMID- 25812661 TI - Placental mesenchymal dysplasia with fetal gastroschisis. PMID- 25812663 TI - A Rare Case of Tumor-to-Tumor Metastasis of Thyroid Papillary Carcinoma within a Pulmonary Adenocarcinoma. PMID- 25812662 TI - A rare case of mixed type a thymoma and micronodular thymoma with lymphoid stroma. PMID- 25812664 TI - Alveolar rhabdomyosarcoma of the lip in an adult with clear cell features. PMID- 25812665 TI - Squamous cell carcinoma of the seminal vesicle from zinner syndrome: a case report and review of literature. PMID- 25812666 TI - Biliary granular cell tumor. PMID- 25812667 TI - Syneresis and delayed detachment in agar plates. AB - Biogels made of crosslinked polymers such as proteins or polysaccharides behave as porous soft solids and store large amounts of solvent. These gels undergo spontaneous aging, called syneresis, which consists of the shrinkage of the gel matrix and the progressive expulsion of solvent. As a result, a biogel originally casted in a container often loses contact with the container sidewalls, and the detachment time is difficult to anticipate a priori, since it may occur over variable time spans (from hours to days). Here we report on syneresis phenomena in agar plates, which consist of Petri dishes filled with a gel mainly composed of agar. Direct observations and speckle pattern correlation analysis allow us to rationalize the delayed detachment of the gel from the sidewall of the Petri dish. The detachment time t* is surprisingly not controlled by the mass loss as one would intuitively expect. Instead, t* is strongly correlated to the gel minimum thickness emin measured along the sidewall of the plate, and increases as a robust function of emin, independently of the prior mass-loss history. Time resolved correlation spectroscopy atypically applied to such weakly diffusive media gives access to the local thinning rate of the gel. This technique also allows us to detect the gel micro-displacements that are triggered by water evaporation prior to the detachment, and even to anticipate the latter from a few hours. Our work provides observables to predict the detachment time of agar gels in dishes, and highlights the relevance of speckle pattern correlation analysis for the quantitative investigation of the syneresis dynamics in biopolymer gels. PMID- 25812668 TI - Type II diabetes patients with proteinuria and the recovery of their metabolic parameters. AB - OBJECTIVE: To provide reasonable guidelines for type II diabetes patients with proteinuria to recover their metabolic parameters. METHODS: A cross-sectional study was conducted in selected groups of type 2 diabetic patients. Hypoglycemic and antihypertensive drug use was recorded. Certain physical examinations were conducted including routine urine test, urinary albumin/creatinine ratio (ACR), metabolic parameters of blood glucose and lipid, and other biochemical indicators. Medication and metabolic indicators were compared between the groups based on the seriousness of the proteinuria. RESULTS: A total of 923 cases were selected for this study, with an average age of 63 years. Based on the proteinuria contents, the cases were divided into three groups of proteinuria negative,microalbuminuria and clinical proteinuria.The recovery rates of the blood pressure control for the groups were 44.2%, 35.3% and 36.3% respectively. The glycated hemoglobin control recovery rates were 22.2%, 18.5% and 15.2% in the groups. The groups' triglyceride control satisfaction rates were 44.4%, 43.3%, and 39.8%. The satisfaction rates of total cholesterol control were 34.5%, 26.8% and 25.7% respectively and the satisfaction rates of LDL-c control of the three groups were 30.6%, 23.8% and 22.1%. This indicated an unregulated use of hypoglycemic agents, antihypertensivesand lipid-lowering drugs and low recovery rates for metabolic indicators of the cases. Amongst the 923 cases, 397 had microalbuminuria or clinical proteinuria, and only 22 patients took angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB) as antihypertensive drugs. CONCLUSION: The use of antihypertensive drugs is not standardized, and only a small portion of patients were treated with ACEI or ARB drugs. Therefore, the proteinuria in diabetic patients should be timely screened and evaluated, as well as renal and metabolic function and antihypertensives and lipid-lowering drugs rationally used. PMID- 25812670 TI - Widely available active sites on Ni2P for electrochemical hydrogen evolution- insights from first principles calculations. AB - We present insights into the mechanism and the active site for hydrogen evolution on nickel phosphide (Ni2P). Ni2P was recently discovered to be a very active non precious hydrogen evolution catalyst. Current literature attributes the activity of Ni2P to a particular site on the (0001) facet. In the present study, using Density Functional Theory (DFT) calculations, we show that several widely available low index crystal facets on Ni2P have better properties for a high catalytic activity. DFT calculations were used to identify moderately bonding nickel bridge sites and nickel hollow sites for hydrogen adsorption and to calculate barriers for the Tafel pathway. The investigated surfaces in this study were the (1010), (1120), (1120), (1121) and (0001) facets of the hexagonal Ni2P crystal. In addition to the DFT results, we present experiments on Ni2P nanowires growing along the <0001> direction, which are shown as efficient hydrogen evolution catalysts. The experimental results add these nanowires to a variety of different morphologies of Ni2P, which are all active for HER. PMID- 25812669 TI - Evidence of glycoproteins and sulphated proteoglycan-like presence in extracellular polymeric substance from anaerobic granular sludge. AB - The protein fraction of extracellular polymeric substance (EPS) from two anaerobic granular sludge samples was characterized with sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and a far western blotting method. SDS-PAGE was used with various staining applications to obtain a protein (silver), glycoprotein [periodic acid-Shiff's (PAS)] or proteoglycan-like (Alcian blue at pH 2.5 (carboxylic group) or 1 (sulphated group)) fingerprint. The fingerprints of the EPS denatured protein from the two sludge samples differed. Some proteins are specific to Soluble (S) or Bound (B)-EPS (20-100 kDa). Denatured proteins with a polysaccharide moieties characterization are more present in B-EPS. Glycoproteins with alpha-d-mannosyl and/or alpha-d-glucosyl (90, 50, 40 kDa) were detected. Proteoglycan-like and sulphated proteoglycan-like substances are also detected, mainly in B-EPS. A 68 kDa sulphated proteoglycan like substance contains two glucidic residue types: alpha-d-mannosyl and/or alpha d-glucosyl and N-acetyl-beta-d-glucosamine. Such heteroproteins are present around the membrane as well as the surface-layer from Archaea and from some bacteria. The glycoprotein and sulphated proteoglycan-like substance are assumed to contribute to anaerobic granule strength, thanks to their ability to perform interactions of various nature (ionic, hydrophobic, Ca(2+) as divalent cation bridging, etc.). PMID- 25812671 TI - Expression levels of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin are associated with middle ear cholesteatoma risk. AB - CONCLUSION: Overexpression of receptor activator of nuclear factor-kappaB ligand (RANKL) and low expression of osteoprotegerin (OPG) are typical features in middle ear cholesteatoma patients. The altered RANKL/OPG protein ratio suggests that alterations in the RANKL-OPG pathway may be major factors in the pathogenesis of middle ear cholesteatoma. OBJECTIVE: Our meta-analysis explored the contribution of one important cytokine pathway, the RANKL and OPG pathway, in the development of middle ear cholesteatoma. METHODS: We screened Embase, the Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine, China National Knowledge Infrastructure, PubMed, and Web of Science for relevant articles. RANKL expression and ratio of RANKL/OPG were analyzed using Comprehensive Meta-Analysis Version 2 software. RESULTS: The electronic literature search identified five studies that contained information on the correlation of RANKL and OPG expression with middle ear cholesteatoma. Increased RANKL expression positively correlated with middle ear cholesteatoma, while OPG expression showed an inverse association (p < 0.05). The ratio of RANKL/OPG in middle ear cholesteatoma cases was higher than in healthy controls, indicating that our observations are applicable to each individual case. Subgroup analysis based on country of study revealed that OPG levels decreased in China and Korea, and high RANKL expression was found in Poland, China, and Korea (all p < 0.05). PMID- 25812672 TI - A Commentary on a recent update of the ovarian cancer risk attributable to menopausal hormone therapy. AB - The incidence of ovarian cancer is tenfold lower than that of breast cancer. The goal of the recently published meta-analysis by Beral and colleagues, using 'individual participant datasets from 52 epidemiological studies', was to provide an updated assessment of the effect of menopausal hormone therapy (MHT) on ovarian cancer risk. The relative risk generated from the cited prospective studies was significantly increased but the relative risk from the retrospective studies was not. This is quite unusual since retrospective studies usually display higher levels of relative risk. No further increase was observed with increasing duration. Moreover, a number of the studies could not be adjusted for important ovarian cancer risk factors. From the meta-analysis, it can be calculated that the absolute excess risk of 5 years of MHT for a 50-year-old UK woman is 1 in 10 000 per year, indicating a very low risk. We conclude that this meta-analysis mostly reflects the previously published data from the Million Women Study, from which the majority of this new publication is derived. PMID- 25812673 TI - Does aberrant expression of cyclooxygenase-2 and prostaglandin-E2 receptor genes lead to abortion in Chlamydia trachomatis-infected women. AB - OBJECTIVE: The aim of the study was to characterize the expression of cyclooxygenase-2 (COX-2) and prostaglandin-E2 (PGE2) genes in spontaneously aborted tissues from women infected with Chlamydia trachomatis. METHODS: A total of 135 spontaneous aborters (Group I) and 45 induced aborters (controls; Group II) attending Obstetrics and Gynaecology Department at Safdarjung hospital (New Delhi, India), were enrolled. Polymerase chain reaction (PCR) assay was performed to detect C. trachomatis DNA in endometrial curettage tissue (ECT). Differential expression of COX-2 and PGE2 receptors at mRNA level was analysed in ECT using reverse transcription PCR and real-time PCR. RESULTS: In total, 14.8% patients were diagnosed as C. trachomatis-positive in Group I whereas all control patients were C. trachomatis-negative. Qualitative expression of COX-2 (p < 0.05) and PGE2 (p < 0.0001) receptors was found increased in C. trachomatis-positive patients (Group I) in comparison to controls. Quantitative real-time PCR analysis also showed upregulation in transcript levels of both COX-2 (p < 0.002) and PGE2 (p < 0.0001) receptors in infected patients (Group I) versus Group II. COX-2 and PGE2 expression was higher (p < 0.002) in recurrent spontaneous aborters in comparison to sporadic spontaneous aborters. CONCLUSIONS: Results suggest that chlamydial infection leads to upregulation of COX-2 in C. trachomatis-positive recurrent spontaneous aborters, which probably mediates increased prostaglandin synthesis. PMID- 25812674 TI - Death or survival with major morbidity in VLBW infants born at Brazilian neonatal research network centers. AB - OBJECTIVE: To analyze unfavorable outcomes at hospital discharge of preterm infants born at Brazilian public university centers. METHODS: Prospective cohort of 2646 inborn infants with gestational age 23-33 weeks and birth weight 400-1499 g, without malformations, born at 20 centers in 2012-2013. Unfavorable outcome was defined as in-hospital death or survival at hospital discharge with >=1 major morbidities: bronchopulmonary dysplasia (BPD) at 36 corrected weeks, intraventricular hemorrhage (IVH) grades 3-4, periventricular leukomalacia (PVL) or surgically treated retinopathy of prematurity (ROP). RESULTS: Among 2646 infants, 1390 (53%) either died or survived with major morbidities: 793 (30%) died; 497 (19%) had BPD; 358 (13%) had IVH 3-4 or PVL; and 84 (3%) had ROP. Logistic regression adjusted by center showed association of unfavorable outcome with: antenatal steroids (OR 0.70; 95%CI 0.55-0.88), C-section (0.72; 0.58-0.90), gestational age <30 (4.00; 3.16-5.07), being male (1.44; 1.19-1.75), small for gestational age (2.19; 1.72-2.78), 5th-min Apgar <7 (3.89; 2.88-5.26), temperature at NICU admission <36.0 degrees C (1.42; 1.15-1.76), respiratory distress syndrome (3.87; 2.99-5.01), proven late sepsis (1.33; 1.05-1.69), necrotizing enterocolitis (3.10; 2.09-4.60) and patent ductus arteriosus (1.69; 1.37-2.09). CONCLUSIONS: More than half of the VLBW infants born at public university level 3 Brazilian hospitals either die or survive with major morbidities. PMID- 25812675 TI - Involvement of T lymphocytes in the placentae with villitis of unknown etiology from pregnancies complicated with preeclampsia. AB - OBJECTIVE: The aim of the study was to compare immunohistochemical expression of different T type lymphocytes in foci of villitis of placentae with villitis of unknown etiology (VUE) without and with preeclampsia (PE). METHODS: Fifty-four placentae were collected from women who had VUE with (N = 27) and without (N = 27) PE. Immunohistochemistry for types of T lymphocytes was performed on formalin fixed and paraffin-embedded sections by use of the CD3, CD4, FOXP3, CD25, CD8 and CD68 antibodies. All data analyses were done by R Development Core Team. RESULTS: There was higher immunohistochemical CD4 positive T lymphocyte count and CD4 positive/CD8 positive ratio in placentae with VUE complicated with PE compared to control group. CONCLUSION: The higher immunohistochemical CD4 positive T lymphocyte count and CD4 positive/CD8 positive ratio in placentae with VUE complicated with PE could point to their role in ethiopathogenesis of PE. PMID- 25812676 TI - Changes in T-cell phenotype and cytokines profile in maternal blood, cord blood and colostrum of diabetic mothers. AB - OBJECTIVE: The present study evaluated the cells and cytokine of maternal blood, cord blood and colostrum of diabetic mothers. METHODS: The women evaluated were divided according to their body mass index (BMI) and glycemic status into non diabetic (ND - N = 15), mild gestational hyperglycemic (MGH - N = 15), diabetes mellitus gestational (DMG - N = 13) and type-2 diabetes mellitus (DM2 - N = 15) groups. The subsets of cells and cytokine profile were determined by flow cytometry. RESULTS: Maternal blood from MGH group had increase percentage of CD3(+)T cells, and DM-2 group had decrease percentage of CD4(+) T cells. The cord blood from hyperglycemic groups showed lower percentage of CD3(+) T cells expressing CD45RO(+) and higher of CD4(+) T cells and CD4(+) T cells expressing CD45RA(+). In the colostrum, the CD4(+) T cells and CD4(+) T cells expressed CD45RA(+) increase in hyperglycemic groups. The DM2 group exhibited higher IL17 levels in maternal blood. IFN-gamma was lower in cord blood from MGH and DMG groups with overweight/obese. Irrespective of the glycemic status, IL6 was higher in colostrum. CONCLUSION: The results obtained suggest that maternal hyperglycemia modifies the phenotypes of T cells and cytokines profile in maternal, cord blood and colostrum. PMID- 25812678 TI - On the importance of shear dissipative forces in coarse-grained dynamics of molecular liquids. AB - In this work we demonstrate from first principles that the shear frictions describing dissipative forces in the direction normal to the vector connecting the coarse-grained (CG) particles in dissipative particle dynamics (DPD) could be dominant for certain real molecular liquids at high-resolution coarse-graining. This is in contrast to previous works on bottom-up DPD modeling and indicates that such liquids cannot be simulated accurately using the conventional form of DPD which relies only on frictions in the radial direction. Specifically, we describe the development of fully bottom-up CG models for liquid hexahydro-1,3,5 trinitro-s-triazine (RDX) which are incorporated into the DPD method. Consistent with the microscopic foundation of DPD dynamics, the conservative part of the DPD models is obtained by the multi-scale coarse-graining (MS-CG) approach, which implements the pairwise decomposition of the atomistic potential of mean force (PMF) in CG coordinates. The radial and shear distant-dependent friction coefficients in a parameter-free form are derived systematically from microscopic velocity and force correlation data along system trajectories using a recently proposed approach [J. Chem. Phys., 2014, 140, 104104]. The shear dissipative forces for the reported system appear to be dominant. We discuss the implications of dominant shear dissipation on dynamical and transport properties of CG liquids such as diffusion and viscosity as revealed by simulations of liquid RDX using the new MS-CG/DPD models. PMID- 25812677 TI - Advanced glycation end-products inhibitors isolated from Schisandra grandiflora. AB - Free radicals scavenging and advanced glycation end-products (AGEs) inhibitory potentials in crude chloroform extract of Schisandra grandiflora were evaluated. Bioassay-guided isolation of the chloroform extract led to the identification of 24 compounds. Among the isolates, ( +/- ) gomisin M1, arisantetralone C and D, macelignan, saurulignan B and SZ-MO displayed potent-free radical scavenging as well as AGEs inhibitory potentials. This is the first report identifying the presence of AGEs inhibitory activity and assigning AGEs inhibitory activity to these compounds. Therefore, our research finds new application of traditional medicinal plant S. grandiflora having capacity to reduce formation and accumulation of AGEs in diabetes. PMID- 25812679 TI - Visible light promoted carbodifluoroalkylation of allylic alcohols via concomitant 1,2-aryl migration. AB - A novel visible light promoted carbodifluoroalkylation of allylic alcohols is disclosed. A series of difluoro 1,5-dicarbonyl compounds were obtained through a tandem radical addition and 1,2-aryl migration process. Mechanistic analysis indicated that the 1,2-aryl rearrangement proceeded via a radical intermediate. PMID- 25812682 TI - Non-quasiparticle states in a half-metallic ferromagnet with antiferromagnetic s d(f) interaction. AB - Non-quasiparticle (incoherent) states which play an important role in the electronic structure of half-metallic ferromagnets (HMF) are investigated consistently in the case of antiferromagnetic s-d(f) exchange interaction. Their appropriate description in the limit of strong correlations requires a rearrangement of perturbation series in comparison with the usual Dyson equation. This consideration provides a solution of the Kondo problem in the HMF case and can be important for first-principle HMF calculations performed earlier for ferromagnetic s-d(f) interaction. PMID- 25812680 TI - Downregulation of miR-518a-3p activates the NIK-dependent NF-kappaB pathway in colorectal cancer. AB - The aim of the present study was to investigate the biological role and underlying mechanisms of action of miR-518a-3p in the progression and invasion of colorectal cancer (CRC). Reverse transcription-quantitative PCR (RT-qPCR) was used to examine the mRNA expression levels of miR-518a-3p in 5 CRC cell lines (SW480, SW620, HCT116, HT29 and LoVo) in a normal colonic cell line, NCM460, as well as in tumor tissues with or without metastases. The biological effects of miR-518a-3p were assessed in the CRC cell lines by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis, and RT qPCR and western blot analyses were employed to evaluate the expression of miR 518a-3p targets. The regulation of NF-kappaB-inducing kinase (NIK) by miR-518a-3p was confirmed using luciferase activity assays. Our results revealed that miR 518a-3p was significantly downregulated in the CRC cell lines compared with the normal colonic cell line (P<0.05), as well as in the CRC tissues with distant metastases compared with the tissues without metastases. The downregulation of miR-518a-3p was associated with tumor size, distant metastasis and TNM stage in the patients with CRC. Moreover, the ectopic expression of miR-518a-3p and the inhibition of NIK by RNA interference markedly reduced cell proliferation and enhanced the apoptosis of CRC cells. Further experiments revealed that NIK, a regulator of NF-kappaB, was a downstream target of miR-518a-3p. The presents findings indicate that miR-518a-3p plays an important role in the progression of CRC by targeting NIK. PMID- 25812683 TI - How to set an educational goal. PMID- 25812681 TI - Translating drug-induced hibernation to therapeutic hypothermia. AB - Therapeutic hypothermia (TH) improves prognosis after cardiac arrest; however, thermoregulatory responses such as shivering complicate cooling. Hibernators exhibit a profound and safe reversible hypothermia without any cardiovascular side effects by lowering the shivering threshold at low ambient temperatures (Ta). Activation of adenosine A1 receptors (A1ARs) in the central nervous system (CNS) induces hibernation in hibernating species and a hibernation-like state in rats, principally by attenuating thermogenesis. Thus, we tested the hypothesis that targeted activation of the central A1AR combined with a lower Ta would provide a means of managing core body temperature (Tb) below 37 degrees C for therapeutic purposes. We targeted the A1AR within the CNS by combining systemic delivery of the A1AR agonist (6)N-cyclohexyladenosine (CHA) with 8-(p sulfophenyl)theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not readily cross the blood-brain barrier. Results show that CHA (1 mg/kg) and 8-SPT (25 mg/kg), administered intraperitoneally every 4 h for 20 h at a Ta of 16 degrees C, induce and maintain the Tb between 29 and 31 degrees C for 24 h in both naive rats and rats subjected to asphyxial cardiac arrest for 8 min. Faster and more stable hypothermia was achieved by continuous infusion of CHA delivered subcutaneously via minipumps. Animals subjected to cardiac arrest and cooled by CHA survived better and showed less neuronal cell death than normothermic control animals. Central A1AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management. PMID- 25812684 TI - Setting school-level educational goal and objectives with the modified delphi method. AB - PURPOSE: The aim of this study was to set the school-level educational goals and objectives, based on the needs analysis, by modified Delphi method. METHODS: A needs analysis and workshops were performed to establish educational goals and objectives. The needs analysis comprised 3 rounds of questionnaires and a panel and reference group that compared the results. Various workshops were held to set, outline, develop, and promote the educational goals and objectives and perform a satisfaction survey. RESULTS: In the needs analysis, we identified 8 keywords for 'ends' and 12 for 'means' with regard to educational goals and 25 keywords for educational objectives, which were summarized in 5 factors (categories). There were significant differences between the panel and reference groups. Through the workshops, we established new educational goal and objectives that met with high satisfaction among members. CONCLUSION: The developmental process with which the educational goals and objectives were established through a needs analysis and workshops was effective, efficient, and supportive in medical education. PMID- 25812685 TI - Analysis of the Characteristics of Discussion Materials that Promote Group Discussion in the Medical Humanities. AB - PURPOSE: This study aims to analyze the characteristics of discussion materials that promote student participation in discussions, satisfaction with student instruction, and tutor intervention in the medical humanities. METHODS: We surveyed 117 premedical students and 7 tutors who attended 4-week group discussions in the medical humanities in 2010. We described the discussion materials using the following 4 characteristics as independent variables: material type, level of understanding, interest, and quantity. Dependent variables were: student participation in the discussion, student instruction satisfaction, and tutor intervention. Correlation analysis, multiple regression analysis, and crosstab were performed using SPSS 15.0. RESULTS: The correlation between the characteristics of the discussion materials differed by grade. When the books were chosen as the discussion material in the instruction of first-year premedical students, the correlation between level of understanding, interest, and quantity was negative. Higher levels of understanding of the material and interest in the material led to an increase in discussion participation among both first- and second-year premedical students. Higher levels of understanding and interest of the discussion material also increased student satisfaction with the instruction, regardless of grade. Finally, levels of understanding of the material affected the degree of tutor intervention. Tutors intervened more often in discussions with first-year premedical students than with second-year premedical students. CONCLUSION: Differences in grades and the understanding of the discussion material should be considered when choosing discussion materials. Further study is required to continue the development of the discussion model and improve methods of facilitate discussion among students in the medical humanities. PMID- 25812686 TI - Instructional analysis of lecture video recordings and its application for quality improvement of medical lectures. AB - PURPOSE: The lecture is a technique for delivering knowledge and information cost effectively to large medical classes in medical education. The aim of this study was to analyze teaching quality, based on triangle analysis of video recordings of medical lectures, to strengthen teaching competency in medical school. METHODS: The subjects of this study were 13 medical professors who taught 1st- and 2nd-year medical students and agreed to a triangle analysis of video recordings of their lectures. We first performed triangle analysis, which consisted of a professional analysis of video recordings, self-assessment by teaching professors, and feedback from students, and the data were crosschecked by five school consultants for reliability and consistency. RESULTS: Most of the distress that teachers experienced during the lecture occurred in uniform teaching environments, such as larger lecture classes. Larger lectures that primarily used PowerPoint as a medium to deliver information effected poor interaction with students. Other distressing factors in the lecture were personal characteristics and lack of strategic faculty development. CONCLUSION: Triangle analysis of video recordings of medical lectures gives teachers an opportunity and motive to improve teaching quality. Faculty development and various improvement strategies, based on this analysis, are expected to help teachers succeed as effective, efficient, and attractive lecturers while improving the quality of larger lecture classes. PMID- 25812687 TI - Reactions of first-year medical students to cadaver dissection and their perception on learning methods in anatomy. AB - PURPOSE: The purpose of this study was to investigate the reactions of medical students to cadaver dissection and their preferred learning methods in studying anatomy. METHODS: Participants were 110 first-year medical students 57 from a pre medical course and 53 from the graduate entry level. A self-reported questionnaire survey was used to assess students' emotional and physical reactions to their encounters with cadavers in the dissecting room and their preferred teaching and learning methods and materials. Frequency, paired t-test, and cross-sectional analyses were conducted. RESULTS: Most students experienced negative physical symptoms, such as eye soreness (72%), mile headache or dizziness (40%), headache (18%), decrease in appetite (17%), nausea (15%), and disgust (10%), in the first encounter with a cadaver in the dissection room. They also experienced adverse emotional responses, such as surprise (38%), depression (37%), sadness (23%), fear (23%) and feelings of guilt (19%), anxiety (17%), and crying (2.7%). However, most of these reactions decreased significantly 8 weeks later, except for nausea. Regarding teaching and learning methods, students reported that lectures and cadaver dissections were the most helpful methods in studying anatomy. CONCLUSION: The results shows that initial encounters with a cadaver in the dissecting room caused emotional and physical distress to first year medical students, but most students adapted gradually to the stressful learning environment. In addition, students regarded cadaver dissection as one of the most helpful learning experiences in studying anatomy. PMID- 25812688 TI - The development and effects of a presentation skill improvement program for medical school students. AB - PURPOSE: The purpose of this study was to develop and examine a program that was designed to improve the presentation skills of medical school students. METHODS: The program was implemented in 2-day workshops for 36 third-grade medical students in 2009, using the following procedures in order: needs assessment; an initial group presentation and peer evaluation; an initial self-evaluation with video recording; viewing of a model presentation; a second presentation in a group and peer evaluation; and a second self-assessment. Two types of survey questionnaires were used: a self-evaluation checklist and a questionnaire on workshop satisfaction and confidence of presentation. RESULTS: Eighty-three percent of the students recognized the importance of presentation skills. There were significant differences in 3 factors of self-evaluation-constructing contents, utilizing audio-visual media, and delivery skills- but not with regard to understanding content. In the post workshop satisfaction survey, participants reported that the workshop was helpful in improving their own presentation skills. They also stated that presentation in a group, peer feedback, and video analysis of the recording were helpful. After the workshop, students claimed that their confidence scores in utilizing audio-visual media were the highest. CONCLUSION: Medical students realize the importance of presentation skills training and workshops in increasing presentation skills and improving confidence in presenting. Video analysis and feedback of each participant's presentation within the group was effective in upgrading the student's presentation skills. PMID- 25812689 TI - Mental health of medical school students and the effects of their strategy for enhancing self-esteem. AB - PURPOSE: This study investigated the mental health status, self-esteem, social comparison, and narcissism among medical school students. In addition, the mediational effect of social comparison between self-esteem and narcissism was also tested with regard to whether the students compared themselves with others to enhance their own self-esteem. METHODS: Data were collected from 427 medical school students at a medical school in Seoul. The questionnaire included the Minnesota Multiphasic Personality Inventory (MMPI) 383 scale, the self-esteem scale, the Iowa-Netherlands Comparison Orientation Measure, and the narcissism scale. Using the MMPI findings, a clinical psychologist screened for possible clinical cases. Then, the frequencies of those with distress were compared between three groups, based on affiliation; premedical, medical, and graduate medical students. Also, the level of self-esteem, social comparison, and narcissism was tested by analysis of (ANCOVA), and the mediational role of social comparison was explored. RESULTS: Irrespective of affiliation, almost 10% of medical school students showed mental illness or distress. Of the clinical scales on the MMPI, the T scores of the Pa (Paranoia), Sc (Schizophrenia), and Ma (Hypomania) scales were higher in premedical and medical school students than in graduate medical school students. In addition, the mediational role of social comparison was confirmed only in medical school students. CONCLUSION: We demonstrated that subjective distress in certain medical school students needs to be addressed. Also, self-esteem was an important factor that correlated with mental health and distress indices. However, comparing oneself with others to enhance self-esteem by derogating or focusing could result in increased narcissism. PMID- 25812690 TI - Relationship between the Content of the Medical Knowledge Written Examination and Clinical Skill Score in Medical Students. AB - PURPOSE: This study was planned to investigate which medical knowledge examination score-written examination on basic medicine, individual clinical medicine, and comprehensive clinical medicine-was closely related to clinical skill score in medical students. METHODS: Scores on basic medicine, clinical medicine, graduation assessment, clinical performance examination (CPX), and objective structured clinical examination (OSCE) for 106 students who graduated Dongguk University Medical School from 2010 to 2011 were included, and correlations between them were analyzed using T scores. RESULTS: All scores of basic medicine, clinical medicine, graduation assessment, CPX, and OSCE correlated significantly with each other. In connection with clinical skill, graduation assessment score showed a strong correlation (r=0.547, p<0.001) with the CPX. Regarding detailed scores on the CPX, history taking score correlated significantly with medical knowledge examination scores (r=0.435~0.406, p<0.001). By regression analysis, the score on graduation assessment was 1 point higher, and that of the CPX increased by 0.538 (p<0.001). CONCLUSION: Based on our study, comprehensive clinical knowledge is required for medical students to gain the appropriate clinical skills. Therefore, clinical skill practice and lectures that are based on the level of comprehensive clinical knowledge are recommended in the education of clinical skills in medical students. PMID- 25812692 TI - The secret of instruction. PMID- 25812691 TI - Correlation of CPX Scores with the Scores on Written Multiple-Choice Examinations on the Certifying Examination for Family Medicine in 2009 to 2011. AB - PURPOSE: Recently, the clinical practice examination (CPX) using standardized patients has been introduced into several specialty certifying examinations in Korea. The purpose of this paper was to determine the correlation of a resident's performance on the CPX with the comprehensive written multiple-choice question (MCQ) examination on the certifying examination for family medicine. METHODS: The subjects of this study were 1,023 residents who completed the 1st and 2nd certifying examination for family medicine between 2009 and 2011. We determined the correlation between the total scores and 4 domain scores (history taking, physical examination, patient education, and patient-physician interaction) on the CPX with the MCQ scores of the 1st written test and 2nd slide examination and the correlation between the total CPX score and scores on the CPX domains. RESULTS: The correlation between CPX score with each MCQ examination (0.21~0.45 with 1st written MCQ, 0.15~0.33 with 2nd slide MCQ) was lower than that between each MCQ examination (0.46~0.59). The CPX score on patient education did not correlate with the 1st written and 2nd MCQ scores. The CPX scores on history taking and physical examination correlated slightly with the 1st written MCQ scores. The global ratings of preceptor examiners had the highest correlation (r=0.68~0.82) with the total CPX scores. CONCLUSION: Considering the mild correlation of CPX scores with each MCQ examination, the CPX is more likely to measure other qualities, such as critical thinking and communication skills. PMID- 25812693 TI - Soft hardware and hard software: new teaching approach with confidence of success. PMID- 25812694 TI - OCT4B modulates OCT4A expression as ceRNA in tumor cells. AB - OCT4 is an essential transcription factor for maintaining the self-renewal and the pluripotency of embryonic stem cells (ESCs). The human OCT4 gene can generate three mRNA isoforms (OCT4A, OCT4B and OCT4B1) by alternative splicing. OCT4A protein is a transcription factor for the stemness of ESCs, while the function of OCT4B isoforms remains unclear. Most types of cancer express a relatively low level of OCT4 protein, particularly the OCT4B isoforms. In the present study, we found that OCT4A and OCT4B mRNA were co-expressed in several types of tumor cell lines and tumor samples, and we demonstrated that OCT4B functioned as a non coding RNA, modulating OCT4A expression in an miRNA-dependent manner [competing endogenous RNA (ceRNA) regulation] at the post-transcription level in the tumor cell lines. This is the first time that ceRNA regulation was observed among spliced isoforms of one gene, and may pave the way for identification of new targets for cancer treatment. PMID- 25812695 TI - Mcl-1 downregulation sensitizes glioma to bortezomib-induced apoptosis. AB - Glioma is the most aggressive form of primary brain tumor, with dismal patient outcome and no effective therapeutic approaches available. Targeting the ubiquitin-proteasome pathway has recently emerged as a potent rational anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma and other hematological malignancies as a single agent or as part of a combination therapy. However, bortezomib alone or in combination showed only minimal effects in the treatment of solid tumors. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein which protects tumor cells against spontaneous and chemotherapy-induced apoptosis. In multiple myeloma, specific downregulation of Mcl-1 induces apoptosis. Furthermore, previous studies demonstrated that proteasome inhibitors induce Mcl-1 accumulation that, in turn, slows down their pro-apoptotic effects, and the cell survival in multiple myeloma is highly dependent on Mcl-1. In the present study, we investigated the role of Mcl-1 downregulation in bortezomib induced apoptosis in gliomas. We observed that bortezomib triggers caspase-3 and PARP activation, upregulates cytochrome c expression and induces apoptosis. Furthermore, we demonstrated that effective targeting of Mcl-1 in glioma cells by gene silencing technology augments the glioma cell sensitivity to bortezomib induced apoptosis. In conclusion, the present study demonstrates that Mcl-1 plays a critical role in bortezomib-induced apoptosis. Mcl-1 inhibitor in combination with bortezomib present a promising novel strategy to trigger cell death pathways in the treatment of gliomas. PMID- 25812696 TI - Determination of dissociation constants of anti-ALP monoclonal antibodies by an ELISA - based method. AB - BACKGROUND: Dissociation constant (Kd) is of major significance in immunoassay. Since affinity may be influenced by the immunoassay methodology it is important to determine this parameter under the condition of the assay used. OBJECTIVE: To employ a rapid and simple ELISA- based method for measuring dissociation constants of two Alkaline Phosphatase (ALP) specific MAbs (A1G8F7 and A1G9G3) established in our laboratory. METHODS: A simple and rapid method on enzyme- linked immunosorbent assay (ELISA) was developed for measuring the dissociation constant of antibody - antigen reactions. In this method the ability of increasing amounts of antigen to bind to antibody measured in the fluid phase. RESULTS: Based on the data obtained from this study, the dissociation constants of A1G8F7 and A1G9G3 MAbs were 3.8 * 10-9 and 4.3 * 10-9 M, respectively. CONCLUSIONS: A1G8F7 and A1G9G3 MAbs with reasonably high affinity are suggested for used in very immunoassay such as ELISA, immunocytochemistry and immunihistochemistry (APAAP method). PMID- 25812697 TI - Development and characterization of monoclonal antibodies against human IgA in Balb/c mice. AB - OBJECTIVE: Immunoglobulin A (IgA) is the second immunoglobulin in human serum. Monoclonal antibodies have many potential uses in diagnosis, treatment and purification. The conjugated monoclonal antibodies against human IgA are utilized in diagnostic kits. METHODS: For production of monoclonal antibodies against human Immunoglobulin A, spleen cells of the immune mouse were fused with SP2/0 as myeloma cells and Poly Ethylene Glycol (PEG). Supernatant of hybridoma cells was screened to determine the antibody by ELISA. The appropriate clones were selected for limiting dilution (L.D). Ultimately, appropriate monoclone was injected intraperitoneally into the mouse that has been primed with Pristane. RESULTS: In current study, 175 clones were obtained of which 5 clones had absorbance values of about 3 were selected for limiting dilution. Between these clones, 3 D5monoclone with IgG1 subclass was selected as appropriate one and it was reproduced in FCS free RPMI 1640. For large scale production in invivo, the appropriate clone was implanted in the peritoneum of the Balb/c mouse and its titer was determined, which showed 1/100,000 dilution for ascitic fluid, having no cross reactivity with IgM & IgG. CONCLUSIONS: Monoclonal antibody was purified by chromatography, confirmed by SDS-PAGE and then conjugated with enzyme and used for diagnostic kits. PMID- 25812698 TI - Targeted therapy of solid tumors by monoclonal antibody specific to epidermal growth factor receptor. AB - Tumor growth and progression depends largely on the activity of cell membrane receptors like epidermal growth factor receptor (EGFR) that plays a pivotal role in the progression and invasion of different solid tumors. As one of the most promising approaches for targeting and therapy, monoclonal antibodies (mAbs) have widely been used in the treatment of various malignancies. However, the clinical effects of mAbs appear to be dependent upon its specificity and potency. In the current investigation, a series of mAbs were produced against human EGFR using hybridoma technology. Balb/c mice were immunized against EGFR-positive A431 cancer cells and the most immune mouse was selected for fusion and generation of anti-EGFR mAbs. Isotyping of the generated mAbs was performed by ELISA method. Of various monoclones produced, IgG1 subclass (mAb BF4) displayed specific binding to the EGFR-expressing A431 cells. Flow cytometry and immunofluorescence staining revalidated its specific reactivity with EGFR and MTT assay revealed significant growth inhibition of A431 cells treated with mAb BF4 mainly through induction of apoptosis. Based on these findings, we propose the produced anti-EGFR mAb BF4 to be exploited for diagnostic and possibly treatment of various malignancies with overexpression of EGFR. PMID- 25812699 TI - Construction of scFv library of human antibodies against tetanus toxin. AB - BACKGROUND: Over the last three decades, monoclonal antibodies have become powerful therapeutics and diagnostics tools. Progress in the antibody engineering, and the appearance of great selection technology such as phage display has made human antibodies production possible against antigens with high affinities. OBJECTIVE: The purpose of this study was to construct an immune antibody library from a vaccinated donor against tetanus toxin. METHODS: A blood sample was drawn from the donor who was vaccinated with tetanus toxoid. PBMC were isolated by using ficoll. After RNA extraction and cDNA synthesis. In order to amplify VH and VL regions, two uniplex PCRs were performed and put considering NcoI & HindIII, MluI & NotI restriction sites respectively for their cloning. These amplicons were cloned to pSEX81 vector and transformed to E. coli XL1blue strain. Eventually, recombinant plasmids were extracted and sequenced. RESULTS: The result showed acceptable similarity between antibody gene library nucleotide sequences and the antibody genes were deposited in this database. CONCLUSION: In this study, the VH and VL genes human antibody library was constructed and confirmed by using DNA sequencing and alignment of sequences with blast database. PMID- 25812700 TI - Novel antiphospholipid antibodies in autoimmune bullous diseases. AB - BACKGROUND: Pemphigus and bullous pemphigoid are two autoimmune diseases that have similar pathogenesis. Both have a genetic predisposition, which promotes the production of auto antibodies targeted against different components of the epidermal desmosome and hemidesmosome. Antiphospholipid antibodies (aPL) are heterogeneous group of antibodies found in patients with autoimmune diseases and inflammatory conditions and are associated with thrombotic events. OBJECTIVE: We sought to determine the expression profile of eight non classical aPLs in ABD patients. METHODS: A cohort of 266 serum samples of patients with pemphigus, bullous pemphigoid and controls was screened for the presence of eight aPL antibodies, using the Bio-Rad BioPlexTM 2200 system. RESULTS: Phosphatidylserine beta-2-glycoprotein-I (aPS-beta2GPI) and anti prothrombin complex (aPT-PT) serum profiles were significantly more prevalent among ABD patients; 20.7% patients with ABD compared to 5.9% of control patients were positive for aPS-beta2GPI IgM. In addition, aPT-PT IgM was more prevalent among ABD patients (31% vs. 14.8%). CONCLUSION: aPL auto antibodies are more prevalent in ABD. Any clinical association should be further determined. PMID- 25812701 TI - Multiple sclerosis and immunological-related risk factors: results from a case control study. AB - AIM: Multiple sclerosis is a demyeliting autoimmune inflammatory disorder of central nervous system (CNS) with unknown etiology, which afflicts more than 2.5 millions of the world's population. The aim of this study was to investigate the association between some immunological-related risk factors (tonsillectomy, appendectomy and hepatitis B vaccination) and multiple sclerosis in 2014 in Hamadan city, west of Iran. METHODS: As a case-control study, data of filled questionnaire with written consents from 250 patients and 250 age and sex matched controls, were collected and analyzed using SPSS version 16 software and Logistic regression test. RESULTS: In both groups, the case and the control, with average age of 33 years, 70% of the participants were women. Statistical analysis showed that there was no significant association between tonsillectomy and appendectomy with the multiple sclerosis (p > 0.05). Also hepatitis B vaccination did not increase the risk of MS significantly (p > 0.05), although there was a trend toward more vaccination rate in the patients. CONCLUSION: Considering previous global investigations on this topic with the result of our study, it seems more studies are needed to determine the definitive association between tonsillectomy, appendectomy and hepatitis B vaccination with multiple sclerosis. PMID- 25812702 TI - [Importance of reproductive biotechnology in cattle in Europe]. AB - Reproductive biotechnology has manifold applications and includes a great innovation potential in livestock. Due to the global changes the new findings and techniques can aid to meet the future challenges. The use of biotechnology in animal production can guarantee enough high quality food for the whole population. Genetic resources of animals can be preserved via sperm and embryo banking. Early diagnosis of hereditary defects, generation of offspring with predetermined sex and the avoidance of animal transports for breeding employing shipment of frozen embryos will improve animal welfare. A special application is the use of animal models for human assisted reproductive technologies. Therefore, not only in Germany research related to the methodologies in reproductive biotechnology and their improvement need to be supported. PMID- 25812703 TI - Factors that predict cognitive decline in patients with subjective cognitive impairment. AB - BACKGROUND: Current evidence supports the concept of a preclinical phase of Alzheimer's disease (AD) where pathological and imaging changes are present in asymptomatic individuals. Subjective cognitive impairment (SCI) may represent the earliest point on the continuum of AD. A better understanding of the baseline characteristics of this group of patients that later decline in cognition will enhance our knowledge of the very early disease processes, facilitate preventive strategies, early diagnosis, timely follow-up and treatment. METHODS: An observational exploratory study which followed up 62 consecutive patients with SCI presenting to a memory clinic and compared baseline characteristics of SCI patients who declined cognitively with those who did not. Cognitive decline was defined as a progression to a diagnosis of amnestic mild cognitive impairment (aMCI) or dementia at follow-up. RESULTS: Patients were followed up for a mean of 44 months (range 12-112 months). At the time of follow up, 24% of patients had declined. Patients that declined were significantly older at onset of symptoms and first presentation to memory clinic, and took significantly more medications for physical illnesses. Patients that declined also performed significantly worse on Trail Making Test (TMT) B and Cambridge Cognitive Examination - Revised (CAMCOG-R) at baseline. Survival analysis identified key variables that predicted decline (later age of onset and later age at first assessment). CONCLUSIONS: Patients who present with subjective memory complaints and are over the age of 61 years are at high risk of cognitive decline and warrant an in-depth assessment and follow-up. PMID- 25812704 TI - Concentration of field and skim latex by microfiltration - membrane fouling and biochemical methane potential of serum. AB - Cross-flow microfiltration was used to concentrate field and skim latex suspensions and recover the smallest compounds (proteins, sugars, etc.) in permeate (serum solutions). The experiments were performed in a lab-scale microfiltration unit equipped with ceramic membranes. In continuous mode, the operations were performed at constant trans-membrane pressure (0.5 bars), constant cross-flow velocity (3 m/s) and constant temperature (28 +/- 2 degrees C). In retentate, the volumetric concentration factor was only close to 2 (about 54% of total solid content, TSC) when concentrating the field latex suspensions, and it reached 10 (close to 40% TSC) when concentrating skim latex suspensions. The quality of retentate suspensions let envisage a significant potential of industrial valorization. The membrane fouling rates appeared as an increasing function of dry rubber content suspension, and the main fouling origin (94%) was linked to a reversible accumulation of suspended compounds on the membrane surface. Permeate appeared as a clear yellow solution containing the smallest soluble organic fractions that show a high degree of biodegradability when using biochemical methane potential tests. The chemical oxygen demand (COD) removal was then higher than 92% and the methane production yield was close to 0.29 NLCH4/gCODremoved. The association of a membrane separation step and anaerobic digestion appeared, then, as a relevant solution to recover rubber content from skim latex suspensions and energy from the anaerobic digestion of serum. PMID- 25812705 TI - Physical training induces expression of TGF-beta in kidney of pregnant hypertensive rats. AB - AIM: This study aimed to determine the morphological renal impairment in pregnant rats spontaneously hypertensive (SHR) submitted to swimming when compared with those who did not perform the activity, and to analyze the relationship of expression of cytokines in inflammatory fibrotic and protrained and sedentary animals. METHODS: SHRs and their respective control normotensive rats (WKY) were submitted or not to a swimming protocol during 9 weeks, resulting in four pregnant experimental groups: sedentary hypertensive (HS), trained hypertensive (HT), sedentary normotensive (NS), and trained normotensive (NT). RESULTS: Pregnant untrained hypertensive rats presented higher resting mean blood pressure (MAP) compared with both sedentary and trained normotensive groups (P<0.05). We can observe too, that the exercise training did not change the heart rate (HR) in both hypertensive and normotensive groups (P=0.127). The HT rats showed lower area of mesangial matrix (MM) compared to NT group (P=0.018). The perceptual of fibrosis (%F) in hypertensive rats was significantly higher compared with the % F in normotensive rats (P<0.001). The rats in the HT group showed higher expression of TGF-b (P<0.001) and of IL-10 (P<0.001) when compared with the other groups. CONCLUSION: The main conclusion is that in SHR rats it is shown a greater expression of TGF-beta, resulting in increased fibrosis in renal parenchyma due to the increased number of inflammatory cells that secrete this cytokine, and thus the practice of swimming can attenuate inflammatory processes, and mitigate the blood pressure of these animals. PMID- 25812706 TI - Redox balance in elite female athletes: differences based on sport types. AB - BACKGROUND: The aim of the present study was to analyze changes in redox balance throughout parameters of oxidative stress and activities of antioxidant enzymes in elite female water polo (N.=15) and football players (N.=19) aged between 20 and 23. Fourteen age-matched sedentary women were also included in the study. METHODS: Blood sampling was performed to measure levels of lipid peroxidation (MDA), total antioxidant status (TAS), superoxide anion radical (O2-), hydrogen peroxide (H2O2), reduced glutathione (GSH), oxidized glutathione (GSSG), nitrites, superoxide dismutase activity (SOD), catalase activity (CAT) and glutathione-peroxidase activity (GPx). RESULTS: Levels of MDA, TAS, GSSG and H2O2 were significantly higher in athletes than in the control women. Football players had higher levels of O2- than the other two groups. Activity of SOD was higher in water polo players when compared with the football and control groups, CAT was increased in all athletes, while GPx did not differ among groups. CONCLUSIONS: Therefore, prolonged intensive training markedly increases oxidative stress in women, which depends on the type of sport. Lower concentration of O2- and increased activity of SOD in water polo players compared to football players suggest that mechanisms of adaptation of antioxidative defense are related to the type of exercise. PMID- 25812708 TI - Prevalence and determinants of symptoms related to mental disorders in retired male professional footballers. AB - OBJECTIVE: The objective of this study was to determine the prevalence of symptoms related to mental disorders (distress, anxiety/depression, sleep disturbance, adverse alcohol behaviour, adverse smoking behaviour, adverse nutrition behaviour) among retired professional footballers, and to explore their associations with stressors i.e. determinants such as severe injury, surgery, life events and career dissatisfaction. METHOD: Cross--sectional analyses were conducted on baseline questionnaires from an ongoing prospective cohort study among retired male professional footballers. Based on validated questionnaires to assess both stressors and symptoms related to mental disorders, an electronic questionnaire was set up and distributed by players' unions in 11 countries across three continents. RESULTS: Prevalence of symptoms related to mental disorders among 219 retired professional footballers ranged from 11% for adverse smoking behaviour and 18% for distress, to 35% for anxiety/depression and 65% for adverse nutrition behaviour. Especially life events that occurred in the previous six months was positively associated with distress (OR=1.3; 95%CI 1.0--1.6), anxiety/depression (OR=1.6; 95%CI 1.2--2.1), sleeping disturbance (OR=1.3; 95%CI 1.1--1.7) and adverse nutrition behaviour (OR=1.4; 95%CI 1.0--1.8). CONCLUSIONS: A high prevalence of symptoms related to mental disorders was found among retired professional footballers, confirming a previous study in a similar study population. Relationships were established between symptoms of mental disorders and severe injuries, recently occurred life events, and career dissatisfaction. PMID- 25812707 TI - The effect of strength training and combination technique on preserving the strength of plantar flexor muscles after a period of detraining. AB - BACKGROUND: Strength training (ST) and/or electrical stimulation (ES) are two methods that have been prescribed for muscles improvement. The purpose of this study was to investigate the effects of six weeks of strength training and combined technique on maximal voluntary isometric contraction (MVIC) in plantar flexor muscles after 4 weeks of detraining. METHODS: Twenty-four healthy and nonathletic female students (age: 20-30 yrs) were randomly assigned to ST, combined training (CT), and control groups. The ST group performed 18 sessions of isometric contraction of plantar flexor muscles in three degrees (15 degrees Dorsiflexion, Neutral, 45 degrees plantarflexion) at 85% of MVIC and the CT group received ES (FES: Phase time of 60 microseconds; stimulation frequency of 40 Hz; duty cycle = 2s on/4s off; isometric contraction; 10 contractions per second at the maximum tolerated intensity without pain) combined with the same protocol as the ST Group. ST and CT subjects were tested before training; after 6 weeks of training; and after 4 weeks of detraining. RESULTS: In comparison with pretest measurers, post-test measures showed that the mean average of plantar flexor strength in the ST group increased from 25.75+/-7.10 to 45.25+/-12.66 in neutral position and increased from 32.75+/-9.66 to 48.00+/-11.56 in DF position. The mean average of plantar flexor strength in the CT group also increased from 24.52+/-7.32 to 43.50+/-10.46 in neutral position and increased from 24.63+/ 11.13 to 34.38+/-7.76 in DF position. Except for MVC in DF in the CT group, all variables reduced to their original values at the post detraining measures. In comparison with induced adaptations in ST and CT, this finding suggests that after 4 weeks of detraining, these adaptations in CT were maintained more than voluntary isometric training. CONCLUSIONS: It seems that strength changes following CT are longer lasting. PMID- 25812709 TI - Confirmatory factorial analysis of the children's attraction to physical activity scale (capa). AB - AIM: Attraction to physical activity (PA) is an important contributor to children's intrinsic motivation to engage in games, and sports. Previous studies have supported the utility of the children's attraction to PA scale (CAPA) (Brustad, 1996) but the validity of this measure for use in Portugal has not been established. The purpose of this study was to cross-validate the shorter version of the CAPA scale in the Portuguese cultural context. METHODS: A sample of 342 children (8--10 years of age) was used. Confirmatory factor analyses using EQS software ( version 6.1) tested t hree competing measurement models: a single- factor model, a five factor model, and a second order factor model. RESULTS: The single--factor model and the second order model showed a poor fit to the data. It was found that a five-factor model similar to the original one revealed good fit to the data (S--B chi 2 (67) =94.27,p=0.02; NNFI=0.93; CFI=0.95; RMSEA=0.04; 90%CI=0.02;0.05). CONCLUSIONS: The results indicated that the CAPA scale is valid and appropriate for use in the Portuguese cultural context. The availability of a valid scale to evaluate attraction to PA at schools should provide improved opportunities for better assessment and understanding of children's involvement in PA. PMID- 25812710 TI - Effect of exercise on depression in university students: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: The aim of this study was to assess the effect of exercise on depression in university students. EVIDENCE ACQUISITION: A systematic literature search was conducted in PubMed, EMBASE and the Cochrane library from their inception through December 10, 2014 to identify relevant articles. The heterogeneity across studies was examined by Cochran's Q statistic and the I2 statistic. Standardized mean difference (SMD) and 95% confidence interval (CI) were pooled to evaluate the effect of exercise on depression. Then, sensitivity and subgroup analyses were performed. In addition, publication bias was assessed by drawing a funnel plot. EVIDENCE SYNTHESIS: A total of 352 participants (154 cases and 182 controls) from eight included trials were included. Our pooled result showed a significant alleviative depression after exercise (SMD=-0.50, 95% CI: -0.97 to -0.03, P=0.04) with significant heterogeneity (P=0.003, I2=67%). Sensitivity analyses showed that the pooled result may be unstable. Subgroup analysis indicated that sample size may be a source of heterogeneity. Moreover, no publication bias was observed in this study. CONCLUSIONS: Exercise may be an effective therapy for treating depression in university students. However, further clinical studies with strict design and large samples focused on this specific population should be warranted in the future. PMID- 25812711 TI - Retrograde Renal Ablation via the Renal Vein as a New Treatment Option for Renovascular Hypertension. PMID- 25812712 TI - Factors associated with short-term local recurrence of liver cancer after percutaneous ablation using irreversible electroporation: a prospective single center study. AB - PURPOSE: To evaluate the risk factors associated with short-term local recurrence of malignant liver lesions after irreversible electroporation (IRE). MATERIALS AND METHODS: Thirty-nine consecutive patients (79 malignant liver lesions) were treated with IRE, of whom 14 were excluded from the analysis (including 12 without 6 mo of follow-up and two with incomplete ablation). The remaining 25 patients (aged 59.4 y +/- 11.2) had 48 malignant liver lesions, including 22 hepatocellular carcinomas (HCCs), six cholangiocellular carcinomas, and 20 metastatic liver cancers. Multivariate analyses were used to evaluate the associations of risk factors with early recurrence. The characteristics of patients, lesions, and IRE procedures were assessed by logistic regression. RESULTS: Fourteen of the 48 treated lesions (29.2%) showed early local recurrence after 6 months. Tumor volume (< 5 cm(3) vs >= 5 cm(3); P = .022) and underlying disease type (HCC, cholangiocellular carcinoma, or metastatic disease; P = .023) were independently associated with early local recurrence. However, distances to the surrounding portal veins (< 0.5 cm vs >= 0.5 cm; P = .810), hepatic veins (P = .170), hepatic arteries (P = .761), and bile ducts (P = .226) were not significantly associated with local recurrence. CONCLUSIONS: Because short distances to the surrounding vessels were not associated with early local recurrence, percutaneous IRE might provide an alternative treatment option for perivascular tumors. However, patients with larger tumor volumes appeared to be poor candidates for percutaneous IRE. Regarding the different types of treated lesions, patients with HCC had significantly better outcomes. PMID- 25812713 TI - Developmental synchrony of thalamocortical circuits in the neonatal brain. AB - The thalamus is a deep gray matter structure and consists of axonal fibers projecting to the entire cortex, which provide the anatomical support for its sensorimotor and higher-level cognitive functions. There is limited in vivo evidence on the normal thalamocortical development, especially in early life. In this study, we aimed to investigate the developmental patterns of the cerebral cortex, the thalamic substructures, and their connectivity with the cortex in the first few weeks of the postnatal brain. We hypothesized that there is developmental synchrony of the thalamus, its cortical projections, and corresponding target cortical structures. We employed diffusion tensor imaging (DTI) and divided the thalamus into five substructures respectively connecting to the frontal, precentral, postcentral, temporal, and parietal and occipital cortex. T2-weighted magnetic resonance imaging (MRI) was used to measure cortical thickness. We found age-related increases in cortical thickness of bilateral frontal cortex and left temporal cortex in the early postnatal brain. We also found that the development of the thalamic substructures was synchronized with that of their respective thalamocortical connectivity in the first few weeks of the postnatal life. In particular, the right thalamo-frontal substructure had the fastest growth in the early postnatal brain. Our study suggests that the distinct growth patterns of the thalamic substructures are in synchrony with those of the cortex in early life, which may be critical for the development of the cortical and subcortical functional specialization. PMID- 25812714 TI - Neural correlates of cognitive style and flexible cognitive control. AB - Human abilities of flexible cognitive control are associated with appropriately regulating the amount of cognitive control required in response to contextual demands. In the context of conflicting situations, for instance, the amount of cognitive control increases according to the level of previously experienced conflict, resulting in optimized performance. We explored whether the amount of cognitive control in conflict resolution was related to individual differences in cognitive style that were determined with the Object-Spatial-Verbal cognitive style questionnaire. In this functional magnetic resonance imaging (fMRI) study, a version of the color-word Stroop task, which evokes conflict between color and verbal components, was employed to explore whether individual preferences for distracting information were related to the increases in neural conflict adaptation in cognitive control network regions. The behavioral data revealed that the more the verbal style was preferred, the greater the conflict adaptation effect was observed, especially when the current trial type was congruent. Consistent with the behavioral data, the imaging results demonstrated increased neural conflict adaptation effects in task-relevant network regions, including the left dorsolateral prefrontal cortex, left fusiform gyrus, and left precuneus, as the preference for verbal style increased. These results provide new evidence that flexible cognitive control is closely associated with individuals' preference of cognitive style. PMID- 25812715 TI - Why do we make mistakes? Neurocognitive processes during the preparation perception-action cycle and error-detection. AB - The event-related potential (ERP) literature described two error-related brain activities: the error-related negativity (Ne/ERN) and the error positivity (Pe), peaking immediately after the erroneous response. ERP studies on error processing adopted a response-locked approach, thus, the question about the activities preceding the error is still open. In the present study, we tested the hypothesis that the activities preceding the false alarms (FA) are different from those occurring in the correct (responded or inhibited) trials. To this aim, we studied a sample of 36 Go/No-go performers, adopting a stimulus-locked segmentation also including the pre-motor brain activities. Present results showed that neither pre stimulus nor perceptual activities explain why we commit FA. In contrast, we observed condition-related differences in two pre-response components: the fronto central N2 and the prefrontal positivity (pP), respectively peaking at 250 ms and 310 ms after the stimulus onset. The N2 amplitude of FA was identical to that recorded in No-go trials, and larger than Hits. Because the new findings challenge the previous interpretations on the N2, a new perspective is discussed. On the other hand, the pP in the FA trials was larger than No-go and smaller than Go, suggesting an erroneous processing at the stimulus-response mapping level: because this stage triggers the response execution, we concluded that the neural processes underlying the pP were mainly responsible for the subsequent error commission. Finally, sLORETA source analyses of the post-error potentials extended previous findings indicating, for the first time in the ERP literature, the right anterior insula as Pe generator. PMID- 25812716 TI - Brain dynamics of meal size selection in humans. AB - Although neuroimaging research has evidenced specific responses to visual food stimuli based on their nutritional quality (e.g., energy density, fat content), brain processes underlying portion size selection remain largely unexplored. We identified spatio-temporal brain dynamics in response to meal images varying in portion size during a task of ideal portion selection for prospective lunch intake and expected satiety. Brain responses to meal portions judged by the participants as 'too small', 'ideal' and 'too big' were measured by means of electro-encephalographic (EEG) recordings in 21 normal-weight women. During an early stage of meal viewing (105-145 ms), data showed an incremental increase of the head-surface global electric field strength (quantified via global field power; GFP) as portion judgments ranged from 'too small' to 'too big'. Estimations of neural source activity revealed that brain regions underlying this effect were located in the insula, middle frontal gyrus and middle temporal gyrus, and are similar to those reported in previous studies investigating responses to changes in food nutritional content. In contrast, during a later stage (230-270 ms), GFP was maximal for the 'ideal' relative to the 'non-ideal' portion sizes. Greater neural source activity to 'ideal' vs. 'non-ideal' portion sizes was observed in the inferior parietal lobule, superior temporal gyrus and mid-posterior cingulate gyrus. Collectively, our results provide evidence that several brain regions involved in attention and adaptive behavior track 'ideal' meal portion sizes as early as 230 ms during visual encounter. That is, responses do not show an increase paralleling the amount of food viewed (and, in extension, the amount of reward), but are shaped by regulatory mechanisms. PMID- 25812718 TI - On the nature of superconductivity in the anisotropic dichalcogenide NbSe2{CoCp2}x. AB - We present a detailed study of the superconducting properties of the weakly pinned, quasi-two-dimensional superconductor 2H-NbSe2, and its intercalated variant NbSe2{CoCp2}0.26. The intercalation of 2H-NbSe2 with the organometallic donor molecule cobaltocene (CoCp2) hardly affects the superconducting properties within the layers. However, the properties perpendicular to the layers change significantly due to the large expansion of the layer spacings of the host lattice in the c-direction by a factor of about two. In particular, the superconducting anisotropy factor Gamma increases from 3.3 in the parent compound 2H-NbSe2 up to 4.4 in the intercalated species. Therefore, NbSe2{CoCp2}0.26 is an excellent candidate to analyze how the anisotropy effects the superconducting mechanism in layered dichalcogenides, and to evaluate the various models proposed in the literature to account for the anisotropy in 2H-NbSe2. While a two-gap model and an anisotropic single-gap model are competing concepts to describe the almost linear T(2)-dependence of DeltaC/T in low-dimensional dichalcogenides, our comparative study suggests that a single-gap model with an anisotropic Fermi surface is sufficient to capture the DeltaC/T(T) behavior in our samples qualitatively. PMID- 25812719 TI - Atomic collisions in suprafluid helium-nanodroplets: timescales for metal-cluster formation derived from He-density functional theory. AB - Collision times for the coinage metal atoms Cu, Ag and Au in He-droplets are derived from helium density functional theory and molecular dynamics simulations. The strength of the attractive interaction between the metal atoms turns out to be less important than the mass of the propagating metal atoms. Even for small droplets consisting of a few thousand helium atoms, the collision times are shortest for Cu, followed by Ag and Au, despite the higher binding energy of Au2 compared to Cu2. PMID- 25812717 TI - Fast and powerful heritability inference for family-based neuroimaging studies. AB - Heritability estimation has become an important tool for imaging genetics studies. The large number of voxel- and vertex-wise measurements in imaging genetics studies presents a challenge both in terms of computational intensity and the need to account for elevated false positive risk because of the multiple testing problem. There is a gap in existing tools, as standard neuroimaging software cannot estimate heritability, and yet standard quantitative genetics tools cannot provide essential neuroimaging inferences, like family-wise error corrected voxel-wise or cluster-wise P-values. Moreover, available heritability tools rely on P-values that can be inaccurate with usual parametric inference methods. In this work we develop fast estimation and inference procedures for voxel-wise heritability, drawing on recent methodological results that simplify heritability likelihood computations (Blangero et al., 2013). We review the family of score and Wald tests and propose novel inference methods based on explained sum of squares of an auxiliary linear model. To address problems with inaccuracies with the standard results used to find P-values, we propose four different permutation schemes to allow semi-parametric inference (parametric likelihood-based estimation, non-parametric sampling distribution). In total, we evaluate 5 different significance tests for heritability, with either asymptotic parametric or permutation-based P-value computations. We identify a number of tests that are both computationally efficient and powerful, making them ideal candidates for heritability studies in the massive data setting. We illustrate our method on fractional anisotropy measures in 859 subjects from the Genetics of Brain Structure study. PMID- 25812720 TI - Effect of team rank and player classification on activity profiles of elite wheelchair rugby players. AB - The aim of the current study was to establish which indicators of mobility are associated with successful wheelchair rugby performance and determine whether these indicators differed across classification. Data were collected from 11 international teams during 30 matches (353 match observations) using a radio frequency-based, indoor tracking system across two tournaments. Players (n = 111) were first grouped by team rank as determined by their International Wheelchair Rugby Federation (IWRF) world ranking (LOW, MID, HIGH) and then into one of four groups based on their IWRF classification: Group I (0.5), Group II (1.0-1.5), Group III (2.0-2.5) and Group IV (3.0-3.5). The volume of activity (relative distance and mean speed), peak speed and time spent within classification specific arbitrary speed zones were calculated for each individual. Although no differences were identified in the volume of activity, playing time was significantly reduced in LOW (34:51 +/- 8:35) compared to MID (48:54 +/- 0:51) and HIGH (45:38 +/- 9:53), which was further supported by the greater number of substitutions performed by LOW. HIGH achieved greater peak speeds (3.55 +/- 0.40 m . s-(1)) than LOW (3.27 +/- 0.42 m . s(-1)) and MID (3.45 +/- 0.41 m . s(-1)). Peak speed was further shown to be classification-dependent (P <= 0.005), whereby HIGH Groups III and IV players achieved greater peak speeds than LOW and MID. The time spent performing high-intensity activities was also greater in HIGH compared to LOW and MID, whilst further influenced by classification (P <= 0.0005). To conclude, peak speed and the ability to perform a greater number of high intensity activities were associated with successful performance in wheelchair rugby. PMID- 25812721 TI - Relationship between intracochlear electrode position and tinnitus in cochlear implantees. AB - CONCLUSION: Cochlear implant electrode position has an impact on the rate of tinnitus suppression and generation. OBJECTIVE: Suppression of pre-operative tinnitus or a generation of a new tinnitus in cochlear implantees is a known effect of cochlear implantation. The aim of the current study was to evaluate different cochlear implant electrode positions and their relationship with tinnitus suppression and tinnitus generation. METHOD: This study retrospectively evaluated four groups of CI recipients with radiologically evaluated electrode positions in relation to their subjective tinnitus quality, as evaluated by an analogue loudness scale (ALS) and a questionnaire. Group 1 consisted of 19 patients with a scalar change of the electrode position. Group 2 consisted of 18 patients with a scala tympani position and a perimodiolar electrode. Group 3 consisted of 10 patients with a scala tympani position and a lateral wall electrode. Group 4 consisted of eight patients with a scala vestibuli position. RESULTS: An overall tinnitus suppression rate of 45.9% and a generation of a new tinnitus or the deterioration of an existing one of 5.6% were observed. A significant difference in tinnitus suppression was found between groups 1 and groups 2, 3, and 4 in tinnitus suppression and tinnitus generation. PMID- 25812722 TI - Facile fabrication of diphenylalanine peptide hollow spheres using ultrasound assisted emulsion templates. AB - The controlled self-assembly of diphenylalanine (FF) into unilocular and multilocular hollow spheres was successfully achieved by an ultrasound-assisted emulsion droplet template method. This novel surfactant-free emulsion droplet template method is envisaged to be applicable to other biomolecules and materials. PMID- 25812723 TI - Effect of cholesterol on the phase behavior of solid-supported lipid vesicle layers. AB - The interest in solid-supported biomimetic membranes stems from their utility in nanotechnology and biosensing. In particular, supported lipid vesicles (SLVs) have become popular in both fundamental biophysical studies and pharmaceutical screening applications. It is thus essential to gain information on the structural properties and phase behavior of SLVs. Here we report on a study on the influence of cholesterol on the phase behavior of SLVs of saturated phospholipids by using quartz crystal microbalance with dissipation monitoring, a label-free and nonintrusive surface-sensitive technique. Two complementary approaches have been used, a Voigt-based viscoelastic model yielding shear viscosity temperature profiles and the first-order derivative of the frequency (mass-sensitive) shifts. Anomalies in the shear viscosity and extrema in the first-order derivative frequency curves stand as a token of the main phase transition and provide information on its gradual suppression upon addition of cholesterol. This method proves convenient for its small sample volume needed, its short temperature equilibration time and the non-necessity of external labels. This work can be regarded as a starting point for further studies on more rare lipid systems and different geometries, such as tethered SLVs or biologically relevant vesicles produced by living cells. PMID- 25812724 TI - Highly Controllable Surface Plasmon Resonance Property by Heights of Ordered Nanoparticle Arrays Fabricated via a Nonlithographic Route. AB - Perfectly ordered nanoparticle arrays are fabricated on large-area substrates (>cm(2)) via a cost-effective nonlithographic route. Different surface plasmon resonance (SPR) modes focus consequently on their own positions due to the identical shape and uniform size and distance of these plasmonic metallic nanoparticles (Ag and Au). On the basis of this and FDTD (finite-difference time domain) simulation, this work reveals the variation of all SPR parameters (position, intensity, width, and mode) with nanoparticle heights, which demonstrates that the effect of heights are different in various stages. On increasing the heights, the major dipole SPR mode precisely blue-shifts from the near-infrared to the visible region with intensity strengthening, a peak narrowing effect, and multipole modes excitation in the UV-vis range. The intensity of multipole modes can be manipulated to be equal to or even greater than the major dipole SPR mode. After coating conformal TiO2 shells on these nanoparticle arrays by atomic layer deposition, the strengthening of the SPR modes with increasing the heights results in the multiplying of the photocurrent (from ~2.5 to a maximum 90 MUA cm(-2)) in this plasmonic-metal-semiconductor incorporated system. This simple but effective adjustment for all SPR parameters provides guidance for the future design of plasmonic metallic nanostructures, which is significant for SPR applications. PMID- 25812725 TI - Perception of the signs and symptoms of temporomandibular disorder in females by using the ProTMDMulti protocol and the visual analog scale before and after acupuncture treatment. AB - OBJECTIVE: To evaluate the perceptions of patients with TMD in relation to the signs and symptoms before and after acupuncture treatment, according to the ProTMDMulti and the VAS. METHOD: 68 patients were divided into groups: muscle TMD treated with acupuncture at local points (MUS-LP), muscle TMD with acupuncture at distant points (MUS-DP), joint and muscle treated with LP (JOI-LP) and joint and muscle treated with DP (JOI-DP). The evaluations were performed at four times: initial, control, final and follow-up. RESULTS: The best results were seen in the JOI-LP and the MUS-DP groups, in which the perceptions of the signs and symptoms were statistically lower in the final assessment than in the initial (P<0.05). In all groups, the final and the follow-up evaluations were similar. CONCLUSIONS: For TMDs with joint components, the best acupuncture treatment involves local points and for the TMDs with muscle components, points at a distance. PMID- 25812726 TI - Toll-like receptor family members in skin fibroblasts are functional and have a higher expression compared to skin keratinocytes. AB - Toll-like receptors (TLRs) are known to recognize not only pathogen-associated molecular patterns but also danger-associated molecular patterns. Recent studies have characterized the expression levels and functions of TLRs in human epidermal cells. However, the characteristics of TLR family members in human dermal fibroblasts have not been thoroughly studied. Therefore, the present study systematically investigated the expression levels of TLRs and their functional responses to each ligand in skin fibroblasts. All 10 TLRs are expressed in skin fibroblasts. Stimulation of skin fibroblasts with each TLR ligand resulted in an increase of the interleukin-6 (IL-6), IL-8 and matrix metalloproteinase-1 proteins, indicating that >= 9 TLRs in skin fibroblasts are functionally active. Furthermore, stimulating skin fibroblasts with TLR1/2, 3 and 4 ligands induced the phosphorylation of inhibitor of nuclear factor kappaBalpha and the active phosphorylation of extracellular-signal regulated kinase 1/2. The expression level of each TLR was much higher in fibroblasts compared to keratinocytes. In particular, the fold-increase in IL-6 and IL-8 mRNA levels upon exposure to a TLR1/2 ligand was much higher in fibroblasts compared to keratinocytes, which appears to reflect the difference in expression levels of TLR1 and 2 between fibroblasts and keratinocytes. Taken together, these results show that all 10 TLRs are constitutively expressed and functional (except TLR10) in skin fibroblasts and suggest that TLRs in skin fibroblasts may play an important role in the detection of and response to different classes of pathogens and danger signals. PMID- 25812727 TI - Trunk control impairment is responsible for postural instability during quiet sitting in individuals with cervical spinal cord injury. AB - BACKGROUND: Individuals with cervical spinal cord injury usually sustain impairments to the trunk and upper and lower limbs, resulting in compromised sitting balance. The objectives of this study were to: 1) compare postural control of individuals with cervical spinal cord injury and able-bodied individuals; and 2) investigate the effects of foot support and trunk fluctuations on postural control during sitting balance. METHODS: Ten able-bodied individuals and six individuals with cervical spinal cord injury were asked to sit quietly during two 60s trials. The forces exerted on the seat and the foot support surfaces were measured separately using two force plates. The global centre of pressure sway was obtained from the measurements on the two force plates, and the sway for each force plate was calculated individually. FINDINGS: Individuals with spinal cord injury had at least twice as large global and seat sways compared to able-bodied individuals, while foot support sway was not significantly different between the two groups. Comparison between global and seat sways showed that anterior-posterior velocity of global sway was larger compared to the seat sway in both groups. INTERPRETATION: Postural control of individuals with cervical spinal cord injury was worse than that of able-bodied individuals. The trunk swayed more in individuals with spinal cord injury, while the stabilization effect of the feet did not differ between the groups. Foot support affected anterior-posterior fluctuations in both groups equally. Thus, trunk control is the dominant mechanism contributing to sitting balance in both able-bodied and spinal cord injury individuals. PMID- 25812728 TI - One- and multi-segment foot models lead to opposite results on ankle joint kinematics during gait: Implications for clinical assessment. AB - BACKGROUND: Biomechanical models representing the foot as a single rigid segment are commonly used in clinical or sport evaluations. However, neglecting internal foot movements could lead to significant inaccuracies on ankle joint kinematics. The present study proposed an assessment of 3D ankle kinematic outputs using two distinct biomechanical models and their application in the clinical flat foot case. METHODS: Results of the Plug in Gait (one segment foot model) and the Oxford Foot Model (multisegment foot model) were compared for normal children (9 participants) and flat feet children (9 participants). Repeated measures of Analysis of Variance have been performed to assess the Foot model and Group effects on ankle joint kinematics. FINDINGS: Significant differences were observed between the two models for each group all along the gait cycle. In particular for the flat feet group, opposite results between the Oxford Foot Model and the Plug in Gait were revealed at heelstrike, with the Plug in Gait showing a 4.7 degrees ankle dorsal flexion and 2.7 degrees varus where the Oxford Foot Model showed a 4.8 degrees ankle plantar flexion and 1.6 degrees valgus. INTERPRETATION: Ankle joint kinematics of the flat feet group was more affected by foot modeling than normal group. Foot modeling appeared to have a strong influence on resulting ankle kinematics. Moreover, our findings showed that this influence could vary depending on the population. Studies involving ankle joint kinematic assessment should take foot modeling with caution. PMID- 25812729 TI - Long-lasting effects of neck muscle vibration and contraction on self-motion perception of vestibular origin. AB - OBJECTIVE: To show that neck proprioceptive input can induce long-term effects on vestibular-dependent self-motion perception. METHODS: Motion perception was assessed by measuring the subject's error in tracking in the dark the remembered position of a fixed target during whole-body yaw asymmetric rotation of a supporting platform, consisting in a fast rightward half-cycle and a slow leftward half-cycle returning the subject to the initial position. Neck muscles were relaxed or voluntarily contracted, and/or vibrated. Whole-body rotation was administered during or at various intervals after the vibration train. The tracking position error (TPE) at the end of the platform rotation was measured during and after the muscle conditioning maneuvers. RESULTS: Neck input produced immediate and sustained changes in the vestibular perceptual response to whole body rotation. Vibration of the left sterno-cleido-mastoideus (SCM) or right splenius capitis (SC) or isometric neck muscle effort to rotate the head to the right enhanced the TPE by decreasing the perception of the slow rotation. The reverse effect was observed by activating the contralateral muscle. The effects persisted after the end of SCM conditioning, and slowly vanished within several hours, as tested by late asymmetric rotations. The aftereffect increased in amplitude and persistence by extending the duration of the vibration train (from 1 to 10min), augmenting the vibration frequency (from 5 to 100Hz) or contracting the vibrated muscle. Symmetric yaw rotation elicited a negligible TPE, upon which neck muscle vibrations were ineffective. CONCLUSIONS: Neck proprioceptive input induces enduring changes in vestibular-dependent self-motion perception, conditional on the vestibular stimulus feature, and on the side and the characteristics of vibration and status of vibrated muscles. This shows that our perception of whole-body yaw-rotation is not only dependent on accurate vestibular information, but is modulated by proprioceptive information related to previously experienced position of head with respect to trunk. SIGNIFICANCE: Tonic proprioceptive inflow, as might occur as a consequence of enduring or permanent head postures, can induce adaptive plastic changes in vestibular dependent motion sensitiveness. These changes might be counteracted by vibration of selected neck muscles. PMID- 25812731 TI - Role of osteal macrophages in bone metabolism. AB - Macrophages have been shown to have pleiotropic functions in various pathophysiologies, especially in terms of anti-inflammatory and regenerative activity. Recently, the novel functions of bone marrow resident macrophages (called osteal macrophages) were intensively studied in bone development, remodeling and tissue repair processes. This review discusses the current evidence for a role of osteal macrophages in bone modeling, remodeling, and fracture healing processes. PMID- 25812730 TI - Utility of transmission electron microscopy in small round cell tumors. AB - Small round cell tumors (SRCTs) are a heterogeneous group of neoplasms composed of small, primitive, and undifferentiated cells sharing similar histology under light microscopy. SRCTs include Ewing sarcoma/peripheral neuroectodermal tumor family tumors, neuroblastoma, desmoplastic SRCT, rhabdomyosarcoma, poorly differentiated round cell synovial sarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, small cell malignant peripheral nerve sheath tumor, and small cell schwannoma. Non-Hodgkin's malignant lymphoma, myeloid sarcoma, malignant melanoma, and gastrointestinal stromal tumor may also present as SRCT. The current shift towards immunohistochemistry and cytogenetic molecular techniques for SRCT may be inappropriate because of antigenic overlapping or inconclusive molecular results due to the lack of differentiation of primitive cells and unavailable genetic service or limited moleculocytogenetic experience. Although usage has declined, electron microscopy (EM) remains very useful and shows salient features for the diagnosis of SRCTs. Although EM is not always required, it provides reliability and validity in the diagnosis of SRCT. Here, the ultrastructural characteristics of SRCTs are reviewed and we suggest that EM would be utilized as one of the reliable modalities for the diagnosis of undifferentiated and poorly differentiated SRCTs. PMID- 25812732 TI - Overexpression of C-reactive Protein as a Poor Prognostic Marker of Resectable Hepatocellular Carcinomas. AB - BACKGROUND: C-reactive protein (CRP) is an acute phase reactant synthesized in the liver. CRP immunoreactivity is a feature of inflammatory hepatocellular adenomas with a higher risk of malignant transformation. A high serum CRP level denotes poor prognosis in hepatocellular carcinoma (HCC) patients. This study was conducted to determine whether CRP is produced in HCC and to assess the clinicopathologic significance of CRP expression in cancer cells. METHODS: CRP immunoreactivity was examined in treatment-naive HCCs (n=224) using tissue microarrays and was correlated with clinicopathologic parameters. The expression of CRP mRNA and protein was also assessed in 12 HCC cases by quantitative real time polymerase chain reaction and immunoblotting. Hep3B and SNU-449 HCC cell lines were used for the analysis of CRP mRNA regulation by interleukin 6 (IL-6). RESULTS: CRP was expressed in 133 of 224 HCCs (59.4%) with a variable degree of immunoreactivity (grade 1 in 25.9%; grade 2 in 20.1%; grade 3 in 13.4%). There was an inverse relationship between grade 3 CRP immunoreactivity and cancer specific survival (p=.0047), while no associations were found with other parameters, including recurrence-free survival. The CRP mRNA expression level was significantly higher in CRP immunopositive cases than in immunonegative cases (p<.05). CRP mRNA expression was increased in Hep3B cells, but was not detected in SNU-449 cells even after IL-6 treatment. CONCLUSIONS: We report the expression of CRP in HCC for the first time. CRP expression was associated with poor cancer specific survival in patients with resectable HCC. PMID- 25812733 TI - The Diagnostic Usefulness of HMGA2, Survivin, CEACAM6, and SFN/14-3-3 delta in Follicular Thyroid Carcinoma. AB - BACKGROUND: Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy and its differential diagnosis includes follicular adenoma (FA) and adenomatous goiter (AG). Several ancillary markers have been suggested to aid in the diagnosis of FTC, but the successful use of these methods still needs to be validated. METHODS: In the present study, we verified the immunoexpression of HMGA2, CEACAM6, survivin, and SFN/14-3-3 delta in lesions including 41 AGs, 72 FAs, and 79 FTCs. We evaluated their diagnostic usefulness, combined with galectin 3, Hector Battifora mesothelial 1 (HBME1), cytokeratin 19, and cyclin D1, in diagnosing FTC. RESULTS: The expressions of HBME1 (65.8%) and HMGA2 (55.7%) were significantly higher in FTCs than in FAs and AGs (p<.001 and p=.005, respectively). HBME1 was the only marker that was more frequently expressed in FTCs than in FAs (p=.021) and it was more frequently expressed in follicular neoplasms than in AGs (p<.001). Among the novel markers, the combination of HMGA2 and HBME1 showed the highest sensitivity (72.2%) and specificity (76.1%) for diagnosing FTC. CEACAM6, survivin, and SFN/14-3-3 delta were barely expressed in most cases. CONCLUSIONS: Our present results show that only HMGA2 can be beneficial in differentiating FTC using the novel markers. PMID- 25812734 TI - Image-guided fine needle cytology with aspiration versus non-aspiration in retroperitoneal masses: is aspiration necessary? AB - BACKGROUND: Although using fine needle cytology with aspiration (FNC-A) for establishing diagnoses in the retroperitoneal region has shown promise, there is scant literature supporting a role of non-aspiration cytology (FNC-NA) for this region. We assessed the accuracy and reliability of FNC-A and FNC-NA as tools for preoperative diagnosis of retroperitoneal masses and compared the results of both techniques with each other and with histopathology. METHODS: Fifty-seven patients with retroperitoneal masses were subjected to FNC-A and FNC-NA. Smears were stained with May-Grunwald Giemsa and hematoxylin and eosin stain. An individual slide was objectively analysed using a point scoring system to enable comparison between FNC-A and FNC-NA. RESULTS: By FNC-A, 91.7% accuracy was obtained in cases of retroperitoneal lymph node lesions followed by renal masses (83.3%). The diagnostic accuracy of other sites by FNC-A varied from 75.0%-81.9%. By FNC-NA, 93.4% diagnostically accurate results were obtained in the kidney, followed by 75.0% in adrenal masses. The diagnostic accuracy of other sites by FNC-NA varied from 66.7%-72.8%. CONCLUSIONS: Although both techniques have their own advantages and disadvantages, FNC-NA may be a more efficient adjuvant method of sampling in retroperitoneal lesions. PMID- 25812735 TI - Oncocytic lipoadenoma: a rare case of parotid gland tumor and review of the literature. AB - Oncocytic lipoadenoma is a rare tumor, with only 18 cases having been reported since the first in 1998. We encountered a case of oncocytic lipoadenoma presenting as a slowly growing parotid mass in a 71-year-old man. This tumor is characteristically comprised of a mixture of oncocytes and adipocytes. The present case is one of five reported cases of oncocytic lipoadenoma showing sebaceous differentiation. The results of immunohistochemical study with DOG1 antibody supported the origination of this tumor in the striated duct. PMID- 25812737 TI - Angiomyomatous hamartoma of popliteal lymph node: an unusual entity. PMID- 25812738 TI - Focal hematopoietic hyperplasia of rib: a rare pseudotumor and review of literature. PMID- 25812736 TI - Fallopian metaplastic papillary tumour: an atypical transdifferentiation of the tubal epithelium? AB - A metaplastic papillary tumor of the Fallopian tube is an extremely uncommon condition, with odd and confusing features that make it difficult to categorize as benign or borderline. Here, we summarize all the published cases to date and document the case of a 41-year-old woman diagnosed with this alteration after her last childbirth and ensuing tubal ligation. One of the tubes was bulky and filled with a caramel-like substance encircling a blurry spot. Light microscopy detailed a slender stalk covered by eosinophilic, columnar plump cells, showing atypical nuclei and focal budding. Mitotic figures were absent. The immunohistochemistry panel was positive for pan-cytokeratin, epithelial membrane antigen, cyclin D1, and hormone receptors. Additionally, a proliferation index of less than 5% was rated using Ki-67. The true nature of this tumor (reactive vs neoplastic) is uncertain. Nonetheless, its association with pregnancy suggests an adaptive change, likely similar to the atypical transdifferentiation proposed for Arias Stella reaction. PMID- 25812739 TI - Unicystic granulosa cell tumor. PMID- 25812740 TI - Retiform hemangioendothelioma of the neck. PMID- 25812741 TI - Metastatic endobronchial adenocarcinoma from the uterine cervix verified by human papillomavirus genotyping. PMID- 25812742 TI - Malakoplakia affecting the umbilical cord. PMID- 25812743 TI - HAlign: Fast multiple similar DNA/RNA sequence alignment based on the centre star strategy. AB - MOTIVATION: Multiple sequence alignment (MSA) is important work, but bottlenecks arise in the massive MSA of homologous DNA or genome sequences. Most of the available state-of-the-art software tools cannot address large-scale datasets, or they run rather slowly. The similarity of homologous DNA sequences is often ignored. Lack of parallelization is still a challenge for MSA research. RESULTS: We developed two software tools to address the DNA MSA problem. The first employed trie trees to accelerate the centre star MSA strategy. The expected time complexity was decreased to linear time from square time. To address large-scale data, parallelism was applied using the hadoop platform. Experiments demonstrated the performance of our proposed methods, including their running time, sum-of pairs scores and scalability. Moreover, we supplied two massive DNA/RNA MSA datasets for further testing and research. PMID- 25812744 TI - RiboTools: a Galaxy toolbox for qualitative ribosome profiling analysis. AB - MOTIVATION: Ribosome profiling provides genome-wide information about translational regulation. However, there is currently no standard tool for the qualitative analysis of Ribo-seq data. We present here RiboTools, a Galaxy toolbox for the analysis of ribosome profiling (Ribo-seq) data. It can be used to detect translational ambiguities, stop codon readthrough events and codon occupancy. It provides a large number of plots for the visualisation of these events. PMID- 25812745 TI - KeBABS: an R package for kernel-based analysis of biological sequences. AB - KeBABS provides a powerful, flexible and easy to use framework for KE: rnel- B: ased A: nalysis of B: iological S: equences in R. It includes efficient implementations of the most important sequence kernels, also including variants that allow for taking sequence annotations and positional information into account. KeBABS seamlessly integrates three common support vector machine (SVM) implementations with a unified interface. It allows for hyperparameter selection by cross validation, nested cross validation and also features grouped cross validation. The biological interpretation of SVM models is supported by (1) the computation of weights of sequence patterns and (2) prediction profiles that highlight the contributions of individual sequence positions or sections. PMID- 25812746 TI - How to make medication error reporting systems work--Factors associated with their successful development and implementation. AB - This study explored factors associated with successful development and implementation of medication error reporting (MER) systems in different healthcare contexts. A descriptive online questionnaire comprising of structured and open-ended questions was responded to by 16 medication safety experts in 16 countries. The present paper describes the rich and multidimensional qualitative data from the experts' narratives from open-ended questions. Several factors related to the national context of MER systems, i.e., the operational environment, were identified to impact successful development and implementation of these systems. The factors were: awareness of deficiencies in medication safety at local and national levels to justify the need for MER systems; gaining political will for the development and implementation actions together with international and governmental support; creating or reforming legislation and national regulations, guidelines and strategies to support MER; allocation of adequate human and financial resources; establishment of an organisation or centre to coordinate and lead MER; and extending systems approach and safety culture to all parts of the operational environment to facilitate openness on and learning from medication errors. In conclusion, operational environments of MER systems must be constructed to support functionality of these systems, and need to be improved in many countries. PMID- 25812747 TI - Competition among pharmacies and the typology of services delivered: The Portuguese case. AB - OBJECTIVE: To analyze the impact of individual and market characteristics (such as competition) on the typology of services delivered by a community pharmacy after a recent Portuguese pro-competitive regulatory change. METHODS: In this paper, market concentration indices are used to identify market competition groups in the sample. These competition groups are then described with regard to the typology of services on offer by pharmacies within the group. Finally, a system of structural equations is estimated to verify if the decision of a pharmacy to offer or not to offer each of the studied pharmaceutical services is affected by local market regulated competition. RESULTS: In some cases, pharmacies belonging to different competition groups do not present significant differences in terms of the typology of services on offer, but according to our regressions, it seems that vaccines and medicines administration services, pharmaceutical care programmes and medicines management programmes are more likely to be offered in pharmacies located in higher competitive markets. These are also urban areas, in which there is already easy access to products sold in pharmacies, and to health services in general. CONCLUSIONS: Access to additional pharmacy services may in some cases increase as market competition increases. Thus, pro-competitive regulatory measures may have led to an asymmetric distribution of pharmacy services across the country, favouring more competitive urban marketplaces. If policy-makers are interested in a more symmetrical distribution of pharmacies services all over the country, they are recommended to take action to ensure equitable access to these services. PMID- 25812749 TI - Disulfiram-like Reaction with Ornidazole. PMID- 25812748 TI - Overexpression of activator of G-protein signaling 3 decreases the proliferation of esophageal squamous cell carcinoma. AB - BACKGROUND: Activator of G-protein Signaling 3 (AGS3, also known as GPSM1), is related to cell cycle progression. We investigated the expression of AGS3 in human esophageal squamous cell carcinoma (ESCC) and the therapeutic effect of chemotherapy drugs. METHODS: Immunohistochemistry and Western blot analysis were performed for AGS3 in 85ESCC samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine its prognostic significance. The effect of overexpression of AGS3 on proliferation of esophageal carcinoma TE1 cells was analyzed by serum starvation. RESULTS: AGS3 was down regulated in ESCC as compared with the adjacent normal tissue. Low expression of AGS3 was associated with tumor grade (P=0.002), and AGS3 was negatively correlated with proliferation marker Ki-67 (P<0.01). Univariate analysis showed that AGS3 expression did have a remarkable prediction for poor prognosis (P=0.004), while in vitro, the expression of AGS3 was down regulated with release from serum starvation of TE1 cells. CONCLUSIONS: This study shows that AGS3 is an important regulator of ESCC proliferation. PMID- 25812750 TI - The isolation and structural elucidation of three new biflavonoid glycosides from Lomatogonium carinthiacum. AB - Three biflavonoid glycosides, named carinoside B, C and D (1, 2 and 3, respectively), were isolated from the n-BuOH crude extract of the aerial part of Lomatogonium carinthiacum (Wulfen) Rchb (L. carinthiacum). The structures of 1, 2 and 3 were elucidated by spectroscopic methods, including UV, IR, HR-ESI-MS and extensive 1D and 2D NMR techniques. PMID- 25812753 TI - Introduction. Multidisciplinary approach to critical limb ischemia. PMID- 25812752 TI - Vein grafting your way out of trouble: Examining the utility and efficacy of vein grafts in microsurgery. AB - INTRODUCTION: There is limited data on the indications, outcomes, and associated complications with use of interpositional vein grafts (IVG) in microsurgery. This study sought to critically examine and update the utility of this microsurgical technique. METHODS: All microsurgical cases at a single institution from 2005 to 2011 were examined for use of IVGs in the primary procedure or during take back or salvage attempts. We examined the cohort overall and performed a subgroup analysis by timing of initial IVG. RESULTS: In the study period, 1718 patients underwent 2368 free flaps. 51 IVGs were utilized in 38 patients (2.2%) and 38 flaps (1.6%). Eight (42.1%) of the primary procedure IVGs (n = 19) were planned preoperatively. Nine total flap losses (24%) occurred when IVGs were utilized, 89% of which occurred in the take back cohort (p = 0.02). However, planned IVG had a 100% success rate, and IVG utilized in the primary procedure overall had a 95% success rate. Importantly, A significantly higher rate of thrombotic events was noted in all primary cases where IVGs were utilized (p = 0.005). CONCLUSIONS: This study demonstrates that IVGs can be utilized in primary free flap reconstructions with success rates exceeding 95%. However, in salvage procedures, the use of vein grafts does not approach the same rate of success likely due to multiple factors. Yet when utilized appropriately with thrombectomy and resection of the thrombosed vessel to healthy intima, IVGs can provide an important tool for flap salvage. LEVEL OF EVIDENCE: prognostic/risk category, level II. PMID- 25812755 TI - Update and validation of the Society for Vascular Surgery wound, ischemia, and foot infection threatened limb classification system. AB - The diagnosis of critical limb ischemia, first defined in 1982, was intended to delineate a patient cohort with a threatened limb and at risk for amputation due to severe peripheral arterial disease. The influence of diabetes and its associated neuropathy on the pathogenesis-threatened limb was an excluded comorbidity, despite its known contribution to amputation risk. The Fontaine and Rutherford classifications of limb ischemia severity have also been used to predict amputation risk and the likelihood of tissue healing. The dramatic increase in the prevalence of diabetes mellitus and the expanding techniques of arterial revascularization has prompted modification of peripheral arterial disease classification schemes to improve outcomes analysis for patients with threatened limbs. The diabetic patient with foot ulceration and infection is at risk for limb loss, with abnormal arterial perfusion as only one determinant of outcome. The wound extent and severity of infection also impact the likelihood of limb loss. To better predict amputation risk, the Society for Vascular Surgery Lower Extremity Guidelines Committee developed a classification of the threatened lower extremity that reflects these important clinical considerations. Risk stratification is based on three major factors that impact amputation risk and clinical management: wound, ischemia, and foot infection. This classification scheme is relevant to the patient with critical limb ischemia because many are also diabetic. Implementation of the wound, ischemia, and foot infection classification system in critical limb ischemia patients is recommended and should assist the clinician in more meaningful analysis of outcomes for various forms of wound and arterial revascularizations procedures required in this challenging, patient population. PMID- 25812754 TI - Contemporary assessment of foot perfusion in patients with critical limb ischemia. AB - Significant progress in limb salvage for patients with peripheral arterial disease and critical limb ischemia has occurred in the past 2 decades. Improved patient outcomes have resulted from increased knowledge and understanding of the disease processes, as well as efforts to improve revascularization techniques and enhance patient care after open and endovascular procedures. An imaging modality that is noninvasive, fast, and safe would be a useful tool for clinicians in assessing lower-extremity perfusion when planning interventions. Among the current and emerging regional perfusion imaging modalities are transcutaneous oxygen monitoring, hyperspectral imaging, indocyanine green dye-based fluorescent angiography, nuclear diagnostic imaging, and laser Doppler. These tests endeavor to delineate regional foot perfusion to guide directed revascularization therapy in patients with critical limb ischemia and foot ulceration. PMID- 25812756 TI - Therapeutic angiogenesis for critical limb ischemia. AB - The application of gene- and cell-based therapies to promote angiogenesis is a novel concept to treat lower-limb critical limb ischemia (CLI) and may provide an unmet need for patients with no options for revascularization. Proof of concept was demonstrated in animal models resulting in clinical trials that have confirmed the feasibility and short-term efficacy of intramuscular injection of angiogenetic tissue growth factors or bone marrow stem cells. The safety of these biologic therapies has been demonstrated in randomized clinical trials with no "off-target" angiogenesis, growth of occult tumors, or progression of diabetic retinopathy. Current phase III randomized clinical trials using a DNA plasmid with the hepatocyte growth factor gene or bone marrow aspirate concentrate of mesenchymal cells are designed to address several crucial issues, including proper patient selection criteria, relevant clinical endpoints, and long-term efficacy. Because effectiveness of these novel therapies remains to be established, ongoing and future randomized clinical trials should be placebo controlled, investigator-blinded, and have amputation-free survival as the primary endpoint. Further development of efficient gene transfer techniques and keeping transplanted stem cells healthy have the potential to make biologic therapies more robust in promoting angiogenesis, tissue regeneration, and resolution of CLI symptoms. If sustained efficacy can be demonstrated, new therapeutic strategies for patients with CLI will be available for clinicians, ie, limb revascularization using angiogenic gene or stem cell therapy alone, or in conjunction with endovascular intervention. PMID- 25812757 TI - Angiosome-directed revascularization for critical limb ischemia. AB - The angiosome hypothesis states that the surface of the lower extremity is supplied by arteries consistently corresponding to regions of the foot. There is limited and conflicting evidence suggesting that angiosome-directed interventions improve wound healing and limb salvage. As peripheral arterial disease progresses, collaterals may develop that confound a predetermined angiosome map. In selecting a revascularization target vessel for patients with tissue loss, good surgical judgment should prevail, including consideration of the angiosome concept to optimize tissue healing. PMID- 25812751 TI - LncRNAs in vertebrates: advances and challenges. AB - Beyond the handful of classic and well-characterized long noncoding RNAs (lncRNAs), more recently, hundreds of thousands of lncRNAs have been identified in multiple species including bacteria, plants and vertebrates, and the number of newly annotated lncRNAs continues to increase as more transcriptomes are analyzed. In vertebrates, the expression of many lncRNAs is highly regulated, displaying discrete temporal and spatial expression patterns, suggesting roles in a wide range of developmental processes and setting them apart from classic housekeeping ncRNAs. In addition, the deregulation of a subset of these lncRNAs has been linked to the development of several diseases, including cancers, as well as developmental anomalies. However, the majority of vertebrate lncRNA functions remain enigmatic. As such, a major task at hand is to decipher the biological roles of lncRNAs and uncover the regulatory networks upon which they impinge. This review focuses on our emerging understanding of lncRNAs in vertebrate animals, highlighting some recent advances in their functional analyses across several species and emphasizing the current challenges researchers face to characterize lncRNAs and identify their in vivo functions. PMID- 25812758 TI - Endovascular intervention for tibial artery occlusive disease in patients with critical limb ischemia. AB - Surgical bypass has traditionally been the gold standard for treating critical limb ischemia caused by isolated infrapopliteal arterial disease (IP CLI). However, as endovascular techniques continue to progress, they are increasingly applied to this patient population, especially to the high-risk surgical cohort or patients with limited surgical options. This enthusiasm to employ endovascular interventions in IP CLI is accompanied by persistent controversies, as demonstrated in the recent literature. Percutaneous transluminal balloon angioplasty has been the predominant endovascular intervention applied to treat IP CLI and recent literature supports its role. The durability of percutaneous transluminal balloon angioplasty is limited, and thus this intervention is recommended for high-risk patients with limited life expectancy. Bare-metal stents for IP CLI currently do not have supportive data to warrant their use as a primary treatment. Newer drug-eluting stents improve patency and prevent restenosis, but they do not significantly improve patient clinical status compared with bare-metal stents alone. Drug-coated balloons are still relatively new tools in this arena and evidence of their safety and clear efficacy are still lacking. The data on atherectomy, in all of its forms, for IP CLI are overall variable, without any clear benefit to justify its increased complication risks and costs over other modalities. Use of retrograde tibial/pedal access for treating IP CLI as a viable alternative to antegrade access and treatment from a totally retrograde approach has recently been described. Level I evidence to aid in clarifying the true efficacy for each of these endovascular modalities is greatly needed. As we await these data, we must remember that, as with any arterial intervention, proper patient selection is extremely important and the intervention, whether endovascular or open surgical repair, should be tailored to the individual patient's anatomy and disease characteristics. PMID- 25812759 TI - Infrainguinal bypass for critical limb ischemia: tips and tricks. AB - A thoughtful but aggressive approach to care of patients with critical limb ischemia (CLI) is required to alleviate lower-extremity pain/tissue injury and achieve durable limb salvage. Specific subsets of CLI patients have been identified to clearly benefit from open surgical revascularization based on presenting signs (extensive tissue loss), multi-level, long-segment arterial occlusive disease, healthy saphenous conduit, and nondiseased tibial artery target vessel with continuous patency to the pedal arch. When other clinical scenarios exist, the treatment strategy requires consideration of patient's medical and surgical risk factors, anatomic distribution of atherosclerotic disease, and the clinical status of the limb affected by CLI. Infrainguinal saphenous vein bypass is the most durable technique for limb salvage and when properly performed is associated with excellent wound healing rates and improvement in quality of life. In this review, we detail our approach to infrainguinal arterial vein bypass in patients with CLI, including patient selection criteria, surgical planning based on arterial imaging studies, and operative technical requirements required for successful open lower-extremity bypass procedures. PMID- 25812760 TI - Offloading the diabetic and ischemic foot: solutions for the vascular specialist. AB - For generations, the use of techniques to defer skin pressure and protect the lower-extremity wound has been a cardinal goal to achieve therapeutic success and healing. Choosing the appropriate postoperative offloading device or shoe is often difficult, as it is challenging to merge optimal mechanical protection with clinical realities and patient needs. The gold standard for offloading remains the total contact cast, yet it receives minimal utilization in the clinical setting. Other devices have shown benefit, including the removable cast walker, instant total contact cast, and depth inlay shoes, for preventative measures. Ultimately, any plantar, lower-extremity wound must receive some form of external pressure reduction to reach acceptable rates of healing. Future technologies will aid these measures by providing body-worn constant monitoring systems and more effective offloading via patient-specific exoskeletons. This review is a supplemental update on the available wound offloading modalities based on logic driven research regarding pressure relief across the diabetic neuropathic or impaired perfusion foot. PMID- 25812761 TI - Surveillance and follow-up after revascularization for critical limb ischemia. AB - The purpose of a structured and cost-effective surveillance program after surgical or endovascular intervention for critical limb ischemia is to optimize limb salvage and preserve arterial repair function. Surveillance programs should include clinical, vascular laboratory, and radiographic follow-up, and, when a high-grade progressive stenosis is identified, appropriately timed intervention should be performed. Because many patients with critical limb ischemia are older and many are frail with limited mobility, optimizing the durability of arterial intervention and keeping these patients ambulatory is an important factor in retaining an independent lifestyle and quality of life. Despite the importance of surveillance after arterial intervention, there is a lack of consensus in the literature regarding the efficacy of surveillance, how it should be performed, and well-defined evidence-based guidelines. This review provides an up-to-date scrutiny on this topic and provides recommendations for optimal testing methods, limitations of surveillance testing, and when and how to intervene. These recommendations should be considered in the care of the patient with critical limb ischemia, but with the understanding that patients vary widely and care should be individualized. PMID- 25812762 TI - The BEST-CLI trial: a multidisciplinary effort to assess whether surgical or endovascular therapy is better for patients with critical limb ischemia. AB - Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease and is associated with a risk of limb loss. This vascular condition is currently treated with limb revascularization by surgery or endovascular intervention performed by a variety of specialists. Because both open vascular bypass and the less invasive endovascular therapy can be performed in selected patients with CLI, there exists significant disagreement as to which therapy should be performed first and which is more successful. The paucity of comparative effectiveness data to guide treatment of CLI has prompted a multidisciplinary effort to organize the Best Endovascular Versus Best Surgical Therapy in Patients With CLI (BEST-CLI) trial. The BEST-CLI trial is a pragmatic, multicenter, open-label, randomized trial that compares best endovascular therapy with best open surgical treatment in patients eligible for both treatments. BEST CLI aims to provide urgently needed clinical guidance for CLI management by using a pragmatic design comparing the effectiveness of established techniques while allowing for the introduction of newer therapies as they become available; a novel primary endpoint that includes limb amputation rates, repeat intervention, and mortality; a multidisciplinary structure that fosters cooperation among interventional cardiologists, interventional radiologists, vascular surgeons, and vascular medicine specialists; and novel techniques to evaluate the cost effectiveness and quality-of-life outcomes of the two treatment strategies being tested. PMID- 25812765 TI - Molecular cloning and expression analysis of a hemolin-like molecule from Antheraea pernyi. AB - Hemolin belongs to the immunoglobulin superfamily and plays an important role in innate immune response of insects. In this study, a hemolin-like cDNA of 1418bp was obtained from Antheraea pernyi (Ap-hemolin-like). Sequence analysis revealed Ap-hemolin-like was homologous to those hemolins from other insect species. Recombinant Ap-hemolin-like protein was expressed in Escherichia coli cells, and polyclonal antibodies were produced against the recombinant proteins. Real-time PCR and western blot analysis showed that the Ap-hemolin-like was expressed in hemolymph, Malpighian tubules, midgut, epidermis and fat body, with the highest expression level in hemolymph. To investigate its role in the immune response against microorganisms, fifth instar larvae were challenged by injecting nucleopolyhedrovirus (NPV), E. coli, or Beauveria bassiana. The results showed that the expression of Ap-hemolin-like in hemolymph and fat body was obviously induced by microorganisms. In addition, the recombinant Ap-hemolin-like protein promoted the agglutination of E. coli in the presence of calcium, which was confirmed by agglutination assay. These results suggested that the Ap-hemolin like protein was involved in innate immune response of A. pernyi against pathogens. PMID- 25812764 TI - Viral activation of cellular metabolism. AB - To ensure optimal environments for their replication and spread, viruses have evolved to alter many host cell pathways. In the last decade, metabolomic studies have shown that eukaryotic viruses induce large-scale alterations in host cellular metabolism. Most viruses examined to date induce aerobic glycolysis also known as the Warburg effect. Many viruses tested also induce fatty acid synthesis as well as glutaminolysis. These modifications of carbon source utilization by infected cells can increase available energy for virus replication and virion production, provide specific cellular substrates for virus particles and create viral replication niches while increasing infected cell survival. Each virus species also likely requires unique metabolic changes for successful spread and recent research has identified additional virus-specific metabolic changes induced by many virus species. A better understanding of the metabolic alterations required for the replication of each virus may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways. PMID- 25812766 TI - Participation of non-neuronal muscarinic receptors in the effect of carbachol with paclitaxel on human breast adenocarcinoma cells. Roles of nitric oxide synthase and arginase. AB - Breast cancer is the most common type of cancer in women and represents a major issue in public health. The most frequent methods to treat these tumors are surgery and/or chemotherapy. The latter can exert not only beneficial effects by reducing tumor growth and metastasis, but also toxic actions on normal tissues. Metronomic therapy involves the use of low doses of cytotoxic drugs alone or in combination to improve efficacy and to reduce adverse effects. We have previously reported that breast tumors highly express functional muscarinic acetylcholine receptors (mAChRs) that regulate tumor progression. For this reason, mAChRs could be considered as therapeutic targets in breast cancer. In this paper, we investigated the ability of a combination of the cytotoxic drug paclitaxel plus carbachol, a cholinergic agonist, at low doses, to induce death in breast tumor MCF-7 cells, via mAChR activation, and the role of nitric oxide synthase (NOS) and arginase in this effect. We observed that the combination of carbachol plus paclitaxel at subthreshold doses significantly increased cytotoxicity in tumor cells without affecting MCF-10A cells, derived from human normal mammary gland. This effect was reduced in the presence of the muscarinic antagonist atropine. The combination also increased nitric oxide production by NOS1 and NOS3 via mAChR activation, concomitantly with an up-regulation of NOS3 expression. The latter effects were accompanied by a reduction in arginase II activity. In conclusion, our work demonstrates that mAChRs expressed in breast tumor cells could be considered as candidates to become targets for metronomic therapy in cancer treatment. PMID- 25812767 TI - Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1. AB - High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. Although glycyrrhizin was known as inhibitor of HMGB1, it is not yet clear underlying mechanism(s). We found that glycyrrhizin activates translocation of Nrf2 from cytosol to nucleus and induces heme oxygenase (HO)-1 expression in RAW 264.7 cells. In addition, deletion of Nrf2 by siRNA significantly reduced mRNA expression of NQO1 and HO-1 suggesting that glycyrrhizin targets Nrf2 gene. The expression of iNOS protein and release of HMGB1 in LPS activated cells were significantly reduced by glycyrrhizin and cells transfected with mouse HO-1 expression vector. The p38MAPK inhibitor (SB203580) but not JNK inhibitor (SP600125) or ERK inhibitor (PD98059) significantly inhibited HO-1 induction by glycyrrhizin, which was confirmed by showing that siP38 transfected cells significantly reduced HO-1 induction. Pretreatment with SB203580 significantly reversed the expression of iNOS and release of NO and HMGB1 in LPS-activated cells. Most importantly, administration of glycyrrhizin (200mg/kg, i.p) significantly reduced hepatic injury and serum HMGB1 in a ZnPPIX-sensitive manner. Thus, it is concluded that glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2 dependent induction of HO-1. PMID- 25812768 TI - Potent therapeutic target of inflammation, virus and tumor: focus on interleukin 27. AB - Interleukin (IL)-27 is an important pleiotropic immunological regulator for having dual effects on the immune responses. Several distinct findings have been highlighted that in certain conditions, neutralizing IL-27 or its subunit IL 27p28 might be a useful strategy to limit inflammation. Recently more insights have revealed that IL-27 could also exert potent inhibitory functions in some other immune circumstances including virus infection and tumor immunity. In this review, we describe IL-27 receptor subunits and the mechanisms of individual IL 27, and summarize the advances of their preclinical application trials. In addition, the potential role of IL-27 as a clinical therapeutic target will also be discussed. PMID- 25812763 TI - Transmission of influenza A viruses. AB - Influenza A viruses cause respiratory infections that range from asymptomatic to deadly in humans. Widespread outbreaks (pandemics) are attributable to 'novel' viruses that possess a viral hemagglutinin (HA) gene to which humans lack immunity. After a pandemic, these novel viruses form stable virus lineages in humans and circulate until they are replaced by other novel viruses. The factors and mechanisms that facilitate virus transmission among hosts and the establishment of novel lineages are not completely understood, but the HA and basic polymerase 2 (PB2) proteins are thought to play essential roles in these processes by enabling avian influenza viruses to infect mammals and replicate efficiently in their new host. Here, we summarize our current knowledge of the contributions of HA, PB2, and other viral components to virus transmission and the formation of new virus lineages. PMID- 25812769 TI - Altered profile of gut microbiota after subchronic exposure to neochamaejasmin A in rats. AB - Neochamaejasmin A, isolated from Stellera chamaejasme L., has been widely used in China. Gut microbiota represent the first barrier against xenobiotics. This study aimed to evaluate the effects of subchronic exposure to neochamaejasmin A on the composition of gut microbiota. We found that neochamaejasmin A altered 21 OTUs in female rats and 46 OTUs in male rats. Among these OTUs, OTU86, OTU338 and OTU482 were shared in neochamaejasmin A-fed groups in both genders, implying that neochamaejasmin A might promote the growth of these three genera. In contrast, little or no effect on 226 OTUs was observed at all doses in both genders, suggesting their resistance to neochamaejasmin A. These findings could help improve our understanding of the health effects of neochamaejasmin A and provide an example of the risk assessment of pharmaceuticals or food contaminants on the gut microbiota composition. PMID- 25812770 TI - Effects of N-Butylphthalide on the expressions of Nogo/NgR in rat brain tissue after carbon monoxide poisoning. AB - Carbon monoxide (CO) intoxication is one of the most common types of poisoning worldwide, and may result in neuropathologic sequelae, yet its pathogenesis is not clear and there is no optimal management strategy for patients with CO poisoning. In this study, the rat model of CO poisoning was established in a hyperbaric chamber by CO exposure. Rats were administered orally N-Butylphthalide (NBP) at a dose of 1 ml/100g. Neuronal apoptosis was assessed by TUNEL stain and flow cytometry. The expressions of neurite outgrowth inhibitor (Nogo), myelin associated glycoprotein (MAG) and Nogo receptor-1 (NgR1) were observed in rat brain tissue by immunohistochemistry and double immunofluorescence staining. As we expected, CO poisoning could start the mechanism of apoptosis. The number of apoptotic cells and the early neuronal apoptosis percentage (EAR) were significantly increased at 1 day, 3 day after CO exposure. NBP treatment obviously reduce neuronal apoptosis and the EAR (P<0.05). CO poisoning could induce Nogo, MAG and NgR1 expressions. The increased Nogo, MAG and NgR1 proteins were still observed at 4 week after CO poisoning. NBP could significantly reduce the levels of Nogo and NgR1 proteins. Then we suspected that the expressions of Nogo, MAG and NGR1 proteins might be associated with brain injury and demyelination induced by CO poisoning. NBP might inhibit neuronal apoptosis and the EAR, down-regulate the expressions of Nogo and NgR1 proteins (but not MAG), and play a neuro-protective role in brain damage after acute CO poisoning. PMID- 25812771 TI - 2,4,6-Trihydroxybenzaldehyde, a potential anti-obesity treatment, suppressed adipocyte differentiation in 3T3-L1 cells and fat accumulation induced by high fat diet in C57BL/6 mice. AB - In the present study, 2,4,6-trihydroxybenzaldehyde (THB) was evaluated for inhibitory effects on adipocyte differentiation in 3T3-L1 cells and anti-obesity effects in mice with high-fat diet (HFD)-induced obesity. Lipid accumulation measurement indicated that THB markedly inhibited adipogenesis, and this involved down-regulation of the expression of the adipogenesis-related proteins, CCAAT/enhancer-binding protein alpha (C/EBPalpha), peroxisome proliferator activated receptor gamma (PPARgamma), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c), in 3T3-L1 pre-adipocyte cells. In a mouse model of HFD-induced obesity, oral administration of THB (5 and 25mg/kg for 13 weeks) reduced the HFD-induced increase in weight gain. THB administration also reduced serum levels of glucose, triglycerides, and total cholesterol. A reduction in the hypertrophy of white adipose tissue was also observed. Furthermore, THB administration inhibited HFD-induced hepatic steatosis. These results provided evidence that administration of THB alleviated HFD-induced obesity in C57BL/6 mice and revealed the potential of THB as a nutraceutical to help prevent or treat obesity and the associated metabolic disorders. PMID- 25812772 TI - Expression of NEDD9 in hepatocellular carcinoma and its clinical significance. AB - Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) plays an integral role in natural and pathological cell biology. Overexpression of NEDD9 protein has been correlated with poor prognosis in various types of cancer. However, few available data address the precise function of the NEDD9 gene in hepatocellular carcinoma (HCC). In the present study, we investigated NEDD9 expression in 40 primary human HCC tissues compared with matched adjacent non tumor hepatic tissues using RT-qPCR and western blot analysis. Immunohistochemistry was performed to analyze the correlations between NEDD9 expression and clinicopathological factors. Statistical analyses were applied to derive prognostic values of NEDD9 in HCC. The results showed that the NEDD9 mRNA and protein expression levels in HCC tissues were significantly higher than those in matched adjacent non-tumor hepatic tissues. High NEDD9 expression was correlated with larger tumor size, advanced tumor grade, metastasis, intrahepatic venous invasion and high UICC TNM stages in HCC patients. Patients with high NEDD9 expression levels exhibited poorer recurrence-free and overall survival than those with a low NEDD9 expression. Additionally, NEDD9 expression status was an independent prognostic factor for survival. This correlation remained significant in patients with early-stage HCC or with normal serum AFP levels. The results of this study suggest that NEDD9 may be a valuable prognostic biomarker for HCC, including early-stage and AFP-normal patients. PMID- 25812773 TI - Malaria RDT diagnosis: Magnifying a curious point. PMID- 25812774 TI - Going viral: embracing the changing culture of social media in travel medicine. PMID- 25812776 TI - Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm. AB - OBJECTIVES: To describe the global phenotypes of pediatric patients with thoracic aortic aneurysm (TAA) who do not have a clinical diagnosis of Marfan syndrome (MFS) or related connective tissue disorders. We hypothesized that the presence of noncardiovascular abnormalities correlate with TAA severity and that medical therapy reduces TAA progression. STUDY DESIGN: This is a retrospective case series of patients with TAA age <= 21 years evaluated in a cardiovascular genetics clinic. Patients meeting clinical criteria for MFS or related disorders were excluded. Repeated measures analyses of longitudinal echocardiographic measurements of the aorta were used to test associations between TAA severity and noncardiovascular phenotype and to assess the impact of medical therapy. RESULTS: Sixty-nine patients with TAA at mean age 12.5 +/- 5.3 years were included. Noncardiovascular abnormalities, including skeletal (65%) or craniofacial (54%) findings, were frequently observed. Increased rate of aortic root enlargement was associated with ocular (P = .002) and cutaneous (P = .003) abnormalities, and increased rate of ascending aorta enlargement was associated with craniofacial (P < .001) abnormalities. Beta blocker or angiotensin receptor blocker therapy (n = 41) was associated with reduction in the rate of aortic root growth (P = .018). CONCLUSIONS: Children with TAA not satisfying diagnostic criteria for MFS or related disorders frequently have noncardiovascular findings, some of which are associated with TAA progression. Because therapy initiation may reduce risk of progression and long-term complications, comprehensive assessment of noncardiovascular findings may facilitate early risk stratification and improve outcomes. PMID- 25812775 TI - Delayed haemolysis after artesunate treatment of severe malaria - review of the literature and perspective. AB - Artesunate has replaced quinine as the recommended first-line treatment of severe malaria as it clears parasites faster and lowers mortality. After artesunate's introduction, however, reports of delayed haemolysis have emerged. Typically, this adverse haemolytic event peaks two to three weeks after the acute phase of malaria, and can be severe enough to make blood transfusions necessary in the management of some patients. Delayed haemolysis has been detected in prospective studies in 7-21% of patients treated with artesunate. A confirmed risk factor in travellers is hyperparasitaemia, while additional in malaria-endemic countries young age has been shown to increase risk. The pathophysiology of this phenomenon has not yet been fully elucidated, but may include various combinations of delayed destruction of "pitted" erythrocytes and autoimmune aetiology. All patients treated with parenteral artesunate should be followed up for at least four weeks to detect signs of haemolysis and to allow appropriate symptomatic treatment. PMID- 25812777 TI - Parenteral nutrition as an unexpected and preventable source of mercury exposure in preterm infants. AB - Perinatal mercury exposure has neurodevelopmental consequences, which may be worse in preterm infants. In our cohort (N = 60), maternal and infant prenatal exposures were low, but infant levels increased during hospitalization and correlated only with duration of parenteral nutrition. A non-negligible exposure resulted from the nutrition preparation on equipment shared with adult preparations. PMID- 25812778 TI - Long-term outcomes of children with intermediate sweat chloride values in infancy. AB - OBJECTIVE: To describe the clinical course of children who have intermediate sweat chloride values on initial screening for cystic fibrosis (CF). STUDY DESIGN: We performed a retrospective review of children with intermediate sweat chloride values (raised immunoreactive trypsinogen/1 copy of p.F508del CF mutation on newborn screening (NBS)/sweat chloride value of 30-59 mmol/L) presenting to The Children's Hospital at Westmead over 15 years. Patients with an intermediate sweat chloride evolving to a formal diagnosis of CF (termed "delayed CF") were matched (2:1) with NBS positive patients with CF (termed "NBS positive CF"). Clinical outcomes were compared. RESULTS: Fourteen of 29 (48%, 95% CI 0.3 0.66) patients with intermediate sweat chloride value evolved to a diagnosis of CF and were matched with 28 NBS positive patients with CF. Delayed CF had less pancreatic insufficiency (OR 0.06, 95% CI 0.01-0.44, P = .006), less colonization with nonmucoid Pseudomonas aeruginosa (OR 0.04, 95% CI 0.01-0.38, P = .005), milder obstructive lung disease (forced expiratory volume in 1 second/forced vital capacity ratio), and overall disease severity (Shwachman scores) at 10 years (mean difference 5.93, 95% CI 0.39-11.46, P = .04; mean difference 4.72, 95% CI 0.9-8.53, P = .015, respectively). Nutritional outcomes were better at 2 years for delayed CF but did not persist to later ages. CONCLUSIONS: In this cohort, approximately one-half of infants with intermediate sweat chloride value were later diagnosed with CF. The clinical course of delayed CF was milder in some aspects compared with NBS positive CF. These results emphasize the importance of ongoing follow-up of infants with intermediate sweat chloride values. PMID- 25812779 TI - Neuroprotection for Perinatal Hypoxic Ischemic Encephalopathy in Low- and Middle Income Countries. PMID- 25812780 TI - Bullying of preterm children and emotional problems at school age: cross culturally invariant effects. AB - OBJECTIVE: To investigate whether adolescents who were born extremely preterm (<26 weeks gestation), very preterm (<32 weeks gestation), or with very low birth weight (<1500 g) are more often bullied, and whether this contributes to higher emotional problem scores. STUDY DESIGN: We used 2 whole population samples: the German Bavarian Longitudinal Study (BLS) (287 very preterm/very low birth weight and 293 term comparison children) and the UK EPICure Study (183 extremely preterm and 102 term comparison children). Peer bullying was assessed by parent report in both cohorts at school years 2 and 6/7. The primary outcome was emotional problems in year 6/7. The effects of prematurity and bullying on emotional problems were investigated with regression analysis and controlled for sex, socioeconomic status, disability, and preexisting emotional problems. RESULTS: Preterm-born children were more often bullied in both cohorts than term comparisons (BLS: relative risk, 1.27; 95% CI, 1.07-1.50; EPICure: relative risk, 1.69; 95% CI, 1.19-2.41). Both preterm birth and being bullied predicted emotional problems, but after controlling for confounders, only being bullied at both ages remained a significant predictor of emotional problem scores in both cohorts (BLS: B, 0.78; 95% CI, 0.28-1.27; P < .01; EPICure: B, 1.55; 95% CI, 0.79 2.30; P < .001). In the EPICure sample, being born preterm and being bullied at just a single time point also predicted emotional problems. CONCLUSION: Preterm born children are more vulnerable to being bullied by peers. Those children who experience bullying over years are more likely to develop emotional problems. Health professionals should routinely ask about peer relationships. PMID- 25812781 TI - Nonlocal mind: a (fairly) brief history of the term. PMID- 25812783 TI - Inpatient staffing needs for registered dietitian nutritionists in 21st century acute care facilities. PMID- 25812785 TI - A historical perspective of the korean society of medical education. PMID- 25812782 TI - Does marital status contribute to the explanation of the hypercholesterolemia paradox in relation to long term mortality in myocardial infarction? Findings from the MONICA/KORA Myocardial Infarction Registry. AB - OBJECTIVE: A recent study found long-term mortality after first acute myocardial infarction (AMI) to be particularly reduced among married individuals with hypercholesterolemia. This study explores, whether statin treatments during the last week prior to AMI offer an explanation to this phenomenon. METHODS: Data were retrieved 2000-2008 from the population-based KORA myocardial infarction registry, located in Bavaria, Germany. The sample included 3162 individuals, alive 28days after first AMI, who received statins both in hospital and at discharge. Associations with long-term mortality were examined via multivariable Cox regression. Among patients with hypercholesterolemia, individuals with and without prior statin treatment were each tested against the reference group "neither (hypercholesterolemia nor statin)" and tested for interaction with "marital status". RESULTS: Among patients with and without prior statins, hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93 and HR 0.72, 95% CI 0.55 0.94, were observed, respectively. Mortality reductions diminished after introduction of the following interaction terms with marital status: HR 0.49, p 0.042 for patients with and HR 0.77, p 0.370, for patients without prior statins. CONCLUSIONS: Prior statin treatments appear to be an underlying factor for long term mortality reduction in married AMI-survivors with hypercholesterolemia. Confirmation of our results in further studies is warranted. PMID- 25812784 TI - Research in medical education: transforming ideas into action. PMID- 25812786 TI - An Effective Method of Teaching Advanced Cardiac Life Support (ACLS) Skills in Simulation-Based Training. AB - PURPOSE: In this study, we compared the effects of constructivist and traditional teaching strategies in teaching advanced cardiac life support (ACLS) skills during simulation-based training (SBT). METHODS: A randomized, pre- and post-test control group study was designed to examine this issue in 29 third-year emergency medical technician (EMT) students. Participants received SBT through constructivist SBT (CSBT) or traditional lecture-based SBT (TSBT) teaching strategies. We evaluated the effects of the simulation training on ACLS knowledge, and performance immediately after practice and at retention. RESULTS: The knowledge and performance of the CSBT group were higher than compared with the TSBT group (mean knowledge 33.3+/-5.03 vs. 29.5+/-5.33, p=0.36; and mean performance 12.20+/-1.85 vs. 8.85+/-3.54, p=0.010). However, there was no difference between two groups in retention between groups 1 month later (mean knowledge 31.86+/-4.45 vs. 31.50+/-4.65, p=0.825; and mean performance 12.13+/ 0.99 vs. 12.57+/-1.78, p=0.283). CONCLUSION: CSBT is more effective with regard to knowledge acquisition and performance than TSBT. Further studies are needed to explore ways of improving retention and transfer of knowledge from simulated to real situations with SBT. PMID- 25812787 TI - A Comparison between Discrimination Indices and Item-Response Theory Using the Rasch Model in a Clinical Course Written Examination of a Medical School. AB - PURPOSE: The reliability of test is determined by each items' characteristics. Item analysis is achieved by classical test theory and item response theory. The purpose of the study was to compare the discrimination indices with item response theory using the Rasch model. METHODS: Thirty-one 4th-year medical school students participated in the clinical course written examination, which included 22 A-type items and 3 R-type items. Point biserial correlation coefficient (C(pbs)) was compared to method of extreme group (D), biserial correlation coefficient (C(bs)), item-total correlation coefficient (C(it)), and corrected item-total correlation coeffcient (C(cit)). Rasch model was applied to estimate item difficulty and examinee's ability and to calculate item fit statistics using joint maximum likelihood. RESULTS: Explanatory power (r2) of Cpbs is decreased in the following order: C(cit) (1.00), C(it) (0.99), C(bs) (0.94), and D (0.45). The ranges of difficulty logit and standard error and ability logit and standard error were -0.82 to 0.80 and 0.37 to 0.76, -3.69 to 3.19 and 0.45 to 1.03, respectively. Item 9 and 23 have outfit > or =1.3. Student 1, 5, 7, 18, 26, 30, and 32 have fit > or =1.3. CONCLUSION: C(pbs), C(cit), and C(it) are good discrimination parameters. Rasch model can estimate item difficulty parameter and examinee's ability parameter with standard error. The fit statistics can identify bad items and unpredictable examinee's responses. PMID- 25812788 TI - Teaching clinical performance examination using action learning techniques. AB - PURPOSE: Action learning is an educational method, whereby participants study their own actions and experiences to improve performance. We aimed to study the effects and share the experiences with action learning to teach clinical performance examination (CPX). METHODS: Twenty-eight fourth-year medical students participated in this study in 2010. This course consisted of three mini-lectures, three CPX practice sessions, and an evaluation. Satisfaction and improved and deficient elements in the CPX practice session were investigated. Internal consistencies of peer evaluation and CPX scores were also investigated using Cronbach's alpha. RESULTS: Average satisfaction was 4.5 on a 5-point scale. Low Cronbach's alpha was noted for the consistencies of peer evaluation and patient physician interaction. The most common improved element was self-confidence, followed by accustoming themselves to conversation with the standard patient. Seven students stated that they were deficient in self-confidence; other deficiencies were sympathy expression, conversation, and physical examination. CONCLUSION: CPX education using action learning by peer evaluation, generating CPX cases by themselves, repeated practices, and feedback, effected self-active learning. However, the educator and educatee must invest much time and effort. Allotting specific, scheduled times for this type of education would be more effective. PMID- 25812789 TI - Development of Task-Based Learning Outcomes according to Clinical Presentations for Clinical Clerkships. AB - PURPOSE: The aim of the study was to introduce our experience of establish task based learning outcomes for core clinical clerkships. METHODS: We first define our educational goal and objectives of the clinical clerkship curriculum according to knowledge, cognitive function and skill, and attitude. We selected clinical presentations and related diseases with expert panels and allocated them to core clinical departments. We classified doctor's tasks into 6 categories: history taking, physical examination, diagnostic plan, therapeutic plan, acute and emergent management, and prevention and patient education. We described learning outcomes by task using behavioral terms. RESULTS: We established goals and objectives for students to achieve clinical competency on a primary care level. We selected 75 clinical presentations and described 377 learning outcomes. CONCLUSION: Our process can benefit medical schools that offer outcome-based medical education, especially for clinical clerkships. To drive effective clerkships, a supportive system including assessment and faculty development should be implemented. PMID- 25812790 TI - Job analysis of standardized patient trainer. AB - PURPOSE: Although standardized patients (SPs) have been used widely in medical education, there has been little research on SP trainers. The purpose of this study was to examine the roles SP trainers by establishing their job description and assessing the importance, frequency, and difficulty of each task element. METHODS: SP trainers' responsibilities were defined and their job descriptions were developed based on a focus group interview (FGI) of 6 panels. The validity of the duties, tasks, and task elements that were elicited from the FGI was examined by the 6 panels and a medical school professor. The data were collected using a questionnaire survey from 24 SP trainers in April 2011. The questionnaire pertained to the importance, frequency, and difficulty of the duties, tasks, and task elements that were identified in SP trainers' job descriptions. RESULTS: The job description of SP trainers consisted of 10 duties, 25 tasks, and 76 task elements. The average level of importance of the 10 duties was 4.29; "SP training" was identified as the most important duty (4.79+/-0.41). Of the 76 task elements, "providing training regarding the scoring criteria and standardizing the scoring system" had the highest levels of importance and frequency (4.83+/ 0.48, 4.08+/-1.06). "Standardizing the acting abilities of SPs" was the most difficult task element (4.50+/-0.66). CONCLUSION: By analyzing the job description of SP trainers, this study is expected to help define the roles of SP trainers and facilitate their deployment. PMID- 25812792 TI - Challenges in communication skills education in medicine: based on personal experience and reflection. PMID- 25812791 TI - Mental Health and Coping Strategies among Medical Students. AB - PURPOSE: Recently, concern of the college students' mental health has increased due to their continuous psychologic problems such as suicidal attempt. This study aimed to examine the correlation among depression, stress, self-esteem, and coping strategies of the medical students and also according to the academic year. METHODS: The subject was 384 medical students of K medical school in Korea. Self-rating depression scale, stress scale, self-esteem scale was used for the survey, and academic stress and coping strategies of the students were asked. Frequency analysis, one-way ANOVA, t-test, correlation analysis was carried out. RESULTS: Third year students were under most stress (F=5.67, p=0.000) and had the most students who were moderately (22.9%) and mildly depressed (6.3%). Stress form academic studies and grade was also the highest in third year students. For English fluency, freshmen students scored the top. Academic career stress and school culture stress were higher for year 3, 4, 5, 6 than year 1, 2 students. Differences of the coping strategies by academic year was significant in emotional display. Students who showed high level of depression and stress, also students with low self-esteem used emotional display as their major coping strategy. CONCLUSION: Depending on their academic year medical students' level of depression and stress was different, and they did not use a variety of coping strategies. Therefore, a program which can give a diverse access to variety of coping strategies to relieve students' stress should be developed taking their characteristics of academic year into consideration. PMID- 25812793 TI - Pocket guide to teaching for medical instructors. PMID- 25812795 TI - Anti-stigma interventions in high- and lower-income settings - a lot remains to be done. PMID- 25812794 TI - Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. AB - TAS-102 is a novel oral nucleoside antitumor agent that consists of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5, and was approved in Japan in March 2014 for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. In the present study, we used colorectal cancer xenografts to assess whether the efficacy of TAS-102 could be improved by combining it with bevacizumab, cetuximab or panitumumab. TAS-102 was orally administered twice a day from day 1 to 14, and bevacizumab, cetuximab and panitumumab were administered intraperitoneally twice a week for 2 weeks. Growth inhibitory activity was evaluated based on the relative tumor volume (RTV) after 2 weeks of drug administration and time taken for the relative tumor volume to increase five-fold (RTV5). Tumor growth inhibition and RTV5 with TAS-102 and bevacizumab combination treatment were significantly better than those with TAS-102 or bevacizumab alone in the SW48 and HCT116 tumor models, and the concentration of phosphorylated FTD in tumors determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was higher in the TAS-102 and bevacizumab combination group than in the TAS-102 monotherapy group. The combination of TAS-102 and cetuximab or panitumumab was also significantly more effective than either monotherapy in the SW48 tumor model. There was no significant difference in the body weight between the mice treated with TAS-102 monotherapy and any of the combination therapies on day 29. Our preclinical findings indicate that the combination therapy of TAS-102, bevacizumab and cetuximab or panitumumab is a promising treatment option for colorectal cancer. PMID- 25812796 TI - Resistance to alveolar shape change limits range of force propagation in lung parenchyma. AB - We have recently shown that if the lung parenchyma is modeled in 2 dimensions as a network of springs arranged in a pattern of repeating hexagonal cells, the distortional forces around a contracting airway propagate much further from the airway wall than classic continuum theory predicts. In the present study we tested the hypothesis that this occurs because of the negligible shear modulus of a hexagonal spring network. We simulated the narrowing of an airway embedded in a hexagonal network of elastic alveolar walls when the hexagonal cells of the network offered some resistance to a change in shape. We found that as the forces resisting shape change approach about 10% of the forces resisting length change of an individual spring the range of distortional force propagation in the spring network fell of rapidly as in an elastic continuum. We repeated these investigations in a 3-dimensional spring network composed of space-filling polyhedral cells and found similar results. This suggests that force propagation away from a point of local parenchymal distortion also falls off rapidly in real lung tissue. PMID- 25812798 TI - Predictors of victim disclosure in child sexual abuse: Additional evidence from a sample of incarcerated adult sex offenders. AB - The under-reporting of child sexual abuse by victims is a serious problem that may prolong the suffering of victims and leave perpetrators free to continue offending. Yet empirical evidence indicates that victim disclosure rates are low. In this study, we perform regression analysis with a sample of 369 adult child sexual offenders to examine potential predictors of victim disclosure. Specifically, we extend the range of previously examined potential predictors of victim disclosure and investigate interaction effects in order to better capture under which circumstances victim disclosure is more likely. The current study differs from previous studies in that it examines the impact of victim and offense variables on victim disclosure from the perspective of the offender. In line with previous studies, we found that disclosure increased with the age of the victim and if penetration had occurred. In addition, we found that disclosure increased when the victim came from a non-dysfunctional family and resisted the abuse. The presence of an interaction effect highlighted the impact of the situation on victim disclosure. This effect indicated that as victims get older, they are more likely to disclose the abuse when they are not living with the offender at the time of abuse, but less likely to do so when they are living with the offender at the time of abuse. These findings are discussed in relation to previous studies and the need to facilitate victim disclosure. PMID- 25812797 TI - Phosphatidylcholine composition of pulmonary surfactant from terrestrial and marine diving mammals. AB - Marine mammals are repeatedly exposed to elevated extra-thoracic pressure and alveolar collapse during diving and readily experience alveolar expansion upon inhalation - a unique capability as compared to terrestrial mammals. How marine mammal lungs overcome the challenges of frequent alveolar collapse and recruitment remains unknown. Recent studies indicate that pinniped lung surfactant has more anti-adhesive components compared to terrestrial mammals, which would aid in alveolar opening. However, pulmonary surfactant composition has not yet been investigated in odontocetes, whose physiology and diving behavior differ from pinnipeds. The aim of this study was to investigate the phosphatidylcholine (PC) composition of lung surfactants from various marine mammals and compare these to a terrestrial mammal. We found an increase in anti adhesive PC species in harp seal (Pagophilus groenlandicus) and California sea lion (Zalophus californianus) compared to dog (Canus lupus familiaris), as well as an increase in the fluidizing PCs 16:0/14:0 and 16:0/16:1 in pinnipeds compared to odontocetes. The harbor porpoise (a representative of the odontocetes) did not have higher levels of fluidizing PCs compared to dog. Our preliminary results support previous findings that pinnipeds may have adapted unique surfactant compositions that allow them to dive at high pressures for extended periods without adverse effects. Future studies will need to investigate the differences in other surfactant components to fully assess the surfactant composition in odontocetes. PMID- 25812799 TI - Matrix metalloproteinase-9 mediates post-hypoxic vascular pruning of cerebral blood vessels by degrading laminin and claudin-5. AB - Vascular remodeling involves a highly coordinated break-down and build-up of the vascular basal lamina and inter-endothelial tight junction proteins. In light of the important role of matrix metalloproteinases (MMPs) in tissue remodeling, the goal of this study was to examine the role of MMP-9 in remodeling of cerebral blood vessels, both in hypoxia-induced angiogenesis and in the vascular pruning that accompanies the switch from hypoxia back to normoxia. In a chronic mild hypoxia model of cerebrovascular remodeling, gel zymography revealed that MMP-9 levels were increased, both during hypoxic-induced angiogenesis and in the post hypoxic pruning response. Interestingly, compared to wild-type mice, MMP-9 KO mice showed no alteration in hypoxic-induced angiogenesis, but did show marked delay in post-hypoxic vascular pruning. In wild-type mice, vascular pruning was associated with fragmentation of vascular laminin and the tight junction protein claudin-5, while this process was markedly attenuated in MMP-9 KO mice. In vitro experiments showed that hypoxia stimulated MMP-9 expression in brain endothelial cells but not pericytes. These results show that while MMP-9 is not essential for hypoxic-induced cerebral angiogenesis, it plays an important role in post-hypoxic vascular pruning by degrading laminin and claudin-5. PMID- 25812803 TI - Statins and aspirin: do they really work in women? AB - Cardiovascular disease continues to be the most common cause of mortality in women in the USA. As a result, greater emphasis has been placed on preventive measures. Studies examining the role of aspirin and HMG-CoA reductase inhibitors (statins) have shown important clinical differences in men versus women in the preventive realm. This has led to inconsistent recommendations by guideline committees and clinicians alike. This review presents a summary of the past and current guidelines. In addition, important clinical trials influencing current era practice are also discussed. Both strengths and limitations of these studies are described in detail, along with recommendations regarding future directions and the scope of aspirin and statin use for primary and secondary prevention of cardiovascular disease. PMID- 25812800 TI - Effect on Symptom Management Education Receiving Patients of Chemotherapy. AB - The study of a planned education in patients receiving chemotherapy can alleviate the side effects of chemotherapy and, thus, can increase the quality of the patients' lives. In accordance with this view, this study was conducted with the purpose of examining the effect of planned education given to patients receiving chemotherapy on their symptom control. The study was quasi-experimental. A sample of 140 patients participated, of which 70 were in the experimental group and 70 were in the control group. A patient data form and the chemotherapy symptom assessment scale (C-SAS) were used in order to collect the data. Median, Mann Whitney U test, and Wilcoxon signed rank test were used to analyze the data. There were statistically significant decreases in the frequencies of the following symptoms: nausea, vomiting, feeling distressed/anxious, feeling pessimistic and unhappy, unusual fatigue, and difficulty sleeping. Also, there were statistically significant decreases in the severity of the 11 symptoms and on the discomfort levels of these symptoms. In the study, the planned education provided by the health-care providers had a positive effect on the symptom control of patients receiving chemotherapy. PMID- 25812805 TI - Is dexmedetomidine really superior to propofol? PMID- 25812806 TI - Co-digestion of manure and industrial waste--The effects of trace element addition. AB - Manure is one of the most common substrates for biogas production. Manure from dairy- and swine animals are often considered to stabilize the biogas process by contributing nutrients and trace elements needed for the biogas process. In this study two lab-scale reactors were used to evaluate the effects of trace element addition during co-digestion of manure from swine- and dairy animals with industrial waste. The substrate used contained high background concentrations of both cobalt and nickel, which are considered to be the most important trace elements. In the reactor receiving additional trace elements, the volatile fatty acids (VFA) concentration was 89% lower than in the control reactor. The lower VFA concentration contributed to a more digested digestate, and thus lower methane emissions in the subsequent storage. Also, the biogas production rate increased with 24% and the biogas production yield with 10%, both as a result of the additional trace elements at high organic loading rates. All in all, even though 50% of the feedstock consisted of manure, trace element addition resulted in multiple positive effects and a more reliable process with stable and high yield. PMID- 25812804 TI - Effect of ondansetron on post-dural puncture headache (PDPH) in parturients undergoing cesarean section: a double-blind randomized placebo-controlled study. AB - PURPOSE: One of the most exhausting complications of spinal anesthesia, especially in parturients, is post-dural puncture headache (PDPH). This headache is not responsive to the usual pain killers. Ondansetron is a 5-HT3 receptor antagonist which is generally used for the prophylactic management of nausea and vomiting; however, studies have found that ondansetron might decrease the incidence of PDPH. Therefore, we aimed to evalute the effect of ondansetron on decreasing the incidence of PDPH. METHODS: In this double-blind randomized placebo-controlled clinical trial, 210 parturients who underwent elective cesarean section under spinal anesthesia were randomly allocated to two groups. The intervention group received 0.15 mg/kg ondansetron, while the control group received 5 ml normal saline. Heart rate and mean arterial pressure (MAP) were recorded during surgery. Furthermore, postoperative nausea and vomiting (PONV) and PDPH in the two groups were noted by an anesthetic nurse for 3 days and compared. RESULTS: The incidence of PDPH in the intervention group was significantly lower than in the control group (P = 0.001). The incidence of PONV was also significantly lower in the intervention group compared to the control group (P < 0.05). However, MAP was significantly higher in the intervention group compared to the control group (P < 0.05). No significant difference was found between the two groups regarding heart rate (P > 0.05). CONCLUSION: Ondansetron (0.15 mg/kg) appeared to reduce the incidence of PDPH, as well as the incidence of hypotension and PONV, in parturients undergoing spinal anesthesia for cesarean section. PMID- 25812807 TI - A study on torrefaction of sewage sludge to enhance solid fuel qualities. AB - Torrefaction is a treatment which serves to improve the properties of biomass in relation to thermochemical processing techniques for energy generation. In this study, the torrefaction of sewage sludge, which is a non-lignocellulosic waste was investigated in a horizontal tubular reactor under nitrogen flow at temperature ranging from 150 to 400 degrees C, for torrefaction residence time varying from 0 to 50 min. The torrefaction kinetics of sewage sludge was studied to obtain the kinetic parameters. The torrefied sewage sludge products were characterized in terms of their elemental composition, energy yield, ash content and volatile fraction. The energy and mass yields decreased with an increase in the torrefaction temperature. From an elemental analysis, the weight percentage of carbon in the sewage sludge increased with an increase in the torrefaction temperature. On the other hand, the weight percentages of hydrogen and oxygen tended to decrease. The gaseous products from torrefaction of sewage sludge were also analyzed. From this work, it was found that the compounds with oxygen were emitted at a temperature lower than that for hydrocarbon gases and the temperatures of 300-350 degrees C were the optimum torrefaction temperatures for sewage sludge. PMID- 25812809 TI - [Ultrasonographic examination of the stifle joint in the dog. Part 1: ultrasonographic anatomy, standardized scanning protocol and common indications]. AB - Ultrasonography is a cost-effective, non-invasive technique, which can be performed in conscious dogs. It frequently contributes valuable and even crucial diagnostic information in cases with hind limb lameness originating from the stifle joint. The first part of the article introduces the technical requirements and limitations as well as the standardized scanning protocol and ultrasonographic anatomy of the stifle joint. Ultrasonographic features encountered in common pathologies of the stifle joint (joint effusion, cranial cruciate ligament rupture and meniscal pathologies) are presented. Sonographic diagnostics of other pathologies of the canine stifle joint will be described in the second part of this article. PMID- 25812808 TI - Halogenated flame-retardant concentrations in settled dust, respirable and inhalable particulates and polyurethane foam at gymnastic training facilities and residences. AB - Halogenated flame-retardants (FRs) are used in a wide array of polymer-containing products. Animal studies and structure-activity modeling exercises suggest that FR exposure may result in detrimental toxicological effects. Workers with extended contact with such polymers (e.g., electronic dismantlers, carpet installers and aircraft personnel) have previously been observed to exhibit elevated body burdens of FRs, e.g., polybrominated diphenyl ethers (PBDEs). Recently, elevated PBDE blood levels were also reported in a non-occupational exposure group, gymnasts. These levels were hypothesized to be related to the large volumes of FR-treated polyurethane foam in gymnastics facilities. To further our understanding of workers' potential exposure, we analyzed FR concentrations in indoor dust and size-fractionated air particulates (respirable (<4 MUm) and inhalable (>4 MUm)) from gymnastic studios. Values were compared to samples from the homes of coaches employed at these facilities. Polyurethane foam blocks (i.e., pit foam) were also analyzed to characterize potential FR sources. FRs examined included those used to flame-retard polyurethane foam: 8 PBDE congeners, two brominated components of Firemaster 550 (2-ethylhexyl 2, 3, 4, 5 tetrabromobenzoate (TBB) and bis(2-ethylhexyl) 3, 4, 5, 6-tetrabromophthalate (TBPH)) and three chlorinated organophosphates (tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP)). Several additional FRs not used in polyurethane were also evaluated. These have also been detected in indoor dust and air and may also lead to adverse health effects. These include: BDE-183 and its replacement product (1, 2-bis(2, 4, 6-tribromophenoxy) ethane (BTBPE), two congeners of the deca-BDE formulation (BDE-206, -209) and their replacement decabromodiphenyl ethane (DBDPE) and hexabromocyclododecane (alpha-, beta-, gamma-HBCD), and tetrabromobisphenol-A (TBBPA)). Pit foam contained multiple FRs at cumulative concentrations of 12,100 to 25,800 MUg g(-1), or 1.2% to 2.6% by weight. TBB and TBPH were the most abundant FRs detected, followed by TDCPP and several PBDEs. The mean total FR burden detected at the gyms was 8.6-fold higher (574 MUg g(-1)) than that observed in the house dust samples (66.8 MUg g(-1)). However, the polyurethane additives TBB and TDCPP were the only FRs that exhibited significantly greater levels (P<0.05) in gym than house dust. Mean levels of five FRs (BDE-99, -100, -153, -209 and TDCPP) were also higher in respirable particulates from the gyms than the homes and four FRs (BDE-47, TBB, TBPH and DBDPE) were higher at the homes than the gyms; these differences were not significant (P>0.05). Several additional FRs were detected in inhalable particulates; mean levels of BDE-66, -206 and TCPP were higher in the homes and BDE-47, -85, -99, -100, -153, -209, TBB, TBPH, and TDCPP were higher at the gyms. But, only the polyurethane additives i.e., BDE-100, TBB and TDCPP were significantly greater (P<0.05) in inhalable particulates from the gyms than at the homes. In conclusion, polyurethane foam collected from gymnastic studios exhibited a variety of FR compositional signatures; likely reflective of changes in FR usage over time and by different manufacturers. FR concentrations and compositional signatures also differed between settled dust, respirable and inhalable particulates between the gyms and homes. Concentrations of FRs used in polyurethane foam were higher in gym air and dust compared to homes, particularly TBB and TDCPP - which were also the primary FRs detected in the pit foam samples. Although these results should be interpreted with caution, as the sample size was small, these findings do suggest that FR concentrations observed in dust and air particulates from the gymnastic studios are further evidence that individuals frequenting these environments are at greater risk for exposure to these polymer additives. PMID- 25812810 TI - High organic loading rate on thermophilic hydrogen production and metagenomic study at an anaerobic packed-bed reactor treating a residual liquid stream of a Brazilian biorefinery. AB - This study evaluated the influence of a high organic loading rate (OLR) on thermophilic hydrogen production at an up-flow anaerobic packed-bed reactor (APBR) treating a residual liquid stream of a Brazilian biorefinery. The APBR, filled with low-density polyethylene, was operated at an OLR of 84.2 kg-COD m(-3) d(-1). This value was determined in a previous study. The maximum values of hydrogen production and yield were 5,252.6 mL-H2 d(-1) and 3.7 mol-H2 mol( 1)(total carbohydrates), respectively. However, whereas the OLR remained constant, the specific organic load rate (sOLR) decreased throughout operation from 1.38 to 0.72 g-Total carbohydratesg-VS(-1) h(-1), this decrease negatively affected hydrogen production. A sOLR of 0.98 g-Total carbohydratesg-VS(-1) h(-1) was optimal for hydrogen production. The microbial community was studied using 454-pyrosequencing analysis. Organisms belonging to the genera Caloramator, Clostridium, Megasphaera, Oxobacter, Thermoanaerobacterium, and Thermohydrogenium were detected in samples taken from the reactor at operation days 30 and 60, suggesting that these organisms contribute to hydrogen production. PMID- 25812811 TI - Unbalanced fermentation of glycerol in Escherichia coli via heterologous production of an electron transport chain and electrode interaction in microbial electrochemical cells. AB - Microbial electrochemical cells are an emerging technology for achieving unbalanced fermentations. However, organisms that can serve as potential biocatalysts for this application are limited by their narrow substrate spectrum. This study describes the reprogramming of Escherichia coli for the efficient use of anodes as electron acceptors. Electron transfer into the periplasm was accelerated by 183% via heterologous expression of the c-type cytochromes CymA, MtrA and STC from Shewanella oneidensis. STC was identified as a target for heterologous expression via a two-stage screening approach. First, mass spectroscopic analysis revealed natively expressed cytochromes in S. oneidensis. Thereafter, the corresponding genes were cloned and expressed in E. coli to quantify periplasmic electron transfer activity using methylene blue. This redox dye was further used to expand electron transfer to carbon electrode surfaces. The results demonstrate that E. coli can be reprogrammed from glycerol fermentation to respiration upon production of the new electron transport chain. PMID- 25812812 TI - A lab-scale anoxic/oxic-bioelectrochemical reactor for leachate treatments. AB - A membraneless, liter-scale bioelectrochemical reactor with both bioanode and biocathode was established for landfill leachate treatment. Anoxic/oxic (A/O) zones at anode compartment and cathode compartment, respectively, were connected with a reflux to facilitate nitrogen removal. With raw landfill leachate of 17,500-22,600 mg L(-1) chemical oxygen demand (COD) and 1170-1490 mg L(-1) NH4(+) N, the tested reactor removed 89.1+/-1.6% of chemical oxygen demand and 99.2+/ 0.1% of NH4(+)-N at 3.0 kg COD m(-3) d(-1). The corresponding maximum power density was 2.71+/-0.09 W m(-3), with internal resistance of 46.7+/-1.6 Omega and open circuit voltage of 727+/-7 mV. The species of Pseudomonas, Desulfovibrio, Bacillus, Enterococcus, Pelospora, Dehalobacter dominated the anodic community, while those of methylotrophs, Rhodobacter, Verrucomicrobiaceae, Geobacter, Flavobacterium, Thauera, Desulfovibrio and Aeromonas dominated the cathodic community. The proposed A/O bioelectrochemical reactor is a prototype for practical treatment of landfill leachate at affordable costs. PMID- 25812813 TI - Detoxification of biomass hydrolysates with nucleophilic amino acids enhances alcoholic fermentation. AB - Carbonyl compounds generated in biomass pretreatment hinder the biochemical conversion of biomass hydrolysates to biofuels. A novel approach of detoxifying hydrolysates with amino acids for ethanol production was developed. Among the 20 amino acids assessed for their detoxification efficiency and nucleophilicity, cysteine was the most effective one. It increased both ethanol productivity and final yield of biomass hydrolysates from 0.18 (untreated) to 1.77 g/L/h and from 0.02 to 0.42 g/g, respectively. Detoxification efficiency was followed by histidine and it increased the final yield to 0.42 g/g, then by lysine, tryptophan and asparagine. It was observed all five effective amino acids contained reactive side-chain functional groups, which played important roles in the amino acid detoxification reaction. The study further showed cysteine and glycine detoxifications were temperature and pH dependent. The mechanistic study using mass spectrometry revealed thiazolidine carboxylic acid, a Schiff base, was formed by condensation of aldehyde and cysteine. PMID- 25812815 TI - Carbon monoxide fermentation to ethanol by Clostridium autoethanogenum in a bioreactor with no accumulation of acetic acid. AB - Fermentation of CO or syngas offers an attractive route to produce bioethanol. However, during the bioconversion, one of the challenges to overcome is to reduce the production of acetic acid in order to minimize recovery costs. Different experiments were done with Clostridium autoethanogenum. With the addition of 0.75 MUM tungsten, ethanol production from carbon monoxide increased by about 128% compared to the control, without such addition, in batch mode. In bioreactors with continuous carbon monoxide supply, the maximum biomass concentration reached at pH 6.0 was 109% higher than the maximum achieved at pH 4.75 but, interestingly, at pH 4.75, no acetic acid was produced and the ethanol titer reached a maximum of 867 mg/L with minor amounts of 2,3-butanediol (46 mg/L). At the higher pH studied (pH 6.0) in the continuous gas-fed bioreactor, almost equal amounts of ethanol and acetic acid were formed, reaching 907.72 mg/L and 910.69 mg/L respectively. PMID- 25812814 TI - Biodegradation of fenoxaprop-P-ethyl (FE) by Acinetobacter sp. strain DL-2 and cloning of FE hydrolase gene afeH. AB - Fenoxaprop-P-ethyl (FE) is widely used as a post-emergence aryloxyphenoxy propionate (AOPP) herbicide in agriculture. An efficient FE-degrading strain DL-2 was isolated from the enrichment culture and identified as Acinetobacter sp. and the metabolite fenoxaprop acid (FA) was identified by HPLC/MS analysis. The strain DL-2 could also degrade a wide range of other AOPP herbicides. A novel FE hydrolase esterase gene afeH was cloned from strain DL-2 and functionally expressed in Escherichia coli BL21(DE3). The specific activities of recombinant AfeH was 216.39 U mg(-1) for FE with Km and Vmax values of 0.82 MUM and 7.94 MUmol min(-1) mg(-1). AfeH could also hydrolyze various AOPP herbicides, p nitrophenyl esters and triglycerides. The optimal pH and temperature for recombinant AfeH were 9.0 and 50 degrees C, respectively; the enzyme was activated by Co(2+) and inhibited by Ca(2+), Zn(2+), Ba(2+). AfeH was inhibited strongly by phenylmethylsulfonyl and SDS and weakly by dimethyl sulfoxide. PMID- 25812816 TI - Anaerobic codigestion of pretreated wheat straw with cattle manure and analysis of the microbial community. AB - Wheat straw (WS) was pretreated with four concentrations of H2O2 (1%, 2%, 3%, and 4%) and was anaerobically codigested with dairy cattle manure (CM) at various ratios from 100:0 to 0:100. Wet-state H2O2 pretreatment effectively enhanced the biodegradability and methane yield of the WS. The optimal concentration of H2O2 for treating WS was 3%. The methane yield was higher with the codigestion of CM and H2O2-treated WS than with untreated WS and higher than with H2O2-treated WS alone or CM alone. A 40:60 ratio of H2O2-treated WS mixed with CM produced the highest yield of methane (320.8 mL g volatile solid (VS)(-1)). Results of high throughput sequencing indicated that the methanogenic community shifted during the codigestion from the acetoclastic methanogens, Methanosarcina, to the hydrogenotrophic methanogens, Methanosphaera and Methanoculleus. PMID- 25812817 TI - Power generation response to readily biodegradable COD in single-chamber microbial fuel cells. AB - Single-chamber microbial fuel cells (MFCs) using domestic wastewater (DWW) and milk processing wastewater (MWW) were operated at different organic loading rates (OLRs). The maximum power density (PDmax) and OLR (readily biodegradable COD [RBCOD] and soluble COD [SCOD]) followed the Lineweaver-Burk equation in all influents. The coefficients of determination were 0.9209 and 0.9975 for SCOD and RBCOD, respectively. OLR based on RBCOD showed better power generation function than that based on SCOD. PDmax (2.9-12.2 W/m(3)) in DWW was lower than that (6.9 24.9 W/m(3)) in MWW but the net energy recovery (kWh/kg-SCOD(removed)) in DWW (0.542-1.108) was larger than that in MWW (0.322-0.602). This was attributed to the higher ratio of RBCOD/SCOD (0.44) and the lower values of RBCOD (40 mg/L) in DWW, compared to RBOCD/SCOD (0.11) and RBCOD (110 mg/L) in MWW. Therefore, RBCOD is an important indicator for estimating power generation. PMID- 25812820 TI - [Brugada type I associated with cellulitis: Review and update]. PMID- 25812818 TI - Understanding methane bioelectrosynthesis from carbon dioxide in a two-chamber microbial electrolysis cells (MECs) containing a carbon biocathode. AB - To better understand the underlying mechanisms for methane bioelectrosynthesis, a two-chamber MECs containing a carbon biocathode was developed and studied. Methane production substantially increased with increasing cathode potential. Considerable methane yield was achieved at a poised potential of -0.9 V (vs. Ag/AgCl), reaching 2.30+/-0.34 mL after 5 h of operation with a faradaic efficiency of 24.2+/-4.7%. Confirmatory tests done at 0.9 V by switching the type of flushed substrates (CO2/N2) or the electrical exposure modes (ON/OFF) demonstrated that cathode serving as an electron donor was the vital driving force for methanogenesis occurring at microbe-electrode surface. Fluorescence in situ hybridization reveled Methanobacteriaceae (particularly Methanobacterium) was the predominant methanogens, supporting the mechanisms of direct electron transfer between cell-electrode. Additionally, the analysis of scanning electron microscope confirmed that the multiple pathways of electron transfer, including direct cathode-to-cell, interspecies exchange and semi-conductive conduits all together ensured the successful electromethanogenesis process. PMID- 25812819 TI - The addition of accessory enzymes enhances the hydrolytic performance of cellulase enzymes at high solid loadings. AB - The pretreatment process used and the nature of the biomass feedstock will influence the role that accessory enzymes can play in synergistically interacting with cellulases to effectively deconstruct the substrate. The work reported here assessed the possible boosting effects of the xylanase and lytic polysaccharide monooxygenase (AA9, formerly known as GH61) on the hydrolytic potential of cellulase enzyme mixtures during hydrolysis of steam pretreated poplar and corn stover at high (10-20% w/v) substrate concentrations. A higher proportion of xylanase was required when the substrate had a relatively high xylan content and at high substrate concentrations. In contrast, a relatively small amount of AA9 (about 2 mg/g cellulose) was enough, regardless of the nature or concentration of the substrate. The overall protein loading required to achieve effective hydrolysis of high concentrations of pretreated biomass substrates could be substantially reduced by optimizing the ratio of enzymes in the "cellulase" mixture. PMID- 25812821 TI - CKD in disadvantaged populations. PMID- 25812822 TI - Nephrotoxic effects of varenicline as the most effective drug used for smoking cessation: a preliminary experimental study. AB - PURPOSE: Varenicline is a new most effective drug for smoking cessation. Its effect on kidney functions remains unclear. This study purposed to investigate whether varenicline causes nephrotoxicity in rats. METHODS: Fifteen rats were randomly assigned to three groups: control, 0.0125 mg kg(-1) varenicline and 0.025 mg kg(-1) varenicline (single dose for 3 days, i.p.). Before and after experimental period, serum neutrophil gelatinase-associated lipocalin, creatinine and urea levels were measured. Total oxidant and antioxidant status were measured in kidney homogenates. Histological examination was performed in kidney. RESULTS: The nephrotoxic effects of varenicline were detected by histopathological and biochemical examinations in the varenicline treatment groups. No change was observed in the control group. CONCLUSIONS: These findings firstly indicate that a 3-day varenicline treatment causes nephrotoxic effects in rats. PMID- 25812823 TI - The preventive effect of tamsulosin on voiding dysfunction after prostate biopsy: a prospective, open-label, observational study. AB - OBJECTIVES: To evaluate the association of prostate biopsy with voiding impairment and to investigate whether tamsulosin treatment given before prostate biopsy could improve voiding dysfunction after the procedure. METHODS: The study included 88 consecutive patients who underwent transrectal ultrasound-guided prostate biopsy without prior BPH medication and were prospectively randomized. Of these 88 patients, 44 patients underwent prostate biopsy only without tamsulosin treatment and served as the control group. The remaining 44 patients were treated with tamsulosin (0.2 mg daily) beginning the day before the biopsy procedure for 7 days. The International Prostate Symptom Score (IPSS) was recorded in all patients before the procedure and on postbiopsy day 7. Maximal flow rate (Q(max)) and postvoid residual urine volume were recorded in all patients before the procedure and on postbiopsy days 1 and 7. RESULTS: No difference was found in baseline characteristics between the two groups. The IPSS (total, storage, and voiding symptom) was not significantly changed after biopsy in both groups. In the control group, the postvoid residual urine volume was increased on postbiopsy days 1 (P < 0.05) and 7, and the Q(max) was significantly decreased on postbiopsy day 7 compared with the baseline value (P < 0.05). In the tamsulosin group, Q(max) was significantly increased on postbiopsy days 1 and 7 (P < 0.01). The postvoid residual urine volume was not increased on postbiopsy days 1 and 7. Acute urinary retention after the biopsy procedure did not develop in any of the patients (0%) in the tamsulosin group, but it developed in two patients (4.5%) of the control group. CONCLUSIONS: The results of our study show that prostate biopsy leads to objective voiding impairment. Therefore, the use of alpha-1 blocker tamsulosin before biopsy in patients without prior BPH medication may decrease this morbidity. PMID- 25812824 TI - Comparison of biomarkers between PLA2RAb+ and PLA2RAb- in patients with idiopathic membranous nephropathy. AB - OBJECTIVE: The presence of antibodies against the M-type phospholipase A2 receptor (PLA2RAb) is considered to be a promising serological diagnostic biomarker of idiopathic membranous nephropathy (IMN). We compare the change in serum Cystain C (CysC), urea, creatinine (CREA), uric acid (UA), total protein (TP), albumin (ALB), IgG4 and 24-h urinary protein (proteinuria, PRO) between PLA2RAb+ and PLA2RAb- of IMN patients. MATERIALS AND METHODS: The serum and urine samples were collected from 120 patients with IMN. The presence of circulating PLA2RAb was determined by indirect immunofluorescence, and their titer was quantified by ELISA. CysC, urea, CREA, UA, TP, ALB and 24-h PRO were examined by automatic biochemical analyzer. RESULTS: Serum IgG4 level was determined by specific protein analyzer. PLA2RAb-positive percentage by ELISA was higher than that by IIF, but no significant difference was found by McNemar's Chi-square test. Serum IgG4 level and 24-h PRO level were significantly higher in PLA2RAb+ than in PLA2RAb- (P < 0.05). In PLA2RAb+ group, PLA2RAb is positively related to serum IgG4 and 24-h PRO and negatively related to serum TP and ALB (P < 0.01). CONCLUSION: This is the first study to show that combined detection of IgG4 concentration and PLA2RAb was usable for IMN patients. PMID- 25812825 TI - Repetitive negative thinking predicts depression and anxiety symptom improvement during brief cognitive behavioral therapy. AB - Repetitive negative thinking (RNT) is a common symptom across depression and anxiety disorders and preliminary evidence suggests that decreases in rumination and worry are related to improvement in depression and anxiety symptoms. However, despite its prevalence, relatively little is known about transdiagnostic RNT and its temporal associations with symptom improvement during treatment. The current study was designed to examine the influence of RNT on subsequent depression and anxiety symptoms during treatment. Participants (n = 131; 52% female; 93% White; M = 34.76 years) were patients presenting for treatment in a brief, cognitive behavior therapy based, partial hospitalization program. Participants completed multiple assessments of depression (Center for the Epidemiological Studies of Depression-10 scale), anxiety (the 7-item Generalized Anxiety Disorder Scale), and repetitive negative thinking (Perseverative Thinking Questionnaire) over the course of treatment. Results indicated statistically significant between and within person effects of RNT on depression and anxiety, even after controlling for the effect of time, previous symptom levels, referral source, and treatment length. RNT explained 22% of the unexplained variability in depression scores and 15% of the unexplained variability in anxiety scores beyond that explained by the control variables. RNT may be an important transdiagnostic treatment target for anxiety and depression. PMID- 25812826 TI - Changes in negative cognitions mediate PTSD symptom reductions during client centered therapy and prolonged exposure for adolescents. AB - OBJECTIVE: To assess whether changes in negative trauma-related cognitions play an important role in reducing symptoms of posttraumatic stress disorder (PTSD) and depression during prolonged exposure therapy for adolescents (PE-A). METHOD: Secondary analysis of data from a randomized controlled trial comparing PE-A with client-centered therapy (CCT) for PTSD. Participants were 61 adolescent female sexual assault survivors ages 13-18 who received 8-14 weekly sessions of PE-A or CCT at a community rape crisis center. PTSD severity was assessed at baseline, mid-treatment, post-treatment, and 3-months post-treatment. Participants also completed self-report measures of negative posttraumatic cognitions and depressive symptoms at the same assessment points. RESULTS: Cross lag panel mediation analyses showed that change in negative trauma-related cognitions mediated change in PTSD symptoms and depressive symptoms whereas change in PTSD and depressive symptoms did not mediate change in negative cognitions. CONCLUSION: Our findings support EPT and suggest that change in negative trauma related cognitions is a mechanism of both PE-A and CCT. PMID- 25812827 TI - A Multicenter Study of Intravenous Immunoglobulin Non-response in Kawasaki Disease. AB - To investigate the relationship between the risk factors associated with intravenous immunoglobulin (IVIG) non-response and the incidence of coronary artery lesions (CAL) in patients with Kawasaki disease (KD). A retrospective study was performed on clinical records of 1953 KD patients who were admitted to hospitals in Shanghai, China, between 1998 and 2007. Related clinical and laboratory findings were studied using univariate and multivariate statistical analyses. Of the 1953 KD patients, 133 (6.8 %) were unresponsive to IVIG therapy, and 356 (18.6 %) developed CAL. The incidence of CAL in the non-responsive IVIG group was significantly different from that in the responsive IVIG group (31.3 vs. 17.6 %). The incidence of IVIG non-response was significantly lower in the patients who received sufficient doses of IVIG than in the patients who received insufficient doses (5.2 vs. 18.1 %). A logistic regression analysis of 1295 patients who received sufficient IVIG doses indicated that cervical lymph node enlargement, CAL, erythrocyte sedimentation rate (ESR) >=75 mm/h, and platelet count (PLT) >=530 * 10(9)/L were independent risk factors of IVIG non-response. IVIG non-responders are prone to develop CAL. Initiation of therapy with sufficient IVIG doses at the early stage of the disease is crucial for preventing IVIG non-response. Lymph node enlargement, ESR >=75 mm/h, and PLT count >=530 * 10(9)/L are independent risk factors for predicting non-response to sufficient IVIG doses. For patients with the tendency of being unresponsive to IVIG therapy, treatment using sufficient IVIG doses combined with hormones or immunosuppressive agents should be considered to reduce the incidence of IVIG non-response and CAL. PMID- 25812828 TI - Do rhesus monkeys (Macaca mulatta) perceive illusory motion? AB - During the last decade, visual illusions have been used repeatedly to understand similarities and differences in visual perception of human and non-human animals. However, nearly all studies have focused only on illusions not related to motion perception, and to date, it is unknown whether non-human primates perceive any kind of motion illusion. In the present study, we investigated whether rhesus monkeys (Macaca mulatta) perceived one of the most popular motion illusions in humans, the Rotating Snake illusion (RSI). To this purpose, we set up four experiments. In Experiment 1, subjects initially were trained to discriminate static versus dynamic arrays. Once reaching the learning criterion, they underwent probe trials in which we presented the RSI and a control stimulus identical in overall configuration with the exception that the order of the luminance sequence was changed in a way that no apparent motion is perceived by humans. The overall performance of monkeys indicated that they spontaneously classified RSI as a dynamic array. Subsequently, we tested adult humans in the same task with the aim of directly comparing the performance of human and non human primates (Experiment 2). In Experiment 3, we found that monkeys can be successfully trained to discriminate between the RSI and a control stimulus. Experiment 4 showed that a simple change in luminance sequence in the two arrays could not explain the performance reported in Experiment 3. These results suggest that some rhesus monkeys display a human-like perception of this motion illusion, raising the possibility that the neurocognitive systems underlying motion perception may be similar between human and non-human primates. PMID- 25812832 TI - Resource limitation alters the consequences of co-infection for both hosts and parasites. AB - Most animals are concurrently infected with multiple parasite species and live in environments with fluctuating resource availability. Resource limitation can influence host immune responses and the degree of competition between co infecting parasites, yet its effects on individual health and pathogen transmission have not been studied for co-infected hosts. To test how resource limitation affects immune trade-offs and co-infection outcomes, we conducted a factorial experiment using laboratory mice. Mice were given a standard or low protein diet, dosed with two species of helminths (alone and in combination), and then challenged with a microparasite. Using a community ecology trophic framework, we found that co-infection influenced parasite survival and reproduction via host immunity, but the magnitude and direction of responses depended on resources and the combination of co-infecting parasites. Our findings highlight that resources and their consequence for host defenses are a key context that shapes the magnitude and direction of parasite interactions. PMID- 25812834 TI - The use of genetically marked infection cohorts to study changes in establishment rates during the time course of a repeated Ascaridia galli infection in chickens. AB - This study investigated the changes in establishment rates during the time course of a 6 week trickle infection of chickens with Ascaridia galli at two different dose levels, using a molecular marker. To differentiate early and late infection, two different egg cohorts (haplotype a and haplotype b, genetically identified using PCR-linked restriction fragment length polymorphism on the cox1 gene of the mitochondrial DNA) were used. Cohort-specific egg batches were produced by harvesting eggs from the uteri of female worms of the specific cohort. Fifty-six 8 week old Lohmann Brown Lite chickens were divided into seven groups and the infectivity of the egg batches was compared between two groups of chickens (P=0.6). The remaining chickens were allocated to four infection regimes and one control group. Group ab100 was trickle infected for 3 weeks with 100 eggs of haplotype a (twice weekly) followed by the same dose of eggs of haplotype b for another 3 weeks. Group ba100 was treated similarly but in the opposite order (haplotype b preceding a). A similar infection regime was applied for groups ab25 and ba25 but with a lower inoculation dose (25 eggs). All of the birds in these five groups (four infected and one control) were euthanased 2 weeks after the last inoculation. It was found that in the low-dose groups both the early and late infections established equally well, whereas in the high-dose groups the early infection was recovered in a significantly (P<0.001) higher proportion of chickens than the late infection, irrespective of genetic cohorts. Moreover, relatively higher proportions of the larvae from both the early and late infections were found in the posterior section of the small intestine. This result indicates the presence of dose-dependent resistance against reinfection and this resistance seems to act by reducing the establishment of late infection and by relocating the larvae from early infection. PMID- 25812833 TI - Revealing praziquantel molecular targets using mass spectrometry imaging: an expeditious approach applied to Schistosoma mansoni. AB - Finding specific molecular targets and the mechanism of action of praziquantel in the treatment of schistosomiasis remains a challenging task. Our efforts were focused on obtaining further information on worm composition before and after exposure to praziquantel in the treatment of schistosomiasis to elucidate the potential sites of action of this drug. Evidence indicates that the lipid bilayer is changed by treatment with praziquantel. Following this rationale, we employed a mass spectrometry imaging-based approach that helped to characterise lipids in specific locations, which are directly involved in the biochemical pathways of the BH strain of Schistosoma mansoni, as well as differentiating the molecular response that each worm sex presents in vivo. Our findings demonstrated significant differences between the chemical markers found in adult worms before and after praziquantel exposure, especially in phospholipids, which were predominantly identified as chemical markers in all samples. Results also indicate that distinct molecular pathways in both male and female worms could be differentially affected by praziquantel treatment. These data shine new light on the mechanism of action of praziquantel, taking a further step towards its full understanding. PMID- 25812835 TI - A linear mitochondrial genome of Cyclospora cayetanensis (Eimeriidae, Eucoccidiorida, Coccidiasina, Apicomplexa) suggests the ancestral start position within mitochondrial genomes of eimeriid coccidia. AB - The near complete mitochondrial genome for Cyclospora cayetanensis is 6184 bp in length with three protein-coding genes (Cox1, Cox3, CytB) and numerous lsrDNA and ssrDNA fragments. Gene arrangements were conserved with other coccidia in the Eimeriidae, but the C. cayetanensis mitochondrial genome is not circular-mapping. Terminal transferase tailing and nested PCR completed the 5'-terminus of the genome starting with a 21 bp A/T-only region that forms a potential stem-loop. Regions homologous to the C. cayetanensis mitochondrial genome 5'-terminus are found in all eimeriid mitochondrial genomes available and suggest this may be the ancestral start of eimeriid mitochondrial genomes. PMID- 25812836 TI - Seroprevalence, disease awareness, and risk factors for Toxocara canis infection among primary schoolchildren in Makoko, an urban slum community in Nigeria. AB - In this study, we investigated the seroprevalence of Toxocara canis infection in southern Nigeria, which previously was unknown, in addition to evaluating disease awareness and potential risk factors for schoolchildren in an urban slum community. In total, 366 primary schoolchildren were investigated for the presence of anti-Toxocara IgG antibodies. Blood was collected and screened by a Western blot analysis based on the excretory-secretory antigens of larval T. canis (TcES), targeting low molecular weight bands of 24-35kDa specific for T. canis. Children were considered seropositive if their serum reacted with TcES when diluted to a titer of 1:32. Questionnaires concerning possible risk factors were given to the schoolchildren to acquire data on this infection. The overall seroprevalence of Toxocara infection was 86.1% (315/366). The logistic regression analysis of risk factors showed that children's age (odds ratio (OR)=2.88, 95% confidence interval (CI)=1.08-7.66, p=0.03), contact with dogs (OR=0.51, 95% CI=0.28-0.94, p=0.03), the age of the dog (OR=0.34, 95% CI=0.18-0.68, p=0.002), the feeding location of the dog (OR=0.31, 95% CI=0.12-0.79, p=0.01), the consumption of raw vegetables (OR=0.89, 95% CI=0.54-1.48, p=0.004), and the drinking of unboiled water (OR=0.48, 95% CI=0.26-0.90, p=0.02) were risk factors associated with Toxocara infection. Although there was a high awareness of dogs being hosts of some parasites in this study, not much was known about T. canis. This is the first serological investigation of T. canis infection among primary schoolchildren in southern Nigeria. The high seroprevalence recorded is an indication of high transmission with the consequent risk of visceral or ocular larval migrans and neurologic toxocariasis in these children. Our findings suggest the need for prompt interventional measures, particularly health education on personal hygiene. PMID- 25812837 TI - Seed priming: state of the art and new perspectives. AB - Priming applied to commercial seed lots is widely used by seed technologists to enhance seed vigour in terms of germination potential and increased stress tolerance. Priming can be also valuable to seed bank operators who need improved protocols of ex situ conservation of germplasm collections (crop and native species). Depending on plant species, seed morphology and physiology, different priming treatments can be applied, all of them triggering the so-called 'pre germinative metabolism'. This physiological process takes place during early seed imbibition and includes the seed repair response (activation of DNA repair pathways and antioxidant mechanisms), essential to preserve genome integrity, ensuring proper germination and seedling development. The review provides an overview of priming technology, describing the range of physical-chemical and biological treatments currently available. Optimised priming protocols can be designed using the 'hydrotime concept' analysis which provides the theoretical bases for assessing the relationship between water potential and germination rate. Despite the efforts so far reported to further improve seed priming, novel ideas and cutting-edge investigations need to be brought into this technological sector of agri-seed industry. Multidisciplinary translational research combining digital, bioinformatic and molecular tools will significantly contribute to expand the range of priming applications to other relevant commercial sectors, e.g. the native seed market. PMID- 25812840 TI - Locally sourced probiotics, the next opportunity for developing countries? AB - We describe factors promoting the exploration of locally sourced probiotics, targeting local populations to balance human needs and market opportunities. This would be particularly beneficial for people in developing countries, who generally lack access to affordable probiotics and are often exposed to poor hygiene conditions, toxic compounds, malnutrition, and chronic enteric infections. PMID- 25812838 TI - Intestinal microbiota-related effects on graft-versus-host disease. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an increasingly important treatment for conditions including hematopoietic malignancies and inherited hematopoietic disorders, and is considered to be the most effective form of tumor immunotherapy available to date. However, graft-versus-host disease (GVHD) remains a major source of morbidity and mortality following allo-HSCT, and understanding the mechanisms of GVHD has been highlighted as a key research priority. During development of GVHD, activation of various immune cells, especially donor T cells, leads to damage of target organs including skin, liver, hematopoietic system, and of particular clinical importance, gut. In addition to histocompatibility complex differences between the donor and recipient, pretransplant conditioning with chemotherapy and irradiation also contributes to GVHD by damaging the gut, resulting in systemic exposure to microbial products normally confined to the intestinal lumen. The intestinal microbiota is a modulator of gastrointestinal immune homeostasis. It also promotes the maintenance of epithelial cells. Recent reports provide growing evidence of the impact of intestinal microbiota on GVHD pathophysiology. This review summarizes current knowledge of changes and effects of intestinal microbiota in the setting of allo-HSCT. We will also discuss potential future strategies of intestinal microbiota manipulation that might be advantageous in decreasing allo-HSCT related morbidity and mortality. PMID- 25812839 TI - Therapeutic benefits targeting B-cells in chronic graft-versus-host disease. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) can be a curative strategy for hematological diseases, and the indications for allo-HCT have broadened widely due to recent progress in supportive strategies. However, patients must overcome various complications and chronic graft-versus-host disease (cGVHD) remains the most common allo-HCT cause of long-term morbidity and mortality. cGVHD is difficult to biologically assess due to the heterogeneity of cGVHD symptoms, and the pathogenesis of cGVHD has yet to be established. Recent experimental model progress has suggested that B-cells play a critical role in cGVHD development. Consistent with these experimental results, some clinical studies investigating B-cell depletion and modulation of B-cell signaling pathways have decreased cGVHD incidence and provided some therapeutic benefit. However, randomized control studies are necessary to confirm the efficacy of B cell targeting drugs for cGVHD. Here, we review the pathophysiology of cGVHD, especially focusing on the role of B-cell immunity, and discuss the efficacy of both B-cell depletion and modulation of B-cell signaling pathways in human cGVHD prevention, initial treatment, and salvage treatment. PMID- 25812841 TI - Rabies vaccine preserved by vaporization is thermostable and immunogenic. AB - A rabies vaccine that is thermostable over a range of ambient environmental temperatures would be highly advantageous, especially for tropical regions with challenging cold-chain storage where canine rabies remains enzootic resulting in preventable human mortality. Live attenuated rabies virus (RABV) strain ERAG333 (R333E) was preserved by vaporization (PBV) in a dry, stable foam. RABV stabilized using this process remains viable for at least 23 months at 22 degrees C, 15 months at 37 degrees C, and 3h at 80 degrees C. An antigen capture assay revealed RABV PBV inactivated by irradiation contained similar levels of antigen as a commercial vaccine. Viability and antigen capture testing confirmed that the PBV process stabilized RABV with no significant loss in titer or antigen content. Live attenuated and inactivated RABV PBV both effectively induced RABV neutralizing antibodies and protected mice from peripheral RABV challenge. These results demonstrate that PBV is an efficient method for RABV stabilization. PMID- 25812843 TI - Assessing the value of routine upper gastrointestinal contrast studies following bariatric surgery: a systematic review and meta-analysis. AB - BACKGROUND: Understanding both the efficacy of upper gastrointestinal (UGI) contrast studies and the factors that impact their accuracy is necessary to optimize postoperative imaging protocols. However, a consensus as to the value of UGI performed after bariatric surgery remains elusive. The objective was to determine the sensitivity and specificity of UGI conducted routinely within 2 days after bariatric surgery for detecting anastomotic leaks. METHODS: We conducted an electronic search of MEDLINE for all English language articles published between 2003 and 2013 concerning diagnostic imaging after bariatric surgery. Nineteen studies evaluating a total of 10,139 patients met the inclusion criteria. The methodological quality of each included study was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 procedure. RESULTS: UGI has an overall sensitivity of .54 and a specificity of 1.00. The standard deviation of the reported sensitivities was .36. Positive and negative predictive values were .67 and .98, respectively. Sensitivity and specificity were negatively correlated. CONCLUSIONS: The sensitivity of UGI for detecting the presence of anastomotic leaks within 2 days of bariatric surgery is moderate overall but fluctuates substantially. The negative correlation between sensitivity and specificity could indicate that the threshold used to distinguish between positive and negative test results varies between institutions. Accordingly, clinicians may consider shifting the threshold for declaring a UGI positive; treating marginal radiological evidence of leakage as presumptively positive may be a simple way to lower specificity, increase sensitivity, and in turn maximize UGI's clinical value. PMID- 25812844 TI - Racial disparity in in-hospital mortality after lobectomy for lung cancer. AB - BACKGROUND: Using data from the Nationwide Inpatient Sample, we investigated the impact of surgical approach and race on in-hospital mortality after lobectomy for lung cancer. METHODS: Logistic regression was used to model odds ratios for in hospital mortality related to surgical technique (thoracotomy vs video assisted thoracoscopic surgery [VATS]) and race using discharge data from the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality (2008 to 2011). RESULTS: VATS lobectomies increased each year (25.9% to 39.2%, P = .001) in the 19,353 patients identified. A racial disparity was noted, with black patients being 66% more likely to die in the hospital (odds ratio 1.66, 95% confidence interval 1.17 to 2.37, P = .005). Excluding 2010 data suggests that there is evidence of benefit associated with VATS; however, no evidence of an association between race and in-hospital mortality exists. CONCLUSIONS: This study elucidates race-related mortality in lobectomy patients. Although racial disparities are present throughout health care, this finding emphasizes one of the challenges in using large databases to assess such disparities. PMID- 25812842 TI - Deaths averted by influenza vaccination in the U.S. during the seasons 2005/06 through 2013/14. AB - BACKGROUND: Excess mortality due to seasonal influenza is substantial, yet quantitative estimates of the benefit of annual vaccination programs on influenza associated mortality are lacking. METHODS: We estimated the numbers of deaths averted by vaccination in four age groups (0.5 to 4, 5 to 19, 20 to 64 and >=65 yrs.) for the nine influenza seasons from 2005/6 through 2013/14. These estimates were obtained using a Monte Carlo approach applied to weekly U.S. age group specific estimates of influenza-associated excess mortality, monthly vaccination coverage estimates and summary seasonal influenza vaccine effectiveness estimates to obtain estimates of the number of deaths averted by vaccination. The estimates are conservative as they do not include indirect vaccination effects. RESULTS: From August, 2005 through June, 2014, we estimated that 40,127 (95% confidence interval [CI] 25,694 to 59,210) deaths were averted by influenza vaccination. We found that of all studied seasons the most deaths were averted by influenza vaccination during the 2012/13 season (9398; 95% CI 2,386 to 19,897) and the fewest during the 2009/10 pandemic (222; 95% CI 79 to 347). Of all influenza associated deaths averted, 88.9% (95% CI 83 to 92.5%) were in people >=65 yrs. old. CONCLUSIONS: The estimated number of deaths averted by the US annual influenza vaccination program is considerable, especially among elderly adults and even when vaccine effectiveness is modest, such as in the 2012/13 season. As indirect effects ("herd immunity") of vaccination are ignored, these estimates represent lower bound estimates and are thus conservative given valid excess mortality estimates. PMID- 25812845 TI - A prospective evaluation of standard versus battery-powered sequential compression devices in postsurgical patients. AB - BACKGROUND: Sequential compression devices (SCDs) reduce deep venous thrombosis in postsurgical patients, but the use is hindered by poor compliance. METHODS: General and orthopedic surgery patients (n = 67) were randomized to standard- or battery-powered SCDs. Compliance was documented hourly. Nurses and patients were issued a survey to assess barriers to compliance and device satisfaction. RESULTS: Compliance with standard SCDs was 47% compared with 85% with battery powered SCDs (P < .001). The most common barriers identified by nurses and patients were ambulation and transfers, which were mitigated with the battery powered device. A majority (79%) of those issued a battery-powered device reported no major problems compared with only 14% of patients issued a standard device (P < .005). CONCLUSIONS: The dual venous thromboembolism prevention strategies of early mobilization and SCD utilization can be met with the appropriate equipment. PMID- 25812846 TI - Design and validation of the surgical ward round assessment tool: a quantitative observational study. AB - BACKGROUND: Ward round skills are essential for the best management of surgical inpatients, but assessment of their quality has received inadequate attention. This study aims to design and validate the surgical ward round assessment tool (SWAT). METHODS: We used modified Healthcare Failure Mode and Effects Analysis to develop the SWAT by identifying ward round steps. We assessed the validity of the SWAT using simulated and real surgical ward rounds. RESULTS: The Healthcare Failure Mode and Effects Analysis identified 30 ward round steps that were developed into the SWAT. Nineteen surgeons completed simulated surgical ward rounds. Eight fully trained surgeons scored significantly higher than 11 trainee surgeons when assessed with the SWAT (P = .001). On average, the participants thought the realism of the simulation was good. Forty-four surgeons completed real surgical ward rounds. Fifteen experts scored significantly higher than 29 trainee surgeons when assessed with SWAT (P = .001). Inter-rater reliability was .85 to .89, respectively. CONCLUSIONS: The SWAT can be used to assess the quality of task-based and nontechnical surgical ward round skills. PMID- 25812848 TI - Making meaningful worlds: role-playing subcultures and the autism spectrum. AB - Every summer, a group of role-playing gamers gathers in an American town. Dressed up as moon goddesses, mad scientists, and other fantastical characters, they act out elaborate, improvised narratives of transformation, destruction, and redemption. For several summers, this group, who I call the Journeyfolk, ran a camp for teenagers on the autism spectrum, engaging campers in therapeutic reconfigurations of self and social role. Through this folk healing practice, the meaning of autism was itself transformed; what had been a source of isolation became a source of commonality and community. This paper takes the camp as a case study for examining the co-productive relationship between culture and neurodiversity. Cognitive tendencies often found in autism are often thought to preclude socio-cultural participation. However, such tendencies can also facilitate the co-creation of innovative cultural spaces, through processes of affinity and affiliation. Drawing on ethnographic fieldwork at the camp, I identify three sites of congruity between the culture of the camp and the cognitive and phenomenological experiences associated with autism, at which this "work of culture" (Obeysekere in The Work of Culture: Symbolic Transformation in Psychoanalysis and Anthropology, University of Chicago Press, Chicago, 1990) took place: the structure of social interactions within roleplaying games, the narratives enacted within these games, and the interpersonal relationships within which the games were embedded. PMID- 25812847 TI - H3K9MTase G9a is essential for the differentiation and growth of tenocytes in vitro. AB - Cell differentiation is controlled by specific transcription factors. The functions and expression levels of these transcription factors are regulated by epigenetic modifications, such as histone modifications and cytosine methylation of the genome. In tendon tissue, tendon-specific transcription factors have been shown to play functional roles in the regulation of tenocyte differentiation. However, the effects of epigenetic modifications on gene expression and differentiation in tenocytes are unclear. In this study, we investigated the epigenetic regulation of tenocyte differentiation, focusing on the enzymes mediating histone 3 lysine 9 (H3K9) methylation. In primary mouse tenocytes, six H3K9 methyltransferase (H3K9MTase) genes, i.e., G9a, G9a-like protein (GLP), PR domain zinc finger protein 2 (PRDM2), SUV39H1, SUV39H2, and SETDB1/ESET were all expressed, with increased mRNA levels observed during tenocyte differentiation. In mouse embryos, G9a and Prdm2 mRNAs were expressed in tenocyte precursor cells, which were overlapped with or were adjacent to cells expressing a tenocyte specific marker, tenomodulin. Using tenocytes isolated from G9a-flox/flox mice, we deleted G9a by infecting the cells with Cre-expressing adenoviruses. Proliferation of G9a-null tenocytes was significantly decreased compared with that of control cells infected with GFP-expressing adenoviruses. Moreover, the expression levels of tendon transcription factors gene, i.e., Scleraxis (Scx), Mohawk (Mkx), Egr1, Six1, and Six2 were all suppressed in G9a-null tenocytes. The tendon-related genes Col1a1, tenomodulin, and periostin were also downregulated. Consistent with this, Western blot analysis showed that tenomodulin protein expression was significantly suppressed by G9a deletion. These results suggested that expression of the H3K9MTase G9a was essential for the differentiation and growth of tenocytes and that H3K9MTases may play important roles in tendinogenesis. PMID- 25812849 TI - Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia. AB - BACKGROUND: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations. OBJECTIVE AND METHOD: In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants. RESULTS: Among the 720 nonsynonymous single nucleotide polymorphisms (SNPs) shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the presenilin 1 (PS1) protein. The presence of this same mutation in a French early-onset Alzheimer's disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity. CONCLUSIONS: Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer's disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia. PMID- 25812850 TI - Cerebrospinal Fluid NrCAM is not a Suitable Biomarker to Discriminate between Dementia Disorders--A Pilot Study. AB - Neuronal Cell Adhesion Molecule (NrCAM) is a proposed new cerebrospinal fluid (CSF) biomarker in Alzheimer's disease (AD). In this pilot study, we aimed to validate and extend previous results and measured NrCAM by ELISA in CSF of patients with AD, frontotemporal dementia, dementia with Lewy bodies, and non demented controls. NrCAM levels were comparable in all groups, but correlated positively with total tau and phosphorylated tau levels. Furthermore, NrCAM had no significant additional diagnostic value when combined with amyloid-beta42, total tau, and phosphorylated tau proteins. Therefore, NrCAM is not a suitable CSF biomarker to differentiate between dementia groups. PMID- 25812851 TI - Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOEE4 Carriers. AB - BACKGROUND: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer's disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. OBJECTIVE: To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. METHOD: Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Abeta42, P-Tau181, and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOEE4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T Tau, and lower CSF Abeta42. RESULTS: No significant main effects of HOMA-IR on P Tau181, T-Tau, or Abeta42 were observed; however, significant interactions were observed between HOMA-IR and APOEE4 on CSF markers related to tau. Among APOEE4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOEE4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Abeta42 levels in CSF. CONCLUSION: IR among asymptomatic APOEE4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life. PMID- 25812854 TI - [Hyperpigmented, asymptomatic, annular plaques with satellite lesions]. PMID- 25812853 TI - Enhanced cancer cell killing of a Pt(IV) prodrug promoted by outer-sphere coordination with polyethyleneimines. AB - The cisplatin prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2)2](2-) (1) forms outer sphere coordination interactions with non-toxic low MW PEI, which results in enhanced cancer cell killing, also achieved using PEI-coated AuNPs. PMID- 25812855 TI - Stable local moments of vacancies, substitutional and hollow site impurities in graphene. AB - The two-sublattice nature of graphene lattice in conjunction with three-fold rotational symmetry, allows for the p-wave hybridization of the impurity state with the Bloch states of carbon atoms. Such an opportunity is not available in normal metals where the wave function is scalar. The p-wave hybridization function V(->k) appears when dealing with vacancies, substitutional adatoms and the hollow site impurities while the s-wave mixing on graphene lattice pertains only to the top site impurities. In this work, we compare the local moment formation in these two cases and find that the local moments formed by p-wave mixing compared to the s-wave one are robust against the changes in the parameters of the model. Furthermore, we investigate the stability of the local moments in the above cases. We find that the quantum fluctuations can destroy the local moments in the case of s-wave hybridization, while the local moments formed by p-wave hybridization survive the quantum fluctuations. Based on these findings, we propose vacancies, substitutional adatoms, and hollow site adatoms as possible candidates to produce stable local moments in graphene. PMID- 25812856 TI - The artfulness of the fake. PMID- 25812857 TI - Tempered pleasure. PMID- 25812852 TI - Calmodulin Binding Proteins and Alzheimer's Disease. AB - The small, calcium-sensor protein, calmodulin, is ubiquitously expressed and central to cell function in all cell types. Here the literature linking calmodulin to Alzheimer's disease is reviewed. Several experimentally-verified calmodulin-binding proteins are involved in the formation of amyloid-beta plaques including amyloid-beta protein precursor, beta-secretase, presenilin-1, and ADAM10. Many others possess potential calmodulin-binding domains that remain to be verified. Three calmodulin binding proteins are associated with the formation of neurofibrillary tangles: two kinases (CaMKII, CDK5) and one protein phosphatase (PP2B or calcineurin). Many of the genes recently identified by genome wide association studies and other studies encode proteins that contain putative calmodulin-binding domains but only a couple (e.g., APOE, BIN1) have been experimentally confirmed as calmodulin binding proteins. At least two receptors involved in calcium metabolism and linked to Alzheimer's disease (mAchR; NMDAR) have also been identified as calmodulin-binding proteins. In addition to this, many proteins that are involved in other cellular events intimately associated with Alzheimer's disease including calcium channel function, cholesterol metabolism, neuroinflammation, endocytosis, cell cycle events, and apoptosis have been tentatively or experimentally verified as calmodulin binding proteins. The use of calmodulin as a potential biomarker and as a therapeutic target is discussed. PMID- 25812858 TI - Dental radiography: use of beading wax. PMID- 25812859 TI - ARF hike: call for resignation. PMID- 25812860 TI - Orthodontics: causes of malocclusion. PMID- 25812861 TI - Orthodontosis and orthodontitis. PMID- 25812862 TI - Periodontology: a vaccine for periodontopathogens. PMID- 25812863 TI - Pharmaceuticals: private prescription. PMID- 25812864 TI - Filling the vacuum. PMID- 25812865 TI - Research: plague preserved in the dental pulp of skeletons. PMID- 25812866 TI - BDA update. PMID- 25812867 TI - The BDJ has a new sister: BDJ Open. PMID- 25812868 TI - Oral health inequalities. PMID- 25812871 TI - Young dentists taught the importance of consent. PMID- 25812870 TI - Online initiative to improve oral health of the elderly. PMID- 25812872 TI - Summer season seminar. PMID- 25812874 TI - Notice to members: burgeoning books. PMID- 25812878 TI - World Oral Health Day. PMID- 25812876 TI - Did you treat these patients? PMID- 25812879 TI - Elaine Halley: 'the future - 3D planning but with the face in motion'. AB - Ahead of her presentation at the 2015 British Dental Conference and Exhibition, the BDJ caught up with Elaine Halley, to find out more about the changing face of cosmetic dentistry, Digital Smile Design and the vision behind her dental spa. PMID- 25812880 TI - The importance of workforce surveillance, research evidence and political advocacy in the context of international migration of dentists. AB - The international migration of dentists is an issue of pressing significance that poses several complex policy challenges. Policy-making is mainly constrained by the lack of workforce surveillance, research evidence and political advocacy - all three are required to work together, yet with different purposes. We first discuss the inconsistencies in migrant dentist surveillance in major country level governmental systems (immigration departments, dentist registration authorities and workforce agencies). We argue that the limitations in surveillance collections affect independent research and in turn scholarly contributions to dental workforce policy. Differences in country-level surveillance collections also hinder valid cross-country comparisons on migrant dentist data, impeding global policy efforts. Due to these limitations, advocacy, or the political process to influence health policy, suffers, but is integral to future challenges on dentist migration. Country-level advocacy is best targeted at improving migrant dentist surveillance systems. Research interest can be invigorated through targeted funding allocations for migration research and by improving the availability of dentist surveillance data for research purposes. At the global level, the WHOs global code of practice for international recruitment of health personnel (a crucial advocacy tool) needs to be strengthened. Global organisations such as the FDI World Dental Federation have an important role to play in advocating for improved migrant dentist workforce surveillance and research evidence, especially in low- and middle-income countries. PMID- 25812882 TI - Corrigendum. PMID- 25812881 TI - Pre- and postoperative management techniques. Part 3: before and after - endodontic surgery. AB - In the last of this series of articles, the author will review some of the current interventions and advice that is most commonly used before and following endodontic surgical procedures. The aim of this article is to review the current evidence in the literature to support or refute current practices, management methods and protocols. The relative strength of the research discussed - including strengths and weaknesses - will be commented on. There are also some medicaments and instructions in dentistry that have no researched basis; some of these will also be identified and discussed. PMID- 25812888 TI - Summary of: is any particular aspect of perceived quality associated with patients tending to promote a dental practice to their friends and colleagues? PMID- 25812883 TI - Restorative dentistry for the older patient cohort. AB - The ageing UK population presents a number of challenges to the restorative dentist as a result of complex treatment needs and a significant maintenance burden. This paper discusses how ageing may influence the provision of dental treatment and outlines a variety of conservative, periodontal, endodontic and prosthodontic considerations that are important in the management of the older patient cohort. PMID- 25812889 TI - Summary of: factors influencing patients' continuing attendance at a given dentist. PMID- 25812890 TI - A study of dental students' clinical knowledge acquisition and experiences in conscious sedation. AB - AIM: To evaluate final year dental students' knowledge acquisition and experiences during their intravenous sedation (IVS) clinical attachment within the sedation department at Newcastle School of Dental Sciences (NSDS). METHODS: Students attending IVS clinical attachments in the period September 2012 - April 2013 completed a novel clinical knowledge test at the beginning and end of their one week attachment; a feedback questionnaire was also completed. RESULTS: A total of 70 students attended the attachment. Clinical knowledge tests were completed by 71.4% (n = 50) of students. The average test result improved from 75.1% in the pre-attachment test to 92.1% in the post-attachment test. Feedback questionnaires were returned by 65.7% (n = 46) of students. All students attained clinical experience of administering sedation and treating sedated patients. 'Teaching and Clinical Support' was rated highest, with 97.8% (n = 45) rating it as excellent. Students commented that hands-on clinical experience and clinical teaching were the most valuable parts of the attachment. Patients failing to attend appointments were considered the least useful part of the attachment. CONCLUSION: This pilot study provides an insight into undergraduate clinical sedation, which is often under reported in the literature. The clinical experience gained at NSDS exceeds GDC recommendations for undergraduate sedation. The clinical knowledge test results suggest that clinical knowledge may be better retained after direct clinical experience. PMID- 25812891 TI - Summary of Royal College of Surgeons' (England) clinical guidelines on management of temporomandibular disorders in primary care. AB - This paper briefly summarises the key points from the Royal College of Surgeons' (England) Faculty of Dental Surgery Clinical Standards Committee's guidance on the management of temporomandibular disorders in primary care. The full guidelines developed by the faculty in conjunction with the UK Specialist Interest Group in Orofacial Pain and Temporomandibular Disorders (USOT) are available at: http://www.rcseng.ac.uk/fds/publications-clinical guidelines/clinical_guidelines. PMID- 25812905 TI - Is any particular aspect of perceived quality associated with patients tending to promote a dental practice to their friends and colleagues? AB - AIMS: To investigate the relationship between perceived quality and patients' tendencies to recommend a practice to friends and colleagues. METHODS: Data from 64 practices using the Denplan Excel Patient Survey (DEPS) were analysed. The Net Promoter Score (NPS max score 100), developed by Reichheld, is reported to each practice using DEPS. It is claimed that the NPS measures the likelihood that patients will recommend the practice to friends and colleagues. A Patient Perception Index (PPI max score 100) is also reported to practices. The PPI is calculated from the responses to the ten core questions of DEPS on perceived quality. The 64 practices were placed into three groups for data analysis according to their NPS result: group one practices receiving an NPS of less than 80, group two practices receiving an NPS of 80-89 and group three practices receiving an NPS of greater than 89. These groups represented practices scoring statistically significantly (to 90% confidence) below the mean NPS (group one), practices close to the mean NPS (group two) and practices statistically significantly (to 90% confidence) above the mean NPS. RESULTS: Group one practices scored a mean PPI of 73, group two scored a mean PPI of 76 and group three a mean PPI of 80. These differences in values of PPI between the groups are statistically significant (to 90% confidence). Of the ten constituent issues which contribute to PPI, the greatest difference in scoring between group one and group three was found to be around perceived value for money. CONCLUSION: The probability of patients recommending a dental practice seems to rise in direct proportion to favourable perceptions of quality. A perception of 'ideal' value for money is the most highly correlated aspect with a high NPS. PMID- 25812906 TI - Factors influencing patients' continuing attendance at a given dentist. AB - AIM: It is the aim of this paper to consider the factors associated with a patient's continuing attendance at a particular dentist's surgery. METHODS: A data set was established consisting of General Dental Services' (GDS) patients whose birthdays were included within a set of randomly selected dates, 20 in each possible year of birth. The data set was restricted to those patients aged 18 or older in 2003 who attended only one dentist in only one postcode area in 2003, and who also attended only one dentist in the same postcode area in 2005, and where the dentist attended in 2003 was also practising in the same postcode area in 2005. The patients were classified by age, gender and charge-paying status, and by whether they had attended a GDS dentist in 2002, and the dentists attended in 2003 were classified by age and gender. The proportion of patients changing dentists between 2003 and 2005 was calculated, together with standard error (se), for each combination of these factors. This was then replicated for each year from 1993-2002. RESULTS: Data for 323,382 patients were included in the analysis for 2003, these patients having not changed address during a two-year period, nor had their dentist changed location. The proportion of patients changing dentist over the period 2003 and 2005 was 15.5% (se 0.06 PCT). This has increased steadily since 1993, when the proportion was 12.4%. CONCLUSIONS: Factors influencing whether a patient changes dentist include patient age and charge paying status, dentist age and gender, and the patient's previous attendance pattern. PMID- 25812908 TI - The Kidney-Gut Axis: Implications for Nutrition Care. AB - There is increasing clinical evidence that patients with chronic kidney disease (CKD) have a distinctly dysbiotic intestinal bacterial community, termed the gut microbiota, which in turn drives a cascade of metabolic abnormalities, including uremic toxin production, inflammation, and immunosuppression, that ultimately promotes progressive kidney failure and cardiovascular disease. As the gut microbiota is intimately influenced by diet, the discovery of the kidney-gut axis has created new therapeutic opportunities for nutritional intervention. This review discusses the metabolic pathways linking dysbiotic gut microbiota with adverse health outcomes in patients with CKD, as well as novel therapeutic strategies for targeting these pathways involving dietary protein, fiber, prebiotics, probiotics, and synbiotics. These emerging nutritional interventions may ultimately lead to a paradigm shift in the conventional focus of dietary management in CKD. PMID- 25812907 TI - Influence of shod/unshod condition and running speed on foot-strike patterns, inversion/eversion, and vertical foot rotation in endurance runners. AB - The aim of this study was to determine the influence of barefoot running on foot strike patterns, eversion-inversion, running speed and vertical foot rotation in endurance runners. Eighty healthy recreational runners (age = 34.11 +/- 12.95 years old, body mass index = 22.56 +/- 2.65 kg . m(-2)) performed trials in shod/unshod running conditions on a treadmill at comfortable and competitive self selected speeds. Data were collected by systematic observation of lateral and back recordings at 240 Hz. McNemar's test indicated significant differences between shod/unshod conditions and foot strike at comfortable and competitive speeds (P < 0.001). Speed was related to vertical foot rotation type for shod (P < 0.01) and unshod conditions (P < 0.05). Significant differences were found between shod/unshod conditions in foot rotation at comfortable running speeds (P < 0.001) and competitive running speeds (P < 0.01). No significant difference was found in inversion or eversion (P >= 0.05). In conclusion, the results suggest that running kinematics, in terms of foot-strike patterns and vertical foot rotation, differ between shod/unshod conditions, while the inversion or eversion degree remains unchanged. PMID- 25812909 TI - Correlation of computed tomography, echo-planar diffusion-weighted magnetic resonance imaging and surgical outcomes in middle ear cholesteatoma. AB - CONCLUSION: Echo-planar diffusion-weighted magnetic resonance imaging (DW MRI) is more reliable than high-resolution computed tomography (HRCT) in predicting the presence and localization of cholesteatoma before tympanomastoid surgery. OBJECTIVES: To evaluate the diagnostic accuracy of HRCT and echo-planar DW MRI in the detection and localization of cholesteatoma. METHODS: Fifty-nine patients were prospectively included in this study. Patients with suspected primary cholesteatoma were evaluated by HRCT and echo-planar DW MRI before tympanomastoid surgery. Radiological findings were correlated with intraoperative findings. RESULTS: HRCT and echo-planar DW MRI accurately predicted the presence or absence of cholesteatoma in 40/59 (67.8%) and 52/59 (88.1%) patients, respectively. The sensitivity, specificity, and positive and negative predictive values of HRCT were 68.97%, 66.67%, 66.67%, and 68.97%, respectively. However, sensitivity, specificity, and positive and negative predictive values of echo-planar DW MRI were 85.71%, 90.32%, 88.89%, and 87.50%, respectively. PMID- 25812910 TI - Effect of Fluoxetine on Periodontal Status in Patients With Depression: A Cross Sectional Observational Study. AB - BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to reduce periodontal disease severity in a rat ligature-induced periodontitis model. The objective of the present study is to investigate the influence of fluoxetine intake on periodontal parameters in patients with periodontitis with clinical depression. METHODS: A sample of 236 patients with chronic periodontitis and clinical depression were assessed for clinical parameters of periodontal disease. Of these, 115 patients were taking fluoxetine (20 mg/day) for >=2 months, and 121 patients were not. Participants taking fluoxetine were further analyzed for correlation between duration of drug intake and periodontal parameters. RESULTS: All periodontal parameters, except plaque index, were significantly lower in participants taking fluoxetine (P <0.01). Partial correlation analysis, adjusted for confounders, revealed a significant and negative correlation between duration of fluoxetine intake and attachment loss (AL) (R(2) = -0.321, P <0.05). Logistic regression analysis revealed that fluoxetine intake was associated with a lower risk of having AL >=3 (odds ratio [OR] = 0.55, 95% confidence interval [CI] = 0.31 to 0.96) and lower odds of increased bleeding on probing (BOP) percentage values (OR = 0.62, 95% CI = 0.34 to 0.97). CONCLUSION: In this observational study, use of fluoxetine was associated with lower BOP percentages and reduced AL. PMID- 25812912 TI - Phylogeny of Rosa sections Chinenses and Synstylae (Rosaceae) based on chloroplast and nuclear markers. AB - Rosa sections Chinenses and Synstylae contain approximately 39 wild species mainly distributed in East Asia and are closely related according to previous studies. But the specific relationships within these two sections were still obscure due to limited sampling, low genetic variation of molecular markers, and complex evolutionary histories. In this study, we used four chloroplast (ndhC trnV, ndhF-rpl32, ndhJ-trnF and psbJ-petA) and two nuclear (ribosomal ITS and GAPDH) markers with an extensive geographic and taxonomic sampling to explore their evolutionary history. Our phylogenetic analyses suggested that Rosa sections Chinenses and Synstylae defined in traditional taxonomic system are not monophyletic and close to sections Caninae and Gallicanae. Additionally, our results showed incongruence between chloroplast and nuclear markers, and the patterns of incongruence might be due to ancient hybridization (genetic introgression). One putative hybrid species and three samples identified as interspecific hybrids are further discussed in terms of topological incongruence, biological characters and distribution patterns. PMID- 25812911 TI - Therapeutic Effects of Melatonin on Alveolar Bone Resorption After Experimental Periodontitis in Rats: A Biochemical and Immunohistochemical Study. AB - BACKGROUND: The present study aims to investigate the effects of systemic melatonin administration on alveolar bone resorption in experimental periodontitis in rats. METHODS: Twenty-four male Sprague-Dawley rats were divided into three groups (control, experimental periodontitis [Ped], and experimental periodontitis treated with melatonin [Mel-Ped]). For periodontitis induction, first molars were ligatured submarginally for 4 weeks. After ligature removal, rats in the Mel-Ped group were treated with a daily single dose of 10 mg/kg body weight melatonin for 15 consecutive days. At the end of the study, intracardiac blood samples and mandible tissues were obtained for histologic, biochemical, and radiographic analysis. Serum markers related to bone turnover, calcium, phosphorus, bone alkaline phosphatase (b-ALP), and terminal C telopeptide of collagen Type I (CTX) were analyzed. Myeloperoxidase levels were determined in gingival tissue homogenates, and receptor activator of nuclear factor-kappa B ligand (RANKL) activation was analyzed in the mandible samples stereologically. Alveolar bone loss was also evaluated radiographically in the mandible samples of each group. RESULTS: Melatonin treatment decreased serum CTX levels and increased b-ALP levels. Serum calcium and phosphorus levels were not statistically different among groups (P >0.05). Alveolar bone resorption and myeloperoxidase activity were statistically higher in the Ped group compared to the Mel-Ped group (P <0.05). Immunohistochemical staining of RANKL and osteoclast activity were significantly lower in the Mel-Ped group compared to the Ped group (P <0.05). CONCLUSION: This study reveals that melatonin treatment significantly inhibits regional alveolar bone resorption and contributes to periodontal healing in an experimental periodontitis rat model. PMID- 25812913 TI - Tunable stress relaxation behavior of an alginate-polyacrylamide hydrogel: comparison with muscle tissue. AB - Factors controlling the time-dependent mechanical properties of interpenetrating network (IPN) hydrogel materials are not well understood. In this study, alginate polyacrylamide IPN were synthesized to mimic the stress relaxation behavior and elastic modulus of porcine muscle tissue. Hydrogel samples were created with single-parameter chemical concentration variations from a baseline formula to establish trends. The concentration of total monomer material had the largest effect on the elastic modulus, while concentration of the acrylamide cross linker, N,N-methylenebis(acrylamide) (MBAA), changed the stress relaxation behavior most effectively. The IPN material was then tuned to mimic the mechanical response of muscle tissue using these trends. Swelling the hydrogel samples to equilibrium resulted in a dramatic decrease in both elastic modulus and stress relaxation behavior. Collectively, the results demonstrate that alginate-polyacrylamide IPN hydrogels can be tuned to closely mimic both the elastic and the viscoelastic behaviors of muscle tissue, although swelling detrimentally affects these desired properties. PMID- 25812916 TI - Nanoporous silicon prepared through air-oxidation demagnesiation of Mg2Si and properties of its lithium ion batteries. AB - Nanoporous silicon has been prepared through the air-oxidation demagnesiation of Mg2Si at 600 degrees C for 10 hours (Mg2Si + O2 -> Si + MgO), followed by HCl washing. Mg2Si was prepared from 200 mesh commercial Si at 500 degrees C for 5 h in an autoclave. The as-prepared Si exhibits a reversible capacity of 1000 mA h g(-1) at 36 A g(-1) and ~1200 mA h g(-1) at 1.8 A g(-1) over 400 cycles. PMID- 25812914 TI - End-targeting proteomics of isolated chromatin segments of a mammalian ribosomal RNA gene promoter. AB - The unbiased identification of proteins associated with specific loci is crucial for understanding chromatin-based processes. The proteomics of isolated chromatin fragment (PICh) method has previously been developed to purify telomeres and identify associated proteins. This approach is based on the affinity capture of endogenous chromatin segments by hybridization with oligonucleotide containing locked nucleic acids. However, PICh is only efficient with highly abundant genomic targets, limiting its applicability. Here we develop an approach for identifying factors bound to the promoter region of the ribosomal RNA genes that we call end-targeting PICh (ePICh). Using ePICh, we could specifically enrich the RNA polymerase I pre-initiation complex, including the selectivity factor 1. The high purity of the ePICh material allowed the identification of ZFP106, a novel factor regulating transcription initiation by targeting RNA polymerase I to the promoter. Our results demonstrate that ePICh can uncover novel proteins controlling endogenous regulatory elements in mammals. PMID- 25812917 TI - Probing single-molecule protein spontaneous folding-unfolding conformational fluctuation dynamics: the multiple-state and multiple-pathway energy landscape. AB - Protein conformational dynamics often plays a critical role in protein functions. We have characterized the spontaneous folding-unfolding conformational fluctuation dynamics of calmodulin (CaM) at thermodynamic equilibrium conditions by using single-molecule fluorescence resonance energy transfer (FRET) spectroscopy. We have identified multiple folding transition pathways and characterized the underlying energy landscape of the single-molecule protein conformational fluctuation trajectories, using a model analysis based on the detailed balance rate process principle. Our results suggest that the folding dynamics of CaM molecules involves a complex multiple-pathway multiple-state energy landscape, rather than an energy landscape of two-state dynamical process. Our probing single-molecule FRET fluctuation experiments demonstrate a new approach of studying spontaneous protein folding-unfolding conformational dynamics at the equilibrium that features recording long time single-molecule conformational fluctuation trajectories. PMID- 25812915 TI - Maturation of the proteasome core particle induces an affinity switch that controls regulatory particle association. AB - Proteasome assembly is a complex process, requiring 66 subunits distributed over several subcomplexes to associate in a coordinated fashion. Ten proteasome specific chaperones have been identified that assist in this process. For two of these, the Pba1-Pba2 dimer, it is well established that they only bind immature core particles (CPs) in vivo. In contrast, the regulatory particle (RP) utilizes the same binding surface but only interacts with the mature CP in vivo. It is unclear how these binding events are regulated. Here, we show that Pba1-Pba2 binds tightly to the immature CP, preventing RP binding. Changes in the CP that occur on maturation significantly reduce its affinity for Pba1-Pba2, enabling the RP to displace the chaperone. Mathematical modelling indicates that this 'affinity switch' mechanism has likely evolved to improve assembly efficiency by preventing the accumulation of stable, non-productive intermediates. Our work thus provides mechanistic insights into a crucial step in proteasome biogenesis. PMID- 25812918 TI - Erratum: Synthesis of large and few atomic layers of hexagonal boron nitride on melted copper. PMID- 25812920 TI - Home Respiratory Therapy: Technological Innovations in Severe Chronic Obstructive Pulmonary Disease. PMID- 25812919 TI - Emulsification and antioxidation of biosurfactant extracts from Chinese medicinal herbs fermentation in vitro. AB - Much attention has been paid to biosurfactants produced using microorganisms, but little direct evidence for the development of natural biosurfactants combined with Chinese medicinal herbs are available. We investigated the emulsification and antioxidation of biosurfactant extracts from Chinese medicinal herb fermentation (BECMHF) in vitro and their application in water retention capacity and the skin prick and allergy test (SPAT) index for skin cells. The results showed that the water retention capacity of BECMHF was positively associated with the emulsification index. The SPAT index of 8 Chinese medicinal herbs was 0 at a 1% or 2% concentration, suggesting no sensitivity or adverse effects on the skin cells. Eight BECMHFs produced using Alcaligenes piechaudii CC-ESB2 exhibited antioxidant capabilities, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and superoxide scavenging activity, and superoxide dismutase (SOD)-like activity at a concentration of 10 mg/ml. The mechanism involved inhibitory effects on nitrite, inducible nitric oxide synthase (iNOS) expression, and reactive oxygen species (ROSs) generation. BECMHFs exhibit favorable antioxidative properties in health food and satisfactory emulsifying and moisturizing characteristics in cosmetic formulations, which have potential applications in the health food and cosmetic industries, respectively. PMID- 25812921 TI - Trametinib in the treatment of melanoma. AB - INTRODUCTION: Aberrant MAPK pathway signaling is a hallmark of melanoma. Mitogen/extracellular signal-regulated kinase (MEK) 1/2 are integral components of MAPK signaling. Several MEK inhibitors have demonstrated activity as single agents and in combination with other therapies. Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAF(V600) mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib. AREAS COVERED: In this article, we discuss the underlying biology of MEK inhibition and its rationale in melanoma treatment with special emphasis on the clinical development of trametinib, from initial Phase I studies to randomized Phase II and III studies, both as monotherapy and in combination with other therapeutics. Furthermore, we briefly comment on trametinib for NRAS mutant and other non-BRAF mutant subsets of melanoma. EXPERT OPINION: Trametinib is a novel oral MEK inhibitor with clinical activity in BRAF(V600) mutant metastatic melanoma alone and in combination with dabrafenib. Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations. Furthermore, to maximize efficacy and overcome acquired resistance, studies evaluating the combination of trametinib with other targeted agents and immunotherapy are underway. PMID- 25812923 TI - Systemic delivery of synthetic microRNA-451 is an effective therapeutic strategy for the treatment of lung cancer. AB - MicroRNAs (miRNAs) can function as tumor suppressors and may provide an efficient strategy for the eradication of cancer. Specific miRNAs can be reintroduced into tumor cells to complement loss of tumor suppression activities. The aim of the present study was to develop miRNA delivery formulation using synthesized miR 451. miR-451 was detected using RT-PCR and tissues were analyzed using immunohistochemical analysis. miRNA delivery formulation proved to be effective either locally or systemically. miR-451 accumulation became evident in tumor cells and exerted an anti-proliferative function. The intravenous delivery of formulated miR-451 did not induce any deregulation in the cytokine levels and liver enzymes. Taken together, the results provide insight into the concept of the systemic delivery of synthetic mimics for tumor suppressor miR-451 and provide potential implications for miRNA therapy in clinical practice. PMID- 25812925 TI - Comparative investigations of the crystal structure and photoluminescence property of eulytite-type Ba3Eu(PO4)3 and Sr3Eu(PO4)3. AB - In this study, the Ba3Eu(PO4)3 and Sr3Eu(PO4)3 compounds were synthesized and the crystal structures were determined for the first time by Rietveld refinement using powder X-ray diffraction (XRD) patterns. Ba3Eu(PO4)3 crystallizes in cubic space group I43d, with cell parameters of a = 10.47996(9) A, V = 1151.01(3) A(3) and Z = 4; Ba(2+) and Eu(3+) occupy the same site with partial occupancies of 3/4 and 1/4, respectively. Besides, in this structure, there exists two distorted kinds of the PO4 polyhedra orientation. Sr3Eu(PO4)3 is isostructural to Ba3Eu(PO4)3 and has much smaller cell parameters of a = 10.1203(2) A, V = 1036.52(5) A(3). The bandgaps of Ba3Eu(PO4)3 and Sr3Eu(PO4)3 are determined to be 4.091 eV and 3.987 eV, respectively, based on the UV-Vis diffuse reflectance spectra. The photoluminescence measurements reveal that, upon 396 nm n-UV light excitation, Ba3Eu(PO4)3 and Sr3Eu(PO4)3 exhibit orange-red emission with two main peaks at 596 nm and prevailing 613 nm, corresponding to the (5)D0 -> (7)F1 and (5)D0 -> (7)F2 transitions of Eu(3+), respectively. The dynamic disordering in the crystal structures contributes to the broadening of the luminescence spectra. The electronic structure of the phosphates was calculated by the first-principles method. The analysis elucidats that the band structures are mainly governed by the orbits of phosphorus, oxygen and europium, and the sharp peaks of the europium f-orbit occur at the top of the valence bands. PMID- 25812924 TI - Subretinal Visual Implant Alpha IMS--Clinical trial interim report. AB - A subretinal visual implant (Alpha IMS, Retina Implant AG, Reutlingen, Germany) was implanted in 29 blind participants with outer retinal degeneration in an international multicenter clinical trial. Primary efficacy endpoints of the study protocol were a significant improvement of activities of daily living and mobility to be assessed by activities of daily living tasks, recognition tasks, mobility, or a combination thereof. Secondary efficacy endpoints were a significant improvement of visual acuity/light perception and/or object recognition (clinicaltrials.gov, NCT01024803). During up to 12 months observation time twenty-one participants (72%) reached the primary endpoints, of which thirteen participants (45%) reported restoration of visual function which they use in daily life. Additionally, detection, localization, and identification of objects were significantly better with the implant power switched on in the first 3 months. Twenty-five participants (86%) reached the secondary endpoints. Measurable grating acuity was up to 3.3 cycles per degree, visual acuities using standardized Landolt C-rings were 20/2000, 20/2000, 20/606 and 20/546. Maximal correct motion perception ranged from 3 to 35 degrees per second. These results show that subretinal implants can restore very-low-vision or low vision in blind (light perception or less) patients with end-stage hereditary retinal degenerations. PMID- 25812927 TI - Potential radiating effects of misusing substances among medical patients receiving brief intervention. AB - BACKGROUND: The societal benefits of substance use interventions are largely driven not by reducing use per se, but by the broader implications of those reductions. This encompasses "potential radiating effects of misusing substances" (PREMiS) such as utilization of high-cost hospital and emergency care, injury, productivity losses, incarceration, and driving while impaired. METHODS: This study is a secondary analysis from a randomized trial comparing in-person vs. computerized brief intervention among 360 adult community health center patients with moderate-risk illicit drug use (N = 302 with complete data through 12 months of follow-up). This study aims to examine four aspects of PREMiS outcomes in this sample: (1) their frequency; and their association with (2) type of brief intervention received (by random assignment), (3) type of drug misused, and (4) baseline drug problem severity (within the moderate risk range). RESULTS: 12 month prevalence was 18.5% for hospitalization (399 cumulative days), 33.1% for emergency department utilization (166 cumulative visits), 39.1% for injury (1818 injury-days), and 8.3% for incarceration (278 days of detention). There were 729 missed work days among those who reported employment. Fifty percent reported driving under the influence (DUI) of substances. There were no differences in PREMiS outcomes by type of brief intervention. Participants with only marijuana misuse at baseline were not at lower risk of experiencing PREMiS events than participants with other drug misuse. Higher baseline drug problem severity was predictive of future hospitalization (p < .05) and number of hospitalization days (p < .01). CONCLUSION: This community health center sample with moderate-risk illicit drug use reported considerable high-cost healthcare utilization, injury, missed work, and DUI. Interventions are needed that can reliably lower risk of negative outcomes among drug users. PMID- 25812929 TI - Physiotherapists may stigmatise or feel unprepared to treat people with low back pain and psychosocial factors that influence recovery: a systematic review. AB - QUESTION: What are physiotherapists' perceptions about identifying and managing the cognitive, psychological and social factors that may act as barriers to recovery for people with low back pain (LBP)? DESIGN: Systematic review and qualitative metasynthesis of qualitative studies in which physiotherapists were questioned, using focus groups or semi-structured interviews, about identifying and managing cognitive, psychological and social factors in people with LBP. PARTICIPANTS: Qualified physiotherapists with experience in treating patients with LBP. OUTCOME MEASURES: Studies were synthesised in narrative format and thematic analysis was used to provide a collective insight into the physiotherapists' perceptions. RESULTS: Three main themes emerged: physiotherapists only partially recognised cognitive, psychological and social factors in LBP, with most discussion around factors such as family, work and unhelpful patient expectations; some physiotherapists stigmatised patients with LBP as demanding, attention-seeking and poorly motivated when they presented with behaviours suggestive of these factors; and physiotherapists questioned the relevance of screening for these factors because they were perceived to extend beyond their scope of practice, with many feeling under-skilled in addressing them. CONCLUSION: Physiotherapists partially recognised cognitive, psychological and social factors in people with LBP. Physiotherapists expressed a preference for dealing with the more mechanical aspects of LBP, and some stigmatised the behaviours suggestive of cognitive, psychological and social contributions to LBP. Physiotherapists perceived that neither their initial training, nor currently available professional development training, instilled them with the requisite skills and confidence to successfully address and treat the multidimensional pain presentations seen in LBP. REGISTRATION: CRD 42014009964. [Synnott A, O'Keeffe M, Bunzli S, Dankaerts W, O'Sullivan P, O'Sullivan K (2015) Physiotherapists may stigmatise or feel unprepared to treat people with low back pain and psychosocial factors that influence recovery: a systematic review.Journal of Physiotherapy61: 68-76]. PMID- 25812930 TI - Biological activities of ophiobolin K and 6-epi-ophiobolin K produced by the endophytic fungus Aspergillus calidoustus. AB - Endophytic fungi represent ubiquitous microbial organisms able to live in the tissues of different plants around the world and represent a prolific source of bioactive metabolites. In the present study, the endophytic fungus Aspergillus calidoustus was isolated from the medicinal plant Acanthospermum australe (Asteraceae), and identified using molecular, physiological and morphological methods. A methylene chloride crude extract of A. calidoustus has been produced and subjected to antifungal bioassay-directed fractionation which resulted in the isolation of the two bioactive compounds: ophiobolin K and 6-epi-ophiobolin K. These pure compounds displayed antifungal activity against fungal plant pathogens, protozoal activity against Trypanosoma cruzi, and cytotoxic activity against human tumoral cell lines. The results show that A. calidoustus was able to produce the antifungal and cytotoxic metabolites ophiobolin K and 6-epi ophiobolin K, which may help the fungus to colonise and occupy the substratum as well as survive in natural environments. PMID- 25812926 TI - Epigenetic modifications and long noncoding RNAs influence pancreas development and function. AB - Insulin-producing beta cells within the pancreatic islet of Langerhans are responsible for maintaining glucose homeostasis; the loss or malfunction of beta cells results in diabetes mellitus. Recent advances in cell purification strategies and sequencing technologies as well as novel molecular tools have revealed that epigenetic modifications and long noncoding RNAs (lncRNAs) represent an integral part of the transcriptional mechanisms regulating pancreas development and beta cell function. Importantly, these findings have uncovered a new layer of gene regulation in the pancreas that can be exploited to enhance the restoration and/or repair of beta cells to treat diabetes. PMID- 25812931 TI - Pulmonary calcifications: a pictorial review and approach to formulating a differential diagnosis. AB - Pulmonary calcifications encompass a wide range of causes, both common and rare, such as calcified pulmonary nodules from chronic fungal infections and pulmonary alveolar microlithiasis. In this pictorial review, we categorize them based on etiology, which includes neoplastic calcifications, nonneoplastic calcified nodules, and iatrogenic- and exposure-related causes of pulmonary calcifications. We also illustrate the most characteristic imaging findings and outline the clinical implications for each of these entities to provide a sensible approach to pulmonary calcifications. PMID- 25812932 TI - Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock. AB - BACKGROUND: Intra-aortic balloon pump counterpulsation (IABP) is currently the most commonly used mechanical assist device for patients with cardiogenic shock due to acute myocardial infarction. Although there has been only limited evidence from randomised controlled trials, the previous guidelines of the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) strongly recommended the use of the IABP in patients with infarction-related cardiogenic shock on the basis of pathophysiological considerations, non-randomised trials and registry data. The recent guidelines downgraded the recommendation based on a meta-analysis which could only include non-randomised trials showing conflicting results. Up to now, there have been no guideline recommendations and no actual meta-analysis including the results of the large randomised multicentre IABP-SHOCK II Trial which showed no survival benefit with IABP support. This systematic review is an update of the review published in 2011. OBJECTIVES: To evaluate, in terms of efficacy and safety, the effect of IABP versus non-IABP or other assist devices guideline compliant standard therapy on mortality and morbidity in patients with acute myocardial infarction complicated by cardiogenic shock. SEARCH METHODS: Searches of CENTRAL, MEDLINE (Ovid) and EMBASE (Ovid), LILACS, IndMed and KoreaMed, registers of ongoing trials and proceedings of conferences were updated in October 2013. Reference lists were scanned and experts in the field contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials on patients with acute myocardial infarction complicated by cardiogenic shock. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the published protocol. Individual patient data were provided for six trials and merged with aggregate data. Summary statistics for the primary endpoints were hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS: Seven eligible studies were identified from a total of 2314 references. One new study with 600 patients was added to the original review. Four trials compared IABP to standard treatment and three to other percutaneous left assist devices (LVAD). Data from a total of 790 patients with acute myocardial infarction and cardiogenic shock were included in the updated meta-analysis: 406 patients were treated with IABP and 384 patients served as controls; 339 patients were treated without assisting devices and 45 patients with other LVAD. The HR for all-cause 30-day mortality of 0.95 (95% CI 0.76 to 1.19) provided no evidence for a survival benefit. Different non fatal cardiovascular events were reported in five trials. During hospitalisation, 11 and 4 out of 364 patients from the intervention groups suffered from reinfarction or stroke, respectively. Altogether 5 out of 363 patients from the control group suffered from reinfarction or stroke. Reocclusion was treated with subsequent re-revascularization in 6 out of 352 patients from the intervention group and 13 out of 353 patients of the control group. The high incidence of complications such as moderate and severe bleeding or infection in the control groups has to be attributed to interventions with other LVAD. Possible reasons for bias were more frequent in small studies with high cross-over rates, early stopping and the inclusion of patients with IABP at randomisation. AUTHORS' CONCLUSIONS: Available evidence suggests that IABP may have a beneficial effect on some haemodynamic parameters. However, this did not result in survival benefits so there is no convincing randomised data to support the use of IABP in infarct-related cardiogenic shock. PMID- 25812933 TI - Taste, olfactory, and food reward value processing in the brain. AB - Complementary neuronal recordings in primates, and functional neuroimaging in humans, show that the primary taste cortex in the anterior insula provides separate and combined representations of the taste, temperature, and texture (including fat texture) of food in the mouth independently of hunger and thus of reward value and pleasantness. One synapse on, in a second tier of processing, in the orbitofrontal cortex, these sensory inputs are for some neurons combined by associative learning with olfactory and visual inputs, and these neurons encode food reward value on a continuous scale in that they only respond to food when hungry, and in that activations correlate linearly with subjective pleasantness. Cognitive factors, including word-level descriptions, and selective attention to affective value, modulate the representation of the reward value of taste and olfactory stimuli in the orbitofrontal cortex and a region to which it projects, the anterior cingulate cortex, a tertiary taste cortical area. The food reward representations formed in this way play an important role in the control of appetite, and food intake. Individual differences in these reward representations may contribute to obesity, and there are age-related differences in these value representations that shape the foods that people in different age groups find palatable. In a third tier of processing in medial prefrontal cortex area 10, decisions between stimuli of different reward value are taken, by attractor decision-making networks. PMID- 25812934 TI - Establishment of an expression platform of OATP1B1 388GG and 521CC genetic polymorphism and the therapeutic effect of tamoxifen in MCF-7 cells. AB - The present study was designed to evaluate the gene polymorphisms of organic anion transporting polypeptide 1B1 (OATP1B1) in predicting the therapeutic efficacy of tamoxifen (TAM) for MCF-7. Established plasmids OATP1Bl wild-type 388GG and 521CC were transfected into MCF-7 cells and used to determine whether the gene polymorphisms affected the therapeutic efficacy of TAM for MCF-7. The established plasmids pcDNA3.1(-)-OATP1B1 wild-type 388GG and 521CC were digested by restriction enzymes and analyzed by gene sequencing. The gene polymorphisms of OATP1Bl in MCF-7 breast cancer cells were examined by RT-PCR and western blot analysis. The results showed that the mutations of OATP1B1 388GG and 521CC led to a decrease of the inhibition and apoptotic rates of MCF-7 cells, albeit not significantly compared to the OATP1B1 group. The G0/G1 phase length ratio was reduced, and the S and G2M phases were increased in the OATP1B1 388GG and 521CC groups, although not significantly compared to the OATP1B1 group. The mutations of OATP1B1 388GG and 521CC inhibited the activity of OATP1B1 protein, restrained the turnover capacity of OATP1B1 and reduced the entrance of TAM into MCF-7 cells, resulting in weakened efficacy of TAM in the treatment of breast cancer. PMID- 25812935 TI - Review-of-systems questionnaire as a predictive tool for psychogenic nonepileptic seizures. AB - Patients with refractory epilepsy undergo video-electroencephalography for seizure characterization, among whom approximately 10-30% will be discharged with the diagnosis of psychogenic nonepileptic seizures (PNESs). Clinical PNES predictors have been described but in general are not sensitive or specific. We evaluated whether multiple complaints in a routine review-of-system (ROS) questionnaire could serve as a sensitive and specific marker of PNESs. We performed a retrospective analysis of a standardized ROS questionnaire completed by patients with definite PNESs and epileptic seizures (ESs) diagnosed in our adult epilepsy monitoring unit. A multivariate analysis of covariance (MANCOVA) was used to determine whether groups with PNES and ES differed with respect to the percentage of complaints in the ROS questionnaire. Tenfold cross-validation was used to evaluate the predictive error of a logistic regression classifier for PNES status based on the percentage of positive complaints in the ROS questionnaire. A total of 44 patients were included for analysis. Patients with PNESs had a significantly higher number of complaints in the ROS questionnaire compared to patients with epilepsy. A threshold of 17% positive complaints achieved a 78% specificity and 85% sensitivity for discriminating between PNESs and ESs. We conclude that the routine ROS questionnaire may be a sensitive and specific predictive tool for discriminating between PNESs and ESs. PMID- 25812936 TI - Structural MRI biomarkers of shared pathogenesis in autism spectrum disorder and epilepsy. AB - Etiological factors that contribute to a high comorbidity between autism spectrum disorder (ASD) and epilepsy are the subject of much debate. Does epilepsy cause ASD or are there common underlying brain abnormalities that increase the risk of developing both disorders? This review summarizes evidence from quantitative MRI studies to suggest that abnormalities of brain structure are not necessarily the consequence of ASD and epilepsy but are antecedent to disease expression. Abnormal gray and white matter volumes are present prior to onset of ASD and evident at the time of onset in pediatric epilepsy. Aberrant brain growth trajectories are also common in both disorders, as evidenced by blunted gray matter maturation and white matter maturation. Although the etiological factors that explain these abnormalities are unclear, high heritability estimates for gray matter volume and white matter microstructure demonstrate that genetic factors assert a strong influence on brain structure. In addition, histopathological studies of ASD and epilepsy brain tissue reveal elevated rates of malformations of cortical development (MCDs), such as focal cortical dysplasia and heterotopias, which supports disruption of neuronal migration as a contributing factor. Although MCDs are not always visible on MRI with conventional radiological analysis, quantitative MRI detection methods show high sensitivity to subtle malformations in epilepsy and can be potentially applied to MCD detection in ASD. Such an approach is critical for establishing quantitative neuroanatomic endophenotypes that can be used in genetic research. In the context of emerging drug treatments for seizures and autism symptoms, such as rapamycin and rapalogs, in vivo neuroimaging markers of subtle structural brain abnormalities could improve sample stratification in human clinical trials and potentially extend the range of patients that might benefit from treatment. This article is part of a Special Issue entitled "Autism and Epilepsy". PMID- 25812938 TI - Using photoplethysmography in heart rate monitoring of patients with epilepsy. AB - Heart rate is a useful neurophysiological sign when monitoring seizures in patients with epilepsy. In an ambulatory setting, heart rate is measured with ECG involving electrodes on the skin. This method is uncomfortable which is burdensome for patients and is sensitive to motion artifacts, which decrease the usability of measurements. In this study, green light photoplethysmography, an optical technique arising from the fitness industry, was evaluated for usefulness in a medical setting. Simultaneous overnight measurements of HR with a commercially available optical heart rate (OHR) sensor and with ECG (HRECG) were performed in 7 patients with epilepsy. Overall, there was no significant difference between OHR and HRECG in random 10-minute periods during wakefulness (p=0.69) and sleep (p=1.00). The Bland-Altman analysis showed negligible mean differences. Limits of agreement were higher during wakefulness and during the occurrence of two seizures possibly because of less reliable HRECG measurements due to motion artifacts. Optical heart rate seems less sensitive to these motion artifacts, and measurements are more user-friendly. The optical heart rate sensor may fill the gap of systems for ambulatory heart rate monitoring and can be especially useful in the context of seizure detection in patients with epilepsy. PMID- 25812937 TI - Survey of risk factors for osteoporosis and osteoprotective behaviors among patients with epilepsy. AB - The prevalence of risk factors for osteoporosis in persons with epilepsy, patients' awareness of their risk, and their engagement in osteoprotective behaviors were assessed in this study. Two hundred and sixty patients with epilepsy (F=51.5%, average age=42) completed a survey tool. Of 106 patients with a dual energy X-ray absorptiometry (DXA) result, 52% had low bone mineral density, and 11% had osteoporosis. The results suggest that the majority of patients with epilepsy do not engage in bone-protective behaviors. Those who have undergone a DXA scan may be more likely to take calcium and vitamin D supplementation compared with those who did not undergo a DXA scan, but they do not engage in other osteoprotective behaviors. Many patients did not accurately report their DXA results, indicating that better patient education is warranted. PMID- 25812939 TI - Interprofessional simulation to improve safety in the epilepsy monitoring unit. AB - OBJECTIVE: Patient safety is critical for epilepsy monitoring units (EMUs). Effective training is important for educating all personnel, including residents and nurses who frequently cover these units. We performed a needs assessment and developed a simulation-based team training curriculum employing actual EMU sentinel events to train neurology resident-nurse interprofessional teams to maximize effective responses to high-acuity events. METHODS: A mixed-methods design was used. This included the development of a safe-practice checklist to assess team response to acute events in the EMU using expert review with consensus (a modified Delphi process). All nineteen incoming first-year neurology residents and 2 nurses completed a questionnaire assessing baseline knowledge and attitudes regarding seizure management prior to and following a team training program employing simulation and postscenario debriefing. Four resident-nurse teams were recorded while participating in two simulated scenarios. Employing retrospective video review, four trained raters used the newly developed safe practice checklist to assess team performance. We calculated the interobserver reliability of the checklist for consistency among the raters. We attempted to ascertain whether the training led to improvement in performance in the actual EMU by comparing 10 videos of resident-nurse team responses to seizures 4-8months into the academic year preceding the curricular training to 10 that included those who received the training within 4-8months of the captured video. RESULTS: Knowledge in seizure management was significantly improved following the program, but confidence in seizure management was not. Interrater agreement was moderate to high for consistency of raters for the majority of individual checklist items. We were unable to demonstrate that the training led to sustainable improvement in performance in the actual EMU by the method we used. CONCLUSIONS: A simulated team training curriculum using a safe-practice checklist to improve the management of acute events in an EMU may be an effective method of training neurology residents. However, translating the results into sustainable benefits and confidence in management in the EMU requires further study. PMID- 25812940 TI - An abnormal GABAergic system in the inferior colliculus provides a basis for audiogenic seizures in genetically epilepsy-prone rats. AB - In this review of neuroanatomical studies of the genetically epilepsy-prone rat (GEPR), three main topics will be covered. First, the number of GABAergic neurons and total neurons in the inferior colliculus of GEPRs will be compared to those of the nonepileptic Sprague-Dawley rat. Next, the number of small neurons in the inferior colliculus will be described in both developmental and genetic analyses of GEPRs and their backcrosses. Last, results from two types of studies on the propagation pathways for audiogenic seizures in GEPRs will be shown. Together, these studies demonstrate a unique GABAergic, small neuron defect in the inferior colliculus of GEPRs that may play a vital role in the initiation and spread of seizure activity during audiogenic seizures. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 25812941 TI - Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification. AB - OBJECTIVE: Focal cortical dysplasias (FCDs) represent a common architectural cortical disorder underlying pharmacoresistant focal epilepsy. The recent ILAE classification defines different types of FCDs based on their histopathological features, MRI imaging, and presumed pathogenesis; however, their clinical features and their prognostic significance are still incompletely defined. In addition, the combination of different histopathological abnormalities can represent "unusual" subtypes that can be difficult to classify. The aim of our study was to analyze the incidence and the significance of these "unusual" subtypes of FCDs in drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: We retrospectively analyzed 133 patients consecutively submitted to tailored anteromesial temporal lobe resection for pharmacoresistant MTLE. Seizure onset, seizure duration, age at surgery, and postoperative seizure outcome were evaluated in relation to the different neuropathological groups defined according to the new ILAE classification. RESULTS: Focal cortical dysplasias were found in 80 out of 133 patients. Six patients were affected by isolated FCD type I, 12 patients by FCD type II, and 44 patients by FCD type III. Furthermore, we found 18 "atypical" cases (20.5% of all FCD cases and 26.6% of FCDs associated with a principal lesion): 10 cases of associated FCD type II-hippocampal sclerosis (HS) and 8 cases associated with FCD II-epilepsy-associated tumors (EATs). CONCLUSION: Our results indicate that "unusual" subtypes of FCDs, in particular associated FCD type II, are not uncommon findings, suggesting that they deserve a classification recognition. Similarities in seizure outcome and immunohistochemical and molecular evidences, shared by FCD type II+EATs and EATs, suggest a common pathogenic link. The choice to create a specific unifying class or, on the contrary, to also include "associated FCD type II" in the definition of the new unifying class FCD type III should be further discussed. PMID- 25812942 TI - Diagnostic assessment and case formulation in psychogenic nonepileptic seizures: A pilot comparison of approaches. AB - Management of psychogenic nonepileptic seizures (PNES) is complex, requiring multidisciplinary care. A standardized assessment approach to PNES is lacking, yet use of a comprehensive model may alleviate problems such as mental health aftercare noncompliance. Although a biopsychosocial (BPS) approach to PNES balancing predisposing, precipitating, and perpetuating (PPP) variables has been described, it is unclear how this formulation style is perceived amongst clinicians. We predicted preference of a comprehensive, "BPS/PPP" assessment style by those most involved in PNES diagnosis and care (i.e., neurologists and psychologists). Sixty epileptologists, psychiatrists, and psychologists completed a survey featuring a fictional PNES case followed by assessment style options ("Multiaxial," "Narrative," and "BPS/PPP"). Epileptologists and psychologists ("nonpsychiatrists") differed from psychiatrists in PNES case formulation choice, with nonpsychiatrists preferring the robust BPS/PPP approach and with psychiatrists opting for less comprehensive Multiaxial and Narrative assessments (p=0.0009). Reasons for choosing the BPS/PPP by nonpsychiatrists included ease of organization, clear therapeutic goals, and comprehensive nature. Alternatively, psychiatrists cited time constraints and familiarity as reasons to prefer briefer Multiaxial or Narrative approaches. This pilot assessment of acceptability of a BPS/PPP approach to PNES case formulation, thus, reveals important gaps in formulation priorities between neurologists and psychiatrists. Implications and future directions are explored. PMID- 25812943 TI - A new fluorescent chemosensor for Pb2+ ions based on naphthalene derivatives. AB - A new naphthalene derivative receptor (L) was synthesized and characterized with common spectroscopic methods. L exhibited a strong fluorescence enhancement in the presence of trace amounts of Pb(2+), attributable to photoinduced electron transfer (PET) effect, which also displayed high selectivity over a series of other metal cations (Na(+), K(+), Cs(+), Mg(2+), Ba(2+), Cr(3+), Mn(2+), Fe(3+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Ag(+)) in acetonitrile/H2O (9:1, v/v) mixture. PMID- 25812944 TI - The electronic donation and frequency shifts on the YCCH?BH4- boron-bonded complexes (Y=H, CH3, CF3 and CCl3). AB - In this theoretical work, the tetrahydroborate ion (BH4(-)) was used as proton acceptor in the formation of the YCC-H?BH4(-) complexes (Y=H, CH3, CCl3 and CF3). Using B3LYP/6-311++G(d,p) level of theory, the results of structure corroborate with the analyses of infrared spectra showing that the changes in the bond lengths are in good agreement with the frequency shifts of the HCC-H, H3CCC-H, Cl3CCC-H and F3CCC-H proton donors. Based on the calculations carried out by the Quantum Theory of Atoms in Molecules (QTAIM), the reductions of electronic density corroborate with the red shifts in the frequencies of the C-H bonds. In addition to that, the C-H bonds are polarized because the contributions of s orbital diminish whereas of p increase. In line with this, the variations on the atomic radii computed via QTAIM calculations show that carbon outweigh hydrogen as follows (DeltarC>DeltarH). This scenario is indirectly supported by the Bent's rule of the chemical bonding. Although the interaction energies (corrected with BSSE and ZPE) vary between -19 and -67 kJ mol(-1), these complexes interact without covalent character. PMID- 25812945 TI - Altered resting-state cerebral blood flow and its connectivity in schizophrenia. AB - Small sample sizes and large inter-subject variations result in inconsistent findings in resting-state cerebral blood flow (CBF) in schizophrenia. The CBF connectivity alterations in schizophrenia remain unclear. Recently, three dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 100 schizophrenia patients and 94 healthy comparison subjects. The normalized CBF was used to reduce the inter subject variations. Both group comparisons in the CBF and correlations between the CBF alterations and clinical parameters were assessed. The CBF connectivity of the brain regions with regional CBF differences was also compared between the groups. Compared with the healthy controls, the schizophrenia patients exhibited increased CBF in the bilateral inferior temporal gyri, thalami and putamen and decreased CBF in the left insula and middle frontal gyrus and the bilateral anterior cingulate cortices and middle occipital gyri. In the schizophrenia patients, significant correlations were identified between the CBF and clinical parameters. Importantly, the schizophrenia patients exhibited CBF disconnections between the left thalamus and right medial superior frontal gyrus and between the left insula and left postcentral gyrus. Our results suggest that schizophrenia patients may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of schizophrenia. PMID- 25812947 TI - CT guided method for access to extremely difficult disc spaces without bony penetration or local anesthesia deeper than skin. AB - Gaining needle access to the intervertebral discs for discography has been performed with fluoroscopic guidance but can be challenging when sedation cannot be used. Avoidance of the exiting L5 nerve roots is particularly challenging when the disc space is severely narrowed with overhanging endplates or osteophytes. We describe our experience on 28 discs in 10 consecutive patients referred for presurgical evaluation using low-dose computed tomography oblique axial and sagittal reformats aligned to the needle for guidance into the disc. PMID- 25812946 TI - Perinatal exposure to low-dose of bisphenol A causes anxiety-like alteration in adrenal axis regulation and behaviors of rat offspring: a potential role for metabotropic glutamate 2/3 receptors. AB - AIMS: The present study focuses on detecting anxiety-like behavior and associated neurochemical alterations in adolescent rats exposed perinatally to bisphenol A (BPA), an estrogen-mimicking endocrine disrupter and investigating the possible involvement of metabotropic glutamate 2/3 receptors (mGlu2/3 receptors) in BPA induced anxiogenic effects. METHODS AND RESULTS: When female breeders were administered orally with BPA (40 MUg/kg/d) during pregnancy and lactation, their pups (here named 'BPA-exposed offspring') developed an anxiety-like phenotype, characterized by the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, impaired glucocorticoid receptor (GR)-mediated negative feedback regulation of the HPA axis, altered hippocampal synaptic plasticity and increased anxiety like behaviors. BPA-exposed offspring also showed a reduced expression of mGlu2/3 receptors in the hippocampus. BPA-exposed offspring further subjected to systemic administration of mGlu2/3 receptor agonist (LY379268, 0.5 mg/kg, i.p.) or antagonist (LY341495, 1.5 mg/kg, i.p.) twice per day for 6 days. The results indicated that chronic LY379268 treatment corrected the anxiety-like behaviors and associated neurochemical and endocrinological alterations in BPA-exposed offspring. CONCLUSION: Our data demonstrate for the first time that the perinatal BPA exposure induces an anxiety-like phenotype in behaviors and -related neuroendocrinology, and suggest that the changes in mGlu2/3 receptor might lie at the core of the pathological reprogramming triggered by early-life adversity. mGlu2/3 receptor may serve as a novel biomarker and potential therapeutic target for anxiety disorders associated with adverse early-life agents including perinatal BPA exposure. PMID- 25812948 TI - Congenital coronary anomaly, a silent enemy of exercise. PMID- 25812949 TI - Annular elastolytic giant cell granuloma. PMID- 25812951 TI - Twenty years of the korean journal of medical education: past, present, and future. PMID- 25812950 TI - Genetic analysis of circulating tumor cells in pancreatic cancer patients: A pilot study. AB - Pancreatic cancer is one of the most aggressive malignant tumors, mainly due to an aggressive metastasis spreading. In recent years, circulating tumor cells became associated to tumor metastasis. Little is known about their expression profiles. The aim of this study was to develop a complete workflow making it possible to isolate circulating tumor cells from patients with pancreatic cancer and their genetic characterization. RESULTS: We show that the proposed workflow offers a technical sensitivity and specificity high enough to detect and isolate single tumor cells. Moreover our approach makes feasible to genetically characterize single CTCs. CONCLUSIONS: Our work discloses a complete workflow to detect, count and genetically analyze individual CTCs isolated from blood samples. This method has a central impact on the early detection of metastasis development. The combination of cell quantification and genetic analysis provides the clinicians with a powerful tool not available so far. PMID- 25812952 TI - Communication skills improvement of medial students according to length and methods of preclinical training. AB - PURPOSE: The purpose of this study is to evaluate the changing pattern of communication skills of medical students according to length and methods of training. METHODS: We evaluated a 1-week communications training course in 2003, a 1-year course in 2004, and a 1-semester course in 2005 during development of our curriculum. We have conducted the 10-minute CPX on abdominal pain annually since 2002 to assess the clinical performance of medical students who have completed the 3rd year clerkship. We selected CPX videos that were appropriate for assessment. One hundred sixty-four videos were available (1-week didactics: 42 cases, 1-week training: 28 cases, 1-semester training: 50 cases, 1-year training: 44 cases). We developed a 10-item global rating checklist to assess communication skills. A 5-point Likert scale was used to evaluate each item (4 very likely, 0-least likely). Two expert standardized patient (SP) raters evaluated the communication skills of students independently. We analyzed the outcomes based on the training length and methods. The reliability (G coefficient) was 0.825 with 2 SPs and 1 station. RESULTS: The communication skills of students improved with practice and longer training, especially with regard to opening the interview, expressing empathy, understanding the patient's perspective, and preparing for the physical examination. Rapport-building, organization of the interview, understandable explanation, nonverbal communication, active listening and consideration during the physical examination was unchanged between durations of training. The scores for empathetic expression, active listening and understanding the patient's perspective were low across all groups. CONCLUSION: We should concentrate our efforts to improve students' skills in empathetic expression, active listening and understanding the patient's perspective. PMID- 25812953 TI - The Relationship between Senior Year Examinations at a Medical School and the Korean Medical Licensing Examination. AB - PURPOSE: Most medical schools prepare for the Korean medical licensing examination (KMLE) with various tests. By assessing the degree to which these exams and the KMLE are related, students, professors, and institutions can be well prepared and some schools use these exams as predictive tools for KMLE scores. Therefore, we determined the relevance of KMLE results to midterm exams and the objective structured clinical examination (OSCE), administered to senior students at a medical school. METHODS: From 2002 to 2004, KMLE results were compared with midterm examinations, the KMLE, and the OSCE. The total score, or T score, of the KMLE was used, as was a pass or nonpass score. Windows SPSS 14.0 and MedCalc 9.0 were used for statistical analysis. RESULTS: The yearly correlation coefficient of the KMLE and school exams was highest for the midterm exams in 2002 and the KMLE in 2003 and 2004. The correlation coefficient of midterm exams and the KMLE were related to a high degree, yet the values were as low as that of the OSCE. Compared with the KMLE results, the sensitivity and specificity of the average midterm exam were 100.0% and 93.8%, and the sensitivity and specificity of the average trial exams were 100.0% and 95.8%, respectively. CONCLUSION: In conclusion, the KMLE results have a strong relationship with midterm exams, trial exams, and the combination of midterm and trial exams, but not with the OSCE. Thus, we believe that using both midterm exams and trial exams to predict KMLE results is superior to the use of only one type of school exam. PMID- 25812954 TI - Experience of implementation of objective structured oral examination for ethical competence assessment. AB - PURPOSE: We developed an objective structured oral examination (OSOE) case to assess the medical ethics of students. The aim of this study was to assess the reliability of OSOE with generalizability theory. METHODS: One 10-minute OSOE that contained key questions was developed. The evaluation sheet consisted of 4 domains: moral sensitivity, moral reasoning, decision making, and attitude. The total number of items was 13. The numbers of checklist items and global rating items were 11 and 2, respectively. Items and key questions were validated by 6 professionals. Standardization of the raters and the pilot study was performed before the OSOE. Fifty-four third-year medical students participated in the OSOE. The OSOE was duplicated, and 2 professors assessed 1 student independently. Each station lasted 8 minutes and was followed by a 2-minute interval,during which raters completed the checklist forms. We analyzed the reliability of the OSOE with the GENOVA program. RESULTS: The reliability (generalizability coefficient) was 0.945, and the interrater agreement was 0.867. The type of item, checklist or global rating, was the largest variance component. The reliability of the checklist alone was 0.668 and that of the global rating alone was 0.363. CONCLUSION: The OSOE is reliable and can be used to assess ethics. More research should focus on achieving validity. PMID- 25812955 TI - Trends of communication skills education in medical schools. AB - PURPOSE: To investigate the past and current status of teaching communication skills in undergraduate medical education and to review how medical education is progressing. METHODS: A selective search was conducted of the literature that was published from 1960 to Jun 2008 in the MEDLINE, EMBASE, ERIC, Psychlnfo, and KMbase databases using "communication." All articles in 13 medical journals (including Academic Medicine, Medical Education, Teaching and Learning in Medicine, Medical Teacher, and Korean Journal of Medical Education) were reviewed. Each article was categorized according to 5 subjects (curriculum, methods, assessment, student factors, and research type). RESULTS: A total of 306 studies met the inclusion criteria for this study. Curriculum was the most frequent subject (n=85), followed by assessment (n=71), student factors (n=48), and methods (n=23). According to this research, the current trends of teaching communication skills in medical school are characterized by curriculum development,' 'blended-methods,' 'multisource assessment,' 'student attitudes,' and 'comparative studies' of education. CONCLUSION: It is time to figure it out optimistic ways to design a formal course. Now, 4 current trends in teaching and learning are emerging in communication skills. Curriculum development is stabilizing a variety of teaching methods are being adopted; a method of multisource assessment is being identified and the need to consider student attitudesis being recognized. In the near future, objective, comprehensive, and sophisticated evaluation is going to be the top priority in teaching communication skills with a variety of research types. PMID- 25812956 TI - Correlations of clinical assessment tools with written examinations. AB - PURPOSE: Despite the goal of medical education, which is 'training to be a primary care physician,' only written examinations (WEs) generally have been used to assess medical student ability. We assessed clinical competence using the CPX (clinical performance examination), PA (portfolio assessment), VMA (video monitoring assessment), CGD (case group discussion), and PCP (primary clinical practice) during students' clerkships in family medicine and correlated these clinical assessment tools with WEs. Also, we correlated these tools with each other to determine the feasibility of each as a replacement of the other tools. METHODS: Thirty-nine fourth year students at University of Ulsan College of Medicine took part in their clerkship in family medicine for 2 weeks during the first session of 2005. They took 1 CPX, 2 VMAs, 6 CGDs, and 2 PCPs and were required to submit their portfolios at the end of the clerkship. We evaluated the correlations of these tools and WEs by the overall scores of each class year and in each subject. RESULTS: The CPX, VMA, and PCP showed no significant correlation,while PA showed strong correlation with 4th year students' overall WEs. The CGD showed strong correlation with all overall scores and with almost all subjects. In addition, the PA correlated significantly with CGD. CONCLUSION: New clinical assessment tools, such as CPX, PA, and VMA, have no significant correlation with WE, even though these tools closely correspond with real clinical practice. Therefore, these tools should be considered as complementary instruments to better assess clinical competence. PMID- 25812957 TI - The Power of the Quiz: The Experience of a Medical English Class using Moodle. AB - PURPOSE: The purpose of this research is to evaluate whether quizzes using moodle are useful for academic achievement in a medical English class and to introduce moodle to educators based on the author's teaching experience. METHODS: After a final examination in a medical English class, the author surveyed (scale of 1 low to 5 high) the degree of satisfaction of students and the usefulness of quizzes provided on the author's homepage using moodle. Students had been recommended to solve the quizzes on the homepage voluntarily. The author analyzed statistical differences of the final examination scores between the students who completed the quizzes and those who did not. RESULTS: A total of 59 students completed the survey (collection rate=81.9%). On the question of satisfaction about the medical English class and the question of usefulness of quizzes, scores of mean, maximum, and minimum were 4.29 (SD=0.56), 5, and 3, and 4.03 (SD=0.72), 5, and 2, respectively. Statistically significant differences in the final examination scores were observed between the students who completed quizzes and those who did not. CONCLUSION: A tool for students' self-directed study is needed for improving academic achievement. In particular, various educational programs and environments provided by moodle are thought to be very useful. The quizzes the author made with moodle were very effective in the aspect of achievement. PMID- 25812958 TI - Correlation of academic achievements with cognitive admission variables and demographics at chungbuk national university graduate medical school. AB - PURPOSE: This study was performed to identify academic and nonacademic predictors of the success of entrants to Chungbuk National University Graduate Medical School (CNUMS) during the first 3 years of completion. METHODS: We analyzed the academic achievements in preclinical education in the first 2 years in students who were admitted in 2005 and 2006 and compared them with cognitive admission variables and demographic characteristics. RESULTS: There was no significant difference in academic achievement between students groups that were classified by gender, age, or academic degree type. Among Medical Education Eligibility Test (MEET) subscale scores, Verbal Reasoning was correlated with 'Medical humanities & social sciences' and 'Basic clinical procedures;' Nature Science Reasoning 1 with 'Basic medical sciences;' and Nature Science Reasoning 2 with 'Basic medical sciences' and 'Clinical medicine.' Undergraduate GPA correlated well with all academic achievements. English test scores did not correlate with academic performance. CONCLUSION: Among all of the variables that were examined, undergraduate GPA score was the most reliable variable in predicting academic achievement during the 2-year preclinical medical education, and MEET scores were a secondary indicator of academic achievement at CNUMS. PMID- 25812959 TI - Students' Response to the Questionnaire about the Usefulness of Concept Maps for Problem-Based Learning and the Forms of Concept Maps. AB - PURPOSE: Concept maps have been studied and used in diverse ways in scientific fields. This study aimed to investigate the usefulness and limitations of using concept maps during problem-based learning (PBL) in Year 3 medical students. METHODS: After each PBL module, we gathered concept maps from each pair of students and questionnaires about the usefulness and limitations of concept maps, and analyzed them. RESULTS: There were two types of concept maps, with some modifications. The students felt that concept maps provided overall understanding, analysis, and reorganization of problem cases. But, they also criticized shortage of disciplines related to drawing skills and rationales for each type of map. A strong need for expert maps and feedback for students resulted. CONCLUSION: For optimal use of concept maps, we recommend that the committee implements a plan to teach drawing skills, explains rationales for each type of map, and gives feedback to students. PMID- 25812961 TI - The Instructional-design According to Different Types of Tasks. PMID- 25812960 TI - Checklist for organizing performance exam. PMID- 25812962 TI - Teaching medical students in primary and secondary care: a resource book (sarah hartley, deborah gill, frances cater). PMID- 25812963 TI - Mistyped pISSN and eISSN. AB - The pISSN of the Korean Journal of Medical Education had been mistyped from Volume 9 Number 1, 1997 to Volume 20 Number 3, 2008 as 1227-8067. It should be 1225-8067. Also the eISSN of the Korean Journal of Medical Education was mistyped in the issue of Volume 20 Number 3, 2008 as 1562-6865. It should be 2005-2367. Those mistypings were corrected in the recent issue, Volume 20 Number 4, 2008. The pISSN had been correctly typed from the first issue, Volume 1, 1989 to the last issues of Volume 8, 1996. The Korean Journal of Medical Education apologizes to the readers and librarians for this fatal mistake of the bibliographic information. From the first issue of Volume 21, new ISSNs are provided since there was a journal title change from Korean (Han guk uihak kyoyuk) to English (Korean Journal of Medical Education). PMID- 25812964 TI - Slug mediates nasopharyngeal carcinoma radioresistance via downregulation of PUMA in a p53-dependent and -independent manner. AB - Slug is involved in the radioresistance and chemoresistance of several types of cancers. In the present study, we first studied the effect of Slug on the radioresistance of nasopharyngeal carcinoma (NPC). We established radioresistant CNE-2 cells (CNE-2-RES) by exposing CNE-2 cells to gradually increasing doses of irradiation (IR). We used lentiviral infection technique to stably knock down Slug and then studied the effects in vitro and in vivo. Western blotting and RT PCR were applied to detect the protein and mRNA expression in NPC cells or xenograft tumor tissues, respectively. Colony forming assay was applied to detect the cell survival after IR. As a result, CNE-2-RES cells were successfully established, CNE-2-RES cells showed relatively higher expression of Slug, higher expression of p53 and lower expression of PUMA. Following inhibition of Slug, the radiosensitivity of NPC was enhanced both in vitro and in vivo. Slug inversely regulated PUMA and p53 expression in both CNE-2 and CNE-2-RES cells. Animal experiments showed the same trend of protein expression as the in vitro results. In conclusion, our study demonstrated that Slug overexpression in CNE-2-RES cells may result in the radioresistance of cells. Slug mediates CNE-2 radioresistance via downregulation of PUMA in both a p53-dependent and p53-independent manner. PMID- 25812965 TI - Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease. AB - A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 MUM). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment. PMID- 25812966 TI - Design and synthesis of celastrol derivatives as anticancer agents. AB - A series of celastrol derivatives as potential telomerase inhibitors were designed and synthesized. The bioassays demonstrated that title compounds displayed potent anticancer activities against SGC-7901, SMMC-7721, MGC-803 and HepG-2 cell lines, among them, compounds 3c and 3d which containing hydrophilicity moieties exhibited high anti-proliferative activities (IC50 = 0.10 1.22 MUM). The preliminary mechanism of antitumor action indicated that title compound 3c could induce significant SMMC-7721 cells apoptosis. A modified TRAP assay showed that compounds 3c and 3d displayed the most potent inhibitory activity with IC50 values at 0.11 and 0.34 MUM, respectively. And there was a good correlation between telomerase inhibition and anti-proliferative inhibition of SMMC-7721 cells. Moreover, molecular docking indicated that the active compound 3c was nicely bound into the telomerase hTERT active site, hydrophobic, van der Waals and two hydrogen bond interactions with conserved residues ASP 628 and TYR 949 were found. PMID- 25812967 TI - Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors. AB - The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 MUM. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity. PMID- 25812969 TI - Xpert MTB/RIF to diagnose tuberculosis in children. PMID- 25812972 TI - Implementing the affordable care act: remaining hurdles. PMID- 25812971 TI - Attitudes Toward Placebo Use in Lebanon. AB - PURPOSE: Placebo use, both in clinical trials and patient care, is a problematic ethical issue surrounded by opposing arguments from those who advocate its use versus those who do not. This problematic aspect of placebo is more challenging in Lebanon where religious ideologies dominate people's beliefs, and where laws that guide medical care are vague. This paper aims to highlight the cultural ideologies that dominate medical care and the perspectives of people associated with the field. METHODS: The method relied on semi-structured interviews with religious leaders, representatives of society and healthcare professionals. Panel discussions incorporating healthcare professionals, academics, scientists and medical researchers were also organized. FINDINGS: The legal environment in Lebanon is characterized by lack of an appropriate legislative guideline that categorically clarifies the value of the human person in medical care. There is a lack of a common ethical standard within a society characterized by social and political dissent. The culturally upheld principles and actual application of the principles of ethics surrounding patient autonomy were overviewed. Medical practitioners failed to agree to a general outline that should guide the use of placebo where it became evident that each practitioner adopted a subjective framework which ultimately undermines patient autonomy. IMPLICATIONS: The paper proposes that until a new legislative code that clarifies ethical principles properly guiding medical care is coined, the process of placebo use will continue to be subject to the paternalistic assessments of medical professionals. PMID- 25812968 TI - Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis. AB - BACKGROUND: Microbiological confirmation of childhood tuberculosis is rare because of the difficulty of collection of specimens, low sensitivity of smear microscopy, and poor access to culture. We aimed to establish summary estimates for sensitivity and specificity of of the Xpert MTB/RIF assay compared with microscopy in the diagnosis of pulmonary tuberculosis in children. METHODS: We searched for studies published up to Jan 6, 2015, that used Xpert in any setting in children with and without HIV infection. We systematically reviewed studies that compared the diagnostic accuracy of Xpert MTB/RIF (Xpert) with microscopy for detection of pulmonary tuberculosis and rifampicin resistance in children younger than 16 years against two reference standards-culture results and culture negative children who were started on anti-tuberculosis therapy. We did meta analyses using a bivariate random-effects model. FINDINGS: We identified 15 studies including 4768 respiratory specimens in 3640 children investigated for pulmonary tuberculosis. Culture tests were positive for tuberculosis in 12% (420 of 3640) of all children assessed and Xpert was positive in 11% (406 of 3640). Compared with culture, the pooled sensitivities and specificities of Xpert for tuberculosis detection were 62% (95% credible interval 51-73) and 98% (97-99), respectively, with use of expectorated or induced sputum samples and 66% (51-81) and 98% (96-99), respectively, with use of samples from gastric lavage. Xpert sensitivity was 36-44% higher than was sensitivity for microscopy. Xpert sensitivity in culture-negative children started on antituberculosis therapy was 2% (1-3) for expectorated or induced sputum. Xpert's pooled sensitivity and specificity to detect rifampicin resistance was 86% (95% credible interval 53-98) and 98% (94-100), respectively. INTERPRETATION: Compared with microscopy, Xpert offers better sensitivity for the diagnosis of pulmonary tuberculosis in children and its scale-up will improve access to tuberculosis diagnostics for children. Although Xpert helps to provide rapid confirmation of disease, its sensitivity remains suboptimum compared with culture tests. A negative Xpert result does not rule out tuberculosis. Good clinical acumen is still needed to decide when to start antituberculosis therapy and continued research for better diagnostics is crucial. FUNDING: WHO, Global TB Program of Texas Children's Hospital. PMID- 25812970 TI - Chryseobacterium limigenitum sp. nov., isolated from dehydrated sludge. AB - An intense yellow pigmented strain (SUR2(T)) isolated from dehydrated activated sludge was studied in detail to clarify its taxonomic assignment. Cells of the isolate showed a rod-shaped morphology and stained Gram-negative. Comparative 16S rRNA gene sequence analysis revealed highest similarities to the type strains of Chryseobacterium polytrichastri YG4-6(T) (98.6 %), Chryseobacterium aahli T68F(T) (97.9 %), Chryseobacterium daeguense K105(T) and Chryseobacterium gregarium DSM 79109(T) (both 97.4 %). 16S rRNA gene-sequence similarities to all other Chryseobacterium species were below 97.3 %. The fatty acid analysis of strain SUR2(T) revealed a Chryseobacterium typical profile composed mainly of the fatty acids C15:0 iso, C15:0 iso 2-OH, C17:1 iso omega9c, and C17:0 iso 3-OH. DNA-DNA hybridizations with the type strains of C. polytrichastri, C. aahli, C. daeguense and C. gregarium resulted in values below 70 %. Differentiating biochemical and chemotaxonomic properties showed differences to the most closely related species and suggest that the isolate SUR2(T) represents a novel species, for which the name Chryseobacterium limigenitum sp. nov. (type strain SUR2(T) = ZIM B1019(T) = CCM 8594(T) = LMG 28734(T)) is proposed. PMID- 25812973 TI - Effects of Pholiota nameko polysaccharide on NF-kappaB pathway of murine bone marrow-derived dendritic cells. AB - This study investigated the effect of a polysaccharide purified from Pholiota nameko (PNPS-1) on the NF-kappaB signaling pathway of murine bone marrow-derived dendritic cells (BMDCs) and relevant mechanisms. The results showed that PNPS-1 could decrease the expression of maturation markers CD40 and CD80 on BMDCs. PNPS 1 also could decrease the mRNA expression of Myd88, TRAF6, TIRAP, IRAKI, IKBKB, NFKB1, NFKB2 and RelA in immature BMDCs determined by RT-PCR, and decreased the IKKbeta and P65 production in BMDCs determined by Western blot, and decreased the NF-kB P65 production determined by ELISA. In addition, the effects of PNPS-1 on BMDCs were significantly impaired by treating the cells with anti-TLR2 antibody prior to PNPS-1 treatment, implying direct interaction between PNPS-1 and TLR2 on cell surface. These results indicate that PNPS-1 regulates BMDCs through TLR2 and downstream NF-kB signalings. PMID- 25812975 TI - "The Poison That Ruined the Nation": Native American Men-Alcohol, Identity, and Traditional Healing. AB - Alcoholism and destructive drinking patterns are serious social problems in many Native American reservation and urban communities. This qualitative study of men from a single Great Lakes reservation community examined the social, cultural, and psychological aspects of their alcohol problems through their life stories. The men were in various stages of recovery and sobriety, and data collection consisted of open-ended interviews and analysis utilizing principles and techniques from grounded theory and ethnographic content analysis. Alcoholism and other serious social problems facing Native American communities need to be understood in the sociocultural and historical contexts of colonization and historical grief and trauma. This study suggests that for Native American men, there are culturally specific perspectives on alcohol that have important implications for prevention and treatment of alcohol abuse. The participants' narratives provided insight into the ways reconnecting with traditional cultural values (retraditionalization) helped them achieve sobriety. For these men, alcohol was highly symbolic of colonization as well as a protest to it. Alcohol was a means for affirming "Indian" identity and sobriety a means for reaffirming traditional tribal identity. Their narratives suggested the ways in which elements of traditional cultural values and practices facilitate healing in syncretic models and Nativized treatment. Understanding the ways in which specific Native cultural groups perceive their problems with drinking and sobriety can create more culturally congruent, culturally sensitive, and effective treatment approaches and inform future research. PMID- 25812976 TI - Selective serotonin reuptake inhibitors: depressing perioperative outcomes? PMID- 25812974 TI - Effect of Zn2+ binding and enzyme active site on the transition state for RNA 2' O-transphosphorylation interpreted through kinetic isotope effects. AB - Divalent metal ions, due to their ability to stabilize high concentrations of negative charge, are important for RNA folding and catalysis. Detailed models derived from the structures and kinetics of enzymes and from computational simulations have been developed. However, in most cases the specific catalytic modes involving metal ions and their mechanistic roles and effects on transition state structures remain controversial. Valuable information about the nature of the transition state is provided by measurement of kinetic isotope effects (KIEs). However, KIEs reflect changes in all bond vibrational modes that differ between the ground state and transition state. QM calculations are therefore essential for developing structural models of the transition state and evaluating mechanistic alternatives. Herein, we present computational models for Zn2+ binding to RNA 2'O-transphosphorylation reaction models that aid in the interpretation of KIE experiments. Different Zn2+ binding modes produce distinct KIE signatures, and one binding mode involving two zinc ions is in close agreement with KIEs measured for non-enzymatic catalysis by Zn2+ aquo ions alone. Interestingly, the KIE signatures in this specific model are also very close to those in RNase A catalysis. These results allow a quantitative connection to be made between experimental KIE measurements and transition state structure and bonding, and provide insight into RNA 2'O-ransphosphorylation reactions catalyzed by metal ions and enzymes. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. PMID- 25812978 TI - Diabetes Team award. PMID- 25812977 TI - Reducing the impact of physical inactivity: evidence to support the case for targeting people with chronic mental and physical conditions. AB - BACKGROUND: Recent evidence suggests that small increases in the physical activity of those considered least active can have a bigger health impact than raising levels of those already achieving or close to achieving recommendations. Profiling the characteristics of those who are least active allows for appropriate targeting of interventions. This study therefore examined the characteristics of people in the lowest physical activity bracket. METHODS: Data were taken from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) funded 'South Yorkshire Cohort', a longitudinal observational dataset of residents of South Yorkshire, England. Five separate outcomes based on a shortened version of the GPPAQ were used to represent the lowest levels of physical activity. Potential predictors examined were age, sex, body mass index, ethnicity, chronic conditions, current employment and deprivation. Descriptive statistics and logistic regression were conducted. RESULTS: Individuals with chronic mental and physical conditions (fatigue, insomnia, anxiety, depression, diabetes, breathing problems, high blood pressure, heart disease, stroke and cancer) were more likely to report the lowest levels of physical activity across all five outcomes. Demographic variations were also observed. CONCLUSIONS: Targeting people with chronic mental and physical conditions has the potential to reduce the impact of physical inactivity. PMID- 25812979 TI - Medical teacher: monster or mystery? PMID- 25812980 TI - The concept and necessity of learning outcome. PMID- 25812981 TI - A review of the patterns of unprofessional behavior and evaluation programs to prevent misconduct by medical students. AB - In recent years, several high-profile cases related with misconduct by doctors and medical students have led to increased media interest and public concern regarding doctors who fail to maintain the expected professional standards. In response to these concerns and the increasing awareness of the social responsibility of medicine, the importance of professionalism in medical school is receiving renewed attention in our medical society. Many studies in other countries have stressed the early detection and intervention of unprofessional behaviors in medical students using an adequate evaluation system. The authors intended to explore strategies that reinforce professionalism education and prevent misconduct in medical students. We conducted an extensive literature review to identify patterns and categorize issues of misconduct and unprofessional behavior by medical students; existing evidence to determine why early detection and intervention of are crucial to prevent future misbehavior and disciplinary action by doctors; and education and evaluation systems to enhance professionalism for medical students. PMID- 25812982 TI - Korean medical students' cognitive, emotional, and social characteristics. AB - PURPOSE: Medical schools and graduate medical schools should understand the personality and psychological qualities of graduate medical students, medical students, and premedical students and link them with the curriculum. METHODS: In this study, through June 2010 we analyzed medical papers that were published in Korea. The search terms were psychological terminology, including emotion, cognition, intelligence, social ability, stress, motivation, judgment, and learning style. RESULTS: In the cognitive and learning aspects, preliminary doctors were under the influence of prior knowledge; cumulative learning; self efficacy; and visual, logical, non-self-led learning types and had external learning motivation. In the emotional adaptive aspects, they appeared to be the ISTJ (introversion, sensing, thinking, judging) personality type with regard to the Myers-Briggs indicators and perfectionists, suffering from severe academic stress. Their motivation on matriculation was associated with their interests and aptitudes, and through community service, they adapted to the learning and living environment of medicine. In the social and moral aspects, they did not have high moral judgment, felt devaluated about their job than before, and tended to have an open and flexible doctor-patient relationship. CONCLUSION: Medical graduate students, medical students, and premedical students have greater likelihood to cultivate their character and capacity for adaptation. PMID- 25812983 TI - Analysis of the Relationship between Students' Seating Preferences and Academic Achievement in Medical School. AB - PURPOSE: This study aimed to explore the relationship between students' seating preferences and academic achievement in medical school. METHODS: The subjects of this study were 109 second-year students in C medical school. The pattern of seat selection of 109 students was surveyed by participant observation for 48 days, and a questionnaire was administered to determine the factors that were considered by students. Using SPSS version 12.0, we analyzed the factors that students considered with regard to seat selection and seat preference and the frequency of seat movements between areas. We performed one-way ANOVA to analyze the differences in academic achievement between students who moved seats versus those who did not. RESULTS: The most common reasons for seat selection were to focus better on the lecture (60 students), to focus better on lecture, and to feel familiar with the same seat (60 students). Students' preferred seats were in rows A4, A7, A5, and A3 (in descending order), which are primarily the central sections, and columns B15, B1, B14, B19 (in descending order), which are primarily both ends of the division. The difference in academic achievement between students who moved seats and those who did not was not significant (p>0.05). Among students who did not move seats, the difference in academic achievement between 9 seating areas was not significant in 6 subjects (p>0.05). CONCLUSION: The results of this study suggest that we should reconsider a professor's general perception regarding academic achievement according to seat location. PMID- 25812984 TI - Experience with Using Multiple Types of Visual Educational Tools during Problem Based Learning. AB - PURPOSE: This study describes the experience of using multiple types of visual educational tools in the setting of problem-based learning (PBL). The author intends to demonstrate their roles in diverse and efficient ways of clinical reasoning and problem solving. METHODS: Visual educational tools were introduced in a lecture that included their various types, possible benefits, and some examples. Each group made one mechanistic case diagram per week, and each student designed one diagnostic schema or therapeutic algorithm per week, based on their learning issues. The students were also told to provide commentary, which was intended to give insights into their truthfulness. Subsequently, the author administered a questionnaire about the usefulness and weakness of visual educational tools and the difficulties with performing the work. Also, the qualities of the products were assessed by the author. RESULTS: There were many complaints about the adequacy of the introduction of visual educational tools, also revealed by the many initial inappropriate types of products. However, the exercise presentation in the first week improved the level of understanding regarding their purposes and the method of design. In general, students agreed on the benefits of their help in providing a deep understanding of the cases and the possibility of solving clinical problems efficiently. The commentary was helpful in evaluating the truthfulness of their efforts. Students gave suggestions for increasing the percentage of their scores, considering the efforts. CONCLUSION: Using multiple types of visual educational tools during PBL can be useful in understanding the diverse routes of clinical reasoning and clinical features. PMID- 25812985 TI - Experience of developing and implementing a motivation induction course for konyang university medical college freshmen. AB - PURPOSE: This study aimed to develop a new course for Konyang University College of Medicine freshmen to motivate them with regard to their vision and medical professionalism and experience various learning methods of medical education. METHODS: The course was developed by 4 faculty members through several intensive meetings throughout the winter of 2010. A 4-credit course was designed for 61 freshmen of Konyang University College of Medicine to provide structured guidance and an introduction to their medical education and increase their motivation with regard to their studies and school life. The course lasted for 4 weeks (February 28 to March 25), and every session of the program was evaluated by the students. RESULTS: The 'motivation induction course' consisted of the following sessions: university-wide: 'leadership camp' and 'special lectures for future vision;' college-wide: 'major immersion session,' 'Enneagram workshop,' 'STRONG workshop,' 'medical professionalism,' and 'team-based learning.' The group results were presented in a poster and by oral presentation and were awarded prizes for the best performance. Special features included: group discussion session on medical ethics, which used scenarios that were developed by a medical humanity course committee and visiting all departments and mentors of the medical college to fulfill their curiosity of their future major or workplace. Overall, the course was evaluated as satisfactory (M=4.22, SD=0.81). CONCLUSION: Although there was some dissatisfaction, the overall experience of the "motivation induction course" was a success. The course will continue to be valuable for freshmen in adapting to medical school and its culture and in defining one's view of a good doctor. PMID- 25812986 TI - The Influence of Gender on ProfessionalismFemale in Trainees. AB - PURPOSE: This study aimed to analyze the experience of female trainees who were trained in hospitals after graduating from medical school, focusing on methods of representing their gender in training courses. METHODS: We interviewed 8 trainees who had been trained in a hospital in Seoul and 4 faculties from June 2010 to October 2010. We analyzed their similarities and differences and developed a vocational identity formation process to represent gender. RESULTS: Gender was represented contradictorily in their training course, affecting their choice of specialties and interactions with patients. But, female trainees did not want to their being distinguished from their male counterparts with regard to being a good doctor to be influenced by meritocracy. It was difficult for them to bear children and balance work and family life due to aspects of the training system, including long work hours and the lack of replacement workers. Consequently, they asked their parents to help with child care, because hospitals are not interested in the maternity system. Female trainees did not consider being a doctor to be a male profession. Likely, they believed that their femininity influenced their professionalism positively. CONCLUSION: The methods of representing gender are influenced by the training system, based a male-dominated apprenticeship. Thus, we will research the mechanisms that influence gender-discriminated choices in specialties, hospitals, and medical schools and prepare a maternity care system for female trainees. Strategies that maximize recruitment and retention of women in medicine should include a consideration of alternative work schedules and optimization of maternity leave and child care opportunities. PMID- 25812987 TI - Changes in background and characteristics in freshmen in one graduate medical school from 2009 to 2011. AB - PURPOSE: We examined the changes in background and characteristics in freshmen in graduate medical school from 2009 to 2011. METHODS: We analyzed the responses to a self-questionnaire which were about sex, age, graduation, major, religion and etc. The data were analyzed by t-test, chi-square test. RESULTS: The freshman population in 2009 and 2011 year was 44% and 58.4% male, and 56% and 41.6% female; had a mean age of 27.3 and 27.4; 41.6% and 32.0% Christian, 33.6% and 47.2% atheist, 76.0% and 68.8% graduates; and 48.0% and 50.4% in the capital region, respectively. With regard to future career, 43.2% and 43.2% of freshmen responded clinical professor, 29.6% and 27.2% private clinics, 8.0% and 13.6% medical researcher, 8.8% and 6.4% public officer, 6.4% and 3.2% basic science faculty, and 4.0% and 6.4% others. With regard to future majors, 20.0% and 20.0% answered internal medicine, 11.2% and 8.0% psychiatrics, 8.8% and 8.8% general surgery, 8.0% and 8.8% pediatrics, 4.8% and 4.8% chest surgery, 33.6% and 36.0% others, and 13.6% and 13.6% undecided, respectively. CONCLUSION: The populations of males, atheists, graduation candidate, and medical researchers increased, those of females, Christian, and those born in Gwangju and Jeonnam decreased, and those of mean age, future careers and majors, birth place in the capital region were unchanged. PMID- 25812988 TI - Presenting your findings. PMID- 25812990 TI - The parental couple relationship in child and adolescent mental health. PMID- 25812991 TI - Pharmacologic vitreolysis with ocriplasmin: rationale for use and therapeutic potential in vitreo-retinal disorders. AB - With increased knowledge about the origins and pathophysiology of vitreo-retinal disorders-and, in particular, the central role of anomalous posterior vitreous detachment in vitreo-maculopathies-a paradigm shift from surgery to pharmacotherapy is taking place with the development of pharmacologic vitreolysis. The first approved agent for pharmacologic vitreolysis therapy is ocriplasmin, a truncated form of the nonspecific serine protease plasmin. Twelve studies comprise the current ocriplasmin clinical trial program, demonstrating the efficacy and safety of a single intravitreal injection of ocriplasmin for the treatment of patients with symptomatic vitreo-macular adhesion or vitreo-macular traction, including patients with macular holes. Although post-approval implementation of ocriplamsin in clinical practice has shown success rates of up to 78%, there have been recent case reports of acute, transient visual dysfunction. There are thus new initiatives to further refine clinical indications for case selection and to identify possible untoward effects. Although more studies are warranted, it appears that ocriplasmin offers a good alternative to surgery. The future lies in pharmacologic vitreolysis, and the future of pharmacologic vitreolysis lies in prevention. Thus, long-term studies are needed to define a role for pharmacologic vitreolysis, in particular with ocriplasmin, in the prevention of progressive diabetic retinopathy and age related macular degeneration. PMID- 25812992 TI - Activation of enzymatic chitin degradation by a lytic polysaccharide monooxygenase. AB - For decades, the enzymatic conversion of recalcitrant polysaccharides such as cellulose and chitin was thought to solely rely on the synergistic action of hydrolytic enzymes, but recent work has shown that lytic polysaccharide monooxygenases (LPMOs) are important contributors to this process. Here, we have examined the initial rate enhancement an LPMO (CBP21) has on the hydrolytic enzymes (ChiA, ChiB, and ChiC) of the chitinolytic machinery of Serratia marcescens through determinations of apparent k(cat) (k(cat)(app)) values on a beta-chitin substrate. k(cat)(app) values were determined to be 1.7+/-0.1 s(-1) and 1.7+/-0.1 s(-1) for the exo-active ChiA and ChiB, respectively and 1.2+/-0.1 s(-1) for the endo-active ChiC. The addition of CBP21 boosted the k(cat)(app) values of ChiA and ChiB giving values of 11.1+/-1.5 s(-1) and 13.9+/-1.4 s(-1), while there was no effect on ChiC (0.9+/-0.1 s(-1)). PMID- 25812993 TI - Branched-chain sugar nucleosides: stereocontrolled synthesis and bioevaluation of novel 3'-C-trifluoromethyl and 3'-C-methyl pyranonucleosides. AB - A new series of 3'-C-trifluoromethyl- and 3'-C-methyl-beta-d allopyranonucleosides of 5-fluorouracil and their deoxy derivatives has been designed and synthesized. Treatment of ketosugar 1 with trifluoromethyltrimethylsilane under catalytic fluoride activation and methyl magnesium bromide, gave 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl (2a) and 3-C-methyl (2b)-alpha-D-allofuranose, respectively, in a virtually quantitative yield and with complete stereoselectivity. Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-trifluoromethyl (3a) and 3-C-methyl (3b)-beta-D allopyranose. Compounds 3a,b were then condensed with silylated 5-fluorouracil and deacetylated to afford the target nucleosides 5a,b. Deoxygenation of the peracylated allopyranoses 3a,b followed by condensation with silylated 5 fluorouracil and subsequent deacetylation yielded the target 3'-deoxy-3'-C trifluoromethyl and 3'-deoxy-3'-C-methyl-beta-d-glucopyranonucleosides 14a,b. The newly synthesized compounds were evaluated for their potential antiviral and cytostatic activities. The 3'-deoxy-3'-C-methyl- ribonucleoside 11b showed significant cytotoxic activity (~7 MUM) almost equally active against a variety of tumor cell lines. PMID- 25812989 TI - Switching roles: the functional plasticity of adult tissue stem cells. AB - Adult organisms have to adapt to survive, and the same is true for their tissues. Rates and types of cell production must be rapidly and reversibly adjusted to meet tissue demands in response to both local and systemic challenges. Recent work reveals how stem cell (SC) populations meet these requirements by switching between functional states tuned to homoeostasis or regeneration. This plasticity extends to differentiating cells, which are capable of reverting to SCs after injury. The concept of the niche, the micro-environment that sustains and regulates stem cells, is broadening, with a new appreciation of the role of physical factors and hormonal signals. Here, we review different functions of SCs, the cellular mechanisms that underlie them and the signals that bias the fate of SCs as they switch between roles. PMID- 25812995 TI - "You Can Lead a Horse to Water ...": Focus Group Perspectives on Initiating and Supporting Hearing Health Change in Older Adults. AB - PURPOSE: The aim of this study was to use focus group discussions to (a) evaluate the use of an educational presentation as an impetus for hearing health change and (b) investigate hearing health from the perspective of older adults. METHOD: Twenty-seven (4 men, 23 women) community-dwelling older adults attended 4 data collection events. Participants attended a presentation titled Hearing Health in Older Adults, which was delivered by a trained presenter in a peer-teaching-peer format. Following each presentation, a focus group discussion took place. Digital audio recordings, field notes, and memos of the discussions were used to create verbatim transcripts. Data were analyzed using qualitative description and thematic analysis techniques. RESULTS: Five central themes emerged when older adult focus groups discussed the presentation and hearing health change: recognizing and admitting, understanding the options, sharing stories and experiences, barriers and facilitators, and the presentation. CONCLUSION: Facilitators to hearing health change identified by participants include widespread education about hearing health; clarification about roles, professional motivation, and cost in hearing care; and opportunities to learn from and share personal stories with peers. PMID- 25812994 TI - The t(11;14)(q13;q32) translocation as a poor prognostic parameter for autologous stem cell transplantation in myeloma patients with extramedullary plasmacytoma. AB - INTRODUCTION: Fluorescence in-situ hybridization (FISH)-detected abnormalities, including del(17p), del(13q), and t(4;14), have been associated with inferior prognosis. However, there are few data about the prognostic significance of cytogenetic abnormalities for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients with extramedullary plasmacytoma (EMP). PATIENTS AND METHODS: Between April 2004 and December 2012, 290 MM patients underwent ASCT at 3 centers. FISH data for bone marrow samples obtained at diagnosis were available for 58 patients who had EMP at diagnosis or during treatment. RESULTS: The t(11;14), t(4;14), del(13q), and 1q gain abnormalities were seen in 14.9%, 6.3%, 25.6%, and 42.9%, respectively. No t(14;16) or del(17p) cytogenetic abnormality was detected in the examined patients. Patients with t(11;14) had a lower response rate compared to patients with other cytogenetic abnormalities. EMP-specific relapse was higher in patients with t(11;14) than in patients with other cytogenetic abnormalities (42.9% vs. 10%-33.3%). Each of the 4 cytogenetic abnormalities predicted shorter median progression-free survival (6-12 months vs. 27-37 months) and shorter overall survival (16-22 months vs. 68 months or not reached) compared to no cytogenetic abnormality. The t(11;14) translocation was an important prognostic factor for both progression-free survival (hazard ratio, 25.154; P < .001) and overall survival (hazard ratio, 7.484; P = .024) in the multivariate analysis. CONCLUSION: In the current study, t(11;14), t(4;14), del(13q), and 1q gain were associated with worse survival in MM patients with EMP. The role of t(11;14) as a prognostic parameter for ASCT in MM patients with EMP should be confirmed with a large, well-designed study. PMID- 25812996 TI - Optimization of cell disruption methods for efficient recovery of bioactive metabolites via NMR of three freshwater microalgae (chlorophyta). AB - This study demonstrates the use of NMR techniques coupled with chemometric analysis as a high throughput data mining method to identify and examine the efficiency of different disruption techniques tested on microalgae (Chlorella variabilis, Scenedesmus regularis and Ankistrodesmus gracilis). The yield and chemical diversity from the disruptions together with the effects of pre-oven and pre-freeze drying prior to disruption techniques were discussed. HCl extraction showed the highest recovery of oil compounds from the disrupted microalgae (up to 90%). In contrast, NMR analysis showed the highest intensity of bioactive metabolites obtained for homogenized extracts pre-treated with freeze-drying, indicating that homogenizing is a more favorable approach to recover bioactive substances from the disrupted microalgae. The results show the potential of NMR as a useful metabolic fingerprinting tool for assessing compound diversity in complex microalgae extracts. PMID- 25812997 TI - Optimization of three-stage Anammox system removing nitrogen from landfill leachate. AB - Advanced nitrogen removal had been realized from mature landfill leachate via three-stage anaerobic ammonium oxidation (Anammox) system during the previous study. However, the Anammox system was influenced by factors such as influent nitrite and organic concentrations and needed to be optimized. To optimize the Anammox system, this study investigated Anammox Sequence Batch Reactor (ASBR) with different feeding modes and influent organic concentrations. The results showed that with influent ammonia and nitrite concentrations of 250+/-20 and 320+/-20mg/L, respectively, a continuous feeding mode reduced the adverse effect of high influent nitrite concentration on Anammox. A small amount of organics improved rather than inhibited nitrogen removal. However, as influent COD increased (from 600+/-50 to 800+/-50mg/L), Anammox was gradually inhibited. Influent organics concentration should be kept below 800mg/L, which facilitated Anammox. PMID- 25812998 TI - Lipid Biomarker and Isotopic Study of Community Distribution and Biomarker Preservation in a Laminated Microbial Mat from Shark Bay, Western Australia. AB - Modern microbial mats from Shark Bay present some structural similarities with ancient stromatolites; thus, the functionality of microbial communities and processes of diagenetic preservation of modern mats may provide an insight into ancient microbial assemblages and preservation. In this study, the vertical distribution of microbial communities was investigated in a well-laminated smooth mat from Shark Bay. Biolipid and compound-specific isotopic analyses were performed to investigate the distribution of microbial communities in four distinct layers of the mat. Biomarkers indicative of cyanobacteria were more abundant in the uppermost oxic layer. Diatom markers (e.g. C25 HBI alkene, C20:4omega6 and C20:5omega3 polar lipid fatty acids (PLFAs)) were also detected in high abundance in the uppermost layer, but also in the deepest layer under conditions of permanent darkness and anoxia, where they probably used NO3 (-) for respiration. CycC19:0, an abundant PLFA of purple sulfur bacteria (PSB), was detected in all layers and presented the most (13)C-depleted values of all PLFAs, consistent with photoautotrophic PSB. Sulfur-bound aliphatic and aromatic biomarkers were detected in all layers, highlighting the occurrence of early sulfurisation which may be an important mechanism in the sedimentary preservation of functional biolipids in living and, thus, also ancient mats. PMID- 25812999 TI - Long-term persistence of a multi-resistant methicillin-susceptible Staphylococcus aureus (MR-MSSA) clone at a university hospital in southeast Sweden, without further transmission within the region. AB - The objective of this study was to characterise isolates of methicillin susceptible Staphylococcus aureus (MSSA) with resistance to clindamycin and/or tobramycin in southeast Sweden, including the previously described ECT-R clone (t002) found in Ostergotland County, focusing on clonal relatedness, virulence determinants and existence of staphylococcal cassette chromosome (SCC) mec remnants. MSSA isolates with resistance to clindamycin and/or tobramycin were collected from the three county councils in southeast Sweden and investigated with spa typing, polymerase chain reaction (PCR) targeting the SCCmec right extremity junction (MREJ) and DNA microarray technology. The 98 isolates were divided into 40 spa types, and by microarray clustered in 17 multi-locus sequence typing (MLST) clonal complexes (MLST-CCs). All isolates with combined resistance to clindamycin and tobramycin (n = 12) from Ostergotland County and two additional isolates (clindamycin-R) were designated as spa type t002, MREJ type ii and were clustered in CC5, together with a representative isolate of the ECT-R clone, indicating the clone's persistence. These isolates also carried several genes encoding exotoxins, Q9XB68-dcs and qacC. Of the isolates in CC15, 83% (25/30) were tobramycin-resistant and were designated spa type t084. Of these, 68% (17/25) were isolated from new-borns in all three counties. The persistence of the ECT-R clone in Ostergotland County, although not found in any other county in the region, carrying certain virulence factors that possibly enhance its survival in the hospital environment, highlights the fact that basic hygiene guidelines must be maintained even when MRSA prevalence is low. PMID- 25813001 TI - Secondary standards for 223Ra revised. AB - Dose calibrator dial settings reported by NIST in 2010 (ARI, v. 68, p. 1367) are now known to give erroneously low (by 10%) activity readings. The original determinations were based on a chain of calibrations; a broken link in this chain was recently discovered. New calibration factors (i.e., dial settings), directly linked to updated NIST primary standards, are reported here. In addition, the raw data used to derive the factors reported in 2010 are revisited. The validity of the reevaluation is established via comparison with the new experiments and revised calibration factors for numerous clinical geometries are reported. The main conclusions of the 2010 report regarding geometry effects remain valid. PMID- 25813000 TI - Development of a freeze-dried kit formulation for the preparation of 99mTc-NTP 15 5, a radiotracer for scintigraphic imaging of proteoglycans. AB - The cartilage-targeting strategy is based on the strong affinity of quaternary ammonium (QA) functions for cartilage proteoglycans. We use a bifunctional agent containing QA moiety and a polyazamacrocycle structure able to complex technetium 99m. (99m)Tc-NTP 15-5 was selected for its high stability and its high affinity for proteoglycans in vivo. Labeling conditions of NTP 15-5 were optimized, and a lyophilized kit was developed for radiolabeling of (99m)Tc-NTP 15-5 (radiochemical yields 94.6+/-1.8%). (99m)Tc-NTP 15-5 was stable and resulted in favorable biological evaluations. PMID- 25813002 TI - Determination of photon emission probabilities for the main gamma-rays of 223Ra in equilibrium with its progeny. AB - The currently published (223)Ra gamma-ray emission probabilities display a wide variation in the values depending on the source of the data. The National Institute of Standards and Technology performed activity measurements on a (223)Ra solution that was used to prepare several sources that were used to determine the photon emission probabilities for the main gamma-rays of (223)Ra in equilibrium with its progeny. Several high purity germanium (HPGe) detectors were used to perform the gamma-ray spectrometry measurements. PMID- 25813003 TI - Tailoring medium energy proton beam to induce low energy nuclear reactions in 86SrCl2 for production of PET radioisotope 86Y. AB - This paper reports results of experiments at Brookhaven Linac Isotope Producer (BLIP) aiming to investigate effective production of positron emitting radioisotope (86)Y by the low energy (86)Sr(p,n) reaction. BLIP is a facility at Brookhaven National Laboratory designed for the proton irradiation of the targets for isotope production at high and intermediate proton energies. The proton beam is delivered by the Linear Accelerator (LINAC) whose incident energy is tunable from 200 to 66 MeV in approximately 21 MeV increments. The array was designed to ensure energy degradation from 66 MeV down to less than 20 MeV. Aluminum slabs were used to degrade the proton energy down to the required range. The production yield of (86)Y (1.2+/-0.1 mCi (44.4+/-3.7) MBq/MUAh) and ratio of radioisotopic impurities was determined by assaying an aliquot of the irradiated (86)SrCl2 solution by gamma spectroscopy. The analysis of energy dependence of the (86)Y production yield and the ratios of radioisotopic impurities has been used to adjust degrader thickness. Experimental data showed substantial discrepancies in actual energy propagation compared to energy loss calculations. PMID- 25813004 TI - Extracellular HSP70 levels in diabetic environment in rats. AB - The expression of HSP70 in embryonic cells of mammals and its role for their normal development and protection is an important aspect to be investigated in pregnancy and/or mild diabetes. In this sense, the present study evaluated the effects of mild diabetes on maternal reproductive parameters and HSP70 levels in Wistar rats at different stages of life and in their offspring. Mild diabetes was induced by a beta-cytotoxic drug (streptozotocin) at birth. Four experimental groups were evaluated: at 90 days of age: nonpregnant nondiabetic (ND90) and nonpregnant mild diabetic (D90) female rats, and at term pregnancy: pregnant female rats of both glycemic status were examined (NDP and DP, respectively). The rats were submitted to oral glucose tolerance test, and blood samples were collected for determination of HSP70 levels. In addition, the reproductive performance of pregnant rats was assessed and HSP70 levels determined in their offspring blood samples. The HSP70 levels and maternal reproductive performance presented no difference between ND and D rats, regardless of the life stage. The HSP70 levels were increased in D90 rats and lower in offspring from D rats. Maternal HSP70 levels were positively correlated to the number of dead embryos. In conclusion, mild diabetes did not affect maternal reproductive performance, but high maternal HSP70 levels compromised embryo development. In addition, offspring from D rats exhibited lower HSP70 levels, showing that this protein can be used as an indicator of metabolic consequences of diabetes and predictor of related disorders in adulthood. PMID- 25813005 TI - Cervical spondylotic myelopathy: posterior decompression and pedicle screw fixation. AB - INTRODUCTION: Posterior decompression by laminoplasty and anterior decompression/fixation have been widely accepted, and they provide sufficient results for cervical spondylotic myelopathy. However, combined procedure of posterior decompression and reconstruction is favorable for some patients accompanying local kyphosis, segmental instability, previously operated conditions on the cervical spine, etc. DISCUSSION: Among posterior cervical instrumentations, pedicle screw fixation is a strong tool of stabilization of unstable segment and correction of deformities in sagittal and/or coronal planes for the patient with cervical spondylotic myelopathy. On the other hand, neurovascular complications including injury to the vertebral artery and nerve root cannot be completely eliminated. Even after surgeons became familiar with placement of cervical pedicle screws, screw malposition rate by freehand technique is high for patients with severe spondylotic condition. Surgeons must especially be careful for inserting pedicle screw in the cervical spine associating marked degenerative changes by spondylosis, and must obtain preoperatively sufficient anatomical information of the pedicle and surrounding structures. CONCLUSION: Combined procedure of posterior reconstructive surgery using a pedicle screw fixation provides better clinical outcomes than laminoplasty alone for cervical spondylotic myelopathy accompanying local kyphosis or segmental instability. Further development of supporting tools for cervical pedicle screw insertion including aiming device, navigation system and neuromonitoring procedure are expected for safer screw insertion. PMID- 25813006 TI - Comparison of clinical outcomes following minimally invasive lateral interbody fusion stratified by preoperative diagnosis. AB - PURPOSE: Lumbar fusion has been shown to be effective in treating a variety of degenerative spinal conditions, though significant differences exist in the magnitude of clinical improvement across different surgical diagnoses. With modern, minimally disruptive approaches for fusion, diagnosis-specific differences in clinical improvement may be reduced. The purpose of this study is to report and compare interim clinical improvements in patients treated with XLIF for various degenerative lumbar conditions. METHODS: 160 patients underwent XLIF for either degenerative spondylolisthesis (n = 68), degenerative disc disease (n = 20), adjacent segment disease (n = 26), or post-laminectomy syndrome (n = 46). Average age was 61 years and 66 % were female. Mean BMI was 28.9 kg/m(2). 37 % were smokers, 23 % had diabetes mellitus, 22 % had depression. Mean age was highest for ASD patients (66 years) and lowest for DDD patients (48 years) (p < 0.001). There were no other baseline demographic differences between groups. Patient-reported clinical outcomes measures were collected at baseline and prospectively at standard intervals. Interim results at an average of 19 months follow-up are reported here. RESULTS: In total, 197 levels were treated with XLIF (mean 1.2 per patient). There were no cases of symptomatic pseudoarthrosis or implant/instrument failure. Overall, 1 patient (0.6 %) had a major complication and 12 % had a minor complication. Approach-related anterolateral thigh/groin sensory changes were present in 14 % and hip flexion weakness in 9 %. At last follow-up, overall ODI decreased 47 % (44.1-23.5), VAS LBP decreased 59 % (6.9 2.8), VAS LP decreased 56 % (7.1-3.1), and SF-36 PCS improved 40 % (30.9-43.2) (all p < 0.001). Baseline ODI was significantly lower for DDD patients (p = 0.052). At last follow-up, mean percent improvements on all outcomes were highest for DSP group, though not all differences were significant. Improvements between diagnostic groups were statistically different for LBP (p = 0.021), but were similar for all other clinical outcomes. Percentage of patients reaching MCID and SCB thresholds ranged from 60 to 95 % in clinical outcomes. Patient satisfaction for the entire group was 93 % when asked whether satisfied with surgical outcome. CONCLUSIONS: XLIF has been demonstrated in the current series to lead to significant improvements in clinical outcomes and high rates of MCID and SCB and reduce the discrepancy in outcomes between well accepted and technically challenging indications compared to traditional open approaches for IBF. Complication rates were low, with only one patient in the series experiencing a major complication. Further investigation with larger cohorts and longer follow up is warranted. PMID- 25813007 TI - The morphological and clinical significance of developmental cervical stenosis. AB - PURPOSE: To investigate the difference of intra-dural space for spinal cord in magnetic resonance imaging between patients with and without developmental cervical stenosis and its clinical significance. METHODS: 445 patients with cervical spondylotic myelopathy who had decompression surgeries were recruited. Based on their lateral radiographs, they were divided into stenosis and non stenosis groups. On the magnetic resonance images, the ratio of the sagittal diameter of the dural sac to that of the vertebral body was measured and calculated as MRI Pavlov ratio at mid-vertebral level on sagittal images, and the ratio of the transverse area of the spinal cord to that of the dural sac was measured and calculated as occupation ratio on axial images from C3 to C7. The two ratios were compared between the two groups. We examined the correlations of the Pavlov ratio and the MRI Pavlov ratio between different vertebral levels. The correlation between the Pavlov ratio of each level and its corresponding MRI Pavlov ratio was also examined. The stenosis group was further divided into space reserving and non-space-reserving subgroups based on their occupation ratios; then, clinical parameters were compared between the two subgroups to determine the clinical significance of the reserving space. RESULTS: The MRI Pavlov ratio of the stenosis group was significantly smaller at C3-C7 (P < 0.001), while the occupation ratio was larger without significance. The Pavlov and MRI Pavlov ratios were correlated significantly at different levels (P < 0.001). The Pavlov ratio correlated significantly with its corresponding MRI Pavlov ratio at each level (P < 0.001). For space-reserving subgroup, the recovery rate was lower (P < 0.05) than that for non-space-reserving group, and was higher in anterior approach than that in posterior approach (P < 0.05). CONCLUSIONS: Developmental cervical stenosis is associated with a smaller sagittal diameter of dural sac, but does not lead to a significant decrease of intra-dural space available for the cord. For patients with normal intra-dural space, the recovery after anterior decompression surgery was better. PMID- 25813008 TI - Osteoclast activators are elevated in intervertebral disks with Modic changes among patients operated for herniated nucleus pulposus. AB - PURPOSE: Modic changes (MC) are associated with low back pain (LBP). Inflammation is considered as a key factor that triggers symptoms in especially type I MC, but so far of the potential inflammatory candidates only TNFalpha has been linked to MC. The objective of the study was to analyze a set of inflammatory mediators in human surgical disk samples and quantify their association with MC in the adjacent vertebral bodies. METHODS: The study sample consisted of 51 intervertebral disk tissue specimens; 20 'No MC' disks, 19 'Type I MC' disks, and 12 'Type II MC' disks. mRNA expression of 46 cytokines was quantified from isolated RNA. Tissue samples were stained using hematoxylin and eosin, toluidine blue, Herovici, CD68 and CD163. RESULTS: No significant differences were found in the amount of macrophages or presence of chondrocyte conglomerates between the MC groups. Of the multiple genes tested, statistically significant associations were observed for M-CSF1 (p = 0.028), RANKL (p = 0.035), RUNX1 (p = 0.032), and RUNX2 (p = 0.047) that were increased in 'Type II MC,' while OSCAR (p = 0.042) was increased in 'Type I MC' group compared to 'No MC.' CONCLUSIONS: Since these cytokines are related to differentiation and proliferation of osteoclasts, our data suggest that the stimulation of vertebral osteoclasts by factors secreted by disk tissue is involved in the pathophysiology of MC. PMID- 25813009 TI - Anterior release posterior internal distraction and subsequent posterior spinal fusion for the treatment of severe kyphoscoliosis. AB - PURPOSE: To evaluate the outcome and complications of anterior release, posterior internal distraction and subsequent posterior spinal fusion for the treatment of severe kyphoscoliosis. METHODS: The medical records and spinal imaging of 17 consecutive severe kyphoscoliosis patients who underwent anterior release, posterior internal distraction and subsequent posterior spinal fusion were reviewed. RESULTS: Patients underwent spinal deformity correction at the mean age of 22.6 +/- 8.4 years (range 15-44 years) with mean follow-up of 37.4 +/- 12.0 months (range 24-60 months). The preoperative thoracic kyphosis of 83.5 degrees +/- 16.3 degrees (range 60 degrees -115 degrees ) was corrected to 37.5 degrees +/- 7.9 degrees (range 20 degrees -49 degrees ) at the final follow-up. The preoperative major curve of 110.1 degrees +/- 16.8 degrees (range 92 degrees 145 degrees ) was corrected to 33.5 degrees +/- 13.9 degrees (range 12 degrees 63 degrees ) at the final follow-up, with a scoliosis correction of 70.3 %. At the most recent follow-up, the correction rate of proximal thoracic curve and thoracolumbar or lumbar curve was 57.1 and 74.8 %, respectively. Transient dyspnoea occurred in one patient after the initial surgery and subsequently resolved. No ventilator support was needed. Three patients complained the pain of concave soft tissue after the first distraction. There were no neurological complications or any deep wound infections. No complication of instrumentation was found at final follow-up. CONCLUSIONS: In the treatment of severe kyphoscoliosis, anterior release, posterior internal distraction and subsequent posterior spinal fusion, which obviates three-column osteotomy, is a good alternative correction method. PMID- 25813010 TI - Minimally invasive versus open transforaminal lumbar interbody fusion for treatment of degenerative lumbar disease: systematic review and meta-analysis. AB - PURPOSE: While open TLIF (O-TLIF) remains the mainstay approach, minimally invasive TLIF (MI-TLIF) may offer potential advantages of reduced trauma to paraspinal muscles, minimized perioperative blood loss, quicker recovery and reduced risk of infection at surgical sites. This meta-analysis was conducted to provide an updated assessment of the relative benefits and risks of MI-TLIF versus O-TLIF. METHODS: Electronic searches were performed using six databases from their inception to December 2014. Relevant studies comparing MI-TLIF and O TLIF were included. Data were extracted and analysed according to predefined clinical end points. RESULTS: There was no significant difference in operation time noted between MI-TLIF and O-TLIF cohorts. The median intraoperative blood loss for MI-TLIF was significantly lower than O-TLIF (median: 177 vs 461 mL; (weighted mean difference) WMD, -256.23; 95% CI -351.35, -161.1; P < 0.00001). Infection rates were significantly lower in the minimally invasive cohort (1.2 vs 4.6%; relative risk (RR), 0.27; 95%, 0.14, 0.53; I2) = 0%; P = 0.0001). VAS back pain scores were significantly lower in the MI-TLIF group compared to O-TLIF (WMD, -0.41; 95% CI -0.76, -0.06; I2 = 96%; P < 0.00001). Postoperative ODI scores were also significantly lower in the minimally invasive cohort (WMD, 2.21; 95% CI -4.26, -0.15; I2 = 93%; P = 0.04). CONCLUSIONS: In summary, the present systematic review and meta-analysis demonstrated that MI-TLIF appears to be a safe and efficacious approach compared to O-TLIF. MI-TLIF is associated with lower blood loss and infection rates in patients, albeit at the risk of higher radiation exposure for the surgical team. The long-term relative merits require further validation in prospective, randomized studies. PMID- 25813012 TI - #36: Prenatal aneuploidy screening using cell-free DNA. AB - Recent advances in technology have created exciting opportunities to expand and improve genetic testing options that are available to women during pregnancy. However, the novelty and complexity of these technologies, combined with the commercial interest to implement these tests rapidly into routine clinical care, have created challenges for physicians and patients and potentially will lead to misunderstanding, misuse, and unintended consequences. The purpose of this document was to aid clinicians in their day-to-day practice of counseling patients regarding prenatal aneuploidy testing options with cell-free DNA screening, which includes how it compares to current testing methods, potential benefits and harms, and its limitations and caveats. PMID- 25813011 TI - Effect of augmentation techniques on the failure of pedicle screws under cranio caudal cyclic loading. AB - PURPOSE: Augmentation of pedicle screws is recommended in selected indications (for instance: osteoporosis). Generally, there are two techniques for pedicle screw augmentation: inserting the screw in the non cured cement and in situ augmentation with cannulated fenestrated screws, which can be applied percutaneously. Most of the published studies used an axial pull out test for evaluation of the pedicle screw anchorage. However, the loading and the failure mode of pullout tests do not simulate the cranio-caudal in vivo loading and failure mechanism of pedicle screws. The purpose of the present study was to assess the fixation effects of different augmentation techniques (including percutaneous cement application) and to investigate pedicle screw loosening under physiological cyclic cranio-caudal loading. METHODS: Each of the two test groups consisted of 15 vertebral bodies (L1-L5, three of each level per group). Mean age was 84.3 years (SD 7.8) for group 1 and 77.0 years (SD 7.00) for group 2. Mean bone mineral density was 53.3 mg/cm3 (SD 14.1) for group 1 and 53.2 mg/cm3 (SD 4.3) for group 2. 1.5 ml high viscosity PMMA bone cement was used for all augmentation techniques. For test group 1, pedicles on the right side of the vertebrae were instrumented with solid pedicle screws in standard fashion without augmentation and served as control group. Left pedicles were instrumented with cannulated screws (Viper cannulated, DePuy Spine) and augmented. For test group 2 pedicles on the left side of the vertebrae were instrumented with cannulated fenestrated screws and in situ augmented. On the right side solid pedicle screws were augmented with cement first technique. Each screw was subjected to a cranio caudal cyclic load starting at 20-50 N with increasing upper load magnitude of 0.1 N per cycle (1 Hz) for a maximum of 5000 cycles or until total failure. Stress X-rays were taken after cyclic loading to evaluate screw loosening. RESULTS: Test group 1 showed a significant higher number of load cycles until failure for augmented screws compared to the control (4030 cycles, SD 827.8 vs. 1893.3 cycles, SD 1032.1; p < 0.001). Stress X-rays revealed significant less screw toggling for the augmented screws (5.2 degrees , SD 5.4 vs. 16.1 degrees , SD 5.9; p < 0.001). Test group 2 showed 3653.3 (SD 934) and 3723.3 (SD 560.6) load cycles until failure for in situ and cement first augmentation. Stress X rays revealed a screw toggling of 5.1 (SD 1.9) and 6.6 (SD 4.6) degrees for in situ and cement first augmentation techniques (p > 0.05). CONCLUSION: Augmentation of pedicle screws in general significantly increased the number of load cycles and failure load comparing to the nonaugmented control group. For the augmentation technique (cement first, in situ augmented, percutaneously application) no effect could be exhibited on the failure of the pedicle screws. By the cranio-caudal cyclic loading failure of the pedicle screws occurred by screw cut through the superior endplate and the characteristic "windshield-wiper effect", typically observed in clinical practice, could be reproduced. PMID- 25813013 TI - Digital Breast Tomosynthesis (DBT) to Characterize MRI-Detected Additional Lesions Unidentified at Targeted Ultrasound in Newly Diagnosed Breast Cancer Patients. AB - OBJECTIVES: Preoperative breast magnetic resonance (MR) often generates additional suspicious findings needing further investigations. Targeted breast ultrasound (US) is the standard tool to characterize MR additional lesions. The purpose of this study is to evaluate the potential role of digital breast tomosynthesis (DBT) to characterize MR detected additional findings, unidentified at targeted breast US. METHODS: This prospective study included women who a) had biopsy-proven, newly diagnosed breast cancers detected at conventional 2D mammography and/or US, referred to breast MR for tumour staging; and b) had DBT if additional MR findings were not detected at targeted ('second look') US. RESULTS: In 520 patients, MR identified 164 (in 114 women, 22%) additional enhancing lesions. Targeted US identified 114/164 (69.5%) of these, whereas 50/164 (30.5%) remained unidentified. DBT identified 32/50 of these cases, increasing the overall characterization of MR detected additional findings to 89.0% (146/164). Using DBT the identified lesions were significantly more likely to be malignant than benign MR-detected additional lesions (p = 0.04). CONCLUSIONS: DBT improves the characterization of additional MR findings not identified at targeted breast US in preoperative breast cancer staging. KEY POINTS: * Targeted US identified 114 of 164 (69.5%) additional enhancing lesions at preoperative breast MRI. * DBT identified a further 32 of the 50 lesions unidentified on targeted US. * DBT improved the characterization of additional MR findings for breast cancer staging. PMID- 25813014 TI - Dual-time-point O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for grading of cerebral gliomas. AB - OBJECTIVE: We aimed to evaluate the diagnostic potential of dual-time-point imaging with positron emission tomography (PET) using O-(2-[(18)F]fluoroethyl)-L tyrosine ((18)F-FET) for non-invasive grading of cerebral gliomas compared with a dynamic approach. METHODS: Thirty-six patients with histologically confirmed cerebral gliomas (21 primary, 15 recurrent; 24 high-grade, 12 low-grade) underwent dynamic PET from 0 to 50 min post-injection (p.i.) of (18)F-FET, and additionally from 70 to 90 min p.i. Mean tumour-to-brain ratios (TBRmean) of (18)F-FET uptake were determined in early (20-40 min p.i.) and late (70-90 min p.i.) examinations. Time-activity curves (TAC) of the tumours from 0 to 50 min after injection were assigned to different patterns. The diagnostic accuracy of changes of (18)F-FET uptake between early and late examinations for tumour grading was compared to that of curve pattern analysis from 0 to 50 min p.i. of (18)F-FET. RESULTS: The diagnostic accuracy of changes of the TBRmean of (18)F FET PET uptake between early and late examinations for the identification of HGG was 81% (sensitivity 83%; specificity 75%; cutoff - 8%; p < 0.001), and 83% for curve pattern analysis (sensitivity 88%; specificity 75%; p < 0.001). CONCLUSION: Dual-time-point imaging of (18)F-FET uptake in gliomas achieves diagnostic accuracy for tumour grading that is similar to the more time-consuming dynamic data acquisition protocol. KEY POINTS: * Dual-time-point imaging is equivalent to dynamic FET PET for grading of gliomas. * Dual-time-point imaging is less time consuming than dynamic FET PET. * Costs can be reduced due to higher patient throughput. * Reduced imaging time increases patient comfort and sedation might be avoided. * Quicker image interpretation is possible, as no curve evaluation is necessary. PMID- 25813015 TI - Evaluation of low-energy contrast-enhanced spectral mammography images by comparing them to full-field digital mammography using EUREF image quality criteria. AB - OBJECTIVE: Contrast-enhanced spectral mammography (CESM) examination results in a low-energy (LE) and contrast-enhanced image. The LE appears similar to a full field digital mammogram (FFDM). Our aim was to evaluate LE CESM image quality by comparing it to FFDM using criteria defined by the European Reference Organization for Quality Assured Breast Screening and Diagnostic Services (EUREF). METHODS: A total of 147 cases with both FFDM and LE images were independently scored by two experienced radiologists using these (20) EUREF criteria. Contrast detail measurements were performed using a dedicated phantom. Differences in image quality scores, average glandular dose, and contrast detail measurements between LE and FFDM were tested for statistical significance. RESULTS: No significant differences in image quality scores were observed between LE and FFDM images for 17 out of 20 criteria. LE scored significantly lower on one criterion regarding the sharpness of the pectoral muscle (p < 0.001), and significantly better on two criteria on the visualization of micro-calcifications (p = 0.02 and p = 0.034). Dose and contrast detail measurements did not reveal any physical explanation for these observed differences. CONCLUSIONS: Low-energy CESM images are non-inferior to FFDM images. From this perspective FFDM can be omitted in patients with an indication for CESM. KEY POINTS: * Low-energy CESM images are non-inferior to FFDM images. * Micro-calcifications are significantly more visible on LE CESM than on FFDM. * There is no physical explanation for this improved visibility of micro-calcifications. * There is no need for an extra FFDM when CESM is indicated. PMID- 25813016 TI - Optimized small molecule antibody labeling efficiency through continuous flow centrifugal diafiltration. AB - Protein immuno-detection encompasses a broad range of analytical methodologies, including western blotting, flow cytometry, and microscope-based applications. These assays which detect, quantify, and/or localize expression for one or more proteins in complex biological samples, are reliant upon fluorescent or enzyme tagged target-specific antibodies. While small molecule labeling kits are available with a range of detection moieties, the workflow is hampered by a requirement for multiple dialysis-based buffer exchange steps that are both time consuming and subject to sample loss. In a previous study, we briefly described an alternative method for small-scale protein labeling with small molecule dyes whereby all phases of the conjugation workflow could be performed in a single centrifugal diafiltration device. Here, we expand on this foundational work addressing functionality of the device at each step in the workflow (sample cleanup, labeling, unbound dye removal, and buffer exchange/concentration) and the implications for optimizing labeling efficiency. When compared to other common buffer exchange methodologies, centrifugal diafiltration offered superior performance as measured by four key parameters (process time, desalting capacity, protein recovery, retain functional integrity). Originally designed for resin based affinity purification, the device also provides a platform for up-front antibody purification or albumin carrier removal. Most significantly, by exploiting the rapid kinetics of NHS-based labeling reactions, the process of continuous diafiltration minimizes reaction time and long exposure to excess dye, guaranteeing maximal target labeling while limiting the risks associated with over-labeling. Overall, the device offers a simplified workflow with reduced processing time and hands-on requirements, without sacrificing labeling efficiency, final yield, or conjugate performance. PMID- 25813017 TI - Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates. AB - BACKGROUND: Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug. METHODS: The drugs were radiolabeled with (11)C (t 1/2 = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (KP) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (VT). Unbound KP (KP u,u) was obtained by correction for the free fraction in brain and plasma. RESULTS: After intravenous injection, the maximum radioactivity concentration (C max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C max, %ID was >2%, indicating a preferential distribution to brain. A lower C max, %ID was observed for morphine, sulpiride, and verapamil. K P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had KP u,u close to unity. For morphine, sulpiride, and verapamil, K P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs. CONCLUSIONS: This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates. PMID- 25813018 TI - Two Chronic Stress Models Based on Movement Restriction in Rats Respond Selectively to Antidepressant Drugs: Aldolase C As a Potential Biomarker. AB - BACKGROUND: Clinically depressed individuals respond to different types of antidepressants, suggesting that different neurobiological mechanisms may be responsible for their depression. However, animal models to characterize this are not yet available. METHODS: We induced depressive-like behaviors in rats using 2 different chronic stress models: restraint in small cages or immobilization in adaptable plastic cones. Both models increased anxiety responses evaluated by novelty-suppressed feeding and the elevated plus-maze; increased learned helplessness evaluated by the tail suspension and forced swimming tests; and increased anhedonia evaluated by the sucrose preference test. RESULTS: We assessed the ability of 2 different types of antidepressants to ameliorate depressive-like behaviors. We administered the serotonin reuptake inhibitor fluoxetine or the noradrenaline reuptake inhibitor reboxetine once daily for 28 days to rats that received either chronic restraint or immobilization stress, or no stress. Behavioral analysis revealed that fluoxetine ameliorated depressive like behaviors when induced by chronic restraint stress, whereas reboxetine ameliorated these behaviors when induced by chronic immobilization stress. To further test biological differences between both models, we evaluated the levels of Aldolase C, an enzyme expressed by forebrain astrocytes that is regulated by antidepressant treatment, in the cerebrospinal fluid: chronic restraint stress, but not immobilization stress, increased the levels of Aldolase C. Moreover, the presence of astrocyte-derived Aldolase C-GFP in the cerebrospinal fluid indicates its central origin. CONCLUSIONS: Two stress paradigms induced depressive-like behaviors that were sensitive to different antidepressant treatments. Biomarkers such as Aldolase C could help determine optimal antidepressant treatments for clinically depressed patients. PMID- 25813019 TI - Relationship between elastic properties of tendon structures and performance in long distance runners. AB - INTRODUCTION: The purpose of this study was to investigate the relationship between running performance (best official record in a 5000 m race) and elastic properties of tendon structures in knee extensors and plantar flexors among a large population of long distance runners. METHODS: Sixty-four highly trained male long distance runners participated in this study. Elongation of tendon structures in the knee extensors and plantar flexors was measured using ultrasonography while subjects performed ramp isometric contractions up to the voluntary maximum. The relationship between the estimated muscle force and tendon elongation was fit to a linear regression, the slope of which was defined as the stiffness of the tendon structures. Muscle and tendon thicknesses were also measured in the knee extensors and plantar flexors using ultrasonography. RESULTS: The best official record in a 5000 m race was negatively correlated to the stiffness of the tendon structures in the knee extensors (r = -0.341, p < 0.01), whereas it was positively correlated to the stiffness of the tendon structures in the plantar flexors (r = 0.414, p < 0.001). In both the knee extensors and plantar flexors, the other measured variables of muscle and tendon structures did not correlate with the best official record in a 5000 m race. CONCLUSION: These results suggested that better long distance runners had stiffer tendon structures in the knee extensors and more compliant ones in the plantar flexors. These results implied that tendon structures in knee extensors and plantar flexors adapted to endurance running training and contributed to running performance of long distance runners separately. PMID- 25813022 TI - A circular dichroism sensor for Ni(2+) and Co(2+) based on L-cysteine capped cadmium sulfide quantum dots. AB - A new circular dichroism sensor for detecting Ni(2+) and Co(2+) was proposed for the first time using chiral chelating quantum dots. The detection principle was based on changing of circular dichroism signals of the chiral quantum dots when forming a chiral complex with Ni(2+) or Co(2+). L-Cysteine capped cadmium sulfide quantum dots (L-Cyst-CdS QDs) were proposed as a chiral probe. The CD spectrum of L-Cyst-CdS QDs was significantly changed in the presence of Ni(2+) and Co(2+). On the other hand, other studied cations did not alter the original CD spectrum. Moreover, when increasing the concentration of Ni(2+) or Co(2+), the intensity of the CD spectrum linearly increased as a function of concentration and could be useful for the quantitative analysis. The proposed CD sensor showed linear working concentration ranges of 10-60 MUM and 4-80 MUM with low detection limits of 7.33 MUM and 1.13 MUM for the detection of Ni(2+) and Co(2+), respectively. Parameters possibly affected the detection sensitivity such as solution pH and incubation time were studied and optimized. The proposed sensor was applied to detect Ni(2+) and Co(2+) in real water samples, and the results agreed well with the analysis using the standard ICP-OES. PMID- 25813020 TI - HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF-Mutant Colorectal Cancer by Downregulation of c-FLIPL. AB - PURPOSE: Activating mutations in the BRAF oncogene are found in 8% to 15% of colorectal cancer patients and have been associated with poor survival. In contrast with BRAF-mutant (MT) melanoma, inhibition of the MAPK pathway is ineffective in the majority of BRAFMT colorectal cancer patients. Therefore, identification of novel therapies for BRAFMT colorectal cancer is urgently needed. EXPERIMENTAL DESIGN: BRAFMT and wild-type (WT) colorectal cancer models were assessed in vitro and in vivo. Small-molecule inhibitors of MEK1/2, MET, and HDAC were used, overexpression and siRNA approaches were applied, and cell death was assessed by flow cytometry, Western blotting, cell viability, and caspase activity assays. RESULTS: Increased c-MET-STAT3 signaling was identified as a novel adaptive resistance mechanism to MEK inhibitors (MEKi) in BRAFMT colorectal cancer models in vitro and in vivo. Moreover, MEKi treatment resulted in acute increases in transcription of the endogenous caspase-8 inhibitor c-FLIPL in BRAFMT cells, but not in BRAFWT cells, and inhibition of STAT3 activity abrogated MEKi-induced c-FLIPL expression. In addition, treatment with c-FLIP-specific siRNA or HDAC inhibitors abrogated MEKi-induced upregulation of c-FLIPL expression and resulted in significant increases in MEKi-induced cell death in BRAFMT colorectal cancer cells. Notably, combined HDAC inhibitor/MEKi treatment resulted in dramatically attenuated tumor growth in BRAFMT xenografts. CONCLUSIONS: Our findings indicate that c-MET/STAT3-dependent upregulation of c FLIPL expression is an important escape mechanism following MEKi treatment in BRAFMT colorectal cancer. Thus, combinations of MEKi with inhibitors of c-MET or c-FLIP (e.g., HDAC inhibitors) could be potential novel treatment strategies for BRAFMT colorectal cancer. PMID- 25813021 TI - Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate. AB - PURPOSE: Glutamine addiction in c-MYC-overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved. EXPERIMENTAL DESIGN: A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model. RESULTS: We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress-mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy. CONCLUSIONS: AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC-overexpressing breast cancers. PMID- 25813023 TI - Estimation of the bio-accessible fraction of Cr, As, Cd and Pb in locally available bread using on-line continuous leaching method coupled to inductively coupled plasma mass spectrometry. AB - A previously developed, efficient and simple on-line leaching method was used to assess the maximum bio-accessible fraction (assuming no synergistic effect from other food and beverage) of potentially toxic elements (Cr, As, Cd and Pb) in whole wheat brown and white bread samples. Artificial saliva, gastric juice and intestinal juice were successively pumped into a mini-column, packed with bread (maintained at 37 degrees C) connected on-line to the nebulizer of an inductively coupled plasma mass spectrometry (ICP-MS) instrument equipped with a collision-reaction interface (CRI) using hydrogen as reaction gas to minimize carbon- and chlorine-based polyatomic interferences. In contrast to the conventional batch method to which it was compared, this approach provides real time monitoring of potentially toxic elements that are continuously released during leaching. Mass balance for both methods was verified at the 95% confidence level. Results obtained from the whole wheat brown and white bread showed that the majority of Cr, Cd and Pb was leached by gastric juice but, in contrast, the majority of As was leached by saliva. While there was higher total content for elements in whole wheat bread than in white bread, a higher percentage of elements were bio-accessible in white bread than in whole wheat bread. Both the on-line and batch methods indicate that 40-98% of toxic elements in bread samples are bio-accessible. While comparison of total analyte concentrations with provisional tolerable daily intake values may indicate some serious health concern for children, when accounting for the bio-accessibility of these elements, bread consumption is found to be safe for all ages. PMID- 25813024 TI - Spectroscopic analyses of chemical adaptation processes within microalgal biomass in response to changing environments. AB - Via photosynthesis, marine phytoplankton transforms large quantities of inorganic compounds into biomass. This has considerable environmental impacts as microalgae contribute for instance to counter-balancing anthropogenic releases of the greenhouse gas CO2. On the other hand, high concentrations of nitrogen compounds in an ecosystem can lead to harmful algae blooms. In previous investigations it was found that the chemical composition of microalgal biomass is strongly dependent on the nutrient availability. Therefore, it is expected that algae's sequestration capabilities and productivity are also determined by the cells' chemical environments. For investigating this hypothesis, novel analytical methodologies are required which are capable of monitoring live cells exposed to chemically shifting environments followed by chemometric modeling of their chemical adaptation dynamics. FTIR-ATR experiments have been developed for acquiring spectroscopic time series of live Dunaliella parva cultures adapting to different nutrient situations. Comparing experimental data from acclimated cultures to those exposed to a chemically shifted nutrient situation reveals insights in which analyte groups participate in modifications of microalgal biomass and on what time scales. For a chemometric description of these processes, a data model has been deduced which explains the chemical adaptation dynamics explicitly rather than empirically. First results show that this approach is feasible and derives information about the chemical biomass adaptations. Future investigations will utilize these instrumental and chemometric methodologies for quantitative investigations of the relation between chemical environments and microalgal sequestration capabilities. PMID- 25813025 TI - An electrochemical DNA-sensor developed with the use of methylene blue as a redox indicator for the detection of DNA damage induced by endocrine-disrupting compounds. AB - An electrochemical biosensor capable of indirect detection of DNA damage induced by any one of the three endocrine-disrupting compounds (EDCs) - bisphenol A (BPA), 4-nonylphenol (NP) and 4-t-octylphenol (OP), has been researched and developed. The methylene blue (MB) dye was used as the redox indicator. The glassy carbon electrode (GCE) was modified by the assembled dsDNA/graphene oxide chitosan/gold nano-particles to produce a dsDNA/GO-CS/AuNPs/GCE sensor. It was characterized with the use of electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and scanning electron microscopy (SEM) techniques. The loading/release of the MB dye by the dsDNA/GO-CS/AuNPs film was investigated, and the results showed that the process was reversible. Based on this, the sensor was used to measure the difference between the loading capabilities of intact and damaged dsDNA in the films. The sensor was then successfully applied to detect DNA damage electrochemically. The differential pulse voltammetry (DPV) peak current ratio for MB, observed before and after DNA damage, increased linearly in the presence the BPA, NP or OP compounds; the treatment range was 10-60 min, and the respective damage rates were 0.0069, 0.0044 and 0.0031 min(-1), respectively. These results were confirmed by the binding constants: 2.09*10(6) M(-1) (BPA DNA), 1.28*10(6) M(-1) (NP-DNA) and 9.33*10(5) M(-1) (OP-DNA), all of which were obtained with the use of differential pulse stripping voltammetry (DPSV). PMID- 25813026 TI - In situ growth and phenyl functionalization of titania nanoparticles coating for solid-phase microextraction of ultraviolet filters in environmental water samples followed by high performance liquid chromatography-UV detection. AB - Based on TiO2-nanoparticles coating fabricated by a one-step anodization method on titanium wire substrate, a novel phenyl functionalized solid-phase microextraction (SPME) fiber coating was prepared by simple and rapid in situ chemical assembling technique between the fiber surface titanol groups and trichlorophenylsilane reaction. The as-fabricated fiber exhibited good extraction capability for some UV filters and was employed to determine the ultraviolet (UV) filters in combination with high performance liquid chromatography-UV detection (HPLC-UV). The main parameters affecting extraction performance were investigated and optimized. Under the optimized conditions, the developed method was applied to detect several UV filters at trace concentration levels with only 8 mL of sample volume. They were determined in the range from 0.005 to 25 MUg L(-1) with detection limits (S/N=3) from 0.1 to 50 ng L(-1). The relative standard deviations (RSDs) for single fiber repeatability varied from 4.6 to 6.5% (n=5) and fiber-to-fiber reproducibility (n=5) ranged from 5.5 to 9.1%. The linear ranges spanned two-four magnitudes with correlation coefficients above 0.9990. Five real water samples including four Yellow River water samples and one rain water sample were determined sensitively with good recoveries ranging from 86.2 to 105.5%. The functionalized fiber coating performed good reproducible manner, high mechanical strength, good stability and long service life. Moreover, this study proposed an efficient sample pretreatment method for the determination of UV filters from environmental water samples. PMID- 25813027 TI - Polyglycerol based coatings to reduce non-specific protein adsorption in sample vials and on SPR sensors. AB - Coatings based on dendritic polyglycerol (dPG) were investigated for their use to control nonspecific protein adsorption in an assay targeted to analyze concentrations of a specific protein. We demonstrate that coating of the sample vial with dPG can significantly increase the recovery of an antibody after incubation. First, we determine the concentration dependent loss of an antibody due to nonspecific adsorption to glass via quartz crystal microbalance (QCM). Complementary to the QCM measurements, we applied the same antibody as analyte in an surface plasmon resonance (SPR) assay to determine the loss of analyte due to nonspecific adsorption to the sample vial. For this purpose, we used two different coatings based on dPG. For the first coating, which served as a matrix for the SPR sensor, carboxyl groups were incorporated into dPG as well as a dithiolane moiety enabling covalent immobilization to the gold sensor surface. This SPR-matrix exhibited excellent protein resistant properties and allowed the immobilization of amyloid peptides via amide bond formation. The second coating which was intended to prevent nonspecific adsorption to glass vials comprised a silyl moiety that allowed covalent grafting to glass. For demonstrating the impact of the vial coating on the accuracy of an SPR assay, we immobilized amyloid beta (Abeta) 1-40 and used an anti-Abeta 1-40 antibody as analyte. Alternate injection of analyte into the flow cell of the SPR device from uncoated and coated vials, respectively gave us the relative signal loss (1 RUuncoated/RUcoated) caused by the nonspecific adsorption. We found that the relative signal loss increases with decreasing analyte concentration. The SPR data correlate well with concentration dependent non-specific adsorption experiments of the analyte to glass surfaces performed with QCM. Our measurements show that rendering both the sample vial and the sensor surface is crucial for accurate results in protein assays. PMID- 25813028 TI - Development of a systematic approach to rapid classification and identification of notoginsenosides and metabolites in rat feces based on liquid chromatography coupled triple time-of-flight mass spectrometry. AB - The present work contributes to the development of a powerful technical platform to rapidly identify and classify complicated components and metabolites for traditional Chinese medicines. In this process, notoginsenosides, the main active ingredients in Panaxnotoginseng, were chosen as model compounds. Firstly, the fragmental patterns, diagnostic product ions and neutral loss of each subfamily of notoginsenosides were summarized by collision-induced dissociation analysis of representative authentic standards. Next, in order to maximally cover low concentration components which could otherwise be omitted from previous diagnostic fragment-ion method using only single product ion of notoginsenosides, a multiple product ions filtering strategy was proposed and utilized to identify and classify both non-target and target notoginsenosides of P.notoginseng extract (in vitro). With this strategy, 13 protopanaxadiol-type notoginsenosides and 30 protopanaxatriol-type notoginsenosides were efficiently extracted. Then, a neutral loss filtering technique was employed to trace prototype components and metabolites in rats (in vivo) since diagnostic product ions might shift therefore become unpredictable when metabolic reactions occurred on the mother skeleton of notoginsenosides. After comparing the constitute profiles in vitro with in vivo, 62 drug-related components were identified from rat feces, and these components were classified into 27 prototype compounds and 35 metabolites. Lastly, all the metabolites were successfully correlated to their parent compounds based on chemicalome-metabolome matching approach which was previously built by our group. This study provided a generally applicable approach to global metabolite identification for the complicated components in complex matrices. PMID- 25813029 TI - Humidity independent mass spectrometry for gas phase chemical analysis via ambient proton transfer reaction. AB - In this work, a humidity independent mass spectrometric method was developed for rapid analysis of gas phase chemicals. This method is based upon ambient proton transfer reaction between gas phase chemicals and charged water droplets, in a reaction chamber with nearly saturate humidity under atmospheric pressure. The humidity independent nature enables direct and rapid analysis of raw gas phase samples, avoiding time- and sample-consuming sample pretreatments in conventional mass spectrometry methods to control sample humidity. Acetone, benzene, toluene, ethylbenzene and meta-xylene were used to evaluate the analytical performance of present method. The limits of detection for benzene, toluene, ethylbenzene and meta-xylene are in the range of ~0.1 to ~0.3 ppbV; that of benzene is well below the present European Union permissible exposure limit for benzene vapor (5 MUg m( 3), ~1.44 ppbV), with linear ranges of approximately two orders of magnitude. The majority of the homemade device contains a stainless steel tube as reaction chamber and an ultrasonic humidifier as the source of charged water droplets, which makes this cheap device easy to assemble and facile to operate. In addition, potential application of this method was illustrated by the real time identification of raw gas phase chemicals released from plants at different physiological stages. PMID- 25813030 TI - An affinity improved single-chain antibody from phage display of a library derived from monoclonal antibodies detects fumonisins by immunoassay. AB - Fumonisin B analogs, particularly FB1, FB2, and FB3, are major mycotoxins found in cereals. Single-chain fragment variable (scFv) antibodies represent a promising alternative immunoassay system. A phage-displayed antibody library derived from four monoclonal antibodies (mAbs) generated against FB1 was used to screen high binding affinity scFv antibodies; the best candidate was designated H2. Surface plasmon resonance measurements confirmed that the H2 scFv displayed a 82-fold higher binding affinity than its parent mAb. Direct competitive enzyme linked immunosorbent assay demonstrated that the H2 antibody could competitively bind to free FB1, FB2, and FB3, with an IC50 of 0.11, 0.04, and 0.10 MUM, respectively; it had no cross-reactivity to deoxynivalenol, nivalenol and aflatoxin. Validation assays with naturally contaminated samples revealed a linear relationship between the H2 antibody-based assay results and chemical analysis results, that could be expressed as y=1.7072x+5.5606 (R(2)=0.8883). Homology modeling of H2 revealed a favorable binding structure highly complementary to the three fumonisins. Molecular docking analyses suggested that the preferential binding of the H2 scFv to FB2 was due to the presence of a hydrogen radical in its R1 position, leading to a proper electrostatic matching and hydrophobic interaction. The H2 scFv antibody can be used for the rapid, accurate, and specific detection of fumonisin contamination in agricultural samples. PMID- 25813031 TI - Direct electron transfer of glucose oxidase and dual hydrogen peroxide and glucose detection based on water-dispersible carbon nanotubes derivative. AB - A water-dispersible multi-walled carbon nanotubes (MWCNTs) derivative, MWCNTs-1 one-dihydroxypyridine (MWCNTs-Py) was synthesis via Friedel-Crafts chemical acylation. Raman spectra demonstrated the conjugated level of MWCNTs-Py was retained after this chemical modification. MWCNTs-Py showed dual hydrogen peroxide (H2O2) and glucose detections without mutual interference by adjusting pH value. It was sensitive to H2O2 in acidic solution and displayed the high performances of sensitivity, linear range, response time and stability; meanwhile it did not respond to H2O2 in neutral solution. In addition, this positively charged MWCNTs-Py could adsorb glucose oxidase (GOD) by electrostatic attraction. MWCNTs-Py-GOD/GC electrode showed the direct electron transfer (DET) of GOD with a pair of well-defined redox peaks, attesting the bioactivity of GOD was retained due to the non-destroyed immobilization. The high surface coverage of active GOD (3.5*10(-9) mol cm(-2)) resulted in exhibiting a good electrocatalytic activity toward glucose. This glucose sensor showed high sensitivity (68.1 MUA mM(-1) cm( 2)) in a linear range from 3 MUM to 7 mM in neutral buffer solution. The proposed sensor could distinguish H2O2 and glucose, thus owning high selectivity and reliability. PMID- 25813032 TI - Statistical analysis of texture in trunk images for biometric identification of tree species. AB - The identification of tree species is a key step for sustainable management plans of forest resources, as well as for several other applications that are based on such surveys. However, the present available techniques are dependent on the presence of tree structures, such as flowers, fruits, and leaves, limiting the identification process to certain periods of the year. Therefore, this article introduces a study on the application of statistical parameters for texture classification of tree trunk images. For that, 540 samples from five Brazilian native deciduous species were acquired and measures of entropy, uniformity, smoothness, asymmetry (third moment), mean, and standard deviation were obtained from the presented textures. Using a decision tree, a biometric species identification system was constructed and resulted to a 0.84 average precision rate for species classification with 0.83accuracy and 0.79 agreement. Thus, it can be considered that the use of texture presented in trunk images can represent an important advance in tree identification, since the limitations of the current techniques can be overcome. PMID- 25813033 TI - Identification of key factors influencing primary productivity in two river-type reservoirs by using principal component regression analysis. AB - To understand the factors controlling algal production in two lakes located on the Han River in South Korea, Lake Cheongpyeong and Lake Paldang, a principal component regression model study was conducted using environmental monitoring and primary productivity data. Although the two lakes were geographically close and located along the same river system, the main factors controlling primary productivity in each lake were different: hydraulic retention time and light conditions predominantly influenced algal productivity in Lake Cheongpyeong, while hydraulic retention time, chlorophyll a-specific productivity, and zooplankton grazing rate were most important in Lake Paldang. This investigation confirmed the utility of principal component regression analysis using environmental monitoring data for predicting complex biological processes such as primary productivity; in addition, the study also increased the understanding of explicit interactions between environmental variables. The findings obtained in this research will be useful for the adaptive management of water reservoirs. The results will also aid in the development of management strategies for water resources, thereby improving total environmental conservation. PMID- 25813035 TI - Modifications in trypsin digestion protocol for increasing the efficiency and coverage. AB - Standard trypsin digestion protocol of proteins followed by MALDI-MS analysis has been realized as an important tool for the identification and characterization of proteins. In this article, we proposed the elimination of the step of 'staining/de-staining of gel pieces' in in-gel digestion protocol in order to improve the efficiency of trypsin digestion. Coomassie dye is known to interfere with digestion of proteins by trypsin and the procedure of staining-de-staining could result in loss of photoaffinity probe, post translational modifications and catalytic activities of enzymes. Further, we studied parameters like hydrophobicity and isoelectric point, and attempted to quantitatively relate it to the efficiency of trypsin digestion. We suggest that properties of proteins should be considered and trypsin digestion protocol should be appropriately modified as per sequence and other information. PMID- 25813034 TI - Double trouble: should double embryo transfer be banned? AB - What role should legislation or policy play in avoiding the complications of in vitro fertilization? In this article, we focus on single versus double embryo transfer, and assess three arguments in favour of mandatory single embryo transfer: risks to the mother, risks to resultant children, and costs to society. We highlight significant ethical concerns about each of these. Reproductive autonomy and non-paternalism are strong enough to outweigh the health concerns for the woman. Complications due to non-identity cast doubt on the extent to which children are harmed. Twinning may offer an overall benefit rather than burden to society. Finally, including the future health costs for children (not yet born) in reproductive policy is inconsistent with other decisions. We conclude that mandatory single embryo transfer is not justified and that a number of countries should reconsider their current embryo transfer policy. PMID- 25813037 TI - Incorporating anti-VEGF pathway therapy as a continuum of care in metastatic colorectal cancer. AB - Metastatic cancer was previously treated with distinctive lines of chemotherapy regimens upon disease progression or toxicity, yet the choices of therapy are actually interrelated, with the selection of a first-line regimen in part determining the choices available for subsequent treatment. Lately the therapeutic approach based on separate lines of treatment, tends to be replaced from a perspective strategical approach, that of the "continuum of care". This strategy targets to an improved overall survival, improved of quality of life and minimization of toxicity through upfront design of treatment selection and sequencing, exposure to all available drugs and minimization of unnecessary treatment. Anti-VEGF treatment has a well-documented role in this approach. Bevacizumab should be included in upfront treatment regimens for all mCRC patients independently of RAS status, unless contraindicated. Upfront bevacizumab could be combined with all available regimens since the optimal choice of backbone chemotherapy is yet to be defined. In RAS wild-type population, when metastasectomy is the target, an anti-EGFR combination is also a valid approach. Maintenance with bevacizumab and fluoropyrimidines should be considered upon intolerance of induction treatment and/or disease stabilization; maintenance with bevacizumab monotherapy should be avoided. In highly selected patients, complete treatment cessation could be also an option. Continuation with bevacizumab upon first progression and switch of the "backbone" chemotherapy is a validated approach. Patients progressing after first-line oxaliplatin regimen including bevacizumab combinations could be treated with an aflibercept-irinotecan combination. When no more options are available, regorafenib monotherapy should be the following choice. Combinations of anti-VEGF and anti-EGFR treatment have no place in this approach and are not indicated. PMID- 25813036 TI - Molecular classification of gastric adenocarcinoma: translating new insights from the cancer genome atlas research network. AB - Gastric cancer is a heterogenous cancer, which may be classified into several distinct subtypes based on pathology and epidemiology, each with different initiating pathological processes and each possibly having different tumor biology. A classification of gastric cancer should be important to select patients who can benefit from the targeted therapies or to precisely predict prognosis. The Cancer Genome Atlas (TCGA) study collaborated with previous reports regarding subtyping gastric cancer but also proposed a refined classification based on molecular characteristics. The addition of the new molecular classification strategy to a current classical subtyping may be a promising option, particularly stratification by Epstein-Barr virus (EBV) and microsatellite instability (MSI) statuses. According to TCGA study, EBV gastric cancer patients may benefit the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies or phosphoinositide 3-kinase (PI3K) inhibitors which are now being developed. The discoveries of predictive biomarkers should improve patient care and individualized medicine in the management since the targeted therapies may have the potential to change the landscape of gastric cancer treatment, moreover leading to both better understanding of the heterogeneity and better outcomes. Patient enrichment by predictive biomarkers for new treatment strategies will be critical to improve clinical outcomes. Additionally, liquid biopsies will be able to enable us to monitor in real-time molecular escape mechanism, resulting in better treatment strategies. PMID- 25813038 TI - AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage. AB - Post-translational modifications of core histones affect various cellular processes, primarily through transcription. However, their relationship with the termination of transcription has remained largely unknown. In this study, we show that DNA damage-activated AKT phosphorylates threonine 45 of core histone H3 (H3 T45). By genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis, H3-T45 phosphorylation was distributed throughout DNA damage-responsive gene loci, particularly immediately after the transcription termination site. H3 T45 phosphorylation pattern showed close-resemblance to that of RNA polymerase II C-terminal domain (CTD) serine 2 phosphorylation, which establishes the transcription termination signal. AKT1 was more effective than AKT2 in phosphorylating H3-T45. Blocking H3-T45 phosphorylation by inhibiting AKT or through amino acid substitution limited RNA decay downstream of mRNA cleavage sites and decreased RNA polymerase II release from chromatin. Our findings suggest that AKT-mediated phosphorylation of H3-T45 regulates the processing of the 3' end of DNA damage-activated genes to facilitate transcriptional termination. PMID- 25813039 TI - H3K4 monomethylation dictates nucleosome dynamics and chromatin remodeling at stress-responsive genes. AB - Chromatin remodeling is essential for proper adaptation to extracellular stimuli. The p38-related Hog1 SAPK is an important regulator of transcription that mediates chromatin remodeling upon stress. Hog1 targets the RSC chromatin remodeling complex to stress-responsive genes and rsc deficient cells display reduced induction of gene expression. Here we show that the absence of H3K4 methylation, either achieved by deletion of the SET1 methyltransferase or by amino acid substitution of H3K4, bypasses the requirement of RSC for stress responsive gene expression. Monomethylation of H3K4 is specifically inhibiting RSC-independent chromatin remodeling and thus, it prevents osmostress-induced gene expression. The absence of H3K4 monomethylation permits that the association of alternative remodelers with stress-responsive genes and the Swr1 complex (SWR C) is instrumental in the induction of gene expression upon stress. Accordingly, the absence of SWR-C or histone H2A.Z results in compromised chromatin remodeling and impaired gene expression in the absence of RSC and H3K4 methylation. These results indicate that expression of stress-responsive genes is controlled by two remodeling mechanisms: RSC in the presence of monomethylated H3K4, and SWR-C in the absence of H3K4 monomethylation. Our findings point to a novel role for H3K4 monomethylation in dictating the specificity of chromatin remodeling, adding an extra layer of regulation to the transcriptional stress response. PMID- 25813040 TI - Intramolecular circularization increases efficiency of RNA sequencing and enables CLIP-Seq of nuclear RNA from human cells. AB - RNA sequencing (RNA-Seq) is a powerful tool for analyzing the identity of cellular RNAs but is often limited by the amount of material available for analysis. In spite of extensive efforts employing existing protocols, we observed that it was not possible to obtain useful sequencing libraries from nuclear RNA derived from cultured human cells after crosslinking and immunoprecipitation (CLIP). Here, we report a method for obtaining strand-specific small RNA libraries for RNA sequencing that requires picograms of RNA. We employ an intramolecular circularization step that increases the efficiency of library preparation and avoids the need for intermolecular ligations of adaptor sequences. Other key features include random priming for full-length cDNA synthesis and gel-free library purification. Using our method, we generated CLIP Seq libraries from nuclear RNA that had been UV-crosslinked and immunoprecipitated with anti-Argonaute 2 (Ago2) antibody. Computational protocols were developed to enable analysis of raw sequencing data and we observe substantial differences between recognition by Ago2 of RNA species in the nucleus relative to the cytoplasm. This RNA self-circularization approach to RNA sequencing (RC-Seq) allows data to be obtained using small amounts of input RNA that cannot be sequenced by standard methods. PMID- 25813042 TI - Epigenetic regulation of intragenic transposable elements impacts gene transcription in Arabidopsis thaliana. AB - Genomes of higher eukaryotes, including plants, contain numerous transposable elements (TEs), that are often silenced by epigenetic mechanisms, such as histone modifications and DNA methylation. Although TE silencing adversely affects expression of nearby genes, recent studies reveal the presence of intragenic TEs marked by repressive heterochromatic epigenetic marks within transcribed genes. However, even for the well-studied plant model Arabidopsis thaliana, the abundance of intragenic TEs, how they are epigenetically regulated, and their potential impacts on host gene expression, remain unexplored. In this study, we comprehensively analyzed genome-wide distribution and epigenetic regulation of intragenic TEs in A. thaliana. Our analysis revealed that about 3% of TEs are located within gene bodies, dominantly at intronic regions. Most of them are shorter and less methylated than intergenic TEs, but they are still targeted by RNA-directed DNA methylation-dependent and independent pathways. Surprisingly, the heterochromatic epigenetic marks at TEs are maintained within actively transcribed genes. Moreover, the heterochromatic state of intronic TEs is critical for proper transcription of associated genes. Our study provides the first insight into how intragenic TEs affect the transcriptional landscape of the A. thaliana genome, and suggests the importance of epigenetic mechanisms for regulation of TEs within transcriptional gene units. PMID- 25813041 TI - The NEIL glycosylases remove oxidized guanine lesions from telomeric and promoter quadruplex DNA structures. AB - G-quadruplex is a four-stranded G-rich DNA structure that is highly susceptible to oxidation. Despite the important roles that G-quadruplexes play in telomere biology and gene transcription, neither the impact of guanine lesions on the stability of quadruplexes nor their repair are well understood. Here, we show that the oxidized guanine lesions 8-oxo-7,8-dihydroguanine (8-oxoG), guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) reduce the thermostability and alter the folding of telomeric quadruplexes in a location-dependent manner. Also, the NEIL1 and NEIL3 DNA glycosylases can remove hydantoin lesions but none of the glycosylases, including OGG1, are able to remove 8-oxoG from telomeric quadruplexes. Interestingly, a hydantoin lesion at the site most prone to oxidation in quadruplex DNA is not efficiently removed by NEIL1 or NEIL3. However, NEIL1, NEIL2 and NEIL3 remove hydantoins from telomeric quadruplexes formed by five TTAGGG repeats much more rapidly than the commonly studied four repeat quadruplex structures. We also show that APE1 cleaves furan in selected positions in Na(+)-coordinated telomeric quadruplexes. In promoter G-quadruplex DNA, the NEIL glycosylases primarily remove Gh from Na(+)-coordinated antiparallel quadruplexes but not K(+)-coordinated parallel quadruplexes containing VEGF or c-MYC promoter sequences. Thus, the NEIL DNA glycosylases may be involved in both telomere maintenance and in gene regulation. PMID- 25813043 TI - Subunit compositions of Arabidopsis RNA polymerases I and III reveal Pol I- and Pol III-specific forms of the AC40 subunit and alternative forms of the C53 subunit. AB - Using affinity purification and mass spectrometry, we identified the subunits of Arabidopsis thaliana multisubunit RNA polymerases I and III (abbreviated as Pol I and Pol III), the first analysis of their physical compositions in plants. In all eukaryotes examined to date, AC40 and AC19 subunits are common to Pol I (a.k.a. Pol A) and Pol III (a.k.a. Pol C) and are encoded by single genes. Surprisingly, A. thaliana and related species express two distinct AC40 paralogs, one of which assembles into Pol I and the other of which assembles into Pol III. Changes at eight amino acid positions correlate with the functional divergence of Pol I- and Pol III-specific AC40 paralogs. Two genes encode homologs of the yeast C53 subunit and either protein can assemble into Pol III. By contrast, only one of two potential C17 variants, and one of two potential C31 variants were detected in Pol III. We introduce a new nomenclature system for plant Pol I and Pol III subunits in which the 12 subunits that are structurally and functionally homologous among Pols I through V are assigned equivalent numbers. PMID- 25813044 TI - SubmiRine: assessing variants in microRNA targets using clinical genomic data sets. AB - MicroRNAs (miRNAs) regulate gene expression by binding to partially complementary sequences on target mRNA transcripts, thereby causing their degradation, deadenylation, or inhibiting their translation. Genomic variants can alter miRNA regulation by modifying miRNA target sites, and multiple human disease phenotypes have been linked to such miRNA target site variants (miR-TSVs). However, systematic genome-wide identification of functional miR-TSVs is difficult due to high false positive rates; functional miRNA recognition sequences can be as short as six nucleotides, with the human genome encoding thousands of miRNAs. Furthermore, while large-scale clinical genomic data sets are becoming increasingly commonplace, existing miR-TSV prediction methods are not designed to analyze these data. Here, we present an open-source tool called SubmiRine that is designed to perform efficient miR-TSV prediction systematically on variants identified in novel clinical genomic data sets. Most importantly, SubmiRine allows for the prioritization of predicted miR-TSVs according to their relative probability of being functional. We present the results of SubmiRine using integrated clinical genomic data from a large-scale cohort study on chronic obstructive pulmonary disease (COPD), making a number of high-scoring, novel miR TSV predictions. We also demonstrate SubmiRine's ability to predict and prioritize known miR-TSVs that have undergone experimental validation in previous studies. PMID- 25813045 TI - Post-conversion targeted capture of modified cytosines in mammalian and plant genomes. AB - We present a capture-based approach for bisulfite-converted DNA that allows interrogation of pre-defined genomic locations, allowing quantitative and qualitative assessments of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) at CG dinucleotides and in non-CG contexts (CHG, CHH) in mammalian and plant genomes. We show the technique works robustly and reproducibly using as little as 500 ng of starting DNA, with results correlating well with whole genome bisulfite sequencing data, and demonstrate that human DNA can be tested in samples contaminated with microbial DNA. This targeting approach will allow cell type-specific designs to maximize the value of 5mC and 5hmC sequencing. PMID- 25813046 TI - Disruption of PARP1 function inhibits base excision repair of a sub-set of DNA lesions. AB - The repair of endogenously induced DNA damage is essential to maintain genomic integrity. It has been shown that XRCC1 and PARP1 are involved in the repair of base lesions and SSBs, although the exact mode of action has yet to be determined. Here we show that XRCC1 is involved in the repair of base lesions and SSBs independent of the cell cycle. However, the rate of repair of damage requiring XRCC1 does reflect the damage complexity. The repair of induced DNA damage occurs by PARP1-dependent and PARP1-independent sub-pathways of BER. It is suggested that the repair of SSBs and purine base damage is by a sub-pathway of BER that requires both XRCC1 and PARP1. Repair of pyrimidine base damage may require XRCC1 but does not require PARP1 activity. Therefore, although BER of simple lesions occurs rapidly, pathway choice and the involvement of PARP1 are highly dependent on the types of lesion induced. PMID- 25813048 TI - RiceNet v2: an improved network prioritization server for rice genes. AB - Rice is the most important staple food crop and a model grass for studies of bioenergy crops. We previously published a genome-scale functional network server called RiceNet, constructed by integrating diverse genomics data and demonstrated the use of the network in genetic dissection of rice biotic stress responses and its usefulness for other grass species. Since the initial construction of the network, there has been a significant increase in the amount of publicly available rice genomics data. Here, we present an updated network prioritization server for Oryza sativa ssp. japonica, RiceNet v2 (http://www.inetbio.org/ricenet), which provides a network of 25 765 genes (70.1% of the coding genome) and 1 775 000 co-functional links. Ricenet v2 also provides two complementary methods for network prioritization based on: (i) network direct neighborhood and (ii) context-associated hubs. RiceNet v2 can use genes of the related subspecies O. sativa ssp. indica and the reference plant Arabidopsis for versatility in generating hypotheses. We demonstrate that RiceNet v2 effectively identifies candidate genes involved in rice root/shoot development and defense responses, demonstrating its usefulness for the grass research community. PMID- 25813047 TI - New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey. AB - Hoogsteen (HG) base pairs (bps) provide an alternative pairing geometry to Watson Crick (WC) bps and can play unique functional roles in duplex DNA. Here, we use structural features unique to HG bps (syn purine base, HG hydrogen bonds and constricted C1'-C1' distance across the bp) to search for HG bps in X-ray structures of DNA duplexes in the Protein Data Bank. The survey identifies 106 A*T and 34 G*C HG bps in DNA duplexes, many of which are undocumented in the literature. It also uncovers HG-like bps with syn purines lacking HG hydrogen bonds or constricted C1'-C1' distances that are analogous to conformations that have been proposed to populate the WC-to-HG transition pathway. The survey reveals HG preferences similar to those observed for transient HG bps in solution by nuclear magnetic resonance, including stronger preferences for A*T versus G*C bps, TA versus GG steps, and also suggests enrichment at terminal ends with a preference for 5'-purine. HG bps induce small local perturbations in neighboring bps and, surprisingly, a small but significant degree of DNA bending (~14 degrees ) directed toward the major groove. The survey provides insights into the preferences and structural consequences of HG bps in duplex DNA. PMID- 25813051 TI - Synthesis and characterization of a new mid-infrared transparent compound: acentric Ba5In4Te4S7. AB - A new noncentrosymmetric (NCS) sulfide, Ba5In4Te4S7, was synthesized by a conventional solid-state reaction in evacuated closed silica tubes. The compound crystallizes in the orthorhombic space group Imm2 (44), with unit cell parameters a = 39.110(3) A, b = 4.3763(3) A, c = 7.3452(6) A, Z = 2, and V = 1257.18(17) A(3). The 3D framework of Ba5In4Te4S7 is composed of infinite 1(infinity)[InS2Te2](5-) and 1(infinity)[In2S3Te2](4-) anionic chains. The optical band gap of Ba5In4Te4S7 is 2.13 eV and it shows the UV-visible cutoff at 0.57 MUm and the infrared transparency extends to 25 MUm. The compound exhibits a powder second harmonic generation (SHG) signal at 2.05 MUm with about half of the AgGaS2 at a particle size of 74-106 MUm. According to first-principles calculation, the calculated major SHG tensor element is d32 = 18.8 pm V(-1). The SHG process of nonlinear optical response of Ba5In4Te4S7 originates from the electronic transitions from occupied S-3p and Te-5p states to unoccupied In-5s and In-5p states. PMID- 25813049 TI - A new approach for annotation of transposable elements using small RNA mapping. AB - Transposable elements (TEs) are mobile genomic DNA sequences found in most organisms. They so densely populate the genomes of many eukaryotic species that they are often the major constituents. With the rapid generation of many plant genome sequencing projects over the past few decades, there is an urgent need for improved TE annotation as a prerequisite for genome-wide studies. Analogous to the use of RNA-seq for gene annotation, we propose a new method for de novo TE annotation that uses as a guide 24 nt-siRNAs that are a part of TE silencing pathways. We use this new approach, called TASR (for Transposon Annotation using Small RNAs), for de novo annotation of TEs in Arabidopsis, rice and soybean and demonstrate that this strategy can be successfully applied for de novo TE annotation in plants.Executable PERL is available for download from: http://tasr pipeline.sourceforge.net/. PMID- 25813050 TI - Regulation of yeast DNA polymerase delta-mediated strand displacement synthesis by 5'-flaps. AB - The strand displacement activity of DNA polymerase delta is strongly stimulated by its interaction with proliferating cell nuclear antigen (PCNA). However, inactivation of the 3'-5' exonuclease activity is sufficient to allow the polymerase to carry out strand displacement even in the absence of PCNA. We have examined in vitro the basic biochemical properties that allow Pol delta-exo(-) to carry out strand displacement synthesis and discovered that it is regulated by the 5'-flaps in the DNA strand to be displaced. Under conditions where Pol delta carries out strand displacement synthesis, the presence of long 5'-flaps or addition in trans of ssDNA suppress this activity. This suggests the presence of a secondary DNA binding site on the enzyme that is responsible for modulation of strand displacement activity. The inhibitory effect of a long 5'-flap can be suppressed by its interaction with single-stranded DNA binding proteins. However, this relief of flap-inhibition does not simply originate from binding of Replication Protein A to the flap and sequestering it. Interaction of Pol delta with PCNA eliminates flap-mediated inhibition of strand displacement synthesis by masking the secondary DNA site on the polymerase. These data suggest that in addition to enhancing the processivity of the polymerase PCNA is an allosteric modulator of other Pol delta activities. PMID- 25813053 TI - Effect of density on traffic and velocity on trunk trails of Formica pratensis. AB - The allocation of large numbers of workers facilitates the swift intake of locally available resources which is essential for ant colony survival. To organise the traffic between nest and food source, the black-meadow ant Formica pratensis establishes permanent trunk trails, which are maintained by the ants. To unravel the ant organisation and potential traffic rules on these trails, we analysed velocity and lane segregation under various densities by experimentally changing feeding regimes. Even under the highest ant densities achieved, we never observed any traffic jams. On the contrary, velocity increased after supplementary feeding despite an enhanced density. Furthermore, inbound ants returning to the nest had a higher velocity than those leaving the colony. Whilst at low and medium density the ants used the centre of the trail, they used the full width of the trail at high density. Outbound ants also showed some degree of lane segregation which contributes to traffic organisation. PMID- 25813054 TI - Experimental comparison of empirical material decomposition methods for spectral CT. AB - Material composition can be estimated from spectral information acquired using photon counting x-ray detectors with pulse height analysis. Non-ideal effects in photon counting x-ray detectors such as charge-sharing, k-escape, and pulse pileup distort the detected spectrum, which can cause material decomposition errors. This work compared the performance of two empirical decomposition methods: a neural network estimator and a linearized maximum likelihood estimator with correction (A-table method). The two investigated methods differ in how they model the nonlinear relationship between the spectral measurements and material decomposition estimates. The bias and standard deviation of material decomposition estimates were compared for the two methods, using both simulations and experiments with a photon-counting x-ray detector. Both the neural network and A-table methods demonstrated a similar performance for the simulated data. The neural network had lower standard deviation for nearly all thicknesses of the test materials in the collimated (low scatter) and uncollimated (higher scatter) experimental data. In the experimental study of Teflon thicknesses, non-ideal detector effects demonstrated a potential bias of 11-28%, which was reduced to 0.1-11% using the proposed empirical methods. Overall, the results demonstrated preliminary experimental feasibility of empirical material decomposition for spectral CT using photon-counting detectors. PMID- 25813055 TI - Young Investigator Perspectives. A delicate balance: career development activities and laboratory research. PMID- 25813058 TI - Cryptogenic stroke: clinical consideration of a heterogeneous ischemic subtype. AB - BACKGROUND: Cryptogenic stroke can be subdivided into 3 distinct categories: stroke of no determined cause (CyNC), stroke due to multiple etiologies (Cy >1), and stroke etiology unclear due to incomplete evaluation. Although these subdivisions may be very different from one another with respect to baseline features and outcomes, they are often reported as a composite group in clinical trials. METHODS: Patients treated at our academic institution between July 2008 and June 2013 for acute ischemic stroke were retrospectively assessed in our prospective registry. CyNC and Cy >1 patients were compared to other Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke subtypes and to each other using univariate analyses and multivariate logistic regression. The primary outcome of interest was good functional outcome, defined as a discharge modified Rankin Scale score of 0-2. RESULTS: Of the 1311 included patients, 260 (19.8%) experienced a CyNC and 49 (3.7%) experienced a Cy >1. Cy >1 classification was associated with history of atrial fibrillation (odds ratio [OR], 3.17; 95% confidence interval [CI], 1.16-6.12; P = .001). In comparison to other TOAST classifications, CyNC strokes were more likely to have good functional outcome (OR, 1.97; 95% CI, 1.38-2.82; P < .001) after adjusting for baseline National Institutes of Health Stroke Scale, admission glucose, age, and intravenous tissue plasminogen activator (IV tPA). CONCLUSIONS: Even after adjusting for higher IV tPA treatment rates, ischemic stroke patients with no identified cause had better outcomes than other TOAST groups. Conversely, patients coded as cryptogenic with more than 1 likely cause represent a different patient subpopulation. These data argue against the consolidation of cryptogenic stroke subcategories in future investigations. PMID- 25813056 TI - Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats. AB - High-fructose feeding impairs copper status and leads to low copper availability, which is a novel mechanism in obesity-related fatty liver. Copper deficiency associated hepatic iron overload likely plays an important role in fructose induced liver injury. Excess iron in the liver is distributed throughout hepatocytes and Kupffer cells (KCs). The aim of this study was to examine the role of KCs in the pathogenesis of nonalcoholic fatty liver disease induced by a marginal-copper high-fructose diet (CuMF). Male weanling Sprague-Dawley rats were fed either a copper-adequate or a marginally copper-deficient diet for 4 wk. Deionized water or deionized water containing 30% fructose (wt/vol) was also given ad libitum. KCs were depleted by intravenous administration of gadolinium chloride (GdCl3) before and/or in the middle of the experimental period. Hepatic triglyceride accumulation was completely eliminated with KC depletion in CuMF consumption rats, which was associated with the normalization of elevated plasma monocyte chemoattractant protein-1 (MCP-1) and increased hepatic sterol regulatory element binding protein-1 expression. However, hepatic copper and iron content were not significantly affected by KC depletion. In addition, KC depletion reduced body weight and epididymal fat weight as well as adipocyte size. Plasma endotoxin and gut permeability were markedly increased in CuMF rats. Moreover, MCP-1 was robustly increased in the culture medium when isolated KCs from CuMF rats were treated with LPS. Our data suggest that KCs play a critical role in the development of hepatic steatosis induced by marginal-copper high fructose diet. PMID- 25813059 TI - Poor outcome of experimental ischemic stroke in type 2 diabetic rats: impaired circulating endothelial progenitor cells mobilization. AB - BACKGROUND: It is well accepted that type 2 diabetic mellitus (T2DM) results in the poor outcome of ischemic stroke. However, the mechanisms by which T2DM causes aggravated cerebral ischemic/reperfusion (I/R) injury are not clear. Recently, endothelial progenitor cells (EPCs) are considered to be related with the outcome of ischemic stroke. More importantly, T2DM can affect the function of circulating EPCs. This study tried to investigate whether T2DM worsens the cerebral I/R injury via affecting circulating EPCs. METHODS: We used high-fat diet-fed and low dose streptozotocin-treated male rats receiving middle cerebral artery occlusion surgery as animal model of focal cerebral I/R injury with T2DM (diabetic operated). And the rats were divided into 4 groups: normal sham, diabetic sham, normal operated, and diabetic operated. We measured the circulating EPCs counts and the levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral plasma of 4 groups. RESULTS: We found that diabetic rats subjected to I/R exhibited significantly severe deterioration in neurologic deficits compared with nondiabetic counterparts, which manifested higher infarct volume and cell apoptosis as well as lower neurologic defective score. There was no significant difference on the plasma glucose of groups before cerebral I/R injury compared with that of the groups posterior to cerebral I/R injury despite cerebral I/R injury had the tendency to increase the plasma glucose no matter in the presence or the absence of T2DM. In addition, there were the marked downregulation of circulating EPCs counts and the levels of VEGF and eNOS in diabetic rats before the cerebral I/R injury. Despite I/R injury without T2DM, there was a significant increase in the circulating EPCs counts, the circulating EPCs counts in I/R injury with T2DM group were significantly decreased compared with those in the other 3 groups. We also observed that the level of eNOS was significantly improved by I/R injury without considering the presence of T2DM. CONCLUSIONS: Thus, our present study suggested that it might be the impaired EPCs mobilization into the blood that contributed to the worse outcome of cerebral I/R injury with T2DM. PMID- 25813057 TI - beta-Nicotinamide adenine dinucleotide acts at prejunctional adenosine A1 receptors to suppress inhibitory musculomotor neurotransmission in guinea pig colon and human jejunum. AB - Intracellular microelectrodes were used to record neurogenic inhibitory junction potentials in the intestinal circular muscle coat. Electrical field stimulation was used to stimulate intramural neurons and evoke contraction of the smooth musculature. Exposure to beta-nicotinamide adenine dinucleotide (beta-NAD) did not alter smooth muscle membrane potential in guinea pig colon or human jejunum. ATP, ADP, beta-NAD, and adenosine, as well as the purinergic P2Y1 receptor antagonists MRS 2179 and MRS 2500 and the adenosine A1 receptor agonist 2-chloro N6-cyclopentyladenosine, each suppressed inhibitory junction potentials in guinea pig and human preparations. beta-NAD suppressed contractile force of twitch-like contractions evoked by electrical field stimulation in guinea pig and human preparations. P2Y1 receptor antagonists did not reverse this action. Stimulation of adenosine A1 receptors with 2-chloro-N6-cyclopentyladenosine suppressed the force of twitch contractions evoked by electrical field stimulation in like manner to the action of beta-NAD. Blockade of adenosine A1 receptors with 8 cyclopentyl-1,3-dipropylxanthine suppressed the inhibitory action of beta-NAD on the force of electrically evoked contractions. The results do not support an inhibitory neurotransmitter role for beta-NAD at intestinal neuromuscular junctions. The data suggest that beta-NAD is a ligand for the adenosine A1 receptor subtype expressed by neurons in the enteric nervous system. The influence of beta-NAD on intestinal motility emerges from adenosine A1 receptor mediated suppression of neurotransmitter release at inhibitory neuromuscular junctions. PMID- 25813060 TI - Treatment of Symptomatic Bilateral Cavernous Carotid Aneurysms: Long-term Results of 6 Cases. AB - BACKGROUND: Bilateral cavernous carotid aneurysms (CCAs) are very rare. A treatment strategy for symptomatic bilateral CCAs has not been established because of their complex pathogenesis. Here we report our treatment strategy and long-term results for 6 cases of symptomatic bilateral CCAs. METHODS: From January 2007 to December 2013, we treated 6 patients (2 men and 4 women; mean age at first treatment, 56.0 years) with symptomatic bilateral CCAs. RESULTS: All patients began to experience unilateral symptoms. Five of the 6 underwent high flow bypass (HFB) with parent artery occlusion (PAO), and 1 received PAO only. Mean follow-up period after the first treatment was 61.3 months. All symptoms improved after the treatment. Five contralateral CCAs became enlarged during the follow-up period. Of these, 4 became symptomatic. One patient received superficial temporal-middle cerebral artery bypass with PAO, 2 received HFB with PAO, and 1 refused treatment. Final modified Rankin Scale scores were 0 in 4 patients, 1 in 1 patient, and 2 in 1 patient. There was no mortality in this series. CONCLUSIONS: HFB with PAO is feasible as the first treatment for symptomatic bilateral CCAs. This treatment strategy steadies and simplifies future treatment of contralateral CCAs should they become symptomatic. PMID- 25813061 TI - Quantitative H2[(15)O]-PET in Pediatric Moyamoya Disease: Evaluating Perfusion before and after Cerebral Revascularization. AB - BACKGROUND: Moyamoya disease (MMD) is an idiopathic intracranial angiopathy with a progressive spontaneous occlusion of the circle of Willis resulting in repeated ischemia if not diagnosed and treated early, especially in children. Prevention of stroke is achieved by revascularization of the affected cerebral regions. Functional imaging techniques such as H2[(15)O]-Positron emission tomography (PET) allow quantification of cerebral perfusion/blood flow (CBF) and in particular cerebrovascular response after acetazolamide (AZA) challenge. The cerebrovascular reserve (CVR) can then be calculated and used to identify regions at risk of infarct, hence allowing surgery to be specifically targeted and personalized. METHODS: Pediatric patients with diagnosed MMD underwent initial H2[(15)O]-PET scans at baseline and after stimulation with AZA. Indication for surgery was then based collectively on the extent of disease observed clinically and on magnetic resonance imaging, on the arterial territories involved, as seen in angiography and the respective regional CVR observed in PET. Cerebral revascularization surgeries were subsequently performed, tailored to the individual patient. Postoperative assessment of clinical outcome was augmented with follow-up PET (median duration after surgery, 10.4 months). CBF at baseline, after AZA and CVR were compared between presurgery and postsurgery scans in the areas supplied by the major cerebral arteries. RESULTS: Parametric images reflecting CBF, response to AZA and CVR clearly showed deficits in cortical but not subcortical regions or cerebellum. AZA-CBF and CVR deficits were most clear in middle cerebral artery and anterior cerebral artery (ACA) regions. In addition to the clinical symptomatology, angiography, AZA-CBF, and CVR images allowed the laterality of deficits to be clearly visualized for tailored surgery and the indication for targeted ACA or posterior cerebral artery revascularization to be assessed. Comparison of baseline CBF, AZA-CBF, and CVR between presurgery and postsurgery scans in revascularized areas revealed a significant improvement in baseline and AZA-CBF after surgery. Although no significant differences in CVR after revascularization surgery were found, a clear improvement of the deficits apparent in AZA-CBF in revascularized regions was found. CONCLUSIONS: We demonstrate that quantitative H2[(15)O]-PET is a highly useful tool to direct surgical intervention in MMD. Detailed quantitative analysis of CBF changes and CVR after surgery supports a targeted surgical approach. PMID- 25813062 TI - The Role of Epicardial Fat Thickness and Neutrophil-to-Lymphocyte Ratio Are Needed to Be Studied in Real-World Stroke Patients. PMID- 25813063 TI - The hospital costs of stroke patients in Chinese island populations: an 11-year tendency analysis. AB - BACKGROUND: The impact of stroke is devastating the life of patients, families, and even the communities. The cost of treatment; however, has the tendency of increasing nowadays, which has brought a heavy burden to patients and their families. Our study aims to collect the data of the hospital cost among stroke patients in Chinese island populations over the past decade and provide the scientific improvement for stroke. METHODS: We retrospectively collected the basic information and hospital costs of the stroke patients in Dalian Changhai Hospital from 2003 to 2013 using the Information Registration System of Inpatient. RESULTS: The total cumulative hospital admissions for stroke in Dalian Changhai Hospital were 1367 and showed a rising tendency from 2003 to 2013. Our results illustrated that the annual cumulative hospital costs of stroke inpatients increased rapidly in the past 11 years (the average rise was 37.71% per year), and the mean hospital cost per admission was 1.66% higher than that before, when the mean length of hospital days showed a downward tendency. Medication cost was found to be the largest part in the overall hospital cost (as a high percentage of 73.94%); however, traditional Chinese medicine only occupied quite a small proportion in the medicines. CONCLUSIONS: The hospital cost for stroke in Dalian Changhai County has brought an increasingly heavy economic burden to the local government and residents. PMID- 25813064 TI - Clinical management provided by board-certificated physiatrists in early rehabilitation is a significant determinant of functional improvement in acute stroke patients: a retrospective analysis of Japan rehabilitation database. AB - BACKGROUND: Early rehabilitation for acute stroke patients is widely recommended. We tested the hypothesis that clinical outcome of stroke patients who receive early rehabilitation managed by board-certificated physiatrists (BCP) is generally better than that provided by other medical specialties. METHODS: Data of stroke patients who underwent early rehabilitation in 19 acute hospitals between January 2005 and December 2013 were collected from the Japan Rehabilitation Database and analyzed retrospectively. Multivariate linear regression analysis using generalized estimating equations method was performed to assess the association between Functional Independence Measure (FIM) effectiveness and management provided by BCP in early rehabilitation. In addition, multivariate logistic regression analysis was also performed to assess the impact of management provided by BCP in acute phase on discharge destination. RESULTS: After setting the inclusion criteria, data of 3838 stroke patients were eligible for analysis. BCP provided early rehabilitation in 814 patients (21.2%). Both the duration of daily exercise time and the frequency of regular conferencing were significantly higher for patients managed by BCP than by other specialties. Although the mortality rate was not different, multivariate regression analysis showed that FIM effectiveness correlated significantly and positively with the management provided by BCP (coefficient, .35; 95% confidence interval [CI], .012-.059; P < .005). In addition, multivariate logistic analysis identified clinical management by BCP as a significant determinant of home discharge (odds ratio, 1.24; 95% CI, 1.08-1.44; P < .005). CONCLUSIONS: Our retrospective cohort study demonstrated that clinical management provided by BCP in early rehabilitation can lead to functional recovery of acute stroke. PMID- 25813065 TI - Increased Expression of NLRP3 Inflammasome in Wall of Ruptured and Unruptured Human Cerebral Aneurysms: Preliminary Results. AB - BACKGROUND: A growing body of evidence suggests that inflammation actively participates in cerebral aneurysm initiation, progression, and rupture. The primary objective of this study was to assess the expression of NLR family, Pyrin domain containing 3 (NLRP3) inflammasome in human cerebral aneurysms. METHODS: Aneurysmal domes (19 ruptured and 17 unruptured) from patients undergoing surgical treatment for ruptured or unruptured cerebral aneurysms were analyzed. A control sample comprising 4 middle cerebral arteries was obtained from autopsy subjects. The expression of NLRP3, apoptotic speck-containing protein with a card (ASC), caspase-1, and interleukin (IL)-1beta were assessed by immunohistochemistry. Immunofluorescence double staining was used to determine NLRP3, ASC, and caspase-1 cellular distribution. RESULTS: Expression of NLRP3, ASC, and caspase-1 were more abundant in ruptured aneurysm tissue than that in unruptured aneurysms, based on a semi-quantitative grading (P < .05). IL-1beta was also overexpressed in the ruptured cerebral aneurysms and associated with increased expression of NLRP3, ASC, and caspase-1 (P < .05). Furthermore, NLRP3, ASC, and caspase-1 immunoreactivity were colocalized with immunoreactivity of CD3 in T lymphocytes and CD68 in macrophages. CONCLUSIONS: NLRP3 inflammasome was expressed in the wall of human cerebral aneurysms and was more abundant in ruptured aneurysms than in unruptured. This study raises the possibility that NLRP3 inflammasome may be involved in the pathogenesis of human intracranial aneurysms, and this requires further study. PMID- 25813067 TI - Health risk of exposure to Bisphenol A (BPA). AB - Bisphenol A (BPA) belongs to chemicals that are produced in large quantities worldwide. It is commonly used as monomer in polycarbonate synthesis, plasticizer in the production of epoxy resins, as well as an additive for the elimination of surfeit of hydrochloric acid during the polyvinyl chloride (PVC) production. BPA is not only used in the production of plastics intended to a direct contact with food, including plastic packaging and kitchenware, but also in inner coatings of cans and jar caps. There are various routes of human exposure to this substance such as oral, by inhalation and transdermal. The main sources of exposure to BPA include food packaging and dust, dental materials, healthcare equipment, thermal paper, toys and articles for children and infants. BPA is metabolized in the liver to form bisphenol A glucuronide and mostly in this form is excreted with urine. Due to its phenolic structure BPA has been shown to interact with estrogen receptors and to act as agonist or antagonist via estrogen receptor (ER) dependent signalling pathways. Therefore, BPA has been shown to play a role in the pathogenesis of several endocrine disorders including female and male infertility, precocious puberty, hormone dependent tumours such as breast and prostate cancer and several metabolic disorders including polycystic ovary syndrome (PCOS). Because of the constant, daily exposure and its tendency to bio accumulation, BPA seems to require special attention such as biomonitoring. This observation should include clinical tests of BPA concentration in the urine, which is not only one of the best methods of evaluation of the exposure to this compound, but also the dependence of the daily intake of BPA and the risk of some endocrine disorders. PMID- 25813066 TI - Prevalence of positive diffusion-weighted imaging findings and ischemic stroke recurrence in transient ischemic attack. AB - BACKGROUND: The relationship between transient ischemic attack (TIA) clinical etiology, positive diffusion-weighted imaging (DWI) findings, and stroke recurrence is controversial. This study aimed to clarify the prevalence of positive DWI findings and TIA recurrence in relation to TIA patient characteristics. METHODS: The subjects were patients admitted to our stroke unit within 7 days after symptom onset between January 2006 and July 2013. We examined DWI findings and TIA recurrence according to etiologic subtypes. RESULTS: We enrolled 139 patients with lacunar TIA (n = 17), atherothrombotic TIA (n = 35), cardioembolic TIA (n = 25), TIA due to other causes (n = 32), or TIA with undetermined etiology (n = 30). The prevalence of positive DWI findings was highest among the cardioembolic TIA patients (56.0%). No association was found between the prevalence of positive DWI findings and symptom duration, motor presence, or ABCD(2) score. Plasma d-dimer level was significantly higher in the DWI-positive group than that in the DWI-negative group (P = .01). The prevalence of TIA recurrence was highest (5 of 35, 14.3%) among the atherothrombotic TIA patients, regardless of positive DWI findings. None of the patients treated with the anticoagulant and antiplatelet combination therapy experienced a recurrence. In contrast, almost all patients with cardioembolic TIA received anticoagulant treatment and none experienced recurrence. CONCLUSIONS: The prevalence of positive DWI findings was high among the cardiogenic TIA patients. TIA recurrence was often observed among the atherothrombotic TIA patients treated with antiplatelets. Management of patients with atherothrombotic TIA requires further aggressive antithrombotic strategy. PMID- 25813068 TI - Dietetic recommendations after bariatric procedures in the light of the new guidelines regarding metabolic and bariatric surgery. AB - The frequency of obesity occurrence is constantly increasing all over the world and becoming global epidemic. Facing the lack of the efficiency of conservative treatment, patients with II and III degree of obesity are qualified for surgical treatment; however, the efficiency of surgical treatment is connected with permanent change of nutritional habits and previous lifestyle of the patient. Modification of the way of nutrition, regardless of the type of bariatric procedure, should especially include the lowering of food energetic value and change of type, consistency and size of consumed food. Nutritional treatment after bariatric procedures is multistage. It includes clear liquid diet, full liquid diet, pureed diet, mechanically altered soft diet and regular diet. Gradual expanding of the diet protects gastrointestinal tract from chemical, mechanical and thermal irritation by the food. It also should prevent nutritional deficiencies. Significant influence on the result of surgical treatment of obesity has also regular intake of food, consuming products with high nutritional value, avoiding confectionery and fat products, consuming proper amounts of protein (60-80 g/day) and vitamin-mineral supplementation. PMID- 25813069 TI - An association between organophosphate pesticides exposure and Parkinsonism amongst people in an agricultural area in Ubon Ratchathani Province, Thailand. AB - BACKGROUND: Parkinson's disease (PD) is a ubiquitous disease. However, PDs prevalence in the population of agricultural communities lacks understanding and there has been no epidemiological study on the association between pesticides exposure factors and risk for PD. OBJECTIVES: To investigate the potential association between organophosphate pesticides exposure and Parkinsonism by using a screening questionnaire in agricultural areas. MATERIAL AND METHODS: Ninety elderly people living in agricultural areas participated in a cross-sectional study conducted at Tambon Hua-Rua Health Promoting Hospital in April 2014. Screening questionnaires for Parkinson's disease, Test-mate ChE (Model 400) for blood cholinesterase (ChE) levels of both blood enzymes erythrocyte cholinesterase (AChE), and plasma cholinesterase (PChE) were used as measurement tools. Descriptive statistics for frequencies and percentage distributions were used primarily to summarize and describe the data. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: The age range of the participants was 50 to 59 years old, with an average age of 53.9+/-2.87 years. The majority of the participants were female (62.2%), 82.2% of respondents were farmers. Most of participants (76.7%) reported that they applied insecticides in their farms. Ninety persons participated and completed the 11 item questionnaire. Of these, 17 (18.9%) felt that they lost balance when turning or that they needed to take a few steps to turn right around and 16.7% of participants indicated that they felt the need to move slowly or stiffly. The study found the prevalence of abnormal AChE levels was 28.9% (95%CI=19.81-39.40) and 17.8% of PChE levels (95%CI=10.52-27.26). To predict Parkinsonism, AChE, and PChE level, with a cutoff score of 5 or higher there had to be a sensitivity of 0.31, specificity of 1.00, positive predictive value (PPV) of 1.00 and negative predictive value (NPV) of 0.78 for AChE. While PChE, the score value of 5 or more had a sensitivity of 0.19, specificity of 0.93, PPV of 0.38 and NPV of 0.84. CONCLUSIONS: This study described an association between pesticides exposure and Parkinsonism. The questionnaire appears to be useful for Thai agriculturists as a screening tool for Parkinsonism and cholinesterase levels regarding to pesticides exposure. PMID- 25813070 TI - Authenticity of food products in the Polish market checked during 2005-2012. AB - BACKGROUND: Food fraud/adulteration has ever increasingly become a dominant food issue of the modern world in both developed and developing countries. It is presumed that globalisation is mainly one of the underlying reasons. OBJECTIVES: To assess and analyse the occurrence of food fraud on the Polish market during 2005-2012. MATERIAL AND METHODS: Adulteration of foodstuffs was determined from official food inspections carried out by the Agricultural and Food Quality Inspection (IJHARS) in 2005-2012. On average, foodstuff manufacturers inspected ranged from 1300 companies in 2011 to 3000 in 2006. The amount of results so collected, allowed a meaningful assessment to be thus made of food fraud on the Polish market. RESULTS: Food fraud was found to vary in the Polish market for the specific areas researched (ie. organoleptic properties, physico-chemistry and labelling) as well as in the agri-food sector. Levels of food fraud were not significantly different to those observed in other countries. CONCLUSIONS: Appropriate control measures, at both national and international levels, are thereby indicated to halt the adulteration of foodstuff products that constitute a health hazard or pose a life-threat to consumers as well as constituting a financial fraud.